PMID- 8640747
TI  - Acidification-and-recovery induces nuclear accumulation of neutral red and DNA
      into human KB oral carcinoma cells.
AB  - In cultures of oral cancers, gene transfer has been achieved by delivery systems
      which introduce DNA into cells but not specifically into the nucleus. We observed
      that acidification and recovery converted the nuclear-insulated interphase KB
      carcinoma cells into intense nuclear-accumulating states. Nuclear sequestration
      of the vital dye neutral red and T7 oligonucleotide was demonstrated
      qualitatively, and quantitatively by image analysis of single cells. pGem beta
      gal plasmids of 6.8 kb were introduced into KB cells by similar acidification and
      recovery pulses. Successful integration into the host KB genome was shown by
      expression of the lacZ gene of the plasmids. Enhanced nucleo-cytoplasmic
      transport demonstrated here in KB oral epidermoid carcinoma cells could
      potentially facilitate gene therapy in oral cancers.

PMID- 8640746
TI  - An attempt to generate an antitumor effect in the regional lymph nodes against
      endometrial cancer cells by inducing antitumor cytokines.
AB  - Phytohemagglutinin-stimulated regional lymph node cells obtained from
      gynecological cancer patients exerted a significant antiproliferative activity
      against an endometrial cancer cell line, RL95-2 on a human tumor clonogenic
      assay, and released a high amount of tumor necrosis factor alpha (TNF alpha), and
      interferons. The activity was thought to be partly due to released TNF alpha,
      because RL95-2 was highly sensitive to recombinant TNF alpha. However, anti-TNF
      alpha failed to inhibit the activity, which indicated the probability of some as
      yet unclarified participation of cytokines. Therefore, the regional lymph nodes
      might be used as sites of endogenous cytokine therapy in endometrial cancer
      patients.

PMID- 8640748
TI  - Rapid and high yield induction of endometrial adenocarcinomas in CD-1 mice by a
      single intrauterine administration of N-ethyl-N-nitrosourea combined with chronic
      17 beta-estradiol treatment.
AB  - Induction of uterine endometrial adenocarcinomas in mice by N-ethyl-N-nitrosourea
      (ENU) and 17 beta-estradiol (E2) was examined. Illumination-induced persistent
      estrous CD-1 mice were divided into three groups at 10 weeks of age. Group 1 was
      given a single intra-uterine administration of polyethylene glycol (PEG) 1 week
      later, while Groups 2 and 3 received ENU (12.5 mg/kg), dissolved in PEG, in the
      same manner. Group 3 mice were also implanted with E2 pellets s.c. 1 week
      previously, and thereafter the pellets were renewed every 8 weeks throughout the
      experiment. At the termination (week 15 after the ENU treatment), all surviving
      mice were killed and the development of uterine proliferative lesions was
      assessed. All groups demonstrated endometrial hyperplasias, the severity being
      greatest in the ENU plus E2-treated animals (Group 3). The incidence of
      adenocarcinomas in Group 3 (20/29, 69%) was significantly higher than in Group 1
      (0/25, 0%) or 2 (0/29, 0%). At 10 weeks after the ENU-treatment, serum E2 and
      progesterone concentrations in Group 3 were significantly higher and lower,
      respectively, than those in Groups 1 and 2. Consequently, the E2/progesterone
      (E2:P) ratio in Group 3 was significantly increased. These results indicate that
      a continuing high level of serum E2 and low level of progesterone are important
      for endometrial adenocarcinoma development in mice, with an increased E2:P ratio
      acting as a promoter for development of the endometrial lesions initiated by ENU
      treatment.

PMID- 8640749
TI  - Comparison of chloroform-induced toxicity in the kidneys, liver, and nasal
      passages of male Osborne-Mendel and F-344 rats.
AB  - Chloroform given by gavage in corn oil at 180 mg/kg per day induced kidney tumors
      in male Osborne-Mendel rats. Chloroform-induced cytotoxicity and regenerative
      cell proliferation have been observed in the kidneys of male F-344 rats. In order
      to compare the acute sensitivity of male Osborne-Mendel with F-344 rats, animals
      from both strains were administered a single gavage dose of 0, 10, 34, 90, 180,
      or 477 mg/kg chloroform and necropsied 48 h later. Known target tissues were
      examined for histological changes. Regenerative cell proliferation was assessed
      as a labeling index (LI, percent of cells in S-phase) as determined by nuclear
      incorporation of bromodeoxyuridine. The epithelial cells of the proximal tubules
      of the kidney cortex were the primary target cells for cytotoxicity and
      regenerative cell proliferation. A dose-dependent increase in the LI was present
      in the kidney of Osborne-Mendel rats given doses of 10 mg/kg chloroform and above
      and in F-344 rats given 90 mg/kg and above. The maximal increase in the LI was
      4.5- or 3.7-fold over control in Osborne-Mendel or F-344 given 477 mg/kg,
      respectively. The only increase in the hepatocyte LI was in the F-344 rats given
      477 mg/kg. Edema and periosteal hypercellularity were observed in the nasal
      passages of both strains at doses of 90 mg/kg and above. These data indicate that
      Osborne-Mendel and F-344 rats are about equally susceptible to chloroform-induced
      nephrotoxicity. These results provide a basis for linking the extensive data base
      on mechanisms of action of chloroform toxicity in F-344 rats to the Osborne
      Mendel rat and support the hypothesis that events secondary to chloroform-induced
      cytolethality and regenerative cell proliferation played a role in the induction
      of renal tumors in the Osborne-Mendel rat.

PMID- 8640750
TI  - p53 accumulation in the organs of low-dose X-ray-irradiated mice.
AB  - In order to search for the direct evidence of cellular response to low-dose
      radiation, we investigated wild-type p53 protein accumulation in several organs
      of mice after exposure to low doses of X-rays. Significant p53 accumulation
      within 24 h was observed in the mouse adrenal glands and pancreas after X-ray
      irradiation at 25 cGy and 50 cGy, but not at 100 cGy. In addition, differential
      p53 accumulation was also observed in the hypophysis, thymus, skin, lung, bone
      marrow and liver at different doses. In contrast, we observed no accumulation of
      p53 protein in the spleen, testis or kidney at any dose used in this experiment.
      The p53 accumulation induced by low-dose X-rays in mice was organ-specific. It is
      suggested that cell type and interactions with other signal transduction pathways
      of the hormone system, immune system and/or nervous system may contribute to the
      variable induction of p53 by low-dose X-ray irradiation. The association of organ
      specific p53 response with radiosensitivity and cancer incidence by radiation in
      each organ was discussed.

PMID- 8640751
TI  - Reappraisal of eight representative carcinogenic and non-carcinogenic compounds
      in a new medium-term rat liver bioassay using D-galactosamine.
AB  - The carcinogenic potential of eight different compounds was assayed in a new
      medium-term carcinogenicity bioassay using D-galactosamine (DGA) as a non
      surgical method to induce regeneration in place of partial hepatectomy (PH). Male
      rats were initially given a single i.p. injection (200 mg/kg) of
      diethylnitrosamine (DEN) and after 2 weeks on basal diet, received two i.p.
      injections of DGA (300 mg/kg) at the end of weeks 2 and 5. They were treated with
      one of the test compounds aflatoxin B1, benzo[a]pyrene, diethylstilbestrol,
      urethane, sodium saccharin, bucetin, D-mannitol and sodium chloride in the diet
      or basal diet alone for weeks 3-8. Carcinogenic potential was assessed by
      comparing the numbers and areas per cm2 of glutathione S-transferase placental
      form-positive (GST-P+) foci in the livers of treated animals with those of the
      control animals given DEN/DGA alone. Positive estimations of carcinogenicity were
      obtained for the hepatocarcinogens aflatoxin B1, diethylstilbestrol or urethane,
      and for the non-liver carcinogen benzo[a]pyrene. Negative values were shown in
      rats treated with the non-carcinogens, D-mannitol and sodium chloride. The two
      other non-liver carcinogens sodium saccharin and bucetin, also did not exert
      positive effects in the system. The present data are consistent with findings in
      previous medium-term bioassays using PH. Our results thus confirm that the
      present bioassay protocol with repeated administration of DGA instead of PH may
      offer a new and sensitive non-invasive method to screen large numbers of
      environmental carcinogens.

PMID- 8640752
TI  - Inhibition of 12-O-tetradecanoylphorbol-13-acetate promoted mouse skin papilloma
      by digalactosyl diacylglycerols from the fresh water cyanobacterium Phormidium
      tenue.
AB  - To search for possible antitumor-promoters, two digalactosyl diacylglycerols
      (DGDGs), which were obtained from the freshwater cyanobacterium Phormidium tenue
      and possessed a single pair of acyl residues, were evaluated for their inhibitory
      effects on the two-stage carcinogenesis test in mouse skin. Papillomas in mouse
      skin were initiated with 390 nmol of 7,12-O-dimethylbenz[a]anthracene and 1 week
      later, were promoted twice a week with 1.7 nmol of 12-O-tetradecanoylphorbol-13
      acetate (TPA). Two DGDGs effectively inhibited tumor formation in the sensitive
      mouse stock even when these compounds were given 1 h before TPA treatment.

PMID- 8640753
TI  - Vascular and perivascular GD3 expression in human glioma.
AB  - A major hallmark of gliomas is their intense neovascularisation. Ganglioside GD3,
      is one of the major gangliosides which has been implicated in tumour
      angiogenesis. Recently we reported that GD3 was a potent stimulator of vascular
      endothelial growth factor release in human glioma cell lines. In the present
      study we were able to detect GD3-immunoreactivity in 10 out of 10 cases of
      glioblastoma multiforme and 7 out of 10 cases of anaplastic astrocytoma while low
      grade tumours were negative. Interestingly, GD3 was intensively expressed in
      hypervascularised areas of high grade gliomas. These data support the involvement
      of this ganglioside in brain tumour angiogenesis.

PMID- 8640754
TI  - Glutathione conjugates of tert-butyl-hydroquinone, a metabolite of the urinary
      tract tumor promoter 3-tert-butyl-hydroxyanisole, are toxic to kidney and
      bladder.
AB  - 3-tert-Butyl-4-hydroxyanisole and tert-butyl-hydroquinone (TBHQ) are antioxidants
      known to promote renal and bladder carcinogenesis in the rat, although the
      mechanisms of these effects are unclear. Because glutathione (GSH) conjugates of
      a variety of hydroquinones are nephrotoxic, and because 2-tert-butyl-5
      (glutathion-S-yl)hydroquinone [5-(GSyl)TBHQ], 2-tert-butyl-6-(glutathion-S
      yl)hydroquinone [6-(GSyl)TBHQ], and 2-tert-butyl-3,6-bis-(glutathion-S
      yl)hydroquinone [3,6-bis-(GSyl)-TBHQ] have been identified recently as
      metabolites of TBHQ in the male rat, we investigated the effects of these
      metabolites in the male rat. At the highest dose tested (400 micromol/kg,i.v.) 5
      (Gsyl)TBHQ and 6-(GSyl)TBHQ caused 2-fold increases in the urinary excretion of
      gamma-glutamyl transpeptidase and alkaline phosphatase, and pigments arising from
      the polymerization of metabolites were deposited in the kidney. 3,6-bis
      (GSyl)TBHQ (200 micromol/kg) was the most potent of the GSH conjugates tested and
      produced significant increases in the urinary excretion of gamma-glutamyl
      transpeptidase, alkaline phosphatase, lactate dehydrogenase, and glucose (2-, 2-,
      22-, and 11-fold increases, respectively). Alterations in the biochemical
      parameters correlated with the degree of single cell and tubular necrosis in the
      S(3)-M segment of the proximal tubule, as observed by light microscopy. In
      addition to nephrotoxicity, 3,6-bis-(GSyl)TBHQ increased the bladder wet weight 2
      fold and caused severe hemorrhaging of the bladder. The half-wave oxidation
      potentials of 5-(Gsyl)TBHQ and 6-(GSyl)TBHQ were similar to that of TBHQ, whereas
      the half-wave oxidation potential of 3,6-bis-(Gsyl)TBHQ was approximately 100 mV
      higher than that of TBHQ. The TBHQ-GSH conjugates also catalyzed the formation of
      8- hydroxydeoxyguanosine, indicating that GSH conjugation does not impair the
      redox activity of TBHQ. Because some chemicals may induce carcinogenesis by a
      mechanism involving cytotoxicity followed by sustained regenerative hyperplasia,
      our results suggest that the toxicity of GSH conjugates of TBHQ to kidney and
      bladder may contribute to the promoting effect of 3-tert-butyl-4-hydroxyanisole
      and TBHQ in these tissues.

PMID- 8640755
TI  - Correlation of regional and nonlinear formaldehyde-induced nasal cancer with
      proliferating populations of cells.
AB  - Formaldehyde induces nonlinear, concentration-related increases in nasal
      epithelial cell proliferation and squamous cell carcinomas (SCC) in rats. A
      formaldehyde carcinogenicity study was conducted in which a major end point was
      correlation of cell proliferation indices with sites of formaldehyde-induced SCC.
      A poor correlation in certain sites led to incorporation of the number of cells
      in each site into the correlation. Rats were exposed (6h/day, 5 days/week) to
      formaldehyde (0, 0.7, 2, 6, 10 or 15 ppm) for up to 24 months with interim
      sacrifice time points at 3, 6, 12, and 18 mo. A unit length labeling index (ULLI;
      S-phase nuclei/mm basement membrane) was determined for specific nasal regions in
      addition to a population-weighted ULLI (PWULLI). The PWULLI was defined as the
      product of regional ULLI and total number of nasal epithelial cells in the
      respective site. Nasal SCC sites of origin were mapped. Formaldehyde induced SCC
      in a highly nonlinear fashion, with no observed effect at the level of 2 ppm, a
      minimal response at 6 ppm, and a sharp increase at 10 and 15 ppm. The tumor
      incidence was 1, 22, and 47% at 6, 10 and 15 ppm, respectively. ULLI was
      significantly (P<0.05) increased at 10 and 15 ppm but not at the lower
      concentrations. There was a good correlation between PWULLI and regional tumor
      incidence (R(2) = 0.88), while the correlation of regional SCC with ULLI was
      relatively poor (R(2) = 0.46). We conclude that target cell population size and
      sustained increases of cell proliferation in these populations, determined by
      differences in regional airflow-driven formaldehyde binding to DNA dose to these
      sites, coupled with the known nonlinear kinetics of formaldehyde binding to DNA,
      can together account for the nonlinearity and site specificity of formaldehyde
      induced nasal SCC in rats.

PMID- 8640756
TI  - Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of Zingiber
      officinale rhizome.
AB  - There is considerable emphasis on identifying potential chemopreventive agents
      present in food consumed by the human population. Ginger rhizome (Zingiber
      officinale), known commonly as ginger, is consumed worldwide in cookeries as a
      spice and a flavoring agent. In prior in vitro studies, it has been shown that
      the water or organic solvent extract of ginger possesses antioxidative and
      antiinflammatory properties. In this study, we evaluated whether ethanol extract
      of ginger (GE) possesses anti-tumor-promoting effects in a mouse skin
      tumorigenesis model. Because skin tumor promoters induced epidermal ornithine
      decarboxylase (ODC), cyclooxygenase, and lipoxygenase activities, and edema and
      hyperplasia are conventionally used markers of skin tumor promotion, first, we
      assessed the effect of GE on these parameters. Preapplication of GE onto the skin
      of SENCAR mice resulted in significant inhibition of 12-0-tetradecanoylphorbol-13
      acetate (TPA)-caused induction of epidermal ODC, cyclooxygenase, and lipoxygenase
      activities and ODC mRNA expression in a does-dependent manner. Preapplication of
      GE to mouse skin also afforded significant inhibition of TPA-caused epidermal
      edema (56%) and hyperplasia (44%). In long-term tumor studies, topical
      application of GE 30 min prior to that of each TPA application to 7,12
      dimethylbenz(a)anthracene-initiated SENCAR mice resulted in a highly significant
      protection against skin tumor incidence and its subsequent multiplicity. The
      animals pretreated with GE showed substantially lower tumor body burdens compared
      with non-GE-treated controls. The results of our study, for the first time,
      provide clear evidence that GE possesses anti-skin tumor-promoting effects, and
      that the mechanism of such effects may involve inhibition of tumor promoter
      caused cellular, biochemical, and molecular changes in mouse skin.

PMID- 8640757
TI  - The blood group ABO gene transcript is down-regulated in human bladder tumors and
      growth-stimulated urothelial cell lines.
AB  - The molecular mechanism that in human bladder tumors leads to the loss of blood
      group ABO glycosyltransferase activity and, thereby, the loss of ABO antigens was
      investigated. In 15 tumors and 3 normal biopsies from blood group AB individuals
      and 7 tumors and 3 normal biopsies from blood group O individuals, mRNA was
      detected by a reverse transcription PCR (RT-PCR) assay, and the ABO blood group
      structure was determined by immunohistology. The RT-PCR spanned several introns
      in the ABO gene to exclude DNA contamination, and the RT-PCR product was shown to
      reflect the ABO gene message by dideoxy sequencing. The ABO mRNA was present in
      normal urothelium and low-grade tumors but disappeared from high grade tumors.
      This correlation to tumor grade was significant (P<0.04). Immunohistochemistry
      with monoclonal anti-blood group antibodies showed a complete correlation between
      the presence of mRNA and the presence of AB carbohydrate structures on cell
      surfaces. In two urothelial cell lines, genotyped as A/- and A/A, growth
      stimulation with the cholera toxin B subunit led to a total loss of ABO mRNA, and
      epidermal growth factor stimulation had an identical effect on one of the cell
      lines. We conclude that the ABO glycosylation in normal and malignant urothelium
      is regulated at the mRNA level, and that a mechanism associated with cell
      proliferation may trigger down-regulation of ABO mRNA.

PMID- 8640758
TI  - Restricted patterns of CD44 variant exon expression in human papillary thyroid
      carcinoma.
AB  - CD44 is a polymorphic family of cell surface proteoglycans and glycoproteins
      implicated in cell-cell and cell-matrix adhesion interactions, cell migration,
      and tumor metastasis. CD44 exists as a standard form and as multiple isoforms
      arising from alternative splicing of variant exons (termed v1-v10) encoding parts
      of the extracellular domain. We demonstrated previously that papillary thyroid
      carcinomas exhibit aberrant patterns of alternative CD44 mRNA splicing (G. Ermak
      et al., Cancer Res., 55: 4594-4598, 1995). In the present report, we use reverse
      transcription-PCR using a new high-performance polymerase formulation (Ex Taq;
      TaKaRa Shuzo Co., Ltd., Otsu, Japan) , followed by Southern hybridization, and
      demonstrate that alternative exon usage in papillary thyroid carcinomas is
      restricted primarily to exons v6, v7, v8, v9, and v10, with weak expression of
      v3. Expression of v8 is tightly linked to v9 and closely related to v10
      expression. Also, v6 and v7 expression are closely related. Papillary thyroid
      cancers exhibit a marked increase in specific mRNA species containing
      combinations of exons v6 to v10. Several isoforms found in papillary cancers are
      not detectable in histologically normal tissue derived from the corresponding
      contralateral thyroid lobes. Examples include a 750-bp v6- and v7-containing PCR
      product and a 650-bp v8- and v9- containing PCR product. Finally, a novel 530-bp
      PCR product was discovered and shown to contain a subsegment from exon 4 joined
      to a subsegment of exon 13 (v8), followed by the complete sequence of exons 14
      (v9) and 15 (v10). This novel isoform was present in both the papillary cancers
      and contralateral tissues. In conclusion, papillary thyroid cancers exhibit
      specific patterns of aberrant alternative CD44 splicing, distinguishing them from
      histologically normal thyroid tissue.

PMID- 8640759
TI  - Transactivation of the PTHrP gene in squamous carcinomas predicts the occurrence
      of hypercalcemia in athymic mice.
AB  - Humoral hypercalcemia of malignancy (HHM) is caused by the secretion of
      parathyroid hormone-related protein (PTHrP) by tumor cells, and tumors of
      squamous histology are the ones most commonly complicated by HHM. To determine
      why some squamous tumors cause HHM and others do not, we quantitated the levels
      of PTHrP mRNA expression and PTHrP secretion in a series of eight squamous tumor
      lines. As anticipated, we found that the level of PTHrP mRNA expression in
      individual lines correlated with their PTHrP secretion rates. However, PTHrP mRNA
      levels varied widely in individual lines, and only those tumor lines with the
      highest levels of PTHrP gene expression were able to cause hypercalcemia in
      athymic mice. We found that a specific segment of the PTHrP promoter could
      reproduce the relative pattern of PTHrP gene expression when cloned in front of a
      chloramphenicol acetyltransferase reporter gene and transiently transfected into
      these squamous lines. Deletional analysis confirmed that specific sequences
      within the PTHrP gene promoter appeared to be involved in the transactivation of
      the gene in tumor lines expressing high levels of PTHrP mRNA. These data suggest
      that the ability of a given squamous tumor to cause HHM is ultimately a function
      of its level of PTHrP gene expression, which in turn appears to be a function of
      the ability of specific transcription factors to transactivate PTHrP gene
      expression.

PMID- 8640760
TI  - High-efficiency in vivo gene transfer using intraarterial plasmid DNA injection
      following in vivo electroporation.
AB  - A novel method for high-efficiency and region- controlled in vivo gene transfer
      was developed by combining in vivo electroporation and intraarterial plasmid DNA
      injection. A mammalian expression plasmid for the Escherichia coli lacZ gene
      (driven with a SV40 early promoter) was injected into the internal carotid artery
      of rats whose brain tumors (from prior inoculation) had been electroporated
      between two electrodes. The lacZ gene was efficiently transferred and expressed
      in the tumor cell 3 days after plasmid injection. However, neither any gene
      transfers nor any elevated lacZ activity was detected in tissues outside the
      electrodes. The plasmid was not transferred without electroporation. Human
      monocyte chemoattractant protein-1 cDNA was also transferred by this method, and
      its long-lasting (3 weeks) expression was confirmed by using the Epstein-Barr
      virus episomal replicon system. The expressed monocyte chemoattractant protein-1
      protein was functional, as evident by the presence of a large number of monocytes
      in tumor tissue. This method, electrogene therapy, which does not require viral
      genes or particles, allows genes to be transferred and expressed in desired
      organs or tissues, and it may lead to the development of a new type of highly
      effective gene therapy.

PMID- 8640761
TI  - Comparison of N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid in the
      regulation of retinoid receptor-mediated gene expression in human breast cancer
      cell lines.
AB  - The activities of N-(4-hydroxyphenyl)retinamide [(4-HPR), Fenretinide] and all
      trans-retinoic acid (RA) were determined for (a) the inhibition of cell
      proliferation; (b) the activation of human retinoid receptor-mediated target gene
      expression; (c) the inhibition of estradiol- and progesterone-induced gene
      activation in breast cancer cell lines; and (d) the regulation of the expression
      of tumor suppressor retinoblastoma protein. Similar to RA, both 4-HPR and its
      active metabolite N-(4-methoxyphenyl)retinamide (4-MPR) effectively impeded the
      growth of MCF7 and T-47D human breast cancer cell lines, except that 4-HPR also
      inhibited the proliferation of RA-resistant BT-20 cells. However, when tested in
      human recombinant retinoic acid receptor (RAR-alpha, RAR-beta, and RAR-gamma)
      induced reporter gene assays, RA was much more potent (>100-fold) than either 4
      HPR or 4-MPR. 4-HPR induced transcriptional activation through all three RAR
      subtypes at 1-10microM, while RA showed comparable activity at 10-100microM.
      Despite the apparent weak interaction at the RAR level, 4-HPR was comparable to
      RA in the inhibition of both estrogen receptor- and progesterone receptor
      mediated transcriptional activation in MCF7 and T-47D cells, respectively.
      Moreover, similar to RA, 4-HPR and 4-MPR caused marked up-regulation of tumor
      suppressor retinoblastoma protein in both MCF7 and T-47D cells. Since RA and 4
      HPR showed comparable activity in the inhibition of estrogen recptor- and
      progesterone receptor-induced gene transcription and in the stimulation of
      retinoblastoma protein expression in MCF7 and T-47D cells, the reduced RAR
      activation by 4-HPR may result in the lack of hepatic toxicity and therefore the
      improved therapeutic efficacy relative to RA.

PMID- 8640762
TI  - Impaired proliferation and tumorigenicity induced by CCAAT/enhancer-binding
      protein.
AB  - A plasmid containing the CCAAT/enhancer-binding protein (C/EBP alpha) gene
      transcriptionally controlled by the metallothionein promoter was constructed. The
      gene was transfected into the human hepatocellular carcinoma cell lines Hep3B and
      HepG2. When cultured in vitro in the presence of 100 microM ZnSO(4), C/EBP alpha
      expression caused reversible growth arrest. In soft agar clonogenic assays, C/EBP
      alpha expression decreased both the colony size and the total number of colonies
      compared with zinc-free controls. C/EBP alpha expressing cells s.c. implanted in
      CD-1 nu/nu mice were essentially nontumorigenic, whereas C/EBP alpha tumor cells
      implanted into immunodeficient SCID mice demonstrated a significantly delayed
      time of tumor appearance compared with cells transfected with a vector control
      plasmid. These studies suggest that the expression of endogenous genes normally
      associated with a quiescent, differentiated state, such as C/EBP alpha, can
      result in impaired proliferative activity and suppressed tumorigenicity of
      hepatoma cell lines.

PMID- 8640763
TI  - Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing
      non-small cell lung cancer cells.
AB  - The HER-2/neu gene product, p185(neu), is a membrane-bound receptor with tyrosine
      kinase activity. High levels of p185(neu) is correlated with intrinsic
      chemoresistance of non-small cell lung cancer (NSCLC) cell lines. We investigated
      the effects of tyrphostin AG825, a selective tyrosine kinase inhibitor
      preferentially inhibiting HER-2/neu kinase, on the chemosensitivities and on the
      drug-induced cell cycle changes of NSCLC cell lines that expressed different
      levels of p185(neu). Compared to the low-p185(neu) expressing cell lines, we
      found that the high-p185(neu) expressing cell lines were more resistant to
      doxorubicin, etoposide, and cis-diamminedichloroplatinum(II) but more sensitive
      to AG825. AG825 was able to significantly enhance the chemosensitivities of the
      high-p185(neu) expressing cell lines, whereas it had little effect on the
      chemosensitivities of the low-p185(neu) expressing cells, with a few exceptions
      in which minor antagonistic effects were observed. Although high concentrations
      of AG825 could reduce the drug-induced G(2) arrest that was accompanied by the
      activation of phosphorylated p34(cdc2), we failed to find any remarkably
      differential effects of AG825 on drug-induced G(2), arrest and the accompanying
      phosphorylation status of p34(cdc2) of the high- and and the low-p185(neu)
      expressing cell lines. In summary, tyrphostin AG825 can enhance chemosensitivity
      in high- but not in low-p185(neu) expressing NSCLC cell lines. This differential
      effect cannot be explained by the alterations of drug-induced cell cycle changes
      by AG825. Our results provide a rationale to develop p185(neu)- specific
      tyrphostin and to test them in combination with anticancer agents in vivo and in
      clinical trials.

PMID- 8640764
TI  - Intraperitoneal photodynamic therapy of human epithelial ovarian carcinomatosis
      in a xenograft murine model.
AB  - The objective of this investigation was to determine the efficacy of i.p.
      photodynamic therapy (PDT) against solid, multifocal ovarian carcinoma using a
      newly described NIH:OVCAR-5 induced murine model. PDT was initiated when diffuse
      microscopic disease and small multifocal tumor nodules were present, similar to
      the extent of residual carcinoma that may persist clinically after laparotomy and
      tumor debulking. The photosensitizer, benzoporphyrin derivative monoacid ring A
      (BPD-MA), was administered in a dose of 0.25 mg/kg body weight i.p. 90 min prior
      to light exposure. An argon-pumped dye laser was used to deliver low intensity
      light (20 J) i.p. through a cylindrically diffusing fiberoptic tip. Treatment
      regimens consisted of a series of three to five treatments at 3-7 day intervals,
      with the extent of macroscopic disease or death from disease being the evaluable
      outcome parameters for tumoricidal and survival studies, respectively. The mean
      tumor burden at necropsy for treated animals was 0.034 +/- 0.014 g compared to
      0.379 +/- 0.065 g in untreated controls (P<0.001). Survival studies were
      initiated in two groups at day 7 and day 14 following cell inoculation. The first
      group received either three or five treatments at 5-day intervals, and both had a
      significant increase in median survival compared to untreated controls (57 and 53
      days, respectively, compared to 43 days, P<0.05). The second group was treated
      every 7 days until death and also had a significant survival advantage over
      controls (57 days compared to 47 days, P<0.05). These studies suggest that
      benzoporphyrin derivative mono acid ring A-mediated PDT is a feasible, well
      tolerated, experimental treatment approach that elicits a tumoricidal response
      against diffuse, solid i.p. disease in tumor-bearing mice, with concomitant
      prolongation of survival and needs careful optimization.

PMID- 8640765
TI  - Gene deletion chemoselectivity: codeletion of the genes for p16(INK4),
      methylthioadenosine phosphorylase, and the alpha- and beta-interferons in human
      pancreatic cell carcinoma lines and its implications for chemotherapy.
AB  - Pancreatic carcinoma cells lines are known to have a high incidence of homozygous
      deletion of the candidate tumor suppressor gene p16 (MTS1/CDKN2), which resides
      in the chromosome 9p21 region. Here we: (a)examined a series of these cell lines
      for the incidence of codeletion of genes located near p16, in particular, the
      gene for the enzyme 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) and the
      genes of the IFN-alpha and -beta cluster (IFNs); and (b) investigated whether
      therapeutic strategies could be developed that target malignant cells that have
      undergone the codeletion of such genes. Five of the eight pancreatic carcinoma
      cell lines were p16(-), MTAP was codeleted in all five cases. Because MTAP
      phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA), generated as a byproduct of
      polyamine synthesis, to the salvageable purine base adenine, loss of this pathway
      in p16(-), MTAP(-) cells might sensitize these cells to methotrexate (MTX), the
      mechanism of action of which involves, in part, an inhibition of purine de novo
      synthesis. MTAP(+) normal keratinocytes and pancreatic carcinoma lines had
      relatively poor sensitivity, in terms of efficacy, to the purine nucleotide
      starving actions of MTX. This may be in part due to the MTAP-dependent salvage of
      adenine moieties from endogenously generated MTA, because the MTAP inhibitor 5'
      chloro-5'-de- oxyformycin A potentiates the antipurine actions of MTX in some of
      these MTAP(+) lines. Also, exogenous MTA (10 microM) reverses the growth
      inhibitory actions of MTX in these lines. In contrast, MTAP(-) cell lines, which
      cannot recycle purines from endogenous MTA, have a relatively high sensitivity to
      the antipurine actions of MTX, which is not modulated by 5'-chloro-5'
      deoxyformycin A or exogenous MTA. Thus the MTAP loss in malignant cells may be an
      example of gene deletion chemoselectivity, in which genetic deletions that occur
      as part of the oncogenic process render these cells more sensitive to particular
      anticancer agents than normal cells, which have not undergone such deletions. We
      also examined whether the loss of IFN genes sensitize cells to the growth
      inhibitory actions of these cytokines. Three of the five p16(-) cell lines bore
      homozygous deletions of IFNA1 and IFNB1 genes, representing each end of the IFN
      alpha,-beta gene cluster; one cell line bore a codeletion of the IFNA1 gene but
      retained the IFNB1 locus. Whereas the cell lines that were most sensitive to the
      growth-inhibitory effects of IFN-beta or IFN-alpha(2b), tended to be those with
      IFN deletions, there were enough exceptions to this pattern to indicate that the
      IFN genotype does not reliably predict IFN responsiveness.

PMID- 8640766
TI  - Resistance mechanisms in human sarcoma mutants derived by single-step exposure to
      paclitaxel (Taxol).
AB  - A fluctuation analysis experiment was performed by exposing 15 expanded
      populations of MES-SA sarcoma cells to paclitaxel (Taxol) at a concentration of
      10 nM for 7 days. The mutation rate was approximately 8 multiplied by 10(-7)/cell
      generation. ANOVA supports a stochastic cell survival mechanism of spontaneous
      mutation rather than induction of an adaptive response under these selection
      conditions. Surviving colonies were found in 12 populations, 9 of which had
      clones that remained resistant to paclitaxel after a 2-month period of
      propagation. Analysis of mdr1 gene expression by reverse transcription PCR
      demonstrated positive clones in 4 of the 9 populations with stable resistance.
      Accumulation of [(3)H]paclitaxel was decreased in these clones but not in the
      mdr1-negative clones compared with parental cells. A high degree of resistance to
      paclitaxel (36- to 93-fold) was selected by this single drug exposure in all 9
      stably resistant mutants. Those with mdr1 activation demonstrated a broad cross
      resistance to vinblastine, doxorubicin, and etoposide, whereas the other 6
      mutants were cross-resistant only to the Vinca alkaloids. Because tubulins are
      the target molecules for paclitaxel cytotoxicity, we evaluated total tubulin
      content by immunoblotting and performed semiquantitative reverse transcription
      PCR analysis for expression of the alpha-tubulin isotypes B alpha 1, K alpha 1
      and H alpha 44, the beta-tubulin isotypes M40, beta9, 5beta, beta2 and beta4, and
      gamma-tubulin. Total tubulin content was decreased significantly in one of the
      single-step mutants. All surviving clones, both resistant and sensitive to
      paclitaxel, displayed reduced expression of the 5beta and beta 4 beta-tubulin
      isotype transcripts in comparison with the parental cell line. These data suggest
      that stringent exposure to paclitaxel selected clones with reduced transcript
      levels of 5beta and beta4 beta-tubulin isotypes, but that these reduced levels
      were not directly involved in the resistance of the clones to paclitaxel. The
      results suggest an important role for non-multidrug-resistant mechanisms of
      resistance to paclitaxel. These mechanisms do not involve reduced drug
      accumulation and provide cross-resistance among both paclitaxel and tubulin
      depolymerizing agents.

PMID- 8640767
TI  - Tissue-targeted antisense c-fos retroviral vector inhibits established breast
      cancer xenografts in nude mice.
AB  - The c-fos proto-oncogene has been implicated as a regulator of estrogen-mediated
      cell proliferation. We have tested the tissue specificity and antitumor efficacy
      of a mouse mammary tumor virus-regulated antisense c-fos retroviral vector.
      Systemically administered vector could be detected in several tissues but was
      only expressed in breast epithelium, thus supporting targeting to mouse mammary
      tumor virus-regulated tissues. Ex vivo transduction of 30-70% of MCF-7 human
      breast cancer cells produced expression of antifos RNA, decreased expression of
      the c-fos target mRNA, induction of differentiation, and inhibition of s.c. tumor
      growth and invasiveness. In vivo transduction of established i.p. MCF-7 tumors
      with a single injection of XM6:antifos inhibited tumor growth in athymic mice
      with a corresponding inhibition of c-fos, transforming growth factor beta1 and
      transforming growth factor alpha expression. Four daily injections with the
      antifos RNA induced a much larger MCF-7 i.p. tumor inhibition, with a marked
      prolongation of survival in the absence of any host tissue toxicity. These
      results indicate that inhibition of key nuclear genes such as c-fos may lead to
      disruption of paracrine factors and an antitumor effect, providing a strategy for
      cancer gene therapy.

PMID- 8640768
TI  - Induction of autologous tumor killing by heat treatment of fresh human tumor
      cells: involvement of gamma delta T cells and heat shock protein 70.
AB  - Autologous tumor killing (ATK) has been implicated as an important prognostic
      factor in cancer patients since the ability of blood lymphocytes to kill freshly
      isolated autologous tumor cells was strongly associated with good prognosis of
      the patients. The present study was designed to induce or enhance ATK sensitivity
      of fresh human tumor cells by heat stress. Brief exposure of fresh human tumor
      cells to elevated temperature increased their susceptibility to lysis by
      autologous blood lymphocytes in a short-term (51)Cr release assay. In addition,
      the heat-elevated ATK sensitivity was confirmed by clonogenic assays. An increase
      in ATK was observed with unstimulated lymphocytes in 42% of the cases and OK432
      (streptococcal preparation)-activated lymphocytes in 80% of the cases.
      Stimulation of blood lymphocytes with autologous, heat-stressed tumor cells and
      OK432 resulted in an increase in number of gamma delta T cells, which was
      associated with elevated ATK activity against the stressed tumor cells. At the
      clonal level, three gamma delta T-cell clones (V gamma 9/V delta 2+) proliferated
      in response to autologous, heat stressed tumor cells and/or OK432 and exhibited
      elevated cytotoxicity against the tumor cells. Western blot analysis revealed an
      increased expression of heat shock protein (HSP) 70 in heat- treated tumor cells.
      Some of them expressed HSP70 on their surfaces. The elevated cytoxicity against
      heat-stressed tumor cells was inhibited by treatment of targets with anti-HSP70
      monoclonal antibody (mAb) or of effector cells with anti-V delta2 mAb. Reactivity
      of gamma delta T cells to autologous, heat- stressed tumor cells was also
      inhibited by anti-HSP70 mAb. These results indicate that exposure to heat of
      tumor cells induces ATK susceptibility, especially to OK432-activated effector
      cells, and suggest that gamma delta T cells may be involved in ATK against
      stressed tumor cells through recognition of HSP70 on the target cells.

PMID- 8640769
TI  - Endothelial intercellular adhesion molecule-1 expression is suppressed in human
      malignancies: the role of angiogenic factors.
AB  - Intercellular adhesion molecule 1 (ICAM-1) is involved in the recirculation of
      blood leukocytes and, presumably, in the infiltration of cytolytic effector
      leukocytes into tumors. The present report describes a down-regulated expression
      of vascular ICAM-1 on tumor-infiltrating endothelial cells (EC) in renal cell
      carcinoma. This finding was obtained by flow cytometric analysis of tumor EC
      compared to EC obtained from healthy tissue. Since growth of solid tumors is
      dependent on the formation of new blood vessels (angiogenesis), we hypothesized
      that angiogenic factors are responsible for the down-regulation of ICAM-1. This
      hypothesis was investigated in vitro using human umbilical vein- and dermis
      derived EC. Using flow cytometry, we found a biphasic regulation of ICAM-1 during
      stimulation of cultured EC with the angiogenic agent basic fibroblast growth
      factor (bFGF). Although 16-24 h after activation a marked up-regulation of ICAM-1
      was observed, expression was significantly decreased after 48h. The longevity of
      this down-regulation was at least 7 days. Northern blot analysis revealed down
      regulation of the steady-state mRNA level of the gene. ICAM-2 showed similar
      results of intial up- and later down-regulation. Functional relevance for the
      changes in ICAM-1 expression was demonstrated by a corresponding biphasic
      regulation of EC-leukocyte adhesion after EC activation by bFGF. The described
      effects are specific for bFGF since other angiogenic factors (such as vascular
      endothelial growth factor, transforming growth factor beta, and interleukin 8)
      did not affect adhesion molecule expression. Subsequent experiments showed that
      angiogenic factors decrease the sensitivity of EC to activation with tumor
      necrosis factor-alpha in regard to adhesion molecule expression. The present
      results reveal a tumor-derived escape mechanism from cytolytic effector
      leukocytes by down-regulation of vascular adhesion molecules in vivo and in vitro
      and decreased responsiveness to proinflammatory cytokines.

PMID- 8640770
TI  - Humanized anti-Lewis Y antibodies: in vitro properties and pharmacokinetics in
      rhesus monkeys.
AB  - ABL 364 is a murine monoclonal IgG3 antibody directed against the Lewis Y
      carbohydrate antigen (Le(y)) expressed on the surface of many epithelial cell
      tumors. The antibody mediates cytotoxicity via activation of human complement or
      human effector cells, and has been evaluated in several clinical trials including
      two Phase I/II trials in relapsed small cell lung cancer and metastatic breast
      cancer. To improve the effector functions of the antibody, increase its half-life
      in circulation, and avoid the human antimouse antibody response, two chimeric and
      several humanized antibodies were constructed for evaluation. The chimeric IgG1
      is more potent than the murine IgG3 in tumor cell lysis via activation of human
      peripheral mononuclear cells (10-fold), but somewhat less effective in complement
      dependent lysis (2-3 fold). The chimeric IgG3 is slightly less potent than the
      IgG1. A humanized IgG1 was constructed by combining the complementarity
      determining regions of the ABL 364 antibody with human framework and constant
      regions. Several additional variants were subsequently constructed to improve the
      binding affinity and increase expression of the antibody. Two of the variants,
      designated I and K, differ by a single amino acid at position 75 of the heavy
      chain. Both variants have affinity within 2-fold of the chimeric IgG1 antibody
      and retain the cytolytic activities toward tumor cell lines. However, it was
      possible to express variant K at a significantly higher level (5- 10-fold) than
      variant I. Pharmacokinetics of the humanized ABL 364 antibody variant K was
      compared with that of the parent murine antibody in rhesus monkeys. It was shown
      that the terminal half-life of the humanized antibody in rhesus monkeys is 14-20
      days, with a mean of 16.3 days, while that of the parent murine antibody is only
      1.9 days.

PMID- 8640771
TI  - Protection against a lethal challenge with SV40-transformed cells by the direct
      injection of DNA-encoding SV40 large tumor antigen.
AB  - Plasmid DNA encoding the large tumor antigen (T- ag) of SV40 was used to actively
      immunize mice to assess the induction of SV40 T-ag-specific immunity. Mice were
      injected with the naked DNA i.m., and immune responses were compared to those
      elicited in mice immunized with the recombinant SV40 T-ag protein. Compared to
      immunization with the recombinant protein, naked DNA induced weak antibody
      responses to SV40 T-ag. No increase in natural killer cell activity was observed
      following either recombinant protein or nucleic acid vaccination. However, the
      recombinant SV40 T-ag failed to induce SV40 T-ag-specific CTL responses, whereas
      the plasmid DNA encoding SV40 T-ag elicited CTL activity specific for SV40 T-ag.
      The SV40 T-ag-specific CTL lysed in vitro only syngeneic target cells (H-2(d))
      expressing SV40 T-ag, indicating that the CTL are MHC restricted. Both the
      recombinant protein and naked DNA preparations induced immune responses that were
      protective against a lethal challenge with syngeneic SV40-transformed cells. A
      comparison of recombinant protein versus nucleic acid immunization indicates that
      both humoral and cell-mediated immune responses may play a role in SV40 T-ag
      immunity. These data indicate that active immunization with genes encoding tumor
      specific antigens may be an efficacious strategy for the induction of tumor
      immunity.

PMID- 8640772
TI  - Interleukin 12 primes macrophages for nitric oxide production in vivo and
      restores depressed nitric oxide production by macrophages from tumor-bearing
      mice: implications for the antitumor activity of interleukin 12 and/or
      interleukin 2.
AB  - Interleukin-12 (IL-12) is a recently described immunoregulatory cytokine with
      potent therapeutic activity in various preclinical models of infectious or
      malignant disease. As part of our ongoing evaluation of potential mechanisms
      accounting for the potent antitumor activity of IL-12, we have investigated the
      influence of IL-12 administration on total serum nitrate/nitrite (NO(x)(-))
      levels and the production of nitric oxide (NO) by peritoneal macrophages from
      normal and tumor-bearing mice. We report here that IL-12 administration to either
      normal or tumor-bearing mice for periods of time ranging from 7-19 days induced
      progressive increases in serum NO(x)(-) levels and primed peritoneal macrophages
      for NO production on subsequent exposure to lipopolysaccharide or IL-2 ex vivo.
      Treatment of resident peritoneal macrophages or the macrophage cell line ANA-1
      with IL-12 alone or IL-12 in combination with various other stimuli failed to
      induce NO production, suggesting that the effects of IL-12 occurred via an
      indirect mechanism. Furthermore, we have shown that not only was the production
      of NO by macrophages from untreated long-term, tumor- bearing mice suppressed
      compared with control mice treated with vehicle or IL-12, but also that IL-12
      administration overcame this suppression and delayed tumor growth. Lastly, we
      have shown that administration of weekly pulses of IL-2 in combination with IL-12
      additively enhanced the priming of macrophages for NO production ex vivo and
      delayed tumor growth far more effectively than either agent alone. These
      observations and reports in the literature regarding the potential influence of
      NO on development of the immune response and on the regulation of tumor growth
      and vascularization suggest that NO may play a significant role in the antitumor
      activity of IL-12 and IL-2.

PMID- 8640773
TI  - Deletion and mutation analyses of the P16/MTS-1 tumor suppressor gene in human
      ductal pancreatic cancer reveals a higher frequency of abnormalities in tumor
      derived cell lines than in primary ductal adenocarcinomas.
AB  - The putative tumor suppressor gene p16/CDKN2 encodes a specific inhibitor of
      cyclin D-cyclin-dependent kinase 4 complexes important in cell-cycle regulation
      and has been found to be deleted or mutated in a variety of human cancers. Thirty
      microdissected primary human ductal pancreatic carcinomas from patients not
      subject to radiotherapy or chemotherapy prior to surgical resection of their
      carcinomas and 18 human pancreatic carcinoma cell lines were analyzed by single
      strand conformation polymorphism (SSCP) and DNA sequence analyses and PCR-based
      deletion analyses for mutations and homozygous deletions of the p16/CDKN2 gene,
      respectively. Homozygous deletions of the gene were found in five cell lines, and
      nonpolymorphic SSCP and DNA sequence alterations were found within exon 1 in four
      cell lines and exon 2 in three lines, for an overall frequency of deletions and
      mutations of 66%. In contrast, homozygous deletions of p16/CDKN2 were observed in
      three primary pancreatic carcinomas, and five primary tumors revealed SSCP and/or
      sequence abnormalities in exon 1 (one case) and exon 2 (four cases), a mutation
      and deletion frequency of 27%. Immunoblotting analyses confirmed the absence of
      p16/MTS-1 expression in actively proliferating cell lines with a homozygous
      deletion of the gene and low-to-moderate levels of p16/MTS-1 expression in cell
      lines possessing a normal RB-1 gene or protein. These findings suggest that,
      although p16/CDKN2 may play a role in the pathobiology of pancreatic cancer,
      inactivation of this putative tumor suppressor gene occurs more frequently in
      cell lines than in primary ductal pancreatic carcinomas.

PMID- 8640774
TI  - Distinct regions of allelic loss on 13q in prostate cancer.
AB  - Loss of heterozygosity (LOH) involving the long arm of chromosome 13 has been
      reported to occur in as many as one third of primary prostate cancers. Candidate
      tumor suppressor genes on 13q that may be important in the development of
      prostate cancer include the retinoblastoma susceptibility gene (RBI) and a gene
      associated with inherited breast cancer (BRCA2). To define the pattern of allelic
      loss of 13q in prostate cancer, LOH analysis was performed using nine mapped
      polymorphic markers spanning the entire chromosomal arm. Nineteen (48%) of 40
      prostate cancer cases obtained following radical prostatectomy demonstrated
      atllelic loss with at least one marker. Furthermore, 13 (33%) of 40 cases had
      evidence of allelic loss involving a region of 13q14 containing RB1. To test the
      hypothesis that RB1 is the targeted tumor suppressor gene in this region, 37 of
      40 cases were assessed for expression of pRB, the protein product of RB1 using
      immunohistochemical techniques. By this analysis, 8 (22%) of 37 prostate tumors
      demonstrated no pRB expression. However, allelic loss at RB1, assessed with an
      intragenic marker, did not correlate with absent pRB expression (Fisher's exact
      test, P=0.375). Taken together, these data confirm that allelic loss of a common
      region of 13q14 occurs in approximately one third of prostate cancers. Lack of
      correlation of LOH at RB1 with absent pRB expression suggests the existence of
      another tumor suppressor gene in this region important in prostate cancer.

PMID- 8640775
TI  - Chromosome 13q deletion mapping in head and neck squamous cell carcinomas:
      identification of two distinct regions of preferential loss.
AB  - Heal and neck squamous cell carcinomas show frequent cytogenetic alterations
      involving the long arm of chromosome 13. To define the extent of 13q deletions
      and to identify the minimal areas of chromosome loss, 48 primary squamous cell
      carcinomas of the head and neck were analyzed for loss of heterozygosity using 11
      different polymorphic loci. About 67% of the tumors displayed loss of genetic
      material at 13q. Most of the cases showed loss of the entire long arm of the
      chromosome. However, the presence of partial deletions in 10 cases provided
      evidence of the existence of two preferential sites of chromosome loss at 13q32
      ter and 13q14.2-q14.3. The colocalization of the 13q14 minimal region of deletion
      with the retinoblastoma (RB) gene, which has been proposed as an oncosuppressor
      in diverse tumor types, prompted us to verify the involvement of this gene in the
      development of head and neck cancer. No significant variation in RB protein or RB
      mRNA expression was detected, thus excluding a role for such a gene in the
      genesis of this type of tumor. Taken together, our data suggest the existence of
      two new tumor suppressor genes (one close to and one distal to RB), which play a
      role in the development and/or progression of head and neck squamous cell
      carcinomas.

PMID- 8640776
TI  - Allelotype of salivary gland tumors.
AB  - To elucidate the genetic alterations that occur in salivary gland tumors, we
      screened every autosomal arm (and the X-chromosome) of 29 primary human salivary
      gland neoplasms (11 pleomorphic adenomas, 10 adenoid cystic carcinomas, 5
      mucopidermoid carcinomas, and 3 carcinomas ex-mixed tumors) for allelic loss
      using 86 microsatellite markers. A minimum of two microsatellite markers were
      used per chromosomal arm to achieve informativity of at least 60% (excluding X).
      The pleomorphic adenomas demonstrated few areas of allelic loss; the most
      prominent chromosomal arm involved was 12q, lost in more than 35% of informative
      cases. The most significant allelic losses in adenoid cystic carcinoma were 1p,
      2p, 6q, 17p, and 20p (>20% of informative cases) and 19q (40% of informative
      cases). Mucoepidermoid carcinoma showed 50% or greater loss at 2q, 5p, 12p, and
      16q. Although losses at 9p, 3p, and 17p are common in squamous cell carcinoma of
      the head and neck, only the carcinoma ex-mixed tumors demonstrated loss at these
      loci, consistent with progression to a more aggressive phenotype. Salivary gland
      tumors display allelic loss patterns different from many other tumor types,
      suggesting distinct genetic pathways in the progression of these tumors.

PMID- 8640777
TI  - Inhibitory effects of activin on the growth and morpholgenesis of primary and
      transformed mammary epithelial cells.
AB  - Activin is a member of the transforming growth factor beta superfamily, which is
      known to have activities involved in regulating differentiation and development.
      By using reverse transcription-PCR analysis on immunoaffinity-purified human
      breast cells, we have found that activin beta a and activin type II receptor are
      expressed by myoepithelial cells, whereas no expression was detected in other
      breast cell types. In examining 15 breast cell lines, we have found only four
      (HBL-100, MCF10-A, PMC-42, and BT 20) to be positive for activin beta a mRNA,
      whereas all expressed the activin type II receptor. Furthermore, we have found
      activin A to be a potent growth inhibitor of MCF- 7 cells (at 2 ng/ml), where it
      causes an arrest in G(1). Activin A does not appear to have an effect on the cell
      cycle of primary myoepithelial or luminal cells. However, we demonstrate that
      activin is an inhibitor of tubule formation by human mammary organoids in vitro.
      These are the first observations of activin and activin receptor in the normal
      human breast and in human breast cell lines and suggest a role for activin in
      mammary cell growth and morphogenesis.

PMID- 8640778
TI  - Wide expression of the human erythrocyte glucose transporter Glut1 in human
      cancers.
AB  - Glucose uptake has been found to be increased in cancer cells. Previous work has
      shown increased expression of the human erythrocyte glucose transporter (Glut1)
      mRNA in some human cancers, indicating that Glut1 may play a significant role in
      glucose uptake by these tumors. The distribution of Glut1 protein in normal and
      malignant human tissues is still largely unknown. Using immunohistochemistry, we
      found that Glut1 is largely undetectable in normal epithelial tissues and benign
      epithelial tumors but is expressed in a significant proportion of a variety of
      human carcinomas. We hypothesize that Glut1 expression by human carcinomas
      indicates an increased glucose uptake, and probably increased utilization of
      energy, which may correlate with an aggressive behavior. The biological
      significance of Glut1 expression needs to be determined.

PMID- 8640779
TI  - Hypoxia arrests ovarian carcinoma cell cycle progression, but invasion is
      unaffected.
AB  - Although hypoxic cells are generally resistant to radiation and chemical
      therapies designed to halt the spread of neoplastic disease, few investigations
      have been carried out with regard to the molecular mechanisms responsible for
      this phenomenon. Here, we report of the development of an in vitro model system
      with which to study the molecular mechanisms involved in the proliferation and
      invasion of human ovarian carcinoma cells under hypoxia. Results from
      [(3)]thymidine incorporation experiments indicate that hypoxia triggers cessation
      of ovarian carcinoma cell DNA synthesis. Flow cytometry analysis of cellular DNA
      content for hypoxic cultures revealed that cell cycle progression was arrested.
      This arrest was found to be reversible upon reoxygenation of the cultures.
      Concomitant with this growth arrest is hypophosphorylation of pRB and a reduction
      in cyclin A abundance, suggesting that hypoxia induces growth arrest by
      regulating the activities of these crucial cell cycle-regulatory proteins. In
      vitro invasion assays revealed that hypoxia has no appreciable effect on the
      invasive ability of these cells. Immunoblotting established that the detected
      proteolytic activity was due to the matrix metalloproteinase MMP-2, the M(r)
      72,000 type IV collagenase that is most closely associated with the metastatic
      phenotype in vitro and in vivo. These data support the notion that populations of
      ovarian carcinoma cells are capable of surviving and invading extracellular
      matrix during hypoxic conditions and, after a more suitable oxygen environment is
      reached, giving rise to new cell colonies.

PMID- 8640780
TI  - The paradoxical association of regression with a poor prognosis in melanoma
      contrasted with a good prognosis in keratoacanthoma.
AB  - Partial regression in cutaneous malignant melanoma has been reported by a number
      of observers, albeit not all, to be associated with a relatively poor prognosis;
      in contrast, a keratoacanthoma, which eventually regresses, does not metastasize.
      The Hammond effect could explain the possibly poor prognosis of the thin
      regressing melanoma. Hammond(W.G. Hammond et al., Cancer J., 8: 130-138, 1995)
      showed that the speed of biological progression to less differentiated phenotypes
      is directly related to the immunocompetences of the tumor hosts. If partial
      regression is a sign of an unusually strong immune reaction, then the melanoma
      that partially regresses might have a relatively poor prognosis because of the
      greater risk of biological progression among the surviving tumor clones. A
      Hammond effect is not associated with regression of a keratoacanthoma. I
      postulate that the growth of this tumor is accelerated, rather than restrained,
      by the immune reaction and that the ultimate regression of the tumor is the
      result, not of immune cytotoxicity, but of a rapid terminal differentiation (a
      reverse Hammond effect); alternatively, very rapid growth might lead to an
      exhaustion of growth potential before progression to clonal immortality could
      occur.

PMID- 8640781
TI  - Tumor oxygenation predicts for the likelihood of distant metastases in human soft
      tissue sarcoma.
AB  - This study was performed to explore the relationship between tumor oxygenation
      and treatment outcome in human soft tissue sarcoma. Twenty-two patients with
      nonmestastatic, high-grade, soft tissue sarcomas underwent preoperative
      irradiation and hyperthermia and pretreatment measurement of tumor oxygenation.
      The 18-month actuarial disease-free survival was 70% for patients with tumor
      median oxygen pressure (pO2) values of >10 mm Hg but only 35% for those with
      median pO2 values of <10 mm Hg (P=0.01). There were eight treatment failures; the
      first site of recurrence was lung in all patients. Median pO2 was 7.5 mm Hg for
      metastasizing tumors versus 20 mm Hg for nonmetastasizing tumors (P=0.03).
      Potential mechanisms and implications for clinical trial design are discussed.

PMID- 8640782
TI  - Molecular cloning of a novel membrane-type matrix metalloproteinase from a human
      breast carcinoma.
AB  - A new member of the matrix metalloproteinase (MMP) family of enzymes has been
      cloned from a human breast carcinoma cDNA library. The isolated cDNA contains an
      open reading frame 1554 bp long, encoding a polypeptide of 518 amino acids. The
      predicted amino acid sequence displays a similar domain organization as the
      remaining MMPs, including a prodomain with the activation locus, the zinc-binding
      site, and the hemopexin domain. In addition, it contains a C-terminal extension,
      rich in hydrophobic residues and similar in size to those present in the
      different membrane-type MMPs (MT-MMPs) identified to date. On the basis of these
      structural characteristics, this novel MMP has been tentatively called MT4-MMP,
      because it represents the fourth member of this subclass of MMPs characterized
      mainly by the occurrence of putative transmembrane domain in their amino acid
      sequences. MT4-MMP also contains a nine-residue insertion between the propeptide
      and the catalytic domain, which is a common feature of MT-MMPs and stromelysin-3.
      This amino acid sequence insertion ends with the consensus sequence R-X-R/K-R,
      which seems to be essential in the activation of these proteinases by furin.
      Northern blot analysis of polyadenylated RNAs isolated from a variety of human
      tissues revealed that the MT4-MMP gene (MMP-17) is expressed mainly in the brain,
      leukocytes, the colon, the ovary, and the testis. The expression of MT4-MMP in
      leukocytes together with its putative membrane localization suggest that this
      enzyme could be involved in the activation of membrane-bound precursors of growth
      factors or inflammatory mediators such as tumor necrosis factor-alpha. In
      addition, MT4-MMP transcripts were detected in all breast carcinomas, as well as
      in all breast cancer cell lines analyzed in the present work. On the basis of
      these expression data in breast tumors, a potential role for human MT4-MMP in the
      tumoral process is also suggested.

PMID- 8640783
TI  - Definition and refinement of a region of loss of heterozygosity at 11q23.3-q24.3
      in epithelial ovarian cancer associated with poor prognosis.
AB  - Previous cytogenetic and loss of heterozygosity (LOH) data suggest that
      disruption of chromosome 11q23-qter occurs frequently in epithelial ovarian
      cancer and is associated with an adverse clinicopathological phenotype. Ten
      polymorphic microsatellite repeat loci were analyzed by PCR from the 11q22-q25
      region between D11S35 and D11S968 in 40 ovarian tumors (including 31 epithelial
      ovarian cancers). Two distinct regions of loss were detected, suggesting possible
      sites for genes involved in epithelial ovarian neoplasia: a large centromeric
      region between D11S35 and D11S933 (11q22-q23.3) and a telomeric 8.5-Mb region
      lying between D11S934 and D11S1320 (11q23.3-24.3) not previously defined. LOH of
      the latter region but not the former one was significantly associated with poor
      survival, despite all tumors in this study having LOH somewhere on chromosome 11.
      This analysis provides a starting point for positional cloning.

PMID- 8640784
TI  - Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are
      not mutated in individuals with attenuated adenomatous polyposis coli.
AB  - Mutation of Pla2g2a, a secretory phospholipase A(2) gene, dramatically increases
      the number of intestinal polyps that develop in the multiple intestinal neoplasia
      (Min) mouse, a murine model for adenomatous polyposis coli in humans. We tested
      the hypothesis that mutation of the human homologue(s) of this gene might be
      responsible for the more severe phenotype (hundreds of polyps) seen in a subset
      of individuals with attenuated adenomatous polyposis coli (AAPC). DNA sequence
      analysis demonstrated that alterations of PLA2G2A, as well as related genes
      PLA2G2C and PLA2G5, were evenly distributed between three classes of AAPC
      subjects: those with small, intermediate, and large numbers of adenomatous
      colonic polyps. Among 67 additional unrelated AAPC subjects, a stop mutation in
      PLA2G2C did not correlate with an increased burden of adenomatous polyps.
      Therefore, mutation of the human homologue(s) of murine Pla2g2a does not appear
      to be responsible for phenotypic variation among subjects with AAPC.

PMID- 8640785
TI  - Function of the integrin alpha 6 beta 1 in metastatic breast carcinoma cells
      assessed by expression of a dominant-negative receptor.
AB  - The involvement of the alpha 6 beta a integrin, a laminin receptor, in breast
      carcinoma progression needs to be addressed rigorously. We report that a human
      breast carcinoma cell line, MDA-MB-435, known to be highly invasive and
      metastatic, expresses three potential integrin laminin receptors: alpha 2 beta 1,
      alpha 3 beta 1, and alpha 6 beta 1, but uses only alpha 6 beta 1 to mediate
      adhesion and migration on laminin matrices. To investigate the contribution of
      alpha 6 beta 1 to the aggressive behavior of these cells, we developed a dominant
      negative strategy for knocking out alpha 6 beta 1 function that involved
      expression of a cytoplasmic domain deletion mutant of the beta 4 integrin subunit
      by cDNA transfection. Stable transfectants of MDA-MB-435 cells that expressed
      this mutant beta 4 subunit were inhibited dramatically in their ability to adhere
      and migrate on laminin matrices, and their capacity to invade Matrigel was
      reduced significantly. These findings support the hypothesis that alpha 6 beta 1
      is important for breast cancer progression. Moreover, this approach is a powerful
      method that should be useful in assessing the role of alpha 6 beta 1 in other
      cells.

PMID- 8640786
TI  - Effect of radiation on interstitial fluid pressure and oxygenation in a human
      tumor xenograft.
AB  - Elevated interstitial fluid pressure (IFP) is a pathophysiological characteristic
      of most human and experimental tumors and may be responsible, in part, for the
      poor distribution of blood-borne therapeutic agents and low blood flow rate in
      tumors. Recent data in cervical carcinomas in patients suggest that fractionated
      radiation can lower tumor IFP and increase oxygen partial pressure (pO (2)) in
      some patients. The goals of this study were to find the minimum dose of radiation
      required to modulate IFP and pO(2) and to determine the time course of IFP
      changes due to radiation in a preclinical model. Xenografts of the LS174T human
      colon adenocarcinoma were grown in the right flank of nude (BALB/c) mice. IFP and
      pO(2) were measured before and 24 h after graded doses of irradiation. The mean
      +/- SD initial IFP in untreated tumors was 12.9 +/- 0.5 mm Hg (n=109), and the
      range was 3.0 to 40.3 mm Hg. The mean +/- SD and median initial pO(2) were 20.2
      +/- 2.4 and 11.9 mm Hg, respectively (n=37). IFP and pO(2) were independent of
      tumor size. Fractionated radiation lowered IFP by 2.5 mm Hg when the total dose
      was 10 or 15 Gy (P<0.05), but IFP did not change in the controls or the 5-Gy
      radiation group (P>0.05). Irradiation increased the proportion of tumors at
      higher oxygen tensions when compared to control tumors. The IFP and tumor volumes
      were followed for up to 10 days after a single dose of 10, 20, or 30 Gy of
      irradiation. IFP decreased for all treatment groups. The decrease was most
      significant for the group receiving 30 Gy. On day five following irradiation, the
      IFP had decreased by 35%. The changes in IFP and pO(2) occurred before any
      macroscopic changes in tumor volume could be observed. The radiation-induced
      decrease in IFP could be, in part, responsible for the increased uptake of
      monoclonal antibodies following single or fractionated radiation that has been
      reported in the literature.

PMID- 8640787
TI  - Switching viral latency to viral lysis: a novel therapeutic approach for Epstein
      Barr virus-associated neoplasia.
AB  - We describe an EBV-driven lytic system (LySED) that can be used to specifically
      target therapy to EBV- containing tumors. This system takes advantage of the
      transactivating properties of EBNA-1, a latency protein expressed in all EBV
      containing cells, to drive the expression of Zta, a gene sufficient for inducing
      the EBV lytic cycle. Thus, EBV provides both the target and the executor for
      mediating tumor-specific cell death, markedly increasing the specificity of the
      system. Transfection of EBV-positive cell lines with the LySED construct resulted
      in a switch to lytic cycle and subsequent cell death, even in the presence of an
      inhibitor of EBV thymidine kinase (acyclovir) without an increase in virion
      production. In contrast, growth of EBV-negative B-cell lines was not affected.

PMID- 8640788
TI  - The estrogen receptor CpG island is methylated in most hematopoietic neoplasms.
AB  - Estrogen appears to be a negative regulator of normal hematopoiesis. Chromosome
      6q, which contains the estrogen receptor (ER) gene, is frequently altered in
      human hematopoietic neoplasms. The ER gene, which has growth and metastasis
      suppressor activity in many different cell types, is inactivated by promoter
      methylation in some ER-negative breast tumors and 100% of colorectal tumors. We
      now report that the promoter region of the ER gene is aberrantly methylated in
      86% of human hematopoietic tumors, including 8 of 9 pediatric acute lymphocytic
      leukemia, 17 of 18 adult acute lymphocytic leukemia, 21 of 23 adult acute
      myelogenous leukemia, 3 of 6 chronic phase chronic myelogenous leukemia, 9 of 9
      blast crisis chronic myelogenous leukemia and 5 of 8 lymphomas. This methylation
      event was also present in all nine leukemia cell lines examined, where it was
      associated with very low or absent ER expression. In addition, rat and mouse
      leukemia cell line also exhibited this change, indicating that ER CpG island
      methylation in leukemias is conserved among species. Our results suggest that ER
      CpG island methylation could be an important step in the genesis of human
      hematopoietic neoplasms and might be a useful molecular marker for monitoring the
      clinical status of these diseases.

PMID- 8640789
TI  - Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3B site
      identified by homozygous deletions in tumor cell lines.
AB  - A number of DNA fragments, identified by representational difference analysis,
      which were homozygously deleted in various cancer cell lines were previously
      mapped to human chromosomal arms. One of these, BE758-6, which was homozygously
      deleted in a number of colon carcinoma cell lines, had been mapped to chromosome
      region 3p. We have further localized the probe to 3p14.2, approximately 350kbp
      telomeric to the 3p14.2 break of the t(3;8) hereditary renal cell carcinoma
      chromosome translocation, within or near the 3p14.2 FRA3B, the most common human
      fragile site. We determined the sizes of the homozygous deletions in a number of
      cancer cell lines after isolation of a yeast artificial chromosome contig and
      development of STS markers which fall between D3S1234 and D2S1481, which flank
      the deletions. Homozygous deletions were observed and sized not only in the cell
      lines originally reported but also in a number of nasopharyngeal carcinoma cell
      lines and a gastric carcinoma cell line. About 50% of uncultured stomach and
      colon carcinomas were then shown to lose heterozygosity for alleles in the same
      region, with a common region of loss between the D3S1234 and D3S1481 markers.
      Thus, it is likely that the homozygous deletion observed in these cancer cell
      lines harbors an important tumor suppressor gene for several tumor types.

PMID- 8640790
TI  - Glucuronidation associated with intrinsic resistance to mycophenolic acid in
      human colorectal carcinoma cells.
AB  - The in vivo efficacy of the antitumor, immunosuppressive antibiotic mycophenolic
      acid is known to be limited by its rapid conversion to the biologically inactive
      7-0-glucuronide, catalyzed by UDP-glucuronosyl transferase activity, which is
      widely distributed among normal tissues, including intestinal epithelium. We have
      found that mycophenolic acid is also converted to its glucuronide by several
      lines of human colorectal carcinoma cells, including HT29, Lovo, and Colo-205. In
      contrast, malignant cell lines not of colorectal origin, including EMT6, HeLa,
      and SKOV3, showed no ability to metabolize mycophenolic acid. The 7-amino
      derivative of mycophenolic acid was not metabolized by HT29 cells. This compound
      was less potent than mycophenolic acid versus EMT6 and HeLa cells but showed
      inhibitory activity against HT29 cells comparable with the parent antibiotic. The
      rapid metabolism of mycophenolic acid by HT29 cells was associated with a
      markedly lower sensitivity to both the antiproliferative activity of the drug and
      to its ability to inhibit GTP synthesis, compared with cells lacking the capacity
      for significant glucuronidation. After an initial decline in cellular GTP in HT29
      cells induced by mycophenolic acid, there was a progressive recovery in GTP over
      48 h, accompanying the metabolism of the antibiotic. This recovery process was
      not observed in EMT6 cells. It is suggested that glucuronosyl transferase
      activity may occur widely in colorectal cancer cells and could contribute to
      resistance to drugs that are susceptible to inactivation by glucuronide
      conjugation.

PMID- 8640791
TI  - Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene
      encoded conjugate export pump.
AB  - Previous studies have identified the ATP-dependent export of glutathione
      conjugates as a physiological function of the multidrug resistance protein (MRP).
      The involvement of MRP in the transport of endogenous and xenobiotic conjugates
      was investigated further using membrane vesicles from MRP-transfected HeLa cells.
      The ATP-dependent transport of the glutathione conjugates [(3)H]leukotriene C(4),
      S-(2,4-dinitrophenyl)-[(3)H]glutathione, and (3)H- labeled oxidized glutathione
      was characterized by determination of the transport efficiency V(max):K(m)
      amounting to 1031, 114, and 7.1 ml multiplied by min(-1), respectively.
      Additional endogenous substrates for MRP-mediated transport included the steroid
      conjugate 17 beta- glucuronosyl [(3)H]estradiol and the bile salt conjugates [6
      alpha-(14)C]glucuronosylhyodeoxycholate and 3 alpha-sulfatolithocholyl
      [(3)H]taurine. The K(m) value of MRP for 17-beta-glucuronosyl [(3)H]estradiol was
      1.5 +/- 0.3 microM, with a V(max):K(m) ratio of 42 ml multiplied by mg protein(
      1) multiplied by min(-1), and a K(i) value of 0.7 microM for the leukotriene
      receptor antagonist MK 571. MRP-mediated ATP-dependent transport was observed for
      the anticancer drug conjugates glucuronosyl [(3)H]etoposide and monocholoro
      mono[(3)H]glutathionyl melphalan, but not for unmodified [(14)C]doxorubicin,
      [(3)H]daunorubicin, or [(3)H]vinblastine. Our results establish that MRP
      functions as an ATP-dependent export pump not only for glutathione conjugates but
      also for glucuronidated and sulfated endogenous as well as exogenous compounds.

PMID- 8640792
TI  - Methyl-donor deficiency due to chemically induced glutathione depletion.
AB  - Dietary deficiency of methionine (Met) is known to deplete cellular Met and cause
      DNA hypomethylation, but depletion of Met and impairment in methylation due to
      chemically induced glutathione (GSH) depletion has escaped recognition. In this
      study, the effect of GSH depletion on the Met pool and methylation capability was
      examined after bromobenzene (BB), a model GSH-depleting hepatotoxin, was
      administered to the Syrian hamster. An i.p. dose of BB (800 mg/kg) caused a rapid
      and extensive depletion of liver GSH; approximately 68% of the initial
      concentration was depleted during the first hour. The lowest level of GSH, only
      4% of the control, was detected at 5 h. GSH depletion was accompanied by a prompt
      increase in liver Met during the first hour. This initial increase was followed
      by an extensive depletion during the next 4 h. At 5 h after BB, liver Met was 12%
      below the control value, and it remained around this concentration throughout the
      24-h experiment. To further confirm these results, the endogenous Met pool was
      labeled with deuterated Met. The administration of (L)- Met-methyl-d(3) to the
      Syrian hamster after GSH had been depleted by BB resulted in a significant
      protection of the liver against necrosis. The protection was accompanied by a
      marked incorporation of deuterated Met into the liver Met pool. The
      incorporation, which was determined by gas chromatography-mass spectrometry,
      shows BB dose dependence. Approximately 53% of the liver Met was labeled when a
      toxic BB dose (800 mg/kg) was used, while only 25% incorporation was found for
      the nontoxic dose (100 mg/kg). These results were different from the controls,
      where only 15% incorporation was found. The differences in the incorporation
      indicate that there are differences in the degree of utilization and/or depletion
      of Met in these hamsters, and these differences apparently are dependent upon the
      degree of toxicity and GSH depletion. The marked incorporation of deuterated Met
      in the high-dose group was accompanied with a striking increase in the
      methylation capability. Urinary excretion of the O- and S-methylated 4- and 5
      bromo-2-hydroxythiophenols and S-methylated 4- and 5-bromo-2-hydroxy-1,2
      dihydrobenzenethiols was significantly increased when compared with the BB
      treated alone. Approximately 40-45% of the methyl groups in these methylated BB
      metabolites were methyl-d(3). These results provide direct evidence that
      depletion of GSH leads to Met depletion and also injures the methylation
      processes.

PMID- 8640793
TI  - Double knockout of the ALL-1 gene blocks hematopoietic differentiation in vitro.
AB  - The ALL-1 gene is involved in translocations with many partner genes in different
      types of the acute leukemias, but it is not clear whether it acts as an oncogene
      or whether the fusion proteins resulting from the translocations have dominant
      negative effects. To distinguish between these two possibilities, we analyzed the
      ability of wild-type AB2.1 embryonal stem (ES) cells and of single or double ALL
      1 gene knockout cells derived from them to differentiate along hematopoietic
      lineages after withdrawal of leukemia inhibitory factor, using in vitro colony
      formation assays. All-1 double knockout ES cells formed a significantly greater
      number of colonies with faster kinetics than wild-type and ALL-1 single knockout
      ES cells. Parental ES cells formed lineage-restricted colonies, whereas single
      and double knockout ES cells developed, at high frequency, immature and/or
      "biphenotypic" colonies, mimicking the aberrant hematopoiesis typical of leukemic
      patients. These data are consistent with the possibility that loss of function of
      the ALL-1 gene is important in leukemogenesis.

PMID- 8640794
TI  - Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas.
AB  - c-erbB-3 and c-erbB-4 protein expression was analyzed using immunohistochemistry
      in 138 fresh-frozen thyroid tissue samples from 106 patients, including 56 cases
      of papillary thyroid carcinoma. Increased expression of c-erbB-3 and c-erbB-4
      proteins was observed in papillary carcinomas compared to nonneoplastic thyroid
      tissue. No amplifications of the c-erbB-3 and c-erbB-4 genes were detected.
      Coexisting overexpression of epidermal growth factor receptor, c-erbB-2, c-erbB
      3, and c-erbB-4 was demonstrated in 36 (64%) of 56 papillary thyroid carcinomas.
      These findings suggest a common regulatory mechanism for the type I (epidermal
      growth factor receptor-related) receptors in papillary thyroid carcinomas and
      provide numerous possibilities for functional receptor interactions.

PMID- 8640795
TI  - Inhibition of fatty acid synthesis delays disease progression in a xenograft
      model of ovarian cancer.
AB  - One of the key limiting factors in the treatment of advanced stage human
      epithelial malignancies is the lack of selective molecular targets for
      antineoplastic therapy. A substantial subset of human ovarian, endometrial,
      breast, colorectal, and prostatic cancers exhibit increased endogenous fatty acid
      biosynthesis and overexpress certain enzymes in the pathway. Cell lines derived
      from these tumors use endogenously synthesized fatty acids for cellular
      functions, whereas normal cells and tissues appear to utilize dietary lipids
      preferentially. We have previously shown that the difference in fatty acid
      biosynthesis between cancer and normal cells is an exploitable target for
      metabolic inhibitors in vitro. Here, we report observations in vivo using the
      i.p. model of the multiply drug-resistant OVCAR-3 human ovarian carcinoma in nude
      mice which demonstrate that: (a) fatty acid synthase overexpression in OVCAR-3 is
      comparable to levels in primary human tumors assessed by immunohistochemistry;
      (b) fatty acid synthetic activity of OVCAR-3 is comparably elevated in vitro and
      in vivo and is 4 to >20-fold higher than normal murine tissues; (c) treatment
      with the specific fatty acid synthase inhibitor, cerulenin, markedly reduces
      tumor cell fatty acid biosynthesis in vivo; (d) fatty acid synthase inhibition
      produces regression of established ascites tumor; and (e) treatment with
      cerulenin causes reduction in ascites incidence, delay in onset of ascites, and
      significantly increased survival (P<0.04).

PMID- 8640796
TI  - Cellular pH gradient in tumor versus normal tissue: potential exploitation for
      the treatment of cancer.
AB  - Although limited data exist, electrode-measured pH values of human tumors and
      adjacent normal tissues, which are concurrently obtained by the same investigator
      in the same patient, consistently show that the electrode pH (believed to
      primarily represent tissue extracellular pH) is substantially and consistently
      lower in the tumor than in normal tissue. In contrast, the 31P-magnetic resonance
      spectroscopy estimated that intracellular pH is essentially identical or slightly
      more basic in tumor compared to normal tissue. As a consequence, the cellular pH
      gradient is substantially reduced or reversed in tumor compared to normal tissue:
      in normal tissue the extracellular pH is relatively basic, and in tumor tissue
      the magnitude of the pH gradient is reduced or reversed. The difference provides
      an exploitable avenue for the treatment of cancer. The extent to which drugs
      exhibiting weakly acid or basic properties are ionized is strongly dependent on
      the pH of their milieu. Weakly acidic drugs which are relatively lipid soluble in
      their nonionized state may diffuse freely across the cell membrane and, upon
      entering a relatively basic intracellular compartment, become trapped and
      accumulate within a cell, leading to substantial differences in the
      intracellular/extracellular drug distribution between tumor and normal tissue for
      drugs exhibiting appropriate pKas.

PMID- 8640797
TI  - Potentiation of enediyne-induced apoptosis and differentiation by Bcl-2.
AB  - Bcl-2 overexpression has been shown to be protective against apoptosis induced by
      a variety of mechanistically diverse chemotherapeutic drugs. Recently, oxygen
      radical species have been implicated in the process of apoptosis, and Bcl-2 has
      been proposed to exert its protective effect by altering the redox state of the
      cell. Unlike most other chemotherapeutic agents, naturally occurring enediynes
      are rendered more cytotoxic in the presence of a higher reducing potential,
      because as prodrugs, they require reduction for activation. We demonstrate herein
      that induction of Bcl-2 expression in PC12 cells potentiates the induction of
      apoptosis and differentiation by the enediyne neocarzinostatin. In
      contradistinction, Bcl-2 abrogates the induction of apoptosis and differentiation
      by the autoactivating enediyne, enediyne-5, and the non-enediyne chemotherapeutic
      agent, cisplatin. We further demonstrate that enediyne potentiation by Bcl-2 is
      related to an increase in cellular glutathione. The present studies suggest that
      enediynes that require reductive activation might be critically useful agents in
      the therapy of tumors such as neuroblastomas and estrogen-responsive breast
      cancers, the resistance of which is related to up-regulation of Bcl-2.

PMID- 8640798
TI  - 5-[211 At]astato-2'-deoxyuridine, an alpha particle-emitting endoradiotherapeutic
      agent undergoing DNA incorporation.
AB  - When labeled with the subcellular range Auger electron emitters 125I and 123I,
      the thymidine analogue 5-iodo-2'deoxyuridine (IUdR) is highly cytotoxic but only
      to cells going through S-phase during exposure to these radiopharmaceuticals.
      Since 211 At emits alpha-particles of high linear energy transfer, but with a
      range of a few cell diameters, an IUdR analogue labeled with 211At could markedly
      improve the homogeneity of tumor dose deposition. Herein we describe the
      synthesis of 5-[211 At]astato-2'-deoxyuridine ([211 At]AUdR) in 85-90%
      radiochemical yield via the astatodestannylation of 5-(trimethylstannyl)-2'
      deoxyuridine. In vitro studies using the human glioma cell line D-247 MG
      demonstrated that [211 At]AUdR was virtually identical to [131I]IUdr; both
      exhibited a linear increase in cell uptake with activity concentration, an
      inhibition of uptake by 10 micrometers IUdR, and the incorporation of about 50%
      of cell-bound activity into DNA. In a clonogenic assay, [211 At]AUdR exhibited a
      high cytotoxicity for D-247 MG cells, with a D(0) equivalent to less than 3 211At
      atoms/cell.

PMID- 8640799
TI  - Particulate naturally processed peptides prime a cytotoxic response against human
      melanoma in vitro.
AB  - For an efficient antitumor cytotoxic response, tumor antigenic peptides need to
      be presented by professional antigen-presenting cells in association with MHC
      class I molecules. We established in vitro short-term human CTL lines from
      healthy and melanoma-bearing subjects, using as antigen-presenting cells
      autologous adherent cells after phagocytosis of latex beads coated with melanoma
      peptides. Melanoma peptides were obtained by acid extraction of melanoma cells
      that matched with donor peripheral blood mononuclear cells, at least for one HLA
      A allele. The cytotoxic activity of the lines was specific for the melanoma from
      which peptides were obtained and for melanoma sharing HLA alleles. These results
      demonstrate that a complex mixture of naturally processed melanoma peptides
      conjugated to a phagocytic substrate that targets them into the MHC class I
      pathway of adherent cells can prime a CTL response in healthy subjects in vitro,
      and that peptides from allogeneic tumors may be used to propagate CTL in melanoma
      patients. Our data support the feasibility of active and passive vaccination
      procedures with nonliving vaccines in cancer patients.

PMID- 8640800
TI  - Genomic organization of the human p57KIP2 gene and its analysis in the G401
      Wilms' tumor assay.
AB  - The p57KIP2 gene encodes an inhibitor of cyclin-dependent kinase activity, which
      negatively regulates cell cycle progression. The human p57 gene is located in
      11p15.5, a region of DNA frequently altered in neoplasia. We have isolated a
      human genomic clone and mapped the p57 gene to a 2.2-kb region between D11S648
      and D11S679. Sequence analysis revealed that the coding DNA of the human p57 gene
      is divided by 0.5-kb intron. A second intron was detected in the 3' untranslated
      region, indicating that the human p57 gene contains at least three exons. Our
      previous work with somatic cell hybrids mapped a tumor suppressor gene for the
      G401 Wilms' tumor cell line to a approximately 500-kb region of 11p15.5 that
      includes p57. Northern blot analysis detected a 0.8-kb p57 transcript in several
      of the G401 hybrid lines. However, p57 expression did not correlate with tumor
      suppression. These results suggest that p57 is not responsible for the tumor
      suppression observed in our somatic cell hybrid assay.

PMID- 8640801
TI  - Cyclin-dependent kinase inhibitor p57KIP2 in soft tissue sarcomas and
      Wilms'tumors.
AB  - Mammalian cyclin-dependent kinase inhibitors fall into two families, the INK4 and
      the CIP/KIP. The CIP/KIP family comprises three structurally related members,
      including p21CiP1/WAF1, p27KIP1, and p57KIP2. These proteins are all capable of
      inhibiting the progression of the cell cycle by binding and inhibiting G(1)
      cyclin/cyclin-dependent kinase complexes. In humans, p57KIP2 is expressed
      specifically in skeletal muscle, heart, brain, kidney, and lung. Human KIP2
      resides in 11p15.5, a chromosomal region that is a common site for loss of
      heterozygosity in certain sarcomas, Wilms' tumors, and tumors associated with the
      Beckwith-Wiedemann syndrome. Because of the function, selective expression, and
      chromosomal location of p57KIP2, we undertook the present study to search for
      potential mutations of KIP2 in a cohort of 126 tumors composed of 75 soft tissue
      sarcomas and 51 Wilms' tumors. The KIP2 gene was characterized by Southern blot,
      comparative multiplex PCR, PCR -single-strand conformational polymorphism, and
      DNA sequencing assays in these neoplasms. Deletions of the KIP2 gene or point
      mutations at the region encoding the cyclin-dependent kinase inhibitory domain
      were not found in the tumors analyzed. The absence of KIP2 mutations might
      indicate that these tumors arise due to defects at a closely linked but separate
      locus. Alternatively, similarly to the mouse homologue, inactivation of KIP2
      could occur via genomic imprinting.

PMID- 8640802
TI  - Suppression of MDA-MB-435 breast carcinoma cell metastasis following the
      introduction of human chromosome 11.
AB  - To determine the relevance of genetic information on chromosome 11 in the
      development of metastatic breast tumors, we introduced a normal human chromosome
      11 into the highly metastatic MDA-MB-435 breast carcinoma cell line via the
      microcell-mediated chromosome transfer technique. Although the MDA-MB-435
      recipient cell line and four randomly selected microcell hybrid clones remained
      tumorigenic in nude mice, the hybrids were >95% suppressed for metastasis to lung
      and regional lymph nodes (p<0.01). We also tested whether chromosome 6 harbors a
      metastasis-suppressor gene for breast cancer as observed previously for human
      melanoma. Grouped together, the four neo6 microcell hybrids had no statistically
      significant reduction in the incidence or number of lung or lymph node metastases
      compared to the weakly metastatic, subcloned parent cell line, MDA-MB-453.7.
      Expression of nm23-H1 (NME1), a known metastasis-suppressor gene in this breast
      cancer cell line, did not correlate with metastasis suppression in the microcell
      hybrids. These results further demonstrate that control of metastasis is
      molecularly distinct from tumorigenic potential. They also indicate that
      chromosome 11 encodes a metastasis-suppressor gene for human breast cancer.

PMID- 8640803
TI  - Allelic imbalance on chromosome 3p in oral dysplastic lesions: an early event in
      oral carcinogenesis.
AB  - We have demonstrated previously a loss of constitutional heterozygosity on the
      short arm of chromosome 3 in approximately 50% of oral squamous cell carcinomas.
      In the present study, we have investigated 30 oral dysplastic lesions (DLs),
      presenting clinically as either erythroplakias or leukoplakias with
      histopathological features of either severe epithelial dysplasia or carcinoma in
      situ, for LOH on chromosome 3p using 15 microsatellite markers. Thirteen of the
      30 LDs (approximately 43%) showed allelic imbalance at one or more loci. The
      pattern of loss in these lesions defined three noncontiguous regions of
      interstitial deletions that overlap with those defined for oral squamous cell
      carcinomas. These data indicate that the alteration of tumor suppressor genes on
      chromosome 3p is probably an early event in oral carcinogenesis. Additionally, 7
      of the 30 DLs showed microsatellite instability. However, the frequency of loci
      showing microsatellite instability per lesion was low.

PMID- 8640804
TI  - Point mutations of the topoisomerase IIalpha gene in patients with small cell
      lung cancer treated with etoposide.
AB  - Reverse transcription-PCR-single-strand conformation polymorphism analysis was
      performed to detect topoisomerase IIalpha mutations using total RNA from 19
      bronchial biopsy specimens obtained from 13 patients with small cell lung cancer.
      An abnormally migrating single-strand conformation polymorphism band was observed
      in one tumor sample from a patient treated with etoposide-containing
      chemotherapy. DNA sequence analysis of this tumor showed two transversions at
      codons 486 (G to A) and 494 (A to G), resulting in two missense mutations (Arg to
      Lys and Glu to Gly, respectively). The codon 486 mutation was identical to that
      previously found in two cell lines selected for amsacrine resistance. These
      results demonstrate that mutations of topoisomerase IIalpha occur in patients
      with small cell lung cancer. The significance of these mutations in the
      development of resistance to etoposide needs further investigation.

PMID- 8640805
TI  - Microsatellite instability in nonneoplastic mucosa from patients with chronic
      ulcerative colitis.
AB  - Microsatellite instability (MIN) has been detected in many cancer types; however,
      recently we also observed it in the nonneoplastic but inflammatory setting of
      pancreatitis. Consequently, we sought to examine whether MIN was present in
      another inflammatory condition, ulcerative colitis (UC). MIN was found in 50% of
      UC patients whose colonic mucosa was negative for dysplasia, 46% of those with
      high-grade dysplasia, and 40% of those with cancer but in none of the ischemic or
      infectious colitis controls (P<0.03). Thus, UC patients may have MIN within
      mucosa that has no histological evidence of neoplastic change. MIN in this
      setting may reflect the inability of DNA repair mechanisms to compensate for the
      stress of chronic inflammation, and may be one mechanism for the heightened
      neoplastic risk in UC.

PMID- 8640806
TI  - Germline and somatic mutations in an oncogene: RET mutations in inherited
      medullary thyroid carcinoma.
AB  - Inherited cancer syndromes predispose an individual to development of specific
      tumors. Somatic and germline mutations in the same tumor suppressor gene, as
      described in Knudson's two-mutation model, are well recognized. Inherited
      mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase,
      predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer
      syndromes. The major component tumor of these syndromes is medullary thyroid
      carcinoma (MTC). To date, somatic mutations in RET have not been identified in
      tumors from individuals with MEN 2, although they have been well documented in
      sporadic MEN 2-related tumors. We have identified, among 16 MEN 2 cases with well
      defined RET germline mutations, a somatic missense mutation at codon 918 of RET
      in 3 of 15 MTCs and in a sample with hyperplastic C-cells (presumed precursor to
      hereditary MTC). We suggest that the presence of a somatic mutation, in addition
      to the preexisting germline mutation in hereditary MTCs, may contribute to
      tumorigenesis in vivo.

PMID- 8640807
TI  - Motility-related protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in
      breast cancer.
AB  - The application of reliable markers is of major importance for predicting the
      prognosis of and instituting the appropriate postsurgical treatment of patients
      with breast cancer. Previously we showed that motility-related protein-1 (MRP-1),
      which is identical to CD9, regulates cell motility, and that cultured tumor cells
      transfected with MRP-1/CD9 cDNA have low motility and low metastatic potential.
      In addition, MRP-1/CD9 immunoblotting and immunohistochemical study with breast
      cancer revealed that MRP-1/CD9 expression diminished as the clinical stage of a
      given breast cancer advanced and that the MRP-1/CD9 gene and protein expression
      in the metastatic lymph nodes was strikingly lower than in the primary breast
      cancers. In this study, we also investigated the expression of MRP-1/CD9 by
      immunoblotting and immunohistochemical analysis in 143 freshly resected invasive
      ductal carcinomas of the breast: 52 tumors were stage I, 61 were stage II, and 30
      were stage III. Tumors were classified as MRP-1/CD9 positive when a band
      intensity of >30% compared with positive control cells, ZR-75-30 were evaluated
      with the antibody M31-15, and those with intensities <30% as negative. Moreover,
      these results were ascertained by immunostaining. Tumor specimens classified as
      MRP-1/CD9 positive using Western blotting had >50% of the cancer cells
      immunostained with M31-15, and those classified as MRP-1/CD9 reduced had <50% of
      the cancer cells immunostained with M31-15. There were 97 patients with MRP-1/CD9
      positive tumors and 46 patients whose tumors had reduced MRP-1/CD9 levels. The
      disease-free rate of the former group of patients was strikingly higher than that
      of the latter (84.7% versus 51.4%, P<0.001). Similarly, the overall survival rate
      was also significantly different between the two groups (93.6% versus 69.6%,
      P=0.004). Multivariate analysis with the Cox regression model indicated that MRP
      1/CD9 positively correlated better with disease-free survival (P<0.001) than
      estrogen receptor, tumor, and lymph node status. Our data suggest that low MRP
      1/CD9 expression by tumors of the breast may be associated with poor prognosis.
      It is conceivable that testing for MRP-1/CD9 may identify node-negative breast
      cancer patients who are at high risk for early disease recurrence.

PMID- 8640808
TI  - Frequency of the BRCA1 185delAG mutation among Jewish women with ovarian cancer
      and matched population controls.
AB  - Among women of Ashkenazi Jewish origin, a frameshift mutation of the BRCA1 gene,
      designated 185delAG, occurs with a carrier frequency of approximately 1% and is
      estimated to account for about 39% of ovarian cancer cases occurring prior to age
      50 years. To determine the actual frequency of this mutation among Jewish women
      with ovarian cancer, we tested DNA collected as part of an ongoing population
      based case-control study of genetic and environmental factors for epithelial
      ovarian cancer in eastern Massachusetts. Using single-stranded conformational
      polymorphism analysis followed by direct sequencing, we found that 6 (19.4%) of
      31 Jewish patients were carriers for a 185delAG mutation compared to 0 of 23
      Jewish controls (P=0.03) Using empiric logic [correction of logits], the
      estimated relative risk for ovarian cancer associated with a 185delAG mutation is
      12.0. The average age of the 6 patients with mutations was 48.3 years,
      significantly younger than the average of 57.4 years observed for the 25 patients
      without the mutation (P-0.05). For ovarian cancer diagnosed prior to age 50
      years, three (37.5%) of eight patients carried the mutation. None of the six
      patients with the mutation had a history consistent with hereditary breast
      ovarian cancer syndrome, although two had a personal history of prior cancer. Our
      results provide empiric conformation of the estimated prevalence of 185delAG
      mutations among Jewish women with ovarian cancer.

PMID- 8640809
TI  - Taxol induces bcl-2 phosphorylation and death of prostate cancer cells.
AB  - Treatment of prostate cancer cell lines expressing bcl-2 with taxol induces bcl-2
      phosphorylation and programmed cell death, whereas treatment of bcl-2-negative
      prostate cancer cells with taxol does not induce apoptosis. bcl-2 phosphorylation
      seems to inhibit its binding to bax since less bax was observed in immunocomplex
      with bcl-2 in taxol-treated cancer cells. These findings support the use of the
      anticancer drug taxol for the treatment of bcl-2-positive prostate cancers and
      other bcl-2-positive malignancies, such as follicular lymphoma.

PMID- 8640810
TI  - Induction of muscle protein degradation and weight loss by a tumor product.
AB  - Splenocytes from mice bearing a cachexia-inducing tumor (MAC16) have been fused
      with mouse myeloma cells to produce hybridomas, which have been cloned to produce
      antibody reactive to a material which copurified with a lipid-mobilizing factor
      isolated from the same tumor. The monoclonal antibody has been used to
      investigate factors potentially involved in the development of cachexia. The
      major protein detectable by immunoprecipitation of a partially purified lipid
      mobilizing factor was M(r) 69,000, whereas Western blotting showed two bands of
      M(r) 69,000 and M(r) 24,000. Although the monoclonal antibody did not neutralize
      lipid-mobilizing activity in an in vitro assay, it did neutralize a serum factor
      capable of protein degradation in isolated gastrocnemius muscle. Affinity
      purification of MAC16 tumor homogenates using the monoclonal antibody yielded two
      immunoreactive bands of M(r) 69,000 and M(r) 24,000, which were further
      fractionated on a hydrophobic column (C8). This material was capable of inducing
      tyrosine release from isolated gastrocnemius muscle, and the effect could be
      blocked with the monoclonal antibody. The two immunoreactive bands from the
      hydrophobic column were capable of inducing weight loss in mice, whereas
      nonimmunoreactive fractions had no effect on body weight. The M(r) 24,000 species
      had a unique amino acid sequence, whereas the M(r) 69,000 species gave the same
      sequence as the M(r) 24,000 material, together with that for albumin. The M(r)
      24,000 species contained carbohydrate, and lectin blotting showed a strong
      reaction with wheat germ and Erythrina crystagalli agglutinins. This suggests
      that the material is a glycoprotein or proteoglycan that shows strong binding
      affinity for albumin, possibly through the carbohydrate residues.

PMID- 8640811
TI  - Defective repair of oxidative damage in the mitochondrial DNA of a xeroderma
      pigmentosum group A cell line.
AB  - Recent evidence has linked mitochondrial DNA (mtDNA) damage to several disease
      processes,including cancer and aging. An important source of such damage is
      reactive oxygen species. These molecules can be generated endogenously via the
      electron transport system or may arise from a host of exogenous sources. It has
      been reported that extracts from cells of individuals with xeroderma pigmentosum
      group A (XP-A) do not repair some types of oxidative DNA damage. The current
      experiments were designed to determine whether there is a correlation between the
      inadequate repair of oxidatively damaged nuclear DNA in XP-A cells and the
      capacity of such cells to repair similar damage to their mtDNA. The ability of
      karyotypically normal human fibroblasts (WI-38) and XP-A fibroblasts to repair
      alloxan-generated oxidative damage to nuclear and mtDNA was assessed using a
      quantitative Southern blot method in conjunction with the repair enzymes
      endonuclease III and formamidopyrimidine DNA glycosylase. The data indicate that
      both nuclear and mtDNA repair of each damage type investigated is more efficient
      in the WI-38 cells. These findings suggest a similarity between the process(es)
      used to repair oxidative damage to nuclear and mtDNA in that both are inhibited
      by the defect in XP-A.

PMID- 8640812
TI  - Copper-dependent formation of miscoding etheno-DNA adducts in the liver of Long
      Evans cinnamon (LEC) rats developing hereditary hepatitis and hepatocellular
      carcinoma.
AB  - Formation of etheno-DNA adducts in the liver was investigated in Long Evans
      cinnamon (LEC) rats, a Long Evans strain with hereditary abnormal copper
      metabolism, which develop spontaneous hepatitis and later hepatocellular
      carcinoma. Using an ultrasensitive immunoaffinity/32P-postlabeling assay (J. Nair
      et al., Carcinogenesis, 16: 613-617, 1995), the etheno adducts 1,N6
      ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytidine (epsilon dC) were
      measured in the liver of 7-, 18-, 30-, and 87-week-old LEC rats. Levels were
      highest in the liver of 18-week old rats 85 +/- 17 (epsilon dA) and 85 +/- 30
      (epsilon dC) adducts per 10(9) parent nucleotides, and the increase in the levels
      of etheno adducts was age dependent. Age-matched Long Evans agouti rats, a tumor
      free sibling line of LEC rats, had much lower levels of both etheno adducts.
      Etheno adduct levels in LEC rats were well correlated with the hepatic copper
      levels, and peak adduct levels coincided with the age of commencement of
      fulminant hepatitis. Our results demonstrate for the first time a copper- and age
      dependent formation of highly miscoding etheno-DNA adducts in the liver of LEC
      rats. These adducts are formed from lipid peroxidation products (F. El-Ghissassi
      et al., Chem. Res. Toxicol., 8: 273-283, 1995) and thus could arise in the liver
      of LEC rats from oxygen radicals generated by copper-catalyzed Fenton-type
      reactions. Etheno-DNA adducts along with other oxidative DNA base damages may
      thus be involved in liver carcinogenesis in LEC rats.

PMID- 8640813
TI  - Influence of liver tumor promoters on apoptosis in rat hepatocytes induced by 2
      acetylaminofluorene, ultraviolet light, or transforming growth factor beta 1.
AB  - DNA damage is recognized widely as a cause of programmed cell death (apoptosis),
      aimed at eliminating cells bearing genotoxic lesions. Therefore, inhibition of
      DNA damage-induced apoptosis may play an important role in carcinogenesis and has
      been suggested as a mechanism of action of tumor-promoting agents. In the present
      study, the effects of treatment with UV light or the carcinogenic aromatic amine
      2-acetylaminofluorene (2-AAF) on apoptosis were studied in rat hepatocytes in
      primary culture. A significantly increased incidence of apoptotic nuclei, showing
      condensed or fragmented chromatin visualized with the fluorescent dye Hoechst
      33258, was found after each type of treatment. After 48 h, the incidence of
      apoptosis had returned to the control level. When the liver tumor promoters
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and phenobarbital were added to the
      medium, apoptosis did not increase in UV- or 2-AAF-treated compared with
      untreated cultures. Furthermore, TCDD and phenobarbital suppressed
      internucleosomal DNA fragmentation elicited by UV irradiation. In contrast, the
      promoters did not suppress apoptosis induced by transforming growth factor beta
      1. Immunoprecipitation of the tumor suppressor gene product p53 demonstrated that
      the increase in p53 observed after UV irradiation was abrogated almost completely
      by TCDD. Apoptosis induced in rat hepatocytes by DNA-damaging agents such as UV
      light or 2-AAF is suppressed by TCDD and phenobarbital. Inhibition of apoptosis
      allowing survival of hepatocytes bearing genotoxic lesions may be crucial for the
      tumor-promoting action of TCDD and phenobarbital in the liver.

PMID- 8640814
TI  - Increased oxidative DNA damage in Helicobacter pylori-infected human gastric
      mucosa.
AB  - Helicobacter pylori causes type B gastritis. It shows strong association with the
      development of gastric carcinoma. A plausible hypothesis for the missing link
      between H. pylori infection and gastric carcinogenesis involves oxygen free
      radical-induced DNA damage. To test this hypothesis, we compared the amount of 9
      hydroxydeoxyguanosine, a marker for oxygen free radical-induced DNA damage, in
      the DNA of human gastric mucosa with and without H. pylori infection. Gastric
      antral biopsies were taken from pediatric patients and volunteers to select H.
      pylori-positive and H. pylori-negative specimens. The 8-hydroxydeoxyguanosine
      content of the gastric mucosal DNA was measured after H. pylori-positive and H.
      pylori-negative volunteers were identified. The increased level of oxidative DNA
      damage suggests the mechanistic link between H. pylori infection and gastric
      carcinoma.

PMID- 8640815
TI  - Evidence that the catechol 3,4-Dihydroxytamoxifen is a proximate intermediate to
      the reactive species binding covalently to proteins.
AB  - Metabolism of tamoxifen by rat and human hepatic microsomal cytochrome P450s
      (CYPs) forms a reactive intermediate that irreversibly binds to microsomal
      proteins (C. Mani and D. Kupfer, Cancer Res., 51: 6052-6058, 1991.). The current
      study examines the nature of the tamoxifen metabolite that is proximate to the
      reactive intermediate(s). The rate of covalent binding of tamoxifen metabolites,
      tamoxifen N-oxide, N-desmethyltamoxifen, and tamoxifen N-oxide-epoxide was
      approximately equal to or less than that of tamoxifen. By contrast, covalent
      binding of 4-hydroxytamoxifen (4-OH-tam) was 3-5-fold higher than that of
      tamoxifen, indicating that among the metabolites examined, 4-OH-tam or its
      metabolite(s) is most proximate to the reactive intermediate(s). Incubation of 4
      OH-tam with liver microsomes from PCN-treated rat yielded three detectable
      metabolites. One was identified as 4-OH-tam N-oxide via its facile reduction back
      to 4-OH-tam by titanium(III) chloride. Another metabolite of 4-OH-tam, assumed to
      be 3,4-dihydroxytamoxifen (3,4-di-OH-tam) catechol, was demonstrated by its
      monomethylation with [3H]S-adenosyl-L-methionine ([3H]SAM) in presence of
      endogenous catechol-O-methyltransferase. Monomethylated catechol from 4-OH-tam
      was formed at a 3-4-fold higher rate than from tamoxifen. It was reasoned that if
      the catechol is most proximate metabolite to the reactive intermediate, then its
      methylation would reduce the formation of the reactive intermediate and result in
      lower rate of covalent binding. In fact, addition of radioinert SAM to
      incubations of tamoxifen inhibited covalent binding by 17-23%. By contrast,
      inclusion of 1.0 mM S-adenosyl-L-homocysteine, a potent inhibitor of catechol-O
      methyltransferase-mediated methylation of 3,4-di-OH-tam, essentially overcame the
      inhibition of the covalent binding by SAM. Additionally, ascorbic acid and
      glutathione, inhibitors of covalent binding of tamoxifen, produced an elevation
      of methylated catechol. These findings collectively indicate that 3,4-di-OH-tam
      is proximate to the ultimate reactive intermediate that results in covalent
      binding to microsomal proteins.

PMID- 8640816
TI  - Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes.
AB  - The association between high intake of fruit and vegetables and low incidence of
      certain cancers is well established. Dietary antioxidants present in these foods
      are thought to decrease free radical attack on DNA and hence to protect against
      mutations that cause cancer, but this causal mechanism remains conjectural. We
      have adopted a molecular epidemiological approach to this question, based on a
      modified alkaline single-cell gel electrophoresis assay ("comet assay") which
      specifically detects oxidation of pyrimidines in the DNA of human lymphocytes. In
      a survey of men 50-59 years of age living in the northeast of Scotland, smokers
      initially showed significantly more base damage than nonsmokers. Correlations
      between oxidative base damage and plasma concentrations of various antioxidants
      were generally negative but not statistically significant. Supplementation of the
      diet for 20 weeks with vitamin C (100 mg/day), vitamin E (280 mg/day), and beta
      carotene (25 mg/day) resulted in a highly significant (P < 0.002) decrease in
      endogenous oxidative base damage in the lymphocyte DNA of both smokers and
      nonsmokers. In addition, lymphocytes of antioxidant-supplemented subjects showed
      an increased resistance to oxidative damage when challenged in vitro with H2O2.
      These findings strongly support the hypothesis that fruit and vegetables exert a
      cancer-protective effect via a decrease in oxidative damage to DNA.

PMID- 8640817
TI  - Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the
      CYP3A subfamily in humans.
AB  - Docetaxel metabolism mediated by cytochrome P450-dependent monooxygenases was
      evaluated in human liver microsomes and hepatocytes. In microsomes, the drug was
      converted into four major metabolites resulting from successive oxidations of the
      tert-butyl group on the synthetic side chain. Enzyme kinetics appeared to be
      biphasic with a V(max) and apparent K(m) for the high-affinity site of 9.2
      pmol/min/mg and 1.1 microm, respectively. the intrinsic metabolic clearance in
      human liver microsomes (V(max)/K(m), 8.4 ml/min/g protein) was comparable to that
      in rat and dog liver microsomes, but lower in mouse liver microsomes. Although
      the metabolic profile was identical in all subjects, a large quantitative
      variation in docetaxel biotransformation rates was found in a human liver
      microsome library, with a ratio of 8.9 in the highest:lowest biotransformation
      rates. Docetaxel biotransformation was correlated significantly (0.7698; P <
      0.0001) with erythromycin N-demethylase activity, but not with aniline
      hydroxylase or debrisoquine 4-hydroxylase. It was inhibited, both in human
      hepatocytes and in liver microsomes, by typical CYP3A substrates and/or
      inhibitors such as erythromycin, ketoconazole, nifedipine, midazolam, and
      troleandomycin. Docetaxel metabolism was induced in vitro in human hepatocytes by
      dexamethasone and rifampicin, both classical CYP3A inducers. These data suggest a
      major role of liver cytochrome P450 isoenzymes of the CYP3A subfamily in
      docetaxel biotransformation in humans. Finally, some Vinca alkaloids and
      doxorubicin were shown to inhibit docetaxel metabolism in human hepatocytes and
      liver microsomes. These findings may have clinical implications and should be
      taken into account in the design of combination cancer chemotherapy regimens.

PMID- 8640818
TI  - Taxol-dependent transcriptional activation of IL-8 expression in a subset of
      human ovarian cancer.
AB  - Taxol is important in the treatment of both primary and drug-resistant ovarian
      cancer. Although Taxol is known to stabilize microtubules and block cell mitosis,
      the effectiveness of this drug exceeds that of other antimitotic agents,
      suggesting it may have an additional mode of action. Stimulated by murine
      macrophage studies indicating cytokine induction by Taxol, we have investigated
      proinflammatory cytokine expression in a series of cell lines and recent explants
      of human ovarian cancer. Taxol induced secretion of interleukin (IL) 8 but not IL
      6, IL-1alpha, or IL-1beta in 4 of 10 samples. Induction was dependent on
      transcriptional activation, and, in contrast to murine macrophage studies, was
      apparently independent of an active lipopolysaccharide signaling pathway.
      Confluent cultures secreted as much IL-8 as proliferating cells. Taxol did not
      induce IL-8 in breast carcinoma, endometrial stromal, or T-lymphocyte or monocyte
      cultures. We propose that the local expression of this chemokine in vivo may
      elicit a host response similar in effectiveness to that of cytokine gene therapy.
      These data are the first to suggest that a chemotherapeutic agent may have a
      direct effect on transcription of cytokine and/or growth factor genes in ovarian
      cancer, and that this effect may not be restricted to proliferating tumor cells.

PMID- 8640819
TI  - Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A.
AB  - The focus of this investigation was to modulate the pharmacokinetics of
      irinotecan and its metabolites, SN-38 and SN-38G, by possibly reducing biliary
      excretion, which in turn could lower irinotecan toxicity. We determined the
      effect of a known cholestatic agent, cyclosporin A (CsA), which is transported
      across the bile canalicular membrane by P-glycoprotein, on the biliary excretion
      of irinotecan and its metabolites. Wistar rats were pretreated with 60 mg/kg CsA
      5 min before an i.v. dose of irinotecan at dose levels of 6, 10, and 20 mg/kg.
      The control groups received irinotecan only. CsA pretreatment resulted in an
      average increase of 339, 361, and 192% in the area under the plasma concentration
      time curve of irinotecan, SN-38, and SN-38G, respectively. Analysis of clearance
      (CL) of irinotecan indicated a 55 and 81% reduction in the average renal and
      nonrenal CLs, respectively, in the pretreated groups. The nonrenal CL, which is
      the primary component of irinotecan CL, includes protein and tissue binding as
      well as the metabolic and biliary CL of irinotecan. There was no change in the
      volume of distribution at steady state (indicative of unchanged binding) and in
      the metabolic conversion of irinotecan to SN-38 due to pretreatment. Therefore,
      the significant reduction in the systemic CL of irinotecan due to CsA
      pretreatment was primarily due to lowered biliary excretion. Studies using a
      photoaffinity analogue of verapamil, [125I]NAS-VP, and membrane vesicles from the
      multidrug-resistant cell line, MCF-7/Adr, revealed that irinotecan and
      metabolites had moderate interaction with P-glycoprotein. Further studies are
      required to determine the mechanism of inhibitory effect of CsA on the biliary
      excretion of irinotecan and its metabolites.

PMID- 8640820
TI  - Comparison of the effects of three different toxin genes and their levels of
      expression on cell growth and bystander effect in lung adenocarcinoma.
AB  - Transduction of malignant cells with toxin genes provides a novel means to
      promote tumor cell destruction. The efficacy of a toxin gene is dependent on the
      cell type targeted, the quantity of exogenous protein synthesized, and the
      mechanisms of growth inhibition and bystander killing. To develop gene therapy
      for targeting metastatic lung adenocarcinoma, the toxic activity of herpes
      simplex virus type 1-thymidine kinase, Escherichia coli cytosine deaminase, and
      human deoxycytidine kinase were investigated in metastatic human lung
      adenocarcinoma cell lines H1437 and H2122. Cells were transduced stably with
      retroviral vectors containing the toxin gene cDNA under the control of either a
      strong [cytomegalovirus (CMV) immediate early promotor and enhancer] or an
      intermediate strength (Moloney murine leukemia virus long terminal repeat)
      promotor. A comparison of toxin gene efficacy was based on the level of specific
      enzyme activity, the concentration of prodrug required to inhibit cell growth by
      50%, and the magnitude of the bystander effect. In lung adenocarcinoma cell
      lines, cytosine deaminase, driven by the CMV promoter, was superior to thymidine
      kinase and deoxycytidine kinase in its ability to achieve high levels of specific
      enzyme activity, to induce growth inhibition, and to affect neighboring cell
      growth. Therefore, cytosine deaminase expressed from the CMV promotor seems to be
      the most promising toxin gene for human lung adenocarcinoma gene therapy.

PMID- 8640821
TI  - Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk
      1-positive endothelial cell proliferation in vitro and angiogenesis in vivo.
AB  - Inhibition of tumor neovascularization has profound effects on the growth of
      solid tumors. An endothelial cell-specific cytotoxic conjugate was prepared by
      chemically linking recombinant vascular endothelial growth factor (VEGF165) and a
      truncated diphtheria toxin molecule (DT385). The treatment of subconfluent
      cultures of human umbilical vein endothelial cells and human microvascular
      endothelial cells with the VEGF165-DT385 conjugate resulted in a selective, dose
      dependent inhibition of growth. Parallel experiments with either the free toxin
      or a mixture of VEGF and the toxin polypeptide did not affect proliferation (DNA
      synthesis) of these cells. The selective cytotoxicity correlated with the
      appropriate receptor expression (KDR/flk-1 positive) on the target cells. VEGF
      toxin conjugate inhibited the growth of a murine hemangioma-derived endothelial
      cell line (Py-4-1), which was positive for flk-1 expression. Under similar
      conditions, the conjugate did not affect the proliferation of a receptor-negative
      ovarian cancer cell line in vitro. In an in vivo model of angiogenesis, the
      VEGF165-DT385 conjugate blocked basic fibroblast growth factor-induced
      neovascularization of the chick chorioallantoic membrane. These studies
      demonstrate the successful targeting of a cytotoxic polypeptide to proliferating
      vascular endothelial cells (normal and tumorigenic) and the potential utility of
      such conjugates in blocking tumor neovascularization.

PMID- 8640822
TI  - Sensitization of human breast cancer cells to cyclophosphamide and ifosfamide by
      transfer of a liver cytochrome P450 gene.
AB  - The cancer chemotherapeutic agent cyclophosphamide (CPA) and its isomer
      ifosfamide (IFA) are alkylating agent prodrugs that require metabolism by liver
      cytochrome P450 (P450) enzymes for antitumor activity. The therapeutic
      effectiveness of these oxazaphosphorines is limited by the hematopoietic, renal,
      and cardiac toxicity that accompanies the systemic distribution of liver-derived
      activated drug metabolites. Transfer of a liver cytochrome P450 gene, CYP2B1,
      into human breast MCF-7 cancer cells is presently shown to greatly sensitize
      these cells to oxazaphosphorine toxicity as a consequence of the acquired
      capacity for intratumoral CPA and IFA activation. Thus, CPA and IFA were highly
      cytotoxic to MCF-7 cells following stable transfection of CYP2B1 but exhibited no
      toxicity to parental tumor cells or to a beta-galactosidase-expressing MCF-7
      transfectant. This cytotoxicity could be appreciably blocked by the CYP2B1
      inhibitor metyrapone. Cell cycle analysis revealed that CPA arrested the CYP2B1
      expressing cells, but not CYP2B1-negative cells, at G(2)-M phase. A strong
      bystander cytotoxicity effect that does not require direct cell-cell contact was
      mediated by CYP2B1-expressing MCF-7 cells on non-CYP2B1 cells. Intratumoral
      CYP2B1 expression conferred a distinct therapeutic advantage when treating MCF-7
      tumors grown in nude mice with CPA, as revealed by a 15-20-fold greater in vivo
      cytotoxicity, determined by tumor excision/colony formation assay, and by the
      substantially enhanced antitumor activity, monitored by tumor growth delay, for
      CYP2B1-e xpressing MCF-7 tumors as compared to CYP2B1-negative control tumors.
      These enhanced therapeutic effects were obtained without any apparent increase in
      host toxicity. To evaluate the extent to which a CPA/P450 gene therapy strategy
      may be generally applicable to other tumor cell types, a replication-defective
      recombinant adenovirus carrying the CYP2B1 gene driven by the cytomegalovirus
      (CMV) promotor ad.CMV-2B1 was constructed and used to infect a panel of human
      tumor cell lines. Ad.CMV-2B1 infection rendered each of the cell lines highly
      sensitive to CPA and IFA cytotoxicity, with substantial chemosensitization seen
      at multiplicities of infection as low as 10. The CPA/P450 prodrug activation
      system may thus serve as a useful paradigm for further development of novel
      cancer gene therapy strategies that utilize drug susceptibility genes to
      significantly potentiate the antitumor activity of conventional cancer
      chemotherapeutic agents.

PMID- 8640823
TI  - Adenovirus-mediated prodrug gene therapy for carcinoembryonic antigen-producing
      human gastric carcinoma cells in vitro.
AB  - We analyzed the ability of a recombinant replication-defective adenovirus vector
      with the carcinoembryonic antigen (CEA) promotor to transfer the thymidine kinase
      gene of herpes simplex virus (HSVtk) into gastric cancer cells to confer
      sensitivity to ganciclovir (GCV). CEA-producing gastric cancer cell lines (MKN28
      and MKN45), a CEA-nonproducing gastric cancer cell line (MKN1), and a human
      uterine cervical cancer cell line (HeLa) were infected with a recombinant
      adenovirus carrying lacZ reporter gene coupled to the CEA promoter (AdCEAlacZ).
      The efficiency of AdCEAlacZ-mediated gene transfer was correlated with the amount
      of CEA produced by each cell line. Furthermore, the 50% growth inhibitory
      concentrations (IC50) of GCV were 21 and 5.8 microm for MKN28 and MKN45,
      respectively, when infected with a recombinant adenovirus carrying the HSVtk gene
      coupled to the CEA promoter (AdCEAtk). However, MKN1 and HeLa cells infected with
      AdCEAtk remained resistant to GCV (IC50 > 300 microm of GCV). In addition, a
      bystander killing effect was demonstrated against MKN45 cells when only 20% of
      AdCEAtk-infected cells were mixed with uninfected cells. These data indicate the
      potential for targeted gene therapy using the cell type-specific promotor of the
      CEA gene against gastric cancers that produce CEA.

PMID- 8640824
TI  - Adenovirus-mediated gene transfer to human breast tumor cells: an approach for
      cancer gene therapy and bone marrow purging.
AB  - To examine the potential use of adenovirus vectors in cancer gene therapy as a
      mechanism for purging bone marrow cells of possible breast cancer contaminants,
      we compared the infection efficiency of adenovirus and the transfection
      efficiency of plasmid DNA in the presence of adenovirus in human breast cancer
      and bone marrow cells. Following infection of breast cancer cells with an
      adenovirus expressing beta-galactosidase gene, high levels of beta-galactoside
      activity were observed. No beta-galactosidase activity was observed in low
      density human bone marrow cells. A replication-deficient adenovirus mutant dl312
      enhanced the transfection efficiency of a plasmid DNA-expressing beta
      galactosidase gene into breast cancer cells, and addition of a liposome,
      lipofectamine, further enhanced the transfection efficiency. In contrast, human
      bone marrow cells treated under the same conditions expressed very low levels of
      transfected beta-galactosidase DNA. Transfection of cells with plasmid DNA
      expressing a truncated but fully active Pseudomonas exotoxin gene in the presence
      of dl312 and lipofectamine resulted in marked breast cancer cell killing, whereas
      colony-forming unit granulocyte-macrophage (CFU-GM) were relatively resistant to
      these treatments. A recombinant adenovirus expressing human wild-type p53 protein
      (AdWTp53) was also highly cytotoxic to breast tumor cells. Infection of breast
      cancer cells with AdWTp53 (100 plaque-forming units/cell) resulted in 100% loss
      of the clonogenicity of breast tumor cells. However, colony formation from CFU-GM
      was relatively resistant to the cytotoxic effects of AdWTp53 alone or in the
      presence of pULI100 plasmid and lipofectamine. On the basis of these results, it
      is proposed that human adenoviruses are potentially useful for cancer gene
      therapy and bone marrow purging.

PMID- 8640825
TI  - Corticotropin-releasing factor decreases vasogenic brain edema.
AB  - We report the first series of studies comparing the anti-edematous effects of
      human corticotropin-releasing factor (hCRF) and dexamethasone in an experimental
      model of vasogenic peritumoral brain edema. Both hCRF and dexamethasone
      effectively decreased blood-brain barrier (BBB) permeability of intracerebral RG2
      gliomas in rats as observed by contrast-enhanced T(1)-weighted magnetic resonance
      imaging. A decrease in the water content of tumor and peritumoral brain tissue
      was observed with proton-density magnetic resonance imaging and confirmed by
      direct wet/dry tissue measurements. The calculated ED(50) for hCRF was 59
      micrograms/kg s.c. twice a day, and that for dexamethasone was 0.61 mg/kg i.m.
      twice a day; the hCRF:dexamethasone dose-potency ratio was 120:1 on a molar
      basis. The anti-edematous action of hCRF is not mediated by the release of
      adrenal corticosteroids. A direct action of hCRF on the tumor microvasculature
      results in restoration of BBB integrity and up-regulation of BBB-specific protein
      expression. The average survival time with chronic treatment was prolonged
      significantly in the hCRF-treated group (35 days) compared with the dexamethasone
      treated group (28 days; P < 0.05) and the saline-treated control group (22 days;
      P < 0.0001). hCRF, as an alternative to corticosteroid therapy, may provide
      substantial benefits with respect to reducing the major side effects encountered
      with long-term, high-dose corticosteroid treatment.

PMID- 8640826
TI  - Treatment of microscopic pulmonary metastases with recombinant autologous tumor
      vaccine expressing interleukin 6 and Escherichia coli cytosine deaminase suicide
      genes.
AB  - Poorly immunogenic tumor cells genetically transduced to simultaneously express
      the cytokine interleukin 6 (IL-6) and the bacterial metabolic suicide gene
      cytosine deaminase (205-IL6-CD) become highly immunogenic. They are rejected by
      normal mice without 5-fluorocytosine prodrug treatment. Mice with preexisting
      wild-type pulmonary micrometastases exhibit prolonged survival and an increased
      rate of cure when treated with live 205-IL6-CD cells as a therapeutic vaccine.
      Treatment with these autologous tumor cells producing both the cytokine and the
      bacterial protein was more effective than treatment with exogenous IL-6 and/or
      irradiated wild-type tumor cells. Irradiation of the 205-IL6-CD cells
      significantly reduced their therapeutic efficacy. Therapeutic vaccination with
      205-IL6-CD was more effective in animals with wild-type 205 tumor than in animals
      bearing an unrelated syngeneic tumor. Vaccine efficacy was significantly reduced
      in animals pretreated with high-dose cyclophosphamide. The results indicate that
      genetically engineered autologous tumor vaccines may be capable of inducing
      significant antitumor immunity in hosts of preexisting micrometastatic disease.

PMID- 8640827
TI  - Regulation of insulin-like growth factor II P3 promotor by p53: a potential
      mechanism for tumorigenesis.
AB  - Human insulin-like growth factor (IGF)-II mRNA has been shown to be expressed at
      high levels in a variety of tumors, including rhabdomyosarcomas. In addition,
      many tumors have alterations in p53 expression. To investigate whether p53
      regulates IGF-II gene expression, we transfected wild-type p53 expression vectors
      and luciferase constructs driven by IGF-II P3 promotors into multiple cell lines.
      We found that p53 reduced, in a dose-dependent manner, both endogenous IGF-II P3
      transcripts and transfected P3 luciferase expression. The inhibition of P3
      luciferase expression by p53 was more pronounced in the two cell lines that
      expressed mutant p53 protein, RD, and HTB114. The element responsible for this
      inhibition was mapped to the minimal promoter region. We also transfected an HPV
      16 E6 expression plasmid into CCL13 cells containing functional p53 and found
      that E6 up-regulated IGF-II P3 activity. Wild-type, but not mutant, p53
      interfered with the binding of TATA-binding protein to the TATA motif of P3,
      although both could directly associate with human TATA-binding protein. Our
      results suggest that p53 may play a role in regulation of IGF-II gene expression.

PMID- 8640828
TI  - Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant
      tumor cells.
AB  - We have examined microsatellite instability and loss of p53 function in human
      tumor cell line models of acquired anticancer drug resistance. We observe
      acquisition of an RER(+) phenotype in cell lines selected for resistance to
      cisplatin or doxorubicin. The majority of independent cisplatin-resistant
      sublines are RER(+), whereas the parental line shows no evidence of
      microsatellite instability. Microsatellite mutations in random, nonselected
      subclones of a cislatin-resistant line are observed in the absence of further
      drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather
      than being transiently induced by DNA damage. Furthermore, a cisplatin-resistant
      derivative shows reduction in a G:T mismatch recognition activity compared to the
      parental line. Independent lines selected by multiple exposure to cisplatin show
      resistance factors of up to a 5-fold by clonogenic assay and have reduced
      cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of
      loss of p53-dependent functions, as measured by a loss of radiation-induced G(1)
      arrest and reduced CIP1 mRNA. Induced loss of p53 function by transfection of
      mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that
      tolerance of DNA damage and expansion of cells with an RER(+) phenotype may
      select for reduced ability to engage apoptosis and loss of p53 function.

PMID- 8640829
TI  - Genetic heterogeneity and unmapped genes for colorectal cancer.
AB  - Colorectal cancer (CRC) has a strong familial component. Candidate genes for
      colorectal cancer have been identified through mutations in four mismatch repair
      genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in
      tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was
      performed in 10 kindreds ascertained for common colorectal cancer from the Utah
      Population Database. Evidence for linkage to candidate genes was assessed using
      two- or three-point logarithm of the odds ratio scores with markers spanning the
      region of localization. One kindred is linked to hMSH2 and also fits the criteria
      for hereditary nonpolyposis colorectal cancer, having early age of onset and high
      penetrance for CRC. The remaining nine kindreds are unlinked to the candidate
      genes tested. These kindreds have a later age of onset and a lower penetrance
      than hereditary nonpolyposis colorectal cancer kindreds. these results indicate
      that further unmapped susceptibility loci may be responsible for much of the
      familial aggregation of CRC.

PMID- 8640830
TI  - Overexpression of cyclin E in the HC11 mouse mammary epithelial cell line is
      associated with growth inhibition and increased expression of p27(Kip1).
AB  - To elucidate the role of cyclin E in cell growth and tumorigenesis in mammary
      epithelial cells, we have used retrovirus-mediated transduction to generate
      derivatives of the nontransformed HC11 mouse mammary epithelial cell line that
      stably express a human cyclin E cDNA (HU4). These derivatives expressed two
      distinct forms of the exogenous cyclin E protein, which were about M(r) 50,000
      and M(r) 42,000, thus corresponding to endogenous cyclin E proteins found in
      human cells. In contrast to results obtained previously in fibroblasts,
      overexpression of the HU4 cyclin E cDNA in HC11 cells was associated with an
      increase in cell size, lengthening of G(1), and inhibition of both anchorage
      dependent and independent growth. Furthermore, when quiescent serum-starved cells
      were restimulated with serum, entry into the S-phase was delayed in the
      overexpressor cells. Under these conditions, there was also delayed induction in
      the expression of the endogenous cyclin E protein and in other events involved in
      the G(1) transition. Despite the high level of expression of the exogenous cyclin
      E, the derivatives did not display increased cyclin E-associated in vitro kinase
      activity. The HC11 cells that overexpressed the exogenous cyclin E displayed an
      increase in the cyclin/cyclin-dependent kinase inhibitor p27(Kip1) in both
      asynchronous exponentially dividing and synchronous cell populations. These
      findings indicate that increased expression of this cyclin E cDNA in HC11 cells
      inhibits rather than stimulates growth and that this may be due to increased
      expression of the inhibitor p27(Kip1).

PMID- 8640831
TI  - Deregulated apoptosis in ataxia telangiectasia: association with clinical
      stigmata and radiosensitivity.
AB  - Ataxia telangiectasia (AT) is a recessive genetic disease featuring
      neurodegeneration, immunodeficiency, chromosomal instability, radiation
      hypersensitivity, and increased predisposition to cancer. Reduced or delayed
      induction of the tumor suppressor protein p53 after gamma -irradiation was
      reported. These characteristics may be compatible with an inability to correctly
      regulate apoptosis. We show here that AT lymphocytes and EBV-transformed
      lymphoblasts demonstrate a significantly higher level of spontaneous apoptosis,
      whereas ionizing radiation-induced apoptosis is reduced compared to normal cells.
      However, neither AT nor normal primary fibroblasts undergo apoptosis after
      irradiation. Consequently, we conclude that the radiosensitivity of the AT cells
      is not related to an increased apoptotic response. Finally, we show that SV40
      transformed AT fibroblasts undergo gamma- ray-induced apoptosis, while SV40
      transformed normal cells do not. This result raises the question of the
      physiological relevance of the latter cellular model with respect to the AT
      phenotype.

PMID- 8640832
TI  - V(D)J recombinase-mediated HPRT mutations in peripheral blood lymphocytes of
      normal children.
AB  - Somatic mutations in the hypoxanthine-guanine phosphoribosyltransferase (hprt)
      gene are rare occurrences in T-lymphocytes of normal individuals. Lacking
      pathogenic significance, these events can serve as reporters for assessing
      environmental genotoxicity. The present molecular analyses of hprt mutations
      arising spontaneously in normal children show that 30-35% of the genomic hprt
      changes in children under 5 years of age have approximately 20 Kb deletions
      encompassing exons 2 and 3. The frequency of these specific changes are
      dramatically decreased in older children. Sequence analysis of these deletion
      breakpoint and joining regions reveal the molecular hallmarks of V(D)J
      recombinase-mediated recombination events. This early childhood hprt mutational
      spectrum is quite distinct from the adult background spectrum but similar to that
      reported previously for newborns, as determined in lymphocytes from placental
      cord blood. The present study also demonstrates that definition of sequences in
      the hprt deletion joining regions that are analogous to the N-nucleotide
      insertion hypervariable regions of rearranged T-cell receptor genes allows the
      same identification of in vivo clonality of mutants as does analysis of the T
      cell receptor gene rearrangements themselves. These methods reveal an in vivo
      clonal amplification of a V(D)J recombinase-mediated hprt mutant clone in one
      child in the present study. This newly found age-frequency distribution of V(D)J
      recombinase-mediated hprt mutations correlates with the age-frequency
      distribution of childhood acute lymphocytic leukemia. A significant number of
      these malignancies, including acute T-cell leukemia, are also characterized by
      V(D)J recombinase-mediated recombinations but in critical regions of the genome.
      hprt, therefore, captures a pathogenic mutagenic mechanism as a harmless mistake
      which, when it occurs in other genetic regions, may result in malignancy.

PMID- 8640833
TI  - Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in
      childhood acute lymphoblastic leukemia.
AB  - We have shown previously that loss of heterozygosity at chromosome band 12p13 is
      among the most frequent genetic abnormalities identified in acute lymphoblastic
      leukemia (ALL) of childhood. Two known genes map within the critically deleted
      region of 12p: TEL, the gene encoding a new member of the ETS family of
      transcription factors, which is rearranged in a variety of hematological
      malignancies; and KIP1, the gene encoding the cyclin-dependent kinase inhibitor
      p27. Both genes are, therefore, excellent candidate tumor suppressor genes. In
      this report, we determined the exon organization of the TEL gene and performed
      mutational analysis of TEL and KIP1 in 33 childhood ALL patients known to have
      loss of heterozygosity at this locus. No mutations in either TEL or KIP1 were
      found; this suggest that neither TEL nor KIP1 is the critical 12p tumor
      suppressor gene in childhood ALL.

PMID- 8640834
TI  - Partial tandem duplication of ALL1 as a recurrent molecular defect in acute
      myeloid leukemia with trisomy 11.
AB  - Gains of a single chromosome are frequent cytogenic findings in human cancer, but
      no molecular rearrangement has been consistently associated with any trisomy. In
      acute myeloid leukemia (AML), trisomy 11 (+11) occurring as a sole abnormality is
      the third most common trisomy. We have shown that the ALL1 gene, located at
      11q23, can be rearranged as a result of a partial tandem duplication in two such
      cases of AML. To test the hypothesis that the partial tandem duplication of ALL1
      is the recurrent molecular defect in cases of AML presenting with +11 as a sole
      cytogenic abnormality, we performed Southern analysis and PCR for defects of ALL1
      in 17 cases of AML and one case of myelodysplastic syndrome with +11 or +11q but
      without cytogenic evidence of a structural abnormality involving 11q23. Twelve
      cases (67%) had rearrangement of ALL1, including 10 of 11 patients (91%) with +11
      as a sole abnormality and 2 of 7 cases (29%) with +11 and other aberrations; all
      were classified as FAB M1 or M2. In 10 of the 12 cases, material was available
      for additional characterization; a partial tandem duplication of ALL1 was
      detected in each of these 10 cases (100%). Four cases demonstrated previously
      unreported duplications, two of which were detectable only by reverse
      transcription-PCR. Four patients with the ALL1 duplication also displayed a loss
      of material from 7q, suggesting an association between these two findings. We
      conclude that the partial tandem duplication of ALL1 is present in most, if not
      all, cases of AML with +11 as a sole abnormality, and can be found in cases of
      AML with +11 or +11q accompanied by other cytogenic abnormalities. The
      duplication is more prevalent in AML than was recognized previously in part
      because its size and location vary considerably, requiring a variety of molecular
      probes for detection. Our finding of the ALL1 duplication as a consistent defect
      in patients with +11 represents the first identification of a specific gene
      rearrangement associated with recurrent trisomy in human cancer.

PMID- 8640835
TI  - Analysis of replication error (RER+) phenotypes in cervical carcinoma.
AB  - Infection of epithelial cells with human papillomavirus is an important early
      event in the development of cervical dysplasia. However, progression to overt
      malignancy appears dependent upon further genetic and/or epigenetic events. We
      have recently developed methodologies for the simultaneous analysis of loss of
      heterozygosity (LOH) at multiple PCR-based microsatellite loci using
      semiautomated fluorescent DNA sequencing technology to determine the locations of
      tumor suppressor genes which are inactivated during tumor progression. While
      examining 30 microsatellite loci for LOH on chromosomes 3p, 4, and 11q, we
      detected novel tumor-specific alleles indicative of microsatellite instability
      (MI). The methodology allowed rapid and accurate comparison of over 3000
      genotypes from 89 primary tumors and 10 cervical carcinoma-derived cell lines and
      showed that five tumors (5.6%) and one human papillomavirus-negative cell line,
      C33A, had genetic features consistent with a replication error (RER+) phenotype
      as defined by MI at two or more loci. In each of the RER+ tumors, LOH was also
      observed at one or more loci on each of the three chromosomes examined. These
      findings suggest that defects in DNA repair-associated genes are rarely acquired
      and do not supersede allelic loss during cervical carcinogenesis. In addition,
      the semiautomated multiplex approach has proven unequivocal in the detection and
      interpretation of MI and should greatly accelerate the rapidity and accuracy of
      analysis of such defects in tumors. Moreover, the number of loci that can be
      relatively easily examined in this way will also allow a detailed statistical
      consideration of the importance of such events.

PMID- 8640836
TI  - Decreased expression of both the low-density lipoprotein receptor-related
      protein/alpha(2)-macroglobulin receptor and its receptor-associated protein in
      late stages of cutaneous melanocytic tumor progression.
AB  - We recently found that the proteins of the proteolytic system of plasminogen
      activation emerge in late stages of melanocytic tumor progression. A large body
      of evidence suggests a role for two proteins, the low-density lipoprotein
      receptor-related protein (LRP)/alpha(2)-macroglobulin receptor and its receptor
      associated protein (RAP), in the internalization of components of the plasminogen
      activation system. Here, we present data on the presence of these two proteins in
      human melanoma cell lines which differ in metastatic capacity, their
      corresponding xenografts, and in cutaneous melanocytic lesions. With flow
      cytometry, we found surface expression of LRP to be restricted to urokinase
      plasminogen activator, producing highly metastatic cell lines. These cell lines
      also produce higher levels of LRP mRNA, whereas RAP mRNA and protein are
      expressed at equal levels in all cell lines and not expressed at the cell
      surface. Xenografts of cell lines producing high levels of LRP remarkably contain
      only a small fraction of LRP-positive tumor cells. Using immunohistochemistry on
      frozen sections of 107 human melanocytic lesions comprising the various stages of
      melanocytic tumor progression, we found that expression of both LRP and RAP
      decreased in tumor progression. Furthermore, we noted that LRP and RAP are
      coexpressed within the same lesion. Using immunofluorescence double staining, we
      found that LRP and RAP colocalize in the same cells in the lesions studied and in
      the same cell structures in the cell lines studied. In conclusion, our results
      indicate that LRP and RAP are coordinately expressed in a decreased fashion in
      melanocytic tumor progression. Based on the staining results in xenografts and in
      human melanocytic lesions, we conclude that a strong correlation between
      expression of LRP and urokinase-type plasminogen activator seems not to exist in
      in vivo melanomas.

PMID- 8640837
TI  - Gene expression of neural cell adhesion molecule L1 in malignant gliomas and
      biological significance of L1 in glioma invasion.
AB  - Neural cell adhesion molecule L1 is a member of the immunoglobulin superfamily
      that is expressed in the nervous system. Its functions have been mainly studied
      in vitro using premature neuronal cells. We show that all glioma cells tested, as
      well as normal glia cells, express a short type of L1, L1cs mRNA. The expression
      of L1 protein in glioma cells was confirmed by Western blotting and flow
      cytometric analysis. Migration assay showed that C6 glioma cells were stimulated
      to migrate to soluble L1 and L1cs released from L1- or L1cs-transfected
      fibroblast cells. The L1-stimulated migration was significantly inhibited by
      antibody that recognizes the immunoglobulin C2-like domain of L1. However,
      antibodies that recognize the fibronectin type III-like domain and the
      cytoplasmic (IC) domain of L1 had no effect on migration. Our in vivo migration
      study demonstrated the migration of L1 on C6 glioma cells that had been
      transfected in rat brains. These results suggest that L1cs expressed on glioma
      cells may play an important role in the adhesion and migration of glioma cells by
      homophilic binding (probably through the extracellular immunoglobulin C2 domain
      of L1) and that L1cs participates in tumor invasion along neuronal fibers.

PMID- 8640838
TI  - Antisense RNA inhibition of phosphoprotein p18 expression abrogates the
      transformed phenotype of leukemic cells.
AB  - Phosphoprotein p18 was identified originally on the basis of its very high level
      of expression in leukemic cells of different lineages. Changes in the level of
      p18 accumulation and phosphorylation associated with induction of differentiation
      of leukemic cells suggested a potential role for this phosphoprotein in cellular
      proliferation and differentiation and possibly in malignant transformation.
      Recent studies have demonstrated that p18 plays an important role in cell cycle
      progression by serving as a substrate for p34(cdc2) kinase. These studies showed
      that inhibition of p18 expression in leukemic cells results in growth retardation
      and accumulation of cells in G(2)-M. In this study, we explore the potential role
      of p18 in cellular transformation by investigating the effects of inhibition of
      p18 expression on the malignant phenotype of K562 erythroleukemia cells. These
      studies show that antisense inhibition of p18 expression in leukemic cells
      results in growth arrest at a lower saturation density, loss of serum
      independence, and loss of anchorage-independent growth in vitro. In addition,
      inhibition of p18 expression results in a marked inhibition of tumorigenicity of
      leukemic cells in vivo in the severe combined immune deficiency mouse model.
      These studies demonstrate that the high level of p18 expression in leukemic cells
      is necessary for the maintenance of the transformed phenotype and suggest p18 as
      a potential target for antileukemic interventions.

PMID- 8640839
TI  - Role of bcl-X(L) in the control of apoptosis in murine myeloma cells.
AB  - The development of an increasing number of tumors has been shown to involve the
      deregulation of not only cell proliferation but also normal cell death by
      apoptosis. Expression of the bcl-2 proto-oncogene has been shown to inhibit the
      apoptotic cell death of many types of cells. Recent work also has revealed the
      existence of several bcl-2-related genes that also can inhibit (e.g., bcl-X(L)
      and Mcl-1) or activate (e.g., bax, bcl-X(s), bag, and bad) apoptosis in several
      systems. Myelomas are antibody-secreting tumor cells derived from terminally
      differentiated B lymphocytes, and previous work from our laboratory showed that
      murine SP2/0 myeloma cells and derived B-cell hybridomas were highly sensitive to
      apoptosis induction by a block of gene expression (cycloheximide). Additional
      work revealed that a related murine myeloma cell line, P3X63Ag8.653, was
      resistant to apoptosis induction in similar conditions. To understand the genetic
      basis of this differential susceptibility, we examined the expression of
      apoptosis-related genes in these cell lines. Northern blot experiments showed no
      significant difference in the expression of myc and bax apoptosis-promoting genes
      in susceptible (SP2/0 and D5) and resistant (P3X63) cell lines. Also, no
      significant expression of the bcl-2 gene could be detected in these cell lines.
      However, a much higher expression level of bcl-X(L) mRNA was observed in
      apoptosis-resistant P3X63Ag8.653 cells. The role of bcl-X(L) was supported by the
      finding that expression of bcl-X(L) cDNA in transfected, apoptosis-sensitive D5
      cells increased the viability of these cells greatly and reduced DNA
      fragmentation following apoptosis induction. Significant bcl-X(L) but not bcl-2
      expression was also detected in three other murine myeloma cell lines (MOPC 315,
      RPC 5.4, and J558) derived from different plasmacytoma tumors. These results
      indicate a predominant role of bcl-X(L) in preventing apoptosis in myeloma cells
      and suggest that the expression of bcl-2 or bcl-X(L) genes in B-cell tumors
      depends on the differentiation stage of the precursor normal cell.

PMID- 8640840
TI  - Growth regulation of human breast and ovarian tumor cells by heregulin: Evidence
      for the requirement of ErbB2 as a critical component in mediating heregulin
      responsiveness.
AB  - Alterations in the expression of the epidermal growth factor (EGF) receptor ErbB
      family are frequently encountered in a number of human cancers. Two of these
      receptors, ErbB3 and ErbB4, are known to bind a family of related proteins termed
      heregulins (HRGs) or neu differentiation factors. In biologically relevant
      systems, interaction of HRG with ErbB3 or ErbB4 results in the transactivation of
      ErbB2. In this report, we show that ErbB2 is a critical component in mediating
      HRG responsiveness in a panel of human breast and ovarian tumor cell lines.
      Because HRGs have been reported to elicit diverse biological effects on cultured
      cells, including growth stimulation, growth inhibition, and induction of
      differentiation, we systematically examined the effect of rHRG beta 1 on tumor
      cell proliferation. HRG binding studies were performed with a panel of breast and
      ovarian tumor cell lines expressing a range of levels of ErbB2. The biological
      responses to HRG were also compared to EGF and to the growth-inhibitory anti
      ErbB2 antibody, 4D5. In most cases, HRG stimulation of DNA synthesis correlated
      with positive effects on cell cycle progression and cell number and with
      enhancement of colony formation in soft agar. On each cell line tested, the HRG
      effects were distinguishable from EGF and 4D5. Our findings indicate that HRG
      induces cell proliferation in a number of tumor cell lines. In addition, we show
      that methods for measuring cell proliferation, as well as experimental
      conditions, are critical for determining HRGs effect on tumor cell growth in
      vitro.

PMID- 8640841
TI  - Human T lymphocyte activation in the presence of acute myelogenous leukaemia
      blasts; studies of normal polyclonal T cells and T lymphocyte clones derived
      early after allogenic bone marrow transplantation.
AB  - T cell clones (CD4+CD8-TCR alpha beta+gamma delta- derived from bone marrow
      transplant recipients were stimulated with phytohaemagglutinin (PHA) +interleukin
      2 (IL-2) in the presence of irradiated (50 Gy) peripheral blood mononuclear cells
      (PBMC) derived from acute Leukaemia patients (leukaemic PBMC containing more than
      95% blast cells). Leukaemic PBMC could function as accessory cells during
      mitogenic T cell activation resulting in both T cell proliferation and a broad T
      cell cytokine response [IL-3, IL-4, IL-10, granulocyte/macrophage-colony
      stimulating factor (GM-CSF) tumour necrosis factor alpha (TNF alpha) and
      interferon gamma (IFN gamma) secretion]. Blockade of IL-1 effects by adding IL-1
      receptor antagonist together with PHA + IL-2 + leukaemia blasts increased T cell
      proliferation, whereas IL-6-neutralizing antibodies did not alter T cell
      proliferation. A qualitatively similar T cell cytokine response and a similar
      cytokine profile (highest levels detected for GM-CSF and IFN gamma) were detected
      when normal polyclonal T cell lines were stimulated with PHA in the presence of
      non-irradiated leukaemic PBMC. When leukaemic PBMC derived from 18 acute
      myelogenous leukaemia patients were cultured with PHA and cells from a polyclonal
      T cell line, increased concentrations of the T cell cytokines IFN gamma and IL-4
      were detected for all patients. We conclude that T cell activation resulting in
      proliferation and a broad cytokine response can take place in the presence of
      excess acute myelogenous leukaemia blasts.

PMID- 8640842
TI  - Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor
      and human Fc gamma RIII.
AB  - 2B1 is a bispecific murine monoclonal antibody (bsmAb) targeting the c-erbB-2 and
      CD16 (Fc gamma RIII) antigens. c-erbB-2 is over-expressed by a variety of
      adenocarcinomas, and CD16, the low-affinity Fc gamma receptor for aggregated
      immunoglobulins, is expressed by polymorphonuclear leukocytes (PMN), natural
      killer (NK) cells and differentiated mononuclear phagocytes. 2B1 potentiates the
      in vitro lysis of c-erb-2 over-expressing tumors by NK cells and macrophages. In
      this report, the interactions between 2B1 and PMN were investigated to assess the
      impact of these associations on in vitro 2B1-promoted tumor cytotoxicity by human
      NK cells. The peak binding of 2B1 to PMN was observed at a concentration of 10
      microgram/ml 2B1. However, 2B1 rapidly dissociated from PMN in vitro at 37
      degrees C in non-equilibrium conditions. This dissociation was not caused by CD16
      shedding. When PMN were labeled witn 125I-2B1 and incubated at 37 degrees C and
      the supernatants examined by HPLC analysis, the Fab regions of dissociated 2B1
      were not complexed with shed CD16 extracellular domain. While most of the binding
      of 2B1 PMN was solely attributable to Fab-directed binding to Fc gamma RIII, PMN
      associated 2B1 also bound through Fc gamma-domain/Fc gamma RII interactions. 2B1
      did not promote in vitro PMN cytotoxicity against c-erbB-2-expressing SK-OV-3
      tumor cells. When PMN were coincubated with peripheral blood lymphocytes, SK-OV-3
      tumor and 2B1, the concentration of 2B1 required for maximal tumor lysis was
      lowered. Although PMN may serve as a significant competitive binding pool of
      systemically administered 2B1 in vivo, the therapeutic potential of the targeted
      cytotoxicity properties of this bsmAb should not be compromised.

PMID- 8640843
TI  - HLA-A2-restricted peripheral blood cytolytic T lymphocyte response to HPV type 16
      proteins E6 and E7 from patients with neoplastic cervical lesions.
AB  - The DNA from human papillomavirus (HPV) can be detected in 90% of cervical
      carcinomas. To address whether patients infected with HPV can mount efficient T
      cell responses to this pathogen we examined the cytotoxic T lymphocyte (CTL)
      response of peripheral blood mononuclear cells (PBMC) from patients with abnormal
      genital epithelial cells. PBMC from 11 HLA-A2+ patients were stimulated with
      CaSki, a cervical carcinoma cell line that is HPV 16+ and HLA-A2+. The CTL were
      screened for reactivity to the cervical carcinoma cell line C33A (HPV-, HLA-A2+)
      transfected with the HPV 16 E6 or E7 genes or the plasmid without insert. The CTL
      of 1 patient showed particularly strong CaSki and HPV E6 or E7 protein-specific
      cytotoxicity in a HLA-A2+-restricted fashion. In contrast, these CTL lysed
      neither a vector-only transfectant, the natural killer cell (NK) target, K562 nor
      the lymphokine-activated killer cell (LAK) target, Daudi. HLA-A2 restriction was
      demonstrated by the lack of recognition of a HLA-A2- CaSki cell line developed in
      our laboratory. The CTL line was cloned and 99 clones were harvested and
      screened; 51 clones lysed CaSki, of which 17 did not lyse the A2- CaSki. Of these
      HLA-A2- restricted clones, 8 did not lyse C33A transfectants, 6 lysed all C33A
      transfectants, 3 lysed C33A-E7 only and none lysed C33A-E6 only. These data imply
      that, within the bulk CTL line, HLA-A2-restricted recognition of antigens was
      restricted to CaSki antigens, antigens common to cervical carcinoma (CaSki plus
      C33A), or HPV-16-E7-derived antigen on the clonal level. The E7-restricted clones
      were negative for recognition of known HLA-A2-binding peptides from E7.

PMID- 8640844
TI  - Therapeutic effectiveness of the immunity elicited by P815 tumor cells engineered
      to express the B7-2 costimulatory molecule.
AB  - It is well accepted that inoculation of B7-1-transfected tumor cells into normal
      mice leads to tumor rejection and subsequent resistance to challenge. However,
      the effectiveness of B7-2-transfected tumor cells in eliciting protective
      antitumor immunity is less clear. Here we show that B7-2-transfected P815 tumor
      cells (B7-2+) are as effective as B7-1-transfected P815 tumor cells (B7-1+) in
      eliciting protective immunity in normal DBA/2 mice. In addition, B7-2+ cells were
      found to be at least as effective as B7-1+ cells retarding tumor progression when
      admixed with parental P815 tumor cells prior to inoculation into normal mice.
      Moreover, the B7-2+ cells and the B7-1+ cells were equivalent in their ability to
      retard tumor growth when administered peritumorally into mice bearing established
      (approx. 3 mm in diameter) parental P815 tumors. Finally, P815 tumor cells
      infected with a recombinant replication-defective adenovirus encoding the murine
      B7-2 gene were effective in retarding the growth of established parental P815
      tumors. Thus, B7-1 and B7-2 are comparable in terms of their ability to stimulate
      the generation of tumor-eradicating immunity in normal mice as well as in mice
      bearing established parental tumors. Moreover, adenovirus vectors can be used to
      generate B7-2-expressing tumor cells effective in the immunotherapy of
      established parental tumors.

PMID- 8640845
TI  - Functional and molecular characterization of tumour-infiltrating lymphocytes and
      clones thereof from a major-histocompatibility-complex-negative human tumour:
      neuroblastoma.
AB  - Neuroblastoma (NB) is a major-histocompatibility-complex(MHC)-negative
      neuroectodermal tumour that is often infiltrated with lymphocytes. A detailed
      characterization of NB-associated tumour-infiltrating lymphocytes (TIL) has never
      been carried out. Here we have investigated the immunophenotype and the cytotoxic
      activities of TIL from nine and seven NB patients respectively. Furthermore, the
      T cell receptor (TcR) variability and the patterns of cytokine gene expression of
      fresh versus recombinant (r) interleukin (IL)-2-cultured TIL were studied in four
      NB cases. The results obtained showed the following: (1) freshly isolated TIL
      were comprised of a mixture of CD4+ and CD8+ T cells partially expressing HLA-DR
      and/or CD25. The CD4/CD8 ratio ranged from 0.5 to 5 in the different cases. Upon
      culture of TIL with rIL-2, an increased proportion of CD56+ and CD8+ lymphocytes
      was consistently observed; (2) IL-2-expanded TIL lysed natural
      killer(NK)sensitive and lymphokine-activated-killer(LAK)-sensitive target cell
      lines; (3) reverse-transcriptase/polymerase-chain-reaction (RT-PCR) experiments
      showed that most TcR V beta genes were expressed both in fresh and in cultured
      TIL, suggesting that such cell populations were polyclonal; (4) interferon gamma,
      IL-4, IL-5, tumour necrosis factor (TNF) alpha, IL-8, IL-10 mRNA and, to a lesser
      extent, IL-2 mRNA were expressed by cultured TIL, as assessed by RT-PCR; the
      corresponding tumour samples consistently contained TNF alpha, IL-8 and IL-10
      mRNA, whereas IL-2 and IFN gamma mRNA were faintly expressed in some NB tumours
      and IL-4 and IL-5 mRNA were never detected. A total of 90 clones were
      subsequently raised from IL-2-expanded TIL from six NB patients; 87/90 clones
      were of T cell lineage with a CD4+ or CD8+ immunophenotype, whereas the 3
      remaining clones were of NK cell origin. Upon triggering of the CD3-TcR complex,
      64% CD4+ and 77% CD8+ T cell clones killed the murine P815 mastocytoma cell line.
      Virtually no T cell clone lysed a LAK-sensitive NB cell line whereas 15% CD4+ and
      17% CD8+ clones mediated NK-like activity against the K562 cell line. Finally,
      the patterns of cytokine production by CD4+ clones were roughly consistent with
      those of a T helper (TH) 1 profile and similar to those observed in CD8+ clones.

PMID- 8640846
TI  - Humoral and cellular responses raised against the human HER2 oncoprotein are
      cross-reactive with the homologous product of the new proto-oncogene, but do not
      protect rats against B104 tumors expressing mutated neu.
AB  - The neu proto-oncogene encodes a plasma membrane protein belonging to the
      epidermal growth factor receptor family. The cell line B104, derived from BDIX
      rat neuroblastoma, carries a point mutation in neu, and forms a tumor when
      injected into these rats. The human homologue of the neu oncogene (here called
      HER2) is overexpressed in certain types of cancer. Rats were immunized with HER2
      protein (HER2) to investigate a possible cross-reaction between the homologous
      proteins which could protect them against subsequent inoculation with B104.
      Specific antibody in the serum was measured by cell-based enzyme-linked
      immunoabsorbent assay and fluorescence immunocytochemistry, and delayed-type
      hypersensitivity by an ear assay. Sera from animals immunized with the HER2
      extracellular domain (HER2-ECD) reacted with both HER2- and neu-expressing cells.
      In the ear assay, a significant cellular response to both HER-ECD (P < 0.05) and
      neu protein (P < 0.001) was observed in HER2-ECD-immunized rats. However, the
      growth of B104 tumors in rats was not affected by preimmunization with HER2-ECD.
      The results indicate that an autoreactive immune response to neu was induced by
      immunization with HER2-ECD, but was too weak to affect the growth of the neu
      bearing tumor.

PMID- 8640847
TI  - Characterisation of the complement-regulatory proteins decay-accelerating factor
      (DAF, CD55) and membrane cofactor protein (MCP, CD46) on a human colonic
      adenocarcinoma cell line.
AB  - To avoid destruction by complement, normal and malignant cells express membrane
      glycoproteins that restrict complement activity. These include decay-accelerating
      factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and protectin (CD59),
      which are all expressed on colonic adenocarcinoma cells in situ. In this study we
      have characterised the C3/C5 convertase regulators DAF and MCP on the human
      colonic adenocarcinoma cell line HT29. DAF was found to be a glycosyl
      phosphatidylinositol-anchored 70-kDa glycoprotein. Blocking experiments with
      F(ab')2 fragments of the anti-DAF monoclonal antibody BRIC 216 showed that DAF
      modulates the degree of C3 deposition and mediates resistance to complement
      mediated killing of the cells. The expression and function of DAF were enhanced
      by tumour necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta).
      Cells incubated with interferon gamma (IFN gamma) did not alter their DAF
      expression. Two MCP forms were expressed, with molecular masses of approximately
      58 kDa and 68 kDa, the lower form predominating. MCP expression was up-regulated
      by IL-1 beta, but not by TNF alpha or INF gamma. Expression of DAF and MCP
      promotes resistance of colonic adenocarcinoma cells to complement-mediated
      damage, and represents a possible mechanism of tumour escape.

PMID- 8640848
TI  - Cellular immune responses to autologous chronic myelogenous leukaemia cells in
      vitro.
AB  - Using a modification of the autologous mixed lymphocyte/tumour cell culture
      (MLTC), it is demonstrated here that lymphocytes from chronic-phase myelogenous
      leukaemia (CML) patients (n = 58), but not from their HLA-identical siblings,
      proliferated upon coculture with autologous tumour cells. However, in most cases,
      the level of proliferation measured was low (stimulation index < 3, n = 37). This
      was most likely related to the amount of interleukin-10 (IL-10) released into the
      culture medium by the CML cells, because addition of neutralizing anti_IL-10
      serum to MLTC markedly enhanced proliferative responses. In addition,
      supplementation of media with IL-1 alpha further enhanced proliferative responses
      and a combination of anti-IL-10 serum and IL-1 alpha was more effective than
      either agent alone. Only HLA-DR-matched CML cells, but not HLA-DR-mismatched CML
      cells or matched or mismatched PBMC restimulated proliferation of IL-2-dependent
      T cell lines derived from MTLC supplemented with IL-1 alpha and anti-IL-10 serum.
      The responding cells under these conditions were predominantly CD4+ and secreted
      IL-2, and interferon gamma; some secreted IL-4, but none secreted IL-10. These
      data therefore suggest the existence of an HLA-DR-restricted DTH/Th1-type of
      tumour-specific immunity in CML patients, which may be down-regulated in vitro by
      excessive secretion of IL-10 together with depressed secretion of IL-1.

PMID- 8640849
TI  - Autoantibodies against p53 are not increased in human ascites and pleural
      effusions.
AB  - Mutated human p53 may give rise to the formation of autoantibodies and may be a
      marker for a worse prognosis. We speculated that ascites or pleural effusions may
      enhance the formation of such autoantibodies in cancer patients and, therefore,
      we measured the presence of autoantibodies in the ascites or pleural effusion of
      40 patients with advanced malignancies. As controls, p53 autoantibodies were
      measured in 15 patients with effusions who did not have a malignancy. Using a
      specific enzyme-linked immunosorbent assay, p53 autoantibodies could only be
      detected in the effusions of 5/40 patients (12.5%) with known malignancies. The
      formation of autoantibodies did not correlate with the presence or absence of
      tumor cells in the effusion. The effusions of the patients without tumor were all
      negative for p53 autoantibodies. Our study shows that malignant or reactive
      effusions do not stimulate the local or systemic production of autoantibodies
      against p53.

PMID- 8640850
TI  - [Transvenous cardioverter-defibrillators: clinical experience at implantation and
      follow-up].
AB  - Thirty-seven patients with ventricular tachyarrhythmias refractory to
      antiarrhythmic drug treatment, guided by electrophysiological testing, were
      submitted to implantation of a cardioverter-defibrillator by the transvenous
      technique. Mean age was 55 +/- 14 years and the underlying heart disease was
      coronary heart disease in 24 patients, cardiomyopathy or other etiologies in 11
      patients. In 2 patients ventricular arrhythmias were idiopathic. Left ventricular
      ejection fraction was < or equal to 40% in 65% of the patients. The following
      devices were implanted: CPI Ventak P in 2 patients, Ventak P2 in 9 patients,
      Ventak PRx in 9 patients, Ventak PRxII in 2 patients, Telectronics Guardian ATP
      III 4215 in 9 patients, Siemens Siecure in 5 patients, Medtronic Jewel PCD in 1
      patient. At implantation defibrillation threshold was lower with biphasic shocks
      than with monophasic shocks (17.0 +/- 3.2 vs 20.9 +/- 3.8 J, p < 0.003) and the
      need for subcutaneous patches was lower when biphasic shocks were employed.
      Operative and perioperative mortality were 0% and no significant complications
      were observed. During the follow-up (16 +/- 11 months) 35% of the patients had
      appropriate shocks and 93% of the patients with antitachycardia pacing
      availability (n = 15) had effective antitachycardia pacing interventions. The
      following complications were observed: lead failure in 4 patients (3 insulation
      breaks and 1 elongation for stretching), late lead dislodgement in 2 patients,
      lead recall in 1 patient, all of which required reintervention. Inappropriate
      shocks occurred in 30% of the patients and were related to lead failure,
      supraventricular arrhythmias or alternating current interference. During the
      follow-up one patient died of sudden death and one was submitted to heart
      transplantation. In conclusion, implantation of a cardioverter-defibrillator by
      the transvenous technique is a procedure relatively free from complications.
      During the follow-up lead failure appears to be one of the most relevant
      complications. Antitachycardia pacing allows effective termination of ventricular
      tachycardias without cardioversion, with a better compliance.

PMID- 8640851
TI  - [Hemodynamic assessment at rest and during dynamic physical exercise in young
      subjects with and without hypertensive parents].
AB  - The aim of this research was to identify any early cardiovascular changes that
      may be predictive of future hypertension in young subjects with family history of
      hypertension. The study was conducted on 25 offspring of hypertensive parents,
      mean age 17 years (22 with hypertension only in 1 parent and 3 with both
      hypertensive parents) and 20 offspring of both normotensive parents, matched by
      age. Subjects were divided into children (7-13 years) and young adults (19 years
      on). All subjects underwent three office blood pressure measurements with a
      mercury sphygmomanometer. On the third control, BoMed thoracic electrical
      bioimpedance at rest and during upright bicycle exercise was performed. Physical
      characteristics were similar in subjects matched by age in the two groups.
      Systolic blood pressure was similar in offspring of normotensives and
      hypertensives, both at rest and during exercise; diastolic blood pressure was
      greater in offspring of hypertensive parents at rest (73.1 +/- 10.5 vs 63.5 +/-
      7.1 mmHg, p < 0.05), during the first minutes of exercise and during the recovery
      phase (p < 0.05). Moreover, at the third blood pressure measurement at rest,
      diastolic blood pressure decreased, with respect to the first measurement, only
      in children and young adult offspring of normotensive parents, while systolic
      blood pressure decreased in the two groups of child subjects. No differences in
      heart rate were observed, both at rest and during physical exercise, between
      offspring of normotensives and hypertensives. Left ventricular end-diastolic
      volume, stroke volume, ejection fraction, cardiac output and systemic vascular
      resistance at rest and their response to decubitus changes and exercise were
      normal and similar in offspring of normotensive and hypertensive parents both in
      children and young adults. In conclusion, a different behavior of diastolic blood
      pressure was found in offspring of hypertensive parents compared to that of
      normotensive parents, both in children and, to a higher degree, in young adults.
      This may be an expression of early vascular change in subjects with a genetic
      predisposition to hypertension.

PMID- 8640852
TI  - [Epidural electrostimulation in the treatment of refractory angina pectoris in
      elderly patients: preliminary results].
AB  - The spinal cord stimulation is an antalgic technique which has been used since
      1967 for the treatment of several painful syndromes. More recently it was
      employed in the cardiology field to treat refractory angina, not suitable for
      revascularization. We applied spinal cord stimulation as alternative therapy in 7
      clients older than 70 years who, for different reasons, could not undergo
      revascularization. We obtained good short- and long-term clinical results,
      without complications. On the basis of our preliminary experience with this
      technique in a small group of elderly patients and after a critical review of the
      literature, we conclude that spinal cord stimulation can be used without
      significant risks, in elderly patients with refractory angina pectoris.

PMID- 8640853
TI  - Peculiarities of myocardial infarction at young age in Southern Croatia.
AB  - The aim of this study was to assess whether acute myocardial infarction (AMI) in
      younger patients (< 45 years) differs from that in the older individuals (> 45
      years). We have studied the records of all patients admitted to the Department of
      Medicine, Clinical Hospital of Split, Croatia, because of AMI from January 1st,
      1987 to December 31st, 1991. The study group consisted of 1406 patients, 130
      (9.2%) below, and 1276 (90.8%) above the age of 45. In the ?young? subgroup there
      were only 9 females (6.9%), significantly less than in the ?old? one (399 out of
      1276 or 31.3%, p < 0.001). There were many more smokers among the younger (100
      out of 130 or 76.9%) than among the older patients (524 out of 1276 or 41.1%, p <
      0.001). The location of myocardial necrosis was also different: inferior
      infarction occurred in 65 out of 130 or 50% young patients and in 442 out of 1276
      or 34.6% old patients; p < 0.001). Finally, the hospital mortality rate among the
      younger AMI patients was quite low (8 out of 130 or 6.2%) when compared to that
      of the older patients (282 out of 1276 or 22.1%, p < 0.001). In conclusion, AMI
      in younger individuals shows relevant peculiarities: the background of such
      patients almost invariably includes cigarette smoking; the female gender is about
      five times less affected, the diaphragmatic location is nearly two times more
      frequent, and the hospital mortality rate of these patients is almost four times
      lower than that of older patients.

PMID- 8640854
TI  - [Prognostic stratification after acute myocardial infarction: evaluation of
      ischemic risk].

PMID- 8640855
TI  - [Implantable cardioverter-defibrillator: prevention of sudden cardiac death and
      impact on survival in patients with malignant ventricular arrhythmias].

PMID- 8640856
TI  - Pathologic changes in a long-term heterotopic heart transplant survivor.
AB  - This report concerns the pathologic findings observed at autopsy in a 10-year-old
      heterotopic heart transplant under cyclosporine treatment. The allograft showed a
      diffuse multivessel atherosclerotic disease whereas in the recipient heart
      coronary arteries and aorta were focally affected by atherosclerosis. The
      proliferating cell nuclear antigen had significantly increased expression in the
      allograft vessels in comparison with the recipient.

PMID- 8640857
TI  - Inhibition of neutrophil function by human milk.
AB  - Human colostrum, the first product of lactation, has antioxidant properties and
      inhibits selected enzyme and bactericidal activities of human neutrophils. We
      examined the subsequent product of lactation, mature human milk, with respect to
      its antioxidant activities, its effects on neutrophil enzyme activities
      (myeloperoxidase, beta-glucuronidase, and lysozyme), and its effects on
      neutrophil bactericidal and phagocytic activities. Mature human milk displayed
      antioxidant characteristics similar to those of human colostrum, reducing
      cytochrome c and consuming H2O2. Mature milk also displayed colostrum-like
      characteristics in depressing neutrophil myeloperoxidase and beta-glucuronidase
      activities, but not in altering lysozyme activity. Neutrophil bactericidal
      activity against Staphylococcus aureus was depressed by both mature milk and
      colostrum, without dramatic effects on phagocytic activity. These data show that
      mature milk shares characteristics with human colostrum that may result in anti
      inflammatory effects, but the magnitude of these effects is generally smaller.

PMID- 8640858
TI  - Interleukin-12 stimulates B cell growth by inducing IFN-gamma.
AB  - Human interleukin-12 (IL-12) is a 70-kDa polypeptide that activates human natural
      killer cells. It has been purified from the culture supernatant of a human
      Epstein-Barr virus-transformed B cell line and cloned. We show that native as
      well as recombinant IL-12 promoted growth of Staphylococcus aureus Cowan I strain
      (SAC) or anti-mu antibody-activated B cells in a dose-dependent manner. IL-12
      also acted in synergy with IL-2 in growth and differentiation of SAC-activated B
      cells. Since anti-interferon (IFN)-gamma antibody completely abrogates B-cell
      growth factor (BCGF) activity of IL-12, the BCGF activity is mediated by IFN
      gamma. This conclusion is clearly supported by the results that IL-12 indeed
      induced IFN-gamma production by activated B cells. These results suggest that the
      B cell proliferative effect of IL-12 may be mediated by autocrine IFN-gamma.

PMID- 8640859
TI  - Lack of MMTV superantigen presentation in MHC class II-deficient mice.
AB  - Mammary tumor viruses (MMTVs) as well as their endogenous counterparts encode
      superantigens which react with T cells expressing particular T cell receptor V
      beta chains. Several lines of evidence indicated that MHC class II is required
      for the functional presentation of these superantigens. Here we provide direct
      proof that the function of superantigens is abrogated in the absence of MHC class
      II expression. No deletion of Mls-1-reactive T cells was observed in MHC class II
      deficient mice, and splenocytes from these animals did not stimulate Mls-1
      reactive T cell hybrids in vitro. Furthermore, the viral spread in MHC class II
      deficient mice, maternally infected with MMTV(C3H), was severely reduced. While
      initial infection in the gut-associated lymphocytes was comparable between MHC
      class II-deficient and normal mice, the level of infection in the spleen and the
      mammary tissue was much lower in the deficient animals. Quantitation of proviral
      DNA in spleen revealed a direct correlation between the magnitude of superantigen
      stimulation and degree of infection. These experiments document the direct effect
      of superantigen stimulation on viral amplification.

PMID- 8640860
TI  - Rat seminal vesicle protein SV-IV and its transglutaminase-synthesized
      polyaminated derivative SPD2-SV-IV induce cytokine release from human resting
      lymphocytes and monocytes in vitro.
AB  - Micromolar amounts of SV-IV, one of the major proteins secreted from the rat
      seminal vesicle epithelium, induce in vitro a marked release of a variety of
      cytokines (interferon-gamma, tumor necrosis factor-alpha, interleukin 6, and
      granulocyte-monocyte colony-stimulating factor) from human resting peripheral
      blood mononuclear cells as well as from isolated resting lymphocytes and
      monocytes. This effect was found to be significantly higher when the spermidine
      adduct of SV-IV (Spd2-SV-IV), synthesized in vitro by the enzyme
      transglutaminase, was used instead of the native protein. Furthermore, the
      pretreatment of monocytes with transglutaminase caused an increase of the
      inducing effect of both native and modified SV-IV on the release of interleukin 6
      from these cells. The inducing effect of these proteins on the cytokine release
      was markedly inhibited by actinomycin D and cycloheximide.

PMID- 8640861
TI  - V beta-specific deletion of mature thymocytes induced by the plant superantigen
      Urtica dioica agglutinin.
AB  - Urtica dioica agglutinin (UDA), a plant protein, is a superantigen activating in
      a MHC class II-restricted manner the V beta 8. 3-bearing T-cells (Galelli and
      Truffa-Bachi, J. Immunol. 151, 1821, 1993). Administration of UDA to adult mice
      provokes the clonal expansion of the responding cells which is followed by the
      deletion of the major fraction of the UDA-sensitive cells, whereas the remaining
      cells become anergic (Galelli et al., J. Immunol. 154, 2600, 1995). We have
      analyzed the effect of UDA on thymocytes. Injection of UDA resulted in a rapid,
      but transient, deletion of a large fraction of the V beta 8.3-bearing mature T
      cells. In contrast to other exogenous superantigens, this deletion was not
      preceded by the clonal expansion of the UDA-responding thymocytes. Moreover, the
      V beta 8.3-bearing mature T-cells escaping the deletion were not anergic to an in
      vitro UDA restimulation. UDA and the other superantigens also differ as the
      general, V beta-unrestricted, thymic atrophy induced by classical superantigens
      was not observed with UDA.

PMID- 8640862
TI  - Native, but not genetically inactivated, pertussis toxin protects mice against
      experimental allergic encephalomyelitis.
AB  - Treatment of SJL mice with 400 ng Bordetella pertussis toxin (PT) either in
      saline or emulsified in incomplete Freund's adjuvant protected the mice against
      experimental autoimmune encephalomyelitis (EAE) induced 28 days later by a
      synthetic peptide of myelin proteolipid protein (PLP139-151) in complete Freund's
      adjuvant. However, treatment with a genetically inactivated pertussis toxin in
      which the catalytic and NAD-binding sites of the ADP-ribosyltransferase subunit
      were modified by site-directed mutagenesis was without effect. In vitro,
      lymphocyte proliferation was considerably enhanced by both the native and the
      inactivated toxin, at concentrations of 0.1-1 microgram/ml. However, strong
      inhibition of proliferation was also observed with the native toxin only, at
      concentrations that were two to three orders of magnitude lower than that
      required for the mitogenic effect (0.1-1 ng/ml). The inhibition of proliferation
      was detectable in the case of high-background proliferation, after stimulation
      with antigen (PLP139-151) or purified protein derivative of Mycobacterium
      tuberculosis), or with anti-CD3 monoclonal antibody, but not after stimulation
      with concanavalin A or phorbol esters and Ca2+ ionophore. These results suggest
      that the inhibitory effect of PT operates by interfering selectively with a T
      cell receptor-dependent signaling pathway. The biological significance of the in
      vitro inhibitory effect of PT was demonstrated by a considerable decrease and/or
      delay in the ability of lymphocytes grown with PLP139-151 and low concentrations
      of PT to transfer EAE to naive recipients.

PMID- 8640863
TI  - Roles of protein phosphatase 1 and 2A in an IL-6-mediated autocrine growth loop
      of human myeloma cells.
AB  - Deregulation of IL-6 production is one of the major causes for human multiple
      myeloma. Exogenous IL-6 stimulated the proliferation of fresh human myeloma cells
      and the myeloma cell line, U266, which produced IL-6 spontaneously. Anti-IL-6
      antibody and IL-6 antisense oligonucleotide suppressed the IL-6 stimulated
      myeloma cell proliferation, indicating that IL-6 induced the myeloma cell
      proliferation via an autocrine loop. Okadaic acid, an inhibitor of protein
      phosphatase 1 and 2A, inhibited the U266 cell proliferation at a concentration of
      less than 1 ng/ml. At this concentration, okadaic acid suppressed the IL-6
      induced IL-6 gene expression of myeloma cells. It seems that the okadaic acid
      blocked the myeloma cell proliferation by reducing IL-6 synthesis in myeloma
      cells. In addition, IL-6 itself also regulated IL-6 receptor expression. Analysis
      by FACScan and RT-PCR showed that anti-IL-6 antibody treatment up-regulated IL-6
      receptor expression. Interestingly, the presence of okadaic acid induced the up
      regulation of IL-6 receptor expression as well as the down-regulation of IL-6
      induced gp130 phosphorylation in the myeloma cells. Taken together, these data
      suggest that protein phosphatase 1 and 2A are involved in IL-6-mediated autocrine
      growth of human myeloma cells by modulating IL-6 signaling and IL-6 receptor
      expression in myeloma cells.

PMID- 8640864
TI  - T-independent activation of B cells by vesicular stomatitis virus: no evidence
      for the need of a second signal.
AB  - Vesicular stomatitis virus (VSV) induces a T helper cell-independent IgM antibody
      response, whereas the IgG response is strictly T helper cell dependent. Since VSV
      induces B cells in complete absence of T helper cells, the question arises as to
      whether this induction occurs in the absence of a second signal or whether it
      depends upon an alternative or replacing signal 2. We therefore asked whether VSV
      has polyclonal B cell stimulator activity and/or whether B cell induction by VSV
      needs costimulation via complement or tumor necrosis factor (TNF) receptor or by
      natural killer (NK) cell activity. In vitro B cell proliferation assays and
      analysis of the in vivo antibody response in CD40-deficient mice excluded that
      VSV has properties of a polyclonal B cell stimulator. C3 depletion by cobra venom
      factor and application of anti-complement receptor antibodies showed that the T
      independent IgM response was largely C3-independent except under very limiting
      antigen doses. Immunization of TNF receptor-deficient mice showed a normal anti
      VSV IgM response, and in a cytotoxicity assay on YAC target cells there was no
      evidence of NK cell activation by VSV. Thus, VSV seems to induce B cells without
      polyclonal activation and/or C3, TNF, or NK cells functioning as a replacing
      second signal.

PMID- 8640865
TI  - Unique T cell antagonist properties of the exact self-correlate of a peptide
      antigen revealed by self-substitution of non-self-positions in the peptide
      sequence.
AB  - The role of self-peptides in shaping the T cell receptor (TCR) repertoire remains
      to be established. While TCR reactive to certain self-peptides are thought to be
      depleted in the thymus, the selection of TCR specificity for foreign peptide
      reactivity appears to require recognition of self-peptide(s) bound to the groove
      of thymic major histocompatibility complex (MHC) molecules. This dichotomy
      suggests that different TCR affinities, accessory signals, and/or different sets
      of self-peptides dictate the eventual fate of any given TCR-bearing clone.
      Recently, it has been established for several T cell epitopes that derivatives
      with substitutions in TCR-contact residues can antagonize the proliferation of T
      cell clones against the wild-type peptide antigen. Moreover, these altered
      peptide ligands have demonstrated activity in the positive selection of
      thymocytes with TCR reactive to the wild-type peptide antigen. We have
      investigated the specificity of T cell antagonism with step-wise substitution of
      self-amino acids into each nonconserved position of a 12-amino-acid foreign
      peptide antigen. Our data demonstrate that the ability to antagonize
      proliferation without competition for MHC binding is unique to the exact self
      derivative, where all five of the self-substitutions are inserted. These
      properties may specifically allow certain self-peptides to downregulate T cell
      activation to the foreign ligand and/or provide a source of stimulation for
      immunologic memory.

PMID- 8640866
TI  - Age-related reductions in the activation of mitogen-activated protein kinases
      p44mapk/ERK1 and p42mapk/ERK2 in human T cells stimulated via ligation of the T
      cell receptor complex.
AB  - Age-related changes in the functional properties of human T cells are well
      described, but less is known about possible changes in T cell signaling pathways.
      The signaling pathways mediated by mitogen-activated protein kinases (MAPK) are
      considered essential for normal cellular growth and function. Several stimuli
      trigger MAPK activation in human T cells and MEK (MAPK or ERK kinases) are
      immediate upstream inducers of MAPK activation. The current study investigated if
      aging might influence the activation and expression of MAPK and MEK in human T
      cells. Exposure of peripheral blood T cells from young subjects to PHA or cross
      linked anti-CD3 monoclonal antibodies stimulated rapid increases in MAPK and MEK
      enzymatic activity. By contrast, significant reductions of MAPK and MEK
      activation were observed in stimulated T cells from 7 of 13 elderly subjects.
      Kinetic studies showed that the age-related impairments represented reduction in
      both the levels and duration of MAPK activation. In addition, Western immunoblot
      analysis did not reveal significant age-related differences in T cell expression
      of p42mapk/ERK2, p44mapk/ERK1, or MEK, suggesting impairments in upstream
      inducers of MEK/MAPK activation. Other experiments determined if agents that
      directly stimulate upstream Ras or Raf kinase components of the early MAPK
      cascade might reverse the age-related impairments of MAPK activation. Treatment
      of elderly T cells with fluoroaluminate (AlF(-)4), phorbol esters/Ca2+
      ionophores, or okadaic acid stimulated increased MAPK activation compared to anti
      CD3. However, these agents failed to restore MAPK activation in elderly T cells
      to the levels seen in young T cells. These results suggest that aberrancies in
      the MAPK activation cascade may underlie the age-related reductions of MAPK
      activation in human T cells stimulated via the TCR/CD3 complex.

PMID- 8640867
TI  - Regulation of cytokine production by sugi allergen-pullulan conjugate.
AB  - Sugi basic protein (SBP), a major allergen of Japanese cedar (Cryptomeria
      japonica) pollen, conjugated to pullulan (alpha-1,4'-, alpha-1,6'-glucan)
      reportedly suppresses IgE anti-SBP antibody production and enhances IgG anti-SBP
      antibody production in mice. We analyzed cytokine production by SBP-specific T
      cells after stimulation with an SBP-pullulan conjugate (SBP-P), native SBP, or a
      mixture of SBP and pullulan. When SBP-specific T cell lines were stimulated with
      the SBP-P conjugate in the presence of antigen-presenting cells (APC), the
      production of IFN-gamma, IL-4, IL-5, and IL-10 decreased compared with the
      cytokine levels produced by SBP-stimulated T cells. However, when these T cells
      were repeatedly stimulated with the SBP-P conjugate, the production of IFN-gamma
      increased progressively, while that of IL-4, IL-5, and IL-10 remained decreased
      compared with the T cells that were repeatedly stimulated with native SBP.
      Stimulation of the T cells with the mixture of SBP and pullulan showed little
      difference in the cytokine production profile from that observed after
      stimulation with native SBP alone. Interestingly, when the T cell lines
      stimulated repeatedly with SBP-P were subsequently stimulated with native SBP, a
      further increase in IFN-gamma production was observed, while IL-10 production
      decreased. Inhibition of IL-4 production was also observed when SBP-specific Th2
      clones were stimulated with SBP-P. These results indicate that stimulation of T
      cells with SBP-P up-regulates Th1 cytokine production, while down-regulating that
      of Th2. It is, therefore, conceivable that immunotherapeutic treatment with the
      SBP-P conjugate rather than with conventional SBP solutions is preferable for
      improving Japanese cedar pollen allergy.

PMID- 8640868
TI  - Inhibition of apoptosis and augmentation of lymphoproliferation in bcl-2
      transgenic Fas/Fas ligand-defective mice.
AB  - Mice defective in Fas (CD95 or APO-1) or its ligand (lpr or gld mice) develop age
      dependent lymphadenopathy and systemic autoimmune disease. T cells accumulating
      in the lymph nodes of these mice express reduced levels of Bcl-2 protein and are
      susceptible to spontaneous and glucocorticoid-induced apoptosis. We backcrossed
      bcl-2 transgenic mice to lpr and gld mice to homozygosity to determine the
      effects of Bcl-2 overexpression. T cells in these mice were resistant to
      spontaneous and glucocorticoid-induced apoptosis in vitro. Moreover, the
      accumulation of CD4(-)CD8(-) T cells in the lymph nodes and the spleens was
      augmented, suggesting that a Bcl-2-dependent mechanism regulating the number of T
      cells residing in the peripheral lymphoid organs in addition to the Fas-mediated
      pathway exists.

PMID- 8640869
TI  - Differential induction of programmed cell death in CD8+ and CD4+ T cells by the B
      subunit of cholera toxin.
AB  - We have recently demonstrated that a short-term treatment of parental splenocytes
      with the B subunit of cholera toxin (CT-B) abrogates the development of acute
      GVHD in F1 hybrid mice transplanted with these cells. In order to obtain better
      insight into the mechanism of the action of CT-B, we studied the effect of CT-B
      on survival of purified murine T cells and their subsets. We show that treatment
      with B subunit stimulates apoptosis in T cells, detectable following incubation
      in vitro. Although apoptosis was noticed in both CD8+ and CD4+ T cell subsets,
      the treatment preferentially stimulates programmed cell death (PCD) in CD8+
      population. Thus, immunosuppressive action of CT-B in vivo may be in part due to
      its ability to eliminate CD8+ T cells.

PMID- 8640870
TI  - T cell receptor germline gene segments and HLA haplotypes control the length of
      the CDR3 of human T cell receptor beta chains.
AB  - The third complementarity determining region (CDR3) is the most variable part of
      alpha beta T cell receptors (TCR) and represents the putative antigen contacting
      site. To identify parameters determining the structural diversity of the CDR3
      region, the CDR3 length distributions of 66 BV-J combinations in peripheral CD4+
      T cells (6 BV and ll BJ gene segments) of 12 unrelated individuals were analyzed.
      The median CDR3 length ranged from 8 to 12.5 amino acids and was partially
      determined by the usage of the BV and BJ gene segment. Beyond the influence of
      germline-encoded TCR gene segments, donors expressed an individual pattern of
      preferred CDR3 size classes. To identify mechanisms determining this individual
      pattern, 17 first-degree relatives from five families were studied. CDR3 length
      profiles were shared by some but not all relatives. Sharing of CDR3 length
      profiles correlated with the inheritance of both HLA-DR haplotypes. These data
      suggest that the length of the TCR beta chain is selected and that restrictions
      on the diversity of the CDR3 length are imposed by germline-encoded TCR gene
      segments as well as by major histocompatibility complex-dependent mechanisms.

PMID- 8640871
TI  - In vivo role of IL-10 and IL-12 during development of Sjogren's syndrome in
      MRL/lpr mice.
AB  - Expression of local cytokine genes including interleukin 10 (IL-10) and IL-12 was
      analyzed in the salivary gland tissues of MRL/lpr mice with Sjogren's syndrome.
      We demonstrate a significant role of IL-10 and IL-12 in vivo during development
      of Sjogren's syndrome in MRL/lpr mice. IL-10 mRNA expression was detected before
      the onset of disease and was upregulated during the course of autoimmune
      sialadenitis by RT-PCR. A predominant level of expression of IL-12 mRNA was also
      detected earlier in the proinflammatory stage of autoimmune sialadenities.
      Moreover, MHC class II (I-Ak) mRNA was detected before the onset of inflammatory
      lesions until older ages in the salivary glands of MRL/lpr mice. These results
      suggest that endogenous IL-10 and IL-12 may play important roles on immune
      mediated destruction of the salivary glands during development of organ-specific
      autoimmunity in MRL/lpr mice.

PMID- 8640872
TI  - Regulation of cytokine mRNA expression in activated lymphocytes by human
      choriocarcinoma JAR cells.
AB  - Because the fetus is semiallogenic to the mother, considerable modulation of the
      maternal immune response must occur in order for pregnancy to be successfully
      carried to term. Some authors have hypothesized that the immunomodulation of
      pregnancy includes an adjustment of cytokine responses away from the Th1 paradigm
      and toward the Th2 pattern. In vivo data from murine pregnancy support this
      hypothesis. However, in humans, the Th1/Th2 model appears to be more complex than
      that in mice, and cytokine expression of mRNA in human decidual tissue does not
      reflect a clear-cut Th2 bias. The experiments described here were undertaken to
      determine whether and how trophoblastic cells modulate cytokine expression in
      activated lymphocytes, and whether there is a trend toward the use of the Th2
      pattern in an experimental model of the maternal-fetal interface. We used reverse
      transcriptase polymerase chain reaction (rtPCR) to detect cytokine mRNA
      expression in human peripheral blood mononuclear cells cocultivated with human
      choriocarcinoma JAR cells. We found that although IL-2 (a paradigmatic Th1
      cytokine) was significantly down-regulated by JAR cells at the mRNA level,
      similar decreases were also seen in IL-10, which participates in the Th2
      paradigm. We were unable to detect changes in either interferon-gamma (IFN-gamma,
      a Th1 cytokine) or IL-4 (a Th2 cytokine) mRNA's or in IL-2R expression by
      fluorescence-activated cell sorting. These studies indicate that human
      choriocarcinoma JAR cells are capable of modifying cytokines in activated
      lymphocytes other than those involved in the Th1 paradigm. While it may be useful
      to view human responses against the background of these patterns established from
      murine systems, it is reasonable to conclude that human pregnancy may not involve
      regulation of Th1 immune responses exclusively.

PMID- 8640873
TI  - UVB irradiation of human-derived peripheral blood lymphocytes induces apoptosis
      but not T-cell anergy: additive effects with various immunosuppressive agents.
AB  - UVB irradiation of bone marrow or pancreatic islets has been shown to prevent
      GVHD and to induce transplant tolerance in experimental animal models. To clarify
      the underlying mechanism(s) responsible for these UVB effects we have examined in
      vitro cell function following UVB irradiation using LDA, FACS analysis, and DNA
      gel electrophoresis to assess the role of UVB-induced anergy and/or cell death.
      To extend our studies to the clinical setting and to promote chimerism and
      tolerance to organ allografts, we have further studied the effects of UVB
      irradiation combined with the commonly used immunosuppressive agents
      (cyclosporine, azathioprine, and methylprednisolone) on human T cells in
      proliferative in vitro assays. When cytotoxic and proliferative responses to
      allogeneic cells or to PHA stimulation were evaluated in LDA, the use of
      increasing doses of UVB irradiation resulted in a dose-dependent decrease in
      proliferative and cytotoxic responses of T-cells as seen by decreases in
      precursor frequencies. The results of proliferative T-cell assays suggest an
      additive immunosuppressive effect of various immunosuppressive drugs when
      combined with UVB irradiation. Gel electrophoresis of DNA derived from resting
      and activated, UVB-irradiated PBLs showed apoptosis at all UVB doses used. FACS
      analysis of UVB-treated CD2+ cells resulted in a UVB dose-related decrease in
      cell numbers that correlated with viability studies. It appears that UVB
      irradiation of both activated and resting PBLs induces programmed cell death but
      not anergy of T-cells.

PMID- 8640874
TI  - Lymphocyte migration across the anterior and posterior blood-retinal barrier in
      vitro.
AB  - The migration of lymphocytes through monolayers of rat retinal pigment epithelium
      (RPE) and retinal vascular endothelium, which form the posterior and anterior
      blood-retinal barrier (BRB) respectively, was investigated in vitro. After a 4-hr
      assay the migration of untreated peripheral lymph node (PLN) cells through RPE
      monolayers was negligible (<1%) with only a small increase found after activation
      of the PLN cells with concanavalin A or by cross-linking CD3. Activation of the
      RPE with IFN-gamma augmented migration with maximal PLN cell migration being
      achieved with a combination of CD3 cross-linking and IFN-gamma activation (17%
      migration). The highest level of lymphocyte migration was observed with three
      CD4+ antigen-specific T cell lines specific for purified protein derivative (PPD;
      33% migration), ovalbumin (OA; 31%), and S-antigen (S-Ag; 57%). Migration of both
      untreated and Con A-activated PLN cells through retinal endothelial cells (EC)
      from PVG rats was negligible, whereas the migration of the antigen-specific T
      cell lines was 23, 29 and 23% for PPD, OA, and S-Ag lines, respectively.
      Migration of these cell lines through retinal endothelium derived from Lewis rats
      was significantly greater (44% for PPD, 39% for OA, and 39% for S-Ag) which
      corresponded with a greater expression of ICAM-1 on the EC.

PMID- 8640875
TI  - The effect of cytokine stimulation on IL-1 receptor mRNA expression by intestinal
      epithelial cells.
AB  - Interleukin-1 (IL-1) can induce intestinal epithelial cells (IEC) to produce
      several cytokines and acute phase proteins, suggesting that IEC may be important
      in a cytokine network at the intestinal mucosa to amplify the effects of IL-1
      during an inflammatory response. However, little is known about the type of IL-1
      receptor expressed by IEC and the effect of cytokines on the expression of these
      receptors. In this study, the expression by IEC of IL-1 receptor Type I (IL-1RI)
      and type II (IL-1RII) mRNA was examined by reverse transcriptase polymerase chain
      reaction. Both isolated rat IEC and the rat IEC-6 intestinal epithelial cell line
      were found to express mRNA for IL-1RI but not IL-1RII. Stimulation of the IEC-6
      cells with IL-1beta or TNF-alpha down-regulated the expression of mRNA for IL-1RI
      at 24 hr, yet transforming growth factor-beta1 was found to have no effect. These
      results suggest a possible mechanism to limit the effect of IL-1 on IEC function
      during the mucosal inflammatory response by down-regulating the expression of the
      Type I IL-1 receptor.

PMID- 8640876
TI  - Deletion of peripheral V beta 14+ T cells by Mtv-2-encoded viral superantigen
      preceded by blastogenesis and DNA synthesis but not by specific expansion.
AB  - Exogenous and endogenous mouse mammary tumor viruses encode superantigen (SAG) in
      the 3' long terminal repeat. We investigated the immune response of lymph node
      cells to the viral SAG encoded by endogenous Mtv-2 (vSAG-2) by i.v. injecting
      splenocytes from Mtv-2+ mice into Mtv-2- congenic counterparts. vSAG-2
      stimulation induced blastogenesis and DNA synthesis but not subsequent specific
      expansion of V beta 14+CD4+ or CD8+ T lymphocytes. Instead, immediate deletion of
      these T cells progressed after vSAG-2 stimulation, and it was more prominent in
      both rapidity and degree in CD4+ than CD8+ population and in I-E+ than I-E- mice.
      vSAG-7 stimulation caused specific expansion of V beta 6+ T cells prior to their
      deletion as reported. vSAG-7 but not vSAG-2 induced IL-2R expression in the
      specific T cells. Moreover, the percentage of 5-bromo-2'-deoxyuridine
      incorporated cells was about twofold higher in Vbeta6+ T cells stimulated with
      vSAG-7 than in V beta 14+ T cells stimulated with vSAG-2. The results suggest
      that vSAG-2 may be a weak mitogen against specific T cells and that T cells
      weakly activated by SAG may die without preceding expansion. In addition,
      proliferation of lymphocytes, especially B cells, and enhancement of the
      expression of IL-2, IL-4, and IFN-gamma messenger RNA were observed. Thus, V beta
      14+ T cells stimulated with vSAG-2 were activated to produce cytokines and
      depleted quickly.

PMID- 8640877
TI  - Functional characterization of porcine CD4+CD8+ extrathymic T lymphocytes.
AB  - The porcine immune system is unique in that the expression of CD4 and CD8
      antigens defines four subpopulations of resting, extrathymic (CD1-) T
      lymphocytes. In addition to CD4-CD8+ and CD4+CD8- T lymphocytes, CD4-CD8- and
      CD4+CD8+ lymphocyte subpopulations are prominent in blood as well as in lymphoid
      tissues. In the present study, a functional comparison was made between CD4+CD8-
      and CD4+CD8+ T lymphocyte subpopulations. In a primary in vitro immune response
      against alloantigenic stimulator cells, both subpopulations proliferated without
      significant differences in their reactivity. Different results were obtained when
      analyzing the antigen-specific functions of the two CD4+ subpopulations in a
      secondary response against recall viral antigen; these experiments were performed
      with T lymphocytes from pseudorabies virus-immunized pigs. The proliferative
      response against viral antigens could be assigned to the CD4+CD8+ subpopulation,
      whereas the CD4+CD8- subpopulation remained nonreactive. Further analyses of the
      virus-specific in vitro immune response revealed a major histocompatibility
      complex (MHC) class II restricted helper T lymphocyte reaction involving CD4 but
      not CD8 molecules as restriction elements. Taken together, these results
      demonstrate that only the extrathymic CD4+CD8+ T lymphocyte subpopulation of
      swine contains MHC class II-restricted antigen-specific memory T helper cells.

PMID- 8640879
TI  - The tetrapeptide AcSDKP, a negative regulator of cell cycle entry, inhibits the
      proliferation of human and chicken lymphocytes.
AB  - The tetrapeptide AcSer-Asp-Lys-Pro (AcSDKP) is a physiological negative regulator
      of hematopoiesis in mammals. It acts by blocking the cell cycle entry of
      quiescent stem cells and progenitors. In the present study we report that AcSDKP
      blocks the proliferation of human as well as chicken lymphocytes. It inhibits by
      25 to 40% the polyclonal mitogen- (phytohemagglutinin (PHA), pokeweed mitogen
      (PWM), or concanavalin A) or mixed lymphocyte reaction-induced proliferation of
      chicken lymphocytes. A comparable degree of inhibition was observed in human
      whole blood cultures stimulated by "T" (PHA) or "T and B" (PWM) mitogens. Our
      results obtained on two phylogenetically distant species show that AcSDKP reduces
      the lymphocyte proliferation probably by blocking or retarding entry into the
      cell cycle as previously demonstrated for hematopoietic progenitors and
      hepatocytes. Therefore, this endogenous, non-species-specific tetrapeptide may be
      involved in the regulation of immune response.

PMID- 8640880
TI  - [Models of focal CNS hypoxia].
AB  - Vascular disease and focal cerebral ischemia still represent the major cause of
      neurological morbidity and mortality. Mechanisms of hypoxic changes are
      associated with energy depletion and impairment of biological membranes.
      Reperfusion after the stroke plays an important role in the development of
      morphological and functional changes of the nervous tissue. In experiments,
      different models of focal cerebral ischemia based on the middle cerebral artery
      occlusion (MCAO) are used. Four main categories of such models are most
      frequently employed: 1. Temporary intraluminal occlusion of part of the circle of
      Willis (via internal carotid artery), 2. Abluminal application of the
      vasoconstrictor peptide (endothelin-1) to the MCA, 3. Tromboembolic models, 4.
      Microclips. Reliable quantification of morphological changes is also possible.
      Discussed models are used for testing different types of treatment of the
      cerebral ischemia, including pharmacological stimulation and blocking of
      individual membrane receptor systems.

PMID- 8640878
TI  - V beta 8.2 transgene expression interferes with development of experimental
      autoimmune thyroiditis in CBA k/q but not k/k mice.
AB  - The thyroiditogenic T cell receptor (TCR) repertoire is not yet well defined in
      murine experimental autoimmune thyroiditis (EAT). Our recent work has shown that,
      while V beta 8+ T cells have no major role in EAT induction with mouse
      thyroglobulin (MTg), V beta 13 may be involved. To examine the effect of skewing
      the TCR repertoire on EAT development, CBA (H2k) mice were mated with B10.Q mice
      harboring an ovalbumin-specific V beta 8.2 TCR transgene (trg), and the trg+ mice
      were backcrossed to CBA. FACS analysis showed that peripheral blood T cells from
      trg+ mice had about 76 and 90% V beta 8.2+ cells in the CD4+ and CD8+ subsets,
      respectively, compared with about 15 and 11% in trg- sibs. The transgenic CBA k/k
      and k/q mice were immunized with MTg and sacrificed 28 days later. In all trg+
      mice, anti-MTg titers and T cell proliferative responses to MTg were
      significantly lowered. However, thyroid infiltration was distinctly different in
      the two strains of transgenic mice; a significant decrease was seen primarily in
      k/q, but not k/k, trg+ mice. Thus, skewing the TCR repertoire to overexpress an
      irrelevant TCR revealed the possession of a less flexible thyroiditogenic TCR
      repertoire in k/q, but not k/k, mice.

PMID- 8640881
TI  - [Programmed neuronal cell death?].
AB  - During normal development of the nervous system, up to 50 percent or more
      neuronal and glial cells die by programmed cell death. In the developing neuron,
      a continual access to neurotrophic factors is required for survival of the cells.
      The death may be a passive process, and the absence of neurotrophic factors leads
      to a loss of metabolic activity and, ultimately to cellular degeneration.
      Alternatively, apoptosis may be a metabolically active process and neurotrophic
      factors are necessary to repress the "suicide" response of the cell. The role of
      intracellular calcium, RNA-synthesis, protein synthesis a gene expression is
      discussed.

PMID- 8640882
TI  - [Magnesium and transport systems].
AB  - Magnesium is sometimes denoted as "the overlooked cation" for although it is the
      second most abundant intracellular cation, the study of its homeostasis and
      regulation has long been neglected. However, at present it is evident that
      magnesium plays an important intracellular regulatory role. Magnesium transport
      systems can be divided into two principal categories: paracellular transport
      systems and transmembrane transport system. Paracellular pathway plays an
      important role in the intestinal and renal magnesium transports. The movement of
      magnesium across biological membranes is discussed from the perspectives of the
      secondary active transport and specific magnesium channels.

PMID- 8640883
TI  - [Physiologic, biochemical and genetic aspects of malignant hyperthermia].
AB  - Malignant hyperthermic syndrome (MHS) is based on a metabolic dysfunction of the
      skeletal muscle. It is characterized by an elevation of muscle metabolism and
      rigidity, accompanied by an increase of arterial pCO2, lactate and potassium
      plasma concentration, and body temperature. In sensitive individuals, MHS can be
      evoked pharmacologically. To identify substances that evoke this syndrome or
      those useful for its therapy, MHS is modelled in pigs. The primary defect
      attributed to MHS is the impairment of sarcoplasmic calcium homeostasis based on
      a dysfunction of one of calcium ion channels. In some cases, genetic mapping has
      shown that MHS is related to changes in 19 chromosome (in humans). Abnormal
      function of the ion channel is probably not sufficient for the expression of MHS.
      The syndrome manifests only when several modifying factors coincide.

PMID- 8640884
TI  - [A model of stochastic activity of the neuron].
AB  - Techniques for modeling of a stochastic activity of neurons are briefly reviewed.
      Our model is proposed, some experimental results with input Gaussian stochastic
      processes are discussed, and the concept of e-curves is introduced.

PMID- 8640885
TI  - [Hemodynamics in the periodontium and gingiva].
AB  - Measurements of hemodynamics in parodontium and gingiva using a reflexive
      photoelectrical plethysmographic recorder, insensitive to salivation changes, has
      been described. Registration is accomplished by means of ECG recorder.

PMID- 8640886
TI  - [Should there be something new in the teaching of physiology in medical
      schools?].

PMID- 8640887
TI  - [History of the Physiology Society].

PMID- 8640888
TI  - [The development of sports medicine education and the role of Charles University
      Medical School].

PMID- 8640889
TI  - [Lectins in pulmonary adenocarcinomas].
AB  - A relatively specific binding of lectins to various glycids enabled authors to
      evaluate the exosecretion characteristic of lung carcinomas closer than by HE,
      investigation of mucins and immunohistochemical epithelial markers. The main
      subtypes of lung adenocarcinomas (usual of acinar, tubulopillary cubocellular or
      cylindrocellular, solid with mucus production), pseudosarcoma, large cell and
      undifferentiated carcinomas from 9 bioptical samples were therefore compared as
      to binding of 5 lectins with preferential affinity to glucose/mannose (CON A),
      acetylglucosamin (WGA) and acetylgalactosamin (PNA, RCA, HPA). All the subtypes
      of adenocarcinoma as well as undifferentiated carcinoma showed a strong binding
      of bean lectin (CON A) and a slighter binding of ricinus (RCA) and wheat germ
      (WGA) lectins. Binding of Helix pomatia lectin (HPA) was nearly parallel to that
      of CON A even in large cell carcinoma (without mucin positivity)-except in
      undifferentiated carcinoma (in HE reminding of squamous carcinoma but CK
      negative). Peanut lectin (PNA) binding correlated with the production of acid
      glycosaminglycans and its lacking might serve as an indirect sign of Clara cell
      origin in some cubocellular bronchioloalveolar carcinomas which was otherwise
      difficult to prove. Lections mostly did not bind to mucus vacuoles and
      cytoplasmic granulary positivities represented secretion granules; marginal
      membranous positivities represented glycocalyx or lipoproteinaceous layer
      released by Clara cells in accordance with the expression of EMA. In
      pseudosarcoma a gradual binding of CON A from sarcomatoid to epithelial areas
      allowed to evaluate their connection better than according to an expression of
      cytokreatin.

PMID- 8640890
TI  - [Alcian Blue and Leu 7 in the diagnosis of thyroid malignancy].
AB  - Alcian blue pH 2.5 and Leu 7 reactivities were tested in biopsy samples of
      thyroid neoplastic and non-neoplastic diseases (n = 30). Typical papillary
      carcinomas exhibited marked positivity in the apical zone of thyrocytes, but the
      negativity of most cases of follicular variants of papillary carcinoma and
      positivity found in the toxic goitres and exceptionally also in the follicular
      adenoma makes alcian blue of nearly no value for the differential diagnosis on
      cytodiagnostic level. The Leu 7 immunohistochemistry was specific for papillary
      carcinomas but with a very low sensitivity. Thus, its cytodiagnostic use would be
      not cost effective.

PMID- 8640891
TI  - [Pitfalls in cytologic diagnosis of thyroid disease associated with pregnancy].
AB  - The activation of the hypothalamo-pituitary thyroidal axis during pregnancy and
      puerperal period may provoke an unusual morphological response that is hard to
      distinguish from malignancy. Moreover, autoimmune thyroiditis (postpartum
      thyroiditis--PPT) becomes manifest or aggravated in some predisposed women prone
      to contract thyroiditis with the termination of the physiological gestation
      immunosuppression. In five cytologically investigated women (some of whom were
      examined repeatedly) during the postpartum period less typical goitre and
      lymphoplasmacytic thyroiditis were observed. In two of them, a tumour was
      diagnosed (borderline oncocytic lesion and medullary carcinoma). Evaluating the
      dynamics of the process in the patients investigated repeatedly and the
      histological findings in others we conclude: 1) given thorough clinical
      observation and favorable development of the cytology picture the less typical
      lesions may be treated conservatively. 2) The diagnostic features of malignancy
      are maintained in the puerperal period. Taking into account the age distribution
      of thyroid malignancies this risk should be taken into account in the puerperal
      period too.

PMID- 8640892
TI  - [Ultrastructural findings in the gastric mucosa in children and adolescents with
      chronic Helicobacter pylori-positive gastritis].
AB  - Gastric mucosa ultrastructure was studied in 32 children and adolescents with
      chronic superficial active and inactive gastritis. Helicobacter pylori was found
      most frequently free in mucous layer without direct contact with the mucosa. But
      in 7 children (21.9%), it occurred quite close to superficial epithelial cells
      and influenced their outlook. In two cases, it was registered in intracytoplasmic
      channels of intact parietal cells. Another two children with massive
      helicobacterial infection showed superficial epithelial cells with big mucus
      vacuoles and sequestration of apical cytoplasm.

PMID- 8640893
TI  - [The second reading of hematologic biopsies].
AB  - Occurrence of differences between the first and the second reading was compared
      in three time periods. The first from the years 1975-1989 showed disagreement in
      34%, the second from 1990-1991 in 86%, the latest from 1994-1995 in 45%. The
      failures of the same sort repeated in 19 from 42 cases. They could be avoided by
      confining capacities of one's own department and using advantage of consulting
      reading by other pathologist. The second reading asked by an oncologist
      represents an independent urgent part of individual patient's treatment and
      should be generally supported and freed from any hindrance.

PMID- 8640894
TI  - [Segmental mediolytic arteriopathy].
AB  - Three cases of segmental mediolytic arteriopathy occurring in abdominal muscular
      arteries are presented. This unusual arterial lesion is noted for cytoplasmic
      vacuolar degeneration of the arterial smooth muscle cells, intercellular vacuoles
      of various sizes, and focal arterial wall defects designated "arterial gaps".
      This spectrum of histologic changes can progress to formation of aneurysms with
      rupture of the vascular wall. The extensive intraabdominal haemorrhage led to the
      death of all our patients. Pathogenesis and differential diagnosis of this lesion
      is discussed.

PMID- 8640895
TI  - [Morphological spectrum of atrioventricular septal defects].
AB  - Morphology of atrioventricular septal defect was studied on 73 heart specimens.
      All of them had a defect of atrioventricular septum and adjoining parts of atrial
      and ventricular septum, a shortening of inflow parts of both ventricles, a
      malformation of atrioventricular valves and changed position of aortic valve.
      There was a great variability of all the studied structures and nearly continuous
      spectrum of specimens was found as for the ventricles' size, localization and
      diameter of the defect, communication between atria and ventricles, anatomy of
      the left ventricle outflow tract as well as the whole atrioventricular valvular
      apparatus and occurrence of associated heart malformations. A common ostium was
      formed in 52 cases (71.2%), two separated ostia were found in 21 cases (28.8%)
      but a continuous transition between both groups was noticed. Both groups showed a
      great variety of single cusps of atrioventricular valves (in shape, number and
      anchoring), of papillary muscles and of the size of atrioventricular
      communication. The finding of frequently associated heart malformations was
      important from the clinical point of view, especially of the obstructive
      malformations of the left ventricle. A great morphological variability needs
      individual surgical solutions, namely reconstruction of valves, closure of septal
      defects and correction of associated heart malformations.

PMID- 8640896
TI  - [Mixed carcinoid-carcinoma of the stomach].
AB  - Bioptical observation of a mixed carcinoid-carcinoma in a 75-year-old man's
      stomach was described. The subcardial tumour was 10-7 cm in diameter with
      secondaries in perigastric lymph nodes. A well differentiated adenocarcinoma with
      mucus production formed a minor marginal part of the carcinoid which expressed
      immunohistochemical markers common in gut cancers: carcinoembryonic antigen,
      epithelial membrane antigen and some cytokeratins. The well differentiated
      adenocarcinoma expressed different cytokeratins detected by AE1-AE3 antibody. The
      carcinoid was positive with Grimelius impregnation and strongly positive with
      chromogranin A and synaptophysin bound antibodies. Transition of both the tumour
      types was continuous.

PMID- 8640897
TI  - [Comments on the suggested new classification of malignant lymphomas].
AB  - New classification of malignant lymphomas is based on a problematic intention of
      weakening the basic importance of topography for their precise evaluation. It is
      quite asymmetrical in establishing leading units. To omit existing coding
      possibilities of the malignant lymphomas is disappointing.

PMID- 8640898
TI  - Stereoselectivity of lipases in supercritical carbon dioxide. I. Dependence of
      the regio- and enantioselectivity of porcine pancreas lipase on the water content
      during the hydrolysis of triolein and its partial glycerides.
AB  - The stereoselectivity of porcine pancreas lipase (PPL) was investigated during
      the enzymatic hydrolysis of triolein and its partial glycerides in the presence
      of supercritical carbon dioxide (SCCO2) as reaction medium. The water content of
      the immobilized lipases was varied. The partial glycerides were separated into
      mono- and diglycerides by TLC, converted to their 3,5-dinitrophenylurethane
      derivatives and subsequently resolved into sn-1,2 and sn-2,3 enantiomers
      (estimation of dioleins) or into sn-1 and sn-3 enantiomers (estimation of
      monooleins) by HPLC on a chiral stationary phase (Sumichiral OA-4100). In all
      reactions under the conditions employed, PPL revealed a distinct preference for
      the sn-3 position of the glycerol. However, the stereoselectivity depends on the
      reaction time, the substances initially used and the enzyme water content. It
      seems that the effect of the enzyme water content on the activity and selectivity
      of porcine pancreas lipase in SCCO2 is based on a modification of the "micro
      environment' of the enzyme by the solution of CO2 in water, causing a decrease of
      the pH value.

PMID- 8640899
TI  - Enzymatic production of hydroperoxides of unsaturated fatty acids by injury of
      mammalian cells.
AB  - Hydroperoxides of unsaturated fatty acids (LOOHs) are generated by homogenisation
      of liver tissue, but not if the liver is boiled before homogenisation. This
      observation indicates that the LOOHs are produced in an enzymatic reaction. This
      assumption is corroborated by an analysis of the reduction products of LOOHs by
      gas chromatography/mass spectrometry (GC/MS). A main part of LOOHs is derived
      from linoleic acid and not from arachidonic acid. Massive cell damage occurs by
      myocardial infarction or other severe injuries; these events were found to be
      connected with generation of LOOHs. We suspect--considering the above outlined
      experiment--that the LOOH production is also mainly caused in these cases by
      activation of enzymes and not--as postulated--by an autocatalytic process.
      Increased amounts of LOOHs are found in many chronic diseases, e.g. in rheuma,
      atherosclerosis or psoriasis, obviously caused by a gradual damage of cells.
      Thus, the common root of an increased LOOH level might be cell injury.

PMID- 8640900
TI  - Aminoglycoside antibiotics prevent the formation of non-bilayer structures in
      negatively-charged membranes. Comparative studies using fusogenic (bis(beta
      diethylaminoethylether)hexestrol) and aggregating (spermine) agents.
AB  - Aminoglycoside antibiotics cause aggregation but not fusion of negatively-charged
      liposomes at an extent proportional to their capacity to interact with acidic
      phospholipids (Van Bambeke et al., 1995, Eur. J. Pharmacol., 289, 321-333). To
      understand why aggregation is not followed by fusion, we have examined here the
      influence of two aminoglycosides with markedly different toxic potential
      (gentamicin > isepamicin) on lipid phase transition in negatively-charged
      liposomes using 31P-NMR spectroscopy, in comparison with spermine (an aggregating
      agent) and bis(beta-diethylaminoethylether)hexestrol or DEH (a fusogenic cationic
      amphiphile). Gentamicin, spermine, and, to a lesser extent, isepamicin inhibit
      the appearance of the isotropic signal seen upon warming of control liposomes and
      denoting the presence of mobile structures. This non-bilayer signal appeared most
      prominently when liposomes were incubated with DEH, a strong fusogenic agent. We
      conclude that aminoglycosides, like spermine, have the potential to prevent
      membrane fusion, by inhibiting the development of a critical change in membrane
      organization, which is associated with fusion. We suggest that this capacity
      could be a determinant in aminoglycoside toxicity.

PMID- 8640901
TI  - Experimental evidence of a temperature-related conformational change of the
      hydrophilic portion of gangliosides.
AB  - The present paper reports the experimental observation of an interesting
      thermodynamic process which could be biologically important: such behaviour,
      shown by some gangliosides, is likely to be peculiar of these glycosidic
      compounds as it has never been observed for other membrane-type amphiphilic
      molecules. In water solution, gangliosides have been found to present a bistable
      behaviour between two stable states (called A and B) which does not involve any
      change in the primary structure of the molecule. The interconversion between
      state A and state B, and vice versa, does not occur spontaneously, but has to be
      triggered by some external agent, which makes this system a potentially regulated
      process with important biological correlations. In the present experiments, state
      B is reached from state A with a temperature rise in the range 30-55 degrees C.
      The new state is stable regardless of any possible temperature cycle. The initial
      state A is then regained when the ganglioside solution is dried and the solute is
      redissolved. The two states are believed to correspond to two different
      conformations of the hydrophilic portion of the molecule. The bistable behaviour
      is shown by the gangliosides GM2, GM1, GD1a, GD1b and Fuc-GD1b, GT1b, however,
      does not show such an effect.

PMID- 8640902
TI  - Antioxidant activity of natural flavonoids is governed by number and location of
      their aromatic hydroxyl groups.
AB  - We studied antioxidant activity of five natural flavonoids in canola oil, an
      emulsion, and rat red blood cell membrane. In the canola oil heated at 105
      degrees C, myricetin most effectively attenuated lipid oxidation, followed by
      quercetin, morin and kaempferol in a decreasing order. When the emulsion
      containing canola oil was incubated at 54 degrees C, quercetin was most
      protective against lipid oxidation, followed by kaempferol, myricetin and morin
      in a decreasing rank. Apigenin demonstrated no antioxidant activity in either the
      canola oil or the emulsion. Of the flavonoids tested, quercetin was the best in
      quenching free radical chain reaction in rat red blood cell membrane. The
      antioxidative characteristics of these flavonoids was determined by multiple
      factors including the system used, the hydrophobicity, and the total number and
      the location of aromatic hydroxyl groups. We conclude that myricetin is an
      effective antioxidant in canola oil, while quercetin is an effective protector
      against lipid oxidation in the cell membrane.

PMID- 8640903
TI  - Identification of 3 beta-hydroxy-5 alpha-cholest-6-ene-5-hydroperoxide in human
      oxidized LDL.
AB  - Oxidized LDL exhibits cytotoxic activity towards endothelial cells, which is
      thought to be mediated by the products derived also from cholesterol oxidation,
      mainly involving the B-ring. By LC-PB-EI-MS and EI-MS/MS analysis, we have
      identified 3 beta-hydroxy-5 alpha-cholest-6-ene-5-hydroperoxide among the
      cholesterol oxidation products in LDL incubated with micromolar concentrations of
      copper ions.

PMID- 8640904
TI  - Plasmalogens and their oxidative degradation products in low and high density
      lipoprotein.
AB  - The kinetics of the autoxidation reaction of LDL and HDL with Fe2+/ascorbate was
      investigated. Aldehydes derived from plasmalogens were determined by conversion
      to 2-alkyl-1,3-dithiolanes. Their oxidation products, 2-hydroxy-aldehydes, were
      trapped by reaction with pentafluorobenzylhydroxylamine. After derivatisation,
      the pentafluorobenzyloximes could be separated from other compounds by thin-layer
      chromatograpy. They were detected by gas chromatography applying an electron
      capture detector. LDL plasmalogens are oxidized nearly completely after 180 min
      while HDL plasmalogens suffer oxidation only to 5%. Oxidation of linoleic and
      arachidonic acid was investigated by simultaneous determination of 2
      hydroxyheptanal.

PMID- 8640905
TI  - An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor
      suppressor gene occurs in hepatocellular carcinomas from Mexico.
AB  - The p53 tumor suppressor gene is commonly mutated in human hepatocellular
      carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a
      high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense
      mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico,
      for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin
      adduct levels of the donors and family members to measure the current AFB1
      exposure in this population. Moreover, the presence of hepatitis B and/or C viral
      infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells
      were microdissected from tissue sections and exon 7 p53 sequences were amplified
      by polymerase chain reaction from genomic DNA and sequenced directly. The
      serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA.
      Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit
      antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of
      the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser
      mutations were found. Serum antibodies recognizing p53 protein were found in one
      of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases.
      The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64
      pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis
      viruses are etiological agents in the molecular pathogenesis of HCC in this
      geographic region of Mexico.

PMID- 8640906
TI  - Quantification of t(14;18) in the lymphocytes of healthy adult humans as a
      possible biomarker for environmental exposures to carcinogens.
AB  - A t(14;18) chromosomal translocation is found in approximately 85% of follicular
      lymphomas by both cytogenetic and molecular analyses. This rearrangement
      deregulates expression of the bcl-2 proto-oncogene by translocation into the
      immuno-globulin heavy chain locus and is probably mediated by illegitimate V(D)J
      recombination. We have developed a quantitative nested PCR method for detecting
      this event in lymphocytes of healthy individuals. Genomic DNA is purified from
      peripheral blood lymphocytes, and 2.5 microg (representing 4 X 10(5) cells) are
      amplified with translocation-specific primers under conditions in which a single
      copy, if present, will give a detectable PCR product. Multiple replicates are
      analyzed for each individual, and Poisson statistics are then used to estimate
      the translocation mutant frequency. We have examined lymphocyte DNA from 34
      healthy individuals by this assay and found the frequency of cells with t(14;18)
      to range from <0.8-96X10(-7). The molecular nature of the translocations has been
      investigated by determining the DNA sequence at the translocation junctions. In
      several individuals, multiple isolates of the same translocation event were
      recovered, indicating that the cell with the original translocation had undergone
      clonal expansion. In addition, multiple independent translocations were shown to
      occur within an individual. Since this translocation appears to be one step in
      the progression of a normal cell to a cancer cell, this assay may have utility as
      an effects biomarker for environmental carcinogen exposure.

PMID- 8640907
TI  - Environmental air pollution and DNA adducts in Copenhagen bus drivers--effect of
      GSTM1 and NAT2 genotypes on adduct levels.
AB  - The lymphocyte bulky PAH-DNA adduct levels have been studied in persons
      occupationally exposed to ambient air pollution. The exposure group consisted of
      90 healthy, nonsmoking bus drivers from the Copenhagen area, divided into three
      exposure groups according to driving area, and 60 rural controls (smokers and non
      smokers). PAH-DNA adducts were determined by 32P-postlabelling with the butanol
      enrichment procedure. The bus drivers answered a comprehensive questionnaire on
      passive smoking, residential area, diet and other potential confounding
      variables. A significantly higher adduct level was observed in bus drivers
      working in central Copenhagen (1.214 fmol/microg DNA, n = 49) compared with both
      those driving in the dormitory (median: 0.507 fmol/microg DNA, P = 0.046, n = 16)
      and suburban (median: 0.585 fmol/microg DNA, P = 0.041, n = 25) areas. All three
      groups had higher adduct levels than rural controls (0.074 fmol/microg DNA, n =
      60, P < 0.001). No significant influence on adduct levels was demonstrated from
      potential confounders, including smoking and diet. The effect of the metabolizing
      enzymes, GSTM1 and NAT2, on adduct levels was investigated. No statistically
      significant effects were observed on adduct levels from GSTM1 or NAT2, either
      individually or combined, but a non-significant trend was seen for individuals
      with GSTM1*0/0 (null), since they had higher adduct levels in all exposure
      groups. This study demonstrated that lymphocyte PAH-DNA adduct levels were
      related to levels of exposure to urban air pollution and indicated that these
      adducts might be helpful as a means of classifying better different exposure
      groups for epidemiological studies. Furthermore, it demonstrated the ability of
      32P-postlabelling to discern small differences in low exposure to ambient air
      pollution and suggested a possible effect of GSTM1*0/0 on DNA adduct levels.

PMID- 8640908
TI  - Presence of N2-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
      (dG-C8-MeIQx) in human tissues.
AB  - One of the mutagenic and carcinogenic heterocyclic amines (HCAs), 2-amino-3,8
      dimethylimidazo[4,5-f]quinoxaline (MeIQx), is present in cooked foods and we are
      chronically exposed to this compound in our daily life. To study the role of HCAs
      in human carcinogenesis, we analyzed MeIQx-DNA adducts in 38 DNA samples obtained
      from surgical and autopsy specimens by the 32P-postlabeling method under adduct
      intensification conditions with the modification of additional digestion with
      nuclease P1 and phosphodiesterase I after 32P-labeling at 5'-hydroxyl termini.
      This modified 32P-postlabeling method can detect N2-(deoxyguanosin-8-yl)-2-amino
      3,8-dimethylimidazo- [4,5-f]quinoxaline 5'-monophosphate (5'-pdG-C8-MeIQx) at
      levels down to 1/10(10) nucleotides. The DNA samples from colon and rectum
      surgical specimens and a kidney taken at autopsy were found to contain an adduct
      spot corresponding to that of standard 5'-pdG-C8-MeIQx on TLC at levels of 14,18
      and 1.8 per 10(10) nucleotides, respectively. Each adduct spot was extracted from
      TLC and identified to be 5'-pdG-C8-MeIQx by HPLC. Thus, MeIQx-DNA adducts
      actually exist in human tissues and this adduct formation may be involved in
      human cancer development.

PMID- 8640909
TI  - Determination of DNA adducts of malonaldehyde in humans: effects of dietary fatty
      acid composition.
AB  - The effects of dietary fatty acid composition on the endogenous formation of DNA
      adducts of malonaldehyde (MA), the major product of lipid peroxidation, were
      investigated in humans. A group of 59 healthy individuals of both sexes and
      different ages was initially fed a milk fat-based diet rich in saturated fatty
      acids for 14 days. Following this initial period, after which the group was
      considered homogeneous with respect to diet, 30 randomly chosen subjects were
      given a sunflower oil-based (rich in polyunsaturated fatty acids) (SO) diet and
      the remaining 29 individuals a low erucic acid rapeseed oil-based (rich in
      monounsaturated fatty acids) (RO) diet for 25 days. The fatty acid composition of
      plasma lipid fractions and the level of DNA adducts of MA in total white blood
      cells were then determined at the end of the SO and RO dietary periods. DNA
      adduct levels were measured by 32p-postlabelling using reversed-phase HPLC with
      on-line detection of radioactivity. Higher concentrations of polyunsaturated
      fatty acids in plasma triglycerides and higher levels of DNA adducts of MA were
      found in the subjects on the SO diet when compared with those in the RO dietary
      group. A large inter-individual variation in adduct levels was observed. The
      average adduct level in the SO diet group was 7.4 +/- 8.7 adducts/10(7)
      nucleotides (n = 23). This level was 3.6-fold higher than that found in
      individuals in the RO diet group (P < 0.001). Our results, in conjunction with
      the mutagenic and carcinogenic properties of MA, thus suggest the interaction of
      lipid peroxidation products such as MA with DNA as one plausible mechanism
      explaining the involvement of dietary fat in carcinogenesis.

PMID- 8640910
TI  - Chemopreventive effect of S-allylcysteine and its relationship to the
      detoxification enzyme glutathione S-transferase.
AB  - Sulfur-containing substances derived from garlic and onion have been shown to
      prevent experimental carcinogenesis. One of the hypotheses explaining the
      mechanisms of the chemopreventive activity of these substances is that they
      activate detoxification systems such as glutathione S-transferase (GST). In this
      study the effects of S-allylcysteine (SAC), a water-soluble organosulfur compound
      derived from garlic, on GST activities in the liver, small intestine and colon
      were investigated. Additionally, we examined SAC for chemopreventive effects on
      aberrant crypt foci, which are the most likely precursors of colon cancers. In
      the rat colonic aberrant crypt assay administration of SAC during the initiation
      period decreased the number of aberrant crypt foci by 33 and 54% in groups given
      40 or 80% maximum tolerated dose (MTD) of SAC respectively. The number of
      aberrant crypt foci, however, was not changed when SAC was given during the
      promotion period. GST activity in the liver was increased significantly by 41% 12
      h after a single oral administration of 3.5 mmol/kg SAC and this elevated GST
      level was maintained over a 72 h period. GST levels were increased significantly
      by the administration of SAC (1.8 mmol/kg/ day for 3 days) not only in the liver
      but also in the proximal and middle small bowel. Isozyme levels of GST after
      administration of SAC were also determined using Western blotting. Hepatic GST
      alpha and GST-mu were significantly increased by 35 and 42% respectively after
      oral administration of SAC. GST-pi levels were lower than the detection limit
      (130 ng/mg/protein) in both the control and SAC-treated groups. These results
      strongly support the previous working hypothesis that SAC exhibits
      chemopreventive activity by exerting specific effects on carcinogen
      detoxification systems.

PMID- 8640911
TI  - The efficacy of conjugated linoleic acid in mammary cancer prevention is
      independent of the level or type of fat in the diet.
AB  - The objective of the present study was to investigate whether the
      anticarcinogenic activity of conjugated linoleic acid (CLA) is affected by the
      amount and composition of dietary fat consumed by the host. Because the
      anticancer agent of interest is a fatty acid, this approach may provide some
      insight into its mechanism of action, depending on the outcome of these fat
      feeding experiments. For the fat level experiment, a custom formulated fat blend
      was used that simulates the fatty acid composition of the US diet. This fat blend
      was present at 10, 13.3, 16.7 or 20% by weight in the diet. For the fat type
      experiment, a 20% (w/w) fat diet containing either corn oil (exclusively) or lard
      (predominantly) was used. Mammary cancer prevention by CLA was evaluated using
      the rat dimethylbenz[a]anthracene model. The results indicated that the magnitude
      of tumor inhibition by 1% CLA was not influenced by the level or type of fat in
      the diet. It should be noted that these fat diets varied markedly in their
      content of linoleate. Fatty acid analysis showed that CLA was incorporated
      predominantly in mammary tissue neutral lipids, while the increase in CLA in
      mammary tissue phospholipids was minimal. Furthermore, there was no evidence that
      CLA supplementation perturbed the distribution of linoleate or other fatty acids
      in the phospholipid fraction. Collectively these carcinogenesis and biochemical
      data suggest that the cancer preventive activity of CLA is unlikely to be
      mediated by interference with the metabolic cascade involved in converting
      linoleic acid to eicosanoids. The hypothesis that CLA might act as an antioxidant
      was also examined. Treatment with CLA resulted in lower levels of mammary tissue
      malondialdehyde (an end product of lipid peroxidation), but failed to change the
      levels of 8-hydroxydeoxyguanosine (a marker of oxidatively damaged DNA). Thus
      while CLA may have some antioxidant function in vivo in suppressing lipid
      peroxidation, its anticarcinogenic activity cannot be accounted for by protecting
      the target cell DNA against oxidative damage. The finding that the inhibitory
      effect of CLA maximized at 1% (regardless of the availability. of linoleate in
      the diet) could conceivably point to a limiting step in the capacity to
      metabolize CLA to some active product(s) which is essential for cancer
      prevention.

PMID- 8640912
TI  - Induction of hepatic aneuploidy in vivo by tamoxifen, toremifene and idoxifene in
      female Sprague-Dawley rats.
AB  - Since tamoxifen is efficacious for the prevention of second primary breast
      neoplasms in humans and has a low reported incidence of acute side effects,
      several structurally related compounds have been developed for the treatment of
      breast cancer including toremifene and idoxifene. We have compared the karyotypic
      alterations that occur after a single per os administration of 35 mg/kg of
      tamoxifen, toremifene or idoxifene to female Sprague-Dawley rats. One day
      following treatment, the rats were sacrificed and the hepatocytes isolated and
      cultured. After 47 h in culture, colcemid was added for 3 h prior to harvest of
      the hepatocytes for karyotypic evaluation. At least 100 metaphase spreads were
      examined for each of five rats per treatment. Toremifene resulted in aneuploidy
      in 50 +/- 7% of the cells examined and idoxifene induced a 57 +/- 4% aneuploidy
      compared with the 85 +/- 7% level induced by tamoxifen. Since the level of
      aneuploidy in solvent-treated rats was 3 +/- 3 %, the induction of aneuploidy in
      at least 50% of the cells from rats treated with tamoxifen, toremifene or
      idoxifene was highly significant. Analysis of electron micrographs of cultures
      treated with these antiestrogens demonstrated a range of phenotypes including
      multipolar spindles in toremifene-treated rats and condensed chromosomes in the
      presence of an intact nuclear envelope in occasional idoxifene-treated rat
      hepatocytes. The exclusion of chromosomes from the spindle apparatus and the
      lagging of some chromosomes on the metaphase plate correlate with the high rate
      of induction of aneuploidy in the rat liver as determined by karyotypic analysis
      of hepatocytes from rats treated with these triphenylethylenes.

PMID- 8640913
TI  - Association of low CYP3A activity with p53 mutation and CYP2D6 activity with Rb
      mutation in human bladder cancer.
AB  - p53 and Rb gene mutations are intermediate biomarkers useful for the prediction
      of neoplastic progression in bladder cancers. Previously, we have shown that low
      CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity,
      assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk
      factors in developing aggressive bladder cancer. However, no information is
      available about the relationship between drug/xenobiotic metabolizing enzyme
      activities and p53/Rb mutations that may suggest mechanisms of bladder
      carcinogenesis. We evaluated in vivo CYP3A activity by the dapsone recovery ratio
      (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19
      activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the
      monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1)
      genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over
      expression of p53 protein was detected with antibody pAb1801 and loss of Rb
      protein expression was evaluated with antibody PMG3-245 in patients with
      transitional cell carcinoma of the bladder. Low CYP3A activity was significantly
      associated with over expression of or mutated p53 protein (P < 0.05). High CYP2D6
      activity (within the extensive metabolizer group) was significantly associated
      with loss of expression of or mutated Rb protein (P < 0.05). Positive p53
      staining also predicted aggressive bladder cancer histopathology (P < 0.05, odds
      ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P < 0.01,
      odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR).
      These selective associations are consistent with the hypothesis that an
      environmental pro-carcinogen fails to be detoxified by CYP3A which may
      preferentially induce p53 mutations, whereas, an alternative pro-carcinogen that
      may be activated by CYP2D6, may selectively induce Rb mutations.

PMID- 8640914
TI  - Enhancement of benzo[a]pyrene diol epoxide mutagenicity by sulfite in a mammalian
      test system.
AB  - Sulfur dioxide, a ubiquitous air pollutant, is a co-carcinogen for benzo[a]pyrene
      (BP). We have demonstrated previously that the interaction between sulfite, the
      physiological form of sulfur dioxide, and (+/-) -7r,8t-dihydroxy-9t,10t-epoxy
      7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), the ultimate carcinogenic form of
      BP, results in an enhanced mutagenic effect in Salmonella typhimurium strains
      TA98 and TA100. We report here that this same co-mutagenic effect of sulfite
      occurs in a mammalian cell line. Treatment of Chinese hamster V79 cells with 50
      nM anti-BPDE, a concentration on the linear portion of the dose-response,
      resulted in a four-fold increase in mutations at the hprt locus relative to the
      spontaneous rate. When V79 cells were exposed to 1 or 10 mM sulfite immediately
      prior to the addition of anti-BPDE, the mutation rate increased by 73% and 210%,
      respectively, over that elicited by anti-BPDE alone. Sulfite itself was
      moderately cytotoxic, but caused no increase in mutation over the spontaneous
      rate. Characterization of the dose- and time-dependance of this enhancement of
      diol epoxide mutagenicity by sulfite closely resembled the effects seen
      previously in the bacterial system. In particular, enhancement by sulfite was
      evident when sulfite was added to the cells between 60 min and 1 min prior to the
      addition of the diol epoxide. Concurrent addition of sulfite and the diol epoxide
      attenuated the enhancement, and the effect was lost altogether when sulfite was
      added 10 min after the diol epoxide. The specificity of this effect of sulfite
      was shown by comparison with sulfate, which at concentrations of either 1 or 10
      mM exhibited modest cytotoxicity, but neither was directly mutagenic nor able to
      enhance the mutagenic effect of anti-BPDE. Binding studies with labeled anti-BPDE
      showed that the addition of 10 mM sulfite increased binding of anti-BPDE to DNA
      by over 43%, corresponding to the observed increase in mutant frequency.
      Interestingly, this difference in level of DNA modification was not apparent
      after 30 min to 2 h exposures, but only emerged at the 4 h time point. The 4 h
      point was routinely used for all mutagenicity studies. Binding of anti-BPDE
      derived materials to cellular RNA was not altered by 10 mM sulfite. The emergence
      of increased DNA modification at the latest time point suggests either a more
      prolonged period of active DNA binding than would occur with diol epoxide, or a
      difference in the ability to recognize and clear specific DNA adducts. Both
      possibilities are discussed in regard to the observed formation of 7r,8t,9t
      trihydroxy-7,8,9,10-tetrahydrobenzo[a] pyrene-10c-sulfonate (BPT-10-sulfonate) in
      those incubations. BPT-10-sulfonate is a relatively stable BP derivative which
      retains the ability to covalently modify DNA. The role of this derivative in the
      enhancement of diol epoxide mutagenicity by sulfite is strongly suggested by
      these data.

PMID- 8640915
TI  - 32P-postlabeling of a DNA adduct derived from 4,4'-methylenedianiline, in the
      olfactory epithelium of rats exposed by inhalation to 4,4'-methylenediphenyl
      diisocyanate.
AB  - Tissues obtained from female Wistar rats exposed to a 0.9 microm aerosol of 4,4'
      methylenediphenyl diisocyanate (MDI) for 17 h per day, 5 days per week, for one
      year, at levels of 0, 0.3, 0.7 and 2.0 mg/m(3), were analyzed for DNA adducts. A
      32P-postlabeling method was used to detect (i), adducts formed by the reaction of
      the isocyanate group(s) of MDI with DNA; and a 32P-postlabeling method was
      adapted to detect (ii), a DNA adduct formed by 4,4'- methylenedianiline (MDA), a
      hydrolysis/decarboxylation product of MDIV. In the lung, neither isocyanate
      adducts nor the arylamine adduct were detectable. The same negative result was
      seen in the liver, the bladder, the kidney, the respiratory epithelium and in
      peripheral lymphocytes. In the olfactory epithelium, on the other hand, the
      arylamine-derived DNA adduct was detected, at the very low levels of 5,9 and 10
      adduct-nucleotides per 10(10) nucleotides, for the three dose groups,
      respectively. The adduct co-chromatographed with the one formed in the liver of
      rats after oral gavage of MDA. The results are discussed in terms of the
      importance of genotoxic versus nongenotoxic aspects of carcinogenesis.

PMID- 8640916
TI  - Thiocyanate-independent nitrosation in humans with carcinogenic parasite
      infection.
AB  - Infection with the liver fluke, Opisthorchis viverrini, is a causative agent of
      cholangiocarcinoma. One possible contributing factor in this carcinogenesis is
      the chronic, local generation of nitric oxide by inflammatory cells expressing
      inducible nitric oxide synthase and the production of N-nitroso compounds via the
      reaction between amines and nitrosating agents derived from nitric oxide. Our
      previous studies provided evidence that nitric oxide synthesis is elevated during
      human liver fluke infection. Here we present data on the same sample of men which
      definitively demonstrates increased nitrosation of proline and thioproline
      (thiazolidine-4-carboxylic acid) among infected men compared to uninfected
      control subjects on a low nitrate diet. This difference was specifically
      abolished by co-administration of ascorbic acid with proline and by elimination
      of parasites by praziquantel treatment. Multivariate statistical models
      demonstrate the importance of salivary thiocyanate levels to variation in the
      nitrosation of proline among uninfected individuals, but not among those with
      current fluke infection. This suggests that considerable generation of
      nitrosating agents (N203/N204) in infected people may be occurring via oxidation
      of arginine by nitric oxide synthase in inflamed tissue which is thiocyanate
      insensitive. Analyses revealed positive associations between N-nitrosoproline
      excretion and nitrate/nitrite levels in urine, plasma and saliva and with usual
      alcohol intake; with variation in these trends between groups. In conclusion, we
      have confirmed the relationship between O.viverrini infection and enhanced
      endogenous nitrosation, showing evidence of its extragastric site. New
      information is also provided on the determinants of N-nitrosamino acid excretion
      in men on a controlled low nitrate diet without smoking, conditions which reduce
      exogenous sources of nitrosating agents.

PMID- 8640917
TI  - Characterization by two-endpoint comparisons of the genetic toxicity profiles of
      vinyl chloride and related etheno-adduct forming carcinogens in Drosophila.
AB  - The genetic toxicity profiles of vinyl chloride (VCl), vinyl bromide (VBr), ethyl
      carbamate (EC), vinyl carbamate (VC) and some structurally related chemicals were
      investigated in both somatic and germ cells of Drosophila melanogaster. In the
      white/white+ eye mosaic assay, a screening system measuring predominantly
      homologous recombination in somatic cells, only marginal genotoxic activities
      were observed for acetyl chloride (ACl), glycolaldehyde (GCA), 2,2'
      dichlorodiethyl ether (DDE) and methyl carbamate (MC), whereas VCl, 2
      chloroacetaldehyde (CAA), VBr, 2-bromoacetaldehyde (BAA) and EC were clearly
      recombinogenic in the assay. Those chemicals proven to be recombinogenic in
      somatic cells were investigated further in postmeiotic male germ cells, utilizing
      as descriptors of their genotoxicity I(CL/RL) and M(exr-)/M(exr+) indices. The
      I(CL/RL) index is the rate of induced chromosome loss (CL), a clastogenic event,
      divided by the forward mutation rate, measured as recessive lethal (RL) mutations
      in 700 loci of the X-chromosome. The M(exr-)/M(exr+) mutation enhancement ratio
      is obtained by determining RL under excision repair deficient versus repair
      proficient conditions. With I(CL/RL) values (2.7-6.9) similar to those obtained
      for cross-linking agents, vinyl chloride, vinyl bromide, ethyl carbamate and
      vinyl carbamate are all efficient clastogenic agents in Drosophila germ cells. In
      the absence of excision repair, however, neither CEO nor CAA gave a
      hypermutability response (M(exr-)/M(exr+) approximately 1). By contrast, VCl,
      VBr, EC and VC showed clearly enhanced M(exr-)/M(exr+) ratios, suggesting that
      these compounds produce some repairable DNA modification(s) that are not
      generated by their epoxides. This unexpected finding points to the formation of
      other, yet unknown, metabolites of vinyl chloride, vinyl bromide, ethyl carbamate
      and vinyl carbamate. Our results support the concept that the epoxides
      chloroethylene oxide (CEO), bromoethylene oxide (BEO) and vinyl carbamate epoxide
      (VCO) are the most essential mutagenic intermediates. Compared to chloroethylene
      oxide (CEO), 2-chloroacetaldehyde (CAA) was approximately 50 times less effective
      in the induction of RL, whereas BAA was inactive as a mutagen. These findings are
      consistent with the general view that CAA and BAA play no major role in the
      genotoxic action of vinyl halides.

PMID- 8640918
TI  - Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by hamster,
      mouse and rat intestine: relevance of species differences.
AB  - We recently demonstrated the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1
      butanone (NNK) in rat intestinal segments, as well as the inducibility of
      intestinal NNK metabolism by starvation or acetone treatment. To improve our
      understanding of intestinal NNK turnover we have additionally investigated NNK
      metabolism in isolated perfused jejunal segments from NMRI mice and Syrian golden
      hamsters. [14C]NNK (1 micromol/l) was metabolized extensively by jejunal segments
      from female NMRI mice (88.5%) and female Syrian hamsters (86.4%), whereas in male
      NMRI mouse segments a slightly lower metabolism (68.8%) was observed. Alpha
      Hydroxylation was the predominant metabolic pathway in mice (58% of total
      metabolism), whereas in female Syrian hamsters N-oxidation accounted for >50% of
      the metabolites [4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol 27%, 4
      (methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone 22% of total radioactivity].
      Formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was low in both
      species. Total NNK metabolism in male NMRI mice was increased by starvation to
      84.4% and by acetone treatment to 90.0% of the absorbed radioactivity. This
      increase was due to an increase in N-oxidation, whereas the amounts of alpha
      hydroxides and NNAL remained unchanged. In female Syrian hamsters acetone
      treatment had only minimal effects upon the metabolite composition. Acetone
      treated NMRI mice and Syrian hamsters were additionally gavaged with the
      chemopreventive agent phenethylisothiocyanate (PEITC). In mice this treatment
      slightly decreased keto acid formation (0.6-fold, P<0.05), whereas in hamsters
      PEITC had no effect. In summary, intestinal metabolism of NNK in rats, mice and
      hamsters differs in both the extent of total metabolism (hamsters > or = mice >
      rats) and the metabolite composition, indicating major species differences.

PMID- 8640919
TI  - Rat liver epithelial cells express functional cytochrome P450 2E1.
AB  - Rat liver epithelial cells (RLECs) isolated by trypsinization of the livers of
      normal 10 day old rats are largely used in co-culture with primary hepatocytes.
      The aim of the present study was to investigate the expression of
      biotransformation enzyme-encoding genes in three preparations of RLEC lines.
      Although no expression of cytochrome P450 1A1/2 (CYP1A1/2), CYP2B1/2, CYP2C6 or
      CYP3A mRNAs could be detected, we found that all of the different preparations of
      RLECs expressed a high level of CYP2E1 mRNA. We demonstrated the presence of the
      CYP2E1 apoprotein in microsomes of RLECs by immunoblot analyses, together with
      chlorzoxazone 6-hydroxylation, an activity known to be mainly catalyzed by
      CYP2E1. In addition, acetone treatment of these cells resulted in an increase in
      both CYP2E1 apoprotein and chlorzoxazone 6-hydroxylation activity levels.
      Finally, we showed the susceptibility of RLECs to N-methyl formamide- and
      diethylnitrosamine-induced toxicity, suggesting metabolic activation by CYP2E1.
      Thus, RLECs may cooperate with hepatocytes to CYP2E1-mediated metabolism in the
      co-culture model. In addition, transfection experiments with a CYP2E1 promoter
      construct, in which the proximal 539 bp containing the binding site for HNF1alpha
      were inserted upstream of the chloramphenicol acetyl transferase gene,
      demonstrated a strong induction upon co-transfection with an HNF1alpha expression
      plasmid. Thus, RLECs provide a useful tool for studying metabolism and
      cytotoxicity of CYP2E1 substrates in the absence of other expressed CYPs, and for
      analyzing CYP2E1 promoter function.

PMID- 8640920
TI  - Prevention of 20-methylcholanthrene-induced sarcoma by a mistletoe extract,
      Iscador.
AB  - Iscador, an extract from the semi-parasitic plant Viscum album, was found to
      inhibit 20-methylcholanthrene-induced carcinogenesis in mice. Intraperitoneal
      administration of Iscador (1 mg/dose) twice weekly for 15 weeks could completely
      inhibit 20-methylcholanthrene-induced sarcoma in mice and protect these animals
      from tumour-induced death. Iscador was found to be effective even at lowered
      doses. After administration of 0.166, 0.0166 and 0.00166 mg/dose 67, 50 and 17%
      of animals respectively did not develop sarcoma.

PMID- 8640921
TI  - Biotransformation of the cyclopenta-fused polycyclic aromatic hydrocarbon
      benz[j]aceanthrylene in isolated rat liver cell: identification of nine new
      metabolites.
AB  - The biotransformation of benz[j]aceanthrylene (B[j]A) was studied in suspensions
      of hepatocytes isolated from Aroclor 1254-treated or untreated rats. Using
      radiolabeled cofactors and metabolic inhibitors combined with UV, mass and 1H-NMR
      spectroscopy, we have detected five known metabolites and characterized nine new
      metabolites: metabolite 1 was tentatively assigned as B[j]A-1,2-dihydrodiol-8
      sulfate; metabolite 2, B[j]A-1,2,9,10-tetrahydrotetrol; metabolite 3, B[j]A-1,2
      dihydrodiol-10-O-glucuronide; metabolite 4, B[j]A-1-one-8-sulfate; metabolite 5,
      B[j]A-1,2-dihydrodiol-10-sulfate; metabolite 6, the sulfate conjugate of B[j]A
      dihydrodiol-phenol; peak 7 in the chromatogram is a mixture of one glutathione
      conjugate and two sulfate conjugates of a B[j]A-metabolite; metabolite 8, B[j]A
      10-O-glucuronide; metabolite 8', B[j]A-1,2-dihydrodiol; metabolite 9, B[j]A-10
      sulfate; metabolite 9', B[j]A-9,10-dihydrodiol and metabolite 10, B[j]A-9,10
      dihydro-9-hydroxy-10-sulfate. The metabolites identified support the notion that
      epoxidation at the cyclopenta region is an important activation step of B[j]A.
      Furthermore, sulfation appears to play a very important role in the conversion of
      hydroxylated B[j]A metabolites into more polar excretable products.

PMID- 8640922
TI  - Genetic analysis of two rat acetyltransferases.
AB  - Single copies of two closely related acetyltransferase genes were detected in
      Sprague-Dawley derived rat DNA by Southern blot analysis using gene-specific
      hybridization probes for the 3' end of the acetyltransferase coding regions.
      Sequence analysis of the two acetyltransferase genes showed that both had
      intronless, 870 bp coding regions and coded for 290 amino acid protein sequences
      that were approximately 85% homologous to one another. The calculated molecular
      weights were 33.4 and 33.9 kDa and the calculated isoelectric points 4.98 and
      5.21 for AT1 and AT2, respectively. The inferred amino acid sequence of both the
      genes and cDNAs indicated that both rat acetyltransferases have cysteines at
      positions 44, 68 and 223 which have been conserved in all known vertebrate
      acetyltransferases. Transcripts for both AT1 and AT2 were detected in brain,
      colon, esophagus, heart, kidney, liver, lung, mammary gland, dorsal prostate,
      ventral prostate, salivary gland, seminal vesicles, small intestine, spleen,
      stomach, testes, urinary bladder and uterus of Sprague-Dawley rats by both
      Northern blot and RT-PCR analysis. A third gene with >80% sequence homology to
      codons 118-158 of acetyltransferase was also detected.

PMID- 8640923
TI  - The relationship between N-nitrosodimethylamine metabolism and DNA methylation in
      isolated rat hepatocytes.
AB  - The metabolism of N-nitrosodimethylamine (NDMA) and its methylation of DNA were
      simultaneously determined in hepatocytes isolated from untreated and saline- and
      pyrazole-treated male Sprague-Dawley rats. Metabolism of NDMA was directly
      measured by monitoring its disappearance via gas chromatography coupled with a
      sensitive and specific detector for N-nitrosamines. DNA methylation was
      determined in the same cells employed in the metabolism studies using a
      monoclonal antibody-based competitive ELISA procedure specific for O6
      methyldeoxyguanosine (6-Me-dG). The apparent Km and Vmax for NDMA metabolism are
      61 microM and 56 pmol/min/10(6) cells respectively for hepatocytes isolated from
      untreated rats. It was found that the addition of pyrazole to the in vitro
      hepatocyte incubations caused a dose-dependent inhibition of both metabolism and
      DNA methylation. However, when DNA methylation is expressed as a function of NDMA
      metabolized, there is no significant difference between hepatocyte incubations
      without or with pyrazole, with an average value of 79 nmol 6-Me-dG/mol dG/nmol
      NDMA metabolized. Based on the pyrazole inhibition studies, cytochrome P450IIE1
      is responsible for at least 60% of the DNA methylation in rat hepatocytes. In
      pyrazole-pretreated rats there was an inconsistent increase in NDMA metabolism,
      but when metabolism was elevated so was DNA methylation. In contrast, microsomes
      isolated from pyrazole-pretreated rats consistently showed elevated metabolism of
      NDMA. Based on the simultaneous determination of adduct levels and metabolism,
      there is approximately 1 6-Me-dG adduct formed/133 000 NDMA molecules metabolized
      in the uninduced hepatocytes.

PMID- 8640924
TI  - O6-methylguanine levels and histopathological changes in the rat esophagus and
      liver following single and repeated administration of N-nitrosomethylbenzylamine.
AB  - In this study we investigated the time course of O6-methylguanine (O6-meGua)
      levels and concomitant histopathological effects in the rat esophagus and liver
      following single and repeated s.c. administration of the esophagus-specific
      carcinogen N-nitrosomethylbenzylamine (NMBA). The primary purpose of this study
      was to determine if differences in the induction and/or persistence of O6-meGua
      might account for differences in the tumorigenicity of NMBA observed with
      treatment regimens of 0.5 mg/kg/dose, 3 doses/week for 5 weeks (a proven
      tumorigenic regimen) and 1.67 mg/kg/dose, 3 doses/week for 2 weeks (an
      essentially non-tumorigenic regimen). Results of the single dose experiment
      indicated that enzymatic activation of NMBA in the rat esophagus was not dose
      limited, at least at doses up to and including 5.0 mg/kg. Results of the repeated
      dose experiment demonstrated that the non-tumorigenic NMBA regimen produced
      significantly higher levels of esophageal O6-meGua compared with the tumorigenic
      NMBA regimen. During the 2 week treatment period of the non-tumorigenic regimen
      esophageal O6-meGua levels decreased progressively, but remained significantly
      higher than in the tumorigenic regimen. In contrast, the relatively lower O6
      meGua levels of the tumorigenic regimen remained essentially unchanged during the
      course of treatment. At 72 h following conclusion of dosing no O6-meGua was
      detected in the esophagi of rats treated with either regimen. Microscopic
      examinations revealed that the non-tumorigenic NMBA regimen produced a marked
      cytotoxic effect on the esophageal epithelium, while microscopic esophageal
      changes observed with the tumorigenic regimen were generally less severe. In the
      liver O6-meGua was detected in only a few rats and no remarkable microscopic
      pathology was observed in this organ. Together these findings indicate that: (i)
      abbreviated NMBA treatment induces tumors in the rat esophagus only at levels
      that induce DNA damage without causing extensive cytotoxicity; (ii) the lack of
      NMBA tumorigenicity in the rat liver may be due, at least in part, to the rapid
      and efficient repair of O6-meGua adducts, coupled with the lack of necrosis and
      compensatory cell division in this organ.

PMID- 8640925
TI  - Characterization of the antitumor-promoting activity of camptothecin in SENCAR
      mouse skin.
AB  - (+)-Camptothecin (CPT), a topoisomerase I inhibitor specifically toxic toward S
      phase cells, was tested topically for its ability to inhibit skin tumor
      initiation by 7,12-dimethylbenz[a]anthracene (DMBA) and complete tumor promotion
      by 12-0-tetradecanoylphorbol-13-acetate (TPA) in SENCAR mice. Even though CPT
      does not prevent the covalent binding of a subcarcinogenic dose of DMBA to DNA,
      it enhances early inhibition of DNA synthesis caused by this initiator and may
      decrease the essential role of DNA replication in tumor initiation. Indeed, CPT
      (400 nmol) applied 4 h before or 1 h after DMBA inhibits the yield, but not the
      incidence, of skin tumors initiated by this compound. Moreover, because it
      inhibits TPA-stimulated DNA synthesis at 16 h when applied 12 h after the tumor
      promoter, CPT partially decreases tumor initiation when DMBA is applied 16 h
      after a TPA pretreatment. CPT (400 nmol) applied 1 h before or 4, 12, 24 or 48 h
      after each promotion treatment with TPA remarkably inhibits the incidence and
      yield of skin tumors promoted by this agent. CPT delays and inhibits promotion of
      skin tumors the most when applied 12-24 h after each TPA treatment, at times when
      it can block the stimulation of DNA synthesis that follows the period of early
      inhibition caused by TPA. The ability of post-treatments with 25, 100 and 400
      nmol CPT to inhibit skin tumor promotion is dose dependent. In the TPA (stage I)
      mezerein (stage 2) protocol CPT (400 nmol) post-treatment inhibits both the first
      and second stages of tumor promotion, related to its ability to decrease the DNA
      and ornithine decarboxylase responses required for stages 1 and 2 respectively.
      The classic model of multistage skin carcinogenesis, therefore, may be valuable
      to determine if novel CPT analogs are more effective than their parent compound
      at inhibiting tumor initiation, promotion and progression.

PMID- 8640926
TI  - Tamoxifen does not form detectable DNA adducts in white blood cells of breast
      cancer patients.
AB  - DNA from white blood cells of seven women receiving tamoxifen as adjuvant therapy
      for breast cancer and of three women who served as healthy controls was analysed
      for the presence of tamoxifen-DNA adducts using 32P-postlabelling with a limit of
      detection of 8 adducts/10(10) nucleotides. No postlabelled adducts with the
      chromatographic properties of known tamoxifen-DNA adducts were detected in any of
      the samples. It is concluded that at therapeutic levels of exposure there is no
      significant formation of DNA adducts by tamoxifen or its metabolites in
      circulating white blood cells.

PMID- 8640927
TI  - Comparative study of DNA repair induced by cyproterone acetate, chlormadinone
      acetate and megestrol acetate in primary cultures of human and rat hepatocytes.
AB  - Cyproterone acetate (CPA), a synthetic progestin recently found to induce
      genotoxic effects in hepatocytes from female rats and from humans of both
      genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol
      acetate (MGA), have been compared for their capacity to induce DNA repair
      synthesis as measured by quantitative autoradiography. Exposure of primary human
      hepatocytes for 20 h to concentrations of CPA, CMA and MGA ranging from 2 to 50
      microM induced positive responses in cultures from donors of both genders and the
      amounts of DNA repair elicited by the three progestins were similar. Under the
      same experimental conditions substantial differences were observed in the amounts
      of DNA repair elicited by the three progestins in primary hepatocytes from female
      rats, their potency decreasing in the following order CPA > CMA > MGA, and the
      three compounds failed to induce DNA repair in hepatocytes from male rats. These
      results, which agree with previous findings, suggest that for these sex steroids
      extrapolation to humans of results obtained in rats might be questionable.

PMID- 8640928
TI  - Differential regulation of mdr genes in response to 2-acetylaminofluorene
      treatment in cultured rat and human hepatocytes.
AB  - Expression of P-glycoprotein (P-gp), the mdr gene product, was investigated in
      primary cultures of rat and human hepatocytes exposed to 2-acetylaminofluorene (2
      AAF). Increased levels of mdr1 mRNAs were evident in 2-AAF-treated rat
      hepatocytes by Northern blot analysis using rat mdr gene-specific probes, while
      transcripts of the mdr2 and mdr3 genes were decreased and unaffected
      respectively. Rat hepatocytes exposed to 2-AAF were also found to accumulate
      doxorubicin, an anticancer drug known to be transported by P-gp, poorly, thereby
      demonstrating that 2-AAF-mediated mdr1 induction resulted in increased P-gp
      activity. In contrast to their rat counterparts, human hepatocytes obtained from
      10 individuals exhibited no change in both MDR1 and MDR2 mRNA levels, as well as
      in doxorubicin intracellular retention, in response to 2-AAF treatment, while
      cytochromes P-450 CYP1A1 and CYP1A2 were induced in both human and rat hepatocyte
      cultures. These data provide strong evidence that regulation of expression of mdr
      genes in liver cells in response to carcinogens such as 2-AAF is gene- and
      species-specific.

PMID- 8640929
TI  - The relationship between p53 status, DNA repair and chromatid aberration
      induction in G2 mouse embryo fibroblast cells treated with bleomycin.
AB  - The involvement of p53 in the formation of chromosome aberrations was assessed by
      analyzing bleomycin-induced, chromatid-type aberrations in G2 phase fibroblasts
      derived from embryos from wild-type and p53 knock-out mice. Cells that were p53+/
      or p53-/- were more sensitive to the induction of aberrations than the p53+/+
      cells, particularly at concentrations of 7.5 and 10.0 microg/ml. The p53
      deficient cells also showed an overdispersed distribution of bleomycin-induced
      chromatid aberrations, a greater amount of overall genomic instability and a
      possible loss of a cell death pathway. These data are interpreted as indicating a
      role for p53 in DNA repair in the G2 phase, with a loss of p53 leading to an
      increased frequency of deletions (incomplete repair) and interchanges
      (misrepair). The specific role remains to be elucidated. The mitotic index
      decreased with increasing bleomycin concentration to a similar extent in all
      three cell lines, indicating that the loss of a G2 checkpoint in p53-/- and p53+/
      cells was not an explanation for the increased sensitivities in these cells
      compared with the p53+/+.

PMID- 8640930
TI  - Characterization of an N6-oxopropenyl-2'-deoxyadenosine adduct in malondialdehyde
      modified DNA using liquid chromatography/electrospray ionization tandem mass
      spectrometry.
AB  - Malondialdehyde (MDA), a product of lipid peroxidation, causes mutations in
      bacterial and mammalian cells and cancer in rats. MDA reacts with
      deoxynucleosides in vitro and the monomeric adduct of MDA with deoxyguanosine
      (M1G-dR) is the major adduct. M1G-dR has been detected in rat and human liver.
      Random mutagenesis studies with MDA-modified DNA and recent 32P-postlabeling
      studies indicate that in addition to M1G-dR, adducts to deoxyadenosine may also
      be formed. We have utilized liquid chromatography coupled with electrospray
      ionization tandem mass spectrometry to characterize an N6-oxopropenyl-2'
      deoxyadenosine adduct (M1A-dR) in calf DNA modified with MDA.

PMID- 8640931
TI  - Nitric oxide synthase activity and expression in human colorectal cancer.
AB  - The present study investigated the activity and cellular localization of
      individual isoenzymes of nitric oxide synthase (NOS) using immunohistochemistry
      and the [3H]citrulline assay in normal colorectal epithelia and neoplastic
      tissue. Intracellular localization of isoenzymes of NOS was detectable by
      immunohistochemistry in normal epithelial cells. Colorectal adenocarcinomas had a
      marked reduction of both Inducible NOS (iNOS) and constitutive NOS (cNOS)
      expression. Expression of iNOS was completely absent in tumour cells (P <
      0.0001), while cNOS was reduced in 66% and absent in 34% of tumours studied when
      compared with controls (P < 0.0001). NOS activity using the [3H]citrulline assay
      was detectable in normal epithelium and was found to be reduced in tumours (P <
      0.001). In addition, colonic adenomas had reduced INOS but not cNOS expression
      when compared with controls (P < 0.003 and P = 0.39 respectively). We conclude
      that NOS is present and active within the epithelium of the normal colon, with
      localization of the individual isoenzymes. Furthermore, there was loss of
      activity and expression of individual isoenzymes in colonic neoplasms.

PMID- 8640932
TI  - Preferential targeting of oxidative base damage to internucleosomal DNA.
AB  - The structure of nuclear chromatin may limit the accessibility of carcinogenic
      agents to DNA. In the case of oxidative DNA strand cleavage mediated by the
      physiologically relevant iron chelate, iron-ADP, histone-associated nucleosomal
      DNA is protected while internucleosomal DNA is susceptible to damage. We now find
      that the distribution of iron-ADP-generated 8-hydroxydeoxyguanosine, a
      potentially mutagenic oxidative base change, shows relative targeting to
      internucleosomal sites (3.5-fold increased oxidative modification of
      internucleosomal compared with nucleosomal DNA as the minimal degree of
      enrichment). In contrast, iron-EDTA, which generates hydroxyl radical in the
      'fluid phase', does not target internucleosomal DNA. Thus, physiologic iron
      chelates may promote site-specific damage and thereby be relevant to mechanisms
      of iron-dependent oxidative mutagenesis and carcinogenesis.

PMID- 8640933
TI  - Kinds of mutations induced by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)
      furanone (MX) in the hprt gene of Chinese hamster ovary cells.
AB  - The kinds of mutations induced by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)
      furanone (MX) in the protein coding region of the hprt gene of Chinese hamster
      ovary (CHO) cells were determined by direct sequencing of polymerase chain
      reaction (PCR)-amplified cDNA. Primary mutations were found in 15 of 19 of the
      mutants: 11 were G:C-->T:A transversions, two were A:T-->T:A transversions and
      two were deletions of single G:C base pairs (-1 frameshifts). The remaining four
      mutants had large alterations in the cDNA that were explained by mRNA splicing
      errors. A group of control mutants had more diverse hprt cDNA alterations than MX
      induced mutants. Transversions yielding an A:T base pair were the predominant
      type of MX-induced mutations, in agreement with previous findings in bacteria.
      This specificity may be explained by the 'A rule', that DNA polymerases
      preferentially insert adenine nucleotides opposite non-instructional lesions.

PMID- 8640934
TI  - Involvement of Escherichia coli exonuclease III and endonuclease IV in the repair
      of singlet oxygen-induced DNA damage.
AB  - Singlet molecular oxygen (1O2) has been implicated in several biological
      processes that may lead to genetic damage. The relevance of various repair
      pathways in plasmid inactivation mediated by 1O2 was investigated. Plasmid
      treated with 1O2, chemically generated, was transfected into Escherichia coli
      strains deficient in genes implicated in the DNA repair of oxidative damage. The
      ability to transform bacteria is significantly reduced in the double mutant
      xth,nfo, deficient in both exonuclease III and endonuclease IV, although it was
      similar to wild-type cells in single mutants. The products of these two genes are
      able to cleave DNA damaged by 1O2 and to remove DNA polymerization blocks from 3'
      termini generated either directly by 1O2 treatment or after the action of the
      formamidopyrimidine-DNA-N-glycosylase (Fpg protein). The results indicate that
      the exonuclease III and endonuclease IV participate in the excision of lethal
      lesions induced in DNA by 1O2.

PMID- 8640935
TI  - The role of adduct site-specific mutagenesis in understanding how carcinogen-DNA
      adducts cause mutations: perspective, prospects and problems.
AB  - Usually, a particular mutagen/carcinogen forms adducts at many sites in DNA,
      making it impossible to determine which type of adduct causes which mutation and
      why. Adduct site-specific mutagenesis studies, in which a single adduct is built
      into a vector, can be used to overcome this problem. The adduct can be situated
      in double-stranded DNA, single-stranded DNA or in a single-stranded gap, and the
      benefit and concerns associated with each are addressed. An adduct site-specific
      study is most useful when it is compared to a mutagenesis study with its
      corresponding mutagen/carcinogen. Mutations induced by a particular
      mutagen/carcinogen can be influenced by DNA sequence context, mutagen/carcinogen
      dose (and other changes in conditions), level of SOS induction, cell type and
      other factors. Thus, it is important to match the conditions of the adduct study
      versus the mutagen/carcinogen study as closely as possible. DNA sequence context
      can profoundly affect the quantitative and qualitative pattern of adduct
      mutagenesis, which is addressed. In vitro studies with DNA polymerases,
      frameshift mutagenesis and semi-targeted mutagenesis, whereby a mutation is
      induced near but not at the site of the adduct, are each discussed. Finally, the
      relationship between structural studies on adducts and mutagenesis is considered.

PMID- 8640936
TI  - Exposure of DMBA-treated female rats in a 50-Hz, 50 microTesla magnetic field:
      effects on mammary tumor growth, melatonin levels, and T lymphocyte activation.
AB  - There is growing public concern about the possible health risks, particularly
      increased cancer risks of exposure to magnetic fields (MF) associated with power
      distribution systems. Recently, we have started a series of animal studies to
      investigate this issue, using the DMBA (7,12-dimethylbenz[a]anthracene) model of
      breast cancer in female rats. In the present study, female rats were chronically
      exposed to a 50-Hz, 50 microTesla (microT) MF with or without DMBA treatment.
      Because alterations in circulating levels of the pineal hormone melatonin and
      impaired immune system functions have been involved in breast cancer growth, and
      both melatonin and immune system are thought to be targets for MF-effects, serum
      melatonin and the proliferative capacity of splenic lymphocytes were determined
      in MF-exposed and sham-exposed rats. For this purpose, 216 female Sprague-Dawley
      rats were divided into four groups. Two of the groups (with 99 animals each)
      received oral applications of DMBA and were either sham-exposed or exposed in a
      50-Hz, 50 microT MF for 24 h/day 7 days/week for a period of 91 days. The other
      two groups (9 animals each) were either sham-exposed or MF-exposed without DMBA
      treatment. The exposure chambers and all other environmental factors were
      identical for MF-exposed and sham-exposed animals. The DMBA-treated animals were
      palpated once weekly to assess the development of mammary tumors. At the end of
      the three-month period of MF exposure, the number and size of mammary tumors was
      determined by autopsy. In controls, DMBA induced tumors in approximately 55% of
      the animals within the 3 month period of sham-exposure. Already 8 weeks after
      DMBA application, the MF-exposed group exhibited significantly more tumors than
      sham-exposed animals. At time of autopsy, significantly more MF-exposed DMBA
      treated rats exhibited macroscopically visible mammary tumors than DMBA-treated
      controls, thus indicating that MF exposure enhances the development and growth of
      cancers in this model. Comparison of the data from 50 microT with recent data
      from other flux densities indicated that long-term MF exposure of DMBA-treated
      rats increases the incidence of palpable and/or macroscopically visible mammary
      tumors in a highly dose-related fashion. Determination of nocturnal serum
      melatonin after 9 and 12 weeks of exposure at 50 microT did not yield significant
      differences between MF-exposed rats and sham-exposed controls, whereas a marked
      suppression of T cell proliferative capacity was seen in MF exposed rats. The
      data add further evidence to the hypothesis that hormone-dependent tissues such
      as breast might be particularly sensitive to MF-effects and indicate that immune
      system depression is involved in the increased breast cancer growth observed in
      MF exposed rats.

PMID- 8640937
TI  - Immunohistochemical quantitation of 4-aminobiphenyl-DNA adducts and p53 nuclear
      overexpression in T1 bladder cancer of smokers and nonsmokers.
AB  - An immunoperoxidase method, using a monoclonal antibody which recognizes 4
      aminobiphenyl (4-ABP)-DNA adducts, was developed for the detection and
      quantitation of DNA damage in bladder tissue and applied to stored paraffin
      blocks of transurethral resection specimens of 46 patients with T1 bladder
      cancer. Mean relative staining intensity for 4-ABP-DNA adducts was significantly
      higher in current smokers (275 +/- 81, n = 24) compared to nonsmokers (113 +/-
      71, n = 22) (P < 0.0001). There was a linear relationship between mean levels of
      relative staining and number of cigarettes smoked with lower levels in the 1-19
      cig/day group (205 +/- 30, n = 5), compared to the 20-40 (289 +/- 40, n = 7) and
      the >40 cig/day group (351 +/- 57, n = 3)(P < 0.001). Nuclear overexpression of
      p53, analyzed by immunoperoxidase staining, was observed in 27 (59%) of the 45
      stage T1 tumors analyzed. There was a significant correlation between p53
      overexpression and recurrence of disease (odds ratio = 12.3, P < 0.01). Nuclear
      staining of p53 was also correlated with smoking status, cig/day and 4-ABP-DNA
      adducts. This work demonstrates that the immunohistochemical method has
      sufficient sensitivity for detection of 4-ABP-DNA adducts in human bladder
      samples. The method has several advantages including small sample size, the
      possibility of retrospective analysis of stored paraffin blocks, the ability to
      analyze binding in specific cell types, and a relatively low cost.

PMID- 8640938
TI  - Sensitive detection of 8-hydroxy-2'deoxyguanosine in DNA by 32P-postlabeling
      assay and the basal levels in rat tissues.
AB  - Oxidative damage from reactive oxygen species including free radicals has been
      considered to play a vital role in many degenerative diseases and measurement of
      8-hydroxy-2'-deoxyguanosine (Oh8dG) in tissue DNA has been used as a benchmark
      for oxidative DNA damage. We report here an ultrasensitive 32P-postlabeling
      method to detect and quantitate Oh8dG in DNA and have determined basal levels of
      Oh8dG in rat tissues. The method is comprised of DNA digestion to 3'
      monophosphates, 5'-32P-labeling, conversion to 5'-monophosphates and separation
      by a 2-directional PEI-cellulose TLC (D1 = 1.5 M formic acid; and D2 = 0.6 M
      ammonium formate, pH 6.0). Under these conditions, all radioactive contaminants
      were either removed from the chromatogram (normal nucleotides and 32Pi) or
      remained at the origin (ATP and other contaminants), while Oh8dG migrated in the
      middle of the chromatogram. Calf thymus DNA incubated with ascorbic acid and H202
      produced predominantly one spot under the chromatography conditions used; a
      chromatographically identical spot was also detected in untreated DNA, but at a
      much lower level (125 +/- 40 Oh8dG/10(6) nucleotides). A chromatographically
      identical spot was also found in dGp incubated with ascorbic acid and H202, but
      not with dAp, dCp or dTp. When applied to rat tissue DNA, the assay readily
      permitted detection of Oh8dG in the liver, lung, kidney, heart, brain, spleen,
      intestines and mammary epithelial cells of 3-month old female Sprague-Dawley
      rats. The tissue Oh8dG levels were found in the range of 87 +/- 29 to 133 +/- 49
      per 10(6) nucleotides, with liver and heart being the highest and kidney and
      brain the lowest. These values are in the vicinity to those found by gas
      chromatography/mass spectrometry but 10-50 times higher than those reported by
      HPLC-electrochemical detection. Because of its high sensitivity (<1 Oh8dG per
      10(5-6) nucleotides) to detect Oh8dG using nanogram quantity of DNA digest, the
      32P-postlabeling method is likely to be valuable in quantitating Oh8dG in human
      tissue biopsies.

PMID- 8640939
TI  - p-Quinone methides are the major decomposition products of catechol estrogen o
      quinones.
AB  - The mechanism of catechol estrogen-induced carcinogenesis could involve
      alkylation of critical cellular macromolecules by electrophilic quinoids. The o
      quinones formed from peroxidase/P450-catalyzed oxidation of catechol estrogens
      have previously been implicated as the ultimate carcinogens. In the present
      study, we have shown that additional reactive intermediates can be produced from
      isomerization of the catechol estrogen o-quinones to highly electrophilic p
      quinone methides (QMs). The o-quinones of the catechol estrogens were incubated
      at 37 degrees C (pH 7.4) in the absence of GSH. Aliquots were removed at various
      times and combined with GSH. The GSH adducts were isolated and characterized by
      1H-NMR, UV, and electrospray mass spectrometry. The o-quinone of 2-hydroxyestrone
      isomerized to two QMs; a QM stabilized by one alkyl substituent in the B ring, 2
      OHE-QM1 (3-hydroxy-1-(10),3(4),5(6)-oestratrien-2,17-dione) and one having two
      alkyl substituents on the methylene group in the C ring, 2-OHE-QM2 (2-hydroxy
      1(2),4(5),9(10)-oestratrien-3,17-dione). Only one QM was observed from the o
      quinone of 4-hydroxyestrone, 4-OHE-QM2 (4-hydroxy-1(2),4(5),9(10)- oestratrien
      3,17-dione) which is analogous to the C ring analog (2-OHE-QM2) from the o
      quinone of 2-hydroxyestrone. The GSH adduct of 4-OHE-QM2 decomposed at pH 7.4 to
      give 9(11)-dehydro-4-hydroxyestrone as the major product. Finally, the
      disappearance of the estrogen o-quinone GSH adducts correlated with the formation
      of the GSH conjugates of the QMs. These data suggest that in cells with low
      levels of GSH, the formation of these potent electrophiles represents the major
      reaction pathway for estrogen o-quinones. The implications of the o-quinone/QM
      pathway for the in vivo effects of catechol estrogens are not known; however,
      given the direct link between excessive exposure to endogenous estrogens and the
      enhanced risk of breast cancer, the potential for formation of additional
      reactive intermediates needs to be explored.

PMID- 8640940
TI  - Expression of transforming growth factor alpha/epidermal growth factor receptor,
      hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast
      growth factor receptors during hepatocarcinogenesis.
AB  - It is widely believed that abnormal production of polypeptide growth factors,
      together with other molecular alterations, play an important role in neoplastic
      development. Transforming growth factor alpha (TGFalpha), hepatocyte growth
      factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major
      growth factors that contribute to liver regeneration occurring via both
      hepatocyte replication and oval cell proliferation. It is not clear, however,
      whether and to what extent these growth factors are also involved in
      hepatocarcinogenesis. In the present study, the gene expression of TGFalpha, HGF
      and aFGF and their corresponding receptors was examined by Northern blotting and
      in situ hybridization during hepatocarcinogenesis induced by the Solt-Farber
      protocol. All three growth factor/receptor systems, TGFalpha/epidermal growth
      factor receptor (EGFR), HGF/c-met and aFGF/FGF receptors (flg and bek) were
      significantly elevated at early time points when oval cells were proliferating.
      Their respective expression decreased after 1 month and remained at a low level
      until the development of liver tumors. In all hepatocellular carcinomas (HCC)
      examined, the transcripts of TGFalpha and aFGF were highly expressed, while those
      of HGF were low. With regard to the receptor expression in the tumors, EGFR was
      present at varying levels, c-met was expressed at higher levels and flg increased
      significantly, whereas bek remained at low levels. These data suggest that
      TGFalpha and aFGF are the major growth factors involved in the progression of
      HCC, and that the signal of aFGF is mainly transduced by the receptor flg in HCC.
      Furthermore, HCC cells were phenotypically very similar to oval cells with regard
      to the gene expression of growth factor/receptor systems. These results, along
      with the finding that all the HCC cells are positive for the oval cell antigen
      OV6, and that cytokeratin 19 is heavily expressed in both tumor and oval cells,
      strongly suggest that at least some of the HCC induced by the Solt-Farber
      protocol may be derived from oval cells.

PMID- 8640941
TI  - Phosphorylation of T antigen and p53 in carcinogen-treated SV40-transformed
      Chinese hamster cells.
AB  - SV40-transformed Chinese hamster C0631 cells pretreated with N-methyl-N'-nitro-N
      nitrosoguanidine (MNNG) display SV40 DNA amplification. This study shows that
      following MNNG treatment elevated T antigen synthesis and a 4.5-fold reduction in
      the extent of its phosphorylation occurred in both pulse-labeled and steady-state
      labeled cells. The decrease in phosphorylation was found to be inversely related
      to carcinogen concentration, i.e. an augmented carcinogen concentration brought
      about a gradual reduction in T antigen phosphorylation and elevated SV40 DNA
      amplification. Although the majority of phosphorylation sites on T antigen
      derived from carcinogen-treated cells were underexpressed, as demonstrated by two
      dimensional phosphopeptide mapping, peptide 12 bearing phosphoThrl24, which is
      known to be essential for DNA replication, was overexpressed. Carcinogen-treated
      cells showed no changes in p53 synthesis, but it was phosphorylated to a lesser
      degree. Two-dimensional mapping revealed that the predicted N-terminal major
      phosphopeptide of p53 extracted from C0631 cells exhibited a lower
      chromatographic mobility than p53 phosphopeptides from SV40-infected monkey BSC-1
      cells. In treated C0631 cells the Rf value of this phosphopeptide was higher than
      that of control p53. This finding could be ascribed to the failure to
      phosphorylate the corresponding amino acid residue in this peptide. Moreover,
      treatment did not affect the halflife of either T antigen or p53 proteins, but
      caused a dramatic rise in the expression of small t antigen, presumably due to
      amplification of SV40 DNA.

PMID- 8640942
TI  - Dose dependence of phenobarbital promotion of preneoplastic hepatic lesions in
      F344 rats and B6C3F1 mice: effects on DNA synthesis and apoptosis.
AB  - Phenobarbital (PB), a non-genotoxic hepatocarcinogen in rodents, has been studied
      extensively but its mechanism of carcinogenic action is unclear. PB appears to
      function as a tumor promoter by selectively inducing the growth of preneoplastic
      hepatocytes. In the present study, the comparative effects of PB at tumor
      promoting and non-promoting doses were examined in male B6C3F1 mice and male F344
      rats. In addition, the mechanism by which PB produced the selective induction of
      preneoplastic cell growth (increased DNA synthesis/cell proliferation and/or
      decreased apoptosis) was investigated. Preneoplastic focal lesions were produced
      using diethylnitrosamine (DEN). After the lesions were histologically apparent,
      mice and rats were fed PB (10, 100, or 500 mg/kg NIH-07 diet) or control diet and
      sampled after 7, 30 and 60 days of treatment In both mice and rats, 100 and 500
      mg PB/kg increased the number and the relative volume of focal lesions. In rats
      and mice, 10 mg PB/kg did not enhance focal lesion growth. The preneoplastic
      lesions that clonally expanded due to phenobarbital treatment were predominantly
      eosinophilic in appearance. In addition, DNA synthesis in focal hepatocytes was
      significantly increased in the 100 and 500 mg PB/kg diet. In PB-treated mice and
      rats, there also was a significant decrease in the rates of apoptosis in focal
      hepatocytes. Therefore, our data showed that PB at doses of 100 and 500 mg/kg
      diet promoted focal hepatic lesion growth both by increasing DNA synthesis and
      cell proliferation and by decreasing the rate of apoptosis.

PMID- 8640943
TI  - Regression and progression characteristics of papillomas induced by chrysarobin
      in SENCAR mice.
AB  - The present study was designed to test the effects of a free radical generating
      tumor promoter, chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone), on the growth
      and progression of papillomas generated in the skin of SENCAR mice. In the first
      set of experiments, papillomas were generated by initiation with 6.4 microg of
      7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with once-weekly
      applications of 52.8 microg chrysarobin for 10 weeks. The fate of individual
      papillomas was then monitored for a 20 week interval following cessation of
      promoter treatment. Five weeks after the cessation of chrysarobin treatment, the
      papilloma response reached a maximum of 13.2 papillomas/mouse. By the end of the
      20 week interval 19% and 18% of the papillomas had regressed or coalesced
      respectively. A three-stage treatment protocol was also utilized to test the
      ability of chrysarobin to enhance the progression of pre-existing papillomas to
      squamous cell carcinomas (SCCs). In stage I, mice were initiated with 0.5 microg
      of DMBA. In stage II, mice were promoted with twice-weekly applications of 1 or 2
      microg of 12-0-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. Then, in stage
      III, mice were treated with acetone, TPA (1 or 2 microg), chrysarobin (52.8
      microg) or benzoyl peroxide (BzPo; 20 mg) for the next 45 weeks. The mean number
      of papillomas per mouse at plateau was very similar for all groups. The carcinoma
      incidence was also similar for all groups regardless of the treatment protocol
      used, as was the mean number of carcinomas per mouse. The ratio of papillomas
      that converted to SCCs in mice treated with chrysarobin during stage III was not
      significantly different from the acetone controls or any of the other treatment
      groups (P > 0.05, Kruskal-Wallis analysis). In addition, BzPo did not enhance the
      progression of papillomas to SCCs under the current experimental conditions.
      Collectively, the results indicate that papillomas promoted by chrysarobin have
      growth properties similar to those promoted by TPA under similar experimental
      conditions. Furthermore, despite its ability to generate free radical
      intermediates, chrysarobin does not enhance the malignant progression of pre
      existing papillomas induced by TPA treatment.

PMID- 8640944
TI  - Analysis of differentiation-associated proteins in rat bladder carcinogenesis.
AB  - Uroplakins are the major integral membrane proteins synthesized in terminally
      differentiated, superficial urothelial cells. Alteration of cell differentiation
      during rat urinary bladder carcinogenesis was analyzed immunohistochemically for
      the expression of uroplakins. Expression of uroplakins was compared in N-[4-(5
      nitro-2-furyl)-2-thiazolyl]-formamide (FANFT)-, uracil-, sodium saccharin- or
      sodium ascorbate-induced urothelial simple hyperplasia, papillary-nodular
      hyperplasia, papilloma and carcinoma. In controls, uroplakins were located only
      in superficial cells, especially the luminal surface membrane. In FANFT-induced
      hyperplasia, including simple hyperplasia, intermediate cells also stained and
      the staining pattern was disorderly and intermittent. In uracil-induced simple
      hyperplasia, intermediate cells were stained but in an orderly fashion. In sodium
      saccharin- or sodium ascorbate-induced simple hyperplasia, superficial cells were
      swollen but alterations were not observed in the staining pattern. In carcinoma
      induced by FANFT and uracil, uroplakin expression was very disorderly and focal,
      usually with no expression on surface cells. It appears that disorderly
      differentiation is an index of bladder malignancy and is an early event in FANFT
      induced lesions but a late event in uracil-, sodium saccharin- and sodium
      ascorbate-induced lesions.

PMID- 8640945
TI  - The antitumor drug fostriecin induces vimentin hyperphosphorylation and
      intermediate filament reorganization.
AB  - Fostriecin is an antitumor drug in phase I clinical trials. We have recently
      shown that it is a potent inhibitor of protein phosphatases 1 and 2A in vitro, a
      property not previously described for an antitumor drug. We have investigated its
      effects on protein phosphorylation in baby hamster kidney cells. Fostriecin
      strongly stimulated the phosphorylation of a single protein, which we identified
      as the intermediate filament vimentin. Fostriecin also caused rounding of the
      cells and a reorganization of the vimentin filaments. These effects are similar
      to those of the known protein phosphatase 1 and 2A inhibitors okadaic acid and
      calyculin A, which are also tumor promoters. Fostriecin induced vimentin
      hyperphosphorylation mostly at two sites, which were sensitive to staurosporine
      and could be phosphorylated by protein kinase C in vitro. Fostriecin-induced
      vimentin hyperphosphorylation also occurred in cells that lack p34cdc2 kinase
      activity. These results suggest that protein kinase C plays a direct or indirect
      role in vimentin hyperphosphorylation during exposure to fostriecin. The results
      also provide strong evidence that fostriecin inhibits protein phosphatases 1 and
      2A in vivo and raise the possibility that it may have tumor-promoting activity.

PMID- 8640946
TI  - Expression of growth factors and growth factor receptors in the liver of
      C57BL/10J mice following administration of phenobarbitone.
AB  - Liver enlargement is a common feature of non-genotoxic rodent hepatocarcinogens
      administered at high doses. In the present study, the expression of growth
      factors and growth factor receptors was investigated in the C57BL/1OJ mouse
      during liver enlargement induced by the non-genotoxic rodent hepatocarcinogen,
      sodium phenobarbitone (PB). Male mice were dosed 0-2500 p.p.m. PB in the diet for
      1, 4 and 13 weeks. There was a dose and time dependent increase in liver weight.
      Hepatocyte replication, assessed by incorporation of bromodeoxyuridine, was
      increased in a dose-dependent manner at week 1 only (18-fold increase at 2000
      p.p.m.) and was predominantly localized in the centrilobular region. At week 1,
      PB (2500 p.p.m.) caused transient increases in transforming growth factor alpha
      (TGFalpha) and epidermal growth factor receptor (EGFR) and decreases in
      transforming growth factor beta1 (TGF-beta1) and mannose-6-phosphate receptor
      (M6PR) in centrilobular hepatocytes which correlated with the replication in this
      region. At week 1, there was an increase in both hepatocyte growth factor (HGF)
      and hepatocyte growth factor receptor (HGFR) which colocalized in centrilobular
      hepatocytes; in some mice or periportal hepatocytes in other mice. After 13
      weeks, HGF and HGFR were localized in the cytoplasm of centrilobular hepatocytes
      of all mice but exhibited a differential intracellular distribution across the
      lobule. At 2500 p.p.m. PB, EGFR and HGFR mRNA were essentially unchanged over the
      13 week dosing period whilst M6PR mRNA was increased 2- to 4-fold. At 2500 p.p.m.
      PB, EGFR protein levels from immunoblots showed a consistent decrease over the 13
      weeks whilst M6PR and HGFR protein levels were essentially unchanged. The protein
      level and mRNA data for EGFR suggest post-transcriptional modification. Thus,
      phenobarbitone caused transient replication of hepatocytes and modulation of
      growth stimulatory and inhibitory factors and their associated receptors in terms
      of overall levels and regional distribution in the liver.

PMID- 8640947
TI  - Endogenous antioxidant status in neoplastic and adjacent tissues in 1,2
      dimethylhydrazine-induced colon cancer in rats: effects of olsalazine.
AB  - There is much evidence suggesting a possible role of reactive oxygen-derived
      substances in the pathogenesis of both ulcerative colitis and colon cancer. The
      antioxidant effects of 5-aminosalicylic acid (the active moiety of olsalazine) on
      induction of colon cancer in an experimental model using 1,2-dimethylhydrazine
      were studied in male Wistar rats. The levels of reduced glutathione were
      significantly (P < 0.01) decreased (by approximately 50%) in neoplastic tissues
      of rats receiving 1,2-dimethylhydrazine alone and olsalazine treatment
      significantly (P < 0.01) reduced the extent of this alteration. Adjacent tissues
      from rats receiving either carcinogen alone or carcinogen and olsalazine showed
      comparable levels of glutathione and these were significantly (P < 0.01) lower
      than corresponding control values and higher than corresponding values from
      neoplastic tissues. Activity of the glutathione regenerating enzyme glutathione
      reductase was significantly (P < 0.01) decreased (by approximately 40%) in
      neoplastic colonic tissue and this alteration was unaffected by olsalazine
      treatment. Neither carcinogen nor olsalazine treatment caused alterations in
      activity of glutathione reductase in adjacent tissue as compared with
      corresponding control values. Activity of the glutathione utilizing enzyme
      glutathione peroxidase was significantly (P < 0.01) increased (almost doubled) in
      neoplastic tissue of rats treated with carcinogen alone. Olsalazine treatment
      significantly (P < 0.01) reduced the elevation in glutathione peroxidase activity
      in neoplastic tissues of rats treated with the carcinogen. Glutathione peroxidase
      showed comparable activity in adjacent tissue from rats treated with either
      carcinogen alone or a combination of carcinogen and olsalazine and these values
      were significantly (P < 0.01) lower than corresponding control values. Colonic
      neoplastic tissues from all experimental groups of animals showed a small, but
      statistically significant (P < 0.05), decrease in superoxide dismutase activity
      compared with that in corresponding tissues from control animals.

PMID- 8640948
TI  - Type II TGF(beta) receptor expression in intestinal cell lines and in the
      intestinal tract.
AB  - The recent identification and cloning of mammalian transforming growth factor
      beta (TGFbeta) receptors permits further analysis of the importance of the
      TGFbeta family in intestinal biology. Expression of the type II TGFbeta receptor
      was examined in gastrointestinal cell lines and tissues. The 5.5 kb type II mRNA
      species was detected in poly-(A) mRNA isolated from the rat small bowel and
      colon. Northern blot analysis of RNA isolated from epithelial and non-epithelial
      small intestinal cell fractions showed the majority of receptor mRNA localized in
      the non-epithelial compartment. Immunohistochemical localization in the small
      intestine and colon supported the RNA findings; that is, expression was greatest
      in the lamina propria and muscularis. Staining was also detectable in the
      epithelium, where it was most prominent in the villus tip cells and absent in
      crypt cells. These findings mirror expression of TGFbeta in the epithelial
      compartment. The IEC-6, IPEC and RIE-1 cell lines, all of which are non
      transformed, were growth inhibited by TGFbeta and expressed type II receptor mRNA
      and protein. By contrast, the ras-transfected RIE-1, HT-29, Caco-2 and SW-620
      transformed lines were not growth inhibited by TGFbeta and all demonstrated a
      marked reduction in type II TGFbeta receptor mRNA expression and protein
      abundance by cross-linking. In conclusion, (i) colocalization of both ligand and
      receptor establishes the existence of potential autocrine and/or paracrine
      pathways for TGFbeta in the normal intestine and (ii) down-regulation of the type
      II TGFbeta receptor occurs in association with cellular transformation and may
      contribute to intestinal carcinogenesis.

PMID- 8640949
TI  - Isolation and biological characterization of morphological transformation
      sensitive Syrian hamster embryo cells.
AB  - Investigations were carried out designed to isolate and biologically characterize
      the subpopulation of cells within the Syrian hamster embryo (SHE) cell population
      which are sensitive to morphological transformation (MT). Biological cloning of
      MT-sensitive cells demonstrated that within the complex SHE cell population, MT
      sensitive cells comprise approximately 27% of the clonally plateable cellular
      population. Importantly, MT-sensitive cells display MT rates of approximately 7%
      following benzo[a]pyrene exposure, a rate which falls to <1% with additional
      passage of the cells, indicating that the ability to undergo MT is a transient
      phenomenon. Biological characterization of the clonal MT-sensitive cells
      indicates that these cells are relatively undifferentiated, since they express
      both cytokeratins and vimentin and respond to a variety of stem cell growth and
      differentiation factors, although the majority appear to be committed progenitor
      cells, since they express either mesenchymal or epithelial cell characteristics.
      Together these data demonstrate that MT-sensitive cells comprise a subpopulation
      of the cells within the complex SHE cell population, that the ability to undergo
      MT is a transient phenomenon and that MT-sensitive cells are relatively
      undifferentiated committed progenitor stem-like cells, all of which gives rise to
      the hypothesis that MT is an alteration in the cellular differentiation state.

PMID- 8640950
TI  - Expression of fibronectin and its receptor in some tumour cell lines and in HIV-1
      infected cells.
AB  - The aim of our study was to evaluate the levels of fibronectin (FN) and its
      classic receptor (FNR) in various transformed cells lines, especially of leukemic
      origin, and also the influence of HIV-1 replication on the expression of these
      proteins (in particular on H9-V cells, chronically infected with HIV-1, and
      acutely infected MT-4 cells). Monoclonal antibodies were used for indirect
      immunofluorescence tests; the fluorescein-conjugated recombinant p14, the product
      of the HIV gene tat, was used as a molecular probe. The results demonstrated a
      high variability of FN and FNR expression among the various cellular lines
      studied. Moreover, deficits of such adhesive proteins did not necessarily
      correlate with a severe reduction of the corresponding receptor. HIV-1
      replication in MT-4 and H9-V cells increased the expression of FNR. This seems to
      correlate with p14-induced phenomena because pretreatment of H9-V cells with
      recombinant p14 showed an enhancing effect on the expression of this receptor.

PMID- 8640951
TI  - Proteoglycan alterations in skin fibroblast cultures from patients affected with
      pseudoxanthoma elasticum.
AB  - Proteoglycans (PGs) were investigated in fibroblast cultures from both apparently
      normal and involved areas of skin from two patients affected with Pseudoxanthoma
      elasticum (PXE) and compared to control normal cells. Biochemical analysis showed
      that cells from the PXE-affected patients produced a PG population with stronger
      polyanion properties, as well as a markedly increased amount of high hydrodynamic
      size PGs. Moreover, PGs from PXE-affected cells showed abnormal hydrophobic
      interaction properties when examined under associative conditions and included
      heparan sulphate (HS)-containing populations with anomalous electrophoretic
      mobility. These phenomena were particularly evident in the case of PGs secreted
      into the growth medium. In agreement with these findings immunohistochemical
      study showed alterations affecting decorin and biglycan, as well as a different
      content and distribution of HS-PGs in PXE-affected cells. The same biochemical
      and morphological alterations were confirmed for both patients on different cell
      cultures and were present in cells from both apparently normal and affected skin
      areas, being more pronounced in the latter. Our results indicate that PXE
      affected fibroblasts in culture exhibit an abnormal PG metabolism, which could
      affect the normal assembly of extracellular matrix.

PMID- 8640952
TI  - Long-term treatment of Swiss 3T3 fibroblasts with dexamethasone attenuates MAP
      kinase activation induced by insulin-like growth factor-I (IGF-I).
AB  - Bone formation is reduced in hyperglucocorticoid states, e.g. Cushing's syndrome
      or long-term treatment with synthetic glucocorticoids during rheumatic diseases.
      possibly related to decreased sensitivity of the target to insulin-like growth
      factor-I (IGF-I). In this study, we have sought to identify postreceptor
      mechanisms for glucocorticoid-induced resistance to insulin-like peptides in a
      model system. Treatment of Swiss 3T3 fibroblasts with 100 nM dexamethasone for
      48h reduced IGF-I-induced activation of mitogen-activated protein kinase (MAP
      kinase). The level of insulin receptor substrate-1 (IRS-1) was reduced in
      dexamethasone-treated cells, as measured by Western blot; however, the pattern of
      tyrosine-phosphorylated protein subsequent to stimulation with IGF-I (1 min) was
      not altered. No inhibitory effect of dexamethasone was observed on the level of
      phosphotyrosine in IRS-1 in extracts from IGF-I-treated cells. The amount of IGF
      I-induced association of insulin receptor substrate-1 and phosphatidylinositol 3
      kinase was increased in steroid treated cells. Addition of IGF-I increased the
      synthesis of lipid, glycogen and protein, and the reduction of a tetrazolium dye,
      MTS, in untreated cells. The response to IGF-I in terms of glycogen synthesis was
      blunted, whereas the effect of IGF-I was unaffected for the other three
      parameters in cells pretreated with dexamethasone. These findings indicate that
      the activation of MAP kinase may be dissociated from IGF-I-induced anabolic
      pathways and tyrosine phosphorylation of IRS-1. The results agree with the
      previously proposed role for the activation of MAP kinase in the regulation of
      glycogen synthesis. Furthermore, they suggest that dexamethasone-induced
      reduction of IRS-1 expression may be important for the impaired activation of MAP
      kinase by insulin-like peptides in steroid-treated cells.

PMID- 8640953
TI  - Hepatic and pancreatic effects of polyenoylphosphatidylcholine in rats with
      alloxan-induced diabetes.
AB  - Polyenoylphosphatidylcholine (PPC: 100 or 300 mg kg-1 b.w., by gastric intubation
      for 30 days) produced a clearcut protection of the liver of rats treated with
      alloxan (150 mg kg-1 b.w., i.p.). The liver of rats treated with alloxan was
      characterized by hydropic dystrophy and lymphocytic infiltrations. Treatment with
      alloxan increased serum gamma-GT and ALAT activities. The liver structure of rats
      treated with PPC did not differ from the liver of control animals. PPC normalized
      the biochemical abnormalities caused by the diabetes. The number of pancreatic
      islets and beta/alpha cell ratio decreased in the diabetic rats. A number of beta
      cells in this group did not contain granules. PPC prevented the decrease in the
      number of islets and the beta/alpha cell ratio in the pancreas of the diabetic
      rats. The intensity of staining of beta-cell granules in the pancreas of PPC
      treated rats had a position intermediate between the control and diabetic groups.
      Alloxan increased the blood glucose content where treatment with PPC decreased
      this. The results suggest that PPC acts as a cytoprotector in the liver and
      pancreas of rats with experimental diabetes induced by alloxan.

PMID- 8640954
TI  - Characterization of gamma-glutamyltranspeptidase in the liver of the frog: 3.
      Response to freezing and thawing in the freeze-tolerant wood frog Rana sylvatica.
AB  - The freeze tolerant wood frog Rana sylvatica was studied to determine the impact
      of the freezing and thawing of this frog on the activity of gamma
      glutamyltranspeptidase in the liver. On exposure to -2.5 degrees C, for 1, 12 and
      24 h, frogs were found to be cool, covered with ice crystals and frozen,
      respectively. Thawing for 24 h at 4 degrees C recovered the frogs completely. A
      45 per cent decrease in the liver weight: body weight ratio was notable after 1 h
      at -2.5 degrees C, suggestive of an early hepatic capacitance response. A
      glycemic response to freezing was observed: blood glucose levels exhibited a 55
      per cent decrease after 1 h at -2.5 degrees C on cooling; a 10.5-fold increase
      after 12 h at -2.5 degrees C on the initiation of freezing; and a 22-fold
      increase after 24 h at -2.5 degrees C in the fully frozen state. Blood glucose
      levels remained elevated four-fold in the thawed state. Plasma insulin levels
      were increased twofold in the frozen state and 1.8-fold in the thawed state,
      while plasma ketone levels were increased 1.8-fold in the frozen state and 1.5
      fold in the thawed state. Plasma total T3 levels were decreased by 22 per cent in
      the frozen state and normalized on thawing. In homogenates and plasma membranes
      isolated from the livers of Rana sylvatica, the activity of gamma-glutamyltrans
      peptidase was found to be elevated at all stages of the freeze-thaw process.
      After 1, 12 and 24 h at -2.5 degrees C, activities were increased 2.5-, 2.3-, 2.4
      fold respectively in the homogenates and 2.5-, 2.2-, 2.4-fold respectively in the
      plasma membranes. After thawing, activities were still increased 1.9-fold in both
      homogenates and plasma membranes. In homogenates prepared from the kidneys of
      Rana sylvatica, the activity of gamma-glutamyltranspeptidase was increased 1.4
      fold after 1 h at -2.5 degrees C after which it returned to normal. The role of
      thyroid hormone in producing the increase in gamma-glutamyltranspeptidase in the
      liver of Rana sylvatica in response to freezing is discussed as is the
      significance of the enzyme increase in terms of hepatic cytoprotection and freeze
      tolerance.

PMID- 8640955
TI  - Susceptibility of gamma-irradiated proteins to in vitro glycation: exposure to
      oxygen free radicals increases glycation-induced modifications.
AB  - Oxidation and glycation are non-enzymatic protein modifications involved in the
      pathogenesis of aging. We evaluated their possible influences in an in vitro
      system: albumin was oxidized by gamma-irradiation and then exposed to glycation
      in vitro. Fluorescence modifications were analysed as signals of protein
      alterations. Both radiolytic oxidation and in vitro glycation provoked a sharp
      decrease of tryptophan fluorescence (278 nm ex./340 nm em.); their effects tended
      to be additive, unless a saturation limit was reached. Both individually and in
      combination, these two non-enzymatic processes induced the appearance of a new
      fluorescence (335 nm ex./415 nm em.); in this case as well there was an additive
      effect, with a trend toward saturation. Radiolytic oxidation and in vitro
      glycation seem to provoke similar damage to the exposed proteins: the observed
      fluorescence alterations may be due to similar conformational changes, breaks or
      the development of fluorophores.

PMID- 8640956
TI  - Alteration of erythrocyte membrane Na, K-ATPase in children with borderline or
      essential hypertension.
AB  - The aim of this study was to evaluate the substrate (ATP) kinetics of erythrocyte
      membrane Na, K-ATPase in children with borderline or essential hypertension.
      Although the activity of Na, K-ATPase in the presence of in vivo concentrations
      of ATP was not significantly altered, kinetic studies showed an obvious
      inhibition of enzyme activity in the erythrocyte membrane of children with
      borderline or essential hypertension. Hanes plot analysis revealed a decrease of
      V(max) from 7.19 in erythrocytes from control subjects to 4.93 and 3.33 in those
      from children with borderline or essential hypertension, respectively. A mean
      value of the K(m) decreased from 0.10 in the control to 0.08 and 0.02 in children
      with borderline or essential hypertension, respectively. The energy status of
      erythrocytes, estimated by ATP, ADP and AMP levels, ATP/ADP ratio, and adenylate
      energy charge (AEC) was not significantly changed in the cells from hypertensive
      children. The use of a free radical-generating system (FeSO4/ascorbate) in vitro
      significantly reduced enzyme activity in the control erythrocytes while in those
      from hypertensive children it was abolished completely. The level of lipid
      peroxides was considerably higher (+ 37 per cent) in the plasma, while that of
      reduced glutathione was significantly lower both in the erythrocytes and the
      plasma of children with essential hypertension than in healthy children. These
      results indicate significant alterations of the antioxidant status which could be
      the cause of the inhibited Na, K-ATPase activity in erythrocyte membranes from
      hypertensive children.

PMID- 8640957
TI  - Effects of methylglyoxal on platelet hydrogen peroxide accumulation, aggregation
      and release reaction.
AB  - Methylglyoxal generates a slight increase in the basal level of hydrogen peroxide
      in platelets. The oxidation effect of methylglyoxal significantly potentiated by
      thrombin, depends on both the ketoaldehyde and the agonist concentrations. A
      further significant increase in hydrogen peroxide accumulation was obtained in
      platelets pretreated with the alkylating agent N-ethylmaleimide which depletes
      GSH and blocks glutathione peroxidase. Resting platelets completely transform the
      ketoaldehyde into D(-)lactate, whereas stimulated platelets transform about 10-15
      per cent of the metabolized methylglyoxal into D(-)lactate. The metabolic
      modifications generated by methylglyoxal such as the GSH depletion and hydrogen
      peroxide accumulation induce modifications in platelet function. Methylglyoxal
      inhibits platelet aggregation induced by several agonists and ATP release induced
      by thrombin.

PMID- 8640958
TI  - Metabolism of glucose and glutamine in lymphocytes from Graves' hyperthyroid
      patients: influence of methimazole treatment.
AB  - Several studies have shown that thyroid hormones are able to influence selected
      immune responses such as cell mediated immunity, differentiation of B lymphocytes
      and the activity of NK cells. These hormones can also regulate the metabolism of
      glucose and glutamine in rat macrophages and their effects seem to occur mainly
      through the Krebs cycle. Alterations in the hexokinase, citrate synthase, glucose
      6-phosphate dehydrogenase and glutaminase activities in lymphocytes from patients
      with Graves' disease, either untreated or on methimazole (MMI) therapy were
      investigated. Experiments were also done in vitro to determine the activities of
      these enzymes in normal lymphocytes cultured for 24 h in the presence of MMI T3
      and T4 using concentrations close to the physiological. Changes in the conversion
      of [U-14C]-glucose and [U-14C]-glutamine to 14CO2 as caused by the addition of
      MMI, T3 or T4 to the culture medium were also evaluated. The results indicate
      that high levels of thyroid hormones might stimulate the metabolism of glucose
      and glutamine for a short period of time but, if the stimulus is maintained, the
      utilization of glutamine by lymphocytes is then suppressed. Moreover, MMI does
      affect lymphocyte metabolism but the significance of this finding for its
      immunosuppressive effect remains to be examined.

PMID- 8640959
TI  - Clumsiness: kinaesthetic perception and translation.
AB  - Earlier findings have suggested that abnormal clumsiness in children is
      associated with a perceptual defect in the kinaesthetic modality, and with a
      defect of the translation between stimulus and response.  In this experiment,
      perception was investigated by manipulating the requirement to discriminate
      between kinaesthetic stimuli, and the translation process by manipulating
      stimulus-response compatibility.  Consistent with earlier findings, the
      kinaesthetic reaction time of clumsy children was found to be longer than that of
      controls; but, although the requirement to discriminate between stimuli and
      incompatibility both lengthened reaction times, the increases were similar for
      clumsy and control groups.  It is suggested that these negative findings may be
      attributable to a practice effect in the former, and to inadequate loading on the
      translation process in the latter.  However, it is also suggested that the
      findings may indicate that clumsiness is associated with a defect in the cross
      modal translation of information.

PMID- 8640960
TI  - Growth screening in schools: an evaluation of the programme in one district.
AB  - It has been recommended that all children should have their height and weight
      measured at school entry, although the disadvantages associated with screening
      and the benefits, in terms of a change in outcome, have not been fully
      established. The measuring equipment used in schools, recording of anthropometric
      data and adherence to local guidelines were assessed across one district. Few
      schools had the recommended equipment, problems with accuracy were common and
      screening coverage was low. The achievement of optical outcome will require a
      reduction in the gap between local practice and recommended policy: guidelines
      should recognize difficulties encountered in the field.

PMID- 8640961
TI  - The Education Act 1993: working with health services to implement the Code of
      Practice.
AB  - Whereas the 1981 Education Act led to emphasis on written statements of special
      educational needs for 2% of pupils, the 1993 Act seeks to recruit help for all
      children with such needs at earlier stages in the teaching process.  Such help
      includes that available from the health services.  The organization of health
      services has gone through considerable change since the 1993 Act was drafted so
      special efforts will be required to implement the intentions of the Act.

PMID- 8640962
TI  - Early presentation in the mucopolysaccharide disorders.
AB  - The findings of an international questionnaire study of 258 children, affected by
      the four main subtypes of mucopolysaccharidosis, are presented. Questionnaires
      were completed by a parent or main carer and all subjects were alive at the time
      of contact and suffering from Hurler, Hunter, Sanfilippo or Morquio syndrome. A
      significant proportion of parents of Hurler children (24%) were unaware that
      anything was wrong with their baby before diagnosis but a larger number (45%) had
      felt concerned about their child's appearance. Similarly, in the case of the
      Morquio children, in 75% of cases, parents had been worried about some aspect of
      their child's physical appearance. In contrast, it was frequently delayed or
      regressing language which alerted parents of Sanfilippo (56%) and Hunter (32%)
      children, and this was associated with behaviour problems in 43% of Sanfilippo
      cases. There were many cases of delayed diagnosis, often occurring more than 2
      years after concerns were first raised.

PMID- 8640963
TI  - Modulation of birthweight through gestational age and fetal growth.
AB  - Several factors are known to affect birthweight and their effects are variously
      mediated through gestational duration or through fetal growth conditional on this
      gestation. In order to quantify independent associations of birthweight
      conditional and unconditional on gestational age, all 2538 mothers of singleton
      babies delivered during 1993 in two Maternity Hospitals in Athens were
      interviewed and their obstetric records abstracted. Birthweight was modelled as
      outcome variable through multiple regression including 32 potentially predictive
      factors. The regression model was fitted with and without gestational age as an
      additional independent variable in order to apportion birthweight associations
      into those independent of, or mediated through, gestational length. The factors
      studied were found to be classifiable into the following categories: factors
      associated with birthweight mostly through increases in gestational duration,
      either positively (age at menarche, long menstrual cycles, parity 4 or higher),
      or negatively (single motherhood, maternal age, tobacco smoking); those
      associated with birthweight mostly through increase of birthweight conditional on
      gestational duration, either positively (male gender, short menstrual cycles,
      maternal pre-pregnancy weight, anaemia, oedema) or inversely (employment during
      pregnancy, stillbirth, primiparity, pregnancy induced hypertension, coffee
      drinking); and those associated with birthweight through apparently dual effects,
      either positively (maternal education) or inversely (perceived stress, bleeding
      during pregnancy). The other studied factors were not demonstrably related to
      birthweight in this data set. Identification and quantification of these
      relations is useful for understanding underlying physiological and
      pathophysiological processes and for increasing specificity in exploring the
      association of birthweight with adult onset diseases, like coronary heart disease
      or cancer.

PMID- 8640964
TI  - Birthweight and health and development at the age of 7 years.
AB  - This study was set up to compare the frequency of health, educational and
      behavioural problems in a geographically defined birth cohort of 7-year-old
      children grouped by weight at birth. The study design was based on a multi-stage
      postal survey, with sampling stratified by birthweight. It took place in the four
      counties of Oxfordshire, Buckinghamshire, Berkshire and Northamptonshire which
      make up the former Oxford region. We studied 1319 live births to women resident
      in the former Oxford region in 1985, including all those with birthweights under
      1500 g, or whose weight was not recorded, and a sample of those who weighed 1500
      2499 g, and of those who weighed 2500 g or more at birth. The children in the
      sample were traced through the National Health Service Central Register (NHSCR)
      and self-administered questionnaires were sent to their parents, general
      practitioners (GP) and teachers. Of the 1169 children who were alive at the age
      of 7 years and were successfully traced, 805 (75%) were followed up by postal
      survey. The use of health services, and of additional educational support was
      higher, and school performance was poorer among children who had weighed less
      than 1500 g at birth than among children who had weighed 2500 g or more, with the
      rates for children who had weighed 1500-2499 g falling in between. This survey
      method identifies the higher rate of health and educational problems in children
      weighing under 2500 g at birth, particularly those with birthweight under 1500 g,
      compared with other children. The method could be developed to provide a way of
      monitoring any changes over time in the prevalence of these problems. This
      information can be used to assess the health and educational needs of 7-year-old
      children in the population.

PMID- 8640965
TI  - Shorthand guide to the congressional budget mess.

PMID- 8640966
TI  - New insights into the cardiac natriuretic peptides.

PMID- 8640967
TI  - Predictive value of electron beam computed tomography of the coronary arteries.
      19-month follow-up of 1173 asymptomatic subjects.
AB  - BACKGROUND: Coronary electron beam computed tomography (EBCT) detects
      atherosclerotic coronary artery disease by measuring calcium deposition in the
      walls of coronary arteries. EBCT-derived coronary artery calcium (CAC) scores
      correlate with the severity of underlying coronary artery disease. METHODS AND
      RESULTS: We followed 1173 asymptomatic patients who underwent EBCT between
      September 1993 and March 1994. During average follow-up of 19 months, 18 subjects
      had 26 cardiovascular events: 1 death, 7 myocardial infarctions, 8 coronary
      artery bypass graft procedures, 9 coronary angioplasties, and 1 nonhemorrhagic
      stroke. For CAC score thresholds of 100, 160, and 680, EBCT had sensitivities of
      89%, 89%, and 50% and specificities of 77%, 82%, and 95%, respectively. Odds
      ratios ranged from 20.0 to 35.4 (P < .0001 for all). CONCLUSIONS: Coronary EBCT
      predicts future atherosclerotic cardiovascular disease events in asymptomatic
      subjects.

PMID- 8640968
TI  - Effectiveness of revascularization in the Emory angioplasty versus surgery trial.
      A randomized comparison of coronary angioplasty with bypass surgery.
AB  - BACKGROUND: The Emory Angioplasty Versus Surgery Trial (EAST) was designed to
      determine whether percutaneous transluminal coronary angioplasty (PTCA) is as
      effective as coronary artery bypass graft surgery (CABG) in restoring arterial
      perfusion capacity in eligible patients with multivessel disease. METHODS AND
      RESULTS: Of 392 patients in EAST, 198 were randomized to PTCA and 194 to CABG.
      Index lesions (2.7 +/- 1.0 per patient) were those with > or = 50% stenosis
      judged treatable by both angioplasty and surgery. Coronary segments jeopardized
      by these index lesions were designated as index segments (4.4 +/- 1.4 per
      patient). Percent stenosis was measured by quantitative angiography at the point
      of greatest obstruction in the main perfusion path of each index segment. The
      EAST primary arteriographic end point was the percent of a patient's index
      segments with < 50% stenosis in the main perfusion pathways at 1 and 3 years. At
      baseline, the percent of index segments for which revascularization was attempted
      was 85% for PTCA and 98% for CABG (P < .0001). At 1 year, PTCA patients had a
      smaller percentage of successfully revascularized index segments than CABG
      patients (59% versus 88%, P < .001). At 3 years, the findings were similar but
      less striking (70% versus 87%, P < .001). When only "high-priority" index
      segments (2.1 +/- 1.6 per patient) were considered, baseline attempts were
      comparable (96% versus 99%, P = NS); despite this, CABG remained more successful
      at 1 (64% versus 93%, P < .001) and 3 (76% versus 89%, P < .01) years. However,
      the mean percent of index segments free of severe stenosis (> or = 70%) did not
      differ between PTCA and CABG patients at 3 years (93% versus 95%, P = NS).
      Furthermore, the frequency of patients with all index segments free of severe
      stenosis did not differ between the two groups at 1 (76% versus 83%, P = NS) or 3
      (82% for both PTCA and CABG) years. CONCLUSIONS: In patients with multivessel
      disease, index segment revascularization was more complete with CABG than PTCA at
      both 1 and 3 years. However, when the physiological priority of the target lesion
      and the measured severity of the residual stenosis are taken into account, the
      advantage of CABG becomes less significant or nonsignificant. This may, in part,
      explain why these two strategies did not differ in terms of the EAST primary
      clinical end points over 3 years.

PMID- 8640969
TI  - Plasma brain natriuretic peptide as an indicator of left ventricular systolic
      function and long-term survival after acute myocardial infarction. Comparison
      with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic
      peptide.
AB  - BACKGROUND: Elevated plasma levels of atrial natriuretic peptide (ANP) and the N
      terminal fragment of the ANP prohormone (N-ANP) are associated with decreased
      left ventricular function and decreased long-term survival after acute myocardial
      infarction (AMI). Previous data suggest that plasma brain natriuretic peptide
      (BNP) may increase proportionally more than plasma ANP after AMI and in chronic
      heart failure. The diagnostic and prognostic value of plasma BNP as an indicator
      of left ventricular dysfunction and long-term survival after AMI, relative to
      that of ANP and N-ANP, remain to be established. METHODS AND RESULTS: Venous
      blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after
      symptom onset from 131 patients with documented AMI. Left ventricular ejection
      fraction was determined by echocardiography in a subsample of 79 patients. Twenty
      eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up
      period (median, 1293 days). All three peptides proved to be powerful predictors
      of cardiovascular mortality by univariate Cox proportional hazards regression
      analyses (ANP: P < .0001; N-ANP: P = .0002; BNP: P < .0001). In a multivariate
      model, plasma BNP (P = .021) but not ANP (P = .638) or N-ANP (P = .782) provided
      additional prognostic information beyond left ventricular ejection fraction.
      Logistic regression analysis showed that ANP (P = .003) and N-ANP (P = .027) but
      not BNP (P = .14) were significantly associated with a left ventricular ejection
      fraction < or = 45%. CONCLUSIONS: These results suggest that plasma BNP
      determination provides important, independent prognostic information after AMI.
      Although plasma ANP appears to be a better predictor of left ventricular
      dysfunction, plasma BNP may have greater potential to complement standard
      prognostic indicators used in risk stratification after AMI because of its
      strong, independent association with long-term survival, enhanced in vitro
      stability, and simplicity of analysis.

PMID- 8640970
TI  - Relation of hormone-replacement therapy to measures of plasma fibrinolytic
      activity. Atherosclerosis Risk in Communities (ARIC) Study Investigators.
AB  - BACKGROUND: The mechanisms by which replacement hormones may reduce the risk of
      coronary heart disease are not fully understood. Of specific interest is a
      potential effect of replacement hormones on plasma fibrinolytic activity, a
      putative determinant of thrombotic events. METHODS AND RESULTS: We investigated
      the relation of current use of replacement hormones to three measures of plasma
      fibrinolytic activity: tissue-type plasminogen activator (TPA) antigen,
      plasminogen activator inhibitor-1 (PAI-1) antigen, and D-dimer. The sample was
      composed of 288 women, free of clinical cardiovascular disease, who were selected
      for a case-control study of atherosclerosis: 142 women with ultrasonographic
      evidence of carotid intimal-medial thickening (cases) and 146 control subjects.
      Twenty percent (59 women) reported current use of replacement hormones. TPA
      antigen and PAI-1 antigen were highly correlated with each other (r = .67),
      whereas D-dimer correlated only weakly with TPA or PAI-1. Compared with nonusers,
      current users of replacement hormones had lower mean levels of TPA and PAI-1
      antigens, suggesting enhanced fibrinolytic potential. In the entire sample, the
      multivariate-adjusted geometric mean values of TPA antigen were 6.3 and 7.3 ng/mL
      among current users and nonusers, respectively (P = .01); the corresponding
      values for PAI-1 antigen were 6.1 and 7.5 ng/mL (P = .13). These results were
      generally consistent for both atherosclerosis cases and their control subjects. D
      dimer levels were lower in current hormone users than in nonusers, but the
      difference was not statistically significant (P > .15) in any of the analyses.
      CONCLUSIONS: The use of replacement hormones appears to be associated with
      enhancement of endogenous fibrinolytic potential. Enhanced plasma fibrinolytic
      activity among hormone users may explain, in part, the inverse association
      between hormone replacement therapy and coronary heart disease.

PMID- 8640971
TI  - Symptoms of depression, acute myocardial infarction, and total mortality in a
      community sample.
AB  - BACKGROUND: Depression has been shown to adversely affect the prognosis of
      patients with established coronary artery disease, but there is comparatively
      little evidence to document the role of depression in the initial development of
      coronary disease. METHODS AND RESULTS: Study participants were 409 men and 321
      women who were residents of Glostrup, Denmark, born in 1914. Physical and
      psychological examinations in 1964 and 1974 established their baseline risk
      factor and disease status and their level of depressive symptomatology. Initial
      myocardial infarction (MI) was observed in 122 participants, and there were 290
      deaths during follow-up, which ended in 1991. A 2-SD difference in depression
      score was associated with relative risks of 1.71 (P = .005) for MI and 1.59 (P <
      .001) for deaths from all causes. These findings were unchanged after we
      controlled for risk factors and signs of disease at baseline. There were no sex
      differences in effect sizes. CONCLUSIONS: High levels of depressive
      symptomatology are associated with increased risks of MI and mortality. The
      graded relationships between depression scores and risk, long-lasting nature of
      the effect, and stability of the depression measured across time suggest that
      this risk factor is best viewed as a continuous variable that represents a
      chronic psychological characteristic rather than a discrete and episodic
      psychiatric condition.

PMID- 8640972
TI  - Sex differences in myocardial infarction and coronary deaths in the Scottish
      MONICA population of Glasgow 1985 to 1991. Presentation, diagnosis, treatment,
      and 28-day case fatality of 3991 events in men and 1551 events in women.
AB  - BACKGROUND: Scottish MONICA used medical and medico-legal records and World
      Health Organization MONICA Project criteria to register coronary events in 25- to
      64-year-old residents of the high-incidence area of north Glasgow from 1985 to
      1991. METHODS AND RESULTS: Age-standardized data from 3991 episodes of nonfatal
      definite myocardial infarction and coronary deaths in men (mean age, 55.5 years)
      were compared with 1551 in women (57.0 years). Many results, such as the overall
      28-day fatality rates of 49.8% in men and 48.5% in women, showed insignificant
      differences. However, 74.3% of deaths in men occurred out of hospital versus
      67.8% in women (P = .0004). After admission to hospital, fatality rates in women
      were 14% higher (P = .07) and after admission to coronary care, 22% higher (P =
      .04). Women were more often widowed. Fewer had a history of previous myocardial
      infarction, but the prevalence of angina pectoris, of smoking, and of chest pain
      in the attack was the same as in men; more had shock, syncope, and
      breathlessness. More consulted a doctor before admission to hospital, which
      delayed their coming under care. More men had ECG Q-wave progression, and more
      women had smaller ECG changes. This, and marginally reduced chances of direct
      admission to coronary care, of thrombolysis, of aspirin, and of beta-blockers,
      did not explain women's excess hospital fatality. CONCLUSIONS: Acute coronary
      events appear to be recognized and treated fairly equally in men and women 25 to
      64 years old in Glasgow, so differences are small but subtle. More men die
      suddenly out of hospital; the reason why more women die after arrival may be
      because the equivalent number of men have already died outside.

PMID- 8640973
TI  - Myocardial perfusion patterns related to thrombolysis in myocardial infarction
      perfusion grades after coronary angioplasty in patients with acute anterior wall
      myocardial infarction.
AB  - BACKGROUND: Epicardial coronary flow is occasionally reduced even after coronary
      intervention despite the absence of vessel obstruction in patients with acute
      myocardial infarction. Our aim was to clarify the cause and outcomes of
      radiocontrast slow filling in patients with reperfused acute anterior myocardial
      infarction by assessing microvascular damage with the use of myocardial contrast
      echocardiography (MCE) and functional outcomes. METHODS AND RESULTS: We carefully
      reviewed the cineangiograms of 86 patients who achieved coronary
      revascularization within 12 hours of the onset and underwent MCE before and soon
      after recanalization with the intracoronary injection of sonicated microbubbles.
      Antegrade coronary flow after recanalization was graded by two observers based on
      Thrombolysis in Myocardial Infarction (TIMI) trial flow grades. Left ventricular
      ejection fraction was measured on the day of infarction and 1 month later. TIMI
      grade 2 was observed in 18 patients (21%), and the other 68 patients manifested
      TIMI grade 3 after recanalization. All patients with TIMI 2 showed substantial
      MCE no reflow, whereas only 11 patients (16%) with TIMI 3 showed MCE no reflow.
      Functional improvement was worse in patients with TIMI 2 than in those with TIMI
      3 (TIMI 2, 38 +/- 8% versus 40 +/- 8%, P = NS [acute versus late]; TIMI 3, 44 +/-
      13% versus 55 +/- 13%, P < .001). Among patients with TIMI 3, significant
      functional improvement was observed only in patients with MCE reflow (MCE reflow,
      46 +/- 13% versus 57 +/- 12%, P < .001; MCE no reflow, 35 +/- 11% versus 45 +/-
      12%, P = NS). CONCLUSIONS: Despite no obstructive lesion of the vessel, TIMI 2 is
      caused by advanced microvascular damage and is a highly specific, although not
      sensitive, predictor of poor functional outcomes in patients with acute
      myocardial infarction. TIMI 3 does not necessarily indicate myocardial salvage,
      and detection of MCE no reflow in these patients is particularly useful for the
      prediction of functional outcome.

PMID- 8640974
TI  - Noninvasive quantification of myocardial blood flow in humans. A direct
      comparison of the [13N]ammonia and the [15O]water techniques.
AB  - BACKGROUND: [13N]Ammonia has been validated in dog studies as a myocardial blood
      flow tracer. Estimates of myocardial blood flow by [13N]ammonia were highly
      linearly correlated to those by the microsphere and blood sample techniques.
      However, estimates of myocardial blood flow with [13N]ammonia in humans have not
      yet been compared with those by an independent technique. This study therefore
      tested the hypothesis that the [13N]ammonia positron emission tomographic
      technique in humans gives estimates of myocardial blood flow comparable to those
      obtained with the [15O]water technique. METHODS AND RESULTS: A total of 30 pairs
      of positron emission tomographic flow measurements were performed in 30 healthy
      volunteers; 15 volunteers were studied at rest and 15 during adenosine-induced
      hypermia. Estimates of average and of regional myocardial blood flow by the
      [13N]ammonia and the [15O]water approaches correlated well (y = 0.02 + 1.02x, r =
      .99, P < .001 SEE = 0.023 for average and y = 0.06 + 1.00x, r = .97, P < .001,
      SEE = 0.025 for regional values) over a flow range of 0.45 to 4.74 mL.min-1.g-1.
      At rest, mean myocardial blood flow was 0.64 +/- 0.09 mL.min-1.g-1 for
      [13N]ammonia and 0.66 +/- 0.12 mL.min-1.g-1 for [15O]water (P = NS). For
      adenosine-induced hyperemia, mean myocardial blood flow was 2.63 +/- 0.75 mL.min
      1.g-1 for [13N]ammonia and 2.73 +/- 0.77 mL.min-1.g-1 for [15O]water (P = NS).
      The coefficient of variation as an index of the observed heterogeneity of
      myocardial blood flow averaged, for [13N]ammonia, 9 +/- 4% at rest and 12 +/- 7%
      during stress and, for [15O]water, 14 +/- 11% at rest and 16 +/- 9% during
      stress. The coefficients of variation for [15O]water were significantly higher
      than those for [13N]ammonia (P = .004 at rest and P = .03 during stress).
      CONCLUSIONS: The two approaches yield comparable estimates of myocardial blood
      flow in humans, which supports the validity of the [13N]ammonia method in human
      myocardium previously shown only in animals. However, the [15O]water approach
      reveals a greater heterogeneity (presumably method-related), which might limit
      the accuracy of sectorial myocardial blood flow estimates in humans.

PMID- 8640975
TI  - Value of dynamic respiratory changes in left and right ventricular pressures for
      the diagnosis of constrictive pericarditis.
AB  - BACKGROUND: Conventional cardiac catheterization criteria for the diagnosis of
      constrictive pericarditis (CP) rely on equalization of intracardiac pressures and
      have many recognized limitations. Recently, Doppler echocardiographic methods
      have been used to examine dynamic respiratory changes of increased ventricular
      interdependence and dissociation of intrathoracic and intracardiac pressures for
      the diagnosis of CP. These pathophysiological features may be best delineated by
      cardiac catheterization. Therefore, we studied the accuracy of these dynamic
      respiratory changes in left ventricular and right ventricular pressure for the
      diagnosis of CP at cardiac catheterization. METHODS AND RESULTS: High-fidelity
      manometric catheters and respirometry were used to study 36 patients: 15 patients
      with surgically proven CP (group 1) and 21 patients with other causes of heart
      failure (group 2). Conventional cardiac catheterization variables used to
      establish the diagnosis of CP lacked sensitivity and specificity and failed to
      distinguish between these groups. However, the finding of discordance between
      right ventricular and left ventricular pressures during inspiration, a sign of
      increased ventricular interdependence, accurately distinguished patients in group
      1 from those in group 2 (P < .05). CONCLUSIONS: Examination of dynamic
      respiratory changes indicating increased ventricular interdependence may be
      helpful in the diagnosis of CP in the cardiac catheterization laboratory.

PMID- 8640976
TI  - Pericardial blood activates the extrinsic coagulation pathway during clinical
      cardiopulmonary bypass.
AB  - BACKGROUND: Coagulation during cardiopulmonary bypass (CPB) traditionally has
      been attributed to activation of the contact system of plasma proteins and the
      intrinsic coagulation pathway by blood contact with negatively charged surfaces
      not lined by endothelium. Recent studies have focused on the possible role of the
      extrinsic coagulation pathway during cardiac surgery. We postulated that the
      wound activates the extrinsic coagulation pathway during CPB by producing
      procoagulant cells and enzymes that enter the general circulation. METHODS AND
      RESULTS: Blood samples taken from 20 consenting patients who had elective cardiac
      surgery were assayed for peripheral blood mononuclear cell tissue factor (TF)
      expression, plasma F1.2, and factor VII and VIIa concentrations. Peripheral blood
      mononuclear cell TF expression increased in the perfusate after the surgical
      incision and after CPB was started and in monocytes that adhered to the perfusion
      circuit. TF on circulating monocytes, however, did not continue to rise during
      CPB. Peripheral blood mononuclear cell TF was elevated in cells isolated directly
      from blood in the pericardial cavity and was twice that detected in simultaneous
      samples from the perfusate (P < .05). F1.2 levels were highest in pericardial
      blood and increased progressively during CPB. Plasma factor VIIa concentrations,
      corrected for hemodilution, and ratios of factor VIIa to factor VII were highest
      in pericardial samples (P < .05) and increased progressively during and
      immediately after CPB. Pericardial biopsies obtained before and after CPB in 7
      patients did not show TF expression by mesothelial cells. CONCLUSIONS: These data
      provide direct evidence of TF expression, activation of the extrinsic coagulation
      pathway, and thrombin formation in the surgical wound. Addition of pericardial
      blood to the perfusate and expression of TF by both circulating and adherent
      monocytes strongly promote thrombus formation during open heart surgery.

PMID- 8640977
TI  - Influence of comorbidity on the outcome of patients treated for out-of-hospital
      ventricular fibrillation.
AB  - BACKGROUND: A number of factors have previously been shown to be predictive of
      survival from out-of-hospital ventricular fibrillation. These include witnessed
      collapse, prompt initiation of cardiopulmonary resuscitation, early application
      of defibrillation, and younger age. Arrests occurring away from home are also
      associated with improved survival. Additionally, hospital mortality after
      successful resuscitation has been related to a history of congestive heart
      failure as well as to some of the factors noted above. An association of
      prearrest comorbidity with outcome has not been systematically evaluated. METHODS
      AND RESULTS: We define here a comorbidity index, which is constructed from
      histories of chronic conditions as well as a number of recent symptoms in 282
      victims of out-of-hospital VF. This indicator of comorbidity is strongly
      associated with outcome (P = .004). However, when analyzing a comprehensive set
      of predictors of survival after out-of-hospital ventricular fibrillation,
      including the index of comorbidity, we could identify overall only about one
      fourth of the variation that one might hope to account for. CONCLUSIONS:
      Comorbidity appears to be an important (but usually overlooked) predictor of
      survival from out-of-hospital ventricular fibrillation. However, most of the
      statistical variability in predicting survival remains unexplained when we
      consider comorbidity in conjunction with previously identified predictors of
      survival.

PMID- 8640978
TI  - Longitudinal clinical and electrophysiological assessment of patients with
      symptomatic Wolff-Parkinson-White syndrome and atrioventricular node reentrant
      tachycardia.
AB  - BACKGROUND: Functional changes of the accessory AV pathways and dual AV node
      pathways are very important for patients with Wolff-Parkinson-White syndrome or
      AV node reentrant tachycardia who refuse to receive long-term medication or
      radiofrequency catheter ablation. However, no studies of serial clinical and
      electrophysiological characteristics in these patients have been performed.
      METHODS AND RESULTS: One hundred thirteen patients with Wolff-Parkinson-White
      syndrome or AV node reentrant tachycardia were included in this study. The first
      and second follow-up electrophysiological studies were performed in years 5 and
      10 after the baseline study, respectively. Conduction properties of the accessory
      pathways became poor over time. After a mean follow-up period of 9 +/- 1 years,
      antegrade ventricular preexcitation and retrograde accessory pathway conduction
      disappeared in 22.5% and 7.8% (P < .01), respectively; dual AV node pathway
      physiology persisted and retrograde fast pathway disappeared in 10.8% of the
      patients. Baseline conduction properties of the antegrade and retrograde
      accessory pathways and the retrograde fast pathway independently predicted late
      loss of conduction. Spontaneous disappearance of the original tachyarrhythmias
      occurred in 10.3% of all patients, and newly developed tachyarrhythmias in 15.2%.
      The incidence (38.5%) of newly developed atrial fibrillation was significantly
      higher in patients with manifest accessory pathways. Furthermore, symptom scores
      and attack frequency increased significantly over time in the patients with
      accessory pathways and AV node reentrant tachycardia. CONCLUSIONS: Disappearance
      of the original tachycardia and changing patterns of tachycardia, also with an
      increase in symptom scores and attack frequency, suggested that a detailed
      evaluation of these events is important and early intervention with
      radiofrequency ablation would be helpful.

PMID- 8640979
TI  - Comparison of sudden and nonsudden coronary deaths in the United States.
AB  - BACKGROUND: The present study was designed to compare risk factor prevalences in
      coronary heart disease deaths in persons dying within 1 hour of onset of
      cardiovascular symptoms (sudden coronary death), those dying without such sudden
      symptoms (nonsudden coronary death), and those with unknown duration of symptoms
      before death (other coronary death). METHODS AND RESULTS: Data from the 1986
      National Mortality Followback Survey and the US Bureau of the Census were
      examined to assess death rates for sudden, nonsudden, and other coronary deaths.
      Multivariate logistic regression methods were used to calculate the odds ratio
      (OR), compared with nonsudden and other coronary deaths, for sudden coronary
      death associated with socioeconomic status variables, the person's location at
      death, and coronary heart disease risk factors. Mortality rates for all coronary
      deaths increased with age, were higher for men than women, and increased with
      decreasing years of schooling. The rate of sudden coronary death was highest for
      Hispanics. In 1986, an estimated 251,000 sudden coronary deaths (95% CI = 238,000
      to 263,000) occurred in the United States. Sudden coronary deaths were less
      likely than nonsudden coronary deaths to occur at home (OR = 0.5, 95% CI = 0.4 to
      0.6), but individuals who died of sudden coronary death were more likely to have
      been current cigarette smokers (OR = 1.3, 95% CI = 1.0 to 1.8). No other
      modifiable risk factors for coronary heart disease distinguished sudden coronary
      deaths from nonsudden coronary deaths. CONCLUSIONS: Contrary to the commonly held
      view, coronary deaths in the home are more likely to be nonsudden than sudden.
      Cigarette smoking more likely results in sudden than nonsudden coronary death,
      perhaps because of nicotine-induced ventricular arrhythmias.

PMID- 8640980
TI  - Effects of brain natriuretic peptide on exercise hemodynamics and neurohormones
      in isolated diastolic heart failure.
AB  - BACKGROUND: Experimental models suggest that brain natriuretic peptide (BNP) can
      modify left ventricular diastolic performance. The aim of this study was to
      evaluate the effects of BNP on resting and exercise hemodynamics and
      neurohormones in patients with isolated diastolic heart failure. METHODS AND
      RESULTS: Six patients with isolated diastolic heart failure were studied. After
      baseline hemodynamic measurements were obtained with use of thermistor-tipped
      pulmonary artery catheters, patients were randomized to receive infusion of BNP
      or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal
      parameters were measured at rest after 30 minutes of infusion and during
      incremental supine bicycle exercise. BNP did not significantly affect resting
      hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure
      (placebo, 23 +/- 2 mm Hg; BNP, 16 +/- 2 mm Hg; P < .01) and mean pulmonary artery
      pressure (placebo, 34 +/- 3 mm Hg; BNP, 29 +/- 3 mm Hg; P < .05) during exercise
      without affecting changes in heart rate, systemic blood pressure, or stroke
      volume. In response to BNP, there was significant suppression of plasma
      aldosterone concentration (placebo, 551 +/- 107 pmol/L; BNP, 381 +/- 56 pmol/L; P
      < .05). CONCLUSIONS: BNP infusion causes beneficial hemodynamic and neurohormonal
      effects during exercise in patients with isolated diastolic heart failure.

PMID- 8640981
TI  - Intramyocardial injections and protection against myocardial ischemia. An attempt
      to examine the cardioprotective actions of adenosine.
AB  - BACKGROUND: Although adenosine has been proposed to be a cardioprotective agent,
      direct examination of such protection is confounded by its short half-life and
      hemodynamic effects. We attempted to avoid these problems by injecting adenosine
      directly into cardiac muscle. METHODS AND RESULTS: We gave four adenosine
      injections (each 0.15 mL, 5 mg.mL-1 saline) into the left ventricular wall of rat
      hearts before a 60-minute occlusion. Although infarcts were smaller in adenosine
      treated hearts (29 +/- 6%) than in controls (52 +/- 5%; P < .05), injection of
      saline also reduced infarct size (29 +/- 7%). Infarcts in hearts subjected to
      needle insertion but no fluid injection differed neither from control nor from
      fluid-treated hearts (38 +/- 4%). Adenosine reduced ectopic beats and the
      incidence of ventricular tachycardia during occlusion. In contrast, saline
      injection prolonged the duration of arrhythmias. To examine the spatial
      relationship between protection and the injection site, we gave 18 saline
      injections (each 0.15 mL) into canine myocardium before a 60-minute occlusion.
      Infarcts were smaller in saline-treated hearts than in controls (P < .01).
      Because infarcts in four hearts occupied < 3% of the risk region, we concluded
      that fluid injection did not itself cause appreciable necrosis and speculated
      that muscle was protected in the vicinity of the injection site. Previous work
      indicated that muscle can be protected by stretch. We examined this hypothesis by
      adding gadolinium chloride (a stretch-activated channel blocker) to the saline
      (0.008 g.mL-1) injection in rat hearts. We again found small infarcts after
      saline injection (26 +/- 5%); however, gadolinium blocked protection (50 +/- 7%;
      P < .03). CONCLUSIONS: Although we were only partially successful in documenting
      adenosine-mediated cardioprotection, we found evidence for myocyte protection via
      a stretch-activated mechanism.

PMID- 8640982
TI  - Long-term angiotensin-converting enzyme inhibition with high-dose enalapril
      retards nitrate tolerance in large epicardial arteries and prevents rebound
      coronary vasoconstriction in vivo.
AB  - BACKGROUND: Rebound myocardial ischemia develops in patients with unstable or
      stable angina pectoris after sudden cessation of nitroglycerin therapy. Long-term
      nitroglycerin infusion is associated with increases in plasma renin activity and
      catecholamine release rates, both of which may lead to excess angiotensin II and
      alpha-adrenergic-mediated vasoconstriction, particularly on withdrawal of
      nitroglycerin. METHODS AND RESULTS: Chronically instrumented dogs were treated
      for 5 days with nitroglycerin (1.5 micrograms.kg-1.min-1 i.v.) alone or in
      combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril (0.1
      mg/kg two times daily or 1 mg/kg). With long-term nitroglycerin therapy, the left
      anterior circumflex artery was maximally dilated 4 hours after the start of
      nitroglycerin infusion (9.5 +/- 0.6%) and returned to baseline levels within the
      third day of treatment (baseline, 2.52 +/- 0.07 mm; day 3, 2.55 +/- 0.07 mm; P =
      NS), indicating a complete loss of nitroglycerin-induced coronary vasodilatation.
      Nitroglycerin infusion also was accompanied by a transient increase in plasma
      renin activity. Sudden withdrawal of nitroglycerin infusion caused a progressive
      constriction of the left anterior circumflex artery, which peaked 4 hours after
      nitroglycerin infusion cessation (-7.8 +/- 0.2%). This occurred in the absence of
      elevated plasma renin activity. Concomitant treatment with high-dose enalapril (1
      mg.kg-1.d-1) markedly reduced the degree of tolerance and prevented the rebound
      constriction on cessation of nitroglycerin therapy. CONCLUSIONS: Long-term ACE
      inhibition with high-dose enalapril reduces nitroglycerin tolerance and prevents
      rebound vasoconstriction in coronary arteries. These phenomena were not
      associated with an activated circulating renin-angiotensin system. This
      observation suggests that during long-term nitroglycerin treatment, intrinsic
      abnormalities of the vascular smooth muscle may have developed that are
      suppressed by concomitant ACE inhibitor therapy. The present study also favors a
      combination of nitroglycerin and ACE inhibitors to maintain nitrate sensitivity
      of the vasculature during long-term nitroglycerin treatment.

PMID- 8640983
TI  - Evidence for load-dependent and load-independent determinants of cardiac
      natriuretic peptide production.
AB  - BACKGROUND: In hypertension with cardiac hypertrophy, the specific contributions
      to increased production of the cardiac natriuretic peptides (NP) atrial
      natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the
      hypertrophic process are not known. In the present work we determine ANF and BNP
      synthesis and secretion in the aortic-banded rat treated with dosage schedules of
      the ACE inhibitor ramipril that result in the prevention or regression of both
      hypertension and hypertrophy (high dosage) or in the prevention or regression of
      hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain
      (MHC) isoform switch was studied as an indicator of ventricular cardiocyte
      hypertrophy as well as the levels of collagen III mRNA as a measure of changes in
      extracellular matrix. METHODS AND RESULTS: Ramipril was administered for 6 weeks
      just after suprarenal aortic banding, or rats were banded for 6 weeks, after
      which ramipril was administered during the following 6 weeks. Banding caused an
      increase in blood pressure, left ventricular weight-to-body weight ratio, plasma
      and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA.
      Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10
      micrograms/kg normalized left ventricular weight-to-body weight ratio but not
      blood pressure. Plasma and ventricular NP content and mRNA levels were partially
      normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented
      increased collagen III mRNA levels but did not affect beta-MHC mRNA levels.
      CONCLUSIONS: (1) NP production and secretion in aortic-banded rats are
      independently related to increased blood pressure and hypertrophy. (2) A load
      dependent component is more important than a load-independent component in
      regulating left ventricular NP production. (3) ANF production is more sensitive
      than BNP production to the load-independent component. (4) Low-dose ramipril
      treatment reverses hypertrophy and the increased collagen III expression but does
      not reverse the increased beta-MHC isoform expression, suggesting that these are
      independently regulated processes. (5) Aortic banding and ACE inhibition do not
      affect atrial NP production and content.

PMID- 8640984
TI  - Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in
      vivo. Acute effects of bosentan, an orally active, mixed endothelin ETA and ETB
      receptor antagonist.
AB  - BACKGROUND: Endothelin-1 (ET-1) has potent effects on cell growth and induces
      hypertrophy of cultured ventricular myocytes. Catecholamines increase expression
      of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in
      catecholamine-induced hypertrophy in vivo by studying the effects of continuous
      norepinephrine infusion on physical and molecular markers of ventricular
      hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute
      effects of bosentan, an orally active ETA and ETB receptor antagonist. METHODS
      AND RESULTS: Seventy male Sprague-Dawley rats (175 to 200 g) were divided into
      four groups: (1) sham-operated rats, (2) norepinephrine-infused rats (600
      micrograms.kg-1.h-1 by subcutaneous osmotic pump, up to 7 days), (3) sham
      operated rats given bosentan, and (4) norepinephrine-infused rats given bosentan.
      Bosentan (100 mg/kg once daily) was administered by gavage for 6 days starting 1
      day before operation. Norepinephrine caused increases in absolute ventricular
      weight and ratios of ventricular weight to body weight and ventricular RNA to
      protein. Ventricular expression of mRNAs for atrial natriuretic factor, skeletal
      alpha-actin, and beta-myosin heavy chain, which in adult rat ventricle are
      indicators of hypertrophy, also increased. Ventricular expression of ET-1 mRNA
      was elevated in the norepinephrine group at 1, 2, and 3 days. By 5 days, this had
      fallen to control levels. In lung, kidney, and skeletal muscle, norepinephrine
      did not significantly increase expression of ET-1 mRNA. Bosentan attenuated
      norepinephrine-induced increases in ventricular weight, ratio of RNA to protein,
      and expression of skeletal alpha-actin mRNA and beta-myosin heavy chain mRNA at 5
      days, but it did not attenuate increased ventricular expression of atrial
      natriuretic factor mRNA. CONCLUSIONS: These data suggest that endogenous ET-1
      plays a direct role in mediating norepinephrine-induced ventricular hypertrophy
      in vivo.

PMID- 8640985
TI  - Change in aortic end-systolic pressure by alterations in loading sequence and its
      relation to left ventricular isovolumic relaxation.
AB  - BACKGROUND: A brief, sustained constriction of the descending and the ascending
      aortas produces systolic loads at different times during ejection, and descending
      intervention prolongs left ventricular (LV) relaxation more than ascending
      intervention. Although alterations in the sequence of loading the ventricle have
      been suggested as a cause of such load-induced relaxation abnormalities, the
      relation of the loading system to relaxation has been unclear. METHODS AND
      RESULTS: LV peak systolic pressure was elevated by approximately 40 mm Hg by
      constricting the descending and ascending aortas in seven anesthetized dogs. The
      descending intervention increased aortic end-systolic pressure (AoESP, 110.4 +/-
      9.3 to 150.8 +/- 11.5 mm Hg; P < .05), reduced aortic flow (P < .05), and
      prolonged LV relaxation (time constant [T], 31.9 +/- 4.4 to 69.8 +/- 12.8 ms; P <
      .05). LV ejection time was reduced, but the systolic time interval was unchanged.
      In contrast, ascending intervention decreased AoESP (111.9 +/- 11.4 to 101.5 +/-
      10.3 mm Hg; P < .05), reduced aortic flow (P < .05), and prolonged T (31.2 +/-
      5.4 to 42.2 +/- 8.3 ms; P < .05), whereas ejection time and systolic time
      interval increased (both P < .01). Prolongation of T was significantly greater
      during descending intervention (P < .05) and was associated with an increase in
      AoESP during descending intervention but a decrease in AoESP during ascending
      intervention. CONCLUSIONS: Descending intervention induced greater prolongation
      of T than ascending intervention. Prolongation of T was closely related to an
      increase in AoESP in the descending intervention but a decrease in AoESP in the
      ascending intervention. These data suggest that not only the loading sequence but
      also the pressure level at the onset of isovolumic relaxation determines LV
      relaxation.

PMID- 8640986
TI  - Images in cardiovascular medicine. Recurrent thrombosis of bileaflet prosthetic
      valves.

PMID- 8640987
TI  - EPILOG and CAPTURE trials halted because of positive interim results.

PMID- 8640988
TI  - Have long-term benefits of antihypertensive therapy been underestimated?
      Provocative findings from the Framingham Heart Study.

PMID- 8640989
TI  - Pure beta-particle-emitting stents inhibit neointima formation in rabbits.
AB  - BACKGROUND: Considerable experimental evidence exists that neointimal hyperplasia
      after angioplasty is inhibited by gamma-irradiation of the treated arteries. A
      beta-particle radiation is absorbed in tissue within a shorter distance away from
      the source than gamma-radiation and may be more suitable for localized vessel
      irradiation. This study outlines a method to implant a beta-particle-emitting
      radioisotope (32P; half-life, 14.3 days) into metallic stents. The effects of
      these stents on the inhibition of neointimal hyperplasia was compared with
      conventional stents in a rabbit model. METHODS AND RESULTS: 32P was produced by
      irradiation of red amorphous phophorus (31P) with neutrons and was implanted into
      Palmaz-Schatz stents (7.5 mm in length) after being kept apart from 31P in a mass
      separator. The radioisotope was tightly fixed to the stents, and the ion
      implantation process did not alter the surface texture. Stent activity levels of
      4 and 13 microCi were chosen for the study. Four and 12 weeks after placement of
      conventional stents and 32P-implanted stents in rabbit iliac arteries, vascular
      injury and neointima formation were studied by histomorphometry. Immunostaining
      for smooth muscle cell (SMC) alpha-actin was performed to determine SMC
      cellularity in the neointima. SMCs were quantified by computer-assisted counting
      of alpha-actin immunoreactive cells. Endothelialization of the stents was
      evaluated by immunostaining for endothelial cell von Willebrand factor. No
      difference in vessel wall injury was found after placement of conventional and
      32P-implanted stents. Neointima formation was potently inhibited by 32P-implanted
      stents only at an activity level of 13 microCi after 4 and 12 weeks. Neointimal
      SMC cellularity was reduced in 32P-implanted stents compared with conventional
      stents. Radioactive stents were endothelialized after 4 weeks, but
      endothelialization was less dense than in conventional stents. CONCLUSIONS:
      Neointima formation in rabbits is markedly suppressed by a beta-particle-emitting
      stent incorporating the radioisotope 32P. In this model, a dose-response relation
      with this type of radioactive stent was observed, indicating that a threshold
      radiation dose must be delivered to inhibit neointima formation after stent
      placement over the long term.

PMID- 8640990
TI  - Enhanced coronary vasoconstriction to endothelin-B-receptor activation in
      experimental congestive heart failure.
AB  - BACKGROUND: Endothelin (ET), a coronary vasoconstrictor, mediates its activity
      through the specific receptors ET-A and ET-B, which may demonstrate different
      activity under pathophysiological conditions. Thoracic inferior vena cava
      constriction (TIVCC) is an experimental model of congestive heart failure that is
      characterized by a decrease in cardiac output and an increase in circulating ET
      concentrations. The present study was designed to test the hypothesis that
      experimental heart failure altered coronary vascular responsiveness to ET-A- and
      ET-B-receptor stimulation in vivo. METHODS AND RESULTS: ET-1 was infused at a
      rate of 2 ng/kg per minute into the left circumflex coronary artery in normal
      dogs (n = 5) and in dogs subjected to TIVCC (TIVCC dogs, n = 6). Similarly,
      sarafotoxin, an ET-B-receptor agonist, was infused at the same dosage in normal
      (n = 5) and TIVCC (n = 6) dogs. Intracoronary infusion of ET-1 significantly
      decreased coronary blood flow and increased coronary vascular resistance in
      normal dogs; this effect was significantly attenuated in TIVCC compared with
      normal dogs. The percent changes in coronary blood flow and coronary vascular
      resistance in the TIVCC compared with the normal dogs was -11 +/- 8% versus -48
      +/- 7% (P < .01) and 29 +/- 10% versus 105 +/- 23% (P < .01), respectively. There
      was no significant effect on coronary blood flow, coronary vascular resistance,
      or coronary artery diameter in normal dogs that received an intracoronary
      infusion of sarafotoxin. In contrast, the administration of intracoronary
      sarafotoxin in TIVCC compared with normal dogs resulted in significant percent
      changes in coronary blood flow and coronary vascular resistance (-31 +/- 4%
      versus -7 +/- 3% [P < .001] and 53 +/- 12% versus 12 +/- 8% [P < .02],
      respectively). CONCLUSIONS: The present study demonstrates an attenuated coronary
      vasoconstrictor response to ET-1 with an enhanced vasoconstrictor response to
      sarafotoxin and suggests an alteration in coronary ET receptor sensitivity in
      experimental heart failure.

PMID- 8640991
TI  - Effect of coronary artery diameter in patients undergoing coronary bypass
      surgery. Northern New England Cardiovascular Disease Study Group.
AB  - BACKGROUND: Coronary artery diameter is known to be inversely associated with
      perioperative mortality related to coronary artery bypass grafting (CABG). This
      association is believed to be responsible for increased risk among women and
      smaller people. However, the associations between sex, body size, and coronary
      size have not been carefully examined because direct information about coronary
      size is rarely available. Also, whether sex has an independent effect on vessel
      size is largely unknown. METHODS AND RESULTS: Height, weight, sex, age, status at
      hospital discharge, and luminal diameter of the midleft anterior descending
      coronary artery (mid-LAD) were recorded prospectively in 1325 patients undergoing
      CABG. Small vessel size was associated with substantially increased risk of in
      hospital mortality (15.8% for 1.0-mm vessels, 4.6% for 1.5- to 2.0-mm vessels,
      and 1.5% for 2.5- to 3.5-mm vessels, P[trend] < .001). Vessel size was strongly
      related to both sex and measures of body size. In multiple linear regression
      analysis, vessel size was positively correlated with body surface area (P[trend]
      < .01), body mass index (P[trend] = .004), height (P[trend] = .001), and weight
      (P[trend] = .001). After controlling for differences in age and body size, sex
      remained an important predictor of coronary size. Within each quartile of each
      body-size measure, mid-LAD diameter in men was greater than that in women (mean
      difference [range], 0.14 to 0.23 mm). CONCLUSIONS: Small mid-LAD diameter is
      associated with substantially increased risk of in-hospital mortality with CABG.
      Although body size is correlated with mid-LAD diameter, women have smaller
      coronary arteries than men after controlling for differences in body size. These
      findings further support the hypothesis that smaller coronary arteries explain
      higher perioperative mortality with CABG in women and smaller people.

PMID- 8640992
TI  - ATP-dependent potassium channel in rat cardiomyocytes is blocked by lidocaine.
      Possible impact on the antiarrhythmic action of lidocaine.
AB  - BACKGROUND: During myocardial ischemia, lidocaine has favorable antiarrhythmic
      properties. Malignant arrhythmias result from heterogeneity between ischemic and
      nonischemic regions in extracellular potassium concentration and action potential
      duration. These effects have been attributed to the activation of ATP-dependent
      potassium (KATP) channels. In this study, we investigated the action of lidocaine
      on the KATP channels to test the possible link between the antiarrhythmic
      properties of lidocaine and its action on the KATP channel. METHODS AND RESULTS:
      The patch-clamp technique was employed on enzymatic dissociated cardiomyocytes of
      adult rats. Lidocaine was applied to the outer side of excised membrane patches
      by means of a multibarrel perfusion system. Lidocaine reversibly blocked the mean
      current of the KATP channels in a concentration-dependent manner (IC50 = 43 +/-
      4.7 mumol/L, E = 0 mV, n = 6), while the amplitude of the single-channel current
      remained unchanged. The half-maximum blocking concentration corresponds to the
      therapeutic range for the antiarrhythmic application of a lidocaine bolus in
      humans. CONCLUSIONS: The open probability but not the conductance of the KATP
      channel in the membrane of rat cardiomyocytes is blocked by lidocaine. This
      action may explain, in part, the favorable antiarrhythmic properties of lidocaine
      during acute myocardial ischemia.

PMID- 8640993
TI  - Value of magnetic resonance imaging in assessing patency and function of coronary
      artery bypass grafts. An angiographically controlled study.
AB  - BACKGROUND: Previous studies have demonstrated the high sensitivity and moderate
      specificity of standard magnetic resonance (MR) spin-echo (SE) and gradient-echo
      (GE) techniques in predicting the patency of coronary artery bypass grafts. These
      techniques, however, do not provide quantitative information. Therefore, the
      objectives of this study were first to investigate whether MR cine GE images,
      performed in addition to standard SE images, have additional value for the
      assessment of graft patency and second to assess the graft function by measuring
      the flow pattern and flow rate with MR phase velocity imaging. METHODS AND
      RESULTS: Forty-seven patients with previous histories of coronary artery bypass
      grafting underwent angiography and MR SE and cine GE phase velocity imaging. SE
      and GE images were evaluated by three independent observers blinded to the
      angiographic results. The spatial mean velocity and volume flow were measured and
      repeated for each image at consecutive 50-millisecond intervals throughout the
      cardiac cycle. The 47 patients had 98 proximal aortotomies, of which 60 were
      single and 38 sequential grafts. Seventy-three grafts were patent; 25 were
      occluded. Eighty-four grafts (86%) were eligible for comparison of the results of
      SE and GE images. Assessment of patency was inconclusive on SE images in 7 grafts
      (5 occluded by angiography) and on GE images in 7 grafts (2 occluded). A
      comparison of the results of contrast angiography and SE and GE MR imaging
      techniques showed that both techniques had a high sensitivity (both 98%) and
      somewhat lower specificity (85% and 88%, respectively) for graft patency.
      Combined analysis of the SE and GE images did not improve the accuracy. The
      strength of the interobserver agreement on GE images was good (kappa = 0.66),
      whereas on SE images the agreement was moderate (kappa = 0.51). Adequate MR phase
      velocity profiles were obtained in 62 (85%) of the 73 angiographically patent
      grafts. Graft flow was characterized by a balanced biphasic forward flow pattern.
      The volume flow of sequential grafts to 3 regions (136 +/- 106 mL/min) was
      significantly higher than in single grafts (63 +/- 41 mL/min, P < .01).
      CONCLUSIONS: Considering the good interobserver agreement and the 85% success
      rate of quantitative flow measurements, cine GE phase velocity mapping is a
      promising clinical tool in the noninvasive assessment of graft patency and
      function.

PMID- 8640994
TI  - Relation between activated clotting time during angioplasty and abrupt closure.
AB  - BACKGROUND: The purpose of this study was to determine whether the degree of
      heparin anticoagulation during coronary angioplasty, as measured by the activated
      clotting time, is related to the risk of abrupt vessel closure. METHODS AND
      RESULTS: Sixty-two cases of in- and out-of-laboratory abrupt closure in patients
      in whom intraprocedure activated clotting times were measured were identified
      from a population of 1290 consecutive patients who underwent non-emergency
      coronary angioplasty. This group was compared with a matched control population
      of 124 patients who did not experience abrupt closure. Relative to the control
      population, patients who experienced abrupt closure had significantly lower
      initial (median, 350 seconds [25th to 75th percentile, 309 to 401 seconds] versus
      380 seconds [335 to 423 seconds], P = .004) and minimum (345 seconds [287 to 387
      seconds] versus 370 seconds [321 to 417 seconds], P = .014) activated clotting
      times. Higher activated clotting times were not associated with an increased
      likelihood of major bleeding complications. Within this population, a strong
      inverse linear relation existed between the activated clotting time and the
      probability of abrupt closure. CONCLUSIONS: This study demonstrates a significant
      inverse relation between the degree of anticoagulation during angioplasty and the
      risk of abrupt closure. A minimum target activated clotting time could not be
      identified; rather, the higher the intensity of anticoagulation, the lower the
      risk of abrupt closure.

PMID- 8640995
TI  - Neovascular expression of E-selectin, intercellular adhesion molecule-1, and
      vascular cell adhesion molecule-1 in human atherosclerosis and their relation to
      intimal leukocyte content.
AB  - BACKGROUND: Leukocyte recruitment is an early event in atherogenesis, and the
      leukocyte adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM
      1), and vascular cell adhesion molecule-1 (VCAM-1) recently have been detected in
      human atherosclerosis. However, no previous study has evaluated either the
      distribution of these three molecules at different sites within the arterial
      intima or their relation to plaque leukocyte content. METHODS AND RESULTS:
      Immunohistochemistry was performed on 99 coronary artery segments (34 controls
      and 65 with atherosclerotic plaque) to identify E-selectin, ICAM-1, VCAM-1,
      macrophages, smooth muscle cells, and T lymphocytes. For each segment, the
      presence or absence of adhesion molecule was determined at the arterial lumen, on
      intimal neovasculature, and on intimal nonendothelial cells. Each segment was
      scored for intimal macrophage and T-lymphocyte densities on a semiquantitative
      scale of 0 to 3. In atherosclerotic plaques, the prevalences of E-selectin, ICAM
      1, and VCAM-1 on plaque neovasculature were twofold higher than their prevalences
      on arterial luminal endothelium. E-selectin was the only adhesion molecule for
      which expression on arterial luminal endothelial cells was more prevalent in
      plaques than in control segments. Increased plaque intimal macrophage density was
      associated with expression of VCAM-1 on neovasculature (P < .01) and on
      nonendothelial cells (P < .01). Increased plaque intimal T-lymphocyte density was
      associated with the presence of both ICAM-1 and VCAM-1 on neovasculature (both P
      < .01) and on nonendothelial cells (both P < .01). CONCLUSIONS: In
      atherosclerotic plaques, the expression of all three leukocyte adhesion molecules
      was more prevalent on intimal neovasculature than on arterial luminal
      endothelium. Further, the presence on neovasculature and nonendothelial cells of
      VCAM-1 and ICAM-1 was strongly associated with increased intimal leukocyte
      accumulation. These findings suggest that leukocyte recruitment through and/or
      activation of intimal neovasculature may play important roles in the pathogenesis
      of human atherosclerosis.

PMID- 8640996
TI  - Absence of focal compensatory enlargement or constriction in diseased human
      coronary saphenous vein bypass grafts. An intravascular ultrasound study.
AB  - BACKGROUND: No in vivo data are available on the occurrence of compensatory
      enlargement or vessel constriction in diseased human coronary saphenous vein
      bypass grafts (SVBGs). The aim of this intravascular ultrasound (IVUS) study was
      to examine to what extent lumen reduction is accompanied by (1) vessel wall
      thickening and (2) arterial wall constriction in SVBGs. METHODS AND RESULTS: We
      used IVUS to examine 43 SVBGs from 42 patients (32 men, 10 women; mean age, 72 +/
      5 years) 8 to 23 (11 +/- 4) years after SVBG. IVUS images were obtained with a
      3.5F monorail ultrasound catheter with a 30-MHz frequency and were analyzed at
      the lesion site, the reference site, and an intermediate site. The lumen area was
      significantly (P < .01) decreased; the vessel wall area (SVBG cross-sectional
      area minus lumen area) and the plaque area (area within the external elastic
      lamina minus lumen area) were significantly (P < .01) increased from the
      reference site through the lesion site. However, SVBG cross-sectional area was
      the same at these three sites (24.0 +/- 8.1 versus 24.4 +/- 8.6 versus 24.5 +/-
      8.6 mm2, P = NS), and the external elastic lamina area was also quite constant in
      each vessel (17.8 +/- 6.0 versus 17.7 +/- 6.4 versus 17.6 +/- 6.2 mm2, P = NS).
      CONCLUSIONS: These in vivo IVUS data from human coronary SVBGs demonstrate that
      (1) no focal compensatory enlargement or vessel constriction occurred in stenotic
      segments compared with the reference segments and that (2) the absence of focal
      compensatory enlargement appears to be a potentially important factor in the
      progression of stenoses in coronary SVBGs.

PMID- 8640997
TI  - Effects of diuretic therapy on the development of tolerance to nitroglycerin and
      exercise capacity in patients with chronic stable angina.
AB  - BACKGROUND: Therapy with diuretics has been reported to prevent the development
      of nitrate tolerance. Importantly, diuretics may have independent antianginal
      effects through their effects on intravascular volume. The present investigation
      was designed to determine whether diuretic therapy could prevent the development
      of tolerance to continuous transdermal nitroglycerin. The study was also designed
      to examine whether diuretic therapy has an independent antianginal effect.
      METHODS AND RESULTS: Twelve patients with chronic stable angina were studied in a
      randomized, double-blind, crossover trial. Patients received diuretic
      (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each
      double-blind treatment period, patients underwent treadmill exercise testing on
      three separate occasions. The first exercise testing was performed after 7 to 10
      days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently,
      exercise testing was repeated on the first day of active transdermal
      nitroglycerin therapy and following 7 to 10 days of continuous transdermal
      nitroglycerin application. Therapy with a diuretic was associated with an
      increase in exercise capacity but had no effect on nitroglycerin tolerance.
      During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an
      increase in treadmill walking time to the development of moderate angina compared
      with placebo (371 +/- 26 versus 288 +/- 16 seconds, diuretic versus placebo, P <
      .01). Similar results were obtained during both acute and sustained nitroglycerin
      therapy. CONCLUSIONS: The results of this study demonstrate that therapy with a
      diuretic has no effect on the development of tolerance to continuous transdermal
      nitroglycerin. Interestingly, diuretic therapy itself has important antianginal
      effects and improves exercise capacity in patients with stable angina.

PMID- 8640998
TI  - Secular trends in long-term sustained hypertension, long-term treatment, and
      cardiovascular mortality. The Framingham Heart Study 1950 to 1990.
AB  - BACKGROUND: Cardiovascular morbidity and mortality result from the chronic
      processes involved in hypertension. However, long-term sustained (LTS)
      hypertension has received little attention. METHODS AND RESULTS: Trends in the
      prevalence of LTS hypertension and its treatment were assessed in 1950, 1960, and
      1970 among three cohorts of men and women in the Framingham Heart Study (Mantel
      Haenszel test). Cardiovascular disease (CVD) incidence and mortality were
      compared between patients with LTS hypertension with and without long-term
      treatment by use of the chi 2 test. Cox proportional hazards regression analysis
      was used to estimate 10-year risk of death as a function of risk factor levels
      and treatment. Prevalence of LTS hypertension rose from 138 to 208 per 1000
      between the 1950 and 1970 male cohorts (P < .01), while prevalence fell from 253
      to 198 per 1000 between the female cohorts (P < .02). Long-term treatment
      increased 51% between the male cohorts and 45% between the female cohorts (both P
      < .001). While CVD incidence was similar (26% versus 25%), all-cause mortality
      was significantly lower among men with long-term treatment (31% versus 43%; P <
      .05), and CVD mortality was less than half (13% versus 28%; P < .01). Among
      treated women, all-cause mortality was 21% (versus 34%; P < .01), and CVD
      mortality was 9% (versus 19%; P < .01). Ten-year risk of CVD death for patients
      with LTS hypertension with long-term treatment compared with those without was
      0.40 (95% CI, 0.27 to 0.60). CONCLUSIONS: This investigation of LTS hypertension,
      its treatment, and its sequelae in a free-living general population confirms the
      reduction in CVD mortality demonstrated in more short-term clinical trials of
      hypertension therapy in select patient groups.

PMID- 8640999
TI  - Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing
      human heart.
AB  - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine
      that produces negative inotropic effects in the heart. Recently, elevated levels
      of TNF-alpha have been reported in patients with advanced congestive heart
      failure. Although TNF-alpha is thought to exert its deleterious effects by
      binding to two cell surface receptors, TNFR1 and TNFR2, the level of expression
      and regulation of TNF receptors in the heart in cardiac disease states is not
      known. METHODS AND RESULTS: We examined mRNA and protein levels for TNFR1, TNFR2,
      and TNF-alpha in explanted hearts from organ donors as well as in patients with
      end-stage dilated cardiomyopathy (DCM) and ischemic heart disease (IHD). Northern
      blot analysis revealed that mRNA for TNFR1 and TNFR2 was present in nonfailing,
      DCM, and IHD hearts. TNFR1 and TNFR2 receptor protein levels, as measured by
      ELISA, were decreased 60% in DCM and IHD patients compared with nonfailing hearts
      (P < .005). To determine a potential mechanism for the decrease in TNF receptor
      expression, we measured levels of circulating soluble TNF receptors (sTNFRs) in
      DCM and IHD patients. This analysis showed that there was a significant one-and-a
      half to threefold increase in sTNFRs in DCM (P < .03) and IHD patients (P <
      .001). Another important finding was that TNF-alpha mRNA and TNF-alpha protein
      were present in the explanted hearts from DCM and IHD patients but not in
      nonfailing hearts. CONCLUSIONS: In summary, the results of this study constitute
      the initial demonstration that TNF receptor proteins are dynamically regulated in
      patients with advanced congestive heart failure. Moreover, the observation that
      failing hearts express elevated levels of TNF-alpha suggests that overexpression
      of this cytokine may be one of several different maladaptive mechanisms
      responsible for the progressive cardiac decompensation that occurs in advanced
      heart failure.

PMID- 8641000
TI  - Abnormal systolic intraventricular flow velocities after valve replacement for
      aortic stenosis. Mechanisms, predictive factors, and prognostic significance.
AB  - BACKGROUND: Dynamic intraventricular flow velocities after valve replacement for
      aortic stenosis have been associated with high in-hospital morbidity and
      mortality. The aims of the present study were to determine the mechanisms and
      preoperative predictors of abnormal flow velocity (AFV) after valve replacement
      for aortic stenosis and to assess the clinical course of patients with AFV after
      surgery. METHODS AND RESULTS: One hundred consecutive patients with pure aortic
      stenosis were studied prospectively before operation by cardiac catheterization
      and Doppler echocardiography. After surgery, intraventricular flow was studied by
      Doppler echocardiography at rest, during nipride infusion, and during dobutamine
      infusion. AFV (defined as a systolic dagger-shaped Doppler spectrum > 2 m/s)
      occurred in 14 patients at rest and in 27 patients during nipride and/or
      dobutamine infusion. In most patients, AFV was associated with left ventricular
      cavity squeezing. Left ventricular end-diastolic diameter, preoperative
      intraventricular flow velocity and septal-to-posterior wall thickness ratio by
      Doppler echocardiography, and mean transvalvular pressure gradient and ejection
      fraction by catheterization emerged as predictors of resting postoperative AFV.
      Patients with resting AFV had a higher incidence of dyspnea or hypotension (64%
      versus 21%, P < .01) and a longer hospital stay (13.1 +/- 5.8 versus 11.1 +/-
      2.5, P < .05) than patients without AFV. In contrast, at a 1-year follow-up, no
      patient with resting AFV died. CONCLUSIONS: First, AFV occurs in 14% of patients
      at rest after valve replacement for aortic stenosis and can be provoked or
      worsened by ventricular unloading or inotropic stimulation. Second, AFV is
      related more frequently to cavity squeezing than to systolic anterior motion of
      the mitral valve apparatus. Third, a typical pattern (small, hyperdynamic, and
      asymmetrically hypertrophied ventricle) is predictive for postoperative AFV and
      should be taken into account for the postoperative management. Finally, the
      presence of AFV at rest is associated with high in-hospital morbidity but good
      long-term prognosis.

PMID- 8641001
TI  - Induction of nitric oxide synthase in the human cardiac allograft is associated
      with contractile dysfunction of the left ventricle.
AB  - BACKGROUND: The mechanisms underlying cardiac contractile dysfunction after
      transplantation remain poorly defined. Previous work has revealed that inducible
      nitric oxide synthase (iNOS) is expressed in the rat heterotopic cardiac
      allograft during rejection; resultant overproduction of nitric oxide (NO) might
      cause cardiac contractile dysfunction via the negative inotropic and cytotoxic
      actions of NO. In this investigation, we tested the hypothesis that induction of
      iNOS may occur and be associated with cardiac allograft contractile dysfunction
      in humans. METHODS AND RESULTS: We prospectively studied 16 patients in the first
      year after cardiac transplantation at the time of serial surveillance
      endomyocardial biopsy. Clinical data, the results of biopsy histology, and
      echocardiographic and Doppler evaluation of left ventricular systolic and
      diastolic function were recorded. Total RNA was extracted from biopsy specimens,
      and mRNA for beta-actin, detected by reverse transcription-polymerase chain
      reaction (RT-PCR) using human specific primers, was used as a constitutive gene
      control; iNOS mRNA was similarly detected by RT-PCR using human specific primers.
      iNOS protein was detected in biopsy frozen sections by immunofluorescence.
      Myocardial cGMP was measured by radioimmunoassay, and serum nitrogen oxide levels
      (NOx = NO2 + NO3) were measured by chemiluminescence. iNOS mRNA was detected in
      allograft myocardium at some point in each patient and in 59 of 123 biopsies
      (48%) overall. In individual patients, iNOS mRNA expression was episodic and time
      dependent; the frequency of expression was highest during the first 180 days
      after transplant (P = .0006). iNOS protein associated with iNOS mRNA was detected
      by immunofluorescence in cardiac myocytes. iNOS mRNA expression was not related
      to the ISHLT histological grade of rejection or to serum levels of NOx but was
      associated with increased levels of myocardial cGMP (P = .01) and with both
      systolic (P = .024) and diastolic (P = .006) left ventricular contractile
      dysfunction measured by echocardiography and Doppler. CONCLUSIONS: These data
      support a relation between iNOS mRNA expression and contractile dysfunction in
      the human cardiac allograft.

PMID- 8641002
TI  - Diagnostic value of echocardiography in suspected endocarditis. An evaluation
      based on the pretest probability of disease.
AB  - BACKGROUND: We hypothesized that for the diagnosis of endocarditis, (1)
      transthoracic echocardiography (TTE) would be most valuable in patients with an
      intermediate clinical probability of the disease and (2) transesophageal
      echocardiography (TEE) would be most useful in patients with an intermediate
      probability when TTE either does not yield an adequate study or indicates an
      intermediate probability of endocarditis. We also sought to investigate the
      influence of echocardiographic results on antibiotic usage and its duration.
      METHODS AND RESULTS: TTE and TEE were performed in 105 consecutive patients with
      suspected endocarditis. Patients were classified as having either low,
      intermediate, or high probability of endocarditis on the basis of clinical
      criteria and separately on the basis of both TTE and TEE findings. TTE and TEE
      classified the majority (82% and 85%, respectively) of the 67 patients with a low
      clinical probability of endocarditis as having a low likelihood of the disease.
      Of the 14 patients with intermediate clinical probability, 12 had technically
      adequate TTE studies; 10 of these (83%) were classified as either high or low
      probability. All patients with intermediate clinical probability were classified
      as high or low probability by TEE. The majority of the 24 patients with high
      clinical probability were placed in the low-likelihood category by
      echocardiography (15 by TTE and 12 by TEE). There was concordance between TTE and
      TEE in 83% of all cases. TEE was useful for the diagnosis of endocarditis in
      patients with prosthetic valves and in those in whom TTE indicated an
      intermediate probability; these constituted < 20% of patients in our study. The
      course of antibiotic therapy was influenced only by the clinical profile and not
      by the echocardiographic results. CONCLUSIONS: Echocardiography should not be
      used to make a diagnosis of endocarditis in those with a low clinical probability
      of the disease. In those with an intermediate or high clinical probability, TTE
      should be the diagnostic procedure of choice. TEE for the diagnosis of
      endocarditis should be reserved only for patients who have prosthetic valves and
      in whom TTE is either technically inadequate or indicates an intermediate
      probability of endocarditis.

PMID- 8641003
TI  - Pathophysiology of chronic left ventricular dysfunction. New insights from the
      measurement of absolute myocardial blood flow and glucose utilization.
AB  - BACKGROUND: Chronically dysfunctional myocardium may improve after coronary
      revascularization. This condition was thought to be due to a chronically reduced
      myocardial blood flow (MBF). Recently, however, it has been shown that in
      patients without previous infarction but with chronic left ventricular
      dysfunction, baseline MBF was normal. METHODS AND RESULTS: To study the
      pathophysiology of chronic left ventricular dysfunction in patients with previous
      infarction, regional MBF (milliliter per minute per gram of water-perfusable
      tissue) and glucose utilization (MRG; micromoles per minute per gram) during
      hyperinsulinemic euglycemic clamp were measured with positron emission tomography
      in 30 patients before bypass. At baseline, 133 myocardial segments were normal,
      and 107 were dysfunctional. After revascularization, 59 of 107 segments improved,
      while 48 of 107 were unchanged. MBF was 0.92 +/- 0.25 mL.min-1.g-1 in normal
      segments, 0.87 +/- 0.31 mL.min-1.g-1 in improved segments (P = NS versus normal),
      and 0.82 +/- 0.40 mL.min-1.g-1 in unchanged segments (P < .05 versus normal). In
      90% of the dysfunctional segments, MBF was > 0.42 mL.min-1.g-1, a cutoff value
      corresponding to the mean MBF minus 2 SD in normal segments. The MRG was 0.71 +/-
      0.14 mumol.min-1.g-1 in 9 age-matched normal subjects, 0.45 +/- 0.19 mumol.min
      1.g-1 (P < .01) in normal segments, 0.44 +/- 0.14 mumol.min-1.g-1 in improved
      segments (P = NS versus normal), and 0.34 +/- 0.17 mumol.min-1.g-1 in unchanged
      segments (P < .01 versus normal and improved). CONCLUSIONS: The results suggest
      that resting MBF measured with 15O-labeled water in chronically dysfunctional
      segments is not reduced and that the myocardium of these patients is less
      sensitive to insulin than that of normal subjects.

PMID- 8641004
TI  - Initial experience with an implantable hemodynamic monitor.
AB  - BACKGROUND: Measurement of intracardiac hemodynamic parameters has been limited
      to brief periods in the acute care setting. We developed and evaluated an
      implantable hemodynamic monitor that is capable of measuring chronic right
      ventricular oxygen saturation and pulmonary artery pressure. METHODS AND RESULTS:
      The device consists of an electronic controller placed subcutaneously and two
      transvenous leads placed in the right ventricle (reflectance oximeter) and
      pulmonary artery (variable capacitance pressure sensor). Implantation was
      performed in 10 patients with severe left ventricular dysfunction. Average
      implant pulmonary artery pressures were systolic, 52 +/- 16 mm Hg; diastolic, 29
      +/- 11 mm Hg; and mean, 40 +/- 12 mm Hg. The mean right ventricular oxygen
      saturation at implant was 51%. Provocative maneuvers, including postural changes,
      sublingual nitroglycerin, and bicycle exercise, demonstrated expected changes in
      measured oxygen saturation and pulmonary artery pressures over time. At follow-up
      of 0.5 to 15.5 months, there were no significant differences between pulmonary
      artery pressures or oxygen saturation values transmitted from the device and
      simultaneous measurement with balloon flotation catheters. Four of the pulmonary
      artery leads dislodged and three demonstrated sensor drift, whereas two of the
      oxygen saturation sensors failed. Four patients died and four received
      transplants. Pathological study did not demonstrate injury to the right
      ventricular outflow tract or pulmonic valve. CONCLUSIONS: Chronic measurement of
      hemodynamic parameters in the outpatient setting with implantable sensor
      technology appears to be feasible. The devices are well tolerated without
      significant untoward effects, and the sensors generally function well over time,
      providing reliable information. Clinical usefulness remains to be established.

PMID- 8641005
TI  - Incidence and clinical significance of multiple consecutive, appropriate, high
      energy discharges in patients with implanted cardioverter-defibrillators.
AB  - BACKGROUND: Some patients with an automatic implantable cardioverter
      defibrillator (ICD) suffer multiple appropriate, consecutive, high-energy
      discharges (MCDs) during follow-up. Such events might represent resistant
      ventricular arrhythmias and might have prognostic significance. METHODS AND
      RESULTS: Eighty consecutive patients with an ICD were followed up for up to 82
      months (mean, 21 +/- 19 months). Thirty-eight patients had survived an out-of
      hospital cardiac arrest and 42 had recurrent ventricular tachycardia. During
      follow-up, 16 patients had MCD (group A), 26 patients had episodes of single
      appropriate discharges (group B), and 38 patients had no appropriate discharges
      (group C). Group A patients had worse functional status (P = .001), lower left
      ventricular ejection fractions (LVEFs) (P = .001), and lower survival rates (log
      rank, P = .003) than the remaining two groups of patients. Cox analysis showed
      LVEF (P = .001) to be an independent predictor of MCD. Independent predictors of
      death or heart transplant were MCD (P = .001), female sex (P = .001), age (P =
      .001), history of cardiac arrest (P = .003), and functional status (P = .003).
      The only independent predictor of total mortality was female sex (P = .002).
      Independent predictors of cardiac death were MCD (P = .007) and female sex (P =
      .018). Independent predictors of arrhythmic death were age (P = .001), female sex
      (P = .02), and MCD (P = .023). CONCLUSIONS: In patients with an ICD, the
      development of MCD is an independent predictor of cardiac and arrhythmic
      mortality. If this finding is confirmed in larger studies, it may help to
      identify patients in whom other therapeutic alternatives, ie, heart
      transplantation, should be considered during follow-up after ICD implantation.

PMID- 8641006
TI  - Chronic treatment with carbachol sensitizes the myocardium to cAMP-induced
      arrhythmia.
AB  - BACKGROUND: The present study investigated biochemical and functional
      consequences of chronic activation of the inhibitory Gi alpha-coupled adenylyl
      cyclase pathway in the heart. METHODS AND RESULTS: Rats (220 to 260 g) were
      treated with 4-day infusions of the M-cholinoceptor agonist carbachol (9.6 mg/kg
      per day) or vehicle. An additional group that received the beta-adrenoceptor
      agonist isoprenaline (2.4 mg/kg per day) served as control. The main finding was
      that chronic infusion of carbachol led to a marked increase in isoprenaline- or
      forskolin-induced arrhythmia in electrically driven papillary muscles (in vitro).
      Compared with control, the potency of isoprenaline and forskolin to induce
      arrhythmia in cardiac preparations from carbachol-treated rats was increased 36-
      and 2.2-fold and the efficacy was increased 7.3- and 2.3-fold, respectively. The
      potency of carbachol to antagonize the isoprenaline- and forskolin-induced
      arrhythmia was decreased 30-fold. These changes were accompanied by a decrease in
      left ventricular M-cholinoceptor density by 15% (P < .05) and a decrease in
      pertussis toxin-sensitive G proteins (Gi alpha) by 26% (P < .05) without a
      decrease in the corresponding mRNAs. beta-Adrenoceptor density and basal and
      stimulated adenylyl cyclase activity remained unchanged. In contrast,
      isoprenaline infusion induced a decrease in arrhythmogenic potency of forskolin
      (P = NS), which was accompanied by a decrease in beta-adrenoceptor density, an
      increase in Gi alpha protein and mRNA levels, and a decrease in basal and
      stimulated adenylyl cyclase activity. CONCLUSIONS: Chronic parasympathetic
      activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes
      may be due to quantitative alterations in functional Gi alpha.

PMID- 8641007
TI  - Processing of chimeric antisense oligonucleotides by human vascular smooth muscle
      cells and human atherosclerotic plaque. Implications for antisense therapy of
      restenosis after angioplasty.
AB  - BACKGROUND: Antisense oligonucleotides have been used in animals to inhibit the
      accumulation of vascular smooth muscle cells (VSMCs) after arterial injury. This
      has raised prospects for an oligonucleotide-mediated approach to prevent
      restenosis in patients undergoing angioplasty. However, little is known about the
      processing of oligonucleotides by human VSMCs or their bioavailability in human
      atherosclerotic tissue. METHODS AND RESULTS: Oligonucleotides were synthesized
      with a mixture of unmodified and sulfur-modified linkages (S-chimeric
      oligonucleotides). These were more stable than unmodified oligonucleotides and
      could be recovered from within human VSMCs after 36 hours. Oligonucleotide
      antisense to human proliferating cell nuclear antigen mRNA specifically reduced
      DNA synthesis (P < .01) and proliferating cell nuclear antigen protein content (P
      < .05) in human VSMCs. Confocal microscopy of both live and fixed cells showed
      modest oligonucleotide uptake that was primarily nuclear. Surprisingly, cationic
      liposomes did not enhance nuclear uptake but led to extensive, punctated
      cytoplasmic loading without an enhanced antisense effect. Oligonucleotides
      incubated with human coronary atherosclerosis fragments associated with cells
      within 1 hour, despite the presence of abundant extracellular matrix.
      CONCLUSIONS: S-chimeric oligonucleotides are stable and can specifically inhibit
      gene expression in human VSMCs. Nuclear transport is a feature of oligonucleotide
      processing by human VSMCs, indicating a potential influence at the nuclear level
      rather than with cytoplasmic mRNA. Cationic liposomes increased oligonucleotide
      uptake but not intracellular bioavailability, and S-chimeric oligonucleotides can
      be incorporated into cells within human atherosclerotic plaque, despite the
      presence of a dense extracellular matrix.

PMID- 8641008
TI  - Role of activation of protein kinase C in the infarct size-limiting effect of
      ischemic preconditioning through activation of ecto-5'-nucleotidase.
AB  - BACKGROUND: We have reported previously that ischemic preconditioning limits
      infarct size by increasing ecto-5'-nucleotidase activity. Since we have also
      reported that protein kinase C activation increases ecto-5'-nucleotidase activity
      in rat cardiomyocytes, we tested whether activation of protein kinase C during
      ischemic preconditioning contributes to the infarct size-limiting effect through
      augmentation of ecto-5'-nucleotidase activity in the canine heart. METHODS AND
      RESULTS: The coronary artery was occluded four times for 5 minutes with
      alternating 5-minute periods of reperfusion (ischemic preconditioning). Then the
      coronary artery was occluded for 90 minutes followed by 6 hours of reperfusion.
      Infarct size, normalized by the risk area, in the ischemic preconditioning group
      was smaller than in the control group (42.6 +/- 3.6% in the control group versus
      7.9 +/- 1.8% in the ischemic preconditioning group, P < .001). Myocardial ecto-5'
      nucleotidase activity was increased after the ischemic preconditioning procedure
      but the increase in ecto-5'-nucleotidase was attenuated by inhibitors of protein
      kinase C (polymyxin B and GF109203X). Both polymyxin B and GF109203X blunted the
      infarct size-limiting effect of ischemic preconditioning (infarct size 33.1 +/-
      6.9% and 35.1 +/- 6.4%, respectively). The infarct size-limiting effect was also
      blunted by an inhibitor of ecto-5'-nucleotidase. Transient administration of
      methoxamine mimicked the increase in ecto-5'-nucleotidase activity and the
      infarct size-limiting effect, both of which were abolished by inhibitors of
      protein kinase C. CONCLUSIONS: We conclude that activation of ecto-5'
      nucleotidase and protein kinase C contributes to the infarct size-limiting effect
      of ischemic preconditioning.

PMID- 8641010
TI  - Differential cardiac effects of growth hormone and insulin-like growth factor-1
      in the rat. A combined in vivo and in vitro evaluation.
AB  - BACKGROUND: Despite their increasing clinical use and recent evidence that growth
      hormone (GH) and insulin-like growth factor-1 (IGF-1) target the heart, there has
      been no systematic investigation of the effects of GH and IGF-1 on the
      cardiovascular system. METHODS AND RESULTS: Sixty normal but growing adult female
      rats were randomized to receive 4 weeks of treatment with GH (3.5 mg.kg-1.d-1),
      IGF-1 (3 mg.kg-1.d-1), a combination of the two, or placebo. Transthoracic
      echocardiograms were performed at baseline and at 2 weeks and 4 weeks of
      treatment. After the final echocardiography, rats underwent either closed-chest
      left ventricular (LV) catheterization or Langendorff perfusion studies. Myocyte
      diameter and interstitial tissue fraction were assessed by morphometric
      histology. Echocardiographic and ex vivo data demonstrated a LV hypertrophic
      response in all three groups of treated animals that was most marked in the GH
      group, which alone exhibited a concentric growth pattern (relative wall
      thickness, 0.52 versus 0.42 to 0.44 in the other groups; P < .001). At 4 weeks,
      cardiac index was significantly higher and total systemic vascular resistance was
      lower in all groups of treated animals than in control animals (both P < .001),
      whereas arterial blood pressure did not differ significantly. All indexes of in
      vivo and in vitro cardiac function were higher in GH- and IGF-1-treated rats than
      in control animals, whereas combination therapy yielded a blunted effect. Myocyte
      diameter was increased in all three treated groups without an increase in
      interstitial tissue. CONCLUSIONS: Exogenous administration of GH and IGF-1 in the
      normal adult rat induces a cardiac hypertrophic response without development of
      significant fibrosis. Cardiac performance is increased both in vivo and in the
      isolated heart.

PMID- 8641009
TI  - Does antithrombotic therapy influence residual thrombus after thrombolysis of
      platelet-rich thrombus? Effects of recombinant hirudin, heparin, or aspirin.
AB  - BACKGROUND: Thrombolysis to normal flow in patients with acute myocardial
      infarction preserves left ventricular function and decreases mortality. Failure
      of early reperfusion, reocclusion, or residual thrombus may be due to concurrent
      activation of the platelet-coagulation system. Thus, we hypothesized that the
      best concomitant antithrombotic therapy (recombinant [r]-hirudin, heparin, or
      aspirin) will maximally accelerate thrombolysis by r-tissue-type plasminogen
      activator (rTPA) and reduce residual thrombus. METHODS AND RESULTS: Occlusive
      thrombi were formed in the carotid arteries of 29 pigs (by balloon dilatation
      followed by endarterectomy at the site of injury-induced vasospasm) and matured
      for 30 minutes before rTPA was started, with or without antithrombotic therapy.
      Thrombolysis was assessed with the use of angiography and measurement of residual
      thrombus. Pigs were allocated to one of five treatments: placebo, rTPA, rTPA plus
      r-hirudin, rTPA plus heparin, or rTPA plus intravenous aspirin. No placebo
      treated pig reperfused. Two of six animals treated with rTPA alone reperfused
      compared with seven of seven animals treated with rTPA plus r-hirudin
      (reperfusion time, 33 +/- 10 minutes), six of seven animals treated with rTPA
      plus heparin (reperfusion time, 110 +/- 31 minutes), and two of six animals with
      rTPA plus aspirin. The activated partial thromboplastin time was prolonged in
      only the rTPA plus r-hirudin group (25 +/- 0.1 times baseline) and the rTPA plus
      heparin group (5.3 +/- 0.2 times baseline). Residual 111In-platelet and 125I
      fibrin(ogen) depositions were lower in the heparin-treated group and lowest in
      the r-hirudin-treated group (heparin versus hirudin, respectively; incidence of
      residual macroscopic thrombus was six of six animals versus two of seven [P =
      .01]; 125I-fibrin(ogen), 170 +/- 76 versus 48 +/- 6 x 10(6) molecules/cm2 [P =
      .02]; 111In-platelets, 47 +/- 15 versus 13 +/- 2 x 10(6)/cm2, P = .10). No pigs
      developed spontaneous bleeding. CONCLUSIONS: Thrombin inhibition with heparin or
      r-hirudin significantly accelerated thrombolysis of occlusive platelet-rich
      thrombosis, but only the best antithrombotic therapy (r-hirudin) eliminated or
      nearly eliminated residual thrombus.

PMID- 8641011
TI  - Heparin and heparan sulfate block angiotensin II-induced hypertrophy in cultured
      neonatal rat cardiomyocytes. A possible role of intrinsic heparin-like molecules
      in regulation of cardiomyocyte hypertrophy.
AB  - BACKGROUND: Heparan sulfate, one of the primary components of extracellular
      matrix, is a potent antigrowth factor in certain types of cells. To elucidate a
      possible role of endogenous heparin-like molecules in regulating cardiomyocyte
      hypertrophy, we investigated the effects of heparin and heparan sulfate on
      angiotensin (Ang) II-induced hypertrophy in cultured neonatal rat cardiomyocytes.
      METHODS AND RESULTS: Competitive [3H]heparin binding assay showed that
      cardiomyocytes had specific binding sites for heparin. In situ [3H]heparin
      binding assay demonstrated that heparin, which rapidly bound to the cardiomyocyte
      surface, was subsequently accumulated around the nuclei, suggesting that heparin
      might work in the nucleus. Cotreatment with heparin (20 micrograms/mL) completely
      inhibited increased cell surface area by Ang II (10(-6) mol/L). Increased
      [3H]leucine incorporation by Ang II was reduced by heparin dose-dependently. The
      inhibitory effect of heparin on Ang II-induced cardiomyocyte hypertrophy also was
      confirmed by Northern blot analysis: heparin dose-dependently inhibited skeletal
      alpha-actin and atrial natriuretic peptide gene expression, genetic markers for
      cardiomyocyte hypertrophy. Heparan sulfate showed similar inhibitory effects on
      cell surface area, [3H]leucine incorporation, and skeletal alpha-actin gene
      expression. Treatment with heparinase I or III, which specifically digests the
      disaccharide chains of endogenous heparin-like molecules, upregulated protein
      synthesis and skeletal alpha-actin and atrial natriuretic peptide gene expression
      in cardiomyocytes. CONCLUSIONS: Our findings in this study strongly suggest that
      heparin and heparan sulfate are potent inhibitors of cardiomyocyte hypertrophy
      and that endogenous heparin-like substances negatively regulate cardiomyocyte
      hypertrophy.

PMID- 8641012
TI  - Mechanism of action of OPC-8490 in human ventricular myocardium.
AB  - BACKGROUND: The quinolinone compounds OPC-8212 (vesnarinone), OPC-18790, and OPC
      8490 are members of a family of unique positive inotropic compounds that have no
      positive chronotropic effects. In subjects with heart failure, the prototypic
      compound OPC-8212 may reduce morbidity and mortality at low doses but increase
      mortality at high doses. METHODS AND RESULTS: To further characterize the
      inotropic mechanism(s) of action of these compounds, we investigated the effects
      of OPC-8490, a water-soluble quinolinone, on the inotropic response, inhibition
      of phosphodiesterase (PDE), and action potential in human ventricular myocardial
      preparations. In isolated right ventricular trabeculae and membranes prepared
      from left ventricular myocardium, OPC-8490 produced dose-related positive
      inotropic effects, inhibited type III PDE activity, and prolonged action
      potential. Comparative experiments with other PDE inhibitors, sodium channel
      agonists, and potassium channel antagonists indicated that the positive inotropic
      effects are due to PDE inhibition, whereas the action potential effects of OPC
      8490 are due to effects on ion channels. CONCLUSIONS: We conclude that OPC-8490
      produces selective positive inotropic effects because of type III PDE inhibition
      combined with ion channel effects, with the latter property inhibiting the
      positive chronotropic response usually associated with agents that increase
      intracellular cAMP concentrations.

PMID- 8641013
TI  - Assessment of flow events at the ductus venosus-inferior vena cava junction and
      at the foramen ovale in fetal sheep by use of multimodal ultrasound.
AB  - BACKGROUND: Previous techniques for the study of the fetal circulation did not
      permit assessment of phasic events associated with the cardiac cycle. We used
      multimodal ultrasound techniques to examine flow events that occur in the major
      veins and across the foramen ovale in the circulation of the fetal lamb. METHODS
      AND RESULTS: We studied eight fetal lambs instrumented with catheters in the
      superior and inferior venae cavae and a peripheral umbilical vein and performed
      ultrasound studies that included M-mode and two-dimensional imaging, pulsed and
      Doppler color flow ultrasound, and contrast echocardiography to evaluate flow in
      the ductus venosus, in both venae cavae, and through the foramen ovale. Two blood
      streams of different flow velocities were identified within the cephalic portion
      of the inferior vena cava. The stream that originated from the narrowed ductus
      venosus had a higher velocity than that from the caudal inferior vena cava (mean
      velocity, 57 +/- 13 versus 16 +/- 3 cm/s; P < .0002). Facilitated by the
      eustachian valve and the septum primum, the ductus venosus stream preferentially
      passed through the foramen ovale to the left atrium. This flow occurred during
      most of the cardiac cycle, except for 19.6 +/- 2.3% of the cycle when the foramen
      ovale was closed during atrial contraction. Superior vena cava flow passed almost
      exclusively into the right atrium and tricuspid valve; a small amount that was
      refluxed from the right atrium into the inferior vena cava subsequently passed
      through the foramen into the left atrium. CONCLUSIONS: Visualization of fetal
      circulatory streaming at the venous sites by ultrasound techniques aids in
      understanding the function of the fetal circulation and may be helpful in
      detecting the human fetus that is hemodynamically compromised.

PMID- 8641014
TI  - Images in cardiovascular medicine. Constrictive pericarditis.

PMID- 8641015
TI  - Images in cardiovascular medicine. Hiatal hernia masquerading as left atrial
      mass.

PMID- 8641016
TI  - Recommendations for safe current limits for electrocardiographs. A statement for
      healthcare professionals from the Committee on Electrocardiography, American
      Heart Association.

PMID- 8641017
TI  - Improving the interface between biomaterials and the blood. The gene therapy
      approach.

PMID- 8641018
TI  - Evolution of echocardiography.
AB  - The evolution of echocardiography has been interesting and dramatic. The
      technology has grown and has become an integral part of the practice of
      cardiology. As with all technology, there are advantages and disadvantages. The
      principal disadvantage is the fact that education and training are imperative to
      provide high-quality examinations and proper interpretations. In addition, many
      of the diagnoses are still qualitative and subjective. The principal advantage is
      the amazing versatility of this technology. The wealth of information that can be
      provided both noninvasively with a transthoracic examination and invasively with
      either transesophageal or intravascular ultrasound is tremendous. The anatomic
      and physiological data provided frequently give definitive diagnoses. If
      performed properly and for the right reason, this test should be very cost
      effective and should be a major asset in the coming era of medical cost
      containment. There are many technological advances that should enhance this
      information. With technology such as digital recordings, it is hoped that the
      clinicians will have better access to these data and will be more comfortable in
      interacting with this important diagnostic tool.

PMID- 8641019
TI  - Inducible carboxypeptidase activity. A role in clot lysis in vivo.
AB  - BACKGROUND: An inducible carboxypeptidase activity in human plasma delays tissue
      type plasminogen activator (TPA)-induced clot lysis in vitro. We investigated
      whether carboxypeptidase activity is induced in vivo during thrombosis and
      thrombolytic therapy in a canine model of myocardial infarction. METHODS AND
      RESULTS: By use of synthetic substrate assays, dog plasma was shown to contain an
      inducible carboxypeptidase activity that is efficiently inhibited by potato
      carboxypeptidase inhibitor. This inhibitor accelerates TPA-mediated clot lysis in
      vitro by an average of 27% (n = 5, P = .046). Analysis of the inducible
      carboxypeptidase activity in plasma samples of dogs with electrically induced
      thrombosis of the circumflex coronary artery treated with TPA revealed that (1)
      inducible carboxypeptidase activity is increased during thrombosis (8.7 +/- 2.0
      U/L, P < .013) and thrombolytic therapy (9.9 +/- 1.8 U/L, P < .024) compared with
      baseline (3.2 +/- 2.0 U/L); (2) thrombosis is a prerequisite of carboxypeptidase
      induction during and after TPA infusion, since carboxypeptidase levels were lower
      in dogs without a coronary thrombus; and (3) a significant positive correlation
      (r = .6, P < .0069) of carboxypeptidase activity with time to restoration of
      blood flow was observed. CONCLUSIONS: These data indicate that carboxypeptidase
      activity is induced in vivo and may influence thrombolysis.

PMID- 8641020
TI  - Endothelial nitric oxide production and insulin sensitivity. A physiological link
      with implications for pathogenesis of cardiovascular disease.
AB  - BACKGROUND: Insulin sensitivity varies up to threefold in apparently healthy
      individuals, but the mechanism for this is unknown. We have examined the
      hypothesis that vascular endothelial nitric oxide production and insulin
      sensitivity are directly related in humans. METHODS AND RESULTS: Nineteen healthy
      male subjects were studied on 3 separate days 1 week apart during which time they
      underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic
      clamp technique (soluble insulin 1.5 mU . kg-1 . min-1) and measurement of in
      vivo basal and stimulated endothelial nitric oxide production by forearm venous
      occlusion plethysmography. There was a correlation between insulin sensitivity
      and forearm vasoconstrictor responses to NG-monomethyl-L-arginine, the substrate
      inhibitor of nitric oxide synthase (r = .52, P < .05). No correlations were
      observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium
      nitroprusside responses. CONCLUSIONS: Endothelial nitric oxide synthesis and
      insulin sensitivity are positively related in healthy humans, which suggests a
      direct physiological link.

PMID- 8641022
TI  - Common DNA polymorphisms at the lipoprotein lipase gene. Association with
      severity of coronary artery disease and diabetes.
AB  - BACKGROUND: DNA variants of the lipoprotein lipase gene are associated with
      changes in lipid metabolism similar to those in diabetes and may relate to the
      development of atherosclerotic lesions, particularly premature lesions. METHODS
      AND RESULTS: To determine whether lipoprotein lipase gene variants are relevant
      to ongoing atherogenesis, we explored relationships between two common
      lipoprotein lipase gene polymorphic markers, Pvu II at intron 6 and HindIII at
      intron 8; the severity of coronary artery disease (CAD); and lipid variables in
      475 white patients 65 years of age or younger. We assessed CAD severity as the
      number of significantly stenosed (> 50% luminal obstruction) major coronary
      arteries at angiography and by the Green Lane coronary score. We found a
      significant association between the Pvu II polymorphism and the number of
      significantly diseased vessels (P = .0099) and coronary score (P = .028), with
      the Pvu II(-) alleles associated with less severe disease. The HindIII
      polymorphism was not associated with severity but had an additive effect with the
      Pvu II polymorphism. There was a close relationship between the Pvu II(+/+)
      genotype and the presence of diabetes (P = .0025), with an OR of 3.12 (95% CI,
      1.30 to 7.49) compared with the Pvu II(-/-) genotype. The interaction between
      these polymorphisms and CAD severity (rather than occurrence) was independent of
      the levels of triglycerides and HDL cholesterol and of other lipid variables.
      There was also a dosage-dependent relationship between the Pvu II polymorphism
      and levels of triglyceride. The Pvu II(-) allele was associated with low levels
      and variances of triglycerides. CONCLUSIONS: We conclude that the lipoprotein
      lipase Pvu II polymorphism is significantly associated with CAD severity and with
      type II diabetes in CAD patients, independent of changes in circulating lipid
      levels. These findings may be relevant to mechanisms mediating atherogenesis.

PMID- 8641021
TI  - Levels of soluble cell adhesion molecules in patients with dyslipidemia.
AB  - BACKGROUND: Increased expression of cell adhesion molecules (CAMs) on the
      vascular endothelium has been postulated to play an important role in
      atherogenesis. Both in vitro and in vivo studies have suggested that dyslipidemia
      may increase expression of CAMs. METHODS AND RESULTS: To determine whether
      dyslipidemia is associated with increased expression of CAMs, we examined the
      levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular
      cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin (sE-selectin) in
      individuals with either hypercholesterolemia or hypertriglyceridemia and in
      control subjects matched for age and sex. Patients with hypertriglyceridemia had
      significantly higher levels of sVCAM-1 (739 +/- 69 ng/mL) compared with patients
      with hypercholesterolemia (552 +/- 63 ng/mL) and control subjects (480 +/- 56
      ng/mL). Levels of sICAM-1 were significantly increased in both the
      hypercholesterolemic and hypertriglyceridemic groups (298 +/- 29 and 342 +/- 31
      ng/mL, respectively) compared with the control group (198 +/- 14 ng/mL). Levels
      of sE-selectin were significantly increased in hypercholesterolemic patients (74
      +/- 9 ng/mL) compared with control subjects (48 +/- 5 ng/mL). Ten
      hypercholesterolemic patients were treated aggressively with atorvastatin alone
      or a combination of colestipol and either atorvastatin or simvastatin for a mean
      of 42 weeks and had an average LDL cholesterol reduction of 51%. Comparison of
      soluble CAMs before and after treatment showed a significant reduction only in sE
      selectin (77 +/- 11 versus 56 +/- 6 ng/mL, P < or = .03) but not for sVCAM-1 or
      sICAM-1. CONCLUSIONS: Although severe hyperlipidemia is associated with increased
      levels of soluble CAMs, aggressive lipid-lowering treatment had only limited
      effects on the levels. Increased levels of soluble CAMs in patients with
      hyperlipidemia may be a marker for atherosclerosis.

PMID- 8641023
TI  - Cigarette smoking potentiates endothelial dysfunction of forearm resistance
      vessels in patients with hypercholesterolemia. Role of oxidized LDL.
AB  - BACKGROUND: Risk factors for atherosclerosis such as hypercholesterolemia and
      hypertension are associated with endothelial dysfunction of conduit and
      resistance vessels; however, the interaction of these risk factors and underlying
      mechanisms affecting endothelial function remain to be determined. The present
      study investigated the role of long-term smoking and hypercholesterolemia and
      their impact on endothelial function of peripheral resistance vessels in relation
      to plasma levels of autoantibodies against oxidized LDL, which has been
      implicated in the development of endothelial dysfunction and atherosclerosis.
      METHODS AND RESULTS: The vascular responses to the endothelium-dependent agent
      acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium
      independent agent sodium nitroprusside (1,3, and 10 micrograms/min) were studied
      in normal control subjects (n = 10), patients with hypercholesterolemia (n = 15),
      long-term smokers (n = 15), and hypercholesterolemic patients who smoked (n =
      15). Drugs were infused into the brachial artery, and forearm blood flow (FBF)
      was measured by venous occlusion plethysmography. The FBF responses to
      acetylcholine were significantly blunted in all three patient groups compared
      with normal control subjects (P < .05). The acetylcholine-induced increase in FBF
      was significantly attenuated in patients with hypercholesterolemia who smoked
      compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (P
      < .05 for both). The response to sodium nitroprusside was not statistically
      different in all four groups. Plasma levels of autoantibody titer against
      oxidized LDL were inversely related to acetylcholine-induced changes in FBF (r = 
      .53, P < .002) and were substantially increased in the group with both risk
      factors. CONCLUSIONS: These results demonstrate that cigarette smoking and
      hypercholesterolemia synergistically impair endothelial function and that their
      combined presence is associated with increased plasma levels of autoantibodies
      against oxidized LDL. These observations raise the possibility that long-term
      smoking potentiates endothelial dysfunction in hypercholesterolemic patients by
      enhancing the oxidation of LDL.

PMID- 8641024
TI  - Coronary plaque erosion without rupture into a lipid core. A frequent cause of
      coronary thrombosis in sudden coronary death.
AB  - BACKGROUND: Coronary thrombosis has been reported to occur most frequently in
      lipid-rich plaques with rupture of a thin fibrous cap and contact of the thrombus
      with a pool of extracellular lipid. However, the frequency of coronary artery
      thrombosis with or without fibrous cap rupture in sudden coronary death is
      unknown. In this study, we compared the incidence and morphological
      characteristics of coronary thrombosis associated with plaque rupture versus
      thrombosis in eroded plaques without rupture. METHODS AND RESULTS: Fifty
      consecutive cases of sudden death due to coronary artery thrombosis were studied
      by histology and immunohistochemistry. Plaque rupture of a fibrous cap with
      communication of the thrombus with a lipid pool was identified in 28 cases.
      Thrombi without rupture were present in 22 cases, all of which had superficial
      erosion of a proteoglycan-rich plaque. The mean age at death was 53 +/- 10 years
      in plaque rupture cases versus 44 +/- 7 years in eroded plaques without rupture
      (P < .02). In the plaque-rupture group, 5 of 28 (18%) were women versus 11 of 22
      (50%) with eroded plaques (P = .03). The mean percent luminal area stenosis was
      78 +/- 12% in plaque rupture and 70 +/- 11% in superficial erosion (P < .03).
      Plaque calcification was present in 69% of ruptures versus 23% of erosions (P <
      .002). In plaque ruptures, the fibrous cap was infiltrated by macrophages in 100%
      and T cells in 75% of cases compared with 50% (P < .0001) and 32% (P < .004),
      respectively, in superficial erosions. Clusters of smooth muscle cells adjacent
      to the thrombi were present in 95% of erosions versus 33% of ruptures (P <
      .0001). HLA-DR expression was more often seen in macrophages and T cells in
      ruptures (25 of 28 cases) compared with expression in macrophages in superficial
      erosion arteries (8 of 22 cases, P = .0002). CONCLUSIONS: Erosion of proteoglycan
      rich and smooth muscle cell-rich plaques lacking a superficial lipid core or
      plaque rupture is a frequent finding in sudden death due to coronary thrombosis,
      comprising 44% of cases in the present study. These lesions are more often seen
      in younger individuals and women, have less luminal narrowing and less
      calcification, and less often have foci of macrophages and T cells compared with
      plaque ruptures.

PMID- 8641025
TI  - Circadian variation of ambulatory myocardial ischemia. Triggering by daily
      activities and evidence for an endogenous circadian component.
AB  - BACKGROUND: The morning peak in myocardial ischemia has been related to diurnal
      variations in physical and mental activities and to postural changes upon
      awakening. This study assesses (1) the effects of exogenous activity triggers at
      different times of the day and (2) the contribution of an endogenous (ie,
      activity- and posture-independent) circadian vulnerability for ambulatory
      ischemia. METHODS AND RESULTS: Sixty-three stable coronary artery disease
      patients underwent ambulatory ECG monitoring and completed a structured diary
      assessing physical and mental activities. During 2519 hours of observation, a
      morning increase in ischemia coincided with increases in physical and mental
      activities, and an evening decrease in ischemia coincided with a decline in
      activities. During the morning, ischemic versus ischemia-free periods were more
      likely to occur with high levels of physical activity (P < .001). High physical
      activity triggered ischemia to a lesser but still significant extent (P < .05) in
      the afternoon but not in the evening (P = NS). High levels of mental activity
      triggered ischemia significantly during the morning (P < .04) and evening (P <
      .04) but not in the afternoon. When a residualized score procedure was used to
      correct ischemic time for each patient's simultaneously measured activities, for
      hourly heart rates, or for activity-related heart rate fluctuations, the
      circadian variation in ischemia was still observed (P < .001), with a peak at 6
      AM. A significant increase in ischemia occurred immediately after awakening (P <
      .05), but activity-adjusted increases in morning ischemia persisted (P < .05) for
      2 hours after awakening. CONCLUSIONS: Exogenous factors (physical and mental
      activities) are most potent as triggers of ischemia during the morning hours, and
      the postural change after awakening contributes to the morning increase in
      ischemia. There is also evidence for an endogenous, activity-independent
      circadian influence on ischemic susceptibility that is independent of exogenous
      factors and that sustains the increase in ischemia upon awakening.

PMID- 8641026
TI  - Body weight, cardiovascular risk factors, and coronary mortality. 15-year follow
      up of middle-aged men and women in eastern Finland.
AB  - BACKGROUND: Body weight is closely related to several known cardiovascular risk
      factors, but it may also have an independent effect on the risk of coronary heart
      disease (CHD). In this study, we analyzed the association between body mass index
      (BMI) and smoking, serum cholesterol, and blood pressure at baseline, as well as
      how BMI and the other risk factors are related to CHD mortality. METHODS AND
      RESULTS: A total of 16 113 men and women aged 30 to 59 years were examined in
      eastern Finland in either 1972 or 1977. Serum cholesterol and blood pressure had
      a positive association and smoking had a negative association with BMI. During
      the 15-year prospective follow-up, mortality from CHD was positively associated
      with BMI. The BMI-associated risk ratio of CHD mortality, adjusted for age and
      study year, estimated from the Cox proportional hazards model was 1.04 (per
      kg/m2) (P < .001) among men. Inclusion of smoking in the model increased the risk
      ratio for BMI, whereas inclusion of serum cholesterol and blood pressure
      decreased it. In the model that included age, study year, and all three major
      cardiovascular risk factors, the BMI-associated risk ratio was 1.03 (P = .027).
      Among women, the BMI-associated risk ratio of CHD mortality adjusted for age and
      study year was 1.05 (P = .023) and the multifactorial adjusted risk ratio was
      1.03 (P = .151). CONCLUSIONS: Obesity is an independent risk factor for CHD
      mortality among men and also contributes to the risk of CHD among women. Part of
      the BMI-associated risk of CHD mortality is mediated through other known
      cardiovascular risk factors. By preventing overweight, a substantial part of CHD
      mortality may be prevented.

PMID- 8641027
TI  - Normalization of abnormal coronary vasomotion by calcium antagonists in patients
      with hypertension.
AB  - BACKGROUND: Endothelial dysfunction with a loss of endothelium-dependent
      vasodilation has been reported in patients with arterial hypertension. The
      purpose of the present study was to evaluate coronary vasomotor response to
      dynamic exercise in patients with coronary artery disease with and without
      arterial hypertension and to determine the effect of calcium antagonists on
      coronary vasomotion. METHODS AND RESULTS: Cross-sectional areas of a normal and a
      stenotic coronary vessel segment were examined in 79 patients with coronary
      artery disease at rest and during supine bicycle exercise (Ex). Change in luminal
      area after acute administration of a calcium antagonist (diltiazem or
      nicardipine), during exercise, and after sublingual nitroglycerin (percent change
      compared with rest = 100%) was assessed by biplane quantitative coronary
      arteriography. Patients were divided into two groups: Group 1 (control) consisted
      of 48 patients without (normotensive subjects, n = 30; hypertensive subjects, n =
      18) and group 2 of 31 patients with (normotensive subjects, n = 15; hypertensive
      subjects, n = 16) pretreatment with a calcium antagonist immediately before
      exercise. The groups did not differ with regard to clinical characteristics or
      hemodynamic data measured during exercise. Mean aortic pressure at rest, however,
      was significantly increased in hypertensive patients compared with normotensive
      subjects in group 1 (103 mm Hg versus 92 mm Hg, P < .01) and group 2 (110 mm Hg
      versus 98 mm Hg, P < .025). In group 1, exercise-induced vasomotor response was
      significantly different between normotensive and hypertensive patients in normal
      (+20% versus +1%, P < .003) and stenotic vessels (-5% versus -20%, P < .025).
      However, in group 2 there was coronary vasodilation in normotensive and
      hypertensive patients for both normal (delta Ex +23% versus +21%, P = NS) and
      stenotic vessel segments (+24% versus +26%, P = NS). CONCLUSIONS: Abnormal
      coronary vasomotion during exercise can be observed in hypertensive patients with
      reduced vasodilator response in normal arteries and enhanced vasoconstrictor
      response in stenotic arteries. Calcium antagonists prevent the abnormal response
      of normal and stenotic coronary arteries to exercise in hypertensive patients and
      thus may compensate for endothelial dysfunction with reduced vasodilator response
      to exercise.

PMID- 8641028
TI  - Heart rate variability assessment early after acute myocardial infarction.
      Pathophysiological and prognostic correlates. GUSTO ECG Substudy Investigators.
      Global Utilization of Streptokinase and TPA for Occluded Arteries.
AB  - BACKGROUND: Diminished heart rate variability is associated with less favorable
      prognosis after myocardial infarction. However, the prognostic value of early
      (first 48 hours) measurement and the influence of thrombolytic strategies,
      myocardial infarction location, left ventricular function, ST-segment shift, and
      infarct-related artery patency on heart rate variability have not been examined
      comprehensively. METHODS AND RESULTS: Heart rate variability and ST-segment
      analysis of 48-hour Holter tapes were performed with the use of a commercial
      system in 204 patients who were part of an ST-monitoring substudy of the Global
      Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) trial. Both
      time-domain measures (SD of the average normal RR interval for all 5-minute
      segments of a 24-hour ECG recording [SDANN] and percent difference between
      adjacent normal RR intervals > 50 ms computed over the entire 24-hour ECG
      recording [pNN50]) and frequency-domain measures (low frequency [LF], high
      frequency [HF], and LF/HF ratio) were assessed on days 1 and 2 after acute
      myocardial infarction. Coronary angiography performed within the first 24 hours
      was also available in 75% of the patients. All heart rate variability measures
      decreased between day 1 and day 2 (P = .001) except the LF/HF ratio. There was no
      difference in heart rate variability among groups assigned to one of four
      different thrombolytic treatment strategies (streptokinase/subcutaneous heparin,
      streptokinase/intravenous heparin, accelerated tissue plasminogen activator, and
      combination streptokinase/tissue plasminogen activator). Heart rate variability
      measures were lower in anterior versus nonanterior infarcts (SDANN, 53 +/- 21
      versus 63 +/- 24 ms; P < .005) and increased with TIMI grade 3 flow (LF, 5.3 +/-
      1.0 versus 4.8 +/- 1.2 ms2; P < .01) and better ejection fraction (r = .2, P <
      .03). An inverse correlation between the duration of ST shift and frequency
      domain measures was observed (LF, r = -.2, P < .009; HF, r = -2, P < .03). Lower
      LF/HF ratio by 24 hours after myocardial infarction was seen in those who
      ultimately died at 30 days (1.0 +/- 0.2 versus 1.3 +/- 0.2, P < .001) or at 1
      year (1.17 +/- 0.14 versus 1.26 +/- 0.19, P = .05). CONCLUSIONS: Changes in heart
      rate variability occurred early after thrombolysis and may be of prognostic
      value. Heart rate variability measures were improved in patients with better
      ejection fraction and greater angiographic patency. This suggests a possible
      mechanism for the enhanced survival observed with TIMI grade 3 flow in the GUSTO
      angiographic substudy. These data indicate that early heart rate variability
      assessment after myocardial infarction may be useful in noninvasive risk
      stratification.

PMID- 8641029
TI  - Left ventricular diastolic function in hypertension and role of plasma glucose
      and insulin. Comparison with diabetic heart.
AB  - BACKGROUND: Experimental production of glucose intolerance has been associated
      with increased diastolic stiffness of the left ventricle, accompanied by
      interstitial fibrosis. Because carbohydrate metabolism is altered in
      hypertension, we undertook the present study to assess the relation of diastolic
      dysfunction in hypertension to plasma glucose and insulin concentrations. The
      latter are also affected by obesity. To facilitate this analysis, we studied
      moderately obese hypertensives. Elucidation of these relations was then sought in
      diabetic subjects. METHODS AND RESULTS: Subjects undergoing catheterization for
      chest pain were included in the study when significant coronary disease was not
      present. In groups 1 (lean), 2 (obese), 3 (lean hypertensive), and 4 (obese
      hypertensives), intraventricular pressures and volumes were determined. Fasting
      plasma glucose, insulin, hemoglobinAIC, and glucose tolerance were assessed.
      Basal ejection fraction and end-systolic wall stress were normal in the four
      groups. Chamber stiffness was significantly elevated in the hypertensives and was
      higher in group 4 than in group 3 (P < .05). Diastolic dysfunction was correlated
      with fasting blood glucose (r = .69, P < .006) but not with plasma insulin or
      left ventricular mass. Chamber stiffness was also increased in diabetics, with a
      larger effect in the obese. CONCLUSIONS: Hypertension is associated with
      increased diastolic stiffness of the left ventricle, which is enhanced by
      moderate obesity, and abnormal carbohydrate metabolism. Experimentally and in
      humans, hypertension is associated with interstitial fibrosis of mycardium, the
      presumed basis for the diastolic dysfunction. Chamber stiffness in group 4
      hypertensives was similar to that in the lean diabetics but less than that in the
      obese diabetics. Although the latter exhibited a correlation with plasma
      hemoglobinAIC, the large rise in stiffness suggests a potential role for growth
      factors in further alteration of myocardial composition.

PMID- 8641030
TI  - Insulin modulation of beta-adrenergic vasodilator pathway in human forearm.
AB  - BACKGROUND: Insulin modulates sympathetic vasoconstriction, but the mechanisms
      underlying this effect are not completely elucidated. We have recently
      investigated the insulin effect on the alpha 1- and alpha 2-adrenergic
      vasoconstriction pathway, where it is still conflicting with the possible insulin
      influence on the beta-adrenergic vasodilator pathway. The aim of the present
      study was to investigate this issue. METHODS AND RESULTS: The study was performed
      on the forearm of healthy humans, and all test substances were infused into the
      brachial artery at systemically ineffective rates. In five subjects, we evaluated
      isoproterenol-induced vasodilation (1, 3, 6, and 9 ng. kg-1. min-1) both under
      control conditions and during insulin infusion (0.05 mU. kg-1. min-1). In another
      group of five subjects, we tested whether the vasorelaxant effect of sodium
      nitroprusside (1, 2, 4, and 8 ng . kg-1 . min-1) was modified by insulin.
      Moreover, to explore whether the interaction between insulin and forearm beta
      adrenergic pathway participates in insulin modulation of sympathetic-evoked
      vasoconstriction, we measured in six normal subjects the forearm vascular
      response to lower-body negative pressure under control conditions and during
      intrabrachial infusion of insulin alone and in combination with a selective beta
      adrenergic blocking agent (propranolol 10 micrograms/100 mL per minute). Finally,
      to verify whether insulin interaction with the beta-adrenergic pathway may also
      account for insulin modulation of alpha 2-adrenergic vasoconstriction, we
      assessed the vascular response to a selective alpha 2-adrenergic agonist before
      and after propranolol administration. Insulin exposure potentiated the vascular
      responsiveness to isoproterenol but did not affect the vasodilator response to
      sodium nitroprusside. Furthermore, the insulin-induced attenuation of sympathetic
      vasoconstriction was partially corrected by propranolol. In contrast, the insulin
      modulation of alpha 2-adrenergic vasoconstriction was not influenced by beta
      adrenergic blockade. CONCLUSIONS: Taken together, our results suggest that
      insulin modulation of sympathetic-induced vasoconstriction is carried out through
      an interaction of the hormone with the pathways of both alpha 2-and beta 
      adrenergic receptors.

PMID- 8641031
TI  - New insights into the pathophysiology of carotid sinus syndrome.
AB  - BACKGROUND: The pathophysiology of carotid sinus syndrome remains poorly
      understood. Currently, two main hypotheses are provided: a lesion at the level of
      carotid sinus receptors or a central defect at the level of the nuclei of the
      autonomic nervous system. The objective of our study was to present arguments in
      favor of one of these two hypotheses. METHODS AND RESULTS: Test selection was
      guided by the following hypothesis: a degenerative central or local lesion could
      be associated with dysfunctions in the structures surrounding or comprising the
      baroreflex centers or their pathways. To test this hypothesis, brain stem
      auditory-evoked potentials; somatosensory-evoked potentials; blink reflexes;
      sympathetic skin responses; and styloglossus, sternocleidomastoid, and superior
      trapezius muscle electromyography were systematically performed from the right
      and left sides in 17 patients with carotid sinus syndrome and in 17 sex- and age
      matched control subjects. Similar responses were found in the two groups for the
      "central" tests. Contrasting with this result, the electromyographic analysis of
      the sternocleidomastoid muscle differed significantly between the groups: 13
      (76%) had pathological responses in the carotid sinus syndrome group compared
      with only 4 (23.5%) in the control group (P < .01). Furthermore, the abnormality
      was found on the right and left sides in 9 patients (53%) in the study group and
      in none of the control group (P < .005). CONCLUSIONS: This study strongly
      suggests that the neuromuscular structures surrounding the carotid
      mechanoreceptors are involved in the carotid sinus syndrome; however, the exact
      mechanism remains speculative.

PMID- 8641032
TI  - Isolated peripheral pulmonary artery stenoses in the adult.
AB  - BACKGROUND: Isolated peripheral pulmonary artery stenosis (PPS) in the adult is
      rare and frequently unsuspected. We review in this article our experience with 12
      adult patients with isolated PPS, half of whom had been previously diagnosed with
      chronic pulmonary thromboembolic disease. METHODS AND RESULTS: The presentation,
      evolution, and management of 12 adults with isolated PPS, 17 to 51 years of age
      (mean, 36.2 +/- 9.7 years), were evaluated. Presenting symptoms were dyspnea and
      fatigue. Three patients had New York Heart Association (NYHA) functional class
      III or greater. Lung perfusion scans revealed multiple segmental abnormalities in
      flow distribution in all patients. Oxygen desaturation at rest was present in 4
      patients. At catheterization, right ventricular (RV) pressure was suprasystemic
      in 2 patients, systemic in 1, and more than half-systemic in 7. All had multiple
      bilateral non-uniform stenoses in segmental and subsegmental arteries. Balloon
      pulmonary angioplasty (BPA) to decrease RV hypertension and improve pulmonary
      flow distribution was performed in 11 patients. After BPA, vessel diameter
      increased > 50% in 10 patients, distal pulmonary artery pressure increased > or =
      30% in 6, and RV pressure decreased > 30% in 5. One patient died shortly after
      BPA as a result of pulmonary hemorrhage. Immediate procedural success was
      achieved in 9 of 11 patients. At a mean follow-up period of 52 +/- 32 months, 7
      patients had sustained symptomatic improvement (NYHA class I-II). CONCLUSIONS: We
      describe a severe syndrome of isolated PPS in the adult that mimics chronic
      pulmonary thromboembolic disease. Pulmonary hemodynamics and angiography are
      required for definitive diagnosis. BPA may offer these patients successful short
      term reduction in RV hypertension and alleviation of symptomatology.

PMID- 8641033
TI  - Apoptosis as a possible cause of gradual development of complete heart block and
      fatal arrhythmias associated with absence of the AV node, sinus node, and
      internodal pathways.
AB  - BACKGROUND: Gradually progressive development of complete heart block in young
      people often is associated with cardiac arrhythmia and sudden death, but the
      pathogenesis remains unexplained. METHODS AND RESULTS: A young woman with
      complete heart block died suddenly. Her mother had serological but no clinical
      evidence of antiphospholipid syndrome. Five brothers of another family had
      arrhythmia and heart block. Three died suddenly; the other two have automatic
      defibrillators and are alive. The hearts from the young woman and two of the
      three brothers who died were available for our histological examination of their
      cardiac conduction systems. In two of the three hearts, the AV node was absent;
      in the third heart, only fragments of the AV node remained. In all three hearts,
      the sinus node was nearly destroyed by a noninflammatory degeneration with no
      abnormal fibrosis or infiltrate. In each heart, the interatrial and internodal
      pathways were similarly involved, and in the young woman, there were no
      myocardial cells in which these pathways normally exist. CONCLUSIONS: In these
      three subjects with progressive development of complete heart block and various
      arrhythmias, all of whom died suddenly, the histological abnormalities of their
      cardiac conduction systems are best interpreted as resulting from apoptosis.
      Programmed cell death is a logical explanation for the pathogenesis of this
      puzzling clinical picture.

PMID- 8641034
TI  - Seeding of vascular grafts with genetically modified endothelial cells. Secretion
      of recombinant TPA results in decreased seeded cell retention in vitro and in
      vivo.
AB  - BACKGROUND: Seeding of small-diameter vascular grafts with endothelial cells
      (ECs) genetically engineered to secrete fibrinolytic or antithrombotic proteins
      offers the potential to improve graft patency rates. METHODS AND RESULTS: Sheep
      venous ECs were transduced with a retroviral vector encoding human tissue
      plasminogen activator (TPA). The ECs were seeded onto 4-mm-ID synthetic (Dacron)
      grafts. Retention of the seeded ECs was measured 2 hours after placement of the
      seeded grafts both in vitro in a nonpulsatile flow system and in vivo (in sheep)
      as femoral and carotid interposition grafts. On exposure to flow in vitro, ECs
      transduced with TPA were retained at a significantly lower rate (median, 67%)
      than either untransduced ECs (81%) or ECs transduced with a control retroviral
      vector producing beta-galactosidase (beta-Gal) (80%) (P < .05 for TPA versus
      either control). On implantation in vivo, ECs transduced with TPA were retained
      at a very low rate (median, 0%), significantly less than the retention of ECs
      transduced with the beta-Gal vector (32%; P < .00001). Decreased in vivo
      retention of ECs transduced with TPA correlated modestly with increased in vitro
      cellular passage level (r2 = .48; P < .0001) but not with in vivo blood flow rate
      (P = .45). Addition of the protease inhibitor aprotinin to the cell culture and
      graft perfusion media resulted in a significant (P < .05) increase in in vitro
      retention of ECs transduced with TPA. CONCLUSIONS: Increased TPA expression
      significantly decreases seeded EC adherence in vitro and in vivo. Gene therapy
      strategies for decreasing graft thrombosis may require expression of
      antithrombotic molecules that lack proteolytic activity.

PMID- 8641035
TI  - Intrinsic myocyte dysfunction and tyrosine kinase pathway activation underlie the
      impaired wall thickening of adjacent regions during postinfarct left ventricular
      remodeling.
AB  - BACKGROUND: Left ventricular remodeling after infarction is accompanied by
      dysfunction of regions adjacent to the infarct. We hypothesized that myocyte
      contractile abnormalities and elongation greater than in remote regions underlie
      adjacent-region dysfunction in the remodeled ventricle. The activation of the
      tyrosine kinase pathway, which mediates in vitro hypertrophy by stretch and/or
      angiotensin, was also assessed in myocytes separately isolated from adjacent and
      remote regions. METHODS AND RESULTS: ECG-gated magnetic resonance imaging short
      axis images were acquired 2 weeks after coronary ligation in rats. After the rats
      were killed, myocytes were isolated from animals with large (n = 7) and small (n
      = 7) infarcts and from 4 sham-operated controls. Regional wall thickening was
      correlated with local myocyte function and morphology. Cytochemistry for tyrosine
      phosphorylated proteins was performed in myocytes from the same regions.
      Remodeled ventricles were dilated relative to controls by 93.7%, and wall
      thickening in adjacent regions was less than in remote regions (27.8 +/- 6.11%
      versus 54.0 +/- 10.1%, P < .01). In large infarcts, cell extent and velocity of
      shortening were reduced in adjacent cells versus controls by 47% and 44%,
      respectively (P < .05). Myocyte shortening was reduced in adjacent versus remote
      regions (P < .06), and cell dysfunction correlated with impaired wall thickening
      (r = .72, P < .05). Myocytes in adjacent regions were longer than in remote
      regions (150.3 +/- 1.89 versus 143.1 +/- 1.76 microns, P < .05) and also showed
      88% more membrane-related phosphotyrosine clusters (P < .05). CONCLUSIONS: After
      infarction, impaired wall thickening in adjacent regions is accompanied by
      greater myocyte dysfunction and elongation than in remote regions. These
      abnormalities are associated with regional differences in the tyrosine kinase
      pathway activation, indicating a potential intracellular mechanism for
      postinfarct myocardial remodeling.

PMID- 8641036
TI  - Biological response to Bard Clamshell Septal Occluders in the canine heart.
AB  - BACKGROUND: The Clamshell Septal Occluder has been used to close various
      congenital heart defects. The purpose of this study was to evaluate the long-term
      biological response to this device after placement in the canine heart. Previous
      in vivo studies with device placement were limited to 60 days. METHODS AND
      RESULTS: An atrial septal defect was created in dogs by blade septostomy followed
      by balloon dilation. Both old and new (redesigned) devices were placed.
      Angiographic follow-up was performed at 1, 3, and 6 months and 1 and 2 years
      after device placement with groups of dogs euthanitized at the same intervals.
      Gross and microscopic assessment was done on the explanted devices. The implants
      were covered at least 50% by neointima at 1 month and covered completely by 3
      months. There was no thrombus formation. Areas of focal hemorrhage were evident
      at 1 month and were not present at 3 months. The fibrous capsule that covered the
      device became more densely organized and neovascularized by 2 years. A focal
      foreign body reaction at the device-tissue interface persisted for 2 years. There
      were no arm fractures with either the old or new devices in these dogs.
      CONCLUSIONS: The Bard Clamshell Septal Occluder is well tolerated in the canine
      heart for at least 2 years and elicits a normal healing process.

PMID- 8641037
TI  - 1H NMR spectroscopic imaging of myocardial triglycerides in excised dog hearts
      subjected to 24 hours of coronary occlusion.
AB  - BACKGROUND: Myocardial ischemic insult causes depression of fatty-acid beta
      oxidation and increased fatty-acid esterification with triglyceride (TG)
      accumulation. This accumulation has been demonstrated to occur in the territory
      with diminished blood flow surrounding an infarct, ie, the region at risk. To
      evaluate whether the extent of TG accumulation in the canine heart after 24 hours
      of ischemia could be detected, we applied myocardial 1H nuclear magnetic
      resonance (NMR) spectroscopic imaging (SI). METHODS AND RESULTS: Seven adult
      mongrel dogs underwent 24 hours of left anterior descending coronary artery
      occlusion. Postmortem, the hearts were excised and the size and location of the
      infarct were determined. With a Philips 1.5-T clinical NMR imaging/spectroscopic
      system, two-dimensional (2D) 1H NMR SI was performed. TG 1H NMR chemical shift
      images were reconstructed from the frequency domain spectra by numerical
      integration. A statistically significant (P < .05) increase in TG signal
      intensity was demonstrated in the region at risk compared with the nonischemic
      control region. There was an intermediate quantity of TG in the infarct region.
      Biochemical determination of tissue TG content (milligrams per gram wet weight)
      in the control, at-risk, and infarct regions confirmed the 1H NMR measurements.
      Histological evaluation with oil red O staining also demonstrated graded TG
      accumulation in myocytes. The highest TG levels were found in the at-risk region
      and the lowest levels in the control region. CONCLUSIONS: By use of 2D 1H NMR SI,
      the present study confirms and extends previous work that demonstrates
      preferential accumulation of TG in the reversibly injured myocardium after 24
      hours of coronary occlusion. This study provides an important step toward the
      clinical application of TG imaging. When TG imaging is ultimately possible,
      resultant data would have diagnostic, prognostic, and therapeutic implications.

PMID- 8641038
TI  - Images in cardiovascular medicine. Intra-aortic thrombus producing embolic
      arterial vascular disease.

PMID- 8641039
TI  - Calcium blockers and risk of myocardial infarction and coronary heart disease
      mortality.

PMID- 8641040
TI  - Nifedipine study.

PMID- 8641041
TI  - Nimodipine in patients with heart disease.

PMID- 8641042
TI  - Nifedipine trials.

PMID- 8641043
TI  - Nifedipine in patients with heart disease.

PMID- 8641044
TI  - Corrections to the nifedipine meta-analysis.

PMID- 8641045
TI  - Properties of prostaglandin E1.

PMID- 8641046
TI  - Inflammatory aneurysm of the ascending aorta mimicking intramural hemorrhage.

PMID- 8641047
TI  - Two isoforms of Xenopus retinoic acid receptor gamma 2 (B) exhibit differential
      expression and sensitivity to retinoic acid during embryogenesis.
AB  - We report the isolation of two retinoic acid receptor isoforms (RAR gamma), which
      differ only in the 5'untranslated and putative N-terminus A regions. The two
      isoforms appear to serve as early markers for the presumptive neural axis;
      however, their expression patterns differ. RAR-gamma 2.1 is first expressed at
      gastrulation at the dorsal lip and subsequently along the presumptive neural
      axis. RAR- gamma 2.2 represents the full-length sequence of a receptor cDNA
      already partially characterized and present as a maternal transcript [Ellinger
      Ziegelbauer and Dreyer (1991); Genes Dev 5:94-104, (1993): Mech Dev 41:31-46;
      Pfeffer and DeRobertis, (1994) Mech Dev: 45:147-153]. Unlike RAR-gamma 2.2, the
      2.1 variant is not expressed either in pre-somitic mesoderm or notochord. RAR
      gamma 2.1 is strongly expressed in branchial arches and to a lesser extent in the
      neural floor plate. The two isoforms also exhibit differential sensitivity to
      retinoic acid. Constitutive expression of RAR gamma 2.2 following neurulation
      appears to be depressed by treatment with retinoic acid, but domains of highest
      expression, namely, the head and tail, remain relatively unaffected, as do
      patterns of expression prior to late neurulation. By contrast, RAR-gamma 2.1 is
      not transcribed in retinoid-inhibited structures. Using microinjection
      techniques, we show that changes of RAR-gamma 2.1 expression in presumptive head
      structures occur as an early and local consequence of retinoic acid
      administration. Since RAR-gamma 2.1 expression is inhibited by retinoic acid, we
      tested to see if other treatments that perturb axis formation had any effect.
      Surprisingly, UV irradiation did not suppress that its inhibition by retinoic
      acid is not due solely to inhibition of anterior neural development. These
      experiments demonstrate a new subdivision of isoforms that undergo differential
      expression during development and that exhibit differential sensitivity to
      retinoic acid and to UV. This sensitivity and the presence of this isoform
      variant in regions that are known to exhibit polarizing activity strengthen the
      hypothesis that these receptors play a primary role during morphogenesis.

PMID- 8641048
TI  - Spatial expression of the hsr-omega (93D) gene in different tissues of Drosophila
      melanogaster and identification of promoter elements controlling its
      developmental expression.
AB  - Developmental expression of the heat shock inducible non-protein coding hsr-omega
      gene in several larval and adult tissues of Drosophila melanogaster was examined
      by in situ hybridization to transcripts in intact organs and by X-gal staining in
      the germline transformants and carrying the lacZ reporter gene under the control
      of hsr-omega promoter. This gene is expressed in a specific spatial pattern in
      all the larval and adult tissue types examined; however, its transcripts were
      specifically absent in certain gonadal cell types like the male as well as female
      gonial cells and in follicle cells and oocytes in ovary. All polytenised tissues
      like the prothoracic and salivary glands, certain regions of larval gut and the
      Malpighian tubules showed a greater abundance of hsr-omega transcripts with a
      strong hybridization in nuclei. Our results with promoter deletion variant
      germline transformants suggest that a region between -346bp to -844bp upstream
      contains major regulatory elements for developmental expression of this gene in
      most of the larval and adult tissues examined; however, this region is not
      sufficient for its normal expression in male and female reproductive systems. An
      analysis of the base sequence of the hsr-omega promoter (upto - 844 bp) reveals
      putative ecdysone receptor element half-sites and two GAGA factor binding sites
      which may be involved in its developmental expression and its ready inducibility.
      The widespread expression in most tissue types and the known lethality associated
      with its homozygous deletion, suggest that the variety of non-protein coding
      transcripts of the hsr-omega gene have vital "house-keeping" functions.

PMID- 8641049
TI  - Developmental alteration of the chromatin state at promoter/replication origin
      region of the aldolase B locus precedes transcriptional activation in the liver.
AB  - Liver-specific expression of the rat aldolase B (AldB) gene is conferred by
      proximal promoter region (-200 bp to + 1 bp), which is centered on an origin
      region of DNA replication. Transcriptional activation of the gene in the liver
      occurs during the late one-third of fetal stage. To know the mechanism involved
      in such activation, we studied developmental changes in chromatin structure and
      in the extent of CpG methylation in the promoter/origin region of the gene. At an
      early fetal stage, when the AldB gene in the liver is not yet activated, the gene
      chromatin had two DNase 1-hypersensitive sites in the promoter region. One
      corresponded to that typical of AldB-expressing cells in the adult. The other,
      located approximately 200 bp upstream of the above site, disappeared as the
      activation of transcription started. A CpG dinucleotide in the promoter/origin
      region was heavily methylated at an early stage of gestation, but progressively
      demethylated as the liver develops. This CpG site is located at the center of an
      important binding site for a transcription factor. These changes occurred early
      in the fetal stage, prior to the gene activation, and were thus thought to be
      associated with differentiation of the liver cell or with cessation of cell
      proliferation.

PMID- 8641050
TI  - Cloning and developmental expression of the ecdysone receptor gene from the
      spruce budworm, Choristoneura fumiferana.
AB  - Degenerate oligonucleotides were designed on the basis of conserved amino acid
      sequences in the DNA and ligand-binding regions of the members of the steroid
      hormone receptor superfamily. Using these oligonucleotides in RNA-PCR, a cDNA
      fragment was isolated from the spruce budworm, Choristoneura fumiferana.
      Comparison of the deduced amino acid sequence of this cDNA fragment with the
      members of the steroid hormone receptor superfamily suggested that this PCR
      fragment is a region of the ecdysone receptor from C. fumiferana. Using this cDNA
      fragment as a probe, 10 clones were isolated from a cDNA library that was
      constructed using the RNA from 4- and 5-day old embryos of C. fumiferana. Two
      cDNA clones (1.3 and 3 kb) that overlap and show amino acid identity with
      Drosophila melanogaster ecdysone receptor B-1 isoform (DmEcR) were characterized
      and sequenced. The longest open reading frame had 539 codons and covered the
      complete EcR coding region. The deduced amino acid sequence of this open reading
      frame had all five of the regions typical for a steroid hormone nuclear receptor.
      The C domain or DNA binding region showed the highest identity wit EcR proteins
      from D. melanogaster, Chironomus tendons, Aedes aegypti, Manduca sexta, and
      Bombyx mori. The A/B region, D domain or hinge region, E domain, or ligand
      binding region also showed significant amino acid similarity with the EcR
      proteins from the five insects mentioned above. The C. fumiferana ecdysteroid
      receptor (CfEcR) cDNA probe detected a 6.0-kb mRNA that was present throughout
      the development of C. fumiferana. The CfEcR mRNA increases in abundance at the
      time of the ecdysteroid peak during the molting phase in the embryonic, larval
      and pupal stages but remains low during the intermolt period. In the 6th instar
      larvae, the 6-kb CfEcR mRNA was detected in the epidermis, fat body, and midgut
      and maximum expression was observed during the prepupal peak of ecdysteroids in
      the hemolymph. CfEcR mRNA was induced in ecdysone treated CF-203 cells as well in
      the epidermis and midgut of larvae that were fed the nonsteroidal ecdysteroid
      agonist, RH-5992. The induction occurred within an hour and reached maximum
      levels around 3 hr, after which it decreased to the basal level by 6 hr. In vitro
      transcription and translation of the CfEcR cDNA yielded a 67-Kda protein that
      bound to the ecdysone response element (EcRE) as a heterodimer, along with the
      ultraspiracle protein.

PMID- 8641051
TI  - Identification of members of the HSP30 small heat shock protein family and
      characterization of their developmental regulation in heat-shocked Xenopus laevis
      embryos.
AB  - In the present study we have characterized the synthesis of members of the HSP30
      family during Xenopus laevis development using a polyclonal antipeptide antibody
      derived from the carboxyl end of HSP30C. Two-dimensional PAGE/immunoblot analysis
      was unable to detect any heat-inducible small HSPs in cleavage, blastula,
      gastrula, or neurula stage embryos. However, heat-inducible accumulation of a
      single protein was first detectable in early tailbud embryos with an additional 5
      HSPs at the late tailbud stage and a total of 13 small HSPs at the early tadpole
      stage. In the Xenopus A6 kidney epithelial cell line, a total of eight heat
      inducible small HSPs were detected by this antibody. Comparison of the pattern of
      protein synthesis in embryos and somatic cells revealed a number of common and
      unique heat inducible proteins in Xenopus embryos and cultured kidney epithelial
      cells. To specifically identify the protein product of the HSP30C gene, we made a
      chimeric gene construct with the Xenopus HSP30C coding sequence under the control
      of a constitutive promoter. This construct was microinjected into fertilized eggs
      and resulted in the premature and constitutive synthesis of the HSP30C protein in
      gastrula stage embryos. Through a series of mixing experiments, we were able to
      specifically identify the protein encoded by the HSP30C gene in embryos and
      somatic cells and to conclude that HSP30C synthesis was first head-inducible at
      the early tailbud stage of development. The differential pattern of heat
      inducible accumulation of members of the HSP30 family during Xenopus development
      suggests that these proteins may have distinct functions at specific embryonic
      stages during a stress response.

PMID- 8641052
TI  - Comparative biochemical and stress analysis of genetically selected Drosophila
      strains with different longevities.
AB  - We have performed a comparative analysis of the effects of age of reproduction on
      the biochemical (protein, lipid, and glycogen content) and stress resistance
      (ability to survive starvation, desiccation, and exogenous paraquat) parameters
      on 10 sister lines of five different Drosophila strains. Four pairs of these
      sister lines were selected under different regimens for either early or delayed
      reproduction; the fifth pair was maintained in a nonselected state and served as
      the baseline strain to which all others were compared. It is generally accepted
      that the early regimens give rise to short-lived phenotypes, whereas the delayed
      regimens give rise to long-lived phenotypes. Our results suggest that a mechanism
      involving lipid and starvation resistance is not operative in our long-lived
      strains. In addition, a mechanism involving glycogen content and desiccation
      resistance is only weakly supported. Finally, there is strong support for a
      mechanism that gives rise to enhanced paraquat resistance and therefore may
      involve regulatory changes in the pattern of ADS gene expression. In addition,
      the 15-day early age of reproduction regimen (M type) shows qualitatively similar
      responses to that of the late age at reproduction regimen (L type). These results
      suggest that correlations between biochemical traits and longevity must be
      interpreted with caution. We discuss possible reasons for these results,
      including the possibility of multiple mechanisms, each leading to a different
      extended longevity phenotype.

PMID- 8641053
TI  - Paraquat resistance and starvation conditions in the selection of longevity
      extremes in Drosophila melanogaster populations previously selected for long and
      short developmental period.
AB  - This paper analyzes the interaction between resistance to free radicals,
      development under starvation conditions, sex, and its consequences to the
      lifespan of Drosophila melanogaster populations selected for developmental time
      and longevity. Our data suggest that the interaction between these physiological
      and environmental parameters is modulated largely by the pre-imaginal
      developmental time, since the response to selection for longevity extremes
      depends strongly on the previous selection for developmental time extremes.

PMID- 8641054
TI  - Operative treatment of intraarticular distal radial fractures.
AB  - Intraarticular fractures of the distal radius are difficult to treat successfully
      by traditional non-operative methods. The goal is to achieve a pain free
      functional wrist, and residual articular step offs of 2 mm or more will prevent
      such a result. Classification systems have evolved to reflect the preeminent
      consideration that must be given to the articular surface, and preoperative
      radiographic evaluation should usually include tomographic imaging to avoid a
      failure to recognize the fragment positions. A number of papers of the past
      decade have demonstrated that operative reduction of intraarticular fragments to
      reconstruct the articular surface and diminish step offs will give better
      clinical results, at least during the first several years of followup so far
      available. Attention to meticulous surgical technique will facilitate good
      results.

PMID- 8641055
TI  - Fractures of the distal interphalangeal joint.
AB  - Fractures at the distal interphalangeal joint present a therapeutic challenge to
      the hand surgeon because of the relatively small bones and joint surfaces
      involved and the limited internal fixation devices available. Knowing which
      patients and which fractures are best treated surgically is key to a successful
      result. The normal anatomy and biomechanics of the joint are outlined and
      overviewed and the anatomy, etiology, therapy, and classification are discussed.
      Comminuted fractures of the articular surface of the distal phalanx are presented
      as are epiphyseal fractures of the distal phalanx. Avulsion of the profundus
      tendon (jersey finger) is discussed, emphasizing Leddy and Packer's Types I, II,
      and III injuries and the recommended treatment. Condylar fractures of the
      articular surface of the middle phalanx at the distal interphalangeal joint are
      the subject of the next section, with London's classification scheme and
      recommended treatment. Finally, complex open injuries and replantation through
      the distal interphalangeal joint are presented with guidelines for salvage and
      treatment.

PMID- 8641056
TI  - Arthroscopically assisted reduction of intraarticular distal radial fractures.
AB  - Anatomic restoration of the joint surface and extraarticular alignment is the
      goal in management of displaced distal radial fractures. Arthroscopy provides
      well lit, magnified conditions in which to reconstruct the fractured joint
      surface and to detect and manage intracarpal soft tissue injures associated with
      distal radial fractures. Percutaneous and limited open reduction techniques
      combined with wrist arthroscopy in the arthroscopically assisted management of
      displaced distal radial fractures is described.

PMID- 8641057
TI  - Distal radioulnar joint injuries associated with fractures of the distal radius.
AB  - The most common cause of residual wrist disability after fractures of the distal
      radius is the distal radioulnar joint. The 3 basic conditions that produce
      radioulnar pain and limitation of forearm rotation are instability, joint
      incongruency, and ulnocarpal abutment. The last 2 entities initiate irreversible
      cartilage damage that eventually leads to degenerative joint disease. Early
      recognition and management in the acute stage aim at the anatomic reconstruction
      of the distal radioulnar joint including bone, joint surfaces, and ligaments in
      an effort to reduce the incidence of painful sequelae and functional deficit.
      This article provides a description and the treatment options of the distal
      radioulnar joint lesions that occur in association with fractures of the distal
      radius, and the results obtained with open and arthroscopic techniques. Both
      acute and chronic disorders are analyzed, and a prognostic and treatment oriented
      classification is presented Furthermore, the pathoanatomy and management of
      chronic distal radioulnar joint derangement after fracture of the distal radius
      are reviewed briefly.

PMID- 8641058
TI  - Early salvage reconstruction of severe distal radius fractures.
AB  - During an 8-year period from 1980 through 1988, 9 distal radius fractures could
      not be restored because of bone loss or extensive comminution and were,
      therefore, salvaged by early arthrodesis in 7 patients and Swanson silicone wrist
      arthroplasty in 2. At a mean of 3.7 years, 4 patients rated good, 2 satisfactory,
      and 3 poor according to a 100-point scoring system based on residual pain,
      motion, grip strength, and occupational recovery. Irreparable distal radial
      fractures with damage largely confined to the skeleton achieved satisfactory or
      good results. Poor results occurred when there was severe soft tissue damage,
      especially neurovascular injury, despite a successful skeletal reconstruction.
      When articular restoration could not be accomplished, early arthrodesis or
      arthroplasty resulted in wrist alignment, stability, and pain control, and
      optimized the opportunity for digital and upper extremity functional recovery.

PMID- 8641059
TI  - Intraarticular osteotomy of distal radial malunions.
AB  - Failure to reduce intraarticular fractures of the distal radius to less than 2 mm
      of residual articular incongruity often will lead to posttraumatic arthrosis.
      Intraarticular osteotomy of the distal radius was performed for intraarticular
      malunions with a step greater than 2 mm in the distal radial articular surface,
      in the absence of arthrosis. The technique involves careful recreation of the
      fracture into the joint and rigid internal fixation of the osteotomy site. Four
      patients were followed up at an average of 23 months postoperatively (range, 12
      43 months). All patients treated with this operation were satisfied with their
      results and their wrists were functioning well at the time of review. All had
      good or excellent Gartland and Werley functional wrist scores. Further followup
      is required to document the long term outcome of these patients.

PMID- 8641060
TI  - Reconstructive osteotomy for malunion of the distal radius.
AB  - Common misconceptions about distal radius fractures result in undertreatment of
      many fractures, particularly in an active population. Loss of reduction of the
      fracture may cause a symptomatic malunion. Fourteen patients with an average age
      of 39 years (range, 21-65 years) underwent reconstructive procedures for radial
      malunions. The common malunion healed in a position of dorsal angulation, loss of
      radial inclination, and radial shortening. Ten patients had been treated by
      closed means, and 4 had undergone earlier surgical procedures without acceptable
      healing position of the fracture. Seven patients underwent a radial osteotomy
      alone, 5 patients had an osteotomy with an ulnar leveling procedure, and 2
      patients had a Sauve-Kapandji procedure alone. The average improvement in radial
      inclination was 14 degrees (range, 0 degrees-34 degrees), volar tilt 21 degrees
      (range, 2 degrees-33 degrees), and improvement in a positive ulnar variance by
      6.8 mm (range, 0-48 mm). The complication rate was 29%, with a followup of 29
      months (range, 12-43 months). Functional improvement was notable in 12 of 14
      patients. Surgical reconstruction for malunions is technically difficult and may
      not completely restore the anatomy. Patient satisfaction, however, in terms of
      increased function, decreased pain, and decreased deformity is sufficiently high
      to warrant reconstructive treatment.

PMID- 8641061
TI  - Combined injuries--soft tissue management.
AB  - The combination of severe bone and soft tissue injuries challenges all hand
      surgeons. Immediate restoration of all damaged structures is the goal whenever
      possible, integrating soft tissue techniques with principles of internal
      fixation. Debridement must be radical and resulting defects in bone, vessel,
      nerve, tendon and skin must be reconstituted with the combination of free and
      vascularized grafts. Rigid internal fixation is mandatory to allow functional
      restoration of the hand to begin with a stable platform against which motor
      tendon units and gliding structures to move. The timing of subsequent
      reconstruction is based on the prerequisites of adequate vascularity and soft
      tissue coverage. Understanding the reconstructive ladder and the nuances of
      techniques regarding skin grafting, local and distant flaps and microsurgical
      reconstruction is necessary to complete reconstruction in a timely and
      appropriate fashion. Various soft tissue techniques are described; from simple
      skin grafting to the use of toe to hand transfers. The decision to amputate
      versus reconstruct is also important, particularly in today's cost conscious
      health care environment. Finally, a well thought out and directed rehabilitation
      program will allow patients to ultimately return to functional status after
      mutilating injuries of the hand. This article provides a comprehensive review of
      the combined injury.

PMID- 8641062
TI  - Posttraumatic stiffness in the hand.
AB  - Maximalization of motion after healing is a primary goal of treatment when the
      surgeon is presented with a hand injury. The contribution of muscle/tendon,
      capsule and ligament, and the joint surface to the problem of posttraumatic
      stiffness is reviewed. Treatment possibilities for posttraumatic stiffness are
      presented and the importance of remobilization to the outcome of the care
      delivered is emphasized.

PMID- 8641063
TI  - Overlooked spine injuries associated with lumbar transverse process fractures.
AB  - Transverse process fractures of the lumbar spine often are considered benign
      fractures related to direct trauma or psoas muscle avulsion. Treatment of these
      usually stable injuries is primarily administered when the patient becomes
      symptomatic. However, significant force often is required to cause these
      injuries, and other injuries may occur concomitantly. For this study, all
      patients who presented with identified lumbar transverse process fractures were
      further evaluated radiographically with computed tomography for the detection of
      other possible spine injuries. Medical and radiology records of 28 consecutive
      patients who had plain radiographs and computed tomography scans taken of their
      lumbar spine were reviewed retrospectively; these patients presented with lumbar
      spine transverse process fractures between January 1, 1989 and June 30, 1992.
      Three of the 28 patients (11%) had a lumbar spine fracture that was identified by
      computed tomography but overlooked on plain radiographs. Approximately 11% of
      patients with major injuries may be misdiagnosed if only plain radiographs are
      used in the evaluation of transverse process fractures. Computed tomography
      scanning of all lumbar spine transverse process fractures resulting from acute
      trauma should be considered because this diagnostic measure decreases the risk of
      overlooking potentially serious injuries.

PMID- 8641064
TI  - Femoral deformity in adults with developmental hip dysplasia.
AB  - Quantitative computed tomography and 3 dimensional modeling were used to portray
      the deformity of the proximal femur in 24 Japanese adults with low subluxations
      to high dislocations secondary to developmental dysplasia of the hip. Periosteal
      and canal bony contours were extracted, 3 dimensional models generated, and
      morphologic parameters were calculated for each femur. Three dimensional
      illustrations of the average deformity and variability were created. Morphologic
      parameters were not found to be statistically correlated with the degree of the
      disease. Interestingly, the major axis of the canal contours of the proximal
      femur was found to be aligned with the plane of the femoral neck (anteversion),
      regardless of the degree of anteversion. Thus, the amount of version correctable
      in an uncemented prosthesis is limited, and at times may require a special
      prosthesis, overreaming, undersizing and cementing, or an osteotomy.
      Additionally, the proximal medial curvature of the dysplastic femurs was
      straighter than that of normal femurs. This necessitated a corresponding
      reduction in the proximal medial curvature of a conventional uncemented
      prosthesis to match the medial curvature of the individual femur and the average
      developmentally dysplastic femur. This objective description of the
      developmentally dysplastic femur corroborates clinical observations, highlights
      some unrecognized findings, provides a rationale for planning reconstructions,
      and aids in the design of prostheses for adult patients with this deformity.

PMID- 8641065
TI  - Modular tibial augmentations in total knee arthroplasty.
AB  - Proximal tibial bony deficiencies are not uncommon in primary and revision total
      knee arthroplasty. Modular tibial augmentations were introduced to address these
      deficiencies. Alterations in strain distribution as a result of medial wedge and
      block augmentations were evaluated for a modular total knee arthroplasty system
      in 6 fresh frozen anatomic specimen tibias. Full-field strain patterns were
      examined using photoelastic coating methods, and high strain regions were
      evaluated using strain gage rosette techniques. The total knee arthroplasty
      installations were tested in static physiologic axial and torsional load
      configurations. The relative effects of sequential wedge and block augmentations
      compared with the nonaugmented case were statistically analyzed. There were no
      overall statistical differences in the 3 treatments in terms of maximal
      (principal) strains. A secondary analysis that evaluated specific location and
      load pattern combinations established several minor statistical differences along
      with insights into the manner in which each construct loads the proximal tibia.
      Although metal wedge augmentation commonly is used, block augmentation seems to
      be an appropriate alternative from a strain distribution standpoint in cases in
      which the block geometry better approximates the bony defect.

PMID- 8641066
TI  - Cerclage fixation for fracture dislocation of the proximal interphalangeal joint.
AB  - Dorsal fracture dislocations of the proximal interphalangeal joint remain 1 of
      the most difficult problems in which to obtain an excellent functional outcome.
      The use of minimally invasive internal fixation techniques improving the biologic
      healing response and yet providing fracture fragment stabilization has met with
      greater popularity in recent years. The results of 12 patients treated by the
      volar cerclage wiring technique are described. At average followup examination of
      2.1 years, 11 of 12 patients were noted to have no degenerative joint changes
      with only 1 patient having evidence of early volar articular surface beaking.
      Average final active arc of motion at the proximal interphalangeal joint was 89
      degrees (range, 72 degrees - 109 degrees). The average degree of extension loss
      at the proximal interphalangeal joint was 8 degrees (range, 0 degrees - 16
      degrees). There were no complications involving implant failure, irritation, or
      infection. A description of the volar cerclage wire technique is presented. This
      technique provides the advantage of avoiding fracture fragment stripping, stable
      restoration of the articular surface, and palmar buttress of the middle phalanx
      at the proximal interphalangeal joint.

PMID- 8641067
TI  - Oblique proximal tibial osteotomy for the correction of tibia vara in the young.
AB  - Proximal tibial osteotomy in the growing patient historically has been associated
      with a high rate of neurovascular complications and malunion. Here is reported a
      technique of valgus proximal tibial osteotomy, of the incomplete closing wedge
      type, that has avoided neurovascular compromise while achieving reliable
      correction and rapid bony union. Oblique proximal tibial valgus osteotomies with
      lateral tension plate fixation were performed on 18 tibiae in 14 patients (age
      range, 5-25 years) with tibia vara. The primary diagnosis was Blount's disease in
      13 tibiae, achondroplasia in 2 tibiae, multiple epiphyseal dysplasia in 2 tibiae,
      and hypochondroplasia in 1 tibia. No postoperative plaster immobilization was
      necessary. All patients were able to bear weight fully by 8 weeks after surgery.
      Average angular correction was 18 degrees. One patient had overcorrection because
      of an unrecognized intraoperative fracture of the media] tibial cortex. There
      were no neurovascular complications. No growth disturbance of the proximal tibial
      physis was noted. Oblique proximal tibial osteotomy with tension plate fixation
      successfully corrected varus deformity of the proximal tibia in the growing
      patient without damage to the proximal tibial physis or neurovascular compromise.

PMID- 8641068
TI  - Surgical treatment of complex fracture of the proximal humerus.
AB  - Sixteen patients aged 19 to 63 years (average, 52 years) were observed from 1.8
      to 5.6 years (average, 3.8 years) after open reduction and internal fixation with
      or without external fixation of 3- and 4-part displaced fractures of the proximal
      humerus. There were 12, 3-part displaced greater tuberosity and surgical neck
      fractures with 6 concomitant dislocations. Four cases were 4-part fractures with
      3 concomitant dislocations. Fixation was achieved with heavy sutures or wire that
      incorporated the rotator cuff tendon, tuberosities, and shaft combined with
      threaded pins or Hoffmann external fixation to enhanced stability for early
      rehabilitation. According to Neer's criteria, 14 (87%) of the 16 patients had
      satisfactory or excellent results. Two (13%) of the 16 had unsatisfactory
      results. The use of a technique of limited soft tissue dissection and internal
      fixation with or without external fixation achieved good fracture stability and a
      high percentage of satisfactory results. The limitations of the procedure include
      (1) patients who could not tolerate anesthesia, (2) complex displaced fractures
      in older patients with osteoporotic bone that cannot hold pins or external
      fixation, (3) older patients with 4-part fracture dislocations in which avascular
      necrosis of the humeral head occurs frequently and in which a subsequent
      endoprosthesis insertion is inappropriate if osteosynthesis fails, and (4) head
      splitting fractures. The described approach provides an alternative method for
      the treatment of complex displaced fractures of the proximal humerus.

PMID- 8641069
TI  - Periprosthetic fractures of the femur. An analysis of 93 fractures.
AB  - A retrospective review of 93 periprosthetic fractures and 102 periprosthetic
      fracture treatments showed that the type of prosthesis (cemented, ingrowth,
      Austin-Moore) and the presence of preexisting stress risers play a role in
      determining where the fractures occur. The site of fracture and the prefracture
      interface influence treatment of periprosthetic fractures. This study suggests
      that fractures associated with a loose interface, cemented or cementless, are
      best treated by removal of the prosthesis, reduction of the fracture, and
      insertion of a long stemmed prosthesis with additional fixation as needed.
      Treatment of a periprosthetic fracture associated with a stable prosthesis
      depends on the site of fracture. Fractures proximal to the tip of a fixed
      prosthesis usually can be treated nonoperatively or with limited internal
      fixation. Fractures at the tip of the prosthesis may be managed by revision or
      internal fixation, and fractures below the prosthesis can be managed operatively
      or nonoperatively.

PMID- 8641070
TI  - Evaluation of suspected osteoid osteoma.
AB  - A technique of computed tomography with intravenous contrast has proven useful in
      the differentiation between osteoid osteoma and other similar appearing lucent
      lesions of bone in 6 cases. The clinical evaluation of benign appearing
      radiolucent lesions of long bones has been greatly improved by the use of modern
      imaging techniques. The differential diagnosis often is narrowed to osteoid
      osteoma and osteomyelitis based on plain radiographs, computed tomography, or
      magnetic resonance imaging. The enhancement of the lucent center of the lesion
      was plotted against time. The rapid uptake of contrast medium by the osteoid
      osteoma was in sharp contrast to the much slower enhancement in osteomyelitis.
      The establishment of a preoperative diagnosis enabled the surgeon to excise the
      lesion without a biopsy. Histologic review verified the preoperative diagnosis in
      all cases.

PMID- 8641071
TI  - Nucleolar organizer regions in parosteal and central osteosarcomas.
AB  - Silver stained nucleolar organizer regions (AgNOR) have revealed differences in
      the biological behavior of certain entities. This study involves a morphometric
      analysis of AgNOR in 6 central, classic osteosarcomas and 6 parosteal
      osteosarcomas. There was a statistically significant difference in the number of
      AgNOR per nucleus between central and parosteal osteosarcomas. Single AgNOR
      volume was smaller in central osteosarcomas as compared to parosteal
      osteosarcomas. However, this difference did not reach statistical significance.
      The parameter AgNOR number per nucleus revealed a cut off value such that 100% of
      central osteosarcoma cases lay above this value and 100% of parosteal
      osteosarcoma cases lay below this value. AgNOR demonstration involves a simple
      technique which can be performed on formalin fixed, paraffin embedded file
      material. Thus, it may be prudent to routinely assess AgNOR as a contributor to
      the determination of the pathophysiology of osteosarcomas.

PMID- 8641072
TI  - Development of angiosarcoma at the site of a bone infarct.
AB  - A 34-year-old man presented with angiosarcoma which developed at the site of a
      preexisting bone infarct in the metaphysis of the right tibia. A malignant bone
      tumor may develop at the site of bone infarct, and its histologic type is most
      frequently malignant fibrous histiocytoma or fibrosarcoma. Few patients with
      osteosarcoma have been reported: only 2 patients who had angiosarcoma that
      developed in a preexisting bone infarct have been reported in the English
      literature. Malignant transformation of bone infarct into angiosarcoma is
      extremely rare.

PMID- 8641073
TI  - In vitro study of knee stability after posterior cruciate ligament
      reconstruction.
AB  - The effect of reconstructing the posterior cruciate ligament on anteroposterior
      laxity of the knee was evaluated in 7 cadaveric knees. A bone-patellar tendon
      bone graft was used. Femoral pilot holes were drilled to locate the most
      isometric sites for attachment of the graft to the femur using an isometer. A
      tension of 89 N was set in the graft using a tensiometer with the knee in 90
      degree flexion while applying an anterior drawer force of 156 N to the tibia.
      Posterior displacement of the knee was measured in 15 degree increments from O
      degree to 90 degrees in the intact knee, in the knee with the posterior cruciate
      ligament transected, and after reconstruction of the posterior cruciate ligament
      in response to 100 N of posteriorly applied force. Graft tension was nearly
      constant between 0 degrees and 90 degrees flexion, indicating the grafts to be
      isometric. The reconstruction reduced posterior translation of the tibia in the
      posterior cruciate ligament excised knee at all angles of flexion; the
      differences were statistically significant. The reconstruction returned posterior
      translation to levels not significantly different from those of the intact knee
      between 0 degrees and 45 degrees flexion but not in the greater angles of flexion
      tested.

PMID- 8641074
TI  - Use of bone morphogenetic protein-2 in the rabbit ulnar nonunion model.
AB  - The ability of the osteoinductive protein and recombinant human bone
      morphogenetic protein-2, combined with polylactic glycolic acid porous
      microspheres and autologous blood clot to heal a large segmental defect was
      tested in a rabbit diaphyseal defect model. Two centimeter nonuniting defects
      were surgically created in the bilateral ulnae of 50 male New Zealand white
      rabbits. Each defect was then implanted with a pastelike polylactic glycolic
      acid/blood clot combination that was mixed with 5 different concentrations of
      recombinant human bone morphogenetic protein-2. The forearms were
      radiographically assessed on a biweekly schedule for 8 weeks. At 8 weeks, all
      animals were sacrificed and forearms radiographed. Radiographs were then scored
      by 3 independent observers for bone formation and union rates. United limbs were
      tested in torsion for mechanical strength using a Burstein torsion tester. All
      nonunited limbs were analyzed histologically as were 2 united limbs from each
      dosage group. Radiographic evaluation revealed that there was a dose dependent
      response in healing of the ulnar defect with a higher bone formation rate in the
      2 higher dose limbs than in the lower dose limbs. Union was achieved in 100% of
      the highest dose limbs, whereas only 50% of the lowest dose limbs achieved bony
      union. No defects implanted with carrier alone achieved union. Biomechanical
      studies revealed significantly stiffer bone than age matched controls. Histologic
      analysis demonstrated normal bone formation with abundant normal appearing
      osteoid. These dose response data further support the role of recombinant human
      bone morphogenetic protein-2 as a potent morphogen in bone regeneration.

PMID- 8641076
TI  - Hinged device for fractures involving the proximal interphalangeal joint.
AB  - Well known complications of proximal interphalangeal joint fractures and fracture
      dislocations are stiffness, chronic instability, and degenerative arthritis. The
      Compass PIP Hinge is a dynamic external fixator that allows protected proximal
      interphalangeal mobilization after closed reduction, open reduction and internal
      fixation, volar plate arthroplasty, or other salvage procedures. To help avoid
      these problems, 20 patients, 12 treated within 2 weeks of injury (Group I) and 8
      treated more than 4 weeks after injury (Group II), are reported. Articular
      surface involvement among Group I cases averaged 66% (range, 50%-90%), and
      postoperative proximal interphalangeal motion for this group averaged 9 degrees
      to 82 degrees. Mild pain with heavy use was present in 3 patients, and 9 patients
      were pain free. Postoperative proximal interphalangeal motion for Group II
      averaged 21 degrees to 77 degrees. Pain was moderate to severe in 2 patients,
      mild with heavy use in 1 patient, and none in 5 patients. One patient from Group
      II underwent surgery to convert to a silicone proximal interphalangeal
      arthroplasty because of painful degenerative arthritis. It is concluded that
      there is a role for hinged external fixation in treating unstable proximal
      interphalangeal fracture dislocations. Outcomes in acute injuries are superior to
      those in chronic or salvage cases.

PMID- 8641075
TI  - Variables affecting pedicle screw plate fixation of an unstable L3-L4 defect.
AB  - Fresh frozen human cadaveric spinal specimens (T8-S1) were subjected to pure
      flexion extension bending moment and pure axial torque loadings while
      intervertebral rotations were recorded at the L3-L4, L2-L3, and Ll-L2 discs. A
      standardized unstable defect was created at the L3-L4 disc, and loading tests
      were repeated after application of bilateral Steffee plates in 2 configurations:
      a short plate with 2 pedicle screws (spanning the defect) and a longer plate with
      3 pedicle screws (spanning the defect and 1 disc above). Each plating
      configuration was tested in the unlocked state (nuts compressing the plate down
      onto the spine) and locked state (nuts above and below the plate tightened
      against each other to clamp the plate to the screws). Locking the plates to the
      screws had no effect on any intervertebral rotation at any disc level. Use of a
      longer plate that also spanned the disc above the defect offered no advantage in
      controlling flexion extension rotations at the defect site. However, mean
      torsional rotation at the defect site with the 3-screw plate was approximately
      50% of the mean for a 2-screw plate. Extension and torsional rotations at the L2
      L3 disc (1 level above the defect site) were unaffected by application of a 2
      screw plate; flexion rotation at this level increased slightly after plating. All
      motions at the L2-L3 disc were reduced (as would be expected) when the 3-screw
      plate spanned this uninjured disc. Plating the defect had no effect on disc
      rotations at the L1-L2 disc (2 levels above the fracture site).

PMID- 8641077
TI  - Callus distraction: a new method? A historical review of limb lengthening.
AB  - The technique of callus distraction can be traced back to the work of Codivilla
      at the beginning of the century. Subsequent to Codivilla, various crude methods
      of limb lengthening were used but resulted in high complication rates. Not until
      the work of Putti and Abbott in the 1920s and their painstaking operative
      technique did the results become verifiable. During the 1930s, various
      modifications were introduced and the apparatus was simplified. However, because
      of an increasing tendency to apply this technique to unsuitable cases, it fell
      into disrepute. After World War II, Anderson, Allan, and Ilizarov developed
      better equipment, allowing for a better understanding of the biologic principles
      of callus distraction. In the 1980s, this method was adopted for treatment of
      major bone defects and shortening of limbs.

PMID- 8641078
TI  - Posterior thigh pain in a 42-year-old woman.

PMID- 8641079
TI  - Calcific myonecrosis.

PMID- 8641080
TI  - Use of the minicondylar plate in metacarpal and phalangeal fractures.
AB  - The minicondylar plate is used for unstable intraarticular and periarticular
      fractures of the phalanges and metacarpals to provide stability and to allow
      early motion. This low profile implant can be placed laterally to avoid injury to
      the extensor mechanism. The authors retrospectively reviewed 53 consecutive
      patients from 2 institutions in whom 68 fractures (41 metacarpal and 27
      phalangeal) had been treated with 1.5-mm or 2-mm minicondylar plates. Common
      mechanisms of injury were gunshot wounds, crush injuries, and assault/beatings.
      Thirty-seven fractures were open, 19 had severe soft tissue injury, and 30
      required a bone graft. The followup period averaged 17 months. There were no
      nonunions or malunions. Sixty-seven complications were associated with 40
      fractures in 29 patients: primarily symptomatic plates or pullout (30
      complications), extensor lag (13 complications), and infections (8
      complications). The complication rate was significantly higher in intraarticular
      and periarticular fractures also involving the middle 1/3 versus proximal 1/3
      fractures; open versus closed fractures; fractures with increased soft tissue
      injury versus minimal injury; and bone grafted versus nongrafted fractures. Final
      arc of total active motion, available for 45 fractures, was excellent (> or = 221
      degrees) for 17 fractures; good/fair (121 degrees to 220 degrees) for 15, and
      poor (< or = 120 degrees) for 13. Metacarpal fractures had a significantly higher
      percentage of excellent results than did phalangeal fractures. Final motion did
      not correlate significantly with complication rate, severity of soft tissue
      injury, location in the bone, open versus closed fracture, or use of bone graft.
      When fractures cannot be restored and stabilized reliably by less invasive
      methods, the minicondylar plate provides secure fixation and can result in
      adequate function, even in the presence of severe combined injuries.

PMID- 8641081
TI  - Fracture of the base of the first metacarpal and a variation that has not yet
      been described. 1910.

PMID- 8641082
TI  - Intramedullary fixation of metacarpal and proximal phalangeal fractures of the
      hand.
AB  - The use of intramedullary fixation for fixation of fractures of the metacarpal
      and proximal phalanx is reported. Flexible intramedullary rods are used for
      unstable transverse and short oblique diaphyseal fractures of the proximal
      phalanx and metacarpal. The fracture site is not opened and the rods are
      introduced under xray control. The rods are cut flush with the bone so that there
      is no soft tissue tethering. Intramedullary spacers are used in comminuted
      metacarpal fractures associated with crush injuries and gunshot wounds. The
      fracture site is opened and a single rod is placed to fill the intramedullary
      canal. A supplementary plate may be used to control rotation, and bone graft is
      usually necessary. A new spacer has been designed that has proximal and distal
      locking screws to control length and rotation. This also is used routinely with
      bone graft. The techniques outlined stabilize the fracture site allowing
      immediate motion postoperatively.

PMID- 8641083
TI  - Impending malunions of the hand. Treatment of subacute, malaligned fractures.
AB  - Malunions of the hand present a challenging problem to the orthopaedic surgeon.
      Angular and rotational deformities, and shortening and articular incongruity, can
      lead to significant functional impairment or dysesthetic appearance. The
      prevention of malunion should remain a primary goal. When displaced fractures of
      the metacarpals or phalanges present within the first or second weeks, properly
      performed closed or open reduction with percutaneous pinning or internal fixation
      are excellent options with predictable results. Malaligned fractures that present
      later frequently cannot be readily reduced. Once fully united, treatment options
      have included corrective osteotomy if function is significantly impaired or if
      appearance is objectionable; for patients who are not suitable for surgery for
      medical or other reasons, or for whom appearance is acceptable, intensive
      occupational therapy to maximize function may yield sufficiently serviceable
      clinical results. During the past several years, the senior author (BL) has
      chosen to be more proactive in the prevention of malunions of the hand. In the
      authors' experience, results of aggressive surgical treatment of subacute,
      malaligned fractures in selected patients have produced results comparable with
      or superior to those reported for later reconstructive procedures. With the
      proliferation of managed care, there has been an increasing frequency of delayed
      referral patterns for fracture treatment by hand specialists. Definitive
      treatment of these "impending malunions" is preferable to passive treatment delay
      and secondary reconstructive procedures, offering both earlier correction of
      alignment and earlier opportunity for return of function.

PMID- 8641084
TI  - Autograft replacement of small joint defects in the hand.
AB  - Intraarticular injuries to the small joints of the hand with attendant loss of
      cartilage can result in the development of posttraumatic arthritis with
      functional disability due to pain and loss of motion. Traditional treatment
      options often have yielded suboptimal results in terms of functional return,
      particularly when applied once contracture or arthritic change already has
      developed. Acute management of cartilage loss by osteochondral reconstruction
      with restitution of the articular surface may diminish the likelihood or severity
      of potential post-traumatic degenerative changes.

PMID- 8641085
TI  - Tenolysis and capsulectomy after hand fractures.
AB  - There are well established operative procedures for salvage of function after
      fracture healing. When hand therapy measures have not achieved a satisfactory
      range of motion, it is reasonable to remove any hardware, if present, and lyse
      tendon adhesions that prevent tendon gliding. The exact cause of restricted
      motion and the location of adhesions are not always predictable preoperatively,
      so the surgeon should anticipate additional procedures such as dorsal/palmar
      capsulectomies in combination with extensor and/or flexor tenolysis. The use of
      local anesthesia for direct patient input during the procedure offers great
      advantages. In the ideal situation there should be a demonstrable functional need
      in a compliant patient with a well healed fracture and workable articular
      surfaces. Competent hand therapy should be available postoperatively. The
      patient's main risk is worsening of the situation if surgery is unsuccessful. A
      marginal finger with poor neurovascular status may be better served by going to
      arthrodesis or even amputation. Tenolysis and capsulectomy, when indicated, are
      useful procedures in the salvage of these difficult problems.

PMID- 8641086
TI  - Bony skier's thumb injuries.
AB  - Avulsion fractures of the ulnar collateral ligament of the thumb
      metacarpophalangeal joint (bony skier's thumb) may result in chronic instability
      with pain and weakness of pinch if improperly treated. Management requires an
      understanding of the relevant anatomy and careful clinical examination including
      stress testing. Undisplaced, or minimally displaced and stable fractures are
      treated conservatively, whereas displaced, rotated and unstable fractures require
      surgical treatment.

PMID- 8641087
TI  - Primary fusion of fracture dislocations of central carpometacarpal joints.
AB  - Six patients with dislocations or fracture dislocations of at least the second
      and third carpometacarpal joints are presented. Closed reduction was attempted in
      all cases. Two dislocations with minimal periarticular fractures were stable and
      were treated with cast immobilization. Four fracture dislocations were unstable
      and were treated with primary arthrodesis of the injured joints. One patient was
      lost to followup and the other 5 were observed for an average of 24 months.
      Establishment of a stable or rigid central carpometacarpal joint produced an
      excellent result in 4 patients and a satisfactory result in 1 patient.

PMID- 8641088
TI  - Fracture healing in the hand. A brief update.
AB  - Before the introduction of internal fixation, the healing of a fracture was an
      unpredictable event. Internal fixation provides stability, and fractures heal
      predictably. Continued research has allowed better understanding of fracture
      healing, and the biology of the bone tissue has become the focus. It has been
      discovered that a higher success of union and an earlier union results from
      avoiding additional vascular injury to the fracture site. Understanding the
      vascularity of bone and improved technology has led to the development of smaller
      implants that minimize surgical trauma and provide sufficient stability.

PMID- 8641089
TI  - Stabilization of ulnar carpometacarpal dislocations or fracture dislocations.
AB  - For the management of ulnar carpometacarpal dislocations or fracture
      dislocations, various authors have suggested closed reduction and percutaneous
      pin fixation, or open reduction and internal fixation with the use of
      transversely oriented pins. The methods can be problematic with failure of
      fixation or injury to tendons or nerves. A stable internal fixation alternative
      uses intramedullary metacarpal Steinmann pins or Kirschner wires, passed across
      the carpometacarpal joint into the hamate. If the fixation devices exit through
      the triquetrum and the lunate, then the finger metacarpal phalangeal joints may
      be left with full active motion. This method has provided ease of placement,
      stability, and no loss of fixation in 9 cases. An associated coronal fracture of
      the hamate may be fixed with small Kirschner wires or with a small lag screw,
      which can be placed through the same incision.

PMID- 8641090
TI  - Revision of failed bone grafting for nonunion of the scaphoid. Treatment options
      and results.
AB  - Failure of bone grafting in scaphoid nonunion presents the hand surgeon a
      perplexing set of problems. Controversy remains as to the best course of
      treatment in this difficult situation. The authors have retrospectively reviewed
      during a 5-year period the patients treated at the Mayo Clinic who have gone on
      to a second nonunion after a failed initial bone grafting procedure. Twenty-five
      patients were identified, 19 of whom had a second bone grafting procedure.
      Depending on the preoperative evaluation, 4 types of bone grafting procedures
      were performed: conventional Russe procedure, 4; Maltese cross bone graft
      procedure, 6; interpositional wedge graft, 5; and vascularized pedicle bone
      graft, 4. Twenty-two of 25 united (88%). Average followup at 57 months (range, 25
      90 months), shows satisfactory results (16% very satisfied and 8% moderately
      satisfied), but varying degrees of pain. Results using a modification of the Mayo
      Wrist Score are somewhat disappointing with 3 excellent, 5 good, 10 fair, and 7
      poor. It must be remembered, however, these wrists have had at least 2 surgeries,
      multiple long periods of immobilization, and often a delay in treatment with a
      prolonged period of abnormal carpal mechanics. It is thought that a second bone
      grafting attempt should be strongly considered. The key to success is matching
      the type of bone graft procedure to the specific unique features of scaphoid
      shortening, carpal instability, and proximal pole vascularity that each patient's
      wrist displays. A treatment algorithm is presented to help decision making in
      this difficult problem.

PMID- 8641091
TI  - A guide to clinical epidemiology for radiologists: Part I study design and
      research methods.

PMID- 8641092
TI  - A guide to clinical epidemiology for radiologists: Part II statistical analysis.

PMID- 8641093
TI  - Pictorial review: Imaging of primary osteosarcoma of the spine.

PMID- 8641094
TI  - Comparison of magnetic resonance angiography with conventional angiography in the
      detection of intracranial aneurysms in patients presenting with subarachnoid
      haemorrhage.
AB  - Thirty-nine patients admitted with proven subarachnoid haemorrhage were imaged
      both with 3-D time of flight (TOF) magnetic resonance angiography (MRA) and
      conventional angiography. As the definitive examination, catheter angiography
      demonstrated 37 aneurysms; ten patients had no aneurysm, the remaining 29
      patients had 37 aneurysms. We found the sensitivity of 3-D TOF MRA for the
      detection of aneurysms to be 81% and specificity to be 100% when the reporting
      radiologist inspects not only the MIP reconstructions but also the MRA source
      data and the axial spin-echo images. The investigation is less accurate if all
      the available imaging data is not considered.

PMID- 8641095
TI  - Ultrasound imaging of the appendix testis and appendix epididymis.
AB  - The appendix testis and epididymis are well visualized on ultrasound examination.
      It is important to recognize the normal anatomy of the appendages to exclude them
      as a cause of pathology and confirm their presence as normal structures. We
      describe the appearances of the appendices testis and epididymis in fifty-one
      consecutive patients presenting to the Southampton Radiology Department. The
      appendix testis was identified on 80% of testes examined by ultrasound and the
      appendix epididymis on 6% of testes.

PMID- 8641096
TI  - Biliary distensibility during per-operative cholangiography as compared to pre
      operative ultrasound: a four year follow-up study.
AB  - INTRODUCTION: It is well recognized that corrected bile duct diameters, as
      measured by endoscopic retrograde cholangiography (ERC), are often significantly
      greater than the corresponding ultrasound measurement. This can be attributed to
      variation in bile duct distensibility and is particularly noted in post
      cholecystectomy patients, possibly due to loss of the gall bladder reservoir
      effect. It has been suggested that increased bile duct distensibility may be
      related to the post-cholecystectomy syndrome. We have observed a similar
      discrepancy between ultrasound and per-operative cholangiography (POC). This
      trial investigates whether the discrepancy between ultrasound and POC
      measurements has clinical significance. METHOD: Seventy-five patients with normal
      pre-operative ultrasound and POC undergoing standard open cholecystectomy (with
      benzodiazepine pre-medication) in 1990 were identified. After allowance for
      magnification, maximum biliary diameters were obtained for the proximal extra
      hepatic bile duct. Follow-up was obtained in 67 patients from clinical case notes
      and contact with general practitioners. RESULTS: Considerable variation of bile
      duct distensibility was recorded (range 83% to 410%) with 12 cases having POC
      biliary diameters outside radiological guidelines (12 mm as recorded on the
      radiograph). This distension is shown to increase with age. After 4 years, 16
      patients had recurrent abdominal pain of which nine had undiagnosed right upper
      quadrant pain. There were no clinical cases of retained stone post-operatively.
      There was no correlation between POC measured bile duct diameter or
      distensibility and post-operative or long term problems. This study suggests that
      the bile duct has a normal variation of distensibility which increases with age
      and that radiological guidelines, as regards the upper limit for normal POC
      biliary diameters can be relaxed.

PMID- 8641097
TI  - PEG -- is the E necessary? A comparison of percutaneous and endoscopic
      gastrostomy.
AB  - We describe our experience of 45 percutaneous gastrostomies using 12 F Wills
      0glesby (Cook, Inc, Bloomington, IN, USA) catheters and 33 percutaneous
      endoscopic gastrostomies using 12 F Bower PEG's (Corpak, Inc, Wheeling, IL, USA).
      Tube displacement was a continued problem with the Wills-Oglesby catheter
      resulting in three patients developing peritonitis with one death. In view of
      this we would recommend as the preferred technique the endoscopic placement of
      Bower PEG catheters unless there are contraindications to the endoscopic
      technique.

PMID- 8641098
TI  - Isolated lymphadenopathy on chest radiographs of HIV-infected patients.
AB  - AIM: To determine the aetiology of isolated intrathoracic lymphadenopathy on
      chest radiographs of HIV-infected patients. PATIENTS AND METHODS: Over a 40 month
      span in 1990-1993, 18 HIV-infected patients (13 men, 5 women) from our New York
      City adult HIV outpatient clinic development isolated intrathoracic
      lymphadenopathy (defined as intrathoracic nodal enlargement without other
      persistent abnormalities on chest radiographs). Serial chest radiographs (n =
      18), CT scans when available (n = 7), and clinical charts (n = 18) were reviewed
      retrospectively. RESULTS: Median patient age was 34 (range 25-49) years. The
      diagnoses associated with adenopathy were Mycobacterium tuberculosis (Mtb) in
      eight (44%), Mycobacterium avium intracellulare complex (MAC) in four (22%), and
      Mtb and MAC co-infection in three (17%). Cryptococcal infection, thymic
      hyperplasia, and spontaneous resolution without diagnosis or treatment occurred
      in one patient each. In 16 (89%) of the 18 patients, lymphadenopathy was present
      in more than one nodal station. Enlarged nodes were found in the following sites:
      paratracheal/tracheobronchial (n = 14), aortopulmonary window (n = 9), hilar (n =
      7), anterior mediastinum (n = 3), subcarinal (n = 2), and left paraesophageal (n
      = 2). CONCLUSION: Mycobacterial infection was the aetiology of isolated
      intrathoracic lymphadenopathy in 15 of 18 (83%) HIV-infected patients. When an
      inner city HIV-infected patient presents with isolated intrathoracic
      lymphadenopathy, we recommend an aggressive work-up for mycobacterial disease.

PMID- 8641099
TI  - The utility of the frontal chest radiograph in the evaluation of chest drain
      placement.
AB  - AIM: To define the utility of the frontal chest radiograph in the assessment of
      chest drain position. PATIENTS AND METHODS: Fifty-six frontal chest radiographs
      in 45 patients with 61 chest drains (18 anterior, 9 interlobar, and 34 posterior
      position) were reviewed retrospectively to determine radiographic
      characteristics. RESULTS: Eighty-nine percent of the anterior drains demonstrated
      a curved appearance at the insertion site, while 50% of posterior drains and all
      interlobar drains were straight at the insertion site. A curved intrapleural
      drain was a common finding when positioned anteriorly and posteriorly (67% and
      59%, respectively). Interlobar drains were often straight throughout their course
      (89%). The tips of interlobar drains were usually positioned at the hilum (89%).
      CONCLUSION: Results suggest that interlobar positioning can be suspected on the
      frontal chest radiograph. A curving chest drain with straight appearance at the
      insertion site was indicative of a posterior location.

PMID- 8641100
TI  - Mammographic features of breast tuberculosis: the skin bulge and sinus tract
      sign.
AB  - Six cases with bacteriologically and/or histologically proven breast tuberculosis
      were analysed out of 1152 consecutive mammograms performed. The objective was to
      identify some factors that may facilitate pre-operative mammographic and
      ultrasonographic diagnosis of breast tuberculosis. Nipple retraction and coarse
      stromal texture occurred in all six cases. In five cases there was an ill-defined
      breast mass, skin thickening, and a reduction in size of the affected breast. A
      unique finding was a sinus tract connecting the breast density to a localized
      skin thickening and bulge which occurred in only two cases. Ultrasonography
      showed cystic masses. The incidence of breast tuberculosis in the studied
      population was 0.52%. A mammographic demonstration of a dense tract connecting an
      ill-defined breast mass to a localized skin thickening and bulge (skin bulge and
      sinus tract sign) is strongly suggestive of tuberculous breast abscess. Change in
      shape and outline of the breast mass can be seen in the standard breast views.

PMID- 8641101
TI  - Idiopathic duro-optic calcification--a new entity?
AB  - This is a report of two patients with intracranial dural and optic nerve/sheath
      calcification. CT and MR features of this previously unreported condition are
      illustrated.

PMID- 8641102
TI  - Pseudotumours of hepatic imaging.
AB  - The diagnosis of liver tumours with CT depends on differential attenuation
      coefficients and enhancement patterns. The sensitivity of CT in defining tumours
      is well established but there remain a variety of conditions that mimic these
      patterns, presenting a 'pseudotumour' appearance. A common illustrative example
      is hepatic steatosis, but less well recorded are the sphingolipidoses and
      intrahepatic arterioportal shunts, either post-traumatic or related to venous
      outflow block. Alpha-1-antitrypsin deficiency and hereditary tyrosinaemia provide
      examples in childhood.

PMID- 8641103
TI  - Technical report: Recanalisation of all three infrapopliteal arteries by
      subintimal angioplasty.

PMID- 8641104
TI  - Case report: Brucella osteomyelitis of the pubic bone.

PMID- 8641105
TI  - Case report: Fibroma of tendon sheath in the distal forearm with associated
      median nerve neuropathy: US, CT and MR appearances.

PMID- 8641106
TI  - Case report: Metastatic dedifferentiated chondrosarcoma.

PMID- 8641107
TI  - Case report: The MR appearances of primary intramuscular hydatid disease.

PMID- 8641108
TI  - Case report: Pseudoglandular hepatocellular carcinoma: discrepancy between CT and
      MR findings.

PMID- 8641109
TI  - Air or CO2 as an insufflation agent for double contrast barium enema.

PMID- 8641110
TI  - Air or CO2 as an insufflation agent for double contrast barium enema.

PMID- 8641111
TI  - Air or CO2 as an insufflation agent for double contrast barium enema.

PMID- 8641112
TI  - The role of pre-operative thallium-technetium subtraction scintigraphy in the
      surgical management of patients with solitary parathyroid adenoma.

PMID- 8641113
TI  - Diabetic medicine: striving and thriving!

PMID- 8641114
TI  - Gastric emptying in diabetes.
AB  - Gastric emptying abnormalities are common in diabetic patients but correlate
      poorly with gastrointestinal symptoms. Poor diabetic control is more likely to
      lead to gastrointestinal complications of diabetes and the converse is also true.
      Gastric emptying may be a previously under-recognized contributor to variations
      in glycaemic control in diabetes. There is evidence for both accelerated and
      delayed gastric emptying. More rapid gastric emptying would result in higher
      postprandial glucose levels and, therefore, pharmacological means to delay the
      rate of gastric emptying may be a new approach to slowing postprandial nutrient
      absorption and improving diabetic control. Hyperglycaemia reduces the rate of
      gastric emptying in both Type 1 (insulin-dependent) and Type 2 (non-insulin
      dependent) diabetic patients. The exact mechanisms responsible for the inhibitory
      action of hyperglycaemia on gastric emptying are unknown. There is insufficient
      data on the effect of hypoglycaemia on gastric emptying but one study has
      reported more rapid gastric emptying.

PMID- 8641115
TI  - Effects of long-term enalapril treatment on persistent microalbuminuria in
      normotensive type 2 diabetic patients: results of a 4-year, prospective,
      randomized study.
AB  - The beneficial effect of long-term treatment with an angiotensin-converting
      enzyme (ACE) inhibitor on urinary microalbumin excretion (UAE) and renal function
      was investigated in a 4 year, randomized prospective study in normotensive
      patients with non-insulin-dependent (Type 2) diabetes mellitus. Sixty-two
      normotensive patients with Type 2 diabetes mellitus and microalbuminuria but
      normal renal function were randomized to receive either enalapril 5 mg day-1 or
      no treatment. In the enalapril-treated patients, UAE was reduced from 115.4 +/-
      80.1 to 95.6 +/- 61.7 mg 24 h-1 after 12 months (p < 0.05) and to 75.3 +/- 44.8
      mg 24 h-1 after 48 months (p < 0.001). In the untreated group, UAE increased
      slowly from 93.9 +/- 69.9 to 150.0 +/- 144.5 mg 24 h-1 after 48 months. No
      changes in creatinine clearance, blood pressure or HbA1C were seen in either
      group during the 4-year period. In normotensive Type 2 diabetic patients with
      early stage of diabetic microalbuminuria. This effect is long-lasting and
      probably independent of the antihypertensive action of the drug.

PMID- 8641116
TI  - Non-insulin-dependent diabetes and 11-year mortality in Asian Indian and
      Melanesian Fijians.
AB  - This study reports 11-year all-cause and cause-specific mortality rates according
      to baseline glucose tolerance for a population-based sample of adult Melanesian
      and Indian Fijians (n = 2638), first surveyed in 1980. Risk factors for all-cause
      and cardiovascular disease (CVD) mortality in subjects with non-insulin-dependent
      diabetes (NIDDM) are also described. The baseline survey included 75 g oral
      glucose tolerance tests, measurements of blood pressure, body mass index, and
      triceps skinfold, assays of plasma cholesterol and triglycerides,
      electrocardiograms, and details of smoking habits and physical activity.
      Mortality status was ascertained for 2546 subjects through surveillance of death
      certificates, medical records and interview of subjects (or relatives). Mortality
      rates were increased in diabetic men and women of both ethnic groups: relative
      risks compared to subjects without diabetes at baseline were 1.7 (CI:0.9-3.1) and
      2.0 (1.1-3.7) in Melanesian and 4.2 (2.7-6.5), 3.2 (1.9-5.7) in Indian men and
      women, respectively. A large proportion of mortality among diabetic subjects was
      attributed to CVD (62%, 66% in Melanesian and 54%, 58% in Indian men and women,
      respectively). Mortality rates tended to be higher in Melanesians than Indians,
      except for diabetic men where Indians had higher total and cardiovascular disease
      rates. In contrast to non-diabetic Fijians, diabetic women of both ethnic groups
      lost their relative protection from coronary heart disease (CHD). Cox regressions
      for diabetic subjects showed age and fasting plasma glucose to be independent
      predictors of all-cause mortality in men, and age, body mass index (inversely)
      and systolic blood pressure in women, but lipid concentrations, and cigarette
      smoking were not related. After accounting for conventional CVD risk factors,
      diabetes conferred significantly increased risk of total, CVD, and CHD mortality.
      The mortality experience of Melanesian and Indian Fijians with NIDDM is similar
      to that documented in developed populations, with excess mortality due to
      cardiovascular causes.

PMID- 8641117
TI  - Human insulin receptor substrate-1: variant sequences in familial non-insulin
      dependent diabetes mellitus.
AB  - The aetiology of NIDDM is uncertain, although family and twin studies indicate an
      important role for genetic factors in disease onset. The function and position of
      IRS-1 within the insulin signalling pathway make it a prime candidate gene for
      the development of insulin resistance and NIDDM. Insulin resistant families were
      identified by studying unaffected first degree relatives from families with 2 or
      more living NIDDM subjects. Insulin sensitivity was determined in the relatives
      using the insulin tolerance test, and 15 families were identified as insulin
      resistant. One NIDDM subject from the 10 most resistant families was selected and
      the entire coding region of IRS-1 analysed by SSCP analysis. Four normoglycaemic
      subjects with no family history of diabetes served as controls. Five variant
      sequences of IRS-1 were identified with the NIDDM subjects; 2 silent
      polymorphisms at codons 235 (GGG to GGA) and 893 (CCG to CCC): 2 non-conservative
      mutations (Ala513Pro; Gly972Arg) and a codon deletion (Ser681-7 to Ser681-6). The
      influence of the non-conservative mutations alone, and in combination with other
      abnormalities of the insulin signalling pathway on peripheral insulin action,
      remains to be determined.

PMID- 8641118
TI  - Plasma lipoprotein composition and cholesteryl ester transfer from high density
      lipoproteins to very low density and low density lipoproteins in patients with
      non-insulin-dependent diabetes mellitus.
AB  - We have examined cholesteryl ester transfer (CET) from HDL to low density and
      very low density lipoproteins (LDL and VLDL) and lecithin: cholesterol acyl
      transferase (LCAT) activity in plasma from 28 men with non-insulin-dependent
      diabetes mellitus (NIDDM) treated with diet alone or diet and sulphonylurea drugs
      and in 27 healthy non-diabetic controls. Patients and healthy subjects had
      similar LCAT activity, but CET was significantly higher in NIDDM 26.1 +/- 11.5
      mumol l-1 h-1) than in healthy men (17.8 +/- 6.5 mumol l-1 h-1) (p = 0.001).
      Diabetic men also had higher CET compared to 15 healthy non-diabetic men (18.7 +/
      5.6 mumol l-1 h-1) (p = 0.001) with similar serum lipids. CET activity was
      similar in patients treated with diet alone (24.8 +/- mumol l-1 h-1) or with
      sulphonylureas (27.7 +/- 15.8 mumol l-1 h-1). The Sf 0-12 fraction was
      significantly enriched with total cholesterol (p = 0.0001) and free cholesterol
      (p = 0.0006) in diabetic subjects whether treated with diet alone or on
      sulphonylureas compared to the 15 non-diabetic controls matched for serum
      triglycerides. The free cholesterol/phospholipid, the free cholesterol/total
      protein and the free cholesterol/mass ratios were increased in the Sf 0-12
      fraction in diabetic subjects (p < 0.01). These findings indicate that CET is
      accelerated in patients with NIDDM and that this may be due to the altered
      composition of acceptor lipoproteins.

PMID- 8641120
TI  - Albuminuria, insulin resistance and dyslipidaemia in Chinese patients with non
      insulin-dependent diabetes (NIDDM).
AB  - In order to examine relationships between albuminuria, insulin resistance, and
      dyslipidaemia in non-insulin-dependent diabetes (NIDDM), we studied 164 Chinese
      patients (68 men, 96 women), treated with diet or oral hypoglycaemic agents, on
      three occasions during a 6-week period. Antihypertensive treatment, if previously
      prescribed, was withdrawn for at least 2 weeks before the study period. Insulin
      resistance was calculated from simultaneous fasting plasma glucose and insulin
      concentrations using the homeostasis model assessment (HOMA) method. Based on two
      of three 24 h urinary collections, 87 (53%) patients had normoalbuminuria, 46
      (28%) microalbuminuria, and 31 (19%) macroalbuminuria. Despite similar glycaemic
      control, patients with abnormal albuminuria had higher mean arterial pressure,
      fasting plasma total cholesterol, triglyceride and serum apo B concentrations and
      were more insulin resistant than normoalbuminuric patients. Albuminuria
      correlated with mean arterial pressure (r = 0.31, p < 0.001), triglyceride (r =
      0.36, p < 0.001), total cholesterol (r = 0.28, p = 0.001), apolipoprotein B (apo
      B) (r = 0.25, p = 0.003), and insulin resistance (r = 0.25, p < 0.002). These
      close associations may contribute to the increased cardiovascular risk in Chinese
      NIDDM patients with abnormal albuminuria.

PMID- 8641119
TI  - Reduction of leucocyte proteolytic enzyme activity in diabetic patients with
      microalbuminuria and proteinuria: its possible role in diabetic nephropathy.
AB  - Mesangium enlargement and glomerular basement membrane thickening are cardinal
      features of diabetic nephropathy. The reasons for these changes are uncertain but
      decreased degradation of extracellular matrix may play a role. Mesangium
      degradation can be modulated by factors intrinsic to the kidney or by factors in
      the circulation. In this study the capacity of leucocyte proteolytic enzymes to
      degrade mesangium matrix materials was investigated. Leucocytes were obtained
      from 57 patients with NIDDM (age 58.3 +/- 8.8 years, duration 9.4 +/- 7.3 years,
      body mass index (BMI) 30 +/- 6 kg m-2, HbA1c 7.7 +/- 2.0%) and 21 control
      subjects (age 55.1 +/- 14.6 years, BMI 25 +/- 4 kg m-2). Leucocyte lysates from
      control and NIDDM subjects with normal AER degraded matrix to the same extent
      (40.6 +/- 8.2% vs 42.9 +/- 13.5%) while lysates from patients with
      microalbuminuria and proteinuria were less able to degrade matrix (33.0 +/- 14.2%
      and 26.1 +/- 12.7%, respectively). There was a significant inverse correlation
      between matrix degradation and AER (r = -0.49) and multiple regression analysis
      showed that AER was the most important factor determining degradation rate (R2 =
      0.24). Degree of metabolic control, age, and blood pressure were not significant
      factors. The major enzyme(s) responsible for the matrix degradation was
      identified as metalloproteinase(s). We conclude that leucocytes from diabetic
      patients with abnormal albumin excretion have a decreased proteolytic capacity to
      degrade extracellular matrix. This may play a role in the glomerular basement
      membrane thickening and mesangium expansion which occurs in diabetic nephropathy.

PMID- 8641122
TI  - Skin capillary density in subjects with impaired glucose tolerance and patients
      with type 2 diabetes.
AB  - In view of recent interest in the role of impaired early development and the
      pathogenesis of cardiovascular disease and carbohydrate intolerance in adults,
      this study examines whether reduced skin capillary density contributes to the
      limited microvascular hyperaemic responses observed in patients with Type 2
      diabetes and subjects with impaired glucose tolerance (IGT). Fifteen patients
      with Type 2 diabetes, 15 subjects with IGT and 15 matched non-diabetic control
      subjects were studied. Capillary videomicroscopy was used to record images of the
      skin capillaries on the dorsum of the middle phalanx of the left middle finger
      before and after 10 min venous occlusion at 35 mmHg. There were no significant
      differences between the three groups in either basal capillary density (112 (71
      144) caps mm-2 Type 2 patients (median and range) vs 107 (76-140) caps mm-2 IGT
      subjects vs 112 (76-138) caps mm-2 control subjects; p = 0.9, Kruskal Wallis), or
      following venous occlusion (122 (87-157) caps mm-2 vs 121 (90-143) caps mm-2 vs
      123 (81-147) caps mm-1; p = 0.9). In addition there were no differences in blood
      pressure, BMI or skin temperature. These results do not support the concept of
      impaired early development of the skin microcirculation in patients with Type 2
      diabetes or IGT and suggest that mechanisms other than reduced capillary density
      are involved in limiting microvascular vasodilation.

PMID- 8641121
TI  - Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a
      controlled trial.
AB  - To investigate the effect of oral antibiotics in purely neuropathic ulcers
      (Wagner grade 1-2, no osteomyelitis), a double blind placebo-controlled study was
      performed. Forty-four patients were enrolled and subjected to standard treatment
      with absolute pressure relief (half shoes), daily wound cleansing (topical
      disinfectant), sterile dressings (specialized nurse). Patients were randomized to
      an antibiotic (amoxicillin plus clavulanic acid), or placebo. The study was
      stopped when the antibiotic proved unsuitable according to swab result, or on
      clinical grounds (no improvement within 6 days of recruitment). Main outcome
      measure was the ulcer closing rate during 20 days, as assessed by standardized
      photographs. All ulcers except one were infected. Of the placebo group (n = 22),
      2 patients had to be withdrawn within 6 days, versus 3 patients of the antibiotic
      group (n = 22). In the placebo group, 10 ulcers were healed versus 6 ulcers in
      the antibiotic group (NS). Mean (95% CI) reduction in ulcer radius was 0.41 (0.21
      0.61) mm day-1 in the placebo group versus 0.27 (0.15-0.39) mm day-1 in the
      antibiotic group (NS). In conclusion, there is no benefit from antibiotic
      treatment with amoxicillin plus clavulanic acid as a supplement to standard
      therapy in uncomplicated neuropathic foot ulcers, provided pressure relief is
      complete, and wound care is performed strictly supervised. However, a Type-II
      statistical error cannot be excluded in this small study.

PMID- 8641123
TI  - Long-term effects of pregnancy on diabetic complications.
AB  - The aim of our study was to establish whether pregnancy affects long-term
      development and progression of retinopathy and nephropathy in diabetic women
      compared to nulliparous diabetic women. Twenty-eight diabetic women who had
      delivered in 1983-85 at Helsinki University Central Hospital and 17 nulliparous
      controls matched according in age, duration of diabetes, and degree of vascular
      complications were personally interviewed and the current retinal status and
      renal function were assessed 7 years later, in 1990-92. Serum creatinine,
      creatinine clearance, nocturnal albuminuria, and HbA1c were measured and colour
      fundus photography carried out. The results were compared to the status in 1983
      85. Of those who had been pregnant, 5 of 26 (19.2%) had experienced worsening of
      retinopathy. In 3 of these, proliferative retinopathy had developed from only
      minimal background changes. In the control group, progression had occurred in 8
      cases of 16 (50%, p < 0.05). The groups did not differ from each other regarding
      progression or development of nephropathy. This suggests that pregnancy does not
      seem to affect development or progression of diabetic nephropathy whereas
      progression of retinopathy seems to occur less often after pregnancy compared to
      nulliparous women.

PMID- 8641124
TI  - Is macrosomia associated with poor glycaemic control in diabetic pregnancy?
AB  - The study aimed to determine the influence of glucose control during pregnancy on
      the incidence of macrosomia in the infants of mothers with insulin-dependent
      diabetes. The prevalence of macrosomia was determined in pregnancies of all such
      women attending the City Hospital Nottingham, between July 1987 and July 1993,
      where it is policy for diabetic patients to aim during pregnancy for preprandial
      capillary glucose levels of less than 6.0 mmol I-1, and postprandial glucose
      levels of less than 8.0 mmol I-1. Macrosomia was defined as a birthweight greater
      than 90th centile using a computer model which takes into account all the major
      determinants of birthweight. Twelve of 29 infants were macrosomic, which is
      greater than expected (p < 0.01). During pregnancy there was no difference in
      mean seven point glucose profiles between those mothers with normal weight babies
      and those with macrosomia, but fructosamine levels at booking were significantly
      higher in the latter 2.5 (1.9-2.9) vs 2.2 (1.2-3.0); p < 0.05. These data confirm
      other studies and suggest that the incidence of macrosomia may be reduced by
      tighter control of diabetes at conception and in the first trimester, but to a
      lesser extent during later pregnancy.

PMID- 8641125
TI  - Creation of a District Diabetes Register using the DIALOG system.
AB  - A District Diabetes Register has been created using the Family Health Services
      Computer Unit system, DIALOG, linked to the Family Health Services Authority
      (FHSA) population register. Initial informal discussions between the Diabetes
      Centre, Public Health, and the FHSA led to a formal proposal being accepted by
      the Local Diabetes Services Advisory Group to pilot the DIALOG software.
      Following installation of DIALOG on a separate computer, electronically linked to
      the main FHSA system, the register was compiled. This was approached in three
      ways. The existing Diabetes Centre Register was downloaded into DIALOG and
      patients matched with the FHSA register. A 'diabetes roadshow' was mounted, with
      Postgraduate Education Allowance approval, to individually visit every general
      practice in the district to explain the aims and objectives of creating a
      diabetes register and to enlist the support of these practices. Where practices
      already held their own diabetes register this was similarly transferred, if not,
      assistance was provided to identify their patients with diabetes. All patients
      were notified in writing that their names were being placed upon a diabetes
      register and that clinical data would be held against their entry. This
      notification included an opportunity to opt out. Additionally, a self
      registrations scheme was introduced whereby all retail pharmacists dispensing any
      diabetes related product and all optometrists seeing a person with diabetes, gave
      the patient a leaflet, describing the register and its purposes and inviting them
      to register themselves. A 'Data Ownership Committee' was established to control
      the use and interpretation of all clinical data held upon the register. The
      process of diabetes annual review is now being prompted across both primary and
      secondary care and clinical data is being returned to the register.

PMID- 8641126
TI  - DIALOG: co-ordination of the annual review process through a District Diabetes
      Register linked to the FHSA database.
AB  - A working party was established by the Population Screening Project Board (UK),
      in conjunction with the Family Health Services Computer Unit, in order to develop
      a system for diabetes care (DIALOG) that would create a District Diabetes
      Register and prompt the process of diabetes annual review across both primary and
      secondary care. To simplify the creation and maintenance of the Diabetes
      Register, DIALOG has been designed to interface with the Family Health Services
      Authority population register to enable realtime download of demographic data.
      The system will also accumulate clinical information for the continuing audit
      diabetes services according to the data items specified in the standard UK
      diabetes dataset and can deliver detailed statistical analyses. Data input can be
      manual or electronic. DIALOG has been created to complement and integrate with
      existing diabetes information systems in primary and secondary care; it is not
      intended to be a clinic management system. It has the potential to become a
      National Diabetes Register.

PMID- 8641127
TI  - Diabetes in pregnancy in Pakistani women: prevalence and complications in an
      indigenous south Asian community.
AB  - The aim of this study was to determine the prevalence and complications as well
      as to correlate maternal and fetal outcome with glycaemic control, in a community
      of Pakistani women. This was a retrospective study of 6830 deliveries over a 5
      year period in a tertiary care hospital in Karachi. Either a 75 g glucose
      tolerance test or a screening 50 g glucose challenge was administered depending
      on risk factors for Gestational Diabetes Mellitus (GDM). Case records of
      deliveries during this period were analysed for presence of GDM or pre-existing
      diabetes; glycaemic control and complications were ascertained for those with
      diabetes. During this period 267 (3.9%) of the 6380 deliveries were identified as
      diabetic pregnancies. Of these 223 (3.3%) had GDM and 44 (0.6%) women had pre
      existing diabetes mellitus. Overall maternal complications were high; pre
      eclampsia (19%), polyhydramnios (4.6%), and threatened abortion (3.4%). Fetal
      complications of macrosomia (13.1%), intrauterine growth retardation (7.1%),
      intrauterine deaths (5.3%) were noted. Complications were higher in poorly
      controlled groups. We conclude that the prevalence of GDM in Pakistani women in
      our study was comparable to their Western counterparts but complication rates
      were higher, possibly due to poorer glycaemic control.

PMID- 8641128
TI  - In-hospital mortality and disposition of diabetic amputees in The Netherlands.
AB  - The purpose of this study is to identify in-hospital mortality of diabetic
      amputees and the disposition of survivors in The Netherlands in 1991 and 1992. A
      database including all hospitalizations in The Netherlands was used. Amputees who
      died while in the hospital were analysed separately. Survivors were categorized
      according to different types of discharge: home, nursing home, rehabilitation
      facility, and other health care facilities. Overall 9.0% of diabetic amputees
      died while in hospital. The age-adjusted mortality incidence for the diabetic
      population was 36.3 per 1000 diabetic amputees (95% CI: 18.7-53.9) and 28.2 per
      1,000 non-diabetic amputees (95% CI: 20.5-35.9). Non-diabetic amputees with PVD
      has proportionally more mortality than diabetic amputees with PVD (P < 0.01),
      diabetic amputees without PVD (P < 0.01), and non-diabetic amputees without PVD
      (P < 0.001). Using Cox regression analysis age (B(age) = 0.023, RR = 1.024) and
      the occurrence of multiple amputations during the hospitalization (Bmultiple =
      0.325, RR = 1.383) were significant negative predictors for survival. As age and
      level of amputation increased, more diabetic and non-diabetic amputees were
      discharged to facilities other than home (P < 0.001).

PMID- 8641129
TI  - Congenital chest wall deformities.

PMID- 8641130
TI  - Report of the sixth international workshop on human chromosome 3 mapping 1995.

PMID- 8641131
TI  - Report of the fourth international workshop on human chromosome 16 mapping 1995.

PMID- 8641132
TI  - Assignment of the human alpha-tropomyosin gene TPM4 to band 19p13.1 by
      fluorescence in situ hybridization.
AB  - Sequence-tagged sites (STSs) were developed for the human alpha-tropomyosin gene
      TPM4. One STS was used to amplify DNA from somatic cell hybrids to localize TPM4
      to chromosome 19. The other, a product from a long-range PCR, was used directly
      as a probe to refine the localization of TPM4 to 19p13.1 by fluorescence in situ
      hybridization to metaphase chromosome spreads.

PMID- 8641133
TI  - Assignment of the gene encoding human Kruppel-related zinc finger protein 4
      (GLI4) to 8q24.3 by fluorescent in situ hybridization.
AB  - The gene for human Kruppel-related protein 4, (HKR4, gene symbol GLI4), a zinc
      finger protein of unknown function, has been localized by fluorescence in situ
      hybridization to chromosome 8q24.3, distal to c-MYC.

PMID- 8641134
TI  - A third P-domain peptide gene (TFF3), human intestinal trefoil factor, maps to
      21q22.3.
AB  - Small peptides displaying a cysteine-rich module (termed P-domain or trefoil
      motif) form a recently increasing group of peptides abundantly expressed at
      mucosal surfaces of specific tissues and are associated with the maintenance of
      surface integrity. The estrogen-inducible pS2 gene (BCEI) and the human homolog
      to the porcine spasmolytic peptide (hsP) gene (SML1) appear synchronously
      expressed in healthy stomach mucosa and several carcinomas of the
      gastrointestinal tract. Both genes were shown to be located at 21q22.3. A new
      trefoil peptide from human intestinal mucosa (hITF/hP1.B) and its gene (TFF3)
      were described recently. By PCR analysis of a somatic cell hybrid panel and FISH
      using two large genomic recombinants (110 kb, 210 kb) cloned in the Bacterial
      Artificial Chromosome (BAC) system, we show that this gene coding for the new
      member of human P-domain/trefoil peptides also maps to chromosome region 21q22.3
      suggesting a physical linkage of all three trefoil peptide genes.

PMID- 8641135
TI  - Localization of the human gene for aquaporin 3 (AQP3) to chromosome 9, region p21
      ->p12, using fluorescent in situ hybridization.
AB  - The chromosome location of the gene encoding aquaporin 3 (AQP3), which functions
      as a channel for water and small polar solutes in the basolateral membrane of the
      collecting duct of the kidney, was determined. In situ hybridization on metaphase
      chromosomes allowed the assignment of human AQP3 to chromosome 9p21-->p12.

PMID- 8641137
TI  - Differences in the distribution and nature of the interstitial telomeric
      (TTAGGG)n sequences in the chromosomes of the Giraffidae, okapai (Okapia
      johnstoni), and giraffe (Giraffa camelopardalis): evidence for ancestral
      telomeres at the okapi polymorphic rob(5;26) fusion site.
AB  - Intrachromosomal telomeric sequences (TTAGGG)n were analyzed in the two members
      of the family Giraffidae, the giraffe and the okapi. The giraffe has a diploid
      chromosome number of 2n = 30, whereas the okapi chromosome number varies from 2n
      = 46 to 2n = 45 and 2n = 44 due to a "recent" Robertsonian fusion event. The
      interstitial telomeres that we detected in these species are of two types: (1) In
      the okapi, a long interstitial telomeric element is present at the fusion site of
      the rob(4;26). The nature of this interstitial telomeric element suggests that it
      is a remnant of the telomeres of the ancestral chromosomes that participated in
      the fusion event. (2) In the giraffe, short stretches or degenerate telomeric
      sequences which are part of the satellite DNA are present at intrachromosomal
      sites. The results of this study provide insights into the origin of interstitial
      telomeric sequences in the Giraffidae.

PMID- 8641136
TI  - +P5 (D1S3309E), a novel target binding site for the Wilms' tumour suppressor 1
      (WT1) gene, maps to human chromosome 1q21-->22.
AB  - The Wilms' tumor suppressor 1 gene (WT1) encodes a zinc finger transcription
      factor critical for normal urogenital development. We have previously isolated a
      DNA fragment, +P5 (D1S3309E), to which all WT1 protein isoforms bind. Using PCR
      of a human x rodent somatic cell hybrid mapping panel, together with two-color
      fluorescence in situ hybridisation of +P5-containing cosmids and previously
      localised human chromosome 1q cosmids, we have mapped the +P5 fragment to
      chromosome 1q21-->q22.

PMID- 8641138
TI  - Assignment of the human prosaposin gene (PSAP) to 10q22.1 by fluorescence in situ
      hybridization. Giraffidae, okapi (Okapiajohnstoni), and giraffe (Giraffa
      camelopardalis): evidence for ancestral telomeres at the okapi polymorphic rob
      (4;26) fusion site.
AB  - The human prosaposin gene (PSAP) was previously localized to 10q21-->q22 by
      isotopic in situ hybridization using a human prosaposin cDNA as a probe. The
      present study, using fluorescence in situ hybridization with a mouse genomic
      prosaposin fragment as probe, confirms the localization of PSAP and precisely
      maps it to band 10q22.1.

PMID- 8641139
TI  - FISH localization of the soluble thymidine kinase gene (TK1) to human 17q25, a
      region of chromosomal loss in sporadic breast tumors.
AB  - Soluble thymidine kinase (TK1) is an important 17q marker in somatic cell
      genetics. Its activity is increased in many malignancies, including breast
      cancer. Through somatic cell hybrid and fluorescence in situ hybridization
      studies, we mapped TK1 to 17q25.2-->25.3, in region demonstrating loss of
      heterozygosity in primary breast tumors. It lies near D17S836 and is proximal to
      the avian erythroblastic leukemia viral oncogene homolog 2-like gene (ERBA2L).

PMID- 8641140
TI  - Human endothelin converting enzyme gene (ECE1) mapped to chromosomal region
      1p36.1.
AB  - The chromosomal localization of the human endothelin converting enzyme gene
      (ECE1) has been identified. Southern blot analysis of human genomic DNA from
      human x mouse somatic cell hybrids demonstrated that ECE1 maps to chromosome 1.
      Fluorescence in situ hybridization of a digoxigenin-labeled human ECE1 probe to
      normal human metaphase chromosomes showed that the gene is located within
      chromosome band 1p36.1.

PMID- 8641141
TI  - Analysis of constitutive heterochromatin by fluorochromes and in situ digestion
      with restriction enzymes in species of the group Callithrix argentata
      (Callitrichidae, Primates).
AB  - The karyotypes of the species belonging to the group Callithrix argentata
      (Callitrichidae, Platyrrhini) are characterized by large amounts of distal
      constitutive heterocharomatin (CH). The CH of the species C. argentata, C.
      humeralifera and C. emiliae was analyzed by banding with the restriction enzymes
      HinfI, MboI, aluI, RsaI, DdeI, HaeIII and MspI, as well as the fluorochromes CMA3
      and DAPI. The results obtained permitted us to classify the CH of these species
      into three distinct types: 1) distal CH with a homogeneous response to enzymatic
      action, which was unchanged (HinfI, MboI, AluI, HaeIII), partially digested
      (DdeI) or fully digested (RsaI), being CMA3+, DAPI-; 2) centromeric CH, generally
      presenting a reduced band size. The varying extent of reduction, ranging from
      none to total, and also the variation of fluorochrome staining indicates that
      there is heterogeneity in this type of CH; 3) CH of the distal portion of the X
      chromosome of C. argentata and of the Y chromosome was CMA3- and unchanged by the
      enzymes, except for RsaI, which caused a reduction in size. MspI was the only
      enzyme unable to induce bands. Sequential C-banding permitted us to perceive
      banding variations that could not be observed simply by RE banding.

PMID- 8641142
TI  - Chromosomal relationships and phylogenetic and clustering analyses on genes
      Callithrix group argentata (Callitrichidae, Primates).
AB  - The karyotypes of three species of marmosets of the Callithrix argentata group
      (C. argentata, C. humeralifera and C. chrysoleuca) were studied. Comparisons were
      made among species and with the previously described karyotypes of C. emiliae, C.
      mauesi (argentata group) and C. jacchus (jacchus group). Two chromosomes
      rearrangements differentiate the argentata (2n=44) and jacchus (2n=46) groups:
      fusion or fission and a paracentric invasion. The argentata group is also
      characterized by the addition of large amounts of distal constitutive
      heterochromatin (CH) in some chromosomes, while the jacchus group shows mainly
      centromeric heterochromatin. The five species of the argentata group differ in
      the amount or location of the distal CH. Interspecific differences were converted
      to a Basic Data Matrix (BDM), that was submitted to phenetic and cladistic
      analyses. For cladistic analyses C. jacchus was the outgroup. The results agree
      with morphological and geographical data.

PMID- 8641143
TI  - Ordering of the human regulator of complement activation gene cluster on 1q32 by
      two-colour FISH.
AB  - The regulator of complement activation (RCA) gene cluster and PTPRC and REN genes
      have been mapped to the 1q31-->q32 band interval. We have used two-colour in situ
      hybridization to determine the chromosomal position of these genes. We report
      here that HF1/F13B are proximal to the C4BP/MCP genes. We also propose that PTPRC
      and REN genes map to a region of the RCA gene cluster between the HF1/F13B and
      C4BP/MCP regions. In summary, we propose the following gene order: centromere
      HF1/F13B-PTPRC-REN-C4BP/MCP-telomere.

PMID- 8641144
TI  - Localization of ZNF164, ZNF146, GGTA1, SOX2, PRLR and EEF2 on homoeologous
      cattle, sheep and goat chromosomes by fluorescent in situ hybridization and
      comparison with the human gene map.
AB  - The six following genes: zinc finger proteins 164 (ZNF164) and 146 (ZNF146),
      alpha-galactosyltransferase 1 (GGTA1), SRY-related HMG-box 2 (SOX2), prolactin
      receptor (PRLR) and elongatin factor 2 (EEF2) have been localized by fluorescent
      in situ hybridization respectively on bovine and caprine chromosomes 17, 18, 11,
      1, 20 and 7 and on sheep chromosomes 17, 14, 3, 1, 16, and 5. The comparison of
      the results with the localization of these genes in man (except for ZNF164)
      confirm the correspondences between human and bovine chromosomes established from
      heterologous chromosome painting data.

PMID- 8641145
TI  - Henri Gastaut (1915-1995).

PMID- 8641146
TI  - The impact of repeated short episodes of circulatory arrest on cerebral function.
      Reassuring electroencephalographic (EEG) findings during defibrillation threshold
      testing at defibrillator implantation.
AB  - The impact of circulatory arrest on EEG features during defibrillation threshold
      testing for implantation of a cardioverter defibrillator has been disputed.
      Cumulation of cerebral ischemic effects during threshold testing has been
      observed, and consequently the advice was given to avoid short intervals between
      tests and to limit the test number. This study investigated the duration of EEG
      signs of cerebral ischemia as well as the occurrence of cumulation. EEGs were
      recorded during standardized general anesthesia. Subsequent tests were performed
      after recovery of EEG, electrocardiogram, systemic arterial blood pressure, and
      heart rate. In 36 consecutive survivors of out-of-hospital cardiac arrest 286
      episodes of induced circulatory arrest were analyzed. Ischemic EEG changes were
      present in all episodes of circulatory arrest, consisting of slowing, progressing
      to absence of activity. The relation between the onset time or recovery time and
      the test number and test interval was studied. A highly significant correlation
      between circulatory arrest and recovery time was found (P < 0.001). A significant
      negative correlation existed between test number and recovery time (P < 0.05).
      Test interval was not related with either onset or recovery time. We conclude
      that repeated threshold tests which are monitored by assessment of EEG and
      hemodynamics are not associated with cumulative EEG changes as a result of
      ischemia. Our results do not support the advice that the number of tests should
      be limited.

PMID- 8641147
TI  - Usefulness of focal rhythmic discharges on scalp EEG of patients with focal
      cortical dysplasia and intractable epilepsy.
AB  - We examined the significance and frequency of occurrence of rhythmic epileptiform
      discharges (REDs) on the scalp EEGs of 74 patients with intractable partial
      epilepsy. We also analyzed the relationship of this abnormality to the continuous
      epileptiform discharges (CEDs) recorded on ECoG. Both REDs and CEDs had been
      found to be highly specific and sensitive indicators of focal cortical dysplastic
      lesions. Thirty-four patients (group I) had focal cortical dysplastic lesions
      (FCDLs) and 40 (group II) had non-dysplastic structural lesions. REDs were
      observed in 15 (44%) of the 34 patients of group I and in none of group II. REDs
      did not occur in isolation, were associated with more intermittent interictal
      spikes involving other regions, but had a greater (P < 0.05) significance for the
      localization of the epileptogenic area. A strong relationship was observed
      between the presence of REDs on scalp EEG and the occurrence of CEDs on ECoG
      recordings. Twelve (80%) of 15 patients with REDs had CEDs. Focal cortical
      dysplastic lesions are likely to be present when rhythmic epileptiform discharges
      are found.

PMID- 8641148
TI  - An approach to seizure detection using an artificial neural network (ANN).
AB  - We have developed an EEG seizure detector based on an artificial neural network.
      The input layer of the ANN has 31 nodes quantifying the amplitude, slope,
      curvature, rhythmicity, and frequency components of EEG in a 2 sec epoch. The
      hidden layer has 30 nodes and the output layer has 8 nodes representing various
      patterns of EEG activity (e.g. seizure, muscle, noise, normal). The value of the
      output node representing seizure activity is averaged over 3 consecutive epochs
      and a seizure is declared when that average exceeds 0.65. Among 78 randomly
      selected files from 50 patients not in the original training set, the detector
      declared at least one seizure in 76% of 34 files containing seizures. It declared
      no seizures in 93% of 44 files not containing seizures. Four false detections
      during 4.1 h of recording yielded a false detection rate of 1.0/h. The detector
      can continuously process 40 channels of EEG with a 33 MHz 486 CPU. Although this
      method is still in its early stages of development, our results represent proof
      of the principle that ANN could be utilized to provide a practical approach for
      automatic, on-line, seizure detection.

PMID- 8641149
TI  - Neural net identification of thumb movement using spectral characteristics of
      magnetic cortical rhythms.
AB  - Neural nets have shown great promise as tools for reducing and examining multi
      dimensional data. When carefully tuned with selected data sets of individual
      subjects neural nets have indisputable potential in identifying distinct stages
      of voluntary finger movements. However, robust, automatized data description
      methods would be needed to eventually extend the use of neural networks into
      visualization of brain activity during more complex, multimodal tasks where the
      cortical processes are not equally well understood. We explored the suitability
      of a self-organizing map (SOM) in the widely studied case of voluntary finger
      movements (left and right thumb), using as input such spectral characteristics
      that showed systematic task-dependent changes when averaged over repeated
      movements. SOMs constructed without individual fine-tuning and with generally
      chosen training parameters from these spectral features identified correctly 85%
      of the ongoing movements but, somewhat surprisingly, not the side of thumb
      movement. Even for this inclusive choice of input, the neural nets were sensitive
      to transient signals, but focused fine tuning, based on a priori known subgroups
      in the data, is clearly required for more detailed classification. Thus, a neural
      net visualization is likely not the most attractive first approach for
      characterization of cortical processing during complex multimodal tasks.

PMID- 8641150
TI  - Post-movement beta synchronization. A correlate of an idling motor area?
AB  - Post-movement beta (around 20 Hz) synchronization was investigated in 2
      experiments with self-paced finger extension and flexion and externally paced
      wrist movement. The electrodes were fixed over the sensorimotor area in distances
      of 2.5 cm. It was found that after a brisk finger movement the desynchronized
      beta rhythm displayed a fast recovery and a short-lasting synchronization within
      1 sec. This post-movement beta synchronization was maximal over the contralateral
      hemisphere and localized slightly more anterior to the maximal desynchronization
      of the hand area mu rhythm. The post-movement beta synchronization is interpreted
      as a correlate of "idling" motor cortex neurons.

PMID- 8641151
TI  - Age-related changes in the electrophysiological response to visual stimulus
      novelty: a topographical approach.
AB  - The relationship of task relevance and stimulus probability to P300 morphology,
      latency and distribution was assessed. Eight year olds and adults completed
      visual oddball tasks of recognition memory with frequent non-target (60%),
      infrequent target (20%), and infrequent novel (20%) stimuli. Stimuli consisted of
      2 female faces posing neutral expressions, and 40 trial unique novel photographs
      depicting scenes, animals, objects or abstract patterns. Event-related potentials
      were recorded from 17 electrodes over frontal, central and parietal scalp,
      including lateral temporal sites. All stimuli elicited P300 responses at parietal
      electrodes, with the largest responses to the target stimuli (relevant and
      infrequent). The P300 responses of adults and children were morphologically
      dissimilar, with children showing broader peaks and latency shifts across
      electrodes. In addition, the eight year olds displayed a frontal negativity to
      novel stimuli which was absent in the responses of adult participants. Results
      suggest that different anatomical or functional circuitry may be involved in the
      processing of novelty for adults as compared to eight year olds.

PMID- 8641152
TI  - The recognition potential and conscious awareness.
AB  - The idea that conscious awareness of a recognizable image is necessary for it to
      evoke the recognition potential (RP) was tested by asking bilingual subjects to
      selectively attend to superimposed English and Chinese word images. The subjects
      detected most of the words in the attended language, but were largely oblivious
      of words in the non-attended language. Attended word images evoked the RP. Non
      attended words did not. RP latency was less for Chinese than for English words.
      This provided a basis for inferring which language a subject was trying to read
      when valid English and Chinese words were both present. A subject was looking for
      Chinese if the latency was short and for English if it was long. The results
      showed that selective attention had a powerful effect on the RP. They supported
      the idea that conscious awareness is necessary for evoking it, though they did
      not rule out the theoretical possibility that some method not yet tested could be
      found that would block conscious awareness without blocking the RP. The
      sensitivity of the RP to what a subject is trying to see and its low variance
      seem to provide advantages for studying visual perception. It provides a short
      latency indicator of image processing that merits further investigation. Use of
      it may lead to a better understanding of visual perceptual processes.

PMID- 8641153
TI  - Event-related EEG desynchronization and synchronization during an auditory memory
      task.
AB  - Event-related desynchronization (ERD) and synchronization (ERS) of the lower (8
      10 Hz) and upper (10-12 Hz) alpha bands of background EEG were studied in 10
      subjects during an auditory memory scanning paradigm. Each experimental trial
      started with the presentation of a visual warning signal, after which an auditory
      4-vowel memory set was presented for memorization. Thereafter the probe, a fifth
      vowel, was presented and identified by the subject as belonging or not belonging
      to the memorized set. In 50% of the cases, the probe was among the previously
      presented memory set. The presentation of the memory set elicited a significant
      ERS in the both alpha frequency bands. In contrast, the presentation of the probe
      elicited a significant bilateral ERD in both alpha frequency bands studied. The
      results suggest that the ERD phenomenon is closely associated with higher
      cortical processes such as memory functions rather than with auditory stimulus
      processing per se. Event-related desynchronization provides a potentially
      valuable tool for studying cortical activity during cognitive processing in the
      auditory stimulus modality.

PMID- 8641155
TI  - An iterative approach to the solution of the inverse problem.
AB  - The bioelectric inverse problem is framed as a search through a feasible set of
      solutions for one that is physiologically plausible. The definition of the
      feasible set of solutions takes into account the important effects of measurement
      noise. This leads to an iterative approach. At each step, a regularized inverse
      is used to limit the amount of brain that need be searched in the next step. The
      approach is tested in a model system that incorporates a digitized cadaver cortex
      into a 3-shell spherical replica of the head.

PMID- 8641154
TI  - High resolution evoked potential imaging of the cortical dynamics of human
      working memory.
AB  - High resolution evoked potentials (EPs), sampled from 115 channels and spatially
      sharpened with the finite element deblurring method, were recorded from 8
      subjects during working memory (WM) and control tasks. The tasks required
      matching each stimulus with a preceding stimulus on either verbal or spatial
      attributes. All stimuli elicited a central P200 potential that was larger in the
      spatial tasks than in the verbal tasks, and larger in the WM tasks than in the
      control tasks. Frequent, non-matching stimuli elicited a frontal, positive peak
      at 305 msec that was larger in the spatial WM task relative to the other tasks.
      Irrespective of whether subjects attended to verbal or spatial stimulus
      attributes, non-matching stimuli in the WM tasks also elicited an enhanced P450
      potential over the left frontal cortex, followed by a sustained potential over
      the superior parietal cortex. A posterior P390 potential elicited by infrequent,
      matching stimuli was smaller in amplitude for both spatial and verbal WM tasks
      compared to control tasks, as was a central prestimulus CNV. These results
      indicate that WM is a function of a distributed system with both task-specific
      and task-independent components. Lesion studies and course temporal resolution
      functional imaging methods, such as PET and fMRI, tend to paint a fairly static
      picture of the cortical regions which participate in the performance of WM tasks.
      In contrast, the fine-grain time resolution provided by imaging brain function
      with EP methods provides a dynamic picture of subsecond changes in the spatial
      distribution of WM effects over the course of individual trials, as well as
      evidence for differences in the activity elicited by matching and non-matching
      stimuli within sequences of trials. This information about the temporal dynamics
      of WM provides a critical complement to the fine-grain spatial resolution
      provided by other imaging modalities.

PMID- 8641156
TI  - Spline Laplacian estimate of EEG potentials over a realistic magnetic resonance
      constructed scalp surface model.
AB  - This paper presents a realistic Laplacian (RL) estimator based on a tensorial
      formulation of the surface Laplacian (SL) that uses the 2-D thin plate spline
      function to obtain a mathematical description of a realistic scalp surface.
      Because of this tensorial formulation, the RL does not need an orthogonal
      reference frame placed on the realistic scalp surface. In simulation experiments
      the RL was estimated with an increasing number of "electrodes" (up to 256) on a
      mathematical scalp model, the analytic Laplacian being used as a reference.
      Second and third order spherical spline Laplacian estimates were examined for
      comparison. Noise of increasing magnitude and spatial frequency was added to the
      simulated potential distributions. Movement-related potentials and somatosensory
      evoked potentials sampled with 128 electrodes were used to estimate the RL on a
      realistically shaped, MR-constructed model of the subject's scalp surface. The RL
      was also estimated on a mathematical spherical scalp model computed from the real
      scalp surface. Simulation experiments showed that the performances of the RL
      estimator were similar to those of the second and third order spherical spline
      Laplacians. Furthermore, the information content of scalp-recorded potentials was
      clearly better when the RL estimator computed the SL of the potential on an MR
      constructed scalp surface model.

PMID- 8641157
TI  - [Obsessive compulsive disorder. Clinical and epidemiologic studies].
AB  - Until recently, Obsessive-Compulsive Disorder (OCD) was considered rare trouble
      with rather poor outcome. Currently progress in behavioral psychology,
      psychopharmacology and methodology of epidemiologic studies multiplying by 50 the
      traditional prevalence rates, give an impetus to the interest in this pathology.
      Recent clinical and epidemiologic data in OCD are reported in this paper.
      Multiple questions are evoked such as the issue of OCD homogeneity, the meaning
      of comorbidity with other psychological disorders: depression, panic attacks,
      schizophrenia, Gilles de la Tourette syndrome, the reality of OCD prevalence rate
      in general and psychiatric populations, the usefulness of classical demarcation
      between psychosis/neurosis in the treatment of OCD, and finally the search for a
      genetic diathesis and risk factors implicated in predisposition to OCD. A close
      relationship between clinical, epidemiologic and genetic approaches seems to be
      required in order to answer these questions and constitutes a first step prior to
      carrying on basic and applied research.

PMID- 8641158
TI  - [Cognition disorders in obsessive disorder].
AB  - The authors present a critical overview of the multiple studies of cognitive
      functions of patients with obsessive compulsive disorder. First are mentioned
      some correlations between neurological diseases and obsessive compulsive
      disorder. Then, the authors analyse the results obtained by the patients in WAIS,
      in the tactual perception memory test, in visual memory and orientation and in
      verbal memory. Verbal behaviour, performances in sensory perception tests, motor
      performances, attention and, lastly, troubles in information processing are
      reviewed. With these results, the authors try to develop the relevant theories
      about the mechanisms in obsessive compulsive disorder: dysfunction of the
      dominant hemisphere and abnormality of the serotoninergic system.

PMID- 8641159
TI  - [Critical analysis of controlled pharmacologic studies in obsessive compulsive
      disorder].
AB  - Controlled pharmacologic studies in obsessive-compulsive disorder (OCD) are
      recent, scare and concern only antidepressants. Clomipramine constitutes the
      reference drug in the treatment of OCD and in comparative studies. The present
      paper includes a compendium of the results of 15 controlled studies and a
      critical approach of their methodologies and conclusions. The discussion
      continues about the genuine anti-obsessive effect of antidepressants, its
      specificity and the underlying neurochemical mechanisms.

PMID- 8641160
TI  - [French version of the Yale-Brown Obsessive Compulsive Scale].
AB  - A French translation and adaptation of the Yale-Brown obsessive compulsive scale
      is presented, with reference to validation studies. This new synthetic and
      specific measurement tool represents an advance and would deserve a French
      validation study.

PMID- 8641161
TI  - [Behavior therapy of obsessive compulsive disorders].
AB  - Obsessive-Compulsive Disorders (OCD) were once considered a relatively rare
      condition and highly refractory to treatment. Behavioral treatments consisting
      primarily of various methods of exposure and response prevention are reported to
      be approximately 70% effective in treating this condition that may affect 2 to 3%
      of the population and, in many cases, the effectiveness of these interventions
      persists over a number of years. However much remains to be done in refining
      these strategies and determining which patients are most likely to respond to
      these interventions.

PMID- 8641162
TI  - [Preliminary study of a list of obsessional thoughts. Validation and factorial
      analysis].
AB  - The validation study and factorial analysis of a list of obsessive thoughts is
      presented. Four groups were compared. They included patients suffering from
      obsessive compulsive disorders (n = 22), depression (n = 21), phobias (n = 16)
      and a control group (n = 21). The four groups were comparable as far as age, sex,
      and educational level were concerned. The list of obsessive thoughts is valid,
      reliable, and has a good internal consistency. The factorial analysis showed a
      first factor (accounting for 37.22% of the variance) reflecting perfectionism,
      and a second factor (accounting for 12.10% of the variance) reflecting a
      pathological sense of responsibility.

PMID- 8641163
TI  - [Anorexia nervosa. A frequent antecedent of obsessive compulsive disorder].
AB  - In a population of 60 patients suffering from obsessive-compulsive disorders, the
      authors find 5 patients (8.3% of the whole group), all female (13.1% of the whole
      female subgroup) with an anorexia nervosa among their antecedents, which
      represents a relatively important rate compared to the rarity of anorexia nervosa
      in the general population. Clinical particularities of the subgroup are then
      studied. Results from this work are partially comparable with those found in the
      single similar study in the literature.

PMID- 8641164
TI  - [Psychometric evaluation of obsessive compulsive disorder. Recent diagnostic
      scales].
AB  - Several standardized instruments have been developed since 1970 to assess
      obsessive-compulsive symptoms. The most commonly used are discussed in this
      article. It appears that relatively little work has been done to evaluate these
      instruments psychometrically. Further research is needed to establish the value
      of these instruments before developing new ones.

PMID- 8641165
TI  - Food for thought--is induction of oral tolerance feasible and practical in human
      thyroid autoimmunity?

PMID- 8641166
TI  - Immunosuppression of thyroiditis.
AB  - Immunization of mice with 50 micrograms human thyroglobulin (TG) in complete
      Freund's adjuvant leads to histological thyroiditis; production of IgG, IgA, and
      IgM anti-TG antibodies; and in vitro proliferative responses after incubation of
      lymphocytes with TG. Oral administration of 500 micrograms TG at four intervals
      before Tg immunization and once afterward causes up to 80% suppression of these
      responses. The effect is antigen specific and dose dependent. Feeding TG after
      immunization produces a 40% reduction in responses. We wished to define the
      mechanism of this antigen-specific oral tolerization. Popliteal lymph nodes (PLN)
      of orally tolerized animals (T) are reduced in size compared to those in
      immunized (I) animals not fed TG. PLN and mesenteric lymph nodes (MLN) of I
      animals produce interleukin-2 (IL-2) and interferon-gamma (IFN gamma) after in
      vitro incubation with TG, typical of an inflammatory immune response. PLN and MLN
      of tolerized animals do not proliferate in response to antigen, do not produce IL
      2 or IFN gamma, but do not produce the cytokines IL-4 and transforming growth
      factor-beta (TGF beta). Mixing in vitro of spleen cells from T and I animals
      causes a reduction in the immune response when incubated with TG, but no
      reduction in response to purified protein derivative (PPD) (the antigen in
      complete Freund's adjuvant). When T splenocytes are incubated with TG and PPD
      together, the response to TG and PPD is suppressed. Partially purified CD8+ cells
      from tolerized animals produce IL-4 and TGF beta after exposure to human TG and
      induce suppression, whereas partially purified CD4+ cells produce IL-2 and IFN
      gamma and do not cause suppression. MLN cells do not proliferate in response to
      antigen, but do produce inhibitory cytokines. T animals appear to shift the
      immune response from a Th-1 helper cell subset response to a Th-2 helper cell
      immunosuppressive response. In this model, oral tolerization produces a dramatic
      reduction in the immune response. Exposure of MLN to oral TG appears to cause the
      production of regulatory cells that migrate to spleen and PLN. In vitro studies
      demonstrate that on exposure to antigen, these regulatory cells produce IL-4 and
      TGF beta, which suppress all aspects of specific immune responsiveness and
      nonspecifically suppress other ongoing immune responses (bystander effect). Oral
      tolerization may include some element of T cell deletion or anergy. This model
      defines an experimental system with possible relevance to immunosuppression of
      human autoimmune thyroid disease.

PMID- 8641167
TI  - Effects of prostaglandins on deoxyribonucleic acid and aggrecan synthesis in the
      RCJ 3.1C5.18 chondrocyte cell line: role of second messengers.
AB  - PGs play an important role in regulating articular chondrocyte function in both
      normal and pathological states. However, the mechanisms of the effects of PG on
      chondrocyte function remain undefined. We, therefore, examined the effects of
      PGE1, PGE2, and PGE2 alpha on second messenger generation in relation to DNA and
      aggrecan synthesis in the nontransformed rat RCJ 3.1C5.18 (RCJ) chondrocyte cell
      line. RCJ cells were grown under minimal attachment conditions on a composite
      collagen-agarose (0.15%/0.8%) gel to maintain a differentiated phenotype. PGE1
      and PGE2 (0.001-100 microM) produced a similar dose-related increase in cAMP
      accumulation, with a maximal 8-fold increase over basal values, whereas PGF2
      alpha produced a minimal 1.3-fold increase in cAMP levels only at 100 microM. On
      the other hand, both PGE2 and PGE2 alpha raised the intracellular free calcium
      ([Ca2+]i) concentration, derived primarily from extracellular sources, whereas
      PGE1 was without effect on [Ca2+]i. These three PGs also had divergent effects on
      DNA synthesis, as measured by [3H]thymidine ([3H]TdR) incorporation. PGF2 alpha
      (0.001-5 microM) produced a dose-related increase in [3H]TdR incorporation, with
      a maximal 1.6-fold increase over baseline values at 5 microM and a slight decline
      to below maximal levels at 10 microM. PGE2 exhibited a contrasting inverse
      biphasic response, with an initial small suppressive effect that was maximal at
      0.1 microM and a secondary stimulatory phase producing a small increase over
      control values at 5 microM. PGE1 had a uniformly suppressive effect, producing a
      30% decrease at 10 microM. Despite the divergent effects of PGE1, PGE2, and PGE2
      alpha on second messenger generation and DNA synthesis, all three PGs produced a
      dose-related stimulation of aggrecan synthesis. PGF2 alpha was the most potent,
      producing significant stimulation at 0.001 microM and a maximal 104% increase at
      5 microM. PGE1 and PGE2 were approximately equipotent and approximately 60% as
      effective as PGF2 alpha in stimulating aggrecan synthesis. Northern analysis
      demonstrated that the effects of PG on aggrecan synthesis were not accompanied by
      changes in aggrecan core protein steady state messenger RNA levels. Thus, the
      effects of PG on aggrecan production in RCJ cells appear to be regulated at the
      posttranscriptional level. Forskolin and (Bu)2cAMP mimicked the suppressive
      effects of PGE1 on [3H]TdR incorporation, as well as the stimulatory effect of
      PGE1 on aggrecan synthesis. In addition, the phorbol ester 12-O-tetradecanoyl
      phorbol acetate mimicked PGF2 alpha stimulation of [3H]TdR incorporation and
      aggrecan synthesis, and the effects of PGE2 alpha on these processes were blocked
      by protein kinase C inhibitors. Therefore, it appears that in mammalian
      chondrocytes, PGE1 primarily activates the cAMP-protein kinase A second messenger
      system, PGE2 alpha affects primarily the Ca2(+)-protein kinase C system, and PGE2
      activates both pathways. Moreover, PG posttranscriptional regulation of aggrecan
      synthesis in chondrocytes involves both the cAMP-protein kinase A and Ca2(+)
      protein kinase C second messenger systems.

PMID- 8641168
TI  - Estrogen blocks parathyroid hormone (PTH)-stimulated osteoclast-like cell
      formation by selectively affecting PTH-responsive cyclic adenosine monophosphate
      pathway.
AB  - Several lines of evidence have previously indicated that estrogen inhibits PTH
      induced bone resorption in vivo and in vitro. However, its mechanism remains
      unknown. Therefore, the present study was performed to investigate the effect of
      estrogen on PTH-stimulated osteoclast-like cell formation and clarify its
      mechanism. 17 beta-estradiol (17 beta-E2) significantly antagonized osteoclast
      like cell formation stimulated by 10(-8) M human (h) PTH-(1-34) as well as 10(-8)
      M hPTH-related peptide (PTHrP)-(1-34)in osteoblast-containing mouse bone cell
      cultures. The conditioned medium derived from osteoblastic SaOS-2 cells or MC3T3
      E1 cells pretreated with both PTH-(1-34) (10(-8)M) and 17 beta-E2(10(-8)M)
      stimulated osteoclast-like cell formation from hemopoietic blast cells more
      weakly than conditioned medium from cells pretreated with PTH-(1-34) alone.
      Moreover, 10(-8) M 17 beta-E2 significantly blocked the formation of osteoclast
      like cells stimulated by 10(-8) M hPTH-(1-34) in spleen cell cultures derived
      from 5-fluorouracil-pretreated mice. On the other hand, 10(-8) M 17 beta-E2
      significantly inhibited osteoclast-like cell formation stimulated by dbcAMP (10(
      4)M) and Sp-cAMPS (10(-4)M), as well as forskolin (10(-5)M) in mouse bone cell
      cultures. In contrast, 10(-8)M 17 beta-E2 did not affect PMA (10(-7)M)-, A23187
      (10(-7)M)-, or BAYK-8644 (5 x 10(-6) M)-stimulated osteoclast-like cell
      formation. In conclusion, the present study demonstrated that estrogen inhibits
      PTH-stimulated osteoclast-like cell formation by directly acting on hemopoietic
      blast cells as well as by indirectly acting on them via osteoblasts. The
      inhibitory effects of estrogen on PTH-stimulated osteoclast-like cell formation
      seemed to be mediated through blocking the cAMP-dependent protein kinase pathway
      but not by blocking calcium/protein kinase C.

PMID- 8641169
TI  - Human endometrial fibroblasts immortalized by simian virus 40 large T antigen
      differentiate in response to a decidualization stimulus.
AB  - Human endometrial fibroblasts have been immortalized by infection with simian
      virus 40 large T antigen and established as a permanent cell line, St-2.
      Biochemical differentiation of this cell line has been demonstrated by the
      ability of a decidualizing stimulus, 8-bromo-cAMP plus medroxyprogesterone
      acetate (MPA), to induce PRL secretion and increase the enzymatic activity of
      estrone sulfatase. MPA, alone or in combination with estradiol, was unable to
      elicit this response, but potentiated the effect of 8-bromo-cAMP on PRL
      production and estrone sulfatase activity. The increase in PRL protein was
      accompanied by an increase in PRL messenger RNA and increased expression of the
      insulin-like growth factor-binding protein-1 messenger RNA. The St-2 cell PRL
      transcript was larger than the pituitary PRL transcript, suggesting its
      initiation from the distal, nonpituitary, PRL promoter. This was confirmed by
      reverse transcription-PCR analysis of PRL transcripts using primers specific for
      the additional sequences present only in the 5'-untranslated region of RNA
      initiated from the distal promoter. Transient transfection of a reporter
      construct containing 3000 bp of DNA 5' to the decidual-specific promoter of the
      human PRL gene demonstrated that cAMP was capable of activating this distal
      promoter in St-2 cells. In conclusion, this novel cell line provides an
      interesting new model in which to pursue aspects of biochemical differentiation
      of human endometrium in vitro.

PMID- 8641170
TI  - Glucocorticoids inhibit keratinocyte growth factor production in primary dermal
      fibroblasts.
AB  - The participation of growth factors in wound healing and tissue repair has been
      well established. Previous studies demonstrated that the expression of
      keratinocyte growth factor (KGF) was greatly elevated shortly after injury and
      that topical application of KGF accelerated healing. Steroidal antiinflammatory
      agents, specifically glucocorticoids, markedly impair wound healing. The
      participation of KGF in wound healing led us to examine the effect of
      glucocorticoids on KGF production. The addition of dexamethasone significantly
      reduced the level of constitutively produced KGF messenger RNA, protein, and
      bioactivity in conditioned medium from dermal fibroblasts. This inhibitory effect
      was observed with a variety of glucocorticoids, whereas nonsteroidal
      antiinflammatory compounds had little effect on KGF synthesis. The mechanisms by
      which dexamethasone decreased KGF production include a combination of a
      diminished transcriptional rate and destabilization of the KGF messenger RNA.
      Cytokines such as interleukin-1 alpha, platelet-derived growth factor-BB, and
      transforming growth factor-alpha, typically up-regulated during wound healing,
      augment KGF expression by dermal fibroblasts. We determined that dexamethasone
      also blocked this inductive effect. These results suggest that glucocorticoids
      could inhibit KGF production in the setting of wound repair, which may contribute
      to the impairment of healing associated with glucocorticoid use.

PMID- 8641171
TI  - Regulation of the insulin-like growth factor system by acute acidosis.
AB  - Many catabolic conditions are characterized by disturbances in acid-base balance
      and concomitant alterations in the insulin-like growth factor (IGF) system.
      However, the influence of acidosis per se on the various components of the IGF
      system has not been extensively examined. The purpose of the present study was to
      determine the effect of acute metabolic acidosis on the plasma and tissue
      concentrations of IGF-I and the various IGF-binding proteins (IGFBPs). Conscious
      unrestrained fasted rats were infused iv with either 0.2 N HCl or an equal volume
      of saline for 4 h. The arterial blood pH decreased within 60 min after starting
      the HCl infusion and remained lower than time-matched control values for the
      entire experimental protocol. Although the plasma IGF-I concentration fell
      gradually and was reduced by 30%, compared to time-matched control values, GH
      levels were unaltered. The IGF-I content of tissues collected at the conclusion
      of the experiment was increased in liver (35%) and kidney (63%), and unchanged in
      skeletal muscle. However, whereas acidosis moderately increased IGF-I messenger
      RNA abundance in liver, no significant alteration in IGF-I expression was
      detected in kidney. Acidosis also increased the plasma levels of IGFBP-1 and -2
      as well as the IGFBP-1 content of liver and kidney. In contrast, the
      concentration of intact IGFBP-3 was decreased in acid-infused rats, and this
      reduction was associated with an increased rate of IGFBP-3 protease activity.
      Acidotic rats demonstrated unremarkable changes in the plasma concentrations of
      glucose and insulin, but corticosterone levels were elevated throughout the
      experiment. The results of the present study demonstrate that in the absence of
      underlying pathology, acute metabolic acidosis decreases circulating levels of
      IGF-I, probably by increasing renal clearance of the peptide, not by decreasing
      hepatic IGF-I synthesis.

PMID- 8641172
TI  - Functional and growth properties of a myometrial cell line derived from
      transgenic mice: effects of estradiol and antiestrogens.
AB  - This study describes the properties of a myometrial cell line, m-M116, that was
      derived from a leiomyoma developed in an adult female transgenic mouse harboring
      the simian virus 40 large T antigen (Tag) under the control of the 5'-regulatory
      sequence of the calbindin D9k (CaBP9k) gene. As the expression of this transgene
      is governed by the CaBP9k estrogen-responsive element, m-M116 cells were grown in
      medium supplemented with 17 beta-estradiol. The cells were long lived, had Tag
      positive nuclei, and were nontumorigenic when injected into nude mice. They
      formed irregular layers of elongated cells with typical features of uterine,
      smooth muscle cells, as assessed by the presence of alpha-smooth muscle actin and
      desmin filaments, estradiol and progesterone receptors, and expression of the
      CaBP9k gene. The rate of cell doublings and the expression of the Tag gene in
      early passaged cells depended on the presence of 17 beta-estradiol. Tamoxifen, a
      mixed estrogen agonist-antagonist, also stimulated the growth of m-M116 cells,
      whereas ICI 182 780, a pure antiestrogen, blocked cell growth. Later passages of
      m-M116 cells still had a smooth muscle phenotype, but proliferated even in the
      absence of 17 beta-estradiol. These mouse uterine smooth muscle cells obtained by
      targeted oncogenesis provide a useful model for studies of the progression of
      steroid-independent carcinomas.

PMID- 8641173
TI  - Apparent nonnuclear regulation of intestinal phosphate transport: effects of 1,25
      dihydroxyvitamin D3,24,25-dihydroxyvitamin D3, and 25-hydroxyvitamin D3.
AB  - The steroid hormone 1,25-(OH)2D3 modulates a number of cellular functions through
      nonnuclear pathways, particularly the stimulation of intestinal calcium transport
      (transcaltachia). The present studies determined whether 1,25-(OH)2D3 rapidly
      enhanced phosphate transport in the perfused duodenal loop of normal chicks.
      Vascular perfusion with 65 pM 1,25-(OH)2D3 significantly stimulated the
      appearance of 33P in the venous effluent within 2-8 min, reaching an average of
      160% of control levels by 40 min. Lumenal perfusion with hormone failed to
      augment levels of 33P in the venous effluent. Vascular perfusion with a range of
      1,25-(OH)2D3 concentrations yielded an apparent biphasic dose-response curve. Two
      additional vitamin D metabolites, 24,25(OH)2D3 and 25(OH)D3, which initiate
      transcaltachia, were tested for their effect on phosphate transport. Neither 6.5
      nM 24,25(OH)2D3 nor 100 nM 25(OH)D3 stimulated 33P movement from the lumen to the
      venous effluent. When duodena were vascularly perfused with 65 pM 1,25-(OH)2D3
      and either 6.5 nM 24,25(OH)2D3 or 100 nM 25(OH)D3, enhanced phosphate transport
      was attentuated or abolished. Phosphate transport was also analyzed at metabolite
      levels 5-fold lower or higher than those in normal chicks. For 24,25(OH)2D3, 1.3
      nM metabolite did not augment phosphate transport, although stimulation did occur
      at 32.5 nM steroid (180 +/- 0.2% of controls). For 25(OH)D3, no stimulation was
      observed at 500 nM metabolite, whereas 20 nM steroid resulted in transport that
      was 160 +/- 0.14% of controls. The presence or absence of lumenal Ca2+ did not
      influence phosphate transport in duodena vascularly perfused with control medium,
      65 pM 1,25-(OH)2D3, or 6.5 nM 24,25(OH)2D3. In contrast, vascular perfusion with
      100 nM 25(OH)D3 stimulated phosphate transport when lumenal Ca2+ was present but
      not when it was absent. The influence of lumenal P(i) on transcaltachia was then
      studied. Although 65 pM 1,25-(OH)2D3, 6.5 nM 24,25(OH)2D3, and 100 nM 25(OH)D3,
      initiate transcaltachia in the presence of lumenal P(i), the absence of the anion
      abolished the stimulatory effects of 1,25-(OH)2D3 and 24,25(OH)2D3 on calcium
      transport but not those induced by 25(OH)D3. These data suggest a complex
      regulation of both calcium and phosphate transport based on relative levels of
      circulating vitamin D metabolites as well as the ionic content of the lumen.

PMID- 8641174
TI  - Enhanced expression of vascular endothelial growth factor in human SaOS-2
      osteoblast-like cells and murine osteoblasts induced by insulin-like growth
      factor I.
AB  - Formation of new capillaries, a critical component of tissue growth and repair,
      is a recognized process in the development, formation, and remodeling of bone.
      Vascular endothelial growth factor (VEGF), a potent angiogenic factor with
      specific mitogenic actions on endothelial cells, is produced in a regulated
      manner by many cell types, including osteoblasts. The aim of the present
      investigation was to test the hypothesis that insulin-like growth factor I (IGF
      I), a known osteogenic factor, modulates VEGF expression in osteoblasts. In human
      SaOS-2 osteoblast-like cells, 10 nM IGF-I increased the abundance of VEGF
      messenger RNA (mRNA) by 4-fold above the control value at 2h, and the elevated
      levels of mRNA returned to near basal by 8 h. IGF-I stimulated VEGF mRNA levels
      at IGF-I concentrations as low as 1-2 nM. The stability of VEGF mRNA was not
      increased after IGF-I treatment, and actinomycin D abrogated the enhanced
      expression of VEGF mRNA by IGF-I, indicating that the action of IGF-I was
      probably mediated by a transcriptional mechanism. The induction of VEGF mRNA by
      IGF-I in SaOS-2 cells was associated with an increase in immunoreactive VEGF
      protein, as detected by immunoblot analysis. IGF-I also increased the expression
      of VEGF mRNA in primary murine osteoblasts, which confirmed that the actions of
      IGF-I were not unique to SaOS-2 cells. We conclude that IGF-I enhances osteoblast
      synthesis of VEGF, which may then act locally on endothelium to stimulate
      angiogenesis, an essential component of bone growth and remodeling.

PMID- 8641175
TI  - Corticotropin-releasing hormone stimulates Ca2+ entry through L- and P-type Ca2+
      channels in rat corticotropes.
AB  - CRH induces corticotrope membrane depolarization and facilitates action potential
      firing. The increase in electrical excitability causes large oscillatory
      increases in cytosolic Ca2+ levels. In this study on highly enriched populations
      of cultured rat corticotropes, inhibitors were used to determine the contribution
      of the Na+ channel and Ca2+ channel subtypes to membrane excitability and
      cytosolic Ca2+ levels. Tetrodotoxin, an inhibitor of the voltage-dependent Na+
      channel, inhibited a rapid initial component of the action potential, but
      generally did not influence spontaneous or CRH-induced firing frequency.
      Tetrodotoxin also had no effect on spontaneous or CRH-induced cytosolic Ca2+
      levels. The L-type Ca2+ channel inhibitor nifedipine abolished spontaneous and
      CRH-induced action potentials and cytosolic Ca2+ transients, but did not
      eliminate the CRH-induced membrane depolarization or completely restore cytosolic
      Ca2+ to basal levels. Inhibition of P-type Ca2+ channels with omega-agatoxin-IVA
      decreased action potential firing frequency and reduced the CRH-induced increase
      in cytosolic Ca2+. The combination of nifedipine and omega-agatoxin-IVA abolished
      the CRH-induced rise in Ca2+, but did not abolish the membrane depolarization.
      Thus, cytosolic Ca2+ is mainly increased by CRH-induced action potentials that
      are completely dependent on L-type Ca2+ channels and partially regulated by P
      type Ca2+ channels. CRH-induced Ca2+ entry also occurs independently of action
      potentials and is due to P-type, and possibly L-type, Ca2+ channels activated by
      the CRH-induced membrane depolarization.

PMID- 8641176
TI  - T lymphocytes play a critical role in the development of cyclosporin A-induced
      osteopenia.
AB  - The T lymphocyte suppressor, cyclosporin A, has been shown to cause high turnover
      osteoporosis. We postulated that cyclosporin A may exert its effects via the T
      cell rather than direct activity on bone. In this study we administered
      cyclosporin A (15 mg/kg.day by gavage) to 11 10-week-old Rowett athymic nude rats
      and to 12 age-matched immunocompetent Sprague-Dawley rats. Placebo was
      administered to control groups (n = 12 for both). After 28 days of treatment, the
      Sprague-Dawley rats displayed high turnover bone loss, but the nude rats were
      largely unaffected by the drug. Sprague-Dawley treated rats had less than half
      the percent trabecular area of their controls as measured at the secondary
      spongiosa of the proximal tibial metaphysis (P < 0.001; strain by treatment, P =
      0.007). The same pattern was evident for trabecular number, separation, and
      thickness (strain by treatment, P = 0.034, P = 0.001, and P = 0.021,
      respectively). Only the Sprague-Dawley rats had an elevated percent eroded
      perimeter and an elevated bone area referent bone formation rate (strain by
      treatment, P = 0.002 and P = 0.0003, respectively). Mass, glucose, ionized
      calcium, PTH, osteocalcin, 1,25-dihydroxyvitamin D, and creatinine all responded
      similarly to cyclosporin A regardless of strain. T Lymphocytes thus appear to be
      a prerequisite for the development of cyclosporin A-induced osteopenia.

PMID- 8641177
TI  - Factors regulating insulin-like growth factor-binding protein-3 binding,
      processing, and potentiation of insulin-like growth factor action.
AB  - In this study, we investigated the effects of various biochemical and
      pharmacological agents on insulin-like growth factor (IGF)-binding protein-3
      (IGFBP-3) cell binding and action in cultured bovine fibroblasts. When cells were
      preincubated for 48 h with 50 nM recombinant human (rh) IGFBP-3, IGF-I-stimulated
      [3H]aminoisobutyric acid ([125H]AIB) uptake was enhanced 2- to 3-fold. The
      addition of cytoskeletal disrupting agents during the preincubation with rhIGFBP
      3 did not affect IGFBP-3 potentiation of IGF-I action, nor did a variety of
      serine, aspartate, and metalloproteinase inhibitors. On the other hand, ammonium
      chloride and chloroquine, weak bases that neutralize the pH of acidic cell
      compartments, blocked IGFBP-3 potentiation of IGF-I-stimulated [3H]AIB uptake.
      Chloroquine and ammonium chloride had no effect alone and did not inhibit IGF-I
      receptor binding or action in the absence of rhIGFBP-3. Bafilomycin A, a specific
      inhibitor of ATP-dependent hydrogen ion pumps, also inhibited IGFBP-3
      potentiation of IGF-I-stimulated [3H]AIB uptake. Competitive [125I]IGF-I binding
      and affinity cross-linking experiments suggested structure/function changes in
      cell-bound IGFBP-3 that were altered in the presence of chloroquine and
      bafilomycin. Heparin markedly decreased initial IGFBP-3 cell adherence, but could
      not promote dissociation of IGFBP-3 from cells after the 48-h preincubation.
      Moreover, heparin did not inhibit IGFBP-3 potentiation of IGF-I action. In
      summary, these data indicate that IGFBP-3 undergoes specific pH-dependent
      structural and/or environmental modifications that mediate the enhancing effect
      of IGFBP-3 on IGF-I action in bovine fibroblasts. They also suggest that IGFBP-3
      binding to heparin-like molecules on the cell surface is not directly involved in
      this process.

PMID- 8641178
TI  - Insulin increases the processing efficiency of messenger ribonucleic acid-S14
      nuclear precursor.
AB  - Feeding a lipogenic diet increases transcription and enhances processing of the
      rat hepatic messenger RNA (mRNA)-S14 gene. To determine the separate roles of
      insulin and increased glucose in these processes, we used the streptozotocin
      induced diabetic rat model. Diabetes caused a reduction in mature mRNA-S14 in
      chow- and lipogenic diet-fed animals (P < 0.006 and P < 0.001, respectively).
      Insulin restored these levels to normal. Despite the known effects of insulin and
      carbohydrate on the transcription of this gene, we were unable to demonstrate
      significant changes in the nuclear proteins that bind to carbohydrate response
      regions. Yet, insulin restored the content of the mRNA by increasing the ratio of
      mature to precursor mRNA-S14. Insulin significantly increased this ratio (P <
      0.0001) independent of diet and diabetes, further supporting the action of
      insulin on increasing processing from precursor to mature mRNA. The mechanism of
      the enhanced processing was studied by ribonuclease mapping and primer extension
      analysis. Ribonuclease mapping showed that lipogenic diet feeding increases the
      efficiency of processing at a step before formation of the branched form of the
      precursor mRNA. Taken together, our data demonstrate for the first time that
      insulin significantly enhances the efficiency of processing of a pre-mRNA.

PMID- 8641179
TI  - Sexually dimorphic transcriptional responses to gonadotropin-releasing hormone
      require chronic in vivo exposure to estradiol.
AB  - GnRH regulates secretion of the gonadotropins, LH and FSH, in a sexually
      dimorphic manner. In the present study, we examined GnRH regulation of the
      gonadotropin alpha-subunit promoter to assess whether sex-dependent hormonal
      effects are manifest at the transcriptional level. Primary cultures of male or
      female rat pituitary cells were transfected with a reporter gene containing the
      alpha-promoter linked to luciferase (-420 alpha-LUC) and then subjected to
      treatment with GnRH for 24 h. Basal alpha-LUC expression was 4.2-fold greater in
      pituitary cells from males than in those from females. alpha-LUC activity was
      stimulated 5.3-fold by GnRH in males, whereas GnRH induced a 148-fold increase in
      alpha-promoter activity in females. The GnRH responsiveness of the transfected
      alpha-promoter did not vary in pituitary cells isolated at different stages of
      the female reproductive cycle, suggesting that acute changes in the hormonal
      milieu are not sufficient to alter transcriptional responses to GnRH. In males,
      orchidectomy minimally influenced alpha-LUC activity, indicating that
      testosterone does not exert a suppressive effect on GnRH responsiveness. In
      ovariectomized females, basal expression of alpha-LUC increased 3.7-fold, and
      GnRH stimulation was reduced from 165- to 11-fold, suggesting that an ovarian
      factor suppresses basal activity and enhances GnRH stimulation. Treatment of
      ovariectomized females with estrogen suppressed basal activity and restored GnRH
      stimulation of alpha-LUC, but the estrogen effects required long term treatment
      (10 days). Addition of progesterone to estrogen or treatment with the
      progesterone antagonist, RU486, had little effect on GnRH responsiveness. We
      conclude that estrogen exerts dual effects to suppress basal expression and to
      dramatically enhance GnRH responsiveness of the alpha-promoter. This model
      reveals potent actions of estrogen at the level of transcription and should
      provide new insights into the mechanisms that control estrogen priming of
      gonadotrope cells.

PMID- 8641180
TI  - 11 beta-Hydroxysteroid dehydrogenase type 2 complementary deoxyribonucleic acid
      stably transfected into Chinese hamster ovary cells: specific inhibition by 11
      alpha-hydroxyprogesterone.
AB  - The 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD-2) enzyme is thought
      to confer aldosterone specificity upon mineralocorticoid target tissues by
      protecting the mineralocorticoid receptor from binding by the more abundant
      glucocorticoids, corticosterone and cortisol. We have developed a Chinese hamster
      ovary cell line stably transfected with a plasmid containing the rat 11 beta HSD
      2 complementary DNA. This cell line has expressed the enzyme consistently for
      many generations. The 11 beta HSD-2 was located primarily in the microsomes, but
      significant amounts also existed in the nuclei and mitochondria. The enzymatic
      reaction was unidirectional, oxidative, and inhibited by the product, 11
      dehydrocorticosterone, with an IC50 of approximately 200 nM. The K(m) for
      corticosterone was 9.6 +/- 3.1 nM, and that for NAD+ was approximately 8 microM.
      The enzyme did not convert dexamethasone to 11-dehydrodexamethasone. Tunicamycin,
      an N-glycosylation inhibitor, had no effect on enzyme activity. 11 alpha
      Hydroxyprogesterone (11 alpha OH-P) was an order of magnitude more potent a
      competitive inhibitor of the 11 beta HSD-2 than was glycyrrhetinic acid (GA)
      (approximate IC50 = 0.9 vs. 15 nM). 11 beta OH-P, progesterone, and GA were
      almost equipotent (IC50 = 10 and 6 nM, respectively), and 5 alpha-pregnandione
      and 5 beta-pregnandione were less potent (IC50 = 100 and 500 nM, respectively)
      inhibitors of the enzyme. When the inhibitory activities were examined with
      intact transfected cells, 11 alpha OH-P was more potent than GA (IC50 = 5 and 150
      nM, respectively). 11 alpha OH-P was not metabolized by 11 beta HSD-2. We were
      unable to demonstrate the presence of 11 alpha OH-P in human urine. In
      conclusion, a cell line stably transfected with the rat 11 beta HSD-2 was
      created, and the enzyme kinetics, including inhibition, were characterized. 11
      alpha OH-P was found to be a potent relatively specific inhibitor of the 11 beta
      HSD-2 enzyme. Its potential importance is that it is the most specific inhibitor
      of the 11 beta HSD-2 so far encountered and would aid in the study of the
      physiological importance of the isoenzyme.

PMID- 8641181
TI  - Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin
      secreting cells: evidence for functional consequences on enzyme activity and
      insulin secretion.
AB  - We report the carboxylmethylation of a 36-kDa protein in intact normal rat islets
      and clonal beta (INS-1) cells. This protein was predominantly cytosolic. Its
      carboxylmethylation, as assessed by vapor phase equilibration assay, was
      resistant to inhibition by N-acetyl-S-trans, trans-farnesyl-L-cysteine, a
      competitive substrate for cysteine methyl transferases. These data suggest that
      the methylated C-terminal amino acid is not cysteine. The methylated protein was
      identified as the catalytic subunit of protein phosphatase 2A (PP2Ac) by
      immunoblotting. The carboxylmethylation of the PP2Ac increased its catalytic
      activity, suggesting a key role in the functional regulation of PP2A. Therefore,
      we studied okadaic acid, a selective inhibitor of PP2A that acts by an unknown
      mechanism. Okadaic acid (but not 1-nor-okadaone, its inactive analog) inhibited
      (Ki = 10 nM) the carboxylmethylation of PP2Ac and phosphatase activity in the
      cytosolic fraction (from normal rat islets and clonal beta-cells) as well as in
      intact rat islets. Furthermore, methylated PP2Ac underwent rapid demethylation (t
      1/2 = 40 min) catalyzed by a methyl esterase localized in islet homogenates.
      Ebelactone, a purported inhibitor of methyl esterases, significantly delayed (>
      200 min) the demethylation of PP2Ac. Furthermore, ebelactone reversibly inhibited
      glucose- and ketoisocaproate-induced insulin secretion from normal rat islets.
      These data identify, for the first time, a methylation-demethylation cycle for
      PP2Ac in the beta-cell and suggest a key functional relationship between PP2A
      activity and the carboxylmethylation of its catalytic subunit. These findings
      thus suggest a negative modulatory role for PP2A in nutrient-induced insulin
      exocytosis.

PMID- 8641182
TI  - Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated
      resorption.
AB  - Current knowledge indicates that osteoblasts play an integral role in
      osteoclastic bone resorption through an osteoclast-stimulating activity produced
      by osteoblasts in response to resorption-promoting osteotropic factors.
      Previously, we have shown that the inhibitory action of the bisphosphonates on
      bone resorption in part is mediated by osteoblasts. The aim of the present study
      was to investigate whether the bisphosphonate-generated inhibition is due to
      these compounds decreasing the synthesis of the osteoclast-stimulating activity
      or is the result of osteoblasts synthesizing an osteoclast resorption inhibitor.
      Using the osteoblastic cell line CRP 10/30, which produces osteoclast-
      stimulating activity, constitutively and employing isolated rat osteoclasts
      cultured on ivory, evidence was obtained indicating that the bisphosphonates
      ibandronate and alendronate at a concentration of 10(-7) M induce osteoblasts to
      synthesize an osteoclast inhibitor that reduces pit formation by more than 50%.
      The inhibitor is heat and proteinase labile and has a molecular mass between 1-10
      kDa. The reduction of resorption pits is paralleled by a decrease in tartrate
      resistant acid phosphatase-positive mono- and multinucleated cells, whereas the
      mean area resorbed per pit was not changed, suggesting that the inhibitor affects
      osteoclast formation and/or survival and probably not the osteoclast resorption
      activity. Rat preosteoblastic cells and rat dermal fibroblasts were found not to
      produce the inhibitor. In conclusion, osteoblasts aside from their role of
      mediating osteoclastic resorption promoters are also involved in inhibiting bone
      resorption through the synthesis of an osteoclast resorption inhibitor.

PMID- 8641183
TI  - Decreased gonadotropin-releasing hormone neurosecretory response to glutamate
      agonists in middle-aged female rats on proestrus afternoon: a possible role in
      reproductive aging?
AB  - Before becoming acyclic, middle-aged rats display an attenuated LH surge and a
      decreased number of activated GnRH neurons. The present study examined whether
      the decreased activation of GnRH neurons in middle-aged rats could be due to
      defective glutamate neurosignaling in the hypothalamus. Arcuate nucleus/median
      eminence (ARC/ME) fragments were isolated from young (2-month-old) and middle
      aged (9- to 11-month-old) rats at 1700 h on proestrus and incubated in vitro with
      or without the specific glutamate agonists, D,L-alpha-amino-3-hydroxy-5-methyl-4
      isoxazole propionic acid (1 mM), kainate (1 mM), and N-methyl-D-aspartate (NMDA;
      50 mM). The results showed that basal GnRH release was similar in the two age
      groups. In contrast, stimulated GnRH release by D,L-alpha-amino-3-hydroxy-5
      methyl-4-isoxazole propionic acid, kainate, and NMDA was significantly attenuated
      in middle-aged vs. young rats. KCl stimulation at the end of the experiments
      confirmed the viability of all ARC/ME fragments. Quantitative reverse
      transcriptase-PCR revealed that messenger RNA levels for the major NMDA receptor
      subunit (NMDAR1) were significantly lower in the preoptic area and ARC/ME of the
      middle-aged rat on proestrus afternoon. As a whole, these findings suggest that a
      defect in hypothalamic glutamate neurosignaling may be an important mechanism
      leading to age-related defects in LH secretion and acyclicity in female animals.

PMID- 8641184
TI  - Binding of [3H]progesterone to the human progesterone receptor: differences
      between individual and mixed isoforms.
AB  - The human progesterone receptor (hPR) exists as two isoforms, hPR-A and hPR-B,
      which differ only in that hPR-A lacks 164 amino acids present at the amino
      terminus of hPR-B. In this study we have separately expressed hPR-A and hPR-B and
      asked whether the progesterone-binding mechanisms are the same or different for
      the two forms of hPR and for their mixture. We investigated 1) the cooperativity
      of binding [3H]progesterone to the receptor, as measured by the Hill coefficient
      (nH); and 2) the dissociation rate of [3H]progesterone from the receptor. To
      compare the effects of dimerization, these ligand-binding properties were
      measured over a range of receptor concentrations. Binding of [3H]progesterone to
      hPR-A was positively cooperative at all concentrations used; the limiting value
      for the Hill coefficient was 1.47 +/- 0.11 at high receptor concentrations (5-19
      nM) and 1.31 +/- 0.06 at low receptor concentrations (1-4 nM). Similarly, little
      change was observed in the dissociation rate constant over the same concentration
      range; the values at high and low concentrations were 4.59 +/- 0.15 and 3.03 +/-
      0.25 x 10(-3) min-1, respectively. By contrast, the hPR-B concentration had a
      marked effect on positive cooperative binding and the dissociation rate of
      progesterone. At high hPR-B concentrations (3-5 nM), the limiting Hill
      coefficient was 1.49 +/- 0.11, which is indicative of moderately strong positive
      cooperativity, whereas at lower hPR-B concentrations (1-3 nM), the Hill
      coefficient was reduced to 1.1, which is essentially noncooperative. The
      [3H]progesterone dissociation rate was 4.52 +/- 0.44 x 10(-3) min-1 at the higher
      concentrations of hPR-B and was increased to 1.6 +/- 0.11 x 10(-3) min-1 at the
      lower concentrations. Thus, over the same concentration range where hPR-A
      exhibited no significant change in positive cooperativity or the dissociation
      rate, these progesterone-binding properties were highly dependent on the
      concentration of hPR-B. When hPR-A and hPR-B were mixed, positive cooperative
      binding and the dissociation rate were more similar to hPR-B than to hPR-A, in
      that both binding parameters were dependent on the concentration of receptor.
      However, the hPR-AB mixture differed from hPR-B alone in that the mixture
      required a greater receptor concentration (7-10 vs. 3-5 nM) to exhibit positive
      cooperativity and the increased dissociation rate. These results show, first,
      that each hPR isoform displays different [3H]progesterone-binding properties,
      which are most prominent at low concentrations of receptor, and second, that one
      isoform can influence the other. As the two receptor forms differ only at the N
      terminus, yet positive cooperativity and changes in the dissociation rate
      constant are indicative of conformational changes affecting hormone binding,
      these results also strongly suggest that the N-terminus may directly or
      indirectly interact with the C-terminal ligand-binding domain.

PMID- 8641185
TI  - Bone sialoprotein stimulates in vitro bone resorption.
AB  - Bone sialoprotein (BSP) is a protein highly specific for bone, which contains an
      arginine-glycine-aspartic acid (RGD) cell attachment sequence involved in
      osteoclast adhesion to bone matrix via the vitronectin receptor. We have
      investigated its role in in vitro bone resorption using the well described
      isolated osteoclast resorption pit assay. BSP significantly stimulates bone
      resorption in a dose-dependent manner, increasing the overall resorbed area on
      ivory slices and the number of lacunae at concentrations as low as 50 nM. Neither
      recombinant osteopontin nor intact vitronectin has any effect on bone resorption,
      suggesting a specific effect of BSP. The stimulation of bone resorption induced
      by BSP could be partially explained by an increase in osteoclast adhesion to bone
      via its RGD sequence, and our results suggest another mechanism of action of BSP
      that might involve another region of the molecule, such as its acidic sequences.
      Although BSP stimulates bone resorption in a coculture system of bone marrow
      cells and osteoblastic cells, it dose dependently inhibits the formation of
      osteoclast-like cells at equivalent concentrations in this culture model. In
      conclusion, we provide evidence that BSP plays an important role in the bone
      resorption process and may regulate bone resorption as well as osteoclast
      formation.

PMID- 8641186
TI  - Effect of constant light on fetal and maternal prolactin rhythms in sheep.
AB  - A 24-h rhythm of plasma PRL is present in fetal sheep. This rhythm is
      synchronized to an environmental clue (zeitgeber). We determined whether the
      light-dark cycle (L:D) is a zeitgeber for the fetal PRL rhythm and, if so,
      whether the mother might convey this zeitgeber to the fetus. We kept nine ewes
      (twin pregnancies) in constant light (L:L) and five ewes (singleton) in 14:10 L:D
      from 110 days gestation. Fetuses and mothers were catheterized at 119 days
      gestation. Blood samples were taken hourly for 24 h after 16 days under L:L or
      L:D. A mean 24-h rhythm of PRL was found (by RIA) in fetuses under L:D, but not
      in those under L:L. However, fetuses under L:L showed individual 24-h PRL rhythms
      (cosinor analysis) whose acrophases were distributed around the clock.
      Nonsynchronized rhythms persisted after 23 and 30 days of L:L. Acrophases of PRL
      rhythms within a set of twins were closer than those between sets, suggesting
      that twins were responding to a common signal. These findings indicate that the
      L:D cycle is a zeitgeber for the PRL rhythm in fetal sheep and suggest that the
      mother might convey the zeitgeber.

PMID- 8641187
TI  - Reduced phosphorylation of mitogen-activated protein kinase kinase in response to
      insulin in cells with truncated C-terminal domain of insulin receptor.
AB  - Insulin-stimulated activity of Raf-1 kinase was examined in Rat-1 fibroblasts
      transfected with wild-type and mutant human insulin receptors. Insulin stimulated
      Raf-1 binding to p21Ras in HIRc (wild-type), delta CT (insulin receptor lacking a
      43-amino acid C-terminal domain), and Y/F2 (tyrosine 1316 and 1322 replaced by
      phenylalanine) cells. Despite equal binding to p21Ras, the activity of Raf-1
      kinase (measured by phosphorylation of its downstream substrate, mitogen
      activated protein/extracellular receptor kinase (MEK) was significantly reduced
      in the delta CT cells. As an association of Raf-1 with p21Ras does not activate
      Raf-1 kinase, but merely targets Raf-1 to the plasma membrane, we examined the
      binding of Raf-1 to 14-3-3 proteins and to the insulin receptor itself. Raf-1 was
      detected in both 14-3-3 and insulin receptor immunoprecipitates. Association of
      Raf-1 with either 14-3-3 protein or insulin receptor was not influenced by
      insulin and was similar in all control and insulin-treated cell lines. These
      results indicate that the delta CT cells are deficient in stimulating Raf-1
      activity despite normal binding of Raf-1 to p21Ras. Thus, an unidentified
      mechanism of Raf-1 activation at the plasma membrane must be impaired in these
      cells.

PMID- 8641188
TI  - Effect of endogenously produced parathyroid hormone-related peptide on growth of
      a human hepatoma cell line (Hep G2).
AB  - A well differentiated human hepatoma cell line (Hep G2) was used to explore
      potential roles for PTH-related peptide (PTHrP) as an autocrine/paracrine growth
      factor. Using Northern analysis or reverse transcription-PCR, Hep G2 cells were
      found to express messenger RNAs for both PTHrP and the cloned PTH/PTHrP receptor,
      and the cells exhibited specific binding for [125I]PTHrP(1-36). Hep G2 growth
      medium was found to contain relatively large amounts of immunoreactive PTHrP (30
      vs. 1-2 pM in medium not exposed to cells), and the PTHrP in growth medium
      (conditioned medium) was shown to contain N-terminal PTHrP biological activity,
      as assessed by the ability of the medium to stimulate cAMP production in rat
      osteosarcoma cells (ROS 17/2.8). Conditioned medium produced a dose-dependent
      severalfold increase in ROS cell cAMP that could be blocked by the PTHrP receptor
      antagonist [Asn10,Leu11,DTrp12]PTHrP-(7-34). PTHrP in Hep G2 cells also was
      detected by immunocytochemistry using antiserum to either synthetic PTHrP-(1-34)
      or recombinant PTHrP-(-5 to 139). Furthermore, these antisera were found to
      inhibit the ability of PTHrP-(1-34) to stimulate ROS cell cAMP production. When
      either antiserum (1:800-1:100 dilution) was added to subconfluent Hep G2 cells in
      medium containing 5% FBS for 3 days, a dose-related 40-50% increase in cell
      number occurred that could be inhibited by concurrent addition of 10 microM
      synthetic PTHrP-(1-36). The results show that Hep G2 cells synthesize and secrete
      both immunoreactive and biologically active PTHrP. As neutralization of PTHrP
      secreted by these cells by the addition of antiserum to PTHrP resulted in
      increased cell growth, the findings suggest that PTHrP can function as an
      autocrine or paracrine growth factor to suppress the growth of these human
      hepatoma cells.

PMID- 8641189
TI  - Transcriptional regulation of insulin-like growth factor-binding protein-5 by
      prostaglandin E2 in osteoblast cells.
AB  - Insulin-like growth factor (IGF)-binding protein-5 (IGFBP-5) is an autocrine and
      paracrine factor that modulates the effects of IGFs. We examined the mechanisms
      that regulate IGFBP-5 synthesis by PGE2 in osteoblast-enriched cells from fetal
      rat calvaria (Ob cells). PGE2 at 1 microM for 2-8 h increased IGFBP-5
      heterogeneous nuclear RNA levels and did not change the half-life of IGFBP-5
      messenger RNA in Ob cells, suggesting that PGE2 stimulates IGFBP-5 transcription.
      To analyze the elements responsible for this effect, regions of the mouse IGFBP-5
      promoter from -2695 to +120 bp were ligated into pGL-2-basic and transiently
      transfected into Ob cells. PGE2 caused a time- and dose-dependent increase in
      IGFBP-5 promoter activity. Further analysis revealed two potential PGE2
      responsive regions in the -2695 to -1470 and the -989 to -332 fragments. The
      effect of PGE2 on IGFBP-5 messenger RNA and heterogeneous nuclear RNA levels was
      mimicked by forskolin and inhibited by the PKA inhibitor H-89, suggesting that
      part of the PGE2 effect was mediated through a cAMP-dependent pathway. H-89 also
      blocked basal and PGE2-stimulated IGFBP-5 promoter activities. We conclude that
      PGE2 regulates IGFBP-5 synthesis in Ob cells by transcriptional mechanisms. PKA
      dependent pathways account for part of the effect of PGE2 on IGFBP-5 expression.
      Deletion analysis of the IGFBP-5 promoter suggests the presence of two PGE2
      responsive regions.

PMID- 8641190
TI  - Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced
      proglucagon-derived peptide secretion from the distal gut.
AB  - The ileal proglucagon-derived peptides (PGDPs) play important roles in the
      regulation of gastric function and insulin secretion. We have previously
      demonstrated the existence of a proximal-distal enteroendocrine loop mediated by
      glucose-dependent insulinotropic peptide (GIP), through which intestinal PGDP
      secretion is stimulated after placement of nutrients in the duodenum. To study
      the possible involvement of neuropeptides in this loop, we infused gastrin
      releasing peptide (GRP) into anesthetized rats at 47, 235, or 470 ng/h. GRP
      stimulated secretion of the intestinal PGDPs only at the highest dose, from 250
      +/- 18 to 321 +/- 9 pg/ml (P < 0.05). Gastrin secretion was also increased by GRP
      infusion (from 20 +/- 7 to 75 +/- 19 pg/ml; P < 0.05); however, GIP release was
      not altered from basal levels. Placement of fat into the duodenum stimulated the
      secretion of both the intestinal PGDPs and GIP (to 618 +/- 221 and 417 +/- 154
      pg/ml above basal, respectively; P < 0.05). However, infusion of the GRP
      antagonist, BW10 (3 ng/h), completely abrogated the PGDP response to duodenal fat
      (P < 0.05). In contrast, the GIP response was reduced by 56 +/- 15% (P < 0.05)
      with BW10 administration, but remained elevated compared to the basal level (P <
      0.05). Removal of the entire intestine distal to the fat-infused duodenal segment
      prevented the rise in intestinal PGDPs, but not that of GIP, demonstrating the
      distal and proximal origins of these peptides, respectively. Thus, placement of
      fat into the duodenum stimulated the release of the PGDPs from the distal
      intestine through a GRP-dependent mechanism. Although GIP plays a role in
      regulating intestinal PGDP secretion in the rat, GRP appears to exert its effects
      independent of changes in GIP.

PMID- 8641191
TI  - Major role of 3',5'-cyclic adenosine monophosphate-dependent protein kinase A
      pathway in corticotropin-releasing factor gene expression in the rat hypothalamus
      in vivo.
AB  - To assess whether the cAMP-dependent protein kinase-A and/or the diacylglycerol
      dependent protein kinase C (PKC) pathways play important roles in the activation
      of CRF neurons in vivo under physiological conditions, we tested the effect of
      microinjection of 8-bromo-cAMP (8-Br-cAMP) or 12-O-tetradecanoyl phorbol 13
      acetate (TPA) into both paraventricular nuclei (PVN) of the hypothalamus in
      conscious rats. Both 8-Br-cAMP and TPA increased plasma ACTH concentrations and
      the POMC messenger RNA (mRNA) concentrations in the anterior pituitary. While
      injection of 8-Br-cAMP also increased CRF mRNA concentrations in hypothalamic
      tissue containing the PVN, TPA injection had no effect on CRF mRNA concentrations
      there. During insulin-induced hypoglycemia, which stimulates CRF gene expression
      and release, c-fos and c-jun mRNA increases in the hypothalamic tissue preceded
      the increase in the CRF mRNA level after insulin-induced hypoglycemia. Antisense
      oligodeoxyribonucleotides (oligos) directed against c-fos, c-jun, or the cAMP
      response element binding protein (CREB) mRNA were injected into both PVN before
      insulin-induced hypoglycemia to assess whether activator protein-1 or CREB
      mediates transcriptional activation of CRF during hypoglycemia. Only antisense
      oligo against CREB mRNA reduced the CRF mRNA level after insulin-induced
      hypoglycemia. These results suggest that protein kinase A may transduce
      intracellular signals in CRF neurons under physiological conditions and raises
      the possibility that CREB may be involved in stress-induced CRF gene expression.

PMID- 8641192
TI  - Transgenic mice with muscle-specific insulin resistance develop increased
      adiposity, impaired glucose tolerance, and dyslipidemia.
AB  - Impaired skeletal muscle insulin receptor function is a feature of common forms
      of insulin resistance, including obesity and noninsulin-dependent diabetes
      mellitus. However, the extent to which this defect accounts for impaired muscle
      glucose disposal or altered in vivo glucose homeostasis remains to be
      established. We recently showed that transgenic mice that overexpress dominant
      negative insulin receptors specifically in striated muscle have a severe defect
      in muscle insulin receptor-mediated signaling and modest hyperinsulinemia. Here
      we performed hindlimb perfusion studies to determine the impact of this defect on
      muscle glucose uptake and metabolism. Maximal rates of insulin-stimulated muscle
      3-O-methylglucose transport were reduced by 32-40% in transgenic mice with
      proportional defects involving total hindlimb [14C]glucose uptake, lactate
      production, and muscle glycogen synthesis. To address the hypothesis that muscle
      insulin resistance could promote an increase in the accretion of body fat,
      carcass analysis was performed using two independent lines of transgenic mice.
      Although body weights were normal, transgenic mice had a 22-38% increase in body
      fat, with a reciprocal decrease (10-15%) in body protein. Mean gonadal fat pad
      weight was also increased in transgenic mice. Skeletal muscle histology and fiber
      type distribution were not affected. To determine whether muscle-specific insulin
      resistance was sufficient to cause impaired glucose tolerance, oral glucose
      tolerance tests were performed with 6-month-old transgenic and control mice.
      Fasting glucose levels were increased by 25%, and peak values were 22-40% higher
      in transgenic mice. Transgenic mice also had a 37% decrease in plasma lactate
      levels and modest increases in levels of plasma triglycerides and FFA (29% and
      15%, respectively). We conclude that 1) severe defects in muscle insulin receptor
      function result in impaired insulin-stimulated glucose uptake and metabolism in
      this tissue; 2) muscle-specific insulin resistance can contribute to the
      development of obesity; and 3) a "pure" defect in insulin-mediated muscle glucose
      disposal is sufficient to result in impaired glucose tolerance and other features
      of the insulin resistance syndrome, including hyperinsulinemia and dyslipidemia.

PMID- 8641193
TI  - Potassium induces multiple steroidogenic enzymes in cultured rat zona glomerulosa
      cells.
AB  - The effects of the extracellular potassium concentration on the expression of
      four steroidogenic cytochromes P-450 (CYP11B2, CYP11B1, CYP11A1, and CYP21A1) in
      cultured rat adrenal zona glomerulosa cells were studied by Northern blot
      analysis. At a potassium concentration of 6.4 mM, the CYP11B2 messenger RNA
      (mRNA) level and aldosterone production were undetectable. Upon increasing the
      potassium concentration to 18 mM, CYP11B2 mRNA and aldosterone production became
      measurable and reached a plateau within 4 days. The high potassium concentration
      also caused distinct increases in the levels of CYP11B1, CYP11A1, and CYP21A1
      mRNA, comparable to those induced by ACTH. ACTH did not affect the CYP11B2 mRNA
      level at the lower potassium concentration. In zona fasciculata cells, CYP11B2
      expression was not inducible by potassium; CYP11B1, CYP11A1, and CYP21A1 mRNA
      levels increased in response to ACTH, but not in response to a high potassium
      concentration. According to these results, potassium initiates CYP11B2
      biosynthesis most likely at the level of transcription or by increasing mRNA
      stability. Potassium also has a zona glomerulosa-specific inductive effect on
      three other steroidogenic enzymes.

PMID- 8641194
TI  - Increased amounts of a high molecular weight insulin-like growth factor II (IGF
      II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of
      diabetic Goto-Kakizaki rats.
AB  - Insulin-like growth factor II (IGF-II), a member of the insulin family, regulates
      cell growth and differentiation. The IGF-II gene is localized close to the
      insulin gene in man and rat. IGF-II peptide binds weakly to the insulin receptor
      and exerts insulin-like effects on the blood glucose level. We studied IGF-II in
      endocrine pancreas in an animal model of noninsulin-dependent diabetes mellitus,
      the Goto-Kakizaki (GK) rat. At the age of 2 months, these rats have structural
      islet changes, with fibrosis and irregular configuration, so-called starfish
      shaped islets. Immunohistochemical investigation revealed IGF-II immunoreactivity
      in the beta-cells in both GK and control rats. Pancreatic extraction, followed by
      size separation using gel chromatography, disclosed a high mol wt form of IGF-II
      in all animals, and RIA measurements revealed a considerably larger amount of the
      IGF-II peptide in the 2-and 6-month-old GK rats than in the 1-month GK and
      control rats. In situ hybridization of 3-month-old GK rats showed increased IGF
      II messenger RNA expression in the starfish-shaped islets of GK rats than in the
      islets with normal structure in both diabetic and control animals. The reason for
      the increased amount of IGF-II is unclear. As the animals are diabetic before the
      islet changes occur, it might be a compensatory effect in response to
      hyperglycemia, but could also be a cause of the islet fibrosis.

PMID- 8641195
TI  - Continuous intrafetal infusion of prostaglandin E2 prematurely activates the
      hypothalamo-pituitary-adrenal axis and induces parturition in sheep.
AB  - This study has investigated the effect of continuous intrafetal infusion of PGE2
      or saline on hormone concentrations and the length of gestation in sheep. Fetal
      and maternal vascular catheters were surgically implanted at 112.3 +/- 1.3 days
      (n = 10), and the infusions were started at 121 +/- 1.2 days of gestation (term =
      147). Fetuses were infused with either PGE2 (n = 5; 2 micrograms/min for 48 h and
      then increased to 4 micrograms/min for the remainder of the experiment) or the
      vehicle solution (n = 5; sterile isotonic saline) via the fetal carotid artery.
      In the PGE2-infused group, fetal and maternal plasma PGE2 concentrations
      increased (P < 0.001) after the change to the higher dose rate (4 micrograms/min)
      and remained elevated, fetal plasma immunoreactive ACTH (ir-ACTH) concentrations
      dramatically increased after the start of the infusion being maximal at 11 h
      before decreasing to match concentrations exhibited by the saline-infused group.
      Fetal plasma cortisol concentrations increased after the start of the PGE2
      infusion (P = 0.05) and increased further after the change to the higher dose
      rate of 4 micrograms/min (P < 0.001). Concentrations of PGE2, ir-ACTH, and
      cortisol in the saline-infused group did not change until labor. Plasma
      concentrations of PGE2 (P < 0.001) and ir-ACTH (P < 0.005) increased on the day
      of labor in both treatment groups, and fetal cortisol concentrations increased (P
      < 0.001) in both groups in the last few days before labor. The proportion of low
      molecular weight ir-ACTH in the plasma of PGE2-infused fetuses was significantly
      higher than that of saline-infused fetuses (P < 0.001) during the first 15 days
      of infusion. In the saline-infused group, the proportion of low molecular weight
      ir-ACTH increased in the last few days before labour (P = 0.001), whereas no
      change was seen in PGE2-infused fetuses at this time. Maternal plasma
      progesterone concentrations decreased in both groups in the last few days before
      labor (P < 0.001). Fetuses infused with PGE2 delivered at 138.4 +/- 2.1 days,
      whereas control fetuses infused with saline delivered at 148.2 +/- 0.5 days (P <
      0.001). The spontaneous increase in PGE2 preceding normal labor may thus play an
      important role in activation and maturation of the hypothalamic-pituitary-adrenal
      axis in fetal sheep.

PMID- 8641196
TI  - Osteopontin activation of c-src in human melanoma cells requires the cytoplasmic
      domain of the integrin alpha v-subunit.
AB  - In human melanoma cells, expression of the alpha v beta 3 integrin is correlated
      with the metastatic potential. The expression of osteopontin (OPN or OP), a
      protein ligand for the integrin alpha v beta 3, also correlates with metastatic
      potential of some tumors. Analysis of signal transduction, stimulated by
      OPN/alpha v beta 3 in human melanoma cells (M21), revealed activation of pp60c
      src associated with the integrin. pp60c-src stimulation by OPN was dose
      dependent, and it was inhibited in vitro by a tyrosine kinase inhibitor,
      herbimycin-A. To determine the need for the cytoplasmic domain of the alpha v
      subunit, in the association of pp60c-src with alpha v beta 3, a cell line
      expressing truncated alpha v was studied. M21-L cells lacked alpha v expression
      but stably transfected with complementary DNAs encoding alpha v full length
      protein alpha v 1018 or alpha v 995 (lacking 23 carboxyl-terminal amino acids),
      and a fibroblast cell line (FG) expressing alpha v beta 5 but not alpha v beta 3,
      were used. Western analysis and immune complex kinase assays of anti- alpha v
      immunoprecipitates demonstrated that M21-L/alpha v995 cells did not exhibit pp60c
      src association with alpha v, whereas the alpha v1018 complementary DNA
      transfected cells and FG cells had pp60c-src associated with the alpha v
      integrins. Immunofluorescence analysis revealed pp60c-src, alpha v beta 3
      integrin, and actin distribution along the plasma membrane of M21 cells. 35S
      labeling of cells and analysis of complexes immunoprecipitated by a monoclonal
      antibody against alpha v beta 3 demonstrated association of actin with the immune
      complexes. We conclude that OPN stimulates pp60c-src kinase activity associated
      with the alpha v beta 3 integrin and that the association requires the
      cytoplasmic tail of the alpha v chain.

PMID- 8641197
TI  - Effect of tumor necrosis factor-alpha on insulin action in cultured rat skeletal
      muscle cells.
AB  - In this study, the acute effects of tumor necrosis factor (TNF)-alpha on insulin
      stimulated glucose uptake, glycogen synthesis, and protein phosphatase-1 (PP-1)
      activation were examined in cultured rat skeletal muscle cell line, L6. Exposure
      of L6 cells to low concentrations of TNF-alpha (10 ng/ml for 60 min) inhibited
      basal and insulin stimulated 2-deoxyglucose uptake (40-50% decrease in basal and
      insulin stimulated glucose uptake respectively, when compared with controls, P <
      0.05). The effect of TNF-alpha was more pronounced when the incubation period was
      extended to 6 and 12 h. TNF-alpha also blocked insulin activation of glycogen
      synthase (GS) and inhibited glycogen synthesis (measured as [14C]-glucose
      incorporated into glycogen). Because GS is activated by dephosphorylation via
      protein phosphatase-1 (PP-1), we examined the effect of TNF- alpha on PP-1
      activation. As reported by us earlier (Srinivasan, M., and N. Begum, J Biol Chem
      269:16662-16667, 1994), insulin rapidly stimulated PP-1 and concomitantly
      inhibited PP-2A activities in L6 cells. Pretreatment with TNF- alpha for 10-60
      min blocked subsequent insulin-induced activation of PP-1. The impaired
      activation of PP-1 was accompanied by a reduction in insulin-stimulated
      phosphorylation of the regulatory subunit of PP-1. cAMP-Rp diastereomer, a cAMP
      antagonist failed to prevent the detrimental effects of TNF-alpha on PP-1. Cell
      permeable ceramide analogs, C2, C6, and Sphingomyelinase mimicked the effects of
      TNF-alpha on PP-1 inhibition. Furthermore, TNF-alpha treatment was accompanied by
      an increase in cellular ceramide levels, with concomitant reductions in
      sphingomyelin. We conclude that TNF-alpha blocks insulin-stimulated glycogen
      synthesis by inhibiting PP-1 activation via ceramide release.

PMID- 8641198
TI  - Characterization and identification of an adrenal age-related nonpolar
      fluorescent substance.
AB  - The adrenal cortexes of humans and rodents accumulate lipofuscin with age, but
      the chemical nature of the substance that produces lipofuscin fluorescence in the
      gland is not known. Analysis of rat adrenal nonpolar lipids revealed a
      fluorescence profile with increased intensity in the lipids extracted from older
      animals (23-24 months > 6 months > 6 weeks). The peak occurred at a wavelength of
      470 +/- 5 nm(n = 26) when excited at 340 nm. After sucrose density gradient
      centrifugation, the fluorescent substance was primarily concentrated in
      subcellular lipid droplets rather than supernatant or particulate. Prolonged
      stimulation of rats with ACTH for 7 consecutive days caused 14-51% decreases in
      the fluorescence levels, with a tendency of return to control levels
      poststimulation regardless of age. In contrast, the nonpolar lipids of mouse
      adrenal tumor (Y1) cells, which contain no lipofuscin, did not display this
      fluorescence in the presence or absence of ACTH. The chromatographic
      characteristics of the substance in a silica gel-60 column resembled those of
      authentic retinyl palmitate and cholesteryl oleate. Analysis of the substance by
      HPLC demonstrated at least three prominent peaks, designated XI-3 in order. X1
      and X2 were minor peaks; X3 was the major peak. Whereas none of the peaks
      comigrated with cholesteryl esters, X1 comigrated with authentic retinyl
      palmitate. Determination of the fatty acid component of the major fluorescent
      substance X3 by gas-liquid chromatography disclosed stearic acid. Retinyl
      stearate was, therefore, synthesized. The fluorescent profiles, HPLC retention
      time and mass spectrometric fragmentation of purified X3 substance were all
      identical to those of the synthetic compound. In contrast, the rat liver
      principally accumulated retinyl palmitate with age. Thus, we conclude that 1) the
      major nonpolar fluorescent substance accumulated in the rat adrenal with age is
      retinyl stearate, which may be a fluorophore of adrenal lipofuscin; 2) ACTH
      action may be related to this accumulation; and 3) the type of retinyl ester
      accumulated in aged animals is organ specific.

PMID- 8641199
TI  - A role for CD8+ T lymphocytes in osteoclast differentiation in vitro.
AB  - Bone loss associated with chronic inflammatory diseases has been attributed to
      the release of cytokines from T lymphocytes. However, the role of T lymphocyte
      subsets in the mediation of osteoclast activity has not been extensively studied.
      Cocultures of murine bone marrow and BALC cells (murine calvarial-derived cell
      line) were used to study osteoclast differentiation. Murine marrow was left
      intact or depleted of cells expressing the CD8 or CD4 antigen by immunomagnetic
      separation and then cocultured with BALC cells in the presence or absence of 1,25
      (OH)2D3. Depleting bone marrow of CD4-positive (CD4+) cells did not affect
      osteoclast differentiation (formation of tartrate-resistant acid phosphatase
      positive cells with three or more nuclei). However, depletion of CD8-positive
      (CD8+) cells resulted in a 40% increase in the number of osteoclasts formed.
      Addition of CD8+ cells to CD8+ cell depleted cocultures via Transwells abolished
      the stimulatory effects on osteoclast differentiation resulting from CD8+ cell
      depletion. Neutralizing antibodies to interleukin-4 and transforming growth
      factor-beta did not affect osteoclast differentiation in these cultures. These
      findings suggest that CD8+ cells may be involved in the regulation of osteoclast
      differentiation and that this effect is not mediated by interleukin-4 or
      transforming growth factor-beta.

PMID- 8641200
TI  - Developmental regulation of unique adenosine 3',5'-monophosphate-specific
      phosphodiesterase variants during rat spermatogenesis.
AB  - Previous studies from our laboratory have shown that messenger RNAs (mRNAs)
      coding for a cAMP-specific phosphodiesterase (PDE4A) are present in mature rat
      and mouse germ cells. However, no information is available about the properties
      of the expressed proteins. To determine their structure and regulation, the PDE4A
      isoforms expressed in the rat testis were identified and compared to the variants
      expressed in the brain. Western blot analysis using an antiserum specific for
      PDE4A demonstrated the presence in testis extracts of two distinct proteins with
      apparent masses of 98.8 and 86 kDa. The electrophoretic mobilities of these
      proteins differ from those of proteins detected in the brain extracts (113 and 76
      kDa). Reverse transcriptase-PCR of the different splicing mRNA variants expressed
      in testis confirmed the presence of at least one novel PDE4A mRNA that is
      distinct from the PDE4A splicing variants identified in the brain and other
      tissues. Expression of the complementary DNA encoding this variant in a
      heterologous system resulted in an increase in PDE activity and the appearance of
      an immunoreactive protein with a mass of 98.8 kDa. No 86-kDa protein could be
      generated with this transfection. Upon fractionation of testis extracts by HPLC
      diethylaminoethyl-chromatography, a peak of cAMP-PDE activity coeluted with the
      two immunoreactive species. During testicular development, the 98.8-kDa protein
      is present in trace amounts at 10 days, and its level increases with the age of
      the animals, reaching a plateau at 40 days. The 86-kDa protein appears at 20 days
      of age and reaches its maximum at 40 days. Studies on the cellular site of
      expression demonstrated that the two polypeptides are most abundant in round
      spermatids and are expressed in trace amounts in pachytene spermatocytes, whereas
      they could not be detected in Sertoli or interstitial cells. The 98.8-kDa, but
      not the 86-kDa, protein was also expressed in epididymal spermatozoa. These data
      demonstrate the expression of novel cAMP-specific PDEs coded by the PDE4A gene.
      The expression of these isoforms is maximal in round spermatids and is maintained
      in mature spermatozoa. The genesis of the lower mol wt species remains to be
      determined.

PMID- 8641201
TI  - Relationship among cellular diacylglycerol, sphingosine formation, protein kinase
      C activity, and parathyroid hormone secretion from dispersed bovine parathyroid
      cells.
AB  - To separate the role of changes in parathyroid diacylglycerol (DG) from other
      effects of extracellular calcium, we studied the effect of inhibition of DG
      metabolism on PTH secretion and cellular DG content in acutely dispersed bovine
      parathyroid cells. R 59 022, an inhibitor of DG kinase, increased cellular DG,
      but significantly decreased PTH secretion. Particulate protein kinase C (PKC)
      activity decreased in bovine parathyroid cells incubated at high extracellular
      calcium or in the presence of R 59 022, which is the opposite of what was
      observed in the presence of the phorbol ester, phorbol myristate acetate.
      Sphinganine, a normal cellular product that is a known inhibitor of PKC,
      significantly inhibited PTH secretion at low extracellular calcium, but had no
      significant effect at normal or high extracellular calcium. We then measured
      sphingosine in bovine parathyroid cells incubated with high extracellular calcium
      or R 59 022. Both conditions were associated with significant elevations of
      cellular sphingosine. These studies suggest that inhibition of PTH secretion and
      PKC activity by enhanced cellular DG may result from the activation of an
      inhibitory second messenger pathway involving the sphingoid lipids.

PMID- 8641202
TI  - Interleukin-1 beta stimulates sphingomyelin hydrolysis in cultured granulosa
      cells: evidence for a regulatory role of ceramide on progesterone and
      prostaglandin biosynthesis.
AB  - In granulosa cells labeled to isotopic steady-state with [3H]serine, addition of
      interleukin-1 beta (IL1 beta) or bacterial sphingomyelinase (SMase) induced a
      rapid decrease (approximately 60% by 10 min) in cellular [3H]Sphingomyelin
      content and a prolonged generation (up to 60 min) of [3H]ceramide, the immediate
      lipid-moiety generated in response to sphingomyelin hydrolysis. In FSH-treated
      cells, IL1 beta (0.3-30 ng/ml) inhibited progesterone biosynthesis in a dose
      dependent manner, an effect that was also observed in cells exposed to increasing
      concentrations of bacterial SMase (0.003-0.3 U/ml) or the membrane-permeable
      ceramide analogue N-hexanoylsphingosine (C6-cer:0.1-10 microM). Abrogation of
      progesterone biosynthesis was not a sole consequence of inadequate cAMP
      biosynthesis because cyclic nucleotide levels remained elevated (3- to 4-fold
      over untreated cultures) after addition of IL1 beta, SMase, or two different cell
      permeable ceramide analogues (C2-cer and C6-cer) to gonadotropin-stimulated
      granulosa cells. Moreover, taken into account that exogenous SMase or C6-cer
      partially abolished progesterone biosynthesis induced by But2cAMP (0.5 mM) or
      cholera toxin (CTX: 1 microgram/ml), the above mentioned results support the
      notion that activation of the sphingomyelin pathway exerts its inhibitory effects
      on granulosa cell steroidogenic activity at site(s) of action both proximal and
      distal to cAMP generation. As determined by RT-PCR analysis, the inhibitory
      effect of IL1 beta, SMase, or C6-cer on gonadotropin-stimulated steroidogenesis
      was accompanied by arrested transcription of the mitochondrial cholesterol side
      chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase/delta 5
      4isomerase, the two FSH-inducible steps involved in progesterone biosynthesis.
      Although bacterial SMase or the ceramide analogue C6-cer alone did not exactly
      reproduce the effect of IL1 beta on granulosa cell prostaglandin E2 (PGE2)
      biosynthesis, both agents augmented net PGE2 production and messenger RNA levels
      of the inducible prostaglandin endoperoxide synthase/cyclooxygenase (PGHS-2) in
      cytokine-treated cells. Although the effect on PGHS-2 messenger RNA may account
      for the facilitatory role of ceramide on IL1 beta-induced PGE2 biosynthesis,
      neither SMase nor the membrane-permeant ceramide analogue were able to augment
      prostaglandin accumulation in the presence of exogenously added arachidonate
      precursor. Collectively, whereas these results show that ceramide triggers a
      negative-effector pathway that is both necessary and sufficient to reproduce the
      inhibitory effect of IL1 beta on FSH-stimulated granulosa cell steroidogenesis,
      they also support the notion that sphingomyelin hydrolysis may be important for
      cytokine-induced PGHS-2 expression but not sufficient to reproduce IL1 beta
      stimulated PGE2 biosynthesis.

PMID- 8641203
TI  - Only the combined treatment with thyroxine and triiodothyronine ensures
      euthyroidism in all tissues of the thyroidectomized rat.
AB  - We have recently shown that it is not possible to restore euthyroidism completely
      in all tissues of thyroidectomized rats infused with T4 alone. The present study
      was undertaken to determine whether this is achieved when T3 is added to the
      continuous sc infusion of T4. Thyroidectomized rats were infused with placebo or
      T4 (0.80 and 0.90 microgram/100 g BW.day), alone or in combination with T3 (0.10,
      0.15, or 0.20 microgram/100 g BW.day). Placebo-infused intact rats served as
      euthyroid controls. Plasma and 12 tissues were obtained after 12 days of
      infusion. Plasma TSH and plasma and tissue T4 and T3 were determined by RIA.
      Iodothyronine deiodinase activities were assayed using cerebral cortex,
      pituitary, brown adipose tissue, liver, and lung. Circulating and tissue T4
      levels were normal in all the groups infused with thyroid hormones. On the
      contrary, T3 in plasma and most tissues and plasma TSH only reached normal levels
      when T3 was added to the T4 infusion. The combination of 0.9 microgram T4 and
      0.15 microgram T3/100 g BW.day resulted in normal T4 and T3 concentrations in
      plasma and all tissues as well as normal circulating TSH and normal or near
      normal 5'-deiodinase activities. Combined replacement therapy with T4 and T3 (in
      proportions similar to those secreted by the normal rat thyroid) completely
      restored euthyroidism in thyroidectomized rats at much lower doses of T4 than
      those needed to normalize T3 in most tissues when T4 alone was used. If pertinent
      to man, these results might well justify a change in the current therapy for
      hypothyroidism.

PMID- 8641204
TI  - Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in
      neurons of normotensive and spontaneously hypertensive rat brains.
AB  - Neuronal cells in primary culture from the hypothalamus-brain stem areas of
      normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive (SH) rat brains
      have been used in the present study to investigate an interaction between the
      brain renin-angiotensin II system and the plasminogen activator system. This is
      an attempt to further our understanding of the role of brain Ang II in the
      control of neuronal development and differentiation through its regulation of the
      extracellular matrix. Ang II caused a 10-fold stimulation of plasminogen
      activator inhibitor-1 (PAI-1) messenger RNA (mRNA) in WKY rat brain neuronal
      cultures. The stimulation was mediated by the AT1 receptor subtype and was
      accompanied by an increase in PAI-1 gene transcription and the synthesis of
      cellular PAI-1 protein. The stimulation involved activation of protein kinase C,
      and alterations in the intracellular Ca2+ pool caused a significant inhibition of
      Ang II stimulation of PAI mRNA. Ang II stimulation of PAI-1 mRNA succeeded its
      action on c-fos mRNA and was attenuated by c-fos antisense oligonucleotide.
      Although PAI-1 gene expression was also stimulated by Ang II in neuronal cultures
      of SH rat brain, two differences between WKY and SH rat brain neurons were
      observed: 1) the level of Ang II stimulation in SH rat neurons was 50% of that in
      WKY rat neurons; and 2) Ang II stimulation of c-fos was 2.4-fold higher in SH
      neurons than in WKY neurons, but c-fos antisense oligonucleotide did not
      attenuate the stimulatory action of Ang II on PAI-1 mRNA in SH neurons. These
      observations suggest that the changes in the Ang II-mediated signaling pathways
      and/or the regulatory region(s) of the PAI-1 gene may contribute to the
      differential actions of Ang II in WKY and SH rat brain neurons.

PMID- 8641205
TI  - Muscarinic activation inhibits T-type Ca2+ current in hen granulosa cells.
AB  - The effect of the muscarinic agonist carbachol on Ca2+ currents in hen granulosa
      cells isolated from the largest ovarian follicle was studied. The major Ca2+
      current observed using the perforated patch technique with a recording solution
      containing 10 mM Ca2+, but no Na+ or K+, exhibited characteristics typical of T
      type Ca2+ current: maximal amplitude at -20 mV, rapid inactivation (half-time of
      42 +/- 3 msec at -20 mV), inhibition by 100 microM Ni2+, and insensitivity to the
      dihydropyridine Ca2+ channel antagonist, nifedipine. In all cell studied,
      carbachol (0.5 mM) caused an inhibition of this current (elicited by depolarizing
      pulses from -70 to -20 mV) to an average maximal decrease of 90 +/- 2% below
      basal values. In some 50% of the cells, the Ca2+ current also partially recovered
      during the 10-min exposure to the muscarinic agonist. These effects were
      prevented by the muscarinic antagonist atropine (1 microM). To test whether this
      inhibition was due to increases in intracellular free Ca2+ concentrations
      ([Ca2+]i), [Ca2+]i was simultaneously measured in fura-2-loaded cells. For cells
      incubated in normal solution, [Ca2+]i was 0.15 +/- 0.02 microM, but increased to
      0.25 +/- 0.6 microM in cells exposed to the recording solution. Under these
      conditions, carbachol failed to produce the expected [Ca2+]i transients, but,
      rather, caused a small decrease (8 +/- 2%) in basal [Ca2+]i attributable to its
      diminution of Ca2+ current. Thus, the results demonstrated an important
      muscarinic inhibition of the T-type Ca2+ current not related to [Ca2+]i
      fluctuations. They indicate, on the other hand, that [Ca2+]i can strongly
      modulate carbachol-induced mobilization of Ca2+ from the intracellular stores.

PMID- 8641206
TI  - Regulation of hen granulosa cell prostaglandin production by transforming growth
      factors during follicular development: involvement of cyclooxygenase II.
AB  - PGs are important physiological regulators of granulosa cell proliferation during
      ovarian follicular development. The rate-limiting step in the synthesis of PGs
      from arachidonic acid is catalyzed by cyclooxygenase (COX). Although two isoforms
      of COX (COX I and COX II) have been identified in the ovary, the nature and
      physiological significance of their regulation by transforming growth factor
      (TGF) alpha and TGF beta are unclear. The object of the present studies was to
      investigate the regulation of hen granulosa cell PG production by TGF alpha and
      TGF beta and the role of COX II in this process. Granulosa cells from the first
      (F1) and fifth and sixth (F5-F6) largest hen preovulatory follicles were cultured
      for up to 21 h in the presence of TGF alpha (0-10 ng/ml) and/or TGF beta (0-20
      ng/ml). COX protein and messenger RNA (mRNA) levels were determined by Western
      blot and Northern analysis, respectively. Granulosa cell PGF and PGE secretion
      was increased by TGF alpha but suppressed by TGF beta in vitro. The increase in
      PG secretion was accompanied by an elevation of COX II content, which was dose
      and time dependent, with maximum response observed within 6-12 h. Maximal
      increase in COX II mRNA abundance was evident at 4 and 8 h in cells from F1 and
      F5-F6, respectively. Although TGF alpha-stimulated PG secretion was higher in
      cells from mature follicle (F1), the magnitude of change in COX II mRNA abundance
      and protein content was, however, not dependent on follicular maturation. TGF
      beta significantly suppressed basal and TGF alpha-induced COX II transcript
      levels. COX I transcript, however, was undetectable irrespective of the presence
      of TGF alpha, duration of culture or the stage of follicular development. In
      conclusion, the mitogenic response of granulosa cells to TGF alpha is mediated by
      changes in PG secretion, which are regulated at the level of COX II. Unlike the
      control of PG secretion, the regulation of COX II by TGF alpha is independent of
      follicular maturation. Whereas COX II may be important in the signaling cascade
      for TGF alpha in the regulation of granulosa cell proliferation, the mechanism(s)
      of regulation of follicular stage-dependent PG secretion by the growth factor is
      complex and requires further investigation.

PMID- 8641207
TI  - Negative influence of O-linked oligosaccharides of high molecular weight equine
      chorionic gonadotropin on its luteinizing hormone and follicle-stimulating
      hormone receptor-binding activities.
AB  - Three equine CG (eCG) forms with identical amino acid sequences but different mol
      wt and monosaccharide compositions were isolated from a crude eCG preparation and
      designated eCG-L (low mol wt), eCG-M (medium mol wt), and eCG-H (high mol wt). No
      differences in primary structure between each form and the known sequence of eCG
      were observed. SDS-PAGE of these preparations under reducing conditions revealed
      that the mol wt differences between them were due only to the different sizes of
      their beta-subunits. Carbohydrate compositions suggested an increase in O
      glycosylation in the higher mol wt forms. N-Linked glycopeptide fragments
      obtained from eCG beta-subunits by endoproteinase Lys-C digestion had identical
      electrophoretic mobilities. Thus, the different molecular sizes of the beta
      subunits were associated only with disparities in O-glycosylation of their C
      terminal extension. When tested in a LH and several FSH radioligand assay
      systems, eCG-H proved to have significantly lower receptor-binding activities
      than eCG-L and eCG-M. Endo-beta-galactosidase digestion increased the FSH
      receptor-binding activity of all eCG forms; however, partially deglycosylated eCG
      H remained the least active form. Thus, the O-linked oligosaccharides of eCG-H
      exert a negative influence on its receptor-binding activity.

PMID- 8641208
TI  - Oligosaccharide mapping reveals hormone-specific glycosylation patterns on equine
      gonadotropin alpha-subunit Asn56.
AB  - Equine gonadotropin alpha-subunit glycosylation was examined by releasing
      oligosaccharides using a sequential enzymatic deglycosylation protocol and
      comparing the released oligosaccharide populations using a high resolution
      oligosaccharide mapping technique. Digestion of native alpha-subunit preparations
      with peptide-N-glycosidase altered their mobilities during SDS-PAGE under
      reducing conditions to positions intermediate between the corresponding native
      alpha-subunit and completely deglycosylated alpha-subunit bands. Complete alpha
      subunit deglycosylation required reduction of disulfide bonds. Results of solid
      phase Edman degradation demonstrated that partial deglycosylation occurred
      exclusively at Asn56. Oligosaccharide mapping of total oligosaccharides obtained
      by enzymatic deglycosylation of reduced, carboxymethylated alpha-subunit
      preparations revealed hormone-specific patterns of glycosylation in eLH alpha and
      eCG alpha. Oligosaccharide mapping of individual glycosylation sites revealed
      that hormone-specific glycosylation was primarily restricted to Asn56 of both
      subunit preparations and revealed a hormone-specific pattern of Asn56
      glycosylation in eFSH alpha that was obscured in the total oligosaccharide map.
      eLH alpha Asn56 oligosaccharides appeared to be primarily seven variants of a
      monoantennary structure. eCG alpha Asn56 oligosaccharides consisted of one of two
      forms, either a sialylated biantennary oligosaccharide that appeared identical to
      a commercial carbohydrate standard or a lactosamine variant of that structure.

PMID- 8641209
TI  - Effect of thyroid hormones on G proteins in synaptosomes of chick embryo.
AB  - We have described a thyroid hormone receptor in synaptosomes of the chick embryo
      brain. To understand how the hormones exert their actions at this level, we
      performed a series of studies to demonstrate that this receptor could be linked
      to G proteins. Guanosine 5'-[gamma-thio]triphosphate (GTP gamma S)(100 muM)
      lowered the binding capacity of the receptor high affinity site from 8.9 +/- 1.3
      to 3.4 +/- 1.3 ng T3/mg protein, a finding consistent with the coupling of
      receptor to G proteins. Furthermore, ADP ribosylation with pertussis toxin showed
      that thyroid hormones induced a dose-dependent increase in the inactive alpha 0
      subunit of the G0 protein. This effect was detected at 10 pM, with a maximal
      increase (mean +/- SEM, 50 +/- 3.6%) at 100 nM, and T4 was as effective as T3.
      Both hormones also decreased the intrinsic guanine triphosphatase activity of G
      proteins by lowering the binding of GTP to the alpha-subunit and their rate of
      hydrolysis. This inhibition was greater with T4 (25 +/- 5%) than with T3 (14 +/-
      2%), suggesting that the former could be the more active hormone at the
      synaptosomal level. The effect on guanine triphosphatase activity confirms that
      the synaptosomal thyroid hormone receptor is coupled to a G(zero) protein. These
      results demonstrate that thyroid hormones increase or favor the ADP ribosylation
      of G alpha(zero) by pertussis toxin. Thus, they enhance the alpha(zero)-GDP form
      of the G(zero) protein, namely its inactive conformation. By decreasing the
      activity of this protein, these hormones may modulate the formation of second
      messengers in synaptosomes and intervene in the regulation of neuronal
      proliferation and differentiation induced by several factors. Therefore, thyroid
      hormones may exert their action on brain maturation at least in part by
      modulating G alpha(zero) through their synaptosomal receptor.

PMID- 8641210
TI  - Stimulation of luteinizing hormone secretion by food intake: evidence against a
      role for insulin.
AB  - In adult male rhesus monkeys, 1 day of fasting leads to a profound suppression of
      LH secretion that is rapidly reversed with refeeding. To test the hypothesis that
      changes in insulin secretion during fasting and refeeding mediate the changes in
      LH secretion, blood samples for LH measurement were obtained between 0900-2400 h
      from adult male rhesus monkeys (n = 9) on 1) a day when monkeys were refed their
      normal meal after a day of fasting, and 2) a day when monkeys were refed their
      normal meal, but endogenous insulin secretion was suppressed. Diazoxide (7.5-9.5
      mg/kg.h) caused a 40-99% suppression of postmeal insulin secretion. However, no
      significant differences in LH pulse frequency, pulse amplitude, or mean serum LH
      levels were detected between control and diazoxide trials, even in animals in
      which insulin was markedly suppressed. Further, no correlation existed between
      the degree of insulin suppression and the magnitude of the meal-induced
      stimulation of LH. We conclude that meal-induced insulin secretion does not
      provide the stimulus mediating the meal-induced increase in LH secretion.

PMID- 8641211
TI  - Prostaglandin E2 activates phospholipase C and elevates intracellular calcium in
      cultured myometrial cells: involvement of EP1 and EP3 receptor subtypes.
AB  - PGE2 is a powerful modulator of uterine contractility, but there is uncertainty
      as to which receptor subtypes (EP1, EP2, EP3, or EP4), G proteins, and second
      messenger systems are activated by PGE2 in myometrium. Here we show that in
      cultured human myometrial cells, PGE2 (1-100 microM) activates phospholipase C
      (PLC) up to 500% over the control level and elevates intracellular calcium
      ([Ca2+]i) from the resting level of 60-90 nM up to 350 nM in a concentration
      dependent manner. Stimulation by the receptor subtype-selective analogs GR63799X
      (EP3), sulprostone (EP3 > EP1), and misoprostol (EP3 > EP2 > EP1) indicates that
      these effects are transmitted through EP3 receptors. Both effects are resistant
      to pertussis toxin (PT). Lower concentrations of PGE2 (1-300 nM) increase [Ca2+]i
      via a PT-sensitive pathway, without PLC activation. This [Ca2+]i increase occurs
      after an inverse dose-related delay and is inhibited by the selective EP1
      antagonist AH6809 and calcium channel blockers. By comparison, oxytocin
      stimulates PLC up to 1000% over the control level and elevates [Ca2+]i up to 800
      nM in a concentration-dependent manner without any measurable delay; both effects
      are partly sensitive to PT. These data provide functional evidence for the
      presence of different stimulatory mechanisms for PGE2 in myometrium: 1) a low
      affinity receptor (probably EP3D) that activates PLC through a PT-insensitive
      pathway; and 2) a high affinity receptor (probably EP1), independent from PLC and
      involving a PT-sensitive G protein (G(i)?). Both pathways lead to elevation of
      [Ca2+]i.

PMID- 8641212
TI  - Comparison of the effects of propylthiouracil and selenium deficiency on T3
      production in the rat.
AB  - Selenium deficiency and propylthiouracil (PTU) treatment both decrease hepatic
      type I T4 5'-deiodinase activity (5'D-I), which is considered to be an important
      regulator of the serum T3 derived from peripheral T4 to T3 conversion (T3
      neogenesis). The effects of PTU treatment or a selenium-deficient diet on T4 and
      T3 kinetics were compared in thyroid-ablated rats infused with stable T4 to
      determine whether PTU treatment is a more potent inhibitor of T3 neogenesis than
      selenium deficiency and to compare the degree of inhibition of T3 production with
      the degree of inhibition of 5'D-I. PTU treatment and selenium deficiency (Se-)
      did not affect the T3 MCR (control, 46.0 +/- 2.5; PTU, 41.7 +/- 2.8; Se-, 41.1 +/
      4.0 ml/h.100 g BW), but did reduce serum T3 concentrations by 29% and 25%,
      respectively (control, 58.7 +/- 2.6; PTU, 41.5 +/- 1.0; Se-, 43.9 +/- 2.7 ng/dl;
      P < 0.01 for PTU or Se- vs. control) and the T3 production rate by 35% and 32%,
      respectively (control, 26.6 +/- 1.0; PTU, 17.3 +/- 2.0; Se-, 18.0 +/- 1.9
      ng/h.100 g BW; P < 0.01 for PTU or Se- vs. Control). PTU treatment and selenium
      deficiency significantly increased serum T4 concentrations by 36% and 32%,
      respectively, due to a decrease in T4 MCR (control, 1.4 +/- 0.1; PTU, 1.1 +/-
      0.1; Se-, 1.1 +/- 0.04 ml/h.100 g BW; P < 0.05 for PTU or Se- vs. control).
      Assuming that the concentration of T4 available for T3 neogenesis is proportional
      to the serum T4 concentration, the increase in serum T4 concentrations caused by
      PTU treatment or Se- would probably have proportionally increased the rate of T3
      neogenesis. Based on these considerations, the apparent decrease in T3 neogenesis
      in the PTU-treated animals was 52%. This is less than the 79% and 67% inhibition
      of 5'D-I noted, respectively, in the liver and kidneys of these rats. Similarly,
      the apparent decrease in T3 neogenesis in the Se- rats was 48%, again less than
      the 85% and 64% inhibition of 5'D-I in their liver and kidneys, respectively.
      These studies suggest that PTU and Se- have similar effects on T3 neogenesis. The
      more potent effects of these treatments on liver and kidney 5'D-I activities than
      on T3 neogenesis suggest that the activities of these enzymes in these tissues
      are not the only important determinants of the serum T3 that is derived from
      nonthyroidal sources.

PMID- 8641213
TI  - Effects of alendronate on plasma calcium levels, urinary calcium excretion, and
      bone resorption markers in normal rats: comparison with elcatonin, synthetic eel
      calcitonin.
AB  - In normal rats given alendronate (0.01-6.25 mg/kg) or elcatonin (synthetic eel
      calcitonin; 0.32-8.0 U/kg), changes in urinary calcium (Ca), pyridinoline (Pyr),
      and deoxypyridinoline (D-Pyr) excretion during the hypocalcemic response were
      assessed. Although the lower doses (0.01-0.25 mg/kg) of alendronate did not
      influence plasma Ca, the high doses (1.25-6.25 mg/kg) significantly decreased
      plasma Ca by the third day after single iv administration. In these groups,
      urinary Ca excretion did not show any significant change, but urinary Pyr and D
      Pyr excretion decreased significantly at high doses. The hypocalcemic effect
      lasted for only 1 or 2 days (2-3 days after injection) even at high doses of
      alendronate. In the group receiving elcatonin (8.0 U/kg, twice daily), a
      significant decrease in plasma Ca was evident as early as 1 day after the start
      of administration. This was accompanied by a marked increase in urinary Ca
      excretion in the early stage without a significant decrease in urinary Pyr or D
      Pyr excretion, and the suppression of bone resorption was more pronounced in the
      late phase of treatment with elcatonin. These results suggest that alendronate
      decreases plasma Ca chiefly by suppressing bone resorption, whereas elcatonin
      decreases plasma Ca by inhibiting bone resorption and accelerating Ca excretion.
      The present data show that both alendronate and elcatonin inhibit bone resorption
      and exert an antihypercalcemic effect, but the mechanism of action is different
      in the two drugs.

PMID- 8641214
TI  - Neural and glial-mediated effects of growth factors acting via tyrosine kinase
      receptors on luteinizing hormone-releasing hormone neurons.
AB  - It is becoming increasingly evident that the secretory activity of LHRH neurons
      is regulated not only by transsynaptic inputs but also by trophic molecules of
      glial and neuronal origin. The present experiments were undertaken to gain
      insights into the potential cell-cell mechanisms by which basic fibroblast growth
      factor (bFGF) and transforming growth factor-alpha (TGF alpha), two growth
      factors produced in the hypothalamus, may affect LHRH neuronal function. Northern
      blot analysis showed that the LHRH-producing cell line GT1-7 contains the
      messenger RNA (mRNA) encoding the type 1 fibroblast growth factor receptor (FGFR
      1) but not that encoding the epidermal growth factor (EGF) receptors, which
      mediates the biological actions of both TGF alpha and EGF. Ligand-induced
      receptor phosphorylation experiments demonstrated that GT1-7 cells possess
      biologically active FGFR-1s but not EGF receptors. Exposure of the cells to bFGF
      resulted not only in FGFR-1 tyrosine phosphorylation, but also in tyrosine
      phosphorylation of phospholipase C gamma, one of the initial enzymes in the
      intracellular signaling cascade initiated by FGFR activation. GT1-7 cells
      proliferated in response to this activation. Despite the presence of biologically
      active receptors, bFGF did not significantly stimulate release of the mature LHRH
      decapeptide. Instead, bFGF increased the steady-state levels of the mRNA encoding
      the LHRH precursor processing endoprotease PC2, with a time course comparable to
      that of phorbol esters, suggesting that, as shown in the companion paper, the
      actions of the growth factor on LHRH neurons involve facilitation of the initial
      step in LHRH prohormone processing. The increase in PC2 gene expression was not
      accompanied by changes in LHRH mRNA levels. Unlike these direct actions of bFGF
      on GT-1 cells, TGF alpha appears to act indirectly via astroglial intermediacy.
      Exposure of GT1-7 cells to TGF alpha or EGF failed to affect several parameters
      of cellular activity including LHRH release, LHRH and PC2 mRNA levels, and cell
      proliferation. In contrast, astrocyte culture medium conditioned by treatment
      with TGF alpha led to sustained stimulation of LHRH release with no changes in
      LHRH gene expression and a transient increase in PC2 mRNA levels. Although no
      definitive evidence for the presence of FGFR-1 in normal LHRH neurons could be
      obtained by either double immunohistochemistry or double in situ hybridization
      procedures, fetal LHRH neurons in primary culture responded to bFGF with neurite
      outgrowth. Thus, normal LHRH neurons may have an FGFR-1 content too low for
      detection by regular histochemical procedures, and/or detectable expression of
      the receptor may be confined to a much earlier developmental stage. The mitogenic
      effect of bFGF on GT1-7 cells supports this possibility and suggests a role for
      FGF in the cell proliferation events that precede acquisition of the LHRH
      neuronal phenotype. It appears that once this phenotype is established, bFGF may
      promote the differentiation of LHRH neurons. The results also suggest that the
      secretory capacity of LHRH neurons develops under a dual trophic influence, one
      on peptide processing exerted directly by bFGF on early neurons, and another on
      LHRH release, exerted by TGF alpha via the intermediacy of astroglial cells.

PMID- 8641215
TI  - Basic fibroblast growth factor regulates the conversion of pro-luteinizing
      hormone-releasing hormone (Pro-LHRH) to LHRH in immortalized hypothalamic
      neurons.
AB  - Growth factors are commonly associated with the regulation of cellular
      proliferation and differentiation. In established cells, growth factors can also
      serve as trophic agents. Immortalized LHRH neurons contain basic fibroblast
      growth factor (bFGF) receptors. Although these receptors are coupled to
      activation of protein kinase C, and phorbol esters are strong activators of
      protein kinase C-stimulated LHRH release, bFGF did not influence LHRH secretion
      from these cells. To clarify this discrepancy, the effects of bFGF and phorbol
      ester on pro-LHRH biosynthesis, protein processing, and secretion were examined
      in GT1-7 cells. Phorbol ester stimulated LHRH secretion, whereas bFGF either had
      no effect or stimulated LHRH release depending upon the antiserum used. Pro-LHRH
      levels in lysate and medium were depressed by phorbol esters; concentrations in
      bFGF-treated cells were somewhat lower than those in unstimulated controls. HPLC
      analyses revealed that both agents enhanced the release of LHRH intermediate
      products into the medium. C-Terminally extended forms of LHRH, especially LHRH
      [Gly11], were prominent in medium from bFGF-stimulated neurons. Levels of LHRH
      were depressed relative to those in the control or phorbol ester groups. These
      data indicate that phorbol esters control the biosynthesis, secretion, and, to
      some extent, processing of pro-LHRH. The effects of bFGF are novel because this
      factor regulates processing of the prohormone so that LHRH-intermediate products
      are predominantly secreted instead of LHRH. By enhancing the secretion of these
      intermediates over that of LHRH, bFGF can control the biological activity of the
      decapeptide and regulate LHRH neuronal function.

PMID- 8641216
TI  - Cyclic adenosine 3',5'-monophosphate-independent regulation of cytosolic calcium
      in Sertoli cells.
AB  - We have examined the cAMP-independent regulation of cytosolic calcium
      concentration in rat Sertoli cells using the effect of vasoactive hormones, known
      as testicular paracrine regulators operating via the non-cAMP pathway, on
      cytosolic calcium. Calcium concentrations were estimated with dual excitation
      fluorimetry, using freshly isolated, fura-2/AM-loaded cells. No increase in the
      cellular cAMP concentration was detected after stimulation with angiotensin II
      (AII), vasopressin, PGF2 alpha, or atrial natriuretic peptide. Whereas both AII
      and vasopressin evoked a rise in cytosolic calcium from a basal level of 81.4 +/-
      4 to 142.5 +/- 18 and 154.4 +/- 11 nM, respectively, PGF2 alpha had only a
      minimal effect (98 +/- 5 nM), and atrial natriuretic peptide no effect (86.6 +/-
      9 nM). The effect of AII on calcium was blocked by the the selective AT2, but not
      by the AT1, receptor antagonist, indicating the selective presence on Sertoli
      cells of AT2 AII receptor. Similarly, the vasopressin-induced calcium response
      was blocked by vasopressin V1, but not by V2 receptor antagonist, consistent with
      the presence of V1 receptor subtype in these cells. Removal of extracellular
      calcium or blockade of calcium channels did not inhibit the calcium increase due
      to AII and vasopressin, suggesting the involvement of intracellular calcium.
      Thapsigargin increased the basal cytosolic calcium concentration to 137 +/- 10
      nM. Depletion of intracellular calcium stores with thapsigargin before
      stimulation with AII or vasopressin abolished both the AII-mediated and the
      vasopressin-mediated calcium rise in the presence as well as the absence of
      extracellular calcium, indicating that the increase in calcium is predominantly
      derived from the thapsigargin-sensitive endoplasmic reticulum. This study
      indicates that calcium homeostasis of Sertoli cells might also be regulated by
      cAMP-independent metabolism apart from the well known cAMP-dependent pathway.
      Furthermore, our findings support the idea that angiotensin and vasopressin might
      be important paracrine regulators of Sertoli cells functions.

PMID- 8641217
TI  - Regulation of insulin secretion and blood glucose metabolism by adrenomedullin.
AB  - Adrenomedullin (AM), a recently discovered hypotensive peptide, is expressed in
      the endocrine pancreas of different species, as demonstrated by
      immunocytochemistry. Electron microscopic studies with double immunogold showed
      colocalization of AM and pancreatic polypeptide. A homogeneous expression of AM
      receptor was found throughout the islet using in situ hybridization. Six
      different insulin- producing cell lines have been analyzed by reverse
      transcription-PCR and showed expression of both AM and its receptor. Two
      experimental models have been used to study the effects of AM in pancreatic
      physiology. 1) Analysis of isolated rat islets shows that AM inhibits insulin
      secretion in a dose-dependent manner. The monoclonal antibody MoAb-G6, which
      neutralizes AM bioactivity, was able to increase insulin release 5-fold; this
      effect was reversed by the addition of synthetic AM. 2) Oral glucose tolerance
      tests showed that iv injection of AM reduces the levels of insulin in the
      bloodstream with a concomitant increase in circulating glucose. These studies
      implicate AM as a newly defined factor of the insulin regulatory system that
      could be involved in disorders such as diabetes and obesity.

PMID- 8641218
TI  - 24R,25-dihydroxyvitamin D3 promotes bone formation without causing excessive
      resorption in hypophosphatemic mice.
AB  - To clarify the differences in the action of 1,25-dihydroxyvitamin D3 [1,25
      (OH)2D3] and 24,25-(OH)2D3 in hypophosphatemic (Hyp) mice, a model for familial X
      linked hypophosphatemic rickets in humans, we carried out histomorphometric
      examinations of the effects of these agents in the lumbar vertebra of these mice.
      The Hyp mice received 1-1000 micrograms/kg.day 24,25-(OH)2D3, 0.01-0.1
      micrograms/kg.day 1,25.(OH)2D3, or vehicle alone given daily for 28 days by ip
      injection. Histomorphometrically, 1,25-(OH)2D3 and 24,25-(OH)2D3 showed similar
      effects on bone formation. The parameters of bone formation, mineralized bone
      volume/bone volume, mineral apposition rate, and bone formation rate/bone
      surface, were improved to a similar extent in a dose-dependent manner by 1,25
      (OH)2D3 and 24,25-(OH)2D3, but there were remarkable differences in the indexes
      of the bone resorption between these two metabolites. In 24,25-(OH)2D3-treated
      Hyp mice, osteoclast number/bone perimeter and osteoclast surface/bone surface,
      the parameters of bone resorption, increased to control levels and did not change
      according to the dose of 24,25-(OH)2D3. However, in 1,25-(OH)2D3-treated Hyp
      mice, these values increased remarkably, exceeding the control level. That is,
      24,25-(OH)2D3 normalized bone resorption in the rachitic mice, whereas 1,25
      (OH)2D3 caused excessive stimulation of bone resorption. This qualitative
      difference between the two compounds contributes to the superior effects exerted
      by 24,25-(OH)2D3 in improving the bone lesion in Hyp mice. At doses from 1-1000
      micrograms/kg.day, 24,25-(OH)2D3 had dose-dependent effects in increasing bone
      formation without promoting excessive bone resorption, as shown by
      histomorphometric analysis.

PMID- 8641219
TI  - Pharmacological characterization of a recently described human beta 3-adrenergic
      receptor mutant.
AB  - The beta 3-adrenergic receptor is the predominant subtype of beta-adrenergic
      receptor expressed in adipose tissue. Recently, a naturally occurring mutation in
      the human beta 3-receptor gene has been described which results in substitution
      of the tryptophan residue at position 64 in the first intracellular loop with an
      arginine residue. The polymorphism, which is prevalent in the human population,
      has been associated with increases in some parameters of obesity and Type II
      diabetes. In order to characterize the pharmacological effects of this amino acid
      substitution, the W64R mutation was made in the human beta 3 receptor gene and
      the resulting mutant receptor expressed in CHO cells. Activation by various
      agonists showed no significant differences (t-test, P > 0.05) between the wild
      type and mutant receptors. These studies show that, when expressed in a
      heterologous system, the W64R mutant receptor is pharmacologically and
      functionally indistinguishable from the wild type beta 3-adrenergic receptor.

PMID- 8641221
TI  - Anomalies in the endocrine axes of the guinea pig: relevance to human physiology
      and disease.

PMID- 8641220
TI  - Growth hormone-releasing factor (GRF) regulates expression of its own receptor.
AB  - Recent studies have demonstrated that passive immunization of neonatal rats to
      GRF inhibited their somatic growth through the suppression of GH secretion. In
      this study, we investigated the changes in pituitary GRF receptor (GRFR)
      expression in GRF antibody (GRF-ab) treated rats. Neonatal rats were treated from
      day 1 to day 10 after birth with every other day sc injection of 50 microliters
      of normal rabbit serum (groups I: control & III) or rabbit serum containing GRF
      ab (groups II & IV). In addition, groups III & IV received twice daily injection
      of recombinant human GH (0.4 microgram/kg, sc). The rats were sacrificed on day
      11 and pituitaries were removed. The pituitary weights in all treatment groups
      were decreased compared to the control group (I). Total pituitary RNA was
      extracted and GRFR mRNA levels were determined by RNase protection assay.
      Receptor RNA levels were quantitated and normalized to an internal standard,
      glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The ratios of GRFR mRNA to
      GAPDH mRNA were significantly decreased to 49.6 +/- 4.9 (mean +/- SD), 73.0 +/-
      8.7, 43.6 +/- 9.5% of control group I in the experimental groups II, III, and IV,
      respectively (P < 0.01). These data suggest that (1) suppression of GH secretion
      in GRF-ab treated animals was due, at least in part, to a decrease in GRFR
      expression, (2) GRF may be necessary for its own receptor expression, (3)
      exogenous administration of GH suppresses pituitary GRFR mRNA.

PMID- 8641222
TI  - Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP/vasoactive
      intestinal polypeptide receptors: actions on the anterior pituitary gland.

PMID- 8641223
TI  - Thyroid hormone metabolism and thyroid diseases in chronic renal failure.
AB  - Patients with ESRD have multiple alterations of thyroid hormone metabolism in the
      absence of concurrent thyroid disease. These may include elevated basal TSH
      values, which may transiently increase to greater than 10 mU/liter, blunted TSH
      response to TRH, diminished or absent TSH diurnal rhythm, altered TSH
      glycosylation, and impaired TSH and TRH clearance rates. In addition, serum total
      and free T3 and T4 values may be reduced, free rT3 levels are elevated while
      total values are normal, serum binding protein concentrations may be altered, and
      disease-specific inhibitors reduce serum T4 binding. Changes in T4 and T3
      transfer, distribution, and metabolism resemble those of other nonthyroidal
      illnesses, while changes in rT3 metabolism are disease specific. Dialysis therapy
      minimally affects thyroid hormone metabolism, while zinc and erythropoietin
      administration may partially reverse thyroid hormone abnormalities. Thyroid
      hormone metabolism normalizes with renal transplantation; however, glucocorticoid
      therapy may induce additional changes. ESRD patients may have an increased
      frequency of goiter, thyroid nodules, thyroid carcinoma, and hypothyroidism.
      Goiter and hypothyroidism may be induced by iodide excess, due to reduced renal
      iodide excretion, and may be reversed with iodide restriction in some patients.
      The increased frequency of thyroid nodules and malignancies in ESRD may relate to
      secondary hyperparathyroidism. After renal transplantation, the higher frequency
      of thyroid malignancies may relate to the immunosuppressed state. Clinical
      symptoms and signs and biochemical features of hypothyroidism and hyperthyroidism
      may be altered by concurrent ESRD. ESRD patients with hyperthyroidism or
      follicular neoplasms require reduced dosages of Na 131-I depending upon type,
      frequency, and duration of dialysis therapy.

PMID- 8641224
TI  - Immune-neuro-endocrine interactions: facts and hypotheses.

PMID- 8641225
TI  - Neuroimaging in epilepsy: is there a future for positron emission tomography.

PMID- 8641226
TI  - Effect of valproate on cerebral metabolism and blood flow: an 18F-2-deoxyglucose
      and 15O water positron emission tomography study.
AB  - We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose
      (CMRGlc) and cerebral blood flow (CBF), measured with 18F-2-deoxyglucose (18FDG)
      and 15O water positron emission tomography (PET), in 10 normal volunteers. Mean
      VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (+/-16.5) for 4 weeks.
      VPA reduced global CMRGlc by 9.4% (9.60 +/- 0.76 vs. 8.59 +/- 1.02 mg Glc/min/100
      g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas).
      VPA diminished global CBF by 14.9% (56.55 +/- 6.70 vs. 47.48 +/- 4.42 ml/min/100
      g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas).
      No significant correlation was noted between VPA level and either global CMRGlc
      or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine
      (CBZ) and phenytoin but less than that of phenobarbital, valium, or combination
      therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the
      thalamus, an effect that may be associated with VPA's mechanism of action against
      generalized seizures.

PMID- 8641227
TI  - Relation between intracarotid amobarbital memory asymmetry scores and hippocampal
      sclerosis in patients undergoing anterior temporal lobe resections.
AB  - The intracarotid amobarbital procedure (IAP) is used to evaluate memory function
      preoperatively in candidates for anterior temporal lobe resections (ATL). We
      examined IAP memory asymmetry scores in 30 patients undergoing ATL (17 R, 13 L),
      as a function of the presence (HS+) or absence (HS-) of hippocampal sclerosis.
      Ictal onset zones were determined by extraoperative recording with subdural strip
      electrodes in all but 3 patients in whom magnetic resonance imaging (MRI) scan
      showed HS. MRI scans were otherwise normal. All patients were left hemisphere
      dominant for language except 1, in whom language was represented bilaterally. IAP
      memory testing involved presentation of eight subjects during anesthesia of each
      hemisphere, followed by recognition testing after patients recovered from
      amobarbital effects. A score of 1 was given for each correctly recognized object,
      and 0.5 was deducted for each false-positive identification. There were 16 foils.
      A total asymmetry score was calculated, which was positive if there was agreement
      between the direction of the symmetry and side of operation and negative if
      reversed. The mean asymmetry score for HS- (n = 8) was 0.9; that for HS+ (n = 22)
      was 4.1 (p < 0.01). IAP memory performance provided lateralizing information
      (asymmetry score > or = + or -2) in 73% of cases; among these, the lateralization
      was correct in 91%. Our data indicate that IAP memory asymmetry predicts both
      laterality of ictal onset and the presence of HS.

PMID- 8641228
TI  - Bilateral magnetic resonance imaging-determined hippocampal atrophy and verbal
      memory before and after temporal lobectomy.
AB  - We investigated pre- and postoperative verbal memory in temporal lobectomy
      patients who had volumetrically symmetric hippocampi. Pre- and postoperative
      verbal memory data based on the Logical Memory subtest of the Wechsler Memory
      Scale-Revised (WMS-R) were obtained from 15 left and 18 right temporal lobectomy
      patients. The difference between hippocampal volumes (R/L) was between -0.1 and
      0.3 cm3, which is indeterminate for lateralizing hippocampal atrophy. Patients
      were divided into four groups based on side of operation and combined hippocampal
      volume expressed as a function of total intracranial volume (R + L volume/total
      intracranial volume). Patients with a combined hippocampal volume that was
      smaller than any combined hippocampal value of a normal control group were
      defined as bilaterally atrophic. Left temporal lobectomy patients demonstrated
      the expected decrease in verbal memory postoperatively regardless of whether the
      volumetrically symmetric hippocampi were nonatrophic or atrophic. Left temporal
      lobectomy patients with bilaterally atrophic hippocampi, however, had the poorest
      verbal memory before and after operation. Right temporal lobectomy patients
      tended to have improved verbal memory after operation whether or not the
      volumetrically symmetric hippocampi were atrophic. We conclude that side of
      operation is a more potent predictor of verbal memory outcome than is hippocampal
      atrophy when hippocampi are bilaterally symmetric and that left temporal
      lobectomy patients with bilateral atrophy may be at risk for greater functional
      deficits after operation.

PMID- 8641229
TI  - Concentration--effect and concentration--toxicity relations with lamotrigine: a
      prospective study.
AB  - This prospective study was designed to ascertain whether measurement of
      lamotrigine (LTG) concentrations in the epilepsy clinic could be used to predict
      the onset of complete seizure control or the emergence of adverse effects. LTG
      was initiated in doses of 25 or 50 mg daily in 69 patients with newly diagnosed
      or poorly controlled epilepsy and was increased monthly in 50-mg increments until
      the patient became seizure-free for at least 6 months or developed adverse
      effects that abated after a reduction in dosage. LTG and other antiepileptic drug
      (AED) concentrations were measured at each clinic visit but were not supplied to
      the investigator examining the patients. Overall, 19 patients either withdrew due
      to lack of efficacy or defaulted from the clinic. Of the remaining 50 patients,
      32 (19 monotherapy, 13 polytherapy) became seizure-free at widely varying daily
      LTG doses (median 200 mg, range 25-850 mg) and concentrations (median 3.8 mg/L,
      range 1.4-18.7 mg/L). Likewise, the 18 patients (5 monotherapy, 13 polytherapy)
      who experienced intolerable side effects showed substantial variations in daily
      LTG doses (median 300 mg, range 100-900 mg) and concentrations (median 4.0 mg/L,
      range 0.4-18.5 mg/L). No useful concentration-effect or concentration-toxicity
      relation with LTG could be demonstrated in this study; therefore, we believe that
      routine therapeutic drug monitoring with this new AED is not currently indicated.

PMID- 8641230
TI  - Double-blind, placebo-controlled trial of topiramate as add-on therapy in
      patients with refractory partial seizures.
AB  - In a double-blind, randomized, parallel-group trial, we compared topiramate (TPM)
      with placebo as add-on therapy in patients with refractory partial epilepsy. TPM
      was titrated either to the target dosage of 800 mg/ day [400 mg twice daily
      (b.i.d)] or to the maximal tolerated dose if lower. Twenty-eight (28) patients
      were randomized to each treatment group. In the intent-to-treat analysis, the net
      median percent reduction relative to placebo in average monthly seizure rate was
      54% for patients in the TPM group (p < 0.001). None of the placebo-treated
      patients and 43% of the patients treated with TPM experienced > or = 50%
      reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75
      100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also
      significantly reduced in the TPM group (p = 0.044). The most common adverse
      events (AE) reported in the TPM group were fatigue, impaired concentration,
      weight loss, dizziness, and paresthesias. AE occurring either during the rapid
      titration of TPM or at high dosages led 21% of TPM-treated patients to withdraw
      from the study. Half of these occurred during the titration study period. No
      serious AE or clinically important changes in clinical laboratory measures were
      observed. The present study further establishes the favorable profile and good
      benefit/risk ratio of TPM in resistant partial epilepsy.

PMID- 8641231
TI  - Remacemide hydrochloride and ARL 15896AR lack abuse potential: additional
      differences from other uncompetitive NMDA antagonists.
AB  - This study was designed to determine the possible abuse liability and
      phencyclidine-like effects of the low-affinity uncompetitive N-methyl-D-aspartate
      (NMDA) antagonists remacemide hydrochloride [(+/-)-2-amino-N-(1-methyl-1,2
      diphenylethyl)-acetamine hydrochloride] and ARL 15896AR [(+)-alpha-phenyl-2
      pyridine-ethanamine dihydrochloride]. For the abuse-liability studies, in rats
      trained to self-administer cocaine intravenously (0.1 mg/kg/injection), doses of
      remacemide HCl, ARL 15896AR, phencyclidine, and saline were made available, and
      the number of injections self-administered was recorded. In different sets of
      rats, we assessed the ability of these drugs to induce phencyclidine-like
      stereotyped behavior. Doses of the compounds were expressed as multiples of the
      50% effective dose (ED50), as determined from the maximal electroshock (MES) test
      by using either oral or intravenous administration. None of the remacemide
      hydrochloride or ARL 15896AR doses was self-administered at a level higher than
      that of the saline vehicle, unlike cocaine and phencyclidine, which were self
      administered at high and moderate levels, respectively. Unlike that with
      remacemide hydrochloride and ARL 15896AR, oral administration of the high
      affinity uncompetitive NMDA receptor-antagonists phencyclidine, ARL 16247 [N-(3
      ethylphenyl)-N-methyl-N'-naphthylguanidine] and MK-801 engendered phencyclidine
      like stereotypy at doses near their MES ED50 values. These data confirm the
      unusual safety of remacemide hydrochloride and ARL 15896AR and demonstrate that
      they do not possess reinforcing properties. As such, they are unlikely to present
      a drug-abuse problem in human beings.

PMID- 8641232
TI  - Postictal psychosis: a comparison with acute interictal and chronic psychoses.
AB  - We studied 30 patients with postictal psychosis and compared them with 33
      patients with acute interictal psychosis and 25 patients with chronic psychosis.
      All patients had either complex partial seizures (CPS) or EEG temporal
      epileptogenic foci. Patients with postictal psychosis had a high incidence of
      psychic auras and nocturnal secondarily generalized seizures. The most striking
      feature that distinguished postictal psychosis from both acute interictal and
      chronic psychoses was phenomenological: the relatively frequent occurrence of
      grandiose delusions as well as religious delusions in the setting of markedly
      elevated moods and feeling of mystic fusion of the body with the universe. In
      addition, postictal psychosis exhibited few schizophreniform psychotic traits
      such as perceptual delusions or voices commenting. Reminiscence, mental diplopia,
      and a feeling of impending death were also fairly frequent complaints of patients
      with postictal psychosis. Interictal acute psychosis and chronic epileptic
      psychosis were psychopathologically similar. Although acute interictal and
      chronic epileptic psychoses could simulate schizophrenia, postictal psychosis
      results in a mental state quite different from that of schizophrenic psychosis.

PMID- 8641233
TI  - Families are content to discontinue antiepileptic drugs at different risks than
      their physicians.
AB  - PURPOSE: To define the risk of seizure recurrence (RSR) that families and
      physicians would accept before discontinuing antiepileptic drugs (AEDs) for
      children with controlled epilepsy. METHODS: A questionnaire was completed by
      families of 76 children with epilepsy > or = 3 months seizure-free and by their
      attending epilepsy specialist (n = 4). RESULTS: Forty-two percent of families
      were unwilling to discontinue AEDs with an RSR of 25%. In contrast, 20% were
      willing to accept a > 75% RSR. Several factors differentiated the risk acceptable
      to families: previous seizure frequency (risk adverse with intermediate
      frequency), multiple seizure types (risk taking), grade or grades repeated in
      school (risk adverse), and the family's strategy of playing lotteries. Although
      families and physicians were prepared to accept similar median RSR (35 and 40%,
      respectively), individual answers did not correlate (r2 = -0.07). Physicians were
      unable to predict the families response (r2 = 0.09). CONCLUSIONS: Our current
      practice is to discontinue AEDs after 2 years of seizure-free results in seizure
      recurrence of 30-40%. This risk may seem excessive to more than half of families,
      whereas other families will risk stopping AEDs at higher risks of recurrence.
      Physicians are poor judges of the degree of risk that is acceptable to a
      particular family, which may account in part for the anxiety manifested by
      families at AED discontinuation.

PMID- 8641234
TI  - The National Hospital Seizure Severity Scale: a further development of the
      Chalfont Seizure Severity Scale.
AB  - Seizure severity scales have recently been identified as an important additional
      outcome measure in trials of new antiepileptic drugs (AEDs). The National
      Hospital Seizure Severity Scale (NHS3) is presented as a refined version of the
      Chalfont Seizure Severity Scale. The principal advantages of the new version are
      that it is quicker and simpler to apply, the limits of reliability are now
      clearly defined, and construct validity for the scale is available. The scale is
      administered by a health professional during an interview with a patient and a
      witness to the seizures. It contains seven seizure-related factors and generates
      a score from 1 to 27. An intraclass correlation coefficient of 0.90 was obtained
      during interobserver and test-retest reliability assessment, suggesting that the
      scale is sufficiently reliable for group studies. Scores for an individual
      patient should be interpreted with caution in light of the limits of agreement
      obtained. Validation experiments indicate that NHS3 measures seizure severity in
      a manner compatible with the subjective impression of people with epilepsy. We
      suggest that the NHS3 is a valid, easily applicable measure of seizure severity
      that is acceptably reliable for use in trials of novel AEDs.

PMID- 8641235
TI  - Objective measure of treatment outcome in epilepsy.
AB  - Treatment outcome in epilepsy is too often a vague, ill-defined subjective
      measure. Based on a proposal of Shoffer and Temkin (1987) of "time to kth
      seizure" as a measure of seizure frequency, we devised the formula: % improvement
      = 100 - [time to X seizure (i*) x 100]/ [time to X seizure (f*)]. This formula
      provides an objective measure of treatment outcome and should prove useful in
      clinical settings and research. We offer examples of practical applications of
      the formula.

PMID- 8641236
TI  - A brief questionnaire to screen for quality of life in epilepsy: the QOLIE-10.
AB  - PURPOSE: To evaluate a brief questionnaire to screen aspects of health-related
      quality of life for persons with epilepsy. METHODS: A study of 304 adults with
      epilepsy was undertaken at 25 seizure clinics in the United States. It was used
      for derivation of a brief screening tool from a longer instrument (QOLIE-89).
      RESULTS: The 10-item questionnaire (QOLIE-10) covers general and epilepsy
      specific domains, grouped into three factors: Epilepsy Effects (memory, physical
      effects, and mental effects of medication), Mental Health (energy, depression,
      overall quality of life), and Role Functioning (seizure worry, work, driving,
      social limits). Scale scores were significantly different among seizure groups (p
      = 0.003). CONCLUSIONS: The QOLIE-10 can be completed by a patient in several
      minutes and reviewed rapidly by the physician. This screening tool could provide
      potentially useful information for initial assessment or follow-up of problem
      areas that are not commonly evaluated during routine clinical visits with
      patients with epilepsy.

PMID- 8641237
TI  - Chronic malnutrition caused by a corn-based diet lowers the threshold for
      pentylenetetrazol-induced seizures in rats.
AB  - The incidence of epilepsy is high in developing countries where malnutrition is
      prevalent. Although malnutrition is not a direct cause of seizures, chronic
      malnutrition may predispose the brain to seizures. In large undernourished human
      groups from Latin America, the most common sources of food are corn and corn
      derivatives. We used a rat model of chronic malnutrition, in which corn tortillas
      were the only solid food intake, to study the possible influence of malnutrition
      at late stages of brain development on the dynamics of experimental seizures
      induced by pentylenetetrazole (PTZ). The threshold and does of PTZ required to
      produce seizures were greatly reduced in malnourished rats. The model of
      malnutrition used in the study imitates a form of malnutrition common among large
      numbers of humans. Our results suggest that chronic malnutrition early in life
      induces changes that lower the seizure threshold and leave the brain more
      susceptible to seizures. Whether this observation relates to the high incidence
      of epilepsy in underdeveloped countries remains to be determined.

PMID- 8641238
TI  - Valproate-induced systemic lupus erythematosus in a patient with partial trisomy
      of chromosome 9 and epilepsy.
AB  - We report a mentally retarded 30-year-old woman with partial trisomy of
      chromosome 9 (46, XX-6, +der(6)t(6,9)pat) who has had epilepsy since age 11
      months. She had been treated with various combinations of drugs. After 1 year of
      treatment with valproate (VPA) and ethosuximide (ESM), the patient developed
      arthralgias, muscle weakness, fatigue, and fever. Laboratory examination showed
      increased sedimentation rate, hypergammaglobulinemia, and high titers of
      antinuclear antibodies (ANA). The possibility of VPA-induced systemic lupus
      erythematosus (SLE) was considered. This diagnosis was supported by detection of
      antihistone antibodies and the HLA-DR4 antigen. VPA dosage was tapered and
      discontinued, with accompanying resolution of clinical, immunological and
      hematological signs of SLE 6 weeks after VPA discontinuation. This is the fourth
      reported case of VPA-induced SLE.

PMID- 8641239
TI  - Case of catatonic mimicking nonconvulsive status epilepticus (NCSE)

PMID- 8641240
TI  - The epidemiology and treatment of chronic and refractory epilepsy.
AB  - In developed countries, the incidence of epilepsy is 50-100 cases per 100,000
      population per year and the prevalence is approximately 5 to 8 cases per 1,000
      population. Epilepsy is by far the most prevalent serious neurologic condition.
      Mortality rates in epilepsy are two to four times those found in matched
      nonepileptic populations. The prognosis of epilepsy can be classified into at
      least four categories, with chronic and refractory cases comprising about 40% of
      all cases. A detailed approach to the management of chronic epilepsy cases is
      recommended. Approximately 20% of patients cannot achieve seizure control with
      existing agents and new antiepileptic drugs are required for these patients.

PMID- 8641241
TI  - Drug interaction profile of topiramate.
AB  - In separate studies, potential pharmacokinetic interactions of topiramate (TPM)
      with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated.
      TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800
      mg/day, after which the baseline drug was discontinued, when possible. Addition
      of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest
      increases in PHT plasma levels in six of 12 patients treated with PHT and TPM,
      and a small mean decrease in VPA levels noted in patients receiving VPA with TPM,
      were considered unlikely to require adjustments in the dosage of the concomitant
      AED when TPM is added or discontinued. When patients were changed from
      concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced
      by approximately 50%, suggesting that an adjustment in TPM dose may be required
      when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in
      plasma TPM levels during monotherapy compared to concomitant therapy with VPA was
      considered clinically insignificant and not likely to require TPM dosage
      adjustment. In another study, oral clearance of digoxin was slightly increased
      when TPM was added, resulting in a small decrease in peak plasma levels of
      digoxin. In vitro studies conducted to date on a number of specific cytochrome
      P450 isoforms show an effect of TPM only on the CYP2Cmeph isoform. The risk for
      clinically meaningful changes in plasma levels of traditional AEDs when TPM is
      added to or discontinued from concomitant regimens appears to be minimal.
      However, adjustments in TPM dosages are likely to be needed when potent enzyme
      inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low
      propensity for clinically significant drug interactions, and its pharmacokinetic
      and drug interaction profiles represent a clear advance over those of the
      traditional AEDs.

PMID- 8641242
TI  - Safety of topiramate: adverse events and relationships to dosing.
AB  - To date, 1,809 individuals have been exposed to topiramate (TPM), primarily
      adults with partial-onset seizures. Of this total, 665 patients have been treated
      for more than 1 year, 177 for more than 3 years, and 67 for more than 5 years.
      The profile of treatment-emergent adverse reactions (TEAEs) observed with TPM at
      various dosages is based primarily on data from five double-blind, placebo
      controlled trials in which 360 patients received TPM at target doses of 200-1,000
      mg/day. Long-term safety is assessed on the basis of 1,001 patients treated with
      TPM in controlled and open trials for up to 5.3 years. Most of the commonly
      reported TEAEs were related to the central nervous system and were observed with
      greater frequency at dosages above the 200-600-mg/day range found to be optimal
      in dose ranging trials. Nephrolithiasis not requiring surgery was seen in 1.5% of
      patients, and mild, dose-related weight loss was associated with TPM therapy. No
      clinically significant treatment-related abnormalities were observed in clinical
      laboratory parameters or in neurologic, electrocardiographic, ophthalmologic, or
      audiologic tests.

PMID- 8641243
TI  - Clinical efficacy of new antiepileptic drugs in refractory partial epilepsy:
      experience in the United States with three novel drugs.
AB  - A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate
      (FBM), and gabapentin (GBP), are approved or believed to be close to approval for
      marketing in the United States. Key efficacy findings for these AEDs in
      refractory partial epilepsy were reviewed. Large and significant drug-placebo
      differences were observed with TPM in two large dose-finding trials conducted in
      the United States. The minimal effective dose of TPM in the population studied
      was determined to be approximately 200 mg/day, and doses above 600 mg/day
      produced good efficacy but little incremental benefit versus the lower dosages
      for the overall study population. FBM is active in partial epilepsy, although
      seizure reduction is less marked and drug interactions complicate the findings.
      GBP is also active in this population, but only the 1,800 mg/day dosage was
      significantly better than placebo with respect to percent responders. It may be
      useful to explore higher dosage ranges for both FBM and GBP if they can be well
      tolerated.

PMID- 8641244
TI  - Expanding antiepileptic drug options: clinical efficacy of new therapeutic
      agents.
AB  - Results of double-blind, placebo-controlled, add-on trials of topiramate (TPM),
      lamotrigine (LTG), and vigabatrin (VGB) in refractory partial epilepsy were
      reviewed. In three European multicenter studies of TPM, the clinical efficacy of
      400-, 600-, and 800-mg/day target dosages was demonstrated. In a similarly
      designed United States trial, LTG was significantly superior to placebo at a 500
      mg/day dosage but not at a 300-mg/day dosage. A meta-analysis of a number of
      smaller trials of VGB suggests that a > or = 50% reduction in seizures is
      observed in approximately 45% of patients with refractory partial epilepsy. All
      of these newer antiepileptic drugs have shown efficacy in well-controlled trials
      and should contribute significantly to our ability to manage partial epilepsy.

PMID- 8641246
TI  - The changing selenium status of New Zealand residents.
AB  - OBJECTIVE: The aim of this paper was to compile all the studies of selenium
      status carried out in Otago and in other areas of New Zealand in order to follow
      the history of selenium status in New Zealand residents over the last 20 years.
      DESIGN: Since 1970 baseline blood samples have been collected from several groups
      of healthy adult subjects, either for the assessment of Se status or to determine
      baseline Se levels as part of a number of other studies. A comparison has been
      made of selenium concentrations recorded in recent published and unpublished
      studies with earlier studies by the Otago research group, and also those by other
      groups in New Zealand. SETTING: Otago and other New Zealand centres. RESULTS:
      Blood selenium concentrations of Otago residents were consistently low from 1972
      until 1988 at around 0.77 mumol/l, apart from a temporary increase in 1985, and
      then rose to reach 1.03 mumol/l in 1991 and 1.19 mumol/l in 1992-3. Blood
      selenium status reflected changes in the importation of Australian wheat.
      Correlations between selenium and glutathione peroxidase in whole blood and
      plasma were consistently high prior to 1989, but were no longer significant from
      1990. CONCLUSIONS: The lack of a correlation between selenium and glutathione
      peroxidase in bloods collected after 1990 indicates that at least for glutathione
      peroxidase, the selenium intake of New Zealanders is now close to that required
      for saturation. Whether this is sufficient to meet the requirements for other
      functional selenoproteins or for a possible cancer prevention effect remains to
      be determined.

PMID- 8641245
TI  - Pharmacokinetic profile of topiramate in comparison with other new antiepileptic
      drugs.
AB  - Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic
      liabilities, including a propensity for clinically meaningful drug interactions.
      Therefore, new AEDs with improved pharmacokinetic characteristics would be
      welcomed. The pharmacokinetic profiles of six newer AEDs--topiramate (TPM),
      gabapentin (GBP), vigabatrin (VGB), lamotrigine (LTG), oxcarbazepine (OCBZ), and
      felbamate--were reviewed. Some of these AEDs offer an improvement in one or more
      pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB,
      and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.

PMID- 8641248
TI  - Vitamin A and vaccines, the importance of side-effects.

PMID- 8641247
TI  - Plasma ascorbic acid concentrations in the Republic of Karelia, Russia and in
      North Karelia, Finland.
AB  - OBJECTIVES: To determine the plasma ascorbic acid concentrations among men in
      North Karelia (Finland) and in Pitkaranta (Republic of Karelia) and to test how a
      short intervention would affect the plasma concentrations. DESIGN: The baseline
      survey was done as a cross-sectional population survey. A subsample was selected
      to the intervention study and randomised to treatment and control groups.
      SETTING: North Karelia province in Finland and the Pitkaranta area in the
      Republic of Karelia. SUBJECTS: In the cross-section population survey the
      stratified random sample of men between 25 and 64 years of age was 1000 in North
      Karelia and 500 in Pitkaranta. Participation rates were 68% and 77%,
      respectively. Plasma ascorbic acid measurements were made in one-third of the
      sample. In Pitkaranta 60 men, having very low plasma ascorbic acid
      concentrations, were invited to the intervention study. INTERVENTIONS: A
      controlled intervention study was made with blackcurrant-strawberry nectar in
      which vitamin C content was approximately 70 mg/100 g. The treatment group drank
      two times daily 200 ml nectar for 4-5 weeks. After intervention plasma ascorbic
      acid concentration was measured from both treatment and control groups. RESULTS:
      Plasma ascorbic acid concentrations were very different in the two areas. In
      Pitkaranta 93% of the men and in North Karelia only 2% of the men had plasma
      levels suggesting severe vitamin C deficiency. After intervention 46% of the men
      in the experimental group compared with 5% in the control group had plasma
      ascorbic acid concentrations exceeding 23 mumol/l (4.0 mg/l). CONCLUSIONS: In
      addition to a high smoking prevalence the very low ascorbic acid concentration
      among men in the Republic Karelia can have an effect on the high cardiovascular
      disease mortality.

PMID- 8641249
TI  - Potential health effects of the dietary flavonol quercetin.

PMID- 8641250
TI  - Human energy expenditure in affluent societies: an analysis of 574 doubly
      labelled water measurements.
AB  - OBJECTIVES: To describe average levels of free-living energy expenditure in
      people from affluent societies and to determine the influence of body weight,
      height, age and sex. DESIGN: Analysis of 574 measurements of total energy
      expenditure (TEE, assessed by the doubly-labelled water method); basal metabolic
      rate (BMR, directly measured or derived from similar directly measured proxy
      measures such as during sleep); activity energy expenditure (AEE, derived as TEE
      BMR); and physical activity level (PAL, derived as TEE/BMR) from people aged 2-95
      years. The dataset was extracted from 1614 published and unpublished measurements
      in 1156 subjects after exclusion of repeat estimates and subjects in special
      physiological or behavioural states (eg pregnancy, athletic or military training
      etc). RESULTS: A separate analysis of data from non-ambulant subjects, and from
      elite endurance athletes (all excluded from the main dataset) established the
      limits of human daily energy expenditure at around 1.2 x BMR and 4.5 x BMR. In
      the main analysis, the validity of PAL as an index of TEE adjusted for BMR was
      tested and confirmed. Regression equations were then derived to describe TEE,
      BMR, AEE and PAL in terms of body weight, height, age and sex. As anticipated,
      TEE, BMR and AEE were all positively related to weight and height, while age was
      a negative predictor, especially of activity. The influence of weight disappeared
      when TEE was expressed as PAL, but height and age remained as highly significant
      predictors. For all three components, females expended 11% less energy on average
      than males after adjustment for weight, height and age. Average levels of energy
      expenditure in different age and sex groups are tabulated. CONCLUSIONS: There now
      exists a large and robust database of energy expenditure measurements obtained by
      the doubly-labelled water method. Analysis of the data from affluent societies
      shows that, in general, levels of energy expenditure are similar to the
      recommendations for energy requirements adopted by FAO/WHO/UNU (1985) and UK
      Department of Health (1991). PAL values for active subjects tend to be higher
      than is currently assumed. The current analysis provides a substantial body of
      normal data against which other estimates can be compared.

PMID- 8641251
TI  - Energy expenditure in overweight and obese adults in affluent societies: an
      analysis of 319 doubly-labelled water measurements.
AB  - OBJECTIVES: To describe the relationship between graded levels of obesity and
      free-living energy expenditure in men and women in affluent societies. DESIGN:
      Analysis of 319 measurements of energy expenditure in adults aged 18-64 years.
      The variables analysed were: total energy expenditure (TEE, assessed by the
      doubly-labelled water method); measured basal metabolic rate (BMR); activity
      energy expenditure (AEE, derived as TEE-BMR); and physical activity level (PAL,
      derived as TEE/BMR). Results were analysed according to four categories of body
      mass index (BMI): < 25.0, 25.0-29.9, 30.0-35.0 and > 35.0 kg/m2. RESULTS: TEE
      increased steadily with increasing BMI (9.5 to 13.5 MJ/d in women, 12.9 to 17.5
      MJ/d in men, ANOVA, P < 0.0001 for both sexes). BMR also increased (5.7 to 8.2
      MJ/d in women, 7.2 to 11.6 MJ/d in men, P < 0.0001 for both). AEE increased
      steadily in women (3.8 to 5.3 MJ/d, P < 0.0003), but in men increased up to the
      third BMI category (5.7 to 7.5 MJ/d, n.s.) and then declined in the most obese
      group (5.9 MJ/d, n.s.). The increases in energy expenditure were not in direct
      proportion to body weight since, when expressed per kg, both TEE and AEE declined
      significantly with increasing BMI. PAL remained quite constant across the three
      lowest BMI groups, indicating similar levels of physical activity. There was a
      non-significant decrease in PAL in the most obese men and women. CONCLUSIONS:
      This analysis confirms that habitual energy expenditure is substantially and
      progressively raised in obesity. It contradicts the claim, based on self-reported
      food intake, that obesity develops and is maintained in spite of very low levels
      of energy intake. The analysis suggests that, except in massive obesity, patterns
      of physical activity are quite similar at different levels of BMI. This does not
      exclude the possibility that an inactive lifestyle may be an important general
      risk factor for the development of obesity.

PMID- 8641252
TI  - Contribution of dieting to the inverse association between energy intake and body
      mass index.
AB  - OBJECTIVE: To examine the association of energy and % energy from fat with body
      mass index (BMI) and determine if self-reported dieting altered observed
      associations. DESIGN: Dietary intake data based on dietary recalls from four
      nonconsecutive days over a 1 year period were examined relative to BMI. The
      relation between energy intake and % energy from fat and BMI was examined by
      linear regression analysis. SUBJECTS: The sample included 1854 free-living women
      aged 19-50 years who participated in the 1985-6 Continuing Surveys of Food
      Intakes by Individuals conducted by the United States Department of Agriculture.
      RESULTS: Reported energy intake was inversely associated with BMI (regression
      coefficient (beta) = -0.001 24, standard error (s.e.) = 0.000 31). Controlling
      for low energy dieting alone reduced the inverse energy intake-BMI association by
      approximately 20% (beta = -0.001 00, s.e. = 0.000 31), compared to reductions of
      16%, 13% and 10%, respectively, when health status, age and education were added
      individually to the energy intake-BMI linear regression. Physical activity,
      smoking status, % energy from fat and report of low fat dieting did not reduce
      the energy intake-BMI association. Controlling for nondietary factors related to
      BMI and potentially influencing energy intake reduced the inverse energy intake
      BMI association by approximately 22% (beta = -0.000 97, s.e. = 0.00025). Further
      adjustment for low energy dieting on day 1 reduced the inverse energy intake-BMI
      association by 40% (beta = -0.000 74, s.e. = 0.000 26), suggesting that
      intermittent energy restriction was a significant factor in the reduced energy
      intake reported among overweight women. Percent energy from fat was not
      associated with BMI (beta = 0.049, s.e. = 0.025, P = 0.055). Exclusion of 37
      women reporting poor health status further attenuated the inverse association
      between energy intake and BMI (beta = -0.000 64), s.e. = 0.000 26), while it
      strengthened the previously non-significant positive association between % energy
      from fat and BMI (beta = 0.062; s.e. = 0.024). CONCLUSION: Intermittent energy
      restriction appeared to be a significant factor in the reduced energy intake
      reported among overweight women in this sample. Adequate assessment of energy
      expenditure is required to correctly interpret the association of energy intake
      to body weight.

PMID- 8641253
TI  - Energy and protein requirements. Proceedings of an IDECG workshop. London, United
      Kingdom, 31 October-4 November 1994.

PMID- 8641254
TI  - Energy requirements of adults: an update on basal metabolic rates (BMRs) and
      physical activity levels (PALs).

PMID- 8641255
TI  - Energy requirements of older individuals.

PMID- 8641257
TI  - The requirements of adult man for indispensable amino acids.

PMID- 8641256
TI  - Protein requirements of infants and children.

PMID- 8641258
TI  - Protein requirements of elderly people.
AB  - Based on N balance calculated in accord with the recommendations of the 1985
      Joint FAO/WHO/UNU Expert Consultation, a summary of conclusions from the six N
      balance studies in elderly people is presented in Table 3. The data, with one
      flawed exception, indicate that the safe level of protein intake for older adults
      may be higher than currently recommended. In the only study directly comparing
      elderly and young subjects (Cheng et al, 1978), no differences in protein
      requirement were found. However, the data suggest that the 0.8 g protein/kg/d
      would be inadequate for both groups. Additional direct comparisons between
      younger and older adults are desirable as a basis for any revised
      recommendations. In the only study directly comparing the protein requirements of
      both elderly men and women (Uauy et al, 1978), the variability was too great to
      allow adequate assessment of possible gender differences. More research is needed
      to determine whether gender-related differences occur.

PMID- 8641259
TI  - Report of the working group on general principles of assessing energy
      requirements.

PMID- 8641260
TI  - Report on the working group on energy requirements of infants, children and
      adolescents.

PMID- 8641261
TI  - Report on the working group on energy requirements for pregnancy and lactation.

PMID- 8641262
TI  - Report on the working group on energy requirements of older individuals.

PMID- 8641263
TI  - Report of the working group on protein and amino acid requirements.

PMID- 8641264
TI  - Criteria for valid nitrogen balance measurement of protein requirements.

PMID- 8641265
TI  - Energy requirements: general principles.

PMID- 8641266
TI  - Energy requirements of infants.

PMID- 8641267
TI  - Energy requirements and dietary energy recommendations for children and
      adolescents 1 to 18 years old.

PMID- 8641268
TI  - Energy requirements of pregnant and lactating women.

PMID- 8641269
TI  - Complete nucleotide sequence of Saccharomyces cerevisiae chromosome X.
AB  - The complete nucleotide sequence of Saccharomyces cerevisiae chromosome X (745
      442 bp) reveals a total of 379 open reading frames (ORFs), the coding region
      covering approximately 75% of the entire sequence. One hundred and eighteen ORFs
      (31%) correspond to genes previously identified in S. cerevisiae. All other ORFs
      represent novel putative yeast genes, whose function will have to be determined
      experimentally. However, 57 of the latter subset (another 15% of the total)
      encode proteins that show significant analogy to proteins of known function from
      yeast or other organisms. The remaining ORFs, exhibiting no significant
      similarity to any known sequence, amount to 54% of the total. General features of
      chromosome X are also reported, with emphasis on the nucleotide frequency
      distribution in the environment of the ATG and stop codons, the possible coding
      capacity of at least some of the small ORFs (<100 codons) and the significance of
      46 non-canonical or unpaired nucleotides in the stems of some of the 24 tRNA
      genes recognized on this chromosome.

PMID- 8641270
TI  - Zonal distribution of sulfotransferase for phenol in olfactory sustentacular
      cells.
AB  - We have immunolocalized phenol sulfotransferase (PST)G, an isoform of PST in
      sustentacular cells which reside in the dorso-medial portion of the nasal cavity
      of the mouse. The same topographical pattern of gene expression has been reported
      for some olfactory neuron-specific genes. When several established (phenol
      containing) odorants were used as substrates, mouse nasal tissue cytosol showed a
      significant level of PST activity, as does mouse liver cytosol. This study is the
      first to demonstrate that gene expression in the olfactory sustentacular cells is
      also organized zonally, and indicates the involvement of sulfo-conjugation in
      olfactory perireceptor processes, such as odorant clearance and xenobiotic
      detoxification.

PMID- 8641271
TI  - Implications for the domain arrangement of axonin-1 derived from the mapping of
      its NgCAM binding site.
AB  - The neuronal cell adhesion molecule axonin-1 is composed of six immunoglobulin
      and four fibronectin type III domains. Axonin-1 promotes neurite outgrowth, when
      presented as a substratum for neurons in vitro, via a neuronal receptor that has
      been identified as the neuron-glia cell adhesion molecule, NgCAM, based on the
      blocking effect of polyclonal antibodies directed to NgCAM. Here we report the
      identification of axonin-1 domains involved in NgCAM binding. NgCAM-conjugated
      microspheres were tested for binding to COS cells expressing domain deletion
      mutants of axonin-1. In addition, monoclonal antibodies directed to axonin-1 were
      assessed for their ability to block the axonin-1-NgCAM interaction, and their
      epitopes were mapped using the domain deletion mutants. The results suggest that
      the four amino-terminal immunoglobulin domains of axonin-1 form a domain
      conglomerate which is necessary and sufficient for NgCAM binding. Surprisingly,
      NgCAM binding to membrane-bound axonin-1 was increased strongly by deletion of
      the fifth or sixth immunoglobulin domains of axonin-1. Based on these results and
      on negative staining electron microscopy, we propose a horseshoe-shaped domain
      arrangement of axonin-1 that obscures the NgCAM binding site. Neurite outgrowth
      studies with truncated forms of axonin-1 show that axonin-1 is a neurite
      outgrowth-promoting substratum in the absence of the NgCAM binding site.

PMID- 8641272
TI  - Degradation of subunits of the Sec61p complex, an integral component of the ER
      membrane, by the ubiquitin-proteasome pathway.
AB  - We have investigated the degradation of subunits of the trimeric Sec61p complex,
      a key component of the protein translocation apparatus of the ER membrane. A
      mutant form of Sec6lp and one of the two associated proteins (Sss1p) are
      selectively degraded, while the third constituent of the complex (Sbh1p) is
      stable. Our results demonstrate that the proteolysis of the multispanning
      membrane protein Sec61p is mediated by the ubiquitin-proteasome pathway, since it
      requires polyubiquitination, the presence of a membrane-bound (Ubc6) and a
      soluble (Ubc7) ubiquitin-conjugating enzyme and a functional proteasome. The
      process is proposed to be specific for unassembled Sec61p and Sss1p. Thus, our
      results suggest that one pathway of ER degradation of abnormal or unassembled
      membrane proteins is initiated at the cytoplasmic side of the ER.

PMID- 8641273
TI  - Formation of reversible disulfide bonds with the protein matrix of the
      endoplasmic reticulum correlates with the retention of unassembled Ig light
      chains.
AB  - Exposed thiols act as intracellular retention elements for unassembled secretory
      molecules. Yet, some free Ig lambda light chains are secreted despite the
      presence of an unpaired cysteine (Cys214). This is due largely to the presence of
      a flanking acidic residue: substitution of Asp213 for Gly or Lys increases pre
      Golgi retention and degradation of free lambda. Secretion is restored by
      exogenous reducing agents or by assembly with heavy chains. In the endoplasmic
      reticulum (ER), lambda chains form covalent complexes with many proteins through
      Cys214. These complexes are absent from the Golgi. They are more abundant in
      transfectants expressing the lambdaGly2I3 and lambdaLys213 mutants that are
      poorly secreted. Radioactive N-ethylmaleimide labels some monomeric lambda chains
      isolated from the ER, but not from the Golgi or from the medium, indicating that
      the Cys214 thiol is masked during ER-Golgi transport. Mass spectrometry reveals
      the presence of a free cysteine residue disulfide-linked to Cys214. We suggest
      that thiol-mediated retention involves the formation of reversible disulfide
      bonds with the protein matrix of the ER. The presence of an acidic residue next
      to the critical cysteine may allow the masking of the thiol and transport to the
      Golgi.

PMID- 8641274
TI  - Regulation of inositol trisphosphate receptors by luminal Ca2+ contributes to
      quantal Ca2+ mobilization.
AB  - The quantal behaviour of inositol trisphosphate (InsP3) receptors allows rapid
      graded release of Ca2+ from intracellular stores, but the mechanisms are unknown.
      In Ca2+-depleted stores loaded with Fura 2, InsP3 caused concentration dependent
      increases in the rates of fluorescence quench by Mn2+ that were unaffected by
      prior incubation with InsP3, indicating that InsP3 binding did not cause
      desensitization. When Fura 2 was used to report the luminal free [Ca2+] after
      inhibition of further Ca2+ uptake, submaximal concentrations of InsP3 caused
      rapid, partial decreases in fluorescence ratios. Subsequent addition of a maximal
      InsP3 concentration caused the fluorescence to fall to within 5% of that recorded
      after ionomycin. Addition of all but the lowest concentrations of InsP3 to stores
      loaded with the lower affinity indicator, Calcium Green-5N, caused almost
      complete emptying of the stores at rates that increased with InsP3 concentration.
      The lowest concentration of InsP3 (10 nM) slowly emptied approximately 80% of the
      stores, but within 3 min the rate of Ca2+ release slowed leaving approximately 7
      microM Ca2+ within the stores, which was then rapidly released by a maximal InsP3
      concentration. In stores co-loaded with both indicators, InsP3-evoked Ca2+
      release appeared quantal with Fura 2 and largely non-quantal with Calcium Green
      5N; the discrepancy is not, therefore, a direct effect of the indicators. The
      fall in luminal [Ca2+] after activation of InsP3 receptors may, therefore, cause
      their inactivation, but only after the Ca2+ content of the stores has fallen by
      approximately 95% to < or = 10 microM.

PMID- 8641275
TI  - Chromaffin granule-associated phosphatidylinositol 4-kinase activity is required
      for stimulated secretion.
AB  - Permeabilized bovine adrenal chromaffin cells have been used to characterize the
      MgATP requirement of processes preceding exocytosis. Incubation of primary
      cultures with the membrane-permeable phenylarsine oxide (PAO) at 20 microM
      inhibited the phosphorylation of phosphatidylinositol (PtdIns) and completely
      blocked secretion. This block could be reversed by addition of 2,3
      dimercaptopropanol to the permeabilized cells. Simultaneous addition of
      [gamma32P]ATP and 2,3-dimercaptopropanol permitted a comparison between recovery
      of secretion and phosphorylation of intracellular components. Recovery of
      secretion closely correlated with phosphorylation of PtdIns and PtdIns4P.
      Subcellular fractionation of permeabilized cells after recovery of secretion
      revealed that the majority of newly phosphorylated PtdIns4P was localized on the
      chromaffin granules. In accordance with these results, PtdIns 4-kinase activity
      was found in protein extracts of permeabilized cells as well as associated with
      purified chromaffin granules, sensitive in both cases to PAO. Additionally,
      PtdIns 4-kinase activity in these two assays was inhibited by quercetin. In
      permeabilized cells, quercetin decreased the levels of labeled PtdIns4P and
      Ptdlns(4,5)P2 and inhibited secretion. Our data suggest that a chromaffin granule
      associated PtdIns 4-kinase acts in the priming of exocytosis.

PMID- 8641276
TI  - ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of
      neurosecretory granules.
AB  - Islet cell autoantigen (ICA) 512 is a novel autoantigen of insulin-dependent
      diabetes mellitus (IDDM) which is homologous to receptor-type protein tyrosine
      phosphatases (++PTPases). We show that ICA 512 is an intrinsic membrane protein
      of secretory granules expressed in insulin-producing pancreatic beta-cells as
      well as in virtually all other peptide-secreting endocrine cells and neurons
      containing neurosecretory granules. ICA 512 is cleaved at its luminal domain and,
      following exposure at the cell surface, recycles to the Golgi complex region and
      is sorted into newly formed secretory granules. By immunoprecipitation, anti-ICA
      512 autoantibodies were detected in 15/17 (88%) newly diagnosed IDDM patients,
      but not in 10/10 healthy subjects. These results suggest that tyrosine
      phosphorylation participates in some aspect of secretory granule function common
      to all neuroendocrine cells and that a subset of autoantibodies in IDDM is
      directed against an integral membrane protein of insulin-containing granules.

PMID- 8641277
TI  - A mutation in protein phosphatase 2A regulatory subunit A affects auxin transport
      in Arabidopsis.
AB  - The phytohormone auxin controls processes such as cell elongation, root hair
      development and root branching. Tropisms, growth curvatures triggered by gravity,
      light and touch, are also auxin-mediated responses. Auxin is synthesized in the
      shoot apex and transported through the stem, but the molecular mechanism of auxin
      transport is not well understood. Naphthylphthalamic acid (NPA) and other
      inhibitors of auxin transport block tropic curvature responses and inhibit root
      and shoot elongation. We have isolated a novel Arabidopsis thaliana mutant
      designated roots curl in NPA (rcn1). Mutant seedlings exhibit altered responses
      to NPA in root curling and hypocotyl elongation. Auxin efflux in mutant seedlings
      displays increased sensitivity to NPA. The rcn1 mutation was transferred-DNA (T
      DNA) tagged and sequences flanking the T-DNA insert were cloned. Analysis of the
      RCN1 cDNA reveals that the T-DNA insertion disrupts a gene for the regulatory A
      subunit of protein phosphatase 2A (PP2A-A). The RCN1 gene rescues the rcn1 mutant
      phenotype and also complements the temperature-sensitive phenotype of the
      Saccharomyces cerevisiae PP2A-A mutation, tpd3-1. These data implicate protein
      phosphatase 2A in the regulation of auxin transport in Arabidopsis.

PMID- 8641278
TI  - Tom7 modulates the dynamics of the mitochondrial outer membrane translocase and
      plays a pathway-related role in protein import.
AB  - The preprotein translocase of the outer mitochondrial membrane is a multi-subunit
      complex with receptors and a general import pore. We report the molecular
      identification of Tom7, a small subunit of the translocase that behaves as an
      integral membrane protein. The deletion of TOM7 inhibited the mitochondrial
      import of the outer membrane protein porin, whereas the import of preproteins
      destined for the mitochondrial interior was impaired only slightly. However,
      protein import into the mitochondrial interior was strongly inhibited when it
      occurred in two steps: preprotein accumulation at the outer membrane in the
      absence of a membrane potential and subsequent further import after the re
      establishment of a membrane potential. The delay of protein import into tom7delta
      mitochondria seemed to occur after the binding of preproteins to the outer
      membrane receptor sites. A lack of Tom7 stabilized the interaction between the
      receptors Tom20 and Tom22 and the import pore component Tom40. This indicated
      that Tom7 exerts a destabilizing effect on part of the outer membrane
      translocase, whereas Tom6 stabilizes the interaction between the receptors and
      the import pore. Synthetic growth defects of the double mutants tom7delta
      tom20delta and tom7delta tom6delta provided genetic evidence for the functional
      relationship of Tom7 with Tom20 and Tom6. These results suggest that (i) Tom7
      plays a role in sorting and accumulation of the preproteins at the outer
      membrane, and (ii) Tom7 and Tom6 perform complementary functions in modulating
      the dynamics of the outer membrane translocase.

PMID- 8641279
TI  - Transfer of rps19 to the nucleus involves the gain of an RNP-binding motif which
      may functionally replace RPS13 in Arabidopsis mitochondria.
AB  - The discovery of disrupted rps19 genes in Arabidopsis mitochondria prompted
      speculation about the transfer to the nuclear compartment. We here describe the
      functional gene transfer of rps19 into the nucleus of Arabidopsis. Molecular
      cloning and sequence analysis of rps19 show that the nuclear gene encodes a long
      N-terminal extension. Import studies of the precursor protein indicate that only
      a small part of this extension is cleaved off during import. The larger part of
      the extension, which shows high similarity to conserved RNA-binding domains of
      the RNP-CS type, became part of the S19 protein. In the Escherichia coli ribosome
      S19 forms an RNA-binding complex as heterodimer with S13. By using immuno
      analysis and import studies we show that a eubacterial-like S13 protein is absent
      from Arabidopsis mitochondria, and is not substituted by either a chloroplastic
      or a cytosolic homologue of this ribosomal protein. We therefore propose that
      either a highly diverged or missing RPS13 has been functionally replaced by an
      RNP domain that most likely derived from a glycine-rich RNA-binding protein.
      These results represent the first case of a functional replacement of a ribosomal
      protein by a common RNA-binding domain and offer a new view on the flexibility of
      biological systems in using well-adapted functional domains for different jobs.

PMID- 8641280
TI  - Sac1, a putative regulator that is critical for survival of Chlamydomonas
      reinhardtii during sulfur deprivation.
AB  - The sac1 mutant of Chlamydomonas reinhardtii is aberrant in most of the normal
      responses to sulfur limitation; it cannot synthesize arylsulfatase, does not take
      up sulfate as rapidly as wild-type cells, and does not synthesize periplasmic
      proteins that normally accumulate during sulfur-limited growth. Here, we show
      that the sac1 mutant dies much more rapidly than wild-type cells during sulfur
      deprivation; this emphasizes the vital role of the acclimation process. The loss
      of viability of the sac1 mutant during sulfur deprivation is only observed in the
      light and is mostly inhibited by DCMU. During sulfur-stress, wild-type cells, but
      not the sac1 mutant, downregulate photosynthesis. Thus, death of the sac1 mutant
      during sulfur deprivation is probably a consequence of its inability to
      downregulate photosynthesis. Furthermore, since SAC1 is necessary for the
      downregulation of photosynthesis, the process must be highly controlled and not
      simply the result of a general decrease in protein synthesis due to sulfur
      limitation. Genomic and cDNA copies of the SAC1 gene have been cloned. The
      deduced amino acid sequence of Sac1 is similar to an Escherichia coli gene that
      may involved in the response of E.coli to nutrient deprivation.

PMID- 8641281
TI  - Characterization of a redox active cross-linked complex between cyanobacterial
      photosystem I and soluble ferredoxin.
AB  - A covalent stoichiometric complex between photosystem I (PSI) and ferredoxin from
      the cyanobacterium Synechocystis sp. PCC 6803 was generated by chemical cross
      linking. The photoreduction of ferredoxin, studied by laser flash absorption
      spectroscopy between 460 and 600 nm, is a fast process in 60% of the covalent
      complexes, which exhibit spectral and kinetic properties very similar to those
      observed with the free partners. Two major phases with t(1/2) <1 micros and
      approximately 10-14 micros are observed at two different pH values (5.8 and 8.0).
      The remaining complexes do not undergo fast ferredoxin reduction and 20-25% of
      the complexes are still able to reduce free ferredoxin or flavodoxin efficiently,
      thus indicating that ferredoxin is not bound properly in this proportion of
      covalent complexes. The docking site of ferredoxin on PSI was determined by
      electron microscopy in combination with image analysis. Ferredoxin binds to the
      cytoplasmic side of PSI, with its mass center 77 angstroms distant from the
      center of the trimer and in close contact with a ridge formed by the subunits
      PsaC, PsaD and PsaE. This docking site corresponds to a close proximity between
      the [2Fe- 2S] center of ferredoxin and the terminal [4Fe-4S] acceptor FII of PSI
      and is very similar in position to the docking site of flavodoxin, an alternative
      electron acceptor of PSI.

PMID- 8641282
TI  - Dependence of Mos-induced Cdc2 activation on MAP kinase function in a cell-free
      system.
AB  - The progression of G2-arrested Xenopus laevis oocytes into meiotic M-phase is
      accompanied by the nearly simultaneous activation of p42 MAP kinase and
      Cdc2/cyclin B. This timing raises the possibility that the activation of one
      kinase might depend upon the other. Here we have examined whether Cdc2 activation
      requires p42 MAP kinase function. We have reconstituted Mos-induced Cdc2
      activation in cell-free Xenopus oocyte extracts, and have found that Mos-induced
      Cdc2 activation requires active p42 MAP kinase, is inhibited by a MAP kinase
      phosphatase and is independent of protein synthesis. These findings indicate that
      p42 MAP kinase is an essential component of the M phase trigger in this system.

PMID- 8641283
TI  - Activation of the unliganded estrogen receptor by EGF involves the MAP kinase
      pathway and direct phosphorylation.
AB  - The estrogen receptor (ER) can be activated as a transcription factor either by
      binding of cognate estrogenic ligand or, indirectly, by a variety of other
      extracellular signals. As a first step towards elucidating the mechanism of
      'steroid-independent activation' of the ER by the epidermal growth factor (EGF),
      we have mapped the ER target domain and determined the signaling pathway. We show
      that the N-terminal transcriptional activation function AF-1, but not the C
      terminal AF-2, is necessary for the EGF response. Both the EGF-induced
      hyperphosphorylation and the transcriptional activation of the unliganded ER
      depend on a phosphorylatable serine residue at position 118. However, its
      phosphorylation is not sufficient and, hence, there must be other target domains
      or proteins which fulfill an additional requirement for EGF signaling through the
      ER. Using dominant-negative Ras and MAP kinase kinase (MAPK kinase) and
      constitutively active MAPK kinase mutants, we show that EGF activates the ER by
      signaling through the MAPK pathway suggesting that MAPK directly phosphorylates
      the critical serine 118. Our results also imply that the steroid-independent
      activation of a variety of ER mutants, which arise during the malignant
      progression of breast tumors, may contribute to tamoxifen resistance.

PMID- 8641284
TI  - Cooperation at a distance between silencers and proto-silencers at the yeast HML
      locus.
AB  - Transcriptional repression at the silent yeast mating type loci is achieved
      through the formation of a particular nucleoprotein complex at specific cis
      acting elements called silencers. This complex in turn appears to initiate the
      spreading of a histone binding protein complex into the surrounding chromatin,
      which restricts accessibility of the region to the transcription machinery. We
      have investigated long-range, cooperative effects between silencers by studying
      the repression of a reporter gene integrated at the HML locus flanked by various
      combinations of wild-type and mutated silencer sequences. Two silencers can
      cooperate over >4000 bp to repress transcription efficiently. More importantly, a
      single binding site for either the repressor activator protein 1 (Rap1), the
      autonomous replicating sequence (ARS) binding factor 1 (Abf1) or the origin
      recognition complex (ORC) can enhance the action of a distant silencer without
      acting as a silencer on its own. Functional cooperativity is demonstrated using a
      quantitative assay for repression, and varies with the affinity of the binding
      sites used. Since the repression mechanism is Sir dependent, the Rap1, ORC and/or
      Abf1 proteins bound to distant DNA elements may interact to create an interface
      of sufficiently high affinity such that Sir-containing complexes bind, nucleating
      the silent chromatin state.

PMID- 8641285
TI  - Rom1p and Rom2p are GDP/GTP exchange proteins (GEPs) for the Rho1p small GTP
      binding protein in Saccharomyces cerevisiae.
AB  - The RHO1 gene encodes a homolog of the mammalian RhoA small GTP binding protein
      in the yeast Saccharomyces cerevisiae. Rho1p is localized at the growth site and
      is required for bud formation. Multicopy suppressors of a temperature-sensitive,
      dominant negative mutant allele of RHO1, RHO1(G22S, D125N), were isolated and
      named ROM (RHO1 multicopy suppressor). Rom1p and Rom2p were found to contain a DH
      (Dbl homologous) domain and a PH (pleckstrin homologous) domain, both of which
      are conserved among the GDP/GTP exchange proteins (GEPs) for the Rho family small
      GTP binding proteins. Disruption of ROM2 resulted in a temperature-sensitive
      growth phenotype, whereas disruption of both ROM1 and ROM2 resulted in lethality.
      The phenotypes of deltarom1deltarom2 cells were similar to those of deltarho1
      cells, including growth arrest with a small bud and cell lysis. Moreover, the
      temperature-sensitive growth phenotype of deltarom2 was suppressed by
      overexpression of RHO1 or RHO2, but not of CDC42. The glutathione-S-transferase
      (GST) fusion protein containing the DH domain of Rom2p showed the lipid-modified
      Rholp-specific GDP/GTP exchange activity which was sensitive to Rho GDP
      dissociation inhibitor. These results indicate that Rom1p and Rom2p are GEPs that
      activate Rho1p in S.cerevisiae.

PMID- 8641286
TI  - Rho-associated kinase, a novel serine/threonine kinase, as a putative target for
      small GTP binding protein Rho.
AB  - The small GTP binding protein Rho is implicated in cytoskeletal responses to
      extracellular signals such as lysophosphatidic acid to form stress fibers and
      focal contacts. Here we have purified a Rho-interacting protein with a molecular
      mass of approximately 164 kDa (p164) from bovine brain. This protein bound to
      GTPgammaS (a non-hydrolyzable GTP analog).RhoA but not to GDP.RhoA or
      GTPgammaS.RhoA with a mutation in the effector domain (RhoAA37).p164 had a kinase
      activity which was specifically stimulated by GTPgammaS.RhoA. We obtained the
      cDNA encoding p164 on the basis of its partial amino acid sequences and named it
      Rho-associated kinase (Rho-kinase). Rho-kinase has a catalytic domain in the N
      terminal portion, a coiled coil domain in the middle portion and a zinc finger
      like motif in the C-terminal portion. The catalytic domain shares 72% sequence
      homology with that of myotonic dystrophy kinase and the coiled coil domain
      contains a Rho-interacting interface. When COS7 cells were cotransfected with Rho
      kinase and activated RhoA, some Rho-kinase was recruited to membranes. Thus it is
      likely that Rho-kinase is a putative target serine/threonine kinase for Rho and
      serves as a mediator of the Rho-dependent signaling pathway.

PMID- 8641287
TI  - RNA polymerase I associated factor 53 binds to the nucleolar transcription factor
      UBF and functions in specific rDNA transcription.
AB  - Mouse RNA polymerase I (Pol I) has, besides its 11 bona fide subunits, three
      polymerase associated factors, termed PAF53, 51 and 49 with respect to the size
      of each molecule. In order to analyze the function of PAFs, cDNA encoding PAF53
      was isolated using an oligonucleotide probe derived from an oligopeptide
      sequence. The cDNA of PAF53 predicts a polypeptide of 434 amino acids with a
      sequence similarity to yeast Pol 1 49 kDa subunit. Anti-PAF53 antibody does not
      block the random transcription activity of Pol I, but blocks specific
      transcription from mouse ribosomal RNA promoter, demonstrating the requirement of
      PAF53 in the accurate initiation of Pol I transcription. Moreover, PAF53
      interacted with mouse UBF in vitro, as revealed by Far-Western blotting and GST
      pull down assays. These results, together with the accumulation of PAF53 in the
      nucleolus of growing cells, suggest that PAF53 is involved in the formation of
      the initiation complex at the promoter by mediating the interaction between Pol I
      and UBF for the active rRNA synthesis.

PMID- 8641288
TI  - The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required
      for transcriptional induction through the stress response element (STRE).
AB  - The MSN2 and MSN4 genes encode homologous and functionally redundant Cys2His2
      zinc finger proteins. A disruption of both MSN2 and MSN4 genes results in a
      higher sensitivity to different stresses, including carbon source starvation,
      heat shock and severe osmotic and oxidative stresses. We show that MSN2 and MSN4
      are required for activation of several yeast genes such as CTT1, DDR2 and HSP12,
      whose induction is mediated through stress-response elements (STREs). Msn2p and
      Msn4p are important factors for the stress-induced activation of STRE dependent
      promoters and bind specifically to STRE-containing oligonucleotides. Our results
      suggest that MSN2 and MSN4 encode a DNA-binding component of the stress
      responsive system and it is likely that they act as positive transcription
      factors.

PMID- 8641289
TI  - The SV40 large T antigen and adenovirus E1a oncoproteins interact with distinct
      isoforms of the transcriptional co-activator, p300.
AB  - p300 is a nuclear phosphoprotein likely to be involved in the control of cell
      growth. Here we show that SV40 large T antigen (Tag) forms a specific complex
      with p300. In various Tag-expressing cell lines, the affinity of Tag for p300 was
      restricted to a newly identified unphosphorylated but ubiquitinated form of the
      protein. Further, Tag did not associate with p300 in an SV40 Tag-producing cell
      line (REV2) in which the original transformed phenotype (SV52) is reverted.
      Biochemical studies demonstrate that both the phosphorylation and the
      ubiquitination profile of p300 are altered in REV2 with respect to the wild-type
      fully transformed SV52 parental cells, wherein Tag-p300 complexes are readily
      detected. In contrast to Tag, the adenovirus early expression product E1a
      interacts with both phosphorylated and unphosphorylated forms of p300. In
      addition, when REV2 cells were infected with adenovirus, E1a-p300 complexes were
      detected, suggesting that the p300 expressed in REV2 has lost the affinity for
      Tag, but not for E1a. We then compared the ability of Tag and E1a to affect the
      transcription levels of the cAMP-responsive promoter (CRE), which is modulated in
      vivo by p300, in REV2 cells. We found that Tag repressed the CRE promoter in all
      of the cell lines in which Tag-p300 complexes were detected, but not in REV2
      cells. In contrast, E1a efficiently inhibited CRE-directed transcription in this
      cell line. The data thus indicate that the different specificities exhibited by
      Tag and E1a towards the various forms of p300 are reflected in vivo as a
      difference in the ability of these viral oncoproteins to modulate the expression
      of CRE-containing genes.

PMID- 8641290
TI  - Multiple substrate binding sites in the ribozyme from Bacillus subtilis RNase P.
AB  - The ribozyme from Bacillus subtilis RNase P (P RNA) recognizes an RNA structure
      consisting of the acceptor stem and the T stem-loop of tRNA substrates. An in
      vitro selection experiment was carried out to obtain potential RNA substrates
      that may interact with the P RNA differently from the tRNA substrate. Using a P
      RNA-derived ribozyme that contains most, if not all, of the structural elements
      thought to be involved in active site formation of P RNA, but lacks the putative
      binding site for the T stem-loop of tRNA, a single RNA substrate was isolated
      after nine rounds of selection. This RNA is a competent substrate for the
      ribozyme used in selection as well as for the full-length P RNA. Biochemical
      characterization shows that this selected substrate interacts at a different site
      compared with the tRNA substrate. The selection experiment also identified a self
      cleaving RNA seemingly different from other known ribozymes. These results
      indicate that a biological ribozyme can contain different binding sites for
      different RNA substrates. This alternate binding site model suggests a simple
      mechanism for evolving existing ribozymes to recognize RNA substrates of diverse
      structures.

PMID- 8641291
TI  - The snRNP core assembly pathway: identification of stable core protein
      heteromeric complexes and an snRNP subcore particle in vitro.
AB  - Stable association of the eight common Sm proteins with U1, U2, U4 or U5 snRNA to
      produce a spliceosomal snRNP core structure is required for snRNP biogenesis,
      including cap hypermethylation and nuclear transport. Here, the assembly of snRNP
      core particles was investigated in vitro using both native HeLa and in vitro
      generated Sm proteins. Several RNA-free, heteromeric protein complexes were
      identified, including E.F.G, B/B'.D3 and D1.D2.E.F.G. While the E.F.G complex
      alone did not stably bind to U1 snRNA, these proteins together with D1 and D2
      were necessary and sufficient to form a stable U1 snRNP subcore particle. The
      subcore could be chased into a core particle by the subsequent addition of the
      B/B'.D3 protein complex even in the presence of free competitor U1 snRNA.
      Trimethylation of U1 snRNA's 5' cap, while not observed for the subcore, occurred
      in the stepwise-assembled U1 snRNP core particle, providing evidence for the
      involvement of the B/B' and D3 proteins in the hypermethylation reaction. Taken
      together, these results suggest that the various protein heterooligomers, as well
      as the snRNP subcore particle, are functional intermediates in the snRNP core
      assembly pathway.

PMID- 8641292
TI  - Nuclear pore proteins are involved in the biogenesis of functional tRNA.
AB  - Los1p and Pus1p, which are involved in tRNA biogenesis, were found in a genetic
      screen for components interacting with the nuclear pore protein Nsp1p. LOS1, PUS1
      and NSP1 interact functionally, since the combination of mutations in the three
      genes causes synthetic lethality. Pus1p is an intranuclear protein which exhibits
      a nucleotide-specific and intron-dependent tRNA pseudouridine synthase activity.
      Los1p was shown previously to be required for efficient pre-tRNA splicing; we
      report here that Los1p localizes to the nuclear pores and is linked functionally
      to several components of the tRNA biogenesis machinery including Pus1p and Tfc4p.
      When the formation of functional tRNA was analyzed by an in vivo assay, the los1(
      ) pus1(-) double mutant, as well as several thermosensitive nucleoporin mutants
      including nsp1, nup116, nup133 and nup85, exhibited loss of suppressor tRNA
      activity even at permissive temperatures. These data suggest that nuclear pore
      proteins are required for the biogenesis of functional tRNA.

PMID- 8641293
TI  - A non-canonical genetic code in an early diverging eukaryotic lineage.
AB  - The nearly invariant nature of the 'Universal Genetic Code' attests to its early
      establishment in evolution and to the difficulty of altering it now, since so
      many molecules are required for, and depend upon, faithful translation.
      Nevertheless, variations on the universal code are known in a handful of genomes.
      We have found one such variant in diplomonads, an early-diverging eukaryotic
      lineage. Genes for alpha-tubulin, beta-tubulin and elongation factor 1 alpha (EF
      1alpha) from two unclassified strains of Hexamitidae were found to contain TAA
      and TAG (TAR) triplets at positions suggesting a variant code in which TAR codes
      for glutamine. We found confirmation of this hypothesis by identifying genes
      encoding glutamine-tRNAs with CUA and UUA anticodons. The alpha-tubulin and EF
      1alpha genes from two other diplomonads, Spironucleus muris and Hexamita inflata,
      were also sequenced and shown to contain no such non-canonical codons. However,
      tRNA genes with the anticodons UUA and CUA were found in H.inflata, suggesting
      that this diplomonad also uses these codons, albeit infrequently. The high GC
      content of these genomes and the presence of two isoaccepting tRNAs compound the
      difficulty of understanding how this variant code arose by strictly neutral
      means.

PMID- 8641294
TI  - Regulation of translation elongation factor-2 by insulin via a rapamycin
      sensitive signalling pathway.
AB  - It is well established that insulin and serum stimulate gene expression at the
      level of mRNA translation in animal cells, and previous studies have mainly
      focused on the initiation process. Here we show that, in Chinese hamster ovary
      cells expressing the human insulin receptor, insulin causes decreased
      phosphorylation of elongation factor eEF-2 and that this is associated with
      stimulation of the rate of peptide-chain elongation. eEF-2 is phosphorylated by a
      very specific Ca 2+/calmodulin-dependent protein kinase (eEF-2 kinase) causing
      its complete inactivation. The decrease in eEF-2 phosphorylation induced by
      insulin reflects a fall in eEF-2 kinase activity. Rapamycin, a macrolide
      immunosuppressant which blocks the signalling pathway leading to the stimulation
      of the 70/85 kDa ribosomal protein S6 kinases, substantially blocks the
      activation of elongation, the fall in eEF-2 phosphorylation and the decrease in
      eEF-2 kinase activity, suggesting that p7O S6 kinase (p70s6k) and eEF-2 kinase
      may tie on a common signalling pathway. Wortmannin, an inhibitor of
      phosphatidylinositide-3-OH kinase, had similar effects. eEF-2 kinase was
      phosphorylated in vitro by purified p70s6k but this had no significant effect on
      the in vitro activity of eEF-2 kinase.

PMID- 8641295
TI  - DNA polymerase epsilon may be dispensable for SV40- but not cellular-DNA
      replication.
AB  - The contributions of DNA polymerases alpha, delta, and epsilon to SV40 and
      nuclear DNA syntheses were evaluated. Proteins were UV-crosslinked to nascent DNA
      within replicating chromosomes and the photolabelled polymerases were
      immunopurified. Only DNA polymerases alpha and delta were detectably
      photolabelled by nascent SV40 DNA, whether synthesized in soluble viral chromatin
      or within nuclei isolated from SV40-infected cells. In contrast, all three
      enzymes were photolabelled by the nascent cellular DNA. Mitogenic stimulation
      enhanced the photolabelling of the polymerases in the alpha>delta>epsilon order
      of preference. The data agree with the notion that DNA polymerases alpha and
      delta catalyse the principal DNA polymerisation reactions at the replication fork
      of SV40 and, perhaps, also of nuclear chromosomes. DNA polymerase epsilon,
      implicated by others as a cell-cycle checkpoint regulator sensing DNA replication
      lesions, may be dispensable for replication of the small, fast propagating virus
      that subverts cell cycle controls.

PMID- 8641296
TI  - A Drosophila ribosomal protein contains 8-oxoguanine and abasic site DNA repair
      activities.
AB  - Ionizing radiation and normal cellular respiration form reactive oxygen species
      that damage DNA and contribute to a variety of human disorders including tumor
      promotion and carcinogenesis. A major product of free radical DNA damage is the
      formation of 8-oxoguanine, which is a highly mutagenic base modification produced
      by oxidative stress. Here, Drosophila ribosomal protein S3 is shown to cleave DNA
      containing 8-oxoguanine residues efficiently, The ribosomal protein also contains
      an associated apurinic/apyrimidinic (AP) lyase activity, cleaving phosphodiester
      bonds via a beta,delta elimination reaction. The significance of this DNA repair
      activity acting on 8-oxoguanine is shown by the ability of S3 to rescue the H2O2
      sensitivity of an Escherichia coli mutM strain (defective for the repair of 8
      oxoguanine) and to abolish completely the mutator phenotype of mutM caused by 8
      oxoguanine-mediated G-->T transversions. The ribosomal protein is also able to
      rescue the alkylation sensitivity of an E.coli mutant deficient for the AP
      endonuclease activities associated with exonuclease III (xth) and endonuclease IV
      (nfo), indicating for the first time that an AP lyase can represent a significant
      source of DNA repair activity for the repair of AP sites. These results raise the
      possibility that DNA repair may be associated with protein translation.

PMID- 8641298
TI  - Can herpes zoster be prevented?

PMID- 8641297
TI  - Membrane regulation of the chromosomal replication activity of E.coli DnaA
      requires a discrete site on the protein.
AB  - The capacity of DnaA protein to initiate DNA synthesis at the chromosomal origin
      is influenced profoundly by the tightly bound nucleotides ATP and ADP. Acidic
      phospholipids can catalyze the conversion of inactive ADP-DnaK protein into the
      active ATP form. Proteolytic fragments of the nucleotide form of DnaA protein
      were examined to determine regions of the protein critical for functional
      interaction with membranes. A 35 kDa chymotryptic and 29 kDa tryptic fragment
      retained the tightly bound nucleotide. The fragments, whose amino-termini are
      within three residues of each other, but differ at their carboxyl ends, showed
      strikingly different behavior when treated with acidic phospholipids. The larger
      chymotryptic fragment released the bound nucleotide in the presence of acidic,
      but not neutral phospholipids. In contrast, the smaller tryptic fragment was
      inert to both forms of phospholipids. Acidic membranes, but not those composed of
      neutral phospholipids, protect from tryptic digestion a small portion of the
      segment that constitutes the difference between the 29 and 35 kDa fragments. The
      resulting 30 kDa tryptic fragment, which possesses this protected region,
      interacts functionally with acidic membranes to release the bound effector
      nucleotide. Inasmuch as the anionic ganglioside GM1, a compound structurally
      dissimilar to acidic glycerophospholipids, efficiently releases the nucleotide
      from DnaA protein, an acidic surface associated with a hydrophobic environment is
      the characteristic of the membrane that appears crucial for regulatory
      interaction with DnaA protein.

PMID- 8641301
TI  - Are outbreaks and sporadic respiratory infections by Mycoplasma pneumoniae due to
      two distinct subtypes?
AB  - Thirty-seven clinical isolates of Mycoplasma pneumoniae, cultured from patients'
      respiratory material between 1986 and 1994, were typed by immunological methods
      and by polymerase chain reaction (PCR). For immunological typing two monoclonal
      antibodies (mAb) were used that recognized the P1 adhesion of Mycoplasma
      pneumoniae strain FH but differed in their ability to inhibit the adherence of
      Mycoplasma pneumoniae to erythrocytes. The mAb P1.58, which was not able to
      inhibit adherence, showed reactions with all patients' isolates in immunoblots,
      whereas the adherence-inhibiting mAb P1.62 reacted with only seven patients'
      isolates. Due to variations within the P1-adhesin genome of Mycoplasma pneumoniae
      group 1 (Mycoplasma pneumoniae type strain M129) and group 2 (Mycoplasma
      pneumoniae type strain FH), two primer sets were designed. According to the size
      of the PCR-amplification products, all clinical isolates that showed no mAb P1.62
      reactivity belonged to Mycoplasma pneumoniae group 1, whereas mAb P1.62-positive
      reacting mycoplasma isolates were characterized as group 2 strains. During an
      outbreak of Mycoplasma pneumoniae diseases in 1992, all 19 clinical isolates
      showed no cross-reactivity in immunoblots with the mAb P1.62 and were typed by
      PCR as Mycoplasma pneumoniae group 1 strains. Furthermore, 206 Mycoplasma
      pneumoniae complement fixation test-positive patient sera (titer > 1:40) from the
      study period were tested for adherence-inhibiting antibodies towards both type
      strains. Thirty-two sera showed adherence-inhibiting antibodies towards group 1
      and 22 towards group 2 mycoplasmas. In only seven sera were adherence-inhibiting
      antibodies directed to both Mycoplasma pneumoniae groups. The serological data of
      the outbreak in 1992 revealed that patients with Mycoplasma pneumoniae group 1
      infections developed adherence-inhibiting antibodies more frequently than did
      patients infected with group 2, which might have implications for the
      pathogenesis of Mycoplasma pneumoniae diseases and subsequent infections.

PMID- 8641300
TI  - Correlation between in vitro resistance to fluconazole and clinical outcome of
      oropharyngeal candidiasis in HIV-infected patients.
AB  - Fifty episodes of oropharyngeal candidiasis in HIV-infected patients were
      analyzed prospectively in order to evaluate the clinical response to fluconazole.
      The minimum inhibitory concentrations (MICs) of fluconazole for the Candida
      strains isolated from the pharynx were correlated with the clinical response.
      Treatment with fluconazole (100 mg/day) was successful in 86% of the cases. A
      good clinical outcome followed in 97% of the cases when a strain sensitive to
      fluconazole was isolated. This figure fell to 22% when the strain was resistant
      to fluconazole (p < 0.001). The rate of post-treatment colonization was high
      (87%), and selection of non-albicans Candida species occurred in 23% of the
      cases. In conclusion, fluconazole treatment for oropharyngeal candidiasis of HIV
      infected patients was useful in most cases, but less sensitive non-albicans
      species can be selected. Most treatment failures were associated with increased
      MICs of fluconazole for the strains isolated before treatment; therefore,
      susceptibility testing is recommended as an aid in clinical decision-making for
      the use of the azole group of drugs.

PMID- 8641302
TI  - Isolation of "Helicobacter heilmannii" from human tissue.

PMID- 8641303
TI  - Performance of European laboratories testing serum samples for Toxoplasma gondii.
AB  - One hundred twenty-nine European laboratories participated in a collaborative,
      multicentre study designed to evaluate the overall reliability of different
      serological techniques for diagnosis of Toxoplasma gondii infection. Five freeze
      dried reference sera were distributed to each laboratory, each of which analysed
      the sera with its routine methods. The enzyme-linked immunosorbent assay was the
      technique used most frequently, followed by the immunofluorescent antibody
      technique. Only nine laboratories performed the Sabin-Feldman dye test. In
      general, there was good concordance between qualitative results, but for sera
      with low concentrations of Toxoplasma gondii-specific IgG antibodies, some false
      negative results were found. For specific IgM and IgA antibodies, the
      immunosorbent agglutination assay proved the most sensitive. The present study
      demonstrates the need for regular assessment of laboratory serodiagnosis of
      Toxoplasma gondii infection.

PMID- 8641299
TI  - Parvovirus B19 infection.
AB  - Human parvovirus B19, discovered in 1974, is a single-stranded DNA virus which
      causes erythema infectiosum, arthralgia, aplastic crisis in patients with red
      cell defects, chronic anaemia in immunocompromised patients, and fetal hydrops.
      Seroprevalence in developed countries is 2-10% in children less than 5 years, 40
      60% in adults more than 20 years, and 85% or more in those over 70 years. The
      virus may be transmitted by the respiratory route and by transfusion of infected
      blood and blood products. After an incubation period of six to eight days,
      viraemia occurs, during which reticulocyte numbers fall dramatically resulting in
      a temporary drop in haemoglobin of 1 g/dl in a normal person. Clearance of
      viraemia is dependent on development of specific antibody to the B19 structural
      proteins, VP1 and VP2. The red cell receptor for the virus is blood group P
      antigen. Diagnosis in immunocompetent persons depends on detection of specific
      IgM in serum. Diagnosis in immunocompromised persons depends on detection of B19
      antigen or DNA in serum. There is no specific treatment for B19 infection;
      however, human normal immunoglobulin may be used as a source of specific antibody
      in chronically infected persons. A recombinant parvovirus B19 vaccine is under
      development.

PMID- 8641305
TI  - Molecular typing of methicillin-resistant Staphylococcus aureus on the basis of
      protein A gene polymorphism.
AB  - The polymorphic X-region of the protein A gene (spa) was used for molecular
      typing of methicillin-resistant Staphylococcus aureus (MRSA) strains. The X
      region is characterized by a variable number (between 3 and 15) of small repeats.
      DNA sequencing of MRSA strains revealed 25 distinct repeats. Analysis of MRSA
      strains grown in vitro and in vivo revealed that the X-region was sufficiently
      stable for epidemiologic typing of MRSA strains. Spa typing of MRSA strains was
      compared to phage typing and, in general, concordance was found between the two
      methods. However, spa typing was more sensitive, allowing differentiation of
      strains within a particular phage type. Results obtained with spa typing suggest
      that hospital outbreaks may be caused by two or more MRSA strains. Spa typing may
      be an important tool in unravelling the spread of MRSA strains within and between
      hospitals.

PMID- 8641304
TI  - In vitro conjugative transfer of VanA vancomycin resistance between Enterococci
      and Listeriae of different species.
AB  - In a study designed to gain data on the in vitro transferability of vancomycin
      resistance from enterococci of the VanA phenotype to listeriae of different
      species, three clinical Enterococcus isolates-Enterococcus faecium LS10,
      Enterococcus faecalis LS4, and Enterococcus faecalis A3208, all harboring a
      plasmid that strongly hybridized with a vanA probe-were used as donors in
      transfer experiments. Strains of five Listeria species were used as recipients.
      From Enterococcus faecium LS10, glycopeptide resistance was transferred to
      Listeria monocytogenes, Listeria ivanovii, and Listeria welshimeri recipients,
      whereas no transfer occurred to Listeria seeligeri or Listeria innocua strains.
      From the two Enterococcus faecalis isolates, no transfer occurred to any Listeria
      recipient. MICs of both vancomycin and teicoplanin were > or = 256 mg/l for all
      transconjugants tested. Furthermore, all transconjugants harbored a plasmid that
      strongly hybridized with the vanA probe, with vanA consistently located in an
      EcoRI fragment of about 4 kb. Exposure of Listeria transconjugants to vancomycin
      resulted in synthesis of a membrane protein similar in size (39 kDa) to a
      vancomycin-induced membrane protein of Enterococcus faecium LS10. In retransfer
      experiments with Listeria transconjugants used as donors, glycopeptide resistance
      was transferred to all Listeria recipients tested, including strains of Listeria
      innocua and Listeria seeligeri, which were unable to receive the resistance from
      Enterococcus faecium LS10. The frequency of vanA transfer to listerial recipients
      was greater in retransfer experiments than in the primary matings. These findings
      suggest that the vanA resistance determinant might spread to the established
      pathogen Listeria monocytogenes, both directly from a resistant enterococcus and
      through strains of nonpathogenic Listeria species acting as intermediate
      resistance vehicles.

PMID- 8641306
TI  - Gender differences in local and systemic reactions to inactivated influenza
      vaccine, established by a meta-analysis of fourteen independent studies.
AB  - In order to determine whether there is a difference between genders in reported
      adverse reactions to inactivated influenza vaccine, a computerized database of
      serological studies was investigated. A standardized questionnaire was used to
      evaluate vaccine reactogenicity. A total of 1,800 vaccinees in 14 studies were
      analyzed separately for two age groups ( < 60 and > or = 60 years of age).
      Females reported significantly more local reactions than males. The pooled odds
      ratio for the outcome measure "any local reaction" was 0.32 (95% confidence
      interval, 0.26-0.40, significant) and 0.54 (95% Cl, 0.41-0.70, significant) for
      young and elderly adults, respectively. Similar results were obtained for the
      outcome measure "any systemic reaction." Previous exposure to influenza or
      influenza vaccine had no influence on reactogenicity. There were no gender
      differences in sero-responses. In conclusion, gender should be regarded as a
      predictor of reported reactions to influenza vaccine in both young and elderly
      adults and should be addressed in future study designs.

PMID- 8641307
TI  - Impact of using an indwelling introducer on diagnosis of Swan-Ganz pulmonary
      artery catheter colonization.
AB  - A prospective study was conducted to determine how the use of an indwelling
      introducer influences the diagnosis of pulmonary artery catheter (PAC)
      colonization. Sixty-six consecutive PACs and introducers were aseptically removed
      over a 15-month period. Two segments of the catheter and the catheter tip (a
      proximal segment from the portion of the catheter beneath the introducer) and two
      segments of the introducer (a proximal intradermal segment and the introducer
      tip) were cultured using a semiquantitative technique. Nineteen of 66 (28.7%)
      PACs showed colonization, representing an incidence of 5.6 episodes per 100
      catheterization-days. Catheter tip cultures identified only 68% of colonized
      PACs; this yield rose to 91% when introducer tip cultures were added. These
      results indicate a need to evaluate both introducer tip cultures and catheter tip
      cultures for an accurate diagnosis of PAC colonization when an indwelling
      introducer is used.

PMID- 8641308
TI  - Empyema thoracis and lung abscess due to Gemella morbillorum.
AB  - A case of empyema and lung abscess in an elderly patient who presented with
      clinical features of congestive cardiac failure is described. Gemella morbillorum
      was cultured from pleural exudate found postmortem to be associated with a lung
      abscess. To our knowledge this is the first reported case of infection with this
      organism in this setting. We discuss the clinical spectrum and management of
      infection with this infrequently encountered organism.

PMID- 8641309
TI  - Seasonality of cryptosporidiosis in children.
AB  - The seasonal distribution of cryptosporidiosis in children in Aragon, a region in
      northeastern Spain, was determined. Over a period of six years (October 1988 to
      September 1994), 10,034 stool samples from 4,508 children with gastrointestinal
      symptoms were analyzed for this purpose. The age of the patients ranged from 1
      month to 14 years. Cryptosporidium oocysts were identified in 87 (1.93%)
      patients. Prevalence was highest (6.20%) in children aged 1 to 3 years old. The
      prevalence was significantly higher in the autumn-winter period (October to
      March) than in the spring-summer period (April to September) in the whole
      population (2.41% vs. 1.35%, p = 0.010) and in the 1- to 3-year-old age group
      (8.44% vs. 3.20%, p = 0.002), but not in the other age groups. A possible
      relationship of this pattern to attendance at child care centres is suggested.

PMID- 8641310
TI  - The value of cerebrospinal fluid enrichment culture in the diagnosis of acute
      bacterial meningitis.
AB  - The records of cerebrospinal fluid (CSF) examinations for the three-year period
      ending 30 September 1991 were studied retrospectively. From 3,161 examinations,
      66 pathogens were detected, 64 of which were from primary agar plate culture.
      Enrichment broth culture yielded 219 isolates of which 217 were likely
      contaminants. Only two pathogens were isolated by enrichment, and in both samples
      the CSF leucocyte counts were abnormal. The use of enrichment broth culture
      should be confined to CSF specimens with abnormal leucocyte counts and/or Gram
      stains.

PMID- 8641311
TI  - Relationship between outer membrane protein profiles and resistance to
      ceftazidime, imipenem, and ciprofloxacin in Pseudomonas aeruginosa isolates from
      bacteremic patients.
AB  - Outer membrane protein (OMP) profiles of 122 Pseudomonas aeruginosa isolates
      recovered from the blood of bacteremic patients were analyzed to relate
      alterations in the expression of OMPs with porin activity to resistance to
      imipenem, ceftazidime, and ciprofloxacin. Imipenem-resistant isolates lacked or
      expressed reduced amounts of porin OprD. In contrast, alterations of OMP profiles
      were absent in most ceftazidime-resistant isolates. Six of 12 ciprofloxacin
      resistant isolates had normal OMP profiles. The remaining isolates showed
      alterations in the expression of either OprC, OprF, or OprD. In addition,
      imipenem- and ceftazidime-resistant isolates displayed a beta-lactamase activity
      compatible with that of a group 1 chromosomal cephalosporinase.

PMID- 8641312
TI  - Changes in susceptibility of Salmonella enteritidis, Salmonella typhimurium, and
      Salmonella virchow to six antimicrobial agents in a Spanish hospital, 1980-1994.
AB  - To determine changes in the susceptibility patterns of Salmonella enteritidis,
      Salmonella typhimurium, and Salmonella virchow over time, resistance to
      ampicillin, chloramphenicol, tetracycline, gentamicin,
      trimethoprim/sulfamethoxazole, and nalidixic acid was studied by the disk
      diffusion method in 1,024, 191, and 61 clinical isolates of these organisms,
      respectively. All isolates were recovered from 1980 to 1994 at a hospital in
      Madrid, Spain. Salmonella enteritidis isolates were less resistant (10.9%) than
      Salmonella typhimurium (43.5%) and Salmonella virchow (36.1%; p < 0.001). The
      incidence of resistance of Salmonella enteritidis to ampicillin increased from
      2.7% during the period 1980-1982 to 15.6% during 1992-1994 (p < 0.001). The
      resistance of Salmonella typhimurium to ampicillin, chloramphenicol, and
      tetracycline increased from 15.2%, 7.6%, and 21.2% respectively in 1980-1982 to
      73.3%, 46.7%, and 73.3% in 1992-1994 (p < 0.001). These marked increases in
      antimicrobial resistance suggest the need for public health interventions,
      several of which are discussed.

PMID- 8641313
TI  - Bacteria involved in the blockage of biliary stents and their susceptibility to
      antibacterial agents.
AB  - Endoscopically inserted stents are used for the palliation of obstructive
      jaundice, but infections and blockage of these stents by biliary sludge and
      bacterial biofilm may develop, presenting major complications. To analyze which
      bacteria are involved in this process, 25 biliary stents were examined. Eighty
      one microorganisms were isolated: 59 gram-negative bacteria (54
      Enterobacteriaceae and 5 Pseudomonas aeruginosa), 19 gram-positive bacteria (all
      Enterococcus spp.), and 3 Candida albicans. The Enterobacteriaceae were sensitive
      to netilmicin (100%), imipenem (98%), ciprofloxacin (96%), cefotaxime (69%), and
      piperacillin (57%), whereas Enterococcus spp. were sensitive to imipenem (79%),
      piperacillin (75%), ciprofloxacin (63%), and ampicillin (58%). The unpredictable
      aetiology and high rates of antibiotic resistance suggest that bacteriological
      monitoring is mandatory to avoid treatment failures in these patients.

PMID- 8641314
TI  - Simultaneous human immunodeficiency virus and Hepatitis C infection following a
      needlestick injury.
AB  - Needlestick injuries to health professionals at the Hospital del Mar, Barcelona
      since 1987 have been prospectively studied; a total of 296 such accidents in 286
      subjects have been registered. We report the first case to our knowledge of
      simultaneous human immunodeficiency virus (HIV) and hepatitis C (HCV) infection
      in a nurse who suffered a needlestick injury after a blood sampling. Forty-four
      days after the accident she had symptoms and laboratory findings of acute
      hepatitis. Subsequent laboratory tests showed elevation in the aminotransferases
      and antibodies against HIV. The seroconversion to HCV was not detected until 109
      days after the injury. The precise sequence of clinical and biological events of
      this case of simultaneous HIV and HCV infection is reported.

PMID- 8641315
TI  - Isolation of a "Helicobacter heilmanii"-like organism from the human stomach.

PMID- 8641316
TI  - Novobiocin-Salmonella-shigella agar for isolation of Salmonella spp.

PMID- 8641317
TI  - Legal opioid consumption in Denmark 1981-1993.
AB  - According to the World Health Organisation, a country's morphine consumption is
      an important indicator of progress in cancer pain relief. Due to its very high
      opioid consumption, Denmark is often pointed out as a country worthy of
      imitation. The aim of the present study was to analyse Danish opioid consumption
      in order to elucidate the usage pattern and to identify the consumers. Total
      opioid consumption increased 353% from 1981 to 1993, exceeding 1.45 million
      defined daily doses per million inhabitants in 1993. Morphine accounted for 39%,
      methadone 22%, ketobemidone 21% and buprenorphine for 14% of the consumption use.
      The consumption of long acting opioids (sustained release morphine, methadone,
      buprenorphine) and short acting opioids (others) increased by 1427% and 105%,
      respectively. Analysis of a sample of 1854 prescriptions for opioids revealed
      that less than 10% of the prescriptions were issued for cancer pain conditions.
      It is concluded: that if other countries consider Denmark as worthy of imitation
      in opioid treatment for cancer pain, attention should be paid to the pattern of
      the Danish opioid consumption, which is outstanding with respect to quantity but
      the quality may be questionable.

PMID- 8641318
TI  - Dysfunction in the beta 2-adrenergic signal pathway in patients with insulin
      dependent diabetes mellitus (IDDM) and unawareness of hypoglycaemia.
AB  - The majority of the impaired symptoms in hypoglycaemia unawareness, such as
      palpitations, tachycardia and tremor, are caused by increased release of
      adrenaline (ADR) and noradrenaline (NA), and induced by stimulation of beta
      adrenergic receptors. Binding of ADR or NA to the beta-adrenergic receptor
      generates a signal, transmitted via a guanine nucleotide binding protein complex
      (G-protein), which in turn activates adenylate cyclase with increased production
      of cAMP. The aim of this study was to show whether IDDM-patients with
      hypoglycaemia unawareness had deficient coupling between beta2-adrenergic
      receptors and G-proteins compared to IDDM-patients with hypoglycaemia unawareness
      and healthy controls. The IDDM-patients were subgrouped as hypoglycaemia aware or
      unaware based on questionnaire answers, clinical information and the results of
      isoprenaline sensitivity tests. Mononuclear leukocytes (MNL) were isolated from
      venous blood. By saturation binding experiments, using [125I]-(-)-iodopindolol ((
      )-IPIN), total receptor number (Bmax) and affinity (Kd) were determined. By
      displacement experiments the relative number of low- and high-affinity receptors
      for the beta-adrenergic agonist (-)-isoprenaline ((-)-ISO) were determined. We
      found no difference in Bmax- or Kd-values. for (-)-IPIN between the subgroups.
      However, there was a reduced capability to form high-affinity binding complexes
      with (-)-ISO in MNL from IDDM-patients with hypoglycaemia unawareness. It was
      concluded that hypoglycaemia unawareness in IDDM was associated with dysfunction
      of the proximal beta2-adrenergic signal pathway.

PMID- 8641319
TI  - Low-dose Iloprost infusion improves insulin action and non-oxidative glucose
      metabolism in hypertensive patients.
AB  - Fourteen hypertensive (174.3/98.3 mmHg) non-diabetic patients were given a
      euglyceamic glucose clamp along with infusion of 0.9% NaCl and the prostacyclin
      (PGI2) analogue Iloprost (0.7 ng x kg x min(-1)). Substrate oxidation was also
      determined by indirect calorimetry. Over the last 60 min of the clamp, Iloprost
      vs saline improved whole body glucose disposal (WBGD) (35 vs 28.3 micromol x kg(
      1) LBM) and non-oxidative glucose metabolism (24.7 vs 18.1 micromol x kg(-1) LBM
      x min(-1). Iloprost delivery was associated with a significant decrease in
      membrane microviscosity (0.253 vs 0.205), but did not affect arterial blood
      pressure and heart rate. In nine patients, skeletal muscle blood flow (SMBF) and
      insulin-stimulated glucose uptake (GU) were also studied. At the end of the
      study, despite a similar SMBF (37 vs 38 ml x min(-1) x kg(-1)), GU (0.55 vs 0.46
      mmol x l(-1)) was significantly increased by Iloprost infusion. Percentage
      decrease in membrane microviscosity was correlated with percentage increase in
      WBGD (r = 0.65) and non-oxidative glucose metabolism (r = 0.68). In conclusion,
      low-dose Iloprost infusion improves insulin action and non-oxidative glucose
      metabolism in hypertensive patients.

PMID- 8641320
TI  - Humoral and haemodynamic effects of idrapril calcium, the prototype of a new
      class of ACE-inhibitors, in essential hypertensive patients.
AB  - Idrapril is the prototype of a new class of ACE inhibitors, characterised by the
      presence of a hydroxdmic group. Six untreated in-patients with essential
      hypertension were given single oral doses of the calcium salt of idrapril,
      idrapril calcium (200 mg) and placebo according to a double blind, randomised
      experimental design. Supine and upright blood pressure, heart rate, plasma
      idrapril serum UCE, active renin and angiotensin II were measured at timed
      intervals for 24 hours after dosing. Plasma idrapril reached a peak after 2 hours
      (3.01 microgm x ml(-1)), and by 12 hours the compound had almost disappeared (67
      ng x ml(-1)). Derived t1/2 was 1.4-2.2 h. ACE activity was suppressed [from 77.9
      to 3.3 after 2 hours and 11.8 after 12 hours nmol(-1) x min(-1) x ml] and
      angiotensin II production inhibited [from 8.8 to 3.1 (after 1 hour) and 7.5
      (after 24 hours) pg x ml(-1)]. Compared to placebo, idrapril calcium
      significantly lowered both supine blood pressure starting at 4 hours (idrapril
      calcium 140/93 mmHg; placebo 157/101 mmHg; placebo 147/100 mmHg), and upright
      blood pressure starting at 3 hours (idrapril calcium 135/95 mmHg; placebo 147/100
      mmHg) up to 24 hours (idrapril calcium 132/92 mmHg; placebo 145/100 mmHg).
      Idrapril calcium appears to be an effective ACE inhibitor in essential
      hypertension, with a hypotensive action for up to 24 h.

PMID- 8641321
TI  - Determination of (+)- and (-)-nicardipine concentrations in human serum and their
      correlation with the antihypertensive effect after oral administration of racemic
      nicardipine.
AB  - Serum (+)- and (-)-nicardipine concentrations were determined after oral
      administration of racemic nicardipine, and the relationship between the
      concentration of each enantiomer and the percentage change in blood pressure was
      investigated. Serum concentrations of (+) and (-)-nicardipine were assayed
      separately by a method combining high-performance liquid chromatography (HPLC)
      with gas chromatography - mass spectrometry (GS-MS). Linear relationships were
      found with serum concentrations of 0.25-80 mg x ml(-1) for both enantiomers of
      nicardipine with correlation coefficients of greater than 0.999. A single oral
      dose of 40 mg racemic nicardipine was given to 15 patients with essential
      hypertension. Serum (+)-nicardipine concentration was 2-3 times higher than the
      concentration of (-)-nicardipine 1, 2, and 3 after drug administration. The
      logarithmically transformed value of the serum (+)-nicardipine concentration was
      inversely correlated with the percentage change in systolic blood pressure, the
      correlation being statistically significant 1 and 2 h after drug administration,
      and also inversely correlated with the percentage change in diastolic blood
      pressure 1, 2 and 3 h after drug administration. However, the logarithmically
      transformed value of serum (-)-nicardipine showed no significant correlations
      with the percentage change in either systolic or diastolic blood pressure.

PMID- 8641322
TI  - Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent
      (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to
      moderate hypertension.
AB  - SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the
      pharmacologically active form of the prodrug SCH 42495. It exerts
      antihypertensive effects by potentiating atrial natriuretic peptide (ANP)
      activity through inhibition of its hydrolysis by NEP. The objective of this study
      was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH
      42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to
      hypertensive men twice daily in a double-blind, placebo controlled multiple-dose
      parallel group design. Plasma SCH 42354 concentration and diastolic blood
      pressure (DBP) data were used to develop a PK-PD model using two approaches. In
      the first (non-integrated) approach, the ?link? model was used to predict effect
      site concentrations, and was applied to data obtained at the 300 and 400 mg BID
      doses only; data at the other (lower) doses were not amenable to modeling because
      of high variability. Effect-site concentration and DBP data were then fit to a
      sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum
      effect (Emax), 8.1 mmHg; no-drug effect (Eo), 3.6 mmHg; concentration
      corresponding to 50% of maximum response (EC50), 0.87 microgram x ml(-1); and
      gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354
      concentration and effect data obtained over the entire dose range were integrated
      with respect to time. Average plasma concentration and DBP data were then fit to
      a simple Emax PD model. PD parameters obtained over the dose range were: Emax,
      10.3 mmHg; Eo, 2.0 mmHg; and EC50 0.7 microgram x ml(-1). These were similar to
      the estimates obtained from the first approach, demonstrating that the integrated
      (average) data allow PK-PD modeling over the (entire) dose range. The analysis
      showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an
      approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH
      42354 concentration attained at this dose was approximately 1.8 microgram x ml(
      1).

PMID- 8641324
TI  - In vitro inhibition of midazolam and quinidine metabolism by flavonoids.
AB  - Studies in humans in vivo have demonstrated that substances found in grapefruit
      juice may increase the bioavailability of dihydropyridine derivatives as a result
      of the inhibition of liver enzyme activities by flavonoids found in grapefruit.
      Since the metabolism of dihydropyridine drugs is mediated by cytochrome P-450
      (CYP) 3A4, it has been hypothesized that flavonoids may also influence the
      metabolism of other drugs, such as midazolam and quinidine, which are
      biotransformed by the same CYP isoform. Three flavonoids, kaempferol, naringenin
      and quercetin, are found in grapefruit juice but not in orange juice. The effect
      of these substances on the metabolism of midazolam and quinidine has been
      investigated in human liver microsomes. In the concentration range 10-160 microM
      the inhibitory potential of flavonoids was the same for both of the tested drugs;
      it decreased in the order quercetin >> kaempferol > naringenin. The data suggest
      that the flavonoids found in grapefruit juice may influence the kinetics of
      midazolam and quinidine in man.

PMID- 8641325
TI  - The effect of pH on the buccal and sublingual absorption of captopril.
AB  - The effect of pH on the buccal and sublingual absorption of captopril was
      evaluated using in vitro techniques and human studies. Partitioning of captopril
      into n-octanol was lowest over the pH range 5 to 8 and highest at pH values 3, 4
      and 9. Using the buccal absorption technique, the partitioning of captopril (2
      mg) was examined in six healthy male volunteers from buffered solutions (pH 3, 4,
      5, 6, 7, 8, and 9). Lowest buccal partitioning occurred at pH 3 while maximal
      buccal partitioning occurred at pH 7. These data clearly indicated that the
      buccal absorption of captopril pharmacokinetic and pharmacodynamic parameters
      were determined after administration of buffered sublingual captopril (pH 7,
      optimal hP for absorption as determined from the buccal partitioning data) and
      unbuffered sublingual captopril. The study was performed in eight healthy
      volunteers in a randomised single-blind cross-over fashion. The tmax for
      captopril was found to be approximately 11 minutes earlier after buffered versus
      unbuffered sublingual administration and AUC0-30 min increased by approximately
      30% in the case of buffered captopril. Cpmas, AUC0-180 min and relative
      bioavailability did not differ between the buffered and unbuffered
      administration. Pharmacodynamic parameters (BP, heart rate and plasma renin
      activity) did not differ significantly between buffered and unbuffered sublingual
      administration. The increased rate of captopril absorption after buffered
      sublingual administration was small and is likely to offer little therapeutic
      advantage over conventional sublingual formulation.

PMID- 8641323
TI  - Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts.
AB  - In a closed metabolic ward the pharmacokinetics of methadone and its primary
      metabolite (EDDP) were studied in 20 long-term opiate addicts. After
      administration of the daily oral dose of methadone HCl (mean 60 mg, range 10-225
      mg) blood samples were taken and analysed, using a newly developed high
      performance liquid chromatography (HPLC) method. The steady-state plasma
      concentrations of the 20 subjects varied from 65-630 ng x ml(-1) and from 5 to 55
      ng x ml(-1), whereas the peak concentrations were 124-1255 ng x ml(-1) and 10-301
      ng x ml(-1) for methadone and the AUC(0-24 h) for EDDP varied from 5.9 to 44.6,
      indicating interindividual differences in metabolic activity. In 19 out of 20
      subjects the pharmacokinetics of methadone are best described using a two
      compartment model. The mean body clearance was 1.64 ml x min(-1) x kg(-1),
      whereas the mean elimination rate constant (beta) and plasma half-life (t1/2beta)
      were 0.026 x h(-1) (range 0.013-0.053 x h(-1)) and 31.2 h (range 13-53 h),
      respectively. Differences of gender were also found. A poor correlation was found
      between the methadone dose and the steady-state level. A much better correlation
      was found between the normalized steady-state level and the body clearance.

PMID- 8641326
TI  - Determination of phenobarbitone population clearance values for South African
      children.
AB  - Non-liner Mixed Effects Modelling (NON-MEM) was used to estimate phenobarbitone
      population clearance values for South African children, using 52 serum levels
      gathered from 32 patients during their routine care. NONMEM was also used to
      evaluate the influence of fixed effects such as weight, age and concomitant
      medication. The final model describing phenobarbitone clearance was CL =
      [Exp(0.0288 Wt - 2.53)]M, where CL clearance (l x h(-1)), Exp = the base of the
      natural logarithm, Wt = patient weight (kg) and M = a scaling factor for
      concomitant medication with a value of 1 for patients on phenobarbitone
      monotherapy, 0.62 for those receiving concomitant valproate and 0.87 for those
      patients receiving concomitant carbamazepine or phenytoin. Mean (95% confidence
      interval) phenobarbitone clearance values were 7.6 ml x h(-1) x kg(-1) (6.2, 9.0
      ml x h(-1) x kg(-1) for the monotherapy group, 5.0 ml x h(-1) x hg(-1) (4.0, 6.0
      ml x h(-1) x kg(-1)) in the presence of concomitant valproate and 6.8 ml x h(-1)
      x kg(-1) (5.6, 8.0 ml x h(-1) x kg(-1)) in the presence of concomitant
      carbamazepine or phenytoin. These values are similar to those previously reported
      from both traditional and NONMEM pharmacokinetic studies.

PMID- 8641327
TI  - Furosemide disposition in patients on CAPD.
AB  - Single doses of oral and intravenous furosemide were given to 8 healthy male
      volunteers (40 mg) and 11 patients with renal failure maintained on continuous
      ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was
      variable. Only one half of the intravenous dose and one third of the oral dose
      was available for renal pharmacological action as judged by the urinary recovery.
      In the patients, absorption was also variable and was markedly delayed (tmax 128
      vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences
      between the two groups were not significant, however (95% C.I.: -90 to 30 and 
      40.4 to 7.5 respectively). The mean elimination half-life was significantly
      longer in the patients following both the oral (228 vs 65.1 min) and intravenous
      dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers
      was 138 ml x min(-1) and this was much lower in the CAPD patients (61.9 ml x min(
      1)) in whom the renal clearance was negligible. Although there were trends
      indicating differences in absorption between the two groups, the significant
      differences in furosemide disposition observed in CAPD patients were due to renal
      failure.

PMID- 8641328
TI  - Effects of lansoprazole on pharmacokinetics and metabolism of theophylline.
AB  - The effect of the new substituted benzimidizole proton pump inhibitor,
      lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied
      in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4
      and 11 of 300 mg aminophylline was simultaneously administered orally and blood
      samples for theophylline analysis were taken over 24 h. Urine samples were
      collected for up to 24 h and were assayed for theophylline and its major
      metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3
      methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were
      determined, and the urinary recovery of unchanged theophylline and its major
      metabolites were calculated. After administration of lansoprazole for 4 days, no
      significant alteration in the terminal elimination half-life (t1/2beta) or the
      mean resistance time (MRT) was detected. However, there was a significant
      decrease of about 13% in the area under the plasma concentration-time curve (AUC)
      and a significant increase of about 19% in the apparent clearance (CLapp).
      Lansoprazole treatment for 11 days caused a significant decrease of approximately
      12% in t1/2beta and about 10% in the MRT of theophylline, although neither AUC
      nor CLapp showed a significant alteration. The excretion of 3-MX in the urine was
      significantly increased by about 20% after lansoprazole treatment for 4 and 11
      days, although there was no significant alteration in the excretion of unchanged
      theophylline, 1,3-DMU or 1-MU. The results indicate that repeated administration
      of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug
      oxidation system that mediates N-1-demethylation of theophylline, consequently
      increasing its metabolism.

PMID- 8641329
TI  - Methyldopa kinetics before and after ingestion of methyldopa for eight weeks.
AB  - Methyldopa urine and plasma levels and urine metabolite levels were assessed
      following intravenous (IV) and oral (PO) methyldopa before, and after ingestion
      of methyldopa (500 mg) daily for eight weeks. There was no increase in
      (estimated) methyldopa absorption (8.4%) or renal clearance (PO 13.9%, IV 2.33%)
      after the eight weeks of methyldopa ingestion. However, the initial methyldopa
      absorption and renal clearance values in this study were higher than that in
      previous studies. There was an inverse relation between the initial methyldopa
      absorption and the change in absorption (r - 0.605) and between the initial
      methyldopa renal clearance and the change in renal clearance (PO r -0.874, IV r 
      0.891). Overall, this study did not confirm our previous studies showing
      induction of methyldopa absorption and renal clearance, possibly due to prior up
      regulation of transporter function. Consistent with methyldopa inducing drug
      transporters, those with low initial absorption and renal clearance values had
      the greatest increases.

PMID- 8641330
TI  - Binding of macrophage colony-stimulating factor to serum proteins.
AB  - Although three molecular forms of macrophage colony-stimulating factor (M-CSF)
      have been reported, Western blot analysis of immunoaffinity-purified M-CSF from
      human blood has shown that the major species of M-CSF in the serum has a
      molecular weight (MW) of 85 kD. Superose-12 gel filtration chromatography of
      immunoaffinity-purified serum M-CSF showed the presence of M-CSF-positive
      fraction in a higher MW area compared with the elution profile of recombinant
      human (rh) 85-kD M-CSF. Western blot analysis of the higher MW fraction showed
      that the M-CSF was the same as rh 85-kD M-CSF (not proteoglycan form of M-CSF),
      indicating that, in the serum, M-CSF exists bound to some serum proteins. To
      detect the serum proteins, we performed M-CSF-bound column chromatography. The
      eluate contained at least three serum proteins including albumin and IgG. This
      result was supported by chromatography using biotinylated M-CSF and avidin
      agarose. The binding between rhM-CSF and albumin or IgG was also demonstrated by
      high-performance liquid chromatography (HPLC) fractionation of the mixture and
      enzyme-linked immunosorbent assay (ELISA) of the fractions. In the serum, a
      fraction of M-CSF seems to be complexed with serum proteins such as albumin and
      IgG.

PMID- 8641331
TI  - Activation of the cAMP-dependent signaling pathway downregulates the expression
      of interleukin-3 and granulocyte-macrophage colony-stimulating factor in
      activated human T lymphocytes.
AB  - Expression of cytokines by T lymphocytes is a highly balanced process, involving
      stimulatory and inhibitory intracellular signaling pathways. We have examined the
      modulating effects of the cAMP-dependent signaling pathway on the expression of
      interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM
      CSF) in activated human T lymphocytes. 2'-O-dibutyryl-cAMP (db-cAMP),
      prostaglandin E2 (PGE2), isoproterenol (ISO), and isobutyl-methyl-xantin (IBMX)
      costimulated with concanavalin A (Con A) or Con A plus the phorbolester phorbol
      myristate acetate (PMA) inhibited IL-3 and GM-CSF mRNA accumulation compared to
      the effects of Con A or Con A plus PMA alone. Nuclear run-on experiments revealed
      that the inhibitory effect of db-cAMP could partially be ascribed to a five-fold
      reduction in transcription rate of both the IL-3 and GM-CSF gene in the presence
      of Con A or Con A plus PMA. mRNA stability studies demonstrated that PMA
      increased the stability of both transcripts. db-cAMP did not affect the stability
      of IL-3 and GM-CSF mRNAs in Con A activated cells. In contrast, in Con A plus PMA
      activated cells, db-cAMP significantly reduced the half-life of both transcripts:
      IL-3 >240 minutes vs. 90 minutes and GM-CSF 90 minutes vs. 60 minutes. Finally,
      in accordance with the mRNA data, db-cAMP, PGE2, and ISO reduced the secretion of
      IL-3 and GM-CSF protein in Con A and Con A plus PMA activated cells. In
      conclusion, these data demonstrate that the protein kinase A (PKA)-dependent
      signaling pathway is an important regulatory mechanism in controlling IL-3 and GM
      CSF gene expression in activated human T lymphocytes.

PMID- 8641332
TI  - Aberrant growth of granulocyte-macrophage progenitors in juvenile chronic
      myelogenous leukemia in serum-free culture.
AB  - We investigated the properties of granulocyte-macrophage (GM) progenitors
      obtained from patients with juvenile chronic myelogenous leukemia (JCML). CD34+
      bone marrow cells from a patient with JCML, unlike normal bone marrow cells,
      generated a large number of cells in serum-containing liquid culture without
      additional hematopoietic factors. In serum-deprived culture, only granulocyte
      colony-stimulating factor (G-CSF) had a modest stimulatory effect on GM colony
      growth in normal controls. In contrast, stem cell factor (SCF), granulocyte
      macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3), as well
      as G-CSF, when tested individually, generated significant numbers of GM colonies
      in some JCML patients. All two-factor combinations generated significantly more
      GM colonies in JCML compared with normal controls. In particular, GM-CSF plus SCF
      exerted an interaction equivalent to the all-factor combination in most patients.
      Significant differences in the size and constituent cells of GM colonies
      stimulated by GM-CSF plus SCF were also observed. These results suggest that one
      possible mechanism for the excessive cell production in JCML is the strong
      proliferation of GM progenitors induced by hematopoietic factors, especially SCF.
      According to immunofluorescent analysis, however, it is unlikely that this
      multiplication is due to an increase in the cell surface expression of c-kit
      receptors on JCML progenitors.

PMID- 8641334
TI  - Homing of fluorescently labeled murine hematopoietic stem cells.
AB  - PKH-26 was used as a viable fluorescent membrane stain for murine hematopoietic
      stem cells. The presence of the dye on the cells was shown not to interfere with
      their ability to form day-8 and -12 spleen colonies in lethally irradiated mice.
      To study their in vivo homing behavior in detail, 10(4) labeled cells from a
      population enriched for CFU-S were injected intravenously into nonirradiated mice
      and into mice irradiated 3 hours previously. At 17, 41, and 65 hours after
      injection, the numbers of labeled cells per organ were quantified using the
      specialty developed flow cytometric fluorescence hypercompensation procedure for
      the detection of rare events, which allows a detection sensitivity of 1 per
      10(6). Spleen homing in irradiated and nonirradiated mice was virtually
      identical, whereas homing to nonirradiated bone marrow was 2.5 times higher than
      to irradiated bone marrow. This indicates a different homing mechanism for spleen
      and bone marrow. The results of this direct homing assay were placed in
      perspective with results of indirect homing studies from the literature,
      introducing a new "h-factor." From the CFU-S data, putative specific enrichment
      factors for spleen-specific and bone marrow-specific homing were derived.
      Examination of the fluorescence intensity distribution among the labeled cell
      population indicated that virtually all cells started to proliferate rapidly
      after injection into both irradiated and nonirradiated animals. This indicates
      that specific signals from stromal elements in the stem cell niches are needed to
      keep the cells quiescent and that the majority of the transplanted stem cells do
      not home to such niches. The potential use of PKH-26 for in vivo characterization
      of stem cell niches is discussed.

PMID- 8641333
TI  - Macrophage colony-stimulating factor induces interleukin-8 production in human
      monocytes.
AB  - We have investigated the stimulatory effect of recombinant human macrophage
      colony-stimulating factor (rhM-CSF) on interleukin-8 (IL-8) production by human
      peripheral blood monocytes. When monocytes were prepared from peripheral blood
      and cultured for 24 hours, the average amount of IL-8 in the culture medium was
      about 8.9 +/- 3.2 ng/2 x 10(5) cells. In contrast, the production of IL-8 by
      monocytes increased to a level of 19.2 +/- 4.7 ng/2 x 10(5) cells in response to
      rhM-CSF. This induction by rhM-CSF was dose-dependent. Northern blot analysis
      showed that expression of IL-8 at the pretranslational level was enhanced after M
      CSF treatment. Kinetic studies showed that secretion of IL-8 from monocytes was
      enhanced within 2 hours after exposure to rhM-CSF, and a saturation level, which
      was reached around 48 hours, was two-fold higher than that of cells without M-CSF
      treatment. In addition, conditioned medium of M-CSF-stimulated monocytes
      activated the chemotaxis of human neutrophils, and this activity was
      significantly inhibited by anti-IL-8 antibody. These results, taken together,
      suggest that M-CSF can affect many cellular functions through regulation of IL-8
      expression in monocytes.

PMID- 8641335
TI  - Cell cycle-specific behavior of erythropoietin.
AB  - The murine erythropoietin-dependent erythroleukemia cell line, HCD-57, was
      employed to study the cell cycle-specific behavior of erythropoietin. Cell cycle
      duration for HCD-57 cells was approximately 12 hours and was uninfluenced by
      erythropoietin. Populations of HCD-57 cells synchronized in G1 by centrifugal
      elutriation were able to pass through one complete cell cycle in the absence of
      erythropoietin but, thereafter, arrested in G1 as identified by propidium iodide
      staining and flow cytometry. Analysis of cell cycle behavior using the
      metachromic dye acridine orange, however, revealed that HCD-57 cells pass through
      a G0 cell cycle phase and, like serum-deprived 3T3 cells, actually arrest in G0
      when deprived of erythropoietin. Expression of the cell cycle regulatory protein
      p34cdc2 was invariant throughout the cell cycle in HCD-57 cells. p34cdc2 was
      constitutively phosphorylated in G0 cells, and this effect was not modified by
      erythropoietin. Erythropoietin receptor distribution was log normal in HCD-57
      cells in each phase of the cell cycle. The affinity of these surface receptors
      for erythropoietin was essentially invariant throughout the cell cycle, but
      receptor expression was upregulated in G2M cells as compared with cells in G1 or
      S phase. Taken together, these data indicate that erythropoietin has an important
      role in the G0-G1 to S phase transition but, based on receptor expression, is
      involved in other phases of the cell cycle as well.

PMID- 8641336
TI  - Suppression of superoxide anion production by interleukin-10 is accompanied by a
      downregulation of the genes for subunit proteins of NADPH oxidase.
AB  - Interleukin-10 (IL-10) inhibited the production of superoxide anion (02-) by both
      unactivated and interferon-gamma (IFN-gamma)-activated human monocytes.
      Simultaneous addition of IL-10 with IFN-gamma at the start of incubation was
      necessary for an optimal inhibitory effect. The degree of inhibition was
      substantially comparable to that of IL-4, and the combination of suboptimal
      concentrations of IL-10 and IL-4 produced an additive effect. A similar effect
      was also obtained when viral IL-10 (vIL-10) was used instead of IL-10. The
      inhibitory effect of IL-10 was accompanied by the reduced accumulation of
      transcripts for heavy chain subunit of cytochrome b558 (gp9l-phox) and 47-kD
      cytosolic factor (p47-phox), components of the O2--generating NADPH oxidase
      system. Reduction of the mRNAs was distinct within 24 hours. On the other hand,
      the induced O2- production by human monocytic leukemia cell lines (THP-1 and
      HL60) was not inhibited by IL-10. The amount of gp9l-phox and p47-phox mRNAs
      remained unchanged even in the presence of excess amount of IL-1O. Taken
      together, these results suggest that IL-10 inhibits 02- production by
      downregulation of the gp9l-phox and p47-phox genes in human monocytes.

PMID- 8641337
TI  - Expression of megakaryocytic and erythroid properties in human leukemic cells.
AB  - Previous studies have suggested that megakaryocytes and erythrocytes may share a
      common precursor cell. However, studies on the commitment to erythroid and
      megakaryocytic lineages have been hampered by the lack of suitable human leukemic
      cell lines having this kind of bipotential differentiation capability. We
      investigated the coexpression of megakaryocytic and erythroid markers in human
      leukemic cell lines as well as the capability of these cells to further
      differentiate upon exposure to differentiation-inducing agents. We report that
      the JK-1 cell line, previously characterized as a typically erythroid cell line
      with spontaneous differentiation to red cells, actually coexpressed
      megakaryocytic cell surface antigens and erythroid spectrins. We also report that
      the JK-1 cells could be induced to differentiate along the megakaryocytic lineage
      by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The other cell
      lines studied variably expressed megakaryocytic and erythroid antigens, the DAMI
      and CMK cells predominantly megakaryocytic properties and the T-33 and K562 cells
      some erythroid markers, whereas the HEL cells expressed markers for both lineages
      of differentiation. Our results suggest that the JK-1 cell line represents an
      immature cell population that has not yet been committed to either of the two
      lineages of differentiation. The JK-1 cell line might provide a useful tool for
      further studies on the transcriptional regulation of erythroid and megakaryocytic
      phenotypes and for studies on the commitment to these lineages of
      differentiation. Our results also suggest that the leukemic cell lines show a
      considerable plasticity in the expression of properties normally specific for
      distinct lineages of differentiation.

PMID- 8641338
TI  - Activation and priming of human monocytes by monocyte chemotactic activating
      factor: cooperation with other inflammatory cytokines and close association
      between an increase in cytoplasmic free Ca2+ and intracellular acidification.
AB  - Both monocyte chemotactic and activating factor (MCAF) and N-formyl-methionyl
      leucyl-phenylalanine (FMLP) stimulated an increase in cytoplasmic free Ca2+
      ([Ca2+]i) and changes in intracellular pH (pHi) in human monocytes in parallel at
      lower concentrations and stimulated superoxide (O2-) release and changes in
      transmembrane potential in parallel at higher concentrations. The changes in pHi
      were characterized by initial rapid acidification followed by sustained
      alkalinization, and the changes in transmembrane potential were characterized by
      initial depolarization followed by partial repolarization. The time courses of
      all responses stimulated by MCAF and FMLP were similar to each other, although
      the magnitude of all responses was less in MCAF-stimulated cells. MCAF by itself
      was a very weak stimulus for inducing O2- release. However, MCAF primed monocytes
      and enhanced O2- release stimulated by FMLP. The priming effect of MCAF was
      maximal within 5 minutes of preincubation, and the dose-response curves for
      priming were identical to those for triggering of an increase in [Ca2+]i.
      Treatment of monocytes with the intracellular Ca2+ chelator, 1,2-bis(2
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), abolished not only the
      increase in [Ca2+]i but also the changes in pHi (both acidification and
      alkalinization) induced by MCAF or FMLP. MCAF further potentiated FMLP-induced O2
      release in tumor necrosis factor (TNF)-, granulocyte-macrophage colony
      stimulating factor (GM-CSF)-, or IL-3-primed monocytes. These findings suggest
      that MCAF, alone or in concert with other cytokines, primes monocytes for
      enhanced release of 02-, and that MCAF- or FMLP-induced intracellular
      acidification and alkalinization are closely associated with an increase in
      [Ca2+]i, but not O2- release.

PMID- 8641339
TI  - Induction of growth factor-independence and GM-CSF secretion by the v-src
      oncogene in murine myeloid cells does not require membrane association of pp60v
      src.
AB  - Introduction of v-src or c-src527F, a transforming mutant of the c-src proto
      oncogene, into the growth factor-dependent cell line FDCP-1 resulted in growth
      factor independence. Temperature-shift studies with cells carrying the tsLA29
      mutant of v-src demonstrated that growth factor independence was oncogene
      dependent; that is, the cells were growth factor-independent at the permissive
      temperature but became growth factor-dependent at the nonpermissive temperature.
      Introduction of the c-src proto-oncogene did not result in growth factor
      independence. The c-src2A,527F mutant, which encodes an activated tyrosine kinase
      but does not transform fibroblasts due to a mutation in the membrane localization
      sequence, induced growth factor independence. This suggests that the presence of
      an activated tyrosine kinase is necessary for this process but that membrane
      localization is not. Bioassays indicated that conditioned medium from growth
      factor-independent cells contained a growth factor identified by antibody
      neutralization studies as granulocyte-macrophage colony-stimulating factor (GM
      CSF). Secretion of GM-CSF was confirmed by a quantitative enzyme-linked
      immunosorbent assay (ELISA) specific for GM-CSF. The presence of GM-CSF mRNA in
      src-infected FDCP-1 cells was demonstrated by PCR amplification of cDNAs with
      primers specific for GM-CSF. While GM-CSF mRNA was detected in FDCP/ts29 cells
      grown at 34 degrees C, it was not observed in cells infected with the tsLA29
      mutant grown at the nonpermissive temperature of 39 degrees C. Transfection of v
      src-infected FDCP-1 cells with a GM-CSF promoter reporter plasmid revealed src
      dependent expression of luciferase; that is, while expression was observed at the
      permissive temperature, no expression was detected in FDCP/ts29 clone 6 cells
      grown at the nonpermissive temperature. No expression of the GM-CSF promoter
      reporter plasmid was observed in uninfected FDCP-1 cells.

PMID- 8641340
TI  - Studies of W mutant mice provide evidence for alternate mechanisms capable of
      activating hematopoietic stem cells.
AB  - Previous studies have suggested that Steel factor (SF) can influence the behavior
      of many types of hematopoietic progenitor cells both in vivo and in vitro,
      although whether these may include the most primitive populations of totipotent
      repopulating cells remains controversial. To approach this question, we measured
      the number of Sca1+Lin-WGA+ cells, the number of cells with demonstrable myeloid
      (long-term culture-initiating cell [LTC-IC]) or both myeloid and lymphoid (LTC
      IC(ML)) potential in 4- to 5-week-old long-term cultures containing irradiated
      primary marrow feeder layers, and the number of multilineage long-term in vivo
      repopulating cells (competitive repopulating unit [CRU]) present in the marrow of
      W42/+ or W41/W41 mice compared to +/+ controls. There was no significant effect
      of either of these W mutations on the number of Sca1+Lin-WGA+ cells and, in
      W41/W41 mice, neither LTC-IC nor LTC-IC(ML) populations appeared to be affected.
      On the other hand, although W41/W41 and W42/+ cells could both be detected in the
      in vivo CRU assay, their numbers were markedly reduced (17- and seven-fold,
      respectively) in spite of the fact that both of these W mutant genotypes
      contained near normal numbers of day-9 and -12 colony-forming units-spleen (CFU
      S). In vitro quantitation of erythroid (burst-forming units-erythroid [BFU-E]),
      granulopoietic (CFU-granulocyte/macrophage [CFU-GM]), multilineage (CFU
      granulocyte/erythrocyte/monocyte/macrophage [CFU-GEMM]), and pre-B clonogenic
      progenitors (CFU-pre-B) also revealed no differences in the numbers (or
      proliferative potential) of any of these cells when W41/W41 or W42/+ and normal
      mice were compared, although day 3 BFU-E from both types of W mutant mice showed
      no response to the typical enhancing effect exerted by SF on their +/+
      counterparts. Taken together, these findings are consistent with the view that SF
      activation of c-kit receptor-induced signaling events is not a rate-limiting
      mechanism controlling red blood cell production during normal development until
      hematopoietic cells differentiate beyond the day-3 BFU-E stage. Nevertheless,
      normal hematopoietic stem cells do appear to be responsive to SF, since their W
      mutant counterparts display a disadvantage in the in vivo setting which is
      exaggerated under conditions of hematopoietic regeneration. On the other hand,
      alternative mechanisms also appear to contribute to the regulation of
      hematopoietic stem cell numbers in vivo and to their detection as LTC-IC in
      vitro.

PMID- 8641341
TI  - Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3
      kinase in 3T3-L1 mouse preadipocytes by interleukin-11.
AB  - Tyrosine phosphorylation is an early event of interleukin-11 (IL-11)-mediated
      signal transduction. The IL-11-responsive cell line 3T3-L1 (mouse preadipocytes)
      was tested for the presence of Src-family protein tyrosine kinases (PTKs). Only
      p62yes, p59fyn, and p60src were found to be expressed. Immune-complex kinase
      reactions using the artificial substrate enolase showed that upon stimulation
      with IL-11, p62yes and p60src were activated, but p59fyn did not appear to be
      activated. These results correlate with antiphosphotyrosine (APT) immunoblots. IL
      11-stimulated cells also revealed increased phosphatidylinositol 3-kinase (PI3K)
      activity. Increased activity of PI3K was found to be associated with tyrosine
      phosphorylated proteins and p62yes, after IL-11 treatment. Immunoprecipitation
      studies with anti-PI3K revealed for the first time that p62yes associated with
      PI3K in response to IL-11. To summarize, IL-11 activates p60src, p62yes and PI3K
      but not p59fyn, and this activation of p62yes leads to its association with PI3K
      and PI3K activation.

PMID- 8641342
TI  - Inhibition of human erythroid colony-forming units by interferons alpha and beta:
      differing mechanisms despite shared receptor.
AB  - Previous investigations have demonstrated that interferons alpha, beta, and gamma
      (alpha-, beta-, and gamma-IFN) are potent inhibitors of erythropoiesis in vitro.
      By utilizing a cell population enriched for human erythroid colony-forming units
      (CFU-E), we have previously demonstrated that the inhibitory effects of beta- and
      gamma-IFNs are direct effects, not requiring the presence of accessory cells, and
      that the inhibitory effect of recombinant human (rh) gamma-IFN could be corrected
      by high concentrations of rh erythropoietin (Epo). In this study, we compared the
      effects of rh(alpha)-IFN on cells enriched for CFU-E to its effects on unpurified
      marrow cells and found that although h(beta)-IFN (which shares a common receptor
      with alpha-IFN) directly inhibits CFU-E colony formation, the effect of rh(alpha)
      IFN is indirect and is mediated by a soluble factor released from T lymphocytes
      in response to rh(alpha)-IFN. However, rh(alpha)-IFN enhanced the direct
      inhibitory effect of rh(gamma)-IFN on CFU-E not inhibited by rh(alpha)-IFN. The
      inhibitory effects of neither alpha- nor beta-IFN could be overcome by high
      levels of rhEpo. These findings imply that alpha- and beta-IFN exert different
      cellular effects despite binding to the same receptor. Failure of rhEpo to
      correct CFU-E colony inhibition by alpha- and beta-IFNs but not by gamma-IFN also
      suggests a mechanism for the differing degrees of response to different doses of
      rhEpo in patients with the anemia of chronic disease.

PMID- 8641343
TI  - Engraftment of W/c-kit mutant mice is determined by stem cell competition, not by
      increased marrow 'space'.
AB  - W/c-kit mutant mice accept engraftment by small numbers of normal hematopoietic
      stem cells without the necessity for myeloablation. One explanation for this
      observation is that a deficiency of Kit receptors reduces the number of primitive
      hematopoietic stem cells and increases the number of available "niches" or
      "space" in the marrow. As a test of this model, we transplanted a series of
      unirradiated W mutant mice with donor marrow cells of the identical mutant
      genotype. Despite the intrinsic anemia and hematopoietic defect of severely
      affected W(X)/W(V) and mildly affected W(V)/+ hosts, donor-derived red blood
      cells (RBC) were not detected for up to 6 months after transplantation with 1-4 x
      10(7) marrow cells of the same W(X)/W(V) and W(V)/+ genotypes, respectively. In
      contrast, both genotypes were engrafted, as judged by sustained proliferation of
      donor-derived RBC, after a second transplant with equal numbers of +/+ cells. The
      inability of W(X)/W(V) marrow to proliferate in W(X)/W(V) hosts was not due to an
      absence of transplantable stem cells, however, as W(X)/W(V) cells were capable of
      sustained engraftment and proliferation in irradiated W(X)/W(V) recipients. We
      conclude that when donor and host are equivalent for Kit receptor function, W
      mutant mice do not accept marrow grafts more readily than wild-type mice. The
      results suggest that a deficiency of host Kit receptor function promotes
      engraftment of normal stem cells not by increasing marrow space, but by providing
      an advantage to donor cells in competition for marrow stroma or for self-renewal
      and differentiation.

PMID- 8641344
TI  - The C-terminal cytoplasmic region of the granulocyte colony-stimulating factor
      receptor mediates apoptosis in maturation-incompetent murine myeloid cells.
AB  - Granulocyte colony-stimulating factor (G-CSF) promotes the survival and
      proliferation of myeloid progenitors and induces maturation of these cells toward
      terminally differentiated neutrophils. Using transfectants of the murine IL-3
      dependent myeloid cell line 32D that express the human G-CSF receptor (32D/WT
      cells), we show here that G-CSF can also exert adverse effects on myeloid cell
      survival. Although initially enhancing IL-3-driven proliferation of 32D/WT cells,
      G-CSF strongly inhibited cell survival at later stages of culture. The loss of
      viability of 32D/WT cells following sustained G-CSF stimulation was not
      accompanied by progressive neutrophilic maturation. Instead, 32D/WT cells
      exhibited features characteristic of apoptosis. The apoptosis-inducing effect of
      G-CSF was seen at concentrations of IL-3 that could support long-term
      proliferation and survival of 32D/WT cells in the absence of G-CSF. Experiments
      with 32D cells expressing mutant forms of the G-CSF receptor revealed that the
      death signals were mediated exclusively through the membrane-distal cytoplasmic
      part of the G-CSF receptor, a region also involved in maturation signaling.

PMID- 8641345
TI  - An antibody to CD44 enhances hematopoiesis in long-term marrow cultures.
AB  - Monoclonal antibody S5, which is specific for CD44, facilitates engraftment of
      major histocompatibility complex (MHC)-mismatched canine bone marrow (BM) when
      infused into recipient animals before total body irradiation (TBI) and marrow
      infusion. The precise mechanism by which S5 facilitates engraftment is not known.
      Previously published data in a murine long-term bone marrow culture (LTBMC) model
      with other anti-CD44 monoclonal antibodies (mAbs) demonstrated an abrogation of
      myelo- and lymphopoiesis in LTBMC. To address this issue in an in vitro setting,
      the effect of S5 on canine myelopoiesis in LTBMC was investigated. The data
      indicate that treatment of LTBMC with S5 causes an absolute increase in the
      number of progenitor cells as measured by a colony-forming unit
      granulocyte/macrophage (CFU-GM) assay compared to cultures treated with control
      mAb (p < 0.0001). This effect was not observed with three other anti-CD44 mAbs
      used (Hermes-1, S3, and IM7). In addition, a concomitant decrease in the
      production of nonadherent cells was noted (p < 0.0001). These effects were
      evident in both autologous and allogeneic LTBMC systems. mAb S5 has been shown to
      enhance natural killer (NK) activity, and more recent data indicate the increased
      cytoxic effect to be partially mediated through CD18. Thus, a possible role for
      modulation of the CD18 antigen in LTBMC by S5 was assessed by addition of the
      anti-CD18 mAb 60.3. While the S5-induced reduction in total nonadherent cell
      production was not changed by addition of 60.3, the increase in progenitor cells
      stimulated by S5 was abrogated. These findings suggest a role for anti-CD44
      antibody in changes in the marrow microenvironment that may be responsible for
      facilitation of donor engraftment and, at least in part, CD18 may be involved in
      this phenomenon. The establishment of this in vitro LTBMC model will enable the
      mechanism to be further dissected.

PMID- 8641346
TI  - Interferon-gamma modulates the lipopolysaccharide-induced expression of AP-1 and
      NF-kappa B at the mRNA and protein level in human monocytes.
AB  - Interferon-gamma (IFN-gamma) modulates the expression of several cytokines by
      human monocytes at the transcriptional level. In view of these findings, we
      analyzed the effects of IFN-gamma on the expression of different transcription
      factors in activated human monocytes. Priming of human monocytes with IFN-gamma
      resulted in the down regulation of c-fos and c-jun mRNA in response to
      stimulation with lipopolysaccharide (LPS) compared to the effects of LPS alone.
      Not only was this effect observed at the mRNA level, but activator protein-1 (AP
      1) DNA binding capacity was affected as well, A strong reduction was observed in
      the LPS-induced DNA-binding activity of AP-1 in the presence of IFN-gamma. LPS
      stimulated monocytes showed an increased expression of p105 mRNA, the precursor
      of the p50 subunit of the transcription factor nuclear factor-kappa B (NF-kappa
      B), while no effect was noticed on the expression of p65 mRNA. In contrast, IFN
      gamma priming did not affect the expression of p105 transcripts but enhanced the
      expression of p65 mRNA (two-fold). Priming with IFN-gamma followed by LPS
      stimulation resulted in a further increase in the expression of p65 mRNA. This
      was due to an increase in the half-life of p65 mRNA (75 vs 150 minutes).
      Electrophoretic mobility shift assays (EMSAs) demonstrated that unstimulated
      monocytes predominantly expressed p50 NF-kappa B. Stimulation with LPS or IFN
      gamma resulted in the expression of p50 and p65 subunits, while the combination
      of IFN-gamma plus LPS caused a further increase in the expression of NF-kappa B.
      With Western blotting, it was shown that nuclear extracts from monocytes
      contained p50 and p65 protein in response to LPS and IFN-gamma stimulation.
      However, the combined stimulation did not result in enhanced p50 and p65 protein
      expression. The effects of IFN-gamma on the transcription factors were specific,
      since no change was observed in the expression of NF-IL-6 or I kappa B alpha, the
      inhibitor of NF-kappa B. We conclude that the effects of IFN-gamma on the
      expression of the transcription factors AP-1 and NF-kappa B may be important for
      the modulatory effects of IFN-gamma on the cytokine expression in activated human
      monocytes.

PMID- 8641347
TI  - Fetal bone marrow CD34+CD41+ cells are enriched for multipotent hematopoietic
      progenitors, but not for pluripotent stem cells.
AB  - We have investigated the expression of CD41a (gpIIbIIIa) on a subpopulation of
      human fetal bone marrow (FBM) CD34+ progenitor cells. Human FBM CD34+Lin- cells
      were subfractionated into CD41a+ and CD41a- subpopulations by flow cytometry. All
      the megakaryocyte colony-forming cells (CFU-MK) and almost all the burst-forming
      units-megakaryocyte (BFU-MK) were found within the CD41a+ subpopulation. In
      addition, a 14-fold greater number of granulocyte-macrophage colony-forming units
      (CFU-GM) and a five-fold greater number of mixed lineage progenitor cells (CFU
      mix) were observed within the CD34+Lin-CD41a+ subpopulation compared to the
      CD34+Lin-CD41a- subpopulation. The high proliferative potential of CD34+Lin
      CD41a+ cells was demonstrated by their capacity to expand in in vitro culture
      containing human plasma and recombinant Mpl ligand (thrombopoietin [Tpo]) with
      production of over 80% CD41b+ (gpIIb+) MKs. However, in long-term bone marrow
      cultures, the CD34+Lin-CD41a- population contained a significantly higher
      frequency of cobblestone area-forming cells (CAFC) than the CD34+Lin-CD41a+
      population, indicating the presence of a primitive hematopoietic stem cell (HSC)
      population within the CD34+Lin-CD41a- subset. These data suggest that fetal
      CD34+Lin-CD41a+ cells are enriched for MK progenitor cells (CFU-MK and BFU-MK),
      myeloid progenitors, and CFU-mix but do not contain the more primitive CAFC.

PMID- 8641348
TI  - Goralatide (AcSDKP) selectively protects murine hematopoietic progenitors and
      stem cells against hyperthermic damage.
AB  - Hyperthermic purging procedures may be improved by methods that selectively
      inhibit the proliferative activity of normal hematopoietic progenitors and stem
      cells, since active proliferation of these subsets is accompanied by increased
      heat sensitivity. For this reason, bone marrow cells from CBA/H mice were
      incubated with Goralatide (tetrapeptide Acetyl-N-Ser-Asp-Lys-Pro), a well-known
      inhibitor of normal hematopoietic progenitor cells to enter the S phase of the
      cell cycle. Subsequently, the cell suspensions were heat-treated at 43 degrees C
      for up to 90 minutes. After an exposure of 8 hours to 10(-9) M Goralatide, the
      number of CFU-GM cells in S phase decreased from 30 to 10%, resulting in an
      almost 10-fold increase in survival after 90 minutes at 43 degrees C. No effect
      on the primitive subsets could be detected because of their quiescent cell cycle
      state in normal bone marrow. To investigate the potential vulnerability of these
      subsets for Goralatide, bone marrow cells from 5-fluorouracil (5-FU)-pretreated
      mice were used. 5-FU induced increase in proliferative activity of the CFU-S-12
      (day-12 colony-forming units-spleen), and the stem cell with marrow repopulating
      ability could be abolished by an incubation period with 10(-9) M Goralatide for
      16 and 24 hours, respectively. Hence, this decrease in proliferative activity
      confers a decrease in hyperthermic sensitivity for the primitive hematopoietic
      subsets. The cytotoxic effect of the incubation on the absolute number of the
      hematopoietic progenitors and stem cells was <10%. Goralatide treatment (10(-8),
      10(-9), and 10(-10) M) up to 24 hours had no effect on the growth kinetics and
      cell cycle distribution and consequently on the hyperthermic sensitivity of L1210
      cells. Based on these results, it can be concluded that Goralatide will have a
      positive effect on the survival of hematopoietic progenitors and stem cells after
      hyperthermia and may lead to a gain in the therapeutic window of this purging
      modality.

PMID- 8641349
TI  - Response of human multiple myeloma-derived cell lines to alkyl-lysophospholipid.
AB  - Clinical studies using high-dose chemotherapy and autologous bone marrow
      transplantation in multiple myeloma report improvement in tumor regression. The
      potential success of this approach may be compromised because of the myeloma cell
      burden. A promising approach is chemopurging of bone marrow with alkyl
      lysophospholipids (ALP), a new class of antitumor agents. Using a limiting
      dilution assay, we tested ALP against several drug-resistant human myeloma cell
      lines: RPMI 8226/S, 8226/DOX40, 8226/LR-5, 8226/MR-20, 8226/DOX1V, and
      8226/MDR10V. IC50 values were approximately 6 microg/mL, for all cell lines
      evaluated. ALP was effective against all cells, with mean log kills ranging from
      2.48 to 4.95. Cytotoxicity was temperature-dependent. Survival curves of cell
      lines exposed to ALP showed a steep slope during the first 4 hours of exposure,
      with little additional cell kill after 24 hours. Dose-response curves after drug
      exposure for 4 and 24 hours reached plateaus at 75 and 25 microg/mL,
      respectively. Increasing concentrations of ALP caused a sustained increase in
      resting [Ca2+]i of sufficient magnitude to induce cell death. These results
      suggest that ALP is an effective cytotoxic agent even in cells known to be
      resistant to alkylating agents and other classes of cytotoxic drugs.

PMID- 8641350
TI  - Stimulation of megakaryocytopoiesis in mice by human modified C-reactive protein
      (mCRP)
AB  - The prototypic human acute phase reactant, C-reactive protein (CRP), and a
      structurally modified form of CRP (mCRP) were studied as agents which could
      stimulate thrombopoiesis in both in vitro and in vivo mouse models. mCRP, but not
      the widely studied (native) pentameric form of CRP, demonstrated significant
      megakaryocyte colony-stimulating activity. This activity was measured in plasma
      clot cultures incubated with pokeweed mitogen-stimulated spleen cell conditioned
      medium (PWM-SCM). mCRP increased the number of mouse megakaryocyte colonies in a
      dose-dependent manner. While significantly more colonies were observed in mCRP
      treated cultures compared to controls, the kinetics of megakaryocyte growth and
      maturation were similar to those measured in cultures stimulated with PWM-SCM
      lacking mCRP. A low level of megakaryocyte growth-promoting activity was noted
      when mCRP was added to plasma clot cultures not incubated with spleen cell
      conditioned medium. However, the most striking activity of mCRP was in
      potentiating stimulated megakaryocyte colony formation (i.e., as a Meg-POT
      factor). In in vivo experiments, mCRP injected subcutaneously into normal mice
      resulted in significant increases in blood platelet numbers compared to control
      mice receiving sham injections. These results suggest that a modified form of CRP
      has thrombopoietic activity in both in vitro and in vivo mouse models, Therefore,
      one important biological role for CRP during an acute-phase response might be to
      contribute, after a structural modification, to the hematopoietic regulation of
      blood platelets.

PMID- 8641352
TI  - Constant subcutaneous infusion of rhIL-11 in mice: efficient delivery enhances
      biological activity.
AB  - Previous studies have shown that subcutaneous (SC) bolus administration of
      recombinant human interleukin-11 (rhIL-11) stimulates megakaryocytopoiesis and
      increases peripheral platelet counts in naive mice. This study was designed to
      determine whether administration of rhIL-11 by constant SC infusion altered
      either the magnitude of the nature of the hematologic response. Female C57BL/6
      mice were implanted subcutaneously with 7-day Alzet mini-osmotic pumps containing
      either rhIL-11 with 0.5% homologous mouse serum (delivery rate of 250
      microg/kg/d) or vehicle alone. Mice were sacrificed on days 3, 7, 10, and 13
      after pump implantation, and the hematopoietic response was compared to mice
      receiving an equivalent dose of rhIL-11 administered by SC injection (250
      microg/kg/d, 7 days) or vehicle controls. Subcutaneous injection of rhIL-11
      resulted in a significant increase in peripheral platelet counts with a maximum
      platelet increase of 44% over controls observed on day 7 of the study. Platelet
      counts subsequently declined (24% by day 10) returning to control values by day
      13. The increase in peripheral platelet counts was accompanied by an increase in
      reticulated platelets on day 7 and a shift to higher ploidy bone marrow
      megakaryocytes on days 3 and 7. Compared to SC injection, both the magnitude and
      duration of the platelet increase were significantly enhanced following
      continuous SC infusion of rhIL-11. Maximum platelet counts were detected on day
      10 (115% above vehicle controls), and platelets remained significantly elevated
      on day 13 (84%), 6 days after rhIL-11 administration had stopped. Consistent with
      the platelet response, the modal ploidy of bone marrow megakaryocytes was shifted
      from 16N to 32N on days 3 and 7, with increases in 32N megakaryocytes still
      apparent on days 10 and 13. There was also a significant increase in reticulated
      platelets detected in the peripheral blood on days 3, 7, and 10 compared to mice
      administered rhIL-11 by SC injection, The changes in reticulated platelets and
      bone marrow megakaryocyte ploidy are consistent with the increased and prolonged
      platelet response following SC infusion of rhIL-11. In addition to the effects
      observed on peripheral platelet counts, constant SC infusion of rhIL-11
      dramatically enhanced splenic hematopoietic activity, increasing spleen weight
      and cellularity as well as splenic megakaryocyte, erythroid, granulocyte, and
      macrophage progenitors compared to mice receiving rhIL-11 by SC injection.

PMID- 8641351
TI  - Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic
      progenitor cells in normal and myelosuppressed mice.
AB  - Thrombopoietin (Tpo), the ligand for the proto-oncogene receptor c-Mpl, increases
      megakaryocyte size, ploidy, and surface expression of platelet-specific
      glycoproteins, is inversely related to platelet mass, and is a potent in vivo
      stimulus of platelet production. However, several features of c-mpl biology, and
      that of its viral counterpart v-mpl, suggest that the action of Tpo may not be
      strictly limited to megakaryocytopoiesis. To investigate the possibility that Tpo
      might affect a multitude of cell lineages, we studied the effects of in vivo
      administration of the hormone on multiple types of marrow and splenic clonogenic
      hematopoietic progenitors. We report that Tpo acts to expand BFU-E, CFU-GM, and
      CFU-Mk and redistribute CFU-E in normal mice and to hasten the recovery of all of
      these progenitor cell types in myelosuppressed animals. These findings argue that
      the hematopoietic progenitor cell compartment responds to Tpo as a whole and that
      the in vivo effects of Tpo administration may be more wide-ranging than
      previously anticipated.

PMID- 8641353
TI  - Expression of c-fos and c-jun proteins and AP-1 binding activity during cell
      cycle progression of HL60 cells and phytohemagglutinin-stimulated lymphocytes.
AB  - The protein products of the c-fos (p62c-fos) and c-jun (p39c-jun) genes are
      members of the AP-1 transcription factor family and are thought to play important
      roles in the regulation of gene expression during the cell cycle. Most studies on
      the expression of these proteins in relation to the cell cycle have been
      performed at the mRNA level, and therefore do not give direct information about
      the presence of the proteins during the cell cycle. We have used Western blotting
      to investigate the presence of these proteins during the cell cycles of two
      different cellular systems: a continuously growing myeloid leukemic cell line,
      HL60, and normal cells stimulated into cycle, phyto- hemagglutinin (PHA)
      stimulated normal human peripheral blood lymphocytes (PBL). The binding activity
      of transcription factor AP-1, which consists of dimers of Fos and Jun family
      proteins, was also studied using a gel shift assay. We found nuclear p62c-fos,
      p39c-jun, and AP-1 binding activity throughout the cell cycle both in HL60 cells
      and in PHA-stimulated PBL, and we postulate that these proteins are required
      throughout the cell cycle and not transiently in the G0 to G1 transition as
      previous mRNA studies have indicated. We demonstrated an uncoupling of AP-1
      binding activity from p62c-fos, and p39c-jun AP-1 activity was expressed more
      strongly in the G1- and G2/M-phase enriched samples than in the S-phase enriched
      samples of HL60 cells, while levels of nuclear p62c-fos and p39c-jun were
      constant. Nuclei of unstimulated PBL from different donors expressed p62c-fos and
      p39c-jun, but AP-1 was not detected in the majority of samples. Following PHA
      stimulation of PBL, the increase in AP-1 activity was delayed with respect to the
      augmentation of p39c-jun expression. We also observed that cytoplasmic p62c-fos
      and p39c-jun were present in HL60 cells and PHA-stimulated PBL. However, no
      cytoplasmic p62c-fos was detected in unstimulated PBL, although in some cases
      cytoplasmic p39c-jun was detected, suggesting that subcellular
      compartmentalization of these proteins may occur under certain circumstances.

PMID- 8641354
TI  - Isolation and characterization of primitive hematopoietic progenitors of murine
      fetal liver.
AB  - We have isolated hematopoietic progenitors from mouse fetal liver using a
      sequential protocol of density gradient centrifugation, panning, and cell
      sorting. Isolated AA4.1+Ly-6A/E+CD43++ cells with density ranging from 1.0631 to
      1.0770 g/cm3 were 480- to 600-fold enriched for multipotential progenitors
      relative to unfractionated cells and showed 40 to 60% colony-forming efficiency.
      We then examined the effects of various cytokines on the colony formation from
      enriched fetal liver cells. Steel factor (SF), interleukin-3 (IL-3), IL-4, IL-6,
      IL-11, and granulocyte colony-stimulating factor (G-CSF) as single agents
      supported formation of significant numbers of colonies, but flt3/flk-2 ligand
      (FL) and IL-12 did not. When the cytokines were combined, FL, SF, IL-3, and IL-4
      each synergized individually with IL-6, IL-11, IL-12, or G-CSF to support
      formation of various types of colonies. Next we analyzed the growth factor
      requirements for proliferation and differentiation of lymphohematopoietic
      progenitors by using the two-step methylcellulose culture assay we established
      recently. None of the early-acting factors were effective as a single agent, but
      combinations of SF or FL with IL-6, IL-11, or G-CSF were effective in supporting
      B cell potential of the primary colonies. Of these, the combination of FL plus IL
      11 appeared to be the most effective.

PMID- 8641355
TI  - A novel aspect of the maturational step of megakaryocytes in thrombopoiesis:
      bundle formation of microtubules in megakaryocytes.
AB  - We demonstrated bundle formation of microtubules both in the cytoplasmic
      processes and in the cytoplasm near the nucleus of cultured megakaryocytes by
      means of electron and immunofluorescent microscopy. To determine whether this
      bundle formation was related to megakaryocyte maturation, we studied the effects
      of recombinant human interleukin-6 (rhIL-6) in vitro and in vivo on this event.
      About 75% of the megakaryocytes in the bone marrow had no fibrous microtubule
      structures in the cytoplasm (type I), and about 25% had bundles of microtubules
      (type II). The formation of these bundles was promoted by rhIL-6 both in vitro
      and in vivo. Considerably more megakaryocytes cultured with recombinant murine
      (rm) IL-3 and rhIL-6 became type II than those cultured with rmIL-3 alone.
      Megakaryocytes from mice given rhIL-6 (10 microg/animal/d) subcutaneously also
      began to form bundles in proportion to an increase in platelet counts. After the
      administration of rhIL-6, about half of the megakaryocytes contained microtubule
      bundles in their cytoplasm. These results indicate that microtubule-bundle
      formation is one maturational event in megakaryocyte development and that rhIL-6
      could accelerate this event.

PMID- 8641356
TI  - Ex vivo expansion of murine hematopoietic progenitor cells generates classes of
      expanded cells possessing different levels of bone marrow repopulating potential.
AB  - The objective of ex vivo expansion of primitive hematopoietic progenitor cells
      (HPC) is to increase the number of progeny cells possessing hematopoietic
      potential similar to the original HPC. In the context of bone marrow (BM)
      transplantation in mice, this implies that expanding a number of HPC sufficient
      for long-term rescue of one lethally irradiated animal should generate enough
      cells to rescue more than one lethally irradiated recipient. In the present
      study, Sca-1+Lin- cells from male C57Bl/6 mice were expanded in vitro with stem
      cell factor (SCF), interleukin-1alpha (IL-1alpha), IL-3, and IL-6 and used to
      transplant lethally irradiated syngeneic female recipients. Expanded cells were
      tracked in vitro with the fluorescent membrane dye PKH2, which becomes evenly
      distributed among dividing daughter cells, and fractionated on day 7 into Sca-1+
      cells which did not divide (Sca-1+PKH2bright), those which had divided 1 to 2
      times (Sca-1+PKH2moderate), or those which had divided four or more times (Sca
      1+PKH2dim). Grafts of expanded cells consisted of either the same number of fresh
      cells proven to rescue lethally irradiated animals [3X10(3) cells; referred to as
      one repopulating dose (1 RD)] or the expansion equivalent (EE) of these cells.
      One EE of cells represented 3X10(3) multiplied by the fold increase in the number
      of cultured cells on day 7. All animals transplanted with 3X10(3) freshly
      isolated Sca-1+Lin- cells survived long-term. Only 53% of animals receiving 1 EE
      of all cultured day-7 cells survived. One RD from all three PKH2 fractions
      (bright, moderate, and dim) of day-7 cultured Sca-1+ cells failed to rescue more
      than 30% of lethally irradiated recipients. Comparable survival rates were
      obtained when 1 EE of Sca-1+PKH2dim or only 4 RD of Sca-1+PKH2bright cells were
      used as grafts, suggesting that a larger frequency of long-term repopulating
      cells may have been retained within the fraction of Sca-1+ cells undergoing
      minimal or no proliferation in culture. Engraftment of male ex vivo expanded
      cells in recipients was confirmed by polymerase chain reaction (PCR) analysis
      with Y chromosome-specific primers. When analyzed for their cell cycle status,
      Sca-1+PKH2bright cells were mostly quiescent, whereas a higher percentage of Sca
      1+PKH2dim cells were in active phases of cell cycle. These data suggest that ex
      vivo expansion does not augment the number of BM repopulating HPC and that ex
      vivo expansion generates classes of progenitor cells with different BM
      repopulating potentials depending on their proliferative history. These studies
      also suggest that the cell cycle status of graft cells may affect the ability of
      these cells to engraft in myeloablated hosts.

PMID- 8641357
TI  - Interaction between a murine myeloma cell line and bone marrow stromal cells.
AB  - Intravenous transplantation of an in vitro maintained murine myeloma cell line,
      5T33, results in progressive growth in the bone marrow of C57Bl/KaLwRiJ mice.
      Concurrent with the growth of the tumor in vivo, the bone marrow stromal cells
      are inhibited, as assayed by their ability to form stromal cell foci and long
      term monolayers in vitro. Inhibition of normal mouse marrow stromal cell growth
      also occurs when 5T33 cells are added to the marrow cells in vitro, and contact
      between the marrow and 5T33 cells is not necessary to achieve inhibition,
      indicating secretion of one or more diffusible inhibitory factors.

PMID- 8641358
TI  - p210BCR/ABL induces formation of complexes containing focal adhesion proteins and
      the protooncogene product p120c-Cbl.
AB  - Chronic myelogenous leukemia (CML) is a myeloproliferative disorder caused by the
      t(9;22) translocation. This translocation creates a unique tyrosine kinase
      oncogene, bcr/abl, whose product, p210BCR/ABL, is localized to the actin
      cytoskeleton. One of the major tyrosine phosphoproteins in cells transformed by
      p210BCR/ABL is the protooncoprotein p120c-Cbl. We have previously shown that
      p210BCR/ABL induces formation of a multimeric complex of proteins which include
      p120c-Cbl, phosphotidylinositol-3' kinase, and p210BCR/ABL itself. Here we show
      that certain focal adhesion proteins are also part of this complex, including
      paxillin and talin. The sites in paxillin required to bind to p120c-Cbl in this
      complex have been partially mapped. The interaction of pl20c-Cbl with paxillin is
      specific, since other focal adhesion proteins, such as p125FAK, vinculin, and
      alpha-actinin, are not in this complex. The binding of p120c-Cbl to the focal
      adhesion protein paxillin could contribute to the known adhesive defects of CML
      cells.

PMID- 8641359
TI  - Paradoxical stimulation of normal and leukemic rat hematopoiesis by monoclonal
      antibody to CSF-1 receptor.
AB  - We have recently developed a rat monoclonal antibody directed against the murine
      M-CSF receptor (c-fms). This reagent also inhibits in vitro colony formation by
      leukemic and normal rat splenocytes in response to M-CSF. At high antibody
      concentrations, the antibody augments, rather than inhibits, colony formation by
      rat cells in the presence of M-CSF, an effect that is not seen when murine cells
      are used as responders. The costimulatory and inhibitory activities of the
      monoclonal antibody preparations copurify in a number of purification methods,
      indicating that the costimulatory activity is intrinsic to the antireceptor
      antibody. Conversion of the antibody into monovalent Fab fragments by papain
      digestion destroys costimulatory activity. This finding raises a cautionary note
      for the in vivo use of intact monoclonal antibodies directed against growth
      factor receptors for the treatment of hematologic malignancies.

PMID- 8641361
TI  - Applications of retrovirus-mediated expression cloning.
AB  - We have recently established a novel expression cloning system using retroviral
      vectors. The system is based on a high-efficiency packaging cell line, BOSC23,
      and a simplified retroviral vector, pBabeX, carrying no selection marker. cDNA
      libraries, constructed in the pBabeX vector, are transiently transfected into
      BOSC23 cells. The supernatant contains more than 3X10(6)/mL, which would cover
      large complexities of cDNA libraries. The retrovirus stock gave 100% infection
      efficiency in NIH3T3 cells and 5-40% infection efficiency in various
      hematopoietic cell lines. In contrast to the conventional expression cloning
      system, in which it is necessary to transfect cDNA libraries transiently into
      particular cell types such as COS cells, retrovirus-mediated expression cloning
      allows us to transduce cDNAs into a wide variety of cell types. This method
      therefore makes it possible to select cells expressing a cDNA of interest by
      various functional assays. When combined with polymerase chain reaction (PCR)
      driven random mutagenesis, this system is also useful in searching for mutations
      of various molecules that will result in alterations of their functions.

PMID- 8641360
TI  - The Dtk receptor tyrosine kinase, which binds protein S, is expressed during
      hematopoiesis.
AB  - Dtk (Tyro 3/Sky/Rse/Brt/Tif) belongs to a recently recognized subfamily of
      receptor tyrosine kinases that also includes Ufo (Axl/Ark) and Mer (Eyk). Ligands
      for Dtk and Ufo have been identified as protein S and the related molecule Gas6,
      respectively. This study examined expression of Dtk during ontogeny of the
      hematopoietic system and compared the pattern of expression with that of Ufo.
      Both receptors were abundantly expressed in differentiating embryonic stem cells,
      yolk sac blood islands, para-aortic splanchnopleural mesoderm, fractionated AA4+
      fetal liver cells, and fetal thymus from day 14 until birth. Although Ufo was
      expressed at moderate levels in adult bone marrow, expression of Dtk in this
      tissue was barely detectable. In adult bone marrow subpopulations fractionated
      using counterflow centrifugal elutriation, immunomagnetic bead selection for
      lineage-depletion and FACS sorting for c-kit expression, very low levels of Dtk
      and/or Ufo were detected in some cell fractions. These results suggest that Dtk
      and Ufo are likely to be involved in the regulation of hematopoiesis,
      particularly during the embryonic stages of blood cell development.

PMID- 8641362
TI  - The sensitivity of in vitro erythropoietic progenitor cells to different
      erythropoietin reagents during development and the role of cell death in culture.
AB  - With the availability of several recombinant erythropoietin (Epo) reagents, it
      has been possible to undertake a systematic study of the relative Epo sensitivity
      of late erythroid colony-forming units (CFU-E) in 8.5-day embryos, 13.5-day fetal
      liver, and adult bone marrow of the mouse. All Epo preparations tested, including
      one from impure sheep and a highly purified human native Epo preparation,
      produced parallel, but displaced, dose-response curves when Epo concentration was
      plotted against percent CFU-E response calculated from the optimal Epo
      concentration. It was found that the CFU-E derived from 8.5-day embryos
      demonstrated the greatest Epo sensitivity which decreased in fetal liver and
      adult bone marrow CFU-E populations. Modifications to the culture system allowed
      CFU-E to be stimulated with as little as 0.003 mU/mL, equivalent to approximately
      0.03 fg Epo. Under these culture conditions, no evidence for apoptosis was found,
      although a normal programmed cell death function cannot be ruled out.

PMID- 8641363
TI  - The effects of human FLT3 ligand on in vitro human megakaryocytopoiesis.
AB  - The human homolog of the murine flt3/flk2 gene product is a tyrosine kinase
      receptor that plays a role in regulating the proliferation and differentiation of
      cells in the hematopoietic system. Using a plasma-clot clonal assay and a long
      term bone marrow culture (LTBMC) system, we studied the effects of the recently
      cloned human flt3 ligand (FL) alone and in combination with granulocyte
      macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), or stem cell
      factor (c-kit ligand [KL]) on human megakaryocytopoiesis. The effects of FL on
      the primitive megakaryocyte (MK) progenitor cell, the burst-forming unit
      megakaryocyte (BFU-MK), and the more differentiated colony-forming unit
      megakaryocyte (CFU-MK) were determined. FL alone had no megakaryocytic colony
      stimulating activity (MK-CSA), but was capable of augmenting the MK-CSA of both
      GM-CSF and IL-3. FL synergized with IL-3 at the level of both CFU-MK and BFU-MK
      and with GM-CSF and KL at the level of CFU-MK. Although FL alone exhibited a
      limited potential in sustaining long-term megakaryocytopoiesis in vitro, it
      synergistically augmented the ability of IL-3 and KL, alone or in association, to
      promote long-term megakaryocytopoiesis. These data indicate that multiple
      cytokines are necessary to optimally stimulate the proliferation of both classes
      of MK progenitor cells and that FL plays a significant role in this process by
      amplifying the MK-CSA of GM-CSF, IL-3, and KL.

PMID- 8641364
TI  - Influence of retroviral-mediated gene transduction of both the recombinant human
      erythropoietin receptor and interleukin-9 receptor genes into single CD34++CD33
      or low cord blood cells on cytokine-stimulated erythroid colony formation.
AB  - Introduction of genes for cytokine receptors into hematopoietic stem/progenitor
      cells (HSC/HPC) may be of clinical use in the future. We recently reported that
      retroviral-mediated transduction of either the human erythropoietin receptor
      (hEpoR) or interleukin-9 receptor (hIL-9R) genes into highly purified HSC/HPC
      from cord blood (CB) resulted in increased numbers of detectable cytokine
      responsive erythroid progenitors (burst-forming units-erythroid [BFU-E]). In the
      present study, we evaluated if this increase could be further enhanced by
      cotransducing both these genes into single isolated HSC/HPC. Single CD34++CD33-or
      low-expressing cells from CB were transduced with viral supernatant containing
      the hEpoR or hIL-9R genes or cotransduced with both genes. In the presence of
      Steel factor (SLF), interleukin-3 (IL-3), granulocyte-macrophage colony
      stimulating factor (GM-CSF), erythropoietin (Epo), and IL-9, the numbers of
      erythroid colonies formed were significantly increased after transduction of
      cells with either the hIL-9R or hEpoR gene compared to mock-transduced cells.
      This increase was significantly enhanced in cells cotransduced with both genes
      compared with either gene alone. Integration and expression of both genes was
      confirmed by polymerase chain reaction (PCR) and reverse-transcriptase (RT)-PCR
      analysis, respectively. The data demonstrate that myeloid progenitors can be
      transduced at the single-cell level with both hEpoR and hIL-9R genes with
      resultant enhanced proliferation of these progenitors in the erythroid lineage by
      combinations of cytokines including Epo and IL-9.

PMID- 8641367
TI  - Activity of Friend mink cell focus-forming retrovirus during myelo-erythroid
      hematopoiesis.
AB  - Friend mink cell focus-forming (FMCF) viruses are recombinants between the Friend
      murine leukemia virus (F-MuLV) and endogenous polytropic retroviruses involved in
      a number of retrovirus-induced malignancies of the myelo-erythroid compartment.
      To analyze the contribution of the viral cis regulatory elements to the host
      range determinants within the hematopoietic system, we performed a series of
      marker gene experiments using both transient transfection and retroviral-mediated
      stable transduction of indicator cell lines representing distinct developmental
      stages. According to our data, the U3 region in the long terminal repeat (LTR) of
      FMCF viruses possesses an enhancer assembly that allows efficient transcription
      in both early and late myelo-erythroid stem and progenitor cells. Retroviral gene
      expression, however, is subjected to stage-dependent transcriptional controls
      during blood cell maturation. We obtained evidence that a repressor element
      overlapping with the primer binding site in the viral leader region compromises
      U3-mediated gene expression in a stage-dependent manner, with the strongest
      restriction observed in the most primitive cells analyzed, FDCP-mix. In addition,
      our data indicate a second hurdle for retroviral gene expression in early
      hematopoietic cells that is independent of the primer binding site and most
      likely related to inefficient utilization of U3-located enhancers. These data
      shed light on the mechanisms of host range restriction within the hematopoietic
      system and define a basis for the design of retroviral vectors aimed to overcome
      transcriptional inefficiency in early hematopoietic cells. Thus, we developed
      novel retroviral vectors combining FMCF-type U3 regions with a permissive leader
      from the murine embryonic stem cell virus. These vectors are highly efficient for
      gene transfer and expression in both early and late myelo-erythroid cells,
      indicating that they will be of great use for a variety of experimental and
      therapeutic applications.

PMID- 8641366
TI  - Augmentation of antitumor immunity using genetically M-CSF-expressing L1210
      cells.
AB  - Macrophage colony-stimulating factor (M-CSF) enhances tumoricidal activities of
      macrophages. We transduced human M-CSF cDNA into the mouse lymphoid cell line,
      L1210, and examined the antitumor effect of the locally expressed M-CSF. Mice
      injected with the M-CSF-producing subline showed improved survival in comparison
      with the mock-transfected cell line or parental cell line plus M-CSF
      administration (20 microg/kg for 3 days) at inoculated cell numbers of 10(2) or 5
      x 10(3). The survival rate at 50 days after injection of 10(6) high M-CSF
      expressing cells was 80%, significantly higher than that after injection of the
      mock-transfected cells, which killed all the mice by day 23. The survival rate
      appeared to depend on the amount of M-CSF produced. Moreover, all surviving mice
      after intravenous injection of the M-CSF-expressing sublines were rechallenged
      with 10(6) parental L1210 cells at day 50, and all survived up to day 100,
      demonstrating that M-CSF-expressing cells induced immune protection against the
      parental cells. The same improvement of survival was observed in mouse M-CSF
      expressing cell lines. These observations imply that M-CSF cDNA is a candidate
      gene for use in gene therapy in leukemia.

PMID- 8641365
TI  - Analysis of the production of soluble ICAM-1 molecules by human cells.
AB  - The adhesion molecule intercellular adhesion molecule-1 (ICAM-1), in addition to
      its membrane-associated form (mICAM-1), also exists as a soluble form (sICAM-1).
      sICAM-1 is capable of binding to lymphocyte function associated antigen-1 (LFA-1)
      molecules, and production of sICAM-1 is therefore thought to have
      immunomodulatory consequences. The present study, which employed normal human
      keratinocytes as a model for sICAM-1-producing cells, was conducted to determine
      the mechanism responsible for the production of sICAM-1 and to develop a strategy
      for specific inhibition of sICAM-1 production. Stimulation of keratinocytes with
      recombinant human gamma-interferon (rhIFN-gamma) induced both expression of mICAM
      1 and production of sICAM-1. Western blot analysis revealed that keratinocyte
      derived sICAM-1, compared to mICAM-1, had a smaller molecular size, approximately
      a 7-kD difference. Neither by Northern blot analysis nor by reverse-transcriptase
      polymerase chain reaction (RT-PCR) was any evidence for alternatively spliced
      ICAM-1 mRNA obtained. Addition of the protease inhibitors iodoacetamide and E-64,
      however, inhibited the production of sICAM-1 in a dose-dependent manner. The
      involvement of proteolytic cleavage in the production of sICAM-1 was corroborated
      in minimal peptide protection assays, in which minimal peptides covering the
      potential cleavage site of ICAM-1 were added to sICAM-1-producing keratinocytes.
      One of these peptides, ICAM cleavage inhibitory peptide (ICAM-CIP), inhibited the
      production of sICAM-1 without affecting mICAM-1 expression. These studies
      demonstrate that sICAM-1 production in human keratinocytes is due to proteolytic
      cleavage, and that the oligopeptide ICAM-CIP may specifically inhibit this
      mechanism. The capacity of ICAM-CIP to selectively prevent production of sICAM-1
      may be useful for the development of novel therapeutic approaches relevant for
      the management of inflammation and cancer.

PMID- 8641369
TI  - Effects of flt3 ligand on acute myeloid and lymphocytic leukemic blast cells from
      children.
AB  - A ligand for the flt3 tyrosine kinase receptor (flt3R) has recently been cloned.
      Forty-three cases of childhood acute myeloid leukemia (AML) and 27 cases of
      childhood acute lymphocytic leukemia (ALL) were examined by flow cytometric
      analysis for cell-surface flt3R and proliferative response in vitro to flt3
      ligand (flt3L). Flt3R was commonly expressed on the cell surface of leukemic
      cells from all AML subclasses and B-ALL, but we did not detect cell-surface flt3R
      on T-ALL. Flt3L alone induced the proliferation of the monocytic AML-M5 cells and
      some erythroleukemic AML-M6 cells. Some isolated instances of weak proliferative
      responses were also noted in other AML subclasses. Interleukin-4 (IL-4) alone
      inhibited the proliferation of a group of AML-M5 cells and, when combined with
      flt3L, suppressed the proliferative effect of flt3L. In general, B-ALL and T-ALL
      cells failed to respond to flt3L alone or in the presence of combinations of IL
      2, IL-3, or IL-7.

PMID- 8641368
TI  - Effects of Flt3 ligand and interleukin-7 on in vitro growth of acute
      lymphoblastic leukemia cells.
AB  - We investigated the effects of Flt3/Flk-2 ligand (FL) and interleukin-7 (IL-7) on
      DNA synthesis and proliferation of blast cells from patients with acute
      lymphoblastic leukemia (ALL). After 7 days of serum-free suspension culture of 19
      samples, FL induced maximal DNA synthesis in two cases, whereas the combination
      of FL and IL-7 did so in another eight samples with a stimulation index (SI) >2.
      However, the number of viable cells after 7 days of liquid culture decreased in
      all but one sample. In this case of a pre-pre-B-ALL with a translocation t(4;11),
      FL induced dose-dependent proliferation (maximal 100 ng/mL) and cells stimulated
      with FL could be cultured for up to 4 weeks. A homogeneous population with 98%
      CD19-positive cells was detected before and after culture, and there was no
      evidence of nonleukemic cell proliferation as determined by immunophenotyping.
      The flt3 gene was transcribed in all seven cases studied by reverse-transcriptase
      polymerase chain reaction (RT-PCR). In the ALL cells responsive to FL, the
      expression of functional Flt3 receptors was confirmed by demonstrating FL
      dependent tyrosine phosphorylation of Flt3. Furthermore, FL-dependent tyrosine
      phosphorylation of cellular proteins of estimated molecular weights of 70, 115,
      and 140 kD was detectable in these cells. These data demonstrate the functional
      heterogeneity of ALL samples and show that functional Flt3 receptors capable of
      mediating FL-dependent mitogenic signaling are expressed in a subset of ALL.

PMID- 8641370
TI  - Selective adhesion of immature thymocytes to bone marrow stromal cells: relevance
      to T cell lymphopoiesis.
AB  - We investigated the interactions between the bone marrow microenvironment and T
      cell populations at different stages of maturation. Thymocytes were seeded onto
      confluent layers of bone marrow stromal cell lines (MBA-13 or 14F1.1). Within a
      few hours two main thymocyte populations were observed; one remained in the
      liquid phase and the other adhered to the stromal cells. After 24 hours of
      culture, most of the adhering cells expressed the phenotype of the precursors,
      double negative (DN) CD4-CD8-, or of immature thymocytes, double positive (DP)
      CD4+CD8+. The number of adhering DN cells did not change during the time of the
      culture, whereas that of the DP declined. The CD4+CD8- or CD4-CD8+ cells did not
      adhere to any significant extent. The expression of CD3 antigen on adherent
      thymocytes was lower than that on nonadherent ones. Sorted thymocytes at a high
      level of purification (>96%) were cultured over stromal layer and, after 24
      hours, 60% of the DN or 22% of the DP cells were found to adhere to the stroma.
      The culture medium was replaced every 24 hours or after 48 hours; no significant
      change was noted in the number of adhering DN and DP cells. The reappearance of
      immature T cells in the liquid phase suggested proliferation of this cell type.
      Thus, early thymocytes, phenotypically characterized as DN and DP, preferentially
      adhere to bone marrow stromal cells. This in vitro phenomenon may represent the
      function of the BM stroma as an extrathymic site of T cell lymphopoiesis.

PMID- 8641371
TI  - Erythropoietin induces Ca2+ mobilization and contraction in rat mesangial and
      aortic smooth muscle cultures.
AB  - Reportedly, recombinant human erythropoietin (rhEpo) can induce constriction of
      isolated resistance vessels. We have studied whether rhEpo affects cytosolic
      calcium concentration, [Ca2+]i, and contraction of cultured smooth-muscle cells
      grown from rat renal corpuscles and aortae. rhEpo at high dose (> or = 20 U/mL)
      induced a transient increase in [Ca2+]i as detected by fura-2 fluorescence
      analysis. The number of cells responding with an increase in [Ca2+]i was dose
      dependent. No significant changes of [Ca2+]i occurred when lower doses of rhEpo
      (< 20 U/mL) were applied. The effect of Epo on contraction was studied by phase
      contrast microscopy. The number of cells responding with contraction was dose
      dependent, too (76% mesangial cells contracting at 200 U rhEpo per mL). The
      receptor mechanism of this unusual action of Epo still needs to be clarified.

PMID- 8641373
TI  - Metabolic regulation--physiological and medical aspects.

PMID- 8641372
TI  - Regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors
      in a GM-CSF-dependent human myeloid leukemia cell line (AML-193) by interleukin
      6.
AB  - AML-193 is a cytokine-dependent human leukemia cell line established from the
      bone marrow of an M5-type acute monocytic leukemia (AML) patient. The effect of
      recombinant human interleukin-6 (rhIL-6) on the proliferation of AML-193 cells
      was investigated. Both granulocyte-macrophage colony-stimulating factor (rhGM
      CSF) and rhIL-3 promoted the DNA synthesis and growth of AML-193 cells in vitro.
      rhIL-6 alone did not support the growth of AML-193 cells, yet pretreatment of AML
      193 cells with rhIL-6 markedly enhanced their proliferative response to
      subsequent rhGM-CSF or rhIL-3 stimulation. The growth-promoting effect induced by
      rhIL-6 was attributable in part to the upregulation of GM-CSF receptors on AML
      193 cells; treatment of AML-193 cells with rhIL-6 for 24 to 48 hours greatly
      increased their GM-CSF binding activity, which occurred in a dose-dependent
      manner. Both the growth-promoting and receptor-upregulating effects induced by
      rhIL-6 could be blocked by treating AML-193 cells with neutralizing anti-gp130
      antibodies (GPX7). Treatment of AML-193 cells with anti-gp130 antibodies alone
      also led to a notable decline in GM-CSF binding activity, suggesting a possible
      role of gpl30 in regulating the expression of GM-CSF receptors. When AML-193
      cells were starved in cytokine-free medium and then restimulated with rhGM-CSF, a
      rapid increase (5 minutes) in lyn kinase activity was observed. A similar
      upregulation of lyn kinase activity by rhIL-6 treatment also was noted in AML-193
      cells, but only after a prolonged incubation of the cells with rhIL-6 (>24
      hours). These findings show that the growth-promoting effects of rhIL-6 are
      mediated through the upregulation of GM-CSF receptors on AML-193 cells by
      mechanisms that appear to involve the activation of both gp130 and lyn kinase.

PMID- 8641374
TI  - Control of adenine nucleotide metabolism and glycolysis in vertebrate skeletal
      muscle during exercise.
AB  - The turnover of adenosine triphosphate (ATP) in vertebrate skeletal muscle can
      increase more than a hundredfold during high-intensity exercise, while the
      content of ATP in muscle may remain virtually unchanged. This requires that the
      rates of ATP hydrolysis and ATP synthesis are exactly balanced despite large
      fluctuations in reaction rates. ATP is regenerated initially at the expense of
      phosphocreatine (PCr) and then mainly through glycolysis from muscle glycogen.
      The increased ATP turnover in contracting muscle will cause an increase in the
      contents of adenosine diphosphate (ADP), adenosine monophosphate (AMP) and
      inorganic phosphate (P(i)), metabolites that are substrates and activators of
      regulatory enzymes such as glycogen phosphorylase and phosphofructokinase. An
      intracellular metabolic feedback mechanism is thus activated by muscle
      contraction. How muscle metabolism is integrated in the intact body under
      physiological conditions is not fully understood. Common frogs are suitable
      experimental animals for the study of this problem because they can readily be
      induced to change from rest to high-intensity exercise, in the form of swimming.
      The changes in metabolites and effectors in gastrocnemius muscle were followed
      during exercise, post-exercise recovery and repeated exercise. The results
      suggest that glycolytic flux in muscle is modulated by signals from outside the
      muscle and that fructose 2,6-bisphosphate is a key signal in this process.

PMID- 8641375
TI  - Flying insects: model systems in exercise physiology.
AB  - Insect flight is the most energy-demanding exercise known. It requires very
      effective coupling of adenosine triphosphate (ATP) hydrolysis and regeneration in
      the working flight muscles. 31P nuclear magnetic resonance (NMR) spectroscopy of
      locust flight muscle in vivo has shown that flight causes only a small decrease
      in the content of ATP, whereas the free concentrations of inorganic phosphate
      (Pi), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) were
      estimated to increase by about 3-, 5- and 27-fold, respectively. These
      metabolites are potent activators of glycogen phosphorylase and
      phosphofructokinase (PFK). Activation of glycolysis by AMP and Pi is reinforced
      synergistically by fructose 2,6-biphosphate (F2,6P2), a very potent activator of
      PFK. During prolonged flight locusts gradually change from using carbohydrate to
      lipids as their main fuel. This requires a decrease in glycolytic flux which is
      brought about, at least in part, by a marked decrease in the content of F2,6P2 in
      flight muscle (by 80% within 15 min of flight). The synthesis of F2,6P2 in flight
      muscle can be stimulated by the nervous system via the biogenic amine octopamine.
      Octopamine and F2,6P2 seem to be part of a mechanism to control the rate of
      carbohydrate oxidation in flight muscle and thus function in the metabolic
      integration of insect flight.

PMID- 8641376
TI  - The plasma level of some amino acids and physical and mental fatigue.
AB  - Tryptophan is converted to 5-hydroxytryptamine (5-HT) in the brain and evidence
      is presented that an increase in the concentration of 5-HT can result in physical
      and mental fatigue during prolonged exercise. The entry of tryptophan in the
      brain is influenced by the plasma level of free tryptophan (that not bound to
      albumin) and, from competition for entry into brain, by the plasma level of
      branched chain amino acids. Hence, oral administration of branched chain amino
      acids could, theoretically, prevent the increase in 5-HT level during exercise
      and therefore delay physical and mental fatigue. Evidence in support of this
      hypothesis is presented.

PMID- 8641377
TI  - Concept of an extracellular regulation of muscular metabolic rate during heavy
      exercise in humans by psychophysiological feedback.
AB  - Efferent motor signals to skeletal muscles concern not only the space/ time
      pattern of motion, but also the setting of muscular performance and through this
      the control of the current metabolic rate. For an optimal adjustment of metabolic
      rate during heavy exercise-e.g. in athletic competitions-a feedback control
      system must exist, including a programmer that takes into consideration a
      finishing point (teleoanticipation). The presented experiments, using Borg's
      scale, indicate the existence and functioning of a system for optimal adjustment
      of performance during heavy exercise and the relevance of teleoanticipatory
      effects. Thus motor learning includes not only somatosensory control, but also
      metabolic control. With regard to migratory birds, such metabolic control would
      have to operate in the individual as well as in the migrating flock as a whole.

PMID- 8641378
TI  - Some thoughts on the importance of insulin in the regulation of the blood glucose
      level.
AB  - Insulin can influence rates of glucose utilization by muscle and possibly other
      tissues via both direct and indirect effects. It can control the rate of fatty
      acid mobilization from adipose tissue and the rate of fatty acid oxidation in
      muscle, and the latter inhibits glucose utilization and oxidation. Insulin may
      influence the levels of insulin-like growth factors I and II, both of which have
      effects on rates of glucose utilization by muscle. The inter-tissue cycle between
      glucose and lactate-the Cori cycle, which is influenced by insulin-may provide
      another novel mechanism for control of blood glucose. How far other anti-insulin
      hormones affect these processes is not clear.

PMID- 8641379
TI  - Hyperinsulinemia, hyperproinsulinemia and insulin resistance in the metabolic
      syndrome.
AB  - For better comprehension of the metabolic syndrome, it is necessary to
      differentiate the effect of insulin on glucose metabolism on the one hand, and on
      other metabolic activities on the other hand. Whereas glucose utilization is
      affected by insulin resistance, the effect of insulin on lipid metabolism, ion
      and aminoacid transport does not seem to be diminished. Lipid metabolism,
      however, seems to play a crucial role in the induction of the vicious cycle.
      Increased energy and fat ingestion may be due to an increased number of galanin
      secreting cells in the hypothalamus. The excessive fat intake results in an
      increased rate of release of insulin and increased influx of triglycerides into
      the blood. From these triglycerides an excess of free fatty acids is released by
      the action of lipoprotein lipase. The increased plasma free fatty acid level then
      results in insulin resistance affecting glucose metabolism. Also, these free
      fatty acids may impair the secretion of insulin. Induction of insulin resistance
      results in higher glucose levels, which may cause hyperinsulinemia.
      Hyperinsulinemia maintains the elevation of triglycerides. When diabetes becomes
      overt and elevated glucose levels prevail, the hyperinsulinism acts on the
      metabolic pathways which are still sensitive to insulin, namely lipid metabolism,
      aminoacid transport and ion transport.

PMID- 8641380
TI  - The Pasteur effect in facultative anaerobic metazoa.
AB  - The existence and the regulatory mechanisms of the Pasteur effect in facultative
      anaerobic metazoa are discussed. There are three reasons for the controversy
      surrounding this phenomenon. 1) The different definitions of the Pasteur effect,
      2) the antagonistic effect of metabolic depression and its species specific
      response to hypoxia, as well as 3) the laboratory-specific differences in the
      experimental procedures for analyzing the Pasteur effect and its regulation. This
      review aims to clarify the confusion about the existence of the Pasteur effect in
      facultative anaerobic metazoa and to offer possible molecular mechanisms.

PMID- 8641381
TI  - Conservation, evolution, and specificity in cellular control by protein
      phosphorylation.
AB  - The glycolytic control enzyme phosphofructokinase from the parasitic nematode
      Ascaris lumbricoides is regulated by reversible phosphorylation. The enzyme is
      phosphorylated by an atypical cyclic adenosine monophosphate (cAMP)-dependent
      protein kinase whose substrate specificity deviates from that of the mammalian
      protein kinase. This variation is explained by structural peculiarities on the
      surface part of the catalytic groove of the protein kinase. Also, the protein
      phosphatases responsible for the reversal of phosphorylation appear to act
      specifically in glycolysis and are different from those participating in
      regulation of glycogenolysis.

PMID- 8641382
TI  - The possible role of glutamine in some cells of the immune system and the
      possible consequence for the whole animal.
AB  - Glutamine is important for the function of lymphocytes and macrophages. A role
      for the high rate of glutamine utilisation by these cells is presented. Since
      muscle syntheses, stores and releases glutamine, this tissue may play a role in
      the immune response. Since the number of immune cells utilising glutamine may be
      large, the demand for glutamine from muscle, especially during trauma, sepsis or
      burns, may be very high. A speculative suggestion is put forward that this
      requirement for glutamine from muscle may play a role in cachexia under some of
      these conditions.

PMID- 8641383
TI  - Mapping and quantification of biomolecules in tumor biopsies using
      bioluminescence.
AB  - Quantitative bioluminescence and single-photon imaging have been applied for
      mapping concentration distributions of metabolites, such as adenosine
      triphosphate (ATP), glucose and lactate, in biopsies of cervical cancers in
      patients. Biopsies were taken before a conventional radiation treatment, and a
      number of clinically relevant data, such as local tumor control, patient
      survival, metastatic spread and so forth, were documented. There was no
      correlation between staging or grading and any of the metabolic parameters
      measured. Local correlations between ATP, glucose and lactate on a pixel-to-pixel
      basis were generally positive, with respective Spearman's correlation
      coefficients less in patients without clinically documented metastasis compared
      with those with metastatic spread. Lactate concentrations were significantly
      higher and scattered over a wider range in tumors with metastatic spread in
      comparison to malignancies in patients without metastasis. Thus, high local
      lactate levels of > or = 20 mumole/g appear to be associated with a high risk of
      metastasis, at least in human cervical tumors.

PMID- 8641384
TI  - Is there a critical tissue oxygen tension for bioenergetic status and cellular pH
      regulation in solid tumors?
AB  - Bioenergetic and metabolic status have been correlated with tissue oxygenation in
      murine fibrosarcomas (FSaII) of varying sizes (44-600 mm3). Ratios of beta
      nucleoside triphosphates to inorganic phosphate (beta NTP/P) and phosphocreatine
      to inorganic phosphate (PCr/P(i)) ratios derived from 31P nuclear magnetic
      resonance spectroscopy (NMR) were positively correlated to median tissue O2
      tension (pO2) values using O2-sensitive needle electrodes. pH declined during
      growth with intracellular acidosis being evident in tumors > 350 mm3. Whereas
      lactic acid formation greatly contributed to this decline in small and medium
      sized tumors, adenosine triphosphate (ATP) hydrolysis and slowing down of the
      activities of pumps involved in cellular pH regulation seem to be major factors
      responsible for intracellular acidification in bulky tumors. PCr levels decreased
      at an early growth stage, whilst ATP concentrations dropped in bulky malignancies
      only, coinciding with a decrease in adenylate energy charge and a substantial
      rise in the levels of total P(i). On average, median pO2 values of ca. 10 mmHg
      represent a critical threshold for energy metabolism. At higher median O2
      tensions, levels of ATP, phosphomonoester (PME) and total P(i) were relatively
      constant. This coincided with intracellular alkalosis or neutrality and stable
      adenylate ratios. On average, median pO2 values < 10 mmHg coincided with
      intracellular acidosis, ATP depletion, a drop in energy charge and rising P(i)
      levels.

PMID- 8641385
TI  - Accumulation of purine catabolites in solid tumors exposed to therapeutic
      hyperthermia.
AB  - Intensified adenosine triphosphate (ATP) degradation following therapeutic
      hyperthermia is often observed in solid tumors. As a result, accumulation of
      purine catabolites can be expected together with formation of protons at several
      stages during degradation to the final product, uric acid. Proton formation in
      turn can contribute to the development of heat-induced acidosis. Furthermore,
      oxidation of hypoxanthine and xanthine may result in generation of reactive
      oxygen species, which may lead to DNA damage, lipid peroxidation and protein
      denaturation, thus also contributing to heat-induced cytotoxicity. In
      hyperthermia experiments a tumor-size-dependent, significant increase in the
      levels of the following catabolites has been demonstrated: [symbol: see text]
      [IMP + GMP] (sum of guanosine and inosine monophosphate levels), inosine,
      hypoxanthine, xanthine and uric acid, along with a drop in ATP and guanosine
      triphosphate (GTP) levels. These data suggest that formation of reactive oxygen
      species and protons during purine degradation may indeed play a significant role
      in the antitumor effect of hyperthermia.

PMID- 8641386
TI  - Spermatozoa: models for studying regulatory aspects of energy metabolism.
AB  - Spermatozoa are highly specialized cells, and they offer advantages for studying
      several basic aspects of metabolic control such as the role of adenosine
      triphosphate-(ATP)-homeostasis for cell function, the mechanisms of fatigue and
      metabolic depression, the metabolic channelling through the cytoplasm and the
      organization and regulation of glycolytic enzymes. Spermatozoa of four species
      with different reproductive modes are introduced and the first results are
      presented: Spermatozoa of the marine worm Arenicola marina are well adapted to
      external fertilization in sea water with fluctuating oxygen tension: they are
      motile for several hours in oxygen-free sea water, even when the ATP level is
      dramatically reduced. Anaerobic ATP production occurs by alanine, acetate and
      propionate fermentation probably by the same pathways known from somatic cells of
      this species. Under aerobic conditions the phosphagen system might function like
      a shuttle for energy-rich phosphate from mitochondria to the dynein-ATPases.
      Storage of turkey and carp spermatozoa for several hours without exogenous
      substrates and oxygen results in the degradation of phosphocreatine and ATP to
      inorganic phosphate and adenosine monophosphate (AMP), respectively. Despite low
      energy charges, stored spermatozoa of both species are capable of progressive
      movements. In carp spermatozoa fatigue of motility is not accompanied by the
      dramatic acidosis one discusses as an important effect in muscle fatigue. Energy
      metabolism of boar spermatozoa is typically based on glycolysis consuming
      extracellular carbohydrates and producing lactate and protons. The sperm seem to
      tolerate low intracellular pH (< 6.5). The lack of a phosphagen system (no energy
      shuttle from mitochondria to the distal dynein-ATPases) is probably compensated
      by a high glycolytic ATP-production in the mitochondria-free piece of the
      flagellum.

PMID- 8641387
TI  - The pathophysiology and management of thrombotic thrombocytopenic purpura.

PMID- 8641388
TI  - The deoxyuridine suppression test in HIV-1 positive patients: the role of
      azydothymidine (AZT).
AB  - The deoxyuridine suppression test (dUST) was used to evaluate human
      immunodeficiency virus type 1 positive (HIV-1) patients with low serum levels of
      vitamin B12 and/or low red cell folate and to assess any possible interferences
      of azydothymidine (AZT) in this test. The dUST was studied in 29 HIV-1 positive
      patients, 18 without low serum vitamin B12 or low red cell folate and 11 with low
      serum vitamin B12 (6 patients), low red cell folate (4 patients) and 1 case with
      both. The role of AZT was studied using different concentrations (0.2, 2.5 and 10
      microM/ml) in 2 groups: 1 group of 5 patients with vitamin B12 and/or folate
      deficiency and another group consisting of 13 healthy subjects. Methotrexate
      (MTX)(50 micrograms/ml) was added to induce a folate megaloblastic pattern in the
      latter group. Results of the dUST in the HIV-1 group without low levels of serum
      vitamin B12 fell within the health-related reference interval values. A vitamin
      B12 deficiency was only detected in 1 case in the HIV-1 group with low serum
      vitamin B12, although a folate deficiency pattern was observed in the 4 patients
      with low red cell folate. In the healthy subjects AZT induced a dose-dependent
      decrease of the MTX-induced folate megaloblastic pattern. The pattern was also
      observed in the group of patients with vitamin B12 or folate deficiency, although
      AZT did not entirely interfere with the dUST. The effect of AZT on the dUST was
      attributed to a decrease in the incorporation of the isotope in the absence of
      deoxyuridine. The dUST is useful in differentiating vitamin B12 deficient
      patients from HIV-1 infected patients with low levels of serum vitamin B12.

PMID- 8641389
TI  - Nucleoside transporters, bcl-2 and apoptosis in CLL cells exposed to nucleoside
      analogues in vitro.
AB  - The purine nucleoside analogues fludarabine (F1) and chlorodeoxyadenosine (2-CdA)
      are considered to be cell cycle specific agents which require DNA synthesis for
      cytotoxicity. However, their efficacy in the treatment of CLL, an indolent
      lymphoid malignancy suggests additional mechanisms of action. Like cytosine
      arabinoside (AraC), F1 and 2-CdA gain access to the cell via a specific
      nucleoside transporter (NST) protein. To investigate the mode of action of these
      drugs in CLL, we used a fluorescent ligand for the NST (5'-(SAENTA- x8)
      fluorescein) and 3-colour flow cytometry to determine NST expression on
      CD5+/CD19+ B-cells from the peripheral blood (PB) of patients with CLL. NST
      levels on these cells was found to be not significantly different from normal
      control lymphocytes (mean = 485 +/- 425) vs. (mean = 553 +/- 178). Exposure to
      varying concentrations (0, 3 microM and 30 microM) of F1 and 2-CdA, however,
      resulted in an upregulation of NST (mean = 1552 +/- 775 with 30 microM FL; mean =
      3392 +/- 2197 with 30 microM 2-CdA) after 48. "Large" lymphoid cells (not present
      in normal PB) were found to express significantly more NST (mean = 2540 +/- 2861)
      and have a higher proliferative capacity than "small" cells (mean = 357 +/- 517
      NST/cell). Incubation of CLL cells with F1 (n = 6) and 2-CdA (n = 8) in vitro
      over 48 h also resulted in an increase in the proportion of cells in S-phase (0
      microM = 0.2 + 2 - 0.1; 30 microM FL = 2.4 +/- 2.0; 30 microM 2-CdA = 3.3 +/-
      1.3) and a significant increase in morphologically identifiable apoptosis.
      Apoptosis was confirmed by flow cytometric DNA analysis (0 microM = 13 +/- 8%; 30
      microM FL = 40 +/- 20%; 30 microM 2-CdA = 48 +/- 11%). In situ hybridization
      using a biotinylated cDNA bcl-2 probe demonstrated that bcl-2 mRNA expression was
      markedly decreased in treated cells after 24 h. These studies have demonstrated
      that: (1) NST expression on CLL lymphocytes is low; (2) in vitro exposure to the
      analogues increases both the level of NST expression and the % cells in S-phase;
      (3) exposure to the analogues downregulates bcl-2 expression and increases
      apoptosis.

PMID- 8641390
TI  - Sequestration patterns of transfused rat neutrophilic granulocytes under normal
      and inflammatory conditions.
AB  - The fate of polymorphonuclear neutrophilic granulocytes (PMN) after their
      mobilization from the bone marrow of healthy individuals is not clearly
      understood. It has been suggested that there is a continuous utilization of these
      cells in widespread, subclinical inflammatory foci, where they are ultimately
      degraded. The goal of the present experiments was to determine whether an
      alternative ecotaxis ("homing") exists, namely sequestration and degradation of
      PMN by mononuclear phagocytes exposed to the bloodstream in the liver, spleen and
      bone marrow. Blood PMN were collected from donor rats, labelled with 51 Cr, and
      injected i.v. into 2 syngeneic rats, one of them having an induced sterile
      peritonitis. After various time intervals up to 18 h, the rats were killed and
      exsanguinated. As expected, we found cell-bound radioactivity in liver, spleen,
      and bone marrow. The bone marrow uptake of PMN appeared to be much lower in the
      inflammation rats than in the normal controls. These findings were confirmed in
      PMN transfer experiments using PVG rats congenic for the RT7 alloantigenic
      system. Here, transfused blood leukocytes were traced with fluorescent,
      monoclonal HIS41 antibodies and flow cytometry. A possible corticosteroid effect
      on the bone marrow sequestration could not be substantiated. Uptake and
      degradation of PMN takes place in organs containing phagocytes exposed to the
      bloodstream. Sequestration of PMN in the bone marrow is apparently down-regulated
      in inflammatory states, perhaps increasing the PMN availability to inflamed
      tissue.

PMID- 8641391
TI  - Prevalence of antibodies to cardiolipin in chronic ITP and reactivity with
      platelet membranes.
AB  - Anti-cardiolipin antibodies (ACLA) have been suggested to play a role in the
      pathogenesis of thrombocytopenia. When sera from 40 patients with chronic
      idiopathic thrombocytopenic purpura (ITP) were analyzed for ACLA, these
      autoantibodies were present in 12 (30%). In 4 sera the antibody activity was
      restricted to the IgG or IgM isotype, respectively, while 4 of the samples
      contained both IgG and IgM antibodies. To elucidate the interaction between
      platelets and ACLA, we studied the reactivity of sera from non-ITP patients with
      ACLA, with fragmented platelet membranes. None of them had a concurrent platelet
      deficiency, but sera from 8 (67%) of them showed increased IgG-binding to
      platelet membranes. Absorbtion with cardiolipin reduced membrane binding in 6
      (50%). C3 levels were normal, while low C4 values occurred in both groups with
      significantly lower levels in ACLA-positive patients (p<0.05). Circulating immune
      complexes (CIC) were common in both groups. CONCLUSION: The prevalence of ACLA is
      increased in ITP and sera from non-ITP patients with ACLA react with fragmented
      platelet membranes. This reactivity is often decreased by absorption with
      cardiolipin, suggesting that ACLA bind to phospholipid epitopes on platelet
      membranes.

PMID- 8641392
TI  - Infectious complications after 2-chlorodeoxyadenosine therapy.
AB  - Infection is a common adverse event after therapy with nucleoside analogs,
      including 2-chlorodeoxyadenosine (CdA). However, the incidence of CdA-related
      infections has been poorly documented. In this study we compare, in the same
      patient population, the incidence of infectious episodes during the 6-month
      period before CdA to their incidence during the 6 months after initiating
      therapy. Ninety-five patients with hematological malignancies were studied. The
      incidence of infectious episodes almost doubled after CdA (0.87 vs. 0.47 during
      the pre-CdA period). The following factors were associated with an increased risk
      of infection after therapy: a history of previous chemotherapy, infection during
      the pre-CdA period and a diagnosis of chronic lymphocytic leukemia or of non
      Hodgkin's lymphoma. Age, neutrophil and lymphocyte count at onset of CdA and time
      interval between diagnosis and therapy with CdA did not correlate with the
      infectious risk. The pattern of infections was modified after therapy with an
      increase of herpes virus infections ( 1 vs. 8 episodes, p=0.04) and of fever of
      unknown origin (6 vs. 17 episodes, p=0.03). In conclusion, a population at high
      risk for developing infectious complications after CdA therapy can be identified.
      Specific measures aimed at reducing the incidence of infectious events should
      concentrate on this population.

PMID- 8641394
TI  - Platelet-specific antibodies in transfused patients.
AB  - Sera of 104 patients with haematological diseases, transfused with platelets and
      sometimes also with red cells, were prospectively investigated in: the
      lymphocytotoxicity test (LCT), the platelet suspension immunofluorescence test
      (PSIFT) and the monoclonal antibody immunobilization of platelet antigens (MAIPA)
      technique. All tests on admission were negative. The overall incidence of
      alloantibodies after transfusions was 30.8%. Platelet-specific antibodies were,
      however, detected much more rarely (9.6%) than anti-HLA (21.3%). The specificity
      against HPA antigens was defined in 4 (3.9%) patients: anti-HPA-la, 2b, 3a and
      5b. In the remaining 6 (5.7%) cases only the glycoproteins on platelets were
      identified (GPIb and GPIIIa) which gave positive reaction with the antibodies.
      Our observations indicate a rather low incidence of platelet-specific antibodies
      after transfusions.

PMID- 8641393
TI  - Characterization and regulation of interleukin-4 receptor in adult T-cell
      leukemia cells.
AB  - We studied the expression of the receptor of interleukin (IL-4), one of the T
      cell growth factors, on fresh peripheral blood leukemic cells from adult T-cell
      leukemia (ATL) patients. Flow cytofluorometric analysis with a monoclonal
      antibody to the IL-4 receptor (IL-4R) were used to investigate whether expression
      of IL-4R on ATL cells is different from that on normal lymphocytes and other
      types of leukemic cells. Leukemic cells from acute type ATL patients synthesize
      IL-4R without stimulation, at levels much higher than normal resting lymphocytes
      and other types of leukemic cells. Furthermore, leukemic cells from acute type
      ATL showed higher IL-4R expression than that of chronic type ATL or human T-cell
      leukemia virus type I carriers. In addition, there was correlation between
      expression of IL-4R on the cell surface and the proliferative response to IL-4.
      Both IL-4 and IL-2 induced upregulation of IL-4R on activated normal T cells but
      not on ATL cells. These results suggest that abnormal expression of IL-4R may
      display different biological activities in ATL compared with other types of
      leukemia. Furthermore, the high expression of IL-4R in ATL may be involved in the
      proliferation of leukemic cells and the leukemogenesis in this disease.

PMID- 8641395
TI  - Immunohistochemical expression of proliferating cell nuclear antigen (PCNA) in
      archival samples of non-Hodgkin's lymphoma. Correlation with flow cytometry
      proliferation results.

PMID- 8641396
TI  - Tumor lysis syndrome induced by fludarabine monophosphate: a case report.

PMID- 8641397
TI  - Combined transplantation with related HLA-identical cord blood and bone marrow in
      a child with severe acquired aplastic anaemia.

PMID- 8641398
TI  - Detection of cells with clone-specific immunoglobulin gene rearrangements in the
      peripheral blood of myeloma patients using immunoglobulin gene fingerprinting.

PMID- 8641399
TI  - Antibiotic proteins of polymorphonuclear leukocytes.
AB  - The polymorphonuclear leukocyte (PMN) plays an essential role in the innate
      defense of the mammalian host against bacterial invaders. Responding
      chemotactically, the PMN delivers a complex antibiotic arsenal to sites of
      infection. Among these cytotoxic systems is an array of antimicrobial proteins
      and peptides that the PMN directs at microorganisms both before (i.e.
      extracellularly) and after sequestration into a phagocytic vacuole. In addition
      to their microbicidal capacity, several of these proteins bind to and neutralize
      the endotoxic activity of Gram-negative bacterial lipopolysaccharides (LPS). In
      this review the principle features of these antibiotic proteins are briefly
      summarized with emphasis on their possible actions in biological settings. In
      many instances, additional functions independent of cytotoxicity have been
      described raising the possibility that some of these proteins subserve multiple
      roles in inflammation.

PMID- 8641400
TI  - Simplification of the blood stem cell transplantation (BSCT) procedure: large
      volume apheresis and uncontrolled rate cryopreservation at -80 degrees C.
AB  - Very high-dose chemotherapy with autologous blood stem cell (BSC) rescue becomes
      more and more widely performed. In order to simplify the technique, a large
      volume apheresis programme combined with an uncontrolled rate cryopreservation at
      -80 degrees C was developed. Twenty-six patients suffering from multiple myeloma
      (n = 8), non-Hodgkin's lymphoma (n = 7), dysgerminoma (n = 4), breast cancer (n =
      3), Hodgkin's disease (n = 2), acute lymphoblastic leukaemia (n = 1) and acute
      myelocytic leukaemia (n = 1) were autografted after a classical high-dose
      chemotherapy regimen. A single large volume apheresis was sufficient to obtain
      the threshold value of CD34+ BSC in 24/26 transplantations. The haematological
      recovery was favourably comparable with the previously published data obtained
      with controlled rate frozen BSC: median time to granulocytes > 1000/microL and to
      a self-supporting platelet count > 20,000/microL, respectively, 10.5 and 12 d.
      The treatment-related mortality was confined to 1/26 BSCT. These results indicate
      that this easy and cost-saving policy of BSCT is efficacious and safe: sustained
      long-term haematopoiesis, reduced morbidity and mortality were observed.

PMID- 8641401
TI  - The effect of desmopressin on platelet aggregation defect in systemic
      amyloidosis: a preliminary report.
AB  - Systemic amyloidosis may often be complicated with haemorrhagic tendency. The
      causes of this manifestation are factor deficiencies, hyperfibrinolysis and
      vasculopathy. In order to investigate the role of platelets, if any, we performed
      platelet aggregation tests with different aggregants in 10 patients with systemic
      amyloidosis due to familial Mediterranean fever and 10 healthy controls. Platelet
      aggregation was defective with different aggregants (ADP, epinephrine, collagen)
      in patients compared with controls. Platelet aggregation tests repeated after
      desmopressin (DDAVP) administration were normalized. These findings may suggest a
      role of a platelet aggregation defect in haemorrhagic diathesis complicating
      systemic amyloidosis. DDAVP may benefit patients with this disease in case of
      bleeding and before surgical interventions.

PMID- 8641402
TI  - Flow cytometric analysis of megakaryocyte ploidy in chronic myeloproliferative
      disorders and reactive thrombocytosis.
AB  - Megakaryocyte (MK) ploidy patterns were analysed by flow cytometry in 29 newly
      diagnosed and previously untreated patients with chronic myeloproliferative
      disorders (MPD) and concomitant thrombocytosis, in 9 patients with reactive
      thrombocytosis (RT) and in 12 healthy individuals. Unfractionated bone marrow
      from routine aspirates was used. MKs were identified with a fluorescein labelled
      monoclonal antibody specific for glycoprotein IIIa (GPIIIa) and DNA was stained
      with propidium iodide. For the 12 healthy volunteers the mean modal ploidy number
      was 16 N; the 9 patients with RT displayed an identical MK ploidy pattern. The
      frequency of MKs with a ploidy > or = 32 N was 45% among the patients with
      essential thrombocythaemia (ET) compared to 32% among the healthy volunteers (p <
      0.001). MKs with ploidy number > or = 64 N, comprising approximately 13% of the
      total number of MKs, was a characteristic finding in the patients with ET.
      Similar findings were present in 8 patients with polycythaemia vera (PV). In
      patients with PV 34% and 6% of the MKs displayed ploidies > or = 32 N and > or =
      64 N, respectively. In contrast, a distinct shift towards lower ploidy number,
      with 63% of MKs < or = 8 N, was found among the 4 patients with chronic myeloid
      leukaemia (CML). The present results indicate that by using flow cytometric
      analysis of MK ploidy distribution in patients with thrombocytosis, those with a
      reactive cause are likely to be discriminated from patients with
      myeloproliferative thrombocytosis, i.e. PV and ET on one hand and CML on the
      other hand. The distinction between ET and PV, however, has to be made on other
      grounds.

PMID- 8641403
TI  - Investigation of megakaryopoiesis in myelosuppressed bone marrow using immunogold
      silver staining (IGSS).
AB  - To determine the frequencies and differential counts of megakaryocytes after
      cytoreductive treatment in nucleated low-density (1.060 g/ml) bone marrow cells
      (BMNC) of dogs an immunogold-silver staining (IGSS) technique with the lineage
      specific monoclonal antibody 2F9 was established. This antibody recognizes the
      glycoprotein IIb/IIIa complex expressed on the surface of canine megakaryocytes
      and platelets. The IGSS technique enables not only the detection of
      megakaryocytes occurring at a low frequency (0.1-0.2%), but also the
      discrimination between the different maturation stages of megakaryocytes due to
      cell size, nuclear morphology and cytoplasmic staining. By the use of this
      technique, small lymphoid megakaryocytic cells were identified. Comparable
      numbers of megakaryocyte colony-forming cells in 2F9-depleted and nondepleted
      BMNC suspensions (25.7 +/- 5.0 vs. 25.3 +/- 5.1 Meg-CFC/10(5) BMNC) indicate that
      these small 2F9 positive cells are nonclonogenic precursors of megakaryoblasts.
      To prove the applicability of IGSS, serial examinations of bone marrow samples
      from dogs treated with recombinant human interleukin-6 (IL-6) after exposure to
      2.4 Gy total body irradiation (TBI) were performed. The results of the
      microscopic evaluation indicate that, in the recovery phase after TBI, IL-6
      induced an earlier and stronger increase in megakaryocyte frequency in comparison
      to the control. Interestingly, all maturation stages of the megakaryocytic
      lineage took part in this IL-6 induced improvement of megakaryocyte recovery.

PMID- 8641404
TI  - Immune recovery after autologous or rhG-CSF primed PBSC transplantation.
AB  - We performed a prospective study in 17 consecutive patients following Autologous
      bone marrow (BM) or rhG-CSF primed peripheral blood item cell (PBSC)
      transplantation, with the objective of comparing immune recovery between both
      procedures and to evaluate results in rhG-CSF mobilized peripheral blood stem
      cell transplantation (PBSCT). Kinetics of immune reconstitution showed
      differences, with a faster recovery of CD3+ and CD8+ T cells, and a more rapid
      and sustained recovery of CD8+/-/CD56+ natural killer (NK) cells in the PBCSCT
      group. Autologous bone marrow transplantation (ABMT) was associated with a
      improved reconstitution of the CD19+/CD5+/-subpopulation. Moreover, rhG-CSF
      mobilized PBSCT generated a greater recovery of CD8+/-/CD56+ cells than previous
      data concerning transplantation with peripheral blood (PB) progenitors collected
      after myelosuppressive chemotherapy or myelosuppressive therapy plus rhG-CSF. Our
      results show differences in the rate and pattern of B and T lymphocytes
      reconstitution after ABMT and PBSCT. Additionally, we state an enhancement of
      CD56+ cells in patients undergoing PBSCT mobilized solely using rhG-CSF.

PMID- 8641405
TI  - FLAG (fludarabine, cytarabine, G-CSF) as a second line therapy for acute
      lymphoblastic leukemia with myeloid antigen expression: in vitro and in vivo
      effects.
AB  - Thirteen consecutive adult patients with primary refractory (n = 5) or relapsed
      (n = 8) acute lymphoblastic leukemia (ALL) were treated by an induction schedule
      (FLAG) consisting of Fludarabine (30 mg/sqm/d) plus high dose Cytarabine (HD-ara
      C: 2 g/sqm/d) (d 1-5) and G-CSF (from d O to polymorphonuclear recovery).
      Patients achieving complete remission (CR) were administered a second FLAG course
      as consolidation and were then submitted to an individualized program of post
      remission therapy, depending on the patient's age and performance status. CR was
      achieved in 8/12 evaluable cases (67%). The median CR duration was 22.5 w. CR
      attainment was significantly related to the co-expression of lymphoid and myeloid
      antigens. ALL/My+ patients achieved CR in 6/6 evaluable cases vs. 2/6 for
      ALL/My+. In vitro 3H ara-C incorporation into cellular DNA resulted significantly
      increased by Fludarabine (in 7/9 tested cases) and, furthermore, by the
      association of Fludarabine G-CSF in 5 evaluable ALL/My+ cases; in contrast, no
      effect of G-CSF addition to Fludarabine was observed in 4 ALL/My.
      Myelosuppression was observed in all patients: the median time to neutrophils >
      0.5 x 10(9)/1 was 16.3 d (range 13-22) and 16.2 d (range 9-29) to platelets > 20
      x 10(9)/1. Nonhematological toxicity was minimal. In conclusion, FLAG is an
      active and tolerable combination in refractory ALL, particularly in cases with
      myeloid antigen expression where G-CSF appears to improve efficacy, probably
      increasing ara-C incorporation into the DNA of leukemic cells.

PMID- 8641406
TI  - p16INK4/p15INK4B gene inactivation is a frequent event in malignant T-cell lines.
AB  - The cell cycle regulators p16INK4 and p15INK4B have been mapped to the minimal
      region of overlap for chromosome 9p21 deletions, observed in a number of
      malignancies, suggesting that they could be tumor suppressor genes (TSGs). In the
      case of p16INK4 this has been further substantiated by the finding of small
      intragenic mutations. In this study we have investigated the p16INK4 and p15INK4B
      genes in 16 malignant T-cell lines by means of Southern blot, PCR and sequence
      analysis. p16INK4 allelic deletions occurred in 15 of 16 cell lines; 12 of which
      were homozygous and 3 hemizygous. In 1 cell line (DND 41) the remaining p16INK4
      allele carried a microdeletion of 29 bp of exon 2, supporting the concept that
      p16INK4 is a target TSG for deletions on 9p21. Most p16INK4 deletions also
      included the p15INK4B gene. However, 4 of the cell lines deleted for p16INK4
      showed no evidence of p15INK4B loss, indicating that p15INK4B is not the target
      in these cell lines.

PMID- 8641407
TI  - Cytologic examination of broncho-alveolar fluid during the retinoic acid
      syndrome.

PMID- 8641408
TI  - Epinephrine injection therapy for peptic ulcer bleeding in hemophilia patients.

PMID- 8641409
TI  - Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after
      treatment with cyclophosphamide, alpha-interferon and betamethasone in a patient
      with multiple myeloma.

PMID- 8641410
TI  - Preliminary results with administration of recombinant human erythropoietin in
      sickle cell/beta-thalassemia patients during pregnancy.

PMID- 8641411
TI  - Low molecular weight heparin-induced thrombocytopenia and thrombosis.

PMID- 8641412
TI  - Removal of domain D2 or D3 of the human urokinase receptor does not affect ligand
      affinity.
AB  - The main ligand-binding determinant of the human urokinase receptor (uPAR) is
      located in the amino terminal domain D1, but when isolated this domain presents a
      1500 fold lower affinity than the intact three-domain uPAR (D1D2D3). uPAR mutants
      missing either domain 2 (D1HD3) or domain 3 (D1D2) were expressed in murine LB6
      cells and showed to be properly GPI-anchored to the cell surface. Binding assays
      with [125I]ATF demonstrated that these mutants possessed a normal (D1D2) or
      slightly reduced (D1HD3) affinity, indicating that a high ligand-affinity may be
      achieved by a combination of D1 with domain D2 or D3.

PMID- 8641413
TI  - Mapping of DNA-binding proteins along the yeast genome by UV-induced DNA-protein
      crosslinking.
AB  - UV-induced crosslinking of DNA-binding proteins to DNA in intact nuclei of
      Saccharomyces cerevisiae and subsequent 'protein image' hybridization were
      applied to map non-histone proteins along single-copy genes of yeast. We detected
      two polypeptides that most probably correspond to core subunits of yeast RNA
      polymerase II in the coding region of transketolase gene (TKL2). Several non
      histone proteins were also detected which bind to the upstream region of TKL2
      gene, and to the intergenic spacer between calmodulin (CMD1) and beta-mannosyl
      transferase (ALG1) genes.

PMID- 8641414
TI  - Asp-59 is not important for the catalytic activity of the restriction
      endonuclease EcoRI.
AB  - The amino acid Asp-59 was proposed to be involved in EcoRI catalyzed DNA cleavage
      (Cheng et al., EMBO J. 13, 3927-35, 1994). We have tested this hypothesis by site
      directed mutagenesis experiments. The four mutants D59A, D59E, D59G, and D59N
      bind with similar stability to the specific recognition sequence as wild type
      EcoRI. The D59E mutant cleaves DNA as fast as the wild type enzyme. Specific
      activities of the other three mutants are five to tenfold lower. Therefore, we
      conclude that Asp-59 is not involved in catalysis of the EcoRI restriction
      endonuclease. Consequences for catalytic mechanisms of EcoRI and other
      restriction enzymes are discussed.

PMID- 8641415
TI  - Expression of porin from Rhodopseudomonas blastica in Escherichia coli inclusion
      bodies and folding into exact native structure.
AB  - The homotrimeric membrane channel porin from Rhodopseudomonas blastica was
      expressed without signal sequence in Escherichia coli. The protein assembled in
      inclusion bodies in the cytosol, from which it could be recovered using urea and
      detergents. After purification by anion-exchange chromatography, the protein
      crystallized under wild-type conditions. The X-ray structure was determined at
      2.2 angstroms resolution, and a comparison with the known wild-type structure
      showed that the recombinant porin is identical at the atomic level. The method
      yields porin and designed mutants thereof in 100 mg amounts, allowing for
      detailed functional and mechanistic studies.

PMID- 8641416
TI  - Translational augmentation of pro-matrix metalloproteinase 3 (prostromelysin 1)
      and tissue inhibitor of metalloproteinases (TIMP)-1 mRNAs induced by epidermal
      growth factor in human uterine cervical fibroblasts.
AB  - The mechanisms by which epidermal growth factor (EGF) enhances the production of
      pro-matrix metalloproteinase 3 (proMMP-3/prostromelysin 1) and tissue inhibitor
      of metalloproteinases (TIMP)-1 were investigated using human uterine cervical
      fibroblasts. The treatment of the cells with EGF for 24 h resulted in about 5-6
      fold increase in the production of proMMP-3 and TIMP-1 compared with the
      untreated control cells. This increase was accompanied by an increase of proMMP-3
      and TIMP-1 mRNAs. However, an about 3- and 2-fold increase in the production of
      proMMP-3 and TIMP-1, respectively, was observed as early as 1 h after the
      treatment of the cells with EGF, and it was not accompanied by any apparent
      increase in proMMP-3 and TIMP-1 mRNAs. This early effect of EGF on the enhanced
      production of proMMP-3 and TIMP-1 was not inhibited by actinomycin D, even though
      actinomycin D inhibited the synthesis of the total RNA in both the EGF-treated
      and untreated cells. These results indicate that EGF enhances the apparent
      production of proMMP-3 and TIMP-1 by two mechanisms: one by the accelerated
      translation of their mRNAs; and the other by the enhanced transcription of their
      genes. The former event takes place much earlier than the latter.

PMID- 8641417
TI  - Conformation of surface exposed N-terminus part of bacteriorhodopsin studied by
      transferred NOE technique.
AB  - Interaction of the monoclonal antibody A5 raised against native bacteriorhodopsin
      (BR) with the synthetic peptide pGlu1-Ala-Gln-Ile-Thr-Gly-Arg7-NH2, corresponding
      to the amino acid sequence 1-7 was studied by transferred nuclear Overhauser
      effect (TRNOE) spectroscopy. The denaturing reagents and the specially designed
      pulse sequences which eliminate broad signals from the TRNOE spectra were used to
      favour evaluation of the TRNOE peaks. On the basis of the data obtained, the
      conformation of peptide bound with A5 was calculated. A model of the mutual
      arrangement of bacteriorhodopsin N-terminus and the first transmembrane alpha
      helical segment 8-32 was proposed.

PMID- 8641418
TI  - Novel 28-kDa secretory protein from rat olfactory epithelium.
AB  - We have isolated a novel secretory 28-kDa protein which is an abundant component
      of the rat olfactory mucosa. The partial sequence of the 28-kDa protein has been
      determined. The amino acid sequence of the 28-kDa protein is similar to that of
      non-selenium glutathione peroxidase from bovine ciliary body. The 28-kDa protein
      catalyzed decomposition of the hydrogen peroxide as well as organic
      hydroperoxides by reduced glutathione and seems to be a member of the glutathion
      peroxidase family.

PMID- 8641419
TI  - The sequence of a small subunit of cytochrome c oxidase from Crithidia
      fasciculata which is homologous to mammalian subunit IV.
AB  - The sequence of subunit 8 of cytochrome c oxidase from Crithidia fasciculata was
      determined by sequencing cDNA and N-terminus of the mature protein (Mr = 15.7
      kDA). The (inferred) protein is homologous to mammalian cox IV and the
      corresponding cox subunits from yeast, Neurospora crassa and Dictyostelium
      discoideum, which is reflected in a very similar hydropathy profile. Elements
      that are conserved in the C. fasciculata sequence include (i) an N-terminal (D/E)
      (K/R)-X-K-(X2)-W-(X2)-(I/L) motif, (ii) a putative membrane-spanning region in
      the middle portion of the protein, and (iii) a C-terminal W-(X13)-(N/D)-P motif.
      The C. fasciculata protein is synthesized with a cleavable presequence.

PMID- 8641420
TI  - Importance of the first external loop for substrate recognition as revealed by
      chimeric Chlorella monosaccharide/H+ symporters.
AB  - It had been shown previously by heterologous expression in Schizosaccharomyces
      pombe, that the two monosaccharide/H+ symporters HUP1 and HUP2 of Chlorella
      kessleri differ significantly concerning their substrate specificity: HUP1
      transports predominantly D-glucose while HUP2 prefers D-galactose. Several
      chimeric transporters were constructed and their substrate specificities
      determined. Surprisingly, it is sufficient to replace the first part of the
      external loop 1 of the HUP1 symporter by the corresponding portion of HUP2 to
      improve transport and also to decrease the Km value for D-galactose. Additional
      data indicating the importance of the first loop for substrate recognition and
      binding are discussed.

PMID- 8641421
TI  - Mobilization of iron from cellular ferritin by ascorbic acid in neuroblastoma SK
      N-SH cells: an EPR study.
AB  - The mobilization of iron from intracellular ferritin by ascorbic acid has been
      analysed in situ by electron paramagnetic resonance (EPR) spectroscopy. EPR
      enables a distinction between ferritins and other Fe(3+)-binding cellular
      components. The ordered iron core of ferritin gives rise to a resonance signal
      which can be observed only at temperatures above 50 K. In the present study we
      clearly demonstrate that ascorbic acid is capable of mobilizing iron from
      ferritin in the cellular system by reduction of the ferric ion core in
      neuroblastoma SK-N-SH cells. This mechanism may open new ways in the therapy of
      this hardly curable tumor in stage IV, especially in combination with some
      cytostatic drugs.

PMID- 8641422
TI  - Chromosomal localization and expression pattern of the RNase L inhibitor gene.
AB  - 2-5A-Dependent RNase (RNase L), an important component of the 2-5A pathway, is
      directly implicated in the molecular mechanism of interferon action. We have
      cloned and sequenced following immunoscreening, a full-length cDNA that encodes
      the RNase L inhibitor (RLI). Northern blot analysis from a variety of human
      tissues revealed that two transcript forms (3.8 kb and 2.4 kb) are ubiquitously
      expressed but differences in levels of expression suggest a tissue-specific
      regulation. The RLI gene was localized to locus 4q31 by in situ hybridization
      indicating that this gene and other enzymes of the 2-5A pathway are not organized
      in cluster in the human genome.

PMID- 8641423
TI  - The role of His117 in the redox reactions of azurin from Pseudomonas aeruginosa.
AB  - The electron-transfer properties of H117G- and wild-type azurin were compared by
      applying both as electron acceptors in the conversion of 4-ethylphenol by 4
      ethylphenol methylenehydroxylase (4-EPMH). The reactivity of H117G-azurin was
      determined in the absence and presence of imidazoles, which can substitute the
      missing fourth ligand. In the absence of imidazoles, H117G-azurin reacted
      directly with 4-ethylphenol; this reaction was abolished in the presence of
      imidazoles. The enzymatic reduction of H117G-azurin by 4-EPMH was 40 times slower
      than that of wild-type azurin. The rate of this reaction was enhanced by some
      imidazoles, diminished by others. In all cases the reduction of H117G-azurin was
      irreversible. These results demonstrate that His117 is vital for electron
      transfer and effectively protects the copper site against aspecific reactions.

PMID- 8641424
TI  - Molecular cloning and expression of a multiubiquitin chain binding subunit of the
      human 26S protease.
AB  - S5a is a subunit of the 26S protease that binds and presumably selects
      multiubiquitinated proteins for destruction. We recently identified an
      Arabidopsis protein, MBP1, that is physically, immunologically and biochemically
      similar to S5a from the human erythrocyte 26S protease. Based upon the MBP1 cDNA
      sequence we have now isolated a HeLa cell cDNA coding for human S5a. The HeLa
      cDNA sequence is highly similar to MBP1 and it encodes peptides obtained directly
      from human erythrocyte S5a. Moreover, expression of the isolated cDNA in E. coli
      results in a recombinant protein with an apparent molecular mass and
      multiubiquitin binding properties that match those of human S5a obtained from the
      purified 26S enzyme.

PMID- 8641425
TI  - Human cone-specific cGMP phosphodiesterase alpha' subunit: complete cDNA sequence
      and gene arrangement.
AB  - Four independent phage clones containing the fragments of cone-specific cGMP
      phosphodiesterase (PDE) alpha' subunit (PDE-alpha') cDNA were isolated from the
      human cDNA library. The screening of the genomic library resulted in isolation of
      four independent phage clones with the fragments of human cone PDEalpha' gene
      including 5'-flanking region and exons ranged from 1 to 14 (overall 32
      kilobases). Structural studies of the clones made it possible to establish the
      complete human cone PDEalpha' cDNA structure (3455 base pairs). The encoding
      polypeptide consists of 858 amino acid residues with a calculated molecular mass
      of 99169 Da. The deduced amino acid sequence displays high homology to the
      earlier analyzed catalytic alpha, beta and alpha' subunits of bovine, human,
      chicken and mouse photoreceptor PDEs.

PMID- 8641426
TI  - Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy
      linked to chromosome 13q12.
AB  - We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral
      component of the dystrophin-glycoprotein complex. Specific antibodies were
      produced against a gamma-sarcoglycan peptide and used to examine the expression
      of gamma-sarcoglycan in skeletal muscle of patients with severe childhood
      autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by
      immunofluorescence and Western blotting that in skeletal muscle from these
      patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan
      are greatly reduced in abundance, whereas other components of the DGC are
      preserved. In addition, we show that in normal muscle alpha-, beta-, and gamma
      sarcoglycan constitute a tightly associated sarcolemma complex which cannot be
      disrupted by SDS treatment.

PMID- 8641427
TI  - In vitro import of pre-ferredoxin-NADP+-oxidoreductase from Cyanophora paradoxa
      into cyanelles and into pea chloroplasts.
AB  - Using a novel cyanelle isolation procedure we showed that pre-ferredoxin-NADP+
      oxidoreductase (pre-FNR) from C. paradoxa is translocated in vitro across the
      peptidoglycan-containing cyanelle envelope. Efficient import was also observed in
      a heterologous system with pea chloroplasts as the recipient organelles. These
      results support the conclusion derived from comparative analysis of plastid
      genome organization, that all plastids originate from a common semi-autonomous
      endosymbiotic ancestor.

PMID- 8641428
TI  - Arachidonic acid activatable electrogenic H+ transport in the absence of
      cytochrome b558 in human T lymphocytes.
AB  - To test the suggested structural relationship between the electrogenic H+
      transporting system and the NADPH oxidase of phagocytes, the existence of the
      enzyme and the transport process was investigated in human tonsillar T
      lymphocytes. It is shown that tonsillar T cells possess an arachidonic acid
      activatable, Cd(2+)- and Zn(2+)-sensitive electrogenic H+ efflux pathway with
      similar properties as reported earlier in various phagocytic cells. The presence
      of cytochrome b558, the membrane component of the oxidase, could not be detected
      in tonsillar T lymphocytes either by immunoblot or by flow cytometric analysis.
      It is suggested that the electrogenic H+ transporting pathway is structurally
      independent of the NADPH oxidase complex.

PMID- 8641429
TI  - High resolution surface structure of E. coli GroES oligomer by atomic force
      microscopy.
AB  - Using atomic force microscopy (AFM) in aqueous solution, we show that the surface
      structure of the oligomeric GroES can be obtained up to 10 angstroms resolution.
      The seven subunits of the heptamer were well resolved without image averaging.
      The overall dimension of the GroES heptamer was 8.4 +/- 0.4 nm in diameter and
      3.0 +/- 0.3 nm high. However, the AFM images further suggest that there is a
      central protrusion of 0.8 +/- 0.2 nm high and 4.5 +/- 0.4 nm in diameter on one
      side of GroES which displays a profound seven-fold symmetry. It was found that
      GroEL could not bind to the adsorbed GroES in the presence of AMP-PNP and Mg2+,
      suggesting that the side of GroES with the central protrusion faces away from the
      GroEL lumen, because only one side of GroES was observed under these conditions.
      Based on the results from both electron and atomic force microscopy, a surface
      model for the GroES is proposed.

PMID- 8641430
TI  - Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite.
AB  - Peroxynitrite (ONOO-) has recently been implicated in connective tissue
      destruction in vivo. We have studied the effect of ONOO- on the activity of
      tissue inhibitor of metalloproteinase-1 (TIMP-1) in vitro. The inactivation of
      TIMP-1 by ONOO- was dose dependent with 50 microM ONOO- reducing the inhibitory
      activity of TIMP-1 towards gelatinase-A by 50%. High concentrations of ONOO- (500
      microM-5 mM) caused protein fragmentation whilst lower concentrations (<250
      microM) inactivated TIMP-1 without altering the molecular weight. Inactivation
      could be blocked by ONOO- scavengers but not by hydroxyl radical scavengers. Our
      results show that ONOO- is capable of inactivating TIMP-1, a process which could
      potentiate metalloproteinase-mediated tissue breakdown.

PMID- 8641431
TI  - SecG plays a critical role in protein translocation in the absence of the proton
      motive force as well as at low temperature.
AB  - SecG is an integral membrane component of E. coli protein translocase. However, a
      discrepancy exists as to the importance of SecG for protein translocation at 37
      degrees C between cells and reconstituted proteoliposomes; protein translocation
      in deltasecG cells is defective at 20 degrees C but normal at 37 degrees C,
      indicating that SecG is dispensable at 37 degrees C, whereas SecG remarkably
      stimulates protein translocation into reconstituted proteoliposomes at 37 degrees
      C. In this study, protein translocation into membrane vesicles containing or not
      containing SecG was examined in the presence and absence of the proton motive
      force at 37 degrees C and 20 degrees C. We found that the absence of the proton
      motive force renders protein translocation strongly dependent on SecG even at 37
      degrees C. Protein translocation into proteoliposomes in the absence of the
      proton motive force thus required SecG whereas that in cells, which always
      generate the proton motive force, did not.

PMID- 8641432
TI  - A functional Spo0A is required for maximal aprE expression in Bacillus subtilis.
AB  - The initiation of sporulation in Bacillus subtilis is under control of the
      transcriptional factor Spo0A. Most Spo0A mutants fail to initiate the sporulation
      process and all the sporulation initiated processes such as the synthesis of
      subtilisin. However, the product of spo0A9V, one of the several spo0A mutants
      characterized, distinguishes itself in the fact that, while it appears to
      effectively repress abrB, it fails to activate the spoIIA operon. The aim of this
      study was to examine the effect of the spo0A9V mutation on aprE expression and we
      found that in different genetic backgrounds, the spo0A9V mutation has a negative
      effect on aprE::lacZ expression.

PMID- 8641433
TI  - Interferons induce accumulation of diadenosine triphosphate (Ap3A) in human
      cultured cells.
AB  - After incubation of human monocytes J96 and human myeloid leukemia HL60 cells
      with interferons (IFN) alpha or gamma, the Ap3A concentration considerably
      increases in parallel with accumulation of tryptophanyl-tRNA synthetase (TrpRS,
      EC 6.1.1.2). The Ap3A formation in response to IFNs is catalysed by an excessive
      amount of TrpRS. Although the Ap3A function still remains unknown, its
      accumulation may imply the Ap3A involvement in the IFN-signalling pathway.

PMID- 8641434
TI  - NF-kappaB p50 subunit cross-linking to DNA duplexes, containing a monosubstituted
      pyrophosphate internucleotide bond.
AB  - The new express technique based on the use of BrCN to synthesize DNA duplexes,
      containing non-substituted or monosubstituted pyrophosphate internucleotide bonds
      has been proposed. Using this technique, DNA duplexes having modified
      internucleotide bonds between dT and dC residues in the human NF-kappaB
      transcription factor recognition sequence in HIV-1 (5'-GGAAAGTCCC-3') have been
      prepared. We demonstrate that these internucleotide bonds within the recognition
      site do not prevent the formation of NF-kappaB p50 subunit complex with the
      corresponding duplexes. The cross-linking of NF-kappaB p50 subunit to the DNA
      duplex containing a monosubstituted pyrophosphate internucleotide bond has been
      successfully performed.

PMID- 8641435
TI  - Ascorbate synthesis-dependent glutathione consumption in mouse liver.
AB  - Ascorbate synthesis causes glutathione consumption in the liver. Addition of
      gulonolactone resulted in an increase of ascorbate production in isolated murine
      hepatocytes. At the same time, a decrease in reduced glutathione (GSH) level was
      observed. In hepatic microsomal membranes, ascorbate synthesis stimulated by
      gulonolactone caused an almost equimolar consumption of GSH. This effect could be
      counteracted by the addition of catalase or mercaptosuccinate, indicating the
      role of hydrogen peroxide formed during ascorbate synthesis in the depletion of
      GSH. The observed phenomenon may be one of the reasons why the evolutionary loss
      of ascorbate synthesis could be advantageous.

PMID- 8641436
TI  - Afg3p, a mitochondrial ATP-dependent metalloprotease, is involved in degradation
      of mitochondrially-encoded Cox1, Cox3, Cob, Su6, Su8 and Su9 subunits of the
      inner membrane complexes III, IV and V.
AB  - The yeast AFG3 gene encodes an ATP-dependent metalloprotease belonging to a
      subgroup of the AAA-family. This protease has been suggested to be essential for
      a metal- and ATP-dependent breakdown of incompletely mitochondrially synthesized
      polypeptides in the inner membrane, a process proposed to be important for
      mitochondrial function (Pajic et al. (1994) FEBS Lett. 353, 201-206). Here, we
      confirm the proteolytic activity by site-directed mutagenesis and demonstrate
      that the proteins Cox1, Cox3, Cob, Su6, Su8 and Su9 are substrates of Afg3p.
      Surprisingly, this proteolytic activity is not required for respiratory function
      and thus presumably also not essential for mitochondrial biogenesis.

PMID- 8641437
TI  - Wild type but not deltaF508 CFTR inhibits Na+ conductance when coexpressed in
      Xenopus oocytes.
AB  - Airway epithelial cells bearing mutations of the cystic fibrosis (CF)
      transmembrane conductance regulator (CFTR) possess an increased Na+ conductance
      along with their well described defect of cAMP dependent Cl- conductance.
      Currently it is not clear, how this occurs, and whether it is due to a CFTR
      control of epithelial Na+ conductances which might be defective in CF patients.
      In the present study, we have tried to identify possible interactions between
      both CFTR and the epithelial Na+ conductance by overexpressing respective cRNAs
      in Xenopus oocytes. The expression of all three (alpha, beta, gamma) subunits of
      the rat epithelial Na+ channel (rENaC) and wild type (wt) CFTR resulted in the
      expected amiloride sensitive Na+ and IBMX (1 mmol/l) activated Cl- currents,
      respectively. The amiloride sensitive Na+ conductance was, however, inhibited
      when the wt-CFTR Cl- conductance was activated by phosphodiesterase inhibition
      (IBMX). In contrast, IBMX had no such effect in deltaF508 and Na+ channels
      coexpressing oocytes. These results suggest that wt-CFTR, but not deltaF508-CFTR,
      is a cAMP dependent downregulator of epithelial Na+ channels. This may explain
      the higher Na+ conductance observed in airway epithelial cells of CF patients.

PMID- 8641438
TI  - Formation of disulfide bonded dimer of mutated heat-labile enterotoxin in vivo.
AB  - One of the two cysteines in the B subunit of heat-labile enterotoxin has been
      changed to a serine by site-directed mutagenesis so that the internal disulfide
      bond cannot form. The mutant protein, like the wild-type protein synthesised in
      the presence of the reducing agent dithiothreitol, does not form pentamers in the
      periplasm but binds to available membranes. Binding to membranes is disrupted by
      chaotropic agents but not by salt. More than half the molecules of mutant protein
      form disulfide-bonded dimers when exported to the periplasm but no dimer is
      detected when the protein is exported to the medium by spheroplasts.

PMID- 8641439
TI  - Isolation and properties of PS II membrane fragments depleted of the non heme
      iron center.
AB  - The functional properties and the content of non heme iron and cytochrome b559
      were investigated by measuring flash induced transient changes of the relative
      fluorescence quantum yield and applying Mossbauer spectroscopy. It was found that
      untreated PS II membrane fragments contain a heterogeneous population of two
      types of non heme iron centers and about 2 cytochrome b559 per PS II. Twofold
      treatment of these samples with a recently described 'iron depletion' procedure
      (MacMillan, F., Lendzian, F., Renger, G. and Lubitz, W. (1995) Biochemistry 34,
      3144-3156) leads to a complete loss (below the detection limit of Mossbauer
      spectroscopy) of the non heme iron center while more than 50% of the PS II
      complexes retain the functional integrity for light induced formation of the
      'stable' radical pair Y(OX)(Z) P680Pheo Q(-.)(A). This sample type deprived of
      virtually all non heme iron in PS II provides a most suitable material for
      magnetic resonance studies that require an elimination of the interaction between
      Fe2+ and nearby radicals.

PMID- 8641440
TI  - Cloning and characterization of a novel receptor to pancreatic polypeptide, a
      member of the neuropeptide Y receptor family.
AB  - We report isolation of a murine gene, NPYR-D, which predicts an intronless novel
      G protein-coupled receptor of 375 amino acids. Percent identities of NPYR-D to
      the clone Y1, Y2, rat Y4/PP1 and human Y4/PP1 receptors are 45, 32, 92 and 76,
      respectively. Southern blots indicate that NPYR-D and human Y4/PP1 receptor genes
      are species homologues. Rat [125I]pancreatic polypeptide ([125I]rPP) bound to
      NPYR-D transfected COS-7 cell membranes with a high affinity, i.e. IC50=90 pM.
      Pharmacological characterization of [125I]rPP binding showed a rank order of
      potency of P >> PYY > or = NPY, such that PYY and NPY were at least 5000-fold
      weaker than PP. Interestingly, [125I]rPYY binding produced the same rank order,
      but PYY and NPY were only 25-fold weaker than PP, which had an IC50 value of
      approximately 120 pM. Tissue distribution studies in mouse and humans suggest
      potential roles of this novel receptor in the gastrointestinal tract, heart,
      prostate, as well as in neural and endocrine signalling.

PMID- 8641441
TI  - Ethanolamine analogues stimulate DNA synthesis by a mechanism not involving
      phosphatidylethanolamine synthesis.
AB  - Dimethylethanolamine (0.5-1 mM), added to serum-starved NIH 3T3 fibroblasts,
      stimulated DNA synthesis 11-32-fold, and it also greatly enhanced the relatively
      modest (15-20-fold) mitogenic effect of insulin. Ethanolamine and
      monomethylethanolamine alone had no effects on DNA synthesis, but they also
      enhanced the stimulatory effect of insulin, although less effectively than
      dimethylethanolamine did. Lower concentrations (2.5-5 microg/ml) of compound D
      609 (tricyclo-9-yl-xanthogenate), which had no effects on phospholipase
      activities, synergistically enhanced the combined effects of ethanolamine analogs
      and insulin on DNA synthesis without affecting the synthesis of ethanolamine
      phospholipids. These results suggest that ethanolamine and its analogues, formed
      by phospholipase D-mediated hydrolysis of ethanolamine phospholipids, may have
      growth regulatory functions independent of their role as phospholipid precursors.

PMID- 8641442
TI  - Identification and characterization of presenilin I-467, I-463 and I-374.
AB  - We cloned a novel isoform of presenilin I (presenilin I-374) besides previously
      published presenilin I-467 and I-463 in human lymphocytes. Presenilin I-463 was
      identical to presenilin I-467 except a 12 bp nucleotides deletion in its amino
      terminal region. Another isoform, presenilin I-374 was produced by an alternative
      splicing with an additional exon consisting of 92 bp nucleotides (exon 11), which
      resulted in the frame shift with a stop codon to generate a truncated presenilin
      consisting of 374 amino acids. The transcripts for presenilin I-467/463 was
      ubiquitously detected while that for presenilin I-374 was selectively detected in
      liver, spleen, kidney. Abnormal behavior of presenilin I on gel electrophoresis
      was found with affinity-purified antibodies against presenilin I.

PMID- 8641443
TI  - Modulation by protein kinase C activation of rat brain delayed-rectifier K+
      channel expressed in Xenopus oocytes.
AB  - The modulation by protein kinase C (PKC) of the RCK1 K+ channel was investigated
      in Xenopus oocytes by integration of two-electrode voltage clamp, site-directed
      mutagenesis and SDS-PAGE analysis techniques. Upon application of beta-phorbol 12
      myristate 13-acetate (PMA) the current was inhibited by 50-90%. No changes in the
      voltage sensitivity of the channel, changes in membrane surface area or selective
      elimination of RCK1 protein from the plasma membrane could be detected. The
      inhibition was mimicked by 1-oleoyl-2-acetyl-rac-glycerol (OAG) but not by
      alphaPMA, and was blocked by staurosporine and calphostin C. Upon deletion of
      most of the N-terminus a preceding enhancement of about 40% of the current was
      prominent in response to PKC activation. Its physiological significance is
      discussed. The N-terminus deletion eliminated 50% of the inhibition. However,
      phosphorylation of none of the ten classical PKC phosphorylation sites on the
      channel molecule could account, by itself or in combination with others, for the
      inhibition. Thus, our results show that PKC activation can modulate the channel
      conductance in a bimodal fashion. The N-terminus is involved in the inhibition,
      however, not via its direct phosphorylation.

PMID- 8641444
TI  - Isolation and identification of glycated aminophospholipids from red cells and
      plasma of diabetic blood.
AB  - Glycosylation is a major pathway for posttranslational modification of tissue
      protein and begins with nonenzymatic addition of carbohydrate to the primary
      amino groups. Excessive glycation of tissue protein has been implicated in the
      pathogenesis of diabetes and ageing. While glycation of aminophospholipids has
      also been postulated, glycated aminophospholipids have not been isolated. Using
      normal phase HPLC with on-line electrospray mass spectrometry we found glycated
      ethanolamine phospholipids to make up 10-16% of the total
      phosphatidylethanolamine (PE) of the red blood cells and plasma of the diabetic
      subjects. The corresponding values for glycated PE of control subjects were 1-2%.

PMID- 8641445
TI  - Evaluation of the relative contribution of nitric oxide and peroxynitrite to the
      suppression of mitochondrial respiration in immunostimulated macrophages using a
      manganese mesoporphyrin superoxide dismutase mimetic and peroxynitrite scavenger.
AB  - Here we report that the cell-permeable superoxide dismutase mimetic
      Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) inhibits the oxidation of
      dihydrorhodamine-123 by peroxynitrite, but does not scavenge nitric oxide (NO).
      MnTBAP protects against the suppression of mitochondrial respiration in J774
      cells exposed to peroxynitrite or to NO donors. MnTBAP and N(G)-methyl-L-arginine
      provide additive protective effect against the suppression of respiration in
      immunostimulated cells. Our data suggest separate contributions of NO and
      peroxynitrite to the suppression of mitochondrial respiration and support the
      role of oxidative stress in the expression of the inducible isoform of NO
      synthase.

PMID- 8641446
TI  - Transformation of Saccharomyces cerevisiae with a cDNA encoding a sterol C
      methyltransferase from Arabidopsis thaliana results in the synthesis of 24-ethyl
      sterols.
AB  - Using an EST-cDNA probe, a full-length cDNA (411) sequence of 1411 bp was
      isolated from A. thaliana. This sequence contained features typical of
      methyltransferases in general and in particular showed 38% identity with ERG6, a
      S. cerevisiae gene which encodes the zymosterol-C-24-methyltransferase. A yeast
      vector containing this ORF (4118-pYeDP60) was used to transform a wild type S.
      cerevisiae which accumulates predominantly ergosterol, a 24-methyl sterol as well
      as a mutant erg6 null mutant accumulating principally zymosterol, a sterol non
      alkylated at C-24. In both cases, several 24-ethyl- and 24-ethylidene sterols
      were synthetized indicating that the 4118 cDNA encodes a plant sterol C
      methyltransferase able to perform two sequential methylations of the sterol side
      chain.

PMID- 8641447
TI  - Role of retinoic acid and oxidative stress in embryonic stem cell death and
      neuronal differentiation.
AB  - Embryonic stem (ES) cells are a suitable system to study events occurring during
      development. In the present work we show that the apoptotic program was activated
      in ES cells, either by simple removal of the reducing agent 2-mercaptoethanol (2
      ME), or by addition of all trans-retinoic (ATRA) to embryoid bodies. In these two
      conditions, there was an increase in reactive oxygen species and antioxidants
      such as catalase, superoxide dismutase or phenol prevented ATRA-induced cell
      death. Neuronal differentiation was observed when undifferentiated ES cells were
      treated with ATRA in the absence of serum and the presence of 2-ME.

PMID- 8641448
TI  - Expression and functional characterization of a melatonin-sensitive receptor in
      Xenopus oocytes.
AB  - Melatonin (MEL) plays a central role in the regulation of seasonal cycles and in
      the control of circadian rhythms in mammals. Functional MEL-sensitive receptors
      were expressed in Xenopus laevis oocytes following injection of poly (A)+ RNA
      from rat brain. Administration of 0.1-100 micromol/l MEL to voltage-clamped
      oocytes (holding potential: -70 mV) elicited oscillatory inward currents
      (reversal potential: -24 mV) which could be blocked by 9-anthracenecarboxylic
      acid and caffeine. After preincubation with pertussis toxin (PTX) the MEL
      response disappeared. The expressed MEL-sensitive receptor probably activates
      Ca(2+)-dependent chloride currents via a PTX-sensitive G protein and the
      phosphoinositol pathway.

PMID- 8641449
TI  - Temporal regulation of gene expression in adipocyte differentiation.
AB  - Cells usually become 'committed' to differentiate long before any actual
      morphological change is apparent. In one model commitment is a decision which
      corresponds to the expression of a control gene, while differentiation is the
      ultimate consequence of that decision. We have been studying adipocyte commitment
      and differentiation at the molecular level. Earlier we showed that the
      introduction of a specific DNA sequence into 'uncommitted' cells renders those
      cells committed to differentiate into adipocytes. Here we report temporal
      regulation of the expression of this DNA sequence; furthermore, we show that this
      RNA is in the non-polyA+ fraction of total cellular RNA. These data suggest that
      coordinate regulation of this and other genes is important in promoting
      differentiation.

PMID- 8641450
TI  - The role of the C-terminal lysine in the hinge bending mechanism of yeast
      phosphoglycerate kinase.
AB  - Treatment of yeast phosphoglycerate kinase (PGK) with trypsin results in a
      fourfold increase in the Vmax of this enzyme, without affecting the Km. This
      activation is shown to be due to the removal of the C-terminal lysine residue.
      The C-terminal sequence folds back over the N-terminal domain and contacts the
      extreme N-terminal sequence which folds onto the C-terminal domain, thus making
      many of the inter-domain contacts in this two domain protein. Previous studies
      have shown that this C-terminal region is important in mediating the
      conformational changes required during catalysis by yeast PGK. Observation of the
      three-dimensional structure of this enzyme suggests that removal of the C
      terminal lysine residue will strengthen the interaction between K5 and E413. This
      indicates that this salt bridge stabilises the enzyme in the higher activity
      form, while the presence of K415 reduces the strength of that interaction.

PMID- 8641451
TI  - Calculation of Cys 30 delta pKa's and oxidising power for DsbA mutants.
AB  - DsbA possesses a redox active disulphide, with the equilibrium strongly shifted
      towards the reduced form as compared to its structural homologue, thioredoxin. It
      is widely believed that the two amino acids that separate the active site
      cysteines play a crucial role in determining oxidising power within the
      thioredoxin family. Data concerning redox and pKa properties for DsbA mutants in
      this region are available. Electrostatics calculations show reasonable agreement
      with the experimental data, and support the suggestion that amino acids outside
      of the CXXC active site sequence are as important in determining oxidising power
      within the thioredoxin family as are those within it.

PMID- 8641452
TI  - Proteolytic processing of nuclear factor kappa B by calpain in vitro.
AB  - Nuclear factor kappaB (NF-kappaB) is a transcription factor that is critical for
      the inducible expression of multiple cellular and viral genes. Using the
      electrophoretic mobility shift assay, we demonstrated that DNA binding activity
      of NF-kappaB was abolished by proteolysis with mu- and m-calpains in vitro. The
      proteolysis of NF-kappaB by calpains and hence the abolition of its DNA binding
      was prevented by calpastatin, calpain inhibitor I and proteasome inhibitor. We
      also provided evidence that calpains degrade the C-terminal domain of NF-kappaB
      by Western blot using anti-NF-kappaB (p65) C-terminal antibody. These
      observations indicate that calpains regulate gene expression through processing
      of NF-kappaB.

PMID- 8641453
TI  - A molecular map of titin/connectin elasticity reveals two different mechanisms
      acting in series.
AB  - In the I-band of skeletal muscle sarcomeres, the elastic region of titin consists
      of immunoglobulin (Ig) domains, and non-modular regions rich in proline,
      hydrophobic, and charged residues (PEVK). Using immunoelectron microscopy with
      sequence-assigned monoclonal antibodies, we demonstrate that extension of the Ig
      regions in M. psoas occurs largely at sarcomere lengths between 2 and 2.8 micron,
      decreasing in slope towards higher lengths. The Ig domains do not unfold. Above
      2.6 micron, length changes are increasingly due to the PEVK-rich regions. We
      therefore propose that rubber-like properties of the PEVK-rich regions are mainly
      contributing to skeletal titin elasticity.

PMID- 8641454
TI  - Initial analysis of 750 MHz NMR spectra of selective 15N-G,U labelled E. coli 5S
      rRNA.
AB  - The overall folding of an RNA molecule is reflected in its base pairing pattern.
      The identification of that pattern provides a first step towards the
      determination of the structure of an RNA molecule. We show that the application
      of heteronuclear NMR methods at 750 MHz to E. coli 5S rRNA (120 nucleotides)
      selectively labelled with 15N in guanine and uridine allows observation of base
      pairing patterns for a larger RNA molecule. We also present evidence that the
      fold of the E-domain of the 5S rRNA (nt 79-97) as a contiguous part of the 5S
      rRNA and as an isolated molecule is virtually the same.

PMID- 8641455
TI  - Multiple palmitoylation of synaptotagmin and the t-SNARE SNAP-25.
AB  - Synaptotagmin, a likely calcium sensor for synaptic transmission, and SNAP-25, a
      t-SNARE of the presynaptic plasma membrane, are key proteins for the docking and
      fusion of synaptic and other vesicles. We report that both synaptotagmin and SNAP
      25 are palmitoylated with their fatty acids attached in a labile thioester-type
      bond. A SNAP-25 mutant with deleted palmitoylation sites is found exclusively in
      the cytosol after cell fractionation, whereas the palmitoylated form of SNAP-25
      is membrane-bound, establishing that SNAP-25 is membrane-anchored via covalently
      linked palmitate.

PMID- 8641456
TI  - A calcium switch for the functional coupling between alpha (hslo) and beta
      subunits (Kv,cabeta) of maxi K channels.

PMID- 8641457
TI  - NMR evidence for helix geometry modifications by a G-U wobble base pair in the
      acceptor arm of E. coli tRNA(Ala).
AB  - A ribooligonucleotide duplex representing the acceptor stem of E. coli RNA(Ala)
      with a G3-U70 wobble base pair, which is the main identity element for the
      recognition by the alanine-tRNA synthetase, has been characterized by 2D-NMR, as
      having two sequence variants with a regular Watson-Crick G3-C70 and an I3-U70
      wobble pair, respectively. As compared to a regular A-RNA, the G-U base pair
      gives rise to variations of the local helix geometry which are reflected in
      distinct local chemical shift changes. Structural differences between the duplex
      possessing an I3-U70 base pair and the wild-type G3-U70 sequence have also been
      found. The nucleotides in the ubiquitous single-stranded NCCA terminus display a
      surprisingly high degree of stacking order, especially between A73, C74, and C75.

PMID- 8641458
TI  - Spermatocyte-specific expression of the gene for mouse testis-specific
      transcription elongation factor S-II.
AB  - Previously, we characterized a rat cDNA for testis-specific transcription
      elongation factor S-II (SII-T1) (Q. Xu et al., J. Biol. Chem. 269, 3100-3103
      (1994)). Here, we isolated a 335-bp fragment of the cDNA for mouse SII-T1, and
      used it to examine the expression of the SII-T1 gene in the testis by in situ
      hybridization. The results indicated that the SII-T1 gene is expressed
      exclusively in spermatocytes, showing no appreciable expression in spermatogonia,
      spermatids, or Leydig cells. RT-PCR experiments using testis RNA from W/Wv mutant
      mice also suggested that SII-T1 is a specific transcription elongation factor
      essential for spermatogenesis.

PMID- 8641459
TI  - Interleukin-4 upregulates the heat shock protein Hsp90alpha and enhances
      transcription of a reporter gene coupled to a single heat shock element.
AB  - Transcription of the heat shock protein Hsp90alpha was strongly upregulated in
      human T-cells by interleukin-4 (IL-4) and to a lesser extent by IL-2, reaching
      peak levels after 2-3 days of stimulation. Heat shock proteins are induced within
      minutes under stress conditions, via heat shock factors (HSF), which activate
      heat shock elements (HSE). IL-4, IL-2 and IL-13 upregulated transcription of a
      reporter gene coupled to a single HSE site and a minimal promoter. HSE may
      therefore be involved in cytokine induced heat shock gene transcription in the
      absence of cellular stress.

PMID- 8641460
TI  - Mechanical unfolding of alpha2-macroglobulin molecules with atomic force
      microscope.
AB  - alpha2-Macroglobulin was derivatized with a sulfhydryl cross-linker and
      sandwiched between a mica substrate and a silicon nitride tip, both coated with
      gold, of an atomic force microscope and force curve measurement was carried out.
      An extensive downward deflection of the cantilever was observed in the retracting
      realm of the curve, when and only when the substrate was covered with the
      derivatized protein. The result was interpreted in terms of the mechanical
      stretching and unfolding of a single or a few protein molecules.

PMID- 8641461
TI  - ATF/CREB site mediated transcriptional activation and p53 dependent repression of
      the cyclin A promoter.
AB  - Cyclin A is a pivotal regulatory protein which, in mammalian cells, is involved
      in the S phase of the cell cycle. Transcription of the human cyclin A gene is
      cell cycle regulated through tight control of its promoter. We have previously
      shown that the ATF/CREB site, present in the cyclin A promoter, mediates
      transcriptional regulation by cAMP responsive element binding proteins. The main
      goal of the present study was to investigate whether this site is involved in
      transcriptional regulation of the gene. We have constructed stable NIH-3T3 cell
      lines that express the luciferase reporter gene under the control of normal or
      mutated versions of the cyclin A promoter. We show that the ATF/CREB is required
      to achieve maximal levels of transcription from the cyclin A promoter starting in
      late G1. We also show that down-regulation of the cyclin A promoter by p53 does
      not implicate a direct binding of p53 to its cognate consensus sequence but
      occurs probably by interference with trans-activating factors. This result
      suggests that p53 can interfere with transcription of the cyclin A gene, in the
      absence of a TATA sequence in the promoter.

PMID- 8641462
TI  - Inulin synthesis by a combination of purified fructosyltransferases from tubers
      of Helianthus tuberosus.
AB  - Sucrose-sucrose 1-fructosyltransferase (1-SST) was purified 100-fold from tubers
      of Helianthus tuberosus L. The purified enzyme was essentially devoid of
      invertase activity and could be separated by isoelectric focusing into five
      isoforms which all were composed of two subunits (59 and 26 kDa). Fructan-fructan
      1-fructosyltransferase (1-FFT) was purified from the same source [M. Luscher et
      al. (1993) New Phytologist 123, 437-442). When incubated individually with
      sucrose, 1-FFT was inactive while 1-SST formed isokestose (trimer) and, upon
      prolonged incubation, some nystose (tetramer). When a combination of the two
      enzymes was incubated with sucrose, a series of oligofructosides with a degree of
      polymerization of up to 20 was formed. Amino acid sequences of tryptic peptide
      fragments from both 1-SST and 1-FFT indicate that these enzymes are highly
      homologous with plant invertases.

PMID- 8641463
TI  - Cytokines activate the nuclear factor kappa B (NF-kappa B) and induce nitric
      oxide production in human pancreatic islets.
AB  - We studied the ability of cytokines to activate the nuclear transcription factor
      NF-kappaB in human pancreatic islets and the putative role of NF-kappaB for
      cytokine-induced NO production. Brief exposure (20 min) of human islets of
      Langerhans to a combination of interleukin-1beta + interferon-gamma + tumor
      necrosis factor-alpha induced a 2.6-fold increase in nuclear NF-kappaB activity
      in gel shift analysis. This increase was prevented by the NF-kappaB inhibitor,
      pyrrolidine dithiocarbamate (PDTC), which also counteracted NO production by
      human islets exposed for 14 h to the cytokine combination. High concentrations of
      interleukin-1beta alone (150 and 250 U/ml) increased NF-kappaB nuclear binding
      but failed to induce NO formation in human islets. The present data are the first
      to demonstrate that cytokines activate NF-kappaB in primary adult human
      pancreatic islets and suggest that activation of NF-kappaB may be a necessary but
      not sufficient signal for cytokine-induced iNOS expression in human islets of
      Langerhans.

PMID- 8641464
TI  - Glucose-induced inactivation of isocitrate lyase in Saccharomyces cerevisiae is
      mediated by the cAMP-dependent protein kinase catalytic subunits Tpk1 and Tpk2.
AB  - Glucose-induced inactivation of isocitrate lyase (Icl) has been related to
      protein phosphorylation. Moreover, since rapid reversible inactivation preceded
      irreversible inactivation of the enzyme, phosphorylation was proposed as the
      triggering reaction that makes the enzyme accessible to the proteolytic
      machinery. The protein kinase involved in the process is unknown at the moment.
      In this work we demonstrate that Tpk1 and Tpk2, the catalytic subunits of cAMP
      dependent protein kinase, are involved in the signalling of short-term and long
      term inactivation processes of Icl. We also demonstrate that threonine 53 is
      involved in a regulatory mechanism necessary for short-term reversible
      inactivation of Icl, probably mediated through its phosphorylation. Other, as yet
      unidentified, residues are likely to be the target of distinct protein kinases
      mediating the irreversible long-term inactivation of Icl.

PMID- 8641465
TI  - Expression of GCAP1 and GCAP2 in the retinal degeneration (rd) mutant chicken
      retina.
AB  - We cloned the guanylate cyclase activating proteins, GCAP1 and GCAP2, from
      chicken retina and examined their expression in normal and predegenerate rdlrd
      chicken retina. Northern analyses show that the amounts of the single transcripts
      encoding GCAP1 and GCAP2 are reduced to about 70% of normal levels in rdlrd
      retina. Western analyses reveal that GCAP2 levels appear normal in this retina,
      while GCAP1 levels are reduced by more than 90%. The specific downregulation of
      GCAP1 in rdlrd retina is consistent with a model for this disease in which
      activation of guanylate cyclase in the photoreceptors is abnormal, resulting in
      low levels of cGMP and an absence of phototransduction.

PMID- 8641466
TI  - Carboxyl group protonation upon reduction of the Paracoccus denitrificans
      cytochrome c oxidase: direct evidence by FTIR spectroscopy.
AB  - The redox reactions of the cytochrome c oxidase from Paracoccus denitrificans
      were investigated in a thin-layer cell designed for the combination of
      electrochemistry under anaerobic conditions with UV/VIS and IR spectroscopy.
      Quantitative and reversible electrochemical reactions were obtained at a surface
      modified electrode for all cofactors as indicated by the optical signals in the
      400-700 nm range. Fourier transform infrared (FTIR) difference spectra of
      reduction and oxidation (reduced-minus-oxidized and oxidized-minus-reduced,
      respectively) obtained in the 1800-1000 cm(-1) range reveal highly structured
      band features with major contributions in the amide I (1620-1680 cm(-1)) and
      amide II (1580-1520 cm(-1)) range which indicate structural rearrangements in the
      cofactor vicinity. However, the small amplitude of the IR difference signals
      indicates that these conformational changes are small and affect only individual
      peptide groups. In the spectral region above 1700 cm(-1), a positive peak in the
      reduced state (1733 cm(-1)) and negative peak in the oxidized st ate (1745 cm(
      1)) are characteristic for the formation and decay of a COOH mode upon reduction.
      The most obvious interpretation of this difference signal is proton uptake by one
      Asp or Glu side chain carboxyl group in the reduced state and deprotonation of
      another Asp or Glu residue. Moreover, both residues could well be coupled as a
      donor-acceptor pair in the proton transfer chain. An alternative interpretation
      is in terms of a protonated carboxyl group which shifts to a different
      environment in the reduced state. The relevance of this first direct observation
      of protein protonation changes in the cytochrome c oxidase for vectorial proton
      transfer and the catalytic reaction is discussed.

PMID- 8641467
TI  - Involvement of intracellular Ca2+ in oxidant-induced NF-kappa B activation.
AB  - In human Jurkat T cells and its subclone Wurzburg cells oxidant challenge
      elevated [Ca2+]i by mobilizing Ca2+ from intracellular stores. In Jurkat cells
      this effect was rapid and transient, but in Wurzburg cells the response was slow
      and sustained. H2O2-induced NF-kappaB activation in Wurzburg cells was not
      influenced by the presence of extracellular EGTA but was totally inhibited in
      cells that were loaded with esterified EGTA. In Jurkat cells that are not
      sensitive to H2O2-induced NF-kappaB activation, H2O2 potentiated NF-kappaB
      activation in the presence of sustained high [Ca2+]i following thapsigargin
      treatment. NF-kappaB regulatory effect of alpha-lipoate and N-acetylcysteine
      appeared to be, at least in part, due to their ability to stabilize elevation of
      [Ca2+]i following oxidant challenge. Results of this study indicate that a
      sustained elevated [Ca2+]i is a significant factor in oxidant-induced NF-kappaB
      activation.

PMID- 8641468
TI  - Effects of peroxynitrite-induced protein modifications on tyrosine
      phosphorylation and degradation.
AB  - The ability of protein tyrosine kinases to phosphorylate a synthetic peptide was
      inhibited 51% by peroxynitrite-mediated nitration of tyrosine. Exposure of
      endothelial cells to peroxynitrite decreased the intensity of tyrosine
      phosphorylated proteins and increased the intensity of nitrotyrosine-containing
      proteins. Peroxynitrite-modified BSA was degraded by human red blood cell
      lysates. However, human plasma in a concentration-, time-, and temperature
      dependent manner, removed the protein nitrotyrosine epitope. These results
      suggest that tyrosine nitration interferes with phosphorylation and targets
      proteins for degradation. Specific enzymatic process(es) for removing
      nitrotyrosine may be present in vivo.

PMID- 8641469
TI  - Identification of the prolyl isomerase domain of Escherichia coli trigger factor.
AB  - E. coli trigger factor is a protein of 48 kDa which was recently identified as a
      ribosome-bound peptidyl-prolyl-cis/transisomerase (PPIase) capable of catalysing
      protein folding in vitro. We found trigger factor in association with nascent
      polypeptide chains, suggesting a function in the co-translational folding of
      proteins. Sequence comparisons revealed a homology of a segment of trigger factor
      with PPIases of the FK506 binding protein (FKBP) family. Here, we report on the
      purification of trigger factor and a domain assignment of its polypeptide chain
      by microsequencing and mass spectroscopy of proteolytic fragments. Two proteases
      generated fragments of 12-13 kDa molecular weight that encompass the predicted
      FKBP domain and possess PPIase activity in vitro. Sequence alignment of the known
      trigger factor proteins demonstrates a high degree of conservation within this
      central functional domain of the protein.

PMID- 8641470
TI  - Site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin: interaction
      between residue 167 and benzimidazole compounds.
AB  - Benzimidazoles are widely used as anthelmintic agents and systemic fungicides. In
      susceptible organisms, benzimidazoles bind to beta-tubulin and block microtubule
      polymerization. To further characterize this interaction, site-directed
      mutagenesis followed by gene replacement was used to change Saccharomyces
      cerevisiae beta-tubulin residue Phe-167 to Tyr. Consistent with previous studies,
      this mutation resulted in at least 3-4-fold decreased sensitivity to the
      benzimidazole derivatives carbendazim and nocodazole. The Tyr-167 mutant was cold
      sensitive, implying a direct effect on benzimidazole binding rather than a
      nonspecific increase in microtubule stability. Surprisingly, the mutant had 8
      fold increased sensitivity to the derivative benomyl, which is structurally
      identical to carbendazim except at position 1. This suggests that residue 167
      interacts with benzimidazoles in the vicinity of the 1-position.

PMID- 8641471
TI  - Isolation of tissue-type plasminogen activator, cathepsin H, and non-specific
      cross-reacting antigen from SK-PC-1 pancreas cancer cells using subtractive
      hybridization.
AB  - We have used subtractive hybridization to isolate cDNAs overexpressed in SK-PC-1
      pancreas cancer cells. Forty-five independent clones corresponding to 11 genes
      were identified. Their expression in cultured pancreas cancer cells, normal
      pancreas tissue, and normal exocrine pancreas cultures was examined by Northern
      blotting. cDNA clones can be grouped into two broad categories: (1) those
      corresponding to genes expressed at high levels both in tumor cell lines and in
      primary cultures of normal pancreas, but not in normal tissue (i.e. thymosin
      beta4(3), cytokeratin 18, beta-actin, pyruvate kinase and mitochondrial genes);
      and (2) those corresponding to genes expressed at high levels in pancreas cancer
      cultures but not in normal pancreas tissue or cultured cells (i.e. tissue-type
      plasminogen activator and cathepsin H). The overexpression of these proteases in
      pancreas cancers suggests that they play a role in the aggressive biological
      behavior of this tumor.

PMID- 8641472
TI  - Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor
      antagonists terfenadine and astemizole.
AB  - The widely used histamine receptor antagonists terfenadine and astemizole were
      shown to prolong the QT interval in electrocardiographic recordings in cases of
      overdose or inappropriate co-medications, indicating a possible interaction with
      cardiac K+ channels. Here, terfenadine and astemizole both inhibited the human
      ether-a-go-go related gene (HERG) encoded channels expressed in Xenopus oocytes
      at nanomolar concentrations in a use- and voltage-dependent fashion. In contrast,
      inhibition of other delayed rectifier (Kv1.1 and IsK) or inward rectifier K+
      channels (IRK1) was much weaker and occurred only at high micromolar
      concentrations. These results suggest that blockade of HERG channels by
      terfenadine and astemizole might contribute to the cardiac side effects of these
      compounds.

PMID- 8641473
TI  - Prediction of potential protein-protein interaction sites from amino acid
      sequence. Identification of a fibrin polymerization site.
AB  - Identification of a protein-protein interaction site is an important step that
      has significant potential to clarify structure-function relationships of proteins
      and drug design. We propose here a unique predictive method to identify protein
      protein interaction sites based on the observation that proline is the most
      common residue found in the flanking segments of interaction sites [Kini, R.M.
      and Evans, H.J. (1995) Biochem. Biophys. Res. Commun. 212, 1115-1124].
      Accordingly, the interaction sites of proteins might be predicted directly from
      the amino acid sequence based on the presence of proline brackets. Using this
      strategy, we have predicted a polymerization site in the epitope of the Aalpha
      chain of fibrinogen recognized by a monoclonal antibody, 9E9 which inhibits
      fibrin polymerization [Cierniewski, C.S. and Budzynski, A.Z. (1992) Biochemistry
      31, 4248-4253]. The synthetic peptide comprising this predicted site inhibited
      the coagulation of human blood and allosterically interfered in fibrin
      polymerization. This is the first known allosteric polymerization site of
      fibrinogen. Thus the results validate the predicted site and the method for
      prediction. This unique predictive method should help in identifying the
      interaction sites of many proteins.

PMID- 8641474
TI  - The myrosinase-glucosinolate interaction mechanism studied using some synthetic
      competitive inhibitors.
AB  - Using synthetic deoxy-glucotropaeolins (6d-GTL, 4d- GTL, 3d-GTL, 2d-GTL) as
      substrates, myrosinase activity was studied in comparison to that determined on
      native glucotropaeolin (GTL) isolated from ripe Lepidium sativum seeds. When the
      deoxy substrates were used, in addition to an overall strong reaction rate
      decline, a significant decrease in the reaction rate was observed in going from
      6d- to 2d-GTL. This finding allows us to propose a mechanism of catalysis which
      appears to be similar in many respects to that established for beta-glucosidases.
      Finally, 2d-GTL was shown to be the first strong competitive inhibitor of
      myrosinase ever reported.

PMID- 8641475
TI  - The C-terminal domain of peptide deformylase is disordered and dispensable for
      activity.
AB  - Upon trypsinolysis, the 18 C-terminal residues of Escherichia coli peptide
      deformylase were removed but the resulting form exhibited full activity.
      Moreover, a mutant fms gene encoding the first 145 out of the 168 residues of the
      enzyme was able to complement a fms(Ts) strain and exhibited full activity. Upon
      progressive truncation up to residue 139, both activity and stability decreased
      up to complete inactivation. Mutagenesis of residues of the 138-145 region
      highlights the importance of Leu-141 and Phe-142. N-Terminal deletions were also
      carried out. Beyond two residues off, the enzyme showed a dramatic instability.
      Finally, NMR and thermostability studies of the full-length enzyme and comparison
      to the 1-147 form strongly suggest that the dispensable residues are disordered
      in solution.

PMID- 8641476
TI  - Shortened amoebapore analogs with enhanced antibacterial and cytolytic activity.
AB  - Amoebapores are cytolytic peptides of Entamoeba histolytica which function by the
      formation of ion channels in target cell membranes. Three isoforms (amoebapore A,
      B, and C) exist in amoebic cytoplasmic granules. They are composed of 77 amino
      acid residues arranged in four alpha-helical domains. In order to analyze the
      structure-function relationships, 15 synthetic peptides of 24-25 residues were
      constructed based on the assumption that the third helix is the membrane
      penetrating domain and on the previous finding that positively charged residues
      are significant for activity. Activity of these short versions of amoebapores was
      determined towards artificial and natural targets, such as liposomes, bacteria,
      erythrocytes and a human tumor cell line. It was found that some of the novel
      peptides were highly active and showed a broader activity spectrum compared to
      the parent molecules.

PMID- 8641477
TI  - The effects of tamoxifen treatment on the endometrium.
AB  - OBJECTIVE: To investigate the association between tamoxifen and endometrial
      cancer. BACKGROUND: Tamoxifen is a nonsteroidal antiestrogenic drug that has been
      used successfully for 15 years in the treatment of all stages of breast
      carcinoma. In light of the positive results, several studies are now being
      conducted to test prolonged tamoxifen treatment as a prophylaxis against breast
      cancer in high-risk women. Although tamoxifen was thought to have only a few side
      effects, reports indicate that it is associated with an increased incidence of
      proliferative and neoplastic changes in the endometrium. As the current trend is
      to administer tamoxifen for prolonged periods and for more indications, the
      detrimental effects on the endometrium have vast implications. METHODS: Review of
      the current literature. RESULTS: Tamoxifen treatment is associated with an
      increased incidence of proliferative and neoplastic changes in the endometrium,
      with a 1.3 to 7.5 relative risk of developing endometrial carcinoma. CONCLUSIONS:
      The results of tamoxifen treatment in breast carcinoma override the risk of
      developing endometrial carcinoma. Any vaginal bleeding in women treated with
      tamoxifen should be investigated carefully and promptly. In the future it may be
      necessary to advise these women to undergo routine uterine cavity examination.

PMID- 8641478
TI  - The time has come.

PMID- 8641479
TI  - Risk factors for ectopic pregnancy: a meta-analysis.
AB  - OBJECTIVE: To review current knowledge on the risk of ectopic pregnancy (EP),
      with the exception of contraceptive methods. DESIGN: Meta-analysis. SETTING: Case
      control and cohort studies published between 1978 and 1994 in English, French,
      German, or Dutch, retrieved by Medline search, crossover search from the papers
      obtained, and hand-search on recent medical journals. PATIENTS: A total number of
      6,718 cases of EP in 27 case control studies and 13,049 exposed women in 9 cohort
      studies. MAIN OUTCOME MEASURES: Detected studies were tested for homogeneity. If
      homogeneity was not rejected, Mantel-Haenszel common odds ratios (OR) and 95%
      confidence intervals were calculated. RESULTS: Previous EP, previous tubal
      surgery, documented tubal pathology, and in utero diethylstilbestrol (DES)
      exposure were found to be associated strongly with the occurrence of EP. Previous
      genital infections (pelvic inflammatory disease [PID], chlamydia, gonorrhoea),
      infertility, and a lifetime number of sexual partners > 1 were associated with a
      mildly increased risk. For gonorrhoea, PID, previous EP, previous tubal surgery,
      and smoking, a higher common OR was calculated when using pregnant controls
      compared with using nonpregnant controls. CONCLUSIONS: The strong risk in women
      with a previous EP, previous tubal surgery, documented tubal pathology, or in
      utero DES exposure justifies the exploration of a screening policy for EP among
      these women. If a risk factor reduces fertility chances, the OR detected when
      using pregnant controls is higher than the OR calculated using nonpregnant
      controls.

PMID- 8641480
TI  - Plasma lipids and desogestrel and ethinyl estradiol: a meta-analysis.
AB  - OBJECTIVE: To review the literature to determine the magnitude of the effect of
      150 micrograms desogestrel-30 micrograms ethinyl E2, an oral contraceptive (OC)
      formulation, on plasma lipid concentrations in healthy women using meta-analysis
      techniques. DATA SOURCES: All English-language published reports (1981 to 1991)
      on lipid parameters in women taking 150 micrograms desogestrel and 30 micrograms
      ethinyl E2 for up to 6 months obtained via an Embase database search and via a
      subsequent review of the reference lists. METHODS OF STUDY SELECTION: Of 98
      articles, 18 met eligibility criteria and were included in the meta-analysis.
      DATA EXTRACTION AND SYNTHESIS: Data on total cholesterol, high-density
      lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and
      triglycerides were extracted. The change in each parameter from baseline to cycle
      6 was estimated as a weighted mean of changes reported in each study; a standard
      error of the estimate was calculated. This procedure was validated by goodness-of
      fit tests. RESULTS: The following statistically significant changes from baseline
      to cycle 6 were estimated (mean +/- SE): HDL-C: 0.15 +/- 0.02 mmol/L (5.80 +/-
      0.62 mg/dL); triglycerides: 0.28 +/- 0.03 mmol/L (24.49 +/- 2.59 mg/dL); and LDL:
      - 0.12 +/- 0.04 mmol/L (-4.53 +/- 1.55 mg/dL). There was a nonsignificant trend
      toward an increase in total cholesterol. CONCLUSION: When given in combination
      with 30 micrograms ethinyl E2, desogestrel increased HDL-C and triglycerides and
      decreased LDL-C. The positive impact on HDL-C and LDL-C suggests that a potential
      cardioprotective benefit (rather than an atherosclerosis risk) may occur with
      prolonged use of such an OC, but this hypothesis will be difficult to prove.

PMID- 8641481
TI  - Effect of preovulatory insertion of Norplant implants over luteinizing hormone
      secretion and follicular development.
AB  - OBJECTIVE: To determine whether the process of ovulation could be interrupted by
      the insertion of Norplant implants (Leiras Pharmaceuticals, Turku, Finland) in
      the advanced preovulatory phase. DESIGN: Prospective study. SETTING: The
      Department of Biomedical Research at the Family Planning Clinic of PROFAMILIA,
      Santo Domingo, Dominican Republic. PATIENTS: Healthy women of reproductive age,
      requesting Norplant implants contraception. Thirteen of 15 women volunteers who
      were admitted completed the study. INTERVENTIONS: Norplant implants were inserted
      when the dominant follicle reached a mean diameter of 16 mm, based on serial
      vaginal ultrasounds (US) beginning on day 10 of the cycle. Blood samples for
      determination of E2, P, LH, and levonorgestrel, were taken and vaginal US
      performed at 0, 4, 24, 48, and 72 hours after insertion. If follicle rupture had
      not occurred at 72 hours after insertion, blood sampling and US were done three
      times per week during 2 additional weeks. RESULTS: Follicle rupture occurred in
      11 of 13 subjects within 72 hours after insertion, with the exception of 1
      subject in whom rupture occurred between 72 and 192 hours. Two women already had
      an LH peak at the time of insertion. In 9 of the remaining 11 women, a
      shortlasting, blunted LH surge was observed at 4 hours postinsertion. In the
      remaining two women, who had the lowest E2 levels, ovulation was inhibited, and a
      persistent follicle developed without luteinization. CONCLUSIONS: The insertion
      of Norplant implants in the advanced follicular phase will not inhibit ovulation
      if sufficient E2 priming has occurred. On the contrary, the exogenous progestin
      may rapidly foster ovulation shortly after.

PMID- 8641482
TI  - Comparison of the effects of ovarian cauterization and gonadotropin-releasing
      hormone agonist and oral contraceptive therapy combination on endocrine changes
      in women with polycystic ovary disease.
AB  - OBJECTIVE: To study the effects of laparoscopic ovarian cauterization and
      combination of long-acting GnRH agonist (GnRH-a) and oral contraceptive (OC)
      therapy on endocrine changes in women with clomiphene citrate (CC)- resistant
      polycystic ovary disease (PCOD). DESIGN: Prospective, randomized. SETTING:
      University-based infertility clinic. PATIENTS: Seventeen women with CC-resistant
      PCOD were included randomly in the study to either laparoscopic ovarian cautery
      or GnRH-a and OC therapy for 3 months. MAIN OUTCOME MEASURES: Serum
      concentrations of LH, FSH, androstenedione (A), T, and sex hormone-binding
      globulin (SHBG) were determined before each therapeutic approach and during the
      follicular phase of first menstrual cycle after the cessation of each treatment.
      RESULTS: The mean serum concentrations and the clinical profiles were similar in
      both groups. Both groups showed significant changes in LH, FSH, A, T, and SHBG
      compared with pretreatment levels. There were no significant differences in the
      final concentrations of LH, FSH, and A between the two study groups after each
      treatment, whereas T and SHBG levels were significantly different in the
      goserelin and OC group. The decrease in LH and increase in SHBG serum
      concentrations were greater in the goserelin and OC-treated women [-59% and +
      5.9% versus - 70% and + 13.5%, respectively]. Although the SHBG concentration
      increased in both groups, the serum SHBG concentration of the goserelin and OC
      group was significantly higher than the other group. CONCLUSION: Both therapeutic
      modalities revealed similar effects on the endocrine profiles in women with CC
      resistant PCOD. Considering the invasiveness, cost, and potential complications
      of laparoscopic ovarian cauterization, noninvasive medical treatment with GnRH-a
      and OC combination may be more effective in restoring the optimal follicular
      environment in women with PCOD.

PMID- 8641483
TI  - RU486 suppresses prolactin production in explant cultures of leiomyoma and
      myometrium.
AB  - OBJECTIVE: To assess the action of RU486 (mifepristone), in the presence and
      absence of P, on PRL production by explant cultures of leiomyoma and myometrium.
      DESIGN: Explant cultures using tissue from nine premenopausal women undergoing
      hysterectomy in the proliferative phase of the menstrual cycle;
      immunohistochemical staining of tissue sections from five patients for P receptor
      (PR) subtype. MAIN OUTCOME MEASURES: Prolactin secretion (measured by RIA),
      lactate dehydrogenase secretion (measured by quantitative colorimetric assay),
      and immunohistochemistry for PR subtype. RESULTS: Prolactin secretion was
      decreased in leiomyomas by RU486 at concentrations of 10(-7) M and 10(-5)M when
      normal serum-containing medium was used. In experiments with all detectable P
      removed from serum, PRL secretion was suppressed in both leiomyomas and
      myometrium at an RU486 concentration of 10(-7)M. Immunohistochemistry results
      suggest that the A form of the PR is the dominant form in both leiomyomas and
      myometrium. CONCLUSIONS: Prolactin production is suppressed in both leiomyomas
      and myometrium after treatment with RU486 in vitro, and this suppression may
      serve as a marker for the clinical effectiveness of agents used in the treatment
      of leiomyomas.

PMID- 8641484
TI  - Spontaneous and induced synthesis of cytokines by peripheral blood monocytes in
      patients with endometriosis.
AB  - OBJECTIVE: To investigate the capacity of peripheral blood monocytes (PBM) from
      women with endometriosis to secrete tumor necrosis factor-alpha (TNF-alpha),
      interleukin (IL) IL-6, IL-8, and IL-10. DESIGN: Peripheral blood monocytes were
      cultured in the presence and absence of lipopolysaccharide for 24 hours before
      assessment of cytokines in supernatants by enzyme immunoassay. SETTING: Institute
      for the Study and Treatment of Endometriosis and university-based research
      laboratories. PATIENTS AND PARTICIPANTS: Fertile controls, n - 10; women with
      endometriosis, n = 20. INTERVENTIONS: None. RESULTS: Basal synthesis of TNF
      alpha, IL-6, and IL-8 and the lipopolysaccharide-stimulated synthesis of TNF
      alpha by PBM from women with endometriosis was significantly greater in
      comparison to that of fertile controls. Endometriosis had no effect on the basal
      or stimulated synthesis of IL-10. CONCLUSIONS: These data show that endometriosis
      is associated with increased basal and stimulated synthesis and secretion of
      several different cytokines by PBM. Each of the cytokines found to be affected
      has the capacity to play a role in the symptomatology or pathogenesis of the
      disease.

PMID- 8641485
TI  - A comparison of cathepsin D levels in endometriotic tissue and in uterine
      endometrium.
AB  - OBJECTIVE: To assay the cathepsin D level in endometriotic tissue, to study the
      difference to uterine endometrium and the correlation to localization. DESIGN:
      Prospective consecutive study on endometriotic tissue and endometrium. SETTING:
      University clinic. PATIENTS: Thirty-five women undergoing laparotomy for clinical
      indications. INTERVENTIONS: Samples of endometriotic tissue and uterine
      endometrium were obtained simultaneously from the same woman at laparotomy, fresh
      frozen, and assayed using an immunoradiometric method. MAIN OUTCOME MEASURE: The
      cathepsin D level in endometrium and endometriotic tissue expressed in pmol/mg
      DNA. RESULTS: The cathepsin D level was significantly higher in endometriotic
      tissue than in endometrium both in follicular and luteal phase. The highest
      values in endometriotic tissue were found in luteal phase, in ovarian lesions,
      and in primary lesions. In endometrium, but not in endometriotic tissue, there
      was a positive correlation between cathepsin D level and serum E2 level.
      CONCLUSION: The level of the proteolytic enzyme cathepsin D is significantly
      higher in endometriotic tissue than in endometrium, which might be of importance
      for implantation and the invasive growth of endometriotic tissue.

PMID- 8641486
TI  - Flow cytometric evaluation of leukocyte subpopulations in the follicular fluids
      of infertile patients.
AB  - OBJECTIVES: To evaluate the leukocyte subpopulations present in follicular fluid
      (FF) of infertile patients undergoing IVF-ET for tubal factor, idiopathic
      infertility, and endometriosis. PATIENTS: Sixty patients undergoing IVF-ET with a
      tubal factor diagnosis (n = 35), idiopathic infertility (n = 13), and
      endometriosis (n = 12) had their subpopulations of FF leukocytes analyzed by flow
      cytometry. MAIN OUTCOME MEASURE: Nonblood-contaminated samples of FF were
      collected under sterile conditions and centrifuged. Cells were labeled with a
      panel of monoclonal antibodies: anti-CD3, -CD4, -CD8, -CD14, -CD20, -CD45, and 
      CD56, and analyzed by cytofluorometry. RESULTS: Follicular fluid leukocytes from
      patients with idiopathic infertility had a significantly higher proportion of T
      lymphocytes than tubal factor and endometriosis patients. Endometriosis patients
      had significantly higher proportions of natural killer (NK) cells, B lymphocytes,
      and monocytes compared with groups of idiopathic infertility and tubal factor.
      CONCLUSIONS: The differences observed in the leukocyte subpopulations from FF of
      patients with idiopathic infertility and endometriosis may affect
      folliculogenesis and oocyte maturation. Moreover, these modifications could be
      one of the factors altering their fertility.

PMID- 8641487
TI  - Core body temperature during menopausal hot flushes.
AB  - OBJECTIVE: To measure core body temperature by ingested radiotelemetry pill and
      rectal temperature during menopausal hot flushes under controlled laboratory
      conditions. DESIGN: Patients were recorded during sleep using both methods in a
      sound-proofed, temperature and humidity-controlled laboratory room. SETTING:
      University medical center. PATIENTS: Eight postmenopausal women who were
      amenorrheic for > or = 1 year and reported frequent hot flushes. RESULTS: Thirty
      seven hot flushes were detected by criterion increases in sternal skin
      conductance level. Significant increases in telemetered but not rectal
      temperature occurred before 24 of the hot flushes. CONCLUSIONS: Core body
      temperature elevations precede a majority of menopausal hot flushes and serve as
      one trigger of this heat-loss phenomenon.

PMID- 8641488
TI  - Hysteroscopy in women with abnormal uterine bleeding on hormone replacement
      therapy: a comparison with postmenopausal bleeding.
AB  - OBJECTIVE: To determine the role of outpatient diagnostic hysteroscopy in
      patients with abnormal uterine bleeding (AUB) on hormone replacement therapy
      (HRT) and to contrast this with a control group of women presenting with
      postmenopausal bleeding. DESIGN: Comparative observational study. SETTING:
      Outpatient hysteroscopy clinic in a university hospital. PATIENTS: Three hundred
      ten patients undergoing outpatient hysteroscopy. INTERVENTIONS: Outpatient
      diagnostic hysteroscopy with endometrial biopsy when indicated. MAIN OUTCOME
      MEASURES: Hysteroscopic findings, need for cervical dilatation and local
      anaesthesia, correlation between hysteroscopy and histologic diagnosis. RESULTS:
      There were 157 (7.1%) patients with AUB on HRT and another 153 (6.9%) with
      postmenopausal bleeding out of 2,203 outpatient hysteroscopies. Hysteroscopy was
      successful in 97% and 92% of patients, respectively, and intrauterine pathology
      was diagnosed in 46.7% and 39.7% of these cases. Functional endometrium was noted
      significantly more often with HRT and endometrial atrophy with postmenopausal
      bleeding. Overall, local anesthesia was used in 126 (40.6%) and shown to be
      associated significantly with the need for cervical dilatation. Endometrial
      biopsy was attempted in 125 (80%) and 119 (78%) patients in the study and control
      groups, but was unsuccessful significantly more often with postmenopausal
      bleeding (38.7%) versus 16%). There were six cases of endometrial carcinoma, all
      in the control group. CONCLUSION: There is a high incidence of intrauterine
      abnormalities in women with menstrual symptoms while taking HRT, but the
      pathology differed from those with postmenopausal bleeding. As focal lesions are
      found commonly in such patients, their detection by diagnostic hysteroscopy
      should improve compliance with HRT as it would allow individualization of
      treatment.

PMID- 8641489
TI  - Production of embryos from in vitro-matured primary human oocytes.
AB  - OBJECTIVE: To determine the factors that influence the number and quality of
      embryos produced from primary oocytes collected from untreated regularly
      ovulating and irregular or anovulatory polycystic women. DESIGN: A direct
      comparison between two patient groups whose oocytes were matured in vitro and a
      comparison of the embryo development of in vitro-matured oocytes from untreated
      patients with in vivo-matured oocytes of superovulated IVF-ET patients obtained
      during the same period. SETTING: The Monash IVF Clinic, involving patients who
      expressed the desire to avoid super-ovulation with fertility drugs. MAIN OUTCOME
      MEASURES: The completion of nuclear maturation of oocytes after 36 or 48 hours
      culture, fertilization in vitro, and embryo development ratio. RESULTS: Oocytes
      from regular cycling patients matured and fertilized at significantly higher
      rates than irregular cycling and anovulatory women and their embryos had
      significantly higher mean embryo development ratio. The mean embryo development
      ratio of embryos of regular cycling patients was similar to superovulated IVF
      patients but irregular cycling and anovulatory patients had a significantly lower
      embryo development ratio. Culture of oocytes for 48 hours increased maturation of
      oocytes from 57% to 82% but did not affect fertilization or cleavage rates.
      Embryo development was not affected significantly by the grade of follicular cell
      cover of oocytes. CONCLUSIONS: The developmental capability of primary oocytes is
      higher in regular cycling women than in irregular cycling and anovulatory women
      with polycystic ovary disease.

PMID- 8641490
TI  - Comparisons of pregnancy loss patterns after intracytoplasmic sperm injection and
      other assisted reproductive technologies.
AB  - OBJECTIVE: To compare outcome of pregnancies after intracytoplasmic sperm
      injection (ICSI) with those of other assisted reproductive technologies. DESIGN:
      Pregnancy outcomes after ICSI were followed prospectively and compared with
      pregnancy outcomes after IVF with fresh and frozen ETs and donor oocyte cycles.
      SETTING: A private tertiary referral center for genetics and infertility in
      Fairfax, Virginia. PATIENTS: One hundred thirty-six couples achieving pregnancy
      after undergoing ICSI, 71 after IVF, 35 donor oocyte recipients, and 19 after
      transfer of frozen-thawed embryos. INTERVENTIONS: In vitro fertilization and/or
      ET for all couples. Dilatation and curettage to obtain products of conception for
      chromosome analysis in 28 women experiencing spontaneous abortion. MAIN OUTCOME
      MEASURES: Pregnancy outcomes were classified as preclinical loss, clinical loss,
      and ongoing pregnancy. RESULTS: The mean frequency of preclinical pregnancy loss
      was 26% after ICSI, 28% after IVF, 3% after ET using donor oocytes, and 11% after
      frozen ET. The rate of clinical loss after ICSI (21%) was compared with IVF
      (18%), donor oocyte cycles (11%), and frozen ETs (21%). CONCLUSIONS:
      Intracytoplasmic sperm injection is not associated with an increase in pregnancy
      losses, clinical or preclinical, compared with conventional IVF.

PMID- 8641491
TI  - Experience with transvaginal ultrasound-guided aspiration of supernumerary
      follicles for the prevention of multiple pregnancies after ovulation induction
      and intrauterine insemination.
AB  - OBJECTIVE: To avoid multiple pregnancies caused by ovulation induction. SETTING:
      Infertile couples treated in the Women's Hospital and the Institute of
      Reproductive Medicine of the University of Munster, Munster, Germany. DESIGN: The
      outcome of ovulation induction in patients in whom supernumerary ovarian
      follicles were aspirated transvaginally was compared with the outcome in patients
      in whom this intervention was not necessary. In a second randomized prospective
      study, the efficacy of a low dosage of gonadotropins was compared with a higher
      dosage. PATIENTS: Two hundred twenty-seven couples suffering from male
      infertility, unexplained infertility, incipient ovarian failure, and polycystic
      ovaries. INTERVENTIONS: Aspirations were performed if more than three follicles
      were sized > 14 mm. MAIN OUTCOME MEASURE: Number of (multiple) pregnancies.
      RESULTS: During 232 ovulation inductions, 127 aspirations of supernumerary
      follicles were performed (54.7%). The pregnancy rate (PR) in these cycles was
      similar to cycles in which aspirations were unnecessary (24.4% versus 21.9%). The
      efficacy of 75 units of FSH administered daily during the recruitment phase of
      follicular development was equivalent to 150 units of FSH (PR: 32.4% versus
      31.6%), but supernumerary follicles were fewer (26.5% versus 76.3%). Six twins,
      two triplets (multiple PR: 10.4%), and no ovarian hyperstimulation syndrome
      occurred. CONCLUSIONS: Transvaginal aspiration of supernumerary follicles does
      not reduce the PR in ovulation induction. Supernumerary follicles can be avoided
      by low-dose administration of gonadotropins without compromising the PR.

PMID- 8641492
TI  - Menotropins alone are superior to a clomiphene citrate and menotropin combination
      for superovulation induction among clomiphene citrate failures.
AB  - OBJECTIVE: To examine the difference in efficacy between two protocols of
      superovulation induction with IUI among infertile couples. DESIGN: A prospective
      randomized trial. SETTING: Normal human volunteers in an infertility clinic.
      PATIENTS: Consecutively treated patients attending our infertility clinic for
      superovulation induction with IUI who had been unsuccessfully treated by
      clomiphene citrate (CC). INTERVENTIONS: Infertile couples were randomized to
      undergo one of two controlled ovarian hyperstimulation protocols. Group A
      patients received daily hMG beginning on cycle day 3, whereas group B patients
      were administered CC days 3 through 7, followed by hMG from day 7 onward.
      Randomization was performed using a random numbers table. In both groups,
      ovulation was triggered by 5,000 IU hCG and IUI was performed by 36 hours. MAIN
      OUTCOME MEASURES: Studied cycle performance parameters included peak E2, number
      of dominant and intermediate-sized follicles recruited, endometrial thickness and
      pattern, and frequency of monitoring. RESULTS: Data analysis demonstrated no
      significant difference between the two groups with respect to patient age,
      parity, weight, indication for superovulation and IUI, number of dominant
      follicles recruited, peak E2, or mean number of total motile sperm inseminated.
      Endometrial thickness and pattern differed between treatments, however, with
      group A demonstrating relatively thicker and proportionately more trilaminar
      patterns than group B. Group A had significantly more serum E2 measurements, as
      well as transvaginal sonograms performed, when compared with group B. Pregnancy
      rates for groups A and B were 0.192 and 0.091, respectively. Of 25 pregnancies in
      group A, 7 (0.28) were multiples, whereas there were no multiple gestations in
      group B. CONCLUSION: For patients undergoing superovulation with IUI, a
      menotropin-alone protocol yields significantly higher pregnancy rates than one
      using a combination of menotropin with CC. These differences could not be
      explained by patient characteristics. Among cycle performance parameters,
      endometrial thickness and pattern differed significantly between the two groups.

PMID- 8641493
TI  - A follicular scoring system for monitoring ovulation induction in polycystic
      ovary syndrome patients based solely on ultrasonographic estimation of follicular
      development.
AB  - OBJECTIVE: To assess the predictive value of a follicular scoring system for
      monitoring ovulation induction in polycystic ovary syndrome (PCOS) patients,
      solely with ultrasound (US). DESIGN: Ultrasound measurements were performed on
      alternate days to define a serial follicular score for monitoring ovulation
      induction with hMG alone, as well as GnRH analogue and hMG, in comparison with E2
      concentration obtained on the same day. SETTING: Outpatient Infertility Clinic,
      Department of Obstetrics and Gynecology. PATIENTS: Thirty-four consecutive PCOS
      patients treated for 63 cycles. MAIN OUTCOME MEASURE: The follicular score was
      established considering the summation of points obtained after measuring the mean
      diameter of each follicle > 5 mm, as follows: 5 to 8 mm = 1 point, 9 to 12 mm =
      1.5 points, 13 to 16 mm = 2 points, > or = 17 mm = 3 points. RESULTS: Follicular
      score correlated positively with E2 concentrations. A score of > or = 30 points
      was associated with E2 levels of concentration that reached > 1,500 pg/mL
      (conversion factor to SI unit, 3.671) and could predict ovarian hyperstimulation.
      A lower follicular score allowed hCG administration. CONCLUSIONS: A follicular
      scoring system may be a safe, simple, and highly efficient method to replace
      serial E2 measurements in monitoring ovulation induction. Moreover, ovarian
      hyperstimulation may be predicted.

PMID- 8641494
TI  - Premature progesterone elevation does not alter oocyte quality in in vitro
      fertilization.
AB  - OBJECTIVE: To clarify whether premature P elevation during controlled ovarian
      hyperstimulation (COH) for IVF-ET affects adversely oocyte-embryo quality.
      DESIGN: Controlled clinical study. PATIENTS: We studied 102 fertile donors
      undergoing 106 oocyte retrievals and 117 recipients undergoing 162 ET.
      INTERVENTIONS: Donors underwent COH with a time-release GnRH agonist and hMG. All
      recipients had inactive or absent ovaries and were primed with E2 and P. MAIN
      OUTCOME MEASURES: Measurement of LH, P and E2; characteristics of COH; cleavage,
      pregnancy, and implantation rates. RESULTS: According to donors' plasma P levels
      on the day of hCG, two groups were defined: P < or = 0.9 ng/mL (conversion factor
      to SI unit, 3.18), group A, and P > 0.9 ng/mL, group B. Similar results of
      cleavage (65% and 72%), clinical (30% and 29%), and ongoing pregnancy (20% and
      18%), and implantation (14% and 15%) rates were observed in both groups,
      respectively. CONCLUSIONS: The lack of difference in cleavage, pregnancy, and
      implantation rates between both groups suggests that preovulation increase in P
      production does not alter oocyte-embryo quality. Hence, the reported adverse
      effects on IVF outcome of pre-hCG elevation of P is likely to reflect an impaired
      endometrial receptivity in the high P group.

PMID- 8641495
TI  - Evaluation of serum CA 125 concentrations as predictors of pregnancy with human
      in vitro fertilization.
AB  - OBJECTIVE: To determine if CA 125, a product of human endometrium, may be an
      indicator of early endometrial function. To test this hypothesis we examined CA
      125 concentrations before oocyte retrieval in IVF cycles. DESIGN: Retrospective
      data analysis of 111 consecutive IVF cycles. SETTING: Tertiary care academic
      medical center. PATIENTS: All women who received luteal leuprolide acetate (LA)
      suppression followed by hMG for IVF and had sera available for analyses were
      entered into the study. MAIN OUTCOME MEASURE: Serum CA 125 was measured in the
      previous luteal cycle, day 7 of hMG, day before, and day of hCG administration.
      Twelve other variables were analyzed. RESULTS: Fifty-six cycles (47 women)
      qualified for evaluation and included 25 pregnant cycles (45%) and 31 nonpregnant
      cycles. Higher serum CA 125 concentrations were associated with pregnancy in both
      endometriosis and nonendometriosis subgroups. CA 125 values on the day of hCG
      administration were the best predictors of pregnancy, with levels > or = 16 U/mL
      having a sensitivity of 72%, specificity of 97%, and a positive predictive value
      of 95% for pregnancy. The other variables were not predictive of pregnancy.
      CONCLUSIONS: With a LA and hMG stimulation protocol, increased CA 125
      concentrations before retrieval are associated with very high pregnancy rates.
      The source(s) of the serum CA 125, although as yet undertermined, may be of
      endometrial origin. The study supports further evaluation of CA 125
      concentrations in IVF as a preretrieval predictor of pregnancy.

PMID- 8641496
TI  - Lower implantation rates in high responders: evidence for an altered endocrine
      milieu during the preimplantation period.
AB  - OBJECTIVE: To determine serum E2 and P levels around the time of implantation in
      normal and high IVF responders. SETTING: In Vitro Fertilization program at the
      Instituto Valenciano de Infertilidad. PATIENTS: Twenty-nine women undergoing IVF,
      who accepted to be studied daily, were classified according to the number of
      oocytes retrieved in normal (n = 16) and high responders (n = 13). DESIGN:
      Prospective study in which blood was drawn daily from the day of hCG
      administration (day 0) up to 7 days later (day 6). MAIN OUTCOME MEASUREMENTS: In
      vitro fertilization parameters (number of ampules, FSH-hMG, number of oocytes,
      fertilization rates, number of transferred embryos, implantation rates, and
      pregnancy rates); serum E2 and P levels during the 7 days of the study. RESULTS:
      Implantation rate was significantly higher in normal (18.5%) as compared with
      high (0%) responders. Estradiol and P levels were elevated significantly in high
      responders. The E2:P ratio was significantly different between normal and high
      responders during the preimplantation period. Pregnancy and implantation rates
      decreased as serum E2 levels increased on days 4 to 6 of the study. CONCLUSIONS:
      A different endocrine milieu between normal and high responders is detected by
      daily steroid measurements up to the preimplantation period, suggesting that this
      difference could be responsible for an impaired implantation in high responder
      patients undergoing IVF. An increase in serum E2 levels seems to be the cause of
      this difference.

PMID- 8641497
TI  - Fertilizing ability of sperm with unexplained in vitro fertilization failures, as
      assessed by the zona-free hamster egg penetration assay: its prognostic value for
      sperm-oolemma interaction.
AB  - OBJECTIVE: To investigate the fertilizing ability of sperm with previous
      unexplained IVF failure using the zona-free hamster egg penetration assay.
      DESIGN: Three hundred ninety-six tests were performed after multiple IVF
      failures. In a subsequent prospective study, 38 IVF attempts using the microdrop
      insemination technique and 81 subzonal inseminations (SUZI) were performed. One
      hundred thirty-two tests with donor sperm were carried out as controls. PATIENTS:
      Three hundred fifty-two patients who had a minimum of two unexplained IVF
      failures including at least 10 metaphase II oocytes were included in the study.
      RESULTS: The ability of the patient sperm to bind to hamster oocytes was lower
      than that of controls. The largest differences were the percentage of oocytes
      with swollen sperm heads and the mean number of decondensed sperm heads per
      penetrated oocyte: both were much lower for patients than controls. Patients with
      a test result nil did not fertilize any oocytes during the SUZI cycles (n = 7; 50
      oocytes), and the post-SUZI fertilization rate for patients with a test value <
      10% was significantly lower than that of others (5.4 +/- 10.3 versus 23.8 +/-
      8.4, respectively). CONCLUSIONS: The defect of sperm involved in IVF failures is
      mainly a reduction of their fusiogenic ability and not their ability to recognize
      and bind to the oolemma. Patients with a test result < 10% had a significantly
      reduced post-SUZI fertilization rate. A test score of zero indicates a major and
      permanent impairment of the sperm fusiogenic ability.

PMID- 8641499
TI  - A new method of the electrolyte-free long-term preservation of human sperm at 4
      degrees C.
AB  - OBJECTIVES: To develop a new method for the long-term preservation of human
      sperm. SETTING: Andrology laboratory of our hospital. PATIENTS: Thirty-one normal
      and 19 asthenozoospermic semen samples obtained from patients attending our
      infertility clinic. The average sperm motility was 70.2% and 36.0% in the normal
      and asthenozoospermic groups, respectively. INTERVENTIONS: Ejaculated sperm were
      centrifuged and washed using the electrolyte-free Percoll gradient and then were
      preserved at 4 degrees C. MAIN OUTCOME MEASURES: The motility of the preserved
      sperm was analyzed using computer-assisted semen analyzer after the addition of
      Ham's modified F-10 (GIBCO, Grand Island, NY). RESULTS: In the normal group,
      motility rate after the addition of Ham's F-10 for 1, 2, and 4 weeks of
      preservation was 65.4%, 40.4%, and 5.5%, respectively. In the asthenozoospermic
      group, motility rate after 1 and 2 weeks of preservation was 31.3% and 18.1%,
      respectively. Preservation solutions containing sodium or potassium decreased
      motility after preservation. Restoration of preserved sperm was not achieved by
      incubation alone; however, reinitiation was induced by incubation together with
      Ham's F-10. CONCLUSIONS: Human sperm in the electrolyte-free solution survived
      for a long period of time at 4 degrees C and reinitiation of sperm motility after
      preservation required the addition of Ham's F-10.

PMID- 8641498
TI  - Induction of immunoresponse by subclinical male genital tract infection?
AB  - OBJECTIVE: To determine the relationship of subclinical infection or inflammation
      of the male genital tract, as evaluated with seminal markers, with local
      antisperm antibodies as potential parameter of immunoresponse. PATIENTS: One
      hundred ninety-one randomly chosen males of subfertile couples who were
      asymptomatic in terms of genital tract infection. SETTING: Outpatient Infertility
      Clinic of the University of Heidelberg, Germany. MAIN OUTCOME MEASURES:
      Determination of leukocytes rates in semen using an immunocytochemical method for
      differentiation of round cells and measurement of polymorphonuclear (PMN)
      granulocyte elastase concentration in seminal plasma in addition to semen
      cultures as screening for subclinical infection of the male genital tract.
      Determination of local antisperm antibodies (Ab) with the mixed antiglobulin
      reaction ([MAR] immunoglobulin [Ig] G and IgA) in aliquots of the same
      ejaculates. RESULTS: Leukocyte rates of the round cells ranged from 0% to 93%,
      leukocytospermia was found in 6.8%. This was not related significantly to the
      presence of local antisperm antibodies of the IgG or IgA class. There was also no
      significant association of antisperm Ab with the concentration of PMN granulocyte
      elastase in seminal plasma and the outcome of semen cultures. CONCLUSIONS: The
      results of this prospective study suggest that when the rate or number of
      leukocytes or the concentration of PMN elastase in semen are taken as markers for
      subclinical infection or inflammation of the male genital tract, this is not
      associated significantly with the production of local antisperm Ab of the IgG or
      IgA class as indicator of immunoreaction.

PMID- 8641500
TI  - The role of potassium ion and extracellular alkalization in reinitiation of human
      spermatozoa preserved in electrolyte-free solution at 4 degrees C.
AB  - OBJECTIVE: To elucidate reinitiation factors in human spermatozoa preserved in
      the electrolyte-free solution at 4 degrees C. SETTING: Andrology laboratory of
      our hospital. PATIENTS: Semen samples were obtained from patients attending our
      infertility clinic. INTERVENTIONS: Ejaculated sperm were centrifuged and washed
      using the electrolyte-free Percoll gradient and then were preserved for 1 week at
      4 degrees C. MAIN OUTCOME MEASURES: The motility of preserved sperm was incubated
      and analyzed after the addition of electrolyte solutions. RESULTS: The motility
      rate was 9.6% when the preserved sperm were incubated directly. The motility
      increased to 35.1% after alkalization (pH 7.8) and further increased to 40.7%
      when 0.1 mM KCl was added. The motility decreased to 1.4% in a weak acidic
      solution (pH 6.8), however, the addition of a > or = 10 mM concentration of NaCl
      or > or = 0.1 mM concentration of KCl increased in motility. The motility rate in
      40 mM NaCl and 40 mM KCl (pH 6.8) was 19.8% and 31.5%, respectively. The
      restoration of motility by NaCl was inhibited by 1 mM amiloride. The motility
      also rose to 54.1% and 32.3% in 0.04% NH3 and 80 mM NH4Cl solution, respectively.
      CONCLUSIONS: The reinitiation of preserved spermatozoa was induced by potassium
      ion and extracellular alkalization.

PMID- 8641501
TI  - Disappearance of the ovulation stigma in baboons (Papio anubis, Papio
      cynocephalus) as determined by serial laparoscopies during the luteal phase.
AB  - OBJECTIVE: To investigate how long an ovulation stigma remains visible as
      determined by serial laparoscopies performed during the luteal phase in baboons.
      SUBJECTS AND SETTING: Sixteen female baboons with a normal pelvis (n = 6) and
      with endometriosis (n = 10) housed at the Institute of Primate Research, Nairobi,
      Kenya. INTERVENTIONS: Fifty-six laparoscopies were carried out before ovulation
      (n = 7) and serially during the luteal phase (n = 49; 3 +/- 1 per baboon): 1 to 2
      days (n = 2), 4 to 5 days (n = 15), 8 to 9 days (n = 11), 12 to 13 days (n = 12),
      and 16 to 17 days (n = 9) after ovulation. MAIN OUTCOME MEASURE: During each
      laparoscopy the ovaries were screened systematically for the presence and size of
      an ovulation stigma and/or corpus luteum (CL). RESULTS: When the laparoscopy was
      done within 5 days after ovulation, a fresh ovulation stigma was observed in all
      nine baboons with a normal pelvis or minimal endometriosis, but only in four of
      seven animals with mild to severe disease. If a fresh ovulation stigma had been
      observed within 5 days after ovulation (n = 13), it gradually became smaller but
      remained visible 8 to 9 days after ovulation in 91%, at 12 to 13 days after
      ovulation in 75%, and at 16 to 17 days after ovulation in 50% of the primates.
      CONCLUSION: If a fresh ovulation stigma was observed in baboons within 5 days
      after ovulation, it diminished in size but remained visible up to 8, 12, and 16
      days after ovulation in 91%, 75%, and 50% of animals, respectively. Therefore,
      diagnostic laparoscopies for the detection of an ovulation stigma in baboons
      should be performed in the early luteal phase.

PMID- 8641502
TI  - Serum from women with polycystic ovary syndrome inhibits fertilization and
      embryonic development in the murine in vitro fertilization model.
AB  - OBJECTIVE: To study the effects of serum collected from women with polycystic
      ovary syndrome (PCOS) on the fertilization and early embryonic development of the
      murine oocyte. DESIGN: Sera from women with anovulation were used as a supplement
      in a murine IVF model. SETTING: Tertiary care academic medical center. PATIENTS:
      Four fertile, four hypothalamic amenorrheic, seven PCOS (three with elevated LH
      and four with elevated T), and three anovulatory women with normal hormone
      levels. RESULTS: When compared with serum from fertile women, serum from women
      with PCOS reduced fertilization rates (60% versus 42%) and subsequent early
      embryonic development rates (87% versus 31%). Serum from women with PCOS and
      elevated T levels had the lowest fertilization rates (22%). Polycystic ovary
      syndrome serum with elevated T or LH levels significantly decreased early
      embryonic development rates in comparison to fertile women (22%, 41% versus 87%).
      CONCLUSIONS: Serum from women with PCOS inhibited fertilization and blastocyst
      development. Because both T and LH caused inhibited blastocyst development, these
      data have implications regarding low pregnancy rates and live birth rates during
      ovulation induction in women with anovulation. These data also raise questions
      regarding the use of serum during IVF.

PMID- 8641503
TI  - Laparoscopic lateral ovarian transposition.
AB  - OBJECTIVE: To determine if the new technique laparoscopic lateral transposition
      of the ovaries before pelvic radiotherapy for anal canal carcinoma prevents
      radiation-related ovarian failure. DESIGN: A case report. SETTING: The operating
      room of a Canadian teaching hospital. PATIENTS: A single patient with anal canal
      carcinoma, requiring pelvic radiotherapy, who desired preservation of ovarian
      function. INTERVENTIONS: Laparoscopic ovarian transposition to the level of the
      pelvic brim. MAIN OUTCOME MEASURES: Follow-up clinical and laboratory evidence of
      ovarian failure. RESULTS: Initially ovarian failure was confirmed with the
      appearance of postmenopausal symptoms and the elevation of serum gonadotropins.
      These symptoms resolved by 8 months after radiotherapy, normal menstrual cycles
      resumed, and normal FSH levels were detected at that time. CONCLUSIONS: The
      laparoscopic, lateral transposition of this patient's ovaries was effective at
      preventing radiation-related ovarian failure.

PMID- 8641504
TI  - Correlation of fecundability and serum estradiol after danazol treatment in
      patients with advanced endometriosis.
AB  - OBJECTIVE: To examine the relationship between pregnancy incidence and the level
      of serum E2 during danazol therapy. DESIGN: Danazol was given by 200 mg four
      times daily for 3 months. Serum E2 level was checked after completing the
      therapy, but before stopping medication. Patients then were advised to conceive
      at the appropriate time over a 6-month period. SETTING: Reproductive and
      Endocrine Laboratory of the Department of Obstetrics and Gynecology, Keelung
      Chang Gung Memorial Hospital, Keelung, Taiwan. PATIENTS: Infertile women with
      invasive endometriosis receiving conservative surgery and danazol treatment.
      INTERVENTIONS: Serum E2 is checked before medication and at the end of danazol
      therapy, but before stopping medication. MAIN OUTCOME MEASURES: Whether pregnancy
      is related to the change of serum E2 caused by danazol therapy. RESULTS: There
      were 24 pregnancies in 38 patients with invasive endometriosis after treatment.
      Pregnant patients had significantly lower serum E2 levels as compared with the
      nonpregnant patients. CONCLUSIONS: After conservative surgery for invasive
      endometriosis associated with infertility, the therapeutic period of danazol
      treatment could be shortened to 3 months. Because there is significant
      correlation of fecundability and serum E2 after danazol medication, serum E2
      could be a guideline for predicting pregnancy or for prolonging or changing of
      treatment after danazol therapy.

PMID- 8641505
TI  - The impact of preoperative gonadotropin-releasing hormone agonist treatment on
      laparoscopic excision of ovarian endometriotic cysts.
AB  - OBJECTIVE: To compare surgical performance and recurrence rates in patients
      submitted to laparoscopy for endometrioma excision following GnRH agonist (GnRH
      a) treatment versus no preoperative medical treatment. DESIGN: Controlled
      clinical study. SETTING: A tertiary care university hospital. PATIENTS: Twenty
      patients with unilateral endometriomas underwent operative laparoscopy after 3
      month GnRH-a treatment, whereas 21 patients underwent laparoscopic excision of
      endometriomas without preoperative medical treatment. INTERVENTIONS: Operative
      laparoscopy was performed with the stripping technique using a four-puncture
      approach. MAIN OUTCOME MEASURE: A blinded videotape review was undertaken to
      evaluate the duration and complexity of the different phases of surgery.
      Recurrence rates were evaluated at 1-year follow-up ultrasonography. RESULTS: No
      significant difference was found between the two groups in total operative time,
      cyst excision time, time needed for cyst capsule stripping and coagulation of
      ovarian parenchyma, and the complexity of the latter phases; recurrence rates
      also were comparable. CONCLUSION: Preoperative GnRH-a treatment for endometriomas
      does not seem to offer any advantage in terms of subsequent surgical performance.

PMID- 8641506
TI  - Future in vitro fertilization pregnancy potential of women with variably elevated
      day 3 follicle-stimulating hormone levels.
AB  - OBJECTIVE: To determine the IVF-ET pregnancy potential of women with variably
      elevated day 3 FSH. DESIGN: Cohort evaluation of 1,868 consecutive IVF-ET cycles
      January 1991 to December 1994. SETTING: University hospital infertility unit.
      PATIENTS: Four cohorts of couples were defined based on day 3 FSH determinations
      with an arbitrary threshold of 20 mIU/mL, only > or = 20 mIU/mL, always < 20
      mIU/mL, current < 20 mIU/mL but one previous > or = 20 mIU/mL, and current < 20
      mIU/mL but two or more previous > or = 20 mIU/mL (conversion factor to SI unit,
      1.00). INTERVENTION: In vitro fertilization-embryo transfer. MAIN OUTCOME
      MEASURE: Fetal heart activity on luteal day 40 transvaginal ultrasound. RESULTS:
      No pregnancies occurred in 53 cycles with day 3 FSH only > or = 20 mIU/mL. In
      1,750 women whose day 3 FSH levels were always < 20 mIU/mL, the pregnancy rate
      (PR) per cycle was 16.5%. In 54 cycles in which day 3 FSH was > or = 20 one time
      only, but < 20 mIU/mL during the treatment cycle, the PR was 5.6%. In 11 cycles
      where two or more previous FSH determinations were > or = 20 mIU/mL but with a
      current day 3 FSH < 20 mIU/mL, no pregnancies occurred. CONCLUSION: Our data
      leads us to the conclusion that day 3 FSH determination precede every IVF cycle
      and that cycles with FSH > or = 20 mIU/mL be canceled. It also suggests that
      women with two previous elevations of day 3 FSH be discouraged from future IVF
      cycles. The 5.6% pregnancy per cycle with one previously elevated FSH warrants
      extreme pessimism in discussion of further cycles.

PMID- 8641507
TI  - Transfer of cryopreserved embryos improved pregnancy rates in patients with
      damage to the functional integrity of the sperm membrane as measured by the hypo
      osmotic swelling test.
AB  - OBJECTIVE: To compare the pregnancy rates (PRs) after transfer of cryopreserved
      embryos in patients who have damage to the functional integrity of the sperm
      membrane as measured by the hypo-osmotic swelling test to those without this
      defect. DESIGN: Prospective clinical study. SETTING: University-associated IVF
      center. PATIENTS: Fifty-four patients enrolled in a matched prospective study to
      evaluate the effects of low HOS scores (<50%) on PRs after IVF-ET were followed
      to determine the PR after transfer of cryopreserved embryos. MAIN OUTCOME
      MEASURE: Clinical PRs and implantation rates. RESULTS: Fourteen patients with low
      hypo-osmotic swelling test scores underwent 21 frozen ET cycles, achieved for
      clinical pregnancies for a PR per cycle of 19.0% and an implantation rate of
      7.1%. Twelve patients with normal hypo-osmotic swelling test scores underwent 21
      frozen ET cycles, achieved five preganancies for a clinical PR per cycle of 23.8%
      and an implantation rate of 9.3%. CONCLUSION: Previous studies have demonstrated
      an adverse effect of low hypo-osmotic swelling test scores on PRs after IVF-ET
      despite normal fertilization. This adverse effect was not found in the transfer
      of cryopreserved embryos from males with hypo-osmotic swelling test scores.
      Further investigation is required to determine how cryopreservation improves the
      chances of implantation of these embryos.

PMID- 8641508
TI  - A prospective, randomized study of embryo transfer results after 3 or 5 days of
      embryo culture in in vitro fertilization.
AB  - OBJECTIVES: To compare the implantation rate of embryos after 3 and 5 days of IVF
      culture. DESIGN: Prospective randomization of ET depending on the weekday of ovum
      pick-up (OPU). SETTING: University Department of Endocrinology and Reproduction.
      PATIENTS: All women entering an outclinic IVF program. INTERVENTIONS: Two hundred
      thirty-three ETs performed on day 3 after OPU and 410 performed on day 5 were
      analyzed. When blastocysts with a clear inner cell mass were available, a maximum
      of two were replaced. RESULTS: On day 3 after OPU, 60 pregnancies per 233 ET
      (26%) and on day 5, 102 pregnancies per 410 ET (25%) were induced. The average
      implantation rate per embryo was 13% and 12%, respectively. After subdivision
      according to embryo morphology, pregnancy rate per ET (n = 59) and implantation
      rate per embryo on day 3 with exclusively unfragmented embryos were 32% and 18%,
      respectively, not significantly different from ET (n = 73) exclusively with
      embryos containing > 0% and < 20% fragments: 27% and 12%. After transfer on day
      5, when one or more cavitating embryos were available (n = 227), pregnancy and
      implantation rates were 40% and 23%, statistically different from ET on day 3. On
      day 5, ET exclusively with morula stages showing signs of starting blastulation
      (n = 26), pregnancy rate and implantation rate were 12% and 11%, respectively,
      from ET (n = 157) with embryos not reaching the latter stage: 6% and 3%.
      CONCLUSIONS: Overall ET results after 3 and 5 days are comparable. After 5 days
      of culture, one to two embryos can be replaced with an average implantation rate
      of > 23% per embryo, minimizing the incidence of triplets.

PMID- 8641509
TI  - Patients with Turner's syndrome may have an inherent endometrial abnormality
      affecting receptivity in oocyte donation.
AB  - OBJECTIVE: To evaluate whether endometrial receptivity is compromised in patients
      with premature ovarian failure (POF) due to Turner's syndrome who undergo oocyte
      donation. DESIGN: Retrospective analysis. SETTING: In vitro fertilization-ET
      units, anonymous oocyte donation program. PATIENTS: The study included 53
      patients with POF who underwent oocyte donation. These included 7 patients with
      Turner's syndrome (45,X) who underwent 22 ET cycles, 15 women with Turner
      variants (mosaics, deletions, or isochromosomes) who underwent 36 ET cycles, and
      31 other patients with POF and a normal karyotype who underwent 69 oocyte
      donation cycles. INTERVENTION: All patients on standby for donation were treated
      with E2 valerate 6 mg/d until oocytes became available; then P 100 mg/d was
      added. Oocyte donors were healthy women < 34 years who underwent IVF themselves.
      MAIN OUTCOME MEASURES: Clinical pregnancy rates (PRs), biochemical pregnancies,
      early abortions, and delivery rates were evaluated. RESULTS: Turner's syndrome
      patients had a significantly higher rate of biochemical pregnancies (22.7% versus
      4.3%), a lower clinical PR (22.7% versus 33.3%), a significantly higher rate of
      early abortions (60% versus 8.7%), and a significantly lower rate of deliveries
      per pregnancy (20.0% versus 73.1%) compared with non-Turner patients.
      CONCLUSIONS: Patients with a complete or partial deficiency of an X chromosome
      have reduced PRs and an increase in early implantation failure after oocyte
      donation. This may indicate an inherent endometrial abnormality, possibly
      associated with a deficiency of X-linked genes regulating endometrial
      receptivity.

PMID- 8641510
TI  - Memory complaints associated with the use of gonadotropin-releasing hormone
      agonists: a preliminary study.
AB  - OBJECTIVES: To study the effect of GnRH agonist (GnRH-a) treatment on memory and
      to assess the role of psychological factors. DESIGN: A randomized prospective
      study. SETTING: An academic teaching hospital. PARTICIPANTS: Women with
      endometriosis and infertility or endometriosis alone. MAIN OUTCOME MEASURES:
      Memory Observation Questionnaire, Profile of Mood States, Health Concerns scale,
      a weekly diary of adverse effects. RESULTS: Perceived memory functioning
      decreased during GnRH-a administration and by the final week of treatment 44% of
      women reported moderate to marked impairment in comparison to community norms.
      Prospective memory was most affected and withdrawal of GnRH-a treatment resulted
      in a return to normal memory functioning. Impairment was not related to excessive
      health concerns or mood changes and was uncorrelated with other adverse effects.
      CONCLUSIONS: Memory disruption may be a more common side effect of GnRH-a
      treatment than currently is recognized. Problems were temporary and more likely a
      result of rapid estrogen depletion than a consequence of mood, somatic distress,
      or personality factors.

PMID- 8641511
TI  - Further thoughts on surgical therapy for polycystic ovary syndrome.

PMID- 8641512
TI  - Further thoughts on surgical therapy for polycystic ovary syndrome.

PMID- 8641513
TI  - Further thoughts on surgical therapy for polycystic ovary syndrome.

PMID- 8641514
TI  - Fertilization--calcium-dependent events.

PMID- 8641515
TI  - Value of growth hormone in ovulation induction?

PMID- 8641516
TI  - Intracytoplasmic sperm injection and sex chromosome abnormalities?

PMID- 8641518
TI  - Would Chlamydia trachomatis recombinant ribonucleic acid be a better target for
      identification?

PMID- 8641517
TI  - Safeguards in embryo donation.

PMID- 8641519
TI  - Progesterone-induced acrosome reaction: one receptor is not enough.

PMID- 8641520
TI  - Host factors affecting disease transmission.
AB  - In prevention of transmission of infectious disease, the host uses a variety of
      protective mechanisms and can elicit many different responses. Nonspecific
      defense mechanisms include an intact integument (skin and mucous membranes). The
      host also can use specialized substances it may secrete, such as mucin or fatty
      acids to prevent colonization or to inhibit growth of potential pathogens.
      Specialized surface structures are also used by the host in prevention of disease
      transmission. These structures include cells composed of keratin and cells with
      cilia. Additionally, nonspecific protection can be achieved through the actions
      of the host's nonpathogenic microflora. If these nonspecific barriers to
      microorganism invasion are breached, other host interactions occur. Complement
      has many nonspecific actions that may be used to control invasion of
      microorganisms. PMLs are an additional line of defense the host has available in
      prevention of infection. These cells are responsible for intracellular killing of
      pathogens through the use of enzymatic and oxidative mechanisms. The mononuclear
      phagocyte system allows for elimination of foreign material and debris from the
      inflammatory reaction. Additionally, the macrophages process and present antigens
      to T lymphocytes. B lymphocytes differentiate to produce plasma cells, which
      produce specific antibodies aimed at the invading microorganism. T lymphocytes
      are involved in the killing of pathogenic microorganisms and in the production of
      powerful immune modulators known as lymphokines. Fever and inflammation also
      serve to stimulate reactions aimed at destroying and removing the pathogen from
      the host system. These factors all play an important role in prevention of
      disease transmission in a human host.

PMID- 8641521
TI  - Dental health care workers at risk.
AB  - Healthy DHCWs do not seem to be at significantly higher risk for occupationally
      acquired diseases when compared with other HCWs. Special attention should be paid
      to DHCWs who are more susceptible to diseases potentially transmitted in a dental
      setting. These DHCWs include pregnant women, due to their immunologic changes,
      and the developing fetus; DHCWs; those with habits such as excessive intake of
      alcohol; DHCWs following splenectomy, radiotherapy, and long-term corticosteroid
      therapy; and DHCWs suffering from diseases that have an impact on the first and
      secondary defense against infections, such as diabetes mellitus, chronic renal
      failure, sickle cell anemia, leukemia, lymphoma, or HIV.

PMID- 8641522
TI  - Hepatitis B virus infection. Current status in dentistry.
AB  - HBV is a serious threat to members of the dental team. Dental personnel who are
      carriers of HBV, many of whom may not be aware of their status, are also at risk
      for hepatitis delta infection. In 1991, the Occupational Safety and Health
      Administration issued an instruction (in the Federal Register Part II, 29 CFR
      Part 1910.1030, 56-235)64175-64182) on Occupational Exposure to Bloodborne
      Pathogens--Final Rule, mandating that HBV vaccine be offered by employers free of
      charge to all at-risk employees. From a public and professional health
      perspective, such a mandate was a significant step forward. It is hoped that this
      update will assist employers to understand better their role in providing HBV
      vaccine and will assist employees in understanding why acceptance of vaccination
      is of prime importance to practitioners and staff, their families, and their
      patients.

PMID- 8641523
TI  - Hepatitis C virus infection.
AB  - Hepatitis C, previously termed parenterally transmitted NANB hepatitis, is caused
      by a single-stranded RNA virus (HCV). Infection with this virus has epidemiologic
      characteristics similar to hepatitis B, with infection from contaminated blood
      appearing to be a primary source of disease. Although 80% to 90% of the viral
      hepatitis associated with blood transfusions used to be the most common mechanism
      for HCV transmission, parenteral drug abuse has become the major documented risk
      factor in the United States. Health care workers face occupational hazards for
      HCV infection primarily through needlestick and other contaminated sharps
      accidents, although the risks are much lower than those historically documented
      for HBV. Current universal bloodborne precautions for infection control appear to
      be effective against occupational cross-infection in patient care settings.
      Ongoing studies in patients with long-term persistent hepatitis C are
      investigating the usefulness of prolonged interferon therapy to reduce hepatic
      damage and HCV chronicity.

PMID- 8641524
TI  - Tuberculosis.
AB  - Dental health care providers must play an active role in preventing the
      transmission of tuberculosis. The information presented here should allow them to
      appropriately identify and refer patients who may be infectious, identify oral
      lesions which may be due to tuberculosis, and develop and implement an infection
      control plan to prevent transmission in the dental setting.

PMID- 8641525
TI  - The role of the dentist in the era of AIDS.
AB  - Dental care providers are constantly redefining their role in response to new
      medical challenges. The AIDS era has invoked stimulating discussions on several
      issues providers need to address as participants in the healthcare dilemmas
      surrounding this disease. This article considers six major issues on which dental
      workers can have a major impact regarding the future of this epidemic.

PMID- 8641526
TI  - Herpesvirus infections.
AB  - There are presently seven known herpes viruses that infect humans. Those viruses
      are important in the fields of oral medicine and dentistry because they cause
      oral lesions, infect saliva, and cause serious and potentially life-threatening
      infections in patients whose immune systems are compromised by cancer
      chemotherapy, immunosuppressive drugs, or HIV infection. This article reviews the
      basic virology and clinical manifestations of the herpes viruses while
      highlighting the clinical aspects of herpes-related diseases important to
      dentistry.

PMID- 8641527
TI  - Syphilis and gonorrhea.
AB  - Syphilis and gonorrhea are prevalent in the United States; thus it is likely that
      the practicing dentist will encounter these sexually transmitted diseases. Oral
      genital contact can result in oral and oropharyngeal lesions of both syphilis and
      gonorrhea. In most states, the law mandates reporting of these sexually
      transmitted diseases to local health departments. Dentists must wear gloves,
      masks, and protective eyewear for all procedures resulting in physical contact
      between the patient and practitioner. Universal infection control procedures must
      be carefully followed to ensure against disease transmission from the symptomatic
      as well as the asymptomatic disease carrier.

PMID- 8641528
TI  - Common infectious diseases.
AB  - Many of the common infectious diseases of humans are highly transmissible, and
      there is ample opportunity within the dental office for spread of these
      infections between patients and staff. Adherence to universal infection control
      procedures, however, introduced to deal with the threat posed by unknown carriers
      of bloodborne viruses, also greatly limits spread of the more common infectious
      agents described in this article.

PMID- 8641529
TI  - Oral manifestations of infectious diseases.
AB  - The oral manifestations of infectious diseases is a major topic since the
      prevalence rate has increased, and usually poses diagnostic and therapeutic
      dilemmas to the oral clinician. The clinical features of the most common and
      important oral infectious diseases are discussed.

PMID- 8641530
TI  - Legal considerations in infectious diseases and dentistry.
AB  - Dentists, similar to other professionals subject to legal regulation, often have
      an overly simple view of the legal system. Communicable diseases present
      questions on the cutting edge of the law, and, as the previous discussion makes
      perhaps painfully clear, there is considerable uncertainty on many important
      legal points. Legal uncertainty is often a reflection of social or scientific
      uncertainty. Clear answers emerge less from the words of lawyers and judges than
      from the actions of professionals themselves, who ultimately set the standard of
      care. In any area of legal uncertainty, the dentist is best advised to adhere to
      the best scientific information available and to meet the ethical standards of
      the profession.

PMID- 8641531
TI  - Infection control.
AB  - From an infectious disease point of view, dentistry has never been safer than it
      is today for both patients and the dental team. This state of affairs has
      resulted from the establishment and practice of strict infection control in the
      office using the concept of universal precautions. Infection control consists of
      a series of procedures directed at reducing the number of microbes shared among
      people. An approach to the management of infection control involves
      identification of an office safety coordinator and total involvement of everyone
      in the office. The procedures of infection control can be grouped into six major
      areas. 1. Handwashing and gloving provides protection to both patients and the
      dental team. 2. Protection against aerosols and spatter involves the use of a
      preprocedure mouthrinse, HVE, rubber dam, saliva ejection, mask, protective
      eyewear, and protective clothing. 3. Instrument processing provides instruments
      that are safe for patient use. 4. Surface asepsis eliminates the involvement of
      environmental surfaces in the spread of disease agents. 5. Management of sharps
      and other regulated waste reduces the chances for sharps injuries and contact
      with potentially infectious material. 6. Aseptic techniques include aseptic
      retrieval of supplies, reducing contamination from dental unit water, aseptic
      radiographic procedures, proper use of disposables, and preventing contamination
      of the dental laboratory.

PMID- 8641533
TI  - Degrees of skill.

PMID- 8641532
TI  - Postexposure protocol.
AB  - This article offers an overview of the major bloodborne and communicable
      diseases. The organisms are classified based on the level of risk they pose to
      the dental care worker (DCW) in the occupational settings. Most recent
      epidemiologic findings and scientific information on occupational exposures are
      discussed. Postexposure management to bloodborne pathogens, including the
      counseling, date collection, serologic testing, and post-exposure prophylaxis, is
      described.

PMID- 8641535
TI  - Autism spectrum disorders in children with physical or mental disability or both.
      I: Clinical and epidemiological aspects.
AB  - The prevalence of autism spectrum disorders was studied in all children with
      mental retardation and/or motor disability in a defined geographical region over
      a two-year follow-up period. In the general population, the prevalence of
      autistic disorder was 0.09% at the end of the follow-up period -a minimum
      estimate, as children with average intelligence were not screened. Autism
      spectrum disorders were found in 19.8% of children with mental retardation,
      including strictly defined autistic disorder (DSM-III-R criteria) in 8.9%; the
      two-year follow-up yielded a higher prevalence of 11.7% with autistic disorder.
      Among children with cerebral palsy, 10.5% had an autism spectrum disorder. Clear
      co-variation was found between mental retardation, epilepsy and autism spectrum
      disorders in this population of children with neurodevelopmental disorders.

PMID- 8641534
TI  - Non-progressive ataxia: origins, brain pathology and impairments in 78 swedish
      children.
AB  - This population-based study refers to 78 Swedish children with non-progressive
      ataxia from a total population of 3.1 million inhabitants. Inclusion criteria
      were ataxic gait without any signs of spasticity, dyssynergia, dysmetria and
      intention tremor. CT and/or MRI studies were available from 70 patients (90%).
      Infratentorial pathology was revealed in 27%, and findings were considered normal
      in 61%. If CT was normal, of recent date and of good quality, MRI did not add any
      new information. In half of the cases with pathological CT, however, MRI provided
      new information. The origin was considered prenatal in 45% (familial in 17%),
      perinatal in 4% and unclassifiable in 51%. 60% were mentally retarded; in the
      rest, cognitive development was near normal (18%) or normal (22%). Speech
      development was delayed in 88%, and 58% had visual dysfunction.

PMID- 8641537
TI  - School-aged children with spina bifida in Western Australia--parental
      perspectives on functional outcome.
AB  - A questionnaire mailed to the parent(s) of all 86 school-aged children with spina
      bifida resident in Western Australia in 1992 who were attending a spinal
      dysfunction clinic or were members of the Spina Bifida Association was returned
      by 72 parents. All 72 of these children (55 with myelomeningocele, 17 with
      meningocele) lived at home with their parent(s). All but two children with
      meningocele were mobile without aids, whereas only 42% of the children with
      myelomeningocele were. Twenty one per cent of the children were naturally
      continent of urine day and night, and 36% were naturally continent of faeces. 76%
      attended a mainstream school although performance at school was rated below
      average for 40%. Nine children with meningocele (56%) and 42 with
      myelomeningocele (76%) were reported to have learning difficulties. This
      information will be useful in counselling parents of unborn and newborn children
      with spina bifida, and in allocating resources for children and young adults with
      spina bifida and their families.

PMID- 8641536
TI  - Autism spectrum disorders in children with physical or mental disability or both.
      II: Screening aspects.
AB  - The Autism Behavior Checklist (ABC) was used as a screening instrument in a study
      of autism spectrum disorders in a population of children with mental retardation
      or physical disability or both. The ABC score clearly reflected behavioural
      problems found in children with mental retardation and not only behaviours
      typical of autism. If the cut-off score used was 45 (lower than recommended by
      the original investigators), children with autistic disorder without multiple
      other disabilities were reliably identified, with an acceptable rate of false
      positive cases. In order not to miss other autism spectrum disorders, all cases
      with several omitted items in their checklists were examined in more detail. The
      Childhood Autism Rating Scale (CARS) distinguished reasonably well between
      autistic disorder and other autism spectrum disorders.

PMID- 8641538
TI  - Sleep patterns in children and young adults with mental retardation and severe
      behavior disorders.
AB  - The 24-hour sleep-wake schedules of 51 individuals (age 3 to 21 years) with
      mental retardation and severe behavior disorders were recorded using a direct
      observation data collection system over an average period of approximately one
      month. The patients in the study had significantly less total sleep and less
      night sleep than their peers of the same age, and 88% had disturbances of sleep:
      delays in getting to sleep, frequent night waking or early waking. 'Appropriate'
      sleep, a measure of the amount and regularity of sleep, correlated positively
      with standardized measures of IQ and expressive language. 'Total' sleep, that is,
      the overall number of hours, was not correlated with measures of cognitive
      functioning. The findings are compared with those from other studies describing
      the sleep of individuals with mental retardation.

PMID- 8641539
TI  - Crying patterns in preterm infants.
AB  - Healthy infants born at term cry most in the first three months of life, with a
      peak and increased crying in the evening during the second month. To determine
      whether the crying of preterm infants manifests similar features, the pattern of
      crying from 40 weeks gestational age through 24 weeks corrected age was described
      for 35 relatively healthy preterm infants born between 28 and 34 weeks
      gestational age. Despite their additional extra-uterine experience, they still
      cried significantly more after 40 weeks gestational age, with a peak and evening
      clustering at 6 weeks corrected age. The age of peak crying was not related to
      gestational age at birth, weight for gestational age, or a variety of perinatal
      and neurological indices. The results support the argument that the early-peak
      pattern is a robust maturational feature of early development and may be
      universal to human infancy.

PMID- 8641540
TI  - Narcolepsy in a 2-year-old boy.
AB  - This report describes the prospective follow-up of a 2-year-old child with
      narcolepsy. The initial clinical diagnosis was confirmed by the onset of
      cataplexy when the child was 5 years old. He does not have the HLA genotype
      characteristic of narcolepsy or an identifiable brain lesion, although he has
      megalencephaly and mild learning difficulties. Treatment with dietary tyrosine
      supplements who are to young to use stimulants safely. The morbidity of
      narcolepsy is high and early diagnosis is therefore important, as treatment is
      effective.

PMID- 8641541
TI  - X-linked hydrocephalus masquerading as spina bifida and destructive porencephaly
      in successive generations in one family.
AB  - The authors report a case of X-linked hydrocephalus which presented as a
      destructive porencephaly. There was asymmetric dilatation of the ventricles of
      prenatal onset, and neuro-imagining studies were suggestive of infection or
      haemorrhage. The child was profoundly handicapped but did not have adducted
      thumbs. Two of his mother's brothers had been stillborn, and postmortem reports
      revealed that the diagnosis had been isolated hydrocephalus and not spina bifida
      as reported by the family. Despite serial ultrasound scans, recurrence of X
      linked hydrocephalus in the mother's subsequent pregnancy was not detected until
      26 weeks gestation, when the ventricles became grossly dilated. The diagnosis was
      confirmed in this family by identification of mutation within the L1CAM gene.

PMID- 8641542
TI  - Marinesco-Sjogren syndrome: clinical and magnetic resonance imaging features in
      three children.
AB  - The authors describe clinical and MRI features of a girl and two boys, aged 9, 17
      and 19 years, respectively, with Marinesco-Sjogren syndrome. The clinical
      findings included the major features of the syndrome, including growth
      deficiency, ataxia, cataracts, hypogonadism (in two) and seizures (in two).
      Truncal hypotonia (in three), microcephaly (in two) and leg spasticity (in two)
      were also present. MRI showed a very small cerebellar vermis in all three
      patients, various supratentorial abnormalities, an apparently small anterior
      pituitary gland in two and the absence of a posterior pituitary gland in all
      three. The MRI features are similar to the few reported pathologic findings for
      persons with Marinesco-Sjogren syndrome. MRI may be helpful in the early
      diagnosis of the disorder.

PMID- 8641543
TI  - 'Immunoglobulin therapy in Guillain-Barre syndrome in children'.

PMID- 8641544
TI  - 'In vivo diagnosis of Hallervorden-Spatz disease'.

PMID- 8641545
TI  - Upregulation of cytokeratins 8 and 18 in human breast cancer T47D cells is
      retinoid-specific and retinoic acid receptor-dependent.
AB  - The mamary gland is chiefly composed of luminal epithelial cells expressing
      cytokeratins (K) 8, 18 and 19, and basal/myoepithelial cells expressing
      cytokeratins 5 and 14. Human breast cancer T47D cells have a luminal phenotype
      and are growth-inhibited by retinoids, a class of compounds known to regulate
      cytokeratin expression. To extend our knowledge of retinoid action in breast
      cancer, we have studied the retinoid regulation of cytokeratin expression in the
      T47D model. We found that retinoid inhibition of T47D cell growth was accompanied
      by increases in K8, K18 and K19 mRNA steady-state levels (Northern blot
      analysis). The effect on K8 was studied in greater detail. This effect was seen
      with as low as 1 nM all-trans retinoic acid (tRA) and was maximal (up to 7 fold
      over control) with 1 microM tRA (the highest dose tested). Time-course studies
      revealed a detectable effect at 1 h and a maximal effect at 8-24 h. Non
      retinoidal growth inhibitors (tamoxifen, BrcAMP and genistein) did not modulate
      K8 expression, demonstrating that the effect of tRA was specific, K8 mRNA
      upregulation was blocked by actinomycin D and cycloheximide, suggesting, in
      accordance with other studies, that tRA exerted a transcriptional effect that was
      secondary to de novo protein synthesis. Five retinoids known to activate retinoic
      acid receptor (RAR) and/or retinoid X receptor (RXR) - tRA; 9-cis-retinoic acid,
      9cRA; 13-cis RA, 13cRA; retinyl acetate; and N-(4-hydroxyphenyl) retinamide 4HPR 
      inhibited T47D cell growth and increased K8 expression, whereas an arotinoid (Ro
      40-8757) that is not a RAR activator caused growth inhibition but did not
      upregulate K8. Activation of RAR alpha contributed to K8 upregulation, since this
      effect was partially blocked by the RAR alpha-selective antagonist Ro-41-5253.
      Analogous results were obtained throughout when blots were reprobed with K18
      cDNA. Western blot and immunocytochemistry experiments demonstrated that protein
      levels of K8 and K18 increased by 2 days of treatment with 1 microM tRA. These
      results show that retinoids enhance the expression of cognate cytokeratin markers
      of luminal differentiation in T47D breast cancer cells.

PMID- 8641546
TI  - Intratumoral heterogeneity and inverse correlation between expression of E
      cadherin and collagenase type IV in human gastric carcinomas.
AB  - We examined the expression of E-cadherin and collagenase type IV in formalin
      fixed, paraffin-embedded specimens of human gastric carcinoma by an in situ mRNA
      hybridization (ISH) technique. The ISH technique revealed intertumoral
      heterogeneity for expression of E-cadherin and collagenase among 12 cases of
      early gastric cancer and 13 cases of advanced gastric cancer. In the majority of
      the tumors, we found an inverse relationship between the reactivities of E
      cadherin and collagenase type IV. Specifically, E-cadherin was expressed at
      higher levels in the center of the neoplasms than in their periphery, whereas
      collagenase type IV was expressed at a higher level in the periphery (invasive
      edge) than in the center. Advanced gastric cancers with high levels of expression
      for collagenase type IV in the periphery had a higher incidence of distant lymph
      node metastasis than those with low expression. The data show an inverse
      relationship between E-cadherin (involved in cell-to-cell adhesion) and
      collagenase type IV (involved in invasion) in different zones of human gastric
      carcinoma and suggest that the relative expression of these independent genes may
      be involved in local invasion and metastasis.

PMID- 8641547
TI  - Stage-dependent genetically-based deformities of the regenerating newt limb from
      4-nitroquinoline-N-oxide mutagenesis: potential embryonic regulation of cancer.
AB  - The effect of the mutagenic carcinogen 4-nitroquinoline-N-oxide (4NQO) on limb
      regeneration was studied in adult Triturus cristatus newts. Delayed limb
      regeneration was observed when a 10- to 15-micrograms crystal of 4NQO was
      implanted at the late dedifferentiation or late bud stage. Additionally, 4NQO
      administration at these stages caused developmental deformities in skeletal
      elements of the subsequent regenerates. In contrast, 4NQO implanted at the wound
      healing stage did not affect skeletal morphogenesis. These critical stages of
      limb regeneration affected by carcinogen exposure (but not other manipulations)
      represent mechanisms distinct from disruption of basement membrane deposition.
      Secondary regeneration, initiated by reamputation of the 4NQO-treated abnormal
      regenerates 4-5 mm proximal to the site of carcinogen implantation, produced
      normal regenerates, setting a limit on the diffusion distance of 4NQO in the
      limb. Distal reamputation through regenerates at the level of the abnormality
      resulted in regeneration of the original bone deformity, suggesting that the
      teratogenic effect of 4NQO is mediated via heritable mutational events in
      blastema cells. These results extend a previously published conclusion that 4-NQO
      is mutagenic in non-regenerative tissue to include regenerative tissue as well.
      However, in spite of mutagenic activity, squamous carcinomas were not induced by
      4NQO exposure at any stage of regeneration. Therefore, the resistance of
      regenerative tissue to 4'-NQO carcinogenesis is not due to resistance to
      mutations, but rather to other mechanisms perhaps similar to those which regulate
      malignant cells in murine embryos.

PMID- 8641548
TI  - Expression of H19 and Igf2 genes in uniparental mouse ES cells during in vitro
      and in vivo differentiation.
AB  - Genomic imprinting is a process that results in the differential expression of
      genes according to their parental inheritance. Two imprinted genes, insulin-like
      growth factor 2 (Igf2) and H19 are closely linked on mouse chromosome 7, and are
      expressed from the paternal and maternal alleles, respectively. The genes show
      striking similarity in their tissue-specific expression patterns, which led to
      the proposal that their transcription is controlled by a common regulatory domain
      that enables only one gene to be active from each chromosome. Evidence is
      accumulating, however, that the expression of H19 and Igf2 genes is not always
      from their respective maternal and paternal alleles. This suggests that their
      expression is regulated independently of imprinting in some tissues and
      teratomas. We have analysed the extent of non-imprinted expression of H19 and
      Igf2 in uniparental mouse embryonic stem (ES) cells during in vitro
      differentiation, and differentiation in teratomas using Northern blot and in situ
      hybridisation analysis. The expression patterns observed indicate that both
      imprinting and non-imprinting mechanisms regulate transcription of these genes.
      Expression of one or the other gene was observed in certain cell types in
      differentiated cultures and in teratomas, suggesting that imprinting regulates
      the expression of H19 and Igf2 genes in some differentiating cell lineages. At
      the same time, in other subpopulations of cells, co-expression of both genes was
      observed, demonstrating that the expression of these genes is not always
      regulated by genomic imprinting.

PMID- 8641549
TI  - Cytokeratin dynamics during oocyte maturation in the hamster requires reaching of
      metaphase I.
AB  - Cytoskeletal components like microfilaments and microtubules are known to play
      important roles during the processes of oocyte maturation, fertilization and
      early embryonic development in mammals. However, the roles of other components
      such as cytoplasmic intermediate filaments, during these critical events remain
      largely unknown. Oocyte maturation is the final step of oogenesis, immediately
      before ovulation. Several cytological changes involving the cytoskeleton take
      place during the maturation process, including meiotic spindle formation,
      redistribution of cell organelles, membrane polarization and first polar body
      emission. In this study we determined the organization and rearrangements of
      cytokeratins during hamster oocyte maturation. Fully grown oocytes were cultured
      and then visualised using microscopic immunolabelling techniques to monitor the
      cytokeratin dynamics at specific meiotic stages of the maturation process. In
      prophase-I-arrested fully grown hamster oocytes, cytokeratins are confined to 4
      10 large cortical aggregates, corresponding to extensive meshworks of
      intermediate filaments. These large aggregates disperse into multiple small spots
      starting at metaphase I until the end of the maturation period at metaphase II,
      where cytokeratin exhibits a homogeneously distributed spotted pattern. However,
      meiotic progression to metaphase II is not necessary for cytokeratin
      redistribution to occur, since precociously arrested metaphase I oocytes also
      exhibit dispersed cytoplasmic foci at the end of the culture period. The
      redistribution of cytokeratins is insensitive to nocodazole and cytochalasin D
      suggesting it occurs independent of microtubules and microfilaments. In contrast,
      both cumulus cells and protein synthesis are required for cytokeratin
      modifications to take place during oocyte maturation. These results show that
      cytokeratin intermediate filaments are present in the fully grown hamster oocyte,
      and that a striking reorganization of cytokeratins, triggered by attainment of
      the metaphase I stage, occurs during maturation.

PMID- 8641550
TI  - Immunological identification and characterization of the desmosomal cadherin Dsg2
      in coupled and uncoupled epithelial cells and in human tissues.
AB  - Cells of epithelia, but also of certain other tissues such as myocardium and the
      dendritic reticulum of lymph node follicles, are interconnected by numerous
      intercellular junctions termed desmosomes. These are characterized by a set of
      transmembrane glycoproteins, i.e. the desmosomal cadherins, desmoglein(s) and
      desmocollin(s). Using cDNA-derived hybridization probes, we have previously shown
      that different desmogleins exist (Dsg1-3) and that only one Dsg isoform, Dsg2, is
      found in diverse kinds of tissues, tumors and cultured cell lines whereas the
      synthesis of Dsg1 and Dsg3 is much more restricted, primarily to stratified
      epithelia [51]. We now report immunocytochemical results obtained with a series
      of monoclonal and polyclonal antibodies specific for either the aminoterminal
      extracellular portion or the carboxyterminal cytoplasmic segment of Dsg2. These
      antibodies detect Dsg2 in all tissues possessing desmosomes, including human
      stratified and single-layered polar epithelia, as well as non-epithelial tissues
      such as myocardium and lymph node follices. They also react with the desmosomes
      of carcinomas and of diverse cultured epithelium-derived cell lines. Moreover,
      antibodies specific for extracellular domain regions of Dsg2 react with the "half
      desmosomes" present on the surfaces of uncoupled intact epithelial cells.
      Remarkably, in stratified squamous epithelia the Dsg2-reaction is not
      homogeneous, as this glycoprotein is detected only in the basal cell layer and
      appears to be absent from suprabasal strata. The potential value of Dsg2-specific
      antibodies in histology and in tumor diagnosis as well as in studies of the
      mechanisms desmosomal cell coupling is discussed.

PMID- 8641551
TI  - Setting the trends in Europe.

PMID- 8641552
TI  - The remarkable P450s: a historical overview of these versatile hemeprotein
      catalysts.

PMID- 8641553
TI  - Introduction: cytochome P450.

PMID- 8641554
TI  - P450s: structural similarities and functional differences.

PMID- 8641555
TI  - Liver regeneration 3: Regulation of signal transduction during liver
      regeneration.
AB  - The liver has a tremendous capacity to regenerate. For example, after extensive
      hepatic resection, remaining hepatocytes proliferate to restore the mass of the
      organ within days to weeks. This proliferative response is fascinating because
      hepatocytes rarely replicate in the healthy adult liver. Instead, these cells
      perform highly specialized functions and exemplify mature, terminally
      differentiated cells. Therefore it is somewhat surprising that the liver can
      repopulate while performing its many obligate, organ-specific functions. Study of
      the regenerating liver remnant after partial hepatectomy has helped to delineate
      mechanisms that regulate proliferation and liver-specific functions in individual
      hepatocytes, as well as those that coordinate the behaviors of different liver
      cell populations to balance organ growth and tissue-specific gene expression.
      Hence, this review will focus on inter- and intracellular signals that regulate
      the hepatocyte phenotype after PH.

PMID- 8641556
TI  - Carotenoids 2: Genetics and molecular biology of carotenoid pigment biosynthesis.
AB  - The crucial roles of carotenoids and their metabolites in photooxidative
      protection and photosynthesis, not to mention nutrition, vision, and cellular
      differentiation, make them an important and complex class of biological pigments.
      Significant advances within the last few years have enhanced our understanding of
      the genetics and molecular biology of carotenoid biosynthesis in bacteria, fungi,
      algae, and plants. All of the genes involved in carotenoid biosynthesis from
      Rhodobacter capsulatus, an anoxygenic photosynthetic bacterium, and from several
      species of Erwinia, nonphotosynthetic bacteria, have been molecularly
      characterized. Recent studies have revealed that two early enzymes of carotenoid
      biosynthesis, geranylgeranyl pyrophosphate synthase and phytoene synthase, are
      structurally and functionally related in all carotenogenic organisms. In
      contrast, the subsequent conversion of phytoene, the first C(40) carotenoid, to
      beta-carotene requires two desaturases and one cyclase in oxygenic photosynthetic
      organisms (cyanobacteria, algae, and higher plants) but only one structurally
      distinct desaturase and a structurally distinct cyclase in other carotenogenic
      bacteria and in fungi. Studies of the enzymes that introduce oxygen-containing
      functional groups into carotenes to produce xanthophylls, the vast majority of
      all carotenoids, are still in their infancy. This review summarizes the most
      recent developments in carotenoid biosynthesis from a molecular genetic
      standpoint.

PMID- 8641557
TI  - DNA damage and cell cycle checkpoints.
AB  - DNA is prone to numerous forms of damage that can injure cells and impair
      fitness. Cells have evolved an array of mechanisms to repair these injuries.
      Proliferating cells are especially vulnerable to DNA damage due to the added
      demands of cellular growth and division. Cell cycle checkpoints represent
      integral components of DNA repair that coordinate cooperation between the
      machinery of the cell cycle and several biochemical pathways that respond to
      damage and restore DNA structure. By delaying progression through the cell cycle,
      checkpoints provide more time for repair before the critical phases of DNA
      replication, when the genome is replicated, and of mitosis, when the genome is
      segregated. Loss or attenuation of checkpoint function may increase spontaneous
      and induced gene mutations and chromosomal aberrations by reducing the efficiency
      of DNA repair. Defects in checkpoint control have been seen in certain hereditary
      cancer syndromes and at early stages of cell transformation. Mutations in
      checkpoint control genes therefore may contribute to the genetic instability that
      appears to drive neoplastic evolution.

PMID- 8641558
TI  - The fibronectin gene as a model for splicing and transcription studies.
AB  - The fibronectin (FN) gene has become paradigmatic to illustrate genome evolution
      by exon shuffling, generation of protein diversity by alternative mRNA splicing,
      and topological coordination between transcription and splicing. Alternative
      splicing in three sites of the primary transcript gives rise to multiple FN
      polypeptides. This process is cell type-, development- and age-regulated. The
      different FN variants seem to play specific roles in FN dimer secretion, blood
      clotting, adhesion to lymphoid cells, skin wound healing, atherosclerosis, and
      liver fibrosis. This review focuses on function assignment to the alternatively
      spliced segments, as well as on the external signals and cis-acting sequences
      that control the mechanisms of alternative splicing. We also discuss FN
      transcriptional regulation in response to viral transformation, growth factors,
      and cyclic AMP in the light of promoter architecture and its interaction with
      specific transcription factors. The relevance of FN RNA "tracks" as assembly
      lines of coordinated transcription and RNA processing is also addressed.

PMID- 8641559
TI  - Antibody-dependent cellular cytotoxicity in HIV infections.
AB  - ADCC is an important immune effector mechanism against tumor and virus-infected
      cells that can be destroyed by the combined action of specific antibodies of IgG
      isotype against cell surface-associated antigens and effector cells,
      predominantly of the NK phenotype. ADCC has been shown to function in vivo in
      several systems. With regard to HIV, it can be readily demonstrated in vitro
      against the viral envelope proteins with serum and/or effector cells obtained
      from HIV-infected subjects. Several studies have demonstrated that the titers of
      the envy-specific ADCC-mediating antibodies decrease in the sera of HIV-infected
      individuals as the infection progresses toward AIDS. The cells that mediate ADCC
      also become functionally compromised in these individuals in early stages of the
      infection, thus depriving the host of the potential benefits of this process.
      Restoration of this process in the infected individuals by the administration of
      functionally competent effector cells (in vitro expanded and lymphokine-activated
      killer cells) and ADCC-mediating antibodies (hyperimmune serum or appropriate
      monoclonal antibodies), alone or in combination, may help slow the disease
      progress. Because of the multicomponent nature of the process, ADCC-mediating
      antibodies may prove a better correlate of protection and prognosis than the
      virus-specific neutralizing antibodies and cytotoxic T cells in assessing anti
      HIV immunization and immunotherapy.

PMID- 8641560
TI  - Liver-enriched transcription factors and hepatocyte differentiation.
AB  - Liver-specific gene expression in adult hepatocytes relies on four families of
      evolutionary conserved transcription factors that are liver-enriched but not
      restricted to this tissue. These factors function in unique combinations, often
      synergistically, to stimulate cell-specific transcription. Each family is
      composed of several members displaying similar, if not identical, DNA recognition
      properties and sharing structural homology in their DNA binding domains. The homo
      and heterodimerization between members of a particular transcription factor
      family adds an additional level of complexity in gene regulation. The
      consequences of inactivating different family members in the mouse by homologous
      recombination, together with recent studies of their regulation, suggest a model
      for liver differentiation involving a regulatory network rather than a completely
      hierarchical genetic circuitry. These studies also indicate that individual
      regulators appear to serve multiple developmental functions. Their possible role
      in the progression through different stages of hepatic cell commitment and
      differentiation is discussed.

PMID- 8641561
TI  - Endothelial control of the cardiovascular system: recent advances.
AB  - The endothelium is uniquely positioned at the interface between the blood and the
      vessel wall. As such, it performs multiple functions: It is involved in the
      regulation of coagulation, leukocyte adhesion in inflammation, vessel tone, and
      vascular smooth muscle cell growth, and also acts as a barrier to transvascular
      flux of liquids and solutes. Far from being a passive participant in these
      events, it is a dynamic tissue, secreting and modifying vasoactive substances,
      influencing the behavior of other cell types, and regulating extracellular matrix
      production and composition. During the past 20 years, the endothelium has been
      the focus of intense experimental work, resulting in the evolution of a new
      appreciation of its potential role in vascular disease. This review will
      concentrate on several areas of endothelial biology in which our knowledge of the
      molecular mechanisms regulating the function of the endothelium has expanded
      considerably, permitting new insights into the pathogenesis of vascular disease.

PMID- 8641562
TI  - Inhibitory effects of PG-H/aggrecan and PG-M/versican on avian neural crest cell
      migration.
AB  - Aggrecans and PG-M/versicans represent two newly defined families of hyaluronan
      binding proteoglycans for which the function is still poorly understood. Using
      the avian neural crest as a model system, we have examined the molecular
      mechanisms entailed in the cell-proteoglycan interaction during embryonic cell
      motility. Both the primary cartilage aggrecan of the avian embryo (PG-H/aggrecan)
      and the largest variant of the avian mesenchymal versican (PG-M/versican VO)
      failed to support neural crest cell adhesion and migration when topographically
      immobilized onto the substrate. Conversely, solely the PG-H/aggrecan, and similar
      aggrecans from other species, counteracted the migration-promoting effect of a
      number of matrix molecules lacking proteoglycan affinity. This inhibitory effect
      was not reproduced by the isolated glycosaminoglycan chains, the isolated core
      protein, the reduced and alkylated macromolecule, or the aggrecan in which the G1
      hyaluronan-binding domain had been inactivated with hyaluronan fragments or
      antibodies. Limited depolymerization of the side chains and preincubation of the
      PG-H/aggrecan with anti-glycosaminoglycan antibodies differentially reduced the
      inhibitory activity of the proteoglycan on cell motility. The results demonstrate
      a diverse inhibitory effect of aggrecans and PG-M/versicans on embryonic cell
      movement and show that the inhibitory action of aggrecans is independent of
      substrate binding, is dependent on a G1 domain-mediated association of the intact
      proteoglycan with cell surface-bound hyaluronan, and is differentially mediated
      by its glycosaminoglycan side chains.

PMID- 8641563
TI  - ATP regulates calcium leak from agonist-sensitive internal calcium stores.
AB  - Under resting conditions, steady-state [Ca] in agonist-sensitive Ca stores
      reflects a balance between active uptake (usually mediated by a thapsigargin
      sensitive Ca-ATPase of the SERCA family) and passive efflux of Ca. Even though
      this pump-leak cycle appears to be a common property of Ca-storing organelles,
      little is known about the nature of the leak pathway. Ca homeostasis in
      thapsigargin-sensitive internal Ca stores of single permeabilized BHK-21
      fibroblasts was examined using digital image processing of compartmentalized mag
      fura-2 (a low-affinity Ca indicator). It is shown here that the leak of Ca from
      internal stores is regulated specifically by the cytosolic ATP concentration. The
      rate of leak was 3.6 times slower in 0.375 mM[ATP] than in 4 mM [ATP] (Na or Mg
      salt). These effects were observed in the presence of 0 Ca/EGTA, thapsigargin,
      heparin, and ruthenium red, and therefore appear to be independent of the Ca
      ATPase, the InsP(3) receptor and the ryanodine receptor. The ATP-stimulated leak
      was seen in a variety of cell types, including rat basophilic leukemia cells and
      mouse pancreatic acinar cells. Other nucleotides (ADP, GTP, CTP, and UTP) and
      nonhydrolyzable ATP analogs (AMP-PNP and ATPgammaS) did not reproduce the action
      of ATP. Changes in cellular metabolism and ensuing alterations in [ATP] will be
      expected to influence the filling state of internal Ca stores through effects on
      the passive leak pathway, potentially leading to modulation of Ca signaling and
      organellar function.

PMID- 8641564
TI  - Thrombin and trypsin-induced Ca(2+) mobilization in human T cell lines through
      interaction with different protease-activated receptors.
AB  - This study was conducted to determine whether serine proteinases may induce
      [Ca(2+)]i mobilization in different hematopoietic cell lines and to analyze their
      mechanisms of action. We show that in addition to thrombin and thrombin receptor
      agonist peptide (TRP, SFLLRN), trypsin induced [Ca(2+)]i mobilization in a highly
      thrombin-sensitive Jurkat T cell clone. Thrombin, TRP, and trypsin were found to
      induce [Ca(2+)]i release in three different Jurkat T cell clones differing in the
      level of T cell receptor expression. Similar results were obtained with a
      prothymocytic leukemic cell line, HPB.ALL, although these cells were much more
      responsive to trypsin than to thrombin and TRP. Other cell types such as THP1, a
      myelomonocytic cell line, or CEM, a CD4(+) positive leukemic cell line, were
      unresponsive to thrombin, TRP, and trypsin. The effect of trypsin was mimicked by
      SLIGRL, a peptide corresponding to the cleaved amino-terminal sequence of the
      recently characterized murine trypsin-activated receptor (PAR2). At suboptimal
      concentrations, the effects of SFLLRN and SLIGRL were additive, whereas
      saturating doses of peptides did not further increase [Ca(2+)]i mobilization in
      Jurkat T cells, indicating that both peptides were able to mobilize the same pool
      of calcium. Northern blot analysis of mRNAs from different leukemic cell lines
      indicated a remarkable correlation between PAR2 expression in different cell
      lines and SLIGRL or trypsin responses in the same cells. The expression of the
      "trypsin receptor" was also confirmed by polymerase chain reaction analysis.
      Moreover, a 24 h treatment of Jurkat cells by an anti-CD3 monoclonal antibody, a
      condition known to down-regulate thrombin receptor expression, induced loss of
      thrombin and TRP responses but only partially affected trypsin stimulation of
      [Ca(2+)]i release. Finally, after a first stimulation with either thrombin or
      trypsin, Jurkat cells were still able to respond to trypsin or thrombin,
      respectively, demonstrating that thrombin and trypsin essentially activated their
      own receptors. Our data provided evidence that 1) the human T leukemic cell line
      Jurkat and other T cell lines express at least two different functional protease
      activated receptors, the thrombin receptor and a highly sensitive trypsin
      receptor, likely the human counterpart of the murine PAR2, and 2) at variance
      with the commonly accepted model, trypsin exerts most of its effect in T leukemic
      cell lines by thrombin receptor-independent mechanisms.

PMID- 8641565
TI  - Effects of calcium-binding proteins (S-100a(o), S-100a, S-100b) on desmin
      assembly in vitro.
AB  - S-100a(o), the alpha alpha isoform of a subfamily of Ca(2+)-binding proteins of
      the EF-hand type expressed in cardiac and skeletal muscle cells, is reported to
      inhibit the assembly of the intermediate filament subunit desmin and to stimulate
      the disassembly of desmin intermediate filaments in the presence of micromolar
      levels of free Ca(2+). These effects are dose-dependent with respect to the S
      100a(o) concentration and maximal at a desmin/S-100a(o) (dimer) molar ratio of
      approximately 2. Other members of the S-100 subfamily [S-100a (alpha beta) and S
      100b (beta beta) and the unfractionated mixture of S-100a plus S-100b produce
      qualitatively similar effects on desmin assembly, with a potency that depends on
      the fraction of S-100alpha subunit (the most potent) or S-100beta subunit (the
      least potent) present in the S-100 isoforms tested. A binding stoichiometry of 2
      mol of desmin/mol of S-100a(o) (dimer) and an affinity in the submicromolar range
      are calculated. The S-100beta subunit also interacts with desmin, but with a
      lower affinity compared with S-100alpha. By contrast, the S-100-like proteins
      calcyclin and p11 neither interact with desmin nor affect desmin assembly. The
      present data suggest that S-100a(o) might play a role in the regulation of the
      state of assembly of desmin intermediate filaments.

PMID- 8641566
TI  - Tumor cell resistance to apoptosis due to a defect in the activation of
      sphingomyelinase and the 24 kDa apoptotic protease (AP24).
AB  - Signal transduction pathways involved in apoptotic cell death are poorly
      understood, although recent studies have implicated sphingomyelin hydrolysis and
      generation of the second messenger, ceramide. Previous work in this laboratory
      demonstrated that a serine protease termed AP24 was activated by TNF or UV light
      and induced DNA fragmentation in isolated nuclei. This study extended these
      findings to examine the role of these enzymes in apoptosis of the U937 cell line
      and the mechanism of resistance of its variant, U9-TR. Although this subclone was
      selected by growth in TNF, it was unexpectedly found to resist apoptosis induced
      by UV light, but was still sensitive to anti-Fas-induced DNA fragmentation. Here
      we show that in contrast to normal U937 cells, UV light and TNF both failed to
      activate neutral or acidic sphingomyelinase or AP24 in the U9-TR variant.
      However, anti-Fas activated both neutral and acidic sphingomyelinase in the
      variant comparable to that seen in parental U937. The U9-TR variant could be
      sensitized to TNF or UV light activation of both sphingomyelinase and DNA
      fragmentation by the protein phosphatase inhibitors okadaic acid and calyculin A.
      Furthermore, exogenous bacterial-derived sphingomyelinase caused U9-TR activation
      of AP24 and DNA fragmentation comparable to that in the parental U937. Exposure
      of permeabilized U937 cells to ceramide caused internucleosomal DNA cleavage that
      was blocked by an inhibitor of AP24. Taken altogether, these findings demonstrate
      that TNF or UV light activate sphingomyelinase that leads to the generation of
      ceramide resulting in activation of AP24 and DNA fragmentation in sensitive
      cells. A selective defect in signals leading to sphingomyelinase activation can
      confer resistance to apoptosis even though the variant is still sensitive to
      downstream apoptotic signals such as nuclear DNA fragmentation by activated
      exogenous AP24.

PMID- 8641567
TI  - Mitochondrial glutathione oxidation correlates with age-associated oxidative
      damage to mitochondrial DNA.
AB  - Mitochondria may be primary targets of free radical damage associated with aging.
      We have found that mitochondrial glutathione is markedly oxidized with aging in
      rats and mice. The oxidized to reduced glutathione ratio rises with aging in the
      liver, kidney, and brain. The magnitude of these changes is much higher than that
      previously found in whole cells of any species previously studied. In the liver,
      this ratio (expressing GSSG as a percent of GSH) changed from 0.77 +/- 0.19%
      (n=5) in young rats to 2.47 +/- 1.25% (n=5) in old ones, i.e., 320% of the
      controls. In the brain and kidney, values for old rats were, respectively, 600
      and 540% higher than those of young rats. A marked oxidation of mitochondrial
      glutathione also occurred in mice. Aging also caused an increase in 8-oxo-7,8
      dihydro-2'-deoxyguanosine levels in mtDNA in rats and mice. Oral antioxidant
      administration protected against both glutathione oxidation and mtDNA damage in
      rats and mice. Finally, we have found a direct relationship between mtDNA damage
      and mitochondrial glutathione oxidation. This occurs both in rats (r=0.95) and in
      mice (r=0.98). This relationship, which has been observed for the first time in
      these studies, underscores the role of glutathione in the protection against free
      radical damage that occurs upon aging.

PMID- 8641568
TI  - Altered brain fyn kinase in a murine acquired immunodeficiency syndrome.
AB  - Mice infected with the replication-defective virus (BM5def) in the LP-BM5 murine
      leukemia virus (MuLV) mixture develop an immune deficiency syndrome and
      encephalopathy characterized by impaired spatial learning and memory as
      demonstrated in the Morris water maze. However, the molecular mechanism (or
      mechanisms) underlying this cognitive deficit remains unknown. Here we report
      that brain fyn kinase, which has been proposed to be involved in spatial learning
      and memory, was unresponsive to glutamatergic stimulation in mice with MAIDS.
      Thus, whereas application of glutamate to hippocampal slices from control mice
      increased fyn protein tyrosine kinase (PTK) activity more than 2.5-fold, these
      changes were significantly impaired in LP-BM5 MuLV-infected mice. Moreover, mice
      with MAIDS exhibited an abnormal histological distribution of fyn PTK in the
      hippocampus. These findings suggest that virus-associated disruption of fyn
      kinase-mediated signaling contributes to the cognitive deficits observed in mice
      with MAIDS and other retrovirus-induced encephalopathies.

PMID- 8641569
TI  - P/O ratios reassessed: mitochondrial P/O ratios consistently exceed 1.5 with
      succinate and 2.5 with NAD-linked substrates.
AB  - The efficiency of ATP synthesis coupled to cell respiration, commonly referred to
      as the P/O ratio, has been the subject of extensive studies for more that 50
      years. The general conclusion from these studies is that respiring mitochondria
      can convert external ADP to ATP at a maximal P/O ratio of 3 for NAD-linked
      substrates and 2 for succinate. However, in recent years the validity of these
      "integral" values has been questioned on both mechanistic and thermodynamic
      grounds, and a mechanistic P/O ratio of 2.5 for NAD-linked substrates and 1.5 for
      succinate have been concluded on the basis of experiments with isolated
      mitochondria. These values have been widely adopted in the scientific literature,
      including several recent textbooks. In this paper we report that under optimal
      conditions with respect to preparation and assay procedures, the P/O ratios
      obtained with isolated rat liver mitochondria consistently exceed 2.5 with NAD
      linked substrates and 1.5 with succinate. These results, although not excluding
      "nonintegral" P/O ratios due to various energy-dissipating side reactions,
      warrant caution in accepting the reported lower values and, in general, in
      referring to mechanistic considerations unless the underlying molecular
      mechanisms are understood.

PMID- 8641570
TI  - Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune
      interaction?
AB  - Inflammation following an infection induces a range of nonspecific symptoms of
      sickness in animals and humans. The cytokine interleukin-1 (IL-1) mediates many
      of the brain-mediated symptoms of sickness. Binding sites for IL-1 have been
      found in mouse brain, but not in the brains of rats. This raises questions as to
      the involvement of these neuronally localized IL-1 binding sites in the induction
      of sickness symptoms. Based on observations of IL-1 receptor mRNA in close
      vicinity to the vasculature in the mouse and rat brain, we studied the
      possibility that endothelial cells in the rat brain exhibit IL-1 receptors to
      transduce information to the brain. Ligand binding studies reveal that cultured
      endothelial cells of adult rat brain exhibit specific binding sites for rat IL
      1beta. Polymerase chain reaction experiments demonstrated that mRNA of the type I
      but not that of the type II IL-1 receptor is present in rat brain endothelial
      cells. Incubation of these endothelial cells with recombinant rat IL-1beta showed
      a dose-dependent increase in interleukin-6, prostaglandin E(2), and prostacyclin
      secretion. Intravenous administration of rat IL-1beta to adult rats enhanced
      prostaglandin E(2) immunoreactivity in endothelial cells of the brain
      microvasculature. These results indicate that functional type I IL-1 receptors
      are present on endothelial cells of adult rat brain. We postulate that
      circulating IL-1 can be translated by brain endothelial cells into other signals
      such as interleukin-6 or prostaglandins that have access to the brain and induce
      sickness symptoms.

PMID- 8641571
TI  - Cytoskeletal control of rectification and expression of four substates in cardiac
      inward rectifier K+ channels.
AB  - Cardiac inward rectifiers may have a three-barrel channel structure, based on
      evidence for three substates in single-channel recordings. However, some reports
      indicate four substates, a feature more compatible with the four-subunit
      structure for which there is evidence in cloned voltage-activated K+ channels.
      Here we show that although the fourth is easily missed, inward rectifier channels
      have four substates whose expression is controlled by intracellular Ca(2+) ions.
      Fourth substate openings also appear after rectification loss in intracellular
      divalent caution-free solution. We find that this process is accelerated by
      cytochalasin, a microfilament disrupter. Cytochalasin also abolishes Ca(2+), but
      not Mg(2+),-induced rectification by restoring fourth substate openings. Thus,
      cytoskeletal elements control Ca(2+)-dependent substate expression and
      rectification in native inwardly rectifying K+ channels.

PMID- 8641572
TI  - The discovery of proto-oncogenes.

PMID- 8641573
TI  - Chromium(III) picolinate.

PMID- 8641574
TI  - [Prognostic significance of the activity of nucleolar organizer regions in
      megakaryocytes from patients with acute lymphoblastic leukemia].
AB  - Bone marrow films from 20 patients with acute lymphoblastic leukemia (ALL) and 40
      patients with acute nonlymphoblastic leukemia (ANLL) were investigated using Ag
      NOR staining. The control group comprised 12 donors. The activity of nucleolar
      organizer regions (NOR) in the whole population of megakaryocytes (MK) and in
      groups of MK with 1-3, 4-6, 7 and more lobules per nucleus was assessed. The
      division into groups made it possible to judge about NOR activity in MK with
      different ploidy. The MK with both high ploidy and high NOR activity in residual
      megakaryocytopoiesis in patients with ALL are associated with good response to
      chemotherapy and complete remission, whereas these with low ploidy and low NOR
      activity suggest poor prognosis. In patients with ANLL no stable correlation
      between NOR activity and prognosis was found.

PMID- 8641575
TI  - [Morphologic structural characteristics of the hematopoietic microenvironment in
      patients with multiple myeloma].
AB  - The authors' investigations found plasmocytic infiltration of bone marrow and
      marked resorption of bone tissue in patients with multiple myeloma (MM). Instead
      of the expected reduction in bone marrow volume the latter slightly increased. MM
      patients have significantly higher quantity of endosteal stromal cells,
      accumulations of osteoblastic cellular elements considered as initial
      osteogenesis. A close correlation was revealed between bone tissue volume, number
      of erythroid elements in bone marrow and red cell count in peripheral blood.
      Volume of fatty tissues in MM patients is low. MM patients demonstrate pronounced
      morphofuctional disturbances in hemopoietic microenvironment of bone marrow.

PMID- 8641576
TI  - [Neutrophil granulocyte function in an acute experiment with cyclophosphane].
AB  - Experiments of mice F1(CBAx57BL) were made to study cyclophosphamide effects on
      the number of circulating neutrophil granulocytes (NG) and on their main
      functions (receptor, phagocytic, function of microbicidal systems). NG count, the
      number of NG carrying receptors to sheep red cells, complementary EAC=POH,
      phagocytic and digestive activities and NBT-test were measured 15 and 60 min
      after administration of small (0.5 mg/kg) and large (150 mg/kg) doses of
      cyclophosphamide. The results suggest clear dose- and time-related effect of the
      drug which can induce both depression and stimulation. The data obtained can be
      utilized in developing approaches to prevention of complications caused by NG
      dysfunctions in immunosuppressive therapy of tumors, lymphoproliferative
      diseases, organ and tissue transplantation.

PMID- 8641577
TI  - [Effect of polyethylene oxide on hemodynamic parameters in infusion therapy of
      irreversible hemorrhagic shock].
AB  - Blood loss in 14 anesthetized cats was completely replaced either by polyglucin
      (control group) or polyglucin with addition of polyethylene oxide (mol. mass
      6x10(6)). Blood of the cats contained 2.6-4.4 x 10(6) g/ml of polyethylene oxide.
      Its introduction promoted advanced recovery of hemodynamic indices and stimulated
      systemic oxygen transport.

PMID- 8641578
TI  - [Use of recombinant alpha2-interferon in combination with myelosan for the
      treatment of patients with chronic myeloid leukemia].
AB  - The authors present results of chronic myeloid leukemia (CML) treatment with
      recombinant and leukocytic interferon in monotherapy and in combination with
      myelosan. The best responses (72% of complete hematological remissions) were
      obtained in patients pretreated with myelosan (one course of 1-1.5 months) in
      combination with natural antioxidants.

PMID- 8641579
TI  - [Current principles of treatment of acute nonlymphoblastic leukemia].
AB  - Present-day chemotherapy warrants complete remissions in 45-70% of patients with
      acute nonlymphoblastic leukemia. However, therapeutic policy at the stages of
      remission induction and residual disease remains disputable. The authors studied
      the role of 3 chemotherapy programs (7 + 3, 7 + 3 + vincristine, C-ROPM) in
      achievement of remission of acute leukemia and effects of long-term standard
      regimens of remission maintenance and bone marrow transplantation on long-term
      relapse-free survival of patients. The addition of vincristine to the program 7 +
      3 failed to make remission more frequent and recurrence-free survival longer. C
      ROMP program warranted remission in 70% of patients, this proportion being
      significantly higher than on programs 7 + 3 and 7 + 3 + vincristine. More
      intensive chemotherapy during remission induction resulted in a rise of 4-year
      recurrence-free survival from 12 to 44%. Bone marrow transplantation used for
      treatment intensification in remission increased 4-year recurrence-free survival
      compared to standard chemotherapy from 44 to 80%.

PMID- 8641580
TI  - [Cyclic fasting as a factor of higher body resistance to acute lymphoid
      leukemia].
AB  - In experiments on mice AKR the authors investigated the effects which could be
      produced by cyclic fasting on the mice survival. It was found that one of the
      variants of this fasting noticeably prolongs the survival of the animals. The
      proportion of the animals that died of acute lymphoid leukemia among other causes
      of death declined.

PMID- 8641581
TI  - [Processing of screening data obtained for peripheral blood of children who were
      victims at the accident at the Chernobyl nuclear power plant].
AB  - The paper describes processing of peripheral blood screening based on methods of
      mathematical statistics and partially ordered sets theory. This allows global
      assay of individual and populational blood, assessment of borderline conditions
      by introduction of global criterion. The above methodology was tried to analyze
      data obtained at screening of peripheral blood from children living in
      radionuclide-contaminated regions. The most considerable contribution to region
      specific populational differences belongs to red cells, monocytes, band
      neutrophils, eosinophils. Hemogram deterioration in children and adolescents
      seems to result rather from chemical pollution and social factors than radiation
      effect (in doses not high than 2.2 rem a year).

PMID- 8641582
TI  - [Massive transfusion syndrome].

PMID- 8641583
TI  - [A modified method of deglycerinization of defrosted erythrocytes, cryopreserved
      in liquid nitrogen].
AB  - Specialists from Research Institute of Hematology and Transfusiology have
      developed a modified method of defrosted red cells deglycerinization which
      implies 2 cycles of centrifugation and using small quantities (625 ml) of low
      cost and available washing solutions of sodium chloride. Simple performance and
      cost efficacy of this method make red cell cryopreservation more convenient for
      practice.

PMID- 8641584
TI  - [Value of cytogenetic research in the process of treating acute myeloblastic
      leukemia].

PMID- 8641585
TI  - [Advances and difficulties of present-day treatment of acute myeloblastic
      leukemia].
AB  - The success in acute myeloblastic leukemia (AML) treatment for the last 10 years
      has been referred to growing intensity of chemotherapy. The efficacy of treatment
      has been assessed in 56 patients under 60 years of age. Double induction of
      remission according to the scheme TAD-9 (2-day administration of cytosar) and
      consolidation by large-dose cytosar (1 g/m2) with rubomycin have increased the
      frequency of 2-year recurrence-free running from 13 to 35%. Resistance to
      treatment was absent. Maintenance prolonged total and recurrence-free survival.
      Mycosis and hepatitis were factors responsible for inadequate intensity of
      chemotherapy. These need more advanced prevention. The intensive double induction
      and consolidation did not raise general toxicity and immediate lethality compared
      to standard regimens which proved inferior to the proposed treatment.

PMID- 8641586
TI  - [Use of autologous hematopoietic stem cells from peripheral blood for
      transplantation in patients with hematologic and solid neoplasms after high-dose
      chemotherapy].
AB  - Peripheral mononuclears under normal hemopoiesis and after chemotherapy or/and
      cytokin were isolated on blood cell separator and cryopreserved. The cells from
      22 patients with different hematological and solid malignancies were examined.
      Mononuclears with high content of hemopoiesis precursors may be collected rapidly
      after stimulation. Fast and persistent recovery of hemopoiesis in transplantation
      of this material after superhigh-dose chemotherapy of prognostically unfavourable
      patients is demonstrated. Cytokin (granulocytic and granulocytic-macrophagal
      growth factors) promoted fast and reliable production of sufficient quantities of
      peripheral blood hemopoiesis cells precursors.

PMID- 8641587
TI  - Pruritic eruption on the ankle. What is the most likely cause of this recurrent
      reaction pattern?

PMID- 8641588
TI  - Parkinson's disease: consider pallidotomy as a therapeutic option.

PMID- 8641589
TI  - Psychotropic drugs in nursing homes are not just 'restraints'.

PMID- 8641590
TI  - Type II diabetes: tips for managing your older patients.
AB  - In older type II diabetics, complications progress more rapidly than in younger
      diabetics for any given degree of hyperglycemia. Therefore, it is important to
      closely monitor blood glucose levels. When their sugars are controlled, older
      diabetics will have less nocturia and polyuria; fewer infections; better wound
      healing; a decrease in the rate of progression of cataracts, diabetic
      retinopathy, and nerve and renal disease; and better control of dyslipidemia. To
      learn some useful tips for managing older patients with type II diabetes,
      GERIATRICS reader David B Jack, MD, interviewed Nancy J.V. Bohannon, MD, for this
      "Ask the Expert" article.

PMID- 8641591
TI  - Seizures and epilepsy in older patients: evaluation and management.
AB  - Seizures and epilepsy in older patients are commonly caused by a previous stroke
      or other organic CNS insult. In patients who have "spells", the first step is to
      determine whether or not the events are epileptic. Rule out other potential
      causes of transients loss of consciousness with a careful history, physical exam,
      lab tests, and imaging studies. An EEG and CT or MRI of the brain are essential.
      Candidates for treatment with an antiepileptic drug include those with recurrent
      unprovoked seizures, those with onset of epilepsy presenting with status
      epilepticus, and those with a strong family history of epilepsy. Monotherapy with
      a drug known to work best for the type of seizure is preferred. Monitor patients
      closely for side effects and potential drug-drug interactions.

PMID- 8641592
TI  - Geriatric assessment: making it work in primary care practice.
AB  - Geriatric assessment has become an established part of medical practice, a trend
      driven by the growing population of older patients, positive patient outcomes,
      and increase interest in controlling healthcare cost. Geriatric assessment is a
      diagnostic process that can be performed in a variety of clinical settings,
      including the primary care office. The interdisciplinary assessment team usually
      includes at least three members: a physician, a nurse,and a social worker.
      Patients who appear to derive the greatest benefit are over age 75, have mild to
      moderate disabilities, may be at risk of nursing home placement, and may have a
      poor social network. For optimal effectiveness, assessment must be coupled with a
      comprehensive therapeutic plan and long-term follow-up.

PMID- 8641593
TI  - Suicide in the elderly: how to identify and treat patients at risk.
AB  - Suicide rates among the elderly are the highest of any age group, perhaps as high
      as double the rate seen in the general population. White men over age 85 are at
      the greatest risk and are the target of a Healthy People 2000 objective. Aging
      and the changes it entails can often bring profound loss for older persons at a
      time when they are least able to handle it. Primary care physicians play a key
      role in recognizing depression among their elderly patients and in providing
      appropriate treatment. Therapies include antidepressants, ECT, and counseling. By
      identifying and treating depression, many suicides can be prevented.

PMID- 8641594
TI  - Tipping the scale back toward the patient.

PMID- 8641595
TI  - Neurosurgery for the elderly: facts and figures.
AB  - A retrospective audit of all patients admitted to a national neurosurgical unit,
      aged 65 years or over, was reviewed. Details of clinical presentation,
      investigations, management and functional outcome were recorded. Our findings
      confirm that elderly patients constitute a major proportion of the neurosurgical
      workload and this has major medical and socio-economic implications.

PMID- 8641596
TI  - Selection for increased longevity in Drosophila melanogaster: reflections on new
      data.
AB  - In recent papers, new data were presented on the late-age reproduction experiment
      initiated by Luckinbill and Clare in 1981: when early- and late-reproduced lines
      were compared simultaneously 10 years after the end of the original experiment,
      differences in the mean life span are observed between the lines. Yet the
      conditions in which these measurements were done are highly questionable. More
      fundamentally, using these data, the analysis of the selection process is
      impossible and conclusions about the determinism of life span are debatable.

PMID- 8641597
TI  - Estradiol modulation of neuron loss in the medial division of medial preoptic
      nucleus in rats during aging.
AB  - The age-related morphological changes in the darkly stained sex-dimorphic nucleus
      (SDN-POA) and the lighter staining surrounding area (non-SDN-POA) within the
      medial division of preoptic nucleus of Long-Evans rats were studied. The long
      term effects of estradiol benzoate (EB) on the changes were also assessed. During
      aging, the neuron loss in 14-(middle-age) and 22-month-old rats as well as
      increased pyknotic ratio of neurons in old male rats were observed in SDN-POA,
      but not in the non-SDN-POA. In female rats, significant neuron loss with
      advancing age was observed both in SDN-POA and the non-SDN-POA. Neuron loss in
      SDN-POA of EB-treated males was more severe than that of the intact males, while
      no significant difference of neuron loss was observed between EB-treated and age
      matched intact female rats. However, neuron loss in SDN-POA of ovariectomized
      female rats was more severe than that of the age-matched intact females. These
      results indicate that age-related neuron loss in medial preoptic nucleus show sex
      specific and area-specific features, and estradiol may play a important role in
      modulating neuron loss during aging.

PMID- 8641598
TI  - Influence of aging on the relaxant responses to omega-3 fatty acids in Fischer
      344 rat aorta.
AB  - The effect of age on the vasorelaxant properties of the omega-3 fatty acids,
      docosahexaenoic (DHA) and eicosapentaenoic (EPA), in isolated rat aortic rings
      were investigated in 4-, 15- and 24-month-old Fischer 344 rats. Increased aortic
      wall thickness was seen in both 15- and 24-month-old rats. Maximal contractile
      responses to norepinephrine (NE) were greater in intact and de-endothelialized
      (ENDO-) rings from 15- and 24-month-old rats; although increased sensitivity to
      NE was exhibited in 4-month-old rings. DHA- and EPA-induced (1-100 mumol/l)
      responses were similar between the three age groups in intact rings. Removal of
      the endothelium enhanced relaxant responses to both DHA and EPA in all three
      groups. EPA-induced (1-100 mumol/l) responses ranged from-4 to 28% for both 4-
      and 15- month ENDO- rings and -1 to -18% in 24-month ENDO-rings. DHA ENDO-ring
      responses (1-100 mumol/l) were- 4 to -13% in 4 months, -5 to -23% in 15 months,
      and -0.8 to -16% in 24 months. Age differences were apparent with the ENDO- ring
      responses to DHA and EPA. These differences were seen with greater relaxant
      responses to both EPA and DHA in the 4- and 15-month-old aortic rings. Increased
      sensitivity and a greater maximal relaxant response to acetylcholine (ACH) was
      noted in the 15-month-old group. Four- and 24-month rings exhibited similar
      sensitivity and maximal relaxant responses to ACH. However, relaxation was
      decreased in 24-month rings at low ACH concentrations. These findings suggest
      that both functional and morphological changes occur with aging. DHA- and EPA
      induced responses are not altered by aging in intact rings; however, removal of
      the endothelium enhances their vasorelaxant properties in all three age groups.
      This may be related to the direct actions of DHA and EPA on vascular smooth
      muscle, rather than on mechanisms associated with generation of endothelium
      derived relaxing factor.

PMID- 8641599
TI  - Subcutaneous fluids in elderly hospital patients with cognitive impairment.
AB  - Sixty patients (mean age 80 years) with cognitive impairment who required
      parenteral fluids for at least 48 h were randomized to receive either intravenous
      (i.v.) or subcutaneous (s.c.) fluids. There was no significant difference in the
      mean volume of fluid prescribed over 48 h in the two groups (s.c. 3.3 litres vs.
      i.v. 3.6 litres) or in the proportion of prescribed fluids actually administered
      (s.c. 0.82 vs. i.v. 0.76). After adjusting for baseline differences, there was no
      difference between serum urea or creatinine levels in the two groups at 48 h.
      Agitation related to the infusion was reported in 11 (37%) patients receiving
      s.c. fluids and 24 (80%) patients receiving i.v. fluids (p < 0.005). The cost of
      the cannulae used during the study was 6.80 pounds for the s.c. group and 28.70
      pounds for the i.v. group. Local oedema was noted in 2 patients in the s.c. group
      and led to re-siting of the infusion in 1 patient. No other complication was
      noted. These results suggest that s.c. fluid therapy is the treatment of choice
      in nonurgent situations for confused patients who require parenteral fluids.

PMID- 8641600
TI  - Are hydrogen breath tests valid in the elderly?
AB  - Hydrogen breath testing (HBT) is frequently used as an alternative to small bowel
      aspiration in the diagnosis of small intestinal bacterial overgrowth (SIBO). The
      role of the glucose HBT was assessed in 30 elderly patients. A positive HBT was
      recorded in 15 of 20 SIBO cases and 7 of 10 culture negatives (sensitivity 75%
      and specificity 30%). The correlation coefficients between hydrogen gas (H2) rise
      and total bacterial count (r = 0.21) and H2 rise and anaerobic count (r = 0) were
      not significant. Fasting H2 levels were raised in only 4 of the 20 SIBO cases.
      This study indicates that the HBT is not reliable in the diagnosis of SIBO in the
      elderly. There was no evidence from the data that different H2 levels or
      bacterial counts would significantly alter the reliability of the HBT. This work
      suggests that factors other than small bowel bacteria are involved in the
      production and expiration of H2 in the elderly, and that these factors need to be
      considered in the interpretation of this breath test.

PMID- 8641601
TI  - Does the supine position worsen respiratory function in elderly subjects?
AB  - The aim of our study was to test whether the supine position or the sitting
      position worsens static, forced expiratory flows and measurements of lung
      mechanics in a group of aged subjects living in a nursing home who were
      clinically stable and without clinical evidence of cardiorespiratory diseases.
      Seventeen subjects (mean age 80 +/- 7 years; 16 f) were studied under baseline
      conditions. Spirometric, breathing pattern and mechanics data by means of an
      esophageal balloon were measured in sitting and supine positions. Analysis of
      sitting results showed aged subjects to have a slight flow limitation in
      peripheral airways, an increase in expiratory airways resistance and mild
      hyperinflation index (PEEPi = 2.2 +/- 1.9 cm H2O). Pressure time index did not
      reach the fatigue level in hardly any patient. Maximal inspiratory pressure
      values (42 +/- 15 cm H2O) were reduced by about 50% in comparison with our normal
      laboratory standards. Arterial blood gas analysis revealed no pathological data
      in any subject. When supine, subjects revealed a significant decrease in forced
      expiratory volume at the first second (p < 0.005), in forced vital capacity (p <
      0.01) and in peak expiratory flow (p < 0.05). Moreover, mechanics and breathing
      pattern data showed a significant decrease in tidal volume (Vt) and dynamic lung
      compliance (Cld) (p < 0.05) and an increase in respiratory rate/Vt ratio (p <
      0.05). Our data confirm the results of previous reports about Cld decrease in
      supine posture in young normal people. Although our aged subjects showed a
      significant decrease in forced expiratory volumes and Vt when the supine position
      was adopted, static mechanics data did not appear modified by the gravitational
      effect of this posture.

PMID- 8641602
TI  - Left-ventricular outflow tract obstruction by mitral valve ring calcification and
      proximal septal hypertrophy in elderly patients. Presentation of 2 clinical
      cases.
AB  - The pathophysiology, clinical presentation and prognosis of left-ventricular
      obstruction still represent an important cardiological problem. Various
      anatomical and/or functional mechanisms can cause this phenomenon. This report
      concerns 2 patients over 75 years old in whom the simultaneous presence of
      localized proximal septal hypertrophy and massive calcification in the anterior
      portion of the mitral valve ring provoked significant systolic intraventricular
      gradients. Cardiac rhythm disturbances and consequent variability of R-R
      intervals, found in both subjects, appear fundamental in determining the value of
      such gradients. Occasionally an anterior mitral ring calcification may bring
      about left-ventricular outflow tract obstruction in aged hearts where localized
      hypertrophy of the proximal portion of the intraventricular septum is present.

PMID- 8641603
TI  - Poor vision and dizziness in the elderly.

PMID- 8641604
TI  - Training influence on age-dependent changes in the gait of rats.
AB  - Stride length, stance width and gait symmetry were measured as parameters of gait
      analysis in young (5 months) and old (28 months) Sprague-Dawley rats following 3
      months of treadmill running as well as in sedentary controls. Stride length
      decreased significantly with age and increased significantly following training
      in both young and old rats. Means of stance width increased significantly with
      age, but were unaffected by training. Gait symmetry declined with age; however,
      treadmill running counteracted the decline of gait symmetry. It was concluded
      that treadmill running compensates for or prevents age-related changes in the
      neuromuscular function of rats, which lead to gait deterioration.

PMID- 8641605
TI  - Can cervical adenocarcinoma in situ be safely managed by conization alone?

PMID- 8641606
TI  - Adenocarcinoma in situ of the uterine cervix: management and outcome.
AB  - OBJECTIVE: To retrospectively review the management of adenocarcinoma in situ of
      the uterine cervix, to determine the outcome of conization versus hysterectomy,
      and to compare the results achieved by different methods of conization. METHODS:
      We performed a retrospective pathology and chart review of 46 patients with
      cervical adenocarcinoma in situ from January 1980 to October 1994. RESULTS: Nine
      patients were managed during the first half of the study period and 37 were
      managed in the second half. The mean age of patients was 38.4 years (range 25
      72). Forty-five of 46 patients were diagnosed as a result of an abnormal Pap
      smear, although only 19 smears indicated adenocarcinoma in situ or other
      glandular abnormalities. Cold knife conization resulted in a 33% rate of positive
      margins for adenocarcinoma in situ compared to 50% for large loop excision of the
      transformation zone (LLETZ). Among 24 conservatively managed patients with
      negative conization margins, there have been 2 (8.3%) recurrences of
      adenocarcinoma in situ. Among patients not undergoing hysterectomy as definitive
      treatment, 1 of 18 (6%) patients undergoing cold knife conization recurred,
      compared to 4 of 14 (29%) managed with LLETZ, despite a 63.4-month shorter mean
      follow-up interval for the LLETZ patients. CONCLUSIONS: Cold knife conization is
      associated with a lower rate of recurrence of cervical adenocarcinoma in situ
      compared to LLETZ. We recommend cold knife conization for patients who are not
      treated with hysterectomy.

PMID- 8641607
TI  - Combination chemotherapy with etoposide, cisplatin, and doxorubicin in mixed
      mullerian tumors of the adnexa.
AB  - Eleven patients with ovarian (9) or fallopian tube (2) mixed mullerian tumors who
      underwent primary surgery at Yale New Haven Medical Center between 1986 and 1994
      were treated with etoposide, cisplatin, and doxorubicin. Responses were observed
      in three (60%) of five evaluable patients with two complete (40%) and one partial
      (20%) response. Median survival time was 17 months with an estimated 3-year
      survival of 18%. Survival may have been improved with earlier stage disease, but
      survival was not significantly improved with optimal surgical cytoreduction in
      patients with advanced disease. Four patients required dose reductions for
      myelosuppression and there was one treatment related death. Toxicity was
      comparable to other combination chemotherapy regimens. EPA has modest therapeutic
      activity in ovarian and fallopian tube MMT.

PMID- 8641608
TI  - Extraperitoneal laparoscopic para-aortic lymph node dissection.
AB  - Extraperitoneal cervical cancer "staging" is considered superior to a
      transperitoneal approach. We developed an entirely extraperitoneal laparoscopic
      technique for para-aortic lymph node dissection in a pig model, followed by human
      subject application. Using latex balloon dissection technology, the technique is
      as follows. A retroperitoneal space is created via a 15-mm left flank incision.
      The collapsed balloon trochar is inserted and the balloon is inflated under
      direct visualization. Subsequently, a CO2 pneumoretroperitoneum is established
      with 12-15 mm Hg and dissection is carried out using a total of three to four
      left flank port sites. For initial technique development and improvement, four
      pigs were used. Excellent bilateral retroperitoneal exposure was achieved. A
      complete dissection was performed from the renal to the iliac vessels.
      Subsequently, a bilateral sampling procedure from the level of the inferior
      mesenteric artery to the liac vessels was performed in four human subjects. A
      mean of 5 nodes (range 1-9) was removed with an EBL of <50 cc. Operative times
      were 120-140 min. There were no intra- or postoperative complications. This
      initial experience demonstrates that laparoscopic extraperitoneal para-aortic
      access and node sampling is feasible. Further study is ongoing to determine the
      extent of dissection possible using this approach. However, since this approach
      mimics the extraperitoneal laparotomy technique, it may have all the advantages
      of adhesion avoidance combined with an outpatient procedure.

PMID- 8641609
TI  - Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and
      radiotherapy (FUMIR) followed by limited surgery in locally advanced and
      recurrent vulvar carcinoma.
AB  - To prospectively evaluate the feasibility and efficacy of neoadjuvant
      chemoradiotherapy locally advanced or recurrent vulvar carcinoma, 58 patients
      referring for primary (41) or recurrent (17) disease received preoperative
      external radiotherapy to a dose of 54 Gy, divided into two courses with an
      interval of 2 weeks. 5-Fluorouracil (750 mg/m2 daily for 5 days) and mitomycin-C
      (15 mg/m2 single bolus) were given at the start of each cycle. Wide local
      excision and inguinal lymphadenectomy were planned after treatment. Eighty-nine
      percent of patients completed the chemoradiotherapeutic treatment, whereas 72%
      underwent surgery. Objective responses were observed in 80% of vulvar diseases
      and in 79% of groin metastases. Pathologic complete response of both the vulvar
      and inguinal disease was confirmed in 13 patients (31%). Early severe toxicity
      was recorded in 3 patients and severe worsening of performance status in 3. Three
      deaths occurred shortly after treatment and at least one is directly related to
      toxic effects. This treatment allows good control of locally advanced and
      recurrent vulvar cancer with acceptable side effects. Further follow-up is
      required to determine the long-term outcome and the effectiveness of the surgical
      procedure.

PMID- 8641610
TI  - Human papilloma virus, vulvar dystrophy, and vulvar carcinoma: differential
      expression of human papillomavirus and vulvar dystrophy in the presence and
      absence of squamous cell carcinoma of the vulva.
AB  - In situ hybridization (ISH) and polymerase chain reaction (PCR) for several
      common HPV types were performed on 41 cases of vulvar dystrophy, 19 of which were
      associated with previous or simultaneous invasive squamous cell carcinoma of the
      vulva. Three of the 19 cases (16%) of dystrophy associated with cancer were found
      to contain HPV-16/18 by PCR. In contrast, 12 of the 22 cases (55%) of dystrophy
      not associated with carcinoma contained HPV-16/18 by PCR (P < 0.01). A control
      group of 10 vulvar specimens without dystrophy or carcinoma was negative for all
      HPV types tested. ISH was negative for all HPV types in all 41 cases. The data
      confirm the association between vulvar carcinoma and hypertrophic/mixed
      dystrophy, and provide evidence for an association between HPV-16/18 and some
      cases of vulvar dystrophy. Cases of vulvar dystrophy not associated with HPV
      16/18 may be at increased risk for the development of vulvar carcinoma.

PMID- 8641611
TI  - Platelet-activating factor enhances production of insulin-like growth factor
      binding proteins in a human adenocarcinoma cell line (HEC-1A)
AB  - We have recently demonstrated the existence of an autocrine growth loop driven by
      platelet-activating factor (PAF) in the human endometrial adenocarcinoma. cell
      line HEC-1A. To investigate a possible cooperation between PAF and the insulin
      like growth factor (IGF) system in this cell line, the effect of PAF on insulin
      like growth factor binding protein (IGFBP) production as well as binding and
      biological activities of IGF-I, IGFv-II, and the analog Des(1-3)IGF-I have been
      evaluated. Analysis of self- and cross-displacement curves of [125I]IGF-I binding
      to HEC-1A cells indicates the presence of a single class of binding sites, with
      affinity constants of 1-4 nM for IGF-I and IGF-II and 70 nM for Des(1- 3)IGF-I,
      which binds to IGFBPs with lower affinity. Insulin does not apparently bind to
      this binding site. Moreover, the addition of increasing concentrations of IGF-I
      leads to a paradoxical increase of binding. These results indicate a similarity
      of this binding site to IGFBPs. The presence of IGFBPs has been demonstrated by
      Western ligand blot analysis of HEC-1A conditioned medium which shows the
      presence of two bands of 32-34 and 40-45 kDa. By Western immunoblotting analysis,
      the two bands were respectively identified as IGFBP-2 and IGFBP-3. Incubation
      with PAF (1 microM) highly increases the release of the two IGFBPs from the
      cells. Such an effect is inhibited by the PAF receptor antagonist L659,989, by
      the PKC inhibitor sangivamycin, and by the tyrosine kinase inhibitor genistein.
      PAF also induces a time-dependent increase of mRNA expression for IGFBP-3,
      suggesting an effect on synthesis of this protein. IGF-I and IGF-II (0.1-100 nM)
      are almost ineffective in inducing [3H]thymidine incorporation, whereas a slight
      proliferative effect is observed with Des(1-3)IGF-I which also increases PAF
      synthesis. These data demonstrate a modulatory action of PAF on IGFBP secretion
      in HEC-1A cells and indicate that the IGF system plays a minor, if any,
      modulatory role on proliferation of this cell line.

PMID- 8641612
TI  - Intratumoral blood flow analysis in endometrial cancer: does it differ among
      individual tumor characteristics?
AB  - To evaluate whether intratumoral blood flow analysis in endometrial cancer
      provides individual tumor characteristics, 36 patients with endometrial cancer (5
      in stage IA, 14 in stage IB, 5 in stage IC, 4 in stage II, and 8 in stage III)
      underwent transvaginal color and pulsed Doppler ultrasound before surgery.
      Histologically, there were 18 patients with well-differentiated adenocarcinoma, 8
      with moderate differentiated adenocarcinoma, 4 with poorly differentiated
      adenocarcinoma, 4 with adenoacanthoma, and 2 with carcinosarcoma. Intratumoral
      blood flow was recorded, and peak systolic velocity (PSV) and resistance index
      (RI) were calculated. Endometrial thickness (ET) was also measured. There were no
      significant differences among PSV and RI values for each stage. There were also
      no significant differences among PSV and RI values for each histological
      diagnosis. ET in stages IA, IB, and II was significantly thinner than that in
      stage III (P < 0.05). Moreover, ET in stage IA was significantly thinner than
      that in stage IC (P < 0.05). There were significant differences in ET for some
      histological diagnoses. These results suggest that intratumoral blood flow
      analysis in endometrial cancer could not predict the tumor staging and
      histological diagnosis. However, in view of the small number of patients, these
      observations must be considered preliminary.

PMID- 8641613
TI  - Octreotide in the management of bowel obstruction in terminal ovarian cancer.
AB  - Intestinal obstruction is a common and distressing clinical complication in
      ovarian cancer. The aim of our study was to assess vomit control in terminal
      ovarian cancer patients with inoperable gastrointestinal obstruction, using a
      symptomatic pharmacological treatment with octreotide which obviates the need for
      nasogastric tube placement. We studied 13 patients, all of whom had advanced
      ovarian cancer FIGO stage IIIc. Seven patients were treated in the Gynecology
      Department of S. Raffaele Hospital, at the University of Milan, and 6 were
      managed in the University of Varese Hospital. Octreotide was administered at
      doses starting with 0.3 up to 0.6 mg (mean 0.44 mg) a day by subcutaneous bolus
      or continuous infusion. Octreotide controlled vomiting in all cases to grade 0 on
      the WHO emesis scale. Complete relief of symptoms was achieved within 3.07 days
      (range 1-6 days). Vomiting stopped within 2-3 days of starting treatment in most
      patients. In 8 patients with a nasogastric tube, drainage decreased from 2000 to
      under 100 ml/day after the start of octreotide treatment. No side effects were
      reported. All patients died with minimal distress or pain.

PMID- 8641614
TI  - A phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of
      the ovary.
AB  - We have conducted a disease specific phase I study of paclitaxel and
      cyclophosphamide in recurrent adenocarcinoma of the ovary. This was done to take
      advantage of the cellular and molecular synergism between paclitaxel and DNA
      damaging agents, with the hope of avoiding paclitaxel-cisplatin toxicities.
      Paclitaxel was given as a 24-hr CIVI, after which cyclophosphamide was given as a
      60-min infusion. Cycles of therapy were repeated every 3 weeks; and granulocyte
      colony-simulating factor (G-CSF) was given in a "flexible" dosing fashion.
      Starting doses were 170 mg/m2 paclitaxel and 750 mg/m2 cyclophosphamide. Dose
      limiting toxicity (DLT) was seen at the doses of 250 mg/m2 paclitaxel and 1250
      mg/m2 cyclophosphamide. DLT was cumulative thrombocytopenia. There were six
      nonhematologic grade 3 or 4 toxicities experienced in the study. Eleven of 20
      evaluable patients (55%) have achieved an objective response (4 CCR;7 PR). Three
      of four CCRs were confirmed by negative findings at peritoneoscopy. The median
      number of prior therapies was 2 (range 1-4) and 17 individuals had platinum
      refractory disease. We conclude that paclitaxel followed by cyclophosphamide is
      an active combination in recurrent ovarian cancer and that further study is
      needed to determine if this combination is truly better than paclitaxel alone.

PMID- 8641615
TI  - Classification of adnexal tumors by transvaginal color Doppler.
AB  - The purpose was to evaluate the validity of transvaginal color Doppler sonography
      for differentiating between benign and malignant ovarian tumors. Color Doppler
      and Duplex measurements were obtained in 212 (144 benign, 68 malignant) ovarian
      and tubarian tumors preoperatively. One hundred and thirty-one patients were
      postmenopausal and 81 premenopausal. An ATL UM9/HDI was used. The following
      criteria were analyzed: minimum and mean resistance index and pulsatility index,
      number and distribution of tumor arteries, diastolic notch, and the maximum,
      minimum, mean, and sum of all peak systolic, maximum enddiastolic, and time
      average maximum velocities. Most criteria showed highly significant differences
      between benign and malignant tumors with variable overlaps. RImin gives a
      sensitivity of 80%, specificity of 69%, and accuracy of 75% for postmenopausal
      patients and 80, 59, and 67% for pre- and postmenopausal patients, respectively.
      PImin gives equivalent results. The number of tumor arteries and the maximum flow
      velocities increase the accuracy. The summation of all flow velocities gives the
      best result with a sensitivity of 93%, specificity of 85%, and accuracy of 87%
      for postmenopausal and 91, 76, and 80% for pre- and postmenopausal tumors,
      respectively. Flow data show no relevant differences between low malignant
      potential tumors and ovarian carcinomas. Serous cystadenomas and benign teratomas
      show higher differences than mucinous cystadenomas, functional cysts, and
      endometriomas in comparison to malignancies. A separate analysis of pre- and
      postmenopausal tumors is important. Differentiation seemed better for post- than
      for premenopausal tumors. The four flow criteria (RImin, number of tumor
      arteries, and maximum and sum of all peak systolic velocities) seemed appropriate
      for tumor differentiation. However, this study confirms that a single measurement
      is not sufficient to differentiate ovarian lesions. Measurements of flow
      velocities (e.g., maximum and sum of all peak systolic velocities) are superior
      compared with RImin and PImin.

PMID- 8641616
TI  - Gynecologic reconstruction with a rectus abdominis myocutaneous flap: an update.
AB  - This series reports the outcomes and significant complications associated with
      the rectus myocutaneous flap when used for pelvic or inguinal reconstruction in
      patients with gynecologic cancers. Perioperative variables were retrospectively
      reviewed to identify social and medical risk factors as well as intraoperative
      and postoperative complications that predisposed to rectus flap failure. Fifteen
      patients with gynecologic malignancies underwent reconstructive procedures using
      a vertically oriented rectus abdominis myocutaneous flap for either vaginal (n =
      14) or inguinal (n = 1) reconstruction. The patients' primary cancers were
      cervical (n = 11), rectal (n = 1), ovarian (n = 1), vulvar (n = 1), and vaginal
      (n = 1). The median age was 50 years. The median follow-up was 17 months. All
      flaps were mobilized in conjunction with a radical salvage operation. There were
      no cases of vaginal prolapse and no abdominal wound infections. However, 4
      patients (27%) had major postoperative morbidity in this small series. There was
      one wound dehiscence and three episodes of necrosis of the subcutaneous and
      cutaneous portions of the flap. All 4 of these patients required additional
      operative intervention or debridement. Eleven patients had complete healing of
      the flap. The rectus abdominis myocutaneous flap is a valuable option for
      gynecologic reconstructive procedures. Perioperative strategies for improving
      flap viability include the identification of risk factors that may compromise
      flap perfusions such as prior abdominal incisions, peripheral vascular disease,
      and obesity. Meticulous surgical technique is required to preserve the vascular
      pedicle. These strategies may be useful in preoperative counseling, the
      perioperative evaluation, and the intraoperative management.

PMID- 8641617
TI  - Clostridium difficile colitis associated with cisplatin-based chemotherapy in
      ovarian cancer patients.
AB  - The purpose of this study was to examine the incidence and cause of Clostridium
      difficile colitis occurring after cisplatin-based combination chemotherapy in
      ovarian cancer patients. Thirty-three patients with primary ovarian malignancy
      were treated with cisplatin-based combination chemotherapy ranging from 1 to 12
      (mean 4.6) cycles. All patients who developed diarrhea after undergoing the
      cancer chemotherapy were examined to determine whether or not they were
      complicated by C difficile colitis. The diagnosis of C. difficile was confirmed
      by a stool-cytotoxin test and endoscopic examination. Severe C. difficile colitis
      occurred in 2 patients (6.1%) after receiving cisplatin-based combination
      chemotherapy for ovarian malignancies. Although both patients recovered from the
      colitis after the administration of vancomycin, the first case demonstrated a
      relapse of the colitis after receiving a subsequent course of the same
      chemotherapy with cisplatin. Both patients were then treated with a carboplatin
      alternative to cisplatin in the following courses, which resulted in neither a
      relapse of the colitis nor a recurrence of the malignancies up to this time. This
      report suggests the importance of searching for the presence of C. difficile and
      its toxin in patients with diarrhea after undergoing cancer chemotherapy since C.
      difficile may cause severe colitis. Based on our findings, it is thus concluded
      that cisplatin may cause C. difficile colitis.

PMID- 8641619
TI  - Evaluation of the prognostic significance of nm23/NDP kinase protein expression
      in cervical carcinoma: an immunohistochemical study.
AB  - The objective of this study was to evaluate the prognostic significance of
      immunohistochemical staining for nm23/nucleoside diphosphate (NDP) kinase in
      cervical carcinoma. A retrospective analysis of 176 patients with cervical
      carcinoma FIGO stage IB treated with radical hysterectomy and pelvic
      lymphadenectomy from 1987 to 1990 was conducted. Immunohistochemical staining
      using the polyclonal nm23-H1/NDP kinase A antibody was correlated to various
      histopathological and morphological characteristics (tumor size, histologic type,
      grade of differentiation, vessel invasion, invasion into parametria, and lymph
      node metastasis) and relapse-free survival. For controls, sections were obtained
      from 10 hysterectomy specimens with normal cervical epithelium. Staining for
      nm23/NDP kinase was observed in 90% of control cases and in 70.5% of cases of
      cervical carcinoma, more frequent in squamous and adenosquamous cell carcinoma
      than in adenocarcinoma and more frequent in poorly differentiated than in more
      highly differentiated tumors. There were no differences related to size of tumor
      or invasion into vessels or parametria or occurrence of lymph node metastasis.
      The relapse-free survival was lower for patients with squamous cell and
      adenosquamous tumors with positive immunostaining for nm23/NDP kinase than for
      those with negative tumors when evaluated in univariate analysis. In multivariate
      analysis with tumor size, vessel invasion, invasion into parametria, grade of
      differentiation, and lymph node metastasis included, this difference was no
      longer significant. In patients with adenocarcinoma no difference was found. In
      conclusion, we did not find immunostaining for nm23/NDP kinase to be a useful
      indicator for prognosis in cancer of the uterine cervix.

PMID- 8641618
TI  - Proliferation index determined by MIB-1 and recurrence in endometrial cancer.
AB  - BACKGROUND: Endometrial carcinoma is the most common gynecologic malignancy in
      developed countries. Stage, grade, DNA index, histologic type, depth of invasion,
      steroid receptor status, and the presence of positive peritoneal cytology have
      all been linked to survival. The monoclonal antibody MIB-1 reacts with the same
      antigen as Ki-67 giving an estimate of proliferation index. The authors
      investigated whether MIB-1 staining, using image analysis, could be used as a
      prognostic indicator of recurrence in endometrial carcinoma. METHODS: The tumors
      from 39 consecutive patients receiving primary surgical therapy for endometrial
      cancer were evaluated with the MIB-1 monoclonal antibody. Proliferation index was
      quantified by image analysis. The patients were followed for a median of 34
      months and their charts were reviewed to determine recurrence, histologic type,
      grade, stage, depth of invasion, and status of peritoneal cytology. RESULTS:
      Eleven of the 39 patients had recurrence of their disease within the 3-year
      observation period of this study. Overall, 22 patients had stage I disease, 3
      patients had stage II disease, 12 patients had stage III disease, and 2 patients
      had stage IV disease. MIB-1 staining was not significantly elevated in advanced
      (stage III and IV) as opposed to early (stage I and II) cancers (P = 0.558).
      Elevated MIB-1 staining was associated with an increased incidence of recurrence
      within 24 months of diagnosis (P = 0.002). Patients whose tumors had MIB-1
      staining of greater than or equal to 39.0% had an increased chance of recurring
      over patients whose tumors stained less than 39.0% (P = 0.003). CONCLUSION: In
      this series of 39 patients with endometrial cancers, MIB-1 monoclonal antibody
      staining was shown to be a prognostic indicator of recurrence.

PMID- 8641620
TI  - Vulvar intraepithelial neoplasia in women infected with human immunodeficiency
      virus-1.
AB  - The purpose of this study was to determine the response of vulvar intraepithelial
      neoplasia (VIN) lesions to standard treatment methods in women infected with
      human immunodeficiency virus (HIV). We reviewed all cases of VIN over a 4-year
      period at an inner-city hospital. We reviewed the clinical records of these women
      to abstract demographic information as well as information about tobacco use,
      injection drug use, results of HIV testing, T cell count, stage of HIV infection,
      colposcopic and cytologic findings, treatment of lesions, and follow-up. Eight of
      the 28 women (29%) with VIN were infected with HIV. The relative risk for
      recurrence or persistence of VIN after treatment was 3.3 (95% confidence
      interval, 1.4-7.4; P = 0.01) in the HIV+ compared with the HIV- group. The high
      rate of HIV infection among women with VIN supports recommendation of HIV testing
      for women with VIN. Women known to have HIV infection should be carefully
      examined for vulvar lesions. Further study is needed to determine the optimum
      treatment for VIN in women infected with HIV.

PMID- 8641621
TI  - Increased radiosensitivity by a combination of 9-cis-retinoic acid and interferon
      y in breast cancer cells.
AB  - Interferons (IFNs) and retinoic acid (RA) are known to possess antiproliferative
      effects in various human cancer cell lines, including squamous cervix carcinoma
      and breast cancer cell lines. Frequently synergistic effects could be observed by
      the combination of both, and in clinical trials high response rates could be
      achieved by IFN-alpha in combination with 13-cis-RA in patients with squamous
      carcinoma of the uterine cervix. Since radiation-potentiating effects of IFNs and
      RA were described, we evaluated the additional impact of irradiation on three
      human breast cancer cell lines and investigated the antiproliferative effects of
      single, double, or triple treatments with IFN-gamma, 9-cis-RA, and irradiation.
      Antiproliferative effects were observed in all cell lines by any single
      treatment. When combining IFN-gamma with 9-cis-RA, synergism could be observed in
      all experiments. The combination of either IFN-gamma or 9-cis-RA with irradiation
      resulted mostly in additive effects. Irradiation contributed additive or further
      synergistic effects to the already synergistic effects of the combination of
      these two drugs. Thus synergism of IFN-gamma and 9-cis-RA always at least
      persisted fully. These results suggest that a regimen of IFN, RA, and
      radiotherapy (RT) might be a promising combination in the therapy of solid
      tumors, where RT is part of the conventional treatment.

PMID- 8641622
TI  - Intraperitoneal mitoxantrone or floxuridine: effects on time-to-failure and
      survival in patients with minimal residual ovarian cancer after second-look
      laparotomy--a randomized phase II study by theSouthwest Oncology Group.
AB  - A randomized phase II study of intraperitoneal (ip) mitoxantrone or floxuridine
      (FUDR) was performed for the treatment of minimal residual epithelial ovarian
      cancer found at second-look laparotomy after initial platinum-based chemotherapy.
      Entry was to take place within 30 days of reassessment laparotomies, with
      documentation of peritoneal metastases either microscopic or gross with
      cytoreduction to less than or equal to 1 cm in largest diameter. Patients were
      stratified by the site of the largest disease present (microscopic to 0.5 cm
      maximum diameter versus greater than 0.5 to 1 cm maximum diameter), by time of
      registration (< 14 days versus up to 30), and by serum CA-125 (< or = 35 versus
      >35 units/ml) prior to randomization to either ip mitoxantrone 10 mg/m2 every 2
      weeks X 9 or ip floxuridine (FUDR) 3 g (total dose)/ day X 3 days every 3 weeks X
      6 cycles. Implantable ip systems and 1.5-2 liters of normal saline were used to
      deliver the drugs of 83 patients registered between December 1988 and January
      1994; there were 6 pathology exclusions and 9 surgical exclusions, and 1
      nonevaluable patient for a total of 39 evaluable on mitoxantrone and 28 on FUDR
      being evaluable. FUDR is the choice for further study because of a progression
      free survival exceeding 15% at 1 year over mitoxantrone and a median overall
      survival of 38 months. It should be emphasized again that the goal of a
      randomized phase II selection design is to select a winner for phase III testing
      should there be a substantial difference between the treatments with respect to
      the primary endpoint. Comparative conclusions between the treatment arms should
      not be attempted due to the inherently much smaller sample sizes. This should
      reemphasize the limitations in a comparison of efficacy; however, the toxicologic
      differences still emerge quite clearly.

PMID- 8641623
TI  - Differential effects of high-dose gamma irradiation on the production of
      transforming growth factor-beta in fresh and established human ovarian cancer.
AB  - Tumor cells from five freshly isolated ovarian tumors and four established human
      ovarian carcinoma cell lines were analyzed for the production of the
      immunoinhibitory cytokine transforming growth factor-beta (TGF-beta) before and
      after exposure to gamma irradiation and/or the cytokines TNF-alpha plus IFN
      gamma. All fresh tumors secreted high levels of TGF-beta when compared to the
      levels produced by the established ovarian carcinoma cell lines. TGF-beta
      produced by fresh tumors was significantly reduced after high doses of gamma
      irradiation (10,000 cGy). In contrast with the established cell lines,
      irradiation significantly increased TGF-beta secretion. Exposure of fresh tumor
      cells to cytokines followed by irradiation caused significant reduction of TGF
      beta released when compared to the amount released after exposure to cytokines
      only. However, in the established cell lines, cytokines followed by irradiation
      again significantly increased TGF-beta production. These data indicate that high
      doses of irradiation in fresh ovarian tumors, unlike established ovarian
      carcinoma cell lines, can significantly reduce the local production of this
      potent immunoinhibitory cytokine. This effect could work to further amplify weak
      immunological responses within the tumor. In addition, these findings indicate
      major differences between fresh tumor samples and established cell lines and warn
      against the sole use of continuous cell lines as models for tumors growing in
      vivo.

PMID- 8641625
TI  - Mature results of a phase II trial of concomitant cisplatin/pelvic radiotherapy
      for locally advanced squamous cell carcinoma of the cervix.
AB  - PURPOSE: Patients with locally advanced squamous cell carcinoma of the cervix
      have a poor prognosis when treated by standard radiotherapy (RT) alone. Factors
      such as large tumor volume or nodal disease result in pelvic and distant
      treatment failures. Cisplatin (CDDP), a known radiosensitizer with documented
      activity in squamous cell carcinomas, was used in a phase II prospective study to
      evaluate the efficacy of combined chemo/radiotherapy in locally advanced squamous
      cell carcinomas of the cervix. METHOD: CDDP was administered (20 mg/m2) daily X 5
      at 21-day intervals with concomitant external beam and intracavity RT. Standard
      RT was delivered at 1.8-2.0 Gy/day, 5 fractions per week for 5 weeks.
      Intracavitary cesium insertions were planned to treat point A to approximately 80
      Gy. RESULTS: Fifty-nine patients were enrolled from March 1986 to July 1990. Four
      patients were voluntarily withdrawn, leaving 55 patients evaluable for response.
      Of these, 16 were Stage IB/IIA, 11 were Stage IIB, 24 were Stage III, and 4 were
      Stage IV. The median age of patients enrolled was 47 years (range 27-79). Median
      follow-up time was 65 months (range 60-113). Histopathologic confirmation of node
      status was available in 33 patients, of whom 45.5% (15/33) had nodal metastases.
      Overall response was 96% (CR = 87%, PR = 9.0%) and 3.6% had progressive disease
      during treatment. Forty-six patients were evaluable at 5 years for overall and
      disease-free survival. Calculations were based on Kaplan-Meier product limit
      estimates. The 5-year survival was 73% for Stage IB/IIA, 60% for Stage IIB, 67%
      for Stage III, and 25% for Stage IV. The disease-free survival at 5 years was 73%
      for Stage for IB/IIA, 50% for Stage IIB, 67% for Stage III, and 25% for Stage IV.
      Hematologic toxicity was severe but tolerable. No treatment-related deaths
      occurred. CONCLUSION: Concomitant CDDP/RT is a safe and tolerable method of
      treating patients with locally advanced squamous cell carcinoma of the cervix.
      Our data suggest a benefit in both disease-free and 5-year survival, particularly
      notable among patients with Stage III disease.

PMID- 8641624
TI  - The practice of surgical staging and its impact on adjuvant treatment
      recommendations in patients with stage I endometrial carcinoma.
AB  - A survey of American gynecologic oncologists was undertaken to assess their
      compliance with current surgical staging criteria in patients with early
      endometrial carcinoma. One hundred forty-four members of the Society of
      Gynecologic Oncologists responded to the survey. Respondents treated an average
      of 22 new cases annually. Tumor grade and intraoperative determination of depth
      of myometrial invasion were demonstrated to influence the frequency of lymphatic
      dissection. In grade 1, 2, and 3 lesions, 76, 60, and 34% of responders,
      respectively, indicated that depth of invasion influenced their decision to
      perform lymphadenectomy. In addition, depth of invasion was important in
      determining type and extent of lymphatic resection. Further, the impact of
      pathologic lymph node status on postoperative adjuvant radiation therapy
      recommendations was evaluated for various stratifications of endometrial
      adenocarcinoma confined to the corpus. The greatest differences in treatment
      recommendations were noted in the 50-66% invasion category. For grade 1 and 2
      cancers, adjuvant therapy recommendations were reduced by 23 and 16% respectively
      when comparing pelvic and combined therapy versus none and vaginal therapy. The
      effect of surgical staging data on clinical decisions is clearly evident. The
      knowledge of pathologically negative lymph node status reduces the recommendation
      for postoperative adjuvant radiotherapy in patients with adenocarcinoma otherwise
      confined to the uterine corpus.

PMID- 8641626
TI  - Suspected idiopathic CD4+ T-lymphocytopenia in a young patient with vulvar
      carcinoma stage IV.
AB  - A case of a woman having a large invasive vulvar carcinoma is reported. Because
      of the early age of onset and recurrent pneumonia, immunodeficiency was
      suspected. There appeared to be a repetitive low CD4+ T-lymphocyte count, without
      evidence of HIV infection or other diseases or therapies known to be clearly
      associated with T-cell depletion. This is suspected for the rare disorder known
      as idiopathic CD4+ T-lymphocytopenia which is often associated with opportunistic
      infections. A case of suspected idiopathic CD4+ T-lymphocytopenia in a patient
      having an invasive vulvar carcinoma is described.

PMID- 8641627
TI  - A case of small cell carcinoma of the uterine cervix presenting Cushing's
      syndrome.
AB  - A proportion of small cell carcinoma of the uterine cervix is known to secrete a
      neuroendocrine substance. However, cases presenting Cushing's syndrome due to
      ACTH secreted from a cervical small cell carcinoma are extremely rare. Here, we
      report a case of small cell carcinoma of the uterine cervix that ectopically
      secreted ACTH and presented Cushing's syndrome. A 42-year-old woman was initially
      admitted to the endocrine unit for investigation of ectopic ACTH syndrome. Serum
      cortisol and plasma ACTH levels were elevated with no diurnal variation. After
      gynecologic examination, her original disease was found to be a stage IIb
      cervical small cell carcinoma. She underwent a radical hysterectomy and pelvic
      lymphadenectomy. The entire tumor was excised and post-TNM classification was
      T2bN1M0. Immunohistochemically, tumor cells stained strongly for ACTH and
      chromogranin. Electronmicroscopic pictures showed typical neurosecretory
      granules. Although plasma ACTH returned to normal after surgery, liver metastasis
      appeared during the course of postoperative irradiation. She died 9 months after
      operation in spite of vigorous systemic chemotherapy.

PMID- 8641628
TI  - Metastatic choriocarcinoma in a postmenopausal woman.
AB  - Trophoblastic disease is usually related to pregnancy and occurs in about 1 in
      1300 pregnancies in Western countries. Since the advent of methotrexate therapy,
      trophoblastic tumors have become one of the most curable malignancies.
      Trophoblastic disease can develop independently of gestation, but this is very
      rare. We report the unusual case of a 58-year-old woman who had a metastatic
      choriocarcinoma 6 years after menopause and 29 years after her last pregnancy.
      The tumor proved to be primarily resistant to monochemotherapy and developed
      chemoresistance to three different polychemotherapeutic regimens. Eleven months
      after the diagnosis of uterine choriocarcinoma the patient died from advanced
      metastatic disease.

PMID- 8641629
TI  - Ovarian hemangioma associated with concomitant stromal luteinization and ascites.
AB  - A 62-year-old female presented with a pelvic mass and ascites. The Papanicolaou
      vaginal smear showed an unusual maturation, maturation index being 0/80/20. The
      serum level of estradiol was 48.7 pg/ml. The preoperative checkup suggested a
      pelvic malignancy with a differential diagnosis of hormone-secreting ovarian
      tumor. On surgical exploration, she had a hemangioma of the ovary without
      malignant cytology in the ascitic fluid. Histologically, this tumor was
      associated with stromal luteinization. This is the first case, reported in the
      literature, possessing ovarian hemangioma with stromal luteinization accompanying
      massive ascites. It should be noted that an ovarian hemangioma can be associated
      with stromal luteinization and ascites, and that MR imaging is sometimes of value
      for making a preoperative diagnosis of ovarian hemangioma.

PMID- 8641630
TI  - Angiographic-guided embolization of metastatic invasive mole.
AB  - BACKGROUND: The friable and hypervascular nature of a metastatic invasive mole
      places the patient at risk for significant hemorrhage. Bleeding is the chief
      cause of morbidity and mortality in patients with a histopathological diagnosis
      of invasive mole. Bleeding from vaginal metastatic lesions can be controlled by
      packing the vagina and local excision if necessary. Often the results are less
      than satisfactory. CASE: This case describes a 43-year-old Hispanic female with
      metastatic invasive mole to the vagina. Following chemotherapy, she underwent
      life-threatening hemorrhage requiring hospitalization and multiple transfusions.
      The metastatic lesions were successfully embolized with gelfoam by selective
      angiography. The patient required minimal additional chemotherapy and is
      currently without evidence of disease. CONCLUSIONS: The technique of angiographic
      embolization is emerging as a successful and minimally invasive procedure as
      illustrated in this presentation. Prophylactic embolization with or prior to the
      administration of chemotherapy in the management of metastatic invasive mole is
      discussed and may play a role in the primary therapy of this condition.

PMID- 8641631
TI  - Polyserositis as an unusual sign of methotrexate toxicity.
AB  - We present a 46-year-old patient who underwent an abdominal hysterectomy with
      bilateral salpingo-oophorectomy for persistent trophoblastic disease. Single
      agent chemotherapy with alternate methotrexate 1 mg/kg/day and leucovorin 0.1
      mg/kg for 8 days was instituted on the first postoperative day. Various adverse
      symptomatology developed, culminating in a unique side effect, polyserositis. To
      the best of our knowledge, the wide spectrum of side effects, the short time
      lapse after onset of chemotherapy, and their severity are uncommon in a patient
      receiving her first chemotherapeutic treatment with MTX.

PMID- 8641632
TI  - Chemotherapy treatment of chyloperitoneum and peritoneal carcinomatosis due to
      cervical cancer--review of literature.
AB  - We report a case of chyloperitoneum and peritoneal carcinomatosis 8 months after
      radiation therapy for cervical cancer and treatment with lowfat diet, diuretics,
      and systemic combination chemotherapy. The literature of chyloperitoneum
      complicating gynecological malignancies is reviewed.

PMID- 8641633
TI  - Pericardial metastasis in carcinoma of the uterine cervix.
AB  - Cardiac metastasis from gynecological malignancies is rare. Only six cases of
      carcinoma of the uterine cervix have been reported where the diagnosis of
      malignant pericardial effusion was made antemortem. The treatment of neoplastic
      pericardial effusion is controversial; both surgical and nonsurgical treatments
      are advocated. We present a patient with pericardial effusion secondary to
      carcinoma of the cervix and recommend subxiphoid pericardial fenestration for
      reliable long-term control of malignant effusion.

PMID- 8641634
TI  - Primary non-clear cell adenocarcinoma of the vagina in older DES-exposed women.

PMID- 8641635
TI  - Adolfo Ferrata: one of the fathers of hematology on the 50th anniversary of his
      death.

PMID- 8641636
TI  - Familial AL-amyloidosis in three Italian siblings.
AB  - BACKGROUND AND METHODS: Familial occurrence of immunoglobulin-related (AL)
      amyloidosis has occasionally been reported. In this work we describe the
      concomitance of systemic amyloidosis and monoclonal gammopathy (one case of
      Waldenstrom's macroglobulinemia and two cases without multiple myeloma or related
      diseases) in three Italian siblings, two males and one female. RESULTS AND
      CONCLUSIONS: All of them showed a common pattern of polyneuropathy to different
      degrees; two presented a sicca syndrome and one also suffered from nephropathy.
      Two of them showed the same HLA typing with the same light chain type (k), but
      had different presenting symptoms. Polyneuropathy and a history of peptic disease
      in two cases was suggestive of type III familial amyloidotic polyneuropathy (FAP)
      occurring in the setting of a familial monoclonal component. However,
      immunohistochemical studies on different tissue specimens using anti
      apolipoprotein A1 and anti-transthyretin antibodies were negative. Further
      screening of DNA samples for transthyretin (TTR) gene mutations was also
      negative. Clinical and laboratory investigations ruled out reactive or senile
      amyloidosis and immunohistochemical studies with anti-light chain antibodies on
      amyloidotic tissue specimens were positive. As a consequence, this family
      represents a new case of familial AL-amyloidosis.

PMID- 8641637
TI  - Reduced taste perception in AL amyloidosis. A frequently unnoticed sensory
      impairment.
AB  - BACKGROUND: Sporadic observations suggest a possible taste impairment in AL
      amyloidosis, but the frequency and intensity of this sensory anomaly are not
      known. MATERIALS AND METHODS: We submitted 21 AL amyloidotic patients, drawn from
      subjects referred to the Amyloidosis Study Center of the Department of Internal
      Medicine and Medical Therapy, University of Pavia, to suprathreshold scaling
      analysis. RESULTS: Taste acuity was reduced in most of them. Every taste showed
      independent behavior, and 90% of these patients were hypogeusic. True ageusia for
      one or two tastes was observed in 35% of patients. No patient was aware of
      reduced taste acuity. Macroglossia did not seem to play a prominent role in
      dulling tastes. CONCLUSIONS: Impairment of taste perception suggests that
      gustative neuropathy is a frequently unnoticed expression of sensory involvement
      in AL amyloidosis.

PMID- 8641638
TI  - Platelet composition and function in patients undergoing cardiopulmonary bypass
      for heart surgery.
AB  - BACKGROUND: Previous studies showed severe biochemical and functional damage to
      platelets in patients undergoing cardiopulmonary bypass for cardiac surgery, and
      suggested that this derived from the proteolytic action of plasmin on the
      platelet surface. METHODS: A double-blind study was carried out to compare
      platelet function and composition in patients randomized to receive the protease
      inhibitor aprotinin or placebo during reoperation for valvular prosthesis
      replacement or coronary artery bypass grafting. RESULTS: Flow cytometry with
      specific monoclonal antibodies and polyacrylamide gel electrophoresis did not
      show any significant proteolysis of platelet glycoprotein Ib and IIb-IIIa either
      in the placebo or the aprotinin group. Functional studies were consistent with
      these results, since ristocetin-induced platelet agglutination was unchanged and
      platelet aggregation and ATP release induced by collagen and ADP were only
      slightly reduced by cardiopulmonary bypass. These mild defects in platelet
      function were partially prevented by aprotinin infusion. CONCLUSIONS: On the
      basis of our data and those from literature, we suggest that platelets may be
      affected very little or severely damaged during cardiopulmonary bypass for
      cardiac surgery, probably depending on some aspects of the technical procedure
      which remain to be identified. Aprotinin infusion significantly protects
      platelets in the latter condition, while its role is obviously slight in the
      former.

PMID- 8641639
TI  - Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG)
      in chronic lymphocytic leukemia. Results of a crossover study.
AB  - BACKGROUND: In a recently reported study, low doses of intravenous
      immunoglobulins (IVIG) were shown to be as effective as high doses in protecting
      chronic lymphocytic leukemia (CLL) patients against infections, although a
      control group was not included. With this background we started a crossover study
      of low-dose IVIG prophylaxis aimed at investigating its superiority over
      empirical treatment of infections. MATERIALS AND METHODS: Forty-two CLL patients
      with hypogammaglobulinemia (IgG < 600 mg/dL) and/or a history of at least one
      episode of severe infection in the 6 months preceding inclusion in the study were
      randomly allocated to receive either an infusion of 300 mg/kg IVIG every 4 weeks
      for 6 months or no treatment. Then they were switched to observation or IVIG for
      another 12 months; finally, they received IVIG or no therapy for 6 more months.
      RESULTS: A significantly lower incidence of infectious episodes was observed
      during IVIG prophylaxis in 30 patients who completed the 6-month period of either
      observation or IVIG therapy. The same applied to the 17 patients who completed 12
      months of either observation or IVIG prophylaxis. Interestingly, the restoration
      of serum IgG levels obtained in 17 out of 25 patients (mean percent value of IgG
      increase, 41.8%) did not parallel a decrease in the number of infectious
      episodes. CONCLUSIONS: A protective effect against infections is demonstrated for
      low-dose IVIG in the present study. A benefit was shown in patients who completed
      either 12 or 6 months of IVIG prophylaxis; however, even this low-dose treatment
      is not a cost effective way to prevent infection in CLL patients.

PMID- 8641640
TI  - Influence of two different Escherichia coli asparaginase preparations on
      fibrinolytic proteins in childhood ALL.
AB  - BACKGROUND: Alterations in hemostasis have frequently been observed in patients
      with leukemia, and thrombotic events are well documented in patients receiving L
      asparaginase (ASP) as a single agent or in combination with vincristine,
      prednisone (sometimes complemented by an anthracycline). The present study was
      designed to evaluate prospectively fibrinolytic parameters in leukemic children
      receiving different E. coli ASP preparations (Kyowa ASP, n = 20; Bayer ASP, n =
      20), and to relate changes in the fibrinolytic system to serum ASP activity.
      MATERIALS AND METHODS: Blood samples for coagulation studies were obtained
      together with serum samples for pharmacokinetic monitoring in the same
      venipuncture (before the first and 6th-7th doses of ASP). RESULTS: Patients
      receiving Kyowa ASP showed significantly (0.0001) enhanced ASP-activity compared
      to children treated with the Bayer preparation. Significantly decreased values of
      fibrinogen (p < 0.001), plasminogen (p < 0.0002) and alpha 2-antiplasmin (p <
      0.0003) were found in the Kyowa group, along with significantly enhanced thrombin
      generation (F1 + 2; p < 0.001), t-P (p < 0.01) and D-dimer levels (p < 0.05). In
      contrast, PAI 1 activity demonstrated no significant difference in the two E.
      coli ASP administered. CONCLUSIONS: Changes in fibrinogen, plasminogen, alpha 2
      antiplasmin and D-dimer are clearly associated with ASP activity during the
      course of ASP administration in children with ALL.

PMID- 8641641
TI  - Cardiac injury as late toxicity of mediastinal radiation therapy for Hodgkin's
      disease patients.
AB  - BACKGROUND: During the last 20 years Hodgkin's disease (HD) has become one of the
      most curable neoplasms; in fact, more than 75-80% of patients are expected to
      achieve long-term relapse-free survival with appropriate therapy. However,
      overall survival has been affected by intercurrent or treatment-induced diseases
      such as the increased risk of cardiac toxicity in patients who received
      mediastinal irradiation. METHODS: The incidence of cardiac abnormalities after
      mediastinal radiotherapy was assessed in 102 consecutive HD patients who
      underwent this treatment from January 1970 to December 1980. Basal investigation
      procedures included electrocardiogram and echocardiography; myocardial perfusion
      scintigraphy with 201-thallium and coronary arteriography were performed in
      selected patients. RESULTS: Eleven patients (10.8%) presented cardiac
      abnormalities, which were asymptomatic in three cases. Eight cases of myocardial
      ischemia and 3 of constrictive pericarditis were observed. The incidence of late
      cardiotoxic effects was related to total mediastinal dose and to the irradiation
      technique. CONCLUSIONS: The increasing duration of follow-up shows that as
      mediastinal irradiation increases so does the risk of late cardiotoxic side
      effects. For this reason, a proper treatment strategy should reduce these risk
      factors through new combined modality protocols and routine evaluation of
      cardiologic follow-up.

PMID- 8641642
TI  - Supradiaphragmatic early stage Hodgkin's disease: does mantle radiation therapy
      still have a role?
AB  - Extended field radiation therapy represents the main therapeutic option in early
      stage Hodgkin's disease with favorable prognostic features. Its role however has
      recently been criticized, mainly due to the high incidence of late complications
      in irradiated tissues. Furthermore, surgical staging, which in the opinion of
      many is mandatory for proper selection of patients for radiotherapy alone, has a
      well-known morbidity, and splenectomy has been associated with a high risk of
      secondary leukemias. Lastly, the failure rate after radiotherapy only is not
      negligible and second-line treatment is not always successful. A review of our
      experience and of the recent literature has allowed us to refute these
      objections. The results of radiotherapy, when properly performed, are highly
      reliable and have been reproducible in many Institutions. Chemotherapy alone
      cannot yet be regarded as an alternative to radiotherapy in these patients since
      data reported on this issue are conflicting. Present knowledge regarding the
      relationship between clinical features and the risk of occult subdiaphragmatic
      spread allows patients with localized disease to be selected without surgical
      staging; the results of radiotherapy in clinically staged patients confirm this
      statement. Concern for the late effects in irradiated tissues is justified, and
      future efforts should be directed at reducing the toxicity of this treatment.
      Associating a short chemotherapy course with low-dose radiotherapy to involved
      sites could help to achieve this goal.

PMID- 8641643
TI  - Recombinant human erythropoietin for long-term treatment of anemia in paroxysmal
      nocturnal hemoglobinuria.
AB  - The long-term effects of recombinant human erythropoietin (rhEPO) administration
      in two consecutive cases of paroxysmal nocturnal hemoglobinuria (PNH) with severe
      anemia are reported. In both patients, a 68-year-old woman and a 66-year-old man,
      a diagnosis of PNH was made on the basis of severe macrocytic anemia associated
      with hemoglobinuria, hemosiderinuria and positivity for the sucrose and Ham
      tests. Subcutaneous treatment with rhEPO, 150 U/Kg body weight daily, was
      followed in both cases by a progressive increase in hemoglobin concentrations,
      which thereafter were maintained above 10 g/dL with lower doses of rhEPO and
      without any relevant side effects for 32 and 29 months of continuous treatment,
      respectively. A clinical response was observed in spite of elevated baseline
      serum erythropoietin concentrations, appropriate to the degree of anemia in both
      patients. These results suggest that rhEPO may be appropriately and safely used
      in the long-term correction of anemia associated with PNH, and that the response
      to the pharmacologic doses of rHEPO administered was not dependent on the level
      of endogenous erythropoietin.

PMID- 8641644
TI  - NADPH oxidase activity and chemotaxis by neutrophils in two patients with
      glycogen storage disease type Ib treated with recombinant human granulocyte
      monocyte colony-stimulating factor.
AB  - Polymorphonuclear neutrophils play an important role against pathogens through
      the production of toxic oxygen metabolites by the NADPH oxidase enzyme, which
      reduces oxygen to superoxide anion in the respiratory burst. Neutropenia,
      infectious complications and impaired neutrophil function are often reported in
      glycogen storage disease type Ib (GSDIb), a metabolic disorder characterized by
      increased glycogen and decreased glucose-6-phosphatase (G-6-P) activity in the
      liver. Two children with GSDIb and associated neutropenia with recurrent
      bacterial infections were treated daily with different doses of rHu-GM-CSF. NADPH
      oxidase activity and chemotaxis in patients were assessed before and during
      therapy in stimulated and unstimulated neutrophils. During rHu-GM-CSF treatment,
      any increase found in the NADPH oxidase activity of patients was not significant
      with respect to that in controls. In one patient chemotaxis was greater than of
      controls. This finding suggests that in patients with GSDIb both neutropenia and
      PMN abnormalities may be responsible for infections, and PMN dysfunction probably
      depends on the degree of inherited functional G-6-P deficit.

PMID- 8641646
TI  - Granulocytic sarcoma in nonleukemic children: report of two new cases
      successfully treated by local radiation therapy and systemic chemotherapy.
AB  - Granulocytic sarcoma (GS) is a rare tumor composed of immature myeloid cells.
      Exceedingly rare in childhood, it has more commonly been described in association
      with acute myeloid leukemia. Occasional nonleukemic patients generally go on to
      develop overt leukemia in a mean period of 10.5 months from diagnosis of GS. We
      report here two new cases of GS diagnosed in nonleukemic children. They were
      successfully treated with local radiation therapy and conventional systemic
      chemotherapy. The need to suspect more often this all too frequently misdiagnosed
      disease is emphasized. The role of optimally delivered radiation therapy in
      achieving and maintaining local control of the tumor is discussed.

PMID- 8641645
TI  - All-trans-retinoic acid and pseudotumor cerebri in a young adult with acute
      promyelocytic leukemia: a possible disease association.
AB  - Pseudotumor cerebri or idiopathic intracranial hypertension is a neurological
      syndrome characterized by signs and symptoms of intracranial hypertension without
      clinical or radiological evidence of infective or space occupying lesions.
      Iatrogenic factors are frequent; in particular, cases of pseudotumor cerebri
      associated with all-trans-retinoic acid treatment in acute promyelocytic leukemia
      (APL) have been frequently described in pediatric patients. We report on a case
      observed in an older patient (young adult age) and give diagnostic and
      therapeutic guidelines.

PMID- 8641647
TI  - Long-term molecular remission after conventional chemotherapy in a patient with
      Philadelphia-negative acute lymphoblastic leukemia.
AB  - Adult Philadelphia (Ph1) negative acute lymphoblastic leukemia (ALL) is usually
      treated with conventional chemotherapy regimens. Long-term disease-free survival
      is often achieved. The rearrangement of immunoglobulin heavy-chain genes has been
      used to evaluate minimal residual disease. A novel nested-polymerase chain
      reaction (PCR) approach was used here to study a patient in long-term complete
      remission (CR) after the BFM regimen. No evidence of tumor cell contamination was
      found in bone marrow cells collected after 93 months of CR. This finding supports
      the hypothesis that conventional chemotherapy can induce long-term molecular
      remission and cure in Ph1 negative ALL.

PMID- 8641648
TI  - Evaluation of hepatitis B and C virus infections in patients with non-Hodgkin's
      lymphoma and without liver disease.
AB  - Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic and
      lymphotropic viruses endemic to Sicily. To evaluate whether these viruses may
      chronically infect patients with non-Hodgkin's lymphoma (NHL) and without liver
      disease, we examined serum samples from 24 such patients. Five cases (20.8%)
      revealed HCV infection, as shown by the detection of viral RNA through the
      polymerase chain reaction technique, while HBV-DNA was not found in any of them
      by the same method. These results provide one more epidemiological element
      supporting the hypothesis that the association between HCV infection and
      lymphoproliferative diseases is not a casual event, and show that HCV may
      chronically infect patients with NHL without producing liver damage.

PMID- 8641649
TI  - Rosai-Dorfman syndrome with extranodal localizations and response to
      glucocorticoids: a case report.
AB  - A case of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman
      syndrome) in a 42-year-old man is described. The disease involved the respiratory
      tract and skeletal apparatus, led to considerable general impairment and was
      unusually responsive to glucocorticoids. Molecular and immunophenotype analysis
      seem to confirm the reactive nature of a disorder that shows profound T-cell
      immunodeficiency.

PMID- 8641650
TI  - FLU-ID (fludarabine and idarubicin) regimen as salvage therapy in pretreated low
      grade non-Hodgkin's lymphoma.
AB  - Fludarabine (FLU) is a new antimetabolite chemotherapeutic agent with promising
      activity in lymphoproliferative disorders and, in particular, in low-grade non
      Hodgkin's lymphoma (LG-NHL). Recently, a few reports have described interesting
      results using FLU in polychemotherapy regimens. In order to evaluate FLU in
      combination with other antineoplastic agents, we used a combination of FLU and
      idarubicin, called the FLU-ID regimen, to treat 10 patients with recurrent LG
      NHL. The FLU-ID regimen was as follows: FLU 25 mg/sqm i.v. on days 1 to 3 and
      idarubicin 12 mg/sqm i.v. on day 1. Of the 10 patients, 2 (20%) achieved complete
      response (CR), 5 (50%) partial response, and the remaining 3 showed no benefit
      from the treatment. The 2 CR patients are still in remission after 6 and 8
      months, respectively. The median duration of overall survival of all patients was
      8 months. The major toxic effects observed were neutropenia (40%) and infections
      and/or febrile episodes (15%); no fatalities due to drug side effects occurred.
      These results indicate the efficacy of the FLU-ID regimen in inducing a good
      remission rate with moderate side effects in recurrent LG-NHL.

PMID- 8641651
TI  - Large granular lymphocyte leukemia associated with hepatocellular carcinoma: a
      case report.
AB  - The association of large granular lymphocyte leukemia (LGL-L) with hepatocellular
      carcinoma in a 55-year-old patient is described. An increased number of LGL was
      seen on peripheral blood smears. The immunophenotype was CD3+, CD4-, CD8+, and a
      study of the TCR gene rearrangement indicated the monoclonal nature of the
      proliferation. A liver mass was detected on CT scan and an ultrasound-guided fine
      needle biopsy revealed the presence of hepatocholangiocellular elements. A right
      hepatectomy was performed. Major neutropenia persisted despite corticosteroids
      and granulocyte colony-stimulating growth factor (G-CSF) therapy. Methotrexate at
      20 mg/week failed to control lymphocytosis after three months of treatment. A new
      nodule of hepatocarcinoma reappeared twelve months after surgery and a liver
      resection was performed.

PMID- 8641652
TI  - Cryoprecipitate-poor plasma fraction (cryosupernatant) in the treatment of
      thrombotic thrombocytopenic purpura at onset. A report of four cases.
AB  - Treatment of thrombotic thrombocytopenic purpura (TTP) with cryoprecipitate-poor
      plasma (cryosupernatant) as substitution liquid has brought a portion of the
      relapsing forms of this syndrome under control. We experimented the use of plasma
      exchange (PE) with CPP as plasma substitute in the initial treatment of four
      patients with TTP at onset, in an attempt to elicit a faster response to therapy.
      We observed a clinical response in the four patients treated; however, laboratory
      indices of complete and stable response (platelet count, serum lactate
      dehydrogenase level) did not normalize in concert with clinical improvement.

PMID- 8641653
TI  - Unrelated bone marrow transplantation in a Wiskott-Aldrich syndrome patient
      sharing two HLA-extended haplotypes with the donor.
AB  - We report a case of BMT from an unrelated donor (MUD) in a patient affected by
      Wiskott- Aldrich syndrome (WAS). The donor-recipient pair was completely
      identical for two HLA-extended haplotypes. The conditioning regimen consisted of
      Bu 14 mg/kg followed by CY 200 mg/kg. GVHD prophylaxis was carried out with CsA
      plus short-term MTX. Allogeneic engraftment was obtained without any signs of
      acute or chronic GVHD. At fifteen months from the transplant the patient was in
      an excellent clinical condition. This case confirms the role of BMT from MUD in
      WAS, and suggests that complete donor-recipient identity for two entire HLA
      extended haplotypes is a particularly favorable immunogenetical condition in this
      type of transplant.

PMID- 8641654
TI  - Extramedullary relapse after allogeneic bone marrow transplantation plus buffy
      coat in two high risk patients.
AB  - In order to obtain an additional graft versus leukemia effect (GVL) and rapid
      engraftment, donor leukocyte infusion (DLI) was added to unseparated, sex
      mismatched allogeneic bone marrow transplantation in two male patients (age 21,
      26) affected by high risk hematological malignancies (refractory T-ALL,
      refractory B-LBL in leukemic phase). Graft versus host disease (GVHD) prophylaxis
      consisted of methotrexate (MTX) alone. DLI were obtained after G-CSF 16 ug/kg/day
      sc. A total of 2.36 and 5.8 x 10(6)/kg MNC, 5.4 and 11 x 10(6)/kg CD34+ cells,
      1.3 and 1.3 x 10(6)/kg CD3+ lymphocytes, respectively, were infused. Hemopoietic
      recovery occurred promptly. Complete chimerism was detected by cytogenetic
      examination. One patient developed an extramedullary relapse that first involved
      the cranial nerves, and then the testes, soft tissue and skin; the other patient
      developed central nervous system disease and then bilateral paravertebral masses
      with progressive paraplegia. Despite complete medullary remission with normal
      female karyotype, both patients died from extramedullary progression of their
      disease. Our observation shows that, at least in high risk patients, no
      additional GVHD or GVL effect was evident after donor leukocyte infusion.
      Extramedullary relapse was not prevented despite good control of medullary
      disease.

PMID- 8641655
TI  - European concerted action on human hematopoietic stem cell: gene transfer into
      hematopoietic stem cells.

PMID- 8641656
TI  - A single cell summarizing the pathogenesis of cytopenias in hemophagocytic
      syndrome.

PMID- 8641657
TI  - Management of L-asparaginase induced prothrombotic state in acute lymphoblastic
      leukemia.

PMID- 8641658
TI  - Inhibitory effects of the dietary antioxidants butylated hydroxyanisole and
      butylated hydroxytoluene on bronchioloalveolar cell proliferation during the
      bleomycin-induced pulmonary fibrosing process in hamsters.
AB  - The effects of dietary antioxidants on bleomycin (BLM)-induced pulmonary fibrosis
      were investigated in Syrian golden hamsters. In addition, the influence on cell
      proliferative activity in bronchioloalveolar hyperplastic lesions during the lung
      fibrosing process was evaluated in terms of argyrophil nucleolar organizer
      regions (AgNORs) and proliferating cell nuclear antigen (PCNA). Male 6-wk-old
      hamsters were divided into six groups. Groups 1-3 were intratracheally instilled
      with BLM at a dose of 2.5 U/kg body weight on days 0 and 14, and then given a
      diet supplemented with 1% butylated hydroxyanisole (BHA), or 1% butylated
      hydroxytoluene (BHT), or basal diet alone for the following 41 days. Groups 4-6
      were given 1% BHA, 1% BHT or basal diet without BLM treatment for the same time
      period as that in those of groups 1-3. The mortality rate of animals in group 1
      (BLM/BHA) (one in 20; 5%) was lower than in those of groups 2 (BLM/BHT) (three in
      20; 15%) and 3 (BLM alone) (four in 20; 20%). BHA and BHT treatments
      significantly inhibited lung weight gains by BLM (P < 0.05). Histopathologically,
      both BHA and BHT reduced BLM-induced pulmonary histopathological changes such as
      fibrosis, macrophage aggregation and epithelial proliferation, with a tendency
      for correlation with accumulation of type III collagen. In addition, antioxidant
      treatment significantly lowered the mean numbers of AgNORs (P < 0.01) and PCNA
      labelling indices (P < 0.05) in the hyperplastic bronchioloalveolar lesions. The
      results thus indicate that these antioxidants exert inhibitory effects on
      proliferation of hyperplastic lesions associated with lung fibrosis.

PMID- 8641659
TI  - Lack of influence of modulators of epoxide metabolism on the genotoxicity of
      trans-anethole in freshly isolated rat hepatocytes assessed with the unscheduled
      DNA synthesis assay.
AB  - The aniseed food flavour trans-anethole was implicated as a weak hepatocarcinogen
      only in female Sprague Dawley-CD rats administered high doses (1% in the diet for
      121 wk). However, this substance is apparently non-genotoxic in a range of test
      systems. Anethole is metabolized in the rat along three primary pathways, one of
      which is epoxidation across the double bond of the side-chain. The epoxides of a
      number of the alkenylbenzene family of food flavours, of which anethole is a
      member, are putative genotoxins, being bacterial mutagens but not mammalian
      carcinogens. The authors have previously shown that the cytotoxicity of anethole
      is enhanced when the cellular epoxide defence mechanisms of conjugation with
      reduced glutathione and hydration by cytosolic epoxide hydrolase are severely
      compromised. They now report, however, that modulation of epoxide metabolism in
      cultured cells by the same mechanisms fails to induce unscheduled DNA synthesis
      (UDS) by anethole nor was there a UDS response in hepatocytes of female rats
      dosed with anethole in vivo. The epoxide of anethole was synthesized for the
      first time in this investigation and tested directly. As expected, it was
      markedly cytotoxic but not genotoxic. Anethole epoxide has chemical
      characteristics that differ from those of other structurally similar epoxides
      being labile to hydrolysis in aqueous media at physiological pH and temperature.
      This gives greater relevance to tests of its genotoxicity after formation within
      the hepatocyte rather than by adding the epoxide extracellularly to the culture
      medium. The direct and indirect demonstration of the lack of induction of UDS by
      anethole epoxide provides further support for the hypothesis that marginal
      hepatocarcinogenicity observed in female rats given 1% anethole in the diet for
      121 wk was not initiated by a genotoxic event.

PMID- 8641660
TI  - Studies of the safety of Chinese wild rice.
AB  - Chinese wild rice has been consumed for over 3000 years, but its safety as a food
      in China has never been established. The grain contains higher amounts of
      protein, ash and crude fibre than white rice. Levels of non-nutritive mineral
      elements such as arsenic, cadmium and lead are very low. The eating patterns of
      110 people ( > 60 yr) showed no ill-effects. The results of acute toxicity tests
      with mice fed diet containing 21.5 g/kg Chinese wild rice [corrected] indicated
      no abnormal reaction and none of the mice died. The bone marrow micronucleus and
      sperm abnormality tests conducted with mice were negative as was the Salmonella
      mutagenicity test. The results of this investigation indicate that Chinese wild
      rice is safe for human consumption.

PMID- 8641661
TI  - Effect of Spirulina maxima consumption on reproduction and peri- and postnatal
      development in rats.
AB  - Spirulina maxima, an edible micro-organism useful in human nutrition, was
      examined for its effect on general reproductive performance and for peri- and
      postnatal toxicity in rats at levels of 0, 10, 20 and 30% (w/w) incorporated into
      the diet. There was no reduction in body weight gain in males or females and no
      deaths or clinical signs of toxicity. Treatment was not associated with any
      adverse effect on any measure of reproductive performance, including male and
      female fertility and duration of gestation. There was no increase in the number
      of abnormal pups at caesarean section or at birth. S. maxima consumption did not
      result in adverse effects on developmental markers of the pups.

PMID- 8641662
TI  - Effect of fumonisin B1 on protein and lipid synthesis in primary rat hepatocytes.
AB  - The effect of fumonisin B1 (FB1) on protein and lipid synthesis was evaluated in
      primary rat hepatocytes. FB1 did not affect incorporation of [3H]leucine into
      hepatocytes at either non-toxic (150 microM) or cytotoxic (500 microM)
      concentrations indicating that protein synthesis was not affected. However, FB1
      significantly (P < 0.01 to P < 0.0001) inhibited incorporation of [14C]palmitic
      acid into hepatocyte cultures implying that lipid synthesis was altered.
      Incorporation of the radiolabel was significantly (P < 0.05 to P < 0.0001)
      lowered in triacylglycerol (TAG) and sphingomyelin fractions and increased in
      phosphatidylcholine (PC) and phosphatidylethanolamine (PEA) in both FB1
      concentrations. The incorporation pattern of [14C]palmitic acid closely resembles
      the changes in phospholipid levels in the treated cells. The sphingolipid,
      sphinganine (Sa), was significantly (P < 0.0001) increased in treated cells but
      there was no significant difference between the toxic and non-toxic dose levels
      implying that the increased Sa level alone is not responsible for the in vitro
      toxicity. FB1 significantly (P < 0.01 to P < 0.001) decreased the level of free
      cholesterol within the cell, resulting in an increased PC:cholesterol ratio
      suggesting a more rigid membrane structure. Subsequent studies on the fatty acid
      (FA) profiles in PC and the neutral lipid, TAG, indicated that FB1 significantly
      (P < 0.05 to P < 0.0001) increased the levels of the polyunsaturated FAs C18:2n-6
      and C20:4n-6 at both concentrations. The FB1-induced changes to cellular
      membranes, specifically those related to FA changes in the major membrane
      phospholipids, and the altered FA content of the hepatocytes are likely to be key
      events in explaining the cytotoxic effects and altered growth responses induced
      by fumonisins in primary hepatocytes.

PMID- 8641663
TI  - Differential effects of T-2 toxin on bone marrow and spleen erythropoiesis in
      mice.
AB  - The 59Fe uptake into bone marrow and spleen was measured as a function of time
      after a single dose of T-2 toxin in mice (2.0 mg/kg, sc). It was found that,
      after a potent initial inhibition, there was a striking difference in the
      apparent repair capacity of both tissues: in spleen activity rapidly recovered
      (48-72 hr), whereas in bone marrow it remained significantly depressed for much
      longer (about 21 days). These results might be taken to indicate that T-2 toxin
      produces some sort of irreversible damage to bone marrow. However, working with T
      2 toxin-related splenectomized mice it was found that bone marrow erythropoietic
      activity was rapidly repaired, indicating that, under the conditions of the
      present experiments, there is no irreversible injury to the marrow haematopoietic
      or stromal cells. Further studies will be required using multiple doses or
      continuous toxin exposure in order to test the potential for long-lasting
      residual injury to the haematopoietic tissue. The present results show that the
      uptake of 59Fe into both spleen and bone marrow provides a rapid and sensitive
      method, suitable for primary evaluation of the extent of the erythropoietic
      damage produced by trichothecene mycotoxins.

PMID- 8641664
TI  - Effect of intratesticular injection of sodium fluoride on spermatogenesis.
AB  - The potential of sodium fluoride to affect spermatogenesis in the rat was
      assessed by intratesticular injection. Experimental rats' left testis was
      injected with sodium fluoride (50, 175 and 250 ppm) in vehicle (0.9%
      physiological saline); control testes were injected with vehicle. The right
      testis served as a non-injected control. Testicular tissues collected 'at' and
      'distal to' the injection site and from the non-injected control testes were
      evaluated microscopically 24 hr and 1, 2 and 3 wk post-injection. Testicular
      tissues obtained at and distal to the injection site in all fluoride-injected
      groups resembled tissues collected from corresponding areas in the controls.
      Seminiferous tubule damage observed in both the vehicle-injected control testes
      and the fluoride-injected testes but not in the non-injected testes was
      attributed to injection trauma. Polymorphonuclear leucocyte infiltration was
      observed 24 hr post injection only at the injection site in the vehicle- and
      fluoride-injected groups. Leydig cells were unaffected. Leucocyte infiltration
      with seminiferous tubule damage was not considered to be a fluoride treatment
      related effect because it was observed in both vehicle- and fluoride-injected
      testes. The results demonstrate that the rat is not adversely affected by direct
      exposure to fluoride at levels 200 times greater than those under normal
      conditions.

PMID- 8641665
TI  - Inhibition of human leukaemia 60 cell growth by mercapturic acid metabolites of
      phenylethyl isothiocyanate.
AB  - Mercapturic acid pathway metabolites of phenylethyl isothiocyanate inhibited the
      growth of human leukaemia 60 (HL60) cells in vitro. The adduct with L-cysteine, S
      (N-phenylethylthiocarbamoyl)cysteine, was the most potent with strong
      antileukaemic activity: the median growth inhibitory concentration (GC50) value
      was 336 +/- 1 nM (N = 18) compared with GC50 values of the precursor formed from
      dietary glucosinolates, phenylethyl isothiocyanate, 1.49 +/- 0.01 microM (N = 8),
      and the initial mercapturic acid pathway metabolite S-(N
      phenylethylthiocarbamoyl)glutathione 5.46 +/- 0.36 microM (N = 18). S-(N
      Benzylthiocarbamoyl)cysteine and S-(N-phenylpropylthiocarbamoyl)cysteine also had
      antiproliferative activity but S-(N-phenylethylthiocarbamoyl)cysteine was the
      most potent compound studied. The latter induced DNA fragmentation in HL60 cells
      but DNA laddering characteristic of apoptosis was not observed. It had low
      toxicity to corresponding differentiated cells, neutrophils, in culture, and
      therefore the cytotoxicity had selectivity for leukaemia cells. The
      antiproliferative activity of S-(N-phenylethylthiocarbamoyl)cysteine was lost
      during preincubation with culture medium, attributed to s-thiocarbamoyl transfer
      to serum proteins, which may decrease its effectiveness in vivo. The
      antiproliferative activity of S-(N-phenylalkylthiocarbamoyl)cysteine derivatives,
      by inhibiting tumour growth in pre-clinical development, may contribute to the
      association of decreased cancer incidence with dietary glucosinolate consumption.

PMID- 8641666
TI  - Single-dose and 13-week repeated-dose neurotoxicity screening studies of
      chlorpyrifos insecticide.
AB  - Chlorpyrifos (CPF), a widely used organophosphate insecticide, was screened for
      neurotoxic effects in Fischer 344 rats using United States Environmental
      Protection Agency 1991 guidelines for single-dose and 13-wk repeated dose
      studies. The studies emphasized a functional observational battery (which
      included grip performance and hindlimb splay tests), automated motor activity
      testing and comprehensive neurohistopathology of perfused tissues. Doses of up to
      100 mg/kg body weight in corn oil by gavage in the single-dose study and up to 15
      mg/kg body weight/day in diet for 13 wk in the repeated dose study were
      administered. It is known that CPF and other phosphorothionates can be activated
      to the oxon in local (extrahepatic) tissues. Local activation could possibly
      cause different effects in different tissues with cholinergic innervation, and
      thereby create syndromes unique to each phosphorothionate according to their
      structure. Consequently, the conduct of CPF neurotoxicity screening studies by
      contemporary guidelines offered opportunity to characterize the CPF over-exposure
      syndrome in rats. Single-dose high levels of oral exposure to CPF caused a range
      of clinical signs characteristic of cholinergic overstimulation. Although there
      was no clinical evidence of wide differences in sensitivity of one cholinergic
      response versus another, motor dysfunction (incoordination etc.) was more
      prominent than other signs, for example soiling. Effects were much more apparent
      in females and regressed over several days. Effects were minimal in the 13-wk
      study, and there was no evidence of accumulation of toxicity during the 13 wk of
      daily dietary exposure. Motor activity was decreased at the high dose in males
      and females at wk 4, but was not significantly different from controls in
      subsequent weeks. The 'normalization' of motor activity later in the study was
      interpreted as tolerance to repeated administration of CPF. Comprehensive
      neuropathological examination revealed no treatment-related lesions in either
      study.

PMID- 8641667
TI  - Toxicological comparison of a muscarinic agonist given to rats by gavage or in
      the diet.
AB  - Corneal opacities and urinary tract sepsis were previously observed by the
      authors in rats given muscarinic agonists mixed in the diet or by gavage. To
      explain the differential toxicity generated by each means of administration,
      toxicokinetics of the muscarinic agonist CI-979 were investigated. In addition,
      the muscarinic antagonist scopolamine was co-administered with CI-979 to evaluate
      the relationship of these effects to pharmacological mechanism of action of CI
      979. Female rats were given CI-979 daily by gavage at 0, 1, 10 and 30 mg/kg body
      weight or in the diet at 0, 1, 10 and 50 mg/kg body weight for up to 14 days.
      Dose-related clinical signs of muscarinic stimulation, such as sialorrhoea and
      dacryorrhoea, were observed predominantly in rats given 10 and 30 mg/kg body
      weight CI-979 by gavage, and corresponded with the high plasma drug
      concentrations. In contrast, hydronephrosis, pyelonephritis, and inflammation and
      necrosis of the kidney, urinary bladder, urethra and urinary papilla were linked
      to sustained, albeit lower plasma drug concentrations attained by dietary
      administration of CI-979 at 10 and 50 mg/kg body weight. Comparable incidences of
      corneal opacities were induced by both means of administration, but lesions
      appeared more rapidly and were generally of greater severity when CI-979 was
      given in the diet. The induction of corneal lesions, as well as urinary sepsis,
      may not relate simply to maximum plasma concentrations or to areas under the
      curve per se, but rather may arise when plasma drug concentrations are sustained.
      Corneal opacification and development of urinary tract pathology were inhibited
      by scopolamine, suggesting that these effects were related to the muscarinic
      mechanism of action of CI-979.

PMID- 8641668
TI  - Dietary contribution to genotoxic risk and its control.
AB  - Both exogenous and endogenous mutagens have the potential to contribute to events
      leading to carcinogenesis. While many dietary exogenous mutagens have been
      characterized, aflatoxins are the only exogenous mutagens in food which have been
      shown to directly increase the risk of liver cancer in humans. Little attention
      has been given so far to endogenous DNA damage, its potential to contribute to
      carcinogenesis, and the influence of genetic and environmental factors such as
      the diet on the process. This paper reviews the use of biomarkers which may
      assist in measuring these effects, their potential use in improving risk analysis
      for dietary mutagens, their application in molecular epidemiology, and their
      potential for studying dietary protective factors.

PMID- 8641669
TI  - [Progress of research on tumor suppressor genes].
AB  - The multistage model of carcinogenesis during tumor progression requires that
      there should be consecutive genetic abnormalities of both oncogenes and tumor
      suppressor genes. As is true of the protein products of oncogenes, tumor
      suppressor proteins are found to have various cellular functions. They are
      involved in the regulation of adhesion, cell-cell interaction, and cytoplasmic
      signal transducers as well as nuclear transcription factors. The recently
      identified hMSH2 (human MutS homolog 2) gene in colorectal carcinomas possesses
      sequence homologies to DNA mismatch repair genes in bacteria and yeast. An
      accumulation of evidence exists to indicate the tumor suppressive functions of
      actin-regulatory proteins. We have shown that both mutant gelsolin His321 and
      human authentic gelsolin, if expressed at increased levels, may have a
      suppressive potential against the tumorigenicity of mouse ras-transformed cells
      (EJ-NIH/3T3). His321 inhibited phosphatidylinositol 4,5-bisphosphate (PIP2)
      hydrolysis by phospholipase C gamma 1 more strongly in vitro than did wild-type
      gelsolin because of its higher binding capacity to phosphoinositide. We have also
      demonstrated that the production of gelsolin was either lost or notably reduced
      in human gastric carcinomas and urinary bladder cancers. The cDNAs encoding mouse
      or human authentic gelsolins were transfected into a urinary bladder cancer cell
      line. The urinary bladder transfectant lost their tumorigenicity in nude mice.
      All these and the facts that vinculin, alpha-actinin, erythrocyte band 4.1 family
      and gelsolin have both tumor-suppressive and phosphoinositides-binding activities
      in common suggest that these actin-regulatory proteins are a new family of
      effective tumor suppressors.

PMID- 8641670
TI  - [New mucin core protein genes and their clinical application].
AB  - Recent molecular biological approach has revealed the primary structure of some
      mucin core proteins. Most prominent characteristic is tandemly repeated
      sequences. cDNA cloning of 8 kinds of mucin core proteins, MUC1-7, have thus been
      performed. Among them, the entire structure was revealed on MUC1,2 and 7. MUC1 is
      a type I transmembrane protein with a large number of tandem repeat consisting of
      20 amino acids. We have found that mouse MoAb MUSE11 against adenocarcinoma,
      which detects circulating MUC1 in patients with gastrointestinal and pancreatic
      cancers, recognizes part of the tandem repeat of MUC1 using synthetic peptides.
      We have transfected MUC1 cDNA to some cell lines, and they indicated that cell
      cell and cell-matrix adhesion, growth rate and reactivity with growth factor were
      suppressed. To date, some of the MoAbs to adenocarcinoma have been shown to react
      with PDTRP sequence in the tandem repeat of MUC1 (MUC1 epitope), suggesting that
      MUC1 epitope could be highly immunogenic in human. Recently, cytotoxic T-cells
      against MUC1 epitope were established from breast and pancreas cancer patients.
      We also induce those T-cells from the patient with multiple myeloma.
      Interestingly, CTL functions in an HLA-unrestricted manner, and may be of use an
      adoptive immunotherapy. MUC2, a large secretory type mucin, cysteine-rich
      subdomains located both upstream and downstream of its central repetitive region,
      and these subdomains have sequence similarity with von Willebrand factor. We have
      shown that anti MUC2 core-protein MoAb CCP58 reacts intestinal metaplasia and
      cancer in stomach, but not normal gastric mucous membrane. Recently we
      established a new monoclonal antibody against purified deglycosylated gastric
      mucin. This antigen was expressed in the deep portion of metaplastic glands and
      cancers in the stomach. Two cDNA clones coding for this antigenic molecule were
      obtained.

PMID- 8641671
TI  - [Current status of diagnosis and treatment of growth retardation].
AB  - During the past 20 years, growth hormone (GH) preparation has been applied for
      the treatment of short children with growth hormone deficiency (GHD) and its
      growth promoting effect has been well documented. GH with normal response to
      pharmacological stimulation tests, was found to be a treatable short stature. In
      these conditions GH therapy is acceptable on a basis of endocrine replacement
      therapy. Clinical trials of GH therapy revealed beneficial effects on final
      height in the patients with Turner syndrome, achondroplasia, and renal failure.
      The trial on constitutional or non-endocrine short stature also showed growth
      promoting effects, however, it has been questioned that GH therapy for healthy
      children except short stature is really beneficial for their final height.
      Another problem is a difficulty of differential diagnosis of constitutional short
      stature and delayed adolescence. Clinical indication of GH therapy is now growing
      rapidly. We should have to decide real indication of GH therapy on the basis of
      both endocrine physiology and clinical philosophy.

PMID- 8641672
TI  - [Necessity of psychiatrist's support for critical care medicine].
AB  - The department of critical care medicine of Sapporo City General Hospital has
      been accepted 9,476 patients for past 10 years since opening. About 20% of all
      the patients who were hospitalized were due to accidents by backgrounds of
      psychiatric disorders. Main disorders are schizophrenia, manic-depressive
      psychosis, neurosis, alcoholism and so on. Suicides and to harm other persons are
      occurred unexpectedly and sometimes make the institute face to serious social
      problems against human rights. For protecting these tragedies, supports by
      psychiatrists are necessary. Our department has been connected very closely with
      our psychiatric department since starting. They suggest us to make correct
      diagnosis and treatment, ways to contact with such patients and their family
      properly. It's still very hard subject to know the possibility of these accidents
      in advance, but we strongly hope to promote these psychiatric sciences for
      protecting tragedies.

PMID- 8641673
TI  - [Current network in Hokkaido University School of Medicine].
AB  - Recently campus LAN (Local Area Network) HINES (Hokkaido university Information
      NEtwork System) has been popularized rapidly in Hokkaido University. A lot of
      personal computers have been connected to HINES. Although many people in our
      school of medicine are coming to be familiar with the Internet, the network has
      not been utilized sufficiently yet. Establishment of efficient education and
      research with network, that is the essential purpose of HINES, is the problem to
      be solved in the near future. In this document, how to set up both modem and ISDN
      (Integrated Services Digital Network) is also referred for the help of access to
      HINES from outside of the campus.

PMID- 8641674
TI  - [Alterations of protein phosphatases, PP2A and PP1, during retinoic acid-induced
      differentiation of HL-60 cells].
AB  - Alterations of protein phosphatases, PP2A and PP1, during the retinoic acid
      induced differentiation of HL-60 cells have been investigated. The PP2A activity
      determined with myelin basic protein (MBP) as a substrate showed a sharp
      transient increase at 18 h of incubation of the cells with retinoic acid, whereas
      during incubation without retinoic acid, the activity remained at the initial
      level. On DEAE-Sepharose column chromatography of the extracts preparted from the
      cells incubated without retinoic acid, the PP2A activities determined with MBP
      were eluted at 0.13 M or 0.23 m NaCl, respectively. The PP2A activity of the
      cells incubated for 18 h with retinoic acid was much more greatly activated by
      protamine compared with the activity of the cells incubated without retinoic
      acid. These results strongly suggest a conversion of PP2A holoenzyme from PP2A1
      to PP2A0 during the initial process of the retinoic acid-induced differentiation.
      On the other hand PP2A activity determined with phosphorylase alpha as a
      substrate showed a sharp transient decrease at 24 h of incubation of the cells,
      irrespective of the presence or the absence of retinoic acid in the incubation
      mixtures. This decrease may be related to the synchronization of the cells at S
      phase, which also occurred irrespective of the retinoic acid stimulation. PP1
      activity determined with MBP was transiently increased between 27 and 36 h of the
      incubation of cells without retinoic acid. The increase was strongly suppressed
      in the cells incubated with retinoic acid, suggesting a role of PP1 in the cell
      proliferation, the activity of which was also inhibited by retinoic acid.

PMID- 8641675
TI  - [Analysis of the allele specific Ag-binding site on murine class II MHC].
AB  - Residues 46 and 54 on pigeon cytochrome c 43-58 (p43-58) analogues function as
      agretopes (sites bound to MHC molecules). Phenylalanine (F) and alanine (A) at
      positions 46 and 54 on p43-58 respectively bind to I-Ab. Aspartic acid (D) and
      alanine at positions 46 and 54 respectively bind to I-Ak. To determine the allele
      specific binding sites (desetope (s)) on class II molecules that are
      correspondent to the agretopes of peptide antigen (Ag), we analyzed directly
      binding capacity of p43-58 analogues with glutamic acid (E) at the epitopic
      position 50 (50E) to L cell transfectants expressing recombinant I-A molecules
      between b and k types. An Ak binding peptide, 46D50E54A, bound to transfectant
      possessing amino acid sequence of k type on N-terminal half of alpha-helix of A
      alpha-chain irrespective of the b type sequence on the other part, whereas an Ab
      binding peptide, 46F50E54A, did not bind to these transfects. Thus, agretopic
      residue 46 of 46D50E54A peptides appeared to bind to N-terminal half of alpha
      helix of A alpha-chain. To define critical residues for the allele specific
      peptide binding, we then analyzed peptide binding capacity of Ak mutants
      substituted one of four polymorphic residues between Ak and Ab molecules. An Ak
      mutant, Ak alpha(56A), where arginine (R) at position 56 of the Ak alpha-chains
      was substituted with alanine located at the same position 56 of the Ab alpha
      chains hardly bound 46D50E54A. By contrast, the Ak alpha(56A) bound 46F50E54A.
      Furthermore, Ak restricted T cell hybridomas responded to 46F50E54A but not to
      46D50E54A in the presence of the Ak alpha(56A) APC. Thus, an amino acid on the
      position 56 of A alpha-chain determines critically specificity of the allele
      specific peptide binding (desetope).

PMID- 8641676
TI  - [Developmental studies on the petrous part of the human temporal bone--special
      references to the morphogenesis of the facial nerve canal].
AB  - Development and formation of the petrous bone was examined in total of 343
      Japanese skulls. The materials used consisted of 310 skulls of Japanese fetuses
      ranging from the fourth to tenth month, 19 skulls of Japanese juveniles from the
      third month to 7 years of age, and 20 temporal bones obtained from 14 adult
      cadavers. A total of six group of ossification centers appear in the petrous part
      during 5th fetal month, and they form the petrous bone at 6th fetal month. The
      firstly-appeared ossification center is just above the round window, and the
      second is on the ampulla of anterior semicircular canal. Other ossifications are
      observed between the cochlea and semicircular canals, on the brim of internal
      acoustic porus, on the superior surface of the petrous apex, and on the summit of
      posterior semicircular canal. The ossification of the facial canal starts at 6th
      fetal month, though the geniculate part and tympanic part do not complete until
      one year old after birth. Even in adults, the facial canal dehiscence are found
      at more than 10% of cases, mainly locating in the tympanic part. On the basis of
      these results, formation of the petrous bone including facial canal and other
      bony structures was discussed from the viewpoints of the ossification and pre-
      and postnatal middle ear development.

PMID- 8641677
TI  - [Disposition behavior and absorption mechanism of trientine, an orphan drug for
      Wilson's disease].
AB  - The disposition behavior of trientine, a selective copper-chelating drug for
      Wilson's disease, and its metabolites in normal patients with Wilson's disease
      and rats were studied. A high concentration of metabolites appeared in blood
      samples of patients and rats in the early stage after administration of
      trientine. Furthermore, large amount of trientine metabolites were excreted into
      the urine of patients. These results suggest that trientine is remarkably
      subjected to a first-pass effect. The drug concentration area under the curve
      (AUC) of the unchanged form and the metabolites of trientine in patients was not
      dependent on the administered dosage. It seems that the absorption process is an
      important factor for the disposition behavior of trientine, we have also
      investigated the uptake characteristics of trientine by rat intestinal brush
      border membrane vesicles. The uptake characteristics of trientine were similar to
      the physiological polyamines, spermine and spermidine. The uptake rate of
      trientine was dose-dependently inhibited by spermine and spermidine. Moreover,
      spermine competitively inhibited the uptake of trientine with a Ki value of 18.6
      muM. This value is very close to the Km value for spermine (30.4 muM). These data
      suggested that the uptake mechanism of trientine in rat small intestinal brush
      border membrane vesicles was almost identical to that of spermine and spermidine,
      and that the physiological polyamines seem to have the ability to inhibit the
      absorption of trientine from the gastrointestinal tract.

PMID- 8641678
TI  - [Nucleotide sequence and restriction fragment length polymorphism (RFLP) analysis
      of the long terminal repeat of human T-cell lymphotropic virus type II (HTLV
      II)].
AB  - Molecular studies have demonstrated the existence of two major subtypes of human
      T-cell lymphotropic virus type II, HTLV-IIa and HTLV-IIb. In attempts to further
      classify this family of viruses we have carried out nucleotide sequence and
      restriction fragment length polymorphism (RFLP) analysis of the long terminal
      repeat (LTR), a region which has been shown in previous studies to have the
      greatest intra-and inter-subtype genomic divergence. Analysis of the nucleotide
      sequences suggested the existence of distinct phylogenetic groups in each
      subtype, and based on predicted differences in restriction endonuclease sites,
      RFLP analysis allowed the identification of four groups within the IIa subtype
      (a1-a4), and six within the IIb subtype (b1-b6). Nucleotide sequence analysis
      also suggested the possible existence of HTLV-II quasispecies. However this
      appeared not to be significant, and preliminary studies suggest that these would
      not be expected to appreciably influence the results of RFLP analysis. The
      validity of the RFLP method was demonstrated in an analysis of thirty-six
      randomly chosen samples from the blood donors from the New York City Blood Center
      where it could be shown that all could be successfully classified. Moreover, the
      RFLP analysis correctly matched the viruses in donors and recipients of
      contaminated blood in four situations where HTLV-II was inadvertently transmitted
      by transfusion. RFLP analysis of the LTR appears to be a rapid and reliable
      method to identify HTLV-II infection. This should prove useful in studies of the
      epidemiology and the characterization of viruses present both in non-indigenous
      in indigenous populations.

PMID- 8641679
TI  - Reflex control of cardiac sympathetic nerve activity in anesthetized rats.
AB  - Reflex control of sympathetic outflow to the heart was evaluated by recording the
      efferent discharges of the interior cardiac sympathetic nerves in anesthetized
      rats. The reflex responses of inferior cardiac sympathetic nerve activity (ICNA)
      to arterial baroreceptor loading by phenylephrine and to arterial/atrial
      baroreceptor unloading by hemorrhagic hypotension were compared with those of
      renal sympathetic nerve activity (RNA) and adrenal sympathetic nerve activity
      (ANA). The reflex decrease in ICNA to the phenylephrine-induced graded increase
      in arterial blood pressure was smaller than that of RNA or ANA. Thus ICNA is less
      sensitive to arterial baroreceptor stimulation. Hemorrhage produced a volume
      dependent decrease in ICNA. The response was significantly smaller than that in
      RNA and was directionally opposite to that in ANA. Cervical vagotomy but not
      sinoaortic denervation abolished the hemorrhage-induced ICNA response, suggesting
      an important role of vagal pathways. These findings demonstrate that the reflex
      responses of sympathetic outflow to the heart were quantitively and qualitatively
      different from those to the kidney and the adrenal gland, indicating the regional
      control of sympathetic nerve activity in the regulation of cardiovascular
      functions.

PMID- 8641680
TI  - [Distribution of ventilation-perfusion ratios in paraquat-induced interstitial
      pneumonia in dogs].
AB  - To clarify the mechanism of hypoxemia observed in interstitial lungs diseases we
      investigated the V(A)/Q distribution in the paraquat-induced pneumonitis of the
      dogs. Sixteen mongrel dogs were given 20mg/kg of paraquat per os repeatedly with
      the dose and times of administration modified according to the general status of
      the dogs. Ventilation-perfusion relationships were measured using multiple inert
      gas elimination techniques, and these parameters were compared to arterial blood
      gases. The same procedures were also done in 11 normal dogs. Arterial oxygen
      tension (Pao2) was significantly lower and alveolar-arterial oxygen gradient )A
      aDo2) was significantly larger in paraquat dogs than normal dogs. In V(A)/Q
      measurement of paraquat dogs, mean shunt was 5.3% (range 0-28.8%), and there was
      a mean of 10.0% of blood flow to very low V(A)/Q units (V(A)/Q < 0.1, range 0
      43.4%). These values were larger than those of normal dogs (p<0.05, respectively)
      but dogs with large shunt or blood flow to low V(A)/Q units were not many in
      paraquat group. In the paraquat dogs, PaO2 significantly correlated with a shunt
      (r=-0.69, p < 0.01) and blood flow to low V(A)/Q (<0.1) units (r=-0.77, p<0.01)
      and it also correlated with dispersion of blood flow (log SD(Q), r=-0.66,
      p,0.01). Pathological study of paraquat lung showed large variety of interstitial
      pneumonia and fibrosis, and morphometical analyses did not demonstrate structure
      function correlation in paraquat dogs. From these results, we concluded that
      V(A)/Q mismatch including increased very low V(A)/Q units is important as a cause
      of arterial hypoxemia in interstitial lung diseases.

PMID- 8641681
TI  - [Effects of IgG-Fc-mitomycin C conjugate on cancer cells].
AB  - The binding of IgF Fc was studied in cultured tumor cells and antitumor effects
      of Fc-mitomycin C conjugate (Fc-MMC) on cultured tumor cells and tumor bearing
      mice were examined. 125I-labeled Fc bound to tumor cells Colon26, HLE, MKN28 and
      MKN74, and its binding was inhibited by the addition of non-labeled Fc. The
      binding increased in the course of exposure time up to 60 minutes and reached a
      value of more than 90% within 30 minutes. The cytotoxicity to the cultured tumor
      cells were not different in the 60 minutes incubation, but in the 30 minutes
      incubation, Fc-MMC showed more than two times as strong cytotoxicity as MMC
      (p<0.005). 2.5 mg/kg of MMC and 2.5 mg/kg of Fc-MMC equivalent to free MMC
      concentration were administered to Colon26 bearing BALB/c mice. The tumor growth
      in Fc-MMC-administered mice was lower than that in MMC-administered mice. 1.25
      mg/kg and 2.5 mg/kg of agents were given to P-388 bearing mice, and the survival
      time in 1.25 mg/kg of Fc-MMC-administered mice was significantly longer than that
      in MMC-administered mice (p < 0.005). The body weight was reduced in MMC 2.5
      mg/kg administered mice, but these reduction was not observed in Fc-MMC group.
      These observation suggest that Fc-MMC may be a promising anticancer agent on
      clinical applications.

PMID- 8641683
TI  - Interstitial deletion of chromosome 6q: precise definition of the breakpoints by
      microdissection, DNA amplification, and reverse painting.
AB  - Routine chromosomal analysis using GTG-banding alone showed a mosaic terminal
      deletion of 6q in a 14-week-old boy with developmental retardation, facial
      anomalies, agenesis of corpus callosum, cleft palate, hypotonia, short neck and
      pterygium colli, and minor anomalies of hands and feet. Discrepancies between the
      clinical findings on our patient and those described in the literature on
      patients having terminal deletions led to a more precise analysis of the
      karyotype. Reverse painting was performed on normal G-banded metaphases for exact
      determination of the breakpoints and on metaphases of the patient for evaluation
      of mosaicism. A DNA library that was obtained by microdissection of three deleted
      chromosomes 6 was used as a painting probe. Subsequent DNA amplification was
      performed with the help of topoisomerase-pretreated degenerate oligonucleotide
      primers. Unexpectedly, the hybridization pattern on normal metaphase chromosomes
      revealed an interstitial deletion with breakpoints at 6q25.1 and 6q27 instead of
      a terminal deletion. Hybridization on metaphases of the patient showed one
      deleted chromosome 6 in all metaphases analyzed at a higher resolution rather
      than mosaicism as previously assumed [karyotype, 46,XY,del(6)(q25.1 --> q27)]. We
      assume that in the single cases of 6q- described in the literature the deletions
      are misclassified. This might be due to difficulties in distinguishing between
      interstitial and terminal deletions at 6q and in precisely defining chromosomal
      breakpoints after GTG-banding alone.

PMID- 8641682
TI  - H-Y antigens.
AB  - H-Y antigen is defined as a male histocompatibility antigen that causes rejection
      of male skin grafts by female recipients of the same inbred strain of rodents.
      Male-specific, or H-Y antigen(s), are also detected by cytotoxic T cells and
      antibodies. H-Y antigen appears to be an integral part of the membrane of most
      male cells. In addition, H-Y antibodies detect a soluble form of H-Y that is
      secreted by the testis. The gene (Smcy/SMCY) coding for H-Y antigen detected by T
      cells has been cloned. It is expressed ubiquitously in male mice and humans, and
      encodes an epitope that triggers a specific T-cell response in vitro. Additional
      epitopes coded for by different Y-chromosomal genes are probably required in vivo
      for the rejection of male grafts by female hosts. The molecular nature of H-Y
      antigen detected by antibodies on most male cells is not yet known. Testis
      secreted, soluble H-Y antigen, however, was found to be identical to Mullerian
      inhibiting substance (MIS). MIS cross-reacts with H-Y antibodies and identical
      findings were obtained for soluble H-Y antigen and MIS, i.e., secretion by
      testicular Sertoli and, to a lesser degree, ovarian cells, binding to a gonad
      specific receptor, induction of gonadal sex reversal in vitro and, in cattle, in
      vivo. H-Y antisera also detect a molecule or molecules associated with the
      heterogametic sex in nonmammalian vertebrates. Molecular data on this antigen or
      antigens are not yet available.

PMID- 8641684
TI  - Extreme variant of the short arm of chromosome 15.
AB  - Using fluorescence in situ hybridization, primed in situ labelling, and
      conventional cytogenetic staining we have characterized an excessively enlarged
      short arm of chromosome 15. The likely mechanism explaining this variant
      chromosome involves amplification of rDNA sequences followed by inverted
      insertional translocation between the enlarged sister chromatids of the short arm
      of chromosome 15.

PMID- 8641685
TI  - Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor
      gene and schizophrenia.
AB  - We examined a Ser-9-Gly polymorphism in the dopamine D3 receptor gene for allelic
      association with schizophrenia in 133 patients currently treated with clozapine
      and 109 controls. Allele 1 (Ser-9) was significantly more frequent in the
      patients (69%) than in the controls (56%) (P = 0.004). The 1-1 genotype was more
      common (43% vs 30%) and the 2-2 genotype less common (5% vs 18%) in patients than
      in controls. When the patient group was subdivided on the basis of clinical
      response to clozapine, using a 20-point improvement in the global assessment
      scale as cut-off, genotype 1-1 was found to be more frequent among the non
      responders (53% vs 36%, P = 0.04). To place our results in the context of
      previous studies of this polymorphism and schizophrenia, we performed a meta
      analysis of all published data including the present sample. The combined
      analysis shows evidence for a modest association between genotype 1-1 and
      schizophrenia (odds ratio 1.25, 95% confidence interval 1.05-1.49, P = 0.01).
      These results suggest that the Ser-9 allele, or a nearby polymorphism in linkage
      disequilibrium, results in a small increase in susceptibility to schizophrenia.

PMID- 8641686
TI  - Localization of the human RGR opsin gene to chromosome 10q23.
AB  - The human RGR gene encodes an opsin protein (retinal G protein-coupled receptor),
      which is expressed in Muller cells and the retinal pigment epithelium and is
      thought to play a role in the visual process. To investigate a possible linkage
      of the RGR gene to retinal dystrophies, the locus of the gene was mapped on human
      metaphase chromosomes. Genomic and cDNA fragments of the human RGR gene were used
      as probes for fluorescence in situ hybridization. Analysis of the fluorescence
      signals on high-resolution banded chromosomes showed that the RGR gene is
      localized to human chromosome 10q23. This result now provides for the rapid
      analysis of this gene with respect to inherited diseases of the retina.

PMID- 8641687
TI  - Novel interleukin-1 receptor antagonist exon polymorphisms and their use in
      allele-specific mRNA assessment.
AB  - A variable number of tandem repeats (VNTR) polymorphism has been described in
      intron 2 of the interleukin-1 receptor antagonist gene. Allele 2 of this
      polymorphism is associated with many chronic inflammatory diseases. Using direct
      sequencing of polymerase chain reaction products from individuals of known
      genotype for the VNTR, we have identified four single base change polymorphisms
      in exons 1ic and 2 and one upstream of exon 1ic, all of which are probably in
      linkage disequilibrium with the intron 2 VNTR. The exonic polymorphisms do not
      alter the encoded amino acid sequence. Using the exon 2 polymorphism as a marker
      for the intron 2 disease-associated allele, we have been able to analyse allele
      specific mRNA in heterozygotic keratinocyte cell lines. The disease-associated
      allele shows no difference from other alleles in this cell type with respect to
      mRNA accumulation.

PMID- 8641688
TI  - Geographic distribution and origin of CFTR mutations in Germany.
AB  - The geographic distribution and origin of CFTR mutations in Germany was evaluated
      in 658 three-generation families with cystic fibrosis (CF). Fifty different
      mutations were detected on 1305 parental CF chromosomes from 22 European
      countries and overseas. The major mutation. delta F508 was identified on 71.5% of
      all CF chromosomes, followed by R553X (1.8%), N1303K (1.3%), G542X (1.1%), G551D
      (0.8%) and R347P (0.8%). According to the grandparents' birthplace, 74% of CF
      chromosomes had their origin in Germany; the delta F508 percentage was 77%, 75%,
      70% and 62% in northern, southern, western and eastern Germany, respectively. Ten
      or more mutant alleles in the investigated CF gene pool originated from Austria,
      the Czech Republic, Poland, Russia, Turkey and the Ukraine. This widespread
      geographic origin of CFTR mutations in today's Germany reflects the many
      demographic changes and migrations in Central Europe during the 20th century.

PMID- 8641689
TI  - Genetic mapping studies of 40 loci and 23 cosmids in chromosome 11p13-11q13, and
      exclusion of mu-calpain as the multiple endocrine neoplasia type 1 gene.
AB  - Forty loci (16 polymorphic and 24 non-polymorphic) together with 23 cosmids
      isolated from a chromosome 11-specific library were used to construct a detailed
      genetic map of 11p13-11q13. The map was constructed by using a panel of 13
      somatic cell hybrids that sub-divided this region into 19 intervals, a meiotic
      mapping panel of 33 multiple endocrine neoplasia type 1 (MEN1) families (134
      affected and 269 unaffected members) and a mitotic mapping panel that was used to
      identify loss of heterozygosity in 38 MEN1-associated tumours. The results
      defined the most likely order of the 16 loci as being: 11pter-D11S871-(D11S288,
      D11S149)-11cen-CNTF-PGA-ROM1-D11S480-PYGM- SEA-D11S913-D11S970-D11S97- D11S146
      INT2-D11S971-D11S533-11qter. The meiotic mapping studies indicated that the most
      likely location of the MEN1 gene was in the interval flanked by PYGM and D11S97,
      and the results of mitotic mapping suggested a possible location of the MEN1 gene
      telomeric to SEA. Mapping studies of the gene encoding mu-calpain (CAPN1) located
      CAPN1 to 11q13 and in the vicinity of the MEN1 locus. However, mutational
      analysis studies did not detect any germ-line CAPN1 DNA sequence abnormalities in
      47 unrelated MEN1 patients and the results therefore exclude CAPN1 as the MEN1
      gene. The detailed genetic map that has been constructed of the 11p13-11q13
      region should facilitate the construction of a physical map and the
      identification of candidate genes for disease loci mapped to this region.

PMID- 8641690
TI  - EagI and NotI linking clones from human chromosomes 11 and Xp.
AB  - EagI and NotI linking libraries were prepared in the lambda vector, EMBL5, from
      the mouse-human somatic cell hybrid 1W1LA4.9, which contains human chromosomes 11
      and Xp as the only human component. Individual clones containing human DNA were
      isolated by their ability to hybridise with total human DNA and digested with
      SalI and EcoRI to identify the human insert size and single-copy fragments. The
      mean (+/- SD) insert sizes of the EagI and NotI clones were 18.3 +/- 3.2 kb and
      16.6 +/- 3.6 kb, respectively. Regional localisation of 66 clones (52 EagI, 14
      NotI) was achieved using a panel of 20 somatic cell hybrids that contained
      different overlapping deletions of chromosomes 11 or Xp. Thirty-nine clones (36
      EagI, 3 NotI) were localised to chromosome 11; 17 of these were clustered in
      11q13 and another nine were clustered in 11q14-q23.1. Twenty-seven clones (16
      EagI, 11 NotI) were localised to Xp and 10 of these were clustered in Xp11. The
      66 clones were assessed for seven different microsatellite repetitive sequences;
      restriction fragment length polymorphisms for five clones from 11q13 were also
      identified. These EagI and NotI clones, which supplement those previously mapped
      to chromosome 11 and Xp, should facilitate the generation of more detailed maps
      and the identification of genes that are associated with CpG-rich islands.

PMID- 8641692
TI  - Hereditary ceruloplasmin deficiency with hemosiderosis.
AB  - Hereditary ceruloplasmin deficiency with hemosiderosis (aceruloplasminemia) is a
      new disease characterized by systemic hemosiderosis, diabetes mellitus,
      neurological abnormalities and pigment degeneration of the retina. Loss of the
      ferroxidase activity of ceruloplasmin results in systemic iron deposition and
      tissue damage. Neuroimaging studies reveal iron deposition in basal ganglia and
      in the red and dentate nuclei. Cerebellar ataxia, extrapyramidal signs and
      dementia develop after middle age. We report a patient with undetectable serum
      ceruloplasmin levels and the above clinical manifestations. Sequence analysis of
      the cDNA of ceruloplasmin from this patient revealed an insertion of adenine in
      exon 3; this produced a premature stop codon.

PMID- 8641691
TI  - Accelerated loss of telomeric repeats may not explain accelerated replicative
      decline of Werner syndrome cells.
AB  - The Werner syndrome (WS) is characterized by the premature onset and accelerated
      rate of development of major geriatric disorders, including atherosclerosis,
      diabetes mellitus, osteoporosis, ocular cataracts, and various neoplasms.
      Cultures of WS skin-fibroblastlike cells have been previously shown to undergo
      accelerated rates of decline of the replicative potentials and to exhibit
      variegated chromosomal translocations and deletions. Since the replicative
      decline of normal somatic cells is associated with a loss of telomeric repeats,
      we investigated the kinetics of telomeric repeat loss in WS cells. The mean
      length of telomere restriction fragments (TRF) from the earliest passages of WS
      cells studied was not shorter than those of controls, possibly reflecting
      selective pressure for subsets of cells with relatively high residual replicative
      capacity. Statistical evidence indicated an accelerated shortening of TRF length
      in serially passaged WS cultures, but the mean TRF lengths of WS cultures that
      had ceased replicating were significantly longer than those of senescent
      controls. Thus, while accelerated loss of telomeric repeats could potentially
      explain the rapid decline in proliferation of WS cells, it is possible that WS
      cells exit the cell cycle via mechanisms that differ from those of replicatively
      senescent cells from control subjects.

PMID- 8641694
TI  - Isolation of the human chromosome 22q telomere and its application to detection
      of cryptic chromosomal abnormalities.
AB  - A number of human telomeres have been successfully cloned using a modified yeast
      artificial chromosome (YAC) vector (half-YAC) cloning strategy, but to date,
      human chromosome 22q has not been identified by this approach. We used an
      alternative approach of genomic walking, starting from a subtelomeric sequence,
      Tel-Bam3.4. present on a number of human chromosomes including 22q. This approach
      was successful in the development of a cosmid contig representing the terminal
      140 kb of human chromosome 22q, providing telomeric closure of the genetic and
      physical maps for 22q. The most distal region of the contig contains subtelomeric
      repeats which crosshybridize to a number of chromosomes, while the proximal
      sequences are unique for 22q. The unique sequence cosmid was used as a 22qter
      specific probe for fluorescence in situ hybridization (FISH) analysis, which
      confirmed that this cosmid was distal to the most telomeric marker previously
      available for chromosome 22. In addition, this cosmid was used to document a 22q
      terminal deletion that was not detectable by conventional cytogenetic analysis.
      Unique telomere-specific FISH probes such as this one will have significant
      diagnostic value in the detection of cryptic deletions and translocations in
      patients with unexplained mental retardation and other patient populations.

PMID- 8641693
TI  - Distribution and frequency of a polymorphic Alu insertion at the plasminogen
      activator locus in humans.
AB  - We have investigated the frequency distribution, across a broad range of
      geographically dispersed populations, of alleles of the polymorphic Alu insertion
      that occurs within the 8th intron of the tissue plasminogen, activator gene
      (PLAT). This Alu is a member of a recently derived subfamily of Alu elements that
      has been expanding during human evolution and continues to be transpositionally
      active. We used a "population tube" approach to screen 10 chromosomes from each
      of 19 human populations for presence or absence of this Alu in the PLAT locus and
      found that all tested populations are dimorphic for presence/absence of this
      insertion. We show that the previously published EcoRI, HincII, PstI, TaqI, and
      XmnI polymorphisms at the PLAT locus all result from insertion of this Alu and we
      use both restriction fragment length polymorphism and polymerase chain reaction
      analysis to examine the frequency of Alu(+) and Alu(-) alleles in a sample of
      1003 individuals from 27 human populations and in 38 nonhuman primates. Nonhuman
      primates are monomorphic for the Alu(-) allele. Human populations differ
      substantially in allele frequency, and in several populations both alleles are
      common. Our results date the insertion event prior to the spread and
      diversification of modern humans.

PMID- 8641695
TI  - Detection of a germline mutation and somatic homozygous loss of the von Hippel
      Lindau tumor-suppressor gene in a family with a de novo mutation. A combined
      genetic study, including cytogenetics, PCR/SSCP, FISH, and CGH.
AB  - von Hippel-Lindau (VHL) disease is a pleiotropic disorder featuring a variety of
      malignant and benign tumors of the eye, central nervous system, kidney, and
      adrenal gland. Recently the VHL gene has been identified in the chromosomal
      region 3p25-26. Prognosis and successful management of VHL patients and their
      descendants depend on unambiguous diagnosis. Due to recurrent hemangioblastomas,
      a29-year-old patient without familial history of VHL disease was diagnosed to be
      at risk for the disease. Histopathological examination of a small renal mass
      identified a clear cell tumor with a G1 grading. Genetic characterization of the
      germline and of the renal tumor was performed. Polymerase chain reaction/single
      strand conformation polymorphism (PCR/SSCP) analysis with primers from the VHL
      gene identified a deletion of a single nucleotide in exon 2 in the patient's
      germline and in the tumor, but not in the DNA of his parents. This deletion
      therefore must be a de novo mutation. Comparative genome hybridization (CGH) and
      fluorescence in situ hybridization (FISH) analysis of the G1 tumor with
      differentially labelled yeast artifical chromosome (YAC) clones showed loss of 3p
      and of the 3p26 signals, respectively. In conclusion, we identified a de novo
      germline mutation in the VHL gene of a young patient and a somatic chromosome 3p
      loss at the homologous chromosome 3 in his renal tumor. Our results suggest a
      recessive mode of inactivation of the VHL gene, providing solid evidence for its
      tumor-suppressor gene characteristics. Our data show the diagnostic potential of
      genetic testing, especially in patients without VHL family history. Furthermore,
      the findings of homozygous inactivation of the VHL gene in a G1 tumor support the
      notion that the inactivation of the VHL gene is an early event in tumorigenesis
      of renal cell carcinoma.

PMID- 8641696
TI  - Extensive polymorphism of ABO blood group gene: three major lineages of the
      alleles for the common ABO phenotypes.
AB  - Polymorphism of the ABO blood group gene was investigated in 262 healthy Japanese
      donors by a polymerase chain reactions-single-strand conformation polymorphism
      (PCR-SSCP) method, and 13 different alleles were identified. The number of
      alleles identified in each group was 4 for A1 (provisionally called ABO*A101,
      *A102, *A103 and *A104 according to the guidelines for human gene nomenclature),
      3 for B (ABO*B101, *B102 and *B103), and 6 for O (ABO*O101, *O102, *O103, *O201,
      *O202 and *O203). Nucleotide sequences of the amplified fragments with different
      SSCP patterns were determined by direct sequencing. Phylogenetic network analysis
      revealed that these alleles could be classified into three major lineages,
      *A/*O1, *B and *O2. In Japanese, *A102 and *B101 were the predominant alleles
      with frequencies of 83% and 97% in each group, respectively, whereas in group O,
      two common alleles, *O101 (43%) and *O201 (53%), were observed. These results may
      be useful for the establishment of ABO genotyping, and these newly described ABO
      alleles would be advantageous indicators for population studies.

PMID- 8641698
TI  - Localization of the human vascular endothelial growth factor gene, VEGF, at
      chromosome 6p12.
AB  - Using overlapping cosmids representing the vascular endothelial growth factor
      (VEGF) locus, the VEGF gene was mapped by fluorescence in situ hybridization to
      chromosome 6p12. This localization permits linkage analysis and the
      identification of gene interaction in the region, as well as alterations of the
      VEGF structure or expression in cancer cells with chromosome abnormalities.

PMID- 8641697
TI  - Routine screening for microdeletions by FISH in 77 patients suspected of having
      Prader-Willi or Angelman syndromes using YAC clone 273A2 (D15S10).
AB  - About 70% of patients with Prader-Willi syndrome (PWS) and Angelman syndrome (AS)
      have a common interstitial de novo microdeletion encompassing paternal (PWS) or
      maternal (AS) loci D15S9 to D15S12. Most of the non-deletion PWS patients and a
      small number of non-deletion AS patients have a maternal or paternal uniparental
      disomy (UPD) 15, respectively. Other chromosome 15 rearrangements and a few
      smaller atypical deletions, some of the latter being associated with an abnormal
      methylation pattern, are rarely found. Molecular and fluorescence in situ
      hybridization (FISH) analysis have both been used to diagnose PWS and AS. Here,
      we have evaluated, in a typical routine cytogenetic laboratory setting, the
      efficiency of a diagnostic strategy that starts with a FISH deletion assay using
      Alu-PCR (polymerase chain reaction)-amplified D15S10-positive yeast artificial
      chromosome (YAC) 273A2. We performed FISH in 77 patients suspected of having PWS
      (n = 66) or AS (n = 11) and compared the results with those from classical
      cytogenetics and wherever possible with those from DNA analysis. A FISH deletion
      was found in 16/66 patients from the PWS group and in 3/11 patients from the AS
      group. One example of a centromere 15 co-hybridization performed in order to
      exclude cryptic translocations or inversions is given. Of the PWS patients, 14
      fulfilled Holm's criteria, but two did not. DNA analysis confirmed the common
      deletion in all patients screened by the D15S63 methylation test and in
      restriction fragment length polymorphism dosage blots. In 3/58 non-deletion
      patients, other chromosomal aberrations were found. Of the non-deleted group, 27
      subjects (24 PWS, 3 AS) were tested molecularly, and three patients with an
      uniparental methylation pattern were found in the PWS group. The other 24/27
      subjects had neither a FISH deletion nor uniparental methylation, but two had
      other cytogenetic aberrations. Given that cytogenetic analysis is indispensable
      in most patients, we find that the FISH deletion assay with YAC 273A2 is an
      efficient first step for stepwise diagnostic testing and mutation-type analysis
      of patients suspected of having PWS or AS.

PMID- 8641699
TI  - Evidence of genetic heterogeneity of Leber's congenital amaurosis (LCA) and
      mapping of LCA1 to chromosome 17p13.
AB  - Leber's congenital amaurosis (LCA) is an autosomal recessive disease responsible
      for congenital blindness. It is the earliest and most severe inherited retinal
      dystrophy in human and its genetic heterogeneity has long been recognised. We
      have recently reported on the first localisation of a disease gene (LCA1) to the
      short arm of chromosome 17 by homozygosity mapping in five families of North
      African origin. Here, we refine the genetic mapping of LCA1 to chromosome 17p13
      between loci D17S938 and D17S1353 and provide strong support for the genetic
      heterogeneity of this condition (maximum likelihood for heterogeneity, 17.20 in
      InL; heterogeneity versus homogeneity, P = 0.0002, heterogeneity versus no
      linkage, P < 0.0001)

PMID- 8641700
TI  - Familial double pericentric inversion of chromosome 5 with some features of cri
      du-chat syndrome.
AB  - Fluorescence in situ hybridization analysis was performed to characterize a
      complex pericentric inversion involving chromosome 5 in a mother and son. The
      mother had hypertelorism, epicanthal folds, and mild mental deficiency while the
      son had additional anomalies that have been observed in patients with cri-du-chat
      syndrome. Both individuals were found to have an identical double pericentric
      inversion [inv5(p15.1q31(inv5(p14q12)))]. Neither inversion breakpoint mapped
      near the chromosomal regions implicated in the cri-du-chat syndrome. The
      phenotype of the son suggests that the inversion process may have affected the
      expression of some of the cri-du-chat syndrome genes, suggestive of a genomic
      imprinting or penetrance effect.

PMID- 8641701
TI  - A PCR-based test suitable for screening for fragile X syndrome among mentally
      retarded males.
AB  - Ever since the identification of the genetic cause of fragile X syndrome as the
      expansion of an unstable trinucleotide sequence, several diagnostic strategies
      have evolved from molecular studies. However, we still lack a simple test
      suitable for population screening. We have therefore developed a nonisotopic
      polymerase chain reaction (PCR)-based technique for the identification of fragile
      X full mutations among men, with easy visualization of the PCR products on silver
      stained polyacrylamide gels. The technique consists of PCR amplification with
      primers that flank the trinucleotide repeats, with a product of 557 bp for the
      (CGG)29 allele. Conditions were established such that full mutations failed to
      amplify and were thus identified with 98% sensitivity compared with Southern blot
      analysis. To produce an indispensable internal control we added to the reaction a
      third primer, internal to this fragment, allowing the multiplex amplification of
      a monomorphic band corresponding to a CG-rich stretch 147 bp upstream of the
      polymorphic region. In trials involving 41 patients and 74 controls, the PCR
      based test here described showed specificity of more than 98.6%, accuracy of 99%
      and a sensitivity of 98%. Thus, although not suitable for medical diagnosis, it
      constitutes a useful tool for screening for the fragile X syndrome in populations
      of mentally retarded males.

PMID- 8641702
TI  - Allele-specific quantification of TNFA transcripts in rheumatoid arthritis.
AB  - Clinical and laboratory studies have suggested a pivotal role for tumor necrosis
      factor alpha (TNFA) in the pathogenesis of rheumatoid arthritis (RA).
      Interindividual variation in the expression of TNFA indicates the existence of
      functionally distinct TNFA alleles that could play a role in susceptibility to
      TNFA-associated diseases such as RA. In order to determine whether differential
      TNFA gene expression is present in RA, we studied the relative contribution of
      TNFA alleles to the total amount of steady-state mRNA in peripheral blood
      mononuclear cells of RA patients and healthy individuals. Moreover, allelic TNFA
      mRNA expression was analyzed in synovial biopsy material of RA patients. For this
      purpose, we used the recently identified C-insertion polymorphism located in the
      5' untranslated region of the first exon. The location of this polymorphism
      within a part of the gene that is transcribed into mRNA allowed us to
      discriminate between the contribution of each allele to the total amount of TNFA
      mRNA in heterozygous individuals. The results of this study do not indicate the
      existence of variation at the level of mRNA transcribed from each TNFA allele by
      in vitro and physiological stimulation conditions in RA patients. Therefore, our
      data do not suggest a role for transcriptionally distinct TNFA alleles in the
      susceptibility to RA.

PMID- 8641703
TI  - The effect of Y-chromosome alpha-satellite array length on the rate of sex
      chromosome disomy in human sperm.
AB  - Trisomy is the leading known cause of mental retardation and pregnancy loss in
      humans, yet virtually nothing is known of the underlying nondisjunctional
      mechanisms. Since studies of other organisms suggest an association between
      centromere size or sequence and meiotic nondisjunction, we recently initiated
      studies to examine the effect of centromere size variation on human
      nondisjunction. In the present report, we summarize studies correlating variation
      in the size of the Y-chromosome centromere with sex chromosome nondisjunction. In
      one set of studies, we used pulsed-field gel electrophoresis to estimate Y
      chromosome alpha-satellite array lengths in normal males, and correlated these
      values with Y-chromosome sperm disomy levels as determined by fluorescence in
      situ hybridization. In a second set of studies, we determined the Y-chromosome
      alpha-satellite array length of 47,XYY males, since the karyotypes of these
      individuals are a consequence of Y chromosome nondisjunction. Neither set of
      studies provided evidence for an effect of Y-chromosome alpha-satellite array
      length on Y-chromosome nondisjunction. Thus, if there is an association between Y
      chromosome centromere size and nondisjunction, the effect is subtle and below the
      detection levels of the present study or involves extreme size variants that were
      not represented in the present study population.

PMID- 8641704
TI  - A family segregating a Friedreich ataxia phenotype that is not linked to the FRDA
      locus.
AB  - Friedreich ataxia is an autosomal recessive neurodegenerative disorder. The
      genetic homogeneity to the FRDA locus on chromosome 9q13-21.1 has been observed
      in families from different ancestries. We report a Spanish family with two
      affected and three unaffected children. The segregated classical Friedreich
      ataxia did not show the expected linkage. The analysis focusses on flanking
      markers FR1, FR2, FR7 and FR5, excluding linkage 1 cM around the FRDA locus. The
      unique clinical hallmark in this family was the absence of cardiomyopathy after a
      long-term follow-up in the two affected children. In both patients serum vitamin
      E levels were normal. The present observations support the existence of a second
      locus in Friedreich ataxia, and we suggest that this form could be clinically
      characterized by the absence of muscular heart disease.

PMID- 8641706
TI  - Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel
      tumour suppressor gene locus.
AB  - Neuroblastoma is a childhood neural crest tumour, genetically characterized by
      frequent deletions of the short arm of chromosome 1 and amplification of N-myc.
      Here we report the first evidence for a neuroblastoma tumour suppressor locus on
      4pter. Cytogenetically we demonstrated rearrangements of 4p in 7 out of 26
      evaluable tumours (27%). Subsequent analysis of loss of heterozygosity (LOH) by
      Southern blotting revealed allelic loss of 4p in 16/82 (19.5%) informative
      neuroblastomas. Taken together cytogenetic and Southern blot analyses showed loss
      of 4p in 20/86 neuroblastomas analysed (23%). The common deleted region was
      bordered by the probe D4S123 and encompassed the distal 34 cM of 4p. We found no
      evidence for genomic imprinting of the 4p locus as the 4p alleles lost in the
      tumours were of random maternal and paternal origin. LOH4p was found at all
      disease stages and in every age group. Furthermore LOH4p was present both in
      cases with and without LOH1p and amplification of N-myc.

PMID- 8641705
TI  - Hb Costa Rica or alpha 2 beta 2 77(EF1)His --> Arg: the first example of a
      somatic cell mutation in a globin gene.
AB  - We have identified a minor hemoglobin component (approximately 5%) in the blood
      of a healthy Costa Rican female, but not in her mother and two brothers (father
      not studied), that has an His --> Arg replacement at position beta 77 (Hb Costa
      Rica). No other amino acid replacements were observed and no beta- or gamma-chain
      like peptides were present. Hb Costa Rica has abnormal stability. Sequence
      analyses of numerous polymerase chain reaction (PCR)-amplified segments of DNA
      that contain exon 2 of the beta gene failed to identify a CAC --> CGC (His -->
      Arg) mutation. The same was the case when cDNA was sequenced, indicating that a
      beta-Costa Rica-mRNA could not be detected with this procedure. Gene mapping of
      genomic DNA with Bg/II, BamHI, and HindIII gave normal fragments only and with
      the same intensity as observed for the fragments of a normal control. The
      quantities of the beta chain variants Hb J-Iran and Hb Fukuyama with related
      mutations at beta 77 vary between 30% and 45% in heterozygotes, whereas that of
      Hb F-Kennestone with the same His --> Arg mutation but in the G gamma-globin
      gene, is a high 40%-45% (as percentage of total G gamma) in a heterozygous
      newborn. These different observations exclude a heterozygosity of the A --> G
      mutation at codon beta 77, as well as a deletion comparable to that of Hbs Lepore
      or Kenya, or a beta-globin gene duplication, and point to a nontraditional
      inheritance of Hb Costa Rica. Allele-specific amplification of cDNA with
      appropriate primers identified the presence of a low level of mutated mRNA in the
      reticulocytes of the patient, which was confirmed by dotblot analysis of the same
      material with 32P-labeled probes. Comparable amplification products were not
      observed in genomic DNA. The A --> G mutation apparently occurred in a somatic
      cell at a relatively early stage in the development of the hematopoietic cell
      system, and Hb Costa Rica accumulated through rapid cell divisions in patchy
      areas in the bone marrow (somatic mosaicism). An unequal distribution of Hb Costa
      Rica over the red cells supports this possibility.

PMID- 8641708
TI  - Six new polymorphic microsatellite markers used for the integration of genetic
      and physical maps of human chromosome 7.
AB  - We report the isolation and characterization of six new polymorphic dinucleotide
      repeat microsatellite markers (D7S1491, D7S1492, D7S1493, D7S1494, D7S1495, and
      D7S1496), their integration into the genetic map of human chromosome 7 by
      analysis of 40 CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees, and their
      use for integration of physical and genetic maps of this chromosome.

PMID- 8641707
TI  - A novel 5'-upstream mutation in the factor XII gene is associated with a TaqI
      restriction site in an Alu repeat in factor XII-deficient patients.
AB  - The factor XII gene from factor XII-deficient patients was screened for mutations
      at the genomic level. In patients negative for cross-reacting material, a T to C
      transition 224 bp upstream of exon 3 was identified (exon 3-224 (T --> C)) that
      creates an additional TaqI restriction site in intron B. This mutation is located
      within a putative hormone responsive element and within a B box promoter of an
      Alu repeat of the Sb0 family. The TaqI site is associated with a G to C
      transversion upstream of the transcription initiation site (exon 1-8 (G --> C)).
      We discuss the possible roles of these elements in factor XII gene regulation.

PMID- 8641709
TI  - Cell surface hydrophobicity and its relation to outer membrane proteins of
      Serratia marcescens.
AB  - Cell surface hydrophobicity measurement of S. marcescens and its two mutants, one
      having capacity of overproducing the red pigment prodigiosin, while another
      carrying no pigment, showed that the hydrophobicity, which always increased with
      ageing of the cells, was not totally due to the pigment present on the surface.
      The mutant having no pigment always exhibited higher hydrophobicity than that of
      two pigmented cells, irrespective of whether the experimented cells were of early
      log phase or static phase. The outer membrane proteins were isolated and
      characterized by SDS-polyacrylamide gel. The non-pigmented cell outer membrane
      showed an extra band of protein (approximately 40 K Da molecular weight) besides
      the other bands common to those of other two pigmented cells. This extra protein
      of outer membrane may be responsible for higher surface hydrophobicity of non
      pigmented mutant of S. marcescens.

PMID- 8641710
TI  - Effect of haloperidol on phospholipid biosynthesis in rat brain.
AB  - Haloperidol, a butyrophenone used in the treatment of various psychoses has been
      clinically used and studied extensively. At the molecular level it is known to
      preferentially block D2 type of dopamine receptors but its other effects are
      unknown. We studied the effect of this drug on phospholipid biosynthesis in vitro
      by following incorporation of 32P into individual classes of phospholipids. It
      was observed that haloperidol inhibits the biosynthesis of almost all major
      phospholipids including phosphatidyl inositol at fairly low concentrations. It
      cannot be concluded from the present experiment which step the inhibition may be
      taking place but acyl transfer reaction is likely to be involved because the drug
      effects almost all the phospholipids. It is suggested that long-term use of the
      drug can effect the organization of synaptic membrane.

PMID- 8641711
TI  - Effect of graded doses of methysergide on basal and pentagastrin stimulated
      gastric secretion in anaesthetised rats.
AB  - The effect of continuous infusion (iv) of graded doses of methysergide (0.1-50
      microgram(s)/kg/hr) was studied on basal and pentagastrin (5 microgram(s)/kg/hr)
      stimulated gastric acid secretion in anaesthetised rats by the slow, continuous
      stomach perfusion method. Both basal and pentagastrin stimulated acid secretion
      indicated a biphasic response. Methysergide induced stimulation at a lower dose
      of 1 microgram(s)/kg/hr and inhibition at higher doses of 20-50
      microgram(s)/kg/hr. The stimulatory effect may be due to postsynaptic receptor
      blockade while the inhibitory effect at higher dose may be due to blockade of
      presynaptic 5-HT autoreceptors, or due to a direct inhibitory effect of unknown
      basis.

PMID- 8641712
TI  - Effect of prenatal undernutrition and phenobarbitone administration on
      discrimination learning and passive avoidance behaviour in rats.
AB  - Effects of prenatal undernutrition and phenobarbitone administration,
      individually and conjointly, was assessed on learning acquisition and subsequent
      retention of a black/white discrimination task and passive avoidance behaviour in
      rats. Undernutrition of the dams was induced by restricting food intake to half,
      throughout the period of gestation, whereas phenobarbitone sodium (2.5 mg/kg, ip)
      treatment was given from day 13 to 20 of gestation, this being the critical
      period for neural development in rats. The pups were subjected to brightness
      discrimination learning, retention of the learning acquisition in a single unit
      black/white T-maze and passive avoidance behaviour test at 8-9 weeks of age. The
      results indicate that prenatal undernutrition induces significant discrimination
      learning and retention deficits in the offsprings. Prenatal phenobarbitone
      treatment also caused significant learning acquisition and retention deficits in
      the discrimination test. Phenobarbitone augmented the learning and retention
      deficits induced by undernutrition. However, both prenatal undernutrition and
      phenobarbitone treatments did not affect the retention of the learned passive
      avoidance. The results indicate that the prenatal interference in the form of
      undernourishment and anticonvulsant barbiturates, may induce functional deficits
      resulting in perturbed cognition in the offsprings.

PMID- 8641713
TI  - Altered biological distribution and decreased neuromuscular toxicity of niosome
      encapsulated vincristine.
AB  - Effects of encapsulation within niosomes (nonionic surfactant vesicles) on the
      biological distribution and toxicity of vincristine-a widely used anticancer drug
      have been investigated. Plasma kinetics, tissue distribution profile and
      neuromuscular toxicity of niosomal vincristine (NVCR) were compared with those of
      free vincristine (FVCR). NVCR was cleared from the plasma much more slowly
      [t1/2(beta) = 1.388 hr] than FVCR [t1/2(beta) = 0.74 hr]. Over the 48 hr period
      of experiment, the niosome formulation delivered significantly more drug to the
      plasma compartment than FVCR and resulted in reduced accumulation of drug in gut
      and skeletal muscle. Encapsulation caused a marked alteration in the tissue
      disposition of the drug. NVCR was less toxic both in terms of mortality and
      morbidity. Importantly, histopathological studies of skeletal muscle, spinal cord
      and sciatic nerve of NVCR treated albino wistar rats demonstrated the less toxic
      potential of encapsulated vincristine. Further, the biochemical studies,
      estimation of enzymes plasma creatine phosphokinase and lactate dehydrogenase,
      confirmed the safety profile of NVCR. The decreased partitioning of NVCR to non
      active sites resulted in a significant amelioration of the toxic side effects,
      gastrointestinal and myological in particular, of the drug. The results indicate
      that the delivery of vincristine by encapsulating it in niosomes offer an
      efficient means of decreasing its toxic effects.

PMID- 8641714
TI  - Influence of components of oral contraceptive on lipid metabolism.
AB  - Oral contraceptives (OC) have been shown to enhance the risk of atherosclerosis.
      In the present study we sought to determine which component of the OC (containing
      0.067 mg estrogen and 0.667 mg of progestin) counts for alteration in lipids
      profile. Female rats were administered with 0.067 mg of 17 beta-estradiol and
      0.667 mg of norethindron acetate/kg body weight. Estrogen treatment exhibited
      higher levels of lipids in the serum and tissues. LDL-cholesterol increased by
      three folds but HDL-cholesterol decreased significantly, while progestin group
      showed decreased levels of lipids and LDL cholesterol. Elevated hepatic
      cholesterogenesis was observed as indicated by increased activity of HMG-CoA
      reductase and elevated incorporation of labelled acetate into liver cholesterol
      in estrogen group. On the other hand, progestin treatment did not alter the
      activity of HMG-CoA reductase and the rate of incorporation of labelled acetate
      into hepatic cholesterol. Hepatic degradation of cholesterol to bile acids
      however, decreased with estrogen treatment. No considerable changes were observed
      in hepatic bile acid levels in progestin group. Release of lipoprotein into
      circulation increased but their clearance from the circulation decreased as
      revealed by the activity of lipoprotein lipase (LPL) of extrahepatic tissues in
      estrogen group. With progestin treatment, activity of LPL increased significantly
      in adipose tissue. Activity of hepatic malic enzyme and glucose 6-phosphate
      dehydrogenase enhanced considerably in estrogen group, while activities of these
      enzymes were depressed with progestin administration. Thus results indicate that
      estrogen component of oral pills counts for major changes in lipid and
      lipoprotein metabolism favouring the development of atherosclerosis.

PMID- 8641715
TI  - Establishment of a cell line from Indian bonnet monkey (Macaca radiata) kidney
      and its characterization.
AB  - A cell line (MRK-90) has been established from a kidney tissue of a macaque
      monkey (Macaca radiata) of India. The cells are in 150th passage and have been
      characterized for morphology, chromosome number, isoenzyme patterns (LDH and MDH)
      and virus susceptibility. These studies indicate that the cells are epithelial
      like, heteroploid (2n = 65) and grow easily on glass surface/plastic surface
      without any difficulty. The cells are susceptible to a broad spectrum of viruses.

PMID- 8641716
TI  - Histochemical changes in host tissues from Plasmodium cynomolgi B infected rhesus
      monkey (Macaca mulatta).
AB  - Plasmodium cynomolgi B has been used to infect the rhesus monkey to study the
      histochemical changes (lipid infiltration, glycogen, protein, DNA and RNA) in
      liver, kidney and spleen during early (exoerythrocytic) and late (chronic) stages
      of malarial infection. Infected liver showed significant lipid infiltration
      during exoerythrocytic and erythrocytic (acute phase) stage of infection. Kidney
      showed lipid deposition during acute phase of infection while spleen sections
      were negative for lipid depositions. As a result of malarial infection there was
      significant depletion of glycogen in liver during exoerythrocytic stage of
      infection. Glycogen content increased in liver and kidney during erythrocytic
      stage of infection. The spleen which is the main target of immunopathology in
      malaria showed no change in glycogen content. During exoerythrocytic phase host
      tissue organs showed no change in protein and nucleic acids while erythrocytic
      phase showed slightly increased proteins in liver and kidney. Nucleic acids
      became decreased in liver and spleen during erythrocytic phase of infection. The
      parasite used in this study has a defined prepatent period, can be cyclically
      passaged with ease and non fatal in nature.

PMID- 8641717
TI  - Transdermal administration of insulin: effect of various penetration enhancers.

PMID- 8641718
TI  - Status of gastric mucosal protective factors in dyspepsia.

PMID- 8641719
TI  - Protective effects of few antioxidants on liver function in rats treated with
      cadmium and mercury.

PMID- 8641720
TI  - Antibodies to serum IgA detected by ELISA in duodenal ulcer and their
      relationship to chronicity of the disease.

PMID- 8641721
TI  - Angiotensin II--receptor subtypes characterization and pathophysiological
      implications.
AB  - In the past decade there have been considerable advances in basic knowledge of
      the renin-angiotensin system (RAS). The most important new development has been
      the appreciation of a tissue based RAS that can be independently regulated from
      the renal and vascular RAS. Greater insight into the mechanism by which
      angiotension-II (AII) exerts its action has been achieved through the study of
      molecular biology and pharmacological characterization of multiple receptor
      subtypes. This review summarises the features and distribution of several binding
      subtypes that may mediate the diverse functions of AII. Of these AT1 subtype is
      the most well known receptor which preferentially binds AII and AIII. The AT1
      receptor site appears to mediate the classic angiotensin responses concerned with
      the body water balance and the maintenance of blood pressure. Less is known about
      the AT2 sites which also bind AII and AIII and may play a role in vascular
      growth. Recently, an AT3 has been discovered in cultured neuroblastoma cells and
      an AT4 site which preferentially binds AIV. It has been implicated in memory
      aquisition and retrieval and in the regulation of blood flow. Another important
      aspect covered is the primary and secondary messengers involved during the signal
      transduction after the binding of AII with receptors. A stress has also been
      given on the regulation of density and affinity of AII receptors by various
      physiological parametres as they affect the responses of RAS. Autoregulation by
      RAS, salt intake, development and aging and some of the hormones are important
      variables which could affect the AII receptors. Interactions of AII with various
      neuroeffector transmission involved in the regulation of water-electrolyte
      balance and BP regulation play an important role in the maintenance of the
      homeostasis. AII has been suggested to increase the NAergic transmission by
      enhancing synthesis, release, inhibiting reuptake by the presynaptic nerve
      terminals as well as enhancing cell responsiveness to the transmitter. The
      finding of existence of AII receptors in vagal afferent nerve terminals suggests
      that its baroreflex inhibitory effect is mediated by inhibiting neurotransmitter
      release at NTS in the baroreflex arc. Moreover, AII acts on the central receptors
      to stimulate AVP and ACTH secretion, drinking and peripherally increase synthesis
      and secretion of aldosterone. Interactions of RAS with kallikrein-kinin system
      and prostaglandins strongly support the existence of a balance between renal
      depressor and pressor substances. AII is now considered a growth promotor in
      cardiovascular tissues and the resultant vascular hypertrophy could contribute in
      the maintenance of hypertension. AII also plays a role in the kidney, not only as
      a regulator of hemodynamics but also in the structural changes occurring in a
      variety of renal disorders. In addition to the more well studied functions of RAS
      in RVH the review also highlights the potential contribution by the RAS to other
      clinically relevant syndromes such as aortoarterities induced RVH,
      hyperaldosteronism, heavy metal induced cardiovascular effects, diabetes mellitus
      and thyroid dysfunction. Although the receptor subtypes involved in these
      pathological states have not been definitely identified, research efforts in this
      direction are ongoing.

PMID- 8641722
TI  - Antimutagenic effects of polyphenols isolated from Terminalia bellerica myroblan
      in Salmonella typhimurium.
AB  - Antimutagenic effect of 2 polyphenolic fractions isolated from T. bellerica in
      TA98 and TA100 strains of S. typhimurium against 2AF, NPD and 4NQNO has been
      characterized. Both the fractions were significantly effective against S9
      dependent 2AF; less effective against NPD and almost not effective against 4NQNO
      in TA100 strain. Using 13C-NMR spectral analysis, the TB-3 fraction, which was
      significantly more effective against 2AF compared to TB-4, was found to be a
      mixture of 3 tannins while TB-4 was non-tannin fraction. Interaction of
      polyphenols with S9 proteins may be the probable cause of inhibitory effect of
      these polyphenols, though the possibility of other mechanisms cannot be ruled
      out.

PMID- 8641723
TI  - Apparent mineralocorticoid excess: genotype is correlated with biochemical
      phenotype.
AB  - The syndrome of apparent mineralocorticoid excess is a form of hypertension
      inherited in an autosomal recessive manner. This disorder results from mutations
      in the HSD11K (HSD11B2) gene, which encodes the kidney isozyme of 11beta
      hydroxysteroid dehydrogenase. This enzyme converts active glucocorticoids such as
      cortisol and corticosterone to their inactive metabolites cortisone and 11
      dehydrocorticosterone. An elevated ratio of cortisol to cortisone metabolites in
      the urine (tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone
      [(THF+aTHF)/THE]) is considered pathognomic for this disorder. To determine
      whether the biochemical phenotype of this disorder is correlated with genotype,
      we expressed enzymes carrying each of the six known missense mutations in
      cultured cells. Only one mutant, R337C, had detectable activity in cell lysates,
      but five of six mutants were partially active in whole cells. Apparent kinetic
      constants for cortisol and corticosterone were determined in whole cells, and the
      apparent first-order rate constant, Vmax/Km, was used as a measure of enzymatic
      activity. The urinary (THF+aTHF)/THE ratio in patients carrying each mutation was
      strongly correlated with in vitro enzymatic activity of the corresponding mutant
      (r=.839, P=.001 with cortisol as the substrate). We conclude that the biochemical
      phenotype of the syndrome of apparent mineralocorticoid excess is largely
      determined by genotype.

PMID- 8641724
TI  - Inhibition of 11-beta-hydroxysteroid dehydrogenase in pregnant rats and the
      programming of blood pressure in the offspring.
AB  - Recent epidemiological studies have linked low birth weight with the later
      occurrence of cardiovascular and metabolic disorders, particularly hypertension.
      We have proposed that fetal exposure to excess maternal glucocorticoids may
      underpin this association. Normally, the fetus is protected from maternal
      glucocorticoids by placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD). We
      have previously shown that treatment of pregnant rats with dexamethasone, a
      synthetic glucocorticoid that is poorly metabolized by the enzyme, reduces birth
      weight and produces elevated blood pressure in the adult offspring. Moreover, low
      activity of placental 11beta-HSD correlates with low birth weight in rats. Here,
      we show that maternal administration of carbenoxolone, a potent inhibitor of 11
      beta-HSD, throughout pregnancy leads to reduced birth weight (mean 20 percent
      decrease) and elevated blood pressures (increase in mean arterial pressure, 9 mm
      Hg in males, 7 mm Hg in females) in the adult offspring of carbenoxolone-treated
      rats. This effect requires the presence of maternal adrenal products, as
      carbenoxolone given to adrenalectomized pregnant rats had no effect on birth
      weight or blood pressure. These data support the hypothesis that excess exposure
      of the fetoplacental unit to maternal glucocorticoids reduces birth weight and
      programs subsequent hypertension and indicate a key role for placental 11beta-HSD
      in controlling such exposure.

PMID- 8641725
TI  - Polymorphism of the apolipoprotein E and angiotensin-converting enzyme genes in
      Japanese subjects with silent myocardial ischemia.
AB  - The apolipoprotein epsilon4 allele and homozygous deletion allele (DD) of the
      angiotensin-converting enzyme gene are reported to be associated with an increase
      in the incidence of ischemic heart disease. In this study, we examined whether
      the apolipoprotein epsilon4 genotype and angiotensin-converting enzyme/DD allele
      are associated with silent myocardial ischemia. We screened 3920 subjects
      undergoing general checkups who no symptoms of ischemic heart disease. Seventy
      subjects (2 percent) showed ischemic ST-segment depression during the double two
      step exercise test. One hundred and twenty control subjects without ischemic ST
      segment depression were recruited from the same population and matched for sex,
      age, and blood pressure. We performed genotyping of the apolipoprotein E gene
      (epsilon2, epsilon3, and epsilon4) and angiotensin-converting enzyme gene (I and
      D) using polymerase chain reaction-restriction fragment length polymorphism and
      polymerase chain reaction, respectively. Allele frequently of epsilon4 of the
      apolipoprotein E gene was higher in the ischemic group (11 percent) than the
      nonischemic group (5 percent) (chi2 = 5.35, P < .05), but there was no
      significant association between the allele or the genotype frequency of the
      angiotensin-converting enzyme gene and the incidence of ischemic ST-segment
      depression. Furthermore, stepwise multiple regression analysis also revealed that
      total cholesterol level and epsilon4 genotype were predictors of ischemic change
      in the exercise tolerance test (chi2 = 12.8, P < .005, R(2) = .051). These
      results suggest that the apolipoprotein epsilon4 allele is an independent genetic
      risk factor for silent myocardial ischemia in Japanese subjects.

PMID- 8641726
TI  - Association of hypertension with beta2- and alpha2c10-adrenergic receptor
      genotype.
AB  - The adrenergic receptors have been implicated in the pathogenesis of essential
      hypertension. We hypothesized that hypertension is associated with variants at
      the beta2-adrenergic receptor locus and at one of the alpha2-adrenergic receptor
      loci. In unrelated individuals, we measured untreated blood pressure and
      characterized each subject as hypertensive or normotensive. We then used genomic
      DNA to identify beta2- and alpha2c10-adrenergic receptor restriction fragment
      length polymorphisms. In 175 subjects (49 percent with hypertension, 55 percent
      black), both hypertension and race were associated with genotype at the beta2
      locus (chi2 for hypertension = 11, P = .004, chi2 for race = 8.8, P = .012). The
      association with hypertension persisted in each race group separately (blacks
      only: chi2 = 9.6, P = .008; whites only; chi2 = 14.2, P = .001). This association
      persisted in a logistic model that controlled for race (P = .01). Genotype was
      also significantly associated with baseline systolic, diastolic, and mean
      arterial blood pressures (P = .05, .01, and .02, respectively). These data
      suggest that the beta2-adrenergic receptor gene is a candidate gene for
      hypertension in blacks and whites. We also genotyped subjects at the alpha2
      adrenergic receptor coded on chromosome 10. There was no association between
      hypertension and genotype at the alpah2c10 locus in the total group or in blacks,
      but there was significant association in whites (chi2 = 6.7, P = .03). These data
      suggest that the beta2- and alph2c10-adrenergic receptor genes may contribute, in
      a race-specific manner, to the inheritance of essential hypertension. Linkage
      studies in related individuals are needed to confirm these findings.

PMID- 8641727
TI  - Tissue-specific regulation of angiotensinogen gene expression in spontaneously
      hypertensive rats.
AB  - Angiotensinogen is expressed in many tissues besides the liver. Recent studies
      have suggested that abnormalities in the regulation of angiotensinogen gene
      expression may be involved in the development of hypertension. However, little
      information is available concerning the functional significance of tissue
      angiotensinogen. In this study, we measured plasma angiotensinogen concentration
      by radioimmunoassay and examined the expression of tissue angiotensinogen by
      Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto
      rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable
      to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of
      age in SHR and became higher than that in WKY. The levels of hepatic
      angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic,
      adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6
      and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in
      WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On
      the other hand, cardiac and fat angiotensinogen mRNA levels were significantly
      increased at 14 weeks of age in SHR. These results demonstrate that the
      expression of tissue angiotensinogen is regulated differently in SHR and WKY and
      indicate that the development of hypertension is accompanied at least temporally
      with increases in plasma angiotensinogen concentration as well as cardiac and
      adipogenic angiotensinogen mRNA in SHR.

PMID- 8641728
TI  - Multiple enhancer elements mediate induction of c-fos in vascular smooth muscle
      cells.
AB  - Previous work from this and other laboratories has demonstrated that the
      vasoconstrictor peptide angiotensin II results in hypertrophy of rat aortic
      smooth muscle cells that is associated with an increase in transcription of the
      early growth response gene c-fos. To explore the molecular mechanism responsible
      for c-fos induction in rat aortic smooth muscle cells, we used a series of
      reporter constructs linked to the chloramphenicol acetyl transferase gene in
      transient transfection experiments in rat aortic smooth muscle cells. Constructs
      containing both the serum response element and cAMP response element exhibited a
      20-fold increase in chloramphenicol acetyl transferase activity in response to
      either serum or angiotensin II, whereas no increase was seen in vehicle-treated
      cells. Mutations in either the serum response element or cAMP response element
      alone, which have been demonstrated to inactivate these elements in other cell
      types, had no effect on chloramphenicol acetyl transferase inducibility. In
      contrast, if both elements were mutated, inducibility was almost abolished.
      Electrophoretic mobility shift assays with oligonucleotides corresponding to
      either serum response element or cAMP response element demonstrated that these
      oligonucleotides are capable of forming specific complexes with proteins from rat
      aortic smooth muscle cell nuclear extracts. One of the proteins binding to the
      serum response element is the previously described serum response factor, since
      it was supershifted by a monospecific antibody. These studies demonstrate that c
      fox induction in smooth muscle occurs by a dual mechanism that can activate
      transcription via the serum response element or cAMP response element. These
      elements appear to act equally and independently, involving a distinct set of
      transacting factors.

PMID- 8641729
TI  - Impaired action of levcromakalim on ATP-sensitive K+ channels in mesenteric
      artery cells from spontaneously hypertensive rats.
AB  - The purpose of the present study was to test the hypothesis that properties of
      ATP-sensitive K+ channels are altered in arterial smooth muscle cells of
      hypertensive rats. Using a patch-clamp technique, we compared effects of a K+
      channel opener, levromakalim, on membrane currents in mesenteric artery cells
      from adult Wistar Kyoto rats (WKY) and age-matched spontaneously hypertensive
      rats (SHR) treated or not treated with hydralazine. Blood pressure was
      significantly higher in SHR than in WKY or hydralazine-treated SHR. Levcromakalim
      evoked a time-independent and voltage-insensitive current in a dose-dependent
      manner in the whole-cell clamp configuration. The reversal potential of the
      evoked current depended on extracellular K+ concentration. Application of 3
      micromol/L glibenclamide, a specific blocker of ATP-sensitive K+ channels,
      abolished the levcromakalim-evoked current; however, the current was unaffected
      by either 1 mmol/L tetraethylammonium or 0.3 micromol/L charybdotoxin. These
      results suggest that the levcromakalim-evoked current was carried through ATP
      sensitive K+ channels. In SHR cells, the maximal slope conductance of the
      levcromakalim-evoked current, normalized by cell capacitance, was decreased, and
      the dose-response curve was shifted to the right compared with WKY cells. The
      levcromakalim action was not impaired in cells from hydralazine-treated SHR. In
      conclusion, the action of levcromakalim on ATP-sensitive K+ channels in SHR
      mesenteric artery muscle cells was impaired compared with WKY cells. This
      impairment was corrected by long-term antihypertensive treatment.

PMID- 8641730
TI  - Adrenomedullin increases inducible nitric oxide synthase in rat vascular smooth
      muscle cells stimulated with interleukin-1.
AB  - We investigated the effects of adrenomedullin on nitric oxide synthesis by
      measuring the production of nitrite, a stable metabolite of nitric oxide, in
      cultured rat vascular smooth muscle cells. Incubation of cultures with
      interleukin-1beta (10 ng/mL) for 24 hours caused a significant increase in
      nitrite generation. The interleukin-1beta-induced nitrite production by vascular
      smooth muscle cells was significantly increased by adrenomedullin in a dose
      dependent manner (10(-10) to 10(-6) mol/L). This effect of adrenomedullin was
      significantly inhibited in the presence of Ng-monomethyl-L-arginine. The
      adrenomedullin-induced nitrite production by interleukin-1beta-stimulated cells
      was accompanied by increased inducible nitric oxide synthase mRNA accumulation.
      In the presence of the phosphodiesterase inhibitor isobutylmethylxanthine,
      interleukin-1beta-induced nitrite accumulation was further increased, but the
      effect of adrenomedullin was not additive or synergistic. Adrenomedullin dose
      dependently increased intracellular cAMP levels of vascular smooth muscle cells.
      These results indicate that adrenomedullin augments nitric oxide synthesis in
      interleukin-1beta-stimulated vascular smooth muscle cells, at least partially
      through a cAMP-dependent pathway.

PMID- 8641731
TI  - Differential contribution of endothelial function to vascular reactivity in
      conduit and resistance arteries from deoxycorticosterone-salt hypertensive rats.
AB  - The purpose of these studies was to compare changes in conduit and resistance
      artery function in deoxycorticosterone-salt hypertensive rats. We hypothesized
      that if there was a common mechanism producing changes in vascular function in
      hypertension, then there would be similar alterations in reactivity of conduit
      and resistance arteries. Helically cut strips of common carotid artery were
      prepared for measurement of isometric force generation, and segments of small
      mesenteric arteries were pressurized for video dimension analysis. Sensitivity of
      arteries to phenylephrine and acetylcholine was determined. Carotid arteries from
      deoxycorticosterone-salt hypertensive rats were more sensitive to phenylephrine
      than arteries from control rats, whereas mesenteric resistance arteries from
      hypertensive rats were less sensitive to phenylephrine. In carotid arteries,
      endothelial denudation or incubation with N psi-nitro-L-arginine increased
      phenylephrine sensitivity in control rats to the level seen in
      deoxycorticosterone-salt rats. These manipulations had no effect on phenylephrine
      sensitivity in arteries from deoxycorticosterone-salt rats. In mesenteric
      resistance arteries, endothelium denudation normalized the depressed
      phenylephrine sensitivity in arteries from hypertensive rats but had no effect on
      arteries from normotensive rats. This depressed phenylephrine sensitivity in
      deoxycorticosterone-salt mesenteric arteries was not reversed by incubation with
      Npsi-nitro-L-arginine. Acetylcholine-induced relaxation was depressed in carotid
      arteries from deoxycorticosterone-salt hypertensive rats, and Npsi-nitro-L
      arginine blocked these relaxations. In contrast, acetylcholine relaxation in the
      mesenteric arteries from normotensive and hypertensive rats did not differ. N psi
      nitro-L-arginine slightly but significantly attenuated acetylcholine dilation
      only in mesenteric resistance arteries from the hypertensive rats. We conclude
      that qualitatively different changes in vasoconstrictor sensitivity to
      phenylephrine occur in carotid arteries and mesenteric resistance arteries of
      deoxycorticosterone-salt hypertensive rats. The increased phenylephrine
      sensitivity in carotid arteries in this model of hypertension is due to the loss
      of endothelium-derived nitric oxide production. In contrast, the decreased
      phenylephrine sensitivity in mesenteric resistance arteries from deoxy
      corticosterone-salt rats is due to a non-nitric oxide-mediated influence of the
      endothelium that is absent in arteries from normotensive rats.

PMID- 8641732
TI  - Renal extraction of atrial natriuretic peptide in hypertensive patients with or
      without renal artery stenosis.
AB  - The renin-angiotensin-aldosterone system plays a major role in renovascular
      hypertension, but the relationship between renin release and the renal fractional
      extraction of atrial natriuretic peptide (ANP) in this condition is not well
      defined. We measured ANP levels in the renal veins and aortas of 49 untreated
      hypertensive patients studied under standardized conditions immediately before
      renal angiography. Twenty-one patients had renal artery stenosis, 13 of which
      were unilateral and 8 bilateral. Five of the 13 patients with unilateral renal
      artery stenosis had an elevated renin ratio (> or = 1.5). Patients with renal
      artery stenosis were older (P < .01) and had higher systolic pressures (P < .05)
      than patients with essential hypertension. Arterial levels of ANP were
      significantly higher in patients with unilateral or bilateral renal artery
      stenosis than in patients with essential hypertension (P < .05). Patients with
      hypertension and left ventricular hypertrophy had significantly higher arterial
      ANP levels than those with no hypertrophy (40 versus 26 pmol/L, P < .05), but in
      patients with renal artery stenosis, arterial ANP levels were similar in those
      with or without hypertrophy. Renal venous ANP levels were significantly higher in
      stenotic than in normal kidneys. Moreover, in unilateral renal artery stenosis,
      stenotic kidneys of patients with an elevated renin ratio (stenotic
      kidney/contralateral kidney > or = 1.5) had a significantly higher renal venous
      ANP level than stenotic kidneys of patients with normal renin ratio (30 versus 17
      pmol/L, P < .05). However, the median fractional extraction of ANP was similar,
      around 0.50 (range, 0 to 0,83), in normal kidneys of hypertensive patients and in
      stenotic and contralateral kidneys of patients with renal artery stenosis. A
      significant inverse correlation between arterial ANP and renal venous active
      plasma renin concentration was found for normal kidneys (r= -.62, P < .01) of
      hypertensive patients without hypertrophy. However, for stenotic kidneys, no such
      relationship was apparent. A significant correlation between arterial ANP and the
      arteriovenous difference of ANP (r = +.92, P < .001) was found. This relationship
      was similar for normal and stenotic kidneys. In conclusion, an inverse
      relationship between arterial ANP and renal venous active plasma renin
      concentration exists in normal kidneys of essential hypertensive patients without
      left ventricular hypertrophy. Furthermore, data of ANP extraction through normal
      and stenotic kidneys suggest that saturation of ANP extraction does not occur.
      Increased levels of ANP in renal artery stenosis are likely caused by enhanced
      cardiac secretion of this peptide.

PMID- 8641733
TI  - Acute and chronic neutral endopeptidase inhibition in rats with aortocaval shunt.
AB  - In heart failure, sodium and water retention develop despite elevated plasma
      levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in
      part by a neutral endopeptidase. Whether neutral endopeptidase inhibition
      improves sodium and water excretion in heart failure is unknown. We determined
      the effect of neutral endopeptidase inhibition on plasma levels of atrial
      natriuretic peptide and the renal response to acute volume expansion in rats with
      aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition
      with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in
      both shunted rats (523 +/- 54 to 1258 +/- 330 pmol/L, P<.05) and controls (184 +/
      28 to 514 +/- 107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal
      action, increased in parallel. However, the diuretic and natriuretic responses to
      acute volume expansion were enhanced only in control rats and not in shunted
      rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition
      with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial
      natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic
      and natriuretic responses to acute volume load were increased by chronic
      endopeptidase inhibition in shunted rats (1789 +/- 154 to 2674 +/- 577 microL/80
      min and 99 +/- 31 to 352 +/- 96 micromol/80 min, respectively; P<.05). Chronic
      endopeptidase inhibition attenuated the cardiac hypertrophic response to
      aortocaval shunt without changing arterial blood pressure. Our data show that the
      renal effects of neutral endopeptidase inhibition are not necessarily dependent
      on changes in atrial natriuretic peptide plasma levels but instead may be
      mediated by local inhibition of the neutral endopeptidase in the kidney. In
      addition, chronic endopeptidase inhibition may attenuate heart failure-induced
      cardiac hypertrophy independent of hemodynamic effects.

PMID- 8641734
TI  - Renin-angiotensin system and cell communication in the failing heart.
AB  - The influence of heart failure on the process of cell communication was
      investigated in cell pairs isolated from the ventricle of cardiomyopathic
      hamsters (11 months old) and the results compared with age-matched normal
      hamsters. The gap junctional conductance (gj) was measured with two voltage-clamp
      amplifiers. The results showed two major populations of cell pairs with respect
      to gj values: one with very low values (0.8 to 2.5 nS) and the other with higher
      values (7 to 35 nS). In normal hamsters, the most frequent gj values were in the
      range of 40 to 100 nS. Angiotensin II (Ang 11, 1 microg/mL) caused cell
      uncoupling in myopathic myocytes with low gj but reduced gj by 53 +/- 6.6 percent
      (+/- SE) in cell pairs with higher gj values (7 to 35 nS). The effect of Ang II
      on gj of myopathic cell pairs was suppressed by losartan (10(-7) mol/L). In
      cardiomyopathic cell pairs with low gj (0.8 to 2.5 nS), enalapril (1 microg/mL)
      caused an appreciable increase in gj (219 +/- 20.3 percent), whereas in cell
      pairs with higher gj (7 to 35 nS), the gj increment was smaller (80 +/- 10.8
      percent) but still larger than that seen in controls (33 +/- 5.4 percent).
      Intracellular dialysis of Ang I (10(-8) mol/L) abolished cell communication in
      myopathic cell pairs with low gj (0.8 to 2.5 nS) and reduced gj by 66 +/- 1.7
      percent in the other pairs (7 to 35 nS). The effect of Ang I on gj was greatly
      reduced by enalaprilat (10(-9) mol/L) added to the cytosol. Dialysis of Ang II
      (10(-8) mol/L) into the myopathic cell reduced gj by 48 +/- 4.2 percent, an
      effect abolished by losartan (10(-8) mol/L). The results indicate that the
      decline in gj seen in the ventricle of cardiomyopathic hamsters is in part due to
      activation of the cardiac renin-angiotensin system.

PMID- 8641735
TI  - Effect of race and hypertension on plasma amylin concentrations.
AB  - Amylin is a recently discovered peptide hormone composed of 37 amino acids that
      is cosecreted with insulin by pancreatic beta cells. Amylin has been reported to
      be present in increased amounts in insulin-resistant subjects who are hyper
      insulinemic. Because blacks and whites differ in the prevalence of both
      hypertension and diabetes, we examined amylin levels in 77 individuals; 42 were
      black (11 hypertensive and 31 normotensive) and 35 were white (10 hypertensive
      and 25 normotensive) individuals who were either healthy control subjects or
      hypertensive subjects not receiving antihypertensive medication. Plasma amylin
      concentrations were measured in two separate monoclonal antibody-based
      immunofluorescent sandwich-type assays. The F002-2 capture antibody binds amylin
      plus at least two additional amylin-like peptides, and the F024-4 capture
      antibody detectably binds only the amylin peptide. There was a significant race
      by-diagnosis interaction for levels of amylin immunoreactivity during a 2-hour
      glucose tolerance test (P<.005 for F002-2 antibody and P<.05 for F024-4
      antibody). Highest levels were found in black hypertensive subjects. The results
      appear to fit with previously observed differences in metabolic status between
      blacks and whites and with the association between hypertension and alterations
      in metabolic status.

PMID- 8641736
TI  - Lack of cross talk between alpha1-adrenergic and angiotensin type 1 receptors in
      neurons of spontaneously hypertensive rat brain.
AB  - Norepinephrine causes downregulation of angiotensin II (Ang II) receptors in
      Wistar-Kyoto rat (WKY) brain neuronal cultures. The aim of this study was to
      compare the cross talk between Ang II and alpha1-adrenergic receptors in these
      neuronal cultures. Norepinephrine causes a 66 percent decrease in Bmax of Ang II
      type 1 (AT1) receptors in neuronal cultures of WKY brain. This decrease is
      mediated by the interaction of norepinephrine with the alpha1a-adrenergic
      receptor subtype. Norepinephrine also causes a decrease in mRNA levels for AT1
      receptors. A maximal decrease of 83 percent in AT1, receptor mRNA is observed in
      8 hours with 100 micromol/L norepinephrine, is blocked by 5-methyluradipil, and
      involves inhibition of AT1 receptor transcription. Furthermore, decreases in the
      AT1 receptor and its mRNA are associated with a significant attenuation of AT1
      receptor-mediated stimulation of norepinephrine transporter mRNA in WKY brain
      neurons. In contrast, norepinephrine does not decrease AT1 receptors or mRNA and
      has no effect on Ang II stimulation of norepinephrine transporter mRNA in
      neuronal cultures of spontaneously hypertensive rat brain. Thus, these data show
      that norepinephrine-mediated downregulation of AT1 receptors is associated with a
      parallel decrease in AT1 mRNA and Ang II stimulation of norepinephrine
      transporter mRNA and involves the alpha1a-adrenergic receptor in neurons of WKY
      brain. This cross talk between the two receptors is lacking in neurons of
      spontaneously hypertensive rat brain.

PMID- 8641737
TI  - Changes in the baroreflex control of heart rate produced by central infusion of
      selective angiotensin antagonists in hypertensive rats.
AB  - We have recently shown that an angiotensin-(1-7) [Ang-(I-7)] analogue, D-Ala7-Ang
      (1-7) (A-779), is a selective Ang-(1-7) antagonist with no significant action on
      angiotensin type 1 or type 2 receptors. The availability of selective angiotensin
      antagonists prompted us to evaluate the role of Ang-(1-7) and Ang II on central
      modulation of the baroreflex control of heart rate in normotensive Wistar rats
      and spontaneously hypertensive rats (SHR). Blood pressure recording and reflex
      changes in heart rate elicited by intravenous bolus injections of phenylephrine
      were made before and within 1 and 3 hours of intracerebroventricular (ICV,
      lateral ventricle) infusion of saline (8 microL/h), A-779 (4 microg/h), DuP 753
      (100 microg/h), or CGP 42112A (50 mu g/h) in conscious rats. The slope of the
      relationship between changes in pulse interval versus changes in mean arterial
      pressure was used as an index of the baroreflex control of heart rate. ICV
      infusion of saline or any of the antagonists did not significantly change basal
      levels of mean arterial pressure and heart rate in SHR (170 +/- 6 mm Hg nd 360 +/
      9 beats per minute, respectively; n = 29) or Wistar rats (108 +/- 2 mm Hg and
      377 +/- 6 beats per minute, respectively; n=29). Three hours of ICV infusion of A
      779 markedly decreased baroreflex sensitivity in Wistar rats (from a basal slope
      of 1.09 +/- O.3). In contrast, A-779 did not significantly alter the depressed
      baroreflex sensitivity of SHR (0.61 +/- O.l). ICV infusion of DuP 753 produced a
      significant increase (60 percent) in baroreflex control of heart rate in both
      Wistar rats and SHR. Saline or CGP 42112A infusions did not significantly alter
      baroreflex control of heart rate. These results suggest that endogenous Ang II
      and Ang-(1-7) are differentially affecting central baroreflex modulation, acting
      probably through distinct receptor subtypes. Although the central Ang II
      inhibitory effect is mediated by the type 1 receptor subtype, the facilitatory
      effect of Ang-(1-7) might be mediated by a different, unidentified receptor.

PMID- 8641738
TI  - Role of gamma-aminobutyric acid B receptors in baroreceptor reflexes in
      hypertensive rats.
AB  - Previous studies demonstrated that stimulation of gamma-aminobutyric acid B
      (GABA(B)) receptors in the nucleus tractus solitarius of spontaneously
      hypertensive rats (SHR) elicited a larger increase in arterial pressure compared
      with control Wistar-Kyoto rats. Since stimulation of GABA(B) receptors in the
      nucleus tractus solitarius attenuates cardiovascular responses evoked by
      electrical stimulation of the aortic depressor nerve in normotensive rats and
      there is evidence of a central neural attenuation of aortic depressor nerve
      evoked responses in SHR, we conducted studies to test the hypothesis that
      enhanced stimulation of GABA(B) receptors in the nucleus tractus solitarius in
      SHR is responsible for the attenuation of the aortic depressor nerve-evoked
      responses. Electrical stimulation of the left aortic depressor nerve resulted in
      frequency-dependent decreases in arterial pressure, heart rate, and splanchnic
      sympathetic nerve activity in urethane-anesthetized control rats. These responses
      were not significantly altered by injection of the GABA(B) receptor antagonist
      CGP 35348 into the ipsilateral nucleus tractus solitarius. The responses evoked
      by aortic depressor nerve stimulation were attenuated in SHR. This attenuation
      was particularly apparent with more prolonged periods (>15 seconds) of high
      frequency (25-Hz) stimulation, with the depressor and sympathetic nerve responses
      diminishing during the course of stimulation. This time- and frequency-dependent
      attenuation of baroreceptor-evoked depressor responses was reversed by injection
      of CGP 35348 into the ipsilateral nucleus tractus solitarius. Rats made
      hypertensive by treatment with deoxycorticosterone plus salt did not have
      attenuated aortic depressor nerve-evoked responses. These results suggest that
      alterations in GABA b-mediated neural transmission in the nucleus tractus
      solitarius contribute to the attenuation of the baroreceptor reflex observed in
      SHR.

PMID- 8641739
TI  - Effect of angiotensin II receptor blockade on fibrinolysis during acute
      hyperinsulinemia in patients with essential hypertension.
AB  - We performed the present study to investigate indirectly the in vivo effects of
      angiotensin II on fibrinolysis and catecholamines by treatment with losartan, a
      selective angiotensin II type 1 receptor antagonist. The effects were evaluated
      in basal conditions as well as in two different models of acute hyperinsulinemia
      physiologically induced by oral glucose ingestion and by a euglycemic glucose
      clamp technique. Twenty subjects with moderate hypertension were included in a
      randomized, double-blind, placebo-controlled crossover study of 4-week treatment
      periods. Plasma levels of catecholamines, tissue plasminogen activator activity
      and antigen, and plasminogen activator inhibitor type 1 activity and antigen were
      unchanged in the basal state after 4 weeks of treatment. During both models of
      hyperinsulinemia, plasminogen activator inhibitor activity and antigen decreased
      significantly (both P<.001), and tissue plasminogen activator activity increased
      significantly (P<.Ol). Norepinephrine did not change during any of the
      procedures, whereas epinephrine increased significantly after 3 hours of the oral
      glucose tolerance test. Changes from baseline did not differ between the
      treatment and placebo regimens during the hyperinsulinemic procedures with regard
      to either of the fibrinolytic variables or the catecholamines. In conclusion, we
      could not demonstrate any effects of 4 weeks of treatment with losartan on plasma
      levels of fibrinolytic variables or catecholamines either in basal conditions or
      during acute hyperinsulinemia. However, the present findings do not preclude more
      direct effects of angiotensin II or involvement of other receptor subtypes on
      fibrinolysis.

PMID- 8641740
TI  - Sodium-lithium countertransport and blood pressure change over time: the Gubbio
      study.
AB  - Sodium-lithium countertransport activity in red blood cells relates to blood
      pressure (BP) and the prevalence of hypertension. This study investigated in
      adults the relation of sodium-lithium (Na-Li) countertransport to BP change from
      baseline to 6-year follow-up. In the Gubbio Population Study, 4210 men and women
      were 18 to 74 years old at baseline (1983-1986), and 3766 had a valid baseline Na
      Li countertransport measurement; of these, 2729 were reexamined at 6 years of
      follow-up (1989-1992) and made up the study cohort. At baseline, data collection
      included age, height, weight, BP, pulse rate, drug treatment, alcohol intake,
      ratio of sodium to potassium in spot urine, plasma cholesterol, and Na-Li
      countertransport in red blood cells. At 6-year follow-up, data for age, BP, and
      drug treatment were collected as at baseline. From baseline, average BP declined
      for people on antihypertensive medication at follow-up and for those with
      baseline BP greater than or equal to 140/90 mm Hg (systolic/diastolic) and did
      not change or increased for the remaining participants. In quartile and
      correlation analyses controlled for sex, baseline BP, and antihypertensive
      treatment, BP change related significantly and directly to baseline Na-Li
      countertransport. In multiple linear regression analyses done for the entire
      cohort with control for other confounders, the regression coefficient of baseline
      Na-Li countertransport to BP change over time was positive and borderline
      significant. The Na-Li countertransport coefficient was positive and significant
      when analyses were done with the use of a categorical value of baseline Na-Li
      countertransport (quartile 4 and quartiles 1 through 3 combined). In both models,
      the Na-Li countertransport coefficient was the strongest for people with baseline
      BP greater than or equal to 120/80 mm Hg or for people with baseline age of 45
      years or older. In conclusion, Na-Li countertransport significantly relates to BP
      change over time in adults.

PMID- 8641741
TI  - Platelet Ca2+ is not increased in stroke-prone spontaneously hypertensive rats:
      comparative study with spontaneously hypertensive rats.
AB  - We have reported that cytosolic Ca2+ concentration ([Ca2+]i) is increased in
      platelets from spontaneously hypertensive rats (SHR) in both basal and thrombin
      stimulated conditions. To determine whether the correlation between blood
      pressure and cellular Ca2+ metabolism exists in stroke-prone SHR (SHRSP), we
      investigated Ca2+ handling using fura 2 and aggregation response in platelets of
      12- to 13-week-old male SHRSP, SHR, and Wistar-Kyoto rats (WKY). Systolic
      pressure was highest in SHRSP and lowest in WKY (213 +/- 8, 172 +/- 7, and 135 +/
      5 mm Hg, respectively). Basal [Ca2+]i was significantly higher in SHR than WKY
      (45.9 +/- 4.5 versus 41.2 +/- 4.8 nmol/L, P<.05), and that in SHRSP (40.2 +/- 2.8
      nmol/L) was similar to that in WKY. Thrombin (0.1 IU/mL)-stimulated [Ca2+]i rise
      was greater in SHR and smaller in SHRSP than in WKY in the presence of
      extracellular Ca2+ (530 +/- 50 and 408 +/- 52 versus 475 +/- 50 nmol/L,
      respectively; P<.05). The recovery rate from the peak [Ca2+]i response to
      thrombin was greatest in SHRSP and least in WKY. Ionomycin (5 micromol/L)
      stimulated [Ca2+]i rise was similar in WKY, SHR, and SHRSP (731 +/- 97, 743 +/-
      88, and 683 +/- 70 nmol/L, respectively). Thrombin-induced maximum platelet
      aggregation response was higher in SHR and lower in SHRSP than WKY (82 +/- 4
      percent and 61 +/- 15 percent versus 73 +/- 6 percent, respectively; P<.05). In
      contrast to SHR, basal [Ca2+]i in SHRSP was similar to that in WKY, and thrombin
      stimulated [Ca2+]i was attenuated. These result suggest that platelet Ca2+
      handling differs between SHR substrains and that an increased [Ca2+]i is not
      obligatory in genetically hypertensive rats.

PMID- 8641742
TI  - Effects of insufficient sleep on blood pressure monitored by a new
      multibiomedical recorder.
AB  - Blood pressure varies in relation to factors such as physical activity, body
      position, ambient temperature, and autonomic nervous system activity. Therefore,
      we have developed a portable multibiomedical (PMB) recorder that monitors five
      parameters: indirect blood pressure, physical activity, body position, ambient
      temperature, and RR interval of the electrocardiogram. In the present study, we
      applied the PMB recorder over a 24-hour period to study the effect of
      insufficient sleep on blood pressure in subjects doing extensive overtime work.
      The parameters listed above were measured by the PMB recorder throughout a normal
      workday (mean period of sleep, 8 hours) and throughout a day with insufficient
      sleep (mean period of sleep, 3.6 hours) in 18 male technical workers aged 23 to
      48 years old. Blood pressure (mean systolic/diastolic pressure +/- SD)
      significantly increased the day after a sleep-insufficient night (129 +/- 8/79 +/
      6 mm Hg) compared with the day after a normal night (123 +/- 8/76 +/- 7 mm Hg,
      P<.05). However, ambient temperature, mean number of steps per minute, and
      percentage of time spent in a standing position showed no significant difference
      between these days. Spectral analysis of RR intervals showed that the ratio of
      the low-frequency component on the RR power spectrum (0.05 to 0.15 Hz) to the
      high-frequency component (0.15 to 0.40 Hz) was higher on the sleep-insufficient
      day (2.17 +/- 0.37 versus 1.81 +/- 0.37), as was the urinary excretion of
      norepinephrine (P<.05). Heart rate was significantly higher on the sleep
      insufficient day (81 +/- ll versus 76 +/- 8 beats per minute), after the data of
      two subjects with abnormal levels of physical activity were excluded (P<.Ol).
      These data suggest that lack of sleep may increase sympathetic nervous system
      activity on the following day, leading to increased blood pressure. The PMB
      recorder was useful for precisely evaluating the relationship between blood
      pressure and environmental factors.

PMID- 8641743
TI  - A diuretic is more effective than a beta-blocker in hypertensive patients not
      controlled on amlodipine and lisinopril.
AB  - The combination of an angiotensin-converting enzyme inhibitor and a calcium
      antagonist has a synergistic effect in patients with more severe hypertension.
      However, when this combination fails to control blood pressure, it is not clear
      which drug is then additive. The aim of this work was to study in a double-blind,
      randomized, crossover design the effect on blood pressure of the addition of
      either a thiazide diuretic (bendrofluazide, 5 mg once daily) or a beta-blocker
      (atenolol, 100 mg once daily) or placebo each for a month in hypertensive
      patients who are not adequately controlled on the combined treatment of
      amlodipine 5 mg once daily and lisinopril 5 mg twice daily. Eighteen patients
      with a supine diastolic pressure of more than 90 mm Hg after at least 1 month on
      the combined treatment of amlodipine and lisinopril were enrolled in the study.
      The results show that in patients whose blood pressures are not controlled by the
      combination of amlodipine and lisinopril, the addition of bendrofluazide 5 mg
      once daily causes a significant fall in blood pressure compared with placebo and
      a significantly greater fall than 100 mg atenolol once daily.

PMID- 8641744
TI  - Renal cytochrome P4504A activity and salt sensitivity in spontaneously
      hypertensive rats.
AB  - Differences in the renal metabolism of arachidonic acid by cytochrome P450 have
      been reported in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rats,
      but the contribution of this system to the development of hypertension is
      unclear. The present study compared renal P450 activity and blood pressure in SHR
      and Brown-Norway rats (BN) under control conditions and in response to an
      elevation in sodium intake; genetic linkage analysis was performed in an F2
      population (n=219) derived from these strains. Basal renal P4504A enzyme activity
      measured by conversion of [C(14)]arachidonic acid to 20-hydroxyeicosatetraenoic
      acid (20-HETE) was significantly greater in the kidneys of adult SHR (n=7) than
      of BN (n=8) (82 +/- 7 versus 60 +/- 5 pmol/min per milligram protein). Renal 20
      HETE production fell 45 percent in SHR and 22 percent in BN in which salt intake
      was elevated by drinking of saline instead of water for 2 weeks. Mean arterial
      pressure averaged 157 +/- 3mm Hg in SHR (n = 9) and 100 +/- 2 mm Hg in BN fed a
      normal salt diet, and it rose to 170 +/- 7 mm Hg (P<.05) in SHR and fell to 90 +/
      3 mm Hg (P<.05) in BN (n=8) after sodium intake was elevated. A polymorphic
      marker, D5Rjr1, that spanned a repeated element in the P4504A gene on chromosome
      5, where all three P4504A isoforms are located, was used for genotyping of the F2
      population. The P4504A genotype did not cosegregate with baseline mean arterial
      pressure in the F2 population; however, significant linkage was observed with the
      change in mean arterial pressure after sodium intake of the rats was elevated.
      The degree of linkage differed in male and female rats, and the highest LOD score
      (3.6) was observed in male F2 rats with a BN grandfather. These findings suggest
      that the difference in renal P450 activity in SHR and BN does not contribute to
      the development of hypertension in this F2 population, but it may play some role
      in determining the blood pressure response to an elevation in salt intake.

PMID- 8641746
TI  - Bosentan ameliorates cyclosporin A-induced hypertension in rats and primates.
AB  - Cyclosporine-induced hypertension is a major problem in transplant therapy. The
      pathophysiology of this disease is unclear. Cyclosporine increases endothelin
      synthesis and release, which may contribute to this hypertension. We examined the
      effects of chronic endothelin receptor blockade with the novel nonpeptide
      endothelin receptor antagonist bosentan in two animal models of cyclosporine
      induced hypertension. Cyclosporine was administered daily to female Wistar rats
      (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20
      days). Control rats received vehicle. Tail-cuff systolic pressure was
      significantly elevated in the cyclosporine-treated animals before the last week
      of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given
      daily to the rats by gavage during the last 5 days of cyclosporine treatment and
      to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff
      systolic pressure was measured daily during bosentan treatment. Bosentan but not
      gum alone significantly lowered blood pressure in the cyclosporine-hypertensive
      rats from 134 +/- l to 122 +/- 3 mm Hg (P<.Ol) and in the cyclosporine
      hypertensive marmosets from 156 +/- 2 to 139+/- 4 mm Hg (P<.Ol). There were no
      differential effects on plasma creatinine concentration, endothelin
      concentration, or end-organ weights. Bosentan had no effect in the vehicle
      treated rats. These data provide further evidence to support a role for
      endothelin in cyclosporine-induced hypertension and demonstrate the effectiveness
      of endothelin receptor antagonism as a novel treatment in cyclosporine-induced
      hypertension.

PMID- 8641747
TI  - Carbenoxolone damages endothelium and enhances vasoconstrictor action in aortic
      rings.
AB  - Carbenoxolone causes hypertension indirectly by inhibition of 11beta
      hydroxysteroid dehydrogenase and consequent elevation of intracellular
      glucocorticoid levels and enhancement of vasoconstrictor action. We performed the
      present study to determine whether carbenoxolone also enhances vascular tone
      directly by mechanisms independent of glucocorticoids and other systemic
      influences. Exposure of rat aortic rings to 10 to 100 micromol/L carbenoxolone in
      aerated Krebs-Henseleit buffer for 24 hours resulted in concentration-dependent
      increases in angiotensin II (Ang II) (100 nmol/L)-stimulated contractions and
      significant shifting of the phenylephrine cumulative contraction curve to the
      left but not increases in KCI (120 mmol/L)-stimulated contractions. Maximal
      enhancement of Ang II contraction was 39 percent. In contrast, brief (15-minute)
      exposure to 100 micromol/L carbenoxolone did not alter Ang II contractions.
      Mechanical denudation of the endothelium obviated enhancement of Ang II
      contractions by carbenoxolone, suggesting interaction of carbenoxolone with the
      endothelium. Endothelium-dependent relaxation of precontracted rings to
      acetylcholine or ATP was reduced by more than 90 percent by 24-hour pretreatment
      with 100 micromol/L carbenoxolone but not with 100 micromol/L deoxycorticosterone
      acetate (a mineralocorticoid) or 100 mu mol/L glycyrrhizic acid (a natural 11beta
      hydroxysteroid dehydrogenase inhibitor). Vascular smooth muscle relaxation with
      sodium nitroprusside was not inhibited by carbenoxolone. Incubation of cultured
      endothelial cells with 100 mu mol/L carbenoxolone for 24 hours did not inhibit
      nitric oxide synthase activity, as measured by conversion of [3H]L-arginine to
      [3H]L-citrulline. Electron micrography demonstrated that endothelial cell
      ultrastructure but not vascular smooth muscle cell ultrastructure was abnormal
      after incubation of rings for 24 hours with 100 micromol/L carbenoxolone. These
      studies suggest that carbenoxolone concentrations higher than 10 micromol/L
      enhance vasoconstrictor action via selective toxicity to the endothelium and
      elimination of endothelium-dependent relaxation.

PMID- 8641745
TI  - Renin regulation in cultured proximal tubular cells.
AB  - Recent studies have documented the presence of a complete renin-angiotensin
      system in the proximal tubule of the kidney: however, little is known about the
      regulation of renin in this proximal tubular system. Therefore, we performed the
      present studies to learn whether the behavior of the renin system in cultured
      proximal tubule is similar to that of the juxtaglomerular renin system. Basal
      renin secretion from rabbit proximal tubular cells in primary culture was low and
      not affected by isoproterenol (10(-5) mol/L), diltiazem (10(-5) mol/L), or a zero
      calcium bath (O nmol/L). Only the calcium ionophore A23187 (10(-4) mol/L)
      significantly reduced renin secretion in these cells (from 2.44 +/- 0.37 to 1.14
      +/- O.08 ng angiotensin I/mg protein per hour, P<.05). When the proximal tubular
      cells were lysed so the effects of the test agents on intracellular renin content
      could be assessed, isoproterenol caused a significant twofold (107 percent)
      increase (from 2.02 +/- 0.56 to 4.18 +/- 0.81 ng angiotensin I/mg protein per
      hour, P<.05), whereas diltiazem, A23187, and zero- and high-calcium baths did not
      produce a significant change. The effects of these agents on renin mRNA were
      examined in rabbit and rat proximal tubular cells in primary culture with the use
      of an S1 nuclease protection assay. Densitometry analysis of renin mRNA and
      either GAPDH mRNA (rat) or alpha-actin (rabbit) showed no significant alterations
      in renin mRNA abundance. In summary, these results confirm the presence of renin
      mRNA in cultured proximal tubular cells and suggest that a low-level,
      constitutive secretion of renin occurs in this system that is decreased by
      A23187. Moreover, the results also suggest that proximal tubular renin is
      regulated, albeit differently from the juxtaglomerular renin system. Finally,
      short-term increments in proximal tubular renin occur without a change in renin
      mRNA.

PMID- 8641748
TI  - Identification and purification of novel internalin-related proteins in Listeria
      monocytogenes and Listeria ivanovii.
AB  - Monoclonal antibodies were generated against a 30-kDa protein fraction derived
      from culture supernatants of a Listeria monocytogenes strain complemented with
      additional copies of the prfA regulator gene. Several of the antibodies reacted
      specifically with a hitherto unidentified, secreted 30-kDa polypeptide. By
      immunoblot analysis, the expression of this 30kDa polypeptide was found to be
      dependent on the presence of the PrfA regulator protein. Microsequencing of
      peptides derived from the partially purified 30-kDa protein revealed homologies
      to the InlA and InlB polypeptides of L. monocytogenes, which are required for the
      internalization of the bacteria into nonphagocytic cell lines. This prompted us
      to term the 30-kDa polypeptide internalin-related protein (Irp). Irp-specific
      monoclonal antibodies cross-reacted with a 24-kDa polypeptide present in culture
      supernatants of Listeria ivanovii, indicating the existence of an Irp-related
      protein in this pathogenic Listeria species.

PMID- 8641749
TI  - Lymphocyte proliferation in response to Brucella abortus RB51 and 2308 proteins
      in RB51-vaccinated or 2308-infected cattle.
AB  - Cattle vaccinated with Brucella abortus strain RB51 (SRB51) or infected with
      strain 2308 (S2308) had lymph node lymphocytes which proliferated most when
      incubated with 32-, 27-, 18-, or <18-kDa proteins of either SRB51 or S2308. Some
      S2308-infected cattle but no SRB51-vaccinated cattle had lymphocytes which
      proliferated in response to 80- and 49-kDa proteins of SRB51 and S2308. These
      results suggest that cattle vaccinated with SRB51 or infected with S2308 have
      lymphocytes which proliferate in response to most of the same S2308 proteins and
      that the immunodominant protein antigens of SRB51 and S2308 have similar
      molecular masses of 32, 27, 18, and <18 kDa.

PMID- 8641750
TI  - Low-dose lipopolysaccharide (LPS) pretreatment of mouse macrophages modulates LPS
      dependent interleukin-6 production in vitro.
AB  - Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of
      cytokines and other inflammatory mediators. Our laboratory previously reported
      that LPS-dependent macrophage-derived tumor necrosis factor alpha (TNF-alpha)
      production could be significantly potentiated by pretreatment with LPS at
      substimulatory LPS priming doses. The observed potentiation was shown to be
      coincident with a down-regulation of LPS-dependent nitric oxide (NO) production
      (X. Zhang and D. C. Morrison, J. Exp. Med. 177: 511-516, 1993). In order to
      determine whether these LPS reprogramming effects in mouse macrophages were
      selective for these two macrophage-derived mediators, we have examined the
      effects of LPS pretreatment on LPS-dependent interleukin 6 (IL-6) production.
      Thioglycolate-elicited mouse peritoneal macrophages were pretreated with various
      subthreshold stimulatory concentrations of LPS for 6 h, washed three times, and
      then stimulated with an effective stimulatory concentration of smooth LPS for 18
      h. In confirmation of earlier studies, pretreatment of mouse macrophages with
      substimulatory doses of LPS inhibited the subsequent LPS-dependent NO production.
      This down-regulation was accompanied by a coordinate up-regulation of LPS
      dependent IL-6 production, similar to what was shown earlier for TNF-alpha
      production. These priming effects with the substimulatory dose of smooth LPS are
      shown to be independent of doses of LPS used for subsequent activation and are
      not restricted to specific LPS stimulation. Moreover, the enhancement of the IL-6
      response by LPS pretreatment is still observed in the presence of neutralizing
      antibody to TNF-alpha. These findings, therefore, provide further support for the
      conclusion that LPS-dependent macrophage reprogramming is likely to involve
      common regulatory pathways that control the secretion of both IL-6 and TNF-alpha.

PMID- 8641751
TI  - Translocation of Yersinia enterocolitica through an endothelial monolayer by
      polymorphonuclear leukocytes.
AB  - An endothelial cell monolayer grown on a microporous membrane coated with
      basement membrane protein matrix was used to study translocation of yersinia
      infected human polymorphonuclear leukocytes (PMNs). PMNs infected with one to
      eight bacteria were able to translocate living yersiniae from the upper chamber
      to the chemoattractant-containing lower chamber. This process may contribute to
      extravasation and dissemination of yersiniae in the infected host.

PMID- 8641752
TI  - Evidence that a region(s) of the Clostridium perfringens enterotoxin molecule
      remains exposed on the external surface of the mammalian plasma membrane when the
      toxin is sequestered in small or large complexes.
AB  - In studies performed to investigate the topology of Clostridium perfringens
      enterotoxin (CPE) when this toxin is associated with intestinal brush border
      membrane (BBMs), it was shown that radiolabeled CPE antibodies react more
      strongly against intact CPE-treated BBMs than against control BBMs.
      Immunoprecipitation studies then demonstrated that CPE antibodies are able to
      react with both small and large CPE-containing complexes while these complexes
      are still present in intact BBMs. Therefore, at least a portion of the CPE
      molecule appears to remain surface exposed in BBMs throughout the action of this
      toxin.

PMID- 8641754
TI  - Antibody responses to Brucella abortus 2308 in cattle vaccinated with B. abortus
      RB51.
AB  - Cattle vaccinated with Brucella abortus rough strain RB51 (SRB51) produced small
      amounts of serum immunoglobulin G (IgG) but no IgM antibody to smooth strain 2308
      (S2308) bacteria and produced no IgG or IgM antibody to S2308 lipopolysaccharide
      (LPS). Western immunoblot analysis revealed that antiserum from SRB51-vaccinated
      cattle contained IgG antibody that reacted with S2308 proteins of 84 to <20 kDa.
      However, antiserum from the vaccinated cattle did not contain agglutinating B.
      abortus antibody in the tube agglutination test for brucellosis. These results
      suggest that SRB51-vaccinated cattle produced no antibody to S2308 LPS, although
      they did produce nonagglutinating IgG antibody that reacted with S2308 bacteria
      and bacterial proteins of 84 to <20 kDa.

PMID- 8641753
TI  - Platelet-activating-factor-mediated pathogenesis in Lyme disease.
AB  - This study describes a role of platelet-activating factor (PAF) as a potential
      inducer of inflammation in infection with Borrelia burgdorferi. Two approaches
      were taken. The first involved the use of a PAF antagonist to show the lack of an
      inflammatory response in skin lesions. The second was to show that the PAF
      antagonist reduced platelet aggregation when the spirochetes were incubated with
      polymorphonuclear leukocytes.

PMID- 8641755
TI  - Detachment of Streptococcus mutans biofilm cells by an endogenous enzymatic
      activity.
AB  - Previous studies have shown that Streptococcus mutans NG8 possesses an endogenous
      surface protein-releasing enzyme (SPRE) activity that liberates its own surface
      proteins (S. F. Lee, Infect. Immun. 60:4032-4039, 1992). The present study was
      initiated to investigate the possible role of the release of surface proteins by
      SPRE in the detachment of biofilm cells in vitro. Initially, the characteristics
      of surface protein release by the strain (S. mutans BM71) used in this study were
      shown to be the same as those previously described for S. mutans NG8. BM71
      displayed characteristics identical to those of NG8 in terms of pH optima and
      inhibitor sensitivity for protein release. Monolayer biofilms of S. mutans BM71
      were formed on hydroxylapatite rods in a modified chemostat. Detachment of the
      biofilm cells was measured by viable cell counts of bacteria liberated after
      incubation of the biofilms in buffers. Results showed that biofilm cells were
      detached in a pH- dependent manner with a maximum rate of pH 5 (P = 0.016) to 6
      (P = 0.002), a range similar to that for optimal surface protein release. The
      detachment of the biofilm cells was found to be inhibited by ZnCl2 (P = 0.002 to
      0.023), which also inhibited surface protein release. Detachment was not
      inhibited significantly by CaCl2 (P = 0.525 to 0.784), precluding an ionic effect
      on inhibition by ZnCl2. The extent of detachment could be increased (P = 0.046)
      by the addition of an SPRE preparation from S. mutans but not heat-inactivated
      SPRE (P = 0.665) or SPRE in the presence of ZnCl2 (P = 0.199). Detachment was
      also studied by using biofilms of resting (viable but not dividing) cells.
      Results similar to those for biofilms formed from growing cells were obtained,
      indicating that cells detached from biofilms were not daughter cells. The results
      presented above show that monolayer biofilm cells of S. mutans under conditions
      of minimal shear force have the ability to detach from a surface and suggest that
      this detachment was mediated by an endogenous SPRE activity.

PMID- 8641756
TI  - Alteration of gonococcal protein expression in acidic culture.
AB  - We grew Neisseria gonorrhoeae under acidic, neutral, and alkaline conditions and
      noted altered expression of at least 12 outer membrane proteins between 31 and
      100 kDa in size. One protein whose expression was upregulated under acidic
      conditions was gonococcal heat shock protein 63. These proteins may contribute to
      the pathogenesis of gonorrhea in the urogenital tract.

PMID- 8641757
TI  - Neutrophils prevent extracellular colonization of the liver microvasculature by
      Salmonella typhimurium.
AB  - The early course of hepatic infection with the facultative intracellular
      bacterial pathogen Salmonella typhimurium was examined in control mice and in
      mice selectively depleted of neutrophils by treatment with a granulocyte-specific
      monoclonal antibody. The results show that >200-fold more salmonellae were
      recovered in livers of the latter group of mice than in livers of the former
      group by 24 h of parenterally initiated infection. Comparative histological
      examination of the livers from both groups of mice indicated that neutrophils
      participate in early anti-Salmonella defense in the liver in part by aborting
      infection in permissive hepatocytes and by inhibiting extracellular bacterial
      colonization of the hepatic microvasculature. It is shown in addition that
      systemic salmonellosis was also severely exacerbated in neutropenic mice infected
      intragastrically with the pathogen.

PMID- 8641758
TI  - Lesions of primary and secondary syphilis contain activated cytolytic T cells.
AB  - This study demonstrates that CD8+ cytotoxic lymphocytes (CTL) are found in both
      primary and secondary syphilis lesions. CD8+ T cells were detected by
      immunohistology, and mRNAs for granzyme B and perforin were detected by reverse
      transcription and PCR, suggesting that CD8+ cytotoxic lymphocytes are activated.

PMID- 8641759
TI  - Sporadic invasion of cultured epithelial cells by Haemophilus influenzae type b.
AB  - While working with an in vitro invasion assay, we observed that Haemophilus
      influenzae type b occasionally exhibits highly invasive behavior. The phenomenon
      is not inhibited by colchicine or cytochalasin but is dependent on the presence
      of supplemental CO2. We propose that sporadic invasiveness may correlate with the
      unknown events that precede Haemophilus influenzae type b bacteremia.

PMID- 8641760
TI  - Identification of T-cell determinants in natural immune responses to the
      Plasmodium falciparum apical membrane antigen (AMA-1) in an adult population
      exposed to malaria.
AB  - AMA-1 of Plasmodium falciparum is a promising candidate antigen in malaria
      vaccine development. In this study, we have mapped the immunodominant T-cell
      determinants in this antigen by using synthetic peptides. From the amphipathic
      scores, 17 putative T-cell determinants were identified. Nine of the 17 peptides
      complementary to the putative T-cell determinants induced proliferation of
      peripheral blood mononuclear cells (PBMC) from Kenyan residents who had lifelong
      exposure to malaria; none of these peptides induced proliferation of PBMC from
      donors who were not previously exposed to malaria. This indicates that AMA-1
      peptides were stimulating T cells that were previously primed by prior exposure
      to P. falciparum. Many positive responders showed reactivity to more than one
      peptide, and some of the potent proliferative T epitopes were found to be
      localized in the highly conserved regions of AMA-1, suggesting that it may be
      possible to induce T-cell memory that can recognize different variant forms of
      the parasite. This information on the natural immune responses against the AMA-1
      vaccine antigen in clinically immune adults will be helpful in the development of
      an AMA-1 antigen-based malaria vaccine and may also guide testing of AMA-1-based
      vaccine formulations.

PMID- 8641761
TI  - Molecular characterization of a ribonucleotide reductase (nrdF) gene fragment of
      Mycoplasma hyopneumoniae and assessment of the recombinant product as an
      experimental vaccine for enzootic pneumonia.
AB  - A Mycoplasma hyopneumoniae clone bank was screened with hyperimmune pig serum.
      One clone exhibited sequence homology to the prokaryotic R2 subunit of
      ribonucleotide reductase and was expressed as an 11-kDa protein fused to beta
      galactosidase. The vaccine potential of the fusion protein was assessed in pig
      trials. Following experimental challenge with a virulent isolate of M.
      hyopneumoniae, gross lung pathology (mean Goodwin lung score) of vaccinated
      animals, irrespective of adjuvant treatment, was significantly reduced compared
      with that of control unvaccinated pigs (P < 0.05).

PMID- 8641762
TI  - The capsular polysaccharide complex of Bacteroides fragilis induces cytokine
      production from human and murine phagocytic cells.
AB  - To stimulate early-phase immunologic events following Bacteroides fragilis
      infection in the peritoneal cavity, we examined the cytokine response of several
      cell types to purified capsular polysaccharide complex (CPC) and
      lipopolysaccharide (LPS) of this organism. Cytokines were produced from murine
      resident peritoneal (MRP) cells as well as human peripheral blood leukocytes. MRP
      cells cocultured with either B. fragilis CPC of LPS in vitro produced tumor
      necrosis factor alpha and interleukin-1alpha (IL-1alpha). In addition, MRP cells
      challenged with CPC produced IL-10. Human peripheral blood monocytes and
      polymorphonuclear leukocytes secreted IL-8 when cultured in the presence of CPC.

PMID- 8641764
TI  - Glycans of bovine lactoferrin function as receptors for the type 1 fimbrial
      lectin of Escherichia coli.
AB  - Bovine lactoferrin strongly inhibited the hemagglutination activity of type 1
      fimbriated Escherichia coli. In addition, it agglutinated these bacteria. The
      agglutination reaction was specifically inhibited by glycopeptides derived from
      bovine lactoferrin or alpha-methyl-D-mannoside. These observations indicate that
      the glycans of bovine lactoferrin can serve as receptors for type 1 fimbrial
      lectin.

PMID- 8641763
TI  - Staphylocidal action of thrombin-induced platelet microbicidal protein is not
      solely dependent on transmembrane potential.
AB  - Thrombin-induced platelet microbicidal protein (tPMP) is a small, cationic,
      antimicrobial peptide released from rabbit platelets when stimulated with
      thrombin. We studied the relationship between staphylococcal transmembrane
      potential (delta psi) and tPMP staphylocidal activity. A genetically related pair
      of Staphylococcus aureus strains, 6850 and JB1, which differ in delta psi
      generation (-143 and -97 mV, respectively) were used. Mutant JB-1 was
      substantially less susceptible to tPMP than the parental strain, 6850. Menadione
      supplementation, which normalized the delta psi of strain JB-1, did not restore
      JB-1 tPMP susceptibility. These findings suggest that the staphylocidal
      activities of tPMP require factors other than or in addition to an intact delta
      psi.

PMID- 8641765
TI  - Increased numbers of interleukin-12-producing cells in human tuberculosis.
AB  - Numbers of interleukin-12 (IL-12) producing cells were quantitated in the
      peripheral blood of healthy donors and tuberculosis patients by the ELISPOT
      assay. We observed that (i) stimulation with mycobacteria increases numbers of IL
      12 producers from healthy donors and (ii) tuberculosis patients have larger
      numbers of IL-12 producers than healthy donors. Our data emphasize the importance
      of Il-12 in immunity to tuberculosis.

PMID- 8641766
TI  - A classical strain of Vibrio cholerae with diminished ability to process the
      proteolytically sensitive site in the A subunit of cholera toxin.
AB  - Vibrio cholerae O1, No. 31, a strain isolated from a patient with mild diarrhea,
      produced mainly the unnicked cholera toxin. The amount of toxin that had
      accumulated in the cells was approximately 200 times lower than that secreted
      into the culture medium. When the unnicked toxin was purified by three successive
      column chromatographies and then extracted from the polyacrylamide gel, the
      unnicked toxin showed two bands corresponding to the A and B subunits by sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis and the A1 fragment was
      detected by trypsinization. Biological and enzymatic activities of the purified
      toxin with trypsinization were identical to those of cholera toxin from V.
      cholerae 569B as seen in the rabbit skin permeability test and the NAD:agmatine
      ADP-ribosyltransferase assay. DNA sequences of the A and B subunits were
      identical to those of the A- and B-subunit genes from the El Tor 2125 and
      classical 0395 strains, respectively. These data suggest that the wild V.
      cholerae strain, No. 31, produces a toxin identical to toxins previously reported
      in the literature and secretes it without accumulation in the cell, as is the
      case with other strains. However, strain No. 31's ability to nick the toxin is
      diminished compared with such abilities of other strains.

PMID- 8641767
TI  - Immunopathology of tuberculosis: roles of macrophages and monocytes.

PMID- 8641768
TI  - Signal transduction in Pneumocystis carinii: characterization of the genes (pcg1)
      encoding the alpha subunit of the G protein (PCG1) of Pneumocystis carinii
      carinii and Pneumocystis carinii ratti.
AB  - Pneumocystis carinii is a eukaryotic organism that causes pneumonia in
      immunocompromised hosts. The cell biology and life cycle of the organism are
      poorly understood primarily because of the lack of a continuous in vitro
      cultivation system. These limitations have prevented investigation of the
      organism's infectious cycle and hindered the rational development of new
      antimicrobial therapies and implementation of measures to prevent exposure to the
      organism or transmission. The interaction of P. carinii with its host and its
      environment may be critical determinants of pathogenicity and life cycle. Signal
      transduction pathways are likely to be critical in regulating these processes. G
      proteins are highly conserved members of the pathways important in many cellular
      events, including cell proliferation and environmental sensing. To characterize
      signal transduction pathways in P. carinii, we cloned a G-protein alpha subunit
      (G-alpha) of P. carinii carinii and P. carinii ratti by PCR amplification and
      hybridization screening. The gene encoding the G-alpha was present in single copy
      on a 450-kb chromosome of P.c. ratti. The 1,062-bp G-alpha open reading frame is
      interrupted by nine introns. The predicted polypeptide showed 29 to 53% identity
      with known fungal G-alpha proteins with greatest homology to Neurospora crassa
      Gna-2. Northern (RNA) blot analysis and immunoprecipitation demonstrated
      expression of the G-alpha mRNA and protein P. carinii isolated from heavily
      infected animals. Some alteration in the level of transcription was noted in
      short-term maintenance in starvation or rich medium. Characterization of signal
      transduction in P. carinii will permit a better understanding of the reproductive
      capacity and other cellular processes in this family or organisms that cannot be
      cultured continuously.

PMID- 8641769
TI  - Proline iminopeptidase from the outer cell envelope of the human oral spirochete
      Treponema denticola ATCC 35405.
AB  - Certain periodontopathic organisms have been shown to exhibit high activity of
      proline iminopeptidase (PIPase). The human oral spirochete Treponema denticola
      ATCC 35405 was found to contain an easily extractable, novel PIPase (EC
      3.4.11.5), which was purified to a sodium dodecyl sulfate- polyacrylamide gel
      electrophoresis-pure form by means of fast protein liquid chromatographic
      procedures. The range of the minimum monomeric molecular mass (280 amino acid
      residues) of the PIPase, based on amino acid analysis, was 30.35 to 30.39 kDa,
      but the likely in vivo form of the enzyme is a tetramer (minimum mass, 120.2 to
      120.4 kDa). The molecular masses based on laser desorption mass spectrometry were
      36.058 kDa for the monomer and 72.596 kDa for a dimer. The PIPase cleaves
      specifically the Pro-Y bond in dipeptides where Y is preferably Arg or Lys. Pro
      Gln, Pro-Asn, and Pro-Ala were also good substrates, while Pro-Glu was hydrolyzed
      slowly and Pro-Asp was not hydrolyzed at all. Tripeptides were poor substrates or
      were not hydrolyzed (an exception was Pro-Gly-Gly, which cleaved at a moderate
      rate). Larger molecules, such as poly-L-Pro, were not hydrolyzed. The T.
      denticola enzyme can be regarded as a true PIPase, since replacing Pro in Pro-Y
      with other amino acid residues resulted in no hydrolysis. The activity of the
      PIPase may depend on an active carboxyl group and on an active seryl residue but
      not on metal cations. Diethylpyrocarbonate inactivated the enzyme in a reaction
      that was not reversible upon addition of NH2OH. The enzyme contains a relatively
      large percentage (ca. 15%) of proline residues. The dominance of the PIPase
      activity among aminopeptidase activities present in T. denticola and the proposed
      location of the enzyme in the outer cell envelope suggest that it has a vital
      function in the propagation of the cells within their biological niche (inflamed
      human periodontal tissues). The biologic role of the PIPase may be envisaged as
      in the termination of the overall peptidolytic cascade (liberating free proline
      and other amino acids), whereby host tissue proteins and peptides are first
      processed and inactivated by other peptidases possibly present within the same
      confines as the PIPase.

PMID- 8641770
TI  - Susceptibility of Chlamydia trachomatis to protegrins and defensins.
AB  - We compared the susceptibilities of Chlamydia trachomatis elementary bodies (EBs)
      to human defensin HNP-2 and porcine protegrin PG-1, cysteine-rich beta-sheet
      antimicrobial peptides produced by mammalian leukocytes. Although both peptides
      protected McCoy cell monolayers from infection by chlamydial EBs, protegrins were
      especially potent. Protegrin-mediated inactivation of chlamydiae occurred
      rapidly, was relatively independent of the presence of serum, and was effective
      against serovars L2, D, and H. Protegrin-treated EBs showed striking
      morphological changes, with obvious damage to their limiting membranes and loss
      of their cytoplasmic contents and nucleoid. Their effectiveness against
      chlamydial EBs and other sexually transmitted pathogens combined with their
      relative lack of cytotoxicity suggests that protegrins and related molecules
      could serve as prototypes for topical agents to prevent sexually transmitted
      chlamydial infection.

PMID- 8641771
TI  - Interleukins 6 and 11 protect mice from mortality in a staphylococcal enterotoxin
      induced toxic shock model.
AB  - BALB/By mice given doses of D-galactosamine plus Staphylococcus aureus
      enterotoxin B die within 48 h of administration. The cause of death is a syndrome
      much like toxic shock syndrome in humans. We used this model to investigate the
      role of two cytokines, interleukin 6 and interleukin 11, which share the signal
      transducing subunit, gp130, of their respective receptors. We observed that
      pretreatment of mice with antibody to interleukin 6 increased mortality from 55%
      to nearly 90% (P < 0.001), while pretreatment with either cytokine reduced death.
      The protection was dose dependent; however, interleukin 6 was about 10-fold more
      potent that interleukin 11. These data indicate that endogenous interleukin 6
      plays a protective role in attenuating acute inflammatory responses; furthermore,
      interleukin 6 and interleukin 11 can abrogate T-cell activation due to triggering
      by superantigen. A possible clinical role for these cytokines in the treatment of
      toxic shock merits further investigation.

PMID- 8641772
TI  - Induction of adherence and degranulation of polymorphonuclear leukocytes: a new
      expression of the invasive phenotype of Shigella flexneri.
AB  - In the present study, the ability of Shigella flexneri to activate
      polymorphonuclear neutrophils (PMN) was examined. The invasive serotype 5 strain
      M90T induced strong PMN adherence, which was dependent on both the multiplicity
      of infection and the duration of incubation. When tested under the same
      experimental conditions, the noninvasive strain BS176 (cured of the 220-kb
      virulence plasmid) was less efficient. Indeed, incubation of PMN for 2 h with
      either M90T or BS176 (multiplicity of infection, 100) induced 51.8% +/- 10.5% and
      15.2% +/- 4.2% adherence, respectively (n = 3; P < 0.05). Stronger PMN activation
      by M90T was confirmed by evaluating PMN degranulation induced by the two strains.
      Whereas M90T triggered significant PMN secretion, BS176 did not. M90T strains
      with mutations in ipa genes were then analyzed. When PMN were incubated with
      these mutants, their activation was of the same intensity as that obtained with
      BS176. These data provide the first evidence for PMN activation induced by S.
      flexneri, a process which appears to be mediated by Ipa invasins.

PMID- 8641773
TI  - Differential contribution of Yersinia enterocolitica virulence factors to evasion
      of microbicidal action of neutrophils.
AB  - The differential contribution of the virulence factors invasin, protein tyrosine
      phosphatase (YopH), cytotoxin (YopE), and adhesin (YadA) of Yersinia
      enterocolitica to evasion of the antibacterial activities of polymorphonuclear
      leukocytes (PMNs) (oxidative burst, phagocytosis, killing) was analyzed. We
      constructed virulence gene knockout mutants and a novel two-plasmid system
      allowing production and secretion of individual virulence factors. Wild-type Y.
      enterocolitica WA-314 harboring the virulence plasmid pYV08 resisted phagocytosis
      and killing by PMNs. Moreover, strain WA-314 was able to inhibit the neutrophil
      oxidative burst upon stimulation with opsonized zymosan independently on
      preincubation with normal human serum or YadA-specific serum. These phenotypic
      properties of strain WA-314 were differentially affected when mutants impaired in
      YadA production or Yop secretion were used. A more detailed analysis revealed
      that YopH plays the dominant role in suppression of the antibacterial action of
      PMNs without damaging the cells. The YopH suppressing effect could be enhanced by
      coproduction of YopE and YadA. The contribution of YadA is attributed to the
      adhesin function promoting interaction with PMNs under both opsonizing and
      nonopsonizing conditions. In contrast, invasin seems to mediate only opsonin
      independent interaction with PMNs. Taken together, our results demonstrate that
      YopH, YopE, and YadA act in concert towards neutrophil attack to enable
      extracellular survival of Y. enterocolitica in host tissue.

PMID- 8641774
TI  - Apoptotic cell death in the response of D-galactosamine-sensitized mice to
      lipopolysaccharide as an experimental endotoxic shock model.
AB  - The apoptotic cell death induced in D-galactosamine-sensitized mice by
      administration of lipopolysaccharide was characterized. Administration of
      lipopolysaccharide caused apoptotic cell death in livers of D-galactosamine
      sensitized mice. Apoptotic cells were also detected in the kidney, thymus,
      spleen, and lymph node. Severe hepatic apoptosis in D-galactosamine-sensitized
      mice was reproduced by transfer of the sera from mice injected with D
      galactosamine and lipopolysaccharide. The hepatocyte apoptosis induced by
      lipopolysaccharide was completely prevented by an anti-tumor necrosis factor
      alpha antibody but not by an anti-gamma interferon antibody. Administration of
      recombinant tumor necrosis factor into D-galactosamine-sensitized mice also
      caused hepatocyte apoptosis. Lipopolysaccharide-induced hepatocyte apoptosis in D
      galactosamine-sensitized mice did not seem to be mediated by Fas antigen. It was
      suggested that lipopolysaccharide- induced hepatic injury and failure in D
      galactosamine-sensitized mice was due to the apoptotic cell death of hepatocytes
      caused by tumor necrosis factor alpha released in the circulation.

PMID- 8641775
TI  - Antibody-mediated inhibition of Aedes aegypti midgut trypsins blocks sporogonic
      development of Plasmodium gallinaceum.
AB  - The peritrophic matrix (PM) that forms around a blood meal is a potential barrier
      of Plasmodium development in mosquitoes. Previously, we have shown that to
      traverse the PM, Plasmodium ookinetes secrete a prochitinase and that an
      inhibitor of chitinase blocks further parasite development. Here we report that
      it is the mosquito trypsin that activates the Plasmodium prochitinase. Trypsin
      was identified as the chitinase-activating enzyme by two criteria: (i) trypsin
      activity and activating activity comigrated on one-dimensional gels, and (ii)
      activating activity and penetration of the PM by Plasmodium parasites were both
      hindered by trypsin-specific inhibitors. Subsequently, we examined the effect of
      antitrypsin antibodies on the parasite life cycle. Antibodies prepared against a
      recombinant blackfly trypsin effectively and specifically inhibited mosquito
      trypsin activity. Moreover, when incorporated into an infective blood meal, the
      antitrypsin antibodies blocked infectivity of Aedes aegypti mosquitoes by
      Plasmodium gallinaceum. This block of infectivity could be reversed by
      exogenously provided chitinase, strongly suggesting that the antibodies act by
      inhibiting prochitinase activation and not on the parasite itself. This work led
      to the identification of a mosquito antigen, i.e., midgut trypsin, as a novel
      target for blocking malaria transmission.

PMID- 8641777
TI  - Evidence of multiple extracellular phospholipase activities of Aspergillus
      fumigatus.
AB  - Extracellular phospholipase activity has been implicated in the pathogenesis of
      several bacterial infections. Recently, extracellular phospholipase activity has
      been proposed as a virulence factor in the opportunistic yeast Candida albicans.
      Aspergillus fumigatus is the most pathogenic member of its genus, responsible for
      > 90% of infections. Previously, no specific virulence factors have been
      determined. We investigated the ability of A. fumigatus to produce extracellular
      phospholipases at 37 degrees C. Fast atom bombardment was used to compare lipid
      containing media before and at 5-h intervals during shaking culture of A.
      fumigatus. Lipids were extracted and analyzed. Many anions corresponding to
      phospholipid breakdown products were identified. Specific anion species
      identified indicated phospholipase A, B, C (PLC), and D activities. PLC activity
      was further investigated by using the synthetic substrate p
      nitrophenylphosphorylcholine. PLC activity was initially observed after 30 h of
      growth and accumulated in broth cultures up to 50 h. At 55 h, there was a sharp
      increase in PLC activity which coincided with cultures reaching the stationary
      phase. Activity of the PLC was measured at different temperatures, with greater
      activity occurring at 37 degrees C than at lower temperatures. Phospholipases
      could represent a virulence determinant in A. fumigatus.

PMID- 8641776
TI  - Plasmodium falciparum induces apoptosis in human mononuclear cells.
AB  - The level of spontaneous apoptosis in short-term lymphocyte cultures was
      evaluated in different human immunodeficiency virus-negative groups of either
      healthy control individuals or patients with clinical malaria. The mean
      percentage of spontaneous apoptosis found in patients during a malaria attack was
      significantly higher than in sex- and age-matched healthy controls. The healthy
      asymptomatic controls were individuals with different degrees of exposure to
      Plasmodium falciparum as reflected by their various mean levels of specific anti
      P. falciparum (immunoglobulin G and M) antibodies. The percentages of apoptotic
      nuclei were found to be significantly higher in lymphocytes from subjects living
      in an area where malaria is holoendemic than in lymphocytes from subjects less
      exposed. Concentrations of soluble plasma interleukin-2 receptor were also higher
      in subjects from areas where malaria is endemic than in other groups, revealing
      different levels of lymphocyte activation. Of particular relevance to the in vivo
      situation, a P. falciparum schizont-rich extract induced a systematic and
      significant elevation of apoptotic nuclei at day 6 in 87.5% (35 of 40) of the
      subjects tested. In additional studies with different concentrations of extract,
      [3H]thymidine incorporation was concomitant with a low or limited level of
      apoptosis. Taken together, our results strongly suggest that acute as well as
      chronic asymptomatic P. falciparum infections were consistently associated with a
      marked increase in the level of mononuclear cell apoptosis. This process could be
      implicated in some of the alterations reported for the proliferative T-cell
      responses in areas where malaria is endemic.

PMID- 8641778
TI  - Cysteine protease of Porphyromonas gingivalis 381 enhances binding of fimbriae to
      cultured human fibroblasts and matrix proteins.
AB  - It has been shown that Porphyromonas gingivalis 381, a suspected
      periodontopathogen, possesses fimbriae on its cell surface. The organism is also
      known to produce proteases which can degrade the host cell surface matrix
      proteins. In this study, we investigated the effect of protease on the binding of
      the purified P. gingivalis fimbriae to cultured fibroblasts or matrix proteins. A
      protease that can hydrolyze benzoyl-L-arginine p-nitroanilide was obtained from
      P. gingivalis 381 cells by sonication in phosphate-buffered 0.2% Triton X-100 and
      was purified by column chromatography. The molecular size of the protease was
      estimated to be 55 kDa by gel filtration or 47 kDa by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis analysis. The enzyme activity was markedly
      inhibited by sulfhydryl reagents, antipain, and leupeptin. The protease degraded
      various host proteins, including collagen and fibronectin, and cleaved the COOH
      terminus of the arginine residue in peptides such as benzoyl-L-arginine p
      nitroanilide. However, P. gingivalis fimbriae were not degraded by protease
      activity. The enzyme activity was enhanced in the presence of reducing agents or
      CaCl2. When cultured fibroblasts were partially treated with the protease, the
      binding of the purified P. gingivalis fimbriae to the fibroblast monolayer was
      increased significantly. However, this enhancing effect was suppressed upon the
      addition of antipain and leupeptin. Similarly, binding of the fimbriae to the
      collagen or fibronectin immobilized on the microtiter wells was also enhanced.
      Addition of these host matrix proteins efficiently inhibited the binding of
      fimbriae to the fibroblast monolayer. The binding assay of fimbriae using
      dipeptidyl ligand affinity column chromatography demonstrated a clear interaction
      between fimbriae and the arginine residue. Taken together, these results indicate
      that the P. gingivalis protease at least partially degrades the host matrix
      proteins, which, in turn, may lead to an increased exposure of the cryptic
      ligands that can result in enhanced fimbria-mediated binding of this organism to
      periodontal tissues.

PMID- 8641779
TI  - Immunoglobulin A response in murine schistosomiasis: stimulatory role of egg
      antigens.
AB  - The immunoglobulin G (IgG) and IgA antibody responses to different Schistosoma
      mansoni antigens have been determined in chronically infected mice as well as in
      unisexually infected animals. With a panel of enzyme-linked immunosorbent assays
      (ELISAs), soluble antigens from furcocercariae, adult worms, and eggs were probed
      with sera collected at 3-week intervals. Bisexually infected animals developed
      significant IgG and IgA antibody responses to the antigens tested, which
      increased after egg deposition. In unisexual infections no significant
      differences were recorded in the IgG antibody profile for furocercaria and adult
      worm antigens, whereas the IgA antibody response was impaired. Both the IgA and
      IgG antibody responses toward egg antigens were reduced compared with those in a
      bisexual infection. Furthermore, a specific mucosal IgA antibody response was
      observed only in the bisexually infected animals. Histological analysis performed
      on bisexually infected mice led to the observation of eggs and granulomatous
      lesions within the Peyer's patch follicles, which are essential sites for the
      induction of mucosal immunity in the intestine. These data suggest a relationship
      between egg deposition and the induction of the IgA antibody response toward
      schistosomes.

PMID- 8641780
TI  - Lipopolysaccharide-induced lethality and cytokine production in aged mice.
AB  - This study was designed to define the lipopolysaccharide (LPS) sensitivity of
      aged mice in terms of lethality and cytokine production and to determine down
      regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal
      doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were
      601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight),
      respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal
      toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per
      kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF
      alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS
      peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups
      of mice. However, the peak values of these cytokines were significantly higher in
      aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable
      at 3 h, and sustained high levels were still detected after 12 h in both age
      groups. Although there were no significant differences in levels of IFN-gamma in
      sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3-
      to 12-h study period. Administration of increasing doses of LPS revealed that
      aged mice had a lower threshold to IL-1alpha production than young mice. In
      addition, aged mice were approximately 4-fold more sensitive to the lethal
      toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per
      kilogram) than young mice. With regard to down-regulating factors, corticosterone
      amounts were similar at basal levels and no differences in kinetics after the LPS
      challenge were observed, whereas IL-10 levels in sera were significantly higher
      in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate
      that aged mice are more sensitive to the lethal toxicities of LPS and TNF than
      young mice. We conclude that a relatively activated, or primed, state for LPS
      induced cytokine production, in spite of full down-regulating responses by
      corticosterone and IL- 10, may explain at least in part LPS sensitivity in aged
      mice.

PMID- 8641781
TI  - Enhanced protection by use of a combination of anticapsule and
      antilipopolysaccharide monoclonal antibodies against lethal Escherichia coli
      O18K5 infection of mice.
AB  - To study antibody-mediated protection against Escherichia coli peritonitis in
      BALB/c mice, monoclonal antibodies (MAbs) were generated against the capsule (K5)
      and the lipopolysaccharide (O18) of E. coli. Flow cytometric analysis with two
      selected immunoglobulin M MAbs revealed that bacteria were antigenically
      heterogeneous. Arbitrarily, three subpopulations in E. coli O18K5 cultures could
      be distinguished by double immunofluorescence. A subpopulation bound only the
      anti-K5 MAb, and another subpopulation bound only the anti-O18 MAb. An
      intermediate subpopulation, however, bound both MAbs. In agreement with this
      result, combinations of both MAbs enhanced phagocytosis of fluorescein
      isothiocyanate-labeled bacteria by human polymorphonuclear leukocytes and mouse
      macrophage J774 cells as well. In protection experiments, combinations of both
      MAbs, preincubated with 3 50% lethal doses of E. coli O18K5, protected all mice
      upon intraperitoneal challenge. Relatively high doses of either MAb alone proved
      to be not fully protective in this infection model. Protection of mice by the
      combination of MAbs was associated with significantly lower (P < 0.02) tumor
      necrosis factor levels in serum 90 min after challenge compared with any other
      treatment group. Similarly, prophylactic administration of MAbs yielded
      significantly lower (P < 0.01) tumor necrosis factor levels in mice that received
      the combination of MAbs than in any other treatment group.

PMID- 8641782
TI  - Intracellular survival of Burkholderia pseudomallei.
AB  - Burkholderia pseudomallei is the causative agent of melioidosis, a disease being
      increasingly recognized as an important cause of morbidity and mortality in many
      regions of the world. Several features of melioidosis suggest that B.
      pseudomallei is a facultative intracellular pathogen. This study was designed to
      assess the ability of B. pseudomallei to invade and survive in eukaryotic cells.
      We have shown that B. pseudomallei has the capacity to invade cultured cell
      lines, including HeLa, CHO, A549, and Vero cells. We have demonstrated
      intracellular survival of B. pseudomallei in professional phagocytic cells,
      including rat alveolar macrophages. B pseudomallei was localized inside vacuoles
      in human monocyte-like U937 cells, a histiocytic lymphoma cell line with
      phagocytic properties. Additionally, electron microscopic visualization of B.
      pseudomallei-infected HeLa cells and polymorphonuclear leukocytes confirmed the
      presence of intracellular bacteria within membrane-bound vacuoles. B.
      pseudomallei was found to be resistant to the cationic peptide protamine and to
      purified human defensin HNP-1.

PMID- 8641783
TI  - Induction of differential T-helper-cell responses in mice infected with variants
      of the parasitic nematode Trichuris muris.
AB  - The resistance or susceptibility of mice to infection with the intestinal
      nematode parasite Trichuris muris is closely correlated with polarization of T
      helper (Th) cell responses to the type 2 (Th2) or type 1 (Th1) subset. Comparison
      of infections with three isolates of T. muris (E/K, E/N, and S) in three inbred
      strains of mice (CBA, C57BL/10, and B10.BR) has shown that host Th response
      phenotype can be parasite determined. Although the mouse strains used show
      genetically determined variation in ability to respond to T. muris (CBA >
      C57BL/10 > B10.BR), the speed of worm expulsion in a given strain depended upon
      the isolate used for infection (E/K > E/N > S). The two isolates that induced the
      most effective resistance (E/K and E/N) elicited parasite-specific host antibody
      responses that were dominated by immunoglobulin G1 (IgG1), and antigen-stimulated
      T cells from infected mice released interleukin-5 in vitro. With the isolate that
      induced the least host resistance (S), the dominant antibody response was IgG2a,
      and T cells released gamma interferon in vitro. These data show clearly that
      parasite variant-specific factors play a major role in Th subset polarization
      during infection.

PMID- 8641784
TI  - Differential interaction with endocytic and exocytic pathways distinguish
      parasitophorous vacuoles of Coxiella burnetii and Chlamydia trachomatis.
AB  - Coxiella burnetii and Chlamydia trachomatis are bacterial obligate intracellular
      parasites that occupy distinct vacuolar niches within eucaryotic host cells. We
      have employed immunofluorescence, cytochemistry, fluorescent vital stains, and
      fluid-phase markers in conjunction with electron, confocal, and conventional
      microscopy to characterize the vacuolar environments of these pathogens. The
      acidic nature of the C. burnetii-containing vacuole was confirmed by its
      acquisition of the acidotropic base acridine orange (AO). The presence of the
      vacuolar-type (H+) ATPase (V-ATPase) within the Coxiella vacuolar membrane was
      demonstrated by indirect immunofluorescence, and growth of C. burnetii was
      inhibited by bafilomycin A1 (Baf A), a specific inhibitor of the V-ATPase. In
      contrast, AO did not accumulate in C. trachomatis inclusions nor was the V-ATPase
      found in the inclusion membrane. Moreover, chlamydial growth was not inhibited by
      Baf A or the lysosomotropic amines methylamine, ammonium chloride, and
      chloroquine. Vacuoles harboring C. burnetii incorporated the fluorescent fluid-
      phase markers, fluorescein isothiocyanate-dextran (FITC-dex) and Lucifer yellow
      (LY), indicating trafficking between that vacuole and the endocytic pathway.
      Neither FITC-dex nor LY was sequestered by chlamydial inclusions. The late
      endosomal-prelysosomal marker cation-independent mannose 6-phosphate receptor was
      not detectable in the vacuolar membranes encompassing either parasite. However,
      the lysosomal enzymes acid phosphatase and cathepsin D and the lysosomal
      glycoproteins LAMP-1 and LAMP-2 localized to the C. burnetii vacuole but not the
      chlamydial vacuole. Interaction of C. trachomatis inclusions with the Golgi
      derived vesicles was demonstrated by the transport of sphingomyelin, endogenously
      synthesized from C6-NBD-ceramide, to the chlamydial inclusion and incorporation
      into the bacterial cell wall. Similar trafficking of C-NBD-ceramide was not
      evident in C. burnetii-infected cells. Collectively, the data indicate that C.
      trachomatis replicates within a nonacidified vacuole that is disconnected from
      endosome-lysosome trafficking but may receive lipid from exocytic vesicles
      derived from the trans-Golgi network. These observations are in sharp contrast to
      those for C. burnetii, which by all criteria resides in a typical phagolysosome.

PMID- 8641785
TI  - Characterization of two conformational epitopes of the Chlamydia trachomatis
      serovar L2 DnaK immunogen.
AB  - Chlamydia trachomatis DnaK is an important immunogen in chlamydial infections.
      DnaK is composed of a conserved N-terminal ATP-binding domain and a variable C
      terminal peptide-binding domain. To locate the immunogenic part of C. trachomatis
      Dnak, we generated monoclonal antibodies (MAbs) against this protein. By use of
      recombinant DNA techniques, we located the epitopes for two MAbs in the C
      terminal variable part. Although the antibodies reacted in an immunoblot assay,
      it was not possible to map the epitopes completely by use of 16-mer synthetic
      peptides displaced by one amino acid corresponding to the C-terminal part of C.
      trachomatis DnaK. To determine the limits of the epitopes, C. trachomatis DnaK
      and glutatione S-transferase fusion proteins were constructed and affinity
      purified. The purified DnaK fusion proteins were used for a fluid-phase
      inhibition enzyme-linked immunosorbent assay with the two antibodies. The
      epitopes were found not to overlap. To obtain DnaK fragments recognized by the
      antibodies with the same affinity as native C. trachomatis DnaK, it was necessary
      to express, respectively, regions of 127 and 77 amino acids. The MAbs described
      in this study thus recognized conformational epitopes of C. trachomatis DnaK.

PMID- 8641786
TI  - Anti-Hsp65 antibodies recognize M proteins of group A streptococci.
AB  - Group A streptococcal M protein and the mycobacterial heat shock protein, hsp65,
      are strong bacterial immunogens that have been linked to arthritis and
      autoimmunity. Recent evidence has shown that streptococcal arthritis and adjuvant
      arthritis may be related to epitopes shared between group A streptococci and
      hsp65. We investigated the possibility that immunological similarities were
      shared between streptococcal M protein and hsp65. Antibodies against the 65-kDa
      heat shock protein of Mycobacterium tuberculosis were tested for reactivity with
      group A streptococci and purified recombinant M proteins (rM5 and rM6). Rabbit
      polyclonal anti-hsp65 serum was highly reactive with M type 5 Streptococcus
      pyogenes and rM5 and rM6 proteins in an enzyme-linked immunosorbent assay
      (ELISA). A mouse anti-hsp65 monoclonal antibody (MAb), IIC8, reacted with
      streptococcal M types 5, 6, 19, 24, and 49 in an ELISA but showed no reactivity
      with an isogenic streptococcal mutant which did not express M protein. Anti-hsp65
      MAb IIC8 recognized rM5 and rM6 proteins in the ELISA, and MAbs IIC8 and IIH9
      reacted strongly with rM6 protein in Western immunoblots. The binding of M
      protein by anti-hsp65 MAbs was shown to be inhibited by both hsp65 and M protein.
      These data show that anti-hsp65 antibodies recognize streptococcal M proteins.

PMID- 8641788
TI  - Invasin of Yersinia pseudotuberculosis activates human peripheral B cells.
AB  - The Yersinia pseudotuberculosis cell surface-located protein invasin was found to
      promote binding between the pathogen and resting peripheral B cells via beta 1
      integrin receptors (CD29). B cells responded by expressing several activation
      markers and by growing, In contrast, T cells did not react, although these cells
      express CD29. An isogenic invA mutant failed to activate B cells. The mutation
      could be complemented by providing the invA+ gene in trans. Purified invasin
      alone did not activate B cells, although it was able to block the binding of
      bacteria to the cells.

PMID- 8641787
TI  - Protection against endotoxic shock and lipopolysaccharide-induced local
      inflammation by tetracycline: correlation with inhibition of cytokine secretion.
AB  - Septic shock results from excessive stimulation of host immune cells,
      particularly monocytes and macrophages, by lipopolysaccharide (LPS) released from
      gram-negative bacteria. Macrophage-derived cytokines, such as tumor necrosis
      factor alpha (TNF-alpha) and interleukin-1beta (IL-1 beta), have been identified
      as central mediators in the pathogenesis of septic shock and the resultant
      mortality. Therefore, these cytokines were targets for experimental therapy for
      septic shock. Because of tetracycline's ability to intervene in cellular
      mechanisms involved in cytokine secretion, we tested the effect of tetracycline
      on LPS-induced septic shock and inflammatory lesions in mice. Tetracycline was
      found to protect mice against LPS-induced lethality and to abolish clinical signs
      of LPS-induced inflammatory lesions. This protection correlates with
      tetracycline's ability to reduce LPS-induced TNF-alpha levels in serum.
      Furthermore, tetracycline was found to inhibit LPS-induced TNF-alpha and IL-1
      beta secretion, but not cytokine mRNA accumulation, in human monocytes in vitro.
      The results presented here suggest that tetracycline is a potent drug for LPS
      induced pathology and that its mechanism of action involves blockage of
      posttranscriptional events of cytokine production.

PMID- 8641789
TI  - Expression of major surface protein 2 antigenic variants during acute Anaplasma
      marginale rickettsemia.
AB  - Antigenic variants of Anaplasma marginale major surface protein 2 (MSP-2), a
      target of protective immune responses, have been detected by use of copy-specific
      monoclonal antibodies reactive with some, but not all, organisms during acute
      rickettsemia. The presence of polymorphic msp-2 genes was confirmed by cloning
      and sequencing two gene copies, 11.2 and DF5, each of which encodes a full-length
      MSP-2 with a unique amino acid sequence. Transcription of msp-2 genes during
      acute rickettsemia was analyzed by use of cDNA cloning of hybrid-selected msp-2
      mRNA. Sequencing of cDNA clones, designated AR1 to AR14, indicated that DF5 msp-2
      was transcribed during acute rickettsemia. Two classes of variant msp-2 genes
      were also transcribed during acute rickettsemia. The first class of variant
      transcripts, typified by clones AR3, AR4, AR7, and AR14, each encoded a single or
      small number of amino acid substitutions relative to DF5. The second type, AR5,
      encoded a large region of amino acid polymorphism, including additions,
      deletions, and substitutions, as compared to DF5. Specific antibody directed
      against the AR5 polymorphic region bound a unique MSP-2 expressed on A. marginale
      that was not recognized by antibody generated against DF5. Similarly, anti-AR5
      peptide antibody reacted with a different MSP-2 that was not bound by anti-DF5
      antibody. This expression confirmed that variant msp-2 transcripts encode
      structurally distinct MSP-2 molecules which bear unique B-cell epitopes. These
      results support the hypothesis that the large msp-2 gene family, which
      constitutes a minimum of 1% of the genome, encodes antigenic variants critical to
      evasion of protective immune response directed against surface MSP-2 epitopes.

PMID- 8641790
TI  - A Legionella pneumophila gene that promotes hemin binding.
AB  - The ability to bind and utilize hemin is a trait common to many human pathogens.
      Nevertheless, the relationship between Legionella pneumophila, the agent of
      Legionnaires' disease, and hemin has received little attention. Thus, we explored
      the capacity of a virulent, serogroup 1 strain of L. pneumophila to bind hemin
      and use it as an iron source. Hemin, but not protoporphyrin IX, restored
      bacterial growth in iron-limiting media, indicating that it can serve as an iron
      source for L. pneumophila. In support of this idea, we observed that wildtype
      legionellae were able to bind 50 to 60% of added hemin, a binding capacity that
      was comparable to those of other pathogens. To begin to identify proteins
      involved in hemin acquisition, we identified a Legionella locus that conferred
      hemin binding upon Escherichia coli. Subcloning and nucleotide sequence analysis
      determined that a single open reading frame, which was designated hbp for hemin
      binding promotion, was responsible for this binding activity. The hbp gene was
      predicted to encode a secreted, 15.5-kDa protein. To ascertain the importance of
      this gene in L. pneumophila biology, we used allelic exchange to construct an hbp
      mutant. Importantly, the mutant displayed a 42% reduction in hemin binding,
      confirming that hbp potentiates hemin acquisition by L. pneumophila. However, the
      strain was unaltered in its ability to grow within macrophage-like cells and
      freshwater amoebae, indicating that hbp is not required for intracellular
      infection. Despite this, Southern hybridization analysis and database searches
      demonstrated that hbp is nearly exclusive to the L. pneumophila species.

PMID- 8641791
TI  - Gamma interferon and interleukin-10 gene expression in innately susceptible and
      resistant mice during the early phase of Salmonella typhimurium infection.
AB  - Previous studies have shown that gamma interferon (IFN-gamma) plays a major role
      in natural resistance to Salmonella typhimurium during the early phase of
      infection. To assess whether the level of natural resistance in mice is related
      to the level of IFN-gamma gene expression, we compared IFN-gamma mRNA levels by
      means of reverse transcriptase-PCR in the spleens of genetically susceptible Itys
      (C57BL/6 and BALB/c) and resistant Ityr (CBA and DBA/2) mice during the first 5
      days of infection. The mRNA expression of interleukin-10 (IL-10), a cytokine
      which antagonizes IFN-gamma effects, was also investigated. Mice were infected
      with 10(3) CFU of the virulent strain S. typhimurium C5, a dose which is lethal
      within a week for susceptible mice only. IFN-gamma mRNA increased to similar
      levels in both susceptible and resistant mice, suggesting that susceptibility to
      S. typhimurium infection is not related to defective IFN-gamma gene expression.
      In contrast, IL-10 mRNA reached much higher levels in susceptible than in
      resistant mice. Similar results were found in Ity congenic mice, confirming a
      link between the presence of the Itys allele and a high level of IL-10 gene
      expression during infection. High levels of IL-10 mRNA in susceptible mice
      correlated with high IL-10 serum levels (on day 5), whereas IL-10 was not
      detectable in the sera of resistant mice. However, administration of neutralizing
      anti-IL-10 monoclonal antibodies did not modify the course of infection. To
      evaluate the influence of bacterial multiplication on IL-10 mRNA expression,
      susceptible mice were infected with an attenuated strain of S. typhimurium. This
      strain induced a low level of IL-10 mRNA expression. When susceptible mice were
      immunized with an attenuated strain and challenged with the virulent strain, they
      inhibited the growth of the challenge bacteria and exhibited a low level of IL-10
      mRNA. In contrast, when resistant mice were infected with a high (lethal) dose of
      the virulent strain, they exhibited a high level of IL-10 mRNA. Taken together,
      these results indicate that the level of IL-10 gene expression correlates with
      the level of bacterial multiplication in the organs and that the high level of IL
      10 mRNA in Itys mice is a consequence rather than the cause of their
      susceptibility to S. typhimurium infection.

PMID- 8641792
TI  - Cloning and characterization of the galE locus of Pasteurella haemolytica A1.
AB  - The enzyme UDP-galactose 4-epimerase (GalE) is involved in one of the major steps
      of galactose metabolism in bacteria. In many cases, GalE is required for the
      biosynthesis of extracellular polysaccharide materials such as lipopolysaccharide
      (LPS) and capsule. Mutants defective in galE have been shown to exhibit reduced
      virulence. Here we describe the cloning and characterization of the galE gene
      from the bovine pathogen Pasteurella haemolytica A1. This was achieved by the
      complementation of a Salmonella typhimurium galE mutant with a P. haemolytica A1
      plasmid bank. Analysis of six clones recovered on minimal media with galactose as
      the carbon source showed that they all contained the same recombinant plasmid
      with a 5-kbp DNA insert. The galE-complementing activity was localized to a 2.2
      kbp DNA region by subcloning. Biochemical, immunological, and phage sensitivity
      analyses of the recombinant LPS in S. typhimurium showed that it is essentially
      identical to that of the wild type. In vivo expression studies showed that a 37
      kDa protein is expressed from the complementing plasmids, and the presence of
      GalE activity was confirmed by an assay for epimerase activity. Nucleotide
      sequence analysis of the cloned DNA identified the galE gene. Comparison of the
      deduced amino acid sequence analysis of P. haemolytica A1 GalE with published
      data showed high-level homology, 81.6%, with the GalE of Haemophilus influenzae
      type b. However, the sequences flanking galE do not show similarity with any
      other gal gene, suggesting that P. haemolytica A1 galE is not linked to the other
      genes of the gal operon, as is the case for Neisseria meningitidis, Neisseria
      gonorrhoeae, and H. influenzae. The separation of galE from the classical gal
      operon genes was confirmed by Southern blot hybridization studies, and a physical
      map showing the relative positions of galE, galT, and galK was constructed.

PMID- 8641793
TI  - Analysis of the superantigenic activity of mutant and allelic forms of
      streptococcal pyrogenic exotoxin A.
AB  - Infections with Streptococcus pyogenes (group A streptococcus) can result in the
      recently described streptococcal toxic shock syndrome (STSS), which is
      characterized by rashes, hypotension, multiorgan failure, and a high mortality
      rate. S. pyogenes isolates associated with STSS usually produce streptococcal
      pyrogenic exotoxin A (SpeA), a bacterial superantigen capable of stimulating host
      immune cells. Most of the symptoms of STSS are believed to result from cytokine
      release by the stimulated cells. To better understand the pathogenesis of STSS,
      we began studies on the SpeA-immune cell interaction. We generated 20 mutant
      forms of SpeA1 (SpeA encoded by allele 1), and the mutant toxins were analyzed
      for mitogenic stimulation of human peripheral blood mononuclear cells, affinity
      for class II major histocompatibility complex molecules (DQ), and disulfide bond
      formation. Residues necessary for each of these functions were identified. There
      are four alleles of speA, and STSS strains usually contain either allele 2 or
      allele 3. The product of allele 2, SpeA2, had slightly higher affinity for the
      class II MHC molecule compared with SpeA1 but not significantly greater mitogenic
      activity. SpeA3, however, was significantly increased in mitogenic activity and
      affinity for class II MHC compared with SpeA1. Thus, we have evidence that the
      toxin encoded by some of the highly virulent S. pyogenes STSS-associated isolates
      is a more active form of SpeA.

PMID- 8641794
TI  - Streptococcal cysteine protease augments lung injury induced by products of group
      A streptococci.
AB  - Streptococcus pyogenes infections in humans may be associated with severe
      clinical manifestations, including adult respiratory distress syndrome and a
      toxic shock-like syndrome. These observations have led to the investigation of
      products of group A streptococci that may contribute to increased virulence.
      Streptococcal pyrogenic exotoxin B is a highly conserved precursor of an
      extracellular cysteine protease that is secreted by S. pyogenes. We investigated
      the ability of this streptococcal cysteine protease (SCP) to act synergistically
      with either streptococcal cell wall antigen (SCW) or streptolysin-O (SLO) to
      augment lung injury in rats. Intratracheal administration of either SCW or SLO
      alone caused lung injury, as measured by pulmonary vascular leak. Bronchoalveolar
      lavage (BAL) fluid analysis showed that SCW induced neutrophil accumulation and
      appearance of interleukin-1beta and tumor necrosis factor alpha. In contrast, SLO
      induced neither neutrophil influx nor significant cytokine elevations in BAL
      fluids. Intratracheal administration of SCP with either SCW or SLO resulted in
      synergistic augmentation of lung vascular permeability and accumulation of BAL
      neutrophils. The synergy was reduced when SCP was either heat inactivated or
      coinstilled with a peptide inhibitor of the protease. SCP in the presence of SCW
      resulted in a significant increase in BAL fluid tumor necrosis factor alpha
      content but not in immunoreactive interleukin-1beta. Moreover, the copresence of
      SAP with SAW resulted in increased BAL fluid nitrite-nitrate levels, indicative
      of nitric oxide production. These data demonstrate that SCP acts synergistically
      with other S. pyogenes products (SCW or SLO) to increase tissue injury and
      provide additional evidence that SCP may function as an important virulence
      factor in group A streptococcal infections.

PMID- 8641795
TI  - Paclitaxel (Taxol)-induced NF-kappaB translocation in murine macrophages.
AB  - Interaction of bacterial lipopolysaccharide (LPS) with macrophages results in the
      induction of a cascade of cytokines that mediate the varied effects of LPS. An
      early intracellular signaling event that follows receptor engagement is the
      activation of transcription factor NF-kappaB. Nf-kappaB has been shown to be
      important for the induction of many LPS-inducible cytokine genes, including tumor
      necrosis factor alpha, interleukin-1beta, and interleukin-6. Previously, we and
      others have shown that the antitumor agent paclitaxel (Taxol) is able to mimic
      bacterial LPS in its ability to activate murine macrophages. In this report, we
      have extended these findings by demonstrating that paclitaxel, like LPS, is able
      to stimulate the translocation of primarily p50-p65 heterodimers of NF-kappaB to
      the nucleus. This activation is dose dependent and requires a concentration of >
      or =5 microM paclitaxel. The kinetics of NF-kappaB activation by paclitaxel are
      slower than those of LPS: by 15 min poststimulation, LPS-induced NF-kappaB
      activation was readily detected, whereas the paclitaxel-induced NF-kappaB
      activation was minimal. Moreover, paclitaxel- and protein-free LPS-induced
      translocation of NF-kappaB was seen only in macrophages derived from LPS
      responsive C3H/OuJ mice and not from the LPS-hyporesponsive C3H/HeJ mice, a
      finding that is consistent with those of previous genetic studies linking
      paclitaxel responsiveness to the Lps gene. Finally, the LPS structural antagonist
      Rhodobacter sphaeroides diphosphoryl lipid A inhibited both LPS-and paclitaxel
      induced NF-kappaB activation, suggesting a common receptor component in this
      activation.

PMID- 8641796
TI  - Biochemical and mutational analysis of the histidine residues of staphylococcal
      enterotoxin A.
AB  - The goal of this study was to examine the role of histidine residues in the
      biological activities of staphylococcal enterotoxin A (SEA). Carboxymethylated
      SEA was unable to stimulate murine T-cell proliferation but was resistant to
      monkey stomach lavage fluid degradation, suggesting that native conformation was
      intact. Site-directed mutagenesis of the histidine residues of SEA was
      subsequently performed. SEA-H44A (SEA with histidine 44 replaced with alanine),
      SEA-H44D, SEA-H50A, SEA-H50D, SEA-H114A, SEA-H114D, SEA-H187A, and SEA-H187D
      retained superantigen and emetic activities, whereas SEA-H225A and SEA-H225D were
      defective in the ability to stimulate T-cell proliferation. These mutants were
      unable to compete with SEA for binding to Raji cells, suggesting that the defect
      in SEA-H225A and SEA-H225D is due to impaired major histocompatibility complex
      class II binding. SEA-H225D provoked an emetic response in monkeys only if fed at
      high doses, while SEA-H225A did not provoke an emetic response at low or high
      doses. In comparison, SEA-H61A and SEA-H61D were defective in emetic activity but
      not in the ability to stimulate murine T-cell proliferation. Overall, these
      studies show that the carboxy-terminal histidine at residue position 225 of SEA
      is important for both the superantigen and emetic activities of this enterotoxin.
      Histidine 61 appears to be important for emetic activity but not for superantigen
      activity, consistent with the hypothesis that the two activities are separable in
      staphylococcal enterotoxins.

PMID- 8641797
TI  - Blood group glycolipids as epithelial cell receptors for Candida albicans.
AB  - The role of glycosphingolipids as possible epithelial cell receptors for Candida
      albicans was examined by investigating the binding of biotinylated yeasts to
      lipids extracted from human buccal epithelial cells and separated on thin-layer
      chromatograms. Binding was visualized by the addition of 125I-streptavidin
      followed by autoradiography. Five C. albicans strains thought from earlier work
      to have a requirement for fucose-containing receptors all bound to the same three
      components in the lipid extract. A parallel chromatogram overlaid with
      biotinylated Ulex europaeus lectin, which is a fucose-binding lectin with a
      specificity for the H blood group antigen, showed that two of these
      glycosphingolipids carried this antigenic determinant. Preparations of crude and
      purified adhesin (a protein with a size of 15.7 kDa which lacked cysteine
      residues) from one of the strains also bound to these same two components. The
      third glycosphingolipid, which bound whole cells but neither preparation of
      adhesin, was recognized by Helix pomatia lectin, indicating that it contained N
      acetylgalactosamine, possibly in the form of the A blood group antigen. Overlay
      assays with a sixth strain of C. albicans (GDH 2023) revealed a completely
      different binding pattern of four receptors, each of which contained N
      acetylglucosamine. These results confirm earlier predictions about the receptor
      specificity of the strains made on the basis of adhesion inhibition studies and
      indicate that blood group antigens can act as epithelial cell receptors for C.
      albicans.

PMID- 8641798
TI  - Different roles for interleukin-4 during the course of Toxoplasma gondii
      infection.
AB  - The course of Toxoplasma gondii infection from initiation of disease perorally
      until day 28 postinfection was compared between interleukin-4 (IL-4) gene
      knockout (IL-4-/-) mice and their wild-type (IL-4+/+) counterparts on a disease
      susceptible genetic background. The rate of mortality was significantly greater
      in mice deficient in Il-4 than in the immunocompetent controls. Although levels
      of T. gondii-specific spleen cell proliferation measured in vitro were similar
      between groups at all time points examined throughout infection, the quantities
      of cytokines released into the culture supernatant differed. Culture supernatants
      from spleen cells derived from IL-4-deficient mice contained significantly more
      gamma interferon than those derived from IL-4+/+ mice at day 7 postinfection.
      Conversely, IL-10 production was significantly greater from the spleen cells
      derived from wild-type mice at day 28 postinfection. Splenocytes from both groups
      of mice had a marked inhibition of proliferation in response to soluble
      tachyzoite antigen as well as reduced proliferation in response to concanavalin A
      between days 7 and 14 postinfection and marked proliferation on days 21 and 28
      postinfection. At day 28 postinfection, histological examination of the brains
      indicated that IL-4+/+ mice had more severe pathological changes and more cysts
      than IL-4-/- mice. In addition, although many nonencysted single organisms were
      present in IL-4+/+ mice within both necrotic lesions and microglial nodules, few
      nonencysted parasites were found, and no necrotic lesions were present in IL-4
      deficient animals. These results suggest that the observed reduction in mortality
      during the early acute phases of infection may be due to the down-regulatory
      effects of Il-4 or associated Th2-derived products on proinflammatory cytokines
      such as gamma interferon. However, the long-term effects of IL-4 are detrimental,
      possibly because of the ability of this cytokine to inhibit proinflammatory
      antiparasitic products. This may explain the increased parasite multiplication
      with cysts observed in the brains of IL-4+/+ mice.

PMID- 8641799
TI  - Surface localization of Helicobacter pylori urease and a heat shock protein
      homolog requires bacterial autolysis.
AB  - Helicobacter pylori is a gram-negative bacterium which causes chronic gastritis
      and is associated with peptic ulcer disease, gastric carcinoma, and gastric
      lymphoma. The bacterium is characterized by potent urease activity, thought to be
      located on the outer membrane, which is essential for survival at low pH. The
      purpose of the present study was to investigate mechanisms whereby urease and
      HspB, a GroEL homolog, become surface associated in vitro. Urease, HspB, and
      catalase were located almost exclusively within the cytoplasm in fresh log-phase
      cultures assessed by cryo- immunoelectron microscopy. In contrast, significant
      amounts of surface-associated antigen were observed in older or subcultured
      preparations concomitantly with the appearance of significant amounts of
      extracellular antigen, amorphous debris, and membrane fragments. By use of a
      variety of biochemical methods, a significant fraction of urease and HspB was
      associated with the outer membrane in subcultured preparations of H. pylori.
      Taken together, these results strongly suggest that H. pylori cells undergo
      spontaneous autolysis during culture and that urease and HspB become surface
      associated only concomitant with bacterial autolysis. By comparing enzyme
      sensitivity to flurofamide (a potent, poorly diffusible urease inhibitor) in
      whole cells with that in deliberately lysed cells, we show that both
      extracellular and intracellular urease molecules are active enzymatically.
      Autolysis of H. pylori is an important phenomenon to recognize since it likely
      exerts significant effects on the behavior of H. pylori. Furthermore, the surface
      properties of H. pylori must be unique in promoting adsorption of cytoplasmic
      proteins.

PMID- 8641800
TI  - Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and
      CTLA-4 expression.
AB  - To characterize the mechanism by which interleukin 10 (IL-10) inhibits Th1
      responses to intracellular pathogens, we evaluated the interaction between IL-10
      and Mycobacterium tuberculosis-induced gamma interferon (IFN-gamma) production by
      peripheral blood mononuclear cells from persons across the spectrum of
      tuberculous infection. M. tuberculosis-induced IFN-gamma production was highest
      in healthy tuberculin reactors, intermediate in human immunodeficiency virus
      (HIV)-negative tuberculosis patients, and lowest in HIV-infected tuberculosis
      patients. Neutralizing antibodies to IL-10 increased IFN-gamma production in HIV
      infected and HIV-negative tuberculosis patients by enhancing monocyte IL-12
      production. Expression of the T-cell-costimulatory molecule CTLA-4 was depressed
      in M. tuberculosis-stimulated peripheral blood mononuclear cells from
      tuberculosis patients, and anti-IL-10 and Il-12 upregulated expression of CTLA-4.
      These findings provide evidence that intracellular pathogens can inhibit Th1
      responses and downregulate expression of specific costimulatory molecules.

PMID- 8641801
TI  - Population structure of Streptococcus agalactiae reveals an association between
      specific evolutionary lineages and putative virulence factors but not disease.
AB  - To evaluate the genetic diversity and relationships in a collection of 85 Danish
      strains of Streptococcus agalactiae (group B streptococcus) we have performed
      restriction fragment length polymorphism analysis on EcoRI- and MspI-digested
      whole-cell DNA using as probes rRNA, DNA fragments representing the genes
      encoding hyaluronidase, C5a-peptidase, alpha-antigen, and beta-antigen as well as
      two randomly selected genomic DNA fragments for which the coding potential is
      unknown. In addition, we have assayed for expression of hyaluronidase activity
      and beta-antigen. Combined analyses of our data and those previously obtained by
      multilocus enzyme electrophoresis and serotyping revealed a population separating
      into six major lineages that correlate with individual serotypes. The significant
      linkage disequilibrium of alleles indicates that the S. agalactiae population
      examined is predominantly clonal. Notably, strains expressing the serotype III
      capsule divide into two distant evolutionary lineages, of which one lacks
      expression of hyaluronidase activity. Six North American isolates of serotype III
      clustered together with multiple Danish serotype III strains, showing that the
      combinations of characters on which the phylogenetic tree was based are conserved
      worldwide. Occurrence of beta-antigen correlated with a specific version of the
      alpha-antigen gene and was exclusively associated with a single major
      phylogenetic lineage. Comparisons with the clinical history of the strains
      revealed no evidence of differences in pathogenic potential among the six major
      genetic divisions.

PMID- 8641802
TI  - In vitro activity of the antimicrobial peptides human and rabbit defensins and
      porcine leukocyte protegrin against Mycobacterium tuberculosis.
AB  - Three independent assay methods were used to investigate the activities of
      antimicrobial peptides (human and rabbit defensins and protegrin from porcine
      leukocytes) against Mycobacterium tuberculosis in vitro. M. tuberculosis H37Ra
      was cultured in the presence of human neutrophil peptide 1, synthetic rabbit
      neutrophil peptide 1, or porcine protegrin 1 at 37 degrees C for 6 to 48 h, and
      antimycobacterial activity was measured by CFU assay. These peptides at a
      concentration of 50 microg/ml showed significant antibacterial effects on M.
      tuberculosis after 24 and 48 h of incubation (85.9 to 97.5% at 24 h and 91.6 to
      99.4% at 48 h). A radiometric method and a radial diffusion assay confirmed these
      observations. Antibacterial activity against M. tuberculosis was independent of
      calcium (1.0 mM) or magnesium (1.0 mM) and not inhibited by sodium chloride (100
      mM). The optimal pH for antibacterial activity against M. tuberculosis was
      greater than 4.0. Three clinical isolates of M. tuberculosis were also studied,
      and these peptides showed 86.3 to 99.0% reduction in CFU of these organisms.
      Morphological studies using scanning electron microscopy showed that defensins
      caused lesions on the surface of H37Ra. These observations suggest that
      antimicrobial peptides such as defensins and protegrins may represent an
      important component of the host defense mechanism against M. tuberculosis and
      offer a potential new approach to therapy.

PMID- 8641803
TI  - Analysis of the specificity of bacterial immunoglobulin A (IgA) proteases by a
      comparative study of ape serum IgAs as substrates.
AB  - Immunoglobulin A (IgA) proteases are bacterial enzymes with substrate specificity
      for human serum and secretory IgAs. To further define the basis of this
      specificity, we examined the ability of IgA proteases of Clostridium ramosum,
      Streptococcus pneumoniae (EC 3.4.24.13), Neisseria meningitidis (EC 3.4.21.72),
      and Haemophilus influenzae (EC 3.4.21.72) to cleave serum IgAs of gorillas,
      chimpanzees, and orangutans. All enzymes cleaved the IgAs of the three apes
      despite differences in ape IgA1 hinge sequence relative to the human prototype.
      To directly compare the ape and human hinge cleavage sites, the sites were
      identified in eight ape IgA digests. This analysis confirmed that ape proteins
      were all cleaved in the IgA hinge region, in all but one case after proline
      residues. The exception, C. ramosum protease, cleaved gorilla and chimpanzee IgAs
      at peptide bonds having no proline, but the scissile bonds were in the same hinge
      location as the Pro-221-Val-222 cleaved in human IgA1. These data indicate that
      proline is not an invariant substrate requirement for all IgA proteases and that
      the location of the scissile bond, in addition to its composition, is a critical
      determinant of cleavage specificity.

PMID- 8641804
TI  - Effect of vaccination of hens with an avirulent strain of Salmonella typhimurium
      on immunity of progeny challenged with wild-Type Salmonella strains.
AB  - The avirulent Salmonella typhimurium chi3985 was used to vaccinate white leghorn
      chickens at 16 and 18 weeks of age, and the effect of maternal antibody on
      Salmonella colonization of progeny of vaccinated hens was assessed with S.
      typhimurium F98 or chi3985. Progeny of hens that had been vaccinated at 1 and 3
      or 2 and 4 weeks of age with chi3985 were used to determine the effect of
      maternal immunity on vaccine efficacy. Vaccination of hens induced long-lasting
      Salmonella-specific antibodies which were transferred into eggs and were detected
      as immunoglobulin G (IgG) in the egg yolk. Maternal antibody was detected in the
      progeny of vaccinated birds as IgG and IgA in serum and intestinal fluid,
      respectively. The titer of maternally transmitted IgG or IgA was highest in the
      first week of life of the progeny and declined with age. Maternal antibodies
      prevented colonization of the chicks by S. typhimurium chi3985 and reduced
      colonization by S. typhimurium F98. Overall, chicks from vaccinated hens had
      significantly higher antibody responses than did the progeny of nonvaccinated
      hens after oral infection with Salmonella strains. Maternal antibody reduced the
      efficacy of vaccination of progeny with chi3985 at 1 and 3 weeks of age. But
      vaccination at 2 and 4 weeks of age induced excellent protection against
      challenge with S. typhimurium F98 or S. enteritidis 27A PT 8 in birds from
      vaccinated hens and in specific-pathogen-free chickens. Vaccination of chickens
      at 2 and 4 weeks of age has been shown to protect the birds against challenge
      with homologous and heterologous Salmonella serotypes. A combination of
      vaccination of adult animals and use of the progeny of vaccinated birds will
      enhance effective control of Salmonella infections in the poultry industry. This
      will complement the present control of Salmonella-associated food poisoning
      caused by Salmonella enteritidis in eggs because the avirulent S. typhimurium
      vaccine strain chi3985 induced excellent protection against S. enteritidis in
      chickens.

PMID- 8641805
TI  - Effects of interleukin-10 on human peripheral blood mononuclear cell responses to
      Cryptococcus neoformans, Candida albicans, and lipopolysaccharide.
AB  - Deactivation of mononuclear phagocytes is critical to limit the inflammatory
      response but can be detrimental in the face of progressive infection. We compared
      the effects of the deactivating cytokine interleukin 10 (IL-10) on human
      peripheral blood mononuclear cell (PBMC) responses to lipopolysaccharide (LPS),
      Cryptococcus neoformans, and Candida albicans. IL-10 effected dose-dependent
      inhibition of tumor necrosis factor alpha (TNF-alpha) release in PBMC stimulated
      by LPS and C. neoformans, with significant inhibition seen with 0.1 U/ml and
      greater than 90% inhibition noted with 10 U/ml. In contrast, even at doses as
      high as 100 U/ml, IL-10 inhibited TNF-alpha release in response to C. albicans by
      only 50%. IL-10 profoundly inhibited release of IL-1beta from PBMC stimulated by
      all three stimuli. TNF-alpha mRNA and release was inhibited even if IL-10 was
      added up to 8 h after cryptococcal stimulation. In contrast, inhibition of IL-1
      beta mRNA was of lesser magnitude and occurred only when IL-10 was added within 2
      h of cryptococcal stimulation. IL-10 inhibited translocation of NF-kappaB in
      response to LPS but not the fungal stimuli. All three stimuli induced IL-10
      production in PBMC, although over 10-fold less IL-10 was released in response to
      C. neoformans compared with LPS and C. albicans. Thus, while IL-10 has
      deactivating effects on PBMC responses to all three stimuli, disparate stimulus-
      and response-specific patterns of deactivation are seen. Inhibition by IL-10 of
      proinflammatory cytokine release appears to occur at the level of gene
      transcription for TNF-alpha and both transcriptionally and posttranscriptionally
      for IL-1beta.

PMID- 8641806
TI  - Selection and phenotypic characterization of nonhemagglutinating mutants of
      Porphyromonas gingivalis.
AB  - To further investigate the relationship between fimbriae and the hemagglutinating
      adhesin HA-Ag2 of Porphyromonas gingivalis, three spontaneous mutants of the type
      strain ATCC 33277 were selected by a hemadsorption procedure. They were
      characterized for hemagglutination, trypsin-like and lectin-binding activities,
      and hydrophobicity and for the presence of fimbriae. The presence of the 42-kDa
      (the fimbrilin subunit) and the 43- and 49-kDa (the HA-Ag2 components)
      polypeptides was investigated by immunoblotting using polyclonal and monoclonal
      antibodies directed to fimbriae and to the hemagglutinating adhesin HA-Ag2. Cells
      from two of the three mutants (M1 and M2) exhibited no or little hemagglutination
      activity and very low trypsin-like activity and did not show the 43- and 49-kDa
      polypeptides. Abnormal fimbriation in M1 was deduced from the following
      observations of cells grown for 18 h: absence of the 42-kDa polypeptide and of a
      14-kDa polypeptide and no fimbriae visible on electron micrographs. While the
      cells of mutant M2, irrespective of the age of the culture, were found to lack
      the 43- and 49-kDa polypeptides and hemagglutination activity, the supernatants
      of cultures grown for 72 h had high hemagglutination and trypsin-like activities
      and revealed the presence of the 42-, 43-, and 49-kDa polypeptides. This suggests
      that M2 may be missing some molecules which anchor the components to the cell
      surface. Mutant M3 showed levels of activities similar to those of the parental
      strain but lacked the 43-kDa polypeptide. Other pleiotropic effects observed for
      the mutants included loss of dark pigmentation and lower hydrophobicity. The data
      from this study fuel an emerging consensus whereby fimbriation, hemagglutination,
      and proteolytic activities, as well as other functions in P. gingivalis, are
      intricate.

PMID- 8641807
TI  - Pasteurella multocida toxin is a mitogen for bone cells in primary culture.
AB  - The effect of recombinant Pasteurella multocida toxin (PMT) on primary cultures
      of embryonic chick bone-derived osteoblastic cells was investigated. It was found
      that PMT was a potent mitogen for primary derived chicken osteoblasts. The toxin
      stimulated DNA synthesis and cell proliferation in quiescent osteoblasts at the
      first passage and accelerated cell growth in subconfluent cultures. Cell
      viability was not affected by PMT, even at relatively high concentrations.
      Osteoblast numbers increased in a dose-dependent manner in response to PMT.
      Intracellular inositol phosphates were elevated in response to PMT, but no
      elevation in cyclic AMP (cAMP) levels was evident. Indeed, PMT inhibited cAMP
      elevation in osteoblasts in response to cholera toxin at a stage before other PMT
      mediated events take place. In addition to increased cell turnover, PMT down
      regulated the expression of several markers of osteoblast differentiation. Both
      alkaline phosphatase and type I collagen were reduced, but osteonectin was not
      affected. The in vitro deposition of mineral in cultures of primary osteoblasts
      and osteoblast-like osteosarcoma cells was also inhibited by the presence of PMT.
      This suggests that PMT interferes with differentiation at a preosteoblastic
      stage.

PMID- 8641808
TI  - Expression of attaching/effacing activity by enteropathogenic Escherichia coli
      depends on growth phase, temperature, and protein synthesis upon contact with
      epithelial cells.
AB  - Enteropathogenic Escherichia coli (EPEC) induces tyrosine phosphorylation of a 90
      kDa protein (Hp90) in infected epithelial cells. This in turn facilitates
      intimate binding of EPEC via the outer membrane protein intimin, effacement of
      host cell microvilli, cytoskeletal rearrangement, and bacterial uptake. This
      phenotype has been commonly referred to as attaching/effacing (A/E). The ability
      of EPEC to induce A/E lesions was dependent on bacterial growth phase and
      temperature. Early-logarithmic-phase EPEC grown at 37 degrees C elicits strong
      A/E activity within minutes after infection of HeLa epithelial cells. EPEC de
      novo protein syntheses during the first minutes of interaction with the host cell
      was required to elicit A/E lesions. However, once formed, bacterial viability was
      not needed to maintain A/E lesions. The type of growth media and partial O2
      pressure level do not seem to affect the ability of EPEC to cause A/E lesions.
      These results indicates that the A/E activity of EPEC is tightly regulated by
      environmental and host factors.

PMID- 8641809
TI  - Induction of antigen-specific antibodies in vaginal secretions by using a
      nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant.
AB  - Immunization of the female reproductive tract is important for protection against
      sexually transmitted diseases and other pathogens of the reproductive tract.
      However, intravaginal immunization with soluble antigens generally does not
      induce high levels of secretory immunoglobulin A (IgA). We recently developed
      safe mucosal adjuvants by genetically detoxifying Escherichia coli heat-labile
      enterotoxin, a molecule with a strong mucosal adjuvant activity, and here we
      describe the use of the nontoxic mutant LTK63 to induce a response in the mouse
      vagina against ovalbumin (Ova). We compared intravaginal and intranasal routes of
      immunization for induction of systemic and vaginal responses against LTK63 and
      Ova. We found that LTK63 is a potent mucosal immunogen when given by either the
      intravaginal or intranasal route. It induces a strong systemic antibody response
      and IgG and long-lasting IgA in the vagina. The appearance of vaginal IgA is
      delayed in the intranasally immunized mice, but the levels of vaginal anti-LTK63
      IgA after repeated immunizations are higher in the intranasally immunized mice
      than in the intravaginally immunized mice. LTK63 also acts as a mucosal adjuvant,
      inducing a serum response against Ova, when given by both the intravaginal and
      intranasal routes. However, vaginal IgA against Ova is stimulated more
      efficiently when LTK63 and antigen are given intranasally. In conclusion, our
      results demonstrate that LTK63 can be used as a mucosal adjuvant to induce
      antigen-specific antibodies in vaginal secretions and show that the intranasal
      route of immunization is the most effective for this purpose.

PMID- 8641810
TI  - Immune selection for antigenic drift of major outer membrane protein P2 of
      Haemophilus influenzae during persistence in subcutaneous tissue cages in
      rabbits.
AB  - During persistence of nonencapsulated Haemophilus influenzae in the respiratory
      tracts of patients with chronic bronchitis, the major outer membrane proteins
      (MOMPs) P2 and P5 show antigenic drift. The hypothesis that appearance of
      antigenic variants is the consequence of antibody-dependent selection was tested
      in a rabbit model. Persistence of H. influenzae d1 was achieved in subcutaneous
      tissue cages for up to 948 days. During persistence in the rabbits, similar
      changes in MOMP P2 of H. influenzae occurred, as observed in isolates from
      chronic bronchitis patients. In rabbits vaccinated with strain d3 and in
      nonvaccinated rabbits, antigenic drift occurred later than in rabbits vaccinated
      with strain d1. High titers of antibodies against H. influenzae were measured in
      tissue cage fluid and serum. Vaccination of the rabbits with H. influenzae d1 or
      d3, an antigenic variant of strain d1, resulted neither in eradication of H.
      influenzae d1 nor in increased antibody titers in serum and tissue cage fluid.
      The sera of nonvaccinated rabbits during persistence had no strain d1-specific
      bactericidal activity in the presence of complement. Vaccination with H.
      influenzae d1 induced serum bactericidal activity against strain d1 in the
      presence of complement. However, a variant of strain d1 appearing in the tissue
      cages was not killed by this serum bactericidal activity. We conclude that
      immunological pressure leads to the selection of MOMP variants of H. influenzae
      and that these variants escape the antibody-mediated strain-specific bactericidal
      activity against H. influenzae.

PMID- 8641811
TI  - Reactivity of mouse T-cell hybridomas expressing human Vbeta gene segments with
      staphylococcal and streptococcal superantigens.
AB  - A panel of 15 mouse T-cell hybridomas, each expressing a different human Vbeta
      gene segment (hVbeta) in an otherwise mouse T-cell receptor (i.e., mouse alpha
      chain and CD3 complex), was constructed by transfection of hVbeta/mouse Cbeta
      chimeric T-cell receptor (TCR)-beta genes into a mouse T-cell hybridoma recipient
      lacking the endogenous TCR-beta chain. Several qualities that are conferred by
      the hVbeta chain of the TCR are retained in the chimeric human-mouse TCR complex:
      a large panel of hVbeta-specific antibodies specifically stained the hVbeta
      expressed by the mouse T-cell hybridomas. Moreover, hVbeta-transfected mouse
      cells could readily produce interleukin 2 when stimulated by superantigens
      presented by antigen-presenting cells. These characteristics made it possible to
      refine the reactivity of 17 superantigen preparations with the available
      transfected Vbetas. Each superantigen gave a characteristic pattern of reactivity
      on the transfectants. Positive reactivities with some of these transfectants,
      which differ only by the expressed hVbeta, demonstrate unambiguously the
      superantigenic character of a protein or fraction and its potential to react with
      the corresponding Vbetas. Therefore, these hVbeta-transfected cells constituted a
      valuable tool for determining "specificity fingerprints" of known or putative
      superantigens. First, commonly used, commercially available superantigens such as
      staphylococcal enterotoxin B and toxic shock syndrome toxin-1 (TSST-1) showed
      additional Vbeta reactivities, compared with those of their recombinant
      counterparts. This stresses the importance of using defined preparations of
      superantigens for the definition of Vbeta specificities. Second, the stimulatory
      pattern of a strain of Streptococcus pyogenes demonstrated that this strain,
      unlike others, produces a potent Vbeta 8-specific superantigen that is an yet
      undefined at the molecular level.

PMID- 8641813
TI  - Hybrid liver support.

PMID- 8641812
TI  - Antibodies to Haemophilus influenzae type b polysaccharide affect bacterial
      adherence and multiplication.
AB  - Since immunization of infants with conjugated Haemophilus influenzae type b (Hib)
      capsular polysaccharide (PS) vaccines results in a reduction of colonization, we
      determined the inhibitory effect of anti-Hib PS on two steps in the colonization,
      i.e., adherence of H. influenzae to nasopharyngeal epithelium and bacterial
      growth. Monoclonal antibody (MAb) E117-5 specific for Hib PS inhibited at a
      concentration of at least 80 microg/ml in vitro the adherence of Hib strain
      770235f+b+ to oropharyngeal epithelial cells by 50% (P <, 0.02), but this MAb and
      sera from children immunized with Hib PS conjugate vaccine (n = 10) were not
      inhibitory in final dilutions containing up to 20 microg of anti-Hib PS per ml.
      The growth of Hib strain 770235f+b+ did completely stop in the presence of 5
      microg of anti-Hib PS MAb E117-5 per ml and human sera with an anti-Hib PS
      concentration of 2 microg/ml or more, in contrast to the growth of the
      nonencapsular variant strain 770235f+b0.

PMID- 8641814
TI  - Cell sources for bioartificial liver support.
AB  - The present review discusses hepatocyte sources for a bioartificial liver.
      Intended requirements for cell sources are for example: synthesis of plasma
      proteins, detoxification and regulation. The need for highly differentiated
      hepatocytes is stressed. Furthermore, the gap between this objective on the one
      hand and the real possibilities as they appear today on the other is shown.
      Alternatives to primarily isolated hepatocytes are discussed, thereby elucidating
      the limits of established cell lines. In summary, it is postulated that the
      results expected from a bioartificial liver, are closely related to the source
      and type of cells used.

PMID- 8641815
TI  - Mass transfer limitations to the performance of membrane bioartificial liver
      support devices.
AB  - A number of membrane bioartificial devices have been proposed for liver support.
      However, their design does not yet ensure the successful treatment of acute liver
      insufficiency. In this paper, the Author reviews the limitations of the mass
      transport phenomena to the performance of a membrane bioartificial liver support
      device. First of all the requirements that an optimal membrane bioartificial
      liver support device has to meet for the therapy to be effective are presented.
      On these grounds, the issues that are still to be addressed to optimize the
      performance of such devices are discussed: particular attention is devoted to the
      mass transport phenomena in each region of the membrane bioartificial device.
      Finally, the main transport features of the membrane bioartificial liver support
      devices proposed so far are illustrated and examined.

PMID- 8641816
TI  - Assessment of bioartificial liver support in acute liver failure.

PMID- 8641817
TI  - Techniques for measurement of oxygen consumption rates of hepatocytes during
      attachment and post-attachment.
AB  - Three techniques for measuring oxygen consumption rate (OCR) of cultured cells
      relevant to the development of bioartificial liver devices are reported. In an
      oxystat apparatus, HepG2 cells immobilised on Cytodex 3 microcarriers at a
      concentration of 10(6) cells ml-1 had a mean OCR of 0.7 nmol s-1/10(6) cells. The
      OCR decreased with increasing cell density, a characteristic previously reported
      for other cell lines. Rat hepatocytes immobilised on single collagen layers in a
      flow cell and challenged with ammonia had a mean OCR of 0.59 nmol s-1/10(6)
      cells. A novel two-compartment oxystat system was used to determine the OCR of
      rat hepatocytes during the attachment phase. OCR declined from 1.0 nmol s-1/10(6)
      immediately after seeding to 0.7 nmol s-1/10(6) cells at nine hours. The low OCR
      for HepG2 reflects loss of certain oxygen dependent metabolic pathways. The OCR
      measured for rat hepatocytes during and post-attachment are significantly higher
      than those reported elsewhere and have major implications for the development of
      bioartificial liver devices.

PMID- 8641818
TI  - Hepatocyte encapsulation--initial intentions and new aspects for its use in
      bioartificial liver support.

PMID- 8641819
TI  - Role of transport proteins in bioartificial liver assist systems.

PMID- 8641820
TI  - Isolation of porcine hepatocytes from slaughterhouse organs.
AB  - Recent developments in the field of hybrid artificial liver research have
      increased the demand for an unlimited supply of primary hepatocytes. At present,
      liver cells are mainly isolated from anesthetized pigs, since slaughterhouse
      organs have been regarded as a cell-source of minor quality. A modified enzymatic
      isolation technique for the successful harvesting of viable porcine liver cells
      from slaughterhouse organs is introduced. Digestion of the left medial liver lobe
      (n = 114) resulted in 1.2 +/- 0.35 x 10E7 viable hepatocytes per gram tissue and
      an overall yield of 2.23 +/- 0.48 x 10E9 cells per isolation (viability: 94 +/-
      2.4%). Morphological integrity of hepatocytes in long-term immobilization culture
      systems was assessed by electron microscopic follow-up. Stable DNA-contents (52
      +/- 2 micrograms) and low alanine-amino-transferase (ALAT) release were measured
      after early culture adaptation. Urea production under NH4Cl, Albumin secretion,
      total bile acid synthesis (3.5 pmol/hr/micrograms DNA) and 7-ethoxicoumarin o
      deethylase (ECOD) activity demonstrated functional activity and maintenance of
      Type IA1 cytochrome P450 (CYP450) dependent metabolism in cultured hepatocytes
      for at least 10 days. Compared to ex vivo isolation results in the literature, we
      could not see any disadvantages in the use of liver cells from slaughterhouse
      organs, but would like to point out four advantages. It saves animal lives,
      labor, costs, and time. Research groups especially with no animal housing and/or
      surgical facilities should evaluate the presented technique for their own needs
      to make use of this unlimited cell source.

PMID- 8641821
TI  - The effect of oxygen transport resistances on the viability and functions of
      isolated rat hepatocytes.
AB  - The treatment of fulminant hepatic failure with a bioartificial liver support
      device relies on the possibility of replacing the detoxification and synthetic
      functions of the injured liver for as long as needed for patient recovery. In
      spite of progress in cell culture techniques, the effective use of isolated
      hepatocytes in liver support devices is currently hampered by a lack of
      information on the metabolic factors limiting long term hepatocyte culture. In
      this paper, we report our investigation on the effects of oxygen transport
      resistances on the viability and functions of isolated rat hepatocytes cultured
      on collagen coated Petri dishes. Detoxification and synthetic functions of the
      hepatocytes were studied with respect to ammonia and phenolsulphonphthalein
      elimination and urea synthesis. Lower resistances to oxygen transport favored
      hepatocyte survival. The isolated hepatocytes synthesized urea at rates that
      decreased as the resistance to oxygen transport increased. The rate at which urea
      was synthesized also decreased during the culture. Neither PSP, nor ammonia
      elimination rate was greatly affected by increasing oxygen transport resistances
      and remained rather constant up to a week of culture.

PMID- 8641822
TI  - Fulminant liver failure: relevance of extracorporeal hybrid liver support
      systems.

PMID- 8641824
TI  - The axial shortening effect of both surgical aphakia and intraocular lenses in
      neonatal rhesus monkeys.

PMID- 8641823
TI  - Matrix-induced liver cell aggregates (MILCA) for bioartificial liver use.
AB  - Ex vivo reproduction of liver microstructure using isolated hepatocytes is
      critical for bioartificial liver use. We have developed a method of producing
      matrix-induced liver cell aggregates (MILCA) using a small number of collagen
      coated beads as a nidus for formation of hepatocyte aggregates. Porcine
      hepatocytes were obtained by EDTA/collagenase digestion. Cell viability was
      assessed by trypan blue exclusion and LDH release. Cytochrome P-450 activity was
      determined at 4 and 24 hours by measuring the formation of 7-hydroxycoumarine (7
      HC) from 7-ethoxycoumarine (7-EC). At 4 hours, the viability of MILCA was 92 +/-
      2%, LDH release was 100 +/- 22 U/L and 7-HC formation was 140 +/- 34 nM/g cells.
      At 24 hours, MILCA viability remained greater than 90%, but 7-HC formation was
      lower than that of parallel control monolayer hepatocyte cultures (194 +/- 43 vs
      481 +/- 78 nM/g cells; p < 0.002). On transmission electron microscopy, MILCA
      ultrastructure resembled that of a normal liver (maintenance of cell polarity,
      gap junctions, bile canaliculi, intact organellae, glycogen granules). MILCA were
      subsequently inoculated into hollow-fiber bioreactors which were perfused for 6
      hours with plasma recovered from patients with fulminant hepatic failure (n = 6;
      5 x 10(9) cells/cartridge, recirculation of 350 ml of plasma at 400 ml/min). In
      these studies, lidocaine (20 micrograms/ml) was cleared in less than 3 hours and
      7-HC production at 6 hours was 71 +/- 8 nM/g cells. Other MILCA effects noted in
      this system included lowering of plasma lactate, bilirubin and ammonia and
      increase in the level of several non-essential amino acids.

PMID- 8641825
TI  - Kinetics of rod outer segment phagocytosis by cultured retinal pigment epithelial
      cells. Relationship to cell morphology.
AB  - PURPOSE: To study phenotypic variation in primary cultures of rat retinal pigment
      epithelium (RPE) and to correlate cell morphology with rates of binding and
      ingestion of rod outer segments (ROS). METHOD: Replicate cultures were prepared
      using RPE cell sheets isolated with Dispase from Royal College of Surgeons normal
      (RCS rdy+ p+) and dystrophic (RCS p+) rats. Retinal pigment epithelial morphology
      was analyzed, and phagocytosis was assessed by fluorescence microscopy in
      cultures fixed at 2-hour intervals from 3 to 19 hours after continuous
      incubations with fluorescein isothiocyanate (FITC)-stained ROS. RESULTS: A wide
      range of RPE cell size, shape, and pigmentation was present at confluence;
      however, distinct morphologic subtypes were recognized, defined as types 1 to 3,
      and studied separately. In both normal and dystrophic cultures, the extent and
      rate of ROS binding varied with RPE phenotype. In normal cultures, highly spread
      pigmented binucleate cells (type 3) bound and rapidly ingested multiple ROS per
      cell starting at 3 hours and reached a peak at 9 hours. Lightly pigmented
      daughter cells (type 2) bound and ingested far fewer ROS per cell than did type 3
      RPE, which had not divided. Patches of hexagonally packed cells with in vivo
      morphology (type 1) bound large numbers of ROS per cell only after prolonged (9-
      to 11-hour) incubations and ingested them synchronously. Comparison of normal
      versus dystrophic RPE subtypes 1 to 3 revealed the known ingestion defect in all
      three mutant phenotypes but indicated delayed ROS binding in type 2 and type 3
      cells as well. CONCLUSIONS: Kinetics of ROS binding and ingestion differ markedly
      among phenotypic variants of RPE cells typically found in primary cultures at
      confluence. Thus, accurate quantitation requires comparison of equivalent
      microscopic fields or like RPE subtypes, and the heterogeneous responses of
      various RPE subtypes should be considered when interpreting phagocytic data
      obtained from entire cultures at a particular time.

PMID- 8641826
TI  - Oral zinc and the second eye in age-related macular degeneration.
AB  - PURPOSE: To investigate the short-term effect of oral zinc substitution on the
      development of age-related macular degeneration in the second eye of patients
      with an exudative form of the disease in the first eye. METHODS: A 2-year, double
      masked, randomized, placebo-controlled study including 112 white patients with
      age-related macular degeneration and exudative lesions (choroidal
      neovascularization, pigment epithelial detachment, or both) in one eye and a
      visual acuity of better than 20/40 and macular degeneration without any exudative
      lesion in the second eye was performed. Patients received either 200 mg of oral
      zinc sulfate or placebo once daily for 24 months. The main outcome parameters
      were visual acuity, contrast sensitivity, color discrimination, and retinal
      grating acuity, as well as serum levels of zinc and copper, red blood cell count,
      hemoglobin, and morphologic changes detected by grading of monochrome fundus
      photographs and fluorescein angiograms. RESULTS: In the treatment group, the mean
      zinc serum level increased significantly (P < 0.0001) from 79 +/- 10
      micrograms/dl to 108 +/- 26 micrograms/dl compared to no change (82 +/- 16
      micrograms/dl to 85 +/- 10 micrograms/dl) in the placebo group. Serum levels of
      copper, hemoglobin, and red blood cell count did not change significantly in
      either group. A choroidal neovascular membrane (CNV) was detected in 14 patients
      during the treatment period (nine in the treatment group, five in the placebo
      group). Seven additional patients (three in the treatment group, four in the
      placebo group) experienced visual loss caused by CNV, and in two patients (one in
      each group), serous pigment epithelial detachment developed without angiographic
      evidence of CNV after the end of treatment, during a mean additional follow-up
      time of 20.8 +/- 8.2 months. In eyes in which exudative lesions did not develop,
      there was no significant change in any of the functional parameters during the 24
      month treatment period, but there was a significant increase in the nonexudative
      alterations (drusen size, drusen confluence, hyperpigmentation, and focal
      degeneration of the retinal pigment epithelium) in both groups. CONCLUSIONS: Oral
      zinc substitution has no short-term effect on the course of age-related macular
      degeneration in patients who have an exudative form of the disease in one eye.

PMID- 8641827
TI  - Photoreceptor loss in age-related macular degeneration.
AB  - PURPOSE: The authors showed previously that parafoveal rods, but not cones,
      decrease during the course of adulthood in donor eyes that were screened to
      exclude the grossly visible macular drusen and pigmentary disturbances typical of
      age-related macular degeneration (AMD). Because AMD begins in the parafovea, this
      selective loss of rods actually may be subclinical AMD not yet visible in the
      fundus. If so, AMD must have a predilection for rods over cones. The authors
      tested this hypothesis by determining the relative numbers of cones and rods in
      donor eyes with mid-to late-stage AMD and in age-matched controls. METHODS:
      Thirteen eyes (from seven donors) with grossly visible macular drusen and
      pigmentary disturbances were either wholemounted for photoreceptor counts or
      sectioned through the fovea for histopathology and carbonic anhydrase
      histochemistry to label red-green cones. Eyes were assigned to AMD or control
      groups on the basis of histopathology and clinical history. RESULTS: Five
      nonexudative AMD (NE-AMD) eyes from three donors showed sparing of foveal cones
      and loss of rods and cones in the parafovea. In two donors, rod loss exceeded
      cone loss at most parafoveal locations, and in one donor, rod density was normal
      and cone density was reduced. In eight exudative AMD (EX-AMD) eyes from five
      donors, photoreceptors surviving along the margins of and overlying disciform
      scars were largely cones. CONCLUSIONS: Photoreceptors are lost in NE-AMD as well
      as in the more severe exudative form, consistent with functional and clinical
      studies. The authors propose that rods die in older eyes without evidence of
      overt retinal pigment epithelial disease. In persons susceptible to AMD, the
      retinal pigment epithelium becomes dysfunctional. Secondarily, rod loss continues
      and cones begin to degenerate. Eventually, only degenerate cones remain;
      ultimately, all photoreceptors may disappear.

PMID- 8641828
TI  - Cone-associated c-fos gene expression in the light-damaged rat retina.
AB  - PURPOSE: To examine whether light-controlled c-fos gene expression is mediated by
      a cone specific pathway in the rat retina. METHODS: To produce a cone-rich
      retina, rats were placed under continuous lighting for 21 days. The illuminance
      in the cages ranged from 1200 to 2000 lux. The presence of cones was determined
      by peanut agglutinin and rods by the monoclonal antibody 1-E7. The presence of c
      fos transcripts in the retinas was analyzed by in situ hybridization using single
      stranded RNA probes. RESULTS: After long-term exposure to continuous light, the 1
      E7 immunoreactivity was not detected in the outer nuclear layer. The cone
      photoreceptors and cells in the ganglion cell (GCL) and inner nuclear layers
      (INL) survived. In normal retinas, there was strong hybridization for c-fos
      expression in the GCL and the INL 30 minutes after the onset of the light cycle.
      Light-damaged retinas also showed hybridization in the GCL but not in the INL
      under the same light regime. CONCLUSIONS: These results suggest that c-fos gene
      expression can be controlled through a cone specific pathway in the retina.

PMID- 8641829
TI  - Cell surface-associated keratan sulfate on normal and migrating corneal
      endothelium.
AB  - PURPOSE: To investigate cell surface-associated keratan sulfate on the corneal
      endothelium. METHODS: Immunolabeling techniques were used at the light, scanning,
      and transmission electron microscopic level to localize keratan sulfate on the
      corneal endothelium. The investigation included human, bovine, and rabbit corneal
      endothelia. A quantitative study of the relationship between cell size and
      keratan sulfate levels was conducted on normal bovine corneal endothelium.
      Changes in the distribution of keratan sulfate and chondroitin sulfate on
      endothelial cell surfaces were investigated on organ cultured bovine corneas
      during endothelial wound healing. Changes in the levels of keratan sulfate during
      endothelial wound healing were investigated in organ cultured human corneas and
      in vivo in rabbit corneas. Inhibition-enzyme-linked immunosorbent assay also was
      used to detect keratan sulfate in the aqueous humor. RESULTS: A variegated
      distribution of keratan sulfate was revealed on normal human, bovine, and rabbit
      corneal endothelia. Some cells had high levels of keratan sulfate on their
      surfaces whereas others, sometimes immediately adjacent, had little or none.
      Wound healing experiments resulted in changes of keratan sulfate levels on the
      migrating endothelial cells in bovine, human, and rabbit. In wounded organ
      cultured bovine corneas, there was a decrease in keratan sulfate levels and an
      increase in chondroitin sulfate levels on migrating endothelial cells. Keratan
      sulfate was detected in bovine aqueous humor. CONCLUSIONS: The pattern of
      occurrence of keratan sulfate and chondroitin sulfate on the corneal endothelial
      cells in normal and wounded cornea suggests that these glycosaminoglycans have
      differing roles in endothelial adhesion and migration.

PMID- 8641830
TI  - The role of macrophages in Acanthamoeba keratitis.
AB  - PURPOSE: Macrophages are thought to be the first line of defense in many
      infectious diseases and are present in high numbers in corneas with Acanthamoeba
      keratitis. Conjunctival macrophage depletion was performed in an animal model of
      Acanthamoeba infection to determine the importance of macrophages in this
      disease. METHODS: Selective elimination of macrophages was achieved by repeated
      subconjunctival injection of liposomes containing dichloromethylene diphosphonate
      in a Chinese hamster model of Acanthamoeba keratitis. RESULTS: Macrophage
      depletion affected the incidence, severity, and chronicity of keratitis. The
      incidence of infection in normal animals was approximately 60% but rose to 100%
      on day 4 in animals treated with liposomes containing dichloromethylene
      diphosphonate (C12MDP-LIP). Moreover, the clinical appearance of the keratitis in
      the C12MDP-LIP group was much more severe than in animals treated with liposomes
      containing phosphate-buffered saline at all time points. There was also a major
      change in the chronicity of keratitis, with an earlier onset and a prolonged and
      chronic course in the C12MDP-LIP treated hamsters. CONCLUSIONS: The profound
      exacerbation of Acanthamoeba keratitis in hamsters treated with C12MDP-LIP
      strongly suggests that macrophages play an important role in corneal infection
      with Acanthamoeba trophozoites, probably by acting as a first line of defense and
      eliminating significant numbers of Acanthamoeba trophozoites.

PMID- 8641831
TI  - Ocular adenovirus gene transfer varies in efficiency and inflammatory response.
AB  - PURPOSE: To study the effects of adenoviral gene transfer to the tissues of the
      anterior segment in vitro by rat and monkey lens organ cultures and in vivo by
      single injection into the anterior chamber of rabbits. METHODS: In vitro, intact
      lens cultures were exposed to 1 to 4 x 10(8) pfu Av1LacZ4 and Av1Luc1 in TC199
      medium containing no serum or growth factors. Av1LacZ4 and Av1Luc1 are
      replication-deficient adenovirus vectors, carrying the reporter genes Escherichia
      coli LacZ and firefly luciferase, respectively. In vivo, the anterior chambers of
      eight rabbits were injected once with 20 mumol Av1LacZ4 (8 x 10(8) pfu) and
      evaluated 48 hours after injection. Enzyme activity of the reporter genes was
      measured biochemically and histochemically. RESULTS: In organ cultures,
      adenovirus delivers reporter genes efficiently to the ciliary processes but
      penetrates poorly into the capsulated lenses. Viral receptors, however, are
      present in rat lens epithelium, as in primary trabecular meshwork and other lens
      cell lines. In vivo, gene transfer was evident in corneal endothelium, iris
      anterior surface, and trabecular meshwork. Presence of the virus did not affect
      lens transparency or provoke external discomfort signs. Infected corneal
      endothelial cells were swollen and partly detached; 3 of 8 infected eyes showed a
      severe inflammatory response in chamber angle, anterior uvea, and limbal
      conjunctiva. CONCLUSIONS: These findings reveal the distinct gene transfer
      potential of each of the tissues of the anterior segment and emphasize the need
      to address the inflammatory response to these first-generation adenoviral
      vectors.

PMID- 8641832
TI  - Corneal endothelial repair. Regulation of prostaglandin E2 synthesis.
AB  - PURPOSE: The authors have investigated the hypothesis that prostaglandin E2
      (PGE2) synthesis is regulated during corneal endothelial wound healing. Previous
      studies have shown that PGE2 is an important mediator of endothelial mitosis,
      migration, and differentiation. METHODS: Biosynthesis of PGE2 was investigated in
      a wound closure model of the cultured rabbit corneal endothelium and in cultures
      treated with experimental agents. Prostaglandin E2 synthesis was measured by
      enzyme-linked immunosorbent assay. Pharmacologic experiments were designed to
      evaluate the contributions of protein kinases, phospholipase A2, and
      cyclooxygenase to endogenous PGE2 synthesis. RESULTS: Prostaglandin E2 synthesis
      is increased markedly in response to injury and is proportional to the extent of
      wounding. Biosynthesis of PGE2 returns to basal levels concurrently with recovery
      of the injury. Synthesis is dependent on the activities of protein kinase C
      (PKC), phospholipase A (PLA), and cyclooxygenase. Two forms of cyclooxygenase are
      present in corneal endothelial cells, and pharmacologic studies indicate that the
      activity of the COX 2 contributes to injury-dependent PGE2 synthesis.
      CONCLUSIONS: Prostaglandin E2 synthesis is increased in injured corneal
      endothelial cells. This synthesis is dependent on the coordinated regulation of
      PKC, PLA, and cyclooxygenase. Prostaglandin E2 synthesis presents an attractive
      target for pharmacologic manipulation of endothelial recovery from injury.

PMID- 8641833
TI  - Expression and release of tumor necrosis factor-alpha by explants of mouse
      cornea.
AB  - PURPOSE: To elucidate a possible target of immunosuppressive agents widely used
      in the treatment of corneal disorders, the authors determined whether corneal
      cells are capable of expressing and releasing tumor necrosis factor-alpha (TNF
      alpha) on lipopolysaccharide (LPS) stimulation, and they investigated whether TNF
      alpha production can be modulated by pharmacologic agents. METHODS: Trephined
      central corneas from C57BL/6 mice were kept in culture for 3 days. Release of TNF
      alpha after a 24-hour stimulation with LPS (1 microgram/ml) into the culture
      medium was determined both by bioassay and by enzyme-linked immunosorbent assay.
      Expression of TNF alpha mRNA after 6-hour stimulation was examined by polymerase
      chain reaction. Immunofluorescent staining on cryostat sections of cultured
      corneas was performed to localize TNF alpha in the tissue. Corneal explants were
      pretreated with immunosuppressive agents (prednisolone, budesonide, cyclosporin
      A) for 48 hours, followed by 6-or 24-hour stimulation with LPS in the continuous
      presence of the agents. RESULTS: Lipopolysaccharide stimulated TNF alpha release
      into the culture medium. The addition of budesonide (10(-7) M) or prednisolone
      (10(-6) M) significantly inhibited LPS-induced TNF alpha release, whereas
      cyclosporin A (10(-7) - 10(-5) M) had no marked effect. Levels of TNF alpha mRNA
      in corneal explants increased fivefold after stimulation with LPS.
      Immunohistochemical staining revealed that TNF alpha was expressed in the
      epithelial cells. Budesonide markedly decreased mRNA expression and abolished
      immunostaining of TNF alpha stimulated by LPS. CONCLUSIONS: TNF alpha is produced
      and released by the epithelial cells of mouse central cornea in response to LPS.
      Contrary to cyclosporin A, corticosteroids such as prednisolone and budesonide
      potently inhibit TNF alpha production.

PMID- 8641834
TI  - Hypoxia regulates vascular endothelial growth factor receptor KDR/Flk gene
      expression through adenosine A2 receptors in retinal capillary endothelial cells.
AB  - PURPOSE: Vascular endothelial growth factor (VEGF) is an endothelial cell
      specific angiogenic factor that serves an important role in numerous ischemic
      retinopathies. The authors studied the hypoxic gene regulation of two known VEGF
      receptors (KDR and Flt) and its mechanism in cultured bovine retinal endothelial
      cells (BREC). METHODS: Confluent monolayers of BREC were exposed to various
      oxygen concentrations using a computer-controlled, infrared, water-jacked CO2
      incubator with reduced oxygen control. Northern blot analysis and 125I-VEGF
      binding analysis were used to identify hypoxia-induced alterations of VEGF
      receptor at mRNA and protein levels. RESULTS: KDR was detectable by Northern blot
      analysis in BREC, whereas Flt was not. Hypoxia decreased KDR gene expression in a
      dose-and time-dependent manner with maximal inhibition to 0.5 +/- 0.2% (P =
      0.019) of normoxic control observed after 24 hours exposure to 0% oxygen and with
      significant inhibition at oxygen concentrations below 5%. Blockade of oxygen
      respiration decreased KDR mRNA expression to 58% +/- 7.1% of control (P = 0.001)
      after 3 hours. CPA, a stable adenosine A1 receptor (A1R) agonist, did not affect
      KDR mRNA expression at A1R stimulatory concentrations, but it decreased KDR mRNA
      levels to 30% +/- 4.9% (P = 0.002) of control at higher concentrations that react
      with A2R. DPMA, an adenosine A2 receptor (A2R) agonist, decreased KDR mRNA in a
      dose-dependent manner with an EC50 of 5 to 10 nM. A1R antagonists, 8-cyclolentyl
      1,3-dipropylxanthine and 8-phenyltheophylline, did not inhibit the hypoxic
      response of KDR mRNA at A1R inhibitory concentrations but did inhibit the
      response at A2R effective doses (P = 0.001). The A2R antagonist, CSC, inhibited
      the KDR hypoxic response by 42% +/- 7.8% (P = 0.008) at 10 microM. Specific VEGF
      binding to BREC was decreased from 15.1% +/- 0.3% to 12.7% +/- 0.4% per milligram
      protein (P < 0.001) after exposure to 1% oxygen for 24 hours. In contrast, long
      term exposure to 1% oxygen (72 hours) resulted in an increase of VEGF binding
      from 13.5% +/- 1.1% to 18.3% +/- 0.8% per milligram protein (P < 0.001).
      Scatchard analysis detected a decrease of receptor binding sites without change
      in binding affinity after 30 hours of exposure to hypoxia but demonstrated an
      increase in specific binding sites (4.2 +/- 0.6 x 10(4) sites/cell to 6.7 +/- 1.0
      x 10(4) sites/cell, P = 0.049) with unaltered receptor affinity after 72 hours of
      hypoxic exposure. CONCLUSIONS: These data suggest that hypoxia induces an initial
      decline in KDR mRNA levels and VEGF binding sites as mediated through adenosine
      binding to the A2R. Exposure to prolonged periods of hypoxia, however, results in
      an increase in VEGF binding sites by an as yet unidentified mechanism.

PMID- 8641835
TI  - Vasoproliferation in the neonatal dog model of oxygen-induced retinopathy.
AB  - PURPOSE: To examine the time course and relative degree of proliferative response
      associated with revascularization after hyperoxic insult in the dog model of
      oxygen-induced retinopathy. METHODS: Mitotic cell profiles (MCPs) were counted in
      serial cross-sections of ADPase flat-embedded retinas of air-reared control 8-,
      15-, and 22-day-old dogs and of age-matched oxygen treated animals (4 days, 100%
      oxygen) after return to normoxia. Sectioning and analysis were performed along
      the radial axis of the forming primary vasculature from optic nerve head to
      periphery. RESULTS: In air-reared control animals, lumenal-associated cell
      mitosis was low, with an average of 9.6 MCPs/mm2 of nerve fiber layer tissue in
      the 8-day-old dogs, 6.5 MCPs/mm2 in the 15-day-old dogs, and 8.4 MCPs/mm2 in the
      22-day-old dogs. In oxygen-treated animals, however, the number of lumenal
      associated MCPs was significantly higher, with an average of 52.5 MCPs/mm2 of
      tissue in the 8-day-old dogs, 45.1 MCPs/mm2 in the 15-day-old dogs, and 26.8
      MCPs/mm2 in the 22-day-old dogs. Additionally, extracellular spaces in avascular
      retina were obliterated in oxygen-treated animals. CONCLUSIONS: This study
      demonstrates that in the neonatal dog, revascularization after hyperoxic insult
      involves a period of marked vasoproliferation that peaks somewhere between 3 to
      10 days after return to room air. Oxygen-induced changes in the extravascular
      milieu are likely to affect the pattern of reforming vasculature and may restrict
      growth anteriorly.

PMID- 8641837
TI  - Visualization and quantitative analysis of leukocyte dynamics in retinal
      microcirculation of rats.
AB  - PURPOSE: Recent studies have demonstrated that leukocytes play an important role
      in microcirculatory flow disturbances. A few methods are available to investigate
      leukocyte dynamics in retinal microcirculation. The authors explored leukocyte
      dynamics in the retina of rats with acridine orange digital fluorography.
      METHODS: Acridine orange digital fluorography produces high-resolution images
      from a scanning laser ophthalmoscope with the use of a fluorescent nuclear dye of
      acridine orange, which has been used for staining nucleic acids of cells in
      histochemical and cytochemical studies. The images were recorded on S-VHS tapes
      and were investigated with a personal computer-based image analysis system.
      RESULTS: Fluorescent leukocytes in the retinal microcirculation were visualized.
      Highly magnified images could be obtained because of the high dioptric power of
      the rat eye compared with the primate eye. It was possible to observe leukocyte
      deformation in narrow capillaries and nuclei of vascular endothelium. At
      arteriolar bifurcations, leukocytes moved preferentially into the branch with the
      higher flow rate. "Preferential channels" were identified in which predominantly
      leukocytes were delivered; the channels were characterized by high flow velocity
      and a straight, short capillary route. The average leukocyte velocities of the
      arteries, veins, and capillaries are 29.5 +/- 7.3, 17.4 +/- 5.3, and 1.4 +/- 0.4
      mm/second, respectively. CONCLUSIONS: This study demonstrates that
      microcirculatory dynamics of leukocytes can be visualized and analyzed
      quantitatively in rats in vivo with acridine orange fluorography. This method may
      be a promising tool to reveal how leukocytes contribute to retinal flow
      disturbances under various pathologic conditions.

PMID- 8641836
TI  - Cloning and mRNA expression of vascular endothelial growth factor in ischemic
      retinas of Macaca fascicularis.
AB  - PURPOSE: To identify and isolate cDNAs for the alternatively spliced vascular
      endothelial growth factor (VEGF) mRNAs present in retina and to compare the
      relative levels of the splice variants and localization of VEGF mRNA in
      nonischemic and ischemic adult simian retinas. METHODS: Retinas of cynomolgous
      monkeys were made ischemic by laser occlusion of the main branch retinal veins.
      Reverse transcription-polymerase chain reaction was used to amplify the VEGF
      coding region of RNA from ischemic and control retinas, and amplification
      products were analyzed by agarose gel electrophoresis, Southern blot, and
      nucleotide sequencing. Analysis of VEGF mRNA expression was accomplished by in
      situ hybridization. RESULTS: Control and ischemic retinas produce mRNAs that
      correspond to the 121 and 165 amino acid diffusible isoforms of VEGF, and
      relatively low levels of VEGF189, the heparin-binding isoform. There was no
      significant difference in the levels of the alternatively spliced VEGF
      transcripts between control and ischemic retinas. Cloning and sequencing revealed
      that simVEGF cDNAs are 99% identical to human VEGFs and are predicted to encode
      proteins identical to their respective human homologues. In situ hybridization of
      nonischemic retinas revealed a low level of VEGF mRNA in retinal ganglion cells
      and in the inner nuclear layer. VEGF mRNA levels were elevated in ischemic
      retinas as early as 1 day after laser vein occlusion, when there was a small but
      reproducible increase in signal. The expression peaked at approximately 13 days,
      coincident with maximal iris neovascularization, and was significantly reduced by
      28 days, when the iris vessels largely regressed. CONCLUSIONS: The elevation of
      simVEGF121 and VEGF165 in ischemic retinas is consistent with a role for
      diffusible, retina-derived angiogenic factors in the development of ocular
      neovascularization.

PMID- 8641838
TI  - Indomethacin and epinephrine effects on outflow facility and cyclic adenosine
      monophosphate formation in monkeys.
AB  - PURPOSE: To investigate the effect of indomethacin inhibition of prostanoid
      production on the epinephrine-stimulated increase in outflow facility and cyclic
      adenosine monophosphate (cAMP) production in the anterior segment of the monkey
      eye. METHODS: Topical indomethacin was given 1 hour before the intracameral
      administration of epinephrine to living cynomolgus monkeys. Outflow facility was
      measured for 45 to 60 minutes, beginning 3 hours after epinephrine
      administration, by two-level constant pressure perfusion of the anterior chamber.
      Cyclic adenosine monophosphate formation was measured in cell membranes isolated
      from rhesus monkey ciliary muscle, ciliary processes, trabecular meshwork, and
      iris in the presence of forskolin, indomethacin, epinephrine, or indomethacin and
      epinephrine combined. RESULTS: Three hours after the intracameral administration
      of 5.5 micrograms epinephrine, facility increased by approximately 40%, a
      putatively maximal response, at which time the intracameral epinephrine
      concentration was approximately 15 microM. Pretreatment with topical indomethacin
      produced a dose-dependent inhibition of epinephrine's facility-increasing effect;
      the maximum inhibition of 50% to 70% occurred at an indomethacin dose of 50 to
      125 micrograms. Doubling the indomethacin dose (250 micrograms) produced no
      further inhibition, whereas a fivefold larger epinephrine dose (27.5 micrograms)
      did not overcome the inhibition. Forskolin and epinephrine both stimulated cAMP
      production in vitro, whereas [indomethacin] > or = 10(-4) M partially inhibited
      both basal and epinephrine-stimulated cAMP production in all four tissues.
      CONCLUSIONS: Approximately half of the epinephrine-induced facility increase is
      inhibited by indomethacin, but it is unclear whether the indomethacin-inhibitable
      fraction is mediated by epinephrine-stimulated prostanoid production or release.

PMID- 8641839
TI  - Glycosaminoglycans of the human trabecular meshwork in primary open-angle
      glaucoma.
AB  - PURPOSE: Glycosaminoglycans (GAGs) contribute to the filtration barrier of
      aqueous outflow through the trabecular meshwork (TM). The purpose of this
      biochemical study was to identify the type and amount of GAGs in normal and in
      primary open-angle glaucoma (POAG) TM and adjacent anterior segment structures.
      METHODS: The GAGs of 21 masked individual normal and POAG human TMs, as well as
      iris, ciliary body, and anterior sclera, were isolated biochemically, identified
      by selective GAG-degrading enzymes, and quantitated by computer-enhanced
      densitometry. RESULTS: In 10 normal TMs (8 donors, 65 to 83 years of age), the
      GAG profile was: hyaluronic acid (0.77 +/- 0.26 ng/microgram dry-defatted weight
      +/- SEM); chondroitin 4(6-) sulfates and dermatan sulfate, collectively referred
      to as chondroitin sulfates (1.90 +/- 0.13 ng); keratan sulfates (0.33 +/- 0.06
      ng); heparitin sulfates (2.02 +/- 0.52 ng); GAG enzyme-resistant material (0.02
      +/- 0.01 ng); and total GAGs (5.05 +/- 0.70 ng). In 10 POAG TMs (6 donors, 67 to
      88 years of age), the GAG profile was: hyaluronic acid (0.18 +/- 0.11 ng; P <
      0.02, a 77% decrease; 6 of 10 TMs contained no detectable hyaluronic acid);
      chondroitin sulfates (2.39 +/- 0.31 ng); keratan sulfates (0.21 +/- 0.06 ng);
      heparitin sulfates (1.36 +/- 0.43 ng); GAG enzyme-resistant material (0.08 +/-
      0.01 ng; P < 0.02); and total GAGs (4.09 +/- 0.33 ng; statistically
      insignificant). In the POAG iris, hyaluronic acid content was less (82% decrease,
      P < 0.02), and the chondroitin sulfates content was higher (72% increase, P <
      0.02). Similarly, the POAG ciliary body and anterior sclera contained less
      hyaluronic acid and more chondroitin sulfates. The GAG profile of a "glaucoma
      suspect" donor specimen was similar to that of the POAG donor specimen.
      CONCLUSIONS: The data provide the first quantitative biochemical profiles of GAGs
      of individual normal and POAG TM, and we suggest that a depletion of hyaluronic
      acid and the accumulation of chondroitin sulfates may increase aqueous outflow
      resistance in the POAG TM:

PMID- 8641840
TI  - The M1 muscarinic antagonist pirenzepine reduces myopia and eye enlargement in
      the tree shrew.
AB  - PURPOSE: To determine the efficacy of the M1-selective muscarinic antagonist,
      pirenzepine, in preventing experimentally induced myopia in a mammalian model,
      the tree shrew. METHODS: Tree shrews were monocularly deprived (MD) using
      translucent goggles or negative lenses for a period of 12 days. In two of the MD
      groups, tree shrews received daily subconjunctival administration of either
      pirenzepine (17.7 mumol; n = 9) or vehicle control (n = 6). Control groups (n =
      6) were used to assess the effects of MD, injection regimen, and drug effects.
      RESULTS: In sham-injected and saline-injected MD tree shrews, 12 days of MD
      produced-13.2 D +/- 0.8 D and -14.1 D +/- 0.5 D of axial myopia, respectively. In
      pirenzepine-injected MD tree shrews, 12 days of MD induced an axial myopia of
      only -2.1 D +/- 1.4 D. The significant reduction in myopia in pirenzepine
      injected MD tree shrews was caused by significantly less vitreous chamber
      elongation of the deprived eye (0.05 mm +/- 0.04 mm) relative to the
      contralateral control eye when compared to sham-injected and saline-injected MD
      tree shrews (0.24 mm +/- 0.02 mm and 0.29 mm +/- 0.01 mm). Mean equatorial
      enlargement and increased eye weight were prevented in pirenzepine-injected MD
      tree shrews (P < 0.01). Pirenzepine also was found to reduce myopia and ocular
      enlargement in lens defocus-induced myopia. Control experiments demonstrated that
      pirenzepine did not cause a significant reduction in amplitude of carbachol
      induced accommodation. CONCLUSIONS: Findings demonstrate that chronic
      administration of the M1-selective muscarinic antagonist, pirenzepine, prevents
      experimentally induced myopia in this mammalian model by a nonaccommodative
      mechanism.

PMID- 8641841
TI  - Form-deprivation myopia induces activation of scleral matrix metalloproteinase-2
      in tree shrew.
AB  - PURPOSE: To investigate whether structural changes to the sclera during form
      deprivation myopia are caused by active tissue remodeling, the gelatinase
      activity of tree shrew scleras was studied in normal animals, form-vision
      deprived animals, and animals recovering from myopia. METHODS: Infant tree shrews
      were monocularly deprived (MD) of form vision with translucent occluders for 5
      days. Recovery animals were allowed 3 days of binocularly unoccluded vision after
      the period of form deprivation. Eyes were removed and dissected to provide
      scleral samples corresponding to equatorial and posterior regions. Gelatinase
      activity was assessed by quantitative sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis or SDS-PAGE, gelatin, zymography of scleral matrix
      metalloproteinase (MMP) extracts. RESULTS: The major gelatinolytic species
      present in tree shrew sclera was found to be MMP-2 (gelatinase A). In normal
      (nondeprived) animals, most of the MMP-2 was found to be in the latent form (the
      ratio of active-to-latent MMP-2 was 0.23 +/- 0.05 and 0.34 +/- 0.06 in equatorial
      and posterior samples, respectively; n = 10 eyes from five animals). After 5 days
      of MD, there was a threefold increase in the amount of active scleral MMP-2 in
      myopic eyes compared to contralateral control eyes, whereas latent MMP-2 activity
      levels were not altered significantly. This increase in active MMP-2 was seen in
      both the equatorial and posterior sclera of myopic eyes (active-to-latent MMP-2
      ratios were 0.53 +/- 0.10 and 0.81 +/- 0.09 in equatorial and posterior regions,
      respectively; n = 6 animals). Contralateral control eyes had levels of both
      active and latent MMP-2 not significantly different from normal eyes. After only
      3 days of unoccluded vision, previously deprived eyes that were now recovering
      from myopia had a fivefold lower level of active MMP-2 than that seen in deprived
      eyes after 5 days of MD. In fact, active (and latent) MMP-2 levels were reduced
      in recovering eyes even below the levels found in their contralateral control
      eyes. Active-to-latent ratios for recovering eyes were 0.11 +/- 0.03 and 0.15 +/-
      0.03 in equatorial and posterior sclera, respectively (n = 5 animals).
      CONCLUSIONS: These results demonstrate that form-deprivation myopia and recovery
      from myopia alter scleral catabolism and provide further support for the theory
      that changes in eye size during mammalian refractive development are the result
      of active tissue remodeling rather than passive scleral stretching alone.

PMID- 8641842
TI  - Morphology of the normal human lens.
AB  - PURPOSE: To provide a quantitative, morphologic description of differentiated
      lens fiber cells in all regions of aged normal human lenses. METHODS: Transparent
      normal human lenses (age range, 44 to 71 years) were examined with correlative
      transmission electron microscopy (TEM) and scanning electron microscopy (SEM).
      Vibratome sections allowed examination of internal structures, whereas dissected
      whole lenses revealed surface characteristics. Additionally, image analysis was
      used to measure cross-sectional areas of fiber cells. RESULTS: Approximate
      regional dimensions (percentage of diameter and thickness, respectively) were
      determined for whole lenses: cortex 16%, 17%; adult nucleus 24%, 21%; juvenile
      nucleus 12%, 9%; fetal nucleus 45%, 49%; and embryonic nucleus 3%, 4%. Cortical
      cells were irregularly hexagonal, and the average cross-sectional area measured
      24 +/- 9 microns2. Adult nuclear cells were flattened with intricate membranous
      interdigitations and an area of 7 +/- 2 microns2. Juvenile nuclear cells had an
      area of 14 +/- 5 microns2. Fetal nuclear cells were rounded with an area of 35 +/
      22 microns2. Embryonic nuclear cells also were rounded and had a variable area
      of 80 +/- 68 microns2. Fiber cell cytoplasm in all lens regions appeared smooth
      in texture and homogeneous in staining density. CONCLUSIONS: Both TEM and SEM are
      necessary to obtain a complete description of fiber cells. Cross-sections of
      fibers give new insights into the lamellar organization of the lens, indicating
      that each region has characteristic cell shapes and sizes. Furthermore, average
      dimensions were used to demonstrate that the number of cells and approximate
      growth rates vary significantly between adjacent regions.

PMID- 8641843
TI  - A role for 12(S)-HETE in the response of human lens epithelial cells to epidermal
      growth factor and insulin.
AB  - PURPOSE: To determine whether the 12-lipoxygenase pathway of arachidonic acid
      metabolism is present in the human lens and whether 12(S)-hydroxyeicosatetraenoic
      acid (12(S)-HETE) plays a role in regulating proto-oncogene expression and DNA
      synthesis in human lens epithelial cells (HLECs). METHODS: Second- and third
      passage primary cultures of HLECs were used for analysis. Human cataract
      epithelia were obtained from surgery. 12-lipoxygenase mRNA was detected by
      reverse transcription-polymerase chain reaction (RT-PCR), and the PCR product was
      sequenced. The 12-lipoxygenase protein was detected by immunoblotting. 12(S)-HETE
      was detected in HLEC-conditioned medium by radioimmunoassay. For studies of
      growth factor-induced mitogenesis, HLECs were serum starved, then stimulated with
      15 ng/ml epidermal growth factor (EGF) and 1 microgram/ml insulin or with 0.3
      microM 12(S)-HETE. The 12-lipoxygenase inhibitor, cinnamyl-3,4-dihydroxy-alpha
      cyanocinnamate (CDC, 10 microM) was used to block endogenous 12-lipoxygenase
      activity. Expression of c-fos mRNA was determined by RT-PCR, and DNA synthesis
      was measured by 3H-thymidine incorporation. RESULTS: 12-lipoxygenase mRNA and
      protein were detected in HLECs and in human cataract tissues. 12(S)-HETE was
      released into the medium by HLECs in the presence of EGF-insulin. Stimulation of
      c-fos mRNA expression and DNA synthesis by EGF-insulin was inhibited when the 12
      lipoxygenase pathway was blocked by CDC. This inhibition was reversed completely
      by exogenously added 12(S)-HETE. However, exogenous 12(S)-HETE was unable to
      stimulate HLEC DNA synthesis in the absence of growth factors. CONCLUSIONS: The
      12-lipoxygenase pathway of arachidonic acid metabolism is present in human lens
      epithelial cells. 12(S)-HETE does not stimulate HLEC DNA synthesis in the absence
      of growth factors but enables the cellular response to EGF and insulin.

PMID- 8641844
TI  - Analysis of progressive change in automated visual fields in glaucoma.
AB  - PURPOSE: To detect and estimate the rate of progression of visual field loss in
      subjects with glaucoma who undergo long-term automated perimetric visual field
      testing. METHODS: Automated visual field data were obtained for subjects with
      glaucomatous visual field loss and a minimum of seven threshold field tests over
      at least 4.5 years. Univariate linear regression was performed with respect to
      mean deviation (MD), corrected pattern standard deviation (CPSD), mean thresholds
      of clusters corresponding to the Glaucoma Hemifield Test (GHT), and thresholds of
      52 individual test locations. Subjects were classified as progressive or stable
      (unchanged or improved) based on the slope and statistical significance of these
      parameters. Adjusted P values were used to maintain the overall type 1 error at
      5%. RESULTS: One hundred ninety-one subjects with a mean follow-up period of 7.1
      years (range, 4.5 to 10.5 years) and a mean number of visual field tests of 9.5
      (range, 7 to 16) were included. Twenty-four subjects (12.6%) showed progression
      in MD (mean slope [95% confidence interval], -1.26 [-1.50, -1.01] dB/year), and
      27 (14.1%) showed progression in CPSD (mean slope [95% confidence interval], 0.71
      [0.58, 0.84] dB/year). Thirty-five subjects (18.3%) had > or = 1 progressive GHT
      cluster. The mean slope in progressive clusters ranged from -1.51 [-1.82, -1.20]
      to -2.84 [-3.39, -2.29] dB/year. Thirty-six subjects (18.8%) had > or = 1
      progressive individual test locations. Fifty-two subjects (27.2%) were classified
      as progressive based on progression of CPSD, > or = 1 cluster and/or > or = 1
      point. CONCLUSIONS: Fewer than 1 in 3 subjects progressed by any one of the
      criteria for progression over an average of 7.1 years. Rates of progression that
      could be statistically confirmed were in the range of approximately 1 to 5
      dB/year, depending on the number of fields, the variability over time, and the
      parameter assessed (global indices, GHT clusters, or individual points). No
      correlation between initial visual field status and the rate of progression was
      found. A minimum of approximately 5 years of follow-up with annual perimetry
      would be required to detect significant changes in the visual field by linear
      regression.

PMID- 8641845
TI  - Descending projections from the cortical accommodation area in the cat.
AB  - PURPOSE: Results in previous studies indicated that the lateral suprasylvian (LS)
      area, the cortical area surrounding the middle suprasylvian sulcus (Mss) of the
      cat, has important roles in the control of accommodation. The current study was
      conducted to investigate descending projections from the accommodation-related
      area in the LS area to the brainstem. METHODS: Wheat germ agglutinin-horseradish
      peroxydase (WGA-HRP) was injected into the accommodation-related area in the
      pretectum or in the rostral superior colliculus (SC) of the cat. These regions
      are thought to be involved in the control of accommodation based on results of
      previous studies. The authors investigated locations of retrogradely labeled
      cells in the LS area. In addition, the authors compared amplitudes of
      accommodative responses evoked by stimulation of the LS area before and after
      neuronal activities in the rostral SC were inhibited by the injection of muscimol
      (gamma-aminobutyric acid agonist) into the accommodation-related area in the
      rostral SC. RESULTS: After injections of WGA-HRP into the accommodation-related
      area in the rostral SC, retrogradely labeled cells were observed in the lower
      part of the medial bank of the Mss, which corresponded to the accommodation
      related area in the LS area. Conversely, after injections of WGA-HRP into the
      accommodation-related area in the pretectum, retrogradely labeled cells were seen
      in the upper part of the medial bank of the Mss, which did not correspond to the
      accommodation-related area in the LS area. Accommodation responses evoked by
      stimulation of the LS area were abolished by the injection of muscimol into the
      accommodation-related area in the rostral SC. CONCLUSIONS: These findings suggest
      that accommodation-related signals from the LS area mainly project to the rostral
      SC, but not to the pretectum.

PMID- 8641846
TI  - Nitric oxide-sensitive and -insensitive contractions of the isolated rabbit iris
      sphincter muscle.
AB  - PURPOSE: The rabbit iris sphincter muscle is innervated by cholinergic and
      tachykinergic nerves that regulate its tone. To clarify the involvement of nitric
      oxide (NO) in the postsynaptic regulation of the rabbit iris sphincter muscle
      tone, the authors examined the effects of NO-related agents on the cholinergic
      contraction induced by carbamylcholine (carbachol) and the tachykinergic
      contraction induced by neurokinin A. METHODS: The motor activity of the ring
      shaped rabbit iris sphincter muscle was measured isometrically. Sodium
      nitroprusside (SNP, a NO donor) was administered between the first and second
      administrations of carbachol and neurokinin A, each of which induced sustained
      contraction. The effects of carboxy-2-phenyl-4,4,5,5,-tetramethyl-imidazoline-l
      oxyl-3-oxide (carboxy-PTIO, a scavenger of NO radicals), NG-monomethyl-L-arginine
      (L-NAME, an inhibitor of NO formation from L-arginine), and methylene blue (an
      inhibitor of soluble guanylate cyclase) on contractions induced by carbachol and
      neurokinin A also were studied. Cyclic guanosine monophosphate (GMP) content in
      the muscle was determined by radioimmunoassay. RESULTS: Sodium nitroprusside
      inhibited carbachol-induced contractions of the iris sphincter muscle in a
      concentration-dependent manner but had no effect on neurokinin A-induced muscle
      contractions. Carboxy-PTIO and methylene blue significantly diminished the
      inhibitory effect of SNP on carbachol-induced contractions. L-NAME had no effect
      on contractions induced by either carbachol or neurokinin A. Sodium nitroprusside
      alone increased cyclic GMP accumulation in a concentration-dependent manner.
      CONCLUSIONS: This study showed that SNP inhibited cholinergic contractions mainly
      through a cyclic GMP-dependent mechanism but did not affect the tachykinergic
      contractions, indicating that cholinergic contraction is NO sensitive, whereas
      tachykinergic contraction is NO insensitive. These findings suggest that in
      rabbits, the cholinergic and tachykinergic responses have distinct features for
      the fine adjustment of the iris sphincter muscle tone.

PMID- 8641847
TI  - In vivo quantitation of peroxides in the vitreous humor by fluorophotometry.
AB  - PURPOSE: To detect intravitreal peroxides in vivo by a new fluorophotometric
      method with a hydrogen peroxide (H2O2)-sensitive fluorescent dye. METHODS: The
      authors used a 2',7'-dichlorofluorescin (DCFH) assay to measure oxidative status
      in the rabbit vitreous. In the presence of H2O2 and lipid hydroperoxides,
      nonfluorescent DCFH in the vitreous is oxidized to highly fluorescent 2',7'
      dichlorofluorescein (DCF; excitation, 495 nm; emission, 520 nm) that is
      detectable by fluorophotometry. Reactions of DCFH with various concentrations of
      H2O2 were investigated in vitro and in vivo. An inhibitory effect of catalase
      also was monitored. Vitreous fluorophotometry with DCFH was performed immediately
      and at 3, 7, and 28 days after constant light exposure to the retina (1800 lux,
      24 hours) as an oxidative stress. RESULTS: In vitro study revealed that H2O2
      oxidized DCFH to DCF in a dose-dependent manner, ranging from 0.1 to 100 mmol/1
      in concentration. Catalase inhibited DCF production. Vitreous fluorophotometry
      demonstrated that H2O2 oxidized DCFH to DCF in vivo in a dose-dependent manner,
      ranging from 0.06 to 60 mmol/1 in concentration. DCF production in the vitreous
      significantly increased immediately (P = 0.03) and at 3 days (P = 0.01) and 7
      days (P = 0.01) after light exposure, and it returned to the pretreatment level
      by day 28. CONCLUSIONS: The results suggest that this fluorophotometric method
      quantitatively can detect intravitreal peroxides in vivo. This method will be
      helpful to study the oxidative status in some experimental pathologic conditions.

PMID- 8641848
TI  - PC-10 as a predictor of prognosis after antigen retrieval in posterior uveal
      melanoma.
AB  - PURPOSE: The immunoexpression of the PC-10 monoclonal antibody for the
      proliferating cell nuclear antigen is claimed to have prognostic value in diverse
      tumors, but previous data on posterior uveal melanoma are conflicting. The aim of
      the current study was to investigate further the potential value of the PC-10
      antibody in predicting tumor-related death after enucleation for posterior uveal
      melanoma. METHODS: One observer calculated the number of cells after antigen
      retrieval that showed immunoreactivity for PC-10 in the high expression areas of
      212 specimens containing posterior uveal melanomas. Survival data for all
      patients were entered into stepwise multivariate Cox regressions that included
      other potential prognostic covariates. The prognostic accuracy was assessed by
      receiver operating characteristic curve analysis. RESULTS: The only covariates of
      statistically significant prognostic value were the number of cells featuring
      immunoreactivity for PC-10 and the largest tumor diameter. When using the median
      PC-10 count as the cutoff, the cumulative 10-year survival proportion was 84% for
      the low PC-10 count group and 40% for patients harboring tumors with high PC-10
      counts. Those with tumors featuring high PC-10 counts had a 5.8 times greater
      risk to die of metastatic melanoma. However, the prognostic accuracy of the PC-10
      count was not significantly better than that of the largest tumor diameter,
      presumably because of insufficient statistical power. CONCLUSIONS: The number of
      cells showing immunoreactivity for the PC-10 antibody may be used to assess
      prognosis in posterior uveal melanoma, provided that antigen retrieval is
      performed. Additional work using a larger sample size is warranted for better
      comparison of the predictive accuracy with that of other prognostic markers.

PMID- 8641849
TI  - Localization of mRNAs for insulin-like growth factor-I (IGF-I), IGF-I receptor,
      and IGF binding proteins in rat eye.
AB  - PURPOSE: To localize mRNAs for insulin-like growth factor (IGF)-I, IGF-I receptor
      (IGF-IR), and IGF binding protein (BP)-1 to IGFBP-6 in the rat eye. METHODS: cDNA
      sequences for IGF-I, IGF-IR, and IGFBP-1 to IGFBP-6 were used to synthesize 35S
      CTP labeled antisense and sense probes for in situ hybridization on 5-microns
      sections of the rat eye, including the retina, choroid, sclera, ciliary body, and
      cornea. RESULTS: IGF-I mRNA was demonstrated over ganglion cells of the retina
      and endothelial cells of the choroid and ciliary processes. IGF-IR mRNA showed
      more extensive distribution, localizing to the retinal ganglion cell layer, inner
      nuclear layer, and outer limiting membrane and also the outer nonpigmented
      epithelium of the ciliary processes and cornea, conjunctiva, and lens. IGFBP-2
      mRNA localized to outer nonpigmented epithelia of the ciliary processes and the
      germinal layer of corneal epithelium as well as iris, conjunctiva, and sclera.
      Messenger RNAs for IGFBP-3 to IGFBP-6 localized to choroidal endothelial cells
      and chromatophores and also to the inner pigmented epithelium of the ciliary
      processes. Messenger RNAs for IGFBP-5 and IGFBP-6 were seen in the inner and
      outer nuclear layers of the neural retina. IGFBP-1 mRNA was not detected within
      the rat eye. CONCLUSIONS: Using in situ hybridization, we have demonstrated mRNAs
      for IGF-I, IGF-IR, and IGFBP-2 to IGFBP-6 in specific histologic layers of the
      retina, choroid, ciliary body, and cornea in the rat. The characterization of the
      IGF system in vivo suggests specific roles in the normal eye and provides a basis
      for studying the IGF system in eye pathology.

PMID- 8641850
TI  - Retinal Thy-1 expression during development.
AB  - PURPOSE: To evaluate the developmental expression of Thy-1 in the retina. Thy-1,
      the most abundant mammalian neuronal surface glycoprotein, is likely to play a
      significant role in retinal development. In the mammalian retina, it is found
      predominantly, if not exclusively, on retinal ganglion cells. METHODS: Rat
      retinae of various ages were stained immunohistochemically for Thy-1 with 2G12, a
      monoclonal Thy-1 antibody. Sections were analyzed digitally to quantify bound
      antibody. Using semiquantitative reverse transcription-polymerase chain reaction
      (RT-PCR), the expression of Thy-1 protein was compared with the levels of mRNA
      detected. RESULTS: Thy-1-dependent fluorescence was detected in rat retinae from
      birth, albeit at low levels. Thy-1 labeling was localized predominantly to the
      ganglion cell layer. Minimal, fine patterns of linear and reticular fluorescence
      were noted in the inner nuclear layer. Thy-1 levels reached a maximal level at
      approximately postnatal day 14. RT-PCR measurements showed a similar time course
      for the increase in Thy-1 expression. CONCLUSIONS: The Thy-1 antigen is present
      in the inner retina at birth. Its level increases steadily after birth and peaks
      during the second week of life. Thy-1 expression is approximately coterminous
      with synaptogenesis of the inner plexiform layer and may play a role in
      synaptogenesis of the inner retina or in other developmental milestones in the
      formation of the visual system.

PMID- 8641851
TI  - Carbachol does not correct the defect in the phagocytosis of outer segments by
      Royal College of Surgeons rat retinal pigment epithelial cells.
AB  - PURPOSE: To investigate the effect of carbachol on the phagocytosis of
      photoreceptor outer segments (OS) in cultures of normal Long-Evans and dystrophic
      Royal College of Surgeons (RCS) rat retinal pigment epithelial (RPE) cells.
      METHODS: Retinal pigment epithelial cells from normal and RCS rats were grown in
      tissue culture. On reaching confluence, they were presented with OS suspended in
      Krebs-Henseleit buffer in the presence or absence of carbachol and LiCl. The
      number of bound and ingested OS was quantitated using double immunofluorescence
      staining. RESULTS: LiCl inhibited the ingestion of OS by more than 90% but had no
      effect on the binding of OS by Long-Evans RPE cells. The addition of carbachol
      further reduced OS ingestion. Carbachol alone decreased OS ingestion by normal
      RPE cells by 30% but had no effect on OS binding. The effect of LiCl and
      carbachol on RCS RPE cells was similar to their effect on normal RPE cells.
      CONCLUSIONS: Carbachol does not increase OS phagocytosis in normal or RCS rat RPE
      cells. The phagocytic defect in RCS rat RPE cannot be reversed or overcome by
      stimulation of the IP3 pathway by carbachol. LiCl strongly inhibits the ingestion
      of OS by normal and by RCS RPE cells, and this effect is enhanced by carbachol.

PMID- 8641852
TI  - The role of the Israel Psychiatric Association at a time of health reform.

PMID- 8641853
TI  - Holocaust survivors fifty years after the end of World War II.

PMID- 8641854
TI  - The sources and signs of Jewish identity.
AB  - In order to resolve some of the complexities and paradoxes involved in the
      concept of Jewish identity, the author suggests making a distinction between a
      core identity and a manifest identity. The former is established early in
      childhood and is shaped by the specifically Jewish experiences of the young
      child. The latter represents the outcome of modifications, whether diluting or
      reinforcing, induced by subsequent experience. The essay includes a list of some
      of the more common "givers" of core Jewish identity, and some of the expressions
      of manifest identity. Usually the parents' expressions of manifest identity
      function as "givers" of the child's identity. The provision of identity cues in
      early childhood facilitates but does not guarantee subsequent Jewish
      identification. Many other personality and fortuitous features, internal or
      external or both, influence the ultimate outcome.

PMID- 8641855
TI  - Demandingness and belligerence in hospitalized depressed Holocaust concentration
      camp survivors as perceived by the staff.
AB  - Twelve staff members, blind to the hypotheses, rated depressed, hospitalized
      concentration camp survivors, 40 years after their liberation, as more demanding,
      belligerent and irritating in their behavior towards staff in comparison with
      their matched counterparts. Survivors' behavior was discussed in terms of
      reenactment of traumatic scenes from their past. Staff shows consistent although
      not significant tendencies to dislike the survivors. Theoretical and clinical
      implications were drawn.

PMID- 8641856
TI  - Two-year trial of maintenance neuroleptic dose reduction in schizophrenic out
      patients: predictors of relapse.
AB  - Low dose maintenance therapy has been proposed as a pharmacological strategy for
      reducing exposure to neuroleptic drugs in schizophrenia. However, reliable
      predictors of post-dose reduction relapse, which could guide clinicians in
      selecting patients suitable for this type of treatment, have not yet been
      determined. In this study, 41 schizophrenic out-patients were assigned, on the
      basis of their previously clinically determined dosages, to one of two reduced
      maintenance fluphenazine decanoate regimes (35 mg/4 wks. or 10 mg/4 wks.) and
      were assessed, subsequently, for a 2-year period. Demographic, clinical and
      treatment characteristics of relapsers (22 patients) and non-relapsers (18
      patients) were compared using univariate and multivariate tests. Four parameters:
      age, course of illness, duration of illness and duration since last psychiatric
      hospitalization, suggested, in univariate tests, significant discrimination
      between relapsers and non-relapsers. Stepwise discriminant function analyses
      defined a highly significant function (p < .01) which included only 3 predictors
      of relapse. In order of importance, these predictors were: (1) a history of
      chronic psychosis (2) male sex, and (3) an illness of short duration. Parameters
      such as age, baseline rating scales scores, magnitude of dose reduction and
      baseline maintenance dose failed to improve the ability to discriminate between
      relapsers and non-relapsers. Implications of these findings for clinical practice
      are discussed.

PMID- 8641858
TI  - Visual-perceptual disturbances in delusional misidentification.
AB  - The delusional misidentification syndromes can involve physical
      misidentification. Delusional misidentification of the physical make-up of the
      self shares delusional dysmorphic symptoms with delusional disorder of the
      somatic type. In this article, we discuss how the study of delusional and
      perceptual symptoms in delusional misidentification syndromes may lead to a
      better understanding of the delusional dysmorphic process.

PMID- 8641857
TI  - Nonaffective acute remitting psychosis: historical and nosological aspects.
AB  - The present paper reviews the different approaches and evolution of the concept
      of nonaffective acute remitting psychoses (NARP) through a historical
      perspective. Although reports and clinical descriptions of nonaffective acute
      remitting psychoses were found as early as the middle of the 19th century there
      has been no consensus on their course and clinical characteristics, and this
      confusion and lack of clarity is expressed in the current major nosological
      systems. This selected review will focus on the main approaches to the definition
      of this group of psychoses and their expression in the current major nosologies.

PMID- 8641859
TI  - Laurence-Moon-Bardet-Biedl syndrome in combination with Cotard's syndrome. Case
      report.
AB  - Laurence-Moon-Bardet-Biedl (LMBB) syndrome is a symptom complex that usually
      presents with retinitis pigmentosa, poly- or syndactyly, mental retardation,
      obesity and hypogenitalism. Cotard's syndrome is a state in which the central
      symptom is a delusion of negation. The case reported here is a combination of
      these two rare conditions.

PMID- 8641860
TI  - Cardiac arrhythmia in a child receiving pericyazine.

PMID- 8641861
TI  - Forensic psychiatry in Israel.

PMID- 8641862
TI  - Neurochemical imaging of the brain in health and disease.

PMID- 8641863
TI  - The N-methyl-D-aspartate receptor and schizophrenia.

PMID- 8641864
TI  - Prediction of mortality in patients awaiting cardiac transplantation: increased
      risk of sudden death in ischemic compared to idiopathic dilated cardiomyopathy.
AB  - A major problem in cardiac transplantation is the death of candidates due to the
      increasing shortage of donors and the consequent longer waiting periods. To
      determine whether clinical markers for death could be identified in these
      patients, 168 adult candidates with heart failure (NYHA class III and IV) listed
      between August 1987 and December 1989 were analyzed. There were 104 patients with
      ischemic cardiomyopathy (ISCM) and 64 with idiopathic dilated cardiomyopathy
      (IDCM). Transplantation was performed in 93 patients (55%). Actuarial 1 year
      survival was 61% in the ISCM group and 78% in the IDCM group (P = NS). Freedom
      from sudden death at one year was significantly lower in the ISCM group (73%)
      than in the IDCM group (96%) (P < 0.01). The rate of patients who did not die
      from terminal myocardial failure was 83% in the ISCM group and 81% in the IDCM
      group (P = NS). There were no significant differences between the two groups in
      right atrial, pulmonary artery, and pulmonary wedge pressures, transpulmonic
      pressure gradient, pulmonary vascular resistance, cardiac index, and ejection
      fraction. We conclude that candidates for cardiac transplantation with ISCM are
      at higher risk for sudden death during the first year on the waiting list than
      patients with IDCM. These results warrant consideration of aggressive arrhythmia
      control measures, including an automatic implantable defibrillator, to "bridge"
      these high risk patients to transplantation.

PMID- 8641865
TI  - Low dose aspirin in patients with ischemic heart disease may precipitate
      secondary myocardial infarction.
AB  - We conducted a retrospective case-control study to compare the frequency of
      myocardial infarction (MI) or unstable angina (UA) precipitated by aspirin
      induced upper gastrointestinal (GI) bleeding among patients with and without
      ischemic heart disease(IHD), and to determine whether the risk of MI or UA is
      related to the hemoglobin level on admission. Of the 51 patients admitted to the
      hospital between 1987 and 1994 because of aspirin-induced upper GI bleeding, 33
      had ischemic heart disease. The prevalence of MI and UA inpatients with IHD and
      aspirin-induced upper GI bleeding was significantly higher than in patients
      without IHD (42% vs. 5.5% respectively) (P < 0.005). Of the patients with upper
      GI bleeding and a hemoglobin concentration of 5-8 g/dl, 75% had either MI or UA
      in comparison to 50% and 18% of the patients with hemoglobin concentrations of 8
      10 and 10-14 g/dl respectively. We conclude that low dose aspirin therapy may
      precipitate MI or UA, especially in patients with IHD, by inducing upper GI
      bleeding. Patients with IHD who use low dose aspirin to prevent MI should be
      instructed how to identify emerging symptoms of peptic ulcer as well as the
      initial signs of upper GI bleeding. Early diagnosis and treatment of these
      patients might prevent the induction of secondary MI or UA.

PMID- 8641866
TI  - Early experience in lung transplantation.
AB  - Lung transplantation is becoming an acceptable mode of therapy worldwide for the
      end-stage lung disease. We present our initial experience with the first 10
      consecutive lung transplant patients at Hadassah University Hospital. There were
      5 males and 5 females with an age range 27 to 59 years. Eight patients underwent
      single lung transplantation, one patient had double lung transplantation and one
      had heart-lung transplantation. Indications were: pulmonary fibrosis in 4,
      emphysema in 4, cystic fibrosis in 1, and cystic bronchiectasis in 1. Two
      patients had primary graft failure (1 death). Nine patients had a serious
      infection after transplantation (1 death). Four patients developed airway
      complications including dehiscence of bronchial anastomosis (1 death), bronchial
      stenosis requiring placement of a stent in 2 patients, and pneumothorax in 1
      patient. One patient required tracheostomy. One patient died of massive brain
      infarction secondary to pulmonary venous thrombosis and embolization. Six
      patients are intermediate-term survivors, with a follow-up period of 4-24 months.
      Four of them had at least one episode of rejection each. In all survivors
      pulmonary functions and quality of life improved and they do not need
      supplemental oxygen. We conclude that lung transplantation is a viable option for
      end-stage lung disease. Better selection of patients and perhaps improved
      immunosuppression agents will further improve outcome in lung transplantation.
      Shortage of donor supply is currently the limiting factor in successful lung
      transplantation in Israel.

PMID- 8641867
TI  - Myopia in neurofibromatosis type 1.
AB  - We studied the prevalence of myopia in 17-year-old Israeli military recruits with
      neurofibromatosis type 1 (NF1). Twenty-four percent of the youngsters with
      neurofibromatosis had myopia, compared to 19% of the controls; this difference
      was statistically significant (P < 0.03). The recruits with NF1 had a slightly
      lower IQ, fewer years of education, and lower height and weight than the
      controls. Thus, these factors, which have been reported to be associated with
      myopia, did not significantly influence the high prevalence of myopia in the
      neurofibromatosis subjects. A high prevalence of myopia seems to be an additional
      feature of NF1.

PMID- 8641868
TI  - Rubella in pregnancy in Israel: 15 years of follow-up and remaining problems.
AB  - Despite extensive vaccination programs introduced in Israel since 1973, rubella
      virus continues to pose a threat to pregnant women. Screening for antibodies from
      women of childbearing age between 1980 and 1994 showed a decrease in
      seronegativity from 15.4% to 7% between the years 1980 and 1988, followed by an
      increase to 9.6% in 1991-92 due in part to the large wave of immigration from the
      former USSR, and a decrease back to 6.9% in 1993-94. The morbidity fluctuated,
      with peaks in 1983, 1987 and 1991, yielding a total of 219 cases in the target
      population of women of childbearing age. Additional problems encountered were
      reinfections, vaccine failures, and false positive results in screening. During
      the study period we confirmed 35 cases of reinfections in pregnancy, 19 of which
      resulted in delivery of healthy babies. In two of four cases of abortion
      following reinfection that we could follow, the fetus was infected. Immunization
      of 15-month-old babies introduced in 1989 and the new policy of two-dose
      vaccination introduced in 1995 are expected to further reduce the spread of
      rubella virus in the coming years.

PMID- 8641869
TI  - Reversible brain atrophy and reversible developmental retardation in a
      malnourished infant.
AB  - An 11-month-old infant suffering from microcephalus, developmental delay, severe
      failure to thrive and marked cortical atrophy on brain CT is presented. The cause
      of this condition was total calorie malnutrition induced by the emotional
      dysfunction of the mother. Improvement of the maternal-infant relationship,
      combined with appropriate nutrition, transformed the infant within 2 months into
      a normally developing baby with body weight and head circumference within the
      normal percentile range. A corresponding improvement was found in the brain CT.

PMID- 8641870
TI  - Severe cerebral accidents postpartum in patients taking bromocriptine for milk
      suppression.
AB  - We report three recent cases of severe acute cerebral accident which occurred in
      the puerperium in women who received bromocriptine for milk suppression. Two
      patients experienced mild pregnancy-induced hypertension antepartum. Marked blood
      pressure elevation, above that which had prevailed previously, occurred
      postpartum in each case. The cerebral accidents manifested between the 6th and
      14th days of the puerperium, the typical time for the occurrence of severe side
      effects from bromocriptine. These complications entailed lasting neurological
      sequelae in the three mothers who, based on their age, medical history and
      general state of health, were not significantly predisposed to cerebral
      accidents.

PMID- 8641871
TI  - Ketotifen is protective against indomethacin-induced intestinal ulceration in the
      rat.
AB  - Ketotifen is an anti-allergic agent that was recently shown to prevent
      experimental gastric and colonic mucosal injury. We studied the effect of
      ketotifen on indomethacin-induced small intestinal ulceration in the rat.
      Ulceration was produced by s.c. injection of 30 mg/kg indomethacin, 30 min after
      refeeding 24 h fasted rats. Total ulcer area (mm2), prostaglandin E2 (PGE2) and
      leukotriene B4 (LTB4) were measured 24 h after indomethacin administration. Study
      groups received ketotifen 100 micrograms/ 100 g body weight 30 min before and 5 h
      after indomethacin administration, either i.p. or orally. There were 7-9 animals
      in each group. Ulcer area was significantly reduced by oral administration of
      ketotifen from 229 +/- 26 to 146 +/- 28 mm2. PGE2 level was reduced by ketotifen
      from 505 +/- 73 to 228 +/- 68 ng/mg protein, and LTB4 was reduced from 289 +/- 68
      to 59 +/- 26 ng/mg protein. Intraperitoneal administration of ketotifen had no
      effect on any of the measured parameters. Ketotifen had a definite protective
      effect on small intestinal mucosa in the rat, which was accompanied by a
      reduction of mucosal inflammatory mediators. Ketotifen may have a role in the
      prevention or treatment of small intestinal damage induced by nonsteroidal anti
      inflammatory drugs.

PMID- 8641872
TI  - Awaiting heart transplantation--a race for survival?

PMID- 8641873
TI  - Lung transplantation: a rational vision.

PMID- 8641874
TI  - Cardiomyoplasty--the beginning of a new era.
AB  - Cardiomyoplasty is a surgical treatment for a well-defined group of patients who
      suffer from congestive heart failure. The procedure is not a contraindication to
      perform a future heart transplantation, when indicated. The clinical results up
      to 7 years after cardiomyoplasty are encouraging, but there is still a gap
      between the significant functional capacity improvement of the patients after
      cardiomyoplasty and the moderate hemodynamic change. Experimental data and recent
      measurements in patients provide new insights in understanding the physiologic
      effect of cardiomyoplasty.

PMID- 8641875
TI  - Minocycline in rheumatoid arthritis.

PMID- 8641876
TI  - Cases 1A and 1B. 1995 intravenous lidocaine infusion for chronic pain therapy.

PMID- 8641877
TI  - Case 2--1995. Seizures associated with propofol anesthesia.

PMID- 8641878
TI  - Visceral leishmaniasis--an emerging zoonosis in the Jerusalem area.

PMID- 8641879
TI  - Vitamin D status of Israeli adults.

PMID- 8641880
TI  - Pioneers in allergy and anaphylaxis.

PMID- 8641882
TI  - [Management of primary malignant melanoma of the skin in German-speaking
      countries 1983-1993. A study of the Malignant Melanoma Central Register of the
      German Society of Dermatology].
AB  - During the past decade more than 90% of all melanoma patients in the German
      speaking countries have been diagnosed with a primary tumour alone. Therefore,
      surgical intervention has been the most important element in the management of
      these patients. The present investigation was performed to analyse the different
      surgical procedures used in the treatment of primary melanoma during the years
      1983-1993. The primary treatment of 15,054 patients with malignant melanoma and
      without recognizable metastasis has been examined. During the time period under
      investigation the percentage of cases treated with two-step surgical management
      increased from 30% to 60%. Primary excision was performed in local anaesthesia in
      40% of all patients in 1983, whereas in 1993 surgical intervention under local
      anaesthesia had increased up to 80%. Over the same time, the average safety
      margin decreased from 33 mm to 21 mm for the final excision of primary melanomas,
      and this decrease was paralleled by marked decrease in the average thickness of
      the tumours excised from 2.1 to 1.5 mm. Elective node dissection was performed in
      5% of all patients in 1983, whereas 9% of patients underwent elective node
      dissection in 1993. The different centres participating were found to differ
      noticeably in the therapeutic procedures applied for similar indications. In
      conclusion, the management of primary malignant melanoma has changed considerably
      during the years 1983-1993 in the German speaking area in favour of a two-step
      surgical procedure, local anaesthesia for the excision of the primary tumour and
      smaller safety margins. It seems that earlier diagnosis of the tumour and also
      ideas about treatment design may be responsible for these changes.

PMID- 8641881
TI  - [Transgenic mice as models for skin diseases].
AB  - Naturally occurring animal models are not available even for most common skin
      diseases. Transgenic technology developed during the 1980s is closing this gap.
      It was initially used as a tool by scientists in basic research, but during the
      last 5 years it has increasingly been applied by clinically oriented basic
      researchers in dermatology. This technique, has made it possible to imitate HIV
      associated diseases and genodermatoses in the murine model and to elucidate their
      pathogenesis. Owing to specifically induced epidermally localized overexpression
      of growth factors and cytokines, the skin of transgenic mice exhibited
      similarities to those of the psoriatic epidermis. Such animals are also useful
      for studying wound healing. Furthermore, transgenic technology enables us to
      induce cutaneous tumors selectively. The availability of animal models for human
      skin diseases is also of value in elucidating experimental therapeutic
      approaches, e.g., the somatic gene therapy.

PMID- 8641883
TI  - [Early onset irritant skin damage in apprentice hair dressers].
AB  - In the course of a cohort study addressing the importance of constitutional and
      occupational risk factors for the development of irritant hand eczema, 859
      hairdressing apprentices were examined in 14 vocational training schools in
      autumn 1993, after an average of 8 weeks of professional exposure. In this cross
      sectional survey at the start of training, 38.2% were suffering from skin damage,
      in most cases mild to moderate and only rarely severe; we observed almost
      exclusively irritant skin damage, mostly localized interdigitally. Logistic
      regression analysis revealed previous hand eczema, an elevated ?atopy score?
      (Diepgen) and, particularly, unprotected work for several hours daily with wet
      hands as significant risk factors for this early onset irritant damage/eczema.
      The high wet workload is mainly caused by very frequent shampooing and by
      permanent waving without wearing gloves; however, other tasks are also often
      performed without appropriate protective gloves. The implications of the
      considerable inter-observer variability are described and discussed.

PMID- 8641884
TI  - [The clinical spectrum of focal dermal hypoplasia].
AB  - Focal dermal hypoplasia (FHD) is an X chromosomal dominant inherited disease with
      unknown gene defect. FDH is characterized by ectodermal and mesodermal
      malformations. It is thought to be lethal in males; however, males may survive as
      mosaics or possibly as Klinefelter syndrome (XXY). When mosaicism involves the
      gonads the disease may be transmitted from father to child. In females, the
      abnormal phenotype is thought to be expressed in a blaschkoid pattern because of
      random X chromosome inactivation. We have collected eight cases of which three
      were males. We present the typical clinical dermatological feature and draw
      attention to cases with minimal skin involvement.

PMID- 8641885
TI  - [Angiokeratoma corporis diffusum without associated metabolic disorder].
AB  - In a 22-year-old woman with mental impairment and some signs of dysmorphism,
      numerous angiokeratomas developed, starting when she was 3 years old and
      resulting in the clinical picture of angiokeratoma corporis diffusum. Extensive
      laboratory analyses did not disclose any associated metabolic disorder,and
      electron microscopy failed to demonstrate lysosomal inclusions. Therefore, this
      patient can be classified as one of the rare cases of angiokeratoma corporis
      diffusum without associated metabolic disease (idiopathic angiokeratoma corporis
      diffusum).

PMID- 8641886
TI  - [Bullous pemphigoid simulation subacute simple prurigo].
AB  - Bullous pemphigoid (BP) is a bullous autoimmune disease of the elderly; it is
      characterized by tense bullae on both erythematous and otherwise apparently
      normal skin. Several clinical variants of BP have been described, and we now add
      our observations of two BP cases mimicking subacute prurigo. Both patients had
      suffered from intensely pruritic excoriated papules for several months before
      presentation. Blisters had never developed and did not occur during follow up.
      Histology showed changes of chronic dermatitis. In the serum of both patients,
      indirect immunofluorescence on NaCl-separated human skin revealed the presence of
      circulating antibodies binding to the roof of the artificial blisters.
      Perilesional skin biopsies showed linear IgG or C3-deposits in the basement
      membrane zone. Immunoblotting of epidermal and dermal extracts demonstrated the
      binding of the antibodies to an epidermal 230-kD protein, which is the known
      major bullous pemphigoid antigen. These cases are described as a basis for
      discussion of the clinical spectrum of bullous pemphigoid.

PMID- 8641887
TI  - [Morbihan disease--chronic persistent erythema and edema of the face].
AB  - Morbihan's disease was first reported as a distinct entity in 1957 by Degos,
      describing a chronic persistent erythema and oedema of the upper half of the
      face. Such conditions have been noted in the literature designated as chronic
      lymphoedema or solid persistent facial oedema in acne or rosacea. The
      characteristic features are a chronic course, a typical clinical picture, lack of
      specific laboratory and histological findings and refractoriness to therapeutic
      measures.

PMID- 8641889
TI  - [Tonsural trichotillomania].
AB  - Tonsure trichotillomania is a subtype of trichotillomania in which the scalp
      exhibits a tonsural pattern of alopecia over the crown, extending to the frontal
      margin and sparing the lateral margins and the nape of the neck. It differs from
      the more common form of childhood trichotillomania in that predominantly female
      adolescents are affected and its incidence is related to quite severely
      pathologic psychodynamics, often with a disturbed relationship to female
      sexuality. The treating physician should be more guarded in assessing the
      prognosis; hair plucking often continues for years. Two patients with tonsure
      alopecia, associated in one case with trichotillomania of the pubic hair and in
      the other with enuresis, are presented.

PMID- 8641888
TI  - [Generalized molluscum contagiosum in an African child with AIDS].
AB  - A 12-year-old girl from Zaire with AIDS (CDC: P2 D1) presented with a generalized
      molluscum contagiosum infection. She had suffered from systemic cryptococcosis
      and from cryptosporidiosis several months before admission. While molluscum
      contagiousum infection is usually a self-limiting disease in immunocompetent
      persons, a fulminant appearance and persistence of giant mollusca occurs with
      advanced immunodeficiency. Histological and immunohistological examinations
      showed a severe diminution of Langerhans and T cell populations that might
      enhance the dissemination of the infection. Molluscum-like lesions of cryptococci
      have been described, and cutaneous cryptococcosis is the main condition to be
      considered in the differential diagnosis. Further differential diagnoses should
      include American and African histoplasmosis, and the cutaneous manifestations of
      mycobacterial infections, of toxoplasmosis and of Pneumocystis carinii infection.

PMID- 8641890
TI  - [Apical ulceration of the glans penis in hypervascularization syndrome. Sequelae
      of revascularization operation in erectile dysfunction].
AB  - We report on a hypervascularization syndrome of the glans penis with localized
      apical ulcerations, which occurred after the unusually long period of 3.5 years
      after revascularization surgery (Hauri technique) for erectile dysfunction.
      Hauri's operation, a relatively new procedure, combines arterial
      revascularization and arteriovenous shunting, and only in rare cases it is rare
      for the complication of postoperative hyperaemia with ulceration of the glans
      penis to be encountered. Since the ulceration was resistant to conservative
      treatment, healing could only be achieved by ligation of the shunt.

PMID- 8641891
TI  - [Risk of atrophy induced by recent topical glucocorticoids].

PMID- 8641892
TI  - [Angioimmunoblastic lymphadenopathy accompanied by Duhring disease-like lesions].

PMID- 8641893
TI  - [Immunology of melanoma].

PMID- 8641894
TI  - [Skin expansion and skin growth. Molecular proof of collagen synthesis in long
      term skin expansion].

PMID- 8641895
TI  - [NIH Consensus Conference on cochlear implants in adults and children, 15 to 17
      May 1995].

PMID- 8641896
TI  - [Complications with cochlear implants in childhood].

PMID- 8641897
TI  - [Pathogenesis of otosclerosis. "State of the art"].
AB  - Women suffer from otosclerosis 1.6 times more often than males. Histologically,
      otosclerotic foci can be found in temporal bones of females 1.9 times more often
      than in those of males. Characteristic topographic regions are the oval window,
      round window niche and promontory. Otosclerosis can also occur principally in any
      area of the enchondral/periosteal layer of the otic capsule. Evidence is
      presented that otosclerosis is an inflammatory tissue reaction associated with
      macrophages, T- and B-lymphocytes, HLA-DR positive cells and plasma cells.
      Dependent on the stage of the osteolytic bone disease present deposits of
      complement and immunoglobulins (IgG, IgA) can be found. These immunoglobulins
      have been identified as antibodies to measles virus proteins. Using the
      polymerase chain reaction we were successful in demonstrating RNA sequences of
      measles viruses in otosclerotic bone from footplates removed during stapes
      surgery. Since most of the otosclerotic lesions were in direct contact to the
      perilymphatic space, it may be expected that the endolymphatic sac--as the immune
      competent organ of the inner ear--specifically reacts to antigens delivered from
      the otosclerosis focus into the perilymph. Perilymph samples from patients were
      collected during stapes surgery and their antibody titers against measles were
      compared with that in corresponding blood serum. All samples revealed a
      significantly elevated-specific anti-measles IgG amount which was significantly
      higher than in the corresponding serum. In contrast, antibody titer in the
      perilymph against herpes simplex or cytomegalo viruses did not differ from that
      of the serum. These findings indicate that otosclerosis is a measles virus
      associated inflammatory osteolytic disease of the temporal bone. Since women
      suffer from severe measles virus infections more often than males, it can be
      hypothesized that females have a higher susceptibility of their cochleo
      vestibular tissues to these infections (organotropism). In addition, estrogens
      are well-known stimulators of osteocytic activity and may play a dominant role
      during ossification of an otospongeotic bone lesion. This may explain the onset
      of a conductive hearing loss due to otosclerosis during pregnancy.

PMID- 8641898
TI  - [Contralateral approach to clivus tumors using the transmaxillary-transethmoid
      approach].
AB  - A modified transmaxillary transethmoid approach to the clivus is described. A
      paranasal incision is performed on the side contralateral to the major tumor
      extension. The approach provides preservation of the lacrimal duct, and the bony
      structures of the pyriform aperture. By removing the frontal process of the
      maxilla and if necessary the medical orbital wall, a wide access is created that
      can be further enlarged by dissecting the medial concha, ethmoid sinus and
      posterior parts of the nasal septum. Cerebrospinal fluid leakage is treated by a
      special technique.

PMID- 8641899
TI  - [Distant metastasis and incidence of second carcinomas in patients with
      oropharyngeal and hypopharyngeal carcinomas].
AB  - Thirteen per cent of oropharyngeal carcinoma patients (n = 23/178) developed a
      secondary carcinoma, and 10% of hypopharyngeal carcinoma patients (n = 11/113).
      The latency time of occurrence of the second carcinoma was 37 months for the
      oropharyngeal tumors and 25 months for the hypopharyngeal tumors. The main
      location of the secondary cancers was the oral cavity and oropharynx. Early
      recognition of secondary cancers by routine follow-up examinations made surgical
      removal possible in most of the patients. The post-operative survival time for
      the oropharyngeal lesions was 59 months and was 34 months for the hypopharyngeal
      cancers. Distant metastases were found in 13% of the patients with oropharyngeal
      cancers and in 17% with hypopharyngeal cancer and were mainly located in the
      lungs. After diagnosis of distant metastases patients with oropharyngeal lesions
      died within 4.5 months and those with hypopharyngeal tumors died within 9 months.

PMID- 8641900
TI  - [Golden tube wire for temporary or permanent implantation].
AB  - Abnormal eustachian tube function has been a major problem in improving hearing
      with middle ear surgery. In 13 patients, a newly developed gold tube conductor
      was placed in the eustachian tube via the middle ear cavity. Patients were
      examined 2-50 months postoperatively, at which time middle ear aeration was found
      to be significantly improved in 11 of the cases.

PMID- 8641901
TI  - [Long-term outcome of tympanoplasty in chronic suppurative middle ear infection
      in childhood].
AB  - Controversy continues regarding tympanoplasty for central perforations due to
      chronic otitis media in children. Between 1972 and 1988, 144 children (160 cases)
      were operated on for central perforations after chronic otitis media and were
      managed at the ENT Hospital of the University of the Saarland, Homburg/Saar.
      Eighty-seven of these children were evaluable for this study. Post-operative
      follow-up was more than 5 years in 94% of the cases. The tympanic membrane was
      closed in 90% of the cases at follow-up examination. The age of the patient did
      not influence the success rate. Social hearing was improved from 49% before
      operation to 86% after operation and at follow-up. At follow-up, air-bone gaps
      were closed to within 10 dB in 67% of the cases, within 20 dB for 88% and within
      30 dB for 96%. These very good and stable results show that an early operation
      can be recommended for children with chronic otitis media to prevent further
      damage to the middle ear.

PMID- 8641903
TI  - [Newly developed vacuum suction valve for microsurgery].
AB  - A vacuum operated suction appliance can be invaluable for all areas of surgery.
      The suction process carries a greater risk (e.g. dizziness, deafness), especially
      in microsurgery of the ear. A newly developed vacuum valve for microsurgery that
      is mechanically adjustable is presented. The surgeon operates the valve with his
      foot outside the aseptic area of surgery. The valve enables him to regulate the
      vacuum or to quickly interrupt the suction process. This allows for swifter,
      safer surgery. Examples of use of the device in microsurgery of the ear are
      described in detail.

PMID- 8641902
TI  - [Chemotherapy of juvenile angiofibroma--an alternative?].
AB  - Since February 1979, 22 juvenile angiofibromas have been treated among 312 tumors
      of the skull base managed in the ENT Department, Fulda. According to a general
      staff consensus the treatment of choice was complete surgical removal. This was
      achieved in 20 cases with one operation and in one case with two operations. In
      addition to removal of tumor, functional and aesthetic aspects had to be
      considered as aims of operative treatment, including among others preservation of
      the facial skeleton, infraorbital nerve, nasolacrimal drainage system and vision.
      In rare cases complete excision of the tumor is not possible. The value of
      cytostatic therapy is demonstrated in one patient with uncommonly advanced
      disease. Considering the extensive regression of tumor achieved in this case
      after chemotherapy with Adriamycin and decarbazine, one has to raise the question
      if the chemotherapeutic approach was more than just palliative. From our
      experience chemotherapy should be considered a possible alternative to radiation
      in the management of unresectable juvenile angiofibromas.

PMID- 8641904
TI  - [Expert evaluation of smell and taste disorders].

PMID- 8641905
TI  - Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials
      on human cerebral gliomas.
AB  - PURPOSE: Evaluation of tolerance, toxicity, and feasibility of combining large
      fraction (5 Gy) radiotherapy with 2-deoxy-D-glucose (2DG), an inhibitor of
      glucose transport and glycolysis, which has been shown to differentially inhibit
      repair of radiation damage in cancer cells. METHODS AND MATERIALS: Twenty
      patients with supratentorial glioma (Grade 3/4), following surgery were treated
      with four weekly fractions of oral 2DG (200 mg/kg body weight) followed by whole
      brain irradiation (5 Gy). Two weeks later, supplement focal radiation to the
      tumor (14 Gy/7 fractions) was given. Routine clinical evaluation, x-ray
      computerized tomography (CT), and magnetic resonance (MR) imaging were carried
      out to study the acute and late radiation effects. RESULTS: All the 20 patients
      completed the treatment without any interruption. The vital parameters were
      within normal limits during the treatment. None reported headache during the
      treatment. Mild to moderate nausea and vomiting were observed during the days of
      combined therapy (2DG + RT) in 10 patients. No significant deterioration of the
      neurological status was observed during the treatment period. Seven patients were
      alive at 63, 43, 36, 28, 27, 19, and 18 months of follow-up. In these patients,
      the clinical and MR imaging studies did not reveal any late radiation effects.
      CONCLUSIONS: Feasibility of administering the treatment (2DG + 5 Gy) is
      demonstrated by the excellent tolerance observed in all 20 patients. Further, the
      clinical and MR studies also show the absence of any brain parenchymal damage.

PMID- 8641906
TI  - Posttreatment follow-up of radiation oncology patients in a managed care
      environment.
AB  - PURPOSE: Health care delivery in the United States is in the midst of a
      structural revolution called managed care. Demands for cost control within the
      managed care environment force radiation oncologists to defend the need and
      obligation to follow their patients. METHODS AND MATERIALS: We have analyzed this
      follow-up requirement from six potential justifications: patient care, medical
      legal, quality assurance, outcome measurement, cost, and improvement of care.
      RESULTS: Practical recommendations for discussing the need for follow-up with the
      medical directors and primary care physicians of managed care entities are given.
      Follow-up without valid documentation of benefit is hard to justify in this era
      of managed care. CONCLUSIONS: Collaborative follow-up between the referring
      physician, the treating radiation oncologist, and the other oncologic specialists
      will allow for outcome measurement and improvement in practice without driving up
      cost or exposing the patient to undue risk.

PMID- 8641907
TI  - Improving treatment planning accuracy through multimodality imaging.
AB  - PURPOSE: In clinical practice, physicians are constantly comparing multiple
      images taken at various times during the patient's treatment course. One goal of
      such a comparison is to accurately define the gross tumor volume (GTV). The
      introduction of three-dimensional treatment planning has greatly enhanced the
      ability to define the GTV, but there are times when the GTV is not visible on the
      treatment-planning computed tomography (CT) scan. We have modified our treatment
      planning software to allow for interactive display of multiple, registered images
      that enhance the physician's ability to accurately determine the GTV. METHODS AND
      MATERIALS: Images are registered using interactive tools developed at the
      University of North Carolina at Chapel Hill (UNC). Automated methods are also
      available. Images registered with the treatment-planning CT scan are digitized
      from film. After a physician has approved the registration, the registered images
      are made available to the treatment-planning software. Structures and volumes of
      interest are contoured on all images. In the beam's eye view, wire loop
      representations of these structures can be visualized from all image types
      simultaneously. Each registered image can be seamlessly viewed during the
      treatment-planning process, and all contours from all image types can be seen on
      any registered image. A beam may, therefore, be designed based on any contour.
      RESULTS: Nineteen patients have been planned and treated using multimodality
      imaging from November 1993 through August 1994. All registered images were
      digitized from film, and many were from outside institutions. Brain has been the
      most common site (12), but the techniques of registration and image display have
      also been used for the thorax (4), abdomen (2), and extremity (1). The registered
      image has been an magnetic resonance (MR) scan in 15 cases and a diagnostic CT
      scan in 5 cases. In one case, sequential MRs, one before treatment and another
      after 30 Gy, were used to plan patient's initial fields and boost, respectively.
      Case illustrations are shown. CONCLUSIONS: We have successfully integrated
      multimodality imaging into our treatment-planning system, and its routine use is
      increasing. Multimodality imaging holds out the promise of improving treatment
      planning accuracy and, thus, takes maximum advantage of three dimensional
      treatment planning systems.

PMID- 8641908
TI  - External beam radiation for retinoblastoma: results, patterns of failure, and a
      proposal for treatment guidelines.
AB  - PURPOSE: To analyze treatment results and patterns of failure following external
      beam radiation for retinoblastoma and propose treatment guidelines according to
      specific clinical variables. METHODS AND MATERIALS: We analyzed 27 patients (34
      eyes) with retinoblastoma who received external beam radiation as initial
      treatment at Hahnemann University Hospital from October 1980 to December 1991 and
      have been followed for at least 1 year. Of the 34 eyes, 14 were Groups I-II
      (Reese-Ellsworth classification), 7 were Group III, and 13 were Groups IV-V.
      Doses ranged from 34.5-49.5 Gy (mean 44.3 Gy, median 45 Gy) in 1.5-2.0 Gy
      fractions generally delivered through anterior and lateral wedged pair fields.
      RESULTS: At a mean follow up of 35.2 months (range 12-93 months), local tumor
      control was obtained in 44% (15 out of 34) of eyes with external beam radiation
      alone. Salvage therapy (plaque brachytherapy, cryotherapy, and/or
      photocoagulation) controlled an additional 10 eyes (29.5%), so that overall
      ocular survival has been 73.5%. Local tumor control with external beam
      radiotherapy alone was obtained in 78.5% (11 out of 14) of eyes in Groups I-II,
      but in only 20% (4 out of 20) of eyes in Groups III-V. A total of 67 existing
      tumors were identified prior to treatment in the 34 treated eyes and local
      control with external beam radiation alone was obtained in 87% (46 out of 53) of
      tumors measuring 15 mm or less and in 50% (7 out of 14) of tumors measuring more
      than 15 mm. When analyzing patterns of failure in the 19 eyes that relapsed, a
      total of 28 failure sites were identified and consisted of progression of
      vitreous seeds in seven instances (25% of failure sites) recurrences from
      previously existing tumors in 10 instances (36% of failure sites) and development
      of new tumors in previously uninvolved retina in 11 instances (39% of failure
      sites). CONCLUSIONS: 1) We find that external beam radiation to a dose of 45 Gy
      in fractions of 1.5 to 2.0 Gy provides adequate tumor control in retinoblastoma
      eyes Groups I-II (Reese-Ellsworth classification) or tumors measuring 15 mm in
      diameter or less. Eyes in more advanced group staging or containing tumors larger
      than the 15 mm seem to require higher radiation doses. We propose treatment
      guidelines for external beam radiation of retinoblastoma that specifically take
      into account the important clinical variables of tumor stage and patient age. 2)
      External beam radiation does not prevent the appearance of new tumors in
      clinically uninvolved retina. Therefore, the traditional belief that external
      beam radiation can treat the retina "prophylactically" should be seriously
      questioned. Due to this finding and their significant less morbidity, focal
      treatment modalities (plaque brachytherapy, photocoagulation, and/or
      cryotherapy), when clinically feasible, should be considered the treatment of
      choice for intraocular retinoblastoma. External beam radiation should be
      considered only when focal treatment modalities are not clinically indicated.

PMID- 8641909
TI  - Topographic distribution of inguinal lymph nodes metastasis: significance in
      determination of treatment margin for elective inguinal lymph nodes irradiation
      of low pelvic tumors.
AB  - PURPOSE: To study the distribution of gross inguinal lymph node metastasis and,
      in particular, its correlation with major pelvic bony structures on a simulation
      film. METHODS AND MATERIALS: Thirty-seven cases of low pelvic tumors having gross
      inguinal lymph node metastasis that were treated with radiation therapy between
      November 1987 and December 1992 were segregated for study. The patient's nodes
      were palpated and marked with lead wire before the simulation film was assumed to
      be the origin of the previously uninfested node. A total of 84 such labeled nodes
      was taken. The geometric center of the usually round or elliptical node on the
      film was obtained from these 37 cases. These centers were transferred to and
      mapped collectively on a new simulation film showing major pelvic bony structures
      of left hemipelvis and upper femur. RESULTS: Distribution of gross inguinal lymph
      nodes was found confined to the following area, as related to major pelvic bony
      structure: laterally, just abutting the tangential line that passes through
      lateral border of the femoral head; medially: 3 cm away from the body's midline
      axis; superiorly: 1 cm below the line that joins both upper borders of the
      femoral head; inferiorly: 2.5 cm below the low borders of ischial tuberosity.
      According to this rectangular boundary, three nodes were out of the field, nine
      nodes near the border less than 1 cm margin. This area adequately covered 86% (72
      of 84) of the studied nodes. CONCLUSION: Distribution study is important in
      determining the treatment margin. In general, an additional 1-2 cm beyond the
      area described above is the recommended treatment margin for elective inguinal
      lymph nodes irradiation with high confidence level of coverage.

PMID- 8641910
TI  - Effect of recombinant human granulocyte colony stimulating factor (R-metHuG-CSF)
      as an adjunct to large-field radiotherapy: a phase I study.
AB  - PURPOSE: To test the feasibility of recombinant human granulocyte colony
      stimulating factor application during large-field radiotherapy. METHODS AND
      MATERIALS: Fifteen patients with clinically and histologically proven malignancy
      who received large-field radiotherapy entered this study. Administration of
      recombinant granulocyte colony stimulating factor (G-CSF) at a dose of 300
      microgram subcutaneously was started on Friday and was continued on Saturday and
      Sunday after the first radiotherapy treatment, which began on the Monday before.
      In this way four courses of G-CSF were applied every Friday, Saturday, and Sunday
      during the radiotherapy period. Absolute neutrophil cell (ANC) and blood counts
      were monitored twice a week and compared to a second group of 15 patients who
      received large-field radiotherapy without G-CSF. Before and at the end of every
      cycle of G-CSF, ANC, blood counts, and biochemistry were measured. We compared
      the myelotoxicity of the patients treated with G-CSF with 15 patients without G
      CSF treated at the same period with large-field radiotherapy, in match pair
      technique. RESULTS: G-CSF increased the ANC throughout the period of irradiation,
      and the treatment time needed for competing radiotherapy was shorter in the group
      who received G-CSF. Fourteen of 15 patients who received G-CSF treatment
      completed large-field radiotherapy without pause. Only 1 of 15 patients not
      receiving G-CSF was able to receive radiation treatment on schedule. Patients
      receiving G-CSF completed treatment with the mantle-field technique in 24 days
      and those with the abdominal bath technique in 26.5 days. Conversely, patients
      treated without G-CSF completed treatment with the mantle-field technique in 30.5
      days and those with the abdominal bath technique in 36 days. The most frequent
      side effect was musculoskeletal pain. CONCLUSION: The prophylactic application of
      G-CSF during large-field radiotherapy before the onset of neutropenia was
      feasible in this schedule. Whether or not this shortening of treatment duration
      will translate into an improvement in efficacy is not clear.

PMID- 8641911
TI  - Early evaluation of abdominal/hepatic irradiation and 5-fluorouracil/leucovorin
      infusion after pancreaticoduodenectomy.
AB  - PURPOSE: To describe the toxicities of a combined modality adjuvant regimen for
      patients with resectable periampullary adenocarcinoma. METHODS AND MATERIALS:
      Fourteen patients with surgically resected periampullary adenocarcinoma were
      treated with adjuvant therapy consisting of prophylactic hepatic irradiation and
      pancreatic bed irradiation and concurrent infusional 5-fluorouracil and
      leucovorin (5-FU/LV). Starting within 60 days of surgery, patients received
      radiation treatments of 1.8 Gy per fraction to the liver and pancreatic bed (13
      fractions), followed by 1.8 Gy per fraction to the pancreatic region (15
      fractions). All radiation treatments were given with infusional 5-FU (200
      mg/m2/day) and leucovorin (5 mg/m2/day) for 5 out of every 7 days during the 38
      day treatment sequence. After a 1-month break, patients were scheduled to receive
      four cycles of infusional 5-FU/LV (2 weeks on/2 weeks off). RESULTS: All 14
      patients completed the initial combination treatment. Toxicities were tolerable;
      three patients had Grade 3/4 toxicities that were primarily gastrointestinal in
      nature. Six patients required hospitalization during therapy for treatment
      related toxicities. Two patients required radiation treatment breaks of less than
      1 week, and two others had radiation held for 2-4 weeks. Three patients required
      chemotherapy dose reductions secondary to toxicities. Toxicities in the
      subsequent chemotherapy-alone cycles were few and primarily manifested by Grade 2
      rises in liver injury tests. Higher toxicity grades were associated with tumor
      progression. Twelve patients have developed recurrent disease with an equal
      number of recurrences occurring in the pancreatic bed as in the liver over the 12
      month median follow-up. Median survival for this cohort is 417 days, not
      significantly different from previously reported adjuvant trials in this patient
      population. CONCLUSION: These data indicate that adjuvant therapy with
      concomitant large-field radiation and infusional chemotherapy is feasible and
      associated with mangeable toxicities in patients undergoing
      pancreaticoduodenectomy for periampullary adenocarcinoma. Improvement in survival
      over other adjuvant regimens has not thus far been observed. Modification of this
      strategy may be required.

PMID- 8641912
TI  - Roentgen Centennial Lecture: discovering the past, inventing the future.

PMID- 8641913
TI  - Three-dimensional stylization of structures of interest from computed tomography
      images applied to radiotherapy planning.
AB  - PURPOSE: Techniques to detect structures of interest and model them as simple
      geometric shapes to enhance their visualization are presented. METHODS AND
      MATERIALS: Three-dimensional visualization techniques can be used to enhance the
      detection of critical structures by enclosing them in a readily perceived
      bounding volume. This article describes stylization techniques that define three
      dimensional shapes that conform to the real shape of the structures in the case
      of the spinal cord and the eyeballs. The term stylization can, thus, be defined
      as a combination of segmentation and the production of a tight bounding volume.
      The stylization techniques attempt to minimize the region that belongs to the
      solid produced and does not belong to the real structure, but they also attempt
      to ensure that the solid produced is a bounding volume to the real structure.
      RESULTS: The results produced by these techniques proved to be efficient and,
      thus, provide a means of easily visualizing the critical regions. CONCLUSION: The
      stylization technique can be seen as an adaptive volumetric contour. With
      potential use in clinical practice, it also provides a platform for further
      investigations of the geometric stylization concept.

PMID- 8641914
TI  - A dynamic match-line wedge.
AB  - PURPOSE: To implement match-line wedges at the abutting edges of x-ray fields
      using dynamic collimation. METHODS AND MATERIALS: Experiments were made using a
      computer-controlled linear accelerator equipped with developmental software that
      allows for collimator jaw motion while the beam is on. The jaws defining the
      abutting field edges were programmed to move from 1.5 cm inside to 1.5 cm outside
      the prescribed field during irradiation. Films were taken in plastic phantoms to
      assess the resulting edge gradient and to evaluate the sensitivity of this
      technique to setup errors. RESULTS: The measured edge gradient for a single field
      was 30% per cm. Parallel-opposed lateral fields produced a gradient of 28% per cm
      along their midline. A simulated central nervous system irradiation with cranial
      and spinal fields kept dose variations in the field-match region to less than 10%
      with setup errors of 3 mm. CONCLUSION: The use of collimator motion during
      irradiation is an effective and simple means of reducing the dose variation in a
      field-match region due to setup errors and system tolerances. Treatment time is
      not increased and labor savings can be achieved when compared to feathering
      techniques commonly used.

PMID- 8641915
TI  - A quantitative study of radionuclide characteristics for radioimmunotherapy from
      3D reconstructions using serial autoradiography.
AB  - PURPOSE: Using 131I-labeled monoclonal antibody (MoAb) data, assess the
      dosimetrical impact of labeling the same MoAb with 186Re or 90Y, under the
      assumption that the biodistribution of the radiolabeled MoAb in tumor relative to
      blood is independent of the radionuclide. METHODS AND MATERIALS: Radial
      radioactivity and dose-rate distributions at 1, 4, and 7 days postinjection were
      derived from three dimensional (3D) reconstructions of serial autoradiographs of
      LS174T human colon cancer xenografts in athymic nude mice treated with a single
      intraperitoneal administration of 300 microCi 131I-labeled MoAb 17-1A. Bone
      marrow dose was calculated taking into account energy deposited external to the
      bone marrow cavity due to the range of the beta particles. RESULTS: For 1 cm
      diameter tumors, uptake was mostly at the tumor surface for earlier postinjection
      times, but exhibited comparable activity levels from the surface to the core of
      the 7-day sample. The computed dose-rate distributions for 186Re and 90Y were
      more uniform than for 131I, but smaller fractions of the dose were deposited
      within the tumor volume due to the larger mean energies of 90Y and 186Re beta
      particles relative to those for 131I. However, when the tumor doses were
      normalized to the production of equivalent bone marrow doses, in the case of
      athymic nude mice, the tumor doses were calculated to be 15.3 Gy (131I), 14.1 Gy
      (186Re), and 12.0 Gy (90Y). For comparison, these calculations were extended to
      the case of human therapy, yielding tumor doses of 16.7 Gy (131I), 18.2 Gy
      (186Re), and 13.4 Gy (90Y). CONCLUSION: In the case of colon cancer xenografts
      where the MoAb uptake is initially concentrated at the tumor surface, we find a
      decreasing tumor dose per constant bone marrow dose for radionuclides of
      increasing mean beta energies and decreasing half-lives. However, a radionuclide
      with larger mean beta energy such as 90Y generates a significantly more uniform
      dose deposition within the tumor, especially concerning the core of the tumor,
      compared to 131I. For human therapy, a gamma component adds little to the tumor
      dose but increases dose to the marrow.

PMID- 8641916
TI  - Radiation therapy of breast carcinoma: confirmation of prescription dose using
      diodes.
AB  - PURPOSE: To quantitate the dose delivered during tangential breast radiation
      therapy and measure the scatter dose to the contralateral breast for three
      different breast setup techniques. METHODS AND MATERIALS: A commercial
      semiconductor diode system is used for dose measurements. The diode
      characteristics were studied by comparing the diode response against a standard
      ionization chamber response in a reference configuration. In vivo dose
      measurements on 11 patients undergoing tangential breast radiation therapy with 6
      MV photons were performed. Medial and lateral field entrance and exit doses were
      measured and compared with the expected values from the treatment planning
      system. Scatter doses to the contralateral breast for three breast setup
      techniques were measured and documented as a function of distance from the field
      edge and various beam modifiers commonly used in breast radiation therapy.
      RESULTS: The diodes used in this study exhibited excellent linearity, dose
      reproducibility, and minimal anisotropy. The in-phantom measurements resulted in
      dose accuracy within +/- 1.5%. Dose measurements on patients resulted in standard
      deviations of 1.2 and 2.3% for the medial entrance and exit doses and 1.7 and
      2.2% for the lateral entrance and exit doses, respectively. In patients, the
      scatter doses to the opposite breast at a 5 cm perpendicular distance from the
      medial field edge resulted in cumulative scatter doses of 2.47 to 5.30 Gy from
      the tangential fields and an additional 0.50 Gy from the supraclavicular or
      axillary field, if included. CONCLUSION: Quantitative verification of the
      prescribed daily dose is important in breast radiation therapy to ensure
      precision in patient setup and accuracy in dose delivery. Diodes provide a
      convenient way of real-time patient dose verification and are easy to use by the
      therapists.

PMID- 8641917
TI  - Radiosurgery instead of resection for solitary brain metastasis: the gold
      standard redefined.

PMID- 8641918
TI  - Demonstration of a brachytherapy boost dose-response relationship in glioblastoma
      multiforme: headed in the right direction.

PMID- 8641919
TI  - Thermal dose response, systemic hyperthermia, and metastases: old friends
      revisited.

PMID- 8641920
TI  - Regarding actuarial late effect analyses: Bentzen et al., IJROBP 32:1531-1534;
      1995 and Caplan et al., IJROBP 32:1547; 1995.

PMID- 8641921
TI  - Regarding Algan et al., IJROBP 33(4):925-930; 1995.

PMID- 8641922
TI  - The International Club of Radiotherapists.

PMID- 8641923
TI  - A multiinstitutional outcome and prognostic factor analysis of radiosurgery for
      resectable single brain metastasis.
AB  - PURPOSE: Recent randomized trials of selected patients with single brain
      metastasis comparing resection followed by whole-brain radiotherapy (WBRT) to
      WBRT alone have shown a statistically significant survival advantage for surgery
      and WBRT. A multiinstitutional retrospective study was performed, which
      identified comparable patients who were treated with stereotactic radiosurgery
      (RS) and WBRT. METHODS AND MATERIALS: The RS databases of four institutions were
      reviewed to identify patients who met the following criteria: single-brain
      metastasis; no prior cranial surgery or WBRT; age > 18 years; surgically
      resectable lesion; Karnofsky Performance Status (KPS) > or = 70 at time of RS;
      nonradiosensitive histology. One hundred twenty-two patients were identified who
      met these criteria. Patients were categorized by: (a) status of the primary, (b)
      status of non-CNS metastasis, (c) age, (d) baseline KPS (from 70-100), (e)
      histology, (f) time from diagnosis of primary to the detection of the brain
      metastasis, (g) gender, and (h) tumor volume. RS was performed with a linear
      accelerator based technique (peripheral dose range was 10-27 Gy, median was 17
      Gy). WBRT was performed in all but five patients who refused WBRT (dose range was
      25-40 Gy, median was 37.5 Gy). RESULTS: The median follow-up for all patients was
      123 weeks. The overall local control rate (defined as lack of progression in the
      RS volume) was 86%. Intracranial recurrence outside of the RS volume was seen in
      27 patients (22%). The actuarial median survival from date of RS is 56 weeks, and
      the 1-year and 2-year actuarial survival rates are 53% and 30%. The median
      duration of functional independence (sustained KPS > or = 70) is 44 weeks.
      Nineteen of 77 deaths were attributed to CNS progression (25% of all deaths).
      Multivariate analysis revealed the following factors to be statistically
      significant predictors of survival: baseline KPS (p < .0001) and absence of other
      sites of metastasis (p = 0.008). CONCLUSION: The RS in conjunction with WBRT for
      single brain metastasis can produce substantial functional survival, especially
      in patients with good performance status and without extracranial metastasis.
      These results are comparable to recent randomized trials of resection and WBRT.
      The advantages of RS over surgery in terms of cost, hospitalization, morbidity,
      and wider applicability strongly suggest that a randomized trial to compare RS
      with surgery is warranted.

PMID- 8641924
TI  - Demonstration of brachytherapy boost dose-response relationships in glioblastoma
      multiforme.
AB  - PURPOSE: To evaluate brachytherapy dose-response relationships in adults with
      glioblastoma undergoing temporary 125I implant boost after external beam
      radiotherapy. METHODS AND MATERIALS: Since June 1987, orthogonal radiographs
      using a fiducial marker box have been used to verify brain implant source
      positions and generate dose-volume histograms at the University of California,
      San Francisco. For adults who underwent brachytherapy boost for glioblastoma from
      June 1987 through December 1992, tumor volumes were reoutlined to ensure
      consistency and dose-volume histograms were recalculated. Univariate and
      multivariate analysis of various patient and treatment parameters were performed
      evaluating for influence of dose on freedom from local failure (FFLF) and
      actuarial survival. RESULTS: Of 102 implant boosts, 5 were excluded because
      computer plans were unavailable. For the remaining 97 patients, analyses with
      adjustment for known prognostic factors (age, KPS, extent of initial surgical
      resection) and prognostic factors identified on univariate testing (adjuvant
      chemotherapy) showed that higher minimum brachytherapy tumor dose was strongly
      associated with improved FFLF (p = 0.001). A quadratic relationship was found
      between total biological effective dose and survival, with a trend toward optimal
      survival probability at 47 Gy minimum brachytherapy tumor dose (corresponding to
      about 65 Gy to 95% of the tumor volume); survival decreased with lower or higher
      doses. Two patients expired and one requires hospice care because of brain
      necrosis after brachytherapy doses > 63 Gy to 95% of the tumor volume with 60 Gy
      to > 18 cm3 of normal brain. CONCLUSION: Although higher minimum tumor dose was
      strongly associated with better local control, a brachytherapy boost dose > 50-60
      Gy may result in life-threatening necrosis. We recommend careful conformation of
      the prescription isodose line to the contrast enhancing tumor volume, delivery of
      a minimum brachytherapy boost dose of 45-50 Gy in conjunction with conventional
      external beam radiotherapy, and reoperation for symptomatic necrosis.

PMID- 8641925
TI  - External beam radiation therapy and retinoblastoma: long-term results in the
      comparison of two techniques.
AB  - PURPOSE: This study compares the long-term actuarial local control, eye
      conservation rate, survival, and ocular complications in children with
      retinoblastoma treated with two different external beam treatment techniques.
      METHODS AND MATERIALS: From 1979-1991, 182 eyes in 123 children (104 bilateral)
      received primary external beam radiation therapy. An anterior lens-sparing
      electron beam technique delivering 38 to 50 Gy in 2.5 Gy fractions was used in 67
      eyes from 1979-1984 and a modified lateral beam technique, delivering 42 to 46 Gy
      in 2 Gy fractions, was used in 113 eyes from 1984-1991. These groups were
      balanced with respect to known prognostic variables. RESULTS: For Group I-III
      eyes, the 5- and 8-year local control was significantly improved using the
      modified lateral beam technique (84%) compared to (38%) using the anterior lens
      sparing technique (p < or = 0.0001). For Group IV-V eyes, the 5- and 8-year local
      control rates were not statistically different, despite a trend favoring the
      modified lateral beam technique. Survival endpoints including eye survival (no
      enucleation), cause-specific survival, and overall survival comparing the two
      treatment techniques were not significantly different. Overall, 22% of eyes
      developed cataracts. There was no difference between the two treatment groups in
      terms of cataract development. No eyes required enucleation for ocular
      complications. CONCLUSION: There is a significant improvement in local control
      using the modified lateral beam technique compared to an anterior lens-sparing
      approach for Group I-III eyes. However, there was no difference in survival end
      points between the two treatment techniques. The incidence of ocular
      complications using these two external beam techniques is acceptable.

PMID- 8641926
TI  - The unfolding of American radiotherapy.

PMID- 8641927
TI  - Cataractogenesis after total body irradiation.
AB  - PURPOSE: To evaluate the prognostic factors and the ophthalmologic follow-up on
      cataract formation following total body irradiation (TBI) prior to bone marrow
      transplantation (BMT). METHODS AND MATERIALS: Between 1980 and 1992, 494 patients
      were referred to our department for TBI prior to BMT. The mean age was 32 +/- 11
      (median: 32, range: 2-63) years and the male to female ratio was 1.6 (304:190).
      The majority of patients were treated for acute leukemia (lymphoblastic, n = 177,
      36%; or nonlymphoblastic , n = 139, 28%); 80 (16%) for chronic myeloid leukemia,
      60 (12%) for non-Hodgkin's lymphoma, 23 (5%) for multiple myeloma, and 15 (3%)
      for other malignancies. Two hundred and fifty-four (51%) patients were grafted in
      the first complete remission (CR), 118 (24%) in second CR. Allogenic BMT was
      performed in 210 (43%) patients, and autologous BMT in 284 (57%). Methotrexate
      combined to steroids (n = 47, 22%) or to cyclosporine (n = 163, 78%) was
      administered for graft-versus-host disease (GvHD) prophylaxis. In 188 patients
      (38%), heparin was used in the prevention of veno-occlusive disease (VOD) of the
      liver. Furthermore, steroid administration was registered in 223 (45%). The
      conditioning chemotherapy consisted of cyclophosphamide (Cy) alone in 332 (67%)
      patients. Total-body irradiation was administered either in single dose (STBI; 10
      Gy in 1 day, n = 291) or in six fractions (FTBI; 12 Gy over 3 consecutive days, n
      = 203) before BMT. The mean instantaneous dose rate was 0.0574 +/- 0.0289 Gy/min
      (0.024-0.1783). It was < 0.048 Gy/min in 157 patients (LOW group), > or = 0.048
      Gy/min and <0.09 Gy/min in 301 patients (MEDIUM group), and > or = 0.09 Gy/min in
      36 patients (HIGH group). RESULTS: When considering all patients, 42 (8.5%)
      patients developed cataracts after 13 to 72 months (median: 42 months) with a 5
      year estimated cataract incidence (ECI) of 23%. Thirty-three (11.3%) out of 291
      patients in the STBI group, and 9 (4.4%) out of 203 patients in the FTBI group
      developed cataracts with 5-year estimated incidences of 34 and 11%, respectively
      (p = 0.0004). Seven (19.4%) out of 36 patients in the HIGH group, 33 (10.9%) out
      of 301 in the MEDIUM group, and 2 (1.2%) out of 157 in the LOW group developed
      cataracts with respective 5-year cataract incidences of 54%, 30%, and 3.5% (HIGH
      vs. MEDIUM, p = 0.07; MEDIUM vs. LOW, p = 0.0001; HIGH vs. LOW, p < 0.0001). On
      the other hand, patients who received heparin as prophylactic treatment against
      VOD of the liver had less cataracts than those who did not receive (5-year ECI of
      16% vs. 28%, respectively; p = 0.01). There was no statistically significant
      difference in terms of 5-year ECI according to age, sex, administration of
      steroids, GvHD prophylaxis, type of BMT, or previous cranial radiotherapy in
      children. Multivariate analysis revealed that the instantaneous dose rate (p =
      0.001), and the administration of heparin against VOD (p = 0.05) were the two
      independent factors influencing the cataract incidence, while age, fractionation,
      and use of steroids were not. Among the 42 patients who developed cataracts, 38
      had bilateral extracapsular cataract extraction and intraocular lens
      implantation, and only 4 (10%) developed secondary cataracts in a median follow
      up period of 39 months. CONCLUSION: Among the abovementioned TBI parameters, high
      instantaneous dose rate seems to be the main risk factor of cataract formation,
      and the administration of heparin appears to have a protective role in
      cataractogenesis. On the other hand, ionizing radiation seems to have a
      protective effect on posterior capsule opacification following extracapsular
      cataract extraction and intraocular lens implantation.

PMID- 8641928
TI  - Comparison of two strategies for the treatment of radiogenic leukopenia using
      granulocyte colony stimulating factor.
AB  - PURPOSE: Radiation-induced leukopenia can cause a delay or discontinuation of
      radiotherapy. This complication can be overcome with the use of granulocyte
      colony-stimulating factor (G-CSF). However, an uncertainty exists regarding the
      mode of application of G-CSF in patients treated with radiotherapy. For this
      reason, the efficacy of two strategies for the administration of G-CSF in
      irradiated patients was compared in a prospective randomized clinical study.
      METHODS AND MATERIALS: Forty-one patients who developed leukopenia (< 2.5 x 10(9)
      per liter) while undergoing radiotherapy were treated with G-CSF at a daily dose
      of 5 microg/kg. The first group received single injections of G-CSF as required
      (n = 21). The second group received G-CSF on at least 3 consecutive days (n =
      20). An analysis was made of the changes in leukocyte counts, the number of days
      on which radiotherapy had to be interrupted, and the side effects of growth
      factor treatment. RESULTS: An increase in leukocyte values in the peripheral
      blood was observed in all patients treated with G-CSF. In the group which
      received G-CSF when required, two injections (range: 1-8) were administered in
      most cases. In the second group, most of the patients received three injections
      (range: 3-9). The average duration of therapy interruptions due to leukopenia was
      4.8 days (0-28) in the first therapy arm and 2.5 (0-20) in the second arm. The
      variance in the duration of therapy interruptions between the two groups was not
      significant (p = 0.2). Radiotherapy had to be terminated in two patients due to
      thrombocytopenia but the application of G-CSF did not seem to be a reason of
      decreasing platelet counts. CONCLUSIONS: Our results reveal that G-CSF is safe
      and effective in the treatment of radiation-induced leukopenia regardless of the
      mode of application. Because the calculated difference related to radiation
      treatment interruptions has no clinical relevance, both approaches examined in
      our study appear reasonable.

PMID- 8641929
TI  - Radiotoxicity of systematically administered [211At]astatide in B6C3F1 and BALB/c
      (nu/nu) mice: a long-term survival study with histologic analysis.
AB  - PURPOSE: The present study undertook to establish the dose (LD) of systematically
      administered (via tail vein) sodium [211At]astatide that would kill 10% (LD10) of
      exposed animals in two mouse models and to evaluate the resulting histologic
      lesions. METHODS AND MATERIALS: Three dose escalation experiments were carried
      out using groups of 10 3- to 4-week-old, 20 +/- 2 g B6C3F1 mice, and one dose
      escalation experiment was carried out with groups of 10 4- to 6-week-old, 22 +/-
      2 g BALB/c (nu/nu) mice. All animals were weighed daily and checked twice daily
      for general health; autopsies were performed within 12 h of death. RESULTS: The
      LD10 (95% confidence interval) level of free [211At]astatide at 360 days was 15.1
      microCi (5.2-19.1 microCi) in B6C3F1 mice and was associated with a 37.8% weight
      difference from saline controls (p < 0.001). In the BALB/c (nu/nu) mice, the LD10
      at 360 days was 7.7 microCi (0-14.2 microCi), while a dose of 10 microCi (0.42
      microCi g(-1)) was associated with a 9.44% weight difference vs. saline controls
      (p < 0.05). Exclusive of the well-known effects on thyroid, [211At]astatide
      activity levels were associated with severe bone marrow depression, testicular
      atrophy, focal alopecia, and nuclear atypia of the epidermoid mucosa of the fore
      stomach in the B6C3F1 mice; at activity levels approximating LD10 at 360 days,
      mild changes in the heart, liver, stomach, and spleen were observed. For BALB/c
      (nu/nu) mice, administration of 10 microCi was associated at autopsy with mild
      histologic lesions in the heart, stomach, liver, and spleen. CONCLUSIONS: These
      studies provide a basis for the design of further investigations of [211At]
      labeled compounds as therapeutic agents.

PMID- 8641931
TI  - Field edge smoothing for multileaf collimators.
AB  - PURPOSE: To smooth the scalloped dose pattern that occurs for stepped leaves at a
      treatment field edge defined by a multileaf collimator. METHODS AND MATERIALS:
      Fields with centers shifted slightly in space were superimposed to blur the
      staggered dose distribution at the field edge. Film dosimetry was used to monitor
      changes. The dose distribution for a single field position was compared to the
      distribution for one and three shifts. Three depths were examined and divergent
      alloy blocks were included in the comparison. RESULTS: The structure that appears
      at an edge for a single field when leaves are staggered was nearly eliminated
      when the field was shifted three times to give a total of four different
      positions. However, shifting the field one time so that two fields were
      superimposed gave an intermediate result with only slight improvement in the
      undulating dose distribution. For the four superimposed fields, the 50% isodose
      pattern converged to a smoothed line running along the center of the original
      undulating pattern. The 80 and 20% isodoses did not converge to the center of
      their scalloped patterns. Instead, these isodose lines were spread leaving a
      larger penumbra width than a divergent alloy block. CONCLUSIONS: Shifting and
      adding fields is an effective method for smoothing the staggered dose
      distribution that results when the leaves of a multileaf collimator are stepped
      to form an irregular field pattern. However, the width of the penumbra for the
      combined fields is wider than the penumbra for a cerrobend block.

PMID- 8641930
TI  - The reproducibility and relationship between single and fractionated dose
      estimates of the surviving fraction at 2 Gy.
AB  - PURPOSE: To evaluate the reproducibility and relationship between the surviving
      fraction at 2 Gy obtained from single-graded dose and multifraction survival
      curve assays. METHODS AND MATERIALS: Single-graded dose and multifraction
      survival curve assays were concurrently performed in five human cell lines. For
      the multifraction studies, five to six doses at 2 Gy per fraction were
      administered with a time interval of 5.5 h between fractions. All surviving
      fraction data was corrected for multiplicity and cell proliferation during
      treatment. Replicate experiments were performed for each cell line. RESULTS: The
      precision of the Sf2 estimates obtained from multifraction studies was
      approximately three times greater than was obtained in the single-dose studies.
      For the single-dose studies, the average difference between the Sf2s obtained in
      the initial vs. repeat experiment was 0.11; for the fractionated-dose studies the
      difference was significantly reduced to 0.032. A rank-order correlation was not
      obtained between the 2 Gy Sfs in the initial and repeat single-dose assays; in
      the multifraction studies, the correlation was significant (p < 0.05). The rank
      order correlation between the single- and fractionated-dose Sf2 assays was
      significant only when the two sets of assays were pooled; however, the
      coefficient of correlation remained low (R(2) = 0.50). CONCLUSIONS: The precision
      of the estimates of the surviving fraction at 2 Gy, obtained from multifraction
      assays, was substantially greater than was obtained in single dose-survival curve
      assays.

PMID- 8641932
TI  - Vascular thermal adaptation in tumors and normal tissue in rats.
AB  - PURPOSE: The vascular thermal adaptation in the R3230 adenocarcinoma, skin and
      muscle in the legs of Fischer rats was studied. METHODS AND MATERIALS: The legs
      of Fischer rats bearing the R3230 AC adenocarcinoma (subcutaneously) were heated
      once or twice with a water bath, and the blood flow in the tumor, skin and muscle
      of the legs was measured with the radioactive microsphere method. RESULTS: The
      blood flow in control R3230 AC tumors was 23.9 ml/100 g/min. The tumor blood flow
      increased about 1.5 times in 30 min and then markedly decreased upon heating at
      44.5 degrees C for 90 min. In the tumors preheated 16 h earlier at 42.5 degrees C
      for 60 min, reheating at 44.5 degrees C increased the tumor blood flow by 2.5
      fold in 30 min. Contrary to the decline in blood flow following an initial
      increase during the 44.5 degrees C heating without preheating, the tumor blood
      flow remained elevated throughout the 90 min reheating at 44.5 degrees C. These
      results indicated that thermal adaptation or thermotolerance developed in the
      tumor vasculatures after the preheating at 42.5 degrees C for 60 min. The
      magnitude of vascular thermal adaptation in the tumors 24 h and 48 h after the
      preheating, as judged from the changes in blood flow, were smaller than that 16 h
      after the preheating. Heating at 42.5 degrees C for 60 min induced vascular
      thermal adaptation also in the skin and muscle, which peaked in 48 h and 24 h,
      respectively, after the heating. CONCLUSION: Heating at 42.5 degrees C for 1 h
      induced vascular thermal adaptation in the R3230 AC tumor, skin, and muscle of
      rats that peaked 16-48 h after the heating. When the tumor blood vessels were
      thermally adapted, the tumor blood flow increased upon heating at temperatures
      that would otherwise reduce the tumor blood flow. Such an increase in tumor blood
      flow may hinder raising the tumor temperature while it may increase tumor
      oxygenation.

PMID- 8641933
TI  - AVMA considers independent Spay Day. Meanwhile, Spay Day USA has cut into future
      overpopulation.

PMID- 8641934
TI  - Freeman: a frank response to issues of the day. Interview by Susan C. Kahler.

PMID- 8641935
TI  - Wisconsin train derailment turns veterinarians into heroes.

PMID- 8641936
TI  - More thoughts on veterinarians' role in aquatic animal health.

PMID- 8641937
TI  - Concern about vaccine study.

PMID- 8641938
TI  - Veterinary bioethics.

PMID- 8641939
TI  - Functions of veterinary colleges and orientations of professional practice in the
      Americas.

PMID- 8641940
TI  - Organizational models of veterinary colleges in the Americas.

PMID- 8641941
TI  - Farm programs and food animal practitioners.

PMID- 8641942
TI  - Practicing part time--a growing trend?

PMID- 8641943
TI  - What is your diagnosis? Supraspinous bursitis (fistulous withers).

PMID- 8641944
TI  - Theriogenology question of the month. Vaginal constriction, probably a congenital
      malformation.

PMID- 8641945
TI  - Breaking the human-companion animal bond.

PMID- 8641946
TI  - Factors affecting starting salaries of veterinary medical graduates, 1993-1995.

PMID- 8641947
TI  - Avoiding sexual harassment liability in veterinary practices.
AB  - Harassment based on gender violates the rule of workplace equality established by
      Title VII of the Civil Rights Act and enforced by the EEOC. In 1986, the US
      Supreme Court, in Meritor Savings Bank v Vinson, established the criteria that
      must be met for a claim of hostile environment sexual harassment to be considered
      valid. Plaintiffs must show that they were subjected to conduct based on their
      gender, that it was unwelcome, and that it was severe and pervasive enough to
      alter their condition of employment, resulting in an abusive working environment.
      There have been few sexual harassment cases involving veterinary professionals,
      and it is our goal to help keep the number of filed actions to a minimum. The
      most effective way to avoid hostile environment sexual harassment claims is to
      confront the issue openly and to adopt a sexual harassment policy for the
      practice. When it comes to sexual harassment, an ounce of prevention is
      unquestionably worth a pound of cure.

PMID- 8641948
TI  - Results of a national survey of rabies control procedures.

PMID- 8641949
TI  - Use of a caudal auricular axial pattern flap in cats.
AB  - A caudal auricular axial pattern flap was used in 3 cats to successfully
      reconstruct large cutaneous defects of the head that were a result of trauma or
      surgical excision of neoplasms. The technique was a convenient, practical, one
      stage procedure for closure of the defects, and flaps up to 7.0 x 12.0 cm were
      developed. All flaps healed without complications. Anatomic landmarks and
      surgical guidelines for developing the flap were determined through anatomic
      dissections and angiographic studies of the cutaneous vasculature of the head and
      neck in feline cadavers. This report confirms findings of a previous study
      describing a platysma myocutaneous flap.

PMID- 8641950
TI  - Pancytopenia associated with administration of captopril to a dog.
AB  - An 11-year-old castrated male Dachshund was determined to have pancytopenia on
      the basis of results of CBC and bone marrow cytologic examination. Pancytopenia
      was believed to have resulted from administration of captopril, which had been
      administered for treatment of chronic mitral insufficiency, because other causes
      of pancytopenia were not found. Treatment consisted of discontinuing captopril
      and stimulating the bone marrow with recombinant human erythropoietin and
      granulocyte colony-stimulating factor. Although neutralizing antibodies will
      develop against the heterologous human protein, recombinant human granulocyte
      colony-stimulating factor should be considered for short-term treatment of
      neutropenias associated with adverse drug reactions, canine parvovirus
      infections, and bone marrow suppression from primary bone marrow disease, cancer
      chemotherapy, or total body irradiation before bone marrow transplantation.

PMID- 8641952
TI  - Penetrating keratoplasty for treatment of recurrent squamous cell carcinoma of
      the cornea in a horse.
AB  - Squamous cell carcinoma involving the cornea and conjunctiva of the left eye in a
      14-year-old horse was treated by superficial keratectomy in combination with beta
      radiation and radiofrequency hyperthermia. The tumor recurred 4 months later in
      the central cornea at the edge of the previous keratectomy site. Penetrating
      keratoplasty was performed in an effort to remove the tumor and retain a visual
      eye. The eye was visual 13 months after surgery. Mild fibrosis and
      vascularization were observed in the area of the penetrating keratoplasty.

PMID- 8641951
TI  - Effect of aluminum hydroxide/magnesium hydroxide antacid and bismuth
      subsalicylate on gastric pH in horses.
AB  - OBJECTIVE: To assess the effect of aluminum hydroxide/magnesium hydroxide antacid
      and bismuth subsalicylate on gastric pH in clinically normal horses and to
      develop guidelines on the use of these agents for treatment of peptic ulcer
      disease in horses. DESIGN: Prospective, randomized, controlled trial. ANIMALS: 5
      clinically normal adult horses with chronically implanted gastric cannulas.
      PROCEDURE: Each horse received all 5 treatments (30 g of aluminum hydroxide/15 g
      of magnesium hydroxide, 12 g of aluminum hydroxide/6 g of magnesium hydroxide,
      10.5 g of bismuth subsalicylate, 26.25 g of bismuth subsalicylate, and 5%
      methylcellulose control) with only 1 experiment performed each day. Gastric pH
      was measured via a glass electrode inserted through the gastric cannula for 1
      hour before treatment and continued for 2 hours after treatment. Food or water
      was not given to the horses during the experiment. Measurements of gastric pH
      obtained during posttreatment hours were compared with pretreatment gastric pH
      values. RESULTS: Only a dose of 30 g of aluminum hydroxide/ 15 g of magnesium
      hydroxide resulted in a significant increase in gastric pH over baseline or
      control values. Mean pH was 5.2 +/- 0.62 and 4.59 +/- 0.48 for posttreatment
      hours 1 and 2, respectively. CLINICAL IMPLICATIONS: Oral administration of 30 g
      of aluminum hydroxide/15 g of magnesium hydroxide to adult horses should result
      in a mean hourly gastric pH > or = 4.0 for at least 2 hours.

PMID- 8641953
TI  - Epidemiologic evaluation of encephalitic listeriosis in goats.
AB  - OBJECTIVE: To evaluate host and environmental factors associated with the
      development of encephalitic listeriosis in goats. DESIGN: Retrospective analysis
      of diagnostic laboratory records and survey of veterinarians and goat producers.
      SAMPLE POPULATION: 355 goat herds accessible through laboratory records; 38
      veterinarians who treated goats and 76 goat producers. PROCEDURE: Data regarding
      breed and use for goats affected with encephalitic listeriosis were obtained from
      surveys and case follow-up information. Listeria monocytogenes isolates from the
      brains of 7 affected goats were serotyped and subjected to DNA restriction
      analysis. RESULTS: Odds ratio for the development of encephalitis listeriosis in
      Angora (mohair-producing) goats was 22.9 by use of diagnostic laboratory records.
      Survey also revealed a high prevalence in herds of Angora and other breeds that
      subsisted on woody browse, although Angora goats feeding predominantly on hay or
      pasture were not affected. Listeria monocytogenes isolates from 4 Angora goats in
      3 herds differed in DNA restriction patterns, although the pattern was identical
      in 3 other goats from another herd. CLINICAL IMPLICATIONS: Encephalitic
      listeriosis can be observed in all goat breeds, but a lifestyle of heavy browse
      consumption seems important to the development of disease in some herds.

PMID- 8641954
TI  - Assessment of two devices for measuring tympanic membrane temperature in swine,
      dairy cattle, and dairy calves.
AB  - OBJECTIVE: To compare tympanic membrane temperature readings obtained with 2
      commercially available devices with rectal temperature readings obtained with a
      standard mercury thermometer in dairy cattle, dairy calves, and swine. DESIGN:
      Clinical trial. ANIMALS: 6 Holstein calves (approx 6 months old), 6 Holstein
      cattle (approx 4 years old), and 5 Landrace-Poland China swine. PROCEDURE:
      Tympanic membrane temperatures were measured, and results were compared with
      rectal temperatures obtained with a standard mercury thermometer. Tympanic
      membrane temperatures were obtained before and after insertion of the rectal
      thermometer. Temperature readings in swine were obtained following passive
      restraint in a cage-like device or restraint using a snare to assess the effect
      of stress on tympanic membrane temperature. RESULTS: Tympanic membrane
      temperature readings from both devices were lower than those obtained using a
      rectal thermometer for all animals. Repeated measurement of tympanic membrane
      temperature of individual cattle resulted in consistent readings for both
      devices. CLINICAL IMPLICATIONS: Because all animals were visibly healthy, results
      suggest that tympanic membrane temperature readings obtained with either device
      may be an adequate assessment of health status.

PMID- 8641955
TI  - Use of corticosteroids alone or combined with glucose to treat ketosis in dairy
      cows.
AB  - OBJECTIVE: To compare relative efficacy of dexamethasone and flumethasone alone
      or in combination with rapid IV infusion of glucose for treatment of ketosis in
      cattle. DESIGN: Clinical trial. ANIMALS: 127 cows with urine acetoacetate
      concentration > or = 60 mg/dl. PROCEDURE: Cows were treated with 500 ml of 50%
      glucose solution. IV, and 40 mg of dexamethasone, IM (group 1), 40 mg of
      dexamethasone, IM (group 2), 5 mg of flumethasone (group 3), or 500 ml of 50%
      glucose solution, IV, and 5 mg of flumethasone (group 4). Treatment success was
      defined as recovery after a single treatment without relapse during the same
      lactation. Uterine disease (retained placenta or metritis), parity, and
      pretreatment plasma glucose, serum beta-hydroxybutyric acid, and urine
      acetoacetate concentrations were evaluated as possible confounding factors
      affecting recovery. RESULTS: Only uterine disease was found to have a significant
      effect on recovery. Treatments 1 and 4 were significantly more efficacious than
      was treatment 2, but efficacy of treatment 2 was not significantly different from
      that of treatment 3. Regardless of treatment, cows with uterine disease were less
      likely to have a successful outcome than were cows without uterine disease. In
      all treatment groups, plasma glucose concentration increased and serum beta
      hydroxybutyric acid and urine acetoacetate concentrations decreased following
      treatment. CLINICAL IMPLICATIONS: In this study, treatment of ketosis in dairy
      cattle with a corticosteriod alone was less efficacious than treatment with
      glucose and a corticosteroid.

PMID- 8641956
TI  - Use of composite milk samples for diagnosis of Staphylococcus aureus mastitis in
      dairy cattle.
AB  - OBJECTIVE: To measure relative sensitivity and relative specificity for use of
      composite milk samples, compared with that of individual gland milk samples, for
      diagnosis of Staphylococcus aureus mastitis. ANIMALS: 505 cows suspected of
      having subclinical mastitis. Of these cows, 172 were considered infected with Sta
      aureus, based on the results from individual gland samples. PROCEDURE: Composite
      and individual gland milk samples were collected from cows suspected of having
      subclinical mastitis, and results of bacteriologic culturing of samples from the
      same cow were compared. Results were interpreted at the cow level. Relative
      sensitivity and relative specificity for composite samples were computed from 2 x
      2 tables, using results from individual gland samples as references. RESULTS:
      Relative sensitivity for use of composite milk samples in diagnosing Sta aureus
      mastitis was 0.63. The relative specificity was 0.98. Factors influencing the
      relative sensitivity for composite samples were the number of infected glands per
      cow, the amount of Sta aureus shedding from infected glands, and the proportion
      of the composite milk obtained from each gland. CLINICAL IMPLICATIONS: Collecting
      composite instead of individual gland milk samples increases the number of false
      negative results in diagnosing Sta aureus mastitis. By collecting consecutive
      samples from the same cow or by increasing the inoculum volume at culturing, this
      problem can be diminished.

PMID- 8641957
TI  - Invasive malignant fibrous histiocytoma in a cow.
AB  - An invasive malignant fibrous histiocytoma associated with the left cornual
      process, and causing lysis of the frontal bone, was diagnosed in a cow. The mass
      compressed the left cerebral hemisphere focally and extended into the frontal
      sinus and ethmoid and nasal turbinates. It was composed of pleomorphic to spindle
      shaped cells with ultra-structural evidence of fibroblastic, myofibroblastic, and
      fibrohistiocytic differentiation. Trauma and chronic inflammation may be
      predisposing factors for development of neoplasia in cattle.

PMID- 8641958
TI  - Clinical application of interferons in large animal medicine.
AB  - Interferons are efficacious therapeutic agents for treatment of several
      clinically important diseases in cattle and horses. In some instances, the
      therapeutic goal of IFN administration is prevention or clinical cure of acute
      viral infections. On the other hand, IFN may serve as adjunctive treatment to
      diminish clinical manifestations of disease and improve the quality of life. Oral
      administration of IFN alpha appears to be a safe and convenient route of
      administration, and the therapeutic benefit likely develops via unique mechanisms
      involving oropharyngeal-associated lymphoid tissue for dissemination and
      amplification of the pharmacologic response. At the time of this writing, IFN has
      not been approved by the USDA or the FDA for use in food-producing animals or
      horses.

PMID- 8641959
TI  - Vitamin D3 as a possible chemopreventive and therapeutic agent of cancers.

PMID- 8641960
TI  - Inhibition of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline-mediated DNA-adduct
      formation by chlorophyllin in Drosophila.
AB  - The effect of chlorophyllin on 2-amino-3,8-dimethyimidazo[4,5-f]quinoxaline
      (MeIQx)-mediated DNA-adduct formation in Drosophila was studied. Third-instar
      larvae of Drosophila were fed MeIQx at 1 mg/6.5 g-feed/bottle, with or without
      chlorophyllin (100-300 mg). After a 6 h feeding exposure to MeIQx, the larvae
      were divided into 2 groups. The first group was examined for covalent DNA adducts
      by 32P-postlabeling assay. The second group was assayed for DNA damage by
      allowing the larvae to develop to adults and measuring the male/female ratio
      (males, DNA repair-deficient; females, DNA repair-proficient). The 32 P
      postlabeling results indicated a significant decrease in DNA adduct levels in
      larvae treated with MeIQx and 300 mg chlorophyllin (1.7 +/- 0.7 adducts/10(7)
      nucleotides) as compared with MeIQx-treated larvae 6.5 +/- 2.1 adducts/10(7)
      nucleotides). The results on male/female sex ratios also indicated a
      chlorophyllin-induced decrease in DNA damage by exposure to MeIQx. The
      suppressive effect of chlorophyllin on the genotoxic actions of a polycyclic
      mutagen, MeIQx, may be a result of complex formation between chlorophyllin and
      the mutagen.

PMID- 8641961
TI  - Non-radioisotopic and semi-quantitative procedure for terminal repeat
      amplification protocol.
AB  - We have used fluorescence-labeled primers and an auto-sequencer to detect
      telomerase activity quickly and easily. The current procedure is superior to the
      original telomeric repeat amplification protocol in several respects: 1) the
      result is obtained in real time during electrophoresis, 2) semi-quantitative
      results are possible without using a photo-capture system, and 3) no radioisotope
      is needed.

PMID- 8641962
TI  - Association between family history and gastric carcinoma among young adults.
AB  - The relationship between family history of gastric carcinoma and gastric
      carcinoma in Japanese under 40 years of age was analyzed. The subjects were 108
      gastric carcinoma patients (86% were diffuse type) at 9 hospitals in the Kanto
      area of Japan. Firstly, incidence of gastric carcinoma among the parents of the
      subjects were compared with that in the general population. Observed/expected
      (O/E) ratios (P-value) were 1.8 (0.06) for all subjects, 1.3 (0.62) for male
      subjects, 2.1 (0.04) for female subjects, 0.5 (0.41) for early carcinoma, 2.6
      (P<0.01) for advanced carcinoma, 2.3 (0.22) for intestinal-type carcinoma and 1.7
      (0.13) for diffuse-type carcinoma. Association between gastric carcinoma and
      parents' history of gastric carcinoma was strong among women and regarding
      advanced carcinoma, and the difference in O/E ratios between early and advanced
      carcinoma was remarkable. Secondly, factors related to advanced-stage gastric
      carcinoma were analyzed. Histological type (diffuse and intestinal types) was not
      related, but family history of gastric carcinoma among parents and grandparents
      was related to advanced stage, and the relationship was independent of other
      factors. The odds ratio (95% confidence interval) was 3.3 (1.1-9.9). Family
      history may be related to stage of gastric carcinoma through its relationship to
      the manner or speed of the tumor's progression. We hypothesis that some genetic
      factor exists which is involved both in progression from early to advanced stage
      and in occurrence of gastric carcinoma.

PMID- 8641963
TI  - Induction of aldose reductase gene expression in LEC rats during the development
      of the hereditary hepatitis and hepatoma.
AB  - We examined age-related changes in the protein and the mRNA expression of aldose
      reductase in livers of Long-Evans with a cinnamon-like color (LEC) rats, which
      develop hereditary hepatitis and hepatoma with aging, using Long-Evans with an
      agouti color rats as controls. The levels of the protein and mRNA of aldose
      reductase increased after 20 weeks, at the stage of acute hepatitis, and were
      maintained at 60 weeks of age, while those of aldehyde reductase seemed to be
      constant at all ages. The expression of aldose reductase was marked in cancerous
      lesions in hepatoma-bearing LEC rat liver compared to uninvolved surrounding
      tissues. These results indicated that elevation of aldose reductase accompanied
      hepatocarcinogenesis and may be related to the acquisition of immortality of the
      cancer cells through detoxifying cytotoxic aldehyde compounds.

PMID- 8641964
TI  - Decreased levels of 2-amino-3-methylimidazo[4,5-f]quinoline-DNA adducts in rats
      treated with beta-carotene, alpha-tocopherol and freeze-dried aloe.
AB  - To assess mechanisms of chemoprevention of hepatocarcinogenesis by trans-beta
      carotene (beta-C), DL-alpha-tocopherol (alpha-T), and freeze-dried whole leaves
      of Kidachi aloe (Aloe), formation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)
      DNA adducts was measured by 32P-post-labeling analysis, and CYP1A1 and CYP1A2
      protein levels were analyzed by ELISA. Group 1 rats were fed diet containing
      0.02% beta-C, 1.5% alpha-T or 30% Aloe over an 8-day period, while group 2 was
      given basal diet alone. On day 7, all animals were subjected to two-thirds
      partial hepatectomy (PH). Twelve hours after PH, they received a single dose of
      the carcinogenic food pyrolysate IQ (100 mg/kg) intragastrically, to initiate
      hepatocarcinogenesis. Rats were killed 6, 12, 24 and 48 h after IQ
      administration. The levels of adducts, expressed as relative adduct labeling
      values in rats treated with beta-C, alpha-T and Aloe, were decreased as compared
      with the control group at hour 24 (36 h after PH), with a significant difference
      in the case of the beta-C group (46.4% of the control value). Similarly, all
      showed a tendency for decrease at hour 48. Furthermore, the levels of CYP1A2,
      known to be responsible for activation of IQ, showed a significant reduction at
      hour 24. It is concluded that beta-C, and possibly also alpha-T and Aloe, have
      the potential to reduce IQ-DNA adduct formation, presumably as a result of
      decreased formation of active metabolites. The results may explain, at least in
      part, the previously observed inhibitory effects of these compounds on induction
      of preneoplastic hepatocellular lesions.

PMID- 8641965
TI  - Chemopreventive effect of a xanthine oxidase inhibitor, 1'-acetoxychavicol
      acetate, on rat oral carcinogenesis.
AB  - The effect of a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), on
      4-nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis was investigated in
      male F344 rats. All rats except those in the ACA-alone and untreated groups were
      given 4-NQO (20 ppm) In the drinking water for 8 weeks to induce oral cancer.
      Starting 1 week before the 4-NQO exposure, animals were fed diet containing 100
      ppm or 500 ppm ACA for 10 weeks, followed by the basal diet without ACA for 22
      weeks. Other groups were fed the diet containing ACA at 100 ppm or 500 ppm for 22
      weeks, starting 1 week after the cessation of 4-NQO exposure. The remaining
      groups consisted of rats given 500 ppm ACA alone or untreated rats. At the
      termination of the experiment (32 weeks), the incidences of tongue neoplasms and
      preneoplastic lesions, polyamine levels in the tongue tissue, and cell
      proliferation activity estimated in terms of 5-bromodeoxyuridine (BrdU)-labeling
      index and by morphometric analysis of silver-stained nucleolar organizer regions'
      protein (AgNORs) were compared among the groups. Feeding of ACA at the two doses
      during initiation or postinitiation significantly decreased the development of
      tongue carcinoma (93-100% reduction, P < 0.001) and preneoplasia (43-50%
      reduction for hyperplasia and 34-48% reduction for dysplasia, P < 0.05). There
      were no such lesions in rats fed ACA alone or those in the untreated control
      group. The number of AgNORs per cell nucleus was significantly decreased by
      feeding of ACA at a high dose (500 ppm) (29% inhibition, P < 0.05). The BrdU
      labeling index was also reduced by dietary administration of ACA (23-32%
      inhibition, P < 0.01). In addition, ACA feeding reduced tongue polyamine levels
      (35-40% inhibition, P < 0.05). These results indicate that ACA inhibited rat oral
      carcinogenesis, and such inhibition might be related to suppression of cell
      proliferation in the oral mucosa by the xanthine oxidase inhibitor.

PMID- 8641966
TI  - Inhibition of in vitro tumor cell invasion by ginsenoside Rg3.
AB  - The effect of plant glycosides on tumor cell invasion was examined. Among the
      glycosides tested, ginsenoside Rg3 was found to be a potent inhibitor of invasion
      by rat ascites hepatoma cells (MM1), B16FE7 melanoma cells, human small cell lung
      carcinoma (OC10), and human pancreatic adenocarcinoma (PSN-1) cells, when
      examined in a cell monolayer invasion model. Structurally analogous ginsenosides,
      Rb2, 20(R)-ginsenoside Rg2 and 20(S)-ginsenoside Rg3 (a stereoisomer of Rg3),
      showed little inhibitory activity. Neither Rh1, Rh2, 20(R)-ginsenosides Rh1, Rb1,
      Rc nor Re had any effect. The effective ginsenoside, Rg3, tended to inhibit
      experimental pulmonary metastasis by highly metastatic mouse melanoma B16FE7
      cells as well. Taking account of our previous finding that 1-oleoyl
      lysophosphatidic add (LPA) induced invasion by MM1 cells in the monolayer
      invasion model, the effect of Rg3 on molecular events associated with the
      invasion induced by LPA was analyzed in order to understand the mechanism of the
      inhibition. Rg3, which suppressed the invasion induced by LPA, dose-dependently
      inhibited the LPA-triggered rise of intracellular Ca2+. Protein tyrosine
      phosphorylation triggered by LPA was not inhibited by Rg3.

PMID- 8641967
TI  - Deletion mapping of chromosome 10 in human glioma.
AB  - We analyzed DNAs from 35 gliomas (27 malignant, grades III and IV; 8 less
      malignant, grades I and II) for loss of heterozygosity (LOH) using microsatellite
      sequences on chromosome 10 as polymorphic markers. An LOH was found in 8 of 11
      (73%) glioblastomas (grade IV) and 4 of 16 (25%) grade III gliomas, but not in
      the less malignant types. We detected three commonly deleted regions. One was
      located in a telomeric region of 10p and the others were relatively large regions
      of 10q. Our results suggested that three putative tumor suppressor genes on
      chromosome 10 are involved in the malignant progression of gliomas.

PMID- 8641968
TI  - p53 accumulation in colorectal cancer with hepatic metastasis.
AB  - The prevalence of immunoreactive p53 and argyrophilic nucleolar organizer region
      (AgNOR) numbers were compared between colorectal cancers with (n=44) and without
      (n=51) hepatic metastasis for at least 5 years. At the same time, the
      distribution of p53-positive cells in primary, metastatic, and xenografted tumors
      from the same individuals were studied. Overall, p53 positivity was found more
      frequently in the cases with hepatic metastasis than in non-metastatic controls,
      regardless of the distribution pattern (P<0.05), whereas AgNOR counts were not
      different between the two groups. Significant heterogeneity in the distribution
      of p53 immunoreactivity was noted in both the primary and metastatic lesions. The
      intratumor distribution patterns of p53 immunoreactive cells in the primary
      (n=33), metastatic (n=33), and xenografted (n=7) tumors of the same individuals
      were consistent in the majority of cases. There were a few cases in which the p53
      immunoreactive cells were more dominant in the metastatic tumor cells. Our
      observations suggest that p53 accumulation in colorectal cancer is associated
      with increased risk for hepatic metastasis, while cell proliferation as
      represented by AgNOR numbers is not. In addition, heterogeneity of abnormal p53
      accumulation in the tumor is maintained during the course of metastasis and even
      after implantation in nude mouse. p53-Immunoreactive cells in the population of
      colorectal cancer cells do not necessarily have higher metastasizing potential.

PMID- 8641969
TI  - Inhibition of cell growth by transforming growth factor beta 1 is associated with
      p53-independent induction of p21 in gastric carcinoma cells.
AB  - Cell cycle regulators such as cyclins, cyclin-dependent kinases (cdks) and their
      inhibitors control the growth of cells. SDI1/CIP1/WAF1/p21 is a potent inhibitor
      of G1 cdks, whose expression is induced by wild-type p53. To elucidate the
      mechanism of growth inhibition by transforming growth factor beta 1 (TGFbeta 1),
      we examined the effect of TGFbeta 1 on the expression of p21, G1 cyclins and cdks
      by human gastric cancer cell lines. TGFbeta 1 induced p21 expression and
      subsequently suppressed cdk2 kinase activity, followed by a reduction in
      phosphorylation of the product of the retinoblastoma tumor suppressor gene in TMK
      1 cells, which are responsive to TGFbeta 1. Coimmunoprecipitation analysis
      demonstrated that TGFbeta 1 increased the level of p21 protein present in
      complexes with cdk2. In contrast, TGFbeta 1 did not induce p21 in TGFbeta 1
      resistant MKN-28 cells. TGFbeta 1 did not affect the levels of p53 mRNA and
      protein in TMK-1 and MKN-28 cells, which contain mutated p53 genes. These mutated
      p53 complementary DNAs, when overexpressed, failed to activate transcription from
      the p21 promoter. Furthermore, TGFbeta 1 caused a reduction in the steady-state
      level of cyclin A protein concomitantly with inhibition of cdk2 kinase activity
      in TMK-1 cells. These results suggest that the growth inhibition of tumor cells
      by TGFbeta 1 is associated with p53-independent induction of p21, subsequent
      suppression of cdk activity and a decrease in cyclin A protein in TMK-1 cells.

PMID- 8641970
TI  - Fibrotic focus in invasive ductal carcinoma: an indicator of high tumor
      aggressiveness.
AB  - Histological examination of invasive ductal carcinoma of the breast often
      demonstrates the presence of an extensive central fibrotic focus (FF). The
      clinicopathological significance of the FF, or scar, in primary invasive ductal
      carcinoma is still ambiguous. One hundred and fifty-three cases of invasive
      ductal carcinoma (IDC) were classified into two groups, those with and those
      without FF. The differences in frequency of immunohistochemically detected
      overexpression of c-erbB-2 protein and nuclear accumulation of p53 protein, and
      the labeling index of proliferating cell nuclear antigen (PCNA), as well as
      histopathological parameters were compared between these two groups. IDCs smaller
      than 50 mm with FF showed a higher frequency of high-grade tumors, a higher
      frequency of lymph node metastasis, and a significantly higher frequency of c
      erbB-2 protein overexpression than those without FF. In tumors of 20 mm or less,
      the incidence of nuclear accumulation of p53 protein was significantly higher in
      tumors with than those without FF. Tumors with FF showed a significantly higher
      PCNA labeling index than those without FF, regardless of tumor size. The present
      results indicate that the presence of FF is an important clinicopathological
      parameter associated with a higher degree of malignancy in IDCs, especially those
      smaller than 50 mm. Therefore, dividing IDCs into those with and those without FF
      appears to be meaningful clinicopathologically.

PMID- 8641971
TI  - Characterization of transendothelial migratory lymphokine-activated killer cells.
AB  - We examined the killing activity of transmigrated lymphokine-activated killer
      (LAK) cells and their surface molecules associated with both transendothelial
      migration and cytotoxicity, using human umbilical vein-derived endothelial cell
      (HUVEC) monolayers on fibronectin with gelatin separating the upper chamber from
      the lower chamber. Migratory LAK cells were significantly more cytotoxic to Daudi
      target cells, expressed more LFA-1, and were more likely to be positive for CD2,
      compared to those LAK cells not adherent to the HUVEC monolayer. In contrast, in
      the absence of the HUVEC monolayer, there was no difference in LAK activity
      between migratory and non-adherent LAK cells. These results indicate that the
      interaction between LAK cells and the HUVEC monolayer allows selective migration
      of LAK cells with cytotoxic activity that is enhanced with respect to some
      surface molecules.

PMID- 8641972
TI  - A quantitative trait locus in major histocompatibility complex determining latent
      period of mouse lymphomas.
AB  - The effects of two host genes on retrovirus-induced murine lymphoma were
      evaluated by studying 114 F2 intercross mice between SL/Kh and AKR/Ms mice. Out
      of 47 T-lymphoma-bearing F2 mice, 45 had the AKR-derived dominant allele at Tism
      1. The length of the lymphoma latent period was not related to type of tumor.
      Instead, it was significantly shortened by a recessive SL/Kh-derived allele at a
      major histocompatibility complex (MHC)-linked locus on Chr. 17. A quantitative
      trait analysis of the latent period yielded a maximal logarithm of likelihood
      ratio for linkage (LOD) score of 7.06 at a class II gene within MHC. The SL/Kh
      derived recessive gene was named lla (lymphoma latency acceleration).

PMID- 8641974
TI  - Improvement of intraperitoneal chemotherapy for rat ovarian cancer using
      cisplatin-containing microspheres.
AB  - Microspheres consisting of L-lactic acid and glycolic acid copolymer containing
      cisplatin (CDDP-PLGA) were developed to improve the delivery of cisplatin. We
      evaluated the effects of intraperitoneal administration of cisplatin prepared as
      CDDP-PLGA in rats with ovarian cancer. The toxicity, platinum distribution, and
      therapeutic effects of CDDP-PLGA were evaluated as compared with those in the
      case of cisplatin aqueous solution. The LD50 of CDDP-PLGA was almost four-fold
      higher than that of cisplatin aqueous solution. CDDP-PLGA released cisplatin
      slowly and achieved a higher concentration in the peritoneal cavity and in
      peritoneal tumors for prolonged periods, while the tissue concentration of
      cisplatin was reduced elsewhere in the body, as compared with the case of
      cisplatin aqueous solution. The survival of rats with peritoneal carcinomatosis
      was increased by this delivery system relative to cisplatin aqueous solution.
      CDDP-PLGA thus allows a higher dose to be given without increasing systemic
      toxicity, enhancing the therapeutic effect of cisplatin.

PMID- 8641973
TI  - A human/mouse chimeric monoclonal antibody against intercellular adhesion
      molecule-1 for tumor radioimmunoimaging.
AB  - A mouse-human chimeric antibody for intercellular adhesion molecule-1 (ICAM-1)
      was established by using heavy chain loss mouse mutant hybridoma and human
      immunoglobulin expression vector. The HA58 hybridoma secreted anti-ICAM-1
      monoclonal antibody (MoAb) (IgG1, kappa). The gene of the mouse variable region
      of heavy chain was amplified and cloned by the polymerase chain reaction
      technique directly from the HA58 hybridoma RNA. The variable region of heavy
      chain was joined with an expression vector which contains human gamma 1 constant
      gene. The expression vector was transfected into heavy chain loss mutant cells
      HA58-7, which produced only murine immunoglobulin light chains. The resultant
      chimeric MoAb HA58, chHA58, retained full-binding reactivity to ICAM-1 compared
      with murine HA58 parental antibody. The chimeric MoAb chHA58 showed little
      antibody dependent cell-mediated cytotoxic activity against cultured tumor cells.
      Biodistribution studies with 99mTc-labeled chHA58 in nude mice bearing human
      gastric carcinoma JRST cells demonstrated that the tumor-blood ratio was 1.55 at
      18 h after injection, when the tumors were clearly visible in gamma scintigraphy.
      These data suggest that chHA58 may be of practical use for radioimmunoimaging of
      a wide variety of tumors.

PMID- 8641975
TI  - Shortened telomere length in hepatocellular carcinomas and corresponding
      background liver tissues of patients infected with hepatitis virus.
AB  - The telomere length in 20 surgically resected human hepatocellular carcinomas
      (HCCs) and adjacent non-cancerous livers with hepatitis virus infection were
      investigated. All the HCC samples examined demonstrated shorter telomere length
      than the corresponding non-cancerous liver tissues, the respective average values
      being 5.4 kbp and 8.8 kbp (P < 0.001). The shortening of telomere length was most
      prominent in HCCs larger than 30 mm in diameter, and in both tumors and non
      cancerous livers it was more marked with hepatitis B virus as compared with
      hepatitis C virus infection. These results indicate that telomere shortening is
      associated with not only progression, but also development of HCC, and there is a
      possible difference in the nature of the association in patients with hepatitis
      viruses of B and C types.

PMID- 8641976
TI  - Molecular genetic diagnosis of von Hippel-Lindau disease: analysis of five
      Japanese families.
AB  - We analyzed deoxyribonucleic acids from blood samples of five Japanese von Hippel
      Lindau (VHL) disease families (three familial cases, two new mutations) for the
      presence of VHL gene mutations by single-strand conformational polymorphism
      analysis and direct sequencing. Four of the five families showed germ line
      mutations in VHL gene, comprising 2 missense mutations, 1 deletion, and 1 splice
      site mutation. Two families had VHL gene mutations at exon 1; 1 family at exon 3;
      and 1 family at the splice-site adjacent to exon 3. Presymptomatic patients were
      accurately diagnosed by these methods. However, one family did not show a VHL
      gene mutation in the germ line but showed a somatic mutation at exon 2 in the
      hemangioblastoma tissue. The consequence of the somatic mutation was a
      microdeletion leading to a frameshift mutation. Our study is the first report of
      VHL gene analyses of Japanese VHL disease families, and suggests that not only
      germ line mutation, but also somatic mutation can lead to development of a tumor
      associated with the VHL disease.

PMID- 8641977
TI  - Murine asialo GM1+CD8+ T cells as novel interleukin-12-responsive killer T cell
      precursors.
AB  - Freshly isolated CD8+ T cells, but not CD4+ T cells, contained 20-30% of asialo
      GM1+ (ASGM1+) T cells which were distinct from ASGM1+NK1.1+ natural killer cells.
      This novel ASGM1+CD8+ T cell subpopulation showed a strong proliferative response
      to interleukin-12 (IL-12) in the presence of IL-2. Culture of ASGM1+CD8+ T cells
      with IL-12 plus IL-2 allowed the generation of anomalous killer T cells
      concomitantly with the accumulation of cytolytic molecules. Moreover, ASGM1+CD8+
      T cells produced high levels of interferon-gamma (IFN-gamma), but not IL-4, upon
      stimulation with IL-12 plus IL-2. Such immune responses were not observed in
      ASGM1-CD8+ T cell subpopulations constituting the majority of CD8+ T cells. These
      results demonstrated that ASGM1+CD8+ T cells are a novel subpopulation of IL-12
      responsive and IFN-gamma-producing killer T cell precursors.

PMID- 8641978
TI  - Gastric tumorigenicity of 1,2-dimethylhydrazine on the background of gastric
      intestinal metaplasia induced by X-irradiation in CD (SD) rats.
AB  - Five-week-old male CD (SD) rats were X-irradiated with a total of 20 Gy in 2
      equal fractions with a 3-day interval. After the second irradiation, rats were
      fed normal diet supplemented with 1% sodium chloride, which is known to increase
      intestinal metaplasia. 1,2-Dimethylhydrazine (DMH) solution was injected i.m.
      into the back musculature at a dose of 20 mg/kg body weight weekly for 10 weeks,
      beginning 20 weeks after the final irradiation. Twelve months after the initial
      carcinogen treatment, gastric tumors in the glandular stomach were observed in 2
      (3 lesions) of 30 animals in the X-irradiated and DMH-treated group fed diet
      supplemented with 1% sodium chloride. No gastric tumors were observed in the
      group which excluded X-irradiation from the experimental protocol.

PMID- 8641979
TI  - Selective reduction in alpha-hydroxypalmitic acid-containing sphingomyelin and
      concurrent increase in hydroxylated ceramides in murine skin tumors induced by an
      initiation-promotion regimen.
AB  - The sphingomyelin cycle is activated to accumulate ceramides in the process of
      epidermal differentiation. We found that sphingomyelin in the epidermis of 4
      different murine strains gave three bands on TLC, the lower band containing alpha
      hydroxypalmitic acid (C16h:0(alpha)). However, in the papillomas induced in the
      skin of SENCAR and SSIN mice by initiation with 7,12-dimethylbenz[a]anthracene
      followed by promotion with 12-O-tetradecanoylphorbol acetate, the concentration
      of C16h:0(alpha)-containing sphingomyelin was selectively diminished with a
      concomitant increase in the concentrations of the ceramides containing alpha
      hydroxy fatty acids. These findings indicate a possible involvement of the
      selective hydrolysis of alpha-hydroxy fatty acid-containing sphingomyelin in the
      process of tumorigenesis in mouse skin.

PMID- 8641980
TI  - Sinusoidal capillarization and arterial blood supply continuously proceed with
      the advance of the stages of hepatocarcinogenesis in the rat.
AB  - Hepatocellular carcinoma (HCC) is supplied only with arterial blood and has
      capillaries instead of sinusoids, unlike the normal hepatic tissue. In order to
      reveal the sequential changes of sinusoidal structure and blood supply during
      hepatocarcinogenesis, we examined hyperplastic nodules (HPN), atypical
      hyperplastic nodules (AHPN) and HCC in F344 rats fed with 2-acetylaminofluorene
      for 25-35 weeks. The extent of arterial blood supply and the degree of sinusoidal
      capillarization were assessed by the staining of hepatic nodules with arterially
      infused ink and by immunohistochemical and ultrastructural analyses of the
      sinusoids, respectively. The proportion of arterialized nodules was 47% in HPN,
      57% in AHPN and 85% in HCC, which indicates that arterialization begins at the
      stage of HPN and a few HCC still receive portal venous blood. The proportion of
      Factor-VIII-related antigen (F-VIII)-positive nodules was 25% in HPN, 40% in AHPN
      and 100% in HCC. Non-arterialized nodules did not express F-VIII, while some F
      VIII-negative nodules were already arterialized. Electron microscopically, non
      arterialized HPN exhibited normal features of sinusoids, while arterialized HPN
      showed disappearance of Kupffer cells and partial defenestration of sinusoidal
      endothelial cells. In non-arterialized and arterialized AHPN, basement membrane
      became continuous and lipid droplet-containing stellate cells were no longer
      seen. In HCC, endothelial fenestrae were diminished and basement membrane became
      thick. The present study has demonstrated that sinusoids are altered in the
      following order as hepatocarcinogenesis advances from HPN to HCC; onset of
      arterialization and decrease of endothelial fenestrae, expression of F-VIII by
      endothelial cells, disappearance of Kupffer cells, diminution of lipid droplets
      in stellate cells and thickening of basement membrane.

PMID- 8641981
TI  - Establishment of a clonal cell line producing granulocyte colony-stimulating
      factor and parathyroid hormone-related protein from a lung cancer patient with
      leukocytosis and hypercalcemia.
AB  - Squamous cell lung carcinoma cells obtained from a patient who presented with
      leukocytosis and hypercalcemia were transplanted into nude mice and a serially
      transplantable cell line, OKa-N-1, was established. The nude mice transplanted
      with OKa-N-1 cells displayed leukocytosis and hypercalcemia. Serum levels of
      granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related
      protein (PTHrP) were both elevated in these mice. In vitro cultivation of this
      tumor cell line gave rise to a clonal cell line, OKa-C-1. Nude mice transplanted
      with the OKa-C-1 cell line also showed leukocytosis and hypercalcemia with high
      serum G-CSF and PTHrP levels. The culture supernatant of OKa-C-1 contained high
      levels of G-CSF and PTHrP. Immunohistochemical studies showed the expression of
      PTHrP in OKa-C-1 cells. Reverse transcription polymerase chain reaction revealed
      the presence of G-CSF and PTHrP mRNA in this cell line. Dexamethasone treatment
      inhibited the transcription of G-CSF and PTHrP genes. This new human squamous
      carcinoma cell line, OKa-C-1, would be useful for studying the mechanism of
      simultaneous production of G-CSF and PTHrP and their control in cancer patients
      with leukocytosis and hypercalcemia.

PMID- 8641982
TI  - Oncogenic collaboration of the cyclin D1 (PRAD1, bcl-1) gene with a mutated p53
      and an activated ras oncogene in neoplastic transformation.
AB  - Cyclin D1 is one of the key regulators in G1 progression in the cell cycle and is
      also a candidate oncogene (termed PRAD1 or bcl-1) in several types of human
      tumors. We report a collaboration of the cyclin D1 gene with ras and a mutated
      form of p53 (p53-mt) in neoplastic transformation. Transfection of cyclin D1
      alone or in combination with ras or with p53-mt was not sufficient for focus
      formation of rat embryonic fibroblasts. However, focus formation induced by co
      transfection of ras and p53-mt was enhanced in the presence of the cyclin D1
      expression plasmid. Co-transfection of ras- and p53-mt-transformants with the
      cyclin D1-expression plasmid resulted in reduced serum dependency in vitro.
      Furthermore, the transformants expressing exogenous cyclin D1 grew faster than
      those without the cyclin D1 plasmid when injected into nude mice. These
      observations strengthen the significance of cyclin D1 overexpression through gene
      rearrangement or gene amplification observed in human tumors as a step in
      multistep oncogenesis; deregulated expression of cyclin D1 may reduce the
      requirement for growth factors and may stimulate in vivo growth.

PMID- 8641983
TI  - Detection of K-ras point mutations at codon 12 in pancreatic juice for the
      diagnosis of pancreatic cancer by hybridization protection assay: a simple method
      for the determination of the types of point mutation.
AB  - The present study was undertaken to detect K-ras oncogene point mutations at
      codon 12 in pure pancreatic juice (PPJ) by the hybridization protection assay
      (HPA) method for the diagnosis of pancreatic cancer (PC). This assay can be
      carried out within 30 min and can determine not only the presence of a mutation,
      but also the mutational type of K-ras at codon 12. The minimal ratio of mutant
      DNA detectable by the HPA was 5-10% of the total DNA. PPJ was collected through a
      cannula under duodenal fiberscope control from 20 patients with PC and 20
      patients with chronic pancreatitis (CP). Analysis of PPJ by the HPA revealed that
      the incidence of K-ras point mutations at codon 12 was 55% (11/20) in patients
      with PC and 0% (0/20) in those with CP. Mutational types of K-ras at codon 12 in
      PC were aspartic acid (Asp) in nine cases, both Asp and cysteine in one case, and
      arginine in one case. Analysis of K-ras point mutations at codon 12 in PPJ using
      the HPA method seems promising as a new genetic test for the diagnosis of PC,
      because the HPA method is simple, and can easily determine the mutational type.

PMID- 8641984
TI  - Detection of low-level expression of P-glycoprotein in ACHN renal adenocarcinoma
      cells.
AB  - A highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay
      and a flow cytometric assay were used to examine ACHN cells for the expression of
      P-glycoprotein. The expression of P-glycoprotein was detected at the RNA and
      protein levels in ACHN cells by RT-PCR and flow cytometry, respectively. However,
      it was below the limit of detection by immunoblotting. The intracellular
      accumulation of adriamycin in ACHN cells was enhanced by verapamil, cyclosporin A
      and medroxyprogesterone acetate. Therefore, this study has demonstrated that low
      level expression of P-glycoprotein detectable only by RT-PCR and flow cytometry
      plays a significant role in reducing the intracellular concentration of antitumor
      agents and thus contributes to the multidrug-resistant phenotype of ACHN cells.

PMID- 8641985
TI  - Inverse correlation between mRNA expression of plasminogen activator inhibitor-2
      and lymph node metastasis in human breast cancer.
AB  - We examined mRNA expressions of urokinase-type plasminogen activator (u-PA), its
      specific receptor (u-PR), and plasminogen activator inhibitors (PAI-1 and PAI-2)
      in 50 human breast cancers by the reverse transcriptase-polymerase chain reaction
      method. The expressions of the genes are discussed in relation to the
      clinicopathological findings. In the overall population in breast cancers, a low
      level of PAI-2 expression was significantly associated with lymph node
      involvement (P < 0.0001). The u-PA, u-PR, and PAM expressions tended to be at
      high levels in such metastatic cancers. Also, positive expression of u-PA, u-PR,
      and PAI-1 was significantly correlated with negative expression of PAI-2. These
      results indicate that PAI-2 may play a critical role in the regulation of
      extracellular matrix degradation during tumor cell invasion and metastasis, and
      the expression of PAI-2 may be useful as a marker to evaluate the prognosis of
      breast cancers.

PMID- 8641986
TI  - A novel monoclonal antibody specific for sialylated MUC1 mucin.
AB  - Development of a new monoclonal antibody (mAb) MY.1E12 which reacts with
      sialylated MUC1 mucins is described. The mAb did not react with any component in
      the lysates of COS-1 cells, whereas it bound to sialylated MUC1 mucins produced
      by COS-1 cells transiently transfected with MUC1 mucin cDNA, strongly suggesting
      that the expression of the epitope of mAb MY.1E12 depends on the presence of the
      MUC1 mucin core peptide. The requirement of sialyl residues for antibody
      recognition was established by Western blotting analysis of extracts of various
      carcinoma cells and in situ desialylation. In all cases, the mAb binding of
      electrophoretically separated MUC1 mucin diminished after desialylation by mild
      acid hydrolysis. When Capan-1 pancreatic carcinoma cells were pretreated with
      benzyl-N-acetylgalactosaminide in culture, the MUC1 mucins produced under these
      conditions, which were detected by core peptide-specific mAbs, did not react with
      mAb MY.1E12. These results suggest that O-linked carbohydrate chains are
      important for the mAb binding.

PMID- 8641987
TI  - Anti-ganglioside GM2 monoclonal antibody-dependent killing of human lung cancer
      cells by lymphocytes and monocytes.
AB  - Ganglioside GM2 (GM2) frequently appears on the cell surface of human cancers of
      neuroendocrine origin. A mouse-human chimeric monoclonal antibody (mAb), KM966,
      against GM2 was previously found to promote the lysis of various cancer cells by
      human blood mononuclear cells (MNC). In this study, we analyzed the effector
      cells responsible for the chimeric mAb-dependent cell-mediated cytotoxicity
      (ADCC) against small cell lung cancer (SCLC) cells and examined the enhancing
      effect of various cytokines on the ADCC activity. The ADCC activity was assessed
      by 4-h 51Cr release assay. Highly purified lymphocytes (> 99%) and monocytes (>
      90%) were separated by centrifugal elutriation from peripheral blood MNC of the
      same healthy donor. KM966 induced lysis of SCLC cells mediated by both
      lymphocytes and monocytes to similar extents, in a dose-dependent manner.
      Pretreatment of lymphocytes with various cytokines [interleukin (IL)-2, IL-12 and
      interferon-gamma] and that of monocytes with macrophage-colony-stimulating factor
      significantly augmented the killer activity against SCLC cells in the presence of
      KM966 mAb. KM966 was also effective for the lysis of non-small cell lung cancer
      cells in direct proportion to the GM2 expression levels. These findings suggest
      that combined treatment of KM966 mAb with cytokines may be therapeutically useful
      for in vivo killing of lung cancer cells expressing GM2 through the ADCC
      reaction.

PMID- 8641988
TI  - Effect of MUC1 mucin, an anti-adhesion molecule, on tumor cell growth.
AB  - MUC1 mucin is expressed in a wide variety of tumors and is considered to function
      as an anti-adhesion molecule which inhibits cell-to-cell interactions. To reveal
      the biological significance of this activity in tumor cells, MUC1 cDNA was
      transfected into EJNIH3T3 cells and human colon cancer cell lines, CHCY1 and
      DLD1. The in vivo growth rate of MUC1+ (MUC1-transfected) EJNIH3T3, CHCY1 and
      DLD1 cells in SCID mice was clearly lower than that of MUC1- (mock transfectant)
      cells. Several in vitro experiments using MUC1+ EJNIH3T3 cells were performed to
      analyze the mechanisms for the decreased in vivo tumor growth. It was found that
      (i) the in vitro growth rate of MUC1+ EJNIH3T3 cells was also decreased compared
      to that of MUC1- cells, (ii)the DNA synthesis of MUC1+ EJNIH3T3 cells after
      stimulation with either growth factor (fetal calf serum or bombesin) or
      extracellular matrix (collagen or fibronectin) was lower than that of MUC1-
      cells, and (iii) MUC1+ EJNIH3T3 cells grew more slowly than MUC1- cells on both
      collagen- and fibronectin-coated dishes. These data suggest that MUC1 mucin may
      regulate tumor cell growth through inhibition of cell-to-cell, growth factor-to
      receptor and cell-to-matrix interactions.

PMID- 8641989
TI  - Correlation between nm23 protein and several cell adhesion molecules in human
      gastric carcinoma.
AB  - The correlation between nm23 protein (nm23) expression and the expression of
      several cell adhesion molecules was studied immunohistochemically in 110 resected
      gastric carcinomas. Formalin-fixed and paraffin-embedded samples were serially
      sectioned and stained with antibodies against nm23, integrin beta1 subfamily
      members (alpha2beta1, alpha3beta1 and alpha4beta1), LFA-1, ICAM-1, sialyl
      Lewis(x) (sLex) and CD44H, -V3, and -V6. Primary carcinomas presenting with
      either lymph node involvement or liver metastasis expressed significantly reduced
      levels of nm23 compared to tumors without metastasis. The percent of tumors
      expressing each adhesion molecule was as follows: alpha2beta1, 27.3%;
      alpha3beta1, 20.0%; alpha4beta1, 14.5%; LFA-1, 14.5%; ICAM-1, 12.7%; sLex, 67.3%;
      CD44H, 55.5%; CD44V3, 20.0%; and CD44V6, 4.5%. Expression of alpha2beta1 integrin
      and high levels of sLex were significantly correlated with lymph node metastasis,
      and expression of alpha3beta1 integrin and high levels of sLex were correlated
      with liver metastasis. Expression of ICAM-1 was inversely correlated with liver
      metastasis. Comparing the expression of each cell adhesion molecule with nm23
      immunoreactivity, expression of sLex was significantly associated with nm23
      expression. Of tumors expressing high levels of sLex, 75% showed reduced nm23
      expression, compared to 52% of tumors with weak or no sLex expression (P < 0.05).
      A similar tendency was also observed in the metastasized secondary tumors. These
      results suggest that reduced nm23 expression may promote the metastatic
      properties of cancer cells in concert with increased sLex expression.

PMID- 8641990
TI  - Antimetastatic effect of a novel indolocarbazole (NB-506) on IMC-HM murine tumor
      cells metastasized to the liver.
AB  - IMC-HM cells were isolated from spontaneously induced ascitic IMC carcinoma cells
      that had been maintained intraperitoneally in CDF1 mice. Metastasis to the liver
      of subcutaneously implanted IMC-HM cells was detected 10 days after implantation
      into the flanks of mice (day 10), but metastasis to other organs was limited.
      Thereafter, however, tumor cells spread rapidly to lymph nodes, lung, spleen,
      ovary and other organs, and the mice died on day 13 to 18. We report here,
      together with the properties of IMC-HM cells, the effects of adriamycin,
      cisplatin, etoposide and a new indolocarbazole antitumor compound (NB-506) on
      this model of metastasis. Although these anticancer agents all inhibited the
      growth of the subcutaneous tumors, their effects on the life span of the tumor
      bearing mice varied. Treatment with NB-506, started on day 1, more than doubled
      the survival period at doses 30 mg/m2 to 900 mg/m2. Further, treatment with NB
      506, started on day 4 after resection of the primary tumor, inhibited growth of
      the metastasized tumor in the liver and other organs. Etoposide also increased
      the life span at a limited range of doses. However, the life-prolonging effects
      of adriamycin and cisplatin were marginal. These results demonstrate that IMC-HM
      carcinoma is a good model for spontaneous metastasis to the liver followed by
      lethal spread to many organs. Moreover, NB-506 was found to be highly effective
      against the growth not only of subcutaneous tumors, but also of tumors
      metastasized to the liver.

PMID- 8641991
TI  - Effects of sex steroids and growth factors on migration and invasion of
      endometrial adenocarcinoma SNG-M cells in vitro.
AB  - Biological effects of sex steroids (estradiol-17beta, E2; progesterone, P;
      medroxyprogesterone acetate, MPA; Danazol, DZ) and growth factors (epidermal
      growth factor, EGF; transforming growth factor, TGF-alpha,beta) on migration and
      invasion of endometrial adenocarcinoma SNG-M cells were investigated by
      haptotactic migration and haptoinvasion assay. The enzymatic degradation of the
      extracellular matrix by tumor cells was also examined. Tumor cell migration along
      a gradient of substratum-bound fibronectin was inhibited by 0.1-10 microM MPA and
      DZ, but promoted by 0.1-10 nM EGF and TGF-alpha in a concentration-dependent
      manner. E2, P and TGF-beta did not have any effect on the motility of tumor
      cells. These effects were also confirmed by wound assay. The invasive activity of
      SNG-M cells into reconstituted basement membrane (Matrigel) was inhibited by the
      presence of 0.1-10 microM MPA and DZ, but promoted by 0.1-10 nM EGF and TGF-alpha
      in a concentration-dependent manner. E2, P and TGF-beta did not have any effect
      on tumor cell invasion. The zymography of tumor-conditioned medium showed that
      the treatment of SNG-M cells with EGF and TGF-alpha resulted in the increase of
      the 68, 72 and 92 kDa type IV collagenases (matrix metalloproteinase, MMP-2 and
      9). Sex steroids and TGF-beta did not have significant effects on MMP-2 and 9.
      Stromelysin (MMP-3), also secreted by SNG-M cells, was not affected by sex
      steroids and growth factors. These results suggest that EGF and TGF-alpha act as
      positive regulators on the invasion process of endometrial adenocarcinoma cells,
      which may partly be associated with the induction of type IV collagenase
      secretion by tumor cells. The inhibitory effects of MPA and DZ on tumor cell
      invasion may depend at least partly on their inhibitory action on the motility of
      tumor cells.

PMID- 8641994
TI  - EI-1507-1 and -2, novel interleukin-1 beta converting enzyme inhibitors produced
      by Streptomyces sp. E-1507.
AB  - EI-1507-1 and -2, novel interleukin-1 beta converting enzyme (ICE) inhibitors,
      were isolated from the culture broths of Streptomyces sp. E-1507. EI-1507-1 and
      EI-1507-2 selectively inhibited the recombinant human ICE activity with IC50
      values of 0.23 and 0.42 microM, respectively. EI-1507-1 and EI-1507-2 also
      inhibited mature interleukin-1 beta secretion from THP-1 cells with IC50 values
      of 1.1 and 1.4 microM, respectively.

PMID- 8641993
TI  - Tumor necrosis factor-alpha gene transfer augments anti-Fas antibody-mediated
      apoptosis in human glioma cells.
AB  - To effectively induce apoptosis in human glioma cells, we tried to transfer the
      tumor necrosis factor (TNF)-alpha gene into glioma cells to produce TNF-alpha
      locally in these cells. The stable transfectants of three glioma cells (U251-SP,
      U251-MG, and T98G) were resistant to exogenous TNF-alpha, but their cell surface
      expression of the Fas antigen was dramatically enhanced by about 10 to 100-fold
      as compared with untransfected glioma cells exposed to exogenous TNF-alpha. The
      Fas antigen is a transmembrane cytokine receptor protein of the nerve growth
      factor/TNF receptor superfamily. Although the untransfected glioma cells tested
      were resistant to anti-Fas antibody-mediated apoptosis, the TNF-alpha gene
      transfected glioma cells exhibited high susceptibility to anti-Fas antibody
      mediated apoptosis. Thus, TNF-alpha gene transfer combined with anti-Fas
      antibodies may be useful for the treatment of malignant glioma.

PMID- 8641992
TI  - Specific growth inhibition of small-cell lung cancer cells by adenovirus vector
      expressing antisense c-kit transcripts.
AB  - Antisense methods to control aberrant gene expression have been investigated as
      therapeutic strategies. A proto-oncogene c-kit, which encodes a transmembrane
      tyrosine kinase, is overexpressed in some malignancies, including small-cell lung
      cancer (SCLC), and is thought to be involved in their pathogenesis. To test the
      feasibility of using adenovirus vectors for antisense strategies and to target c
      kit in SCLC therapy, we constructed replication-deficient recombinant adenovirus
      vectors which express fragments of c-kit transcripts in antisense (Ad.kitAS) or
      sense orientation (Ad.kitS: control). In vitro infection of SBC-1 cells, which
      are c-Kit protein-producing SCLC cells, by these vectors resulted in the
      expression of artificial c-kit transcripts. The Ad.kitAS-infected SBC-1 cells
      showed reductions in the amount of c-Kit protein. As expected, at 10 days after
      infection (1 multiplicity of infection), Ad.kitAS-infected SBC-1 cells showed
      approximately 40% growth inhibition compared to uninfected or Ad.kitS-infected
      cells in vitro. Such a significant growth inhibition by Ad.kitAS was not induced
      in SBC-5 cells, which are SCLC cells producing no c-Kit protein. These results
      demonstrate the usefulness of adenovirus vectors in antisense strategies, and the
      feasibility of targeting c-kit in the therapy of c-Kit-producing SCLC.

PMID- 8641995
TI  - YM-47522, a novel antifungal antibiotic produced by Bacillus sp. I. Taxonomy,
      fermentation, isolation and biological properties.
AB  - YM-47522, a novel antibiotic, was isolated from the culture broth of Bacillus sp.
      YL-03709B. The antibiotic was purified by centrifugal partition chromatography
      and ODS column chromatography. It exhibited potent in vitro antifungal activity
      especially against Rhodotorula acuta and Pichia angusta (MIC: 0.05 and 0.75
      microgram/ml, respectively). It also showed moderate or weak antifungal activity
      against Candida albicans and Cryptococcus neoformans (MIC: 25 and 6.25
      micrograms/ml, respectively), whereas it was inactive against filamentous fungi
      and bacteria.

PMID- 8641996
TI  - YM-47522, a novel antifungal antibiotic produced by Bacillus sp. II. Structure
      and relative stereochemistry.
AB  - YM-47522 (1) was isolated from the fermentation broth of Bacillus sp. YL-03709B
      as an antifungal antibiotic. The structure of 1 was elucidated by spectroscopic
      analyses. YM-47522 (1) consisted of C13 carboxylic acid amide and cinnamate
      moieties. The relative stereochemistry was also proposed on the basis of chemical
      transformation into a 1,3-diol acetonide and its NMR data.

PMID- 8641997
TI  - Direct fermentative production of acyltylosins by genetically-engineered strains
      of Streptomyces fradiae.
AB  - A tylosin-producer, Streptomyces fradiae, was transformed with plasmids carrying
      genes from Streptomyces thermotolerans that are involved in acyl modification of
      macrolide antibiotics. A transformant with pMAB3, in which macrolide 4"-O
      acyltransferase gene (acyB1) and its regulatory gene (acyB2) are subcloned,
      produced several types of 4"-O-acyltylosins. A transformant with pAB11 delta EH
      containing macrolide 3-O-acyltransferase gene (acyA) in addition to the above two
      genes produced 3-O-acetyltylosin and 3-O-acetyl-4"-O-acyltylosins. Among the
      products of the latter transformant, 3-O-acetyl-4"-O-isovaleryltylosin (AIV) was
      detected as a minor component. When L-leucine, a precursor of isovaleryl-CoA, was
      added to the medium at the late stage of the fermentation, AIV content among the
      total macrolides increased ten-fold and AIV became a main product. This fact
      suggests that a high level of endogenous isovaleryl-CoA may be essential for the
      selective production of AIV by S. fradiae carrying pAB11 delta EH.

PMID- 8641999
TI  - Morphology reversion activity of phosmidosine and phosmidosine B, a newly
      isolated derivative, on src transformed NRK cells.
AB  - An antifungal antibiotic, phosmidosine (1) was previously isolated (J.
      Antibiotics 44: 375 approximately 381, 1991). Phosmidosine derivatives,
      phosmidosines B (2) and C (3) were newly isolated as detransforming compounds
      from the fermentation broth of Streptomyces sp. strain RK-16 which is a producer
      strain of phosmidosine (1). The structures of 2 and 3 were established by
      spectroscopic methods, including UV, HRFAB-MS, and NMR. 1 and 2 showed the
      inhibitory activity of the cell cycle progression and the morphological reversion
      activity on srcts-NRK cells. On the other hand, 3 had no activity. These results
      indicate that the prolyl group in phosmidosine derivatives plays an important
      role in the inhibitory activity against the cell cycle progression and the
      morphological reversion activity on srcts-NRK cells.

PMID- 8641998
TI  - New anthracycline metabolites produced by the aklavinone 11-hydroxylase gene in
      Streptomyces galilaeus ATCC 31133.
AB  - Transformation of Streptomyces galilaeus ATCC 31133 with the aklavinone 11
      hydroxylase gene (dnrF) resulted in the production of many red pigments. The new
      metabolites were purified and their structures were determined as 11-hydroxylated
      aclacinomycin A, B and T by spectral analysis. This result indicated that the
      dnrF was stably expressed in the strain S. galilaeus ATCC 31133 to give rise to
      hybrid aclacinomycins. In addition, a new aclacinomycin analog named 11
      hydroxyaclacinomycin X was isolated from the same culture. Its structure was
      elucidated as 2"'-amino-11-hydroxyaclacinomycin Y. It showed strong cytotoxicity
      against several human tumor cell lines, especially leukemia and melanoma cell
      lines.

PMID- 8642000
TI  - Binding of benanomicin A to fungal cells in reference to its fungicidal action.
AB  - An antifungal antibiotic, benanomicin A, binds in the presence of Ca2+ to
      susceptible fungi and some bacteria, but not to antibiotic-resistant bacteria and
      mammalian cells. With the susceptible yeast Saccharomyces cerevisiae, benanomicin
      A binds similarly to whole cells and to protoplasts. Studies using benanomicin A
      and three structurally related derivatives suggested that a carboxylic acid in
      the D-alanine moiety and a sugar moiety in the benanomicin A molecule are
      essential for both binding and antifungal activities against growing S.
      cerevisiae. An amino substituent on the sugar moiety can be replaced with a
      hydroxyl group without the loss of activities. Benanomicin A binds to various
      yeast mannans which differ in glycosidic linkages. These results indicate that
      binding of benanomicin A to the mannan portion of fungal cells is essential for
      exertion of the antifungal activity.

PMID- 8642001
TI  - Novel spirodihydrobenzofuranlactams as antagonists of endothelin and as
      inhibitors of HIV-1 protease produced by Stachybotrys sp. II. Structure
      determination.

PMID- 8642002
TI  - Syntheses and antimicrobial activities of five-membered ring heterocycles coupled
      to indole moieties.
AB  - Indole-substituted oxazolidinones, oxazolones, pyrrolidinone, imidazolidinone and
      imidazolones were synthesized. Their inhibitory potencies towards protein kinase
      C and protein kinase A were determined and their in vitro activities against
      Streptomyces chartreusis, Streptomyces griseus, Bacillus cereus, Candida albicans
      and Escherichia coli were examined. The inhibition of Streptomyces sporulation
      observed for some of them could not be linked to in vitro protein kinase C
      inhibition. All proved inactive against C. albicans but three of them exhibited a
      marked activity towards E. coli. This effect extends to other Gram-negative
      bacteria.

PMID- 8642003
TI  - Relationship between structure and biological activity of novel R106 analogs.
AB  - The retro-aldol reaction at residue 8 of R106-1 produced a chemical handle, in
      the form of a sarcosine residue, that was amenable to classical aldol alkylation
      conditions. In vitro assay of several new hydroxylated analogs have shown that L
      isomers exhibit more potent antifungal activity than D isomers. However, all
      analogs exhibited a significant decrease in activity against Cryptococcus
      neoformans. By contrast, structural modifications of R 106 were tolerated by some
      Candida spp., but the potency of activity was diminished as compared to that of
      the natural product R106-1. The full structure-activity relationship of the new
      R106 analogs has provided important information about the steric and electronic
      requirements of binding to target receptors. Furthermore, comparison of the
      structural differences between R106-1 and other derivatives, suggested that the
      potential for hydrogen bonding (at residue 8) was a key structural feature that
      was required to maintain activity against Cryptococcus neoformans.

PMID- 8642004
TI  - Chemistry of pseudomonic acid. Part 16. Aryl and heteroaryl ketone derivatives of
      monic acid.
AB  - The synthesis, antibacterial activities, murine pharmacokinetic and infection
      model data for a range of aryl and heteroaryl ketone derivatives of monic acid
      (2a) are reported. The best results were found for the 3-furyl and 2-methoxy
      thiazol-5-yl analogues.

PMID- 8642006
TI  - Two novel spiramycins obtained from commercial samples: isolation and elucidation
      of structure.

PMID- 8642007
TI  - Structure-activity relationships of cephalosporin derivatives against methicillin
      resistant Staphylococcus aureus and Enterococcus faecalis.

PMID- 8642005
TI  - Potent inhibitors of cysteine proteases from the marine fungus Microascus
      longirostris.

PMID- 8642008
TI  - Synthesis and biological activity of C-3 direct heterocyclylcarbon-substituted
      novel cephalosporins.

PMID- 8642009
TI  - Variations in R-plasmid DNA concentrations of Escherichia coli during starvation
      in sewage and brackish waters.
AB  - Cell culturability and plasmid stability in Escherichia coli containing plasmids
      RP1, R388 and pUB824 were studied in raw and treated wastewater, and in brackish
      water. The E. coli strain survived well in the three samples of water employed.
      Moreover, the three plasmids were maintained under all conditions studied.
      Interestingly, plasmid DNA concentration of individual plasmids followed the same
      evolution as the culturable bacteria in the corresponding selective medium when
      the bacteria grew in raw or treated wastewater. In contrast, in brackish water,
      the stress due to the oligotrophic and salinity conditions of the medium produced
      an initial paradoxical increase in plasmid DNA concentration, followed by a
      decrease in the number of culturable bacteria in the corresponding selective
      medium. Maintenance of RP1 (56 kbp) and R388 (33 kbp) was markedly influenced by
      nutritive conditions, which caused a segregation of the plasmids from cells. The
      results of the present study suggest that variations in plasmid DNA
      concentrations in an aquatic environment depend on the quality of the water and
      also on the molecular weight of the plasmid considered.

PMID- 8642010
TI  - A modified chemostat system to study the ecology of oral biofilms.
AB  - Previously, we developed a chemostat system to study the behaviour and properties
      of a community of up to 10 species of oral bacteria. The present study describes
      modification of this system to incorporate removable and replaceable
      hydroxyapatite (the major mineral in human dental enamel) disks on which biofilms
      could develop. Hydroxyapatite disks were immersed in the chemostat for known time
      periods, and the bacterial content of biofilms determined by viable counting.
      Initial deposition rates were rapid, with all 10 species detected after 1 h, and
      the numbers of bacteria in biofilms continued to increase for 21 d. The species
      composition of biofilms reflected that of the surrounding fluid phase, and showed
      only limited signs of the type of 'species succession' which is observed in
      developing dental plaque in vivo, although anaerobic species increased in
      proportion in older biofilms. Four-day biofilms showed the least variability and
      were chosen as the 'standard biofilm' for more detailed study. Variability in the
      bacterial composition of 4-d biofilms was comparable both within a single
      chemostat run and between independent chemostat runs. Glucose pulsing in the
      absence of pH control resulted in the selection of cariogenic species; the
      disruption of the biofilm community was less marked than that of the equivalent
      planktonic culture. The model system has considerable potential in studying the
      effects of a variety of factors on biofilm development, as well as in comparing
      the efficacy of antimicrobial systems against biofilms.

PMID- 8642011
TI  - Influence of pH, temperature and initial yeast:bacteria ratio on the stimulation
      of Lactobacillus hilgardii by Saccharomyces florentinus isolated from sugary
      kefir grains.
AB  - The effects of pH, temperature and initial yeast:bacteria ratio on Lactobacillus
      hilgardii and Saccharomyces florentinus cultivated either in pure or mixed
      culture were studied. Quadratic polynomial as a function of factors was proposed
      to express the lactic acid production at different sampling times, and the
      percentage increase in lactic acid production by Lact. hilgardii in mixed culture
      compared with pure culture. Temperature was the factor which had the main
      influence on lactic acid production in mixed culture, whereas stimulation of
      bacteria depended greatly on pH value. In the range 0.1-20%, the initial yeast
      bacteria ratio had no effect on these responses, but presence of the yeast was
      absolutely necessary to obtain high production of lactic acid. Optimum culture
      conditions were determined to maximize these characteristics.

PMID- 8642012
TI  - Ribotypes and AP-PCR fingerprints of thermophilic campylobacters from marine
      recreational waters.
AB  - Thirty-two strains of thermophilic campylobacters isolated from marine
      recreational water and seven reference strains were biotyped and analysed by
      chromosomal DNA HaeIII ribopatterns and AP-PCR profiles based on a random 10-mer
      primer (5'-CAA TCG CCG T-3'). The majority of seawater isolates (90%) were
      Campylobacter coli, and three strains were Camp. jejuni. Southern blot
      hybridization analysis showed differences between the strains, and in a numerical
      analysis three main clusters were formed at the 45% similarity level, that
      corresponded to Camp. jejuni subsp. jejuni, Camp. coli, and a combination of
      Camp. coli and Camp. jejuni subsp. doylei. AP-PCR profiles also differentiated
      between the species but were less discriminatory than ribotyping because six
      strains (17%) could not be typed by this method. Numerical analysis gave four
      main clusters at the 45% similarity level, corresponding to Camp. jejuni subsp.
      jejuni, Camp. coli (two clusters) and Camp. lari. The study shows that strains
      within each species are diverse genomically. Both molecular methods were highly
      discriminatory, although some strains with identical ribotypes could be
      distinguished by AP-PCR, and they are valuable new alternatives to traditional
      typing in epidemiological studies of environmental campylobacters.

PMID- 8642013
TI  - Differentiation of Listeria isolates by PCR amplicon profiling and sequence
      analysis of 16S-23S rRNA internal transcribed spacer loci.
AB  - The 16S-23S rRNA internal transcribed spacer region (ITS) in genomic DNA from
      Listeria species was amplified and sequenced so as to find sequence differences
      that would allow rapid species and strain differentiation. Agarose gel profiles
      of amplicons generated with primers designed to amplify ITS loci indicated that
      Listeria DNA can contain at least two distinct ITS regions. The direct sequencing
      of the smaller of these ITS amplicons (330 bp) was found useful for the rapid and
      accurate differentiation of various Listeria species. On the other hand analysis
      of ITS amplicons generated from a total of 27 L. monocytogenes strains indicated
      that 4/27 of these strains could be distinguished on the basis of their ITS
      profile (the presence of a unique 350 bp amplicon). The lack of sequence
      heterogeneity in the small 333 bp amplicon did not permit rapid strain
      differentiation.

PMID- 8642014
TI  - An oligonucleotide hybridization assay for the identification and enumeration of
      F-specific RNA phages in surface water.
AB  - F-specific RNA phages can be used as model organisms for enteric viruses to
      monitor the effectiveness of sewage treatment, and to assess the potential
      contamination of surface water with these viruses. In this paper a method is
      described which identifies RNA phages quantitatively by a plaque hybridization
      assay. Oligonucleotide probes were developed that can assign phages to their
      phylogenetic subgroups. Such a distinction is important, since some subgroups
      preferentially occur in sewage of human origin, while others tend to be
      associated with animal wastewater. The method has been tested on a large number
      of isolates and represents an improvement in time and reliability over the
      previously used serological classification.

PMID- 8642016
TI  - Effect of pre- and post-heat shock temperature on the persistence of
      thermotolerance and heat shock-induced proteins in Listeria monocytogenes.
AB  - The effect of incubation temperature, before and after a heat shock, on
      thermotolerance of Listeria monocytogenes at 58 degrees C was investigated.
      Exposing cells grown at 10 degrees C and 30 degrees C to a heat shock resulted in
      similar rises in thermotolerance while the increase was significantly higher when
      cells were grown at 4 degrees C prior to the heat shock. Cells held at 4 degrees
      C and 10 degrees C after heat shock maintained heat shock-induced thermotolerance
      for longer than cells held at 30 degrees C. The growth temperature prior to
      inactivation had negligible effect on the persistence of heat shock-induced
      thermotolerance. Concurrent with measurements of thermotolerance were
      measurements of the levels of heat shock-induced proteins. Major proteins showing
      increased synthesis upon the heat shock had approximate molecular weights of 84,
      74, 63, 25 and 19 kDa. There was little correlation between the loss of
      thermotolerance after the heat shock and the levels of these proteins.
      Thermotolerance of heat shocked and non-heat shocked cells was described by
      traditional log-linear kinetics and a model describing a sigmoidal death curve
      (logistic model). Employing log-linear kinetics resulted in a poor fit to a major
      part of the data whereas a good fit was achieved by the use of a logistic model.

PMID- 8642015
TI  - Effects of substrates and phosphate on INT (2-(4-iodophenyl)-3-(4-nitrophenyl)-5
      phenyl tetrazolium chloride) and CTC (5-cyano-2,3-ditolyl tetrazolium chloride)
      reduction in Escherichia coli.
AB  - The effects of substrates of primary aerobic dehydrogenases, and inorganic
      phosphate on aerobic INT and CTC reduction in Escherichia coli were examined. In
      general, INT produced less formazan than CTC, but INT (+) cell counts remained
      near values of CTC (+) cells. INT and CTC (+) cell numbers were higher than plate
      counts on R2A medium using succinate, formate, lactate, casamino acids, glucose,
      glycerol (INT only) and no substrate. Formate resulted in the greatest amount of
      INT and CTC formazan. Reduction of both INT and CTC was inhibited above 10 mmol l
      1 phosphate, and this appeared to be related to decreased rates of O2
      consumption. Formation of fluorescent CTC (+), but not INT (+) cells was also
      inhibited in a concentration dependent manner by phosphate above 10 mmol l-1.
      From light microscopic observations it appeared CTC formed increasing amounts of
      poorly or non-fluorescent formazan with increasing phosphate. Therefore, use of
      phosphate buffer in excess of 10 mmol l-1 may not be appropriate in CTC and INT
      reduction assays.

PMID- 8642017
TI  - Comparison of chemical dehydration and critical point drying for the
      stabilization and visualization of aging biofilm present on interior surfaces of
      PVC distribution pipe.
AB  - In this study, fixation of attached glycocalyx on the interior surfaces of
      polyvinyl chloride distribution pipe remnants was compared with and without
      ruthenium red/osmium tetroxide and, in the final preparatory phase, with chemical
      dehydration and critical point drying. SEM examination of interior surface of the
      polyvinyl chloride pipe showed varying concentrations of adherent bacteria,
      depending on the preparatory technique used. It was concluded that using a
      combination of ruthenium red/osmium tetroxide and critical point drying is the
      optimum method for visually demonstrating aging biofilm on the interior surface
      of contaminated polyvinyl chloride pipe.

PMID- 8642018
TI  - Biopsy: complicated and risky.

PMID- 8642019
TI  - Diagnostic accuracy and charge-savings of outpatient core needle biopsy compared
      with open biopsy of musculoskeletal tumors.
AB  - We performed a prospective study of sixty-two patients who were managed with a
      closed core needle biopsy in an outpatient clinic for a soft-tissue mass or a
      bone tumor with soft-tissue extension between August 1, 1992, and June 1, 1994.
      Eight (13 percent) of the closed core needle biopsies yielded no neoplastic
      tissue. Two needle biopsies (3 percent), which were of myxomatous masses, did not
      allow distinction between a benign and a malignant neoplasm; both masses were
      extraskeletal myxoid chondrosarcomas. Additionally, the histological grade of
      four resected specimens (6 percent) differed from that determined with the closed
      needle biopsy. The diagnostic accuracy of the closed needle biopsies was 84
      percent (fifty-two of sixty-two). All ten diagnostic errors involved soft-tissue
      tumors. A retrospective study of a similar cohort of patients who had open biopsy
      in an outpatient operating room by the same surgeon in a contemporary period in
      the same institution and with analysis by the same pathologist, revealed a
      diagnostic accuracy of 96 percent (forty-eight of fifty). The hospital charges
      for the closed core needle biopsy were $1106, compared with $7234 for the open
      biopsy. We concluded that core needle biopsy can be performed in an outpatient
      clinic with use of local anesthesia and that it is substantially less expensive
      and more convenient than open biopsy. This technique has an acceptable but
      definitely lower rate of accuracy compared with open biopsy, especially for soft
      tissue tumors, and it should be used only in a small subset of patients (those
      who have a large soft-tissue mass or a bone tumor with palpable soft-tissue
      extension). However, given the small size of the tissue sample, the clinician
      must recognize possible disadvantages, including a non-diagnostic biopsy, an
      indeterminate biopsy, or a potential error in the histological grade. These
      problems are much more likely to occur after core needle biopsy of soft-tissue
      masses. Because of the potential for errors in diagnosis when core needle biopsy
      is used, the musculoskeletal oncologist must rely on his or her clinical acumen.
      When a diagnosis is in reasonable doubt, there is no radiographic confirmation,
      the biopsy shows no tumor cells, or there is a combination of these findings,
      operative decisions should be made as if no biopsy had been performed. The
      management of patients who, after core needle biopsy, have a diagnosis of a bone
      or soft-tissue tumor, is best carried out by an experienced musculoskeletal
      oncologist working in close collaboration with an experienced musculoskeletal
      pathologist.

PMID- 8642020
TI  - Residual disease following unplanned excision of soft-tissue sarcoma of an
      extremity.
AB  - Sixty-five patients who had been referred to our unit for additional management
      after an unplanned excision of a soft-tissue sarcoma of an extremity at another
      institution were studied retrospectively to determine the prevalence of residual
      tumor and to identify factors that predict which patients will have a tumor
      following such an excision. Unplanned excision was defined as excisional biopsy
      or unplanned resection of the lesion without benefit of preoperative imaging and
      without regard for the necessity to resect the lesion with a margin of normal
      tissue. In each patient, histological evaluation of the specimen removed at the
      unplanned excision had demonstrated positive resection margins, but postoperative
      physical examination on our unit revealed no gross evidence of residual tumor and
      no tumor was identified on cross-sectional imaging of the local site. Patients
      who had evidence of residual disease on physical examination or on imaging were
      thought to have definite evidence of sarcoma at the site of the operative wound
      and were therefore excluded from the study. After multidisciplinary consultation,
      all patients had a repeat resection at our cancer center. Extensive pathological
      sampling of the specimen from this second procedure was carried out, with
      sections obtained at mean intervals of 1.2 +/- 0.7 centimeters. Nodules initially
      thought to indicate disease were identified grossly in twenty-seven (42 percent)
      of the sixty-five patients, but histological evaluation confirmed the presence of
      tumor in only sixteen (59 percent). Histological evidence of sarcoma was
      identified in seven additional patients in whom gross nodules were not apparent
      in the specimen. Thus, sarcoma was identified in a total of twenty-three (35
      percent) of the sixty-five patients. The mean duration of follow-up was forty-six
      months (range, twenty-four to eighty months; median, thirty-nine months). The
      margins of the second resection were positive in nine (39 percent) of the twenty
      three patients who had residual sarcoma. Five (22 percent) of the twenty-three
      had a local recurrence. Four of the five patients who had a local recurrence had
      positive margins on repeat resection. This rate of local recurrence (five of
      twenty-three patients) was significantly higher than that in the remainder of our
      patients who had a soft-tissue sarcoma of an extremity (sixteen [7 percent] of
      227) (p = 0.03). There was no association between the detection of sarcoma at the
      second procedure and the initial size or grade of the tumor, the use of
      irradiation preoperatively, or the interval between the initial, unplanned
      excision and referral to our cancer center. These data indicate that it is not
      possible to predict which patients will have residual tumor at the site of the
      operative wound. Therefore, it is prudent to advise repeat excision for all
      patients who have had an unplanned excision of a soft-tissue sarcoma of an
      extremity. Unplanned excision complicates decision-making in the treatment of
      this disease and should be avoided.

PMID- 8642021
TI  - The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor
      Society.
AB  - In 1982, members of the Musculoskeletal Tumor Society, representing sixteen
      centers for the treatment of bone and soft-tissue cancer, compiled data regarding
      the hazards associated with 329 biopsies of primary malignant musculoskeletal
      sarcomas. The investigation showed troubling rates of error in diagnosis and
      technique, which resulted in complications and also adversely affected the care
      of the patients. These data were quite different when the biopsy had been carried
      out in a treatment center rather than in a referring institution. On the basis of
      these observations, the Society made a series of recommendations about the
      technical aspects of the biopsy and stated that, whenever possible, the procedure
      should be done in a treatment center rather than in a referring institution. In
      1992, the Musculoskeletal Tumor Society decided to perform a similar study to
      determine whether the rates of complications, errors, and deleterious effects
      related to biopsy had changed. Twenty-five surgeons from twenty-one institutions
      submitted the cases of 597 patients. The results were essentially the same as
      those in the earlier study. The rate of diagnostic error for the total series (in
      which cases from referring institutions and treatment centers were combined) was
      17.8 percent. There was no significant difference in the rate of patients for
      whom a problem with the biopsy forced the surgeon to carry out a different and
      often more complex operation or to use adjunctive irradiation or chemotherapy
      (19.3 percent in the current study, compared with 18 percent in the previous
      one). There was also no significant differences in the percentage of patients who
      had a change in the outcome, such as the need for a more complex resection that
      resulted in disability, loss of function, local recurrence, or death,
      attributable to problems related to the biopsy (10.1 percent in the current
      study, compared with 8.5 percent in the 1982 study). Eighteen patients in the
      current study had an unnecessary amputation as a result of the biopsy, compared
      with fifteen in the previous study. Errors, complications, and changes in the
      course and outcome were two to twelve times greater (p < 0.001) when the biopsy
      was done in a referring institution instead of in a treatment center.

PMID- 8642022
TI  - Dislocation of hip in myelomeningocele. The McKay hip stabilization.
AB  - We reviewed the clinical and radiographic results of varus osteotomy of the
      proximal aspect of the femur and transfer of the adductor and external oblique
      muscles (the McKay procedure) in thirty-four children (sixty-six hips) who had an
      unstable hip secondary to a myelomeningocele at the middle or caudad lumbar
      level. the average age at the time of the operation was twenty months (range,
      seven to forty-two months). The average duration of follow-up was 10.9 years
      (range, 0.7 to 20.0 years). An open reduction was performed in ten hips. None of
      the children had had any previous operative treatment. The index operation helped
      to maintain the stability of thirty-seven of the fifty-one hips twenty-six
      children who remained neurologically stable: seventeen of nineteen hips that were
      at risk, two of three hips with acetabular dysplasia, fifteen of sixteen
      subluxated hips, one of three dislocated hips that had been previously reduced
      with a Pavlik harness, one of two dislocatable hips, and one of seven previously
      untreated dislocated hips. The index operation was not successful for one
      dislocated hip that had been treated with closed reduction and application of a
      spica cast. The operation was a success for eight of the fifteen hips in eight
      children who had a progressive loss of neurological function: three of five hips
      that were at risk, one hip with acetabular dysplasia, two of four subluxated
      hips, one of two that had been previously reduced with a Pavlik harness, and one
      dislocatable hip. Two dislocated hips redislocated. Initially the index operation
      was performed on all children who had a myelomeningocele at the third or fourth
      lumbar level. Recent data have shown that the hips in these children are not all
      at risk, and we now perform the operation only if there is documented instability
      of the hip.

PMID- 8642023
TI  - Longitudinal deficiency of the fibula. Operative treatment.
AB  - We reviewed the results of early amputation and prosthetic fitting in twenty-five
      children (thirty-one extremities) who had longitudinal deficiency of the fibula
      and were managed between 1977 and 1992. The median age at the time of the initial
      operation was thirteen months (range, eight months to nine years and eight
      months). The median duration of follow-up was eight years and ten months (range,
      two years and six months to sixteen years and eleven months). A Syme amputation
      was performed on fifteen extremities (thirteen children), and a modified Boyd
      amputation (which included resection of the distal tibial physis) was performed
      on sixteen extremities (thirteen children). (One child had a Syme amputation on
      one side and a Boyd amputation on the other and is thus included in both groups).
      In twenty-seven extremities, simultaneous excision of the fibular anlage was
      performed to prevent the development of a deformity secondary to the potential
      tethering effect. In twelve extremities, a diaphyseal osteotomy of the tibia also
      was performed to correct tibial bowing and to improve the mechanical alignment of
      the extremity. At the time of follow-up, the patients who had had a Syme
      amputation had more problems related to reformation of the calcaneus, instability
      of the heel pad, prosthetic suspension, and excessive length of the residual
      extremity. The modified Boyd amputation improved the function of the heel pad and
      the prosthetic suspension and provided the optimum length of the residual
      extremity. We also found that an early diaphyseal osteotomy of the tibia to
      correct severe bowing improved prosthetic fitting. This study did not support the
      concept that early resection of the fibular anlage or a diaphyseal osteotomy of
      the tibia prevents the development of hypoplasia of the lateral femoral condyle
      and associated genu valgum deformity.

PMID- 8642024
TI  - Congenital hip disease in adults. Classification of acetabular deficiencies and
      operative treatment with acetabuloplasty combined with total hip arthroplasty.
AB  - We describe three distinct types of congenital hip disease in adults. The first
      type is dysplasia, in which the femoral head is contained within the original
      true acetabulum. The second type is low dislocation, in which the femoral head
      articulates with a false acetabulum, the inferior lip of which contacts or
      overlaps the superior lip of the true acetabulum, giving the appearance of two
      overlapping acetabula. The third type is high dislocation, in which the femoral
      head has migrated superoposteriorly and there is no contact between the true and
      the false acetabulum. We describe and classify the acetabular abnormalities and
      deficiencies found with these three types. If the anterior, posterior, and
      superior aspects of the acetabular component cannot be covered during a total hip
      arthroplasty because of a deficient acetabulum in an adult who has congenital hip
      disease, we advocate and acetabuloplasty technique (which we have named a
      cotyloplasty) that involves medial advancement of the acetabular floor by the
      creation of a controlled comminuted fracture of its medial wall, autogenous bone
      grafting, and the implantation of a small acetabular component with cement. This
      procedure was performed in sixty-six patients (eighty-six hips). Forty-nine of
      the hips had a high dislocation, thirty-one had a low dislocation, and six were
      dysplastic. Two to fifteen years (mean, seven years) after the operation, the
      clinical and radiographic results were satisfactory. Only two acetabular
      components needed to be revised for aseptic loosening, at 5.3 and 7.5 years
      postoperatively. Moreover, the cumulative success rate for the acetabular
      components was 100 percent at five years and 93.2 percent at ten years.

PMID- 8642025
TI  - Revision of the acetabular component of a total hip arthroplasty with a massive
      structural allograft. Study with a minimum five-year follow-up.
AB  - The results of the placement of a massive structural acetabular allograft in
      conjunction with a revision total hip arthroplasty in thirty-two patients (thirty
      tree hips) were evaluated at a minimum of five years. The graft supported more
      than 50 percent of the cup in all of the patients. The goals of a revision
      operation in a hip that has massive loss of bone are to provide support for the
      cup, to approximate the normal anatomy, to restore the length of the lower limb,
      and to restore bone stock should a future revision be necessary. Clinical and
      radiographic review at an average of seven years (range, five to eleven years)
      after the revision revealed that eighteen hips had needed no additional
      operation, seven hips had needed a repeat revision but the structural allograft
      was intact and had been used to support the cup at the repeat revision, and eight
      hips had had failure of both the prosthesis and the allograft. The result was
      considered a clinical and radiographic success when the hip score had increased
      at least 20 points, the cup was stable, the allograft had united, and no
      additional operation was necessary. According to these criteria, the rate of
      success was 55 percent (eighteen of thirty-three hips.) The only factor that was
      found to be clinically important with respect to outcome was the method of
      reconstruction. Seven of the eight hips that had been reconstructed with use of a
      roof-reinforcement ring and a structural allograft had a successful result at an
      average of 7.5 years (range, five to eleven years). The findings of the present
      study support the use of a structural allograft in the presence of massive loss
      of bone in order to achieve the goals of a revision hip replacement. Because of
      the high rate of success with acetabular reinforcement rings, we now use this
      method of reconstruction whenever a massive allograft is employed on the
      acetabular side.

PMID- 8642026
TI  - Primary total hip replacement with insertion of an acetabular component without
      cement and a femoral component with cement. Follow-up study at an average of six
      years.
AB  - We performed a retrospective study of a consecutive series of patients who had
      had a primary total hip replacement with so-called hybrid fixation of the
      components (an acetabular component inserted without cement and a femoral
      component inserted with cement) between September 1985 and June 1989. Clinical
      data were available for 114 patients (125 hips), of whom 110 (121 hips) also had
      radiographic data. The minimum duration of follow-up was fifty-six months or
      until revision, and the average duration was seventy-two months. The average
      Harris hip score improved from 47 points preoperatively to 91 points
      postoperatively (for the 109 patients who did not have subsequent revision of the
      femoral component). Only three patients who did not have a revision had more than
      slight pain in the hip. Four hips (3 percent) were revised for aseptic loosening
      of the femoral component at an average of fifty-five months; two of these four
      had a fracture of the femoral component. One patient had resection arthroplasty
      for late infection. One patient had disassembly of an acetabular polyethylene
      liner, and another had dissociation of a modular femoral head; both patients had
      a reoperation. Radiographically, two femoral components were definitely loose, as
      determined by subsidence of the component in one patient and a fracture of the
      cement in the other. Ten hips (8 percent) had endosteal lysis of the femur. Over
      all, 5 percent (six) of 121 femoral components were either revised for loosening
      or had definite radiographic evidence of loosening, but no acetabular component
      was loose. The clinical results in the 104 patients (115 hips) for whom clinical
      and radiographic data were available were excellent at the time of intermediate
      follow-up. Since few hips had progressive radiolucent lines about the acetabular
      of femoral component, we are optimistic that the long-term results will also be
      satisfactory.

PMID- 8642027
TI  - Patient outcomes after reoperation on the lumbar spine.
AB  - A consecutive series of thirty-nine patients who had had a reoperation of the
      lumbar spine was followed up for an average of forty-eight months (range, twenty
      four to eighty-six months). The patients were evaluated with regard to pain,
      functional status, and work status. Twenty-eight patients (72 percent) had a
      successful outcome, as determined by their ability to return to work, their lack
      of a need for narcotic analgesics, and their satisfaction with the operative
      results. Factors that were significantly associated with a successful outcome
      included a younger age (p < 0.02), working outside the home (p < 0.05), an
      initial period of improvement after the previous (index) operation (p < 0.01),
      fewer spinal levels operated on previously (p < 0.05), and a revision procedure
      incorporating anterior interbody arthrodesis (p < 0.02).

PMID- 8642028
TI  - Repair of a pseudarthrosis of the lumbar spine. A functional outcome study.
AB  - Eighty-six patients had a total of eighty-eight primary attempts at repair of a
      pseudarthrosis that had developed after a localized arthrodesis in the lumbar
      spine. A follow-up questionnaire was sent to all patients at a mean of fifty-one
      months (range, twenty-five to seventy-eight months) after the operation; seventy
      two patients (84 percent) completed to questionnaire. A solid fusion was
      ultimately achieved after the treatment of eighty-one (94 percent) of the eighty
      six pseudarthroses for which radiographic data were available. With the numbers
      available, we could find no significant association between a solid fusion and
      the patient's age, gender, body-mass index, return to work, or outcome score.
      Despite the high rate of fusion after the index repair and subsequent procedures,
      only nineteen (26 percent) of the seventy-two patients who completed the
      questionnaire eventually had a good or excellent outcome. Seven (10 percent) had
      an excellent result (90 to 100 points), twelve (17 percent) had a good result (70
      to 89 points), fourteen (19 percent) had a fair result (50 to 69 points), and
      thirty-nine (54 percent) had a poor result (less than 50 points). Nevertheless,
      fifty-one patients (71 percent) reported that the operation led to some
      improvement, and fifty-five (76 percent) said that they would have the operation
      again if the circumstances were similar to those before the repair of the
      pseudarthrosis. Thirty-four of the seventy-two patients were smokers and thirty
      eight were non-smokers at the time of the operation. There was a negative linear
      association between the outcome scores and the number of pack-years (p = 0.02).
      Cessation of smoking before the operation positively affected the outcome; the
      patients who had stopped smoking had a mean outcome score of 65 points, compared
      with 45 points for those who had not stopped (p = 0.03). Patients who had stopped
      smoking were also more likely to return to work full time (p < 0.001). At the
      latest follow-up evaluation, twenty of the seventy-two patients had returned to
      full-time employment. Patients who had been receiving Workers' Compensation at
      the time of the operation generally did poorly on the outcome questionnaire, but,
      with the numbers available, they did not have a significantly different rate of
      solid fusion than patients who had not been receiving Workers' Compensation.
      Also, the outcome score and the rate of fusion were nor significantly affected by
      age or by obesity.

PMID- 8642029
TI  - Repair of partial-thickness defects in articular cartilage: cell recruitment from
      the synovial membrane.
AB  - Partial-thickness defects evolving in mature articular cartilage do not heal
      spontaneously. This type of defect was created in the articular cartilage of
      adult rabbits and Yucatan minipigs, and the effects of chondroitinase ABC or
      trypsin, fibrin clots, and mitogenic growth factors on the healing process were
      examined histologically at intervals ranging from one to forty-eight weeks. The
      effect of chondroitinase ABC or trypsin was examined initially. Articular
      cartilage contains macromolecules, including proteoglycans, which render the
      surfaces of this tissue, and of partial-thickness defects within it,
      antiadhesive. Chondroitinase ABC digests the glycosaminoglycan chains of
      cartilage proteoglycans, and trypsin degrades their core proteins. To test the
      hypothesis that mesenchymal cells may be prevented from adhering to and migrating
      over the surfaces of partial-thickness defects by proteoglycans, we removed a
      superficial layer of these macromolecules from the surface of the defect with use
      of one of these enzymes. The treatment evoked an increase in the coverage of the
      defect surface with mesenchymal cells; when combined with the local application
      of a mitogenic growth factor (basic fibroblast growth factor, transforming growth
      factor-beta 1, epidermal growth factor, insulin-like growth factor-1, or growth
      hormone), the coverage was more extensive but mesenchymal cells did not extend
      into and completely fill the volume of the defect. When the surface of the defect
      was treated with chondroitinase ABC and the cavity of the defect was filled with
      a fibrin clot to furnish a matrix or scaffolding for the migration of cells
      therein, there was migration and proliferation of cells throughout the volume of
      the defect but at a low population density. Mesenchymal cells remodeled the
      deposited fibrin matrix, which was replaced by a loose fibrous connective tissue.
      When defects that had been treated with chondroitinase ABC were filled with a
      fibrin clot containing a mitogenic growth factor, mesenchymal cells filled the
      entire cavity of the defect, and the density of the cells was greatly increased,
      particularly when transforming growth factor-beta 1 was used. Histological
      studies revealed a continuous layer of mesenchymal cells extending from the
      synovial membrane across the superficial tangential zone of normal articular
      cartilage into the defect, indicating that the cells that were recruited for the
      repair process were of synovial origin. At forty-eight weeks, the entire cavity
      of the defect remained filled with a fibrous connective tissue.

PMID- 8642030
TI  - Intra-articular injection of bupivacaine in knee-replacement operations. Results
      of use for analgesia and for preemptive blockade.
AB  - The effectiveness of an intra-articular injection of bupivacaine, administered
      before the incision or after closure of the wound, was studied in an effort to
      decrease the need for postoperative narcotics and to improve analgesia for
      patients who have elective knee replacement. Eighty-two patients received two
      intra-articular injections in a random, double blind fashion. Twenty-eight of
      them received thirty milliliters of 0.5 percent bupivacaine and 1:200,000
      epinephrine in saline solution before the incision and an injection of thirty
      milliliters of plain saline solution after closure of the wound (Group 1). Twenty
      seven patients received an injection of thirty milliliters of plain saline
      solution before the incision and thirty milliliters of 0.5 percent bupivacaine
      and 1:200,000 epinephrine in saline solution after closure of the wound (Group
      2). Twenty-seven patients were given thirty milliliters of plain saline solution
      (a placebo) for both injections (Group 3). The patients who had received
      bupivacaine after closure of the wound (Group 2) used less morphine from the
      patient-controlled analgesia pumps than the patients who had received bupivacaine
      before the incision (Group 1) and the patients who had received the placebo
      (Group 3). In the first twenty-four hours after the operation, the administration
      of morphine (mean and standard deviation) was 59 +/- 27 milligrams for Group 2
      compared with 68 +/- 30 milligrams for Group 1 (p = 0.26) and 81 +/- 30
      milligrams for Group 3 (p = 0.006). At the time of discharge from the hospital,
      the patients in Group 2 also had a significantly greater mean range of motion
      (85.2 +/- 8.0 degrees) compared with that of the patients in Groups 1 (80.6 +/-
      6.8 degrees, p = 0.02) and 3 (80.1 +/- 6.2 degrees, p = 0.009). However, there
      was no difference among the groups with respect to the effectiveness of the
      analgesia, as measured with use of either the visual-analog or the verbal pain
      rating scale, or in the prevalence of side effects, including somnolence, urinary
      retention, nausea and vomiting, or pruritus. Serum concentrations of bupivacaine
      were well below toxic levels. It was our conclusion that that and intra-articular
      injection of thirty milliliters of 0.5 percent bupivacaine and 1:200,000
      epinephrine in saline solution after closure of the wound decreases the need for
      narcotics and increases the range of motion after an elective knee replacement.
      The clinical importance of the amount of increased motion is questionable and
      needs long-term monitoring.

PMID- 8642031
TI  - A comparison of early and late reconstruction of malunited fractures of the
      distal end of the radius.
AB  - We retrospectively evaluated the results for ten patients in whom a malaligned
      fracture of the distal end of the radius had been treated with early
      reconstruction (an average of eight weeks [range, six to fourteen weeks] after
      the injury) consisting of an osteotomy through the site of the fracture,
      autogenous cancellous iliac-crest bone-grafting, and internal fixation. The
      results for these patients were compared with those for ten patients in whom
      functional limitation after complete healing of a fracture of the distal end of
      the radius in a malreduced position had been treated with late reconstruction (an
      average of forty weeks [range, thirty to forty-eight weeks] after the injury)
      consisting of an osteotomy, corticocancellous bone-grafting, and internal
      fixation. The average duration of follow-up was forty-eight months (range, twenty
      to 120 months) after the early reconstructions and thirty-four months (range,
      twenty-four to forty-eight months) after the late reconstructions. After the
      early reconstructions, flexion of the wrist averaged 45 degrees; extension of the
      wrist, 52 degrees; pronation of the forearm, 79 degrees; and supination of the
      forearm,77 degrees, compared with 42, 45, 77, and 68 degrees, respectively, after
      the late reconstructions. Grip strength averaged forty-two kilograms after the
      early reconstructions, compared with twenty-five kilograms after the late ones.
      One patient from each cohort had mild pain in the radiocarpal joint. According to
      the scale of Fernandez, there were seven excellent and three good results after
      the early reconstructions, and one excellent, seven good, and two fair results
      after the late reconstructions. Complications included a rupture of the extensor
      pollicis longus tendon twelve weeks after one of the early reconstructions,
      persistent pain at the donor site of the iliac-crest bone graft after a late
      reconstruction, and a delayed union that necessitated a second procedure after
      another late reconstruction. We believe that the results of early and late
      reconstruction of malunited fractures of the distal end of the radius are
      comparable. For patients who have radiographic characteristics that are
      predictive of persistent functional limitation, early reconstruction is
      technically easier and reduces the over-all period of disability.

PMID- 8642032
TI  - Aspiration of the hip joint before revision total hip arthroplasty. Clinical and
      laboratory factors influencing attainment of a positive culture.
AB  - The value of routine aspiration of the hip joint before revision of a hip
      arthroplasty remains controversial. We reviewed the results of such aspirations
      in an attempt to determine clinical or laboratory factors that could help the
      surgeon to identify hips that are infected and that should be aspirated
      preoperatively. One hundred and fifty consecutive revision total hip
      arthroplasties were performed by one of us. Preoperative aspiration was not
      performed or data were excluded for eight hips; no fluid was obtained from one of
      these hips (0.7 percent of the 150). Of the remaining 142 hips, 128 had
      preoperative aspiration once and fourteen, twice. Twenty-one (15 percent) of the
      142 hips were infected, as demonstrated by the intraoperative culture. The
      intraoperative culture for two of these hips, however, was considered to be false
      positive. The initial aspiration was considered to be positive only if an
      organism grew on the solid medium or if grossly purulent fluid was obtained. The
      initial aspiration was positive for nineteen hips; on culture of specimens from
      one hip, Bacteroides thetaiotaomicron grew in the liquid medium only; and
      purulent fluid was obtained from one hip but no organisms grew on culture.
      Fourteen aspirations were repeated for various reasons, most commonly to confirm
      the presence of an unusual organism. The repeat aspiration did not change the
      diagnosis for these hips. When the two hips with a false-positive intraoperative
      culture were excluded, preoperative aspiration had a sensitivity of 92 percent, a
      specificity of 97 percent, and an accuracy of 96 percent. Seventeen of the
      nineteen truly infected hips were associated with an abnormally elevated
      erythrocyte-sedimentation rate (mean, 80.8 millimeters per hour). However, fifty
      eight (50 percent) of the 116 hips that were not infected, and for which the
      results were available, also had an abnormally elevated erythrocyte-sedimentation
      rate (mean, 32.0 millimeters per hour). This difference was significant (p =
      0.001, Fischer exact test). The peripheral leukocyte count was not helpful in
      predicting infection. Hips in which the implants had been in situ for more than
      five years were less likely to be infected (p = 0.008, Fisher exact test) than
      those in which the implants had been in situ for five years or less. None of the
      infected hips in which the implants had been in situ for more than five years
      were associated with a normal erythrocyte-sedimentation rate. In this study,
      preoperative aspiration of the hip joint had an excellent sensitivity and
      specificity with regard to the prediction of infection, On the basis of our
      findings, we now favor a selective approach to aspiration, as determined by the
      erythrocyte sedimentation rate and the amount of time that the implant has been
      in situ.

PMID- 8642033
TI  - The porous-coated anatomic total hip prosthesis: failure of the metal-backed
      acetabular component.
AB  - One hundred and ninety-nine total hip arthroplasties were performed, between 1983
      and 1987, in 173 patients by three surgeons using the initial design of the
      porous-coated anatomic prosthesis. The acetabular component was a preassembled,
      metal-backed polyethylene device, with beads sintered to the metal backing to
      allow bone ingrowth and two pegs for initial fixation. Twenty-three acetabular
      components (12 percent) failed because of either migration or severe osteolysis.
      The radiographic appearance of osteolysis was positively associated with the
      duration that the implant had been in situ (p < 0.001). The prevalence of
      osteolysis was also significantly greater in acetabular components with an outer
      diameter of fifty-five millimeters or less (a polyethylene thickness of 8.5
      millimeters or less) (p = 0.03). Thirteen hips were revised at a mean of 69.5
      months (range, thirty-three to ninety-one months) after the index operation.
      Examination of the retrieved acetabular components revealed extensive
      polyethylene damage on the articular and back surfaces of the liners. Cracks in
      the polyethylene rim of the liner and deformation of the anti-rotation notch in
      the polyethylene rim were common findings. The density of the polyethylene was
      greater than expected, and more particles than anticipated had not fused with the
      surrounding polyethylene. The results of this study suggest that factors related
      to both the design and the material contributed to the failure of these porous
      coated anatomic acetabular components.

PMID- 8642034
TI  - Adult-onset mitochondrial myopathy coexistent with lumbar disc disease. A case
      report.

PMID- 8642035
TI  - Ureteral injury associated with anterior lumbosacral arthrodesis in a patient who
      had crossed renal ectopia, malrotation, and fusion of the kidneys. A case report.

PMID- 8642036
TI  - Bilateral primary cystic arthrosis of the acetabulum. A case report.

PMID- 8642037
TI  - Tissue ingrowth and differentiation in the bone-harvest chamber in the presence
      of cobalt-chromium-alloy and high-density-polyethylene particles.

PMID- 8642038
TI  - Avascular necrosis of the capital femoral epiphysis after intramedullary nailing
      for a fracture of the femoral shaft. A case report.

PMID- 8642039
TI  - Autogenous bone grafts from the femoral head for the treatment of acetabular
      deficiency in primary total hip arthroplasty with cement, long-term results.

PMID- 8642040
TI  - 125 years of European-Japanese cooperation in the field of medicine with emphasis
      on Japanese-German cancer research.

PMID- 8642042
TI  - Autocrine growth stimulation of SW403 colon carcinoma cell line is caused by
      transforming-growth-factor-alpha-mediated epidermal growth factor receptor
      activation.
AB  - Results of recent studies indicate that some cultured human carcinoma cell lines
      are capable of proliferating autonomously in serum-free medium as a result of the
      synthesis and secretion of transforming growth factor alpha (TGF alpha). TGF
      alpha interacts with epidermal growth factor receptor (EGFR) and induces its
      activation. In an attempt to extend these observations, we evaluated TGF alpha
      mediated autonomous growth and constitutive EGFR activation in the human
      adenocarcinoma cell line SW403. The cell line shows synthesis of EGF receptors
      and TGF alpha but not EGF, and exhibits constitutive phosphorylation of the 170
      kDa EGFR. Use of blocking anti-EGFR monoclonal antibodies (mAb) inhibits
      autonomous growth of SW403 cells and leads to a significant reduction of receptor
      phosphorylation. The inhibitory effect of the blocking anti-EGFR mAb is
      reversible upon addition of TGF alpha. In contrast, autonomous proliferation of
      SW403 cells is not inhibited by addition of neutralizing anti-EGF mAb. Our
      findings suggest that the proliferation of cells of the human SW403
      adenocarcinoma cell line is regulated by an autocrine TGF alpha loop and that
      this regulatory pathway can be interrupted by using anti-EGFR mAb.

PMID- 8642041
TI  - Lessons from the p53 mutant mouse.
AB  - The use of the mouse as a model organism in cancer research has a long and
      productive history, from the earliest studies of chemical carcinogenesis to the
      recent advances in gene targeting. Many of the basic principles of tumorigenesis
      have been formed in whole or in part through the study of tumor development in
      the mouse. Over the past decade, the major experimental approach has been to
      generate cancer-prone strains, either through transgenic technologies or, more
      recently, gene targeting. Here, I will review the state of the field of gene
      targeting of tumor-suppressor genes and concentrate on the p53 mutant strains and
      the lessons learned from the p53 mutant mouse.

PMID- 8642044
TI  - Hyperthermia, radiation carcinogenesis and the protective potential of vitamin A
      and N-acetylcysteine.
AB  - The in vivo carcinogenic risk of hyperthermia, alone or in combination with
      irradiation, and the anti-carcinogenic potential of vitamin A and N
      acetylcysteine (AcCys) were investigated. Starting 1 month before treatment, 160
      rats were divided into four diet groups: no additives, vitamin A-enriched diet,
      AcCys and the combination vitamin A + AcCys. In 10 animals per diet group, the
      hind leg was treated with either X-irradiation alone (16 Gy), hyperthermia alone
      (60 min at 43 degrees C), hyperthermia 5 h prior to irradiation or hyperthermia 5
      h after irradiation. Animals were observed for 2 years after treatment with
      regard to the development of tumours either inside or outside the treated volume.
      After 16 Gy alone 12 +/- 5% of the animals developed a tumour. Tumour incidence
      increased to 37 +/- 9% (borderline significance P = 0.07 versus treatment with X
      rays alone) when hyperthermia was applied prior to X-rays, and to 24 +/- 8% (NS)
      with hyperthermia after irradiation. The relative risk ratio (RRR) for tumour
      induction was increased to 2.4 by hyperthermia if combined with X-irradiation.
      Pathological characterization of induced tumours showed that these were of the
      fibrosarcoma, osteosarcoma and carcinoma type. Vitamin A alone or in combination
      with AcCys slightly protected against the induction of tumours by X-rays without
      or with hyperthermia (RRR of 0.4). However, morphological changes such as lipid
      accumulation in hepatocytes and damage to the parenchyma were noticed in livers
      from all animals that were given a vitamin-A-enriched diet (P < 0.0001). Data
      from the present and past reports show that hyperthermia alone is not
      carcinogenic, but that it may increase radiation carcinogenesis. Treatment
      temperature and time of exposure to heat in addition to the radiation dose
      applied are important factors in the carcinogenic process. The enhancement of
      radiation carcinogenesis seems to occur independently of the sequence and time
      interval between irradiation and hyperthermia. However, not all data are
      consistent with this interpretation.

PMID- 8642043
TI  - Suppression of the proliferation and migration of oncogenic ras-dependent cell
      lines, cultured in a three-dimensional collagen matrix, by flavonoid-structured
      molecules.
AB  - The effects of 7-hydroxycoumarin, genistein and quercetin on two ras-oncogene
      driven tumour cells (rat breast adenocarcinoma and human bladder carcinoma) were
      investigated using cellular (proliferation and migration) and molecular targets
      (p21ras GTPase activity and intracellular amount of p21ras protein). All three
      compounds inhibited the growth of both cell lines. Genistein was the most
      effective substance. Furthermore, 7-hydroxycoumarin and genistein affected the
      motile machinery of both cell lines because major fractions of the cells were
      slowed down or stopped locomotion. The phorbol ester, phorbol 12-myristate 13
      acetate (PMA), a well-known tumour promoter, increased the locomotion behaviour
      of the cells; the time of migration, the velocity and the distance of migration
      increased under the control of PMA. 7-Hydroxycoumarin decreased the relative
      amount of intracellular p21ras, and concomitantly a PMA-induced decrease of
      p21ras GTPase activity could be partially antagonized by 7-hydroxycoumarin.
      Because of the low toxicity and the mode of action evaluated, it is likely that
      the best role for these substances may be adjuvant therapy of some malignancies
      following surgery. Profiles directed to migration and proliferation inhibition
      make these drugs exceptional candidates for chemopreventive strategies in tumours
      diagnosed as having increased ras oncogene levels.

PMID- 8642045
TI  - Immunohistochemical study of metallothionein in pancreatic carcinomas.
AB  - Metallothioneins are a family of intracellular metalloproteins that have been
      thought to be involved in anticancer drug resistance. However, the role of
      metallothioneins in pancreatic cancer has not been investigated in detail. The
      immunohistochemical localization of metallothionein was examined in normal human
      adult pancreas tissue and in 75 pancreatic duct cell carcinomas, using monoclonal
      anti-metallothionein antibody. Furthermore, in vitro studies on the sensitivity
      of pancreatic cancer to cisplatin were performed in 10 cases of pancreatic
      carcinoma. Metallothionein staining was weakly positive in the acinar and islet
      cells and intralobular ducts but was negative in the large pancreatic ducts. In
      pancreatic carcinomas, metallothionein staining was diffusely positive in 6 (8%),
      focally positive in 25 (33%) and negative in 44 (59%) of the 75 pancreatic
      carcinomas. The expression of metallothioneins in pancreatic tumors was related
      to metastasis, poor prognosis and poor histological grading (poorer glandular
      differentiation and nuclear anaplasia). The in vitro study of tumor sensitivity
      to cisplatin showed no significant correlation between metallothionein expression
      and resistance to cisplatin. Metallothionein-positive pancreatic carcinoma will
      be potentially highly malignant or acquire an enhanced ability to produce
      metallothioneins as the malignant potential increases. The expression of
      metallothionein could be a prognostic indicator in pancreatic carcinomas.

PMID- 8642046
TI  - Expression of vitamin D receptor in lung cancer.
AB  - The active metabolite of vitamin D 1,25-dihydroxycholecalciferol is a hormone
      like agent that regulates cell differentiation and proliferation. Various vitamin
      D derivatives have been shown to induce differentiation in neoplastic cells. The
      prerequisite for any hormone action is the presence of its receptor. We studied
      the expression of vitamin D receptor in human lung cancer cell lines and in
      primary lung cancer tissue. Employing the polymerase chain reaction, 10 out of 11
      cell lines stemming from small-cell lung cancer and 15 out of 15 cell lines
      stemming from non-small-cell lung cancer demonstrated vitamin D receptor
      expression. An immunohistochemical analysis, using a specific monoclonal
      antibody, demonstrated vitamin D receptor protein expression in 31 out of 117
      (26%) primary small-cell lung cancer cases tested. Positive cells exhibited a
      nuclear reaction pattern. Twenty-one out of 37 primary non-small-cell lung cancer
      cases, particularly adenocarcinomas (9/14) and squamous-cell carcinomas (10/15),
      exhibited vitamin D receptor. Results indicate that a subset of lung cancer cases
      may be susceptible to the differentiating effects of vitamin D analogues.

PMID- 8642047
TI  - The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in
      gastric and colorectal cancers.
AB  - We previously reported that introduction of the wild-type p53 gene into human
      cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy
      [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could
      be a potent determinant of the therapeutic efficacy of DNA-damaging cancer
      therapy. We analyzed 24 patients with gastric or colorectal cancer for p53
      mutations and apoptotic changes in surgical specimens. Out of 11 patients with
      gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of
      13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53
      mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of
      colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA
      damaging therapies increased the number of apoptotic cells in wild-type-p53
      expressing tumors; tumors with mutant p53, however, significantly showed fewer
      apoptotic cells compared with those expressing wild-type p53. The p53-inducible
      WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing
      tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1.
      Taken together, we conclude that p53 mutations are associated with the poor
      response of chemotherapy and radiotherapy.

PMID- 8642048
TI  - Circulating intercellular adhesion molecule 1 predicts non-specific elevation of
      alpha 1-fetoprotein.
AB  - Molecules governing cellular interactions have been suggested to be involved in
      the spurious elevation of alpha 1-fetoprotein (AFP) in non-neoplastic liver
      disease. To explore this controversial issue, we measured AFP, circulating
      intercellular adhesion molecule 1 (cICAM-1), and common liver function tests in
      111 patients (71 male, 40 female). Eighty-four patients had non-neoplastic
      chronic liver disease and 27 had hepatocellular carcinoma. The concentration of
      cICAM-1 was determined immunoenzymatically. In patients with non-neoplastic
      chronic liver disease, univariate analysis demonstrated a significant correlation
      between AFP and cholinesterase (R = -0.397, P < 0.001), aspartate
      aminotransferase (R = 0.421, P < 0.001), bilirubin (R = 0.231, P < 0.05) and
      cICAM-1 (R = 0.430, P < 0.001). Multivariate analysis among these variables and
      AFP indicated cICAM-1 to be the strongest independent predictor of AFP. We
      conclude that cICAM-1 compares favourably with liver function tests in predicting
      non-specific AFP variations in non-neoplastic chronic liver disease, suggesting a
      link between targeting of the inflammatory damage to the hepatocyte and
      development of neoplasia.

PMID- 8642049
TI  - Clinical implications of cytogenetic classification in adult acute lymphoblastic
      leukaemia patients.
AB  - Cytogenetic analysis performed on pretreated unstimulated, bone marrow/peripheral
      blood samples of 46 adult patients with acute lymphoblastic leukaemia (ALL)
      showed sufficient metaphases in 39 patients and insufficient metaphases in 7
      patients. G-banded karyotype analysis of these 39 patients revealed non-random
      clonal chromosome abnormalities in 31 patients and apparently normal karyotypes
      in 8 patients. Numerical abnormalities involving chromosome trisomies and
      structural abnormalities involving different types of chromosomal translocations
      and deletions were encountered in varying percentages. These patients were
      grouped into various cytogenetic subsets on the basis of their karyotype pattern
      and followed-up to evaluate their prognosis. Patients with apparently normal
      karyotypes showed good prognosis and those with 6q- showed intermediate
      prognosis. But all other patients with hyperdiploid, pseudodiploid and
      hypodiploid karyotypes were associated with poor prognosis. Cytogenetic
      classification of ALL patients is thus of clinical importance, as it helps the
      early identification of clinically important prognostic groups.

PMID- 8642050
TI  - International symposium on control mechanisms of carcinogenesis. September 1995,
      Mainz, Germany.

PMID- 8642051
TI  - The effect of dam strain on the craniofacial morphogenesis of CL/Fr mouse
      fetuses.
AB  - The embryo transfer technique and cephalometry were used to investigate the
      effect of dam strain in intrauterine craniofacial growth and the severity of
      cleft lip and palate (CLP) in a CLP-susceptible CL/Fr strain of embryos. The
      CL/Fr strain of embryos at early blastocyst stage was transferred to the same dam
      strain and to the CLP-resistant C57BL dam strain. On the 18th gestational day,
      each dam was laparotomized to take out the fetuses. The spontaneous incidence of
      CLP in the fetuses was checked and a cephalometric observation of the
      craniofacial complex of each fetus was done just after laparotomy. The
      dorsoventral craniofacial size of the unaffected fetuses and the severity of CLP
      i the affected ones were compared between both dam strains. The following results
      were obtained: 1) The overall craniofacial sizes of the unaffected fetuses
      observed in the CL/Fr dam strain were significantly smaller than those seen in
      the C57/BL dam strain. Those of the affected fetuses observed in the CL/Fr dam
      strain were smaller than those seen in the C57BL dam strain although the
      interstrain difference was not significant. 20 The dam strain had a highly
      significant effect on the craniofacial size of the unaffected fetuses. 3) The CLP
      frequency in the CL/Fr dam strain was significantly higher than that in the C57BL
      dam strain. 4) The severity of CLP in the affected fetuses observed in the CL/Fr
      dam strain was significantly more serious than that seen in the C57BL dam strain.
      These results indicated that the CLP-susceptible CL/Fr dam strain retarded the
      intrauterine craniofacial growth of the fetuses and that the cleft condition in
      the affected fetuses observed in the CL/Fr dam strain was more seriously affected
      than that seen in the CLP-resistant C57BL dam strain. Thus, it can be concluded
      that the effect of the dam strain played an important role in the craniofacial
      morphogenesis of the CL/Fr strain of mouse fetuses that developed from the embryo
      transferred to the CL/Fr and C57BL dam strains along with the genotype of
      embryos.

PMID- 8642052
TI  - Growth allometry of the mandibles of giant transgenic mice: an analysis based on
      the finite-element scaling method.
AB  - Transgenic mice genetically engineered to produce increased levels of growth
      hormones, accelerated somatic growth, and larger terminal sizes [Palmiter et al.,
      1982, 1983] offer an intriguing model with which to investigate the genetic and
      developmental control of skeletal proportions. In this study, form differences in
      the mandible between giant transgenic mice (MT-rGH) and their normal litter-mate
      controls are examined using data generated by finite-element scaling analysis
      (FESA). Finite-element scaling analysis is a tensor based method developed to
      study morphological differences between forms. The method uses landmark data to
      provide measures of size and shape differences local to those landmarks of
      mandibular size and shape differences for 18 landmarks were compared between the
      two mouse samples. Bivariate and multivariate analyses were completed to
      ascertain 1) whether the mandible of larger transgenic mice differed
      significantly from normal controls, and 2) if observed proportion change resulted
      from the general allometric affects of overall mandibular size increase.
      Comparisons of local size and shape differences against a measure of total size
      difference reveal similar trajectories of growth allometry, indicating that
      proportion differences between adult control and transgenic mice result from
      ontogenic scaling.

PMID- 8642053
TI  - The strain effect of dam on intrauterine incisal growth in mouse fetuses.
AB  - The embryo transfer technique was carried out to examine the strain effect of
      dams on the intrauterine incisal growth of mouse fetuses. A mean of nine DDD/Qdj
      embryos was transferred to each female recipient of the four strains (DDD/Qdj,
      C3H/Qdjl C57BL/Qdj, and DBA/IJ Sea). The dam's weight, the litter size, the
      gestation period and the newborn offspring weight were recorded. The mandibular
      incisal size of the newborn offspring was measured two-dimensionally by means of
      an image analyzing system. Statistical analyses of the incisal size of the
      DDD/Qdj newborn offspring delivered from the four strains of recipients showed
      the following results: 1) There were significant interstrain differences in the
      dam's weight and the newborn offspring weight, but not in the litter size and the
      gestation period among the four strains of recipients. 2) There was an inverse
      relation between the litter size and the mandibular incisal size while there were
      direct relations between the dam's weight and the mandibular incisal size, and
      between the newborn offspring weight and the mandibular incisal size. 3) There
      was a significant strain effect of the dam on the mandibular incisal size of the
      newborn offspring. 4) After eliminating the effects of the litter size, the
      gestation period, and the newborn offspring weight on the mandibular incisal size
      of the DDD/Qdj newborn offspring developed in the four strains of dams, a
      significant interstrain difference in the adjusted mandibular incisal size was
      found (C3H/Qdj > DBA/IJ Sea > C57BL/Qdj > DDD/Qdj), suggesting that the uteri of
      the C3H/Qdj strain of dams provided a more suitable environment for the
      intrauterine incisal growth than those of the other three strains of dams. Thus,
      it is concluded that the strain effect of dam played an important role in the
      intrauterine incisal growth of mouse fetuses.

PMID- 8642054
TI  - Effects of caffeine and nicotine administration on growth and ossification of the
      ICR mouse fetus.
AB  - The objective of this study was to determine how fetal effects are altered when
      nicotine (N) and caffeine (CA) are administered concurrently at dosages that
      individually produce minimal effects to the fetus. Female ICR mice were bred
      overnight and were assigned to four groups: CA (125 mg/kg), N (12mg/kg), CA plus
      N (125 mg/kg plus 12 mg/kg, respectively) treated, and control (distilled water)
      groups. Dams were intubated with these dosages three times daily during
      gestational days (GD) 6-18 and were euthanized on GD 18. Live fetuses were sexed,
      weighed, and examined for external malformations. One-half of the fetuses were
      fixed in 10% formalin and examined for internal malformations using Wilson's
      method. The remaining half was fixed in 95% ethanol (ETOH), stained, and cleared
      (Inouye's method) for skeletal examinations. Ossification was assessed by staging
      and measuring craniofacial bones, and counting ossification centra in sternbrae
      and in cervical and sacrococcygeal vertebrae. Data were analyzed by analysis of
      variance (ANOVA) followed by Student-Newman-Keuls post-hoc tests set at p < .05
      significance level. The litter was used as the unit of measure and the ANOVA main
      effects were CA, N, and an interaction term (CA+N). In comparison to controls, CA
      treatment resulted in reduced bone measurements or reduced ossification scores in
      5 of the 19 parameters examined, whereas for N only five parameters were
      significant. The main effects for interaction of CA+N were significant for seven
      parameters measured. Although it is difficult to assign the specific type of drug
      interaction that occurred because results were not completely consistent for all
      parameters measured, it may be concluded that in most parameters measured both CA
      and CA+N were different from controls, but CA was not different from CA+N. Under
      the experimental conditions of this study, we found that of the two drugs,
      caffeine had a significantly greater effect on fetal growth and ossification than
      nicotine.

PMID- 8642055
TI  - The adenohypophysis and the cranial base in early human development.
AB  - The purpose of the present study is to chart the normal human development of the
      adenohypophyseal part of the pituitary gland and of the cranial base, with
      special attention given to the possible presence of pharyngeal remnants of
      adenohypophyseal tissue. From 31 human embryos and fetuses (7-21 weeks of
      gestation) midsagittal, paraffin-embedded tissue blocks of the cranial base,
      including the pituitary gland and the pharyngeal wall, were investigated
      histologically. The identification of adenohypophyseal tissue included
      immunohistochemical methods. In early stages, the adenohypophysis of the
      pituitary gland. From this stage in development adenohypophyseal tissue is not
      demonstrated pharyngeally. The cartilaginous cranial base is visible in its full
      antero-posterior extent before ossification starts. Cranio-pharyngeal canals are
      not registered in the cranial base. This study intends to define a standard for
      subsequent autopsy descriptions of the pituitary gland region in craniofacial
      malformations.

PMID- 8642056
TI  - Craniofacial morphology as a marker of predisposition to isolated cleft palate.
AB  - The etiology and pathogenesis of isolated cleft palate (CP) is largely unknown.
      Undoubtedly, bot genetic and environmental factors play a role in initiating this
      malformation. Although the predictions of the multifactorial threshold model have
      never been satisfied when subjected to statistical analysis, there is no a priori
      reason to dismiss the possibility that multiple genes may be segregating in CP
      families that give rise to specific and predictive phenotypes in the parents of
      CP offspring. We examined a sample composed of 52 parent pairs whose children
      were born with CP, as well as 75 normal controls with no family history of CP.
      Using anthropometric and roentgencephalometric methods, along with discriminant
      function analysis, we searched for craniofacial variables predictive of parents
      who were ?at risk? for CP offspring. For fathers of CP children, 32 of the
      studied variables differed significantly from controls; for mothers of CP
      children 25 variables differed significantly from controls. These results support
      the hypothesis that there are characteristic morphometric signs in the
      craniofacies of the parents of children with CP. To confirm these findings, it
      will be necessary to prospectively ascertain the incidence of CP in the offspring
      of ?at risk? parents and ?not at risk? parents from families with and without a
      history of CP in other family members.

PMID- 8642057
TI  - Deficient and delayed primary palatal fusion and mesenchymal bridge formation in
      cleft lip-liable strains of mice.
AB  - During mammalian primary palate formation, the facial prominences enlarge around
      the nasal pit, fuse and then merge to give rise to the tissue of the upper lip
      and premaxillary region. The mechanisms involved in successful primary palate
      formation and how they are affected in the cleft lip genotype remain poorly
      understood. The purpose of this study was to compare morphometrically internal
      development and growth of the primary palate in five different strains of mice.
      Two of the strains, BALB/cByJ, and C57BL/6J, have normal primary palate
      development, and three of the strains, A/J, A/WySn, and CL/Fr, have stable
      frequencies of cleft lip associated with genotype. In the present study,
      frequencies of 4, 23, and 24%, respectively, were observed on day 13. For palatal
      growth analysis, embryos were collected on days 10 and 11, staged by number of
      tail somites (TS), and the heads were photographed and serially sectioned for
      measurement of primary palate components. The heights of the epithelial seam and
      the mesenchyme bridge between the facial prominences were measured on serial
      sections and areas of contact were calculated. The position or depth of the
      maxillary prominence was determined from the number of frontal sections from its
      tip to the rostral end of the nasal fin. Analysis of measurements showed that in
      cleft lip strains enlargement of the epithelial seam and replacement of epithelia
      by a mesenchymal bridge were both delayed relative to somite stages. Measurements
      from day 11 embryos with complete failure of contact were excluded from the
      growth analyses. The mesenchymal bridge formed at 12--13 TS in noncleft strains,
      14 TS in the A/J strains with higher cleft lip frequency, and 15--17 TS in A/WySn
      and CL/Fr strains with higher cleft lip frequency. Forward growth of the
      maxillary prominence was highly correlated with the primary palate measurements
      and mesenchymal bridge formation in all strains. In both cleft and noncleft
      strains, the primitive choanae open at 18--20 TS and the medial nasal region
      narrows with advancing embryonic development. As a result, cleft lip-liable
      strains have a narrower window in development in which a robust mesenchymal
      bridge must form, thus increasing the liability to cleft lip.

PMID- 8642058
TI  - Selective induction of cytokines in mouse brain infected with canine distemper
      virus: structural, cellular and temporal expression.
AB  - We have previously shown that, in experimentally inoculated mice, canine
      distemper virus (CDV), a neurotropic virus, selectively infects certain brain
      structures (hypothalamus, hippocampus, monoaminergic nuclei, etc). Here we
      demonstrate that tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and
      IL-6 transcripts are selectively expressed in these CDV-targeted structures,
      except in the dentate gyrus, where cytokines are induced without prior CDV
      replication. The time-course of TNF-alpha expression vs. viral replication in the
      hypothalamus was different from that in hippocampus. In addition, we show that a
      substantial number of neurons express TNF-alpha and IL-6. These findings provide
      new insights into the possible participation of cytokines in the neurological
      disorders triggered by CDV infection.

PMID- 8642059
TI  - A monoclonal autoantibody which promotes central nervous system remyelination is
      highly polyreactive to multiple known and novel antigens.
AB  - A monoclonal antibody (mAb), designated SCH94.03, which promotes central nervous
      system remyelination in susceptible mice infected with Theiler's virus, has been
      proposed to be a natural autoantibody based on its germline immunoglobulin
      sequence. To identify the potential antigens recognized by mAb SCH94.03, a rat
      brain lambda gtll cDNA expression library was screened with this antibody. Nine
      independent clones were identified. Five clones were identical or highly similar
      to known cDNAs or proteins (rat kinesin light chain, mouse thrombospondin 1,
      mouse oncofetal antigen, RNA polymerase beta subunit and nuclear phosphoprotein).
      Four clones, designated REM#1, REM#2, REM#3 and REM#4, contained open reading
      frames, but were not homologous to any known genes or proteins. The reactivity of
      SCH94.03 with all nine clones was specific in that all nine clones identified
      contained continuous open reading frames and none of nine control IgM mAbs showed
      reactivity with any of the nine cDNA clones. The precise specificity of binding
      of mAb SCH94.03 was demonstrated by the absence of reactivity to the identified
      clones with IgM Ab from B cell lymphoma (CH12) which has identical cDNA sequences
      with mAb SCH94.03, but differ only in the heavy chain CDR3 N region. Our studies
      support the hypothesis that highly polyreactive natural autoantibodies can play a
      role in promoting central nervous system remyelination.

PMID- 8642060
TI  - Regulation of human B lymphocyte activation by opioid peptide hormones.
      Inhibition of IgG production by opioid receptor class (mu-, kappa-, and delta-)
      selective agonists.
AB  - Opioid peptides have been reported by many laboratories to modulate in vitro and
      in vivo cell-mediated and humoral immune responses. However, less attention has
      been afforded to the class or classes of opioid receptors involved in these
      immunomodulatory effects. Previous studies by this laboratory indicated that beta
      endorphin and methionine-enkephalin were potent inhibitors of Staphylococcus
      aureus, Cowen strain I (SAC)-induced IgG production by human B lymphocytes.
      Results obtained from the present studies indicate that, at pharmacological
      concentrations, mu-, delta-, and kappa-receptor-selective agonists are potent
      inhibitors of SAC-induced IgG-secreting cells (IgG-ISC) by human B lymphocytes.
      Moreover, the suppression of IgG-ISC formation was reversed by mu-, delta-, and
      kappa-receptor class-selective antagonists, [D'Tic]cTAP, ICI 174,864, and nor
      BNI, respectively. These findings are in agreement with other studies showing
      that more than one class of receptors are involved in opioid peptide-mediated
      immunoregulation. Additional studies indicated that all three class-selective
      receptor agonists were found to suppress SAC-induced IL-6 production in intact
      PBMC cultures. As observed for suppression of IgG-ISC formation, inhibition of IL
      6 production was found to be reversed by the appropriate receptor class-selective
      antagonist. These results support the hypothesis that one mechanism of opioid
      peptide-mediated inhibition of antibody production is via the down regulation of
      cytokine synthesis.

PMID- 8642061
TI  - Opposing effects of CTLA4-Ig and anti-CD80 (B7-1) plus anti-CD86 (B7-2) on
      experimental allergic encephalomyelitis.
AB  - The roles of the B7 receptors, CD80 and CD86, during actively induced
      experimental allergic encephalomyelitis were examined with specific monoclonal
      antibodies and CTLA4-Ig. Injection of CTLA4-Ig on day 2 post-immunization
      resulted in decreased incidence and severity of resultant disease. Anti-CD80
      injection on day 2 blocked development of the first disease episode. Subsequent
      relapses were unaffected. In contrast, injection of anti-CD86 alone had no
      effect. Surprisingly, combined anti-CD80 + anti-CD86 monoclonal antibody
      injection on day 2 resulted in marked exacerbation of disease. Examination of
      cytokine production in the draining lymph node cells demonstrated a reduction in
      both interferon (IFN)-gamma and interleukin (IL)-2 producing cells, but a
      dramatic increase in tumor necrosis factor (TNF)-alpha secretion in animals
      receiving both monoclonal antibodies. These results suggest distinct roles for
      CD80 and CD86 in the initiation of EAE, resulting in the diverse clinical
      outcomes observed in this model of EAE.

PMID- 8642062
TI  - Effects of cyclosporin treatment on prolactin pulsatility in chronic
      hyperprolactinemic male rats.
AB  - Neuroendocrine effects of cyclosporin (CsA) have been demonstrated, but the
      mechanisms involved are poorly understood. This work was designed to analyse (i)
      if chronic CsA administration could influence the episodic secretion of prolactin
      in adult male rats; and (ii) the effects of the chronic administration of the
      drug, in adult animals with elevated plasma prolactin levels. Male rats were
      implanted with one anterior pituitary gland under the kidney capsule or were sham
      operated, at 30 days of age. Both pituitary-grafted and sham-operated rats were
      injected subcutaneously with vehicle or CsA (5 micrograms/kg/day) for 9 days
      beginning at the 60th day of age. In pituitary-grafted male rats, mean prolactin
      levels, absolute prolactin pulse amplitude and mean half-life of the hormone
      increased, while the pulse frequency and relative amplitude of the peaks
      decreased, as compared with sham-operated rats. CsA administration to sham
      operated rats decreased the relative pulse amplitude of prolactin but increased
      the mean half-life of the hormone, the pulse duration and the mean hormone
      levels, as compared with rats of the same group treated with vehicle. However,
      CsA treatment to pituitary-grafted rats decreased mean prolactin levels and the
      absolute amplitude of its peaks and increased the relative amplitude of its
      pulses, whereas all the other parameters showed no change. When considering
      circulating values of prolactin in plasma from the trunk blood, CsA
      administration was followed by changes similar to those described when mean
      values of the serial samples were considered. These data suggest the existence of
      an interrelationship between elevated circulating prolactin levels and CsA, which
      probably takes place at the hypothalamic level, to regulate the pulsatile pattern
      of prolactin secretion in male rats, although a direct effect of the drug on the
      ectopic gland in pituitary-grafted male rats cannot be excluded.

PMID- 8642063
TI  - Characterisation of a functional polyamine site on rat mast cells: association
      with a NMDA receptor macrocomplex.
AB  - Polyamines can modulate activation of N-methyl-D-aspartate (NMDA) receptors by
      binding to a specific polyamine site associated with a NMDA receptor
      macrocomplex. Polyamines induce histamine release from mast cells, although the
      mechanism had not been defined. We have examined whether spermine, a natural
      polyamine, and compound 48/80, regarded as a synthetic polyamine, activate mast
      cells by a polyamine site associated with a NMDA receptor macrocomplex. Spermine
      induced secretion of histamine from rat peritoneal mast cells and rat brain mast
      cells in a concentration-dependent manner. Rat peritoneal mast cells were used as
      a model system to explore the effects of NMDA antagonists on polyamine-induced
      histamine release. Ifenprodil, MK801 and arcaine inhibited histamine secretion
      from mast cells exposed to polyamines; the percentage inhibition was greater
      against spermine than compound 48/80. These data support the proposal that
      spermine (and possibly compound 48/80) induce histamine release from mast cells
      by interacting with a specific polyamine site on a NMDA receptor complex.

PMID- 8642064
TI  - Identification of a mitogen-activated protein kinase site in human myelin basic
      protein in situ.
AB  - Ultrastructural localization of a specific phosphorylated isomer of myelin basic
      protein (MBP) has been achieved with a monoclonal antibody specific for human MBP
      sequence, 89-105, in which Thr98 was phosphorylated. Cryosections of human brain
      white matter revealed that gold particles were found localized almost exclusively
      to the major dense line demonstrating that threonine 98 in the sequence Thr-Pro
      Arg-Thr-Pro-Pro-Pro, a mitogen-activated protein kinase-specific site, was
      phosphorylated in vivo. In two cases of multiple sclerosis, the density of gold
      particles in myelin was reduced by about 30%, in one case by 42%, and by 80% in a
      fourth case. However, gold labelling was seen in areas of demyelination
      suggesting that the phosphorylated threonyl peptide was protected from
      degradation.

PMID- 8642065
TI  - Circulating L-selectin in multiple sclerosis patients with active, gadolinium
      enhancing brain plaques.
AB  - Leukocyte migration into inflammatory lesions is controlled by adhesion
      molecules. L-selectin is the adhesion molecule on leukocytes that is responsible
      for making the initial contact with endothelium. After establishing this contact,
      L-selectin is shed from the cell surface and present in the circulation as a
      functional soluble receptor. To investigate this initial adhesive event, we
      evaluated the presence of soluble L-selectin (sL-selectin) in serum and CSF of
      patients with multiple sclerosis (MS), viral encephalitis, and controls. MS
      patients with active, gadolinium-enhancing lesions on magnetic resonance imaging
      had significantly higher sL-selectin serum levels than controls (P < 0.05). These
      levels in MS patients correlated with the size of the enhancing lesions (P <
      0.05), and with sL-selectin levels in CSF (P < 0.001). In viral encephalitis, in
      contrast, sL-selectin is elevated in CSF only (P < 0.001) and may derive from
      intrathecal leukocytes. These results show that the earliest adhesive events
      mediated by L-selectin indeed operate in active MS, and that sL-selectin will be
      of value in quantitating the extent of this inflammatory process.

PMID- 8642066
TI  - Human microglia activate lymphoproliferative responses to recall viral antigens.
AB  - The capacity of adult human microglia to activate memory T-lymphocyte responses
      to recall viral antigens in autologous peripheral blood lymphocytes (PBL) was
      examined using measles and influenza viruses. Microglia and peripheral blood
      macrophages were isolated form 6 patients who underwent surgical brain biopsies.
      Microglial cultures readily expressed high levels of HLA class II molecules under
      basal culture conditions. However, compared to macrophages, microglia appeared to
      express much lower levels of CD45, a phenotype that has been associated with the
      ability of rat brain macrophage/microglia to present antigen. PBL were depleted
      of macrophages (D-PBL) and the efficacy of the depletion was assessed by a
      reduction in the T-cell response to concanavalin A. D-PBL were reconstituted with
      macrophages, microglia, or in some cases microglia pretreated with interferon
      gamma (IFN gamma). It was observed that microglia were as efficient as
      macrophages in presenting viral antigens. Pretreatment of microglia with IFN
      gamma did not enhance further antigen presentation. Oligodendrocytes which lack
      constitutive or inducible HLA class II molecules failed to present viral
      antigens. The results have implications of the direct function of microglia as
      perpetuators and possibly initiators of immune responses to virus infection in
      the central nervous system compartment.

PMID- 8642067
TI  - Circulating antibodies directed against conjugated fatty acids in sera of
      patients with multiple sclerosis.
AB  - Using an adapted ELISA assay, we have tested sera from multiple sclerosis (MS)
      patients for antibodies directed against ten fatty acids conjugated to bovine
      serum albumin. In serum samples from 68 MS patients and 20 patients suffering
      from rheumatoid arthritis (RA), a significant antibody titer elevation to the ten
      tested fatty acids was found when compared to sera of 40 healthy subjects and 82
      patients with other neurological and autoimmune diseases. G-200 purified IgM of
      MS patients reacted specifically with the aliphatic chains with an avidity of 3 x
      10(-7) M. These results suggest that in MS and RA, autoepitopes on cell membranes
      that are normally hidden from the immune system become immunogenic. This may
      arise because of previous membrane disruption by oxidative processes.

PMID- 8642068
TI  - Overall pattern of callosal connections in visual cortex of normal and enucleated
      cats.
AB  - The effect of neonatal bilateral enucleation on the overall distribution of
      callosal connections in striate and extrastriate visual cortex of the cat was
      studied using tangential sections from the physically unfolded and flattened
      cortex. Callosal neurons were labeled by administering the anatomical tracer
      horseradish peroxidase directly to the transected corpus callosum. The pattern of
      callosal connections in binocularly enucleated cats showed both consistent
      differences and consistent similarities with the pattern in normal cats. In
      agreement with previous studies, it was found that callosal labeling at the 17/18
      border of enucleated cats was considerably sparser than in normal cats. Moreover,
      we found that the strip containing the majority of labeled cells at the 17/18
      border was narrower than in normal cats. In both normal and enucleated cats,
      scattered cells were distributed on either side of the 17/18 callosal strip, well
      into areas 17 and 18. In much of extrastriate cortex, the pattern of callosal
      connectivity in enucleated cats looked surprisingly normal. Details of the
      callosal pattern that were consistently found in normal cats could also be
      recognized in binocularly enucleated cats, such as two to four bridges of
      labeling spanning areas 18 and 19. Also, four zones that were free of callosal
      connectivity in area 7, on the banks of the suprasylvian sulcus, and in the
      posterior suprasylvian sulcus were found in both normal and enucleated cats.
      Finally, as in normal cats, dense cell labeling occurred on the crown of the
      suprasylvian gyrus at its posterior end, from which it extended laterally across
      both banks of the suprasylvian sulcus and into the fundus of this sulcus. The
      results of this study suggest that, although the stabilization of callosal
      connections at the 17/18 border region appears to depend on visual input, this
      input plays a less prominent role in the stabilization of callosal connections in
      extrastriate visual cortex.

PMID- 8642069
TI  - GABAergic neurons in the rat pontomesencephalic tegmentum: codistribution with
      cholinergic and other tegmental neurons projecting to the posterior lateral
      hypothalamus.
AB  - The present study was undertaken to determine the frequency and distribution of
      GABAergic neurons within the rat pontomesencephalic tegmentum and the
      relationship of GABAergic cells to cholinergic and other tegmental neurons
      projecting to the hypothalamus. In sections immunostained for glutamic acid
      decarboxylase (GAD), large numbers of small GAD-positive neurons (approximately
      50,000 cells) were distributed through the tegmentum and associated with a high
      density of GAD-positive varicosities surrounding both GAD-positive and GAD
      negative cells. Through the reticular formation, ventral tegmentum, raphe nuclei,
      and dorsal tegmentum, GAD-positive cells were codistributed with larger cells,
      which included neurons immunostained on adjacent sections for glutamate, tyrosine
      hydroxylase (TH), serotonin, or choline acetyltransferase (ChAT). In sections
      dual-immunostained for GAD and ChAT, GABAergic neurons were seen to be
      intermingled with less numerous cholinergic cells (approximately 2,600 GAD+ to
      approximately 1,400 ChAT+ cells in the laterodorsal tegmental nucleus, LDTg).
      Retrograde transport of cholera toxin (CT) was examined from the posterior
      lateral hypothalamus, where a major population of cortically projecting neurons
      are located. A small number of GABAergic cells were retrogradely labeled,
      representing a small percentage of all the GABAergic neurons (approximately 1%)
      and of all the hypothalamically projecting neurons (approximately 6%) in the
      tegmentum. The double-labeled GAD+/CT+ cells were commonly found ipsilaterally
      within 1) the deep mesencephalic reticular field, codistributed with putative
      glutamatergic projection neurons; 2) the ventral tegmental area, substantia nigra
      compacta, and retrorubral field, codistributed with dopaminergic projection
      neurons; 3) dorsal raphe, codistributed with serotonergic projection neurons; and
      4) laterodorsal and pedunculopontine tegmental nuclei, codistributed with and in
      similar proportion to cholinergic projection cells (20-30% in LDTg). Acting as
      both projection and local neurons, the pontomesencephalic GABAergic cells would
      have the capacity to modulate the influence of the "ascending reticular
      activating system" and its chemically specific constituents upon cortical
      activation.

PMID- 8642070
TI  - Anuran dorsal column nucleus: organization, immunohistochemical characterization,
      and fiber connections in Rana perezi and Xenopus laevis.
AB  - As part of a research program on the evolution of somatosensory systems in
      vertebrates, the dorsal column nucleus (DCN) was studied with
      (immuno)histochemical and tract-tracing techniques in anurans (the large green
      frog, Rana perezi, and the clawed toad, Xenopus laevis). The anuran DCN contains
      some nicotinamide adenine dinucleotide phosphate diaphorase-positive neurons,
      very little calbindin D-28k, and a distinct parvalbumin-positive cell population.
      The anuran DCN is innervated by primary and non-primary spinal afferents, by
      primary afferents from cranial nerves V, VII, IX, and X, by serotonin
      immunoreactive fibers, and by peptidergic fibers. Non-primary DCN afferents from
      the spinal cord appear to arise throughout the spinal cord, but particularly from
      the ipsilateral dorsal gray. The present study focused on the efferent
      connections of the DCN, in particular the targets of the medial lemniscus. The
      medial lemniscus could be traced throughout the brainstem and into the
      diencephalon. Along its course, the medial lemniscus gives off collaterals to
      various parts of the reticular formation, to the octavolateral area, and to the
      granular layer of the cerebellum. At mesencephalic levels, the medial lemniscus
      innervates the lateral part of the torus semicircularis as well as various
      tegmental nuclei. A striking difference between the two species studied is that
      while in R. perezi medial lemniscal fibers do not reach the tectum mesencephali,
      in X. laevis, intermediate and deep tectal layers are innervated. Beyond the
      midbrain, both dorsal and ventral thalamic areas are innervated by the medial
      lemniscus. The present study shows that the anuran "lemniscal pathway" is
      basically similar to that of amniotes.

PMID- 8642071
TI  - Structural and functional characterization of a muscle tendon proprioceptor in
      lobster.
AB  - A morphological and electrophysiological study was made on a unique primary
      mechanosensory neuron, the anterior gastric receptor (AGR), previously shown to
      arise from power-stroke muscle gm1 of the gastric mill system in the lobster
      foregut. Ultrastructural analysis of horseradish peroxidase injected AGR
      demonstrated that its peripheral dendrites do not ramify in muscle but are
      confined strictly to the connective tissue/epidermal interface in the tendon of
      gm1. These terminals are rich in mitochondria and at their very endings are free
      of glial cell wrapping, suggesting that they are the site at which mechano
      transduction occurs. Extracellular axonal recordings from an in vitro
      neuromuscular preparation consisting of the gm1 muscle still attached to the
      stomatogastric nervous system, revealed that AGR is activated by passive stretch
      of gm1. The response to ramp stimuli displays dynamic and static components, both
      of which increase with the amplitude of applied stretch, while the dynamic
      component is also velocity sensitive. AGR is also activated by muscle contraction
      here elicited either by application of exogenous acetylcholine, the excitatory
      neurotransmitter for gm1, or by electrical stimulation of the motoneurons (GM)
      themselves. Consistent with a receptor lying in-series with its muscle,
      therefore, the effective stimulus of AGR in vivo is probably an increase in
      tension exerted on the tendon during active muscle contraction. In neuromuscular
      preparations including the bilateral commissural ganglia, stretching gm1 reflexly
      activates GM motoneurons at low stimulus strengths but leads to an inactivation
      of GM motoneurons at high stimulus strengths. This is consistent with earlier
      findings that both responses can be elicited by direct electrical stimulation of
      AGR. The functional implications of AGR's anatomical relationship with muscle
      gm1, the receptor's response properties, and its central effects on motor output
      to gm1 are discussed. Comparison is also drawn between this first reported
      example of a true tendon receptor in invertebrates and muscle receptors of
      vertebrates.

PMID- 8642072
TI  - Cytoskeleton gradients in three dimensions during neurulation in the rabbit.
AB  - Morphogenetic movements leading to the formation of the neural tube and cellular
      differentiation leading to neuronal and glial cell lineages are both part of
      early development of the vertebrate nervous system. In order to analyze the
      degree of overlap between these processes, cellular differentiation during the
      shaping of the neural plate is investigated immunohistochemically by using
      monoclonal intermediate filament protein antibodies and the 7.5-8.0-day-old
      rabbit embryo as a model. Western blotting is used to confirm the specificity of
      the antibodies, which include a new monoclonal vimentin antibody suitable for
      double-labeling in combination with monoclonal cytokeratin (and fibronectin)
      antibodies. Starting in the early somite embryo and concomitant with neural plate
      folding, a gradual loss of cytokeratin 8 (and 18) expression in the
      neuroepithelium is mirrored by a gain in vimentin expression with partial
      coexpression of both proteins. At the prospective rhombencephalic and spino
      caudal levels, vimentin expression, in particular, changes (i.e., increases)
      along gradients in three dimensions: along the longitudinal axis of each
      neuroepithelial cell from basal to apical, in the transverse plane of the embryo
      from dorsolateral to ventromedial and along the craniocaudal axis from
      prospective rhombencephalic toward spino-caudal levels of the neural plate. At
      the prospective mes- and prosencephalic levels, the expression change also
      proceeds from basal to apical within each neuroepithelial cell, but along the
      other axes described here, the progress in expression change is more complex.
      Although the functional meaning of these highly ordered expression changes is at
      present unclear, the gradients suggest a novel pattern of neuroepithelial
      differentiation which may be functionally related to the process of interkinetic
      nuclear migration (Sauer [1935] J. Comp. Neurol. 62:377-402) and which partially
      coincides with the morphogenetic movements involved in the shaping of the neural
      plate.

PMID- 8642073
TI  - Axotomy induces a different modulation of both low-affinity nerve growth factor
      receptor and choline acetyltransferase between adult rat spinal and brainstem
      motoneurons.
AB  - Adult rat spinal and brainstem motoneurons re-express low-affinity nerve growth
      factor receptor (p75) after their axotomy. We have previously reported and
      quantified the time course of this reexpression in spinal motoneurons following
      several types of injuries of the sciatic nerve. Other studies reported the
      reexpression of p75 in axotomized brainstem motoneurons. Results of these
      previous studies differed regarding the type of the most effective triggering
      injury for p75 reexpression, the relative duration of this reexpression and the
      decrease of choline acetyltransferase (ChAT) immunoreactivity (-IR) following a
      permanent axotomy of spinal or brainstem motoneurons. These differences suggest
      that these two populations of motoneurons respond to axotomy with a different
      modulation of p75 and ChAT expression. The aim of the present study was to
      determine whether differential modulation exists. We have analyzed and quantified
      the presence of p75- and ChAT-IR motoneurons in the hypoglossal nucleus following
      the same types of injury and the same time course we previously used for sciatic
      motoneurons. The results show that a nerve crush is the most effective triggering
      injury for p75 and that it induces similar temporal patterns of p75 and ChAT
      expression for sciatic and hypoglossal motoneurons. In contrast, a cut injury of
      the sciatic and hypoglossal nerves resulted in distinct temporal courses of both
      p75 and ChAT expression between these two populations of motoneurons. In fact, a
      permanent axotomy of the hypoglossal motoneurons induced i) a much longer
      maintenance phase for p75 than in sciatic motoneurons and ii) a progressive loss
      of ChAT-IR with a successive return to normal values in contrast to the modest
      decrease in the sciatic motoneurons. This evidence indicates that spinal and
      brainstem motoneurons respond to a permanent axotomy with a different modulation
      of p75 and ChAT expression. Altogether, the present data and the reported
      evidence of a differential post-axotomy cell death support the hypothesis that
      these two populations of motoneurons undergo different dynamic changes after
      axotomy.

PMID- 8642074
TI  - Axon terminals immunolabeled for dopamine or tyrosine hydroxylase synapse on GABA
      immunoreactive dendrites in rat and monkey cortex.
AB  - Dopamine afferents to the cortex regulate the excitability of pyramidal neurons
      via a direct synaptic input. However, it has not been established whether
      dopamine also modulates pyramidal cell activity indirectly through synapses on
      gamma-aminobutyric acid (GABA) interneurons, and whether such inputs differ
      across cortical regions and species. We sought to address these issues by an
      immunocytochemical electron microscopic approach that combined peroxidase
      staining for dopamine or tyrosine hydroxylase (TH) with a pre-embedding gold
      silver marker for GABA. In the deep layers of the rat prefrontal cortex and in
      the superficial layers of the monkey prefrontal and primary motor cortices,
      terminal varicosities immunoreactive for dopamine or TH formed primarily thin,
      symmetric synapses on distal dendrites. Both GABA-immunoreactive dendrites as
      well as unlabeled spines and dendrites were contacted by dopamine- or TH
      immunoreactive terminals. Synaptic specializations were detected at some, but not
      all of these contacts. The relative frequency of these appositional and synaptic
      contacts did not appear to differ between the rat and monkey prefrontal cortex,
      or between the monkey prefrontal and motor cortices. Across regions and species,
      labeled and unlabeled targets of dopamine- or TH-positive terminals received
      additional synaptic input from unlabeled, and occasionally GABA-immunoreactive
      terminals. Close appositions between dopamine- or TH-immunoreactive and GABA
      positive terminals were observed only rarely. These findings indicate that
      dopamine afferents provide direct synaptic inputs to GABA local circuit neurons
      in a consistent fashion across cortical regions and species. Thus, dopamine's
      cellular actions involve direct as well as modulatory effects on both GABA
      interneurons and pyramidal projection neurons.

PMID- 8642075
TI  - In situ labeling of apoptotic cell death in the cerebral cortex and thalamus of
      rats during development.
AB  - Apoptosis is a form of naturally occurring cell death that plays a fundamental
      role during development and is characterized by internucleosomal DNA
      fragmentation. In this study we used specific in situ labeling of DNA breaks
      (Gavrieli et al. [1992] J. Cell. Biol. 119:493-501) to analyze the distribution
      of apoptotic cells in rat cerebral cortex and thalamus at different developmental
      stages from embryonic day 16 to adulthood. Control experiments and electron
      microscopy confirmed that the reaction product was confined to the nucleus of
      selected cells. Plotting and counting of labeled nuclei in counterstained
      paraffin sections showed that apoptosis occurred mainly during the first
      postnatal week and was absent in embryonic and adult samples. In the cortex, the
      number of apoptotic cells progressively increased from birth to the first
      postnatal week, with a peak between postnatal (P) day 5 and P8, and subsequently
      decreased. At the time of maximal expression of apoptosis, labeled nuclei were
      present mainly in layer VIb and underlying white matter and at the border between
      cortical plate and layer I. Only a few apoptotic cells were found scattered in
      the thalamus, without a particular concentration in selected areas, but with a
      peak at P5. Differences in the number of apoptotic cells between cortex and
      thalamus suggest that apoptotic cell death may have a different functional
      significance in the two brain areas.

PMID- 8642076
TI  - Morphogenesis of the photoreceptive site and development of the electrical
      responses in the butterfly genital photoreceptors during the pupal period.
AB  - This paper describes the process of morphogenesis of the photoreceptive site of
      the butterfly genital photoreceptors. Associated development of the electrical
      responses is also described. The photoreceptor is a sensory neuron whose cell
      body is located in the genitalia and has a photoreceptive site of the phaosome
      type. This consists of the distal processes and the tubular membranes, which
      protrude from the tip of distal processes. Phaosome morphogenesis was studied
      using electron microscopy. The results indicate that morphogenesis occurs in the
      latter half of the pupal period and that the process is divided into five phases.
      First, the tubular membranes appear as small membrane protrusions (phase I). The
      short tubular membranes emerge from several portions of the cell body forming
      several membrane clusters (phase II). The clusters then collect to form a small
      phaosome. Short distal processes become evident (phase III). The phaosome volume
      increases, mainly due to the extensive elongation and bifurcation of both tubular
      membranes and distal processes (phase IV). Phase V achieves final adult
      morphology. The photoreceptors of phase II are already able to produce spikes in
      response to light stimulation, although the sensitivity was about one tenth of
      the adult. The sensitivity increase occurred in parallel with the increase in the
      phaosome volume.

PMID- 8642077
TI  - Dependence of developing group Ia afferents on neurotrophin-3.
AB  - At birth, group Ia proprioceptive afferents and muscle spindles, whose formation
      is Ia afferent-dependent, are absent in mice carrying a deletion in the gene for
      neurotrophin-3 (NT-3-/-). Whether Ia afferents contact myotubes, resulting in the
      formation of spindles which subsequently degenerate, or whether Ia afferents and
      spindles never form was examined in NT-3-/- mice at embryonic days (E) 10.5-18.5
      by light and electron microscopy. Three sets of data indicate that Ia neurons do
      not develop and spindles do not form in NT-3-deficient mice. First, peripheral
      projections of Ia afferents did not innervate hindlimbs of NT-3-/- mice, as
      reflected by a deficiency of nerve fibers in limb peripheral nerves and an
      absence of afferent nerve-muscle contacts and spindles in the soleus muscle at
      E13.5-E18.5. Second, central projections of Ia afferents did not innervate the
      spinal cord in the absence of NT-3, as shown by an atrophy of the dorsal spinal
      roots and absence of afferent projections from limb musculature to spinal motor
      neurons at E13.5 or E15.5. Lastly, the lumbar dorsal root ganglia (DRGs) at E10.5
      E14.5, the stages of development that precede or coincide with the innervation of
      the spinal cord and hindlimbs by Ia afferents, were 20-64% smaller in mutant than
      in wild-type mice, presumably because the cell bodies of Ia neurons were absent
      in embryos lacking NT-3. The failure of Ia neurons to differentiate and/or
      survive and Ia afferent projections to form in early fetal mice lacking NT-3
      suggests that NT-3 may regulate neuronal numbers by mechanisms operating prior to
      neurite outgrowth to target innervation fields. Thus, developing Ia neurons may
      be dependent on NT-3 intrinsic to the DRGs before they reach a stage of potential
      dependence on NT-3 retrogradely derived from skeletal muscles or spinal motor
      neurons.

PMID- 8642078
TI  - Localization of alpha 7 nicotinic receptor subunit mRNA and alpha-bungarotoxin
      binding sites in developing mouse somatosensory thalamocortical system.
AB  - Previous studies in rat, showing a transient pattern of expression of the alpha 7
      nicotinic acetylcholine receptor in the ventrobasal thalamus and barrel cortex
      during the first 2 postnatal weeks, suggest that these receptors may play a role
      in development of the thalamocortical system. In the present study, in situ
      hybridization and radiolabeled ligand binding were employed to examine the
      spatiotemporal distribution of alpha 7 mRNA and alpha-bungarotoxin binding sites
      in the thalamocortical pathway of mouse during early postnatal development. As in
      the rat, high levels of alpha 7 mRNA and alpha-bungarotoxin binding sites are
      present in the barrel cortex of mouse during the first postnatal week. Both alpha
      7 mRNA and its receptor protein are observed in all cortical laminae, with the
      highest levels seen in the compact cortical plate, layer IV, and layer VI. When
      viewed in a tangential plane, alpha 7 mRNA and alpha-bungarotoxin binding sites
      delineate a whisker-related barrel pattern in layer IV by P3-5. Quantitative
      analysis reveals a dramatic decrease in the levels of expression of alpha 7 mRNA
      and alpha-bungarotoxin binding sites in the cortex by the end of the second
      postnatal week. Unlike in the rat, only low levels of alpha 7 mRNA or alpha
      bungarotoxin binding sites are present in the ventrobasal complex of the mouse
      thalamus. The broad similarities between the thalamocortical development of rat
      and mouse taken together with the present results suggest that alpha 7 receptors
      located on cortical neurons, rather than on thalamic neurons, play a role in
      mediating aspects of thalamocortical development.

PMID- 8642079
TI  - Anatomy of the antennal motoneurons in the brain of the honeybee (Apis
      mellifera).
AB  - This paper describes the morphology and location of the cerebral motoneurons that
      control the movement of the antennae in the honeybee. The position of each
      antenna is controlled by two muscle systems; the basal segment (scape) is moved
      by four muscles within the head capsule, and two muscles within the scape control
      the distal segments (flagellum) of the antenna. The motor system of the scape is
      controlled by nine motoneurons, and that of the flagellum by six motoneurons. All
      of these motoneurons share the dorsal lobe as a common projection area where
      their dendritic fields overlap extensively. These motoneurons do not have
      contralateral projections. The cell bodies of the antennal motoneurons are
      located in the soma layer lateral to the dorsal lobe. The somata for each muscle
      system are arranged in three clusters; two clusters are located in a region of
      the cortex dorsal to the dorsal lobe and one cluster is located in the cortex
      ventral to the dorsal lobe. In the cortex dorsal to the dorsal lobe, one cluster
      of each muscle system shares the same region. Altogether five groups of cell
      bodies can be distinguished. Double labeling of the motoneurons and presumptive
      mechanosensory primary antennal afferents with fluorescent dyes has shown that
      there is an extensive overlap of axonal projections of antennal mechanosensory
      afferents with dendritic fields of antennal motoneurons.

PMID- 8642080
TI  - Immunohistochemistry in diagnostic dermatopathology.
AB  - Immunopathology continues to be important in diagnostic dermatopathology.
      Immunopathology is an invaluable tool for assessing the tissue of origin or
      direction of differentiation of cells. In some cases this can result in a more
      precise diagnosis. This article reviews the role of immunopathology in
      determining the biologic behavior of hematolymphoid infiltrates. It explores the
      methodology of immunoperoxidase, discusses the most commonly used antibody
      reagents, and presents a series of diagnostic dilemmas in which immunopathology
      can be useful. In each case a strategy is established that maximizes the
      likelihood of making a definitive diagnosis.

PMID- 8642081
TI  - Effects of alpha-hydroxy acids on photoaged skin: a pilot clinical, histologic,
      and ultrastructural study.
AB  - BACKGROUND: alpha-Hydroxy acids (AHAs) have been reported to improve aging skin.
      The mechanisms of action of AHAs on epidermal and dermal compartments need
      clarification. OBJECTIVE: Our purpose was to determine the effects of AHAs on
      photoaged human skin by clinical and microanalytic means. METHODS: Patients
      applied a lotion containing 25% glycolic, lactic, or citric acid to one forearm
      and a placebo lotion to the opposite forearm for an average of 6 months.
      Thickness of forearm skin was measured throughout the study. Biopsy specimens
      from both forearms were processed for analysis at the end of the study. RESULTS:
      Treatment with AHAs caused an approximate 25% increase in skin thickness. The
      epidermis was thicker and papillary dermal changes included increased thickness,
      increased acid mucopolysaccharides, improved quality of elastic fibers, and
      increased density of collagen. No inflammation was evident. CONCLUSION: Treatment
      with AHAs produced significant reversal of epidermal and dermal markers of
      photoaging.

PMID- 8642082
TI  - Increased factor XIIIa transglutaminase expression in dermal dendrocytes after
      treatment with alpha-hydroxy acids: potential physiologic significance.
AB  - BACKGROUND: Topical alpha-hydroxy acids (AHAs) have been shown to improve
      photoaging in human skin. OBJECTIVE: We studied factor XIIIa transglutaminase
      expression in dermal dendrocytes (DDs) and mast cell degranulation after
      treatment of the skin with AHAs. METHODS: Skin biopsy specimens obtained from
      patients after 4 to 8 months of treatment with lotions containing 25% AHAs were
      evaluated for factor XIIIa transglutaminase expression with immunoperoxidase and
      electron microscopy. Immunoperoxidase-stained sections were studied by means of
      semiquantitative methods and image analysis. Mast cell degranulation was studied
      by image analysis. RESULTS: Increased factor XIIIa transglutaminase expression
      was seen after treatment with AHAs. All treated sites had increased scores
      compared with control sites by semiquantitative methods. Seventy-five percent of
      treated sites showed an increased mean area over control sites of factor XIIIa
      transglutaminase positivity with image analysis. These results correlated with an
      increased level of mast cell degranulation in treated sites and with activation
      of DDs as seen by electron microscopy. CONCLUSION: Treatment of the skin with
      AHAs leads to mast cell degranulation and increased expression of factor XIIIa
      transglutaminase by activated DDs. Mast cell degranulation may lead to activation
      of DDs and increased factor XIIIa transglutaminase expression, via the action of
      tumor necrosis factor-alpha. We speculate that clinical and histologic
      improvement in photoaged skin after treatment with AHAs may be somehow related to
      this process.

PMID- 8642083
TI  - Fibrinolytic abnormalities in two different cutaneous manifestations of venous
      disease.
AB  - BACKGROUND: Chronic venous insufficiency may be associated with
      lipodermatosclerosis or atrophie blanche. Coagulation abnormalities may be
      related to these cutaneous disorders. OBJECTIVE: Our purpose was to determine
      whether fibrinolytic abnormalities exist in patients with lipodermatosclerosis or
      atrophie blanche. METHODS: A case control study of patients with venous disease
      and atrophie blanche or lipodermatosclerosis was performed. Plasma levels of
      tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1)
      in a resting and venous occluded state were measured. RESULTS: Plasma levels of
      PAI-1 were different between the two groups of patients. The lipodermatosclerosis
      group had significantly higher levels of PAI-1 in both the resting and venous
      occluded states (p < 0.001). Patients with atrophie blanche had milder elevations
      of PAI-1 in the resting and venous occluded state (p = 0.06). CONCLUSION:
      Fibrinolytic abnormalities are present in patients with venous disease. These
      abnormalities are different between patients with lipodermatosclerosis and
      patients with atrophie blanche.

PMID- 8642084
TI  - Long-term sun exposure alters the collagen of the papillary dermis. Comparison of
      sun-protected and photoaged skin by northern analysis, immunohistochemical
      staining, and confocal laser scanning microscopy.
AB  - BACKGROUND: Long-term solar irradiation produces both morphologic and functional
      changes in affected skin. Because collagen is the major structural component of
      skin, any alteration in its production or degradation could have profound effects
      on cutaneous functional integrity. OBJECTIVE: Our purpose was to investigate
      alterations in the production and morphology of collagen fibers brought about by
      long-term sun exposure. METHODS: We compared collagen and collagenase gene
      expression and collagen immunohistochemical staining and used confocal laser
      scanning microscopy for morphologic examination of dermal collagen fibers in
      photodamaged compared with sun-protected skin from the same persons. RESULTS:
      Despite a large increase in elastin messenger RNA in sun-damaged skin, collagen
      and collagenase gene expression remained essentially unchanged. However, striking
      alterations in the papillary dermis of photoaged skin were found, which revealed
      large, abnormally clumped elastic fibers and deformed collagen fibers of various
      diameters, replacing the normal architecture of the papillary dermis. CONCLUSION:
      Our data provide evidence for normal collagen gene expression in sun-damaged skin
      and suggest that degradation and remodeling of collagen take place in the
      papillary dermis accompanied by deposition of other matrix components,
      predominantly abnormal elastic fibers.

PMID- 8642085
TI  - Chronic hepatitis C, cryoglobulinemia, and cutaneous necrotizing vasculitis.
      Clinical, pathologic, and immunopathologic study of twelve patients.
AB  - BACKGROUND: Several patients with chronic hepatitis C infection and cutaneous
      vasculitis have been described. OBJECTIVE: The objective of this study was to
      define better the features of necrotizing vasculitis and mixed cryoglobulinemia
      in patients with hepatitis C infection. METHODS: A retrospective review of 611
      patients with hepatitis C antibodies was conducted. Patients with clinical and
      histopathologic findings of cutaneous necrotizing vasculitis were identified.
      Clinical, histologic, and laboratory data were recorded. RESULTS: Twelve patients
      with necrotizing vasculitis and chronic hepatitis C infection were identified.
      Palpable purpura was the most common clinical presentation. Onset of skin lesions
      was usually more than 10 years after infection. The lower extremities were
      affected in all patients. Cryoglobulinemia of the mixed type II was present in 10
      of 11 patients. Liver function tests were evaluated at the time of vasculitis in
      most of the patients. Rheumatoid factor was elevated in all nine patients tested.
      Total complement was decreased in seven of nine patients, and C4 was decreased in
      six of seven patients. CONCLUSION: Cutaneous vasculitis associated with
      cryoglobulinemia and hypocomplementemia is not uncommon in the course of chronic
      active hepatitis C infection. The triad of necrotizing vasculitis, chronic
      hepatitis C infection, and cryoglobulinemia occurs late after initial infection
      with hepatitis C. Antibodies to hepatitis C virus should be determined in a
      patient with necrotizing vasculitis, especially if liver function tests are
      elevated.

PMID- 8642086
TI  - Mycobacteria in prurigo nodularis: the cause or a consequence?
AB  - BACKGROUND: Prurigo nodularis (PN) is a chronic skin disorder; its cause remains
      unknown. OBJECTIVE: We evaluated mycobacteria as a possible cause of PN. METHODS:
      Forty-three patients with PN were examined. Skin biopsy specimens were obtained
      for microbiologic and histopathologic studies. The patients were tested for
      intracutaneous reactivity to 12 mycobacterial antigens with the Mantoux
      technique. RESULTS: Six specimens (14%) grew mycobacteria in culture: M. avium
      intracellulare (3), M. malmoense (1), and Mycobacterium sp. (2).
      Histopathologically, 12 samples (28%) were positive for acid-fast bacilli, and
      granulomatous changes were present in one sample. Patients whose cultures were
      positive for mycobacteria had significantly larger skin reactions to
      mycobacterial antigens. Two patients underwent 2 years of antituberculous
      chemotherapy; one had an excellent response and the other a partial response.
      CONCLUSION: Detection of mycobacteria by culture or staining, combined with
      elevated skin reactivity to mycobacteria in a high proportion of patients with
      PN, suggests a mycobacterial cause.

PMID- 8642087
TI  - Eosinophilic panniculitis: diagnostic considerations and evaluation.
AB  - BACKGROUND: Eosinophilic panniculitis is characterized by a prominent
      infiltration of subcutaneous fat with eosinophils. It has been identified in
      patients who have a variety of associated clinical conditions. OBJECTIVE: Our
      purpose was to describe clinical conditions associated with eosinophilic
      panniculitis. METHODS: We describe five patients with eosinophilic panniculitis.
      These patients had a variety of clinical conditions including arthropod bites,
      gnathostomiasis, and polyarteritis nodosa. We review the literature on patients
      with eosinophilic panniculitis. RESULTS: Eosinophilic panniculitis most often
      presents as a nodule. Gnathostomiasis, leukocytoclastic vasculitis, and erythema
      nodosum appear to be the most common conditions associated with eosinophilic
      panniculitis. Other disorders include atopic and contact dermatitis, eosinophilic
      cellulitis, injection granuloma, arthropod bites, streptococcal and other
      bacterial infections, toxocariasis, B- and T-cell lymphoma, and refractory anemia
      with excess blasts. CONCLUSION: Once a diagnosis of eosinophilic panniculitis has
      been established, appropriate evaluation for an associated clinical condition
      should be performed.

PMID- 8642088
TI  - A comparison of wire brush and diamond fraise superficial dermabrasion for
      photoaged skin. A clinical, immunohistologic, and biochemical study.
AB  - BACKGROUND: Superficial dermabrasion has a proven beneficial effect on photoaged
      skin, but little is known about the differences between the two major modalities
      used in dermabrasion, the diamond fraise (DF) and the wire brush (WB). OBJECTIVE:
      We compared the clinical, immunohistologic, and biochemical changes after
      superficial dermabrasion with DF and WB. METHODS: Eight photoaged patients (mean
      age, 68 years; range, 49 to 80 years) underwent facial dermabrasion to the level
      of the papillary dermis. Clinical assessments were performed at baseline and at 3
      and 12 weeks after dermabrasion. Biopsy specimens were taken from both
      dermabraded halves at the same time points and assessed by routine histologic and
      immunohistologic examinations, western blot analysis, and radioimmunoassay.
      Scoring of intracellular and extracellular transforming growth factor-beta 1 was
      based on a semiquantitative ordinal scale (0 = no staining to 4 = maximum
      staining) in half-unit increments. The score for each specimen represents the
      average of values obtained from four high-power fields. RESULTS: Both methods of
      dermabrasion resulted in significant resolution of actinic keratoses, lentigines,
      and wrinkling. No statistical significance was noted between the two methods in
      regard to clinical efficacy. Significantly fewer milia occurred after DF than
      after WB. Solar elastosis decreased with both the WB and DF. Immunohistologic
      examination demonstrated a highly significant increase in papillary dermal
      fibroblast staining for amino terminal procollagen I (type I pN-collagen) at 3
      weeks for both DF and WB compared to baseline. Staining at 12 weeks had decreased
      from the peak noted at week 3, but was still significantly increased from
      baseline. Western blotting of type I pN-collagen demonstrated a 5.4-fold (p =
      0.01) increase from baseline at 3 weeks and a 4.9-fold (p = 0.002) increase at 12
      weeks after dermabrasion with the WB. Similarly, the DF produced a 4.9-fold (p =
      0.006) increase at 3 weeks and a 5.1-fold (p = 0.008) increase at 12 weeks after
      dermabrasion. Western blotting of amino terminal procollagen III (type III pN
      collagen) showed a 6.1-fold (p = 0.07) increase from baseline at 3 weeks and a
      3.9-fold (p = 0.04) increase at 12 weeks after dermabrasion with the DF. The WB
      showed a 3.8-fold (p = 0.07) increase from baseline at 3 weeks and a 5.1-fold (p
      = 0.05) increase at 12 weeks. Transforming growth factor-beta 1 demonstrated a
      significant increase in extracellular staining with DF (3.3 +/- 0.2) and WB (3.7
      +/- 0.2) from baseline (1.2 +/- 0.2, p < 0.001) at 3 weeks. CONCLUSION:
      Superficial dermabrasion with DF and WP appears to be similarly efficacious in
      the treatment of photoaged skin. Significant increases in type I pN-collagen,
      type III pN-collagen, and TGF-beta 1 occurred in the papillary dermis after both
      types of dermabrasion. These results suggest that increased fibroblast activity
      and consequent collagen I and III synthesis underlie the clinical improvement.

PMID- 8642089
TI  - Treatment of severe cutaneous lupus erythematosus with a chimeric CD4 monoclonal
      antibody, cM-T412.
AB  - BACKGROUND: Monoclonal CD4 antibodies are among the most potent immunomodulatory
      agents in various experimental models of autoimmune disease, including murine
      lupus erythematosus. OBJECTIVE: The aim of this study was to evaluate the
      toxicity and therapeutic efficacy of a chimeric monoclonal CD4 antibody, cM-T412,
      in patients with cutaneous lupus erythematosus (LE). METHODS: Five patients with
      severe cutaneous LE lesions received intravenously a total of 275, 400, or 475 mg
      of cM-T412 in single doses of 20 to 50 mg during a period of 5 to 8 weeks.
      RESULTS: CD4 antibody treatment induced a long-lasting decrease in disease
      activity. It resulted in healing of LE skin lesions, a reconstituted
      responsiveness to conventional treatment, or both. Despite a substantial
      depletion of circulating CD4+ T lymphocytes, no clinical signs of
      immunosuppression were noted. CONCLUSION: Monoclonal CD4 antibodies should be
      considered as a novel treatment for the management of severe cutaneous LE.

PMID- 8642090
TI  - Confluent and reticulated papillomatosis: response to minocycline.
AB  - BACKGROUND: Confluent and reticulated papillomatosis (CRP) of Gougerot and
      Carteaud is an uncommon disorder of unknown cause for which a variety of
      treatments have been proposed. OBJECTIVE: We attempted to evaluate the
      effectiveness of oral minocycline. METHODS: Nine patients with CRP were treated
      with oral minocycline, 50 mg twice a day, for 6 weeks. The average follow-up
      period was 11 months. Recurrence rate, side effects, and effectiveness of therapy
      were assessed. RESULTS: All patients except two had a 90% to 100% response to
      therapy. Recurrences were noted in three patients, all of whom responded to re
      treatment with minocycline. None of the nine patients had an adverse reaction.
      CONCLUSION: Minocycline, 50 mg twice a day, is safe and effective for CRP.

PMID- 8642091
TI  - Leishmaniasis.
AB  - Leishmaniasis is a protozoan disease whose diverse clinical manifestations are
      dependent both on the infecting species of Leishmania and on the immune response
      of the host. Transmission of the disease occurs through the bite of a sand fly
      infected with Leishmania parasites. Infection may be restricted to the skin in
      cutaneous leishmaniasis, limited to the mucous membranes in mucosal
      leishmaniasis, or spread throughout the reticuloendothelial system in visceral
      leishmaniasis or kala azar. Three rare clinical variants of cutaneous
      leishmaniasis include diffuse cutaneous leishmaniasis, leishmaniasis recidivans,
      and post-kala-azar dermal leishmaniasis.

PMID- 8642093
TI  - Surgical pearl: nail micronizer.

PMID- 8642092
TI  - Present and potential diagnostic techniques in onychomycosis.
AB  - The problem of onychomycosis has been frequently addressed during recent years.
      To make the diagnosis of onychomycosis dermatologists have relied on clinical
      presentation, culture, and microscopy. These approaches are hampered by false
      negative and false-positive results that have confused treatment outcomes. Two
      new diagnostic techniques, immunohistochemistry and flow cytometry, provide an
      effective means of identifying different dermatophytes, yeasts, and
      nondermatophytic molds. Immunohistochemistry employs antibodies to certain fungi
      to enable positive identification in situ, whereas flow cytometry differentiates
      fungi on the basis of molecular differences. These techniques provide new
      evidence that nondermatophytic molds and yeasts can actively invade nail tissue
      and that mixed infections occur. These findings could have important implications
      for the treatment of onychomycosis.

PMID- 8642094
TI  - Guidelines of care for superficial mycotic infections of the skin: tinea
      corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis.
      Guidelines/Outcomes Committee. American Academy of Dermatology.

PMID- 8642095
TI  - Guidelines of care for superficial mycotic infections of the skin: Pityriasis
      (tinea) versicolor. Guidelines/Outcomes Committee. American Academy of
      Dermatology.

PMID- 8642097
TI  - Dyshidrotic cutaneous T-cell lymphoma.

PMID- 8642096
TI  - Guidelines of care for superficial mycotic infections of the skin: tinea capitis
      and tinea barbae. Guidelines/Outcomes Committee. American Academy of Dermatology.

PMID- 8642098
TI  - Allergic contact dermatitis to east Indian rosewood (Dalbergia latifolia Roxb).

PMID- 8642099
TI  - Mycosis fungoides expressing gamma/delta T-cell receptors.

PMID- 8642100
TI  - Autosomal dominant pattern of distal subungual onychomycosis caused by
      Trichophyton rubrum.

PMID- 8642101
TI  - Pseudo-mycosis fungoides in a patient taking clonazepam and fluoxetine.

PMID- 8642102
TI  - Intracranial malignant meningioma mimicking frontalis-associated lipoma of the
      forehead.

PMID- 8642103
TI  - Angiosarcoma of the eyelid: yellow plaques causing ptosis.

PMID- 8642104
TI  - Elevated levels of interleukin-8 in blister fluid of bullous pemphigoid compared
      with suction blisters of healthy control subjects.

PMID- 8642105
TI  - Hypersensitivity to paclitaxel manifested as a bullous fixed drug eruption.

PMID- 8642106
TI  - Proceedings of the Psoriasis Combination and Rotation Therapy Conference. Deer
      Valley, Utah, Oct. 7-9, 1994.

PMID- 8642107
TI  - Nail apparatus melanoma.

PMID- 8642108
TI  - Current therapy for cutaneous melanoma.

PMID- 8642109
TI  - Antipsoriatic effect of fumaric acid derivates.

PMID- 8642110
TI  - Granuloma inguinale: self-assessment.

PMID- 8642112
TI  - The nonlinear interaction of two plane waves in a viscous medium.
AB  - Earlier studies [P.J. Westervelt, J. Acoust. Soc. Am. 29, 199-203, 934-935
      (1957)] of the mutual nonlinear interaction of two plane waves of sound with each
      other are extended to include the viscous effect. The viscous effect is
      considered both from the equations of motion and the equation of state of the
      medium. An analytical solution to the lowest-order scattering process is obtained
      if the viscous effect of second order and higher can be neglected.

PMID- 8642111
TI  - Urine delivery of cyromazine for suppressing house and stable flies (diptera:
      muscidae) in outdoor dairy calf hutches.
AB  - In a series of 4 trials, dairy calves housed in outdoor hutches were administered
      technical cyromazine daily at rates of 0, 0.1, 0.5, and 1.0 mg/kg body weight.
      Cyromazine was excreted primarily in the urine. The 2 highest rates prevented the
      development of immature stages of both the house fly, Musca domestica L., and the
      stable fly, Stomoxys calcitrans (L.). Analysis of calf body tissues for
      cyromazine and its metabolite, melamine, indicated that highest combined residues
      ( < or = 0.35 ppm) were found in the kidney. Lower levels of residues were found
      in kidney fat and liver, and occasionally in round muscle.

PMID- 8642113
TI  - Acoustically enhanced bubble growth at low frequencies and its implications for
      human diver and marine mammal safety.
AB  - Computations are made of the conditions necessary to obtain bubble growth by
      rectified diffusion under a variety of conditions associated with low-frequency
      sonar propagation in the ocean. The complex issue of microbubble nuclei
      stabilization is treated by assuming either a sufficient level of supersaturation
      to stabilize the initial bubble size, or by examining a microbubble nucleus with
      zero surface tension. The bubble growth rates and thresholds are obtained for a
      ranged of sound-pressure levels (re: 1 microPa) from 150-220 dB, for initial
      bubble radii from 1-10 microns, and for levels of the dissolved gas concentration
      from 100% to 223% of saturation. It was determined that for the range of
      conditions examined, it was necessary to utilize three different formulations of
      the equations for bubble growth. The results of these calculations (and
      assumptions concerning nuclei stabilization) indicate that for SPL's in excess of
      210 dB, significant bubble growth can be expected to occur, and divers and marine
      mammals exposed to these conditions could be at risk. For SPL's below about 190
      dB, however, except under relatively extreme conditions of supersaturation,
      significant bubble growth is unexpected.

PMID- 8642114
TI  - Sources and effects of low-frequency noise.
AB  - The sources of human exposure to low-frequency noise and its effects are
      reviewed. Low-frequency noise is common as background noise in urban
      environments, and as an emission from many artificial sources: road vehicles,
      aircraft, industrial machinery, artillery and mining explosions, and air movement
      machinery including wind turbines, compressors, and ventilation or air
      conditioning units. The effects of low-frequency noise are of particular concern
      because of its pervasiveness due to numerous sources, efficient propagation, and
      reduced efficacy of many structures (dwellings, walls, and hearing protection) in
      attenuating low-frequency noise compared with other noise. Intense low-frequency
      noise appears to produce clear symptoms including respiratory impairment and
      aural pain. Although the effects of lower intensities of low-frequency noise are
      difficult to establish for methodological reasons, evidence suggests that a
      number of adverse effects of noise in general arise from exposure to low
      frequency noise: Loudness judgments and annoyance reactions are sometimes
      reported to be greater for low-frequency noise than other noises for equal sound
      pressure level; annoyance is exacerbated by rattle or vibration induced by low
      frequency noise; speech intelligibility may be reduced more by low-frequency
      noise than other noises except those in the frequency range of speech itself,
      because of the upward spread of masking. On the other hand, it is also possible
      that low-frequency noise provides some protection against the effects of
      simultaneous higher frequency noise on hearing. Research needs and policy
      decisions, based on what is currently known, are considered.

PMID- 8642115
TI  - Low-frequency coupling between eardrum and manubrium in a finite-element model.
AB  - The mechanical coupling between the eardrum and the manubrium was studied by
      means of a finite-element model of the cat eardrum. Previous calculations of the
      effect of varying the eardrum curvature were extended, demonstrating the critical
      role of curvature in the behavior of the eardrum. A new procedure was developed
      for directly studying the coupling of forces from different points on the eardrum
      to the manubrium, and the distribution of load-coupling values over the eardrum
      surface was calculated. A geometrically simplified eardrum with a circular
      outline was also studied. It was found that certain regions of the eardrum are
      more effective in driving the manubrium than can be explained on the basis of
      their distance from the axis of rotation. This enhanced coupling depends on the
      curvature of the eardrum but, unlike the mechanism hypothesized by Helmholtz,
      requires neither tension nor anisotropy.

PMID- 8642116
TI  - Sound-power collection by the auditory periphery of the mongolian gerbil Meriones
      unguiculatus. II. External-ear radiation impedance and power collection.
AB  - Acoustic power flow into the external and middle ear of the gerbil is computed
      from acoustic measurements and models of the external ear and used to predict the
      behavioral auditory threshold. The external-ear radiation impedance from the
      tympanic ring ZE measured in six gerbil ears with a calibrated acoustic source at
      frequencies from 10 Hz to 18 kHz is mass dominated below about 8 kHz, with a mean
      mass of 2720 kg/m4. ZE shows resonant behavior near 8 and 14 kHz. The frequency
      dependence of ZE is similar to that measured in cat, chinchilla, and models of
      the human external ear, but the mass and the resonant frequencies are higher. The
      power utilization ratio (PUR) computed from ZE and measurements of the middle-ear
      input impedance ZT presented previously [Ravicz et al., J. Acoust. Soc. Am. 92,
      157-177 (1992)] suggests that appreciable power is transmitted to the middle ear
      only above 1.5 kHz. Mathematical external-ear models, consisting of tube segments
      and conical horns that include viscous and thermal losses, were developed from
      anatomical dimensions to match ZE over the entire frequency range of measurement.
      The radiation efficiency eta R computed from the models is near unity only above
      12 kHz and falls to 10(-5) as frequency decreases to 10 Hz. Predictions of the
      mean pressure gain from an external diffuse sound field to the tympanic membrane
      resemble measurements in another gerbilline species. The effective area of the
      ear in a diffuse sound field at the tympanic membrane EATMDF computed from PUR
      and eta R approaches the anatomical area of the pinna opening, 71 mm2, above 1.5
      kHz and the geometric limit of lambda 2 /4 pi determined by the wavelength lambda
      above 12 kHz but decreases sharply below 1.5 kHz to 0.002 mm2 at 10 Hz. The
      diffuse-field sound pressure required to deliver 5 x 10(-17) W to the middle ear
      between 10 Hz and 18 kHz resembles the behavioral auditory threshold [Ryan, J.
      Acoust. Soc. Am. 54, 1222-1226 (1976)]. This result supports the idea that the
      cochlea acts as a power detector at the auditory threshold.

PMID- 8642117
TI  - Effects of pinna position on head-related transfer functions in the cat.
AB  - To measure the effects of the pinna position on spectral sound localization cues,
      the head-related transfer function (HRTF) from the free-field to a point in the
      ear canal was measured for anesthetized cats with their pinnae in three
      positions: the relaxed, anesthetized position; pulled forward into an
      approximation of the "alert cat" posture; and pulled back. The general features
      of HRTFs are not changed by moving the pinna, although the mapping of particular
      HRTF features onto directions in space is changed. As an approximation, the pinna
      behaves like a fixed-shaped sound collector, so that HRTFs shift with the pinna
      when it moves; however, pinna movement changes some quantitative details of HRTFs
      beyond what is predicted by this approximation. When viewed as directional gain,
      pinna movements serve to optimize listening conditions. However, when considering
      sound localization, pinna movements lead to ambiguities regarding source
      location. If pinna position is not incorporated into the computation, and
      spectral cues alone are used for localization, the ambiguity is about 60 degrees
      in azimuth and 30 degrees in elevation. Pinna movements produce similar azimuthal
      ambiguity in interaural level differences. Interaural time difference cues could
      be used to reduce the ambiguity in azimuth, but a knowledge of pinna position
      seems to be necessary to resolve ambiguities in elevation.

PMID- 8642118
TI  - Click- and tone-burst-evoked otoacoustic emissions in normal-hearing and hearing
      impaired ears.
AB  - Click-evoked otoacoustic emission (COAE) and tone-burst-evoked otoacoustic
      emission (TBOAE) input/output (I/O) functions and group latencies were measured
      in normal-hearing and hearing-impaired ears to determine the extent to which
      these two types of transient-evoked otoacoustic emissions (TEOAEs) were similar.
      When stimulus levels measured in 1/3 octave bands centered at 500, 1000, 2000,
      and 4000 Hz were similar, TBOAE and COAE I/O functions were essentially identical
      in regions of normal hearing. This held true in subjects who had normal hearing
      from 250 to 8000 Hz as well as for subjects who had normal hearing across some
      frequency ranges but hearing impairment across others. The high degree of
      correlation offers support to the view that both types of transient emissions
      share common generators. There were no significant differences in group delay
      between TBOAEs measured from normal-hearing and hearing-impaired subjects.

PMID- 8642119
TI  - Two-tone suppression in cochlear mechanics.
AB  - Mechanical responses to one- and two-tone stimuli were recorded from the basilar
      membrane (BM) in the hook region of the guinea-pig cochlea. The most sensitive or
      "best" frequencies (BFs) for the sites studied were approximately 25-30 kHz. Two
      tone suppression (2TS) of the responses to near BF probe tones was noted using
      suppressor tones either above or below the BF. Rates of growth of 2TS were
      highest (approximately 1 dB/dB) when the suppressor tones were presented below
      the BF. Below-BF suppression thresholds (the suppressor intensities causing
      approximately 10% reduction in the probe-evoked responses) corresponded to BM
      displacements of approximately 1-5 nm. Above-BF suppression thresholds
      corresponded to much smaller displacements at the location studied. Both above-
      and below-BF suppressor tones changed the phase of the probe tone responses in
      the same way that increases in the probe tone intensity did (they evoked small
      phase-lags for below-BF probes, and small phase-leads for near- and above-BF
      probes). Low-frequency suppressor tones ( < approximately 7 kHz) evoked a
      frequency- and intensity-dependent mixture of phasic (ac) and tonic (dc)
      suppression. Peak (ac) suppression was observed around the times of peak BM
      displacement (not velocity). These findings are discussed in relation to those of
      other workers.

PMID- 8642121
TI  - The effects on comodulation masking release of systemic variations in on- and off
      frequency masker modulation patterns.
AB  - Detection thresholds were obtained for a 500-Hz tone added to a masker comprised
      of an amplitude-modulated tone centered at the signal frequency (on-frequency
      masker) and an array of amplitude modulated tones centered at 300, 700, 800, 900,
      1000, and 1100 Hz (off-frequency maskers). The shapes of the amplitude modulation
      patterns of the on- and off-frequency maskers were either matched or mismatched.
      In the shape-matched conditions the on- and off-frequency masker modulation
      patterns were the same, either sinusoidally or square-wave amplitude modulated.
      In the shape-mismatched conditions, the on-frequency masker was sinusoidally
      amplitude modulated and the off-frequency maskers were square-wave amplitude
      modulated. The rate of modulation was either 10 or 20 Hz, and the duty cycle of
      square-wave modulation was systemically varied. The relative phases of the on-
      and off-frequency modulators were either in-phase, out-of-phase, or random-phase.
      Comodulation masking release (CMR) was defined as the difference between
      thresholds in the in-phase and random-phase conditions. CMRs as large as 12 dB
      were obtained for the shape-matched as well as the shape-mismatched conditions.
      Thresholds in the out-of-phase condition were on average 2.6 dB higher than those
      in the random-phase condition. Results are consistent with a cued listening model
      where off-frequency modulation minima trigger sampling at the output of the
      auditory filter centered on the signal frequency.

PMID- 8642120
TI  - Stimulus features affecting psychophysical detection thresholds for electrical
      stimulation of the cochlea. III. Pulse polarity.
AB  - Effects of initial-phase polarity on psychophysical detection thresholds for
      electrical stimulation of the cochlea were examined in four nonhuman primates
      using trains of biphasic and triphasic charge-balanced pulses. Initial-phase
      polarity had small but consistent effects on the levels and slopes of threshold
      versus phase duration functions. These effects were consistent with the
      hypothesis that the initial-phase polarity affects the site of action potential
      initiation. Thresholds for biphasic pulses were lower than those for triphasic
      pulses, suggesting that the system is responsive to both positive and negative
      phases of the stimulus. Interactions between initial-phase polarity, pulse
      waveform, and phase duration were observed.

PMID- 8642122
TI  - A comparison of hearing-aid array processing techniques.
AB  - Microphone arrays have proven effective in improving speech intelligibility in
      noise for hearing-impaired listeners, and several array processing techniques
      have been proposed for hearing aids. Among the signal-processing approaches are
      classical delay-and-sum beamforming, superdirective arrays, and adaptive arrays.
      To directly compare the effectiveness of these different processing strategies, a
      10-cm-long linear array was built using five uniformly spaced omnidirectional
      microphones. This array was used in the end-fire orientation to acquire speech
      and noise signals for a variety of array placements in two representative rooms.
      Both digital and simulated analog processing techniques were considered, with the
      array processing implemented in the frequency domain. The performance metric was
      the steady-state array gain weighted to represent the relative importance of the
      different frequency regions in understanding speech. The processing comparison
      indicates that digital systems are more effective than the simulated analog
      processing, and that both superdirective and adaptive digital array processing
      can provide more than 9 dB of weighted array gain.

PMID- 8642123
TI  - The effects of static indentation on vibrotactile threshold.
AB  - Vibrotactile thresholds were measured on the thenar eminence and the volar
      forearm at different static depths of skin indentation. Three stimulus
      frequencies (1, 20, and 200 Hz) were delivered through either a 0.008- or a 2.9
      cm2 contractor. The indentation depths ranged from 0 to 1 mm (0.25-mm steps)
      relative to the point of skin contact with the stimulator. There was a
      significant effect of indentation in all stimulus combinations of contactor size,
      location, and frequency. These results resolve an apparent discrepancy in the
      literature regarding threshold reduction with increasing contactor size observed
      on the forearm at low frequencies.

PMID- 8642124
TI  - Duration and fundamental frequency correlates of phrase boundaries in productions
      by children and adults.
AB  - Two experiments examined how children and adults produce acoustic correlates for
      phrase boundaries during speech. Adult and children (ages 5 and 7) were asked to
      describe groupings of colored blocks, first in a relatively spontaneous manner
      and next under more structured conditions designed to elicit grouping information
      concerning "which blocks go together." In the spontaneous condition, adults gave
      elaborate descriptions of block positions and color, whereas children produced
      short descriptions such as "pink, green, white;" "pink, green, and white;" and
      "pink and green and white." In the structured condition, all subjects produced
      utterances corresponding to three syntactic bracketings of the phrase "pink and
      green and white:" [pink and (green and white)]; [(pink and green) and white]; and
      [pink and green and white]. Acoustic analyses indicated that adults reliably
      control both duration and fundamental frequency (F0) to signal phrase boundaries,
      whereas children of both age groups demonstrate little evidence of either type of
      information being used. We interpret these finding as suggesting that children as
      old as age 7 do not produce prosodic cues for this type of standing ambiguity in
      their everyday speech. Possible reasons for this lack of phrase boundary prosodic
      correlates are examined.

PMID- 8642125
TI  - Young children's production of syllable stress: an acoustic analysis.
AB  - The acoustic characteristics of stress were examined in young children's
      productions of minimal pairs of novel words (e.g., sofi versus so'fi). Fourteen 2
      year-olds participated as subjects. Their productions were analyzed in terms of
      vowel duration, syllable duration, peak amplitude, and peak fundamental
      frequency. The analyses revealed that children produced stressed and unstressed
      syllables distinctly along each of the dimensions examined. The absolute and
      relative (unstressed/stressed) values of the children's productions were compared
      to those of the single adult experimenter, who modeled the novel words,
      permitting a unique comparison of input to children's productions. One systematic
      difference was the relative values; the children's stressed and unstressed
      syllables were less distinct than the adults along each of the acoustic
      correlates. Furthermore, the acoustic features of both stressed and unstressed
      syllables appear to be subject to developmental change. The results are discussed
      in terms of their implications for young children's production capabilities and
      for the relationship between input and children's production characteristics.

PMID- 8642126
TI  - Cross-language identification of consonants. Part 1. Korean perception of
      English.
AB  - Twenty native Korean-speaking subjects heard 22 English word-initial consonants
      in three vowel contexts produced by three native English talkers. The subjects
      orthographically labeled each English consonant as the closest Korean consonant.
      They then judged how similar the English consonant was to the Korean consonant on
      a scale of 1 to 5. Some English consonants were labeled consistently as a single
      Korean consonant and judged to be very similar. Other English consonants were
      labeled consistently as a single Korean consonant but judged to be less similar.
      Still other English consonants were inconsistently labeled. Korean acoustic cues,
      vowel context, and token differences appeared to influence labeling choices.

PMID- 8642127
TI  - Deformation models and correlation analysis in elastography.
AB  - Cross-correlation functions are derived with the purpose of determining how
      strain inhomogeneities affect the displacement estimates used in ultrasound-based
      elastography. Variations in the strain profile occur in most imaging situations
      and are caused by fluctuations in the stress field or elastic modulus of the
      sample. An analytical framework for developing signal processing strategies in
      elastography is described, and the limitations of correlation-based methods for
      measuring displacements in tissuelike media caused by static compression are
      emphasized. This paper includes (1) an accurate approximation for an inverse
      coordinate transformation that release pre- and postcompression reflectivity
      profiles of the media, (2) a derivation of the echo-signal cross-correlation
      function in media with deterministic or stochastic strain profiles; (3)
      mathematical and graphical descriptions of the consequences that nonuniformities
      in the strain profile impose upon the uncertainty of displacement estimation; and
      (4) a demonstration of the advantages of echo signal conditioning and ultrasonic
      pulse shaping to reduce the nonstationary effects that attenuate the cross
      correlation peak and reduce the signal-to-noise ration for displacement
      estimation.

PMID- 8642128
TI  - Ultrasonic properties of tendon: velocity, attenuation, and backscattering in
      equine digital flexor tendons.
AB  - Ultrasound velocity, attenuation, and backscattering were measured in vitro in
      samples of equine digital flexor tendon sandwiched between plane, parallel
      rexolite buffer rods. The buffer rods were coupled to transmitting and receiving
      transducers (nominally 10 MHz) mounted in-line and facing one another on the jaws
      of a digital caliper. Six superficial digital flexor (SDF) tendons and six deep
      digital flexor (DDF) tendons were measured in three orthogonal directions: along
      the long axis of the tendon (D), and across the tendon in the dorsal-volar (C),
      and lateral (L) directions. Substantial anisotropy was apparent in all the
      measured properties. The velocity data, which in both tendons showed a higher
      velocity along the fibers than across (e.g., in the DDF tendon at 0 degrees C:
      1713 +/- 9 m/s in the D direction compared with 1650 +/- 5 m/s in the C
      direction), were consistent with a composite comprising stiff fibers embedded in
      a less stiff medium of lower speed. The apparent backscattering coefficient
      adjusted for the tissue's frequency-dependent attenuation (e.g., in the C
      direction of the DDF tendon at 0 degrees C: 7.4 x 10(-3) cm-1 sr-1), was
      independent of frequency in both transverse directions and larger than that
      measured along the long axis of the tendon (e.g., in DDF tendon at 0 degrees C:
      1.2 x 10(-3) cm-1 sr-1 at 7 MHz) in which direction the apparent backscattering
      coefficient increased with frequency as f4.0 +/- 1.2. The frequency-independent
      backscattering was thought to be due to specular reflection from the boundaries
      between the fascicles, i.e., the bundles of fibers making up the tendon, while
      backscattering along the axis was due to structures of unknown origin, but of a
      size much smaller than 45 microns. Attenuation of ultrasound directed along the
      fibers was higher than that across (at 7 MHz in DDF tendon at 0 degrees C: 58
      dB/cm in the D direction compared with 11.3 dB/cm in the C direction).
      Calculations indicated that the attenuation was primarily caused by absorption
      rather than scattering.

PMID- 8642129
TI  - Comments on "Manipulations of the duration and relative onsets of two-tone
      forward maskers" [J. Acoust. Soc. Am. 94, 1269-1274 (1993)].

PMID- 8642130
TI  - Voice development under training with and without the influence of real-time
      visually presented biofeedback.
AB  - This paper describes an investigation into the developmental nature of the voice
      under training with and without the influence of real-time visually presented
      biofeedback. Two subjects who had not previously experienced any form of vocal
      training took six singing lessons. One was taught conventionally, while the other
      was taught with the aid of a system known as Acoustic and Laryngeal Biofeedback
      Enhancement Real Time (ALBERT). Real-time biofeedback was presented based upon
      measures of (i) larynx closed quotient (CQ), (ii) spectral amplitude in the
      singer's formant frequency band relative to the spectral amplitude of the full
      band (ratio), and (iii) both parameters combined in a manner based on previously
      observed correlations between them. Results indicate generally increased sound
      pressure levels (SPL) of acoustic output and generally consistent increases in
      the level of CQ and ratio across consecutive lessons for both subjects.

PMID- 8642131
TI  - You and your life's work.

PMID- 8642132
TI  - Managed care 'what ifs?'.

PMID- 8642133
TI  - Occlusal splints.

PMID- 8642134
TI  - Promoting the profession.

PMID- 8642135
TI  - Blaming the exam.

PMID- 8642136
TI  - Examination patients.

PMID- 8642137
TI  - More on licensure.

PMID- 8642138
TI  - Identifying a neurobiologic basis for drug therapy in TMDs.
AB  - Emerging results from clinical and basic research indicate that persistent pain
      results in changes in the central nervous system. These changes may help explain
      chronic orofacial pain and lead to new therapies. The authors review data that
      support the use of tricyclic antidepressants for neurogenic or atypical pain, and
      benzodiazepines for musculoskeletal pain. Dentists must weigh the benefits of the
      chronic administration of a drug for the management of temporomandibular
      disorders against the equivocal scientific support for the use of many drug
      classes and the potential for serious toxicity with prolonged administration.

PMID- 8642139
TI  - Endodontic treatment outcomes: do patients perceive problems?
AB  - Patient's perceived problems related to endodontically treated teeth are an
      important consideration for all dental practitioners. Chronic pain or restorative
      problems may occur that are not reported back to the attending dentist in a
      timely manner and thus may not be resolved. The authors conducted a study
      involving a one-year follow-up of endodontically treated patients. They offer
      suggestions for interventions that could minimize the reported problems.

PMID- 8642140
TI  - Does the elimination of Medicaid reimbursement affect the frequency of emergency
      department dental visits?
AB  - In an attempt to save costs, the state of Maryland in February 1993 eliminated
      Medicaid reimbursement to dentists for treatment of adults with dental
      emergencies. The authors analyzed data from the University of Maryland Hospital's
      emergency department to determine if this change resulted in increased use of the
      emergency department by Medicaid recipients for treatment of dental conditions.
      After the policy change, the rate of dental visits to the emergency department by
      Medicaid recipients increased by 21.8 percent. This increase occurred during the
      same period in which the percentage of all emergency department visits by
      Medicaid recipients was decreasing.

PMID- 8642141
TI  - Backflow in low-volume suction lines: the impact of pressure changes.
AB  - A previous study indicated that fluid can flow backward in low-volume suction
      lines when patients close their lips around the saliva ejector tip. The authors
      investigated this phenomenon further. They documented physical and mechanical
      parameters of saliva ejector backflow in low-volume suction lines and concluded
      that backflow is possible but can be avoided with simple precautions.

PMID- 8642142
TI  - Avoiding prescribing errors: a systematic approach.
AB  - With the number of prescription and over-the-counter drugs growing every year,
      health professionals who write prescriptions need to be particularly cautious to
      avoid mishaps. The author outlines eight pitfalls commonly encountered when
      writing prescriptions and urges dentists to adopt a systematic approach when
      prescribing medications.

PMID- 8642143
TI  - Altering anticoagulation therapy: a survey of physicians.
AB  - Patients who take antithrombotic medications, such as warfarin sodium or aspirin,
      are more likely than others to experience bleeding problems after some dental
      treatments. Withdrawing the medication before treatment, however, may place these
      patients at risk of medical complications. The authors surveyed physicians about
      the conditions under which such pharmacotherapies should be altered. They not
      only found a difference of opinion among the respondents, but also learned that
      many respondents misunderstood the nature of certain dental procedures and the
      likelihood that those procedures would cause significant postoperative bleeding.

PMID- 8642144
TI  - Assessing pre-procedural subgingival irrigation and rinsing with an antiseptic
      mouthrinse to reduce bacteremia.
AB  - In this controlled clinical study, the authors examined the effect of subgingival
      irrigation and rinsing with an antiseptic mouthrinse before ultrasonic scaling of
      a quadrant containing inflamed gingivae. The results showed that pre-procedural
      subgingival irrigation and rinsing can significantly reduce the level of
      bacteremia associated with ultrasonic scaling. These results support the American
      Heart Association's recommendation of adjunctive subgingival irrigation prior to
      invasive procedures in patients at risk of developing bacterial endocarditis.

PMID- 8642145
TI  - Assessing the characteristics of patients with oral lichen planus.
AB  - The authors assessed the medical history, lifestyles and health habits of 146
      patients with oral lichen planus as confirmed by biopsy. The results support a
      relationship between stress and the development of oral lichen planus. Fifty-one
      percent of the subjects reported that they had experienced stressful events at
      the time of the lichen planus onset. Practitioners may want to consider the
      benefits of stress management and bereavement counseling in managing patients
      with oral lichen planus.

PMID- 8642146
TI  - Ridge preservation: why not?
AB  - Ridge preservation should be a commonly used dental procedure. However, it is
      not. Simple ridge preservation techniques, using materials such as HTR, provide
      undeniable esthetic and functional benefits to patients and dentists.

PMID- 8642147
TI  - Infection control recommendations for the dental office and the dental
      laboratory. ADA Council on Scientific Affairs and ADA Council on Dental Practice.
AB  - This report is based on the recommendations of the Centers for Disease Control
      and Prevention and other publications in the medical and dental literature. The
      recommendations here, which have been accepted by the ADA Council on Scientific
      Affairs and the ADA Council on Dental Practice, are intended to offer general
      guidance for dental offices and laboratories on infection control. They are not
      intended to establish a standard of care or industry custom, nor are they
      intended to deprive the dentist of the ability to exercise his or her
      professional judgment.

PMID- 8642148
TI  - Meeting the challenges of craniofacial-oral-dental birth defects.

PMID- 8642149
TI  - Can a dentist ethically remove serviceable amalgam restorations?

PMID- 8642151
TI  - Restrictive left ventricular filling patterns in very old patients with
      congestive heart failure: clinical correlates and prognostic significance.
AB  - OBJECTIVES: In certain younger patients with congestive heart failure (CHF),
      Doppler/echocardiography has identified a "restrictive" pattern of early
      diastolic ventricular filling characterized by very rapid early filling and a
      steep deceleration slope. We asked whether a similar restrictive pattern can be
      identified in very old patients with CHF, and if so, what are its clinical
      correlates and prognostic implications. DESIGN: Retrospective cohort with
      prospective follow-up. SETTING: Academic long-term care facility. PARTICIPANTS:
      Thirty-nine residents with clinical CHF (age 89 +/- 5 (SD) years) MEASUREMENTS:
      Transmitral Doppler flow, clinical characteristics, recurrent CHF episodes,
      hospitalizations, and mortality were measured. RESULTS: Fifteen (38%) of the
      subjects had restrictive filling patterns, characterized by a ratio of early to
      late flow (E/A) > 1.00 and 24 (62%) had nonrestrictive patterns. The restrictive
      pattern was associated with a longer duration of CHF, more angina, and higher
      rate of symptomatic recurrences of CHF. CONCLUSION: A restrictive diastolic
      filling pattern may represent a late stage in the evolution of congestive heart
      failure when left ventricular filling pressure is markedly increased. The
      treatment of CHF in older patients may need to account for different patterns of
      diastolic filling.

PMID- 8642150
TI  - Physical restraint use and falls in nursing home residents.
AB  - OBJECTIVE: To examine the relationship between restraint use and falls while
      controlling for the effect of psychoactive drug use among nursing home residents,
      including subgroups of nursing home residents with high rates of restraint use
      and/or falls. DESIGN: Secondary analysis of data from a longitudinal clinical
      trial designed to reduce restraint use. SETTING: Three nursing homes.
      PARTICIPANTS: Subjects (n = 322) were either restrained (n = 119) or never
      restrained (n = 203) at each observation point during a 9.5-month data collection
      period that preceded the intervention phase of the clinical trial. MEASUREMENTS:
      We evaluated restraint status (independent variable) three times during the data
      collection period by direct observation over a 72-hour period. Incident reports
      documenting falls and fall-related injuries (dependent variables) were reviewed.
      Cognitive status was measured using the Folstein Mini-Mental State Exam and
      functional status (including ambulation status) by the Psychogeriatric Dependency
      Rating Scale. Psychoactive drug use profile was obtained through record review.
      MAIN RESULTS: Using multiple logistic regression, we compared the effect of
      restraint use on fall risk between a confused ambulatory subgroup and the
      remaining sample and found a significant difference in the odds ratio for falls
      and recurrent falls (P = .02; chi-square = 5.24, df = 1; P = .003, chi-square =
      9.12, df = 1). In the confused ambulatory subgroup, restraint use was associated
      with increased falls (odds ratio: 1.65, 95% CI: 0.69, 3.98) as well as recurrent
      fall risk (odds ratio: 2.46, 95% CI: 1.03, 5.88). Increased falls and recurrent
      fall risk was not observed in the remaining sample (falls odds ratio: 0.49, 95%
      CI: 0.28, 0.87; recurrent falls odds ratio: 0.42, 95% CI: 0.20, 0.91). One
      subgroup, the nonconfused ambulatory residents, were never restrained; after
      removing this subgroup, the confused ambulatory continued to be associated,
      though not significantly, with a higher risk of falls and injuries. Only
      nonconfused nonambulatory restraints were associated with a lower risk of all
      three outcomes: falls (odds ratio: 0.28, 95% CI: 0.05, 1.58), recurrent falls
      (odds ratio: 0.48, 95% CI: 0.05, 4.72), and injurious falls (odds ratio:0.42, 95%
      CI: 0.04, 4.01); these results, however, were not statistically significant.
      There was no evidence that the effect of restraint use on fall risk depended upon
      the use of psychoactive drugs (chi square = 4.43; df = 2, P = .11). CONCLUSION:
      Restraints were not associated with a significantly lower risk of falls or
      injuries in subgroups of residents likely to be restrained. These findings
      support individualized assessment of fall risk rather than routine use of
      physical restraints for fall prevention. Researchers and clinicians should
      continue to focus efforts on developing a variety of approaches that reduce risk
      of falls and injuries and promote mobility rather than immobility.

PMID- 8642152
TI  - Iatrogenic congestive heart failure in older adults: clinical course and
      prognosis.
AB  - OBJECTIVE: To determine the prevalence, risk factors, clinical course, and
      prognosis of iatrogenic congestive heart failure in older patients. DESIGN AND
      SETTING: Prospective observational study at a university teaching hospital.
      PARTICIPANTS: A total of 401 patients 70 years of age or older hospitalized with
      congestive heart failure. The mean age was 80 +/- 6 years; 59% were female, and
      65% were white. MEASUREMENTS: Comprehensive data, including an assessment of the
      etiology and precipitating factors leading to the development of heart failure,
      were collected at the time of diagnosis. Iatrogenic heart failure was defined as
      heart failure precipitated by medications or excessive fluid administration, or
      occurring as a procedural complication. All patients were followed for 1 year,
      and the primary outcome measure was total mortality. RESULTS: Using strict
      criteria, 28 patients (7.0%) were considered to have iatrogenic heart failure.
      Compared with noniatrogenic patients (n = 373), iatrogenic cases had less severe
      premorbid cardiac disease but more marked noncardiac disability and longer
      hospital stays (29 +/- 24 vs 13 +/- 12 days, P < .001). Hospital mortality was
      32% in iatrogenic heart failure patients compared with 9% in noniatrogenic cases
      (P < .001). Cumulative mortality at 1 year was 68% in iatrogenic patients versus
      39% in noniatrogenic patients (P < .01). Using a Cox proportional hazards model,
      iatrogenic congestive heart failure was associated with a relative mortality risk
      during follow-up of 2.5 (95% confidence interval 1.5-4.3) after adjusting for
      age, sex, prior history of heart failure, New York Heart Association class,
      diabetes mellitus, systolic blood pressure, hemoglobin, blood urea nitrogen, and
      serum albumin. CONCLUSIONS: Frail, debilitated older patients are at increased
      risk for developing iatrogenic heart failure, even in the absence of clinically
      evident cardiac disease. In this population, iatrogenic heart failure serves as a
      marker for poor short- and long-term prognosis, but further study is required to
      determine the optimal approach to management of these patients.

PMID- 8642153
TI  - A home-based exercise program for nondisabled older adults.
AB  - OBJECTIVES: This paper describes a videotaped, home-based, strength training
      program, titled Strong-for-Life and reports on its effectiveness in improving
      muscle strength, psychological well-being, and health status in a sample of older
      persons. DESIGN AND SETTING: We enrolled 102 nondisabled, community-dwelling
      older people aged 66 to 87, identified from the Medicare beneficiary list, into a
      randomized, controlled trial. MEASUREMENTS: Effectiveness was based on change in
      isokinetic upper and lower extremity muscle strength, psychologic well-being, and
      health status. RESULTS: Results revealed several statistically significant short
      term benefits after 12 to 15 weeks of exercise, especially for men. Younger older
      adults demonstrated a 10% improvement in knee extensor strength relative to
      control subjects. Older male exercisers achieved significant differences relative
      to controls in perceived anger, tension, and overall social functioning. Male
      exercisers, in general, achieved significant improvement in perceived vigor.
      Women did not report psychological benefits following participation in the
      program. CONCLUSION: Study results reveal that the Strong for Life program,
      designed to be widely disseminated to the nondisabled older population, has many
      short-term positive benefits.

PMID- 8642154
TI  - Medical screening of older drivers as a traffic safety measure--a comparative
      Finnish-Swedish evaluation study.
AB  - OBJECTIVES: To evaluate the safety effect of age-related medical screening of
      older drivers by comparing the licensing laws and accident rates for older road
      users in Finland and Sweden. DESIGN: Post hoc comparison of Sweden and Finland
      with respect to three different risk variables. SETTING: Nationwide Swedish and
      Finnish accident, licensing, and population data from the year 1990 were provided
      for the present study by the local authorities responsible for tabulating these
      data. PARTICIPANTS: Data about all citizens born in 1960 or earlier, i.e., aged
      30 years or more in the year of measurement, are included. MEASUREMENTS: Rates of
      police-reported private car accidents leading to personal injury, fatality rates
      of private car drivers and passengers, and fatality rates of unprotected road
      users. RESULTS: The age-related variation in private car accident and private car
      fatality trends was similar in both countries. Fatalities among unprotected road
      users (i.e., pedestrians, cyclists, and mopedists) increased more sharply with
      age among the older Finnish population than among the Swedish population.
      CONCLUSION: We found no safety-related reasons to implement age-related medical
      screening of older drivers of the kind practiced in Finland. On the contrary, by
      producing a modal shift toward a more risky mode of travelling, this screening
      may indirectly lead to higher fatality rates among older road users.

PMID- 8642155
TI  - A study of the characteristics of the dementia patients and caregivers in
      dementia-nonspecific adult day care programs.
AB  - OBJECTIVE: To determine if basic differences exist between the patients and
      caregivers of a representative group of dementia-nonspecific medical versus
      social adult day care centers with specific programs for dementia patients.
      DESIGN: A telephone interview questionnaire survey. SETTING: North Central North
      Carolina. PARTICIPANTS: A total of 242 adult day care dementia patients and
      caregivers from three medical and three social nondementia-specific adult day
      care centers. MEASUREMENTS: Dementia patient variables: Day care subtype (medical
      or social); length of stay; number of days attended; age; sex; race; educational
      level; marital status; religious affiliation; income; living status; number of
      medical conditions; number of prescription medications; function; ADL status
      (walking, eating, bathing, dressing, grooming, toileting); continence status;
      number and type of abnormal behaviors; formal help status (hospitalization during
      day care, part or full-time nursing home attendance, or home healthcare
      assistance); transportation; and financial assistance. Caregiver variables: day
      care subtype; age; sex; race; educational level; marital status; religious
      affiliation; income; number of medical conditions; number of prescription
      medications; informal help (family friends or other non-paid help); paid help
      (friend, other, home health, or nursing home); relationship to patient;
      employment status; and level of caregiver burden. MAIN RESULTS: There were 144
      medical and 62 social adult day care dementia patients and caregivers who agreed
      to participate. The average age of the patient was 77.9 years (SD +/- 8.4), and
      that of the caregiver was 57.7 years (SD +/- 13.9); 68.4% of the patients and
      75.4% of the caregivers were females. Dementia patients in the medical subtype
      day care had a shorter length of stay than social day care patients; this did not
      reach statistical significance. There were significantly more white patients and
      caregivers in the medical than in the social subtype day care, 83.1% versus 50%
      and 83.3% versus 50.8%, respectively. Dementia patients of the medical subtype
      also had significantly more education, income, less function, and more symptoms
      of depression than dementia patients in the social subtype. Dementia patients of
      the medical subtype also had more abnormal psychological behaviors than their
      social subtype counterparts, with borderline significance (P = .071). There were
      more married caregivers in the medical subtype than in the social subtype day
      care. Caregivers of dementia patients in the medical subtype had significantly
      more paid help and caregiver burden than did caregivers of dementia patients in
      the social subtype. CONCLUSIONS: In this study, there appear to be key
      differences between the dementia patients and caregivers of medical versus social
      adult day care centers as to demographic and health-related variables. The
      differences in demographic variables appear to be associated with socioeconomic
      factors, whereas the decreased function and greater number of depressive symptoms
      of the medical dementia patients may reflect poorer health as reflected by the
      greater amount of paid help and increased caregiver burden experienced by the
      caregivers of medical dementia patients. These findings should be verified in
      prospective studies.

PMID- 8642156
TI  - Measuring capacity to complete an advance directive.
AB  - OBJECTIVE: To validate reference standards for the assessment of capacity to
      complete an advance directive and to develop and test three simple screening
      instruments. METHODS: We administered five measures of capacity to 96 older
      subjects from nursing homes, retirement homes, and homes for the aged. The
      measures included two reference standard evaluations: an assessment by a
      specially trained nurse in collaboration with a multidisciplinary team
      (Competency Clinic assessment) and geriatrician assessment using a decisional
      aid. Three screening instruments were also included: a Generic Instrument
      designed for any advance directive, a Specific Instrument designed for the "Let
      Me Decide" advance directive, and the Standardized Mini-Mental Status Examination
      (SMMSE). The screening instruments and the geriatrician's assessment were
      administered twice to half of the respondents to determine interrater agreement.
      RESULTS: The chance-corrected agreement for the assessment by two geriatricians
      was 0.78, and for agreement between the geriatricians and Competency Clinic
      assessments it was 0.82. Agreement for the Generic and Specific screening
      instrument assessments by two observers was 0.77 and 0.90, respectively. The
      areas under the Receiver Operating Characteristic curve relating the results of
      the three screening instruments to the Competency Clinic assessment were 0.82 for
      the Generic Instrument, 0.90 for the Specific Instrument, and 0.94 for the SMMSE;
      chance is an unlikely explanation for the difference between these three values
      (P < or = .01). CONCLUSIONS: Using rigorous methods, health workers can make
      reproducible and valid assessments of capacity to complete an advance directive.
      The SMMSE accurately differentiates people who can learn about and ultimately
      complete advance directives from those who cannot.

PMID- 8642157
TI  - The clinical usefulness of serum pepsinogens, specific IgG anti-HP antibodies and
      gastrin for monitoring Helicobacter pylori treatment in older people.
AB  - OBJECTIVE: To evaluate the clinical usefulness of Pepsinogen A (PGA) and C (PGC),
      PGA/PGC ratio, gastrin, and specific IgG anti-HP antibodies (anti-HP Ab) in
      monitoring the effect of cure for Helicobacter pylori (HP) infection in older
      people. DESIGN: We studied the changes in serum parameters (PGA, PGC, PGA/PGC
      ratio, gastrin and anti-HP Ab) in older patients before and 2 months after
      stopping therapy for the cure of HP infection. PATIENTS: Eighty-eight older
      patients (M = 43, F = 45, mean age = 73.3, range = 60-89) with chronic gastritis
      (42), gastric ulcer (14) or duodenal ulcer (32) were found HP-positive by
      histology of gastric antral and body biopsies and the rapid urease test.
      INTERVENTIONS: Two different associations of antibiotics and antiulcer drugs
      (omeprazole, metronidazole, azithromycin, or clarithromycin) for 2-4 weeks.
      MEASUREMENTS: At the beginning of the study and 2 months after treatment
      withdrawal, the subjects were studied by upper G.I. endoscopy with at least two
      antral and two body gastric biopsies (Giemsa stain and rapid urease test for HP);
      serum PGA (RIA method, microgram/mL), PGC (RIA method, microgram/mL), PGA/PGC
      ratio, gastrin (RIA method, picogr/mL), and anti-HP Ab (ELISA method, Biolife,
      MU/mL) were also determined. Statistical analysis was based on either the
      Wilcoxon test, for paired data, the chi-square test, the Kruskal Wallis test, or
      the Mann-Whitney test for unpaired data. The choice of the best cut-off value in
      the different parameters was performed by receiver operating characteristics
      curves (ROC) and by Youden index. The correlation between HP density in the
      gastric mucosa and gastritis activity was verified by Spearman rank correlation
      test. RESULTS: After therapy, 56/88 patients proved HP-negative (HP-eradicated: M
      = 30, F = 26, mean age = 73.0, range = 60-87 years), whereas 32/88 were not cured
      (HP-persistent: M = 13, F = 19, mean age = 73.0, range = 60-89 years). After
      therapy, in HP-eradicated cases, a statistically significant change was found in
      anti-HP Ab (75.23 +/- 8.94 vs 47.32 +/- 5.26, P < .001), PGC (21.58 +/- 1.97 vs
      14.34 +/- 1.75, P < .001), and PGA/PGC ratio (8.46 +/- 0.68 vs 11.54 +/- 0.89, P
      < .001), but not in PGA and gastrin. On the other hand, in HP-persistent cases,
      anti-HP Ab, PGA, PGC, PGA/ PGC ratio and gastrin did not change after therapy.
      The sensitivity and specificity were, respectively, 0.62 and 0.56 for anti-HP Ab
      and 0.75 and 0.56 for the PGA/PGC ratio, which demonstrated the best diagnostic
      accuracy (68%). CONCLUSIONS: The eradication of HP from the stomach of older
      patients induces a rapid and significant decrease in serum levels of IgG anti-HP
      antibodies and PGC, with an increase in PGA/PGC ratio but not in gastrin.
      Unchanged serum levels of IgG anti-HP antibodies, PGC, and PGA/PGC ratio 2 months
      after completing HP eradication therapy are indicative of ongoing HP infection.
      The PGA/PGC ratio showed the best diagnostic accuracy among serum measures
      tested.

PMID- 8642158
TI  - Cognitive and functional status of the oldest old.
AB  - OBJECTIVE: To compare the cognitive performance and functional status of the
      normal oldest old (85 + years) with that of normal older persons aged 65 to 84
      years to identify age-associated changes in cognition in individuals considered
      clinically normal. BACKGROUND: Advancing age appears to be a risk factor for
      dementia. DESIGN/METHODS: Analysis of performance on an extensive
      neuropsychological battery and the Pfeffer Outpatient Disability Scale in 243
      normal individuals age 65 to 99 years. RESULTS: Fifty-two normal subjects who
      were 85 years of age and older (mean age 88.2 +/- 3.1) and 191 normal subjects
      aged 65-84 years (mean age 75.8 +/- 5.0) were compared. Mean education for both
      groups was not statistically different. No significant differences in functional
      disability were found between the two groups. Normal subjects aged 85 years and
      older performed significantly less well than their younger counterparts on verbal
      and nonverbal memory, psychomotor/executive tasks, and category verbal fluency.
      CONCLUSIONS: Advancing age in normal subjects is accompanied by a decrease in
      cognitive function, measured by various neuropsychological tests, but is not
      accompanied by functional impairment.

PMID- 8642159
TI  - Age, education, and changes in the Mini-Mental State Exam scores of older women:
      findings from the Nun Study.
AB  - OBJECTIVE: To describe the relationship of Mini-Mental State Exam (MMSE) scores
      and changes over time in MMSE scores to age and education in a population of
      older women. DESIGN: A prospective study of a defined population. SETTING:
      Various motherhouses and church-run health care facilities in the Eastern,
      Midwestern, and Southern regions of the United States. PARTICIPANTS: Catholic
      sisters (nuns) participating in the Nun Study, a study of aging and Alzheimer's
      Disease. The 678 participants were 75 to 102 years old (mean 83.3, standard
      deviation 5.5, median 82.3) at the time of the first functional assessment.
      Second assessments were obtained an average of 1.6 years later on 575 survivors.
      MEASUREMENTS: The outcome variables were MMSE scores at the first assessment
      (Time-one), and MMSE scores at the second assessment (Time-two). The independent
      variables were age at Time-one, and education (bachelor's degree or no bachelor's
      degree). RESULTS: Time-one MMSE scores decreased with age at Time-one. The
      decrease in MMSE scores with age was less in sisters with bachelor's degrees than
      in sisters without bachelor's degrees. The changes in MMSE scores had a "U
      shaped" relationship with Time-one score, where the greatest declines occurred in
      sisters with intermediate Time-one scores. Stratified analysis by age, education,
      and Time-one MMSE scores of 20 or greater because of the small numbers of sisters
      with Time-one scores less than 20. In sisters with Time-one MMSE scores in the
      categories 20 to 23, 24 to 26, or 27 to 30, older ages at Time-one were
      associated with greater decline in those with bachelor's degrees, but not in
      those without bachelor's degrees. Also, lower education was associated with
      greater decline in sisters aged 75 to 84 years at Time-one, but this education
      effect disappeared or reversed in sisters who were 85 years of age or older at
      Time-one. CONCLUSIONS: Cognitive function as measured by the MMSE decreased with
      age at Time-one, most steeply as a function of age in those without bachelor's
      degrees. Cognitive function declined over 1.6 years within individuals, and the
      extent of decline increased with age in the sisters with bachelor's degrees. The
      extent of decline varied with age and education in an interactive manner, which
      may have been attributable to a hardy survivor effect in lower educated sisters.
      It may be necessary to consider such interactions whenever changes in function
      are studied, particularly when analyses are stratified by the initial level of
      function.

PMID- 8642160
TI  - Patterns of diagnoses, comorbidities, and treatment in late-middle-aged and older
      affective disorder patients: comparison of mental health and medical sectors.
AB  - OBJECTIVE: To compare the diagnoses, psychiatric and medical comorbidities, and
      prior and current treatment received by late-middle-aged and older affective
      disorder patients in mental health and medical service settings and to identify
      predictors of these patients' length of inpatient care. DESIGN: Department of
      Veterans Affairs (VA) nationwide databases are used to examine the prevalence,
      diagnoses, and inpatient and outpatient treatment received by affective disorder
      patients in mental health and medical units in Fiscal Year 1990. RESULTS:
      Compared with late-middle-aged and older index medical patients (n = 11,701),
      index mental health patients (n = 9039) were more likely to have affective
      psychoses and major depressive disorder and less likely to have depressive
      disorder NOS. Almost 60% of affective disorder patients in mental health settings
      had comorbid psychiatric diagnoses; this was true of 30% of patients in medical
      settings. Moreover, more than 80% of affective disorder patients in mental health
      settings had concomitant medical disorders. Affective disorder patients also had
      very high rates of prior mental health and medical care. Patients who had more
      severe affective disorders and comorbid psychiatric and medical diagnoses had
      longer episodes of inpatient care; in contrast, more intensive prior medical and
      mental health outpatient care was associated with shorter episodes of inpatient
      care. CONCLUSIONS: The findings highlight affective disorder patients' high rates
      of comorbidity and intensive use of health care resources, emphasize the value of
      outpatient care in reducing the amount of subsequent inpatient care, and
      underscore the need for closer integration of mental health and medical care.

PMID- 8642161
TI  - Using a mailed survey to predict hospital admission among patients older than 80.
AB  - OBJECTIVE: To determine if the results of a questionnaire mailed to older
      patients can help identify those patients at greatest risk of hospital admission.
      DESIGN: A longitudinal cohort study. SETTING: A prepaid managed care plan in the
      Denver metropolitan area. PARTICIPANTS: Of the 4414 eligible patients at least 81
      years old, 3745 (84.8%) responded. MEASUREMENTS: We studied the predictive power
      of self-reported demographic, health status, medical history, health habits,
      functional status (including Katz' activities of daily living and OARS
      instrumental activities of daily living), and socioeconomic status data to
      identify those older adults at greatest risk of hospitalization within 4.5 months
      of completing the survey. We derived our predictive model on one-half the
      subjects and tested its validity it on the other half. RESULTS: Univariate
      analysis revealed 25 variables significantly associated with hospital admission.
      In a logistic regression model, four significant variables successfully
      stratified the patients by risk of admission. These four variables are: the
      presence of heart disease, the presence of diabetes, need for help preparing
      meals, and limited physical independence (requiring the help of a person or
      mechanical aid to get around). In addition, there was an antagonistic interaction
      between the presence of heart disease and limited physical independence. The
      model stratified patients from low risk (4.5% chance of admission) to high risk
      (39% chance of admission). As measured by the Hosmer-Lemeshow statistic and the
      area under a receiver-operator characteristic (ROC) curve, this model fit both
      the derivation and validation subjects well. CONCLUSIONS: A mailed questionnaire
      achieved a high response rate, and the information collected produced an
      effective model predictive of hospitalization in the short term. Four easily
      ascertained pieces of information identify those patients older than age 81 at
      increased risk.

PMID- 8642162
TI  - Risk of napping: excessive daytime sleepiness and mortality in an older community
      population.
AB  - OBJECTIVE: To describe the demographic and health-related factors related to
      excessive daytime sleepiness. To estimate the risk of mortality associated with
      excessive daytime sleepiness independent of nightime sleep problems and other
      factors that limit survival. DESIGN: Four-year prospective cohort study with
      annual interviews. SETTING: One urban and four rural counties in north-central
      North Carolina. PARTICIPANTS: Adults 65 years and older (n = 3962) living in the
      community. MAIN OUTCOME MEASURES: Excessive daytime sleepiness was measured as,
      "How often do you get so sleepy during the day or evening that you have to take a
      nap?" Mortality was based on continuous surveillance of the population by field
      investigators and abstraction of death certificates. RESULTS: Point prevalence of
      excessive daytime sleepiness in this population was 25.2%. Frequent daytime
      nappers were more likely than infrequent nappers to report nighttime sleep
      complaints and were more likely to be male and urban-dwellers, to report more
      depressive symptoms, more limited physical activity, and more functional
      impairment, and were more likely to be overweight. Of the frequent nappers, 23.9%
      died, compared with 15.4% of infrequent nappers. In an adjusted Cox proportional
      hazard model, the 4-year mortality rate was accelerated 1.73 times among older
      people who nap most of the time and make two or more errors on a cognitive status
      examination. CONCLUSION: Excessive napping is associated with impaired sleep
      hygiene as well as with a broad range of activity-related health deficits among
      community-dwelling older adults. Frequent napping was associated with impaired
      sleep hygiene, male gender, urban-dwelling, depressive symptoms, physical
      activity deficits, functional impairment, and excess weight. Mortality risk was
      elevated selectively among the most cognitively impaired subjects.

PMID- 8642163
TI  - Hepatitis B virus vaccination for older adults.
AB  - OBJECTIVE: To compare in adults more than 50 years old the tolerability and
      immunogenicity of vaccination with recombinant hepatitis B surface antigen (HBs)
      compared with vaccination with recombinant hepatitis B protein PreS2 + S, and to
      investigate the safety and immunogenicity of a fourth vaccine dose in poor and
      non-responders. DESIGN: Randomized, double-blind prospective study. SETTING:
      General clinical research center for outpatient evaluation and vaccination.
      SUBJECTS: Adults older than age 50 who were in general good health and with no
      known risk factors for acquiring or serologic evidence of hepatitis B virus
      infection. INTERVENTION: Subjects were randomized to receive 10 mcg HBs
      (Recombivax, Merck, Sharp and Dohme), 12 mcg PreS2 + S, or 24 mcg PreS2 + S
      vaccine at 0, 1, and 6 months. Poor and non-responders (anti-Hbs < 10 mIU/mL at
      month 9 and/or 12) were encouraged to receive a fourth vaccine injection.
      MEASUREMENTS: Diary records of temperature and local and systemic reactions
      following each vaccination were maintained by all subjects. Anti-HBs levels were
      measured by radioimmunoassay before the first injection, at 1, 2, 3, 6, 7, 9, and
      12 months after for all subjects, and 1 month after the fourth injection for the
      group of poor and non-responders. MAIN RESULTS: Twenty men and nine women (mean
      age +/- SD, 66 +/- 8.0 years) were enrolled. Ten subjects received HBs vaccine,
      nine received 12 mcg PreS2 + S vaccine, and 10 received 24 mcg PreS2 + S vaccine.
      One subject in the HBs group dropped out, and data were analyzed for the
      remaining 28 subjects. There were no differences in rates of side effects
      reported by each of the three groups. Overall, minor local adverse reactions
      occurred in 12 (40%) after at least one of the first three vaccinations. Systemic
      side effects occurred in five (17%) after the first vaccination, in one after the
      second, but in none after the third. The 24-mcg PreS2 + S vaccine was not more
      immunogenic than the HBs vaccine, and the 12-mcg PreS2 + S vaccine was judged
      inadequate. Nineteen of 22 (86%) poor and non-responders received a fourth
      vaccination. Minor local adverse reactions were reported by six (32%), and none
      reported a systemic side effect. For the 12 subjects receiving a fourth injection
      of HBs or 24 mcg PreS2 + S vaccine, the proportion of responders 1 month
      following the fourth injection was greater than for 1 month following the third
      injection (11 of 12 [92%] versus 12 of 19 [63%], respectively, P < .05).
      CONCLUSION: For adults more than 50 years of age who have low anti-HBs levels
      after three vaccine injections, a fourth injection is well tolerated and results
      in improved immunogenic response.

PMID- 8642164
TI  - Impact of sample selection on APOE epsilon 4 allele frequency: a comparison of
      two Alzheimer's disease samples.
AB  - OBJECTIVE: In a highly selected sample of unrelated Alzheimer's disease (AD)
      patients, we found that the APOE epsilon 4 allele frequency was higher than
      previously reported. Differing selection and ascertainment criteria may lead to
      these differences. To address this possibility, we compared the epsilon 4 allele
      frequency in two samples of AD patients selected from the same geographical area.
      SETTING AND PARTICIPANTS: Cases (n = 55) and controls (n = 99) from a research
      clinic-based sample were compared with subjects (n = 537) from a community-based
      AD patient sample. The samples consisted of unrelated cases who met NINCDS/ADRDA
      criteria for probable AD. DESIGN AND MEASUREMENTS: Clinical characteristics and
      APOE genotype data were obtained from AD cases and controls from both samples.
      RESULTS: Frequency of APOE epsilon 4 allele in the research cases compared with
      the community cases (0.45 vs 0.36) was nearly significant. We compared
      demographic and clinical characteristics that might account for this difference
      and found that the research cases were younger, had an earlier age of onset, and
      had more advanced disease than the community cases. After onset age was
      controlled, there was no overall difference between epsilon 4 allele frequency of
      the two samples. CONCLUSIONS: We found that the epsilon 4 allele frequency tended
      to be higher in the research AD sample compared the community-based sample. The
      two samples differed in several demographic and clinical characteristics. We
      conclude that research-based samples may lead to enrollment of younger patients
      with more severe disease who have higher APOE epsilon 4 allele load. This
      potential selection bias must be considered in the interpretation of studies of
      APOE allele frequency.

PMID- 8642165
TI  - The utilization of antithrombotic prophylaxis for atrial fibrillation in a
      geriatric rehabilitation hospital.
AB  - OBJECTIVE: To determine the utilization of anticoagulant and antithrombotic
      agents in older patients with atrial fibrillation. DESIGN: Retrospective chart
      review. SETTING: A geriatric rehabilitation hospital. PATIENTS: Subjects were 102
      patients with atrial fibrillation as an intermittent or prevailing cardiac rhythm
      during a hospital admission in the 1993 fiscal year. MEASUREMENTS: Age, sex, and
      mental status of the patients; duration and etiology of atrial fibrillation;
      presence of contraindications to anticoagulants or antithrombotic agents; and
      utilization of these agents in this population. RESULTS: Of 102 older patients
      with atrial fibrillation at admission, only 51 were taking some form of
      anticoagulant or antithrombotic therapy proven effective for stroke prophylaxis
      (19 warfarin and 32 aspirin). Although 67 patients had relative contraindications
      to anticoagulation with warfarin, only 25 of the 35 with no contraindications
      were taking warfarin at the time of discharge. In addition, of the 43 patients
      with contraindications to warfarin but no contraindications to aspirin, only 28
      were prescribed antithrombotic therapy. CONCLUSIONS: Although anticoagulation or
      antithrombotic therapies for atrial fibrillation appear to be relatively widely
      used, there are still significant windows of opportunity for the improvement of
      clinician practice patterns and clinical outcomes in older patients.

PMID- 8642166
TI  - Improved reliability of the Standardized Alzheimer's Disease Assessment Scale
      (SADAS) compared with the Alzheimer's Disease Assessment Scale (ADAS).
AB  - OBJECTIVES: To compare the interrater and intrarater reliability of the
      Alzheimer's Disease Assessment Scale (ADAS) with the Standardized Alzheimer's
      Disease Assessment Scale (SADAS). DESIGN: A randomized, double blind trial.
      Sixteen university students were randomized to administer either version of the
      instrument. Subjects were randomized to three assessments, at 2-week intervals,
      using the ADAS or the SADAS. Each subject's first and third tests were
      administered by the same rater, the second by a different rater. SETTING: A
      geriatric outpatient clinic in a university teaching hospital. PARTICIPANTS:
      Fifty-four patients with possible or probable Alzheimer's disease living in the
      community or in a long-term care facility. MEASUREMENTS: The primary outcome was
      the interrater reliability of total ADAS and SADAS scores. Secondary outcomes
      were ADAS and SADAS cognitive scores, noncognitive scores, duration of testing,
      and sample size estimates. RESULTS: The interrater reliability of the SADAS total
      score was significantly better than that of the ADAS (interrater ICC 0.93 SADAS
      vs 0.83 ADAS), and the interrater standard deviation of the total SADAS score was
      lower than that of the ADAS (38%, P < .05). The SADAS cognitive subscale inter
      and intrarater reliability, although higher than the ADAS, was not significantly
      different when used by different raters (interrater ICC 0.91 SADAS vs 0.90 ADAS;
      intrarater ICC 0.88 SADAS vs 0.86 ADAS). The SADAS noncognitive subscale was
      significantly more reliable than the ADAS (interrater ICC 0.89 SADAS vs 0.42
      ADAS; intrarater ICC 0.87 SADAS vs 0.70 ADAS; P < or = .05) and had a lower
      standard deviation between raters (59%; P < .01) and within raters (40%; P < .05)
      compared with the ADAS. CONCLUSION: The improved reliability of the SADAS total
      score means that investigators can now use this score as a primary outcome
      measure, and important behavioral symptomatology can be included as a marker for
      treatment efficacy in AD. The smaller standard deviation of the SADAS means that
      clinical trials using the SADAS as a primary outcome will demonstrate
      differences, if present, with smaller sample sizes than with the ADAS.

PMID- 8642167
TI  - Use of genetically engineered mice as models for understanding human
      neurodegenerative disease.

PMID- 8642168
TI  - A 73-year-old woman with anemia and thrombocytopenia.

PMID- 8642169
TI  - To use physical restraints or not?

PMID- 8642170
TI  - Doppler assessment of diastolic function comes of age.

PMID- 8642171
TI  - Assisted suicide and euthanasia.

PMID- 8642172
TI  - Advance directives and older adults: a critical care perspective.

PMID- 8642173
TI  - The natural history of Alzheimer's disease.

PMID- 8642174
TI  - Reply to Whitehouse and Deal editorial.

PMID- 8642176
TI  - Prevalence and risk factors of peripheral arterial disease among older patients
      living in nursing homes.

PMID- 8642175
TI  - Long-term intravenous and oral flumazenil treatment of acute diazepam overdose in
      an older patient.

PMID- 8642177
TI  - Aspergillus flavus meningitis and pontine hemorrhage in an older patient.

PMID- 8642178
TI  - Epidemiology of anemia in older patients with hip fracture.

PMID- 8642179
TI  - Sexual abuse by grandparents: two clinical cases.

PMID- 8642181
TI  - The role of toxicology in the evaluation of new agrochemicals.
AB  - The use of agrochemicals like crop protecting agents, veterinary disinfectants,
      and wood preservatives may result in (un)intentional exposure of the environment,
      animals and man. This paper deals with current testing strategies to assess the
      potential health risks for humans exposed to these chemicals during production or
      application or via consumption of foods containing pesticide residues. Principles
      and procedures for safety assessment of pesticide residues in food as developed
      by WHO/FAO are described. Different types of toxicity studies in mammalian test
      animal species are discussed and a strategy is outlined in order to characterize
      the toxicity profile of a compound and the relationship between applied doses and
      adverse effects. Safety testing of agrochemicals should be carried out in
      relation to its intended use, and in particular attention will be paid to
      toxicity testing of residues of pesticides in food. Extraplation of results from
      animal studies to humans and the use of safety factors is discussed. Besides the
      use of animal protocol studies for safety testing of agrochemicals, the potential
      use of in-vitro models derived from organs and tissues of animals is discussed.
      Data on the in-vitro metabolism of thiabendazole, aldicarb and alachlor are
      discussed in order to demonstrate that such data may complement or partly
      substitute whole animal experimentation. Principles and procedures for safety
      testing of residues of agrochemicals in foods as applied during the last three
      decades, constitute a 'safety-first' approach, providing sufficient safety
      margins for the consumer of foods which may contain low levels of residues of
      agrochemicals.

PMID- 8642180
TI  - Pesticides in ground water in the United States: monitoring, modeling, and risks
      from the U.S. perspective.
AB  - Scientific and regulatory interest in ground water contamination by pesticides
      increased significantly in 1979. This was prompted by findings of the nematicide
      1,2-dibromo-3-chloropropane (DBCP) and the nematicide/insecticide aldicarb
      (Temik) in ground water in several states. Since that time, at least 130
      pesticides and pesticide metabolites have been detected in ground water in over
      150 studies, but detection frequencies are 4-10% nationally. Detection
      frequencies of pesticides over Health Advisory Levels are generally lower.
      Screening-level models and detailed computer simulation models are useful for
      risk assessments and regulatory decisions. Attenuation Factor, CMLS, PRZM2,
      GLEAMS, and LEACHM are all useful models.

PMID- 8642182
TI  - Rapid assays for environmental and biological monitoring.
AB  - Rapid, inexpensive, sensitive, and selective enzyme-linked immunosorbent assays
      (ELISAs) now are utilized in environmental science. In this laboratory, many
      ELISAs have been developed for pesticides and other toxic substances and also for
      their metabolites. Compounds for which ELISAs have recently been devised include
      insecticides (organophosphates, carbaryl, pyrethroids, and fenoxycarb),
      herbicides (s-triazines, arylureas, triclopyr, and bromacil), fungicides
      (myclobutanil), TCDD, and metabolites of naphthalene and toluene. New rapid
      assays have been developed for mercury.

PMID- 8642183
TI  - Between practice and theory: Melanie Klein, Anna Freud and the development of
      child analysis.
AB  - An examination of the early history of child analysis in the writings of Melanie
      Klein and Anna Freud reveals how two different and opposing approaches to child
      analysis arose at the same time. The two methods of child analysis are rooted in
      a differential emphasis on psychoanalytic theory and practice. The Kleinian
      method derives from the application of technique while the Anna Freudian method
      is driven by theory. Furthermore, by holding to the Freudian theory of child
      development Anna Freud was forced to limit the scope of child analysis, while
      Klein's application of Freudian practice has led to new discoveries about the
      development of the infant psyche.

PMID- 8642184
TI  - New meta-analysis of treatment trials of hypertension: improving the estimate of
      therapeutic benefit.
AB  - The objectives of this sub group meta-analysis on the treatment of hypertension
      was to: (1) high-light specific results of well-designed trials; (2) group trials
      according to their specific clinical context; (3) express results of the meta
      analysis in absolute reduction terms; and (4) estimate the bias of withdrawal
      because of blood pressure increase. This meta-analysis is based on summarised
      published results from randomised controlled trials, comparing a drug treatment
      versus placebo or no treatment, with morbi-mortality as the principle outcome.
      The following data were analysed: (1) total mortality; (2) cardiovascular
      mortality; (3) stroke; (4) major coronary events; and (5) congestive heart
      failure. The treatment significantly reduced the incidence of all outcomes in
      trials involving older patients, avoiding up to nine strokes (OR = 0.66, 95% Cl:
      0.56-0.77) and four major coronary events (OR = 0.79, 95% Cl: 0.68-0.92) every
      1000 patient-years when the bias of withdrawal was taken into account. The only
      outcome significantly influenced by treatment in younger patients with mild-to
      moderate hypertension was stroke, with one stroke avoided every 1000 patient
      years (OR = 0.51, 95% Cl: 0.39-0.66). There was insufficient statistical power in
      the trials which enrolled patients with non-moderate hypertension to reach
      clinical significance, except for the reduction in the incidence of congestive
      heart failure. However, the results indicated a trend towards greater absolute
      benefit under treatment. Trials enrolling patients with post-stroke hypertension
      also had insufficient power, but suggested benefit by the reduction of the
      incidence of stroke recurrence and congestive heart failure under treatment. In
      conclusion, the most constant treatment benefit concerned stroke, although the
      absolute reduction was very modest in younger patients with mild-to-moderate
      hypertension. Only the results from trials in older patients showed a significant
      reduction of major coronary events. Such results need further analyses, ideally
      based on individual patient data.

PMID- 8642185
TI  - Use of home blood pressure measurements to diagnose "white coat hypertension' in
      general practice.
AB  - Mercury sphygmomanometers are the gold standard in blood pressure (BP)
      measurement. However, white coat hypertension can only be diagnosed by using
      either continuous ambulatory monitoring or home BP recording. Between 10% and 20%
      of patients under treatment for hypertension have white coat hypertension and
      most do not need medication. There have been no reports from general practice in
      the UK of the use of home recording which seems well suited to it. The aim of
      this study was to confirm the feasibility of carrying out validation procedures
      of a UA751 semi-automatic sphygmomanometer and to use it to diagnose white coat
      hypertension in one practice. Firstly, the validation consisted of tests based on
      the British Hypertension Societies (BHS) published methods. Simultaneous BP
      measurements were made with the UA751 and a mercury sphygmomanometer, using a t
      tube, of 45 random normotensive and hypertensive patients. Validation readings
      were mercury instrument means 155/83 (s.d.s 25 and 11), UA751 means 156/85 (s.d.s
      25 and 10). The proportion of acceptable differences between the readings placed
      the UA751 in the BHS Guidelines Grade 'B'. Secondly, to detect white coat
      hypertension, 52 consecutive new or poorly controlled hypertensive patients took
      a series of home BP readings. Five patients with white coat hypertension were
      found. We concluded that it is feasible to use the UA751 to diagnose white coat
      hypertension in general practice where most hypertensive patients are exclusively
      managed. Used for this specific purpose, it would be extremely cost effective,
      precluding many patients from unnecessary medication and saving substantial costs
      in drugs and other resources.

PMID- 8642186
TI  - Design and baseline characteristics of a hypertension intervention program in a
      South African village.
AB  - The Mamre Hypertension Project was initiated in response to studies indicating
      that hypertension and cardiovascular disease were prevalent in a rural community
      of Mamre, located in the Western Cape, South Africa. A survey was done to collect
      baseline information on the prevalence of hypertension and other cardiovascular
      disease risk factors. The age-adjusted prevalence of hypertension in people aged
      15 years or more was 13.9% in men and 16.3% in women. Of the hypertensive
      subjects, 27% were not aware of their hypertension, a further 14.4% were not on
      treatment, and only 16.8% had their blood pressure (BP) controlled at under
      140/90 mm Hg. There was a high prevalence of smoking, heavy alcohol use (in men),
      obesity (in women) and physical inactivity. The survey results will be used to
      assess the impact of the intervention programme using a before and after design,
      and are being used to direct interventions. The intervention programme comprises
      a BP station catering primarily for people with hypertension, and a health
      education and promotion programme directed at the general community. The BP
      station screens for hypertension, monitors BP and compliance with medication in
      hypertensives, and encourages risk factor modification. Health promotion
      activities include a smoking cessation group and a weight reduction and exercise
      group. These are run by community volunteers with support from outside
      consultants. The effects of the programme will be assessed after 4-5 years.

PMID- 8642187
TI  - Lack of linkage between the endothelial nitric oxide synthase gene and
      hypertension.
AB  - Nitric oxide is an important vasodilator formed in many tissues, including the
      vascular endothelium. Because of the relationship between nitric oxide and basal
      vascular tone, genes regulating nitric oxide have been suggested as candidate
      genes involved with the development of hypertension. At least three isoforms of
      nitric oxide synthase have been identified. Two of the isoforms, endothelial and
      inducible nitric oxide synthase, may have particular importance in hypertension.
      The gene coding for endothelial nitric oxide synthase on chromosome 7 has been
      cloned. Polymorphic dinucleotide repeats within this nitric oxide synthase gene
      were used to test for linkage to hypertension in 259 hypertensive siblings from
      112 Utah hypertensive sibships. The resulting 194 sibpairs shared 108 alleles
      identical by state compared to the expected 108.1 alleles shared as estimated
      from CEPH allele frequencies. After weighting for different sibship sizes, there
      was only a 3.9% excess allele sharing (P = 0.21). Allele sharing in more severe
      hypertensive sibpairs (either two antihypertensive medications or an unmedicated
      diastolic blood pressure (BP) of 100 mm Hg or higher) showed a 6% excess over
      expected sharing of alleles (P = 0.28). There was no difference between male and
      female sibpair sharing of alleles (5.2% vs 7.8%, respectively, both not
      significant). Therefore, there was no evidence that the gene for endothelial
      nitric oxide synthase was linked to hypertension in these sibpairs.

PMID- 8642188
TI  - Angiotensin converting enzyme gene I/D polymorphism, blood pressure and the renin
      angiotensin system in Caucasian and Afro-Caribbean peoples.
AB  - The objectives of this study were to assess relations between ACE gene I/D
      polymorphism, essential hypertension, plasma renin activity and aldosterone in
      white (European descent) and black (Afro-Caribbean descent) peoples. Measurements
      were carried out on a total of 320 subjects (210 white: 116 men, 94 women; 110
      black: 65 men, 45 women); all were on their usual sodium intake; none was on anti
      hypertensive therapy and none had secondary hypertension. Genomic DNA was
      isolated from blood cells and ACE I/D genotype was established using polymerase
      chain reaction. Plasma hormones were measured by radioimmunoassay and blood
      pressure (BP) with an ultrasound sphygmomanometer. All subjects were grouped into
      normotensive, borderline and hypertensive according to WHO guidelines. The
      distribution of the I/D genotype in the white people was approximately 1:2:1; by
      contrast, in the Afro-Caribbean people there was a significantly higher frequency
      of the D allele (chi 2P = 0.04). Within the white people there was no significant
      association between ACE genotype and high BP; however, within the black people
      there was a positive association between the frequency of the D allele and
      increasing BP ( chi 2 for trend P = 0.03). In either group, there were no
      associations between ACE I/D genotype and plasma renin activity and aldosterone
      suggesting that ACE genotype does not contribute to the expression of the
      circulating renin-angiotensin system. This study highlights differences in ACE
      I/D polymorphism between white and black peoples and suggests the possibility of
      racial differences in the association between ACE genotype and BP.

PMID- 8642189
TI  - Prostacyclin biosynthesis in essential hypertension before and during treatment.
AB  - Protacyclin biosynthesis was investigated in 133 untreated newly diagnosed
      patients with uncomplicated essential hypertension. Urinary excretion of 6-oxo
      prostaglandin F1 alpha and of 2,3-dinor-6-oxo-prostaglandin F1 alpha, stable
      breakdown products of prostacyclin, was measured following a 1 month run-in
      period. To determine whether lowering blood pressure (BP) influenced prostacyclin
      biosynthesis, 106 consenting patients with diastolic pressure 90-120 mm Hg were
      allocated randomly to treatment with bendrofluazide, metoprolol, quinapril or
      amlodipine in an open parallel group design. Dose was increased to reduce
      diastolic arterial pressure to <90 mm Hg. Terazosin was added if this target BP
      was not achieved, and its dose increased if necessary. Urinary excretion rates of
      prostaglandins were measured after 1 year in patients in whom the target
      diastolic pressure was achieved. Mean arterial pressure varied from 106-168 mm Hg
      in untreated patients and excretion of both prostacyclin-derived products varied
      from <5 to >350 ng/g creatinine. Arterial pressure and prostaglandin excretion
      were not significantly correlated. In 57 patients in whom target pressure was
      achieved, BP before treatment was 166 +/- 2/100 +/- 1 at baseline and 144 +/-
      2/86 +/- 1 mm Hg at 1 year. Excretion rates of each prostacyclin-derived product
      were similar before treatment and at 1 year, with no significant differences
      between the drugs. These findings do not support the hypothesis that deficient
      prostacyclin biosynthesis contributes to the pathogenesis of essential
      hypertension, or that increased prostacyclin biosynthesis plays a part in the
      response to treatment with antihypertensive medication.

PMID- 8642190
TI  - Heart rate variability before sudden blood pressure elevations or complex cardiac
      arrhythmias in phaeochromocytoma.
AB  - In phaeochromocytoma, sudden hypertensive or arrhythmic episodes are believed to
      be associated with excessive free catecholamine excretion. However, lack of
      correlation between blood pressure (BP) and plasma catecholamine levels has been
      reported. Therefore an attempt was made to assess the sympathovagal balance
      before and during episodes of BP elevation or complex cardiac arrhythmias in this
      disease. Ten patients with phaeochromocytoma and 10 matched controls with
      essential hypertension underwent simultaneous 24 h Holter ECG and BP monitoring.
      BP elevation was diagnosed when the BP exceeded the mean 24 h values by 40 mm Hg
      systolic or 30 mm Hg diastolic, respectively. Heart rate variability (HRV) was
      measured for 5 min periods 1 h before, 15 min before and during 13 episodes of BP
      elevation in phaeochromocytoma and 13 episodes in the control group, as well as
      at 1 h, 15 min and immediately before five arrhythmic events in
      phaeochromocytoma. In phaeochromocytoma, vagal activity measured 1 h before BP
      elevation was markedly higher than in control hypertensives. However, in both
      groups at 15 min before and during the hypertensive events, the vagal tone
      decreased significantly. In contrast, just before the arrhythmic events HRV
      remained unaltered with a slight insignificant increase in sympathetic activity.
      We conclude that in phaeochromocytoma, pronounced BP elevations during daily
      activities are preceded by a parasympathetic withdrawal, similar to the findings
      in essential hypertension. Such a sequence does not seem to precede sudden
      complex arrhythmic events in phaeochromocytoma.

PMID- 8642191
TI  - Antihypertensive effects of trandolapril and nitrendipine in the elderly: a
      controlled trial with special emphasis on time effect profiles.
AB  - The aim of this double-blind randomized study was to compare the antihypertensive
      effects of trandolapril and nitrendipine in the elderly. After a 2-week placebo
      period, patients received either trandolapril 0.5 mg or nitrendipine 10 mg, once
      daily for 15 days. At the end of this period, according to a forced titration,
      the dose was increased to 2 mg of trandolapril or 20 mg of nitrendipine once
      daily for 2 months. Seventy-three hypertensive patients, aged 65 and over,
      entered the study. Demographic data and initial blood pressure (BP) level were
      comparable in the two groups. The antihypertensive effect, measured with a
      mercury sphygmomanometer, was assessed in 64 patients: SBP decreased by 18.6 +/-
      12.1 mm Hg in the trandolapril (P < 0.001) and by 21.0 +/- 13.7 mm Hg in the
      nitrendipine group (P < 0.001); DBP decreased by 13.4 +/- 8.5 mm Hg in the
      trandolapril group (P < 0.001) and by 15.4 +/-8.2 mm Hg in the nitrendipine group
      (P < 0.001). No statistically significant difference was seen between the two
      treatment groups. A sub-group of 42 patients were evaluated by 24 h ambulatory BP
      monitoring. Mean 24 h ambulatory SBP/DBP decreases were 6.6 +/- 18.0/8.4 +/- 8.5
      mm Hg in the trandolapril group (P < 0.001) and 5.7 +/- 11.1/7.2 +/-9.6 mm Hg in
      the nitrendipine group (P < 0.001). The differences between the two treatment
      groups were not statistically significant. The antihypertensive action of
      trandolapril was sustained throughout the 24 h period with a trough-to-peak ratio
      of 70.2% for SBP and 70.9% for DBP. Nitrendipine exerted its action mainly during
      the day, with a very modest antihypertensive effect during the night and early
      morning; its trough/peak ratio was 25.9% for SBP and 28% for DBP. The tolerance
      of both treatments were good; seven patients were withdrawn from the trial for
      adverse events (four in the nitrendipine group, three in the trandolapril group).

PMID- 8642192
TI  - Unique cause of renovascular hypertension: melorheostosis associated with a
      malformation of the renal arteries.
AB  - We describe the case of a 17-year-old patient with melorheostosis and
      renovascular hypertension, an association that has not been reported before. Also
      the patient's aortic valve insufficiency could be attributed to underlying
      mesenchymal and vascular dysplasia.

PMID- 8642193
TI  - Evaluation of the Takeda TM-2420 in the elderly.

PMID- 8642194
TI  - Office, nurse, basal and ambulatory blood pressure as predictors of hypertensive
      target organ damage in male and female patients.
AB  - The objective of this study was to assess the value of two substitutes for
      ambulatory blood pressure (BP) monitoring: nurse-measured BP and BP measured by
      an automated device during 1 h resting in the clinic (basal BP). Hypertensive
      patients in an academic out-patients clinic were selected consecutively. We
      compared the relation of indices of early target organ damage
      (echocardiographically determined left ventricular mass index (LVMI) and urinary
      albumin excretion (expressed as albumin/creatinine ratio: ACR) to physician
      measured and nurse measured basal and ambulatory BP. The relation of BP to LVMI
      and the logACR were also studied for both sexes separately. Sixty-two patients
      (28 men, 34 women) were included, all untreated for >3 months. Systolic office BP
      was not significantly related to the LVMI (r2 = 0.04, P > 0.05), whereas nurse
      measured (r2 = 0.11, P < 0.05), basal (r2 = 0.13, P < 0.01) and ambulatory
      daytime (r2 = 0.13, P < 0.05) and night time (r2 = 0.17, p < 0.001) SBP did have
      a significant relation to LVMI. There was no difference in the relation of
      office, nurse, basal or ambulatory BP to logACR. In contrast to the highly
      significant relation of SBP to LVMI for male patients (day: r2 = 0.29, P < 0.01,
      night: r2 = 0.46, P < 0.001) this relation was non-existent for female patients
      (day: r2 = 0.09, P > 0.05, night: r2 = 0.02, P > 0.05). The relation between BP
      and logACR did not differ between the sexes. We conclude that: (1) to some degree
      nurse measured and basal BP may be considered as better predictors of early
      hypertensive target organ damage than physician measured BP; and (2) there is a
      pronounced sex difference in the relation of BP to left ventricular mass.

PMID- 8642195
TI  - Immunogenicity of new heterobifunctional cross-linking reagents used in the
      conjugation of synthetic peptides to liposomes.
AB  - We have investigated the immunogenicity of six thiol-reactive heterobifunctional
      cross-linking reagents that permit the conjugation of cysteine carrying peptides
      to the surface of liposome containing monophosphoryl lipid A. Such constructs
      elicit an immune response against short synthetic peptides and our aim was to
      find the least immunogenic linkers to limit potential carrier-induced epitopic
      suppression. For that purpose the properties of three new polyoxyethylene linkers
      of different lengths and thiol-reactive moieties (maleimide, bromoacetyl,
      dithiopyridine) were compared to known derivatives obtained by reacting the
      classical reagents SMPB and SPDP or N-succinimidyl bromoacetate with
      phosphatidylethanolamine. The least immunogenic linkers were the bromoacetate
      derivatives whereas those containing a maleimide group evoked a significant anti
      linker immune response. In addition, using IRGERA as a model peptide, we found
      that all six liposomal constructs strongly elicited the production of anti
      peptide IgG antibodies. This immune response was therefore independent of the
      length of the linkers (ranging between 0.3 and 1.6 nm) and of the nature of the
      linkage. between the peptide and the thiol-reactive moieties of the cross
      linkers, i.e. stable thioether or bio-reducible disulfide bonds.

PMID- 8642196
TI  - Fractionation of perforin and granzymes by immobilized metal affinity
      chromatography (IMAC).
AB  - Cytotoxic lymphocytes and natural killer cells kill their targets by releasing
      pore-forming granules or by Fas ligand-Fas initiated death. The granules contain
      the pore-forming protein perforin, proteoglycan and multiple serine proteases
      termed granzymes. In this paper we describe two options for isolating perforin
      and granzymes. Both options separate the proteins by their ability to bind to
      immobilized metal affinity chromatography (IMAC) columns. The first option, with
      Cu2+ as the metal (Cu2+-IMAC), separates both perforin and granzymes while the
      second, with Co2+ as the metal (Co2+-IMAC), separates only perforin. After Cu2+
      IMAC perforin is > 20-fold enriched with excellent recovery of lytic activity.
      Only two proteins are substantial contaminants. After Cu2+-IMAC, the perforin is
      dilute and requires concentration before additional steps of purification. The
      second option, with Co2+ as the metal Co2+-IMAC), yields perforin that is
      concentrated in a sharp peak. The concentrated perforin is immediately suitable
      for further purification. The first option, with Cu2+, isolates the granzymes
      while the second option, Co2+-IMAC, does not. After isolation, the perforin lytic
      and granzyme activities are stable for weeks at 4 degrees C, an advantage to
      previous isolation methods for these proteins. The excellent recoveries of
      perforin and granzymes also indicate that these proteins are less than 4% and 15%
      of the total lymphocyte granule protein, respectively.

PMID- 8642197
TI  - Direct assessment of junctional diversity in rearranged T cell receptor beta
      chain encoding genes by combined heteroduplex and single strand conformation
      polymorphism (SSCP) analysis.
AB  - In order to define the extent of T cell heterogeneity and clonality, unique DNA
      sequences in the junctional region in rearranged T cell receptor (TcR) genes can
      be studied. For this purpose we have adapted a non-denaturing nucleic acid gel
      electrophoresis procedure to detect TcR junctional diversity. Detection of
      junctional diversity is based upon electrophoretic separation of single stranded
      (ss) and double stranded (ds) DNA molecules via mobility shifts due to nucleotide
      sequence polymorphism. To examine the capacity of this nucleic acid gel
      electrophoresis procedure to detect nucleotide sequence polymorphism in the CDR 3
      region within TcR V beta gene family sequences polymerase chain reaction (PCR)
      amplified TcR V beta 5.1/5.4 and V beta 14 cDNA sequences were analyzed. The
      results of this study showed that (1) the single strand conformation polymorphism
      (SSCP) procedure has a low capacity to discriminate between diverse TcR V beta
      cDNA sequences due to comigration of the ssDNA molecules, which results in an
      underestimation of the heterogeneity in a given T cell population; (2)
      comigrating ssDNA and/or dsDNA (homoduplex) molecules can be separated by the
      formation of heteroduplex molecules; these heteroduplex molecules provide
      essential additional information on the degree of nucleotide sequence
      polymorphism in the CDR 3 region within the TcR V beta cDNA sequences; (3) the
      double strand conformation polymorphism (DSCP) procedure provides a fast and
      reliable procedure to detect junctional diversity within the sequences tested.
      Using DSCP a more detailed assessment of amplified TcR V beta cDNA sequences can
      be obtained as compared with SSCP analysis only. Data obtained by gel analysis
      were very similar to those obtained by conventional bacterial cloning and DNA
      sequencing procedures on the corresponding cDNA clones. In conclusion, this new
      gel electrophoresis procedure allows a direct assessment of the extent of T cell
      heterogeneity and clonality by screening junctional diversity in TcR chain
      encoding sequences in clinical conditions with (oligo)clonal expansion of T
      lymphocytes.

PMID- 8642198
TI  - Use of peptide immunization for porcine insulin of a very high homology with a
      host protein.
AB  - An anti-peptide antibody was obtained against a peptide corresponding to the 12
      amino acids of the C-terminal region of porcine insulin B chain. The adsorption
      characteristics of this antibody were compared with those of anti-porcine insulin
      and anti-sheep insulin antibodies. Immunization of rabbits using the peptide
      corresponding to the C-terminal region of porcine insulin B chain produced an
      anti-peptide antibody which reacted with native porcine insulin with a much
      higher association constant than that of an anti-porcine insulin antibody. In
      addition, this immunization technique did not cause any observable
      physiologically harmful effects, such as hypoglycemia, in the immunized rabbits.
      Thus, peptide immunization may be a useful strategy when target proteins have
      biological activity and/or toxicity, and also have a very high degree of homology
      with the corresponding proteins of the immunized animal, which may inhibit the
      production of antibodies with a high association constant.

PMID- 8642200
TI  - A convenient method for epitope competition analysis of two monoclonal antibodies
      for their antigen binding.
AB  - Choosing optimum pair of capturing antibody and detecting antibody when
      developing monoclonal antibody (MAb)-based, sandwich enzyme-linked immunosorbent
      assays is a time-consuming process requiring the coupling of individual
      antibodies to an enzyme like horseradish peroxidase or alkaline phosphatase. The
      MAbs required for the two-site sandwich ELISA should bind to distinct epitopes of
      the antigen, and their binding should not be mutually exclusive. To determine if
      two monoclonal antibodies would occupy distinct sites of their antigen in
      binding, an enzyme-linked immunosorbent assay was devised, which is easy-to-use
      and does not require any coupling of monoclonal antibodies to enzymes. Microplate
      wells are coated with rabbit polyclonal antibodies raised against the same
      antigen of MAbs. After blocking, a limited amount of the antigen is added for
      incubation with the rabbit antibodies. Mouse monoclonal antibody 1 (MAb 1) is
      added to saturation. A serial dilution of MAb 2 (for analysis) or MAb 1 (for
      control) is added subsequently. An enzyme-labeled, goat anti-mouse secondary
      antibody and its substrates are added for color development. Thus, the epitope
      competition of two MAbs for their antigen binding is easily determined by the
      measurement and comparison of color development between the two MAb additions.

PMID- 8642199
TI  - A method for titration of inhibiting antibodies to bacterial immunoglobulin A1
      proteases in human serum and secretions.
AB  - Bacterial IgA1 proteases specifically cleave IgA1, including S-IgA1, molecules
      into Fab alpha and Fc alpha fragments. Hereby these enzymes interfere with the
      protective functions of antibodies belonging to this isotype. Antibodies
      inhibiting IgA1 proteases have been detected in humans, but the titration of such
      antibodies is a matter of methodological concern. Because human serum and
      secretions contain IgA1 substrate, it is impossible to provide uniform substrate
      conditions for samples of IgA1 protease incubated with inhibitors differing in
      their origin and state of dilution. This study demonstrates that such variations
      in substrate are not prohibitive for a reliable titration of inhibiting
      antibodies. This was evident from experiments demonstrating that the variations
      do not interfere with the quantification of residual IgA1 protease activity
      provided the activity is measured in terms of the proportion of IgA1 substrate
      cleaved during incubation. Proportions of cleaved IgA1 were measured by
      exploiting the differential reactivity of cleaved and intact IgA1 molecules in an
      ELISA using anti-Fc alpha and enzyme-conjugated anti-light chain antibodies for
      catching and development, respectively. A protocol for the titration of IgA1
      protease-inhibiting antibodies based on this ELISA is described. By application
      of the protocol to chromatographic fractions of saliva, IgA1 protease-inhibiting
      activity was found to co-purify with salivary S-IgA.

PMID- 8642201
TI  - Microtiter plate immunoassay for the evaluation of platelet adhesion to
      fibronectin.
AB  - Investigations of platelet adhesion to adhesive proteins have been pursued to
      understand the basic mechanisms of hemostasis and thrombosis. Most assays used to
      determine platelet adhesion under stasis conditions rely on radiolabeled
      platelets. We describe a new microtiter immunoassay to study platelet adhesion to
      adhesive proteins under stasis conditions. Direct comparison of platelet adhesion
      to fibronectin using a standard platelet adhesion assay based on 51Cr-labeled
      platelets and the new immunoassay showed that the optical density values obtained
      with the immunoassay are directly proportional to the number of platelets bound.
      The choice of platelet suspension buffer crucial for the design of such
      experiments, because the adhesion of resting platelets to fibronectin is
      increased in response to thrombin stimulation. This increase buffer rather than
      Tris buffer. Platelet adhesion to fibronectin is increased in response to
      thrombin stimulation. This increase can be inhibited by synthetic RGD peptides.
      The thrombin-induced increase of platelet adhesion to fibronectin could be
      detected with antibodies against actin and glycoprotein IIb-IIIa, but not against
      the alpha-granule constituent platelet factor 4 (PF4). This assay is very
      versatile, because it avoids the use of radioactivity, and allows the parallel
      processing of a large number of samples. In addition, the parallel use of
      antibodies against different platelet antigens allows the screening for platelet
      activation events associated with the measured platelet adhesion.

PMID- 8642202
TI  - Clarification of immunoblots on polyvinylidene difluoride (PVDF) membranes for
      transmission densitometry.
AB  - The opacity of polyvinylidene difluoride (PVDF) transfer membrane can be reduced
      by infiltration with liquid. A mixture of 9:1 v/v ethylene glycol/glycerol gives
      complete transparency; clarification by this mixture is stable due to the low
      volatility of the components and is reversed by washing in water without loss of
      band intensity. The mixture is easy to apply to the membrane and being water
      soluble, non-corrosive and relatively non-toxic, is convenient to use.
      Clarification and densitometric analysis of stained immunoblots of PVDF membranes
      is at least as effective as that previously described for nitrocellulose, but the
      greater ease of use of the new mixture makes PVDF the membrane of choice for
      transmission densitometry. Using a blot onto PVDF of monoclonal IgG probed with
      anti-mouse antibody, laser transmission densitometry revealed that the stained
      peak area was related to loading in a linear fashion over a 60-fold range on a
      single blot.

PMID- 8642203
TI  - The use of reverse transcription polymerase chain reaction to analyse large
      numbers of mRNA species from a single cell.
AB  - A PCR method is described for determining the expression of multiple
      heterogeneous mRNAs from single cells. The total mRNA pool of a single selected
      cell is subjected to reverse transcription and subsequent tailing with poly(dA).
      This cDNA is preamplified by a sequence non-specific PCR protocol using oligo(dT)
      containing primers. The single cell cDNA library obtained permits the analysis of
      virtually unlimited numbers of mRNA species per cell using sequence-specific PCR.
      This procedure of multiple mRNA analysis enables phenotyping of any cell for its
      mRNA composition and could be used to study the cytokine mRNA expression of
      individual human T cells ex vivo. The method should greatly facilitate the
      analysis of combinatorial expression of known genes in any cell.

PMID- 8642204
TI  - Evaluation of six anti-gliadin antibody assays.
AB  - Two in-house methods developed in gastroenterological laboratories for the
      detection and quantitation of IgG and IgA antibodies to gliadin (AGA) were
      compared with three commercially available ELISAs (gluten IgG/IgA EIA, Kabi
      Pharmacia, Sweden; alpha-Gliatest, Eurospital, Italy; AGA Orkit, Labodia,
      Switzerland) and one qualitative rapid assay (Gliastick, Eurospital, Italy). 67
      acute, biopsy confirmed coeliac disease cases were compared with 54 biopsy
      confirmed disease controls. The result of anti-endomysium antibody (AEA) testing
      was available from all cases. The testing of 121 sera in different test systems
      permitted comparison of the range of concentration and sensitivity of the
      quantitative IgG and IgA anti-gliadin tests. Each test uses its own arbitrary
      calibration. To permit direct comparison of the different test ranges the values
      of the different positive reference sera were converted into Pharmacia arbitrary
      units (AU). The AGA and IgG tests ranged from 0 to a maximum of 157-430 AU and
      the maximum IgA test results from 81 to 855 AU. This illustrates the need for an
      internationally accepted standard. All three EIA kits met the performance claims
      of the manufacturers and were easy to use. Most results agreed with the clinical
      diagnosis when the sera were positive for anti-endomysium antibodies. However,
      AEA negative specimens showed a considerable incidence of positive AGA in non
      coeliacs. The study emphasises the need to test for both AGA and AEA in order to
      reliably diagnose coeliac disease. The qualitative test showed a high degree of
      false positive results and could be used to monitor the dietary compliance of
      coeliac patients.

PMID- 8642205
TI  - Tween 20 selectively enhances naturally occurring anticardiolipin antibody
      binding in ELISA procedures.

PMID- 8642206
TI  - Two-graph receiver operating characteristic (TG-ROC): update version supports
      optimisation of cut-off values that minimise overall misclassification costs.
AB  - TG-ROC was recently introduced as a novel PC-assisted device for cut-off
      optimisation and evaluation of quantitative serodiagnostic tests (Greiner, 1995,
      J. Immunol. Methods 185, 145; Greiner et al., 1995, J. Immunol. Methods 185,
      123). In this notice a recent extension of the programme is described which
      facilitates the cut-off selection when estimates of costs associated with false
      positive and false-negative results are available.

PMID- 8642207
TI  - [From the Smart alpha 2-macroglobulin to single molecule biochemistry].

PMID- 8642208
TI  - [Mercaptopyruvate sulfurtransferase is a rhodanese family].

PMID- 8642209
TI  - [Cyclin D1 in oncogenesis].

PMID- 8642210
TI  - [Biological roles of choline kinase].

PMID- 8642211
TI  - [Structure and function of beta gamma subunits of heterotrimeric G proteins].

PMID- 8642212
TI  - [Colon cancer and vitamin D--in vivo growth inhibition of colon cancer by a
      fluorinated analogue of 1,25-(OH)2D3, DD-003].

PMID- 8642213
TI  - Prevention of impairment in leprosy; results from a collaborative project in
      China.
AB  - OBJECTIVE: to evaluate programs of prevention and treatment of impairments due to
      leprosy in 8 geographical areas in the People's Republic of China. DESIGN: follow
      up of cohorts of leprosy patients receiving a range of different interventions.
      SETTING: 8 different geographical areas in China, varying in urban and rural
      characteristics from 6 provinces and 2 municipalities. SUBJECTS: leprosy patients
      who were receiving or had completed a course of antileprosy chemotherapy.
      INTERVENTIONS: a range of interventions, including steroids, self-care training,
      adapted footwear, surgery and provision of prostheses. MAIN OUTCOME MEASURES:
      changes in eye, hand and foot impairments between baseline assessment and
      assessment at 2 years. RESULTS: 232 out of 3571 patients assessed monthly over 2
      years developed acute neuritis and, in most areas, were promptly and adequately
      treated. Regular self care of eyes was established in 238 out of 313 patients
      with lagophthalmos and was associated with reduction in the prevalence of
      conjunctivitis. Regular self care of hands was established in 730 out of 1010
      patients with neurological impairment of the hand; this was associated with a
      reduction (80%) in hand cracks and wounds. Regular self care of feet was
      established in 745 out of 1094 patients with neurological impairment of the feet;
      this was associated with a 83% reduction in patients with cracks and a 33%
      reduction in patients with sole wounds. A footwear program was established in all
      8 areas providing footwear to 4698 patients over the 2-year period; this was
      associated with a reduction of 61% and 21% in patients with cracks and wounds,
      respectively. Management of complicated sole wounds in 256 patients resulted in
      69% of these patients being free of sole wounds at 2 years. Targets for
      reconstructive surgery and amputations were not fully attained, but lower limb
      prostheses were provided for 306 patients. CONCLUSIONS: leprosy is a chronic
      disease characterized by peripheral neuropathies which can result in increasing
      secondary impairments and disabilities. The emphasis, in countries such as China
      where the chemotherapy programs have been effectively implemented, is shifting to
      prevention and treatment of impairments. This innovative program in China has
      successfully demonstrated that it is possible to prevent and reverse impairments
      due to leprosy.

PMID- 8642214
TI  - CD4+ T-cell responses to recombinant hsp65 and hsp18 of M. leprae and their
      trypsin-digested fragments in leprosy: diversity in HLA-DR restriction.
AB  - Mycobacterium leprae heat-shock proteins hsp65 and hsp18 have received immense
      attention as major T-cell target antigens in leprosy. Both of these hsps and
      their tryptic fragments were characterized for their ability to stimulate CD4+ T
      cells derived from polar leprosy cases and healthy contacts. The optimal
      digestion of hsps with trypsin yielded four fragments of hsp65--TDB65-1 (24 kDa),
      TDB65-2 (18 kDa), TDB65-3 (17 kDa), TDB65-4 (14 kDa)-- and three of hsp18--TDB18
      1 (10 kDa), TDB18-2 (5 kDa), TDB18-3 (3 kDa). While all of these tryptic
      fragments and undigested hsps triggered CD4+ T cells from tuberculoid (TT)
      leprosy patients and healthy contacts (SI > 2), only two fragments--TDB65-2 and
      TDB18-3--were found to be stimulatory in anergic lepromatous (LL) leprosy
      patients (SI = 5.27 and 3.0, respectively). Blocking studies using allele
      specific anti-DR monoclonal antibodies revealed multiple HLA-Dr restriction, with
      DR2 providing the strongest restriction in both TT as well as LL leprosy. These
      findings indicate that M. leprae hsps and their trypsin-digested fragments are
      promiscuous and recognizable in the context of diverse HLA alleles, of which DR2
      is the most efficient restriction element. The 18-kDa fragment of hsp65 and the 3
      kDa fragment of hsp18 are the most versatile fragments that could elicit in vitro
      proliferation in both polar forms of leprosy.

PMID- 8642215
TI  - Pupil cycle time in leprosy patients without clinically apparent ocular
      pathology.
AB  - The pupil cycle time (PCT) was estimated in 384 leprosy patients whose eyes
      looked normal on clinical examination and in an equal number of healthy controls.
      A statistically significant increase in PCT (p < 0.05) was noticed in leprosy
      patients, and corroborates the view that the ocular autonomic system may be
      affected without any visible clinical pathology in the eye. The clinical value
      and application of this finding is uncertain since the difference is only a few
      milliseconds. Young females with leprosy showed a conspicuous lengthening of PCT
      for which no plausible explanation is offered. There was a general trend for the
      PCT to increase as the spectrum of disease moved toward the lepromatous pole and
      a significantly higher PCT (p < 0.01) was found among multibacillary patients
      compared to paucibacillary patients. Patients who had had erythema nodosum
      leprosum (ENL) reactions showed a higher PCT than did those who had not had ENL.
      Patients who had had reversal reactions showed a decrease in PCT, which may be a
      statistical oddity in this hospital-based study. Patients whose duration of the
      disease was over 10 years showed a higher PCT, while smear positivity of a
      patient did not alter the PCT significantly.

PMID- 8642216
TI  - Prevalence rates of leprosy in Cambodia; results of a sample survey.
AB  - A total population survey was carried out in early 1994 in 13 villages around
      Battambang (northwest Cambodia). Coverage was 87.5% (12,992 out of 14,842). Among
      the 12,922 household members examined 21 known patients and 20 new patients were
      found. Five of the 21 known and none of the newly found patients had
      disabilities. Among males total prevalence rates (known and newly found patients
      combined) appear to rise up to the age of 25 to 34, after which rates remain
      roughly stable until they start to decline in the 65 to 74-year age group. Among
      females prevalence rates reach a plateau in the 35 to 44-year age group.

PMID- 8642217
TI  - Study on the roles of CD4+ and CD8+ T cells in the expression of host resistance
      to Mycobacterium leprae infection induced in athymic nude mice.
AB  - The contribution of CD4+ or CD8+ T cells in the host resistance to Mycobacterium
      leprae was investigated. Athymic BALB/c nude mice were infected subcutaneously
      with M. leprae into the foot pads 1 or 3 weeks after adoptive transfer with
      whole, CD4 T cell-depleted, or CD8 T cell-depleted lymphocyte fractions prepared
      from spleen cells (SPCs) of euthymic BALB/c mice. SPCs from all of the recipient
      mice showed nearly the same levels of proliferative responses to
      phytohemagglutinin (PHA) and lipopolysaccharide, except that those of mice
      transferred with CD4 T cell-depleted lymphocytes showed somewhat reduced
      mitogenic responses to PHA. Significantly potentiated host resistance to the
      infection was seen, as evidenced by the obviously reduced bacterial growth in all
      three groups of recipient mice compared to that seen in control mice, that is,
      4.7- to 6.4-log unit decreases in the bacterial loads were observed. Levels of
      the reduction conferred by CD 4 T cell-depleted lymphocytes were comparable to
      that of CD8 T cell-depleted lymphocytes. This suggests that both CD4 and CD8 T
      cells are important for the expression of resistance to M. leprae infection.

PMID- 8642218
TI  - Immune response of armadillos (Dasypus novemcinctus). I. Use of lectins to
      identify lymphocyte subpopulations and to evaluate cell proliferation.
AB  - Lectins have been used to study populations and discrete differentiation stages
      of lymphocytes. Likewise, lectins have been of practical importance in promoting
      mitogenic stimulation of lymphocytes in numerous species. In this research
      project, we took advantage of these tools in an attempt to identify specific
      subsets of peripheral blood lymphocytes obtained from healthy nine-banded
      armadillos (Dasypus novemcinctus). The same cell source served to evaluate
      mitogenic stimulation. Twelve FITC-labeled lectins were used; 5 (ConA, LcH, RCA,
      WGA and UEA) reacted with almost 100% of the lymphocytes and 7 (PNA, DBA, SBA,
      PCA, PHA-L, PWM and VVA) recognized variable percentages (< 100% of these cells).
      This latter group of lectins may be useful in the identification of armadillo
      lymphocyte subsets, or may correlate with discrete stages of differentiation of
      these cells. The same lectins served to evaluate mitogenic stimulation in an
      aliquot of the same peripheral blood mononuclear cells. Of the 12 lectins
      studied, 5 (ConA, PHA-L, PWM, DBA and SBA) had the capacity to induce mitogenic
      stimulation in the whole mixture of mononuclear cells, giving rise to variable
      degrees in the corresponding mitogenic index obtained for each of the 5 lectins.
      Those lectins that gave an indication of selective identification of lymphocytes,
      that is, the percentages at or below 75%, may prove useful in the evaluation of
      the immune response of healthy armadillos as well as the evolution of progression
      stages of lepromatous leprosy in armadillos inoculated with the same strain of
      Mycobacterium leprae that affects humans.

PMID- 8642219
TI  - Use of facility-based assessment in the evaluation of a comprehensive leprosy
      training program in Nepal.
AB  - A facility-based assessment (FBA) was done to evaluate a comprehensive leprosy
      training program in Nepal. The training course was developed to prepare the Basic
      Health Services staff for integrated leprosy work. FBA is a coordinated set of
      data collection activities designed to determine the extent to which patients are
      properly diagnosed, treated, and cared for in the treatment facility. During the
      present evaluation, the data collection activities included: observation of
      health worker performance, exit interviews with leprosy patients, interviews with
      health workers, inventory of essential equipment and supplies, and collection of
      routine statistical data. The objectives of the training course were used as
      guidelines for the evaluation. Surveys and observation visits were done
      repeatedly and compared with a (untrained) control group. Different actors
      involved in leprosy care were used as informants, and different data collection
      methods were used which enabled cross-checking of the information. Part of the
      data collection activities was already routinely carried out. FBA proved to be a
      very useful and effective tool for the evaluation of a leprosy training program.
      Those parts of the training which need extra attention during the course itself
      as well as during refresher training and supervision visits became obvious.

PMID- 8642220
TI  - Eliminating leprosy as a public health problem; why the optimism is justified.

PMID- 8642221
TI  - An unusual presentation of facial palsy in leprosy; a case report.

PMID- 8642222
TI  - Is pentoxifylline a viable alternative in the treatment of ENL?

PMID- 8642223
TI  - Antileprosy vaccine; an apprehension.

PMID- 8642224
TI  - Differences in M. leprae-induced nerve damage in Swiss white and C57BL/6 mice.

PMID- 8642225
TI  - "Flu" syndrome on monthly rifampin dose; first case reported from Yemen.

PMID- 8642227
TI  - 30th U.S.-Japan tuberculosis research conference, leprosy research conference and
      tuberculosis/leprosy symposium. Fort Collins, Colorado, 19-21 July 1995.
      Abstracts.

PMID- 8642226
TI  - Regarding analysis of vaccines.

PMID- 8642228
TI  - Antibiotic resistance: a self-inflicted problem.

PMID- 8642229
TI  - How to evaluate interaction between causes: a review of practices in
      cardiovascular epidemiology.
AB  - To increase the knowledge of interaction or synergy between risk factors in an
      important task in medical research. Still, current literature in cardiovascular
      epidemiology reflects major misconceptions as how to evaluate interaction. This
      paper presents Rothman's model of causation from which strict empirical criteria
      of interaction can be derived. In principle, the method to apply consists of
      comparing risk differences for one risk factor of interest across strata of the
      other. Commonly used but incorrect approaches are exemplified and discussed.
      These include reporting risk of disease among those with combined exposure,
      comparing relative risks for one exposure after stratification by level of the
      other, and including an interaction term in the regression model and drawing
      conclusions from its P-value.

PMID- 8642230
TI  - Strategies for the prevention of senile (type II) osteoporosis: an update.
AB  - Hip fractures in the elderly represent a global issue, associated with
      significant morbidity and mortality. Considering the magnitude of the problem,
      any substantial reduction in the hip fracture burden depends on prevention. In
      view of the complex pathogenesis of senile (type II) osteoporosis, preventive
      strategies should focus on the frequency of falling in the elderly as well as on
      the prevalence of compromised femoral integrity as a consequence of bone loss.
      Although many risk factors for senile osteoporosis are potentially preventible or
      reversible with targeted interventions, the beneficial effects of most strategies
      have not yet been adequately documented, indicating the need for additional long
      term controlled studies.

PMID- 8642231
TI  - Sarcoidosis causes abnormal seasonal variation in 1,25-dihydroxy-cholecalciferol.
AB  - OBJECTIVES: The spontaneous seasonal variations in the calcium regulating
      hormones 1,25-dihydroxy-cholecalciferol (1,25-DHCC) and parathyroid hormone (PTH)
      were investigated in patients with sarcoidosis. DESIGN: Controlled, prospective
      observational study with measurements in the winter and summer seasons,
      respectively. SUBJECTS: Twelve patients (age: median 33, range 21-54 years) with
      biopsy-verified (n = 8) sarcoidosis were included as well as 11 age-matched
      healthy control subjects. MAIN OUTCOME MEASURES: Serum values of calcium, ionized
      calcium, phosphate, chloride, bicarbonate, creatinine, albumin, angiotensin
      converting enzyme, alkaline phosphatase, 1,25-DHCC, and PTH. Also, 24-h whole
      body retention of 99mTc methylene-diphosphonate was assessed. RESULTS: The
      patient group showed an increased level of 1,25-DHCC in the summer season (w:146
      +/- 67, s:198 +/- 73 pmol L-1; P < 0.01) in contrast to the opposite finding
      among controls (w:161 +/- 34, s:144 +/- 43 pmol L-1; P < 0.05). Comparing the
      individual seasonal changes between the two groups, the difference was marked (P
      < 0.001). Compared with controls, total serum calcium was elevated in the summer
      season in the patient group (P < 0.05), in which the same parameter correlated
      positively with 1,25-DHCC (r = 0.658; P < 0.01). PTH was increased two to three
      times above the control values throughout the year (patients: w:0.37 +/- 0.13,
      s:0.24 +/- 0.08 micrograms L-1; controls: w:0.14 +/- 0.09, s:0.10 +/- 0.04
      micrograms L-1; P < 0.001); although, the level of this hormone was still found
      within the reference interval. 24-h whole body bone scintigraphy failed to show
      any seasonal variation in bone metabolism. In contrast, serum alkaline
      phosphatase was found to be increased during the summer season compared with the
      control group (P < 0.001). Angiotensin-converting enzyme showed no seasonal
      variation. CONCLUSIONS: In sarcoidosis, 1,25-DHCC is abnormally regulated
      throughout the year, with a significantly higher serum level in the summer
      season. Uncontrolled production of 1,25-DHCC in sarcoid pulmonary alveolary
      macrophages is possibly responsible for hypercalcaemic episodes, and this
      parameter should be used as a marker of disease activity.

PMID- 8642232
TI  - Acute administration of metoprolol and enalaprilat reduces insulin-stimulated
      thermogenesis and skin blood flow.
AB  - OBJECTIVE: To examine the acute effects of intravenous metoprolol and enalaprilat
      on energy expenditure, thermogenesis, blood flow and insulin sensitivity. DESIGN:
      Randomized, single-blind, placebo-controlled trial. SETTING: Helsinki University
      Central Hospital, Finland SUBJECTS: Seven moderately insulin-resistant
      nondiabetic subjects. INTERVENTIONS: Each subjects was studied three times at 2-3
      week intervals: metoprolol (5 mg), enalaprilat (2 mg) or saline infusions were
      used. METHODS: A 150-min euglycaemic/hyperinsulinaemic clamp combined with
      indirect calorimetry and blood flow measurements were performed. MAIN OUTCOME
      MEASURES: Glucose uptake, forearm and skin blood flow, and energy expenditure.
      RESULTS: Blood pressure was decreased to the same degree by both drugs. Forearm
      blood flow (plethysmography) was lower with metoprolol compared to enalaprilat
      (2.1 +/- 0.2 vs. 2.8 +/- 0.4 mL per 100 mL min-1; P < 0.05). Glucose-plus-insulin
      stimulated thermogenesis and total energy expenditures were reduced both by
      metoprolol (71 and 5.2%; P < 0.05 in both) and enalaprilat (59%, P = 0.06; and
      7.6%, P < 0.05) as compared to the control study. Skin blood flow (laser Doppler)
      increased by 100% (P < 0.01) during the glucose-plus-insulin infusion, but this
      increment was inhibited by both drug infusions. Forearms and whole-body glucose
      uptake was not influenced by metoprolol or enalaprilat administration.
      CONCLUSIONS: (i) Both metoprolol and enalaprilat inhibit glucose-plus-insulin
      induced thermogenesis and a rise in skin blood flow. (ii) Metoprolol further
      reduces forearm blood flow compared to enalaprilat. (iii) Neither drug has any
      acute effect on insulin sensitivity. (iv) The interference of a physiological
      response to insulin by ACE inhibitors or beta-blocking agents may have
      implications both for energy balance and thermoregulation during periods of
      hyperinsulinaemia in man.

PMID- 8642233
TI  - Hyperlipidaemia in renal transplant patients.
AB  - OBJECTIVES: The aim of study was to assess the prevalence and severity of
      hyperlipidaemia in renal transplant patients in a Nordic country. DESIGN:
      Multicentre, cross-sectional study. SETTING: Outpatients and ward inpatients
      registered from 23 hospitals covering all regions of the country. SUBJECTS: Renal
      transplant patients with a functioning graft were registered: 406 patients in
      all; that is, 43% of the national renal transplant population. All patients used
      prednisolone, 71% used cyclosporine, either with (51%) or without (20%)
      azathioprine. Total cholesterol values from general population were obtained from
      a national survey. MAIN OUTCOME MEASURES: Blood lipids and their relation to
      clinical parameters. RESULTS: Total cholesterol was significantly higher in
      transplant patients than in the general population for both genders and all age
      groups (P < 0.01). Female patients had higher total cholesterol (mean +/- SD:
      7.49 +/- 1.61 mmol L(-1)) than males (7.01 +/- 1.55 mmol L(-1); P < 0.001), and
      also higher HDL cholesterol (1.55 +/- 0.43 vs. males: 1.32 +/- 0.46 mmol L(-1); P
      < 0.001). Triglycerides were equally elevated in both genders, and 33% had values
      above 2.2 mmol L(-1). Reduced creatinine clearance, a high body-mass index,
      female gender, hypertension, and coronary artery disease were independently
      associated with higher total cholesterol. Beta blockers were associated with
      lower HDL cholesterol and higher triglycerides, and diuretics with higher
      triglycerides. Blood lipid levels were not associated with cyclosporine
      immunosuppression. CONCLUSION: Hyperlipidaemia is prevalent after renal
      transplantation, and is associated with impaired graft function, hypertension,
      and with the use of beta blockers and diuretics, but not with the use of
      cyclosporine.

PMID- 8642234
TI  - Daytime sleepiness in an adult, Finnish population.
AB  - OBJECTIVES: To investigate the prevalence of and the factors associated with
      daytime sleepiness occurring every or almost every day. DESIGN: A cross
      sectional, questionnaire survey. SUBJECTS: A total of 11,354 adults (aged 33-60
      years) representative of the Finnish population. MAIN OUTCOME MEASURES: Frequency
      of daytime sleepiness, naps and sleep attacks; occurrence of emotion-associated
      muscle weakness, sleep debt, insomnia, sleep apnoeas and type of snoring; Beck
      Depression Inventory score; and the use of hypnotics and tranquillisers. RESULTS:
      A total of 11.0% of women and 6.7% of men suffered from daytime sleepiness every
      or almost every day. Amongst those with sleepiness (n = 1,026) 19.5% of women and
      42.3% of men reported snoring > or = 3 nights per week, 25% had scores suggesting
      moderate to severe depression, 11% used hypnotics or tranquilizers on more than
      180 days per year, and 9% reported insufficient sleep. Insomnia at least every
      other day was reported by 20.7% of women and by 28.6% of men. Amongst those with
      sleepiness, narcolepsy was found in 0.3%, with the diagnosis confirmed in a sleep
      laboratory evaluation. CONCLUSIONS: Daytime sleepiness occurring daily or almost
      daily is most often associated with depression, insomnia and sleep-disordered
      breathing. In most cases, indications of the cause of sleepiness can be obtained
      by using simple screening questions.

PMID- 8642235
TI  - Progression of atherosclerosis in middle-aged men: effects of multifactorial
      intervention.
AB  - OBJECTIVE: To determine the effect of multifactorial intervention against
      cardiovascular risk factors on ultrasound-determined progression of
      atherosclerosis in healthy middle-aged men. DESIGN: One hundred and forty-nine
      healthy middle-aged men were assigned to an intervention group (IG) or a control
      group (CG). SUBJECTS: The participants had moderately increased risk-factor
      scores for cardiovascular disease. They were recruited from a health screening
      programme at the Preventive Medicine Section, Department of Medicine, Lund
      University, University Hospital, Malmo. During the study period, 32 of the
      subjects were lost to follow-up, leaving 59 in the IG and 58 in the CG.
      INTERVENTION: The IG subjects underwent multifactorial intervention for 2 years,
      the goal being to help them stop smoking and to reduce their blood lipids and
      blood pressure. MAIN OUTCOME MEASURES: Intima-media thickness and plaque score in
      the right carotid artery were ultrasonographically determined initially and after
      2 years. Blood lipids and blood pressure were measured at the same time, and in
      the IG also after 3, 6, 12 and 18 months after entry into the study. RESULTS: At
      the entry into the study, there were no significant differences in major risk
      factors or ultrasound variables between IG and CG. Blood lipids and smoking
      decreased significantly during the 2 years of intervention in the IG, whilst
      these factors remained unchanged in the CG. Intima-media thickness and plaque
      scores increased significantly in both groups. CONCLUSIONS: No effects on
      ultrasound variables could be detected after 2 years of multifactorial
      intervention. A more aggressive intervention programme, possibly more dependent
      on pharmacological treatment, may be required to obtain reduced progression or
      regression of atherosclerosis.

PMID- 8642236
TI  - The white blood cell count: its relationship to plasma insulin and other
      cardiovascular risk factors in healthy male individuals.
AB  - OBJECTIVES: To evaluate the relationships of total and differential white blood
      cell (WBC) count to the components of the so-called insulin resistance syndrome.
      SUBJECTS AND DESIGN: The study population consisted of a random sample of 90 38
      year-old healthy men with normal glucose tolerance. INTERVENTIONS: A 75 g oral
      glucose tolerance test was performed in all participants. MAIN OUTCOME MEASURES:
      Total and differential WBC count, lipids, blood pressure, plasma glucose, C
      peptide and insulin (at fasting and 2 h after glucose load). RESULTS: Total WBC
      count correlated consistently with plasma 2-h glucose (r = 0.38; P < 0.001),
      fasting and 2-h postload insulin (r = 0.26 and r = 0.33; P < 0.01-0.001,
      respectively) and C-peptide (r = 0.28 and r = 0.32; P < 0.01-0.001)
      concentrations. Smokers had significantly higher total leukocytes (P < 0.01),
      neutrophils and lymphocytes than nonsmokers. Furthermore, total WBC count
      correlated positively with body mass index, blood pressure, plasma triglycerides,
      fibrinogen, and negatively with HDL cholesterol concentration. As differential
      WBC count, most variables correlated essentially to neutrophils and/or
      lymphocytes, whereas plasma insulin and C-peptide concentrations correlated
      essentially to lymphocytes and monocytes, but not to neutrophils. In a multiple
      linear regression analysis, only 2-h plasma glucose (P < 0.01) and fibrinogen (P
      < 0.05) were positive predictors of total WBC count after adjusting for all
      potentially confounding variables. CONCLUSIONS: The results indicate that
      increased, albeit normal, WBC count associates with the cluster of metabolic and
      haemodynamic disorders typical of the insulin resistance syndrome, and suggest
      that increased WBC count may be yet another component of this syndrome.

PMID- 8642237
TI  - Evolution of heart rate variability in cardiac transplant recipients: a clinical
      study.
AB  - OBJECTIVES: To investigate in cardiac transplant patients whether post
      transplantation time, graft arteriosclerosis, allograft rejection, or earlier
      cytomegalovirus infection affect the neural regulatory mechanisms of the donor
      heart. DESIGN: A consecutive series of heart transplant patients during a 12
      month period. SETTING: A university hospital in Finland. SUBJECTS: Consecutive
      cardiac transplant recipients (n = 38) attending the hospital for their annual
      clinical examination were studied. Their mean (SD) age was 45.4 (11.5) years, 37
      were male, and the median (range) time since transplantation was 36 (12-72)
      months. INTERVENTIONS: Power spectral analysis of R-R intervals (during 5 min of
      controlled breathing, the Valsalva manoeuvre, and deep breathing), routine
      coronary arteriography, cytomegalovirus serology. RESULTS: R-R interval (r =
      0.67; P < 0.001), the root mean square difference of successive R-R intervals (r
      = 0.38; P < 0.05), the total R-R interval power (r = 0.45; P < 0.01), the power
      of the very low frequency (0.0-0.07 Hz) component (r = 0.53; P < 0.01), and the
      power of the nonrespiratory (0.0-0.15 Hz) component (r = 0.49; P < 0.01) were
      related to the length of time since the operation. Patients having had a
      transplantation 3 years ago or more had significantly greater median (range)
      total R-R interval power than those having had the operation less than 3 years
      ago (59 [10-265] vs. 20 [3-113] ms2; P = 0.02). There was also a difference
      between the two groups in the very low frequency component (18 [1-226] vs. 5 [0
      45] ms2; P = 0.01), in the nonrespiratory component (30[1-227] vs. 9 [0-53]ms2; P
      = 0.02), and in the Valsalva ratio (0.995 [0.955-1.065] vs. 1.020 [0.975-1.155];
      P = 0.03). Patients with and without graft arteriosclerosis, episodes of
      rejection, or earlier cytomegalovirus infection showed no difference in the power
      spectral measures. CONCLUSIONS: The donor heart rate variability increases with
      post-transplantation time. Heart rate variability in transplant recipients is not
      related to the extent of graft arteriosclerosis, episodes of allograft rejection,
      or earlier cytomegalovirus infection.

PMID- 8642238
TI  - Nitrogen dioxide pneumonitis in ice hockey players.
AB  - Exposure to the toxic gases carbon monoxide and nitrogen dioxide (NO2) in indoor
      ice arenas occasionally occurs and may result in severe symptoms. The gases are
      produced by ice resurfacing machines operating on hydrocarbons, and in certain
      conditions toxic levels accumulate. The damage to lung tissues caused by NO2 may
      not be evident until after a latency time of 1/2-2 days. The role of
      corticosteroids in the treatment is controversial, but there are clinical
      experiences as well as experimental data supporting their use. We report two
      cases of toxic pneumonitis, with delayed onset, due to NO2 exposure during an ice
      hockey game in an indoor arena. Signs and symptoms were cough, dyspnoea,
      haemoptysis, hypoxaemia and reduced peak expiratory flow. Chest radiographs
      showed parenchymatous infiltrative lesions and alveolar consolidation. Both
      patients were treated with high doses of corticosteroids by inhalation and orally
      or intravenously. Their condition rapidly improved and pulmonary function was
      restored.

PMID- 8642239
TI  - Mediastinal mass following chemotherapy in patients with Ewing sarcoma and
      osteosarcoma.
AB  - Thymic hyperplasia following combination chemotherapy for malignant disease is
      very uncommon in adolescents and adults. Our experience includes a thymic
      enlargement noted on the sequential computed tomography (CT) in three patients
      who were disease-free after chemotherapy for Ewing sarcoma (2) and osteosarcoma
      (1). The development of an anterior mediastinal mass after successful
      chemotherapy does not always imply relapse of malignant disease. To prevent
      inappropriate treatment, the possibility of benign aetiology must be considered.

PMID- 8642240
TI  - The dissemination of false data through inadequate citation.

PMID- 8642241
TI  - T cell populations primed by hapten sensitization in contact sensitivity are
      distinguished by polarized patterns of cytokine production: interferon gamma
      producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing
      (Th2) negative regulatory CD4+ T cells.
AB  - Contact hypersensitivity (CHS) is a T cell-mediated response to hapten
      sensitization of the epidermis. The roles of CD4+ and CD8+ T cells in CHS have
      remained unclear, however, as studies to define either subset as the T cells
      mediating CHS have provided conflicting results. The goal of this study was to
      correlate the in vivo function of CD4+ and CD8+ T cells in CHS with the cytokines
      produced by each T cell population. Antibody-mediated depletion of CD4+ T cells
      before sensitization of BALB/c mice with 2,4-dinitrofluorobenzene (DNFB) or
      oxazolone (Ox) resulted in increased and prolonged CHS responses, indicating CD4+
      T cells as negative regulators of the response. Depletion of CD8+ T cells
      resulted in low or abrogated responses, indicating CD8+ T cells as the effector
      cells in CHS. Sensitization with DNFB or Ox induced lymph node cell populations
      of CD8+ T cells producing interferon (IFN)-gamma and no interleukin (Il) 4 or Il
      10, and CD4+ T cells producing Il-4 and Il-10 and no or little detectable IFN
      gamma. The polarized patterns of cytokine production were stimulated by culture
      of hapten-primed lymph node cells either on anti-T cell receptor antibody-coated
      wells or with semipurified Langerhans cells isolated from hapten-sensitized mice.
      Stimulation of cytokine production during culture of hapten-primed CD4+ or CD8+ T
      cells with Langerhans cells was hapten specific and restricted to class II or
      class I major histocompatibility complex, respectively. The induction of the CD4+
      and CD8+ T cells producing the polarized patterns of cytokines was not restricted
      to BALB/c mice, as cells from Ox sensitized C57B1/6 and B10.D2 mice produced the
      same patterns. Collectively, these results expose the induction of two polarized
      and functionally opposing populations of T cells by hapten sensitization to
      induce CHS: IFN-gamma-producing effector CD8+ T cells and Il-4/Il-10-producing
      CD4+ T cells that negatively regulate the response.

PMID- 8642243
TI  - The main lytic factor of Trypanosoma brucei brucei in normal human serum is not
      high density lipoprotein.
AB  - Natural immunity of humans to the cattle pathogen Trypanosoma brucei brucei has
      been attributed to the presence in normal human serum (NHS) of lytic factors for
      the parasites. We and others have shown that NHS contains two trypanolytic
      factors (herein termed TLF1 and TLF2) that can be separated by gel filtration.
      TLF1 copurifies with a subclass of high density lipoprotein (HDL), whereas TLF2
      has a much higher molecular weight and does not appear to be a lipoprotein. We
      find that the trypanolytic activity of purified TLF1 is totally inhibited by
      exogenous haptoglobin (Hp) at concentrations (0.1 mg/ml) lower than those present
      in NHS (0.2-2 mg/ml). In contrast, exogenous Hp (up to 2.5 mg/ml) has no effect
      on the lytic activity of either NHS or isolated TLF2. Hp-depleted sera from
      patients with intravascular hemolysis is severalfold more trypanolytic than NHS.
      These sera contain only TLF1, and their lytic activity is totally abolished upon
      the addition of Hp (0.1 mg/ml). When NHS containing different Hp allotypes is
      fractionated by gel filtration, TLF1 activity is either revealed or remains
      masked, depending on whether it coelutes with Hp. Masked TLF1 activity in the
      column fractions is revealed if Hp is removed by density gradient
      ultracentrifugation. We conclude that endogenous Hp inhibits TLF1 activity, and
      that TLF2 is the main trypanolytic factor in NHS.

PMID- 8642242
TI  - Inhibition of endothelial cell activation by adenovirus-mediated expression of I
      kappa B alpha, an inhibitor of the transcription factor NF-kappa B.
AB  - During the inflammatory response, endothelial cells (EC) transiently upregulate a
      set of genes encoding, among others, cell adhesion molecules and chemotactic
      cytokines that together mediate the interaction of the endothelium with cells of
      the immune system. Gene upregulation is mediated predominantly at the
      transcriptional level and in many cases involves the transcription factor nuclear
      factor (NF) kappa B. We have tested the concept of inhibiting the inflammatory
      response by overexpression of a specific inhibitor of NF-kappaB, I kappa B alpha.
      A recombinant adenovirus expressing I kappa B alpha was constructed (rAd.I kappa
      B alpha) and used to infect EC of human and porcine origin. Ectopic expression of
      IkappaBalpha resulted in marked, and in some cases complete, reduction of the
      expression of several markers of EC activation, including vascular cell adhesion
      molecule 1, interleukins 1, 6, 8, and tissue factor. Overexpressed I kappa B
      alpha inhibited NF-kappa B specifically since (a) in electrophoretic mobility
      shift assay, NF-kappa B but not AP-1 binding activity was inhibited, and (b) von
      Willebrand factor and prostacyclin secretion that occur independently of NF-kappa
      B, remained unaffected. Functional studies of leukocyte adhesion demonstrated
      strong inhibition of HL-60 adhesion to I kappa B alpha-expressing EC. These
      findings suggest that NF-kappa B could be an attractive target for therapeutic
      intervention in a variety of inflammatory diseases, including xenograft
      rejection.

PMID- 8642244
TI  - A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver
      destruction but not from rapid death induced by anti-Fas antibody injection.
AB  - Stimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of
      cells, usually triggers a process of programmed cell death. Systemic injection of
      anti-Fas antibody into mice leads to fulminant liver destruction resulting from
      massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not
      express Bcl-2, a protein that plays, in a number of conditions, a protective role
      against apoptosis. We have generated mice whose liver expresses Bcl-2 as the
      result of bcl-2 transgene placed under the control of the hepatocyte-specific
      alpha1-anti-trypsin gene promoter, but is otherwise not distinguishable from that
      of normal mice. These mice display a marked to almost total resistance to liver
      damage induced by anti-Fas antibody injection. This protective effect of Bcl-2
      occurs in the absence of significant variations, in the stimulated livers, in the
      level of expression of other proteins also involved in resistance or sensitivity
      to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers,
      however, die almost as rapidly as normal mice, which indicates that acute
      lethality results from stimulation of Fas receptors present on other target
      organs or cells.

PMID- 8642245
TI  - Role of the ceramide-signaling pathway in cytokine responses to P-fimbriated
      Escherichia coli.
AB  - Escherichia coli express fimbriae-associated adhesins through which they attach
      to mucosal cells and activate a cytokine response. The receptors for E. coli P
      fimbriae are the globoseries of glycosphingolipids; Gal alpha 1-->4Gal beta
      containing oligosaccharides bound to ceramide in the outer leaflet of the lipid
      bilayer. The receptors for type 1 fimbriae are mannosylated glycoproteins rather
      than glycolipids. This study tested the hypothesis that P-fimbriated E. coli
      elicit a cytokine response through the release of ceramide in the receptor
      bearing cell. We used the A498 human kidney cell line, which expressed functional
      receptors for P and type 1 fimbriae and secreted higher levels of interleukin
      (IL)-6 when exposed to the fimbriated strains than to isogenic nonfimbriated
      controls. P-fimbriated E. coli caused the release of ceramide and increased the
      phosphorylation of ceramide to ceramide 1-phosphate. The IL-6 response to P
      fimbriated E. coli was reduced by inhibitors of serine/threonine kinases but not
      by other protein kinase inhibitors. In contrast, ceramide levels were not
      influenced by type 1-fimbriated E. coli, and the IL-6 response was insensitive to
      the serine/threonine kinase inhibitors. These results demonstrate that the
      ceramide-signaling pathway is activated by P-fimbriated E. coli, and that the
      receptor specificity of the P fimbriae influences this process. We propose that
      this activation pathway contributes to the cytokine induction by P-fimbriated E.
      coli in epithelial cells.

PMID- 8642246
TI  - Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice
      to infection with virulent Mycobacterium tuberculosis.
AB  - The superior resistance of some strains of mice over others to infection with
      certain intracellular pathogens, including the vaccine strain of Mycobacterium
      bovis, bacillus Calmette Guerin (BCG), is determined by a gene associated with a
      small segment of chromosome 1 designated by Ity/Lsh/Bcg locus, referred to here
      as the Bcg locus. DBA/2 mice containing the dominant resistant allele of the Bcg
      gene (Bcgr), major histocompatibility complex-compatible BALB/c mice containing
      the recessive susceptible allele (Bcgs), and congenic C.D2-N20 Bcgr, which are
      genetically the same as BALB/c mice except for possessing a small piece of DBA/2
      chromosome 1 containing the Bcg locus, were used to determine whether the Bcg
      gene determines resistance to infection with the virulent H37Rv strain of
      Mycobacterium tuberculosis (Mtb). According to the survival times of Bcgr and
      Bcgs mice infected via either the intravenous or respiratory route, Bcgr mice
      proved much less, rather than more, resistant to Mtb infection than Bcgs mice.
      Shorter survival times of Bcgr mice were associated with an inferior capacity to
      control Mtb growth in their lungs and to retard the development of Mtb-induced
      pathology in this organ. Resistance to Mtb infection was a dominant trait in the
      F1 progeny of Bcgr and Bcgs mice. The results show that resistance to Mtb is not
      determined by the resistance allele of the Bcg gene nor by the recently isolated
      candidate Bcg gene Nramp1, located in the Bcg locus.

PMID- 8642247
TI  - Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and
      ZAP-70 in murine thymocytes.
AB  - The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are
      required for T cell receptor (TCR) functions. We provide evidence that the Src
      family PTK Lck is responsible for regulating the constitutive tyrosine
      phosphorylation of the TCR zeta subunit in murine thymocytes. Moreover, ligation
      of the TCR expressed on thymocytes from Lck-deficient mice largely failed to
      induce the phosphorylation of TCR-zeta, CD3 epsilon, or ZAP-70. In contrast, we
      find that the TCR-zeta subunit is weakly constitutively tyrosine phosphorylated
      in peripheral T cells isolated from Lck-null mice. These data suggest that Lck
      has a functional role in regulation of TCR signal transduction in thymocytes. In
      peripheral T cells, other Src-family PTKs such as Fyn may partially compensate
      for the absence of Lck.

PMID- 8642248
TI  - Genetic evidence for a new type of major histocompatibility complex class II
      combined immunodeficiency characterized by a dyscoordinate regulation of HLA-D
      alpha and beta chains.
AB  - Major histocompatibility complex (MHC) class II combined immunodeficiency (CID),
      also known as type II bare lymphocyte syndrome, is an autosomal recessive genetic
      disorder characterized by the complete lack of expression of MHC class II
      antigens. The defect results from a coordinated lack of transcription of all
      class II genes. Cell fusion studies using many patient- and experimentally
      derived class II-negative cell lines have identified four distinct genetic
      complementation groups. In this report, we present genetic evidence that cell
      lines derived from two newly described MHC class II-deficient patients, KER and
      KEN, represent a fifth complementation group. In addition, the KER and KEN cell
      lines display a unique pattern of dyscoordinate regulation of their MHC class II
      genes, which is reflected in a new phenotype of in vivo promoter occupancy as
      revealed by in vivo genomic footprinting. These data point to a new defect that
      can result in the MHC class II-deficient phenotype.

PMID- 8642249
TI  - Expansion of cytokine-producing CD4-CD8- T cells associated with abnormal Fas
      expression and hypereosinophilia.
AB  - The mechanisms of sustained overproduction of eosinophils in the idiopathic
      hypereosinophilic syndrome and in some human immunodeficiency virus (HIV)-1
      infected individuals are largely unknown. We hypothesized that T cells may
      release soluble products that regulate eosinophilia in these patients, as has
      been previously shown in bronchial asthma. We identified one patient with
      idiopathic hypereosinophilic syndrome and one HIV-1-infected individual with
      associated hypereosinophilia who demonstrated high numbers of CD4-CD8- T cells in
      peripheral blood. CD4-CD8- T cells from both patients, although highly activated,
      did not express functional Fas receptors. In one case, the lack of functional Fas
      receptors was associated with failure of Fas mRNA and protein expression, and in
      another, expression of a soluble form of the Fas molecule that may have
      antagonized normal signaling of Fas ligand. In contrast to the recently described
      lymphoproliferative/autoimmune syndrome, which is characterized by accumulation
      of CD4-CD8- T cells and mutations within the Fas gene, this study suggests
      somatic variations in Fas expression and function quite late in life. Both
      genetic and somatic abnormalities in regulation of the Fas gene are therefore
      associated with failures to undergo T cell apoptosis. Furthermore, the expanded
      population of CD4-CD8- T cells from both patients elaborated cytokines with
      antiapoptotic properties for eosinophils, indicating a major role of these T
      cells in the development of eosinophilia. Thus, this study demonstrates a
      sequential dysregulation of apoptosis in different cell types.

PMID- 8642250
TI  - Major histocompatibility complex class II-associated peptides control the
      presentation of bacterial superantigens to T cells.
AB  - Recent studies have shown that only a subset of major histocompatibility complex
      (MHC) class II molecules are able to present bacterial superantigens to T cells,
      leading to the suggestion that class-II associated peptides may influence
      superantigen presentation. Here, we have assessed the potential role of peptides
      on superantigen presentation by (a) analyzing the ability of superantigens to
      block peptide-specific T cell responses and (b) analyzing the ability of
      individual peptides to promote superantigen presentation on I-Ab-expressing T2
      cells that have a quantitative defect in antigen processing. A series of peptides
      is described that specifically promote either toxic shock syndrome toxin (TSST) 1
      or staphylococcal enterotoxin A (SEA) presentation. Whereas some peptides
      promoted the presentation of TSST-1 (almost 5,000-fold in the case of one
      peptide), other peptides promoted the presentation of SEA. These data demonstrate
      that MHC class II-associated peptides differentially influence the presentation
      of bacterial superantigens to T cells.

PMID- 8642251
TI  - Mature T cell reactivity altered by peptide agonist that induces positive
      selection.
AB  - Recent studies have investigated how defined peptides influence T cell
      development. Using a T cell receptor-transgenic beta2-microglobulin-deficient
      model, we have examined T cell maturation in fetal thymic organ cultures in the
      presence of various peptides containing single-alanine substitutions of the
      strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains
      an altered T cell contact residue, resulted in efficient positive selection.
      Several in vitro assays demonstrated that A4Y was a moderate agonist relative to
      p33. Although A4Y promoted positive selection over a wide concentration range,
      high doses of this peptide could not induce clonal deletion. Thymocytes maturing
      in the presence of A4Y were no longer able to respond to A4Y, but could
      proliferate against p33. These studies demonstrate that (a) peptides that induce
      efficient positive selection at high concentrations are not exclusively
      antagonists; (b) some agonists do not promote clonal deletion; (c) positive
      selection requires a unique T cell receptor-peptide-major histocompatibility
      complex interaction; and (d) interactions with selecting peptides during T cell
      ontogeny may define the functional reactivity of mature T cells.

PMID- 8642252
TI  - The sequence of the Mycoplasma arthritidis superantigen, MAM: identification of
      functional domains and comparison with microbial superantigens and plant lectin
      mitogens.
AB  - Mycoplasma arthritidis, an agent of chronic proliferative arthritis of rodents,
      secretes a potent soluble superantigen, MAM, that is active for both murine and
      human T and B lymphocytes. We now report the complete nucleotide and amino acid
      sequence of MAM and show it to be distinct from other proteins and not closely
      related phylogenetically to other superantigens. Two functional domains on MAM
      are identified based on the ability of peptides encompassing these regions to
      inhibit lymphocyte proliferation by the intact MAM molecule. One of these domains
      shares short sequences or epitopes with other microbial superantigens. The second
      domain contains the consensus legume lectin motif-beta, which is important for T
      cell activation by concanavalin (Con) A. MAM and Con A peptides containing this
      motif are functionally cross reactive, suggesting a novel secondary pathway for T
      cell activation by MAM.

PMID- 8642253
TI  - Critical role for the common cytokine receptor gamma chain in intrathymic and
      peripheral T cell selection.
AB  - The common cytokine receptor gamma chain (gammac), which is a functional subunit
      of the receptors for interleukins (IL)-2, -4, -7, -9, and -15, plays an important
      role in lymphoid development. Inactivation of this molecule in mice leads to
      abnormal T cell lymphopoiesis characterized by thymic hypoplasia and reduced
      numbers of peripheral T cells. To determine whether T cell development in the
      absence of gammac is associated with alterations of intrathymic and peripheral T
      cell selection, we have analyzed gammac-deficient mice made transgenic for the
      male-specific T cell receptor (TCR) HY (HY/gammac- mice). In HY/gammac- male
      mice, negative selection of autoreactive thymocytes was not diminished; however,
      peripheral T cells expressing transgenic TCR-alpha and -beta chains (TCR
      alphaT/betaT) were absent, and extrathymic T cell development was completely
      abrogated. In HY/gammac- female mice, the expression of the transgenic TCR
      partially reversed the profound thymic hypoplasia observed in nontransgenic
      gammac- mice, generating increased numbers of thymocytes in all subsets,
      particularly the TCR-alphaT/betaT CD8+ single-positive thymocytes. Despite
      efficient positive selection, however, naive CD8+ TCR-alphaT/betaT T cells were
      severely reduced in the peripheral lymphoid organs of HY/gammac- female mice.
      These results not only underscore the indispensible role of gammac in thymocyte
      development, but also demonstrate the critical role of gammac in the maintenance
      and/or expansion of peripheral T cell pools.

PMID- 8642255
TI  - Utilization of an alternative open reading frame of a normal gene in generating a
      novel human cancer antigen.
AB  - Tumor infiltrating lymphocytes (TILs) derived from tumor-bearing patients
      recognize tumor-associated antigens presented by major histocompatibility complex
      (MHC) class I molecules. The infusion of TIL586 along with interleukin (IL) 2
      into an autologous patient with metastatic melanoma resulted in the objective
      regression of tumor. A gene encoding a tumor antigen recognized by TIL586 was
      recently isolated and shown to encode gp75. Here we report that an antigenic
      peptide, MSLQRQFLR, recognized by TIL586 was not derived from the normal gp75
      protein. Instead, this nonamer peptide resulted from translation of an
      alternative open reading frame of the same gene. Thus, the gp75 gene encodes two
      completely different polypeptides, gp75 as an antigen recognized by
      immunoglobulin G antibodies in sera from a patient with cancer, and a 24-amino
      acid product as a tumor rejection antigen recognized by T cells. This represents
      the first demonstration that a human tumor rejection antigen can be generated
      from a normal cellular gene using an open reading frame other than that used to
      encode the normal protein. These findings revealed a novel mechanism for
      generating tumor antigens, which may be useful as vaccines to induce tumor
      specific cell-mediated immunity against cancer.

PMID- 8642254
TI  - CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel
      lymphocyte-endothelial cell primary adhesion pathway.
AB  - The extravasation of leukocytes from the blood into tissues occurs as a multistep
      process: an initial transient interaction ("rolling"), generally thought to be
      mediated by the selectin family of adhesion molecules, followed by firm adhesion,
      usually mediated by integrins. Using a parallel plate flow chamber designed to
      approximate physiologic flow in postcapillary venules, we have characterized a
      rolling interaction between lymphoid cells and adherent primary and cultured
      endothelial cells that is not selectin mediated. Studies using blocking
      monoclonal antibodies indicate that this novel interaction is mediated by CD44.
      Abrogation of the rolling interaction could be specifically achieved using both
      soluble hyaluronate (HA) and treatment of the adherent cells with HA-reactive
      substances, indicating that HA is the ligand supporting this rolling interaction.
      Some B and T cell lines, as well as normal lymphocytes, either constitutively
      exhibit rolling or can be induced to do so by phorbol ester or in vivo antigen
      activation. These studies indicate that CD44 and its principal ligand hyaluronate
      represent another receptor/carbohydrate ligand pair mediating a novel activation
      dependent pathway of lymphocyte/endothelial cell adhesion.

PMID- 8642256
TI  - Genetic control of the frequency of hematopoietic stem cells in mice: mapping of
      a candidate locus to chromosome 1.
AB  - The genetic elements that govern the differentiation and proliferation of
      hematopoietic stem cells remain to be defined. We describe here marked strain
      specific differences in the frequency of long-term culture-initiating cells (LTC
      IC) in the bone marrow of different strains of mice. Mice of C57Bl/6 background
      showed the lowest levels of stem cells in marrow, averaging 2.4 +/- .06 LTC
      IC/10(5) cells, BALB/c is intermediate (9.1 +/- 4.2/10(5) cells), and DBA/2 mice
      contained a 11-fold higher frequency of LTC-IC (28.1 +/- 16.5/10(5) cells) than
      C57Bl/6 mice. The genetic factors affecting the size of the stem cell pool were
      analyzed in the C57Bl/6 X DBA/2 recombinant inbred strains; LTC-IC frequencies
      ranged widely, indicating that stem cell frequencies are controlled by multiple
      genes. Quantitative trait linkage analysis suggested that two loci that have
      major quantitative effects are located on chromosome 1 near Adprp and Acrg,
      respectively. The mapping of the locus near Adprp was confirmed by finding an
      elevated stem cell frequency in B6.C-H25, a C57Bl/6 congenic strain that carries
      a portion of chromosome 1 derived from BALB/c mice. We have named this gene Scfr1
      (stem cell frequency regulator 1). The allelic forms of this gene may be an
      important predictor of stem cell number and thus would be useful for evaluating
      cell sources in clinical stem cell transplantation.

PMID- 8642257
TI  - Neisserial porins induce B lymphocytes to express costimulatory B7-2 molecules
      and to proliferate.
AB  - The neisserial porins are the major protein components of the outer membrane of
      the pathogenic Neisseria (N. meningitidis and N. gonorrhoeae). They have been
      shown to be able to enhance the immune response to poorly immunogenic substances
      (e.g., polysaccharides, peptides, glycolipids, etc.). To explore the basis of
      their potent adjuvant activity, the effect of the neisserial porins on T-B cell
      interactions and T cell costimulation was examined. Neisserial porins increased
      the surface expression of the costimulatory ligand B7-2 (CD86) but did not affect
      the expression of B7-1 (CD80). In addition, incubation with the neisserial porins
      increased the T lymphocyte costimulatory ability of B lymphocytes, which was
      inhibited by anti-B7-2 but not anti-B7-1 monoclonal antibodies. Upregulation of
      B7-2 on the surface of B lymphocytes may be the mechanism behind the
      immunopotentiating activity of neisserial porins.

PMID- 8642258
TI  - B lymphocytes secrete antigen-presenting vesicles.
AB  - Antigen-presenting cells contain a specialized late endocytic compartment, MIIC
      (major histocompatibility complex [MHC] class II-enriched compartment), that
      harbors newly synthesized MHC class II molecules in transit to the plasma
      membrane. MIICs have a limiting membrane enclosing characteristic internal
      membrane vesicles. Both the limiting membrane and the internal vesicles contain
      MHC class II. In this study on B lymphoblastoid cells, we demonstrate by
      immunoelectron microscopy that the limiting membrane of MIICs can fuse directly
      with the plasma membrane, resulting in release from the cells of internal MHC
      class II-containing vesicles. These secreted vesicles, named exosomes, were
      isolated from the cell culture media by differential centrifugation followed by
      flotation on sucrose density gradients. The overall surface protein composition
      of exosomes differed significantly from that of the plasma membrane. Exosome
      bound MHC class II was in a compact, peptide-bound conformation. Metabolically
      labeled MHC class II was released into the extracellular medium with relatively
      slow kinetics, 10 +/- 4% in 24 h, indicating that direct fusion of MIICs with the
      plasma membrane is not the major pathway by which MHC class II reaches the plasma
      membrane. Exosomes derived from both human and murine B lymphocytes induced
      antigen-specific MHC class II-restricted T cell responses. These data suggest a
      role for exosomes in antigen presentation in vivo.

PMID- 8642259
TI  - A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is
      encoded by an intron sequence of the N-acetylglucosaminyltransferase V gene.
AB  - A cytolytic T lymphocyte (CTL) clone that lyses many HLA-A2 melanomas was derived
      from a population of tumor-infiltrating lymphocytes of an HLA-A2 melanoma
      patient. The gene coding for the antigen recognized by this CTL was identified by
      transfection of a cDNA library. It is the gene which has been reported to code
      for N-acetylglucosaminyltransferase V (GnT-V). Remarkably, the antigenic peptide
      recognized by the CTL is encoded by a sequence located in an intron. In contrast
      to the fully spliced GnT-V mRNA, which was found in a wide range of normal and
      tumoral tissues, the mRNA containing the intron region coding for the antigen was
      not found at a significant level in normal tissues. This mRNA was observed to be
      present in about 50% of melanomas. Our results suggest that a promoter located
      near the end of the relevant intron is activated in melanoma cells, resulting in
      the production of an mRNA coding for the antigen.

PMID- 8642260
TI  - A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by
      tumor infiltrating lymphocytes.
AB  - A number of antigens recognized by tumor-reactive T cells have recently been
      identified. The antigens identified in mouse model systems appear, with one
      exception, to represent the products of mutated genes. In contrast, most of the
      antigens recognized by human tumor-reactive T cells reported to date appear to
      represent the products of non-mutated genes. Here we report the isolation of a
      cDNA clone encoding beta-catenin, which was shown to be recognized by the tumor
      infiltrating lymphocyte (TIL) 1290, a HLA-A24 restricted melanoma-specific CTL
      line from patient 888. The cDNA clone, which was isolated from the autologous
      melanoma cDNA library, differed by a single base pair from the published beta
      catenin sequence, resulting in a change from a serine to a phenylalanine residue
      at position 37. Normal tissues from this patient did not express the altered
      sequence, nor did 12 allogeneic melanomas, indicating that this represented a
      unique mutation in this patient's melanoma. A peptide corresponding to the
      sequence between amino acids 29 and 37 of the mutant gene product was identified
      as the T cell epitope recognized by TIL 1290. The observation that HLA-A24
      binding peptides contain an aromatic or hydrophobic residue at position 9
      suggested that the change at position 37 may have generated a peptide (SYLDSGIHF)
      which was capable of binding to HLA-A24, and a competitive binding assay
      confirmed this hypothesis. The beta-catenin protein has been shown previously to
      be involved in cell adhesion mediated through the cadherin family of cell surface
      adhesion molecules. The high frequency of mutations found in members of cellular
      adhesion complexes in a variety of cancers suggests that these molecules may play
      a role in development of the malignant phenotype.

PMID- 8642261
TI  - Interactions of human alpha/beta and gamma/delta T lymphocyte subsets in shear
      flow with E-selectin and P-selectin.
AB  - We have compared the ability of human alpha/beta and gamma/delta T lymphocytes to
      adhere to selectin-bearing substrates, an interaction thought to be essential for
      homing and localization at sites of inflammation. Both T cell populations form
      rolling adhesions on E- and P-selectin substrates under physiologic flow
      conditions. Although equivalent to alpha/beta T cells in binding to E-selectin,
      gamma/delta T cells demonstrated greater ability to adhere to P-selectin that was
      purified or expressed on the surface of activated, adherent platelets. Under
      static conditions, 80% of gamma/delta T cells and 53% of alpha/beta T cells
      formed shear-resistant adhesions to P-selectin, whereas only 30% of gamma/delta
      and alpha/beta T cells adhered to E-selectin. The enhance ability of gamma/delta
      T cells to adhere to P-selectin cannot be attributed to differences in expression
      of the P-selectin glycoprotein ligand (PSGL-1), as all alpha/beta T cells versus
      approximately 75% of gamma/delta T cells expressed PSGL-1. Both cell populations
      expressed a similar percentage of the carbohydrate antigens sialyl LewisX and
      cutaneous lymphocyte-associated antigen. Depletion of lymphocyte populations or T
      cell clones bearing these oligosaccharides with the monoclonal antibody CSLEX-1
      and HECA-452, respectively, resulted in a substantial reduction in adhesion to E
      selectin and slight reduction in adhesion to P-selectin under flow conditions.
      Treatment of cells with an endopeptidase that selectively degrades O-sialomucins
      such as PSGL-1, abolished P-selectin but not E-selectin adhesion. Removal of
      terminal sialic acids with neuraminidase or protease treatment of cells abrogated
      cell adhesion to both selectin substrates. These results provide direct evidence
      for the presence of distinct E- and P-selectin ligands on T lymphocytes and
      suggest that gamma/delta T cells may be preferentially recruited to inflammatory
      sites during the early stages of an immune response when P-selectin is
      upregulated.

PMID- 8642262
TI  - Blocking the transcription factor E2F/DP by dominant-negative mutants in a normal
      breast epithelial cell line efficiently inhibits apoptosis and induces tumor
      growth in SCID mice.
AB  - The transcription factor E2F is regulated during the cell cycle through
      interactions with the product of the retinoblastoma susceptibility gene and
      related proteins. It is thought that E2F-mediated gene regulation at the G1/S
      boundary and during S phase may be one of the rate-limiting steps in cell
      proliferation. It was reported that in vivo overexpression of E2F-1 in
      fibroblasts induces S phase entry and leads to apoptosis. This observation
      suggests that E2F plays a role in both cell cycle regulation and apoptosis. To
      further understand the role of E2F in cell cycle progression, cell death, and
      tumor development, we have blocked endogenous E2F activity in HBL-100 cells,
      derived from nonmalignant human breast epithelium, using dominant-negative
      mutants under the control of a tetracycline-dependent expression system. We have
      shown here that induction of dominant-negative mutants led to strong
      downregulation of transiently transfected E2F-dependent chloramphenicol acetyl
      transferase reporter constructs and of endogenous c-myc, which has been described
      as a target gene of the transcription factor E2F/DP. In addition, we have shown
      that blocking of E2F could efficiently protect from apoptosis induced by serum
      starvation within a period of 10 d, whereas control cells started to die after 24
      h. Surprisingly, blocking of E2F did not alter the rate of proliferation or of
      DNA synthesis of these cells; this finding indicates that cell-cycle progression
      could be driven in an E2F-independent manner. In addition, we have been able to
      show that blocking of endogenous E2F in HBL-100 cells led to rapid induction of
      tumor growth in severe combined immunodeficiency mice. No tumor growth could be
      observed in mice that received mock-transfected clones or tetracycline to block
      expression of the E2F mutant constructs in vivo. Thus, it appears that E2F has a
      potential tumor-suppressive function under certain circumstances. Furthermore, we
      provide evidence that dysregulation of apoptosis may be an important step in
      tumorigenesis.

PMID- 8642264
TI  - Expression of variants of the major surface glycoprotein of Pneumocystis carinii.
AB  - Previously, we have shown that a multicopy family of related but unique genes
      encodes the major surface glycoprotein (MSG) of Pneumocystis carinii. To examine
      whether different members of this gene family are expressed by P. carinii,
      antisera were prepared against peptides whose sequences were determined from the
      deduced amino acid sequences of variants of rat-derived MSG. Immunohistochemical
      staining of serial sections of rat lungs of infected animals showed that at least
      three variants of MSG were expressed in an individual lobe, that there was a
      focal expression of these variants within the lung, and that the relative numbers
      of these foci were different. Indirect immunofluorescent staining of purified P.
      carinii organisms using these antisera revealed that at least three variants of
      MSG were present in organisms isolated from an individual rat and that both cysts
      and trophozoites reacted with each antiserum. A substantial difference in the
      fraction of organisms reacting with a specific antipeptide antiserum was seen
      when comparing organisms isolated from rats raised in a single colony over a
      period of two years as well as organisms isolated at one time point from rats
      raised in different colonies. This demonstration of antigenic variation in P.
      carinii supports the hypothesis that P. carinii utilizes such variation for
      evading host defense mechanisms.

PMID- 8642263
TI  - Human Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home
      preferentially to and induce selective regressions of autologous EBV-induced B
      cell lymphoproliferations in xenografted C.B-17 scid/scid mice.
AB  - C.B-17 scid/scid (severe combined immunodeficiency [SCID]) mice inoculated with
      peripheral blood lymphocytes from Epstein-Barr virus (EBV)-seropositive donors,
      or with EBV-transformed lymphoblastoid B cell lines (EBV-LCL), develop lethal
      human EBV+ B cell lymphoproliferative disorders (EBV-LPD) with characteristics
      similar to those arising in immunodeficient patients. Using this model, we
      examined the capacity of human effector cells to control human EBV-LPD. SCID mice
      received rabbit anti-asialo GM1 antiserum to abrogate endogenous natural killer
      cell function. Preliminary experiments showed that adoptive transfer of
      peripheral blood mononuclear cells (PBMC), purified T cells, interleukin (IL) 2
      activated PBMC or anti-CD3-activated T cells derived from EBV-seropositive donors
      did not result in improved survival of treated mice (in vivo effector/target
      ratio 2:1 to 1:1). In contrast, EBV-specific cytotoxic T lymphocytes (CTL),
      derived from EBV-seropositive donors and expanded in vitro, exhibited strong EBV
      specific and HLA-restricted activity both in vitro and in vivo. SCID mice
      inoculated intraperitoneally with autologous but not with HLA-mismatched EBV-LCL
      had significantly improved survival relative to untreated mice after inoculation
      of EBV-specific CTL either intraperitoneally (P<0.001) or intravenously (P<0.001)
      (in vivo effector/target ratio 1:1). SCID mice bearing large subcutaneous EBV+
      tumors and treated intravenously with 10(7) EBV-specific CTL achieved complete
      tumor regression. Both CTL- and CTL-plus-IL-2-treated mice survived significantly
      longer than untreated animals or animals treated with IL-2 alone (P = 0.0004 and
      P<0.02, respectively). SCID mice bearing two subcutaneous EBV+ tumors, one
      autologous and the other HLA mismatched to the EBV-specific CTL donor, had
      regression of only the autologous tumor after intravenous infusion of 10(7) EBV
      specific CTL. Moreover, we could demonstrate preferential homing of PKH26-labeled
      EBV-specific CTL to autologous but not to HLA-mismatched EBV+ tumors as early as
      24 h after intravenous adoptive transfer. Immunophenotypic analyses also
      demonstrated preferential infiltration of T cells into the autologous EBV+ tumor
      in SCID mice bearing both the autologous and either fully HLA-mismatched or
      genotypically related haplotype-sharing EBV+ tumors. The human T cells
      infiltrating EBV+ tumors were CD3+ and, predominantly, CD8+CD4-. Our results
      indicate that EBV-specific CTL preferentially localize to and infiltrate EBV+
      tumors bearing the appropriate HLA antigens and thereafter induce targeted
      regressions of disease.

PMID- 8642265
TI  - Bone marrow-derived cells fail to induce positive selection in thymus
      reaggregation cultures.
AB  - The requirements for inducing positive selection of T cells were examined in
      thymus reaggregation cultures, a system in which dispersed populations of
      immature CD4+8+ cells and purified thymic epithelial cells (TEC) are reaggregated
      in tissue culture. Studies with TEC from mice selectively lacking major
      histocompatibility complex (MHC) class I (I-II+), class II (I+II-), or both class
      I and II (I-II-) molecules showed that class II expression was essential for the
      differentiation of CD4+8+ cells into CD4+8- cells. Unexpectedly, the generation
      of TCRhi CD4-8+ cells from CD4+8+ cells was apparent with I-II+ TEC but not with
      I-II- TEC, perhaps reflecting cross-reactive specificity of CD4-8+ cells for
      class II molecules. Significantly, the failure of I-II- TEC to generate TCRhi
      CD4+8- or CD4-8+ cells could not be overcome by adding MHC+ bone marrow-derived
      cells. These findings, together with experiments on purified subsets of TEC,
      suggest that positive selection in thymus reaggregation cultures is an exclusive
      property of cortical TEC.

PMID- 8642266
TI  - Transcription of the murine iNOS gene is inhibited by docosahexaenoic acid, a
      major constituent of fetal and neonatal sera as well as fish oils.
AB  - Macrophage activation is deficient in the fetus and neonate when the serum
      concentrations of docosahexaenoic acid (DHA) are 150 microM, or 10-50-fold higher
      than in the adult. We now show that DHA inhibits production of nitric oxide (NO)
      by macrophages stimulated in vitro by IFNgamma plus LPS, or by IFNgamma plus
      TNFalpha. The half-maximal inhibitory activity of DHA was approximately 25
      microM. There were strict biochemical requirements of the fatty acid for
      inhibition. Polyenoic fatty acids with 22 carbons were more inhibitory than those
      with 20 carbons. Among 22-carbon fatty acids, those with a greater number of
      double bonds and a double bond in the n-3 position were more inhibitory. DHA was
      the most inhibitory of the polyenoic acids we tested. Inducible nitric oxide
      synthase (iNOS) is the enzyme responsible for the production of NO by
      macrophages. NO production is initiated after new iNOS enzyme is synthesized
      following transcription of the iNOS gene. In macrophages stimulated by IFNgamma
      plus LPS, DHA inhibited accumulation of iNOS mRNA, as measured by Northern
      blotting, and iNOS transcription, as measured by nuclear run-on assays. We
      transfected RAW 264.7 macrophages with a construct containing the iNOS promoter
      fused to the chloramphenicol acetyl transferase gene. DHA inhibited activation of
      this promoter by IFN gamma plus LPS. By inhibiting iNOS transcription in the
      fetus and neonate, DHA may contribute to their increased susceptibility to
      infection.

PMID- 8642267
TI  - Critical amino acids in the lymphocyte function-associated antigen-1 I domain
      mediate intercellular adhesion molecule 3 binding and immune function.
AB  - We have identified amino acid residues within the evolutionarily conserved I
      domain of the alpha-chain (CD11a) of the leukocyte integrin leukocyte function
      associated antigen (LFA) 1 that are critical for intercellular adhesion molecule
      (ICAM) 3 (CD50) binding. ICAM-3, a ligand of LFA-1, is thought to mediate
      intercellular adhesion essential for the initiation of immune responses. Using a
      panel of human/murine I domain chimeras and point mutants, we observed that the
      Ile-Lys-Gly-Asn motif, located in the NH2-terminal part of the CD11a I domain, is
      required for ICAM-3 but not ICAM-1 binding. These findings demonstrate that the I
      domain of CD11a contains distinct functional subdomains for ligand specific
      binding. An aspartic acid located at position 137, which is essential to ICAM
      1/LFA-1 interactions (Edwards, C.P., M. Champe, T. Gonzalez, M.E. Wessinger, S.A.
      Spencer, L.G. Presta, P.W. Berman, and S.C. Bodary. 1995. J. Biol. Chem.
      270:12635-12640), was also critical for ICAM-3 binding, whereas Ser at position
      139 did not effect ICAM-1 or ICAM-3 binding. A synthetic peptide containing the
      Ile-Lys-Gly-Asn motif inhibited ICAM-3-dependent adhesion and proliferation of T
      cells at micromolar concentrations, suggesting that this peptide interferes with
      immune recognition. These observations underscore the importance of ICAM-3 in
      leukocyte function, and may lead to development of a new category of
      immunosuppressive agents.

PMID- 8642268
TI  - HLA-DQB1 codon 57 is critical for peptide binding and recognition.
AB  - The association of specific HLA-DQ alleles with autoimmunity is correlated with
      discrete polymorphisms in the HLA-DQ sequence that are localized within sites
      suitable for peptide recognition. The polymorphism at residue 57 of the DQB1
      polypeptide is of particular interest since it may play a major structural role
      in the formation of a salt bridge structure at one end of the peptide-binding
      cleft of the DQ molecules. This polymorphism at residue 57 is a recurrent feature
      of HLA-DQ evolution, occurring in multiple distinct allelic families, which
      implies a functional selection for maintaining variation at this position in the
      class II molecule. We directly tested the amino acid polymorphism at this site as
      a determinant for peptide binding and for antigen-specific T cell stimulation. We
      found that a single Ala-->Asp amino acid 57 substitution in an HLA-DQ3.2 molecule
      regulated binding of an HSV-2 VP-16-derived peptide. A complementary single
      residue substitution in the peptide abolished its binding to DQ3.2 and converted
      it to a peptide that can bind to DQ3.1 and DQ3.3 Asp-57-positive MHC molecules.
      These binding studies were paralleled by specific T cell recognition of the class
      II-peptide complex, in which the substituted peptide abolished T cell reactivity,
      which was directed to the DQ3.2-peptide complex, whereas the same T cell clone
      recognized the substituted peptide presented by DQ3.3, a class II restriction
      element differing from DQ3.2 only at residue 57. This structural and functional
      complementarity for residue 57 and a specific peptide residue identifies this
      interaction as a key controlling determinant of restricted recognition in HLA-DQ
      specific immune response.

PMID- 8642269
TI  - Reconstitution of human Fc gamma RIII cell type specificity in transgenic mice.
AB  - The human low affinity receptors for the Fc domain of immunoglobulin G, Fc gamma
      RIII, are encoded by two genes (IIIA and IIIB) which share >95% sequence identity
      in both coding and flanking sequences. Despite this extraordinary sequence
      conservation, IIIA is expressed in natural killer (NK) cells and macrophages and
      is absent in neutrophils, whereas IIIB is expressed only in neutrophils. To
      determine the molecular basis for this differential expression, we have generated
      transgenic mice using the genomic sequences of IIIA and IIIB. IIIA and IIIB
      transgenic mice show faithful reconstitution of this human pattern of cell type
      specificity. To determine the cis acting sequence elements that confer this
      specificity, we constructed chimeric genes in which 5.8 kb of 5' sequences of the
      IIIB gene has been replaced with a homologous region from the IIIA gene, and
      conversely, IIIA 5' sequences have been substituted for the analogous region of
      the IIIB gene. Promoter swap transgenic mice that carry IIIA 5' flanking
      sequences express Fc gamma RIII in macrophages and NK cells. In contrast,
      promoter swap transgenic mice that contain IIIB 5' sequences express Fc gamma
      RIII in neutrophils only. These studies define the elements conferring the cell
      type-specific expression of the human Fc gamma RIII genes within the 5' flanking
      sequences and first intron of the human Fc gamma RIIIA and Fc gamma RIIIB genes.

PMID- 8642270
TI  - An immunoglobulin E-dependent recombinant histamine-releasing factor induces
      interleukin-4 secretion from human basophils.
AB  - A novel recombinant histamine-releasing factor (rHFR), which stimulates secretion
      from a subpopulation of human basophils that express a particular type of
      immunoglobulin E (IgE) or IgE+, was found to induce interleukin-4 (IL-4)
      production from cells isolated from these same donors. The secretion of IL-4
      protein induced by rHRF significantly correlated with histamine release and the
      amount of protein generated, and the kinetics were identical to those caused by
      anti-IgE activation. Furthermore, the ability of rHRF to induce IL-4 protein
      production from cells not normally responsive to this protein was transferred by
      passive sensitization with plasma containing IgE+ antibody. That this novel
      protein stimulates both mediator release and the secretion of IL-4 protein from
      human basophils suggests a prominent role for this molecule in allergic disease.

PMID- 8642271
TI  - A potential mechanism of "cross-talk" between the p55 tumor necrosis factor
      receptor and Fas/APO1: proteins binding to the death domains of the two receptors
      also bind to each other.
AB  - The p55 tumor necrosis factor (TNF) receptor and Fas/APO1 induce cell death via
      distinct regions in their intracellular domains. Three cytoplasmic proteins that
      bind to these receptor regions have been identified recently. One, MORT1 (also
      called FADD), binds to Fas/APO1 but not to p55-R; another, TRADD, binds to the
      p55 TNF receptor but not to Fas/APO1; and the third, RIP, binds weakly to both
      receptors. The regions within these proteins that are involved in binding to the
      receptors and the receptor regions to which they bind share a common sequence
      motif, that of the "death domain." This study shows that the death domain motifs
      in MORT1, TRADD, and RIP bind effectively to each other, a mode of binding that
      may allow "cross-talk" between the functional expression of the p55 TNF receptor
      and Fas/APO1.

PMID- 8642272
TI  - Stringent V beta requirement for the development of NK1.1+ T cell receptor
      alpha/beta+ cells in mouse liver.
AB  - The liver of C57BL/6 mice contains a major subset of CD4+8- and CD4-8- T cell
      receptor (TCR)-alpha/beta+ cells expressing the polymorphic natural killer NK1.1
      surface marker. Liver NK1.1+TCR-alpha/beta+ (NK1+ T) cells require interaction
      with beta2-microglobulin-associated, major histocompatibility complex I-like
      molecules on hematopoietic cells for their development and have a TCR repertoire
      that is highly skewed to Vbeta8.2, Vbeta7, and Vbeta2. We show here that congenic
      C57BL/6.Vbeta(a) mice, which lack Vbeta8- expressing T cells owing to a genomic
      deletion at the Vbeta locus, maintain normal levels of liver NK1+ T cells owing
      to a dramatic increase in the proportion of cells expressing Vbeta7 and Vbeta2
      (but not other Vbetas). Moreover, in C57BL/6 congenic TCR-V Vbeta3 and -Vbeta8.1
      transgenic mice (which in theory should not express other Vbeta, owing to allelic
      exclusion at the TCR-beta locus), endogenous TCR-Vbeta8.2, Vbeta7, and Vbeta2
      (but not other Vbetas) are frequently expressed on liver NK1+T cells but absent
      on lymph node T cells. Finally, when endogenous V beta expression is prevented in
      TCR-Vbeta3 and Vbeta8.1 transgenic mice (by introduction of a null allele at the
      C beta locus), the development of liver NK1+T cells is totally abrogated.
      Collectively, our data indicate that liver NK1+T cells have a stringent
      requirement for expression of TCR-Vbeta8.2, Vbeta7, or Vbeta2 for their
      development.

PMID- 8642273
TI  - CD4/CD8 lineage commitment: back to instruction?

PMID- 8642274
TI  - The role of B cells in the programming of T cells for IL-4 synthesis.

PMID- 8642275
TI  - Fas and the art of lymphocyte maintenance.

PMID- 8642276
TI  - Human tumor antigens recognized by T lymphocytes.

PMID- 8642277
TI  - The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells.
AB  - Thymocytes must bind major histocompatibility complex (MHC) proteins on thymic
      epithelial cells in order to mature into either CD8+ cytotoxic T cells or CD4+
      helper T cells. Thymic precursors express both CD8 and CD4, and it has been
      suggested that the intracellular signals generated by CD8 or CD4 binding to class
      I or II MHC, respectively, might influence the fate of uncommitted cells. Here we
      test the notion that intracellular signaling by CD4 directs the development of
      thymocytes to a CD4 lineage. A hybrid protein consisting of the CD8 extracellular
      and transmembrane domains and the cytoplasmic domain of CD4 (CD884) should bind
      class I MHC but deliver a CD4 intracellular signal. We find that expression of a
      hybrid CD884 protein in thymocytes of transgenic mice leads to the development of
      large numbers of class I MHC-specific, CD4 lineage T cells. We discuss these
      results in terms of current models for CD4 and CD8 lineage commitment.

PMID- 8642278
TI  - Importance of low affinity Elf-1 sites in the regulation of lymphoid-specific
      inducible gene expression.
AB  - Elf-1 is an Ets family transcription factor that regulates a number of inducible
      lymphoid-specific genes, including those encoding interleukin 3 (IL-3),
      granulocyte/macrophage colony-stimulating factor (GM-CSF), and the IL-2 receptor
      (IL-2R) alpha chain. A minimal oligonucleotide spanning the IL-2R alpha Elf-1
      site (-97/-84) bound Elf-1 poorly, but binding activity markedly increased when
      this oligonucleotide was multimerized or flanking sequences were added. This
      result is consistent with the requirement of accessory proteins for efficient Elf
      1 binding, as has been demonstrated for the GM-CSF and IL-3 promoters. A binding
      site selection analysis revealed the optimal Elf-1 consensus motif to be
      A(A/t)(C/a)CCGGAAGT(A/S), which is similar to the consensus motif for the related
      Drosophila E74 protein. This minimal high affinity site could bind Elf-1 and
      functioned as a stronger transcription element than the -97/-84 IL-2R alpha
      oligonucleotide when cloned upstream of a heterologous promoter. In contrast, in
      the context of the IL-2R alpha promoter, conversion of the naturally occurring
      low affinity Elf-1 site to an optimal site decreased inducible activation of a
      reporter construct in Jurkat cells. This finding may be explained by the
      observation that another Ets family protein, ER GB/Fli-1, can efficiently bind
      only to the optimal site, and in this context, interferes with Elf-1 binding.
      Therefore, high affinity Elf-1 sites may lack sufficient binding specificity,
      whereas naturally occurring low affinity sites presumably favor the association
      of Elf-1 in the context of accessory proteins. These findings offer an
      explanation for the lack of optimal sites in any of the known Elf-1-regulated
      genes.

PMID- 8642279
TI  - Dendritic cells but not B cells present antigenic complexes to class II
      restricted T cells after administration of protein in adjuvant.
AB  - We have analyzed the relative contribution of dendritic cells (DC) and B cells in
      the presentation of peptide-class II complexes in an inflammatory situation in
      vivo. Draining lymph node cells from mice immunized subcutaneously with hen egg
      white lysozyme (HEL) in adjuvant display HEL peptide-major histocompatibility
      complex class II complexes able to stimulate, in the absence of any further
      antigen addition, specific T hybridoma cells. The antigen-presenting capacity of
      three different antigen-presenting cell (APC) populations recruited in lymph
      nodes, DC (N418+, class II+, B220-, low buoyant density), large B cells (B220+,
      low buoyant density), and small B cells (B220+, high buoyant density), was
      analyzed. After immunization with HEL in adjuvant, DC are the only lymph node APC
      population expressing detectable HEL peptide-class II complexes. These results
      indicate that lymph node DC and not B cells are the APC initiating the immune
      response in vivo after administration of antigen in adjuvant.

PMID- 8642280
TI  - Low zone tolerance to contact allergens in mice: a functional role for CD8+ T
      helper type 2 cells.
AB  - Normal skin is permeable to low molecular hydrophobic substances, including
      allergenic chemicals. Whereas such foreign matter appears to enter the skin
      naturally, it rarely induces contact hypersensitivity. This suggests that
      immunological tolerance would be the normal state of affairs. In search of a
      suitable model, we painted picryl chloride or oxazolone once or repeatedly on
      normal skin of BALB/c or C57B1/6 mice and found subsensitizing doses to be
      tolerogenic. The most effective doses in inducing tolerance were doses between
      those at the point of inflection from no responses to threshold sensitivity. But
      even doses three orders of magnitude lower than these suppressed subsequent
      sensitization if applied repeatedly. C57B1/6 mice (low responders) were
      consistently easier to make tolerant than BALB/c mice (high responders). The
      tolerant state established by a single painting was found to be fully developed
      at 48 h after initiation and long-lasting (>14 d). It could be adoptively
      transferred by intravenous injection of total spleen cells (SC), lymph node cells
      (LNC), or purified T cells and shown to be hapten specific. Pretreatment with
      cyclophosphamide (Cy) prevented tolerization. The T cells capable of transferring
      suppressive activity were found to be generated irrespective of the dose applied.
      On day 2 after painting, tolerance could be transferred with LNC from both
      tolerant and sensitized animals. On day 5, however, only cells from tolerant
      donors transferred tolerance. But by action of Cy, suppression was shown to be
      part of every sensitization, although masked. Production of hapten-specific
      antibodies was suppressed as well. Through depletion by monoclonal antibody in
      vitro the T suppressor cells were shown to belong to the murine CD8+ subset
      (Lyt2+). Upon restimulation in vitro by haptenized and irradiated normal SC, LNC
      from tolerant donors produced predominantly interleukin (IL)-4, IL-5, and IL-10.
      In contrast, LNC from sensitized donors produced preferentially IL-2 and
      interferon-gamma. Thus we demonstrate that painting subsensitizing doses of
      contact sensitizers on normal murine skin generates CD8+ Th2-like cells that give
      rise to hapten-specific tolerance. The model may have broader significance and
      apply to other species, including humans.

PMID- 8642281
TI  - Does B7-1 expression confer antigen-presenting cell capacity to tumors in vivo?
AB  - Tumors engineered to express the costimulatory molecule B7-1 can elicit CD8+
      cytotoxic T lymphocyte (CTL)-dependent antitumor responses in immunocompetent
      mice. It has been postulated that this result reflects direct priming of CTL by
      the modified tumor in vivo. Previous studies of the immune response to a B7-1-
      murine colon carcinoma expressing influenza nucleoprotein (NP) as a model tumor
      antigen have demonstrated the crucial role of bone marrow-derived antigen
      presenting cells (APCs) in the priming of NP-specific CTL in vivo. In this
      system, no evidence of direct CTL priming by tumor was detected. We have
      performed a similar analysis to determine if B7-1 transfectant of this tumor
      results in the direct priming of CTL, and to compare this response to that primed
      by host APCs. When H-2b-->H-2bxd bone marrow chimeras were immunized with a
      single injection of CT26/NP/B7-1 (H-2d), NP-specific CTL were detected that were
      restricted to the bone marrow haplotype (H-2b), but not to the tumor haplotype.
      In contrast, CTL recognizing the NP antigenic epitope in the context of the
      tumor's major histocompatibility complex were detectable only after multiple
      immunizations. These results suggest that whereas B7-1+ tumor vaccines result in
      some degree of direct presentation to CD8+ T cells, the dominant mechanism of CTL
      priming is through the uptake and presentation of tumor antigens by bone marrow
      deprived APCs. However, repeated immunization with B7-1+ tumor cells can
      efficiently expand the directly primed CD8+ CTL population.

PMID- 8642282
TI  - A cell type-specific enhancer in the human B7.1 gene regulated by NF-kappaB.
AB  - The costimulatory molecule B7.1 provides a second signal critical for T cell
      activation. The distribution of this integral membrane protein is restricted to
      certain tissues where its level of expression is modulated by multiple exogenous
      stimuli. To identify the molecular basis for specificity and inducibility, the
      chromatin configuration of the human B7.1 gene was examined in intact nuclei from
      various cell types. The identification of a tissue-specific deoxyribonuclease I
      hypersensitive site approximately 3kb upstream of the transcription start site
      led to the characterization of a cell type-specific enhancer region. This 183-bp
      region was both cell type specific and responsive to two distinct stimuli,
      lipopolysaccharide and dibutyryl cAMP, known to regulate B7.1 expression.
      Deletional and site-directed mutagenesis revealed the presence of multiple
      functionally critical cis elements within this region, one of which was a nuclear
      factor (NF)-kappaB consensus sequence. In B7.1-positive B cells, this element
      bound several members of the NF-kappaB family, transcription factors already
      implicated in signal transduction pathways relevant to B7.1 expression. This is
      the first description, to our knowledge, of regulatory elements that control
      expression of a gene encoding a B7 costimulatory molecule.

PMID- 8642283
TI  - B7-CD28 costimulation unveils the hierarchy of tumor epitopes recognized by major
      histocompatibility complex class I-restricted CD8+ cytolytic T lymphocytes.
AB  - Immunization of mice with tumors genetically engineered to express the B7
      costimulatory molecules amplifies the antitumor immune response mediated by CD8+
      cytolytic T lymphocytes (CTL). In this report, we examined the effect of B7-CD28
      costimulation on the hierarchy of tumor epitopes. Using a combination of affinity
      chromatography/reversed-phase high performance liquid chromatography and CTL
      cloning, we show that major histocompatibility complex (MHC) class I molecules
      from EL4 lymphoma cells can present at least six distinct CTL epitopes presented
      by MHC class I molecules. Nevertheless, mice immunized with wild-type B7-negative
      EL4 cells develop CTL only to one immunodominant epitope. In contrast,
      immunization with B7-transduced EL4 cells led to not only the amplification of
      the CTL response to this immunodominant epitope, but also to the recognition of
      five otherwise silent subdominant epitopes. The adoptive transfer of a CTL clone
      against such a subdominant epitope cured mice bearing EL4 lymphoma growing as an
      ascites tumor. The fact that CTL response can be spread to normally silent
      epitopes as a result of B7-CD28 costimulation suggests a novel approach to
      manipulate the hierarchy of CTL epitopes and offers an opportunity to explore
      novel targets for T cell-mediated cancer therapy.

PMID- 8642284
TI  - The relative contribution of the CD28 and gp39 costimulatory pathways in the
      clonal expansion and pathogenic acquisition of self-reactive T cells.
AB  - The zona pellucida (ZP), an ovarian extracellular structure, contains three major
      glycoproteins: ZP1, ZP2, and ZP3. A ZP3 peptide contains both an autoimmune
      oophoritis-inducing T cell epitope and a B cell epitope that induces autoantibody
      to ZP. This study investigates two major T cell costimulation pathways in this
      disease model. Herein we show that blockage of glycoprotein (gp)39 and CD40
      interaction with gp39 monoclonal antibody (mAb) results in the failure to induce
      both autoimmune oophoritis and autoantibody production. Inhibition of ligand
      binding to the CD28 receptor with the fusion protein, murine CTLA4-immunoglobulin
      (Ig), also results in failure to generate antibody to ZP and significantly
      reduces disease severity and prevalence. Surprisingly, the frequencies of antigen
      specific T cells in anti-gp39 mAb-treated mice, CTLA4-Ig treated mice, and in
      mice given control hamster IgG or control fusion protein L6, were equivalent as
      determined by limiting dilution analysis (approximately equals 1:5,000). These T
      cells, which produced comparable amounts of interleukin 4 and interferon gamma in
      vitro, were able to transfer oophoritis to normal recipients. When anti-gp39 mAb
      and CTLA4-Ig were given together, the effect was additive, leading to inhibition
      of T cell activation as determined by in vitro proliferation and limiting
      dilution analysis (approximately equals 1:190,000); disease and antibody
      responses were absent in these mice. By studying these two costimulatory pathways
      in parallel, we have shown that autoimmune disease and autoantibody production
      are inhibitable by blocking either the gp39 or the CD28 pathway, whereas
      inhibition of clonal expansion of the effector T cell population occurs only when
      both pathways are blocked.

PMID- 8642286
TI  - Thrombin functions as an inflammatory mediator through activation of its
      receptor.
AB  - A rat model of inflammation was used to investigate the biological effects of
      thrombin. The thrombin-specific inhibitor Hirulog markedly attentuated the
      carrageenin-induced edema of the paw of the rat. Injection of thrombin into the
      paw also produced edema. The effect of thrombin was due to activation of its
      receptor; a thrombin receptor activating peptide (TRAP) reproduced the effects of
      thrombin in causing edema. TRAP also increased vascular permeability as
      demonstrated by extravasation of Evans blue and 125I-labeled serum albumin. The
      release of bioactive amines played an important role in mediating the TRAP
      induced edema; the serotonin/histamine antagonist cryproheptadine and the
      histamine H2 receptor antagonist cimetidine reduced significantly the edema
      caused by TRAP. Treatment of rats with the mast cell degranulator 48/80 to
      deplete these cells of their stores of histamine and serotonin abolished
      completely the ability of TRAP to produce edema. Histochemical examination
      confirmed that TRAP treatment led to mast cell degranulation. Thus, it has been
      possible to demonstrate that thrombin acts as an inflammatory mediator in vivo by
      activating its receptor, which in turn leads to release of vasoactive amines from
      mast cells.

PMID- 8642285
TI  - Tyrosyl phosphorylation and DNA binding activity of signal transducers and
      activators of transcription (STAT) proteins in hematopoietic cell lines
      transformed by Bcr/Abl.
AB  - Bcr/Abl is a chimeric oncogene that can cause both acute and chronic human
      leukemias. Bcr/Abl-encoded proteins exhibit elevated kinase activity compared to
      c-Abl, but the mechanisms of transformation are largely unknown. Some of the
      biological effects of Bcr/Abl overlap with those of hematopoietic cytokines,
      particularly interleukin 3 (IL-3). Such effects include mitogenesis, enhanced
      survival, and enhanced basophilic differentiation. Therefore, it has been
      suggested that p210Bcr/Abl and the IL-3 receptor may activate some common signal
      transduction pathways. An important pathway for IL-3 signaling involves
      activation of the Janus family kinases (JAKs) and subsequent tyrosyl
      phosphorylation of STAT proteins (signal transducers and activators of
      transcription). This pathway directly links growth factor receptors to gene
      transcription. We analyzed JAK activation, STAT protein phosphorylation, and the
      formation of specific DNA-binding complexes containing STAT proteins, in a series
      of leukemia cell lines transformed by Bcr/Abl or other oncogenes. We also
      examined these events in cell lines transformed by a temperature sensitive (ts)
      mutant of Bcr/Abl, where the kinase activity of Abl could be regulated. STAT1 and
      STAT5 were found to be constitutively phosphorylated in 32D, Ba/F3, and TF-1
      cells transformed by Bcr/Abl, but not in the untransformed parental cell lines in
      the absence of IL-3. Phosphorylation of STAT1 and STAT5 was also observed in the
      human leukemia cell lines K562 and BV173, which express the Bcr/Abl oncogene, but
      not in several Bcr/Abl-negative leukemia cell lines. Phosphorylation of STAT1 and
      STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could
      be activated or deactivated by temperature shifting of cells expressing the
      Bcr/Abl ts mutant. DNA-STAT complexes were detected in all Bcr/Abl-transformed
      cell lines and they were supershifted by antibodies against STAT1 and STAT5. DNA
      STAT complexes in 32Dp210Bcr/Abl cells were similar, but not identical, to those
      formed after IL-3 stimulation. It is interesting to note that JAK kinases (JAK1,
      JAK2, JAK3, and Tyk2) were not consistently activated in Bcr/Abl-positive cells.
      These data suggest that STATs can be activated directly by Bcr/Abl, possibly
      bypassing JAK family kinase activation. Overall, our results suggest a novel
      mechanism that could contribute to some of the major biological effects of
      Bcr/Abl transformation.

PMID- 8642287
TI  - Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated
      with susceptibility to tuberculoid leprosy.
AB  - Evaluation of human histocompatibility leukocyte antigen (HLA) class II genes in
      54 cases of tuberculoid leprosy (TL) and 44 controls has shown a positive
      association with HLA-DRB1 alleles that contain Arg13 or Arg70-Arg71. Among TL
      patients, 87% carry specific alleles of DRB1 Arg13 or Arg70-Arg71 as compared to
      43% among controls (p = 5 x 10(-6)) conferring a relative risk of 8.8. Thus,
      susceptibility to TL involves three critical amino acid positions of the beta
      chain, the side chains of which, when modeled on the DR1 crystal structure, line
      a pocket (pocket 4) accommodating the side chain of a bound peptide. This study
      suggests that disease susceptibility may be determined by the independent
      contribution of polymorphic residues participating in the formation of a
      functional arrangement (i.e., pocket) within the binding cleft of an HLA
      molecule.

PMID- 8642288
TI  - Erythropoietin-independent erythrocyte production: signals through gp130 and c
      kit dramatically promote erythropoiesis from human CD34+ cells.
AB  - Erythropoietin (EPO) is the primary humoral regulator of erythropoiesis and no
      other factor has previously been reported to support proliferation and terminal
      maturation of erythroid cells from hemopoietic stem cells. Here we show that
      stimulation of glycoprotein (gp130) by a combination of recombinant human soluble
      interleukin 6 receptor (sIL-6R) and IL-6 but not sIL-6R or IL-6 alone can support
      proliferation, differentiation, and terminal maturation of erythroid cells in the
      absence of EPO from purified human CD34+ cells in suspension culture containing
      stem cell factor (SCF). A number of erythroid bursts and mixed erythroid colonies
      also developed in methylcellulose culture under the same combination. The
      addition of anti-gp130 monoclonal antibodies but not anti-EPO antibody to the
      same culture completely abrogated the generation of erythroid cells. These
      results clearly demonstrate that mature erythroid cells can be emerged from
      hemopoietic progenitors without EPO in vitro. Together with the previous reports
      that human sera contain detectable levels of sIL-6R, IL-6, and SCF, current data
      suggest that gp130 signaling in association with c-kit activation may play a role
      in human erythropoiesis in vivo.

PMID- 8642289
TI  - Cytokine imbalance and autoantibody production in T cell receptor-alpha mutant
      mice with inflammatory bowel disease.
AB  - Spontaneous inflammatory bowel disease (IBD) resembling human ulcerative colitis
      develops in mice mutant for the T cell receptor alpha gene (TCR-alpha-/-). TCR
      alpha-/- mice lack TCR-alpha/beta+ cells but contain TCR-gamma/delta+ cells and a
      small population of a unique CD4+, TCR-alpha-/beta+(low) cells. Since all the
      immunoglobulin (Ig) classes are present in these mice, help to B cells must be
      provided by cells other than TCR-alpha/beta+ cells. In the present study, we
      found serum levels of IgG1 and IgG2 to be markedly increased in TCR-alpha-/- mice
      with IBD as compared to TCR-alpha-/- mice without IBD or TCR-alpha+/- controls.
      An increase in IgG1-, IgG2a- and IgA- but not IgM-secreting mesenteric lymph node
      (MLN) B cells was detected in TCR-alpha-/- mutant mice. There was also a marked
      increase in MLN B cells secreting autoantibody (IgG) to tropomyosin, a
      cytoskeletal protein. Examination of the hyperplastic MLN showed a marked
      increase in the number of B, TCR-delta+, and CD4+ TCR-alpha-/beta+ cells, similar
      to the cell population observed at the site of colonic inflammation. Analysis of
      spontaneous cytokine production by MLN cells using an enzyme-linked immunospot
      assay, immunohistochemistry, and reverse transcription/polymerase chain reaction
      showed a decrease of interleukin 2 (IL-2) but a marked increase of IL-4 and
      interferon gamma (IFN-gamma) production in TCR-alpha-/- mice with IBD as compared
      to TCR-alpha-/- mice without IBD and TCR alpha+/- control mice. Both TCR-alpha
      /beta+ and TCR-delta+ cells were found to be capable of producing IL-4; IFN-gamma
      was produced mostly by non-T cells, many of which were shown to be CD3- NK 1.1+
      cells. We propose that the cytokine imbalance present in these mice results in
      expansion of B cells, production and switching of autoantibodies to IgG2
      subclass, and development of IBD. It is possible that the unusual CD4+ TCR-alpha
      /beta+ population and expanded TCR-gamma/delta+ population present in TCR-alpha-/
      mice plays a central role in this abnormal immune response.

PMID- 8642290
TI  - An insulin peptide that binds an alternative site in class II major
      histocompatibility complex.
AB  - We report that a peptide from the B chain of insulin, B(10-30), binds with high
      affinity to multiple class II proteins, including IAb,d,k, IEd,k, and DR1. The
      ability of B(10-30) to inhibit the binding of other peptide antigens to class II
      does not correlate with its affinity for class II. B(10-30) only weakly inhibits
      the binding of antigenic peptides. Conversely, peptides with high affinity for
      the peptide-binding groove of various class II proteins do not inhibit B(10-30)
      binding. The rate of association of B(10-30) with class II is unusually rapid,
      approaching saturation in 1-2 h compared with 1-2 d for classical peptide
      antigens in the same conditions. The dissociation rate is also relatively rapid.
      The B(10-30) peptide inhibits the binding of the super-antigen staphylococcal
      enterotoxin B (SEB) to IAk. It also inhibits SEB-mediated T cell activation.
      These observations support the conclusion that B(10-30) binds to a site outside
      the peptide-binding groove. Our findings indicate that short-lived peptide-class
      II complexes can be formed through interactions involving the SEB-binding site
      and raise the possibility that alternative complexes may serve as T cell receptor
      ligands.

PMID- 8642292
TI  - Inactivation of human immunodeficiency virus (HIV)-1 envelope-specific CD8+
      cytotoxic T lymphocytes by free antigenic peptide: a self-veto mechanism?
AB  - Free peptide has been found to inhibit cytotoxic T lymphocyte (CTL) activity, and
      veto cells bearing peptide-major histocompatibility complex (MHC) complexes have
      been found to inactivate CTL, but the two phenomena have not been connected. Here
      we show that a common mechanism may apply to both. CD8+ CTL lines or clones
      specific for a determinant of the human immunodeficiency virus (HIV) 1 IIIB
      envelope protein gp160, P18IIIB, are inhibited by as little as 10 min exposure to
      the minimal 10-mer peptide, I-10, within P18IIIB, free in solution, in contrast
      to peptide already bound to antigen-presenting cells (APC), which does not
      inhibit. Several lines of evidence suggest that the peptide must be processed and
      presented by H-2Dd on the CTL itself to the specific T cell receptor (TCR) to be
      inhibitory. The inhibition was not killing, in that CTL did not kill 51Cr-labeled
      sister CTL in the presence of free peptide, and in mixing experiments with CTL
      lines of different specificities restricted by the same MHC molecule, Dd, the
      presence of free peptide recognized by one CTL line did not inhibit the activity
      of the other CTL line that could present the peptide. Also, partial recovery of
      activity could be elicited by restimulation with cell-bound peptide, supporting
      the conclusion that neither fratricide nor suicide (apoptosis) was involved. The
      classic veto phenomenon was ruled out by failure of peptide-bearing CTL to
      inactivate others. Using pairs of CTL lines of differing specificity but similar
      MHC restriction, each pulsed with the peptide for which the other is specific, we
      showed that the minimal requirement is simultaneous engagement of the TCR and
      class I MHC molecules of the same cell. This could occur in single cells or pairs
      of cells presenting peptide to each other. Thus, mechanistically, the inhibition
      is analogous to veto, and might be called self-veto. As a clue to a possible
      mechanism, we found that free I-10 peptide induced apparent downregulation of
      expression of specific TCR as well as interleukin 2 receptor, CD69, lymphocyte
      function-associated antigen 1, and CD8. This self-veto effect also has
      implications for in vivo immunization and mechanisms of viral escape from CTL
      immunity.

PMID- 8642291
TI  - Signaling through the lymphotoxin beta receptor induces the death of some
      adenocarcinoma tumor lines.
AB  - Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-beta chains
      that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis
      factor (TNF) family of receptors. The biological function of this receptor-ligand
      system is poorly characterized. Since signaling through other members of this
      receptor family can induce cell death, e.g., the TNF and Fas receptors, it is
      important to determine if similar signaling events can be communicated via the LT
      beta-R. A soluble form of the surface complex was produced by coexpression of LT
      alpha and a converted form of LT-beta wherein the normally type II LT-beta
      membrane protein was changed to a type I secreted form. Recombinant LT-alpha
      1/beta 2 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB
      468, and HT-3 when added with the synergizing agent interferon (IFN) gamma. When
      immobilized on a plastic surface, anti-LT-beta-R monoclonal antibodies (mAbs)
      induced the death of these cells, demonstrating direct signaling via the LT-beta
      R. Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell
      death, whereas others were found to potentiate the activity of the ligand when
      added in solution. The human WiDr adenocarcinoma line forms solid tumors in
      immunocompromised mice, and treatment with an anti-LT-beta-R antibody combined
      with human IFN-gamma arrested tumor growth. The delineation of a biological
      signaling event mediated by the LT-beta-R opens a window for further studies on
      its immunological role, and furthermore, activation of the LT-beta-R may have an
      application in tumor therapy.

PMID- 8642293
TI  - B cells solicit their own help from T cells.
AB  - We have made use of T cell receptor (TCR)-transgenic mice with CD4+ T cells
      expressing a receptor specific for the self-antigen C5 (fifth component of
      complement) to study the role of different antigen-presenting cells in the
      determination of CD4+ T cell effector type. Contact of T cells from C5 TCR
      transgenic mice with C5 protein or C5 peptide in vivo or in vitro induces biased
      T helper cell (Th) 1 type responses resulting in exclusive production of high
      levels of interferon gamma and interleukin (IL) 2. Transgenic mice, in contrast
      to nontransgenic littermates, do not generate an antibody response to C5. We show
      in this paper that B cell presentation in vitro induces a switch to the Th2
      subset indicated by production of IL-4, and targetting C5 to B cells in vivo
      results in the generation of C5-specific antibodies.

PMID- 8642294
TI  - Reversibility of T helper 1 and 2 populations is lost after long-term
      stimulation.
AB  - Commitment of T helper 1 (Th1) or Th2 populations developing during an immune
      response to a pathogen, or an inappropriate immune response to an allergen or
      autoantigen, may determine the difference between health and chronic disease. We
      show that strongly polarized Th1 and Th2 populations assessed by immunoassay are
      heterogeneous using flow cytometry to detect single cells producing interferon
      gamma (IFN-gamma) and interleukin 4 (IL-4). Th1 populations arising after 1 wk of
      stimulation in IL-12 plus anti-IL-4 antibodies could convert to Th2 cells when
      restimulated in IL-4. Th2 populations resulting from stimulation for 1 wk in IL-4
      could give rise to Th1 cells upon restimulation in IL-12 plus anti-IL-4. In
      contrast, the cytokine profiles of long-term Th1 and Th2 populations arising
      originally from repeated stimulation in IL-12 or IL-4 appeared more homogeneous
      and were not reversible, although IL-4 dramatically reduced the number of IFN
      gamma-producing Th1 cells. This may explain previous reports that Th1 cells can
      be converted to Th2 cells.

PMID- 8642295
TI  - The life span of major histocompatibility complex-peptide complexes influences
      the efficiency of presentation and immunogenicity of two class I-restricted
      cytotoxic T lymphocyte epitopes in the Epstein-Barr virus nuclear antigen 4.
AB  - We have investigated the reactivity to two human histocompatibility leukocyte
      antigen (HLA) A11-restricted cytotoxic T lymphocyte (CTL) epitopes derived from
      amino acids 416-424 (IVTDFSVIK, designated IVT) and 399-408 (AVFDRKSVAK,
      designated AVF) of the Epstein-Barr virus (EBV) nuclear antigen (EBNA) 4. A
      strong predominance of CTL clones specific for the IVT epitope was demonstrated
      in polyclonal cultures generated by stimulation of lymphocytes from the EBV
      seropositive donor BK with the autologous B95.8 virus-transformed lymphoblastoid
      cell line (LCL). This was not due to intrinsic differences of CTL efficiency
      since clones specific for the two epitopes lysed equally well A11-positive
      phytohemagglutinin blasts and LCLs pulsed with the relevant synthetic peptide.
      Irrespective of the endogenous levels of EBNA4 expression, untreated LCLs were
      lysed more efficiently by the IVT-specific effectors, suggesting that a higher
      density of A11-IVT complexes is presented at the cell surface. In accordance, 10
      50-fold higher amounts of IVT peptides were found in high-performance liquid
      chromatography fractions of acid extracts corresponding to an abundance of about
      350-12,800 IVT and 8-760 AVF molecules per cell. Peptide-mediated competition of
      CTL sensitization, transport assays in streptolysin-O permeabilized cells, and
      induction of A11 expression in the transporter associated with antigen
      presentation-deficient T2/A11 transfectant demonstrated that the IVT and AVF
      peptides bind with similar affinities to A11, are translocated with equal
      efficiency to the endoplasmic reticulum, and form complexes of comparable
      stability over a wide range of temperature and pH conditions. A rapid surface
      turnover of A11 molecules containing the AVF peptide was demonstrated in
      metabolically active T2/A11 cells corresponding to a half-life of approximately
      3.5 as compared to approximately 2 h for molecules induced at 26 degrees C in the
      absence of exogenous peptides and >12 h for IVT-containing complexes. This
      difference in persistence is likely to determine the representation of individual
      class I-restricted CTL epitopes within the cell surface pool of molecules, and
      may be an important factor contributing to their immunogenicity.

PMID- 8642296
TI  - Suppression of proinflammatory cytokines in monocytes by a tetravalent
      guanylhydrazone.
AB  - An overproduction of proinflammatory cytokines by activated macrophages/monocytes
      mediates the injurious sequelae of inflammation, septic shock, tissue injury, and
      cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI
      1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO)
      production in macrophages, and protects mice against lethal endotoxemia and
      carrageenan-induced inflammation. During these investigations we noticed that CNI
      1493 effectively prevented lipopolysaccharide (LPS)-induced NO production, even
      when added in concentrations 10-fold less than required to competitively inhibit
      L-arginine uptake, suggesting that the suppressive effects of this
      guanylhydrazone compound might extend to other LPS-induced responses. Here, we
      report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory
      cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage
      inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear
      cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either
      the constitutive synthesis of transforming growth factor beta or the upregulation
      of major histocompatibility complex class II by interferon gamma (IFN-gamma). In
      contrast to the macrophage suppressive actions of dexamethasone, which are
      overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive
      effects even in the presence of IFN-gamma. The mechanism of cytokine-suppressive
      action by CNI-1493 was independent of extracellular L-arginine content and NO
      production and is not restricted to induction by LPS. As a selective inhibitor of
      macrophage activation that prevents TNF production, this tetravalent
      guanylhydrazone could be useful in the development of cytokine-suppressive agents
      for the treatment of diseases mediated by overproduction of cytokines.

PMID- 8642297
TI  - Interleukin-10 induces immunoglobulin G isotype switch recombination in human
      CD40-activated naive B lymphocytes.
AB  - Upon activation, B lymphocytes can change the isotype of the antibody they
      express by immunoglobulin (Ig) isotype switch recombination. In previous studies
      on the regulation of human IgG expression, we demonstrated that interleukin 10
      (IL-10) could stimulate IgG1 and IgG3 secretion by human CD40-activated naive
      (sIgD+) tonsillar B cells. To assess whether IL-10 actually promotes the DNA
      recombination underlying switching to these isotypes, we examined the effect of
      IL-10 on the generation of reciprocal products that form DNA circles as by
      products of switch recombination. The content of reciprocal products
      characteristic of mu-gamma recombination was elevated after culture of CD40
      activated tonsillar sIgD+ B cells with either IL-4 or IL-10, although high levels
      of IgG secretion were observed only with IL-10. Unlike IL-4, IL-10 did not induce
      reciprocal products of mu-epsilon and gamma-epsilon switch recombination. These
      results demonstrate that IL-10 promotes both switching to gamma and IgG
      secretion.

PMID- 8642298
TI  - Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro
      myocardial cell depression induced by human septic shock serum.
AB  - Previous studies have demonstrated the presence of myocardial depression in
      clinical and experimental septic shock. This depression is associated with the
      presence of a circulating myocardial depressant substance with physical
      characteristics consistent with cytokines. The present study utilized an in vitro
      myocardial cell assay to examine the role of various human recombinant cytokines,
      including tumor necrosis factor (TNF)alpha and interleukin (IL)1beta, in
      depression of cardiac myocyte contractile function induced by serum from humans
      with septic shock. The extent and velocity of electrically paced rat cardiac
      myocytes in tissue culture was quantified by a closed loop video tracking system.
      Individually, TNF-alpha and IL-1beta each caused significant concentration
      dependent depression of maximum extent and peak velocity of myocyte shortening in
      vitro. In combination, TNF-alpha and IL-1beta induced depression of myocardial
      cell contractility at substantially lower concentrations consistent with a
      synergistic effect. Using immunoabsorption, removal of both TNF-alpha and IL
      1beta (but not either alone) from the serum of five patients with acute septic
      shock and marked reversible myocardial depression resulted in elimination of
      serum myocardial depressant activity. IL-2, -4, -6, -8, -10, and interferon gamma
      failed to cause significant cardiac myocyte depression over a wide range of
      concentrations. These data demonstrate that TNF-alpha and IL-1beta cause
      depression of myocardial cell contraction in vitro and suggest that these two
      cytokines act synergistically to cause sepsis-associated myocardial depression in
      humans.

PMID- 8642299
TI  - Relative contribution of T and B cells to hypermutation and selection of the
      antibody repertoire in germinal centers of aged mice.
AB  - The immune system of aged individuals often produces antibodies that have lower
      affinity and are less protective than antibodies from young individuals. Recent
      studies in mice suggested that antibodies produced by old individuals may be
      encoded by distinct immunoglobulin (Ig) genes and that the somatic hypermutation
      process in these individuals is compromised. The present study employed Ighb scid
      mice reconstituted with normal lymphocytes from young (2-3-mo-old) and aged (20
      25-mo-old) donors and immunized with a protein conjugate of the hapten (4-hydroxy
      3-nitrophenyl)acetyl (NP) to determine whether the molecular changes in antibody
      repertoire reflect senescence in the B cells or whether they are mediated by the
      aging helper T lymphocytes. The NP-reactive B cells from splenic germinal centers
      (GC) were recovered by microdissection of frozen tissue sections and their
      rearranged Ig heavy chain variable region (VH) genes of the V186.2/V3 families
      were sequenced. It was found that the VH gene repertoire of the GC B cells was
      strongly influenced by the source of the CD4+ T cells. When T cells were donated
      by young mice, the anti-NP response in GC was dominated by the canonical V186.2
      gene, even if the responder B cells came from aged donors. However, when the mice
      were reconstituted with T cells from aged donors, the expression of the V186.2
      gene by young B cells was diminished and the response was dominated by the C1H4
      gene, another member of the V186.2/V3 family. In contrast, the somatic
      hypermutation process in the GC B cells followed a different pattern. The
      mutation frequencies in the animals that were reconstituted with both B and T
      cells from young donors (1/50 to 1/150 bp) were comparable to the frequencies
      previously reported for NP-immunized intact young/adult mice. However, when
      either lymphocyte subset was donated by the aged mice, the mutation frequencies
      declined. Thus, mice reconstituted with T cells from the aged and B cells from
      the young had severely compromised mutational mechanism. Likewise, the recipients
      of aged B and young T cells had diminished mutations even though the repertoire
      of their anti-NP response was dominated by the canonical V186.2 gene. It appears
      that the change in germine-encoded repertoire and the decrease of somatic
      hypermutation represent distinct mechanisms of immunosenescence and that the
      aging of helper T cells plays a pivotal role in both of these processes.

PMID- 8642300
TI  - Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc,
      P53, and Bax but not the survival gene bcl-2.
AB  - During T cell-dependent antibody responses, B cells within germinal centers (GC)
      alter the affinity of their antigen receptor by introducing somatic mutations
      into variable region of immunoglobulin (IgV) genes. During this process, GC B
      cells are destined to die unless positively selected by antigens and CD40-ligand.
      To understand survival/death control of germinal center B cell, the expression of
      four apoptosis-inducing genes, Fas, c-myc, Bax, and P53, together with the
      survival gene bcl-2, has been analyzed herein among purified tonsillar naive, GC,
      and memory B cells. IgD+CD38- naive B cells were separated into CD23- (mature B
      cell [Bm]1) subset and CD23+ (Bm2), IgD-CD38+ GC B cells were separated into
      subsets of CD77+ centroblasts (Bm3) and CD77- centrocytes (Bm4), whereas IgD-CD38
      cells represented the Bm5 memory B cell subset. Sequence analysis of IgV region
      genes indicated that somatic hypermutation was triggered in the Bm3 centroblast
      subset. Here we show that bcl-2 is only detectable with naive (Bm1 and 2) and
      memory B cell (Bm5) subsets, whereas all four apoptosis-inducing genes were most
      significantly expressed within GC B cells. Fas was equally expressed in Bm3
      centroblasts and Bm4 centrocytes, whereas Bax was most significantly expressed in
      Bm4 centrocytes. c-myc, a positive regulator of cell cycle, was most
      significantly expressed in proliferating Bm3 centroblasts, whereas P53, a
      negative regulator of cell cycle, was most signficantly expressed in
      nonproliferating Bm4 centrocytes. The present results indicate that the
      survival/death of GC B cells are regulated by the up- and downregulation of
      multiple genes, among which the expression of c-myc and P53 in the absence of bcl
      2 may prime the proliferating Bm3 centroblasts and nonproliferating Bm4
      centrocytes to apoptosis.

PMID- 8642301
TI  - The T cell-B cell interaction via OX40-OX40L is necessary for the T cell
      dependent humoral immune response.
AB  - Recent in vitro studies have established that activated B cells express OX40
      ligand (L), a member of the tumor necrosis factor/nerve growth factor family of
      cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig)
      after cross-linking of OX40L by its counterreceptor OX40, which is expressed on
      activated T cells. In the present study we investigated the in vivo role of this
      receptor-ligand pair for the interaction of T and B cells in the course of the T
      dependent B cell response against 2,4,6 trinitro-phenyl-keyhole limpet
      hemocyanin. First, we showed that OX40 is maximally expressed by T cells in the
      periarteriolar lymphoid sheath (PALS) 3 d after primary immunization. These OX40+
      cells are located in close proximity to antigen-specific, activated B cells.
      Second, we demonstrated that blocking of OX40-OX40L interaction with polyclonal
      anti-OX40 antibody or with antibodies against certain peptide sequences within
      its extracellular domain resulted in a profound decrease of the anti-hapten IgG
      response, whereas the antihapten IgM response was grossly unchanged. Third, we
      showed that this antibody treatment leads to an inhibition of the development of
      PALS-associated B cell foci, whereas the formation of germinal centers remained
      intact. Finally, our data suggest that, whereas B cell memory development was not
      impaired by anti-OX40 administration, OX40-OX40L interaction seems to be crucial
      in the secondary immune response. We conclude from these data that the OX40-OX40L
      interaction in vivo is necessary for the differentiation of activated B cells
      into highly Ig-producing cells, but is not involved in other pathways of antigen
      driven B cell differentiation such as memory cell development in the germinal
      centers.

PMID- 8642302
TI  - Interaction of Ipa proteins of Shigella flexneri with alpha5beta1 integrin
      promotes entry of the bacteria into mammalian cells.
AB  - Shigella is a genus of highly adapted bacterial pathogens that cause bacillary
      dysentery in humans. Bacteria reaching the colon invade intestinal epithelial
      cells by a process of bacterial-directed endocytosis mediated by the Ipa
      proteins: IpaB, IpaC, and IpaD of Shigella. The invasion of epithelial cells is
      thought to be a receptor-mediated phenomenon, although the cellular components of
      the host that interact with the Ipa proteins have not yet been identified. We
      report here that in a Shigella flexneri invasive system and Chinese hamster ovary
      (CHO) cell monolayers, the Ipa proteins were capable of interacting directly with
      alpha5beta1 integrin. The invasive capacity of S. flexneri for CHO cells
      increased as levels of alpha5beta1 integrin were elevated. When CHO cells were
      infected with S. flexneri, the tyrosine phosphorylation both of pp 125FAK, an
      integrin-regulated 125 K focal adhesion kinase, and of paxillin was stimulated.
      In contrast, an isogenic strain of S. flexneri that was defective in invasion
      owing to a mutation in its spa32 gene failed to induce such phosphorylation.
      Under in vitro and in vivo conditions, the released IpaB, IpaC, and IpaD proteins
      bound to alpha 5 beta 1 integrin in a manner different from that of soluble
      fibronectin but similar to that of the tissue form of fibronectin. At the site of
      attachment of S. flexneri to CHO cells, alpha5beta1 integrin converged with
      polymerization of actin. These data thus suggest that the capacity of Ipa
      proteins to interact with alpha5beta1 integrin may be an important Shigella
      factor in triggering the reorganization of actin cytoskeletons.

PMID- 8642303
TI  - Proteolysis and the biochemistry of life-or-death decisions.

PMID- 8642304
TI  - Clonal anergy of B cells: a flexible, reversible, and quantitative concept.

PMID- 8642305
TI  - Apopain/CPP32 cleaves proteins that are essential for cellular repair: a
      fundamental principle of apoptotic death.
AB  - Proteolysis mediated by the interleukin 1 beta-converting enzyme (ICE) homologues
      is an important mechanism of the apoptotic process. The ICE homologue apopain/CPP
      32/Yama (subsequently referred to as apopain) cleaves poly(ADP-ribose)polymerase
      (PARP) early during apoptosis. Additional apoptosis-specific protein cleavages
      have been observed in which the direct involvement of ICE-like proteases has been
      postulated. These substrates include the 70-kD protein component of the U1
      ribonucleoprotein (U1-70kD), and the catalytic subunit of the DNA-dependent
      protein kinase (DNA-PKcs). The present studies demonstrate that U1-70kD and DNA
      PKcs are excellent substrates for apopain, with cleavage occurring at sites that
      are highly similar to the cleavage site within PARP. The fragments generated from
      isolated protein substrates by apopain are identical to those observed in intact
      apoptotic cells, in apoptotic cell extracts, and in normal cell extracts to which
      apopain has been added. Like PARP, cleavage of these substrates in apoptotic cell
      extracts is abolished by nanomolar concentrations of Ac-DEVD-CHO and micromolar
      amounts of Ac-YVAD-CHO, confirming the involvement of apopain or an apopain-like
      activity. We propose that a central function of apopain or similar homologues in
      apoptosis is the cleavage of nuclear repair proteins, thereby abolishing their
      critical homeostatic functions.

PMID- 8642306
TI  - Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase
      epitopes.
AB  - Tyrosinase was the first melanoma-associated antigen shown to be recognized by
      CD4+ T cells. In this study, we have identified two HLA-DRB1*0401-restricted
      peptides recognized by these T cells: Ty 56-70 and Ty 448-462. As with many of
      the MHC class I-restricted melanoma epitopes, both are nonmutated self peptides
      that have intermediate and weak MHC binding affinities, respectively. Mutated and
      truncated versions of these peptides were used to define their MHC binding anchor
      residues. Anchor residues were then modified to derive peptides with increased
      MHC binding affinities and T cell stimulatory properties. Ty 56-70 and Ty 448-462
      enhance the list of immunogenic HLA-A2-, A24-, and B44-restricted tyrosinase
      peptides already described. Thus, tyrosinase provides a model for anti-melanoma
      vaccines in which a single molecule can generate multivalent immunization
      incorporating both CD4+ and CD8+ T cell responses.

PMID- 8642307
TI  - Hybrid antibody mediated veto of cytotoxic T lymphocyte responses.
AB  - Strategies are being sought that allow the induction of specific tolerance to
      allogeneic transplants without affecting other immune functions. The so-called
      veto effect has been described as one such technology where CD8+ cells suppress
      responses of class I MHC-restricted T-lymphocyte precursors to antigens expressed
      by those CD8+ veto cells. Yet, veto inhibition will not be able to provide
      complete tolerance to allogeneic grafts since it only operates on cell
      populations that express CD8. Other types of cells prevalent in most organs
      express different tissue-specific antigens that are recognized by alloreactive T
      cells. Therefore, complete tolerance to an allogeneic transplant can only be
      achieved if all cellular components within the graft acquire the immune
      inhibitory function. Here, we studied whether the veto effect could be exploited
      for this purpose nevertheless. We produced a hybrid antibody (HAb) combining a
      mAb specific for a class I MHC molecule with a soluble CD8 molecule. We found
      that this HAb specifically and effectively transferred veto inhibition to
      different stimulator cell populations. Thus, we have developed a strategy that
      promises to selectively and completely tolerize graft-specific CTLs without
      affecting normal immune responses.

PMID- 8642308
TI  - Vesiculo-vacuolar organelles and the regulation of venule permeability to
      macromolecules by vascular permeability factor, histamine, and serotonin.
AB  - In contrast to normal microvessels, those that supply tumors are strikingly
      hyperpermeable to circulating macromolecules such as plasma proteins. This
      leakiness is largely attributable to a tumor-secreted cytokine, vascular
      permeability factor (VPF). Tracer studies have shown that macromolecules cross
      tumor vascular endothelium by way of a recently described cytoplasmic organelle,
      the vesiculo-vacuolar organelle or VVO (VVOs are grapelike clusters of
      interconnected, uncoated vesicles and vacuoles). However, equivalent VVOs are
      also present in the cytoplasm of normal venules that do not leak substantial
      amounts of plasma protein. To explain these findings, we hypothesized that VPF
      increased the permeability of tumor blood vessels by increasing VVO function and
      that the VVOs of normal venules were relatively impermeable in the absence of VPF
      stimulation. To test this hypothesis, VPF was injected intradermally in normal
      animals after intravenous injection of a soluble macromolecular tracer, ferritin,
      whose extravasation could be followed by electron microscopy. VPF caused normal
      venules to leak ferritin, and, as predicted by our hypothesis, ferritin
      extravasated by way of VVOs, just as in hyperpermeable tumor microvessels.
      Ultrathin (14-nm) serial electron microscopic sections and computer-aided three
      dimensional reconstructions better defined VVO structure. VVOs occupied 16-18% of
      endothelial cytoplasm in normal venules. Individual VVOs were clusters of
      numerous (median, 124) interconnected vesicles and vacuoles that formed complex
      pathways across venular endothelium with multiple openings to both luminal and
      abluminal surfaces. Like VPF, histamine and serotonin also stimulated ferritin
      extravasation across venules by way of VVOs. Together, these data establish VVOs
      as the major pathway by which soluble plasma proteins exit venules in response to
      several mediators that increase venular hyperpermeability. These same mediators
      also increased the extravasation of colloidal carbon, but this large particulate
      nonphysiological tracer exited venules primarily through endothelial gaps.

PMID- 8642309
TI  - A cysteine residue located in the transmembrane domain of CD44 is important in
      binding of CD44 to hyaluronic acid.
AB  - In the transmembrane domain and cytoplasmic domain of human CD44 protein there
      are two cysteine residues. These two cysteines are conserved in all known
      mammalian CD44 proteins. The functions of these cysteine residues are not known.
      Site-specific mutagenesis was used to create CD44 mutant proteins lacking either
      one or both of these cysteine residues. Wild-type CD44 and mutant CD44 genes were
      transfected into CD44- Jurkat cells to establish stable transfectants. These
      transfectants were used to study whether these two cysteine residues are
      important in the binding of CD44(H) to fluorescein-conjugated hyaluronic acid (F
      HA). Jurkat transfectant bearing wild-type CD44 did not bind F-HA, unless they
      were stimulated in vitro with immobilized anti-CD3 monoclonal antibody. Anti-CD3
      antibody also stimulated the binding of F-HA in Jurkat CD44.C295A transfectant in
      which the cytoplasmic cysteine residue has been replaced with alanine. In
      contrast, anti-CD3 antibody failed to stimulate the binding of F-HA in Jurkat
      transfectant (CD44.C286A), in which the transmembrane domain cysteine 286 has
      been replaced with an alanine, and in Jurkat transfectant CD44.2C2A, in which
      both of the cysteine residues have been altered. Binding can also be induced with
      a monoclonal anti-CD44 antibody (F-44-10-2) in Jurkat wild-type CD44 and Jurkat
      CD44.C295A transfectants but not in CD44. C286A transfectant. These results
      provide evidence that the transmembrane domain of CD44, more specifically the
      cysteine residue in the transmembrane domain, is important for both activation
      induced and anti-CD44 antibody-induced binding of soluble HA.

PMID- 8642310
TI  - The alpha 4-integrin supports leukocyte rolling and adhesion in chronically
      inflamed postcapillary venules in vivo.
AB  - A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been
      implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to
      sites of inflammation. However, the adhesive interactions (i.e., tethering,
      rolling, and adhesion) mediated by the alpha 4-integrin have not been
      characterized in vivo. The objective of this study was to establish a model
      wherein postcapillary venules were chronically inflamed, and then use intravital
      microscopy to identify the adhesive interactions mediated by the alpha 4-integrin
      in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum,
      animals developed a systemic vasculitis characterized by large increases in the
      numbers of rolling and adhering leukocytes within mesenteric venules. The
      selectins could only account for approximately 50% of the leukocyte rolling
      whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti
      alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in
      this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin)
      monoclonal antibody (mAb) did not reduce adhesion. A serum against
      polymorphonuclear leukocytes (PMNs) was used to confirm that a significant
      proportion of rolling cells, and most of the adhering cells were PBMCs.
      Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated
      that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial
      leukocyte tethering via the alpha 4-integrin could not be demonstrated in this
      model, whereas L-selectin did support leukocyte tethering. These data suggest
      that the alpha 4-integrin can mediate both rolling and adhesion in the multistep
      recruitment of PMBCs in vivo, and these interactions occur independently of the
      selectins and beta 2-integrins.

PMID- 8642311
TI  - Induction of passive Heymann nephritis with antibodies specific for a synthetic
      peptide derived from the receptor-associated protein.
AB  - Passive Heymann nephritis (pHN) is an experimental rat model for human membranous
      glomerulopathy. In pHN, the formation of subepithelial immune deposits (ID)
      involves as antigenic targets the membrane glycoprotein gp330/megalin and the 44
      kD receptor-associated protein (RAP). A single binding site for ID- inducing
      antibodies (Abs) was previously mapped to the 86 NH2-terminal amino acids of RAP
      (RAP1-86). To further narrow this epitope, Abs eluted from the glomeruli were
      immunoblotted on membranes that were loaded with overlapping synthetic peptides
      representing the amino acid sequence of RAP (SPOTs system). Two adjacent Ab
      binding domains with the sequences PVRLAF, (amino acids 39-44) and HSD-LKIQE
      (amino acids 46-53), which were separated by a single L residue at amino acid 45,
      were detected. Rabbit Abs raised against synthetic peptides containing these
      domains individually (P31-44 and P46-53) failed to procedure glomerular IDs. By
      contrast, Abs raised against a larger composite peptide (P31-53) induced IDs
      within 3d that were firmly cross linked to the glomerular basement membrane.
      These data suggest that Ab binding in vivo depends on the conformation of the
      antigenic target sequence that is preserved in the synthetic peptide P31-53,
      which covers the entire Ab-binding domain of RAP but not in its subdomains, P31
      44 and P46-53. Collectively, these results locate the sole ID-inducing epitope of
      RAP to amino acids 39-53.

PMID- 8642312
TI  - Anergic T cells are defective in both jun NH2-terminal kinase and mitogen
      activated protein kinase signaling pathways.
AB  - T helper type 1 cells (Th1) become anergic when stimulated through the antigen
      receptor in the absence of costimulation. They do not produce IL-2 or proliferate
      in response to subsequent stimulation. Previous studies have indicated that
      anergic T cells are defective in the trnsactivational activity of the
      transcription factor, AP-1, which is required for optimal IL-2 transcription.
      Using two murine Th1 cell clones, we demonstrate that anergic Th1 cells have
      defects in both jun NH2-terminal kinase (JNK) and extracellular signal-regulated
      kinase (ERK) activities. These kinases have been shown to be important for the
      upregulation of AP-1 activity. Furthermore, our data show that ERK and JNK
      activities are restored when anergy is induced in the presence of the protein
      synthesis inhibitor cycloheximide, or when anergic T cells are allowed to
      proliferate in response to exogenous IL-2. These treatments have previously been
      shown to prevent or reverse the anergic state. Our results suggest that defects
      in both JNK and ERK may result in the decreased AP-1 activity and the reduced IL
      2 transcription observed in anergic T cells.

PMID- 8642313
TI  - T cell leukemia-associated human Notch/translocation-associated Notch homologue
      has I kappa B-like activity and physically interacts with nuclear factor-kappa B
      proteins in T cells.
AB  - Translocation-associated Notch homologue (TAN-1), a gene originally cloned from
      the translocation breakpoint of a human T cell leukemia carrying a 9:7(q34.3)
      translocation, encodes a protein belonging to the Notch/Lin-12/Glp-1 receptor
      family. These receptors mediate the specification of numerous cell fates during
      development in invertebrates and vertebrates. The intracellular portion of
      Notch/TAN-1 contains six ankyrin repeats that are similar to those found in
      cytoplasmic I kappa B proteins. I kappa B proteins are specific inhibitors of
      nuclear factor (NF)-kappa B/Rel transcription factors. Here we show that TAN-1
      has functional properties of an I kappa B-like regulator with specificity for the
      NF-kappa B p50 subunit. A recombinant polypeptide corresponding to the
      cytoplasmic portion of TAN-1 (TAN-1C) specifically inhibited the DNA binding of
      p50-containing NF-kappa B complexes. When overexpressed in an appropriate cell
      line, TAN-1C prevented kappa B-dependent transactivation in transient reporter
      gene assays in a fashion similar to the structurally related protein, Bcl-3. TAN
      1C could activate kappa B-dependent gene expression by attenuating the inhibitory
      effect of an excess of p50 homodimers. Immunoprecipitation experiments showed
      that the TAN-1 from a T cell line is associated with NF-kappa B containing p50
      and p65 subunits. These observations indicate that TAN-1C may directly engage NF
      kappa B transcription factors and modulate nuclear gene expression.

PMID- 8642314
TI  - Positive selection is not required for thymic maturation of transgenic gamma
      delta T cells.
AB  - Previously published reports describing thymic differentiation in two TCR gamma
      delta transgenic mouse models have suggested that gamma delta T cells require MHC
      mediated positive selection to reach full maturity. Recent studies indicate that
      recognition of antigen by mature gamma delta T cells is not MHC restricted,
      raising the issue of why developing gamma delta T cells would even require MHC
      driven positive selection. Therefore, we have reinvestigated the requirements for
      development and selection in G8 gamma delta T cell receptor (TCR) transgenic
      mice. Analyses of absolute cell numbers, phenotypic subsets, and functional
      competence of thymic and peripheral G8 gamma delta T cells indicate that these
      cells can fully mature in class I MHC-deficient mice. Moreover, mixed bone marrow
      chimeras demonstrate that gamma delta T cells of mutant B2-microglobulin (beta 2m
      zero) origin are partially deleted in the presence of H-2d-bearing thymocytes
      (previously believed to be the haplotype mediating positive selection). We
      conclude that there is no requirement for class I-like molecules for the
      maturation/development of these transgenic gamma delta T cells and that the
      differences in thymocyte phenotype and number observed are, instead, attributable
      to effects of clonal deletion.

PMID- 8642315
TI  - Modulation of promiscuous T cell receptor recognition by mutagenesis of CDR2
      residues.
AB  - The T cell receptor (TCR) recognizes a ligand composed of a major
      histocompatibility complex (MHC) molecule and a peptide antigen. Prior studies of
      murine T cell clones have demonstrated that residues in the CDR3 region of TCR
      interact with amino acids in the peptide during MHC-restricted antigen
      recognition. However, the questions of whether direct TCR MHC contacts are made
      and where such contact sites might map in the TCR have not been resolved. In this
      study, we have taken advantage of the promiscuous recognition of a peptide from
      influenza virus (HA 307-319) by human T cell clones to map sites in the TCR that
      mediate differences in human leukocyte antigen-D related (HLA-DR) restriction in
      the presence of a common peptide antigen. Site-specific mutagenesis of cloned TCR
      genes and transfection into Jurkat cells were used to demonstrate that single
      amino acid substitutions in CDR2 of the TCR-alpha chain controlled whether a T
      cell was restricted by the product of a single DR allele (DR7) or would respond
      to the HA 307-319 peptide when presented by the products of one of several
      different DR alleles (DR1, DR4, DR5, or DR7). Because the relevant DR alleles are
      defined by polymorphism in the DR-beta chain, these results also suggest a
      rotational orientation for recognition in which TCR-alpha interacts with DR beta.

PMID- 8642316
TI  - Tracing the development of single memory-lineage B cells in a highly defined
      immune response.
AB  - To study the development of B lymphocyte memory, we identified and isolated
      splenic B cells expressing a highly defined antibody variable region that
      constitutes a reproducible and predominant component of the memory antibody
      response to p-azophenylarsonate (Ars). Isolation was achieved during the primary
      immune response by surface staining and flow cytometry using a specific anti
      idiotypic antibody called E4, which recognizes this canonical V region, encoded
      by one set of V gene segments. The isolated E4+ cells displayed all of the
      phenotypic characteristics of germinal center centrocytes, including a low level
      of surface Ig, a lack of surface IgD, a high level of receptor for peanut
      agglutinin, and expression of mutated antibody V genes. E4+ B cells were first
      detected in the spleen 7-8 d after primary immunization, reached peak numbers
      from days 10-13, and waned by day 16. Surprisingly, at their peak, E4+ cells
      comprised only 40,000 of all splenocytes, and half of these failed to bind Ars.
      Using this number, we estimate the total number of Ars-specific memory-lineage
      cells in the spleen to be no more than 50,000 (0.1%) at any one time, and
      presumably far fewer that are committed to the memory pool. Chromosomal copies of
      rearranged V genes from single E4+ cells were amplified by nested PCR, and the
      amplified products were sequenced directly without cloning, using standardized
      conditions that disclose virtually no Taq polymerase errors. V gene sequence
      analyses of E4+ cells isolated from single mice confirmed their canonical nature
      and revealed that they were derived from few precursors. In the average mouse,
      the E4+ pool was derived from fewer than five canonical precursors. Somatic
      mutations were found within the V genes of almost all cell isolates. At day 13, a
      significant fraction of E4+ cells had mutations known to increase antibody
      affinity for Ars, suggesting they were products of at least one cycle of post
      mutational antigen-driven selection. However, the lack of shared mutations by
      clonally related cells indicated that the selective expansion of mutant subclones
      typical of memory responses had not yet taken place. This was supported by the
      observation that half of the E4+ cells failed to bind Ars. Collectively, our
      results indicate that the memory compartment is a highly selected entity, even at
      relatively early stages of the primary immune response when somatic mutation and
      clonal selection are still in progress. If germinal centers are the source of
      memory B cells, our data suggest that B cell memory may be derived from only a
      small fraction of all germinal centers.

PMID- 8642317
TI  - Characterization of apoptosis-resistant antigen-specific T cells in vivo.
AB  - Clonal deletion via activation-induced apoptosis (AIA) of antigen-specific T
      cells (ASTC) plays a very important role in the induction of peripheral
      tolerance. However, none of the studies performed so far has shown a complete
      deletion of ASTC, a small population always persisting in the periphery. The
      mechanism by which this small population of ASTC escapes AIA has not been
      determined. Since the existence of these ASTC may influence the outcome of
      autoimmune diseases and long-term graft survival, we have characterized the
      properties of these residual ASTC in vivo with the objective of determining
      mechanisms that may contribute to their persistence. It was found that the
      resistance of the residual ASTC to AIA is not due to lack of activation or
      Fas/Fas-L expression. Compared to those susceptible to AIA, the residual ASTC
      express a high level of Th2-type cytokines that may help them to escape from AIA.
      Furthermore, they are able to suppress proliferation of other ASTC, suggesting
      they may, in fact, prolong tolerance in vivo.

PMID- 8642318
TI  - Negative selection of human germinal center B cells by prolonged BCR cross
      linking.
AB  - The antigen receptors on T and B lymphocytes can transduce both agonist and
      antagonist signals leading either to activation/survival or anergy/death. The
      outcome of B lymphocyte antigen receptor (BCR) triggering depends upon multiple
      parameters which include (a) antigen concentration and valency, (b) duration of
      BCR occupancy, (c) receptor affinity, and (d) B cell differentiation stages.
      Herein, using anti-immunoglobulin kappa and lambda light chain antibodies, we
      analyzed the response of human naive, germinal center (GC) or memory B cells to
      BCR cross-linking regardless of heavy chain Ig isotype or intrinsic BCR
      specificity. We show that after CD40-activation, anti-BCR (kappa + gamma) can
      elicit an intracellular calcium flux on both GC and non-GC cells. However,
      prolonged BCR cross-linking induces death of CD40-activated GC B cells but
      enhances proliferation of naive or memory cells. Anti-kappa antibody only kills
      kappa + GC B cells without affecting surrounding gamma + GC B cells, thus
      demonstrating that BCR-mediated killing of GC B lymphocytes is a direct effect
      that does not involve a paracrine mechanism. BCR-mediated killing of CD40
      activated GC B cells could be partially antagonized by the addition of IL-4.
      Moreover, in the presence of IL-4, prestimulation through CD40 could prevent
      subsequent anti-Ig-mediated cell death, suggesting a specific role of this
      combination in selection of GC B cells. This report provides evidence that in
      human, susceptibility to BCR killing is regulated along peripheral B cell
      differentiation pathway.

PMID- 8642319
TI  - Role of chain pairing for the production of functional soluble IA major
      histocompatibility complex class II molecules.
AB  - Structural studies of cellular receptor molecules involved in immune recognition
      require the production of large quantities of the extracellular domains of these
      glycoproteins. The murine major histocompatibility complex (MHC) class II
      restricted response has been extensively studied by functional means, but the
      engineering and purification of the native, empty form of the most-studied murine
      MHC class II molecule, IA, has been difficult to achieve. IA molecules, which are
      the murine equivalent of human histocompatibility leukocyte antigen-DQ molecules,
      have a low efficiency of chain pairing, which results in poor transport to the
      cell surface and in the appearance of mixed isotype pairs. We have engineered
      soluble IA molecules whose pairing has been forced by the addition of leucine
      zipper peptide dimers at their COOH-terminus. The molecules are secreted "empty"
      into the extracellular medium and can be loaded with single peptide after
      purification. These IA molecules have been expressed in milligram quantity for
      crystallization as well as for activation of T cells and measurement of MHC class
      II-T cell receptor interactions.

PMID- 8642320
TI  - The two membrane proximal domains of CD4 interact with the T cell receptor.
AB  - During T cell activation, CD4 is intimately involved in colocalizing the T cell
      receptor (TCR) with its specific peptide ligand bound to class II molecules of
      the major histocompatibility complex (MHC). Previously, the COOH-terminal
      residues, Trp62/63, which flank the immunodominant epitope of hen egg lysozyme
      (HEL 52-61), were shown to have a profound effect on TCR recognition. CD4
      maintains the fidelity of this interaction when short peptides are used. To
      determine which portion of CD4 was responsible for this effect, a series of CD4
      mutants were made and transfected into CD4 loss variants of two HEL 52-61
      specific T cell hybridomas. Surprisingly, some CD4 mutants that failed to
      interact with MHC class II molecules (D2 domain mutant) or with p56kk
      (cytoplasmic-tailless mutant) restored responsiveness. Nevertheless, a
      significant reduction in association between cytoplasmic-tailless CD4 and the
      TCR, as determined by fluorescence resonance energy transfer, was observed. Thus,
      neither colocalization of CD4 and the TCR nor signal transduction via CD4 was
      solely responsible for the functional restoration of these T cell hybridomas by
      wild-type CD4. However, substitution of the two membrane proximal domains of
      murine CD4 (D3 and D4) with domains from human CD4 or intercellular adhesion
      molecule 1 not only abrogated its ability to restore function, but also
      substantially reduced its ability to associate with the TCR. Furthermore, the
      mouse/human CD4 chimera had a potent dominant negative effect on T cell function
      in the presence of equimolar concentrations of wild-type CD4. These data suggest
      that the D3/D4 domains of CD4 may interact directly or indirectly with the TCR
      CD3 complex and influence the signal transduction processes. Given the striking
      structural differences between CD4 and CD8 in this region, these data define a
      novel and unique function for CD4.

PMID- 8642322
TI  - Evidence for limited B-lymphopoiesis in adult rabbits.
AB  - Rabbits are born with a limited VDJ gene repertoire formed primarily by
      rearrangement of one VH gene, VH1. The VDJ genes are undiversified at birth but
      become diversified by approximately 2 mo of age. To investigate more closely the
      time during which this diversity occurs, we determined the nucleotide sequences
      of VDJ genes from peripheral blood leukocytes taken from young rabbits at various
      time points, and we examined the extent of the diversification of the VDJ genes.
      At 4 wk of age there were, on average, 3 nucleotide changes per VH region, with
      approximately 75% of the genes showing some diversification. The number of
      nucleotide changes per VH region increased to 12 by 6-8 wk of age, and all but 1
      of the 35 sequences analyzed were diversified. Because only a limited number of
      genes can be examined by nucleotide sequence analysis, we used an RNase
      protection assay to examine a large number of genes and we determined the level
      of undiversified VH1 mRNA in lymphoid organs of both young and adult rabbits. In
      young rabbits, we found a high level of undiversified VDJ genes, but the level
      was greatly reduced by 2 mo of age. By adulthood, essentially all VDJ genes of
      cells from appendix, peripheral blood, and bone marrow were diversified. Because
      we had expected B lymphopoiesis to be ongoing in the bone marrow of adult
      rabbits, we were surprised not to find undiversified VDJ genes from the newly
      generated B cells. Therefore, we searched for evidence of ongoing B lymphopoiesis
      in bone marrow by isolating and examining circular DNA for the presence of VD and
      DJ recombination signal joints. We found highly reduced levels of recombination
      signal joints in bone marrow of adult rabbits relative to the levels found in
      bone marrow of newborn rabbits. These data indicate that limited VD and DJ gene
      rearrangements occur in bone marrow of adult rabbits, and we therefore suggest
      that B lymphopoiesis is limited in adults.

PMID- 8642321
TI  - Qualitative and quantitative contributions of the T cell receptor zeta chain to
      mature T cell apoptosis.
AB  - Engagement of the T cell receptor (TCR) of mature T lymphocytes can lead either
      to activation/proliferation responses or programmed cell death. To understand the
      molecular regulation of these two fundamentally different outcomes of TCR
      signaling, we investigated the participation of various components of the TCR-CD3
      complex. We found that the TCR-zeta chain, while not absolutely required, was
      especially effective at promoting mature T cell apoptosis compared with the CD3
      epsilon, gamma, or delta chains. We also carried out mutagenesis to address the
      role of the immunoreceptor tyrosine-based activation motifs (ITAMs) that are the
      principal signaling components found three times in the TCR-zeta chain and once
      in each of the CD3 epsilon, gamma, or delta chains. We found that the ability of
      the TCR-zeta chain to promote apoptosis results both from a quantitative effect
      of the presence of multiple ITAMs as well as qualitatively different
      contributions made by individual ITAMs. Apoptosis induced by single chain
      chimeras revealed that the first zeta ITAM stimulated greater apoptosis than the
      third zeta ITAM, and the second zeta ITAM was unable to trigger apoptosis.
      Because microheterogeneity in the amino acid sequence of the various ITAM motifs
      found in the TCR-zeta and CD3 chains predicts interactions with distinct src
      homology-2-domain signaling proteins, our results suggest the possibility that
      individual ITAM motifs might play unique roles in TCR responses by engaging
      specific signaling pathways.

PMID- 8642324
TI  - Development of insulitis without diabetes in transgenic mice lacking perforin
      dependent cytotoxicity.
AB  - It is widely accepted that T cells play an important role in the destruction of
      beta cells leading to autoimmune type I diabetes, but the involved effector
      mechanisms have remained unclear. We addressed this issue by testing the role of
      perforin-dependent cytotoxicity in a disease model involving transgenic mice
      expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the
      beta cells of the endocrine pancreas. In such mice, LCMV infection leads to a
      potent LCMV-GP-specific T cell response resulting in rapid development of
      diabetes. We report here that in perforin-deficient LCMV-GP transgenic mice, LCMV
      infection failed to induce diabetes despite the activation of LCMV-GP-specific T
      cells. Deletion of nu beta 6+ T cells in Mls-1a perforin-deficient mice and the
      activation of LCMV-GP-specific T cells in perforin-deficient LCMV-GP transgenic
      mice, however, indicated that thymic tolerance induction by negative selection
      was not affected by the disruption of the perforin gene and that there is no
      fundamental difference between the T cell repertoires of normal control and
      perforin-deficient mice. In addition, adoptive transfer of LCMV-GP-specific TCR
      transgenic perforin-deficient T cells activated by LCMV-GP recombinant vaccinia
      virus led to marked insulitis with infiltration of CD4+ and CD8+ T cells without
      the development of diabetes. These findings indicate that perforin-dependent
      cytotoxicity is not required for the initiation of insulitis but is crucial for
      the destruction of beta cells in the later phase of the disease process. Other
      mechanisms or soluble factors present in the inflammatory islet infiltrate
      apparently lack the ability to efficiently induce diabetogenic beta cell damage.

PMID- 8642323
TI  - CD40L-deficient mice show deficits in antiviral immunity and have an impaired
      memory CD8+ CTL response.
AB  - The ligand for CD40 (CD40L) is expressed on the surface of activated CD4+ T cells
      and its role in T-B cell collaborations and thymus-dependent humoral immunity is
      well established. Recently, by generating CD40L-knockout mice, we have confirmed
      its previously described role in humoral immunity and defined another important
      function of this molecule in the in vivo clonal expansion of antigen-specific
      CD4+ T cells. Here, we investigated the potential in vivo role of CD40L in
      antiviral immunity by examining the immune response mounted by CD40L-deficient
      mice following infection with lymphocytic choriomeningitis virus (LCMV), Pichinde
      virus, or vesicular stomatitis virus. Humoral immune responses of CD40L-deficient
      mice to these viruses were severely compromised, although moderate titres of
      antiviral IgM and some IgG2a were produced by virus-infected CD40L-deficient mice
      by a CD4+ T cell-independent mechanism. By contrast, CD40L-deficient mice made
      strong primary CTL responses to all three viruses. Interestingly however,
      although memory CTL activity was detectable in CD40L-deficient mice two months
      after infection with LCMV, the memory CTL response was much less efficient than
      in wild-type mice. Together, the results show that CD40-CD40L interactions are
      required for strong antiviral humoral immune responses, and reveal a novel role
      for CD40L in the establishment and/or maintenance of CD8+ CTL memory.

PMID- 8642325
TI  - Long-lasting CD8 T cell memory in the absence of CD4 T cells or B cells.
AB  - The cellular basis of immunological memory has been a debated issue. It is not
      clear whether CD8 T cell memory is maintained by long-lived cells or by specific
      or nonspecific restimulation. Here, we have approached the question from a
      different angle, asking whether the cellular interactions that are required to
      maintain memory are the same as those necessary to activate cytotoxic T
      lymphocytes. We studied the CD8 memory response to the male antigen H-Y in mice
      deficient in CD4 cells, or B cells and found that memory in these mice was
      virtually unimpaired. These results suggest that CD8 memory is CD4 independent
      and that there is no requirement for long term retention of immune complexes on
      follicular dendritic cells, nor for B cells as antigen-presenting cells.

PMID- 8642326
TI  - CD8 T cell memory in B cell-deficient mice.
AB  - Antigen presentation by B cells and persistence of antigen-antibody complexes on
      follicular dendritic cells (FDC) have been implicated in sustaining T cell
      memory. In this study we have examined the role of B cells and antibody in the
      generation and maintenance of CD8+ cytotoxic T lymphocyte (CTL) memory. To
      address this issue we compared CTL responses to lymphocytic choriomeningitis
      virus (LCMV) in normal (+/+) versus B cell-deficient mice. The CTL response to
      acute LCMV infection can be broken down into three distinct phases: (a) the
      initial phase (days 3-8 after infection) of antigen-driven expansion of virus
      specific CD8+ T cells and the development of effector CTL (i.e., direct ex vivo
      killers); (b) a phase of death (between days 10 and 30 after infection) during
      which >95% of the virus-specific CTL die and the direct effector activity
      subsides; and (c) the phase of long-term memory (after day 30) that is
      characterized by a stable pool of memory CTL that persist for the life span of
      the animal. The role of B cells in each of these three phases of the CTL response
      was analyzed. We found that B cells were not required for the expansion and
      activation of virus-specific CTL. The kinetics and magnitude of the effector CTL
      response, as measured by direct killing of infected targets by ex vivo isolated
      splenocytes, was identical in B cell-deficient and +/+ mice. Also, the expansion
      of CD8+ T cells was not affected by the absence of B cells and/or antibody; in
      both groups of mice there was an approximately 10,000-fold increase in the number
      of LCMV-specific CTL and a greater than 10-fold increase in the total number of
      activated (CD44hi) CD8+ T cells during the first week after virus infection.
      Although no differences were seen during the "expansion" phase, we found that the
      "death" phase was more pronounced in B cell-deficient mice. However, this
      increased cell death was not selective for LCMV-specific CTL, and during this
      period the total number of CD8+ T cells also dropped substantially more in B cell
      deficient mice. As a result of this, the absolute numbers of LCMV-specific CTL
      were lower in B cell-deficient mice but the frequencies were comparable in both
      groups of mice. More significantly, the memory phase of the CTL response was not
      affected by the absence of B cells and a stable number of LCMV-specific CTL
      persisted in B cell-deficient mice for up to 6 mo. Upon reinfection, B cell
      deficient mice that had resolved an acute LCMV infection were able to make
      accelerated CTL responses in vivo and eliminated virus more efficiently than
      naive B cell-deficient mice. Thus, CTL memory, as assessed by frequency of virus
      specific CTL or protective immunity, does not decline in the absence of B cells.
      Taken together, these results show that neither B cells nor antigen-antibody
      complexes are essential for the maintenance of CD8+ CTL memory.

PMID- 8642327
TI  - Rat blood neutrophils express very late antigen 4 and it mediates migration to
      arthritic joint and dermal inflammation.
AB  - Blood neutrophils contribute to joint injury in human and experimental models of
      arthritis. Neutrophil migration out of the blood in joint inflammation involves
      both the CD18 (beta2) integrins and a CD18 integrin-independent pathway. To
      investigate this migration, radiolabeled rat blood neutrophils were used to
      measure neutrophil accumulation in the inflamed joints of rats with adjuvant
      arthritis and the role of leukocyte integrins in migration to these joints and to
      dermal inflammation was determined. Neutrophils migrated rapidly (<2 h) to the
      inflamed joints 14-18 d after immunization with adjuvant. Blocking monoclonal
      antibodies (mAbs) to both LFA-1 and Mac-1 together, as well as a mAb to CD18,
      inhibited neutrophil accumulation in the inflamed joints by 50-75%. However,
      migration to dermal inflammation induced by C5a(des Arg)' tumor necrosis factor
      alpha, lipopolysaccharide, and poly-inosine:cytosine was inhibited by
      approximately 90%. Flow cytometry revealed the expression of low levels of very
      late antigen 4 (VLA-4) on nearly all rat blood neutrophils. Treatment with anti
      VLA-4 plus anti-LFA-1 but neither mAb alone, strongly (60-75%) inhibited
      neutrophil accumulation in arthritic joints. This mAb combination also inhibited
      neutrophil migration to dermal inflammatory reactions by 30-70%. Blocking VLA-4
      together with the CD18 integrins inhibited neutrophil accumulation by 95-99%,
      virtually abolishing neutrophil accumulation in cutaneous inflammation. A similar
      blockade of VLA-4 and CD18 decreased neutrophil accumulation in the inflamed
      joints by 70-83%, but a significant portion of the neutrophil accumulation to
      these joints still remained. In conclusion, rat blood neutrophils express
      functional VLA-4 that can mediate neutrophil migration to both inflamed joints
      and dermal inflammatory sites. VLA-4 appears to be able to substitute for LFA-1
      in this migration and is particularly important for accumulation in inflamed
      joints. However, there exists an additional CD18- and VLA-4-independent pathway
      of neutrophil migration to arthritic joints that is not involved in acute dermal
      inflammation.

PMID- 8642328
TI  - The human OX40/gp34 system directly mediates adhesion of activated T cells to
      vascular endothelial cells.
AB  - Fresh leukemic cells from patients with adult T cell leukemia (ATL) and some ATL
      derived T cell lines show adhesion to human umbilical vein endothelial cells
      (HUVECs) mainly through E-selectin, but a proportion of this binding remains
      unaffected by the addition of combinations of antibodies against known adhesion
      molecules. By immunizing mice with one of such cell lines, we established
      monoclonal antibodies (mAbs), termed 131 and 315, that recognize a single cell
      surface antigen (Ag) and inhibit the remaining pathway of the adhesion. These
      mAbs did not react with normal resting peripheral blood mononuclear cells (PBMC)
      or most of the cell lines tested except for two other human T cell leukemia virus
      type I (HTLV-I)-infected T cell lines. After stimulation with phytohemagglutinin
      (PHA), PBMC expressed Ag 131/315 transiently, indicating that these mAbs define a
      T cell activation Ag. Western blotting and immunoprecipitation revealed that Ag
      131/315 has an apparent molecular mass of 50 kD. Expression cloning was done by
      transient expression in COS-7 cells and immunological selection to isolate a cDNA
      clone encoding Ag 131/315. Sequence analysis of the cDNA indicated that it is
      identical to human OX40, a member of the tumor necrosis factor/nerve growth
      factor receptor family. We then found that gp34, the ligand of OX40, was
      expressed on HUVECs and other types of vascular endothelial cells. Furthermore,
      it was shown that the adhesion of CD4+ cells of PHA-stimulated PBMC to
      unstimulated HUVECs was considerably inhibited by either 131 or 315. Finally,
      OX40 transfectants of Kit 225, a human interleukin 2-dependent T cell line, were
      bound specifically to gp34 transfectants of MMCE, a mouse epithelial cell line,
      and this binding was blocked by either 315 or 5A8, an anti-gp34 mAb. These
      results indicate that the OX40/gp34 system directly mediates adhesion of
      activated T cells or OX40+-transformed T cells to vascular endothelial cells.

PMID- 8642329
TI  - An autosomal dominant locus, Nka, mapping to the Ly-49 region of a rat natural
      killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes.
AB  - Natural Killer (NK) cells can recognize and kill MHC-incompatible normal bone
      marrow-derived cells. Presently characterized MHC-binding receptors on NK cells,
      including the Ly-49 family in the mouse, transmit inhibitory signals upon binding
      to cognate class I MHC ligands. Here we study in vivo NK-mediated lysis of normal
      allogeneic lymphocytes in crosses between alloreactivity-competent PVG rats and
      alloreactivity-deficient DA rats. NK cells from both strains are able to lyse
      standard tumor targets. We identify an autosomal dominant locus, Nka, that
      controls NK-mediated alloreactivity. Individuals carrying the dominant PVG allele
      in single dose were fully competent in eliminating allogeneic target cells,
      suggesting that Nka encodes or regulates a gene product inducing or activating
      alloreactivity. By linkage analysis and pulsed field gel electrophoresis, a
      natural killer gene complex (NKC) on rat chromosome 4 is described that contains
      the rat NKR-P1 and Ly-49 multigene families plus a rat NKG2D homologue. Nka maps
      within the NKC, together with the most telomeric Ly-49 family members, but
      separate from NKG2D and the NKR-P1 family. The Nka-encoded response, moreover,
      correlates with the expression of transcripts for Ly-49 receptors in NK cell
      populations, as Northern blot analysis demonstrated low expression of Ly-49 genes
      in DA NK cells, in contrast to high expression in alloreactivity-competent PVG,
      (DA X PVG)F1, and PVG.1AVI NK cells. The low Ly-49 expression in DA is not
      induced by MHC haplotype, as demonstrated by high expression of Ly-49 in the DA
      MHC-congenic PVG.1AVI strain. Finally, we have cloned and characterized the first
      four members of the rat Ly-49 gene family. Their cytoplasmic domains demonstrate
      substantial heterogeneity, consistent with the hypothesis that different Ly-49
      family members may subserve different signaling functions.

PMID- 8642332
TI  - A novel role for the Fc receptor gamma subunit: enhancement of Fc gamma R ligand
      affinity.
AB  - The Fc receptors (FcR), which belong to the immunoglobulin (Ig) superfamily, bind
      to specific Ig isotypes with varying affinities triggering complex immune defense
      responses. Several of the FcR that lack signaling motifs in their cytoplasmic
      domains rely on associated subunits to transmit signals. Two classes of FcR that
      bind the Fc portion of IgG, Fc gamma RI, and Fc gamma RIIIa associate with a
      subunit shared among several FcR, the gamma chain, which is involved in receptor
      expression and signal transduction. In this report, we propose that a novel role
      for gamma chain is to enhance the affinity of Fc gamma R for ligand. Our findings
      demonstrate that Fc gamma RI requires gamma -chain association to attain high
      affinity binding for monomeric IgG, and suggest that the intermediate binding
      affinity of the Fc gamma RIIIa isoform results from its association with gamma
      chain. The affinity increase conferred by gamma chain appears to be mediated
      through the transmembrane domain of the Fc gamma R, with no requirement for the
      cytoplasmic domain of the receptor.

PMID- 8642331
TI  - Regulation of cell division cycle progression by bcl-2 expression: a potential
      mechanism for inhibition of programmed cell death.
AB  - Expression of the bcl-2 gene has been shown to effectively confer resistance to
      programmed cell death under a variety of circumstances. However, despite a wealth
      of literature describing this phenomenon, very little is known about the
      mechanism of resistance. In the experiments described here, we show that bcl-2
      gene expression can result in an inhibition of cell division cycle progression.
      These findings are based upon the analysis of cell cycle distribution, cell cycle
      kinetics, and relative phosphorylation of the retinoblastoma tumor suppressor
      protein, using primary tissues in vivo, ex vivo, and in vitro, as well as
      continuous cell lines. The effects of bcl-2 expression on cell cycle progression
      appear to be focused at the G1 to S phase transition, which is a critical control
      point in the decision between continued cell cycle progression or the induction
      programmed cell death. In all systems tested, bcl-2 expression resulted in a
      substantial 30-60% increase in the length of G1 phase; such an increase is very
      substantial in the context of other regulators of cell cycle progression. Based
      upon our findings, and the related findings of others, we propose a mechanism by
      which bcl-2 expression might exert its well known inhibition of programmed cell
      death by regulating the kinetics of cell cycle progression at a critical control
      point.

PMID- 8642330
TI  - CD40-CD40 ligand interactions are critical in T-B cooperation but not for other
      anti-viral CD4+ T cell functions.
AB  - CD40-CD40 ligand (CD40L) interaction is required for the generation of antibody
      responses to T-dependent antigens as well as for the development of germinal
      centers and memory B cells. The role of the CD40-CD40L interaction in the
      induction of antigen-specific. Th cells and in mediating Th cell effector
      functions other than cognate help for B cells is less well understood. Using CD40
      and CD40L-deficient mice together with lymphocytic choriomeningitis virus and
      vesicular stomatitis virus as viral model antigens, this study corroborates
      earlier findings that no lg isotype switching of virus-specific antibodies was
      measurable upon infection of CD40- or CD40L-deficient mice. In contrast, in vivo
      induction of virus-specific CD4+ T cells measured by proliferation and cytokine
      secretion of primed virus-specific Th cells in vitro was not crucially dependent
      on the CD40-CD40L interaction. In addition, virus-specific Th cells primed in a
      CD40-deficient environment, adoptively transferred into CD40-competent
      recipients, were able to mediate lg isotype switch. Th-mediated effector
      functions distinct from and in addition to T-B collaboration were analyzed in
      CD40- and CD40L-deficient and normal mice: (a) local inflammatory reactions upon
      LCMV infection mediated by LCMV-specific Th cells were not dependent on a
      functional CD40-CD40L interaction, (b) cytokine-mediated protection by CD4+ T
      cells primed by vesicular stomatitis virus against a challenge infection with
      recombinant vaccinia virus expressing the glycoprotein of vesicular stomatitis
      virus was found to be equivalent in CD40L-deficient and normal mice. Thus, CD40
      CD40L interaction plays a crucial role in T-B interactions for Th-dependent
      activation of B cells but not, or to a much lesser extent, in T cell activation,
      antigen-specific Th cell responses in vitro, and for interleukin-mediated Th cell
      effector functions in vivo.

PMID- 8642333
TI  - Antigen-induced generation of lyso-phospholipids in human airways.
AB  - The goal of the current study was to examine the formation of phospholipids, 1
      radyl-2-lysosn-glycero-phospholipids (lyso-PL) and 2-acetylated phospholipids
      (such as PAF) as well as mechanisms responsible for generating these
      phospholipids in bronchoalveolar lavage fluid (BAI.F) from allergic subjects
      challenged with antigen. Bronchoalveolar lavage was performed in normal and
      allergic subjects before, 5-30 min, 6 h, and 20 h after segmental antigen
      challenge via a wedged bronchoscope. Levels of 1-hexadecyl-2-lyso-phospholipids
      and 1-hexadecyl-2-acetyl-phospholipids were initially determined by negative ion
      chemical ionization gas chromatography/mass spectrometry (NICI-GC/MS). Antigen
      dramatically elevated quantities of 1-hexadecyl-2-lyso-phospholipids in allergic
      subjects 20 h after challenge when compared to non-allergic controls. In
      contrast, there was not a significant increase in levels of 1-hexadecyl-2-acetyl
      phospholipids after antigen challenge. Closer examination of 1-radyl-2-lyso-sn
      glycero-3-phosphocholine (GPC) revealed that 1-palmitoyl-2-lyso-GPC, 1-myristoyl
      2-lyso-GPC and 1-hexadecyl-2-lyso-GPC were three major molecular species produced
      after antigen challenge. 1-palmitoyl-2-lyso-GPC increased sevenfold to levels of
      222 +/- 75 ng/ml of BALF 20 h after antigen challenge. The elevated levels of
      lyso-PL correlated with levels of albumin used to assess plasma exudation induced
      by allergen challenge. In contrast, the time course of prostaglandin D2 (PGD2) or
      9 alpha, 11 beta PGF2 (11 beta PGF2) formation did not correlate with lyso-PL
      generation. To examine the mechanism leading to lyso-phospholipid formation in
      antigen-challenged allergic subjects, secretory phospholipase A2 (PI.A2) and
      acetyl hydrolase activities were measured. There was a significant increase in
      PLA2 activity found in BALF of allergic subjects challenged with antigen when
      compared to saline controls. This activity was neutralized by an antibody
      directed against low molecular mass, (14 kD) human synovial PLA2 and
      dithiothreitol. Acetyl hydrolase activity also markedly increased in BALF
      obtained after antigen challenge. This study indicates that high levels of lyso
      PLs are present in airways of allergic subjects challenged with antigen and
      provides evidence for two distinct mechanisms that could induce lyso-PL
      formation. Future studies will be necessary to determine the ramifications of
      these high levels of lyso-phospholipids on airway function.

PMID- 8642334
TI  - Influence of antigen dose and costimulation on the primary response of CD8+ T
      cells in vitro.
AB  - The influence of costimulation on the primary response of CD8+ T cells to class I
      alloantigens was studied with the aid of a T cell receptor transgenic model and
      defined peptides as antigen. With small doses of antigen, the proliferative
      response of CD8+ cells was high early in culture but was of brief duration and
      declined to low levels by day 4; this abbreviated response was associated with
      limited production of interleukin 2 (IL-2) and was strongly dependent upon
      costimulation via CD8-major histocompatibility complex class I and CD28-B7
      interactions. The response to large doses of antigen was quite different in two
      respects. First, large doses of antigen inhibited the early (day 3) proliferative
      response but caused a marked elevation of the response late in culture (day 5);
      these altered kinetics were associated with increased production of IL-2. Second,
      the initial proliferative response to large doses of antigen did not require
      costimulation: indeed, blocking costimulation with CTLA4lg or anti-CD8 monoclonal
      antibody enhanced the early proliferative response. However, blocking
      costimulation impaired IL-2 production and prevented the late proliferative
      response. These findings indicate that the requirement for costimulation of T
      cells can be partly overcome by increasing the dose of antigen to a high level.
      However, costimulation plays a key role in prolonging the response, presumably by
      triggering strong and sustained production of IL-2.

PMID- 8642335
TI  - Induction of long-lived germinal centers associated with persisting antigen after
      viral infection.
AB  - Vesicular stomatitis virus (VSV) induces an early T cell-independent neutralizing
      lgM response that is followed by a long-lived, T cell-dependent lgG response. We
      used the specific amplification factor of several 100x of VSV-virions for
      immunohistology to analyze the localization of VSV-specific B cells at different
      time points after immunization. At the peak of the IgM response (day 4), VSV
      specific B cells were predominantly present in the red pulp and marginal zone but
      not in the T area. These B cells were mostly stained in the cytoplasm,
      characterizing them as antibody secreting cells. By day 6 after immunization,
      germinal centers (GC) containing surface-stained VSV-specific B cells became
      detectable and were fully established by day 12. At the same time, large VSV
      specific B cell aggregates were present in the red pulp. High numbers of VSV
      specific GC associated with persisting antigen were present 1 mo after
      immunization and later, i.e., considerably longer than has been observed for
      haptens. Some GC, exhibiting follicular dendritic cells and containing VSV
      specific, proliferating B cells were still detectable up to 100 d after
      immunization. Long-lived GC were also observed after immunization with
      recombinant VSV-glycoprotein in absence of adjuvants. Thus some anti-virally
      protective (memory) B cells are cycling and locally proliferate in long-lived GC
      in association with persisting antigen and therefore seem responsible for long
      term maintenance of elevated antibody levels. These observations extend earlier
      studies with carrier hapten antigens in adjuvant depots or complexed with
      specific IgG; they are the first to show colocalization of antigen and specific
      memory B cells and to analyze a protective neutralizing antibody response against
      an acute viral infection.

PMID- 8642336
TI  - Germinal center formation, immunoglobulin class switching, and autoantibody
      production driven by "non alpha/beta" T cells.
AB  - The production of class-switched antibodies, particularly immunoglobulin (Ig) G1
      and IgE, occurs efficiently in T cell receptor (TCR) alpha-/- mice that are
      congenitally devoid of alpha/beta T cells. This finding runs counter to a wealth
      of data indicating that IgG1 and IgE synthesis are largely dependent on the
      collaboration between B and alpha/beta T cells. Furthermore, many of the
      antibodies synthesized in TCR alpha-/- mice are reactive to a similar spectrum of
      self-antigens as that targeted by autoantibodies characterizing human systemic
      lupus erythematosus (SLE). SLE, too, is most commonly regarded as an alpha/beta T
      cell-mediated condition. To distinguish whether the development of autoantibodies
      in TCR alpha-/- mice is due to an intrinsic de-regulation of B cells, or to a
      heretofore poorly characterized collaboration between B and "non-alpha/beta T"
      cells, the phenotype has been reconstituted by transfer of various populations of
      B and non-alpha/beta T cells including cloned gamma/delta T cells derived from
      TCR alpha-/- mice, to severe combined immunodeficient (SCID) mice. The results
      establish that the reproducible production of IgG1 (including autoantibodies) is
      a product of non-alpha/beta T cell help that can be provided by gamma/delta T
      cells. This type of B-T collaboration sustains the production of germinal
      centers, lymphoid follicles that ordinarily are anatomical signatures of
      alpha/beta T-B cell collaboration. Thus, non-alpha/beta T cell help may drive Ig
      synthesis and autoreactivity under various circumstances, especially in cases of
      alpha/beta T cell immunodeficiency.

PMID- 8642337
TI  - Exclusive development of T cell neoplasms in mice transplanted with bone marrow
      expressing activated Notch alleles.
AB  - Notch is a highly conserved transmembrane protein that is involved in cell fate
      decisions and is found in organisms ranging from Drosophila to humans. A human
      homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint
      of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9)
      chromosomal translocation; however, its role in oncogenesis has been unclear.
      Using a bone marrow reconstitution assay with cells containing retrovirally
      transduced TAN1 alleles, we analyzed the oncogenic potential of both nuclear and
      extranuclear forms of truncated TAN1 in hematopoietic cells. Although the Moloney
      leukemia virus long terminal repeat drives expression in most hematopoietic cell
      types, retroviruses encoding either form of the TAN1 protein induced clonal
      leukemias of exclusively immature T cell phenotypes in approximately 50% of
      transplanted animals. All tumors overexpressed truncated TAN1 of the size and
      subcellular localization predicted from the structure of the gene. These results
      show that TAN1 is an oncoprotein and suggest that truncation and overexpression
      are important determinants of transforming activity. Moreover, the murine tumors
      caused by TAN1 in the bone marrow transplant model are very similar to the TAN1
      associated human tumors and suggest that TAN1 may be specifically oncotropic for
      T cells.

PMID- 8642338
TI  - Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients
      with tuberculosis.
AB  - The high-output pathway of nitric oxide production helps protect mice from
      infection by several pathogens, including Mycobacterium tuberculosis. However,
      based on studies of cells cultured from blood, it is controversial whether human
      mononuclear phagocytes can express the corresponding inducible nitric oxide
      synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed
      directly after bronchopulmonary lavage. An average of 65% of the macrophages from
      11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted
      with an antibody documented herein to be monospecific for human NOS2. In
      contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each
      of five clinically normal subjects. Tuberculosis patients' macrophages displayed
      diaphorase activity in the same proportion that they stained for NOS2, under
      assay conditions wherein the diaphorase reaction was strictly dependent on NOS2
      expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus,
      macrophages in the lungs of people with clinically active Mycobacterium
      tuberculosis infection often express catalytically competent NOS2.

PMID- 8642339
TI  - Immunoglobulin switch transcript production in vivo related to the site and time
      of antigen-specific B cell activation.
AB  - Immunoglobulin (Ig) class switch recombination is associated with the production
      and splicing of germline IgCH messenger RNA transcripts. Levels of gamma 1
      transcripts in mouse spleen sections were assessed by semiquantitative analysis
      of reverse transcriptase polymerase chain reaction (PCR) products during primary
      and secondary antibody responses to chicken gamma globulin (CGG). This was
      correlated with the appearance of CGG-specific B cells and their growth and
      differentiation to plasma cells. After primary immunization with CGG, gamma 1
      switch transcripts appeared after 4 d, peaked at a median of six times starting
      levels between 10 and 18 d after immunization, and returned to background levels
      before secondary immunization at 5 wk. By contrast, after secondary challenge
      with CGG, a sevenfold increase in transcripts occurs during the first d. The
      level again doubles by day 3, when it is six times that which is seen at the peak
      of the primary response. After day 4, there was a gradual decline over the next 2
      3 wk. Within 12 h of secondary immunization, antigen-specific memory B cells
      appeared in the outer I zone and by 24 h entered S phase, presumably as a result
      of cognate interaction with primed T cells. Over the next few hours, they
      migrated to the edge of the red pulp, where they grew exponentially until the
      fourth day, when they synchronously differentiated to become plasma cells. The
      same pattern was seen for the migration, growth, and differentiation of virgin
      hapten-specific B cells when CGG-primed mice were challenged with hapten protein.
      The continued production of transcripts after day 3 indicates that switching also
      occurs in germinal centers, but in a relatively small proportion of their B
      cells. The impressive early production of switch transcripts during T cell
      dependent antibody responses occurs in cells that are about to undergo massive
      clonal expansion. It is argued that Ig class switching at this time, which is
      associated with cognate T cell-B cell interaction in the T zone, has a major
      impact on the class and subclasses of Ig produced during the response.

PMID- 8642341
TI  - Infectious susceptibility and severe deficiency of leukocyte rolling and
      recruitment in E-selectin and P-selectin double mutant mice.
AB  - During the initial phase of the inflammatory response, leukocytes marginate and
      roll along the endothelial surface, a process mediated largely by the selectins
      and their ligands. Mice with mutations in individual selectins show no
      spontaneous disease and have mild or negligible deficiencies of inflammatory
      responses. In contrast, we find that mice with null mutations in both endothelial
      selectins (P and E) develop a phenotype of leukocyte adhesion deficiency
      characterized by mucocutaneous infections, plasma cell proliferation,
      hypergammaglobulinemia, severe deficiencies of leukocyte rolling in cremaster
      venules with or without addition of TNF-alpha, and an absence of neutrophil
      emigration at 4 h in response to intraperitoneal Streptococcus pneumoniae
      peritonitis. These mice provide strong evidence for the functional importance of
      selectins in vivo.

PMID- 8642340
TI  - The fate of self-reactive B cells depends primarily on the degree of antigen
      receptor engagement and availability of T cell help.
AB  - Self-reactive B cells from tolerant double-transgenic (Dbl-Tg) mice coexpressing
      hen egg lysozyme (HEL) and rearranged anti-HEL immunoglobulin genes have a
      relatively short life span when compared to normal B cells, irrespective of
      whether they are exposed to antigen in multivalent membrane-bound form (mHEL-Dbl
      Tg mice) or soluble form (sHEL-Dbl-Tg mice). The factors responsible for
      determining the fate of these B cells after encounter with self-antigen were
      investigated using a cell-tracking technique in which anti-HEL Ig-Tg spleen cells
      were labeled with the intracellular dye 5-carboxyfluorescein diacetate
      succinimidyl ester (CFSE) and injected either into non-Tg recipients or a variety
      of HEL-Tg hosts. In non-Tg recipients, HEL-binding B cells persisted in the
      circulation and could be detected in the follicles of the spleen for at least 5
      d. On transfer into either mHEL-Tg or sHEL-Tg hosts, they underwent activation
      and then rapidly disappeared from the blood and spleen over the next 3 d,
      consistent with the short life span reported previously. Immunohistology of
      spleens from sHEL-Tg recipients indicated that the transferred B cells had
      migrated to the outer margins of the periarteriolar lymphoid sheath (PALS), where
      they were detectable for 24 h before being lost. The positioning of B cells in
      the outer PALS depended on a critical threshold of Ig receptor binding
      corresponding to a serum HEL concentration between 0.5 and 15 ng/ml, but was not
      restricted to endogenously expressed HEL in that the same migratory pattern was
      observed after transfer into non-Tg recipients given exogenous (foreign) HEL.
      Moreover, bone marrow-derived immature Ig-Tg B cells homed to the outer PALS of
      sHEL-Tg mice and then disappeared at the same rate as mature B cells, indicating
      that the stage of maturation did not influence the fate of self-reactive B cells
      in a tolerant environment. On the other hand, HEL-binding B cells transferred
      into sHEL-Dbl-Tg recipients persisted over the 3-d period of study, apparently
      due to insufficient availability of antigen, as indicated by the fact that the
      degree of Ig receptor downregulation on the transferred B cells was much less
      than in sHEL-Tg recipients. If T cell help was provided to Ig-Tg B cells at the
      time of transfer into sHEL-Tg recipients in the form of preactivated CD4+ T cells
      specific for major histocompatibility complex-peptide complexes on the B cell
      surface, HEL-binding B cells migrated through the outer PALS of the spleen to the
      follicle, where they formed germinal centers, or to adjacent red pulp, where they
      formed proliferative foci and secreted significant amounts of anti-HEL antibody.
      Taken together, these results indicated that the outcome of the interaction
      between self-antigen and B cells is largely determined by a combination of the
      degree of receptor engagement and availability of T cell help.

PMID- 8642342
TI  - Spontaneously increased production of nitric oxide and aberrant expression of the
      inducible nitric oxide synthase in vivo in the transforming growth factor beta 1
      null mouse.
AB  - Transforming growth factor beta 1 null mice (TGF-beta 1-/-) suffer from
      multifocal inflammation and die by 3-4 wk of age. In these mice, levels of nitric
      oxide (NO) reaction products in serum are elevated approximately fourfold over
      levels in controls, peaking at 15-17 d of life. Shortterm treatment of TGF-beta 1
      /- mice with NG-monomethyl-L-arginine suppressed this elevated production of NO.
      Expression of inducible NO synthase (iNOS) mRNA and protein is increased in the
      kidney and heart of TGF-beta 1-/- mice. These findings demonstrate that TGF-beta
      1 negatively regulates iNOS expression in vivo, as had been inferred from
      mechanistic studies on the control of iNOS expression by TGF-beta 1 in vitro.

PMID- 8642343
TI  - Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody
      and complement.
AB  - Reperfusion of ischemic tissue induces an acute inflammatory response that can
      result in necrosis and irreversible cell injury to both local vascular
      endothelium and parenchyma. To examine the pathogenesis of ischemia/reperfusion
      injury, we have used mice deficient in complement components C3, C4, or serum
      immunoglobulin in a hindlimb model of ischemia. We found that mice homozygous
      deficient in C3 or C4 were equally protected against reperfusion injury based on
      a significant reduction in leakage of radiolabeled albumin out of the
      vasculature. This demonstrates that classical pathway complement is an important
      factor in the initiation of inflammation following reperfusion. Furthermore, mice
      deficient in serum immunoglobulin were equally protected and this protection
      could be reversed by reconstitution with serum from normal mice. Thus, this
      report describes a novel mechanism for reperfusion injury that involves antibody
      deposition and activation of complement leading to inflammation permeability.

PMID- 8642344
TI  - Cloning, expression, and characterization of the human eosinophil eotaxin
      receptor.
AB  - Although there is a mounting body of evidence that eosinophils are recruited to
      sites of allergic inflammation by a number of beta-chemokines, particularly
      eotaxin and RANTES, the receptor that mediates these actions has not been
      identified. We have now cloned a G protein-coupled receptor, CC CKR3, from human
      eosinophils which, when stably expressed in AML14.3D10 cells bound eotaxin, MCP-3
      and RANTES with Kds of 0.1, 2.7 and 3.1 nM, respectively. CC CKR3 also bound MCP
      1 with lower affinity, but did not bind MIP-1 alpha or MIP-1 beta. Eotaxin,
      RANTES, and to a lessor extent MCP-3, but not the other chemokines, activated CC
      CKR3 as determined by their ability to stimulate a Ca(2+) -flux. Competition
      binding studies on primary eosinophils gave binding affinities for the different
      chemokines which were indistinguishable from those measured with CC CKR3. Since
      CC CKR3 is prominently expressed in eosinophils we conclude that CC CKR3 is the
      eosinophil eotaxin receptor. Eosinophils also express a much lower level of a
      second chemokine receptor, CC CKR1, which appears to be responsible for the
      effects of MIP-1 alpha.

PMID- 8642345
TI  - Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal
      through thymic shared antigen-1/stem cell antigen-2.
AB  - During T cell development in the thymus, the expression of thymic shared antigen
      1 (TSA-1)/stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)
      anchored differentiation antigen, is developmentally regulated. The expression
      level of TSA-1 is the highest in most immature CD4- CD8- thymocytes, high in CD4+
      CD8+ thymocytes, but barely detectable in mature CD4+ CD8- or CD4- CD8-
      thymocytes and peripheral T cells. We have previously shown that surface TSA-1
      expression in peripheral T cells is induced upon activation and that anti-TSA-1
      mAb inhibits the T cell receptor (TCR) signaling pathway in activated T cells. In
      the present study, we have analyzed a role of TSA-1 in thymic selection events,
      especially in TCR-mediated apoptosis. In in vitro experiments, anti-TSA-1 blocked
      anti-CD3-induced cell death of T cell hybridomas. When anti-TSA-1 was injected
      into newborn mice in vivo together with anti-CD3 epsilon or anti-TCR-beta,
      TCR/CD3-mediated apoptosis of thymocytes was almost completely blocked. The
      blockade of apoptosis was defined by the inhibition of, first, the decrease in
      total number of thymocytes; second, the decrease in percentages of CD4+ CD8+
      thymocytes; and third, the induction of DNA fragmentation. However, anti-TSA-1
      did not block either steroid- or radiation-induced apoptosis, indicating that a
      signal via TSA-1 does not inhibit a common pathway of thymocyte apoptosis. Since
      TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that
      TSA-1/Sca-2 is an important cell surface molecule regulating the fate of a
      developing T cell.

PMID- 8642346
TI  - T cell-mediated eradication of murine metastatic melanoma induced by targeted
      interleukin 2 therapy.
AB  - Induction of a T-cell mediated antitumor response is the ultimate goal for tumor
      immunotherapy. We demonstrate here that antibody-targeted IL2 therapy is
      effective against established pulmonary and hepatic melanoma metastases in a
      syngeneic murine tumor model. The effector mechanisms involved in this tumor
      eradication are not dependent on NK cells, since the therapeutic effect of
      antibody-IL2 fusion protein was not altered in NK cell-deficient mice. In
      contrast, T cells are essential for the observed antitumor effect, since therapy
      with antibody IL2 fusion proteins is unable to induce tumor eradication in T cell
      deficient SCID mice. In vivo depletion studies characterized the essential
      effector cell population further as CD8 + T cells. Such CD8 + T cells, isolated
      from tumor bearing mice after antibody-directed IL2 therapy, exerted a MHC class
      I-restricted cytotoxicity against the same tumor in vitro. These data demonstrate
      the ability of antibody-targeted IL2 delivery to induce a T cell-dependent host
      immune response that is capable of eradicating established melanoma metastases in
      clinically relevant organs.

PMID- 8642347
TI  - Differentiation of follicular dendritic cells and full antibody responses require
      tumor necrosis factor receptor-1 signaling.
AB  - Using mice double deficient for tumor necrosis factor (TNF) and lymphotoxin alpha
      (LT alpha), we demonstrated that TNF and/or LT alpha are necessary for
      development of a normal splenic microarchitecture and for isotype switch after
      immunization with sheep red blood cells (SRBC). In the present study, we extended
      these observations by determining which TNF receptor (TNFR) is involved in
      morphological and functional differentiation of the spleen. Spleen morphology and
      antibody response were investigated in wild-type, TNFR1-/-, TNFR2-/- and TNF/LT
      alpha-/- mice immunized with SRBC. TNF/LT alpha-/- mice, which have a complete
      disruption of the TNF/LT alpha signaling system including the LT beta-receptor
      pathway, displayed an abnormal microarchitecture, and isotype switch did not take
      place. TNFR1-/- and TNFR2-/- mice displayed a normal spleen microarchitecture and
      mounted an IgM and IgG antibody response to SRBC. However, the IgG production in
      TNFR1-/- mice was minimal, with citers leveling off 6 d after immunization. In
      this strain, immunofluorescence revealed a lack of follicular dendritic cells
      (FDC) network, detected with FDC-M1 as well as anti-CR1, and a lack of germinal
      centers, detected with peanut agglutinin. In conclusion, whereas normal splenic
      microarchitecture and isotype switch might require the LT beta receptor,
      differentiation of FDC network, development of germinal centers, and full IgG
      response depend on signaling via TNFR1.

PMID- 8642348
TI  - Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop
      in murine macrophages.
AB  - Macrophages play an important role in the acute tissue inflammatory response
      through the release of cytokines and growth factors in response to stimuli such
      as lipopolysaccharide (LPS). Macrophage inflammatory effector functions are also
      influenced by interactions with the extracellular matrix (ECM). Such macrophage
      ECM interactions may be important in regulating chronic inflammatory responses.
      Recent evidence has suggested that hyaluronan (HA), a glycosaminoglycan (GAG)
      component of ECM can induce inflammatory gene expression in murine macrophages.
      HA exists in its native form as a large polymer, but is found as smaller
      fragments under inflammatory conditions. The NF-kappa B/I-kappa B transcriptional
      regulatory system has been shown to be a critical component of the host
      inflammatory response. We examined the effects of high molecular weight HA and
      lower molecular weight HA fragments on NF-kappa B activation in mouse
      macrophages. Only the smaller HA fragments were found to activate NF-kappa B DNA
      binding activity. After HA stimulation, I-kappa B alpha mRNA was induced and I
      kappa B alpha protein levels, which initially decreased, were restored. The
      induction of I-kappa Balpha expression was not observed for other GAGs. The time
      course of I-kappa B alpha protein regeneration in response to HA fragments was
      consistent with an autoregulatory mechanism. In support of this mechanism, in
      vitro translated murine I-kappa B alpha inhibited HA fragment-induced NF-kappa B
      DNA binding activity. The NF-kappa B DNA binding complex in HA-stimulated
      extracts was found to contain p50 and p65 subunits. Activation of the NF-kappa
      B/I-kappa B system in macrophages by ECM fragments may be an important mechanism
      for propagating the tissue inflammatory response.

PMID- 8642349
TI  - Monocyte chemotactic protein 4 (MCP-4), a novel structural and functional
      analogue of MCP-3 and eotaxin.
AB  - A novel human CC chemokine complementary DNA was identified in a library
      constructed from human fetal RNA, cloned into a baculovirus vector, and expressed
      in Sf9 insect cells. The mature recombinant protein that was released had the NH2
      terminal sequence pyro-QPDALNVPSTC...and consisted of 75 amino acids. Minor
      amounts of two variants of 77 and 82 residues (NH2 termini: LAQPDA...and
      FNPQGLAQPDA...) were released as well. The novel chemokine was designated
      monocyte chemotactic protein 4 (MCP-4) and the variants were designated (LA)MCP-4
      and (FNPQGLA)MCP-4. MCP-4 shares the pyroglutamic acidproline NH2-terminal motif
      and 56-61% sequence identity with the three known monocyte chemotactic proteins
      and is 60% identical to eotaxin. It has marked functional similarities to MCP-3
      and eotaxin. Like MCP-3, MCP-4 is a chemoattractant of high efficacy for
      monocytes and T lymphocytes. On these cells, it binds to receptors that recognize
      MCP-1, MCP-3, and RANTES. On eosinophils, MCP-4 has similar efficacy and potency
      as MCP-3, RANTES, and cotaxin. It shares receptors with eotaxin and shows full
      cross-desensitization with this cosinophil-selective chemokine. Of the two
      variants, only (LA)MCP-4 could be purified in sufficient quantities for testing
      and was found to be at least 30-fold less potent than MCP-4 itself. This suggests
      that the 75-residue form with the characteristic NH2 terminus of an MCP is the
      biologically relevant species.

PMID- 8642350
TI  - Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus is a new
      transmissible virus that infects B cells.
AB  - Herpesviral DNA fragments isolated from AIDS-associated Kaposi's sarcoma (KS)
      tissue (KSHV-DNA) share homology with two lymphotropic oncogenic gamma
      herpesviruses, Epstein-Barr virus and Herpesvirus saimiri, and are present in the
      lesions of more than 95% of HIV and non-HIV-associated forms of KS, AIDS-related
      body cavity-based lymphomas, and AIDS-related multicentric Castleman's disease.
      Here we show that BC-1, a KSHV-DNA-positive, body cavity-based lymphoma cell
      line, produces infective herpesviral particles carrying a linear 270-kb genome
      that specifically transmits KSHV-DNA to CD19+ B cells. Transmission of KSHV-DNA
      is dependent upon a biologically active, replicating virus, since it is blocked
      by UV irradiation and foscarnet, an inhibitor of viral DNA-polymerase. This study
      represents the first isolation and transmission of the human herpesvirus-8/KS
      associated herpesvirus.

PMID- 8642351
TI  - Interferon gamma production by natural killer (NK) cells and NK1.1+ T cells upon
      NKR-P1 cross-linking.
AB  - Natural killer (NK) cells play an important role in immune response by producing
      interferon gamma (IFN-gamma) as well as exhibiting cytotoxic function. IFN-gamma
      produced by NK cells has been suggested to be involved in differentiation of T
      helper cells. On the other hand, the NKR-P1 molecule was recently identified as
      one of the important NK cell receptors, and it recognizes certain kinds of
      oligosaccharides on target cells and triggers NK cells for cytotoxicity. In the
      present study, we found that NK cells produce great amounts of IFN-gamma upon
      cross-linking of the NKR-P1 molecule. In contrast, stimulation of NK cells with
      IL-2 induced proliferation without producing IFN-gamma. Similar to NK cells,
      NK1.1+ T cells also produced IFN-gamma upon NKR-P1 cross-linking. NK1.1+ T cells
      produced IFN-gamma but not interleukin 4 (IL-4) upon NKR-P1 cross-linking,
      whereas they secreted both IFN-gamma and IL-4 upon T cell receptor cross-linking.
      These results indicate that NKR-P1 is a receptor molecule on NK and NK1.1+ T
      cells that induces not only cytotoxicity but also IFN-gamma production. Our
      findings provide a new pathway for IFN-gamma production by NK and NK1.1+ T cells
      through NKR-P1 molecules; it may be essential for immune regulation.

PMID- 8642352
TI  - RANTES and macrophage inflammatory protein 1 alpha selectively enhance
      immunoglobulin (IgE) and IgG4 production by human B cells.
AB  - We studied the effects of various chemokines including neutrophil-activating
      peptide 2 (NAP-2), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4),
      melanoma growth stimulating activity (GRO), gamma interferon-induced protein (IP
      10), regulated on activation, normal T expressed and secreted (RANTES),
      macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 beta, and monocyte
      chemotactic protein 1 (MCP-1) on Immunoglobulin (IgE) and IgG4 production by
      human B cells. None of these chemokines with or without interleukin (IL-4), anti
      CD40 or -CD58 monoclonal antibody (mAb), induced IgE and IgG4 production by B
      cells from nonatopic donors. However, RANTES and MIP-1 alpha selectively enhanced
      IgE and IgG4 production induced by IL-4 plus anti-CD40 or -CD58 mAb without
      affecting production of IgM, IgG1, IgG2, IgG3, IgA1, or IgA2, whereas other
      chemokines failed to do so. Enhancement of IgE and IgG4 production by RANTES and
      MIP-1 alpha was specifically blocked by anti-RANTES mAb and anti-MIP-1 alpha
      antibody (Ab), respectively, whereas anti-IL-5 mAb, anti-IL-6 mAb, anti-IL-10 Ab,
      anti-IL-13 Ab, and anti-tumor necrosis factor-alpha mAb failed to do so. Purified
      surface IgE positive (slgE4) and slgG4+ B cells generated either in vitro or in
      vivo spontaneously produced IgE and IgG4, respectively, whereas sIgE- and sIgG4-
      B cells failed to do so. RANTES and MIP-1 alpha enhanced spontaneous IgE and IgG4
      production in slgE+ and slgG4- B cells, respectively, whereas neither RANTES nor
      MIP-1 alpha did so in sIgE- or sIgG4- B cells. Purified sIgE4+ and sIgG4+, but
      not sIgE- or sIgG4- B cells, generated in vitro and in vivo expressed receptors
      for RANTES and MIP-1 alpha, whereas they failed to express receptors for other
      chemokines. These findings indicate that RANTES and MIP-1 alpha enhance IgE and
      IgG4 production by directly stimulating sIgE+ and sIgG4+ B cells.

PMID- 8642354
TI  - Technique for freehand newborn circumcision.

PMID- 8642355
TI  - ACE inhibitors and renoprotection.

PMID- 8642353
TI  - Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low
      avidity of TCR/MHC-tumor peptide interactions.
AB  - Coculture of melanoma cells and T cell clones derived from tumor-infiltrating
      lymphocytes (TIL) generally results in lysis of the antigen-bearing tumor cells
      but to inefficient proliferation and IL-2 secretion by responder T cells. This
      suboptimal activation is classically explained by an inability of tumor cells to
      provide costimulatory signals. Here we analyzed the responses to synthetic
      peptides of HLA-A2.1-restricted CTL clones specific for melanoma antigens MART-1
      and NA17-A. We showed that peptide concentrations ranging from 1 pM to 10 nM
      efficiently sensitized the peptide transporter-deficient T2 cells to lysis. T2
      cells pulsed with melanoma peptides also induced TIL proliferation and detectable
      secretion of IL-2, IFN-gamma and GM-CSF, but only for peptide concentrations 10-
      to 10,000-fold higher than those required for lysis. Hence this suggests that
      partial triggering of TIL clones by melanoma cells could be due to expression of
      appropriate MHC-peptide complexes at subthreshold levels. In support of this, we
      showed that melanoma cells, unable to trigger IL-2 secretion, developed this
      ability when incubated with the appropriate peptide. These results indicate that
      the level of antigens expressed on melanoma tumors critically affects TIL
      activation status and thus, the efficiency of specific immune reactions mediated
      by these cells.

PMID- 8642356
TI  - Are eye patches necessary for corneal abrasions?

PMID- 8642357
TI  - Immunotherapy in adult asthma.

PMID- 8642358
TI  - Acellular vaccines for pertussis.

PMID- 8642359
TI  - Single vs multiple daily dosing of aminoglycosides.

PMID- 8642360
TI  - Treatment of Parkinson's disease.

PMID- 8642362
TI  - Using humor in the office setting: a pediatric perspective.

PMID- 8642361
TI  - t-PA for treating acute ischemic stroke.

PMID- 8642363
TI  - Predictors of persistent palpitations and continued medical utilization.
AB  - BACKGROUND: The aim of this study was to determine the predictors of persistent
      palpitations and continued medical utilization in a sample of medical patients
      referred for ambulatory electrocardiographic monitoring. METHODS: A prospective
      telephone follow-up was conducted with patients who had undergone ambulatory
      electrocardiographic monitoring 3 months earlier. At inception, patients
      completed in-person interviews and self-report questionnaires, assessing
      somatization, hypochondriacal attitudes, bodily amplification (high degree of
      sensitivity to bodily sensations), and two types of life stress (minor daily
      irritants and major life changes). At follow-up, patients completed a structured
      interview about their clinical course, palpitations, and utilization of medical
      care during the interval. RESULTS: At 3-month follow-up, 55 of the inception
      cohort of 67 patients were interviewed again. The mean severity of palpitations
      for the entire sample declined significantly, but 46 (83.6%) patients continued
      to experience their presenting symptoms. Stepwise multiple linear regression
      revealed that the interaction of bodily amplification and daily life stress at
      inception uniquely explained 10.0% of the variance in palpitation severity at
      follow-up. A four-step model composed of these two interaction terms and age and
      education level accounted for 21.4% of the variance in palpitations. The medical
      utilization findings are complementary in that the interaction of amplification
      and daily irritants at baseline predicted the number of unscheduled medical
      visits over the subsequent 3 months. The total number of ventricular premature
      contractions occurring during ambulatory monitoring was not a significant
      predictor of palpitations. CONCLUSIONS: Palpitations are more persistent in
      persons who are both highly sensitive to bodily sensations and who experience a
      greater number of minor daily irritants. The existence of either predictor alone
      is not sufficient to perpetrate this functional somatic symptom; it requires the
      combination of these predictors.

PMID- 8642365
TI  - Physician ability to predict appointment-keeping behavior of prenatal patients.
AB  - BACKGROUND: Prenatal appointment-keeping is considered an important component of
      adequate prenatal care. Interventions designed to increase the frequency with
      which patients keep prenatal appointments would be most effective if directed
      toward patients at greatest risk of missing prenatal appointments; however, it is
      difficult to identify this population of patients. The purpose of this study was
      to determine whether physicians could accurately predict the appointment-keeping
      behavior of their prenatal patients. METHODS: A simple questionnaire was
      completed by physicians at the time of the initial visit for prenatal care. On
      these surveys, physicians made predictions concerning each patients's subsequent
      appointment-keeping behavior. At the conclusion of prenatal care, predictions
      were compared with actual appointment-keeping as determined by chart audits.
      RESULTS: More than one half (57%) of patients kept at least 80% of their
      scheduled appointments. Physicians predicted fair to poor appointment-keeping for
      23% of the patients, but 43% of all patients met the criteria for fair to poor
      appointment-keeping. There was no correlation between physician predictions and
      actual appointment-keeping. The physician's sex, level of training, and degree of
      certainty about his or her predictions had no impact on the accuracy of the
      predictions. In identifying patients at high risk of missing appointments,
      physician predictions had a sensitivity of 26%, a specificity of 79%, and a
      positive predictive value of only 47%. CONCLUSIONS: Physician prediction was not
      found to be an accurate method of identifying patients at risk for missing
      appointments.

PMID- 8642364
TI  - Complications of spinal manipulation: a comprehensive review of the literature.
AB  - BACKGROUND: Spinal manipulative therapy (SMT) is a frequently applied therapy for
      back and neck pain. Serious complications of SMT are presented primarily in case
      reports. Many patients seen by physicians also seek care from therapists applying
      manipulative techniques. Therefore, background information on the risks of SMT is
      essential for physicians. METHODS: Relevant case reports, surveys, and review
      articles were identified using a comprehensive search of online and
      bibliographical databases. For every case, a record was made of first author,
      publication year, country, age and sex of the patient, background of the
      manipulator, preexisting conditions, type of complication, and course of the
      complication. Based on case reports and surveys, an estimation was made of the
      risk for the most frequently reported complications: vertebrobasilar accidents
      (VBAs) and cauda equina syndrome (CES). RESULTS: We derived 295 complications of
      spinal manipulations from the literature: 165 VBAs; 61 cases with disc herniation
      or progression to CES; 13 cerebral complications other than VBAs; and 56 other
      types of complications. The average age of patients with VBA was 38 years.
      Vertebrobasilar accidents occur mainly after a cervical manipulation with a
      rotatory component. Estimates of VBA range from 1 per 20,000 patients to 1 per 1
      million cervical manipulations. The incidence of CES is estimated to be less that
      1 per 1 million treatments. CONCLUSIONS: It is difficult to estimate the
      incidence of SMT complications, as they are probably underreported in the
      literature. Most non-VBA complications can be prevented by excluding patients
      with contraindications for SMT. Patients who develop complications such as CES
      should be treated as soon as possible. VBAs, however, are difficult to prevent
      and treat. Referral for SMT should not be made to practitioners applying rotatory
      cervical manipulation. Information about the risk of VBA should be included in an
      informed consent procedure for cervical manipulation with thrust techniques.

PMID- 8642366
TI  - Universal newborn hearing screening: feasibility in a community hospital.
AB  - BACKGROUND: The National Institutes of Health and the Joint Committee on Infant
      Hearing have recommended universal newborn hearing screening. The feasibility of
      universal newborn hearing screening in a community hospital, however, has not
      been demonstrated. We initiated a universal newborn hearing screening program
      using transient evoked otoacoustic emissions (TEOAE) at a community hospital to
      assess the feasibility of universal hearing screening in this setting. METHODS: A
      screening team composed of a family practice physician, family medicine resident,
      audiologist, and four technicians was developed. The study compared testing time
      between the technicians and the audiologist and assessed whether the technicians
      were able to perform hearing testing accurately and reliably. RESULTS: A total of
      627 infants were screened. Of those, 11 (1.8%) failed TEOAE screening and were
      referred to a tertiary care center for further evaluation. Six of the 11
      referrals were found to have a hearing impairment. Trained technicians were found
      to be capable of performing the screening accurately and reliably. CONCLUSIONS:
      Universal newborn hearing screening using transient evoked otoacoustic emissions
      is feasible in a community hospital.

PMID- 8642367
TI  - Nonurgent use of hospital emergency departments: urgency from the patient's
      perspective.
AB  - BACKGROUND: Patients often seek care from hospital emergency departments (EDs)
      for conditions medical personnel perceive as nonurgent. The purpose of this study
      was to examine ED patients' perceptions of urgency, and to determine whether
      patients with no regular source of medical care are more likely to use the ED for
      problems they perceive as nonurgent. METHODS: We surveyed 268 patients in an
      urban ED waiting area who were considered nonurgent by the ED triage nurse. Using
      structured interviews, we determined patients' perceptions, about the urgency of
      their medical condition, whether they had a regular source of medical care, and
      their reasons for choosing the ED for care. After controlling for other
      variables, we determined whether having non regular source of care was associated
      with patient-rated nonurgent ED utilization. RESULTS: Eighty-two percent of
      patients rated their condition as urgent. Patient-rated urgency was not
      associated with having a regular source of care. The most common reason for
      seeking care in the ED was expediency. CONCLUSIONS: A large majority of ED
      patients perceive the problems for which they seek care from an ED as urgent,
      even when they are assessed as nonurgent by a health professional. Lack of a
      regular source of care has no significant impact on ED utilization for problems
      that patients perceive as nonurgent. Simply providing patients with a regular
      source of care is unlikely to have a significant impact on nonurgent ED
      utilization without efforts to manage utilization and ensure adequate access to
      primary care.

PMID- 8642368
TI  - Analysis of outpatient referral failures.
AB  - BACKGROUND: The purpose of this study was to measure the rate at which outpatient
      referrals failed to be completed, and to analyze predisposing factors for
      referral failure in the family practice of a medical center. METHODS: Structured
      questionnaires were completed by referring physicians whenever a referral was
      initiated during a 4-month period. On the 60th day after referral, an
      investigator contacted the referred patients by telephone and also reviewed their
      charts. RESULTS: During the 4-month period, 604 referrals (2.28%) were made from
      26,476 encounters at the study clinic. Sixty-four patients (10.6%) failed to
      complete the referral processes within a 60-day period. The most frequent reasons
      for referral failure were administrative factors, ie, too long a wait (59.4%),
      and the patient's belief that the referral was not necessary (23.4%). The
      physician's or patients's opinion of referral necessity, the level of experience
      of the referring physician, and the method of contact with the consultant all had
      significant influence on the referral failure rate. CONCLUSIONS: Improving
      administrative efficiency, enhancing communication between physicians and between
      physicians and patients, assessing the willingness of patients to follow through
      on a referral, and the method used to initiate the referral by the physician may
      reduce the referral failure rate.

PMID- 8642369
TI  - Questions asked by family physicians who want to serve as medical student
      preceptors.
AB  - This article addresses the needs of family physician preceptors who teach medical
      students in their community-based practices. Responses are provided to 20 typical
      questions that a family physician might ask when considering whether to become a
      preceptor. Areas covered by the questions and responses include physician
      motivation for becoming a preceptor, characteristics of good preceptors, specific
      issues related to working with students in the office, what to teach students,
      how to give students feedback, evaluation of students, and relationships with the
      medical school.

PMID- 8642370
TI  - Diagnosing and treating onychomycosis.
AB  - Onychomycosis is a persistent fungal infection of the toenails or fingernails
      that is usually not painful but is unsightly and can affect a patient's quality
      of life by interfering with footwear. It may affect up to 30% of the population
      by age 60. In more that 99% of cases, it is caused by dermatophytes, the most
      common of which are Trichophyton rubrum and Trichophyton mentagrophytes. Each of
      the four clinical types of onychomycosis, as defined by the route of fungal
      invasion, has a characteristic appearance, but other diseases, particularly
      psoriasis, may have a similar appearance. Proper management, therefore, includes
      confirmation of fungal infection by potassium hydroxide slide preparation and
      culture. Traditionally, pharmacologic treatment has been less than optimal. In
      many cases, griseofulvin, the first oral agent approved for onychomycosis in the
      United States, must be given for 1 year or more to be effective. Low cure rates
      are related to poor bioavailability and the fungistatic rather than fungicidal
      effect of the drug. Newer agents, such as oral itraconazole and oral terbinafine,
      promise to substantially increase cure rates while shortening treatment duration.
      Oral terbinafine is potently fungicidal against dermatophytes and has proven
      efficacious with regimens as brief as 12 weeks when the nail is not 100%
      involved.

PMID- 8642371
TI  - Renal emboli and atrial septal aneurysm.
AB  - A 53-year-old woman presented with flank pain and hematuria. She was suspected of
      having a renal stone but instead was found to have segmental renal infarction.
      Further evaluation revealed an atrial septal aneurysm, which was presumed to be
      the source of an embolism. Renal emboli should be considered when more common
      cause of flank pain are excluded. Atrial septal aneurysm should be considered
      when embolic events occur without an evident source. Transesophageal
      echocardiography is the best test to diagnose atrial septal aneurysms.

PMID- 8642372
TI  - Short hospital stays for mothers and newborns.

PMID- 8642373
TI  - Chronic infection and asthma.

PMID- 8642374
TI  - MMA test to detect vitamin B12 deficiency.

PMID- 8642375
TI  - Treatment of bacterial vaginosis.

PMID- 8642376
TI  - Carotidynia rurally revisited.

PMID- 8642377
TI  - Psychological management in family practice.

PMID- 8642378
TI  - "Window of opportunity" in managed care.

PMID- 8642379
TI  - Latin redux.

PMID- 8642380
TI  - Sweetheart.

PMID- 8642382
TI  - Neurological signs, age, and illness duration in schizophrenia.
AB  - Although increased prevalence of neurological signs in schizophrenia may reflect
      the presence of subtle brain dysfunctions, it is not clear whether there is
      progressive deterioration in such neurological function as the illness advances.
      This study compared neurological signs in patients with different durations of
      illness, controlling for age and education level. No deterioration in
      neurological signs as a function of illness duration was observed. Although there
      was an increase in neurological signs with age, there was a parallel increase in
      a control group. In addition, no change in the profile of subgroups of
      neurological signs was detected. These data provide further evidence for the
      stability of neurological dysfunction in schizophrenia. The findings are
      discussed in the context of the developmental origin of neurological dysfunction
      in schizophrenia.

PMID- 8642381
TI  - Eye movements and psychopathology in schizophrenia and bipolar disorder.
AB  - The aim of this study was to examine multivariate patterns of relationships
      between oculomotor performance, psychopathology, and neuropsychology. Performance
      on smooth pursuit and saccadic eye movement tasks was assessed in three DSM-III-R
      diagnosis-based groups of subjects; normal (N = 55), schizophrenic (N = 29), and
      bipolar disorder (N = 26) and analyzed in relation to age, gender, scale for the
      Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms,
      and Brief Psychiatric Rating Scale scores, Shipley intelligence quotient, and
      Wisconsin Card Sorting Test Performance. The greatest difference was a higher
      proportion of errors in the antisaccade task in the schizophrenic and bipolar
      groups, which was related to worse Wisconsin Card Sorting Test performance and
      was not accounted for by gender, age, education, or intelligence quotient. A
      significant gender and bipolar interaction showed bipolar women to have worse
      antisaccade performance. Abnormal smooth pursuit was more specific to
      schizophrenia. Antisaccade task and sine wave root-mean-square error were
      correlated in bipolar but not schizophrenic subjects. Scale for the Assessment of
      Negative Symptoms and Scale for the Assessment of Positive Symptoms scores had
      independent associations with the antisaccade task. Faster reaction times in the
      schizophrenic group to antisaccade errors were observed, suggesting an
      abnormality in visual attention processing and perhaps sensory gating functions.
      These results confirm abnormal smooth pursuit in schizophrenia and suggests that
      impairments in saccadic function are less specific to diagnostic group.
      Oculomotor performance and psychopathology seem related in complex ways to age,
      gender, intelligence quotient, and executive neuropsychological and possibly
      visual attention functions.

PMID- 8642383
TI  - The effects of welfare status on psychological distress among Southeast Asian
      refugees.
AB  - It has been established in the general population that there is a relationship
      between welfare status and psychological well-being. There are few studies,
      however, which investigate the effects of welfare dependency on Southeast Asian
      refugees, a population that is highly dependent on welfare. This study examined
      the relationship between welfare status and psychological well-being among
      Vietnamese, Cambodian, Laotian, and Hmong refugees. The study compared three
      welfare groups: those who have never been on welfare, those who were once
      dependent on welfare and are no longer on welfare, and those who are still
      welfare-dependent. The results supported three hypotheses: a) a high percentage
      of all four refugee groups were still dependent on welfare even after being in
      the United States for an average of 5 to 6 years, b) a significant relationship
      was found between welfare dependency and psychological distress, and c)
      dependence on welfare had long-term effects for all four groups. An interesting
      finding that emerged for the Vietnamese, Cambodians, and Laotians was that
      individuals who were once on welfare but who are no longer receiving welfare
      benefits are at similar risk as their counterparts who are currently on welfare
      of developing psychological distress. The findings therefore showed that for this
      population, if individuals had been touched by welfare at any period in their
      lives, they were at risk of developing psychological distress. There was an
      unexpected different finding for the Hmong; individuals who were no longer on
      welfare were more at risk than those who continued to receive or never had
      received welfare. Reasons for the intergroup differences and why refugees tended
      to stay on welfare longer than the general population were explored, along with a
      discussion about the implications of the findings for refugee policy.

PMID- 8642384
TI  - Malignant Post-Vietnam Stress Syndrome revisited.
AB  - Malignant Post-Vietnam Stress Syndrome describes a severe form of combat-related
      posttraumatic stress disorder. We update the concept of Malignant Post-Vietnam
      Stress Syndrome, considering the effects of repeated severe traumatization,
      exposure to atrocities, and a variety of comorbid conditions. An illustrative
      case report demonstrates an interdisciplinary treatment approach, combining case
      management, brief hospitalizations, symptom-directed use of medications, and
      supportive psychotherapy.

PMID- 8642385
TI  - Rapid improvement in the defense style of depressed women and men.
AB  - The purpose of this study was to determine whether the defense style of
      hospitalized depressed adults improved over the course of treatment. Thirty-one
      inpatients (24 women and 7 men) with an admitting diagnosis of major depression
      completed the 40-item Defense Style Questionnaire and the 20-item Center for
      Epidemiologic Studies-Depression Scale. Participants completed the Defense Style
      Questionnaire and the Center for Epidemiologic Studies-Depression Scale within 48
      hours after admission and within 24 hours before or after discharge. The average
      admission and discharge Center for Epidemiologic Studies-Depression Scale ratings
      (+/-SD) were 41.93+/-9.93 and 26.45+/-12.19, respectively. The average hospital
      length of stay was 7.1+/-2.8 days. Two-tailed t-test comparisons of the Defense
      Style Questionnaire admission and discharge ratings showed significantly higher
      discharge mature ratings, significantly lower discharge immature ratings, and
      stable neurotic ratings. We concluded that for some depressed women and men,
      improvement in defense style can occur within days after the initiation of
      standard inpatient treatment.

PMID- 8642386
TI  - Sociotropy, autonomy, stress, and depression in Cushing syndrome.
AB  - Cognitive theory ascribes nonendogenous depression to latent dysfunctional
      beliefs activated by stressors impinging upon core values (e.g., rejection for a
      sociotropic person). To address ambiguities in past tests of the theory, this
      study measured personality (Sociotropy-Autonomy Scale) and recent stressors (Life
      Experience Survey and Hassles Scale) among 14 Cushing syndrome patients and 12
      controls. Patients scored nonsignificantly higher in sociotropy, and sociotropy
      correlated positively with depression among patients. Because depression in
      Cushing syndrome presumably results from biological dysfunction rather than from
      the interaction of personality and relevant stressors, these results imply that
      sociotropy may be a consequence of depression as opposed to a contributory cause.
      There was no congruence between personality and types of stressors reported,
      which suggest that mood-dependent recall does not account for past evidence of
      congruence.

PMID- 8642387
TI  - Quality of life in peritoneal dialysis patients.
AB  - In 49 patients receiving continuous ambulatory peritoneal dialysis, we assessed
      the relative influences of adequacy of dialysis (assessed by kinetic
      transfer/volume urea) and psychological symptoms (depression and anxiety) upon
      the patients' evaluation of their overall quality of life (QoL). Subjects
      completed self-rating forms for anxiety, depressive, and somatic symptoms, for
      discrete areas relevant to QoL, and for overall QoL; clinicians also rated QoL.
      Depressive symptoms proved a much stronger correlate of overall QoL than did the
      biochemical measure of dialysis adequacy, and they remained influential even
      after adjustment for anxiety, kinetic transfer/volume, and somatic symptoms. In
      contrast, the effects of kinetic transfer/volume, anxiety symptoms, and somatic
      symptoms dropped sharply when adjusted for the other variables. Because
      psychological (especially depressive) symptoms may be stronger determinants of
      patients' overall QoL than is adequacy of dialysis, assessing QoL and
      psychological status should be part of the care of end-stage renal disease
      patients.

PMID- 8642388
TI  - The psychological legacy of war and atrocity: the question of long-term and
      transgenerational effects and the need for a broad view.

PMID- 8642389
TI  - Frustrated aggression in psychiatric casualties of Operation Uphold Democracy.

PMID- 8642390
TI  - Prevalence and diagnostic correlates of DSM-IV catatonic features among
      psychiatric inpatients.

PMID- 8642392
TI  - The stress of caring for disabling mental disorders in a home-based
      rehabilitation service.

PMID- 8642391
TI  - A pilot study of residential treatment for dual diagnoses.

PMID- 8642393
TI  - Two models for multiple sclerosis: experimental allergic encephalomyelitis and
      Theiler's murine encephalomyelitis virus.
AB  - In this review, we compare and contrast two popular models for multiple sclerosis
      (MS), Theiler's murine encephalomyelitis virus (TMEV) disease and experimental
      allergic encephalomyelitis (EAE). These models are used to investigate the viral
      and autoimmune etiology of MS, respectively. Infection with live TMEV is an
      essential component of TMEV demyelinating disease. TMEV-specific cellular and
      humoral immunity and apoptosis of infected cells eliminate virus from the gray
      matter of the central nervous system (CNS) during the acute phase of TMEV
      disease. In contrast, during the chronic phase, TMEV persistently infects glial
      cells and/or macrophages in the white matter. During the chronic phase,
      recruitment of macrophages, TMEV-specific T cells and antibody, with the
      induction of apoptosis are harmful to the host, leading to inflammation and
      demyelination. In EAE, induction of encephalitogenic CD4+ T cells is an important
      component for disease. After stimulation and activation, these T cells upregulate
      adhesion molecules and are able to enter the CNS. Th1 cytokines augment the
      recruitment of mononuclear cells in the CNS. Macrophages and/or glial cells
      secrete cytotoxic factors leading to demyelination in conjunction with B cells
      secreting anti-myelin antibody. Although immunopathological pathways during the
      course of the demyelination in TMEV infection and EAE are not always the same,
      oligodendroglial apoptosis is observed in both models, suggesting that their
      demyelinating processes share a common terminal pathway and finally lead to quite
      a similar clinical and pathological picture.

PMID- 8642395
TI  - The paralyse mouse mutant: a new animal model of anterior horn motor neuron
      degeneration.
AB  - The survival and morphometric characteristics of lumbar spinal motoneurons were
      examined in the paralyse mouse mutant. Affected (par/par) mice can be first
      recognized at approximately postnatal day (PN) 7 to 8 and are characterized by
      their smaller-than-normal body size, a progressive generalized muscle weakness,
      and lack of coordination. Mutant mice die by PN16-18, when they have become
      almost completely paralyzed. Previously, we have shown that this mutation
      involves alteration of several developmental aspects of the neuromuscular system.
      However, whether ventral (or anterior) horn motoneurons degenerate and die during
      the course of the disease was unknown. We report here that at the time the mutant
      phenotype can be first identified (i.e. approximately PN8), lumbar motoneuron
      numbers in the lateral motor column of the spinal cord of paralyse mice were not
      significantly different from those of control littermates. In contrast, by PN14,
      there was a significant (30 to 35%) decrease in motoneuron numbers in mutant
      compared to control mice. Furthermore, motoneuron (nuclear and soma) sizes were
      significantly decreased in the mutants at both stages examined, i.e. PN8 and
      PN14. These results show that the paralyse mutation involves atrophy and
      subsequent death of anterior horn motoneurons. Together with the rapid
      progression and the severity of the disease, these results suggest that the
      paralyse mouse may represent a good animal model for studying early-onset human
      motor neuron diseases such as spinal muscular atrophy.

PMID- 8642394
TI  - Myoblast transplantation in monkeys: control of immune response by FK506.
AB  - Myoblasts were grown from monkey muscle biopsies and infected in vitro with a
      defective retroviral vector containing a cytoplasmic beta-galactosidase (beta
      gal) gene. These myoblasts were then transplanted to 14 different monkeys, 6 of
      which were immunosuppressed with FK506. Without immunosuppression, only a few
      myoblasts and myotubes expressing beta-gal were observed 1 week after the
      transplantation, but no cells expressing beta-gal were observed after 4 weeks.
      This result was attributed to immune responses since infiltration by CD4+ or CD8+
      lymphocytes was abundant 1 week after transplantation but not after 4 weeks. The
      expression of interleukin 6 (IL-6), interleukin 2 (IL-2), granulocyte/macrophage
      colony stimulating factor (GM-CSF), transforming growth factor-beta (TGF-beta)
      and granzyme B mRNAs was increased in the myoblast-injected muscle indicating
      that the infiltrating lymphocytes were activated. Moreover, antibodies against
      the donor myoblasts were detected in 3 out of 6 cases. When the monkeys were
      immunosuppressed with FK506, muscle fibers expressing beta-galactosidase (beta
      gal) were present 1, 4 and 12 weeks after the transplantation. There was neither
      significant infiltration by CD4 or CD8 lymphocytes, nor antibodies detected. The
      mRNA expression of most cytokines was significantly reduced as compared to the
      nonimmunosuppressed monkeys. These results indicate that FK506 is effective in
      controlling short-term immune reactions following myoblast transplantation in
      monkeys and suggest that it may prove useful for myoblast transplantation in
      Duchenne Muscular Dystrophy patients.

PMID- 8642396
TI  - Colocalization of lysosomal hydrolase and beta-amyloid in diffuse plaques of the
      cerebellum and striatum in Alzheimer's disease and Down's syndrome.
AB  - The lysosomal hydrolases, cathepsin D (Cat D) and beta-hexosaminidase A (HEX),
      which are normally intracellular enzymes, colocalize with beta-amyloid in a
      subgroup of diffuse plaques in the cerebellum and striatum of individuals with
      Alzheimer's disease or Down's syndrome. Using specific antisera in combination
      with single- and double-label immunocytochemical techniques, extracellular
      hydrolase was detected in 30 to 40% of the diffuse plaques in the cerebellar
      molecular layer and nearly all of the diffuse plaques in the striatum. In both
      Alzheimer's disease and Down's syndrome, about 5 to 10% of the cerebellar
      Purkinje cells contained abnormally increased numbers of hydrolase-positive
      lysosomes despite their normal appearance by conventional histologic stains.
      Occasional atrophic Purkinje cells identified by Nissl stain were intensely
      immunostained. By confocal imaging analysis, abnormal hydrolase-laden Purkinje
      cell dendrites were seen coursing through some hydrolase-positive plaques and
      were continuous with dendritic branches that terminated within deposits of
      extracellular hydrolase and beta-amyloid. In the striatum, intensely
      immunostained abnormal-appearing neurons were commonly associated with
      extracellular deposits of hydrolase immunoreactivity and beta-amyloid within
      diffuse plaques and in the less commonly seen classical plaques. In both brain
      regions, other hydrolase-negative beta-amyloid deposits were seen, these being
      associated with blood vessels. The presence of HEX immunoreactivity in neurons,
      but not in glia, and its abundance in plaques support earlier studies, suggesting
      that neurons are the principal source of plaque hydrolase. An endosomal-lysosomal
      system upregulation, with increased hydrolase expression and extracellular enzyme
      deposition in plaques, is, like beta-amyloid deposition, an early marker of
      metabolic dysfunction potentially related to primary etiologic events in
      Alzheimer's disease and Down's syndrome.

PMID- 8642397
TI  - A monoclonal antibody that specifically recognizes a novel mitochondrial protein
      of human astrocytes.
AB  - We established a monoclonal antibody to human astrocytes using a human glial cell
      rich fraction as the immunogen. The antibody, named PRAS-4, specifically labeled
      populations of astrocytes in a fine granular manner immunohistochemically. In
      formalin-fixed, paraffin-embedded tissue sections, PRAS-4-positive astrocytes
      were extensively distributed in the gray matter of the central nervous system,
      namely the cerebral cortex, basal ganglia, diencephalon, midbrain, various nuclei
      of the brain stem, cerebellar cortex and nuclei, and spinal cord. In the white
      matter, a few positive astrocytes were located mostly in the perivascular area.
      The reaction was lost after protease digestion and it resisted periodic acid,
      suggesting that the epitope is of a protein. The molecular weight of the antigen
      was estimated as 62 kDa. Ultrastructurally, the immunoreaction was localized on
      the outer and inner membranes of astrocytic mitochondria, and unlabeled
      mitochondria coexisted in the same cells. Extra-mitochondrial regions were not
      stained. PRAS-4 preferentially labeled astrocytes of the protoplasmic type, and
      may be applicable to studies on the development, specific functions and neoplasms
      of astrocytes.

PMID- 8642398
TI  - Anti-inflammatory treatment influences neuronal apoptotic cell death in the
      dentate gyrus in experimental pneumococcal meningitis.
AB  - Apoptotic neuronal death and the increase of neuron-specific enolase (NSE) in
      cerebrospinal fluid (CSF) were studied in a rabbit model of experimental
      pneumococcal meningitis after treatment with antimicrobial (ceftriaxone) and
      antiinflammatory agents (dexamethasone, monoclonal antibodies against the beta
      subunit of beta 2-integrins [anti-CD18 mAb]). Twenty-four hours after infection,
      apoptotic cell death was found solely in the granular cell layer of the dentate
      gyrus. Neurons with DNA fragmentation were quantified with the in situ tailing
      (IST) reaction. Dexamethasone and anti-CD18 mAb inhibited the NSE increase in CSF
      significantly (p = 0.003, p = 0.011). After administration of dexamethasone the
      density of apoptotic neurons was significantly higher than in control animals
      receiving only ceftriaxone (p = 0.044). The median of the density of apoptotic
      neurons was lower in the dentate gyrus in animals receiving anti-CD18 mAb and
      ceftriaxone vs those receiving only ceftriaxone, although the difference did not
      reach statistic significance (p = 0.058). In conclusion, apoptotic cell death
      occurs in the dentate gyrus during the early phase of bacterial meningitis. The
      extent was influenced by antiinflammatory therapy. The systemic administration of
      glucocorticoids increased the quantity of apoptotic neurons in the dentate gyrus
      but reduced overall neuronal damage as indicated by low levels of NSE
      concentration in CSF.

PMID- 8642399
TI  - DNA amplification in glial cells of progressive multifocal leukoencephalopathy:
      an image analysis study.
AB  - JC virus (JCV), the agent of progressive multifocal leukoencephalopathy (PML),
      has been shown by both immunohistochemistry and flow cytometry to be associated
      with p53 protein stabilization. Since stabilization/inactivation of p53 is
      associated with the development of genomic instability, abnormal cell DNA
      contents are to be expected in JCV-infected cells of PML. This work explores that
      possibility by image analysis evaluation of DNA content in PML-infected
      oligodendrocytes and bizarre astrocytes. Brain paraffin sections of PML lesions
      from five adult male patients with the acquired immune deficiency syndrome (AIDS)
      were treated with the Feulgen technique to obtain a stochiometric staining of DNA
      and analyzed with a microscope image processor. Inclusion-bearing
      oligodendrocytes exhibited near tetraploid DNA indices in each of the five cases,
      whereas atypical astrocytes were in the hypertetraploid range in all cases and
      were polyploid in four instances. This evidence of DNA amplification in PML glial
      cells is congruent with the functional abolition of p53 protein in association
      with JCV infection and lends further support to the role of p53 as a keeper of
      diploid status and guardian of genomic stability.

PMID- 8642400
TI  - Temporal and spatial expression of major myelin proteins in the human fetal
      spinal cord during the second trimester.
AB  - Immunohistochemical identification of myelin basic protein (MBP) is a sensitive
      method for assessing myelination in the human fetal central nervous system (CNS).
      However, the temporospatial relationship of expression of two other major myelin
      proteins, proteolipid protein (PLP) and myelin-associated glycoprotein (MAG) to
      that of MBP during fetal development has not been assessed in human tissues.
      Vibratome sections of cervical, thoracic and lumbosacral levels from 37 normal
      spinal cords of < or = 10 to 24 gestational week (GW) fetuses were analyzed using
      immunohistochemical methods. Using light microscopy, MBP was the first
      oligodendrocyte marker detected, present by 10 GW at more rostral levels. PLP and
      MAG were detected rostrally between 12 to 14 GW. All myelin proteins were
      expressed in anterior to posterior and rostral to caudal gradients. By the late
      second trimester, expression of MBP, PLP and MAG was noted in all locations in
      the spinal white matter except for the corticospinal tract. Expression of MAG was
      particularly marked in the posterior root entry zone and propriospinal tracts.
      The results suggest that PLP and MAG are expressed later than MBP but follow
      similar spatial gradients.

PMID- 8642401
TI  - Multiple structural elements determine subunit specificity of Mg2+ block in NMDA
      receptor channels.
AB  - In NMDA receptor channels, subtype-specific differences of Mg2+ block are
      determined by the NR2 subunits. Channels assembled from the NR1-NR2A or NR1-NR2B
      subunits are blocked more strongly than channels formed by the NR1-NR2C or NR1
      NR2D subunits, predominantly reflecting a difference in voltage dependence. A
      determinant of Mg2+ block common to the NR2 subunits is located in the M2 domain
      (N-site or Q/R/N-site). However, subunit-specific differences of block suggested
      that additional structural elements exist. Chimeric NR2 subunits were constructed
      by replacing segments of the least sensitive NR2C subunit with homologous
      segments of the most sensitive NR2B subunit. Mutant NR2 subunits were coexpressed
      with wild-type NR1 in Xenopus oocytes, and Mg2+ block was quantified. Replacement
      of the entire M1-M4 region resulted in a chimera with a sensitivity of Mg2+ block
      similar to that of the NR2B wild type. Replacing smaller segments or introducing
      point mutations did not generate channels with Mg2+ block characteristic of NR2B
      wild type. However, combining in a single chimera three small segments (M1, M2-M3
      linker, M4), each independently mediating an increase in Mg2+ block, produced
      channels close to NR2B wild type. Thus, differences in Mg2+ block as controlled
      by the NR2 subunits cannot be explained by a single structural determinant in
      addition to the N-site. Moreover, three elements of the NR2 subunit are the major
      determinants of subtype-specific differences of Mg2+ block in heteromeric NMDA
      receptor channels.

PMID- 8642402
TI  - IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially
      expressed in the adult rat brain.
AB  - Molecular cloning together with functional characterization has shown that the
      newly identified family of inwardly rectifying K+ channels consists of several
      closely related members encoded by separate genes. In this report we demonstrate
      the differential mRNA expression and detailed cellular localization in the adult
      rat brain of seven members of the IRK and GIRK subfamilies. Using both
      radiolabeled cRNA riboprobes and specific oligonucleotide probes directed to
      nonconserved regions of both known and newly isolated rat brain cDNAs, in situ
      hybridization revealed wide distribution with partly overlapping expression of
      the mRNAs of IRK1-3 and GIRK1-4. Except for the low levels of GIRK4 transcripts
      observed, the overall distribution patterns of the other GIRK subunits were
      rather similar, with high levels of expression in the olfactory bulb,
      hippocampus, cortex, thalamus, and cerebellum. Marked differences in expression
      levels existed only in some thalamic, brainstem, and midbrain nuclei, e.g., the
      substantial nigra, superior colliculus, or inferior olive. In contrast, IRK
      subunits were expressed more differentially: all mRNAs were abundant in dentate
      gyrus, olfactory bulb, caudate putamen, and piriform cortex. IRK1 and IRK3 were
      restricted to these regions, but they were absent from most parts of the
      thalamus, cerebellum, and brainstem, where IRK2 was expressed predominantly.
      Because channel subunits may assemble as heteromultimers, additional functional
      characterization based on overlapping expression patterns may help to decipher
      the native K+ channels in neurons and glial cells.

PMID- 8642403
TI  - Nucleus-specific expression of GABA(A) receptor subunit mRNAs in monkey thalamus.
AB  - Expression of 10 GABAA receptor subunit genes was examined in monkey thalamus by
      in situ hybridization using cRNA probes specific for alpha 1, alpha 2, alpha 3,
      alpha 4, alpha 5, beta 1, beta 2, beta 3, gamma 1, and gamma 2 subunit mRNAs.
      These displayed unique hybridization on patterns with significant differences
      from rodents. Alpha 1, beta 2, and gamma 2 transcripts were expressed at high
      levels in all dorsal thalamic nuclei, but expression was significantly higher in
      sensory relay nuclei-especially the dorsal lateral geniculate nucleus. Other
      transcripts showed nucleus-specific differences in levels of expression and in
      the range expressed. Alpha 5 and alpha 4 subunit transcripts were expressed in
      all nuclei except the intralaminar nuclei. Levels of alpha 2, alpha 3, beta 1,
      beta 3, and gamma 1 expression were very low, except in intralaminar nuclei. In
      the reticular nucleus, most subunit transcripts were not expressed, and only
      gamma 2 transcripts were consistently detected at modest levels. Thalamic GABAA
      receptors may be assembled from nucleus-specific groupings of subunit
      polypeptides.

PMID- 8642404
TI  - Predominant expression of platelet-activating factor receptor in the rat brain
      microglia.
AB  - Cellular localization of platelet-activating factor (PAF) receptor in the rat
      brain was determined by (1) in situ hybridization, (2) Northern blot analysis in
      primary cell cultures of neurons, microglia, astrocytes, and fibroblasts, and (3)
      Ca2+ imaging in hippocampal culture. In situ hybridization revealed that the PAF
      receptor mRNA is expressed intensely in microglia and moderately in neurons.
      Northern blot analysis revealed that PAF receptor mRNA is the most abundant in
      microglia. In primary hippocampal cultures, PAF elevated intracellular Ca2+
      concentration in microglia and also in neurons, but to a lesser extent. These
      results suggest predominant presence of PAF receptor in microglia. Cultured
      microglia also expressed cPLA2 mRNA the most intensely. PAF-activated microglia
      released arachidonic acid in a Ca(2+)-dependent manner and without conversion to
      its derivatives. We propose that microglia as well as neurons contribute to PAF
      related events in the CNS by releasing arachidonic acid.

PMID- 8642405
TI  - Tau is enriched on dynamic microtubules in the distal region of growing axons.
AB  - It is widely held that tau determines the stability of microtubules in growing
      axons, although direct evidence supporting this hypothesis is lacking. Previous
      studies have shown that the microtubule polymer in the distal axon and growth
      cone is the most dynamic of growing axons; it turns over more rapidly and is more
      sensitive to microtubule depolymerizing drugs than the polymer situated
      proximally. We reasoned that if the stability of axonal microtubules is directly
      related to their content of tau, then the polymer in the distal axon should have
      less tau than the polymer in the proximal axon. We tested this proposition by
      measuring the relative tau content of microtubule along growing axons of cultured
      sympathetic neurons immunostained for tau and tubulin. Our results show that the
      tau content of microtubules varies along the axon, but in the opposite way
      predicted. Specifically, the relative tau content of microtubules increases
      progressively along the axon to reach a peak near the growth cone that is
      severalfold greater than that observed proximally. Thus, tau is most enriched on
      the most dynamic polymer of the axon. We also show that the gradient in tau
      content of microtubules does not generate corresponding gradients in the extent
      of tubulin assembly or in the sensitivity of axonal microtubules to nocodazole.
      On the basis of these findings, we propose that tau in growing axons has
      functions other than promoting microtubule assembly and stability and the key
      sites for these functions are the distal axon and growth cone.

PMID- 8642407
TI  - Developmental changes of inhibitory synaptic currents in cerebellar granule
      neurons: role of GABA(A) receptor alpha 6 subunit.
AB  - Eye opening and increased motor activity after the second postnatal week in rats
      imply an extensive development of motor control and coordination. We show a
      parallel development change in spontaneous IPSC (sIPSC) kinetics in cerebellar
      granule neurons. sIPSCs were studied by whole-cell recordings in cerebellar
      slices, prepared from 7-30 postnatal day old rats. Early in development, sIPSCs
      had slow decay kinetics whereas in older rats faster decaying sIPSCs were found
      in larger proportion. Currents elicited by 1 mM GABA pulses (GABACs) in nucleated
      patches excised from cerebellar granule neurons revealed that GABACs kinetics
      better approximate sIPSC decay in young but not in more developed rats. The
      expression of alpha 6 subunit of GABAA receptors, unique in cerebellar granule
      neurons, has been shown to increase during development. Therefore, we took
      advantage of the recently reported selective inhibition of GABAA receptors by
      furosemide to characterize the relative contribution of alpha 6 subunits to
      native receptors in inhibitory synapses of cerebellar granule neurons. Although
      furosemide inhibition of sIPSCs amplitude was highly variable among distinct
      granule cells, it increased during development. At the same time, furosemide
      failed to inhibit sIPSCs recorded from Purkinje neurons. From the comparison of
      furosemide inhibition and kinetics of sIPSCs with GABACs recorded from mammalian
      HEK293 cells transfected with combinations of alpha 1 and alpha 6 GABAA receptor
      subunits together with beta 2 gamma 2 subunits, we propose that an increased
      alpha 6 subunit contribution in the molecular assembly of postsynaptic receptors
      in cerebellar glomeruli is responsible for the developmental changes observed.

PMID- 8642406
TI  - 17 beta-Estradiol potentiates kainate-induced currents via activation of the cAMP
      cascade.
AB  - Evidence for nongenomic actions of steroids is now coming from a variety of
      fields of steroid research. Mechanisms of steroid action are being studied with
      regard to the membrane receptors and the activation of second messengers. The
      present study investigated the mechanism for the rapid effect of estrogen on
      acutely dissociated hippocampal CA1 neurons by using the whole-cell, voltage
      clamp recording. Under the perforated patch configuration, 17 beta-estradiol
      potentiated kainate-induced currents in 38% of tested neurons. The potentiation
      was stereospecific, rapid in onset, and reversible after the removal of the
      steroid. Dose-response curves show that the potentiation by 17 beta-estradiol was
      evident at a concentration as low as 10 nM and saturated at 10 microM. 17 beta
      Estradiol did not affect the kinetics (i.e., affinity and cooperativity) and
      reversal potential of kainate-induced currents. This suggests that the
      potentiation did not result from direct interaction with kainate receptors nor
      the activation of ion channels other than kainate receptor-channels. The
      potentiation by 17 beta-estradiol was similar to the enhancement of kainate
      induced currents evoked by 8-bromo-cAMP, and was modulated by an inhibitor of
      phosphodiesterase (IBMX). The estrogen potentiation was blocked by a specific
      blocker of PKA (Rp-cAMPS). Under standard recording configuration, the effect was
      significantly affected by intracellular perfusing with GDP-beta-S or GTP-gamma-S.
      The data suggest that the potentiation of kainate-induced currents by 17-beta
      estradiol was likely a G-protein(s) coupled, cAMP-dependent phosphorylation
      event. By involvement of this non-genomic mechanism, estrogen may play a role in
      the modulation of excitatory synaptic transmission in the hippocampus.

PMID- 8642409
TI  - Actions of endogenous opioids on NMDA receptor-independent long-term potentiation
      in area CA3 of the hippocampus.
AB  - The opioid peptides represent a major class of neurotransmitter in the vertebrate
      nervous system and are prevalent in the hippocampus. There is considerable
      interest in the physiological function of the opioids contained in the mossy
      fiber pathway. The release of opioids from mossy fibers shows a strong frequency
      dependence. Long-term potentiation (LTP) at this synapse, an NMDA receptor
      independent form of LTP, also depends on high-frequency synaptic activity, and
      this has led to speculation that endogenous opioids may be a critical factor in
      LTP induction. Previous reports using extracellular recordings have provided
      evidence for and against a role for opioids in mossy fiber LTP. Using single-cell
      recording techniques, we have tested the hypothesis that endogenous opioids are
      required for mossy fiber LTP induction. We recorded from a defined population of
      synapses that had EPSCs with fast rise times, short latencies, and monophasic
      decays, consistent with a proximally terminating synapse. The opioid antagonist
      naloxone prevented mossy fiber LTP in the rat, but had no effect on the
      commissural/associational system, a nonopioid-containing pathway. The action of
      naloxone was not mediated through disinhibition because GABAA receptors were
      pharmacologically blocked in these experiments. We also tested the hypothesis
      that variations in postsynaptic receptor subtype distribution between species
      might explain previous controversies regarding the role of endogenous opioids. In
      contrast to the rat, LTP of the mossy fiber field potential in guinea pig was not
      blocked by naloxone. Our data suggest that opioids may be the presynaptically
      released, frequency-dependent, associative factor for mossy fiber LTP induction.

PMID- 8642408
TI  - Identification and characterization of a 47 base pair activity-dependent enhancer
      of the rat nicotinic acetylcholine receptor delta-subunit promoter.
AB  - Nicotinic acetylcholine receptor (nAChR) genes are regulated by muscle electrical
      activity. E-box sequences found in their promoters are necessary for this
      regulation. However, many muscle genes contain E-boxes, yet are not regulated by
      muscle depolarization. This suggests that other elements are necessary, perhaps
      working in conjunction with E-boxes, to confer depolarization-dependent control
      onto promoter activity. We have used direct DNA injection into muscle as an in
      vivo assay to identify and characterize these additional elements. Mutagenesis
      and expression assays identified multiple elements within the first 81 base pairs
      (bp) of the nAChR delta-subunit promoter that contribute to its regulation by
      muscle electrical activity. Within this 81 bp sequence, two regions of DNA were
      identified that were capable of conferring activity-dependent regulation onto a
      heterologous promoter. The stronger of these two putative enhancers was
      characterized further. It is a 47 bp sequence that contains an E-box along with
      sequences similar to the SV40 core enhancer and an SP1 site. Site-directed
      mutagenesis identified residues within each of these sequences that were
      necessary for enhancer activity. Furthermore, methylation interference DNA
      footprinting assays showed increased nuclear protein binding to sequences within
      both these enhancers after muscle denervation, and this pattern of binding was
      very similar to that observed with nuclear protein isolated from myotube
      extracts. These latter results suggest that similar mechanisms may mediate
      increased nAChR expression during muscle development and after muscle
      denervation.

PMID- 8642410
TI  - Identification and characterization of a Ca(2+)-sensitive nonspecific cation
      channel underlying prolonged repetitive firing in Aplysia neurons.
AB  - The afterdischarge of Aplysia bag cell neurons has served as a model system for
      the study of phosphorylation-mediated changes in neuronal excitability. The
      nature of the depolarization generating the afterdischarge, however, has remained
      unclear. We now have found that venom from Conus textile triggers a similar
      prolonged discharge, and we have identified a slow inward current and
      corresponding channel, the activation of which seems to contribute to the onset
      of the discharge. The slow inward current is voltage-dependent and Ca(2+)
      sensitive, reverses at potentials slightly positive to O mV, exhibits a
      selectivity of K approximately equal to Na >> Tris > N-methyl-D-glucamine (NMDG),
      and is blocked by high concentrations of tetrodotoxin. Comparison of these
      features with those observed in channel recordings provides evidence that a
      Ca(2+)-sensitive, nonspecific cation channel is responsible for a slow inward
      current that regulates spontaneous repetitive firing and suggests that modulation
      of the cation channel underlies prolonged changes in neuronal response
      properties.

PMID- 8642411
TI  - Activation of delta-opioid receptors inhibits neuronal-like calcium channels and
      distal steps of Ca(2+)-dependent secretion in human small-cell lung carcinoma
      cells.
AB  - Human small-cell lung carcinoma (SCLC) cells express neuronal-like voltage
      operated calcium channels (VOCCs) and release mitogenic hormones such as
      serotonin (5-HT). Opioid peptides, on the other hand, have been shown to reduce
      SCLC cell proliferation by an effective autocrine pathway. Here we show that in
      GLC8 SCLC cells, only delta-opioid receptor subtype mRNA is expressed.
      Consistently, the selective delta-opioid agonist [D-Pen2-Pen5]-enkephalin
      (DPDPE), but not mu and kappa agonists, potently and dose-dependently inhibits
      high-threshold (HVA) VOCCs in these cells. As in peripheral neurons, this
      modulation is largely voltage-dependent, mediated by pertussis toxin (PTX)
      sensitive G-proteins, cAMP-independent, and mainly affecting N-type VOCCs. With
      the same potency and selectivity, DPDPE also antagonizes the Ca(2+)-dependent
      release of [3H]serotonin ([3H]5-HT) from GLC8 cells. However, DPDPE inhibits not
      only the depolarization-induced release, but also the Ca(2+)-dependent secretion
      induced by thapsigargin or ionomycin. This suggests that besides inhibiting HVA
      VOCCs, opioids also exert a direct depressive action on the secretory apparatus
      in GLC8 cells. This latter effect also is mediated by a PTX-sensitive G-protein
      but, contrary to VOCC inhibition, it can be reversed by elevations of cAMP
      levels. These results show for the first time that opioids effectively depress
      both Ca2+ influx and Ca(2+)-dependent hormone release in SCLC cells by using
      multiple modulatory pathways. It can be speculated that the two mechanisms may
      contribute to the opioid antimitogenic action on lung neuroendocrine carcinoma
      cells.

PMID- 8642412
TI  - A novel type of programmed neuronal death in the cervical spinal cord of the
      chick embryo.
AB  - We examined the massive early cell death that occurs in the ventral horn of the
      cervical spinal cord of the chick embryo between embryonic days 4 and 5 (E4 and
      E5). Studies with immunohistochemical, in situ hybridization, and retrograde
      tracing methods revealed that many dying cells express Islet proteins and Lim-3
      mRNA (motoneuron markers) and send their axons to the somatic region of the
      embryo before cell death. Together, these data strongly suggest that the dying
      cells are somatic motoneurons. Cervical motoneurons die by apoptosis and can be
      rescued by treatment with cycloheximide and actinomycin D. Counts by motoneuron
      numbers between E3.5 and E10 revealed that, in addition to cell death between E4
      and E5, motoneuron death also occur between E6 and E10 in the cervical cord.
      Studies with [3H]thymidine autoradiography and morphological techniques revealed
      that in the early cell-death phase (E4-E5), genesis of motoneurons, axonal
      elongation, and innervation of muscles is still ongoing. However, studies with
      [3H]thymidine autoradiography also revealed that the cells dying between E4 and
      E5 become postmitotic before E3.5. Increased size of peripheral targets,
      treatment with neuromuscular blockade, and treatment with partially purified
      muscle or brain extracts and defined neurotropic agents, such as NGF, BDNF,
      neurotrophin-3, CNTF, bFGF, PDGF, S100-beta, activin, cholinergic differentiation
      factor/leukemia inhibitory factor, bone morphogenetic protein-2, IGF-I,
      interleukin-6, and TGF-beta 1, were all ineffective in rescuing motoneurons dying
      between E4 and E5. By contrast, motoneurons that undergo programmed cell death at
      later stages (E6-E10) in the cervical cord are target-dependent and respond to
      activity blockade and trophic factors. Experimental approaches revealed that
      early cell death also occurs in a notochord-induced ectopic supernumerary
      motoneuron column in the cervical cord. Transplantation of the cervical neural
      tube to other segmental regions failed to alter the early death of motoneurons,
      whereas transplantation of other segments to the cervical region failed to induce
      early motoneuron death. These results suggest that the mechanisms that regulate
      motoneuron death in the cervical spinal cord between E4 and E5 are independent of
      interactions with targets. Rather, this novel type of cell death seems to be
      determined by signals that either are cell-autonomous or are derived from other
      cells within the cervical neural tube.

PMID- 8642414
TI  - Functional anatomy of a prelearned sequence of horizontal saccades in humans.
AB  - We have used positron emission tomography (PET) to study the functional anatomy
      of the repetition of a prelearned sequence of horizontal saccadic eye movements.
      Five subjects had to memorize a sequence of six successive horizontal saccades.
      The subjects were scanned in total darkness under three different conditions: at
      rest, during the execution of self-paced horizontal saccades, and while repeating
      a prelearned saccades sequence. The repetition of the prelearned saccades
      sequence led to specific normalized regional cerebral blood flow (NrCBF)
      increases at the depth of the superior frontal sulcus as well as at the rostral
      part of the supplementary motor area, whereas at the parietal level an important
      activation was observed in the intraparietal sulcus extending up to the
      precuneus. In addition, it was noticed that compared with the resting control
      condition, both oculomotor tasks activated a common set of cortical and
      subcortical areas. At the cortical level, this network was composed of the
      frontal eye fields, the supplementary eye fields, the median part of the
      cingulate gyrus, and the insula. At the subcortical level, the lenticular nucleus
      and the thalamus as well as the cerebellar vermis were activated consistently. A
      direct comparison of our results with those of other PET studies on spatial
      vision suggest that the dorsal visuospatial pathway could be extended toward the
      frontal premotor region. In such a scheme, visuospatial information computed in
      the intraparietal sulcus would be transmitted to the frontal premotor cortex to
      optimize a spatial-oriented behavior. This is consistent with the early proposal
      that perceptual and intentional components of spatial information are mediated
      through superior parietal and frontal areas, respectively.

PMID- 8642413
TI  - Inhibition of the NT-3 receptor TrkC, early in chick embryogenesis, results in
      severe reductions in multiple neuronal subpopulations in the dorsal root ganglia.
AB  - To assess functions of neurotrophins at defined times in development, we have
      prepared antibodies of the extracellular domains of each of the trk receptors.
      Here, antibodies to trkC, the major receptor for NT-3, are used to examine trkC
      expression and function during the formation and maturation of the chick dorsal
      root ganglion (DRG). Our results show that in the immature DRG, the majority of
      cells express trkC, and inhibition of trkC activation results in reductions in
      neuronal numbers before the period of target-mediated cell death, the time when
      neurotrophins previously have been shown to regulate survival. Furthermore,
      blockade of trkC in ovo induced reductions in subpopulations of DRG neurons known
      to be dependent on NGF, in addition to those dependent on NT-3 during the target
      regulated cell death period. An early function for NT-3 on immature DRG neurons
      is supported further by data presented here that demonstrate that whereas BDNF
      and NGF can support a subset of immature DRG neurons in vitro, activation of the
      trkC receptor either by NT-3 binding or via antibody-mediated cross-linking
      induces the most robust survival response. When all three neurotrophins are
      combined, the number of surviving neurons does not exceed that supported by NT-3
      alone. Together, these data are consistent with coexpression of more than one trk
      receptor family member on immature sensory neurons, and they demonstrate that
      inhibition of trkC activation has surprisingly early and pleiotrophic effects on
      the development of spinal sensory ganglia.

PMID- 8642415
TI  - Dopamine receptor agonists regulate levels of the serotonin 5-HT2A receptor and
      its mRNA in a subpopulation of rat striatal neurons.
AB  - The effects of dopamine receptor agonists on the levels of the striatal serotonin
      5-HT2A receptor and its mRNA were investigated in rats lesioned with 6-OHDA as
      neonates. The mRNA encoding for the 5-HT2A receptor was detected by in situ
      hybridization histochemistry and the binding of 5-HT2A receptors was revealed
      with [125I](2,5-dimethoxy-4-iodophenyl)2-aminopropane ([125I]DOI). In adult
      control unlesioned rats, labeling with the 5-HT2A cRNA probe and with [125I]DOI
      was concentrated in medial sectors of the striatum. In 6-OHDA-lesioned rats,
      labeling with the 5-HT2A cRNA probe or with [125I]DOI was increased in the
      striatum, particularly in its lateral subdivisions. These increases were
      abolished after chronic systemic administration of the dopamine receptor agonists
      apomorphine or SKF-38393. The mRNA levels encoding for the 5-HT2A receptor were
      further measured in individual striatal neurons after double-labeling of sections
      with a 5-HT2A and a preproenkephalin (PPE) cRNA probe. In control unlesioned
      rats, 5-HT2A mRNA labeling was distributed in PPE-labeled as well as in PPE
      unlabeled striatal neurons. In 6-OHDA-lesioned rats, increased 5-HT2A mRNA
      labeling was found only in PPE-unlabeled neurons and it was abolished after
      apomorphine or SKF-38393 administration. These results demonstrate that agonists
      of dopamine receptors inhibit the expression of 5-HT2A receptors in a
      subpopulation of presumed striato-nigral neurons. We propose that this regulation
      plays an important role in the control of motor activity by dopamine and 5-HT in
      the basal ganglia.

PMID- 8642416
TI  - Specific involvement of human parietal systems and the amygdala in the perception
      of biological motion.
AB  - To explore the extent to which functional systems within the human posterior
      parietal cortex and the superior temporal sulcus are involved in the perception
      of action, we measured cerebral metabolic activity in human subjects by positron
      emission tomography during the perception of simulations of biological motion
      with point-light displays. The experimental design involved comparisons of
      activity during the perception of goal-directed hand action, whole body motion,
      object motion, and random motion. The results demonstrated that the perception of
      scripts of goal-directed hand action implicates the cortex in the intraparietal
      sulcus and the caudal part of the superior temporal sulcus, both in the left
      hemisphere. By contrast, the rostrocaudal part of the right superior temporal
      sulcus and adjacent temporal cortex, and limbic structures such as the amygdala,
      are involved in the perception of signs conveyed by expressive body movements.

PMID- 8642418
TI  - Network analysis of positron emission tomography regional cerebral blood flow
      data: ensemble inhibition during episodic memory retrieval.
AB  - Two important objectives in the neuroscience of memory are (1) identification of
      neural pathways involved in memory processes; and (2) characterization of the
      pattern of interactions between these pathways. Functional neuroimaging can
      contribute to both of these goals. Using image subtraction analysis of regional
      cerebral blood flow data measured with positron emission tomography, we
      identified brain regions that changed activity during episodic memory retrieval
      (visual work recognition). Relative to a baseline reading task, decreased
      activity was observed in bilateral prefrontal, bilateral anterior and posterior
      temporal, and posterior cingulate cortices. Brain regions showing increased
      activity were the right prefrontal (different from deactivated regions), left
      anterior cingulate, and left occipital cortices, and vermis of cerebellum. We
      then performed a network analysis with structural equation modeling to test the
      hypothesis that regional decreases came about through active inhibition by
      regions showing increased activity during retrieval. This analysis demonstrated
      that the influence of activated regions on deactivated regions was more negative
      during retrieval than during reading, confirming the inhibition hypothesis. Such
      confirmation could not have been made from the subtraction analysis alone because
      decreases can come about, at the very least, through reduction of functional
      influences as well as by active inhibition. The concepts of ensemble excitation
      and inhibition, as defined through network analysis, are introduced. We argue
      that is is critical to examine the combined pattern of excitatory and inhibitory
      influences to fully appreciate the neural basis of episodic memory.

PMID- 8642417
TI  - Endogenous substance P mediates cold water stress-induced increase in interleukin
      6 secretion from peritoneal macrophages.
AB  - Previous studies from this laboratory had shown that exposure of mice to cold
      water stress leads to an increase in the secretion of interleukin-1 (IL-1) and
      tumor necrosis factor-alpha (TNF alpha) from their peritoneal macrophages. We now
      report that the secretion of IL-6 from peritoneal macrophages is also increased
      after cold water stress and that the peptide substance P (SP) participates in
      this stress-induced response. The stress paradigm involved subjecting male
      C57BL/6J mice to 5 min swim tests in 10 +/- 2 degrees C water twice daily for 4
      d. Cold water stress augments the lipopolysaccharide-induced IL-6 secretion from
      peritoneal macrophages, elevates immunoreactive SP (iSP) in the peritoneal wash
      fluid, and reduces iSP in certain peritoneum-containing tissues or organs (i.e.,
      diaphragm, abdominal wall, ileum, and rectum). The 10 d stress time studies
      indicate that increased IL-6 secretion is positively related to elevated iSP in
      the peritoneal wash fluid and inversely related to reduced iSP in certain
      peritoneum-containing tissues. Pretreatment with capsaicin, which depletes SP in
      the sensory nerve endings, eliminates stress-control differences in the
      peritoneal wash fluid and in certain peritoneal tissues. Moreover, RP67,580, a
      specific SP antagonist, eliminates the cold water stress-induced augmentation of
      IL-6 secretion from peritoneal macrophages. These results suggest that cold water
      stress promotes the release of SP from peritoneal tissues into the peritoneal
      cavity, where it participates in the cold water stress-induced macrophage
      functional alterations.

PMID- 8642419
TI  - Metabotropic glutamate receptor activation in cerebellar Purkinje cells as
      substrate for adaptive timing of the classically conditioned eye-blink response.
AB  - To understand how the cerebellum adaptively times the classically conditioned
      nictitating membrane response (NMR), a model of the metabotropic glutamate
      receptor (mGluR) second messenger system in cerebellar Purkinje cells is
      constructed. In the model, slow responses, generated postsynaptically by mGluR
      mediated phosphoinositide hydrolysis and calcium release from intracellular
      stores, bridge the interstimulus interval (ISI) between the onset of parallel
      fiber activity associated with the conditioned stimulus (CS) and climbing fiber
      activity associated with unconditioned stimulus (US) onset. Temporal correlation
      of metabotropic responses and climbing fiber signals produces persistent
      phosphorylation of both AMPA receptors and Ca(2+)-dependent K+ channels. This is
      responsible for long-term depression (LTD) of AMPA receptors. The phosphorylation
      of Ca(2+)-dependent K+ channels leads to a reduction in baseline membrane
      potential and a reduction of Purkinje cell population firing during the CS-US
      interval. The Purkinje cell firing decrease disinhibits cerebellar nuclear cells,
      which then produce an excitatory response corresponding to the learned movement.
      Purkinje cell learning times the response, whereas nuclear cell learning can
      calibrate it. The model reproduces key features of the conditioned rabbit NMR:
      Purkinje cell population response is timed properly; delay conditioning occurs
      for ISIs of up to 4 sec, whereas trace conditioning occurs only at shorter ISIs;
      mixed training at two different ISIs produces a double-peaked response; and ISIs
      of 200-400 msec produce maximal responding. Biochemical similarities between
      timed cerebellar learning and photoreceptor transduction, and circuit
      similarities between the timed cerebellar circuit and a timed dentate-CA3
      hippocampal circuit, are noted.

PMID- 8642420
TI  - A primary acoustic startle pathway: obligatory role of cochlear root neurons and
      the nucleus reticularis pontis caudalis.
AB  - Davis et al. (1982) proposed a primary acoustic startle circuit in rats
      consisting of the auditory nerve, posteroventral cochlear nucleus, an area near
      the ventrolateral lemniscus (VLL), nucleus reticularis pontis caudalis (PnC), and
      spinal motoneurons. Using fiber-sparing lesions, the present study reevaluated
      these and other structures together with the role of neurons embedded in the
      auditory nerve [cochlear root neurons (CRNs)], recently hypothesized to be
      involved in acoustic startle. Small electrolytic lesions of the VLL of
      ventrolateral tegmental nucleus (VLTg) failed to eliminate startle. Large
      electrolytic lesions including the rostral ventral nucleus of the trapezoid body
      (rVNTB) and ventrolateral parts of PnC or lesions of the entire PnC blocked
      startle. However, small NMDA-induced lesions of the rVNTB failed to block
      startle, making it unlikely that the rVNTB itself is part of the startle pathway.
      In contrast, NMDA lesions of the full extension of the ventrolateral part of the
      PnC blocked startle completely, suggesting that the ventrolateral part of the PnC
      is critically involved. Bilateral kainic acid lesions of CRNs also blocked the
      startle reflex completely, providing the first direct evidence for an involvement
      of CRNs in startle. This blockade probably was not caused by damage to the
      auditory nerve, because the lesioned animals showed intact compound action
      potentials recorded from the ventral cochlear nucleus. Hence, a primary acoustic
      startle pathway may involve three synapses onto (1) CRNs, (2) neurons in PnC, and
      (3) spinal motoneurons.

PMID- 8642421
TI  - Industry's responsibility to the consumer.
AB  - The responsibility of industry to the consumer is to provide products derived
      from biotechnology that are effective as labeled and safe for their intended use
      on animals, plants and in the environment. Moreover, food products from the
      animals and plants receiving the drugs or chemicals must be safe for human
      consumption. To fulfill these responsibilities, industry must provide an accurate
      label for the drug or chemical, ensure drug or chemical product consistency so
      that every batch of the drug or chemical is similar to every other batch,
      complete studies to document that the drug or chemical is safe for use in the
      animal or on the plant, complete studies designed to provide data to ensure that
      the food derived from the use of the drug or chemical is safe for human
      consumption and complete studies to document that the drug or chemical is safe
      for use in the environment. The process of requiring data to be derived from
      sound experimental science, completion of the studies under scrutiny by
      regulatory personnel and extensive scientific review of the data by regulatory
      personnel results in products derived from biotechnology that are safe and
      effective.

PMID- 8642422
TI  - A government agency's responsibility to the consumer.
AB  - The U.S. Department of Agriculture's Office of Agricultural Biotechnology
      developed a proactive stance for informing consumers about biotechnology in 1987.
      Using a variety of information vehicles, the Office of Agricultural Biotechnology
      has developed a dialogue with various groups having different and sometimes very
      strident opinions about the use of genetic engineering in plants and animals. At
      the same time, the government agency has fulfilled its mandate to neither promote
      nor discourage the use of biotechnology methods in research, but rather to
      present the data and thus allow consumers to make an informed decision.

PMID- 8642423
TI  - The administration's responsibility to the consumer.
AB  - Biotechnology offers the promise of good jobs that produce products fulfilling
      the public's need for food, fiber and pharmaceuticals. It could provide a growing
      market for American products abroad, and it also offers the potential of
      environmentally sound solutions to some current problems. Government is therefore
      accountable for implementing policies to protect the public health, while at the
      same time promoting the growth and development of the industry. Such policies
      should stimulate research, ensure the safety of new products, protect the
      environment, encourage business to innovate and invest and lead to a literate
      public capable of holding those high technology jobs. Stewardship of the federal
      government's $70 billion annual investment in science and technology entails the
      following: 1) setting an overall policy framework and managing the effort
      efficiently within that framework; 2) supporting the conduct of fundamental
      science critical to achieving the stated goals; and 3) providing an environment
      that encourages private investment in innovation and technology development.

PMID- 8642424
TI  - Biotechnology and society: we scientists have responsibilities too.
AB  - When a new technology is introduced, scientists can help improve public
      understanding and acceptance. In the case of biotechnology, scientists should
      communicate more effectively: to provide accurate scientific data to facilitate
      policy analysis; to clarify issues in active political debate; to explain science
      to the lay public to dispel general ignorance and enable rational choice; to
      assist the media in producing more thoughtful journalism; to share expertise to
      allow beneficial applications in developing countries; and to advance scientific
      discovery.

PMID- 8642425
TI  - Dietary guidelines for children: a focus on fat. Introduction.

PMID- 8642426
TI  - A review of the Canadian "Nutrition recommendations update: dietary fat and
      children.".
AB  - A joint Working Group from the Canadian Paediatric Society and Health Canada met
      in the early 1990s to consider the applicability of recommendations to restrict
      total and saturated fat in children > or = 2 y of age. The Group weighed
      information from the literature on the nutritional needs for growth and
      development against evidence relating diet to risk of nutrition-related diseases.
      The Group concluded that the efficacy of the fat-restricted diet could not be
      assumed. There was no evidence that implementation of the diet would reduce
      illness in later life or provide benefit to children as children. Regarding
      safety, some children consuming self-selected diets with low fat intakes have
      lower energy intakes and food patterns that may compromise the intake of certain
      key nutrients. The primary recommendations of the Group were that the provision
      of adequate energy and nutrients to ensure adequate growth and development
      remains the most important consideration in the nutrition of children and that
      during the preschool and childhood years, nutritious food choices should not be
      eliminated or restricted because of fat content. Once linear growth has stopped,
      fat intake as currently recommended (30:10) is appropriate.

PMID- 8642427
TI  - Dietary guidelines for children: U.S. recommendations.
AB  - The primary goal for pediatric dietary guidelines is to provide nutrients to
      support optimal growth and development at different ages from infancy through the
      end of adolescence. Over the past 15 years increasing attention has been directed
      toward developing nutrition recommendations that may lower the risk of chronic
      illness later in life. Recent evidence supports earlier studies that demonstrate
      that atherogenesis begins in childhood, is an evolving process and is influenced
      by environmental factors. As a result, in part, because of nutritional
      recommendations to lower the fat content of the diet, total fat and saturated fat
      as a percentage of total energy intake have declined in the diet of children and
      adolescents over the past 20 years. At the same time there has been no increase
      in the prevalence of growth failure; children, in fact, are heavier than their
      counterparts of 15 years ago. With a decrease in dietary fat, the mean serum
      cholesterol of the population as a whole has decreased steadily over the past 20
      years. Children can safely eat a lower fat diet in which fat contributes 30% of
      total energy and saturated fat < 10% of total energy.

PMID- 8642428
TI  - Considerations about dietary fat restrictions for children.
AB  - Expert panels recommend reduction of dietary fat and cholesterol, because
      excessive fat intake may lead to known health hazards. However, there are no data
      demonstrating beneficial effects of such diets starting in childhood for all
      children, including those with normal serum cholesterol levels. Dietary
      restrictions in early life may not necessarily induce a long-lasting decrease in
      blood cholesterol levels in children persisting into adulthood or reduce disease
      incidence. On the other hand, the result of such diets may be suboptimal growth
      and development. Furthermore, low fat diets may lower high density lipoprotein
      cholesterol levels and not specifically low density lipoprotein cholesterol. In
      addition, low serum cholesterol levels may be associated with increased
      mortality, including deaths due to accidents, which is most important in
      children. Recently, increased attention has been drawn to the association between
      short stature and/or nutritional status and deficiencies in intrauterine and
      early life with coronary artery disease in adulthood. Also, the problems of
      associated psychological consequences, family conflicts and cost should not be
      ignored while implementing a low fat diet. In this review, we discuss the
      controversies on dietary fat restrictions for children.

PMID- 8642429
TI  - Dietary guidelines in perspective.
AB  - To assess whether dietary guidelines for Americans are appropriate for young
      children, the evolution of dietary guidance, the nature of the guidelines,
      evidence used to support the concept of diet modification to prevent heart
      disease and the rationale for extending application of the guidelines to children
      have been examined. As health improved during this century, life expectancy
      lengthened, and diseases associated with aging became major causes of death. As a
      consequence, emphasis on dietary advice for selecting a nutritionally adequate
      diet--the primary need of children--declined, whereas emphasis on dietary advice
      for preventing chronic and degenerative diseases increased. It is clear from
      reading the text accompanying the guidelines that they were proposed to prevent
      diseases of aging by reducing consumption of animal products. Critical evaluation
      of evidence bearing on the concept of the guidelines reveals that there are
      grounds for skepticism about claims for the effectiveness of diet modification as
      a measure for reducing the incidence of heart disease. Also, the rationale for
      extending the guidelines to young children is based on inferences from
      observations on adults, not on direct evidence that children will benefit from
      following them. There is, thus, ample justification for proposing separate
      dietary guidelines for children.

PMID- 8642430
TI  - Formation, metabolism and physiologic effects of oxidatively modified low density
      lipoprotein. Overview.

PMID- 8642431
TI  - The role of oxidized low density lipoprotein in atherogenesis.
AB  - An elevated level of low density lipoprotein (LDL) cholesterol constitutes a
      major risk factor for atherosclerotic disease. Although the precise mechanism(s)
      via which LDL promotes atherogenesis remains to be elucidated, the oxidative
      modification of LDL may be a crucial mechanism. Several lines of evidence support
      a role for oxidatively modified LDL in atherogenesis. LDL can be oxidatively
      modified in cell-free systems by transition metals and by all the major cells of
      the arterial wall. Oxidatively modified LDL (Ox-LDL) is taken up by macrophage
      scavenger receptors, promoting cholesterol ester accumulation and foam cell
      formation. It also promotes atherosclerosis by recruitment and retention of
      monocytes in the intima, by its cytotoxicity toward endothelial cells and by
      stimulating monocyte adhesion to the endothelium. Several lines of evidence
      support the in vivo existence of Ox-LDL. The LDL of patients with atherosclerosis
      are more prone to oxidation; antibodies against epitopes on Ox-LDL have been
      positively correlated with the progression of atherosclerosis. The oxidation of
      LDL has been shown to be reduced by antioxidants, and in animal models, these
      antioxidants decrease atherosclerotic lesion formation. Thus, much evidence
      supports a role for oxidized LDL in atherogenesis.

PMID- 8642432
TI  - Dietary fatty acids, low density lipoprotein composition and oxidation and
      primate atherosclerosis.
AB  - Low density lipoproteins (LDL) were isolated from nonhuman primates fed
      isocaloric diets rich in different types of fatty acids. These diets contained
      35% of calories as fat enriched in fatty acids from the following sources: lard
      that is rich in saturated fatty acids, safflower oil rich in oleic acid,
      safflower oil rich in linoleic acid and menhaden oil that is rich in n-3 fatty
      acids. LDL composition reflected the dietary fats. LDL were subjected to
      oxidation using copper ions and azobis(2-amidinopropane) x 2HCl. In general, the
      sensitivity of LDL to oxidation depended on both the poly-unsaturated fatty acid
      and vitamin E content. However, the lag times calculated for the copper ion
      catalyzed oxidations did not show the linear dependence on vitamin E content that
      was found for azobis(2-amidinopropane) catalyzed oxidation.

PMID- 8642433
TI  - Mechanisms of metal ion-dependent oxidation of human low density lipoprotein.
AB  - Although either copper or iron is essential for oxidation of human low density
      lipoprotein (LDL) by vascular cells, the mechanism is unknown. In our experiments
      copper- and iron-mediated LDL oxidation was found to proceed by different
      mechanisms. Oxidation of LDL by iron requires superoxide and proceeds by a
      hydroxyl radical-independent mechanism involving reduction of iron from the
      ferric to the ferrous form. In contrast, copper-mediated LDL oxidation involves
      direct reduction of copper from the cupric to the cuprous form by LDL.

PMID- 8642434
TI  - Prevention of atherosclerosis with dietary antioxidants: fact or fiction?
AB  - The notion that oxidation of lipids and lipoproteins may contribute to the
      pathogenesis of atherosclerosis is supported by a large body of evidence. It is
      hypothesized that dietary antioxidants may help prevent development and
      progression of atherosclerosis. The available evidence helps substantiate this
      hypothesis but is not yet conclusive. The results of several ongoing large
      randomized intervention trials will provide valuable information about the
      efficacy and safety of supplemental dietary antioxidants in prevention of
      atherosclerosis.

PMID- 8642435
TI  - Oxidized low density lipoproteins alter macrophage lipid uptake, apoptosis,
      viability and nitric oxide synthesis.
AB  - Uptake of oxidized low density lipoproteins (LDL) by monocyte macrophages to form
      "foam" cells occurs during formation of atherosclerotic lesions. Inducible nitric
      oxide synthase (iNOS) has been identified in foam cells. To investigate
      interactions between oxidized LDL, monocyte macrophage viability and iNOS,
      studies were performed with J774.Al macrophages. iNOS mRNA, protein and enzyme
      activity were induced in J774.Al macrophages by IFN-gamma lipopolysaccharide
      (LPS). Neither iNOS induction nor inhibition of nitric oxide (NO) formation was
      associated with significant alterations in the binding, uptake or degradation of
      native or oxidized LDL. Nontoxic doses of native LDL or of oxidized LDL did not
      influence iNOS mRNA or protein in macrophages. However, oxidized LDL, but not
      native LDL or acetyl LDL, inhibited NO production by macrophages in a dose- and
      time-dependent fashion. Inhibition of iNOS was not correlated with cholesteryl
      ester formation but with the degree of LDL oxidation. Inhibition of iNOS did not
      require the scavenger receptor or directed endocytosis and exhibited
      noncompetitive kinetics. Inhibition of iNOS activity in J774.Al macrophages was
      produced by lipid from oxidized LDL but not by lipid from native LDL and by PC
      vesicles containing LPC but not by PC vesicles alone. Inhibition of NO formation
      diminished apoptosis of the activated macrophages. The data suggest NO production
      by iNOS and inhibition of the enzyme by oxidized LDL lipid may influence cell
      viability, cell-cell interactions and vasomotor tone during atherogenesis.

PMID- 8642436
TI  - Biological effects of dietary arachidonic acid. Introduction.
AB  - The intent of this symposium is to assemble current knowledge of the role of
      arachidonic acid (AA) in the diet to provide a conceptual and mechanistic
      framework for future research. The principal focus is on the varied biological
      effects of dietary AA, including opposing effects of n-3 and n-6 polyunsaturated
      fatty acids (PUFA); regulation of n-6 PUFA metabolism, eicosanoid synthesis and
      gene expression; the importance of AA in infant nutrition and the contemporary
      Western diet in general; and the effects of AA on tumor promotion. Through its
      myriad actions and remarkably ubiquitous presence in cells, AA can be argued to
      affect every cell of the body. Although the varied molecular events associated
      with the metabolism of AA have been subjects of intense investigation, the
      ability of AA in the diet to alter AA levels in cellular membranes is poorly
      described and is thus the focus of this symposium.

PMID- 8642437
TI  - Is dietary arachidonic acid necessary for feline reproduction?
AB  - A study was carried out to determine whether corn oil-based diets devoid of
      arachidonic acid, 20:4(n-6), are capable of supporting feline reproduction. One
      group of four adult female felines were acclimated to a 10 weight% (wt%) fat diet
      consisting of 1 wt% corn oil and 9 wt% hydrogenated coconut oil for 1 mo before
      mating. One female produced two live offspring, and the other three females
      delivered either stillborn fetuses or offspring that were severely deformed and
      died shortly after birth. Two of these females were subsequently placed on a 1
      wt% corn oil diet that was supplemented with 20:4(n-6) (200 mg/ kg of diet), and
      after 2 mo they were mated. Offspring resulting from the second mating were
      healthy. A third group of females that were maintained on a 10 wt% fat diet
      consisting of 3 wt% corn oil were also mated. The offspring from these matings
      appeared healthy at birth. Neonates from each diet group were killed, and the
      fatty acyl composition of the livers, plasma and brains was analyzed. In the
      offspring livers and plasma, the level of 20:4(n-6) from both the 1 wt% or 3 wt%
      corn oil diet groups was about half that of offspring from those receiving 20:4(n
      6) in the diet. There were no differences in the level of 20:4(n-6) in the
      neonate brains among any of the groups. This study suggests that nutritional
      factors unrelated to the tissue accumulation of arachidonic acid in the offspring
      may be responsible for the high percentage of stillbirths and deformities
      associated with maternal diets containing low amounts of essential fatty acids
      but that diets that contain a higher percentage of corn oil can support feline
      reproduction.

PMID- 8642438
TI  - Antagonistic effects of dietary arachidonic acid and n-3 polyunsaturated fatty
      acids.
AB  - Arachidonic acid (AA) is a polyunsaturated fatty acid (PUFA) found exclusively in
      animal products and is one of the most important fatty acids associated with
      membrane phospholipids. When liberated from membrane phospholipids, AA can be
      oxidized to a variety of eicosanoids, compounds important in cell-cell signaling.
      Dietary n-3 PUFA have been effectively used to attenuate tissue AA levels and
      subsequent eicosanoid formation. However, only recently have the effects of
      dietary AA been investigated. This review discusses the antagonistic effects of
      dietary AA and n-3 PUFA, eicosanoid formation and the evidence suggesting
      divergent effects with regard to circulating triglycerides, beta-oxidation and
      tumor necrosis factor.

PMID- 8642439
TI  - Arachidonic acid status of human infants: influence of gestational age at birth
      and diets with very long chain n-3 and n-6 fatty acids.
AB  - In three randomized, double-blind clinical trials, preterm infants were fed
      typical preterm or term formulas and experimental formulas supplemented with n-3
      and n-6 long-chain fatty acids. The effect of these feedings on the concentration
      of plasma phosphatidylcholine arachidonic acid (AA), an indicator of AA status,
      was contrasted with equivalent data from infants born at term. Preterm infants
      appear to have poorer AA status than breast-fed term infants at the corrected
      ages of 0 and 2 mo. The addition of marine oil eicosapentaenoic acid (EPA) (0.3%)
      and docosahexaenoic acid (DHA) (0.2%) to formula further decreased AA status
      (Study 1). The same amount of marine oil DHA (0.2%) but with less EPA (0.06%) fed
      for a shorter interval did not decrease plasma phosphatidylcholine AA
      concentration compared with controls (Study 2). Preterm infants fed both AA
      (0.43%) and DHA (0.1%) had better AA status than controls. These observations are
      discussed in relation to evidence from these same studies that AA status and the
      n-6/n-3 rates are related to growth of preterm infants.

PMID- 8642441
TI  - Polyunsaturated fatty acid regulation of hepatic gene transcription.
AB  - Polyunsaturated fatty acids (PUFA) modulate the rate of gene transcription for a
      number of different genes including hepatic lipogenic and glycolytic genes,
      adipose Glut-4 and stearoyl-CoA desaturase and interleukins. Some of the
      transcriptional effects of PUFA appear to be mediated by eicosanoids, but the
      PUFA suppression of lipogenic and glycolytic genes is independent of eicosanoid
      synthesis and appears to involve a nuclear mechanism directly modified by PUFA.
      With the recent cloning of a fatty acid-activated nuclear factor termed
      peroxisome-proliferator- activated receptor (PPAR) has come the suggestion that
      PPAR may be the PUFA response factor. However, this review presents several lines
      of evidence that indicate that the PPAR and PUFA regulation of gene transcription
      involves separate and independent mechanisms, and the PPAR is not the PUFA
      response factor.

PMID- 8642440
TI  - Arachidonate has protumor-promoting action that is inhibited by linoleate in
      mouse skin carcinogenesis.
AB  - Previous studies demonstrated a requirement for arachidonic acid metabolites in
      tumor development in mouse skin. The goal of this study was to determine whether
      the arachidonate content of epidermal phospholipids could be altered by
      increasing dietary levels of linoleate and whether specific metabolites of
      linoleate and arachidonate have dissimilar biological effects. In a series of
      tumor studies in which the quantity of dietary linoleate was incrementally
      increased, a slight reduction in phospholipid levels of arachidonate was observed
      that correlated with an increased phospholipid level of linoleate and a
      suppression in tumor yield. A comparison of the arachidonate lipoxygenase
      metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) with the 13
      hydroxyoctadecadienoic acid (13-HODE) lipoxygenase metabolite of linoleate
      revealed that 12-HETE has biological activities that mimic the phorbol ester
      tumor promoters, whereas 13-HODE has antithetical effects. Specifically, 12(S)
      HETE enhanced the activation of protein kinase C by phorbol esters, mimicked
      phorbol ester-induced adhesion of keratinocytes to fibronectin and mimicked
      phorbol ester repression of expression of a differentiation-related gene, keratin
      1. 13-HODE blocked 12-HETE-induced cell adhesion and prevented 12-HETE-induced
      suppression of keratin-1 expression. Overall, these studies suggest that
      arachidonate and linoleate have opposing functions in the epidermis, particularly
      with regard to events involved in tumor development.

PMID- 8642442
TI  - Short-term diets rich in arachidonic acid influence plasma phospholipid
      polyunsaturated fatty acid levels and prostacyclin and thromboxane production in
      humans.
AB  - Two small-scale dietary intervention studies were conducted to examine the effect
      of diets rich in arachidonic acid (AA) and n-3 long-chain polyunsaturated fatty
      acids (n-3 LCP), on the in vivo production of prostacyclin (PGI2) and thromboxane
      (TXA2). The first was a pilot study and contained insufficient numbers for
      statistical analyses. It involved a 7-d intervention with 10 subjects divided
      into three groups, consuming diets rich in AA (500 mg/d), rich in AA and
      docosahexaenoic acid (DHA) (500 mg/d of each), or rich in DHA and
      eicosapentaenoic acid (EPA) (approximately 1500 mg/d of n-3 LCP). Plasma
      phospholipid (PL) levels of AA increased in all subjects in groups 1 (n = 4) and
      2 (n = 3). DHA levels increased in all subjects in Groups 2 and 3 (n = 3), and
      EPA levels increased in all subjects from Group 3 but fell in all subjects from
      Group 1. The in vivo production of PGI2, measured as its urinary metabolite, was
      increased in two subjects in Group 1 and one subject in Group 2, with all other
      subjects showing little change. Urinary TXA2 metabolite increased in all subjects
      from Group 1. The second study was conducted in seven subjects, who consumed a
      low fat diet for 2 wk: the 1st wk was a vegetarian diet (no LCP) followed by a
      2nd wk where the subjects were required to consume 500 g (raw weight) of kangaroo
      meat daily (305 mg/d AA, 325 mg/d n-3 LCP). The meat diet was associated with a
      marked rise in the serum PL levels of AA, EPA and docosapentaenoic acid 22:5(n-3)
      and with a significant increase in the urinary output of the prostacyclin
      metabolite, but no effect on TXA2 production, as measured by its urinary
      metabolite level. The results of these studies have shown that diets that contain
      both AA and n-3 LCP are associated with an increase in PGI2 production, without
      affecting TXA2 production. Further studies with purified LCP are warranted.

PMID- 8642443
TI  - Enteral glutamine supplementation for the very low birthweight infant: plasma
      amino acid concentrations.

PMID- 8642444
TI  - Characterization of glutaminase in the developing rat small intestine.
AB  - As a primary substrate in the small intestine, glutamine is a very important
      source of energy. Glutaminase (GA) is the enzyme involved in the deamination of
      glutamine to glutamate, which is utilized for energy production via the TCA
      cycle. Although the enzymatic activity of GA in the small intestine is known to
      undergo maturational changes, the tissue localization of the protein and its
      mRNA, the intracellular processing of this enzyme and levels of its mRNA in the
      small intestine at different maturational stages have not yet been described. In
      this study, using immuno-histochemical staining, we confirm previous studies
      using other techniques that suggested GA is localized in the epithelial layer of
      the rat small intestine. Some GA is also found in cells of the lamina propria and
      crypt epithelium. Using in situ hybridization studies, we have corroborated the
      presence of the protein in the epithelial cells of the villi by localizing the
      mRNA of this protein to the same layer and its precursor layer in the crypt
      region. An ontogenic analysis of GA mRNA and protein from rat small intestines,
      using RNA dot blots, gel blots and protein immunoblotting revealed differences in
      immunoreactive GA protein and mRNA during maturation. Immunoreactive GA and
      steady-state levels of GA mRNA increased around the 3rd wk of life, coincident
      with weaning and the endogenous glucocorticoid surge. Whether these findings have
      nutritional or pathophysiological implications remains speculative.

PMID- 8642445
TI  - The role of glutamine as an energy source in the developing rat lung.
AB  - Because multiple substrates have been shown to play a role in the metabolic
      homeostasis of different tissues, a series of studies were initiated to examine
      the role of alternate substrates in the lung. In these studies, we measured rates
      of oxidation of glutamine, glucose, lactate and 3-hydroxybutyrate in fibroblasts
      isolated from d 19 fetal rat lungs by measuring the production of 14CO2 from
      labeled substrates and compared them with earlier studies of isolated Type II
      cells. The rate of glutamine oxidation was 16.04 nmol 14CO2 x mg protein(-1) x
      hr(-1) in the fibroblasts compared with 24.36 in Type II cells. Three
      hydroxybutyrate had a rate of 10.75 in the fibroblasts and 14.9 in the Type II
      cells. Lactate oxidation in fibroblasts was similar to that of glutamine, with a
      rate of 18.49; however, in Type II cells the rate of lactate oxidation was
      significantly higher at 40.29. Glucose was oxidized at a rate significantly lower
      than the other three substrates. In the fibroblasts, that rate was 1.22 and in
      Type II cells it was 2.13. To examine the interactions of substrates normally
      found in the intracellular milieu, we measured the effect of unlabeled substrates
      as competitors on labeled substrate in the fibroblasts, similar to our studies
      with Type II cells that identified multiple metabolic compartments of energy
      metabolism in these cell populations. Glucose, but not lactate, inhibited the
      oxidation of glutamine, suggesting a compartmentation of tricarboxylic acid cycle
      activity rather than simple dilution by glucose. Glucose and lactate had
      reciprocal inhibition in the Type II cells. Our data suggest at least two
      separate compartments in developing lung cells for substrate oxidation: one for
      glutamine metabolism and a second for glucose metabolism. In summary, we have
      documented that glutamine and other alternate substrates are oxidized
      preferentially over glucose for energy metabolism in the d 19 fetal rat lung.

PMID- 8642446
TI  - Enteral glutamine modulates renal glutamine utilization.
AB  - Enteral glutamine feeding effect on renal glutamine utilization was assessed from
      the perspective of gamma glutamyltransferase activity-dependent cellular
      glutamate modulation of phosphate-dependent glutaminase. After 4d, rats fed an
      elemental diet supplemented with glutamine exhibited a 2 1 % higher kidney
      glutamate content and 27% reduction in ammonium excretion, both P < 0.05.
      Glutamine removal from plasma was depressed 62% in the glutamine-fed group (324
      +/- 155 vs. 780 +/- 154 nmol x min(-1) x 100 g body weight (-1), P < 0.05)
      despite an elevated arterial plasma glutamine load delivered to the kidney.
      Administration of acivicin, 36 mg/kg body weight, to glutamine-fed rats inhibited
      gamma glutamyltransferase > 90% and decreased kidney glutamate content 42%. This
      reduction in kidney glutamate was associated with a 3.3-fold enhancement in both
      glutamine extraction (474 +/- 184 to 1548 +/- 255 nmol x min(-1) x 100 g body
      weight (-1)) and ammonium excretion (295 +/- 30 to 978 +/- 96 nmol x min(-1) x
      100 g body weight(-1)), both P < 0.01. These findings are consistent with enteral
      glutamine regulation of renal glutamine utilization through an elevation of the
      cellular glutamate level.

PMID- 8642447
TI  - Glutamine metabolism and transport in skeletal muscle and heart and their
      clinical relevance.
AB  - The glutamine and glutamate transporters in skeletal muscle and heart appear to
      play a role in control of the steady-state concentration of amino acids in the
      intracellular space and, in the case of skeletal muscle at least, in the rate of
      loss of glutamine to the plasma and to other organs and tissues. This article
      reviews what is currently known about transporter characteristics and mechanisms
      in skeletal muscle and heart, the alterations in transport activity in
      pathophysiological conditions and the implications for anabolic processes and
      cardiac function of altering the availability of glutamine. The possibilities
      that glutamine pool size is part of an osmotic signaling mechanism to regulate
      whole body protein metabolism is discussed and evidence is shown from work on
      cultured muscle cells. The possible uses of glutamine in maintaining cardiac
      function perioperatively and in promoting glycogen metabolism are discussed.

PMID- 8642448
TI  - Nutritional advances in human bone metabolism. Introduction.

PMID- 8642449
TI  - Calcium, phosphorus and human bone development.
AB  - Calcium intakes by girls and adult females should approximate or exceed the
      Recommended Dietary Allowances so that peak bone mass can be achieved during
      early adulthood and bone mass can be maintained thereafter until the menopause.
      Investigations of the relationship between dietary calcium consumption and
      measurements of bone mass or density strongly support the contention that
      adequate intakes of calcium by females contribute to greater values of bone mass
      through adolescence and into adulthood. Prospective studies have especially been
      robust in support of this relationship. Inadequate calcium intakes early in life
      may lead to low bone mass because of several possibilities. Three potential
      mechanisms for the development of low bone mass are proposed, and in all a role
      for elevated parathyroid hormone is emphasized. A likely mechanism contributing
      to low bone mass in the United States involves a low calcium:high phosphorus
      intake ratio, but this possibility has not been adequately tested with a
      prospective design. Future investigations are needed to address the etiologic
      risk factors influencing less than optimal development of bone mass in females
      living in affluent nations.

PMID- 8642450
TI  - Vitamin D and bone health.
AB  - Vitamin D plays an essential role in maintaining a healthy mineralized skeleton
      for most land vertebrates including humans. Sunlight causes the photoproduction
      of vitamin D3 in the skin. Once formed, vitamin D3 is metabolized sequentially in
      the liver and kidney to 1,25-dihydroxyvitamin D. The major biological function of
      1,25-dihydroxyvitamin D is to keep the serum calcium and phosphorus
      concentrations within the normal range to maintain essential cellular functions
      and to promote mineralization of the skeleton. Most foods do not contain any
      vitamin D. Foods fortified with vitamin D have a variable amount present and
      cannot be depended on as a sole source of vitamin D nutrition. Exposure to
      sunlight provides most humans with their vitamin D requirement. Aging, sunscreen
      use and the change in the zenith angle of the sun can dramatically affect the
      cutaneous production of vitamin D3. Vitamin D insufficiency and vitamin D
      deficiency is now being recognized as a major cause of metabolic bone disease in
      the elderly. Vitamin D deficiency not only causes osteomalacia but can exacerbate
      osteoporosis. It is generally accepted that an increase in calcium intake to 1000
      1500 mg/d along with an adequate source of vitamin D of at least 400 IU/d is
      important for maintaining good bone health.

PMID- 8642451
TI  - Calcium and vitamin D nutritional needs of elderly women.
AB  - Because osteoporosis is irreversible, the most effective approach to reduce
      morbidity and mortality from this disease is to maximize peak bone mass and
      minimize bone loss. This presentation reviews the evidence that calcium and
      vitamin D influence rates of bone loss in postmenopausal women. In the first five
      or more years after menopause, women lose bone very rapidly. During this period,
      high dose calcium supplementation modestly reduces cortical loss from long bones
      but has minimal effect on more trabecular sites such as the spine. In addition,
      vitamin D appears to enhance the effectiveness of supplemental calcium. Late
      postmenopausal women are generally more responsive to added calcium, and those
      with the lowest dietary calcium intakes benefit the most. In calcium-replete
      women, supplementation with vitamin D reduces bone loss and fracture incidence.
      Available evidence indicates that postmenopausal women should consume 1000-1500
      mg of calcium and 400 to 800 IU of vitamin D per day to minimize bone loss.

PMID- 8642452
TI  - Changing phosphorus content of the U.S. diet: potential for adverse effects on
      bone.
AB  - The dietary intake of phosphorus in the United States is high relative to
      calcium. Intake estimates from the 1989-1991 Continuing Surveys of Food Intakes
      by Individuals conducted by the U.S. Department of Agriculture show that for both
      men and women, median calcium intakes do not meet the 1989 Recommended Dietary
      Allowances (RDAs) for most age groups over 10 y of age, whereas phosphorus
      intakes exceed the RDAs for most age groups. The use of phosphorus-containing
      food additives in the processing of foods contributes substantially to the daily
      phosphorus intake, and their use is increasing. Because much of the phosphorus
      through food additive use is not reflected in the estimates of phosphorus intakes
      derived from national food consumption surveys, these estimates underestimate
      true dietary intakes of phosphorus. High phosphorus intake has been shown to
      cause secondary hyperparathyroidism and bone loss in several animal models. High
      phosphorus, low calcium consumption consistent with current observed intake
      levels resulted in changes in calcium-regulating hormones that were not conducive
      to optimizing peak bone mass in young women. Evidence that such high phosphorus
      intakes may impair synthesis of the active metabolite of vitamin D and disrupt
      calcium homeostasis particularly in older women are discussed.

PMID- 8642453
TI  - Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K
      with special reference to bone health.
AB  - Vitamin K occurs in nature as a series of compounds with a common 2-methyl- 1,4
      naphthoquinone nucleus and differing isoprenoid side chains at the 3 position.
      They comprise a single major plant form, phylloquinone with a phytyl side chain
      and a family of bacterially synthesized menaquinones (MKs) with multiprenyl side
      chains. The major dietary source to humans is phylloquinone for which the chief
      food contributors are green, leafy vegetables followed by certain vegetable oils
      (soybean, rapeseed and olive oils). Recent analyses by high pressure liquid
      chromatography are now providing a wide-ranging database of phylloquinone in
      foods. Menaquinones are found in moderate concentrations in only a few foods such
      as cheeses (MK-8 and MK-9). A wider spectrum of MKs is synthesized by the gut
      microflora, and their intestinal absorption probably accounts for most of the
      hepatic stores, particularly those with very long side chains (MKs-10--13)
      synthesized by members of the genus Bacteroides. The site of absorption of floral
      MKs is not known, but reasonable concentrations are found in the terminal ileum
      where bile salt-mediated absorption is possible. Both phylloquinone and
      menaquinones are bioactive in hepatic gamma-carboxylation but long-chain MKs are
      less well absorbed. Liver stores of vitamin K are relatively small and
      predominantly MKs-7--13. The hepatic reserves of phylloquinone (approximately 10%
      of the total) are labile and turn over at a faster rate than menaquinones.
      Trabecular and cortical bone appear to contain substantial concentrations of both
      phylloquinone and menaquinones. A majority (approximately 60-70%) of the daily
      dietary intake of phylloquinone is lost to the body by excretion, which
      emphasizes the need for a continuous dietary supply to maintain tissue reserves.

PMID- 8642454
TI  - Effects of vitamin K on bone mass and bone metabolism.
AB  - Vitamin K is involved in blood coagulation and in bone metabolism via the
      carboxylation of glutamate residues in (hepatic) blood coagulation factors and
      (osteoblastic) bone proteins. The bioavailability of nutritional vitamin K
      depends on the type of food, the dietary fat content, the length of the aliphatic
      side chain in the K-vitamer and probably also the genetically determined
      polymorphism of apolipoprotein E. Although undercarboxylation of blood
      coagulation factors is very rare, undercarboxylated osteocalcin (bone Gla
      protein) is frequently found in postmenopausal women. Supplementation of these
      women with extra vitamin K causes the markers for bone formation to increase. In
      parallel, a decrease of the markers for bone resorption is frequently seen.
      Insufficient data are available to conclude that the regular administration of
      vitamin K concentrates will reduce the loss of bone mass in white women at risk
      for developing postmenopausal osteoporosis.

PMID- 8642455
TI  - Transport of vitamin K to bone in humans.
AB  - Molecules with vitamin K activity are important for optimal bone health. The
      major compound of this group in bone is vitamin K1 (phylloquinone), which is
      derived exclusively from plant foods in the diet. Vitamin K1 is absorbed along
      with dietary fat from the small intestine and transported by chylomicrons in
      blood. In serum obtained after an overnight fast from healthy men more than half
      of the vitamin K1 was recovered from the density fraction that contains
      chylomicrons and chylomicron remnants (CR), and only a quarter was associated
      with the major lipoprotein in serum, low density lipoprotein. The concentration
      of vitamin K1 in serum is closely related to the triglyceride concentration.
      Another determinant of vitamin K1 concentration in serum is the presence of
      specific variants of apolipoprotein E (apoE). ApoE is a small protein through
      which the vitamin K-rich CR bind to lipoprotein receptors. The three most common
      variants of apoE promote CR clearance from circulation with very different
      efficiency, in the order E2>E3>E4. The variant that promotes CR clearance best is
      associated with low vitamin K1 concentration in serum and increased response to
      vitamin K antagonists. Vitamin K1 concentration in serum is linked to vitamin K
      status of bone. The bone protein osteocalcin tends to be less completely
      carboxylated in people with low vitamin K concentrations in serum. Many
      hemodialysis patients with a history of bone fractures have indications of poor
      vitamin K status. The same patients also appear to have a greatly increased
      prospective bone fracture risk.

PMID- 8642456
TI  - Prooxidant effects of antioxidant vitamins. Introduction.

PMID- 8642457
TI  - Oxidant-antioxidant status alterations in cancer patients: relationship to tumor
      progression.
AB  - A significant change of vitamin E and malondialdehyde plasma concentrations was
      reported in breast cancer patients. This change was unexpected because vitamin E
      was higher and malondialdehyde lower in cases than in controls, and the
      difference was more significant in young rather than older women. The first aim
      of this study was to determine whether these changes were associated only with
      breast cancer, or with hormone-related cancers, and/or cancers associated with
      nutritional risk factors or with all types of cancers. Measurements were
      performed before therapy on 269 hospital-based controls and on 146 patients with
      various carcinomas. Vitamin E:total cholesterol increased and malondialdehyde
      plasma concentration decreased with tumor size and progression, without relation
      to the site. The second aim was to understand the difference in the change
      observed between young and old breast cancer patients. These analytes were
      measured in 365 breast cancer patients according to three prognosis factors:
      pathology, tumor size and estrogen receptors. Vitamin E:total cholesterol
      significantly decreased with estrogen receptor amount. Malondialdehyde plasma
      concentration decreased with severity of pathology and tumor size. Together,
      these data support the association of an altered oxidant-antioxidant profile in
      cancer patients with tumor growth and progression.

PMID- 8642458
TI  - Benefits and liabilities of vitamin A and carotenoids.
AB  - Vitamin A and carotenoids are often cited as members of a family of antioxidant
      vitamins that can show protective effects against oxidative stress and some
      chronic diseases. The great advantages of aerobic metabolism are offset in part
      by adverse physiological effects that can be caused by highly reactive forms of
      oxygen and its reduction products. Nature has developed a variety of
      sophisticated defenses against these undesirable side effects of oxygen. Vitamin
      A and carotenoids can serve chemically both as electron acceptors and donors
      (i.e., as oxidants and reductants), although in nature vitamin A seems to be
      protected from oxidation by other physiological antioxidants rather than serving
      a protective role itself. Furthermore, large doses of vitamin A are toxic.
      Carotenoids may serve a broader protective role in humans as they do in plants
      and microorganisms, but the evidence supporting such a role in humans is mixed.
      The widely used term antioxidant vitamins is too narrow in scope for the
      properties attributed to them. A much better term is physiological modulators,
      which broadens both the set of compounds that are included and the possible
      nature of their actions, whether beneficial or adverse.

PMID- 8642459
TI  - Vitamin C-driven free radical generation from iron.
AB  - Circulating free iron is lethal. Humans have two circulating iron binding
      proteins to soak up free iron to prevent it from generating toxic quantities of
      free radicals. These proteins are transferrin, a high-affinity, low-capacity
      protein (2 atoms of iron per molecule of transferrin) for which there are
      receptors on the surface of every iron-requiring cell; and ferritin, a lower
      affinity, high-capacity protein (maximum of 4500 atoms of iron per molecule of
      ferritin) for which there are receptors only on the surface of iron-storage cells
      such as RE (reticulo-endothelial) cells. Iron is trapped inside the ferritin
      protein shell as harmless Fe3. When there is a high serum level of reduced
      ascorbic acid, it drives through the pores of the ferritin protein shell to the
      inside surface, where it converts the Fe3 to catalytic Fe2, which then leaks out
      of the pores of the ferritin protein shell and generates billions of free
      radicals. In normal individuals, per milliliter of serum, there are approximately
      300,000 molecules of transferrin per molecule of ferritin. Ferritin protein is an
      acute phase reactant that sharply rises in the presence of inflammation of any
      kind, whereas transferrin is a reverse acute phase reactant that falls in the
      presence of inflammation of any kind.

PMID- 8642460
TI  - The dual roles of nutrients as antioxidants and prooxidants: their effects on
      tumor cell growth.
AB  - The development of a beneficial or a detrimental cellular response by a nutrient
      will depend on the nutrient's antioxidant or prooxidant characteristics, which in
      turn are a product of the cellular oxygen environment. Nutrients such as
      carotenoids, tocopherols or ascorbate derivatives will demonstrate an antioxidant
      or prooxidant characteristic depending on the redox potential of the individual
      molecule and the inorganic chemistry of the cell. Nutrients acting as
      chemopreventives, inhibit the continual growth of transformed clones of cells
      through their prooxidant activity. In contrast, when an antioxidant activity
      occurs in transformed cells an enhanced growth may result. In addition, when an
      inappropriate prooxidant activity develops in normal cells, the reactive oxygen
      metabolites generated could damage the DNA and cellular membranes. The cellular
      response is usually a loss of normal regulatory function and activity, depressing
      cellular integrity. Therefore, the labile redox character of each nutrient must
      be considered in terms of the extracellular and intracellular microoxygen
      environment. To predict if a specific nutrient will have a beneficial or
      detrimental effect on a particular tissue or cell, it is important to identify
      markers that will characterize the biologic activities of each nutrient and
      elucidate a possible mechanism of action for that nutrient. In various tissues
      chemopreventive agents derived from nutrients have been shown in laboratory
      animal studies and in some human intervention trials to inhibit the growth and
      development of premalignant or malignant lesions. Examples of these tissues
      include oral tissues, esophagus, gastric cardia and lung tissues. Recently, some
      clinical studies demonstrated no reduction in the incidence of premalignant
      change, but, to the contrary, statistical evidence indicated an increase in
      cancer development. In general, the results of clinical intervention trials
      remains equivocal. The use of chemopreventive agents without considering their
      pharmacologic, oxygen-responsive characteristics will produce unwanted iatrogenic
      side effects or further cloud evidence of these nutrients' biologic activities.

PMID- 8642461
TI  - Symposium on the subcellular compartmentation of folate metabolism.

PMID- 8642462
TI  - Homocysteine, vitamins and arterial occlusive disease: an overview.

PMID- 8642463
TI  - Plasma homocyst(e)ine: a risk factor for arterial occlusive diseases.
AB  - Results of basal plasma homocyst(e)ine concentrations in patients reported in the
      literature are reviewed, with emphasis on the series of subjects analyzed by the
      author. Findings support the hypothesis that plasma homocyst(e)ine is a risk
      factor for coronary, cerebral and peripheral arterial occlusive diseases, as well
      as for carotid thickening. Results of four studies show that heritability
      influences plasma homocyst(e)ine. Moreover, data suggest that a graded risk for
      atherothrombotic disease is distributed across the entire distribution of plasma
      homocyst(e)ine levels. Elevated levels of homocyst(e)ine can be decreased
      effectively by supplementary folate, occasionally requiring the addition of
      vitamin B-12, vitamin B-6, choline or betaine. Consequently, it is important that
      placebo-controlled clinical trials be conducted to determine whether the clinical
      evolution of arterial occlusive diseases is influenced by those supplements.

PMID- 8642464
TI  - The Hordaland homocysteine study: the opposite tails odds ratios reveal
      differential effects of gender and intake of vitamin supplements at high and low
      plasma total homocysteine concentrations.
AB  - Both female sex and intake of vitamin supplements are known to be associated with
      a low mean plasma homocysteine level. In the present study, we used multiple
      logistic regression analyses to investigate the relation between these two
      variables and plasma homocysteine at the extreme ends of the plasma homocysteine
      distribution curve. We propose that the obtained set of odds ratios for hyper-
      and hypohomocysteinemia, referred to as the opposite tails odds ratios, may be an
      alternative approach to study determinants of plasma homocysteine.

PMID- 8642465
TI  - Relationship among homocyst(e)ine, vitamin B-12 and cardiac disease in the
      elderly: association between vitamin B-12 deficiency and decreased left
      ventricular ejection fraction.
AB  - We evaluated the association of moderate hyperhomocyst(e)inemia and vitamin B-12
      status with coronary artery disease (CAD) and left ventricular ejection fraction
      in 367 elderly patients undergoing coronary angiography. The extent of CAD was
      scored, left ventricular ejection fraction was assessed and vitamins B-12 and
      folate and the metabolites homocyst(e)ine, methylmalonic acid and 2-methylcitric
      acid were measured. There was no significant trend in change in homocyst(e)ine as
      the extent of CAD increased. There was an association between vitamin B-12
      deficiency, i.e., vitamin B-12 < 221 pmol/l and homocyst(e)ine > 16 nmol/ml and
      low left ventricular ejection fraction (P = 0.014). Of 105 samples, selected for
      vitamin B-12 < 221 pmol/l or high normal vitamin B-12 and folate levels,
      metabolites including methylmalonic acid revealed a specific diagnosis of vitamin
      B-12 deficiency in 18 patients. The trend among these vitamin B-12-deficient
      patients and low left ventricular ejection fraction was significant (P = 0.028).
      In vitro studies on rat heart revealed that nitrous oxide in the presence of 200
      microM/l methionine reduced contractility of the heart. In conclusion, vitamin B
      12-deficient patients had significantly lower left ventricular ejection fractions
      than nonvitamin B-12-deficient patients. Whether low left ventricular ejection
      fraction results in malabsorption of vitamin B-12 and vitamin B-12 deficiency, or
      conversely, whether vitamin B-12 and its marker, elevated homocyst(e)ine, depress
      left ventricular function warrants further evaluation.

PMID- 8642466
TI  - Plasma homocysteine concentrations in a population with a low coronary heart
      disease prevalence.
AB  - To evaluate hyperhomocysteinemia as a possible coronary heart disease risk
      factor, the South African black population as example of a population with a low
      coronary heart disease prevalence was investigated and compared with a population
      prone to coronary heart disease (South African Whites). In traditionally living
      adult black men, plasma homocysteine concentrations were significantly lower
      compared with Whites. The plasma homocysteine frequency distribution in Whites
      was positively skewed; individuals with high plasma homocysteine concentrations
      probably acquire these during or after young adulthood, because the plasma
      homocysteine frequency distribution in children was normal. Compared with Blacks,
      young adult Whites showed methionine intolerance expressed as high plasma
      homocysteine concentrations after an oral methionine load test. The results
      indicate that Blacks generally have lower circulating plasma homocysteine
      concentrations and more effective homocysteine metabolism after oral methionine
      loading, which may partially explain their relative resistance against coronary
      heart disease.

PMID- 8642467
TI  - Relationship between plasma homocysteine, vitamin status and extracranial carotid
      artery stenosis in the Framingham Study population.
AB  - Recent studies demonstrated associations between occlusive vascular disease and
      hyperhomocysteinemia of both genetic and nutritional origin. In the present study
      we analyzed plasma samples from the 20th biannual examination of the Framingham
      Heart Study cohort to determine distribution of plasma homocysteine
      concentrations with emphasis on relationships to B vitamins and prevalence of
      carotid artery stenosis. Results showed that homocysteine exhibited strong
      inverse association with plasma folate and weaker associations with plasma
      vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely
      associated with intakes of folate and vitamin B-6, but not vitamin B-12.
      Prevalence of high homocysteine (>14 micromol/l) was 29.3% in this cohort, and
      inadequate plasma concentrations of one or more B vitamins appear to contribute
      to 67% of the cases of high homocysteine. Prevalence of stenosis > or = 25% was
      43% in men and 34% in women with an odds ratio of 2.0 for individuals in the
      highest homocysteine quartile (> or = 14.4 micromol/l) compared with those in the
      lowest quartile (< or = 9.1 micromol/l), after adjustment for sex, age, high
      density lipoprotein cholesterol, systolic blood pressure and cigarette smoking
      (Ptrend < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and
      folate intake were inversely associated with extracranial carotid stenosis after
      adjustment for age, sex and other risk factors.

PMID- 8642468
TI  - The use of homocysteine and other metabolites in the specific diagnosis of
      vitamin B-12 deficiency.
AB  - Vitamin B-12 (cobalamin) is a cofactor for only two enzymes, methionine synthase
      and L-methylmalonyl-CoA mutase. The serum vitamin B-12 concentration has been
      shown to have limitations in specificity and sensitivity in diagnosing vitamin B
      12 deficiency and predicting response to therapy in subjects with clinical
      deficiency syndromes. Serum methylmalonic acid and/or total homocysteine
      concentrations have been shown to be elevated in almost every patient who has a
      clinical response to vitamin B-12. In elderly populations serum methylmalonic
      acid concentrations are elevated in the majority (60-66%) of subjects who have
      elevated total homocysteine concentrations, suggesting that vitamin B-12
      deficiency (with or without associated folate deficiency) and/or chronic renal
      insufficiency may be the primary cause of most of the elevated total homocysteine
      concentrations in elderly populations. In such subjects vitamin B-12 and folate
      concentrations are both frequently in the low or low normal range, making
      differentiation of the clinical syndromes by use of serum vitamin concentrations
      problematic. Elevations of 2-methylcitric acid and cystathionine also result from
      vitamin B-12 deficiency. Serum N-methylglycine concentrations are normal in
      cobalamin deficiency but are increased in 40% of patients deficient in folate. In
      conclusion, elevations of methylmalonic acid and total homocysteine are very
      sensitive and specific in diagnosing vitamin B-12 deficiency and can be used to
      help differentiate vitamin B-12 deficiency from folate deficiency. Elevated total
      homocysteine concentrations that may have been attributed to folate deficiency in
      elderly subjects may in many instances be the result of vitamin B-12 deficiency
      even though serum vitamin B-12 concentrations are within normal limits.

PMID- 8642469
TI  - Treatment of hyperhomocyst(e)inemia: physiological basis.
AB  - Hyperhomocyst(e)inemia (HCY) is caused either by genetic or nongenetic defect(s),
      and the clinical severity of HCY is correlated with the biochemical abnormality.
      Treatment of HCY is approached on the basis of its etiology and severity of
      defect. The preferred method of treatment for genetic HCY is activation of mutant
      enzyme activity with the cofactor or the precursor of cofactor. If HCY does not
      respond to this treatment, pharmacological doses of betaine or folic acid should
      be used to enhance the alternative pathway of homocysteine turnover. Phenotypic
      expression of minor genetic defects, such as heterozygous cystathionine synthase
      deficiency and thermolabile methylenetetrahydrofolate reductase (MTHFR) can be
      amplified or masked by nongenetic (nutritional) factor(s). Hence, supplementation
      of folic acid, vitamin B-12, pyridoxine and choline to maintain their serum
      concentrations above low normal range may satisfactorily prevent the development
      of moderate HCY due to a minor genetic defect.

PMID- 8642470
TI  - Vitamins as homocysteine-lowering agents.
AB  - Moderate hyperhomocysteinemia is, today, considered an established risk factor
      for cardiovascular disease. A graded dose-response relationship between plasma
      homocysteine concentration over its full range and cardiovascular risk strongly
      supports causality. Therefore, intervention studies with homocysteine-lowering
      vitamins are needed. This mini review shows that supplementation with folic acid
      not only markedly reduces elevated plasma homocysteine concentrations but also
      reduces normal homocysteine concentrations. Folic acid doses of < 1 mg/d may be
      effective. Supplementation with a combination of folic acid and cyanocobalamin
      will secure full homocysteine-lowering effect and prevent occurrence of vitamin B
      12 deficiency during the course of therapy.

PMID- 8642471
TI  - Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols
      in plasma comprise the redox thiol status--a possible element of the
      extracellular antioxidant defense system.
AB  - Reduced, oxidized and protein-bound forms of homocysteine (Hcy), cysteine and
      cysteinylglycine in plasma interact via redox and disulphide exchange reactions,
      and these aminothiol species comprise a dynamic system referred to as redox thiol
      status. Notably, in plasma reduced cysteine is the most abundant low molecular
      weight sulfhydryl compound. Elevation of plasma Hcy (hyperhomocysteinemia) causes
      changes in redox thiol status. Protein-bound Hcy increases up to a maximum
      capacity of about 140 micromol/L, and there is a concurrent displacement of
      protein-bound cysteine. When the Hcy binding approaches saturation, free oxidized
      and reduced Hcy show a substantial increase. The resulting increase in
      reduced/total ratio for Hcy causes a parallel change in this ratio for the other
      aminothiols. These dynamics were observed during both chronic
      hyperhomocysteinemia (due to cobalamin deficiency or homocystinuria) and acute
      hyperhomocysteinemia (induced by methionine or Hcy loading). In addition, changes
      in redox thiol status have been observed in patients with vascular disease
      (decreased reduced/total ratio for cysteine), renal failure (low reduced/total
      ratio for aminothiols) or HIV infection (high level of reduced Hcy), which
      suggest primary imbalance between prooxidant and antioxidant processes in these
      patients. In conclusion, redox thiol status is a dynamic system which is probably
      linked to the extracellular antioxidant defence system. This must be taken into
      account when designing future experimental or epidemiological studies on Hcy and
      cardiovascular disease.

PMID- 8642472
TI  - Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis.
AB  - Growing evidence suggests that moderately elevated levels of homocysteine are
      associated not only with arterial thrombosis and atherosclerosis but also with
      venous thrombosis as well. We have reviewed recent studies that indicate that
      homocysteine inhibits several different anticoagulant mechanisms that are
      mediated by the vascular endothelium. The protein C enzyme system appears to be
      one of the most important anticoagulant pathways in the blood. Homocysteine
      inhibits the expression and activity of endothelial cell surface thrombomodulin,
      the thrombin cofactor responsible for protein C activation. Homocysteine inhibits
      the antithrombin III binding activity of endothelial heparan sulfate
      proteoglycan, thereby suppressing the anticoagulant effect of antithrombin III.
      Homocysteine also inhibits the ecto-ADPase activity of human umbilical vein
      endothelial cells (HUVECS). Because ADP is a potent platelet aggregatory agent,
      this action of homocysteine is prothrombotic. Homocysteine also interferes with
      the fibrinolytic properties of the endothelial surface because it inhibits the
      binding of tissue plasminogen activator. Homocysteine stimulates HUVEC tissue
      factor activity. We have found that lipoprotein(a) [Lp(a)] also stimulates HUVEC
      tissue factor activity. The combination of Lp(a) plus homocysteine induced more
      tissue factor activity than either agent alone. These disruptions in several
      different vessel wall-related anticoagulant functions provide plausable
      mechanisms for the occurrence of thrombosis in hyperhomocysteinemia.

PMID- 8642473
TI  - Homocysteine, EDRF, and endothelial function.
AB  - Nitric oxide, a heterodiatomic molecule, serves as an endothelium-dependent
      vasodilator and an antithrombotic agent in the vasculature. Because of its
      reactivity under physiological conditions, accumulating data suggest that nitric
      oxide forms adducts with several classes of biologic compounds, one of which is
      the sulfhydryl functionality, to form thionitrites or S-nitrosothiols. In this
      overview, we will examine the effects of S-nitrosothiols in the vascular system
      as modulators of tone and inhibitors of platelet activation to understand better
      what role these compounds may play in physiological and pathological states. With
      this background, we will review the role nitric oxide (EDRF) plays in helping to
      ameliorate vascular injury by homocysteine.

PMID- 8642474
TI  - Human homocysteine catabolism: three major pathways and their relevance to
      development of arterial occlusive disease.
AB  - Two separate metabolic pathways that methylate homocysteine to methionine are
      known in humans, utilizing, respectively, 5-methyltetrahydrofolate and betaine as
      methyl donors. Deficiency of the folate-dependent methylation system is linked to
      hyperhomocysteinemia. Our data suggest that this deficiency leads to concurrent
      metabolic down-regulation of homocysteine transsulfuration that may contribute to
      hyperhomocysteinemia. By contrast, no instances have been reported of
      hyperhomocysteinemia resulting from deficiencies of betaine-dependent
      homocysteine methylation. Long-term betaine supplementation of 10 patients, who
      had pyridoxine-resistant homocystinuria and gross hyperhomocysteinemia due to
      deficiency of cystathionine beta-synthase activity, caused a substantial lowering
      of plasma homocysteine, which has now been maintained for periods of up to 13
      years. Betaine had to be taken regularly because the effect soon disappeared when
      treatment was stopped. In conclusion, depressed activity of the transsulfuration
      pathway may contribute to hyperhomocysteinemia because of primary deficiencies of
      enzymes of either the transsulfuration or of the folate-dependent methylation
      pathways. Stimulation of betaine-dependent homocysteine remethylation causes a
      commensurate decrease in plasma homocysteine that can be maintained as long as
      betaine is taken.

PMID- 8642475
TI  - Molecular aspects of vitamin and mineral nutrition during avian development.

PMID- 8642476
TI  - Sudden death of chicken embryos with hereditary riboflavin deficiency.
AB  - Riboflavin-binding protein (RfBP) mediates the deposition of riboflavin during
      the formation of eggs in birds. Hens of a strain of Single-Comb White Leghorn
      chickens, which are genetically unable to produce RfBP, lay eggs containing
      insufficient riboflavin to sustain embryogenesis beyond 13 or 14 d of incubation.
      Embryos in these eggs grow normally until the day of death, and their heart rate
      is normal to within an hour of death. The effects of riboflavin-deficiency first
      appear after d 10 of incubation when embryos become severely hypoglycemic and
      begin to accumulate intermediates of fatty acid oxidation. Although the
      activities of flavin-dependent enzymes are reduced generally, the 80% reduction
      in the activity of medium-chain acyl-CoA dehydrogenase further suggests that the
      major metabolic consequence of riboflavin deficiency is a severe impairment of
      fatty acid oxidation. The riboflavin-deficient strain provides numerous insights
      into the metabolism of normal hens and chicken embryos and may be a useful model
      for sudden death syndromes in humans.

PMID- 8642477
TI  - Developmental expression and vitamin D regulation of calbindin-D28K in chick
      embryonic yolk sac endoderm.
AB  - The yolk is an important calcium source for the developing chick embryo. The
      epithelial yolk sac endodermal cells lie in direct contact with the yolk and are
      the principal nutrient-transporting cell type. We previously reported that
      vitamin D treatment stimulated yolk calcium mobilization and that the vitamin D
      dependent Ca2+-binding protein, calbindin-D28K, is present in the yolk sac. We
      report here the developmental expression and regulation of calbindin-D28K in the
      yolk sac. Calbindin-D28K is expressed as early as incubation d 3 and is found
      exclusively within the cytoplasm of endodermal cells. Comparative protein and
      mRNA analyses of yolk sac and dissociated yolk sac endodermal cells as a function
      of development and treatment with calcitriol (1,25-dihydroxyvitamin D3) in vitro
      and in vivo showed a development-specific and vitamin D-inducible expression of
      calbindin-D28K. Northern analysis revealed the expression of vitamin D receptor
      mRNA in the yolk sac, beginning as early as d 3, strongly indicating that the
      extraembryonic yolk sac is an early vitamin D target tissue. Cultured yolk sac
      endodermal cells should serve as a useful in vitro cell model for analyzing the
      cellular and molecular mechanisms of vitamin D action.

PMID- 8642478
TI  - Avian metallothioneins: structure, regulation and evolution.
AB  - This article reviews studies of the molecular biology of the avian
      metallothionein (MT) genes. Analysis of cloned genes and/or cDNAs from chicken,
      turkey, pheasant and quail suggests that each of these species possesses a very
      simple MT gene family. The MT from these birds is a cysteine-rich protein of 63
      amino acids that shares extensive structural homology with the mammalian MTs,
      and, remarkably, the deduced amino acid sequence of the major metallothionein is
      identical in each of these birds. The chicken MT gene is inducible by dietary or
      injected metal ions [i.e., zinc (Zn) and copper (Cu)], bacterial
      lipopolysaccharide and oxidative stress. Furthermore, it is expressed during
      liver development. The turkey and chicken MT genes are identical in gross
      structure to other functional MT genes. They consist of three exons separated by
      two intervening sequences. Comparisons of the nucleotide sequences of the turkey
      and chicken MT genes revealed regions of exceptionally high sequence
      conservation, suggesting important functions such as splicing, polyadenylation
      and transcriptional activation. Structure-function studies of the chicken MT
      promoter using transient transfection assays and transgenic mice have revealed
      cis-acting promoter sequences involved in the induction of chicken MT gene
      expression by metals ions. A metal-responsive enhancer was located in the
      proximal 107-bp of the chicken MT promoter in a region highly conserved in both
      the turkey and chicken MT genes. Function of this enhancer element apparently
      requires cooperation of transcription factors interacting with an Sp 1 binding
      site and a single palindromic metal-responsive element. In this regard, the
      structure of the proximal region of the chicken and turkey MT promoters is
      unique. Our current studies suggest that this enhancer regulates gene expression
      in a position-independent manner in transgenic mice.

PMID- 8642479
TI  - Altering ruminal nitrogen metabolism to improve protein utilization.
      Introduction.

PMID- 8642481
TI  - Effect of rumen protozoa on nitrogen utilization by ruminants.
AB  - Results obtained during the past decade indicate clearly that protozoa are
      actively involved in the degradation of dietary and microbial proteins in the
      rumen. Because of the great ability of protozoa to ingest the particulate matter
      suspended in the rumen, protozoa are more active in degrading insoluble than
      soluble proteins. This indicates that studies carried out using lysed and
      sonicated protozoa are not appropriate for quantifying the actual contribution of
      protozoa to protein degradation in the rumen. In vivo trials have confirmed that
      duodenal flow of both undegraded dietary protein plus bacterial protein generally
      is increased by defaunation. The decrease in ruminal ammonia concentration
      consistently observed after defaunation accounts for the lower urinary nitrogen
      (N) excretion found in defaunated animals, whereas the increase in fecal N
      excretion in the same animals probably results from a shift of plant cell wall
      digestion from the rumen to the large intestine. Total N excretion is not altered
      significantly by defaunation. A summary of literature data indicates there are
      contradictory effects of defaunation on ruminant performance. This implies that
      animal response to defaunation may depend on the specific nutrient-limiting
      performance on the one hand and on the modifications of digestion and metabolism
      resulting from defaunation on the other. Different methods are proposed to either
      eliminate or decrease the numbers of ruminal protozoa or to alter their makeup.
      However, none of these approaches has been tested under practical feeding
      conditions.

PMID- 8642480
TI  - Ruminal microbial metabolism of peptides and amino acids.
AB  - Peptides and amino acids, either present in the diet or arising from proteolysis
      in the rumen, are potential nutrients for the growth of ruminal microorganisms
      but also are liable to be degraded to ammonia and lost from the rumen. In both
      cases, peptides generally are metabolized by the mixed population more rapidly
      than amino acids. The predominant mechanism of peptide degradation is biphasic,
      via dipeptidyl peptidases, which cleave dipeptides from larger peptides followed
      by the action of dipeptidases. Peptides blocked at the N-terminus, or with
      glycine or proline as the N-terminal or penultimate N-terminal residue, are more
      slowly degraded than others. Dipeptidyl peptidase activity occurs only in
      Prevotella ruminicola among the common ruminal microbial species. In contrast,
      dipeptidase is present in many species, including P. ruminicola, and is
      particularly high in ruminal protozoa. Deamination of amino acids is carried out
      by a combination of numerous low activity bacteria and protozoa and a much
      smaller number of high activity species. Ammonia production is probably carried
      out mainly by the low activity species, which again include P. ruminicola, but
      proliferation of the high activity species may be a problem when certain diets
      are fed. Excessive ammonia production can be controlled by ionophores, which slow
      peptide metabolism, suppress growth of the high activity deaminating bacteria and
      cause the residual ionophore-resistant population to break down amino acids more
      slowly.

PMID- 8642482
TI  - Maximizing microbial protein synthesis in the rumen.
AB  - Microbial protein supply to the duodenum should be maximized for efficient use of
      feed protein and energy. High producing ruminants often are fed significant
      concentrations of cereal grains and fat in their diets. Increasing starch in the
      diet decreases ruminal pH, which often decreases extent of ruminal fiber
      digestion and also may decrease efficiency of microbial protein synthesis because
      of energy-spilling reactions. In contrast, higher grain feeding increased
      efficiency of microbial protein synthesis in some studies because ruminal passage
      rate was increased. Ruminal degradation of carbohydrates and protein must be
      synchronized for optimal microbial efficiency, but the microbes appear to
      withstand transient periods of asynchronous nutrient supply in many cases.
      Protozoa extensively prey upon bacteria, and a higher proportion of protozoa than
      bacteria lyse within the rumen, recycling significant amounts of protein. Feeding
      moderate amounts of unsaturated fat appears to reduce, especially on relatively
      low forage diets, protozoal numbers and the extent of intraruminal recycling.
      Indirect and direct calculations have been derived from models to estimate
      microbial protein transactions within the rumen; however, models need further
      definition and more detailed inputs from published literature to further their
      predictive ability.

PMID- 8642483
TI  - Therapeutic intervention for nonvariceal gastrointestinal hemorrhage.
AB  - The choice of therapeutic endoscopic technique depends on the training and
      equipment available to the endoscopist. If the technique is properly performed,
      the results are similar using injection, thermal coagulation, or laser therapy.
      We recommended that pediatric endoscopists concentrate on one thermal and one
      injection technique, since individual bleeding lesions may be more amenable to
      one method than another based on their anatomic location or briskness of
      bleeding.

PMID- 8642485
TI  - Correlation of hydrogen and methane production to rice carbohydrate malabsorption
      in Burmese (Myanmar) children.
AB  - Rice carbohydrate malabsorption is common in Burmese village children and adults
      and may contribute to diminished growth. Its diagnosis depends on a rice breath
      hydrogen test, which has limitations. Almost 20% of Burmese children under age 5
      produce methane, compared with less than 7% of children in Africa and Hong Kong.
      If an increased carbohydrate load in the colon due to rice malabsorption provides
      increased substrate for methanogenic bacteria in the left colon, higher fasting
      breath methane concentrations might be a simpler method of diagnosing rice
      malabsorption. We tested breath hydrogen and methane over a 4-h period and did
      anthropometric measurements in 142 subjects, 79 children, and 63 adults. Seventy
      percent of children were rice-malabsorbers. Methane production occurred in 20% of
      children under 5 years of age and increased to 60% of adults. There is an
      association of rice malabsorption with reduced length. There was not correlation
      between rice malabsorption and breath methane, and the concentration of breath
      methane does not, therefore, indicate rice absorption status and cannot replace
      rice breath hydrogen tests.

PMID- 8642484
TI  - Effect of infant formula zinc and iron level on zinc absorption, zinc status, and
      immune function in infant rhesus monkeys.
AB  - To evaluate the effects of marginal zinc (Zn) deficiency on Zn absorption and
      metabolism, three groups of infant rhesus monkeys (n = 4/group) were fed from
      birth to 5 months of age either a regular infant formula (5 mg Zn/L) or a low-Zn
      formula (1 mg Zn/L). Since iron (Fe) intake may affect Zn absorption, the low-Zn
      formula was given without (1 mg Fe/L) or with Fe fortification (12 mg/L). At
      monthly intervals, Zn absorption and retention were assessed by gavage feeding
      with 65Zn and whole-body counting immediately after and on days 4, 7, and 11
      after intubation. Blood samples were drawn before dosing for analyses of various
      potential markers of Zn status. Infants fed low-Zn formula had lower weight gain
      than controls; however, length growth was similar in all groups. 65Zn retention
      was considerably higher in both groups fed low-Zn formula (40%) than in the
      control group (20%), whereas plasma Zn levels were normal in all infants. Plasma
      metallothionein levels were generally very low and detectable in only 5 samples
      of 48; however, 4 of these were found in control infants. Neutrophil chemotaxis
      assessed at the end of the study was impaired in low-Zn infants compared to
      controls. In addition, low-Zn infants had increased levels of interleukin-2 at
      the end of the study. No differences were seen between the groups in hemoglobin
      levels, total white blood cells/absolute neutrophil counts, or plasma activities
      of 5'-nucleotidase or angiotensin converting enzyme. In conclusion, marginal Zn
      intake in infant rhesus monkeys resulted in increased Zn retention, which was not
      enough to completely compensate for the lower Zn intake. The higher level of iron
      fortification studied did not affect Zn retention significantly.

PMID- 8642486
TI  - Helicobacter pylori and recurrent abdominal pain in children.
AB  - Recurrent abdominal pain is one of the most common presentations to
      pediatricians; yet an organic etiology can be found in only 10% of cases. Because
      infection with Helicobacter pylori in adults and children results in gastritis, a
      causative role for the organism has been postulated. To investigate this theory,
      we conducted a prospective case-control study in children with recurrent
      abdominal pain using serum H. pylori IgG antibodies measured by an enzyme
      immunoabsorbent assay. Age, sex, ethnicity, and socioeconomic status were
      adjusted in the statistical model. Five subjects (5.1%) and 14 controls (14.3%)
      had raised serum IgG antibodies to H. pylori (adjusted OR, 0.21; 95% confidence
      interval, 0.05, 0.85). The negative association between H. pylori and recurrent
      abdominal pain indicates that this organism is unlikely to have an important
      etiologic role in this disorder.

PMID- 8642487
TI  - Colonic strictures in patients with cystic fibrosis: results of a survey of 114
      cystic fibrosis care centers in the United States.
AB  - We describe 15 cases of stricture of the colon requiring surgery in cystic
      fibrosis patients identified from a survey of 114 cystic fibrosis care centers in
      the United States. Patient ages ranged from 2 to 8 years, seven of the 15
      patients were female. A history of meconium ileus was reported in nine of the 15
      cases. Fibrosis of the submucosa was described in 14 surgical pathology reports.
      Pancreatic enzyme use history was available from 14 reports. All had taken
      delayed-release products for 6-96 months at average doses ranging from 6,700 to
      29,100 units lipase/kg/meal, but only eight of them used products containing
      >20,000 units lipase per capsule prior to surgery.

PMID- 8642488
TI  - Improved steatocrit results obtained by acidification of fecal homogenates are
      due to improved fat extraction.
AB  - Conflicting results have been reported on the value of the steatocrit as a
      screening test for steatorrhea. We recently modified the test procedure by fecal
      acidification with the hope of improving fat extraction and consequently the
      sensitivity of the test. The aim of the present study was to ascertain whether or
      not fecal acidification led to improved fat extraction by comparing the fat
      content of both fatty and solid layers obtained by centrifugation of 12 acidified
      (acid steatocrit) and unacidified (classical steatocrit) steatorrheal stool
      samples. The fat content of fatty and solid layers was evaluated using the
      semiquantitative (+ = 1, +2 = 2, +3 = 3) scoring system described by Drummey for
      the interpretation of the Sudan microscopic method for fecal fat. The fatty
      layers sum of scores for the 12 samples examined was 31 and 16 for the acid and
      classical steatocrit, respectively. The solid layers sum of scores for the 12
      samples was 13 and 24 for the acid and classical steatocrit, respectively. Fat
      extraction from stool samples was significantly improved after fecal sample
      acidification (p < 0.005). Acid steatocrit results agreed better with chemically
      measured fecal fat than classical steatocrit results. We conclude that fecal
      acidification, by improving fat extraction, increases the reliability of the
      steatocrit method for the detection of steatorrhea.

PMID- 8642489
TI  - Limited fat digestion in infants with bronchopulmonary dysplasia.
AB  - In 10 hyaline membrane disease patients with development of bronchopulmonary
      dysplasia, 16 hyaline membrane disease patients without development of
      bronchopulmonary dysplasia, and 12 very-low-birthweight infants without major
      medical problems, we measured the lipase and trypsin activity as well as the bile
      acids concentrations in preprandially aspirated duodenal juice. In addition, fat
      and nitrogen balances were performed during the 5th and 6th weeks of postnatal
      life. The mean duodenal lipase activity in the patients with bronchopulmonary
      dysplasia was significantly lower than those of the patients without
      bronchopulmonary dysplasia (4.41 +/- 3.0 versus 9.95 +/- 3.0 U/ml, p < 0.05) and
      of the controls (19.94 +/- 6.8 U/ml). The mean total bile acid concentration was
      below the critical micellar concentration of 4 mmol/L only in the patients with
      bronchopulmonary dysplasia. The fecal fat excretion rate in the patients with
      bronchopulmonary dysplasia was significantly higher than in the patients without
      bronchopulmonary dysplasia (21.4 +/- 4.6% versus 11.3 +/- 3.4% of intake, p <
      0.01) as well as that of the controls (7.9 +/- 2.8% of intake). The serum urea
      concentrations were similar in the patients without bronchopulmonary dysplasia
      and in the controls (1.97 +/- 0.6 and 1.89 +/- 0.4 mmol/L, respectively) but
      significantly higher in the patients with bronchopulmonary dysplasia (2.54 +/-
      0.5 mmol/L). The lowest weight gain was found in the patients with
      bronchopulmonary dysplasia (8.2 +/- 4.7 g/kg/day). It was significantly lower
      than one of the patients without bronchopulmonary dysplasia or the controls (13.5
      +/- 4.0 and 16.2 +/- 3.7 g/kg/day, respectively). The data indicate that patients
      who develop bronchopulmonary dysplasia have a limited fat absorption, which may
      help to explain the inadequate weight gain.

PMID- 8642491
TI  - Fatty acid composition of human milk in Spain.
AB  - The fatty acid composition of mature human milk obtained from 40 Spanish women
      was analyzed by capillary gas chromatography. The women were from two regions in
      Spain, Navarre and Catalonia. Milk samples were collected between 20 and 30 days
      postpartum. The fatty acid composition was expressed as weight percentage (%
      wt/wt of all fatty acids detected with a C8 to C22 chain length). Monounsaturated
      fatty acids represent 41.97%, mostly 18:1 n-9/n-7 (38.39%). The second major
      fraction was formed by saturated fatty acids, 41.09%. Polyunsaturated fatty acid
      fraction (15.23%), included seven long chain polyunsaturated fatty acids (LCPs;
      2.21%). Among LCPs, 1.6% accounted for the n-6 series and 0.64% for the n-3
      series. LCPn-6/LCPn-3 ratio was 2.51. Mothers reporting a high fish consumption
      showed higher (p < 0.05) 22:6 n-3 and 20:5 n-3 content. The use of olive oil as
      the preferential fat source showed higher 18:1 n-9/n-7 and lower 18:2 n-6 content
      (p < 0.0001), while the use of sunflower oil instead of olive oil significantly
      (p < 0.0001) increased 18:2 n-6 and decreased 18:1 n-9/n-7. Regional differences
      (p < 0.05) were detected only for the n-6 LCP and the total LCP content. The
      higher n-6 LCP and total LCP content was found in Navarre. This could have been
      due to different diet habits, like higher egg consumption.

PMID- 8642490
TI  - Dietary fiber in weaning cereals: a study of the effect on stool characteristics
      and absorption of energy, nitrogen, and minerals in healthy infants.
AB  - We evaluated the effect of increased dietary fiber (DF) content in weaning
      cereals based on wheat/soy (8.0 and 1.8% DF) and wheat/milk (5.3 and 2.0% DF) in
      healthy, formula-fed infants 7-17 weeks old. The study had a cross-over design,
      each infant acting as his or her own control. Stool characteristics and
      anthropometry were monitored over 4-week periods in groups of 34 (wheat/soy) and
      23 (wheat/milk) infants. Absorption of zinc (Zn) and calcium (Ca) was studied by
      measuring the fecal excretion of stable isotopes during 72 h (70Zn and 42Ca) in a
      subgroup of the infants consuming wheat/soy cereals. Iron (Fe) bioavailability
      was evaluated by analysis of the incorporation of 58Fe into erythrocytes 14 days
      after administration. Fractional absorption (X +/- SD: 8.0 versus 1.8% DF) was
      45.3 +/- 27.5 versus 41.2 +/- 19.4% of 70Zn and 63.4 +/- 15.8 versus 64.4 +/-
      10.6% of 42Ca. Bioavailability of 58Fe varied between 1.0% and 5.4% (8.0% DF) and
      from <0.9% to 9.1% (1.8% DF). No significant difference in energy (95.3 +/- 2.0%
      versus 95.7 +/- 1.2%) or nitrogen (92.6 +/- 2.3% versus 93.0 +/- 1.6%) apparent
      absorption from the total diet was found during consumption of cereal with 8.0
      and 1.8% DF. The intake of cereal decreased with higher DF content in the
      wheat/soy product: 34 +/- 23 g/d (8.0% DF) versus 42 +/- 23 g/d (1.8% DF), p <
      0.01. While consuming the 8.0% DF product, 11 infants were reported to have
      "gritty stools"; no other differences were observed between different groups in
      stool characteristics or anthropometry. These results demonstrate no negative
      effect on the absorption of energy and nutrients with higher dietary fiber intake
      in primarily formula-fed infants. The impact of increased dietary fiber levels
      remains unknown in less well-nourished infants.

PMID- 8642493
TI  - A comparison of small-intestinal mucosal biopsies in children obtained by blind
      suction capsule with those obtained by endoscopy.

PMID- 8642492
TI  - Effects of native and hydrolyzed whey protein on intestinal repair of severely
      starved rats at weaning.
AB  - The aim of this study was to evaluate the effect of two sources of dietary
      nitrogen (isolated whey protein and hydrolyzed whey protein) on the intestinal
      repair of malnourished rats at weaning. The malnutrition was achieved by a 3
      days' starvation period. Normally fed male Wistar rats were used as controls.
      Intestinal repair was studied after a refeeding period of 4 days. The parameters
      studied included nitrogen balance, lactase, sucrase, isomaltase, and maltase
      activities of the jejunum; liver acetylcholinesterase and glutamate dehydrogenase
      activities; and the serum amino acid profile. In addition, tests of intestinal
      permeability to macromolecules were performed by measurement of ovalbumin and
      beta-lactoglobulin in serum. Both diets of led to the recovery of the severely
      starved rats, in terms of the values of all the parameters evaluated. The serum
      beta-lactoglobulin was the only exception, because its concentration was
      significantly lower in the normally fed animals. This study suggests that the
      intestinal mucosal barrier is not completely repaired, even after a 4-day
      refeeding period, to the point of being suitable to accept an increase in the
      uptake of antigens.

PMID- 8642494
TI  - Gut permeability to human alpha-lactalbumin, beta-lactoglobulin, mannitol, and
      lactulose in celiac disease.
AB  - Our objective was to examine the permeability of the gut to protein
      macromolecules and sugar probes and their possible association in celiac disease
      patients. We studied the permeability to human alpha-lactalbumin, beta
      lactoglobulin, mannitol, and lactulose on 46 occasions in 33 celiac disease
      patients in various phases of the disease; in addition, mannitol and lactulose
      permeability was studied in 18 healthy controls. Lactalbumin absorption was
      detected in 19 of 42 patients tested, more often in celiac disease patients with
      villous atrophy than in those with normal jejunal biopsy (p = 0.01). Higher
      absorption of lactalbumin was found in patients with subtotal villous atrophy
      than in those with normal biopsy (p = 0.02). beta-lactoglobulin was found in four
      of 42 patients tested. Less mannitol was absorbed by patients with either
      subtotal or partial villous atrophy than by those with normal histology (p =
      0.001 and 0.006, respectively). Lactulose recovery was higher in newly diagnosed
      patients and patients with subtotal villous atrophy than in controls (p = 0.007
      and 0.03, respectively). The lactulose/mannitol ratio was higher in newly
      diagnosed patients and patients with villous atrophy than in controls (p = 0.002
      and 0.002, respectively). The correlation between permeability to lactalbumin and
      mannitol and lactulose was poor. We conclude that permeability to proteins and
      sugar molecules is abnormal in celiac disease patients with mucosal damage and
      that they probably reflect different mechanisms of penetration.

PMID- 8642495
TI  - Cecal volvulus following gastroduodenoscopy in Cornelia de Lange syndrome.

PMID- 8642496
TI  - Esophageal stricture caused by a retained percutaneous gastrostomy tube remnant.

PMID- 8642497
TI  - Ganglioneuromatosis involving the small intestine and pancreas of a child and
      causing hypersecretion of vasoactive intestinal polypeptide.

PMID- 8642498
TI  - Diffuse fibrosis of the colon complicating cystic fibrosis.

PMID- 8642499
TI  - Acid steatocrit.

PMID- 8642500
TI  - Necrotising enteritis.

PMID- 8642501
TI  - Mucosal microcirculation in juvenile polyps in children.

PMID- 8642502
TI  - Technique of small intestinal biopsy: use of a pediatric Watson intestinal biopsy
      capsule combined with administration of cisapride.

PMID- 8642503
TI  - Evaluation of tissue plasminogen activator and plasminogen activator inhibitor-I
      levels in acute myocardial infarction.
AB  - Fluctuations in tissue plasminogen activator (t-PA) activity, t-PA antigen, and
      plasminogen activator inhibitor-I (PAI-1) antigen levels were evaluated in blood
      samples obtained from 84 patients with initial uneventful acute myocardial
      infarction (AMI) and 35 patients with reinfarction and fatal infarction (patients
      with bad prognoses). Patients with initial AMI had significantly higher levels of
      t-PA activity than those of 14 patients with angina pectoris. Tissue plasminogen
      activator activity peaked between day 7 and 19 after the initial attack of AMI.
      Plasminogen activator inhibitor-I antigen level decreased significantly between
      day 2 and 19, then returned to the baseline levels of patients with angina
      pectoris nearly 4 weeks later. The t-PA activity levels of patients with
      reinfarction were significantly lower than those in patients without events
      between day 0 and 3 and between day 7 and 19. The percentage stenosis in the
      coronary arteries measured by coronary angiography was negatively correlated with
      t-PA activity. This information may help in selecting aggressive treatments such
      as thrombolysis by recombinant t-PA and predicting the prognosis for patients
      with AMI.

PMID- 8642504
TI  - [Usefulness of percutaneous transluminal coronary angioplasty in silent
      myocardial ischemia].
AB  - The usefulness of percutaneous transluminal coronary angioplasty (PTCA) was
      assessed in patients with exercise-induced asymptomatic myocardial ischemia
      (silent ischemia) and compared with exercise-induced symptomatic myocardial
      ischemia (symptomatic ischemia). Patients with single vessel coronary artery
      disease (51 with angina pectoris, 40 with old myocardial infarction) and evidence
      of stress-induced ischemia on thallium-201 single photon emission computed
      tomography (SPECT) underwent successful PTCA. Thirty-seven percent of angina
      patients and 60% of infarction patients showed asymptomatic exercise-induced
      ischemia. There was no significant difference in population characteristics
      between silent and symptomatic patients. Patients with silent angina had
      significantly higher percentage thallium uptake and washout rate than symptomatic
      patients. After PTCA, both percentage diameter stenosis and percentage thallium
      uptake were improved in all patients with angina irrespective of the presence or
      absence of symptoms. There were no significant differences in percentage thallium
      uptake and washout rate between patients with silent and symptomatic infarction.
      After PTCA, percentage diameter stenosis, percentage thallium uptake, and washout
      rate improved in all infarction patients irrespective of the symptoms. Zero
      percent of silent angina patients, 12% of symptomatic angina patients, 12% of
      silent infarction patients, 19% of symptomatic infarction patients had cardiac
      events during about 4.5 years after PTCA. The incidence of cardiac events did not
      significantly differ in any patient group. PTCA improved myocardial perfusion in
      all patients, and the incidence of cardiac events did not differ between the
      silent and symptomatic groups. Revascularization with PTCA is suitable for
      patients with silent as well as symptomatic ischemia.

PMID- 8642505
TI  - [Clinicopathologic study of mitral regurgitation due to abnormal chordae
      tendineae].
AB  - Severe mitral regurgitation (MR) due to abnormal chordae tendineae as a primary
      cause is rare. This clinicopathologic study included four such cases which
      occurred among 6,500 consecutive autopsies on persons older than 60 years. This
      paper describes three of these cases. Case 1 was a 76-year-old woman with
      congestive heart failure, MR and atrial fibrillation. She died of acute
      myocardial infarction. The heart weighed 360 g. Mitral regurgitation was caused
      by a thick and long abnormal chorda originating from the posteromedial papillary
      muscle and protruding into the atrial surface of the middle scallop of the
      posterior mitral leaflet associated with prolapsed anterior mitral leaflet. Case
      2 was an 81-year-old woman with MR and congestive heart failure. She died of
      acute myocardial infarction. The heart weighed 480 g. There were abnormal chordae
      tendineae with very few branches at the posterior commissure. Parts of both
      mitral leaflets on the sides of posterior commissure were also prolapsed. Case 3
      was a 91-year-old man with MR and atrial fibrillation. He died of congestive
      heart failure. The heart weighed 530 g. Abnormal chordae tendineae with reticular
      structures originated from the anterolateral papillary muscle and protruded into
      the anterior mitral leaflet, which induced severe MR. These cases had abnormally
      protruding chordae tendineae, abnormal branching, and abnormal structures of the
      chordae tendineae, respectively. These abnormal chordae tendineae were considered
      to be congenital anomalies. Clinically all patients had a holosystolic murmur
      (Levine III-IV degrees), refractory congestive heart failure and atrial
      fibrillation. The etiology of the MR in these three patients was suspected to be
      ruptured chordae tendineae demonstrated on echocardiograms. These patients had
      heavy hearts (mean 457 g) with enlarged left atria and thickened mitral valves,
      which corresponded to the appearance of severe MR.

PMID- 8642507
TI  - [Evaluation of left ventricular volume and ejection fraction using three
      dimensional transesophageal echocardiography].
AB  - Left ventricular (LV) volume and ejection fraction (EF) derived from three
      dimensional echocardiography using a multiplane transesophageal probe (3D-TEE)
      were compared with LV volume and EF obtained from left ventriculography (LVG) in
      14 patients (mean age: 61 years). Left ventricular volumes were calculated using
      a summation of disks algorithm based on multiple reconstructed short-axis cross
      sections from 3D data. Left ventricular volume (end-diastole and end-systole) and
      EF from 3D-TEE were compared with those from LVG using linear regression
      analysis. Three-dimensional TEE demonstrated excellent correlations with LVG for
      measuring LV volume (r = 0.97, SEE = 11 ml) and EF (r = 0.95, SEE-4%),
      respectively. Three-dimensional TEE is useful for the measurement of LV volume
      and EF in the clinical setting.

PMID- 8642506
TI  - [Short- and long-term effects of the new oral prostacyclin analogue, beraprost
      sodium, in patients with severe pulmonary hypertension].
AB  - Prostacyclin (PGI2) is a bioactive substance produced by vascular endothelial
      cells, which exerts powerful vasodilative and anti-platelet actions. Patients
      with pulmonary hypertension have an imbalance between vasodilative PGI2 and
      vasoconstrictive thromboxane B2 (TXB2). Treatment with vasodilative agents is
      essential for such patients. Continuous intravenous infusion of PGI2 is an
      effective treatment of primary pulmonary hypertension in terms of exercise
      capacity and survival rate. We tested a new stable PGI2 analogue, beraprost
      sodium (Procyclin, Dornar) suitable for oral administration, in patients with
      primary and secondary pulmonary hypertension. A short-term study of cardiac
      catheterization in four patients with primary pulmonary hypertension showed a 15
      +/- 12% reduction in mean pulmonary artery pressure in three of the four
      patients, and a 24 +/- 22% decrease in pulmonary vascular resistance in all four
      patients. Cardiac index increased by 27 +/- 14% in three of the four patients.
      Among three patients with secondary pulmonary hypertension, there was a 7%
      reduction in pulmonary artery pressure in one patient, and a 24 +/- 14% decrease
      in pulmonary vascular resistance in all three patients. In a long-term study (23
      +/- 11 months), NYHA functional class improved from 3.0 +/- 0.7 to 2.4 +/- 0.5 in
      two of the five patients with primary pulmonary hypertension. Although the
      radiographic cardiothoracic ratio was not significantly improved, cardiac index
      increased by 78 +/- 60% in four of the five patients. Only two patients, one with
      primary and one with secondary pulmonary hypertension, died during the long-term
      follow-up period. Plasma TXB2/6-keto prostaglandin F1 alpha ratio decreased from
      8.1 +/- 8.7 to 1.5 +/- 0.4. The optimal dose remains uncertain, but the initial
      dosage of 40-60 micrograms/day given in three to four doses for adult patients is
      considered to be acceptable. Side effects such as flushing face, headache,
      vomiting, and nausea were mild and resolved when the dose was reduced. Oral PGI2,
      beraprost, appears to be an effective and possibly adequate substitute for
      intravenous vasodilators in pulmonary hypertension for both short- and long-term
      management.

PMID- 8642508
TI  - [Usefulness of the newly developed transtelephonic electrocardiogram and computer
      supported response system].
AB  - The "Cardiophone System" is a system designed to expand the relationship between
      patients and medical services using a transtelephonic electrocardiogram and
      computer-assisted answering system. The transtelephonic electrocardiogram, or so
      called "Cardiophone", developed by Nihon Kohden, Inc., allows the patients to
      carry a "Cardiophone" to record electrocardiograms during paroxysmal occurrences
      of palpitation, chest pain, and other symptoms. The Cardiophone may function as a
      terminal of the host computer at the hospital, which stores the electrocardiogram
      and print it as soon as the computer receives the electrocardiogram over the
      phone. Cardiologists can examine the electrocardiogram immediately after it is
      printed. Cardiologists and operators are on duty 24 hours a day. Judgments based
      on the electrocardiogram are made by the cardiologist on duty, and stored in the
      computer by the operator. The patients may listen to the judgment over the phone
      within 30 min of sending the electrocardiogram. In the case of potentially lethal
      findings on the electrocardiogram, the cardiologist on duty calls the patient
      directly to give a medical advice. We studied 184 outpatients who were enrolled
      in the Cardiophone System of our hospital. The average number of transtelephonic
      electrocardiograms was 10 per day. Abnormal electrocardiographic changes were
      observed in 42 patients, and the diagnoses were as follows: paroxysmal
      supraventricular tachycardia in 18 patients, paroxysmal atrial fibrillation in
      17, ventricular tachycardia in 3, and angina in 7. Among seven patients in whom
      ST changes were documented by Cardiophone, six were diagnosed as variant angina.
      In several patients with diagnoses already made by Holter monitoring, the
      Cardiophone was used to monitor the drug effects and the correlations between
      symptoms and arrhythmic events. We conclude that the Cardiophone System is useful
      for diagnosing the causes of paroxysmal cardiac symptoms in some patients and for
      improving home medical services.

PMID- 8642509
TI  - [A 70-year-old woman complaining of shortness of breath despite decreased
      pericardial effusion].

PMID- 8642510
TI  - [Clinical significance and mechanism of ST-segment changes during the post
      exercise recovery period in male patients with coronary artery disease].
AB  - The treadmill exercise test (TET) is evaluated by exercise-induced ST-segment
      depression (delta ST). However, the depression sometimes only appears during the
      post-exercise period. Depression appearing only during the post-exercise period
      may be as useful as depression during exercise to predict coronary artery
      disease, but little is known about factors that may affect ST depression after
      exercise. The clinical significance and mechanism of post-exercise ST depression
      were investigated in patients with coronary artery disease. Target heart rate- or
      symptom-limited TET was performed in 531 male patients with definitive effort
      angina pectoris or myocardial infarction using the Bruce protocol. Patients were
      divided into four groups according to delta ST during exercise and 1-2 min after
      exercise; 1) no TET or post-exercise delta ST (Nn, n = 192), 2) only post
      exercise delta ST (Np, n = 36), 3) only TET delta ST (Pn, n = 112), 4) both TET
      and post-exercise delta ST (Pp, n = 66). Patient profiles, parameters during TET,
      echocardiographic and coronary angiographic findings and outcome during the year
      after TET were compared between the Nn and Np or Pn and Pp groups. The percentage
      of patients treated with beta-blocker was higher in the Np than that in the Nn
      group (Nn: 45%, Np: 64%, p < 0.05) and systolic blood pressure declined at 1 min
      after exercise from peak exercise in the Nn, but not in the Np group (Nn: 175 -->
      167 mmHg, p < 0.05; Np: 170 --> 170 mmHg, not significant). There was no
      difference in age, other parameters during TET, echocardiographic and coronary
      angiographic findings and outcome between the Nn and Np group. The incidence of
      right coronary artery stenosis and that of patients with multi-vessel disease
      were higher in the Pp than those in the Pn group (Pn: 41%, 58%, Pp: 65%, 73%,
      both p < 0.05). The occurrence of chest pain during exercise was higher in the Pp
      than the Pn group in spite of less delta ST at peak exercise. However, systolic
      blood pressure declined after exercise in the Pn group, but not in the Pp group
      (Pn: 164 --> 158 mmHg, p < 0.05; Pp: 166 --> 164 mmHg, not significant). These
      results confirmed that the clinical significance of post-exercise delta ST in
      patients without TET delta ST differs from that in patients with TET delta ST and
      suggests that post-exercise delta ST without delta ST during exercise may be
      associated with an abnormal response to imbalances in the cardiovascular
      sympathetic system in the post-exercise period rather than with myocardial
      ischemia.

PMID- 8642511
TI  - [Relationship between ischemic ST depression and oxygen uptake kinetics during
      ramp exercise test in patients with effort angina].
AB  - The relationship between ischemic ST depression and oxygen uptake kinetics was
      examined during cardiopulmonary exercise test using the ramp protocol in 22
      patients (17 males and 5 females, mean age 61.4 +/- 8.1 years) with ischemic ST
      change (horizontal or down sloping ST depression over 1 mm) during a previous
      multi-stage exercise test (Bruce method). Patients were classified into three
      groups according to coronary angiographic findings: absence of significant
      stenosis group (control, n = 7), single-vessel disease group (n = 7) and
      multivessel disease (MVD) group (n = 8). Peak exercise time, peak heart rate,
      peak systolic blood pressure, anaerobic threshold, peak oxygen uptake (peak Vo2),
      exercise time, heart rate, systolic blood pressure, and oxygen uptake at
      appearance of ischemic ST change were measured. The ratio of oxygen uptake
      increase at appearance of ischemic ST change was calculated. Peak Vo2 was lower
      in the MVD group than in the control group (20.9 +/- 6.2 vs 27.3 +/- 3.3
      ml/min/kg, p < 0.05), and exercise time from the beginning of ramp exercise to
      the appearance of ischemic ST depression was shorter in the MVD group than in the
      control group (5.2 +/- 2.1 vs 8.2 +/- 1.9 ml/min/kg, p < 0.05). The ratio of
      oxygen uptake increase was smaller in the MVD group than in the control group
      (0.7 +/- 0.3 vs 1.2 +/- 0.2, p < 0.01). These results could be caused by impaired
      increase of cardiac output due to myocardial ischemia occurring during exercise.
      In the clinical setting, these phenomena could be used as a parameter for
      differentiating ischemic from non-ischemic ST depression or evaluating the
      sensitivity of ischemic heart disease.

PMID- 8642512
TI  - [Projection of epicardial U-wave change to surface precordial electrocardiogram
      in coronary artery disease].
AB  - U-wave changes on the intracoronary electrocardiogram (ECG) during anterior or
      inferoposterior myocardial ischemia were correlated with the U-wave changes in
      the precordial leads of the body surface ECG in 28 patients who underwent
      coronary angioplasty of the left anterior descending (LAD group; 17 patients) or
      left circumflex (LC group; 11 patients) coronary artery. The intracoronary ECG
      was recorded simultaneously with the body surface multiple precordial leads at
      the baseline and during angioplasty. The amplitude of the U-wave on the
      intracoronary ECG was measured quantitatively, and U-wave changes from baseline
      to angioplasty were assessed qualitatively on the body surface ECG. Three
      different patterns of U-wave changes were distinguishable on the intracoronary
      ECG from baseline to angioplasty: change to positivity; no change; and change to
      negativity. The incidence of each pattern was similar in the LAD and LC groups
      (35 vs 36%; 30 vs 18%; 35 vs 46%, respectively). The intracoronary ECG was more
      sensitive for detecting U-wave changes during angioplasty than body surface
      precordial ECG (LAD group 71 vs 47%; LC group 82 vs 27%). When compared to the
      intracoronary ECG, concordant U-wave changes occurred in the surface precordial
      ECG in 67% (8/12) of the LAD group with accompanying epicardial U-wave changes,
      and discordant changes in 33% (3/9) of the LC group with epicardial U-wave
      changes. The present study provides fundamental information for understanding the
      correlation of U-wave changes between epicardial and surface precordial ECGs
      during myocardial ischemia in humans. As well as primary U-wave changes in
      anterior myocardial ischemia, reciprocal U-wave changes may also be prominent in
      the surface precordial ECGs in some cases of posterior myocardial ischemia.

PMID- 8642513
TI  - [Phasic flow velocity characteristics of the right coronary artery in patients
      with aortic stenosis: a Doppler guide wire study].
AB  - This study investigated the characteristics of the phasic flow velocity pattern
      of the right coronary artery and the relationship to hemodynamic parameters in
      patients with aortic stenosis. Coronary flow velocities were recorded at the
      proximal (segment 1) and the distal (segment 4PD) portion of the right coronary
      artery using a Doppler guide wire (0.014-in, 15 MHz) in 10 patients with aortic
      stenosis and 8 control subjects with normal coronary arteries. The diastolic to
      systolic peak velocity ratio at both the proximal and distal portion were
      significantly greater in patients with aortic stenosis than in control subjects.
      Systolic flow reversal was not seen in the right coronary artery in control
      subjects, but it was observed in 5 patients (50%) at the proximal portion and in
      10 patients (100%) at the distal portion. Peak velocity of flow reversal at the
      distal portion showed a significant correlation with mean pressure gradient
      across the aortic valve (y = -1.3x + 37.3, r = 0.71, p = 0.02). Systolic flow
      reversal is characteristic in the right coronary artery, especially at the distal
      portion, in patients with aortic stenosis. This may be related to the pressure
      difference across the aortic valve through the posterior descending artery.

PMID- 8642514
TI  - [New method for automatic tracking of the endocardial boundary in clinical use].
AB  - This study attempted to detect the left ventricular endocardial boundary in six
      healthy men (volunteers) using a newly developed computerized two-dimensional
      echocardiography method. Automatic detection of the left ventricular endocardium
      was achieved by; sampling of pictures, noise reduction of the pictures,
      filtering, decision of the early loop, detection of the left ventricular
      endocardial boundary, smoothing the boundary, and correction of the boundary.
      This process requires only 2-3 sec. Areas of the short-axis cross-sections in
      systolic and diastolic phases of one cardiac cycle were obtained and the percent
      change rate of these areas on a cardiac cycle were calculated. These were
      compared with the results obtained by the manual method. The boundary of the left
      ventricular endocardium detected by the computerized method almost coincided with
      that found by the manual method. Areas and the change rates obtained were
      correlated with those by the manual method (areas: r = 0.86, % change rate of
      area: r = 0.94). This new method is suitable for clinical use.

PMID- 8642516
TI  - [A 42-year-old man complaining of shortness of breath after aortic valve
      replacement].

PMID- 8642515
TI  - [Change in argatroban concentration within the vessel wall after local
      administration using hydrogel-coated balloon catheter].
AB  - Acute coronary occlusion after percutaneous transluminal coronary angioplasty is
      one of the major problems in coronary intervention. This study evaluated the
      hydrogel-coated balloon delivery of argatroban to the arterial wall and
      argatroban persistence after angioplasty in 17 rabbits. A hydrogel-coated balloon
      was immersed three times in argatroban/saline solution (1 mg/ml) and inflated at
      6 atm pressure for 1 min in the common carotid artery. The transfer of argatroban
      to the vascular wall was measured by high-performance liquid chromatography. The
      concentrations of argatroban at 0, 5, and 15 min after deflation were 14.8, 4.2,
      and 3.9 nmole/g.wet weight. The hydrogel-coated balloon catheter can deliver
      argatroban to the local arterial wall during balloon inflation.

PMID- 8642517
TI  - Failure of a hydroxyapatite-coated endosteal dental implant: a clinical report.

PMID- 8642518
TI  - Spontaneous regeneration of a resected mandible in a preadolescent: a clinical
      report.

PMID- 8642519
TI  - Effect of provisional luting agents on polyvinyl siloxane impression material.
AB  - Eugenol-containing cements have been traditionally selected for seating
      provisional restorations, but incomplete polymerization of polyvinyl siloxane
      impression materials has been attributed to these cements. This study clinically
      evaluated the inhibitory effect on polymerization of a specific polyvinyl
      siloxane impression material with five luting agents used for provisional
      restorations. Three of these luting agents contained eugenol, whereas two interim
      cements did not contain eugenol. A total of 60 human posterior teeth were
      prepared for complete crowns, fitted for provisional crowns, and cemented with
      interim luting agents. After 2.5 weeks the provisional crowns were removed, the
      cement on tooth preparations was removed with an explorer, and impressions were
      made. The results revealed that none of the luting agents in this investigation
      had an inhibitory effect on polymerization of polyvinyl siloxane impression
      materials.

PMID- 8642520
TI  - Three-year effect of unfilled resin dilution on water sorption of a light-cured
      microfill and hybrid composite resin.
AB  - This in vitro study compared water sorption for various intervals over a 3-year
      period for visible light-cured microfill and hybrid composite resin with and
      without unfilled resin dilutions. Statistically significant sorption increases
      were evident for the 960-day interval for certain dilutions. At 3 years the
      microfill control revealed a 0.72% relative water sorption increase and its
      various dilutions 1.92% to 2.36%. By comparison, the hybrid control exhibited an
      increase of 0.4% and its dilutions were 0.72% to 0.98%.

PMID- 8642521
TI  - Castability, opaque masking, and porcelain bonding of 17 porcelain-fused-to-metal
      alloys.
AB  - Seventeen porcelain-fused-to-metal alloys, which represented a cross section of
      the various alloy types available, were evaluated for castability, opaque
      masking, and porcelain bond strength. The base metal alloys generally cast more
      completely than the noble alloys, with the presence of beryllium as an important
      factor for greater castability among the base metal alloys. Statistically
      significant differences were observed in the ability of an opaque porcelain to
      mask the different alloy substrates but no systematic effect of alloy type was
      observed. Porcelain bond testing revealed that nickel-chromium-beryllium alloys
      produced significantly better porcelain-metal bonds than nickel-chromium alloys
      without beryllium. In addition, it was found that palladium-copper alloys
      produced significantly better bonds with porcelain than palladium-cobalt alloys.

PMID- 8642522
TI  - Restoration of pulpless teeth: application of traditional principles in present
      and future contexts.
AB  - Posts were recommended more than 100 years ago to retain artificial crowns.
      Recent studies suggest that posts can weaken teeth; therefore restorative
      procedures that help preserve pulpal vitality and eliminate the need for posts
      are desirable. If endodontic therapy is unavoidable, conservation of remaining
      tooth structure is most important. When a post is required to retain a core for
      an artificial crown, a custom cast post is the most effective means of conserving
      tooth structure. The length of the post should not be compromised, although 4 to
      5 mm of apical gutta-percha must be maintained. The restorative prognosis is
      improved if the width of the post does not exceed one half the width of the root,
      and the cemented artificial crown should extend apical to the core to provide a
      1.5 to 2 mm ferrule. Complex procedures have allowed the dentist to restore
      extensively damaged teeth. However, extraction and replacement with implant
      supported prosthodontics may be more prudent with severely compromised teeth.

PMID- 8642523
TI  - Acrylic resin denture repair with adhesive resin and metal wires: effects on
      strength parameters.
AB  - The fracture of acrylic resin dentures is an unresolved problem in
      prosthodontics. In this study one brand of denture base acrylic resin was used to
      make specimens in the form of strips and maxillary denture bases. The specimens
      were cut and repaired with one type of an autopolymerizing adhesive resin and
      metal wires. The mechanical properties of the repaired specimens were measured,
      and the efficiency of each method was evaluated. The statistical results of this
      study revealed that geometric characteristics of a maxillary denture combined
      with the shape and pretreatment of reinforcement were the controlling factors for
      the overall mechanical behavior. Furthermore this study revealed that data with
      clinical significance can only be obtained by testing specimens similar to the
      original items used in dental practice.

PMID- 8642524
TI  - An extended replication study of dental factors associated with temporomandibular
      joint sounds.
AB  - A previous study demonstrated associations between dental factors and joint
      sounds. To support these findings, this replication study was carried out in
      another sample of nonpatients. It was found that temporomandibular joint sounds
      are common in nonpatients. Their prevalence in young adults exceeded the
      prevalence in adults. The small size of the control group rendered the results of
      multivariate analysis statistically inconclusive. Tentative interpretation
      suggests that attrition of the anterior teeth or generally in the dentition,
      unilateral non-working-side interferences, morphologic occlusion, and premolar
      contacts are related to the presence of sounds. Temporomandibular joint sounds in
      nonpatients are considered to be normal and not a manifestation of subclinical
      problems. Definite answers on the causality of temporomandibular joint sounds
      will have to be based on prospective longitudinal studies.

PMID- 8642525
TI  - Jaw muscle pain and its effect on gothic arch tracings.
AB  - Perceived changes in occlusion and decreased range of motion are often expressed
      by patients with masticatory muscle pain. The adverse loading of craniomandibular
      tissues that results from an inadequate maxillomandibular relationship in
      combination with the coexisting dysfunction is widely regarded as the cause of
      pain. This study was designed to test whether pain can cause significant changes
      in position of the mandible and therefore form the basis for any perceived
      changes in the maxillomandibular relationship. A second objective was to
      determine whether pain can cause changes in the mandibular range of motion. Five
      subjects who rated pain intensity on a visual analog scale were used in a single
      blind, randomized, repeated-measures study design. Tonic muscle pain was induced
      by infusion of 5% hypertonic saline solution into the central portion of the
      superficial masseter muscle. Isotonic saline solution was used as a control, with
      subjects blinded to the type of substance given. The effect of pain on the
      position of the apex of the gothic arch tracing, the direction of the lateral
      mandibular border movements, and the mandibular range of motion was studied in a
      horizontal plane with minimal occlusal separation. Pain significantly affected
      the position of the apex of the gothic arch tracing in anterior (F = 11.46, p =
      0.03) and transverse (F = 35.0, p = 0.004) directions. Similarly, pain affected
      the orientation of the mandibular lateral border movements (F = 12.44, p = 0.02)
      and their magnitude (F = 14.97, p = 0.01). All pain-induced effects proved to be
      reversible. The observed effect of pain can explain the perceived change of bite
      that is frequently noted by patients with orofacial pain. This study provided
      evidence of an alternative causal relationship between pain and changes in
      occlusal relationship and questions occlusal therapy as treatment, directed
      toward the elimination of the underlying cause in patients with masticatory
      muscle pain.

PMID- 8642526
TI  - Elongated styloid process in a temporomandibular disorder sample: prevalence and
      treatment outcome.
AB  - An elongated styloid process is an anatomic anomaly present in 2% to 30% of
      adults; it is occasionally associated with pain. Its prevalence among patients
      with classic temporomandibular disorder pain symptoms is unknown. The effect of
      conservative treatment on patients who have symptoms of temporomandibular
      disorders and an elongated styloid process is also unknown. The objectives of
      this study were to determine the prevalence of the elongated styloid process in a
      sample of patients with temporomandibular disorders and to compare patients with
      and without the elongated styloid process on initial presenting signs and
      symptoms and treatment outcome. A total of 100 panoramic radiographs of patients
      with symptomatic temporomandibular disorders were examined to ascertain the
      presence or absence of an elongated styloid process. All patients participated in
      a conservative treatment program of biofeedback and stress management and a flat
      plane intraoral appliance. Initial symptoms and treatment outcome of patients
      with and without an elongated styloid process were compared by use of
      multivariate analysis of variance on several oral-paraoral and psychosocial
      behavioral methods. The prevalence of an elongated styloid process in this clinic
      sample of temporomandibular disorders was 27%. The patients with or without an
      elongated styloid process were not significantly different in pretreatment
      symptoms, and both groups exhibited substantial treatment gains. However,
      patients with an elongated styloid process showed significantly less improvement
      on unassisted mandibular opening without pain than did patients who did not have
      an elongated styloid process. This suggests that an elongated styloid process may
      place structural limitations on pain-free maximum mandibular opening. The results
      support conservative management of patients with symptoms of temporomandibular
      disorders when an elongated styloid process is present.

PMID- 8642527
TI  - Assessment of shoulder dimensions and angles of porcelain bonded to metal crown
      preparations.
AB  - The metal ceramic crown is the most popular extracoronal restoration in the
      United Kingdom. These restorations may fail because of fracture or esthetics. A
      potential cause of failure is the quality and width of the facial shoulder
      preparation. In this study 24 extracted human teeth were prepared to receive
      metal ceramic crowns by one of three dentists. Preparations were replicated and
      scanned in the midfacial plane by a coordinate measuring machine with a
      noncontact probe. The x, y, and z surface coordinates were recorded. The results
      indicated a mean (+/-SD) shoulder width value of 0.752 mm (+/-0.174 mm) and a
      shoulder angle of 108.54 (+/-15.06) degrees. From these data it would appear that
      there are deficiencies in shoulder preparations, particularly in width. These
      inadequacies may have implications for longevity of the restoration and
      periodontal health in a clinical situation.

PMID- 8642528
TI  - Consistency and softness of soft liners.
AB  - Consistency is evaluated by an initial flow test that allows the clinician to
      select the material of choice for relining procedures according to the size and
      shape of the ridge and the condition of the soft tissue. In this study, the
      consistency of four autopolymerized soft liners was compared and tested to
      determine whether they meet the new International Standards Organization (ISO)
      10139-1 specifications. Softness, assessed with a Shore A durometer, was compared
      with that of two heat-cured silicone soft liners, because the latter are known
      for their steady softness over long periods of time. The consistencies of all
      four autopolymerized soft liners complied with ISO specifications and their disk
      diameter ranged from 41.3 to 72.2 mm. The softness of all four soft liners
      changed with time, unlike the silicones whose softness remained consistent.
      Softness readings varied significantly with sample thickness and indicated the
      need to develop criteria for measuring softness properties and determining the
      minimal thickness required for clinical performance.

PMID- 8642529
TI  - Hardness, strength, and ductility of prefabricated titanium rods used in the
      manufacture of spark erosion crowns.
AB  - Depending on the size of the prepared tooth spark eroded and milled, Procera
      crowns (Nobelpharma AB, Goteborg, Sweden) are manufactured from one of five
      diameters of pure titanium rods. In this study microindentation hardness tests
      were performed on the outer 400 microns and center of 10 samples for each type of
      rod. Five tensile samples were also machined for each of the diameters and tested
      in tension in a universal testing machine. Cast titanium samples were similarly
      prepared and tested. Some significant differences in hardness and considerable
      differences in strength and ductility were identified between the prefabricated
      rods. In comparison, cast titanium was significantly harder and stronger but less
      ductile.

PMID- 8642530
TI  - Denture stomatitis: quantification of interleukin-2 production by mononuclear
      blood cells cultured with Candida albicans.
AB  - Denture stomatitis is usually associated with the presence of yeast, particularly
      Candida albicans, and several bacteria. In this study mononuclear blood cells
      were grown in the presence of Candida albicans from a single colony, and
      interleukin-2 production induced in T lymphocytes was measured. Blood cells were
      from a population of patients with denture stomatitis and a control group of
      denture wearers without stomatitis. Induction of interleukin-2 production was
      correlated with factors that condition denture stomatitis, namely, isolation of
      Candida albicans in selective medium, age of the denture, and diabetes.
      Concentrations of interleukin-2 in supernatant and serum were also compared.
      Significant differences in interleukin-2 production were found between patients
      with denture stomatitis and controls. Statistical analysis demonstrated a
      significant association between isolation of Candida albicans and elevated
      interleukin-2 production in cultures from patients with and without denture
      stomatitis.

PMID- 8642531
TI  - Procedure for combining a facial porcelain veneer with a metal lingual and
      occluding surface.
AB  - This article describes a procedure for making a crown that combines an all
      porcelain facial veneer with a metal lingual and occluding surface. The procedure
      combines both the conventional lost wax technique and the use of a refractory
      cast for firing porcelain. The crown retains the advantages of the traditional
      all-porcelain crown restoration but reduces the risk of damage to the opposing
      teeth associated with an all-ceramic occluding surface. Furthermore, compared
      with porcelain, the metal surface allows more control over the occlusal and
      lingual contours during construction of the crown. Although the construction of
      the anterior crown is described, the procedure is equally applicable to posterior
      full-coverage restorations.

PMID- 8642532
TI  - Positioning jig for implant abutments: procedures and clinical applications.
AB  - A custom-milled abutment may be positioned in six different orientations on a
      hexed implant. When more than one implant abutment is to be placed, the number of
      possible orientations increases and makes this step time consuming. It is
      imperative that the abutment be held in a fixed position while the abutment screw
      is tightened. Occasionally the master working cast is not accurate and a
      procedure to correct the cast without making a new impression is required. This
      article describes a procedure for making and using a positioning jig to alleviate
      these problems.

PMID- 8642533
TI  - Corrected master cast procedure for intraoral luted implant frameworks.
AB  - Large cast frameworks rarely fit multiple implant abutments passively without
      time-consuming labor-intensive adjustment procedures. Intraoral luting of
      components has been suggested to achieve a passive fit and eliminate most
      adjustment procedures. When the intraoral luted framework is returned to the
      master cast, the implant analogs may not be properly aligned to framework
      abutments. To complete the restoration, master cast modification or replacement
      may be required. The procedure described in this article produces a corrected
      master cast that fits the final framework and preserves the tissue topography of
      the original master cast.

PMID- 8642534
TI  - Intraoral recontouring aid.
AB  - This article describes a procedure and a device to expedite the intraoral
      recontouring of teeth to receive removable partial dentures. This procedure is
      particularly useful when heights of contour are lowered on posterior teeth and
      the path of insertion is perpendicular to the plane of occlusion.

PMID- 8642535
TI  - Making the framework try-in, altered-cast impression, and occlusal registration
      in one appointment.
AB  - Making a bilateral distal extension removable partial denture usually requires
      multiple appointments for metal-framework try-in, altered cast impression, and
      occlusal registration. This article describes an altered cast impression
      procedure that uses the prefabricated impression trays and record base for
      obtaining the jaw relation record. This method allows the framework try-in,
      altered cast impression, and jaw relation record to be efficiently completed in a
      single appointment.

PMID- 8642536
TI  - A simplified procedure for boxing elastomeric impressions.
AB  - Although it is taught in most dental schools, the boxing of impressions is often
      avoided by dentists after their graduation. This article presents a simple and
      efficient procedure that makes boxing impressions more acceptable. Irreversible
      hydrocolloid and the subsequent stone mix are confined with a magnetic boxing
      strip that can be easily removed and replaced. The procedure is described for
      boxing edentulous and partially edentulous altered cast impressions made with
      elastomeric impression materials.

PMID- 8642537
TI  - Preliminary silicone putty casts: diagnosis to final impression for complete
      dentures.
AB  - Silicone putty casts are useful for articulating existing dentures for evaluation
      and problem solving before relining procedures are performed or a new prosthesis
      is made. Tissue health may require significant modification of the existing
      dentures and treatment with tissue-conditioning material before final impressions
      are made. This practical procedure uses a functional impression that substitutes
      for a quality preliminary impression and combines tissue conditioning, a
      functional impression, silicone putty cast, custom final impression tray, and a
      final impression for a complete denture.

PMID- 8642538
TI  - Composition and effect of denture base resin surface primers for reline acrylic
      resins.
AB  - This study investigated the effect of resin surface primers for reline acrylic
      resins on the surface texture of denture base resin by use of scanning electron
      microscopy. Analysis of the composition of the primers was also conducted. The
      composition of the primers was classified into three groups: solvent based,
      monomer based, and monomer and polymer based. Scanning electron microscopic
      observation revealed various effects of the primers on the denture base resin
      surface, which depended on the composition of primers.

PMID- 8642539
TI  - Hardness and shock absorption of silicone rubber for mouth guards.
AB  - Silicone rubbers have general properties that make them suitable for the
      fabrication of custom-made mouth guards. This study evaluated the shock
      absorption properties and Shore A hardness of several silicone rubbers and
      derived products, compared their values with those of materials commonly used for
      the manufacture of mouth guards, and correlated the shock absorption and
      transmission abilities of these different materials with their Shore hardness.
      Silicone rubbers absorb shock better than the materials currently used for custom
      made mouth guards. In addition, to adapt mouth guards to particular sports, the
      properties of the silicone rubbers can be appropriately modified by the addition
      of oils or glass fiber reinforcement. Statistical analysis of hardness values and
      transmitted forces for the 27 materials tested indicates that the maximum
      transmitted force increases with hardness. However, this relationship is not
      linear, and departure from linearity is greatest for minimal and maximal hardness
      values.

PMID- 8642540
TI  - Custom-made mouth prop.

PMID- 8642541
TI  - Maternal exposure to influenza and risk of schizophrenia: a 22 year study from
      The Netherlands.
AB  - We investigated any effect of prenatal exposure to influenza during gestation on
      subsequent risk of schizophrenia using a national sample from The Netherlands.
      Dates of births of all Dutch-born schizophrenia (ICD-9) patients (n = 10,630)
      admitted to hospitals for the first time between 1970 and 1992 were examined in
      relation to the occurrence of influenza epidemics between 1947 and 1969. As a
      measure of prevalence of influenza, the number of deaths from influenza per month
      in The Netherlands was used. A Poisson regression analysis revealed that an
      increase in the prevalence of influenza 3 months prior to birth was followed by
      an increase in births of preschizophrenics, although this fell outside
      statistical significance (p = .11). However, the effect became marked in typical
      schizophrenics (n = 4726), but not in less typical cases (n = 5389). For typical
      schizophrenics, the parameter estimate derived from the regression model
      indicates that there was a 10% increase (95% confidence interval: -1 to 22%) in
      preschizophrenic births for every 500 deaths from influenza 3 months before
      birth.

PMID- 8642542
TI  - The concordance between symptom information gathered from remitted schizophrenic
      patients and their relatives.
AB  - The concordance between symptom information gathered from remitted schizophrenic
      out-patients and the relatives with whom they live was assessed for different
      schizophrenic symptom clusters. It was hypothesized that the positive symptoms
      would show the greatest patient-relative concordance. Patients and relatives were
      also compared for levels of overall symptom reporting. It was hypothesized that
      long-term memory problems, anosognosia, and underreporting in order to appear
      healthy, would cause patients to report fewer symptoms than their relatives. An
      alternative hypothesis was that relatives would under report symptoms to avoid
      "blame" for their relatives' illness, and because they did not have direct
      experience of the symptomatology. The 24-item version of the Brief Psychiatric
      Rating Scale (BPRS) was administered to 41 schizophrenic patients (chart
      diagnoses were validated by a DSM-III-R diagnostic checklist). Fourteen of the
      BPRS items were then used to glean information about patients' symptomatology
      from 41 relatives of the patients. Interviews with patients revealed
      significantly more symptomatology than interviews with patients' relatives for
      total and non-positive symptoms (both p-values < .01), but not positive symptoms.
      Intraclass correlations (ICC) between patients' and relatives' assessments were
      moderate for positive symptoms (ICC = .54, p < .01), low for total symptoms (ICC
      = .26, p = .05) and negligible for non-positive symptoms (.13, ns). Despite the
      potential for underreporting due to factors like anosognosia and long-term memory
      problems, patients are still the best source of information for schizophrenic
      symptomatology.

PMID- 8642544
TI  - Comorbidity in the anxiety disorders: the use of a life-chart approach.
AB  - Findings of comorbidity across the anxiety and depressive disorders have
      implications for aetiology, diagnosis and treatment. This paper describes a
      method to assess one aspect of the relationship between comorbid disorders: the
      degree to which one illness experience is believed to be caused by the earlier
      experience of a different illness. The life-chart method involves the use of a
      semi-structured interview to document the lifetime course of disorders. The
      method was reliable in a sample of patients treated at a specialized treatment
      unit for anxiety disorders. Patients fell into three major groupings: those with
      one disorder only (19%); those who fulfilled criteria for two or more disorders,
      but with one disorder primary and other disorders secondary to it (55%); and
      those who fulfilled criteria for two or more independent disorders (26%).

PMID- 8642543
TI  - Research diagnosis of current depressive disorder: a comparison of methods using
      current symptoms and lifetime history.
AB  - Data from the WHO international study of Psychological Problems in General Health
      Care were used to compare two alternative algorithms for diagnosing current major
      depression using the Composite International Diagnostic Interview: the
      traditional method based on lifetime diagnosis and an alternative method based on
      number of current symptoms. Using DSM-IV criteria for current major depression,
      6.2% of 5394 primary care patients were diagnosed by both methods, 2.0% by the
      lifetime-based method only, and 1.9% by the current symptom method only. Measures
      of severity (current symptoms, lifetime symptoms, disability, and comorbid
      anxiety) indicated that those diagnosed by only one method were only slightly
      less ill than those diagnosed by both. While the symptom-based method identifies
      a slightly more ill group, use of either method alone may exclude many who differ
      little from those classified as cases.

PMID- 8642545
TI  - The feasibility of suicide rates as an evaluation criterion in community
      psychiatry: methodological problems.
AB  - Over the last 30-40 years the reform of psychiatric care in many countries has
      led to deinstitutionalization and treatment of many patients in community
      psychiatric services. There is an ongoing discussion on whether this process may
      lead to a higher suicide rate. There are only a few studies addressing this
      issue, and empirical data are scarce. Several methodological problems make it
      difficult to use suicide rates as an evaluation criterion for community
      psychiatry. These problems are briefly discussed.

PMID- 8642547
TI  - Selection biases during recruitment of patients and relatives for a family study
      in the elderly.
AB  - The aim of the present study was to examine selection effects during recruitment
      of patients, controls and relatives for a family study in the elderly. The
      primary sample consisted of 368 in-patients (aged above 60 years) admitted in the
      years 1992 and 1993. One-hundred and eighty-four subjects (50%) suffering from
      dementia of Alzheimer type or major depression fulfilled the diagnostic inclusion
      criteria. Finally, 100 subjects participated in the family study. Demographic
      data of participants, ineligible subjects, uncooperative candidates, and control
      subjects from the general population was examined. Demographic parameters,
      reasons for refusal of personal interviews, and family history information were
      compared in first-degree relatives of participants and of 40 control subjects.
      According to demographic data, participants were representative for the whole
      sample of demented or depressed patients, and were comparable with the control
      sample. Demographic parameters of relatives were also equivalent in both groups.
      Rates of psychiatric disorders were equal in interviewed and unavailable
      relatives of patients (18.0% and 18.8%, respectively). However, interviewed
      relatives of controls had significantly fewer psychiatric disorders than
      unavailable relatives (7.8% vs 20%). This selection effect indicates the need for
      family history information on unavailable relatives in family studies on
      geriatric patients. Equivalence of demographic data alone was not a sufficient
      indicator of sample comparability. A second hospitalized comparison group might
      serve to increase the validity of conclusions resulting from comparative family
      studies.

PMID- 8642546
TI  - Lack of effect of 6 g inositol treatment of post-ECT cognitive function in
      humans.
AB  - Cholinergic agonists have been reported to ameliorate ECT-induced memory
      impairment. Inositol metabolism is involved in the second messenger system for
      several muscarinic cholinergic receptors. Inositol 6 g daily was given in a cross
      over double-blind manner for 5 days before the 5th or 6th ECT in a series of
      patients. No effect was found on post-ECT cognitive impairment.

PMID- 8642548
TI  - 11-Ketotigogenin cellobioside (pamaqueside): a potent cholesterol absorption
      inhibitor in the hamster.

PMID- 8642549
TI  - Drug delivery systems. 2. Camptothecin 20-O-poly(ethylene glycol) ester transport
      forms.

PMID- 8642550
TI  - 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an
      antagonist with high affinity and selectivity for the human dopamine D4 receptor.

PMID- 8642551
TI  - 5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)isoxazole: a
      potent, selective antagonist at human cloned dopamine D4 receptors.

PMID- 8642552
TI  - Design and synthesis of 2-naphthoate esters as selective dopamine D4 antagonists.

PMID- 8642553
TI  - Screening derivatized peptide libraries for tight binding inhibitors to carbonic
      anhydrase II by electrospray ionization-mass spectrometry.
AB  - This paper describes the use of electrospray ionization-mass spectrometry (ESI
      MS) to screen two libraries of soluble compounds to search for tight binding
      inhibitors for carbonic anhydrase II (EC 4.2.1.1). The two libraries,
      H2NO2SC6H4C(O)NH-AA1-AA2-C(O)NHCH2CH2CO2H where AA1 and AA2 are L-amino acids
      (library size: 289 compounds) or D-amino acids (256 compounds), were constructed
      by attaching tripeptides to the carboxyl group of 4-carboxybenzenesulfonamide.
      Screening of both libraries yielded, as the tightest binding inhibitor, compound
      1 (AA1 = AA2 = L-Leu; binding constant Kb = 1.4 x 10(8) M-1). The ability of ESI
      MS to estimate simultaneously the relative binding affinities of a protein to
      soluble ligands in a library, if general, should be useful in drug development.

PMID- 8642554
TI  - Asymmetric syntheses, opioid receptor affinities, and antinociceptive effects of
      8-amino-5,9-methanobenzocyclooctenes, a new class of structural analogues of the
      morphine alkaloids.
AB  - Several 8-amino-5,9-methanobenzocyclooctenes have been prepared by asymmetric
      organic synthesis techniques. Opioid receptor affinity studies have revealed the
      virtual absence of enantioselectivity for receptor binding, particularly at the
      mu-receptor, for the (+)-3a-f and the (-)-3a-f series. It is noteworthy that
      inversion of configuration at the nitrogen-bearing carbon atom [5S,8S,9S)-8-amino
      3-hydroxy-5, 9-methano-9-(methoxymethyl)-5-methylbenzocyclooctene, (+)-3a vs
      (5S,8S,9R)-8-amino-3-hydroxy-5, 9-methano-9-(methoxymethyl)-5
      methylbenzocyclooctene, (dl)-22] resulted in a > 10-fold increase in kappa
      receptor affinity. Antinociceptive studies demonstrated that (dl)-22 was a full
      kappa-agonist while (+)-3a and (-)-3a did not possess kappa-activity. Although
      both (dl)-22 and (+)-3a/(-)-3a had high affinity for the mu-receptor, these
      compounds did not act as high-affinity agonists or antagonists at this receptor.

PMID- 8642556
TI  - Antitumor agents. 166. Synthesis and biological evaluation of 5,6,7,8-substituted
      2-phenylthiochromen-4-ones.
AB  - As a continuation of our structure--activity relationship study of substituted 2
      phenyl-4-quinolones and flavonoids as antitumor and antiviral agents, a series of
      5,6,7,8-substituted-2-phenylthiochromen-4-ones has been synthesized by
      condensation of substituted thiophenols and ethyl benzoylacetates. Target
      compounds were evaluated for biological activity. Among them, compounds 7, 10,
      12, and 13 displayed significant growth inhibitory action against a panel of
      tumor cell lines including human ileocecal carcinoma (HCT-8), murine leukemia (P
      388), human melanoma (RPMI), and human central nervous system tumor (TE671)
      cells. Compounds 10, 12, and 19 displayed DNA topoisomerase I inhibitory activity
      in vitro and compound 11 was an in vitro, inhibitor of DNA topoisomerase II.
      Compound 11 was most active (ED50 value, 0.65 microM) against HIV in acutely
      infected H9 lymphocytes and had a therapeutic index of about 5.

PMID- 8642555
TI  - (Aminoalkyl)indole isothiocyanates as potential electrophilic affinity ligands
      for the brain cannabinoid receptor.
AB  - A series of (aminoalkyl)indole compounds, naphthalene analogs of pravadoline (1),
      has been shown to exhibit cannabinoid agonist activities such as antinociception
      in animals, inhibition of adenylate cyclase in brain membranes, and binding to
      the cannabinoid receptor. These pravadoline analogs were selected for the
      preparation of potential electrophilic affinity ligands based on the synthesis of
      isothiocyanate derivatives. One isothiocyanatonaphthalene derivative (8)
      displaced [3H]CP-55940 binding to a rat brain P2 membrane preparation with an
      IC50 of 690 nM, which was 10-fold less potent than the parent molecule (IC50 = 73
      nM). Isothiocyanate substitution at various positions on the naphthalene moiety
      of the desmethyl analog 10 gave compounds that displaced [3H]CP-55940 with IC50
      values between 400 and 1000 nM, compared with 46 nM for the parent compound 10.
      However, 6-isothiocyanato substitution on the indole ring of the desmethyl analog
      provided isothiocyanate 12 that displaced [3H]CP-55940 binding with an IC50 and
      160 nM. After pretreatment of brain membranes with this high-affinity
      isothiocyanato ligand followed by washing out the ligand, the membranes were
      depleted of 90% of the cannabinoid receptor binding capacity. Loss of receptor
      binding capacity was half-maximal at 300 nM of the derivative under standard
      assay conditions. As a control, pretreatment with the parent compound at
      concentrations that were 20 times the Kd failed to alter subsequent binding
      activity. This study demonstrates that an isothiocyanato (aminoalkyl)-indole (12)
      can behave as an affinity ligand which binds irreversibly to the cannabinoid
      receptor in brain and which precludes subsequent binding of the cannabinoid
      ligand [3H]CP-55940.

PMID- 8642557
TI  - Decomposition pathways and in vitro HIV inhibitory effects of isoddA
      pronucleotides: toward a rational approach for intracellular delivery of
      nucleoside 5'-monophosphates.
AB  - The decomposition pathways and kinetics in various biological media and the in
      vitro anti-HIV-1 and anti-HIV-2 activities of four derivatives of the 5'
      mononucleotide of isoddA incorporating carboxylate esterase-labile transient
      phosphate protecting groups are reported and compared: namely, two mononucleoside
      aryl phosphoramidate derivatives 1a,b and two mononucleoside phosphotriester
      derivatives incorporating two S-acyl-2-thioethyl groups 2a,b. All four compounds
      show better antiviral activity, compared to the parent nucleoside analog isoddA.
      The results highlight that both types of compounds act as pronucleotides, i.e.
      they exert their antiviral effect via intracellular delivery of the 5'
      mononucleotide of isoddA. The results may give insights for the design of new
      more efficient pronucleotides.

PMID- 8642558
TI  - Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships
      of P1/P1' compounds: correlation between lipophilicity and cytotoxicity.
AB  - A series of novel aminodiol inhibitors of HIV protease based on the lead compound
      1 with structural modifications at P1' were synthesized in order to reduce the
      cytotoxicity of 1. We have observed a high degree of correlation between the
      lipophilicity and cytotoxicity of this series of inhibitors. It was found that
      appropriate substitution at the para position of the P1' phenyl group of 1
      resulted in the identification of equipotent (both against the enzyme and in cell
      culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased
      cytotoxicity.

PMID- 8642559
TI  - Rational design of true hirudin mimetics: synthesis and characterization of
      multisite-directed alpha-thrombin inhibitors.
AB  - We describe here the design, synthesis, and activity of a novel class of alpha
      thrombin inhibitors named hirunorms. They were rationally designed to interact
      through their N-terminal end with the alpha-thrombin active site in a
      nonsubstrate mode and to specifically bind the fibrinogen recognition exosite. An
      appropriate spacer that is able to properly orient the N-terminal end in the
      active site was also selected. This spacer allowed the size of the inhibitors to
      be reduced to about one-third of the amino acid residues in the hirudin sequence.
      Hirunorms specifically inhibit the amidolytic action of human alpha-thrombin
      toward a small chromogenic substrate. The most active compounds of the series,
      hirunorms IV and V, inhibit alpha-thrombin catalyzed hydrolysis of Tos-Gly-Pro
      Arg-p-nitroanilide with K(i) = 0.09 and K(i) = 0.21 nM, respectively. Comparison
      of the anticoagulant properties of hirunorms, natural hirudin from the European
      leech Hirudo medicinalis, and the synthetic analog hirulog-1 revealed that
      hirunorm IV is about 10-fold and 3-fold more active, on a molar base, than
      hirudin and hirulog-1 in increasing the aPTT, PT, and TT of normal human plasma.
      The peculiar structure of hirunorms makes them stable to the amidolytic action of
      thrombin without the introduction of any peptide bond modification. These
      molecules display long-lasting activity in human plasma, due to the presence of
      several unnatural amino acids in susceptible positions. Hirunorms are potential
      candidates for injectable anticoagulants, due to their potency, specificity of
      action, long-lasting activity, and safety profiles.

PMID- 8642560
TI  - Oxidation chemistry of (-)-norepinephrine in the presence of L-cysteine.
AB  - The noradrenergic neurotransmitter (-)-norepinephrine (1) is very easily oxidized
      at physiological pH to an o-quinone (2) that normally cyclizes and subsequently
      oxidatively polymerizes to black melanin. In this investigation it is
      demonstrated that L-cysteine (CySH) can divert the melanin pathway by efficiently
      scavenging o-quinone 2 to give, initially, 5-S-cysteinylnorepinephrine (6) and 2
      S-cysteinylnorepinephrine (7). These cysteinyl conjugates are appreciably more
      easily oxidized than 1 to o-quinones that, in part, are further attacked by CySH
      to give 2,5-bi-S-cysteinylnorepinephrine (8), an even more easily oxidized
      compound. The o-quinone intermediates formed upon oxidation of 6-8 can also
      undergo facile intramolecular cyclizations to bicyclic o-quinone imines that
      oxidize the cysteinyl conjugates from which they are derived in a reaction
      sequence that leads initially to a number of dihydrobenzothiazines. At least two
      of these compounds, 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5- hydroxy-2H-1,4
      benzothiazine-3-carboxylic acid (9) and 8-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5
      hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (10) are lethal when administered
      into the brains of mice. The in vitro chemical pathways elucidated in this
      investigation might be of relevance to the depigmentation and degeneration of
      neuromelanin-pigmented noradrenergic cell bodies in the locus ceruleus in
      Parkinson's Disease and to the degeneration of noradrenergic nerve terminals in
      Alzheimer's Disease and following transient cerebral ischemia (stroke).

PMID- 8642561
TI  - Partially modified retro-inverso pseudopeptides as non-natural ligands for the
      human class I histocompatibility molecule HLA-A2.
AB  - Syntheses of a series of partially modified retro-inverso analogues of the
      antigenic peptide M58-66 derived from the influenza virus matrix protein are
      reported. The retro-inverso modification phi(NH-CO) was obtained by replacement
      of two successive amino acid residues with a 2-substituted malonate derivative
      and gem-diaminoalkyl residue. The resulting compounds 1-8 were tested for their
      binding to the human histocompatibility class I molecule HLA-A2 in an assembly
      assay using lysates of peptide transporter-deficient cells T2. Specific peptide
      dependent HLA-A2 assembly was revealed by an enzyme-linked immunosorbent assay.
      Significant HLA-A2 assembly was detected in the presence of analogues [gGly58
      (S)mLeu59]-M58-66 (1a), [gGly61-(R,S)mPhe62]M58-66 (4), [gVal63-(R,S)mPhe64]M58
      66 (6), and [gPhe64-(R,S)mAla65]M58-66 (7). The introduction of the retro-inverso
      modification between P2-P3, P3-P4, P5-P6, and P8-P9 (compounds 2, 3, 5, and 8,
      respectively) however led to a dramatic reduction in peptide binding to HLA-A2.
      Interestingly, compound 1a which contains modification between P1-P2 was found to
      be the most potent analogue, being able to retain the original HLA-A2 binding
      profile of the parent peptide M58-66. Taken together, these results and recent
      binding data obtained in the context of murine MHC class I molecule H-2Kd suggest
      that the incorporation of peptide bond surrogates in MHC class I-restricted
      epitopes is a useful approach to design molecules having both increased stability
      and high MHC-binding capacity. Depending on their agonist or antagonist effects
      at the T-cell receptor, such non-natural MHC ligands are likely to find many
      applications in the development of peptide-based vaccines or as potential
      therapeutic agents in the treatment of allergies and autoimmune diseases.

PMID- 8642562
TI  - Synthesis of novel Se-substituted selenocysteine derivatives as potential kidney
      selective prodrugs of biologically active selenol compounds: evaluation of
      kinetics of beta-elimination reactions in rat renal cytosol.
AB  - Eighteen Se-substituted selenocysteine derivatives were synthesized as potential
      kidney selective prodrugs which can be activated by renal cysteine conjugate beta
      lyase to selenium-containing chemoprotectants or antitumor agents. Selenocysteine
      derivatives with aliphatic and benzylic Se-substituents were synthesized by
      reducing selenocystine to selenocysteine followed by a reaction with the
      corresponding alkyl and benzyl halogenides. Selenocysteine derivatives with
      aromatic Se-substitutes were synthesized by reaction of beta-chloroalanine with
      substituted phenylselenol compounds, which were formed by reducing substituted
      diphenyl diselenides by NaBH4. The enzyme kinetic parameters (apparent Km and
      Vmax) of the beta-elimination reaction of the selenocysteine conjugates were
      studied in rat renal cytosol. The results suggest that Se-substituted L
      selenocysteine conjugates are extremely good substrates for renal cysteine
      conjugate beta-lyases as indicated by low apparent Km and high Vmax values. The
      benzyl-substituted Se-conjugates appeared to be better substrates than the phenyl
      and alkyl-substituted Se-conjugates. Corresponding L-cysteine S-conjugates were
      too poor substrates to obtain proper enzyme kinetics. Recently, local activation
      of cysteine S-conjugates by renal cysteine conjugate beta-lyases was proposed as
      a new strategy to target antitumor agents to the kidney. The present results show
      that Se-substituted selenocysteine conjugates may be more promising prodrugs
      because these compounds are much better substrates for beta-lyase.

PMID- 8642563
TI  - Discovery of novel, non-peptide HIV-1 protease inhibitors by pharmacophore
      searching.
AB  - Fifteen novel non-peptide HIV-1 protease inhibitors were identified by flexible
      3D database pharmacophore searching of the NCI DIS 3D database. The pharmacophore
      query used in the search was derived directly from the X-ray determined
      structures of protease/inhibitor complexes. These 15 inhibitors, belonging to
      nine different chemical classes, are promising leads for further development. The
      two best inhibitors found, NSC 32180, a "dimer" of 4-hydroxycoumarin, and NSC
      117027, a "tetramer" of 2-hydroxy quinone, had ID50 values of 0.32 and 0.75
      microM for HIV-1 protease inhibition, respectively, and two other inhibitors had
      ID50 values close to 1 microM. Among the potent inhibitors, NSC 158393 not only
      demonstrated activity against HIV-1 protease (ID50 1.7 microM) but also exhibited
      promising antiviral activity in HIV-1-infected CEM-SS cells (EC50 = 11.5 microM).
      Validation of the pharmacophore used in the search was accomplished by
      conformational analysis. The binding modes of the most potent inhibitor found in
      our studies, NSC 32180, were predicted employing docking and molecular dynamics
      techniques.

PMID- 8642564
TI  - Studies on selectin blockers. 2. Novel selectin blocker as potential therapeutics
      for inflammatory disorders.
AB  - As a part of our studies of selectin blockers, we prepared 1-(2
      tetradecylhexadecyl)-3'-O-sulfo Le(X) 1 and 1-(2-tetradecylhexadecyl) sLe(X) 2
      and examined their inhibitory activities against natural ligand (sLe(X)) binding
      to E-, P-, and L-selectins. Compounds 1 and 2 were 2 times more potent than the
      sLe(X) tetrasaccharide toward E-selectin binding and up to 4 times more potent
      than sLe(X) toward P- and L-selectin binding. Interestingly, compound 1 provided
      dose-dependent protective effects against an immunoglobulin E-mediated skin
      reaction in mouse ears. This protective effect was associated with diminished
      tissue accumulation of neutrophils in the ear (as assessed by myeloperoxidase).
      These findings indicate that the modification of sLe(X) or 3'-O-sulfo Le(X) with
      a "branched anchor", a 2-tetradecylhexadecyl group, is useful in the design of a
      more potent selectin blocker, which has broad inhibitory activities toward all
      selectins.

PMID- 8642565
TI  - Inhibitors of human immunodeficiency virus type 1 protease containing 2
      aminobenzyl-substituted 4-amino-3-hydroxy-5-phenylpentanoic acid: synthesis,
      activity, and oral bioavailability.
AB  - Systematic modifications of HIV protease inhibitor (2R,3S,4S)-4
      [[(benzyloxycarbonyl)-L-valyl]-amino]-3-hydroxy-2-[(4- methoxybenzyl)amino]-5
      phenylpentanoyl)-L-valine 2-(aminomethyl)- benzimidazole amide led to a novel
      series of inhibitors with shortened, modified carboxy terminus. Their synthesis,
      in vitro enzyme inhibitory data, and antiviral activities are reported. Of
      particular interest are derivatives featuring the (1S,2R)-1-amino-2-hydroxyindan
      moiety at the P2'-position since some of them exhibit substantial oral
      bioavailability in mice. The influence of aqueous solubility and structural
      parameters on the oral resorption of the inhibitors is discussed. Optimum
      enhancement of oral bioavailability was observed with L-tert-leucine in P2
      position, resulting in the discovery of (2R,3S,4S)-4-[[(benzyloxycarbonyl)-L-tert
      leucyl]- amino]-3-hydroxy-2-[(4-methoxybenzyl)amino]-5-phenylpentanoic acid
      (1S,2R)-1-amino-2-hydroxyindan amide which combines high antiviral activity (IC50
      = 250 nM) with a good pharmacokinetic profile (AUC = 82.5 microM.h at a dose of
      125 mg/kg po in mice).

PMID- 8642566
TI  - Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and
      biological evaluation of piperazinopyrrolothienopyrazines.
AB  - A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine
      derivatives were prepared and evaluated in order to determine the necessary
      requirements for high affinity on the 5-HT3 receptors and high selectivity versus
      other 5-HT receptor subtypes. Various substitutions on the piperazine and the
      thiophene ring of the pyrrolothienopyrazine moieties were systematically explored
      as well as replacement of the piperazine by other cyclic amines. The best
      compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to
      very high selectivity (up to 10,000 for 14b). These high-affinity compounds have
      in common a benzyl- or allylpiperazine substituent with no substitutions on the
      thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been
      evaluated on the Von Bezold-Jarisch reflex and were characterized as partial
      agonists. One of them, 13a, has shown in vivo at very low dose a potent
      anxiolytic-like activity in the light/dark test.

PMID- 8642567
TI  - Probes for narcotic receptor-mediated phenomena. 21. Novel derivatives of 3
      (1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol- 6-yl)
      phenols with improved delta opioid receptor selectivity.
AB  - Derivatives of racemic and optically pure levorotatory 3-(1,2,3,4,5,11-hexahydro
      3-methyl-2,6-methano-6H-azocino[4,5-b]in dol-6-yl)phenols containing methoxy
      substituents in the C10', C9', and C8' positions (compounds 9-11, respectively)
      were synthesized and characterized by spectroscopic and X-ray methods. The
      binding affinities for the mu, delta and kappa 1 opioid receptors and activity in
      the guinea pig ileum (GPI) and mouse vas deferens (MVD) functional bioassays were
      determined for these compounds. A methoxy substituent in the C8' position
      decreases the binding affinity for both the mu and delta receptors, while a C10'
      methoxy substituent has little effect on either binding affinity. Interestingly,
      a methoxy group at the C9' position in the levorotatory series provides compound
      (-)-10 which exhibits both enhanced in vitro affinity and selectivity for the
      delta opioid receptor relative to the unsubstituted derivative (-)-8 and is the
      most selective (mu/delta IC50 ratio 17.9, kappa 1/delta IC50 ratio 314) and
      highest affinity (IC50 3.7 nM) delta receptor ligand for this novel class of
      compounds. The results of the GPI and MVD bioassays are more dramatic and
      indicate that (-)-10 is an agonist for the delta receptor (IC50 49.0 nM) with
      substantial selectivity for the delta versus the mu receptor borne out by a
      GPI/MVD IC50 ratio of > 612.

PMID- 8642568
TI  - Structure-activity relationships of boronic acid inhibitors of dipeptidyl
      peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides.
AB  - A series of prolineboronic acid (boroPro) containing dipeptides were synthesized
      and assayed for their ability to inhibit the serine protease dipeptidyl peptidase
      IV (DPPIV). Inhibitory activity, which requires the (R)-stereoisomer of boroPro
      in the P1 position, appears to tolerate a variety of L-amino acids in the P2
      position. Substitution at the P2 position which is not tolerated include the D
      amino acids, alpha,alpha-disubstituted amino acids, and glycine. Specificity
      against DPPII and proline specific endopeptidase is reported. A correlation
      between the ability to inhibit DPPIV in cell culture and in the human mixed
      lymphocyte reaction is demonstrated. A synthesis of prolineboronic acid is
      reported as well as conditions for generating the fully unprotected boronic acid
      dipeptides in either their cyclic or acyclic forms.

PMID- 8642569
TI  - Design and synthesis of new linear and cyclic bradykinin antagonists.
AB  - We report here on the synthesis and pharmacological properties of a new series of
      small linear and cyclic peptides derived from the five C-terminal amino acid
      residues of second-generation bradykinin receptor antagonists. Variations of the
      two first residues of the pentapeptide (Thi-Ser-D-Tic-Oic-Arg) were shown to
      modulate the biological activities of the analogs on bradykinin-induced smooth
      muscle contractions in rabbit jugular vein (RJV), a tissue preparation specific
      of the B2 bradykinin receptor. Several analogs showed pA2 values around 7 on this
      tissue preparation, and one cyclic compound, c[-Gly-Thi-D-Tic-Oic-Arg-], 24, in
      which Thi-Ser was replaced by Gly-Thi, displayed a pA2 of 7.4 on RJV. On the
      basis of these results, three cyclic molecules and their linear counterparts
      (compounds 22-24 and 4-6, respectively) were tested on human umbilical vein, a
      tissue specific of the human B2 receptor. The pKB values obtained for these
      compounds on these tissue preparations were equivalent to those obtained for the
      decapeptide NPC 567 (4.8 < pA2 < 5.1). NMR and molecular modeling studies
      performed on compound 24 clearly demonstrated a type II' beta-turn structure.
      This analog may serve as a new lead for the design of nonpeptide ligands of the
      bradykinin B2 receptor subtype.

PMID- 8642570
TI  - Experimental infection of Wistar rats with 'Gastrospirillum suis'.
AB  - In order to develop a model for the study of gastric spiral bacteria, and based
      on the observation that Wistar rats do not carry urease-positive spiral bacteria
      in their gastric mucosa, mucus from a pig naturally colonised by 'Gastrospirillum
      suis' (an organism with I6S rDNA 99.5% similar to that of 'G. hominis' type 1),
      was inoculated into 35 Wistar rats (test group). Fourteen rats were given mucus
      taken from 'G. suis'-negative swine (control group). Five test animals and two
      controls were killed 1, 2, 4, 8, 12, 26, and 52 weeks after inoculation. 'G.
      suis' was observed in the antral mucosa of all test rats but not in the gastric
      mucosa of any control animal. The number of organisms was high from the beginning
      of the infection and increased over the period of observation. The bacteria were
      seen deep in the gastric antral glands, especially in the advanced stages of
      infection. Histological study of two test rats killed 1 week after inoculation
      and of all rats killed from the second week after infection revealed the presence
      of a mild inflammatory response characterised by the infiltration of small
      numbers of mononuclear cells and scarce polymorphonuclear cells in the
      subglandular region of the antral mucosa. Lymphoid aggregates were observed in
      the antral mucosa of rats killed from 1 month onwards, and increased in size and
      number over the period of infection. Control animals did not have any
      histological changes in the gastric mucosa. The natural transmission of the
      bacterium from rat to rat was also investigated. Five non-inoculated animals
      (contact group) and rats of the test group were maintained in the same cage and
      killed after 12 weeks. Two animals of the contact group showed slight
      infiltration of mononuclear cells in the antral mucosa, although they were not
      colonised by 'G. suis', a finding that supports the hypothesis of faecal-oral
      transmission of gastric Helicobacter spp. This animal model could be used not
      only to understand different aspects of the relationship between spiral bacteria
      and the gastric mucosa but also to obtain large numbers of the organism, free
      from other spiral bacteria to study some of its properties.

PMID- 8642571
TI  - Enhancement of Clostridium difficile toxin production in biotin-limited
      conditions.
AB  - The effect of biotin on toxin production by Clostridium difficile was examined in
      a defined medium. When toxin production by strain KZ 1647, which was isolated
      from a healthy adult, was examined in relation to its biotin requirement, it was
      found that with decreasing concentrations of biotin, bacterial growth was
      decreased, but production of both toxins A and B were remarkably increased,
      particularly with 0.05 nM biotin. The time course of production of both toxins in
      biotin-limited conditions was similar to that in biotin-enriched conditions. The
      biotin effect on toxin production was also observed in 15 other strains,
      suggesting that the effect occurs frequently amongst toxigenic C. difficile
      strains. The biotin effect is discussed in relation to the pathogenesis of C.
      difficile colitis.

PMID- 8642572
TI  - Cell surface properties of Clostridium difficile: haemagglutination, relative
      hydrophobicity and charge.
AB  - Five well characterised strains of Clostridium difficile of differing virulence
      and two Escherichia coli strains, a verotoxigenic O157:H7 isolate and a urinary
      isolate, were examined for cell surface hydrophobicity and charge, and
      haemagglutinating ability. Phase partition in hexadecane or octan-1-ol was
      similar for C. difficile and E. coli, as was retention by hydrophobic interaction
      chromatography (HIC), indicating moderate hydrophobicity. The salt agglutination
      test showed E. coli to be hydrophobic and C. difficile to be hydrophilic.
      Relative hydrophobicity determined by HIC when charge effects were not nullified,
      i.e., to reflect more closely conditions in vivo, showed C. difficile to bind
      less well. Growth of C. difficile in caecal emulsions to simulate conditions in
      vivo did not alter the cell surface hydrophobicity. The phase partition method
      for charge determination indicated that E. coli and C. difficile had a net
      negative charge, although this was weaker for C difficile than E. coli. However,
      although E. coli exhibited a net negative charge as determined by immuno-gold
      electronmicroscopy (IGEM), in keeping with the results of the phase partition
      method, C. difficile was shown to be predominantly positively charged by IGEM,
      and by movement in a charged field as determined by paper electrophoresis and a
      novel method based on light microscope observation. A cell-wall deficient mutant
      of C. difficile was weakly positively charged, showing that most of the charge
      resides in the cell wall.

PMID- 8642573
TI  - Genetic regulation of fatty acid modifying enzyme from Staphylococcus aureus.
AB  - Fatty acid modifying enzyme (FAME) is an extracellular enzyme that inactivates
      staphylocidal lipids by catalysing the esterification of these lipids to
      cholesterol. In-vitro expression of FAME began at the start of the stationary
      phase. This expression of FAME was very similar to other staphylococcal
      extracellular proteins controlled by the global regulators Agr and Sar. A
      staphylococcus aureus strain ISP546 (Agr-) produced c. 80% less FAME than an
      isogenic Agr+ strain ISP479C. Similar results were obtained with the isogenic
      Agr+/Agr- strain pair RN6390 and RN6911. A S. aureus strain R (Sar-) produced c.
      86% less FAME than an isogenic Sar+ strain RN6390. However, lipase assays on the
      same culture filtrates from the Sar+/Sar- strains did not demonstrate any affect
      on lipase production by the sar mutation.

PMID- 8642574
TI  - Immune response to Fusobacterium nucleatum and Prevotella intermedia in patients
      with infectious mononucleosis.
AB  - The role of four oral flora organisms (Fusobacterium nucleatum, Prevotella
      intermedia, Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans)
      was investigated in 22 patients with infectious mononucleosis. Immunoglobulin-G
      class antibody titres to these organisms were measured by enzyme-linked
      immunosorbent assay. Serum levels in the patients were determined at day 1 and 42
      56 days later. Significantly higher antibody levels to F. nucleatum and Pr.
      intermedia were found in the second serum sample of patients as compared to their
      first sample. The elevated antibody levels to F. nucleatum and Pr. intermedia,
      known oral pathogens, suggest a potential pathogenic role for these organisms in
      the pharyngo-tonsillitis associated with infectious mononucleosis.

PMID- 8642575
TI  - Increased expression of Fc gamma receptors on neutrophils and monocytes may
      reflect ongoing bacterial infection.
AB  - The Fc gammaR receptors for IgG, Fc gammaRI, Fc gammaRII and Fc gammaRIII were
      measured on neutrophils and monocytes from 36 patients suspected of systemic
      infection. These results were compared with 30 blood donor controls to assess the
      level of expression as an early indicator of bacterial infection. Fc gammaRI
      expression on neutrophils was found to be significantly increased from patients
      with systemic or localised infections, when compared to non-infected patient
      group, i.e., patients with no cultural evidence of bacterial infections, (p=0.02,
      p=0.04) or normal controls (p<0.0001, p=0.0005). Fc gammaRI expression on
      monocytes was also significantly increased in both of the infected groups
      compared to normal controls (p<0.0001, p=0.001); however, no significant
      difference could be seen when compared with the non-infected patients. Fc
      gammaRIII was found to be significantly increased on a subset of monocytes in
      patients with systemic or localised infections compared to the non-infected group
      (p=0.009, p=0.006) and compared to the normal controls (p=0.009, p=0.003).
      Infections caused by gram-negative bacilli induced a higher Fc gammaR response
      than infection with either streptococci or staphylococci. These data suggest that
      the measurement of Fc gammaRI on neutrophils and Fc gammaRIII on monocytes may be
      a useful rapid indicator of bacterial infection.

PMID- 8642576
TI  - Reactivity of various leishmanial antigens in a direct agglutination test and
      their value in differentiating post-kala azar dermal leishmaniasis from leprosy
      and other skin conditions.
AB  - A direct agglutination test (DAT) for the detection of post-kala azar dermal
      leishmaniasis (PKDL) was evaluated in conditions that simulate the disease
      clinically or immunologically. A reference strain of Leishmania donovani (LEM
      1399), and antigen preparations from Leishmania isolates from Bangladeshi
      patients with post-kala azar dermal leishmaniasis or visceral leishmaniasis were
      used. A titre of at least 51,200 was obtained in tests of patients with PKDL with
      all three antigens, whereas a maximum titre of 1600 was recorded in patients with
      cutaneous leishmaniasis, mucocutaneous leishmaniasis or leprosy. Antigens from
      dermal isolates of L. tropica (LV 140) and L. braziliensis (LV 65) yielded titres
      of 1600-6400 in patients with PKDL. The lowest titre recorded in 70 patients
      tested with the homologous PKDL antigen was 409,600. In patients with leprosy,
      cutaneous leishmaniasis, syphilis, onchocerciasis, tuberculosis, blastomycosis or
      vitiligo, titres ranged from 100 to 1600. Tha DAT is better than current
      parasitological and histopathological methods for the diagnosis of PKDL in areas
      in which leprosy is co-endemic.

PMID- 8642578
TI  - Enterovirus typing by immune electronmicroscopy.
AB  - A simple method of typing enteroviruses by immune electronmicroscopy (IEM) is
      given. Forty-four of 50 picornavirus strains typed by both IEM and neutralisation
      in cell culture gave identical results. Four strains could not be typed by one or
      other method. Two rhinovirus isolates were untypable by both methods. There were
      no discrepant results. The IEM method is convenient and has considerable savings
      in time and reagents.

PMID- 8642577
TI  - Evaluation of verification assays in EIA specimens presumptively positive for
      Chlamydia trachomatis.
AB  - Verification of specimens positive for Chlamydia trachomatis by enzyme
      immunoassay (EIA) has been recommended when testing low prevalence populations.
      This study compared direct fluorescent antibody (DFA) and blocking antibody (BLA)
      verification assays in specimens presumptively positive for C. trachomatis by the
      Syva Microtrak II EIA. Of 1785 specimens originally tested by EIA, 96 were
      presumptively positive for C. trachomatis. Verification assays were concordant in
      86 specimens (69 positive, 17 negative); nine of the remaining samples gave
      positive results in a second EIA and one was unresolved. Both verification assays
      gave some false-negative results. When initial EIA absorbance values were
      correlated with verified results, all EIA false positive results had absorbances
      in the low range (less than a three-fold increase over assay cut-off values).
      Verification of EIA results by both DFA and BLA was effective in detecting false
      positive results, but confining verification to low-value positive specimens
      could be considered for cost effective C. trachomatis testing.

PMID- 8642579
TI  - Q fever: still a query after all these years.

PMID- 8642580
TI  - Susceptibility of oral bacterial biofilms to antimicrobial agents.
AB  - There is great interest in the use of antimicrobial agents for the prevention and
      treatment of plaque-related oral diseases and many publications have reported the
      results of studies in which the minimum inhibitory concentrations of agents for
      cariogenic and periodontopathogenic bacteria have been determined. However, such
      data are relevant only to situations where the organisms of interest are in
      aqueous suspension, whereas in caries and the inflammatory periodontal diseases
      the target organisms are in the form of biofilms. On the basis of studies with
      medically important bacteria, it has been established that bacteria in biofilms
      are invariably less susceptible to antimicrobial agents than their planktonic
      counterparts. Therefore, in the laboratory assessment of agents which may be
      suitable for treating plaque-related diseases, the target organisms should be in
      the form of biofilms. While laboratory evaluation of chemical agents for the
      prevention of plaque formation has usually employed biofilm-based models, the
      search for antimicrobial agents effective in the treatment of plaque-related
      diseases has not. Therefore, there are few data available regarding those
      characteristics of antimicrobial agents (e.g., their biofilm eliminating
      concentrations or biofilm killing concentrations) that could be used to judge
      their suitability for treating plaque-related diseases. In this review the
      limited information available concerning the antimicrobial susceptibility of oral
      bacteria in biofilms is presented.

PMID- 8642582
TI  - Effect of growth condition on in-vitro susceptibility of Shigella dysenteriae
      type 1 killing by murine peritoneal macrophages.
AB  - The intracellular fate of Shigella dysenteriae type 1 strains grown in casamino
      acid-yeast extract (CYE) broth and nutrient broth (NB) was studied in casein
      elicited mouse peritoneal macrophages. Virulent strains 14731 and W30864 cultured
      in NB and opsonised with normal mouse serum were susceptible to killing by
      peritoneal macrophages (66 SEM 1.7% killing by 2 h). In contrast, both strains
      grown in CYE broth and opsonised with normal mouse serum showed resistance to
      killing by peritoneal macrophages (76 SEM 1.4% survival by 2 h).
      Electronmicroscopy demonstrated that the bacteria escaped from the phagosome
      compartment by lysing the phagocytic vacuole and remained within the cytoplasm.
      Lipopolysaccharide (LPS) stimulated peritoneal macrophages to kill the opsonised
      strains 14731 and W30864 grown in CYE broth (85.4 SEM 1.6% killing by 2 h).
      Recombinant murine gamma interferon (rIFN-gamma) also stimulated macrophages to
      kill CYE-grown bacteria (52.1 SEM 1.3% killing by 2 h). However, an avirulent
      rough mutant strain W30864-22 grown in either NB or CYE broth showed marked
      susceptibility to killing by peritoneal macrophages, which was similar to that of
      NB-grown strain 14731 or W30864. The results of the present study suggest that in
      vitro growth conditions may modulate the susceptibility of S. dysenteriae type 1
      to killing by phagocytes.

PMID- 8642581
TI  - Investigation of outbreaks of Enterobacter aerogenes colonisation and infection
      in intensive care units by random amplification of polymorphic DNA.
AB  - During a 4-month period, 41 isolates of Enterobactor aerogenes were cultured from
      different specimens from a 14-bed intensive care unit (ICU1). These were obtained
      from 12 patients out of a total of 187 patients admitted to the ICU. Sixteen E.
      aerogenes isolates were cultured from another ICU (ICU2) 6 months later. Six non
      outbreaks associated strains were included as controls and all the isolates were
      compared by random amplification of polymorphic DNA (RAPD), with three different
      10-mer oligonucleotide primers. RAPD fingerprinting with primer AP12h was as
      discriminatory as the combined results from all three primers and defined 22
      different patterns for the 41 isolates from the ICU1. In nine instances, isolates
      with indistinguishable RAPD patterns were detected in two-to-five patients over a
      3-15-day period, suggesting patient-to-patient transmission. During their stay in
      ICU1, patients harboured one-to-12 distinguishable isolates. Isolates from ICU2
      were indistinguishable by RAPD analysis with the three different primers. These
      findings suggest that the cluster of colonisations and infections in ICU1 was a
      'false outbreak', consisting of successive patient-to-patient transmission of
      different E. aerogenes strains. In contrast, the outbreak on ICU2 probably
      involved the extensive spread of a single strain.

PMID- 8642583
TI  - Visualization of volume data in confocal microscopy: comparison and improvements
      of volume rendering methods.

PMID- 8642584
TI  - Real-time two-photon confocal microscopy using a femtosecond, amplified
      Ti:sapphire system.
AB  - The bilateral imaging approach known from confocal applications operating in the
      line mode was used to realize real-time two-photon imaging. It is shown that the
      sectioning inherent to two-photon imaging could be improved by the introduction
      of a confocal line aperture in the imaging path. Using a high-power, low
      repetition-rate amplified Ti:sapphire system, various biological objects were
      visualized including live boar sperm.

PMID- 8642585
TI  - Simple modification of a commercial scanning laser microscope to incorporate dark
      field imaging.
AB  - Dark-field imaging modes have attracted less interest in biological confocal
      microscopy than the extensive applications of immunofluorescence imaging. There
      are, however, certain biological and materials science applications where it is
      necessary to use a confocal imaging mode that is capable of partial or full
      rejection of light specularly reflected from coverslips, microscope slides or
      specimen surfaces. In this paper we present a simple modification of a commercial
      confocal microscope to incorporate dark-field imaging. We discuss theoretical
      aspects of the resulting dark-field imaging mode and also give experimental
      examples.

PMID- 8642586
TI  - Microwave-enhanced fixation of rabbit articular cartilage.
AB  - Cartilage, being highly aqueous, is difficult to preserve for electron microscopy
      without artefacts. Microwave-enhanced fixation is suggested as a standard method
      for block samples of this material, with dimensions of up to 12 x 7 x 3 mm.
      Cartilage samples from the tibial plateau of adult rabbits were fixed by
      conventional, cryo- or microwave-enhanced fixation. Constant or cyclical
      microwave irradiation of samples, immersed in fixatives, was carried out to
      varying final solution temperatures. Microwave-enhanced fixation and staining is
      shown to be both rapid and reproducible, giving fine structural preservation.
      Below 323 K microwave fixation always gave excellent preservation of the fine
      structure within seconds. At higher temperatures thermal artefacts were
      introduced. In this study the microwave-enhanced fixation is equal in quality to
      the test conventional immersion fixation and is nearly as fast as cryo
      preservation. It provides a standardized, reproducible fixation for morphological
      studies on cartilage with good process control.

PMID- 8642587
TI  - A rapid-flow perfusion chamber for high-resolution microscopy.
AB  - Perfusion chambers employing laminar flow have dead volumes and unstirred layers
      which limit the minimum time required to effect a change in the local chemical
      environment of the sample. We have fabricated and tested a chamber capable of
      developing turbulent flow at reasonable flow rates of aqueous solutions.
      Transition to turbulence occurred at approximately equal to 1 mLs-1. To minimize
      dead space, a dual-exit cross-flow pattern was employed. The chamber was designed
      to mount on optical microscope stages for visual sample observation supplemented
      by a variety of techniques, such as fluorescence, light scattering and
      electrochemical monitoring. As indicated by fluorescence from a fluorescein
      labelled protein film adherent to the chamber wall, local pH changes were
      produced within 200 ms. Use of the chamber is illustrated by measurements of
      stopped-flow kinetics in both calcium-triggered cortical granule exocytosis and
      influenza virus haemagglutinin-mediated cell-cell fusion.

PMID- 8642588
TI  - Prediction of alpha-helices in proteins based on thermodynamic parameters from
      solution chemistry.
AB  - Current studies on the protein folding problem are chiefly pursued by two
      approaches; one statistically investigates the three-dimensional structures of
      proteins and the other focuses on their thermodynamic properties in solution. It
      remains to be demonstrated that information from these two sources are consistent
      and complementary. Using two sets of thermodynamic parameters experimentally
      obtained from solution studies, namely the helix propensities derived from small
      model peptides and hydrophobicity based on solvent transfer free energies for
      amino acids, we predict alpha-helices in native proteins. The correlation
      coefficient of our predictions on 98 non-homologous proteins is 0.26, a value
      comparable to that of the statistical prediction of Chou & Fasman but less than
      that from the state of the art prediction (0.39) based on neural network
      methodology. Helix propensities derived from different experimental systems in
      aqueous solutions are highly consistent for predicting alpha-helices in proteins.
      The helix propensities and amphiphilicity in primary sequences make independent
      contributions to the occurrence of alpha-helices. We also show that, with
      appropriate models, statistical analyses of known three-dimensional structures
      can provide thermodynamically relevant quantities. These findings indicate that
      for practical helix prediction, various sets of propensities have reached
      reasonable consensus. The report also suggests integrating solution thermodynamic
      studies with protein structural analyses, and the role of supersecondary
      structures on helices in proteins.

PMID- 8642589
TI  - Late events in translation initiation. Adjustment of fMet-tRNA in the ribosomal P
      site.
AB  - The requirements for the adjustment of fMet-tRNA in the ribosomal P-site have
      been analyzed by studying the formation of fMet-puromycin in a Bacillus
      stearothermophilus system. The binding of fMet-tRNA to the 30 S ribosomal subunit
      is not drastically affected by the omission of GTP, mRNA, mRNA and GTP, or by
      replacing GTP with GTP analogues. The adjustment of fMet-tRNA in the P site has
      stricter requirements and fMet-puromycin formation occurred at its maximum rate
      and extent when fMet-tRNA was bound to 30 S subunits programmed with the AUG
      triplet or with an mRNA in the presence of GTP. Neither GTP nor the mRNA,
      however, were found to be essential. Omission of GTP caused only a slight
      reduction in the rate of fMet-puromycin formation without a significant change of
      the activation energy, while omission of the template resulted in a requirement
      for a higher activation energy. In the absence of both GTP and template, however,
      essentially no fMet-puromycin was formed, indicating that these components
      cooperate in the adjustment of the initiator tRNA in the P-site. The contribution
      of various structural elements of the mRNA in determining this adjustment was
      investigated. It was found that the codon-anticodon interaction and the filling
      of the ribosomal mRNA channel with a polyribonucleotide are necessary (but not
      sufficient singly) for the correct orientation of the initiator tRNA in the
      absence of GTP. The nature of the initiation triplet and the occurrence and/or
      the strength of the Shine-Dalgarno interaction were also found to contribute to
      the orientation of the bound fMet-tRNA.

PMID- 8642590
TI  - On the mechanism of leftward frameshifting at several hungry codons.
AB  - We have used lacZ reporter genes to assess leftward ribosome frameshifting on
      sequences containing the quadruplet U UUC followed by several different triplets
      coding for lysine, isoleucine, or leucine. Limitation for lysine-tRNA provokes
      leftward frameshifting when the slippery quadruplet is followed by either lysine
      codon aag or aaa, but not when followed by an isoleucine or leucine codon.
      Limitation for isoleucine provokes frameshifting when the quadruplet is followed
      by either isoleucine codon aua or auc, but not when it is followed by a lysine
      codon. We conclude that the quadruplet promotes shifting when the ribosome is
      stalled at any "hungry" codon immediately after it. Changing the quadruplet to U
      AGC, at which peptidyl-tRNA cognate to the AGC triplet will be mismatched at all
      three anticodon positions if it slips left, abolishes frameshifting when the
      ribosome is stalled at the next position. We conclude that the U UUC quadruplet
      promotes frameshifting by virtue of its ability to pair with a left-slipped
      peptidyl-tRNA. The frameshift promoted by isoleucine-tRNA limitation of the U UUC
      aua sequence was analyzed by amino acid sequencing of the protein product. It
      occurs through reading of the Cau histidine codon overlapping the hungry codon
      from the left. This result rules out a "simultaneous slippage" type of mechanism.
      It strongly suggests instead that starvation-promoted frameshifting occurs
      primarily by slippage of peptidyl-tRNA just upstream of the stall site, followed
      by decoding of the triplet overlapping the stall site from the left or 5' side. A
      secondary finding is that the last base of the "hungry" codon has a moderate
      effect on its shiftiness, aag being shiftier than aaa, and aua being shiftier
      than auc.

PMID- 8642591
TI  - Major identity determinants in the "augmented D helix" of tRNA(Glu) from
      Escherichia coli.
AB  - By a kinetic analysis of 59 variant transcripts of Escherichia coli tRNA(Glu)
      with glutamyl-tRNA synthetase (GluRS), the U11.A24 base-pair, the U13.G22..A46
      base-triple, and the lack of residue 47 (delta47) were found to serve as major
      determinants for tRNA(Glu) identity. This is the first system for which major
      identity determinants are reported to be clustered in the "augmented D helix",
      consisting of the D stem with some neighboring residues and the variable loop.
      Other identity determinants are U34, U35, C36 and A37 in the anticodon loop, and
      G1.C72 and U2.A71 in the acceptor stem. Phosphate-group protection by GluRS from
      ethylnitrosourea was observed most strongly for the minor groove side of D-stem
      helix, indicating that GluRs tightly binds to the D stem for recognition, on the
      minor groove side, of the potent identity-determinant groups of the U11.A24 and
      U13.G22 base-pairs. A46 is not involved in direct recognition by GluRS; the
      U13.G22..A46 base-triple is required probably for formation of the structural
      features that are recognized by GluRS. In this context, the essential role of
      characteristic delta47 in tRNA(Glu) identity may be to maintain the U13.G22..A46
      base-triple.

PMID- 8642592
TI  - Comprehensive comparison of structural characteristics in eukaryotic cytoplasmic
      large subunit (23 S-like) ribosomal RNA.
AB  - Comparative modeling of secondary structure is a proven approach to predicting
      higher order structural elements in homologous RNA molecules. Here we present the
      results of a comprehensive comparison of newly modeled or refined secondary
      structures for the cytoplasmic large subunit (23 S-like) rRNA of eukaryotes. This
      analysis, which covers a broad phylogenetic spectrum within the eukaryotic
      lineage, has defined regions that differ widely in their degree of structural
      conservation, ranging from a core of primary sequence and secondary structure
      that is virtually invariant, to highly variable regions. New comparative
      information allows us to propose structures for many of the variable regions that
      had not been modeled before, and rigorously to confirm or refine variable region
      structures previously proposed by us or others. The present analysis also serves
      to identify phylogenetically informative features of primary and secondary
      structure that characterize these models of eukaryotic cytoplasmic 23 S-like
      rRNA. Finally, the work summarized here provides a basis for experimental studies
      designed both to test further the validity of the proposed secondary structures
      and to explore structure-function relationships.

PMID- 8642593
TI  - Analyses of the first chemical step in Flp site-specific recombination: Synapsis
      may not be a pre-requisite for strand cleavage.
AB  - The site-specific recombination reaction mediated by the Flp recombinase occurs
      within a protein-DNA complex containing four monomers of Flp and two DNA
      substrates. The reaction requires that the strand-exchange region (also called
      the spacer or overlap region) of the recombining partners be perfectly
      homologous. A single Flp monomer bound to its recognition sequence is sufficient
      to orient the scissile phosphodiester adjacent to it for the phosphoryl transfer
      reaction that induces strand breakage. Cleavage is inhibited when two to three
      spacer positions adjacent to the reactive phosphodiester are non-complementary.
      This requirement for Watson-Crick base-pairing can be overcome under conditions
      that promote formation of a Flp-Flp dimer across the spacer sequence. Synapsis
      between two Flp-occupied DNA substrates does not appear to be a pre-requisite for
      triggering strand cleavage. The reaction is likely initiated when a functional
      Flp dimer is established across the spacer within a single recombination target
      site. In the absence of a compatible partner, the cleavage reaction is quickly
      reversed by resealing the nick. Therefore accumulation of strand breakages is
      avoided. Coordinated partner cleavages within a synaptic complex can lead to
      strand joining across partners, thus leading the system towards recombination.
      Our results are consistent with the generally accepted view that homology between
      recombining partners is not tested till after strand cleavage has occurred.

PMID- 8642594
TI  - Atomic structure of the degraded procapsid particle of the bacteriophage G4:
      induced structural changes in the presence of calcium ions and functional
      implications.
AB  - Bacteriophage G4 and phiX174 are members of the Microviridae family. The degree
      of similarity of the structural proteins ranges from 66% identity of the F
      protein to 40% identity of the G protein. The atomic structure of the phiX174
      virion had previously been determined by X-ray crystallography. Bacteriophage G4
      procapsids, consisting of the structural proteins F, G, D, B, H, and small traces
      of J but no DNA, were set up for crystallization. However, the resultant crystals
      were of degraded procapsid particles, which had lost the assembly scaffolding
      proteins D and B, resulting in particles that resembled empty virions. The
      structure of the degraded G4 procapsid has been determined to 3.0 angstrom
      resolution. The particles crystallized in the hexagonal space group P6(3)22 with
      unit cell dimensions a=b=414.2(5) angstrom and c=263.0(3) angstrom. The
      diffraction data were collected at the Cornell High Energy Synchrotron Source
      (CHESS) on film and image plates using oscillation photography. Packing
      considerations indicated there were two particles per unit cell. A self-rotation
      function confirmed that the particles were positioned on 32 point group special
      positions in the unit cell. Initial phases were calculated to 6 angstrom
      resolution, based on the known phiX174 virion model. Phase information was then
      extended in steps to 3.0 angstrom resolution by molecular replacement electron
      density modification and particle envelope generation. The resulting electron
      density map was readily interpretable in terms of the F and G polypeptides, as
      occur in the mature capsid of phiX174. In a few regions of the electron density
      map there were inconsistencies between the density and the published amino acid
      sequence. Redetermining the amino acid sequence confirmed that the density was
      correct. The r.m.s. deviation between the Calpha backbone of the mature capsid of
      phiX174 and the degraded G4 procapsid was 0.36 angstrom for the F protein and
      1.38 angstrom for the G protein. This is consistent with the greater conservation
      of the F protein compared to the G protein sequences among members of the
      Microviridae family. Functionally important features between phiX174 and G4 had
      greater conservation. Calcium ions (Ca2+) were shown to bind to G4 at a general
      site located near the icosahedral 3-fold axis on the F protein capsid, equivalent
      to sites found previously in phiX174. Binding of Ca2+ also caused the ordering of
      the conserved region of the DNA binding protein J, which was present in the
      degraded procapsid particle in the absence of DNA.

PMID- 8642595
TI  - Crystal structures of apolipoprotein(a) kringle IV37 free and complexed with 6
      aminohexanoic acid and with p-aminomethylbenzoic acid: existence of novel and
      expected binding modes.
AB  - Kringles are protein modules found within a wide variety of fibrinolytic and
      coagulation-related proteins that show binding affinity for lysine, lysine
      analogs and for fibrin. We report here the crystal structures of
      apolipoprotein(a) kringle IV37 (apo(a) K4(37)) in its free state and in separate
      complexes with two omega-amino acids, 6-aminohexanoic acid (6AHA) and p
      aminomethylbenzoic acid (PAMBA). The structures of the unliganded form and of
      both complexes have been determined and refined by restrained least-squares
      methods to about 2.0 angstrom. The overall kringle architecture is essentially
      identical with that determined in other kringles but it shows some small
      significant structural changes in the lysine binding site. Ther is virtually no
      difference in conformation between the unliganded and complexed forms, suggesting
      that apo(a) K4(37) does not undergo any conformational rearrangement upon
      binding. The 6AHA molecule binds to apo(a) K4(37) in a completely different way
      from that observed with the kringle 4 of plasminogen (PGK4). Its amino group
      makes an ion pair interaction with the two aspartate residues (Asp55/Asp57) of
      the anionic center and its carboxylate group faces out into the solvent making
      water-mediated contacts with the protein. The mode of binding of PAMBA resembles
      more that decribed for 6AHA when bound to PGK4. The PAMBA molecule is bound by
      ion pair interactions with the two aspartate residues (Asp55/Asp57) and with
      Arg71 from the cationic center and by van der Waals contacts. The relative
      importance of the cationic center from kringles for binding zwitterionic ligands
      is discussed.

PMID- 8642596
TI  - Crystal structures of CO-, deoxy- and met-myoglobins at various pH values.
AB  - The distal histidine residue, His64(E7), and the proximal histidine residue,
      His93(F8), in myoglobin (Mb) are important for the function of the protein. For
      example, the increase in the association rate constant for CO binding at low pH
      has been suggested to be caused by the protonation of these histidine residues.
      In order to investigate the influence of protonation on the structure of
      myoglobin, we determined the crystal structures of sperm whale myoglobin to 2.0 A
      or better in different states of ligation (MbCO, deoxyMb and metMb) at pH values
      of 4, 5 and 6. The most dramatic change found at low pH is that His64 swings out
      of the distal pocket in the MbCO structure at pH 4, opening a direct channel from
      the solvent to the iron atom. This rotation seems to be facilitated by
      conformational changes in the CD corner. The benzyl side-chain of Phe46(CD4),
      which has been suggested to be a critical residue in controlling the rotation of
      His64, moves away from His64 at pH 4 in the deoxyMb structure, allowing more free
      rotation of His64. Arg45(CD3) is also important for the dynamics of myoglobin,
      since it influences the pK(a) of His64 and forms a hydrogen bond lattice that
      hinders the rotation of His64 at neutral pH. This hydrogen-bond lattice
      disappears at low pH. Although His64 rotates out of the distal pocket in the MbCO
      structure at pH 4, leaving more space for the CO ligand, the Fe-C-O angle refines
      to about 130 degrees, the same as those at pH 5 and 6. In the MbCO structure at
      pH 4, significant conformational changes appear in the EF corner. The peptide
      plane between Lys79(EF2) and Gly80(EF3) flips about 150 degrees. The occupancy of
      this conformation in the MbCO structures increases with decreases in pH. On the
      proximal side of the heme, the bond between the heme iron atom and N(epsilon) of
      His93 remains intact under the experimental conditions in the MbCO and deoxyMb
      structures, but appears elongated in the metMb structure at pH 4, representing
      either a weakened bond or the breakage of the bond in some fraction of the
      molecules in the crystal.

PMID- 8642597
TI  - Crystal structure of T state haemoglobin with oxygen bound at all four haems.
AB  - The cooperative binding of oxygen by haemoglobin results from restraints on
      ligand binding in the T state. The unfavourable interactions made by the ligands
      at the haems destabilise the T state and favour the high affinity R state. The T
      <==> R equilibrium leads, in the presence of a ligand, to a rapid increase in the
      R state population and therefore generates cooperative binding. There is now
      considerable understanding of this phenomenon, but the interactions that reduce
      ligand affinity in the T state have not yet been fully explored, owing to the
      difficulties in preparing T state haemoglobin crystals in which all the subunits
      are oxygenated. A protocol has been developed to oxygenate deoxy T state adult
      human haemoglobin (HbA) crystals in air at 4 C at all four haems without
      significant loss of crystalline order. The X-ray crystal structure, determined to
      2.1 A spacing, shows significant changes in the alpha and beta haem pockets as
      well as changes at the alpha(1)beta(2) interface in the direction of the R
      quaternary structure. Most of the shifts and deviations from deoxy T state HbA
      are similar to, but larger than, those previously observed in the T state met and
      other partially liganded T state forms. They provide clear evidence of haem-haem
      interaction in the T state.

PMID- 8642598
TI  - Thermodynamic stability effects of single peptide bond hydrolysis in protein
      inhibitors of serine proteinases.
AB  - Kunitz type soybean trypsin inhibitor (STI) and basic pancreatic trypsin
      inhibitor (BPTI) were used as model proteins to measure the thermodynamic
      consequences of single peptide bond hydrolysis. For each inhibitor the reactive
      site cleaved form was prepared and, additionally, each inhibitor was selectively
      cleaved at a Met residue. Selective cleavage generally led to reducing of the
      T(den) value from 7 K up to 75 K. For STI cleaved at Met84 a slight stabilization
      (increase of T(den) by 1.0 K) was observed. In terms of deltaG(den), the
      difference between the most extreme cleavage effect was 11.44 kcal/mole, much
      larger than resulting from the theoretical effects of crosslinks. It was found
      that hydrolysis of a single peptide bond affects not only entropy, but also
      enthalpy and heat capacity parameters. Moreover, the sign of change is opposite
      for two inhibitors: deltaH(den) and deltaS(den) increase for both cleaved forms
      of STI, while they decrease for two nicked forms of BPTI. To understand the
      stability effects, a thermodynamic cycle analysis was applied based on comparison
      of stabilities of intact and cleaved protein with peptide bond hydrolysis
      equilibria in native and denatured states. The cycle revealed a good agreement of
      the theoretical effect of crosslink elimination with a free energy difference for
      hydrolysis of a single peptide bond in a denatured protein. It appears that
      hydrolysis constants for single peptide bonds in a native protein span over at
      least 20 orders of magnitude. They are very low for peptide bonds placed in alpha
      helices and very high if cleavage reaction leads to a formation of a new
      secondary structure element.

PMID- 8642599
TI  - The C-terminal domain revealed in the structure of RNA polymerase II.
AB  - The location of the CTD in the structure of RNA polymerase II has been determined
      by electron crystallography at 16 A resolution. Difference maps between wild-type
      enzyme and that lacking the CTD, or with an antibody fragment bound in place of
      the CTD, disclose the site of attachment of the CTD to the polymerase.
      Appropriate display of the polymerase structure reveals the CTD as an element
      projecting from this site of attachment into solution. A low relative density and
      large volume of this element identify the CTD as a conformationally mobile
      region.

PMID- 8642600
TI  - The dynamic structure of EF-G studied by fusidic acid resistance and internal
      revertants.
AB  - We have previously identified 20 different fusidic acid-resistant alleles of
      fusA, encoding mutant forms of the ribosomal translocase EF-G. One of these,
      P413L, is used here as the starting point in selections for internal revertants,
      identifying 20 different pseudo-wild-type forms of EF-G. We have also identified
      two alleles of fusA previously isolated as suppressors of 4.5 S RNA deficiency.
      All of these mutants are analysed in terms of their effects on the structural
      dynamics of EF-G. Most mutation conferring fusidic acid-resistance interfere with
      conformational changes of EF-G, but some may be located at a possible fusidic
      acid binding site. Revertants of the P413L mutations restore the function of EF-G
      with or without affecting the level of resistance to fusidic acid. The revertant
      mutations probably restore the balance between the GDP and GTP conformations of
      EF-G off the ribosome, and most of them are located close to the interface
      between the G domain and domain II. The procedure for the isolation of pseudo
      wild-type forms of EF-G can be used to direct evolution progressively away from
      the wild-type while still maintaining the essential functions of EF-G.

PMID- 8642601
TI  - cis-acting elements within an RNA coliphage genome: fold as you please, but fold
      you must!!
AB  - Using an in vivo complementation system, we conducted a mutational analysis of
      the bacteriophage Q beta readthrough cistron. In the Q beta cDNA-containing
      plasmid, pQ beta m100, we constructed six defined Q beta deletion cDNA genomes,
      each missing between 86 and 447 nucleotides from within the readthrough cistron.
      These deletion plasmids were introduced into host cells that are constitutively
      supplied with Q beta readthrough protein from the plasmid pQ beta RT. Under these
      conditions, all six deletion genomes spontaneously generated phage particles,
      each exhibiting a characteristic plaque phenotype and virus forming potential.
      Isolated readthrough-defective phage particles were subsequently used to infect
      host cells that carried helper readthrough protein. Passaged viruses yielded both
      larger plaques and higher titers, compared with those of the parent phages.
      Sequence analysis revealed that the genomes of the passaged viruses had deleted
      additional regions of readthrough RNA sequence. We discuss the possibilities that
      (1) the disruption of a well-defined structural domain in Q beta RNA was
      selectively disadvantageous to phage infection, and that (2) the evolved viral
      populations were selected by virtue of their ability to restore critical
      integrity of short and/or long-range nucleotide interactions within this region
      of Q beta RNA.

PMID- 8642602
TI  - Distribution of restriction enzyme recognition sequences on broad host range
      plasmid RP4: molecular and evolutionary implications.
AB  - IncP alpha plasmids, exemplified by RP4, are remarkable for their broad host
      range. They contain strikingly few cleavage sites for many commonly used type II
      restriction enzymes but an overabundance of sites for certain enzymes that target
      G + C-rich sequences. To identify factors responsible for these distributions,
      the recently compiled nucleotide sequence of RP4 was analysed to determine the
      frequency of tetra- and hexanucleotide motifs in the 49 kb plasmid backbone. This
      is defined as the sectors encoding basic plasmid functions. The overabundant
      restriction targets in RP4 are concentrated in the backbone and contain
      overlapping copies of CGGC/GCCG, identified as the most abundant tetranucleotide
      motif in the plasmid. Motif frequencies in the RP4 backbone are shown to be
      similar to those in Pseudomonas aeruginosa, a natural host of RP4, with the
      notable exception that a number of 6-bp palindromes are underrepresented in the
      plasmid. It is proposed that 6-bp palindromes were counterselected as type II
      restriction enzyme recognition sequences. Conjugative transfer of RP4 and R751
      (IncP beta) is unusually sensitive to restriction compared to enterobacterial
      plasmids of the IncFII and IncI1 groups, implying that IncP plasmids experienced
      particularly strong selection for loss of restriction targets. Pseudomonas spp.
      of rRNA homology group I specify many type II restriction enzymes that target 6
      bp palindromes and are candidates for the evolutionary hosts of IncP alpha
      plasmids.

PMID- 8642603
TI  - DNA bending and unwinding associated with actinomycin D antibiotics bound to
      partially overlapping sites on DNA.
AB  - Actinomycin D (ActD) is a potent anti-tumor antibiotic, that preferentially
      targets (G-C).(G-C) steps on duplex DNA. We have reported on the solution
      structure of the ActD-d(A-A-A-G-C-T-T-T) complex (one drug per duplex) based on a
      combined application of NMR and molecular dynamics calculations. This study
      established that ActD binds to DNA through intercalation of the phenoxazone
      chromophore between (G-C).(G-C) steps with the benzenoid and quinonoid-linked
      cyclic pentapeptide lactone rings spanning two base-pairs in opposite directions
      in the minor groove of the helix. This research is now extended to the binding of
      two ActD molecules to adjacent complexation sites within a (G-C-G-C).(G-C-G-C)
      segment in the self-complementary d(A1-A2-G3-C4-G5-C6-T7-T8) duplex. The
      occupation of the central (C4-G5).(C4-G5) segment between the two intercalation
      sites by the inwardly pointing cyclic pentapeptide lactone rings from adjacent
      bound ActD molecules should result in a potential steric clash in the center of
      the helix. The NMR data and its analysis on the ActD-d(A-A-G-C-G-C-T-T) complex
      (two drugs per duplex) establish that two ActD molecules intercalate into
      symmetry-related (G3-C4).(G5-C6) steps with their attached benzenoid and
      quinonoid cyclic pentapeptide lactone rings positioned in the minor groove and
      directed towards the center and the ends of the helix, respectively. The solution
      structure of the complex was solved by using NMR restraints to guide distance
      geometry-simulated annealing and restrained molecular dynamics calculations
      including intensity-based refinements. The DNA helix exhibits a pronounced kink
      and is fully unwound at the central (C4-G5).(C4-G5) step which results in an
      opening and widening of the minor groove to generate additional space for
      accommodation of the inwardly pointing benzenoid cyclic pentapeptide lactone
      rings in the complex. The outwardly and inwardly pointing cyclic pentapeptide
      lactone rings of symmetry-related ActD molecules retain similar conformations
      with the largest difference observed for the L-MeVal residues in the complex. The
      present study defines how structural changes primarily in the DNA associated with
      the directional bending of the helix towards the major groove and away from the
      bound drug opens up and widens the minor groove to accommodate two intercalated
      ActD molecules bound at partially overlapping sites on the DNA.

PMID- 8642604
TI  - Molecular recognition in the FMN-RNA aptamer complex.
AB  - We report on a combined NMR-molecular dynamics calculation approach that has
      solved the solution structure of the complex of flavin mononucleotide (FMN) bound
      to the conserved internal loop segment of a 35 nucleotide RNA aptamer identified
      through in vitro selection. The FMN-RNA aptamer complex exhibits exceptionally
      well-resolved NMR spectra that have been assigned following application of two,
      three and four-dimensional heteronuclear NMR techniques on samples containing
      uniformly 13C, 15N-labeled RNA aptamer in the complex. The assignments were aided
      by a new through-bond NMR technique for assignment of guanine imino and adenine
      amino protons in RNA loop segments. The conserved internal loop zippers up
      through the formation of base-pair mismatches and a base-triple on complex
      formation with the isoalloxazine ring of FMN intercalating into the helix between
      a G.G mismatch and a G.U.A base-triple. The recognition specificity is associated
      with hydrogen bonding of the uracil like edge of the isoalloxazine ring of FMN to
      the Hoogsteen edge of an adenine at the intercalation site. There is significant
      overlap between the intercalated isoalloxazine ring and its adjacent base-triple
      platform in the complex. The remaining conserved residues in the internal loop
      participate in two G.A mismatches in the complex. The zippered-up internal loop
      and flanking stem regions form a continuous helix with a regular sugar-phosphate
      backbone except at a non-conserved adenine, which loops out of the helix to
      facilitate base-triple formation. Our solution structure of the FMN-RNA aptamer
      complex is to our knowledge the first structure of an RNA aptamer complex and
      outlines folding principles that are common to other RNA internal and hairpin
      loops, and molecular recognition principles common to model self-replication
      systems in chemical biology.

PMID- 8642605
TI  - Conservation and variability in the structures of serine proteinases of the
      chymotrypsin family.
AB  - The chymotrypsin-like serine proteinases are a widely divergent family of enzymes
      appearing in animals, bacteria and viruses. All comprise two homologous domains
      containing six-stranded beta-barrels, with the active site between the domains.
      What are the structural constraints to which these proteins have been subject
      during their evolution, and how have the molecules explored the limits these
      constraints impose? We have analysed the structures of 13 widely divergent serine
      proteinases determined by X-ray crystallography to high resolution and well
      refined. We have identified the regions of the molecule that evolution has
      preserved both within each of the two domains and in the interdomain interface.
      An alignment of the sequences is presented based on structural superpositions.
      From this we analyse the conserved structural patterns and the interactions
      crucial to maintaining the structure and the active side.

PMID- 8642606
TI  - On the prevalence of certain codons ("RNY") in genes for proteins.
AB  - J.C. Shepherd notes that codons of the type RNY (R = purine, N = any nucleotide
      base, Y = pyrimidine) predominate over RNR in the genes for proteins. He has
      hypothesized that RNY codons are the relics of "a primitive code" composed of
      repeating RNY triplets. He found that RNY codons predominated in fourfold RNN
      codon sets (family boxes). These family boxes code for valine, threonine,
      alanine, and glycine. We argue that the proposed "comma-less" code composed of
      RNY never existed, and that, in any case, survival of such a code would have long
      since been erased by mutations. The excess of RNY codons in family boxes is
      probably attributable to preference for the corresponding tRNAs.

PMID- 8642607
TI  - Evolution of fragmented mitochondrial ribosomal RNA genes in Chlamydomonas.
AB  - The fragmented mitochondrial ribosomal RNAs (rRNAs) of the green algae
      Chlamydomonas eugametos and Chlamydomonas reinhardtii are discontinuously encoded
      in subgenic modules that are scrambled in order and interspersed with protein
      coding and tRNA genes. The mitochondrial rRNA genes of these two algae differ,
      however, in both the distribution and organization of rRNA coding information
      within their respective genomes. The objectives of this study were (1) to examine
      the phylogenetic relationships between the mitochondrial rRNA gene sequences of
      C. eugametos and C. reinhardtii and those of the conventional mitochondrial rRNA
      genes of the green alga, Prototheca wickerhamii, and land plants and (2) to
      attempt to deduce the evolutionary pathways that gave rise to the unusual
      mitochondrial rRNA gene structures in the genus Chlamydomonas. Although
      phylogenetic analysis revealed an affiliation between the mitochondrial rRNA gene
      sequences of the two Chlamydomonas taxa to the exclusion of all other
      mitochondrial rRNA gene sequences tested, no specific affiliation was noted
      between the Chlamydomonas sequences and P. wickerhamii or land plants.
      Calculations of the minimal number of transpositions required to convert
      hypothetical ancestral rRNA gene organizations to the arrangements observed for
      C. eugametos and C. reinhardtii mitochondrial rRNA genes, as well as a limited
      survey of the size of mitochondrial rRNAs in other members of the genus, lead us
      to propose that the last common ancestor of Chlamydomonas algae contained
      fragmented mitochondrial rRNA genes that were nearly co-linear with conventional
      rRNA genes.

PMID- 8642609
TI  - Untranslated sequence upstream of MarA in the multiple antibiotic resistance
      locus of Escherichia coli is related to the effector-binding domain of the XylS
      transcriptional activator.
AB  - MarA, the 129-amino-acid (aa) protein which plays a crucial role in the multiple
      antibiotic resistance (Mar) phenotype in Escherichia coli, shows homology to
      members of the XylS/AraC family of transcriptional regulators. Although these
      proteins vary in size from around 100 to 350 aa they all contain a DNA-binding
      domain with a helix-turn-helix motif. The larger ones, e.g., XylS, AraC, and Rob,
      contain an additional domain either at their amino- or at their carboxyterminus.
      This domain is important for effector-binding or dimerization or of unknown
      function. MarA consists only of the DNA-binding component. Nevertheless, a
      sequence with a coding potential of 141 aa upstream of its ATG start-codon showed
      20.5-26.9% aa identity with the corresponding section within the effector-binding
      domain of XylS from the TOL plasmid of Pseudomonas putida when translated in the
      same reading frame as MarA. However, the reading frame was interrupted by 11
      translational stops. In another frame, this upstream sequence actually codes for
      a real protein, MarR, that is completely unrelated to XylS. Implications for the
      putative evolution of regulatory proteins through translocation of domains
      followed by adaptation are discussed.

PMID- 8642608
TI  - Mutational mechanisms, phylogeny, and evolution of a repetitive region within a
      clock gene of Drosophila melanogaster.
AB  - The D. melanogaster clock gene period (per) is an internally repetitive gene
      encoding a tandem array of Thr-Gly codons that are highly polymorphic in length
      in European natural populations. The two major length variants, (Thr-Gly)20 and
      (Thr-Gly)17, show a highly significant latitudinal cline. In this study we
      present the complete sequence of the Thr-Gly region of 91 individuals from 6
      natural populations of D. melanogaster, 5 from Europe and 1 from North Africa. We
      further characterized these 91 individuals for polymorphic sites in two other
      regions, one upstream and one downstream of the Thr-Gly repeat. We used the
      haplotypic combinations of Thr-Gly allele with flanking markers in an attempt to
      identify the mechanisms involved in the evolution of the D. melanogaster Thr-Gly
      region and to infer the phylogenetic relationship existing among the Thr-Gly
      alleles. We observe evidence for both intra- and interallelic mutational
      mechanisms, including replication slippage, unequal crossing-over, and gene
      conversion.

PMID- 8642610
TI  - The tryptophan biosynthetic pathway of aphid endosymbionts (Buchnera): genetics
      and evolution of plasmid-associated anthranilate synthase (trpEG) within the
      aphididae.
AB  - The bacterial endosymbionts (Buchnera) from the aphids Rhopalosiphum padi, R.
      maidis, Schizaphis graminum, and Acyrthosiphon pisum contain the genes for
      anthranilate synthase (trpEG) on plasmids made up of one or more 3.6-kb units.
      Anthranilate synthase is the first as well as the rate-limiting enzyme in the
      tryptophan biosynthetic pathway. The amplification of trpEG on plasmids may
      result in an increase of enzyme protein and overproduction of this essential
      amino acid, which is required by the aphid host. The nucleotide sequence of trpEG
      from endosymbionts of different species of aphids is highly conserved, as is an
      approximately 500-bp upstream DNA segment which has the characteristics of an
      origin of replication. Phylogenetic analyses were performed using trpE and trpG
      from the endosymbionts of these four aphids as well as from the endosymbiont of
      Schlechtendalia chinensis, in which trpEG occurs on the chromosome. The resulting
      phylogeny was congruent with trees derived from sequences of two chromosome
      located bacterial genes (part of trpB and 16S ribosomal DNA). In turn, trees
      obtained from plasmid-borne and bacterial chromosome-borne sequences were
      congruent with the tree resulting from phylogenetic analysis of three aphid
      mitochondrial regions (portions of the small and large ribosomal DNA subunits, as
      well as cytochrome oxidase II). Congruence of trees based on genes from host
      mitochondria and from bacteria adds to previous support for exclusively vertical
      transmission of the endosymbionts within aphid lineages. Congruence with trees
      based on plasmid-borne genes supports the origin of the plasmid-borne trpEG from
      the chromosomal genes of the same lineage and the absence of subsequent plasmid
      exchange among endosymbionts of different species of aphids.

PMID- 8642611
TI  - Intron position as an evolutionary marker of thioredoxins and thioredoxin
      domains.
AB  - In contrast to prokaryotes, which typically possess one thioredoxin gene per
      genome, three different thioredoxin types have been described in higher plants.
      All are encoded by nuclear genes, but thioredoxins m and f are chloroplastic
      while thioredoxins h have no transit peptide and are probably cytoplasmic. We
      have cloned and sequenced Arabidopsis thaliana genomic fragments encoding the
      five previously described thioredoxins h, as well as a sixth gene encoding a new
      thioredoxin h. In spite of the high divergence of the sequences, five of them
      possess two introns at positions identical to the previously sequenced tobacco
      thioredoxin h gene, while a single one has only the first intron. The recently
      published sequence of Chlamydomonas thioredoxin h shows three introns, two at the
      same positions as in higher plants. This strongly suggests a common origin for
      all cytoplasmic thioredoxins of plants and green algae. In addition, we have
      cloned and sequenced pea DNA genomic fragments encoding thioredoxins m and f. The
      thioredoxin m sequence shows only one intron between the regions encoding the
      transit peptide and the mature protein, supporting the prokaryotic origin of this
      sequence and suggesting that its association with the transit peptide has been
      facilitated by exon shuffling. In contrast, the thioredoxin f sequence shows two
      introns, one at the same position as an intron in various plant and animal
      thioredoxins and the second at the same position as an intron in thioredoxin
      domains of disulfide isomerases. This strongly supports the hypothesis of a
      eukaryotic origin for chloroplastic thioredoxin f.

PMID- 8642612
TI  - Molecular evolution of nitrate reductase genes.
AB  - To understand the evolutionary mechanisms and relationships of nitrate reductases
      (NRs), the nucleotide sequences encoding 19 nitrate reductase (NR) genes from 16
      species of fungi, algae, and higher plants were analyzed. The NR genes examined
      show substantial sequence similarity, particularly within functional domains, and
      large variations in GC content at the third codon position and intron number. The
      intron positions were different between the fungi and plants, but conserved
      within these groups. The overall and nonsynonymous substitution rates among
      fungi, algae, and higher plants were estimated to be 4.33 x 10(-10) and 3.29 x
      10(-10) substitutions per site per year. The three functional domains of NR genes
      evolved at about one-third of the rate of the N-terminal and the two hinge
      regions connecting the functional domains. Relative rate tests suggested that the
      nonsynonymous substitution rates were constant among different lineages, while
      the overall nucleotide substitution rates varied between some lineages. The
      phylogenetic trees based on NR genes correspond well with the phylogeny of the
      organisms determined from systematics and other molecular studies. Based on the
      nonsynonymous substitution rate, the divergence time of monocots and dicots was
      estimated to be about 340 Myr when the fungi-plant or algae-higher plant
      divergence times were used as reference points and 191 Myr when the rice-barley
      divergence time was used as a reference point. These two estimates are consistent
      with other estimates of divergence times based on these reference points. The
      lack of consistency between these two values appears to be due to the uncertainty
      of the reference times.

PMID- 8642613
TI  - Geographical variation in insertion site number of retrotransposon 412 in
      Drosophila simulans.
AB  - The insertion site number of the retrotransposable element 412 was analyzed in
      natural populations of Drosophila simulans of worldwide origin by in situ
      hybridization. We observe a gradient in copy number ranging from as high as 23 in
      Europe to 1-10 in South Africa, while populations in Madagascar and the Indian
      Islands, which are the cradle of D. simulans, have only 3-7 copies. We find very
      different copy numbers in some local populations of Australia and the Pacific
      Islands (with around 60 copies in 1 sample and only 5 in another), suggesting
      spontaneous transposition bursts in local populations. Such bursts occurring now
      and then in local natural populations followed by fly migration could lead to the
      progressive invasion of the entire species by the transposable element mobilized,
      explaining the gradient in 412 copy number between northern and southern
      hemispheres.

PMID- 8642614
TI  - Evolution in a chronic RNA virus infection: selection on HTLV-I tax protein
      differs between healthy carriers and patients with tropical spastic paraparesis.
AB  - HTLV-I causes T-cell leukemia and tropical spastic paraparesis (TSP) in a
      minority of infected people, whereas the majority remain healthy. The virus
      differs little in sequence between isolates but has been shown to have a
      quasispecies structure. Using the Nei and Gojobori algorithm, we have shown that
      the proportion of nonsynonymous to synonymous changes in HTLV-I proviral tax gene
      sequences from healthy seropositive subjects (Dn/Ds = 0.9 to 1.3) is
      significantly higher than those from TSP patients (Dn/Ds = 0.3 to 0.6). Here we
      show that the distinction between healthy seropositives and TSP patients can only
      be seen with proviral tax sequences, but not with cDNA, the amino-terminal or
      carboxy-terminal half of tax, or the rex gene. The Dn/Ds ratio of proviral tax
      sequences was used to analyze two TSP patients with atypical features and to
      investigate the influence of cytotoxic T cells (CTL) on the viral quasispecies.

PMID- 8642615
TI  - Model of amino acid substitution in proteins encoded by mitochondrial DNA.
AB  - Mitochondrial DNA (mtDNA) sequences are widely used for inferring the
      phylogenetic relationships among species. Clearly, the assumed model of
      nucleotide or amino acid substitution used should be as realistic as possible.
      Dependence among neighboring nucleotides in a codon complicates modeling of
      nucleotide substitutions in protein-encoding genes. It seems preferable to model
      amino acid substitution rather than nucleotide substitution. Therefore, we
      present a transition probability matrix of the general reversible Markov model of
      amino acid substitution for mtDNA-encoded proteins. The matrix is estimated by
      the maximum likelihood (ML) method from the complete sequence data of mtDNA from
      20 vertebrate species. This matrix represents the substitution pattern of the
      mtDNA-encoded proteins and shows some differences from the matrix estimated from
      the nuclear-encoded proteins. The use of this matrix would be recommended in
      inferring trees from mtDNA-encoded protein sequences by the ML method.

PMID- 8642616
TI  - Anomalous phylogenies based on bacterial catalase gene sequences.
AB  - Phylogenies based on nine prokaryotic catalase sequences demonstrate no
      relationship to phylogenies based on rDNA sequences or other known criteria. When
      this observation is considered together with the monophyletic relationship
      observed for eukaryotic catalase sequences, it seems likely that the catalase
      gene sequence has migrated repeatedly from eukaryotes to prokaryotes.

PMID- 8642617
TI  - Y-chromosome DNA haplotypes in Basques.
AB  - One Y-specific DNA polymorphism (p49/ TaqI) was studied in a sample of 97 French
      Basques and compared with those found in 7 other French, Iberian, and Italian
      populations. A particularly high frequency (72.2%) of Y-haplotype XV was observed
      in Basques, compared to values (mean of 41%) obtained in other Western Europeans.
      Basques were also characterized by virtual absence, or presence at a low level,
      of the South or Near Eastern haplotypes XII, VII, and VIII. Considered together,
      these results confirm that Basques are a very ancient European population which
      has had little previous contact with the Neolithics.

PMID- 8642619
TI  - Catalase and superoxide dismutase activities as biomarkers of oxidative stress in
      workers exposed to mercury vapors.
AB  - For this article we investigated the role of three blood antioxidant enzyme
      activities and total antioxidant status (TAS) as biological markers of oxidative
      stress in workers exposed to mercury (Hg(o)) vapors. Twenty-two female workers
      took part in the study. The examination included a questionnaire on age,
      educational level, occupational history, actual health status, previous accidents
      and diseases, smoking and dietary habits, and alcohol consumption. Blood and
      urine sampling for biological analyses completed this examination. The workers
      were classified into three subgroups according to their creatinine-corrected Hg
      concentration in urine. Blood antioxidant enzyme activities and TAS were compared
      between groups with nonparametric distribution-free methods. A significant
      difference existed in catalase activity and a slight, but not significant,
      difference existed in Cu2+/Zn2+ superoxide dismutase (Cu2+/Zn2+ SOD) activity
      between the three groups. No differences were observed in either the glutathione
      peroxidase activity or the TAS between these groups. Catalase and Cu2+/Zn2+ SOD
      activities were increased in the groups of workers with higher creatinine
      corrected urinary Hg concentrations when compared with the group of lower
      creatinine-corrected urinary Hg concentrations. Catalase activity was positively
      correlated with the creatinine-corrected concentration of Hg in urine, and
      Cu2+/Zn2+ SOD activity was slightly correlated with the creatinine-corrected
      concentration of Hg in urine. The role of erythrocyte catalase and Cu2+/Zn2+ SOD
      activities we have measured is in agreement with the hypothesis of the
      involvement of reactive oxygen species production as an important event in
      chronic exposure to Hg(o) vapors in humans. In spite of the small size of the
      sample, these results indicate that erythrocyte catalase and Cu2+/Zn2+ SOD
      activities could be considered as markers of biological effect in workers exposed
      to Hg(o) vapors.

PMID- 8642618
TI  - Unbiased estimation of symmetrical directional mutation pressure from protein
      coding DNA.
AB  - The most generally applicable procedure for obtaining estimates of the
      symmetrical, or strandnonspecific, directional mutation pressure (microD) on
      protein-coding DNA sequences is to determine the G+C content at synonymous codon
      sites (Psyn), and to divide Psyn by twice the arithmetic mean of the G+C content
      at synonymous codon sites of a large number of randomly generated, synonymously
      coding DNA sequences (Psyn). Unfortunately, the original procedure yields biased
      estimates of Psyn and microD and is computationally expensive. We here present a
      fast procedure for estimating unbiased microD values. The procedure employs
      direct calculation of Psyn (approximately Psyn) and two normalization procedures,
      one for Psyn < or = Psyn and another for Psyn > or = Psyn. The normalization
      removes a bias sometimes caused by codons specifying arginine, asparagine,
      isoleucine, and leucine. Consequently, comparison of protein-coding genes that
      are translated using different genetic codes is facilitated.

PMID- 8642620
TI  - Effects of metal ions on lipid peroxidation in cultured rat hepatocytes loaded
      with alpha-linolenic acid.
AB  - We investigated the ability of various redox-active metal ions to induce lipid
      peroxidation in normal and alpha-linolenic acid-loaded (LNA-loaded) cultured rat
      hepatocytes. Lipid peroxidation was estimated by the accumulation of
      malondialdehyde (MDA) in the culture medium. At low concentrations induction was
      highest with ferrous ions (Fe), whereas at high concentrations, vanadium (V) and
      copper ions (Cu) had the greatest effect on both groups of hepatocytes. With any
      one of the three metal ions, the extent of lipid peroxidation in LNA-loaded
      hepatocytes was several times greater compared to normal cells. In addition, upon
      the addition of Fe or V, LNA-loaded hepatocytes were injured whereas normal cells
      were not. The addition of Cu caused substantial cell injury in normal
      hepatocytes, and even greater injury in LNA-loaded cells. The prevention of lipid
      peroxidation in LNA-loaded hepatocytes by addition of an antioxidant like N,N'
      diphenyl-p-phenylene-diamine (DPPD) almost completely prevented Fe- and V-induced
      cell injury, and reduced Cu-induced cell injury. alpha-Tocopherol behaved in a
      way similar to but less effective than DPPD. .OH radical scavengers such as
      mannitol and dimethyl sulfoxide (DMSO) had no effect on lipid peroxidation
      induced by any metal ions in LNA-loaded hepatocytes. Addition of cadmium ions
      (Cd), which required the lowest concentration to cause cell injury, induced a
      slight increase in lipid peroxidation in normal hepatocytes, but did not induce
      lipid peroxidation to the same extent as seen in LNA-loaded cells treated with
      any of the three metal ions already mentioned. The inhibition of lipid
      peroxidation by DPPD scarcely protected LNA-loaded hepatocytes from Cd-induced
      cell injury. None of the other metal ions including aluminum (Al), chromium (Cr),
      manganese (Mn), nickel (Ni), lead (Pb), and tin (Sn) ions, effectively induced
      lipid peroxidation in either group of hepatocytes, except cobalt ions (Co), which
      had a peroxidative effect in LNA-loaded cells only.

PMID- 8642621
TI  - Ultrasonic assessment of calcaneus in inhabitants in a cadmium-polluted area.
AB  - We used ultrasound (US) transmission to evaluate the speed of sound (SOS) and
      broadband ultrasonic attenuation (BUA) in the calcaneus in 17 male and 18 female
      inhabitants of a Cd-polluted area and 23 men and 45 women living in a nonpolluted
      area. Significant decreases in SOS and stiffness (Stiff), which was an index
      empirically derived from SOS and BUA, were found in Cd-exposed women. To evaluate
      the usefulness of the US measurements for detecting bone abnormality in Cd
      exposed people, we examined the associations with the bone measurements of
      metacarpus by the previously used microdensitometry (MD) method and the grade of
      renal tubular damage due to Cd exposure. Bone density estimated by MD, sigmaGS/D,
      was significantly correlated with BUA, SOS, and Stiff in the Cd-exposed men and
      with BUA and Stiff in the Cd-exposed women. Further, in the Cd-exposed women, the
      decreases in BUA and Stiff correlated significantly with the increases in urinary
      beta 2-microglobulin, while sigmaGS/D by the MD method did not. These results
      suggest that the measurement of the calcaneus using US is not only radiation free
      but also can be used as a tool for population surveys aiming to evaluate bone
      damage in people, especially women, showing renal tubular damage due to
      environmental Cd exposure.

PMID- 8642622
TI  - Evaluation of the disodium salt of 4,4'-diamino-2,2'-stilbene disulfonic acid for
      estrogenic activity.
AB  - 4,4'-Diamino-2,2'-stilbene disulfonic acid (DAS), a key intermediate in the
      synthesis of dyes and fluorescent whitening agents, has been purported to have
      weak estrogenic properties based on apparent structural similarity with
      diethylstibestrol (DES) and unsubstantiated reports of male reproductive
      dysfunction in an industrial setting. In weanling rats, high doses of DAS (300
      mg/kg ip; 1000-3000 mg/kg oral) have been associated with modest increases in the
      uterus/body weight ratio (Smith & Quinn, 1992). In order to more directly and
      definitively determine if DAS possesses estrogenic activity, in vitro studies
      were conducted to establish its relative binding affinity to the human estrogen
      receptor (ER) in MCF-7 cells, a well-characterized breast cancer cell line. At
      concentrations approaching its solubility limit (10(-4) M), DAS failed to display
      [3H]-17beta-estradiol (E2) from the ER. In contrast, DES and E2 demonstrated
      characteristic competitive binding curves (50% displacement of 3H-E2 at 3.33 x
      10(-9) and 1.33 x 10(-8) M, respectively). Parallel in vivo comparisons of DAS
      (10 or 30 mg/animal) and DES (1 or 3 microgram/animal) were also conducted to
      assess uterotropic effects. After three daily subcutaneous injections, DAS did
      not induce uterine weight gain. In contrast, DES consistently and markedly
      increased uterine weight and induced uterine water imbibition, with the latter
      effect being absent in DAS-treated rats. Under these experimental conditions, DAS
      was shown to possess negligible, if any, estrogenic activity, despite apparent
      structural similarity with known estrogens.

PMID- 8642623
TI  - Teratogenic potential of atrazine and 2,4-D using FETAX.
AB  - The teratogenic potential of commercial formulations of atrazine (40.8%) and 2,4
      D was evaluated using FETAX (frog embryo teratogenic assay--Xenopus). Because
      these herbicides have been detected in ground and surface water, this study was
      designed to determine the adverse effects in buffer and natural water for both
      herbicides. All treatments showed a significant concentration-response effect on
      exposed embryos, except for the 2,4-D natural water sample. Atrazine (solubility
      of the commercial formula used 70 mg/L at 20 degrees C), compared to 2,4-D
      (solubility = 311 mg/L at pH = 1 and 25 degrees C), had a significantly greater
      teratogenic effect in both the buffer (atrazine EC50 = 33 mg/L, LC50 = 100 mg/L,
      TI = 3.03; 2,4-D EC50 = 245 mg/L, LC50 = 254 mg/L, TI = 1.04) and natural water
      samples (atrazine EC50 < 8 mg/L, LC50 = 126 mg/L; 2,4-D EC50 and LC50 > 270
      mg/L). The 2,4-D EC50 and LC50 values for the buffer were similar at 245 mg/L and
      254 mg/L. These similar values and the teratogenic index (TI) of 1.04 suggested
      that 2,4-D was more embryotoxic than teratogenic to frog embryos at high
      concentrations. Atrazine in natural water demonstrated a significantly greater
      EC50 (100% abnormality at 8 mg/L, the lowest test concentration) to frog embryos
      than the buffer experiment (EC50 = 33 mg/L). The extrapolated lowest observable
      adverse effect concentration (LOAEC) for the natural water experiment was 1.1
      mg/L. These results suggest that atrazine toxicity is enhanced by the synergistic
      or additive effects of some component of the water or atrazine was already
      present in the sample. In contrast to atrazine, 2,4-D was less toxic in natural
      water than buffer. These results suggest that both atrazine and 2,4-D pose little
      threat, since their embryotoxicity and teratogenicity to frog embryos occur at
      high concentrations approaching their maximum solubility levels in water.

PMID- 8642624
TI  - Study on pineal function and DMBA-induced breast cancer formation in rats during
      exposure to a 100-mG, 50 Hz magnetic field.
AB  - Reduction of circulating melatonin levels by pinealectomy or constant light has
      previously been shown to enhance the development and growth of mammary cancers
      induced by the polyaromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) in
      female rats. Since pineal melatonin production can also be disturbed by
      electromagnetic field exposure, we studied whether there is an association
      between melatonin depression by magnetic field (MF) exposure and DMBA-induced
      breast cancer growth in female rats. In the present experiments, 216 female
      Sprague-Dawley rats were divided into 4 groups. Two of the groups (with 99
      animals each) received oral applications of DMBA and were either sham-exposed or
      exposed in a 50-Hz, 100-mG (10 microT) MF for 24 h/d, 7 d/wk, for a period of 91
      d. The other two groups (nine animals each) were either sham-exposed or MF
      exposed without DMBA treatment. The exposure chambers and all other environmental
      factors were identical for MF-exposed and sham-exposed animals. The animals were
      palpated once weekly to assess the development of mammary tumors. At the end of
      the exposure period, all animals were sacrificed for autopsy and determination of
      nocturnal melatonin levels in pineal and serum. In controls, DMBA induced
      palpable tumors in about 55% of the animals within 3 mo after first application.
      There was a tendency to an enhanced tumor incidence in MF-exposed rats throughout
      the period of exposure, which, however, was not statistically significant. At
      autopsy, 60.6% of the sham-exposed and 66.6% of the MF-exposed rats had developed
      macroscopically visible mammary tumors. Tumor size and tumor burden were similar
      in both groups. Compared to the groups without DMBA treatment, DMBA-treated rats
      had significantly lower nocturnal pineal melatonin levels without difference in
      terms of MF exposure. MF-exposed rats, however, had significantly lower nocturnal
      melatonin levels in serum than sham-exposed animals. The data demonstrate that
      although exposure of female rats to a 50-Hz, 100-mG MF significantly decreases
      circulating melatonin, this is not associated with a significant effect on
      development or growth of DMBA-induced mammary tumors. In view of the fact that,
      by using the same model, we recently demonstrated a tumor-copromoting effect of
      MF exposure at a 10 times higher flux density, the effects of MF exposure on DMBA
      induced mammary carcinogenesis appear to be dose dependent.

PMID- 8642625
TI  - Factors in standardizing automated cholinesterase assays.
AB  - A scientific panel assembled by the U.S. Environmental Protection Agency (EPA)
      determined that variability in cholinesterase (ChE) activities in the agency's
      pesticide/animal study database likely was due to a lack of accepted guidelines
      for ChE methodology. A series of trials was held in which participating
      laboratories measured ChE activity in blood and brain samples from untreated and
      pesticide-treated rats using a colorimetric assay method. The degree of
      inhibition of ChE activity in plasma and brain samples compared to controls was
      consistent among most of the laboratories. The ChE activity in erythrocyte
      samples differed more between laboratories due to a high blank, low erythrocyte
      AChE activity and hemoglobin absorption at the wavelength of the assay.
      Strategies are suggested for minimizing the variability of ChE activity in
      hemoglobin-rich samples.

PMID- 8642626
TI  - Effects of D&C yellow no. 11 ingestion on F344/N rats and B6C3F1 mice.
AB  - D&C yellow no. 11 (CAS no. 8003-22-3) was administered in the feed at
      concentrations of 500-50,000 ppm to groups of F344/N rats and B6C3F1 mice of each
      sex for 13 wk to determine the toxicity. In addition, a perinatal study was
      conducted to determine the effects of feeding diets containing D&C yellow no. 11
      to female rats during reproduction and to their offspring. Although the estimated
      intake (g/kg) of D&C yellow no. 11 of mice was more than twice that of rats, the
      results were generally similar for both rats and mice. In both species, D&C
      yellow no. 11 caused no mortality, but it did reduce body weight gain slightly in
      both sexes of rats exposed to 17,000 and 50,000 ppm. Absolute and relative liver
      weights were significantly increased in all groups of rats and mice administered
      D&C yellow no. 11 in the feed. There was minimal to mild degeneration of the
      periportal hepatocytes in rats at doses of 1700 ppm and higher and in mice at
      5000 ppm and above. A dose-related yellow-brown pigment was observed in
      hepatocytes, Kupffer cells, and biliary epithelium of the liver of both sexes of
      both species and in the renal tubule epithelium in both sexes of rats. In male
      rats, all treated groups had increased number and size of hyaline droplets in the
      renal tubule epithelium of the cortex and outer medulla. To determine if these
      renal and hepatic lesions were reversible, male rats were administered 5000 ppm
      dietary D&C yellow no. 11 for 70 d and then examined at 3, 14, and 28 d after the
      chemical was removed from the diet. Pigment persisted in the kidney and liver for
      as long as 28 d following removal of D&C yellow no. 11 from the diet, but
      hepatocellular degeneration and cytoplasmic alteration in the kidney completely
      resolved by d 3 and 14, respectively. In the perinatal toxicity study, body
      weight gain in rat dams given diets containing as much as 50,000 ppm D&C yellow
      no. 11 for 4 wk before mating to untreated males was similar to that of controls
      at the time of mating but was lower at parturition and weaning. However,
      fertility, gestation length, litter size, and pup birth weights were unaffected
      by treatment. At weaning, there was a significant dose-related decrease in pup
      body weights from the 5000, 17,000, and 50,000 ppm groups. At 8 wk of age, pups
      fed the same dosed-feed concentrations as the dams had depressed body weights in
      the 17,000 and 50,000 ppm treated groups. Microscopic lesions in the liver and
      kidney of the pups in all dose groups were similar to those described in the 13
      wk study. The results of these studies indicate that compound-related effects
      occurred at all dietary concentrations of D&C yellow no. 11. Liver weights were
      increased in dosed rats and mice, minimal to mild hepatocellular degeneration was
      seen in rats receiving dietary concentrations of 1700 ppm and above and in mice
      at 5000 ppm and above, and there was an increase in the number and size of
      hyaline droplets in all dosed groups of male rats. Similar compound-related
      effects were also seen in all dosed rats in the perinatal toxicity study. With
      the exception of pigment accumulation, the treatment-related kidney and liver
      lesions in male rats were reversible by 14 d after chemical was withdrawn from
      the diet.

PMID- 8642627
TI  - Herpes simplex virus type 1 alkaline nuclease is required for efficient
      processing of viral DNA replication intermediates.
AB  - Mutations in the alkaline nuclease gene of herpes simplex type 1 (HSV-1) (nuc
      mutations) induce almost wild-type levels of viral DNA; however, mutant viral
      yields are 0.1 to 1% of wild-type yields (L. Shao, L. Rapp, and S. Weller,
      Virology 195:146-162, 1993; R. Martinez, L. Shao, J.C. Bronstein, P.C. Weber, and
      S. Weller, Virology 215:152-164, 1996). nuc mutants are defective in one or more
      stages of genome maturation and appear to package DNA into aberrant or defective
      capsids which fail to egress from the nucleus of infected cells. In this study,
      we used pulsed-field gel electrophoresis to test the hypothesis that the defects
      in nuc mutants are due to the failure of the newly replicated viral DNA to be
      processed properly during DNA replication and/or recombination. Replicative
      intermediates of HSV-1 DNA from both wild-type- and mutant-infected cells remain
      in the wells of pulsed-field gels, while free linear monomers are readily
      resolved. Digestion of this well DNA with restriction enzymes that cleave once in
      the viral genome releases discrete monomer DNA from wild-type virus-infected
      cells but not from nuc mutant-infected cells. We conclude that both wild-type and
      mutant DNAs exist in a complex, nonlinear form (possibly branched) during
      replication. The fact that discrete monomer-length DNA cannot be released from
      nuc DNA by a single-cutting enzyme suggests that this DNA is more branched than
      DNA which accumulates in cells infected with wild-type virus. The well DNA from
      cells infected with wild-type and nuc mutants contains XbaI fragments which
      result from genomic inversions, indicating that alkaline nuclease is not required
      for mediating recombination events within HSV DNA. Furthermore, nuc mutants are
      able to carry out DNA replication-mediated homologous recombination events
      between inverted repeats on plasmids as evaluated by using a quantitative
      transient recombination assay. Well DNA from both wild-type- and mutant-infected
      cells contains free U(L) termini but not free U(S) termini. Various models to
      explain the structure of replicating DNA are considered.

PMID- 8642628
TI  - Stably expressed antisense RNA to cytomegalovirus UL83 inhibits viral
      replication.
AB  - The human cytomegalovirus (HCMV) open reading frame UL83 encodes a phosphoprotein
      of 64 to 68kDa (pp65) which is a major constituent of this virion and dense
      bodies. To determine the importance of the HCMV gene in the virus cycle, we
      studied HCMV replication in astrocytoma cells stably transfected with a
      retroviral vector carrying an antisense UL83 cDNA. Reverse transcription-PCR
      detected antisense RNA in the cytoplasm. The steady-state level of a 4-kb RNA
      containing coding sequences for pp65 was significantly reduced after infection of
      antisense cells. Concomitant with this, levels of expression of pp65 and pp71
      (UL82) were severely reduced. Extracellular HCMV production was almost completely
      blocked, irrespective of the multiplicity of infection or the time after
      infection studied. The block occurred at an early phase, since immediate-early
      protein synthesis occurred normally, while several late proteins (e.g., pp150
      [ppUL32] and assembly protein [UL80]) were absent or strongly inhibited. Normal
      replication of herpes simplex virus and of a pp65 deletion mutant of HCMV
      (RVAd65), lacking target sequences of antisense RNA, demonstrated the specificity
      of the block for wild-type HCMV in the antisense-stabilized cells and indicated
      that the block was not due to indirect interference with cellular genes. Our
      results appear to contradict those of Schmolke et al (S. Schmolke, H.F. Kern, P.
      Drescher, G. Jahn, and B. Plachter, J. Virol. 69:5959-5968, 1995), which show
      that UL83 is a nonessential gene for HCMV replication in vitro. This
      contradiction is discussed in light of the fact that the 4-kb mRNA, which codes
      for pp65 and was targeted in UL83-antisense cell lines, may be a bicistronic mRNA
      which also codes for pp71 (UL82). Thus, interference of expression from the genes
      encoding pp65 and pp71 by blocking of this putative bicistronic message leads to
      severe impairment of viral replication.

PMID- 8642629
TI  - Moloney murine leukemia virus-induced lymphomas in p53-deficient mice:
      overlapping pathways in tumor development?
AB  - The effect of Moloney murine leukemia virus (MoMLV) infection was examined in
      mice lacking a functional p53 gene. Virus-infected p53-/- mice developed tumors
      significantly faster than uninfected p53-/- or virus-infected p53+/+ littermates.
      However, the degree of synergy between MoMLV and the p53 null genotype was weaker
      than the synergy between either of these and c-myc transgenes. A similar range of
      T-cell tumor phenotypes was represented in all p53 genotype groups, including p53
      /- mice, which developed thymic lymphomas as the most common of several
      neoplastic diseases. Lack of p53 was associated with higher rates of metastasis
      and the ready establishment of tumors in tissue culture. Loss of the wild-type
      allele was a common feature of tumors in p53+/- mice and was complete in tumor
      cells in vitro, but this appeared to occur by a mechanism other than proviral
      insertion at the wild-type allele. A lower average MoMLV proviral copy number was
      observed in tumors of the p53 null and heterozygote groups, suggesting that the
      absence of a functional p53 gene reduced the number of steps required to complete
      the malignant phenotype. Mink cell focus-forming virus-like proviruses were
      detected in tumors of all infected mice but were relatively rare in p53 null
      mice. Analysis of c-myc, pim-1, and pal-1 showed that these loci were occupied by
      proviruses in some cases but at similar frequencies in p53 wild-type and null
      mice. In conclusion, while inactivation of p53 in the germ line predisposes mice
      to tumors similar in phenotype to those induced by MoMLV, it appears that virus
      induced tumors generally occur without p53 loss. We speculate that a bcl-2-like
      function carried or induced by MoMLV may underlie this p53-independent pathway.

PMID- 8642630
TI  - Human T-cell lymphotropic virus type 1 Tax mediates enhanced transcription in
      CD4+ T lymphocytes.
AB  - Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T
      cell leukemia/lymphoma and is associated with a variety of immunoregulatory
      disorders. HTLV-1 has been shown to bind to and infect a variety of hematopoietic
      and nonhematopoietic cells. However, both in vivo and in vitro, the provirus is
      mostly detected in and preferentially transforms CD4+ T cells. The molecular
      mechanism that determines the CD4+ T-cell tropism of HTLV-1 has not been
      determined. Using cocultures of purified CD4+ and CD8+ T cells with an HTLV-1
      producing cell line, we measured viral transcription by using Northern (RNA) blot
      analysis, protein production by using a p24 antigen capture assay and flow
      cytometric analysis for viral envelope, and proviral integration by using DNA
      slot blot analysis. We further measured HTLV-1 long terminal repeat-directed
      transcription in purified CD4+ and CD8+ T cells by using transient transfection
      assays and in vitro transcription. We demonstrate a higher rate of viral
      transcription in primary CD4+ T cells than in CD8+ T cells. HTLV-1 protein
      production was 5- to 25-fold greater in CD4+ cocultures and mRNA levels were 5
      fold greater in these cultures than in the CD8+ cocultures. Transient
      transfection and in vitro transcription indicated a modest increase in basal
      transcription in CD4+ T cells, whereas there was a 20-fold increase in reporter
      gene activity in CD4+ T cells cotransfected with tax. These data suggest that
      unique or activated transcription factors, particularly Tax-responsive factors in
      CD4+ T cells, recognize regulatory sequences within the HTLV-1 long terminal
      repeat, and this mediates the observed enhanced viral transcription and
      ultimately the cell tropism and leukemogenic potential of the virus.

PMID- 8642632
TI  - Adenovirus type 5 and 7 capsid chimera: fiber replacement alters receptor tropism
      without affecting primary immune neutralization epitopes.
AB  - The efficient uptake of adenovirus into a target cell is a function of adenovirus
      capsid proteins and their interaction with the host cell. The capsid protein
      fiber mediates high-affinity attachment of adenovirus to the target cell.
      Although the cellular receptor(s) for adenovirus is unknown, evidence indicates
      that a single receptor does not function as the attachment site for each of the
      49 different serotypes of adenovirus. Sequence variation of the fiber ligand,
      particularly in the C- terminal knob domain, is associated with serotype-specific
      binding specificity. Additionally, this domain of fiber functions as a major
      serotype determinant. Fiber involvement in cell targeting and its function as a
      target of the host immune response make the fiber gene an attractive target for
      manipulation, both from the perspective of adenovirus biology and from the
      perspective of using adenovirus vectors for gene transfer experiments. We have
      constructed a defective chimeric adenovirus type 5 (Ad5) reporter virus by
      replacing the Ad5 fiber gene with the fiber gene from Ad7A. Using the
      chloramphenicol acetyltransferase reporter gene, we have characterized this virus
      with respect to infectivity both in vitro and in vivo. We have also characterized
      the role of antifiber antibody in the host neutralizing immune response to
      adenovirus infection. Our studies demonstrate that exchange of fiber is a
      strategy that will be useful in characterizing receptor tropism for different
      serotypes of adenovirus. Additionally, the neutralizing immune response to Ad5
      and Ad7 does not differentiate between two viruses that differ only in their
      fiber proteins. Therefore, following a primary adenovirus inoculation, antibodies
      generated against fiber do not constitute a significant fraction of the
      neutralizing antibody population.

PMID- 8642631
TI  - The turnip yellow mosaic virus tRNA-like structure cannot be replaced by generic
      tRNA-like elements or by heterologous 3' untranslated regions known to enhance
      mRNA expression and stability.
AB  - The tRNA-like structure (TLS) at the 3' end of the turnip yellow mosaic virus
      genome was replaced with heterologous tRNA-like elements, and with a poly(A)
      tail, in order to assess its role. Replacement with the valylatable TLSs from two
      closely related tymoviruses resulted in infectious viruses. In contrast, no
      systemic symptoms on plants, and only low viral accumulations in protoplasts,
      were observed for three chimeric genomes with 3' sequences known to enhance mRNA
      stability and translatability. One of these chimeras had a poly(A) tail, and the
      others had the TLS with associated upstream pseudoknot tracts from the 3' ends of
      brome mosaic and tobacco mosaic viruses. The latter two chimeric RNAs were shown
      to be appropriately folded by demonstrating their aminoacylation in vitro with
      tyrosine and histidine, respectively. The results show that enhancement of genome
      stability or gene expression is not the major role of the turnip yellow mosaic
      virus TLS. The major role is likely to be replicational, dependent on features
      present in tymoviral TLSs but not in generic tRNA-like structures.

PMID- 8642633
TI  - Identification and characterization of a small modular domain in the herpes
      simplex virus host shutoff protein sufficient for interaction with VP16.
AB  - The herpes simplex virus transactivator VP16 and the virion host shutoff protein
      vhs are viral structural components that direct the activation of immediate-early
      gene expression and the arrest of host protein synthesis, respectively, during an
      infection. Recent studies show that VP16 and vhs physically interact with each
      other in vitro and in infected cells, suggesting that their respective regulatory
      functions are coupled. In this report, we used the yeast two-hybrid system and
      affinity chromatography with purified VP16 fusion proteins to precisely map a
      region in vhs that directs interaction with VP16. Deletion analysis of vhs
      demonstrated that a 21-amino-acid-long domain spanning residues 310 to 330
      (PAAGGTEMRVSWTEILTQQIA) was sufficient for directing complex formation with VP16
      in vivo and in vitro when fused to a heterologous protein. Site-directed
      mutagenesis of this region identified tryptophan 321 as a crucial determinant for
      interaction with VP16 in vitro and in vivo and additional residues that are
      important for stable complex formation in vitro. These findings indicate that vhs
      residues 310 to 330 constitute an independent and modular binding interface that
      is recognized by VP16.

PMID- 8642634
TI  - Pathogen-derived resistance to dengue type 2 virus in mosquito cells by
      expression of the premembrane coding region of the viral genome.
AB  - The full-length premembrane (prM) coding region of the dengue virus type 2 (DEN
      2; Jamaica) genome was expressed in C6/36 (Aedes albopictus) cells in either the
      sense or the antisense orientation from a double subgenomic Sindbis (dsSIN)
      virus. Northern (RNA) blot analysis confirmed the expression of sense or
      antisense DEN-2 prM RNA in infected C6/36 cells. PrM protein was demonstrated in
      cells infected with dsSIN virus expressing DEN-2 sense RNAs by an
      immunofluorescence assay. C6/36 cells were infected with each dsSIN virus at a
      multiplicity of infection (MOI) of 50 and challenged 48 h later with DEN-2 virus
      at an MOI of 0.1. Whereas C6/36 cells infected with a control of dsSIN virus
      supported high levels of DEN-2 replication, C6/36 cells infected with the dsSIN
      virus expressing prM antisense RNA were completely resistant to DEN-2 challenge.
      Cells expressing prM protein or untranslatable prM sense RNA also were resistant
      to DEN-2 challenge. Cells expressing prM protein demonstrated some breakthrough
      of DEN-2 virus when challenged at an MOI of 10. However, expressed untranslatable
      sense prM RNA conferred complete protection to challenge at the high MOI.

PMID- 8642635
TI  - Identification of cell surface molecules that interact with pseudorabies virus.
AB  - The alphaherpesvirus pseudorabies virus (PrV) has been shown to attach to cells
      by interaction between the viral glycoprotein gC and cell membrane proteoglycans
      carrying heparan sulfate chains (HSPGs). A secondary binding step requires gD and
      presumably another, hitherto unidentified cellular receptor. By use of a virus
      overlay protein binding assay (VOPBA), cosedimentation analyses, and affinity
      chromatography, we identified three species of cell membrane constituents that
      bind PrV. By treatment with EDTA, peripheral HSPGs of very high apparent
      molecular mass (>200 kDa) could be extracted from Madin-Darby bovine kidney
      cells. Binding of PrV to these HSPGs in the VOPBA was sensitive to enzymatic
      digestion with heparinase or papain. Cosedimentation analyses indicated that
      binding between PrV and high-molecular-weight HSPG depended on the presence of gC
      in the virion. In addition, adsorption of radiolabeled PrV virions to cells could
      be inhibited by the addition of purified high-molecular-weight HSPG. By using
      urea extraction buffer, a second species of HSPG of approximately 140 kDa could
      be solubilized. Binding of PrV to this HSPG in the VOPBA was also dependent on
      the presence of heparan sulfate, since reactivity was abolished after suppression
      of glycosaminoglycan biosynthesis with NaClO3 and after heparinase treatment. In
      addition to HSPG, in cellular membrane extracts obtained by treatment with mild
      detergent, a 85-kDa membrane protein was demonstrated to bind PrV in the VOPBA
      and affinity chromatography. In summary, we identified three species of cell
      membrane constituents that bind PrV: a peripheral HSPG of high molecular weight,
      an integral HSPG of approximately 140 kDa, and an integral membrane protein of 85
      kDa. It is tempting to speculate that interaction between PrV and the two species
      of HSPG mediates primary attachment of PrV and that the 85-kDa protein is
      involved in a subsequent attachment step.

PMID- 8642636
TI  - Effects of zidovudine-selected human immunodeficiency virus type 1 reverse
      transcriptase amino acid substitutions on processive DNA synthesis and viral
      replication.
AB  - Certain amino acid substitutions in the reverse transcriptase (RT), including
      D67N, K70R, T215Y, and K219Q, cause high-level resistance of human
      immunodeficiency virus type 1 (HIV-1) to zidovudine (3'-azidothymidine; AZT) and
      appear to approximate the template strand of the enzyme-template-primer complex
      in structural models. We studied whether this set of mutations altered RT
      template-primer interaction as well as their effect on virus replication in the
      absence of inhibitor. When in vitro polymerization was limited to a single
      association of an RT with an oligodeoxynucleotide-primed heteropolymeric RNA
      template (a single processive cycle), recombinant-expressed mutant 67/70/215/219
      RT synthesized 5- to 10-fold more high-molecular-weight DNA products (>200
      nucleotides in length) than wild-type RT. This advantage was maintained as
      deoxynucleoside triphosphate (dNTP) concentrations were decreased to limiting
      levels. In contrast, no difference was seen between wild-type and mutant RTs
      under conditions allowing repeated associations of enzyme with template-primer.
      Because intracellular dNTP concentrations are low prior to mitogenic stimulation,
      we compared replication of mutant 67/70/215/219 virus and wild-type virus in
      peripheral blood mononuclear cells (PBMC) stimulated before and after infection.
      In the absence of inhibitor, mutant 67/70/215/219 virus had a replication
      advantage in PBMC stimulated with phytohemagglutinin and interleukin-2 after
      infection, but virus replication was similar in PBMC stimulated before infection
      in vitro. The results confirm that RT mutations D67N, K70R, T215Y, and K219Q
      affect an enzyme-template-primer interaction in vitro and suggest that such
      substitutions may affect HIV-1 pathogenesis during therapy by increasing viral
      replication capacity in cells stimulated after infection.

PMID- 8642637
TI  - A new antisense tRNA construct for the genetic treatment of human
      immunodeficiency virus type 1 infection.
AB  - Different strategies proposed in the literature to attempt gene therapy of AIDS
      are based mainly on the intracellular production of RNA and protein therapeutics.
      This report describes the construction and the anti-human immunodeficiency virus
      type 1 (HIV-1) activity of a new type of antisense tRNA directed against a
      nucleotide region in the first coding exon of HIV-1 tat (nucleotides 5924 to
      5943; Los Alamos data bank) which is conserved among many HIV-1 clones. The anti
      tat antisense sequence was inserted into a tRNA(Pro) backbone by replacement of
      the anticodon loop, without altering the tRNA canonic tetraloop structure. The
      antisense tRNA was able to interact effectively with its target in vitro. Jurkat
      cells that constitutively expressed the anti-tat tRNA following retroviral vector
      transduction exhibited significant resistance to HIV-1 de novo infection.
      Resistance seemed to correlate with the level of antisense expression. This is
      the first time that such a tRNA antisense strategy has been shown to be effective
      as a genetic treatment of HIV-1 infection in tissue culture. The construct design
      proposed in this report has some intrinsic advantages: the transcript is driven
      by a polymerase III promoter, the short length of the RNA minimizes effects of
      intramolecular base pairing that may impair target recognition, and the antisense
      RNA has the stability and intracellular fate of a native tRNA molecule.

PMID- 8642638
TI  - Anti-human cytomegalovirus activity of cytokines produced by CD4+ T-cell clones
      specifically activated by IE1 peptides in vitro.
AB  - The control of latent cytomegalovirus (CMV) infections by the immune system is
      poorly understood. We have previously shown that CD4+ T cells specific for the
      human CMV major regulatory protein IE1 are frequent in latently infected healthy
      blood donors. In order to learn about the possible role of these cells, we have
      developed IE1-specific CD4+ T-cell clones and, in this study, analyzed their
      epitope specificity and function in vitro. We measured their cytokine production
      when stimulated with specific IE1 peptides or whole recombinant IE1 protein.
      Their cytokine profiles, as deduced from gamma interferon (IFN-gamma), tumor
      necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4) and IL-6 production,
      were of the Th0- and Th1-like phenotypes. Supernatants from IE1-specific clones
      producing IFN-gamma and TNF-alpha were shown to inhibit CMV replication in U373
      MG cells. This effect was due, as found by using cytokine-specific neutralizing
      antibodies, mostly to IFN-gamma, which was secreted at higher levels than TNF
      alpha. To better assess the anti-CMV activity of cytokines, recombinant IFN-gamma
      and TNF-alpha were used and shown to have a synergistic effect on the inhibition
      of CMV replication and protein expression. Thus, IE1-specific CD4+ T cells
      display in vitro anti-CMV activity through cytokine secretion and may play a role
      in the control of in vivo latent infections.

PMID- 8642639
TI  - Cellular pathways involved in the ex vivo expression of bovine leukemia virus.
AB  - Bovine leukemia virus (BLV) is the etiologic agent of enzootic bovine leukosis.
      The virus adopts a strategy based on the lack of viral expression in vivo; only
      very rare BLV-infected B lymphocytes express viral information. When the cells
      are isolated from animals in persistent lymphocytosis and cultivated ex vivo, a
      tremendous increase in viral expression occurs. To gain insight into this
      mechanism, we employed a general approach using chemicals that interfere
      specifically with cellular pathways involved in signal transduction from the cell
      membrane to the nucleus. Our data demonstrate that BLV expression is not
      correlated with the activity of protein kinase A (PKA) and is even inhibited by
      cyclic AMP (cAMP). The cAMP/PKA pathway is thus apparently not involved in ex
      vivo viral expression. In contrast, PKC appears to play a key role in this
      process. Phorbol myristate acetate can directly activate viral expression in B
      cells (in the absence of T cells). Furthermore, calphostin C, a highly specific
      inhibitor of PKC, partly decreases ex vivo BLV expression. Our data further
      demonstrate that calmodulin and calcineurin, a calmodulin-dependent phosphatase,
      play a key role in the induction of viral expression. The involvement of this
      calmodulin-dependent pathway could explain the induction of expression that
      cannot be assigned to PKC. Furthermore, it appears that the activation of viral
      expression requires a calmodulin but not a PKA-dependent pathway. These data
      highlight major differences between transient transfection and ex vivo
      experiments. Finally, despite their homologies, BLV and human T-cell leukemia
      virus appear to use different signal transduction pathways to induce viral
      expression.

PMID- 8642641
TI  - Identification of domains in rubella virus genomic RNA and capsid protein
      necessary for specific interaction.
AB  - In rubella virus-infected cells, genomic 40S and subgenomic 24S RNAs are present
      in the cytoplasm of infected cells. However, encapsidation by rubella virus
      capsid protein is specific for 40S genomic RNA. As a first step toward
      understanding the assembly of rubella virus nucleocapsid at the molecular level,
      the interaction between capsid protein and genomic RNA was studied by
      Northwestern (RNA-protein) blot analysis. RNA probes prepared by in vitro
      transcription were used to localize the RNA sequence that participates in binding
      to the capsid protein. We have identified a 29-nucleotide RNA sequence
      (nucleotides 347 to 375) that is essential for the binding. By using overlapping
      synthetic peptides of capsid protein, a peptide domain (residues 28 to 56) that
      displays specific RNA-binding activity of capsid protein has been located. This
      result suggests that the specific recognition of viral RNA during rubella virus
      assembly involves, at least in part, the nucleocapsid protein.

PMID- 8642640
TI  - The prevalence of proviral bovine leukemia virus in peripheral blood mononuclear
      cells at two subclinical stages of infection.
AB  - The bovine leukemia virus (BLV) is an oncogenic retrovirus that is associated
      with the development of persistent lymphocytosis (PL) and lymphoma in cattle.
      While B lymphocytes have been shown to be the primary cellular target of BLV,
      recent studies suggest that some T lymphocytes and monocytes may be infected by
      the virus. Because virally altered functions of monocytes and/or T cells could
      contribute to the development of lymphoproliferative disease, we sought to
      clarify the distribution of the BLV provirus in subpopulations of peripheral
      blood mononuclear cells in seropositive cows with and without PL. CD2+ T cells,
      monocytes, and CD5+ and CD5- B cells were sorted by flow cytometry and tested for
      the presence of BLV by single-cell PCR. We did not obtain convincing evidence
      that peripheral blood monocytes or T lymphocytes contain the BLV provirus in
      seropositive cows with or without PL. In seropositive cows without PL (n=14), BLV
      infected CD5+ and CD5- B cells accounted for 9.2% +/- 19% and 0.1% +/- 1.8% of
      circulating B lymphocytes, respectively. In cows with PL (n=5), BLV-infected CD5+
      and CD5- B cells accounted for 66% +/- 4.8% and 13.9% +/- 6.6% of circulating B
      lymphocytes, respectively. The increase in lymphocyte numbers in cows with PL was
      entirely attributable to the 45-fold and 99-fold expansions of infected CD5+ and
      CD5- B-cell populations, respectively. Our results demonstrate that B cells are
      the only mononuclear cells in peripheral blood that are significantly infected
      with BLV. On the basis of the absolute numbers of infected cells in seropositive,
      hematologically normal animals, there appear to be differences in susceptibility
      to viral spread in vivo that may be under the genetic control of the host.

PMID- 8642642
TI  - Glycoprotein D-negative pseudorabies virus can spread transneuronally via direct
      neuron-to-neuron transmission in its natural host, the pig, but not after
      additional inactivation of gE or gI.
AB  - Envelope glycoprotein D (gD) is essential for entry of pseudorabies virus (PRV)
      into cells but is not required for the subsequent steps in virus replication.
      Phenotypically complemented gD mutants can infect cells and can spread, both in
      vitro and in mice, by direct cell-to-cell transmission. Progeny virions released
      by infected cells are noninfectious because they lack gD. The aim of this study
      was to determine the role of gD in the neuropathogenicity of PRV in its natural
      host, the pig. We investigated whether gD-negative PRV can spread transneuronally
      via synaptically linked neurons of the olfactory and trigeminal routes. High
      doses of a phenotypically complemented gD mutant and gD mutants that are unable
      to express either gI or gI plus gE were inoculated intranasally in 3- to 5-week
      old pigs. Compared with the wild-type virus, the virulence of the gD mutant was
      reduced. However, pigs inoculated with the gD mutant still developed fever and
      respiratory signs. Additional inactivation of either gI or gI plus gE further
      decreased virulence for pigs. Immunohistochemical examination of infected pigs
      showed that a PRV gD mutant could replicate and spread transneuronally into the
      central nervous system (CNS). Compared with the wild-type virus, the gD mutant
      had infected fewer neurons of the CNS on day 2. Nevertheless, on day 3, the gD
      negative PRV had infected more neurons and viral antigens were present in second-
      and third-order neurons in the olfactory bulb, brain stem, and medulla oblongata.
      In contrast, gD mutants which are unable to express either gI or gI plus gE
      infected a limited number of first-order neurons in the olfactory epithelium and
      in the trigeminal ganglion and did not spread transneuronally or infect the CNS.
      Thus, transsynaptic spread of PRV in pigs can occur independently of gD. Possible
      mechanisms of transsynaptic transport of PRV are discussed.

PMID- 8642643
TI  - cis Requirement for N-specific protein sequence in bovine coronavirus defective
      interfering RNA replication.
AB  - A naturally occurring 2.2-kb defective interfering (DI) RNA of the bovine
      coronavirus, structurally a simple fusion of the genomic termini, contains a
      single contiguous open reading frame (ORF) or 1.7 kb composed of the 5'-terminal
      288 nucleotides of polymerase gene 1a and all 1,344 nucleotides of the
      nucleocapsid protein (N) gene. The ORF must remain open throughout most of its
      sequence for replication to occur. To determine the qualitative importance of the
      N portion of the chimeric ORF in DI RNA replication, transcripts of mutated
      reporter-containing constructs were tested for replication in helper virus
      infected cells. It was determined that the N ORF could not be replaced by the
      naturally occurring internal I protein ORF, accomplished by deleting the first
      base in the N start codon which leads to a +1 frameshift, nor could it be
      replaced by the chloramphenicol acetyltransferase ORF. Furthermore, 3'-terminal
      truncations of the N gene leaving less than 85% of its total length were likewise
      not tolerated. Small in-frame deletions and in-frame foreign sequence insertions
      of up to 99 nucleotides within certain regions of the N ORF were tolerated,
      however, but the rate of DI RNA accumulation in these cases was lower. These
      results indicate that there is a requirement for translation of most if not all
      of the N protein in cis for optimal replication of the bovine coronavirus DI RNA
      and suggest that a similar requirement may exist for viral genome replication.

PMID- 8642644
TI  - Filovirus-induced endothelial leakage triggered by infected
      monocytes/macrophages.
AB  - The pathogenetic mechanisms underlying hemorrhagic fevers are not fully
      understood, but hemorrhage, activation of coagulation, and shock suggest vascular
      instability. Here, we demonstrate that Marburg virus (MBG), a filovirus causing a
      severe form of hemorrhagic fever in humans, replicates in human
      monocytes/macrophages, resulting in cytolytic infection and release of infectious
      virus particles. Replication also led to intracellular budding and accumulation
      of viral particles in vacuoles, thus providing a mechanism by which the virus may
      escape immune surveillance. Monocytes/macrophages were activated by MBG infection
      as indicated by tumor necrosis factor alpha (TNF-alpha) release. Supernatants of
      monocyte/macrophage cultures infected with MBG increased the permeability of
      cultured human endothelial cell monolayers. The increase in endothelial
      permeability correlated with the time course of TNF-alpha release and was
      inhibited by a TNF-alpha specific monoclonal antibody. Furthermore, recombinant
      TNF-alpha added at concentrations present in supernatants of virus-infected
      macrophage cultures increased endothelial permeability in the presence of 10
      micron H2O2. These results indicate that TNF-alpha plays a critical role in
      mediating increased permeability, which was identified as a paraendothelial route
      shown by formation of interendothelial gaps. The combination of viral replication
      in endothelial cells (H.-J. Schnittler, F. Mahner, D. Drenckhahn, H.-D. Klenk,
      and H. Feldmann, J. Clin. Invest. 19:1301-1309, 1993) and monocytes/macrophages
      and the permeability-increasing effect of virus-induced cytokine release provide
      the first experimental data for a novel concept in the pathogenesis of viral
      hemorrhagic fever.

PMID- 8642646
TI  - Identification of baculovirus gene that promotes Autographa californica nuclear
      polyhedrosis virus replication in a nonpermissive insect cell line.
AB  - A gene that promotes Autographa californica M nuclear polyhedrosis virus (AcMNPV)
      replication in IPLB-Ld652Y cells, a cell line that is nonpermissive for AcMNPV,
      was identified in Lymantria dispar M nuclear polyhedrosis virus (LdMNPV).
      Cotransfection of AcMNPV DNA and a plasmid carrying the LdMNPV gene into IPLB
      Ld652Y cells results in AcMNPV replication. The gene maps between 43.3 and 43.8
      map units on the 162-kbp genome of LdMNPV. It comprises a 218-codon open reading
      frame and encodes a polypeptide with a predicted molecular mass of 25.7 kDa. The
      predicted polypeptide is glutamic acid and valine rich and negatively charged,
      with a pI of 4.61. No protein sequence motifs were identified, and no matches
      with known nucleotide or peptide sequences were found in the AcMNPV genome or
      database searches that suggest how this gene might function. A recombinant AcMNPV
      bearing the LdMNPV gene overcomes a block in protein synthesis observed in AcMNPV
      infected IPLB-Ld652Y cells. Using Southern blotting techniques, we were unable to
      identify a homolog in Orgyia pseudotsugata M nuclear polyhedrosis virus, a
      baculovirus that is routinely propagated in IPLB-Ld652Y cells. This suggests that
      the LdMNPV host range is unique among the baculoviruses studied to date. We named
      this gene hrf-1 (for host range factor 1).

PMID- 8642645
TI  - Temporal changes in chromatin, intracellular calcium, and poly(ADP-ribose)
      polymerase during Sindbis virus-induced apoptosis of neuroblastoma cells.
AB  - Sindbis virus (SV) induces apoptosis in many vertebrate cells, but the mechanism
      is unknown. To gain insight into this mechanism, the nature and time course of
      intracellular changes related to programmed cell death were studied in SV
      infected mouse neuroblastoma cells. New virus production began at 5 h after
      infection and reach a peak at 12 h. Hoechst 33342 staining of DNA analyzed by
      flow cytometry demonstrated changes in chromatin beginning 6 h after infection.
      These chromatin changes were cell cycle dependent, affecting cells in G0/G1 but
      not S phase. Apoptosis was not dependent on increases in intracellular Ca2+ and
      occurred more rapidly in the absence of extracellular Ca2+. Nuclear changes were
      accompanied by activation of the DNA repair enzyme poly(ADP-ribose) polymerase
      (PARP), resulting in increased consumption of NAD which was apparent by 10 h
      after infection. SV-induced apoptosis also involved the proteolytic cleavage of
      PARP. This cleavage was detectable at 16 h after infection approximately the same
      time that DNA fragmentation was apparent by agarose gel electrophoresis. We
      conclude that SV-induced apoptosis of neuroblastoma cells is dependent on viral
      replication, is not dependent on a rise in intracellular Ca2+, and is accompanied
      by activation of PARP and of a protease that cleaves PARP.

PMID- 8642647
TI  - ts1-Induced spongiform encephalomyelopathy: physical forms of high-mobility DNA
      in spinal cord tissues of paralyzed mice are products of premature termination of
      reverse transcription.
AB  - ts1 is a temperature-sensitive mutant of Moloney murine leukemia virus that
      causes hind-limb paralysis in mice. In tissues of the central nervous systems of
      paralyzed moribund FVB/N mice, a major component of the unintegrated viral DNA of
      ts1 consists of highly mobile physical forms of viral-specific DNA (HM DNA).
      Previous studies with ecotropic virus-specific polarity probes showed that the
      gp70-coding region of the env gene in the HM DNA was minus-sense single-stranded
      DNA. The physical forms of the HM DNA have now been characterized in more detail
      with additional ecotropic virus-specific probes that hybridized to the p15E
      coding region of the env gene and two locations within the U3 region of the long
      terminal repeat. Two major classes of HM DNA were found: class I molecules
      consist of short minus-sense single-stranded DNA; class II molecules are partial
      DNA duplexes that are longer than the class I molecules. The two classes of HM
      DNA molecules are intermediate products of reverse transcription of the viral RNA
      of ts1. Since tissues that are infected with cytopathic retroviruses may contain
      high levels of unintegrated viral DNA, the HM DNA may have a role in inducing
      neurodegeneration in the central nervous systems of mice that are infected with
      ts1.

PMID- 8642648
TI  - Calnexin acts as a molecular chaperone during the folding of glycoprotein B of
      human cytomegalovirus.
AB  - Human cytomegalovirus glycoprotein B (gB) is synthesized as a 105-kDa
      nonglycosylated polypeptide and cotranslationally modified by addition of N
      linked oligosaccharides to a 160-kDa precursor in the endoplasmic reticulum (ER).
      It is then transported to the Golgi complex, where it is endoproteolytically
      cleaved to form the disulfide-linked mature gp55-116 complex. Pulse-chase
      experiments demonstrate that the 160-kDa gB precursor was transiently associated
      with calnexin, a membrane-bound chaperone, in the ER. The association was maximal
      immediately after synthesis, and they dissociated with a half-time of 15 min.
      Complete inhibition of binding by tunicamycin or castanospermine indicates the
      importance of N-linked oligosaccharides for it. Nonreducing sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis demonstrated that during an initial
      stage in the biogenesis, the 160-kDa gB precursor was first synthesized as a
      fully reduced form and rapidly converted to an oxidized form, with a half-time of
      18 min. Both forms of the gB precursor could bind to calnexin. The kinetics of
      the conversion from the fully reduced to the oxidized form coincided with that of
      dissociation of the 160-kDa gB precursor from calnexin, suggesting that the two
      steps are closely related.

PMID- 8642649
TI  - Construction and characterization of replication-competent simian
      immunodeficiency virus vectors that express gamma interferon.
AB  - We report the construction and characterization of several replication-competent
      simian immunodeficiency virus (SIV) vectors with a deletion in the viral nef gene
      (SIV(delta nef)) that express gamma interferon (IFN-gamma). The expression of the
      cytokine gene was controlled either by the simian virus 40 early promoter or by
      the SIV 5' long terminal repeat regulatory sequences, utilizing the nef gene
      splice signals. To enhance the expression of IFN-gamma, the two in-frame nef
      start codons were mutated without altering the Env amino acid sequence
      (SIV(HyIFN)). Plasmids containing full-length proviral genomes were used to
      obtain high-titer stocks of each recombinant virus in cell cultures. Expression
      of IFN-gamma by SIV(HyIFN) reached levels as high as 10(6) U/ml after 11 days in
      culture. The IFN-gamma gene was unstable and sustained deletions after serial
      passage of SIV(delta nef) vectors in CEM-X-174 cells. The degree of instability
      appears to depend on size and orientation of the insert and the expression of IFN
      gamma. Only one virus, SIV(HyIFN), expressed detectable levels of IFN-gamma up to
      the sixth passage. Prospects for the use of IFN-gamma and other lymphokines to
      enhance the safety and efficacy of live attenuated vaccines are discussed.

PMID- 8642651
TI  - Expression of L protein of vesicular stomatitis virus Indiana serotype from
      recombinant baculovirus in insect cells: requirement of a host factor(s) for its
      biological activity in vitro.
AB  - The 241-kDa large (L) protein of vesicular stomatitis virus (VSV) Indiana
      serotype, a multifunctional catalytic subunit of the viral RNA polymerase, has
      been expressed in Spodoptera frugiperda cells infected with recombinant
      baculovirus BacPAK6-L containing the L gene under the control of a polyhedrin
      promoter. The recombinant L protein was biologically active and supported viral
      mRNA synthesis in vitro. When the expressed L protein was purified by
      phosphocellulose column chromatography, it eluted in two peaks, one at 0.4 M NaCl
      (peak I) and the second at 0.75 M NaCl (peak II). The L protein in peak I showed
      significant transcriptional activity in an in vitro transcription reconstitution
      experiment, whereas the L protein in peak II was inactive. Interestingly, the
      addition of cytoplasmic extract from uninfected Sf21 cells to peak II completely
      restored transcription in vitro, indicating the requirement of a host factor(s)
      for the activity of the L protein. This factor is relatively heat stable and is
      dissociable from the recombinant L protein. It is also present in BHK, COS, and
      HeLa cells in detectable levels. The role of the putative host protein(s) in the
      activation of the L protein is discussed.

PMID- 8642650
TI  - A 348-base-pair region in the latency-associated transcript facilitates herpes
      simplex virus type 1 reactivation.
AB  - Latency-associated transcript (LAT) promoter deletion mutants of herpes simplex
      virus type 1 have a reduced capacity to reactivate following adrenergic induction
      in the rabbit eye model. We have mapped a reactivation phenotype within LAT and
      describe the construction of recombinants in which poly(A) addition sites have
      been placed at intervals within the LAT region to form truncated LAT transcripts.
      These mutants localize the induced reactivation phenotype to the 5' end of LAT.
      To further define this region, we constructed a recombinant containing a 348-bp
      deletion located 217 bp downstream of the transcription start site of the 8.5-kb
      LAT. This virus, 17delta348, expresses LAT but exhibits a significantly reduced
      ability to reactivate following epinephrine iontophoresis into the cornea.
      Quantitative DNA PCR analysis reveals that 17delta 348 establishes a latent
      infection within rabbit trigeminal ganglia with the same efficiency as does
      either the rescuant or wild-type virus. The region deleted in 17delta348 encodes
      three potential translational initiators (ATGs) which we have mutated and
      demonstrated to be dispensable for epinephrine-induced reactivation. In addition,
      three smaller deletions within this region have been constructed and were shown
      to reactivate at wild-type (parent) frequencies. These studies indicate that an
      undefined portion of the 348-bp region is required to facilitate induced
      reactivation. Sequence analysis of this 348-bp region revealed a CpG island which
      extends into the LAT promoter and which possesses homology to conserved elements
      within the mouse and human XIST transcript encoded on the X chromosome. Possible
      implications of these elements in the regulation of LAT expression are discussed.

PMID- 8642652
TI  - Raf-1 kinase targets GA-binding protein in transcriptional regulation of the
      human immunodeficiency virus type 1 promoter.
AB  - The serine/threonine protein kinase Raf-1 is a component of a conserved
      intracellular signaling cascade that controls responses to various extracellular
      stimuli. Transcription from several promoters, including the oncogene-responsive
      element in the polyomavirus enhancer, the c-fos promoter, as well as other AP-1-
      and Ets-dependent promoters, can be induced by Raf-1 kinase. Previously, we have
      shown that activated Raf-1 kinase transactivates the human immunodeficiency virus
      type 1 (HIV-1) long terminal repeat and have identified the NF-kappaB binding
      motif as a Raf-1-responsive element (RafRE). We now report that Raf-1 kinase
      induced transactivation from the HIV RafRE involves the purine-rich-repeat
      binding protein (GABP), which is composed of two distinct subunits (alpha and
      beta). GABP alpha is an Ets oncogene-related DNA-binding protein, and GABP beta
      contains four ankyrin-like repeats that have been shown to be essential in
      protein-protein interactions. In electrophoretic mobility shift assays using
      nuclear extracts from human Jurkat T cells, a protein-DNA complex which was
      supershifted with antiserum against GABP alpha and GABP beta was observed.
      Purified recombinant GABP alpha and beta interact with the HIV RafRE as judged
      from DNA binding assays. Cotransfection experiments with GABP alpha and beta and
      Raf-1 kinase demonstrate synergistic transactivation of the HIV-1 promoter. Point
      mutations in the HIV RafRE abolished the Raf-1 kinase as well as GABP alpha- and
      beta-induced transactivation. The observed Raf-1-GABP synergism presumably
      involves phosphorylation of GABP subunits, as treatment of cells with Raf-1
      kinase activators serum and 12-O-tetradecanoylphorbol-13-acetate increases
      phosphorylation of GABP in vivo. However, GABP is not a target of Raf-1 kinase;
      instead, it is a substrate of mitogen-activated protein kinase (MAPK/ERK), since
      in vitro phosphorylation of GABP alpha and beta was achieved by the reconstituted
      protein kinase cascade but not with purified Raf-1 or MEK. These results suggest
      that Raf-1 kinase- induced activation of the HIV-1 promoter is mediated by the
      classical cytoplasmic cascade resulting in MAPK/ERK-mediated phosphorylation of
      GABP alpha and beta. Because the HIV RafRE corresponds to a region within the
      promoter which is essential for regulation of HIV-1 expression, the data indicate
      that in addition to NK-kappaB, GABP transcription factors are important for
      induced expression of HIV.

PMID- 8642653
TI  - A large region within the Rous sarcoma virus matrix protein is dispensable for
      budding and infectivity.
AB  - All retroviruses have a layer of matrix protein (MA) situated directly beneath
      the lipid of their envelope. This protein is initially expressed as the amino
      terminal sequence of the Gag polyprotein, where it plays an important role in
      binding Gag to the plasma membrane during the early steps of the budding process.
      Others have suggested that MA may provide additional functions during virion
      assembly, including the selective incorporation of viral glycoproteins and the
      RNA genome into the emerging virion. To further study the role of the Rous
      sarcoma virus MA sequence in the viral replication cycle, we have pursued an
      extensive deletion analysis. Surprisingly, the entire second half of MA (residues
      87 to 155) and part of the neighboring p2 sequence were found to be dispensable
      not only for budding but also for infectivity in avian cells. Thus, all of the
      functions associated with the Rous sarcoma virus MA sequence must be contained
      within its first half.

PMID- 8642654
TI  - Protease-induced infectivity of hepatitis B virus for a human hepatoblastoma cell
      line.
AB  - The human hepatoblastoma cell line HepG2 produces and secretes hepatitis B virus
      (HBV) after transfection of cloned HBV DNA. Intact virions do not infect these
      cells, although they attach to the surface of the HepG2 cell through binding
      sites in the pre-S1 domain. Entry of enveloped virions into the cell often
      requires proteolytic cleavage of a viral surface protein that is involved in
      fusion between the cell membrane and the viral envelope. Recently, we observed
      pre-S-independent, nonspecific binding between hepatitis B surface (HBs)
      particles and HepG2 cells after treatment of HBs antigen particles with V8
      protease, which cleaves next to a putative fusion sequence. Chymotrypsin removed
      this fusion sequence and did not induce binding. In this study, we postulate that
      lack of a suitable fusion-activating protease was the reason why the HepG2 cells
      were not susceptible to HBV. To test this hypothesis, virions were partially
      purified from the plasma of HBV carriers and treated with either staphylococcal
      V8 or porcine chymotrypsin protease. Protease-digested virus lost reactivity with
      pre-S2-specific antibody but remained morphologically intact as determined by
      electron microscopy. After separation from the proteases, virions were incubated
      with HepG2 cells at pH 5.5. Cultures inoculated with either intact or
      chymotrypsin-digested virus did not contain detectable levels of intracellular
      HBV DNA at any time following infection. However, in cultures inoculated with V8
      digested virions, HBV-specific products, including covalently closed circular
      DNA, viral RNA, and viral pre-S2 antigen, could be detected in a time-dependent
      manner following infection. Immunofluorescence analysis revealed that 10 to 30%
      of the infected HepG2 cells produced HBV antigen. Persistent secretion of virus
      by the infected HepG2 cells lasted at least 14 days and was maintained during
      several reseeding steps. The results show that V8-digested HBV can productively
      infect tissue cultures of HepG2 cells. It is suggested that proteolysis-dependent
      exposure of a fusion domain within the envelope protein of HBV is necessary
      during natural infection.

PMID- 8642655
TI  - Possible role of splice acceptor site in expression of unspliced gag-containing
      message of Moloney murine leukemia virus.
AB  - Moloney murine leukemia virus (MLV) having the gag coding region alone, G3.6,
      produced a low level of mRNA (1/10 of the wild-type level). Ligation of 441
      nucleotides (nt) containing a splice acceptor (SA) site to the downstream portion
      of the remaining gag region restored the level of the unspliced message,
      simultaneously activating a cryptic splice donor (SD) site in the middle of the
      p30 coding region (between nt 1596 and 1597). Ligation of the 441 nt in the same
      site in the inverted orientation also increased the level of the unspliced
      message, activating the same SD site (between nt 1596 and 1597) and a new SA site
      just in front of the inserted 441 nt (between nt 4770 and 4771). Deletion or
      inversion of the 441-nt SA sequence from the wild-type MLV or from int in-frame
      deletion or int frameshift mutant MLVs of nearly full size resulted in the loss
      of spliced mRNA and concomitantly in a severe reduction of the unspliced mRNA,
      particularly at 37 degrees C. Deletion of the 5' SD site did not result in the
      reduction of the unspliced-mRNA level. When the gag region in G3.6 was replaced
      with a Neo(r) coding region, the level of expression was high. The data taken
      together suggest that the presence of an SA signal is necessary for high-level
      expression of unspliced mRNA encoding Gag or Gag-Pol.

PMID- 8642656
TI  - The adenovirus death protein (E3-11.6K) is required at very late stages of
      infection for efficient cell lysis and release of adenovirus from infected cells.
AB  - Adenovirus (Ad) infection is concluded by assembly of virions in the cell nucleus
      followed by lysis of cells by an unknown mechanism. We have described an Ad
      nuclear membrane glycoprotein of 11,600 kDa (E3-11.6K) which is encoded by the E3
      transcription unit and which is synthesized in small amounts from the E3 promoter
      at early stages of infection but in large amounts from the major late promoter at
      very late stages of infection. We now report that E3-11.6K is required for the
      efficient lysis (death) of Ad-infected cells, and we propose that the function of
      E3-11.6K is to mediate the release of Ad progeny from infected cells. We have
      renamed E3-11.6K the Ad death protein (ADP). Virus mutants that lack ADP
      replicated as well as adp+ Ad, but the cells lysed more slowly, virus release
      from the cell was retarded, and the plaques were small and developed slowly.
      Cells infected with adp+ viruses began to lyse at 2 or 3 days postinfection
      (p.i.) and were completely lysed by 5 or 6 days p.i. In contrast, cells infected
      with adp mutants did not begin significant lysis until 5 or 6 days p.i. Cell
      lysis and viability were determined by plaque size, extracellular virus, cell
      morphology, release of lactate dehydrogenase, trypan blue exclusion, the 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for
      mitochondrial activity, RNA degradation, and DNA degradation as determined by
      agarose gel electrophoresis and the terminal deoxynucleotidyltransferase end
      labeling assay. Protein synthesis was almost nonexistent at 3 days p.i. in cells
      infected with adp+ Ads, but it was still increasing in cells infected with adp
      mutants. Host cell protein synthesis was undetectable at 1 day p.i. in cells
      infected with adp+ Ads or adp mutants. Cells infected with adp mutants showed Ad
      cytopathic effect at 1 or 2 days p.i. in that they rounded up and detached, but
      the cells remained metabolically active and intact for >5 days p.i. When examined
      by electron microscopy, the nuclei were extremely swollen and full of virus, and
      the nuclear membrane appeared to be intact. ADP is unrelated in sequence to other
      known cell death-promoting proteins.

PMID- 8642658
TI  - The minimal conserved transcription stop-start signal promotes stable expression
      of a foreign gene in vesicular stomatitis virus.
AB  - A new transcription unit was generated in the 3' noncoding region of the
      vesicular stomatitis virus (VSV) glycoprotein gene by introducing the smallest
      conserved sequence found at each VSV gene junction. This sequence was introduced
      into a DNA copy of the VSV genome from which infectious VSV can be derived. It
      contained an 11-nucleotide putative transcription stop/polyadenylation signal for
      the glycoprotein mRNA, an intergenic dinucleotide, and a 10-nucleotide putative
      transcription start sequence preceding a downstream foreign gene encoding the
      bacterial enzyme chloramphenicol acetyltransferase. Infectious recombinant VSV
      was recovered from this construct and was found to express high levels of
      functional chloramphenicol acetyltransferase mRNA and protein. The recombinant
      virus grew to wild-type titers of 5 x 10(9)/ml, and expression of the foreign
      gene was completely stable for at least 15 passages involving 10(6)-fold
      expansion at each passage. These results define functionally the transcription
      stop/polyadenylation and start sequences for VSV and also illustrate the utility
      of VSV as a stable vector that should have wide application in cell biology and
      vaccine development.

PMID- 8642657
TI  - Factors regulating baculovirus late and very late gene expression in transient
      expression assays.
AB  - Eighteen genes of Autographa californica nuclear polyhedrosis virus are necessary
      and sufficient to transactivate expression from the late vp39 promoter in
      transient-expression assays in SF-21 cells. These 18 genes, known as late
      expression factor genes (lefs), are also required to transactivate the very late
      promoter of the polyhedrin gene, polh, but expression from this promoter is
      relatively weak compared with expression from the vp39 promoter. To further
      define the factors required for late and very late promoter expression, we first
      determined that the eighteen lefs were also required for expression from two
      other major baculovirus promoters: the late basic 6.9-kDa protein gene, p6.9, and
      the very late 10-kDa protein gene, p10. We next examined the effect of the very
      late expression factor 1 gene (vlf-1), a gene previously identified by analysis
      of a temperature-sensitive mutant, in the transient expression assay and found
      that vlf-1 specifically transactivated the two very late promoters but not the
      two late promoters. We then surveyed the Autographa californica nuclear
      polyhedrosis virus genome for additional genes which might specifically regulate
      very late gene expression; no additional vlf genes were detected, suggesting that
      VLF-1 is the primary regulator of very late gene expression. Finally, we found
      that the relative contribution of the antiapoptosis gene p35, which behaves as a
      lef in these transient-expression assays, depended on the nature of the other
      viral genes provided in the cotransfection mixtures, suggesting that other viral
      genes also contribute to the ability of the virus to block apoptosis.

PMID- 8642659
TI  - Human immunodeficiency virus type 1 cell cycle control: Vpr is cytostatic and
      mediates G2 accumulation by a mechanism which differs from DNA damage checkpoint
      control.
AB  - Vpr is a 96-amino-acid protein encoded by human immunodeficiency virus type 1
      (HIV-1) that prevents proliferation of infected cells. We have established a
      system for infection of 100% of a T-cell population with HIV and use this system
      to show that within the context of HIV-1 infection, Vpr is primarily cytostatic
      rather than cytotoxic. Vpr acts upstream of dephosphorylation of the mitotic
      cyclin-dependent kinase, and causes infected cells to accumulate in the G2 stage
      of the cell cycle. However, some HIV-1 infected cells increase in ploidy and
      size, accumulating DNA to an 8N level. Furthermore, the mechanism of the Vpr
      mitotic block is qualitatively different from that of G2 DNA damage checkpoint
      control.

PMID- 8642660
TI  - The Ras-Raf pathway is activated in human immunodeficiency virus-infected
      monocytes and particpates in the activation of NF-kappa B.
AB  - Persistent human immunodeficiency virus (HIV) infection of human monocytes and
      macrophages increases I kappa B alpha degradation, resulting in the activation of
      NF-kappa B, a key transcription factor in the regulation of the HIV long terminal
      repeat. The signal transduction pathways leading to NF-kappa B activation in
      cells of the monocytic lineage, especially those regulated by HIV infection, and
      their relevance in regulating viral persistence remain unknown. Both p21ras and
      its downstream Raf-1 kinase participate in the transduction of signals initiated
      from a variety of cell surface receptors and in the regulation of transcription
      factors. We have studied whether the Ras-Raf pathway is functional and
      participates in HIV-mediated NF-kappa B activation in monocytic cells.
      Constitutively active p21ras (v-H-Ras) activated NF- kappa B-dependent
      transcription and induces the nuclear translocation of a bona fide p65/p50
      heterodimer by targeting I kappa B alpha. In addition, the constitutively active
      form of Raf (RafBXB) also increases the NF-kappa B-dependent transcriptional
      activity. Because of the similarity between HIV and Ras-Raf-induced NF-kappa B
      activation in monocytic cells, we next tested whether HIV-induced NF-kappa B
      activation was mediated by the Ras-Raf signal transduction pathway. Negative
      dominant forms of both Ras (Ras N17) and Raf (Raf 301) decreased the HIV- but not
      lipopolysaccharide-dependent NF-kappa B activation in U937 cells. Moreover, Raf-1
      kinase activity was greater in HIV-infected than uninfected monocytic cells in in
      vitro kinase assays. Altogether, these results indicate that the Ras-Raf pathway
      is unregulated in HIV monocytic cells and participates in the virus-induced
      activation of NF-kappa B.

PMID- 8642661
TI  - Identification of a differentiation-inducible promoter in the E7 open reading
      frame of human papillomavirus type 16 (HPV-16) in raft cultures of a new cell
      line containing high copy numbers of episomal HPV-16 DNA.
AB  - Gene expression of human papillomaviruses (HPV) is tightly linked to
      differentiation processes within the pluristratified epithelium. To analyze
      changes in the transcription pattern of HPV-16 during epithelial cell
      differentiation, we established a permanently growing HPV-16 positive cell line,
      designated KG, from a vulvar intraepithelial neoplasm. KG cells of early passages
      harbored multiple copies of the HPV-16 DNA as episomes and were able to form a
      stratified epithelium in an organotypic raft culture system. Analysis of viral
      gene expression revealed the known transcription pattern of the early region of
      HPV-16 with the exception of a so far undefined mRNA class with start sites in
      the E7 open reading frame. Quantitative analysis of primer extension experiments
      with RNA from KG cells grown in monolayer and raft culture showed a strong
      induction of this transcript in differentiated KG cells, whereas the level of the
      mRNAs initiated at the early promoter P97 remained almost constant. Primer
      extension analyses with four different primers and direct sequencing of the
      extension product revealed that the differentiation-inducible transcript
      initiated at a novel promoter with a major start site around nucleotide position
      670 (P670) in the E7 open reading frame of HPV-16. Sequence analysis of cDNAs
      derived from RNA of KG cells grown in raft culture suggested that the transcripts
      initiated at P670 have a coding potential for an E1E4 fusion protein and for the
      E5 protein.

PMID- 8642663
TI  - Influenza A virus RNA-dependent RNA polymerase: analysis of RNA synthesis in
      vitro.
AB  - Influenza A virus RNA-dependent RNA polymerase, purified from virion
      ribonucleoprotein particles and from which endogenous genomic RNA (vRNA) has been
      depleted by treatment with micrococcal nuclease, was used to study transcription
      initiation, elongation, and termination in vitro. Templates that contained either
      minus- or plus-sense influenza virus nucleoprotein minigenes with conserved 5'
      and 3' termini and the uridylate tract were constructed. The dinucleotide ApG and
      alfalfa mosaic virus RNA4 (AlMV4) were used as primers. ApG primed the synthesis
      of full-length positive-strand or cRNA products and shorter transcripts,
      depending upon the molar ratio between the nucleoprotein and the vRNA template.
      Sequence analysis of the ends of these transcripts demonstrated that the 5'
      termini of both transcripts and the 3' terminus of the full-length product were
      complementary to the 3' and 5' termini of the vRNA template, respectively,
      whereas the 3' terminus of the incomplete product corresponded to a sequence
      located 40 bases downstream from the 5' terminus of the template and was about 20
      nucleotides downstream from the uridylate tract, which is the putative signal for
      polyadenylation. Binding of the cap structure of AlMV4 by the polymerase
      activated RNA synthesis by ligation-elongation of small genomic RNA fragments
      which were likely derived from a genome segment protected by the polymerase from
      micrococcal nuclease digestion. The sequence of these fragments mapped to a
      region 14 to 28 nucleotides upstream of the 3' terminus of the viral genome.
      Polymerase subunit involvement in transcription initiation with ApG or AlMV4 was
      characterized by studying the effect of purified polyclonal antisubunit
      immunoglobulins of the G class (IgGs) in transcription assays. These results
      showed that anti-PB2 IgG inhibited transcription initiation in both ApG- and
      AlMV4-primed reactions, whereas anti-PB1 antibodies also blocked transcription
      initiated with AlMV4. The differences observed in product size, product sequence,
      and differential inhibition by antisubunit IgGs are discussed. These observations
      would support the notion that the influenza virus RNA-dependent RNA polymerase
      undergoes a conformational change after the binding of the cap structure of host
      cell heterogeneous nuclear RNA by PB2, which then usually leads to
      endonucleolytic cleavage of the capped primer 13 nucleotides downstream from the
      cap.

PMID- 8642662
TI  - Nuclear transport of human immunodeficiency virus type 1, visna virus, and equine
      infectious anemia virus Rev proteins: identification of a family of transferable
      nuclear export signals.
AB  - The human immunodeficiency virus type 1 Rev trans activator binds directly to
      unspliced viral mRNA in the nucleus and activates its transport to the cytoplasm.
      In additon to the sequences that confer RNA binding and nuclear localization, Rev
      has a carboxy-terminal region, the activation domain, whose integrity is
      essential for biological activity. Because it has been established that Rev
      constitutively exits and reenters the nucleus and that the activation domain is
      required for nuclear exit, it has been proposed that Rev's activation domain is a
      nuclear export signal (NES). Here, we used microinjection-based assays to
      demonstrate that the activation domain of human immunodeficiency virus type 1 Rev
      imparts rapid nuclear export after its transfer to heterologous substrates. NES-
      mediated export is specific, as it is sensitive both to inactivation by missense
      mutation and to selective inhibition by an excess of the wild-type, but not
      mutant, activation domain peptide. Examination of the Rev trans activators of two
      nonprimate lentiviruses, visna virus and equine infectious anemia virus, revealed
      that their activation domains are also potent NESs. Taken together, these data
      demonstrate that nuclear export can be determined by positively acting peptide
      motifs, namely, NESs, and suggest that Rev proteins activate viral RNA transport
      by providing export ribonucleoproteins with specific information that targets
      them to the cytoplasm.

PMID- 8642664
TI  - Transactivation of a cellular promoter by the NS1 protein of the parvovirus
      minute virus of mice through a putative hormone-responsive element.
AB  - The promoter of the thyroid hormone receptor alpha gene (c-erbA-1) is activated
      by the nonstructural protein 1 (NS1) of parvovirus minute virus of mice
      (prototype strain [MVMp]) in ras-transformed FREJ4 cells that are permissive for
      lytic MVMp replication. This stimulation may be related to the sensitivity of
      host cells to MVMp, as it does not take place in parental FR3T3 cells, which are
      resistant to the parvovirus killing effect. The analysis of a series of deletion
      and point mutants of the c-erbA-1 promoter led to the identification of an
      upstream region that is necessary for NS1-driven transactivation. This sequence
      harbors a putative hormone-responsive element and is sufficient to render a
      minimal promoter NS1 inducible in FREJ4 but not in FR3T3 cells, and it is
      involved in distinct interactions with proteins from the respective cell lines.
      The NS1-responsive element of the c-erbA-1 promoter bears no homology with
      sequences that were previously reported to be necessary for NS1 DNA binding and
      transactivation. Altogether, our data point to a novel, cell-specific mechanism
      of promoter activation by NS1.

PMID- 8642666
TI  - Transcription of the JC virus archetype late genome: importance of the kappa B
      and the 23-base-pair motifs in late promoter activity in glial cells.
AB  - The transcription control region of the archetype strain of the human
      polyomavirus JC virus (JCV(Cy)), unlike its neurotropic counterpart (JCV(Mad-1)),
      contains only one copy of the 98-bp enhancer/promoter repeat with the 23-bp and
      the 66-bp insertion blocks. Early studies by us and others have indicated that
      the structural organization of JCV(Mad-1) is critical for glial cell-specific
      transcription of the viral genome. In addition, the kappa B regulatory motif
      found in the JCV(Mad-1) genome, which also exists in JCV(Cy), confers
      inducibility to the JCV(Mad-1) early and late promoters in response to
      extracellular stimuli. In this study, we have investigated the regulatory role of
      the 23- and the 66-bp blocks and their functional relationship to the kappa B
      motif in stimulating transcription of the Cy early and late promoters in glial
      cells. We demonstrate that mutations in the kappa B motif reduce the basal
      activity of the Cy early promoter and decrease the levels of its induction by
      phorbol myristate acetate or factors derived from activated T cells. Under
      similar circumstances, mutation in the kappa B motif completely abrogated the
      basal and the induced levels of transcription of the viral late promoter. Using
      deletion and hybrid promoter constructs, we have demonstrated that the 23-bp
      block of the Cy promoter plays a critical role in the observed inactivation of Cy
      late promoter transcription in glial cells. Results from DNA binding studies have
      indicated the formation of a common nucleoprotein complex with the 23-bp
      sequence, mutant kappa B (kappa B(mut)), and wild-type kappa B (kappa B(wt)).
      Analysis of this complex by UV cross-linking has identified a 40-kDa protein
      which binds to the 23-bp sequence and the kappa B motif. The importance of these
      findings for the activation of JCV(Cy) under various physiological conditions is
      discussed.

PMID- 8642665
TI  - BK virus large T antigen: interactions with the retinoblastoma family of tumor
      suppressor proteins and effects on cellular growth control.
AB  - BK virus (BKV) is a polyomavirus which infects a large percentage of the human
      population. It is a potent transforming agent and is tumorigenic in rodents. BKV
      DNA has also been found in human brain, pancreatic islet, and urinary tract
      tumors, implicating this virus in neoplastic processes. BKV T antigen (TAg) is
      highly homologous to simian virus 40 TAg, particularly in regions required for
      mitogenic stimulation and binding to tumor suppressor proteins, The experiments
      presented in this report show that BKV TAg can bind the tumor suppressor protein
      p53. BKV TAg also has the ability to bind to members of the retinoblastoma (pRb)
      family of tumor suppressor proteins both in vivo and in vitro. However, these
      interactions are detected only when large amounts of total protein are used,
      because the levels of BKV TAg normally produced from viral promoter-enhancer
      elements are too low to bind a significant amount of the pRb family proteins in
      the cell. The low levels of BKV TAg produced by the viral promoter elements are
      sufficient to affect the levels and the phosphorylation patterns of these
      proteins and to induce serum-independent growth in these cells. Additional
      events, however, are required for full transformation. These data further support
      the notion that BKV TAg can affect cellular growth control mechanisms and may in
      fact be involved in neoplastic processes.

PMID- 8642667
TI  - A recombinant adenovirus expressing an Epstein-Barr virus (EBV) target antigen
      can selectively reactivate rare components of EBV cytotoxic T-lymphocyte memory
      in vitro.
AB  - While the bulk of a virus-induced cytotoxic T-lymphocyte (CTL) response may focus
      on a few immunodominant viral antigens, in certain tumor virus systems the
      detectability of clones recognizing other, subdominant antigens can assume
      particular importance. By using the human CTL response to Epstein-Barr virus
      (EBV) as a model system, here we show that even rare components of virus-specific
      memory can be selectively reactivated in vitro when the relevant target antigen
      is expressed in autologous stimulator cells from a recombinant adenovirus (RAd)
      vector. We generated a replication-deficient adenovirus, RAd-E3C, which in skin
      fibroblast cultures expressed the EBV nuclear antigen EBNA3C at a 10- to 100-fold
      higher level than that naturally present in EBV-transformed lymphoblastoid cell
      lines (LCLs). Initial experiments with a donor whose polyclonal CTL response to
      LCL stimulation contained a strong EBNA3C-specific component showed that these
      CTLs could be efficiently reactivated by in vitro stimulation either with RAd-E3C
      infected fibroblasts or with RAd-E3C-infected peripheral blood mononuclear cells.
      Then we studied donors whose responses to LCL stimulation contained little if any
      detectable EBNA3C reactivity but were dominated by clones recognizing other EBV
      target antigens; in vitro stimulation with RAd-E3C-infected peripheral blood
      mononuclear cells selectively reactivated EBNA3C-specific CTL clones from these
      individuals, with the epitope specificities of responses subsequently identified
      at the peptide level. This RAd-based approach could be applied more generally to
      screen for human CTL responses against any candidate target antigen expressed by
      tumor cells.

PMID- 8642668
TI  - A pseudoknot ribozyme structure is active in vivo and required for hepatitis
      delta virus RNA replication.
AB  - The ribozymes of hepatitis delta virus (HDV) have so far been studied primarily
      in vitro. Several structural models for HDV ribozymes based on truncated HDV RNA
      fragments, which are different from the hammerhead or the hairpin/paperclip
      ribozyme model proposed for plant viroid or virusoid RNAs, have been proposed.
      Whether these structures actually exist in vivo and whether ribozymes actually
      function in the HDV replication cycle have not been demonstrated. We have now
      developed an in vivo ribozyme self-cleavage assay capable of detecting self
      cleavage of dimer or trimer HDV RNA in vivo. By site-directed mutagenesis and
      compensatory mutations to disrupt and restore potential base pairing in the
      ribozyme domain of the full-length HDV RNA according to the various structural
      models, a close correlation between the detected in vivo and the predicted in
      vitro ribozyme activities of various mutant RNAs was demonstrated. These results
      suggest that the proposed in vitro ribozyme structure likely exists and functions
      during the HDV replication cycle in vivo. Furthermore, the pseudoknot model most
      likely represents the structure responsible for the ribozyme activity in vivo.
      All of the mutants that had lost the ribozyme activity could not replicate,
      indicating that the ribozyme activities are indeed required for HDV RNA
      replication. However, some of the compensatory mutants which have restored both
      the cleavage and ligation activities could not replicate, suggesting that the
      ribozyme domains are also involved in other unidentified functions or in the
      formation of an alternative structure that is required for HDV RNA replication.
      This study thus established that the ribozyme has important biological functions
      in the HDV life cycle.

PMID- 8642669
TI  - The virion host shutoff protein of herpes simplex virus type 1: messenger
      ribonucleolytic activity in vitro.
AB  - Shortly after tissue culture cells are infected with herpes simplex virus (HSV)
      type 1 or 2, the rate of host protein synthesis decreases 5- to 10-fold and most
      host mRNAs are degraded. mRNA destabilization is triggered by the virion host
      shutoff (vhs) protein, a virus encoded, 58-kDa protein located in the virion
      tegument. To determine whether it can function as a messenger RNase (mRNase), the
      capacity of vhs protein to degrade RNA in vitro in absence of host cell
      components was assessed. Two sources of vhs protein were used in these assays:
      crude extract from virions or protein translated in a reticulocyte-free system.
      In each case, wild-type but not mutant vhs protein degraded various RNA
      substrates. Preincubation with anti-vhs antibody blocked RNase activity. These
      studies do not prove that vhs protein on its own is an mRNase but do demonstrate
      that the protein, either on its own or in conjunction with another factor(s), has
      the biochemical property of an mRNase, consistent with its role in infected
      cells.

PMID- 8642670
TI  - E5 oncoprotein transmembrane mutants dissociate fibroblast transforming activity
      from 16-kilodalton protein binding and platelet-derived growth factor receptor
      binding and phosphorylation.
AB  - The E5 oncoprotein of bovine papillomavirus type 1 is a 44-amino-acid,
      hydrophobic polypeptide which localizes predominantly in Golgi membranes and
      appears to transform cells through the activation of tyrosine kinase growth
      factor receptors. In fibroblasts, E5 interacts with both the 16-kilodalton
      vacuolar ATPase subunit and the platelet-derived growth factor receptor (PDGF-R)
      via its hydrophobic transmembrane domain and induces autophosphorylation of the
      receptor. To further analyze the correlation between E5 biological activity and
      its ability to bind these cellular proteins, a series of nine E5 transmembrane
      mutants was evaluated. In 32D mouse hematopoietic cells, there was an incomplete
      correlation between the abilities of the E5 mutant proteins to associate the PDGF
      R and to transform cells. However, all transforming E5 mutant proteins induced
      PDGF-R tyrosine phosphorylation. In NIH 3T3 and C127 mouse fibroblasts, both
      transforming and nontransforming E5 mutant proteins were defective for PDGF-R
      binding. In addition, while most of the transforming E5 proteins induced PDGF-R
      phosphorylation, one hypertransforming mutant (serine 17) neither bound nor
      induced receptor autophosphorylation. These findings support the hypothesis that
      the transformation of fibroblasts by E5 transmembrane mutants can involve
      alternative cellular targets or potentially independent activities of the E5
      protein. In addition, these results underscore the critical role of the
      transmembrane domain in mediating E5 biological activities.

PMID- 8642671
TI  - The role of human adenovirus early region 3 proteins (gp19K, 10.4K, 14.5K, and
      14.7K) in a murine pneumonia model.
AB  - Products of human adenovirus (Ad) early region 3 (E3) inhibit both specific
      (cytotoxic T lymphocytes [CTLs]) and innate (tumor necrosis factor alpha [TNF
      alpha]) immune responses in vitro. The E3 gp19K protein prevents CTL recognition
      of Ad-infected fibroblasts by sequestering major histocompatibility complex class
      I proteins in the endoplasmic reticulum. E3 proteins 10.4K, 14.5K, and 14.7K
      function to protect infected cells from TNF-alpha cytolysis. To address the in
      vivo functions of these proteins, Ad mutants that lack the E3 genes encoding
      these proteins were inoculated intranasally into C57BL/10SnJ (H-2b) mice. Mutants
      that lack the gp19K gene failed to alter CTL generation or to affect Ad-induced
      pulmonary infiltrates. Since gamma interferon (IFN-gamma) is capable of
      overcoming gp19K suppression of CTL lysis in vitro, mice were depleted of IFN
      gamma and inoculated with gp19K mutants. Even when IFN-gamma was depleted, gp19K
      was incapable of altering pulmonary lesions. These resuls are not in accord with
      the function of gp19K in vitro and suggest that gp19K does not affect immune
      recognition in vivo during an acute virus infection, yet they do not exclude the
      possibility that gp19K blocks immune recognition of Ad during a persistent
      infection. In contrast, when mice were inoculated with Ad mutants that lack the
      TNF resistance genes (14.7K and either 10.4K or 14.5K), there was a marked
      increase in alveolar infiltration and no change in the amounts of
      perivascular/peribronchiolar infiltration compared with wild-type-Ad-induced
      pathology. These findings demonstrate the importance of TNF susceptibility and
      TNF by-products for recruiting inflammatory cells into the lungs during Ad
      infections.

PMID- 8642672
TI  - Interaction of wild-type and mutant adeno-associated virus (AAV) Rep proteins on
      AAV hairpin DNA.
AB  - Both the Rep68 and Rep78 proteins of adeno-associated virus type 2 (AAV) bind to
      AAV terminal repeat hairpin DNA and can mediate site-specific nicking in vitro at
      the terminal resolution site (trs) within the terminal repeats. To define the
      regions of the Rep proteins required for these functions, a series of truncated
      Rep78 derivatives was created. Wild-type and mutant proteins were synthesized by
      in vitro translation and analyzed for AAV hairpin DNA binding, trs endonuclease
      activity, and interaction on hairpin DNA. Amino-terminal deletion mutants which
      lacked the first 29 or 79 amino acid residues of Rep78 did not bind hairpin DNA,
      which is consistent with our previous identification of a DNA-binding domain in
      this region. Progressive truncation of the carboxyl-terminal region of Rep78 did
      not eliminate hairpin DNA binding until the deletion reached amino acid 443. The
      electrophoretic mobility of the Rep-specific protein-DNA complexes was inversely
      related to the molecular weight of the Rep derivative. Analysis of the C-terminal
      deletion mutants by the trs endonuclease assay identified a region (amino acids
      467 to 476) that is essential for nicking but is not necessary for DNA binding.
      When endonuclease-positive, truncated Rep proteins that bound hairpin DNA were
      mixed with full-length Rep78 or Rep68 protein in electrophoretic mobility shift
      assays, a smear of protein-DNA complexes was observed. This smear migrated at an
      intermediate position with respect to the bands generated by the proteins
      individually. An antibody recognizing only the full-length protein produced a
      novel supershift band when included in a mixed binding assay containing Rep68 and
      a truncated Rep mutant. These experiments suggest that the Rep proteins can form
      hetero-oligomers on the AAV hairpin DNA.

PMID- 8642673
TI  - Retroviral insertional activation in a herpesvirus: transcriptional activation of
      US genes by an integrated long terminal repeat in a Marek's disease virus clone.
AB  - Insertional activation of host proto-oncogenes has been recognized as a basic
      mechanism by which nonacute retroviruses induce cancer. Our previous work has
      demonstrated that retroviruses can efficiently integrate into DNA virus genomes.
      Specifically, coinfection of cultured fibroblasts with a chicken herpesvirus,
      Marek's disease virus (MDV), and a chicken retrovirus results in frequent stable
      retroviral insertions into the herpesvirus genome. Such insertions could alter
      the expression of herpesvirus genes, possibly resulting in novel phenotypic
      properties. In this article, we report the characterization of a replication
      competent clone of MDV with integrated retroviral sequences. This virus was
      isolated from a chicken following injection of fibroblasts coinfected with MDV
      and the retrovirus, reticuloendotheliosis virus. Transcripts originating from the
      reticuloendotheliosis virus long terminal repeat promoters were found to encode
      the adjoining MDV genes, SORF2, US1, and US10. This virus replicates well in
      culture but has an unusual phenotype in chickens, characterized by an attenuated
      virulence which produces no nerve lesions but, rather, severe thymic atrophy.
      While the causal relationship between the insertion and the observed phenotypes
      remains to be established, our data provide the first evidence of retroviral
      insertional activation of herpesvirus genes.

PMID- 8642674
TI  - The N-terminal half of EBNA2, except for seven prolines, is not essential for
      primary B-lymphocyte growth transformation.
AB  - Previous molecular genetic analyses of Epstein-Barr virus nuclear protein 2
      (EBNA2) identified a negative effect of deletion of codons 19 to 33 on
      transformation and gene transactivation, while deletion of codons 19 to 110 was a
      null mutation for transformation and gene transactivation. We here report the
      surprising finding that codons 2 to 88, which encode the highly conserved unique
      N terminus (amino acids 1 to 58) and most of the polyproline repeat (amino acids
      59 to 95), can be deleted with only minimal effects on transformation. Codons 97
      to 122 can also be deleted with only minimal effects on transformation. However,
      deletion of 35 of the 37 prolines (amino acids 59 to 93) or deletion of codons 2
      to 95 results in a null transforming phenotype. Although EBNA2 from which codons
      59 to 93 were deleted was a null mutation for transformation, it was similar to
      some transforming mutants of EBNA2 in abundance, in interaction with RBPJK, and
      in transactivation of the LMP1 promoter in transient transfection assays. These
      data indicate that between three and seven prolines are critical for EBNA2
      structure or for intermolecular interaction. Aside from these seven prolines,
      codons encoding the rest of the N-terminal half (amino acids 2 to 230) of EBNA2
      are nonessential for primary B-lymphocyte growth transformation.

PMID- 8642675
TI  - Evidence for CD8+ antiviral activity in cats infected with feline
      immunodeficiency virus.
AB  - Human immunodeficiency virus (HIV) causes a long, asymptomatic infection
      characterized by normal to elevated numbers of circulating CD8+ cells and a
      progressive decline in CD4+ cells. It has been speculated that HIV-specific
      antiviral activity driven by CD8+ T cells may control viral replication during
      this period and maintain the clinically asymptomatic stage of disease. The
      disease induced in cats by feline immunodeficiency virus (FIV) is similar to HIV
      in that it is characterized by a long asymptomatic stage with a progressive
      decline in CD4+ cells, culminating in AIDS. In the present study, we demonstrate
      that FIV is more readily isolated from CD8+ T-cell-depleted peripheral blood
      mononuclear cells (PBMC) of FIV-infected cats than from unfractionated PBMC
      cultures. In addition, CD8+ T cells isolated from FIV-positive cats demonstrating
      anti-FIV activity in PBMC cultures inhibit FIV infection of FCD4E cells in vitro.
      Anti-FIV activity is not found in FIV- negative cats and is not characteristic of
      cats acutely infected with FIV but is present in the majority of chronically
      infected, clinically asymptomatic and symptomatic cats. Decreases in plasma and
      cell-associated viremia during the acute-stage FIV infection appears to precede
      the appearance of CD8+ anti-FIV cells in the circulation. In summary, this study
      demonstrates a population(s) of CD8+ T cells in chronically FIV-infected cats
      capable of suppressing FIV replication in cultured PBMC. The significance of anti
      FIV CD8+ cells in the immunopathogenesis of the infection and disease progression
      has yet to be determined.

PMID- 8642676
TI  - Epstein-Barr virus nuclear antigen 3C is a powerful repressor of transcription
      when tethered to DNA.
AB  - The expression of Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) is
      essential for the activation and immortalization of human B lymphocytes by EBV.
      EBNA3C consists of 992 amino acids and includes a potential bZIP motif and
      regions rich in acidic, proline, and glutamine residues. Thus, EBNA3C resembles
      several trans regulators of gene expression. It has recently been shown that a
      fragment of EBNA3C can activate reporter gene expression when fused to the DNA
      binding domain of GAL4 (D. Marshall and C. Sample, J. Virol. 69:3624-3630,1995).
      Although EBNA3C binds DNA, a specific site for EBNA3C binding has not been
      identified; to test the ability of full-length EBNA3C to regulate transcription,
      EBNA3C (amino acids 11 to 992) was fused to the DNA-binding domain of GAL4. We
      show that this fusion protein does not transactivate but rather is a potent
      repressor of reporter gene expression. Repression is dependent on the dose of
      GAL4-EBNA3C and on the presence of GAL4-binding sites within reporter plasmids.
      Repression is not restricted to B cells nor is it species or promoter specific.
      Repression is independent of the location of the GAL4-binding sites relative to
      the transcription start site. A fragment of EBNA3C (amino acids 280 to 525) which
      represses expression in a manner which is nearly identical to that of the full
      length protein has been identified; this fragment is rich in acidic and proline
      residues. A second, less potent repressor region located C terminal to amino
      acids 280 to 525 has also been identified; this domain is rich in proline and
      glutamine residues. We also show binding of EBNA3C, in vitro, to the TATA-binding
      protein component of TFIID, and this suggests a mechanism by which EBNA3C may
      communicate with the basal transcription complex.

PMID- 8642677
TI  - Unusually high frequency of Epstein-Barr virus genetic variants in Papua New
      Guinea that can escape cytotoxic T-cell recognition: implications for virus
      evolution.
AB  - Cytotoxic T lymphocytes (CTLs) which recognize viral antigens in association with
      human leukocyte antigens (HLAs) play an important role in controlling persistent
      virus infections. These viruses use several mechanisms to evade the immune
      response, including mutations that affect either T-cell receptor recognition or
      binding of viral epitopes to the HLA. It has recently been proposed that the
      distribution of HLA frequencies and the specific CTL response may influence the
      long-term evolution of Epstein-Barr virus (EBV) by selecting variants which lack
      immunodominant CTL epitopes. To test this hypothesis, we have studied EBV
      isolates from two genetically distinct Papua New Guinea (PNG) populations,
      residing in coastal and highland regions, for polymorphism within seven viral CTL
      epitope sequences restricted through several class I HLAs. Surprisingly, all EBV
      isolates analyzed displayed identical amino acid substitutions within HLA A11-,
      B35- and B8-restricted CTL epitope sequences which completely abrogated CTL
      recognition and binding of synthetic peptides to HLA molecules. Furthermore,
      these substitutions revealed no correlation with the contemporary distribution of
      HLAs in the different PNG populations, which argues for a minimal influence of
      immune pressure. The sequence homology between EBV isolates from coastal and
      highland PNG suggests that the virus may have had a single origin and, more
      importantly, that these isolates are genetically distinct from those present in a
      Caucasian population.

PMID- 8642678
TI  - Pseudotransduction of hepatocytes by using concentrated pseudotyped vesicular
      stomatitis virus G glycoprotein (VSV-G)-Moloney murine leukemia virus-derived
      retrovirus vectors: comparison of VSV-G and amphotropic vectors for hepatic gene
      transfer.
AB  - Recombinant retrovirus vectors are widely used for gene transfer studies. The
      recent development of a pseudotyped Moloney murine leukemia virus vector that
      contains the G envelope protein from the vesicular stomatitis virus allows for
      efficient concentration of vector and offers hope for potential use of these
      vectors for gene expression in vivo. A standard amphotropic vector expressing a
      serum marker protein, human alpha 1-antitrypsin, was infused into regenerating
      mouse liver and was 10-fold more efficient at achieving stable gene expression
      than was an equivalent pseudotyped vector. Discrepant results were obtained with
      cultured hepatocytes infected with an Escherichia coli beta-galactosidase
      producing pseudotype and amphotropic vector. High rates of beta-galactosidase
      positive cells were detected with the vesicular stomatitis virus G glycoprotein
      vector under culture conditions known to be relatively nonpermissive for
      retrovirus-mediated gene transfer. Subsequent studies demonstrated that beta
      galactosidase protein was concentrated and copurified during pseudotype vector
      preparation, resulting in high rates of protein transfer rather than stable gene
      transfer, a process referred to as pseudotransduction. The cotransfer of protein
      with concentrated pseudotyped retroviruses indicates that caution must be used
      when interpreting gene transduction efficiencies in gene therapy experiments.

PMID- 8642679
TI  - Plasma viral RNA load predicts disease progression in accelerated feline
      immunodeficiency virus infection.
AB  - Viral RNA load has been shown to indicate disease stage and predict the rapidity
      of disease progression in human immunodeficiency virus type 1 (HIV-1)-infected
      individuals. We had previously demonstrated that feline immunodeficiency virus
      (FIV) RNA levels in plasma correlate with disease stage in infected cats. Here we
      expand upon those observations by demonstrating that plasma virus load is 1 to 2
      logs higher in cats with rapidly progressive FIV disease than in long-term
      survivors. Differences in plasma FIV RNA levels are evident by 1 to 2 weeks after
      infection and are consistent throughout infection. We also evaluated humoral
      immune responses in FIV-infected cats for correlation with survival times. Total
      anti-FIV antibody titers did not differ between cats with rapidly progressive FIV
      disease and long-term survivors. These findings indicate that virus replication
      plays an important role in FIV disease progression, as it does in HIV-1 disease
      progression. The parallels in virus loads and disease progressions between HIV-1
      and FIV support the idea that the accelerated disease model is well suited for
      the study of therapeutic agents directed at reducing lentiviral replication.

PMID- 8642680
TI  - Genome organization of the Kresse strain of porcine parvovirus: identification of
      the allotropic determinant and comparison with those of NADL-2 and field
      isolates.
AB  - The Kresse strain of porcine parvovirus (PPV) was cloned into pUC19, and
      independent infectious clones were sequenced. The PPV Kresse and NADL-2 strains,
      which have different pathogenicities, shared an identical genomic organization
      and a high degree of sequence identity. Partial genomes (1.5 or 1.6 kb) of 15
      field isolates were also amplified by PCR in regions with significant sequence
      differences between the laboratory strains. Five amino acid differences were
      consistently present within the VP1/VP2 coding region of the Kresse strain and
      virulent field isolates. A number of inconsistent point mutations were also found
      throughout the genomes of field isolates. In addition, among those with the
      vaccine amino acid profile, all but one isolate (IAF-3) contained a 127-bp
      noncoding direct repeat downstream of the capsid protein gene. The one exception
      was also the only vaccine-type PPV obtained from a mummified fetus. In order to
      identify genetic elements responsible for the distinct tropism (and possibly the
      pathology) of the Kresse strain, in vitro cell systems which differentiated the
      virulent from the vaccinal strains were established. Subsequently, chimeric
      infectious clones of the Kresse and NADL-2 strains were used to identify the
      allotropic determinant located in the VP1/VP2 region. The transfer of the BglII
      fragment of the Kresse genome, containing three amino acid differences, into the
      NADL-2 background, or the opposite construct, caused the phenotype of the target
      genome to revert to that of the parent strain of the BglII fragment. Prediction
      of the localization of amino acid differences on the basis of canine parvovirus
      capsid structure indicates that each is located on or near the outer surface of
      the virion. In particular, the position of one mutation (S-436-->P) maps by
      analogy to the threefold spike, the most accessible region of the capsid.

PMID- 8642681
TI  - Vpr-induced cell cycle arrest is conserved among primate lentiviruses.
AB  - We previously reported that expression of human immunodeficiency virus type 1
      strain NL4-3 (HIV-1(NL4-3))vpr causes cells to arrest in the G2 phase of the cell
      cycle. We examined the induction of cell cycle arrest by other HIV-1 isolates and
      by primary lentiviruses other than HIV-1. We demonstrate that the vpr genes from
      tissue culture-adapted or primary isolates of HIV-1 are capable of inducing G2
      arrest. In addition, we demonstrate that induction of cell cycle arrest is a
      conserved function of members of two other groups of primate lentiviruses, HIV
      2/simian immunodeficiency virus strain sm (SIVsm)/SIVmac and SIVagm. vpr from HIV
      1, HIV-2, and SIVmac induced cell cycle arrest when transfected in human (HeLa)
      and monkey (CV-1) cells. vpx from HIV-2 and SIVmac did not induce detectable cell
      cycle arrest in either cell type, and SIVagm vpx was capable of inducing arrest
      in CV-1 but not HeLa cells. These results indicate that induction of cell cycle
      perturbation is a general property of lentiviruses that infect primates. The
      conservation of this viral function throughout evolution suggests that it plays a
      key role in virus-host relationships, and elucidation of its mechanism may reveal
      important clues about pathology induced by primary lentiviruses.

PMID- 8642682
TI  - Human T-cell lymphotropic virus type 1 Tax1 activation of NF-kappa B: involvement
      of the protein kinase C pathway.
AB  - Human T-cell lymphotropic virus type 1 Tax1 induces the activation and nuclear
      localization of the cellular transcription factor, NF-kappa B. Treatment of cells
      with calphostin C, a protein kinase C (PKC) inhibitor, blocked induction of NF
      kappa B DNA binding activity in human T-cell lymphotropic virus type 1
      transformed C81 cells and Tax1-stimulated murine pre-B cells, suggesting that PKC
      was an important intermediate in the NF-kappa B induction pathway. We further
      demonstrate that Tax1 associates with, and activates, PKC. PKC was
      coimmunoprecipitated with anti- Tax1 sera from Tax1-expressing MT4 extracts and
      Jurkat extracts in the presence of exogenous Tax1 protein. In addition, the
      glutathione-S-transferase-Tax1 protein bound specifically to the alpha, delta,
      and eta PKC isoenzymes synthesized in rabbit reticulocyte lysates. The addition
      of Tax1 to in vitro kinase reaction mixtures leads to the phosphorylation of Tax1
      and an 18-fold increase in the autophosphorylation of PKC. Transfection of Jurkat
      cells with wild-type Tax1 stimulated membrane translocation of PKC. In contrast,
      Tax1 mutant M22, which fails to stimulate NF-kappa B-dependent transcription,
      failed to stimulate membrane translocation of PKC. Tax1 did not directly increase
      PKC phosphorylation of I kappa B alpha. Our results are consistent with a model
      in which Tax1 interacts with PKC and stimulates membrane translocation and
      triggering of the PKC pathway. Subsequent steps in the PKC cascade likely
      stimulate phosphorylation of I kappa B alpha.

PMID- 8642683
TI  - Ligand-independent dimerization of oncogenic v-erbB products involves covalent
      interactions.
AB  - Mutant v-erbB products of avian c-erbB1 have previously been used to correlate
      structural domains of the receptor encoded by this proto-oncogene with tissue
      specific transformation potential. In these studies, deletion of the ligand
      binding domain of the receptor has been shown to be required for transformation
      of erythroblasts, fibroblasts, and endothelial cells. It has, therefore, been
      postulated that deletion of this domain results in an allosteric change in the
      receptor analogous to the ligand-bound state of the epidermal growth factor
      receptor; i.e., it induces a receptor conformation that is constitutively active
      with respect to mitogenic signaling. While oncogenic v-erbB products have been
      shown to be expressed on the cell surface of both fibroblasts and erythroblasts,
      no comprehensive analysis of the oligomeric potential of these products has been
      conducted. Since the first event known to follow epidermal growth factor binding
      to its receptor is oligomerization, and receptor dimerization has been correlated
      with mitogenic signaling, we have carefully analyzed the ability of several v
      erbB products to oligomerize in the three target cell types transformed by these
      oncogenes. In this report, we demonstrate the v-erbB products can efficiently
      homodimerize in all three target tissues, that this dimerization is ligand
      independent and occurs at the cell surface, and that there is no apparent
      correlation between v-erbB dimerization and transformation of avian fibroblasts.
      Furthermore, both oncogenic and nononcogenic v-erbB products can heterodimerize
      with the native c-erbB1 product in chicken embryo fibroblasts, suggesting that
      heterodimerization between v-erB and native c-erbB1 is not sufficient to result
      in c-erbB1-mediated sarcomagenesis.

PMID- 8642685
TI  - Suppression of long-distance movement of tobacco etch virus in a nonsusceptible
      host.
AB  - To investigate host functions involved in the tobacco etch potyvirus (TEV)
      infection process, a tobacco line (V20) with a strain-specific defect in
      supporting systemic infection was analyzed. Using a modified TEV encoding a
      reporter protein, beta-glucuronidase (GUS), genome amplification, cell-to-cell
      movement, and long-distance movement were measured in V20 and a susceptible line,
      Havana425. Comparable levels of TEV-GUS genome amplification were measured in
      inoculated protoplasts from both tobacco lines. The rates of cell-to-cell
      movement of virus in inoculated leaves were nearly identical in V20 and Havana425
      between 48 and 72 h postinoculation. In contrast, long-distance movement from
      leaf to leaf was markedly restricted in V20 relative to Havana425. In situ
      histochemical analysis of inoculated leaves revealed that infection foci expanded
      radially over time, providing the potential for contact of virus with veins.
      Immunocytochemical analysis of V20 tissue from infection foci indicated that TEV
      GUS entered the phloem parenchyma or companion cells adjacent to the sieve
      elements, suggesting that the block in long-distance movement was associated with
      entry into, or exit from, sieve elements. The genetic basis for the V20
      restriction was characterized in a segregation analysis of a cross between V20
      and Havana425. The heterozygous F1 progeny displayed the susceptible phenotype,
      indicating that the V20 restriction was a recessive trait. Segregation in the F2
      progeny indicated that the restriction was likely due to the interaction of
      recessive genes at two nonlinked loci. These data support the hypothesis that
      long-distance movement requires a set of host functions that are distinct from
      those involved in cell-to-cell movement.

PMID- 8642684
TI  - Activation of the Epstein-Barr virus DNA polymerase promoter by the BRLF1
      immediate-early protein is mediated through USF and E2F.
AB  - The Epstein-Barr virus (EBV) DNA polymerase (pol) is essential for the
      replication of viral genomes during productive EBV infection. We have previously
      reported that the EBV DNA pol promoter, which is TATA-less and constitutively
      inactive, is activated by a genomic clone expressing both immediate-early viral
      transactivators, BZLF1Z and BRLF1 (R), in EBV-infected lymphoid cells. Here we
      demonstrate that R alone is sufficient to activate the pol promoter in EBV
      negative B cells. Unlike other early promoters to which the R protein binds
      directly, its effect on the pol promoter does not appear to involve a direct DNA
      binding mechanism. Instead, we found that two cellular transcription factors, an
      upstream stimulatory factor USF, and a member of the E2F family of proteins, bind
      directly to the pol promoter at positions -795 to -786 and -186 to -170,
      respectively, regions previously identified as important for activation of the
      pol promoter. These two sites contribute to or are essential for transactivation
      of the pol promoter by R in EBV-noninfected B cells. These data suggest that the
      R immediate-early protein may activate a key early EBV promoter (pol) through
      both USF and E2F.

PMID- 8642686
TI  - The Epstein-Barr virus-encoded nuclear antigen EBNA-5 accumulates in PML
      containing bodies.
AB  - EBNA-5 is one of the Epstein-Barr virus (EBV)-encoded nuclear proteins required
      for immortalization of human B lymphocytes. In the nuclei of EBV-transformed
      lymphoblastoid cell lines EBNA-5 is preferentially targetted to distinct nuclear
      foci. Previously we have shown (W.Q. Jiang, L. Szekely, V. Wendel-Hansen, N.
      Ringertz, G. Klein, and A. Rosen, Exp. Cell Res. 197:314-318, 1991) that the same
      foci also contained the retinoblastoma (Rb) protein. Using a similar double
      immunofluorescence technique, we now show that these foci colocalize with nuclear
      bodies positive for PML, the promyelocytic leukemia-associated protein.
      Artificial spreading of the chromatin by exposure to the forces of fluid surface
      tension disrupts this colocalization gradually, suggesting that the bodies
      consist of at least two subcomponents. Heat shock or metabolic stress induced by
      high cell density leads to the release of EBNA-5 from the PML-positive nuclear
      bodies and induces it to translocate to the nucleoli. In addition to their
      presence in nuclear bodies, both proteins are occasionally present in nuclear
      aggregates and doughnut-like structures in which PML is concentrated in an outer
      shell. Nuclear bodies with prominent PML staining are seen in resting B
      lymphocytes. This staining pattern does not change upon EBV infection. In freshly
      infected cells EBNA-5 antigens are first distributed throughout the nucleoplasm.
      After a few days intensely staining foci develop. These foci coincide with PML
      positive nuclear bodies. At a later stage and in established lymphoblastoid cell
      lines EBNA-5 is almost exclusively present in the PML-positive nuclear foci. The
      colocalization is restricted to EBV-infected human lymphoblasts. The data
      presented indicate that the distinct EBNA-5 foci are not newly formed structures
      but the result of translocation of the viral protein to a specialized domain
      present already in the nuclei of uninfected cells.

PMID- 8642687
TI  - Antibody to the ligand for CD40 (gp39) inhibits murine AIDS-associated
      splenomegaly, hypergammaglobulinemia, and immunodeficiency in disease-susceptible
      C57BL/6 mice.
AB  - Infection of genetically susceptible C57BL/6 mice with the LP-BM5 isolate of
      murine retroviruses cause profound splenomegaly, hypergammaglobulinemia,
      lymphadenopathy, and an immunodeficiency syndrome which includes the development
      of terminal B-cell lymphomas. Because many of these and the other manifestations
      of LP-BM5 virus-induced disease are similar to those seen in AIDS, this syndrome
      has been named murine AIDS, or MAIDS. Previous reports have shown that the onset
      of MAIDS depends on the presence of both CD4+ T cells and B cells and have
      suggested that CD4+ T-cell-B-cell interactions are important to disease
      pathogenesis. Here, we assessed the possibility that interactions between CD40
      and its ligand on activated CD4+ T cells, CD40 ligand/gp39, are involved in the
      development of MAIDS. To test this hypothesis, LP-BM5-infected B6 mice were
      treated in vivo with anti-gp39 monoclonal antibody. As a result, MAIDS-associated
      splenomegaly, hypergammaglobulinemia, germinal center formation, and the loss of
      in vitro responsiveness to the T- and B-cell mitogens concanavalin A and
      lipopolysaccharide were inhibited. Anti-gp39 monoclonal antibody-treated LP-BM5
      infected mice were also able to mount essentially normal alloantigen-specific
      cytolytic T-lymphocyte responses. These results support the possibility that
      molecular interactions between CD40 and gp39 are critical to the development of
      MAIDS.

PMID- 8642688
TI  - The noncoding and surface envelope coding sequences of myeloblastosis-associated
      virus are respectively responsible for nephroblastoma development and renal
      hyperplasia.
AB  - The use of chimeric viruses allowed us to establish that myeloblastosis
      associated virus long terminal repeat sequences are necessary and sufficient for
      induction of nephroblastoma in chickens and that the blastemal hyperplasia
      induced by env SU is not a prerequisite for tumor development but rather
      constitutes a predisposing stage.

PMID- 8642689
TI  - High-efficiency gene transfer into CD34+ cells with a human immunodeficiency
      virus type 1-based retroviral vector pseudotyped with vesicular stomatitis virus
      envelope glycoprotein G.
AB  - Currently, amphotropic retroviral vectors are widely used for gene transfer into
      CD34+ hematopoietic progenitor cells. The relatively low levels of transduction
      efficiency associated with these vectors in human cells is due to low viral
      titers and limitations in concentrating the virus because of the inherent
      fragility of retroviral envelopes. Here we show that a human immunodeficiency
      virus type 1 (HIV-1)-based retroviral vector containing the firefly luciferase
      reporter gene can be pseudotyped with a broad-host-range vesicular stomatitis
      virus envelope glycoprotein G (VSV-G). Higher-efficiency gene transfer into CD34+
      cells was achieved with a VSV-G-pseudotyped HIV-1 vector than with a vector
      packaged in an amphotropic envelope. Concentration of virus without loss of viral
      infectivity permitted a higher multiplicity of infection, with a consequent
      higher efficiency of gene transfer, reaching 2.8 copies per cell. These vectors
      also showed remarkable stability during storage at 4 degrees C for a week. In
      addition, there was no significant loss of titer after freezing and thawing of
      the stock virus. The ability of VSV-G-pseudotyped retroviral vectors to achieve a
      severalfold increase in levels of transduction into CD34+ cells will allow high
      efficiency gene transfer into hematopoietic progenitor cells for gene therapy
      purposes. Furthermore, since it has now become possible to infect CD34+ cells
      with pseudotyped HIV-1 with a high level of efficiency in vitro, many important
      questions regarding the effect of HIV-1 on lineage-specific differentiation of
      hematopoietic progenitors can now be addressed.

PMID- 8642690
TI  - Effective ex vivo neutralization of human immunodeficiency virus type 1 in plasma
      by recombinant immunoglobulin molecules.
AB  - We tested the ability of human monoclonal antibodies (immunoglobulin G1b12
      [IgG1b12] and 19b) and CD4-based molecules (CD4-IgG2 and soluble CD4 [sCD4]) to
      neutralize human immunodeficiency virus type 1 directly from the plasma of
      seropositive donors in an ex vivo neutralization assay. IgG1b12 and CD4-IgG2, at
      concentrations from 1 to 25 micrograms/ml, were found to be effective at reducing
      the HIV-1 titer in most plasma samples. When viruses recovered from plasma
      samples were expanded to produce virus stocks, no correlation between the
      neutralization sensitivities to IgG1b12 and CD4-IgG2 of the in vitro passaged
      stocks and those of the ex vivo neutralizations performed directly on the plasma
      was observed. These differences could be due to changes in neutralization
      sensitivity that occur after one passage of the virus in vitro, or they could be
      related to the presence of complement or antibodies in the plasma. Furthermore,
      differences in expression of adhesion molecules on plasma-derived and
      phytohemagglutinin-activated peripheral blood mononuclear cell-derived viruses
      could be involved. These studies suggest that IgG1b12 and CD4-IgG2 have broad and
      potent neutralizing activity in both in vitro and ex vivo neutralization assays
      and should be considered for use as potential immunoprophylactic or therapeutic
      agents.

PMID- 8642692
TI  - Nonspecific alcoholysis, a novel endonuclease activity of human immunodeficiency
      virus type 1 and other retroviral integrases.
AB  - Retroviral integrase (IN) exhibits a previously unrecognized endonuclease
      activity which we have termed nonspecific alcoholysis. This action occurred at
      every position in nonviral DNA sequences except those near 5' ends and is clearly
      distinguished from, and was not predicted by, the site-specific alcoholysis
      activity previously described for IN at the processing site near viral DNA
      termini. The integrases of human immunodeficiency virus type 1, visna virus, and
      Rous sarcoma virus exhibited different target site preferences in this new assay.
      The isolated central domain of human immunodeficiency virus type 1 IN preferred
      the same sites as the full-length protein. Nonspecific alcoholysis may provide
      insights into the structure and function of IN and other endonucleases and
      suggests that stimulators of some activities possessed by retroviral enzymes
      should be sought as antiviral agents.

PMID- 8642691
TI  - Genetic analysis of the zinc finger in the Moloney murine leukemia virus
      nucleocapsid domain: replacement of zinc-coordinating residues with other zinc
      coordinating residues yields noninfectious particles containing genomic RNA.
AB  - The effect of changing zinc (Zn2+)-coordinating residues in the nucleocapsid
      protein of Moloney murine leukemia virus was investigated by introducing a His-34
      to-Cys or Cys-39-to-His mutation into the putative Zn2+ finger. Mutant virions
      contained normal levels of properly processed Gag and Env proteins and wild-type
      levels of full-length viral RNA. However, the specific infectivity of the mutants
      was approximately 4 x 10(-4) that of wild-type particles. They were probably
      noninfectious because of the inability of the particles to synthesize cDNA
      transcripts, since full-length viral DNA could not be detected in Hirt
      supernatants of NIH 3T3 cells infected with the CCCC or CCHH virus. These mutants
      will provide an extremely valuable tool for analysis of the role of retroviral
      Zn2+ fingers in infection processes, independent of viral RNA recognition and
      packaging.

PMID- 8642693
TI  - Polyprotein processing in Southampton virus: identification of 3C-like protease
      cleavage sites by in vitro mutagenesis.
AB  - A genomic clone of the small, round-structured virus Southampton virus (SV) was
      constructed from a set of overlapping PCR amplicons. Sequence analysis confirmed
      the absence of mutations and accurate ligation of the PCR products. The SV cDNA
      was cloned into a vector for in vitro production of RNA and subsequent
      translation by rabbit reticulocyte lysate. Two polypeptides corresponding to the
      N-terminal and C-terminal regions of the viral polyprotein were expressed in
      Escherichia coli and used to produce murine antisera for detection of translation
      products. Three major translation products of 113, 48, and 41 kDa were identified
      in a coupled transcription-translation system. The large 113-kDa protein reacted
      with antisera raised against the C-terminal region of the polyprotein and
      represents a precursor of the viral RNA polymerase. The 48-kDa protein detected
      in vitro reacted specifically with antisera raised against the polyprotein N
      terminus, showing that translation was initiated in SV at the three tandem in
      frame AUG codons at the 5' end of the genome. A series of nested 3' deletions of
      the large open reading frame encoding the viral polyprotein was used to define
      the translation initiation site and genomic location of the viral protease. The
      results are consistent with a model in which translation of the viral genome is
      initiated at one of the three in-frame AUG codons starting at nucleotide position
      5 and in which active viral protease is produced following translation of a
      region located between NheI (nucleotide 3052) and SphI (nucleotide 4056),
      resulting in rapid cleavage of a large precursor protein. Abolition of the viral
      3C-like protease activity by site-directed mutagenesis of the putative active
      site cysteine (Cys-1238) resulted in production of a large protein of
      approximately 200 kDa which reacted with both N-terminal and C-terminal antisera.
      Two potential polyprotein cleavage sites containing the preferred picornaviral QG
      recognition site were identified on either side of the putative 2C-like helicase
      region of the polyprotein. Proteolysis at these positions would give rise to
      products with relative molecular masses identical to those of the products
      detected in the rabbit reticulocyte system. Site-directed mutagenesis was used to
      introduce a single base change which resulted in the substitution of glutamine
      residues with proline residues at amino acids 399 and 762. These mutations
      completely abolished cleavage of the polyprotein at these positions and gave rise
      to alternative products with molecular masses which matched the predicted sizes
      for a single cleavage at either Q-399 or Q-762. These data indicate that the
      small, round-structured virus Southampton virus produces a 3C-like protease which
      has two primary cleavage sites at positions 399 and 762. Proteolytic cleavage at
      these positions releases the putative viral 2C-like helicase.

PMID- 8642694
TI  - Mutational analysis of the vaccinia virus E3 protein defines amino acid residues
      involved in E3 binding to double-stranded RNA.
AB  - Alanine-substitution mutations were targeted to 14 amino acid residues within the
      double-stranded (ds) RNA binding motif (dsRBM) of the vaccinia virus E3 protein.
      Substitutions at six positions--Glu-124, Phe-135, Phe-148, Lys-167, Arg-168, and
      Lys-171--caused significant reductions in dsRNA binding. These six residues are
      conserved in the two dsRBMs for which structural information is available
      (Escherichia coli RNase III and Drosophila melanogaster staufen) and in many
      other members of the dsRBM protein family. Residues we show to be important for
      dsRNA binding by vaccinia virus E3 map to the same face of the dsRBM structure
      and are thus likely to compose part of the RNA binding site.

PMID- 8642695
TI  - Vaccinia virus RNA helicase: nucleic acid specificity in duplex unwinding.
AB  - Vaccinia virus RNA helicase (NPH-II) catalyzes nucleoside triphosphate-dependent
      unwinding of duplex RNAs containing a single-stranded 3' RNA tail. In this study,
      we examine the structural features of the nucleic acid substrate that are
      important for helicase activity. Strand displacement was affected by the length
      of the 3' tail. Whereas NPH-II efficiently unwound double-stranded RNA substrates
      with 19- or 11-nucleotide (nt) 3' tails, shortening the 3' tail to 4 nt reduced
      unwinding by an order of magnitude. Processivity of the helicase was inferred
      from its ability to unwind a tailed RNA substrate containing a 96-bp duplex
      region. NPH-II exhibited profound asymmetry in displacing hybrid duplexes
      composed of DNA and RNA strands. A 34-bp RNA-DNA hybrid with a 19-nt 3' RNA tail
      was unwound catalytically, whereas a 34-bp DNA-RNA hybrid containing a 19-nt 3'
      DNA tail was 2 orders of magnitude less effective as a helicase substrate. NPH-II
      was incapable of displacing a 34-bp double-stranded DNA substrate of identical
      sequence. 3'-Tailed DNA molecules with 24- or 19-bp duplex regions were also
      inert as helicase substrates. On the basis of current models for RNA-DNA hybrid
      structures, we suggest the following explanation for these findings. (i)
      Unwinding of duplex nucleic acids by NPH-II is optimal when the polynucleotide
      strand of the duplex along which the enzyme translocates has adopted an A-form
      secondary structure, and (ii) a B-form secondary structure impedes protein
      translocation through DNA duplexes.

PMID- 8642696
TI  - Studies of neutralizing monoclonal antibody to human immunodeficiency virus type
      1 reverse transcriptase: antagonistic and synergistic effects in reactions
      performed in the presence of nucleoside and nonnucleoside inhibitors,
      respectively.
AB  - We have assessed interactions between the reverse transcriptase (RT) of human
      immunodeficiency virus type 1 (HIV-1) and a neutralizing monoclonal antibody
      (1E8) that hinders binding of deoxynucleoside triphosphate (dNTP) substrates.
      Steady-state reactions with homopolymeric template-primers revealed that 1E8
      antagonized inhibition of RT activity mediated by 3'-azido-3'-deoxythymidine
      triphosphate and 2',3'-dideoxycytidine triphosphate. However, an additive or
      synergistic inhibition of RT polymerase activity was noted when 1E8 and the
      nonnucleoside RT inhibitors nevirapine and delavirdine were studied. Chain
      elongation and dNTP incorporation studies using an HIV-1 genome-derived
      heteropolymeric template and either oligodeoxynucleotide or tRNA3(Lys) as the
      primer yielded results consistent with the above observations. 1E8 also increased
      pausing at certain sites during synthesis of negative-strand, strong-stop DNA,
      whether or not ddNTP and nonnucleoside RT inhibitors were present.

PMID- 8642697
TI  - Human cytotoxic T-cell memory: long-lived responses to vaccinia virus.
AB  - Peripheral T lymphocytes can be classified into two groups: naive and memory T
      cells. The focus of this study was to examine the duration of T-cell memory in
      humans. Vaccinia virus replicates in the cytoplasm of infected cells and is not
      thought to persist or become latent after the acute phase of infection. We
      identified long-lived vaccinia virus-specific memory cytotoxic T cells in adults
      who had been immunized against smallpox as children. Initially, we detected
      vaccinia virus-specific T cells in peripheral blood mononuclear cells while
      screening for human immunodeficiency virus type 1 (HIV-1)-specific T-cell
      responses in HIV-1-seropositive subjects. These individuals had not had contact
      with vaccinia virus since their primary immunization in early childhood. Several
      vaccinia virus-specific CD4+ T-cell clones were derived from these donors and
      characterized. Healthy, HIV-1-seronegative donors who had been immunized against
      smallpox many (35 to 50) years earlier were also screened for vaccinia virus
      specific T-cell immunity. We found significant CD8+ and CD4+ cytotoxic T-cell
      responses to vaccinia virus after in vitro stimulation, indicating that these
      memory cells are maintained in vivo for many years. The peripheral blood
      mononuclear cells of young adults with no history of immunization against
      smallpox did not develop vaccinia virus-specific T-cell responses after in vitro
      stimulation. Precursor frequency analysis of the vaccinia virus-specific memory
      CD4+ T cells from a donor immunized with vaccinia virus 35 years earlier revealed
      a frequency of 1 in 65,920 CD4+ T cells. We concluded that specific vaccinia
      virus T-cell immunity can persist for up to 50 years after immunization against
      smallpox in childhood in the presumed absence of exposure to vaccinia virus.

PMID- 8642698
TI  - Analysis of the receptor-binding site of murine coronavirus spike protein.
AB  - It has been found that a domain composed of 330 amino acids of the N terminus of
      murine coronavirus spike protein [S1N(330)] is involved in receptor-binding
      activity (H. Kubo, Y.K. Yamada, and F. Taguchi, J. Virol. 68:5403-5410, 1994). To
      delineate the amino acid sequences involved in receptor-binding activity, we have
      compared the S1N(330) proteins of seven different mouse hepatitis virus MHV
      strains that are able to utilize the MHV receptor protein. Three conserved
      regions (sites I, II, and III) were found to consist of more than 10 identical
      amino acids, and they were analyzed for receptor-binding activity by site
      directed mutagenesis. S1N(330) with a substitution at position 62 from the N
      terminus of S1 in region I and that with substitutions at positions 212, 214, and
      216 in region II showed no receptor-binding activity. The S1N(330) mutants
      without receptor-binding activity were not able to prevent virus binding to the
      receptor. These results suggest that the receptor-binding site on S1N(330) is
      composed of regions located apart from each other in the protein's primary
      structure, in which Thr at position 62 as well as amino acids located at
      positions 212, 214, and 216 are particularly important.

PMID- 8642699
TI  - Adenovirus E1A activates cyclin A gene transcription in the absence of growth
      factors through interaction with p107.
AB  - Using the infection of quiescent human fibroblasts with adenovirus type 5 and
      various deletion mutants, we show that E1A can stimulate transcription of the
      cyclin A gene in the absence of exogenous growth factors. Required for this
      activity is conserved region 2 (CR2), while both the N-terminal part of E1A and
      CR1 are dispensable. This indicates that activation of cyclin A gene expression
      requires the binding of E1A to p107, while binding to either pRB or p300 is not
      involved in transcriptional activation. We demonstrate that p107 represses the
      cyclin A promoter through its cell cycle-regulatory E2F binding site and that 12S
      E1A can activate the cyclin A promoter, essentially by counteracting its
      repression by p107. Since Cr2 is required for cell transformation,
      transcriptional activation of the cyclin A gene by E1A appears to be important
      for its capacity to override control of cellular growth.

PMID- 8642700
TI  - Release of virus-like particles from cells infected with poliovirus replicons
      which express human immunodeficiency virus type 1 Gag.
AB  - The effectiveness of attenuated poliovirus vaccines when given orally to induce
      both systemic and mucosal immune responses against poliovirus has resulted in an
      effort to develop poliovirus-based vectors to express foreign proteins. We have
      previously described the construction of poliovirus genomes (referred to as
      replicons) in which the complete human immunodeficiency virus type 1 (HIV-1) gag
      gene was substituted for the capsid gene (P1) (D.C. Porter, D.C. Ansardi, and
      C.D. Morrow, J. Virol. 69:1548-1555, 1995). Infection of cells with encapsidated
      replicons resulted in the expression of a 55-kDa protein. To further characterize
      the biological features of the HIV-1 Gag proteins expressed in cells infected
      with encapsidated replicons, we utilized biochemical analysis and electron
      microscopy. Expression of the 55-kDa protein in cells infected with encapsidated
      replicons resulted in myristylation of the Pr55gag protein. The Gag precursor
      protein was released from infected cells; analysis on sucrose density gradients
      revealed that the precursor sedimented at a density consistent with that of an
      HIV-1 virus-like particle. Analysis of replicon-infected cells by electron
      microscopy demonstrated the presence of condensed structures at the plasma
      membrane and the release of virus-like particles. These studies demonstrate that
      poliovirus-based vectors can be used to express foreign proteins which require
      posttranslational modifications, such as myristylation, and assemble into higher
      order structures, providing a foundation for the future use of poliovirus
      replicons as vaccine vectors.

PMID- 8642701
TI  - Cytokine regulation by virus infection: bovine viral diarrhea virus, a
      flavivirus, downregulates production of tumor necrosis factor alpha in
      macrophages in vitro.
AB  - Bovine bone marrow-derived macrophages were infected in vitro with noncytopathic
      or cytopathic strains of bovine viral diarrhea virus. Infection with both
      biotypes resulted in a decreased production of tumor necrosis factor alpha upon
      stimulation with heat-inactivated Salmonella dublin or lipopolysaccharide. Other
      macrophage functions were not downregulated, indicating that the observed effect
      was not due to a loss in macrophage viability. The downregulated production of
      tumor necrosis factor alpha in infected macrophages may contribute to the well
      documented immunosuppression in animals infected with bovine viral diarrhea
      virus.

PMID- 8642702
TI  - Human endogenous retrovirus expression and reverse transcriptase activity in the
      T47D mammary carcinoma cell line.
AB  - We have examined the human mammary tumor cell line T47D and have found that these
      cells produce virus-like particles which band at the typical density for
      retroviral particles on a sucrose gradient, possess reverse transcriptase
      activity, and package HERV-K10-like sequences. Using this information and a
      bacterial expression system to identify long open reading frames, we have
      identified individual clones which have full-length open reading frames for
      reverse transcriptase and RNase H and which could encode the reverse
      transcriptase activity detected in these cells.

PMID- 8642703
TI  - Genetic organization, size, and complete sequence of early region 3 genes of
      human adenovirus type 41.
AB  - The complete nucleotide and predicted amino acid sequences for open reading
      frames (ORFs) of the human adenovirus type 41 (Ad41) early region 3 (E3) gene
      have been determined. The sequence of the Ad41 E3 gene (map units 74 to 83.9)
      consists of 3,373 nucleotides and has one TATA box and two polyadenylation
      signals (AATAAA). Analysis of the nucleotide sequence reveals that the E3 gene
      can encode six ORFs, designated RL1 to RL6. These are all expressed at the mRNA
      level, as determined by reverse transcription-PCR analysis of AD41-infected cell
      RNA. When compared with known E3 sequences of most other human adenoviruses
      deposited in GenBank, the sequences of RL1 to RL3 were found to be unique to
      subgroup F adenoviruses (Ad40 and Ad41). They encode putative proteins of 173
      amino acids (19.4 kDa) and 276 amino acids (31.6 kDa) in one reading frame as
      well as a 59- amino-acid (6.7 kDa) protein in an overlapping reading frame. RL4
      encodes a 90-amino-acid protein (10.1 kDa) with 40% homology to the Ad2 E3 10.4
      kDa protein, which induces degradation of the epidermal growth factor receptor
      and functions together with the Ad2 E3 14.5-kDa protein to protect mouse cell
      lines against lysis. RL5 encodes a protein of 107 amino acid residues (12.3 kDa)
      and is analogous to the Ad E3 14.5-kDa protein. RL6 codes for a protein of 122
      amino acids (14.7 kDa) that is analogous to the Ad2 14.7-kDa protein, which
      functions to protect Ad-infected cells from tumor necrosis factor-induced
      cytolysis. This finding of three unique (RL1 to RL3) E3 gene ORFs may explain why
      subgroup F adenoviruses differ substantially from other human adenoviruses in
      their host range; i.e., they replicate predominantly in the host's
      gastrointestinal rather than respiratory tract. A recent phylogenetic study that
      compared subgroup F Ad40 DNA sequences with representatives of subgroups B (Ad3),
      C (Ad2), and E (Ad4) reached a similar conclusion about the uniqueness of RL1 and
      RL2.

PMID- 8642704
TI  - The membrane-binding domain of the Rous sarcoma virus Gag protein.
AB  - The Gag protein of Rous sarcoma virus (RSV) can direct particle assembly and
      budding at the plasma membrane independently of the other virus-encoded products.
      A previous deletion analysis has suggested that the first 86 amino acids of RSV
      Gag constitute a large membrane-binding domain that is absolutely required for
      these processes. To test this hypothesis, we inserted these residues in place of
      the N-terminal membrane-binding domain of the pp60v-src, a transforming protein
      whose biological activity requires plasma membrane localization. The ability of
      the Src chimera to induce cellular transformation suggests that the RSV sequence
      indeed contains an independent, functional domain.

PMID- 8642707
TI  - Physicians find their place in Zuniland.

PMID- 8642705
TI  - Human immunodeficiency virus type 2 glycoprotein enhancement of particle budding:
      role of the cytoplasmic domain.
AB  - Previous studies have shown that the glycoprotein cytoplasmic domains of human
      immunodeficiency virus type 2 (HIV-2) or simian immunodeficiency virus of
      macaques modulate biological activities of the viral glycoprotein complex,
      including syncytium formation, exterior glycoprotein conformation, and
      glycoprotein incorporation into budding virus particles. We have now utilized a
      recombinant expression system to study interactions of full-length or truncated
      HIV-2 glycoproteins with coexpressed HIV-2 Gag proteins which self-assemble and
      bud as virus-like particles. Interestingly, budding of HIV-2 virus-like particles
      from cells was enhanced 5- to 24-fold when Gag was coexpressed with the full
      length HIV-2 glycoprotein, compared with Gag expressed either alone or with a
      truncated HIV-2 glycoprotein. The results obtained in this model system indicate
      that an additional effect of the lengthy cytoplasmic domain of the glycoprotein
      of HIV-2 is enhancement of particle budding. We speculate that the cytoplasmic
      domain of the viral glycoprotein of HIV-2 enhances budding by (i) potentiation of
      Gag structure or function or (ii) membrane modulation.

PMID- 8642708
TI  - For some American Indians, casino profits are a good bet for improving health
      care.

PMID- 8642709
TI  - First Americans face their latest challenge: Indian health care meets state
      medicaid reform.

PMID- 8642710
TI  - From the Centers for Disease Control and Prevention. Outbreak of
      cryptosporidiosis at a day camp--Florida, July-August 1995.

PMID- 8642706
TI  - Two species of Rev proteins, with distinct N termini, are expressed by caprine
      arthritis encephalitis virus.
AB  - Several cDNA clones representing alternatively spliced Rev-specific transcripts
      were isolated from a cDNA library prepared from Himalayan tahr cells infected
      with caprine arthritis encephalitis virus (CAEV). We previously characterized two
      rev-like cDNA species, d1 and d2, and a tat e1 cDNA containing the rev coding
      sequence downstream to the tat. In these cDNAs, the rev coding domain derives its
      amino terminus from the N terminus of env, which is spliced to the 3' open
      reading frame encoding the putative Rev protein. In this study, we report the
      genetic structure of a fourth rev-like cDNA (designated g1), which lacks the 5'
      env-derived sequences. All of these rev transcripts, including cDNA g1, increased
      the level of chloramphenicol acetyltransferase expression when cotransfected with
      a reporter plasmid containing the CAEV Rev-response element-spanning region
      downstream of the cat coding sequences. Western blot (immunoblot) analysis showed
      that each transfected cDNA species gave rise to a 16-kDa protein lacking env
      encoded amino-terminal epitopes. In contrast, CAEV-infected Himalayan tahr cells
      expressed only a 20-kDa protein, whose N terminus, in contrast, is derived from
      the env. Moreover, only the 20-kDa protein was also detected in the mature CAEV
      virions. These observations suggest that the transcripts d1, d2, and e1 can
      potentially, in appropriate cellular context, encode two Rev isoforms differing
      in their N termini, whereas the g1 transcript encodes only the 16-kDa species.
      Elucidation of the significance of the 16-kDa Rev protein in CAEV biology must
      await further studies.

PMID- 8642711
TI  - Contempo 1996.

PMID- 8642712
TI  - Addiction medicine.

PMID- 8642713
TI  - Allergy and immunology.

PMID- 8642714
TI  - Anesthesiology.

PMID- 8642715
TI  - Cardiovascular disease.

PMID- 8642716
TI  - Critical care medicine.

PMID- 8642717
TI  - Dermatology.

PMID- 8642718
TI  - Economics.

PMID- 8642719
TI  - Emergency medicine.

PMID- 8642720
TI  - Endocrinology.

PMID- 8642721
TI  - Ethics.

PMID- 8642722
TI  - Family medicine.

PMID- 8642724
TI  - Geriatric medicine.

PMID- 8642723
TI  - General internal medicine.

PMID- 8642725
TI  - Hematology.

PMID- 8642726
TI  - Infectious diseases.

PMID- 8642727
TI  - Law and medicine.

PMID- 8642728
TI  - Medical genetics.

PMID- 8642729
TI  - Medical informatics.

PMID- 8642730
TI  - Neonatology.

PMID- 8642731
TI  - Neurological surgery.

PMID- 8642732
TI  - Neurology.

PMID- 8642733
TI  - Nutrition.

PMID- 8642734
TI  - Obstetrics and gynecology.

PMID- 8642735
TI  - Occupational and environmental medicine.

PMID- 8642736
TI  - Oncology.

PMID- 8642737
TI  - Ophthalmology.

PMID- 8642739
TI  - Otolaryngology-head and neck surgery.

PMID- 8642738
TI  - Orthopedic surgery.

PMID- 8642740
TI  - Pathology and laboratory medicine.

PMID- 8642742
TI  - Physical medicine and rehabilitation.

PMID- 8642741
TI  - Pediatrics and adolescent medicine.

PMID- 8642743
TI  - Plastic surgery.

PMID- 8642744
TI  - Preventive medicine and public health.

PMID- 8642745
TI  - Psychiatry.

PMID- 8642746
TI  - Pulmonary medicine.

PMID- 8642747
TI  - Quality health care.

PMID- 8642748
TI  - Radiation oncology.

PMID- 8642749
TI  - Radiology.

PMID- 8642750
TI  - Surgery.

PMID- 8642751
TI  - Urology.

PMID- 8642752
TI  - [Growth patterns of colorectal carcinoma and mucin property of transitional
      mucosa].
AB  - To examine the relationship of growth pattern of colorectal carcinoma with mucin
      property and cellular proliferation of transitional mucosa (TM), 49 lesions of
      colorectal carcinomas invading to the muscularis propria were studied. Growth
      patterns were classified as polypoid growth (PG), non-polypoid growth (NPG), or
      intermediate type basically according to Shimoda's classification. Mucin property
      of TM was examined using HID-AB staining. Cellular proliferation was assessed
      from PCNA staining. NPG carcinomas were smaller in size, found in younger age,
      and more often to have lymph node metastasis than PG carcinoma. Mucin property of
      TM significantly correlated with growth pattern of carcinoma; sulphomucin
      dominance in TM was found in 5 out of 12 PG carcinomas where as it was found in
      only 1 out of 22 NPG carcinomas. In addition, none of the 8 carcinomas whose TM
      showed a sulphomucin dominance had lymph node metastasis. However cellular
      proliferation in TM did not differ by the growth pattern of carcinoma or the
      mucin property of TM. Preoperative assessment of the growth pattern of lesions
      and the mucin property of TM appears to be useful for predicting lymph node
      metastasis of colorectal carcinomas invading to the muscularis propria.

PMID- 8642754
TI  - [The evaluation of therapeutic effect on partial splenic embolization (PSE) for
      liver cirrhosis patients].
AB  - Partial splenic embolization (PSE) was performed on fifty cases with liver
      cirrhosis underwent no therapy. We evaluated changes of platelet count, ICGR15,
      GPT and Child-Pugh score which were significantly recovered by PSE. About liver
      cirrhosis before PSE, K.ICG, GPT, Alb, platelet count and splenic volume were
      selected as total characteristic factors by principal component analysis. We
      showed predicting formulas after PSE by multiple regression analysis between five
      factors selected by principal component analysis and platelet count, HPT, PT,
      Alb, ICGR15, K.ICG, GOT, GPT and Child-Pugh score after PSE. In conclusion, it is
      suggested that PSE is useful for recovering of platelet count and liver function.
      We made it possible to estimate therapeutic effect by predicting formulas before
      PSE.

PMID- 8642753
TI  - [The clinical evaluation of hepatic arterial infusion chemotherapy in patients
      with liver metastases from colorectal cancer employing an implanted port system].
AB  - Between 1986 and 1994, 66 patients with unresectable liver metastases from
      colorectal cancer were treated by repeated hepatic arterial infusion chemotherapy
      employing an implantable port system. In this study, 44 patients who received
      intermittent hepatic arterial infusion of high dose 5-FU (1000mg/m2) were
      analysed according to a response rate, survival rates, developments of
      extrahepatic lesions, periods of hepatic arterial infusion, and the rates at
      home. Two cases (4.5%) achieved a complete response (CR) and 27 cases (61.4%) a
      partial response (PR). The overall one-year and two-year survival rates were
      56.7% and 37.8% respectively. The 50% survival time for all patients was 17.2
      months. During the course of observation, extrahepatic lesions developed in 16 of
      the 39 patients (41.0%) and many responders died due to deterioration of
      extrahepatic lesions. The over all rates at home were more than 85%. Hepatic
      arterial infusion of the 5-FU at 1000mg/m2 every week showed a high response rate
      in colorectal cancer patients with hepatic metastases, and the responders showed
      a low rate of death due to the hepatic metastases. However, in many patients the
      prognosis-determining-factor was extrahepatic lesions. Thus, countermeasures were
      necessary for extrahepatic lesions.

PMID- 8642755
TI  - [A case of gastric cancer associated with esophageal-hiatus hernia presenting
      with upside down stomach].

PMID- 8642756
TI  - [A case of signet-ring cell gastric cancer appearing an elevated type].

PMID- 8642757
TI  - [A case of gastric duplication cyst containing papillary adenocarcinoma].

PMID- 8642758
TI  - [A case of segmental aganglionosis localized descending colon].

PMID- 8642759
TI  - [A case of schwannoma of descending colon].

PMID- 8642760
TI  - [A case of primary biliary cirrhosis complicated with autoimmune hepatitis].

PMID- 8642761
TI  - [Contrast enhanced color Doppler sonography in a hepatocellular carcinoma case
      with portal tumor thrombus].

PMID- 8642762
TI  - [Two cases of mediastinal pancreatic pseudocyst improved with conservative
      treatment].

PMID- 8642763
TI  - [A case report of intraductal papillary adenoma with carcinoma in situ of the
      pancreas with a repeated history of acute pancreatitis].

PMID- 8642764
TI  - [The detection of Helicobacter pylori by the 13C-urea breath test (13C-UBT) using
      automated breath 13C analyser].

PMID- 8642765
TI  - [Correlation between serum anti CagA antibody and gastric disease].

PMID- 8642766
TI  - [Clinical significance of "acceleration time index" for the judgement of
      gallbladder carcinoma with ultrasonic Doppler method].

PMID- 8642767
TI  - [Measurement of the plasma transforming growth factor-beta 1 (TGF-beta 1) level
      in patients of gastric carcinoma--compared with the serum IAP level and the
      lymphocyte subsets (CD3, CD4, CD8)].
AB  - We evaluated the clinical significance of the plasma TGF-beta 1 by enzyme-linked
      immunosorbent assay (ELISA) in 40 patients with gastric carcinoma before
      operation who were hospitalized at our department between August 1992 and March
      1993. Moreover, we examined the correlation of the immunosuppressive acidic
      protein (IAP) in the serum with the plasma TGF-beta 1 level. The lymphocyte
      subsets were analyzed with monoclonal antibodies (CD3, CD4, CD8) and compared
      with the plasma TGF-beta 1 level. Results 1) The plasma TGF-beta 1 was
      significantly high in patients with advanced stage of gastric carcinoma (with
      respect to the depth invasion) and poorly differentiated adenocarcinoma
      (histological type) (p < 0.01). When the carcinoma was macroscopically found to
      be advanced, TGF-beta 1 was higher in the invasive type than in the noninvasive
      type (p < 0.05). 2) We found a significant correlation between the plasma TGF
      beta 1 and IAP in the serum (n = 25, r = 0.677, p < 0.01). 3) The lymphocyte
      fraction of CD3, CD4 was decreased in patients with a high level of TGF-beta 1,
      and was related with the plasma TGF-beta 1 level. Thus, TGF-beta 1 was presumed
      to be deeply associated with in the growth and progression of gastric carcinoma
      and related to systemic immunosuppressive reaction.

PMID- 8642768
TI  - [Clinical study of ten cases with acute abdomen after eating raw firefly squid
      (Watasenia scintillans, Hotaruika), which are probably due to type X larvae of
      the suborder spirurina].
AB  - We studied ten cases with abdominal pain after eating raw firefly squid,
      Watasenia scintillans, Hotaruika. Characteristic clinical features were abdominal
      pain, nausea, vomiting, diarrhea, creeping eruption and ileus with ascites. In
      ten patients, there were all cases with abdominal pain, nine with nausea and
      vomiting, four with diarrhea, one with creeping eruption, six with ileus.
      Laboratory examination revealed eosinophilia on peripheral blood in ten cases and
      high serum IgE value in nine cases. The infection rate of type X lavae of the
      suborder spirurina in Watasenia scintillans is almost 3%, so we measured the
      antibody to type X larvae of the suborder spirurina in nine patients by indirect
      fluorescent antibody method and the antibody titer was positive in seven cases.
      Most patients recovered in several days from first visit. But one patient was
      diagnosed peritonitis and operated with partial ileectomy. Pathological finding
      of resected specimen showed an erosion in the mucosal layer and an inflammation
      with marked eosinophilia in the submucosal layer. These results suggest that
      abdominal complaints after eating Watasenia scintillans are due to type X larvae
      of the suborder spirurina.

PMID- 8642769
TI  - [Association of Epstein-Barr virus with primary malignant lymphomas of the
      digestive tract].
AB  - The association of Epstein-Barr virus (EBV) with 85 non-Hodgkin lymphomas of the
      digestive tract in nonimmunocompromised cases was investigated, using in situ
      hybridization technique to detect EBV encoded small RNAs in paraffin sections. 85
      cases (83 B-cell type and 2 T-cell type) included 3 gingivas, 1 tongue, 3
      palates, 10 tonsils, 43 stomachs, 2 jejunums, 12 ileums, 3 ileo-cecal regions, 5
      colons and 3 rectums. Out of 85 cases, 4 (4.7%) were EBV-positive, comprising 1 B
      cell lymphoma of the tonsil, 2 B-cell lymphomas of the stomach, and 1 T-cell
      lymphoma of the rectum. On the other hand, EBV-positive rate in
      nasal/nasopharyngeal lymphomas examined for comparison was very high, 81.8% (9
      out of 11). These results show that EBV is associated with only a small
      proportion of lymphomas of the digestive tract in nonimmunocompromised case,
      suggesting the existence of the other oncogenetic factors in the pathogenesis of
      this group of lymphomas.

PMID- 8642770
TI  - [Measurement of portal and splenic venous flow volume (PV and SV), congestion
      index (CI) and SV/PV% in various liver diseases using by Doppler echo
      sonography].
AB  - We measured the portal and splenic venous flow volume (PV and SV), congestion
      index (CI) and SV/PV% in various stages of the liver diseases chronic inactive
      hepatitis (CIH), chronic active hepatitis (CAH), liver cirrhosis without
      esophageal varices (LCvarix(-)), and liver cirrhosis with esophageal varices
      (LCvarix(+))?, and normal volunteers (NC). The results were as follows: PV was
      869.4 +/- 184.0 ml/min in NC, 920.4 +/- 242.5ml/min in CIH, 900.0 +/- 216.9ml/min
      in CAH, 841.8 +/- 253.0 ml/min in LCvarix(-) and 909.7 +/- 430.7ml/min in
      LCvarix(+). SV was 241.0 +/- 80.0 ml/min in NC, 289.4 +/- 131.6 ml/min CIH, 286.4
      +/- 108.8 ml/min CAH, 272.7 +/- 135.7 ml/min in LCvarix(-), 398.0 +/- 280.5
      ml/min in LCvarix(+). SV/PV% was 28.1 +/- 10.1 in NC, 31.4 +/- 14.0 CIH, 32.1 +/-
      9.6 in CAH, 32.4 +/- 16.0 in LCvarix(-), 43.1 +/- 23.7 in LCvarix(+). CI was 0.06
      +/- 0.019 in NC, 0.07 +/- 0.028 in CIH, 0.09 +/- 0.05 in CAH, 0.11 +/- 0.03 in
      LCvarix(-), 0.145 +/- 0.047 in LCvarix(+). These results suggested that: (1) From
      the measurement of CI, portal venous pressure is begun to increase at the stage
      of chronic active hepatitis. (2) Increasing of splenic venous flow volume is
      begun at the stage of chronic hepatitis and it effects to the portal hypertension
      of liver cirrhosis. (3) The change of component of intrahepatic portal venous
      blood flow and decreasing of liver function tests was affected by increasing of
      splenic venous flow volume. (4) SV/PV% may be useful parameter to evaluate the
      decreasing of liver function tests and to estimate the complication of esophageal
      varices at the liver cirrhosis.

PMID- 8642771
TI  - [Evaluation of factors in fragment disappearance after extracorporeal shock wave
      lithotripsy for gallstones].
AB  - To identify which factors are important determinants of fragment disappearance
      after extracorporeal shock wave lithotripsy (ESWL), 67 cases in which gallstones
      were fragmented to under 3 mm in diameter were retrospectively analyzed using
      data obtained by cholescintigraphy, ERCP, ultrasonography, computed tomography,
      and abdominal radiography. Cholescintigraphic findings showed that in the
      fragment-free group, the gallbladder appearance time was significantly longer,
      the ejection fraction was significantly higher, and the gallbladder discharge
      volume was significantly larger compared with the residual fragments group (p <
      0.05). In addition, there was no bile reflux in the fragment-free group, ERCP
      studies showed no difference between both groups in the diameter of the cystic
      duct or the maximum diameter of the common bile duct and the pancreatic duct. The
      disappearance rate of stones was significantly higher in patients with type I a
      or I b gallstones according to Tsuchiya's classification when compared with
      patients who had non-I a, I b stones (p < 0.01) or stones showing low CT density
      values. These results suggest that normal coordination between the gallbladder
      and the sphincter of Oddi is important for the complete disappearance of
      fragments after ESWL in addition to the qualitative features of the gallstones.

PMID- 8642772
TI  - [A case of nutcracker esophagus associated with ischemic heart disease].

PMID- 8642773
TI  - [A case report of ectopic esophago-gastric duplication cyst with difficult
      differential diagnosis from pancreatic pseudocyst].

PMID- 8642774
TI  - [Acute superior mesenteric artery thrombosis due to stress erythrocytosis].

PMID- 8642775
TI  - [Numerical chromosome aberrations in two cases of malignant lymphoma of the
      colon].

PMID- 8642776
TI  - [A case of goblet cell carcinoid of the appendix].

PMID- 8642777
TI  - [A case of refractory ascites successfully treated with transjugular intrahepatic
      portosystemic shunt].

PMID- 8642778
TI  - [Hepatic metastases of pancreatic gastrinoma associated with sclerosing
      hepatocellular carcinoma].

PMID- 8642779
TI  - [A case study of nonfunctioning islet cell tumor in patient with splenic tumor
      and increased AFP].

PMID- 8642780
TI  - Cardiac myosin-induced myocarditis: target recognition by autoreactive T cells
      requires prior activation of cardiac interstitial cells.
AB  - Immunization with cardiac myosin causes T cell-mediated myocarditis in
      genetically predisposed mice and serves as a model for autoimmune heart disease.
      The normal heart is not susceptible to T cells autoreactive with cardiac myosin;
      therefore, we investigated the conditions that are required to facilitate
      recognition of the target tissue. A.SW mice were immunized with cardiac myosin on
      Days 0 and 7. Major histocompatibility antigen (MHC Ag) and intercellular
      adhesion molecule-1 (ICAM-1) expression in the heart tissue was investigated by
      immunohistochemical techniques shortly before disease onset (ie, on Day 9). At
      this time point, cardiac interstitial cells expressing class II but not class I
      MHC Ag were significantly increased. In addition, endothelial ICAM-1 expression
      was strongly up-regulated. Myofibers did not show expression of these markers,
      and T cells were virtually absent. Because lipopolysaccaride (LPS) induced a
      similar distribution of class II MHC Ag and ICAM-1 in the myocardial tissue and
      because these molecules could be crucial to disease onset, we determined whether
      treatment with this immunomodulator renders the heart susceptible to passively
      transferred myosin-reactive T cells. We found that concanavalin A-activated
      spleen cells from myosin-immunized donors induced myocarditis in LPS-primed
      recipients, whereas normal mice were resistant to the injection of such cells.
      Increased class II MHC Ag expression after LPS-treatment was mediated by TNF
      because LPS-primed mice genetically lacking the TNF receptor failed to increase
      class II MHC Ag expression in the heart tissue. In summary, these results suggest
      that in cardiac myosin-induced myocarditis, expression of interstitial class II
      MHC Ag and/or endothelial ICAM-1 is a prerequisite for target organ recognition
      by autoreactive T cells.

PMID- 8642781
TI  - Pathology of acute fatal babesiosis in hamsters experimentally infected with the
      WA-1 strain of Babesia.
AB  - A strain of Babesia (strain WA-1), recently isolated from a human in Washington
      State, was found to be unusually virulent for hamsters; it caused acute infection
      and death in a large proportion of animals 5 to 7 days after inoculation. To
      assess the basic pathologic lesions associated with this infection, 30 male
      Syrian hamsters (Mesocricetus auratus) were inoculated intraperitoneally with the
      WA-1 strain. Twelve animals (40%) died within 5 to 6 days. The other 18 animals,
      all infected and clinically ill, were killed on the sixth or seventh day for
      biochemical study. All 12 animals that died from the infection showed high
      parasitemia, heavy intravascular hemolysis, and pronounced vascular stasis with
      red-cell sequestration in the spleen, liver, lungs, kidneys, and brain. Serologic
      study revealed severe anemia (mean hematocrit, 29) with hemolyzed serum and
      marked elevation of the serum transaminases. The mechanism of death was thought
      to be diffuse anoxic tissue damage secondary to vascular stasis, which led to
      multiorgan failure.

PMID- 8642782
TI  - Induction of vascular permeability enhancement by human tryptase: dependence on
      activation of prekallikrein and direct release of bradykinin from kininogens.
AB  - Tryptase is a trypsin-type serine protease that is released from mast cells.
      Bradykinin (BK) is released directly from kininogens or through activation of
      either Hageman factor or subsequent plasma prekallikrein. Its nasal
      administration or inhalation induces allergy-like symptoms. Although elevated
      levels of tryptase and BK in allergic fluids have been detected, the role of this
      proteinase and the mechanism of BK production at allergic reaction sites are
      still unknown. To investigate the pathologic functions of tryptase, the enzyme,
      purified from human lung, was incubated with normal human plasma, deficient
      plasmas, kininogens, or prekallikrein. High molecular weight kininogen was then
      added, and the mixtures were examined for vascular permeability enhancement (VPE)
      activity, a representative function of bradykinin, using guinea pig skin.
      Tryptase-treated plasma induced VPE in a dose-dependent manner; activity was lost
      in the absence of a kininase inhibitor but not an antihistamine drug. Tryptase
      produced VPE activity from normal or Hageman factor-deficient plasma, but only
      30% of this activity was produced from prekallikrein-deficient plasma.
      Significantly, no activity was obtained from kininogen-deficient plasma.
      Deficient plasma that were reconstituted with each missing factor resulted in VPE
      inducing capacity by tryptase, equivalent to that found with normal plasma.
      Incubation of tryptase with high or low molecular weight kininogen induced VPE
      activity in a dose- and incubation time-dependent manner. Prekallikrein incubated
      with tryptase also generated a soybean trypsin inhibitor-sensitive VPE-inducing
      activity from high molecular weight kininogen. The loss of tryptase VPE-producing
      activity as a function of incubation time was found to be a result of spontaneous
      inactivation of the enzyme and not of the degradation of high molecular weight
      kininogen by the enzyme. We conclude that tryptase induces VPE by releasing BK,
      primarily through prekallikrein activation, but also through direct release from
      kininogens. This indicates that this mast cell-derived proteinase contributes to
      kinin production in allergic diseases.

PMID- 8642783
TI  - In vivo cell lineage analysis during chemical hepatocarcinogenesis using
      retroviral-mediated gene transfer.
AB  - We have studied the proliferation of cells in two models of chemical
      hepatocarcinogenesis. The cells were genetically labeled in vivo using
      retrovirally mediated transfer of the Escherichia coli beta-galactosidase marker
      gene coupled to a nuclear localization signal (nls-lacZ gene). In the first
      carcinogenic model, rats were fed a choline-deficient diet containing 2
      acetylaminofluorene, and their livers were perfused with recombinant retrovirus
      at the onset of oval cell proliferation. The second model was based on the
      administration of diethylnitrosamine coupled with a partial hepatectomy and is
      thought to induce cancer with no involvement of oval cells. Analysis of beta
      galactosidase expression in the liver at various times after gene transfer
      revealed the presence of large clusters of positive cells in both models.
      Moreover, the beta-galactosidase-positive cells displayed morphologic, antigenic,
      and enzymatic profiles consistent with a hepatocyte phenotype. Our results,
      therefore, provide evidence for a strikingly similar clonal proliferation of
      apparently normal hepatocytes during the course of 2-acetylaminofluorene- as well
      as diethylnitrosamine-induced liver carcinogenesis.

PMID- 8642784
TI  - The pathogenesis of multicystic dysplastic kidney disease: insights from the
      study of fetal kidneys.
AB  - The pathogenesis of multicystic dysplastic kidney disease (MCDKD) is unknown.
      Most morphologic studies of MCDKD kidneys have been performed when the kidneys
      are resected postnatally, when their architecture has been distorted by massive
      cyst enlargement. We obtained two MCDKD kidneys at an early stage of development
      (14 and 19 weeks' gestation) and examined the pattern of nephrogenesis in detail.
      In both affected kidneys, we identified islands of spatially dislocated
      metanephric blastema adjacent to zones containing all the normal structural
      elements of nephrogenesis, including aggregates of induced mesenchyme, S-shaped
      bodies and maturing glomerull, and proximal and distal tubules. Metanephric
      blastemal cells displayed characteristic vimentin and smooth muscle actin
      immunoreactivity and insulin-like growth factor II gene expression, whereas
      induced elements exhibited appropriate cytokeratin immunoreactivity and Wilms'
      tumor gene expression. In most other zones, renal cysts were lined with epithelia
      varying from a flattened squamous to a cuboidal morphology and expression of
      markers suggested their origin to be from all portions of the nephron including
      Bowman's space, proximal tubule, and collecting duct. In some cysts, small
      clusters of epithelial cells were identified within the cyst lumen. These studies
      suggest that in the early stages of MCDKD, normal nephrogenesis occurs in what
      seems to be a normal metanephric blastema; however, an intrinsic abnormality in
      the branching morphogenesis of the ureteric duct might be responsible for the
      development of the histopathologic changes described.

PMID- 8642785
TI  - Osteogenic potential of murine osteosarcoma cells: comparison of bone-specific
      gene expression in in vitro and in vivo conditions.
AB  - Bone tissue formation and the expression of osteoblast-specific genes were
      compared in vitro and in vivo for two well characterized murine clonal
      osteosarcoma cell lines (K7 and K8). In vitro studies were carried out under
      conditions that promoted extracellular matrix morphogenesis and mineralization.
      The K8 cells showed 8-fold greater alkaline phosphatase activity and mineral
      accumulation than did K7 cells during 21 days of in vitro growth. The K8 cell
      line showed high levels of bone sialoprotein (BSP), collagen type I (COL I), and
      alkaline phosphatase (APase) mRNA expression throughout its growth in vitro. In
      contrast, K7 cells showed an almost complete absence of BSP and COL I and very
      low levels of APase throughout the culture period. In vitro, both cell lines
      expressed very low levels of osteocalcin (OC). For in vivo studies, we used a
      three-dimensional culture device that permitted analysis of tissue formation by
      the cells after their implantation into syngeneic mice. The K8 cells consistently
      generated extensive mineralized woven bone after their subcutaneous implantation.
      The striking features distinguishing the bone formed by the implanted cells from
      normal recipient bone were the complete absence of osteoclasts or matrix
      resorption, the absence of OC protein, and very low levels of OC mRNA expression
      in the tissues formed by these cell lines. BSP, APase, and COL I expressions were
      maintained at high levels in the K8-produced tissues. In contrast to their near
      absence in vitro, APase, BSP, and COL I were expressed by K7 cells and increased
      with time in vivo. These findings demonstrate that the K7 cells in vitro are less
      differentiated than K8 cells, but that K7 cells in vivo undergo osteogenic
      maturation. Thus, expression of bone-specific genes in these osteogenic cell
      lines was dependent on systemic or local factors in recipient animals and was
      distinct for these cell lines when grown under in vitro conditions. OC protein
      does not appear to be needed for the mineralization of the extracellular matrix
      but may be needed to provide the necessary signals for the resorption and
      remodeling of the tissue.

PMID- 8642787
TI  - Human transplant coronary artery disease: pathological evidence for Fas-mediated
      apoptotic cytotoxicity in allograft arteriopathy.
AB  - Cytotoxicity mediated by cytolytic T cells occurs exclusively through Fas- and
      perforin-based pathways. Such mechanisms may be important in transplant coronary
      artery disease (TxCAD). We studied Fas and perforin expression and apoptosis
      using immunohistochemical methods, in situ terminal deoxyribonucleotide
      transferase-mediated dUTP nick-end labeling (TUNEL), and morphologic analysis of
      vessels with TxCAD taken from 12 transplant patients, which we compared with
      vessels of 10 patients with native coronary artery disease (CAD) and vessels from
      14 patients with normal coronary arteries. Fas was detected in all TxCAD
      specimens. Fas-positive cells were mainly endothelial cells (EC); 100% of EC and
      approximately one-third of T cells and macrophages were positive for Fas. Almost
      all TUNEL-positive cells were Fas-expressing cells. Of the T cells and
      macrophages that expressed Fas, 18% appeared apoptotic in the mild and moderate
      to-severe TxCAD group as compared with 78% in severe TxCAD patients (p = 0.0124).
      By contrast, EC damage was less evident in the vessels with greater intimal
      disease severity: 10% in severe TxCAD versus 75% in the mild and moderate-to
      severe TxCAD group (p = 0.0122). Perforin was positive in 5% of the total intimal
      T cells in 3 of 12 arteriopathy specimens. Fas and perforin were virtually
      negative in vessels taken from CAD patients. TUNEL was diffusely positive in CD68
      positive foam cells in the lipid-rich core, but Fas was negative in all CAD
      specimens. In normal arteries, 8 of 14 specimens contained a few TUNEL-positive
      and Fas-positive EC and T cells. Perforin was negative. We conclude that EC
      damage in TxCAD seems to be brought about through a Fas-based apoptotic pathway
      and that CD4-positive cytolytic T cells may be the major lytic cells involved in
      TxCAD.

PMID- 8642786
TI  - In vivo enzymatic removal of alpha 2-->6-linked sialic acid from the glomerular
      filtration barrier results in podocyte charge alteration and glomerular injury.
AB  - The epithelial polyanion (podocalyxin) on the foot processes (pedicels) of
      podocytes plays a pivotal role in maintaining slit pore integrity and excluding
      proteins from the glomerular filtrate. Chromatographically purified recombinant
      sialidase from Vibrio cholerae, a corresponding heat-inactivated enzyme,
      truncated enzyme (missing the last 17 amino acids from the carboxyl terminus),
      and the sialidase from Salmonella typhimurium strain LT2 were inoculated
      intraperitoneally into mice, and the resultant renal alterations were documented
      by a variety of functional, morphologic, and histochemical techniques.
      Proteinuria and renal failure developed in a dose-dependent manner after a single
      inoculation of sialidase from Vibrio cholerae, but not with the corresponding
      heat-inactivated enzyme, truncated enzyme, or the sialidase from Salmonella
      typhimurium strain LT2. Biotinylated lectins of known sialyl linkage specificity
      demonstrated that Vibrio cholerae sialidase primarily removed alpha 2-->6-linked
      sialic acids from the glomerulus. Furthermore, the use of a poly-L-lysine
      cationic gold ultrastructural probe confirmed a transient loss of charge from the
      endothelium and epithelium of the glomerular filtration barrier. Loss of the
      epithelial polyanion was accompanied by the effacement of pedicels and the
      apparent formation of tight junctions between adjacent podocytes. The anionic
      charge returned to endothelial and epithelial sites within 2 days of sialidase
      inoculation, but the foot process loss remained. This animal model, in addition
      to providing an opportunity to study basic mechanisms of renal physiology, seems
      to mimic minimal change disease in children, diabetic nephropathy, and the renal
      effects of some bacterial infections.

PMID- 8642788
TI  - A novel method for gene analysis of colorectal carcinomas using a crypt isolation
      technique.
AB  - Genetic studies of tumor masses require relatively pure populations of tumor
      cells. Substantial contamination by stromal cells, however, usually prevents
      detailed analysis of tumor cells. To improve the accuracy of gene analysis of
      tumor cells, a crypt isolation technique was introduced to separate neoplastic
      crypts from nonneoplastic stromal cells. Thirty-five specimens of colorectal
      carcinomas were examined for genetic alterations by using a PCR-based method
      combined with crypt isolation. K-ras gene mutations were detected by single
      strand conformation polymorphism analysis. Allelic deletions of the p53 loci were
      estimated quantitatively based on loss of heterozygosity as determined by an
      automated DNA sequencer. Mutations of K-ras genes and allelic deletions at the
      p53 loci were detected in 18 (51%) and 15(68%) of 22 cases, respectively. The
      crypt isolation technique reduced ambiguity and provided quantitatively better
      results than conventional procedures. Evaluation of the allelic ratio for cases
      with loss of heterozygosity revealed that isolated neoplastic crypts were an
      almost pure population of tumor cells at the DNA level (>90%). Crypt isolation
      allowed sensitive and reliable analysis of the genetic alterations in colorectal
      carcinomas. This technique is applicable to biologic studies of colorectal
      tumorigenesis and genetic heterogeneities. To our knowledge, this is the first
      study in which genetic information has been derived directly from surgically
      resected primary colorectal carcinomas.

PMID- 8642789
TI  - Apoptosis in progressive crescentic glomerulonephritis.
AB  - Recent studies in the experimental proliferative glomerulonephritis (GN) indicate
      that apoptosis is the major mechanism that mediates the resolution of glomerular
      hypercellularity during the repair process of experimental GN. The role of
      apoptosis during progressive GN, however, has not yet been well understood. We
      have, therefore, examined the role of apoptosis during the progression of
      experimental crescentic GN to end-stage renal failure. A progressive model of
      antiglomerular basement membrane GN was induced in Wistar-Kyoto rats with a
      single injection of anti-rat glomerular basement membrane antibody. Renal
      function and histologic studies were performed chronologically from Day 0 to Week
      8 after disease induction. The incidence of apoptosis in glomeruli as well as
      glomerular crescents was examined during the progression of crescentic GN to end
      stage kidney disease. Many leukocytes infiltrated glomeruli from the early phase
      of GN, and severe necrotizing and mesangiolytic glomerular damage was observed
      from Day 5 to Week 3. After glomerular damage, mesangial hypercellularity with
      mesangial cell proliferation and extracellular matrix accumulation began with
      crescent formation. Thereafter, glomerular inflammation continued with marked
      extracellular matrix accumulation until Week 4, and the renal function
      deteriorated. The proliferative glomerular lesions subsequently progressed to
      sclerotic lesions and eventually to chronic renal failure in Week 8. Although the
      number of proliferating cells and infiltrating leukocytes slowly decreased,
      glomerular inflammation resolved with scar formation as mesangial sclerosis.
      Significant apoptosis was present from Day 7 (mean +/- SEM, 0.53 +/- 0.12
      cells/glomerular cross-section) and gradually increased in number with the
      proliferating lesions as glomerular inflammation continued. Moreover, apoptosis
      increased during the resolution of the glomerular inflammation, and many
      apoptotic cells were present in the sclerotic lesions in Week 8 (1.97 +/- 0.27
      cells/glomerular cross-section). As glomerular inflammation subsided, cellular
      crescents progressed to fibrous crescents with a reduction of cellularity by Week
      8, and apoptosis increased significantly within these lesions. These findings
      indicate that apoptosis plays an essential role in the resolution of intra- and
      extraglomerular inflammation and in the elimination of glomerular cells within
      the scarring regions for progressive crescentic GN. The regulation of the
      apoptotic phenomenon during crescentic GN may be important in the progression of
      glomerular inflammation and the development of pathologic glomerular sclerosis.

PMID- 8642790
TI  - Mice lacking angiotensin-converting enzyme have low blood pressure, renal
      pathology, and reduced male fertility.
AB  - Mammals produce two isozymes of angiotensin-converting enzyme (ACE). Somatic ACE
      plays an important role in the control of blood pressure. The function of testis
      ACE, produced by male and germ cells, is not known. To examine the roles of these
      isozymes, we used targeted homologous recombination to introduce a modified ACE
      allele into a mouse line. Mice homozygous for this mutant allele lack both ACE
      isozymes and have markedly reduced blood pressures. Contrary to a previous
      report, we found heterozygous male mice to have normal blood pressures.
      Homozygous mutant mice also have severe renal disease. The renal papilla is
      markedly reduced, and the intrarenal arteries exhibit vascular hyperplasia
      associated with a perivascular inflammatory infiltrate. These animals cannot
      effectively concentrate urine. They also have an abnormally low urinary sodium to
      potassium ratio despite reduced levels of aldosterone. Homozygous mutant male
      mice sire significantly smaller litters than wild-type male mice; however, no
      defect in sperm number, morphology, or motility was detected. ACE-deficient
      animals demonstrate the role of this enzyme in systemic blood pressure, renal
      development and function, and male fertility.

PMID- 8642791
TI  - Vesicular transport of Charcot-Leyden crystal protein in tumor-promoting phorbol
      diester-stimulated human basophils.
AB  - Secretion from human basophils (HB) that are stimulated with a phorbol ester
      takes place with slower kinetics than typically regulated secretion, which is
      stimulated by the IgE-mediated mechanism associated with classical granule
      exocytosis. Phorbol ester stimulation of HB induces emptying of granule contents
      (with retention of granule containers) and increases the number of cytoplasmic
      vesicles, an anatomic process similar to one termed piecemeal degranulation
      (PMD), which is a secretory process originally described in HB that migrate from
      the blood in vivo into contact allergy skin lesions. Charcot-Leyden crystal (CLC)
      protein is a basophil granule-associated protein that is readily imaged by using
      a postembedding immunogold procedure. This method was used to localize this
      granule protein in phorbol ester-stimulated, isolated human peripheral blood
      basophil cytoplasmic vesicles in samples collected within a time frame for which
      histamine was secreted. The results of this study showed that the proportion of
      cytoplasmic vesicles that were gold-labeled in stimulated HB, which indicated the
      presence of CLC protein, increased significantly over unstimulated cells at 2, 5,
      and 10 minutes after stimulation. Additionally, CLC protein-labeled vesicles in
      the cells that were stimulated for 10 minutes significantly exceeded the number
      in stimulated cells at 0, 30, and 45 minutes after exposure to phorbol ester.
      Thus, transport vesicles carrying a granule-associated protein (CLC protein) were
      increased in phorbol ester-stimulated HB in the time frame for histamine
      secretion and the anatomic development of PMD. These findings support vesicular
      transport as a major mechanism for effecting PMD, which is morphologically the
      most frequent activation anatomy displayed by HB in human disease in vivo.

PMID- 8642792
TI  - Inflammatory cells infiltrating human colorectal carcinomas express HLA class II
      but not B7-1 and B7-2 costimulatory molecules of the T-cell activation.
AB  - Colon cancer cells express potentially immunogenic proteins but are not rejected
      by the immune system. To induce an effective immune response, antigenic peptides
      have to be presented to T lymphocytes by professional antigen-presenting cells in
      association with HLA class II molecules. Antigen-presenting cells also have to
      express B7 family molecules, B7-1 and B7-2, which deliver the costimulatory
      signals that are required to prevent T cell anergy. We studied B7-1 and B7-2
      expression by the antigen-presenting cells that infiltrate colorectal cancer
      stroma. In 25 samples of colorectal carcinomas, a panel of monoclonal antibodies
      was used to label macrophages, dendritic cells, and T lymphocytes that infiltrate
      the tumor stroma and the morphologically normal distant mucosa. The expression of
      HLA class II and B7 molecules involved in T-cell activation was studied using
      specific monoclonal antibodies. Biopsy pieces from two patients with active
      Crohn's disease were used as controls. All of the samples were heavily
      infiltrated by macrophages and/or dendritic cells that strongly expressed HLA
      class II molecules. In contrast, antibodies to B7-1 and/or B7-2 stained no cells
      in 16 of the 25 samples of colorectal tumors and less than 1% of the inflammatory
      cells that infiltrated tumor stroma of the other nine tumor samples. B7 molecules
      were also poorly expressed by rare cells in the lamina propria of the
      morphologically normal colorectal mucosa. In contrast, many inflammatory cells
      that infiltrated the two Crohn's disease samples strongly expressed B7-1 and B7
      2, especially in the granulomas. We conclude that most HLA class II+ inflammatory
      cells that infiltrate colorectal cancers do not express the B7-1 and B7-2
      costimulatory molecules. This defect may contribute to the failure of the immune
      system to recognize tumor cells as antigenic.

PMID- 8642793
TI  - Radiological assessment of severity of canine nasal tumours and relationship with
      survival.
AB  - A radiological assessment of 35 canine nasal tumours using an objective scoring
      system was carried out and related to patient survival. The scoring system
      demonstrated significant increases in disease-free interval and survival for dogs
      with scores of less than 12 compared to those with scores of 12 or above.

PMID- 8642794
TI  - Long-term follow-up of avascular necrosis of the femoral head in the dog.
AB  - In a clinical study of 35 dogs with avascular necrosis of the femoral head, 60
      per cent were Yorkshire terriers; the mean age of 33 of the dogs at onset of
      clinical signs was seven months. The dogs had the following signs: muscle atrophy
      (n = 25), shortening of the affected leg (n = 14), pain on passive movement of
      the hip joint (n = 28), and crepitation of the hip joint (n = 8). Radiographic
      findings were irregular density and flattening of the femoral head in combination
      with degenerative joint disease. Conservative treatment consisted of exercise
      therapy, and surgical treatment of a standard femoral head and neck excision. In
      17 of the dogs the results of therapy were evaluated with the help of a
      questionnaire. It is concluded that femoral head and neck excision is indicated
      when conservative treatment fails to lead to clinical improvement within four
      weeks. Femoral head and neck excision has a good long term prognosis; however,
      slight intermittent lameness may remain.

PMID- 8642795
TI  - Sedative effects of romifidine in the dog.
AB  - The sedative and physiological effects of intravenous romifidine at 0, 20, 40, 80
      and 120 micrograms/kg were investigated in five clinically normal adult male
      beagle dogs in a blind study using a Latin square design. Following the injection
      of romifidine, the dogs became ataxic and stood with a wide-based stance, they
      exhibited signs of skeletal muscle relaxation and their heads were lowered. All
      the dogs became recumbent and there was a reduction in the heart and respiratory
      rates. Increasing the dose from 20 to 40 micrograms/kg, or higher, produced a
      significant reduction in heart rate. There was am increase in the sedation score
      following even low doses of romifidine, and although measures of sedation showed
      no differences among romifidine doses, subjectively, the higher doses produced a
      more consistent effect. Dogs given lower doses of romifidine regained a standing
      position more rapidly than following the higher doses, although this effect was
      not significantly different. A second blind study compared the sedative effects
      of intravenous romifidine, at 40 and 80 micrograms/kg, with medetomidine at 10
      micrograms/kg in six adult beagles. The cardiopulmonary and sedative effects were
      not significantly different between all regimens, although medetomidine at 10
      micrograms/kg appeared to be intermediate in effect between romifidine at 40 and
      80 micrograms/kg. The sedative and physiological effects of romifidine in dogs
      appear to be similar to other alpha2-adrenoceptor agonists. Intravenous
      administration provided sedation which might be clinically useful.

PMID- 8642796
TI  - Dorsal cross pinning of the atlantoaxial joint: new surgical technique for
      atlantoaxial subluxation.
AB  - The subluxated atlantoaxial joint of a tetraplegic Yorkshire terrier was reduced
      and secured in position by means of cross pinning applied via a dorsal approach.
      The dog made a very satisfactory recovery. The surgical technique for this new
      procedure is described. Further investigations into the biomechanics of such
      fixation, and long term follow-up of treated cases, will be required to evaluate
      accurately the value of this technique.

PMID- 8642797
TI  - Per rectal portal scintigraphy in the diagnosis and management of feline
      congenital portosystemic shunts.
AB  - Five cats with a congenital portosystemic shunt (CPSS) were examined using
      transcolonic portal scintigraphy before and after surgical ligation of the
      shunting vessel. The mean shunt index before surgery was 52 per cent (range 45 to
      61 per cent). Repeat portal scintigraphy, six to eight weeks after surgery,
      indicated a significant reduction in shunt index (mean 13 per cent, range 5 to 25
      per cent) in four cats. In one of these cats a marked reduction in the shunt
      index, as determined by scintigraphy, preceded normal fasting blood ammonia. In
      the fifth cat there was no significant change in the shunt index, fasting serum
      bile acids and blood ammonia six months after surgery, although its clinical
      signs of hepatic encephalopathy had improved. Portal scintigraphy is useful in
      the diagnosis of CPSS and enables a quantitative assessment of the effects of
      surgery and may be a more accurate indicator of the degree of shunting after
      surgery than blood ammonia and serum bile acids.

PMID- 8642798
TI  - Imidazoline receptors: from basic concepts to recent developments.
AB  - The existence is now fully demonstrated of binding sites specifically recognizing
      the imidazoline structure or similar chemical structures, both in the brain and
      in certain peripheral tissues, including the kidney, some of which participate in
      the control of blood pressure. These binding sites are different from alpha 2
      adrenoceptors, both functionally and biochemically. The fact that at least
      medullary binding sites are associated with a precise function, i.e., modulation
      of sympathetic activity of central origin and therefore the regulation of
      vasomotor tone, indicates that they are true receptors. These imidazoline
      receptors of the ventrolateral region of the medulla play an important role in
      the mechanism of the hypotensive action of substances such as clonidine or
      rilmenidinc. Confirmation of dual pharmacological mechanisms involved in the
      hypotensive and sedative effects, respectively, of these drugs has justified
      attribution of the hypotensive effect to involvement of imidazoline receptors in
      the region of the medulla mentioned and the sedative effect to activation of
      classic alpha 2-adrenoceptors of the locus ceruleus. This distinction between to
      mechanisms opens up a novel approach to the development of new centrally acting
      antihypertensive substances free of the troublesome adverse effects of the first
      generation. Many questions remain unanswered, including the precise nature of the
      endogenous ligand(s) of imidazoline receptors, the structure of the receptor and
      its mechanisms of coupling to second messenger, the possible existence of
      variants of these receptors, their mode of interaction with alpha-adrenoceptors,
      and identification of true subtypes of these imidazoline receptors.

PMID- 8642799
TI  - Imidazoline Receptors in a Comprehensive Approach to Hypertension. Proceedings of
      an international symposium. Berlin, Germany, September 10, 1994.

PMID- 8642800
TI  - Pressure natriuresis and long-term blood pressure control.
AB  - The relationship between arterial pressure and the rate of Na+ excretion is
      regulated by a number of mechanisms- some well known, some newly discovered, and
      probably some yet to be discovered. These mechanisms affect either the amount of
      Na+ filtered at the glomerulus or its rate of reabsorption from the proximal or
      distal tubule. Other than physical factors (plasma protein concentration,
      glomerular capillary and tubular pressures) and glomerular ultrafiltration
      properties (Kr), important regulators of both filtration and reabsorption include
      the renin-angiotensin system, aldosterone, and renal nerves, although much
      remains to be learned about renal sympathetic innervation, especially neural
      control of renal tubular function. It has recently become evident that other
      factors may also be important, in particular, nitric oxide, endothelin, and
      medullipin. The latter is a vasodepressor hormone released from the renal medulla
      by increased arterial pressure, and its role in pressure-related Na+ excretion is
      only now being studied. Despite the central importance of this mechanism in the
      regulation of arterial pressure, there has been little study of many other
      potentially important mechanisms, especially those capable of affecting active
      Na+ transport across the tubule, including the imidazoline-preferring receptors.
      New techniques to study the relationship between arterial pressure and Na+
      excretion are becoming available, and these will allow a better assessment of the
      potential of pharmacologic agents capable of modifying this relationship.

PMID- 8642801
TI  - Sympathetic nervous system: contribution to human hypertension and related
      cardiovascular diseases.
AB  - Sympathetic nervous system activation has been documented in several
      cardiovascular disorders. In some, characterized by cardiac failure and portal
      hypertension accompanying hepatic cirrhosis, the sympathetic nervous stimulation
      is reflex and, to some extent, compensatory but has adverse consequences. For
      example, in cardiac failure, the sympathetic nerves of the heart are
      preferentially stimulated, providing adrenergic support to the failing myocardium
      but at the probable cost of arrhythmogenesis and progressive myocardial
      deterioration. The sympathetic activation present in patients with essential
      hypertension, which involves the sympathetic outflows to skeletal muscle, heart,
      and kidneys and is seen particularly in younger patients, differs from these
      examples in that the sympathetic nervous stimulation is apparently not reflex and
      the primary cause is unknown. There is, however, evidence that activation of
      forebrain pressor noradrenergic nuclei may be of importance as an underlying
      central nervous system mechanism. This sympathetic nervous stimulation in
      patients with essential hypertension, in addition to initiating the blood
      pressure elevation, may also contribute to the commonly associated metabolic
      abnormalities of insulin resistance and hyperlipidemia, with neural
      vasoconstriction having metabolic consequences, impairing glucose delivery and
      causing insulin resistance in muscle, and retarding postprandial clearing of
      lipids in liver. Trophic effects of sympathetic activation on cardiovascular
      growth are claimed but have yet to be demonstrated conclusively in humans.

PMID- 8642802
TI  - Rilmenidine in patients with left ventricular hypertrophy: beyond the reduction
      of left ventricular mass.
AB  - It is generally accepted that the development of left ventricular hypertrophy
      (LVH) represents a multifactorial phenomenon that also involves neurohormonal
      mechanisms. This finding may account for the ability of angiotensin-converting
      enzyme inhibitors to induce faster and more complete reversal of LVH than that
      observed with other antihypertensive treatments. The sympathetic system is also
      involved in the genesis of hypertension-induced LVH. We assessed the effects of
      satisfactory long-term treatment with rilmenidine, a new oxazoline with a potent
      antihypertensive action, on cardiovascular structural abnormalities and cardiac
      endocrine function in hypertensive patients with left ventricular hypertrophy.
      Eleven patients underwent M-mode and two-dimensional Doppler echocardiography,
      peripheral pulsed Doppler flowmetry, determination of plasma atrial natriuretic
      factor [(ANF) pg/ml] and renin activity, and 24-h urine electrolyte excretion
      under control conditions, after 4 weeks of blood pressure normalization, after 1
      year of satisfactory antihypertensive treatment and, finally, 4 weeks after
      therapy withdrawal. I.VH (g/m2 body surface area) was reversed after 1-year
      treatment (from 152 +/- 5 to 131 +/- 4, p < 0.05). One-year treatment induced an
      improvement in brachial artery compliance (cm4/dyne.10(7)) (from 0.92 +/- 0.06 to
      1.16 +/- 0.08, p < 0.05) that persisted after withdrawal of treatment (1.17 +/-
      0.06, p < 0.05). Plasma renin activity and urinary electrolyte excretion did not
      change throughout the study, whereas ANF remained unchanged after blood pressure
      normalization (48.4 +/- 6.2 versus 44.7 +/- 2.9, NS), fell after reversal of LVH
      (28.6 +/- 3.4, p < 0.05), and remained significantly lower than under control
      conditions after therapy withdrawal (27.5 +/- 2.9, p < 0.05). These results
      demonstrate that a satisfactory long-term antihypertensive treatment with
      rilmenidine is able to reverse cardiovascular structural changes and to restore
      cardiac endocrine function.

PMID- 8642803
TI  - Lipid profile and antihypertensive efficacy in hyperlipidemic hypertensive
      patients: comparison of rilmenidine and captopril.
AB  - In hypertensive patients with lipid abnormalities, an ideal antihypertensive
      agent would control blood pressure without interfering with lipid metabolism. The
      aim of the present study was to assess whether in addition to angiotensin
      converting enzyme inhibitors, calcium antagonists, and alpha 1-antagonists,
      rilmenidine (RIL), the first antihypertensive drug that is selective to
      imidazoline receptors, fulfills these requirements. To assess the effects of RIL
      (daily doses of 1 mg o.d. or b.i.d.) in comparison to captopril (CAP) (doses of
      25 or 50 mg b.i.d.), an 8-week, double-blind, randomized, parallel-group study
      was carried out. Fifty-one patients (mean age: 56.3 +/- 1.5 years) with mild-to
      moderate hypertension (supine systolic/diastolic blood pressure, 165.1 +/-
      2.0/99.1 +/- 0.6 mm Hg) and type 2a or 2b hyperlipidemia (low-density lipoprotein
      (LDL) cholesterol: 5.38 +/- 0.16 mmol/L) were included in the study, and they
      were followed by their general practitioner at 4-week intervals. Twenty-six
      patients received RIL, and 25 received CAP. The permanence of
      hypercholesterolemia was checked twice before inclusion into the study, at 3-week
      intervals, for patients who had already been on a hypocholesterolemic diet for 6
      weeks. Plasma lipid evaluation included total, LDL and high-density lipoprotein
      (HDL) cholesterol, triglycerides, apolipoproteins A1 and B, lipoprotein (a), and,
      last, a uric acid assay. Assays were centralized at the Lipid Laboratory, CHU
      Pitie-Salpetriere, Paris. In each group, 1 patient withdrew from the study for
      personal reasons, and four patients required a dose adjustment (double dose) at
      the week 4 visit. After 8 weeks of therapy, systolic blood pressure decreased
      significantly in both groups, with no statistically significant difference
      between groups (RIL, 20.5 mm Hg; CAP, 21.3 mm Hg; NS). Diastolic blood pressure
      also decreased (RIL, 13.9 mm Hg; CAP, 15.1 mm Hg; NS). No difference between
      groups was observed on the changes of lipid parameters between week 0 and week 8
      visits. No severe adverse event occurred other than an asymptomatic atrial
      fibrillation in a CAP group patient at week 8. This study provides evidence that
      over a follow-up period of 8 weeks, both RIL and CAP are efficient and well
      tolerated drugs in the first-line treatment of hypertensive patients with lipid
      abnormalities.

PMID- 8642804
TI  - Rilmenidine prevents epinephrine-induced arrhythmias in halothane-anesthetized
      dogs.
AB  - Stimulation of central alpha 2-adrenoceptors has been known to prevent
      epinephrine-induced arrhythmias in halothane-anesthetized dogs. Because recent
      studies suggested that several physiological processes that were traditionally
      attributed to activation of alpha 2-adrenoceptors, such as hypotensive action,
      are mediated through imidazoline receptors (IRs), it may be likely that IRs are
      involved in the antiarrhythmic action. We investigated the hypotensive effect of
      rilmenidine, a selective IR agonist (1, 3, and 10 micrograms/kg i.v.), and the
      antiarrhythmic effects of the drug on epinephrine-induced arrhythmias during
      halothane anesthesia in dogs. Although the hypotensive effect of rilmenidine was
      not remarkable in the dose range we tested, rilmenidine increased the
      arrhythmogenic threshold for epinephrine in a dose-dependent manner during
      halothane anesthesia, achieving statistical significance at 10 micrograms/kg, the
      highest dose we examined. These results suggest that rilmenidine prevents
      epinephrine-induced arrhythmias during halothane anesthesia and that this effect
      is more potent than its hypotensive action.

PMID- 8642805
TI  - Comparative effects of rilmenidine and atenolol on tests of autonomic function
      and mental and dynamic exercise in patients with essential hypertension.
AB  - The aim of the present study was to compare the effects of rilmenidine (1-2
      mg/day) and atenolol (50-100 mg/day) on tests of mental arithmetic, bicycle
      exercise, and autonomic function. Twelve male patients with mild-to-moderate
      hypertension (blood pressure, 160/95 +/- 15/7 mm Hg; age range, 32 to 60 years)
      completed a randomized, double-blind, crossover study. Both drugs were well
      tolerated and, after 4 weeks of monotherapy, were associated with significant
      reductions in supine and erect BP. Hemodynamic responses to mental arithmetic
      were similar for both drugs, and neither agent affected mental performance as
      judged by psychomotor testing. The increase in heart rate during bicycle exercise
      was significantly greater with rilmenidine (50 vs. 41 beats/min, p = 0.04), and
      during the postexercise recovery phase, areas under the curve for diastolic blood
      pressure and heart rate were smaller after atenolol than after rilmenidine:
      46,450 versus 51,400 mm Hg.s (p = 0.02) and 49,445 versus 63,597 beats/min.s (p =
      0.001), respectively. In conclusion, rilmenidine and atenolol exert comparable
      antihypertensive effects both at rest and during mental and dynamic exercise.
      Although atenolol blunted the heart rate responses to dynamic exercise and the
      Valsalva maneuver, rilmenidine showed no interference with physiological
      hemodynamic responses of blood pressure and heart rate during tests of
      sympathetic and parasympathetic function.

PMID- 8642807
TI  - Brain structures involved in the hypotensive effects of rilmenidine: evaluation
      by [14C]2-deoxyglucose autoradiography.
AB  - The centrally acting, antihypertensive drug rilmenidine has activity at both
      imidazoline-preferring receptors (IPRs) and alpha 2-adrenoceptors: the IPR has
      been proposed to be the predominant receptor responsible for the hypotensive
      effects of rilmenidine. In the present study, the neuroanatomic regions of the
      brain involved in mediating the hypotensive response to rilmenidine were
      investigated in spontaneously hypertensive rats with the use of [14C]2
      deoxyglucose autoradiography. The selective alpha 2-adrenoceptor agonist B-HT 933
      was also studied for comparison. Rilmenidine (1 mg/kg s.c.) and B-HT 933 (2 mg/kg
      s.c.) induced significant and similar reductions in mean arterial pressure (-24
      +/- 2 and -18 +/- 5 mm Hg. respectively) and in heart rate (-62 +/- 29 and -69 +/
      14 beats/min. respectively), whereas the vehicle had no significant hemodynamic
      effects. [14C]2-Deoxyglucose autoradiography revealed significant reductions in
      glucose use in the following structures of rilmenidine-treated rats:
      intermediolateral cell column of the thoracic spinal cord, area postrema,
      ventrolateral medulla, nucleus tractus solitarius, and cuneate nucleus, B-HT 933
      did not significantly influence glucose use in any neuroanatomic structure
      examined. These results provide support for the functional involvement of
      brainstem cardiovascular control centres and the involvement of IPRs in the
      hypotensive response to rilmenidine.

PMID- 8642806
TI  - Effects of rilmenidine and clonidine on the electroencephalogram, saccadic eye
      movements, and psychomotor function.
AB  - Rilmenidine is a novel oxazoline derivative that is effective in the treatment of
      hypertension. Studies in animals have indicated that rilmenidine may reduce blood
      pressure without the associated central alpha 2 side effects of clonidine. The
      aim of this double-blind, crossover, placebo-controlled study was to evaluate the
      hypotensive and central sedative effects of single oral doses of rilmenidine (1
      or 2 mg), clonidine (150 or 300 micrograms), and lorazepam (2.5 mg) in 12 healthy
      male volunteers. Drug effects were assessed with a test battery composed of
      resting electroencephalogram, auditory evoked responses (AERs), saccadic eye
      movements, psychomotor performance, and subjective ratings as well as blood
      pressure and heart rate. Rilmenidine and clonidine produced similar dose
      dependent reductions in blood pressure without an effect on heart rate. Saccadic
      eye movements were not significantly impaired after rilmenidine (1 mg) treatment
      in contrast to after clonidine (150 micrograms) treatment. Peak saccadic velocity
      was impaired by all drugs except rilmenidine (1 mg), which was indistinguishable
      from placebo. The electroencephalographic spectral analysis also demonstrated
      greater sedation with lorazepam than with the other drugs and greater vigilance
      with placebo and rilmenidine (1 mg) than with lorazepam. AERs showed a
      differentiation in sedative effects between lorazepam and clonidine (300
      micrograms) relative to placebo, rilmenidine (1 mg), and clonidine (150
      micrograms). These results are consistent with the hypothesis that at lower
      doses, rilmenidine may act preferentially through imidazoline receptors, whereas
      at higher doses, alpha 2-adrenoceptors may become activated.

PMID- 8642808
TI  - Selectivity of rilmenidine for I1-imidazoline-binding sites in rabbit proximal
      tubule cells.
AB  - Imidazoline and imidazoline-like compounds may elicit their pharmacological
      activities through the interaction with three membrane proteins: alpha 2
      adrenergic receptors (alpha 2-AR), I1-binding sites (I1BS), and I2-binding sites
      (I2BS). We have recently shown that these three proteins are co-expressed in the
      renal proximal tubule cells, where they could mediate the renal effects of
      imidazoline and structurally related antihypertensive drugs such as clonidine and
      rilmenidine. To identify the receptor involved in regulation of the tubular
      effects of clonidine and rilmenidine, we performed binding studies on isolated
      cells from rabbit kidney proximal tubule using [3H]idazoxan, an I1/I2 ligand, and
      [3H]rauwolscine, a selective alpha 2-adrenergic antagonist. Competition studies
      of [3H]idazoxan binding showed that rilmenidine and clonidine interact with both
      I1BS and I2BS. The comparison of inhibition constants (rilmenidine: Ki for I1BS.
      7.1 +/- 3.5 nM; Ki for I2BS, 5,189 +/- 1,816 nM; clonidine: Ki for I1BS, 58.2 +/-
      17.3 nM; Ki for I2BS, 4,179 +/- 2,633 nM) demonstrated that rilmenidine and
      clonidine are 731-and 72-fold, respectively, more selective for I1BS than for
      I2BS. In addition, in competition experiments with [3H]-rauwolscine, rilmenidine
      poorly interacted with alpha 2-AR (Ki 2,440 +/- 322 nM), whereas clonidine
      displayed an affinity (Ki, 32 +/- 12 nM) close to that observed for I1BS. Taken
      together, these data show that although clonidine is not able to discriminate
      alpha 2-AR from I1BS, rilmenidine selectively binds only to I1BS. This suggests
      that the renal effects of rilmenidine are related to its selective interaction
      with this class of binding site.

PMID- 8642809
TI  - Renal I1-imidazoline receptor-selective compounds mediate natriuresis in the rat.
AB  - In the present study, we investigated the renal actions of two compounds reported
      to interact with the imidazoline receptor: rilmenidine (I1-receptor selective,
      centrally acting antihypertensive) and agmatine (an endogenous clonidine
      displacing substance). Rilmenidine (saline vehicle, 3 or 30 nmol/kg/min) or
      agmatine (saline vehicle, 3 or 30 nmol/kg/min) was infused directly into the
      renal artery of anesthetized (pentobarbitone) Sprague-Dawley rats (280-300 g)
      that had undergone a unilateral nephrectomy 7 to 10 days before the experiment.
      Rilmenidine produced an increase in urine flow rate at doses that failed to
      significantly alter blood pressure, creatinine clearance, or heart rate. The
      increase in urine flow rate was secondary to an increase in osmolar clearance,
      primarily composed of sodium. Free water clearance was not altered at these
      infusion rates. Agmatine also increased urine flow rate at doses that failed to
      alter blood pressure, creatinine clearance, and heart rate. The increase in urine
      flow rate was secondary to an increase in osmolar clearance, again primarily
      composed of sodium. The natriuretic action of rilmenidine and agmatine, at doses
      that do not lower blood pressure acutely, could be beneficial in the
      antihypertensive actions of these centrally acting agents.

PMID- 8642810
TI  - Baroreflexes and cardiovascular regulation in hypertension.
AB  - The primary purpose of the arterial baroreflex is to keep blood pressure close to
      a particular set point over a relatively short period of time. The rapid
      resetting of arterial baroreceptor afferents toward any sustained new level of
      blood pressure ensures that the reflex acts as an effective buffer of short-term
      blood pressure fluctuations that accompany daily life but also ensures that
      arterial baroreflexes play little role in setting the long-term level of blood
      pressure. Nevertheless, the minimization of blood pressure variability by
      baroreflex mechanisms is important as studies suggest that a diminished
      baroreflex is an independent risk factor or sudden death after myocardial
      infarction. In hypertensive humans and animals, the baroreflex control of heart
      rate is diminished. Using the steady-state method for assessment of the cardiac
      baroreflex in rats, we have shown that the change in baroreflex sensitivity is
      due to a reduction in the vagal range. Although the cardiac sympathetic component
      of the baroreflex is normal, the level of cardiac sympathetic activity is
      enhanced, particularly in young hypertensive rats. We have shown that there is a
      stronger inverse relationship between vagal heart rate range and levels of
      cardiac hypertrophy than with other variables, such as blood pressure,
      hypertension, or indexes of vascular hypertrophy. Treatments that reduce cardiac
      hypertrophy restore cardiac vagal function. Centrally acting antihypertensive
      agents increase the sensitivity of vagal baroreceptor heart rate reflexes, mainly
      through an action on central alpha 2-adrenoceptors. They also reduce cardiac
      sympathetic activity and diminish cardiac sympathetic baroreflexes through a non
      alpha 2-adrenoceptor, possibly an imidazoline receptor mechanism. Both of these
      effects are beneficial in hypertension, where cardiac sympathetic function is
      enhanced and vagal activity is reduced. Thus, these actions would be expected to
      cause a desirable reduction in blood pressure variability. The effect of
      hypertension on baroreflex control of sympathetic vasomotor function is less
      clear. Studies have shown diminished, normal, and enhanced sympathetic vasomotor
      baroreflex control. Basal renal sympathetic drive, however, appears to be
      increased in human essential hypertension. Our studies in conscious rabbits have
      shown that rilmenidine reduces renal sympathetic baroreflex function. Rilmenidine
      acts principally at the level of the rostral ventrolateral medullary imidazoline
      receptors to markedly reduce the basal renal sympathetic nerve activity and the
      maximum response to transient fluctuations in blood pressure. Thus, in addition
      to their antihypertensive actions, centrally acting agents, such as rilmenidine,
      reduce cardiac and renal sympathetic baroreflex responses and increase cardiac
      vagal baroreflex sensitivity. This provides an ideal profile of action for the
      restoration of baroreflex function in addition to reversal of cardiac and
      vascular hypertrophy in hypertension.

PMID- 8642811
TI  - Lymph nod involvement, recurrence, and prognosis in resected small, peripheral,
      non-small-cell lung carcinomas.

PMID- 8642812
TI  - Lymph node involvement, recurrence, and prognosis in resected small, peripheral,
      non-small-cell lung carcinomas: are these carcinomas candidates for video
      assisted lobectomy?
AB  - To determine the clinicopathologic characteristics of peripheral non-small-cell
      carcinomas, the cases of 337 patients undergoing major pulmonary resection with
      complete lymphadenectomy were retrospectively reviewed with regard to lymph node
      involvement, recurrence, and prognosis. All of the tumors were 3.0 cm or less in
      diameter and were categorized as T1 (318 patients) or T2 (19). Eighty-eight
      patients (26.1%) had lymph node involvement: 32 (9.5%) at N1 nodes, 55 (16.3%) at
      N2 nodes, and 1 (0.3%) at N3 nodes. Although the prevalence of lymph node
      involvement did not differ significantly with tumor histologic type, it was quite
      low in squamous cell carcinomas 2.0 cm or less in diameter. Of the 56 N2/3
      metastases, 14 (25%) occurred in a "skipping" manner, and all but one had a
      nonsquamous histologic makeup. Of the 213 patients with a follow-up period of 5
      years or more, 59 patients (27.7%) showed cancer recurrence. This occurred at a
      distant site in 67.8% of the cases. Five-year survival rates based on nodal
      status were 91.9% (NO), 61.8% (N1), 44.5% (N2), and 0% (N3). Because of the
      relatively high prevalence of lymph node involvement, complete hilar/mediastinal
      lymphadenectomy should be routinely done regardless of tumor histologic type and
      size, as long as patients are at good risk. However, in squamous cell histologic
      types, mediastinal lymphadenectomy might be dispensable if the tumor is less than
      2.0 cm in diameter, or if the hilar node is proved to be tumor-free on pathologic
      examination of the frozen section during operation. Although video-assisted major
      pulmonary resection currently has limited application, this new technique may
      represent a surgical option in resection without complete lymphadenectomy.

PMID- 8642813
TI  - Barretts's esophagus: does an antireflux procedure reduce the need for endoscopic
      surveillance?
AB  - Barrett's esophagus, a premalignant condition associated with chronic
      gastroesophageal reflux, carries an approximate 40-fold increase in the incidence
      of adenocarcinoma. Between 1975 and 1994, 113 patients with Barrett's esophagus
      underwent antireflux procedures at the Mayo Clinic. The antireflux procedure was
      performed more than 3 months after the diagnosis of Barrett's disease in 39
      patients (34.5%) and during the initial preoperative evaluation in 74 (65.5%).
      Uncut Collis-Nissen fundoplication was performed in 69 patients (61.1%), Nissen
      fundoplication was performed in 16 (14.2%), cut Collis-Nissen fundoplication was
      performed in 12 (10.6%), Belsey repair was performed in nine (8.0%), Collis
      Belsey repair was performed in six (5.3%), and Nissen fundoplication with an
      anterior gastropexy was performed in one (0.9%). There was one operative death
      (0.9% mortality). Morbidity occurred in 41 patients (36.3%), including cardiac
      arrhythmia in eight (7.0%), pneumonia in six (5.3%), empyema in five (4.4%),
      hemorrhage in four (3.6%), myocardial infarction in two (1.8%), and wound
      dehiscence, wound infection, perforated duodenal ulcer, and postoperative leak in
      one each (0.9%). Median follow-up for the 112 survivors of operation was 6.5
      years (range 4 months to 18.2 years). Excellent or good alleviation of symptoms
      was obtained in 92 patients (82.2%). Ninety-nine patients (88.4%) are currently
      alive and 13 (11.6%) have died. Three patients (2.7%) subsequently had
      adenocarcinoma of the esophagus after the antireflux procedure at 13, 25, and 39
      months; two of these died of cancer. The incidence of esophageal carcinoma in
      this select group of patients was one in 273.8 patient-years of follow-up. We
      conclude that although antireflux procedures in patients with Barrett's esophagus
      result in long-term control of reflux symptoms, the possibility of esophageal
      cancer still exists. Endoscopic surveillance should therefore be recommended.

PMID- 8642814
TI  - Benign anastomotic strictures after transhiatal esophagectomy and cervical
      esophagogastrostomy: risk factors and management.
AB  - Benign stricture formation at the cervical anastomosis after transhiatal
      esophagectomy with gastric tube interposition is an important source of
      morbidity. In a large group of patients (n = 269) who had undergone transhiatal
      esophagectomy with gastric tube interposition, we examined surgical and
      nonsurgical risk factors for the development of benign strictures at the cervical
      anastomosis. In addition, we evaluated the results of endoscopic bougie dilation
      in patients in whom an anastomotic stricture developed. RESULTS: During follow
      up, 114 patients (42%) had a benign anastomotic stricture. Only a history of
      cardiac disease (P = 0.03), postoperative leakage at the anastomosis (p = 0.002),
      and a stapled rather than a hand-sewn anastomosis (p = 0.04) were found to be
      independent risk factors for the development of a stricture. In 27 of 60 patients
      with anastomotic leakage, contrast swallow examination demonstrated only a leak
      at the anastomosis. Endoscopic bougie dilation of anastomotic strictures was
      successful in 78% of patients after a median of three dilation sessions (range 1
      to 28). In 3% of patients dilations were still being performed, and 19% of
      patients had died before normal swallowing had been achieved. In two of 519
      (0.4%) dilation sessions a major complication occurred. CONCLUSIONS: (1) Patients
      with preoperative cardiac disease are at an increased risk for anastomotic
      stricture. (2) Even in patients having no symptoms, a contrast swallow can detect
      anastomotic leakage that results in an increased risk for the development of
      anastomotic strictures. (3) The benefit of the stapler device for anastomosis
      remains to be determined. (4) Endoscopic bougie dilation with the patient mildly
      sedated is a safe and effective method for the treatment of anastomotic
      strictures.

PMID- 8642815
TI  - Morphologic determinants favoring surgical aortic valvuloplasty versus pulmonary
      autograft aortic valve replacement in children.
AB  - The pulmonary autograft is being used with increasing frequency to replace the
      diseased aortic valve in the pediatric population. Attempted surgical aortic
      valvuloplasty with an unacceptable result and return to cardiopulmonary bypass
      for aortic valve replacement with a pulmonary autograft results in prolonged
      bypass time and increased potential for morbidity. Therefore, the ability to
      predict an unsuccessful outcome for valvuloplasty would be of significant
      clinical benefit. This issue is addressed in the present study. METHODS: Twenty
      two patients (median age 5.7 years, range 3 weeks to 14 years) with bicuspid (n =
      11), tricuspid (n = 9), or quadricuspid (n = 2) aortic valves underwent
      valvuloplasty for aortic stenosis (n = 9), aortic regurgitation (n = 7), or a
      combination (n = 6). Previous related procedures included balloon aortic
      valvuloplasty (n = 3) and open surgical valvotomy (n = 1). Median pressure
      gradient across the aortic valve was 80 mm Hg. Surgical valvuloplasty techniques
      included thinning of leaflets (n = 18), commissurotomy (n = 15), suspension of
      reconstructed leaflet to the aortic wall (n = 10), closure of leaflet
      fenestration (n = 5), shortening of free edge of prolapsed cusp (n = 4), repair
      of torn leaflets (n = 3), and augmentation of scarred leaflets with autologous
      pericardium (n = 3). Concomitant subvalvular and supravalvular stenosis were
      repaired in nine and four patients, respectively. In five patients, during the
      same hospital stay, a failed valvuloplasty was converted into a valve replacement
      with a pulmonary autograft because of residual or resultant stenosis (n = 3) or
      regurgitation (n = 2). RESULTS: No early or late deaths occurred. At a median
      follow-up of 16.3 months the median pressure gradient across the aortic valve in
      the 15 patients with preoperative stenosis or combined stenosis and regurgitation
      was 16 mm Hg (p < 0.01 versus preoperative gradient). Of the 22 patients, the
      aortic valve functioned normally (defined as < or = mild stenosis or
      regurgitation, or both) in 14 patients (including five patients with valve
      replacement); four patients had stenosis (gradients 40, 45, 60, and 60 mm Hg),
      two patients had regurgitation, and two patients had combined stenosis (gradients
      40 and 50 mm Hg) and regurgitation. Three of the patients with recurrent stenosis
      underwent secondary surgical valvuloplasty without improvement. Outcome after
      valvuloplasty was examined according to valve structure: six of nine tricuspid
      valves functioned normally, whereas only three of 13 nontricuspid valves
      functioned normally (P = 0.07). Patients with a nontricuspid aortic valve and
      regurgitation had a high probability of requiring immediate valve replacement (P
      = 0.009). The actuarial freedom from significant native valve stenosis or
      regurgitation at 24 months was 82% for tricuspid valves and 36% for nontricuspid
      valves (P = 0.007). CONCLUSIONS: (1) Surgical aortic valvuloplasty should be the
      preferred approach when the aortic valve is tricuspid. (2) In contrast, aortic
      valve replacement with a pulmonary autograft should be the preferred strategy in
      the presence of a nontricuspid aortic valve (especially when the aortic valve is
      regurgitant) and after failed surgical valvuloplasty.

PMID- 8642816
TI  - Long-term follow-up (10 to 17 years) after Mustard repair for transposition of
      the great arteries.
AB  - BACKGROUND: The management strategies of patients who underwent Mustard repair
      for transposition (of the great arteries were changed in the 1970s: infants
      became eligible for direct surgical repair, so Blalock-Hanlon atrioseptostomy
      could be avoided, and cold cardioplegia was introduced for myocardial
      preservation. Data are lacking, however, regarding whether these changes have had
      positive effects on the long-term outcome. We therefore conducted a follow-up
      study on all 91 patients who underwent a Mustard repair for transposition of the
      great arteries in our institution between 1973 and 1980 to assess the incidence
      and clinical importance of sequelae as well as health-related quality of life for
      these patients. METHODS: Patients who were alive and could be traced through
      local registrar's offices received an invitation to participate in the follow-up
      study, which consisted of an interview, physical examination, echocardiography,
      exercise testing, and standard 12-lead and 24-hour electrocardiography. RESULTS:
      Patients operated on in the first 4 years had a significantly higher mortality
      rate and higher incidence of sinus node dysfunction than did patients operated on
      in the subsequent 4 years (25% vs 2% and 41% vs 3%, respectively). In contrast,
      the incidence of baffle obstruction necessitating reoperation was significantly
      higher in the second group. There were no significant differences in
      echocardiographic findings and exercise capacity between patients operated on in
      the first 4 years and in the subsequent 4 years. None of the patients had right
      ventricular failure; a mild degree of baffle leakage or obstruction was seen in
      22% of the patients, and the mean exercise capacity was decreased to 84% +/- 16%
      of normal. CONCLUSION: The changes introduced between 1973 and 1980 have resulted
      in a considerable reduction of mortality and incidence of sinus node dysfunction
      but have also resulted in a more frequent need for reoperation.

PMID- 8642817
TI  - Conversion of modified Fontan procedure to lateral atrial tunnel cavopulmonary
      anastomosis.
AB  - After modified Fontan procedures with atriopulmonary anastomoses or right atrium
      right ventricle conduits, some patients have progressive exercise intolerance,
      effusions, arrhythmias, or protein-losing enteropathy. Theoretic advantages of a
      lateral atrial tunnel cavopulmonary anastomosis and published clinical results
      suggest that conversion of other Fontan procedures to the lateral atrial tunnel
      may afford clinical improvement for some patients. Eight patients (8 to 25 years
      old) with tricuspid atresia (n =4), double-inlet left ventricle (n = 3), and
      double-outlet right ventricle (n=1) underwent conversion to a lateral tunnel
      procedure between December 1990 and November 1994. An arbitrary clinical score
      was assigned before the lateral tunnel procedure and at follow-up. Before
      conversion, patients had decreased exercise tolerance (n = 8), arrhythmias (n =
      6), effusions (n = 4), and protein-losing enteropathy (n = 8). At
      catheterization, all had a low cardiac index (1.9 +/- 0.7 L x min(-1) x M(-2),
      five had elevated pulmonary vascular resistance (>3 Wood units), and three had
      right pulmonary venous return obstruction by compression of an enlarged right
      atrium. Fenestrated lateral tunnel construction was undertaken 7.3 +/- 3.6 years
      after atriopulmonary anastomosis, with one early death related to low cardiac
      output. After the lateral tunnel procedure, two patients had no clinical
      improvement (no change in clinical score) but five patients had either marked or
      partial improvement. The right pulmonary vein compression present in three
      patients was resolved after conversion. The mean clinical scores improved from
      4.5 +/- 1 to 3.0 +/- 2 (p < 0.04). In conclusion, conversion to a lateral tunnel
      procedure led to clinical improvement in five of eight patients at short-term
      follow-up and may be particularly indicated for patients with giant right atria
      or pulmonary vein compression who have symptoms. Pulmonary vein compression
      should be looked for in patients after modified Fontan procedures and can be
      relieved by conversion to the lateral tunnel procedure.

PMID- 8642818
TI  - Reoperation after valve repair for mitral regurgitation: early and intermediate
      results.
AB  - To better understand late outcomes of mitral valve repair, we reviewed the cases
      of 49 consecutive patients who underwent reoperation between January 1974 and May
      1992 for recurrent valve dysfunction after previous valvuloplasty for mitral
      regurgitation. There were 27 men (55%) and 22 women, with a median age of 63
      years (range 20 to 84 years). Original procedures included annuloplasty and
      posterior leaflet repair in 15 patients (31%), annuloplasty and anterior leaflet
      repair in 15 (31%), commissural plication in 13 (27%), and complex bileaflet
      repairs in six (12%). Median time between initial mitral repair and reoperation
      was 2.4 years (range 2 months to 25.3 years). Indications for reoperation
      included recurrent severe mitral regurgitation in 34 patients (70%), hemolytic
      anemia from mitral regurgitation in seven (14%), mixed mitral regurgitation and
      stenosis in seven (14%), and isolated mitral stenosis in one (2%). Before
      reoperation, 36 patients were in New York Heart Association functional class III
      and 11 were in class IV. Initial repairs were intact at the second operation in
      32 patients (65%), and the etiology of recurrent mitral regurgitation in these
      patients was fibrosis or calcification of the anulus or leaflets in 22 patients,
      newly ruptured chordae in seven, and perforated leaflets in three. The causes of
      mitral regurgitation in the 17 patients whose initial repair had failed included
      dehiscence of commissural repairs in nine patients, dehiscence of ring
      annuloplasty in four, and break-down of chordal or leaflet repair in four.
      Patients with original repairs involving the anterior leaflet had a significantly
      shorter time between operations (p = 0.006). In eight patients (16%), the mitral
      valve was repaired again; in the remaining 41 patients (84%), prosthetic
      replacement was performed. Operative mortality rate was 4% (two patients). All
      eight patients who underwent mitral valve rerepair had no mitral regurgitation,
      trivial regurgitation, or mild regurgitation at discharge from the hospital.
      Follow-up was 100% complete at a mean of 5.1 years (range 1 to 19 years). Forty
      one patients (87% were in New York Heart Association functional class I or II,
      and survival at 5 years was 75.3%. Of the eight patients who underwent a second
      repair, seven had no regurgitation, trivial regurgitation, or mild regurgitation
      at a median of 4 years' follow-up. The low mortality associated with reoperation
      supports an aggressive approach toward mitral regurgitation with initial repair.
      A second repair can be performed in selected patients with durable results at 4
      years.

PMID- 8642819
TI  - Cost reduction by combined carotid endarterectomy and coronary artery bypass
      grafting.
AB  - A significant cost reduction is likely if patients who require coronary artery
      bypass grafting with significant carotid stenosis have simultaneous carotid
      endarterectomy and bypass grafting, provided risk is not increased. To
      investigate this issue, we retrospectively identified cases from February 1977 to
      May 1994 with first-time isolated carotid endarterectomy, coronary bypass, or
      combined procedures. In the isolated carotid endarterectomy population, median
      age was 69 years and 58% (85/146) were male, as compared with 68 years and 68%
      (68/100) male in the combined group; median age of the coronary bypass cohort was
      65 years and 76% (381/500) male. A significantly higher percentage of patients in
      the coronary bypass versus combined group were in New York Heart Association
      functional class IV. In the combined group there was a significantly higher
      incidence of older age, diabetes, hypertension, hyperlipidemia, renal failure,
      and congestive heart failure. There was no difference among the three groups with
      respect to hospital mortality (0%, 3.4%, and 4.0%, respectively) and permanent
      stroke (0.7%, 1.2%, and 0%, respectively). Hospital costs were $4,896, $10,959
      and $11,089, respectively, with a savings of $4,766 (30%), and Medicare hospital
      reimbursement was $8,575, $23,071, and $23,071, respectively, with a savings of
      $10,077 (25.3%). Thus, in appropriate patients, a combined procedure is cost
      effective, eliminating a second surgical procedure and the cost of the
      postoperative stay (3.7 +/- 2.4 days) associated with isolated carotid
      endarterectomy. Risk of permanent stroke or death is not increased.

PMID- 8642820
TI  - Randomized comparison of ultrasonic aspiration versus conventional electrocautery
      for dissection of the human internal thoracic artery.
AB  - The most common technique currently employed to harvest the internal thoracic
      artery for coronary artery bypass grafting is conventional electrocautery. This
      study compared an alternative method, electrocautery with an ultrasonic
      aspirator, for harvesting the internal thoracic artery. Patients were randomly
      assigned to one of six experimental groups (conventional electrocautery,
      ultrasonic aspirator at settings of 60%, 80%, and 100% power output, and
      ultrasonic aspirator in 100% CAVI-Pulse modes 1 and 3). Ring segments of internal
      thoracic artery were studied in an organ bath. Contraction responses were
      elicited with 123 mmol/L potassium physiologic salt solution, KPSS, KPSS solution
      containing noradrenaline, and a cumulative noradrenaline dose-contraction curve.
      Relaxation studies were performed with the vasodilators acetylcholine,
      bradykinin, and sodium nitroprusside. Forty percent of the electrocauterized
      vessels were traumatized or damaged and failed to respond to contractile stimuli,
      whereas only 10% of the vessels in ultrasonic aspirator groups 60%, 80%, and 100%
      failed to respond. All vessels in the group harvested by ultrasonic aspirator in
      100% CAVI-Pulse mode 1 responded, whereas 20% of the vessels in the group
      harvested by ultrasonic aspirator in 100% CAVI-Pulse mode 3 failed to respond.
      All settings of electrocautery with an ultrasonic aspirator produced a greater
      contractile response to KPSS and noradrenaline. Acetylcholine and sodium
      nitroprusside produced similar relaxations in all groups, but the bradykinin
      responses were significantly improved in all groups undergoing 100%
      electrocautery with an ultrasonic aspirator. These results suggest that 100%
      electrocautery with an ultrasonic aspirator, particularly in 100% CAVI-Pulse mode
      1, resulted in less damage and trauma than conventional electrocautery during
      harvesting of the internal thoracic artery.

PMID- 8642821
TI  - Risk factors for deep sternal wound infection after sternotomy: a prospective,
      multicenter study.
AB  - Several risk factors for deep sternal wound infection after sternotomy remain
      unclear. To assess and compare risk factors among units, a prospective study
      included 1830 patients in 10 units during a 4-month period: 960 underwent
      coronary artery bypass grafting and 870 underwent other procedures. According to
      the Centers for Disease Control and Prevention definitions, 2.3% of patients
      (42/1830) acquired a deep sternal wound infection. Independent risk factors for
      deep sternal wound infection were obesity, coronary artery bypass grafting,
      reoperation, and postoperative inotropic support. Independent risk factors after
      coronary artery bypass grafting were obesity, bilateral internal thoracic artery
      grafting, reoperation, and postoperative inotropic support. In all five of the
      units usually performing bilateral internal thoracic artery graftings, this
      procedure was associated with high risk of deep sternal wound infection. Duration
      of operation was a major risk factor in comparison of the unit with the highest
      risk of deep sternal wound infection with the other nine units; this suggests
      that parameters related to the perioperative period were involved. Multicenter
      surveillance is useful to determine reliable risk factors for deep sternal wound
      infection, to define a high-risk population before operation, and to assess unit
      specific risk factors.

PMID- 8642822
TI  - Early postoperative angiographic assessment of radial grafts used for coronary
      artery bypass grafting.
AB  - Despite a revival of interest in using the radial artery as an alternative
      conduit for myocardial revascularization, little angiographic documentation of
      early postoperative results has been presented, particularly in North America.
      Accordingly, 60 of 150 patients who underwent coronary artery bypass with radial
      arteries from November 1993 to July 1995 have had postoperative cardiac
      catheterization at our institution. The patency rate of the radial artery grafts
      was 95.7% (90 of 94 grafts patent) with an average internal diameter of 2.51 mm.
      Four radial artery grafts showed diffuse narrowing. The patency rate of the
      internal thoracic artery grafts was 100% with an average internal diameter of
      2.25 mm. Three of 62 grafts demonstrated diffuse narrowing. Two of 24 (7.7%)
      saphenous vein grafts were occluded; the average internal diameter was 3.23 mm.
      The internal thoracic artery, the radial artery, and saphenous vein grafts were,
      respectively, 7.5%, 19.5%, and 53.3% larger than the anastomosed native coronary
      arteries. Graft-dependent flow was found in 81.1% of the radial artery grafts.
      CONCLUSION: The results of this study demonstrate that the short-term patency
      rate of radial artery grafts is excellent.

PMID- 8642823
TI  - Perioperative microbiologic monitoring of tracheal aspirates as a predictor of
      pulmonary complications after cardiac operations.
AB  - The value of preoperative and early postoperative microbiologic testing of
      tracheal aspirates as a prognostic indicator of the development of pneumonia was
      evaluated in a prospective study of 213 cardiac surgical patients. Tracheal
      aspirates were obtained immediately after intubation and after the patient's
      arrival at the intensive care unit. Diagnosis of pneumonia was accepted if at
      least three of the following criteria were fulfilled: leukocytosis > 15,000
      cells/mm3, body temperature >38.5 degrees C, positive results of auscultation,
      positive results of radiography (new infiltrates that seemed to be consistent
      with pneumonia), and increased core-reactive protein for more than 2 days after
      operation. Potentially pathogenic microorganisms were found in 54 (25.4%) of the
      preoperative tracheal aspirates and in 27 (12.7%) of the early postoperative
      tracheal aspirates. Positive microbiologic findings correlated with pneumonia in
      the postoperative course in 24.1% (p < 0.001) if the preoperative culture results
      were positive, in 48.2% (p < 0.001) if the postoperative culture results were
      positive, and in 44.0% (p < 0.001) if both were positive. The risk of pneumonia
      was increased in male patients (p < 0.05) and in patients with chronic
      obstructive pulmonary disease (p < 0.05). Demographic variables, smoking, acute
      pulmonary symptoms, temperature, leukocyte count at the day of the operation, and
      data on the operation and the extracorporeal circulation were not significantly
      related to pneumonia in the early postoperative course. The risk of development
      of postoperative pneumonia is significantly higher among patients with
      colonization of the lower respiratory tract. Positive culture results in routine
      microbiologic monitoring of tracheal aspirates are predictive of pulmonary
      complications after cardiac operations.

PMID- 8642824
TI  - Effects of acute rejection and antirejection therapy on arteries and veins from
      canine single lung allografts.
AB  - Experiments were designed to compare the function of the endothelium and smooth
      muscle in intralobar pulmonary arteries and veins of transplanted lungs during
      acute rejection and after treatment of rejection. Single lung allografts were
      performed in dogs. Dogs were monitored for 5 days to allow good recovery from the
      operation and resolution of early chest radiographic changes. In group I,
      immunosuppression (cyclosporine A, azathioprine, and methylprednisone) was
      withdrawn to allow rejection, which typically occurred after 3 days. In group II,
      immunosuppression was reinstituted at this time during acute rejection until the
      chest roentgenograms again cleared (approximately after 6 days). The blood
      vessels were studied at this time. Rings were cut from intralobar pulmonary
      arteries and veins of the allotransplanted lungs and suspended for the
      measurement of isometric force in organ chambers. Contractions of arteries and
      veins to phenylephrine but not endothelin-1 were significantly reduced during
      acute rejection. In arteries and veins, endothelium-dependent relaxations to
      bradykinin but not the calcium ionophore A23187 were reduced with rejection.
      Relaxations of the smooth muscle to histamine increased with rejection in both
      blood vessels. Relaxations to nitric oxide were reduced with rejection in veins
      but not arteries. Treatment of rejection reversed all responses toward those
      observed in arteries and veins in lungs from dogs not undergoing transplantation.
      These results suggest that responses of the endothelium and smooth muscle of
      pulmonary arteries and veins of transplanted lungs are altered similarly during
      rejection. Further, treatment of rejection restores function of the pulmonary
      blood vessels of lung allografts toward that observed in unoperated lungs.

PMID- 8642825
TI  - Cardiac allograft vasculopathy in partially inbred miniature swine. I. Time
      course, pathology, and dependence on immune mechanisms.
AB  - To assess the role of the immune system in cardiac allograft vasculopathy in
      large animals, heterotopic heart transplantation was done between partially
      inbred miniature swine, animals in which transplantation can be done across
      defined major histocompatibility barriers in a reproducible fashion. Porcine
      hearts transplanted into untreated recipients across a class I, class II, or full
      major histocompatibility mismatch were acutely rejected in 6 to 8 days (n = 4).
      Hearts transplanted into untreated recipients across minor histocompatibility
      barriers survived for 21 to 44 days (n = 5) and showed no evidence of cardiac
      allograft vasculopathy. When recipients were treated with a 12-day course of
      cyclosporine, hearts transplanted across minor histocompatibility barriers
      survived 42, 64, and 56 days and did not develop vascular lesions. However,
      hearts transplanted into cyclosporine-treated recipients across a full major
      histocompatibility disparity survived 20, 22, and 23 days and all three developed
      biopsy-proven vasculopathy. In one animal, the progression of intimal
      proliferation was followed in vivo by intracoronary ultrasonography. The degree
      of intimal thickening documented by ultrasonography correlated well with the
      intimal proliferation found on tissue histologic samples. These results are the
      first to show that in large animals, an immune response stimulated by donor major
      histocompatibility antigens is involved in the induction of cardiac allograft
      vasculopathy. In addition, these studies point out the utility of a large-animal
      model of cardiac allograft vasculopathy in which transplantation across defined
      major histocompatibility barriers can be done reproducibly and in which accurate
      determinations of the progression or regression of coronary vascular lesions in
      individual animals can be accurately assessed in vivo.

PMID- 8642826
TI  - Nitric oxide inhibition attenuates systemic hypotension produced by protamine.
AB  - BACKGROUND: Protamine reversal of heparin anticoagulation often causes systemic
      hypotension, and in vitro studies suggest that this may be mediated by release of
      nitric oxide from the endothelium. The present investigations were designed to
      evaluate the direct myocardial effects of protamine and to determine in vivo
      whether nitric oxide inhibition can prevent hypotension during protamine
      infusion. METHODS/RESULTS: Protamine sulfate (50 microg/ml) was added to
      perfusate of eight isolated rabbit heart preparations; in six other preparations,
      a similar concentration of prolamine was added to heparinized (5 U/ml) Krebs
      perfusate. Left ventricular developed pressure, maximum rate of pressure rise,
      and heart rate declined significantly (p < 0.01) in hearts exposed to protamine
      only (65.0% +/- 6.6%, 55.5% +/- 6.0%, and 87.6% +/- 2.5% of baseline,
      respectively), whereas protamine added to heparinized perfusate caused little
      change in developed pressure, maximum rate of pressure rise, and heart rate
      (85.3% +/- 5.4%, 84.9% +/- 5.5%, and 98.8% +/- 1.6%). To study systemic effects
      of protamine, we measured hemodynamic parameters in 12 heparinized dogs (150
      U/kg). During protamine infusion (1.5 mg/kg intravenously over 30 seconds), mean
      blood pressure decreased by 46% +/- 7% from baseline (P < 0.05), cardiac output
      decreased by 38% +/- 4% (p < 0.05), and systemic vascular resistance decreased bv
      by 14& +/- 9%. After hemodynamic stabilization, Ng-monomethyl-L-arginine (2
      mg/kg), a competitive inhibitor of nitric oxide synthesis, was administered to
      six dogs, and methylene blue (2 mg/kg), an inhibitor of cyclic guanosine
      monophosphate synthesis, was administered to the remaining six dogs. After
      treatment with Ng-monomethyl-L-arginine and methylene blue, the second infusion
      of protamine sulfate caused no significant change in blood pressure or cardiac
      output. In an additional six dogs, Ng-monomethyl-L-arginine pretreatment (5
      mg/kg) blocked the effects of the first dose of protamine. The effect of Ng
      monomethyl-L-arginine could be reversed by the addition of (6 mg/kg) L-arginine
      but not D-arginine. CONCLUSIONS: Protamine-heparin complex does not cause direct
      myocardial depression but does lead to severe hypotension in vivo. The finding
      that hypotension can be blocked by inhibitors of the nitric oxide pathway
      confirms previous in vitro studies indicating that the effects of protamine are
      mediated, in part, by the vascular endothelium. Further, these studies suggest a
      novel approach to prevention of hemodynamic complications caused by heparin
      reversal after cardiopulmonary bypass.

PMID- 8642828
TI  - Developmental differences in myocyte contractile response after cardioplegic
      arrest.
AB  - Although developmental differences in left ventricular function after
      cardioplegic arrest and rewarming have been postulated, whether differences exist
      at the level of the myocyte remains unexplored. This project tested the
      hypothesis that there is a differential effect of hypothermic hyperkalemic
      cardioplegic arrest with subsequent rewarming on contractile function of immature
      compared with adult ventricular myocytes. Myocytes were isolated from the left
      ventricular free wall of five immature and five adult rabbits and incubated for 2
      hours in hyperkalemic modified Ringer's solution at 4 degrees C (cardioplegia) or
      for 2 hours in cell culture medium at 37 degrees C (normothermia). Myocytes were
      resuspended ("rewarmed") in 37 degrees C cell culture medium after the incubation
      protocol. Normothermic baseline contractile performance was lower in immature,
      compared with adult, myocytes. Specifically, myocyte shortening velocity was 62
      +/- 4 microm/sec in immature and 112 +/-6 microm/sec in adult myocytes (p <
      0.01). After cardioplegia and rewarming, immature myocyte contractile function
      was unchanged, whereas adult myocyte contractile function was significantly
      diminished. For example, myocyte shortening velocity was 65 +/- 4 microm/sec in
      immature and 58 +/- 3 microm/sec in adult myocytes (p < 0.01 versus
      normothermic). Myocyte surface area, which reflects myocyte volume, was increased
      after cardioplegia and rewarming in adults (3582 +/- 55 versus 3316 +/- 46
      microm2, p < 0.01), but remained unchanged in immature myocytes (2212 +/- 27
      versus 2285 +/- 28 microm2, P = not significant). These unique findings
      demonstrate a preservation of myocyte contractile function and volume regulation
      in immature myocytes after cardioplegic arrest and rewarming. Thus this study
      directly demonstrates that developmental differences exist in myocyte responses
      to hypothermic hyperkalemic cardioplegic arrest with subsequent rewarming.

PMID- 8642827
TI  - Effects of cardiopulmonary bypass and circulatory arrest on endothelium-dependent
      vasodilation in the lung.
AB  - Endothelial injury with failure of pulmonary endothelium-dependent vasodilatation
      has been proposed as a possible cause for the increased pulmonary vascular
      resistance observed after cardiopulmonary bypass, but the mechanisms underlying
      this response are not understood. An in vivo piglet model was used to investigate
      the role of endothelium-dependent vasodilatation in postbypass pulmonary
      hypertension. The pulmonary vascular responses to acetylcholine, a receptor
      mediated endothelium-dependent vasodilator, and nitric oxide, an endothelium
      independent vasodilator, were studied in one group of animals after
      preconstriction with the thromboxane A2 analog U46619 (n = 6); a second group was
      studied after bypass with 30 minutes of deep hypothermic circulatory arrest (n =
      6). After preconstriction with U46619, both acetylcholine and nitric oxide caused
      significant decreases in pulmonary vascular resistance (34% +/- 6% decrease, p =
      0.007, and 39% +/- 4% decrease, p = 0.001). After cardiopulmonary bypass with
      circulatory arrest, acetylcholine did not significantly change pulmonary vascular
      resistance (0% +/- 8% decrease, p = 1.0), whereas nitric oxide produced a 32% +/-
      4% decrease in pulmonary vascular resistance (p = 0.007). These results
      demonstrate a loss of receptor-mediated endothelium-dependent vasodilatation with
      normal vascular smooth muscle function after circulatory arrest. Administration
      of the nitric oxide synthase blocker Ngamma-nitro-L-arginine-methyl-ester after
      circulatory arrest significantly increased pulmonary vascular resistance; thus,
      although endothelial cell production of nitric oxide may be diminished, it
      continues to be a major contributor to pulmonary vasomotor tone after
      cardiopulmonary bypass with deep hypothermic circulatory arrest. In summary,
      cardiopulmonary bypass with deep hypothermic circulatory arrest results in
      selective pulmonary endothelial cell dysfunction with loss of receptor-mediated
      endothelium-dependent vasodilatation despite preserved ability of the endothelium
      to produce nitric oxide and intact vascular smooth muscle function.

PMID- 8642829
TI  - Alpha-stat acid-base regulation during cardiopulmonary bypass improves
      neuropsychologic outcome in patients undergoing coronary artery bypass grafting.
AB  - Neuropsychologic impairment in patients undergoing cardiopulmonary bypass may be
      associated with cerebral blood flow changes arising from different management
      protocols for carbon dioxide tension during bypass. Seventy patients having
      coronary artery bypass grafting were randomized to either pH-stat or alpha-stat
      acid-base management during cardiopulmonary bypass with a membrane oxygenator. In
      each patient, cerebral blood flow (xenon 133 clearance), middle cerebral artery
      blood flow velocity (transcranial Doppler sonography), and cerebral oxygen
      metabolism (cerebral metabolic rate and cerebral extraction ratio) were measured
      during four phases of the operation: before bypass, during bypass (at hypothermia
      and at normothermia), and after bypass. A battery, of neuropsychologic tests were
      also conducted before and 6 weeks after the operation. During hypothermic (28
      degrees C) bypass, cerebral blood flow was significantly (p < 0.001) greater in
      the pH-stat group (41 mlx100 gm(-1)xmin(-1); 95% confidence interval 39 to 43
      mlx100 gm(-1)xmin(-1)) than in the alpha-stat group (24 mlx100 gm(-1)xmin(-1);
      confidence interval 22 to 26 mlx100 gm(-1)xmin(-1)) at constant pressure and How.
      Arterial carbon dioxide tensions were 41 mm Hg (40 to 41 mm Hg) and 26 mm Hg (25
      to 27 mm Hg), respectively; pH was 7.36 (7.34 to 7.38) and 7.53 (7.51 to 7.55),
      respectively. Middle cerebral artery flow velocity was significantly (p < 0.05)
      reduced in the alpha-stat group to 87% (77% to 96%) of the prebypass value,
      whereas it was significantly (p < 0.05) increased (152%; 141% to 162%) in the pH
      stat group. Cerebral extraction ratio for oxygen demonstrated relative cerebral
      hyperemia during hypothermic (28 degrees C) bypass in both the pH-stat and alpha
      stat groups (0.12 [0.11 to 0.14] and 0.25 [0.22 to 0.28], respectively); however,
      hyperemia was significantly more pronounced in the pH-stat group, indicating
      greater disruption in cerebral autoregulation. Neuropsychologic impairment
      criteria of deterioration in results of three or more tests revealed that a
      significantly (Fisher's exact test, p = 0.02) higher proportion of patients in
      the pH-stat group fared poorly than in the alpha-stat group at 6 weeks (17/35,
      48.6% [32% to 65.1%], and 7/35, 20% [6.7% to 33.2.2%], respectively). In
      conclusion, patients receiving alpha-stat management had less disruption of
      cerebral autoregulation during cardiopulmonary bypass, accompanied by a reduced
      incidence of postoperative cerebral dysfunction.

PMID- 8642830
TI  - Thoracoscopic evacuation of dead hydatid cyst.

PMID- 8642831
TI  - Ventilatory support with a cuirass respirator after resection of bullous
      emphysema: report of a case.

PMID- 8642832
TI  - Mediastinal histoplasmosis causing massive hematemesis.

PMID- 8642833
TI  - Upper airway obstruction caused by low-grade tracheal papillary adenocarcinoma:
      an usual flow-volume loop pattern.

PMID- 8642834
TI  - Transposition of the great arteries.

PMID- 8642835
TI  - Location of the conduction tissue in double-inlet left ventricle with leftward
      rudimentary right ventricle.

PMID- 8642836
TI  - Surgical technique and atrial arrhythmias after total cavopulmonary connection.

PMID- 8642837
TI  - Intrapulmonary benign fibrous tumor of the pleura.

PMID- 8642838
TI  - Historical perspectives of the American Association for Thoracic Surgery. Rudolph
      Matas (1860-1957).

PMID- 8642839
TI  - Incidence and time trends for lymphomas, leukemias and myelomas: hypothesis
      generation. Working Group on the Epidemiology of Hematolymphopoietic Malignancies
      in Italy.
AB  - Epidemiological hypotheses on disease etiology, generated by the observation of
      geographic distribution and time trends, can be confirmed or refuted by
      analytical investigations on specific risk factors. In the case of leukemias,
      lymphomas and myelomas, however, hypothesis generation is limited by the use of
      the ICD classification in mortality and incidence statistics. We compared recent
      incidence data in different parts of the world and at different times for
      leukemias, lymphomas and myelomas. The incidence rate of non-Hodgkin's lymphomas
      (NHL) is increasing in most Western countries, while trends for the other
      hematolymphopoietic malignancies are strikingly stable. To formulate hypotheses
      on the causes of this pattern would require a more appropriate classification of
      descriptive data. Excesses of non-Hodgkin's lymphomas have been observed in
      populations exposed to phenoxy-acetic acid herbicides, to insecticides and to
      organic solvents. Some of these exposures, in particular TCDD, which is a
      contaminant of phenoxy herbicides, DDT and chlorinated solvents, have been
      reported to alter cell-mediated immunity. The incidence of NHL is also increased
      among subjects with HIV infection and subjects undergoing heart or kidney
      transplantation, all of whom experience immunodeficiency. A hypothesis that has
      been put forward recently is that the NHL increase is related to increased
      exposure to sunlight, which has immunosuppressive effects. From a mechanistic
      point of view, one can hypothesize that NHL is caused by exposures that induce
      proliferation and immortalization of B-cells, followed by T-cell impairment
      entailing cell-mediated immune deficiency.

PMID- 8642840
TI  - Differential interleukin-6 (IL-6) responses of three established myeloma cell
      lines in the presence of soluble human IL-6 receptors.
AB  - We investigated the possible influence of recombinant (r) sIL-6R on the growth of
      three IL-6 non-responsive or weakly IL-6 responsive long-term myeloma cell lines.
      The three cell lines chosen for the study (U266, L363 and Fravel) all expressed
      gp130 but differed in their expression of IL-6R and IL-6. mRNA analysis by
      northern blot and reverse transcriptase polymerase reaction showed that the cell
      line U266 was the only one that expressed IL-6 mRNA. Only U266 and L363 expressed
      IL-6R mRNA. 125I-rIL-6 binding studies and FACS analysis, using biotinylated IL-6
      and antibodies directed against the IL-6R and gp130, showed corresponding results
      on the protein level. Addition of rsIL-6R resulted in induction of IL-6
      responsiveness in L363 cells, whereas the 3H-thymidine incorporation of the cell
      lines U266 and Fravel was unaffected by rsIL-6R addition. In conclusion, the IL-6
      unresponsive growth of several long-term myeloma cell lines in vitro can in some,
      but not all cases, be due to a deficiency in exogenous sIL-6R.

PMID- 8642841
TI  - Therapeutic strategies for inhibition of interleukin-6 mediated multiple myeloma
      cell growth.

PMID- 8642842
TI  - The effects of cisplatin and methotrexate on the expression of human
      immunodeficiency virus type 1 long terminal repeat.
AB  - Previous work by many groups has documented the induction of HIV-LTR (human
      immunodeficiency virus-long terminal repeat) following exposure of cells or whole
      animals to ultraviolet (UV) light and other DNA damaging agents. In these
      experiments we set out to determine whether exposure to the cancer
      chemotherapeutic agents methotrexate and cisplatin had any effect on the
      expression of the HIV-LTR. Using HeLa cells stably transfected with a construct
      in which HIV-LTR drives the expression of the reporter gene chloramphenicol
      acetyl transferase (CAT), we demonstrated induction of HIV-LTR 24-48 h following
      exposure to 50 microM cisplatin. When UV exposure (10 Jm-2) was coupled with
      cisplatin (50 microM) treatment (which also causes DNA damage), HIV-LTR induction
      was additive relative to either treatment alone. Methotrexate, which depletes the
      medium of tetrahydrofolate and does not induce DNA damage, induced HIV-LTR at
      later (6-7 days) time points than cisplatin or UV treatments. When methotrexate
      (128 microM) and UV (10 Jm-2) treatments were combined, the agents were
      synergistic with regard to HIV induction. For both drugs, though, induction was
      not due to generalized transcriptional activation since both cisplatin and
      methotrexate induced a repression of total transcription as measured in nuclear
      run-on assays.

PMID- 8642843
TI  - Doppa induces cell death but not differentiation of U937 cells: evidence for the
      involvement of PKC-beta 1 in the regulation of apoptosis.
AB  - Recent reports have claimed that activation of protein kinase C (PKC)-beta is
      sufficient for both differentiation and apoptosis in promyeloid HL60 cells.
      Phorbol esters which differentially activate PKC isoenzymes in vitro were used to
      induce differentiation and apoptosis in U937 cells; TPA and Dopp activate all
      U937 PKC isoenzymes, except PKC-zeta and Doppa activate only PKC-beta l. At
      concentrations of Doppa below 50 nM, only PKC-beta l was activated by 2 min and
      apoptosis was induced, but there was no differentiation of cells towards
      monocytes. TPA (1-25 nM) and Dopp (5-100 nM) activated PKC-alpha, -beta l and
      gamma within 2 min and induced differentiation, but only increased apoptosis at
      the highest concentrations used. Thus, initial activation of PKC-beta l is
      insufficient for differentiation of U937 cells, but may lead to the induction of
      apoptosis.

PMID- 8642844
TI  - Clinical significance of LEA-1 expression in adult acute myeloid leukemia.
AB  - In this study, we examined expressions of several adhesion molecules (AdMs), i.e.
      leukocyte function antigen-1 (LFA-1: CD11a/CD18), Hermes homing receptor (CD44)
      and intercellular adhesion molecule-1 (ICAM-1: CD54), on leukemia cells from 51
      adult patients with newly diagnosed acute myeloid leukemias (AMLs) to elucidate
      clinical significance of these AdM expressions. Those expressions in lymphoid
      malignancies have been correlated with tumor evolutions, but CD44 was detected in
      all the AML cases examined and CD54 expression did not associate with their
      clinical characteristics or outcomes. However, we found that LFA-1 expressions
      significantly correlated with splenomegaly, resistance to induction
      chemotherapies and short survival periods in AML patients.

PMID- 8642845
TI  - Detection of in vivo differentiation of murine WEHI-3B D+ leukemia cells
      transfected with the lac-Z marker gene using two-color flow cytometry.
AB  - The in vivo induction of the differentiation of murine WEHI-3B D+ myelomonocytic
      leukemia cells was measured by flow cytometry, simultaneously staining leukemia
      cells for the marker exogenous beta-galactosidase and for differentiation by the
      antigen Mac-1 (CD11b/CD18). The WEHI-3B D+ leukemia cells were transfected with
      the E. coli lac-Z gene by electroporation and subclones that constitutively
      expressed high levels of the lac-Z gene product beta-galactosidase were
      established. Flow cytometric analyses of cells in the peritoneal cavities of mice
      bearing leukemia cells showed that cells continued to express beta-galactosidase
      for at least 14 days, and they were distinguishable from host-derived cells in
      vivo by their expression of the transfected gene. Simultaneous determination of
      the beta-galactosidase activity and Mac-1 content of cells in the peritoneal
      cavities of mice revealed that administration of recombinant human granulocyte
      colony-stimulating factor (rhG-CSF) to the mice enhanced the expression of Mac-1
      antigen by beta-galactosidase-positive cells. The results demonstrate that G-CSF
      may have clinical potential as a therapeutic differentiating agent, and that flow
      cytometric analysis provides a useful in vivo system to evaluate the therapeutic
      potential of agents capable of inducing terminal differentiation.

PMID- 8642846
TI  - Dibutyl phthalate purged autologous bone marrow transplant in the treatment of
      leukemia.
AB  - It has been proved that di-N-butyl phthalate (DBP) is singular in killing
      leukemic cells selectively or accelerating the deterioration of residual leukemic
      cells in long-term marrow culture in vitro. Based on this principle, the DBP
      purged autologous bone marrow transplant has been applied to the treatment of a
      group of 14 patients suffering from acute nonlymphocytic leukemia. After 5-10
      days of in vitro co-culture of marrow cells with DBP at a concentration of 50
      micrograms/ml, the recovery of total nucleated cells and the amount of CFU-GM
      were 67.5% and 68.1%, respectively. In all patients, the reconstitution of
      hematopoiesis was observed after pre-conditioning and transfusion of purged
      marrow cells. Among these, two patients had a relapse, two patients died from
      complications of transplant, one patient died from non-leukemic disease, and the
      others are all alive and free of disease; the mean survival time as calculated
      recently was 15 months. These preliminary clinical data support that marrow
      culture in the presence of DBP is a safe and effective measure for treating
      leukemia in purged autologous bone marrow transplant.

PMID- 8642847
TI  - Characterization of acute lymphoblastic leukemia subtypes in Brazilian patients.
AB  - The distribution of the acute lymphoblastic leukemia (ALL) subsets in 225
      consecutive Brazilian patients was determined by an immunophenotypic study with
      an extensive panel of monoclonal antibodies. All subsets were detected and their
      relative frequencies were similar to those described in developed countries,
      except for the B-mature subset which had a higher frequency, especially in
      adults. Associated myeloid markers were expressed by 11% of the ALL and CD10 by
      15.9% of T-ALL cases. Besides, the incidence rates determined for the region of
      Ribeirao Preto showed that the overall incidence of ALL was 12.5 cases/10(6)
      people years (PY) (5 cases/10(6) PY in non-Whites versus 14 cases/10(6) PY in
      Whites); the incidence of childhood ALL was 25.5 cases/10(6) PY (8.1 versus 29.8
      cases/10(6) PY in non-Whites and Whites, respectively) and the incidence of ALL
      in adults was 6.2 cases/10(6) PY (5.5 versus 6.1 cases/10(6) Py in non-Whites and
      Whites, respectively). The significantly lower incidence rate of ALL in non-White
      children was associated with a selective deficit of the common subtype and a lack
      of the typical age peak of incidence in this group. The ALL features demonstrated
      here in Brazilian non-White children resemble those described in the American non
      Whites before the seventies and those in British and American Whites at the
      beginning of the century.

PMID- 8642849
TI  - Molecular vaccines in infection and cancer.

PMID- 8642848
TI  - Expression of CD26/dipeptidyl peptidase IV in adult T cell leukemia/lymphoma
      (ATLL).
AB  - The association of CD26/dipeptidyl peptidase IV (DPPIV) and human T lymphotropic
      virus type I (HTLV-I) was studied by two approaches. First, we examined the
      expression of CD26 in peripheral blood mononuclear cells (PBMC) from the patients
      with adult T cell leukemia/lymphoma (ATLL), an HTLV-I-related malignancy. The
      expression of CD26 on the surface of PBMC was decreased in all 20 patients with
      ATLL compared with those from normal individuals (P < 0.01) and the expression of
      the CD26 gene transcript was not detectable in seven out of eight patients with
      ATLL. Then we compared the quantity of viral DNA in CD26-negative (CD26-) and
      CD26-positive (CD26+) cells obtained from 17 HTLV-I healthy carries by using a
      polymerase chain reaction method. The CD26-cells had a higher copy number of
      viral DNA than CD26+ cells. These findings indicate that HTLV-I has in vivo
      tropism to CD26- cells, suggesting that some phenotypes of ATLL cells reflect the
      in vivo cellular tropism of HTLV-I.

PMID- 8642850
TI  - Younger age observation in myelodysplastic syndrome.

PMID- 8642851
TI  - Autografting in chronic myeloid leukemia: an overview.
AB  - Autografting could become a promising treatment for patients with chronic myeloid
      leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or
      failed to respond to recombinant alpha-interferon (IFN). In this review, we
      analyze the results which have been published for patients transplanted in
      chronic phase and which suggest that autografting could prolong survival, at
      least in some patients. We also discuss the different methods of purging whose
      clinical efficacy remains to be assessed.

PMID- 8642852
TI  - A prospective randomized trial of idarubicin vs daunorubicin in combination
      chemotherapy for acute myelogenous leukemia of the age group 55 to 75.
AB  - A prospective randomized study was conducted comparing the efficacy and toxicity
      of two anthracyclines for the treatment of patients with acute myeloid leukemia
      (AML) between 55 and 75 years. A total of 220 patients were randomized to receive
      as induction chemotherapy cytosine arabinoside (Ara-C: 100 mg/m2/day; continuous
      infusion for 7 days) combined with either daunorubicin (DNR: 50 mg/m2/day, i.v.
      bolus for 3 days) (n=108) or idarubicin (IDA: 8 mg/m2/day, i.v. bolus for 5 days)
      (n=112). The complete remission (CR) rate was similar (P=0.296) after IDA
      (76/112; 68%) and DNR (66/108; 61%) (P=0.3). For patients aged 55-65, the CR rate
      was significantly higher after IDA (39/47; 83%) than after DNR (29/50; 58%)
      (P=0.007). Persistent leukemia was more frequent after DNR (26/108) than after
      IDA (13/112; P=0.015). Hematological and extra-hematological toxicities were
      similar. The CR patients were given a consolidation course of chemotherapy with
      Ara-C: 50 mg/m2/12 h, subcutaneously for 5 days, combined with either DNR:30 mg
      m2/day, i.v. bolus for 3 days or IDA:8 mg/m2/day i.v. bolus for 3 days according
      to the initial randomization, and then received a continuous maintenance
      treatment for 2 years. The survival and disease-free survival (DFS) were similar
      in both groups; there was no difference in the risk of relapse. However, there
      was a trend for a longer event-free survival (EFS) in the IDA group than for the
      DNR patients (P=0.07). Our results seem to indicate that IDA is probably more
      efficient than DNR for AML patients between 55 and 75 years, and confirm the data
      published in other studies comparing prospectively IDA and DNR in adults.

PMID- 8642853
TI  - Evaluation of CI-973, a platinum analogue, in refractory or relapsed acute
      leukemia.
AB  - The purpose of the study was to define the maximally tolerated dose (MTD), major
      toxicities, and possible antitumor activity of CI-973 a new platinum analogue, in
      patients with refractory or relapsed acute leukemia. CI-973 was given as a 5-day
      continuous infusion every 3 to 4 weeks to patients with refractory or relapsed
      acute leukemia, at doses ranging from 150 mg/m2 to 1350 mg/m2 per course. Thirty
      six patients were treated including 18 patients with acute myelogenous leukemia
      (AML), four with acute lymphocytic leukemia (ALL) and 14 with chronic myelogenous
      leukemia in blastic phase (CML-BP). Severe gastrointestinal and renal side
      effects were the dose-limiting toxicities occurring in four of five patients
      treated with CI-973 1200 to 1350 mg/m2 per course. At the MTD of 1000 mg/m2 per
      course, three of 13 patients treated (23%) had moderate to severe nausea and
      vomiting, three (23%) had moderate diarrhea and one had moderate mucositis. Among
      21 patients treated at > or = 1000 mg/m2 (15 AML, 6 CML-BP) no objective complete
      or partial responses were observed. Twelve of 18 patients (66%) with evaluable
      marrows on day 14 showed significant suppression of marrow blasts percentage and
      marrow leukemic infiltrate percentage. Tests for measurement of DNA adduct
      formation in leukemic cells in vivo after CI-973 therapy, and in vitro following
      exposure of leukemic cells to CI-973 were developed. This study defined the MTD
      of CI-973 to be 1000 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks
      in patients with refractory or relapsed acute leukemia. Gastrointestinal and
      renal side-effects were dose-limiting. No objective responses were noted in this
      heavily resistant population. Correlations between CI-973-induced DNA adduct
      formation and individual patient response to CI-973 will help to define its role
      in leukemia subsets.

PMID- 8642854
TI  - Autologous bone marrow transplantation in late first complete remission improves
      outcome in acute myelogenous leukemia.
AB  - We evaluated the role of ABMT in late 1st CR AML adult patients using busulfan
      plus cyclophosphamide as preparative regimen. Fifty-one adult patients (mean age
      36 years, range 15-59) with AML underwent ABMT in 1st CR. Three of them had a
      prior diagnosis of myelodysplastic syndrome; one patient had a secondary
      leukemia. The median interval between CR and ABMT was 8 months (range 4-20).
      Patients received busulfan, 4 mg/kg/day for 4 days plus cyclophosphamide 50
      mg/kg/day for 4 days or 60 mg/kg/day for 2 days. No maintenance chemotherapy was
      administered after ABMT. Median days to reach 0.5 x 10(9)/I PMN and 20 x 10(9)/I
      platelets were 26 (range 12-250) and 74 (range 16-740), respectively. No
      transplant-related deaths were observed. Five-year actuarial overall survival
      rate is 76.9%; actuarial leukemia-free survival rate is 70.6%. Mean follow-up
      from ABMT is 35 months. Leukemia-free survival of this group was compared with
      that of 38 non-transplanted patients younger than 60 years, who maintained a CR
      longer than 8 months in the same period. This analysis shows a statistically
      significant difference in favor of ABMT patients. These results suggest that,
      even if performed late after 1st CR as post-remission intensification, ABMT can
      improve the outcome of AML patients.

PMID- 8642855
TI  - Post-transcriptional regulation of bcl-2 in acute myeloblastic leukemia:
      significance for response to chemotherapy.
AB  - The blast stem cells of acute myeloblastic leukemia become more sensitive in
      culture to the chemotherapeutic agents cytosine arabinoside (Ara-C) and
      daunorubicin (DNR) when exposed to all-trans retinoic acid (ATRA) after drug. We
      have proposed that down regulation of bcl-2 by ATRA is part of the mechanism of
      sensitization. The hypothesis is based on reduced expression of bcl-2 mRNA, as
      seen in Northern blots, after ATRA. Nuclear run on experiments, however, failed
      to account completely for the effect at the transcriptional level. Accordingly,
      we looked for post-transcriptional effects of ATRA on bcl-2, using metabolic
      labelling of the protein to measure stability. We found that the half-life of bcl
      2 protein is markedly shortened after treatment with ATRA. Hydrocortisone (HC)
      protects cells against the toxic effects of Ara-C or DNR when given before drug.
      HC does not alter bcl-2 expression at the level of mRNA; however, metabolic
      labelling shows that newly synthesized bcl-2 protein is stabilized in blast cells
      treated with HC. Response to Ara-C by growth factor responsive blast cells is
      influenced by the factor in the cultures; cells are more sensitive in cultures
      with G-CSF and less sensitive when GM-CSF is present. We compared two blast cell
      lines, OCI/AML-5, primarily responsive to GM-CSF, and OCI/AML-10, primarily
      responsive to G-CSF. Growth factor did not influence the stability of bcl-2
      protein in either line. In contrast, Western blots showed that the amount of bcl
      2 protein was greater in cultures with GM-CSF or GM-CSF in combination with G-CSF
      than in cultures with G-CSF or no added factor. This pattern was seen regardless
      of the mitogenic response to G-CSF or GM-CSF. We interpret our findings as
      indicating that bcl-2 protein is transcriptionally activated; that the stability
      of the protein is decreased after ATRA and increased after HC; that the amount of
      bcl-2 protein is greater in cultures with GM-CSF than in cultures with G-CSF,
      regardless of which factor gives the greater mitogenic response. We propose that
      these post-transcriptional modifications of transcriptionally activated bcl-2
      account, in part, for the regulation of drug sensitivity by ATRA, HC and growth
      factors.

PMID- 8642857
TI  - Expression of PKC isozyme and MDR-associated genes in primary and relapsed state
      AML.
AB  - For investigation of relative differences in mRNA expression levels and of
      correlations in the expression of genes possibly involved in multidrug resistance
      (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain
      reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P
      glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II
      alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi,
      protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and
      cyclin A. In a first descriptive study comprising samples of childhood or adult
      AML we calculated the mean values from primary (n=14) or relapsed (n=23) states
      of the diseases, respectively. We found in the latter significant increases of
      MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression
      levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as
      topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727,
      P<0.0001, n=35). Within the group of relapsed state AML a significant negative
      correlation between the gene expression levels of MDR1 and topoisomerase II alpha
      (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive
      correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC
      theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).

PMID- 8642856
TI  - Daunorubicin-induced internucleosomal DNA fragmentation in acute myeloid cell
      lines.
AB  - The study was designed to evaluate the implication of apoptosis in myeloid
      leukemic cell death induced by daunorubicin (DNR) and to identify the possible
      factors which may influence this process. DNR-induced apoptosis was characterized
      by morphology and DNA fragmentation in six leukemic myeloid cell lines which
      expressed different differentiation phenotypes. In phenotypically mature HL-60
      and U937 cells, DNR induced typical apoptosis with characteristic morphological
      changes and intense internucleosomal DNA fragmentation within a narrow
      concentration range (0.5-2 microM). When these cells were treated with higher
      doses of DNR, large DNA fragments (100 kbp), but not internucleosomal fragments,
      were identified. DNR-induced DNA fragmentation in HL-60 and U937 was inhibited by
      antioxidants such as N-acetylcysteine (N-ac) or pyrrolidine-dithiocarbamate
      (PDTC). In the phenotypically immature KG1a, KG1, HEL and ML1 cell lines DNR
      induced no characteristic apoptotic morphological features as well as very low
      levels of internucleosomal DNA fragmentation, whereas large DNA fragments (200
      kbp) were observed in KG1a treated with 7 microM DNR. Since the latter expressed
      P-glycoprotein (P-gp), the role of P-gp in the lack of apoptotic response to DNR
      was investigated. One P-gp inhibitor (verapamil) slightly improved DNR-induced
      DNA fragmentation in KG1a cells whereas the combination of verapamil and
      buthionine-sulfoximine (BSO), which depletes glutathion store, further increased
      internucleosomal DNA fragmentation. In conclusion, DNR induced internucleosomal
      DNA fragmentation in some but not all AML cells; the magnitude of this process
      being influenced by both intracellular drug concentration and oxidative balance.

PMID- 8642858
TI  - Expression of BCL-2 proto-oncogene in adult acute lymphoblastic leukemia.
AB  - The products of the BCL-2 gene prolong survival of lymphohematopoietic cells by
      inhibition of programmed cell death. We studied bcl-2 protein expression in a
      series of 43 adult acute lymphoblastic leukemia (ALL) at diagnosis, using a
      specific monoclonal antibody and flow cytometry. All samples expressed bcl-2 with
      a mean percentage of positive cells of 77.9. The level of bcl-2 in positive cells
      expressed as mean equivalent of soluble fluorescence (MESF) was highly variable
      ranging from 5 x 10(3) to 552 x 10(3) (mean +/- s.d.: 96.5 +/- 109 x 10(3)).
      Neither the percentage of positive cells nor bcl-2 MESF levels were correlated
      with initial characteristics including blood counts, immunological phenotype, or
      cytogenetics. The survival of leukemic cells maintained in cytokine-free liquid
      culture was not correlated with bcl-2 expression. However, cells from ALL with
      higher white blood cell (WBC) counts, with t(9;22) translocation, or expressing
      myeloid surface antigens exhibited significantly longer survival in this culture
      system. The outcome after intensive chemotherapy did not differ according to bcl
      2 expression. Factors associated with poor outcome included WBC counts, presence
      of t(9;22) translocation, presence of myeloid antigens and prolonged survival of
      cultured cells. These results indicate that high levels of bcl-2 are not
      associated with distinct clinical or biological characteristics in ALL.

PMID- 8642859
TI  - Mutations in the gene for human dihydrofolate reductase: an unlikely cause of
      clinical relapse in pediatric leukemia after therapy with methotrexate.
AB  - Resistance to methotrexate (MTX) in some sublines of mammalian cells is reported
      to be due to one of the following amino acid substitutions in dihydrofolate
      reductase (DHFR) that lower inhibition by MTX: Gly15 to Trp, Leu22 to Arg or Phe
      or Phe31 to Trp or Ser. We have produced variants of human DHFR (hDHFR) with
      these substitutions by directed mutagenesis. Recombinant hDHFR variants expressed
      in Escherichia coli have greatly decreased inhibition by MTX, but decreased
      catalytic efficiency, and in one case decreased stability. When a retroviral
      vector encoding wild-type (wt) hDHFR or one of these variants was introduced into
      murine fibroblasts or bone marrow progenitors, modest protection from MTX was
      conferred, even by wt. Relapsed pediatric patients with acute lymphoblastic
      leukemia who have received multiple courses of high-dose MTX seem most likely to
      develop such MTX resistance. cDNA was reverse transcribed from blast mRNA from 17
      of these patients. However, upon amplification and sequencing of DHFR cDNA, no
      resistance mutation was found. The explanation for this probably lies in the need
      for considerable gene amplification to offset lowered catalytic efficiency, and
      the need for two-base changes for most substitutions, both of which are probably
      infrequent events.

PMID- 8642860
TI  - Resistance to apoptotic cell death in a drug resistant T cell leukaemia cell
      line.
AB  - In this study, we investigated the responses of the T cell leukaemia cell line,
      CCRF-CEM, and a vincristine-resistant subline, CEM/VCR R, to the induction of
      cell death by serum withdrawal. This treatment was used to overcome any
      contribution of P-glycoprotein-mediated drug resistance to the responses of the
      CEM/VCR R cells. Following serum withdrawal both cell lines exhibited typical
      apoptotic responses including morphological changes and nucleosomal cleavage of
      the DNA. However, using several different assays for cell death the CEM/VCR R
      cell line was shown to undergo apoptosis at a slower rate than the parental CCRF
      CEM cell line. Expression of c-Myc, Bcl-2 and p53 was found to be similar in both
      cell lines, discounting involvement of these proteins in the observed difference
      in apoptotic response. Given our previous finding that reorganisation of tubulin
      is involved in apoptosis, we examined the expression of alpha-, beta- and
      acetylated alpha-tubulin in the parental and resistant lines. The CEM/VCR R cell
      line had altered tubulin expression when compared to that of the CCRF/CEM line.
      Transnuclear microtubule networks were observed in log phase CEM/VCR R cells. In
      addition, increased expression of the acetylated form of the alpha-tubulin
      isotype suggested that a more stable microtubule network was present in the
      CEM/VCR R cells. These findings imply that the drug-resistance phenotype in the
      CEM/VCR R cells may involve the suppression of apoptosis, and that the
      development of an altered microtubule network may contribute to this suppression.

PMID- 8642861
TI  - Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the
      induction of apoptosis and clinical outcome.
AB  - Transcriptional deregulation of the Bcl-2 gene has been demonstrated to extend
      cell viability via an inhibition of apoptotic cell death. Chronic lymphocytic
      leukemia (CLL) cells are inherently susceptible to apoptosis during short-term
      culture. Because increased expression of the Bcl-2 gene has been reported in CLL,
      we sought to correlate Bcl-2 protein expression with the in vitro propensity
      towards apoptosis and also clinical outcome. Immunoblot analysis of Bcl-2 protein
      revealed interpatient variability with nine of 42 (21%) cases demonstrating
      similar or greater expression than a t(14;18) containing lymphoma cell line and
      18 of 42 (43%) cases demonstrating a level of expression similar to or less than
      that seen in normal peripheral blood lymphocytes. Bcl-2 expression did not
      correlate with clinical features, or with apoptosis, as measured by an in vitro
      DNA fragmentation assay. However, analysis of survival in the 33 untreated
      patients revealed significant differences based on the level of Bcl-2 expression,
      with higher expression being an adverse feature (P<0.02). This data suggests that
      Bcl-2 is important in the pathogenesis and progression of CLL and that
      quantitation of Bcl-2 protein may provide useful prognostic information.

PMID- 8642862
TI  - Protection of human myeloid leukemic cells against doxorubicin-induced apoptosis
      by granulocyte-macrophage colony-stimulating factor and interleukin 3.
AB  - Hematopoietic cells require certain cytokines to maintain viability by preventing
      apoptotic cell death. These cytokines can also protect leukemic cell lines
      against induction of apoptosis by cytotoxic anticancer compounds. We now show
      that the cytokines granulocyte-macrophage colony-stimulating factor and
      interleukin 3 can protect primary human myeloid leukemic cells against
      doxorubicin-induced apoptosis. Protection was detected in cells from 72% of the
      myeloid leukemic patients tested. The results indicate that these, and perhaps
      other, hematopoietic cytokines can decrease the effectiveness of cytotoxic
      anticancer therapy in some human myeloid leukemias. Leukemic cell sensitization
      to cytotoxic therapy may, therefore, require decreasing the availability of
      certain cytokines.

PMID- 8642863
TI  - Erythropoiesis in myelodysplastic syndrome: expression of receptors for
      erythropoietin and kit ligand.
AB  - Ineffective erythropoiesis due to an impaired response to erythropoietin (EPO) is
      a prominent abnormality in myelodysplastic syndromes (MDS). The growth factor kit
      ligand (KL) may restore the in vitro erythroid colony-forming response to EPO in
      a subset of patients. The inability of MDS erythroid progenitors to react
      properly to EPO and/or KL has not been resolved. We have investigated
      erythropoietin receptor (EPO-R) and KL receptor (c-kit) expression in 15 cases of
      MDS by FACS analysis. The percentage of bone marrow cells expressing the EPO-R
      from patients with MDS were comparable to normal marrow. No apparent correlation
      was found between the number of MDS cells coexpressing the EPO-R and CD34 and
      impaired erythroid response. C-kit was expressed in most MDS patients, including
      those not responding to KL in EPO-induced cultures. In nine MDS cases the
      different splice variants of the EPO-R were analyzed. MDS cells, like normal
      marrow, expressed the full length EPO-R. These results show that impaired
      erythroid response in MDS cannot be explained by a quantitative lack of receptors
      for EPO or KL and that most likely suppression of erythroid response is caused by
      defective receptor signalling following ligand binding, representing a functional
      defect within the receptor itself or at a level downstream of the receptor.

PMID- 8642864
TI  - Acute lymphoblastic leukemia following preleukemic syndromes in adults.
AB  - Preleukemic syndromes (PLS) evolve to acute myeloid leukemia (AML) in 15-50% of
      cases, but rarely transform to acute lymphoblastic leukemia (ALL). AML following
      preleukemic syndromes has a poor prognosis, but little is reported about the
      outcome of secondary ALL. From the adult leukemia database at MD Anderson Cancer
      Center, nine patients with ALL following myelodysplastic syndrome (MDS) (n=6),
      smoldering leukemia (n=1), or cytopenias with dysplastic features (n=2) were
      identified. Clinical and laboratory features were abstracted from the database,
      patient charts, review of the bone marrows and special laboratory studies. The
      median interval from diagnosis of PLS to ALL was 6 months. Blasts with lymphoid
      morphology and terminal deoxynucleotidyltransferase (TdT) and periodic acid
      Schiff (PAS) staining were present in eight of nine cases and four of six cases
      respectively. T cell and myeloid markers were expressed in the majority of cases,
      but T cell gene rearrangements were not detected. Only one patient had electron
      microscopic myeloperoxidase-positive staining. Two patients later transformed to
      AML. Patients were predominantly male (89%) with a median age of 69 years. The
      complete remission (CR) rate with ALL-directed chemotherapy (78%) was comparable
      to that of other adult ALL patients (74%) (n=327) without excess
      myelosuppression. Marrow dysplasia persisted in CR in three of seven cases. The
      median remission duration of 16 months (range 4.5 to 51+ months) and the median
      overall survival of 21 months (range 1 to 55+ months) were comparable to that of
      ALL patients overall. ALL following preleukemic syndromes is a distinct syndrome
      with T cell and myeloid markers and responds well to ALL-directed therapy. The
      presence of myeloid and lymphoid markers suggests the transformation of an early
      stem cell.

PMID- 8642865
TI  - Natural killer cell activity and cytokine production as prognostic factors in
      adult acute leukemia.
AB  - We studied the natural killer (NK) cell activity and in vitro production of the
      cytokines which can enhance NK activity (interleukin-1 beta (IL-1 beta),
      interferon gamma (IFN gamma), and interleukin-2 (IL-2)) after stimulation in 44
      patients with acute leukemia (AL) and 14 normal controls. We also studied the
      influence of these parameters on relapse and the relapse-free survival (RFS)
      (after the date of assay) of the AL patients. The NK activity and the production
      of cytokines in the peripheral blood mononuclear cells (PBMNC) from 16 patients
      at the untreated or relapsed stage as well as from 12 patients after
      consolidation were significantly lower than those from controls (both P<0.01),
      and those from the 16 patients at maintenance or off treatment were also
      significantly lower than those from the controls (P<0.01 or P<0.05). RFS after
      the date of assay of the patients in remission with NK activity above the median
      value was significantly longer than that of the patients below the median
      (P<0.05). The production of cytokines in the PBMNC from patients who showed
      continuous complete remission for at least 6 months was higher than that from the
      patients who relapsed early. These findings suggest that impaired NK cell
      function and cytokine production are associated with early relapse of AL
      regardless of remission status.

PMID- 8642866
TI  - Autologous MHC-dependent leukaemia-reactive T lymphocytes in a patient with
      chronic myeloid leukaemia.
AB  - We have investigated the presence of T cells capable of recognizing autologous
      leukaemia cells in a patient with CML. We demonstrated that these cells were
      anergic to the leukaemia cells. They were estimated to be present at a frequency
      of 1:4000 T cells in the peripheral blood. However, following incubation with
      high dose rIL-2, these effector cells were able to proliferate, secrete TH1
      cytokines and lyse target cells upon challenging with fresh autologous leukaemia
      cells. Both CD4 and CD8 T cells were involved in the proliferative responses.
      Moreover, the immune response was blocked by monomorphic anti-HLA antibodies,
      suggesting that the MHC molecules are needed by the T cells for leukaemia
      cell/antigen recognition. This work therefore indicates a potential reservoir of
      effector cells in CML patients which may be exploited for the modulation of
      leukaemia cell growth. It also provides evidence for a distinct T cell population
      capable of mediating GVL responses.

PMID- 8642868
TI  - Zeta chain and CD28 are poorly expressed on T lymphocytes from chronic
      lymphocytic leukemia.
AB  - We have analyzed the expression of the zeta chain of the T cell receptor/CD3
      complex and the co-stimulatory molecule CD28 by dual colour immunofluorescence on
      T lymphocytes from patients with B cell chronic lymphocytic leukemia (CLL). Zeta
      chain was significantly reduced on CD3-positive lymphocytes from 33 patients
      compared with normal controls (P<0.0001). The values were lower in stages B and C
      than in stage A. In five patients tested in partial remission the values were
      normal. CD28, investigated in CD3, CD4 and CD8 positive T cells from 18 CLL
      patients appeared to be reduced in the three subsets but more marked in CD8
      positive lymphocytes. The loss of zeta chain and CD28 in a proportion of
      circulating T lymphocytes from CLL may underlie some of the known functional
      abnormalities of these cells and the immunodeficiency associated with the
      disease.

PMID- 8642867
TI  - Proliferation of B cell malignancies in all stages of differentiation upon
      stimulation in the 'CD40 system'.
AB  - Stimulation of the CD40 antigen on normal B cells by crosslinking of anti-CD40
      mAbs via their Fc receptor using a Fc gamma RII(CD32)-transfected mouse
      fibroblast cell line ('CD40 system') results in activation and proliferation. Not
      only normal B cells, but also malignant B cells fitting in the low-grade
      malignancy category such as chronic lymphocytic leukemia (CLL), hairy cell
      leukemia and follicular lymphoma could be induced to proliferation upon CD40
      stimulation. Here, the 'CD40 system' has also been used to culture intermediate
      and high grade malignancies. Proliferation was measured by 3H-thymidine
      incorporation and cell counting after culture. Time curves showed that at day 7
      most cultures were optimal. By flow cytometry, morphology and assessment of light
      chain restriction the monoclonal nature of the cultured B cells was proven. We
      confirmed that B cell malignancies with a more slowly evolving course, such as
      CLL (n=11), PLL (n=5), and low-grade NHL (immunocytoma and follicular cb/cc n=9),
      could successfully be cultured in the 'CD40 system'. In contrast, four out of
      seven cases of mantle cell lymphoma did not proliferate. Cases of precursor B
      lineage ALL (n=7), high grade NHL (n=3) and multiple myeloma (n=10) showed a
      heterogenous growth pattern. We conclude that the 'CD40 system', although not
      always successful, is a useful tool to culture a whole variety of B cell
      malignancies.

PMID- 8642869
TI  - Direct contact with stroma inhibits proliferation of human long-term culture
      initiating cells.
AB  - Significantly less long-term culture initiating cells (LTC-IC) are recovered from
      cultures in which progenitors are cultured in contact with stroma (stroma
      contact) than when cultured separated from stroma by a transwell (stroma
      noncontact). This suggests that direct contact with stroma inhibits either
      proliferation or survival of LTC-IC. Using the membrane intercallating
      fluorochrome, PKH-26, we demonstrated that significantly less LTC-IC plated for
      14 days in stroma-contact cultures proliferated than in stroma-noncontact
      cultures (16+/-7 vs 50+/-10%). Furthermore, when LTC-IC were sorted singly in
      stroma-contact cultures for 2 weeks, only 25+/-4% of individual LTC-IC progeny
      could initiate two secondary stromal cultures and had therefore proliferated,
      whereas 45+/-6% of single sorted LTC-IC progeny proliferated when cultured in
      stroma-conditioned medium without stromal feeder. However, LTC-IC survival was
      similar in both culture systems. Finally, proliferation inhibition occurred even
      when LTC-IC were cultured in contact with glutaraldehyde-fixed stroma, which is
      no longer capable of producing growth inhibitory or stimulatory cytokines. Thus,
      direct adhesive interactions between LTC-IC and stromal components inhibits their
      proliferation.

PMID- 8642870
TI  - Isolation and characterization of c-fos-expressing murine bone marrow stromal
      cell lines supporting myeloid differentiation.
AB  - We have previously reported that constitutive expression of c-fos oncogene allows
      long-term proliferation of primary mouse bone marrow stromal cells favoring the
      granulocytic differentiation of myeloid precursors in an in vitro assay.
      Retrovirus-mediated gene transfer of the human c-fos gene was used here for
      immortalizing nine mouse bone marrow cell lines which were studied in detail.
      However, due to low expression of the ectopic c-fos gene, none of them showed
      characteristics of transformation as assayed by dependence upon serum for growth,
      the inability to form colonies in agar and contact inhibition. All of them
      displayed a fibroblastoid phenotype, as deduced from morphological observation
      and analysis of several differentiation markers. They mostly supported the
      granulocytic differentiation of bone marrow myeloid precursors in a GM-assay, as
      did c-fos-expressing primary stromal cells. Their potential for supporting
      myeloid progenitor proliferation was however significantly lower than that of the
      whole adherent layer of the Dexter-type long-term bone marrow culture they
      derived from (STNT cells). They showed significant variations with respect to
      their cytokine gene expression analyzed at the RNA level in keeping with the
      notion of stromal cell heterogeneity in the bone marrow. Interestingly, none of
      them secreted GM-CSF, SCF or IL-3, which are cytokines reputed for their ability
      to stimulate hematopoietic progenitors, and strikingly, only two of them were
      able to produce detectable levels of G-CSF in culture supernatants despite the
      propensity of all of them to favor granulocyte differentiation. Finally, in
      coculture assay, bone marrow cells were able to diminish the expression of
      several cytokine genes albeit at a much lower degree than in the original STNT
      cells.

PMID- 8642871
TI  - Effects of irradiation of CBA/CA mice on hematopoietic stem cells and stromal
      cells in long-term bone marrow cultures.
AB  - Following 200 cGy total body irradiation, 20-25% of CBA/Ca mice and their CBA/B
      and CBA/H sublines develop myeloid leukemia. To determine whether hematologic
      changes in vitro were detectable, long-term marrow cultures (LTBMCs) were
      established from the right and left hind limbs of 11 individual control and 11
      CBA/B mice 100-114 days after 200 cGy total body irradiation. Individual cultures
      were studied weekly for cumulative production of nonadherent cells and colony
      forming, hematopoietic progenitor cells. Control cultures produced significantly
      more nonadherent cells over 25 weeks in long-term marrow culture compared to
      those from irradiated (treated) mice. Permanent stromal cell lines were
      established from control and irradiated CBA/B mouse LTBMCs and clonal sublines
      were established. The stromal cell lines from LTBMCs of in vivo irradiated CBA/B
      mice had uniformly lower plating efficiencies, and only one formed a permanent
      clonal subline at 100-fold lower frequency compared to stromal cell lines from
      control mouse LTBMCs. The irradiation sensitivity of both uncloned and clonal
      sublines was similar by single-hit, multi-hit or by linear quadratic formula.
      Cocultivation of an IL-3 dependent hematopoietic progenitor cell line established
      from a control CBA/B, LTBMC with control of irradiated stromal cell lines derived
      from either a control (CC3) or the one successfully cloned in vivo irradiated
      (CT4) LTBMC, produced few cobblestone islands in the presence of IL-3. In
      contrast, formation of cobblestone islands in the presence of L cell-condition
      medium as a source of M-CSF was significantly greater, and these persisted for 21
      days on both CC3 and CT4 stromal lines. The data provide evidence for irradiation
      induced changes in the bone marrow stromal cell compartment of CBA/B mice which
      persist and are detectable in vitro 6 months after explant of the cells to
      culture. These marrow stromal cell lines may provide valuable resources for
      analyzing the molecular biologic changes in the hematopoietic microenvironment
      during irradiation leukemogenesis.

PMID- 8642872
TI  - Oncogenic effects of overexpression of the interleukin-3 receptor on
      hematopoietic cells.
AB  - To elucidate the relationship between malignant transformation and cytokine
      receptor expression, the interleukin-3 receptor (IL-3R) complex was examined in
      an IL-3-dependent parental line and cells transformed by cytokines and oncogenes.
      In IL-3-dependent cells grown in medium containing optimum amounts of IL-3, the
      IL-3R complex was detected at low levels indicating that the receptor was down
      regulated in response to IL-3. However, upon depletion of IL-3, IL-3R levels
      increased documenting that its expression correlated inversely with the
      concentration of IL-3 provided. In contrast, more IL-3 receptors were observed
      constitutively in autocrine-transformed derivative lines, which secreted
      suboptimal amounts of IL-3. To examine the effects of activated oncogenes on IL
      3R expression in autocrine-transformed cells, the cells were infected with
      retroviral vectors containing various oncogenes. Decreased levels of IL-3R
      expression were observed in the oncogene-infected cells. These studies imply that
      important regulatory cross-talk occurs between ligands and their cognate
      receptors in cytokine-dependent hematopoietic cells. Deregulation of this ligand
      receptor interaction in the oncogene-infected cells may be a consequence of the
      cells using modified signal transduction pathways which bypass the IL-3:IL-3R
      interaction. To determine the effects of IL-3 receptor overexpression on the
      cytokine dependency of hematopoietic cells, IL-3R alpha and beta cDNAs were
      inserted into retroviral vectors. Overexpression of either the alpha or beta
      chains did not directly relieve factor dependency, however, constitutive
      expression of the IL-3R alpha allowed the cells to proliferate in suboptimal
      concentrations of IL-3. Moreover, factor-independent transformants were
      subsequently isolated from pools of cells infected with viruses containing either
      the alpha or beta receptor cDNAs at a frequency of approximately 1 in 10(3) to
      10(4) cells whereas such cells were not recovered from control cells.
      Deregulation of IL-3 receptor chain gene expression may provide a proliferative
      advantage to hematopoietic cells growing under conditions in which the cytokine
      is limiting and allow the development of a leukemia.

PMID- 8642873
TI  - A mutant form of p135tyk2, an interferon-alpha inducible tyrosine kinase,
      suppresses the transformed phenotype of Daudi cells.
AB  - The type I interferons induce an anti-viral state and suppress cell growth. The
      p135tyk2 non-receptor tyrosine kinase appears to initiate, at least in part, the
      type I interferon signal transduction pathway, and thereby activates type I
      interferon-dependent gene expression. To determine if p135tyk2 can suppress
      growth and/or tumorigenesis, derivatives of the tyk2 gene were introduced into
      the tumorigenic cell line Daudi. Transfectants expressing a tyk2 construct
      missing the carboxy-terminal 22 amino acids cloned with a greatly reduced
      efficiency in soft agar and displayed a partial decrease in the ability to form
      tumors in athymic mice. In addition, transfectants producing a kinase deficient
      version of tyk2 show an increase in both growth rate and agar cloning efficiency,
      suggesting that the inactive kinase can act in a dominant-negative manner.
      Surprisingly, the carboxyl-terminal deleted protein lacks both auto-kinase
      activity, and activity towards a putative substrate, even though it induces a
      phenotype which is precisely the opposite of that produced by another kinase
      deficient tyk2 mutant containing an altered ATP binding site. Thus, while these
      results add tyk2 to a growing list of interferon-alpha regulated proteins that
      might be able to suppress tumor formation, the biochemical basis of this activity
      remains unknown.

PMID- 8642874
TI  - HTLV-I associated adult T cell leukemia/lymphoma: report of two cases from an
      Amerindian population in coastal northwest British Columbia.
AB  - Epidemiological studies of HTLV-I infection have demonstrated the presence of
      this virus in certain Amerindian populations in Central and South America. We
      have recently reported the first evidence of endemic HTLV-I infection in North
      American Amerindians from the coastal regions of British Columbia, Canada. While
      the predominant HTLV-I-associated disease observed in British Columbia
      Amerindians is the HTLV-I associated neurological disease (HTLV-I-associated
      myelopathy/tropical spastic paraparesis), we report here the first two cases of
      HTLV-I-associated adult T cell leukemia/lymphoma (ATL). Clinical and PCR evidence
      to support the diagnosis of HTLV-I-associated ATL in these two Amerindians is
      presented. Both cases of ATL were found in the same tribe although neither
      patient was directly related to each other. While reports of HTLV-I-associated
      ATL have been reported in Circumartic native peoples, reports of ATL in North
      American single ancestry Amerindians have not been previously made to our
      knowledge.

PMID- 8642875
TI  - Acute lymphoblastic leukemias from relapse engraft more rapidly in SCID mice.
AB  - It is generally believed that relapse of acute leukemia heralds progression of
      the disease into a more aggressive stage. The biological behavior of leukemic
      cells collected from four patients with adult acute lymphoblastic leukemia (ALL)
      prior to treatment and at relapse was studied after engraftment into 28
      unconditioned mice with severe combined immunodeficiency (SCID). Leukemic cells
      engrafted in all but one mouse, with major differences observed in the growth and
      aggressiveness of the leukemias. Recipient mice of cells derived from all
      patients at relapse died more rapidly in overt leukemia than those which were
      injected with cells obtained prior to induction treatment (P=0.0002). SCID mice
      that received cells from one patient at the time of diagnosis also died in
      terminal leukemia. Other SCID mice however, that received cells from the
      remaining three patients prior to treatment developed occult leukemia that was
      detectable in the blood or bone marrow with the use of polymerase chain reaction
      (PCR) or flow cytometry only. Leukemic cells recovered from mice with terminal
      leukemia exhibited a larger proliferating fraction than cells originally injected
      (P=0.004). Our results demonstrate, that during the evolution from initial
      presentation to relapse, ALL cells may acquire biological properties which render
      them more aggressive in SCID mice.

PMID- 8642876
TI  - The effect of IL-1 receptor antagonist on the proliferation of hematopoietic
      progenitor cells in regenerating bone marrow.
AB  - To evaluate the involvement of IL-1 on bone marrow granulocyte-macrophage (CFU
      GM) and erythroid (BFU-E and CFU-E) progenitor cell regeneration during the
      recovery of hematopoiesis after sublethal irradiation of CBA mice, we examined
      the effects of IL-1 receptor blockade by recombinant human IL-1 receptor
      antagonist (rhIL-1ra). The actual number of progenitors and proportion of these
      cells in S phase of the cell cycle were determined in regenerating bone marrow
      cells obtained 3 days after 2 Gy irradiation both following the in vivo
      administration of rhIL-1ra, as well as after the in vitro preincubation with
      increasing amounts of rhIL-1ra. The results revealed that rhIL-1ra decreased the
      number and the proportion of CFU-GM in the S phase in regenerating bone marrow.
      As concerning erythroid progenitors, rhIL-1ra treatment suppressed BFU-E and
      enhanced CFU-E-derived colony growth, indicating that the biological effects of
      IL-1 might be different depending on the stage of differentiation. The observed
      effects pointed to the importance of the basal levels of IL-1, as well as IL-1
      receptor expression during the recovery of hematopoiesis.

PMID- 8642877
TI  - St Jude Children's Research Hospital's International Outreach Program.
AB  - Over 80% of children with cancer live in developing countries, where access to
      medical services is limited to varying degrees. In many of these countries,
      economic conditions and general health care have improved sufficiently to permit
      the development of more sophisticated medical services. The introduction of
      pediatric oncology programs becomes appropriate as deaths from malnutrition and
      infections decrease and cancer emerges as an important cause of childhood
      mortality. In the absence of such services, the worldwide war against pediatric
      cancer will ultimately be lost because of the rapidly growing pediatric
      populations in developing countries that now lack the facilities and expertise to
      treat childhood malignancies. We believe that the development of pediatric cancer
      centers in many of these countries is both appropriate and feasible. Partnerships
      in which established pediatric oncology centers work with the governments and
      private sectors of developing nations to implement key facilities are an
      efficient and cost-effective way to introduce such services. The challenges of
      these outreach efforts are significant -- as are the expected benefits.

PMID- 8642879
TI  - Retinoic acid syndrome: a report of two cases.

PMID- 8642878
TI  - Establishment of a new human pre-B leukemia cell line (CEMO-1) with the
      translocation (1;14)(q21;q32)

PMID- 8642880
TI  - Early Mayo connections with Johns Hopkins.

PMID- 8642881
TI  - Efficacy of nocturnal nasal ventilation in stable, severe chronic obstructive
      pulmonary disease during a 3-month controlled trial.
AB  - OBJECTIVE: To evaluate the efficacy of nocturnal nasal ventilation (NNV) in
      patients with rigidly defined, severe but stable chronic obstructive pulmonary
      disease (COPD) and hypercapnia. DESIGN: By randomization, eligible patients were
      assigned to an active or a sham treatment arm. Data from these two groups were
      analyzed statistically. MATERIAL AND METHODS: Initially, 35 patients with severe
      COPD (forced expiratory volume in 1 second [FEV1] of less than 40% predicted) and
      daytime hypercapnia (arterial carbon dioxide tension [PaCO2] of more than 45 mm
      Hg) were enrolled in a 3-month NNV trial. After a minimal observation period of 6
      weeks, 13 patients were judged to be clinically stable and were randomized to NNV
      (N = 7) or sham (N = 6) treatment, consisting of nightly use of a bilevel
      positive airway pressure (PAP) device set to deliver an inspiratory pressure of
      either 10 or 0 cm of water (H2O). The device was used in the spontaneous or timed
      mode and set to a minimal expiratory pressure of 2 cm H2O. Patients underwent
      extensive physiologic testing including polysomnography and were introduced to
      the bilevel PAP system during a 2.5-day hospital stay. RESULTS: The NNV and sham
      treatment groups were similar in mean age (71.0 versus 66.5 years), PaCO2 (54.7
      versus 48.5 mm Hg), and FEV1 (0.62 versus 0.72 L). Only four of seven patients in
      the NNV group were still using the bilevel PAP device at the completion of the
      trial, as opposed to all six patients in the sham group. Only one patient had a
      substantial reduction in PaCO2 - from 50 mm Hg at baseline to 43 mm Hg after 3
      months of NNV. He declined further NNV treatment with bilevel PAP. Sham treatment
      did not lower PaCO2. Lung function, nocturnal oxygen saturation, and sleep
      efficiency remained unchanged in both groups. CONCLUSION: Disabled but clinically
      stable patients with COPD and hypercapnia do not readily accept and are unlikely
      to benefit from NNV.

PMID- 8642883
TI  - Postsurgical changes of the breast that mimic inflammatory breast carcinoma.
AB  - OBJECTIVE: To characterize a clinical syndrome that occurs in some women who have
      undergone breast or axillary lymph node biopsy or partial mastectomy. MATERIAL
      AND METHODS: Six case reports are presented, the clinical and histopathologic
      findings are described, and the implications for recognition of this entity are
      discussed. RESULTS: Patients who had undergone partial mastectomy, breast biopsy,
      or axillary lymph node excision shortly thereafter had clinical signs (most
      notably, erythema and edema) suggestive of infectious mastitis or inflammatory
      breast cancer. Representative histologic sections of involved skin revealed
      dilated dermal vessels without specific evidence of infection or cancer. Although
      antibiotic therapy was generally ineffective, the clinical findings resolved with
      time (from 2 months to 1 year). This condition should be considered in the
      differential diagnosis when this circumscribed patient population has such
      intervention-related symptoms. CONCLUSION: This clinical syndrome may mimic an
      infectious or neoplastic process, but we hypothesize that it is due to
      interruption of lymphatic vessels. Appropriate recognition may alter the use of
      antibiotic therapy or surgical intervention.

PMID- 8642882
TI  - Frequency and clinical implications of increased pulmonary artery pressures in
      liver transplant patients.
AB  - OBJECTIVE: To characterize the pulmonary hemodynamics and identify predictors of
      pulmonary hypertension in a group of patients before liver transplantation and to
      determine whether pulmonary hypertension in these patients is related to
      survival. MATERIAL AND METHODS: In 362 patients before their first liver
      transplantation (between 1985 and 1993), the clinical history, laboratory data,
      and results of pulmonary function tests were recorded. Pulmonary artery (PA)
      catheterization was performed after induction of anesthesia at the time of
      transplantation. Monthly follow-up was maintained. RESULTS: A hyperdynamic
      circulation was often present -- an increased mean cardiac output (7.6 L/min),
      increased mean PA pressure (20.9 mm Hg), correlation of mean PA pressure with
      cardiac output (r = 0.25; P<0.001), and decreased mean pulmonary vascular
      resistance (60 dynes times s/cm5). Mean PA pressures were more than 25 mm Hg in
      72 patients (20%). Pulmonary hypertension (defined as mean PA pressure of more
      than 25 mm Hg and pulmonary vascular resistance in excess of 120 dynes times
      s/cm5) occurred in 15 patients (4%). Pulmonary function tests revealed
      obstruction in 7%, restriction in 18%, and low diffusing capacity in 46%. By
      univariate analysis, lower forced expiratory volume in 1 second, forced vital
      capacity, and total lung capacity were the only preoperative factors associated
      with pulmonary hypertension (P<0.05). Survival was significantly lower in
      patients with acute fulminant hepatitis (P<0.001), the group with the highest
      mean PA pressure, than in those with other diagnoses. Increased PA pressures or
      mild to moderate pulmonary hypertension was not found to be associated with a
      worse survival by univariate or multivariate analysis. CONCLUSION: Increased PA
      pressure is common in liver transplant patients (20%). "True" pulmonary
      hypertension occurred in only 4% of our patients and was not associated with an
      adverse outcome.

PMID- 8642885
TI  - Trochanteric bursitis (greater trochanter pain syndrome).
AB  - Trochanteric bursitis, a common regional pain syndrome, is characterized by
      chronic, intermittent aching pain over the lateral aspect of the hip. The
      incidence of trochanteric bursitis peaks between the fourth and sixth decades of
      life, but cases have been reported in all age-groups. The diagnosis may be
      elusive, especially if symptoms are atypical. This condition can be associated
      with pain and limitation of function. Treatment includes physical therapy
      measures, analgesics, and local glucocorticoid injection. In this article, we
      review the pathogenesis, common initial symptoms, diagnostic approach, and
      treatment options for trochanteric bursitis.

PMID- 8642884
TI  - Immediate and long-term results of percutaneous Inoue balloon mitral
      commissurotomy with use of a simple height-derived balloon sizing method for the
      stepwise dilation technique.
AB  - OBJECTIVE: To assess the short- and long-term efficacy of Inoue balloon
      percutaneous transvenous mitral commissurotomy (PTMC) with use of our simple
      balloon sizing method based on patient height. DESIGN: Data from 105 consecutive
      patients with symptomatic mitral stenosis who underwent 107 PTMC procedures
      between October 1991 and April 1995 at our hospital were analyzed. RESULTS: All
      PTMC procedures were successfully completed with no instances of cardiac
      perforation, systemic embolism, severe mitral regurgitation (grade 3 or more
      angiographically), or death. The mean mitral valve area increased from 0.8 +/-
      0.2 cm2 to 1.7 +/- 0.4 cm2 (P = 0.0001), as assessed echocardiographically.
      Optimal results -- defined as an improvement in valve area of 50% or more or a
      final valve area of 1.5 cm2 or more without significant mitral regurgitation (an
      increase in mitral regurgitation of two or more grades or a final regurgitation
      of grade 3 or more) -- were obtained in 96% of patients. At a mean follow-up
      interval of 20 months, symptomatic benefit was maintained in 97% of patients.
      Echocardiographic evidence of restenosis (loss of more than 50% initial gain in
      valve area, a valve area of less than 1.5 cm2, or both) was noted in 9.8%.
      CONCLUSION: Inoue balloon PTMC with use of our simple balloon sizing method
      yielded excellent short- and long-term results in terms of mitral valve
      enlargement and sustained symptomatic benefit without the creation of severe
      mitral regurgitation.

PMID- 8642886
TI  - Causes of epilepsy: contributions of the Rochester epidemiology project.
AB  - The contributions of the Rochester (Minnesota) Epidemiology Project and Mayo
      Clinic studies in the evaluation of the causes of epilepsy are summarized. The
      development of the unique population-based medical records-linkage resource is
      chronicled, and the measures of occurrence and association used in epidemiologic
      study designs to assess the causes of epilepsy are presented. The historical
      cohort design is optimal for the study of the relationship between common central
      nervous system insults and seizures, and case-control studies are best used for
      analysis of relatively rare seizure disorders. The major findings about the
      etiologic roles of traumatic brain injuries, central nervous system infections,
      cerebrovascular disease, brain tumors, neurodegenerative diseases, developmental
      disabilities, perinatal insults, and familial factors are discussed. The role of
      genetic factors in epilepsy has been controversial, perhaps because of the
      numerous causes of seizures and their episodic nature. Both potential
      environmental and genetic causes will continue to be assessed.

PMID- 8642887
TI  - Descriptive epidemiology of epilepsy: contributions of population-based studies
      from Rochester, Minnesota.
AB  - Studies based on the Rochester Epidemiology Project medical records-linkage
      system have provided important insights into the epidemiology of epilepsy. The
      incidence of all convulsive disorders in Rochester, Minnesota, during a 50-year
      period exceeded 130 per 100,000 person-years. The age-adjusted incidence of
      epilepsy was 44 per 100,000 person-years; of a first unprovoked seizure, 61; and
      of acute symptomatic seizures excluding febrile convulsions, 31. In addition, 2%
      of the population experienced a febrile convulsion before the age of 5 years. The
      cumulative incidence of epilepsy through age 74 years was 3.0%, of all unprovoked
      seizures was 4.1%, and of any convulsive disorder approached 10%. For epilepsy,
      single unprovoked seizures, and acute symptomatic seizures, the incidence was
      significantly higher in males than in females, and it was high in the first year
      of life but highest in those age 75 years or older. For epilepsy alone,
      approximately 60% of incidence cases experienced partial seizures, and two-thirds
      had no clearly identified antecedent. Cerebrovascular disease was the most
      commonly identified antecedent of epilepsy, accounting for 11% of cases. Over
      time, the incidence of epilepsy and of unprovoked seizures decreased in children
      and increased in the elderly population. The age-adjusted prevalence of active
      epilepsy on Jan. 1, 1980, was 6.8 per 1,000 residents. Prevalence was low in the
      first decade of life, increased to a plateau in the adult years, and further
      increased in the elderly population. Almost 1.5% of the population older than 75
      years of age had active epilepsy. About 25% of prevalence cases had an identified
      cause; 60% experienced partial epilepsy.

PMID- 8642888
TI  - Nutrition support in hospitalized patients with diabetes mellitus.
AB  - Many physicians will manage the care of hospitalized patients with diabetes
      mellitus who require parenteral nutrition or enteral tube feeding. The
      nutritional assessment, indications for nutrition support, estimate of
      nutritional needs, and biochemical monitoring guidelines for critically ill
      patients with diabetes are similar to those for nondiabetic patients. In general,
      a weight loss of up to 10% of body weight is well tolerated and, in the absence
      of severe stress, the provision of dextrose-containing crystalloid solutions and
      electrolytes is adequate for as long as 7 to 10 days. Studies that demonstrate a
      beneficial influence of nutrition support on clinical outcome administered
      nutrition for a minimum of 1 week. No data have established that support for a
      briefer duration is of clinical benefit. An important goal in the care of the
      hospitalized patient with diabetes is to avoid the extremes of hypoglycemia and
      hyperglycemia. Herein we provide our approach to achieving glucose control in
      stressed hospitalized patients with diabetes mellitus who are receiving
      parenteral and enteral nutrition. Although evidence is increasing that
      hyperglycemia impairs immune function, well-designed prospective randomized
      trials are needed to determine the risks, costs, and benefits of achieving
      glucose control and of providing nutrition support to hospitalized patients with
      diabetes mellitus.

PMID- 8642889
TI  - Endobronchial thrombolysis with streptokinase for airway obstruction due to blood
      clots.
AB  - To our knowledge, only four reports have previously described endobronchial
      thrombolysis with streptokinase for airway obstruction due to blood clots; the
      highest dose used was 80,000 U. Herein we describe a 21-year-old woman with
      pulmonary embolism who experienced life-threatening airway obstruction due to a
      large blood clot in the distal trachea. Streptokinase (120,000 U), injected
      through a fiberoptic bronchoscope, partially dissolved the clot. The rest of the
      clot was removed easily with forceps and suctioning. No complications occurred.

PMID- 8642890
TI  - Hans von Euler-Chelpin--Noble laureate.

PMID- 8642891
TI  - Role of plasmapheresis in thrombocytopenic purpura associated with Waldenstrom's
      macroglobulinemia.
AB  - A 67-year-old man with Waldenstrom's macroglobulinemia had a relapse of chronic
      idiopathic thrombocytopenic purpura (ITP), which had been refractory to
      corticosteroids, splenectomy, vinca alkaloids, and high-dose intravenous gamma
      globulin therapy. A biclonal gammopathy (IgM kappa and IgG lambda) was detected
      in his serum and was likely responsible for his refractory thrombocytopenia. He
      was treated with chlorambucil and prednisone. Plasmapheresis was effective in
      temporarily maintaining platelet counts and in decreasing morbidity until
      immunosuppression was completely effective against the production of the
      monoclonal protein. The previously reported experiences with use of
      plasmapheresis in patients with chronic ITP are discussed. Plasmapheresis may be
      of value in the treatment of selected patients with severe ITP and monoclonal
      gammopathy.

PMID- 8642892
TI  - 70-year-old man with abdominal pain amd weight loss.

PMID- 8642894
TI  - Nonulcer dyspepsia: a look into the future.

PMID- 8642893
TI  - Thrombolytic therapy for obstruction of mechanical prosthetic valves.
AB  - This report describes two patients who were treated for obstruction of St. Jude
      tricuspid valve prostheses. In the patient with the hypereosinophilic syndrome,
      right heart failure developed 15 days after valve replacement. The other patient
      had symptoms of right heart failure for 8 weeks; these occurred 15 months after
      valve implantation. In both patients, thrombolytic therapy was successful and
      without major sequelae. Herein we review the literature on the use of
      thrombolysis for obstructed mechanical prosthetic valves and completely summarize
      the English literature; the efficacy of thrombolysis for obstructed prosthetic
      valves and the associated morbidity and mortality are emphasized. Recommendations
      for thrombolysis in clinical practice are provided.

PMID- 8642895
TI  - Absorption of nitroglycerin and isosorbide dinitrate by infusion tubing.

PMID- 8642897
TI  - Altered endothelium-mediated relaxation by sympathectomy in isolated rabbit
      carotid artery rings.
AB  - The influence of cervical and periarterial sympathectomy on endothelium-dependent
      and endothelium-independent relaxations of the mature rabbit carotid artery was
      studied in vitro. The responses to adenosine, vasoactive intestinal polypeptide
      and substance P in sympathectomized and control rabbit carotid artery rings were
      recorded and analyzed. The effects of endothelium removal were also investigated.
      The maximal relaxation achieved by substance P, which produces endothelium
      dependent relaxation, was significantly inhibited in 3 weeks in postsympathectomy
      arterial preparations as compared to controls. Adenosine and vasoactive
      intestinal polypeptide, which produce endothelium-independent relaxation,
      elicited similar relaxation in all tissues. These results demonstrated that the
      response to substance P was impaired by cervical and periarterial sympathectomy.
      The decreased maximum response to substance P may be the result of a decreased NK
      1 receptor subtype density or excitation/response coupling, or it may be due to
      an impaired production and/or liberation of endothelium-derived relaxing factor
      (EDRF).

PMID- 8642896
TI  - Comparative studies of Ca N-acetylhomotaurinate and Ca N-acetyltaurinate. II.
      Preventive and opposing actions of the acute ethanol depletive effect on the
      ionic transfer through the isolated human amnion.
AB  - Ethanol reduces the ionic paraplacental transfer through the human amnion. This
      effect is exerted on the cationic paracellular pathway, the coupling between two
      adjacent epithelial cells, the monovalent cation pump and the antiport system. In
      this study, the preventive and opposing actions of two taurine and homotaurine
      derivatives (Ca N-acetyltaurinate: ATACa, Ca N-acetylhomotaurinate: AOTACa) were
      observed. One the maternal side, ATACa and AOTACa demonstrated protective actions
      on cationic paracellular pathways and on the Na/K-ATPase pump with AOTACa only.
      On the fetal side, the effect of ATACa was limited to the sodium paracellular
      pathway. This effect was total at 5 mM. On the maternal side, ATACa and AOTACa
      exhibited an opposing action on the same components of the conductance. But on
      the fetal side, ATACa increased the ethanol effect and AOTACa exerted an
      antagonistic effect on the cation pump only. These results indicate that two
      closely related molecules may have different effects on a membranous ethanol
      model.

PMID- 8642898
TI  - Antiulcer activity of pentacaine and some of its derivatives: effect on
      experimentally induced gastric and duodenal lesions and on gastric acid secretion
      in rats.
AB  - The antiulcer, gastroprotective, and antisecretory effects of selected
      carbanilates were tested in rats. The compounds K-1905 and K-2002 were found to
      have beneficial effects similar to those of pentacaine in phenylbutazone- and
      ethanol-induced gastric injury and in cysteamine-induced duodenal lesions; their
      antisecretory activity was also comparable to pentacaine in pylorus-ligated rats.
      Compounds P2 and P3 were generally less effective than pentacaine, and compound
      P1 was gastrotoxic. Thus pentyloxy-substitution on the benzene ring of the parent
      structure (K-1905 and K-2002) is more suitable for antiulcer and gastroprotective
      activity than methoxy-substitution on the meta-position (P3) or alkyloxy
      substitution on the para-position (P2, P1). The results indicate that the two
      carbanilates K-1905 and K-2002 can be considered prospective antiulcer drugs.

PMID- 8642899
TI  - Antiperoxidative effects of platelet activating factor antagonists against iron
      dependent lipid peroxidation in murine ventricular membranes.
AB  - Platelet activating factor (PAF) antagonists have been recently documented to
      possess beneficial effects on ischemia and ischemia-reperfusion-induced
      myocardial injury. Moreover, their ameliorative effect has been ascribed to their
      capacity to scavenge or impair oxygen free radical generation. In the present
      study, the effect of PAF antagonists BN 52021, BN 52030 and BN 52039 on iron
      initiated lipid peroxidation (LPO) was investigated in murine ventricular
      membranes and compared with a potent antioxidant, U-74500A ( a lazaroid). Fe2+ 
      Vitamin C induced a concentration and time-dependent LPO, measured as
      thiobarbituric acid reactive substances (TBARS) by standard malondialdehyde (MDA)
      curve. PAF antagonists were pretreated to ventricular membranes in 5 microM and
      higher concentrations. All three agents inhibited Fe2+ -Vitamin C-initiated LPO
      in a concentration-dependent manner with an IC50 value ranging from 103.7 to
      373.5 microM; however, they were less potent than U-74500A (IC50 6.8 microM).
      Inhibition of LPO may not be due to their classical pharmacological actions, but
      may be attributed to characteristic chemical structure or their physicochemical
      interactions with biological membranes. Inhibition of LPO may provide additional
      cardioprotective activity and thus reaffirms their use in ischemic heart disease.

PMID- 8642900
TI  - Involvement of Ca2+ and alpha 1-adrenoceptors in endothelin-1 effects on the tone
      and electrically evoked contractions of rabbit ear central artery.
AB  - Endothelin-1 (ET-1) is a neuropeptide strongly involved in the functions of the
      cardiovascular system. The aim of the present study was to reveal the role of
      alpha1-adrenoceptors and of Ca2+ in the effects of ET-1 on blood vessels.
      Preparations isolated from the proximal part of ear central arteries (REA) of
      male Chinchilla rabbits were used. A 30-40 mm long segment, cannulated at both
      ends, was fixed in an organ bath with Krebs-Henseleit solutions aerated with 95%
      O2 and 5% CO2. The preparations were perfused at a rate of 3.0 ml/min maintaining
      the arterial pressure in the range of 40-60 HPa and were allowed a 120-min
      adaptation at 37.5 degree C. Contractions were induced by low-frequency
      electrical stimulation (ES) and the effects of ET-1 (applied intralumenally or
      extralumenally) on the arterial tone and on the Es-evoked contractions were
      studied. Extralumenal ET-1 (1 x 10(-12)M-1 x 10(-9)M) did not change the tone and
      ES evoked contractions of REA. In concentrations of 1 x 10(-8)M-1 x 10(-7)M ET-1
      slightly increased arterial tone and moderately potentiated ES contractions. ET
      1, in concentrations higher than 1 x 10(-7)M, sharply, strongly and long
      lastingly increased the smooth muscle tone and slightly enhanced the ES
      contractions. A 100 microM bolus injection with ET-1 (1 x 10(-9)M-1 x 10(-8)M)
      resulted in potentiation of the ES contractions and the arterial tone was not
      markedly affected. 100 microM of 1 x 10(-7)M ET-1 increased more than 2-fold the
      tone of the segments and moderately reduced the ES-evoked contractions. A 30-min
      perfusion with ET-1 (1 x 10(-12)M-1 x 10(-9)M) strongly increased the arterial
      tone and completely abolished the ES contractions. Perfusion with 1 x 10(-8)M ET
      1 resulted in a 3-fold increase of the tone of the isolated segments. A 30-min
      perfusion with 1 x 10(-6)M prazosin (PRZ) did not affect the arterial tone and
      prevented the ES-evoked contractions. PRZ markedly reduced the contractile
      effects of 1 x 10(-12)M-1 x 10(-9)M ET-1 and the effect of 1 x 10(-8)M ET-1 on
      REA tone was even enhanced by PRZ. Under the same conditions 1 x 10(-6)M
      flunarizine (FLU) inhibited the ES-induced contractions of the isolated
      preparations and decreased their tone. FLU reduced the contractile effects of ET
      1 (1 x 10(-12)M-1 x 10(-8)M). Applied extralumentally 1 x 10(-6)M FLU also
      decreased EG-1 effects on REA. The results obtained strongly support the
      assumption that alpha1-receptors and Ca2+ are involved in ET-1 contractile
      effects on blood vessels smooth muscles.

PMID- 8642901
TI  - A comparative study of guinea pig and rat tracheal reactivity.
AB  - Species differences in behavior and responses of guinea pig (GPT) and rat (RT)
      tracheal smooth muscle to electrical field stimulation (EFS) and chemicals were
      investigated under semi-isometric conditions. Indomethacin augmented and
      papaverine reduced the contractions elicited by EFS in both tissues. They relaxed
      the GPT and did not affect the tone decline in the RT. Experiments with different
      load, cartilage content, thread and rubber strips suggest the role of elastic
      elements in passive elongation of the RT. This was independent of muscarinic,
      adrenergic, histaminergic and serotoninergic receptors, nitric oxide, eicosanoids
      and metabolic processes. The second response on repeated administration of
      acetylcholine was augmented and that of serotonin attenuated in both GPT and RT.
      Upon repeated elevation of [K+]o the tissues responded in an opposite manner.
      Further data are provided on similarities (modulation of cholinergic transmission
      by prostaglandins, sensitization to acetylcholine and desensitization to
      serotonin) and differences (innervation, responses to repeated elevation of
      [K+]o, presence/absence of prostaglandin-regulated basal tone and spontaneous
      activity) in reactivity of GPT and RT.

PMID- 8642902
TI  - Slow penetration of [3H] tiazofurin into guinea pig brain by a saturable
      mechanism.
AB  - The aim of this study was to investigate the transport of tiazofurin (2-beta-D
      ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) using
      brain vascular perfusion and capillary depletion method in the guinea pig. Values
      for volume of distribution of [3H] tiazofurin in brain increased slowly and
      almost linearly in time, from 1% of its plasma concentration at 1 min to 5% after
      15 min of perfusion. Unidirectional transport constant Kin was 2.61 +/- 0.21 x
      10(-3) ml/min/g. According to these results, it is evident that tiazofurin slowly
      penetrates the BBB. Addition of unlabeled tiazofurin to the perfusing medium
      caused a significant decrease in the uptake of [3H] labeled tiazofurin (Kin =
      0.77 +/- 0.1 x 10(-3) ml/min/g). Therefore, penetration of tiazofurin from blood
      into brain seems to be a saturable process. Presence of potential inhibitors of
      tiazofurin blood-to-brain transport (adenosine and dipyridamole) did not cause
      complete inhibition of tiazofurin brain uptake. Thus, it could be assumed that
      transport of tiazofurin from blood into brain is only partially mediated by the
      nucleosides transport system. The results obtained using capillary depletion
      method show that tiazofurin that passes across the BBB is accumulated mostly in
      the brain tissue and not in brain capillaries endothelial cells.

PMID- 8642903
TI  - Isolation and characterization of sulphoxidation metabolites of moricizine in rat
      and human biological fluids.
AB  - The sulphoxidation metabolites of moricizine, moricizine sulphoxide (M
      sulphoxide) and moricizine sulphone (M-sulphone) were isolated and identified in
      the rat bile and urine and in human plasma and urine following administration of
      moricizine hydrochloride. The sulphoxide and sulphone were synthesized chemically
      by peroxidation of moricizine hydrochloride with hydrogen peroxide at 25 degree C
      and 60 degree C, respectively, and were characterized by melting point
      determination (MP), infrared spectroscopy (IR), mass spectroscopy (MS), thin
      layer chromatography (TLC) and high performance liquid chromatography (HPLC). In
      the rats (n=7), which were kept in metabolic cages and given intravenous
      moricizine (0.72 mg), the mean +/- SD percentages recovered in the urine as
      moricizine, M-sulphoxide and M-sulphone were 0.11 +/- 0.09%, 0.74 +/- 0.45% and
      5.16 +/- 4.24%, respectively. The corresponding recoveries in the bile were 0.13
      +/- 0.04% as moricizine, 3.39 +/- 1.62% as M-sulphoxide and 2.16 +/- 1.07% as M
      sulphone. After an oral dose of moricizine HCl (300 mg) the plasma concentrations
      of moricizine, M-sulphoxide and M-sulphone at 4 h in two healthy subjects were
      0.43, 0.11 and 0.10 microg/ml and 0.32, 0.17 and 0.27 microg/ml, respectively for
      Subject 1 and Subject 2. The percentages of dose recovered in the urine as
      moricizine, M-sulphoxide and M-sulphone were 0.14 and 0.02%, 0.27 and 0.36%, and
      0.30 and 0.24%, respectively for Subject 1 and Subject 2. It is suggested that an
      investigation of the disposition of moricizine and its sulphoxidation metabolites
      in patients will be valuable for elucidating the prolonged effects in the
      treatment of ventricular arrhythmias.

PMID- 8642905
TI  - [Copenhagen may have the solution of problems in Stockholm].

PMID- 8642906
TI  - [Important enough to draw interest. How to write a successful application to the
      EEC].

PMID- 8642904
TI  - A noninvasive evaluation of baroreceptor sensitivity with the Valsalva maneuver
      and phenylephrine methods.
AB  - In a double-blind crossover study, we compared baroreceptor sensitivity (BS) and
      latency, derived from the phenylephrine method with BS and latency derived from
      phase IV of the Valsalva maneuver (VM), using the Finapres, a noninvasive blood
      pressure monitor. Ten healthy volunteers were enrolled in the study and BS was
      determined with placebo, atropine (0.03 mg/kg) and atenolol (10 mg) and was
      expressed as the linear relation between the change in RR interval following the
      blood pressure rise induced by either phenylephrine or phase IV of the VM (i.e.,
      after cessation of straining). Baseline baroreceptor sensitivity (p<0.001) and
      baroreceptor sensitivity in the presence of atropine (p<0.02) was smaller with
      the VM but no differences in baroreceptor sensitivity between the two methods
      were evident after atenolol. Although no linearity existed between the two
      methods under any of the experimental conditions, baroreceptor sensitivity in the
      presence of atropine was significantly smaller (p<0.01)(and latency delayed
      (p<0.08)) compared to atenolol-induced changes with both methods. We found
      excellent correlation between baroreceptor sensitivity derived from the ECG
      tracing and Finapres recorded beat-to-beat pulse intervals (p<0.001; r>0.8, under
      all conditions) although the correlation after atropine was not as close (p<0.01;
      r=0.7). The smaller baroreceptor sensitivity induced by the Valsalva maneuver
      with placebo and atropine, but not with atenolol, suggests a parasympathetically
      influenced vasodilation, and sympathetically medicated tachycardia during phase
      IV of the VM.

PMID- 8642907
TI  - [Accreditation in practice: "stimulation for personnel, good for competition"].

PMID- 8642908
TI  - [SEQLA (Swedish External Quality Assurance) external quality assurance through
      surveying differences].

PMID- 8642909
TI  - [Cooperation for quality development in primary health care: the new laboratory
      committee will become "a long arm" of SEQLA].

PMID- 8642910
TI  - [How should health care prioritize during war? Comparison with ethical bases in
      peace-time].

PMID- 8642911
TI  - [Mobilization and stretching one more time].

PMID- 8642912
TI  - [Conscious intubation should be used more often!].

PMID- 8642913
TI  - [Misleading advice on the P-pill].

PMID- 8642914
TI  - [Connection between dietary fat and breast cancer. A cherished hypothesis
      abandoned?].

PMID- 8642915
TI  - [The inverse inspiration-expiration relationship. Alternative ventilation in
      severe acute pulmonary failure].

PMID- 8642916
TI  - [Vaccination of health personnel against hepatitis B. Local adaptation based on
      recommendations by the National Board of Health and Welfare].

PMID- 8642917
TI  - [Altered T-cells against rheumatoid arthritis. Markers as tools for early
      prognosis].

PMID- 8642918
TI  - [Cytokines slow down the progression of MS. Successful animal experiments with a
      vaccine].

PMID- 8642919
TI  - [Gene scanning discovers the regions of MS and RA].

PMID- 8642920
TI  - [Ischemic complications of dissecting aneurysm of the aorta. Treatment with
      percutaneous stents and fenestration].

PMID- 8642921
TI  - [Stent graft technique in thoracic aortic aneurysm. A new alternative to
      conventional surgery].

PMID- 8642922
TI  - [Expert physicians are important in insurance claim processing. Medical
      assessment is the basis for correct compensation].

PMID- 8642923
TI  - [Medical research in the fourth frame program of the EEC. Favourable outcome for
      Swedish scientists].

PMID- 8642924
TI  - [A Chinese edition of Scandinavian medical journals].

PMID- 8642925
TI  - [Prior to new drug approval: improve the routines of license prescriptions].

PMID- 8642926
TI  - [A debate on pertussis vaccines. The monocomponent vaccine has many advantages].

PMID- 8642927
TI  - [Compare pertussis vaccines--but do it accurately].

PMID- 8642928
TI  - [Varmland concentrates on physicians on duty. Correctly trained interns are
      competent in primary emergency service].

PMID- 8642929
TI  - [More physicians should be engaged in standardization procedures].

PMID- 8642930
TI  - [Cannabis should remain illegal!].

PMID- 8642931
TI  - [Follow-up of IVF-children (in vitro fertilization) is important].

PMID- 8642932
TI  - [Health care can learn from industry].

PMID- 8642933
TI  - [Take care of blood donors!].

PMID- 8642934
TI  - [Follow-up for risk of metastases after laparoscopy is important].

PMID- 8642935
TI  - [Right and wrong in thalassemia diagnosis].

PMID- 8642937
TI  - [Be careful in dealing with respondents to questionnaires!].

PMID- 8642936
TI  - [The national registry on diabetes--simple things are being complicated].

PMID- 8642938
TI  - [Orthopedic medicine, some basic facts].

PMID- 8642939
TI  - [News concerning total parenteral nutrition. From hyperalimentation to nutrition
      pharmacology].

PMID- 8642940
TI  - [Swedish classification of cranial injuries needs to be changed!].

PMID- 8642941
TI  - [Transesophageal echocardiography: revealing the source of cardiac embolism].

PMID- 8642942
TI  - [Considerable differences in the management of stroke. A study of structured vs.
      conventional care].

PMID- 8642943
TI  - [Gangrene formation leading to fatal hemolysis].

PMID- 8642944
TI  - [Older women have lower resistance to tetanus].

PMID- 8642945
TI  - [Preventive medical work is important but difficult. Shortage of time and
      information is main obstacle].

PMID- 8642946
TI  - [Ecology or convention? No big differences between the different means in
      agriculture].

PMID- 8642947
TI  - [Physicians should keep a record of their own antibiotic prescriptions! Over
      prescribing should be obvious].

PMID- 8642948
TI  - [Medical history of Uppsala collected. Instruments from the 17th century among
      the treasures].

PMID- 8642949
TI  - Big cities, small targets.

PMID- 8642950
TI  - Genetic screening for breast cancer in Ashkenazi women.

PMID- 8642951
TI  - Orthoses for rheumatoid feet: does it matter what's underfoot?

PMID- 8642952
TI  - Quandary about treatment of aspergillomas persists.

PMID- 8642953
TI  - Cholesterol crystal embolism: an important "new" diagnosis for the general
      physician.

PMID- 8642954
TI  - Safely to school?

PMID- 8642955
TI  - Germline BRCA1 185delAG mutations in Jewish women with breast cancer.
AB  - BACKGROUND: We aimed to find out the proportion of breast cancers in Ashkenazi
      Jewish women attributable to the frameshift mutation at position 185 involving
      the deletion of adenine and guanine (185delAG) in the breast cancer gene BRCA1.
      METHODS: We studied 107 Ashkenazi Jewish women with breast cancer seen at medical
      oncology and genetic counseling clinics in New York over a three and a half year
      period beginning in 1992. 80 of the women were diagnosed before age 42 years; the
      other 27 were diagnosed between 42 and 50 years and had a positive family
      history. Genomic DNA testing by PCR amplification was done to identify any
      185delAG mutations of the BRCA1 gene. FINDINGS: Of the 80 women diagnosed before
      the age of 42 years, 16 (20%, 95% CI 11.2-28.8) were heterozygous for the
      mutation. All 16 women had at least one first-degree or second-degree relative
      with breast or ovarian cancer. Of 27 probands diagnosed with breast cancer
      between the ages of 42 and 50 years who had at least one first-degree relative
      affected with breast or ovarian cancer, 8 (30%, 95% CI 12-47) had 185delAG
      mutations. INTERPRETATION: These data suggest that screening for the 185delAG
      mutation may be useful in genetic counselling of these women where options for
      detection and prevention of possible cancers can be discussed.

PMID- 8642956
TI  - Jewish religion and risk of breast cancer.
AB  - BACKGROUND: The excess risk of breast cancer among Jewish women has been
      attributed to the effects of difference in lifestyle and reproductive patterns,
      but there is now evidence that Jewish women may be more likely than other women
      to inherit mutations in breast-cancer genes. We investigated whether any
      excessive risk among Jewish women is confined to those with a family history of
      breast cancer. METHODS: We assessed the effect of Jewish religion on breast
      cancer in a large population-based case-control study (6611 women with breast
      cancer and 9026 controls) in USA. Participants were given telephone interviews
      and asked about known and suspected risk factors for breast cancer. FINDINGS:
      Overall, Jewish women had only a slightly raised relative risk of breast cancer
      (1.10 [95% CI 0.84-1.44]; p=0.49). However, the relative risk was much higher for
      Jewish women with a first-degree relative who had breast cancer (3.78 [1.74
      8.16]; p<0.001). The effect of family history was greater in Jewish women than in
      women of other religions (p interaction = 0.05). INTERPRETATION: These results
      are consistent with data suggesting that certain groups of Jewish women have a
      higher than expected rate of mutation in the breast-cancer gene BRCA1.

PMID- 8642957
TI  - Perinatal intervention trial in Africa: effect of a birth canal cleansing
      intervention to prevent HIV transmission.
AB  - BACKGROUND: Perinatal transmission of human immunodeficiency virus (HIV) type 1
      contributes significantly to infant mortality. Exposure in the birth canal may
      account for some transmission. We examined the efficacy of a birth canal washing
      procedure in reducing perinatal transmission in Malawi. METHODS: The infection
      status of infants of 3327 control women (conventional delivery procedures) was
      compared with that of 3637 infants of intervention-delivered women. The infants'
      HIV status was determined by polymerase chain reaction on dried blood spots
      collected at 6 and 12 weeks of age. The intervention consisted of manual
      cleansing of the birth canal with a cotton pad soaked in 0.25% chlorhexidine,
      which was done on admission in labour and every 4 h until delivery. FINDINGS: No
      adverse reactions to the intervention procedure were seen. 2094 (30%) of the
      enrolled women were HIV-infected, and 59% of their infants were seen in follow
      up. Among 982 vaginal vertex singleton deliveries to HIV-infected women, 269
      (27%) infants were infected. The intervention had no significant impact on HIV
      transmission rates (27% in 505 intervention women compared with 28% in 477
      control women), except when membranes were ruptured more than 4 h before delivery
      (transmission 25% in the intervention group vs 39% in the control group).
      INTERPRETATION: If birth canal exposure is an important risk factor, different or
      additional methods to reduce the risk of perinatal HIV transmission should be
      tested. Alternatively, perhaps birth canal exposure is not a major contributor to
      perinatal infection risk.

PMID- 8642958
TI  - Bowel dysfunction in spinal-cord-injury patients.
AB  - BACKGROUND: This study aimed to determine the prevalence, nature, and effects-
      both physical and psychological--of spinal-cord-injury (SCI) on bowel function.
      METHODS: 115 consecutive hospital outpatients (89 male, median age 38 years) with
      chronic SCI (median duration 62 months, range 9-491 months, 48% cervical, 47%
      thoracic, 5% lumbar) completed a questionnaire about pre and post injury bowel
      function, the Hospital Anxiety and Depression Scale (HADS), and self assessment
      of the impact of their disabilities and symptoms. FINDINGS: Nausea, diarrhoea,
      constipation, and fecal incontinence were all much more common (p<0.0001) after
      SCI. 95% of patients required at least one therapeutic method to initiate
      defaecation. Half the patients became dependent on others for toileting. 49% took
      more than 30 min to complete their toilet procedure. Bowel function was a source
      of distress in 54% of patients and this was significantly (p=0.005) associated
      with the time required for bowel management and frequency of incontinence
      (p=0.001). There was a highly significant correlation between the HADS scores and
      the time taken for bowel management. On a scale of 0 (for no perceived problem)
      to 10 (maximum perceived problem), patients rated their loss of mobility as a
      mean of 6.8 (SD 3.3) and their bowel management as 5.1 (SD 3.6). INTERPRETATION:
      Bowel function is a major physical and psychological problem in SCI patients.

PMID- 8642959
TI  - Effects of artemisinin derivatives on malaria transmissibility.
AB  - BACKGROUND: On the western border of Thailand the efficacy of mefloquine in the
      treatment of falciparum malaria has declined while gametocyte carriage rates have
      increased, which suggests increased transmissibility of these resistant
      infections. We compared the following antimalarial drugs in relation to
      subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine,
      quinine, and the artemisinin derivatives. METHODS: Between 1990 and 1995 we
      assessed gametocytaemia in a series of prospective studies of antimalarial drug
      treatment in 5193 adults and children with acute uncomplicated falciparum malaria
      in an area of malarious hill forest on the western border of Thailand. Weekly
      parasite counts from thick and thin blood films were done during the 4-week (1990
      93) or 9-week (1993-95) follow-up period. Gametocyte positivity rates and person
      gametocyte week (PGW) rates were calculated to measure gametocyte carriage and
      transmission potential. FINDINGS: In primary P falciparum infections the
      gametocyte carriage rate was significantly higher after treatment with mefloquine
      than after treatment with the artemisinin derivatives (PGW 34.1 [95% CI 25.2
      42.9] vs 3.9 [1.9-5.9] per 1000 person weeks; relative risk 8.0 [4.1-15.6];
      p<0.0001). Recrudescent infections were associated with increased gametocyte
      carrier rates (relative risk 2.2 [1.6-3.0]; p<0.0001), but retreatment with
      artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98]
      compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with
      quinine retreatment (p<0.001). The introduction of the artemisinin derivatives in
      routine treatment at this study site in mid 1994 was associated with a reduction
      in the subsequent incidence of falciparum malaria of 47 (25-69)% INTERPRETATION:
      Although environmental changes affect vector numbers, and hence malaria
      incidence, artemisinin derivatives were found to reduce the transmission
      potential of falciparum malaria. Widespread introduction of artemisinin
      derivatives in the treatment of falciparum malaria may prevent the spread of
      multidrug resistance.

PMID- 8642960
TI  - Changes in metabolism of collagen in genitourinary prolapse.
AB  - BACKGROUND: Genitourinary prolapse is a common problem, the pathophysiology of
      which is unknown. METHODS: We analysed vaginal-epithelial tissue from
      premenopausal women with genitourinary prolapse and compared them with controls.
      FINDINGS: We found that genitourinary prolapse is associated with a reduction in
      total collagen content and a decrease in collagen solubility. Both intermediate
      intermolecular cross-links and advanced glycation cross-links were increased in
      prolapse tissue. Collagen turnover, as indicated by matrix metalloproteinase
      activity, was up to four times higher in prolapse tissue. Collagen-type ratios,
      mature cross-link pyridinoline and total elastin content were similar in both
      prolapse and control tissues. Increased collagenolytic activity causes loss of
      collagen from prolapse tissue. INTERPRETATION: Based on these findings, we have
      identified a probable mechanism for genitourinary prolapse. Development of agents
      to inhibit collagenolytic activity may help in the treatment of this condition.

PMID- 8642961
TI  - Persisting fever after gastroenteritis.

PMID- 8642963
TI  - Remak, father and son.

PMID- 8642962
TI  - Abortion and fertility regulation.
AB  - To achieve their desired fertility, women use a combination of contraception and
      abortion, and some societies also place constraints on marriage and sexual
      activity. The degree to which these means are adopted varies considerably, but
      for the foreseeable future abortion will remain an important element of fertility
      regulation. Globally, complications of unsafe abortion affect hundreds of
      thousands of women each year, and account for as many as 100,000 deaths annually
      (about two in ten maternal deaths), mainly in poor countries, where abortion
      typically remains illegal. Access to safe abortion is both essential and
      technically feasible and should be provided in combination with good quality
      family planning services.

PMID- 8642965
TI  - Returning home: reflections on the USA's response to the HIV/AIDS epidemic.

PMID- 8642964
TI  - A role for businesses in HIV prevention in Asia.

PMID- 8642966
TI  - AIDS vaccines are the way to halt epidemic.

PMID- 8642967
TI  - No-needle HIV test approved by FDA.

PMID- 8642968
TI  - p75 blockade--can it prevent neuronal death?

PMID- 8642969
TI  - British medical academic work faces "triple whammy".

PMID- 8642970
TI  - Medicare trustees warn bankruptcy closer than ever.

PMID- 8642972
TI  - Vitamin E and coronary heart disease.

PMID- 8642973
TI  - Vitamin E and coronary heart disease.

PMID- 8642971
TI  - Patients sue "AIDS-cure" Kenyan scientist.

PMID- 8642974
TI  - Vitamin E and coronary heart disease.

PMID- 8642975
TI  - Vitamin E and coronary heart disease.

PMID- 8642976
TI  - Vitamin E and coronary heart disease.

PMID- 8642977
TI  - Vitamin E and coronary heart disease.

PMID- 8642978
TI  - Ice pops to prevent melphalan-induced stomatitis.

PMID- 8642979
TI  - Molecular analysis of effectiveness of Mohs' surgical technique.

PMID- 8642980
TI  - Liver haemangioma and pregnancy.

PMID- 8642981
TI  - Liver haemangioma and pregnancy.

PMID- 8642982
TI  - Rubella immunisation-learning from developed countries.

PMID- 8642983
TI  - Conservative treatment for rheumatoid cervical spine.

PMID- 8642984
TI  - Value of preoperative pregnancy test in risk management.

PMID- 8642985
TI  - Preimplantation genetic diagnosis of beta-thalassaemia major.

PMID- 8642986
TI  - Evidence and tardive dyskinesia.

PMID- 8642987
TI  - Jet "leg", pulmonary embolism, and hypoxia.

PMID- 8642988
TI  - Near-fatal intra-abdominal bleeding from a ruptured follicle during thrombolytic
      therapy.

PMID- 8642989
TI  - Physician-assisted suicide for progressive neurological diseases.

PMID- 8642990
TI  - Physician-assisted suicide for progressive neurological diseases.

PMID- 8642991
TI  - Revolving drug funds in Asia and Latin America.

PMID- 8642992
TI  - Early warnings about drugs.

PMID- 8642993
TI  - Mycophenolate mofetil to rescue children with acute renal transplant rejection.

PMID- 8642994
TI  - Surveillance for HIV-1 subtypes O and M in Kenya.

PMID- 8642995
TI  - No HHV8 in non-Kaposi's sarcoma mucocutaneous lesions from immunodeficient HIV
      positive patients.

PMID- 8642996
TI  - Brain reorganisation after injury in infancy.

PMID- 8642998
TI  - Seasonal incidence of stroke.

PMID- 8642997
TI  - Treatment of kala azar.

PMID- 8642999
TI  - Tuberculosis control in China.

PMID- 8643000
TI  - Seasonal incidence of stroke.

PMID- 8643001
TI  - Seasonal incidence of stroke.

PMID- 8643003
TI  - Creutzfeldt-Jakob disease.

PMID- 8643002
TI  - A herpesvirus inhibitor from bovine whey.

PMID- 8643004
TI  - Creutzfeldt-Jakob disease.

PMID- 8643005
TI  - Creutzfeldt-Jakob disease.

PMID- 8643006
TI  - Long-term effect of vitamin A with vaccines.

PMID- 8643007
TI  - Public health risk from Salmonella-based rodenticides.

PMID- 8643008
TI  - Dementia in twins.

PMID- 8643009
TI  - Polymorphism at the tumour necrosis factor locus: a marker of genetic
      predisposition to colorectal cancer?

PMID- 8643010
TI  - Will today be the day YOU hear from "J"?

PMID- 8643011
TI  - [Diagnostic approach in patients with kidney tumors].
AB  - The basic reason for the rationalization of diagnostic procedure is the cost
      benefit relation and making of the diagnostic course algorithms. On the basis of
      the Receiver Operating Characteristic (ROC) analysis of the diagnostic procedure
      (excretory urography, ultrasonography, computed tomography, digital subtraction
      angiography) the significance ranking has been established for certain kidney
      tumor diagnostic procedures. Angiography has been determined to be the most
      precise method, but the high degree of sensitivity (98%) and accurate diagnosis
      probability (98%), as well as noninvasiveness and relative inexpensiveness of
      ultrasonographic examination procedure, all argue for ultrasonography as the
      cornerstone, of renal tumor diagnosis. Using conditional probabilities and the
      Bayes analysis the advantage of the newly suggested over the standard diagnostic
      course has been calculated. The study has shown a significant decrease in the
      number of examinations: in 60 patients 16 excretory urographies, 10 computed
      tomographies, and 22 digital subtraction angiographies can be spared.

PMID- 8643012
TI  - [Safety of transfusion therapy with special emphasis on inactivated viruses in
      products made from human blood].
AB  - The most common complication of blood transfusion therapy is the transfusion
      transmitted infection. The decrease of the risk had been achieved by several
      measures such as: the change from paid to all voluntary donor system, education
      of the population and potential donor groups as regards the risk factors, and the
      selection of donors without the risk factors, testing of donor blood for the
      presence of the hepatitis B and C viruses, HIV and syphilis, fractionation of
      plasma with the partition of viruses and their inactivation. In spite of all
      these efforts zero risk blood transfusion therapy has not been achieved and it is
      very unlikely that it will be achieved in the future. Clinicians must have
      sufficient background information on different procedures for viral inactivation
      in order to be able to select the least risky blood product.

PMID- 8643013
TI  - [Bacteremia and sepsis in patients hospitalized at the Dr. Fran Mihaljevic Clinic
      for Infectious Diseases in Zagreb 1987-1991].
AB  - A total number of 836 episodes of bacteremia and fungemia were examined in 823
      hospitalized patients in the University Hospital of Infectious Diseases "Dr Fran
      Mihaljevic" Zagreb from the beginning of 1987 to the end of 1991. Twenty-five
      percent of them were nosocomial bacteremias and 5% were polymicrobial
      bacteremias. The most frequently isolated causative agents were Salmonella spp.
      (26%), Escherichia coli (17%), Streptococcus pneumoniae (11%) and Staphylococcus
      aureus (8%). There were 34% of gram-positive bacteremias. The increased frequency
      of nosocomial bacteremias caused by coagulase-negative staphylococci was
      recorded. The frequency of coagulase-negative staphylococci strains resistant to
      gentamicin and Klebsiella spp. strains resistant to cefotaxime was increased.
      Shock was present in 19% of episodes. Relation between septic shock occurrence
      and causative agent of bacteremia was not proved. Mortality in patients with
      bacteremia was 13%, and total mortality was 20%. The outcome of the disease was
      in direct relation with causative agent of bacteremia. The initial empiric
      antimicrobial therapy was prolonged in 91% of episodes of bacteremia after blood
      culture results were known.

PMID- 8643014
TI  - [Blunt heart injuries and diagnostic difficulties].
AB  - The authors present their experiences with blunt heart injuries treated in the
      University Surgical Hospital in Split, Croatia. The diagnostic approach
      hospitalization and follow-up of these patients are described. The heart
      contusion was diagnosed using several repeated electrocardiographic and enzymatic
      tests combined with two-dimensional echocardiography. We treated 67 patients with
      heart contusions within two-year period. Out of them, 63 (94%) were dismissed
      from the hospital as cured, and 4 (6%) of them died. Results of treatment depend
      on the severity of injury, but also on a timely and adequate management.

PMID- 8643015
TI  - [Cockayne syndrome].
AB  - A 9-year-old girl with characteristic clinical signs of Cockayne's syndrome type
      I (cachectic dwarfism, "senile" like appearance, mental retardation, progressive
      neurologic and retinal degeneration) is presented. Computerized tomography and
      magnetic resonance imaging of the brain have shown a large malformation in
      cerebral posterior fossa. The case also has unusual aspects: pronounced
      congenital hypertrichosis and dark pigmented teeth. To our knowledge, these signs
      have never been described in the literature in connection with this rare
      syndrome.

PMID- 8643016
TI  - [Treatment of gonarthrosis with arthroscopic abrasion].
AB  - From 1988 to 1992 at the Department of orthopaedic surgery, School of medicine,
      University of Zagreb 21 arthroscopic knee joint abrasions were performed as
      palliative treatment of osteoarthritis. There were 13 male patients (61.9%) and
      eight female patients (38.1%); the age of the patients ranged from 17 to 69 years
      (the average of 42.2 years). The femorotibial angle ranged from -2 to 10 degrees
      (the average of 5.3 degrees). The average degree of osteoarthritis was 2.1 and of
      chondromalacia 3.5 degrees. In the majority of cases the abrasion was performed
      in the medial femoral condyle and the patella; in a smaller number of cases it
      was performed in the medial tibial condyle, and in the lateral tibial condyle in
      only one patient. Also, debridement was performed in most of the patients; in
      four patients cleansing of the medial menisci was made, while in two patients
      loose joint bodies had to be removed. The average follow-up time was 2.8 years,
      ranging from 12 months to 5 years. According to HSS score, treatment results were
      excellent and very good in 15 patients (71.4%), satisfactory in four patients
      (19.0%) and poor in two patients (9.5%). The authors conclude that the
      arthroscopic abrasion is good, non-invasive palliative method of treatment of
      primary knee osteoarthritis. The arthroscopic abrasion method yields good short
      term results (from 2 to 5 years) in view of reducing pain and improving joint
      function.

PMID- 8643017
TI  - [Management of surgery patients with implanted cardiac pacemakers].
AB  - Patients having cardiac pacemaker implanted may be subjected to various general
      surgery procedures. Application of electrosurgery for the purpose of resection
      and coagulation, provides a high frequency electric field which produces electric
      voltage on the electrodes of the pacing system. This voltage may be detected
      within the pacing system, and various arrhythmias can be provoked in correlation
      with underlying rhythm and mode of pacing. Preoperative patient control and
      proper pacemaker programming can prevent the pacing malfunctions due to the
      electrosurgery application. Appropriate positioning of the neutral electrode in
      relation to the pacing system avoids the electric fields intersection and
      decreases their interference.

PMID- 8643018
TI  - [Treatment of Guillain-Barre syndrome].
AB  - The purpose of this article is to review the most up-to-date information on the
      treatment of Guillain-Barre syndrome-acute polyradiculoneuritis. Several
      different treatments for GBS are currently under investigation-plasmapheresis
      (plasma exchange), high-dosed intravenous gammaglobulin and intravenous
      corticosteroids. Controlled trials have shown that treatment with plasmapheresis
      reduced the time spent on a ventilator, in the intensive care unit, and the time
      needed to regain independent walking. It is generally accepted that
      plasmapheresis is indicated in severe GBS and for patients who are still in the
      first two weeks of the disease. High-dosed intravenous immunoglobulins showed
      their efficacy, at a dosage of 0.4 g/kg/daily for five days. The treatment is
      easier and morbidity is lower, but both therapies are very expensive.
      Corticosteroids cannot be considered useful therapy for GBS after two randomized
      controlled trials, one using conventional doses and the other high doses--500 mg
      methylprednisolone daily for five days. One pilot study on 25 patients has shown
      that combined treatment with high dose methylprednisolone and immunoglobulins was
      more effective than immunoglobulins alone. In the treatment of chronic
      polyradiculoneuritis corticosteroids do have a place. General medical care and
      supportive therapy in the intensive care unit are of the greatest importance.

PMID- 8643020
TI  - [Present status and perspectives of plastic surgery in Croatia].
AB  - Medical treatment in the field of plastic surgery has been known since 5000 B. C.
      Despite that, it was only since World War I that plastic surgery developed as a
      new branch of surgery a separate organization. In Croatia, plastic surgery
      started after World War II. Today Croatia has already the seventh generation of
      surgeons educated in plastic surgery. The Health Legislation of 1994 recognized
      plastic surgery as a subspecialty of general surgery. This kind of organization
      is also known in the world. Education of this type is necessary considering a
      great need for sophisticated reconstruction procedures in plastic surgery. During
      the war in Croatia, which started in 1991, a small number of surgeons practising
      plastic surgery successfully treated a great number of casualties. However, in
      the post-war period emerged the need for secondary reconstructions in many
      patients. A new centre for plastic surgery, where surgeons with microsurgical
      skills who are able to do complicated microsurgical reconstructions would work,
      should solve this problem.

PMID- 8643019
TI  - [Clinical and laboratory significance of inducible beta-lactamases].
AB  - Many species of bacteria have inducible expression of beta-lactamase and the
      enzyme production in these bacteria is normally held at a low level by a
      repressor mechanism, but in the presence of a beta-lactamase inducer this
      repression is lifted and enzyme production is greatly increased. Inducible
      synthesis of beta-lactamase was first described for the gram-positive organism
      Bacillus licheniformis. After that inducible expression of beta-lactamase was
      discovered in gram-negative bacteria like Enterobacter cloacae, Citrobacter
      freundii, Pseudomonas aeruginosa, Morganella morganii, Proteus vulgaris, Serratia
      spp and Aeromonas spp. Inducible beta-lactamases belong into class I according to
      Richmond and Sykes. They are chromosomally mediated cephalosporinases. beta
      lactam antibiotics differ in their inducing power. Cefoxitin and imipenem are
      among the strongest inducers. Induction of beta-lactamase caused by these
      substances can lead to antagonism with other beta-lactam antibiotics if they are
      used in combination. The most important clinical problem connected with inducible
      beta-lactamases is the emergence of multiple resistant strains which are
      associated with therapeutic failures. It is important to distinguish induction
      from derepression. Induction is a temporary phenomenon in which an inducer
      interacts with a functional AmpD protein, which consequently prevents complexing
      of the AmpD and ampR proteins. In contrast, genetic derepression is permanent and
      results from synthesis of a defective AmpD protein unable to complex with the
      AmpR protein.

PMID- 8643021
TI  - [Successful treatment of rapidly progressive glomerulonephritis associated with
      Henoch-Schoenlein purpura with high doses of methylprednisolone].

PMID- 8643022
TI  - Group interview methods in community health research.
AB  - Scholarly development of group interview techniques within the social sciences
      has lagged behind the rapid popularization of this method. This article offers
      conceptual clarification regarding different types of group interviews and
      analyzes case examples to highlight important methodologic issues in the
      application of group interviews to community health research. Selected problem
      areas and desirable future directions in the refinement of group interview
      methods are discussed. An appendix traces the historical development of focus
      group interviews in social science research.

PMID- 8643023
TI  - Examining ethnomedical diagnoses and treatment choices for diarrheal disorders in
      Lubumbashi Swahili.
AB  - This article examines the basis of ethnomedical classification of diarrheal
      disease among the Swahili speaking population of Lubumbashi, Zaire and the
      association of specific diagnoses with treatments given. Results from two
      research methods are reported: group interviews and large sample surveys. A
      series of group interviews with mothers of small children provided information
      about how they commonly diagnose illnesses related to childhood diarrheal disease
      as well as which symptoms, causes, and treatments they associate with those
      illnesses. Data from the interviews were used to formulate questions about the
      diagnosis of illness and treatments given for recent cases of diarrhea. A
      baseline and a follow-up survey provided information about the symptoms
      associated with reported episodes of illness and about the treatments given at
      home. The results provide evidence that ethnomedical diagnoses are based on
      observed symptoms, that they affect how and why oral rehydration therapy (ORT) is
      used or not used for diarrhea, and that the terms chosen by survey researchers to
      ask about diarrhea and ORT may affect survey results in predictable and
      systematic ways.

PMID- 8643024
TI  - Socialization to the family caregiving role within a continuing care retirement
      community.
AB  - Although family members provide the bulk of care given to infirm elderly in the
      United States (Brody 1990), little is known about the process of socialization to
      the informal caregiver role. What represents "appropriate" care to a family
      caregiver, and how does he or she learn to provide it? The "culture of
      caregiving" that developed among family caregivers of persons with dementia
      within one continuing care retirement community is discussed. The social norms
      that defined appropriate care and the process of conveying these norms through
      role models, information networks, and feedback in response to "deviant"
      caregiving behavior are described. Implications for caregiver education and
      support programs are discussed.

PMID- 8643025
TI  - Yellow fever: ecology, epidemiology, and role in the collapse of the Classic
      lowland Maya civilization.
AB  - Mystery has long surrounded the collapse of the Classic lowland Mayan
      civilization of the Peten region in Guatemala. Recent population reconstructions
      derived from archaeological evidence from the central lowlands show population
      declines from urban levels of between 2.5 and 3.5 million to around 536,000 in
      the two hundred year interval between 800 A.D. and 1000 A.D., the period known as
      the Classic Maya Collapse. A steady, but lesser rate of population decline
      continued until the time of European contact. When knowledge of the ecology and
      epidemiology of yellow fever and its known mosquito vectors are compared with
      what is known of the ecological conditions of lowland Guatemala as modified by
      the Classic Maya, provocative similarities are observed. When infection and
      mortality patterns of more recent urban yellow fever epidemics are used as models
      for a possible series of Classic Maya epidemics, a correlation is noted between
      the modeled rate of population decline for a series of epidemics, and population
      decline figures reconstructed from archaeological evidence.

PMID- 8643026
TI  - Acid-extractable amino acid pool in Escherichia coli: possible role in energy
      independent amino acid accumulation and protein synthesis.
AB  - The acid extractable amino acid pool (AEP) demonstrates time and concentration
      dependent saturation kinetics in cold-incubated (0-2 degrees C) Escherichia coli
      cells. Attention is drawn in particular to the contribution of the AEP to the
      total non-covalently bound amino acid intracellular levels (total pool) at low
      exogenous amino acid concentrations. Amino acids compete with one another for
      associations which internally constitute the AEP. Although physicochemically
      related amino acids tend to be better competitors than other amino acids, the
      physicochemical relatedness was by no means the sole, or necessarily the main,
      factor determining competitiveness. On the return of cells to incubation
      temperatures allowing protein synthesis to proceed, the contribution of the AEP
      to protein synthesis was explored.

PMID- 8643027
TI  - Antibacterial activity of essential oils from Cymbopogon: inter- and intra
      specific differences.
AB  - The influence of the genetic background of a plant on the antibacterial activity
      of essential oil derived from it was investigated. Essential oils from six
      distinct strains of Cymbopogon were tested against eighteen bacteria.
      Interspecific and intra-specific differences were evident in the antibacterial
      activity of the essential oils derived from the the six Cymbopogon strains.

PMID- 8643028
TI  - Quantitative genetic variation photoinduced by 8-methoxypsoralen in yeast.
AB  - The variation in cell mass production within cultured populations of
      Saccharomyces cerevisiae derived from untreated cells and from cells treated with
      8-methoxypsoralen plus near-UV light (8MOP-NUV) was determined. Spontaneous
      mutation was not significant source of variation, since no genetic component of
      variance was detected in the untreated population. Following mutagenesis
      significant levels of genetic variation were found, showing that 8MOP-NUV was
      effective in inducing quantitative genetic variation among clonal populations of
      the yeast. The magnitudes of the estimates of the heritability and of the genetic
      coefficient of variation, indicate that, in phenotypic selection, greater genetic
      progress can be expected after mutagenic treatment than with untreated
      populations. The highest estimate of genetic gain was obtained at the
      intermediate survival level.

PMID- 8643029
TI  - Effect of 3-amino-1-propanol, indomethacin and 4-bromophenacyl bromide on the
      hormone binding of insulin pretreated Tetrahymena: influence of phospholipid
      metabolism disturbances on hormonal imprinting.
AB  - The compound 3-amino-1-propanol which replaces ethanolamine in phosphatidyl
      ethanolamine and inhibits transformation of it, hindered insulin imprinting of
      Tetrahymena. Indomethacin, an inhibitor of prostaglandin synthesis and
      arachidonate metabolism provoked negative imprinting. 4-Bromophenacyl bromide, a
      phospholipase A2 inhibitor, hindered imprintability by insulin. Immediately after
      treatment these substances inhibited insulin binding. The experiment calls
      attention to the importance of intactness of metabolic pathways and second
      messenger systems in the mechanism of imprinting.

PMID- 8643030
TI  - Growth and exotoxin production at low temperatures by Aeromonas strains in meat
      slurries.
AB  - The ability of enterotoxigenic strains of Aeromonas hydrophila and Aeromonas
      sobria to produce exotoxins (haemolysin and enterotoxin) and exoenzymes (protease
      and lipase), as well as their growth in meat slurries stored at low temperatures
      (5 and 12 degrees C) was investigated. The results showed that Aeromonas grew
      well in meat slurries stored at low temperatures in the presence of background
      flora. Exotoxins and exoenzymes were not detected in filtrates from meat slurries
      inoculated with enterotoxigenic Aeromonas strains after 5 and 8 days incubation
      at both incubation temperatures. The significance of the competitive growth of
      aeromonads in foods at refrigeration temperatures is discussed.

PMID- 8643031
TI  - Analysis of the papillomavirus type 16 DNA amplification by PCR in SiHa and SLT
      cell lines.
AB  - The tumoral cell line SiHa had incorporated in its genome a small part of the
      viral DNA of the human papillomavirus type 16 (HPV-16), an aetiological agent of
      cancer of cervix. The genetic transfection in SiHa cells with the plasmid LTneo
      by the technique of coprecipitation of calcium phosphate followed by selection
      with G-418 produced a new cell called SLT. The SLT cells were different from
      SiHa, the parental cell line. Analysis of the amplification of the viral DNA by
      the polymerase chain reaction showed that HPV-16 was amplified in SiHa cells and
      was not amplified in SLT cells. This result confirmed that HPV-16 DNA was deleted
      from the cellular genome and that in this context the polyomavirus LT antigen
      known as an immortalizing oncogene in the process of carcinogenesis in multiple
      steps had produced an antioncogenic effect.

PMID- 8643032
TI  - Seroprevalence of human toxoplasmosis.
AB  - A comparative study of the prevalence of infection by Toxoplasma gondii in
      Southern Spain in different population groups was carried out using serological
      markers. The presence of IgG antitoxoplasma antibodies was investigated in serum
      samples of several population groups. Infection by T. gondii was very prevalent,
      especially among intravenous drug users (47.6%). An IgG antibody prevalence of
      49.6% was obtained from immunocompetent adults with suspected active
      toxoplasmosis. In infants IgG antibodies were detected in 12.2%, and in pregnant
      women there was 30% IgG antitoxoplasma antibodies.

PMID- 8643033
TI  - The relationship of the endoplasmic reticulum to the Golgi complex in Tetrahymena
      pyriformis.
AB  - The endoplasmic reticulum (ER) and the closely connected, single dictyosomal
      Golgi apparatus of Tetrahymena pyriformis cells showed random distribution in the
      cytoplasm. Ribosomes were evident, and coated vesicles pinched off from the ER
      were seen. The membranes of the endoplasmic reticulum generally formed a tube
      like structure, although after histamine treatment multiple, folded and circular
      structures were observed. The number of coated vesicles detaching from the
      endoplasmic reticulum increased as a result of histamine treatment.

PMID- 8643034
TI  - In vitro trypanocidal activities of a novel series of N, N-dimethyl-2-propen-1
      amine derivative.
AB  - The trypanocidal activity of several 3-(4'-bromo-[1,1-biphenyl]-4-yl) -3-(4-X
      phenyl)-N,N-dimethyl-2-propen-1-amine derivatives of the three evolutionary
      stages of Trypanosoma cruzi, namely the bloodstream trypomastigote form and both
      the proliferative epimastigote and amastigote forms, were studied. For both
      proliferative forms of T. cruzi, total lysis occurred at 10-60 microM for
      trypomastigotes at 40-200 muM. The following order of susceptibility was
      established: amastigotes > epimastigotes > trypomastigotes. The most were the
      bromo (X = g) and unsubstituted (X = b) compounds, which had 13- and 8-fold
      higher activity against trypomastigotes, respectively, than nifurtimox.
      Cytotoxicity in the Chinese hamster V-79 cell line, measured as inhibition of
      cell proliferation showed that all the compounds had the same range of IC50 (7.0
      12.4 muM). The halogen (X = a,g,h) and the unsubstituted derivatives (X = b) were
      the least toxic in the series together with the compound (X = f).

PMID- 8643035
TI  - [Luminescent bacteria--producers of specific restriction endonucleases].
AB  - Luminescent bacteria isolated from the waters of the Black Sea and of the Indian
      and Pacific Oceans were tested for the presence of restriction endonucleases. For
      12 of 19 restriction enzyme producers revealed, restriction sites were
      determined. The enzymes were identified as isoschizomers of AfIII, BanI, HaeIII,
      PstI, Sau3AI, and Sau96I. Possible participation of the restriction and
      modification enzymes in the interaction of bacterial symbionts with the animal
      macrosymbiont is discussed.

PMID- 8643036
TI  - [Protective and reactive effect of a cellular extract from propionic acid
      bacteria on Candida guilliermondii and Escherichia coli, inactivated by
      ultraviolet radiation].
AB  - Dialyzed soluble proteins of Propionibacterium freudenreichii subsp. shermanii
      cell extract (dialyzate) were found to exert a protective and reactivating effect
      on Candida guilliermondii and Escherichia coli cells inactivated by UV light of C
      and B ranges. Reactivation occurred when dialyzate was added to irradiated
      bacterial suspensions immediately after irradiation or 15 min afterwards. Some
      common features of dialyzate effect on irradiated prokaryotic and eukaryotic
      cells were established. No reactivation was observed when the cells were
      irradiated with the light of visible (400-600 nm) or entire optical (> 290 nm)
      ranges. The possible mechanisms of a reactivating effect of dialyzate are
      discussed.

PMID- 8643037
TI  - [Detection of methylotrophs in natural samples by amplifying a fragment of the
      moxF gene].
AB  - A method for detection of methylotrophic microorganisms with the help of the
      polymerase chain reaction was developed. Two primers were synthesized, designed
      on the basis of comparing conservative sequences of the genes encoding the large
      subunit of methanol dehydrogenase. The developed system was tested with six
      strains of methylotrophic bacteria and with natural samples collected in the
      Bunger Hills oasis, eastern Antarctica. The results suggested a possibility of
      application of the developed method for qualitative detection of methylotrophs in
      natural samples.

PMID- 8643038
TI  - [Use of polymerase chain reaction for detecting the RBPC gene in natural
      samples].
AB  - A method was developed allowing detection of the ribulose bisphosphate
      carboxylase (RuBisCo)-encoding gene in natural samples. The method is based on
      polymerase chain reaction (PCR) in the presence of oligonucleotide primers
      complementary to the conserved fragments of the rbcL gene from oxy- and
      anoxygenic phototrophic bacteria and some chemoautotrophic bacteria. Use of this
      method made it possible to detect the rbcL gene in samples of natural water and
      sediments from Antarctic lakes of the Bunger Hills oasis and in samples of
      Antarctic ground. A correlation was revealed between the results obtained by the
      PCR-based method and the data on the incorporation of 14CO2 via RuBisCo in
      natural samples.

PMID- 8643039
TI  - [A new psychroactive bacterium, Clostridium fimentarium, isolated from cattle
      manure fermented at a low temperature].
AB  - A new psychroactive saccharolytic anaerobic organism was isolated from cattle
      manure digested at 6 degrees C. The organism is a Gram-positive oligosporous
      motile rod measuring 0.5-0.6 by 2.1-5.0 microns. It utilizes glucose, fructose,
      maltose, arabinose, xylose, cellobiose, galactose, and mannose. Fermentation
      products are acetate, ethanol, lactate, formate, H2, and CO2. Growth is possible
      within a temperature range of 1-30 degrees C, with an optimum at 20-25 degrees C,
      and a pH range of 5.5-8.3, with an optimum at 6.8. The DNA GC content is 35.6 mol
      %. The organism was classified as a new species of the genus Clostridium, C.
      fimetarium sp. nov. The type strain is Z-2189.

PMID- 8643040
TI  - [Bacterial processes of photosynthesis and dark assimilation of carbon dioxide in
      the lakes of Bunger Hills Oasis in Eastern Antarctica].
AB  - Photosynthetic and dark assimilation of carbon dioxide was studied in both
      perennially and temporarily ice-covered lakes of the antarctic oasis Bunger
      Hills. The intensity of these processes in the lakes studied varied from 0.08 to
      326 mg C/(m3 day) and correlated with water mineralization. Irrespective of the
      character of ice-cover, a chemical composition of water in antarctic water
      ecosystems affected the organic matter photo-production to a greater extent than
      the intensity of photosynthetically available radiation. With the method of
      polymerase chain reaction, the predominance of oxygenic phototrophic
      microorganisms carrying RuBisCo genes was revealed in all the lakes examined. The
      results obtained and the literature data unambiguously point to the
      photosynthetic production of organic matter by cyanobacteria as the main
      biogeochemical process that determines all the other metabolic strategies in
      antarctic water ecosystems studied hitherto.

PMID- 8643041
TI  - Function of topoisomerase II and the consequences of inhibition.

PMID- 8643042
TI  - p53 tumor suppressor gene: implications for iatrogenic cancer and cancer therapy.

PMID- 8643043
TI  - Regulation of cellular proliferation effects on alteration of normal signaling
      pathways.

PMID- 8643044
TI  - Genetics of retinoblastoma: implications for other human cancers.

PMID- 8643045
TI  - Cancer following irradiation in childhood and adolescence.
AB  - The child appears more sensitive than the adult to the carcinogenic effects of
      radiation for certain sites such as the breast and thyroid. However, there are
      few studies of persons who were exposed as children and adolescents who have been
      followed for 40 or 50 years into the adult ages. Thus, it is extremely important
      that follow-up studies of children continue to evaluate the lifetime cancer risk
      that might be related to radiation exposures in childhood.

PMID- 8643046
TI  - Colorectal cancer: molecular genetic studies and their future clinical
      applications.

PMID- 8643047
TI  - Methodologic issues in the study of second malignant neoplasms and pregnancy
      outcomes.
AB  - For future studies of late effects, it will be necessary for investigators to
      consider methodologic issues carefully as a means of insuring the quality of
      research in this increasingly important area. Recognizing the advantages and
      limitations in univariate and multivariate analyses will help in selecting the
      best analytic approach. There are many methods for denoting risk. Selection of
      the method will often be dependent on study design, but should also be the one
      believed most effective for communicating the study results. There is little
      question there is a need for well-designed studies for second malignancies,
      especially those designed to evaluate late-occurring second cancer (i.e., in the
      second, third, and fourth decade following treatment). With the aging of the
      childhood cancer survivor population, questions regarding pregnancy issues are
      increasing. These questions range from those relating to fertility to others
      associated with mutagenesis. When considering studies of these late effects, it
      is important to recognize the need for selecting the most appropriate study
      design and statistical methods.

PMID- 8643048
TI  - [Acute painful neuropathy--2 case reports].
AB  - Diabetic neuropathy, clinically established, occurs in up to 50% of diabetics,
      sometimes even prior to detection of diabetes mellitus. Distal symmetric
      polyneuropathy is the most frequent clinically established lesion of the nervous
      system. Other clinical entities, however, are not so rare, if they are studied
      with attention using differential diagnostic procedure. In this paper authors
      present two patients with sub-types of one of the rare forms of diabetic
      peripheral neuropathy--so called acute painful neuropathy: the first case
      associated with unregulated diabetes mellitus and in the second patient it
      occurred as a consequence of abrupt normalization of glycemic control with so
      called insulin neuritis. The authors described the most important clinical
      characteristics of patients, differential diagnosis, therapy and the course of
      the disease.

PMID- 8643049
TI  - [100 years since the discovery of roentgen rays].

PMID- 8643050
TI  - [Analysis of the cause of death in patients with aortocoronary bypass implants].
AB  - This paper analyzes causes of death in 91 autopsied patients in whom
      aortocoronary bypass surgery was performed as a therapy of ischemic heart
      disease. Patients who died within 30 days after surgery made up the group of so
      called "early deaths", while those who died 30 or more days after the surgery
      made up the group of so-called "late deaths". The leading cause of death in the
      group of "early deaths" was myocardial infarction (51%) and then causes of death
      connected to other systems of organs (38%). Hematopericardium and consequential
      cardiac tamponade was the cause of death in 8% of cases, while in 3% of cases it
      was cardiac decompensation. In the group of "late deaths" the most important
      cause of death was myocardial infarction (56%), and then cardiac decompensation
      (27%), as well as causes of death connected to other systems of organs (17%).

PMID- 8643051
TI  - [Cognitive deficits in alcoholics--significance of cognitive evoked potentials (P
      300)].
AB  - Method of event related potential has proved to be very useful in estimation of
      higher nerve functions damage, especially P-300 component as a precise indicator
      of cognitive and perceptual functioning. According to data available in
      literature, significant degree of correlation exists between evoked potential
      parameters (amplitude and latency) and deficit of psychic functions. The sample
      consisted of 37 patients (male and female) who had signs or alcohol-induced
      organic mental disorder (according to ICD-10). "Oddball" paradigm of P-300 was
      used. The results were compared with control group of 20 healthy persons. The
      results emphasized lower amplitude and prolonged latencies in the group of
      alcoholics. These findings were more significant in female subsample and may
      suggest that females are more vulnerable to alcohol than males. Our findings lead
      to the conclusion that method of event related potential (P-300) may help in
      estimating organic deficit in alcoholic patients.

PMID- 8643052
TI  - [The Epstein-Barr virus and chronic fatigue syndrome].
AB  - Lately discovered chronic fatigue syndrome is associated with Epstein-Barr virus
      infection. The objective of this paper was to detect this syndrome in our
      patients. 31 patients with cured acute infective mononucleosis were examined by
      questionnaire, physical check-up and laboratory analyses in order to detect
      disorders characteristic for chronic fatigue syndrome. Six months after they had
      been cured, out of 7 patients 5 patients complained of frequent sore throat,
      fatigue and exhaustion, and a year later, all 5 patients were sleepy and tired
      all the time. More than a year after the acute illness 19 patients were examined
      and in 5.6% frequent sore throat and enlarged neck lymph nodes occurred. The
      gathered results point to disorders characteristic for chronic fatigue syndrome
      in a high percentage. This pilot study should only be the beginning of
      examinations of this kind.

PMID- 8643053
TI  - [Neurohumoral regulation of Fallopian tube motility].
AB  - Motility of Fallopian tubes is essential for transport of ova from peritoneal
      cavity uterus. Numerous substances were found to affect motility of the tubes.
      Catecholamines cause both relaxation and contraction isolated Fallopian tubes; it
      depends on type of receptor they bind for. Acetylcholine, neurotensin and
      oxytocin stimulate motility of the tubes, while gamma-aminobutyric acid,
      vasoactive intestinal peptide and substance P have an inhibitory role. Numerous
      cytokines and their receptors were found in human oviducts; their effects on
      motility remain to be established. The whole sequence of events in regulation of
      oviducts motility is still unknown so further investigation in the field is
      required.

PMID- 8643054
TI  - [Modern approach to classification of precancerous conditions and vulvar
      dystrophy].
AB  - Precancerous conditions of vulva are diseases which can exceed into carcinomas
      and are called preblastomatoses. These are all sorts of various diseases:
      intraepithelial vulvar neoplasias, Paget's disease, precancerous circumscript
      melanosis, malignant melanoma of the first Clark level, verrucous type of
      leukoplakia, vulvar dystrophy with atypia, giant Buschke-Lowenstein's condyloma
      and chronic skin damages. Vulvar dystrophy belongs to medical terminology since
      1966 and includes a group of diseases known as leukoplakia and kraurosis, primary
      vulvar atrophy and hyperplastic vulvitis. According to classification from 1987
      vulvar dystrophies are divided into: squamocellular hyperplasia, lichen sclerosus
      and other dermatoses. The term vulvar leukoplakia is not a special disease, but
      is used for a whole group of different lesions of white color due to leukoderma,
      vitiligo, chronic infections, benign tumors, dystrophies and even invasive
      carcinomas.

PMID- 8643055
TI  - [Importance of the eustachian tube in middle ear function].
AB  - This paper reviews ventilation, drainage and protection as Eustachian tube
      functions which influence the middle ear. The most frequent etiologic factors
      which cause disorders of these functions and possible consequences on the middle
      ear are illustrated. The paper also reviews classification of the degree of
      Eustachian tube ventilation disorders, the most frequent causes of its
      dysfunction, as well as methods which are used for checking Eustachian tube
      ventilation.

PMID- 8643056
TI  - [Clinical characteristics of depressive disorders].
AB  - In this article authors investigated the clinical distinction between endogenous
      and neurotic depression. The endogenous depression was equivalent to severe
      depressive episode without psychotic symptoms, according to ICD-X criteria, and
      neurotic depression was equivalent to dysthymia. The results showed that
      endogenous depressive patients were much older than neurotic depressives, and
      that they had more severe symptoms of depression. On the other hand endogenous
      depressive patients responded better to antidepressive therapy, and consequently
      they had better prognosis than neurotic depressive patients.

PMID- 8643058
TI  - [Reform of the organization and financing of health care worldwide].
AB  - Almost all countries face reforms of health care systems in regard to
      organization and financing. Most often this is caused by coordination of health
      consumption with real material possibilities as well as by changes in reference
      to socio-political and economic systems. As a rule, reforms occur in
      administration, health insurance system, payment of health care delivery and
      organization of health care on different levels of realization. Experiences have
      shown that reforms represent a very complex and long-term process and that
      numerous factors influence the results, whereas the subjective ones often play
      the most important role. The complexity of reforms results from the fact that
      health care should not be ruled by laws of free market and that the right to
      health care, as one of the basic human rights, demands strong legal guarantees
      that it will be possible to realize, although in many countries it led to
      strengthening of the role of the country.

PMID- 8643057
TI  - [Use and efficacy of radioiodine therapy in the treatment of hyperthyroidism].
AB  - Radioiodine (131J) therapy is a method of radical treatment for hyperthyroidism.
      In our study in the period 1971-1993, we administered radioiodine therapy in 163
      patients with hyperthyroidism. We performed a long-term follow-up, from one
      month, to 21 years after the radioiodine therapy. The cured rate was 83.4%:
      euthyroid state was found in 43.6% of patients and hypothyroidism appeared in
      39.9% of patients. After the radioiodine therapy hyperthyroidism was found in
      16.6% of cases. Radioiodine therapy is very efficient, non-invasive, radical
      treatment of hyperthyroidism, not expensive and easy to administer. It has
      practically no immediate or long-term complications, except hypothyroidism.

PMID- 8643059
TI  - [Treatment of penetrating craniocerebral injuries from the Vukovar conflict, 1991
      1992. Analysis of a series].
AB  - Throughout the course of Vukovar conflict from July, 1991, to May, 1992, there
      were 37 patients with war craniocerebral injuries evacuated to our Clinic. 29
      patients suffered penetrating missile craniocerebral injuries, in 14 (48%) there
      were fragment wounds and in 15 (52%) gunshot wounds. The series was analyzed
      according to wounding agents, sites of head penetration, CT scan findings,
      neurological findings, operative and postoperative complications, and mortality.
      We have found significant difference in mortality between wounded who sustained
      fragment wounds (14%) and those with gunshot wounds (27%). Further we emphasize
      the necessity of CT scanning, concerning a high haematoma incidence of 27
      percent. Presence of retained in-driven bone or metal fragments in our series had
      no influence on development of either seizure disorder or an infectious
      complication. This supports a thesis of a limited brain debridement as a correct
      approach in the treatment of penetrating missile injuries.

PMID- 8643061
TI  - [Effect of the First Congress of Serbian Physicians and Naturalists on the Slavic
      population at the time].
AB  - After the First Congress of Serbian Physicians and Naturalists held in Belgrade
      in 1904, numerous reviews and comments were published in the Serbian and foreign
      magazines. This paper deals with the review of reports published in Belgrade,
      Zagreb, Ljubljana, Prague and Zadar. Beside some comments of the Serbian
      reporters pertaining to the professional level of the Congress, the general
      estimation was that the Congress was a great success in the professional,
      organization and social aspect. Furthermore, the Congress stirred up an intensive
      Yugoslav and Slavic temper in the participants which resulted in the initiative
      for the establishment of the Association of the Slavic Physicians and
      Naturalists.

PMID- 8643060
TI  - [Fractures of the spine in patients with ankylosing spondylitis].
AB  - Eight patients with spine fractures in chronic ankylosing spondylitis have been
      analyzed. The purpose of this article is to determine possibilities of spine
      injuries accompanied with this specific rheumatic disease and to show
      difficulties in diagnosis and problems in treatment. Ankylosing spondylitis
      affects spine in the way that it ossifficate ligaments, synovial joints and other
      soft tissue structures. Fractures that occur through these areas involve both
      bones and ligaments, producing an unstable condition, similar to a shearing type
      of classic spine injuries. The radiologic diagnosis of these injuries is
      difficult because the bone is frequently osteoporotic and displacement is of
      minor degree. In this study, 41.67% of the patients were not diagnosed initially
      and 16.67% were, for this reason, deteriorated neurologically. Therefore,
      patients known to have ankylosing spondylitis should be examined regarding the
      possibility of a fracture, and if pains persist after an injury, they should be
      thoroughly investigated radiologically to rule out a potentially serious problem.
      Reduction of the displacement and adequate stabilization, preferably by surgery,
      should be achieved whenever possible.

PMID- 8643062
TI  - [The role and importance of plasmid resistance in certain pathogenic
      enterobacteria].
AB  - Conjugation, as a process of gene recombination where R-plasmids are transferred
      from resistant to sensitive genera of bacteria, is very important in the onset
      and development of infective multiple resistance to the bacterial division
      potential, whereas it enables fast spreading of resistant genera in the human
      population. Problems in regard to etiologic therapy of intestinal infections are
      most serious in shigellosis which is shown in our results of examining 450 genera
      of Shigella-sonnei isolated during the period January 1990-December 1994. Thus,
      resistance to ampicillin occurs in 99.4%, while resistance to streptomycin and
      cotrimoxazole occurs in 94%. Results of gene resistance transmission from
      Shigella-sonnei genera, potential donors into recipients by conjugation in vitro,
      show high frequency of transfer to ampicillin which points to the fact that it is
      determined by plasmids and transposons-mobile extrachromosomal gene structure.
      Similar results are gained by multiple-resistant genera of Salmonella wien.
      However, the stereotype which is dominant in our region and which makes more than
      70% of all isolated salmonellas, Salmonella enteritidis is still sensitive to all
      most commonly used antimicrobial drugs. On the basis of gathered results it may
      be concluded that the antibiotics of choice in the etiologic therapy of
      intestinal infections are quinolone-norfloxacin and ciprofloxacin because the
      resistance which may occur is chromosomally determined.

PMID- 8643063
TI  - [Activity and function of neurons in the globus pallidus in Parkinson's disease].
AB  - We investigated the activity and functional distribution of globus pallidus
      neurons in Parkinson's disease patients and recorded single cell activity of
      globus pallidus medialis and changes related to the movements of different joints
      in 31 patients during stereotactic ventral pallidotomy procedure. We showed that
      discharge rates of 19% of medial globus pallidus neurons were modulated by
      passive contralateral movements; 77.2% of these pallidal units showed changes
      related solely to single joint movement and 22.8% showed different patterns of
      activity in relation to two and more joints. We also identified somatotopically
      arranged cell clusters that alter the discharge rate with related movements; oro
      facial movement-related cells in caudo-ventral region and, leg-related cells in
      dorso-rostral part and arm-related cells between these two parts of medial globus
      pallidus. These findings suggest a partial somatotopic organization of human
      globus pallidus medialis.

PMID- 8643064
TI  - [Atherosclerotic plaque hemorrhage as one form of a complicated atherosclerotic
      lesion].
AB  - Atherosclerotic plaque hemorrhage is a form of a complicated atherosclerotic
      lesion. It is a finding of extravasation of erythrocytes (fresh hemorrhage) or
      siderophages (old hemorrhage) in the defined atherosclerotic changes. 510
      segments of the main epicardial coronary arteries (right coronary artery,
      anterior interventricular branch of the left coronary artery, circumflex branch
      of the left coronary artery) were microscopically examined in 50 obduction cases
      of patients with ischemic heart diseases. Fresh hemorrhage in the atherosclerotic
      plaque was established in 25 cases, that is in 40 microscopically examined
      coronary artery segments. It was established in all cases where there was a
      atherosclerotic plaque rupture, in some segments where process of thrombotic
      organization occurred, as well as in some segments of arteries which supply the
      region of early myocardial infarction. All hemorrhages occur inside lipidic and
      fibrolipidic atherosclerotic changes of intima. The average length of fresh
      hemorrhage was 0.8 cm. 92.50% of segments with fresh hemorrhages occur in the
      first 4 cm of the examined arteries. 88% of plaque hemorrhages occur in segments
      with 76-100% lumen obstruction. Signs of old hemorrhages most often occur in
      segments with 51-75% and 76-100% lumen obstruction. Siderophages mostly occur in
      complicated atherosclerotic changes and thrombotic organization.

PMID- 8643066
TI  - [The Vancouver regulations and publishing in biomedical journals].
AB  - The paper deals with structure, importance and advantage as well as the path of
      development of the Uniform requirements for manuscripts submitted to biomedical
      journals (Vancouver style) from 1978, when they were established and firstly
      published, through changes and amendments up to their last--fourth edition.
      Authorship, abstract, key words and literature citation are fields dealt with in
      detail with appropriate discussions. The 16 year long existence of the Vancouver
      style, a great number of journals with high impact factor which conform to its
      requirements, as well as its advantages presented in the paper, should be a
      sufficient reason for scientists, explorers and editors of biomedical journals to
      conform to the requirements if they have not conformed to them yet.

PMID- 8643065
TI  - [Histogenesis of renal cell carcinoma].
AB  - Immunomorphological characteristics of 27 renal cell carcinomas--18 clear cell, 6
      granular, 2 chromophobic, 1 sarcomatoid--as well as 1 oncocytoma were analyzed.
      The investigation was performed on cryostat sections with indirect
      immunoperoxidase technique using monoclonal antibodies to intermediate filaments
      cytokeratin and vimentin--and renal differentiation antigens--CD10 and CD24. All
      carcinomas, with the exception of chromophobic type, showed cytokeratin/vimentin
      coexpression together with strong CD24 and weak (or absent) CD10 staining
      indicating at primitive cells with initial differentiation toward proximal tubule
      epithelium as most probable site of origin. In chromophobic cells only
      cytokeratin and CD24 antigen presence was observed, pattern similar to that seen
      in oncocytoma. It could be supposed that those two tumors have closely related
      histogenesis, originating from more differentiated cells with tendency to develop
      toward distal tubule epithelium.

PMID- 8643067
TI  - [The prostaglandin system in the kidney].

PMID- 8643068
TI  - [Life change events and the development of mental disorders].
AB  - The role of biologic, psychological and social factors and their interactions in
      etiology of psychotic disorders, is the objective of studies in psychiatry during
      the last 20 years. These changes in the outside world and social environment as
      well as life events may affect the development of psychopathologic phenomena in
      "sensitive" persons. This paper presents life events as predisposing factors
      (connection between life events in childhood and psychopathology in adulthood)
      and precipitating factors (life events which occur during the period which
      precedes the onset of the diseases) of psychotic disorders.

PMID- 8643069
TI  - [Radionuclide purity of 99mTC eluate for use in nuclear medicine].
AB  - The radionuclide purity of 99mTc eluates obtained by the elution on the
      commercially available 99Mo/99mTc generators based of fission-produced 99Mo was
      determined by gamma spectrometry. The following parameters were determined: the
      content of radionuclide impurities and their distribution in the eluates during
      the 10 days elution of the generator. The main radiocontaminant is 99Mo. In all
      eluates three long-living gamma emitters 103Ru, 106Ru and 131I were found. 125Sb
      appears only in the first three eluates. After that its activity falls under the
      detection limit. These four radioisotopes are fission products. They are formed
      in the fission of 235U and follow 99Mo during the separation and purification
      steps. It was found that the highest activity in eluates is due to the presence
      of 103Ru. By comparison of the obtained results and the prescribed criteria of
      the radio-nuclide purity of 99mTc eluates it could be concluded that all the
      found radionuclide impurities are under the permitted levels. Therefore 99mTc
      eluates fulfill the criteria for the nuclear-medical applications.

PMID- 8643070
TI  - [The effect of adenoidectomy on eustachian tube function].
AB  - 301 adenoidectomised and tonsilloadenoidectomised children were tympanometrically
      tested. The control group consisted of 89 children in whom adenoidectomy was to
      be performed. Eustachian tube dysfunction was analyzed in both groups. By
      standard statistic methods it was established that the number of Eustachian tube
      dysfunctions after adenoidectomy is statistically significantly reduced. On the
      basis of these findings, it can be concluded that well indicated, on time and
      technically well performed adenoidectomy statistically significantly reduces the
      number of Eustachian tube dysfunctions and that is why it is justified in
      therapeutic management of acute and secretory otitis media relapses.

PMID- 8643071
TI  - [Epidemiologic analysis of emergency conditions in the diabetic population as
      observed in the work of emergency medical services in the area of Novi Sad].
AB  - The authors analyzed a group of 236 diabetic patients in the municipality of Novi
      Sad who asked for the help of the Emergency medical service of the Health Center
      "Novi Sad". A special emergency team which manages vitally endangered patients
      acted on their requests. After anamnestic data were gathered and physical
      examination done, electrocardiographic monitoring was performed. Glycemia was
      determined from semiquantitative analysis of the capillary blood, while
      glycosuria and acetonuria from urine. In regard to these patients the gathered
      results point to predominant presence of chronic, degenerative complications,
      especially of the cardiovascular apparatus. However, this was the case due to the
      fact that these were elderly persons (62.78 +/- 12.21 years of age) suffering
      from diabetes mellitus for about 8 years, which is sufficient for development of
      chronic, degenerative complications of diabetes. Although the studied group was
      metabolically unregulated (glycemia: 18.13 +/- 5.43 mmol/l, glycosuria positive
      in 4.54%, acetonuria in 2.20% of patients) there were no elements for diagnosis
      of some acute metabolic complications. The decrease of acute metabolic
      complications may be connected to better organization of the antidiabetic service
      in the municipality of Novi Sad. It is especially important to point out the
      occurrence of serious hypoglycemias caused by oral hypoglycemics (64.28%) which
      require, according to contemporary approach, a long-term hospital treatment.

PMID- 8643072
TI  - [Infectious diseases: discovery of new diseases and the spread old diseases. Has
      science lost the battle with microorganisms?].

PMID- 8643073
TI  - [Nutritional status in women and estrogen production in surgical menopause].
AB  - The objective of this study was to examine how nutritional status, in women with
      bilateral ovariectomy and after preservation of ovaries, influences estrogen
      production. After bilateral ovariectomy statistically significant low values of
      urinary estrogens were recorded (21.76 nmol) in regard to ovarian preservation
      (87.80 nmol). Urinary estrogen values correlated with obesity in women with
      bilateral ovariectomy: in undernourished they were 10.50 nmol, in normally
      nourished 21.05 nmol, and in obese women 25.05 nmol. These differences are
      statistically significant. This can be explained by a higher conversion of
      androstendione to estrone, in the massive tissue, which is the main source of
      estrogen in postmenopause. This correlation does not exist in women with
      preserved ovaries, because in that case they are the basic source of estrogen.

PMID- 8643074
TI  - [Case report of a female patient with post-infection depression].
AB  - In this article the authors present a case of a secondary depression in woman, 75
      years old, without previous psychiatric anamnesis or heredity. She had post
      herpetic intercostal neuralgia and developed symptoms of depression. This case is
      an example which points to necessity of cooperation of other medical branches
      with psychiatry.

PMID- 8643075
TI  - [Case report of a rare cause of hypopituitarism].
AB  - Hypopituitarism is an illness of the hypophysis with deficit of one or more
      pituitary hormones. It can be congenital or acquired. Etiologic factors of
      acquired hypophyseal insufficiency are numerous. Pituitary gland infarction is a
      frequent cause of hypopituitarism. Extracorporeal circulation, applied in cardiac
      surgery procedures, may also, by mechanism of ischemic necrosis, cause
      hypophyseal lesions and development of hypopituitarism. This paper presents a
      case of a female patient suffering from panhypopituitarism which developed after
      extracorporeal circulation during aortocoronary bypass surgery. The authors point
      to the extracorporeal circulation as a rare etiologic factor in development of
      hypopituitarism, as well as unusual clinical picture with dominant psychic
      disorders and diagnostic and treatment procedures.

PMID- 8643076
TI  - Coexpression with potassium channel subunits used to clone the Y2 receptor for
      neuropeptide Y.
AB  - Xenopus oocytes were injected with RNAs for the two inward-rectifier potassium
      channel subunits Kir3.1 (GIRK1) and Kir3.4 (rcKATP or CIR) in addition to RNA
      from the neuroblastoma cell line KAN-TS. Potassium currents were evoked by
      neuropeptide Y in oocytes injected with polyadenylated RNA or with cRNA from
      pools of a neuroblastoma (KAN-TS) cDNA library, and progressive subdivision of
      responding pools yielded a single cDNA. The encoded protein contains 381 amino
      acids, has the seven hydrophobic domains characteristic of G protein-coupled
      receptors, and is 31% identical to the Y1 receptor: potassium currents were
      induced by neuropeptide Y (EC50=60pm) and Y2-selective analogues. Coexpression
      with potassium channel subunits will be a generally useful method for the cloning
      of G protein-coupled receptors.

PMID- 8643077
TI  - The aryl-hydrocarbon receptor, but not the aryl-hydrocarbon receptor nuclear
      translocator protein, is rapidly depleted in hepatic and nonhepatic culture cells
      exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
AB  - Western blot analysis and indirect immunofluorescence microscopy were used to
      evaluate the fate of the aryl-hydrocarbon receptor (AhR) and aryl-hydrocarbon
      receptor nuclear translocator (Arnt) protein in culture cell models exposed to
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In wild-type (WT) murine Hepa-1c1c7
      cells, AhR protein was depleted by 85% after 4 hr of TCDD treatment as measured
      in total cell lysates. In contrast, the concentration of Arnt protein was
      unaffected by TCDD treatment in WT cells. Analysis of the AhR with
      immunofluorescence microscopy revealed that nuclear translocation of the liganded
      AhR preceded its depletion from cells. AhR protein was depleted from Hepa-1 type
      I variants (that contain a concentration of AhR that is 10% of WT) with a similar
      time course and to the same maximal level observed in WT cells (85%). The EC50
      for AhR depletion in Hepa-1 cells was 39 pm TCDD and correspond to the EC50 for
      induction of P4501A1 protein. Murine embryonic fibroblasts (NIH-3T3), rat aortic
      smooth muscle cells (A7), and murine skeletal muscle cells (C2C12) all exhibited
      >90% depletion of the AhR after 2-4 hr of TCDD treatment. Arnt concentration was
      not affected by TCDD in these cell lines. These results indicate that the
      liganded AhR is rapidly depleted within the nuclear compartment of hepatic and
      nonhepatic cells in a manner independent of the Arnt protein.

PMID- 8643078
TI  - Epidermal growth factor-mediated inhibition of neurotransmitter glutamate release
      from rat forebrain synaptosomes.
AB  - We investigated the possibility that receptor tyrosine kinases are involved in
      modulating neurotransmitter release from isolated nerve terminals. We examined
      the effects of epidermal growth factor on the release of neurotransmitter
      glutamate evoked from rat forebrain synaptosomes by KCI and 4-aminopyridine. We
      detected a significant inhibition of the Ca2+-dependent component of release.
      This effect appears to be mediated by a reduction in the depolarization-evoked
      increase in cytosolic free calcium levels, in the absence of significant effects
      on the plasma membrane potential. On depolarization, a Ca2+-dependent increase
      was observed in the phosphotyrosine content of bands at molecular masses of
      approximately 107 and approximately 40 kDa. The addition of epidermal growth
      factor before depolarization induced a significant phosphorylation of the growth
      factor receptor in the absence of detectable changes in the phosphotyrosine
      pattern of total synaptosomal proteins, suggesting that phosphorylation of a
      minor protein is responsible for the epidermal growth factor-mediated inhibition
      of glutamate release.

PMID- 8643079
TI  - Role of Cu/Zn-superoxide dismutase in xenobiotic activation. I. Chemical
      reactions involved in the Cu/Zn-superoxide dismutase-accelerated oxidation of the
      benzene metabolite 1,4-hydroquinone.
AB  - Cu/Zn-superoxide dismutase (Cu/Zn-SOD) has been shown to modulate the
      autoxidation of a variety of phenoic compounds, including 1,4-hydroquinone (HQ),
      a benzene-derived metabolite. The acceleration of autoxidation of HQ by Cu/Zn-SOD
      results in the production of 1,4-benzoquinone (BQ). It has been proposed that the
      chemical mechanism involved in the Cu/Zn-SOD-catalyzed autoxidation of HQ may be
      occur through either its conventional activity as a superoxide:superoxide
      oxidoreductase or as a semiquinone:superoxide oxidoreductase. However, Cu/Zn-SOD
      accelerated oxidation of HQ has not been resolved experimentally. In this study,
      with ESR spectroscopy we investigated further the chemical reactions involved in
      the SOD-accelerated oxidation of HQ. In phosphate-buffered saline (PSB), HQ
      underwent a slow autoxidation to BQ, which was accelerated by Cu/Zn-SOD, Mn-SOD,
      or Fe-SOD with similar efficiency. In contrast, among free metals, only Cu(II)
      strongly mediated the oxidation of HQ to BQ. Mn(II) exhibited a slight capacity
      to oxidize HQ, whereas neither FE(II) nor FE(III) was capable of modulating the
      autoxidation of HG. The presence of either form of SOD also dramatically enhanced
      the formation of semiquinone anion radicals SQ-. from HQ. The SOD-accelerated
      oxidation of HQ was also accompanied by the generation of H202. In PBS containing
      bovine serum albumin (BSA) (PBS/BSA), HQ did not undergo autoxidation to SQ-.,
      and as such the presence of SOD was unable to induce the formation of either SQ-.
      or BQ or the consumption of O2. The addition of 10 microM BQ to HQ (100 or 1000
      microM) in PBS/BSA resulted in the formation of SQ-. and initiated a slow rate of
      oxidation of HQ to BQ. In this case, the presence of Cu/Zn-SOD strongly
      accelerated the oxidation of HQ to SQ-. and BQ and the utilization of O2.
      Furthermore, the enhancement by Cu/Zn-SOD of the generation of SQ-. or BQ from HQ
      in PBS/BSA was extensively inhibited under anaerobic conditions. The enhancement
      of SQ-. generation from HQ by all three forms of SOD does not support the
      possibility that Cu/Zn-SOD can oxidize SQ-. to BQ. Taken together, this study
      demonstrates that unlike free copper, Cu/Zn-SOD does not directly interact with
      HQ to cause its oxidation to BQ. Rather, the autoxidation of HQ to SQ-. is a
      prerequisite for the enhancing capacity of Cu/Zn-SOD, and the dismutation of
      superoxide anion radicals generated from the SQ-. in the presence of O2 appears
      to be the underlying mechanism responsible for the enhancement by Cu/Zn-SOD of
      the oxidation of HQ.

PMID- 8643080
TI  - Role of Cu/Zn-superoxide dismutase in xenobiotic activation. II. Biological
      effects resulting from the Cu/Zn-superoxide dismutase-accelerated oxidation of
      the benzene metabolite 1,4-hydroquinone.
AB  - Cu/Zn-superoxide dismutase (SOD)-accelerated oxidation of the benzene metabolite
      1,4-hydroquinone (HQ) results in the enhanced formation of semiquinone anion
      radicals, electrophilic 1,4-benzoquinone (BQ), and H202. We selected bone marrow
      stromal cells and phiX-174 double stranded plasmid DNA as model systems to
      investigate the cytotoxicity and DNA cleaving activity of the Cu/Zn-SOD-mediated
      activation of HQ. The addition of either Cu/Zn-SOD or Min-SOD to the primary bone
      marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity,
      which could be completely prevented by adding reduced glutathione (GSH) or
      dithiothreitol but not be adding catalase. Incubation of the plasmid DNA with the
      HQ/Cu/Zn-SOD system resulted in the induction of single- as well as double-strand
      breaks, which could be inhibited by catalase and the Cu(I) chelators,
      bathocuproinedisulfonic acid (BCS) and GSH. Although Mn-SOD could enhance HQ
      induced cytotoxicity to stromal cells, the activation of HQ by Mn-SOD did not
      contribute to the induction of DNA strand breaks. Similar to the HQ/Cu(II) and
      H202/Cu(II) systems, the DNA strand breaks mediated by HQ/Cu/Zn-SOD could not be
      effectively inhibited by the hydroxyl radical scavengers, including
      dimethylsulfoxide, mannitol, and 5,5-dimethyl-1-pyrroline N-oxide, but could be
      protected by sodium azide. Low-temperature electron spin resonance experiments
      showed that incubation of Cu/Znu-SOD with HQ resulted in the release of copper
      from the Cu/Zn-SOD, which could be prevented by catalase. Alpha-(4-Pyridyl-1
      oxide)-N-tert-butylnitrone (POBN)/spin-trapping studies demonstrated that the
      interaction of HQ with Cu/Zn-SOD, but not with Mn-SOD, resulted in the
      significant formation of POBN-CH3 adduct in the presence of dimethylsulfoxide,
      suggesting the production of hydroxyl radical or its equivalent from this
      enzyme/xenobiotic interaction. The formation of the POBN-CH3 adduct from the
      HQ/Cu/Zn-SOD could be inhibited by catalase, BCS or GSH, indicating the important
      role for H202 and Cu(I) in the production of reactive oxygen species. Addition of
      human myeloperoxidase to the HQ/Cu/Zn-SOD synergistically enhanced the formation
      of BQ from HQ. This enhancement could be abolished by catalase. Taken together,
      these results demonstrate that activation of HQ by either Cu/Zn-SOD or Mn-SOD
      results in cytotoxicity to primary bone marrow stromal cells through the
      formation of electrophilic BQ. Interaction of HQ with Cu/Zn-SOD causes oxidative
      damage to Cu/Zn-SOD, leading to the release of copper from the enzyme. The
      further reaction between the released copper and H202 generates reactive oxygen
      species that participate in the induction of strand breaks in plasmid DNA. The
      H202 generated from the Cu/Zn-SOD-accelerated oxidation of HQ can also be
      utilized by myeloperoxidase resulting in additional conversion of HQ to BQ.

PMID- 8643081
TI  - Changes in the carboxyl-terminal domain of metabotropic glutamate receptor 1 by
      alternative splicing generate receptors with differing agonist-independent
      activity.
AB  - The metabotropic glutamate receptors (mGluRs) share no sequence homology and show
      different structural features compared with most other G protein-coupled
      receptors (GPCRs). In particular, some isoforms of the phospholipase C (PLC)
      coupled mGluRs (mGluR1a, mGluR5a, and mGluR5b) have a surprisingly long carboxyl
      terminal intracellular domain of more than 350 residues, whereas the splice
      variants mGluR1b and mGluR1c have a much shorter carboxyl terminus. In the
      current study, the different splice variants of mGluR1 were expressed in porcine
      kidney epithelial (LLC-PK1) or the human embryonic kidney (HEK 293) cells, and
      their levels of expression were examined with the use of Western blot analysis.
      Expression of the short isoforms mGluR1b and mGluR1c did not modify the basal
      inositol phosphate production. In contrast, expression to similar levels of
      mGluR1a resulted in a 2-fold increase in the basal inositol phosphate formation.
      This increase in basal PLC activity was due to neither the presence of a low
      concentration of glutamate in the incubation medium nor a modification of the PLC
      pathway, resulting, for example, from the constant activation of mGluR1a++ by
      glutamate during the culture. Surprisingly none of the known competitive
      antagonists of mGluR1 inhibited the basal PLC activity, indicating that none of
      these molecules act as inverse agonists. Taken together, these results indicate
      that the long carboxyl-terminal domain confers a small agonist-independent
      activity to mGluR1. This indicates that, as already observed for other GPCRs,
      little constitutive activity of wild-type mGluRs can be detected. Our results
      also add to the splice variants and further suggest that the long carboxyl
      terminal domain of mGluR1a confers better coupling efficiency to the G proteins.

PMID- 8643082
TI  - Variants of human dihydrofolate reductase with substitutions at leucine-22:
      effect on catalytic and inhibitor binding properties.
AB  - We investigated the enzyme kinetic and antifolate inhibitory properties of human
      dihydrofolate reductase enzyme with mutations at position 22. Leu-22 was changed
      to isoleucine, methionine, phenylalanine, and tyrosine to generate the various
      mutant enzymes. The overall catalytic efficiency (kcat/Km) for methionine and
      phenylalanine mutants was reduced approximately 3-fold and >6-fold for isoleucine
      and tyrosine mutants. An arginine mutant (L22R) was also expressed but had a
      dramatically reduced catalytic potential (kcat>250-fold lower than wild-type) and
      therefore was not studied in detail. The Ki for antifolates, methotrexate,
      aminopterin, and trimetrexate are more dramatically affected (increased) than the
      Km for dihydrofolate, particularly for phenylalanine and tyrosine mutants. One
      remarkable feature is that the phenylalanine mutant is as potently inhibited by
      piritrexim as is the wild-type human enzyme, although the Ki values for
      methotrexate and aminopterin were increased 88- and 118-fold, respectively. This
      is likely related to different positioning of the methoxyphenyl side chain of
      piritrexim relative to the side chains of other compounds tested. A Chinese
      hamster cell line harboring the L22F mutant also demonstrated an increased
      sensitivity of piritrexim relative to antifolates.

PMID- 8643083
TI  - Mechanisms of desensitization and resensitization of G protein-coupled
      neurokinin1 and neurokinin2 receptors.
AB  - We compared the desensitization of neurokinin1 and neurokinin2 (NK1 and NK2)
      receptors expressed in Chinese hamster ovary cells to substance P and neurokinin
      A, respectively. Substance P and neurokinin A stimulated a rapid increase in
      intracellular Ca2+ concentration ([Ca2+]i) for both receptors, which was due to
      release of Ca2+ from intracellular stores. This was followed by a plateau in
      [Ca2+]i, which was due to influx of extracellular Ca2+, and was more sustained
      for the NK2 receptor. When Ca2+ was present in the extracellular solution, the
      Ca2+ response of the NK1 receptor, but not the NK2 receptor, rapidly desensitized
      and slowly resensitized to two exposures to agonist. In contrast, the [Ca2+]i
      response, measured in Ca2+-free solution, and inositol triphosphate generation
      desensitized and resensitized similarly for the NK1 and NK2 receptors. Thus,
      differences in desensitization between the NK1 receptor and the NK2 receptor may
      be related to differences in entry of extracellular Ca2+. We compared endocytosis
      of the NK1 and NK2 receptors to determine whether disparities could account for
      differences in desensitization. Fluorescent and radiolabeled substance P and
      neurokinin A were internalized similarly by cells expressing NK1 and NK2
      receptors. Thus, disparities in internalization cannot account for differences in
      desensitization. We used inhibitors to examine the contribution of endocytosis,
      recycling, and phosphatases to desensitization and resensitization of the NK1
      receptor. Desensitization did not require endocytosis. However, resensitization
      required endocytosis, recycling, and phosphatase activity. This suggests that the
      NK1 receptor desensitizes by phosphorylation and resensitizes by
      dephosphorylation in endosomes and recycling.

PMID- 8643084
TI  - Endothelin-1-induced mitogenic responses of Chinese hamster ovary cells
      expressing human endothelinA: the role of a wortmannin-sensitive signaling
      pathway.
AB  - In the current study, endothelin-1 (ET-1) worked as a mitogen on Chinese hamster
      ovary cells stably expressing human endothelinA; when applied to serum-deprived
      cells, ET-1 caused dose-dependent increase in [3H]thymidine incorporation and
      cell proliferation. No synergism was observed between the effect of ET-1 and that
      of insulin-like growth factor-1/basic fibroblast growth factor. Both the
      inhibition of intracellular Ca2+ response by phospholipase C inhibitor U73122 and
      the down-regulation of protein kinase C (PKC) by pretreatment with phorbol 12
      myristate-13-acetate (PMA) partially blocked the ET-1-induced mitogenic
      responses. Wortmannin, a phosphatidylinositol-3-kinase inhibitor, caused dose
      dependent inhibition of the ET-1-induced mitogenic responses in both PMA-treated
      and -untreated cells. Wortmannin also inhibited ET-1-induced increase in
      phosphatidylinositol trisphosphate formation and activation of mitogen-activated
      protein kinase (MAPK), whereas it failed to inhibit PMA-induced activation of
      MAPK. In accordance with its effect on MAPK activation, wortmannin inhibited ET-1
      induced activation of Raf-B, whereas it failed to inhibit the effect of PMA.
      These results suggested the role of a Ca2+/PKC-independent, wortmannin-sensitive
      signaling pathway that linked ETA and MAPK cascade in the mitogenic signaling
      activated by ETA.

PMID- 8643085
TI  - Expression and zonal distribution of CYP2D16 in the guinea pig adrenal cortex:
      relationship to xenobiotic metabolism.
AB  - We recently cloned a CYP2D subfamily member (CYP2D16) from a guinea pig adrenal
      cDNA library and investigated the expression of CYP2D16 in the guinea pig adrenal
      cortex and its relationship to adrenal xenobiotic metabolism. A modified sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis technique revealed three major
      bands in the molecular mass range of cytochromes P450 in guinea pig adrenal
      microsomes. Two of the bands were immunoreactive with anti-CYP17 (54 kDa) or anti
      CYP21 (52 kDa) antibody. The third band (50 kDa) was immunoreactive with antibody
      raised against CYP2D1 and with anti-CYP1A1/1A2 antibody. Microsequencing of the
      50-kDa band yielded an amino-terminal sequence of 38 amino acids identical to
      that deducted from the CYP2D16 cDNA. In addition, Northern blot analyses
      indicated the CYP1A1 was not expressed in the adrenal gland, suggesting that only
      CYP2D16 composed the microsomal 50-kDa band. Sodium dodecyl sulfate
      polyacrylamide gel electrophoresis and Western blot analyses demonstrated greater
      expression of CYP2D16 in microsomes from the inner zone (zona reticularis) of the
      adrenal cortex than from the outer zones, coinciding with the major site of
      adrenal xenobiotic metabolism. Bufuralol-1'-hydroxylase activity, a marker for
      CYP2D isozymes, was also greater in inner- than in outer-zone microsomal
      preparations and was highly correlated with CYP2D16concentrations. Northern blot
      analysis with a full-length CYP2D16 cDNA as the probe gave strong bands with
      adrenal inner zone RNA preparations and relatively weak bands with outer zone
      RNA. CYP2D16 mRNA was also detectable in liver and kidney RNA preparations, but
      at lower levels than in the adrenal inner zone, and it was not detectable in
      testes, lung, intestines, or heart. Overall, the results demonstrate that CYP2D16
      is expressed at highest levels in the inner zone of the guinea pig adrenal cortex
      and suggest a major role for this isozyme in adrenal xenobiotic metabolism.

PMID- 8643086
TI  - Comparison of Na+-dependent glutamate transport activity in synaptosomes, C6
      glioma, and Xenopus oocytes expressing excitatory amino acid carrier 1 (EAAC1).
AB  - Several subtypes of sodium-dependent high affinity (SDHA) glutamate transporters
      have been pharmacologically differentiated in brain tissue. Recently, four
      distinct cDNAs (EAAC1, GLT1, GLAST, and EAAT4) encoding Na+-dependent glutamate
      transporters have been isolated, but the properties of some of these transporters
      do not fully match the properties of transport observed in brain tissue or
      astrocyte-enriched cultures. The purpose of the current investigation was to
      determine whether the pharmacological properties of EAAC1 parallel those observed
      in cortical or cerebellar synaptosomes, C6 glioma, or primary astrocyte-enriched
      cultures. EAAC1 cRNA was expressed in Xenopus oocytes, an expression system with
      no detectable endogenous Na+-dependent glutamate transport activity. EAAC1
      mediated glutamate transport was >98% Na+ dependent, and the transport was
      saturable and consistent with a single site. Glutamate transport activates in
      EAAC1-injected oocytes and C6 glioma have similar Km values for glutamate (Km =
      15-24 microM) and Na+ (apparent Km = 35-50mM), and these values markedly differ
      from those observed in rat synaptosomes (glutamate, Km = 1-5 microM; Na+, Km = 13
      20 mM). Several excitatory amino acid analogues were tested as inhibitors of L
      [3H] glutamate transport in oocytes expressing EAAC1 cRNA. The potencies of
      several compounds for inhibition of EAAC1-mediated transport differed from those
      previously observed in cerebellar synaptosomes and astrocyte-enriched cultures.
      Although EAAC1-mediated transport and cortical synaptosomal transport have
      similar pharmacological profiles, five excitatory amino acid analogues were > or=
      3-fold more potent as inhibitors of transport into cortical synaptosomes than of
      transport into EAAC1-injected oocytes. For example, L-trans-pyrrolidine-2,4
      dicarboxylate was approximately 5-fold more potent in cortical synaptosomes, and
      dihydrokainate was approximately 10-fold more potent in cortical synaptosomes
      than in EAAC1-injected oocytes. In contrast, all of the compounds examined
      inhibit transport observed in C6 glioma wtih potencies similar to that observed
      in oocytes injected with EAAC1 cRNA. Consistent with these data, C6 glioma
      expressed EAAC1- but not GLT1- and GLAST-like immunoreactivity. Although this
      immunoreactivity migrated as proteins of slightly different molecular masses in
      each system, treatment with N-glycosidase F shifted all proteins to a molecular
      mass consistent with that predicted from the cDNA sequence. In cortical
      synaptosomes, EAAC1-, GLT1-, and GLAST-like immunoreactives were apparent. These
      results indicate that (i) EAAC1 but not GLAST or GLT1 transporters are expressed
      in C6 glioma, (ii) synaptosomes contain a heterogeneous population of
      transporters, (iii) EAAC1 does not account for the pharmacology previously
      observed in cortical synaptosomes, and (iv) based on the pharmacology and tissue
      distribution of EAAC1, GLT1, GLAST, and EAAT4, it appears that there are
      additional glutamate transporter subtypes.

PMID- 8643087
TI  - Differences in agonist-independent and -dependent 5-hydroxytryptamine2C receptor
      mediated cell division.
AB  - Previous studies have shown that agonist activation of the 5-hydroxytryptamineC
      (5-HT2C) receptor expressed in NIH-3T3 fibroblasts results in development of a
      transformed phenotype. In light of recent evidence from our laboratory
      demonstrating constitutive 5-HT2C receptor activity, we examined the contribution
      of this agonist-independent activity to basal cell division. 5-HT2C receptor
      ligands modulated [3H]thymidine incorporation, DNA amounts, and cell number in
      serum-starved NIH-3T3 fibroblasts transfected with 5-HT2C receptor cDNA. Three
      classes of 5-HT2C receptor ligands were distinguished in transfected, but not
      nontransfected, fibroblasts. Basal [3H]thymidine incorporation was increased by
      agonists and decreased by inverse agonists, whereas neutral antagonists had
      little or no effect alone. Neutral antagonists did, however, block the effects of
      both agonists and inverse agonists. The rank order of potencies of inverse
      agonists to decrease basal [3H]thymidine incorporation was consistent with their
      rank order to decrease basal 5-HT2C receptor-mediated phosphoinositide
      hydrolysis. However, two antagonists previously classified as inverse agonists
      based on their ability to eliminate basal phosphoinositide hydrolysis did not
      elicit comparable reductions in basal [3H]thymidine incorporation. For example,
      mesulergine had no effect on basal cell division, even though it eliminates the
      phosphoinositide hydrolysis response. Pertussis toxin, which inactivates G
      proteins in the Gi and Go families, had no effect on basal [3H]thymidine
      incorporation or basal phosphoinositide hydrolysis but partially inhibited these
      responses when elicited by an agonist. Thus, agonist occupation of the 5-HT2C
      receptor apparently activates different or additional G proteins compared with
      constitutive 5-HT2C receptor activation. In conclusion, our findings suggest that
      constitutively active 5-HT2C receptors stimulate cell division in transfected
      fibroblasts in the absence of an agonist. In addition, the 5HT2C receptor may use
      multiple signaling pathways to mediate its effects.

PMID- 8643089
TI  - Homomeric beta 1 gamma-aminobutyric acid A receptor-ion channels: evaluation of
      pharmacological and physiological properties.
AB  - The ubiquitous distribution of gamma-aminobutyric acid A (GABAA) receptor beta
      subunits throughout the central nervous system is in accord with a vital role in
      receptor structure and function. Homomeric beta subunits have been reported to be
      either GABA-gated or capable of forming anion-selective channels that lacked GABA
      gating properties. With electrophysiological recording techniques, we examined
      the properties of the murine Beta 1 subunit, addressed whether the homomeric
      receptor is expressed independently from the host cell's genome, and investigated
      whether these channels can open spontaneously. Murine beta 1 subunits, expressed
      in Xenopus oocytes or A293 cells, were unaffected by GABA or bicuculline;
      however, the resting membrane conductances were reduced by picrotoxin, zinc, or
      penicillin-G. In comparison, the expression of bovine beta1 subunits formed GABA
      gated C1- channels. For murine beta 1 subunits, both pentobarbitone and propofol
      increased the membrane conductance, although the benzodiazepine ligands
      flurazepam, flumazenil, and methyl-6,7-dimethoxy-4 ethyl-beta-carboline-3
      carboxylate were inactive. Oocytes injected with murine beta 1 cRNA in the
      presence of actinomycin D (to block host cell DNA transcription) expressed beta1
      channels that were indistinguishable from those derived from previous cDNA
      injections in cells capable of normal transcription. Single-channel recording
      from murin beta 1 cDNA-injected oocytes revealed spontaneously opening channels
      with a main state conductance of 18 pS. Picrotoxin inhibited the channel openings
      by reducing the probability of opening. We concluded that murine beta 1 subunits
      can form functional ion channels that are not gated by GABA but can be closed by
      some noncompetitive GABA antagonists. Interestingly, previous observations of
      spontaneously opening ion channels with properties similar to those found for the
      murine beta 1 receptor suggest that a limited expression of homomeric beta
      subunit-ion channels may exist in vivo.

PMID- 8643088
TI  - Activation of 5-hydroxytryptamine4 receptors causes calcium influx in
      adrenocortical cells: involvement of calcium in 5-hydroxytryptamine-induced
      steroid secretion.
AB  - 5-Hydroxytryptamine (5-HT) stimulates corticosteroid secretion from adrenal cells
      through activation of 5-HT4 receptors positively coupled to adenylyl-cyclase. In
      the present study, we investigated in frog adrenocortical cells the effect of 5
      HT4 receptor agonists on cytosolic calcium concentration ([Ca2+]i) and determined
      the sequence of events associated with 5-HT4 receptor agonist zacopride (10[-8]
      to 10[-5]M each in the vicinity of cultured adrenocortical cells caused a dose
      dependent increase in [Ca2+]i. Preincubation of the cells with the selective 5
      HT4 receptor antagonist [1-[2-(methylsulfonylamino)ethyl]-4- piperidinyl]methyl-1
      methyl-1H-indole-3-carboxylate maleate totally blocked the 5-HT-induced
      stimulation of [Ca2+]i. Chelation of extracellular calcium with ethylene glycol
      bis (beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid (10 MM) suppressed the
      stimulatory effect of 5-HT on [Ca2+]i. Conversely, thapsigargin, an inhibitor of
      calcium ATPase activity, had no effect on the [Ca2+]i rise. The calcium influx
      induced by 5-HT4 receptor agonists was not affected by nifedipine and omega
      conotoxin GVIA but was totally blocked by pimozide, a T-type calcium channel
      antagonist. The [Ca2+]i response to zacopride was potentiated by the
      phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and markedly reduced by
      the protein kinase A inhibitor adenosine-3',5'-cyclic monophosphorothioate. We
      studied in perifused frog adrenal slices the involvement of [Ca2+]i rise and cAMP
      formation in the mechanism of action of 5-HT4 receptor agonists. Zacopride
      induced steroidogenesis was significantly reduced in the presence of adenosine
      3'5'-cyclic monophosphorothioate or after suppression of calcium in the
      perifusion medium. The stimulatory effect of zacopride on corticosteroid
      secretion was not affected by nifedipine and omega-conotoxin GVIA but was
      significantly inhibited by pimozide. Taken together, these data indicate that
      activation of 5-HT4 receptors in adrenocortical cells causes stimulation of
      adenylyl cyclase and subsequently increases calcium influx through a T-type
      calcium channel. Both the increased in cAMP formation and the calcium rise are
      involved in the stimulatory effect of 5-HT on corticosteroid secretion.

PMID- 8643090
TI  - Gastrin-releasing peptide receptor signaling resulting in growth inhibition.
AB  - We demonstrate that gastrin-releasing peptide (GRP) can inhibit the proliferation
      of human immortal nontumorigenic (184-B5) mammary epithelial cells ectopically
      expressing the human GRP receptor. Growth of Balb 3T3 cells ectopically
      expressing relatively high levels of the GRP receptor was also inhibited by GRP;
      however, growth of transfectants expressing lower levels of the receptor was not
      inhibited. Compared with Balb 3T3 cells, mammary epithelial cells could be
      rendered sensitive to growth inhibition by GRP by the expression of fewer GRP
      receptors. GRP also stimulated DNA synthesis in quiescent, serum-starved Balb 3T3
      transfectants. In clones that were sensitive to growth inhibition by GRP by
      virtue of their expression of relatively high levels of the GRP receptor, the
      dose-response curve of GRP-stimulated DNA synthesis was bell shaped. This is
      consistent with our conclusion that the growth-inhibiting activity of GRP
      required the activation of a relatively large pool of receptors in Balb 3T3
      cells. Significantly, prostaglandin H synthase inhibitors, which block the
      production of prostaglandins from arachidonic acid, reduced GRP-inhibitory
      effects on DNA synthesis. We also compared a number of GRP-stimulated signaling
      pathways in Balb 3T3 clones that were sensitive or insensitive to growth
      inhibition by GRP, including cAMP formation, phospholipase C activation, calcium
      mobilization, and arachidonic acid formation. Taken together, these results
      demonstrate a novel GRP receptor-coupled signal pathway promoting growth
      inhibition in which prostaglandin H synthase plays a significant role.

PMID- 8643091
TI  - Metabolism of all-trans, 9-cis, and 13-cis isomers of retinal by purified
      isozymes of microsomal cytochrome P450 and mechanism-based inhibition of retinoid
      oxidation by citral.
AB  - The involvement of a series of microsomal cytochrome P450 (P450) isozymes in all
      trans-retinoid metabolism, including the conversion of all-trans-retinal to all
      trans-retinoic acid, was previously described. In the current study, we examined
      the role of seven liver microsomal P450 isozymes in the oxidation of three
      isomers of retinal. P450 1A1, which was not tested previously, is by far the most
      active in the conversion of all-trans-, 9-cis-, and 13-cis-retinal to the
      corresponding acids, as well as in the 4-hydroxylation of all-trans- and 13-cis
      retinal. In contrast, P450s 2B4 and 2C3 are the most active in the 4
      hydroxylation of 9-cis-retinal, with turnover numbers approximately 7 times as
      great as that of P450 1A1. The inclusion of cytochrome b5 in the reconstituted
      enzyme system is without effect or inhibitory in most cases but stimulates the 4
      hydroxylation of 9-cis-retinal by P450 2B4, giving a turnover of 3.7 nmol of
      product/min/nmol of this isozyme, the highest for any of the retinoid conversions
      we have studied. Evidence was obtained for two additional catalytic reactions not
      previously attributed to P450 oxygenases: the oxidation of all-trans- and 9-cis
      retinal to the corresponding 4-oxo derivatives by isoform 1A2, and the oxidative
      cleavage of the acetyl ester of vitamin A (retinyl acetate) to all-trans-retinal,
      also by isoform 1A2. The physiological significance of the latter reaction, with
      a Km for the ester of 32 microM and a Vmax of 18 pmol/min/nmol of P450, remains
      to be established. We also examined the effect on P450 of citral, a terpenoid
      alpha, beta-unsaturated aldehyde and a known inhibitor of cytosolic retinoid
      dehydrogenases. Evidence was obtained that citral is an effective mechanism-based
      inactivator of isozyme 2B4, with a KI of 44 microM as determined by the oxidation
      of 1-phenylethanol to acetophenone, and by isozyme 1A2 in the oxidation of all
      trans-retinal to the corresponding acid and by isozyme 2B4 in the 4-hydroxylation
      of all-trans-retinol and retinoic acid. Thus, citral is not suitable for use in
      attempts to distinguish between retinoid conversions catalyzed by dehydrogenases
      in the cytoplasm and by P450 cytochromes in the endoplasmic reticulum.

PMID- 8643092
TI  - Phenobarbital induction of hepatic CYP2B1 and CYP2B2: pretranscriptional and post
      transcriptional effects of gender, adult age, and phenobarbital dose.
AB  - Chemical induction of hepatic monooxygenases should not be viewed as an
      extracorporal process but rather as one that is liable to be influenced by
      numerous endogenous factors. In this regard, we examined the interactions of
      gender, adult age, and barbiturate dose on the course of phenobarbital induction
      of hepatic CYP2B1 and CYP2B2. We observed that femaleness and youth were
      associated with the greatest inhibition, so that both the rate and initiation of
      CYP2B1 and CYP2B2 induction were suppressed most in the young adult (65 days of
      age) females, followed by the mature adult (150 days of age) females and then by
      the young adult males, with the mature adult males exhibiting the least
      suppression of phenobarbital induction. The differential expression rates of
      hepatic CYP2B1 mRNA in the young and mature male and female rats, similarly
      reflected at the protein level, suggest that gender- and age-dependent
      suppression of CYP2B1 occurs at a pretranscriptional or transcriptional level. In
      contrast, transcript levels of CYP2B2 were unaffected by gender or age. However,
      accumulation of cytochrome P450 (P450) 2B2 protein was affected by the animal's
      age and gender, suggesting regulation of a post-transcriptional event. Highly
      selective (androstenedione 16beta-hydroxylase) as well as nonspecific (total P450
      and hexobarbital hydroxylase) P450 2B1- and 2B2-dependent catalytic activities
      were in agreement with protein levels. Determination of gender- and age-dependent
      circulating growth hormone profiles indicates that the continuous secretion of
      the hormone characteristic of the female is more suppressive of CYP2B induction
      than the episodic pattern growth hormone secretion found in males. The
      considerably elevated growth hormone pulse amplitudes observed in the young rats
      of both genders seem to be an additional inhibitory signal antagonizing
      phenobarbital induction of CYP2B1 and CYP2B2. Phenobarbital administration did
      not interfere with the normal gender- and age-dependent growth hormone secretory
      profiles. Last, although as little as 1 mg/kg phenobarbital increased CYP2B1 mRNA
      concentrations by 100%, there was no translation into detectable levels of
      protein. In contrast, the same low dose of barbiturate inducing an equal percent
      increase in CYP2B2 mRNA did result in an expression of protein. Unlike use of the
      10 mg/kg dose, CYP2B1 and CYP2B2 induction by phenobarbital at 1 mg/kg was
      unaffected by age or gender.

PMID- 8643093
TI  - Relation among the resistance factor, kinetics of uptake, and kinetics of the P
      glycoprotein-mediated efflux of doxorubicin, daunorubicin, 8-(S)
      fluoroidarubicin, and idarubicin in multidrug-resistant K562 cells.
AB  - Multidrug resistance (MDR) is frequently associated with decreased cellular drug
      accumulation resulting from enhanced drug efflux. This is correlated with the
      presence of a membrane protein, the P-glycoprotein, which pumps a wide variety of
      drugs out of cells, reducing their intracellular concentration and thus their
      toxicity. The influx and efflux of drugs across the cell membrane are in large
      part responsible for their intracellular concentrations, and in the search for
      new compounds able to overcome MDR, it is of prime importance to determine the
      molecular parameters whose modification would lead to an increase in the kinetics
      of uptake and/or to a decrease in the P-glycoprotein-medicated efflux. Four
      anthracycline derivatives, doxorubicin, daunorubicin, 8-(S)-fluoroidarubicin, and
      idarubicin, which have the same amino sugar, were used to analyze the respective
      contribution of the kinetics of uptake and the P-glycoprotein-mediated efflux in
      their impaired accumulation in MDR cells. The kinetics of uptake of the four
      drugs vary over a very large range: the kinetics of uptake of daunorubicin, 8-(S)
      fluoroidarubicin, and idarubicin are 16, 200, and 400 times higher than that of
      doxorubicin, respectively. However, the four drugs are extruded by P-glycoprotein
      at comparable rates. The apparent Km values for P-glycoprotein-mediated
      transport, the intracellular free cytosolic drug concentrations at half-maximal
      velocity for the cell lines used, were approximately 2.2 microM for daunorubicin
      and and approximately 1 microM for idarubicin and 8-(S)-fluoroidarubicin.

PMID- 8643094
TI  - Antagonist pharmacology of kainate- and alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid-preferring receptors.
AB  - Whole-cell recordings were used to study the antagonist pharmacology of two
      subtypes of non-N-methyl-D-aspartate glutamate receptors: the kainate-preferring
      subtype expressed by rat dorsal root ganglion (DRG) neurons and the alpha-amino-3
      hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring subtype expressed by
      neurons from rat cerebral cortex. A series of quinoxaline derivatives were tested
      for the ability to distinguish between AMPA and kainate receptors, as determined
      by differential potency. Of the nine compounds studied, 2,3-dihydroxy-6-nitro-7
      sulfamoylbenzo(f)quinoxaline (NBQX) showed the highest selectivity for AMPA
      preferring receptors, whereas 5-chloro-7-trifluoromethyl-2,3-quinoxalinedione
      (ACEA-1011) showed the highest selectivity for the kainate-preferring subtype.
      NBQX blocked non-N-methyl-D-aspartate currents in cortical cells with a Kb of 0.3
      mircroM, but in DRG neurons the Kb for NBQX was 3-fold higher (0.9 microM). ACEA
      1011 also blocked the currents in DRG cells with a Kb of approximately 1 microM,
      but in cortical neurons the kb for this drug was 10-12 microM. Several the Kb for
      this drug was 10-12 micron. Several additional compounds were tested for
      selective potency, including 5-nitro-6,7,8,9-tetrahydrobenzo[G]indole-2,3-dione-3
      oxime, gamma-D-glutamylaminomethylsulphonic acid, and derivatives of kynurenic
      acid and 1-benzazepine. 5-Nitro-6,7,8,9-tetrahydrobenzo- [G]indole-2,3-dione-3
      oxime displayed the highest selectivity in this group, blocking kainate receptors
      with a Kb of 6 microM while inhibiting AMPA receptors with a Kb of >100 microM.
      The remaining antagonists showed <3-fold selectivity between AMPA and kainate
      receptor subtypes. Our results suggest that most competitive antagonists block
      native AMPA and kainate receptors with approximately similar potencies, which is
      in marked contrast to the substantial differences in potency that have been
      observed with receptor agonists.

PMID- 8643095
TI  - N-[5-nitro-2-furfurylidene]-3-amino-2-oxazolidinone activation by the human
      intestinal cell line Caco-2 monitored through noninvasive electron spin resonance
      spectroscopy.
AB  - The pathways participating in the metabolism of the nitrofuran antimicrobial drug
      N-[5-nitro-2-furfurylidene]-3-amino-2-oxazolidinone (furazolidone) in intact
      cells were investigated in the human intestinal cell line Caco-2. One-electron
      reduction of furazolidone led to the formation of a free radical intermediate
      that could be monitored in dense cell suspensions by noninvasive electron spin
      resonance spectroscopy. The effects of enzyme inhibitors on the kinetics of
      radical production and decay were used to estimate the relative contribution of
      different enzymes to the reductive activation of the drug. Although many enzymes
      are known to reduce nitrofurans in vitro (e.g., xanthine oxidase, aldehyde
      oxidase, DT-diaphorase, mitochondrial redox chain components), their
      contributions were insignificant in living Caco-2 cells. The first reducing
      equivalent required for the formation of the nitroanion derivative of
      furazolidone appeared to be provided essentially by the microsomal cytochrome
      P450 reductase. This was confirmed through studies of the NADPH-dependent radical
      formation by microsomes. Differentiated Caco-2 cells, an established enterocyte
      model, showed only modestly increased radical formation and the same enzyme
      specificity pattern as undifferentiated cells. Consistently, only a small
      increase in P450 reductase activity was found in differentiated cells, in
      contrast to the 10-fold increase seen in typical differentiation marker enzymes.
      With the electron spin resonance method that we describe, it is possible to
      distinguish between sites of bioactivation of redox active drugs in intact cells.

PMID- 8643096
TI  - Are 5-hydroxytryptamine7 receptors involved in [3H]5-hydroxytryptamine binding to
      5-hydroxytryptamine 1nonA-nonB receptors in rat hypothalamus?
AB  - We assayed [3H]5-hydroxytryptamine ([3H]5-HT) binding in rat hypothalamic
      membranes to confirm the possible of measuring 5-HT7 receptors. Binding was
      tested in the presence of 3 microM (+/-)-pindolol, a concentration higher than
      previously suggested for the same purpose (0.1 micron). This higher concentration
      was, however, needed to fully saturate 5-HT1A and 5-HT1B receptors without
      interaction with 5-HT7 receptors. Under these conditions, [3H]5-HT binding could
      be further inhibited with methiothepin (used to determine nonspecific binding)
      and with 5-HT, with an IC50 of 1.4 nM and a slope of 1. The inhibition curves of
      (+/-)-8-hydroxy-dipropylaminotetralin, ritanserin, and mianserin were shallow
      (slopes, 0.35-0.58) and could be better analyzed with the two-site model,
      indicating that the pindolol-insensitive [3H]5-HT binding sites in rat
      hypothalamic membranes are heterogeneous. Although the IC50 of the compounds
      tested suggests that one population of sites is actually associated with 5-HT7
      receptors, our data clearly indicate that this binding assay does not selectively
      label 5-HT7 receptors in native tissues. These results challenge a previous
      report and suggest that the proposed down-regulation of 5-HT7 receptors after
      fluoxetine treatment should be considered with caution. The development of more
      selective and sensitive binding assays will probably offer significant advantage.

PMID- 8643097
TI  - Sequestration of the short and long isoforms of dopamine D2 receptors expressed
      in Chinese hamster ovary cells.
AB  - The short (D2S) and long (D2L) isoforms of dopamine D2 receptors were stably
      expressed in Chinese hamster ovary cells, and dopamine-induced sequestration was
      examined by measuring the loss of binding of the hydrophilic ligand [3H]sulpiride
      from the cell surface. Dopamine treatment of Chinese hamster ovary cells
      expressing D2S for 30 min at 37 degrees caused a 43.8 +/- 3.4% decrease in
      [3H]sulpiride binding activity measured by incubation of the treated cells with
      [3H]sulpiride at 4 degrees for 4 hr after the dopamine was washed out. The half
      life of the decrease in binding was estimated to be 18.7 +/- 1.6 min, and the
      concentration of dopamine giving a half-maximal effect (EC50) was estimated to be
      180 +/- 90 nM. The decrease was reversible, and the binding activity was
      recovered by washing out the dopamine and incubating the cells at 37 degrees for
      30 min but was not reversible when the cells were incubated at 4 degrees. The
      binding activity of [3H]spiperone, a hydrophobic ligand, was not affected by the
      dopamine treatment under the same experimental conditions. These results indicate
      that approximately one half of the D2S receptors undergo agonist-induced
      sequestration, probably endocytosis, in a reversible and temperature-dependent
      manner. Sequestration of D2L receptors was not as apparent as that of D2S
      receptors; the decrease in [3H]sulpiride binding activity was 21.6 +/- 0.9% and
      the rate of the decrease was delayed, with a half-life of 33.2 +/- 7.8 min,
      although effective concentrations of dopamine were similar, with EC50 = 170 +/-
      50 nM. A D2S receptor variant containing a missense mutation changing Ser311 in
      the third intracellular loop to cysteine was found to be sequestered to a
      significantly lesser extent than with wild-type D2S receptors. This finding was
      discussed with respect to the report that this variant gene is found more
      frequently in schizophrenic patients than in control subjects.

PMID- 8643098
TI  - Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms.
AB  - Analysis of the composition of cerebellar gamma-aminobutyric acidA (GABAA)
      receptors (GABARs) with in situ hybridization of GABAR subunit subtype mRNAs [J.
      Neurosci 12:1063-1076 (1992)] and Western blot analysis and quantitative binding
      of radioligands to immunopurified receptors from the rat cerebellum [J. Biol.
      Chem. 269:16020-16028 (1994)] have suggested that GABAR isoforms likely to occur
      in the cerebellum of adult rats are alpha1betaxgamma2, alpha6betaxgamma2, and
      alpha6betaxdelta isoforms. Based on these data, GABARs composed of different
      combinations of rat alpha1, alpha6, beta2, beta3, gamma2L, and delta subunits,
      corresponding to the three putative cerebellar GABAR isoforms, were transiently
      expressed in mouse fibroblast cells (L929 cells). Whole-cell currents were
      recorded from acutely transfected cells to determine whether the
      alpha1beta2/3gamma2L, alpha6beta2/3gamma2L, and alpha6beta2/3delta GABAR isoforms
      could form functional receptor channels in L929 cells and to compare their
      electrophysiological and pharmacological properties. All three putative
      cerebellar GABAR isoforms showed a high efficiency of expression of functional
      GABARs. We chose to study the beta3 and gamma2L subtypes as major representatives
      of the native subunit subtype proteins. The recombinant alpha1beta3gamma2L,
      alpha6beta3gamma2L, and alpha6beta3delta GABAR isoforms displayed different
      affinities (EC50 values) for GABA, differential sensitivity to block by the
      divalent cation zinc and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3
      carboxylate, and differences in enhancement by diazepam. Our results provide an
      initial characterization of the electrophysiological and pharmacological
      properties of possible in vivo cerebellar GABAR isoforms and demonstrate that
      subunit compositions of different GABAR isoforms play a crucial role in
      determining their properties.

PMID- 8643099
TI  - Synthesis and immunological characterization of 104-mer and 102-mer peptides
      corresponding to the N- and C-terminal regions of the Plasmodium falciparum CS
      protein.
AB  - We investigated the immunogenicity and the conformational properties of the non
      repetitive sequences of the Plasmodium falciparum circumsporozoite (CS) protein.
      Two polypeptides of 104 and 102 amino acids long, covering, respectively, the N-
      and C-terminal regions of the CS protein, were synthesized using solid phase Fmoc
      chemistry. The crude polypeptides were purified by a combination of size
      exclusion chromatography and RP-HPLC. Sera of mice immunized with the free
      polypeptides emulsified in incomplete Freund's adjuvant strongly reacted with the
      synthetic polypeptides as well as with native CS protein as judged by ELISA and
      IFAT assays. Most importantly, these antisera inhibited the sporozoite invasion
      of hepatoma cells. In addition, sera derived from donors living in a malaria
      endemic area recognized the CS 104- and 102-mers. Conformational studies of the
      CS polypeptides were also performed by circular dichroism spectroscopy showing
      the presence of a weakly ordered structure that can be increased by addition of
      trifluoroethanol. The obtained results indicate that the synthetic CS
      polypeptides and the natural CS protein share some common antigenic determinants
      and probably have similar conformation. The approach used in this study might be
      useful for the development of a synthetic malaria vaccine.

PMID- 8643100
TI  - The effect of the removal of sialic acid, galactose and total carbohydrate on the
      functional activity of Campath-1H.
AB  - A monoclonal human IgG1, Campath-1H, was digested with glycosidases to assess the
      effect of carbohydrate on the functional activities of an IgG1. Removal of the
      complete carbohydrate moiety abolished complement lysis activity and antibody
      dependent cell-mediated cytotoxicity, but left antigen binding activity and
      protein A binding activity intact. Removal of terminal sialic acid residues
      through glycopeptidase F digestion was not found to affect any of the tested IgG
      activities. Removal of the majority of the galactose residues from desialylated
      Campath-1H was found to reduce but not abolish complement lysis activity. Other
      activities were not affected by degalactosylation. This indicates a rare
      separation of complement lysis activity and antibody-dependent cell-mediated
      cytotoxicity of IgG in the way they behave under controlled conditions. This
      paper underlines the overall importance of carbohydrate in IgG function and
      stresses the relative contributions of some of the carbohydrate residues.

PMID- 8643101
TI  - Dependence of the murine antibody response to an anti-CDR2 VH peptide on
      immunogen formulation.
AB  - A peptide corresponding to the second complementarity determining region of the
      heavy chain (CDR2 VH) from a murine anti-CD4 monoclonal antibody, designated
      L202, was synthesized by solid phase methodology in a number of different
      antigenic forms, for the purpose of comparing the effectiveness of different
      adjuvant-carrier systems in the induction of a murine antibody response against
      the immunizing peptide and parent antibody molecule. Two of the synthetic
      constructs contained the palmitoyl and N-palmitoyl-cysteinyl-S-(2,3-palmitoyloxy)
      propanediol (PAM3Cys) moieties, respectively, attached to the peptide amino
      terminus with the immunogen comprising liposomal formulations of each. A third
      immunogen consisted of the CDR2 VH peptide admixed with the PAM3Cys non
      covalently and incorporated into liposomes (PAM3Cys + CDR2 VH). A fourth
      composition comprised the CDR2 VH peptide conjugated to KLH via the sulfhydryl of
      an added N terminal cysteine (KLH-CDR2 VH) and injected with Complete Freund's
      adjuvant (CFA). A fifth immunogen consisted of the CDR2 VH peptide synthesized on
      an octameric, branched polylysine core as a multiple antigenic peptide (MAP-CDR2
      VH) injected in the presence of Freund's adjuvant. Groups of five mice were
      injected intramuscularly with each of these immunogens and bled at two week
      intervals. The highest anti-peptide gamma-immunoglobulin (IgG) responses (against
      uncoupled peptide by ELISA) after 56 days were obtained with mice receiving the
      PAM3Cys-CDR2 VH peptide. However, when screened against the CDR2 V(H) peptide
      present as the MAP derivative by ELISA, IgG raised against the cognate MAP-CDR2
      peptide was much more reactive than IgG raised against the liposomal PAM3Cys-CDR2
      VH immunogen. In either case, IgG raised against the KLH-CDR2VH conjugate was
      poorly reactive. These differences in reactivity to the two forms of the CDR2 VH
      peptide by ELISA did not correspond to major differences in reactivities to the
      intact L202 Ab by ELISA. Although the IgG against the MAP immunogen was slightly
      more reactive than the other antisera against the l202 Ab, all titers were less
      than 1:100. These data illustrate some limitations of using anti-peptide
      responses as indicators of potential reactivity against the native protein, but
      suggest that alternate formulations including lipoidal peptides are more
      effective than corresponding KLH-peptide conjugates in eliciting Ab responses
      against poorly immunogenic epitopes.

PMID- 8643102
TI  - Variable region cDNA sequences and characterization of murine anti-human
      interferon gamma receptor monoclonal antibodies that inhibit receptor binding by
      interferon gamma.
AB  - Murine monoclonal antibodies (mAbs) are described that recognize the
      extracellular human interferon gamma receptor alpha-chain (IFN gamma R) and
      inhibit the binding to it of interferon gamma. The inhibitory activities (IC50s)
      of these mAbs, quantified by radioimmunoassay using native receptor on human Raji
      cells, lie in the range 0.5-24 nM, whereas their relative affinities for the
      immobilised recombinant extracellular receptor, determined using surface plasmon
      resonance technology, are in the range 0.6-40.9 nM. Nine mAbs derived from one
      immunization, were shown by variable region cDNA sequencing to be clonally
      related, with mAb A6 from this group showing the highest affinity for the
      receptor. Another two mAbs, gamma R38 and gamma R99, derived from a separate
      immunization, are clonally unrelated to each other and to those in the A6 family.
      From the V-region sequences, the L-chains of mAbs A6, gamma R38 and gamma R99
      were shown to belong to the V kappa 34C, V kappa 34C and V kappa 1 families,
      whereas the H-chains belong to the 3069, J606 and J558 families, respectively.
      The mAbs A6 and gamma R38 recognize overlapping epitopes on the N-terminal Ig
      like domain of the IFN gamma R, whereas the gamma R99 epitope is located largely
      in the membrane proximal Ig-like domain. Sequence comparisons with Ig structures
      solved by X-ray diffraction allowed deductions concerning likely CDR canonical
      conformations. These studies provide essential information for crystallographic
      and mutagenesis experiments aimed at understanding the molecular basis of the
      interactions of these mAbs with the extracellular IFN gamma R.

PMID- 8643103
TI  - Antibodies against human CD63 activate transfected rat basophilic leukemia (RBL
      2H3) cells.
AB  - CD63 is a widely expressed glycoprotein member of the transmembrane 4 superfamily
      (TM4SF) that is present on activated platelets, monocytes and macrophages and
      many non-lymphoid cells. It has been proposed that CD63 and other members of the
      TM4SF couple to intracellular signal transduction pathways and may have a role in
      cellular adhesion, proliferation and activation. We have investigated the
      functions of human CD63 by expression in the rat basophilic leukemia cell line,
      RBL-2H3, which has previously been reported to respond to antibodies against the
      rat homolog of CD63. Using a panel of antibodies against human CD63 we have shown
      that high levels of granular secretion from transfected RBL cells can be
      stimulated by some, but not all, of the antibodies. The specificity of this
      response suggests that these activating antibodies may be mimicking a natural
      ligand for CD63. The secretory response to crosslinking of the high affinity IgE
      receptor and also that to non-receptor stimuli (phorbol ester and calcium
      ionophore) is inhibited by an antibody that appears to recognise both human and
      rat homologs of CD63. These results suggest that stimulus-secretion coupling can
      occur through human CD63 and that RBL cells transfected with this protein will
      constitute a valuable tool in elucidating its function.

PMID- 8643104
TI  - Two kappa immunoglobulin light chains are secreted by an anti-DNA hybridoma:
      implications for isotypic exclusion.
AB  - An anti-DNA hybridoma derived from an MRL/lpr mouse secretes two different kappa
      light chains in combination with a single heavy chain. Multiple single cell
      clones express and secrete immunoglobulin containing both kappa light chains. The
      N-terminal protein sequences of the light chains correspond to sequences
      predicted from functionally rearranged mRNAs subjected to reverse transcription
      and amplified by polymerase chain reaction (PCR). Karyotype analysis of the
      hybridoma indicates a clonal line derived from the fusion of two cells. By amino
      acid sequence comparison and PCR analysis, both functional kappa light chains are
      derived from the MRL/lpr spleen. The two functional light chain cDNAs were cloned
      and co-transfected into COS-7 cells with the heavy chain cDNA. Only one of the
      light chains in combination with mAb 3E10 heavy chain confers anti-DNA
      reactivity. The presence of two separate kappa light chains and, therefore, two
      separate antigen receptors on a single B cell may have ramifications for both
      polyclonal activation and toleration of lupus B cells.

PMID- 8643105
TI  - Both MHC and background gene heterozygosity alter T cell receptor repertoire
      selection in an antigen-specific response.
AB  - Many autoimmune diseases are associated with specific class II MHC alleles;
      however, this association is not complete. One explanation for the variable
      expression of disease in susceptible individuals is that variability in the TCR
      repertoire may alter the potential to generate pathogenic autoreactive T cells.
      The current study was undertaken to examine the possibility that MHC and
      background heterozygosity, which is the norm in the outbred human population,
      alters the expressed TCR repertoire and, if so, whether this has an impact on
      peptide recognition and antigenic specificity. We, therefore, systematically
      analysed the beef insulin-specific TCR repertoire in inbred BALB/c mice before
      and after introduction of MHC heterozygosity (BALB/c x BALB.K)F1 mice, or MHC and
      background gene heterozygosity (BALB/c x A/J)F1 mice. We show that T cells from
      all three repertoires are predominantly Ad-restricted and recognize the same
      immunodominant peptide. Despite this, the beef insulin-specific TCR repertoires
      in F1 mice differ from those seen in BALB/c mice with the most dramatic changes
      seen in (BALB/c x A/J)F1 mice. These changes are accompanied by subtle
      differences in the antigenic specificity of the T cells. The results demonstrate
      that both MHC and background gene heterozygosity affect TCR repertoire selection,
      suggesting that the variable expression of autoimmune disease in individuals with
      a susceptible MHC allele may result, in part, from variability in the TCR
      repertoire introduced by this heterozygosity.

PMID- 8643106
TI  - Aberrant regulation of the IgH 3' enhancer by c-myc in plasmacytoma cells.
AB  - The identification of enhancers at the 3' end of the IgH locus has prompted a re
      evaluation of the regulation of Ig gene expression. Moreover, these elements may
      provide a possible explanation as to how the c-myc oncogene becomes dysregulated
      upon translocation into the IgH locus with the IgH intragenic enhancer on the
      reciprocal chromosome. These 3' enhancers have also been shown to redirect
      promoter utilization on c-myc reporter gene constructs in transient transfection
      experiments. This region of the locus also contains the B cell specific IgH 3'
      enhancer. This temporally regulated enhancer has been implicated in the
      mechanisms that control class switch recombination. Here we demonstrate that
      overexpression of the c-myc protein in mouse plasmacytoma cells (MPC-11) and HeLa
      cells can transcriptionally upregulate a reporter gene construct driven by a
      subregion (domain C) of the IgH 3' enhancer. Domain C contains a functional dual
      symmetry E-box motif, CACGTG. The DNA binding experiments demonstrate that USF
      was the major factor interacting with this motif. Based on these observations, we
      speculate that the c-myc protein may upregulate expression of translocated c-myc
      in mouse plasmacytomas possibly via an USF-binding E-box motif in the IgH 3'
      enhancer.

PMID- 8643107
TI  - Fine chemical modifications at N- and C-termini enhance peptide presentation to T
      cells by increasing the lifespan of both free and MHC-complexed peptides.
AB  - We investigated the effect of modifying the N- and/or C-termini of the snake
      toxin peptide 24-36 on its presentation to T cells. Acetylation at the N-terminus
      as well as amidation at the C-terminus enhanced the capacity of the peptide to
      activate T cells. Simultaneous modifications further increased the stimulating
      activity, the peptide becoming approximately 100-fold more potent than the
      unmodified peptide. Clearly, the introduced modifications increased the lifetime
      of the peptide free in solution, by decreasing its proteolytic degradation,
      during the T cell stimulation assays. Paradoxically, however, at similar
      concentrations of free peptides, the modified ones, especially those having an
      acetylated N-terminus, were much more active than the unmodified peptide,
      irrespective of the experimental conditions. These observations suggested that
      components other than protection from proteolytic degradation should be
      associated with the higher stimulating activities of the modified peptides.
      Accordingly, chasing experiments with APC revealed that acetylation at N-terminus
      caused a higher persistence of the peptides at APC surface. Together, our data
      indicate that (i) the T cell stimulating capacity of a peptide is associated with
      its lifespans in the free and MHC II bound states; and (ii) these lifespans can
      be greatly enhanced by introducing fine chemical modifications at N- and C
      termini. These data may have some implications in designing more potent peptidic
      immunomodulators.

PMID- 8643108
TI  - A phage display system for detection of T cell receptor-antigen interactions.
AB  - The process of T cell recognition involves a complex set of interactions between
      the various components of the TCR/MHC/peptide trimolecular complex. We have
      developed a system for exploring the specific binding interactions contributed by
      the constituent subunits of TCR complexes for components of their ligands. We
      utilized an M13 phage display system, designed for multivalent receptor display,
      to explore specific binding interactions between various TCR alpha chains and
      specific antigen in the absence of MHC. The multivalent TCR-phage display system
      was sensitive enough to reveal some TCR alpha chains capable of binding directly
      to antigen with the same fine specificity shown by the MHC-restricted T cells
      from which the alpha chains were derived. Cross-specificity analysis using two
      antigen-binding TCR alpha chains derived from T cells with different polypeptide
      antigen specificities confirmed the fidelity of this binding. In mixtures of
      antigen-binding and non-binding TCR alpha-displaying phage, specific selection
      was achieved at a starting frequency of 1/1000, suggesting that this system can
      be employed for selection and analysis of TCR-displaying phage libraries. While
      the binding specificities exhibited by these TCRs are unusual, they provide a
      novel perspective from which to study the specific binding interactions that
      constitute TCR antigen binding.

PMID- 8643109
TI  - Human recombinant CD4 and CD4-derived synthetic peptides agglutinate
      immunoglobulin-coated latex particles. Evidence that residues 25-28 and 35-38 of
      human CD4 form two separate immunoglobulin binding sites.
AB  - It has been shown previously that amino acid residues 21-49 of the first
      extracellular domain of human CD4 form the core of an immunoglobulin (Ig) binding
      site. Synthetic peptides of human CD4 that encompass this region also bind Ig
      and, with higher affinity, antigen/antibody complexes. Synthetic peptides also
      enhance binding of both monomeric and aggregated Ig to monocytic U937 cells and
      Staphylococcus aureus Protein A. To better characterize the nature of the Ig
      binding site on CD4, we tested the ability of human recombinant CD4 (rCD4) to
      agglutinate polystyrene particles coated with Ig. Evidence is presented that
      soluble rCD4 and CD4 peptide p21-49 were capable of specific agglutination of
      polystyrene particles coated with polyclonal Ig of either human or sheep origin.
      Agglutination could be blocked by soluble human polyclonal IgG or F(ab')2
      fragments. Both heparin and sulfated dextrans also inhibit agglutination,
      suggesting that charged residues on rCD4 played an important role in
      agglutination mediated by rCD4 or CD4 peptide. Similarly, aurintricarboxylic acid
      (ATA) also blocked agglutination of Ig-coated particles by rCD4. Agglutination
      mapping studies performed using truncated peptides revealed the existence of two
      discrete, closely related Ig binding sites (residues 25-28 and 35-38).

PMID- 8643110
TI  - Production and characterization of bispecific single-chain antibody fragments.
AB  - We report the construction, expression and purification of a bispecific single
      chain Fv antibody fragment produced in Escherichia coli. The protein possesses a
      dual specificity: the single-chain FvB1 portion is directed to the Idiotype of
      BCL1 lymphoma cells, the single-chain Fv2C11 moiety binds to the CD3 marker on T
      cells. The two domains are joined by a flexible peptide linker. Using Immobilized
      Metal Affinity Chromatography, the recombinant protein was purified from
      bacterial insoluble membrane fractions. After refolding of the bispecific
      protein, it was affinity-purified. As demonstrated by flow cytometry, both
      binding sites are retained in the refolded protein. Retargeted cytotoxicity and T
      cell proliferation assays further prove the biological activity and specificity
      of the bispecific single-chain Fv. Thus, these bispecific molecules show a
      potential anti-tumor activity.

PMID- 8643111
TI  - Construction and characterization of a humanized, internalizing, B-cell (CD22)
      specific, leukemia/lymphoma antibody, LL2.
AB  - The murine monoclonal antibody, LL2, is a B-cell (CD22)-specific IgG2a which has
      been demonstrated to be clinically significant in the radioimmunodetection of non
      Hodgkin's B-cell lymphoma. The antibody carries a variable region-appended
      glycosylation site in the light chain and is rapidly internalized upon binding to
      Raji target cells. Humanization of LL2 was carried out in order to develop LL2 as
      a diagnostic and immunotherapeutic suitable for repeated administration. Based on
      the extent of sequence homology, and with the aid of computer modeling, we
      selected the EU framework regions (FR) 1, 2 and 3, and the NEWM FR4 as the
      scaffold for grafting the heavy chain complementarity determining regions (CDRs),
      and REI FRs for that of light chains. The light chain glycosylation site,
      however, was not included. Construction of the CDR-grafted variable regions was
      accomplished by a rapid and simplified method that involved long DNA
      oligonucleotide synthesis and the polymerase chain reaction (PCR). The humanized
      LL2 (hLL2), lacking light chain variable region glycosylation, exhibited
      immunoreactivities that were comparable to that of chimeric LL2 (cLL2), which was
      shown previously to have antigen-binding properties similar to its murine
      counterpart, suggesting that the VK-appended oligosaccharides found in mLL2 are
      not necessary for antigen binding. Moreover, the hLL2 retained its ability to be
      internalized into Raji cells at a rate similar to its murine and chimeric
      counterparts.

PMID- 8643112
TI  - Real-time analysis of Oct protein-octamer interaction and transcription complex
      assembly.
AB  - Specific interactions between the protein-binding sequence of the immunoglobulin
      transcription regulatory element, the octamer, and Oct proteins have been
      investigated using a biosensor based on surface plasmon resonance. By analysis of
      in vitro translated Oct1 and Oct2A with a consensus octamer probe, it was shown
      that the affinity constant, association rate constant and dissociation rate
      constant of Oct1 were higher than for Oct2A. The biggest difference was in the
      association rate constants, but this difference was reduced when an octamer motif
      containing a point mutation was used as a probe. Elements in the octamer flanking
      sequence could increase the on-rate of Oct proteins to a mutated octamer while
      not decreasing the off-rate. Oct-octamer interaction in whole nuclear extracts
      could be detected readily in the biosensor and adapter interactions with template
      bound proteins were revealed. Thus, biosensor analysis represent a fast and
      convenient alternative approach to study specific protein-DNA and protein-protein
      interactions in analysis of transcriptional regulation.

PMID- 8643114
TI  - Identification of two variants of the human integrin alpha 4 subunit.

PMID- 8643113
TI  - Correct disulfide pairing and efficient refolding of detergent-solubilized single
      chain Fv proteins from bacterial inclusion bodies.
AB  - In vitro folding of denatured proteins has remained an inefficient and empirical
      process that has limited the use of bacterially expressed recombinant proteins.
      In this paper we show that in vitro folding of recombinant single-chain Fv (sFv)
      proteins is markedly facilitated when disulfide bonds are formed in detergent
      solution. sFv proteins from three different antibodies were expressed as
      bacterial cytoplasmic inclusion bodies and solubilized in the weak ionic
      detergent, sodium lauroylsarcosine (SLS). Upon oxidation in air in the presence
      of metal ion catalysts, all three sFvs quantitatively formed intrachain disulfide
      bonds which ran as a single band in SDS-polyacrylamide gel electrophoresis under
      non-reducing conditions. By contrast, oxidation from 6 M urea gave large amounts
      of disulfide linked aggregates, and three closely spaced bands of monomeric
      protein. Detergent was removed from the oxidized sFvs by addition of 6 M urea and
      absorption with an ion exchange resin. After dialysis and gel filtration in non
      denaturing solution, moderate to high yields of monomeric sFv were obtained,
      depending upon the sFv. All three sFvs gave single bands on isoelectric focussing
      and SDS-PAGE gels and had similar or identical binding specificities and
      affinities as the parental Fabs, implying that the final products contained
      correctly paired disulfide bonds. The correct disulfide pairing suggests that the
      disulfide loops within the detergent-solubilized sFvs adopt a native-like
      structure.

PMID- 8643116
TI  - Clastogenic effects of copper sulphate in chick in vivo test system.
AB  - The clastogenic potential of copper sulphate was evaluated in chicks, employing
      chromosome aberration (CA) and micronucleus test (MNT) assays. For CA dose,
      route, time-response and acute vs. subacute studies have been done while only
      route and dose-response studies were done for MNT. Three different doses were
      administered intraperitoneally, and only the highest dose was administered per
      oral. Neonatal chicks were killed after different time intervals. One-fifth of
      the highest dose was injected repeatedly with a gap of 24 h in-between for sub
      acute regimen. A statistically significant (p<0.05) increase of CA was observed
      by the two higher doses in i.p. route and by the highest dose in p.o. route. In
      time-response studies, significant (P<0.05) results were obtained after 24 and 48
      h of exposures. A significant increase in micronucleus counts was also observed
      with the two higher doses in both bone marrow and peripheral blood erythrocytes
      by the i.p. route and only by the highest dose in bone marrow erythrocytes by the
      p.o. route. The present results reveal the genotoxic potential of CuSO4 in chick
      in vivo.

PMID- 8643115
TI  - Effect of chlorophyllin on gamma ray induced micronuclei in polychromatic
      erythrocytes of murine peripheral blood determined by the ABC strategy.
AB  - The effect of chlorophyllin on micronucleated polychromatic erythrocyte (MN-PCE)
      induction by gamma ray exposure in peripheral blood of mice was studied. The area
      beneath the curve (ABC) of MN-PCE frequency versus time was used as an index of
      total MN-PCE induction. The dose of 200 mg chlorophYllin per kg of body weight
      caused a slight, but not significant, reduction of the MN-PCE caused by 1.0 Gy
      exposure. This result indicates that chlorophyllin did not protect the cells
      against MN induction. In previous studies it was observed that the same
      chlorophyllin dose was able to protect 100% against sister chromatid exchange
      (SCE) induction by 1.0 gamma rays in both murine spermatogonia and bone marrow
      cells. These contradictory results indicate that chlorophyllin did not protect
      cells by scavenging free radicals, but by other mechanism, i.e. stimulating
      repair of lesions involved in SCE induction.

PMID- 8643117
TI  - Mutagenic nitroarenes, diesel emissions, particulate-induced mutations and
      cancer: an essay on cancer-causation by a moving target.
AB  - Initial analyses of the lung tumors seen in rats exposed for their lifetime to
      elevated levels of the emissions of diesel engines suggested that they were due
      to powerful mutagens and carcinogens (PAHs, nitro PAHS) absorbed onto the diesel
      particles. However, further studies showed that carcinogenicity occurred only
      under conditions that resulted in impaired lung clearance ('overloading') leading
      to inflammatory reactions and other pathologic sequelae. These observations
      together with the findings that carbon black, a model for diesel particles devoid
      of organic mutagens and carcinogens, also induced lung cancers under conditions
      of overloading led to the suggestion that the cancers resulted from a non
      genotoxic mechanism. However, the further finding that inert particulate
      carcinogens devoid of organics, induce mutations has led to a re-evaluation of
      the role of mutations in lung carcinogenesis caused by particles and the
      relevance of the rat model to humans. This is especially timely as
      epidemiological studies suggest that humans may develop lung cancers following
      occupational exposure to diesel emission by a mechanism unlikely to involve lung
      overloading. Finally, the recent recognition that environmental PM-10
      (respiratory size particles) may be responsible for a significant portion of
      human morbidity and mortality, ensures that the health effect of diesel emissions
      will continue to receive scrutiny as they contribute to the PM-10 load.

PMID- 8643118
TI  - Cytogenetic monitoring of a group of Italian floriculturists: no evidence of DNA
      damage related to pesticide exposure.
AB  - The induction of sister chromatid exchanges (SCE), structural chromosome
      aberrations (CA) or micronuclei (MN) was investigated in peripheral lymphocytes
      of a group of Italian floriculturists exposed to a mixture of pesticides. No
      statistically significant difference in the frequencies of cytogenetic damage was
      detected between exposed and control subjects. Assessment of the effect of
      confounding factors indicated that smoking affected both SCE and CA frequencies.
      Multiple regression analysis showed that in heavy smokers (> or = 20
      cigarettes/day), SCE and CA levels increased significantly by 17% and 54%,
      respectively, as compared to non-smokers.

PMID- 8643119
TI  - Inhibition of mutagenicity of N-nitrosamines by tobacco smoke and its
      constituents.
AB  - Tobacco smoke is a complex chemical mixture including pyridine alkaloids and N
      nitrosamines, with the concentration of the former several orders of magnitude
      higher that that of the N-nitrosamines. The major biologically important N
      nitrosamines present in tobacco smoke are N-nitrosodimethylamine (NDMA), 4
      (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N(1)-nitrosonornicotine
      (NNN). These nitrosamines require metabolic activations by cytochrome P-450s for
      the expression of mutagenicity. Although nicotine, the major pyridine alkaloid in
      tobacco, has been shown to inhibit the metabolic activation of NNK, its effect on
      the mutagenicity of NNK and other N-nitrosamines has not been reported, In the
      present study, the ability of three pyridine alkaloids (nicotine, cotinine,
      nornicotine) and aqueous cigarette smoke condensate extract (ACE) to inhibit the
      mutagenicity of tobacco-related N-nitrosamines was tested on Salmonella
      typhimurium strain TA1535 in the presence of a metabolic activation system (S9).
      All three of the pyridine alkaloids tested, as well as ACE, inhibited the
      mutagenicity of NDMA and NNK, but not NNN, in a concentration-dependent manner.
      The induction of SCEs in mammalian cells (CHO) by NNK in the presence of
      metabolic activation was also significantly reduced by nicotine and cotinine.
      None of the observed reductions in mutagenicity could be explained by
      cytotoxicity. These results demonstrate that tobacco smoke contains chemicals,
      pyridine alkaloids and other unidentified constituent(s), which inhibit the
      mutagenicity of N-nitrosamines.

PMID- 8643120
TI  - An evaluation of the genotoxic properties of some chosen dyes using the
      micronucleus test in vivo.
AB  - The frequency of micronucleated polychromatic erythrocytes and the polychromatic
      to normochromatic erythrocyte ratio was studied in BalbC mice treated with four
      azo dyes: Direct Blue 74, Direct Blue 296, Direct Blue 297 and Direct Green 98 at
      two (40% and 80% LD50/kg body weight) concentrations. None of the studied
      compounds revealed a genotoxic activity in the micronucleus test. However, it was
      found that two dyes, direct Blue 297 at doses 40% and 80% LD50 and Direct Green
      98 at dose 80% LD50, cause a significant decrease in the ration of polychromatic
      to normochromatic erythrocytes in bone marrow of mice, which means that at the
      doses specified above they can affect the proliferation of the blood cells.

PMID- 8643121
TI  - Mutual interactions among ingredients of betel quid in inducing genotoxicity on
      Chinese hamster ovary cells.
AB  - The purpose of this study is to explore the mutual interactions among the
      chemical ingredients of betel quid including arecoline, sodium fluoride, catechin
      and glycyrrhizin in producing genotoxicity on Chinese hamster ovary (CHO) cells
      using the micronucleus method. Our results show that arecoline at a rather low
      concentration of 0.2-2 microM which could be in the oral cavity during betel quid
      chewing and NaF(0.8-2.4 mM) significant elevated the number of micronucleated
      cells in a concentration-dependent manner. In addition, significant prolongation
      of cell cycles was observed by treatment with arecoline (> or = 2.0 microM) or
      NaF (2.4 nM) in CHO cells. Both catechin and glycyrrhizin could antagonize not
      only the increased micronucleated cells induced by arecoline and NaF but also the
      prolonged cell cycle induced by arecoline in CHO cells. This find implies that
      the adjuvant ingredients, catechu and liquorice root extract provide not only a
      flavor but also an antagonist against the genotoxicity of arecoline and fluoride
      containing betel quid.

PMID- 8643123
TI  - Trapping of viruses in high-frequency electric field cages.

PMID- 8643124
TI  - First finding of epsilon-crystallin outside the archosaurian lineage.

PMID- 8643126
TI  - Manufacture and use of tools in wild Sumatran orangutans. Implications for human
      evolution.

PMID- 8643125
TI  - Mitochondrial DNA sequence relationships of the extinct blue antelope Hippotragus
      leucophaeus.

PMID- 8643127
TI  - [Anal blood loss: remember the thermometer!].

PMID- 8643122
TI  - Embryonic angiogenesis: a review.
AB  - Supply with nutrients is essential from early embryonic stages onwards.
      Therefore, circulatory organs form the first functioning organ system. With the
      exception of the heart, this system is at first formed by only one cell type, the
      endothelial cell. Emergence, behavior, and differentiation of endothelial cells
      are discussed in this review. At first, endothelial cells develop from
      angioblasts (primary angiogenesis/angioblastic development), later they develop
      from preexisting endothelial cells (secondary angiogenesis/angiotrophic growth).
      The composition of the extracellular matrix may promote or inhibit angiogenesis.
      Various growth factors which can be bound to the extracellular matrix may have
      been found, but only two of them (VEGF, P1GF) seem to influence endothelial cell
      behavior directly. Heterogeneity and organ-typical differentiation of endothelial
      cells seem to be dependent on cell-cell signaling within each organ.

PMID- 8643128
TI  - [Pulmonary surfactant system].

PMID- 8643129
TI  - [Effect of adjuvant drug therapy following successful electroconvulsive therapy
      for therapy-resistant depression is still disappointing].

PMID- 8643130
TI  - [Applications of positron-emission tomography in oncology].

PMID- 8643131
TI  - [Functional MRI: imaging of motor cortex function].
AB  - OBJECTIVE: To image the motor cortex with functional MRI (fMRI), and locate the
      activated area with the proportional grid of Talairach. DESIGN: Descriptive.
      SETTING: St. Radboud Academic Hospital Nijmegen. METHODS: In ten volunteers
      functional images of the motor cortex were made during execution of a motor task
      (finger movements). From the functional images the positions of activated areas
      were calculated using the 3D Talairach grid system. RESULTS: fMRI of the motor
      cortex was possible using a 1.5 T MRI scanner. Task activation of the motor
      cortex gave a signal increase in Brodmann's area 4, the precentral gyrus.
      CONCLUSION: Imaging of the active motor cortex with fMRI is feasible. The use of
      the 3D Talairach proportional grid system for the calculation of the position of
      an activated area in the motor cortex is possible with adequate accuracy.

PMID- 8643132
TI  - [Findings in cerebral proton spin resonance spectroscopy in newborn infants with
      asphyxia, and psychomotor development].
AB  - OBJECTIVE: To determine the relationship between the results of cerebral proton
      magnetic resonance spectroscopy (1H-MRS) and neuromotor development in neonates
      with hypoxia. DESIGN: Descriptive. SETTING: Wilhelmina Childrens' Hospital and
      University Hospital, Utrecht, The Netherlands. METHODS: 32 infants with hypoxic
      ischaemic encephalopathy (Sarnat grade I (mild; n = 5), grade II (moderate; 20),
      grade III (severe; 7)) were examined at a mean of 8 days following the hypoxic
      event (range 2-22). 1H-MRS of the periventricular white matter and part of the
      basal ganglia was performed in a 1.5 T field: TR/TE: 2000/272 ms. Peak-to-peak
      NAA/Cho ratios were calculated. The presence of a lactate resonance was
      considered abnormal. Assessment of neuromotor development of the survivors was
      performed at 6, 9 and 18 months of age. RESULTS: 6 patients died (all grade III),
      10 survived with handicaps (I grade III, 9 grade II). Handicaps consisted of
      spastic quadriplegia (n = 7), hemiplegia and mental retardation (n = 1), and
      global developmental delay (n = 2). The other 16 survivors were normal at 18
      months. 1H-MRS showed NAA/Cho ratios of 0.97 (SD:0.13) in the patients with a
      normal outcome and 0.74 (0.17) in the patients with an adverse outcome (handicaps
      or death); p < 0.0001 (t-test). Lactate was demonstrated in all 7 grade III
      neonates, but not in any of the other infants. CONCLUSION: Cerebral 1H-MRS was
      related to neurodevelopmental outcome of neonates with HIE. A low NAA/Cho ratio
      and presence of a lactate resonance predicted an adverse outcome.

PMID- 8643133
TI  - [Temporary results only in electroconvulsive therapy in therapy-resistant
      depression; retrospective study].
AB  - OBJECTIVE: To evaluate the use and efficacy of electroconvulsive therapy (ECT) in
      refractory major depression according to DSM-III-R criteria, and to look for
      factors predicting response in the acute phase and the occurrence of relapse or
      recurrence after recovery. DESIGN: Retrospective. SETTING: University Hospital
      Rotterdam, The Netherlands. METHODS: Of all patients who received ECT between
      January 1988 and July 1993 data were collected by study of clinical records and
      of information by treating physicians after discharge. Every patient was visited
      once, or received an outpatient department appointment, to obtain informed
      consent, take a follow-up history and evaluate social functioning by scoring
      Global Assessment of Functioning and Sickness Impact Profile rating scales.
      RESULTS: 35 patients received ECT. In clinical practice, the guidelines of the
      Netherlands Psychiatric Association were not violated; most patients had received
      adequate pharmacological pretreatment before the decision to start ECT was made.
      Two patients died in hospital (not from ECT). In the acute phase 25 of the 33
      patients still alive upon discharge showed good recovery. Seven of these suffered
      relapse within six months. The number of patients with a return of depressive
      symptoms rose to 12 by the end of the first year of follow-up. Sociodemographic
      variables and treatment characteristics did not appear to influence the result of
      treatment in the acute phase, nor the occurrence of relapse or recurrence. With
      less intensive pre- and post-ECT drug treatment the chances of relapse were
      increased. CONCLUSIONS: ECT is an effective treatment in the acute phase of a
      depression. Results after a longer period of follow-up are less satisfactory.

PMID- 8643134
TI  - [Problems in weaning from artificial ventilation: 'motor neuron disease'].
AB  - Three patients, two men aged 71 and one aged 73 years, were given artificial
      respiration because of acute respiratory failure. Subsequently they could not be
      weaned from artificial respiration, due to causes that were not immediately
      clear. It was ultimately found that the patients suffered from 'motor neuron
      disease', in two of them due to progressive spinal muscular atrophy, while the
      third, apart from loss of anterior horn motor cells, also had thoracic
      hydromelia. The patients died after termination of the artificial respiration.

PMID- 8643135
TI  - [Acute myopathy during treatment of status asthmaticus].
AB  - Two patients with chronic pulmonary disease, a woman of 38 and a man of 54 years
      old, who had developed a status asthmaticus, had difficulties being weaned from
      artificial ventilation. They suffered from an acute myopathy caused by a
      combination of high-dose corticosteroids and muscle relaxants (pancuronium,
      vecuronium). This acute myopathy is characterised by generalised flaccid
      quadriplegia with muscle atrophy and areflexia, difficulties being weaned from
      artificial ventilation, myoglobinuria and high levels of creatine kinase activity
      in serum. The prognosis is good; almost complete recovery occurs. Muscle biopsy
      may reveal necrotising myopathy and occasionally, selective loss of thick
      myofilaments.

PMID- 8643136
TI  - [Tendinitis of the short biceps tendon following axillary node dissection].

PMID- 8643137
TI  - [Applications of protons in the treatment of malignant tumors].

PMID- 8643138
TI  - [Applications of protons in the treatment of malignant tumors].

PMID- 8643139
TI  - [Glucose intolerance in the elderly in The Netherlands; the Twello Study].

PMID- 8643140
TI  - [Pelvic pain and pregnancy].

PMID- 8643141
TI  - [Gentamicin skin ointment: 200 kilos too much].

PMID- 8643142
TI  - [The value of diagnostic tests in infertility].

PMID- 8643143
TI  - [100 years of radiology in The Netherlands. IX. Clinical radiobiology].

PMID- 8643144
TI  - [The pharmacology of addiction].

PMID- 8643145
TI  - [From the library of the Nederlands Tijdschrify voor Geneeskunde: Heinrich
      Haeser's textbook of the History of Medicine (1811-1884) translated into Dutch by
      Abraham Hartog Israels].

PMID- 8643146
TI  - [Home care: between idea and reality].

PMID- 8643147
TI  - [Multiple pulmonary emboli in nursing home patients recognizable by alertness to
      certain aspecific symptoms].

PMID- 8643148
TI  - [Expectant management concerning the breast in 5 patients with occult breast
      carcinoma].

PMID- 8643150
TI  - Essential hypertension--are we on the way to identify primary defects?

PMID- 8643149
TI  - Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of
      comparative trials.
AB  - Whether ACE inhibitors (ACEi) differ from other antihypertensives in their
      efficacy to lower proteinuria is controversial. We therefore performed a meta
      analysis of articles on this subject. The secondary objective in our meta
      analysis was to study whether there is any difference between diabetic and non
      diabetic patients in antiproteinuric response to blood pressure reduction. To
      identify all articles we performed a computer search using the bibliographic
      databases. To minimize publication bias, only trials in which a direct comparison
      was made between an ACEi and another antihypertensive were included. Studies
      performed both in diabetic and in non-diabetic patients were eligible. Included
      were 41 studies, comprising 1124 patients, of which 558 had non-diabetic renal
      disease. The mean antiproteinuric effect of ACEi was significantly greater than
      that of their comparator drugs: -39.9% (95% confidence interval: -42.8 to 36.8%)
      versus -17.0% (-19.0 to -15.1%) respectively (difference 24% (19.5 to 28.6%)).
      The blood-pressure-lowering effect was equal: -12.0% (-12.8 to -11.2%) versus 
      11.4% (-11.7 to -11.1%) respectively (difference -0.8% (-1.8 to 0.2%)). Thus it
      may be concluded that ACEIs confer an antiproteinuric effect beyond that
      attributable to their blood-pressure-lowering effect. A wide interstudy variation
      in antiproteinuric response to non-ACEI antihypertensives was observed. Multiple
      variable regression analysis was performed to assess which factors may explain
      this heterogeneity. From the comparator drugs, the class was of no importance:
      calcium-channel antagonists (CCA), beta-blockers, and a rest group of other drug
      types showed a similar response. Patient characteristics such as initial GFR and
      blood pressure partly explained the variation in response, but most of it
      appeared dependent on the blood pressure reduction achieved. Furthermore the type
      of CCA is of importance, with nifedipine having the least effect. A significantly
      greater antiproteinuric effect of 'non-ACEI' antihypertensives was found in
      diabetic patients compared to non-diabetics. However, this coincided with a
      greater blood pressure reduction in diabetics. Adjusted for differences in blood
      pressure control, diabetics showed even a slightly lesser antiproteinuric
      response to non-ACEI antihypertensive compared to non-diabetics.

PMID- 8643151
TI  - Apoptosis: will cell death add life to nephrology?

PMID- 8643152
TI  - New insight into the pathogenesis of the 'idiopathic nephrotic syndrome'.

PMID- 8643153
TI  - Treatment of idiopathic membranous nephropathy: the dilemma of who, when, and
      how.

PMID- 8643155
TI  - The kidney in essential hypertension: a Cinderella of hypertension research.

PMID- 8643154
TI  - Parathyroid-hormone-related protein: a previously unrecognized renal vasodilator.

PMID- 8643156
TI  - Subclavian haemodialysis access: is it still justified in 1995?

PMID- 8643158
TI  - Continuous treatment modalities in acute renal failure.
AB  - Continuous treatment modalities have become well established in the treatment of
      severely ill patients with acute renal failure since the introduction of
      continuous arteriovenous haemofiltration. However, this simple blood-pressure
      driven treatment often fails to control azotaemia, especially in haemodynamically
      unstable patients with hypercatabolism. The common feature of further
      developments in continuous treatment modalities, such as continuous arteriovenous
      haemodialysis, venovenous haemofiltration, or venovenous haemodialysis is their
      higher efficacy in controlling azotaemia. Venovenous forms of treatment involve
      considerably higher technical requirements. The main advantages of continuous
      forms of treatment as opposed to intermittent haemodialysis are greater
      haemodynamic stability and the possibility of adapting nutrition without
      restriction to the needs of the critically ill. The uninterrupted necessity for
      anticoagulants is the most important disadvantage. The question of whether
      patients may profit from the continuous elimination of mediators involved in
      acute renal or multiple organ failure is still open. In retrospective analysis
      continuous methods appear to reduce mortality in acute renal failure, but
      prospective randomized studies are necessary to clearly demonstrate a benefit of
      these methods as opposed to intermittent haemodialysis.

PMID- 8643157
TI  - Prevention of clinical acute tubular necrosis with drug therapy.

PMID- 8643159
TI  - Acute renal failure in eastern India.
AB  - The present study included 426 patients with acute renal failure age range 7
      months to 85 years, during 8-year period (1984-1992). Medical, surgical and
      obstetric causes were responsible for ARF in 68.3, 17.8, and 14% of cases
      respectively. The main aetiological factors encountered were volume depletion
      secondary to gastrointestinal fluid loss (35.2%), acute glomerulonephritis
      (10.3%), nephrotoxin (8.6%), falciparum malaria (4.2%), obstructive uropathy
      (13%), post-abortal (10.5%), and miscellaneous factors (1.4%) of patients. The
      overall mortality was 19.2%. Thus our observation revealed that diarrhoeal
      diseases (35.2%), obstructive uropathy (13.3%), and septic abortion (10.5%) were
      the main causes for ARF in medical, surgical, and obstetric groups respectively.
      In contrast to our studies, acute renal failure associated with diarrhoeal
      diseases, septicaemia, falciparum malaria and septic abortion are rare in
      European countries.

PMID- 8643160
TI  - Observations on renal replacement services in Russia, Belarus and Lithuania.
AB  - This report describes the current financial, technical and medical status of
      nephrology, dialysis and renal transplant services in these countries with the
      hope of helping our colleagues there to upgrade their standards of care. The
      general impression is that physicians as well as administrators in these
      countries are eager to improve conditions of patient care despite a disastrous
      economical climate. Our view is that we can help by providing literature,
      textbooks, journals, travel funds, by offering visiting fellowships to individual
      physicians, and by forming partnerships between nephrology centres.

PMID- 8643161
TI  - Report on Update in Nephrology lecture tour in Russia and Estonia.

PMID- 8643162
TI  - Effects of vitamin D3 and cyclosporin A on HgCl2-induced autoimmunity in brown
      Norway rats.
AB  - BACKGROUND: Mercuric chloride (HgCl2) induces a lymphoproliferative disorder and
      autoimmune glomerulonephritis in Brown Norway (BN) rats. This syndrome is the
      consequence of T cell-dependent polyclonal B cell activation and autoantibody
      production. We have previously shown that HgCl2-induced autoimmune perturbations
      can be prevented in BN rats by the administration of cyclosporin A (CsA). The
      most potent vitamin D3 metabolite 1,25(OH)2 D3 (Vit D3) shares certain
      immunomodulatory properties with CsA. We therefore chose to compare the effects
      of Vit D3 to those of CsA in BN rats treated with HgCl2 in order to establish
      whether Vit D3 either alone or in combination with CsA can attenuate an
      autoimmune syndrome in vivo. METHODS: BN rats were treated with HgCl2 according
      to a standard protocol. Subgroups of rats were also given CsA alone, Vit D3 or
      synthetic analogues of Vit D3 alone, or combinations of both agents. Different
      doses and routes of administration were compared. The following markers of
      disease activity were evaluated: mortality, peak proteinuria, serum IgE
      concentrations, and renal immunoglobulin deposition. RESULTS: Disease activity
      was markedly attenuated in all rats treated with CsA alone. Vit D3 and certain of
      its synthetic analogues administered alone also tempered the autoimmune process,
      but to a lesser extent than did CsA. The effect of CsA alone was so potent, that
      no additive or synergistic effects could be demonstrated when CsA was
      administered in combination with Vit D3. CONCLUSIONS: Despite similar described
      immunomodulatory effects in vitro, CsA is clearly more effective than Vit D3 in
      preventing HgCl2 autoimmune disease in BN rats. This suggests that there is a
      difference in the cellular targets of these two agents in vivo, and/or a
      difference in the potency with which HgCl2-triggered immune activation is
      suppressed.

PMID- 8643163
TI  - Extracellular ATP augments mesangial cell growth induced by multiple growth
      factors.
AB  - BACKGROUND: ATP is released into the extracellular milieu during tissue injury
      and platelet aggregation and has a modest mitogenic effect on cultured rat
      glomerular mesangial cells (MCs). In this study we investigated the interaction
      of ATP with multiple growth factors during MC mitogenesis. METHODS: Replication
      of MCs was determined by direct cell counting and DNA synthesis was measured by
      3H-thymidine uptake. Activity of phosphatidylinositol-specific phospholipase C
      (PI-PLC) was assessed by measuring formation of inositol phosphates from 3H
      labelled precursors. RESULTS: Extracellular ATP (1-100 microM) exerted a powerful
      synergistic effect on DNA synthesis of MCs when used simultaneously with various
      mitogens, including epidermal growth factor (EGF), basic fibroblast growth factor
      (bFGF), platelet-derived growth factor (PDGF-BB), endothelin-1 (ET-1), arginine
      vasopressin (AVP), thrombin (Thr), serotonin (5-HT), and interleukin-1 beta (IL-1
      beta). ATP synergized with these factors by increasing the maximum of DNA
      synthesis, without changing the half-maximal concentration of the growth factor.
      In addition cell counts revealed that ATP significantly augments MC growth
      induced by EGF, bFGF, PDGF-BB, ET-1, AVP, Thr, 5-HT, and IL-1 beta. ATP caused
      activation of PI-PLC, but did not synergize with any of the tested growth factors
      in this respect. ATP-induced PI-PLC activation was inhibited by preincubation
      with pertussis toxin by 40-93%. This treatment did not suppress DNA synthesis
      induced by ATP alone, by PDGF, or by PDGF plus ATP. The calcium antagonists, TMB
      8 and verapamil, as well as the inhibitors of protein kinase C, calphostin C and
      H7, had no effect on DNA synthesis induced by ATP or PDGF plus ATP. Also, ATP
      synergistically stimulated DNA synthesis in combination with the direct activator
      of protein kinase C, phorbol myristate acetate (PMA), and with the reaction
      product of phospholipase D, phosphatidic acid. Finally, ATP was mitogenic in an
      MC line of higher passage which did not respond with PI-PLC activation.
      CONCLUSIONS: Extracellular ATP synergistically augments MC growth induced by
      multiple growth factors. While the ATP-induced mitogenic signal is presently
      unclear, our observations support the concept that ATP may play a role during the
      course of glomerulonephritis when multiple growth factors are released from
      glomerular and inflammatory cells.

PMID- 8643164
TI  - Evolution of renal injury in a chronic model of IgA immune-complex-associated
      nephropathy.
AB  - BACKGROUND: IgA nephropathy (IgAN) is characterized by intense and diffuse IgA
      mesangial deposits, a variety of histopathological changes and unpredictable
      clinical course. To elucidate the cause of the discrepancy between the unvariable
      IgA deposition and the histological picture, we examined the short- and long-term
      influence of glomerular IgA immune complexes (IgA-IC) on the progression of renal
      lesions in experimental IgAN. METHODS: IgA-IC renal deposits were induced by
      sequential administration of IgA antiphosphorylcholine and pneumococcal C
      polysaccharide. Mice treated every other day by three injections (groups A) or
      nine injections (groups B) were sacrificed 24 h and 1, 4, or 8 weeks (groups 1-4)
      after cessation of treatment. RESULTS: Group A1 showed segmental glomerular
      necrosis and thrombosis. Lesions then converted to segmental mesangial
      proliferation (A2), more pronounced in A3 and minimal in A4. Group B1 showed
      severe proliferative glomerulonephritis and segmental necrosis. The pattern
      altered to mesangial expansion with glomerular/interstitial infiltration in B2,
      milder features in B3 and residual mesangial proliferation in B4. Proteinuria
      increased progressively during treatment reaching its maximum in group B1, but it
      returned to near normal levels in group B4. The development of proteinuria
      paralleled glomerular/interstitial T cell infiltration. CONCLUSIONS: These
      findings demonstrate that renal histopathological alterations observed in
      experimental IgA nephropathy are sustainable only by continuous deposition of
      nephritogenic IgA-IC.

PMID- 8643165
TI  - Blood-pressure-independent wall thickening of intramyocardial arterioles in
      experimental uraemia: evidence for a permissive action of PTH.
AB  - BACKGROUND: Abnormalities in cardiovascular structures, e.g. LV hypertrophy and
      thickening of vessels (arteries, arterioles, veins) are hallmarks of renal
      failure. They are in part independent of elevated blood pressure. Parathyroid
      hormone (PTH) has been shown to affect cardiac function and has also been
      identified as a permissive factor in the genesis of cardiac fibrosis. PURPOSE OF
      THE STUDY: The present study in rats with experimental renal failure was designed
      to examine whether PTH was permissive for wall thickening of intramyocardial
      arterioles as well. METHODS: Male SD rats were sham operated or subtotally
      nephrectomized and maintained for 2 weeks. Subgroups of subtotally nephrectomized
      (SNX) rats were parathyroidectomized (PTX). Saline or rat 1, 34 PTH was
      administered by osmotic minipump. Eucalcaemia was maintained in PTX animals by a
      high-calcium diet (3%). Serum calcium was not statistically different between the
      groups. After perfusion fixation, intramyocardial arterioles were assessed using
      stereological techniques (wall thickness; wall/lumen ratio; minimal lumen
      diameter; length density). RESULTS: In random samples of the left ventricle, wall
      thickness of arterioles was 2.2 +/- 0.25 microns in sham-op controls and 2.76 +/-
      0.41 in SNX (n = at least 8 animals per group). SNX-PTX animals+solvent did not
      differ significantly from sham-op controls (2.08 +/- 0.42 microns), while SNX-PTX
      animals+PTH had values not significantly different from SNX (2.59 +/- 0.54
      microns). Differences in wall thickness were not paralleled by differences in
      systolic blood pressure (sham-op 110 +/- 13.3 mmHg; SNX 138 +/- 8.4 mmHg, SNX
      PTX+solvent 142 +/- 5.2 mmHg; SNX-PTX+PTH 148 +/- 5.7 mmHg). PTH treated animals
      showed signs of marked vascular smooth-muscle cell and endothelial-cell
      activation. CONCLUSIONS: The data suggest that wall thickening of intramyocardial
      arterioles in short-term experimental uraemia is dependent upon the presence of
      PTH (permissive effect).

PMID- 8643166
TI  - Effect of recurrent pregnancies on the evolution of adriamycin nephropathy.
AB  - BACKGROUND: In rats with incipient adriamycin nephropathy, pregnancy increases
      urine protein excretion and mean arterial pressure, with no changes in the
      glomerular filtration rate. Renal histology is normal and the glomerular
      TxB2/PGE2 ratio is increased. METHODS: In the present study we evaluated the
      influence of repeated pregnancies on the evolution of adriamycin nephropathy. Two
      weeks after a first delivery, rats were mated again and were followed till 35
      days after the second delivery. RESULTS: In pregnant rats with adriamycin
      nephropathy, urine protein excretion and mean arterial pressure returned to
      values identical to those found in age-sex-matched virgin rats with adriamycin
      nephropathy. At the end of the second pregnancy, mean arterial pressure and urine
      protein excretion were again elevated, compared with virgin rats with adriamycin
      nephropathy. Thirty-five days after the second delivery, urine protein excretion
      and mean arterial pressure remained elevated, 296 +/- 50 mg/day vs 115 +/- 26 and
      121 +/- 4 vs 110 +/- 1 mmHg respectively, P < 0.05. Glomerular filtration rate
      remained unchanged 0.84 +/- 0.09 vs 0.79 +/- 0.09 ml/min in virgin rats with
      adriamycin nephropathy. The glomerular TxB2/PGE2 ratio was decreased, contrasting
      with the first pregnancy. At the end of the second pregnancy, histological
      examination of the kidneys in rats with adriamycin nephropathy revealed a
      significant increase in mesangial expansion. It was even more marked 35 days
      later, at the last follow-up, with a semiquantitative score of 162 +/- 29 vs 81
      +/- 20 in virgin adriamycin nephropathy rats, P < 0.05. CONCLUSIONS: In rats with
      adriamycin nephropathy, repetitive pregnancies seem to aggravate the natural
      course of the disease in an irreversible fashion. The earlier changes in
      glomerular prostanoid synthesis, particularly on thromboxane, may play a
      pathogenic role by activating mesangial cell matrix synthesis.

PMID- 8643167
TI  - Report on intensive treatment of extracapillary glomerulonephritis with focus on
      crescentic IgA nephropathy.
AB  - PURPOSE AND DESIGN OF STUDY: In this retrospective analysis the effects of
      combined treatment with steroid pulses, cyclophosphamide and plasma exchange on
      six crescentic IgA glomerulonephritis (IgAGN) patients, selected on a
      histological basis, were examined. The histological criteria included involvement
      of more than 40% of glomeruli by cellular crescents. The effects of this
      treatment were compared to those observed in three untreated crescentic IgAGN
      patients and 12 treated patients who had extracapillary glomerulonephritis of
      different origins, i.e. ANCA-associated systemic or renal-limited vasculitis. All
      patients, except the three crescentic untreated IgAGN patients, received the same
      2-month treatment according to a standardized protocol: steroid boli 15 mg/kg
      methylprednisolone for 3 consecutive days by intravenous infusion, followed by
      prednisone per os (1 mg/kg/day for 4 weeks, 0.75 mg/kg/day for 4 more weeks),
      cyclophosphamide per os 2.5 mg/kg/day for 8 weeks, and plasma exchange. RESULTS:
      After this 2-month course of therapy, substantial clinical improvement was
      observed in both IgAGN and vasculitis patients. However, a second biopsy revealed
      that florid crescents persisted in IgAGN patients and, unlike the vasculitis
      group, during the long-term the initial clinical amelioration disappeared in one
      half of the treated IgAGN cases. Nevertheless, even in the progressive cases,
      intensive treatment seemed to substantially delay the onset of dialysis.
      CONCLUSIONS: Despite some clinical benefits of therapy, short-term reversal of
      active crescents appears less likely to occur in crescentic IgAGN than in
      vasculitis-associated crescentic GN. Intensive treatment seems sufficient to
      arrest, but inadequate to reverse, phlogistic lesions in IgAGN before development
      of chronic changes.

PMID- 8643168
TI  - The pulsatility index and the resistive index in renal arteries in patients with
      hypertension and chronic renal failure.
AB  - BACKGROUND: The pulsatility index (PI) and the resistive index (RI) are used as
      pulsed-wave Doppler measurement of downstream renal artery resistance. Little
      information is available on their value in chronic renal failure and their
      correlation to parameters of renal function and haemodynamics. The aim was to
      compare PI and RI of renal arteries in healthy volunteers and in patients with
      hypertension and chronic renal failure, and furthermore to study the correlation
      of these indices to measurements of renal haemodynamics and function by standard
      methods in patients with renal failure and hypertension. METHODS: Twenty-five
      hypertensive patients (10 females, 15 males, mean age 52 years (24-74) with a
      glomerular filtration rate (GFR) less than 50 ml/min and an arterial blood
      pressure above 140 mmHg systolic and 95 mmHg diastolic were included in the
      study. Ten healthy, normotensive volunteers (4 females and 6 males, mean age 43
      years (30-62)) served as controls in the Doppler examinations. Doppler
      examinations were performed in segmental arteries by an Acuson 128. The PI and
      the RI was calculated from the blood flow velocities. RESULTS: Both the PI and
      the RI were significantly higher in the patient group (P) than in the control
      group (C) (PI, P 1.65 (1.31-1.86), C 1.19 (0.93-1.25), P = 0.003; RI, P 0.76
      (0.69-0.81), C 0.67 (0.64-0.70), P = 0.003). Both PI and RI correlated
      significantly with effective renal plasma flow (PI: r = -0.5, P = 0.02; RI: r = 
      0.5, P = 0.006), renal vascular resistance (PI: r = 0.4, P = 0.05; r = 0.5, P =
      0.02), filtration fraction (PI: r = 0.6, P = 0.005; RI: r = 0.5, P = 0.01) and
      clearance of creatinine (PI: r = -0.6, P = 0.008; RI: r = -0.6, P = 0.006). Only
      RI correlated significantly to GFR (r = -0.5, P = 0.02). The indices did not
      correlate to serum creatinine, or mean arterial blood pressure. CONCLUSION: PI
      and RI seems to be closely related to parameters of renal haemodynamics and
      clearance of creatinine in patients with chronic renal failure and hypertension.

PMID- 8643169
TI  - Inhibition by uraemic sera of CD4+ T-cell adhesion to extracellular matrix
      components.
AB  - BACKGROUND: T-cell-mediated immune responses are impaired in patients with
      chronic renal failure. The migration, proliferation, differentiation, biological
      functioning, and interaction with other T cells are mediated by cell surface
      adhesion proteins, which include integrins. METHODS: To elucidate how uraemia can
      impair T-cell-mediated responses in vivo, the effects of sera from uraemic
      patients on T-cell proliferation and adhesion to extracellular matrix (ECM)
      components were examined. RESULTS: Preincubation of human CD4+ T cells with sera
      from undialysed and dialysed (haemodialysis or peritoneal dialysis) uraemic
      patients inhibited the capacity of the cells to be stimulated by
      phytohaemmagglutinin and by anti-CD3 monoclonal antibody plus immobilized
      fibronectin (FN). Sera from uraemic and dialysed patients, but not from healthy
      individuals, inhibited significantly, and in a dose-dependent fashion, human CD4+
      T cell adhesion to immobilized FN and laminin (LN). The degree of inhibition of
      adhesion was similar whether the sera were continuously present, even during the
      adhesion assay, or removed by washing. The adhesion inhibiting capacity of the
      uraemic sera was not due to modification of the expression of beta 1 integrins on
      the surfaces of the T cells. CONCLUSIONS: These results suggest that uraemia can
      impair the proliferative capacity and adhesion of immune cells, and thus may
      affect normal immune processes and contribute to the overall immune deficiency
      observed in patients with renal failure.

PMID- 8643170
TI  - Importance of iron supply for erythropoietin therapy.
AB  - BACKGROUND: rHuEpo and iron therapy corrects renal anaemia. However, dosage,
      route of administration, and monitoring of iron and rHuEpo therapy in uraemic
      patients remains controversial. METHODS: Therefore a 22-month i.v. iron
      substitution trial, subdivided into four study periods, was initiated in 64 iron
      depleted chronic haemodialysis (HD) patients receiving i.v. rHuEpo therapy.
      Within the first period (6 months) patients were treated with high-dose iron (100
      mg at the end of HD treatment, mean cumulative i.v. iron saccharate dosage was
      2538 +/- 810 mg per patient) in order to replete the iron stores. During the 2nd
      period (6 months) the available iron pool was maintained with low-dose iron by
      administration of 10, 20, or 40 mg iron at each HD, depending on haemoglobin,
      serum ferritin and transferrin saturation levels. During the 3rd period (4
      months), the iron-replete patients were randomized to i.v. or s.c. route of
      rHuEpo administration. During the 4th period (3 months) iron substitution was
      omitted to exclude severe iron overload. RESULTS: In the first study period, high
      dose iron therapy dramatically reduced the weekly rHuEpo requirement by 70% of
      the initial dose (from 217 +/- 179 to 62.6 +/- 70.2 U/kg/week). In the 2nd period
      iron storage pools were easily maintained. Serum ferritin and transferrin
      saturation levels remained stable during this study period. Randomization for
      thrice-weekly i.v. or s.c. administration of rHuEpo in the 3rd study period
      revealed comparable efficacy for both administration routes in iron-replete
      patients. In well-nourished patients (serum albumin > 40 g/l) without
      hyperparathyroidism (parathyroid hormone levels < 100 pg/ml), 50-60 U/kg/week
      rHuEpo were required in contrast to > 100 U/kg/week in patients with
      hyperparathyroidism. In the 4th study period, withdrawal of iron administration
      led to a rapid decrease of serum ferritin and transferrin saturation levels,
      indicating the absence of severe iron overload. CONCLUSIONS: Long-term thrice
      weekly i.v. low-dose iron therapy (10-20 mg per HD treatment) proved to be a very
      effective, economical and safe treatment schedule for iron-replete HD patients.
      Intravenous and s.c. rHuEpo therapy was equally efficacious in iron-replete, well
      nourished patients. HD patients with increased parathyroid hormone levels require
      significantly more rHuEpo than HD patients with parathyroid hormone levels values
      < 100 pg/ml).

PMID- 8643171
TI  - Expression of inflammatory cytokines and adhesion molecules in haemodialysis
      associated amyloidosis.
AB  - BACKGROUND: The occurrence of various arthropathies including carpal-tunnel
      syndrome (CTS) in dialysis-associated amyloidosis, a condition caused by the
      deposition of beta 2 microglobulin (beta 2MG), has been emphasized for several
      years. We attempted to analyse the pathogenesis of CTS in haemodialysis
      associated amyloidosis (HA). METHODS: The expression of cell adhesion molecules
      and inflammatory cytokines in tenosynovial tissues was determined by using both
      reverse-transcriptase polymerase chain reaction (RT-PCR) and immunostaining.
      RESULTS: There was a marked expression of ICAM-1, VCAM-1, E-selectin mRNAs
      together with increased mRNA expression of inflammatory cytokines (IL-1 beta, TNF
      alpha, IL-6 and MCP-1) in proliferating synovial tissues. ICAM-1 was expressed
      not only on vascular endothelial cells, but also on synovial cells. In contrast,
      both VCAM-1 and E-selectin were exclusively expressed on endothelial cells.
      Mononuclear cells bearing CD13, CD14, CD33 and HLA-DR with macrophage-like
      morphology were accumulated in the perivascular area and expressed VLA-4, LFA-1
      and Mac-1. Moreover, synovial lining cells, vascular endothelial cells and
      infiltrated mononuclear cells expressed chemokines such as MCP-1 and MIP-1 alpha.
      CONCLUSIONS: These data suggest that upregulated expression of inflammatory
      cytokines and adhesion molecules promotes activation and infiltration of
      macrophages causing CTS in haemodialysis-associated amyloidosis patients.

PMID- 8643172
TI  - Calcium balance and intact PTH variations during haemodiafiltration.
AB  - BACKGROUND: Recent approaches to prevent and treat secondary hyperparathyroidism
      in dialysis patients include decreasing dialysate Ca content from 1.75 to 1.5 mM
      or lower. We have recently observed that by decreasing dialysate Ca to 1.25 mM a
      rise in intact parathormone serum levels occurs despite adequately controlled
      predialysis Ca and phosphate serum levels. In that study complementary treatment
      with high-dose 1 alpha(OH) vitamin D3 was required to suppress the parathormone.
      In the present study we aimed to assess the total Ca balance as well as the
      modifications in parathormone induced by the dialysis session in order to
      understand the reasons for which the rise in parathormone was induced. METHODS:
      Fourteen HD patients treated with haemodiafiltration three times/week gave their
      informed consent for the study. They were distributed in two groups with
      identical treatment but for the dialysate Ca content which was 1.5 and 1.25 mM
      respectively and for the amount of oral CaCO3 received. Total and ionized Ca,
      phosphate, pH, and albumin as well as parathormone were measured in serum before
      and after dialysis and in the spent dialysate during two dialysis sessions.
      RESULTS: Serum ionized Ca (normalized to pH 7.4) did not change during 1.25 mM
      dialysate Ca and significantly increased with 1.5 mM (P < 0.001). The end
      dialysis values being 1.25 +/- 0.02 and 1.38 +/- 0.02 mM respectively. Total Ca
      significantly decreased with 1.25 mM dialysate Ca (P < 0.04) and increased with
      1.5 mM (P < 0.003), the end-dialysis values being 2.51 +/- 0.03 and 2.75 +/- 0.04
      mM respectively. In the dialysate the difference in ionized Ca concentrations,
      fresh minus spent dialysate was -1.78 +/- 1.12 mmol/l (NS) and 4.26 +/- 1.47
      mmol/l (P < 0.02) respectively for 1.25 and 1.5 mM dialysate Ca. The difference
      in total Ca concentrations, fresh minus spent dialysate was -0.1 +/- 0.01 mmol/l
      (P < 0.05) and -0.002 +/- 0.01 mmol/l (NS) respectively. Phosphate removal was
      higher in 1.25 mM dialysate-Ca-treated patients (40.4 +/- 1.75 mmol/session
      versus 34 +/- 1.3 mmol/session respectively, P < 0.015). The use of 1.25 mM
      dialysate Ca did not result in a change in serum parathormone, while the use of
      1.5 mM resulted in a decrease of 43 +/- 15% (P < 0.02) in patients with marked
      hyperparathyroidism. CONCLUSIONS: Our data remind us of the difficulty in
      assessing Ca balances and identifies the phosphate content as one of the factors
      influencing the amount of ionized Ca in the dialysate. Although the long-term
      parathormone increase we observed using 1.25 mM dialysate Ca may well not be
      explained only by the acute intradialytic modifications, the negative Ca balance
      identified here (which was missed with the analysis of ionized Ca alone), and the
      lack of parathormone inhibition may participate in the relapse of
      hyperparathyroidism.

PMID- 8643173
TI  - Mitral annular calcification in CAPD patients with a low degree of
      hyperparathyroidism. An analysis of other possible risk factors.
AB  - Chronic renal failure has been suggested as a risk factor for mitral annular
      calcification (MAC), a degenerative process of the mitral annulus. The objective
      of the present study was to define MAC risk factors at the start of dialysis and
      'de-novo' appearance after medium- or long-term CAPD, in a non-selected
      population (135 patients) with a low degree of secondary hyperparathyroidism.
      Echocardiographic studies were performed at the beginning of CAPD and every 1-1.5
      years thereafter. Diagnosis of MAC was established by M mode and 2-D study.
      Seventeen of 135 patients studied at the start of dialysis showed MAC. Patients
      who showed MAC were older and presented a higher mean systolic blood pressure.
      The other anthropometric/demographic parameters did not show statistically
      significant differences. MAC thickness: mean 6.21 +/- 3.65 mm (range 3-17.2 mm).
      The posterior annulus was universally affected and in four patients the anterior
      annulus was involved. Seventeen of 76 patients included in the follow-up study
      developed MAC. No significant differences for demography, except age, with MAC
      patients being older, were found. Mean time on CAPD until de-novo MAC diagnosis
      was 49.7 +/- 26.9 months. MAC thickness: mean 4.97 +/- 1.6 mm (range 3-8.42 mm).
      The posterior annulus was affected in all patients except for one and in four
      patients the anterior annulus was involved. The most remarkable echocardiographic
      feature is the almost constant association of MAC with left atrial dilatation
      (LAD). The last one does not seem a consequence of mitral insufficiency, or
      systolic dysfunction. Left ventricular hypertrophy was universally found, with no
      different intensities for patients with or without MAC. In conclusion, a high
      incidence of mitral annular calcification has been found in CAPD patients. Our
      data do not confirm the role of classical invoked risk factors. Blood CaP product
      under 75, a moderate to mild degree of hyperparathyroidism and/or hypertension
      with left ventricular hypertrophy do not seem to be isolated risk factors during
      the CAPD period. Length of time on CAPD, for unknown reasons, seems to favour the
      appearance of MAC. At starting dialysis, high systolic blood pressure and left
      ventricular hypertrophy seem to be related to MAC. Diabetes appears to represent
      an additional risk factor. Further research on mitral annular calcification
      pathogenesis and its consequences is urgently required.

PMID- 8643174
TI  - Bone loss after kidney transplantation: a longitudinal study in 115 graft
      recipients.
AB  - BACKGROUND: Bone loss is an important problem in renal transplant recipients
      immediately after surgery. No data are available about the bone loss beyond the
      first post-transplantation year. METHODS: In a longitudinal, uncontrolled
      observational study bone mineral density (BMD) was measured by dual X-ray
      absorptiometry in 115 renal graft recipients starting at different times after
      transplantation (0-20 years after transplantation) with a follow-up time of 12
      months. RESULTS: A total of 56 patients showed a reduction of BMD during the
      observation period. Bone loss depended on the time after transplantation. Mean
      reduction of BMD at lumbar spine was 7 +/- 10%, 1 +/- 9% during the first and
      second postoperative year. Beyond the third year bone mineral density did not
      change or even increased slightly (0 +/- 4% during 3-5th year, 1 +/- 6% during 6
      10th year and 2 +/- 4% during 11-20th year after transplantation). Decrease of
      BMD correlated with a higher mean daily prednisone dosage (P < 0.001), a higher
      cumulative prednisone dose (P < 0.01), a more frequent and more steroid-resistant
      rejection (P < 0.001) and a higher initial parathyroid hormone level (P < 0.001).
      Patients with 25-OH-cholecalciferol therapy (P < 0.05) or more physical activity
      (P < 0.05) had a smaller bone loss. CONCLUSIONS: Reduction of BMD after
      transplantation is highest within the first post-transplant year. The effects of
      acute graft rejection, prednisone dosage and initial parathyroid hormone level
      are predominant among the multiple factors associated with pronounced bone loss.

PMID- 8643175
TI  - Nephrogenic metaplasia: long-term haemodialysis and anuria as potential risk
      factors and reversibility with renal transplantation.
AB  - AIM: To determine the incidence of nephrogenic metaplasia in patients with
      defunctionalized bladders due to long-term end-stage renal failure on
      haemodialysis. METHODS: From the dialysis registry of the Princess Alexandra
      Hospital 13 anuric patients who had been on haemodialysis for 10 or more years
      were identified. Of these, seven were currently awaiting renal transplantation
      and six had successful transplants. Endoscopic assessment of their lower urinary
      tracts was performed. RESULTS: Three cases of nephrogenic metaplasia were
      identified. In one case this led to significant haematuria following
      transplantation. However, the changes of nephrogenic metaplasia disappeared over
      the subsequent 18 months without specific treatment. CONCLUSIONS: It appears that
      a chronically defunctionalized bladder in the presence of end-stage renal failure
      is associated with an increased risk of nephrogenic metaplasia. These changes may
      spontaneously regress following transplantation and restoration of bladder
      function.

PMID- 8643176
TI  - Recombinant alpha-interferon in renal allograft recipients with chronic hepatitis
      C.
AB  - BACKGROUND: Although chronic hepatitis C infection is one of the factors that can
      lead to morbidity and mortality in renal allograft recipients, treatment
      procedures have not been well documented. Interferon treatment has been shown to
      be effective in the normalization of biochemical hepatitis C and in the clearing
      of hepatitis C virus RNA. However, little is known concerning the efficacy and
      safety of interferon treatment in renal allograft recipients with chronic
      hepatitis C. Interferon has also been accused of increasing renal allograft
      rejection. METHODS: Recombinant alpha-interferon in a dose of 4.5 million units
      three times per week was given to five renal-allograft recipients with chronic
      hepatitis C for 6 months. Besides biochemical investigations, liver
      histopathologies before and after the treatment course were also studied.
      RESULTS: Interferon treatment was effective in two of the patients, in another
      two cases renal function deteriorated during the treatment. In the last case ALT
      increased again after cessation of interferon therapy. CONCLUSION: We conclude
      that interferon seems to be moderately effective in treating chronic hepatitis C
      in renal allograft recipients, but a risk of renal functional deterioration and
      rejection remains.

PMID- 8643177
TI  - Angiotensin-converting enzyme inhibitors and higher erythropoietin requirement in
      chronic haemodialysis patients.

PMID- 8643178
TI  - Plasma advanced glycosylation end-products in maintenance haemodialysis patients.
AB  - BACKGROUND: Pentosidine is a useful marker of advanced glycation end-products
      (AGE) which form cross-links between proteins and have been found elevated in
      plasma and tissues of uraemic and haemodialysed subjects. The origin and fate of
      these molecules are not clearly understood, but they might play a role in the
      cardiovascular complications of end stage renal failure. The aim of this study
      was to evaluate the effect of different types of substitutive therapy on the
      removal of pentosidine. METHODS: Pentosidine was measured by a two-step HPLC
      methodology. Its concentration was evaluated in plasma before and after dialysis
      session, in 24-h urine, and in dialysate of subjects treated with three types of
      chronic substitutive therapy: bicarbonate haemodialysis, acetate-free
      biofiltration, and haemofiltration. Pentosidine levels were compared among the
      three therapy modalities and correlated with clinical and biochemical parameters.
      RESULTS: Plasma pentosidine level was extremely high (23.7 +/- 2.0 pmol/mg
      protein) in the patients treated with the different dialysis modalities. The
      dialysis session had no significant effect on its plasma concentration, but
      haemofiltration seemed to be the most efficient method (300-2000 nmol of
      pentosidine removed per session versus 250-700 nmol per session with the two
      other approaches). An interesting correlation was found between pentosidine and
      blood urea nitrogen (r = 0.58, P < 0.01) and pentosidine with uric acid (r =
      0.48, P < 0.05). CONCLUSIONS: These results suggest that none of the methodology
      showed a good removal of pentosidine, but among them haemofiltration has the best
      efficiency. The statistical relationships between pentosidine and urea and uric
      acid respectively might provide insight into the origin of pentosidine. The
      accumulation of reactive AGE in uraemic patients may be implicated in the organ
      and tissue damage observed in uraemia.

PMID- 8643179
TI  - Dilemma of assessing volume state--the use and the limitations of a clinical
      score.

PMID- 8643180
TI  - Monitoring of central venous dual-lumen catheter placement in haemodialysis:
      improvement of a technique for the practising nephrologist.
AB  - Mismanagement in the placement of central venous catheter (CVC) may occur in up
      to 20% of cases. The catheter can be inadvertently placed in the contralateral
      brachiocephalic vein, the ipsi or contralateral internal jugular vein, and
      usually a thoracic radiograph is necessary to evaluate its location. We propose a
      technique first described by Serafini et al. to establish the position of a CVC
      by endocavitary electrocardiography (EC-ECG) and its employment in a large number
      of uraemic patients requiring haemodialysis. This technique uses the tip of the
      CVC as reference lead in a standard electrocardiograph. The best employment of
      this technique has been obtained by echotomographic visualization of the internal
      jugular vein executed just before transcutaneous puncture of the vessel. For 13
      months we have successfully applied this technique in CVC placement in 81
      patients requiring haemodialysis. In our opinion this method is a safe and simple
      technique that avoids the need for thoracic radiographs and time lost waiting for
      radiographs that prolong the start of the haemodialysis session. According to our
      experience, we confirm that the EC-ECG technique provides a method for ensuring
      compliance with Food and Drug Administration guidelines regarding catheter tip
      location in uraemic patients.

PMID- 8643181
TI  - Concurrent gradient defect renal tubular acidosis and autoimmune lymphocytic
      thyroiditis.

PMID- 8643182
TI  - Malignant hypertension in a haemodialysis patient treated by ultrafiltration.

PMID- 8643183
TI  - IgA nephropathy in a patient with paroxysmal nocturnal haemoglobinuria.

PMID- 8643184
TI  - Nephrotic syndrome, renal vein thrombosis, and folate deficiency in a young man:
      is there a relationship to homocysteine metabolism?

PMID- 8643185
TI  - Association of membranous nephropathy with familial resistance to activated
      protein C.

PMID- 8643186
TI  - Anticoagulation for heparin-induced thrombocytopenia with spontaneous platelet
      aggregation in a patient requiring haemodialysis.

PMID- 8643187
TI  - Abdominal emergency in a dialysis patient: haemolysis from kinking of dialysis
      tubing.

PMID- 8643188
TI  - Visual loss complicating OKT3 monoclonal antibody therapy in a renal transplant
      recipient.

PMID- 8643189
TI  - William Bowman's description of the microscopic anatomy of the kidney.

PMID- 8643190
TI  - Use of pulsed Doppler ultrasound in detecting renal arteriovenous fistula.

PMID- 8643191
TI  - Chronic arthropathy and rectal bleeding in a long-term haemodialysis patient.

PMID- 8643192
TI  - Anaphylactoid reactions during haemodialysis in sheep are mediated by bradykinin
      and can be prevented by bradykinin receptor antagonist.

PMID- 8643193
TI  - Low-dose captopril and proteinuria.

PMID- 8643194
TI  - Calcitriol and calcium carbonate therapy in early chronic renal failure.

PMID- 8643195
TI  - Serum phosphate control: what about calcium salts of keto-amino acids?

PMID- 8643196
TI  - Limitations of the peritoneal equilibration test.

PMID- 8643197
TI  - Eluate from beta 2MG adsorbent beads enhances the expression of IL-1 beta from
      human monocyte.

PMID- 8643198
TI  - Low molecular weight heparin ('fragmin') in haemodialysis: is laboratory
      monitoring worthwhile?

PMID- 8643199
TI  - Effect of recombinant human erythropoietin on soluble interleukin 2 receptor (SIL
      2R) levels in haemodialysis patients.

PMID- 8643200
TI  - Association of high-flux dialysers and bacterial contamination of dialysate
      induced chronic release of cytokines in haemodialysis patients.

PMID- 8643201
TI  - Worsening of renal function in a renal transplant patient treated with
      granulocyte colony-stimulating factor.

PMID- 8643202
TI  - Renal effects of calcium antagonists.

PMID- 8643203
TI  - Effects of ACE inhibitors and calcium channel blockers on the development of
      glomerular sclerosis in models of renal damage.

PMID- 8643204
TI  - Renal scarring: the role of angiotensin II.

PMID- 8643205
TI  - Cellular effects of calcium channel blockers on vascular cells.

PMID- 8643206
TI  - Effect of ACE inhibitors, calcium channel blockers and their combination on renal
      and extrarenal structures in renal failure.

PMID- 8643207
TI  - Therapeutic efficacy of different antihypertensive drugs in human diabetic
      nephropathy: an updated meta-analysis.

PMID- 8643208
TI  - Comparison of the effects of ACE inhibitors and calcium channel blockers on the
      progression of renal failure.

PMID- 8643209
TI  - Effects of ACE inhibitors and calcium channel blockers on insulin sensitivity and
      other components of the syndrome.

PMID- 8643210
TI  - Effects of ACE inhibitors and calcium antagonists alone or combined on
      progression of diabetic nephropathy.

PMID- 8643211
TI  - Hypertension and the kidney: new insights from results of renal transplantation
      studies.

PMID- 8643212
TI  - Nutrition evaluation of dietary fat substitutes.
AB  - In response to US dietary guidelines and health goals, the food industry has
      introduced a variety of innovative food products designed to help the American
      public lower its fat intake. The physical characteristics and safety
      considerations of these products are reviewed, as well as their association with
      chronic disease prevention.

PMID- 8643213
TI  - Results of surveys to assess iron status in Europe.
AB  - Many studies have been undertaken to assess the iron status of Europeans.
      However, differences in dietary patterns, methodology, contraceptive choice, and
      epidemiologic factors lead to confounding factors that need consideration as the
      data from available studies are reviewed.

PMID- 8643214
TI  - Homocysteine--an atherogenic and a thrombogenic factor?
AB  - A recent study found that hyperhomocysteinemia is associated with an increased
      risk of extracranial carotid artery stenosis, while another study demonstrated
      that hyperhomocysteinemia is a common risk factor for recurrent venous
      thrombosis. It seems as if an elevated circulating homocysteine is atherogenic as
      well as thrombogenic, possibly indicating extensive involvement of homocysteine
      in the pathogenesis of coronary heart disease.

PMID- 8643215
TI  - Weekly versus daily oral iron administration: are we asking the right questions?
AB  - The separation of oral iron doses to conform to cycle of intestinal mucosa
      turnover has been suggested by some as a method to improve the efficiency of
      uptake for therapeutic doses of iron. A short-term study in healthy American
      women failed to confirm a superior absorption of radioiron with a 7-day interval
      versus everyday administration of a 50-mg iron dose, but the iron status of the
      experimental subjects may have produced an inappropriate population on which to
      test a question relevant to Third World populations.

PMID- 8643216
TI  - Do dairy products improve bone density in adolescent girls?
AB  - Previous studied have shown that when calcium is supplemented in adolescents who
      normally consume less than 1000 mg calcium, bone mineral accretion improves
      between 1 and 5%. This increment in bone accretion is improved up to 10% when
      dairy products are used as a source of supplemental calcium in adolescent girls.
      Because the addition of dairy foods is a simple, inexpensive intervention that
      carries no risk and because it substantially increases bone accretion with
      potential long-term benefits, adolescents should be encouraged to include dairy
      products in their diet.

PMID- 8643217
TI  - What are American children eating? Implications for public policy (Nutr Rev
      1995;53:111-26)

PMID- 8643218
TI  - Breast cancer chemoprevention: clinical trials and research.
AB  - We have reviewed the literature regarding the chemoprevention of breast cancer.
      Several clinical trials using retinoid, tamoxifen, or low-fat dietary
      intervention for the prevention of breast cancer are ongoing. In the next few
      years, the implementation of these clinical chemoprevention trials will take
      place. Moreover, combinations of such chemopreventive agents, as well as the
      development of new chemopreventive compounds, will require testing in clinical
      settings. Even though there is probably a substantial delay before such
      chemopreventive approaches have a significant effect, it is clear that
      chemoprevention will complement other approaches in controlling breast cancer.

PMID- 8643219
TI  - Ki-67 immunoreactivity, ploidy and S-phase fraction as prognostic factors in
      patients with gastric carcinoma.
AB  - Expression of the Ki-67 antigen was determined by immunohistochemical analysis of
      paraffin-embedded specimens from 242 patients with gastric adenocarcinoma and the
      prognostic value of Ki-67 immunoreactivity was compared with ploidy and S-phase
      fraction (SPF) obtained by DNA flow cytometry. A high percentage of Ki-67
      immunostaining was associated with the intestinal type of cancer (p = 0.0002) and
      male sex (p = 0.003), but correlated only weakly with the SPF (rs = 0.343) and
      not at all with ploidy. The intestinal type of gastric carcinoma was more
      frequently aneuploid and had a higher SPF than diploid tumours (p < 0.0001 for
      both). While the SPF was associated with male sex and stage of disease, both
      ploidy and SPF were associated with nodal status and age. There was no
      association between SPF or ploidy and tumour location or the presence of distant
      metastases. Both SPF and ploidy correlated with survival according to the
      univariate analysis. In a multivariate survival analysis, the stage of disease,
      DNA ploidy and presence of distant metastases emerged as independent prognostic
      parameters. There was no significant difference in survival between patients
      having tumours with high and low Ki-67 labelling, neither in univariate nor in
      multivariate survival analyses. In patients with gastric carcinoma, the level of
      Ki-67 immunoreactivity added no prognostic information to that obtained by DNA
      flow cytometry.

PMID- 8643220
TI  - Overexpression of c-ErbB-2 protein in gastric cancer by immunohistochemical
      stain.
AB  - An immunohistochemical stain to the c-ErbB-2 protein was performed in 225
      paraffin-embedded tissue blocks from patients with locally advanced gastric
      cancer who underwent curative resection. The overexpression of the c-ErbB-2
      protein was observed in 27.4% of the patients. The c-ErbB-2 positivity showed a
      statistically significant correlation with nodal status and stage. The patients
      with an overexpression of the c-ErbB-2 protein had a tendency to a shorter
      survival than those without, but it was not statistically significant (p = 0.08).
      The 5-year survival rate after surgery was 54% in the negative staining group to
      the c-ErbB-2 protein and 49% in the positive staining group. This suggests that
      the c-ErbB-2 protein has a possible role in lymph node metastasis. Therefore
      overexpression of the c-ErbB-2 protein is a useful indicator of disease
      progression in gastric carcinoma patients who received curative surgery.

PMID- 8643221
TI  - Significance of methotrexate serum level achieved in patients with
      gastrointestinal malignancies treated with sequential methotrexate, L-folinic
      acid and 5-fluorouracil.
AB  - Twenty-one patients affected by advanced carcinoma of the digestive tract, all
      but 2 previously treated, received on day 1 every 2 weeks a 2-hour intravenous
      (i.v.) infusion of methotrexate (MTX), 250 mg/m2, followed 24 h later by a 2-hour
      i.v. infusion of L-folinic acid (LFA), 250 mg/m2, and 5-fluorouracil (FU), 600
      mg/mg2 as an i.v. bolus. Only 1 previously untreated patient obtained a partial
      response. The MTX serum level assessed 24 h after its infusion (24-hour sMTX)
      ranged from 0.3 to 5.7 (median: 0.9) microM, and in only 8/21 patients reached a
      concentration > or = 1 microM. A further 46 patients (of whom 22 had been
      previously treated) received the same treatment as above but with a double dosage
      (500 mg/m2) of MTX. Twelve of these 46 patients (26%, 95% confidence interval =
      14-41%) achieved a partial response with this regimen. Responses were obtained in
      chemotherapy-naive patients (8/24) and in previously treated patients (4/22). The
      24-hour sMTX ranged from 1.2 to 9.5 microM)(median: 2.3) and was > or = 2 microM
      in 30/46 patients. Among patients showing a 24-hour sMTX value > or = 2 microM,
      the response rate was 39% (45% in previously untreated patients), while no
      patient with a 24-hour sMTX value below 2 microM at 24 h obtained a major
      response (p = 0.0017). Our findings demonstrate that 500 mg/m2 of MTX given as a
      2-hour i.v. infusion is required to reach a serum concentration of at least 1
      microM for 24 h. Furthermore, the double biochemical modulation of FU may obtain
      an objective response in patients previously treated with fluoropyrimidines.

PMID- 8643222
TI  - Clinical presentation, diagnostic work-up and therapeutic choices in two
      consecutive series of patients with hepatocellular carcinoma.
AB  - In two consecutive series of patients with hepatocellular carcinoma (HCC), we
      compared clinico-laboratory and ultrasonographic characteristics, diagnostic work
      up, survival of untreated patients and, finally, therapeutic choices. In addition
      of the clinical examination, we tested for blood serum alpha-fetoprotein levels,
      HBsAg and anti-HCV antibodies. Ultrasonography was performed in all the patients.
      In most cases, a pathologic diagnosis was obtained by ultrasound-guided fine
      needle biopsy. As curative treatment we considered open surgery, percutaneous
      alcohol injection and radio frequency thermal ablation. In the second series, we
      observed an increased number of patients with compensated cirrhosis and with
      small HCCs, therefore the number of patients undergoing a potentially curative
      treatment was higher. The percentage of multiple tumours was comparable in two
      series implying the presence of two kinds of HCC, different ?ab initio'. The
      survival rate of untreated patients was better in the second series.

PMID- 8643223
TI  - Response of brain metastases from lung cancer to systemic chemotherapy with
      carboplatin and etoposide.
AB  - 30 consecutive patients suffering from cerebral metastases from lung cancer [12
      small cell lung cancer (SCLC), 18 non-small cell lung cancer (NSCLC)] were given
      systemic chemotherapy with carboplatin (300 mg/m2/day 1 every 4 weeks) associated
      with etoposide (120 mg/m2 days 1-3 every 4 weeks). 21 patient were untreated; 9
      patients had had previous chemotherapy, 8 with platinum derivatives. Altogether
      98 cycles of chemotherapy were administered. The results were as follows: 3
      complete response (3 SCLC; 10%), 7 partial response (4 SCLC, 3 NSCLC; 23.3%), 5
      stable disease (1 SCLC, 4 NSCLC; 16.7%), 15 progressive disease (4 SCLC, 11
      NSCLC; 50%). The overall response was 33.3%. Of the 10 patients who responded to
      treatment, 4 had had previous chemotherapy with platinum derivatives. Treatment
      was generally well tolerated; 5 patients experienced grade 4 bone marrow
      toxicity; in 4 treatment was suspended because of progression, and 1 patient died
      after the 4th cycle due to pneumonia with bone marrow aplasia. Mean survival of
      patients responsive to treatment was 38.6 weeks (range 15-99); overall survival
      was 24.8 weeks (range 2-99), in SCLC 23 weeks (range 6-52) and in NSCLC 29.8
      weeks (range 2-99). The combination of carboplatin and etoposide is highly
      successful in the treatment of cerebral metastases from lung cancer and it could
      be a valid alternative to the traditional radiotherapy.

PMID- 8643224
TI  - Local hyperthermia, radiation, and chemotherapy in locally advanced malignancies.
AB  - Tumor size is a significant prognostic variable for attaining complete regression
      (CR) with local hyperthermia (HT) and radiation therapy (RT). The addition of
      weekly chemotherapy was evaluated to improve the efficacy of thermoradiotherapy
      in poor-prognosis lesions (i.e. > or = 7 cm2 or > or = 14 cm3) which have an
      expected CR rate of approximately 30 +/- 8%. Patients were entered into a two-arm
      phase-II study: arm 1 = breast cancer (10 patients), ifosfamide (1.5 g/m2) +
      epirubicin (20 mg/m2) + HT + RT; arm 2 = sarcoma (7 patients) and head and neck
      cancer (9 patients), cisplatin (40 mg/m2) + HT + RT. Therapy encompassing 106
      triple-modality sessions was generally well tolerated for both arms; 2 instances
      of grade-3 and 1 of grade-4 (arm 2) local toxicity (WHO criteria) were observed.
      There were 4 instances of grade-3 myelosuppression (arm 1). The CR rates for arms
      1 and 2 were 70 and 19%, respectively, suggesting that the combination of
      ifosfamide/epirubicin/HT/RT deserves further investigation in the context of
      localized breast cancer.

PMID- 8643225
TI  - A preliminary report of neoadjuvant chemotherapy NSH-7 study in osteosarcoma:
      preoperative salvage chemotherapy based on clinical tumor response and the use of
      granulocyte colony-stimulating factor.
AB  - Eleven patients with high-grade osteosarcoma of an extremity were treated with
      neoadjuvant chemotherapy with NSH-7 protocol. NSH-7 is a refinement of the T-12
      Rosen protocol. Preoperative chemotherapy is initiated with a doxorubicin (ADM)
      and high-dose methotrexate combination. If the primary tumor progresses after the
      first cycle, the preoperative chemotherapy is switched to a combination of
      cisplatin and ADM. Postoperative adjuvant chemotherapy was selected based on
      histological response of the primary tumor. In addition, recombinant human
      granulocyte colony-stimulating factor was used to prevent leukocytopenia and to
      increase the dose intensity of the chemotherapy. In 1 patient, preoperative
      chemotherapy was switched to salvage treatment. Of the 156 courses given, there
      were 10 delays and 4 dose reductions. Leukocytopenia accounted for only 1 delay.
      All 11 patients completed the chemotherapy and 5 patients were fully able to
      tolerate the protocol without delay or dose reduction. Nine patients remained
      alive and continuously free of disease at an average follow-up of 35 months. The
      rate of continuous disease-free survival at 3 years was 81%, which was
      significantly better than that of the T-12 study of our group. These observations
      suggest that the NSH-7 protocol is a safe and effective treatment regimen for
      osteosarcoma.

PMID- 8643227
TI  - Immunohistochemistry of p53 protein in transitional-cell carcinoma of the bladder
      using an image analyzer.
AB  - The p53 protein is known to be the product of the tumor suppressor gene p53. To
      elucidate the biological characteristics of p53 protein in transitional-cell
      carcinoma (TCC) of the bladder, the positive rate (PR) and positive intensity
      (PI) of p53 immunostaining in 72 TCCs of the bladder were quantified and compared
      with clinicopathological findings, prognosis and expression of proliferating-cell
      nuclear antigen (PCNA). The immunoreactivity for p53 and PCNA was evaluated using
      the CAS 200 Image Analyzer (Cell Analysis System, Elmhurst, Ill., USA). Intense
      immunoreactivity for p53 protein was observed not only near the basal cell layer
      but also at the invasive border. Both PR and PI of p53 were significantly
      correlated with histological grade (p < 0.05 and P < 0.02, respectively),
      histological stage (p < 0.02 and p < 0.02, respectively). Both PR and PI of p53
      were significantly higher in patients who died of bladder cancer and in patients
      who developed metastatic progression. Using a univariate analysis, the survival
      was significantly short in subjects with high PR (> 40%) or high PI (> 70%) of
      p53 (p < 0.01 in both cases). However, using a multivariate analysis, the
      prognostic value of p53 immunoreactivity was not superior to histological stage.
      These findings suggested that, although p53 immunoreactivity appears to be
      related to proliferative activity in TCCs of the bladder, the prognostic
      relevance of p53 immunoreactivity was rather limited when evaluating the
      biological attitude of individual TCC of the bladder.

PMID- 8643226
TI  - Randomized trial of dietician counseling to try to prevent weight gain associated
      with breast cancer adjuvant chemotherapy.
AB  - This study was developed to test whether prospective dietician counseling could
      abrogate the unwanted weight gain seen among women receiving adjuvant
      chemotherapy for resected breast cancer. It was also designed to examine
      predictive factors for weight gain in an exploratory manner. Premenopausal women
      starting adjuvant chemotherapy for primary breast cancer were recruited for this
      trial. After appropriate stratification, they were randomized to a group which
      received monthly dietician counseling primarily aimed at weight maintenance
      versus a control group (whose attending physicians and nurses told them about
      possible weight gain but provided no formalized dietician counseling). One
      hundred and seven evaluable women were equally divided between the two protocol
      arms. The median weight changes 6 months after start of chemotherapy were gains
      of 2.0 kg in the dietician counseling group versus 3.5 kg in the control group.
      The median changes in average calorie consumption were reductions of 120 versus
      46 cal/day on weekdays and 196 versus 20 cal/day on weekends for the counseling
      and control groups, respectively. Study data suggest that more weight was gained
      by patients with higher Quetelet's indices (p = 0.01) and patients who had been
      on a diet in the preceding 6 months (p = 0.02). Routine prospective dietician
      counseling aimed at weight maintenance appeared to produce small but
      statistically insignificant reductions in both calorie consumption and weight
      gain in this group of patients.

PMID- 8643228
TI  - Effect on leukemia cell numbers of in vivo administration of immunotherapeutic
      agents is age-dependent.
AB  - On the basis of our previous findings that erythroleukemia-bearing mice of
      different ages responded positively to immunotherapy [indomethacin +/-
      recombinant interleukin (rIL-2)] in vivo [stimulated natural killer (NK) cells
      and increased life span], we aimed, in the present study, to determine if changes
      in these parameters could be correlated to change in erythroleukemia cell
      numbers. Infant (< 3 weeks old), young adult (5-8 weeks) and aged (> 10 months)
      DBA/2 mice were injected with erythroleukemia cells. Some mice remained untreated
      for the 10-day duration of the tumor-bearing period, while others were treated
      with either indomethacin alone for the 10 days from tumor inoculation, rIL-2
      alone for the last 4 days of the 10-day tumor-bearing period, or with both
      indomethacin and rIL-2 as above. In all cases, both treated and untreated mice
      were killed at 10 days after tumor inoculation. Cytospot preparations from single
      cell suspensions of spleen and bone marrow, in all cases, were stained with
      MacNeal's tetrachrome hematologic stain and the relative and absolute number of
      erythroleukemia cells in these organs were determined using light microscopy. The
      results show that indomethacin- and/or rIL-2 treated leukemic infant and young
      adult mice have significantly lower numbers of erythroleukemia cells in both the
      spleen and bone marrow relative to untreated, leukemic mice of corresponding age.
      Leukemic aged mice, however, show no change in erythroleukemia cell numbers in
      either organ, regardless of treatment, paralleling our observations of a lack of
      immunotherapeutic value of these agents on NK cell production/function in aged
      mice.

PMID- 8643229
TI  - Inhibitory effect of oral administration of Monascus pigment on tumor promotion
      in two-stage carcinogenesis in mouse skin.
AB  - Monascus pigment was extracted from red malted rice, Monascus anka. It has been
      used as coloring matter for foodstuffs in Japan and certain Asian countries. Oral
      administration of Monascus pigment suppressed the tumor promotion by 12-O
      tetradecanoylphorbol-13-acetate in mice following initiation by 7,12
      dimethylbenz[a]anthracene.

PMID- 8643230
TI  - In vitro-in vivo correlation in anticancer drug sensitivity test using AUC-based
      concentrations and collagen gel droplet-embedded culture.
AB  - To improve the ability of an in vitro drug sensitivity test to predict in vivo
      effects, we applied a drug concentration that was pharmacokinetically equivalent
      to plasma levels and collagen gel droplet-embedded culture with a high cloning
      efficiency. We reported that the cell-killing effect of cell cycle phase
      nonspecific drugs such as mitomycin C, cisplatin and Adriamycin depends on the
      area under the drug concentration-time curve (AUC). The plasma AUC values of
      these drugs were estimated after an injection into nude mice at the maximal
      tolerated doses (MTD). Tumor cells isolated from human tumor xenografts implanted
      into nude mice and cultured in collagen gel droplets were exposed to drugs under
      conditions that can reproduce the plasma AUC in vitro. The in vitro sensitivity
      to a drug was compared with the in vivo response of the same tumor treated with
      the MTD of the drug. When the criterion of sensitivity was taken as 50% or less
      of the growth inhibition (growth rate of treated group/that of control group,
      T/C), the correlation between the in vitro and in vivo growth inhibition of all 3
      drugs tested was relatively high (86% of the true-positive rate, 82% of the true
      negative rate and 83% of the correlation rate).

PMID- 8643231
TI  - Infection by Alcaligenes xylosoxidans subsp. xylosoxidans in neutropenic
      patients.
AB  - Alcaligenes xylosoxidans subsp. xylosoxidans (A. x. xylosoxidans) is a
      nonfermenting gram-negative peritrichous rod and opportunistic pathogen. The
      organism is frequently found in an aqueous environment. In the past few years,
      nosocomial infections caused by A. x. xylosoxidans have become more evident. The
      literature suggests that systemic infections are severe and often lethal and an
      optimal antibiotic therapy is not well established. This report describes
      nosocomial infections in 11 patients of a hematology ward over a 2-month period.
      Primary infection occurred during the neutropenic phase after cytotoxic
      chemotherapy. Reinfection spread from central venous catheters that had been
      implanted before the first infection. The bacteremia was successfully treated by
      imipenem. None of the 11 patients died from the bacteremia, but 3 died of their
      underlying diseases. Despite an intensive search for the source, the route of
      infection remained uncertain. Nosocomial infections by A. x. xylosoxidans are of
      growing importance in high-risk patients. Although the source of infection often
      remains unknown, infection seems to originate from contaminated solutions.
      Treatment with imipenem and the removal of central venous catheter systems
      successfully eliminated A. x. xylosoxidans, which adheres to plastic material.

PMID- 8643232
TI  - ICG and AMPPPE.

PMID- 8643233
TI  - Cataract surgery in one eye or both.

PMID- 8643234
TI  - MMC in ONS decompression.

PMID- 8643235
TI  - Anterior chamber paracentesis and carbogen treatment of acute CRAO.

PMID- 8643236
TI  - Pressure patching versus no patching for corneal abrasions.

PMID- 8643237
TI  - Pressure patching versus no patching for corneal abrasions.

PMID- 8643238
TI  - Pressure patching versus no patching for corneal abrasions.

PMID- 8643239
TI  - Corneal curvature changes with corneal tunnel phacoemulsification.

PMID- 8643240
TI  - Clinical trials: the gold standard for evaluation of therapy.

PMID- 8643241
TI  - Risk factors of age-related maculopathy in a population 70 years of age or older.
AB  - PURPOSE: To evaluate possible risk factors for age-related maculopathy (ARM) in
      an epidemiologic cross-sectional population study of inhabitants 70 years of age
      or older in a rural area in Oulu County, Northern Finland. METHODS: Five hundred
      of the 560 (89 percent) eligible subjects were examined. The diagnosis of ARM was
      based on fundus photographs in 83 percent of the population or on ophthalmoscopic
      findings in 13 percent; in 4 percent, the fundi could not be seen. Both early and
      late forms of ARM were included. RESULTS: The prevalence of ARM increased
      steadily with age without overall significant difference between men and women.
      The condition was, however, related to high body mass index in men. The ARM
      appeared to be also associated with the presence of cataract, broad peripapillary
      atrophy, and severe sclerosis of the retinal arteries, but after controlling for
      age, these associations were nonsignificant. No association was found between ARM
      and systemic hypertension, diabetes, smoking, working outside, myopia, glaucoma,
      or the presence of exfoliation. In logistic regression analysis, age was the only
      statistically significant risk factor for ARM in both sexes. In men, a high body
      mass index also was found to be a predictor for ARM. CONCLUSIONS: The presence of
      ARM was associated with cataract and signs of age-related vascular changes in the
      eyes. Of the general factors, age in both sexes and high body mass index in men
      were found to be the only predictors of ARM.

PMID- 8643242
TI  - Radiation therapy for subretinal neovascularization.
AB  - PURPOSE: To evaluate low-dose external beam irradiation and plaque radiotherapy
      for the treatment of subretinal neovascularization. METHODS: The authors treated
      137 patients with radiation therapy for subretinal neovascularization. Herein,
      they examine a subset of 75 patients with exudative age-related macular
      degeneration who were treated with (4- or 6-MV photons) external beam irradiation
      at a dose of 1200 to 1500 cGy to the affected macula. In addition, six patients
      were treated with palladium 103 ophthalmic plaque brachytherapy to an equivalent
      retinal apex dose of 1200 to 1500 cGy. The authors compared the intralesional,
      intraocular, and intracranial radiation dose distributions of each treatment
      modality. Early Treatment Diabetic Retinopathy Study-type visual acuity
      determinations, ophthalmic examinations, and angiography were performed before
      and after treatment. Clinical evaluations were performed in a nonrandomized and
      unmasked fashion. RESULTS: Episcleral plaque brachytherapy was found to provide a
      higher average radiation dose within the neovascular tissues while delivering
      less radiation to most normal ocular (both eyes) and all intracranial structures.
      Both forms of radiotherapy were associated with decreased hemorrhages, exudates,
      and leakage of neovascular membranes. Ten (13 percent) patients receiving
      external beam radiotherapy had transient epiphora and ocular irritation.
      CONCLUSION: Observation and laser photocoagulation of subfoveal
      neovascularization have been associated with poor visual outcomes. Pilot
      experience suggests that low-dose radiotherapy offers a method to treat
      subretinal neovascularization without destroying the overlying retina. Although
      the authors' radiation distribution studies favored plaque radiotherapy,
      additional factors such as relative efficacy, expense, convenience, and safety
      must be investigated.

PMID- 8643243
TI  - Asthma caused by topical application of ketorolac.
AB  - BACKGROUND: Ketorolac tromethamine 0.5 percent ophthalmic solution is a widely
      used nonsteroidal anti-inflammatory drug (NSAID) in ophthalmology. Ketorolac eye
      drops have not been implicated previously as a cause of NSAID-induced asthma.
      STUDY DESIGN: A patient with severe asthma after topical application of ketorolac
      is described. The current ophthalmic indications for topical application of
      ketorolac and reported hypersensitivity reactions with systemic use of ketorolac
      are reviewed. RESULTS: A 44-year-old woman with chronic asthma, rhinosinusitis,
      and nasal polyps inadvertently was given ketorolac to be applied topically. After
      applying the first dose of ketorolac, an exacerbation of her asthma developed,
      necessitating hospital admission. CONCLUSIONS: Topical application of ketorolac
      is safe in the vast majority of ophthalmology patients. However, NSAID eye drops
      should not be prescribed for patients with aspirin or NSAID allergy or the
      combination of asthma and nasal polyps unless the patient is known to tolerate
      aspirin without trouble.

PMID- 8643244
TI  - Clinical features of progressive bifocal chorioretinal atrophy: a retinal
      dystrophy linked to chromosome 6q.
AB  - PURPOSE: The gene for progressive bifocal chorioretinal atrophy (PBCRA) has been
      linked to chromosome 6q, near the genomic assignment for North Carolina macular
      dystrophy. A study was undertaken to define the clinical features of a large
      PBCRA pedigree and to determine whether PBCRA and North Carolina macular
      dystrophy are phenotypically distinct entities. METHODS: Fifteen affected
      individuals from 1 large family were examined clinically, which included
      angiography and electrophysiologic studies. RESULTS: The PBCRA is an autosomal
      dominant chorioretinal dystrophy of early onset characterized by large atrophic
      macular and nasal retinal lesions, nystagmus, myopia, poor vision, and slow
      progression. A large atrophic macular lesion and nasal subretinal deposits are
      evident soon after birth. An atrophic area nasal to the optic nerve head appears
      in the second decade, which enlarges progressively. Electro-oculographic and
      electroretinographic studies indicated marked, diffuse abnormalities of rod and
      cone function. Fluorescein and indocyanine green angiography showed a large
      circumscribed area of macular choroidal atrophy with staining of deposits in the
      peripheral retina. In addition to previously documented features, nasal retinal
      abnormalities from a few weeks of age, marked photopsia in a number of patients,
      and retinal detachments in three eyes are reported as new features of the
      disease. CONCLUSIONS: An extended description of PBCRA is presented highlighting
      that the phenotype is distinct from North Carolina macular dystrophy, although
      some phenotypic similarities exist between the two conditions. These disorders
      may be the result of different mutations on the same gene or nearby genes.

PMID- 8643245
TI  - Ophthalmologic manifestations of acquired immune deficiency syndrome-associated
      progressive multifocal leukoencephalopathy.
AB  - PURPOSE: Progressive multifocal leukoencephalopathy (PML) is increasingly
      described as a late complication of the acquired immune deficiency syndrome
      (AIDS). The purpose of this study is to evaluate retrospectively the
      ophthalmologic, clinical, and investigational aspects of AIDS-associated PML.
      METHODS: The authors evaluated ten patients in whom ophthalmologic manifestations
      developed in the course of AIDS-associated PML. Findings at clinical examination
      and their progression over time, neuroimaging correlates, the results of
      pathologic investigation, and visual outcomes were reviewed. RESULTS: Progressive
      multifocal leukoencephalopathy was the AIDS-defining illness in six of ten
      patients. Homonymous visual field defects were the presenting symptom in three
      patients and detected in six patients overall. Occipital blindness developed in
      one patient. Cerebellar signs and brain stem nuclear and supranuclear palsies
      also were common. Confluent white matter lesions with increased intensity on T2
      weighted magnetic resonance imaging were supratentorial in seven patients and
      infratentorial in three patients. With incomplete data, the median survival time
      was 3 months from PML onset. Histopathologic confirmation of PML diagnosis was
      available for nine of the ten patients. CONCLUSIONS: The development of
      progressive retrochiasmal visual field defects, supranuclear and nuclear cranial
      nerve palsies, or nystagmus ataxia in the relatively young patient should alert
      the ophthalmologist to the possibility of PML, particularly in the presence of
      long-tract central nervous system signs or dementia. Progressive multifocal
      leukoencephalopathy will often be human immunodeficiency virus associated. Human
      immunodeficiency virus encephalopathy, cerebral toxoplasmosis, lymphoma, and
      infarction need to be discriminated. Effective therapy is required urgently for
      this devastating disease.

PMID- 8643246
TI  - Automated suprathreshold static perimetry screening for detecting neuro
      ophthalmologic disease.
AB  - PURPOSE: To devise and evaluate a rapid, accurate, and cost-effective method of
      detecting neuro-ophthalmologic visual field defects. METHODS: One hundred fifty
      nine consecutive patients were evaluated with 76-point, central 30 degree
      automated static threshold perimetry on the Humphrey Visual Field Analyzer, as
      well as by a 76-point, central 30 degree suprathreshold examination with the
      central reference levels set at 2 or 4 dB lower than the estimated normal median
      central reference level adjusted for age. Six masked readers reviewed the fields.
      Their readings were compared with those of the other observers, as well as with
      the final diagnoses as determined from all available clinical information.
      RESULTS: In detecting abnormality, the full-threshold 30 degree test had a
      sensitivity (percent of eyes with true field defects identified by the field
      test) of 93 percent or 99 percent (depending on whether borderline results were
      counted as a positive or negative test) and a specificity (percent of cases
      without true field defects appropriately identified by the field test) of 71
      percent or 91 percent. In comparison, the 4-dB offset suprathreshold test had a
      sensitivity (averaged over all reviewers) of 79 percent or 87 percent and a
      specificity of 81 percent or 89 percent, whereas the 2-dB test had a sensitivity
      of 87 percent or 94 percent and a specificity of 73 percent or 85 percent. The
      mean duration of the suprathreshold tests was 3.5 +/- 1.0 minute, compared with
      14.8 +/- 2.8 minutes for the full-threshold technique. CONCLUSION: The central 30
      degree, 76-point, 2-dB offset suprathreshold automated perimetry is more rapid
      and nearly as effective as the full-threshold test in detecting visual field
      abnormalities due to neuro-ophthalmologic disease. More quantitative, full
      threshold perimetric strategies should be used in all equivocal cases and to
      follow progression of established disease.

PMID- 8643247
TI  - Vertical strabismus after cataract surgery.
AB  - PURPOSE: To compare anesthesia methods with resultant strabismus patterns in
      patients with vertical diplopia after cataract surgery. METHODS: The authors
      analyzed 28 consecutive patients with acquired vertical diplopia after cataract
      surgery to identify the strabismus pattern. The method of anesthesia
      administration was available in 21 patients. Three orbital dissections with
      simulated retrobulbar blocks were performed on cadavers to ascertain the
      possibility of injuring the vertical rectus muscles at the time of injection.
      RESULTS: Fifty percent of the involved muscles were overactive, 39 percent were
      restricted, and 11 percent were paretic. Eleven patients received retrobulbar,
      and ten received peribulbar anesthesia. The inferior rectus in 17 patients and
      the superior rectus muscle in 11 were involved. The odds of damaging the inferior
      rectus, as opposed to the superior rectus muscle, with peribulbar anesthesia was
      4.8 times higher than with retrobulbar blocks. Cadaveric dissections showed the
      likelihood of direct needle injury to either vertical recti with retrobulbar
      blocks. CONCLUSIONS: In this patient population, permanent vertical strabismus
      after cataract surgery results more often from overacting or restricted muscles
      than from primary muscle paresis. Both the superior and inferior recti can be
      injured with retrobulbar anesthesia, but peribulbar injections affect the
      inferior rectus muscle more frequently.

PMID- 8643248
TI  - The one-year surgical outcome after prism adaptation for the management of
      acquired esotropia.
AB  - PURPOSE: To report the 1-year motor and sensory outcomes for patients with
      acquired comitant esotropia managed with preoperative prism adaptation. METHODS:
      Patients entered a multicenter randomized prospective evaluation of prism
      adaptation before strabismus surgery. Prism responders were randomized to surgery
      with the target angle based on either the entry angle or the adapted angle of
      esotropia. Three hundred five patients (92 percent of cohort) completed 1-year
      postoperative follow-up. RESULTS: The overall motor success rate for all patients
      in the study was 74 percent. Prism responders operated on for the adapted
      esotropic target angle had a satisfactory motor outcome more often than those
      operated on for the entry angle, 90 percent compared with 75 percent (P = 0.04).
      Significant predictors of a satisfactory motor outcome after surgery were prism
      adaptation, female sex, and hyperopia greater than or equal to +3.00 D. Prism
      responders operated on for the adapted angle showed fusion of the Worth 4-dot at
      substantially more often than did those operated on for the entry angle, 75
      percent compared with 60 percent (P = 0.12). CONCLUSION: Prism adaptation
      significantly improves the 1-year motor outcome after esotropia surgery in prism
      responders. There is no increase in the number of overcorrections. These results
      confirm the value of allotting the extra time and potential expense needed for
      this technique.

PMID- 8643249
TI  - Primary orbital melanomas.
AB  - PURPOSE: Primary orbital melanomas are rare tumors with a poorly defined biologic
      course. Most recorded experiences concern single case reports. The authors
      evaluated the applicability of several of the histopathologic prognostic
      indicators used for uveal melanomas to a series of primary orbital melanomas with
      known clinical follow-up. METHODS: Twenty-one primary orbital melanomas, each
      with at least a 1-year follow-up after diagnosis, were evaluated for (1) modified
      Callender cell type, (2) mitotic count per 40 high-power fields, (3) lymphocyte
      count (less than versus greater than 100/20 high-power fields), (4) blue nevus
      component, and (5) largest tumor diameter. RESULTS: All patients for whom race
      was recorded were white. The mean age at diagnosis was 42 years (range, 15-84
      years). There was an associated blue nevus in 19 patients (90 percent), and in 10
      patients (47.5 percent) there was some form of congenital melanosis. With a mean
      follow-up period of 4.5 years (range, 1-13 years), mortality from metastatic
      tumor occurred in 8 (38 percent) of 21 patients. Of these eight patients, there
      were liver metastases in seven (88 percent) and brain metastases in one (12
      percent). Indicators of poor prognosis were tumors of mixed cell type with high
      mitotic count and greater patient age with underlying congenital melanosis.
      CONCLUSION: Most primary orbital melanomas occur in white patients and are
      associated with blue nevi. These tumors are similar to uveal melanomas with
      respect to prognostic indicators and pattern of metastasis.

PMID- 8643250
TI  - Orbital lesions in the blue rubber bleb nevus syndrome.
AB  - PURPOSE: To identify ophthalmologic manifestations of the blue rubber bleb nevus
      syndrome, a rare cutaneovisceral hemangiomatosis. METHODS: The authors report two
      patients with a diagnosis of blue rubber bleb nevus syndrome with orbital
      hemangiomas. RESULTS: In one patient, the orbital lesion presented with signs and
      symptoms similar to an orbital varix and in the other with lid ecchymosis from an
      eyelid lesion. CONCLUSION: Patients with the blue rubber bleb nevus syndrome may
      have vascular orbital lesions associated with intermittent proptosis.
      Ophthalmologists should be familiar with the syndrome and its life-threatening
      complication of gastrointestinal hemorrhage.

PMID- 8643251
TI  - Invasive keratoacanthoma of the eyelid and ocular adnexa.
AB  - PURPOSE: To report three patients with superficially invasive crateriform
      squamous proliferations of periocular tissue. METHODS: The authors identified
      three patients with superficially invasive periocular tumors that had clinical
      features of keratoacanthoma. Clinical histories, radiographs, and surgical
      pathologic specimens were reviewed. RESULTS: All three tumors arose over several
      weeks, had a crateriform configuration, and exhibited superficial invasion of
      underlying tissues, including perineural invasion and infiltration into skeletal
      muscle. All three tumors were classified as invasive keratoacanthoma. One tumor
      exhibited late perineural extension into the cavernous sinus and convincing
      histologic features consistent with squamous cell carcinoma. CONCLUSION: The
      clinical importance of recognizing invasive keratoacanthoma is that although the
      tumor has the potential for spontaneous involution, locally aggressive behavior
      with deep perineural invasion is possible. This tumor is considered to represent
      a variant of squamous cell carcinoma. The authors recommend complete surgical
      excision of crateriform squamous proliferations with frozen section control of
      margins of resection.

PMID- 8643252
TI  - Localized hypertrichosis associated with periorbital neurofibroma: clinical
      findings and differential diagnosis.
AB  - BACKGROUND: Congenital localized hypertrichosis in the periorbital region is an
      uncommon finding. The authors report two patients with hypertrichosis and
      cutaneous hyperpigmentation overlying a periorbital neurofibroma. METHODS: In
      addition to a complete ophthalmic and systemic examination, the patients
      underwent computed tomography of the head and biopsy of the tumor. RESULTS: Case
      1 previously had received a diagnosis of neurofibromatosis type I. On
      examination, hyperpigmentation, hypertrichosis, and swelling in the right
      supraorbital region were noted. A computed tomographic scan showed a tumor in the
      same region. The tumor was removed, and a plexiform neurofibroma was diagnosed.
      Case 2 was admitted with hyperpigmentation, hypertrichosis, and swelling of the
      left half of her face. Other signs of neurofibromatosis were absent. A computed
      tomographic scan showed a tumor, which was underlying the skin changes. Results
      of histologic examination of the biopsy specimen showed a plexiform neurofibroma.
      CONCLUSION: Neurofibroma-associated hypertrichosis should be considered in the
      differential diagnosis of congenital localized hypertrichosis.

PMID- 8643253
TI  - Atypical retinal astrocytic hamartoma diagnosed by fine-needle biopsy.
AB  - BACKGROUND: Retinal astrocytic hamartoma and retinoblastoma may be very similar
      clinically, and their differentiation in atypical cases can be difficult, even
      with the use of ancillary methods such as fluorescein angiography,
      ultrasonography, and computed tomography. To the authors knowledge, fine-needle
      aspiration biopsy has not been used to diagnose astrocytic hamartoma in such
      cases. PATIENTS AND METHODS: A 7-week-old boy had a minimally calcified retinal
      mass in the macular area of the left eye associated with an extensive secondary
      retinal detachment. The differential diagnosis included retinal astrocytic
      hamartoma and retinoblastoma. A transvitreal fine-needle aspiration biopsy was
      performed. RESULTS: The cytology of the needle biopsy showed benign spindle and
      stellate cells, which were compatible with glial cells. The lesion had
      immunoreactivity for glial fibrillary acidic protein, further supporting the
      diagnosis of astrocytic tumor. CONCLUSION: Fine-needle aspiration biopsy is
      diagnostically useful in unusual cases where the differential diagnosis between
      retinoblastoma and astrocytic hamartoma is difficult.

PMID- 8643254
TI  - Orbital fractures in women due to sexual assault and domestic violence.
AB  - PURPOSE: Because domestic violence and sexual assault have a widespread societal
      and medical impact, this retrospective study was designed to determine the
      frequency of sexual assault and domestic violence as causes of orbital fractures
      in women. METHODS: The records of 54 consecutive patients with orbital fractures
      presenting to the Ophthalmic Plastic and Orbital Surgery service of Penn State
      University's Department of Ophthalmology were reviewed. The type of trauma
      resulting in each patient's orbital injury was identified. The frequency of
      orbital fractures resulting from sexual assault or domestic violence was
      determined. RESULTS: The study included 35 male and 19 female patients, ranging
      in age from 27 months to 63 years. Orbital fracture was the result of sexual
      assault or domestic violence in one third of the female patients, but no male
      patients. Motor vehicle accidents accounted for another 31.6 percent of orbital
      fractures in female patients. CONCLUSIONS: Based on this retrospective study,
      sexual assault and domestic violence are frequent causes of orbital fractures in
      women. Healthcare workers evaluating female patients with orbital fractures
      should have a high index of suspicion regarding sexual assault or domestic
      violence as a possible origin of the injury. A pointed but sensitive approach may
      be necessary to elicit this history from the patient.

PMID- 8643256
TI  - Trabeculectomy with intraoperative sponge 5-fluorouracil.
AB  - PURPOSE: To retrospectively assess the outcome of trabeculectomy surgery
      performed using intraoperative sponge 5-fluorouracil (5-FU) (50 mg/ml). METHODS:
      Trabeculectomy with intraoperative sponge 5-FU was performed on 140 eyes of 119
      patients. The reduction in intraocular pressure (IOP), the number of
      supplementary postoperative injections, and any treatment complications were
      noted. RESULTS: The mean preoperative IOP was 25.7 +/- 8.6 mmHg. The mean
      postoperative IOP was 12.5 +/- 5.7 mmHg with a mean IOP reduction of 52 percent
      (P < 0.0001). One hundred twenty-one (86.4 percent) eyes required no
      postoperative glaucoma medications, with the mean number of glaucoma medications
      dropping from 2.5 +/- 1.1 before operation to 0.3 +/- 0.8 after operation (P <
      0.001). One hundred five eyes received a mean of 5.3 +/- 2.7 postoperative 5-FU
      injections. There was no significant difference in final IOP or success rate
      between low- and high-risk eyes, but high-risk eyes seemed to require
      supplementary postoperative 5-FU. Corneal epithelial damage arose in 52 (37
      percent) eyes and correlated strongly with postoperative 5-FU supplementation.
      CONCLUSION: Intraoperative sponge 5-FU is a reasonably safe and effective adjunct
      to trabeculectomy surgery.

PMID- 8643255
TI  - Long-term follow-up of Graves ophthalmopathy in an incidence cohort.
AB  - PURPOSE: To provide long-term follow-up data on patients with Graves
      ophthalmopathy in an incidence cohort of 120 patients. METHODS: Data were
      obtained from a comprehensive review of each patient's community medical record,
      a follow-up survey, or both. RESULTS: The median interval between the initial
      ophthalmic examination and most recent follow-up was 9.8 years (range, 64 days to
      17.4 years). Follow-up of more than 5 years was available for 96 patients (80.0
      percent), whereas follow-up exceeding 10 years was achieved for 59 patients (49.2
      percent). Persistent visual loss from optic neuropathy occurred in two eyes, with
      final visual acuities of 20/30 and 20/60, respectively. None of the patients
      reported deterioration of vision attributable to Graves ophthalmopathy in the
      interval since their last ophthalmic examination at the authors' institution. Two
      patients (2.2 percent) had constant diplopia, but it was correctable with
      spectacles (prisms) in each case. Nearly one third of respondents had had ocular
      discomfort during the preceding 4 weeks; the most frequent cause in 72 percent of
      patients was dry eyes. Among the respondents to the survey, 60.5 percent believed
      that the appearance of their eyes had not returned to what it had been before the
      development of thyroid disease, 51.6 percent thought that their eyes appeared
      abnormal, and 37.9 percent were dissatisfied with the appearance of their eyes.
      CONCLUSIONS: Although with treatment few patients have long-term functional
      impairment from Graves ophthalmopathy, more than one third of patients are
      dissatisfied with their ultimate appearance. The psychologic, aesthetic,
      economic, and social sequelae of the disorder require further definition by
      formal outcomes studies.

PMID- 8643257
TI  - Outcomes of vitrectomy for retained lens fragments.
AB  - PURPOSE: Retained lens fragments after cataract surgery is an infrequent, but
      potentially serious surgical complication. The aim of this study is to evaluate
      outcomes after vitrectomy has been performed for removal of retained lens
      material. METHODS: A retrospective review was conducted to evaluate all cases of
      pars plana vitrectomy for removal of retained lens fragments performed at Wills
      Eye Hospital from April 1991 through August 1994. RESULTS: A total of 121 eyes of
      121 patients underwent pars plana vitrectomy with removal of retained lens
      material over the 3 1/2-year period. Visual acuity on presentation was 20/200 or
      worse in 95 eyes (79 percent). Visual acuity after vitrectomy was 20/40 or better
      in 82 eyes (68 percent). The postoperative visual acuity was 20/50 to 20/400 in
      21 eyes (17 percent), and counting fingers or worse in 18 eyes (15 percent).
      Nineteen eyes (16 percent) had retinal detachment (RD), 8 were noted at the time
      of vitrectomy and 11 occurred after vitrectomy. Of the 19 eyes with RD, visual
      acuity was 20/200 or worse in 12 (63 percent) and counting fingers or worse in 6
      (32 percent) at the time of last follow-up. The use of posterior segment
      phacofragmentation was associated with higher rate of RD, but the difference did
      not reach statistical significance. Major causes of poor final visual outcome
      included RD (6 eyes), cystoid macular edema (4 eyes), and glaucoma (2 eyes).
      CONCLUSION: The timing of vitrectomy did not have a statistically significant
      impact on visual outcome. Neither the type of intraocular lens nor the timing of
      lens implantation significantly altered the final visual acuity. Most eyes with
      retained lens fragments do well after vitrectomy, with the majority recovering
      good vision. However, the risk of RD is increased, and visual outcome may be
      adversely affected if RD occurs.

PMID- 8643258
TI  - A modified preparation technique for closed-system ocular surgery of human eyes
      obtained postmortem: an improved research and teaching tool.
AB  - PURPOSE: In addition to use for corneal transplantation, human autopsy eyes also
      are used for teaching and vision research. The valuable posterior video technique
      of Miyake usually is done with an "open-sky" preparation. Closed-system surgery
      in postmortem eyes is difficult because of postmortem decrease of corneal clarity
      and myosis. The authors have developed an improved preparation technique that
      allows closed-system ocular surgery in human postmortem eyes. METHOD: The cornea
      is dehydrated using a hyper osmolar (15 percent) dextran solution (Swinger
      Kornmehl solution), which clarifies the cornea for several hours. The pupil is
      dilated mechanically by injecting dextran solution into the anterior chamber, and
      the iris is fixated using formaldehyde (10 percent) and Karnovsky solution.
      RESULTS AND CONCLUSIONS: This technique can be used in autopsy eyes up to 4 days
      postmortem without other fixation. Incision techniques, capsulorhexis,
      phacoemulsification, and intraocular lens implantation, as well as other surgical
      procedures such as glaucoma surgery, transcleral fixation of posterior chamber
      lenses and vitrectomies, can be performed. Neodymium:YAG laser capsulectomies or
      other laser surgical procedures are also possible. This technique is not only
      excellent for residency training and postgraduate wet laboratories, but is also a
      viable tool for research purposes.

PMID- 8643259
TI  - Epikeratoplasty.

PMID- 8643260
TI  - Evolution of otolaryngic allergy and the American Academy of Otolaryngic Allergy.

PMID- 8643261
TI  - Cost-effectiveness considerations in otitis media treatment.
AB  - The costs of treatment of children with otitis media with effusion comprise a
      substantial part of the total health care expenditure. However, there is little
      information about the value of therapy expressed in cost-effectiveness terms, and
      disagreement still exists about optimal therapy. This article considers the
      elements of cost-effectiveness analysis as they pertain to treatment of young
      children with otitis media with effusion and develops a first approximation model
      using data from several sources. The assumptions on which this model is based
      need to be validated by additional research. Otitis media with effusion treatment
      costs are high because of the large, and apparently increasing, number of
      symptomatic cases. Medical therapy, which is the primary treatment modality,
      consumes two thirds of the expenditures for otitis media with effusion. Surgical
      therapy is a cost-effective treatment for children in whom medical therapy for
      otitis media with effusion fails. Medical and surgical therapy are complementary,
      and each should be included in the analysis of cost-effectiveness.

PMID- 8643262
TI  - Levels of eosinophil cationic protein and myeloperoxidase from chronic middle ear
      effusion in patients with allergy and/or acute infection.
AB  - BACKGROUND AND OBJECTIVE: Allergy may play a role in the middle ear inflammation
      that leads to otitis media with effusion. The purpose of this study was to
      determine whether an elevated mediator correlated with the patient's disease and
      thus could be used to differentiate allergy vs. infection as the cause of the
      middle ear inflammation. METHODS: WE evaluated 57 individuals with otitis media
      with effusion, 32 with persistent effusion but no recent acute infection, 14 with
      recent infection and purulent otitis media with effusion, and II healthy
      subjects. The mediator activity of eosinophils and neutrophils in effusion was
      studied in patients characterized as having allergy by positive intradermal skin
      test results and positive radioallergosorbent test results. Eosinophils were
      characterized by measurement of eosinophil cationic protein in the effusion.
      Neutrophils were characterized by measurement of myeloperoxidase in the effusion.
      The levels of eosinophil cationic protein and myeloperoxidase in patients with
      and without allergy were correlated to patient history. RESULTS: Significantly
      elevated levels of both eosinophil cationic protein and myeloperoxidase indicated
      that inflammation in the ear of patients with otitis media with effusion was
      characterized by a pronounced involvement of both eosinophils and neutrophils.
      Eighty-nine percent of all patients with disease had allergy. A higher ratio of
      myeloperoxidase to eosinophil cationic protein in patients with purulent otitis
      media with effusion indicated that in patients with a superimposed acute
      infection, neutrophil activity was increased even further. The level of
      eosinophil cationic protein was elevated only during the effusion of patients
      with allergies as compared with controls (p < 0.01). Among 29 cases of
      nonpurulent otitis media with effusion, 96.5% had allergic immune-mediated
      disease proved by skin testing, which was related clinically to their ear
      disease. Eighty-nine percent (89.6%) of these patients had eosinophil cationic
      protein levels greater than 10 microgram/L. CONCLUSION: Middle ear eosinophil
      cationic protein may be used as a marker of related allergy.

PMID- 8643263
TI  - Positional nystagmus in asymptomatic human subjects.
AB  - Nystagmus produced by static placement of the head in different orientations is
      termed positional nystagmus and is known to occur in human subjects who are free
      of vestibular symptoms. This study provides quantitative data for horizontal
      positional nystagmus occurrence in 49 normal human subjects, in whom the number
      of nystagmus beats, the slow-phase velocity of each beat, and distribution
      statistics were determined. A metric for the possible differentiation of
      physiologic positional nystagmus from pathologic nystagmus is described.

PMID- 8643264
TI  - Assessment of the infant airway with videorecorded flexible laryngoscopy and the
      objective analysis of vocal fold abduction.
AB  - Accurate diagnosis of upper airway abnormalities by flexible laryngoscopy in
      infants is hampered by rapid laryngeal motion and lack of patient cooperation.
      This study evaluates the added role of videorecorded flexible laryngoscopy and
      the objective measurement of vocal fold abduction in improving the diagnosis of
      upper airway abnormalities in infants. Seventy-eight infants had videorecorded
      flexible laryngoscopy performed as part of their evaluation of a suspected airway
      disorder. These recordings were reviewed by three otolaryngologists for
      confirmation of the clinical diagnosis. From the video image, the maximum angle
      of vocal fold abduction was measured with image analysis software. Of 78 patients
      40 had supraglottic or glottic abnormalities, 9 had nasal or nasopharyngeal
      obstruction, 9 had subglottic abnormalities (diagnosed subsequent to
      videolaryngoscopy), and 15 patients had normal findings on examination. Of those
      with laryngeal abnormalities, laryngomalacia was the most common diagnosis (23 of
      78). Vocal fold paralysis was present in 4 patients. A separate group (9 of 78)
      of patients was identified as having symmetric bilateral limitation of vocal fold
      abduction. Laryngeal dyskinesia was diagnosed in these 9 patients. The mean
      values of maximal vocal fold abduction were as follows: (1) normals, 59.5
      degrees; (2) laryngomalacia, 57.0 degrees; (3) paralysis, 26.6 degrees; and (4)
      incomplete abduction with laryngeal dyskinesia, 27.6 degrees. Videolaryngoscopy
      is a valuable tool for documentation, parent education, and analysis of infant
      laryngeal abnormalities. Repeat viewing of the video examination and frame-by
      frame analysis improve the diagnostic accuracy. Using this approach, we have
      calculated the anterior glottic abduction angle in the normal and abnormal infant
      larynx. In addition, we have identified a group of infants with incomplete
      abduction of the vocal folds that appears to be different from that found in
      vocal cord paralysis.

PMID- 8643265
TI  - Role of allergy in eustachian tube blockage and otitis media with effusion: a
      review.
AB  - Recent studies continue to support a role for allergy in the pathogenesis of
      otitis media with effusion. Although a variety of mechanisms have been proposed
      to relate these two disease conditions causally, none has been completely
      validated by experimental or clinical studies. This review suggests that the
      observed relationship between allergy and otitis media with effusion is caused by
      mediators of inflammation and cytokines and colony-stimulating factors released
      by mucosal mast cells and other inflammatory and epithelial cells in the nose and
      nasopharynx. These mediators produce blockage of the eustachian tube through a
      number of mechanisms, which may include local injury or vascular- or neural
      mediated changes in the eustachian tube opening pressure and in middle ear
      perfusion. It is likely that the nasal allergic response in patients predisposes
      to eustachian tube blockage and, if prolonged, causes changes in gas absorption
      in the middle ear space. This gas exchange primarily involves nitrogen
      absorption, which may take several days to develop. This persistent underpressure
      will then lead to middle ear effusion. Irrespective of the theoretical mechanism,
      the relationship between allergy and otitis media with effusion will remain
      controversial until well-controlled clinical studies are conducted documenting
      that in select populations antiallergy therapy is efficacious in preventing or
      limiting the duration of otitis media with effusion.

PMID- 8643266
TI  - Stoma recurrence after laryngectomy: an analysis of risk factors.
AB  - Data from 130 patients who underwent total laryngectomy for squamous cell
      carcinoma of the larynx were reviewed. Patients were treated either by primary
      laryngectomy and planned postoperative radiotherapy or by primary radiotherapy
      and subsequent salvage laryngectomy. Patients with other treatment modalities and
      patients with positive margins of resection and laryngectomies for hypopharyngeal
      cancers were excluded from the study. The stomal recurrence rate with reference
      to several risk factors, such as primary tumor stage, location of tumor, lymph
      node metastases, timing of tracheotomy, and presence of a postoperative
      pharyngoperistomal fistula, was analyzed. The overall incidence of stomal
      recurrence was 10%. The treatment modality appeared to have an impact on
      subsequent stomal recurrence: stomal recurrence developed more often after
      salvage laryngectomy (18.4%) than after primary laryngectomy with planned
      postoperative radiation (4.8%). Advanced T stage, N stage, subglottic
      involvement, and preoperative tracheotomy are risk factors for stomal recurrence
      only in patients with a primary laryngectomy. Stomal recurrence developed in only
      four patients after primary laryngectomy with planned radiation. All four
      patients had more than one risk factor: primary tumor stage T4 (four times),
      subglottic involvement (three times), and preoperative tracheotomy (three times).
      The presence of a postoperative pharyngoperistomal fistula likewise may represent
      a risk factor for the development of a stomal recurrence.

PMID- 8643267
TI  - Recovery after tonsillectomy: electrodissection vs. sharp dissection techniques.
AB  - Previous studies have suggested that electrodissection tonsillectomy is
      associated with increased pain and delayed healing in comparison with sharp
      techniques for tonsillectomy. To better define the clinical significance of this
      difference, a detailed study of the time course of recovery was undertaken in
      adults and children after tonsillectomy or adenotonsillectomy by the sharp or
      electrodissection method. For electrodissection tonsillectomy, electrocautery set
      to 20 W was used for dissection and hemostasis, and after sharp dissection the
      suction electrocautery was used only selectively at bleeding sites. Daily pain
      scores were recorded for 2 weeks, and return to normal diet and activities was
      monitored. In adults the electrodissection tonsillectomy (n = 26) resulted in an
      average delay of 2 days in recovery from pain (p < 0.05) and a 2-day delay in
      return to a normal diet (p < 0.05) compared with sharp tonsillectomy (n = 24). In
      children (aged 2 to 12 years) the electrodissection technique (n = 26) resulted
      in an average delay trend of 1 to 1.5 days (not significant) compared with the
      sharp method (n = 24). Electrodissection tonsillectomy results in an average
      delay in recovery of 2 days for adults and in a lesser delay in pediatric
      patients.

PMID- 8643268
TI  - Tinnitus reclassified; new oil in an old lamp.
AB  - This article represents a compilation of study, research, and patient care during
      a 30-year period. Its development was based on two tenets: (1) keep it simple and
      (2) be inclusive. The purpose of the classification system was to provide
      professionals with a vehicle for describing tinnitus and its location, probable
      cause, loudness, degree of annoyance, and pitch. The system uses two mnemonics to
      follow the word tinnitus: (1) A, B, or C for tinnitus Aurium, Binaural, or
      Cerebri; and C-CLAP for Cause, Composition, Loudness, Annoyance, and Pitch. Four
      descriptions are presented on how this classification system may be used in the
      clinician's report.

PMID- 8643269
TI  - Vestibular neuritis: clinical-pathologic correlation.
AB  - Postmortem examination of the brain and temporal bones of a patient with well
      documented vestibular neuritis showed selective neuronal loss in Scarpa's ganglia
      on the side with absent caloric response. There was loss of hair cells and an
      "epithelialization" of the utricular macule and semicircular canal cristae on the
      deafferented side, and synaptic density in the vestibular nuclei on the
      deafferented side was decreased compared with that on the normal side. All
      findings were consistent with an isolated viral infection of Scarpa's ganglia.
      This is the first description of the effects of chronic deafferentation on the
      vestibular sensory epithelia and the vestibular nuclei in a human being.

PMID- 8643271
TI  - Submandibular swelling in patients with fibrodysplasia ossificans progressiva.
AB  - Fibrodysplasia ossifcans progressive (FOP) is a rare genetic disorder
      characterized by congenital malformation of the great toes and by progressive
      heterotopic ossification of soft tissues. Although ankylosis of the
      temporomandibular joint occurs commonly in the late stages of the disease, only
      one well-documented case of submandibular heterotopic ossification in a patient
      who had FOP exists. Twelve (11 %) of our 107 patients who have FOP had
      submandibular heterotopic ossification that was mistaken initially in seven of
      the patients for mumps, angioneurotic edema, abscess, mononucleosis, or neoplasm.
      Two male patients and 40 female patients ranging in age from 6 to 47 years (mean,
      21 years) were studied. Ten patients survived following assiduous precautionary
      measures. One patient who required emergency tracheostomy and ventilatory support
      also survived. Another patient died of inanition from chronic swallowing
      difficulty. An effective treatment program includes early identification of the
      submandibular flare-up, nutritional support, and glucocorticoid therapy.
      Submandibular swelling in patients who have FOP can be a medical emergency and
      requires intensive precautionary measures to avoid catastrophic clinical
      deterioration. These measures include avoidance of lesional manipulation, airway
      monitoring, and aspiration precautions. Submandibular swelling should be
      recognized as a variable feature of FOP.

PMID- 8643270
TI  - Outpatient biopsies of the palatine tonsil: access to lymphoid tissue for
      assessment of human immunodeficiency virus RNA titers.
AB  - OBJECTIVES: Our objective was to assess the feasibility of using tonsillar
      lymphoid biopsy specimens obtained on an outpatient basis to quantitate a
      patient's lymphoid human immunodeficiency virus (HIV) RNA titers. DESIGN: A pilot
      cohort study was performed. PATIENTS: We evaluated ten HIV-seropositive patients
      who ranged in age from 26 to 48 years and had CD4+ cell counts ranging from 110
      to 833 at enrollment. MAIN OUTCOME MEASURES: The main outcome measures were
      tolerance and safety of outpatient tonsil biopsies and quantitation of HIV RNA
      titers in tonsillar lymphoid biopsy specimens, plasma, and peripheral blood
      mononuclear cells determined by a new method of HIV RNA signal amplification with
      branched DNA probes. RESULTS: Outpatient tonsil biopsies were well tolerated and
      were performed without complications. Nine of 10 tonsil biopsies from the HIV
      seropositive patients examined were positive for significant concentrations of
      HIV RNA, ranging from 106 to 101 HIV RNA equivalents per gram of tissue. All of
      the HIV RNA-positive tonsillar lymphoid specimens had HIV RNA titers that were
      101 to 104 times greater than those recovered from plasma (per milliliter) of the
      same patient obtained at the time of biopsy. CONCLUSIONS: Sufficient tonsillar
      tissue can be obtained in an outpatient clinic setting to quantitate lymphoid HIV
      titers by the new branched-DNA signal amplification method with relative ease and
      without complication. The biopsy method described here affords ready access to
      the lymphoreticular system, which may help to advance our understanding of the
      pathogenesis of myriad immune diseases without the need for excisional node
      biopsies.

PMID- 8643272
TI  - Rapid intraoperative facial nerve expansion.
AB  - The repair of nerve length defect presents a reconstructive challenge after
      trauma and oncologic resection. This study examined rapid intraoperative nerve
      expansion as a method of repairing nerve length defects with the cat facial nerve
      model. We compared expanded nerves with grafted nerves and intact nerves 1 year
      after repair using the criteria of gross function (symmetry and blink reflex
      according to a modified House scale), electromyography thresholds, nerve
      conduction velocity, morphology, and axon count. Three of the five expanded
      nerves regenerated, and all of the grafted nerves regenerated. Functional results
      were similar for the regenerated expanded and the grafted facial nerves, and both
      methods achieved an equivalent level of function. The facial nerves of the
      regenerated expanded group, grafted group, and intact group had mean
      electromyography thresholds of 132 mV, 98 mV, and 134 mV, respectively, and mean
      conduction velocities of 48.3 mg/second, 47.9 m/second, and 44.7 m/second,
      respectively. Morphologic examination of all five expanded nerves immediately
      after the expansion process revealed an intact fascicular structure. However, 1
      year after excision of the expanded segment and repair, only three of the five
      nerves regenerated. Axon count at 1 year was as follows: 404 for the regenerated
      expanded nerves, 449 for the grafted nerves, and 403 for the intact nerves. The
      potential advantages of rapid intraoperative nerve expansion over nerve grafting
      for the repair of nerve gap defects include a single suture line and absence of
      donor site morbidity. This pilot study demonstrates that rapid intraoperative
      nerve expansion and regeneration is possible and can be used to repair a nerve
      length deficit. The development of a rapid and reliable method of intraoperative
      nerve expansion deserves further study.

PMID- 8643273
TI  - Dorsal cochlear nucleus blood flow during acoustic stimulation.
AB  - Dynamic in vivo changes in dorsal cochlear nucleus blood flow during pure-tone
      stimulation were assessed with intravital microscopy. Subjects were stimulated
      with 5-, 10-, or 15-kHz pure tones at 70, 80, and 90 dB sound pressure level.
      Measurements in red blood cell velocity and vessel diameter were made in
      capillaries overlying the 10-kHz isofrequency band of the dorsal cochlear
      nucleus. Stimulation with 10 kHz induced intensity-dependent increases in local
      blood flow in the 10-kHz isofrequency band of the dorsal cochlear nucleus.
      Stimulation with 5 kHz and 15 kHz, frequencies represented in remote locations on
      the dorsal cochlear nucleus surface, did not significantly alter blood flow in
      the defined 10-kHz isofrequency band. These data demonstrate a direct
      relationship between spectral and intensity-dependent pure-tone stimulation of
      the dorsal cochlear nucleus and increases in local blood flow. These findings
      suggest that tonal stimulation of the dorsal cochlear nucleus induces an increase
      in local metabolic demands with resultant rapid blood flow increases.

PMID- 8643274
TI  - Effects of radiation therapy on reconstruction of mandibular defects with a
      titanium reconstruction plate.
AB  - Titanium fixation plates are commonly used in reconstruction of mandibular
      defects resulting from tumor resections in head and neck surgery. The effects of
      radiation therapy on the interface of bone, plate, and soft tissue were examined
      in this in vivo study. Four conditioned beagles had 1-cm segmental mandibular
      defects that were reconstructed with titanium plates. Two of the four also had
      placement of vascularized bone grafts. Healing was evaluated with or without
      postoperative radiotherapy. After collection of tissues using histologic methods
      and analysis with energy-dispersive spectroscopy, we found that the effects of
      radiation on bone-plate and bone-screw interfaces is minimal. Although radiation
      decreased the bone density and the rate of bone repair at the bone-screw
      interface, this did not appear to affect stability of the plate repair or the
      viability of bone tissue.

PMID- 8643275
TI  - Retropharyngeal lipoma causing symptoms of obstructive sleep apnea.

PMID- 8643276
TI  - Temporal bone hemangiopericytoma.

PMID- 8643277
TI  - Ointment granuloma complications after cosmetic and otologic surgery.

PMID- 8643278
TI  - Conductive hearing loss caused by hereditary incus necrosis: a study of familial
      expansile osteolysis.

PMID- 8643279
TI  - Laryngeal involvement in Waldenstrom's macroglobulinemia: a case report.

PMID- 8643280
TI  - Malignant melanoma of the external auditory canal.

PMID- 8643281
TI  - Management of the frontal sinus with inverted papilloma.

PMID- 8643282
TI  - Nasal T-cell lymphoma and the lethal midline granuloma syndrome.

PMID- 8643283
TI  - Giant cell carcinoma of the parotid gland.

PMID- 8643284
TI  - Upper airway involvement in multicentric reticulohistiocytosis.

PMID- 8643285
TI  - Allergic otitis media with gelatinous mucoid fluid containing eosinophils.

PMID- 8643286
TI  - Head and neck surgery in the Jehovah's Witness patient.

PMID- 8643287
TI  - An unusual intubation injury.

PMID- 8643288
TI  - Power microdebrider for functional endoscopic sinus surgery.

PMID- 8643289
TI  - Carotid body tumor resection with the surgical ultrasonic dissector aspirator.

PMID- 8643290
TI  - Lingual granuloma gravidarum.

PMID- 8643292
TI  - Academy Foundation Distinguished Award for Contributions in Clinical Otology.
      Forty years of ear after ear, year after year.

PMID- 8643291
TI  - Historic development of bronchoesophagology.

PMID- 8643293
TI  - Earlens tympanic contact transducer: a new method of sound transduction to the
      human ear.
AB  - This article is an initial report on a new method of transducing sound to the
      human ear. The report describes the shortcomings of conventional acoustic
      amplification devices, the potential advantages afforded by the Earlens system
      (ReSound Corp., Redwood City, Calif.), a description of the system, and
      preliminary clinical results. The system is composed of two elements: a
      transducer that is composed of a magnet mounted on a thin, conical silicone
      platform and a device that generates a magnetic field which causes the Earlens to
      vibrate. The Earlens transducer is placed on the umbo area of the tympanic
      membrane and maintains its position there by floating on a droplet of mineral
      oil. Two configurations of the magnetic field device are described: one that is
      placed within the external auditory canal and another that is worn around the
      neck. This feasibility study was done in seven patients during a 3-month period.
      All patients in the study maintained the position of the transducer for the
      duration of the study, and the tympanic membranes showed no evidence of
      inflammation or other problems. The presence of the transducer caused an average
      5-dB threshold depression in the speech frequencies. In the neck-worn device,
      maximum mean functional gain was 25 dB at 2000 Hz. Variability in the functional
      gain at different frequencies was noted with poorer gain above 2000 Hz.

PMID- 8643294
TI  - Videolaryngoscopic evaluation of laryngeal intubation injury: incidence and
      predictive factors.
AB  - Bedside videolaryngoscopy of 73 cardiovascular surgical patients was performed
      before and after intubation to identify risk factors, incidence, and site of
      injury to the larynx. Nineteen of 44 patients with abnormal preintubation
      examination findings had granulation tissue present on a vocal process, compared
      With 3 of 20 patients who had normal findings on preintubation examination (p <
      0.05). Recent smoking history was elicited from 2 of 20 patients who had normal
      findings on preintubation examination and from 20 of the 44 patients who had
      abnormal findings on preintubation examination (p < 0.01). Laryngeal nerve
      paresis was identified in 21 of 64 patients after extubation and was present in 7
      patients before intubation. Videolaryngoscopy provides a high-quality permanent
      record of the laryngeal examination and is easily obtained in the critical care
      setting. Preintubation videolaryngeal evaluation may identify those at risk for
      more significant intubation injury.

PMID- 8643295
TI  - Extraparotid Warthin's tumor: clinical manifestations, challenges, and
      controversies.
AB  - Extraparotid Warthin's tumors continue to challenge the head and neck surgeon's
      diagnostic and therapeutic skills. A series of six extraporotid Warthin's tumors
      are presented to illustrate the need to keep a high index of suspicion for this
      lesion in the workup of cystic masses involving cervical levels II and III or in
      the event of a concomitant neck mass and a parotid Warthin's tumor. Discussion of
      the debate surrounding the embryogenesis and histogenesis of extraparotid
      Warthin's tumors follows. Clinical guidelines are suggested for the diagnosis,
      treatment, and follow-up of patients with extraparotid Warthin's tumors.

PMID- 8643296
TI  - Endoscopic treatment of sphenoid sinusitis.
AB  - Juxtaposed between the posterior nasal cavity and skull base, the diseased
      sphenoid sinus presents unique challenges when surgical drainage is required.
      Endoscopic techniques have gained widespread popularity for the treatment of
      sphenoid sinusitis, yet the efficacy of such treatment remains largely unknown.
      Thirty-four patients who underwent endoscopic sphenoidotomy were monitored over a
      period of 6 months to 5 years. Surgery was performed with the superior turbinate
      used as the key landmark for identification and enlargement of the natural
      sphenoid ostium. Surgical access was through either a transnasal or transethmoid
      approach, depending on whether disease was limited to the sphenoid sinus.
      Prospective analysis of 26 patients with established outcome measures
      demonstrated a significant reduction in facial pain, nasal drainage, and
      congestion 6 months after surgery (p < 0.0001). Medication use was also reduced
      but to a lesser extent (p < 0.05). Endoscopic sphenoidotomy appears to be a safe
      technique that effectively reduces patient morbidity associated with sphenoid
      sinusitis.

PMID- 8643297
TI  - If functional sinus surgery fails: a radical approach to sinus surgery.
AB  - Radical surgery of the nose and paranasal sinuses was performed in 56 patients as
      a last resort for severe recurrent treatment-resistant rhinosinusitis. Surgery
      consists of removal of all walls between the nasal fossa and the paranasal
      sinuses, creating one cavity. All patients were permanently relieved of sinusitis
      and nasal obstruction, and other symptoms were greatly reduced. Morbidity is low
      in relation to preoperative symptoms. We conclude that radical sinus surgery is
      an effective last resort if functional sinus surgery repeatedly falls.

PMID- 8643298
TI  - Ethics of cochlear implantation in young children.
AB  - Certain leaders of the Deaf community are attempting to generate opposition to
      cochlear implants in children by pitting the rights of deaf children and their
      families against the needs of deaf society. They have labeled physicians as
      unethical and CIs as "child abuse," resulting in misunderstanding, anger, and
      violence. However, the arguments of these leaders are internally contradictory:
      they hold that deafness is not a disability but support disability benefits for
      the deaf; they maintain both that cochlear implants do not work and that they
      work so well that they are "genocidal" (i.e., they will eliminate deafness).
      Their positions oppose the ethical principles of beneficence and autonomy as they
      relate to self-determination and privacy. Ethical standards hold that the best
      interests of the child precede those of a special interest group and that parents
      have the responsibility to determine their children's best interests.

PMID- 8643299
TI  - Pediatric gunshot wounds to the head and neck.
AB  - Gunshot wounds to the head and neck in the pediatric population have become
      alarmingly common. They often result in death of the victim, devastate families,
      and inflict a considerable financial burden to hospitals and society. We present
      a retrospective study of cases treated at a level I trauma center in Houston,
      Texas, from July 1990 to July 1993. We identified 115 cases of gunshot wounds in
      children, 32 of which were exclusively confined to the head and neck region.
      There were 26 male and 6 female patients. Ages ranged from 3 to 17 years. The
      cranial cavity was involved in 13 cases, leading to 9 deaths and 1
      institutionalization. The shootings took place at home in 11 cases, and they
      involved play in 12 cases. The shooter was known to 14 of the victims, and the
      wounds were self-inflicted in 7 cases. The most common type of weapon was the .22
      caliber pistol, which caused four of the deaths. Two of our cases involved BB air
      rifles, one of which mandated a craniotomy for the evacuation of an epidural
      hematoma. Our findings indicate that gunshot wounds to head and neck in children
      are in most instances preventable and result in high fatality rates because of
      common intracranial involvement, even when low-energy missiles are used.

PMID- 8643300
TI  - Assessing the clinical utility of the magnetic stimulator for measuring response
      latencies in the laryngeal muscles.
AB  - Our purpose was to assess the use of magnetic stimulation for measuring
      conduction time of the recurrent and superior laryngeal nerves In 10 normal
      volunteers (7 male, 3 female). Subjects underwent laryngeal electromyography and
      magnetic stimulation of the vagus nerve bilaterally at the mastoid tip with a
      figure 8 coil. Mean muscle response latencies were measured and examined for
      consistent differences. Thyroarytenoid muscle response latencies were
      consistently longer than those in the cricothyroid muscle. Left thyroarytenoid
      muscle latencies were consistently longer than those on the right in agreement
      with bilateral asymmetry of these nerves. No appreciable differences were
      observed in cricothyroid muscle latencies when the right side was compared with
      the left. Results were consistent and reproducible within a broad range, but
      appreciable intersubject variability was observed. The limited sample size was
      unable to support a correlation with anthropometric variables, although an
      association was indicated. Magnetic stimulation with this technique has great
      potential for use in neurolaryngologic studies.

PMID- 8643301
TI  - Inhibition of cholesteatoma migration in vitro with all-trans retinoic acid.
AB  - Retinoids have recently become of interest to clinicians because of their ability
      to inhibit migration and proliferation of premalignant squamous cells while
      enhancing growth and proliferation of normal cells. An in vitro investigation was
      undertaken to determine whether retinoic acid exhibits similar inhibitory effects
      on cholesteatoma cells. Cholesteatoma specimens were obtained intraoperatively
      from 10 patients undergoing mastoidectomy or revision mastoidectomy for chronic
      ear disease. Cholesteatoma explant growth and en mass migration were observed
      daily, and topographic maps were constructed at various time intervals to
      quantity rate and direction of explant migration in the presence or absence of
      all-trans retinoic acid. Before all-trans retinoic acid administration, explants
      migrated very rapidly (1 to 2 mm/day). A maximum threefold inhibition of
      migratory rate occurred, with explants exposed to 0.1 micromol/L retinoic acid
      when compared with controls. A sixfold maximum inhibition was observed at higher
      retinoic acid concentrations (5 micromol/L). On removal of all-trans retinoic
      acid, twofold and fourfold increases in migratory rates were observed. The
      direction of explant migration varied significantly for long periods of time and
      appeared not to be affected by retinoic acid. This investigation suggests that
      all-trans retinoic acid has an inhibitory effect on cholesteatoma cell migration.
      Retinoids may have a role in controlling cholesteatoma disease in the future.

PMID- 8643302
TI  - Partial labyrinthectomy with hearing preservation: an experimental study in
      guinea pigs.
AB  - Recent advances in neurotologic surgery have challenged the traditional belief
      that violating the labyrinth is incompatible with hearing. Our aim in this study
      was to define the conditions that result in hearing preservation and hearing loss
      after surgery on the labyrinth. A guinea pig model was developed. Click-evoked
      auditory brain stem responses were used to determine hearing thresholds. Animals
      underwent surgical destruction of part or all of the vestibular labyrinth.
      Transection and plugging of the lateral semicircular canal resulted in normal
      hearing. Transection of multiple semicircular canals also resulted in hearing
      preservation. Intentional suctioning of perilymph from a transected canal led to
      transient hearing loss with complete recovery. Sequential destruction of the
      entire lateral semicircular canal resulted in preserved hearing as long as the
      vestibule was not opened. Wide vestibulotomy resulted in hearing loss.
      Preliminary histologic studies showed that cochlear hair cells were preserved in
      most cases. The results of our experiments demonstrate the feasibility of
      preservation of hearing after partial labyrinthectomy and provide physiologic
      criteria for developing new operations on the inner ear in human subjects.

PMID- 8643304
TI  - Rapid progression of head and neck squamous carcinoma after hyperbaric
      oxygenation.
AB  - We present four head and neck cancer patients who apparently had rapid
      progression of clinically occult disease during or soon after undergoing
      hyperbaric oxygenation. This led us to review existing knowledge about the
      interaction of HBO with tumors. The literature can be summarized as follows: 1.
      HBO is a useful tool in several situations commonly encountered by head and neck
      surgeons-infections, radionecrosis, and wound-healing problems. 2. The use of HBO
      as a hypoxic cell sensitizer during radiation therapy has been extensively
      studied, with evidence supporting only marginal advantage to this logistically
      difficult undertaking. 3. Most reports regarding the interaction of HBO with
      transplanted tumor cells suggest no effect on tumor growth or metastases. 4.
      Studies of chemically induced carcinogenesis are less conclusive. Some evidence
      supports a role for HBO in enhancing growth of preexisting tumors. Better
      understanding of the interaction of HBO with existing tumors is required to
      ensure that informed choices-weighing potential risks and benefits of HBO
      treatment--may be made by head and neck surgeons and their patients. Further
      research into the interaction between HBO and tumor cells is warranted.

PMID- 8643303
TI  - Epidermal growth factor regulates topoisomerase II activity and drug sensitivity
      in human KB cells.
AB  - Because of its unique DNA-cleaving and strand-passing activities, topoisomerase
      II is involved in many aspects of DNA metabolism, including replication,
      transcription, recombination, and repair. The cytotoxic potential of
      topoisomerase II-targeted drugs, such as etoposide, is related to their ability
      to stabilize covalently linked enzyme-DNA complexes, which are intermediates in
      the enzyme's catalytic cycle. Epidermal growth factor receptor is expressed on
      the cell surface of the majority of squamous cell carcinomas, and epidermal
      growth factor binding is known to stimulate a number of cellular transduction
      pathways, including tyrosine kinase, protein kinase C, and phospholipase C.
      Because topoisomerase II is a proliferation-dependent protein and has been shown
      to be a high-affinity substrate for many of these cellular transduction pathways,
      the effects of epidermal growth factor on cellular regulation and sensitivity to
      etoposide were studied with the human oral cavity squamous cell line, KB.
      Topoisomerase II catalytic activity was rapidly and transiently inhibited after
      the addition of epidermal growth factor to the cellular growth media. Western
      blot on nuclear extracts did not demonstrate alterations in topoisomerase II
      polypeptide levels to account for changes in catalytic activity. Epidermal growth
      factor treatment also led to the formation of stabilized, covalently linked
      enzyme-DNA complexes. Furthermore, epidermal growth factor-induced, topoisomerase
      II-mediated DNA strand breaks were additive to those induced by etoposide. This
      study indicates that epidermal growth factor specifically regulates the catalytic
      and DNA-cleaving activities of topoisomerase II in KB cells. This may direct
      clinical strategies for circumventing the intrinsic cellular resistance to
      chemotherapy commonly observed in squamous cell carcinomas of the head and neck.

PMID- 8643305
TI  - Vascular leiomyoma of the nasal septum.

PMID- 8643306
TI  - Staged endoscopic treatment of laryngeal amyloidosis.

PMID- 8643307
TI  - Soft palate perforation: a complication posterior nasal packing.

PMID- 8643308
TI  - Central nervous system metastases from esthesioneuroblastoma.

PMID- 8643309
TI  - Swallowing dysfunction after tonsillectomy.

PMID- 8643310
TI  - Actinomycosis of the paranasal sinuses: a case report and review.

PMID- 8643311
TI  - Carcinoid tumor of the trachea in a pediatric patient.

PMID- 8643312
TI  - Primary small cell carcinoma of the parotid gland.

PMID- 8643313
TI  - Rhino-orbito-cerebral mucormycosis.

PMID- 8643314
TI  - Columella stapes.

PMID- 8643315
TI  - CHE guidelines for Meniere's disease.

PMID- 8643316
TI  - CHE guidelines for Meniere's disease.

PMID- 8643317
TI  - Smoking and middle ear disease.

PMID- 8643318
TI  - Endoscopic sinus surgery in patients with cystic fibrosis.

PMID- 8643319
TI  - Nasal tuberculosis.

PMID- 8643320
TI  - Health impact of chronic sinusitis.

PMID- 8643321
TI  - Dynamic posturography.

PMID- 8643322
TI  - Children with asthma: we can do better.

PMID- 8643323
TI  - Assessment of respiratory distress in the asthmatic child: when should we be
      concerned?
AB  - The physician caring for the acutely ill asthmatic child has a wide variety of
      signs and systems to assist in assessment. An assessment of the severity of the
      disease should be based on the medical history, and signs and symptoms due to
      hypoxia on various target organs. Laboratory evaluation, while helpful, has
      limited applicability in the young child but should be used as an adjunct to
      clinical assessment where necessary. Based on the history, physical examination,
      and laboratory assessment (when appropriate), acute asthma symptoms should be
      categorized as mild, moderate, or severe. Treatment then can be tailored to
      disease severity.

PMID- 8643324
TI  - Use of magnesium sulfate in asthma in childhood.

PMID- 8643325
TI  - Exercise-induced bronchospasm in children: effects and therapies.

PMID- 8643326
TI  - Cough and asthma in children.

PMID- 8643328
TI  - Vision is getting easier every day.

PMID- 8643327
TI  - Chronic persistent cough: diagnosis and treatment update.
AB  - The approach to patients with chronic cough has been well defined and evaluated
      in the literature through a number of prospective studies. Meticulous attention
      to detail of the afferent loop of the cough reflex has helped identify the cause
      of cough in most patients. The most common causes appear to be similar in both
      children and adults and include asthma, postnasal drip syndromes,
      gastroesophageal reflux diseases, and aspiration. In children, recurrent viral
      infections and infections with atypical organisms also are very prevalent.
      Specific therapy directed at the cause alleviates the cough in most patients. In
      some patients, there may be more than one cause of cough. Invasive testing (eg,
      bronchoscopy and esophageal pH probing) is rarely necessary. In patients in whom
      a specific cause cannot be identified or in whom cough modifiers are necessary
      while specific therapy is taking hold, antitussives of both the narcotic and
      nonnarcotic variety are helpful.

PMID- 8643329
TI  - Local-level and global-level form characteristics in apparent-motion
      correspondence.
AB  - This study addressed the "correspondence" problem of apparent-motion (AM)
      perception in which parts of a scene must be matched with counterparts separated
      in time and space. Given evidence that AM correspondence can be mediated by two
      distinct processes--one based on a low-level motion-detection mechanism (the
      Reichardt process), the other involving the tracking of objects by visual
      attention (the attention-based process)--the present study explored how these
      processes interact in the perception of apparent motion between hierarchically
      structured figures. In three experiments, hierarchical figures were presented in
      a competition motion display so that, across frames, figures were identical at
      either the local or the global level. In experiment 1 it was shown that AM
      occurred between locally identical figures. Furthermore, with the Reichardt AM
      component eliminated in experiments 3 and 4, no preference was obtained for
      either level. While evidence from previous studies that form extraction for
      hierarchically structured figures proceeds from the global to the local levels,
      the present results indicate the irrelevance of such a global precedence in AM
      correspondence. In addition, it is suggested that Reichardt AM correspondence
      between local elements constrains attention-based AM correspondence between
      global figures so that both components move in the same direction. It is argued
      that this constraining process represents an elegant means of achieving AM
      correspondence between objects undergoing complex transformation.

PMID- 8643330
TI  - Spatial-gradient limit on perception of multiple motion.
AB  - Motion is perceived whenever a subject is presented with an appropriate
      spatiotemporal visual pattern. Like many other visual tasks, motion perception
      involves both local and global processing, and thus might be subject to the well
      known paradox that arises from the fact that local features and observations form
      the basis for global perception, but sometimes this global percept can not be
      easily derived from any single local observation, as is best exemplified by the
      aperture problem. Globally, dual (transparent) motion can be readily perceived.
      Spatial limits on the local ability to perceive multiple motion are sought. By
      using the framework of apparent motion, it is found that dual, orthogonally
      oriented motion can be perceived only when the dots that constitute the two
      motions are separated by some spatial limit. For short-range apparent motion, the
      limit is found to be comparable to D(max), and the visual system cannot perceive
      more than a single coherent motion in a local "patch" of radius D(max). It was
      also found that this spatial limit on local-motion perception is not constant,
      but depends linearly on the spatial organisation of the stimuli, and vanishes for
      stimuli having reverse contrast. The lower bound on the ability to perceive
      multiple motion is compared with some well-known bounds in stereopsis, and a
      cortical columnar architecture that might account for it is proposed.

PMID- 8643331
TI  - Temporal-discontinuity detection with contrast-modulated gratings.
AB  - Three experiments on temporal-discontinuity detection were carried out. In
      experiment 1, temporal-discontinuity thresholds were measured for sinusoidal
      gratings by the use of the double-staircase method. A sinusoidal grating was
      presented twice successively. The subject judged whether or not an interval was
      present. The temporal-discontinuity threshold increased as the spatial frequency
      of the grating increased, but decreased as the contrast of the grating increased.
      In experiment 2, contrast-modulated gratings were used instead of the sinusoidal
      grating. The temporal-discontinuity threshold increased as the carrier frequency
      increased, and the threshold for each contrast-modulated grating was similar to
      that for the no-modulation (sinusoidal) grating whose contrast was the same as
      the maximum local contrast of the contrast-modulated grating. In experiment 3,
      temporal-discontinuity thresholds were measured for low-contrast (3%) sinusoidal
      gratings. The thresholds were very low, even for such low-contrast gratings.
      These results suggest that the low-spatial-frequency channels are not involved in
      detecting the modulation frequency of the contrast-modulated grating. Rather, the
      local contrast seems to be the determinant of the detection of the contrast
      modulated grating itself.

PMID- 8643332
TI  - Presaccadic processes in the generation of pro and anti saccades in human
      subjects--a reaction-time study.
AB  - It has been widely acknowledged that the generation of anti saccade, ie a saccade
      towards the direction opposite to that of a visual stimulus, requires the correct
      function of special brain structures. In the present study attempts were made to
      measure the time consumption of brain processes preceding the execution of pro
      and anti saccades. The saccadic eye movements of five adult human subjects were
      investigated in a series of combined pro/anti saccade tasks with the aid of the
      gap and the overlap paradigms. The type of trial--pro saccade and anti saccades-
      was defined by the structure of the stimulus. In some sessions the subjects were,
      in addition, preinformed about the actual command by a cue at different lead
      times before stimulus onset. Pro-saccade and anti-saccade trials were randomly
      intermixed in equal proportions. High error rates (> 30% of all trials in some
      subjects) occurred in the test sessions without preinformative cues. These errors
      had long reaction times (approximately 200 ms), whereas the latencies of correct
      pro or correct anti saccades were even longer (approximately 350 ms). Analysis of
      the errors revealed that they were related to the situation in the previous
      trial: a correct response in the previous trial enhanced the chance of making a
      saccade of the same type in the actual trial by up to 30%. This pretrial effect
      occurred whether the actual trial was a pro-saccade or an anti-saccade command.
      With a cue lead time of 100 ms the numbers of errors decreased, but the latencies
      of the correct pro or anti saccades were about 70 ms longer than those obtained
      in the nonrandom control. With a 200 ms cue lead time the reaction times
      corresponded to those in the control condition. The results suggest that the
      situation in a given trial creates a kind of default program for the saccade
      preparation in the next trial. When a cue about the actual command is given early
      enough, the default program is overridden correspondingly. The perception of the
      cue and the programming of the corresponding saccade take an additional 150 to
      200 ms.

PMID- 8643333
TI  - "Reversed' illusion with three-dimensional Muller-Lyer shapes.
AB  - The purpose of this study was to determine whether the Muller-Lyer illusion is
      produced by a mechanism which uses information defined in the retinal
      coordinates, or by a mechanism taking into account the three-dimensional (3-D)
      shape of the illusion figure. The classical Muller-Lyer figure could not be used
      to address this question since it is two-dimensional. Three-dimensional Muller
      Lyer figures were created to see if the illusion they produce is correlated with
      the shape of the projected retinal image, or with the shape of these figures
      defined in a 3-D coordinate frame. In the experiments retinal image shape was
      juxtaposed against the 3-D shape of the illusion displays. For some displays the
      direction in which the fins pointed, relative to the shafts, in the 3-D frame was
      the "opposite" of the direction in which they pointed in the retinal images. For
      such displays, the illusion predicted on the basis of the 3-D structure was the
      opposite of that predicted on the basis of retinal image shapes. For another 3-D
      display the fins were oriented such that each projected a single straight line in
      the retinal image, thus the typical retinal image (< >, > <) was replaced by
      straight lines (symbol: see text). For all the displays the observed illusion was
      consistent with how the fins were oriented relative to the shaft in the 3-D
      coordinate frame, ie with the 3-D shape of the illusion displays. The retinal
      image shape appeared to play little, if any, role. One conclusion that emerges is
      that the specific retinal image shape projected by the classical line-drawn
      pattern is neither necessary nor sufficient for producing the illusion. The
      present findings are inconsistent with two well known theories of the Muller-Lyer
      illusion: inappropriate constancy scaling and selective filtering.

PMID- 8643334
TI  - The detection of gaze direction: a stare-in-the-crowd effect.
AB  - A visual-search paradigm was used to explore the relative ease with which the
      direction of gaze can be detected. Straight-gaze stimuli were presented as
      targets within a variable number of distractors with left-averted or right
      averted gaze. Reaction time in this case was compared with that when either the
      left-averted or right-averted gaze stimuli were the targets among distractors of
      the two remaining gaze directions. The data were examined for the existence of a
      search asymmetry favoring the straight-gaze targets. Such an asymmetry was found
      with stimuli that were realistically drawn renditions of pairs of human eyes, as
      well as with similar schematic stimuli representing pairs of human eyes. The
      asymmetry, however, was not found with geometric control stimuli, which also
      presented the critical feature in the central, the left-lateral, or the right
      lateral position within the stimulus, but were not eyelike. It was also not found
      for schematic stimuli consisting of only one eye. It was concluded that the
      straight gaze direction is a special stimulus with eyelike stimuli, which the
      visual system is set up to process faster and with fewer errors than averted gaze
      directions. The results are discussed in terms of the evolutionary significance
      of the straight gaze direction.

PMID- 8643335
TI  - Trajectory mapping: a new nonmetric scaling technique.
AB  - Trajectory mapping is a new scaling technique designed to recover the
      parameterizations, axes, and paths used to traverse a feature space. Unlike with
      multidimensional scaling, there is no assumption that the space is homogeneous or
      metric. Although some metric ordering information is obtained with trajectory
      mapping, the main output is the feature parameterizations that partition the
      given domain of object samples into different categories. After an introductory
      example, the technique is further illustrated by using first a set of colors and
      then a collection of textures.

PMID- 8643336
TI  - Phenomena of illusory form: can we bridge the gap between levels of explanation?
AB  - The study of illusory brightness and contour phenomena has become an important
      tool in modern brain research. Gestalt, cognitive, neural, and computational
      approaches are reviewed and their explanatory powers are discussed in the light
      of empirical data. Two well-known phenomena of illusory form are dealt with, the
      Ehrenstein illusion and the Kanizsa triangle. It is argued that the gap between
      the different levels of explanation, bottom-up versus top-down, creates
      scientific barriers which have all too often engendered unnecessary debate about
      who is right and who is wrong. In this review of the literature we favour an
      integrative approach to the question of how illusory form is derived from
      stimulus configuration which provide the visual system with seemingly incomplete
      information. The processes that can explain the emergence of these phenomena
      range from local feature detection to global strategies of perceptual
      organisation. These processes may be similar to those that help us restore
      partially occluded objects in everyday vision. To understand better the
      Ehrenstein and Kanizsa illusions, it is proposed that different levels of
      analysis and explanation are not mutually exclusive, but complementary. Theories
      of illusory contour and form perception must, therefore, take into account the
      underlying neurophysiological mechanisms and their possible interactions with
      cognitive and attentional processes.

PMID- 8643337
TI  - Symposium on RNA biology. I. RNA-Protein Interactions. Research Triangle Park,
      North Carolina, October 13-15, 1995.

PMID- 8643338
TI  - RNA interactions in the regulation of transcription.
AB  - In this overview we describe interactions between RNA, DNA, and proteins that are
      involved in the regulation of the various functional cycles of E. coli
      transcription. The role of the RNA terminator hairpin in destabilizing the
      transcription elongation complex and controlling the efficiency of termination at
      various template positions near intrinsic terminators are discussed, as are the
      mechanisms whereby rho protein triggers RNA release at rho-dependent terminators.
      Mechanisms used by phage 1-coded antitermination factor N in "fine-tuning"
      termination efficiencies are also considered, as are the roles of kinetically
      different elongation complex conformations in controlling transcriptional
      fidelity. General principles of the control of transcription by such RNA-protein
      interaction mechanisms are discussed.

PMID- 8643339
TI  - How many different RNA enzymes.

PMID- 8643340
TI  - Double-stranded RNA: the variables controlling its degradation by RNases.
AB  - The kinetics of single-stranded (SS) and double-stranded (ds) polyribonucleotides
      cleavage by three mammalian pancreatic type ribonucleases have been studied under
      low and high salt conditions. The values kcat, Km, and kcat/Km for
      depolymerization of poly(U), poly(A).poly(U), poly(I) and poly(I).poly(C) by
      bovine RNase A, bovine seminal RNase, and human seminal RNase have been
      determined and compared to each other. The Km values of bovine RNase A for (ss)
      or (ds) substrates were of the same order of magnitude under low and high ionic
      strength conditions, while their kcat values were found to differ considerably.
      Qualitatively similar results were obtained with bovine and human seminal RNases,
      i.e., the activity ratios (ssRNA/dsRNA) were mostly determined by the ratio of
      kcat values. It was shown that the modest levels of activity toward dsRNAs shown
      by single-strand-preferring RNases may occur by a mechanism consisting in the
      binding of the RNase to single nucleotides which are wound off the double helix
      because of thermal fluctuations. A higher activity and its enhancement as a
      function of number and location of the positive charges present on the RNase
      surface (human seminal RNase > bovine seminal RNase > bovine RNase A), as well as
      its increase under low ionic strength conditions, could instead be explained by
      the increased occurence of the splitting mechanism based on the binding of the
      RNase to single-stranded RNA sequences transiently exposed from the RNA double
      helix.

PMID- 8643341
TI  - Does the Pb(2+)-catalyzed depolymerization of RNA occur in vivo.
AB  - In order to determine if Pb2+ depolymerizes RNA, reticulocytes were transfused
      into rabbits that had been dosed with lead acetate and also into untreated
      controls. The messenger RNA from these reticulocytes was the examined to
      determine if in vivo exposure to the Pb2+ had impaired the integrity of the mRNA.
      The total amount of mRNA did not vary between controls and Pb(2+)-treated
      rabbits. However, when the ability of the mRNA to program protein synthesis in
      cell-free hemolysates was tested, a marked loss in biological activity of the
      mRNA from the Pb(2+)-treated rabbits was observed. That the loss in biological
      activity was due to the depolymerization of the mRNA in vivo was shown by an
      increase in the number of free 5' hydroxyl groups in the poly (A+) RNA from the
      Pb(2+)-treated rabbits. The ratio of polyribosomes to monoribosomes was also
      decreased. In vitro experiments on the effects of Pb2+ on globin mRNA were also
      performed and showed that at micromolar Pb2+ concentrations the mRNA was attacked
      in the vicinity of the 5' end with little damage to the rest of the molecule.
      These data show that Pb2+ catalyzes cleavage of phosphodiester bonds resulting in
      loss of template activity of mRNA in vivo as well as in vitro.

PMID- 8643342
TI  - Specificity of binding of Saccharomyces cerevisiae ribosomal protein L32 to model
      RNAs.

PMID- 8643343
TI  - Structural specificity of nuclease from wheat chloroplasts stroma.
AB  - A single-strand-specific nuclease from wheat chloroplasts (ChS nuclease) was
      tested as a tool for RNA secondary and tertiary structure investigations, using
      yeast tRNA(Phe) and yeast tRNA(Asp) as models. In tRNA(Phe) the nuclease
      introduced main primary cleavages at positions U33, A35 and A36 in the anticodon
      loop and G18 and G19 in the D-loop. In tRNA(Asp) the main primary cleavages
      occurred at positions U33, G34 and U35 in the anticodon-loop and the lower one at
      position C20:1 in the D-loop. No primary cleavages were observed within the
      double-stranded stems. Because ChS nuclease has (i) a low molecular weight, (ii)
      a wide pH range of action (5.0 to 7.5) (iii) no divalent cation requirement in
      the reaction mixture and (iv) can be obtained as a pure protein in rather large
      quantities it appeared to be a very good tool for secondary and tertiary
      structural studies of RNAs.

PMID- 8643344
TI  - Autoimmune derived combinatorial phage display libraries: methods in construction
      of and affinity selection for anti-RNA Fabs.
AB  - Display of antibody fragments (Fab) on the surface of filamentous bacteriophage
      and selection of phage that bind to a particular antigen has enabled the
      isolation of Fab with numerous specificities. We have examined the possibility of
      isolating RNA-binding Fab by constructing and screening combinatorial libraries
      of phage displaying Fab derived from the antibody repertoires of autoimmune
      humans. The genes and corresponding Fabs will allow for examination of the
      mechanism by which antibodies recognize RNA. Patients selected exhibit mixed
      connective tissue disease (MCTD), which is a subset of systemic lupus
      erythematosus (SLE), MCTD patients contain antibodies reactive against various
      nucleic acid, protein, and nucleoprotein complexes, most notably those involved
      in RNA processing. The cDNA libraries were constructed from total RNA derived
      from leukophoresed patient samples and the resulting Fab genes were expressed in
      E. oli using the pComb system1. Affinity selection procedures have been designed
      to isolate anti-RNA Fabs from these libraries. Results demonstrate the ability to
      enrich for anti-RNA Fabs using biotinylated RNA-streptavidin capture
      methodologies.

PMID- 8643345
TI  - Advances in the chemical synthesis and purification of RNA.
AB  - Significantly developments that improve the chemical synthesis and purification
      of oligoribonucleotides have been attained. Introduction of a 2'-O-acetyl
      function on the nucleoside bound to the polystyrene support enhanced the yield of
      the oligoribonucleotide after cleavage. Higher coupling efficiency was achieved
      by the activation of phosphoramidites with a 0.75M solution of 5-ethylthio-1 H
      tetrazole. Removal of the 2'-O-t-butyldimethylsilyl groups was effected rapidly
      at elevated temperatures with triethylamine trihydrofluoride in DMF. Fully
      deprotected RNA was then directly desalted and precipitated by the addition of 1
      butanol. Purified RNA was isolated by the addition of 1-propanol to the collected
      HPLC purified fractions thus avoiding laborious desalting and solvent evaporation
      processes. These advancements have been extended to synthesis of ribozymes and
      tRNA.

PMID- 8643346
TI  - Production of RNA strands containing nucleotide analogs in only one section.
AB  - RNA molecules containing randomly placed 4-thio-U residues only in the 3' one
      fifth of the molecule were produced using E. coli RNA polymerase. To achieve this
      distribution of residues, an EcoRI site was engineered into the template at a
      position four-fifths of the way from the promoter to the end of the template. A
      tight-binding EcoRI(gln111) mutant protein was bound to this site. The presence
      of this protein resulted in paused transcription complexes that were purified
      using a Centricon 100 filtration device. The nucleotide composition was changed
      after filtration, and transcription was allowed to continue to the end of the
      template in buffer containing 0.5 M KCl, which caused the EcoRI(gln111) protein
      to be released from the DNA template. Analogous RNA molecules for other studies
      of protein-RNA interactions could be produced using this procedure.

PMID- 8643347
TI  - Comparison of Milli-Q PF plus water with DEPC-treated water in the preparation
      and analysis of RNA.
AB  - The Milli-Q PF Plus water polishing system is equipped with high-purity ion and
      organic removal media and a capillary fiber ultrafiltration device. The system
      produces ultrapure water practically free of ribonuclease contamination. The
      necessity for diethyl pyrocarbonate (DEPC) treated solutions in RNA molecular
      biological procedures was tested by preparing RNA from a variety of tissues and
      tissue cultured cells using either DEPC-treated, autoclaved solutions or pure
      Milli-Q PF water dispensed directly from the system. Tissue sources included
      rabbit brain, heart, lung, liver, kidney, and bladder as well as cultured human
      corpus cavernosum smooth muscle cells (HCCSMC). RNA was prepared by
      solubilization in guanidinium isothiocyanate, phenol/chloroform extraction, and
      isopropanol precipitation followed by Northern blot analysis. Hybridization with
      fibronectin (approximately 7.6kb) and glyceraldehyde-3-phosphate dehydrogenase
      (1.2kb) revealed that water from a Milli-Q PF water system performed as well as
      DEPC-treated, autoclaved solutions. RNA stability at 37 degrees C was examined
      for various times using rabbit lung RNA in either DEPC-treated water or Milli-Q
      PF water. Intact RNA was detected after 6 hours in total RNA and by Northern
      blots hybridized with fibronectin. There was no significant difference in RNA
      degradation between DEPC-treated water or Milli-Q PF water. We conclude that
      Milli-Q PF water is an acceptable substitute to DEPC-treated water for the
      preparation of RNA and Northern blot analysis.

PMID- 8643348
TI  - Double-stranded RNA binding proteins and their substrates.
AB  - Double-stranded RNA (dsRNA) binding proteins (dsRBPs) pose unique questions in
      regard to how proteins interact with RNA. This article presents a general
      overview of these questions and also introduces specific dsRBPs that are studied
      by my laboratory.

PMID- 8643350
TI  - The fidelity of human telomerase.
AB  - The ribonucleoprotein enzyme telomerase is a RNA dependent DNA polymerase. The
      function of telomeres is mediated by the proteins which bind telomeric repeats.
      The binding of those proteins is sequence specific. We determined the fidelity of
      the DNA polymerization reaction of human telomerase in order to understand the
      origin of non-canonical telomeric repeats in human telomeres and to gain insight
      into the reaction mechanism of telomerase. By cloning and sequencing a large
      number of in vitro generated telomeric repeats we found the error rate for human
      telomerase to be approximately 2 x 10(-3) per nucleotide or one non-TTAGGG repeat
      for every 100 TTAGGG repeats. All the nucleotide changes observed were A --> C
      changes for a positional error rate of 1.2 x 10(-2). All the other positions had
      no observed errors for a positional error rate no greater than 1.2 x 10(-3).

PMID- 8643349
TI  - Antibodies specific for the DNA quadruplex [d(CGC G4 GCG)4] isolated from
      autoimmune mice.
AB  - An autoantibody specific for a DNA quadruplex structure has been isolated and
      cloned from three-month-old autoimmune "viable motheaten" mice. This antibody
      (mev-alpha Q1) has been tested extensively in vitro and found to bind
      specifically and preferentially to the parallel-stranded quadruplex structure
      formed by the oligonucleotide d(CGC G4 GCG). The anti-quadruplex antibody does
      not show specific affinity for single-, double-, or triple-stranded
      oligonuclotides of similar CG-rich sequence motifs.

PMID- 8643351
TI  - Characterization of RNA-binding protein genes in cyanobacteria.
AB  - A number of genes that encode RNA-binding proteins belonging to the RNP family
      have been identified in cyanobacteria. All of them are predicted to encode small
      proteins with a single RNA recognition motif, containing both the RNP1 and RNP2
      conserved motifs, and a short auxiliary motif which in many cases contains an
      abundance of glycine residues. Mutagenesis experiments to characterize the
      function of some of these gene products are being carried out. In Synechococcus
      sp. PCC 7942, interruption of the rbpA gene results in slower growth with an
      altered pigment composition.

PMID- 8643352
TI  - Evidence for a model ancestral viroid.
AB  - The generation of a phylogenetic tree of viroids and viroid-like plant satellite
      RNAs via computer analysis, coupled with several conspicuous biochemical
      characteristics of the rolling circle replication of these RNAs -including both
      self-cleavage and self-ligation- leads us to propose the peach latent mosaic
      viroid (PLMVd) as a current "living fossil" dating from a precellular world.
      Incorporated within this proposal is a revised mechanism of PLMVd rolling circle
      replication which requires a minimal protein involvement.

PMID- 8643353
TI  - Structural and thermodynamic characteristics of the binding of the lambda N
      protein to a RNA hairpin.
AB  - The specific binding of the lambda N protein to a 15 nucleotide RNA oligomer that
      forms a hairpin structure has been investigated by biophysical methods. Using
      fluorescence spectroscopy and equilibrium ultra-centrifugation, it was found that
      the N protein binds specifically to this RNA hairpin as a monomer. Circular
      dichroism experiments show that both the N protein and the RNA hairpin undergo
      structural change upon association of the complex.

PMID- 8643354
TI  - An RNA pocket for the planar aromatic side chains of phenylalanine and
      tryptophane.
AB  - This is a preliminary report of RNA's with affinity for the aromatic side chains
      of the amino acids phenylalanine and tryptophane that have been isolated
      utilizing in vitro selection to phenylalanine-affinity matrix. Cloning and
      sequencing of a binding pool identified a frequently occurring 6-9 base motif (
      CUCGUGU-) common to most of the RNA's; other potential binding motifs were
      revealed but occurred less frequently. Four of five clones analyzed bind free
      phenylalanine and tryptophane with dissociation constants in the low millimolar
      range, the fifth binds resin only. Isolate F7, the most common sequence in the
      binding pool, demonstrated moderate specificity for aromatic rings, no
      stereoselectivity was observed. Preliminary Pb cutting structural analysis agrees
      with the most stable predicted secondary structure. A striking similarity between
      the sequence and predicted structure of F7 and the bridged-biphenylisomerase RNA
      (J.R. Prudent, T. Uno, and P.G. Schultz, Science 264,1924 (1994)) suggests a 19
      base loop contains the important aromatic binding elements.

PMID- 8643355
TI  - Generation of nuclease resistant circular RNA decoys for HIV-Tat and HIV-Rev by
      autocatalytic splicing.
AB  - Circular exon sequences can be generated by splicing permuted intron-exon (PIE)
      sequences. The Anabaena pre-tRNA group I self-splicing PIE sequence was modified
      to generate circular forms of the HIV-TAR and the high affinity region of the HIV
      RRE (RBE). RNA products containing TAR and the RBE were purified from splicing
      reactions and demonstrated to be circular. The circular form of these sequences
      was shown to be resistant to nuclease degradation in cellular extracts. Gel shift
      assays demonstrate that the circular form of the RBE is specifically bound by a
      Rev derived peptide. These data suggest that PIE-circularization of RNA may be an
      effective way to express small stable RNAs designed for therapeutics (eg-decoys).

PMID- 8643356
TI  - A simple code for protein:RNA interactions.
AB  - The Tat and Rev proteins of HIV-1 and the Rex protein of HTLV-I do not interact
      with their cognate ligands via a particular structural motif but instead
      specifically recognize RNA molecules by using agglomerations of arginine residues
      (1). These proteins are members of the so-called arginine-rich motif (ARM)
      family. There is little data to support (or contradict) the hypothesis that a few
      simple arginine:RNA interactions govern how ARMs recognize their viral targets.
      Not only is it unclear how ARM proteins other than Tat interact with their
      cognate RNA ligands, for the most part it is not even known how structurally
      complex these RNA ligands are. In order to fully explore the range of RNA
      sequences and structures that can bind to ARMs we have carried out in vitro
      genetic selections with two disparate viral proteins: Rev and Rex.

PMID- 8643357
TI  - Double-stranded RNA adenosine deaminase binds Z-DNA in vitro.
AB  - A Z-DNA binding protein of 140,000 M(r) has been purified from chicken lungs by
      sedimentation through 40%(w/w) sucrose and Z-DNA affinity chromatography.
      Specificity of the protein for Z-DNA was confirmed by competition with polyd(CG)
      that had been stabilized in the Z-DNA conformer by chemical bromination and also
      with a supercoiled plasmid that contains a Z-DNA-forming insert. In addition to a
      Z-DNA binding site, the protein also has a separate binding site for double
      stranded RNA. Peptide sequence of the protein shows that it has high similarity
      to the RNA editing enzyme double-stranded RNA adenosine deaminase (dsRAD), which
      deaminates adenosine in dsRNA to form inosine. The Z-DNA binding protein has this
      enzymatic activity, confirming its identity to dsRAD. Recombinant human dsRAD
      also binds to Z-DNA. Z-DNA is stabilized in a sequence-dependent manner by
      negative supercoiling, which occurs in actively transcribed genes upstream to RNA
      polymerase. It is proposed that Z-DNA links editing to transcription by
      localizing dsRAD to a particular region of a gene and thus determines the
      efficiency with which an RNA is edited. The presence of Z-DNA forming elements in
      many genes raises the possibility that RNA editing by dsRAD is far more prevalent
      than is currently thought.

PMID- 8643358
TI  - Cloning and sequencing of the first plant GlnRS and GluRS genes.
AB  - We have cloned and sequenced glutamate-tRNA synthetase (GluRS) and glutaminyl
      tRNA synthetase (GlnRS) from Arabidopsis thaliana. They have conservative motifs
      found in all known GlxRS genes. For Lupinus luteus we found only one gene of
      GlxRS. At the moment we do not know exactly, whether it corresponds to GlnRS or
      GluRS.

PMID- 8643359
TI  - Interaction of mitochondrial elongation factors Tu.Ts with aminoacyl-tRNA.
AB  - The interaction between the bovine mitochondrial translational elongation factor
      Tu.Ts complex (EF-Tu.Tsmt) and aminoacyl-tRNA has been investigated using a
      nuclease protection assay and fluorescence enhancement of [AEDANS-s2C]Tyr
      tRNA(Tyr). The equilibrium dissociation constant, Kd, for the EF-Tu.Tsmt:GTP:E.
      coli Phe-tRNA complex is approximately 50 nM. A similar binding constant (30 nM)
      is obtained using bovine mitochondrial Phe-tRNA. The equilibrium binding constant
      for the EF-Tu.Tsmt:GTP:yeast [AEDANS-s2C]Tyr-tRNA(Tyr) complex is approximately 4
      nM when determined using the fluorescence enhancement assay.

PMID- 8643360
TI  - tRNA selection by a class II aminoacyl-tRNA synthetase: the role of accessory
      domains and inter-domain communication in RNA recognition.
AB  - We have used a secondary site suppression approach to investigate the basis of
      tRNA selection by the E. coli histidyl-tRNA synthetase. This enzyme recognizes a
      unique G-1:C73 base pair located in the acceptor stems of prokaryotic histidyl
      tRNAs. A genetic selection system was constructed in which growth on glycerol was
      dependent on histidine specific amber suppression of a triose phosphate isomerase
      (tpi) gene containing an amber codon at His 95. Three independent revertants
      linked to hisS were isolated and sequenced, and the resulting mutant proteins
      were characterized biochemically. These studies are interpreted in light of the x
      ray structure of the E. coli HisRS adenylate complex, and show that the C
      terminal domain and its interactions with the catalytic domain play a
      biologically significant role in tRNA selection.

PMID- 8643361
TI  - Investigating the structure and function of translation initiation factor 1 in
      Escherichia coli.

PMID- 8643362
TI  - RNA recognition based on a pair of tertiary hydrogen interaction.
AB  - The recognition of transfer RNAs (tRNAs) by aminoacyl tRNA synthetases is a
      critical step in establishing the fidelity of translation. For E. coli cysteine
      tRNA synthetase, recognition of tRNA(Cys) and discrimination from all other tRNAs
      is based on the U73 discriminator base, the GCA anticodon, and a G15:G48 tertiary
      base pair. While the discriminator base and the anticodon sequence are often used
      by many synthetases as the determinants for tRNA recognition, the dependence on a
      tertiary interaction in the cognate tRNA for recognition is unique to the
      cysteine enzyme. Here the structural basis for recognition at the G15:G48
      tertiary interaction of E. coli tRNA(Cys) is explored by structural modeling,
      chemical modifications, and kinetic analysis. The results established an unusual
      RNA tertiary interaction that provides a plausible mechanism for recognition by
      cysteine tRNA synthetase.

PMID- 8643363
TI  - Molecular recognition of tRNA(Pro) by Escherichia coli proline-tRNA synthetase.
AB  - We have investigated the molecular recognition of tRNA(Pro) by Escherichia coli
      proline tRNA synthetase (ProRS) in vitro using semi-synthetic tRNAs and site
      directed mutagenesis of full-length tRNA transcripts. These studies have led to
      an improved understanding of how this class II synthetase interacts with its tRNA
      substrate. The ability to efficiently aminoacylate a tRNA(Pro) molecule assembled
      by annealing together a shorter, chemically synthesized oligonucleotide and a 3/4
      tRNA prepared enzymatically, has facilitated the identification of RNA structural
      features that are critical for aminoacylation by ProRS. This approach has been
      successful using either a 3'-3/4 tRNA annealed to a 5'-oligonucleotide or a 5'
      3/4 tRNA annealed to a 3'-oligonucleotide. These studies show that ProRS appears
      to be particularly sensitive to mutations that result in structural changes in
      the core region of tRNA(Pro). Moreover, the so-called "variable pocket"
      nucleotides appear to be dispensable for aminoacylation. We have also identified
      a specific 2'-hydroxyl-base interaction between the ribose of U8 and the 2-amino
      group of G46 that makes a thermodynamically significant contribution to tRNA(Pro)
      aminoacylation by E. coli ProRS.

PMID- 8643365
TI  - The phosphofructokinase-uncharged tRNA interaction in metabolic and cell cycle
      control: an interpretive review.
AB  - When the tRNA of mammalian cells is incompletely charged due to amino acid
      deficiency or by analogs which cannot be activated, many metabolic events become
      limited. This rapid demise of cell function appears to be because of the
      inhibition of phosphofructokinase (PFK) by uncharged tRNA (FEBS Lett. 302: 113
      (1992)). Charged tRNA has been shown to be "sequestered within the protein
      synthetic machinery", (Negrutskii, B.S. and Deutscher, M.P., Proc. Natl. Acad.
      Sci. USA 89 3601 (1992) and would therefore be removed from an inhibitory role.
      Besides the direct demonstration that tRNA inhibits PFK in an assay regarded as
      indicative of its control mechanism, several reports in the literature support
      this model. These include 1) The rapid onset of inhibition of glycolysis and
      glucose uptake by intact cells upon amino acid deficiency and the similar lesion
      at the 43S ribosomal subunit on glucose or amino acid deprivation. 2) The
      recognition that unusually high concentrations of cAMP required to stimulate
      protein synthesis in energy depleted or gel filtered lysates correlates with its
      action on PFK as an analog of the positive effector, adenosine-5'-monophosphate.
      3)The often repeated observation that the product of PFK activity, fructose-1,6
      diphosphate, is a stimulant of protein synthesis (see Jackson, R.J., et al. Eur.
      J. Biochem. 131: 289-313 (1983)). This diphosphate has been shown to be the
      proximate effector binding to eIF-2B, the guanine nucleotide exchange factor
      (Singh, L.P. Arror, A.R. and Wahba, A.J., FASEB J. 8 279 (1994)) which by
      releasing GDP bound to the inactive GDP:eIF-2 complex, permits the factor to
      initiate a new peptide chain. The above information supports the view that the
      block at the G1 restriction point in the cell cycle of normal cells brought about
      by amino acid deprivation is a result of inhibition of protein synthesis through
      the phosphofructokinase-uncharged tRNA mechanism. This is consistent with
      observations in the literature that tumor and transformed cells, which are more
      resistant to this block (Pardee, A.B., Proc. Natl. Acad. Sci. U.S.A. 71:1286-1291
      (1974)) have a higher phosphofructokinase activity or higher levels of fructose
      1,6-diphosphate.

PMID- 8643364
TI  - Oligomer biology and polymer biology: primitive RNA-protein interactions.
AB  - It is discussed that oligopeptides extracted from the active centers of aminoacyl
      tRNA-synthetases, peptidyl-transferases, and template-directed RNA polymerases
      can mimic the catalytic activities of each enzyme. Hairpin type primitive tRNAs
      with the anticodon at the 5' end were specifically aminoacylated from the cognate
      aminoacyladenylates in the above scheme. These results suggest that primitive RNA
      protein interactions among oligomers of ribonucleotides and amino acids might
      have played an important role in the self-organization of the biomolecules in the
      early history of life.

PMID- 8643367
TI  - A chimeric tRNA(Lys3)-ribozyme inhibits HIV replication following virion
      assembly.
AB  - Co-localization of ribozymes with their appropriate target is one method utilized
      to increase their effectiveness in vivo. Effective antiviral ribozymes will
      likely rely on mechanisms which direct the ribozyme to the genomic or subgenomic
      RNAs. Exploiting the fact that a specific host cellular tRNA primer is bound by
      viral proteins and co-packaged with viral genomes in newly synthesized virions,
      ribozymes were fused to the 3'-terminus of tRNA(Lys3) in an attempt to direct
      their activity to cleave the HIV-1 genome. This chimeric ribozyme is
      catalytically active in vitro, and is efficiently recognized and bound by HIV-1
      reverse transcriptase with affinities similar to tRNA(Lys3). The intragenic RNA
      polymerase III promoter entity of the tRNA allows for high levels of expression
      of the tRNA-RBZ and the preferential localization of transcript within the
      cytoplasm in transfected cells. This ribozyme was effective in reducing the
      infectivity of a viral stock which was produced from transiently transfected
      cells bearing the chimeric gene. These results demonstrate the feasibility of
      using tRNAs as a means of co-localizing ribozymes with their viral genomic RNA
      targets. The possibility exists to fuse stable RNAs to ribozymes as a means of
      increasing their stability and localizing them to their appropriate target sites.

PMID- 8643366
TI  - Peptidyl-tRNAs promote translational frameshifting.
AB  - Programmed translational frameshifting is a ubiquitous, though rare, mechanism of
      gene expression in prokaryotes and eukaryotes. Research on many such sites has
      led to a general understanding that frameshifting depends on slippage of one or
      two ribosome-bound tRNAs on the mRNA. We recently found an example of an
      efficient frameshift in the Ty3 retrotransposon of the yeast Saccharomyces
      cerevisiae which occurs without tRNA slippage. Frameshifting appears to occur by
      misplacement of aminoacyl-tRNA in the ribosomal A site. Most of the eight tRNAs
      which induce measurable amounts of +1 frameshifting are predicted to slip only
      very poorly. In fact, frameshifting by tRNA slippage appears an unusual event in
      yeast, and where it occurs depends on peptidyl-tRNAs which employ two-out-of
      three decoding. In addition, frameshifting either by slippage or by aminoacyl
      tRNA misplacement depends on adequate availability of the first +1 frame tRNA. We
      present two models to explain how the tRNA which reads the shifted frame codon
      could promote +1 translational frameshifting.

PMID- 8643368
TI  - Conformational properties of oligonucleotides.
AB  - Vast libraries of oligonucleotide sequences can be made. Such libraries have been
      screened and/or selected to identify individual molecules showing various
      properties, including high affinity/high specificity binding (to something) or
      new enzymatic activity. The SELEX protocol is used to identify these interesting
      oligonucleotides; two recent reviews of the SELEX protocol and its power have
      appeared recently. Oligonucleotides derived through the SELEX process have
      applications in diagnostics and therapeutics, and have additional value as
      research reagents and compounds that provide chemical plausibility to some ideas
      about evolution of the biosphere. Oligonucleotide conformations are shockingly
      robust and potent.

PMID- 8643369
TI  - A conformational switch in a regulated mRNA involves tertiary structure.
AB  - The E. coli alpha operon mRNA is autogenously regulated by binding the repressor
      ribosomal protein S4. Repression occurs via a novel mechanism in which S4 traps
      the mRNA in a conformation that prevents formation of the complete initiation
      complex. The conformations have similar stabilities but separated by a high
      activation energy which is a criterion for a conformational switch. The
      conformation switch is likely to involve alteration in tertiary structure as
      indicated by gel electrophoresis and thermal denaturation experiments. It was
      found that Mg2+ stabilizes the repressed form and tertiary structure, and H+
      stabilizes the translated form and have complicated effects on tertiary
      structure.

PMID- 8643370
TI  - 15N NMR and CD studies of the IRE (iron regulatory element in ferritin mRNA with
      single base substitution in the hairpin loop.
AB  - Noncoding sequences regulate mRNA and DNA function. IREs are a highly conserved
      family of noncoding mRNA sequences which coordinate ferritin mRNA translation and
      transferrin receptor mRNA stability by interactions with specific negative
      regulator protein, the IRP. RNA interactions with the IRP are modulated by
      cellular iron. The protein IRP binds to the entire IRE causing conformational
      changes in flanking region [Harrell et al. (1991) PNAS 88:4166-4170). The IRE+FL
      is the first RNA element encoding both positive and negative translational
      control and serves as a model mRNA regulatory elements. Folding of the IREs
      indicated previously by reactivity with chemical and enzymatic probes [E.C Theil
      (1994) Biochem. J., 304:1-11) is confirmed by using 1H, 15N and 31P (1) NMR) and
      CD to show that IRE secondary structure [hairpin-hexaloop (HL)/stem/internal loop
      or bulges] is folded, CD spectra display Mg2+ dependent structural changes in the
      temperature range used in the studies of IRE function. G/A substitution was shown
      by NMR and UV-vis to decrease stability of the folded IRE [H.Sierzputowska-Gracz
      et al. (1995) Nucl. Acids Res. 23:146-153]. A hairpin loop mutation affected only
      negative translational control.

PMID- 8643371
TI  - Factors in a chloroplast extract specifically bind to the 5' untranslated regions
      of chloroplast mRNAs.
AB  - The spinach chloroplast large ATP synthase cluster encodes five genes, the last
      four of which encode chloroplast ATP synthase subunits. Because the stoichiometry
      of the ATP synthase polypeptide products differs substantially from that of the
      primary transcripts, we have chosen this system as a model to study
      posttranscriptional mechanisms that regulate chloroplast gene expression. Here we
      present data on a chloroplast extract containing factors that bind to the 5'
      untranslated regions of chloroplast ATP synthase transcripts. The binding is
      transcript-specific. This binding may influence translational efficiency of
      chloroplast transcripts.

PMID- 8643372
TI  - Hel-N1, an RNA-binding protein, is a ligand for an A + U rich region of the GLUT1
      3' UTR.
AB  - Hel-N1, is an RRM protein which is a mammalian homologue of the Drosophila
      melanogaster RNA binding protein, ELAV (embryonic lethal abnormal vision). Hel-N1
      binds to RNA containing short stretches of uridylates similar to those found in
      the 3' untranslated regions (3'-UTRs) of oncoprotein and cytokine mRNAs. The
      GLUT1 glucose transporter has an extensive 3' UTR that is AU-rich reminiscent of
      the 3'UTR of an oncogene mRNA. An in vitro RNA binding assay using Hel-N1
      demonstrated binding to a specific portion of the GLUT1 3'UTR. Analysis of the
      folding pattern of this region depicted the retention of a stem loop structure,
      wherein the loop is composed of a stretch of uridylates. To further analyze the
      potential function of Hel-N1, stable transfectants were made in the 3T3-L1 cell
      line. The transfectants have been characterized, and the presence of the Hel-N1
      DNA and protein verified. Data indicate Hel-N1 is a ligand for GLUT1 and its
      binding affects the stability and translatability of the GLUT1 message.

PMID- 8643373
TI  - Post-transcriptional regulation of collagen alpha 1(I) mRNA in hepatic stellate
      cells.
AB  - Posttranscriptional events may play an important role in regulating collagen
      alpha 1(I) mRNA in hepatic stellate cells. Quiescent stellate cells contain a
      very low level of this mRNA, but treatment of the cells with Actinomycin D or
      cycloheximide increases the mRNA accumulation 5 fold in 3 hours. The same
      treatment has no effect on activated stellate cells, which produce a large amount
      of the collagen alpha 1(I) mRNA. This suggests that there is a labile degrading
      activity which normally prevents accumulation of the mRNA in quiescent cells.
      Half life of the mRNA in activated cells is about 48 hours. We detected a
      sequence specific RNA binding activity present in these cells which binds to the
      C-rich sequence in the 3' UTR of collagen mRNA. Such binding can not be detected
      in quiescent cells and may be responsible for the stabilization of the mRNA in
      activated stellate cells. Thus, collagen alpha 1(I) mRNA levels in stellate cells
      may be modulated by negative regulation in quiescent cells and by positive
      regulation in activated cells.

PMID- 8643374
TI  - Regulated splicing of gamma2 pre-messenger RNA in neuronal cells.
AB  - The pre-mRNA encoding the gamma 2 subunit of the gamma-aminobutyric acid Type A
      receptor is spliced in a tissue-specific manner in mammalian brain resulting in
      mRNAs containing or lacking a 24 nucleotide exon, gamma 2L and gamma 2S,
      respectively. The gamma 2S mRNA predominates in pituitary, whereas the gamma 2L
      predominates in brainstem, spinal cord and cerebellum. In this study, a cell line
      derived from rat cerebellum that qualitatively reproduces regulated splicing of
      gamma 2 pre-mRNA was identified and used to dissect cis-regulatory elements.
      Sequence elements that alter the selection of the 24 nucleotide exon fall into
      two functional classes-activating elements and inhibitory elements. We identified
      several inhibitory elements that inhibit splicing of the 24 nucleotide exon in
      all cell types as well as specific inhibitory elements which repress splicing in
      non-neuronal cells. Activating elements are localized within conserved intron
      regions, as judged by a comparison of rat and human gene sequences, and appear to
      function generally in activating splicing of the 24 nucleotide exon in the cell
      types tested so far. These results are compatible with a hypothesis in which the
      mechanism of regulation involves a release from inhibition. Current experiments
      are aimed toward the development of tools to identify the trans-regulatory
      components.

PMID- 8643375
TI  - Reconstitution of exon-bridging activity with purified U2AF and U1 snRNP
      components.
AB  - For pre-mRNAs containing multiple introns, the exon definition hypothesis has
      been proposed to account for the interactions that specify relatively short exons
      and prevent inappropriate exon-skipping [1]. Support for this hypothesis includes
      the finding that naturally occurring, or engineered mutations in 5' splice sites
      that weaken base complementary to U1 snRNA result in exon skipping due to a
      decrease in upstream 3' splice site activity. The reciprocal effect is also
      observed. For example, we found previously that the selection of the
      alternatively spliced rat preprotachykinin exon 4 is improved under conditions in
      which the adjacent 5' splice site is converted to a site with strengthened base
      pairing to U1 snRNA [2]. In the latter study, 3' splice site activity is improved
      in parallel with strengthened U1 snRNP binding to the downstream 5' splice site.
      Subsequent RNA-protein crosslinking experiments have provided evidence for exon
      bridging interactions between U2AF bound to the 3' splice site and U1 snRNP bound
      to the downstream 5' splice site in the preprotachykinin substrates [3]; see
      Figure 1. U2AF, a polypyrimidine tract binding protein composed of 65 and 35 kD
      subunits, is required for U2 snRNP binding to the adjacent branch site [4], [5].
      In this work we have reconstituted exon bridging activity with purified
      components. These results show that U1 snRNP in addition to U2AF are the two
      components required to reconstitute full activity in vitro. The purified system
      has been used to test variants of U2AF and U1 snRNP. Our results show that the U1
      A and U1-C proteins are dispensable for exon bridging activity. In addition, the
      35 kD subunit of U2AF appears to be dispensable, at least under certain
      conditions.

PMID- 8643376
TI  - Splicing of two weak 3' splice sites from the adenovirus major late region is
      enhanced in nuclear extracts from adenovirus infected cells.
AB  - The adenovirus major late transcription unit (MLTU) is an example of a complex
      alternatively spliced gene, in which more than 15 different 3' splice sites can
      be joined to a common 5' splice site. Maturation of the full repertoire of
      possible mRNAs requires late viral protein synthesis and occurs only at late
      stages of the infectious cycle (16-24 hpi). We are trying to decipher the
      mechanisms regulating alternative 3' splice site choice during the infectious
      cycle. Therefore, we examined the splicing activity of several 3' splice sites
      from the MLTU in vitro in nuclear extracts prepared from adenovirus infected
      cells (Ad NE) and from uninfected cells. The results suggest that pre-mRNAs with
      "weak" 3' splice sites (short, atypical polypyrimidine tracts) are activated and
      pre-mRNAs with long, prototypical polypyrimidine tracts are repressed in Ad NE.
      In fact, our data show a reciprocal correlation between the strength of a
      polypyrimidine tract, defined by its affinity for U2AF65K in vitro, and the
      efficiency of splicing in Ad NE. We are currently investigating the possible
      mechanisms responsible for this observed shift in 3' splice site choice during an
      adenovirus infection.

PMID- 8643377
TI  - The branch site adenosine is recognized differently for the two steps of pre-mRNA
      splicing.
AB  - The functional groups responsible for branch site identity in the two steps of
      pre-mRNA splicing as well as for spliceosome assembly were tested by
      incorporation of site-specific modifications at the branch site of a pre-mRNA.
      These results show that recognition of the adenosine occurs early in complex
      formation and that the branch site adenosine is recognized differently before the
      first step and for the second step. Further, direct UV cross-linking with these
      modified RNAs was used to identify a factor whose interaction was dependent upon
      the identity of the branch site nucleotide.

PMID- 8643378
TI  - The evolutionary conservation of the splicing apparatus between fission yeast and
      man.
AB  - The removal of intervening sequences from pre-mRNA is an important step in gene
      regulation. Pre-mRNA processing takes place within the spliceosome, a dynamic
      structure composed of small nuclear RNA (snRNA) and proteins. The function of the
      spliceosome is currently being studied in many eukaryotic systems including
      mammal and yeast. Here we review pre-mRNA splicing in fission yeast and man and
      propose that spliceosomal structure and function has been evolutionarily
      conserved between the two organisms.

PMID- 8643379
TI  - The binding of a subunit of the general polyadenylation factor cleavage
      polyadenylation specificity factor (CPSF) to polyadenylation sites changes during
      B cell development.
AB  - During the development of mouse B cells there is a regulated shift from the
      production of membrane (mb) to secretory-specific (sec) forms of immunoglobulin
      (Ig) mRNA. The mRNAs are produced from one gene that is alternatively processed
      at the 3' end. We have previously shown that there is an increase in
      polyadenylation efficiency accompanying the developmentally regulated shift to
      secretory-specific forms of Ig mRNA by DNA transfection experiments (1). When we
      look in vitro at nuclear extracts prepared from early/memory versus late
      stage/plasma B cells, we see cell stage-specific differences in the proteins
      which are crosslinked to poly(A) site-containing RNAs. Here we show that one of
      these proteins is the mouse homologue of 100 kDa subunit of Hela CPSF by
      immunoprecipitation and Western analysis of UV crosslinked material. The amount
      of 100 kDa protein and its mobility on two-dimensional gels do not change between
      the B cell stages. However, the binding of the 100 kDa polypeptide to poly(A)
      sites increases in the late stage/plasma cell lines relative to the binding seen
      in early/memory cell lines. The increased binding may reflect an increase in
      polyadenylation efficiency at the sec poly(A) site in plasma cells versus
      early/memory cells seen in vivo.

PMID- 8643380
TI  - Selection of high affinity RNA ligands to a synthetic peptide of human rhinovirus
      14 coat protein.
AB  - We have used the in vitro evolution system (SELEX) to isolate high affinity RNAs
      which block the canyon region of Human Rhinovirus 14 (HRV 14). Since the genetic
      diversity of HRV has hampered the development of general anti-rhinovirus
      vaccines, high affinity RNAs may have good advantage for therapeutic application
      for the human cold.

PMID- 8643381
TI  - The polyribosomal protein bound to the 3' end of histone mRNA can function in
      histone pre-mRNA processing.
AB  - Histone mRNAs end in a conserved 26 nt sequence which can form a stem-loop with a
      six-base stem and a four base loop. The 3' end of histone mRNA functions in the
      nucleus in pre-mRNA processing and mRNA transport and in the cytoplasm in
      translation and regulation of histone mRNA stability. The stem-loop binding
      protein (SLBP), found in both the polyribosomes and the nucleus, binds to the 3'
      end of histone mRNA. A nuclear extract which efficiently processes histone pre
      mRNA has been prepared from mouse myeloma cells. The factors which bind the 3'
      end of histone mRNA can be depleted from this extract using a biotinylated
      oligonucleotide. Using the depleted extract, we show that the SLBP found in the
      polyribosomes can function in histone pre-mRNA processing, suggesting that the
      SLBP associates with histone pre-mRNA in the nucleus and accompanies the mature
      mRNA to the cytoplasm.

PMID- 8643382
TI  - The 41 kDa protein component of the spinach chloroplast petD mRNA 3' stem
      loop:protein complex is a nuclear encoded chloroplast RNA-binding protein.
AB  - Spinach chloroplast petD gene encodes subunit IV of the cytochrome b6/f complex.
      Like many chloroplast mRNAs, the spinach petD mRNA contains a 3'UTR stem-loop
      structure that determines correct 3' processing of the pre-mRNA and stability of
      the mature mRNA. RNA-protein interactions with this structure may be involved in
      the regulation of petD mRNA processing and/or stability. In this report, a
      spinach chloroplast 41 kD protein has been identified as a component of the petD
      mRNA 3'stem-loop:protein complex. The 41 kD protein has been purified and four
      internal peptide sequences were obtained. Based on the peptide sequences, a 585
      bp fragment was amplified from a spinach cDNA library by PCR. And, a 1404 bp cDNA
      clone was then isolated by using the initial PCR fragment as probe. Nucleic acid
      sequence analysis of the cDNA clone identified an ORF encoding a predicted 36 kD
      mature protein. An apparent N-terminal transit peptide in the coding region and a
      3' poly(A) tail exist in the cDNA clone indicated that this chloroplast protein
      as nuclear encoded. The mature protein was expressed in E. coli, and the
      expressed product with a molecular mass of 41 kD was purified. A gel mobility
      shift assay demonstrated that the expressed 41 kD protein interacts with the petD
      mRNA 3' UTR to form an RNA-protein complex.

PMID- 8643383
TI  - The isolation of U1 RNA-binding antibody fragments from autoimmune human-derived
      bacteriophage display libraries.
AB  - Almost seventy percent of systemic lupus erythematosus (SLE) patients produce
      autoantibodies specific for U1 RNA, the RNA component of the U1snRNP complex
      involved in pre-mRNA splicing. Human anti-U1 RNA antibodies from SLE patients
      provide an ideal model for studying protein-RNA interactions. In addition, a more
      in depth look at the mechanism by which an antibody interacts with U1 RNA will
      lend insight into immune disregulation and may have therapeutic potential in the
      treatment of autoimmune disease. The possibility of cloning an anti-U1 RNA
      antibody has been investigated using "phage Fab display," a method involving the
      display of Fab fragments on the outer surface of filamentous phage. Human Fab
      cDNA libraries were constructed using total RNA collected from leukophoresed anti
      U1 RNA antibody-positive SLE patient sera. The resulting Fab genes were subcloned
      into a phagemid expression vector which produced phage displaying Fab fragments
      in E.coli1. Libraries were enriched for U1 RNA-binding clones after several
      rounds of affinity selection against purified, in vitro transcribed U1 RNA.
      Putative U1 RNA-binding clones were identified by colony lift and the
      corresponding Fab genes were expressed and purified from E.coli for binding
      studies. Results demonstrate that RNA-binding Fab can be isolated from
      combinatorial phage display libraries.

PMID- 8643384
TI  - The RRM domain is dispensable for yeast U1-70K function.
AB  - The Saccharomyces cerevisiae SNP1 gene encodes the U1 snRNP specific protein U1
      70K. The RRM and glycine rich domains are well conserved from yeast to metazoan
      U1-70K proteins, with over 80% amino acid similarity. We have demonstrated that
      yeast strains in which the SNP1 gene was disrupted were viable, but exhibited
      greatly increased doubling rates and severe temperature sensitivities. In
      addition snp1-null strains were defective in nuclear, pre-mRNA splicing. We have
      tested deletion alleles of SNP1 for their ability to complement these phenotypes.
      We found that the highly conserved RRM and glycine rich domains of Snp1 were not
      required for complementation of the snp1-null growth or splicing defects.
      However, the amino terminal domain of Snp1, which is not highly conserved, was
      necessary and sufficient for complementation.

PMID- 8643385
TI  - Factors affecting activation of the 'cloaked' Zea maize ribosome inactivating
      protein (RIP) zymogen. 1. 'LID' peptide hydrophobicities and oxidative structural
      changes.
AB  - We want to understand how environmental factors influence zymogen activation of
      the "cloaked' active site of the 'Ribosome Inactivating Protein' (RIP) from corn
      kernels. In this study, we focus on how likely chemical effectors in the
      immediate environment of the 'lid' conspire to unleash the active site upon
      encountering target membranes of invading pests. Octanol-H2O partitioning free
      energies of peptides which (i) straddle the proteolysis site, and (ii) form the
      'side' and 'bottom' of the proposed 'lid' were found to only slightly favor H2O,
      suggesting that the peptide is poised to detach from the less polar surface
      surrounding the RIP active site. Circular dichroism results obtained upon
      catalase/H2O2 oxidation of the 'lid' peptide suggest that the structure shifts
      from primarily alpha-helical to primarily beta-like. These results suggest that
      the active site is more easily 'uncloaked' as a result of the lowered solvent
      polarity conditions and higher oxidant concentrations in the presence of pest
      membranes encountered during crucial stages of seed germination.

PMID- 8643386
TI  - The central region of the yeast U4 snRNA is not important for hammerhead
      catalysis, but may act as a domain spacer.
AB  - Several distinct domains of U4 small nuclear (sn)RNA interact with other
      components of the spliceosome and are essential for pre-mRNA splicing. We have
      previously shown that single point mutations (Hu et al., 1995) in the central
      domain of the yeast U4 snRNA do not effect cell growth. In contrast to our
      results, this region has been reported to possess metal-binding or catalytic
      activity in vitro (Yang et al., 1994). In order to test if large mutations in the
      central domain effect cell growth and/or in vivo splicing, we have carried out
      further mutational analyses of this domain. A deletion of nucleotides from 62 to
      88, including all those corresponding to the invariable positions of the
      hypothetical hammerhead, does not affect cell growth at/or above 25 degrees C. In
      addition, the central region (nucleotides 69-88) can be replaced by two copies of
      a 38-nt spacer inserted in the same orientation without any effect on cell growth
      or nuclear RNA splicing. These results suggest that the central domain of U4
      snRNA functions primarily to separate the 5'- and 3'- domains of the snRNA by an
      optimal distance.

PMID- 8643387
TI  - Importance of modified nucleosides to the structure and function of tRNAs.
AB  - Although a few modifications are found in DNA, 93 modified nucleosides have been
      found in the various RNAs. For the most part, the chemistry and structure that
      modified nucleosides, individually and in combination, uniquely contribute to DNA
      or RNA function have yet to be explained. However, there are ten physicochemical
      contributions that can be attributed to modified nucleosides. Of particular
      interest is the increasingly documented relationship between the presence of
      modified nucleosides in tRNAs, and the site and affinity of Mg2+ binding to RNA
      and its effect on function.

PMID- 8643388
TI  - RNA-protein interactions of the bacteriophage RB69 RegA translational repressor
      protein.
AB  - We report the RNA-protein interactions of phage RB69 RegA and RegA691 proteins.
      In RNase protection assays, RB69 RegA protects from 10 (44 mRNA) to >70 (rpbA)
      nucleotides; for rpbA in particular, the length of the protected region is RegA
      concentration dependent. Quantitative fluorescence quenching measurements with
      RB69 wildtype RegA and RegA691 show that both proteins bind poly(U) similarly,
      but RegA691 binds with lower affinity to both 44 and rpbA RNA. The results
      indicate that both RB69 RegA RNA-protein and protein-protein interactions
      contribute to a translational repression hierarchy.

PMID- 8643389
TI  - A candidate gene for RNA export carrier protein has two RBDs (RNA binding domain
      and Ran binding domain).
AB  - The human Ras-related nuclear protein Ran/TC4 is the member of a well conserved
      family of GTPases that can regulate cell-cycle progression, nuclear structure,
      protein import, and RNA export through nuclear pore complex (NPC). Translocation
      of RNA through the NPC also needs a RNA-binding protein as a possible mediator of
      export. By a low-stringency hybridization with a PCR fragment encoding RNA
      binding domain as a probe, we obtained a partial human cDNA from skeletal muscle
      cDNA library. The deduced amino acid sequence indicated that the gene possessed
      both RNA-binding domain and Ran-binding domain, therefore it is a candidate gene
      for RNA export carrier protein. RNA blot analysis showed that this gene appeared
      approximately 8-10 kilo base in length and that the gene expression level in
      several human tissues is ubiquitous. The function of the gene will be discussed.

PMID- 8643390
TI  - In vivo selection of RNA sequences involved in nucleocytoplasmic RNA trafficking.
AB  - We used Xenopus oocytes and microinjection techniques to select for RNAs
      containing nuclear localization signals. A 20 nucleotide long randomized sequence
      was inserted into a U1-like carrier RNA giving a pool of over 10(12) possible RNA
      sequences. RNAs that were found in the nucleus 20 hours after nuclear or
      cytoplasmic injection were amplified and used for the next round of selection and
      amplification. After 12 rounds, the pools were highly enriched for RNAs that
      remained in, or were transported into, the nucleus. When individual RNAs of these
      pools were cloned and sequenced two different types of nuclear localization
      signals were identified. Some RNAs contain a binding site (whose consensus is
      AAUUUUUGG) for the Sm proteins common to spliceosomal snRNPs; the 5' caps of
      these RNAs are hypermethylated during nuclear localization and the RNAs follow
      the transport pathway of snRNAs. Other molecules could be folded to make long
      duplexes at their 5' ends; nuclear localization of these RNAs is independent of
      the 5' caps, and transport from the cytoplasm resembles the pathway for protein
      import.

PMID- 8643391
TI  - Formation and metabolism of histone mRNAs with mutant 3' ends formed by snRNA
      termination signals.
AB  - Histone mRNAs are the only non-polyadenylated mRNAs, ending in a conserved 26 nt
      sequence which can form a stem-loop. It has not been possible to make histone
      mRNAs with mutant stem-loops since most mutations in the stem-loop interfere with
      the 3' processing reaction. The snRNA genes transcribed by RNA polymerase II form
      their 3' ends by transcription termination directed by a signal which is located
      entirely 3' of the snRNA coding sequence. Chimeric genes which express RNAs
      ending in a histone 3' end or in mutant histone 3' ends formed by snRNA
      termination signals were constructed. The mRNAs from these genes were efficiently
      transported from the nucleus after injection of the genes into frog oocytes. This
      was true even for RNAs which end in mutant stem-loops suggesting that the snRNA
      termination signals promote transport of the transcripts.

PMID- 8643392
TI  - Substrate selection by aminoacyl-tRNA synthetases.
AB  - The integration of genetic and biochemical approaches to study the crystal
      structure of the glutaminyl-tRNA synthetase (GlnRS):tRNA(Gln):ATP complex has
      elucidated the mechanism by which GlnRS selects its cognate tRNA for
      aminoacylation. Three principal types of interaction have been identified:
      interaction with specific bases in the cognate tRNA, rejection of non-cognate
      tRNAs, and activation of the active site upon cognate tRNA binding. The recent
      solving of the crystal structure of tryptophanyl-tRNA synthetase (TrpRS) has
      allowed comparable studies to be initiated in an aminoacyl-tRNA synthetase which,
      unlike GlnRS, does not require tRNA binding prior to amino acid activation.

PMID- 8643393
TI  - Interaction of the 11-subunit trp RNA-binding attenuation protein (TRAP) with its
      RNA target.
AB  - The trp RNA-binding attenuation protein (TRAP) regulates expression of the B.
      subtilis trp operon by binding to an RNA target composed of 11 G/UAG repeats in
      the trp leader transcript. TRAP contains 11 identical subunits arranged in a
      ring. The binding of 11 molecules of L-tryptophan to sites formed between
      adjacent subunits activates TRAP to bind trp leader RNA. We propose that the trp
      leader RNA forms a matching circle on the surface of TRAP when it binds. RNA
      binding is relatively insensitive to changes in ionic strength and pH, and is
      apparently driven by changes in entropy. Two lysine residues on the surface of
      TRAP have been shown to be important for RNA binding.

PMID- 8643394
TI  - Interaction of HIV Rev peptides with the Rev response element RNA.
AB  - As a model system for understanding RNA-protein interactions, we are studying the
      structure of peptides derived from HIV Rev in complex with an RNA derived from
      the Rev Response Element (RRE) using NMR spectroscopy. Formation of the Rev
      peptide-RRE complex is accompanied by formation of two purine-purine base pairs
      in the RRE. These base pairs create an unusual geometry that widens the major
      groove of the RRE RNA. The Rev peptide is predominantly in an alpha-helical
      conformation in the complex. The specific recognition of the RRE by Rev involves
      widening of the major groove to accommodate the Rev alpha-helix.

PMID- 8643396
TI  - Protein recognition of a ribosomal RNA tertiary structure.
AB  - Ribosomal protein L11 recognizes a highly conserved, 58 nucleotide domain of
      large subunit ribosomal RNA. This domain has a set of tertiary interactions that
      are specifically stabilized by Mg2+ and NH4+ ions. The protein recognizes this
      tertiary structure, in the sense that ions stabilizing the tertiary structure
      also promote L11 binding, and a heat stable form of the protein (from Bacillus
      stearothermophilus) prevents RNA unfolding. We also find that these RNA-binding
      properties are confined to a approximately 75 amino acid domain of the protein.
      The larger issue of L11 function within the ribosome is discussed in light of
      these findings.

PMID- 8643395
TI  - Generation of nuclease resistant circular RNA decoys for HIV-Tat and HIV-Rev by
      autocatalytic splicing.
AB  - Circular exon sequences can be generated by splicing permuted intron-exon (PIE)
      sequences. The Anabaena pre-tRNA group I self-splicing PIE sequence was modified
      to generate circular forms of the HIV-TAR and the high affinity region of the HIV
      RRE (RBE). RNA products containing TAR and the RBE were purified from splicing
      reactions and demonstrated to be circular. The circular form of these sequences
      was shown to be resistant to nuclease degradation in cellular extracts. Gel shift
      assays demonstrate that the circular form of the RBE is specifically bound by a
      Rev derived peptide. These data suggest that PIE-circularization of RNA may be an
      effective way to express small stable RNAs designed for therapeutics (eg.
      decoys).

PMID- 8643397
TI  - Purification and properties of the first specific 5S rRNA binding protein from
      plants which shows transcription factor IIIA activity.
AB  - Eukaryotic transcription factor IIIA (TF IIIA) is know to activate specifically
      transcription of 5S rRNA gene. It also interacts with mature 5S rRNA. The best
      known TF IIIA has been purified from Xenopus laevis. Up to know this protein has
      not been isolated from plants. In this paper we show for the first time
      purification and properties of TF IIIA like protein from tulip (Tulipa
      whittalli). It shows 5S rRNA and 5S rRNA gene binding activity.

PMID- 8643398
TI  - Studies on interaction of different zinc-finger domains of Xenopus laevis TFIIIA
      with eukaryotic 5S rRNAs.
AB  - We studied interactions between various domains of transcriptional factor IIIA
      (TFIIIA) from Xenopus laevis containing variable number of zinc finger with 5S
      ribosomal RNA (5S rRNA) from plants. The results clearly show that the complexes
      of peptide-RNA are formed in addition they strongly support that the tertiary
      structure of 5S rRNA is well conserved among eukaryotes. We optimalized
      conditions of complex formation reaction in order to study topography of these
      complexes.

PMID- 8643399
TI  - Photolabile oligoDNA probes of internal Escherichia coli ribosomal structure.
AB  - We are examining the spatial arrangement of ribosomal components in the vicinity
      of rRNA sequences of particular significance for ribosome structure and function
      through the use of radioactive, photolabile derivatives of oligoDNAs
      complementary to such sequences. The oligoDNA probes bind to their target
      sequences in intact ribosomal subunits, and, on photolysis, incorporate into
      neighboring ribosomal components. Labeled ribosomal proteins are subsequently
      identified by SDS-PAGE, RP-HPLC and immunoprecipitation. Labeled rRNA is
      identified at the nucleotide level by RNase H cleavage and primer extension. The
      results obtained provide a description of the neighborhood surrounding a
      particular rRNA sequence and impose important constraints on the evolving three
      dimensional models of both the 30S and 50S subunits, since they typically oblige
      several ribosomal components to fall within defined distances of the targeted
      rRNA. Our results will be discussed in terms of these models, emphasizing their
      consistency or inconsistency.

PMID- 8643400
TI  - Involvement of multiple basic amino acids in yeast ribosomal protein L1 in 5S
      rRNA recognition.
AB  - The role of basic amino acid residues located at the C-terminal region of the
      yeast ribosomal protein L1 in 5S rRNA binding was characterized in vitro and in
      vivo. Mutant proteins containing single or multiple amino acid substitutions were
      generated by site-directed mutagenesis of the L1 gene carried on a plasmid. In
      vitro RNP formation was examined by production of the mutant protein in the
      presence of the RNA molecule. The thermostability of the resultant RNP was also
      studied. Effects of these mutations on cell viability and ribosome assembly were
      characterized by transformation of a conditional null L1 yeast mutant with the
      mutated L1 gene expressed from the plasmid. Substitution of any one of the lysine
      or arginine residue did not affect significantly RNA binding in vitro or cell
      growth in vivo. However, several mutant proteins with substitutions of two of
      these basic amino acids bound RNA weakly and the RNPs were less stable. Cells
      expressing these mutant proteins were lethal. Theoretical structural prediction
      of these amino acids further provided information regarding their collective
      contributions to RNA recognition and to interaction between the RNP and other
      components of the 60S ribosomal subunit.

PMID- 8643401
TI  - Probing Drosophila 5S RNA loop C using an in vitro processing model.

PMID- 8643402
TI  - Three dimensional model for the 16S ribosomal RNA in the Escherichia coli
      ribosome.
AB  - Molecular modeling has been performed to help correct and refine an approximate
      three dimensional structure for Eschericia coli 16S rRNA that originated as hand
      built wire model. The wire model was built to accommodate the base pairs in 16S
      rRNA (1), mRNA.16S rRNA interactions (2,3), rRNA.ribosomal protein interactions
      (see 4), ribosomal protein-ribosomal protein distances (5), intramolecular RNA
      RNA UV-crosslinks (6,7) and site-directed mutagenesis experiments (8). In the
      computer model, individual base-paired regions were constructed separately and
      then were installed into the expected locations to produce the entire structure.
      We describe here the considerations, steps and results of this refinement
      process.

PMID- 8643403
TI  - Mutations at three sites in the Escherichia coli 23S ribosomal RNA binding region
      for protein L11 cause UGA-specific suppression and conditional lethality.
AB  - A single nucleotide change, G to A, at nucleotide position 1093 of E. coli 23S
      ribosomal RNA was found to cause UGA-specific suppression (D.K. Jemiolo, F.T.
      Pagel and E.J. Murgola, Proc. Natl. Acad. Sci. USA, in press). To obtain new
      kinds of UGA-specific suppressors in 23S rRNA, we used segment-directed mutagenic
      PCR, and targeted first the 1405 nucleotide SnaBI/I-CeuI segment, which includes
      position 1093, of the rrnB operon cloned into a multicopy plasmid. The
      mutagenized fragments were subcloned into the plasmid vector and used to
      transform to ampicillin resistance (Ampr) a recipient strain containing a UGA
      mutation in trpA. The Ampr transformants were then screened for suppression of
      UGA. After purification, Trp+ transformants were tested for association of the
      suppressor phenotype first with the plasmid and then specifically with the
      SnaBI/I-CeuI fragment. In one screening, four different kinds of mutational
      change were found, all at three sites within a highly conserved hexanucleotide
      loop in domain II of 23S rRNA. This region is part of the site for binding of the
      large subunit protein L11, which has been shown to be involved in peptide chain
      termination in a specific way. All of the mutants (G1093A, G1093 delta, A1095
      delta, and U1097 delta) suppress UGA mutations, but not UAA or UAG mutations, and
      all four types exhibit high-temperature conditional lethality when highly
      expressed. Several mechanisms can be suggested for the UGA-specific suppression
      exhibited by these mutants, including altered interaction with protein L11,
      Second-site mutations that overcome the conditional lethality of G1093A indicate
      that intramolecular interactions within 23S rRNA may play a role in peptide chain
      termination at the UGA stop codon.

PMID- 8643404
TI  - The role of nucleotide modifications in the yeast mitochondrial ribosome.
AB  - Post-transcriptionally modified nucleotides in ribosomal RNA, and the modifying
      enzymes themselves, could influence the assembly, structure, and function of the
      ribosome. The PET56 gene in yeast encodes the enzyme responsible for formation of
      2'-O-methylguanosine at a specific nucleotide in the peptidyl transferase center
      of the mitochondrial large subunit ribosomal RNA. While PET56 is normally
      essential for the formation of functional mitochondrial ribosomes, extragenic
      mutations have been obtained that suppress, albeit weakly, pet56 loss-of-function
      mutations. Thus neither the Pet56p-catalyzed ribose methylation nor the Pet56
      protein itself is absolutely required for the synthesis of a functional ribosome.

PMID- 8643405
TI  - Three dimensional model for the 16S ribosomal RNA that incorporates information
      for the mRNA track.
AB  - A three dimensional model for the 16S rRNA in the ribosome is described that
      accommodates information for mRNA.16S rRNA interactions as well as accommodating
      information that has been used as constraints for determining the internal 16S
      rRNA structure. mRNA.16S rRNA interactions have been summarized from experiments
      that employ photoaffinity crosslinking to identify sites at which the mRNA comes
      into close contact with the 16S rRNA. The mRNA track that has been constructed
      follows a path completely around the middle of the 30S subunit, occupying a space
      above 16S rRNA domains I and II and below 16S rRNA domain III. The mRNA track
      contains regions associated with contacts with the 16S rRNA in, and just upstream
      of, the P tRNA site, associated with contacts around the A site and associated
      with neighborhoods upstream of the Shine-Dalgarno region and downstream of the
      decoding region. Structural constraints that come from UV-induced RNA-RNA
      crosslinks, suggest that the mRNA decoding region lies in a groove between three
      16S rRNA duplex regions facing the 50S subunit.

PMID- 8643406
TI  - Comparison of features of the RNase activity of 5'-exonuclease-1 and 5'
      exonuclease-2 of Saccharomyces cerevisiae.
AB  - Features of the catalytic specificities of 5'-exonuclease-1 (Xrn1) and 5'
      exonuclease-2 of Saccharomyces cerevisiae have been compared. For analysis of in
      vitro properties, 5'-exonuclease-2 has been highly purified, and data show that
      it is present in yeast cells at about 5-10% of the level of Xrn1. The basic
      features of the exonuclease activity of the two enzymes, i.e., their activities
      with RNA and ssDNA and their mode of action, are similar. We have initiated an
      analysis of structural elements (artificial and natural) that stall the
      exonucleolytic hydrolysis by the enzymes. A (G)18 artificial sequence in MFA2
      mRNA stalls the hydrolysis by both enzymes, yielding a 3' stall fragment. The
      specific structural element(s) involved is being investigated. To access a
      similar in vivo specificity of the two enzymes, the effect of overexpression of
      the essential HKE1 gene encoding exonuclease-2 on several of the phenotypes of
      xrn1 cells has been examined. The results show that the slow growth rate is
      partially overcome and that the level of accumulation of specific cytoplasmic
      RNAs (fragments of the internal transcribed spacer 1 of pre-rRNA and poly (A)
      deficient mRNAs) is reduced to 30-40% of the value found in the xrn1 cells.

PMID- 8643407
TI  - Structural characterization of Escherichia coli ribosomal protein S8 and its
      binding site in 16S ribosomal RNA.

PMID- 8643408
TI  - RNase P and 3'-tRNase processing matrices in the analysis of Drosophila transfer
      RNA D/T loop tertiary contacts.

PMID- 8643409
TI  - Autoregulation of RNase E synthesis in Escherichia coli.
AB  - RNase E plays a central role in controlling mRNA degradation in E. coli. We have
      investigated the mechanism of RNase E autoregulation. Our data indicate that
      RNase E autoregulates its synthesis by controlling the decay rate of its own
      transcript (rne mRNA), which is unusually sensitive to the level of cellular
      RNase E activity. Feedback regulation is mediated in cis by the rne 5'
      untranslated region (5' UTR), which can confer this property onto heterologous
      mRNAs to which it is fused. The marked sensitivity of rne mRNA to regulation by
      RNase E is also due in part to the susceptibility of nascent rne transcripts to
      RNase E-mediated degradation.

PMID- 8643410
TI  - Analysis of conserved positions in nuclear RNase P RNA.
AB  - Secondary structure models of eubacterial and eukaryotic nuclear RNase P RNA
      subunits show extensive structural similarities, allowing the identification of
      highly conserved nucleotide positions and molecular modeling of the enzyme
      substrate complex in three dimensions. Based on this information, we present a
      preliminary tertiary structure model of the yeast nuclear RNase P RNA. In
      addition, the most conserved positions in the structure have been subjected to
      sequence randomization, with viable sequence variations identified by selection
      in vivo and characterized for phenotypic consequences.

PMID- 8643412
TI  - Spinach chloroplast RNase P: a putative protein enzyme.
AB  - Ribonuclease P (RNase P) is the enzyme responsible for endonucleolytically
      separating the 5'-leader sequence from precursor tRNA molecules. In bacteria, and
      in the nuclei and mitochondria of all eukaryotes studied so far, RNase P contains
      an RNA subunit which is necessary for activity in vitro and in vivo. In contrast,
      we showed earlier that partially-purified RNase P from spinach chloroplasts had
      physical properties inconsistent with the presence of any RNA. We now report that
      the properties of the chloroplast enzyme, after 500 to 1500-fold purification,
      are consistent with enzymatic activity residing in a approximately 70 kDa
      polypeptide. Gel filtration chromatography on Sephacryl S-200 and S-300 provides
      a mass for chloroplast RNase P of approximately 70 +/- 5 kDa. A single
      polypeptide of approximately 70-80 kDa can be crosslinked to iodoUMP-substituted
      pre-tRNA. The labeling intensity of this polypeptide corresponds closely to the
      peak of RNase P activity on Sephacryl S-200 chromatography. Unlike the bacterial
      ribozyme-type RNase P, chloroplast RNase P is not a metalloenzyme. We showed
      previously that phosphodiester bond cleavage by the E. coli RNA enzyme absolutely
      requires Mg2+ or Mn2+ coordinated to the pro-Rp oxygen of the scissile
      phosphodiester phosphate. In contrast, we now find that chloroplast RNase P has
      no such requirement, and can accurately and efficiently cleave pre-tRNA
      containing an Rp-thio-substitution at the scissile bond. These data are entirely
      consistent with the hypothesis that RNase P in plant chloroplasts is not a
      ribozyme, but a conventional protein enzyme.

PMID- 8643411
TI  - Generation and characterization of circular Bacillus subtilis RNase P RNA;
      activation by RNase P protein.
AB  - A circular form of Bacillus subtilis ribonuclease P RNA (C-P RNA) was generated
      in vitro by splicing permuted intron-exon (PIE) sequences containing the P RNA
      sequence. Steady-state cleavage of pre-tRNA(Asp) catalyzed by circular P RNA is
      slightly faster than the linear form. Furthermore, steady-state turnover
      catalyzed by circular RNase P RNA is activated by the addition of the Bacillus
      subtilis protein component of RNase P, to a rate constant equal to the linear
      holoenzyme under identical conditions. Also, the circles are resistant to
      nuclease degradation, have less sequence heterogeneity, and may enhance the
      formation of a unique structure. Therefore, circular forms of RNase P RNA should
      prove useful for mutagenesis and structural studies.

PMID- 8643413
TI  - The binding of apobec-1 to mammalian apo B RNA is stabilized by the presence of
      complementation factors which are required for post-transcriptional editing.
AB  - C to U RNA editing in mammalian intestinal apolipoprotein B mRNA creates an in
      frame translational stop and the synthesis of a truncated protein called apo B48.
      This site specific cytidine deamination is mediated by an enzyme complex of which
      the catalytic component (apobec-1) is a 27 kDa zinc-binding protein. apobec-1,
      expressed in bacteria, will bind to mammalian apo B RNA as well as a number of
      other AU-rich RNA templates. Apo B RNA-binding activity can be competed by the
      addition of tRNA, an effect which can be overcome by the addition of
      complementation factors such as chick enterocyte S-100 extracts. Thus, apobec-1
      may be a non-specific RNA binding protein which requires the presence of
      complementation factors to stabilize and enhance its binding in the setting of
      the holo-enzyme.

PMID- 8643414
TI  - [Evaluation of bone mass in insulin dependent diabetes during ultrasonic
      examination].
AB  - The study group included 34 patients with insulin-dependent diabetes mellitus
      lasting for over 5 years, receiving intensive functional insulin therapy. Apart
      from the evaluation of chronic complications (retinopathy, nephropathy,
      neuropathy) all the patients were also examined with respect to diabetes
      normalization (HbAlc, mean daily glycemia) and bone density measured with the use
      of Achilles Lunar. T-score was found to be significantly higher in diabetes with
      higher mean glycemia and higher AbAlc. Lowering of T-score was seen in younger
      women than in men. Decreased T-score was found in patients with retinopathy and
      nephropathy as compared with those without the complications. A significantly
      lower (p < 0.05) T-score was seen in patients with peripheral and autonomic
      neuropathy as compared with those without the complications. The present findings
      indicate that lack of diabetes normalization contributes into the development of
      osteoporosis in insulin-dependent diabetes mellitus. An important role is also
      played by chronic diabetes complications, especially diabetic nephropathy
      mediated by neurotrophic mechanism.

PMID- 8643415
TI  - [Decreased bone mineral density in patients with insulin-dependent-diabetes].
AB  - The aim of study was an evaluation of bone mineral density (BMD) measured by
      LUNAR DPX-L System in lumbar spine (AP), total body and distal site of forearm
      (Forearm) in patients with insulin-dependent diabetes mellitus (IDDM), in
      relation to duration of the disease, degree of metabolic control and serum
      osteocalcin (OC). The study was performed on 58 patients with IDDM (26 F, 32 M;
      mean age: 40.1 +/- 10 yrs, mean duration of IDDM: 17.2 +/- 8 yrs) and 33 healthy,
      age-matched subjects (18 F, 15 M). Patients with overt nephropathy, concomitant
      diseases known to affect bone metabolism and women after menopause were excluded
      from the study. BMD was decreased in patients with IDDM in comparison with the
      controls: 1.13 +/- 0.1 vs 1.25 +/- 0.15 g/cm2, p < 0.001 in AP, 1.12 +/- 0.07 vs
      1.2 +/- 0.07 g/cm2, p < 0.001 in Total body oraz 0.37 +/- 0.05 vs 0.4 +/- 0.05
      g/cm2, p < 0.05 in Forearm. The degree of metabolic control of IDDM evaluated by
      serum HbAlc levels did not influence the values of BMD. Similarly, duration of
      IDDM did not correlate with BMD. OC level was significantly higher in diabetic
      patients than in control group: 4.88 +/- 2.2 vs 3.89 +/- 1.2 ng/ml, p < 0.05.
      CONCLUSIONS: 1) In patients with long-standing IDDM, Total Body, AP Spine and
      Forearm BMD were significantly decreased in comparison with the controls, and the
      decrease of BMD was higher in men than in women. 2) In patients with IDDM the
      decrease of BMD did not depend on the degree of metabolic control and duration of
      the disease. 3) Serum OC determinations may help in the identification of cases
      with risk of development of diabetic osteopenia.

PMID- 8643416
TI  - [Evaluation of osteoporosis risk using densitometric examinations of the forearm
      in randomized probes of the provincial population of Warsaw].

PMID- 8643417
TI  - [Measurements of calcaneus bone density by ultrasonography in children and
      adolescents].
AB  - In recent years the interest in growing in the use of ultrasonographic method for
      the assessment of bony tissue density. However, studies using this method were
      conducted almost exclusively in adult patients. The aim of this study was to
      apply this method for measurements in children in wide age range (7-18 years) and
      to determine value range of the parameters SOS, BUA and Stiffness for children in
      Warsaw in age and sex groups. The studies included 233 children of either sex,
      aged 7-18 years, healthy on medical examination coming from Warsaw schools.
      Achilles (Lunar Corp. WI, USA) bone densitometer was used with producer's
      software, 1.5c version. During examination with the Achilles device, the
      velocities of ultrasound beam passage through the calcaneus (SOS m/s) and the
      damping factor of ultrasound wave depending on its frequency (BUA db/MHz) were
      measured. Additionally the so called "stiffness factor" was calculated. The
      Achilles device was adapted for measurements in children reducing the diameter of
      the measuring beam to 1 cm and using pads positioning the child's foot in the
      device. Equal increase of SOS, BUA and Stiffness parameters with age was observed
      with the exception of the SOS parameter in girls which increased intensively from
      7 to 12 years of age while over 12 years of age its increase was slight. Using
      linear regression analysis it was found that the values of SOS, BUA and Stiffness
      parameters depended directly proportionally on age, body weight and height.
      Respective correlation factors (r) were from 0.49 (body weight-SOS to 0.80
      (height-BUA). The observed dependence of the SOS, BUA and Stiffness parameters on
      body weight, height and especially age enables presuming that the results of
      calcaneus density measurements by ultrasonographic method reflect the skeletal
      development in children.

PMID- 8643418
TI  - [Quantitative computerized tomography of peripheral body parts (pQCT)--results of
      measurements in healthy women from the Polish population].
AB  - The authors present a new method in densitometry-quantitative computerized
      tomography of peripheral body parts (pQCT). It takes into account the volume of
      measured bones expressing the results as density in physical sense, and makes
      possible differentation of internal bone structure with a very low exposure (up
      to 6 mrem for a complete measurement). The authors have begun also work on
      gathering reference data for the Polish population and they present the
      preliminary results of measurements in an initial group of 97 women.

PMID- 8643419
TI  - [Comparison of bone density in various skeletal parts in women during peri and
      postmenopause with previous Colles fracture].
AB  - Forearm fracture of Colles type is one of the most frequently observed
      osteoporotic fractures in women in postmenopausal period. It is proved that the
      group of women who had Celles fractures (n = 63) has lower bone mineral density
      in all measured sites except hip comparing to the controls (n = 53). Osteopenia
      found involves trabecular bone. Women with previous forearm fracture can be
      treated as the group of increased risk for spine and femoral neck fracture in the
      future.

PMID- 8643420
TI  - [Menopause and andropause as a public health problem].

PMID- 8643421
TI  - [Evaluation of bone density using the DEXA method and ultrasonography in women
      after menopause during treatment with vitamin D].
AB  - A new group of drugs-oestrogen agonists-antagonists (tamoxifen and raloxifen) is
      discussed. In view of their potentially favourable effects on the bone and lipids
      and lacking unfavourable action on the uterus and mammary gland, after successful
      completion of clinical studies, these preparations may be possibly important for
      the prophylaxis and treatment of osteoporosis.

PMID- 8643422
TI  - [Evaluation of bone mineral density in selected regions of the skeleton in
      children with osteogenesis imperfecta and hypophosphatemic rickets].

PMID- 8643423
TI  - [Effect of calcitonin treatment on bone mineralization in patients with multiple
      myeloma].
AB  - The aim of the study was to evaluate the efficacy of half-year treatment of bone
      mineral disturbances with calcitonin in the patients with multiple myeloma.
      Thirty five patients (11 men and 24 women) were examined. They were treated among
      other with prednisone. Nineteen patients (15 patients with normal bone mineral
      density of lumbar spine and femoral neck and 4 with low bone mineral density who
      could not be treated with calcitonin) were treated only with chemotherapy. Other
      16 patients with low bone mineral density have received also calcitonin (100
      units subcutaneous daily) with vitamin D3 and calcium carbonate. Bone mineral
      density was evaluated with dual energy X-ray absorptiometry in lumbar spine and
      femoral neck. After treatment with calcitonin there was more pronounced influence
      on bone mineral density in lumbar spine and femoral neck than after treatment
      with chemotherapy only but the difference was not statistically significant.
      Because the bone mineral disturbances in the patients with multiple myeloma is
      the big problem there is a need for further and longer evaluation of the
      treatment of these disturbances.

PMID- 8643424
TI  - [Comparative analysis of three treatment regimens for treating gonarthritis with
      calcitonin, naproxen and flavonoids based on EULAR criteria and visual analogue
      scale (VAS)].
AB  - The newest laboratory and clinical elaborations have described a stimulatory
      effect of salmon calcitonin (sCT) on cultivated chondrocytes and cartilage
      explants in regard to their secretory function of glycosaminoglycans, collagen t.
      II and hyaluonic acid as well as have shown anticatabolic effect of sCT on
      numerous animal models of osteoarthropathy. Moreover, very few clinical indicated
      profitable effect of CT on degenerative joint diseases and on rheumatoid
      arthritis. The aim of the present study is to compare the curative effect of sCT
      (Miacalcic, Sandoz, nasal spray, 2 x 100 IU/day ) vs flavonoides (VR, Venoruton,
      Zyma, 2 x 0.6 + Vit. C. 0.2/day) with or without naproxen sodium (AP, Apranax, 2
      x 0.550/day) in 30 patients suffering from gonarthritis, treated in 10 months in
      one of the three regimes: I--(n = 10, BMI-33.3, aged 59.5 y., Larsen gr. -2.5):
      1st month-VR, 2 and 3-sCT, 4 and 5-VR, 6 and 7-AP, 8.9 and 10-VR; II--(n = 10,
      BMI-28.8, aged 56 y., Larsen gr. 2.95): 1st m.-VR, 2 and 3-Ap, 4 and 5-VR, 6 and
      7-sCT, 9.9 and 10-VR; III--(n = 10, BMI-31.4, aged 58 y., Larsen gr.-2.8): 1st m.
      VR, 2 and 3-sCT, 4 and 5-VR, 6 and 7-sCT, 8.9 and 10-VR. Clinical effects of
      treatment were evaluated by EULAR criteria, VAS, and the paracetamol consumption.
      RESULTS: The best results according to all three criteria of improvement have
      been observed in group III treated only with sCT and VR followed by group I in
      which sCT was given as the first active drug. This effect lasted until three
      months after the withdrawal of sCT and/or naproxen. This results supported our
      opinion on antiosteoarthritic ability of salmon calcitonin and marked curative
      effect of flavonoides in the treatment of osteoarthritis.

PMID- 8643425
TI  - [Agonists-antagonists of estrogens, their potential use in prophylaxis and
      treatment of osteoporosis].
AB  - A new group of drugs-oestrogen agonists-antagonists (tamoxifen and raloxifen) is
      discussed. In view of their potentially favourable effects on the bone and lipids
      and lacking unfavourable action on the uterus and mammary gland, after successful
      completion of clinical studies, these preparations may be possibly important for
      the prophylaxis and treatment of osteoporosis.

PMID- 8643426
TI  - [Use of third generation bisphosphonates in treatment of neoplastic
      hypercalcemia].

PMID- 8643427
TI  - [Effect of bisphosphonates (HEBP, CL2MBP) on the process of biological
      mineralization in fresh bone and bone tissue de novo as a result of experimental
      osteogenesis induction in guinea pigs].
AB  - It is known from the literature that bisphosphonates inhibit mineralization
      process in skeletal tissues. To study in vivo the effects of HEBP (etidronate)
      and Cl2MBP (clodronate) both on preexisting bone mineral as well as on the early
      stages of the mineralization process the experimental model of heterotopical bone
      induction was chosen. Urinary bladder mucosa was used as an inductor of
      osteogenesis. Using this model it is possible to compare the effects of
      bisphosphonates on preexisting mineral on ortothopic bones as well as on the
      early stages of mineral deposition in the newly formed bone induced in
      heterotopic sites. HEBP and Cl2MBP doesn't inhibit heterotopic bone induction,
      but HEBP deeply inhibits the mineralization process; the small amount of
      deposited mineral does not contain crystalline fraction.

PMID- 8643428
TI  - [Calcium metabolism in bone].

PMID- 8643429
TI  - [Menopause in women--hormonal replacement therapy].

PMID- 8643430
TI  - [Vitamin D and osteoporosis].
AB  - The role is discussed of adequate vitamin D supply for calcium-phosphate
      homeostasis. The use of parental preparations and active vitamin D metabolites is
      presented in the prophylaxis and treatment of postmenopausal and involutional
      osteoporosis.

PMID- 8643432
TI  - [Can parathormone be used to treat osteoporosis?].

PMID- 8643431
TI  - [Use of bisphosphates in treatment of primary and secondary osteoporosis].
AB  - Bisphosphonates are chemically stable and not metabolized. They express
      antiresorptive properties on the bone by inhibiting osteoclastic activity. The
      potency of antiresorptive activity and inhibition of bone mineralisation depend
      on chemical structure of different bisphosphonates. Etidronate is so far the best
      known drug used in therapy of postmenopausal osteoporosis. This is shown through
      increased bone density of the spine and femoral neck with simultaneously
      decreased risk of subsequent vertebral fractures. Other bisphosphonates
      (clodronate, pamidronate, tiludronate, alendronate, risedronate) are undergoing
      clinical trials, with so far, promising results regarding their clinical efficacy
      and safety of it's use. Etidronate has been investigated as a drug to prevent
      corticosteroid induced osteoporosis. Further studies are required to long-term
      beneficial effects of bisphosphonates on bone metabolism and safety of their
      prolonged use.

PMID- 8643433
TI  - [Role of densitometric examination in diagnosis of osteoporosis].
AB  - Densitometric studies gain even wider acceptance in the monitoring, treatment and
      diagnosis of metabolic bone diseases. The paper includes a number of views on the
      ways of using densitometric equipment in screening for osteoporosis, and remarks
      on the interpretation of the obtained results.

PMID- 8643434
TI  - [Rehabilitation tactics in osteoporosis].

PMID- 8643435
TI  - Origin of genetic code: A needle in the haystack of tRNA sequences.

PMID- 8643436
TI  - Does DG42 synthesize hyaluronan or chitin?: A controversy about oligosaccharides
      in vertebrate development.

PMID- 8643437
TI  - Retinitis pigmentosa: unfolding its mystery.

PMID- 8643439
TI  - The presence of codon-anticodon pairs in the acceptor stem of tRNAs.
AB  - A total of 1268 available (excluding mitochondrial) tRNA sequences was used to
      reconstruct the common consensus image of their acceptor domains. Its structure
      appeared as a 11-bp-long double-stranded palindrome with complementary triplets
      in the center, each flanked by the 3'-ACCD and NGGU-5' motifs on each strand (D,
      base determinator). The palindrome readily extends up to the modern tRNA-like
      cloverleaf passing through an intermediate hairpin having in the center the
      single-stranded triplet, in supplement to its double-stranded precursor. The
      latter might represent an original anticodon-codon pair mapped at 1-2-3 positions
      of the present-day tRNA acceptors. This conclusion is supported by the striking
      correlation: in pairs of consensus tRNAs with complementary anticodons, their
      bases at the 2nd position of the acceptor stem were also complementary.
      Accordingly, inverse complementarity was also evident at the 71st position of the
      acceptor stem. With a single exception (tRNA(Phe)-tRNA(Glu) pair), the
      parallelism is especially impressive for the pairs of tRNAs recognized by
      aminoacyl-tRNA synthetases (aaRS) from the opposite classes. The above
      complementarity still doubly presented at the key central position of real single
      stranded anticodons and their hypothetical double-stranded precursors is
      consistent with our previous data pointing to the double-strand use of ancient
      RNAs in the origin of the main actors in translation- tRNAs with complementary
      anticodons and the two classes of aaRS.

PMID- 8643440
TI  - Cells expressing the DG42 gene from early Xenopus embryos synthesize hyaluronan.
AB  - DG42 is one of the main mRNAs expressed during gastrulation in embryos of Xenopus
      laevis. Here we demonstrate that cells expressing this mRNA synthesize
      hyaluronan. The cloned DG42 cDNA was expressed in rabbit kidney (RK13) and human
      osteosarcoma (tk-) cells using a vaccinia virus system. Lysates prepared from
      infected cells were incubated in the presence of UDP-N-acetylglucosamine and UDP
      [14C]glucuronic acid. This yielded a glycosaminoglycan with a molecular mass of
      about 200,000 Da. Formation of this product was only observed in the presence of
      both substrates. The glycosaminoglycan could be digested with testicular
      hyaluronidase and with Streptomyces hyaluronate lyase but not with Serratia
      chitinase. Hyaluronan synthase activity could also be detected in homogenates of
      early Xenopus embryos, and the activity was found to correlate with the
      expression of DG42 mRNA at different stages of development. Synthesis of
      hyaluronan is thus an early event after midblastula transition, indicating its
      importance for the ensuing cell movements in the developing embryo. Our results
      are at variance with a recent report (Semino, C. E. & Robbins, P. W. (1995) Proc.
      Natl. Acad. Sci. USA 92, 3498-3501) that DG42 codes for an enzyme that catalyzes
      the synthesis of chitin-like oligosaccharides.

PMID- 8643438
TI  - Onconeural antigens and the paraneoplastic neurologic disorders: at the
      intersection of cancer, immunity, and the brain.
AB  - Paraneoplastic neurologic disorders (PNDs) are believed to be autoimmune neuronal
      degenerations that develop in some patients with systemic cancer. A series of
      genes encoding previously undiscovered neuronal proteins have been cloned using
      antiserum from PND patients. Identification of these onconeural antigens suggests
      a reclassification of the disorders into four groups: those in which
      neuromuscular junction proteins, nerve terminal/vesicle-associated proteins,
      neuronal RNA binding proteins, or neuronal signal-transduction proteins serve as
      target antigens. This review considers insights into basic neurobiology, tumor
      immunology, and autoimmune neuronal degeneration offered by the characterization
      of the onconeural antigens.

PMID- 8643442
TI  - Structure and function in rhodopsin: correct folding and misfolding in two point
      mutants in the intradiscal domain of rhodopsin identified in retinitis
      pigmentosa.
AB  - The rhodopsin mutants P23H and G188R, identified in autosomal dominant retinitis
      pigmentosa (ADRP), and the site-specific mutants D190A and DeltaY191-Y192 were
      expressed in COS cells from synthetic mutant opsin genes containing these
      mutations. The proteins expressed from P23H and D190A partially regenerated the
      rhodopsin chromophore with 11-cis-retinal and were mixtures of the correctly
      folded (retinal-binding) and misfolded (non-retinal-binding) opsins. The mixtures
      were separated into pure, correctly folded mutant rhodopsins and misfolded
      opsins. The proteins expressed from the ADRP mutant G188R and the mutant
      DeltaY191-Y192 were composed of totally misfolded non-retinal-binding opsins. Far
      UV CD spectra showed that the correctly folded mutant rhodopsins had helical
      content similar to that of the wild-type rhodopsin, whereas the misfolded opsins
      had helical content 50-70% of the wild type. The near-UV CD spectra of the
      misfolded mutant proteins lack the characteristic band pattern seen in the wild
      type opsin, indicative of a different tertiary structure. Further, whereas the
      folded mutant rhodopsins were essentially resistant to trypsin digestion, the
      misfolded opsins were degraded to small fragments under the same conditions.
      Therefore, the misfolded opsins appear to be less compact in their structures
      than the correctly folded forms. We suggest that most, if not all, of the point
      mutations in the intradiscal domain identified in ADRP cause partial or complete
      misfolding of rhodopsin.

PMID- 8643441
TI  - Homologs of the Xenopus developmental gene DG42 are present in zebrafish and
      mouse and are involved in the synthesis of Nod-like chitin oligosaccharides
      during early embryogenesis.
AB  - The Xenopus developmental gene DG42 is expressed during early embryonic
      development, between the midblastula and neurulation stages. The deduced protein
      sequence of Xenopus DG42 shows similarity to Rhizobium Nod C, Streptococcus Has
      A, and fungal chitin synthases. Previously, we found that the DG42 protein made
      in an in vitro transcription/translation system catalyzed synthesis of an array
      of chitin oligosaccharides. Here we show that cell extracts from early Xenopus
      and zebrafish embryos also synthesize chitooligosaccharides. cDNA fragments
      homologous to DG42 from zebrafish and mouse were also cloned and sequenced.
      Expression of these homologs was similar to that described for Xenopus based on
      Northern and Western blot analysis. The Xenopus anti-DG42 antibody recognized a
      63-kDa protein in extracts from zebrafish embryos that followed a similar
      developmental expression pattern to that previously described for Xenopus. The
      chitin oligosaccharide synthase activity found in extracts was inactivated by a
      specific DG42 antibody; synthesis of hyaluronic acid (HA) was not affected under
      the conditions tested. Other experiments demonstrate that expression of DG42
      under plasmid control in mouse 3T3 cells gives rise to chitooligosaccharide
      synthase activity without an increase in HA synthase level. A possible
      relationship between our results and those of other investigators, which show
      stimulation of HA synthesis by DG42 in mammalian cell culture systems, is
      provided by structural analyses to be published elsewhere that suggest that
      chitin oligosaccharides are present at the reducing ends of HA chains. Since in
      at least one vertebrate system hyaluronic acid formation can be inhibited by a
      pure chitinase, it seems possible that chitin oligosaccharides serve as primers
      for hyaluronic acid synthesis.

PMID- 8643443
TI  - Structure and function in rhodopsin: correct folding and misfolding in point
      mutants at and in proximity to the site of the retinitis pigmentosa mutation Leu
      125-->Arg in the transmembrane helix C.
AB  - L125R is a mutation in the transmembrane helix C of rhodopsin that is associated
      with autosomal dominant retinitis pigmentosa. To probe the orientation of the
      helix and its packing in the transmembrane domain, we have prepared and studied
      the mutations E122R, I123R, A124R, S127R, L125F, and L125A at, and in proximity
      to, the above mutation site. Like L125R, the opsin expressed in COS-1 cells from
      E122R did not bind 11-cis-retinal, whereas those from I123R and S127R formed the
      rhodopsin chromophore partially. A124R opsin formed the rhodopsin chromophore
      (lambda max 495 nm) in the dark, but the metarhodopsin II formed on illumination
      decayed about 6.5 times faster than that of the wild type and was defective in
      transducin activation. The mutant opsins from L125F and L125A bound 11-cis
      retinal only partially, and in both cases, the mixtures of the proteins produced
      were separated into retinal-binding and non-retinal-binding (misfolded)
      fractions. The purified mutant rhodopsin from L125F showed lambda max at 500 nm,
      whereas that from L125A showed lambda max at 503 nm. The mutant rhodopsin L125F
      showed abnormal bleaching behavior and both mutants on illumination showed
      destabilized metarhodopsin II species and reduced transducin activation. Because
      previous results have indicated that misfolding in rhodopsin is due to the
      formation of a disulfide bond other than the normal disulfide bond between Cys
      110 and Cys-187 in the intradiscal domain, we conclude from the misfolding in
      mutants L125F and L125A that the folding in vivo in the transmembrane domain is
      coupled to that in the intradiscal domain.

PMID- 8643445
TI  - Functional interaction and colocalization of the herpes simplex virus 1 major
      regulatory protein ICP4 with EAP, a nucleolar-ribosomal protein.
AB  - The herpes simplex virus 1 infected cell protein 4 (ICP4) binds to DNA and
      regulates gene expression both positively and negatively. EAP (Epstein-Barr virus
      encoded small nuclear RNA-associated protein) binds to small nonpolyadenylylated
      nuclear RNAs and is found in nucleoli and in ribosomes, where it is also known as
      L22. We report that EAP interacts with a domain of ICP4 that is known to bind
      viral DNA response elements and transcriptional factors. In a gel-shift assay, a
      glutathione S-transferase (GST)-EAP fusion protein disrupted the binding of ICP4
      to its cognate site on DNA in a dose-dependent manner. This effect appeared to be
      specifically due to EAP binding to ICP4 because (i) GST alone did not alter the
      binding of ICP4 to DNA, (ii) GST-EAP did not bind to the probe DNA, and (iii) GST
      EAP did not influence the binding of the alpha gene trans-inducing factor
      (alphaTIF or VP16) to its DNA cognate site. Early in infection, ICP4 was
      dispersed throughout the nucleoplasm, whereas EAP was localized to the nucleoli.
      Late in infection, EAP was translocated from nucleoli and colocalized with ICP4
      in small, dense nuclear structures. The formation of dense structures and the
      colocalization of EAP and ICP4 did not occur if virus DNA synthesis and late gene
      expression were prevented by the infection of cells at the nonpermissive
      temperature with a mutant virus defective in DNA synthesis, or in cells infected
      and maintained in the presence of phosphonoacetate, which is an inhibitor of
      viral DNA synthesis. These results suggest that the translocation of EAP from the
      nucleolus to the nucleoplasm is a viral function and that EAP plays a role in the
      regulatory functions expressed by ICP4.

PMID- 8643444
TI  - Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      (MPTP)-induced dopaminergic neurotoxicity.
AB  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal
      dopaminergic pathway damage similar to that observed in Parkinson disease (PD).
      To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP
      into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole
      (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP
      injected mice against indices of severe injury to the nigrostriatal dopaminergic
      pathway, including reduction in striatal dopamine contents, decreases in numbers
      of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained
      degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not
      due to alterations in striatal pharmacokinetics or content of 1-methyl-4
      phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically
      the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the
      nNOS gene. Mutant mice are significantly more resistant to MPTP-induced
      neurotoxicity compared with wild-type littermates. These results indicate that
      neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The
      similarity between the MPTP model and PD raises the possibility that NO may play
      a significant role in the etiology of PD.

PMID- 8643446
TI  - Single cell Ca2+/cAMP cross-talk monitored by simultaneous Ca2+/cAMP fluorescence
      ratio imaging.
AB  - The spatial and temporal dynamics of two intracellular second messengers, cAMP
      and Ca2+, were simultaneously monitored in living cells by digital fluorescence
      ratio imaging using FlCRhR, a single-excitation dual-emission cAMP indicator, and
      fura-2, a dual-excitation single-emission Ca2+ probe. In single C6-2B glioma
      cells, isoproterenol- or forskolin-evoked cAMP accumulation (measured in vivo as
      an increased FlCRhR emission ratio) was reduced when cytosolic free Ca2+
      concentration was elevated before, simultaneously with, or after cAMP activation.
      However, in REF-52 fibroblasts, Ca2+ neither prevented nor reduced forskolin
      stimulated cAMP production. These results provide novel in vivo evidence for the
      Ca2+ modulation of the cAMP transduction pathway in C6-2B cells. The simultaneous
      microscopic measurement of cAMP and Ca2+ kinetics in single cells makes it now
      possible to study the regulatory interactions between these second messengers at
      the cellular and even the subcellular level.

PMID- 8643447
TI  - Antigenic peptides containing large PEG loops designed to extend out of the HLA
      A2 binding site form stable complexes with class I major histocompatibility
      complex molecules.
AB  - Recognition of peptides bound to class I major histocompatibility complex (MHC)
      molecules by specific receptors on T cells regulates the development and activity
      of the cellular immune system. We have designed and synthesized de novo cyclic
      peptides that incorporate PEG in the ring structure for binding to class I MHC
      molecules. The large PEG loops are positioned to extend out of the peptide
      binding site, thus creating steric effects aimed at preventing the recognition of
      class I MHC complexes by T-cell receptors. Peptides were synthesized and cyclized
      on polymer support using high molecular weight symmetrical PEG dicarboxylic acids
      to link the side chains of lysine residues substituted at positions 4 and 8 in
      the sequence of the HLA-A2-restricted human T-lymphotrophic virus type I Tax
      peptide. Cyclic peptides promoted the in vitro folding and assembly of HLA-A2
      complexes. Thermal denaturation studies using circular dichroism spectroscopy
      showed that these complexes are as stable as complexes formed with antigenic
      peptides.

PMID- 8643449
TI  - Trafficking of Plasmodium chabaudi adami-infected erythrocytes within the mouse
      spleen.
AB  - Plasmodium chabaudi adami causes a nonlethal infection in mice. We found that
      crisis, the time of rapidly dropping parasitemia, was abrogated by splenectomy,
      indicating the role of spleen in parasite killing. The factors that mediate
      spleen-dependent immunity are not known. An earlier study in Plasmodium berghei
      infected rats showed an association between increased clearance of heat-treated
      erythrocytes and the onset of crisis [Wyler, D. J., Quinn, T. C. & Chen, L.-T.
      (1982) J. Clin. Invest. 67, 1400-1404]. To determine the potential effects of
      different vascular beds in parasite killing, we studied the distribution of
      parasitized erythrocytes and bacteria in the spleens of P. chabaudi adami
      infected mice during precrisis (a period of rising parasitemia) and during
      crisis. After intravenous injection, bacteria were localized predominantly in the
      marginal zone. In contrast, parasitized erythrocytes were found in the red pulp.
      We also found that during precrisis, a time of no immunity, the uptake of
      radiolabeled infected erythrocytes by the spleen was increased, not decreased.
      These data imply that no change occurs in the flow of parasitized erythrocytes
      through the spleen during the transition to an immune state (crisis). Our
      observations suggest that immune effector mechanisms, not circulatory changes,
      account for spleen-dependent parasite killing during a P. chabaudi adami
      infection in mice.

PMID- 8643448
TI  - Viral cross talk: intracellular inactivation of the hepatitis B virus during an
      unrelated viral infection of the liver.
AB  - Hepatitis B virus (HBV) infection is thought to be controlled by virus-specific
      cytotoxic T lymphocytes (CTL). We have recently shown that HBV-specific CTL can
      abolish HBV replication noncytopathically in the liver of transgenic mice by
      secreting tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN
      gamma) after antigen recognition. We now demonstrate that hepatocellular HBV
      replication is also abolished noncytopathically during lymphocytic
      choriomeningitis virus (LCMV) infection, and we show that this process is
      mediated by TNF-alpha and IFN-alpha/beta produced by LCMV-infected hepatic
      macrophages. These results confirm the ability of these inflammatory cytokines to
      abolish HBV replication; they elucidate the mechanism likely to be responsible
      for clearance of HBV in chronically infected patients who become superinfected by
      other hepatotropic viruses; they suggest that pharmacological activation of
      intrahepatic macrophages may have therapeutic value in chronic HBV infection; and
      they raise the possibility that conceptually similar events may be operative in
      other viral infections as well.

PMID- 8643450
TI  - Controlling protein association and subcellular localization with a synthetic
      ligand that induces heterodimerization of proteins.
AB  - Extracellular growth and differentiation factors induce changes in gene
      expression in the nucleus by initiating a series of protein associations that
      alter the subcellular localization of intracellular signaling proteins. Initial
      events involve receptor homo- or heterodimerization and subsequent recruitment of
      cytosolic signaling proteins to the inner leaflet of the plasma membrane.
      Intermediate events involve the translocation of proteins into the nucleus. Late
      events involve the recruitment of transcriptional activators to the vicinity of
      specific genes in the nucleus, resulting in increased gene transcription. The
      ability to induce signals at each of these three phases of signaling pathways is
      illustrated by the use of a heterodimeric chemical inducer of dimerization that
      causes a proximal relationship between two different target proteins.

PMID- 8643451
TI  - The hard-soft acid-base principle in enzymatic catalysis: dual reactivity of
      phosphoenolpyruvate.
AB  - In this paper, the chemical reactivity of C3 of phosphoenolpyruvate (PEP) has
      been analyzed in terms of density functional theory quantified through quantum
      chemistry calculations. PEP is involved in a number of important enzymatic
      reactions, in which its C3 atom behaves like a base. In three different enzymatic
      reactions analyzed here, C3 sometimes behaves like a soft base and sometimes
      behaves like a hard base in terms of the hard-soft acid-base principle. This dual
      nature of C3 of PEP was found to be related to the conformational change of the
      molecule. This leads to a testable hypothesis: that PEP adopts particular
      conformations in the enzyme-substrate complexes of different PEP-using enzymes,
      and that the enzymes control the reactivity through controlling the dihedral
      angle between the carboxylate and the C==C double bond of PEP.

PMID- 8643452
TI  - The platelet-derived growth factor alpha-receptor is encoded by a growth-arrest
      specific (gas) gene.
AB  - Using the Escherichia coli lacZ gene to identify chromosomal loci that are
      transcriptionally active during growth arrest of NIH 3T3 fibroblasts, we found
      that an mRNA expressed preferentially in serum-deprived cells specifies the
      previously characterized alpha-receptor (alphaR) for platelet-derived growth
      factor (PDGF), which mediates mitogenic responsiveness to all PDGF isoforms. Both
      PDGFalphaR mRNA, which was shown to include a 111-nt segment encoded by a DNA
      region thought to contain only intron sequences, and PDGFalphaR protein
      accumulated in serum-starved cells and decreased as cells resumed cycling.
      Elevated PDGFalphaR gene expression during serum starvation was not observed in
      cells that had been transformed with oncogenes erbB2, src, or raf, which prevent
      starvation-induced growth arrest. Our results support the view that products of
      certain genes expressed during growth arrest function to promote, rather than
      restrict, cell cycling. We suggest that accumulation of the PDGFalphaR gene
      product may facilitate the exiting of cells from growth arrest upon mitogenic
      stimulation by PDGF, leading to the state of "competence" required for cell
      cycling.

PMID- 8643453
TI  - Myocyte-specific enhancer factor 2 acts cooperatively with a muscle activator
      region to regulate Drosophila tropomyosin gene muscle expression.
AB  - MEF2 (myocyte-specific enhancer factor 2) is a MADS box transcription factor that
      is thought to be a key regulator of myogenesis in vertebrates. Mutations in the
      Drosophila homologue of the mef2 gene indicate that it plays a key role in
      regulating myogenesis in Drosophila. We show here that the Drosophila tropomyosin
      I (TmI) gene is a target gene for mef2 regulation. The TmI gene contains a
      proximal and a distal muscle enhancer within the first intron of the gene. We
      show that both enhancers contain a MEF2 binding site and that a mutation in the
      MEF2 binding site of either enhancer significantly reduces reporter gene
      expression in embryonic, larval, and adult somatic body wall muscles of
      transgenic flies. We also show that a high level of proximal enhancer-directed
      reporter gene expression in somatic muscles requires the cooperative activity of
      MEF2 and a cis-acting muscle activator region located within the enhancer. Thus,
      mef2 null mutant embryos show a significant reduction but not an elimination of
      TmI expression in the body wall myoblasts and muscle fibers that are present.
      Surprisingly, there is little effect in these mutants on TmI expression in
      developing visceral muscles and dorsal vessel (heart), despite the fact that MEF2
      is expressed in these muscles in wild-type embryos, indicating that TmI
      expression is regulated differently in these muscles. Taken together, our results
      show that mef2 is a positive regulator of tropomyosin gene transcription that is
      necessary but not sufficient for high level expression in somatic muscle of the
      embryo, larva, and adult.

PMID- 8643454
TI  - Genomic structure of the human retinoblastoma-related Rb2/p130 gene.
AB  - The human Rb2/p130 gene shares many structural and functional features with the
      retinoblastoma gene and the retinoblastoma-related p107 gene. In the present
      study, we have cloned and partially sequenced the gene coding for the Rb2/p130
      protein from human genomic libraries. The complete intron-exon organization of
      this gene has been elucidated. The gene contains 22 exons spanning over 50 kb of
      genomic DNA. The length of individual exons ranges from 65 to 1517 bp. The
      largest intron spans over 9 kb, and the smallest has only 82 bp. The 5' flanking
      region revealed a structural organization characteristic of promoters of
      "housekeeping" and growth control-related genes. A typical TATA or CAAT box is
      not present, but there are several GC boxes and potential binding sites for
      numerous transcription factors. This study provides the molecular basis for
      understanding the transcriptional control of the Rb2/p130 gene and for
      implementing a comprehensive Rb2/p130 mutation screen using genomic DNA as a
      template.

PMID- 8643455
TI  - Regulation of the retinoblastoma protein-related protein p107 by G1 cyclin
      associated kinases.
AB  - p107 is a retinoblastoma protein-related phosphoprotein that, when overproduced,
      displays a growth inhibitory function. It interacts with and modulates the
      activity of the transcription factor, E2F-4. In addition, p107 physically
      associates with cyclin E-CDK2 and cyclin A-CDK2 complexes in late G1 and at G1/S,
      respectively, an indication that cyclin-dependent kinase complexes may regulate,
      contribute to, and/or benefit from p107 function during the cell cycle. Our
      results show that p107 phosphorylation begins in mid G1 and proceeds through late
      G1 and S and that cyclin D-associated kinase(s) contributes to this process. In
      addition, E2F-4 binds selectively to hypophosphorylated p107, and G1 cyclin
      dependent p107 phosphorylation leads to the dissociation of p107-E2F-4 complexes
      as well as inactivation of p107 G1 blocking function.

PMID- 8643456
TI  - Expression cloning of a cDNA for human ceramide glucosyltransferase that
      catalyzes the first glycosylation step of glycosphingolipid synthesis.
AB  - We have isolated a cDNA encoding human ceramide glucosyltransferase
      (glucosylceramide synthase, UDP-glucose:N-acylsphingosine D-glucosyltransferase,
      EC 2.4.1.80) by expression cloning using as a recipient GM-95 cells lacking the
      enzyme. The enzyme catalyzes the first glycosylation step of glycosphingolipid
      synthesis and the product, glucosylceramide, serves as the core of more than 300
      glycosphingolipids. The cDNA has a G+C-rich 5' untranslated region of 290
      nucleotides and the open reading frame encodes 394 amino acids (44.9 kDa). A
      hydrophobic segment was found near the N terminus that is the potential signal
      anchor sequence. In addition, considerable hydrophobicity was detected in the
      regions close to the C terminus, which may interact with the membrane. A
      catalytically active enzyme was produced from Escherichia coli transfected with
      the cDNA. Northern blot analysis revealed a single transcript of 3.5 kb, and the
      mRNA was widely expressed in organs. The amino acid sequence of ceramide
      glucosyltransferase shows no significant homology to ceramide
      galactosyltransferase, which indicates different evolutionary origins of these
      enzymes.

PMID- 8643457
TI  - Peroxo-iron and oxenoid-iron species as alternative oxygenating agents in
      cytochrome P450-catalyzed reactions: switching by threonine-302 to alanine
      mutagenesis of cytochrome P450 2B4.
AB  - Among biological catalysts, cytochrome P450 is unmatched in its multiplicity of
      isoforms, inducers, substrates, and types of chemical reactions catalyzed. In the
      present study, evidence is given that this versatility extends to the nature of
      the active oxidant. Although mechanistic evidence from several laboratories
      points to a hypervalent iron-oxenoid species in P450-catalyzed oxygenation
      reactions, Akhtar and colleagues [Akhtar, M., Calder, M. R., Corina, D. L. &
      Wright, J. N. (1982) Biochem. J. 201, 569-580] proposed that in steroid
      deformylation effected by P450 aromatase an iron-peroxo species is involved. We
      have shown more recently that purified liver microsomal P450 cytochromes,
      including phenobarbital-induced P450 2B4, catalyze the analogous deformylation of
      a series of xenobiotic aldehydes with olefin formation. The investigation
      presented here on the effect of site-directed mutagenesis of threonine-302 to
      alanine on the activities of recombinant P450 2B4 with N-terminal amino acids 2
      27 deleted [2B4 (delta2-27)] makes use of evidence from other laboratories that
      the corresponding mutation in bacterial P450s interferes with the activation of
      dioxygen to the oxenoid species by blocking proton delivery to the active site.
      The rates of NADPH oxidation, hydrogen peroxide production, and product formation
      from four substrates, including formaldehyde from benzphetamine N-demethylation,
      acetophenone from 1-phenylethanol oxidation, cyclohexanol from cyclohexane
      hydroxylation, and cyclohexene from cyclohexane carboxaldehyde deformylation,
      were determined with P450s 2B4, 2B4 (delta2-27), and 2B4 (delta2-27) T302A.
      Replacement of the threonine residue in the truncated cytochrome gave a 1.6- to
      2.5-fold increase in peroxide formation in the presence of a substrate, but
      resulted in decreased product formation from benzphetamine (9-fold), cyclohexane
      (4-fold), and 1-phenylethanol (2-fold). In sharp contrast, the deformylation of
      cyclohexane carboxaldehyde by the T302A mutant was increased about 10-fold. On
      the basis of these findings and our previous evidence that aldehyde deformylation
      is supported by added H202, but not by artificial oxidants, we conclude that the
      iron-peroxy species is the direct oxygen donor. It remains to be established
      which of the many other oxidative reactions involving P450 utilize this species
      and the extent to which peroxo-iron and oxenoid-iron function as alternative
      oxygenating agents with the numerous isoforms of this versatile catalyst.

PMID- 8643458
TI  - Signal transduction in the archaeon Halobacterium salinarium is processed through
      three subfamilies of 13 soluble and membrane-bound transducer proteins.
AB  - Eubacterial transducers are transmembrane, methyl-accepting proteins central to
      chemotaxis systems and share common structural features. We identified a large
      family of transducer proteins in the Archaeon Halobacterium salinarium using a
      site-specific multiple antigenic peptide antibody raised against 23 amino acids,
      representing the highest homology region of eubacterial transducers. This
      immunological observation was confirmed by isolating 13 methyl-accepting taxis
      genes using a 27-mer oligonucleotide probe, corresponding to conserved regions
      between the eubacterial and first halobacterial phototaxis transducer gene htrI.
      On the basis of the comparison of the predicted structural domains of these
      transducers, we propose that at least three distinct subfamilies of transducers
      exist in the Archaeon H. salinarium: (i) a eubacterial chemotaxis transducer type
      with two hydrophobic membrane-spanning segments connecting sizable domains in the
      periplasm and cytoplasm; (ii) a cytoplasmic domain and two or more hydrophobic
      transmembrane segments without periplasmic domains; and (iii) a cytoplasmic
      domain without hydrophobic transmembrane segments. We fractionated the
      halobacterial cell lysate into soluble and membrane fractions and localized
      different halobacterial methyl-accepting taxis proteins in both fractions.

PMID- 8643459
TI  - A circadian clock regulates rod and cone input to fish retinal cone horizontal
      cells.
AB  - In the vertebrate retina, the light responses of post-receptor neurons depend on
      the ambient or background illumination. Using intracellular recording, we have
      found that a circadian clock regulates the light responses of dark-adapted fish
      cone horizontal cells. Goldfish were maintained on a 12-hr light/12-hr dark
      cycle. At different times of the day or night, retinas were superfused in
      darkness for 90 min ("prolonged darkness"), following which horizontal cells were
      impaled without the aid of any light flashes. In some of the experiments, fish
      were kept in constant darkness for 3-48 hr prior to surgery. After prolonged
      darkness during the night, but not during the day, the light responses of L-type
      cone horizontal cells resembled those of rod horizontal cells with respect to
      threshold, waveform, intensity-response functions, and spectral sensitivity.
      Following light sensitization during the night and day, the light responses of
      rod and cone horizontal cells were clearly different with respect to threshold,
      waveform, intensity-response functions, and spectral sensitivity. Under
      conditions of constant darkness for two full light/dark cycles, average responses
      of cone horizontal cells to a bright light stimulus during the subjective day
      were greater than during the subjective night. Prior reversal of the light/dark
      cycle reversed the 24-hr rhythm of cone horizontal cell responses to bright
      lights. In addition, following one full cycle of constant darkness, average cone
      horizontal cell spectral sensitivity during the subjective night closely matched
      that of rod horizontal cells, whereas average cone horizontal cell spectral
      sensitivity during the subjective day was similar to that of red (625 nm) cones.
      These results indicate that the effects of dark adaptation depend on the time of
      day and are regulated by a circadian clock so that cone input to cone horizontal
      cells predominates in the day and rod input predominates in the night.

PMID- 8643460
TI  - Cloning and functional expression of cDNAs encoding human and rat pancreatic
      polypeptide receptors.
AB  - PCR was used to isolate nucleotide sequences that may encode novel members of the
      neuropeptide Y receptor family. By use of a PCR product as a hybridization probe,
      a full-length human cDNA was isolated that encodes a 375-aa protein with a
      predicted membrane topology identifying it as a member of the G-protein-coupled
      receptor superfamily. After stable transfection of the cDNA into human embryonic
      kidney 293 cells, the receptor exhibited high affinity (Kd = 2.8 nM) for 125I
      labeled human pancreatic polypeptide (PP). Competition binding studies in whole
      cells indicated the following rank order of potency: human PP = bovine PP > or =
      human [Pro34]peptide YY > rat PP > human peptide YY = human neuropeptide Y.
      Northern blot analysis revealed that human PP receptor mRNA is most abundantly
      expressed in skeletal muscle and, to a lesser extent, in lung and brain tissue. A
      rat cDNA clone encoding a high-affinity PP receptor that is 74% identical to the
      human PP receptor at the amino acid level was also isolated. These receptor
      clones will be useful in elucidating the functional role of PP and designing
      selective PP receptor agonists and antagonists.

PMID- 8643461
TI  - Dexamethasone responsiveness of a major glucocorticoid-inducible CYP3A gene is
      mediated by elements unrelated to a glucocorticoid receptor binding motif.
AB  - Elements responsible for dexamethasone responsiveness of CYP3A23, a major
      glucocorticoid-inducible member of the CYP3A gene family, have been identified.
      DNase I footprint analysis of the proximal promoter region revealed three
      protected sites (sites A, B, and C) within the sequence defined by -167 to -60.
      Mutational analysis demonstrated that both sites B and C were necessary for
      maximum glucocorticoid responsiveness and functioned in a cooperative manner.
      Interestingly, neither site contained a glucocorticoid responsive element.
      Embedded in site C was an imperfect direct repeat (5'-AACTCAAAGGAGGTCA-3'),
      showing homology to an AGGTCA steroid receptor motif, typically recognized by the
      estrogen receptor family, while site B contained an ATGAACT direct repeat; these
      core sequences were designated dexamethasone response elements 1 and 2 (DexRE-1
      and -2), respectively. Neither element has previously been associated with a
      glucocorticoid-activated transcriptional response. Conversion of the DexRE-1 to
      either a perfect thyroid hormone or vitamin D3 responsive element further
      enhanced induction by dexamethasone. Gel-shift analysis demonstrated that
      glucocorticoid receptor did not associate with either DexRE-1 or -2; hence,
      glucocorticoid receptor does not directly mediate glucocorticoid induction of
      CYP3A23. These unusual features suggest an alternate pathway through which
      glucocorticoids exert their effects.

PMID- 8643462
TI  - A general additive distance with time-reversibility and rate variation among
      nucleotide sites.
AB  - As additivity is a very useful property for a distance measure, a general
      additive distance is proposed under the stationary time-reversible (SR) model of
      nucleotide substitution or, more generally, under the stationary, time
      reversible, and rate variable (SRV) model, which allows rate variation among
      nucleotide sites. A method for estimating the mean distance and the sampling
      variance is developed. In addition, a method is developed for estimating the
      variance-covariance matrix of distances, which is useful for the statistical test
      of phylogenies and molecular clocks. Computer simulation shows (i) if the
      sequences are longer than, say, 1000 bp, the SR method is preferable to simpler
      methods; (ii) the SR method is robust against deviations from time-reversibility;
      (iii) when the rate varies among sites, the SRV method is much better than the SR
      method because the distance is seriously underestimated by the SR method; and
      (iv) our method for estimating the sampling variance is accurate for sequences
      longer than 500 bp. Finally, a test is constructed for testing whether DNA
      evolution follows a general Markovian model.

PMID- 8643463
TI  - Responses of the phototransduction cascade to dim light.
AB  - The biochemistry of visual excitation is kinetically explored by measuring the
      activity of the cGMP phosphodiesterase (PDE) at light levels that activate only a
      few tens of rhodopsin molecules per rod. At 23 degrees C and in the presence of
      ATP, the pulse of PDE activity lasts 4 s (full width at half maximum).
      Complementing the rod outer segments (ROS) with rhodopsin kinase (RK) and
      arrestin or its splice variant p44 does not significantly shorten the pulse. But
      when the ROS are washed, the duration of the signal doubles. Adding either
      arrestin or p44 back to washed ROS approximately restores the pulse width to its
      initial value, with p44 being 10 times more efficient than arrestin. This
      supports the idea that, in vivo, capping of phosphorylated R* is mostly done by
      p44. When myristoylated (14:0) recoverin is added to unwashed ROS, the pulse
      duration and amplitude increase by about 50% if the free calcium is 500 nM. This
      effect increases further if the calcium is raised to 1 microM. Whenever R*
      deactivation is changed--when RK is exogenously enriched or when ATP is omitted
      from the buffer--there is no impact on the rising slope of the PDE pulse but only
      on its amplitude and duration. We explain this effect as due to the unequal
      competition between transducin and RK for R*. The kinetic model issued from this
      idea fits the data well, and its prediction that enrichment with transducin
      should lengthen the PDE pulse is successfully validated.

PMID- 8643464
TI  - Activated Ras signals differentiation and expansion of CD4+8+ thymocytes.
AB  - We describe a novel approach to assay the ability of particular gene products to
      signal transitions in lymphocyte differentiation in vivo. The method involves
      transfection of test expression constructs into RAG-1-deficient embryonic stem
      cells, which are subsequently assayed by the RAG-2-deficient blastocyst
      complementation approach. We have used this method to demonstrate that expression
      of activated Ras in CD4-8- (double negative, DN) prothymocytes in vivo induces
      their differentiation into small CD4+8+ (double positive, DP) cortical thymocytes
      with accompanying expansion to normal thymocyte numbers. However, activated Ras
      expression in DP cells does not cause proliferation or maturation to CD4+8- or
      CD4-8+ (single positive) thymocytes. Therefore, signaling through Ras is
      sufficient for promoting differentiation of DN to DP cells, but further
      differentiation requires the activity of additional signaling pathways.

PMID- 8643465
TI  - Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent,
      pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors
      of poly(ADP-ribose) polymerase.
AB  - Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D
      aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death
      in acute and chronic neurological diseases. We have investigated whether
      excitotoxicity may occur in peripheral organs, causing tissue injury, and report
      that NMDA receptor activation in perfused, ventilated rat lungs triggered acute
      injury, marked by increased pressures needed to ventilate and perfuse the lung,
      and by high-permeability edema. The injury was prevented by competitive NMDA
      receptor antagonists or by channel-blocker MK-801, and was reduced in the
      presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was
      nitric oxide (NO) dependent: it required L-arginine, was associated with
      increased production of NO, and was attenuated by either of two NO synthase
      inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of
      poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO
      synthesis, both acting by inhibiting a toxic action of NO that is critical to
      tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung
      (and probably elsewhere outside the central nervous system), (ii) excessive
      activation of these receptors may provoke acute edematous lung injury as seen in
      the "adult respiratory distress syndrome," and (iii) this injury can be modulated
      by blockade of one of three critical steps: NMDA receptor binding, inhibition of
      NO synthesis, or activation of poly(ADP-ribose) polymerase.

PMID- 8643466
TI  - Hippocampal acetylcholine release during memory testing in rats: augmentation by
      glucose.
AB  - Several lines of evidence indicate that a modest increase in circulating glucose
      levels enhances memory. One mechanism underlying glucose effects on memory may be
      an increase in acetylcholine (ACh) release. The present experiment determined
      whether enhancement of spontaneous alternation performance by systemic glucose
      treatment is related to an increase in hippocampal ACh output. Samples of
      extracellular ACh were assessed at 12-min intervals using in vivo microdialysis
      with HPLC-EC. Twenty-four minutes after an intraperitoneal injection of saline or
      glucose (100, 250, or 1000 mg/kg), rats were tested in a four-arm cross maze for
      spontaneous alternation behavior combined with microdialysis collection. Glucose
      at 250 mg/kg, but not 100 or 1000 mg/kg, produced an increase in spontaneous
      alternation scores (69.5%) and ACh output (121.5% versus baseline) compared to
      alternation scores (44.7%) and ACh output (58.9% versus baseline) of saline
      controls. The glucose-induced increase in alternation scores and ACh output was
      not secondary to changes in locomotor activity. Saline and glucose (100-1000
      mg/kg) treatment had no effect on hippocampal ACh output when rats remained in
      the holding chamber. These findings suggest that glucose may enhance memory by
      directly or indirectly increasing the release of ACh. The results also indicate
      that hippocampal ACh release is increased in rats performing a spatial task.
      Moreover, because glucose enhanced ACh output only during behavioral testing,
      circulating glucose may modulate ACh release only under conditions in which
      cholinergic cells are activated.

PMID- 8643467
TI  - Reconstitution of the hippocampal mossy fiber and associational-commissural
      pathways in a novel dissociated cell culture system.
AB  - Synapses of the hippocampal mossy fiber pathway exhibit several characteristic
      features, including a unique form of long-term potentiation that does not require
      activation of the N-methyl-D-aspartate receptor by glutamate, a complex
      postsynaptic architecture, and sprouting in response to seizures. However, these
      connections have proven difficult to study in hippocampal slices because of their
      relative paucity (<0.4%) compared to commissural-collateral synapses. To overcome
      this problem, we have developed a novel dissociated cell culture system in which
      we have enriched mossy fiber synapses by increasing the ratio of granule-to
      pyramidal cells. As in vivo, mossy fiber connections are composed of large
      dynorphin A-positive varicosities contacting complex spines (but without a
      restricted localization). The elementary synaptic connections are glutamatergic,
      inhibited by dynorphin A, and exhibit N-methyl-D-aspartate-independent long-term
      potentiation. Thus, the simplicity and experimental accessibility of this
      enriched in vitro mossy fiber pathway provides a new perspective for studying
      nonassociative plasticity in the mammalian central nervous system.

PMID- 8643468
TI  - A presynaptic locus for long-term potentiation of elementary synaptic
      transmission at mossy fiber synapses in culture.
AB  - The complex circuitry of the CA3 region and the abundance of collateral
      connections has made it difficult to study the mossy fiber pathway in hippocampal
      slices and therefore to establish the site of expression of long-term
      potentiation at these synapses. Using a novel cell culture system, we have
      produced long-term potentiation of the elementary synaptic connections on single
      CA3 pyramidal neurons following tetanic stimulation of individual dentate gyrus
      granule cells. As is the case for the hippocampal slice, this potentiation was
      independent of N-methyl-D-aspartate receptor activation, was simulated by
      application of forskolin, and its induction did not require any modulatory input.
      The increase in synaptic strength was accompanied by a reduction in the number of
      failures of transmission and by an increase in the coefficient of variation of
      the responses and was prevented by presynaptic injection of an inhibitor of
      protein kinase A. These findings show that mossy fiber long-term potentiation has
      a presynaptic locus and that its expression is dependent on protein kinase A.

PMID- 8643469
TI  - Arabidopsis mutant analysis and gene regulation define a nonredundant role for
      glutamate dehydrogenase in nitrogen assimilation.
AB  - Glutamate dehydrogenase (GDH) is ubiquitous to all organisms, yet its role in
      higher plants remains enigmatic. To better understand the role of GDH in plant
      nitrogen metabolism, we have characterized an Arabidopsis mutant (gdh1-1)
      defective in one of two GDH gene products and have studied GDH1 gene expression.
      GDH1 mRNA accumulates to highest levels in dark-adapted or sucrose-starved
      plants, and light or sucrose treatment each repress GDH1 mRNA accumulation. These
      results suggest that the GDH1 gene product functions in the direction of
      glutamate catabolism under carbon-limiting conditions. Low levels of GDH1 mRNA
      present in leaves of light-grown plants can be induced by exogenously supplied
      ammonia. Under such conditions of carbon and ammonia excess, GDH1 may function in
      the direction of glutamate biosynthesis. The Arabidopsis gdh-deficient mutant
      allele gdh1-1 cosegregates with the GDH1 gene and behaves as a recessive
      mutation. The gdh1-1 mutant displays a conditional phenotype in that seedling
      growth is specifically retarded on media containing exogenously supplied
      inorganic nitrogen. These results suggest that GDH1 plays a nonredundant role in
      ammonia assimilation under conditions of inorganic nitrogen excess. This notion
      is further supported by the fact that the levels of mRNA for GDH1 and
      chloroplastic glutamine synthetase (GS2) are reciprocally regulated by light.

PMID- 8643470
TI  - DNA sequencing by delayed extraction-matrix-assisted laser desorption/ionization
      time of flight mass spectrometry.
AB  - Matrix-assisted laser desorption/ionization (MALDI) time of flight mass
      spectrometry was used to detect and order DNA fragments generated by Sanger
      dideoxy cycle sequencing. This was accomplished by improving the sensitivity and
      resolution of the MALDI method using a delayed ion extraction technique (DE
      MALDI). The cycle sequencing chemistry was optimized to produce as much as 100
      fmol of each specific dideoxy terminated fragment, generated from extension of a
      13-base primer annealed on 40- and 50-base templates. Analysis of the resultant
      sequencing mixture by DE-MALDI identified the appropriate termination products.
      The technique provides a new non-gel-based method to sequence DNA which may
      ultimately have considerable speed advantages over traditional methodologies.

PMID- 8643471
TI  - Mos/mitogen-activated protein kinase can induce early meiotic phenotypes in the
      absence of maturation-promoting factor: a novel system for analyzing spindle
      formation during meiosis I.
AB  - Mitogen-activated protein kinase (MAPK) is selectively activated by injecting
      either mos or MAPK kinase (mek) RNA into immature mouse oocytes maintained in the
      phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). IBMX arrests
      oocyte maturation, but Mos (or MEK) overexpression overrides this block. Under
      these conditions, meiosis I is significantly prolonged, and MAPK becomes fully
      activated in the absence of p34cdc2 kinase or maturation-promoting factor. In
      these oocytes, large openings form in the germinal vesicle adjacent to condensing
      chromatin, and microtubule arrays, which stain for both MAPK and centrosomal
      proteins, nucleate from these regions. Maturation-promoting factor activation
      occurs later, concomitant with germinal vesicle breakdown, the contraction of the
      microtubule arrays into a precursor of the spindle, and the redistribution of the
      centrosomal proteins into the newly forming spindle poles. These studies define
      important new functions for the Mos/MAPK cascade in mouse oocyte maturation and,
      under these conditions, reveal novel detail of the early stages of oocyte meiosis
      I.

PMID- 8643472
TI  - Polynitrosylated proteins: characterization, bioactivity, and functional
      consequences.
AB  - Chemical modification of proteins is a common theme in their regulation.
      Nitrosylation of protein sulfhydryl groups has been shown to confer nitric oxide
      (NO)-like biological activities and to regulate protein functions. Several other
      nucleophilic side chains -- including those with hydroxyls, amines, and aromatic
      carbons -- are also potentially susceptible to nitrosative attack. Therefore, we
      examined the reactivity and functional consequences of nitros(yl)ation at a
      variety of nucleophilic centers in biological molecules. Chemical analysis and
      spectroscopic studies show that nitrosation reactions are sustained at sulfur,
      oxygen, nitrogen, and aromatic carbon centers, with thiols being the most
      reactive functionality. The exemplary protein, BSA, in the presence of a 1-, 20-,
      100-, or 200-fold excess of nitrosating equivalents removes 0.6 +/- 0.2, 3.2 +/-
      0.4, 18 +/- 4, and 38 +/- 10, respectively, moles of NO equivalents per mole of
      BSA from the reaction medium; spectroscopic evidence shows the proportionate
      formation of a polynitrosylated protein. Analogous reaction of tissue-type
      plasminogen activator yields comparable NO protein stoichiometries. Disruption of
      protein tertiary structure by reduction results in the preferential nitrosylation
      of up to 20 thus-exposed thiol groups. The polynitrosylated proteins exhibit
      antiplatelet and vasodilator activity that increases with the degree of
      nitrosation, but S-nitroso derivatives show the greatest NO-related bioactivity.
      Studies on enzymatic activity of tissue-type plasminogen activator show that
      polynitrosylation may lead to attenuated function. Moreover, the reactivity of
      tyrosine residues in proteins raises the possibility that NO could disrupt
      processes regulated by phosphorylation. Polynitrosylated proteins were found in
      reaction mixtures containing interferon-gamma/lipopolysaccharide-stimulated
      macrophages and in tracheal secretions of subjects treated with NO gas, thus
      suggesting their physiological relevance. In conclusion, multiple sites on
      proteins are susceptible to attack by nitrogen oxides. Thiol groups are
      preferentially modified, supporting the notion that S-nitrosylation can serve to
      regulate protein function. Nitrosation reactions sustained at additional
      nucleophilic centers may have (patho)physiological significance and suggest a
      facile route by which abundant NO bioactivity can be delivered to a biological
      system, with specificity dictated by protein substrate.

PMID- 8643474
TI  - Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate
      receptor activation.
AB  - Behavioral stress has detrimental effects on subsequent cognitive performance in
      many species, including humans. For example, humans exposed to stressful
      situations typically exhibit marked deficits in various learning and memory
      tasks. However, the underlying neural mechanisms by which stress exerts its
      effects on learning and memory are unknown. We now report that in adult male
      rats, stress (i.e., restraint plus tailshock) impairs long-term potentiation
      (LTP) but enhances long-term depression (LTD) in the CA1 area of the hippocampus,
      a structure implicated in learning and memory processes. These effects on LTP and
      LTD are prevented when the animals were given CGP39551 (the carboxyethylester of
      CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), a competitive N
      methyl-D-aspartate (NMDA) receptor antagonist, before experiencing stress. In
      contrast, the anxiolytic drug diazepam did not block the stress effects on
      hippocampal plasticity. Thus, the effects of stress on subsequent LTP and LTD
      appear to be mediated through the activation of the NMDA subtype of glutamate
      receptors. Such modifications in hippocampal plasticity may contribute to
      learning and memory impairments associated with stress.

PMID- 8643473
TI  - The control of hematopoiesis and leukemia: from basic biology to the clinic.
AB  - Hematopoiesis gives rise to blood cells of different lineages throughout normal
      life. Abnormalities in this developmental program lead to blood cell diseases
      including leukemia. The establishment of a cell culture system for the clonal
      development of hematopoietic cells made it possible to discover proteins that
      regulate cell viability, multiplication and differentiation of different
      hematopoietic cell lineages, and the molecular basis of normal and abnormal blood
      cell development. These regulators include cytokines now called colony
      stimulating factors (CSFs) and interleukins (ILs). There is a network of cytokine
      interactions, which has positive regulators such as CSFs and ILs and negative
      regulators such as transforming growth factor beta and tumor necrosis factor
      (TNF). This multigene cytokine network provides flexibility depending on which
      part of the network is activated and allows amplification of response to a
      particular stimulus. Malignancy can be suppressed in certain types of leukemic
      cells by inducing differentiation with cytokines that regulate normal
      hematopoiesis or with other compounds that use alternative differentiation
      pathways. This created the basis for the clinical use of differentiation therapy.
      The suppression of malignancy by inducing differentiation can bypass genetic
      abnormalities that give rise to malignancy. Different CSFs and ILs suppress
      programmed cell death (apoptosis) and induce cell multiplication and
      differentiation, and these processes of development are separately regulated. The
      same cytokines suppress apoptosis in normal and leukemic cells, including
      apoptosis induced by irradiation and cytotoxic cancer chemotherapeutic compounds.
      An excess of cytokines can increase leukemic cell resistance to cytotoxic
      therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also
      be suppressed by cytokines. The oncogene mutant p53 suppresses apoptosis.
      Hematopoietic cytokines such as granulocyte CSF are now used clinically to
      correct defects in hematopoiesis, including repair of chemotherapy-associated
      suppression of normal hematopoiesis in cancer patients, stimulation of normal
      granulocyte development in patients with infantile congenital agranulocytosis,
      and increase of hematopoietic precursors for blood cell transplantation.
      Treatments that decrease the level of apoptosis-suppressing cytokines and
      downregulate expression of mutant p53 and other apoptosis suppressing genes in
      cancer cells could improve cytotoxic cancer therapy. The basic studies on
      hematopoiesis and leukemia have thus provided new approaches to therapy.

PMID- 8643475
TI  - Sequence-specific DNA-binding dominated by dehydration.
AB  - Fluorescence spectroscopy and isothermal titration calorimetry were used to study
      the thermodynamics of binding of the glucocorticoid receptor DNA-binding domain
      to four different, but similar, DNA-binding sites. The binding sites are two
      naturally occurring sites that differ in the composition of one base pair, i.e.,
      an A-T to G-C mutation, and two sites containing chemical intermediates of these
      base pairs. The calorimetrically determined heat capacity change (Delta
      C(p)o(obs)) for glucocorticoid receptor DNA-binding domain binding agrees with
      that calculated for dehydration of solvent-accessible surface areas. A dominating
      effect of dehydration or solvent reorganization on the thermodynamics is also
      consistent with an observed linear relationship between observed enthalpy change
      (Delta Ho(obs)) and observed entropy change (Delta So(obs)) with a slope close to
      the experimental temperature. Comparisons with structural data allow us to
      rationalize individual differences between Delta Ho(obs) (and Delta So(obs)) for
      the four complexes. For instance, we find that the removal of a methyl group at
      the DNA-protein interface is enthalpically favorable but entropically
      unfavorable, which is consistent with a replacement by an ordered water molecule.

PMID- 8643476
TI  - Synaptophysin, a major synaptic vesicle protein, is not essential for
      neurotransmitter release.
AB  - Synaptophysin (syp I) is a synaptic vesicle membrane protein that constitutes
      approximately 7% of the total vesicle protein. Multiple lines of evidence
      implicate syp I in a number of nerve terminal functions. To test these, we have
      disrupted the murine Syp I gene. Mutant mice lacking syp I were viable and
      fertile. No changes in the structure and protein composition of the mutant brains
      were observed except for a decrease in synaptobrevin/VAMP II. Synaptic
      transmission was normal with no detectable changes in synaptic plasticity or the
      probability of release. Our data demonstrate that one of the major synaptic
      vesicle membrane proteins is not essential for synaptic transmission, suggesting
      that its function is either redundant or that it has a more subtle function not
      apparent in the assays used.

PMID- 8643477
TI  - Age-related losses of cognitive function and motor skills in mice are associated
      with oxidative protein damage in the brain.
AB  - The hypothesis that age-associated impairment of cognitive and motor functions is
      due to oxidative molecular damage was tested in the mouse. In a blind study,
      senescent mice (aged 22 months) were subjected to a battery of behavioral tests
      for motor and cognitive functions and subsequently assayed for oxidative
      molecular damage as assessed by protein carbonyl concentration in different
      regions of the brain. The degree of age-related impairment in each mouse was
      determined by comparison to a reference group of young mice (aged 4 months)
      tested concurrently on the behavioral battery. The age-related loss of ability to
      perform a spatial swim maze task was found to be positively correlated with
      oxidative molecular damage in the cerebral cortex, whereas age-related loss of
      motor coordination was correlated with oxidative molecular damage within the
      cerebellum. These results support the view that oxidative stress is a causal
      factor in brain senescence. Furthermore, the findings suggest that age-related
      declines of cognitive and motor performance progress independently, and involve
      oxidative molecular damage within different regions of the brain.

PMID- 8643478
TI  - Selective attention to stimulus location modulates the steady-state visual evoked
      potential.
AB  - Steady-state visual evoked potentials (SSVEPs) were recorded from the scalp of
      human subjects who were cued to attend to a rapid sequence of alphanumeric
      characters presented to one visual half-field while ignoring a concurrent
      sequence of characters in the opposite half-field. These two-character sequences
      were each superimposed upon a small square background that was flickered at a
      rate of 8.6 Hz in one half-field and 12 Hz in the other half-field. The amplitude
      of the frequency-coded SSVEP elicited by either of the task-irrelevant flickering
      backgrounds was significantly enlarged when attention was focused upon the
      character sequence at the same location. This amplitude enhancement with
      attention was most prominent over occipital-temporal scalp areas of the right
      cerebral hemisphere regardless of the visual field of stimulation. These findings
      indicate that the SSVEP reflects an enhancement of neural responses to all
      stimuli that fall within the "spotlight" of spatial attention, whether or not the
      stimuli are task-relevant. Recordings of the SSVEP provide a new approach for
      studying the neural mechanisms and functional properties of selective attention
      to multi-element visual displays.

PMID- 8643479
TI  - Genetic interactions among cytoplasmic dynein, dynactin, and nuclear distribution
      mutants of Neurospora crassa.
AB  - Cytoplasmic dynein is a multisubunit, microtubule-associated, mechanochemical
      enzyme that has been identified as a retrograde transporter of various membranous
      organelles. Dynactin, an additional multisubunit complex, is required for
      efficient dynein-mediated transport of vesicles in vitro. Recently, we showed
      that three genes defined by a group of phenotypically identical mutants of the
      filamentous fungus Neurospora crassa encode proteins that are apparent subunits
      of either cytoplasmic dynein or dynactin. These mutants, designated ropy (ro),
      display abnormal hyphal growth and are defective in nuclear distribution. We
      propose that mutations in other genes encoding dynein/dynactin subunits are
      likely to result in a ropy phenotype and have devised a genetic screen for the
      isolation of additional ro mutants. Cytoplasmic dynein/dynactin is the largest
      and most complex of the cytoplasmic motor proteins, and the genetic system
      described here is unique in its potentiality for identifying mutations in
      undefined genes encoding dynein/dynactin subunits or regulators. We used this
      screen to isolate > 1000 ro mutants, which were found to define 23
      complementation groups. Unexpectedly, interallelic complementation was observed
      with some allele pairs of ro-1 and ro-3, which are predicted to encode the
      largest subunits of cytoplasmic dynein and dynactin, respectively. The results
      suggest that the Ro1 and Ro3 polypeptides may consist of multiple, functionally
      independent domains. In addition, approximately 10% of all newly isolated ro
      mutantsdisplay unlinked noncomplementation with two or more of the mutants that
      define the 23 complementation groups. The frequent appearance of ro mutants
      showing noncomplementation with multiple ro mutants having unlinked mutations
      suggests that nuclear distribution in filamentous fungi is a process that is
      easily disrupted by affecting either dosage or activity of cytoplasmic dynein,
      dynactin, and perhaps other cytoskeletal proteins or regulators.

PMID- 8643480
TI  - p53 as a target for cancer vaccines: recombinant canarypox virus vectors
      expressing p53 protect mice against lethal tumor cell challenge.
AB  - The p53 protein is an attractive target for immunotherapy, because mutations in
      the p53 gene are the most common genetic alterations found in human tumors. These
      mutations result in high levels of p53 protein in the tumor cell, whereas the
      expression level of wild-type p53 in nonmalignant tissue is usually much lower.
      Several canarypox virus recombinants expressing human or murine p53 in wild-type
      or mutant form were constructed. Immunization with these viruses protected BALB/c
      mice from a challenge with an isogenic and highly tumorigenic mouse fibroblast
      tumor cell line expressing high levels of mutant p53. The tumor protection was
      equally effective regardless of whether wild-type or mutant p53 was used for the
      immunization, indicating that the immunologic response was not dependent on any
      particular p53 mutation and that immunization with this live virus vaccine works
      effectively against mutant p53 protein expressed in a tumor cell. In tumors
      escaping immunologic rejection, the expression of the p53 protein was commonly
      down-regulated.

PMID- 8643481
TI  - Targeted replacement of the mycocerosic acid synthase gene in Mycobacterium bovis
      BCG produces a mutant that lacks mycosides.
AB  - A single gene (mas) encodes the multifunctional enzyme that catalyzes the
      synthesis of very long chain multiple methyl branched fatty acids called
      mycocerosic acids that are present only in slow-growing pathogenic mycobacteria
      and are thought to be important for pathogenesis. To achieve a targeted
      disruption of mas, an internal 2-kb segment of this gene was replaced with
      approximately the same size hygromycin-resistance gene (hyg), such that hyg was
      flanked by 4.7- and 1.4-kb segments of mas. Transformation of Mycobacterium bovis
      BCG with this construct in a plasmid that cannot replicate in mycobacteria
      yielded hygromycin-resistant transformants. Screening of 38 such transformants by
      PCR revealed several transformants representing homologous recombination with
      single crossover and one with double crossover. With primers representing the hyg
      termini and those representing the mycobacterial genome segments outside that
      used to make the transformation construct, the double-crossover mutant yielded
      PCR products expected from either side of hyg. Gene replacement was further
      confirmed by the absence of the vector and the 2-kb segment of mas replaced by
      hyg from the genome of the mutant. Thin-layer and radio-gas chromatographic
      analyses of the lipids derived from [1-14C]propionate showed that the mutant was
      incapable of synthesizing mycocerosic acids and mycosides. Thus, homologous
      recombination with double crossover was achieved in a slow-growing mycobacterium
      with an intron-containing RecA. The resulting mas-disrupted mutant should allow
      testing of the postulated roles of mycosides in pathogenesis.

PMID- 8643482
TI  - Dimerization specificity of Arabidopsis MADS domain homeotic proteins APETALA1,
      APETALA3, PISTILLATA, and AGAMOUS.
AB  - The MADS domain homeotic proteins APETALA1 (AP1), APETALA3 (AP3), PISTILLATA
      (PI), and AGAMOUS (AG) act in a combinatorial manner to specify the identity of
      Arabidopsis floral organs. The molecular basis for this combinatorial mode of
      action was investigated. Immunoprecipitation experiments indicate that all four
      proteins are capable of interacting with each other. However, these proteins
      exhibit "partner-specificity" for the formation of DNA-binding dimers; only AP1
      homodimers, AG homodimers, and AP3/PI heterodimers are capable of binding to CArG
      box sequences. Both the AP3/PI heterodimer and the AP1 or AG homodimers are
      formed when the three corresponding proteins are present together. The use of
      chimeric proteins formed by domain swapping indicates that the L region (which
      follows the MADS box) constitutes a key molecular determinant for the selective
      formation of DNA-binding dimers. The implications of these results for the ABC
      genetic model of flower development are discussed.

PMID- 8643483
TI  - High resolution ultrastructural mapping of total calcium: electron spectroscopic
      imaging/electron energy loss spectroscopy analysis of a physically/chemically
      processed nerve-muscle preparation.
AB  - We report on a procedure for tissue preparation that combines thoroughly
      controlled physical and chemical treatments: quick-freezing and freeze-drying
      followed by fixation with OsO4 vapors and embedding by direct resin infiltration.
      Specimens of frog cutaneous pectoris muscle thus prepared were analyzed for total
      calcium using electron spectroscopic imaging/electron energy loss spectroscopy
      (ESI/EELS) approach. The preservation of the ultrastructure was excellent, with
      positive K/Na ratios revealed in the fibers by x-ray microanalysis. Clear, high
      resolution EELS/ESI calcium signals were recorded from the lumen of terminal
      cisternae of the sarcoplasmic reticulum but not from longitudinal cisternae, as
      expected from previous studies carried out with different techniques. In many
      mitochondria, calcium was below detection whereas in others it was appreciable
      although at variable level. Within the motor nerve terminals, synaptic vesicles
      as well as some cisternae of the smooth endoplasmic reticulum yielded positive
      signals at variance with mitochondria, that were most often below detection.
      Taken as a whole, the present study reveals the potential of our experimental
      approach to map with high spatial resolution the total calcium within individual
      intracellular organelles identified by their established ultrastructure, but only
      where the element is present at high levels.

PMID- 8643484
TI  - The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10
      gene and CALM, encoding a new member of the AP-3 clathrin assembly protein
      family.
AB  - The translocation t(10;11)(p13;q14) is a recurring chromosomal abnormality that
      has been observed in patients with acute lymphoblastic leukemia as well as acute
      myeloid leukemia. We have recently reported that the monocytic cell line U937 has
      a t(10;11)(p13;q14) translocation. Using a combination of positional cloning and
      candidate gene approach, we cloned the breakpoint and were able to show that AF10
      is fused to a novel gene that we named CALM (Clathrin Assembly Lymphoid Myeloid
      leukemia gene) located at 11q14. AF10, a putative transcription factor, had
      recently been cloned as one of the fusion partners of MLL. CALM has a very high
      homology in its N-terminal third to the murine ap-3 gene which is one of the
      clathrin assembly proteins. The N-terminal region of ap-3 has been shown to bind
      to clathrin and to have a high-affinity binding site for phosphoinositols. The
      identification of the CALM/AF10 fusion gene in the widely used U937 cell line
      will contribute to our understanding of the malignant phenotype of this line.

PMID- 8643485
TI  - Bc1-2 protects mice against fatal alphavirus encephalitis.
AB  - Virus-induced apoptosis has been well characterized in vitro, but the role of
      apoptosis in viral pathogenesis is not well understood. The suicide of a cell in
      response to viral infection is postulated to be an important host defense for the
      organism, leading to a reduction in its total viral burden. However, virus
      induced death of nonregenerating cells in the central nervous system may be
      detrimental to the host. Therefore, to investigate the role of apoptosis in the
      pathogenesis of fatal encephalitis, we constructed a recombinant alphavirus
      chimera that expresses the antiapoptotic gene, bcl-2, in virally infected neural
      cells. Infection of neonatal mice with the alphavirus chimera expressing human
      bcl-2 [Sindbis virus (SIN)/bcl-2] resulted in a significantly lower mortality
      rate (7.5%) as compared with infection with control chimeric viruses containing a
      chloramphenicol acetyltransferase (CAT) reporter gene (SIN/CAT) (78.1%) or bcl-2
      containing a premature stop codon (SIN/bcl-2stop) (72.1%) (P < 0.001). Viral
      titers were reduced 5-fold 1 day after infection and 10-fold 6 days after
      infection in the brains of SIN/bcl-2-infected mice as compared to SIN/CAT or
      SIN/bcl-2stop-infected mice. In situ end labeling to detect apoptotic nuclei
      demonstrated a reduction in the number of foci of apoptotic cells in the brains
      of mice infected with SIN/bcl-2 as compared with SIN/bcl-2stop. The reduction in
      apoptosis was associated with a reduction in the number of foci of cells
      expressing alphavirus RNA. Thus, the antiapoptotic gene, bcl-2, suppresses viral
      replication and protects against a lethal viral disease, suggesting an
      interaction between cellular genetic control of viral replication and cell death.

PMID- 8643486
TI  - Prostaglandin H synthase 2 is expressed abnormally in human colon cancer:
      evidence for a transcriptional effect.
AB  - Evidence from epidemiological studies, clinical trials, and animal experiments
      indicates that inhibitors of prostaglandin synthesis lower the risk of colon
      cancer. We tested the hypothesis that abnormal expression of prostaglandin H
      synthase 2 (PHS-2), which can be induced by oncogenes and tumor promoters, occurs
      during colon carcinogenesis by examining its level in colon tumors. Human colon
      cancers were found to have an increased expression of PHS-2 mRNA compared with
      normal colon specimens from the same patient (n = 5). In situ hybridization
      showed that the neoplastic colonocytes had increased expression of PHS-2 (n = 4).
      Additionally, five colon cancer cell lines were shown to express high levels of
      PHS-2 mRNA even in the absence of a known inducer of PHS-2. To study the basis
      for this increased gene expression, we transfected a colon cancer cell line, HCT
      116, with a reporter gene containing 2.0 kb of the 5' regulatory sequence of the
      PHS-2 gene. Constitutive transcription of the reporter gene was observed, whereas
      normal control cell lines transcribed the reporter only in response to an
      exogenous agonist. We conclude that PHS-2 is transcribed abnormally in human
      colon cancers and that this may be one mechanism by which prostaglandins or
      related compounds that support carcinogenesis are generated.

PMID- 8643487
TI  - Predominant role of alpha 4-integrins for distinct steps of lymphoma metastasis.
AB  - To analyze the role of alpha4-integrins in lymphoma metastasis, sublines of the T
      cell lymphoma LB were generated by retrovirus-mediated gene transfer that differ
      exclusively in the expression of alpha4-integrins. Using LB-alpha4 and control LB
      NTK cells, we demonstrate that expression of alpha4-integrins strongly suppresses
      metastasis formation of LB lymphoma cells in secondary lymphoid organs such as
      spleen, mesenteric and peripheral lymph nodes, or Peyer's patches after i.v.
      injection into syngeneic BALB/c mice. Moreover, alpha4-integrin expression
      inhibited development of metastatic tumors in liver, lung, and kidney. Expansion
      of LB lymphoma cells in bone marrow was not affected by alpha4-integrin
      expression. In vivo migration assays using 51Cr-labeled lymphoma cells
      demonstrated that low-metastatic LB-alpha4 cells accumulated with the same
      efficiency as high-metastatic LB-NTK cells in all target organs examined and were
      even enriched in mucosal lymphoid organs. Collectively, these results indicate
      that alpha4-integrins inhibit metastasis formation of lymphoma cells at a stage
      subsequent to the invasion of target organs.

PMID- 8643488
TI  - Sensitivity and selectivity of the DNA damage sensor responsible for activating
      p53-dependent G1 arrest.
AB  - The tumor suppressor p53 contributes to maintaining genome stability by inducing
      a cell cycle arrest or apoptosis in response to conditions that generate DNA
      damage. Nuclear injection of linearized plasmid DNA, circular DNA with a large
      gap, or single-stranded circular phagemid is sufficient to induce a p53-dependent
      arrest. Supercoiled and nicked plasmid DNA, and circular DNA with a small gap
      were ineffective. Titration experiments indicate that the arrest mechanism in
      normal human fibroblasts can be activated by very few double strand breaks, and
      only one may be sufficient. Polymerase chain reaction assays showed that end
      joining activity is low in serum-arrested human fibroblasts, and that higher
      joining activity occurs as cells proceed through G1 or into S phase. We propose
      that the exquisite sensitivity of the p53-dependent G1 arrest is partly due to
      inefficient repair of certain types of DNA damage in early G1.

PMID- 8643489
TI  - Neuregulins with an Ig-like domain are essential for mouse myocardial and
      neuronal development.
AB  - Neuregulins are ligands for the erbB family of receptor tyrosine kinases and
      mediate growth and differentiation of neural crest, muscle, breast cancer, and
      Schwann cells. Neuregulins contain an epidermal growth factor-like domain located
      C-terminally to either an Ig-like domain or a cysteine-rich domain specific to
      the sensory and motor neuron-derived isoform. Here it is shown that elimination
      of the Ig-like domain-containing neuregulins by homologous recombination results
      in embryonic lethality associated with a deficiency of ventricular myocardial
      trabeculation and impairment of cranial ganglion development. The erbB receptors
      are expressed in myocardial cells and presumably mediate the neuregulin signal
      originating from endocardial cells. The trigeminal ganglion is reduced in size
      and lacks projections toward the brain stem and mandible. We conclude that IgL
      domain-containing neuregulins play a major role in cardiac and neuronal
      development.

PMID- 8643490
TI  - Huntingtin-associated protein (HAP1): discrete neuronal localizations in the
      brain resemble those of neuronal nitric oxide synthase.
AB  - Huntington disease stems from a mutation of the protein huntingtin and is
      characterized by selective loss of discrete neuronal populations in the brain.
      Despite a massive loss of neurons in the corpus striatum, NO-generating neurons
      are intact. We recently identified a brain-specific protein that associates with
      huntingtin and is designated huntingtin-associated protein (HAP1). We now
      describe selective neuronal localizations of HAP1. In situ hybridization studies
      reveal a resemblance of HAP1 and neuronal nitric oxide synthase (nNOS) mRNA
      localizations with dramatic enrichment of both in the pedunculopontine nuclei,
      the accessory olfactory bulb, and the supraoptic nucleus of the hypothalamus.
      Both nNOS and HAP1 are enriched in subcellular fractions containing synaptic
      vesicles. Immunocytochemical studies indicate colocalizations of HAP1 and nNOS in
      some neurons. The possible relationship of HAP1 and nNOS in the brain is
      reminiscent of the relationship of dystrophin and nNOS in skeletal muscle and
      suggests a role of NO in Huntington disease, analogous to its postulated role in
      Duchenne muscular dystrophy.

PMID- 8643491
TI  - Visualization of glucocorticoid receptor translocation and intranuclear
      organization in living cells with a green fluorescent protein chimera.
AB  - A highly fluorescent mutant form of the green fluorescent protein (GFP) has been
      fused to the rat glucocorticoid receptor (GR). When GFP-GR is expressed in living
      mouse cells, it is competent for normal transactivation of the GR-responsive
      mouse mammary tumor virus promoter. The unliganded GFP-GR resides in the
      cytoplasm and translocates to the nucleus in a hormone-dependent manner with
      ligand specificity similar to that of the native GR receptor. Due to the
      resistance of the mutant GFP to photobleaching, the translocation process can be
      studied by time-lapse video microscopy. Confocal laser scanning microscopy showed
      nuclear accumulation in a discrete series of foci, excluding nucleoli. Complete
      receptor translocation is induced with RU486 (a ligand with little agonist
      activity), although concentration into nuclear foci is not observed. This
      reproducible pattern of transactivation-competent GR reveals a previously
      undescribed intranuclear architecture of GR target sites.

PMID- 8643493
TI  - How cellular slime molds evade nematodes.
AB  - We have found a predator-prey association between the social amoeba Dictyostelium
      discoideum and the free soil living nematode Caenorhabditis elegans. C. elegans
      feeds on the amoebae and multiplies indefinitely when amoebae are the sole food
      source. In an environment created from soil, D. discoideum grows and develops,
      but not in the presence of C. elegans. During development, C. elegans feeds on
      amoebae until they aggregate and synthesize an extracellular matrix called the
      slime sheath. After the sheath forms, the aggregate and slug are protected. Adult
      nematodes ingest Dictyostelium spores, which pass through the gut of the worm
      without loss of structure and remain viable. Nematodes kill the amoebae but
      disperse the spores. The sheath that is constructed when the social amoebae
      aggregate and the spore coats of the individual cells may protect against this
      predator. Individual amoebae may also protect themselves by secreting compounds
      that repel nematodes.

PMID- 8643492
TI  - Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of
      proliferative retinopathy.
AB  - Diseases characterized by retinal neovascularization are among the principal
      causes of visual loss worldwide. The hypoxia-stimulated expression of vascular
      endothelial growth factor (VEGF) has been implicated in the proliferation of new
      blood vessels. We have investigated the use of antisense phosphorothioate
      oligodeoxynucleotides against murine VEGF to inhibit retinal neovascularization
      and VEGF synthesis in a murine model of proliferative retinopathy. Intravitreal
      injections of two different antisense phosphorothioate oligodeoxynucleotides
      prior to the onset of proliferative retinopathy reduced new blood vessel growth a
      mean of 25 and 31% compared with controls. This inhibition was dependent on the
      concentration of antisense phosphorothioate oligodeoxynucleotides and resulted in
      a 40-66% reduction in the level of VEGF protein, as determined by Western blot
      analysis. Control (sense, nonspecific) phosphorothioate oligodeoxynucleotides did
      not cause a significant reduction in retinal neovascularization or VEGF protein
      levels. These data further establish a fundamental role for VEGF expression in
      ischemia-induced proliferative retinopathies and a potential therapeutic use for
      antisense phosphorothioate oligodeoxynucleotides.

PMID- 8643494
TI  - Crystal structure of a human TATA box-binding protein/TATA element complex.
AB  - The TATA box-binding protein (TBP) is required by all three eukaryotic RNA
      polymerases for correct initiation of transcription of ribosomal, messenger,
      small nuclear, and transfer RNAs. The cocrystal structure of the C-terminal/core
      region of human TBP complexed with the TATA element of the adenovirus major late
      promoter has been determined at 1.9 angstroms resolution. Structural and
      functional analyses of the protein-DNA complex are presented, with a detailed
      comparison to our 1.9-angstroms resolution structure of Arabidopsis thaliana TBP2
      bound to the same TATA box.

PMID- 8643495
TI  - Two Arabidopsis cyclin promoters mediate distinctive transcriptional oscillation
      in synchronized tobacco BY-2 cells.
AB  - Cyclins are cell cycle regulators whose proteins oscillate dramatically during
      the cell cycle. Cyclin steady-state mRNA levels also fluctuate, and there are
      indications that both their rate of transcription and mRNA stability are under
      cell cycle control. Here, we demonstrate the transcriptional regulation of higher
      eukaryote cyclins throughout the whole cell cycle with a high temporal
      resolution. The promoters of two Arabidopsis cyclins, cyc3aAt and cyc1At,
      mediated transcriptional oscillation of the beta-glucuronidase (gus) reporter
      gene in stably transformed tobacco BY-2 cell lines. The rate of transcription
      driven by the cyc3aAt promoter was very low during G1, slowly increased during
      the S phase, peaked at the G2 phase and G2-to-M transition, and was down
      regulated before early metaphase. In contrast, the rate of the cyc1At-related
      transcription increased upon exit of the S phase, peaked at the G2-to-M
      transition and during mitosis, and decreased upon exit from the M phase. This
      study indicates that transcription mechanisms that seem to be conserved among
      species play a significant role in regulating the mRNA abundance of the plant
      cyclins. Furthermore, the transcription patterns of cyc3aAt and cyc1At were
      coherent with their slightly higher sequence similarity to the A and B groups of
      animal cyclins, respectively, suggesting that they may fulfill comparable roles
      during the cell cycle.

PMID- 8643496
TI  - Novel retinoic acid receptor ligands in Xenopus embryos.
AB  - Retinoids are a large family of natural and synthetic compounds related to
      vitamin A that have pleiotropic effects on body physiology, reproduction,
      immunity, and embryonic development. The diverse activities of retinoids are
      primarily mediated by two families of nuclear retinoic acid receptors, the RARs
      and RXRs. Retinoic acids are thought to be the only natural ligands for these
      receptors and are widely assumed to be the active principle of vitamin A.
      However, during an unbiased, bioactivity-guided fractionation of Xenopus embryos,
      we were unable to detect significant levels of all-trans or 9-cis retinoic acids.
      Instead, we found that the major bioactive retinoid in the Xenopus egg and early
      embryo is 4-oxoretinaldehyde, which is capable of binding to and transactivating
      RARs. In addition to its inherent activity, 4-oxoretinaldehyde appears to be a
      metabolic precursor of two other RAR ligands, 4-oxoretinoic acid and 4
      oxoretinol. The remarkable increase in activity of retinaldehyde and retinol as a
      consequence of 4-oxo derivatization suggests that this metabolic step could serve
      a critical regulatory function during embryogenesis.

PMID- 8643497
TI  - 4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid
      receptors.
AB  - All-trans-retinoic acid (at-RA) induces cell differentiation in a wide variety of
      cell types, including F9 embryonic teratocarcinoma cells, and can influence axial
      pattern formation during embryonic development. We now identify a novel retinoid
      synthetic pathway in differentiating F9 cells that results in the intracellular
      production of 4-oxoretinol (4-oxo-ROL) from retinol (vitamin A). Approximately 10
      15% of the total retinol in the culture is metabolized to 4-hydroxyretinol and 4
      oxo-ROL by the at-RA-treated, differentiating F9 cells over an 18-hr period, but
      no detectable metabolism of all-trans-retinol to at-RA or 9-cis-retinoic acid is
      observed in these cells. Remarkably, we show that 4-oxo-ROL can bind and activate
      transcription of the retinoic acid receptors whereas all-trans-retinol shows
      neither activity. Low doses of 4-oxo-ROL (e.g., 10(-9) or 10(-10 M) can activate
      the retinoic acid receptors even though, unlike at-RA, 4-oxo-ROL does not contain
      an acid moiety at the carbon 15 position. 4-oxo-ROL does not bind or
      transcriptionally activate the retinoid X receptors. Treatment of F9 cells with 4
      oxo-ROL induces differentiation without conversion to the acid and 4-oxo-ROL is
      active in causing axial truncation when administered to Xenopus embryos at the
      blastula stage. Thus, 4-oxo-ROL is a natural, biologically active retinoid that
      is present in differentiated F9 cells. Our data suggest that 4-oxo-ROL may be a
      novel signaling molecule and regulator of cell differentiation.

PMID- 8643498
TI  - Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of
      inflammation: possible role of cyclooxygenase-2.
AB  - Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c
      mice results in a chronic peritonitis associated with high tissue levels of
      interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2)
      synthesis causes induction of IL-6 and that expression of an inducible
      cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are
      elevated in inflammatory exudates from pristane-treated mice compared with lavage
      samples from untreated mice. The Cox-2 gene is induced in the peritoneal
      macrophage fraction isolated from the mice. A cause and effect relationship
      between increased macrophage PGE2 and IL-6 production is shown in vitro. When
      peritoneal macrophages are activated with an inflammatory stimulus (polymerized
      albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases,
      with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin
      inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but
      has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits
      catalytic activity of the cyclooxygenase but does not affect expression of the
      gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA
      synthesis, indicating that the eicosanoid stimulates IL-6 production at the level
      of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of
      indomethacin. Taken together with the earlier finding that indomethacin
      diminishes the elevation of IL-6 in pristane-treated mice, the results show that
      PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2
      gene in the regulation of this cytokine.

PMID- 8643499
TI  - Complementation analysis of mutants of nitric oxide synthase reveals that the
      active site requires two hemes.
AB  - For catalytic activity, nitric oxide synthases (NOSs) must be dimeric. Previous
      work revealed that the requirements for stable dimerization included binding of
      tetrahydrobiopterin (BH4), arginine, and heme. Here we asked what function is
      served by dimerization. We assessed the ability of individually inactive mutants
      of mouse inducible NOS (iNOS; NOS2), each deficient in binding a particular
      cofactor or cosubstrate, to complement each other by generating NO upon
      cotransfection into human epithelial cells. The ability of the mutants to
      homodimerize was gauged by gel filtration and/or PAGE under partially denaturing
      conditions, both followed by immunoblot. Their ability to heterodimerize was
      assessed by coimmunoprecipitation. Heterodimers that contained only one COOH
      terminal hemimer and only one BH4-binding site could both form and function, even
      though the NADPH-, FAD-, and FMN-binding domains (in the COOH-terminal hemimer)
      and the BH4-binding sites (in the NH2-terminal hemimer) were contributed by
      opposite chains. Heterodimers that contained only one heme-binding site (Cys-194)
      could also form, either in cis or in trans to the nucleotide-binding domains.
      However, for NO production, both chains had to bind heme. Thus, NO production by
      iNOS requires dimerization because the active site requires two hemes.

PMID- 8643500
TI  - Efficient transfer of genetic material into mammalian cells using Starburst
      polyamidoamine dendrimers.
AB  - Starburst polyamidoamine dendrimers are a new class of synthetic polymers with
      unique structural and physical characteristics. These polymers were investigated
      for the ability to bind DNA and enhance DNA transfer and expression in a variety
      of mammalian cell lines. Twenty different types of polyamidoamine dendrimers were
      synthesized, and the polymer structure was confirmed using well-defined
      analytical techniques. The efficiency of plasmid DNA transfection using
      dendrimers was examined using two reporter gene systems: firefly luciferase and
      bacterial beta-galactosidase. The transfections were performed using various
      dendrimers, and levels of expression of the reporter protein were determined.
      Highly efficient transfection of a broad range of eukaryotic cells and cell lines
      was achieved with minimal cytotoxicity using the DNA/dendrimer complexes.
      However, the ability to transfect cells was restricted to certain types of
      dendrimers and in some situations required the presence of additional compounds,
      such as DEAE-dextran, that appeared to alter the nature of the complex. A few
      cell lines demonstrated enhanced transfection with the addition of chloroquine,
      indicating endosomal localization of the complexes. The capability of a dendrimer
      to transfect cells appeared to depend on the size, shape, and number of primary
      amino groups on the surface of the polymer. However, the specific dendrimer most
      efficient in achieving transfection varied between different types of cells.
      These studies demonstrate that Starburst dendrimers can transfect a wide variety
      of cell types in vitro and offer an efficient method for producing permanently
      transfected cell lines.

PMID- 8643501
TI  - In vivo suppression of the renal Na+/Pi cotransporter by antisense
      oligonucleotides.
AB  - A 20-mer phosphorothioate oligonucleotide (AS1) was designed to hybridize to the
      message for the rat kidney sodium phosphate cotransporter NaPi-2 close to the
      translation initiation site. Single intravenous doses of this oligonucleotide
      were given to rats maintained on a low phosphorus diet to increase NaPi-2
      expression. At 3 days after oligonucleotide infusion, rats receiving 2.5 micromol
      of AS1 exhibited a reduction in renal NaPi-2 to cyclophilin mRNA ratio by 40% +/-
      17%, and rats receiving 7.5 micromol of AS1 exhibited a reduction in NaPi-2 to
      cyclophilin mRNA ratio by 46% +/- 21%. Reversed-sequence AS1 was without effect.
      The higher dose of 7.5 micromol of AS1 also reduced the rate of phosphate uptake
      into renal brush border membrane vesicles and the expression of NaPi-2 protein
      detected by Western blotting in these vesicles. Reversed sequence AS1 was again
      without effect on these parameters. These results suggest that systemically
      infused oligonucleotides can exert antisense effects in the renal proximal
      tubule.

PMID- 8643502
TI  - Using ubiquitin to follow the metabolic fate of a protein.
AB  - We describe a method that can be used to produce equimolar amounts of two or more
      specific proteins in a cell. In this approach, termed the
      ubiquitin/protein/reference (UPR) technique, a reference protein and a protein of
      interest are synthesized as a polyprotein separated by a ubiquitin moiety. This
      tripartite fusion is cleaved, cotranslationally or nearly so, by ubiquitin
      specific processing proteases after the last residue of ubiquitin, producing
      equimolar amounts of the protein of interest and the reference protein bearing a
      C-terminal ubiquitin moiety. In applications such as pulse-chase analysis, the
      UPR technique can compensate for the scatter of immunoprecipitation yields,
      sample volumes, and other sources of sample-to-sample variation. In particular,
      this method allows a direct comparison of proteins' metabolic stabilities from
      the pulse data alone. We used UPR to examine the N-end rule (a relation between
      the in vivo half-life of a protein and the identity of its N-terminal residue) in
      L cells, a mouse cell line. The increased accuracy afforded by the UPR technique
      underscores insufficiency of the current "half-life" terminology, because in vivo
      degradation of many proteins deviates from first-order kinetics. We consider this
      problem and discuss other applications of UPR.

PMID- 8643503
TI  - DNA analysis and diagnostics on oligonucleotide microchips.
AB  - We present a further development in the technology of sequencing by hybridization
      to oligonucleotide microchips (SHOM) and its application to diagnostics for
      genetic diseases. A robot has been constructed to manufacture sequencing
      "microchips." The microchip is an array of oligonucleotides immobilized into gel
      elements fixed on a glass plate. Hybridization of the microchip with
      fluorescently labeled DNA was monitored in real time simultaneously for all
      microchip elements with a two-wavelength fluorescent microscope equipped with a
      charge-coupled device camera. SHOM has been used to detect beta-thalassemia
      mutations in patients by hybridizing PCR-amplified DNA with the microchips. A
      contiguous stacking hybridization technique has been applied for the detection of
      mutations; it can simplify medical diagnostics and enhance its reliability. The
      use of multicolor monitoring of contiguous stacking hybridization is suggested
      for large-scale diagnostics and gene polymorphism studies. Other applications of
      the SHOM technology are discussed.

PMID- 8643504
TI  - Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a
      potential mechanism for its inactivation.
AB  - The neuroendocrine protein 7B2 contains two domains, a 21-kDa protein required
      for prohormone convertase 2 (PC2) maturation and a carboxyl-terminal (CT) peptide
      that inhibits PC2 at nanomolar concentrations. To determine how the inhibition of
      PC2 is terminated, we studied the metabolic fate of the 7B2 CT peptide in RinPE
      7B2, AtT-20/PC2-7B2, and alphaTC1-6 cells. Extracts obtained from cells labeled
      for 6 h with [3H]valine were subjected to immunoprecipitation using an antibody
      raised against the extreme carboxyl terminus of r7B2, and immunoprecipitated
      peptides were separated by gel filtration. All three cell lines yielded two
      distinct peaks at about 3.5 kDa and 1.5 kDa, corresponding to the CT peptide and
      a smaller fragment consistent with cleavage at an interior Lys-Lys site. These
      results were corroborated using a newly developed RIA against the carboxyl
      terminus of the CT peptide which showed that the intact CT peptide represented
      only about half of the stored CT peptide immunoreactivity, with the remainder
      present as the 1.5-kDa peptide. Both peptides could be released upon phorbol 12
      myristate 13-acetate stimulation. We investigated the possibility that PC2 itself
      could be responsible for this cleavage by performing in vitro experiments. When
      125I-labeled CT peptide was incubated with purified recombinant PC2, a smaller
      peptide was generated. Analysis of CT peptide derivatives for their inhibitory
      potency revealed that CT peptide 1-18 (containing Lys-Lys at the carboxyl
      terminus) represented a potent inhibitor, but that peptide 1-16 was inactive.
      Inclusion of carboxypeptidase E (CPE) in the reaction greatly diminished the
      inhibitory potency of the CT peptide against PC2, in line with the notion that
      the CT peptide cleavage product is not inhibitory after the removal of terminal
      lysines by CPE. In summary, our data support the idea that PC2 cleaves the 7B2 CT
      peptide at its internal Lys-Lys site within secretory granules; deactivation of
      the cleavage product is then accomplished by CPE, thus providing an efficient
      mechanism for intracellular inactivation of the CT peptide.

PMID- 8643505
TI  - Translational regulation of mammalian and Drosophila citric acid cycle enzymes
      via iron-responsive elements.
AB  - The posttranscriptional control of iron uptake, storage, and utilization by iron
      responsive elements (IREs) and iron regulatory proteins (IRPs) provides a
      molecular framework for the regulation of iron homeostasis in many animals. We
      have identified and characterized IREs in the mRNAs for two different
      mitochondrial citric acid cycle enzymes. Drosophila melanogaster IRP binds to an
      IRE in the 5' untranslated region of the mRNA encoding the iron-sulfur protein
      (Ip) subunit of succinate dehydrogenase (SDH). This interaction is
      developmentally regulated during Drosophila embryogenesis. In a cell-free
      translation system, recombinant IRP-1 imposes highly specific translational
      repression on a reporter mRNA bearing the SDH IRE, and the translation of SDH-Ip
      mRNA is iron regulated in D. melanogaster Schneider cells. In mammals, an IRE was
      identified in the 5' untranslated regions of mitochondrial aconitase mRNAs from
      two species. Recombinant IRP-1 represses aconitase synthesis with similar
      efficiency as ferritin IRE-controlled translation. The interaction between
      mammalian IRPs and the aconitase IRE is regulated by iron, nitric oxide, and
      oxidative stress (H2O2), indicating that these three signals can control the
      expression of mitochondrial aconitase mRNA. Our results identify a regulatory
      link between energy and iron metabolism in vertebrates and invertebrates, and
      suggest biological functions for the IRE/IRP regulatory system in addition to the
      maintenance of iron homeostasis.

PMID- 8643506
TI  - Expression of transduced genes in mice generated by infecting blastocysts with
      avian leukosis virus-based retroviral vectors.
AB  - Transgenic mouse lines have been developed that express the tv-a receptor under
      the control of the chicken beta-actin promoter. These mice express the tv-a
      receptor in most or all tissues and in the early embryo. An avian leukosis virus
      (ALV)-based retroviral vector system was used for the efficient delivery of genes
      into preimplantation mouse embryos from these transgenic lines. Experimental
      animals could be generated quickly and easily by infecting susceptible
      blastocysts with ALV-based retroviral vectors. Expression of the delivered genes
      was controlled by either the constitutive viral promoter contained in the long
      terminal repeat or an internal nonviral tissue-specific promoter. Mating the
      infected founder chimeric animals produced animals that carry the ALV provirus as
      a transgene. A subset of the integrated proviruses expressed the chloramphenicol
      acetyltransferase reporter gene from either the promoter in the long terminal
      repeat or an internal promoter, which we believe indicates that many of the sites
      that are accessible to viral DNA insertion in preimplantation embryos are
      incompatible with expression in older animals. This approach should prove useful
      for studies on murine cell lineage and development, providing models for studying
      oncogenesis, and testing gene therapy strategies.

PMID- 8643507
TI  - Two-dimensional protein crystallization via metal-ion coordination by naturally
      occurring surface histidines.
AB  - A powerful and potentially general approach to the targeting and crystallization
      of proteins on lipid interfaces through coordination of surface histidine
      residues to lipid-chelated divalent metal ions is presented. This approach, which
      should be applicable to the crystallization of a wide range of naturally
      occurring or engineered proteins, is illustrated here by the crystallization of
      streptavidin on a monolayer of an iminodiacetate-Cu(II) lipid spread at the air
      water interface. This method allows control of the protein orientation at
      interfaces, which is significant for the facile production of highly ordered
      protein arrays and for electron density mapping in structural analysis of two
      dimensional crystals. Binding of native streptavidin to the iminodiacetate-Cu
      lipids occurs via His-87, located on the protein surface near the biotin binding
      pocket. The two-dimensional streptavidin crystals show a previously undescribed
      microscopic shape that differs from that of crystals formed beneath biotinylated
      lipids.

PMID- 8643508
TI  - Quantitative long-term imaging of the functional representation of a whisker in
      rat barrel cortex.
AB  - In this study, we implement chronic optical imaging of intrinsic signals in rat
      barrel cortex and repeatedly quantify the functional representation of a single
      whisker over time. The success of chronic imaging for more than 1 month enabled
      an evaluation of the normal dynamic range of this sensory representation. In
      individual animals for a period of several weeks, we found that: (i) the average
      spatial extent of the quantified functional representation of whisker C2 is
      surprisingly large--1.71 mm2 (area at half-height); (ii) the location of the
      functional representation is consistent; and (iii) there are ongoing but
      nonsystematic changes in spatiotemporal characteristics such as the size, shape,
      and response amplitude of the functional representation. These results support a
      modified description of the functional organization of barrel cortex, where
      although a precisely located module corresponds to a specific whisker, this
      module is dynamic, large, and overlaps considerably with the modules of many
      other whiskers.

PMID- 8643509
TI  - GRIP1, a novel mouse protein that serves as a transcriptional coactivator in
      yeast for the hormone binding domains of steroid receptors.
AB  - The yeast two-hybrid system was used to isolate a clone from a 17-day-old mouse
      embryo cDNA library that codes for a novel 812-aa long protein fragment,
      glucocorticoid receptor-interacting protein 1 (GRIP1), that can interact with the
      hormone binding domain (HBD) of the glucocorticoid receptor. In the yeast two
      hybrid system and in vitro, GRIP1 interacted with the HBDs of the glucocorticoid,
      estrogen, and androgen receptors in a hormone-regulated manner. When fused to the
      DNA binding domain of a heterologous protein, the GRIP1 fragment activated a
      reporter gene containing a suitable enhancer site in yeast cells and in mammalian
      cells, indicating that GRIP1 contains a transcriptional activation domain.
      Overexpression of the GRIP1 fragment in mammalian cells interfered with hormone
      regulated expression of mouse mammary tumor virus-chloramphenicol
      acetyltransferase gene and constitutive expression of cytomegalovirus-beta
      galactosidase reporter gene, but not constitutive expression from a tRNA gene
      promoter. This selective squelching activity suggests that GRIM can interact with
      an essential component of the RNA polymerase II transcription machinery. Finally,
      while a steroid receptor HBD fused with a GAL4 DNA binding domain did not, by
      itself, activate transcription of a reporter gene in yeast, coexpression of this
      fusion protein with GRIP1 strongly activated the reporter gene. Thus, in yeast,
      GRIP1 can serve as a coactivator, potentiating the transactivation functions in
      steroid receptor HBDs, possibly by acting as a bridge between HBDs of the
      receptors and the basal transcription machinery.

PMID- 8643510
TI  - Role of the regulatory subunit of bovine pyruvate dehydrogenase phosphatase.
AB  - Bovine pyruvate dehydrogenase phosphatase (PDP) is a Mg2+-dependent and Ca2+
      stimulated heterodimer that is a member of the protein phosphatase 2C family and
      is localized to mitochondria. Insight into the function of the regulatory subunit
      of PDP (PDPr) has been gained. It decreases the sensitivity of the catalytic
      subunit of PDP (PDPc) to Mg2+. The apparent Km of PDPc for Mg2+ is increased
      about 5-fold, from about 0.35 mM to 1.6 mM. The polyamine spermine increases the
      sensitivity of PDP but not PDPc to Mg2+, apparently by interacting with PDPr.
      PDPc but not PDP can use the phosphopeptide RRAT(P)VA as a substrate. These
      observations are interpreted to indicate that PDPr blocks or distorts the active
      site of PDPc and that spermine produces a conformational change in PDPr that
      reverses its inhibitory effect. These findings suggest that PDPr may be involved
      in the insulin-induced activation of the mitochondrial PDP in adipose tissue,
      which is characterized by a decrease in its apparent Km for Mg2+.

PMID- 8643512
TI  - Electrical microstimulation suggests two different forms of representation of
      head-centered space in the intraparietal sulcus of rhesus monkeys.
AB  - We examined the effects of eye position on saccades evoked by electrical
      stimulation of the intraparietal sulcus (IPS) of rhesus monkeys. Microstimulation
      evoked saccades from sites on the posterior bank, floor, and the medial bank of
      the IPS. The size and direction of the eye movements varied as a function of
      initial eye position before microstimulation. At many stimulation sites, eye
      position affected primarily the amplitude and not the direction of the evoked
      saccades. These "modified vector saccades" were characteristic of most
      stimulation-sensitive zones in the IPS, with the exception of a narrow strip
      located mainly on the floor of the sulcus. Stimulation in this "intercalated
      zone" evoked saccades that moved the eyes into a particular region in head
      centered space, independent of the starting position of the eyes. This latter
      response is compatible with the stimulation site representing a goal zone in head
      centered coordinates. On the other hand, the modified vector saccades observed
      outside the intercalated zone are indicative of a more distributed representation
      of head-centered space. A convergent projection from many modified vector sites
      onto each intercalated site may be a basis for a transition from a distributed to
      a more explicit representation of space in head-centered coordinates.

PMID- 8643511
TI  - Hemodynamic effects of epidermal growth factor in conscious rats and monkeys.
AB  - The therapeutic application of growth factors to human disease has become closer
      to reality with the advent of faster means of synthesizing these molecules and
      novel drug delivery strategies. Epidermal growth factor (EGF) belongs to a large
      family of molecules with the ability to modulate growth. Purified extracts of EGF
      have been used clinically to modulate gastrointestinal secretion of hormones and
      accelerate healing. EGF is also reported to have both vascular smooth muscle
      contractile and relaxing activity Cardiovascular studies were performed with the
      bioactive 48-amino acid fragment of human EGF in rodents and primates to
      determine the effects of EGF on blood pressure and heart rate in conscious
      animals. Intravenous infusion of EGF induced an initial pressor response in rats
      followed by a prolonged decrease in blood pressure. In contrast, in monkeys, EGF
      had dose-related blood pressure-lowering effects only; significant hypotension
      was observed at doses ranging from 3 to 300 microg/kg i.v. Hypotension was
      associated with modest tachycardia in both species. To our knowledge, this is the
      first report of hemodynamic effects of EGF in primates, and it clearly documents
      that the mitogenic role of growth factors such as EGF is but one aspect of their
      physiology.

PMID- 8643513
TI  - An AML-1 consensus sequence binds an osteoblast-specific complex and
      transcriptionally activates the osteocalcin gene.
AB  - Tissue and cell-type specific expression of the rat osteocalcin (rOC) gene
      involves the interplay of multiple transcriptional regulatory factors. In this
      report we demonstrate that AML-1 (acute myeloid leukemia-1), a DNA-binding
      protein whose genes are disrupted by chromosomal translocations in several human
      leukemias, interacts with a sequence essential for enhancing tissue-restricted
      expression of the rOC gene. Deletion analysis of rOC promoter-chloramphenicol
      acetyltransferase constructs demonstrates that an AML-1-binding sequence within
      the proximal promoter (-138 to -130 nt) contributes to 75% of the level of
      osteocalcin gene expression. The activation potential of the AML-1-binding
      sequence has been established by overexpressing AML-1 in osteoblastic as well as
      in nonosseous cell lines. Overexpression not only enhances rOC promoter activity
      in osteoblasts but also mediates OC promoter activity in a nonosseous human
      fibroblastic cell line. A probe containing this site forms a sequence specific
      protein-DNA complex with nuclear extracts from osteoblastic cells but not from
      nonosseous cells. Antisera supershift experiments indicate the presence of AML-1
      and its partner protein core-binding factor beta in this osteoblast-restricted
      complex. Mutations of the critical AML-1-binding nucleotides abrogate formation
      of the complex and strongly diminish promoter activity. These results indicate
      that an AML-1 related protein is functional in cells of the osteoblastic lineage
      and that the AML-1-binding site is a regulatory element important for osteoblast
      specific transcriptional activation of the rOC gene.

PMID- 8643514
TI  - Cloning and expression of apoptosis inhibitory protein homologs that function to
      inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.
AB  - Baculovirus inhibitors of apoptosis (IAPs) act in insect cells to prevent cell
      death. Here we describe three mammalian homologs of IAP, MIHA, MIHB, and MIHC,
      and a Drosophila IAP homolog, DIHA. Each protein bears three baculovirus IAP
      repeats and an N-terminal ring finger motif. Apoptosis mediated by interleukin
      1beta converting enzyme (ICE), which can be inhibited by Orgyia pseudotsugata
      nuclear polyhedrosis virus IAP (OpIAP) and cowpox virus crmA, was also inhibited
      by MIHA and MIHB. As MIHB and MIHC were able to bind to the tumor necrosis factor
      receptor-associated factors TRAF1 and TRAF2 in yeast two-hybrid assays, these
      results suggest that IAP proteins that inhibit apoptosis may do so by regulating
      signals required for activation of ICE-like proteases.

PMID- 8643516
TI  - How optimization of potential functions affects protein folding.
AB  - The relationship between the optimization of the potential function and the
      foldability of theoretical protein models is studied based on investigations of a
      27-mer cubic-lattice protein model and a more realistic lattice model for the
      protein crambin. In both the simple and the more complicated systems,
      optimization of the energy parameters achieves significant improvements in the
      statistical-mechanical characteristics of the systems and leads to foldable
      protein models in simulation experiments. The foldability of the protein models
      is characterized by their statistical-mechanical properties--e.g., by the density
      of states and by Monte Carlo folding simulations of the models. With optimized
      energy parameters, a high level of consistency exists among different
      interactions in the native structures of the protein models, as revealed by a
      correlation function between the optimized energy parameters and the native
      structure of the model proteins. The results of this work are relevant to the
      design of a general potential function for folding proteins by theoretical
      simulations.

PMID- 8643515
TI  - Exchanges are not equally able to enhance meiotic chromosome segregation in
      yeast.
AB  - Homologous chromosomes pair, and then migrate to opposite poles of the spindle at
      meiosis I. In most eukaryotic organisms, reciprocal recombinations (crossovers)
      between the homologs are critical to the success of this process. Individuals
      with defects in meiotic recombination typically produce high levels of aneuploid
      gametes and exhibit low fertility or are sterile. The experiments described here
      were designed to test whether different crossovers are equally able to contribute
      to the fidelity of meiotic chromosome segregation in yeast. These experiments
      were performed with model chromosomes with which it was possible to control and
      measure the distributions of meiotic crossovers in wild-type cells. Physical and
      genetic approaches were used to map crossover positions on model chromosomes and
      to correlate crossover position with meiotic segregation behavior. The results
      show that crossovers at different chromosomal positions have different abilities
      to enhance the fidelity of meiotic segregation.

PMID- 8643517
TI  - Induction of alloantigen-specific tolerance by B cells from CD40-deficient mice.
AB  - Interaction between CD40 on B cells and CD40 ligand molecules on T cells is
      pivotal for the generation of a thymus-dependent antibody response. Here we show
      that B cells deficient in CD40 expression are unable to elicit the proliferation
      of allogeneic T cells in vitro. More importantly, mice immunized with CD40-/- B
      cells become tolerant to allogeneic major histocompatibility complex (MHC)
      antigens as measured by a mixed lymphocyte reaction and cytotoxic T-cell assay.
      The failure of CD40-/- B cells to serve as antigen presenting cells in vitro was
      corrected by the addition of anti-CD28 mAb. Moreover, lipopolysaccharide
      stimulation, which upregulates B7 expression, reversed the inability of CD40-/- B
      cells to stimulate an alloresponse in vitro and abrogated the capacity of these B
      cells to induce tolerance in vivo. These results suggest that CD40 engagement by
      CD40 ligand expressed on antigen-activated T cells is critical for the
      upregulation of B7 molecules on antigen-presenting B cells that subsequently
      deliver the costimulatory signals necessary for T-cell proliferation and
      differentiation. Our experiments suggest a novel strategy for the induction of
      antigen-specific tolerance in vivo.

PMID- 8643518
TI  - Escherichia coli exhibits negative chemotaxis in gradients of hydrogen peroxide,
      hypochlorite, and N-chlorotaurine: products of the respiratory burst of
      phagocytic cells.
AB  - Escherichia coli can respond to gradients of specific compounds, moving up
      gradients of attractants and down gradients of repellents. Stimulated phagocytic
      leukocytes produce H2O2, OCl-, and N-chlorotaurine in a response termed the
      respiratory burst. E. coli is actively repelled by these compounds. Catalase in
      the suspending medium eliminated the effect of H2O2. Repulsion by H2O2 could be
      demonstrated with 1 microM H2O2, which is far below the level that caused overt
      toxicity. Strains with defects in the biosynthesis of glutathione or lacking
      hydroperoxidases I and II retained this response to H2O2, and 2.0 mM CN- did not
      interfere with it. Mutants with defects in any one of the four known methyl
      accepting chemotaxis proteins also retained the ability to respond to H2O2, but a
      "gutted" mutant that was deleted for all four methyl-accepting chemotaxis
      proteins, as well as for CheA, CheW, CheR, CheB, CheY, and CheZ, did not respond
      to H2O2. Hypochlorite and N-chlorotaurine were also strongly repellent.
      Chemotaxis down gradients of H2O2, OCl-, and N-chlorotaurine may contribute to
      the survival of commensal or pathogenic microorganisms.

PMID- 8643519
TI  - Mutagenesis and gene identification in Dictyostelium by shotgun antisense.
AB  - We have developed a mutagenesis technique that uses antisense cDNA to identify
      genes required for development in Dictyostelium discoideum. We transformed
      Dictyostelium cells with a cDNA library made from the mRNA of vegetative and
      developing cells. The cDNA was cloned in an antisense orientation immediately
      downstream of a vegetative promoter, so that in transformed cells the promoter
      will drive the synthesis of an antisense RNA transcript. We find that individual
      transformants typically contain one or occasionally two antisense cDNAs. Using
      this mutagenesis technique, we have generated mutants that fail to aggregate,
      aggregate but fail to form fruiting bodies, or aggregate but form abnormal
      fruiting bodies. The individual cDNA molecules from the mutants were identified
      and cloned using PCR. Initial sequence analysis of the PCR products from 35
      mutants has identified six novel Dictyostelium genes, each from a transformant
      with one antisense cDNA. When the PCR-isolated antisense cDNAs were ligated into
      the antisense vector and the resulting constructs transformed into cells, the
      phenotypes of the transformed cells matched those of the original mutants from
      which each cDNA was obtained. We made homologous recombinant gene disruption
      transformants for three of the novel genes, in each case generating mutants with
      phenotypes indistinguishable from those of the original antisense transformants.
      Shotgun antisense thus is a rapid way to identify genes in Dictyostelium and
      possibly other organisms.

PMID- 8643520
TI  - Identification of functional domains and evolution of Tc1-like transposable
      elements.
AB  - Tc1-like transposable elements from teleost fish have been phylogenetically
      examined to determine the mechanisms involved in their evolution and conserved
      domains of function. We identified two new functional domains in these elements.
      The first is a bipartite nuclear localization signal, indicating that transposons
      can take advantage of the transport machinery of host cells for nuclear uptake of
      their transposases. The second is a novel combination of a paired domain-related
      protein motif juxtaposed to a leucine zipper-like domain located in the putative
      DNA-binding regions of the transposases. This domain coexists with a special
      inverted repeat structure in certain transposons in such phylogenetically distant
      hosts as fish and insects. Our data indicate that reassortment of functional
      domains and horizontal transmission between species are involved in the formation
      and spread of new types of transposable elements.

PMID- 8643521
TI  - Functional complementation of xeroderma pigmentosum complementation group E by
      replication protein A in an in vitro system.
AB  - Xeroderma pigmentosum (XP) is caused by a defect in nucleotide excision repair.
      Patients in the complementation group E (XP-E) have the mildest form of the
      disease and the highest level of residual repair activity. About 20% of the cell
      strains derived from XP-E patients lack a damaged DNA-binding protein (DDB)
      activity that binds to ultraviolet-induced (6-4) photoproducts with high
      affinity. We report here that cell-free extracts prepared from XP-E cell strains
      that either lacked or contained DDB activity were severely defective in excising
      DNA damage including (6-4) photoproducts. However, this excision activity defect
      was not restored by addition of purified DDB that, in fact, inhibited removal of
      (6-4) photoproducts by the human excision nuclease reconstituted from purified
      proteins. Extensive purification of correcting activity from HeLa cells revealed
      that the correcting activity is inseparable from the human replication/repair
      protein A [RPA (also known as human single stranded DNA binding protein, HSSB)].
      Indeed, supplementing XP-E extracts with recombinant human RPA purified from
      Escherichia coli restored excision activity. However, no mutation was found in
      the genes encoding the three subunits of RPA in an XP-E (DDB-) cell line. It is
      concluded that RPA functionally complements XP-E extracts in vitro, but it is not
      genetically altered in XP-E patients.

PMID- 8643522
TI  - Epitope-specific tolerance induction with an engineered immunoglobulin.
AB  - Isologous and heterologous immunoglobulins have been shown to be extremely
      effective as tolerogenic carriers for nearly 30 years. The efficacy of these
      proteins is due in part to their long half-life in vivo, as well as their ability
      to crosslink surface IgM with Fc receptors. The concept of using IgG as a carrier
      molecule to induce unresponsiveness in the adult immune system has been exploited
      for simple haptens, such as nucleosides, as well as for peptides. To further
      evaluate the in vivo potential of these molecules for inducing tolerance to a
      defined epitope, we have engineered a fusion protein of mouse IgG1 with the
      immunodominant epitope 12-26 from bacteriophage lambda cI repressor protein. This
      15-mer, which contains both a B-cell and T-cell epitope, has been fused in-frame
      to the N terminus of a mouse heavy chain IgG1 construct, thus creating a "genetic
      hapten-carrier" system. We describe a novel in vitro and in vivo experimental
      system for studying the feasibility of engineered tolerogens, consisting of a
      recombinant flagellin challenge antigen and a murine IgG1 tolerogen, both
      expressing the lambda repressor epitope 12-26. Herein, we show that peptide
      grafted IgG molecules injected i.v., or expressed by transfected, autologous B
      cells, can efficiently modulate the cellular and humoral immune responses to
      immunodominant epitopes. This model displays the feasibility of "tailor
      designing" immune responses to whole antigens by selecting epitopes for either
      tolerance or immunity.

PMID- 8643523
TI  - Loss of tramtrack gene activity results in ectopic R7 cell formation, even in a
      sina mutant background.
AB  - We have screened a collection of transposable-element-induced mutations for those
      which dominantly modify the extra R7 phenotype of a hypomorphic yan mutation. The
      members of one of the identified complementation groups correspond to disruptions
      of the tramtrack (ttk) gene. As heterozygotes, ttk alleles increase the
      percentage of R7 cells in yan mutant eyes. Just as yan mutations increase ectopic
      R7 cell formation, homozygous ttk mutant eye clones also contain supernumerary R7
      cells. However, in contrast to yan, the formation of these cells in ttk mutant
      eye tissue is not necessarily dependent on the activity of the sina gene.
      Furthermore, although yan mutations dominantly interact with mutations in the
      Ras1, Draf, Dsor1, and rolled (rl) genes to influence R7 cell development, ttk
      mutations only interact with yan and rl gene mutations to affect this signaling
      pathway. Our data suggest that yan and ttk both function to repress inappropriate
      R7 cell development but that their mechanisms of action differ. In particular,
      TTK activity appears to be autonomously required to regulate a sina-independent
      mechanism of R7 determination.

PMID- 8643524
TI  - Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene,
      sod2, in Saccharomyces cerevisiae.
AB  - In the fission yeast, Schizosaccharomyces pombe, tolerance to high sodium and
      lithium concentrations requires the functioning of the sod2, Na+/H+ antiporter.
      We have directly measured the activity of this antiporter and demonstrated
      reconstitution of the activity in gene deletion strains. In addition, we have
      shown that it can be transferred to, and its antiporter activity detected in, the
      budding yeast, Saccharomyces cerevisiae, where it also confers sodium and lithium
      tolerance. Proton flux through the S. pombe Na+/H+ antiporter was directly
      measured using microphysiometry. The direction of transmembrane proton flux
      mediated by this antiporter was reversible, with protons being imported or
      exported in response to the external concentration of sodium. This bidirectional
      activity was also detected in S. cerevisiae strains expressing sod2 and
      expression of this gene complemented the sodium and lithium sensitivity resulting
      from inactivation of the ENA1/PMR2 encoded Na+-exporting ATPases. This suggests
      that antiporters or sodium pumps can be utilized interchangeably by S. cerevisiae
      to regulate internal sodium concentration. Potent inhibitors of mammalian Na+/H+
      exchangers were found to have no effect on sod2 activity. The proton flux
      mediated by sod2 was also found to be unaffected by perturbation of membrane
      potential or the plasma membrane proton gradient.

PMID- 8643525
TI  - Expansion of polyglutamine repeat in huntingtin leads to abnormal protein
      interactions involving calmodulin.
AB  - Huntington's disease (HD) is an inherited neurodegenerative disorder associated
      with expansion of a CAG repeat in the IT15 gene. The IT15 gene is translated to a
      protein product termed huntingtin that contains a polyglutamine (polyGln) tract.
      Recent investigations indicate that the cause of HD is expansion of the polyGln
      tract. However, the function of huntingtin and how the expanded polyGln tract
      causes HD is not known. We investigate potential protein-protein interactions of
      huntingtin using affinity resins. Huntingtin from brain extracts is retained on
      calmodulin(CAM)-Sepharose in a calcium-dependent fashion. We purify rat
      huntingtin to apparent homogeneity using a combination of DEAE-cellulose column
      chromatography, ammonium sulfate precipitation, and preparative SDS/PAGE.
      Purified rat huntingtin does not interact with CAM directly as revealed by 125I
      CAM overlay. Huntingtin forms a large CAM-containing complex of over 1,000 kDa in
      the presence of calcium, which partially disassociates in the absence of calcium.
      Furthermore, an increased amount of mutant huntingtin from HD patient brains is
      retained on CAM-Sepharose compared to normal huntingtin from control patient
      brains, and the mutant allele is preferentially retained on CAM-Sepharose in the
      absence of calcium. These results suggest that huntingtin interacts with other
      proteins including CAM and that the expansion of polyGln alters this interaction.

PMID- 8643526
TI  - Exploring the active site of chorismate mutase by combinatorial mutagenesis and
      selection: the importance of electrostatic catalysis.
AB  - Chorismate mutase (EC 5.4.99.5) catalyzes the intramolecular rearrangement of
      chorismate to prephenate. Arg-90 in the active site of the enzyme from Bacillus
      subtilis is in close proximity to the substrate's ether oxygen and may contribute
      to efficient catalysis by stabilizing the presumed dipolar transition state that
      would result upon scission of the C--O bond. To test this idea, we have developed
      a novel complementation system for chorismate mutase activity in Escherichia coli
      by reengineering parts of the aromatic amino acid biosynthetic pathway. The codon
      for Arg-90 was randomized, alone and in combination with that for Cys-88, and
      active clones were selected. The results show that a positively charged residue
      either at position 88 (Lys) or 90 (Arg or Lys) is essential. Our data provide
      strong support for the hypothesis that the positive charge is required for
      stabilization of the transition state of the enzymatic chorismate rearrangement.
      The new selection system, in conjunction with combinatorial mutagenesis, renders
      the mechanism of the natural enzyme(s) accessible to further exploration and
      opens avenues for the improvement of first generation catalytic antibodies with
      chorismate mutase activity.

PMID- 8643527
TI  - Low ethanol concentrations enhance GABAergic inhibitory postsynaptic potentials
      in hippocampal pyramidal neurons only after block of GABAB receptors.
AB  - Despite considerable evidence that ethanol can enhance chloride flux through the
      gamma-aminobutyric acid type A (GABA/A/) receptor-channel complex in several
      central neuron types, the effect of ethanol on hippocampal GABAergic systems is
      still controversial. Therefore, we have reevaluated this interaction in
      hippocampal pyramidal neurons subjected to local monosynaptic activation combined
      with pharmacological isolation of the various components of excitatory and
      inhibitory synaptic potentials, using intracellular current- and voltage-clamp
      recording methods in the hippocampal slice. In accord with our previous findings,
      we found that ethanol had little effect on compound inhibitory postsynaptic
      potentials/currents (IPSP/Cs) containing both GABA/A/ and GABA/B/ components.
      However, after selective pharmacological blockade of the GABA/B/ component of the
      IPSP (GABA/B/-IPSP/C) by CGP-35348, low concentrations of ethanol (22-66 mM)
      markedly enhanced the peak amplitude, and especially the area, of the GABA/A/
      component (GABA/A/-IPSP/C) in most CA1 pyramidal neurons. Ethanol had no
      significant effect on the peak amplitude or area of the pharmacologically
      isolated GABA/B/-inhibitory postsynaptic current (IPSC). These results provide
      new data showing that activation of GABAB receptors can obscure ethanol
      enhancement of GABA/A/ receptor function in hippocampus and suggest that similar
      methods of pharmacological isolation might be applied to other brain regions
      showing negative or mixed ethanol-GABA interactions.

PMID- 8643528
TI  - Two different but related mechanisms are used in plants for the repair of genomic
      double-strand breaks by homologous recombination.
AB  - Genomic double-strand breaks (DSBs) are key intermediates in recombination
      reactions of living organisms. We studied the repair of genomic DSBs by
      homologous sequences in plants. Tobacco plants containing a site for the highly
      specific restriction enzyme I-Sce I were cotransformed with Agrobacterium strains
      carrying sequences homologous to the transgene locus and, separately, containing
      the gene coding for the enzyme. We show that the induction of a DSB can increase
      the frequency of homologous recombination at a specific locus by up to two orders
      of magnitude. Analysis of the recombination products demonstrates that a DSB can
      be repaired via homologous recombination by at least two different but related
      pathways. In the major pathway, homologies on both sides of the DSB are used,
      analogous to the conservative DSB repair model originally proposed for meiotic
      recombination in yeast. Homologous recombination of the minor pathway is
      restricted to one side of the DSB as described by the nonconservative one-sided
      invasion model. The sequence of the recombination partners was absolutely
      conserved in two cases, whereas in a third case, a deletion of 14 bp had
      occurred, probably due to DNA polymerase slippage during the copy process. The
      induction of DSB breaks to enhance homologous recombination can be applied for a
      variety of approaches of plant genome manipulation.

PMID- 8643529
TI  - A synthetic random basic copolymer with promiscuous binding to class II major
      histocompatibility complex molecules inhibits T-cell proliferative responses to
      major and minor histocompatibility antigens in vitro and confers the capacity to
      prevent murine graft-versus-host disease in vivo.
AB  - Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted
      donor T cells recognizing host alloantigens. Data presented in this report show,
      to our knowledge, for the first time that a synthetic copolymer of the amino
      acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000
      8500) [corrected], termed GLAT, with promiscuous binding to multiple major
      histocompatibility complex class II alleles is capable of preventing lethal GVHD
      in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility
      barriers. Administration of GLAT over a limited time after transplant
      significantly reduced the incidence, onset, and severity of disease. GLAT also
      improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice
      survived > 140 days after transplant compared to 2/26 of saline-treated or to
      1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors
      were documented to be fully chimeric by PCR analysis of a polymorphic
      microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the
      mixed lymphocyte culture in a dose-dependent fashion across a variety of major
      barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched
      T cells to syngeneic antigen-presenting cells presenting minor histocompatibility
      antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the
      proliferative response, suggesting that GLAT inhibits antigen presentation.

PMID- 8643530
TI  - Spatial localization of calcium channels in giant fiber lobe neurons of the squid
      (Loligo opalescens).
AB  - Whole-cell voltage clamp was used to investigate the properties and spatial
      distribution of fast-deactivating (FD) Ca channels in squid giant fiber lobe
      (GFL) neurons. Squid FD Ca channels are reversibly blocked by the spider toxin
      omega-Agatoxin IVA with an IC50 of 240-420 nM with no effect on the kinetics of
      Ca channel gating. Channels with very similar properties are expressed in both
      somatic and axonal domains of cultured GFL neurons, but FD Ca channel conductance
      density is higher in axonal bulbs than in cell bodies at all times in culture.
      Channels presumably synthesized during culture are preferentially expressed in
      the growing bulbs, but bulbar Ca conductance density remains constant while Na
      conductance density increases, suggesting that processes determining the
      densities of Ca and Na channels in this extrasomatic domain are largely
      independent. These observations suggest that growing axonal bulbs in cultured GFL
      neurons are not composed entirely of "axonal" membranes because FD Ca channels
      are absent from the giant axon in situ but, rather, suggest a potential role for
      FD Ca channels in mediating neurotransmitter release at the motor terminals of
      the giant axon.

PMID- 8643531
TI  - Glucocorticoid and progestin receptors are differently involved in the
      cooperation with a structural element of the mouse mammary tumor virus promoter.
AB  - We have previously characterized a regulatory element located between -294 and 
      200 within the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). This
      element termed AA element cooperates with the glucocorticoid response elements
      (GREs) for glucocorticoid activation. Here we show that in a MMTV LTR wild type
      context, the deletion of this element significantly reduces both glucocorticoid
      and progestin activation of the promoter. Deletion of the two most distal GREs
      forces the glucocorticoid receptor (GR) and the progestin receptor (PR) to bind
      the same response elements and results in a dramatic decrease in the inducibility
      of the MMTV promoter by the two hormones. The simultaneous deletion of the two
      distal GREs and of the AA element abolishes completely the glucocorticoid-induced
      activation of the promoter. In contrast it restores a significant level of
      progestin-induced activation. This different effect of the double deletion on
      glucocorticoid- and progestin-induced MMTV promoter activation is not cell
      specific because it is also observed, and is even stronger, when either GR or PR
      is expressed in the same cell line (NIH 3T3). This is the first description of a
      mutated MMTV promoter that, although retaining GREs, is activated by progestins
      and not by glucocorticoids. This suggests a different functional cooperation
      between protein(s) interacting with the AA element and GR or PR. Cotransfections
      with constructs containing wild-type or mutated MMTV LTR with either PR lacking
      its C-terminal domain or GR/PR chimeras in which the N-terminal domains have been
      exchanged demonstrate that the N-terminal domains of the receptors specify the
      different behavior of GR and PR regarding the AA element.

PMID- 8643532
TI  - The impact of interindividual variation in NAT2 activity on benzidine urinary
      metabolites and urothelial DNA adducts in exposed workers.
AB  - Several epidemiologic studies indicate that NAT2-related slow N-acetylation
      increases bladder cancer risk among workers exposed to aromatic amines,
      presumably because N-acetylation is important for the detoxification of these
      compounds. Previously, we showed that NAT2 polymorphisms did not influence
      bladder cancer risk among Chinese workers exposed exclusively to benzidine (BZ),
      suggesting that NAT2 N-acetylation is not a critical detoxifying pathway for this
      aromatic amine. To evaluate the biologic plausibility of this finding, we carried
      out a cross-sectional study of 33 workers exposed to BZ and 15 unexposed controls
      in Ahmedabad, India, to evaluate the presence of BZ-related DNA adducts in
      exfoliated urothelial cells, the excretion pattern of BZ metabolites, and the
      impact of NAT2 activity on these outcomes. Four DNA adducts were significantly
      elevated in exposed workers compared to controls; of these, the predominant
      adduct cochromatographed with a synthetic N-(3'- phosphodeoxyguanosin-8-yl)-N'
      acetylbenzidine standard and was the only adduct that was significantly
      associated with total BZ urinary metabolites (r = 0.68, P < 0.0001). To our
      knowledge this is the first report to show that BZ forms DNA adducts in
      exfoliated urothelial cells of exposed humans and that the predominant adduct
      formed is N-acetylated, supporting the concept that monofunctional acetylation is
      an activation, rather than a detoxification, step for BZ. However, because almost
      all BZ-related metabolites measured in the urine of exposed workers were
      acetylated among slow, as well as rapid, acetylators (mean +/- SD 95 +/- 1.9% vs.
      97 +/- 1.6%, respectively) and NAT2 activity did not affect the levels of any DNA
      adduct measured, it is unlikely that interindividual variation in NAT2 function
      is relevant for BZ-associated bladder carcinogenesis.

PMID- 8643533
TI  - An increased risk of Crohn's disease in individuals who inherit the HLA class II
      DRB3*0301 allele.
AB  - The role of inflammatory T cells in Crohn's disease suggests that inherited
      variations in major histocompatibility complex (MHC) class II genes may be of
      pathogenetic importance in inflammatory bowel disease. The absence of consistent
      and strong associations with MHC class II genes in Caucasian patients with
      inflammatory bowel disease probably reflects the use of less precise typing
      approaches and the failure to type certain loci by any means. A PCR-sequence
      specific oligonucleotide-based approach was used to type individual alleles of
      the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative
      colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls.
      Detailed molecular typing of the above alleles has previously not been reported
      in patients with inflammatory bowel disease. A highly significant positive
      association with the HLA-DRB3*0301 allele was observed in patients with Crohn's
      disease (P = 0.0004) but not in patients with ulcerative colitis. The relative
      risk for this association was 7.04. Other less significant HLA class II
      associations were also noted in patients with Crohn's disease. One of these
      associations involved the HLA-DRB1*1302 allele, which is known to be in linkage
      disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an
      infrequently typed HLA class II locus is strongly associated with Crohn's disease
      and that MHC class II molecules may be important in its pathogenesis.

PMID- 8643534
TI  - Ozone-induced responses in Arabidopsis thaliana: the role of salicylic acid in
      the accumulation of defense-related transcripts and induced resistance.
AB  - Exposure of Arabidopsis thaliana to ozone results in the expression of a number
      of defense-related genes that are also induced during a hypersensitive response.
      A potential common link between the activation of defense gene expression during
      a hypersensitive response and by ozone treatment is the production of active
      oxygen species and the accumulation of hydrogen peroxide. Here we report that
      salicylic acid accumulation, which can be induced by hydrogen peroxide and is
      required for the expression of both a hypersensitive response and systemic
      acquired resistance, is also required for the induction of some, but not all,
      ozone-induced mRNAs examined. In addition, we show that ozone exposure triggers
      induced resistance of A. thaliana to infection with virulent phytopathogenic
      Pseudomonas syringae strains. Infection of transgenic plants expressing
      salicylate hydroxylase, which prevents the accumulation of salicylic acid, or
      npr1 mutant plants, which are defective in the expression of systemic acquired
      resistance at a step downstream of salicylic acid, demonstrated that the
      signaling pathway activated during ozone-induced resistance overlaps with the
      systemic acquired resistance activation pathway and is salicylic acid dependent.
      Interestingly, plants expressing salicylate hydroxylase exhibited increased
      sensitivity to ozone exposure. These results demonstrate that ozone activates at
      least two distinct signaling pathways, including a salicylic acid dependent
      pathway previously shown to be associated with the activation of pathogen defense
      reactions, and that this latter pathway also induces a protective response to
      ozone.

PMID- 8643535
TI  - A yeast manganese transporter related to the macrophage protein involved in
      conferring resistance to mycobacteria.
AB  - A novel Saccharomyces cerevisiae mutant, unable to grow in the presence of 12.5
      mM EGTA, was isolated by replica plating. The phenotype of the mutant is caused
      by a single amino acid change (Gly149 to Arg) in the essential yeast gene CDC1.
      The mutant could be suppressed by overexpression of the SMF1 gene, which was
      isolated as an extragenic high-copy suppressor. The SMF1 gene codes for a highly
      hydrophobic protein and its deletion renders the yeast cells sensitive to low
      manganese concentration. In accordance with this observation, the smf1 null
      mutant exhibits reduced Mn2+ uptake at micromolar concentrations. Using a
      specific antibody, we demonstrated that Smf1p is located in the yeast plasma
      membrane. These results suggest that Smf1p is involved in high-affinity Mn2+
      uptake. This assumption was also tested by overexpressing the SMF1 gene in the
      temperature-sensitive mutant of the mitochondrial processing peptidase (MAS1).
      SMF1 overexpression as well as addition of 1 mM Mn2+ to the growth medium
      complemented this mutation. This also suggests that in vivo Mas1p is a manganese
      dependent peptidase. The yeast Smf1p resembles a protein from Drosophila and
      mammalian macrophages. The latter was implicated in conferring resistance to
      mycobacteria. A connection between Mn2+ transport and resistance or sensitivity
      to mycobacteria is discussed.

PMID- 8643536
TI  - The cloned rat pancreatic polypeptide receptor exhibits profound differences to
      the orthologous receptor.
AB  - Pancreatic polypeptide (PP) is produced in the islets of Langerhans and released
      in response to meals. It belongs to a family of peptides that also includes
      neuropeptide Y and peptide YY. In the present communication, we describe a rat
      receptor with high affinity for PP, therefore named PP1. Clones for the PP1
      receptor were obtained by PCR using sequence information for the neuropeptide Y
      receptor Y1 from several species. The PP1 receptor has 46% overall amino acid
      sequence identity to the rat Y1 receptor and 56% identity in the transmembrane
      regions. The PP1 receptor displays a pharmacological profile that is distinct
      from previously described neuropeptide Y-family receptors. In competition with
      iodinated bovine PP, it binds rat PP with an affinity (K(i)) of 0.017 nM, while
      the affinities for peptide YY and neuropeptide Y are substantially lower with
      K(i) values of 162 and 192 nM, respectively. In stably transfected CHO cells, the
      PP1 receptor inhibits forskolin-stimulated cAMP synthesis. Northern blot
      hybridizations to a panel of mRNAs detected transcripts in testis and lung. A
      faint band was seen in colon and total brain. In contrast, the human receptor is
      expressed primarily in colon and small intestine. Whereas rat and human PP1 bind
      PP with the same affinity, the rat receptor has much lower affinity than its
      human ortholog for peptide YY and neuropeptide Y. Interestingly, the amino acid
      sequence identity between rat and human PP1 is only 75%. Thus, the sequence, the
      tissue distribution, and the binding profile of the PP1 receptor differ
      considerably between rat and human.

PMID- 8643537
TI  - Oxidative stress is involved in heat-induced cell death in Saccharomyces
      cerevisiae.
AB  - The cause for death after lethal heat shock is not well understood. A shift from
      low to intermediate temperature causes the induction of heat-shock proteins in
      most organisms. However, except for HSP104, a convincing involvement of heat
      shock proteins in the development of stress resistance has not been established
      in Saccharomyces cerevisiae. This paper shows that oxidative stress and
      antioxidant enzymes play a major role in heat-induced cell death in yeast.
      Mutants deleted for the antioxidant genes catalase, superoxide dismutase, and
      cytochrome c peroxidase were more sensitive to the lethal effect of heat than
      isogenic wild-type cells. Overexpression of catalase and superoxide dismutase
      genes caused an increase in thermotolerance. Anaerobic conditions caused a 500-
      to 20,000-fold increase in thermotolerance. The thermotolerance of cells in
      anaerobic conditions was immediately abolished upon oxygen exposure. HSP104 is
      not responsible for the increased resistance of anaerobically grown cells. The
      thermotolerance of anaerobically grown cells is not due to expression of heat
      shock proteins. By using an oxidation-dependent fluorescent molecular probe a 2-
      to 3-fold increase in fluorescence was found upon heating. Thus, we conclude that
      oxidative stress is involved in heat-induced cell death.

PMID- 8643538
TI  - Ancient single origin for Malagasy primates.
AB  - We report new evidence that bears decisively on a long-standing controversy in
      primate systematics. DNA sequence data for the complete cytochrome b gene,
      combined with an expanded morphological data set, confirm the results of a
      previous study and again indicate that all extant Malagasy lemurs originated from
      a single common ancestor. These results, as well as those from other genetic
      studies, call for a revision of primate classifications in which the dwarf and
      mouse lemurs are placed within the Afro-Asian lorisiforms. The phylogenetic
      results, in agreement with paleocontinental data, indicate an African origin for
      the common ancestor of lemurs and lorises (the Strepsirrhini). The molecular data
      further suggest the surprising conclusion that lemurs began evolving
      independently by the early Eocene at the latest. This indicates that the Malagasy
      primate lineage is more ancient than generally thought and places the split
      between the two strepsirrhine lineages well before the appearance of known Eocene
      fossil primates. We conclude that primate origins were marked by rapid speciation
      and diversification sometime before the late Paleocene.

PMID- 8643539
TI  - The C-proteinase that processes procollagens to fibrillar collagens is identical
      to the protein previously identified as bone morphogenic protein-1.
AB  - Bone morphogenic protein-1 (BMP-1) was originally identified as one of several
      BMPs that induced new bone formation when implanted into ectopic sites in
      rodents. BMP-1, however, differed from other BMPs in that it its structure was
      not similar to transforming growth factor beta. Instead, it had a large domain
      homologous to a metalloendopeptidase isolated from crayfish, an epidermal growth
      factor-like domain, and three regions of internal sequence homology referred to
      as CUB domains. Therefore, BMP-1 was a member of the "astacin families" of zinc
      requiring endopeptidases. Many astacins have been shown to play critical roles in
      embryonic hatching, dorsal/ventral patterning, and early developmental decisions.
      Here, we have obtained amino acid sequences and isolated cDNA clones for
      procollagen C-proteinase (EC 3.4.24.19), an enzyme that is essential for the
      processing of procollagens to fibrillar collagens. The results demonstrate that
      procollagen C-proteinase is identical to BMP-1.

PMID- 8643540
TI  - Mitochondrial diversity and the origins of African and European cattle.
AB  - The nature of domestic cattle origins in Africa are unclear as archaeological
      data are relatively sparse. The earliest domesticates were humpless, or Bos
      taurus, in morphology and may have shared a common origin with the ancestors of
      European cattle in the Near East. Alternatively, local strains of the wild ox,
      the aurochs, may have been adopted by peoples in either continent either before
      or after cultural influence from the Levant. This study examines mitochondrial
      DNA displacement loop sequence variation in 90 extant bovines drawn from Africa,
      Europe, and India. Phylogeny estimation and analysis of molecular variance verify
      that sequences cluster significantly into continental groups. The Indian Bos
      indicus samples are most markedly distinct from the others, which is indicative
      of a B. taurus nature for both European and African ancestors. When a calibration
      of sequence divergence is performed using comparisons with bison sequences and an
      estimate of 1 Myr since the Bison/Bos Leptobos common ancestor, estimates of 117
      275,000 B.P. and 22-26,000 B.P. are obtained for the separation between Indians
      and others and between African and European ancestors, respectively. As cattle
      domestication is thought to have occurred approximately 10,000 B.P., these
      estimates suggest the domestication of genetically discrete aurochsen strains as
      the origins of each continental population. Additionally, patterns of variation
      that are indicative of population expansions (probably associated with the
      domestication process) are discernible in Africa and Europe. Notably, the genetic
      signatures of these expansions are clearly younger than the corresponding
      signature of African/European divergence.

PMID- 8643541
TI  - Human V delta 2+ gamma delta T-cell tolerance to foreign antigens of Toxoplasma
      gondii.
AB  - Little is known about the mechanisms involved in human gammadelta T-cell
      tolerance to self or to foreign antigens. Patients with congenital toxoplasmosis
      offer a unique opportunity to examine Vdelta2+ gammadelta T-cell tolerance.
      Analysis of gammadelta T cells in patients with congenital toxoplasmosis revealed
      evidence for anergy of these cells with or without clonal Vdelta2+ gammadelta T
      cell expansion in the acute phase of the Toxoplasma infection. T cells in general
      were unresponsive and did not proliferate upon exposure to mitogens or to
      Toxoplasma lysate antigens or in response to live Toxoplasma-infected cells when
      the congenitally infected infants were 1 month of age, and they exhibited
      selective anergy to Toxoplasma lysate antigens and live Toxoplasma-infected cells
      when the infants were aged 5 months. During the chronic phase of congenital
      toxoplasmosis in the patients who were more than I year of age, the repertoires
      of the gammadelta T-cell receptors were found to be within normal ranges. In
      addition, in the chronic phase, the gammadelta T cells proliferated and secreted
      gamma-interferon in response to exposure to live Toxoplasmia-infected cells. By
      contrast, alphabeta T cells remained anergic. Vdelta2+ gammadelta T cells have
      been considered to undergo extrathymic maturation and thus to be subject to
      development of peripheral tolerance. Our findings indicate that Vdelta2+
      gammadelta T-cell tolerance was lost in these infected infants earlier than
      alphabeta T-cell tolerance. These findings suggest that gammadelta T cells play a
      role in protection against Toxoplasma gondii in the chronic phase when
      congenitally infected children are more than 1 year of age, especially in those
      in whom alphabeta T cells continue to exhibit deficits in specific immune
      responses to Toxoplasma antigens.

PMID- 8643542
TI  - Preferential induction of a Th1 immune response and inhibition of specific IgE
      antibody formation by plasmid DNA immunization.
AB  - We compared the antigen-specific antibody isotypes and lymphokine secretion by
      CD4+ T cells in BALB/c mice immunized intradermally with either Escherichia coli
      beta-galactosidase (beta-gal) or plasmid DNA (pDNA) encoding beta-gal in a
      cytomegalovirus-based expression vector (pCMV-LacZ). pCMV-LacZ induced mainly
      IgG2a, whereas beta-gal in saline or alum induced IgG1 and IgE beta-gal-specific
      antibodies. In addition, splenic CD4+ T helper (Th) cells isolated from pDNA
      immunized mice secreted interferon-gamma but not interleukin (IL)-4 and IL-5,
      whereas Th cells from beta-gal-injected mice secreted IL-4 and IL-5 but not
      interferon-gamma after in vitro stimulation with antigen. Together these data
      demonstrate that pDNA immunization induced a T helper type 1 (Th1) response,
      whereas protein immunization induced a T helper type 2 (Th2) response to the same
      antigen. Interestingly, priming of mice with pCMV-LacZ prevented IgE antibody
      formation to a subsequent i.p. beta-gal in alum injection. This effect was
      antigen-specific, because priming with pCMV-LacZ did not inhibit IgE anti
      ovalbumin antibody formation. Most importantly, intradermal immunization with
      pCMV-LacZ (but not pCMV-OVA) of beta-gal in alum-primed mice caused a 66-75%
      reduction of the IgE anti-beta-gal titer in 6 weeks. Also, pCMV-LacZ induced
      specific IgG2a antibody titers and interferon-gamma secretion by Th cells in the
      beta-gal in alum-primed mice. The data demonstrate that gene immunization induces
      a Th1 response that dominates over an ongoing protein-induced Th2 response in an
      antigen-specific manner. This suggests that immunization with pDNA encoding for
      allergens may provide a novel type of immunotherapy for allergic diseases.

PMID- 8643543
TI  - Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells
      from normal cells in tissue culture.
AB  - The neurodegeneration and amyloid deposition of sporadic Alzheimer disease (AD)
      also occur in familial AD and in all trisomy-21 Down syndrome (DS) patients,
      suggesting a common pathogenetic mechanism. We investigated whether defective
      processing of damaged DNA might be that mechanism, as postulated for the
      neurodegeneration in xeroderma pigmentosum, a disease with defective repair not
      only of UV radiation-induced, but also of some oxygen free radical-induced, DNA
      lesions. We irradiated AD and DS skin fibroblasts or blood lymphocytes with
      fluorescent light, which is known to cause free radical-induced DNA damage. The
      cells were then treated with either beta-cytosine arabinoside (araC) or caffeine,
      and chromatid breaks were quantified. At least 28 of 31 normal donors and 10 of
      11 donors with nonamyloid neurodegenerations gave normal test results. All 12 DS,
      11 sporadic AD, and 16 familial AD patients tested had abnormal araC and caffeine
      tests, as did XP-A cells. In one of our four AD families, an abnormal caffeine
      test was found in all 10 afflicted individuals (including 3 asymptomatic when
      their skin biopsies were obtained) and in 8 of 11 offspring at a 50% risk for AD.
      Our tests could prove useful in predicting inheritance of familial AD and in
      supporting, or rendering unlikely, the diagnosis of sporadic AD in patients
      suspected of having the disease.

PMID- 8643545
TI  - Inducible expression of an antibiotic peptide gene in lipopolysaccharide
      challenged tracheal epithelial cells.
AB  - Mammals continually confront microbes at mucosal surfaces. A current model
      suggests that epithelial cells contribute to defense at these sites, in part
      through the production of broad-spectrum antibiotic peptides. Previous studies
      have shown that invertebrates can mount a host defense response characterized by
      the induction in epithelia] cells of a variety of antibiotic proteins and
      peptides when they are challenged with microorganisms, bacterial cell
      wall/membrane components, or traumatic injury [Boman, H.G. & Hultmark, D. (1987)
      Annu. Rev. Microbiol. 41, 103-126J. However, factors that govern the expression
      of similar defense molecules in mammalian epithelial cells are poorly understood.
      Here, a 13-fold induction of the endogenous gene encoding tracheal antimicrobial
      peptide was found to characterize a host response of tracheal epithelia] cells
      (TECs) exposed to bacterial lipopolysaccharide (LPS). Northern blot data
      indicated that TECs express CD14, a well-characterized LPS-binding protein known
      to mediate many LPS responses. A monoclonal antibody to CD14 blocked the observed
      tracheal antimicrobial peptide induction by LPS under serum-free conditions.
      Together the data support that CD14 of epithelial cell origin mediates the LPS
      induction of an antibiotic peptide gene in TECs, providing evidence for the
      active participation of epithelial cells in the host's local defense response to
      bacteria. Furthermore, the data allude to a conservation of this host response in
      evolution and suggest that a similar inducible pathway of host defense is
      prevalent at mucosal surfaces of mammals.

PMID- 8643544
TI  - In its active form, the GTP-binding protein rab8 interacts with a stress
      activated protein kinase.
AB  - Rab8 is a small GTP-binding protein that plays a role in vesicular transport from
      the trans-Golgi network to the basolateral plasma membrane in polarized
      epithelial cells (MDCK), and to the dendritic surface in hippocampal neurons. As
      is the case for most other rab proteins, the precise molecular interactions by
      which rab8 carries out its function remain to be elucidated. Here we report the
      identification and the complete cDNA-derived amino acid sequence of a murine rab8
      interacting protein (rab8ip) that specifically interacts with rab8 in a GTP
      dependent manner. Rab8ip displays 93% identity with the GC kinase, a
      serine/threonine protein kinase recently identified in human lymphoid tissue that
      is activated in the stress response. Like the GC kinase, rab8ip has protein
      kinase activity manifested by autophosphorylation and phosphorylation of the
      classical serine/threonine protein kinase substrates, myelin basic protein and
      casein. When coexpressed in transfected 293T cells, rab8 and the rab8ip/GC kinase
      formed a complex that could be recovered by immunoprecipitation with antibodies
      to rab8. Cell fractionation and immunofluorescence analyses indicate that in MDCK
      cells endogenous rab8ip is present both in the cytosol and as a peripheral
      membrane protein concentrated in the Golgi region and basolateral plasma membrane
      domains, sites where rab8 itself is also located. In light of recent evidence
      that rab proteins may act by promoting the stabilization of SNARE complexes, the
      specific GTP-dependent association of rab8 with the rab8ip/GC kinase raises the
      possibility that rab-regulated protein phosphorylation is important for vesicle
      targeting or fusion. Moreover, the rab8ip/GC kinase may serve to modulate
      secretion in response to stress stimuli.

PMID- 8643546
TI  - Oscillations in KATP channel activity promote oscillations in cytoplasmic free
      Ca2+ concentration in the pancreatic beta cell.
AB  - Pancreatic beta cells exhibit oscillations in electrical activity, cytoplasmic
      free Ca2+ concentration ([Ca2+](i)), and insulin release upon glucose
      stimulation. The mechanism by which these oscillations are generated is not
      known. Here we demonstrate fluctuations in the activity of the ATP-dependent K+
      channels (K(ATP) channels) in single beta cells subject to glucose stimulation or
      to stimulation with low concentrations of tolbutamide. During stimulation with
      glucose or low concentrations of tolbutamide, K(ATP) channel activity decreased
      and action potentials ensued. After 2-3 min, despite continuous stimulation,
      action potentials subsided and openings of K(ATP) channels could again be
      observed. Transient suppression of metabolism by azide in glucose-stimulated beta
      cells caused reversible termination of electrical activity, mimicking the
      spontaneous changes observed with continuous glucose stimulation. Thus,
      oscillations in K(ATP) channel activity during continuous glucose stimulation
      result in oscillations in electrical activity and [Ca2+](i).

PMID- 8643547
TI  - Distinct pharmacological properties and distribution in neurons and endocrine
      cells of two isoforms of the human vesicular monoamine transporter.
AB  - A second isoform of the human vesicular monoamine transporter (hVMAT) has been
      cloned from a pheochromocytoma cDNA library. The contribution of the two
      transporter isoforms to monoamine storage in human neuroendocrine tissues was
      examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2.
      Central, peripheral, and enteric neurons express only VMAT2. VMAT1 is expressed
      exclusively in neuroendocrine, including chromaffin and enterochromaffin, cells.
      VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla.
      VMAT2 alone is expressed in histamine-storing enterochromaffin-like cells of the
      oxyntic mucosa of the stomach. The transport characteristics and pharmacology of
      each VMAT isoform have been directly compared after expression in digitonin
      permeabilized fibroblastic (CV-1) cells, providing information about substrate
      feature recognition by each transporter and the role of vesicular monoamine
      storage in the mechanism of action of psychopharmacologic and neurotoxic agents
      in human. Serotonin has a similar affinity for both transporters. Catecholamines
      exhibit a 3-fold higher affinity, and histamine exhibits a 30-fold higher
      affinity, for VMAT2. Reserpine and ketanserin are slightly more potent inhibitors
      of VMAT2-mediated transport than of VMAT1-mediated transport, whereas
      tetrabenazine binds to and inhibits only VMAT2. N-methyl-4-phenylpyridinium,
      phenylethylamine, amphetamine, and methylenedioxymethamphetamine are all more
      potent inhibitors of VMAT2 than of VMAT1, whereas fenfluramine is a more potent
      inhibitor of VMAT1-mediated monamine transport than of VMAT2-mediated monoamine
      transport. The unique distributions of hVMAT1 and hVMAT2 provide new markers for
      multiple neuroendocrine lineages, and examination of their transport properties
      provides mechanistic insights into the pharmacology and physiology of amine
      storage in cardiovascular, endocrine, and central nervous system function.

PMID- 8643548
TI  - Diverse strategies for tetracycline-regulated inducible gene expression.

PMID- 8643549
TI  - The viruses in all of us: characteristics and biological significance of human
      endogenous retrovirus sequences.
AB  - Human endogenous retroviruses (HERVs) are very likely footprints of ancient germ
      cell infections. HERV sequences encompass about 1% of the human genome. HERVs
      have retained the potential of other retroelements to retrotranspose and thus to
      change genomic structure and function. The genomes of almost all HERV families
      are highly defective. Recent progress has allowed the identification of the
      biologically most active family, HTDV/HERV-K, which codes for viral proteins and
      particles and is highly expressed in germ-cell tumors. The demonstrable and
      potential roles of HTDV/HERV-K as well as of other human elements in disease and
      in maintaining genome plasticity are illustrated.

PMID- 8643550
TI  - Rapid retroviral delivery of tetracycline-inducible genes in a single
      autoregulatory cassette.
AB  - We describe a single autoregulatory cassette that allows reversible induction of
      transgene expression in response to tetracycline (tet). This cassette contains
      all of the necessary components previously described by others on two separate
      plasmids that are introduced sequentially over a period of months [Gossen, M. &
      Bujard, H. (1992) Proc. Natl. Acad. Sci. USA 89, 5547-5551]. The cassette is
      introduced using a retrovirus, allowing transfer into cell types that are
      difficult to transfect. Thus, populations of thousands of cells, rather than a
      few clones, can be isolated and characterized within weeks. To avoid potential
      interference of the strong retroviral long terminal repeat enhancer and promoter
      elements with the function of the tet-regulated cytomegalovirus minimal promoter,
      the vector is self-inactivating, eliminating transcription from the long terminal
      repeat after infection of target cells. Tandem tet operator sequences and the
      cytomegalovirus minimal promoter drive expression of a bicistronic mRNA, leading
      to transcription of the gene of interest (lacZ) and the internal ribosome entry
      site controlled transactivator (Tet repressor-VP16 fusion protein). In the
      absence of tet, there is a progressive increase in transactivator by means of an
      autoregulatory loop, whereas in the presence of tet, gene expression is
      prevented. Northern blot, biochemical, and single cell analyses have all shown
      that the construct yields low basal levels of gene expression and induction of
      one to two orders of magnitude. Thus, the current cassette of the retroviral
      construct (SIN-RetroTet vector) allows rapid delivery of inducible genes and
      should have broad applications to cultured cells, transgenic animals, and gene
      therapy.

PMID- 8643551
TI  - Crystal structure at 2.6-A resolution of human macrophage migration inhibitory
      factor.
AB  - Macrophage migration inhibitory factor (MIF) was the first cytokine to be
      described, but for 30 years its role in the immune response remained enigmatic.
      In recent studies, MIF has been found to be a novel pituitary hormone and the
      first protein identified to be released from immune cells on glucocorticoid
      stimulation. Once secreted, MIF counterregulates the immunosuppressive effects of
      steroids and thus acts as a critical component of the immune system to control
      both local and systemic immune responses. We report herein the x-ray crystal
      structure of human MIF to 2.6 angstrom resolution. The protein is a trimer of
      identical subunits. Each monomer contains two antiparallel alpha-helices that
      pack against a four-stranded beta-sheet. The monomer has an additional two beta
      strands that interact with the beta-sheets of adjacent subunits to form the
      interface between monomers. The three beta-sheets are arranged to form a barrel
      containing a solvent-accessible channel that runs through the center of the
      protein along a molecular 3-fold axis. Electrostatic potential maps reveal that
      the channel has a positive potential, suggesting that it binds negatively charged
      molecules. The elucidated structure for MIF is unique among cytokines or hormonal
      mediators, and suggests that this counterregulator of glucocorticoid action
      participates in novel ligand-receptor interactions.

PMID- 8643552
TI  - Cloning and expression in Escherichia coli of the OGG1 gene of Saccharomyces
      cerevisiae, which codes for a DNA glycosylase that excises 7,8-dihydro-8
      oxoguanine and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine.
AB  - A spontaneous mutator strain of Escherichia coli (fpg mutY) was used to clone the
      OGG1 gene of Saccharomyces cerevisiae, which encodes a DNA glycosylase activity
      that excises 7,8-dihydro-8-oxoguanine (8-OxoG). E. coli (fpg mutY) was
      transformed by a yeast DNA library, and clones that showed a reduced spontaneous
      mutagenesis were selected. The antimutator activity was associated with pYSB10,
      an 11-kbp recombinant plasmid. Cell-free extracts of E. coli (fpg mutY) harboring
      pYSB10 possess an enzymatic activity that cleaves a 34-mer oligonucleotide
      containing a single 8-oxoG opposite a cytosine (8-OxoG/C). The yeast DNA fragment
      of 1.7 kbp that suppresses spontaneous mutagenesis and overproduces the 8-OxoG/C
      cleavage activity was sequenced and mapped to chromosome XIII. DNA sequencing
      identified an open reading frame, designated OGG1, which encodes a protein of 376
      amino acids with a molecular mass of 43 kDa. The OGG1 gene was inserted in
      plasmid pUC19, yielding pYSB110. E. coli (fpg) harboring pYSB110 was used to
      purify the Ogg1 protein of S. cerevisiae to apparent homogeneity. The Ogg1
      protein possesses a DNA glycosylase activity that releases 8-OxoG and 2,6-diamino
      4-hydroxy-5-N-methylformamidopyrimidine. The Ogg1 protein preferentially incises
      DNA that contains 8-OxoG opposite cytosine (8-OxoG/C) or thymine (8-OxoG/T). In
      contrast, Ogg1 protein does not incise the duplex where an adenine is placed
      opposite 8-OxoG (8-OxoG/A). The mechanism of strand cleavage by Ogg1 protein is
      probably due to the excision of 8-OxoG followed by a beta-elimination at the
      resulting apurinic/apyrimidinic site.

PMID- 8643553
TI  - Quantal acetylcholine release induced by mediatophore transfection.
AB  - Mediatophore is a protein of approximately 200 kDa able to translocate
      acetylcholine in response to calcium. It was purified from the presynaptic plasma
      membranes of the electric organ nerve terminals. Mediatophore is a homooligomer
      of a 16-kDa subunit, homologous to the proteolipid of V-ATPase. Cells of the
      N18TG-2 neuronal line are not able to produce quantal acetylcholine release. We
      show here that transfection of N18TG-2 cells with a plasmid encoding the
      mediatophore subunit restored calcium-dependent release. The essential feature of
      such a release was its quantal nature, similar to what is observed in situ in
      cholinergic synapses from which mediatophore was purified.

PMID- 8643554
TI  - Absolute mRNA levels and transcriptional initiation rates in Saccharomyces
      cerevisiae.
AB  - We quantitate the absolute levels of individual mRNAs per yeast cell by
      hybridizing total yeast RNA with an excess of gene-specific 32P-oligonucleotides,
      and digesting the resulting RNA-DNA hybrids with S1 nuclease. By comparing the
      his3 hybridization signal from a known amount of yeast cells to the signal
      generated by a known amount of his3 RNA synthesized in vitro, we determine that
      yeast strain KY114 growing in yeast extract/peptone/glucose medium at 30 degrees
      C contains seven molecules of his3 mRNA per cell. Using a galactose shut-off
      procedure, we determined that the half-life of his3 mRNA is approximately 11 min
      under these conditions. From these observations, we calculate that one his3 mRNA
      molecule is synthesized every 140 s. Analysis of other his3 promoter derivatives
      suggests that the maximal transcriptional initiation rate in yeast cells is one
      mRNA molecule every 6-8 s. Using his3 as an internal standard, the number of mRNA
      molecules per cell have been determined for ded1, trp3, rps4, and gall under a
      variety of growth conditions. From these results, the absolute mRNA level of any
      yeast gene can be determined in a single hybridization experiment. Moreover, the
      rate of transcriptional initiation can be determined for mRNAs whose decay rates
      are known.

PMID- 8643555
TI  - Immunotargeting of antioxidant enzyme to the pulmonary endothelium.
AB  - Oxidative injury to the pulmonary endothelium has pathological significance for a
      spectrum of diseases. Administration of antioxidant enzymes, superoxide dismutase
      (SOD) and catalase (Cat), has been proposed as a method to protect endothelium.
      However, neither these enzymes nor their derivatives possess specific affinity to
      endothelium and do not accumulate in the lung. Previously we have described a
      monoclonal antibody to angiotensin-converting enzyme (ACE) that accumulates
      selectively in the lung after systemic injection in rats, hamsters, cats,
      monkeys, and humans. In the present work we describe a system for selective
      intrapulmonary delivery of CuZn-SOD and Cat conjugated with biotinylated anti-ACE
      antibody mAb 9B9 (b-mAb 9B9) by a streptavidin (SA)-biotin bridge. Both enzymes
      biotinylated with biotin ester at biotin/enzyme ratio 20 retain enzymatic
      activity and bind SA without loss of activity. We have constructed tri-molecular
      heteropolymer complexes consisting of b-mAb 9B9, SA, and biotinylated SOD or
      biotinylated Cat and have studied biodistribution and pulmonary uptake of these
      complexes in the rat after i.v. injection. Biodistribution of biotinylated
      enzymes was similar to that of nonmodified enzymes. Binding of SA markedly
      prolonged lifetime of biotinylated enzymes in the circulation. In contrast to
      enzymes conjugated with nonspecific IgG, other enzyme derivatives, and
      nonmodified enzymes, biotinylated enzymes conjugated with b-mAb 9B9 accumulated
      specifically in the rat lung (9% of injected SOD/g of lung tissue and 7.5% of
      injected Cat/g of lung tissue). Pulmonary uptake of nonmodified enzymes or
      derivatives with nonspecific IgG did not exceed 0.5% of injected dose/g. Both SOD
      and Cat conjugated with b-mAb 9B9 were retained in the rat lung for at least
      several hours. Trichloracetic acid-precipitable radiolabeled Cat was associated
      with microsomal and plasma membrane fractions of the lung tissue homogenate.
      Thus, modification of antioxidant enzymes with biotin and SA-mediated conjugation
      with b-mAb 9B9 prolongs the circulation of enzymes resulting in selective
      accumulation in the lung and intracellular delivery of enzymes to the pulmonary
      endothelium. These results provide the background for an approach to provide
      protection of pulmonary endothelium against oxidative insults.

PMID- 8643556
TI  - The rat extracellular superoxide dismutase dimer is converted to a tetramer by
      the exchange of a single amino acid.
AB  - Extracellular superoxide dismutase (EC-SOD) is a secreted Cu and Zn-containing
      glycoprotein. While EC-SOD from most mammals is tetrameric and has a high
      affinity for heparin and heparan sulfate, rat EC-SOD has a low affinity for
      heparin, does not bind to heparan sulfate in vivo, and is apparently dimeric. To
      examine the molecular basis of the deviant physical properties of rat EC-SOD, the
      cDNAs of the rat and mouse EC-SODs were isolated and the deduced amino acid
      sequences were compared with that of human EC-SOD. Comparison of the sequences
      offered no obvious explanation of the differences. Analysis of a series of
      chimeric and point mutated EC-SODs showed that the N-terminal region contributes
      to the oligomeric state of the EC-SODs, and that a single amino acid, a valine
      (human amino acid position 24), is essential for the tetramerization. This
      residue is replaced by an aspartate in the rat. Rat EC-SOD carrying an Asp -->
      Val mutation is tetrameric and has a high heparin affinity, while mouse EC-SOD
      with a Val --> Asp mutation is dimeric and has lost its high heparin affinity.
      Thus, the rat EC-SOD dimer is converted to a tetramer by the exchange of a single
      amino acid. Furthermore, the cooperative action of four heparin-binding domains
      is necessary for high heparin affinity. These results also suggest that
      tetrameric EC-SODs are not symmetrical tetrahedrons, but composed of two
      interacting dimers, further supporting an evolutionary relationship with the
      dimeric cytosolic Cu and Zn-containing SODs.

PMID- 8643557
TI  - A structural model for a homeotic protein-extradenticle-DNA complex accounts for
      the choice of HOX protein in the heterodimer.
AB  - The genes of the homeotic complex (HOX) encode DNA binding homeodomain proteins
      that control developmental fates by differentially regulating the transcription
      of downstream target genes. Despite their unique in vivo functions, disparate HOX
      proteins often bind to very similar DNA sequences in vitro. Thus, a critical
      question is how HOX proteins select the correct sets of target genes in vivo. The
      homeodomain proteins encoded by the Drosophila extradenticle gene and its
      mammalian homologues, the pbx genes, contribute to HOX specificity by
      cooperatively binding to DNA with HOX proteins. For example, the HOX protein
      labial cooperatively binds with extradenticle protein to a 20-bp oligonucleotide
      that is sufficient to direct a labial-like expression pattern in Drosophila
      embryos. Here we have analyzed the protein-DNA interactions that are important
      for forming the labial-extradenticle-DNA complex. The data suggest a model in
      which labial and extradenticle, separated by only 4 bp, bind this DNA as a
      heterodimer in a head-to-tail orientation. We have confirmed several aspects of
      this model by characterizing extradenticle-HOX binding to mutant
      oligonucleotides. Most importantly, mutations in base pairs predicted to contact
      the HOX N-terminal arm resulted in a change in HOX preference in the heterodimer,
      from labial to Ultrabithorax. These results demonstrate that extradenticle
      prefers to bind cooperatively with different HOX proteins depending on subtle
      differences in the heterodimer binding site.

PMID- 8643558
TI  - Malignant conversion of chemically transformed normal human cells.
AB  - Two structurally unrelated chemicals, aflatoxin B1 and propane sultone,
      transformed human foreskin cells to a stage of anchorage-independent growth.
      Isolation from agar and repopulation in monolayer culture of these transformed
      cells was followed by transfection with a cDNA library, which resulted in cells
      that exhibited an altered epithelioid morphology. Chemically
      transformed/nontransfected cells and transfected normal cells did not undergo a
      significant morphological change. These epithelioid-appearing, transfected cells,
      when inoculated into nude mice, form progressively growing tumors. The tumors are
      histopathologically interpreted as carcinomas. All of the first generation tumors
      in the surrogate hosts exhibited characteristic rates of growth similar to those
      of transplants of spontaneous human tumors. In the second generation of tumor
      xenografts, the progressively growing tumors derived from the transfected cells
      exhibited a more rapid rate of growth. Southern analysis and reverse
      transcription PCR confirmed that a 1.3-kb genetic element was integrated into the
      genome and was actively being transcribed. Examination of the metaphase
      chromosomes in normal human cells revealed that the genetic element responsible
      for this conversion was located at site 31-32 of the q arm of chromosome 7. The
      DNA sequence of this 1.3-kb genetic element contains a coding region for 79 amino
      acids and a long 3'-untranslated region and appears to be identical to CATR1.3
      isolated from tumors produced by methyl methanesulfonate-converted,
      nontransplantable human tumor cells.

PMID- 8643559
TI  - Traumatic brain damage prevented by the non-N-methyl-D-aspartate antagonist 2,3
      dihydroxy-6-nitro-7-sulfamoylbenzo[f] quinoxaline.
AB  - The mechanisms of neuronal degeneration following traumatic head injury are not
      well understood and no adequate treatment is currently available for the
      prevention of traumatic brain damage in humans. Traumatic head injury leads to
      primary (at impact) and secondary (distant) damage to the brain. Mechanical
      percussion of the rat cortex mimics primary damage seen after traumatic head
      injury in humans; no animal model mimicking the secondary damage following
      traumatic head injury has yet been established. Rats subjected to percussion
      trauma of the cortex showed primary damage in the cortex and secondary damage in
      the hippocampus. Morphometric analysis demonstrated that both cortical and
      hippocampal damage was mitigated by pretreatment with either the N-methyl-D
      aspartate (NMDA) antagonist 3-((+/-)- 2-carboxypiperazin-4-yl)-propyl-1
      phosphonate (CPP) or the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl
      benzo[f]quinoxaline (NBQX). Neither treatment prevented primary damage in the
      cortex when therapy was started after trauma. Surprisingly, delayed treatment of
      rats with NBQX, but not with CPP, beginning between 1 and 7 hr after trauma
      prevented hippocampal damage. No protection was seen when therapy with NBQX was
      started 10 hr after trauma. These data indicate that both NMDA- and non-NMDA
      dependent mechanisms contribute to the development of primary damage in the
      cortex, whereas non-NMDA mechanisms are involved in the evolution of secondary
      damage in the hippocampus in rats subjected to traumatic head injury. The wide
      therapeutic time-window documented for NBQX suggests that antagonism at non-NMDA
      receptors may offer a novel therapeutic approach for preventing deterioration of
      the brain after head injury.

PMID- 8643560
TI  - Arachidonate lipoxygenases as essential regulators of cell survival and
      apoptosis.
AB  - Arachidonic acid (AA) metabolites derived from both cyclooxygenase (COX) and
      lipoxygenase (LOX) pathways transduce a variety of signals related to cell
      growth. Here, we report that the AA LOX pathway also functions as a critical
      regulator of cell survival and apoptosis. Rat Walker 256 (W256) carcinosarcoma
      cells express 12-LOX and synthesize 12(S)- and 15(S)-hydroxyeicosatetraenoic
      acids as their major LOX metabolites. W256 cells transfected with 12-LOX-specific
      antisense oligonucleotide or antisense oligonucleotides directed to conserved
      regions of LOXs underwent time- and dose-dependent apoptosis. Likewise, treatment
      of W256 cells with various LOX but not COX inhibitors induced apoptotic cell
      death, which could be partially inhibited by exogenous 12(S)- or 15(S)
      hydroxyeicosatetraenoic acids. The W256 cell apoptosis induced by antisense
      oligos and LOX inhibitors was followed by a rapid downregulation of bcl-2
      protein, a dramatic decrease in the bcl-2/bax ratio, and could be suppressed by
      bcl-2 overexpression. In contrast, p53, which is wild type in W256 cells, did not
      undergo alterations during apoptosis induction. The results suggest that the LOX
      pathway plays an important physiological role in regulating apoptosis.

PMID- 8643561
TI  - Long-term culture of lymphohematopoietic stem cells.
AB  - Pluripotent hematopoietic stem cells (PHSCs) show self-renewal and give rise to
      all blood cell types. The extremely low number of these cells in primary
      hematopoietic organs and the lack of culture systems that support proliferation
      of undifferentiated PHSCs have precluded the study of both the biology of these
      cells and their clinical application. We describe here cell lines and clones
      derived from PHSCs that were established from hematopoietic cells from the fetal
      liver or bone marrow of normal and p53-deficient mice with a combination of four
      growth factors. Most cell lines were Sca-1+, c-Kit+, PgP-1+, HSA+, and Lin- (B
      220-, Joro 75-, 8C5-, F4/80-, CD4-, CD8-, CD3-, IgM-, and TER 119-negative) and
      expressed three new surface markers: Joro 177, Joro 184, and Joro 96. They did
      not synthesize RNA transcripts for several genes expressed at early stages of
      lymphocyte and myeloid/erythroid cell development. The clones were able to
      generate lymphoid, myeloid, and erythroid hematopoietic cells and to reconstitute
      the hematopoietic system of irradiated mice for a long time. The availability of
      lymphohematopoietic stem cell lines should facilitate the analysis of the
      molecular mechanisms that control self-renewal and differentiation and the
      development of efficient protocols for somatic gene therapy.

PMID- 8643562
TI  - Expression of a recoded nuclear gene inserted into yeast mitochondrial DNA is
      limited by mRNA-specific translational activation.
AB  - Genetic code differences prevent expression of nuclear genes within Saccharomyces
      cerevisiae mitochondria. To bridge this gap a synthetic gene, ARG8m, designed to
      specify an arginine biosynthetic enzyme when expressed inside mitochondria, has
      been inserted into yeast mtDNA in place of the COX3 structural gene. This
      mitochondrial cox3::ARG8m gene fully complements a nuclear arg8 deletion at the
      level of cell growth, and it is dependent for expression upon nuclear genes that
      encode subunits of the COX3 mRNA-specific translational activator. Thus,
      cox3::ARG8m serves as a mitochondrial reporter gene. Measurement of cox3::ARG8m
      expression at the levels of steady-state protein and enzymatic activity reveals
      that glucose repression operates within mitochondria. The levels of this reporter
      vary among strains whose nuclear genotypes lead to under- and overexpression of
      translational activator subunits, in particular Pet494p, indicating that mRNA
      specific translational activation is a rate-limiting step in this organellar
      system. Whereas the steady-state level of cox3::ARG8m mRNA was also glucose
      repressed in an otherwise wild-type strain, absence of translational activation
      led to essentially repressed mRNA levels even under derepressing growth
      conditions. Thus, the mRNA is stabilized by translational activation, and
      variation in its level may be largely due to modulation of translation.

PMID- 8643563
TI  - Ultraviolet-B photodestruction of a light-harvesting complex.
AB  - Cyanobacteria are important contributors to global photosynthesis in both marine
      and terrestrial environments. Quantitative data are presented on UV-B-induced
      damage to the major cyanobacterial photosynthetic light harvesting complex, the
      phycobilisome, and to each of its constituent phycobiliproteins. The
      photodestruction quantum yield, phi295 nm, for the phycobiliproteins is high
      (approximately 10(-3), as compared with approximately 10(-7) for visible light).
      Energy transfer on a picosecond time scale does not compete with
      photodestruction. Photodamage to phycobilisomes in vitro and in living cells is
      amplified by causing dissociation and loss of function of the complex. In
      photosynthetic organisms, UV-B damage to light-harvesting complexes may
      significantly exceed that to DNA.

PMID- 8643564
TI  - Functional testicular tissue does not masculinize development of the zebra finch
      song system.
AB  - Current theories of sexual differentiation maintain that ovarian estrogen
      prevents masculine development of the copulatory system in birds, whereas
      estrogen derived from testicular androgens promotes masculine sexual
      differentiation of neuroanatomy and sexual behavior in mammals. Paradoxically,
      some data suggest that the neural song system in zebra finches follows the
      mammalian pattern with estrogenic metabolites of testicular secretions causing
      masculine development. To test whether the removal of estrogen from males during
      early development would prevent the development of masculine song systems, zebra
      finches were treated embryonically with an inhibitor of estrogen synthesis. In
      addition, this treatment in genetic female zebra finches induced both functional
      ovarian and testicular tissue to develop, thus allowing the assessment of the
      direct effects of testicular secretions on song system development. In males, the
      inhibition of estrogen synthesis before hatching had a small but significant
      effect in demasculinizing one aspect of the neural song system. In treated
      females, the song systems remained morphologically feminine. These results
      suggest that masculinization of the song system is not determined solely by
      testicular androgens or their estrogenic metabolites.

PMID- 8643566
TI  - Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin
      2 signaling.
AB  - Stimulation via the T-cell growth factor interleukin 2 (IL-2) leads to tyrosine
      phosphorylation of Shc, the interaction of Shc with Grb2, and the Ras GTP/GDP
      exchange factor, mSOS. Shc also coprecipitates with the IL-2 receptor (IL-2R),
      and therefore, may link IL-2R to Ras activation. We have further characterized
      the Shc-IL-2R interaction and have made the following observations. (i) Among the
      two phosphotyrosine-interaction domains present in Shc, the phosphotyrosine
      binding (PTB) domain, rather than its SH2 domain, interacts with the tyrosine
      phosphorylated IL-2R beta chain. Moreover, the Shc-PTB domain binds a
      phosphopeptide derived from the IL-2R beta chain (corresponding to residues
      surrounding Y338, SCFTNQGpYFF) with high affinity. (ii) In vivo, mutant IL-2R
      beta chains lacking the acidic region of IL-2Rbeta (which contains Y338) fail to
      phosphorylate Shc. Furthermore, when wild type or mutant Shc proteins that lack
      the PTB domain were expressed in the IL-2-dependent CTLL-20 cell line, an intact
      Shc-PTB domain was required for Shc phosphorylation by the IL-2R, which provides
      further support for a Shc-PTB-IL-2R interaction in vivo. (iii) PTB and SH2
      domains of Shc associate with different proteins in IL-2- and T-cell-receptor
      stimulated lysates, suggesting that Shc, through the concurrent use of its two
      different phosphotyrosine-binding domains, could assemble multiple protein
      complexes. Taken together, our in vivo and in vitro observations suggest that the
      PTB domain of Shc interacts with Y338 of the IL-2R and provide evidence for a
      functional role for the Shc-PTB domain in IL-2 signaling.

PMID- 8643565
TI  - Inhibition of immunoglobulin folding and secretion by dominant negative BiP
      ATPase mutants.
AB  - A group of resident ER proteins have been identified that are proposed to
      function as molecular chaperones. The best characterized of these is BiP/GRP78,
      an hsp70 homologue that binds peptides containing hydrophobic residues in vitro
      and unfolded or unassembled proteins in vivo. However, evidence that mammalian
      BiP plays a direct role in protein folding remains circumstantial. In this study,
      we examine how BiP interacts with a particular substrate, immunoglobulin light
      chain (lambda LC), during its folding. Wild-type hamster BiP and several well
      characterized BiP ATPase mutants were used in transient expression experiments.
      We demonstrate that wild-type lambda LCs showed prolonged association with mutant
      BiP which inhibited their secretion. Both wild-type and mutant BiP bound only to
      unfolded and partially folded LCs. The wild-type BiP was released from the
      incompletely folded LCs, allowing them to fold and be secreted, whereas the
      mutant BiP was not released. As a result, the LCs that were bound to BiP mutants
      were unable to undergo complete disulfide bond formation and were retained in the
      ER. Our experiments suggest that LCs undergo both BiP-dependent and BiP
      independent folding steps, demonstrating that both ATP binding and hydrolysis
      activities of BiP are essential for the completion of LC folding in vivo and
      reveal that BiP must release before disulfide bond formation can occur in that
      domain.

PMID- 8643567
TI  - Cloning of thermostable DNA polymerases from hyperthermophilic marine Archaea
      with emphasis on Thermococcus sp. 9 degrees N-7 and mutations affecting 3'-5'
      exonuclease activity.
AB  - Five extremely thermophilic Archaea from hydrothermal vents were isolated, and
      their DNA polymerases were cloned and expressed in Escherichia coli. Protein
      splicing elements (inteins) are present in many archaeal DNA polymerases, but
      only the DNA polymerase from strain GB-C contained an intein. Of the five cloned
      DNA polymerases, the Thermococcus sp. 9 degrees N-7 DNA polymerase was chosen for
      biochemical characterization. Thermococcus sp. 9 degrees N-7 DNA polymerase
      exhibited temperature-sensitive strand displacement activity and apparent Km
      values for DNA and dNTP similar to those of Thermococcus litoralis DNA
      polymerase. Six substitutions in the 3'-5' exonuclease motif I were constructed
      in an attempt to reduce the 3'-5' exonuclease activity of Thermococcus sp. 9
      degrees N-7 DNA polymerase. Five mutants resulted in no detectable 3'-5'
      exonuclease activity, while one mutant (Glul43Asp) had <1% of wild-type activity.

PMID- 8643569
TI  - Late Holocene human-induced modifications to a central Polynesian island
      ecosystem.
AB  - A 7000-year-long sequence of environmental change during the Holocene has been
      reconstructed for a central Pacific island (Mangaia, Cook Islands). The research
      design used geomorphological and palynological methods to reconstruct vegetation
      history, fire regime, and erosion and depositional rates, whereas archaeological
      methods were used to determine prehistoric Polynesian land use and resource
      exploitation. Certain mid-Holocene environmental changes are putatively linked
      with natural phenomena such as eustatic sea-level rise and periodic El Nino
      Southern Oscillation events. However, the most significant changes were initiated
      between 2500 and 1800 years and were directly or indirectly associated with
      colonization by seafaring Polynesian peoples. These human-induced effects
      included major forest clearance, increased erosion of volcanic hillsides and
      alluvial deposition in valley bottoms, significant increases in charcoal influx,
      extinctions of endemic terrestrial species, and the introduction of exotic
      species.

PMID- 8643568
TI  - Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195
      kDa protein with a large regulatory domain.
AB  - The coding sequence of rat MEK kinase 1 (MEKK1) has been determined from
      multiple, independent cDNA clones. The cDNA is full-length based on the presence
      of stop codons in all three reading frames of the 5' untranslated region. Probes
      from the 5' and the 3' coding sequences both hybridize to a 7-kb mRNA. The open
      reading frame is 4.5 kb and predicts a protein with molecular mass of 161,225 Da,
      which is twice the size of the previously published MEKK1 sequence and reveals
      801 amino acids of novel coding sequence. The novel sequence contains two
      putative pH domains, two proline-rich regions, and a cysteine-rich region.
      Antisera to peptides derived from this new sequence recognize an endogenous
      protein in human and rodent cells of 195 kDa, consistent with the size of the
      expressed rat MEKK1 clone. Endogenous and recombinant rat MEKK1 are enriched in
      membranes; little of either is found in soluble fractions. Expression of
      recombinant rat MEKK1 leads to activation of three mitogen-activated protein
      kinase modules in the order c-Jun N-terminal kinase/stress-activated protein
      kinase > p38 mitogen-activated protein kinase = extracellular signal-regulated
      kinase 2.

PMID- 8643570
TI  - Heat-shock protein 104 expression is sufficient for thermotolerance in yeast.
AB  - In all organisms, mild heat pretreatments induce tolerance to high temperatures.
      In the yeast Saccharomyces cerevisiae, such pretreatments strongly induce heat
      shock protein (Hsp) 104, and hsp104 mutations greatly reduce high-temperature
      survival, indicating Hsp1O4 plays a critical role in induced thermotolerance.
      Surprisingly, however, a heat-shock transcription factor mutation (hsf1-m3) that
      blocks the induction of Hsps does not block induced thermotolerance. To resolve
      these apparent contradictions, we reexamined Hsp expression in hsf1-m3 cells.
      HsplO4 was expressed at a higher basal level in this strain than in other S.
      cerevisiae strains. Moreover, whereas the hsf1-m3 mutation completely blocked the
      induction of Hsp26 by heat, it did not block the induction of Hsp1O4. HSP104
      could not be deleted in hsf1-m3 cells because the expression of heat-shock factor
      (and the viability of the strain) requires nonsense suppression mediated by the
      yeast prion [PSI+], which in turn depends upon Hsp1O4. To determine whether the
      level of Hsp1O4 expressed in hsf1-m3 cells is sufficient for thermotolerance, we
      used heterologous promoters to regulate Hsp1O4 expression in other strains. In
      the presence of other inducible factors (with a conditioning pretreatment), low
      levels of Hsp1O4 are sufficient to provide full thermotolerance. More remarkably,
      in the absence of other inducible factors (without a pretreatment), high levels
      of Hsp1O4 are sufficient. We conclude that Hsp1O4 plays a central role in
      ameliorating heat toxicity. Because Hsp1O4 is nontoxic and highly conserved,
      manipulating the expression of Hsp1OO proteins provides an excellent prospect for
      manipulating thermotolerance in other species.

PMID- 8643571
TI  - Adenine phosphoribosyltransferase-deficient mice develop 2,8-dihydroxyadenine
      nephrolithiasis.
AB  - Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal
      recessive syndrome characterized by the urinary excretion of adenine and the
      highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney
      stones or renal failure. Targeted homologous recombination in embryonic stem
      cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt
      allele excrete adenine and DHA crystals in the urine. Renal histopathology showed
      extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in
      severity between different mouse backgrounds. Thus, biochemical and histological
      changes in these mice mimic the human disease and provide a suitable model of
      human hereditary nephrolithiasis.

PMID- 8643572
TI  - The transcription factors c-myb and GATA-2 act independently in the regulation of
      normal hematopoiesis.
AB  - The transcription factors c-myb and GATA-2 are both required for blood cell
      development in vivo and in vitro. However, very little is known on their
      mechanism(s) of action and whether they impact on complementary or overlapping
      pathways of hematopoietic proliferation and differentiation. We report here that
      embryonic stem (ES) cells transfected with c-myb or GATA-2 cDNAs, individually or
      in combination, underwent hematopoietic commitment and differentiation in the
      absence of added hematopoietic growth factors but that stimulation with c-kit and
      flt-3 ligands enhanced colony formation only in the c-myb transfectants. This
      enhancement correlated with c-kit and flt-3 surface receptor up-regulation in c
      myb-(but not GATA-2-) transfected ES cells. Transfection of ES cells with either
      a c-myb or a GATA-2 antisense construct abrogated erythromyeloid colony-forming
      ability in methyl cellulose; however, introduction of a full-length GATA-2 or c
      myb cDNA, respectively, rescued the hematopoiesis-deficient phenotype, although
      only c-myb-rescued ES cells expressed c-kit and flt-3 surface receptors and
      formed increased numbers of hematopoietic colonies upon stimulation with the
      cognate ligands. These results are in agreement with previous studies indicating
      a fundamental role of c-myb and GATA-2 in hematopoiesis. Of greater importance,
      our studies suggest that GATA-2 and c-myb exert their roles in hematopoietic gene
      regulation through distinct mechanisms of action in nonoverlapping pathways.

PMID- 8643573
TI  - Bcl-2 interrupts the ceramide-mediated pathway of cell death.
AB  - Ceramide, a product of sphingomyelin turn-over, has been proposed as a novel
      lipid second messenger with specific roles in mediating antiproliferative
      responses including apoptosis and cell cycle arrest. In this study, we examine
      the relationship between the ceramide-mediated pathway of growth suppression and
      the bcl-2 protooncogene. In ALL-697 leukemia cells, the addition of the
      chemotherapeutic agent vincristine resulted in a time-dependent growth
      suppression characterized by marked apoptosis. The effects of vincristine on cell
      death were preceded by a prolonged and sustained accumulation of endogenous
      ceramide levels reaching -10.4 pmol ceramide/nmol phospholipids at 12 hr
      following the addition of vincristine--an increase of 220% over vehicle-treated
      cells. Overexpression of bcl-2 resulted in near total protection of cell death in
      response to vincristine. However, the ceramide response to vincristine was not
      modulated by overexpression of bcl-2, indicating that bcl-2 does not interfere
      with ceramide formation. Overexpression of bcl-2 prevented apoptosis in response
      to ceramide, suggesting that bcl-2 acts at a point downstream of ceramide. On the
      other hand, bcl-2 did not interfere with the ability of ceramide to activate the
      retinoblastoma gene product or to induce cell cycle arrest, suggesting that the
      effects of ceramide on cell cycle arrest can be dissociated from the effects on
      apoptosis. These studies suggest that ceramide and bcl-2 partake in a common
      pathway of cell regulation. The results also cast ceramide as a gauge of cell
      injury rather than an "executor" of cell death with clearly dissociable
      biological outcomes of its action depending on downstream factors.

PMID- 8643574
TI  - NMR studies of muscle glycogen synthesis in insulin-resistant offspring of
      parents with non-insulin-dependent diabetes mellitus immediately after glycogen
      depleting exercise.
AB  - To examine the impact of insulin resistance on the insulin-dependent and insulin
      independent portions of muscle glycogen synthesis during recovery from exercise,
      we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of
      individuals with non-insulin-dependent diabetes mellitus and eight age-weight
      matched control (CON) subjects after plantar flexion exercise that lowered muscle
      glycogen to approximately 25% of resting concentration. After approximately 20
      min of exercise, intramuscular glucose 6-phosphate and glycogen were
      simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise
      rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the
      initial insulin independent portion (0-1 hr of recovery) were similar in the two
      groups (IR, 15.5 +/- 1.3 mM/hr and CON, 15.8 +/- 1.7 mM/hr); however, over the
      next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the
      IR group [IR, 0.1 +/- 0.5 mM/hr and CON, 2.9 +/- 0.2 mM/hr; (P < or = 0.001)].
      After exercise there was an initial rise in glucose 6-phosphate concentrations
      that returned to baseline after the first hour of recovery in both groups. In
      summary, we found that following muscle glycogen-depleting exercise, IR offspring
      of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of
      muscle glycogen synthesis during the insulin-independent phase of recovery from
      exercise and (ii) severely diminished rates of muscle glycogen synthesis during
      the subsequent recovery period (2-5 hr), which has previously been shown to be
      insulin-dependent in normal CON subjects. These data provide evidence that
      exercise and insulin stimulate muscle glycogen synthesis in humans by different
      mechanisms and that in the IR subjects the early response to stimulation by
      exercise is normal.

PMID- 8643575
TI  - Expression of Norwalk virus capsid protein in transgenic tobacco and potato and
      its oral immunogenicity in mice.
AB  - Alternatives to cell culture systems for production of recombinant proteins could
      make very safe vaccines at a lower cost. We have used genetically engineered
      plants for expression of candidate vaccine antigens with the goal of using the
      edible plant organs for economical delivery of oral vaccines. Transgenic tobacco
      and potato plants were created that express the capsid protein of Norwalk virus,
      a calicivirus that causes epidemic acute gastroenteritis in humans. The capsid
      protein could be extracted from tobacco leaves in the form of 38-nm Norwalk virus
      like particles. Recombinant Norwalk virus-like particle (rNV) was previously
      recovered when the same gene was expressed in recombinant baculovirus-infected
      insect cells. The capsid protein expressed in tobacco leaves and potato tubers
      cosedimented in sucrose gradients with insect cell-derived rNV and appeared
      identical to insect cell-derived rNV on immunoblots of SDS/polyacrylamide gels.
      The plant-expressed rNV was orally immunogenic in mice. Extracts of tobacco leaf
      expressing rNV were given to CD1 mice by gavage, and the treated mice developed
      both serum IgG and secretory IgA specific for rNV. Furthermore, when potato
      tubers expressing rNV were fed directly to mice, they developed serum IgG
      specific for rNV. These results indicate the potential usefulness of plants for
      production and delivery of edible vaccines. This is an appropriate technology for
      developing countries where vaccines are urgently needed.

PMID- 8643576
TI  - Direct observation of iron-induced conformational changes of mitochondrial DNA by
      high-resolution field-emission in-lens scanning electron microscopy.
AB  - When respiring rat liver mitochondria are incubated in the presence of Fe(III)
      gluconate, their DNA (mtDNA) relaxes from the supercoiled to the open circular
      form dependent on the iron dose. Anaerobiosis or antioxidants fail to completely
      inhibit the unwinding. High-resolution field-emission in-lens scanning electron
      microscopy imaging, in concert with backscattered electron detection, pinpoints
      nanometer-range iron colloids bound to mtDNA isolated from iron-exposed
      mitochondria. High-resolution field-emission in-lens scanning electron microscopy
      with backscattered electron detection imaging permits simultaneous detailed
      visual analysis of DNA topology, iron dose-dependent mtDNA unwinding, and
      assessment of iron colloid formation on mtDNA strands.

PMID- 8643577
TI  - Expression of a renal type I sodium/phosphate transporter (NaPi-1) induces a
      conductance in Xenopus oocytes permeable for organic and inorganic anions.
AB  - Two distinct molecular types (I and II) of renal proximal tubular brush border
      Na+/Pi cotransporters have been identified by expression cloning on the basis of
      their capacity to induce Na+-dependent Pi influx in tracer experiments. Whereas
      the type II transporters (e.g., NaPi-2 and NaPi-3) resemble well known
      characteristics of brush border Na+/Pi cotransport, little is known about the
      properties of the type I transporter (NaPi-1). In contrast to type II, type I
      transporters produced electrogenic transport only at high extracellular Pi
      concentrations (> or =3 mM). On the other hand, expression of NaPi-1 induced a Cl
      conductance in Xenopus laevis oocytes, which was inhibited by Cl- channel
      blockers [5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) > niflumic acid >>
      4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid]. Further, the Cl- conductance
      was inhibited by the organic anions phenol red, benzylpenicillin (penicillin G),
      and probenecid. These organic anions induced outwardly directed currents in the
      absence of Cl-. In tracer studies, we observed uptake of benzylpenicillin with a
      Km of 0.22 mM; benzylpenicillin uptake was inhibited by NPPB and niflumic acid.
      These findings suggest that the type I Na+/Pi cotransporter functions also as a
      novel type of anion channel permeable not only for Cl- but also for organic
      anions. Such an apical anion channel could serve an important role in the
      transport of Cl- and the excretion of anionic xenobiotics.

PMID- 8643578
TI  - Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to
      induce filamentous growth in Saccharomyces cerevisiae.
AB  - RAS2val19, a dominant activated form of Saccharomyces cerevisiae Ras2, stimulates
      both filamentous growth and expression of a transcriptional reporter
      FG(TyA)::lacZ but does not induce the mating pathway reporter FUS1::lacZ. This
      induction depends upon elements of the conserved mitogen-activated protein kinase
      (MAPK) pathway that is required for both filamentous growth and mating, two
      distinct morphogenetic events. Full induction requires Ste20 (homolog of
      mammalian p65PAK protein kinases), Ste11 [an MEK kinase (MEKK) or MAPK kinase
      (MEK) kinase], Ste7 (MEK or MAPK kinase), and the transcription factor Ste12.
      Moreover, the Rho family protein Cdc42, a conserved morphogenetic G protein, is
      also a potent regulator of filamentous growth and FG(TyA)::lacZ expression in S.
      cerevisiae. Stimulation of both filamentous growth and FG(TyA)::lacZ by Cdc42
      depends upon Ste20. In addition, dominant negative CDC42Ala118 blocks RAS2val19
      activation, placing Cdc42 downstream of Ras2. Our results suggest that
      filamentous growth in budding yeast is regulated by an evolutionarily conserved
      signaling pathway that controls cell morphology.

PMID- 8643579
TI  - Three-dimensional structure of human protein kinase C interacting protein 1, a
      member of the HIT family of proteins.
AB  - The three-dimensional structure of protein kinase C interacting protein 1 (PKCI
      1) has been solved to high resolution by x-ray crystallography using single
      isomorphous replacement with anomalous scattering. The gene encoding human PKCI-1
      was cloned from a cDNA library by using a partial sequence obtained from
      interactions identified in the yeast two-hybrid system between PKCI-1 and the
      regulatory domain of protein kinase C-beta. The PKCI-1 protein was expressed in
      Pichia pastoris as a dimer of two 13.7-kDa polypeptides. PKCI-1 is a member of
      the HIT family of proteins, shown by sequence identity to be conserved in a broad
      range of organisms including mycoplasma, plants, and humans. Despite the ubiquity
      of this protein sequence in nature, no distinct function has been shown for the
      protein product in vitro or in vivo. The PKCI-1 protomer has an alpha+beta
      meander fold containing a five-stranded antiparallel sheet and two helices. Two
      protomers come together to form a 10-stranded antiparallel sheet with extensive
      contacts between a helix and carboxy terminal amino acids of a protomer with the
      corresponding amino acids in the other protomer. PKCI-1 has been shown to
      interact specifically with zinc. The three-dimensional structure has been solved
      in the presence and absence of zinc and in two crystal forms. The structure of
      human PKCI-1 provides a model of this family of proteins which suggests a stable
      fold conserved throughout nature.

PMID- 8643581
TI  - Near-membrane [Ca2+] transients resolved using the Ca2+ indicator FFP18.
AB  - (Ca2+)-sensitive processes at cell membranes involved in contraction, secretion,
      and neurotransmitter release are activated in situ or in vitro by Ca2+
      concentrations ([Ca2+]) 10-100 times higher than [Ca2+] measured during
      stimulation in intact cells. This paradox might be explained if the local [Ca2+]
      at the cell membrane is very different from that in the rest of the cell. Soluble
      Ca2+ indicators, which indicate spatially averaged cytoplasmic [Ca2+], cannot
      resolve these localized, near-membrane [Ca2+] signals. FFP18, the newest Ca2+
      indicator designed to selectively monitor near-membrane [Ca2+], has a lower Ca2+
      affinity and is more water soluble than previously used membrane-associating Ca2+
      indicators. Images of the intracellular distribution of FFP18 show that >65% is
      located on or near the plasma membrane. [Ca2+] transients recorded using FFP18
      during membrane depolarization-induced Ca2+ influx show that near-membrane [Ca2+]
      rises faster and reaches micromolar levels at early times when the cytoplasmic
      [Ca2+], recorded using fura-2, has risen to only a few hundred nanomolar. High
      speed series of digital images of [Ca2+] show that near-membrane [Ca2+], reported
      by FFP18, rises within 20 msec, peaks at 50-100 msec, and then declines. [Ca2+]
      reported by fura-2 rose slowly and continuously throughout the time images were
      acquired. The existence of these large, rapid increases in [Ca2+] directly
      beneath the surface membrane may explain how numerous (Ca2+)-sensitive membrane
      processes are activated at times when bulk cytoplasmic [Ca2+] changes are too
      small to activate them.

PMID- 8643582
TI  - Disruption of the aldolase A tetramer into catalytically active monomers.
AB  - The fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) homotetramer has been
      destabilized by site-directed mutagenesis at the two different subunit
      interfaces. A double mutant aldolase, Q125D/E224A, sediments as two distinct
      species, characteristic of a slow equilibrium, with velocities expected for the
      monomer and tetramer. The aldolase monomer is shown to be catalytically active
      following isolation from sucrose density gradients. The isolated aldolase monomer
      had 72% of the specific activity of the wild-type enzyme and a slightly lower
      Michaelis constant, clearly indicating that the quaternary structure is not
      required for catalysis. Cross-linking of the isolated monomer confirmed that it
      does not rapidly reequilibrate with the tetramer following isolation. There was a
      substantial difference between the tetramer and monomer in their inactivation by
      urea. The stability toward both urea and thermal inactivation of these oligomeric
      variants suggests a role for the quaternary structure in maintaining the
      stability of aldolase, which may be an important role of quaternary structure in
      many proteins.

PMID- 8643580
TI  - Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9
      angstrom resolution.
AB  - The x-ray crystal structures of the sulfide oxidase antibody 28B4 and of antibody
      28B4 complexed with hapten have been solved at 2.2-angstrom and 1.9-angstrom
      resolution, respectively. To our knowledge, these structures are the highest
      resolution catalytic antibody structures to date and provide insight into the
      molecular mechanism of this antibody-catalyzed monooxygenation reaction.
      Specifically, the data suggest that entropic restriction plays a fundamental role
      in catalysis through the precise alignment of the thioether substrate and
      oxidant. The antibody active site also stabilizes developing charge on both
      sulfur and periodate in the transition state via cation-pi and electrostatic
      interactions, respectively. In addition to demonstrating that the active site of
      antibody 28B4 does indeed reflect the mechanistic information programmed in the
      aminophosphonic acid hapten, these high-resolution structures provide a basis for
      enhancing turnover rates through mutagenesis and improved hapten design.

PMID- 8643583
TI  - Ancestral major histocompatibility complex DRB genes beget conserved patterns of
      localized polymorphisms.
AB  - Genes within the major histocompatibility complex (MHC) are characterized by
      extensive polymorphism within species and also by a remarkable conservation of
      contemporary human allelic sequences in evolutionarily distant primates.
      Mechanisms proposed to account for strict nucleotide conservation in the context
      of highly variable genes include the suggestion that intergenic exchange
      generates repeated sets of MHC DRB polymorphisms [Gyllensten, U. B., Sundvall, M.
      & Erlich, H. A. (1991) Proc. Natl. Acad. Sci. USA 88, 3686-3690; Lundberg, A. S.
      & McDevitt, H. 0. (1992) Proc. Natl. Acad. Sci. USA 89, 6545-6549]. We analyzed
      over 50 primate MHC DRB sequences, and identified nucleotide elements within
      macaque and baboon DRB6-like sequences with deletions corresponding to specific
      exon 2 hypervariable regions, which encode a discrete alpha helical segment of
      the MHC antigen combining site. This precisely localized deletion provides direct
      evidence implicating segmental exchange of MHC-encoded DRB gene fragments as one
      of the evolutionary mechanisms both generating and maintaining MHC diversity.
      Intergenic exchange at this site may be fundamental to the diversification of
      immune protection in populations by permitting alteration in the specificity of
      the MHC that determines the repertoire of antigens bound.

PMID- 8643584
TI  - Phenotypic variations among paternal centrosomes expressed within the zygote as
      disparate microtubule lengths and sperm aster organization: correlations between
      centrosome activity and developmental success.
AB  - This study describes a paternal effect on sperm aster size and microtubule
      organization during bovine fertilization. Immunocytochemistry using tubulin
      antibodies quantitated with confocal microscopy was used to measure the diameter
      of the sperm aster and assign a score (0-3) based on the degree of radial
      organization (0, least organized; 3, most organized). Three bulls (A-C) were
      chosen based on varying fertility (A, lowest fertility; C, highest fertility) as
      assessed by nonreturn to estrus after artificial insemination and in vitro
      embryonic development to the blastocyst stage. The results indicate a
      statistically significant bull-dependent difference in diameter of the sperm
      aster and in the organization of the sperm astral microtubules. Insemination from
      bull A resulted in an average sperm aster diameter of 101.4 microm (76.3% of
      oocyte diameter). This significantly differs (P < or = 0.0001) from the average
      sperm aster diameters produced after inseminations from bull B (78.2 microm;
      60.8%) or bull C (77.9 microm; 57.8%), which themselves displayed no significant
      differences. The degree of radial organization of the sperm aster was also bull
      dependent. Sperm asters organized by bull A-derived sperm had an average quality
      score of 1.8, which was higher than that of bull B (1.4; P < or = 0.0005) or bull
      C (1.2; P < or = 0.0001). Results with bulls B and C were also significantly
      different (P < or = 0.025). These results indicate that the paternally derived
      portion of the centrosome varies among males and that this variation affects male
      fertility, the outcome of early development, and, therefore, reproductive
      success.

PMID- 8643585
TI  - Vip3A, a novel Bacillus thuringiensis vegetative insecticidal protein with a wide
      spectrum of activities against lepidopteran insects.
AB  - A novel vegetative insecticidal gene, vip3A(a), whose gene product shows activity
      against lepidopteran insect larvae including black cutworm (Agrotis ipsilon),
      fall armyworm (Spodoptera frugiperda), beet armyworm (Spodoptera exigua), tobacco
      budworm (Heliothis virescens), and corn earworm (Helicoverpa zea) has been
      isolated from Bacillus thuringiensis strain AB88. VIP3-insecticidal gene
      homologues have been detected in approximately 15% of Bacillus strains analyzed.
      The sequence of the vip3A(b) gene, a homologue of vip3A(a) isolated from B.
      thuringiensis strain AB424 is also reported. Vip3A(a) and (b) proteins confer
      upon Escherichia coli insecticidal activity against the lepidopteran insect
      larvae mentioned above. The sequence of the gene predicts a 791-amino acid (88.5
      kDa) protein that contains no homology with known proteins. Vip3A insecticidal
      proteins are secreted without N-terminal processing. Unlike the B. thuringiensis
      5-endotoxins, whose expression is restricted to sporulation, Vip3A insecticidal
      proteins are expressed in the vegetative stage of growth starting at mid-log
      phase as well as during sporulation. Vip3A represents a novel class of proteins
      insecticidal to lepidopteran insect larvae.

PMID- 8643586
TI  - Extremely sensitive, background-free gene detection using binary probes and beta
      replicase.
AB  - We have developed a specific and sensitive nucleic acid amplification assay that
      is suitable for routine gene detection. The assay is based on a novel molecular
      genetic strategy in which two different RNA probes are hybridized to adjacent
      positions on a target nucleic acid and then ligated to form an amplifiable
      reporter RNA. The reporter RNA is then replicated up to a hundred billion-fold in
      a 30-min isothermal reaction that signals the presence of the target. The assay
      can detect fewer than 100 nucleic acid molecules; it provides quantitative
      results over a wide range of target concentrations and it employs a universal
      format that can detect any infectious agent.

PMID- 8643588
TI  - Mechanism of photoreceptor cGMP phosphodiesterase inhibition by its gamma
      subunits.
AB  - cGMP phosphodiesterase (PDE) is the key effector enzyme of vertebrate
      photoreceptor cells that regulates the level of the second messenger, cGMP. PDE
      consists of catalytic alpha and beta subunits (Palpha and Pbeta) and two
      inhibitory gamma subunits (Pgamma) that block PDE activity in the dark. The major
      inhibitory region has been localized to the C terminus of Pgamma. The last C
      terminal residues -IleIle form an important hydrophobic domain critical for the
      inhibition of PDE activity. In this study, mutants of Pgamma were designed for
      cross-linking experiments to identify regions on Palpha and Pbeta subunits that
      bind to the Pgamma C terminus. In one of the mutants, the cysteine at position 68
      was substituted with serine, and the last four C-terminal residues of Pgamma were
      replaced with a single cysteine. This mutant, Pgamma83Cys, was labeled with
      photoprobe 4-(N-maleimido) benzophenone (MBP) at the cysteine residue. The
      labeled Pgamma83CysMBP mutant was a more potent inhibitor of PDE activity than
      the unlabeled mutant, indicating that the hydrophobic MBP probe mimics the Pgamma
      hydrophobic C terminus. A specific, high-yield cross-linking of up to 70% was
      achieved between the Pgamma83CysMBP and PDE catalytic subunits. Palpha and the N
      terminally truncated Pbeta (lacking 147 aa residues) cross-linked to
      Pgamma83CysMBP with the same efficiency. Using mass spectrometric analysis of
      tryptic fragments from the cross-linked PDE, we identified the site of cross
      linking to aa residues 751-763 of Palpha. The corresponding region of Pbeta,
      Pbeta-749-761, also may bind to the Pgamma C terminus. Our data suggest that
      Pgamma blocks PDE activity through the binding to the catalytic site of PDE, near
      the NKXD motif, a consensus sequence for interaction with the guanine ring of
      cGMP.

PMID- 8643587
TI  - Molecular cloning and expression of a cyclic AMP-activated chloride conductance
      regulator: a novel ATP-binding cassette transporter.
AB  - Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-regulated,
      cAMP-activated chloride channel located in the apical membrane of many epithelial
      secretory cells. Here we report cloning of a cAMP-activated epithelial
      basolateral chloride conductance regulator (EBCR) that appears to be a
      basolateral CFTR counterpart. This novel chloride channel or regulator shows 49%
      identity with multidrug resistance-associated protein (MRP) and 29% identity with
      CFTR. On expression in Xenopus oocytes, EBCR confers a cAMP-activated chloride
      conductance that is inhibited by the chloride channel blockers niflumic acid, 5
      nitro-2-(3-phenylpropylamine)benzoic acid, and 4,4'-diisothiocyanatostilbene-2,2'
      disulfonic acid. Northern blot analysis reveals high expression in small
      intestine, kidney, and liver. In kidney, immunohistochemistry shows a conspicuous
      basolateral localization mainly in the thick ascending limb of Henle's loop,
      distal convoluted tubules and to a lesser extent connecting tubules. These data
      suggest that in the kidney EBCR is involved in hormone-regulated chloride
      reabsorption.

PMID- 8643589
TI  - Intrasarcomere [Ca2+] gradients in ventricular myocytes revealed by high speed
      digital imaging microscopy.
AB  - Cardiac muscle contraction is triggered by a small and brief Ca2+ entry across
      the t-tubular membranes, which is believed to be locally amplified by release of
      Ca2+ from the adjacent junctional sarcoplasmic reticulum (SR). As Ca2+ diffusion
      is thought to be markedly attenuated in cells, it has been predicted that
      significant intrasarcomeric [Ca2+] gradients should exist during activation. To
      directly test for this, we measured [Ca2+] distribution in single cardiac
      myocytes using fluorescent [Ca2+] indicators and high speed, three-dimensional
      digital imaging microscopy and image deconvolution techniques. Steep cytosolic
      [Ca2+] gradients from the t-tubule region to the center of the sarcomere
      developed during the first 15 ms of systole. The steepness of these [Ca2+]
      gradients varied with treatments that altered Ca2+ release from internal stores.
      Electron probe microanalysis revealed a loss of Ca2+ from the junctional SR and
      an accumulation, principally in the A-band during activation. We propose that the
      prolonged existence of [Ca2+] gradients within the sarcomere reflects the
      relatively long period of Ca2+ release from the SR, the localization of Ca2+
      binding sites and Ca2+ sinks remote from sites of release, and diffusion
      limitations within the sarcomere. The large [Ca2+] transient near the t-tubular/
      junctional SR membranes is postulated to explain numerous features of excitation
      contraction coupling in cardiac muscle.

PMID- 8643590
TI  - Recombinational repair of gaps in DNA is asymmetric in Ustilago maydis and can be
      explained by a migrating D-loop model.
AB  - Recombinational repair of double-stranded DNA gaps was investigated in Ustilago
      maydis. The experimental system was designed for analysis of repair of an
      autonomously replicating plasmid containing a cloned gene disabled by an internal
      deletion. It was discovered that crossing over rarely accompanied gap repair. The
      strong bias against crossing over was observed in three different genes
      regardless of gap size. These results indicate that gap repair in U. maydis is
      unlikely to proceed by the mechanism envisioned in the double-stranded break
      repair model of recombination, which was developed to account for recombination
      in Saccharomyces cerevisiae. Experiments aimed at exploring processing of DNA
      ends were performed to gain understanding of the mechanism responsible for the
      observed bias. A heterologous insert placed within a gap in the coding sequence
      of two different marker genes strongly inhibited repair if the DNA was cleaved at
      the promoter-proximal junction joining the insert and coding sequence but had
      little effect on repair if the DNA was cleaved at the promoter-distal junction.
      Gene conversion of plasmid restriction fragment length polymorphism markers
      engineered in sequences flanking both sides of a gap accompanied repair but was
      directionally biased. These results are interpreted to mean that the DNA ends
      flanking a gap are subject to different types of processing. A model featuring a
      single migrating D-loop is proposed to explain the bias in gap repair outcome
      based on the observed asymmetry in processing the DNA ends.

PMID- 8643591
TI  - Differential effects of staphylococcal toxic shock syndrome toxin-1 on B cell
      apoptosis.
AB  - Superantigens, such as toxic shock syndrome toxin 1 (TSST-1), have been
      implicated in the pathogenesis of several autoimmune and allergic diseases
      associated with polyclonal B cell activation. In this report, we studied the in
      vitro effects of TSST-1 on B cell activation. We show herein that TSST-1 produced
      antagonistic effects on Ig synthesis by peripheral blood mononuclear cells (PBMC)
      from normal subjects, depending on the concentration used; Ig production was
      inhibited at 1000 pg/ml (P < 0.01) and enhanced at 1 and 0.01 pg/ml (P < 0.01) of
      toxin. Cultures of PBMC were then examined for morphologic features and DNA
      fragmentation characteristic for apoptosis. B cells exhibited a significantly
      higher (P < 0.01) incidence of apoptosis after stimulation with 1000 pg/ml of
      TSST-1 compared with 1 or 0.01 pg/ml of toxin or medium alone. Abundant
      expression of Fas, a cell surface protein that mediates apoptosis, was detected
      on B cells after stimulation with 1000 pg/ml of TSST-1 and was significantly
      higher on B cells undergoing apoptosis than on live cells (P = 0.01).
      Additionally, increased Fas expression and B cell death occurred at
      concentrations of TSST-1 inducing the production of high amounts of gamma
      interferon (IFN-gamma), and both events could be blocked by neutralizing anti-IFN
      gamma antibody. These findings suggest that high concentrations of TSST-1 can
      induce IFN-gamma-dependent B cell apoptosis, whereas at low concentrations it
      stimulates Ig synthesis by PBMC from normal subjects. These findings support the
      concept that staphylococcal toxins have a role in B cell hyperactivity in
      autoimmunity and allergy.

PMID- 8643592
TI  - Targeted disruption of the mZP3 gene results in production of eggs lacking a zona
      pellucida and infertility in female mice.
AB  - Mammalian eggs are surrounded by a thick extracellular coat, the zona pellucida,
      that plays important roles during early development. The mouse egg zona pellucida
      is constructed of three glycoproteins, called mZP1, mZP2, and mZP3. The gene
      encoding mZP3 is expressed only by growing oocytes during a 2- to 3-week period
      of oogenesis. Here, the mZP3 gene was disrupted by targeted mutagenesis using
      homologous recombination in mouse embryonic stem cells. Viable female mice
      homozygous for the mutated mZP3 allele (mZP3-/-) were obtained. These mice are
      indistinguishable in appearance from wild-type (mZP3+/+) and heterozygous (mZP3+/
      ) littermates. However, although ovaries of juvenile and adult mZP3-/- females
      possess growing and fully grown oocytes, the oocytes completely lack a zona
      pellucida. Consistent with this observation, eggs recovered from oviducts of
      superovulated, adult mZP3-/- females also lack a zona pellucida. Thus far, mZP3-/
      females mated with wild-type males have failed to become pregnant.

PMID- 8643593
TI  - Purification and cDNA cloning of a second apoptosis-related cysteine protease
      that cleaves and activates sterol regulatory element binding proteins.
AB  - We have purified from hamster liver a second cysteine protease that cleaves and
      activates sterol regulatory element binding proteins (SREBPs). cDNA cloning
      revealed that this enzyme is the hamster equivalent of Mch3, a human enzyme that
      is related to the interleukin 1beta converting enzyme. We call this enzyme
      Mch3/SCA-2. It is 54% identical to hamster CPP32/SCA-1, a cysteine protease that
      was earlier shown to cleave SREBPs at a conserved Asp between the basic helix
      loop-helix leucine zipper domain and the membrane attachment domain. This
      cleavage liberates an NH2-terminal fragment of approximately 460 amino acids that
      activates transcription of genes encoding the low density lipoprotein receptor
      and enzymes of cholesterol synthesis. Mch3/SCA-2 and CPP32/SCA-I are synthesized
      as inactive 30-35 kDa precursors that are thought to be cleaved during apoptosis
      to generate active fragments of approximately 20 and approximately 10 kDa. The
      current data lend further support to the notion that SREBPs are cleaved and
      activated as part of the program in programmed cell death.

PMID- 8643594
TI  - Conserved motifs in prokaryotic and eukaryotic polypeptide release factors: tRNA
      protein mimicry hypothesis.
AB  - Translation termination requires two codon-specific polypeptide release factors
      in prokaryotes and one omnipotent factor in eukaryotes. Sequences of 17 different
      polypeptide release factors from prokaryotes and eukaryotes were compared. The
      prokaryotic release factors share residues split into seven motifs. Conservation
      of many discrete, perhaps critical, amino acids is observed in eukaryotic release
      factors, as well as in the C-terminal portion of elongation factor (EF) G. Given
      that the C-terminal domains of EF-G interacts with ribosomes by mimicry of a tRNA
      structure, the pattern of conservation of residues in release factors may reflect
      requirements for a tRNA-mimicry for binding to the A site of the ribosome. This
      mimicry would explain why release factors recognize stop codons and suggests that
      all prokaryotic and eukaryotic release factors evolved from the progenitor of EF
      G.

PMID- 8643595
TI  - Evolutionary relationships of the coelacanth, lungfishes, and tetrapods based on
      the 28S ribosomal RNA gene.
AB  - The origin of land vertebrates was one of the major transitions in the history of
      vertebrates. Yet, despite many studies that are based on either morphology or
      molecules, the phylogenetic relationships among tetrapods and the other two
      living groups of lobe-finned fishes, the coelacanth and the lungfishes, are still
      unresolved and debated. Knowledge of the relationships among these lineages,
      which originated back in the Devonian, has profound implications for the
      reconstruction of the evolutionary scenario of the conquest of land. We collected
      the largest molecular data set on this issue so far, about 3,500 base pairs from
      seven species of the large 28S nuclear ribosomal gene. All phylogenetic analyses
      (maximum parsimony, neighbor-joining, and maximum likelihood) point toward the
      hypothesis that lungfishes and coelacanths form a monophyletic group and are
      equally closely related to land vertebrates. This evolutionary hypothesis
      complicates the identification of morphological or physiological preadaptations
      that might have permitted the common ancestor of tetrapods to colonize land. This
      is because the reconstruction of its ancestral conditions would be hindered by
      the difficulty to separate uniquely derived characters from shared derived
      characters in the coelacanth/lungfish and tetrapod lineages. This molecular
      phylogeny aids in the reconstruction of morphological evolutionary steps by
      providing a framework; however, only paleontological evidence can determine the
      sequence of morphological acquisitions that allowed lobe-finned fishes to
      colonize land.

PMID- 8643596
TI  - Mechanism for transcriptional gain of function resulting from chromosomal
      translocation in alveolar rhabdomyosarcoma.
AB  - The t(2;13) translocation of alveolar rhabdomyosarcoma results in tumor-specific
      expression of a chimeric transcription factor containing the N-terminal DNA
      binding domain of PAX3 and the C-terminal transactivation domain of FKHR. Here we
      have tested the hypothesis that PAX3-FKHR gains function relative to PAX3 as a
      consequence of switching PAX3 and FKHR transactivation domains, which were
      previously shown to have similar potency but distinct structural motifs. In
      transient cotransfection assays with human expression constructs, we have
      demonstrated the increased ability of PAX3-FKHR to activate transcription of a
      reporter gene located downstream of multimerized e5, PRS-9, or CD19 DNA-binding
      sites in three cell lines. For example, PAX3-FKHR was 100-fold more potent than
      PAX3 as an activator binding to e5 sites in NIH 3T3 cells. To compare
      transactivation potency independent of PAX3-specific DNA binding, we tested GAL4
      fusions of full-length PAX3 and PAX3-FKHR or their respective C-terminal
      transactivation domains on a reporter with GAL4 DNA-binding sites. In this
      context, full-length PAX3-FKHR was also much more potent than PAX3. Additionally,
      the activity of each full-length protein was decreased relative to its C-terminal
      domain, demonstrating that N-terminal sequences are inhibitory. By deletion
      analysis, we mapped a bipartite cis-acting inhibitory domain to the same
      subregions within the DNA-binding domains of both PAX3 and PAX3-FKHR. We have
      shown, however, that the structurally distinct transactivation domains of PAX3
      and PAX3-FKHR differ 10- to 100-fold in their susceptibility to inhibition, thus
      elucidating a mechanism by which PAX3 gains enhanced function during oncogenesis.

PMID- 8643597
TI  - Irreversible inactivation of interleukin 2 in a pump-based delivery environment.
AB  - The physical stability of pharmaceutical proteins in delivery environments is a
      critical determinant of biological potency and treatment efficacy, and yet it is
      often taken for granted. We studied both the bioactivity and physical stability
      of interleukin 2 upon delivery via continuous infusion. We found that the
      biological activity of the delivered protein was dramatically reduced by
      approximately 90% after a 24-hr infusion program. Only a portion of these losses
      could be attributed to direct protein deposition on the delivery surfaces.
      Analysis of delivered protein by size exclusion chromatography gave no indication
      of insulin-like, surface-induced aggregation phenomena. Examination of the
      secondary and tertiary structure of both adsorbed and delivered protein via
      Fourier-transform infrared spectroscopy, circular dichroism, and fluorescence
      spectroscopy indicated that transient surface association of interleukin 2 with
      the catheter tubing resulted in profound, irreversible structural changes that
      were responsible for the majority of the biological activity losses.

PMID- 8643598
TI  - The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase,
      contains a protein kinase domain, and has separate rac-specific and rho-specific
      guanine nucleotide exchange factor domains.
AB  - rho-like GTP binding proteins play an essential role in regulating cell growth
      and actin polymerization. These molecular switches are positively regulated by
      guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP for
      GTP. Using the interaction-trap assay to identify candidate proteins that bind
      the cytoplasmic region of the LAR transmembrane protein tyrosine phosphatase (PT
      Pase), we isolated a cDNA encoding a 2861-amino acid protein termed Trio that
      contains three enzyme domains: two functional GEF domains and a protein
      serine/threonine kinase (PSK) domain. One of the Trio GEF domains (Trio GEF-D1)
      has rac-specific GEF activity, while the other Trio GEF domain (Trio GEF-D2) has
      rho-specific activity. The C-terminal PSK domain is adjacent to an Ig-like domain
      and is most similar to calcium/calmodulin-dependent kinases, such as smooth
      muscle myosin light chain kinase which similarly contains associated Ig-like
      domains. Near the N terminus, Trio has four spectrin-like repeats that may play a
      role in intracellular targeting. Northern blot analysis indicates that Trio has a
      broad tissue distribution. Trio appears to be phosphorylated only on serine
      residues, suggesting that Trio is not a LAR substrate, but rather that it forms a
      complex with LAR. As the LAR PTPase localizes to the ends of focal adhesions, we
      propose that LAR and the Trio GEF/PSK may orchestrate cell-matrix and
      cytoskeletal rearrangements necessary for cell migration.

PMID- 8643599
TI  - The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing
      mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages
      of the disease.
AB  - Dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase have been
      found in members of certain families with familial amyotrophic lateral sclerosis
      (ALS). To better understand the contribution of SOD1 mutations in the
      pathogenesis of familial ALS, we developed transgenic mice expressing one of the
      mutations found in familial ALS. These animals display clinical and pathological
      features closely resembling human ALS. Early changes observed in these animals
      were intra-axonal and dendritic vacuoles due to dilatation of the endoplasmic
      reticulum and vacuolar degeneration of mitochondria. We have reported that the
      Golgi apparatus of spinal cord motor neurons in patients with sporadic ALS is
      fragmented and atrophic. In this study we show that spinal cord motor neurons of
      transgenic mice for an SOD1 mutation display a lesion of the Golgi apparatus
      identical to that found in humans with sporadic ALS. In these mice, the stacks of
      the cisternae of the fragmented Golgi apparatus are shorter than in the normal
      organelle, and there is a reduction in Golgi-associated vesicles and adjacent
      cisternae of the rough endoplasmic reticulum. Furthermore, the fragmentation of
      the Golgi apparatus occurs in an early, presymptomatic stage and usually precedes
      the development of the vacuolar changes. Transgenic mice overexpressing the wild
      type human superoxide dismutase are normal. In familial ALS, an early lesion of
      the Golgi apparatus of motor neurons may have adverse functional effects, because
      newly synthesized proteins destined for fast axoplasmic transport pass through
      the Golgi apparatus.

PMID- 8643600
TI  - Ca2+ channel blockers modulate metabolism of collagens within the extracellular
      matrix.
AB  - The extracellular matrix (ECM) is an intricate network composed of an array of
      macromolecules capable of regulating the functional responsiveness of cells. Its
      composition greatly varies among different types of tissue, and dysregulation of
      its metabolism may contribute to vascular remodeling during the pathogenesis of
      various diseases, including atherosclerosis. In view of their antiatherosclerotic
      effects, the role of Ca2+ channel blockers in the metabolism of ECM was examined.
      Nanomolar concentrations of the five Ca2+ channel blockers amlodipine,
      felodipine, manidipine, verapamil, or diltiazem significantly decreased both the
      constitutive and platelet-derived growth factor BB-dependent collagen deposition
      in the ECM formed by human vascular smooth muscle cells and fibroblasts. The
      drugs inhibited the expression of fibrillar collagens type I and III and of
      basement membrane type IV collagen. Furthermore, Ca2+ channel blockers
      specifically increased the proteolytic activity of the 72-kDa type IV collagenase
      as shown by gelatin zymography and inhibited the transcription of tissue
      inhibitor of metalloproteinases-2.

PMID- 8643601
TI  - A locus on chromosome 7 determines myocardial cell necrosis and calcification
      (dystrophic cardiac calcinosis) in mice.
AB  - Dystrophic cardiac calcinosis, an age-related cardiomyopathy that occurs among
      certain inbred strains of mice, involves myocardial injury, necrosis, and
      calcification. Using a complete linkage map approach and quantitative trait locus
      analysis, we sought to identify genetic loci determining dystrophic cardiac
      calcinosis in an F2 intercross of resistant C57BL/6J and susceptible C3H/HeJ
      inbred strains. We identified a single major locus, designated Dyscalc, located
      on proximal chromosome 7 in a region syntenic with human chromosomes 19q13 and
      11p15. The statistical significance of Dyscalc (logarithm of odds score 14.6) was
      tested by analysis of permuted trait data. Analysis of BxH recombinant inbred
      strains confirmed the mapping position. The inheritance pattern indicated that
      this locus influences susceptibility of cells both to enter necrosis and to
      subsequently undergo calcification.

PMID- 8643602
TI  - Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted
      aequorin: significance for the regulation of pyruvate dehydrogenase activity.
AB  - Specific targeting of the recombinant, Ca2+ -sensitive photoprotein, aequorin to
      intracellular organelles has provided new insights into the mechanisms of
      intracellular Ca2+ homeostasis. When applied to small mammalian cells, a major
      limitation of this technique has been the need to average the signal over a large
      number of cells. This prevents the identification of inter- or intracellular
      heterogeneities. Here we describe the imaging in single mammalian cells (CHO.T)
      of [Ca2+] with recombinant chimeric aequorin targeted to mitochondria. This was
      achieved by optimizing expression of the protein through intranuclear injection
      of cDNA and through the use of a charge-coupled device camera fitted with a dual
      microchannel plate intensifier. This approach allows accurate quantitation of the
      kinetics and extent of the large changes in mitochondrial matrix [Ca2+]
      ([Ca2+](m)) that follow receptor stimulation and reveal different behaviors of
      mitochondrial populations within individual cells. The technique is compared with
      measurements of [Ca2+](m) using the fluorescent indicator, rhod2. Comparison of
      [Ca2+](m) with the activity of the Ca2+ -sensitive matrix enzyme, pyruvate
      dehydrogenase (PDH), reveals that this enzyme is a target of the matrix [Ca2+]
      changes. Peak [Ca2+](m) values following receptor stimulation are in excess of
      those necessary for full activation of PDH in situ, but may be necessary for the
      activation of other mitochondrial dehydrogenases. Finally, the data suggest that
      the complex regulation of PDH activity by a phosphorylation-dephosphorylation
      cycle may provide a means by which changes in the frequency of cytosolic (and
      hence mitochondrial) [Ca2+] oscillations can be decoded by mitochondria.

PMID- 8643603
TI  - Cellular and subcellular localization of the vasopressin- regulated urea
      transporter in rat kidney.
AB  - The renal urea transporter (RUT) is responsible for urea accumulation in the
      renal medulla, and consequently plays a central role in the urinary concentrating
      mechanism. To study its cellular and subcellular localization, we prepared
      affinity-purified, peptide-derived polyclonal antibodies against rat RUT based on
      the cloned cDNA sequence. Immunoblots using membrane fractions from rat renal
      inner medulla revealed a solitary 97-kDa band. Immunocytochemistry demonstrated
      RUT labeling of the apical and subapical regions of inner medullary collecting
      duct (IMCD) cells, with no labeling of outer medullary or cortical collecting
      ducts. Immunoelectron microscopy directly demonstrated labeling of the apical
      plasma membrane and of subapical intracellular vesicles of IMCD cells, but no
      labeling of the basolateral plasma membrane. Immunoblots demonstrated RUT
      labeling in both plasma membrane and intracellular vesicle-enriched membrane
      fractions from inner medulla, a subcellular distribution similar to that of the
      vasopressin-regulated water channel, aquaporin-2. In the outer medulla, RUT
      labeling was seen in terminal portions of short-loop descending thin limbs. Aside
      from IMCD and descending thin limbs, no other structures were labeled in the
      kidney. These results suggest that: (i) the RUT provides the apical pathway for
      rapid, vasopressin-regulated urea transport in the IMCD, (ii) collecting duct
      urea transport may be increased by vasopressin by stimulation of trafficking of
      RUT-containing vesicles to the apical plasma membrane, and (iii) the rat urea
      transporter may provide a pathway for urea entry into the descending limbs of
      short-loop nephrons.

PMID- 8643604
TI  - Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid
      change in reverse transcriptase are responsible for the loss of human
      immunodeficiency virus type 1 RNA load suppression by zidovudine.
AB  - The association between human immunodeficiency virus type I (HIV-1) RNA load
      changes and the emergence of resistant virus variants was investigated in 24 HIV
      1-infected asymptomatic persons during 2 years of treatment with zidovudine by
      sequentially measuring serum HIV-1 RNA load and the relative amounts of HIV-1 RNA
      containing mutations at reverse transcriptase (RT) codons 70 (K-->R), 41 (M-->L),
      and 215 (T-->Y/F). A mean maximum decline in RNA load occurred during the first
      month, followed by a resurgence between 1 and 3 months, which appeared
      independent of drug-resistance. Mathematical modeling suggests that this
      resurgence is caused by host-parasite dynamics, and thus reflects infection of
      the transiently increased numbers of CD4+ lymphocytes. Between 3 and 6 months of
      treatment, the RNA load returned to baseline values, which was associated with
      the emergence of virus containing a single lysine to arginine amino acid change
      at RT codon 70, only conferring an 8-fold reduction in susceptibility. Despite
      the relative loss of RNA load suppression, selection toward mutations at RT
      codons 215 and 41 continued. Identical patterns were observed in the mathematical
      model. While host-parasite dynamics and outgrowth of low-level resistant virus
      thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine
      continues to select for alternative mutations, conferring increasing levels of
      resistance.

PMID- 8643605
TI  - The adipocyte specific transcription factor C/EBPalpha modulates human ob gene
      expression.
AB  - The ob gene product, leptin, apparently exclusively expressed in adipose tissue,
      is a signaling factor regulating body weight homeostasis and energy balance. ob
      gene expression is increased in obese rodents and regulated by feeding, insulin,
      and glucocorticoids, which supports the concept that ob gene expression is under
      hormonal control, which is expected for a key factor controlling body weight
      homeostasis and energy balance. In humans, ob mRNA expression is increased in
      gross obesity; however, the effects of the above factors on human ob expression
      are unknown. We describe the structure of the human ob gene and initial
      functional analysis of its promoter. The human ob gene's three exons cover
      approximately 15 kb of genomic DNA. The entire coding region is contained in
      exons 2 and 3, which are separated by a 2-kb intron. The first small 30-bp
      untranslated exon is located >10.5 kb upstream of the initiator ATG codon. Three
      kilobases of DNA upstream of the transcription start site has been cloned and
      characterized. Only 217 bp of 5' sequence are required for basal adipose tissue
      specific expression of the ob gene as well as enhanced expression by C/EBPalpha.
      Mutation of the single C/EBPalpha site in this region abolished inducibility of
      the promoter by C/EBPalpha in cotransfection assays. The gene structure will
      facilitate our analysis of ob mutations in human obesity, whereas knowledge of
      sequence elements and factors regulating ob gene expression should be of major
      importance in the prevention and treatment of obesity.

PMID- 8643606
TI  - The protection receptor for IgG catabolism is the beta2-microglobulin-containing
      neonatal intestinal transport receptor.
AB  - More than 30 years ago, Brambell published the hypothesis bearing his name
      [Brambell, F. W. R., Hemmings, W. A. & Morris, 1. C. (1964) Nature (London) 203,
      1352-1355] that remains as the cornerstone for thinking on IgG catabolism. To
      explain the long survival of IgG relative to other plasma proteins and its
      pattern of increased fractional catabolism with high concentrations of IgG,
      Brambell postulated specific IgG "protection receptors" (FcRp) that would bind
      IgG in pinocytic vacuoles and redirect its transport to the circulation; when the
      FcRp was saturated, the excess unbound IgG then would pass to unrestricted
      lysosomal catabolism. Brambell subsequently postulated the neonatal gut transport
      receptor (FcRn) and showed its similar saturable character. FcRn was recently
      cloned but FcRp has not been identified. Using a genetic knockout that disrupts
      the FcRn and intestinal IgG transport, we show that this lesion also disrupts the
      IgG protection receptor, supporting the identity of these two receptors. IgG
      catabolism was 10-fold faster and IgG levels were correspondingly lower in mutant
      than in wild-type mice, whereas IgA was the same between groups, demonstrating
      the specific effects on the IgG system. Disruption of the FcRp in the mutant mice
      was also shown to abrogate the classical pattern of decreased IgG survival with
      higher IgC concentration. Finally, studies in normal mice with monomeric antigen
      antibody complexes showed differential catabolism in which antigen dissociates in
      the endosome and passes to the lysosome, whereas the associated antibody is
      returned to circulation; in mutant mice, differential catabolism was lost and the
      whole complex cleared at the same accelerated rate as albumin, showing the
      central role of the FcRp to the differential catabolism mechanism. Thus, the same
      receptor protein that mediates the function of the FcRn transiently in the
      neonate is shown to have its functionally dominant expression as the FcRp
      throughout life, resolving a longstanding mystery of the identity of the receptor
      for the protection of IgG. This result also identifies an important new member of
      the class of recycling surface receptors and enables the design of protein
      adaptations to exploit this mechanism to improve survivals of other therapeutic
      proteins in vivo.

PMID- 8643607
TI  - Cloning and characterization of a specific coactivator, ARA70, for the androgen
      receptor in human prostate cells.
AB  - The androgen receptor (AR) is a member of the steroid receptor superfamily that
      plays an important role in male sexual differentiation and prostate cell
      proliferation. Mutations or abnormal expression of AR in prostate cancer can play
      a key role in the process that changes prostate cancer from androgen-dependent to
      an androgen-independent stage. Using a yeast two-hybrid system, we were able to
      isolate a ligand-dependent AR-associated protein (ARA70), which functions as an
      activator to enhance AR transcriptional activity 10-fold in the presence of 10(
      10) M dihydrotestosterone or 10(-9) M testosterone, but not 10(-6) M
      hydroxyflutamide in human prostate cancer DU145 cells. Our data further indicated
      that ARA70 Will only slightly induce the transcriptional activity of other
      steroid receptors such as estrogen receptor, glucocorticoid receptor, and
      progesterone receptor in DU145 cells. Together, these data suggest that AR may
      need a specific coactivator(s) such as ARA70 for optimal androgen activity.

PMID- 8643608
TI  - The replication initiator protein pi of the plasmid R6K specifically interacts
      with the host-encoded helicase DnaB.
AB  - The replication initiator protein pi of plasmid R6K is known to interact with the
      seven iterons of the gamma origin/enhancer and activate distant replication
      origins alpha and beta (ori alpha and ori beta) by pi-mediated DNA looping. Here
      we show that pi protein specifically interacts in vitro with the host-encoded
      helicase DnaB. The site of interaction of pi on DnaB has been localized to a 37
      aa-long region located between amino acids 151 and 189 of DnaB. The surface of pi
      that interacts with DnaB has been mapped to the N-terminal region of the
      initiator protein between residues 1 and 116. The results suggest that during
      initiation of replication, the replicative helicase DnaB is first recruited to
      the gamma enhancer by the pi protein. In a subsequent step, the helicase probably
      gets delivered from ori gamma to ori alpha and ori beta by pi-mediated DNA
      looping.

PMID- 8643609
TI  - Regulation of cardiac sodium-calcium exchanger by beta-adrenergic agonists.
AB  - Na+-Ca2+ exchanger and Ca2+ channel are two major sarcolemmal Ca2+-transporting
      proteins of cardiac myocytes. Although the Ca2+ channel is effectively regulated
      by protein kinase A-dependent phosphorylation, no enzymatic regulation of the
      exchanger protein has been identified as yet. Here we report that in frog
      ventricular myocytes, isoproterenol down-regulates the Na+-Ca2+ exchanger,
      independent of intracellular Ca2+ and membrane potential, by activation of the
      beta-receptor/adenylate-cyclase/cAMP-dependent cascade, resulting in suppression
      of transmembrane Ca2+ transport via the exchanger and providing for the well
      documented contracture-suppressant effect of the hormone on frog heart. The beta
      blocker propranolol blocks the isoproterenol effect, whereas forskolin, cAMP, and
      theophylline mimic it. In the frog heart where contractile Ca2+ is transported
      primarily by the Na+-Ca2+ exchanger, the beta-agonists' simultaneous enhancement
      of Ca2+ current, ICa, and suppression of Na+-Ca2+ exchanger current, INa-Ca would
      enable the myocyte to develop force rapidly at the onset of depolarization
      (enhancement of ICa) and to decrease Ca2+ influx (suppression of INa-Ca) later in
      the action potential. This unique adrenergically induced shift in the Ca2+ influx
      pathways may have evolved in response to paucity of the sarcoplasmic reticulum
      Ca2+-ATPase/phospholamban complex and absence of significant intracellular Ca2+
      release pools in the frog heart.

PMID- 8643610
TI  - Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway.
AB  - The orphan nuclear receptor Nur77/N10 has recently been demonstrated to be
      involved in apoptosis of T cell hybridomas. We report here that chronic
      expression of Nur77/N10 in thymocytes of transgenic mice results in a dramatic
      reduction of CD4+CD8+ double-positive as well as CD4+CD8- and CD4-CD8+ single
      positive cell populations due to an early onset of apoptosis. CD4-CD8- double
      negative and CD25+ precursor cells, however, are unaffected. Moreover, nur77/N10
      transgenic thymocytes show increased expression of Fas ligand (FasL), while the
      levels of the Fas receptor (Fas) are not increased. The mouse spontaneous mutant
      gld (generalized lymphoproliferative disease) carries a point mutation in the
      extracellular domain of the FasL gene that abolishes the ability of FasL to bind
      to Fas. Thymuses from nur77/N10-transgenic mice on a gld/gld background have
      increased cellularity and an almost normal profile of thymocyte subpopulations.
      Our results demonstrate that one pathway of apoptosis triggered by Nur77/N10 in
      double-positive thymocytes occurs through the upregulation of FasL expression
      resulting in increased signaling through Fas.

PMID- 8643611
TI  - Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.
AB  - Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a
      genetic disorder that is characterized by hyperuricemia, choreoathetosis,
      dystonia, and compulsive self-injury. To establish that DA deficiency is present
      in LND, the ligand WIN-35,428, which binds to DA transporters, was used to
      estimate the density of DA-containing neurons in the caudate and putamen of six
      patients with classic LND. Comparisons were made with 10 control subjects and 3
      patients with Rett syndrome. Three methods were used to quantify the binding of
      the DA transporter so that its density could be estimated by a single dynamic
      positron emission tomography study. These approaches included the caudate- or
      putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic
      analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal
      partition coefficients in the striatum and the cerebellum, and graphical analysis
      of the binding potential. Depending on the method of analysis, a 50-63% reduction
      of the binding to DA transporters in the caudate, and a 64-75% reduction in the
      putamen of the LND patients was observed compared to the normal control group.
      When LND patients were compared to Rett syndrome patients, similar reductions
      were found in the caudate (53-61%) and putamen (67-72%) in LND patients.
      Transporter binding in Rett syndrome patients was not significantly different
      from the normal controls. Finally, volumetric magnetic resonance imaging studies
      detected a 30% reduction in the caudate volume of LND patients. To ensure that a
      reduction in the caudate volume would not confound the results, a rigorous
      partial volume correction of the caudate time activity curve was performed. This
      correction resulted in an even greater decrease in the caudate-cerebellar ratio
      in LND patients when contrasted to controls. To our knowledge, these findings
      provide the first in vivo documentation of a dopaminergic reduction in LND and
      illustrate the role of positron emission tomography imaging in investigating
      neurodevelopmental disorders.

PMID- 8643612
TI  - Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated
      protein.
AB  - Cyclooxygenases (COXs) 1 and 2 are 72-kDa, intralumenal residents of the
      endoplasmic reticulum (ER) and nuclear envelope, where they catalyze the rate
      limiting steps in the conversion of arachidonate to the physiologically dynamic
      prostanoids. Recent studies, including the generation of knockout mice, show COX
      1 and COX-2 to have biologically distinct roles within cells and organisms. Also
      apparent is that arachidonate substrate is selectably metabolized by COX-2 after
      mitogen stimulation in many cells that contain both isoforms. Because COX-1 and
      COX-2 are highly conserved in all residues needed for catalysis and in their
      purified forms have almost identical kinetic properties, we have searched for COX
      interacting ER proteins that might mediate these unique isoenzymic properties.
      Using COXs as bait in the yeast two-hybrid system, we identified autoimmunity-
      and apoptosis-associated nucleobindin (Nuc) as a protein that specifically
      interacts with both isoenzymes. COX-Nuc binding was substantiated by
      immunoprecipitation experiments, which showed that COX-1 and, to a lesser extent,
      COX-2 form complexes with Nuc in vitro. When overexpressed in COS-1 cells, Nuc
      was found to be extracellularly released. However, when Nuc was co-overexpressed
      with COX-1 or COX-2, its release was reduced by >80%. This finding suggests that
      COX isoenzymes participate in the retention of Nuc within the lumen of the ER,
      where COX may regulate the release of Nuc from the cell. It also identifies Nuc
      as a potential regulator of COXs through this interaction.

PMID- 8643614
TI  - Microfabricated structures for integrated DNA analysis.
AB  - Photolithographic micromachining of silicon is a candidate technology for the
      construction of high-throughput DNA analysis devices. However, the development of
      complex silicon microfabricated systems has been hindered in part by the lack of
      a simple, versatile pumping method for integrating individual components. Here we
      describe a surface-tension-based pump able to move discrete nanoliter drops
      through enclosed channels using only local heating. This thermocapillary pump can
      accurately mix, measure, and divide drops by simple electronic control. In
      addition, we have constructed thermal-cycling chambers, gel electrophoresis
      channels, and radiolabeled DNA detectors that are compatible with the fabrication
      of thermocapillary pump channels. Since all of the components are made by
      conventional photolithographic techniques, they can be assembled into more
      complex integrated systems. The combination of pump and components into self
      contained miniaturized devices may provide significant improvements in DNA
      analysis speed, portability, and cost. The potential of microfabricated systems
      lies in the low unit cost of silicon-based construction and in the efficient
      sample handling afforded by component integration.

PMID- 8643613
TI  - Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase:
      deductions from the structure of methionine synthase.
AB  - Inherited defects in the gene for methylmalonyl-CoA mutase (EC 5.4.99.2) result
      in the mut forms of methylmalonic aciduria. mut- mutations lead to the absence of
      detectable mutase activity and are not corrected by excess cobalamin, whereas mut
      mutations exhibit residual activity when exposed to excess cobalamin. Many of
      the mutations that cause methylmalonic aciduria in humans affect residues in the
      C-terminal region of the methylmalonyl-CoA mutase. This portion of the
      methylmalonyl-CoA mutase sequence can be aligned with regions in other B12
      (cobalamin)-dependent enzymes, including the C-terminal portion of the cobalamin
      binding region of methionine synthase. The alignments allow the mutations of
      human methylmalonyl-CoA mutase to be mapped onto the structure of the cobalamin
      binding fragment of methionine synthase from Escherichia coli (EC 2.1.1.13),
      which has recently been determined by x-ray crystallography. In this structure,
      the dimethylbenzimidazole ligand to the cobalt in free cobalamin has been
      displaced by a histidine ligand, and the dimethylbenzimidazole nucleotide "tail"
      is thrust into a deep hydrophobic pocket in the protein. Previously identified
      mut0 and mut- mutations (Gly-623 --> Arg, Gly-626 --> Cys, and Gly-648 --> Asp)
      of the mutase are predicted to interfere with the structure and/or stability of
      the loop that carries His-627, the presumed lower axial ligand to the cobalt of
      adenosylcobalamin. Two mutants that lead to severe impairment (mut0) are Gly-630 
      -> Glu and Gly-703 --> Arg, which map to the binding site for the
      dimethylbenzimidazole nucleotide substituent of adenosylcobalamin. The
      substitution of larger residues for glycine is predicted to block the binding of
      adenosylcobalamin.

PMID- 8643615
TI  - Ordered yeast artificial chromosome clones representing the Dictyostelium
      discoideum genome.
AB  - High resolution gene maps of the six chromosomes of Dictyostelium discoideum have
      been generated by a combination of physical mapping techniques. A set of yeast
      artificial chromosome clones has been ordered into overlapping arrays that cover
      >98% of the 34-magabase pair genome. Clones were grouped and ordered according to
      the genes they carried, as determined by hybridization analyses with DNA
      fragments from several hundred genes. Congruence of the gene order within each
      arrangement of clones with the gene order determined from whole genome
      restriction site mapping indicates that a high degree of confidence can be placed
      on the clone map. This clone-based description of the Dictyostelium chromosomes
      should be useful for the physical mapping and subcloning of new genes and should
      facilitate more detailed analyses of this genome. cost of silicon-based
      construction and in the efficient sample handling afforded by component
      integration.

PMID- 8643616
TI  - The timing of synaptic vesicle endocytosis.
AB  - Alternative models to describe the endocytosis phase of synaptic vesicle
      recycling are associated with time scales of vesicle recovery ranging from
      milliseconds to tens of seconds. There have been suggestions that one of the
      major models, envisioned as a slow process that occurs only after complete fusion
      of the vesicle membrane with the neurolemma, might be applicable only under
      conditions of heavy, nonphysiological stimulation. Using FM 1-43 and similar
      fluorescent probes to label recycling synaptic vesicles in rat hippocampal
      neurons, we have measured the kinetics of endocytosis with a wide range of action
      potential-driven exocytotic loads. Our results indicate that when either 5% or
      25% of the vesicle pool is used, vesicles are recovered with a half-time on the
      order of 20 s (24 degrees C). This endocytosis rate was not influenced by
      operations designed to alter intracellular Ca2+ during membrane retrieval,
      suggesting that residual Ca2+ after strong stimuli probably does not greatly
      retard endocytosis. Finally, we have shown that vesicle-destaining kinetics are
      not strongly influenced by the substantially differing rates at which two marker
      dyes tested dissociate from membranes. This observation suggests that vesicles
      remain open long enough for essentially complete dissociation of even the slower
      dye (a few seconds) or, alternatively, that both dyes readily escape vesicle
      membrane by lateral diffusion through any exocytotic opening. These data seem
      most consistent with applicability of the slow-endocytosis, complete-fusion model
      at low as well as high levels of exocytosis.

PMID- 8643617
TI  - A loop-loop "kissing" complex is the essential part of the dimer linkage of
      genomic HIV-1 RNA.
AB  - RNA-RNA interactions govern a number of biological processes. Several RNAs,
      including natural sense and antisense RNAs, interact by means of a two-step
      mechanism: recognition is mediated by a loop-loop complex, which is then
      stabilized by formation of an extended intermolecular duplex. It was proposed
      that the same mechanism holds for dimerization of the genomic RNA of human
      immunodeficiency virus type 1 (HIV-1), an event thought to control crucial steps
      of HIV-1 replication. However, whereas interaction between the partially self
      complementary loop of the dimerization initiation site (DIS) of each monomer is
      well established, formation of the extended duplex remained speculative. Here we
      first show that in vitro dimerization of HIV-1 RNA is a specific process, not
      resulting from simple annealing of denatured molecules. Next we used mutants of
      the DIS to test the formation of the extended duplex. Four pairs of
      transcomplementary mutants were designed in such a way that all pairs can form
      the loop-loop "kissing" complex, but only two of them can potentially form the
      extended duplex. All pairs of mutants form heterodimers whose thermal stability,
      dissociation constant, and dynamics were analyzed. Taken together, our results
      indicate that, in contrast with the interactions between natural sense and
      antisense RNAs, no extended duplex is formed during dimerization of HIV-1 RNA. We
      also showed that 55-mer sense RNAs containing the DIS are able to interfere with
      the preformed HIV-1 RNA dimer.

PMID- 8643618
TI  - Activation of the translational suppressor 4E-BP1 following infection with
      encephalomyocarditis virus and poliovirus.
AB  - Infection of cells with picornaviruses, such as poliovirus and
      encephalomyocarditis virus (EMCV), causes a shutoff of host protein synthesis.
      The molecular mechanism of the shutoff has been partly elucidated for poliovirus
      but not for EMCV. Translation initiation in eukaryotes is facilitated by the mRNA
      5' cap structure to which the multisubunit translation initiation factor eIF4F
      binds to promote ribosome binding. Picornaviruses use a mechanism for the
      translation of their RNA that is independent of the cap structure. Poliovirus
      infection engenders the cleavage of the eIF4G (formerly p220) component of eIF4F
      and renders this complex inactive for cap-dependent translation. In contrast,
      EMCV infection does not result in eIF4G cleavage. Here, we report that both EMCV
      and poliovirus activate a translational repressor, 4E-BP1, that inhibits cap
      dependent translation by binding to the cap-binding subunit eIF4E. Binding of
      eIF4E occurs only to the underphosphorylated form of 4E-BP1, and this interaction
      is highly regulated in cells. We show that 4E-BP1 becomes dephosphorylated upon
      infection with both EMCV and poliovirus. Dephosphorylation of 4E-BP1 temporally
      coincides with the shutoff of protein synthesis by EMCV but lags behind the
      shutoff and eIF4G cleavage in poliovirus-infected cells. Dephosphorylation of 4E
      BP1 by specifically inhibiting cap-dependent translation may be the major cause
      of the shutoff phenomenon in EMCV-infected cells.

PMID- 8643619
TI  - Glutamate receptor blockade at cortical synapses disrupts development of
      thalamocortical and columnar organization in somatosensory cortex.
AB  - The segregation of thalamocortical inputs into eye-specific stripes in the
      developing cat or monkey visual cortex is prevented by manipulations that perturb
      or abolish neural activity in the visual pathway. Such findings show that proper
      development of the functional organization of visual cortex is dependent on
      normal patterns of neural activity. The generalisation of this conclusion to
      other sensory cortices has been questioned by findings that the segregation of
      thalamocortical afferents into a somatotopic barrel pattern in developing rodent
      primary somatosensory cortex (S1) is not prevented by activity blockade. We show
      that a temporary block of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate
      receptors in rat S1 during the critical period for barrel development disrupts
      the topographic refinement of thalamocortical connectivity and columnar
      organization. These effects are evident well after the blockade is ineffective
      and thus may be permanent. Our findings show that neural activity and
      specifically the activation of postsynaptic cortical neurons has a prominent role
      in establishing the primary sensory map in S1, as well as the topographic
      organization of higher order synaptic connections.

PMID- 8643620
TI  - Active barnase variants with completely random hydrophobic cores.
AB  - The central structural feature of natural proteins is a tightly packed and highly
      ordered hydrophobic core. If some measure of exquisite, native-like core packing
      is necessary for enzymatic function, this would constitute a significant obstacle
      to the development of novel enzymes, either by design or by natural or
      experimental evolution. To test the minimum requirements for a core to provide
      sufficient structural integrity for enzymatic activity, we have produced mutants
      of the ribonuclease barnase in which 12 of the 13 core residues have together
      been randomly replaced by hydrophobic alternatives. Using a sensitive biological
      screen, we find that a strikingly high proportion of these mutants (23%) retain
      enzymatic activity in vivo. Further substitution at the 13th core position shows
      that a similar proportion of completely random hydrophobic cores supports enzyme
      function. Of the active mutants produced, several have no wild-type core
      residues. These results imply that hydrophobicity is nearly a sufficient
      criterion for the construction of a functional core and, in conjunction with
      previous studies, that refinement of a crudely functional core entails more
      stringent sequence constraints than does the initial attainment of crude core
      function. Since attainment of crude function is the critical initial step in
      evolutionary innovation, the relatively scant requirements contributed by the
      hydrophobic core would greatly reduce the initial hurdle on the evolutionary
      pathway to novel enzymes. Similarly, experimental development of novel functional
      proteins might be simplified by limiting core design to mere specification of
      hydrophobicity and using iterative mutation-selection to optimize core structure.

PMID- 8643621
TI  - Pea formaldehyde-active class III alcohol dehydrogenase: common derivation of the
      plant and animal forms but not of the corresponding ethanol-active forms (classes
      I and P).
AB  - A plant class III alcohol dehydrogenase (or glutathione-dependent formaldehyde
      dehydrogenase) has been characterized. The enzyme is a typical class III member
      with enzymatic parameters and substrate specificity closely related to those of
      already established animal forms. Km values with the pea enzyme are 6.5 microM
      for NAD+, 2 microM for S-hydroxymethylglutathione, and 840 microM for octanol
      versus 9, 4, and 1200 microM, respectively, with the human enzyme. Structurally,
      the pea/human class III enzymes are closely related, exhibiting a residue
      identity of 69% and with only 3 of 23 residues differing among those often
      considered in substrate and coenzyme binding. In contrast, the corresponding
      ethanol-active enzymes, the long-known human liver and pea alcohol
      dehydrogenases, differ more (47% residue identities) and are also in functionally
      important active site segments, with 12 of the 23 positions exchanged, including
      no less than 7 at the usually much conserved coenzyme-binding segment. These
      differences affect functionally important residues that are often class
      distinguishing, such as those at positions 48, 51, and 115, where the plant
      ethanol-active forms resemble class III (Thr, Tyr, and Arg, respectively) rather
      than the animal ethanol-active class I forms (typically Ser, His, and Asp,
      respectively). Calculations of phylogenetic trees support the conclusions from
      functional residues in subgrouping plant ethanol-active dehydrogenases and the
      animal ethanol-active enzymes (class I) as separate descendants from the class
      III line. It appears that the classical plant alcohol dehydrogenases (now called
      class P) have a duplicatory origin separate from that of the animal class I
      enzymes and therefore a paralogous relationship with functional convergence of
      their alcohol substrate specificity. Combined, the results establish the
      conserved nature of class III also in plants, and contribute to the molecular and
      functional understanding of alcohol dehydrogenases by defining two branches of
      plant enzymes into the system.

PMID- 8643622
TI  - Vitamin E prevents oxidative modification of brain and lymphocyte band 3 proteins
      during aging.
AB  - Antioxidants may play an important role in preventing free radical damage
      associated with aging by interfering directly in the generation of radicals or by
      scavenging them. We investigated the effects of a high vitamin E and/or a high
      beta-carotene diet on aging of the anion transporter, band 3, in lymphocytes and
      brain. The band 3 proteins function as anion transporters, acid base regulators,
      C02 transporters, and structural proteins that provide a framework for membrane
      lipids and that link the plasma membrane to the cytoskeleton. Senescent cell
      antigen (SCA), which terminates the life of cells, is a degradation product of
      band 3. This study was conducted as a double-blind study in which eight groups of
      middle-aged or old mice received either high levels of beta-carotene and/or
      vitamin E or standard levels of these supplements in their diets. Anion transport
      kinetic assays were performed on isolated splenic lymphocytes. Immunoreactivity
      of an antibody that recognizes aging changes in old band 3 preceding generation
      of SCA was used to quantitate aged band 3 in brain tissue. Results indicate that
      vitamin E prevented the observed age-related decline in anion transport by
      lymphocytes and the generation of aged band 3 leading to SCA formation. beta
      Carotene had no significant effect on the results of either assay. Since
      increased aged band 3 and decreased anion transport are initial steps in band 3
      aging, which culminates in the generation of SCA and cellular removal, vitamin E
      prevents or delays aging of band 3-related proteins in lymphocytes and brain.

PMID- 8643623
TI  - Nitric oxide inhibits creatine kinase and regulates rat heart contractile
      reserve.
AB  - Cardiac myocytes express both constitutive and cytokine-inducible nitric oxide
      syntheses (NOS). NO and its congeners have been implicated in the regulation of
      cardiac contractile function. To determine whether NO could affect myocardial
      energetics, 31P NMR spectroscopy was used to evaluate high-energy phosphate
      metabolism in isolated rat hearts perfused with the NO donor S
      nitrosoacetylcysteine (SNAC). All hearts were exposed to an initial high Ca2+
      (3.5 mM) challenge followed by a recovery period, and then, either in the
      presence or absence of SNAC, to a second high Ca2+ challenge. This protocol
      allowed us to monitor simultaneously the effect of SNAC infusion on both
      contractile reserve (i.e., baseline versus high workload contractile function)
      and high-energy phosphate metabolism. The initial high Ca2+ challenge caused the
      rate-pressure product to increase by 74 +/- 5% in all hearts. As expected, ATP
      was maintained as phosphocreatine (PCr) content briefly dropped and then returned
      to baseline during the subsequent recovery period. Control hearts responded
      similarLy to the second high Ca2+ challenge, but SNAC-treated hearts did not
      demonstrate the expected increase in rate-pressure product. In these hearts, ATP
      declined significantly during the second high Ca2+ challenge, whereas
      phosphocreatine did not differ from controls, suggesting that phosphoryl transfer
      by creatine kinase (CK) was inhibited. CK activity, measured biochemically, was
      decreased by 61 +/- 13% in SNAC-treated hearts compared to controls. Purified CK
      in solution was also inhibited by SNAC, and reversal could be accomplished with
      DTT, a sulfhydryl reducing agent. Thus, NO can regulate contractile reserve,
      possibly by reversible nitrosothiol modification of CK.

PMID- 8643624
TI  - Two mutant prion proteins expressed in cultured cells acquire biochemical
      properties reminiscent of the scrapie isoform.
AB  - Prion diseases are a group of fatal neurodegenerative disorders that are unique
      in being infectious, genetic, and sporadic in origin. Infectious cases are caused
      by prions, which are composed primarily of PrPSc, a posttranslationally modified
      isoform of the normal cellular prion protein PrPC. Inherited cases are linked to
      insertional or point mutations in the host gene encoding PrPC. To investigate the
      molecular mechanisms underlying inherited prion diseases, we have constructed
      stably transfected Chinese hamster ovary cells that express mouse PrPs homologous
      to two human PrPs associated with familial Creutzfeldt-Jakob disease. One mouse
      PrP molecule carries a Glu-->Lys substitution at codon 199, and the other carries
      an insertion of six additional octapeptide repeats between codons 51 and 90. We
      find that both of these mutant PrPs display several biochemical hallmarks of
      PrPSc when synthesized in cell culture. Unlike wild-type PrP, the mutant proteins
      are detergent insoluble and are relatively resistant to digestion by proteinase
      K, yielding an N-terminally truncated core fragment of 27-30 kDa. Pulse-chase
      labeling experiments demonstrate that these properties are acquired
      posttranslationally, and are accompanied by increased metabolic stability of the
      protein. Our results provide the first evidence that a molecule with properties
      reminiscent of PrPSc can be generated de novo in cultured cells.

PMID- 8643625
TI  - Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42.
AB  - Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with the
      most severe pathology in the T lymphocytes and platelets. The disease arises from
      mutations in the gene encoding the WAS protein. T lymphocytes of affected males
      with WAS exhibit a severe disturbance of the actin cytoskeleton, suggesting that
      the WAS protein could regulate its organization. We show here that WAS protein
      interacts with a member of the Rho family of GTPases, Cdc42. This interaction,
      which is guanosine 5'-triphosphate (GTP)-dependent, was detected in cell lysates,
      in transient transfections and with purified recombinant proteins. A weaker
      interaction was also detected with Rac1 using WAS protein from cell lysates. It
      was also found that different mutant WAS proteins from three affected males
      retained their ability to interact with Cdc42 and that the level of expression of
      the WAS protein in these mutants was only 2-5% of normal. Taken together these
      data suggest that the WAS protein might function as a signal transduction adaptor
      downstream of Cdc42, and in affected males, the cytoskeletal abnormalities may
      result from a defect in Cdc42 signaling.

PMID- 8643626
TI  - Two mitochondrial group I introns in a metazoan, the sea anemone Metridium
      senile: one intron contains genes for subunits 1 and 3 of NADH dehydrogenase.
AB  - Mitochondrial genes for cytochrome c oxidase subunit I (COI) and NADH
      dehydrogenase subunit 5 (ND5) of the sea anemone Metridium senile (phylum
      Cnidaria) each contain a group I intron. This is in contrast to the reported
      absence of introns in all other metazoan mtDNAs so far examined. The ND5 intron
      is unusual in that it ends with A and contains two genes (ND1 and ND3) encoding
      additional subunits of NADH dehydrogenase. Correctly excised ND5 introns are not
      circularized but are precisely cleaved near their 3' ends and polyadenylylated to
      provide bicistronic transcripts of ND1 and ND3. COI introns, which encode a
      putative homing endonuclease, circularize, but in a way that retains the entire
      genome-encoded intron sequence (other group I introns are circularized with loss
      of a short segment of the intron 5' end). Introns were detected in the COI and
      ND5 genes of other sea anemones, but not in the COI and ND5 genes of other
      cnidarians. This suggests that the sea anemone mitochondrial introns may have
      been acquired relatively recently.

PMID- 8643627
TI  - A novel iron-regulated metal transporter from plants identified by functional
      expression in yeast.
AB  - Iron is an essential nutrient for virtually all organisms. The IRT1 (iron
      regulated transporter) gene of the plant Arabidopsis thaliana, encoding a
      probable Fe(II) transporter, was cloned by functional expression in a yeast
      strain defective for iron uptake. Yeast expressing IRT1 possess a novel Fe(II)
      uptake activity that is strongly inhibited by Cd. IRT1 is predicted to be an
      integral membrane protein with a metal-binding domain. Data base comparisons and
      Southern blot analysis indicated that IRT1 is a member of a gene family in
      Arabidopsis. Related sequences were also found in the genomes of rice, yeast,
      nematodes, and humans. In Arabidopsis, IRT1 is expressed in roots, is induced by
      iron deficiency, and has altered regulation in plant lines bearing mutations that
      affect the iron uptake system. These results provide the first molecular insight
      into iron transport by plants.

PMID- 8643628
TI  - Cellular stress inhibits transposition of the yeast retrovirus-like element Ty3
      by a ubiquitin-dependent block of virus-like particle formation.
AB  - Many stress proteins and their cognates function as molecular chaperones or as
      components of proteolytic systems. Viral infection can stimulate synthesis of
      stress proteins and particular associations of viral and stress proteins have
      been documented. However, demonstrations of functions for stress proteins in
      viral life cycles are few. We have initiated an investigation of the roles of
      stress proteins in eukaryotic viral life cycles using as a model the Ty3
      retrovirus-like element of Saccharomyces cerevisiae. During stress, Ty3
      transposition is inhibited; Ty3 DNA is not synthesized and, although precursor
      proteins are detected, mature Ty3 proteins and virus-like particles (VLPs) do not
      accumulate. The same phenotype is observed in the constitutively stressed ssa1
      ssa2 mutant, which lacks two cytoplasmic members of the hsp70 family of
      chaperones. Ty3 VLPs preformed under nonstress conditions are degraded more
      rapidly if cells are shifted from 30 degrees C to 37 degrees C. These results
      suggest that Ty3 VLPs are destroyed by cellular stress proteins. Elevated
      expression of the yeast UBP3 gene, which encodes a protease that removes
      ubiquitin from proteins, allows mature Ty3 proteins and VLPs to accumulate in the
      ssa1 ssa2 mutant, suggesting that, at least under stress conditions,
      ubiquitination plays a role in regulating Ty3 transposition.

PMID- 8643630
TI  - A functional peptide encoded in the Escherichia coli 23S rRNA.
AB  - A pentapeptide open reading frame equipped with a canonical ribosome-binding site
      is present in the Escherichia coli 23S rRNA. Overexpression of 23S rRNA fragments
      containing the mini-gene renders cells resistant to the ribosome-inhibiting
      antibiotic erythromycin. Mutations that change either the initiator or stop
      codons of the peptide mini-gene result in the loss of erythromycin resistance.
      Nonsense mutations in the mini-gene also abolish erythromycin resistance, which
      can be restored in the presence of the suppressor tRNA, thus proving that
      expression of the rRNA-encoded peptide is essential for the resistance phenotype.
      The ribosome appears to be the likely target of action of the rRNA-encoded
      pentapeptide, because in vitro translation of the peptide mini-gene decreases the
      inhibitory action of erythromycin on cell-free protein synthesis. Thus, the new
      mechanism of drug resistance reveals that in addition to the structural and
      functional role of rRNA in the ribosome, it may also have a peptide-coding
      function.

PMID- 8643629
TI  - The contrasting roles of ICE family proteases and interleukin-1beta in apoptosis
      induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down
      regulation.
AB  - We compare here the mechanisms of apoptotic death of PC12 cells induced by down
      regulation of Cu2+,Zn2+ superoxide dismutase (SOD1) and withdrawal of trophic
      support (serum/nerve growth factor). Our previous results indicated that the
      initiating causes of death are different in each paradigm. However, bcl-2 rescues
      cells in either paradigm, suggesting common downstream elements to the cell death
      pathway. To determine whether the ICE [interleukin 1beta converting enzyme]
      family of proteases, which is required for apoptosis on trophic factor
      withdrawal, is also required for apoptosis induced by oxidative stress, we have
      developed a novel peptide inhibitor that mimics the common catalytic site of
      these enzymes and thereby blocks their access to substrates. This differs from
      the more usual pseudosubstrate approach to enzyme inhibition. Blockade of ICE
      family proteases by either this inhibitor or by a permeant competitive ICE family
      antagonist rescues PC12 cells from apoptotic death following apoptosis induced by
      down-regulation of SOD1, as well as from trophic factor/nerve growth factor
      deprivation. SOD1 down-regulation results in an increase in interleukin 1beta (IL
      1beta) production by the cells, and cell death under these conditions can be
      prevented by either blocking antibodies against IL-1beta or the IL-1 receptor
      antagonist (IL-1Ralpha). In contrast, trophic factor withdrawal does not increase
      IL-1beta secretion, and the blocking antibody failed to protect PC12 cells from
      trophic factor withdrawal, whereas the receptor antagonist was only partially
      protective at very high concentrations. There were substantial differences in the
      concentrations of pseudosubstrate inhibitors which rescued cells from SOD1 down
      regulation and trophic factor deprivation. These results suggest the involvement
      of different members of the ICE family, different substrates, or both in the two
      different initiating causes of cell death.

PMID- 8643631
TI  - A truncated mutant (residues 58-140) of the hepatitis B virus X protein retains
      transactivation function.
AB  - The hepatitis B virus X protein (HBx) sequence (154 aa) has been divided into six
      regions (A-F) based on its sequence homology with X proteins of other mammalian
      hepadnaviruses. Regions A, C, and E are more conserved and include all the four
      conserved cysteines (C7, C61, C69, and C137). To localize the regions of HBx
      important for transactivation, a panel of 10 deletion mutants (X5-X14) and 4
      single point mutants (X1-X4), each corresponding to a conserved cysteine residue,
      was constructed by site-directed mutagenesis. A HBx-specific monoclonal antibody
      was developed and used to confirm the expression of mutants by Western blot.
      Transactivation property of the HBx mutants was studied on Rous sarcoma virus
      long terminal repeat (RSV-LTR) in transient transfection assays. We observed that
      deletion of the most conserved region A or substitution of the N-terminal
      cysteine (C7) had no effect on transactivation. Deletion of the nonconserved
      regions B or F also had no deleterious effects. Deletions of regions C and D
      resulted in a significant loss of function. Substitution of both C61 and C69
      present in region C, caused almost 90% loss of activity that could be partially
      overcome by transfecting more expression plasmid. The fully conserved 9 amino
      acid segment (residues 132 to 140) within region E including C137 appeared to be
      crucial for its activity. Finally, a truncated mutant X15 incorporating only
      regions C to E (amino acids 58-140) was able to stimulate the RSV-LTR quite
      efficiently, suggesting a crucial role played by this domain in transactivation
      function.

PMID- 8643632
TI  - Characterization of a unique variant of bat rabies virus responsible for newly
      emerging human cases in North America.
AB  - The silver-haired bat variant of rabies virus (SHBRV) has been identified as the
      etiological agent of a number of recent human rabies cases in the United States
      that are unusual in not having been associated with any known history of
      conventional exposure. Comparison of the different biological and biochemical
      properties of isolates of this virus with those of a coyote street rabies virus
      (COSRV) revealed that there are unique features associated with SHBRV. In vitro
      studies showed that, while the susceptibility of neuroblastoma cells to infection
      by both viruses was similar, the infectivity of SHBRV was much higher than that
      of COSRV in fibroblasts (BHK-21) and epithelial cells (MA-104), particularly when
      these cells were kept at 34 degrees C. At this temperature, low pH-dependent
      fusion and cell-to-cell spread of virus is seen in BHK-21 cells infected with
      SHBRV but not with COSRV. It appears that SHBRV may possess an unique cellular
      tropism and the ability to replicate at lower temperature, allowing a more
      effective local replication in the dermis. This hypothesis is supported by in
      vivo results which showed that while SHBRV is less neurovirulent than COSRV when
      administered via the intramuscular or intranasal routes, both viruses are equally
      neuroinvasive if injected intracranially or intradermally. Consistent with the
      above findings, the amino acid sequences of the glycoproteins of SHBRV and COSRV
      were found to have substantial differences, particularly in the region that
      contains the putative toxic loop, which are reflected in marked differences in
      their antigenic composition. Nevertheless, an experimental rabies vaccine based
      on the Pittman Moore vaccine strain protected mice equally well from lethal doses
      of SHBRV and COSRV, suggesting that currently used vaccines should be effective
      in the postexposure prophylaxis of rabies due to SHBRV.

PMID- 8643633
TI  - Constitutively active human Notch1 binds to the transcription factor CBF1 and
      stimulates transcription through a promoter containing a CBF1-responsive element.
AB  - Notch is a transmembrane receptor that plays a critical role in cell fate
      determination. In Drosophila, Notch binds to and signals through Suppressor of
      Hairless. A mammalian homologue of Suppressor of Hairless, named CBF1 (or RBPJk),
      is a ubiquitous transcription factor whose function in mammalian Notch signaling
      is unknown. To determine whether mammalian Notch can stimulate transcription
      through a CBF1-responsive element (RE), we cotransfected a CBF1-RE-containing
      chloramphenicol acetyltransferase reporter and N1(deltaEC), a constitutively
      active form of human Notch1 lacking the extracellular domain, into DG75, COS-1,
      HeLa, and 293T cells, which all contain endogenous CBF1. N1(deltaEC) dramatically
      increased chloramphenicol acetyltransferase activity in these cells, indicating
      functional coupling of Notch1 and CBF1. The activity was comparable to that
      produced by the Epstein-Barr virus protein EBNA2, a well-characterized, potent
      transactivator of CBF1. To test whether CBF1 and Notch1 interact physically, we
      tagged CBF1 with an epitope from the influenza virus hemagglutinin or with the N
      terminal domain of gal4, and transfected the tagged CBF1 plus N1(deltaEC) into
      COS-1 cells. Cell lysates were immunoprecipitated and immunoblotted with several
      anti-Notch1 antibodies [to detect N1(deltaEC)] or with antibodies to
      hemagglutinin or gal4 (to detect CBF1). Each immunoprecipitate contained a
      complex of N1(deltaEC) and CBF1. In summary, we find that the truncated, active
      form of human Notch1, N1(deltaEC), binds CBF1 and activates transcription through
      a CBF1-RE-containing promoter. We conclude that CBF1 is a critical downstream
      protein in the human Notch1 signaling pathway.

PMID- 8643635
TI  - Conserved catalytic machinery and the prediction of a common fold for several
      families of glycosyl hydrolases.

PMID- 8643634
TI  - OB protein binds specifically to the choroid plexus of mice and rats.
AB  - Binding studies were conducted to identify the anatomical location of brain
      target sites for OB protein, the ob gene product. 125I-labeled recombinant mouse
      OB protein or alkaline phosphatase-OB fusion proteins were used for in vitro and
      in vivo binding studies. Coronal brain sections or fresh tissue from lean, obese
      ob/ob, and obese db/db mice as well as lean and obese Zucker rats were probed to
      identify potential central OB protein-binding sites. We report here that
      recombinant OB protein binds specifically to the choroid plexus. The binding of
      OB protein (either radiolabeled or the alkaline phosphatase-OB fusion protein)
      and its displacement by unlabeled OB protein was similar in lean, obese ob/ob,
      and obese db/db mice as well as lean and obese Zucker rats. These findings
      suggest that OB protein binds with high affinity to a specific receptor in the
      choroid plexus. After binding to the choroid plexus receptor, OB protein may then
      be transported across the blood-brain barrier into the cerebrospinal fluid.
      Alternatively, binding of OB protein to a specific receptor in the choroid plexus
      may activate afferent neural inputs to the neural network that regulates feeding
      behavior and energy balance or may result in the clearance or degradation of OB
      protein. The identification of the choroid plexus as a brain binding site for OB
      protein will provide the basis for the construction of expression libraries and
      facilitate the rapid cloning of the choroid plexus OB receptor.

PMID- 8643636
TI  - Pufferfish and new paradigm for comparative genome analysis.

PMID- 8643637
TI  - Conservation of synteny between the genome of the pufferfish (Fugu rubripes) and
      the region on human chromosome 14 (14q24.3) associated with familial Alzheimer
      disease (AD3 locus)
AB  - The genome of the pufferfish (Fugu rubripes) (400 Mb) is approximately 7.5 times
      smaller than the human genome, but it has a similar gene repertoire to that of
      man. If regions of the two genomes exhibited conservation of gene order (i.e.,
      were syntenic), it should be possible to reduce dramatically the effort required
      for identification of candidate genes in human disease loci by sequencing
      syntenic regions of the compact Fugu genome. We have demonstrated that three
      genes (dihydrolipoamide succinyltransferase, S31iii125, and S20i15), which are
      linked to FOS in the familial Alzheimer disease focus (AD3) on human chromosome
      14, have homologues in the Fugu genome adjacent to Fugu cFOS. The relative gene
      order of cFOS, S31iii125, and S20i15 was the same in both genomes, but in Fugu
      these three genes lay within a 12.4-kb region, compared to >600 kb in the human
      AD3 locus. These results demonstrate the conservation of synteny between the
      genomes of Fugu and man and highlight the utility of this approach for sequence
      based identification of genes in human disease loci.

PMID- 8643640
TI  - Interisland and interarchipelago transfer of stone tools in prehistoric
      Polynesia.
AB  - Tracing interisland and interarchipelago movements of people and artifacts in
      prehistoric Polynesia has posed a challenge to archaeologists due to the lack of
      pottery and obsidian, two materials most readily used in studies of prehistoric
      trade or exchange. Here we report the application of nondestructive energy
      dispersive x-ray fluorescence (EDXRF) analysis to the sourcing of Polynesian
      artifacts made from basalt, one of the most ubiquitous materials in Polynesian
      archaeological sites. We have compared excavated and surface-collected basalt
      adzes and adze flakes from two sites in Samoa (site AS-13-1) and the Cook Islands
      (site MAN-44), with source basalts from known prehistoric quarries in these
      archipelagoes. In both cases, we are able to demonstrate the importing of basalt
      adzes from Tutuila Island, a distance of 100 km to Ofu Island, and of 1600 km to
      Mangaia Island. These findings are of considerable significance for Polynesian
      prehistory, as they demonstrate the movement of objects not only between islands
      in the same group (where communities were culturally and linguistically related)
      but also between distant island groups. Further applications of EDXRF analysis
      should greatly aid archaeologists in their efforts to reconstruct ancient trade
      and exchange networks, not only in Polynesia but also in other regions where
      basalt was a major material for artifact production.

PMID- 8643638
TI  - Mapping nucleosome position at single base-pair resolution by using site-directed
      hydroxyl radicals.
AB  - A base-pair resolution method for determining nucleosome position in vitro has
      been developed to com- plement existing, less accurate methods. Cysteaminyl EDTA
      was tethered to a recombinant histone octamer via a mutant histone H4 with serine
      47 replaced by cysteine. When assembled into nucleosome core particles, the DNA
      could be cut site specifically by hydroxyl radical-catalyzed chain scission by
      using the Fenton reaction. Strand cleavage occurs mainly at a single nucleotide
      close to the dyad axis of the core particle, and assignment of this location via
      the symmetry of the nucleosome allows base-pair resolution mapping of the histone
      octamer position on the DNA. The positions of the histone octamer and H3H4
      tetramer were mapped on a 146-bp Lytechinus variegatus 5S rRNA sequence and a
      twofold-symmetric derivative. The weakness of translational determinants of
      nucleosome positioning relative to the overall affinity of the histone proteins
      for this DNA is clearly demonstrated. The predominant location of both histone
      octamer and H3H4 tetramer assembled on the 5S rDNA is off center. Shifting the
      nucleosome core particle position along DNA within a conserved rotational phase
      could be induced under physiologically relevant conditions. Since nucleosome
      shifting has important consequences for chromatin structure and gene regulation,
      an approach to the thermodynamic characterization of this movement is proposed.
      This mapping method is potentially adaptable for determining nucleosome position
      in chromatin in vivo.

PMID- 8643639
TI  - Reconstitution of repair-gap UV mutagenesis with purified proteins from
      Escherichia coli: a role for DNA polymerases III and II.
AB  - Using a cell-free system for UV mutagenesis, we have previously demonstrated the
      existence of a mutagenic pathway associated with nucleotide-excision repair gaps.
      Here, we report that this pathway can be reconstituted by using six purified
      proteins: UvrA, UvrB, UvrC, DNA helicase II, DNA polymerase III core, and DNA
      ligase. This establishes the minimal requirements for repair-gap UV mutagenesis.
      DNA polymerase II could replace DNA polymerase III, although less effectively,
      whereas DNA polymerase I, the major repair polymerase, could not. DNA sequence
      analysis of mutations generated in the in vitro reaction revealed a spectrum
      typical of mutations targeted to UV lesions. These observations suggest that
      repair-gap UV mutagenesis is performed by DNA polymerase III, and to a lesser
      extent by DNA polymerase II, by filling-in of a rare class of excision gaps that
      contain UV lesions.

PMID- 8643641
TI  - Structure of the N intermediate of bacteriorhodopsin revealed by x-ray
      diffraction.
AB  - X-ray diffraction experiments revealed the structure of the N photointermediate
      of bacteriorhodopsin. Since the retinal Schiff base is reprotonated from Asp-96
      during the M to N transition in the photocycle, and Asp-96 is reprotonated during
      the lifetime of the N intermediate, or immediately after, N is a key intermediate
      for understanding the light-driven proton pump. The N intermediate accumulates in
      large amounts during continuous illumination of the F171C mutant at pH 7 and 5
      degrees Celsius. Small but significant changes of the structure were detected in
      the x-ray diffraction profile under these conditions. The changes were reversible
      and reproducible. The difference Fourier map indicates that the major change
      occurs near helix F. The observed diffraction changes between N and the original
      state were essentially identical to the diffraction changes reported for the M
      intermediate of the D96N mutant of bacteriorhodopsin. Thus, we find that the
      protein conformations of the M and N intermediates of the photocycle are
      essentially the same, in spite of the fact that in M the Schiff base is
      unprotonated and in N it is protonated. The observed structural change near helix
      F will increase access of the Schiff base and Asp-96 to the cytoplasmic surface
      and facilitate the proton transfer events that begin with the decay of the M
      state.

PMID- 8643642
TI  - A heterotrimeric G protein complex couples the muscarinic m1 receptor to
      phospholipase C-beta.
AB  - We addressed the question as to which subtypes of G protein subunits mediate the
      activation of phospholipase C-beta by the muscarinic m1 receptor. We used the rat
      basophilic leukemia cell line RBL-2H3-hm1 stably transfected with the human
      muscarinic m1 receptor cDNA. We microinjected antisense oligonucleotides into the
      nuclei of the cells to inhibit selectively the expression of G protein subunits;
      48 hr later muscarinic receptors were activated by carbachol, and the increase in
      free cytosolic calcium concentration ([Ca2+]i) was measured. Antisense
      oligonucleotides directed against the mRNA coding for alpha(q) and alpha11
      subunits both suppressed the carbachol-induced increase in [Ca2+]i. In cells
      injected with antisense oligonucleotides directed against alpha(o1) and alpha14
      subunits, the carbachol effect was unchanged. A corresponding reduction of
      Galpha(q), and Galpha11 proteins by 70-80% compared to uninjected cells was
      immunochemically detected 2 days after injection of a mixture of alpha(q) and
      alpha11 antisense oligonucleotides. Expression of Galpha(q) and Galpha11
      completely recovered after 4 days. Cells injected with antisense oligonucleotides
      directed against the mRNAs encoding for beta1, beta4, and gamma4 subunits showed
      a suppression of the carbachol-induced increase in [Ca2+]i compared to uninjected
      cells measured at the same time from the same coverslip, whereas in cells
      injected with antisense oligonucleotides directed against the beta2, beta3,
      gamma1, gamma2, gamma3, gamma5, and gamma7 subunits, no suppression of carbachol
      effect was observed. In summary, the results from RBL-2H3-hm1 cells indicate that
      the m1 receptor utilizes a G protein complex composed of the subunits alpha(q),
      alpha11, beta1, beta4, and gamma4 to activate phospholipase C.

PMID- 8643643
TI  - Kinetic discrimination in T-cell activation.
AB  - We propose a quantitative model for T-cell activation in which the rate of
      dissociation of ligand from T-cell receptors determines the agonist and
      antagonist properties of the ligand. The ligands are molecular complexes between
      antigenic peptides and proteins of the major histocompatibility complex on the
      surfaces of antigen-presenting cells. Binding of ligand to receptor triggers a
      series of biochemical reactions in the T cell. If the ligand dissociates after
      these reactions are complete, the T cell receives a positive activation signal.
      However, dissociation of ligand after completion of the first reaction but prior
      to generation of the final products results in partial T-cell activation, which
      acts to suppress a positive response. Such a negative signal is brought about by
      T-cell ligands containing the variants of antigenic peptides referred to as T
      cell receptor antagonists. Results of recent experiments with altered peptide
      ligands compare favorably with T-cell responses predicted by this model.

PMID- 8643644
TI  - Correlation between the effects of bombesin antagonists on cell proliferation and
      intracellular calcium concentration in Swiss 3T3 and HT-29 cell lines.
AB  - Bombesin (BN) acts as an autocrine mitogen in various human cancers. Several
      pseudononapeptide BN-(6-14) analogs with a reduced peptide bond between positions
      13 and 14 have been shown to suppress the mitogenic activity of BN or gastrin
      releasing peptide (GRP) when assessed by radioreceptor or proliferation assays
      and may have significant clinical applications. The search for potent and safe BN
      antagonists requires the evaluation of a large series of analogs in radioreceptor
      and proliferation assays. In this paper, we report that the ability of BN analogs
      to inhibit BN-induced calcium transients in Swiss 3T3 cells shows a high
      correlation with their inhibitory potency as evaluated by classical proliferation
      tests. The assay of calcium transients allows a rapid characterization of new BN
      analogs (in terms of minutes rather than days) and can be adapted as a labor and
      cost-effective screening step in the selection of potentially relevant BN
      antagonists for further characterization in cell proliferation systems. We also
      observed that results from the assay of calcium transients in Swiss 3T3 cells can
      be correlated with the results of the proliferative response in HT-29 cells, a
      cell line that does not seem to use the same early transmembrane ionic signal
      system. This result suggests that the calcium pathway is not mandatory for
      triggering cell division by the BN receptor.

PMID- 8643645
TI  - Poliovirus chimeras replicating under the translational control of genetic
      elements of hepatitis C virus reveal unusual properties of the internal ribosomal
      entry site of hepatitis C virus.
AB  - Chimeric genomes of poliovirus (PV) have been constructed in which the cognate
      internal ribosomal entry site (IRES) element was replaced by genetic elements of
      hepatitis C virus (HCV). Replacement of PV IRES with nt 9-332 of the genotype Ib
      HCV genome, a sequence comprising all but the first eight residues of the 5'
      nontranslated region (5'NTR) of HCV, resulted in a lethal phenotype. Addition of
      366 nt of the HCV core-encoding sequence downstream of the HCV 5'NTR yielded a
      viable PV/HCV chimera, which expressed a stable, small-plaque phenotype. This
      chimeric genome encoded a truncated HCV core protein that was fused to the N
      terminus of the PV polyprotein via an engineered cleavage site for PV proteinase
      3CPpro. Manipulation of the HCV core-encoding sequence of this viable chimera by
      deletion and frameshift yielded results suggesting that the 5'-proximal sequences
      of the HCV open reading frame were essential for viability of the chimera and
      that the N-terminal basic region of the HCV core protein is required for
      efficient replication of the chimeric virus. These data suggest that the bona
      fide HCV IRES includes genetic information mapping to the 5'NTR and sequences of
      the HCV open reading frame. PV chimeras replicating under translational control
      of genetic elements of HCV can serve to study HCV IRES function in vivo and to
      search for anti-HCV chemotherapeutic agents.

PMID- 8643646
TI  - Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in
      Aspergillus nidulans.
AB  - Sterigmatocystin (ST) and the aflatoxins (AFs), related fungal secondary
      metabolites, are among the most toxic, mutagenic, and carcinogenic natural
      products known. The ST biosynthetic pathway in Aspergillus nidulans is estimated
      to involve at least 15 enzymatic activities, while certain Aspergillus
      parasiticus, Aspergillus flavus, and Aspergillus nomius strains contain
      additional activities that convert ST to AF. We have characterized a 60-kb region
      in the A. nidulans genome and find it contains many, if not all, of the genes
      needed for ST biosynthesis. This region includes verA, a structural gene
      previously shown to be required for ST biosynthesis, and 24 additional closely
      spaced transcripts ranging in size from 0.6 to 7.2 kb that are coordinately
      induced only under ST-producing conditions. Each end of this gene cluster is
      demarcated by transcripts that are expressed under both ST-inducing and non-ST
      inducing conditions. Deduced polypeptide sequences of regions within this cluster
      had a high percentage of identity with enzymes that have activities predicted for
      ST/AF biosynthesis, including a polyketide synthase, a fatty acid synthase (alpha
      and beta subunits), five monooxygenases, four dehydrogenases, an esterase, an 0
      methyltransferase, a reductase, an oxidase, and a zinc cluster DNA binding
      protein. A revised system for naming the genes of the ST pathway is presented.

PMID- 8643647
TI  - Localization of 17beta-hydroxysteroid dehydrogenase and characterization of
      testosterone in the brain of the male frog.
AB  - Several enzymes involved in the formation of steroids of the pregnene and
      pregnane series have been identified in the brain, but the biosynthesis of
      testosterone has never been reported in the central nervous system. In the
      present study, we have investigated the distribution and bioactivity of 17beta
      hydroxysteroid dehydrogenase (17beta-HSD) (EC 1.1.1.62; a key enzyme that is
      required for the formation of testosterone and estradiol) in the brain of the
      male frog Rana ridibunda. By using an antiserum against human type I placental
      17beta-HSD, immunoreactivity was localized in a discrete group of ependymal glial
      cells bordering the telencephalic ventricles. HPLC analysis of telencephalon and
      hypothalamus extracts combined with testosterone radioimmunoassay revealed the
      existence of two peaks coeluting with testosterone and 5alpha
      dihydrotestosterone. After HPLC purification, testosterone was identified by gas
      chromatography/mass spectrometry. Incubation of telencephalon slices with
      [3H]pregnenolone resulted in the formation of metabolites which coeluted with
      progesterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone,
      androstenedione, testosterone, and 5alpha-dihydrotestosterone. The newly
      synthesized steroid comigrating with testosterone was selectively immunodetected
      by using testosterone antibodies. These data indicate that 17beta-HSD is
      expressed in a subpopulation of gliocytes in the frog telencephalon and that
      telencephalic cells are capable of synthesizing various androgens, including
      dehydroepiandrosterone, androstenedione, testosterone, and 5alpha
      dihydrotestosterone.

PMID- 8643648
TI  - Adrenocortical suppression blocks the memory-enhancing effects of amphetamine and
      epinephrine.
AB  - This study examined glucocorticoid-adrenergic interactions in modulating
      acquisition and memory storage for inhibitory avoidance training. Systemically
      (s.c.) administered amphetamine (1 mg/kg), but not epinephrine (0.1 mg/kg) or the
      peripherally acting amphetamine derivative 4-OH amphetamine (2 mg/kg), given to
      rats shortly before training facilitated acquisition performance in a continuous
      multiple-trial inhibitory avoidance (CMIA) task. Adrenocortical suppression with
      the 11beta-hydroxylase inhibitor metyrapone (50 mg/kg; s.c.), given to rats 90
      min before training, did not block the effect of amphetamine and did not affect
      acquisition performance of otherwise untreated animals. Retention of CMIA and one
      trial inhibitory avoidance was enhanced by either pre- or posttraining injections
      of amphetamine as well as 4-OH amphetamine and epinephrine. The finding that
      injections of amphetamine and epinephrine have comparable effects on memory is
      consistent with the view that amphetamine may modulate memory storage, at least
      in part, by inducing the release of epinephrine from the adrenal medulla.
      Metyrapone pretreatment blocked the memory-enhancing effects of amphetamine, 4-OH
      amphetamine, and epinephrine but did not affect retention performance of
      otherwise untreated animals. Posttraining injections of different doses of
      epinephrine (ranging from 0.0001 to 1.0 mg/kg) produced a dose-dependent memory
      enhancement for inhibitory avoidance training and metyrapone blocked the memory
      enhancing effects of all these doses. These findings provide further evidence
      that the sympathoadrenal and adrenocortical systems are intimately coupled during
      processes of memory storage.

PMID- 8643649
TI  - The human lysozyme promoter directs reporter gene expression to activated
      myelomonocytic cells in transgenic mice.
AB  - The 5' region of the human lysozyme gene from -3500 to +25 was fused to a
      chloramphenicol acetyltransferase (CAT) reporter gene and three transgenic
      founder mice were obtained. All three transgenic lines showed the same pattern of
      CAT enzyme expression in adult mouse tissues that was consistent with the
      targeting of elicited, activated macrophages in tissues and developing and
      elicited granulocytes. In normal mice high CAT enzyme activity was found in the
      spleen, lung, and thymus, tissues rich in phagocytically active cells, but not in
      many other tissues, such as the gut and muscle, which contain resident
      macrophages. Cultured resident peritoneal macrophages and cells elicited 18 hr
      (granulocytes) and 4 days (macrophages) after injection of sterile thioglycollate
      broth expressed CAT activity. Bacillus Calmette-Guerin infection of transgenic
      mice resulted in CAT enzyme expression in the liver, which contained macrophage
      rich granulomas, whereas the liver of uninfected mice did not have any detectable
      CAT enzyme activity. Although the Paneth cells of the small intestine in both
      human and mouse produce lysozyme, the CAT gene, under the control of the human
      lysozyme promoter, was not expressed in the mouse small intestine. These results
      indicate that the human lysozyme promoter region may be used to direct expression
      of genes to activated mouse myeloid cells.

PMID- 8643650
TI  - E2F1 and E1A(12S) have a homologous activation domain regulated by RB and CBP.
AB  - The E2F1 transcription factor has a well-characterized activation domain at its C
      terminus and the E1A protein has a recently defined activation domain at its N
      terminus. Here we show that these activation domains are highly related in
      sequence. The sequence homology reflects, at least partly, the conservation of
      common binding sites for the RB and CBP/p300 proteins, which are preserved in the
      same relative order along E2F1 and E1A. Furthermore, the interaction of RB and
      CBP with these two activation domains results in the same functional
      consequences: RB represses both activation domains, whereas CBP stimulates them.
      We conclude that the activation domains of E1A(12s) and E2F1 belong to a novel
      functional class, characterized by specific protein binding sites. The
      implication of this conservation with respect to E1A-induced stimulation of E2F
      activity is discussed.

PMID- 8643652
TI  - Heat shock induces a loss of rRNA-encoding DNA repeats in Brassica nigra.
AB  - Stress-induced mutations may play an important role in the evolution of plants.
      Plants do not sequester a germ line, and thus any stress-induced mutations could
      be passed on to future generations. We report a study of the effects of heat
      shock on genomic components of Brassica nigra Brassicaceae. Plants were submitted
      to heat stress, and the copy number of two nuclear-encoded single-copy genes,
      rRNA-encoding DNA (rDNA) and a chloroplast DNA gene, was determined and compared
      to a nonstressed control group. We determined whether genomic changes were
      inherited by examining copy number in the selfed progeny of control and heat
      treated individuals. No effects of heat shock on copy number of the single-copy
      nuclear genes or on chloroplast DNA are found. However, heat shock did cause a
      statistically significant reduction in rDNA copies inherited by the F1
      generation. In addition, we propose a DNA damage-reppair hypothesis to explain
      the reduction in rDNA caused by heat shock.

PMID- 8643651
TI  - Tiggers and DNA transposon fossils in the human genome.
AB  - We report several classes of human interspersed repeats that resemble fossils of
      DNA transposons, elements that move by excision and reintegration in the genome,
      whereas previously characterized mammalian repeats all appear to have accumulated
      by retrotransposition, which involves an RNA intermediate. The human genome
      contains at least 14 families and > 100,000 degenerate copies of short (180-1200
      bp) elements that have 14- to 25-bp terminal inverted repeats and are flanked by
      either 8 bp or TA target site duplications. We describe two ancient 2.5-kb
      elements with coding capacity, Tigger1 and -2, that closely resemble pogo, a DNA
      transposon in Drosophila, and probably were responsible for the distribution of
      some of the short elements. The deduced pogo and Tigger proteins are related to
      products of five DNA transposons found in fungi and nematodes, and more
      distantly, to the Tc1 and mariner transposases. They also are very similar to the
      major mammalian centromere protein CENP-B, suggesting that this may have a
      transposase origin. We further identified relatively low-copy-number mariner
      elements in both human and sheep DNA. These belong to two subfamilies previously
      identified in insect genomes, suggesting lateral transfer between diverse
      species.

PMID- 8643653
TI  - Physical and functional independency of p70 and p58 natural killer (NK) cell
      receptors for HLA class I: their role in the definition of different groups of
      alloreactive NK cell clones.
AB  - Natural killer (NK) cells express clonally distributed receptors for different
      groups of HLA class I alleles. The Z27 monoclonal antibody described in this
      study recognizes a p70 receptor specific for HLA-B alleles belonging to the Bw4
      supertypic specificity. Single amino acid substitutions in the peptide-binding
      groove of HLA-B2705 molecules influenced the recognition by some, but not all,
      p7O/Z27+ clones. This suggests the existence of a limited polymorphism within the
      p7O family of receptors. The pattern of reactivity of monoclonal antibody Z27
      revealed that Bw4-specific receptors may be expressed alone or in combination
      with different (GL183 and/or EB6) p58 molecules. Analysis of NK clones
      coexpressing p58 and p7O receptors allowed us to demonstrate that the two
      molecules represent physically and functionally independent receptors. The
      expression of p7O molecules either alone or in combination with EB6 molecules
      provided the molecular basis for understanding the cytolytic pattern of two
      previously defined groups of "alloreactive" NK cell clones ("group 3" and "group
      5").

PMID- 8643655
TI  - Biosynthesis of major histocompatibility complex molecules and generation of T
      cells in Ii TAP1 double-mutant mice.
AB  - Major histocompatibility complex (MHC) class I and II molecules are loaded with
      peptides in distinct subcellular compartments. The transporter associated with
      antigen processing (TAP) is responsible for delivering peptides derived from
      cytosolic proteins to the endoplasmic reticulum, where they bind to class I
      molecules, while the invariant chain (Ii) directs class II molecules to endosomal
      compartments, where they bind peptides originating mostly from exogenous sources.
      Mice carrying null mutations of the TAP1 or Ii genes (TAP10) or Ii0,
      respectively) have been useful tools for elucidating the two MHC/peptide loading
      pathways. To evaluate to what extent these pathways functionally intersect, we
      have studied the biosynthesis of MHC molecules and the generation of T cells in
      Ii0TAP10 double-mutant mice. We find that the assembly and expression of class II
      molecules in Ii0 and Ii0TAP10 animals are indistinguishable and that formation
      and display of class I molecules is the same in TAP10 and Ii0TAP10 animals.
      Thymic selection in the double mutants is as expected, with reduced numbers of
      both CD4+ CD8- and CD4- CD8+ thymocyte compartments. Surprisingly, lymph node T
      cell populations look almost normal; we propose that population expansion of
      peripheral T cells normalizes the numbers of CD4+ and CD8+ cells in Ii0TAP10
      mice.

PMID- 8643654
TI  - Superior efficacy of secreted over somatic antigen display in recombinant
      Salmonella vaccine induced protection against listeriosis.
AB  - Vaccination provides the most potent measure against infectious disease, and
      recombinant (r) viable vaccines expressing defined pathogen-derived antigens
      represent powerful candidates for future vaccination strategies. In a new
      approach we constructed r-aroA- Salmonella typhimurium displaying p60 or
      listeriolysin (Hly) antigen of Listeria monocytogenes in secreted or somatic form
      in the host cell. Vaccination of mice with r-aroA- S. typhimurium induced
      protection against the intracellular pathogen L. monocytogenes only with secreted
      and not with somatic antigen. Secreted Hly was slightly more potent in inducing
      protective immunity than secreted p60. Both r-aroA- S. typhimurium secreting p60
      in the endosome and r-aroA- S. typhimurium secreting Hly in the cytosol induced
      protective CD4+ and CD8+ T-cells suggesting CD8+ T-cell stimulation independent
      from intracellular residence of r-aroA- S. typhimurium carriers. Hence, not only
      the type of antigen but also its display by the r-carrier within the host cell
      critically influences vaccine efficacy.

PMID- 8643656
TI  - Self-renewal of primitive human hematopoietic cells (long-term-culture-initiating
      cells) in vitro and their expansion in defined medium.
AB  - A major goal of experimental and clinical hematology is the identification of
      mechanisms and conditions that support the expansion of transplantable
      hematopoietic stem cells. In normal marrow, such cells appear to be identical to
      (or represent a subset of) a population referred to as long-term-culture
      initiating cells (LTC-ICs) so-named because of their ability to produce colony
      forming cell (CFC) progeny for > or = 5 weeks when cocultured with stromal
      fibroblasts. Some expansion of LTC-ICs in vitro has recently been described, but
      identification of the factors required and whether LTC-IC self-renewal divisions
      are involved have remained unresolved issues. To address these issues, we
      examined the maintenance and/or generation of LTC-ICs from single CD34+ CD38-
      cells cultured for variable periods under different culture conditions. Analysis
      of the progeny obtained from cultures containing a feeder layer of murine
      fibroblasts engineered to produce steel factor, interleukin (IL)-3, and
      granulocyte colony-stimulating factor showed that approximately 20% of the input
      LTC-ICs (representing approximately 2% of the original CD34+ CD38- cells)
      executed self-renewal divisions within a 6-week period. Incubation of the same
      CD34+ CD38- starting populations as single cells in a defined (serum free) liquid
      medium supplemented with Flt-3 ligand, steel factor, IL-3, IL-6, granulocyte
      colony-stimulating factor, and nerve growth factor resulted in the proliferation
      of initial cells to produce clones of from 4 to 1000 cells within 10 days,
      approximately 40% of which included > or = 1 LTC-IC. In contrast, in similar
      cultures containing methylcellulose, input LTC-ICs appeared to persist but not
      divide. Overall the LTC-IC expansion in the liquid cultures was 30-fold in the
      first 10 days and 50-fold by the end of another 1-3 weeks. Documentation of human
      LTC-IC self-renewal in vitro and identification of defined conditions that permit
      their extensive and rapid amplification should facilitate analysis of the
      molecular mechanisms underlying these processes and their exploitation for a
      variety of therapeutic applications.

PMID- 8643657
TI  - Regulation of phosducin phosphorylation in retinal rods by Ca2+/calmodulin
      dependent adenylyl cyclase.
AB  - The phosphoprotein phosducin (Pd) regulates many guanine nucleotide binding
      protein (G protein)-linked signaling pathways. In visual signal transduction,
      unphosphorylated Pd blocks the interaction of light-activated rhodopsin with its
      G protein (Gt) by binding to the beta gamma subunits of Gt and preventing their
      association with the Gt alpha subunit. When Pd is phosphorylated by cAMP
      dependent protein kinase, it no longer inhibits Gt subunit interactions. Thus,
      factors that determine the phosphorylation state of Pd in rod outer segments are
      important in controlling the number of Gts available for activation by rhodopsin.
      The cyclic nucleotide dependencies of the rate of Pd phosphorylation by
      endogenous cAMP-dependent protein kinase suggest that cAMP, and not cGMP,
      controls Pd phosphorylation. The synthesis of cAMP by adenylyl cyclase in rod
      outer segment preparations was found to be dependent on Ca2+ and calmodulin. The
      Ca2+ dependence was within the physiological range of Ca2+ concentrations in rods
      (K1/2 = 230 +/- 9 nM) and was highly cooperative (n app = 3.6 +/- 0.5). Through
      its effect on adenylyl cyclase and cAMP-dependent protein kinase, physiologically
      high Ca2+ (1100 nM) was found to increase the rate of Pd phosphorylation 3-fold
      compared to the rate of phosphorylation at physiologically low Ca2+ (8 nM). No
      evidence for Pd phosphorylation by other (Ca2+)-dependent kinases was found.
      These results suggest that Ca2+ can regulate the light response at the level of
      Gt activation through its effect on the phosphorylation state of Pd.

PMID- 8643658
TI  - cGMP mediates the vascular and platelet actions of nitric oxide: confirmation
      using an inhibitor of the soluble guanylyl cyclase.
AB  - The L-arginine:nitric oxide (NO) pathway is believed to exert many of its
      physiological effects via stimulation of the soluble guanylyl cyclase (SGC);
      however, the lack of a selective inhibitor of this enzyme has prevented
      conclusive demonstration of this mechanism of action. We have found that the
      compound 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) inhibits the
      elevation of cGMP induced by the NO donor S-nitroso-DL-penicillamine in human
      platelets and rat vascular smooth muscle (IC50 = 10-60 nM and <10 nM,
      respectively) and that this is accompanied by prevention of the platelet
      inhibitory and vasodilator actions of NO donors. ODQ also inhibited the
      antiaggregatory action of NO generated by the platelets but did not affect the
      action of prostacyclin or that of a cGMP mimetic. In addition, ODQ inhibited the
      vasodilator actions of endogenously released NO and of NO generated after
      induction of NO synthase in vascular preparations. It did not, however, affect
      the increase in vascular smooth muscle cGMP or the dilatation induced by atrial
      natriuretic factor. ODQ had no effect on NO synthase activity, nor did it react
      with NO. It did, however, potently (IC50 approximately 10 nM) inhibit the
      activity of the SGC in cytosol obtained from crude extract of rat aortic smooth
      muscle. Thus ODQ prevents the actions of NO on platelets and vascular smooth
      muscle through its potent inhibitory effect on the SGC.

PMID- 8643659
TI  - Determinants of the G protein-dependent opioid modulation of neuronal calcium
      channels.
AB  - The modulation of a family of cloned neuronal calcium channels by stimulation of
      a coexpressed mu opioid receptor was studied by transient expression in Xenopus
      oocytes. Activation of the morphine receptor with the synthetic enkephalin [D
      Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) resulted in a rapid inhibition of
      alpha1A (by approximately 20%) and alpha1B (by approximately 55%) currents while
      alpha1C and alpha1E currents were not significantly affected. The opioid-induced
      effects on alpha1A and alpha1B currents were blocked by pertussis toxin and the
      GTP analogue guanosine 5'-[beta-thio]diphosphate. Similar to modulation of native
      calcium currents, DAMGO induced a slowing of the activation kinetics and
      exhibited a voltage-dependent inhibition that was partially relieved by
      application of strong depolarizing pulses. alpha1A currents were still inhibited
      in the absence of coexpressed Ca channel alpha2 and beta subunits, suggesting
      that the response is mediated by the alpha1 subunit. Furthermore, the sensitivity
      of alpha1A currents to DAMGO-induced inhibition was increased approximately 3
      fold in the absence of a beta subunit. Overall, the results show that the alpha1A
      (P/Q type) and the alpha1B (N type) calcium channels are selectively modulated by
      a GTP-binding protein (G protein). The results raise the possibility of
      competitive interactions between beta subunit and G protein binding to the alpha1
      subunit, shifting gating in opposite directions. At presynaptic terminals, the G
      protein-dependent inhibition may result in decreased synaptic transmission and
      play a key role in the analgesic effect of opioids and morphine.

PMID- 8643660
TI  - In vivo protein-DNA interactions at human DNA replication origin.
AB  - Protein-DNA interactions were studied in vivo at the region containing a human
      DNA replication origin, located at the 3' end of the lamin B2 gene and partially
      overlapping the promoter of another gene, located downstream. DNase I treatment
      of nuclei isolated from both exponentially growing and nonproliferating HL-60
      cells showed that this region has an altered, highly accessible, chromatin
      structure. High-resolution analysis of protein-DNA interactions in a 600-bp area
      encompassing the origin was carried out by the in vivo footprinting technique
      based on the ligation-mediated polymerase chain reaction. In growing HL-60 cells,
      footprints at sequences homologous to binding sites for known transcription
      factors (members of the basic-helix-loop-helix family, nuclear respiratory factor
      1, transcription factor Sp1, and upstream binding factor) were detected in the
      region corresponding to the promoter of the downstream gene. Upon conversion of
      cells to a nonproliferative state, a reduction in the intensity of these
      footprints was observed that paralleled the diminished transcriptional activity
      of the genomic area. In addition to these protections, in close correspondence to
      the replication initiation site, a prominent footprint was detected that extended
      over 70 nucleotides on one strand only. This footprint was absent from
      nonproliferating HL-60 cells, indicating that this specific protein-DNA
      interaction might be involved in the process of origin activation.

PMID- 8643661
TI  - Unusual dynamics of extinction in a simple ecological model.
AB  - Studies on natural populations and harvesting biological resources have led to
      the view, commonly held, that (i) populations exhibiting chaotic oscillations run
      a high risk of extinction; and (ii) a decrease in emigration/exploitation may
      reduce the risk of extinction. Here we describe a simple ecological model with
      emigration/depletion that shows behavior in contrast to this. This model displays
      unusual dynamics of extinction and survival, where populations growing beyond a
      critical rate can persist within a band of high depletion rates, whereas
      extinction occurs for lower depletion rates. Though prior to extinction at lower
      depletion rates the population exhibits chaotic dynamics with large amplitudes of
      variation and very low minima, at higher depletion rates the population persists
      at chaos but with reduced variation and increased minima. For still higher
      values, within the band of persistence, the dynamics show period reversal leading
      to stability. These results illustrate that chaos does not necessarily lead to
      population extinction. In addition, the persistence of populations at high
      depletion rates has important implications in the considerations of strategies
      for the management of biological resources.

PMID- 8643663
TI  - Numerical representations in primates.
AB  - Research has demonstrated that human infants and nonhuman primates have a
      rudimentary numerical system that enables them to count objects or events. More
      recently, however, studies using a preferential looking paradigm have suggested
      that preverbal human infants are capable of simple arithmetical operations, such
      as adding and subtracting a small number of visually presented objects. These
      findings implicate a relatively sophisticated representational system in the
      absence of language. To explore the evolutionary origins of this capacity, we
      present data from an experiment with wild rhesus monkeys (Macaca mulatta) that
      methodologically mirrors those conducted on human infants. Results suggest that
      rhesus monkeys detect additive and subtractive changes in the number of objects
      present in their visual field. Given the methodological and empirical
      similarities, it appears that nonhuman primates such as rhesus monkeys may also
      have access to arithmetical representations, although alternative explanations
      must be considered for both primate species.

PMID- 8643662
TI  - Mutagenesis of the potato ADPglucose pyrophosphorylase and characterization of an
      allosteric mutant defective in 3-phosphoglycerate activation.
AB  - ADPglucose pyrophosphorylase (glucose-1-phosphate adenylyltransferase; ADP:alpha
      D-glucose-1-phosphate adenylyltransferase, EC 2.7.7.27) catalyzes a key
      regulatory step in alpha-glucan synthesis in bacteria and higher plants. We have
      previously shown that the expression of the cDNA sequences of the potato tuber
      large (LS) and small (SS) subunits yielded a functional heterotetrameric enzyme
      capable of complementing a mutation in the single AGP (glgC) structural gene of
      Escherichia coli. This heterologous complementation provides a powerful genetic
      approach to obtain biochemical information on the specific roles of LS and SS in
      enzyme function. By mutagenizing the LS cDNA with hydroxylamine and then
      coexpressing with wild-type SS in an E. coli glgC- strain, >350 mutant colonies
      were identified that were impaired in glycogen production. One mutant exhibited
      enzymatic and antigen levels comparable to the wild-type recombinant enzyme but
      required 45-fold greater levels of the activator 3-phosphoglycerate for maximum
      activity. Sequence analysis identified a single nucleotide change that resulted
      in the change of Pro-52 to Leu. This heterologous genetic system provides an
      efficient means to identify residues important for catalysis and allosteric
      functioning and should lead to novel approaches to increase plant productivity.

PMID- 8643664
TI  - Differentiation of the immortalized adult neuronal progenitor cell line HC2S2
      into neurons by regulatable suppression of the v-myc oncogene.
AB  - A regulatable retroviral vector in which the v-myc oncogene is driven by a
      tetracycline-controlled transactivator and a human cytomegalovirus minimal
      promoter fused to a tet operator sequence was used for conditional
      immortalization of adult rat neuronal progenitor cells. A single clone, HC2S2,
      was isolated and characterized. Two days after the addition of tetracycline, the
      HC2S2 cells stopped proliferating, began to extend neurites, and expressed the
      neuronal markers tau, NeuN, neurofilament 200 kDa, and glutamic acid
      decarboxylase in accordance with the reduced production of the v-myc oncoprotein.
      Differentiated HC2S2 cells expressed large sodium and calcium currents and could
      fire regenerative action potentials. These results suggest that the suppression
      of the v-myc oncogene may be sufficient to make proliferating cells exit from
      cell cycles and induce terminal differentiation. The HC2S2 cells will be valuable
      for studying the differentiation process of neurons.

PMID- 8643665
TI  - Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial
      cells in fetal, adult, and polycystic kidney.
AB  - Polycystic kidney disease 1 (PKD1) is the major locus of the common genetic
      disorder autosomal dominant polycystic kidney disease. We have studied PKD1 mRNA,
      with an RNase protection assay, and found widespread expression in adult tissue,
      with high levels in brain and moderate signal in kidney. Expression of the PKD1
      protein, polycystin, was assessed in kidney using monoclonal antibodies to a
      recombinant protein containing the C terminus of the molecule. In fetal and adult
      kidney, staining is restricted to epithelial cells. Expression in the developing
      nephron is most prominent in mature tubules, with lesser staining in Bowman's
      capsule and the proximal ureteric bud. In the nephrogenic zone, detectable signal
      was observed in comma- and S-shaped bodies as well as the distal branches of the
      ureteric bud. By contrast, uninduced mesenchyme and glomerular tufts showed no
      staining. In later fetal (>20 weeks) and adult kidney, strong staining persists
      in cortical tubules with moderate staining detected in the loops of Henle and
      collecting ducts. These results suggest that polycystin's major role is in the
      maintenance of renal epithelial differentiation and organization from early fetal
      life. Interestingly, polycystin expression, monitored at the mRNA level and by
      immunohistochemistry, appears higher in cystic epithelia, indicating that the
      disease does not result from complete loss of the protein.

PMID- 8643666
TI  - beta2 knockout mice develop parenchymal iron overload: A putative role for class
      I genes of the major histocompatibility complex in iron metabolism.
AB  - Hemochromatosis (HC) is an inherited disorder of iron absorption, mapping within
      the human major histocompatibility complex (MHC). We have identified a multigene
      system in the murine MHC that contains excellent candidates for the murine
      equivalent of the human HC locus and implicate nonclassical class I genes in the
      control of iron absorption. This gene system is characterized by multiple copies
      of two head-to-head genes encoded on opposite strands and driven by one common
      regulatory motif. This regulatory motif has a striking homology to the promoter
      region of the beta-globin gene, a gene obviously involved in iron metabolism and
      hence termed beta-globin analogous promoter (betaGAP). Upstream of the betaGAP
      sequence are nonclassical class I genes. At least one of these nonclassical class
      I genes, Q2, is expressed in the gastrointestinal tract, the primary site of iron
      absorption. Also expressed in the gastrointestinal tract and downstream of the
      betaGAP motif is a second set of putative genes, termed Hephaestus (HEPH). Based
      on these observations, we hypothesized that the genes that seem to be controlled
      by the betaGAP regulatory motifs would be responsible for the control of Fe
      absorption. As a test of this hypothesis, we predicted that mice which have
      altered expression of class I gene products, the beta2-microglobulin knockout
      mice, [beta2m(-/-)], would develop Fe overload. This prediction was confirmed,
      and these results indicate beta2m-associated proteins are involved in the control
      of intestinal Fe absorption.

PMID- 8643667
TI  - Mutational properties of the primary aflatoxin B1-DNA adduct.
AB  - The mutagenic activity of the major DNA adduct formed by the liver carcinogen
      aflatoxin B1 (AFB1) was investigated in vivo. An oligonucleotide containing a
      single 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) adduct was
      inserted into the single-stranded genome of bacteriophage M13. Replication in SOS
      induced Escherichia coli yielded a mutation frequency for AFB1-N7-Gua of 4%. The
      predominant mutation was G --> T, identical to the principal mutation in human
      liver tumors believed to be induced by aflatoxin. The G --> T mutations of AFB1
      N7-Gua, unlike those (if the AFB1-N7-Gua-derived apurinic site, were much more
      strongly dependent on MucAB than UmuDC, a pattern matching that in intact cells
      treated with the toxin. It is concluded that the AFB1-N7-Gua adduct, and not the
      apurinic site, has genetic requirements for mutagenesis that best explain
      mutations in aflatoxin-treated cells. While most mutations were targeted to the
      site of the lesion, a significant fraction (13%) occurred at the base 5' to the
      modified guanine. In contrast, the apurinic site-containing genome gave rise only
      to targeted mutations. The mutational asymmetry observed for AFB1-N7-Gua is
      consistent with structural models indicating that the aflatoxin moiety of the
      aflatoxin guanine adduct is covalently intercalated on the 5' face of the guanine
      residue. These results suggest a molecular mechanism that could explain an
      important step in the carcinogenicity of aflatoxin B1.

PMID- 8643669
TI  - Reaction of the Escherichia coli quinol oxidase cytochrome bo3 with dioxygen: the
      role of a bound ubiquinone molecule.
AB  - We have studied the kinetics of the oxygen reaction of the fully reduced quinol
      oxidase, cytochrome bo3, using flow-flash and stopped flow techniques. This
      enzyme belongs to the heme-copper oxidase family but lacks the CuA center of the
      cytochrome c oxidases. Depending on the isolation procedure, the kinetics are
      found to be either nearly monophasic and very different from those of cytochrome
      c oxidase or multiphasic and quite similar to cytochrome c oxidase. The
      multiphasic kinetics in cytochrome c oxidase can largely be attributed to the
      presence Of CuA as the donor of a fourth electron, which rereduces the originally
      oxidized low-spin heme and completes the reduction of O2 to water. Monophasic
      kinetics would thus be expected, a priori, for cytochrome bo3 since it lacks the
      CuA center, and in this case we show that the oxygen reaction is incomplete and
      ends with the ferryl intermediate. Multiphasic kinetics thus suggest the presence
      of an extra electron donor (analogous to CuA). We observe such kinetics
      exclusively with cytochrome bo3 that contains a single equivalent of bound
      ubiquinone-8, whereas we find no bound ubiquinone in an enzyme exhibiting
      monophasic kinetics. Reconstitution with ubiquinone-8 converts the reaction
      kinetics from monophasic to multiphasic. We conclude that a single bound
      ubiquinone molecule in cytochrome bo3 is capable of fast rereduction of heme b
      and that the reaction with O2 is quite similar in quinol and cytochrome c
      oxidases.

PMID- 8643668
TI  - Distinct ligand preferences of Src homology 3 domains from Src, Yes, Abl,
      Cortactin, p53bp2, PLCgamma, Crk, and Grb2.
AB  - Src homology 3 (SH3) domains are conserved protein modules 50-70 amino acids long
      found in a variety of proteins with important roles in signal transduction. These
      domains have been shown to mediate protein-protein interactions by binding short
      proline-rich regions in ligand proteins. However, the ligand preferences of most
      SH3 domains and the role of these preferences in regulating SH3-mediated protein
      protein interactions remain poorly defined. We have used a phage-displayed
      library of peptides of the form X6PXXPX6 to identify ligands for eight different
      SH3 domains. Using this approach, we have determined that each SH3 domain prefers
      peptide ligands with distinct sequence characteristics. Specifically, we have
      found that the Src SH3 domain selects peptides sharing the consensus motif
      LXXRPLPXpsiP, whereas Yes SH3 selects psiXXRPLPXLP, Abl SH3 selects
      PPXthetaXPPPpsiP, Cortactin SH3 selects +PPpsiPXKPXWL, p53bp2 SH3 selects
      RPXpsiPpsiR+SXP, PLCgamma SH3 selects PPVPPRPXXTL, Crk N-terminal SH3 selects
      psiPpsiLPpsiK, and Grb2 N-terminal SH3 selects +thetaDXPLPXLP (where psi, theta,
      and + represent aliphatic, aromatic, and basic residues, respectively).
      Furthermore, we have compared the binding of phage expressing peptides related to
      each consensus motif to a panel of 12 SH3 domains. Results from these experiments
      support the ligand preferences identified in the peptide library screen and
      evince the ability of SH3 domains to discern subtle differences in the primary
      structure of potential ligands. Finally, we have found that most known SH3
      binding proteins contain proline-rich regions conforming to the ligand
      preferences of their respective SH3 targets.

PMID- 8643670
TI  - Cell-cell communication regulates the effects of protein aspartate phosphatases
      on the phosphorelay controlling development in Bacillus subtilis.
AB  - Rap phosphatases are a recently discovered family of protein aspartate
      phosphatases that dephosphorylate the Spo0F--P intermediate of the phosphorelay,
      thus preventing sporulation of Bacillus subtilis. They are regulators induced by
      physiological processes that are antithetical to sporulation. The RapA
      phosphatase is induced by the ComP-ComA two-component signal transduction system
      responsible for initiating competence. RapA phosphatase activity was found to be
      controlled by a small protein, PhrA, encoded on the same transcript as RapA. PhrA
      resembles secreted proteins and the evidence suggests that it is cleaved by
      signal peptidase I and a 19-residue C-terminal domain is secreted from the cell.
      The sporulation deficiency caused by the uncontrolled RapA activity of a phrA
      mutant can be complemented by synthetic peptides comprising the last six or more
      of the C-terminal residues of PhrA. Whether the peptide controls RapA activity
      directly or by regulating its synthesis remains to be determined. Complementation
      of the phrA mutant can also be obtained in mixed cultures with a wild-type
      strain, suggesting the peptide may serve as a means of communication between
      cells. Importation of the secreted peptide required the oligopeptide transport
      system. The sporulation deficiency of oligopeptide transport mutants can be
      suppressed by mutating the rapA and rapB genes or by introduction of a spo0F
      mutation Y13S that renders the protein insensitive to Rap phosphatases. The data
      indicate that the sporulation deficiency of oligopeptide transport mutants is due
      to their inability to import the peptides controlling Rap phosphatases.

PMID- 8643671
TI  - Trinucleotide repeats and long homopeptides in genes and proteins associated with
      nervous system disease and development.
AB  - Several human neurological disorders are associated with proteins containing
      abnormally long runs of glutamine residues. Strikingly, most of these proteins
      contain two or more additional long runs of amino acids other than glutamine. We
      screened the current human, mouse, Drosophila, yeast, and Escherichia coli
      protein sequence data bases and identified all proteins containing multiple long
      homopeptides. This search found multiple long homopeptides in about 12% of
      Drosophila proteins but in only about 1.7% of human, mouse, and yeast proteins
      and none among E. coli proteins. Most of these sequences show other unusual
      sequence features, including multiple charge clusters and excessive counts of
      homopeptides of length > or = two amino acid residues. Intriguingly, a large
      majority of the identified Drosophila proteins are essential developmental
      proteins and, in particular, most play a role in central nervous system
      development. Almost half of the human and mouse proteins identified are homeotic
      homologs. The role of long homopeptides in fine-tuning protein conformation for
      multiple functional activities is discussed. The relative contributions of strand
      slippage and of dynamic mutation are also addressed. Several new experiments are
      proposed.

PMID- 8643672
TI  - cdc18+ regulates initiation of DNA replication in Schizosaccharomyces pombe.
AB  - In the fission yeast Schizosaccharomyces pombe the cdc18'+gene is required both
      for initiation of DNA replication and for coupling mitosis to the completion of S
      phase. Cells lacking Cdc18 fail to enter S phase but still undergo nuclear
      division. Expression of cdc18+ is sufficient to drive a G1-arrested cdc10ts
      mutant into the S phase of the cell cycle, indicating that cdc18+ represents a
      critical link between passage through START and the initiation of DNA
      replication. Here we show that Cdcl8 is a highly unstable protein that is
      expressed only once per cell cycle at the boundary between GI and S phase. De
      novo synthesis of Cdc18 is required before, but not after, the initiation of DNA
      replication, indicating that Cdc18 function is not necessary once the initiation
      event has occurred. Overproduction of the protein results in an accumulation of
      cells with DNA content of greater than 2C and delays mitosis, suggesting that
      Cdc18 is sufficient to cause reinitiation of DNA replication within a given cell
      cycle. Our data indicate that the synthesis of Cdc18 protein is a critical rate
      limiting step in the initiation of DNA replication during each cell cycle. The
      extreme lability of the protein may contribute to the prevention of reinitiation.

PMID- 8643673
TI  - Impaired hippocampal plasticity in mice lacking the Cbeta1 catalytic subunit of
      cAMP-dependent protein kinase.
AB  - Neural pathways within the hippocampus undergo use-dependent changes in synaptic
      efficacy, and these changes are mediated by a number of signaling mechanisms,
      including cAMP-dependent protein kinase (PKA). The PKA holoenzyme is composed of
      regulatory and catalytic (C) subunits, both of which exist as multiple isoforms.
      There are two C subunit genes in mice, Calpha and Cbeta, and the Cbeta gene gives
      rise to several splice variants that are specifically expressed in discrete
      regions of the brain. We have used homologous recombination in embryonic stem
      cells to introduce an inactivating mutation into the mouse Cbeta gene,
      specifically targeting the Cbeta1-subunit isoform. Homozygous mutants showed
      normal viability and no obvious pathological defects, despite a complete lack of
      Cbeta1. The mice were analyzed in electrophysiological paradigms to test the role
      of this isoform in long-term modulation of synaptic transmission in the Schaffer
      collateral-CA1 pathway of the hippocampus. A high-frequency stimulus produced
      potentiation in both wild-type and Cbeta1-/- mice, but the mutants were unable to
      maintain the potentiated response, resulting in a late phase of long-term
      potentiation that was only 30% of controls. Paired pulse facilitation was
      unaffected in the mutant mice. Low-frequency stimulation produced long-term
      depression and depotentiation in wild-type mice but failed to produce lasting
      synaptic depression in the Cbeta1 -/- mutants. These data provide direct genetic
      evidence that PKA, and more specifically the Cbeta1 isoform, is required for long
      term depression and depotentiation, as well as the late phase of long-term
      potentiation in the Schaffer collateral-CA1 pathway.

PMID- 8643675
TI  - Cationic facial amphiphiles: a promising class of transfection agents.
AB  - A promising class of compounds for DNA transfection have been designed by
      conjugating various polyamines to bile-acid-based amphiphiles. Formulations
      containing these compounds were tested for their ability to facilitate the uptake
      of a beta-galactosidase reporter plasmid into COS-7 cells. Dioleoyl phosphatidyl
      ethanolamine (DOPE) formulations of some of the compounds were several times
      better than Lipofectin at promoting DNA uptake. The most active compounds
      contained the most hydrophilic bile acid components. The activity is clearly not
      related to affinity for DNA: the hydrophobic bile acid conjugates were found to
      form stable complexes with DNA at lower charge ratios than the hydrophilic
      conjugates. We suggest that the high activity of the best compounds is related to
      their facial amphiphilicity, which may confer an ability to destabilize
      membranes. The success of these unusual cationic transfection agents may inspire
      the design of even more effective gene delivery agents.

PMID- 8643674
TI  - Peptides containing a consensus Ras binding sequence from Raf-1 and theGTPase
      activating protein NF1 inhibit Ras function.
AB  - A key event in Ras-mediated signal transduction and transformation involves Ras
      interaction with its downstream effector targets. Although substantial evidence
      has established that the Raf-1 serine/threonine kinase is a critical effector of
      Ras function, there is increasing evidence that Ras function is mediated through
      interaction with multiple effectors to trigger Raf-independent signaling
      pathways. In addition to the two Ras GTPase activating proteins (GAPs; p120- and
      NF1-GAP), other candidate effectors include activators of the Ras-related Ral
      proteins (RalGDS and RGL) and phosphatidylinositol 3-kinase. Interaction between
      Ras and its effectors requires an intact Ras effector domain and involves
      preferential recognition of active Ras-GTP. Surprisingly, these functionally
      diverse effectors lack significant sequence homology and no consensus Ras binding
      sequence has been described. We have now identified a consensus Ras binding
      sequence shared among a subset of Ras effectors. We have also shown that peptides
      containing this sequence from Raf-1 (RKTFLKLA) and NF1-GAP (RRFFLDIA) block NF1
      GAP stimulation of Ras GTPase activity and Ras-mediated activation of mitogen
      activated protein kinases. In summary, the identification of a consensus Ras-GTP
      binding sequence establishes a structural basis for the ability of diverse
      effector proteins to interact with Ras-GTP. Furthermore, our demonstration that
      peptides that contain Ras-GTP binding sequences can block Ras function provides a
      step toward the development of anti-Ras agents.

PMID- 8643676
TI  - An RNA structure involved in feedback regulation of splicing and of translation
      is critical for biological fitness.
AB  - While studies of the regulation of gene expression have generally concerned
      qualitative changes in the selection or the level of expression of a gene, much
      of the regulation that occurs within a cell involves the continuous subtle
      optimization of the levels of proteins used in macromolecular complexes. An
      example is the biosynthesis of the ribosome, in which equimolar amounts of nearly
      80 ribosomal proteins must be supplied by the cytoplasm to the nucleolus. We have
      found that the transcript of one of the ribosomal protein genes of Saccharomyces
      cerevisiae, RPL32, participates in such fine tuning. Sequences from exon I of the
      RPL32 transcript interact with nucleotides from the intron to form a structure
      that binds L32 to regulate splicing. In the spliced transcript, the same
      sequences interact with nucleotides from exon II to form a structure that binds
      L32 to regulate translation, thus providing two levels of autoregulation. We now
      show, by using a sensitive cocultivation assay, that these RNA structures and
      their interaction with L32 play a role in the fitness of the cell. The change of
      a single nucleotide within the 5' leader of the RPL32 transcript, which abolishes
      the site for L32 binding, leads to detectably slower growth and to eventual loss
      of the mutant strain from the culture. Experiments designed to assess
      independently the regulation of splicing and the regulation of translation are
      presented. These observations demonstrate that, in evolutionary terms, subtle
      regulatory compensations can be critical. The change in structure of an RNA, due
      to alteration of just one noncoding nucleotide, can spell the difference between
      biological success and failure.

PMID- 8643677
TI  - In vivo and in vitro characterization of the B1 and B2 zinc-binding domains from
      the acute promyelocytic leukemia protooncoprotein PML.
AB  - Acute promyelocytic leukemia (APL) has been ascribed to a chromosomal
      translocation event which results in a fusion protein comprising the PML protein
      and retinoic acid receptor alpha. PML is normally a component of a nuclear
      multiprotein complex which is disrupted in the APL disease state. Here, two newly
      defined cysteine/histidine-rich protein motifs called the B-box (B1 and B2) from
      PML have been characterized in terms of their effect on PML nuclear body
      formation, their dimerization, and their biophysical properties. We have shown
      that both peptides bind Zn2+, which induces changes in the peptides' structures.
      We demonstrate that mutants in both B1 and B2 do not form PML nuclear bodies in
      vivo and have a phenotype that is different from that observed in the APL disease
      state. Interestingly, these mutations do not affect the ability of wild-type PML
      to dimerize with mutant proteins in vitro, suggesting that the B1 and B2 domains
      are involved in an additional interaction central to PML nuclear body formation.
      This report in conjunction with our previous work demonstrates that the PML RING
      Bl/B2 motif plays a fundamental role in formation of a large multiprotein
      complex, a function that may be common to those unrelated proteins which contain
      the motif.

PMID- 8643678
TI  - Overexpression of a Rrp1 transgene reduces the somatic mutation and recombination
      frequency induced by oxidative DNA damage in Drosophila melanogaster.
AB  - Recombination repair protein 1 (Rrp1) includes a C-terminal region homologous to
      several DNA repair proteins, including Escherichia coli exonuclease III and human
      APE, that repair oxidative and alkylation damage to DNA. The nuclease activities
      of Rrp1 include apurinic/apyrimidinic endonuclease, 3'-phosphodiesterase, 3'
      phosphatase, and 3'-exonuclease. As shown previously, the C-terminal nuclease
      region of Rrp1 is sufficient to repair oxidative- and alkylation-induced DNA
      damage in repair-deficient E. coli mutants. DNA strand-transfer and single
      stranded DNA renaturation activities are associated with the unique N-terminal
      region of Rrp1, which suggests possible additional functions that include
      recombinational repair or homologous recombination. By using the Drosophila w/w+
      mosaic eye system, which detects loss of heterozygosity as changes in eye
      pigmentation, somatic mutation and recombination frequencies were determined in
      transgenic flies overexpressing wild-type Rrp1 protein from a heat-shock
      inducible transgene. A large decrease in mosaic clone frequency is observed when
      Rrp1 overexpression precedes treatment with gamma-rays, bleomycin, or paraquat.
      In contrast, Rrp1 overexpression does not alter the spot frequency after
      treatment with the alkylating agents methyl methanesulfonate or methyl
      nitrosourea. A reduction in mosaic clone frequency depends on the expression of
      the Rrp1 transgene and on the nature of the induced DNA damage. These data
      suggest a lesion-specific involvement of Rrp1 in the repair of oxidative DNA
      damage.

PMID- 8643679
TI  - Agrobacterium tumefaciens-mediated transformation of yeast.
AB  - Agrobacterium tumefaciens transfers a piece of its Ti plasmid DNA (transferred
      DNA or T-DNA) into plant cells during crown gall tumorigenesis. A. tumefaciens
      can transfer its T-DNA to a wide variety of hosts, including both dicotyledonous
      and monocotyledonous plants. We show that the host range of A. tumefaciens can be
      extended to include Saccharomyces cerevisiae. Additionally, we demonstrate that
      while T-DNA transfer into S. cerevisiae is very similar to T-DNA transfer into
      plants, the requirements are not entirely conserved. The Ti plasmid-encoded vir
      genes of A. tumefaciens that are required for T-DNA transfer into plants are also
      required for T-DNA transfer into S. cerevisiae, as is vir gene induction.
      However, mutations in the chromosomal virulence genes of A. tumefaciens involved
      in attachment to plant cells have no effect on the efficiency of T-DNA transfer
      into S. cerevisiae. We also demonstrate that transformation efficiency is
      improved 500-fold by the addition of yeast telomeric sequences within the T-DNA
      sequence.

PMID- 8643680
TI  - Persistent elevations of cerebrospinal fluid concentrations of corticotropin
      releasing factor in adult nonhuman primates exposed to early-life stressors:
      implications for the pathophysiology of mood and anxiety disorders.
AB  - There is increasing evidence for an important role of adverse early experience on
      the development of major psychiatric disorders in adulthood. Corticotropin
      releasing factor (CRF), an endogenous neuropeptide, is the primary physiological
      regulator of the mammalian stress response. Grown nonhuman primates who were
      exposed as infants to adverse early rearing conditions were studied to determine
      if long-term alterations of CRF neuronal systems had occurred following the early
      stressor. In comparison to monkeys reared by mothers foraging under predictable
      conditions, infant monkeys raised by mothers foraging under unpredictable
      conditions exhibited persistently elevated cerebrospinal fluid (CSF)
      concentrations of CRF. Because hyperactivity of CRF-releasing neurons has been
      implicated in the pathophysiology of certain human affective and anxiety
      disorders, the present finding provides a potential neurobiological mechanism by
      which early-life stressors may contribute to adult psychopathology.

PMID- 8643682
TI  - Core binding factor beta-smooth muscle myosin heavy chain chimeric protein
      involved in acute myeloid leukemia forms unusual nuclear rod-like structures in
      transformed NIH 3T3 cells.
AB  - Patients with the M4Eo subtype of acute myeloid leukemia almost invariably are
      found to have an inversion of chromosome 16 in their leukemic cells, which
      results in a gene fusion between the transcription factor called core binding
      factor beta (CBFbeta) on 16q and a smooth muscle myosin heavy chain (SMMHC) gene
      on 16p. Subcellular localizations of the wild-type CBFbeta and the CBFbeta-SMMHC
      fusion protein were determined by immunofluorescence of NIH 3T3 cells that
      overexpress wild-type or fusion protein. Normal CBFbeta showed an unexpected
      perinuclear pattern consistent with primary localization in the Golgi complex.
      The CBFbeta-SMMHC fusion protein had a very different pattern. Nuclear staining
      included rod-like crystalline structures as long as 11 microm. The heterodimeric
      partner of CBFbeta, CBFalpha, formed part of this complex. Cytoplasmic staining
      included stress fibers that colocalized with actin, probably as a consequence of
      the myosin heavy chain component of the fusion protein. Deletion of different
      regions of the CBFbeta portion of the fusion protein showed that binding to
      CBFalpha was not required for nuclear translocation. However, deletion of parts
      of the SMMHC domain of the fusion protein involved in myosin-mediated filament
      formation resulted in proteins that did not form rod-like structures. These
      observations confirm previous indirect evidence that the CBFbeta-SMMHC fusion
      protein is capable of forming macromolecular nuclear aggregates and suggests
      possible models for the mechanism of leukemic transformation.

PMID- 8643681
TI  - Surface blebs on apoptotic cells are sites of enhanced procoagulant activity:
      implications for coagulation events and antigenic spread in systemic lupus
      erythematosus.
AB  - The restriction of phosphatidylserine (PtdSer) to the inner surface of the plasma
      membrane bilayer is lost early during apoptosis. Since PtdSer is a potent surface
      procoagulant, and since there is an increased incidence of coagulation events in
      patients with systemic lupus erythematosus (SLE) who have anti-phospholipid
      antibodies, we addressed whether apoptotic cells are procoagulant and whether
      anti-phospholipid antibodies influence this. Apoptotic HeLa cells, human
      endothelial cells, and a murine pre-B-cell line were markedly procoagulant in a
      modified Russell viper venom assay. This procoagulant effect was entirely
      abolished by addition of the PtdSer-binding protein, annexin V, confirming that
      it was PtdSer-dependent. The procoagulant effect was also abolished by addition
      of IgG purified from the plasma of three patients with anti-phospholipid antibody
      syndrome, but not IgG from normal controls. Confocal microscopy of apoptotic
      cells stained with fluorescein-isothiocyanate-conjugated-annexin V demonstrated
      (Ca2+)-dependent binding to the surface of membrane blebs o apoptotic cells, but
      not to intracellular membranes. Recent data indicate that the surface blebs of
      apoptotic cells constitute an important immunogenic particle in SLE. We propose
      that the PtdSer exposed on the outside of these blebs can induce the production
      of anti-phospholipid antibodies, which might also enhance the immunogenicity of
      the bleb contents. When apoptosis occurs in a microenvironment in direct contact
      with circulating plasma, the unique procoagulant consequences of the apoptotic
      surface may additionally be expressed. This might explain the increased incidence
      of pathological intravascular coagulation events that occur in some lupus
      patients who have anti-phospholipid antibodies.

PMID- 8643683
TI  - Immunocytochemical localization of the endogenous neuroexcitotoxin quinolinate in
      human peripheral blood monocytes/macrophages and the effect of human T-cell
      lymphotropic virus type I infection.
AB  - Quinolinate (Quin), a metabolite in the kynurenine pathway of tryptophan
      degradation and a neurotoxin that appears to act through the N-methyl-D-aspartate
      receptor system, was localized in cultured human peripheral blood
      monocytes/macrophages (PBMOs) by using a recently developed immunocytochemical
      method. Quin immunoreactivity (Quin-IR) was increased in gamma interferon (IFN
      gamma)-stimulated monocytes/macrophages (MOs). In addition, the precursors,
      tryptophan and kynurenine, significantly increased Quin-IR. Infection of MOs by
      human T-cell lymphotropic virus type I (HTLV-I) in vitro substantially increased
      both the number of Quin-IR cells and the intensity of Quin-IR. At the peak of the
      Quin-IR response, about 40% of the cells were Quin-IR positive. In contrast, only
      about 2-5% of the cells were positive for HTLV-I, as detected by both
      immunofluorescence for the HTLV-I antigens and PCR techniques for the HTLV-I Tax
      gene. These results suggest that HTLV-I-induced Quin production in MOs occurs by
      an indirect mechanism, perhaps via cytokines produced by the infection but not
      directly by the virus infection per se. The significance of these findings to the
      neuropathology of HTLV-I infection is discussed.

PMID- 8643684
TI  - Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in
      myeloid leukemia and produces a new member of the PR domain family.
AB  - The EVI1 gene, located at chromosome band 3q26, is overexpressed in some myeloid
      leukemia patients with breakpoints either 5' of the gene in the t(3;3)(q21;q26)
      or 3' of the gene in the inv(3)(q21q26). EVI1 is also expressed as part of a
      fusion transcript with the transcription factor AML1 in the t(3;21)(q26;q22),
      associated with myeloid leukemia. In cells with t(3;21), additional fusion
      transcripts are AML1-MDS1 and AML1-MDS1-EVI1. MDS1 is located at 3q26 170-400 kb
      upstream (telomeric) of EVI1 in the chromosomal region in which some of the
      breakpoints 5' of EVI1 have been mapped. MDS1 has been identified as a single
      gene as well as a previously unreported exon(s) of EVI1 We have analyzed the
      relationship between MDS1 and EVI1 to determine whether they are two separate
      genes. In this report, we present evidence indicating that MDS1 exists in normal
      tissues both as a unique transcript and as a normal fusion transcript with EVI1,
      with an additional 188 codons at the 5' end of the previously reported EVI1 open
      reading frame. This additional region has about 40% homology at the amino acid
      level with the PR domain of the retinoblastoma-interacting zinc-finger protein
      RIZ. These results are important in view of the fact that EVI1 and MDS1 are
      involved in leukemia associated with chromosomal translocation breakpoints in the
      region between these genes.

PMID- 8643685
TI  - Human immunodeficiency virus type 1 viral background plays a major role in
      development of resistance to protease inhibitors.
AB  - The observed in vitro and in vivo benefit of combination treatment with anti
      human immunodeficiency virus (HIV) agents prompted us to examine the potential of
      resistance development when two protease inhibitors are used concurrently.
      Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations
      associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or
      had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral
      clones containing the same mutations yielded viruses that were severely impaired
      in growth or nonviable, confirming that combination therapy may be advantageous.
      However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either
      saquinavir or SC52151, which represented sequential drug treatment, produced
      viable viruses resistant to both BMS-186318 and the second compound. The
      predominant breakthrough virus contained the G48V/A71T/V82A protease mutations.
      The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective
      NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct
      protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated
      that the RF-specific protease sequence, specifically the Ile at residue 10,
      enabled the NL4-3 strain with the triple mutant to grow. Our results clearly
      indicate that viral genetic background will play a key role in determining
      whether cross-resistance variants will arise.

PMID- 8643686
TI  - Learning and recall of form discriminations during reversible cooling
      deactivation of ventral-posterior suprasylvian cortex in the cat.
AB  - Extrastriate visual cortex of the ventral-posterior suprasylvian gyrus (vPS
      cortex) of freely behaving cats was reversibly deactivated with cooling to
      determine its role in performance on a battery of simple or masked two
      dimensional pattern discriminations, and three-dimensional object
      discriminations. Deactivation of vPS cortex by cooling profoundly impaired the
      ability of the cats to recall the difference between all previously learned
      pattern and object discriminations. However, the cats' ability to learn or
      relearn pattern and object discriminations while vPS was deactivated depended
      upon the nature of the pattern or object and the cats' prior level of exposure to
      them. During cooling of vPS cortex, the cats could neither learn the novel object
      discriminations nor relearn a highly familiar masked or partially occluded
      pattern discrimination, although they could relearn both the highly familiar
      object and simple pattern discriminations. These cooling-induced deficits
      resemble those induced by cooling of the topologically equivalent inferotemporal
      cortex of monkeys and provides evidence that the equivalent regions contribute to
      visual processing in similar ways.

PMID- 8643687
TI  - An abundantly expressed mucin-like protein from Toxocara canis infective larvae:
      the precursor of the larval surface coat glycoproteins.
AB  - Evasion of host immunity by Toxocara canis infective larvae is mediated by the
      nematode surface coat, which is shed in response to binding by host antibody
      molecules or effector cells. The major constituent of the coat is the TES-120
      glycoprotein series. We have isolated a 730-bp cDNA from the gene encoding the
      apoprotein precursor of TES-120. The mRNA is absent from T. canis adults but
      hyperabundant in larvae, making up approximately 10% of total mRNA, and is trans
      spliced with the nematode 5' leader sequence SL1. It encodes a 15.8-kDa protein
      (after signal peptide removal) containing a typical mucin domain: 86 amino acid
      residues, 72.1% of which are Ser or Thr, organized into an array of heptameric
      repeats, interspersed with proline residues. At the C-terminal end of the
      putative protein are two 36-amino acid repeats containing six Cys residues, in a
      motif that can also be identified in several genes in Caenorhabditis elegans.
      Although TES-120 displays size and charge heterogeneity, there is a single copy
      gene and a homogeneous size of mRNA. The association of overexpression of some
      membrane-associated mucins with immunosuppression and tumor metastasis suggests a
      possible model for the role of the surface coat in immune evasion by parasitic
      nematodes.

PMID- 8643688
TI  - Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism.
AB  - Cytochrome P450 1A2 (CYP1A2) is a predominantly hepatic enzyme known to be
      important in the metabolism of numerous foreign chemicals of pharmacologic,
      toxicologic, and carcinogenic significance. CYP1A2 substrates include aflatoxin
      B1, acetaminophen, and a variety of environmental arylamines. To define better
      the developmental and metabolic functions of this enzyme, we developed a CYP1A2
      deficient mouse line by homologous recombination in embryonic stem cells. Mice
      homozygous for the targeted Cyp1a2 gene, designated Cyp1a2(-/-), are completely
      viable and fertile; histologic examination of 15-day embryos, newborn pups, and 3
      week-old mice revealed no abnormalities. No CYP1A2 mRNA was detected by Northern
      blot analysis. Moreover, mRNA levels of Cyp1a1, the other gene in the same
      subfamily, appear unaffected by loss of the Cyp1a2 gene. Because the muscle
      relaxant zoxazolamine is a known substrate for CYP1A2, we studied the Cyp1a2(-/-)
      genotype by using the zoxazolamine paralysis test: the Cyp1a2(-/-) mice exhibited
      dramatically lengthened paralysis times relative to the Cyp1a2(+/+) wild-type
      animals, and the Cyp1a2(+/-) heterozygotes showed an intermediate effect.
      Availability of a viable and fertile CYP1A2-deficient mouse line will provide a
      valuable tool for researchers wishing to define the precise role of CYP1A2 in
      numerous metabolic and pharmacokinetic processes.

PMID- 8643689
TI  - An induction gene trap screen in embryonic stem cells: Identification of genes
      that respond to retinoic acid in vitro.
AB  - We have developed a novel induction gene trap approach that preselects in vitro
      for integrations into genes that lie downstream of receptor/ligand-mediated
      signaling pathways. Using this approach, we have identified 20 gene trap
      integrations in embryonic stem cells, 9 of which were induced and 11 of which
      were repressed after exposure to exogenous retinoic acid (RA). All but one of
      these integrations showed unique spatially restricted or tissue-specific patterns
      of expression between 8.5 and 11.5 days of embryogenesis. Interestingly,
      expression was observed in tissues that are affected by alterations in RA levels
      during embryogenesis. Sequence analysis of fusion transcripts from six
      integrations revealed five novel gene sequences and the previously identified
      protooncogene c-fyn. To date, germ-line transmission and breeding has uncovered
      one homozygous embryonic lethal and three homozygous viable insertions. These
      studies demonstrate the potential of this induction gene trap approach for
      identifying and mutating genes downstream of signal transduction pathways.

PMID- 8643690
TI  - Signal transduction by activated mNotch: importance of proteolytic processing and
      its regulation by the extracellular domain.
AB  - Previous studies imply that the intracellular domain of Notch1 must translocate
      to the nucleus for its activity. In this study, we demonstrate that a mNotch1
      mutant protein that lacks its extracellular domain but retains its membrane
      spanning region becomes proteolytically processed on its intracellular surface
      and, as a result, the activated intracellular domain (mNotchIC) is released and
      can move to the nucleus. Proteolytic cleavage at an intracellular site is blocked
      by protease inhibitors. Intracellular cleavage is not seen in cells transfected
      with an inactive variant, which includes the extracellular lin-Notch-glp repeats.
      Collectively, the studies presented here support the model that mNotch1 is
      proteolytically processed and the cleavage product is translocated to the nucleus
      for mNotch1 signal transduction.

PMID- 8643692
TI  - Sequence scanning: A method for rapid sequence acquisition from large-fragment
      DNA clones.
AB  - A strategy of "sequence scanning" is proposed for rapid acquisition of sequence
      from clones such as bacteriophage P1 clones, cosmids, or yeast artificial
      chromosomes. The approach makes use of a special vector, called LambdaScan, that
      reliably yields subclones with inserts in the size range 8-12 kb. A number of
      subclones, typically 96 or 192, are chosen at random, and the ends of the inserts
      are sequenced using vector-specific primers. Then long-range spectrum PCR is used
      to order and orient the clones. This combination of shotgun and directed
      sequencing results in a high-resolution physical map suitable for the
      identification of coding regions or for comparison of sequence organization among
      genomes. Computer simulations indicate that, for a target clone of 100 kb, the
      scanning of 192 subclones with sequencing reads as short as 350 bp results in an
      approximate ratio of 1:2:1 of regions of double-stranded sequence, single
      stranded sequence, and gaps. Longer sequencing reads tip the ratio strongly
      toward increased double-stranded sequence.

PMID- 8643691
TI  - The 145-kDa protein induced to associate with Shc by multiple cytokines is an
      inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5
      phosphatase.
AB  - A 145-kDa tyrosine-phosphorylated protein that becomes associated with Shc in
      response to multiple cytokines has been purified from the murine hemopoietic cell
      line B6SUtA1. Amino acid sequence data were used to clone the cDNA encoding this
      protein from a B6SUtA1 library. The predicted amino acid sequence encodes a
      unique protein containing an N-terminal src homology 2 domain, two consensus
      sequences that are targets for phosphotyrosine binding domains, a proline-rich
      region, and two motifs highly conserved among inositol polyphosphate 5
      phosphatases. Cell lysates immunoprecipitated with antiserum to this protein
      exhibited both phosphatidylinositol 3,4,5-trisphosphate and inositol 1,3,4,5
      tetrakisphosphate polyphosphate 5-phosphatase activity. This novel signal
      transduction intermediate may serve to modulate both Ras and inositol signaling
      pathways. Based on its properties, we suggest the 145-kDa protein be called SHIP
      for SH2-containing inositol phosphatase.

PMID- 8643693
TI  - Induction of cellular immunity in chimpanzees to human tumor-associated antigen
      mucin by vaccination with MUC-1 cDNA-transfected Epstein-Barr virus-immortalized
      autologous B cells.
AB  - Aberrant glycosylation of the mucin molecule (encoded by the gene MUC-1) on human
      epithelial cell tumors leads to the exposure of tumor-associated epitopes
      recognized by patients' antibodies and cytotoxic T cells. Consequently, these
      epitopes could be considered targets for immunotherapy. We designed a cellular
      vaccine, employing, instead of tumor cells, autologous Epstein-Barr virus (EBV)
      immortalized B cells as carriers of tumor-associated mucin, to take advantage of
      their costimulatory molecules for T-cell activation. The vaccine was tested in
      chimpanzees because of the identity of the human and chimpanzee MUC-1 tandem
      repeat sequence. EBV-immortalized B cells derived from two chimpanzees were
      transfected with MUC-1 cDNA, treated with glycosylation inhibitor phenyl-N-acetyl
      alpha-D-galactosaminide to expose tumor-associated epitopes, irradiated, and
      injected subcutaneously four times at 3-week intervals. One vaccine preparation
      also contained cells transduced with the interleukin 2 (IL-2) cDNA and producing
      low levels of IL-2. Already after the first injection we found in the peripheral
      blood measurable frequency of cytotoxic T-cell precursors specific for
      underglycosylated mucin. The highest frequency observed was after the last boost,
      in the lymph node draining the vaccination site. Delayed-type hypersensitivity
      reaction to the injected immunogens was also induced, whereas no appearance of
      mucin-specific antibodies was seen. Long-term observation of the animals yielded
      no signs of adverse effects of this immunization. Autologous antigen-presenting
      cells, like EBV-immortalized B cells, expressing tumor-associated antigens are
      potentially useful immunogens for induction of cellular anti-tumor responses in
      vivo.

PMID- 8643694
TI  - Zn2+ interaction with Alzheimer amyloid beta protein calcium channels.
AB  - The Alzheimer disease 40-residue amyloid beta protein (AbetaP[1-40]) forms cation
      selective channels across acidic phospholipid bilayer membranes with spontaneous
      transitions over a wide range of conductances ranging from 40 to 4000 pS. Zn2+
      has been reported to bind to AbetaP[1-40] with high affinity, and it has been
      implicated in the formation of amyloid plaques. We now report the functional
      consequences of such Zn2+ binding for the AbetaP[1-40] channel. Provided the
      AbetaP[1-40] channel is expressed in the low conductance (<400 pS) mode, Zn2+
      blocks the open channel in a dose- dependent manner. For AbetaP[1-40] channels in
      the giant conductance mode (>400 pS), Zn2+ doses in the millimolar range were
      required to exert substantial blockade. The Zn2+ chelator o-phenanthroline
      reverses the blockade. We also found that Zn2+ modulates AbetaP[1-40] channel
      gating and conductance only from one side of the channel. These data are
      consistent with predictions of our recent molecular modeling studies on AbetaP[1
      40] channels indicating asymmetric Zn(2+)-AbetaP[1-40] interactions at the
      entrance to the pore.

PMID- 8643695
TI  - The treatment of chronic progressive multiple sclerosis with cladribine.
AB  - A 2-year, placebo-controlled, double-blind, crossover study was started in 1992
      to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic
      progressive multiple sclerosis. In the first year patients were given cladribine
      0.10 mg/kg per day for 7 days as four monthly courses for a total of 2.8 mg/kg or
      placebo. During the second year patients treated with placebo during the first
      year were given i.v. infusions of 0.10 mg, 0.05 mg, and 0.05 mg of cladribine per
      kg of body weight per day for 7 consecutive days in three successive monthly
      courses, for a total dose of 1.4 mg/kg. Patients who had been treated previously
      with cladribine were crossed over to placebo. Analysis of the results revealed a
      favorable influence on the neurological performance scores, both in the Kurtze
      extended disability status and the Scripps neurological rating scale, and on MRI
      findings in patients treated with cladribine. In the first year the most striking
      finding was that while clinical deterioration continued in the placebo-treated
      patients, the condition of patients who received cladribine stabilized or even
      improved slightly. Toxicity and therapeutic response were dose-related.

PMID- 8643699
TI  - The effects of dietary change on serum cholesterol.

PMID- 8643698
TI  - Determination of the transiently lowered pKa of the retinal Schiff base during
      the photocycle of bacteriorhodopsin.
AB  - Reprotonation of the transiently deprotonated retinal Schiff base in the
      bacteriorhodopsin photocycle is greatly slowed when the proton donor Asp-96 is
      removed with site-specific mutagenesis, but its rate is restored upon adding
      azide or other weak acids such as formate and cyanate. As expected, between pH 3
      and 7 the rate of Schiff base protonation in the photocycle of the D96N mutant
      correlates with the concentrations of the acid forms of these agents. Dissection
      of the rates in the biexponential reprotonation kinetics of the Schiff base
      between pH 7 and 9 yielded calculated rate constants for the protonation
      equilibrium. Their dependencies on pH and azide or cyanate concentrations are
      consistent with both earlier suggested mechanisms: (i) azide and other weak acids
      may function as proton carriers in the protonation equilibrium of the Schiff
      base, or (ii) the binding of their anionic forms may catalyze proton conduction
      to and from the Schiff base. The measured rate constants allow the calculation of
      the pKa of the Schiff base during its reprotonation in the photocycle of D96N. It
      is 8.2-8.3, a value much below the pKa determined earlier in unphotolyzed
      bacteriorhodopsin.

PMID- 8643696
TI  - Ca(2+)-independent reduction of N-methyl-D-aspartate channel activity by protein
      tyrosine phosphatase.
AB  - Regulation of ion channel function by intracellular processes is fundamental for
      controlling synaptic signaling and integration in the nervous system. Currents
      mediated by N-methyl-D-aspartate (NMDA) receptors decline during whole-cell
      recordings and this may be prevented by ATP. We show here that phosphorylation is
      necessary to maintain NMDA currents and that the decline is not dependent upon
      Ca2+. A protein tyrosine phosphatase or a peptide inhibitor of protein tyrosine
      kinase applied intracellularly caused a decrease in NMDA currents even when ATP
      was included. On the other hand, pretreating the neurons with a membrane-permeant
      tyrosine kinase inhibitor occluded the decline in NMDA currents when ATP was
      omitted. In inside-out patches, applying a protein tyrosine phosphatase to the
      cytoplasmic face of the patch caused a decrease in probability of opening of NMDA
      channels. Conversely, open probability was increased by a protein tyrosine
      phosphatase inhibitor. These results indicate that NMDA channel activity is
      reduced by a protein tyrosine phosphatase associated with the channel complex.

PMID- 8643697
TI  - Decreased food intake does not completely account for adiposity reduction after
      ob protein infusion.
AB  - The effects of recombinantly produced ob protein were compared to those of food
      restriction in normal lean and genetically obese mice. Ob protein infusion into
      ob/ob mice resulted in large decreases in body and fat-depot weight and food
      intake that persisted throughout the study. Smaller decreases in body and fat
      depot weights were observed in vehicle-treated ob/ob mice that were fed the same
      amount of food as that consumed by ob protein-treated ob/ob mice (pair feeding).
      In lean mice, ob protein infusion significantly decreased body and fat-depot
      weights, while decreasing food intake to a much lesser extent than in ob/ob mice.
      Pair feeding of lean vehicle-treated mice to the intake of ob protein-treated
      mice did not reduce body fat-depot weights. The potent weight-, adipose-, and
      appetite-reducing effects exerted by the ob protein in ob protein-deficient mice
      (ob/ob) confirm hypotheses generated from early parabiotic studies that suggested
      the existence of a circulating satiety factor of adipose origin. Pair-feeding
      studies provide compelling evidence that the ob protein exerts adipose-reducing
      effects in excess of those induced by reductions in food intake.

PMID- 8643700
TI  - Energy balance and health in SENECA participants. Survey in Europe on Nutrition
      and the Elderly, a Concerted Action.

PMID- 8643701
TI  - The British National Diet and Nutrition Survey of people aged 65 years or over:
      protocol and feasibility study.

PMID- 8643702
TI  - Some nutritional aspects of ageing in dogs and cats.

PMID- 8643703
TI  - McCay's hypothesis: undernutrition and longevity.

PMID- 8643704
TI  - Effects of exercise training in the elderly: impact of progressive- resistance
      training on skeletal muscle and whole-body protein metabolism.
AB  - The declines in functional capacity and muscle function with advancing age are
      well-documented. In addition, it appears that the age-related changes in body
      composition have profound effects on functional capacity and nutrient
      requirements. The overwhelming evidence presented in the present review suggests
      that the loss of muscle strength and function observed with advancing age is
      reversible even in the frail elderly. Along with the profound functional
      improvement in older individuals in response to progressive-resistance training,
      several studies have reported increases in resting energy expenditure and
      increased requirements for dietary protein. Exercise programmes designed to
      improve muscle strength be recommended for older individuals as an effective
      countermeasure to the sarcopenia of old age.

PMID- 8643705
TI  - Functional ability and nutritional status of free-living elderly people.

PMID- 8643706
TI  - Cost-effectiveness of nutritional support in the elderly.
AB  - There is clear evidence that nutritional support is effective in elderly
      patients, reducing mortality, morbidity and in some cases hospital stay. Its
      effectiveness depends upon its being part of an overall management strategy,
      including screening for patients at risk and appropriate nutritional policies.
      The extra cost of meals of high energy density, extra snacks and food supplements
      is minimal compared with the potential benefit. Artificial feeding by the enteral
      or parenteral route is extremely effective, especially when carried out by an
      expert team and in appropriately-selected patients in whom the outcome justifies
      the additional expenditure.

PMID- 8643707
TI  - The dyslipophobias: a view of the psychopathologies involved and the hazards of
      construing anorexia nervosa and bulimia nervosa as 'eating disorders'.

PMID- 8643708
TI  - Practical management of eating disorders.

PMID- 8643709
TI  - Is obesity an eating disorder?

PMID- 8643710
TI  - Social influences on food choice and dietary change: a sociological attitude.

PMID- 8643711
TI  - Unrealistic optimism about diet-related risks: implications for interventions.

PMID- 8643712
TI  - Parental influences on children's diets.

PMID- 8643713
TI  - Looking for 'fresh' food: diet and lone parents.

PMID- 8643714
TI  - An anatomically based study of the mechanism of eyebrow ptosis.
AB  - The development of eyebrow ptosis with aging is commonly attributed to
      progressive laxity of scalp and forehead soft tissues. If the change in eyebrow
      position with aging resulted entirely from this basic mechanism of tissue
      stretching, uniform lowering of the medial and lateral eyebrow segments should
      occur. Clinical observations show, however, that the lateral eyebrow segment
      usually becomes ptotic earlier than the medial segment, indicating that a more
      complex mechanism exists. To clarify this process, anatomic studies were done on
      20 (40 half-head) fresh cadaver specimens. Histologic studies also were performed
      to complement the gross anatomic findings. These studies confirm that the
      mechanism producing eyebrow ptosis has a relatively greater effect on the lateral
      eyebrow segment. The lateral eyebrow has less support from deeper structures than
      the medial eyebrow, and the balance of forces acting on the eyebrow selectively
      depresses the lateral segment. Structures that may promote mobility and
      gravitational descent of the eyebrow, especially the lateral eyebrow segment, are
      (1) the galea fat pad, (2) the preseptal fat pad, and (3) the subgalea fat pad
      glide plane space. Three forces that act on the lateral eyebrow are (1) frontalis
      muscle resting tone, which suspends that eyebrow segment medial to the temporal
      fusion line of the skull, (2) gravity, which causes the soft-tissue mass lateral
      to the temporal line to slide over the temporalis fascia plane and push the
      lateral eyebrow segment downward, and (3) corrugator supercilii muscle
      hyperactivity in conjunction with action of the lateral orbicularis oculi muscle,
      which can antagonize frontalis muscle activity and directly facilitate descent of
      the lateral eyebrow. The axis point for these forces is the temporal fusion line
      of the skull near the superior orbital rim. The interaction of those structures
      and forces contributing to the mechanism producing eyebrow ptosis is discussed.
      Derived concepts are applied to the execution of the forehead lift procedure.

PMID- 8643715
TI  - Limited-incision forehead lift for eyebrow elevation to enhance upper
      blepharoplasty.
AB  - Treatment of eyebrow ptosis to enhance the cosmetic effect from blepharoplasty is
      commonly done with a forehead lift using a coronal incision approach. The coronal
      scalp incision is associated with the annoying sequelae of frontoparietal scalp
      numbness, itching, and paresthesias, all of which can be permanent. A forehead
      lift technique with temporal scalp incisions only 4.5 to 5.0 cm in length can
      produce a result comparable with that of the coronal incision approach when
      combined with transpalpebral resection of the corrugator supercilii muscles and
      transection of the procerus muscle. This eyebrow elevation technique, like the
      endoscopic approach, minimizes the risk of permanently injuring the supraorbital
      nerve branches that innervate the frontoparietal scalp. Unlike the approach using
      only endoscopy, however, this technique can effectively treat cases of advanced
      eyebrow ptosis. The appropriate area of eyelid skin for excision may be difficult
      to assess when a forehead lift and upper blepharoplasty are done concomitantly.
      The described forehead lift incorporates a method to determine this area. This
      forehead lift technique, combined with a technique for protecting against
      overresecting upper eyelid skin, is described as used effectively on 140
      blepharoplasty cases followed for 3 months to 4 years.

PMID- 8643716
TI  - Correlation between brow lift outcomes and aesthetic ideals for eyebrow height
      and shape in females.
AB  - This study correlates brow lift outcomes published in the plastic surgical
      literature with aesthetic criteria for ideal female eyebrow height and shape.
      Aesthetic criteria were determined by testing the opinions of 11 cosmetic
      surgeons and 9 cosmetologists. Eyebrow height and shape were altered with
      computer graphics to isolate those changes as the only variables of appearance.
      Plastic surgeons and cosmetologists preferred (p = 0.01) medial eyebrows below or
      at the supraorbital rim and disliked the medial eyebrow above the rim. Both
      groups preferred (p = 0.01) eyebrow shape to have an apex lateral slant. One
      hundred preoperative and 100 postoperative photographs from 16 frequently
      referenced articles on brow lifts were evaluated. There was a significant (p =
      0.0008) increase in the number of medial eyebrows elevated above the rim. The
      number of medial apex eyebrows increased, and the number of flat brows decreased
      (p = 0.01). There was no significant increase in the number of apex lateral
      eyebrows. Three conclusions are made about female eyebrows: (1) The medial
      eyebrow should be located at or below the supraorbital rim but not above it. (2)
      Eyebrow shape should have an apex lateral slant. (3) Standard open and endoscopic
      brow lift operations frequently result in unsatisfactory eyebrow height and
      shape, judged by these criteria.

PMID- 8643717
TI  - Vertical orbital dystopia.
AB  - Many pathologic processes may lead to vertical orbital dystopia. We reviewed 47
      consecutive cases seen over a 13-year period. Twenty-nine patients underwent eye
      leveling procedures to improve cosmesis, 2 of these by camouflage procedures and
      27 by orbital translocation. Ten patients had 16 secondary operations. There was
      one death, serious complications occurred in 3 patients, and nuisance
      complications occurred in 20 others. Seven patients developed diplopia
      postoperatively, and in 6 patients it was troublesome. In these, it resolved
      fully in 2 patients, improved to be of no consequence in 2, and in the remaining
      2 troublesome symptoms persisted requiring inferior oblique muscle recession in
      1. Binocular vision was never restored when not present preoperatively, and in 3
      patients temporary loss occurred. There was an overall modest but significant
      improvement in appearance after surgery. It is concluded that vertical orbital
      translocation is rewarding and worthwhile.

PMID- 8643718
TI  - Late correction of sagittal synostosis in children.
AB  - Twelve patients with sagittal synostosis underwent correction between 8 months
      and 8 years of age. The patients underwent expansion in the parietal region of 4
      cm and had a reduction in length of 3 cm following dural plication. Average
      follow-up was 2.2 +/- 0.8 years (mean +/- SD). While optimal treatment for
      sagittal synostosis may be obtained in the first few months of life, late
      correction of sagittal synostosis may be obtained in a safe and effective manner.

PMID- 8643720
TI  - Lidocaine and epinephrine levels in tumescent technique liposuction.
AB  - The safety of lidocaine dosing in the tumescent technique has been well
      documented, but there is little evidence regarding the safety of combining
      tumescent lidocaine infiltration with subcutaneous lidocaine infiltration
      required in other aesthetic surgery. The safety of lidocaine and epinephrine
      dosing was investigated in 10 patients undergoing tumescent technique liposuction
      alone and in 10 patients undergoing tumescent liposuction with concurrent facial
      and aesthetic breast surgery by determining serum lidocaine and epinephrine
      levels at 3, 12, and 23 hours following infiltration of the tumescent solution
      and the subcutaneous lidocaine. The mean lidocaine dose of all patients was 22.3
      mg/kg. All patients demonstrated safe lidocaine levels at all intervals, with the
      highest levels occurring in patients who received intravenous lidocaine at the
      induction of anesthesia. The peak epinephrine levels occurred at the 3-hour blood
      draw and were approximately four times physiologic. No patient demonstrated any
      subjective or objective signs of lidocaine or epinephrine toxicity.

PMID- 8643719
TI  - The effect of cleft lip repair on maxillary morphology in patients with
      unilateral complete cleft lip and palate.
AB  - This study was performed to investigate the isolated effects of cleft lip repair
      on maxillary morphology in patients with complete unilateral cleft lip and
      palate. We compared 10 adult patients with unilateral cleft lip and palate who
      had only lip repair in childhood and no palatal repair (group 1) with 30 adult
      patients with unilateral cleft lip and palate who had both their lip and palate
      repaired in childhood (group 2). Both groups of patients also were compared with
      24 adult individuals who had normal occlusion and no cleft anomalies. Evaluation
      of lateral cephalograms showed that both group 1 and group 2 had significant
      degrees of maxillary retrusion compared with normal individuals. The magnitude of
      maxillary retrusion was not increased by cleft palate repair, and none of the
      cephalometric measurements were significantly different between groups 1 and 2.

PMID- 8643721
TI  - The combined flap based on a single vascular source: a clinical experience with
      32 cases.
AB  - This article provides a retrospective review of 32 combined flap transfers. It
      consists of two or more flaps based on independent vascular branches from a
      single vascular source. This series included the combined flap based on the
      subscapular-circumflex scapular-thoracodorsal vascular system in 24 patients and
      the profunda femorislateral circumflex femoral vascular system in 8 patients.
      Twenty-four combined flaps were transferred as free flaps and eight as pedicled
      flaps. The combined flap based on the subscapular system has very good
      indications for massive and three-dimensional composite defects in the head and
      neck region. The combined flap based on the lateral circumflex femoral-profunda
      femoris system is useful for reconstruction of large defects in the groin,
      perineal, and lower abdominal regions.

PMID- 8643722
TI  - Soft-tissue fungal infections: surgical management of 12 immunocompromised
      patients.
AB  - Isolated fungal soft-tissue infections are uncommon but may cause severe
      morbidity or mortality among transplant recipients and other immunosuppressed
      patients. Twelve immunocompromised patients illustrating three patterns of
      infection were treated recently at the Duke University Medical Center. These
      groups comprised (I) locally aggressive infections, (II) indolent infections, and
      (III) cutaneous manifestations of systemic infection. Patient diagnoses included
      organ transplant, leukemia, prematurity, chronic obstructive pulmonary disease,
      and rheumatoid arthritis. Time from immunosuppression to biopsy ranged from 5.5
      to 31 weeks. Organisms included Aspergillus, Rhizopus, Fusarium, Paecilomyces,
      Exophiala, and Curvularia. Patients presented with necrotic ulcerations or
      nodules. Surgical treatment ranged from radical debridement to excisional biopsy
      to none. Antifungal chemotherapy also was employed in some cases. The mortality
      rate was 33 percent, two patients dying without evidence of fungal infection. Six
      of the eight survivors cleared their infections. Necrotic skin lesions with
      surrounding erythema in this population call for prompt examination, biopsy, and
      culture. Group I lesions mandate radical excision with rapid intraoperative
      microscopic control and systemic antifungal medication. Group II requires
      surgical control with or without antifungal therapy. Group III requires systemic
      antifungal therapy for metastatic infection. In our opinion, treatment of fungal
      soft-tissue infection should be tailored to infection type and requires a team
      approach of surgeon and expert infectious disease consultation.

PMID- 8643723
TI  - Anatomic studies and clinical experience with fasciocutaneous flap closure of
      large myelomeningoceles.
AB  - Thirteen patients have undergone reconstruction of large lumbosacral
      myelomeningoceles with bilateral paralumbar fasciocutaneous flaps.
      Fasciocutaneous flap closure is supported by a rich vascular network with three
      main dominant vascular territories. In the middle third of the flaps, a prominent
      transverse segmental vascular pattern originating from the muscular perforators
      and lateral cutaneous branches of the costal groove segment of the lower
      intercostal arteries was noted. The parascapular and scapular fascial branches of
      the circumflex scapular artery supplied the upper lateral portion of the flaps.
      Prominent lateral extensions of the superficial circumflex iliac arterial system
      formed the dominant fascial vasculature of the lower lateral flap, richly
      arborizing with the middle segmental intercostal extensions. All 13 patients
      tolerated the procedure without blood transfusion and without perioperative
      complications. Stable, durable cutaneous coverage was achieved in all patients.
      Two postmortem neonate humans with large lumbosacral myelomeningoceles were
      studied angiographically. Radiopaque silicone-rubber-lead-chrome matrix
      (Microfil) was infused under physiologic pressures in a 7-day neonate after
      successful defect closure with bilateral fasciocutaneous flaps. The flaps were
      reevaluated postmortem, and high-contrast, digitally enhanced computed
      radiographic imaging confirmed the rich vascular support of the bilateral
      fasciocutaneous flaps, identifying the dominant vascular pedicles. Rich
      vascularity was further documented by photographing the orange opaque Microfil
      cast vessels through the reelevated flaps. A second postmortem (stillborn)
      myelomeningocele specimen was studied with barium infusion with particular
      emphasis on the anomalous lumbar aorta. Angiographic studies provide a new
      understanding of the unique vascular anatomy of both the anomaly and the
      paralumbar fasciocutaneous flap.

PMID- 8643724
TI  - Autoradiographic analysis of expanded skeletal muscle in rats.
AB  - The use of tissue expanders in reconstructive surgery is now common. However, the
      physiologic mechanisms by which expansion is achieved are not well understood. A
      recent study demonstrated that rapid expansion of skeletal muscle is accompanied
      by an increase in the number of sarcomeres within a muscle fiber. This is in
      contrast to previous animal studies whose results suggested that synthesis of
      sarcomere units was limited to the perinatal period. To further investigate
      potential increases in sarcomeres and attempt to localize the active sites of
      sarcomere synthesis, labeled adenosine (3H) was injected into rats during the
      expansion of skeletal muscle. Adenosine was taken up by the muscle fibers and
      incorporated in the newly formed actin as part of light chains. An
      autoradiographic analysis of histologic sections of the expanded muscle
      demonstrated a statistically significant increase in radioactivity within the
      expanded muscle. The distribution of the radioactivity followed a proximal-to
      distal gradient, with the proximal sections exhibiting more than 50 percent
      greater activity than the distal aspects. These data suggest a preference for
      sarcomere synthesis in the proximal portion of the expanding skeletal muscle. The
      significance of this finding is uncertain. However, we suspect that sarcomere
      synthesis is tension-dependent and likely to be related to local tension applied
      to a portion of the muscle fibers rather than to an anatomic site of preference.

PMID- 8643725
TI  - Research on soft-tissue expander permeability to metronidazole and procaine.
AB  - This in vitro study was designed to determine if in fact silicone expanders are
      readily permeable to metronidazole and procaine. The expanders were filled with
      0.2% metronidazole or 2% procaine through the filler valves and then immersed
      wholly in normal saline. At several intervals over 120 hours, a certain amount of
      the surrounding saline was sampled and the drug levels subsequently determined.
      In this study, the silicone expanders were indeed readily permeable to the drugs,
      as measured with an ultraviolet spectrophotometer. A consistent diffusion curve
      was demonstrated. The rate of diffusion of a drug is inversely proportional to
      its molecular weight; i.e., the smaller the given drug's molecular weight, the
      greater is its ability to permeate an expander. In view of this, in the course of
      expansion, 0.2% metronidazole could be used in clinical expansion instead of
      normal saline, and a certain amount of antibiotic would diffuse out of the
      expander to prevent and control the infection.

PMID- 8643726
TI  - Factors contributing to patient satisfaction with breast reconstruction using
      silicone gel implants.
AB  - Recently, concerns have been raised about risks and benefits of silicone gel
      implants for breast reconstruction. Using a survey conducted during the silicone
      controversy that began in 1990, this study examines patient satisfaction in 174
      women with silicone breast implants. Overall satisfaction was high; 43 percent
      indicated complete satisfaction, and only 3 percent stated they were "not at all"
      satisfied. Satisfaction was correlated with each woman's assessment of how
      reconstruction met her expectations, particularly expectations about clothes
      fitting better, feeling whole, looking normal, and having similar-appearing
      breasts. Higher levels of satisfaction also were associated with lower body mass
      index and absence of medical problems. While patients appeared satisfied with
      their reconstructions, 34 percent said they would be completely unlikely to
      choose silicone implants today. Further research is needed to understand the
      impact of the silicone breast implant debate on women who have had or may
      consider breast reconstruction.

PMID- 8643727
TI  - Capsular synovial metaplasia as a common response to both textured and smooth
      implants.
AB  - Recent reports suggested that the presence of synovial metaplasia in the capsular
      tissues of breast implants is greater with textured-shelled implants compared
      with smooth. Textured implants, however, have become popular only in the last few
      years. Therefore, the studies do not address the possibility that synovial
      metaplasia may be a dynamic process related to time (e.g., implant age) rather
      than implant shell surface. In the current study, 159 implant capsules (85
      patients) removed between February of 1992 and July of 1993 at UCLA Medical
      Center were evaluated histologically and correlated with clinical data, including
      the age of implants. Synovial metaplasia was identified in 40 percent (64 of 159)
      of the capsule specimens. A logistic regression analysis that removed the effect
      of implant age demonstrated no correlation of implant shell type (textured versus
      smooth) with the presence of synovial metaplasia. Gel bleed, implant location,
      pericapsular fluid, implant rupture, and capsular contracture also did not have
      any significant association with synovial metaplasia in the current study. The
      incidence of synovial metaplasia appears to decrease with age (77 percent at < 5
      years; 22 percent at > 15 years). Our findings suggest that synovial metaplasia
      is not rare and in fact may be a fairly common transitional histologic finding.
      It may be part of the common progression that occurs at the implant-capsule
      interface. The clinical significance remains unknown.

PMID- 8643728
TI  - Gore-Tex patch repair of the anterior rectus sheath in free rectus abdominis
      muscle and myocutaneous flaps.
AB  - Reconstruction of the breast and other tissues by the free transverse rectus
      abdominis myocutaneous (TRAM) flap is an accepted, reliable technique with a high
      success rate. Closure of the anterior rectus sheath defect that results from this
      flap and the related rectus abdominis muscle-only (RAM) free flap has been the
      subject of debate, since hernia formation is considered a risk. Some authors
      prefer direct closure, while others recommend a variety of synthetic mesh
      reinforcements. We have reviewed 81 patients from a consecutive series of free
      TRAM and RAM flaps performed by one surgeon (Pennington) over an 8-year period.
      The majority of patients had repair of the anterior rectus sheath with a 1-mm
      thick synthetic patch of polytetrafluoroethylene (Gore-Tex), used in 52 of 71
      patients having the TRAM flap and 4 of 10 patients having the RAM flap. There
      were 5 wound infections (6.2 percent) overall, 3 of which occurred in the Gore
      Tex group (5.4 percent). In all 3 of the latter patients, Gore-Tex was removed,
      although usually only after some months. Even after patch removal, no hernias
      developed subsequently. The two other infections occurred in patients with a
      Prolene mesh patch and no patch, respectively. One hernia was found in 71
      patients with TRAM flaps, and that was in a patient in whom no patch was used. No
      hernias occurred in 52 TRAM flap patients with Gore-Tex patches. Hernia formation
      was noted in 6 of 10 RAM flap patients, although only 1 hernia occurred in the 4
      patients with Gore-Tex patches. We conclude that the 1-mm polytetrafluoroethylene
      (Gore-Tex) patch is a satisfactory method for repair of the anterior rectus
      sheath after harvesting of either free RAM or TRAM flaps. Even if removal of the
      patch is required because of infection, the risk of subsequent hernia formation
      appears minimal.

PMID- 8643729
TI  - A prospective study of changes in muscle dimensions following free-muscle
      transfer measured by ultrasound and CT scanning.
AB  - A retrospective study demonstrated that noninnervated free-muscle flaps do not
      lose bulk when evaluated at a mean of 41 months. The purpose of the present study
      was to evaluate changes in muscle bulk in noninnervated free-muscle transfers
      prospectively. This study included 22 flaps (17 latissimus dorsi, 4 rectus
      abdominis, and 1 gracilis). The thickness of the muscle was measured by
      ultrasonography preoperatively and 2 and 6 weeks and 3, 6, 9, 12, 15, 18, and 23
      months postoperatively. The volume of the muscle was measured by computed
      tomographic (CT) scan preoperatively and 2 and 6 weeks and 3, 6, and 9 months
      postoperatively. Postoperative data were normalized to the preoperation
      measurements. The results demonstrated that the thickness of the muscle increased
      by a mean of 2.4 times (range 0.9 to 3.9) compared with the initial thickness in
      a 2-week period (p < 0.05), 2.0 times (range 0.9 to 4.2) in 6 weeks (p < 0.05),
      1.7 times (range 0.8 to 4.2) in 3 months (p < 0.05), 1.5 times (range 0.6 to 3)
      in 6 months (p < 0.05), and 1.2 times (range 0.4 to 2.8) in 9 months (not
      significant). Thereafter, the mean thickness was the same as the initial
      thickness. CT scan measurements of the muscles confirmed the ultrasound findings.
      Our prospective study of free-muscle flaps found significant swelling that peaks
      at 2 weeks and extends until 6 months after the operation. This study also
      demonstrated that ultrasound evaluation of thickness gives the same conclusion as
      volumetric measurement by CT scanning.

PMID- 8643730
TI  - What is adequate fill? Implications in breast implant surgery.

PMID- 8643731
TI  - Questioning patient care: when closed mouths must speak.

PMID- 8643732
TI  - The new deep plane face lift dissections versus the old superficial techniques: a
      comparison of neurologic complications.

PMID- 8643733
TI  - From the other side of the bed sheets: the physician as patient.

PMID- 8643734
TI  - Chronic expanding hematoma within a periprosthetic breast capsule.
AB  - Three cases of chronic expanding hematoma occurring within the capsule
      surrounding breast implants are described. All developed at least 4 years after
      the last operation. No identifiable etiology could be demonstrated. Although this
      pathologic entity has been widely reported in other anatomic locations, a
      periprosthetic chronic expanding hematoma of the breast has not been described
      previously.

PMID- 8643735
TI  - A surgical solution to the deep nasolabial fold.
AB  - A persistent problem for restoration of youthful appearance is the nasolabial
      fold, despite the many techniques that have been proposed for its improvement.
      The anatomic assessments have led me to use the technique described herein, which
      is certainly not the final solution but which at the moment produces a
      significant improvement if it is done properly. It is a simple procedure that can
      be done on an outpatient basis or at the same time as a face lift.

PMID- 8643736
TI  - Use of the expanded thoracoepigastric myocutaneous flap in the closure of cloacal
      exstrophy.
AB  - We describe the first reported use of an expanded thoracoepigastric myocutaneous
      flap in the closure of cloacal exstrophy. This approach offers several distinct
      advantages. The expander increases the available cutaneous surface area of the
      thoracoepigastric region, improves vascularity, induces a fibrous capsule that
      augments the abdominal wall, permits primary closure, and avoids prosthetic
      adjuncts that increase scarring and hinder delayed urinary tract reconstruction.
      Osteotomy and spica casting may be obviated by using this flap, but mesh may be
      required eventually. We anticipate its use in all future cases in which the
      abdomen cannot be closed safely at the primary procedure at this institution.
      This technique also should be considered for classic bladder exstrophy or any
      other large congenital or acquired defect of the lower abdomen.

PMID- 8643737
TI  - Modified approach to the subperiosteal rhytidectomy.
AB  - Our technique modifications include a systematic preauricular approach to the
      zygomatic arch and preservation of the temporal fat pad, which is left
      undisturbed. The preauricular extension permits greater access along the
      zygomatic arch, which may additionally reduce the risk of injury to the frontal
      branch of the facial nerve. Leaving the temporal fat pad undisturbed may help
      prevent a recently described late complication of temporal region depression that
      may be due to temporal fat atrophy from surgical trauma. By following the
      aforementioned steps, this technique can be performed efficiently and safely even
      if it is used infrequently.

PMID- 8643738
TI  - The instep free flap to resurface palmar defects of the hand.
AB  - Large and deep soft-tissue defects of the hand require adequate resurfacing by
      free or distant pedicle flaps. A free flap of suitable size corresponding to the
      extended palm defect may be harvested from the instep region without encroaching
      on the weight-bearing area. Following Gillies's concept that "losses must be
      replaced in kind," and taking into consideration all possibilities of a free-flap
      reconstruction of the hand, we can conclude that an innervated fasciocutaneous
      free instep flap provides normal contour, texture, and color and thus an optimal
      functional, aesthetic, and anatomic reconstruction of the palm with acceptable
      donor-site morbidity.

PMID- 8643739
TI  - Endonasal premaxillary osteotomy.
AB  - In our hands, the endonasal premaxillary osteotomy is an improvement over the
      buccal sulcus tunnel and transpalatal techniques not only because of preservation
      of the blood supply but also because of improved visualization to the premaxilla.
      We have found the technique to be particularly useful in the bilateral cleft
      patient in whom the palate has been closed before Le Fort I osteotomy.

PMID- 8643741
TI  - Transconjunctival blepharoplasty.

PMID- 8643740
TI  - Submucous cleft palate: diagnostic methods and outcomes of surgical treatment.
AB  - The following statements summarize our interpretation of the literature regarding
      submucous cleft palate: Incidence and Diagnosis of Submucous Cleft Palate 1. In
      surveys of classic stigmata of submucous cleft palate among the general
      population, the incidence has been reported to be 0.02 to 0.08 percent. In the
      larger of these series, the incidence of velopharyngeal inadequacy among patients
      identified to have submucous cleft palate was 1 to 9. The incidence of occult
      submucous cleft palate is not known, since these patients will only be detected
      during the evaluation of patients who present with velopharyngeal inadequacy. 2.
      The diagnosis of submucous cleft palate is made by identification of the classic
      stigmata on physical examination. The diagnosis of occult submucous cleft palate
      is only pursued if the patient has velopharyngeal inadequacy. 3. For consistency
      in evaluating and reporting data, patients with an overt cleft of the secondary
      palate that extends beyond the uvula should be reported as having a cleft palate,
      and not a submucous cleft palate, even if a submucous cleft exists in a portion
      of the palate anterior to the overt cleft. 4. The true incidence of otitis media
      with effusion in the presence of submucous cleft palate has yet to be determined
      using a prospective study. Surgical Treatment of Velopharyngeal Inadequacy in
      Patients with Submucous Cleft Palate 1. The technique that has most consistently
      been documented to result in a significant correction of velopharyngeal
      inadequacy is the pharyngeal flap. There is recent evidence from one large center
      supporting the efficacy of the Furlow Z-plasty in selected patients with
      submucous cleft palate. Both these procedures appear to be most effective in
      patients with good lateral pharyngeal wall motion. 2. If a pharyngeal flap is
      performed as the primary procedure to act as an obturator against which the
      lateral pharyngeal walls appose for closure, we do not see the need for
      adjunctive palatal procedures. The dynamic component of velopharyngeal competence
      following such a pharyngeal flap consists of lateral wall motion, which is not
      enhanced by further surgical manipulation of the palate. However, a pharyngeal
      flap may be performed as an adjunctive procedure to a palatal pushback in order
      to provide lining for the resultant defect in the nasal mucosa. 3. The present
      literature does not support "prophylactic" operations on patients who present
      with the physical stigmata of submucous cleft palate prior to reaching an age at
      which it can be demonstrated by perceptual speech assessment that velopharyngeal
      inadequacy remained refractory to speech therapy. A significant number of
      patients will never develop velopharyngeal inadequacy; therefore, surgery would
      be unnecessary. In addition, objective data regarding the outcomes of different
      surgical techniques cannot be gathered if patients with submucous cleft palate
      are operated on without having had velopharyngeal inadequacy documented prior to
      those operations. 4. In order to objectively compare the outcomes of different
      surgical techniques, any future studies should be prospective and utilize uniform
      means of assessment. As minimum criteria, these would include preoperative and
      postoperative perceptual speech assessments performed by a trained speech
      pathologist and preoperative nasopharyngoscopy and multiview videofluoroscopy.
      The latter two studies should be repeated postoperatively only in those patients
      who have persistent velopharyngeal inadequacy.

PMID- 8643742
TI  - Preoperative liposuction fat estimation.

PMID- 8643743
TI  - Vacuum extraction of breast prostheses.

PMID- 8643744
TI  - Kenalog warning.

PMID- 8643745
TI  - The nonsticking skin hook.

PMID- 8643746
TI  - Air bag-bruised face.

PMID- 8643747
TI  - Light at the end of the carpal tunnel.

PMID- 8643748
TI  - Alopecia and sure-closure.

PMID- 8643749
TI  - Dynamic mutations and psychiatric genetics.

PMID- 8643750
TI  - Service utilization by schizophrenic patients in Groningen and South-Verona: an
      event-history analysis.
AB  - The question addressed to in this paper is whether severely mentally ill patients
      are treated differently in a community mental health service without the back-up
      of a mental hospital (south-Verona, Italy) compared with an institution-based
      system in which mental hospitals, although highly modernized, are still
      predominant (Groningen, The Netherlands). Using the psychiatric case-registers in
      both areas, the patterns of care in 2 years of follow-up of schizophrenic
      patients were constructed. Survival analysis was used to analyse in-, day- and
      out-patient episodes of care. Three-quarters of the Groningen and half of the
      south-Verona patients experienced at least one episode of hospitalization; 20% of
      the Groningen and 5% of the south-Verona patients were long-stay patients at the
      end of the observation period. The south-Verona patients had more episodes of in
      patient and especially of day-patient and out-patient care. Cox's regression
      showed that the duration of episodes controlled for the history of events and
      sociodemographic characteristics, was significantly shorter in south-Verona. One
      of the main conclusion was that hospitalizations for the severely mental ill are
      also needed in a community-based system of care, supporting the assumption of a
      'bed-rock' of mental illness. However, the south-Verona community mental health
      service seems to be able to reduce the duration of hospitalizations considerably.

PMID- 8643751
TI  - Life events, social support and marital relationships in the outcome of severe
      depression.
AB  - The effects of life events, social support and marital relationships on outcome
      were examined in a predominantly recurrent in-patient sample of depressives
      studied longitudinally every 3 months to remission and up to 15 months
      thereafter. Outcomes examined were length of time to remission, presence of
      residual symptoms at remission, and subsequent relapse. There were few
      associations between these outcomes and the social variables. These findings add
      to other recent evidence that psychosocial factors are relatively unimportant in
      the subsequent course of severe and recurrent depressions, in contrast to their
      contribution to onset of such depressions and subsequent outcome of milder
      depressions.

PMID- 8643752
TI  - Post-natal depression in an urban area of Portugal: comparison of childbearing
      women and matched controls.
AB  - The point prevalence of depression measured on one occasion between 2 and 5
      months after childbirth was estimated to be 13.1% in 352 mothers living in urban
      Portugal; the criterion was a score of 13 or more on a translated version of the
      Edinburgh Post-natal Depression Scale (EPDS). More detailed comparisons were made
      between a subgroup of 118 mothers and 118 matched controls who had not borne a
      child in the previous 2 years. Post-natal women were twice as likely as non
      childbearing controls to meet the EPDS criterion for depression In comparison
      with controls, they were also more severely depressed as judged by their total
      scores on another questionnaire, the Zung Scale. Comparisons of individual
      symptom scores (Zung Scale) showed that childbearing women, as a whole, reported
      more somatic symptoms than controls, but when only those women judged to be
      depressed or dysphoric by the EPDS were compared, this difference disappeared.
      Stepwise logistic analyses of symptoms contributing to the categorization of a
      'case' of post-natal versus non-post- natal depression did not reveal any very
      clear divergences in self-reported psychopathology. In childbearing women, two
      factors were found significantly to contribute to higher depression scores; women
      with more children and those from lower socio-economic groups were most at risk.

PMID- 8643753
TI  - Season of birth and Alzheimer's disease: a population-based study in Saguenay-Lac
      St-Jean/Quebec (IMAGE Project).
AB  - The birth distribution of 399 cases of Alzheimer's disease (AD) identified in the
      region of Saguenay-Lac-St-Jean (Quebec) was compared with that of: (a) the
      population currently living in the area; and (b) the population born during the
      same period in the same area. AD cases have been recruited since 1986 by the
      IMAGE Project. Cases and controls were grouped according to the month of birth
      and according to the day of birth using density estimation. Analyses showed a
      significant deficit of births in the month of May. We believe these preliminary
      results deserve further attention and we suggest two possible explanations that
      could lead to a deficit of AD births at specific periods during the year.

PMID- 8643754
TI  - Neuropsychological and structural brain changes in anorexia nervosa before and
      after refeeding.
AB  - The neuropsychological performance and Magnetic Resonance Imaging (MRI) brain
      appearance of a consecutive series of 46 in-patients with anorexia nervosa (AN)
      was compared with that of 41 normal-weight controls. The groups were matched for
      sex, age, estimated pre-morbid intelligence and education. AN patients who had
      gained at least 10% of their body weight were retested and rescanned. Controls
      were retested after a similar interval. The AN group performed significantly
      worse than the controls on tasks measuring attention, visuospatial ability and
      memory. On tasks assessing flexibility and learning, no group differences were
      evident although an examination of deficits in individuals revealed that more
      anorexics were impaired on both. Following treatment, the AN group improved
      relative to the control group only on those tasks assessing attention. Comparison
      of MRI measures showed a significant proportion of anorexics had enlarged lateral
      ventricles and dilated sulci on both cortical and cerebellar surfaces, but no
      dilatation was evident for the third and fourth ventricular measures.
      Improvements were found after treatment on some of the radiological measures but
      many differences remained. Relationships between morphological brain changes and
      cognitive impairments were weak. Lower weight, but not duration of illness, was
      associated with poorer performance on tasks assessing flexibility/inhibition and
      memory, and with greater MRI ventricular size.

PMID- 8643755
TI  - A comparison of DSM-III-R and ICD-10 personality disorder criteria in an out
      patient population.
AB  - This study reports the results of a comparison of DSM-III-R and ICD-10
      personality disorder criteria by application of both sets of criteria to the same
      group of patients. Despite the clinical relevance of these disorders and the need
      for reliable diagnostic criteria, such a comparison has not previously been
      reported. DSM-III-R and ICD-10 have converged in their classification of
      personality disorders, but some important differences between the two systems
      remain. Personality disorder diagnoses from both systems were obtained in 52 out
      patients, using the Standardized Assessment of Personality (SAP), a brief,
      informant-based interview which yields diagnoses in both DSM-III-R and ICD-10.
      For individual personality disorder diagnoses, agreement between systems was
      limited. Thirty-four subjects received a personality disorder diagnosis that had
      an equivalent form in both systems, but only 10 subjects (29%) received the same
      primary diagnosis in each system. There was a difference in rate of diagnosis,
      with ICD-10 making significantly more personality disorder diagnoses. The lower
      diagnostic threshold of the ICD-10 contributed most of this effect. Further
      modifications in ICD-10 Diagnostic Criteria for Research (DCR) and DSM-IV to the
      personality disorder category have been considered. The omission in DSM-IV of
      three categories unique to that system and the raising of the threshold in ICD-10
      DCR, do seem to have been helpful in promoting convergence.

PMID- 8643756
TI  - Psychopathological syndromes in the functional psychoses: associations with
      course and outcome.
AB  - The aim of this study was to identify underlying dimensions of psychopathology in
      a cohort of patients with functional psychosis of recent onset, and to examine
      their prognostic value. Factor analysis of the psychopathological features of 166
      consecutively admitted patients with functional psychosis of recent onset
      revealed seven psychopathological dimensions, which explained 63% of the
      variance. Five of these seven syndromes bore differential associations with
      subsequent treatment and illness course, independent of: (i) associations with
      DSM-III-R diagnosis; (ii) associations with other prognostic factors; and (iii)
      associations with the baseline values of outcome variables. The most striking
      associations were shown for an early and insidious onset syndrome with affective
      flattening, which predicted a more disabled course of illness on three of four
      outcome dimensions, and which was more common in males and unmarried individuals.
      A second syndrome, characterized by bizarre behaviour, inappropriate affect,
      catatonia, and poor rapport showed similar, slightly less striking, associations
      with illness course, as well as with poor pre-morbid social functioning. A third
      syndrome, characterized by positive psychotic symptoms was to a lesser degree
      associated with poorer outcome, whereas a fourth syndrome distinguished by manic
      symptomatology predicted a more benign illness course. A fifth syndrome
      identified by lack of insight predicted more time in hospital and admission under
      a section of the Mental Health Act during the follow-up period. A further finding
      was that dimensional representations of psychopathological features were
      considerably more useful than categorical representations (DSM-III-R and ICD-10)
      as predictors of illness course and treatment decisions.

PMID- 8643757
TI  - The auditory hallucination: a phenomenological survey.
AB  - A comprehensive semi-structured questionnaire was administered to 100 psychotic
      patients who had experienced auditory hallucinations. The aim was to extend the
      phenomenology of the hallucination into areas of both form and content and also
      to guide future theoretical development. All subjects heard 'voices' talking to
      or about them. The location of the voice, its characteristics and the nature of
      address were described. Precipitants and alleviating factors plus the effect of
      the hallucinations on the sufferer were identified. Other hallucinatory
      experiences, thought insertion and insight were examined for their inter
      relationships. A pattern emerged of increasing complexity of the auditory-verbal
      hallucination over time by a process of accretion, with the addition of more
      voices and extended dialogues, and more intimacy between subject and voice. Such
      evolution seemed to relate to the lessening of distress and improved coping.
      These findings should inform both neurological and cognitive accounts of the
      pathogenesis of auditory hallucinations in psychotic disorders.

PMID- 8643758
TI  - A case study of temporal lobe development in familial schizophrenia.
AB  - Case studies of patients with familial schizophrenia may help to define the
      pathophysiology of this illness and indicate potential candidate genes for
      genetic linkage studies. In this regard, the clinical, radiological and
      pathological assessments of a 39-year-old affected man from a pedigree with
      familial schizophrenia are presented. Brain imaging with CT indicated moderate
      cortical atrophy, particularly of the temporal lobes. Neuropathological
      examination revealed granular ependymitis, indicating possible past ventricular
      pathology. Granular ependymitis was reported to occur in genetic developmental
      disorders with neuronal migration abnormalities. In the present case, heterotopic
      clusters of neurons were visualized in the entorhinal cortex, suggesting that
      temporal lobe development was not entirely normal. This case study suggests that
      genetic factors could be investigated further as one possible aetiology of
      certain neurodevelopmental abnormalities observed in schizophrenia.

PMID- 8643760
TI  - Psychotic illness in ethnic minorities: clarification from the 1991 census.
AB  - Age and sex-adjusted first admission rates for operationally-defined
      schizophrenia and other non-affective psychosis in different ethnic groups were
      calculated over the period 1988-1992 in a defined catchment area in South London.
      Standardized rates for schizophrenia, corrected for age- and gender-related under
      reporting in the 1991 census and a 20% underestimate of the size of the ethnic
      minority populations in the area, were not only higher in the Afro-Caribbean
      group (SMR: 3.1; 95% C1:2.0-4.7), but also in the African group (SMR: 4.2; 95%
      C1: 2.8-6.2). It was further found that higher rates were not specific to
      schizophrenia. These findings suggest that some common factor associated with
      ethnic minority membership is important in producing an excess of psychotic
      illness.

PMID- 8643759
TI  - Personality traits in LLPDD and normal controls during follicular and luteal
      menstrual-cycle phases.
AB  - In 15 women with Late Luteal Phase Dysphoric Disorder (LLPDD) and in 15 normal
      control subjects, personality traits were assessed using the Millon Clinical
      Multiaxial Inventory (MCMI) during follicular and luteal menstrual-cycle phases.
      Compared with controls, LLPDD subjects had less compulsive but more
      passive/aggressive and borderline/cycloid traits, and more depression and
      hypomania. Menstrual-cycle phase did not significantly affect personality
      variables in either group. In particular, depression and hypomania in LLPDD
      subjects suggests a relationship with affective disorders.

PMID- 8643761
TI  - Functional anatomy of inner speech and auditory verbal imagery.
AB  - The neural correlates of inner speech and of auditory verbal imagery were
      examined in normal volunteers, using positron emission tomography (PET). Subjects
      were shown single words which they used to generate short, stereotyped sentences
      without speaking. In an inner speech task, sentences were silently articulated,
      while in an auditory verbal imagery condition, subjects imagined sentences being
      spoken to them in an another person's voice. Inner speech was associated with
      increased activity in the left inferior frontal gyrus. Auditory verbal imagery
      was associated with increases in the same region, and in the left premotor
      cortex, the supplementary motor area and the left temporal cortex. The data
      suggest that the silent articulation of sentences involves activity in an area
      concerned with speech generation, while imagining speech is associated with
      additional activity in regions associated with speech perception.

PMID- 8643762
TI  - Verbal fluency in schizophrenia: relationship with executive function, semantic
      memory and clinical alogia.
AB  - To examine whether poor verbal fluency in schizophrenia represents a degraded
      semantic store or inefficient access to a normal semantic store, 25 normal
      volunteers and 50 DSM-III-R schizophrenic patients, matched for age, sex and IQ,
      were recruited. Although schizophrenic patients were impaired on both letter and
      category fluency, they showed a normal pattern of output in that category was
      superior to letter fluency, and an improvement in category fluency when a cueing
      technique was employed (Randolph et al. 1993). These results resemble those found
      in disorders of frontostriatal systems (Parkinson's and Huntington's disease) and
      suggest that poor verbal fluency in schizophrenia is because of inefficient
      access to semantic store. A measure of improvement with cueing was directly
      related to performance on the Stroop executive task. Of all symptom measures
      derived from SANS and Manchester Scales, only alogia was related to verbal
      fluency in that superior improvement correlated inversely with the degree of
      alogia. It is suggested that both alogia and poor verbal fluency are mediated by
      the same underlying cognitive abnormality that reflects frontostriatal
      dysfunction.

PMID- 8643763
TI  - Reported parental behaviour and adult affective symptoms. 1. Associations and
      moderating factors.
AB  - Associations between retrospective ratings of parental behaviour and adult
      affective symptoms were investigated in a British national sample. Symptom scores
      at ages 36 and 43 years showed low but significant correlations with care
      (negative) and control (positive), as measured by the Parental Bonding
      Instrument. Prevalence of high symptom scores was much greater in respondents
      with low care-high control (affectionless control) parents than in those with
      high care-low control parents, but there was no synergistic effect of combined
      care and control. Degree of affectionless control was progressively related to
      risk of depression. No significant gender differences were found in these
      associations. Findings could not be explained as spurious relationships resulting
      from association with other features of childhood adversity, and there was
      evidence that distorted recall arising from contemporaneous depressed mood was
      not responsible. Work is needed to establish the causal mechanisms underlying
      observed associations, including inter-relationships between parental style and
      other early adversity, and factors mediating or moderating the long-term of
      parental behaviour.

PMID- 8643764
TI  - Reported parental behaviour and adult affective symptoms. 2. Mediating factors.
AB  - Potential mediators of the modest association between retrospectively rated
      parental behaviour and adult affective symptoms in offspring were investigated in
      a national longitudinal study of a cohort followed to the age of 43. Personality
      measures from adolescence could account for a small part of this association.
      Personal relationships in adulthood were more strongly associated with both
      parental behaviour and symptoms: marital history, emotional support, social
      network and availability of help in a crisis. Poor parenting did not lead to a
      general vulnerability to later life events, and socio-economic status and
      financial hardship were not implicated in the link between parental behaviour and
      adult symptoms. However, parental affectionless control was associated with
      certain types of life stressors in adulthood, i.e. interpersonal as opposed to
      non-interpersonal life events. Collectively, aspects of personal relationships
      accounted for much of the elevated symptom levels in those rating parents as low
      on care or high on control. Findings were consistent with the notion that
      interpersonal competence is important in the continuity between childhood
      experience and adult mental health, but other possible interpretations are
      discussed.

PMID- 8643765
TI  - Enhanced adrenal sensitivity to adrenocorticotrophic hormone (ACTH) is evidence
      of HPA axis hyperactivity in Alzheimer's disease.
AB  - Adrenal sensitivity was assessed in 16 non-depressed patients with NINCDS/ADRDA
      Alzheimer's disease (AD) and 18 control subjects by measuring cortisol response
      to low dose (0.05 microgram/kg i.v.) exogenous adrenocorticotrophic hormone
      (ACTH). Controlling for sex and medication, both peak cortisol level (peak
      baseline) and area under cortisol response curve (AUC above baseline) were
      significantly greater in AD subjects. This shows that HPA axis hyperactivity, as
      demonstrated by enhanced adrenal sensitivity to ACTH, occurs in AD. Similar
      findings have been reported to occur in depression. Among AD subjects, AUC
      cortisol response correlated with current age (r = 0.70, P = 0.001) and age at
      onset of dementia (r = 0.73, P = 0.001) and an inverse correlation was seen
      between cortisol AUC and cognitive test (CAMCOG) score (r = -0.51, P = 0.044).
      Our findings suggest that HPA axis hyperactivity in AD is associated with
      advancing age and cognitive dysfunction. Such changes may be cause, or
      consequence, of neuronal loss.

PMID- 8643767
TI  - A comprehensive public mental health programme in Guinea-Bissau: a useful model
      for African, Asian and Latin-American countries.
AB  - From 1983-1994 a community mental health programme was set up in Guinea- Bissau.
      The first part of the programme concentrated on epidemiological aspects: rural
      and urban study areas were selected on socio-economic level and participation in
      the liberation war. A two-stage design was used to screen 351 adult consecutive
      general health care attenders and 100 children in a rural and an urban area for
      mental disorder. Psychiatric disorders have a morbidity of 12% among adults seen
      in Primary Health Care. Disorders were mainly neuroses (74%), but more psychoses
      were found than in other countries. No statistically significant difference in
      morbidity was found between rural-urban areas or between previous war and non-war
      zones. The diagnostic sensitivity of the Primary Health Care workers was 31%,
      their diagnostic specificity 88%. Thirteen per cent of the children showed
      neuropsychiatric disturbances. There were no sociocultural impediments to this
      public mental health approach. During the following intervention programme 850
      Primary Health Care workers were trained and supervised nationwide. The
      diagnostic sensitivity of major mental disorders and epilepsy increased from 31%
      to an average of 85%. Before the training, their knowledge of the treatment of
      these disorders was nil whereas after training 82% of the patients received
      appropriate treatment. Moreover, this model programme shows a profitable
      cost/benefit ratio and a high sustainability over the last 10 years.

PMID- 8643766
TI  - Childhood parental loss and alcoholism in women: a causal analysis using a twin
      family design.
AB  - Childhood parental loss may be an important risk factor for psychiatric illness
      in adulthood. While this association has been carefully examined for depression,
      little is known about the role of parental loss in predisposing to alcoholism. We
      examined an epidemiological sample of female twin pairs with the same history of
      continuity or disruption in parent-child relationships (N=1018 pairs; mean age 30
      years), using a range of definitions of alcoholism. Childhood parental loss
      through separation, but not death, substantially increased the risk in adulthood
      for all definitions of alcoholism. Furthermore, both paternal and maternal
      alcoholism substantially increased the probability of parental separation from
      their children. Proposing a structural equation twin-family model that
      incorporates childhood parental loss as a specified environmental risk factor, we
      examined how much of the association between childhood parental loss and
      alcoholism was causal (i.e. mediated by environmental factors) v. non-causal
      (mediated by genetic factors, with parental loss serving as an index of parental
      genetic susceptibility to alcoholism). Both the causal and non-causal paths were
      significant for all definitions of alcoholism. However, the causal-environmental
      pathway consistently accounted for most of the association. While a significant
      proportion of the association is due to non-causal genetic mechanisms, childhood
      parental loss (or the familial discord that precedes or follows it) is probably a
      direct and significant environmental risk factor for the development of
      alcoholism in women.

PMID- 8643768
TI  - Delayed matching to complex samples and the formation of stimulus classes in
      children.
AB  - In two experiments (ns = 3 plus a previously tested child, and 2, respectively),
      children learned delayed matching with complex samples, each consisting of a form
      and a printed nonsense word. Forms or printed words were comparison stimuli. For
      form comparisons, selecting the form identical to that in the preceding sample
      was reinforced. For printed word comparisons, selecting the word identical to
      that in the preceding sample was reinforced. During testing, the children then
      matched the forms and printed words to one another. In subsequent training, the
      samples were (a) old forms combined with new words or (b) old words combined with
      new forms. Novel matching performances among forms and words appeared across
      these training phases. Word-form contiguity in a matching-to-sample context may
      contribute to the formation of classes of stimuli that may be equivalent.

PMID- 8643769
TI  - Work hardening: evidence for success of a program.
AB  - The effectiveness of a work hardening program in facilitating gains in physical
      strength and return to work in 40 chronic low back-pain clients was assessed.
      Statistically significant gains in physical strength were found. Also, 27 of the
      32 clients reached by follow-up telephone calls returned to work full time.

PMID- 8643770
TI  - Correspondence between students' scores on the Millon Clinical Multiaxial
      Inventory-II and Personality Diagnostic Questionnaire-Revised.
AB  - The relation between two measures of personality disorders was examined in a
      nonclinical sample of 113 college students (86 women, 27 men) who completed the
      Millon Clinical Multiaxial Inventory-II and the Personality Diagnostic
      Questionnaire-Revised. Raw scores for 10 of 11 corresponding scales on the two
      instruments were significantly correlated (median r = .49). Compared to Millon's
      inventory, the Personality Diagnostic Questionnaire-Revised designated more
      subjects as having eccentric personality disorders but fewer as having anxious
      personality disorders. The significant association between scores on the
      inventories suggests that they assess personality traits that vary continuously
      in nonclinical samples. However, the finding that they differ significantly in
      their assignment of clinical labels shows that they should not be used to
      diagnose personality disorders in nonclinical populations.

PMID- 8643772
TI  - Blame and punishment: attitudes to juvenile and criminal offending.
AB  - Responses of 139 undergraduate social welfare students and 79 community members
      to a questionnaire regarding contemporary issues in juvenile and general justice
      were partially accounted for by a Punitive-Internal factor. Scores on a resultant
      8-item index of punitive-internal attitudes were positively correlated with
      scores on belief in a just world and were lower for social welfare students than
      for community members. In a follow-up study with a second sample of 78 community
      members, scores on the Punitive-Internal index were significantly related to
      ratings on measures of attitude toward authority and political conservatism but
      not to reported experience of crime. Findings are consistent with previous
      research and indicate that opinions on juvenile offending have a similar
      attitudinal basis to opinions on offending in general.

PMID- 8643773
TI  - Researching the Oklahoma City bombing.
AB  - The authors present a literature retrieval strategy for investigators who plan to
      conduct research on the Oklahoma City bombing. To facilitate a comprehensive
      review of the scholarly research on disasters, mass emergencies, and terrorism, a
      multidatabase search strategy is strongly encouraged. Secondly, a wealth of
      current information and data on the bombing are available on "popular" and "news"
      files.

PMID- 8643771
TI  - The toxicity of car exhaust and its use as a method for suicide.

PMID- 8643774
TI  - Children and exposure to the sun: relationships among attitudes, knowledge,
      intentions, and behavior.
AB  - This study examined the relationships among measures of knowledge of skin cancer,
      attitudes toward sun exposure, intentions to use sunscreen, and self-reported use
      of sunscreen by 105 fifth-grade children. Positive correlations were obtained
      between knowledge and intentions to use sunscreen, knowledge and healthier
      attitudes, and intentions to use sunscreen and healthier attitudes toward sun
      exposure. Surprisingly, knowledge, attitudes, and intentions were not
      significantly associated with reported use of sunscreen. Researchers designing
      interventions to effect behavioral change, i.e., sunscreen use, in children might
      further explore the predictive utility of these constructs as well as examine the
      utility of other important variables not measured here.

PMID- 8643775
TI  - Validity of the Amsterdam Child Behavior Checklist: a short rating scale for
      children.
AB  - The Amsterdam Child Behavior Checklist is a short behavior checklist meant to
      distinguish between attention problems and several other common behavioral and
      emotional problems of children in primary education. The list has four scales,
      Attention Behavior, Restlessness, Aggressive Behavior, and Fear/Uncertainty. We
      examined the relationships among the scores on the scales and similar scales of
      the Teacher Report Form, the teachers' version of the Child Behavior Checklist.
      Teachers from 94 schools rated 454 children on both lists. Analysis showed that
      the associations between the scores of the scales of the Amsterdam Child Behavior
      Checklist and of similar scales of the Teacher Report Form ranged from moderate
      to strong. These data support the validity of the scales of the Amsterdam Child
      Behavior Checklist.

PMID- 8643776
TI  - Dubious value of the "reasonable woman" standard in understanding sexual
      harassment.
AB  - There are problems with the "reasonable woman" concept for sexual harassment
      cases. Also, the 1995 findings of Baird, et al., although statistically
      significant, identify very small differences between men and women subjects.
      "Reasonable woman," as employed in sexual harassment cases, is a culture-bound
      concept used by some feminists to present a specific worldview in which women are
      seen in the victim's role, and men are viewed negatively.

PMID- 8643777
TI  - Effects of delay of reinforcement with reduction of confinement in the goal-box
      and elimination of handling immediately following runway traversal.
AB  - 24 male rats were randomly assigned into one of three groups. The first group was
      immediately reinforced with food pellets upon entering a wide goal-box area after
      running down a straight alley. The second group was reinforced with food pellets
      10 sec. after they placed their noses above the goal cup. A third group was
      reinforced 30 sec. after they placed their noses above the goal cup. All animals
      were given a total of 72 trials (four trials per day). The results indicated that
      rats given immediate reinforcement ran faster than those with a 10-sec. delay
      which were faster than those with a 30-sec. delay. These findings suggest that
      the results of the previous studies were due to delay of reinforcement effects
      and not confinement in the goal-box or handling following a run.

PMID- 8643778
TI  - Maternal characteristics of adolescent mothers and older mothers of infants.
AB  - Cognitive status and childrearing attitudes of adolescent mothers were compared
      with those of older women from the same socioeconomic status when their children
      were infants. The 106 adolescent mothers were significantly lower than the 47
      older women on measures of cognitive status but significantly higher in
      authoritarian attitudes.

PMID- 8643779
TI  - Use of educational resource materials with South African children in day care.
AB  - The psychometric scores of black South African children (N = 248) in 16 day-care
      centers were assessed before (n = 119) and after (n = 129) the introduction of an
      enrichment package, which consisted of a range of educational toys and cost US
      $12 per child. Analysis indicated that the enrichment was associated with
      significant improvements on a number of psychometric measures. Results are
      critically examined in terms of methodological issues, the effects of a low-cost
      enrichment scheme, and aspects of the package which merited subsequent
      improvement.

PMID- 8643781
TI  - Men's preferences in romantic partners: obesity vs addiction.
AB  - Fewer men responded to a personal advertisement in which a woman identified
      herself as obese than to one in which she indicated a history of drug addiction.
      The men who responded to the two advertisements also disclosed their own obesity
      or addiction.

PMID- 8643780
TI  - Gender differences in the financing of nursing home care.
AB  - Gender was associated with one type of fund used for financing nursing home care,
      assistance from children. Female nursing home residents were more likely to
      receive assistance from adult children than were male residents.

PMID- 8643782
TI  - Associations of scores on the White-Campbell Psychological Birth Order Inventory
      and the Kern Lifestyle Scale.
AB  - This study investigated the relations among psychological birth order, actual
      birth order, and lifestyle. The study also further examined the convergent
      validity of the White-Campbell Psychological Birth Order Inventory. This
      inventory and Kern's Lifestyle Scale were administered to 126 individuals in a
      southeastern urban university. The several analyses of variance and canonical
      correlation analysis (1) supported a stronger relationship between psychological
      birth order and lifestyle than between actual birth order and lifestyle, (2)
      identified differential relationships between particular birth-order positions
      and lifestyle scales that were predicted and in accord with Adlerian theory, and
      (3) further supported the validity of the inventory. The results reaffirmed the
      lifestyle pattern and birth-order characterizations of Adlerian theory.

PMID- 8643783
TI  - Career motivations of male and female medical students.
AB  - Australian medical students (N = 645) were asked at the beginning of their
      training to rank the importance of a list of motivations relevant to their choice
      of medicine as a career. Both male and female students ranked the desire to help
      others as the most important motivation, closely followed by the scientific
      nature and the intellectual challenge of the profession of medicine. Both genders
      rated considerations of status and prestige as of low importance. These findings
      are similar to surveys from other countries that have reported altruism and
      intellectual challenge as prime motivations for both genders.

PMID- 8643784
TI  - Behavioral effects of felbamate in childhood epileptic encephalopathy (Lennox
      Gastaut syndrome).
AB  - The behavioral effects of felbamate were assessed in 20 persons, (ages 2 to 19
      years) who were participating in a compassionate plea protocol for children with
      Lennox-Gastaut syndrome. Parents completed a questionnaire concerning aspects of
      behavioral change once all medications were in a constant regimen. Significant
      improvements were suggested in social functioning, intellectual functioning,
      motor functioning, attention and concentration, alertness, initiative,
      variability in performance, and memory. There was a tendency for these effects to
      reverse when the drug was discontinued.

PMID- 8643785
TI  - Women ages 30-60 and their crisis events.
AB  - Not much attention has been given to differences among women between the ages of
      30 and 60 years when discussing crisis events. 370 women were asked to respond to
      items regarding midlife crisis, i.e., whether they had experienced a midlife
      crisis, the intensity of the crisis, and their ability to identify the
      precipitating event. Most of the 264 women who had experienced a crisis
      identified "Changes in Self" as the precipitating event. Also identified were
      work-related events. As in the literature, work is infrequently addressed in this
      context.

PMID- 8643786
TI  - Suicide and domestic integration in Spain: the effect of the source of suicide
      statistics.

PMID- 8643787
TI  - Systemic perspective on obesity in childhood: a preliminary study on power
      interactions between mother and child.
AB  - 33 mother-child dyads with an obese child (aged 9 to 12 years) and a similar
      control group were studied. The power interaction was used as an indicator of the
      style of the relationship between mother and child. To analyse the interactions
      the model of Watzlawick, Beavin, and Jackson was used because it considers three
      different possible situations of complementarity, symmetry, and parallelism. A
      revised version of the Scoresby Relationship Style Inventory was given. Analysis
      showed that dyads with obese children differ in some ways from the control dyads.
      These differences include the mother's dominant position in the relationship and
      the tendency of the obese child to avoid conflict and symmetry and to adopt a
      "one-down' complementary position. We conclude it is important to improve the
      study of childhood obesity from a systemic perspective and to extend this
      analysis to other aspects of the complex familial picture to prevent overweight
      or to maintain it within reasonable limits thereby avoiding more serious
      complications.

PMID- 8643789
TI  - Does smoking really kill anybody?
AB  - Statements that so many people are killed by smoking use the term "kill" in a
      very unusual manner which is easily misunderstood by people not expert in
      epidemiology. In addition, the usual calculations leave out of account the fact
      that smoking interacts synergistically with other risk factors, so that it is a
      combination of risk factors rather than any specific one that is likely to have a
      causal influence on mortality. Strictly speaking it is quite inappropriate to
      state that smoking kills anybody, if we use the term "kill" in a meaningful
      fashion.

PMID- 8643788
TI  - Characteristics of substance-abusing veterans attempting suicide: a national
      study.
AB  - Demographic, diagnostic, and service utilization characteristics of veterans
      diagnosed with suicide attempt, substance dependence, both, or neither at
      discharge from Department of Veterans Affairs (DVA) hospitals in fiscal year 1994
      (FY94) were compared using the DVA's discharge abstract database. Four groups of
      veterans were studied: (1) substance-abusing suicidal inpatients (n = 1,459), (2)
      substance-abusing nonsuicidal inpatients (n = 123,808), (3) nonsubstance-abusing
      suicidal inpatients (n = 632), and (4) nonsubstance-abusing nonsuicidal
      inpatients (n = 402,906). Substance-abusing suicidal veterans had higher rates of
      substance abuse than substance-abusing nonsuicidal veterans. Substance-abusing
      suicidal veterans had a higher mean number of inpatient treatment episodes and a
      larger proportion of discharges against medical advice than the other three
      inpatient groups. Psychiatric and substance use disorders are more prevalent
      among substance-abusing suicidal veterans than among veterans with only substance
      use disorders or suicidal conduct.

PMID- 8643790
TI  - Does pressure from the work community increase risk taking?
AB  - Based on the zero-risk theory, it was assumed that the pressure created by the
      work community is an "extra motive" for increased risk taking. The pressure from
      the work community was operationalized as the influence of coworkers, foremen,
      and customers. A risk-taking scale was constructed based on the interviews of 72
      victims of serious occupational accidents. Analysis did not confirm the
      hypothesis because there was no significant difference between risk takers and
      risk avoiders in the influence of coworkers, foremen, and customers. The pressure
      of the work community may not be such an "extra motive" as the zero-risk theory
      assumes.

PMID- 8643791
TI  - Ethical implications of charging for missed sessions.
AB  - The argument is made that the common practice of charging psychotherapy patients
      for missed sessions constitutes unethical conduct from which the therapist
      benefits at the patient's expense. Although various rationales and
      rationalizations have been put forth to justify the practice, the essential facts
      are that therapists are being paid for a service not performed and the patient
      therapist relationship is often damaged, with the result that the patient's
      progress is impeded. The practice is therefore alien to the basic goals of
      psychotherapy, an enterprise that involves human interactions centering on
      positive bonding and collaborative problem solving. It is suggested that mental
      health workers' professional associations scrutinize the practice more closely
      and make stronger recommendations to discourage it.

PMID- 8643792
TI  - Sex-role orientation and satisfaction with life.
AB  - The hypothesis that androgynous people are more satisfied with life than others
      was tested by administering the Personal Attributes Questionnaire and the
      Satisfaction with Life Scale to 245 undergraduates (111 men and 134 women).
      Results strongly supported the tested hypothesis for men but not for women.

PMID- 8643793
TI  - Psychological, interpersonal, and behavioral correlates of chronic self
      destructiveness: an exploratory study.
AB  - In this study, we selected individuals high and low on a measure of chronic self
      destructiveness--the tendency to perform behaviors that later reduce positive
      consequences and increase the probability of experiencing negative ones--and
      attempted to differentiate high and low scorers based on a set of hypothesized
      antecedent and concurrent psychological, interpersonal, and behavioral
      correlates. Men and women were equally represented in high- and low-scoring
      groups. High scorers reported experiencing more interpersonal exploitation,
      greater depression, lower self-esteem, more externalizing attitudes, and less
      control in relationships than low scorers. High-scoring individuals also engaged
      in more frequent acts of acute self-destructiveness, including attempted suicide.
      A significant age covariate effect emerged: high-scoring men and women were
      younger than low-scoring individuals. These findings underscore the importance of
      studying chronic self-destructiveness within a developmental framework and
      suggest that issues of safety and self-care may be particularly germane to
      educational and clinical interventions aimed at young adults.

PMID- 8643794
TI  - Which nations establish suicide prevention centers?

PMID- 8643795
TI  - Relation between the Tolerance Questionnaire (nicotine dependence) and assessment
      of carbon monoxide in smokers who participated in treatment for smoking.
AB  - It is very important to have objective measurements of nicotine dependence or
      tobacco addiction, especially in the treatment of smokers. The most utilized
      physiological assessment is the carbon monoxide (one of the components of tobacco
      smoke) in expired air. A noninvasive measure of nicotine dependence is the
      Fagerstrom's Tolerance Questionnaire. In our study we compared responses on the
      Tolerance Questionnaire of 217 smokers who participated in a treatment to stop
      smoking and also measurements of carbon monoxide in expired air (evaluated with a
      Mini Smokerlyzer EC-50). Analysis showed the utility of the Tolerance
      Questionnaire in the discrimination of number of cigarettes smoked prior to and
      after treatment and at follow-up.

PMID- 8643796
TI  - Some comments on a factor analysis of the 16PF and the NEO Personality Inventory
      Revised.
AB  - This paper comments on unusual results recently published by Byravan and
      Ramanaiah. Their factor analysis of the 16PF and the NEO Personality Inventory
      Revised showed the scales of the two tests to be largely unrelated. However, two
      recent factor analyses of these tests show strong relationships between the two
      sets of global factors--as strong as between the NEO Personality Inventory
      Revised five factors and Goldberg's big-five factors. Possible reasons for the
      discrepancy are discussed.

PMID- 8643797
TI  - Suicide and alternative measures of domestic integration.

PMID- 8643799
TI  - Husbands' involvement in housework: effects of relative earning power and
      masculine orientation.
AB  - A survey of 138 husbands in dual-earner households examined factors influencing
      participation in two household tasks, cleaning and cooking. Path analyses showed
      that husbands were more involved in these tasks if they had a nontraditional view
      of masculinity and if they perceived little conflict between their work and
      family life. Also, the greater the wives' contribution to family income, the
      greater the husbands' participation in cleaning and cooking. Finally, a
      traditional view of masculinity tended to decrease involvement in household tasks
      by increasing the perception of conflict between work and home life.

PMID- 8643798
TI  - Religiosity, AIDS, and sexuality knowledge, attitudes, beliefs, and practices of
      black South-African first-year university students.
AB  - This study investigated the association of religiosity with sexuality and AIDS
      knowledge, attitudes, beliefs, and practices of 1,817 black first-year students
      in South Africa. On a structured questionnaire, consenting students rated
      themselves on scales of religiosity, attitudes toward homosexuality,
      intrafamilial communication about contraception, AIDS attitudes, and AIDS
      knowledge. Negative attitudes toward homosexuality were significantly associated
      with negative attitudes towards AIDS, high knowledge of AIDS, and high
      religiosity. Religious commitment diminished propensity to engage in sexual
      intercourse and delayed age for onset of sexual intercourse.

PMID- 8643800
TI  - Fundamentalism, suicide, and homicide.

PMID- 8643801
TI  - Learning set spatial navigation performance in three mouse strains.
AB  - Swiss Webster (SW), Dilute Brown Agouti (DBA), and Deer Mice (DM) were tested for
      acquisition and retention of a learning set place task in the Morris water maze.
      The learning set consisted of daily placing the hidden platform sequentially at 1
      of 4 separate locations in the pool. All animals swam for 63 days in this version
      of the water task. SW animals were unable to find the platform reliably. The time
      taken by DBA and DM animals in escaping the pool declined rapidly, reaching
      asymptote within 21 days. The DM animals reached the platform significantly
      faster than either SW or DBA mice. Analyses of swim path selection used by the 3
      strains indicated clearly that DM mice were the most systematic in the selecting
      and sequencing from a variety of potential strategies the appropriate methods
      necessary for the most efficient solution of the problem. The present results
      suggest that in light of the differences between strains observed in swimming
      behaviors, investigation of strain differences in the neuroanatomic structures
      believed to be related to the solving of spatial problems might be useful.

PMID- 8643802
TI  - Serum cholesterol and perception of anger and sadness.
AB  - Analysis of cholesterol levels in 34 forensic patients indicated significant
      associations with measures of the patients' perceptions of the emotional content
      in auditory stimuli. In particular, patients with low cholesterol showed
      hypersensitivity in the detection of anger and sadness. The authors hypothesize
      the involvement of serotonin in the hypersensitivity effects. Organicity and age
      were ruled out as contributing factors.

PMID- 8643803
TI  - Association between history of abuse and borderline personality disorder for
      hospitalized adolescent girls.
AB  - Records of 38 hospitalized female adolescents were analyzed to evaluate the
      relationship between a history of earlier physical and/or sexual abuse and
      borderline personality. Those with histories of abuse were significantly more
      likely to score as Borderline Personality Disorder when assessed by the
      Diagnostic Interview for Borderlines--Revised.

PMID- 8643804
TI  - Assessing Machiavellianism and Morality-Conscience Guilt.
AB  - If Machiavellians behave relatively morally or ethically as stated by Leary and
      colleagues in 1986, then hypotheses regarding their immorality should be
      reexamined. 84 MBA students in a program at Fairleigh Dickinson University
      completed Christie and Geis' 1970 Mach IV scale and the Guilty-Conscience
      subscale of Mosher's 1988 Revised Mosher Guilt Inventory. Results indicate that
      some students scored high on both Machiavellianism and Morality-Conscience Guilt.

PMID- 8643805
TI  - Dimensionality of burnout: testing for invariance across Jordanian and Emirati
      teachers.
AB  - This study was designed to assess the structure of the Maslach Burnout Inventory
      for 218 Jordanian and 162 Emirati teachers. LISREL was used to test the
      invariance of factor structure across the two Middle Eastern samples.
      Coefficients alpha were computed for the three subscales of the inventory for the
      samples. The results indicated that the parameter estimates were invariant across
      the two samples; however, not all factor correlations were invariant. Factor
      correlations of Jordanian teachers were larger than those of the Emirati
      teachers. Coefficients alpha ranged between .71 and .84 for the Jordanians and
      between .68 and .83 for the Emiratis. The inventory appears to be valid and
      reliable for nonWestern teachers as well as Western teachers.

PMID- 8643806
TI  - Use of adventure experiences in traditional counseling interventions.
AB  - Use of adventure as an intervention in traditional counseling was explored with
      84 adolescent clients from two community-based counseling agencies and residents
      from two boys' homes. The adolescents were assigned to conditions of counseling
      plus adventure experiences, counseling only, adventure only, or a control.
      Analysis indicated limited support for increasing self-esteem and social skills
      by adding adventure experiences to on-going counseling.

PMID- 8643807
TI  - Name that tune: eliciting the tip-of-the-tongue experience using auditory
      stimuli.
AB  - An experiment was conducted to assess whether auditory stimuli could elicit the
      tip-of-the-tongue state. Subjects were presented segments of 50 television theme
      songs and asked to indicate the title of the corresponding show. Twenty-one
      percent of all retrieval attempts resulted in an experience of the tip-of-the
      tongue state, with women reporting more such experiences than men. The majority
      of these experiences contained partial information about the target such as the
      show's characters, actors, or outline. Subjects in the tip-of-the-tongue state
      were also able to identify the genre and era of the target show with high
      accuracy and pick it out amongst distractors in a recognition test. Competing
      responses were relatively infrequent and were usually semantically related to the
      target show. The similarities and differences between auditory-induced tip-of-the
      tongue states and those for other stimuli are discussed.

PMID- 8643808
TI  - Cooperative selection of movements: the optimal selection model.
AB  - How one selects a movement when faced with alternative ways of doing a task is a
      central problem in human motor control. Moving the fingertip a short distance can
      be achieved with any of an infinite number of combinations of knuckle, wrist,
      elbow, shoulder, and hip movements. The question therefore arises: how is a
      unique combination chosen? In our model, choice is achieved by consideration of
      the similarity between the task requirements and the optimal biomechanical
      performance of each limb segment. Two variants of the model account for the
      movements that are selected when subjects freely oscillate the fingertip and when
      they tap against an obstacle. An important feature of both is that the impulse of
      collision with an obstacle (as in drumming with the hand or tapping with the
      finger) is assumed to be controlled in part by aiming for a point beyond the
      surface being struck. Thus, a force-related control variable may be represented
      and controlled spatially.

PMID- 8643809
TI  - Coordination in visual working memory.
AB  - Coordination of mental procedures is considered in terms of control processes
      (Baddeley, 1989) in visual working memory and appears to be a separable aspect of
      the demand imposed by cascaded serial processes (Carlson & Lundy, 1992). The main
      task required subjects to indicate whether symbolically suggested rotations and
      reflections correctly describe the difference between matrix patterns of filled
      in squares within a 3 x 3 grid or between line drawings. Experiments were carried
      out to show that coordination is a separable component in this transformation
      task. A marker for coordination is the difference between the time taken to
      execute two transformations as a whole and the sum of the component
      transformations in isolation. The separate coordination demand was found in an
      experiment with matrix patterns mentioned, in an experiment with letter-like line
      drawings, and also in an experiment that forced subjects to maintain whole
      pattern representations. A last experiment checked whether coordination is
      carried out by an autonomous control unit. There was a self-paced control of
      serial presentation of transformation symbols instead of a simultaneous
      presentation of those symbols. This additional external triggering resulted in a
      substantial decrease in the demand for coordination. Coordination of mental
      procedures and temporary representations is a fundamental constraint on the use
      of working-memory processes.

PMID- 8643810
TI  - A new attack on smoking using an old-time remedy.
AB  - This article first will explain the reasons behind and goals of state recoupment
      actions against the major cigarette manufacturers, their lobbying arm and trade
      association, and their public relations firms (collectively referred to as the
      "tobacco industry") for the recovery of Medicaid and other indigent care
      expenditures on smoking-related illnesses. These are, primarily, to relieve the
      heavy financial burden on state treasuries and to stop the tobacco industry from
      targeting children in advertising and promotions. To put this new legal approach
      in perspective, the article presents a brief historical background to the tobacco
      industry's litigation strategy: to wear down opponents through delay and
      intimidation, to cast doubt on science, and to wrongfully invoke the attorney
      client privilege against disclosure of incriminating evidence. Next authors
      discuss the states' strategy: each filing one suit seeking equitable remedies
      under theories of restitution/unjust enrichment, indemnity, public nuisance, and
      injunctive relief to protect the interests of minors, instead of maintaining
      thousands of product liability claims on behalf of individual smokers. This will
      be followed by a critique of the industry's response to state actions: political
      attacks against attorneys general and trial lawyers and charges that the lawsuits
      would hurt business as well as a variety of legal challenges, including an
      imaginative but risky defense that if smoking indeed causes disease and attendant
      health care expenditures, then the tobacco industry ought to be given a credit
      against those expenditures for the taxes generated by its business and the
      "savings" which inure to the states from the premature deaths of smokers (the
      cost of geriatric care, for example). The article will wrap up by impressing on
      health officials and other readers what is at stake in these actions and what
      their success or failure will mean for the Medicaid program.

PMID- 8643811
TI  - EMFs: cutting through the controversy.
AB  - SOME SCIENTISTS ALLEGE that exposure to electric and magnetic fields generated by
      electric power delivery systems is responsible for certain cancers (particularly
      among children), reproductive dysfunction, birth defects, neurological disorders,
      and Alzheimer's disease. Some activist groups believe the hazard to be so great
      that they are calling for closure of schools and other public facilities near
      power lines and restructuring of the entire electric power delivery system. Some
      utilities, with equally strong beliefs, claim that there is no proof of risk.
      They argue that the science is sufficient to confirm the alleged associations and
      that no action is warranted. This article provides a broad overview of the
      current scientific data on the association between magnetic fields and disease,
      providing summary risk estimates and highlighting the uncertainties in the data.
      Building on this information, three complementary policy perspectives are
      presented. From a fiscally conservative perspective, the cost of mitigation
      already instituted far exceeds the health protection offered and mitigation of
      other environmental risks is more important. From a cost-benefit view, only
      limited, low-cost mitigation should be considered. These measures, however, would
      substantially reduce many exposures. From an aggressive exposure reduction
      perspective, much can be done to reduce exposure by personal and societal
      actions. If the suggested association is validated, substantially reducing
      magnetic field exposure could lower health risks.

PMID- 8643812
TI  - The ethics of excess.

PMID- 8643814
TI  - The likelihood of returning to work after breast cancer.
AB  - OBJECTIVE: This is an examination of factors associated with returning to work
      after the diagnosis of breast cancer. METHODS: Three months after being diagnosed
      with breast cancer, 296 employed women from the Detroit metropolitan area (52
      black and 244 white women) were interviewed. These women were part of a larger
      cohort of 1,011 breast cancer patients ages 40 to 84 interviewed for the study
      "Health and Functioning in Women with Breast Cancer". RESULTS: Although most
      employed women returned to work within three months of the diagnosis of breast
      cancer, black women were twice as likely as white women to be on medical leave
      three months after diagnosis (OR = 1.94; 95% CI 1.04 to 3.62). Being on leave was
      found to be associated with the need for assistance with transportation,
      limitations in upper-body strength, and employment in jobs requiring physical
      activity. After adjusting for these factors, the racial difference was reduced
      and no longer statistically significant (OR = 1.34; 95% CI 0.67, 2.70).
      CONCLUSION: Breast cancer rehabilitation programs should not only address the
      patient's physical capacity but also the daily demands she is likely to face once
      she leaves the hospital and returns to work.

PMID- 8643815
TI  - Complex interactions with the work environment.

PMID- 8643813
TI  - Fungal infections: a growing threat.
AB  - THE EMERGENCE OF newly identified fungal pathogens and the reemergence of
      previously uncommon fungal diseases is primarily related to increases in the
      numbers of susceptible persons: people with HIV infection, bone marrow and organ
      transplant recipients, cancer patients being treated with chemotherapy,
      critically ill persons, and very low birth weight ( < or = 1500 g) infants. These
      immunocompromised populations are at risk for infection not only with
      opportunistic pathogens (for example, Pneumocystis, Candida, Cryptococcus,
      Trichosporon, Malassezia, Aspergillus, Penicillium marneffei, and numerous other
      moulds or yeasts) but also with fungal pathogens that usually infect otherwise
      healthy persons not previously exposed to endemic fungi (for example,
      Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis) and
      Sporothrix schenckii. Morbidity, mortality, and health care costs associated with
      fungal infections are high. Addressing the emergence of fungal diseases will
      require increased surveillance coupled with the availability of rapid,
      noninvasive diagnostic tests; monitoring the development of resistance to
      antifungal agents; and research focused on the understanding, prevention, and
      control of fungal infections.

PMID- 8643817
TI  - Tuberculosis surveillance using death certificate data, New York City, 1992.
AB  - OBJECTIVE: To determine the accuracy and frequency of reporting tuberculosis as
      either the contributing or underlying cause of death on death certificates in New
      York City during 1992. METHODS: Death certificates from 1992 that listed
      tuberculosis were matched with the New York City tuberculosis registry. For those
      persons who had tuberculosis listed as a cause of death, but who were not listed
      in the registry, medical records were reviewed. The frequency of reporting
      tuberculosis on death certificates in patients who died with active tuberculosis
      was evaluated in the second part of this study. Death certificates of patients
      with active tuberculosis (persons who died within six months of starting anti
      tuberculosis medications) in 1992 were reviewed. RESULTS: Tuberculosis was listed
      on 635 death certificates; 377 (59%) were confirmed cases based on registry data.
      Reviews of medical records were possible for 230 (89%) of the remaining 258
      patients and confirmed only two additional tuberculosis cases. Of 310 persons who
      died with active tuberculosis in 1992 (second part of the study), only 104 (34%)
      had tuberculosis listed on their death certificates. CONCLUSIONS: In New York
      City, a diagnosis of tuberculosis on death certificates is an inaccurate measure
      of tuberculosis burden.

PMID- 8643816
TI  - Mammography and pap smear use by older rural women.
AB  - OBJECTIVE: To compare the characteristics of older women who did and did not have
      screening mammograms and Pap smears during the first two years both services were
      a Medicare Part B benefit. METHODS: A prospective study was conducted in five
      rural Pennsylvania counties of 2205 female community-dwelling Medicare Part B
      beneficiaries who volunteered to participate in a Medicare prevention
      demonstration project. The baseline health risk appraisal included information on
      demographics, insurance status, disease history, symptomatology, and functional
      and cognitive status. These variables were tested for their association with the
      use of mammography and Pap smear using Medicare utilization claims data from 1991
      to 1992. RESULTS: Of 2175 women still alive after three years, 44.6% had had a
      mammogram and 14.6% had had a Pap smear in either 1991 or 1992. Multivariate
      logistic regression revealed that women were more likely to have a mammogram if
      they were younger, were more educated, had supplemental insurance, did not need
      assistance with activities of daily living, and did not have diabetes or
      arthritis. Younger, college educated, and non-widowed women were more likely to
      have Pap smears than women in other categories. CONCLUSIONS: With cost less of a
      barrier, more aggressive efforts to persuade older women to have mammograms and
      Pap smears must be developed.

PMID- 8643818
TI  - Firearm ownership and health care workers.
AB  - OBJECTIVE: Health professionals have increasingly become aware of the public
      health hazards caused by firearms. This study was designed to determine the
      firearm ownership and storage practices of a group of health care workers.
      METHODS: All 6436 nonphysician employees of a large health maintenance
      organization were surveyed as part of an ongoing effort to enhance the
      organization's effectiveness. Two questions regarding firearm ownership and
      storage practices were included in the 85-question survey instrument. A total of
      4999 surveys were returned, for a response rate of 78%. RESULTS: Forty-two
      percent of the health workers surveyed reported keeping a firearm in their home,
      and 35% of firearm owners stored that firearm loaded. Men were more likely than
      women to report having a firearm in the home. Firearm ownership and storage of a
      loaded firearm decreased with higher levels of education in both sexes. A measure
      of increased alcohol consumption was related to higher rates of firearm ownership
      and storage of loaded firearms in men. CONCLUSIONS: A substantial number of
      health care workers had firearms in their homes and did not store them safely.
      Counseling regarding the risks associated with easy access to firearms should be
      considered for inclusion in employee health programs as well as in employee
      assistance and alcohol treatment programs.

PMID- 8643819
TI  - Health care access of poverty-level older adults in subsidized public housing.
AB  - OBJECTIVE: To assess the health status, access and use of health care and unmet
      health care needs of poverty-level residents of the Seattle Housing Authority
      over the age of 62. METHODS: An in-person interview survey of a quota sample of
      community residents. RESULTS: About half of SHA residents reported problems
      accessing care and sixteen percent reported being denied care. Multivariate
      analysis showed that encountering barriers of health care use were associated
      with having insufficient funds for monthly living expenses and lack of
      transportation. Over 90% of the population knew where to seek health care, so
      knowledge about sources of care did not appear to be a barrier. SHA residents met
      or exceeded national goals for completion of six out of nine recommended exams
      and procedures. SHA residents had unmet needs for services not covered by
      Medicare or provided by visiting nurse services. CONCLUSIONS: The results suggest
      that SHA residents know how to access medical care, and that visiting nurse
      services may be remarkably effective in meeting some medical care needs of SHA
      residents. It appears access to care by residents of subsidized housing could be
      improved by addressing transportation and financial barriers, and by providing
      more services to residents on site.

PMID- 8643820
TI  - The prevalence of selected risk factors for chronic disease among American
      Indians in Washington State.
AB  - Despite great improvements in recent decades, the health status of American
      Indians continues to lag behind that of other Americans. Continued health
      improvement will depend largely on changes in individual behavior. Until
      recently, however, few data existed on health risk behaviors among American
      Indians. We conducted personal interviews among the adult population of an Indian
      Health Service Unit in Washington State to estimate the prevalence of some health
      risk behaviors. This analysis focuses on three of the many topics covered in the
      survey: tobacco use, alcohol consumption, and weight. Cigarette smoking was more
      prevalent among both men and women than it was in the general population in the
      same area with 43% of men and 54% of women among the American Indians interviewed
      reported that they currently smoked. However, they tended to smoke much less
      heavily than smokers in the general population. Smokeless tobacco use was
      concentrated among young men, with the overall prevalence similar to that found
      in the general population. Acute heavy drinking was found to be common with 40%
      of men and 33% of women reporting this behavior for the previous month. The
      prevalence of substantial overweight was 45% among men and 43% among women,
      considerably higher than in the general population. Tribal leaders and the Indian
      Health Service are using the findings to design disease prevention and health
      promotion activities. In addition to providing valuable information about the
      surveyed populations, the survey served as a pilot for similar studies of other
      American Indian groups.

PMID- 8643821
TI  - The race for life.

PMID- 8643823
TI  - FDA's proposed regulation of the sale and promotion of tobacco products to
      minors.

PMID- 8643822
TI  - Improving representation of linguistic minorities in health surveys.

PMID- 8643825
TI  - The fragmentation of 510 MeV/nucleon iron-56 in polyethylene. II. Comparisons
      between data and a model.
AB  - The results of a Monte Carlo model for calculating fragment fluences and LET
      spectra are compared to data taken with 600 MeV/nucleon iron ions incident on an
      accelerator beamline configured for irradiation of biological samples, with no
      target and with 2, 5 and 8 cm of polyethylene. The model uses a multi-generation
      nuclear fragmentation code, coupled with a formulation of ionization energy loss
      based on the Bethe-Bloch equation. In the region where the data are reliable and
      the experimental acceptance is well understood, many of the features of the
      experimental spectra are well replicated by the model. To obtain good agreement
      with the experimental data, the model must allow for at least two generations of
      fragment production in the target.

PMID- 8643826
TI  - Yields of OH in gamma-irradiated DNA as a function of DNA hydration: hole
      transfer in competition with OH formation.
AB  - In this work, we report the yields of hydroxyl radicals, as G values and
      "destruction constants," in the DNA hydration shell as a function of the level of
      hydration. Electron spin resonance spectroscopy of gamma-irradiated DNA at low
      temperatures is employed for detection of the hydroxyl radical. Due to the glassy
      nature of the DNA hydration layer at low temperature, the hydroxyl radical gives
      a broad ESR resonance which is easily distinguished from the hydroxyl radical in
      a polycrystalline ice phase; thus .OH in both glassy and ice regions is
      quantified. Three regimes of radiological behavior for waters of hydration in DNA
      are found. For the first approximately 9 waters/nucleotide (which are glassy), no
      significant amounts of .OH are found, suggesting hole transfer to DNA. The second
      regime of hydration waters comprises up to about 12 additional glassy
      waters/nucleotide (gamma = 21). In this regime, substantial amounts of glassy .OH
      are found, suggesting that only a few holes which escape recombination in spurs
      charge-transfer to the DNA. In these two glassy regimes no trapped electrons are
      found, which is in accord with previous work that has reported that all electrons
      which do not undergo recombination in spurs transfer to DNA. The third regime of
      hydration water is comprised of bulk (or bulk-like) polycrystalline ice which
      forms when levels of hydration over 21 waters/nucleotide are reached. These
      waters form a separate phase from the DNA/glassy-water system, and neither hole
      nor substantial electron transfer to the DNA occurs; .OH in this ice phase is
      observed with G values that vary slightly with the amount of water in the ice
      phase, but which are close to the values found for pure ice.

PMID- 8643824
TI  - The fragmentation of 510 MeV/nucleon iron-56 in polyethylene. I. Fragment fluence
      spectra.
AB  - The fragmentation of 510 MeV/nucleon iron ions in several thicknesses of
      polyethylene has been measured. Non-interacting primary beam particles and
      fragments have been identified and their LETs calculated by measuring ionization
      energy loss in a stack of silicon detectors. Fluences, normalized to the incident
      beam intensity and corrected for detector effects, are presented for each
      fragment charge and target. Histograms of fluence as a function of LET are also
      presented. Some implications of these data for measurements of the biological
      effects of heavy ions are discussed.

PMID- 8643827
TI  - Characterization of radiation-induced thymine-tyrosine crosslinks by electrospray
      ionization mass spectrometry.
AB  - Exposure to ionizing radiation leads to formation of covalent crosslinks between
      DNA and proteins. The nature, extent and site of the modifications are not well
      understood due to the difficulty in assessing free radical-induced damage in
      biopolymers. Electrospray ionization mass spectrometry (ESI-MS) permits direct
      analyses of intact oligopeptides, permitting characterization of the radiation
      induced DNA-protein covalently crosslinked constituents. Our first application of
      this methodology to free radical-induced damage was in a model system where
      angiotensin, a small 10-amino acid peptide, is irradiated at various doses in the
      presence of excess thymine. The relative yield of crosslinks, which ranged from
      0.1 to 15%, was linearly related to radiation dose for doses from 0.1 to 100 Gy.
      Detection of thymine-tyrosine moieties in this model system was possible at doses
      as low as 0.1 Gy with a signal-to-noise ratio of 4 to 1. ESI-MS revealed that the
      site of crosslink was located exclusively on the tyrosine residue as expected.

PMID- 8643828
TI  - Effects of gamma rays in the 0.5-50-cGy range on the conformation of chromatin in
      mammalian cells.
AB  - The effects of 137Cs gamma-ray quanta in mammalian cells were studied using the
      method of anomalous viscosity time dependence (AVTD). Several different cell
      types were exposed: VH-10 human fibroblasts, BALB/c mouse splenocytes and Sprague
      Dawley rat thymocytes. The cells were irradiated with doses of 0.1-50 cGy and
      then lysed for viscosity measurements. It was established for all types of cells
      that exposure to a dose of 0.5 cGy resulted in a statistically significant
      reduction in viscosity peaks. This reduction reached a maximum value
      approximately 40-60 min after irradiation. The reduction of viscosity was
      revealed at doses up to 4 cGy for human fibroblasts with the maximum effect
      observed at about 2 cGy. The opposite response, an increase in viscosity, was
      observed after exposing the cells to 10-50 cGy. From the linear approximation of
      this dose dependence, the increase in viscosity started at doses above 4 cGy. The
      effect of increased viscosity disappeared with time after irradiation, with
      kinetics similar to that of DNA repair. Repair of this effect of AVTD depended
      strongly on temperature in the 0-37 degrees C range. In contrast, the kinetics of
      the effect of 0.5 cGy did not depend on temperature. Thus two different responses
      of chromatin were observed in mammalian cells after low (<4 cGy) and high (>4
      cGy) doses of radiation. The specific inhibitor of DNA topoisomerase II,
      etoposide, was shown to increase the peaks of AVTD significantly. These data
      provide further evidence that the effects of AVTD correlate with changes in
      chromatin conformation.

PMID- 8643829
TI  - Breast cancer mortality between 1950 and 1987 after exposure to fractionated
      moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study
      and a comparison with breast cancer mortality in the atomic bomb survivors study.
AB  - The relationship between exposure to low-linear energy transfer ionizing
      radiation and subsequent breast cancer mortality risk is reported based on a
      further 7 years of follow-up in the Canadian fluoroscopy study. Amongst 31,917
      women first treated for tuberculosis in a Canadian institution between 1930 and
      1952, a total of 688 breast cancer deaths were observed between 1950 and 1987.
      There is a strong linear trend of increasing risk with increasing dose (P <
      0.0001), with the excess relative risk per sievert decreasing with age at
      exposure (P = 0.0003). The excess relative risk is approximately constant between
      5 and 39 years after exposure, with a suggestion of a decrease between 40 and 57
      years after exposure, though this could be a chance effect (P = 0.22). Combined
      analyses of the Canadian fluoroscopy data and the data for the atomic bomb
      survivors with respect to breast cancer mortality are also reported. In general
      the two studies are reasonably consistent, the only distinct difference being the
      much greater excess relative risk per sievert amongst women exposed to very high
      doses in the province of Nova Scotia (P, heterogeneity <0.0001). Based on the
      combined data sets a simple relative risk (RR) model for the effect of a dose of
      D sieverts at age A years is developed: RR(D) = 1.0 + 0.52D exp[-0.10(A-15)].
      This model fits the combined data well, and is used to predict excess lifetime
      risks of breast cancer mortality after radiation exposure from routine annual
      mammography.

PMID- 8643830
TI  - Susceptibility of fetal, virgin, pregnant and lactating rats for the induction of
      mammary tumors by gamma rays.
AB  - Pregnant Wistar-MS rats received a whole-body irradiation of 0-2.6 Gy gamma rays
      at day 20 of pregnancy. The mother rats were implanted with a diethylstilbestrol
      (DES) pellet 30 days after weaning, and the female pups delivered by the
      irradiated mother were treated with DES after maturation. Lactating rats were
      irradiated with gamma rays 21 days after parturition and then treated with DES.
      Virgin rats 70 days of age were also irradiated and then administered DES. The
      rats which received intrauterine irradiation did not develop mammary tumors at
      doses less than 2.1 Gy and showed a low incidence of tumors at 2.6 Gy. In virgin
      rats, the maximum tumor incidence was obtained with 1 Gy. The incidence of total
      mammary tumors in the mother rats and lactating rats increased in a dose
      dependent manner with increasing doses of gamma rays up to 2.1 Gy. With 0.1-1 Gy,
      the incidence of adenocarcinoma in the mother rats was significantly lower than
      that observed in the lactating rats. However, the incidence in the mother rats
      irradiated with 1.0-1.5 Gy was significantly higher than that of virgin rats
      treated with the corresponding gamma-ray doses. These findings suggest that the
      susceptibility of the mammary glands to radiation depends upon the
      differentiation at the time of exposure.

PMID- 8643831
TI  - Expression of lethal mutations is suppressed in neoplastically transformed cells
      and after treatment of normal cells with carcinogens.
AB  - Recent evidence from our laboratory suggests that the fraction of cells with
      lethal mutations is lost from the population by apoptosis. The relationship of
      this process to genetic instability and carcinogenesis is unclear. To examine
      this, tumorigenic cell populations derived from spontaneously occurring,
      neoplastically transformed C3H 1OT1/2 foci and from radiation-induced foci were
      compared with wild-type C3H 10T1/2 cell populations to determine the frequency of
      induction of lethal mutations postirradiation. Lethal mutations did not occur in
      the progeny of cells from type 3 foci derived from cultures of spontaneously
      occurring or radiation-induced neoplastically transformed cells but were very
      frequent in the progeny of irradiated wild-type cells. Normal human cells (HPV
      immortalized human keratinocytes and primary human normal uroepithelium) were
      then treated with carcinogens or transfected with the Ha-ras oncogene to see if
      these carcinogenic events affected the yield of lethal mutations postirradiation.
      In each case, cells which were exposed to a carcinogenic agent had reduced
      numbers of lethal mutations, elevated levels of stable p53 and Bcl-2 proteins and
      reduced evidence of apoptosis. It is suggested that lethal mutations may
      represent an active safety mechanism which may deal with radiation-induced
      genomic instability and which is disabled early in carcinogenesis.

PMID- 8643832
TI  - Radiosensitive target in the mouse embryo chimera assay: implications that the
      target involves autocrine growth factor function.
AB  - Mouse preimplantation embryos express at least two functional cell surface growth
      factor receptors that are radiosensitive in other cell types, the epidermal
      growth factor receptor (EGF receptor) and the insulin-like growth factor I
      receptor (IGF-I receptor). These embryos also express ligands that bind to and
      activate these receptors, including transforming growth factor alpha (TGF-alpha)
      and insulin-like growth factor II (IGF-II), which bind to the EGF receptor and
      IGF-I receptor, respectively. Embryo-expressed IGF-II and TGF-alpha increase
      embryo cell number--a measure of proliferation rate--and stimulate blastocoele
      formation--a measure of cell differentiation--allowing the embryo to self
      modulate cell proliferation and morphogenesis into a blastocyst (Paria and Dey,
      Proc. Natl. Acad. Sci. USA 87, 4756-4760, 1990; Dardik and Schultz, Development
      113, 919-930, 1991; Rappolee et al., Genes Dev. 6, 939-952, 1992). In this work,
      we tested the hypothesis that IGF-I receptor and/or EGF receptor function may be
      impaired to produce the radiation-induced competitive cell proliferation
      disadvantage that is expressed by irradiated embryos that are aggregated with
      nonirradiated embryos in chimeras. Cleavage-stage embryos were irradiated with
      137Cs gamma rays (0.5 or 1.0 Gy) and paired with nonirradiated same-stage embryos
      to form groups of chimeras that were cultured in control medium or medium
      containing IGF-II, insulin, EGF or TGF-alpha. The cell proliferation disadvantage
      expressed by the irradiated embryos within chimeras was completely eliminated by
      IGF-II or insulin. In contrast to the rescue action of IGF-II or insulin in
      chimeras, neither EGF nor TGF-alpha could prevent the cell proliferation
      disadvantage exhibited by irradiated embryos paired with nonirradiated embryos in
      chimeras. For irradiated conventionally cultured zona-enclosed embryos, IGF-II
      and TGF-alpha did not increase mean embryo cell number significantly, although
      both IGF-II and TGF-alpha did increase blastocoele formation significantly.
      Collectively, these results support the following conclusions: (1) Ligands for
      the IGF-I receptor can rescue irradiated embryos from competitive cell
      proliferation disadvantage in chimeras, while ligands for the EGF receptor
      cannot; (2) IGF-I receptor function and EGF receptor function are affected
      differently by ionizing radiation with respect to competitive cell proliferation
      and are affected similarly by ionizing radiation with respect to blastocoele
      formation; (3) EGF receptor-dependent stimulation of competitive cell
      proliferation and cell differentiation are affected differently by ionizing
      radiation in preimplantation embryos.

PMID- 8643833
TI  - Chromosome aberrations in human fibroblasts induced by monoenergetic neutrons. I.
      Relative biological effectiveness.
AB  - The relative biological effectiveness (RBE) of neutrons for many biological end
      points varies with neutron energy. To test the hypothesis that the RBE of
      neutrons varies with respect to their energy for chromosome aberrations in a cell
      system that does not face interphase death, we studied the yield of chromosome
      aberrations induced by monoenergetic neutrons in normal human fibroblasts at the
      first mitosis postirradiation. Monoenergetic neutrons at 0.22, 0.34, 0.43, 1, 5.9
      and 13.6 MeV were generated at the Accelerator Facility of the Center for
      Radiological Research, Columbia University, and were used to irradiate plateau
      phase fibroblasts at low absorbed doses from 0.3 to 1.2 Gy at a low dose rate.
      The reference low-LET, low-dose-rate radiation was 137Cs-gamma rays (0.66 MeV). A
      linear dose response (Y = alphaD) for chromosome aberrations was obtained for all
      monoenergetic neutrons and for the gamma rays. The yield of chromosome
      aberrations per unit dose was high at low neutron energies (0.22, 0.34 and 0.43
      MeV) with a gradual decline with the increase in neutron energy. Maximum RBE
      (RBEm) values varied for the different types of chromosome aberrations. The
      highest RBE (24.3) for 0.22 and 0.43 MeV neutrons was observed for
      intrachromosomal deletions, a category of chromosomal change common in solid
      tumors. Even for the 13.6 MeV neutrons the RBEm (11.1) exceeded 10. These results
      show that the RBE of neutrons varies with neutron energy and that RBEs are
      dissimilar between different types of asymmetric chromosome aberrations and
      suggest that the radiation weighting factors applicable to low-energy neutrons
      need firmer delineation. This latter may best be attained with neutrons of well
      defined energies. This would enable integrations of appropriate quality factors
      with measured radiation fields, such as those in high-altitude Earth atmosphere.
      The introduction of commercial flights at high altitude could result in many more
      individuals being exposed to neutrons than occurs in terrestrial workers,
      emphasizing the necessity for better-defined estimates of risk.

PMID- 8643835
TI  - Heat-induced modifications in the association of specific proteins with the
      nuclear matrix.
AB  - Nuclei isolated from heat-shocked mammalian cells have an increased protein
      content which reflects an enhanced protein binding to nuclear structures. These
      nuclear changes are correlated with cell survival and inhibition of DNA
      replication, transcription and repair of DNA damage. It appears that most of the
      altered protein binding occurs in association with the nuclear matrix. The
      present study was conducted to determine if measurements of specific proteins in
      isolated nuclei reflect changes that occur at the nuclear matrix. The amounts of
      various proteins associated with HeLa cell nuclei and nuclear matrices after heat
      shock were measured by (1) densitometric scans of Coomassie blue-stained gels,
      (2) immunoblotting with antibodies to nuclear proteins and (3) antisera raised
      against nuclear matrix proteins from heated cells. These measurements revealed
      heat-induced increases in the levels of many nuclear matrix proteins. While a
      number of proteins show similar changes in both nuclei and nuclear matrices, for
      many the extent of increased association with the nuclear matrix is not reflected
      in the measured changes in the nuclei. These results are essential for
      understanding and studying further the relationships between the cellular
      response to hyperthermia and heat-altered associations of specific proteins with
      either nuclei or nuclear matrices.

PMID- 8643834
TI  - Changes in clonogen number and radiation sensitivity in mouse jejunal crypts
      after treatment with dimethylsulfoxide and retinoic acid.
AB  - Retinoic acid (RA) and the drug carrier dimethylsulfoxide (DMSO) have been shown
      to reduce cellular radiation sensitivity in vitro because of their hydroxyl
      radical scavenging properties. Both agents have also been shown to induce
      differentiation in vitro and in vivo. As intestinal crypts are multicellular
      systems, crypt survival after irradiation depends not only on the cellular
      sensitivity of the clonogenic cells, but also on the number of clonogenic cells
      in each crypt, which may be changed by treatments with agents which induce
      differentiation. In the present experiments we examined the effects of DMSO and
      RA on the radiosensitivity of mouse jejunal crypts in vivo using the microcolony
      assay. Mice were treated with five daily intraperitoneal doses of 0-500 microgram
      RA in 0.1 ml DMSO per mouse, the last dose applied 4 h before the start of
      irradiation. The results showed a clear protection by 100 and 500 micrograms/day
      RA in 0.1 ml DMSO for crypt survival over the dose range of 9-16 Gy. The D0 was
      increased from 1.30 Gy for untreated controls to 1.59 Gy after treatment with
      DMSO alone, and to 1.85 Gy after treatment with 100 micrograms/day RA in DMSO.
      Split-dose experiments showed a reduction in the number of clonogens by a factor
      of about 2 from DMSO treatment alone, with no additional effect of RA on the
      number of clonogens. Despite this reduction, the number of BrdUrd-labeled cells
      per crypt remained roughly the same, as did the count of cells per longitudinal
      villus section. We conclude that, in addition to the protective effects of RA in
      DMSO, there is induced differentiation of crypt clonogens which is counteracted
      by increased proliferative activity of transit cells with the result that villus
      cellularity is maintained.

PMID- 8643836
TI  - Nutritional support for adaptation to radiation-induced suppression of mucosal
      immunity in the intestine of the rat.
AB  - Appropriate enteral nutrition provided immediately after injury or trauma to the
      gastrointestinal tract may limit or reverse damage to the mucosal barrier. In
      this regard, diets containing amino acids, such as arginine and glutamine, or
      fish oil have been identified as beneficial. This report assesses the role of
      amino acids as "essential nutrients" in the repair of intestinal mucosa damaged
      by gamma radiation. Rats were used experimentally to test the hypothesis that the
      recovery of the immune responses in the intestinal mucosa, which are suppressed
      by radiation, can be improved by feeding an elemental amino acid diet, referred
      to hereafter as the diet, immediately after irradiation. The objective was to
      assess the impact of the diet on the expression of type I hypersensitivity or
      anaphylaxis in the jejunal mucosa. The local expression of this immunological
      response, which involves several radiosensitive cell types, was studied in rats
      immunized by oral infection with the nematode parasite, Trichinella spiralis.
      Rats that recover from infection become immunized and their small intestine
      undergoes anaphylaxis when subsequently challenged with parasite-derived antigen.
      This hypersensitivity response is expressed, in part, as Cl- secretion and can be
      observed in vitro or in vivo. When challenge is provided by a secondary inoculum
      of infective T. spiralis larvae, Cl- secretion is accompanied by fluid secretion
      and by the rapid expulsion of the parasite from the intestine. Immunized rats
      maintained on a stock diet and exposed to 7 Gy of total-abdominal irradiation
      from a cobalt-60 gamma-ray source failed to express antigen-induced Cl- secretion
      fully for up to 14 days postirradiation, and rejection of the parasite was
      suppressed for at least 30 days postirradiation. The suppression of immune
      responsiveness is associated with the disappearance of intestinal mucosal mast
      cells, which normally trigger the anaphylactic response. When rats are maintained
      on the diet after irradiation, the capacity to reject the parasite remains
      suppressed. However, the ability to express anaphylaxis-mediated Cl- secretion
      returns by 3 days postirradiation. The quick, diet-supported recovery of antigen
      induced Cl- secretion occurs despite the continued absence of mast cells.
      Although the recovery of anaphylaxis-mediated responses suppressed by irradiation
      is only partial, our experimental results underscore the potential for enhancing
      the recovery process through nutritional support.

PMID- 8643837
TI  - Early and persistent alterations in the expression of interleukin-1 alpha,
      interleukin-1 beta and tumor necrosis factor alpha mRNA levels in fibrosis
      resistant and sensitive mice after thoracic irradiation.
AB  - Fibrosis, characterized by the accumulation of collagen, is a consequence of a
      chronic inflammatory response. The purpose of this study was to determine if
      tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and IL
      1 beta mRNA expression are altered acutely after irradiation, during the so
      called "latent" phase of pulmonary injury, and to examine if these alterations
      persist through the development of pneumonitis and fibrosis. Further, we wished
      to determine if these changes differ between two strains of mice which vary in
      their sensitivity to radiation. Fibrosis-sensitive (C57BL/6) and fibrosis
      resistant (C3H/HeJ) mice were irradiated with a single dose of 5 or 12.5 Gy to
      the thorax. Total lung RNA was prepared and immobilized by slot blotting and
      hybridized with radiolabeled cDNA probes encoding for TNF-alpha, IL-1 alpha and
      IL-1 beta. Autoradiographic data were quantified by video densitometry and
      results normalized to a control probe encoding for glyceraldehyde-3-phosphate
      dehydrogenase. It was found that TNF-alpha mRNA levels were increased in C57BL/6
      mice at days 1 and 7 postirradiation after 5 Gy and day 14 postirradiation after
      both 5 and 12.5 Gy, and IL-1 alpha mRNA levels were increased in C57BL/6 mice at
      days 56, 112 and 182 postirradiation after both 5 and 12.5 Gy, and IL-1 beta mRNA
      levels in the C3H/HeJ mice were increased at days 56 and 182 postirradiation
      after 12.5 Gy. In summary, these studies demonstrated early and persistent
      alterations in TNF-alpha, IL-1 alpha and IL-1 beta mRNA levels even at the lower
      dose (5 Gy). The temporal relationship between the elevation of these cytokines
      and the strain-dependent variation in fibrosis response suggests that IL-1 alpha
      and TNF-alpha contribute to the radiation-induced component of pulmonary
      fibrosis, whereas IL-1 beta may have a protective function.

PMID- 8643838
TI  - Exposure to ultraviolet B radiation increases the tolerance of mouse skin to
      daily X irradiation.
AB  - Based on the hypothesis that acceleration of repopulation in skin during
      fractionated irradiation is triggered by an inflammatory response of the dermis
      to radiation-induced epidermal hypoplasia, we produced a mild erythema by
      exposure to UVB radiation before applying different X-irradiation schedules. At
      different times ranging from 6 h to 14 days after a single exposure to UVB
      radiation which caused a distinct erythema, a 2-cm skin field on the legs of mice
      was irradiated with either different single doses or five daily fractions of 3 Gy
      followed by different single top-up doses of 300 kV X rays. Skin reactions were
      scored daily for 4 weeks and the occurrence of moist desquamation was taken to
      construct dose-response curves and to calculate ED50 values. Five days after
      exposure to UVB radiation and later, radioresistance of epidermis to single and
      fractionated X irradiation was significantly increased. Results were analyzed
      using the linear-quadratic formalism to identify possible mechanisms for this UV
      radiation-induced radioresistance. The data suggest that exposure to UVB
      radiation led to a gradual increase in the number of epidermal stem cells and
      their repopulation rate.

PMID- 8643839
TI  - Polyamine-induced compaction and aggregation of DNA--a major factor in
      radioprotection of chromatin under physiological conditions.
AB  - Spermine at physiological levels and ionic strength induces compaction and
      aggregation of SV40 DNA and minichromosomes resulting in marked radioprotection
      of the DNA against gamma-ray-induced formation of single-strand breaks. This
      phenomenon, termed the PICA effect, results in yields of single-strand breaks in
      DNA and minichromosomes comparable to those found with intact cells and is
      considered to be a major mechanism responsible for radioprotection of cellular
      DNA.

PMID- 8643840
TI  - [Clinical medicine and echography].

PMID- 8643841
TI  - [Magnetic resonance in primary bone tumors: a review of 10 years of activities].
AB  - All the MR exams of primary bone tumors performed during ten years were reviewed
      by three different radiologists. In all, 484 exams in 220 patients were
      considered--namely, 160 exams (33.1%) for staging purposes, 219 (45.2%) during
      therapy and 105 (21.7%) performed more than 8 months after the last treatment.
      Its well-known accuracy in the assessment of intra/extraosseous spread confirms
      the major role of MRI in the staging of primary bone tumors. During treatment,
      the overall accuracy of this method decreased to 88.8% because of the presence of
      therapy-induced tissue changes. MRI was 95.2% reliable in the detection of
      persistent disease or relapse in the exams performed long after therapy.
      Conventional radiology is still the method of choice in the study of primary bone
      tumors at presentation as it detects the lesion, differentiates malignant tumors
      and usually suggests the possible histotype. Nevertheless, MRI seems to be needed
      to depict actual tumor extent and to find the correct therapeutic approach. In
      the follow-up, MRI is the best single method to assess the response to therapy
      and to detect tumor persistence.

PMID- 8643842
TI  - [Magnetic resonance in the study of the painful shoulder. The surgical comparison
      in 30 consecutive cases].
AB  - Eighty patients complaining of shoulder pain were examined with MRI from January,
      1993, through December, 1994. Thirty of them were submitted to surgery, with an
      exhaustive inspection of shoulder structures and the treatment of abnormal
      findings. In this subgroup of surgical patients, MRI had depicted 16 complete
      tears of the rotator cuff, 4 partial tears, 8 cases of subacromial impingement, I
      humeral head osteochondritis and, finally, I humeral head osteochondritis with
      complete rotator cuff tear. Surgical findings confirmed MR diagnosis in 97% of
      cases. MR findings were then compared with literature data and some atypical
      features were observed in our series. MRI was totally reliable in complete cuff
      tears (16/30 patients), always showing the involvement of supraspinatus tendons
      and, in some cases, of other cuff tendons. In partial cuff tears (4/30 patients),
      besides the classic pattern of a fissure in the deep/superficial supraspinatus
      tendon, we observed intra- and peritendinous changes, with no tendon
      interruption, due to diffuse microlesions. When impingement due to subacromial
      space narrowing, with no cuff tear, was present (8/30 patients), MRI depicted
      different causes--e.g., acromioclavear arthrosis, coracoacromial ligament
      hypertrophy and posttraumatic changes. MRI showed tendinosis in all patients but
      overestimated it in one case where partial cuff tear was not confirmed surgically
      -the only false positive in our series. At surgery, all these cases were
      classified as stage I-II impingement (according to Neer's classification).
      Finally, MRI was very reliable in the study of bone conditions (osteochondritis),
      both isolated and associated with cuff tears. The diagnostic accuracy of MRI in
      the study of the painful shoulder was very high (97%), in agreement with
      literature data. This is very important because many different causes of shoulder
      conditions (abnormal tendons, bones and mechanics) may present with similar
      clinical symptoms. MRI appears as the only imaging method yielding complete and
      accurate pieces of information in the patients with a painful shoulder.

PMID- 8643843
TI  - [The combined diagnosis of male breast lesions: a review of a series of 748
      consecutive cases].
AB  - The authors reviewed a series of 748 consecutive male patients referred for
      breast screening; their average age was 50.5 years. A malignant lesion was
      detected in 20 patients (18 infiltrating ductal carcinomas, 1 intraductal
      carcinoma and 1 myxosarcoma). Of 18 infiltrating carcinomas, 17 were found in
      patients over 60 years of age; pT classes were pT1c in 13 patients, pT2 in 2,
      pT4b in 1, pT4d in 1 and pTx in one patient. Biopsy demonstrated 92 benign
      lesions (74 gynecomastia cases and 18 other lesions), whereas 636 lesions were
      considered benign at direct or cancer registry follow-up. Sensitivity was 85% for
      palpation, 88.8% for mammography, 93.7% for cytology and 100% for US. Specificity
      was 95.3%, 94%, 95.6% and 97.9%, respectively. Combined palpation and mammography
      had 100% sensitivity. Sixty-five of 92 benign lesions were submitted to biopsy,
      even in the absence of suspicion, for psychological/cosmetic reasons. Negative
      cytology spared unnecessary biopsy in 9 cases, which were fairly suspicious at
      other exams. To conclude, we confirm the role of this multimodality clinical
      instrumental diagnostic approach, with a special emphasis on the role of US.
      Cytology was as useful to avoid unnecessary open biopsy in men as it is in women.
      Male breast cancer has the same semiology as female breast cancer, though with a
      prevalence of opacities with blurred outline and in the absence of scirrhous
      stellate patterns. The diagnostic protocol we used to diagnose breast cancer in
      women seems to be fully indicated also in men.

PMID- 8643844
TI  - [Lobular carcinoma in situ: the mammographic aspects and the therapeutic
      problems].
AB  - Lobular carcinoma in situ is an uncommon noninvasive breast neoplasm; it accounts
      for about 0.8-3.8% of breast cancers and presents 3 peculiar characteristics:
      multicentricity (60-90%), bilaterality (35-59%), and the risk of invasive cancer
      (17-37%). The latter feature led some authors to consider this lesion as a marker
      of the development of an invasive cancer rather than a real malignant neoplasm.
      The main problem after histologic diagnosis is the choice of treatment: follow-up
      or surgery? Some authors reported, in the patients with lobular carcinoma in
      situ, the same incidence of ipsilateral invasive carcinoma as that in the normal
      population, which suggests a "wait and see" policy. This study, carried out on 27
      patients (mean age: 49 years) with histologic diagnosis of lobular carcinoma in
      situ yielded the following aspecific mammographic findings: clustered
      microcalcifications; stellate masses and irregular nodular lesions with or
      without calcifications; architectural distortion with calcifications. In 10
      surgical patients, 2 ductal carcinomas were demonstrated near the lobular
      carcinoma in situ. In the 17 patients submitted to follow-up, lobular carcinoma
      in situ recurrences were found in 4 patients at biopsy; a comedocarcinoma
      associated with a metastatic axillary node was found in one patient. Thus, we
      conclude that, in the patients with lobular carcinoma in situ, a "wait and see"
      policy of close observation should be adopted.

PMID- 8643845
TI  - [The measurement parameters in dental radiography: a comparison between
      traditional and digital technics].
AB  - Digital and conventional techniques for dental, panoramic and intraoral
      radiography, were compared to assess measurement accuracy. The study was carried
      out on two plastic models of maxillary and mandibular arches, each containing 14
      teeth extracted and positioned in their anatomical site. The teeth were prepared
      by opening the pulpal cavity and inserting endodontic wires within the canals.
      Intraoral x-ray images were taken with long-cone technique using a commercial
      high-resolution film and with a charge coupled device (CCD) sensor
      (radiovisiography). The models were then submitted to panoramic tomography with
      photostimulable phosphor plates. The length of the canals was measured on each
      image and compared to the length of the inserted wires. For the digital pictures,
      the measurement was performed directly on the monitor with the aid of electronic
      calipers. Magnification averages 3.40%, 9.47% and 14.11% for anterior teeth in
      intraoral radiography, in radiovisiography and panoramic radiography,
      respectively. The results demonstrate the presence of some degree of
      magnification for every radiographic procedure. This effect becomes statistically
      significant for both radiovisiography and digital panoramic techniques,
      especially in the latter. In spite of their well-known practical and dosimetric
      advantages, digital techniques in dental radiology must be used carefully
      whenever a reliable measurement is required.

PMID- 8643846
TI  - [Pneumocystis carinii lung infections in AIDS patients: a study with high
      resolution computed tomography (HRCT)].
AB  - In 1993, a hundred and fifty AIDS patients were submitted to high-resolution CT
      (HRCT). In 102 patients, bronchoalveolar lavage and/or transbronchial biopsy
      findings suggested the diagnosis of Pneumocystis carinii pneumonia--a pure
      Pneumocystis carinii infection in 75 patients and associated with other
      pathogenic agents in 27. We report the most common HRCT patterns, such as ground
      glass opacities, cysts, interstitial changes and nodules. Ground-glass opacities
      were demonstrated in 57.8% of cases, cysts in 44.1%, interstitial involvement in
      52.9% and nodules in 28.4%. HRCT permitted lung disease to be demonstrated in 55%
      of our patients, suffering from impaired breathing, with negative chest films.
      Respiratory function tests and gallium scintigraphy show their low specificity in
      the diagnosis of Pneumocystis carinii infection because, although depicting
      diffuse interstitial involvement, they fail to detect the pathogenic agent. As
      for hemogasanalysis, in the presence of hypoxia, this technique can suggest the
      diagnosis of Pneumocystis carinii infection, while the pathogenic agent can be
      isolated with bronchoalveolar lavage, which demonstrates the simultaneous
      decrease in CD4 and increase in CD8 lymphocytes, respectively. To conclude, HRCT
      does detect the basic changes occurring in Pneumocystis carinii pneumonia, thus
      contributing to the diagnosis of this condition.

PMID- 8643847
TI  - [Invasive aspergillosis in the hematologic patient: the usefulness of computed
      tomographic and high-resolution computed tomographic studies].
AB  - Invasive aspergillosis is an emerging cause of death in hematologic patients.
      Several patterns of lung involvement are described: acute tracheobronchitis,
      bronchopneumonia, pleural aspergillosis and angioinvasive aspergillosis. The
      latter pattern is the most common one; it is characterized by different signs,
      some of which, supported by clinical data, are quite suggestive for fungal
      etiology. Particularly, nodules and/or wedge-shaped lesions with a ground-glass
      halo are a useful early feature, best detected by HRCT. Early therapy with
      amphotericin B may improve survival chances. Therefore, in neutropenia patients
      we decided, when possible, to perform high-resolution computed tomography (HRCT)
      as soon as fever appears. This was feasible in 8 of 32 patients with invasive
      aspergillosis examined with HRCT. Immediate treatment with amphotericin B in one
      such patient showing a nodule with the halo sign allowed the lesion to completely
      disappear. The authors describe the frequency of different radiologic signs in 32
      patients, as observed in 54 HRCT exams; the results are compared with those
      obtained with conventional CT and chest X-ray. Compared to chest X-ray, CT
      detects more lesions and is more sensitive to small pneumothorax and minimal
      pleural effusion or thickening. HRCT is more suitable to detect initial
      cavitation and thin ground-glass haloes.

PMID- 8643848
TI  - [Lung transplantation: the physiopathological considerations and imaging
      diagnosis problems].
AB  - In the last years, lung transplantation has become a widely accepted treatment
      for the patients suffering from end-stage chronic lung disease. This study was
      aimed at investigating the role of diagnostic imaging techniques before and after
      lung transplantation, in the light of the physiopathological changes occurring in
      transplanted lungs. Our study included 4 patients (3 men and 1 woman, age range:
      33-58 years): 3 of them underwent single lung transplantation and one double lung
      transplantation. All the operations were successful. Chest radiographs and HRCT
      showed the main early and late complications that occurred after transplantation.
      In the early postoperative period, the reperfusion syndrome was observed in 2
      patients and acute rejection in the 3 patients submitted to single lung
      transplantation. In the late postoperative period, chronic rejection occurred in
      the patient submitted to left lung transplantation. None of our patients
      presented any infection or such airway complications as bronchial dehiscence or
      strictures. Both literature data and our personal experience show that
      preoperative diagnostic imaging allows the assessment of lung conditions, which
      helps choose the better side for transplantation. Moreover, lung size must be
      studied to match the donor's lung to the recipient's chest. In the postoperative
      period, both early and late complications must be investigated, all of them
      characterized by aspecific radiologic findings. Currently, time plays a major
      diagnostic role but we hope that more accurate interpretation of radiologic
      findings will improve the clinical assessment of lung transplant recipients.

PMID- 8643850
TI  - [Magnetic resonance with fat-saturation sequences in studying the upper abdomen:
      the normal semeiological aspects].
AB  - The fat-saturation (FAT-SAT) MR technique decreases the signal intensity of fat
      in tissues, though yielding the T1, T2 and proton-density (PD) information
      available on spin-echo (SE) sequences. To investigate the potentials of FAT-SAT
      sequences in MRI of the upper abdomen, the authors carried out a prospective
      study including 129 subjects, namely 12 normal volunteers and 117 patients with
      different abdominal conditions. The patients were submitted to T1-weighted SE
      sequences (TR 500-600 ms, TE 15 ms), T2W SE (TR 1600-1730 ms, TE 80 ms) and PD SE
      (TR 1600-1730 ms, TE 20 ms). The images obtained with and without fat suppression
      were compared both qualitatively and quantitatively, with a special emphasis on
      the normal anatomy of the upper abdomen: we investigated the efficacy of
      subcutaneous and retroperitoneal fat suppression (116/129 cases, 90%), the
      reduction in respiratory and chemical shift artifacts (112/129 cases, 87%) and
      the better visualization of parenchyma (119/129 cases, 93%) and of other
      abdominal structures. Concerning the quantitative study, we calculated the signal
      to-noise ratio (S/N) for liver, spleen, pancreas, adrenal glands, renal cortex
      and medulla, the improvement of contrast in these organs after retroperitoneal
      fat suppression (conspicuity) and the increase in contrast between organs
      (dynamic range). The statistical analysis showed significant differences between
      the sequences with and those without fat suppression. Correlations were found
      between observers' and quantitative evaluations, suggesting that the better yield
      of FAT-SAT sequences is probably due to three factors: 1) retroperitoneal and
      subcutaneous fat suppression; 2) increase in S/N ratio for pancreas and renal
      cortex on T1W images; 3) reduction in the dynamic range of signal intensity,
      which increases contrast between pancreas, adrenal glands and renal cortex
      relative to adjacent structures, especially on T2W or PD sequences. The results
      of this study suggest that FAT-SAT sequences are useful because fat suppression
      increases contrast and improves image quality, reducing respiratory and chemical
      shift artifacts.

PMID- 8643849
TI  - [Anatomico-functional correlations between the pulmonary and portal circulations:
      the prerequisites for a modern functional imaging diagnosis].
AB  - This study was aimed at investigating the current knowledge on the similarities
      between pulmonary and portal circulation to try to improve the diagnostic
      capabilities of functional radiology in these two districts. These two organs are
      similar both from an anatomical and a functional viewpoints, sharing the same
      microarchitecture and a double vascular system with similar hemodynamic
      characteristics. In the past, the parameters to evaluate pulmonary flow and
      pressure consisted in the analysis of the distribution, diameter and number of
      vessels with conventional radiology, but today, HRCT permits the regional
      assessment of perfusion and air volume, using density values. Dynamic density
      changes (expiratory and prone scanning), together with the morphological features
      of peripheral bronchial and vascular structures, play a fundamental diagnostic
      role in differentiating small airway conditions from normal and hemodynamic
      changes. When HRCT shows a "mosaic" pattern--i.e., regions with different density
      values--reduced perfusion can be distinguished, because in this case hypodense
      areas are vascularized by fewer, and smaller, vessels. Expiratory scanning can
      exclude abnormal ventilation. Hyperperfusion is characterized by higher density
      areas vascularized by more, and bigger, vessels. Doppler US and MRA show, once
      again, their limitations in calculating the absolute values of flow velocity and
      flow volume in the splanchnic district; in clinical studies, only the
      semiquantitative data yielded by Doppler US are considered reliable. Therefore,
      also in this district, relative data must be preferred to absolute ones; for
      instance, it is interesting to analyze the hemodynamic changes occurring in
      patients under different physiologic or experimental conditions. We believe that,
      in the near future, technological progress and growing operators' skills will
      make functional radiology a major tool helping the clinician approach and treat
      these patients correctly.

PMID- 8643851
TI  - [Peripheral intrahepatic cholangiocarcinoma. The role of imaging diagnosis and
      fine-needle biopsy].
AB  - Peripheral intrahepatic cholangiocarcinoma (ICC) is a fairly uncommon type of
      cancer in Italy which may be misdiagnosed as a metastasis from extrahepatic
      adenocarcinoma. In all, 22 cases of intrahepatic cholangiocarcinoma were
      diagnosed at the Radiology Department of the University of Brescia, Italy, from
      1989 to 1994. The patients were 15 men and 7 women and their age ranged 30-77
      years. Most of them underwent US examinations because of abdominal pain, weight
      loss or a general malaise and, less frequently, for signs of cholestasis. Hepatic
      cirrhosis was found in 8 patients. US showed a single nodular lesion with
      irregular margins in 6 cases and a large nodule with adjacent smaller satellite
      nodules in 12 cases. In the other 4 subjects, an infiltrative and diffuse lesion
      with no apparent nodules was observed. US showed hypoechoic lesions in 17 cases
      and both hypo- and hyperechoic areas in the other patients. The main nodular
      lesion was 1-3 cm in diameter in 2 cases, 3-10 cm in 15 and over 10 cm in 6
      cases. Both hepatic lobes were involved in 14 patients. Twenty-one of 22 patients
      were submitted to CT and 3 to MR examinations. Both techniques confirmed US
      findings of an intrahepatic tumor but they did not help locating its origin in
      the intrahepatic biliary tract. Therefore, every patient was submitted to US
      guided fine needle biopsy which allowed the correct diagnosis to be made in 12
      cases. The remaining 10 patients had an initial diagnosis of adenocarcinoma
      metastases and only further studies of the histologic specimens, performed after
      a series of useless and negative exams (e.g., barium enema and endoscopy),
      allowed ICC to be correctly diagnosed. Since no typical pattern of this type of
      cancer can be observed with US, CT or MR examinations, we suggest that US-guided
      fine needle biopsy be used as the method of choice, which however needs a
      fruitful cooperation between the radiologist and the pathologist.

PMID- 8643852
TI  - [Lithiasis of the common bile duct: the role of cholangiography and magnetic
      resonance].
AB  - The aim of our study was to evaluate the sensitivity, specificity and diagnostic
      accuracy of Magnetic Resonance Cholangiography (MR-CP) in patients with suspected
      choledocholithiasis. Sixty-two patients (mean age: 56.3 years) previously
      submitted to US, were examined with MRCP. MR exams were performed with an 0.5 T
      superconductive magnet (Gyroscan T5-II; Philips, Medical System, Best, NL) and a
      body coil. 3D-TSE sequences (TR/TE/ETL = 5.000/244/45 ms) were acquired, with 14
      min 10 sec acquisition time. In the last 21 patients, acquisition time was
      reduced down to 3 min, by optimizing the parameters as follows: TR/TE/ETL =
      3.000/700/128 ms. The images, obtained on the coronal plane, were then
      reconstructed with the MIP algorithm. MRCP images were studied both as MIP
      reconstructions and as single slices. The diagnosis was always compared with
      endoscopic or percutaneous findings. MRCP images were of diagnostic quality in
      all cases, with 91.7% sensitivity, 100% specificity and 96.8% diagnostic
      accuracy. MRCP had 100% positive predictive value and 95% negative predictive
      value. In conclusion, this technique is extremely useful to examine the patients
      with obstructive jaundice secondary to lithiasis.

PMID- 8643854
TI  - [Induratio penis plastica: the diagnostic possibilities of gradient-echo
      sequences (magnetic resonance angiography)].
AB  - The authors investigated the diagnostic capabilities of gradient echo sequences
      (magnetic resonance angiography) in the study of induratio penis plastica. Twenty
      patients (mean age: 39 years) were examined. MRA was performed with a
      superconductive magnet (1.5 T) and a Helmoutz coil; the dynamic test with PGE (20
      40 mg) was also carried out. The images acquired on the axial and sagittal planes
      were processed according to the MIP. The FLASH 2D sequence was used with the
      following parameters: FA 18 degrees, TR 40 ms, TE ms, MA 256 x 256, slice
      thickness 5 mm. A multiple choice card was filled in by a reader with the
      following diagnostic information: identification and localization of the plaques
      and involvement by the plaques of the albuginea, corpora cavernosa, septum and
      dorsal vein; surgery was the gold standard. MRA showed 10/11 plaques ranging 8-30
      mm in diameter and missed a 5-mm plaque. Moreover, MRA depicted the infiltration
      of the albuginea in 10/10 cases, of the septum in 3/3 cases, of the dorsal vein
      in 4/4 cases and of the corpora cavernosa in 9/9 cases. Our preliminary
      experience shows that in the study of induratio penis plastica, the gradient echo
      sequence (MRA) permits better depiction of the plaques and of the infiltration of
      the corpora cavernosa, septum and albuginea.

PMID- 8643855
TI  - [AIDS-related neoplasms: a clinico-radiological study].
AB  - Although high-grade non-Hodgkin's lymphoma (NHL) and an unusually aggressive form
      of Kaposi's sarcoma (KS) remain the most common malignancies seen in AIDS
      patients, other tumors such as cervical cancer, Hodgkin's disease and others,
      have been increasingly observed, probably because these patients now live longer.
      We report the imaging findings of 80 AIDS patients with pathologically confirmed
      neoplasms from a series of 340 AIDS patients examined 1986-1994. Twenty-four of
      80 patients had NHL, 4 Hodgkin's disease, 31 KS, 4 cervical cancer, 2 leukemia, 2
      testicular, 1 larynx, 2 lung, 2 breast, 1 esophagus, 1 stomach, 1 liver, 2 kidney
      and 3 adrenal carcinomas. Twenty of 24 NHLs exhibited extranodal involvement--to
      the liver (13/24), brain (9/24), lung (7/24) and gastrointestinal tract (6/24).
      Visceral KS involved the gastrointestinal tract (6/32), lung (4/32) and liver
      (2/32). The most accredited pathogenetic theories concerning the role of HIV
      infection in oncogenesis advocate the effect of multiple growth factors produced
      by HIV-infected lymphocytes (KS) or the disregulation of B-cells caused by T-cell
      destruction (NHL). The atypical morphostructural features of AIDS-related tumors
      are discussed--e.g., atypical presentation, occurrence in younger individuals,
      aggressive clinical course and poor response to conventional therapy--together
      with the differential diagnostic problems, especially vs. opportunistic
      infections.

PMID- 8643853
TI  - [Transrectal prostatic echography in the study of hemospermia. An assessment of
      an 85-patient case load].
AB  - Eighty-five patients with hemospermia were examined with blood tests, sperm
      culture, transrectal US (TRUS) and cystourethroscopy. Blood tests and sperm
      culture demonstrated bacterial inflammation in 48 patients (56.47%). At
      cystourethroscopy, the urethra was normal or hyperemic in all patients. TRUS
      demonstrated 40 cases (47.05%) of periurethral calcifications and also with
      calcifications in the two glandular lobes. TRUS also demonstrated prostatic
      inflammation in progress or its outcome in 21 patients (24.70%), ectasia and
      seminal vesicle inflammation in 10 patients (11.76%), a prostatic tumor in 3
      patients (3.52%). No patient had cysts, stones or cancers in the seminal
      vesicles. In 11 patients (12.94%), no specific cause of hemospermia was detected,
      even though 4 of these patients (4.70%) had received anticoagulants for former
      heart ischemia. Benign prostatic hypertrophy was found in 44 patients (51.76%)
      but we did not consider it a possible cause of hemospermia because of the high
      frequency of this condition in the male population. To conclude, TRUS could
      demonstrate the cause of hemospermia in most of our patients, which makes us
      suggest it as the diagnostic technique of choice in the patients with ejaculatory
      conditions, after clinical exams and laboratory tests, because it allows to study
      the prostate, the seminal vesicles and the urethra.

PMID- 8643857
TI  - [The importance of using computed tomographic scanning in breast irradiation
      after conservative treatment].
AB  - Conservative surgery followed by radiotherapy is the current treatment of choice
      for primary breast cancer: indeed, this protocol ensures local control,
      relatively good cosmetic results and NED survival values similar to those of more
      invasive surgery. Radiotherapy requires the optimization of the irradiation
      technique to minimize the dose to the organs at risk. To this purpose, 30
      patients submitted to quadrantectomy for breast carcinoma and then to
      radiotherapy on the residual breast were examined, January through December,
      1994, at the Radiotherapy Service of the Ivrea Hospital, to investigate if CT can
      help optimize treatment planning, sparing as much of the pulmonary tissue
      underlying the residual breast as possible. Our series of patients was then
      compared with a literature series whose treatment had been planned only on the
      mapping of body outline. Some interesting considerations follow from our results:
      1) With CT, larger fields can be used than those used with the body outline, so
      that the planned target volume can be more closely approached; 2) Larger fields
      can be used because the critical organ included in the irradiation field is more
      correctly and precisely defined; 3) The comparison with the literature shows that
      in the past the fields were larger, because the target volume and the critical
      organ were more difficult to define. The use of larger fields means a higher dose
      to the lung and thus maybe a higher risk of radiation pneumonia.

PMID- 8643856
TI  - [Transcatheter embolization in 39 cases of hyperactive arteriovenous
      malformation].
AB  - Hyperdynamic arteriovenous malformations are a relevant therapeutic problem
      because of the complexity and variability of their presentation. The incidence of
      this angiodysplasia is quite low, so that only few institutions have treated more
      than a few patients, which certainly does not help treatment optimization. The
      role that transcatheter embolization has gained during the last years has
      fostered growing interest in this method, even though surgery remains the
      treatment of choice. Transcatheter embolization is a highly effective treatment,
      which can ensure long-lasting, although rarely definitive, hemodynamic results.
      The authors report their experience in 39 patients affected with hyperdynamic
      arteriovenous malformations. The total number of percutaneous embolization
      sessions was 81. In 11 patients a preoperative treatment was performed 48 hours
      before surgery. In all cases polyvinyl alcohol particles were used, whose
      diameter ranged 250-500 micron. The results, with a mean follow-up of 53 months,
      are reported. In the 11 patients who underwent combined surgery plus embolization
      treatment, conservative surgical resection was radical in 73% of cases. As for
      the other patients, the result was substantial in 46% of cases, partial in 27%
      and modest or insignificant in 27% of cases. The total incidence of major
      complications was 6.2%. Our experience confirms that transcatheter embolotherapy,
      although yielding effective long-term results, has a mostly palliative role.

PMID- 8643858
TI  - [Can the prophylactic treatment of mycotic mucositis improve the time of
      performing radiotherapy in head and neck tumors?].
AB  - Radiotherapy-related mucositis is the most frequent complication in the patients
      submitted to irradiation for head and neck cancers. Many such patients may
      develop mycotic infections which may lead to treatment discontinuation, with
      possible consequences on the local control of these cancers. In this study, we
      investigated the efficacy of fluconazole in preventing mycotic mucositis in 80
      patients undergoing radiation therapy for head and neck cancers. The patients
      were randomized to two groups: 41 patients in group A received the supporting
      treatment we usually administer, plus fluconazole (50 mg/day) starting from the
      6th irradiation session throughout the treatment; 39 patients in group B received
      the same baseline treatment, but were given the drug only when mycotic infections
      appeared. The clinical characteristics, treated sites, treatment doses and
      volumes were similar in the two groups of patients. Fluconazole was well
      tolerated and no early or late toxicity was observed. We had 1 mycotic mucositis
      and 14 non-scheduled treatment discontinuations in group A, vs. 19 and 30,
      respectively, in group B. Radiation therapy lasted 52.3 days (mean) in group A
      and 55.6 days (mean) in group B; the differences were statistically significant.
      In our experience, fluconazole, used prophylactically from the 6th radiotherapy
      session on, reduced the number of mycotic infections and improved radiotherapy
      schedule in our head and neck cancer patients.

PMID- 8643859
TI  - [The combined radiochemotherapy of inoperable esophageal neoplasms: a feasibility
      study].
AB  - January, 1994, through January, 1995, eighteen patients (17 men; median age:
      59.9, range: 32-73) with biopsy-proved squamous cell carcinoma (n = 15),
      adenocarcinoma (n = 2) or undifferentiated carcinoma (n = 1) of the esophagus
      were treated with concurrent chemo-radiotherapy. All patients had inoperable
      lesions for unresectable disease (11 patients) or concomitant illness (7
      patients); median Karnofsky score was 70 (range: 60-80). According to the 1988
      American Joint Committee on Cancer Staging system, one patient was graded as
      Stage IIA (T2N0 + oropharyngeal cancer T4N1), two Stage IIB (T2N1), twelve Stage
      III (8 T3N1, 1 T4N0, 3 T4N1) and three Stage IV (2 T3N0M1, 1 T4N0M1). Treatment
      consisted of two courses of chemotherapy by cisplatin (75 mg/m2 i.v. on days 1
      and 29) and 5-FU (1000 mg/m2/24 hours by continuous infusion from days 1 to 4 and
      from days 29 to 32) along with one course of concomitant radiotherapy at 45 Gy
      (1.8 Gy per fraction, one fraction per day and 5 fractions a week). After 15-30
      days, the patients were treated with a boost dose of 7 Gy by high-dose-rate
      intraluminal brachytherapy. All patients are assessable for toxicity and
      seventeen for response. The combined treatment was generally well tolerated, with
      only one case of WHO grade III toxicity (thrombocytopenia). Eight of the eighteen
      patients had a complete response (47%); four a partial response (24%); four a
      minimal response (24%) and one showed stable disease (5%). Only one patient
      developed local progression, and four distant metastases. All the eight patients
      with CR are alive without local recurrence (two distant metastases) with a mean
      follow-up of 6 months. This treatment regimen provides good local tumor
      resolution with no major toxicity. The value of this study protocol will be
      determined by the rate of long-term survivors.

PMID- 8643861
TI  - [A quantitative in-vitro analysis of the effects of magnetic fields and
      radiofrequencies on amino acid metabolism].
AB  - The extensive use of magnetic resonance imaging in medical diagnosis needs
      experimental confirmation of the real biological harmlessness of magnetic fields
      and radiofrequencies in the imaging process. To date, no unquestionable
      conclusions have been drawn and experimental results differ in various literature
      reports. We investigated the effects of radiofrequencies and magnetic fields on
      the amino acid content of plasma samples from 10 healthy volunteers aged 25 to 30
      years; the samples were exposed for 60 minutes to MR fields at 0.5 T with the
      sequences commonly used in clinical practice. After exposure to magnetic fields,
      the samples were analyzed with chromatography and the results compared with those
      of plasma samples not exposed to MR fields. Thirty-four different amino acids
      were investigated and no significant changes were observed in the total
      concentration of any of them. Our results show that, at least in a cell-free
      system, exposure to a magnetic field at 0.5 T causes no significant quantitative
      changes in amino acid composition, at least no changes demonstrable at
      chromatography. On the other hand, our preliminary observation does not exclude
      that exposure to nonionizing radiation may modify in vivo enzyme kinetics with
      transient qualitative, but not quantitative, changes.

PMID- 8643860
TI  - [The evaluation of the physical characteristics of a volumetric computer
      tomograph].
AB  - Spiral or volumetric computed tomography (CT) is a new scanning technique which
      allows the scanning of body regions with a continuously rotating system based on
      the slip ring technology; the patient is also moved continuously, synchronously
      with data acquisition. The physical characteristics of spiral CT image
      acquisition were compared with those of conventional CT images. The modulation
      transfer function (MTF) has the same values for medium-resolution filters, but
      lower values for spiral CT for high-resolution and frequency-enhancement filters.
      The slice sensitivity profile (SSP) describes the longitudinal image resolution
      for multiplanar reconstructions and was measured in terms of FWHM of the SSP
      curve. We obtained, for 10-mm slice thickness, a FWHM = 10.4 mm (conventional
      CT), versus 10.7 mm (Spiral CT), while, for 5-mm slice thickness, the
      corresponding values were 5.2 mm (conventional CT) and 5.5 mm (spiral CT). Noise
      was evaluated simply by measuring the standard deviation of the CT numbers, in a
      region of interest, of a uniform image and with the power spectrum or Wiener
      spectrum of the same image. To assess overall image quality and yield, the noise
      equivalent quanta (NEQ) value was also calculated. The values were a little lower
      for the spiral technique, particularly with high-resolution and enhancement or
      convolution filters. Dosimetric evaluation of the computed tomography dose index
      (CTDI) and of the multiple scan average dose (MSAD) was done using an acquisition
      protocol for average lung dose, in an anthropomorphic phantom and with TL
      dosimeters. The MSAD was 6.17 +/- 0.20 cGy for conventional CT and 5.98 +/- 0.23
      cGy for Spiral CT, while lung dose was 3.25 +/- 0.12 cGy and 3.01 +/- 0.16 cGy,
      respectively.

PMID- 8643863
TI  - [Raeder's syndrome (the paratrigeminal syndrome): its etiology related to carotid
      artery dissection. A case report].

PMID- 8643862
TI  - Pineal germinoma with cranial nerve metastasis.

PMID- 8643864
TI  - [Magnetic resonance in a case of lobular adenocarcinoma of the breast].

PMID- 8643866
TI  - [A giant unifocal biliary cystadenoma: a chance finding in a young asymptomatic
      athlete].

PMID- 8643867
TI  - [Hemobilia due to a portobiliary fistula as a complication of a fine-needle liver
      biopsy].

PMID- 8643868
TI  - [Imaging diagnosis in a case of adrenal cystic ganglioneuroblastoma in a child].

PMID- 8643865
TI  - [Rhodococcus equi lung infection in AIDS patients. A report of 4 cases].

PMID- 8643869
TI  - [An impassable iatrogenic lesion of the common bile duct at its junction: its
      recanalization via a combined percutaneous-endoscopic approach. A case].

PMID- 8643870
TI  - [Selective embolization with an adhesive fluid of complicated aneurysms of the
      hepatic artery: 3 cases].

PMID- 8643872
TI  - [Obesity in childhood and adolescence. A problem not to be underestimated].

PMID- 8643871
TI  - [Pulmonary arteriovenous fistulae and brain abscesses: a report of 2 cases
      treated by embolization and a review of the literature].

PMID- 8643873
TI  - [Vaccination against influenza in patients with rheumatoid arthritis: clinical
      and antibody response].
AB  - The question whether influenza vaccine could lead to a clinical flare in patients
      with rheumatoid arthritis (RA), and whether it could induce an effectively
      protective antibody response to the infection is still much debated. Based on
      these data, we have performed an open study in 40 patients with RA. Patients were
      divided into two groups according to their disease activity (those with RA in
      remission and those with active RA, respectively), and their clinical and serum
      antibody response was assessed following the vaccine administration in the 1991
      92 winter seasons. A group of age and sex matched, healthy controls were also
      vaccinated. Our results suggest that immunization against influenza does not
      modify the clinical picture of RA, even though some differences between the two
      groups mentioned above were noticed. In addition, side-effects or adverse
      reactions occurred with similar frequency in patients with RA and in the
      controls; as to the antibody response in patients with RA, in the majority of
      cases the immune response proved adequate to provide significant protection from
      the infection.

PMID- 8643874
TI  - [Spontaneous bacterial peritonitis in liver cirrhosis. What tests to perform on
      the ascitic fluid?].
AB  - Spontaneous bacterial perionitis (SBP) is a relatively frequent complication of
      liver cirrhosis and is associated with a high mortality if not early recognized
      and immediately treated. The text-books of Medicine available in Italy suggest
      the use of traditional laboratory tests (gravity, total protein concentration,
      Rivalta's test) to whom add white blood cell count for the assessment of the
      nature transudative (not infected) or exudative (infected) of ascitic fluid;
      nevertheless, in every day clinical practice, the association between total
      protein concentration and type of ascitic fluid may be misleading with respect to
      the diagnosis of SPB. The aim of this retrospective study, undertaken on 86
      patients with liver cirrhosis consecutively admitted and separated in two groups,
      one without and the other with PSB (white blood cell count > 500/mm3), was to
      identify criteria for diagnosis of PSB. The traditional laboratory tests were
      significantly different in the two groups but Rivalta's test. Yet, none of them
      showed a diagnostic measurement sufficient for the use in the diagnosis of PSB
      (positive predittive value: gravity 41%, Rivalta's test 36%, total protein
      concentration 40%). The results of this work show the traditional laboratory
      tests unable to define the nature of the ascitic fluid. For the diagnosis of PSB
      the only reliable parameter is the white blood cell count.

PMID- 8643876
TI  - [Is early diagnosis of amyloidosis AL possible? Consideration on a representative
      case].
AB  - A male patient, 53 year-old, affected by with amyloidosis AL (AAL) with MGUS IgG
      lambda shows the renal function and the spiro-index yet normal. There is a
      cardiomyopathy by amyloidosis, but the kinaemia is yet normal. We think to treat
      the patient with high dose therapy and PBSCs. The appearance of a heart failure
      and an asystole after the anaesthesia of marrow-harvest precludes this treatment:
      once more the diagnosis of amyloidosis AL was late. Is the early diagnosis of AAL
      possible?

PMID- 8643875
TI  - [Factors predicting the response to alpha-interferon therapy in patients with
      chronic hepatitis C].
AB  - Objective of the study was to identify predictive factors of response to
      treatment with interferon in patients with anti-HCV positive chronic liver
      disease. 92 anti-HCV positive patients, 51 with chronic hepatitis and 41 with
      active cirrhosis, were treated for 12 months with recombinant alpha 2a interferon
      at a starting dose of 6 MU TIW/6 months, followed by 3 MU TIW/6 months. Patients
      were considered responders (RS) when they presented normal serum ALT values both
      at the end of treatment and after 6 months of follow-up; relapsers (RC) those
      with normal ALT values at the end of treatment but with increase during the 6
      months of follow-up and non-responders (NR) patients who had no beneficial effect
      on ALT levels during treatment. 21 patients were RS, 11 RC and 60 cases NR.
      Univariate analysis of pre-treatment factors showed that response to interferon
      was associated with absence of cirrhosis and lower gamma-GT levels in RS than in
      RC. Multiple logistic regression of these variables showed that gamma-GT levels
      and absence of cirrhosis were the only independent factors associated with
      response to treatment. In conclusion, in our series of patients, only two factors
      were confirmed useful in predicting response to interferon treatment and it is
      concluded that they must always be evaluated before starting treatment with
      interferon which is not without side effects and may not have beneficial effect.

PMID- 8643878
TI  - Relationship among volume of paracentesis, portal blood flow and renal resistive
      index, evaluated by duplex Doppler ultrasonography in cirrhosis with tense
      ascites.

PMID- 8643877
TI  - Neocytoapheresis in the treatment of polycythemia vera.
AB  - In absence of thrombocytosis, periodic bloodlettings represent the elective
      therapy of polycythemia vera. In the present study we tested if neocytoapheresis,
      a method able to remove large quantities of younger, and then bigger red cells
      could represent an alternative therapeutic choice in these patients. We found
      that the employment of neocytoapheresis produced a remarkable delay in the time
      of procedures with a mean interval of 100 +/- 55 days. The mean value of
      hematocrit before neocytopheresis is resulted statistically different in
      comparison with the hematocrit after the procedure (p = 0.0001). The reticulocyte
      count is resulted higher in apheresis product in comparison with the blood
      control measured before procedure (p = 0.0001). In the same way, the mean
      corpuscular volume in the collection bags was higher than the volume measured
      before neocytoapheresis (p = 0.0095). We did not find any variation about the
      mean values of white blood cells and platelets before and after neocytoapheresis
      in the patients examined. These preliminary data seem to underline a better
      withdrawal of big size cells by this technique suggesting the efficacy of
      neocytoapheresis in the treatment of polycythemia vera.

PMID- 8643879
TI  - [The family physician and the clinician].

PMID- 8643880
TI  - [Ischemic preconditioning to pharmacologic activation of the ATP-dependent
      potassium channels].

PMID- 8643881
TI  - [The Mediterranean diet in the prevention of arteriosclerosis].
AB  - It is well-known that mortality from coronary heart disease (CHD) is much lower
      in Italy and the Mediterranean countries than in Northern Europe and United
      States. Diet is one of the major environmental factors playing an important
      etiological role in different CHD incidence rates in these areas. The Seven
      Countries Study demonstrated that the average consumption of saturated fatty
      acids and cholesterol was directly related to CHD death rates, these being higher
      in Northern Europe and United States and lower in the Mediterranean countries and
      the Far East. Olive oil, particularly rich in oleic acid, could play a beneficial
      role in CHD prevention, as reported in the Italian Nine Communities Study carried
      out in the early 80s. Another multicenter study, the Intersalt Study, has clearly
      shown lower blood pressure in participants with lower intake of both sodium and
      alcohol and higher intake of potassium. Recent findings have also shown that two
      helping of fish per week and antioxidant vitamins, particularly vitamin E and
      beta carotene, are related to lower CHD incidence rate in the Mediterranean area
      compared to other countries. In conclusion, based on the reported findings, the
      Mediterranean diet represents an useful and effective mean for the prevention of
      CHD.

PMID- 8643882
TI  - Global tests for combination drug studies in factorial trials.
AB  - To test the hypothesis that there are some studied dose combinations more
      effective in treating a disease than their respective component doses of two
      drugs, Hung, Chi and Lipicky proposed two alpha-level tests for normally
      distributed data. This paper extends the utilities of these tests to the outcome
      variable that has variance as a function of its mean, such as with a binomially
      distributed outcome, and to incomplete factorial design settings where some cells
      are not studied. I explore the impacts of excluding cells from study on the power
      performances of these tests.

PMID- 8643883
TI  - Statistical reporting of clinical trials with individual changes from allocated
      treatment.
AB  - We consider clinical trials in which information is available about subjects'
      treatment changes after randomization. To understand whether any difference
      between randomized groups in the intention-to-treat analysis can be explained by
      such treatment changes, we need analysis strategies which take account of
      treatment actually received. Selection bias is then a potentially serious
      problem. We relate risk in a time-dependent proportional hazards model to current
      treatment, with treatment combinations coded in two alternative ways. To reduce
      selection bias, treatment history (number of treatments dropped) and baseline
      covariates can be added to the model. Including current risk markers would also
      reduce selection bias but makes interpretation difficult. The methods are
      illustrated using data from the British Medical Research Council (MRC) elderly
      hypertension trial, with time to cardiovascular death as an outcome. Results for
      the comparison of diuretic and beta-blocker treatment are similar in all
      analyses, suggesting that selection bias is small and adding support to the
      hypothesis that the observed treatment differences are due to the randomized
      treatments themselves.

PMID- 8643885
TI  - Autoregressive age-period-cohort models.
AB  - Age-period-cohort analysis of vital data has received much attention recently,
      and it is already well known that the exact linear relation of the three time
      factors creates a non-identifiability problem. Previous studies have shown that
      the curvature terms of these factors are estimable but the linear trends are not.
      However, little attention has been paid to the possibility that the effects due
      to cohort and/or period might change through time stochastically rather than
      deterministically and hence display a stochastic trend. In this paper, we model
      the cohort effects as an AR(1) process and use lung cancer mortality data from
      1966 to 1990 for males in Taiwan as an example. The parameters are identifiable
      in the proposed model and the estimates are found to be stable. However, the
      assumption made in the model should be carefully considered before using our
      methodology.

PMID- 8643886
TI  - Interval censored survival data: a generalized linear modelling approach.
AB  - A method is described for weak parametric modelling of arbitrarily interval
      censored survival data using generalized linear models. The method makes use of
      an associated Bernoulli model, with standard errors based on the observed
      information matrix. Three types of models are discussed: additive and
      multiplicative hazard models with piecewise constant baseline hazard, and a
      proportional hazards model with discrete baseline survivor function. These models
      may be fitted in the statistical package GLIM.

PMID- 8643884
TI  - Randomized and non-randomized patients in clinical trials: experiences with
      comprehensive cohort studies.
AB  - In clinical research, randomized trials are widely accepted as the definitive
      method of evaluating the efficacy of therapies. Random assignment of patients to
      treatment ensures internal validity of the comparison of new treatments with
      controls. An assessment of external validity can best be achieved by comparing
      the randomized study sample to the population of patients who met the eligibility
      criteria but did not consent to randomization. The Comprehensive Cohort Study
      (CCS) is designed to recruit all patients fulfilling the clinical eligibility
      criteria regardless of their consent to randomization. The CCS concept was
      adopted in the major clinical trials of the German Breast Cancer Study Group
      (GBSG) conducted between 1983 and 1989. In this period 124 centres recruited 2084
      patients in three clinical trials. 734 (35 per cent) of these patients accepted
      being randomized, while 1350 (65 per cent) chose one of the treatments under
      study; the randomization rates differed remarkably between trials. In this paper
      we examine the representativeness of the randomized patients in the three trials.
      Based on a median follow-up of about 5 years we present results on the external
      validity of the treatment effects estimated in the randomized patients by means
      of Cox's proportional hazards model and compare them between trials. We discuss
      advantages and disadvantages of the CCS design and conclude that its use is only
      justified under extraordinary circumstances.

PMID- 8643887
TI  - Measurement error models for ordinal exposure variables measured with error.
AB  - In dietary epidemiology, the key nutrient variables are often expressed in the
      quintile scale. The nutrients are often measured with error and it is of interest
      to consider estimates of relative risk for exposures in the quintile scale
      corrected for measurement error. In this paper, I propose a measurement error
      model that relates diet record (true) nutrient values to food frequency (noisy)
      nutrient values when expressed in the quintile scale. I estimate this measurement
      error model from validation study data and then apply it to obtain corrected
      estimates of breast cancer risk in relation to intake of fat and alcohol with use
      of data from the Nurses' Health Study.

PMID- 8643888
TI  - Reporting delay: a review with a simulation study and application to Spanish AIDS
      data.
AB  - To correct for the effect of reporting delay on incidence data relating to AIDS,
      three methods of estimation have been analysed: Poisson log-linear; log-linear
      logistic mixed regression (log-logit), and truncation. The first two methods
      transform the data in a contingency table. The difference between them is the
      hypothesis of delay stationarity, which is only assumed by the former. A
      correction is proposed for the first method to improve its asymptotic properties.
      The truncation method is based on the product-limit estimator. A simulation study
      was carried out to examine the behaviour (means, variances and mean squared
      errors) of the three methods. All were applied to data from the National
      Commission on AIDS (Spain), showing an improvement in reporting efficiency.

PMID- 8643889
TI  - A generalized linear model for analysing receiver operating characteristic
      curves.
AB  - We present a continuation ratio model for analysing ordinal categorical data and
      we apply the model to the problem of estimating receiver operating characteristic
      (ROC) curves. We apply the methods to post-prandial capillary blood glucose
      measurements as a criterion for a potential screening test for diabetes mellitus.
      One can obtain point estimates of sensitivity and specificity and their
      associated standard errors at any value along the observed range of post-prandial
      capillary blood glucose measurements. Also, in comparison to the models for ROCs
      described by Tosteson and Begg, ROC curves based on the continuation ratio model
      have the desired features that allow ROCs to be concave but not necessarily
      symmetric.

PMID- 8643890
TI  - [What is your diagnosis? Pericardial cyst].

PMID- 8643891
TI  - [Intracoronary ultrasound: scientific aspects and clinical possibilities].
AB  - The recent development of miniaturized ultrasound devices incorporated at the tip
      of flexible angiographic catheters permits, for the first time in vivo,
      visualization of the full circumference of the vessel wall from a single
      tomographic view, similar to a histological study. Potential advantages of
      intracoronary ultrasound as compared to coronary angiography include
      characterization of the intramural anatomy of the vessel wall in normal and
      atherosclerotic segments as well as quantification of luminal dimensions and
      severity of stenoses using planimetry even in vessels with complex plaque
      morphology. Intracoronary ultrasound has therefore been called the new gold
      standard for vascular imaging. The method has been validated in vitro and in vivo
      and is highly reproducible. The complication rate of intracoronary ultrasound
      imaging is low. In addition to research applications, there are several emerging
      clinical applications for intracoronary ultrasound in the diagnosis of coronary
      artery disease, for instance for angiographically indeterminate lesions, in the
      assessment of transplant vasculopathy or in planning and guiding of coronary
      interventional procedures.

PMID- 8643892
TI  - [Acute decompensation in chronic obstructive respiratory insufficiency.
      Pathogenesis of edema and role of noninvasive mechanical ventilation].
AB  - Chronic obstructive pulmonary disease (COPD) is rather common. It is nearly
      always associated with excessive smoking. In advanced stages of COPD, patients
      have severe obstruction of airways and develop often acute episodes of
      respiratory failure, commonly due to broncho-pulmonary infections. This review
      addresses nonpharmacological treatment of these episodes of acute decompensation.
      The value of mechanical ventilation is discussed in view of two recent advances:
      noninvasive ventilation by face or nose mask as alternative to tracheal
      intubation and improved notions about the pathogenesis of fluids and salt
      retention as causes of occasionally occurring edema.

PMID- 8643893
TI  - [Current didactic concepts--243 participants evaluate Rheuma 2000].
AB  - The Swiss League against Rheumatic diseases in collaboration with rheumatologists
      organized a special educational program for general practitioners. An evaluation
      questionnaire was filled in by 238 of the 243 participants. With an average value
      of 4.57 points out of possible 5.0 the new educational concept was very
      successful. The interactive learning process in small groups seems to be a good
      alternative to formal lectures.

PMID- 8643894
TI  - [Clinico-pharmacological case (2). Bradycardia and ventricular tachycardia of the
      torsades de pointes type as a side effect of vasopressin: 3 case reports].
AB  - We present three patients with ornipressin-induced bradycardia, one of which
      developed also ventricular tachycardia of the torsade de pointes type. All three
      patients were treated with this vasopressin derivative because of bleeding
      esophageal varices due to portal hypertension in liver cirrhosis. Bradycardia
      ceased after discontinuing ornipressin therapy. One patient was treated
      successfully with atropine, one with isoprenalin and magnesium (he had to be
      defibrillated); the third patient recovered after cessation of ornipressin
      administration. Bradycardia is a known but rarely reported side effect of
      vasopressin and its derivatives. Animal studies suggest that this effect is due
      to its cardiodepressive action and also to a vagus-mediated reflex following
      vasopressin-induced increase in blood pressure. When injected directly into the
      ventricles of the brain, vesopressin leads to a decrease of the heart rate
      without affecting blood pressure; however, it remains unclear whether this
      mechanism is responsible for bradycardia after intravenous administration.
      Careful monitoring is essential during the treatment with vasopressin and its
      derivatives.

PMID- 8643895
TI  - [A 17-year-old female patient with recurring fever, chills, exanthema, myalgia
      and polyserositis].
AB  - The 17-year-old was admitted for investigation of a fever persisting for three
      weeks in spite of antibiotic treatment. Based on the clinical picture presenting
      with fugitive exanthema during febrile episodes, myalgia, polyserositis,
      leucocytosis with toxic granulations and-- after an antibiotic window--negative
      cultures of all investigated fluids (blood, pleural and peritoneal fluid), adult
      type Still's disease was diagnosed. Treatment with steroids and indomethacine was
      only temporarily successful. Therapeutic stabilization first occurred under
      administration of phenylbutazone. The course was complicated by three surgical
      abdominal interventions because of an unclear acute abdomen, a strangulation
      ileus and a small-bowel perforation.

PMID- 8643896
TI  - [A case from practice (344). Neuralgic shoulder amyotrophy or plexus neuritis].

PMID- 8643897
TI  - [Integrative concept on the treatment of highly malignant non-Hodgkin lymphomas].
AB  - With CHOP, the standard protocol for the treatment of high-grade non-Hodgkin's
      lymphomas, about 40% of long term survival has been reported. A recent randomized
      comparison of CHOP vs. ProMACE-Cyta-BOM vs. m-BACOD vs. MACOP-B showed no
      advantage of these third generation protocols. The analysis of prognostic factors
      in several controlled trials and the results of the International Non-Hodgkin's
      Lymphoma Prognostic Factors Project identified stage, LDH, performance status and
      number of extranodal sites as the most important pretreatment factors. Already
      the pretreatment LDH-level (normal vs. enhanced) defines accurately cohorts of
      patients with low or high risk. Based on these results two cooperative trials
      were initiated: In trial A we are currently evaluating in a randomised fashion
      the concept of high dose chemotherapy (BEAM) with autologous stemcell rescue vs.
      a standard treatment for high risk patients < 60 years. In trial B low risk
      patients or high risk patients > 60 years are randomised to receive either CHOP
      or CHOEP at two or three weeks intervals.

PMID- 8643898
TI  - [Therapy of low-grade non-Hodgkin lymphomas].
AB  - Low-grade non-Hodgkin's lymphomas are characterized by a low proliferative
      activity and prolonged clinical course. Most of them reveal distinct cytogenetic
      and molecular aberrations, such as the translocation t (14; 18) in
      centrocytic/centroblastic or follicular lymphomas, which is combined with an
      overexpression of the bcl 2 oncogene or the translocation t (11; 14), which is
      associated with a deregulation of the PRAD 1 gene and is mainly found in
      centrocytic or mantle-cell lymphomas. The therapy of low-grade non-Hodgkin's
      lymphoma depends on the extent of the disease. In early stages I and II, in which
      only 15 to 25% of low-grade lymphomas are diagnosed, radiotherapy represents the
      treatment of choice and may be applied with curative intention. The appropriate
      treatment of more advanced stages III and IV is a matter of controversial
      debates. Currently, it still seems justified to watch the natural course of the
      disease and to start therapy not before the occurrence of B-symptoms,
      hematopoietic insufficiency or progression of lymphoma. Intensification of
      initial cytoreductive chemotherapy does not result in a prolonged survival or a
      higher remission rate. However, maintenance therapy with interferon alpha
      following successful initial cytoreductive chemotherapy appears to have a
      favorable impact on disease-free and possibly also overall survival. New
      perspectives result from the introduction of new cytostatic compounds and the
      purine analogues in particular as well as the development of effective
      immunotoxins and antibody-conjugated radio-isotoes. Furthermore, myeloablative
      radiochemotherapy followed by autologous bone marrow or peripheral stem cell
      transplantation provides a promising approach with curative potential even in
      advanced stages of the disease.

PMID- 8643899
TI  - [Clinical aspects and primary therapy of Hodgkin's lymphomas].
AB  - In spite of intensive research, the etiology and the pathogenesis of Hodgkin's
      lymphoma are still unclear. Hodgkin's lymphoma is clinically characterized by the
      appearance of enlarged lymph nodes and systemic symptoms. The diagnosis is
      exclusively based on the identification of the typical Reed-Sternberg cells
      surrounded by a mixture of reactive cells. Careful staging aims at determining
      disease extent and other risk factors which have therapeutic relevance. The
      appropriate use of modern radio- and chemotherapy results in the cure of
      approximately 75% of all patients with Hodgkin's lymphoma. The prognosis of
      patients in limited or intermediate stages is particularly favourable. New
      treatment strategies aim at reducing therapy related long-term toxicity while
      preserving the high chance of cure. In contrast, the prognosis of patients in
      advanced stages is still unsatisfactory. The main goal of the clinical research
      is to improve treatment results for these patients.

PMID- 8643900
TI  - [Radiotherapy of lymphogranulomatosis in adulthood].
AB  - Hodgkin's disease is a highly curable disease. In clinical stages I to II (A and
      B) of Hodgkin's disease radiotherapy alone is curative in more than 80% of the
      patients. Challenges remain, however, to further refine our therapy, identify and
      cure the minority of patients who continue to succumb to this disease. Innovative
      therapies or significant modifications of current standard therapies are very
      much needed. The sequential approach of drugs and radiation therapy could reduce
      the length (not the dose!) of primary chemotherapy as well as the extent and the
      dose of additive radiation. An effective polydrug regimen not including
      alkylating agents may avoid the risk of infertility and second malignancies. In
      patients with Hodgkin's disease presenting with massive mediastinal involvement
      the efficacy of combined modality therapy has been proven by all research groups.
      In patients with clinical stage III (A and B) as well as selected stage IV
      Hodgkin's disease the percentage of nodal relapse is not negligible even after a
      very effective chemotherapy. Radiotherapy limited to the initial site(s) of bulky
      lymphoma is not enough to avoid the risk of nodal relapse in adjacent nodal
      areas. And here, too, avoiding the administration of alkylating agents may
      drastically reduce some of the serious long-term toxicities.

PMID- 8643901
TI  - [Indications, technique and risks in bone marrow transplantation in adulthood].
AB  - The option of bone marrow transplantation (BMT) significantly improved prognosis
      of adult patients with hematologic malignancies aged less than 50 years.
      Allogeneic BMT using the marrow of an HLA-identical family member still provides
      the most effective method of BMT. Conventional indications for this form of BMT
      are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk
      factors, myelodysplastic syndromes and severe aplastic anemia. If performed early
      in the disease course (e.g. during the chronic phase of CML or first remission of
      acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die
      of therapy related complications, e.g. graft versus host disease (GvHD), fatal
      infections or venoocclusive disease of the liver (VOD) and about 20% of patients
      succumb to relapse of their hematologic disorder. 80% presenting with severe
      aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis
      without previous immunosuppressive therapy and blood transfusions. BMT with the
      marrow of a matched unrelated donor or autologous BMT are increasingly used as
      alternative procedures. A rate of lethal complications as high as 50% hinders
      rapid extension of BMT with unrelated donors. Therefore, this form of BMT should
      be restricted to young patients with leukemias, who cannot achieve long-term
      remission with conventional chemotherapy (in case of acute leukemias) or alpha
      interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after
      peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT.
      Therefore, PBSCT will replace autologous BMT in most cases. Most favourable
      results of PBSCT have been reported in patients with malignant lymphomas after
      relapse or inferior response to primary induction therapy. Due to the higher
      relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients.
      Trials are required to clarify the potential role of myeloablative therapy with
      stem cell support in the treatment of patients with solid tumors. Many of the
      preliminary results already published are unsatisfactory and data of larger
      trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally
      for the therapy of patients with solid tumors.

PMID- 8643902
TI  - [What is your diagnosis? Mesenterial infarction (in atrial fibrillation)].

PMID- 8643903
TI  - [Psychotropic substances, delinquency and criminal responsibility].

PMID- 8643904
TI  - [Hypertension and coronary heart disease. Global risk moderation through control
      of body weight].
AB  - The moderation control of blood pressure is one key strategy to control the
      progression of coronary artery disease. In the pathogenesis of coronary artery
      disease, hypertension should not be viewed on its own; however, other risk
      factors, which may influence hypertension and atherogenesis at the same time,
      should be evaluated carefully. In primary and also secondary prevention of
      coronary artery disease, overweight and obesity play an important modulating
      role. Especially the abdominal (visceral) form of obesity should be controlled.
      The reduction of dietary fat intake seems to be the major strategy to control
      body fat accumulation and weight gain, since the intake of excess fat does not
      lead to an increased oxidation of fat. The reduction of fat intake is also the
      major nonpharmacological strategy to promote regression of atherosclerosis and to
      control body weight.

PMID- 8643906
TI  - [Abdominal pain].
AB  - A 37-year-old female patient was admitted to our outpatient clinic because of
      abdominal pain and absence of stool for five days. A diagnosis of acute
      intermittent porphyria was made by determination of porphyrins in the urine and
      the stool, the absence of skin symptoms and the measurement of urosynthase
      activity. As triggering event we suspect a viral infection. Neurological and
      neuropsychiatric symptoms were absent.

PMID- 8643905
TI  - [Arterial hypertension in the elderly. Is there still room for diuretics?].
AB  - Hypertension (HTA), whether systolic and diastolic or as isolated systolic
      hypertension, has been firmly established as a major risk factor of morbidity and
      cardiovascular mortality in elderly patients. Despite recent controversies that
      have appeared in the literature on the metabolic disturbances caused by
      diuretics, especially hypokalemia, and the absence of a significant advantage on
      coronary mortality, these drugs should nevertheless be considered as extremely
      important in the treatment of HTA. Prescribed at small doses, their long-term
      effects are by far the best documented of all antihypertensive drugs. Their
      mechanisms as well as their main side effects are described below. Finally, the
      authors give some simple guidelines on their use, more specifically in elderly
      patients.

PMID- 8643907
TI  - [Radiological case of the week (4). Paralytic ileus in sclerosing peritonitis
      during CAPD].

PMID- 8643908
TI  - [A case from practice (341). 1. HLA-B27-negative ankylosing spondylitis
      (Bechterew's disease)--sacroiliitis, right-sided leg length shortening of about 1
      cm, left convex thoracic scoliosis. 2. Chronic bronchitis--chronic nicotine abuse
      of about 10-pack year. 3. Normochromic, normocytic anemia at time of diagnosis].

PMID- 8643909
TI  - Corticosteroids and performance.

PMID- 8643910
TI  - Osteoporosis and former athletes.
AB  - Osteoporotic changes are one of most frequent causes of compliant in both female
      and male older populations. Former female athletes have an even higher incidence
      due to greater risk factors. Frequency and risk of damage in the musculoskeletal
      system for older athletes and a complete analysis of therapeutic effects are
      covered. An emphasis is given to the significance of a rational daily regimen and
      exercise. Examinations of 405 patients with these troubles were carried out over
      a period of twelve months.

PMID- 8643911
TI  - The human hand.

PMID- 8643912
TI  - Isokinetic principle in cycle ergometry.

PMID- 8643913
TI  - KARDIOSPIROX--the device for continual cardiopulmonary examination.

PMID- 8643914
TI  - Physical fitness and CHD risk factors in operators and managers of nuclear and
      thermal power plants situated in environmentally different regions of the Czech
      Republic.
AB  - Nuclear and thermal power plants are seen as one of the threats to human health.
      Most investigations explore the potential hazards of radiation and the potential
      impact of a polluted environment. Less attention is being paid to the human
      factor, i.e. to the people who actually are directly involved in the generation
      of electrical power and whose sudden collapse could result in a disaster. In this
      paper dealing with the prevention of CHD we submit, in a condensed form, the
      results of our long-term testing of operators and managers from one nuclear and
      two thermal power plants, located in totally dissimilar regions of the Czech
      Republic. In our investigations, which are still going on, we are using a whole
      battery of methods--case history, anthropological, clinical and functional tests.
      Our test subjects are middle-aged men, an age group most prone to CHD. The most
      favourable results of the vast majority of tests were obtained at the nuclear
      power plant in southern Moravia, while the most adverse ones--with respect to the
      danger of CHD--in the men from the thermal power plant in Prague. For the most
      part these results, in the light of a thorough analysis of the case history,
      anthropological, clinical, functional and biochemical investigations of these
      middle-aged men, should be seen as the cumulative effect of both their way of
      life (locomotor activities, nutrition) and the environment, in which they live.
      The men working at the nuclear power plant live in the least polluted
      environment. People's way of life may to some extent be influenced and some
      preventive steps along these lines have already been taken.

PMID- 8643916
TI  - A few recollections of the first lectures given by Professor Kral on the subject
      of medicine in physical education as seen by former students of physical
      education.

PMID- 8643915
TI  - Medical and anthropological study of a world and Olympic champion, long-distance
      runner, 35 years after the end his racing career.
AB  - E.Z. former world champion and holder of several gold and silver medals from
      Olympic Games as long-distance runner, underwent at the age of 71 comprehensive
      investigations. In 1993 following methods were used to establish E.Z. body build
      and health: Family, personal and sports history, anthropometry, somatotype, body
      composition posture values, sports medicine examination, ECG at rest, X-rays of
      the lung and heart, echocardiography at rest, systolic time intervals at rest,
      spirography at rest, hematology, biochemistry, X-rays of bones, exercise ECG
      changes and spiroergometry. Today, a typical feature of E.Z.'s bodybuild is a
      great amount of body fats, flabby musculature, faulty posture, restricted
      mobility of the spinal column and surprisingly good foot arches. The clinical
      findings are appropriate for his age, on his ECG at rest are signs of
      subendocardial ischemia above the left ventricle, atrial fibrillation and
      ventricular extrasystoles (Lown 1 a-b). Exercise ECG resulted in a deepening of
      the ischaemic changes already at a working load of 50 W. Hematology revealed
      normochromic macrocyt anaemia, biochemistry a borderline mineralogram,
      hyperuricaemia, higher S-GMT and HDL-C, T-C at the limit of normal values. X-rays
      of the bones were remarkable in two findings of that age. The pelvis, lumbar
      spine and knee joints were free of the usual pathological findings
      (osteoarthrosis), but presented with an exceptionally advanced osteoporosis.

PMID- 8643917
TI  - Issue dedicated to Professor Jiri Kral on 95th anniversary.

PMID- 8643918
TI  - Professor Jiri Kral, M.D., co-founder of sports medicine is ninety five.

PMID- 8643919
TI  - The 1st Medical Faculty of the Charles University in Prague--its share in the
      start and development of tuition in sports medicine.

PMID- 8643920
TI  - Age, physical fitness and health.

PMID- 8643921
TI  - A healthy lifestyle, physical fitness and prevention of disease.

PMID- 8643922
TI  - The impact of physical activity in preventive and rehabilitative cardiology.
AB  - Worldwide exercise training is used for purposes of the preventive and the
      rehabilitative cardiology. After some historical remarks the consequences of
      prolonged bed rest as a type of lack of exercise are described. It follows the
      recommendation of a suitable quality, quantity and intensity of exercise training
      for preventive medicine. Peripheral and central adaptations are described as well
      as the significance for hemodynamic and metabolic changes. Animal trials with
      primates give also a clear evidence about positive effects of exercise training.
      First convincing results are also delivered by the cardiac rehabilitation of
      heart infraction patients in connection with physical training. The main reasons
      for a protective importance of endurance training may be peripheral and central
      metabolic and hemodynamic adaptations with reduce the oxygen demand of the heart
      muscle. The flow properties of the blood are improved, combined with an anti
      thrombotic effect. Endurance training induces alterations in the lipoprotein
      metabolism which could be useful for protection against atherosclerosis as well
      as changes in the hormonal regulation. Most of the epidemiological studies
      confirm the physiologically expected results.

PMID- 8643923
TI  - Comparison of two protocols used in exercise testing in chronic heart failure
      patients.
AB  - Spiroergometrical testing with the load graded upto symptom-limited maximum with
      the determination of anaerobic threshold begins to be a routine method in
      exercise testing of cardiac patients. Functional parameters according to
      available data depend on the source of load and may be influenced by the protocol
      of testing, too. That is why we decided to compare two protocols used in chronic
      heart failure patients exercise testing. 11 male and 3 female patients (NYHA II,
      III) suffering from chronic heart failure were subjected to the symptom-limited
      tests (protocol A-0.25 W.kg (-1/3 minutes with one minute breaks; protocol B-25 W
      + 10 W/2 minutes). There was no statistically significant differences in the
      symptom-limited values of main functional parameters. The AT level parameters did
      not differ significantly, as well. Anaerobic threshold could be determined in all
      patients using the protocol A and in 11 cases using the protocol B. The
      difference in rates was not statistically significant. The workload duration
      using the protocol B was significantly shorter (9.7 +/- 3.8 minutes vs. 16.4 +/-
      3.6 minutes). CONCLUSIONS: Protocol B is less time demanding and therefore it is
      more suitable for determination of the symptom-limited parameters in the clinical
      routine. Anaerobic threshold can be determined by protocol A more often than by
      protocol B. Therefore, protocol A appears to be more suitable for the individual
      prescription of the appropriate physical activity and for scientific purposes,
      too.

PMID- 8643924
TI  - Aerobic and anaerobic energy output in children.
AB  - The adaptation of children to the exercise is discussed. The principles of
      adaptation are in children different of those of adults. The anaerobic metabolism
      of carbohydrates has lower activity and lower levels of LA by the lack of rate
      limiting enzyme phosphofructokinase and by earlier and higher increase of oxygen
      consumption in prepubertal children. The a-v O difference is higher in children;
      this contributes to perfection of the adaptation pattern of the cardiorespiratory
      system. Local flow in peripheral circulation in the working muscle is higher by
      30% in children than in adults.

PMID- 8643925
TI  - Survival and clinical results up to 26 years after repair of tetralogy of Fallot.
AB  - Repair of tetralogy of Fallot was performed on 165 patients (median age 7 years,
      range 4 months-54 years) in 1966-1976. The 30-day mortality rate was 15%. High
      postrepair right ventricular/left ventricular pressure ratio (P(RV/LV)) was a
      predictor of early mortality. Complete atrioventricular block of varying
      duration, though associated with 42% of the early deaths, was not an independent
      risk factor in multivariate analysis. The 20-year survival rate (excluding early
      deaths) was 84%. Reoperation was done in ten patients. Of the 16 late deaths,
      eight were sudden. Old age at repair and use of transannular patch correlated
      with risk of late death. Complete atrioventricular block, acyanosis, year of
      surgery, sex, and P(RV/LV) did not significantly influence long-term survival.
      Follow-up (median 19, range 13-26 years) comprised 110 survivors, 95% of whom
      were asymptomatic, 77% in employment, 65% had participated in school athletics
      and 58% regularly exercised, but 40% did not have regular medical examinations.
      Operation at age 3-5 years had the most favourable prognosis.

PMID- 8643926
TI  - Jatene correction of the ventricular geometry in postinfarction left ventricular
      aneurysm. Results of 62 operations.
AB  - Jatene correction of left ventricular aneurysm was performed on 62 patients
      (including 11 emergency operations) with mean age 60 years, 80% of them in NYHA
      class 3-4, with mean left ventricular ejection fraction c. 30%and mean left
      ventricular end-diastolic pressure c. 24 mm. Concomitant bypass grafting was
      performed in 58 cases (mean grafts per patient 3.7). Perioperative mortality was
      12.9%. One patient had peroperative myocardial infarction. Postoperatively 13
      patients had low cardiac output, requiring intra-aortic balloon pump in seven
      cases. There were no bleeding problems and 28 patients (45%) had no postoperative
      complications. The average hospital stay was 10.2 days. Left ventricular cavity
      size (echocardiography) showed significant reduction 1 week postoperatively,
      which was unchanged after 1 month. The left ventricular ejection fraction was
      significantly increased 1 month postoperatively. After follow-up averaging 15
      months there was significant improvement in mean NYHA class. One patient
      underwent heart transplantation and died, but there were no other late deaths or
      cardiac-related complications. Jatene correction of left ventricular aneurysm is
      simple, carries acceptable mortality and low morbidity and significantly improves
      left ventricular function.

PMID- 8643927
TI  - Atherosclerosis of the inferior epigastric and internal mammary arteries.
AB  - Atherosclerosis of the inferior epigastric artery (IEA) and the internal mammary
      artery (IMA) was evaluated in 21 patients with coronary heart disease. Both
      arteries were used simultaneously in coronary artery bypass grafting. Histologic
      samples were obtained from the proximal and distal segments of IEA and from the
      distal segment of IMA. Morphologic findings in regard to atherosclerosis were
      classified semiquantitatively as normal (0), or luminal narrowing <25% (1), 25
      50% (2) or >50% (3), or as overt atherosclerosis and calcification (4).
      Atherosclerosis was absent or minimal (1) in distal samples from both arteries.
      Only one IMA showed moderate (2) luminal atherosclerotic obstruction. Two samples
      from proximal IEA showed moderate (2) or severe (4) atherosclerotic changes which
      limited their use as free grafts. These finding suggest that atherosclerosis is
      minimal and comparable in distal IEA and IMA in their natural environments even
      in patients with coronary heart disease. The long-term effect of aortic pressure
      on free IEA graft is still unclear.

PMID- 8643928
TI  - Risk factors for graft occlusion after coronary artery bypass grafting.
AB  - A cohort of 610 well-characterized patients undergoing coronary artery bypass
      grafting were followed through the first postoperative year. Graft patency was
      angiographically assessed in 578 (94.8%) of the patients on average 12.1 (SD 1.5)
      months postoperatively and was related to characteristics of grafts and patients.
      For internal mammary artery grafts the incidence of graft occlusion was higher in
      women than in men and was inversely related to body surface area. In multivariate
      analysis the influence of gender was no longer significant when adjusted for body
      surface area. With vein grafts the incidence of occlusion was inversely related
      to body surface area and was positively associated with ejection fraction.
      Occlusion of vein grafts was less common in patients treated with beta-blockers
      pre- and peroperatively.

PMID- 8643929
TI  - Pulmonary function 3-13 months after pneumonectomy, lobectomy or bilobectomy for
      lung cancer.
AB  - Pulmonary function was studied 3 and 12 months after pulmonary resection for lung
      cancer in 37 patients, ten of whom had undergone pneumonectomy, 17 lobectomy and
      eight bilobectomy. The resection was right-sided in 25 cases and left-sided in
      12. Tumour site and diameter were registered, arterial blood gases measured and
      spirometry performed Three months after all types resection there was significant
      decrease in forced vital capacity (FVC), and forced expiratory volume/1 second
      (FEV1), but not in FEV1/FVC%. At 12 months pneumonectomy had reduced FVC to 58%
      of predicted values, FEV1 to 50% and FEV1/FVC% to 70%. After lobectomy the
      corresponding figures were 86%, 73% and 67% and after bilobectomy they were 88%,
      78% and 70%. Between 3 and 12 months postoperatively, FVC increased in all
      groups, significantly in those with lobectomy or bilobectomy (p<0.01 and 0.05,
      respectively).

PMID- 8643930
TI  - Thoracoscopic resection of parenchymal blebs in spontaneous pneumothorax.
      Indications, operative management and results.
AB  - The success rate of thoracoscopic resection of parenchymal blebs in spontaneous
      pneumothorax was evaluated after 54 thoracoscopies (cases) in 52 patients. Switch
      to open thoracotomy was necessitated by interpleural adhesions or large bullae in
      five cases, while 49 were treated thoracoscopically. The median duration of the
      operation was 75 (25-240) min, and the postoperative hospital stay was 7 (3-25)
      days. Early postoperative complications were haemothorax and recurrence of
      pneumothorax, each in one case, treated with thoracoscopy and chest drain,
      respectively. Forty-six patients were followed up for a median of 11 (1-32)
      months. there were two recurrences (at 4 and 6 months). One was successfully
      treated with thoracoscopy and the other with thoracotomy. Only five patients
      complained of slight sensitivity in the scar area, caused by weather changes.
      Thoracoscopic bleb resection is an effective alternative to thoracotomy, with low
      rates of complications and recurrent pneumothorax.

PMID- 8643931
TI  - A technique for correct placement of the Wilson Cook oesophageal prosthesis in
      malignant tracheo-oesphageal fistula.
AB  - A simple technique is described for accurate placement of the Wilson Cook
      prosthesis in the management of malignant tracheo-oesophageal fistula. This
      cuffed tube permits effective occlusion of the fistula while earlier problems of
      oesophageal intubation (migration, erosion, etc.) are avoided.

PMID- 8643932
TI  - Life-saving pericardiectomy in cardiogenic shock due to impairment of diastolic
      pump function by myocardial swelling.
AB  - Pericardiectomy was remarkably effective in relieving intractable cardiogenic
      shock resulting from impaired diastolic pump function due to severe myocardial
      swelling in a 40-year-old woman. The operation restored cardia pump function by
      counteracting the reduction of left ventricular compliance.

PMID- 8643933
TI  - Subtotal rarefication of one aortic leaflet in a bicuspid aortic valve due to
      large aneurysm of left Valsalva's sinus.
AB  - In a 39-year-old man an isolated, unruptured extracardiac aneurysm of the left
      sinus of Valsalva led to almost complete rarefication of one aortic valve
      leaflet, causing insufficiency of the valve. At operation the aneurysm entrance
      was closed with a patch and prosthetic replacement of the bicuspid aortic valve
      was performed. The result was satisfactory.

PMID- 8643934
TI  - Modified supra-arterial myotomy for intermittent coronary obstruction by
      myocardial bridges.
AB  - Coronary artery narrowing secondary to myocardial bridging, with consequent
      clinical manifestation, is a known but uncommon entity. A modified supra-arterial
      myotomy in a case of myocardial bridge causing medication-refractory angina is
      described.

PMID- 8643935
TI  - Solitary, thin-walled cavitary lung metastasis of osteogenic sarcoma.
AB  - Three years after removal of a femoral osteosarcoma, a solitary, thin-walled
      cavitary lesion (diameter 1 cm) appeared in the lung of a young man. When the
      lesion enlarged, it was resected. Histology showed sarcoma metastasis with
      central necrosis and involving a peripheral bronchus. Cavitary metastasis can
      occasionally result from drainage of necrotizing tumor cells via a peripheral
      bronchus.

PMID- 8643936
TI  - Intracranial metastases from malignant pleural mesothelioma.
AB  - Although intracranial metastases from malignant pleural mesothelioma are rare,
      their presence should be suspected in cases of high-grade mesothelioma and should
      possibly be included in routine preoperative evaluation. An unusual case of
      cerebral metastases from pleural mesothelioma is presented and the literature is
      reviewed.

PMID- 8643937
TI  - [Electromyography as a diagnostic aid in tetanus].
AB  - In developing countries tetanus is still a real problem because of its high
      incidence and mortality. In all countries with high medical standards it has
      become rare. For this reason many clinicians are no longer familiar with the
      disease and its diagnosis. Until now no laboratory test has been readily
      available to confirm or rule out tetanus. However, the diagnosis can be performed
      by a simple and readily available electromyogram (EMG). We performed EMGs in 13
      patients in whom tetanus was suspected but whose case history or clinical
      findings left some doubt. In 7 cases the EMG was typical for tetanus, showing
      spontaneous activity of motor units which could not be suppressed voluntarily and
      with shortening or absence of the silent period after a stretch reflex or after
      electrical stimulation of the nerve. In 2 cases we found one of the two
      diagnostic features. In all these 9 cases the diagnosis of tetanus was confirmed
      by the further development of the disease. In the remaining 4 patients the EMG
      was normal and in the course it was confirmed that they were not suffering from
      tetanus. Therefore, we consider electromyography a very useful and reliable tool
      either to confirm or rule out the diagnosis of tetanus.

PMID- 8643938
TI  - [Should postoperative thromboembolism prevention be extended to the post
      hospitalization phase?].
AB  - A large number of patients medically treated for deep vein thrombosis and
      pulmonary embolism have a history of surgery in the immediate past. We therefore
      inquired whether it is possible to identify specific risk factors which would
      allow general recommendations for anticoagulation therapy in the postdischarge
      period. During the 30-month study period 325 patients were treated at the
      Cantonal Hospital, Aarau, for DVT and/or pulmonary embolism. 35 (10.8%) had
      undergone surgery 8 weeks previous to admission. Perioperative management
      (anticoagulation, chronology, mobility etc.) was analyzed retrospectively. 20% of
      the 35 patients with postdischarge deep vein thrombosis and/or pulmonary embolism
      had previously undergone an ambulatory surgical procedure. A large number of
      thromboembolic complications occurred between the 4th and 12th day after
      discharge. In 40% of the patients, however, they occurred after the 14th
      posthospital day. High- and low-risk patients were impossible to define on the
      basis of the type of surgery, length of hospital stay and time course of
      thromboembolic complications. We conclude that prophylaxis of thromboembolism in
      ambulatory surgery should be re-thought: patients undergoing arthroscopy should
      receive prophylaxis for thromboembolism for at least 4-6 weeks post discharge.

PMID- 8643939
TI  - [Fulminant, rapidly reversible hepatitis and life-threatening anaphylaxis
      following rifampicin in an HIV-positive female patient with latent adrenal cortex
      insufficiency].
AB  - We report the case of a 28-year-old-prostitute from Thailand with HIV infection
      stage B2 associated with retroperitoneal lymph node tuberculosis. 6 days after
      the beginning of anti-tuberculous therapy (isoniazid, rifampicin, pyrazinamid and
      ethambutol) the temperature rose to 40.5 degrees C, diarrhea, vomiting, and
      tachycardia developed and systolic blood pressure fell to 80 mm Hg. Liver
      function tests revealed acute hepatic failure (ALT 800 IU/l rising to 1500; serum
      bilirubin 89 mumol/l rising to 238.0; alkaline phosphatase 199 IU/l; glucose 1.8
      mmol/l; prothrombin time 20%). Isoniazid, rifampicin, and pyrazinamid were
      replaced by streptomycin and PAS. A few days after withdrawal the liver profile
      returned to normal. Hours after the reintroduction of rifampicin total body
      erythema, pruritus, vomiting and severe hypotension developed, requiring saline
      methylprednisolone and epinephrine administration. The next reexposure to
      intravenous rifampicin produced a rash and was rapidly discontinued. Liver
      function tests remained normal. Later mild adverse reactions to streptomycin and
      pyrazinamid occurred, two drugs which had been well tolerated before.
      Subsequently the diagnosis of adrenal insufficiency was established. After
      initiation of steroid replacement (50 mg prednisolone) the antituberculous
      therapy with isoniazid, pyrazinamid and ethambutol was well tolerated. We
      conclude that the shock in this HIV-infected patient was either due to severe
      anaphylaxis to rifampicin or acute adrenal insufficiency ensuing on this drug.
      The reversible fulminant acute hepatic failure represents either an adverse
      effect of antituberculous drugs, especially hepatotoxic interactions of drug
      combinations, or an ischemic liver injury during hypotension caused by
      anaphylaxis. The case illustrates the complex nature of side effects of
      antituberculous drugs in HIV patients and their aggravation by adrenal
      insufficiency.

PMID- 8643940
TI  - [High-resolution computerized tomography of the lungs: bases, findings,
      indications].
AB  - High resolution computed tomography (HRCT) of the lungs uses thin-section CT (1-
      to 2-mm collimation scans) combined with a targeted reconstruction with a high
      spatial frequency algorithm. HRCT is currently the most sensitive non-invasive
      imaging method for parenchymal and bronchoscopically inaccessible bronchial
      abnormalities of the lung. The following indications for HRCT of the pulmonary
      parenchyma are established: (1.) complementary examination in symptomatic
      patients with normal chest radiographs and/or normal pulmonary function testing;
      (2.) morphologic characterization of a nonspecific radiographic pattern; (3.)
      assessment of the activity and follow-up of a parenchymal disease; (4.)
      localization of a lung biopsy; (5.) localization of bronchiectasis.

PMID- 8643941
TI  - [Primary ciliary dyskinesia, immotile cilia syndrome, and Kartagener syndrome:
      diagnostic criteria].
AB  - Primary ciliary dyskinesia is the generic term for a heterogeneous group of
      inherited diseases in which ciliary ultrastructure is defective and as a
      consequence ciliary motility is disturbed. An international consensus on the
      diagnostic criteria has not yet been reached. This paper reviews some recent
      findings which are useful in the diagnosis of the disease and attempts to
      establish the best diagnostic criteria. The marker symptoms are chronic
      bronchitis, otitis, and sinusitis since childhood. Additionally, one or more of
      the following criteria must be present: Kartagener syndrome, a dextrocardia
      situation, markedly reduced frequency in ciliary motility, or an essential
      ultrastructure deviation in more than 20% of the square cuts (e.g. reduced number
      of dynein arms). Biopsy of the ciliated mucosa is usually required for the above
      criteria and is studied by vital microscopy and transmission electron microscopy.
      Primary and secondary ciliary dyskinesia can be distinguished by these methods
      and the rare case of PCD without ultrastructure deficiency ruled out. In special
      cases a cell culture is recommended for the diagnosis. Practical aspects of the
      sampling methods and diagnostic pitfalls are reviewed.

PMID- 8643942
TI  - [Benign paroxysmal postural vertigo: basis and its therapy in clinical practice].
AB  - The theory of canalolithiasis assumes that benign paroxysmal vertigo and
      nystagmus is due to particles within the semicircular canal which move freely in
      the endolymph under gravitational forces, thereby deflecting its cupula.
      According to this theory the particles could be removed from the posterior canal
      by manoeuvres applying a succession of different head positions. We describe the
      pathophysiological mechanism of benign paroxysmal vertigo and our experience with
      one of these manoeuvres, the Semont manoeuvre. The success rate is impressive and
      the therapy is highly rewarding in a vertigo syndrome which can cause disability
      in the patients.

PMID- 8643943
TI  - [Visceral and neurological complications in Varicella infections of adults].
AB  - Primary varicella-zoster virus (VZV) infections in adults generally follow a more
      severe course than in children and are more often associated with life
      threatening complications. In the years 1992 to 1995 we observed 7
      immunocompetent adults with a severe course of primary VZV infection. All 7
      patients presented initially with a characteristic rash. In 6 patients the
      diagnosis of VZV was confirmed by ELISA on material taken from the lesions, and
      in all of them it was confirmed by serology. The following complications were
      observed: pneumonia (5x), elevated liver enzymes (4x), myocarditis (1x),
      encephalitis (1x) and myelitis (1x). Pulmonary lesions were characterized by
      bilateral interstitial infiltrates on chest-x-ray and required mechanical
      ventilation in 2 patients. The liver enzymes were only slightly elevated and
      clinically not significant. Myocarditis in one case was postulated in view of
      elevated creatine kinase levels, ECG-repolarization changes and AV-block III
      which required the insertion of a transitory pacemaker. Encephalitis presented as
      abnormal behaviour at work followed by seizures. Myelitis was suspected due to
      ascending sensory motor tetraparesis and confirmed by MRI. All patients were
      treated with high doses of parenteral acyclovir (3 x 10 mg/kg body weight i.v.
      per day) for 5-12 days. 6 patients recovered completely and only the patient with
      myelitis has residual neurological deficits 3 months after discharge. Although we
      cannot exclude the possibility that supportive therapy without acyclovir would
      have had the same outcome, we recommend high-dose parenteral acyclovir for
      treatment of visceral and neurological complications in primary VZV infections in
      adults.

PMID- 8643944
TI  - [Shoulder problems in leisure athletes: physical examination, diagnosis and
      therapy. Sensible procedures in daily practice].
AB  - At first sight the anatomy of the shoulder may seem simple (see Fig. 1). However,
      for the physician treating a patient suffering from shoulder pain, the scapulo
      thoracal interplay of 5 joints and 19 muscles, providing a wide and varied range
      of motion, may constitute an obstacle difficult to overcome. In the leisure
      athlete acute injuries must be distinguished from degenerative disease. Contact
      sports in particular tend to involve risks of falling on the shoulder, injuring
      the shoulder girdle or the elbow and wrist, sometimes with major consequences:
      complex fractures, dislocations, ligament and tendon lesions or joint
      instabilities. Thorough, rapid and cost-effective diagnostic evaluation of the
      athlete, involving clinical examination (function tests), radiographic imaging
      (shoulder a.p., y-view) and in selected cases ultrasonography (compared with the
      other side) may be necessary in starting early and effective therapy.

PMID- 8643945
TI  - Senile words.

PMID- 8643946
TI  - AIDS cases reported, 1994-1995.

PMID- 8643947
TI  - Ultrasound's new phase. A major advance yields deeper, clearer views of the body.

PMID- 8643948
TI  - Mind readings. Researchers can now predict what a monkey will draw--before it
      even moves.

PMID- 8643949
TI  - Testing, testing. Unusual proteins could improve cancer diagnosis and reduce
      deaths.

PMID- 8643950
TI  - Training the Olympic athlete.

PMID- 8643951
TI  - Confronting the nuclear legacy--Part III. Can nuclear waste be stored safely at
      Yucca Mountain?

PMID- 8643952
TI  - Taxoids: new weapons against cancer.

PMID- 8643953
TI  - Uptake of mercury species by transplanted mussels Mytilus galloprovincialis under
      estuarine conditions (Krka river estuary).
AB  - Biometric features and physico-chemical conditions are responsible for many of
      the variables for metal concentrations in indigenous populations of mussels. In
      order to reduce variations and promote the utility of mussels as bioindicator
      organisms for environmental mercury concentration levels, individuals of
      approximately uniform biometric characteristics, selected from a culture of 1
      year-old mussels (Mytilus galloprovincialis, Lmk., were transplanted to four
      locations in the Krka river estuary and nearby coastal area (Eastern Adriatic
      coast). Biometric parameters of mussels and their total and methylmercury content
      were analysed four times over a period of 270 days in 1988/89. It was found that
      total and methylmercury concentrations were significantly correlated with shell
      weight, wet weight and dry weight of mussels. The estimate of minimal
      methylmercury concentration in the water of the Krka River Estuary (approximately
      20 pg/l), derived from the mussels data, is in a good agreement with recently
      determined concentration levels of methylmercury (between 50 and 100 pg/l) in
      waters of the same area. The accumulation efficiency for methylmercury is about
      20-50 times higher than for total mercury. Only 1% of the total mercury content,
      and 20-50% of the methylmercury content in water filtered by the mussels, is
      accumulated in the shellfish tissues.

PMID- 8643954
TI  - Determination of selenium in cereals, legumes and dry fruits from southeastern
      Spain for calculation of daily dietary intake.
AB  - Hydride generation atomic absorption spectrometry was used to determine selenium
      content in cereals, legumes and dry fruits from the coast of the province of
      Granada (southeastern Spain). Accuracy was assured using both a NIST SRM 1572 and
      recovery experiments. The precision expressed as relative standard deviation
      (R.S.D.) varied between 6.50% for seeds and 15.98% for bread. The highest
      selenium concentrations were found for dry fruits (294.6 ng/g), followed by
      legumes (111.8 ng/g), and the lowest for cereals (27.8 ng/g). Considering the
      average daily individual consumption of these foods in Andalusia (southern
      Spain), the daily dietary intake of selenium supplied by this source is 15.36
      micrograms/day for an adult. The content of total selenium in corn samples taken
      from the zone is independent of both human and industrial activities (P > 0.05).

PMID- 8643955
TI  - Cadmium contents in rice samples from various areas in the world.
AB  - Rice samples consumed by local populations were collected in 17 areas in the
      world, mostly from Asia, i.e. ten areas, but eight areas outside of Asia were
      also included during the period of 1990 to 1995. The samples amounted to 1546 in
      total, and were analyzed for cadmium (Cd) by electrothermal atomic absorption
      spectrometry. The data show that the highest and the lowest geometric means of Cd
      contents in rice from Asia was 55.70 and 2.67 ng/g, respectively, and 133.20 and
      0.88 ng/g outside of Asia. The geometric mean Cd contents in rice from Japan was
      55.70 ng/g, which is essentially similar to the levels determined in the early
      1980s. We conclude that a substantial difference exists in Cd contents in rice
      for local consumption depending on the areas in the world, and that there is no
      significant changes in Cd levels in rice harvested in Japan over the past 10
      years.

PMID- 8643957
TI  - The form and bioavailability of non-ionic organic chemicals in sewage sludge
      amended agricultural soils.
AB  - The application of sewage sludges to agricultural land may increase the
      concentrations of many toxic organic chemicals in soils which could have adverse
      effects on wildlife and human health if these compounds enter foodchains.
      Chlorobenzenes (CBs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated
      biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) are
      amongst those compounds currently receiving most attention. The "form' in which
      these, and other organic chemicals, are present in soils and their potential to
      be lost by various processes including leaching, volatilisation and
      (bio)degradation is shown to be dependent on the physicochemical characteristics
      of the soil and sewage sludge, environmental conditions and the properties of the
      chemicals themselves. The distinction is made between those compounds that are
      labile, reversibly sorbed and irreversibly sorbed by sewage sludge-amended soils.
      The implications of the form in which the chemicals are present in soil for their
      "availability' to transfer from the soil to bacteria, fungi, earthworms, grazing
      livestock and food crops followed by the potential for further transfers,
      metabolism or bioaccumulation are discussed. The importance of the timing and
      method of sewage sludge application to soil on "form' and "availability' are also
      considered.

PMID- 8643956
TI  - Impact of reduction of lead in gasoline on the blood and hair lead levels in the
      population of Tarragona Province, Spain, 1990-1995.
AB  - The limitation in the use of lead in Spanish gasoline has induced a resulting
      decrease in atmospheric lead concentrations, a remarkable reduction in the lead
      levels of edible vegetables, as well as a marked decrease in the dietary lead
      intake of the population of Tarragona Province (Catalonia, N.E. Spain). The
      present study evaluates the impact of such decreases on blood lead values and
      hair lead concentrations in an adult and children population of that region. A
      total of 250 adult participants between 16-65 years of age and 252 children were
      included in the study. Blood and hair samples were subjected to lead analyses by
      graphite furnace atomic absorption spectrophotometry and inductively coupled
      plasma spectrometry, respectively. A substantial decline in both, blood lead
      levels in adults (47.5%) and lead concentrations in children's hair (53%) was
      observed. During the period 1990-1995, blood levels were reduced from 12.0
      micrograms dl-1 to 6.3 micrograms dl-1, while the hair lead concentrations
      decreased from 8.8 micrograms g-1 to 4.1 micrograms g-1. These decreases were
      noted for all the subgroups (sex, age and place of residence) examined, and were
      mainly attributable to the reduced leaded gasoline consumption.

PMID- 8643958
TI  - Sources, behaviour and fate of organic contaminants during sewage treatment and
      in sewage sludges.
AB  - Recent concern over the environmental impact of sewage sludge application to
      agricultural land has drawn particular attention to the wide range of organic
      contaminants that may enter sewage treatment processes and persist in biosolids
      for disposal. This paper discusses processes influencing the fate and behaviour
      of organic contaminants during wastewater treatment and reviews literature
      relating to specific contaminants identified in sewage sludge. The difficulties
      associated with the development of specific methods for the analysis of trace
      residues of organic contaminants in complex matrices such as sludge are
      discussed. Some potential issues relating to impact of sewage sludge disposed to
      agricultural land are also considered.

PMID- 8643959
TI  - Screening the environmental fate of organic contaminants in sewage sludges
      applied to agricultural soils: 1. The potential for downward movement to
      groundwaters.
AB  - The potential for organic contaminants present in sewage sludge to leach and
      cause groundwater contamination following sludge application to agricultural land
      has been assessed. Models used to predict compound mobility in soil on the basis
      of physico-chemical parameters were applied to a range of contaminants
      prioritised and/or detected in sludge and a provisional list of potential
      "leachers' compiled. In addition, theoretical soil water concentrations following
      sludge application were calculated using mean reported sludge contaminant
      concentrations and soil/water partition coefficients. These estimated aqueous
      phase concentrations were compared with Dutch groundwater quality standards in
      the absence of appropriate UK standards to identify those compounds which could
      be present in groundwater at levels of concern. The two prioritised lists were
      used to identify compounds in sludge which could pose a possible threat to
      groundwater. Appropriate experimental data were not available to qualify model
      results. However, the screening exercise indicated that under routine operation
      practice with typical sludge application rates, and the usual range of compound
      concentrations detected in sludge, groundwater quality standards were unlikely to
      be exceeded. However, data variability, reliability and scarcity limited the
      usefulness of this screening approach.

PMID- 8643960
TI  - Screening the environmental fate of organic contaminants in sewage sludges
      applied to agricultural soils: II. The potential for transfers to plants and
      grazing animals.
AB  - This is the second of two papers which screen the environmental fate of sludge
      organic contaminants when applied to agricultural land. A simple screening model
      has been developed to assess the likelihood of organic contaminants accumulating
      into the food-chain following the application of sludge into arable and pasture
      land. The purpose of this exercise is to highlight those compounds that have the
      potential to accumulate into plants and animal tissues using data on physico
      chemical properties of the compounds of interest. Over 300 organic compounds or
      groups of compounds which have been identified as potential pollutants in sludge
      have been screened for their potential to transfer from sludge-amended soils to
      plants via retention by root surfaces, root uptake and translocation, foliar
      uptake and animal intake via soil and herbage ingestion. Various organic
      contaminants have been identified as having a high potential to transfer into the
      food-chain through plant and animal accumulation. Two priority lists have been
      produced to include (a) those compounds which are shown as being of sufficient or
      suspected importance, but for which further sludge concentration data and fate
      studies would be necessary to check on their status, and (b) those compounds
      which have been highlighted in the screening processes as having a high potential
      to accumulate up the food-chain. This screening approach can be adapted to other
      chemicals as information on new chemicals and their physico-chemical properties
      becomes available.

PMID- 8643961
TI  - Organic compounds in sludge-amended soils and their potential for uptake by crop
      plants.
AB  - Numerous toxic organic chemicals (TOs), with a wide range of chemical properties,
      can occur in sewage sludges. The vast majority of sludge-borne TOs occur at low
      concentrations, and even lower TO concentrations are expected in sludge-amended
      soils. Further, most TOs are so strongly reactive in the soil-sludge matrix that
      their bioavailabilities to plants are expected to be low. A host of experimental
      techniques have been employed to measure TO plant uptake and to relate
      bioavailability to TO chemical and physical properties. The strengths and
      weaknesses of several experimental approaches are examined, and the resulting
      data are evaluated. Sound experimental data, especially field data and/or data
      from studies with endogenously sludge-borne TOs, indicate negligible
      contamination of crop plants with TOs in sludge-amended soils. Assessing the
      potential for plant uptake of sludge-borne TOs involves determining: (a) which
      TOs are most likely present in biosolids and what are their toxicities; (b) what
      quantities of TOs are likely to be added to the growth media via biosolids
      application; (c) what effects various dissipation/dispersion reactions have on
      the potential bioavailability of TOs; and (d) what are the various mechanisms for
      plant uptake/metabolism of TOs.

PMID- 8643962
TI  - Ingestion of sludge applied organic chemicals by animals.
AB  - Intake of sludge-borne chemicals is related to the crop and animal management
      systems, the species and physiological status of animals, and the properties of
      the chemicals. The greatest intake occurs when sludge is applied to established
      crops and animals have immediate access. Intake is reduced when access is delayed
      to allow losses by weathering and dilution by plant growth, or when sludge is
      incorporated into soil because vapour transport from soil to plants and lower
      concentrations at the surface reduce intake via soil ingestion. Animals that
      consume forage are the most subject to contaminant exposure, which is maximized
      when pasture is the major component of the diet because soil ingestion is an
      additional exposure pathway. Of the many organic contaminants in sludges, only
      lipophilic halogenated hydrocarbons accumulate in animal tissues and products.
      Compounds like phthalate esters, PAHs, acid phenolics, nitrosamines, volatile
      aromatics, and aromatic surfactants are metabolized and do not accumulate. Among
      halogenated hydrocarbons, compounds with low degrees of halogenation are
      metabolized and do not accumulate, but higher degrees of halogenation block
      metabolism, and concentrations in milk and tissue fat may be several-fold greater
      than in the diets.

PMID- 8643963
TI  - Combination regimens of paclitaxel and the platinum drugs as first-line regimens
      for ovarian cancer.
AB  - A platinum compound combined with paclitaxel (Taxol; Bristol-Myers Squibb
      Company, Princeton, NJ) has supplanted a platinum compound and cyclophosphamide
      as standard chemotherapy in the United States for patients with previously
      untreated ovarian cancer. Numerous studies are under way to determine the optimal
      use of these drugs as first-line treatment. Among the critical issues being
      explored are the length of the paclitaxel infusion, the optimum number of cycles,
      and paclitaxel dose intensity. The Gynecologic Oncology Group is pursuing studies
      of paclitaxel and carboplatin, based on promising results from a phase I/II
      study. Carboplatin is equivalent to cisplatin in terms of efficacy, but has only
      myelosuppression as a dose-limiting toxicity. Other novel approaches being
      investigated in ongoing Gynecologic Oncology Group trials include an evaluation
      of interval debulking surgery as one arm of a trial in which patients with
      suboptimal stage III and IV disease are receiving paclitaxel/cisplatin.

PMID- 8643964
TI  - Treatment of metastatic breast cancer with paclitaxel and doxorubicin.
AB  - The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company,
      Princeton, NJ) against untreated and previously treated metastatic breast cancer
      (documented in anthracycline-resistant disease and in extensively pretreated
      patients as well) has prompted investigations of the optimal doses and schedules
      of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been
      administered in either a 24- or a 3-hour infusion, while the administration times
      for doxorubicin vary from bolus injection to a 72-hour infusion. Results of these
      completed phase I and II trials are reviewed. Also reported are two ongoing
      European trials that have achieved promising preliminary results. In Milan, a
      phase I trial has achieved a preliminary response rate exceeding 90% in 30
      chemotherapy-naive patients treated with an alternating schedule of paclitaxel
      over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2
      and doxorubicin 60 mg/m2, the dose-limiting toxicity is leukopenia and mucositis.
      Furthermore, congestive heart failure has occurred in six patients. We are
      conducting a phase I/II study in minimally pretreated patients, with a 30-minute
      doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks. Of 24
      patients evaluable for response, five have achieved partial responses and three
      complete responses. (Another five partial and two complete responses need
      confirmation.) Of the two dose levels now given, all responses occurred at the
      higher paclitaxel/doxorubicin level, 175 and 60 mg/m2, respectively. Despite
      grades 3 and 4 neutropenia in 31% and 60% of courses, respectively, only six
      patients have been hospitalized for febrile neutropenia. Of concern, the left
      ventricular ejection fraction has decreased to below normal in six patients and
      two have developed symptomatic congestive heart failure. Whether lowering the
      peak doxorubicin concentration will preclude this effect, which has been observed
      only in the studies using short infusions of both drugs, is under investigation.

PMID- 8643966
TI  - Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: a
      phase II trial.
AB  - Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated
      significant antineoplastic activity against different tumor types, notably
      ovarian and breast carcinoma. Two phase II trials of 24-hour paclitaxel infusions
      in chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer
      (NSCLC) reported response rates of 21% and 24%. Leukopenia was dose limiting: as
      many as 62.5% of patients experienced grade 4 leukopenia. We investigated the
      efficacy and toxicity of a 3-hour paclitaxel infusion in a phase II trial in
      patients with inoperable stage IIIB or IV NSCLC. The 58 patients treated (41 men
      and 17 women) had a median age of 59 years (age range, 25 to 75) and a
      performance status of 0 through 2. Most patients (72.4%) had stage IV NSCLC.
      Paclitaxel 225 mg/m2 was infused over 3 hours every 3 weeks with standard
      prophylactic premedication. Of 50 patients evaluable for response, 12 (24%) had
      partial remission, 26 (52%) had no change, and 12 had disease progression (24%).
      Hematologic toxicities were mild: only one patient (2%) developed grade 3 or 4
      neutropenia, while 29% had grade 1 or 2. Grade 1 or 2 polyneuropathy affected 56%
      of patients while only one (2%) experienced severe polyneuropathy. Similarly,
      grade 1 or 2 myalgia/arthralgia was observed in 63.2% of patients, but only 14.3%
      experienced grade 3 or 4. Nausea and vomiting were infrequent, with 14% of
      patients experiencing grade 1 or 2 and only 2% experiencing grade 3 or 4.
      Paclitaxel is thus an active single agent in this patient population, with a 3
      hour infusion proving comparably effective to a 24-hour infusion and superior in
      terms of the incidence of hematologic and nonhematologic toxicity. Further phase
      II studies with paclitaxel combined with other drugs active against NSCLC are
      indicated, and phase III studies comparing paclitaxel with standard chemotherapy
      remain to be completed.

PMID- 8643965
TI  - Sequential adjuvant therapy with doxorubicin/paclitaxel/cyclophosphamide for
      resectable breast cancer involving four or more axillary nodes.
AB  - The results of both retrospective and prospective studies suggest that the
      effectiveness of systemic adjuvant chemotherapy with doxorubicin and
      cyclophosphamide for breast cancer may be related to the dose intensity of these
      agents. Recent trials also have demonstrated the high activity of paclitaxel
      (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) against metastatic breast
      cancer. Clinically, paclitaxel appears to be noncross-resistant with doxorubicin,
      but the unique and overlapping toxicities of these three agents might preclude
      concurrent adjuvant administration. A possible solution is sequential rather than
      concurrent administration, an approach that kinetic modelling predicts to be
      superior. A pilot study testing dose-intensive sequential administration of
      doxorubicin/paclitaxel/cyclophosphamide enrolled 42 patients with a median age of
      42 years who had resected breast cancer metastatic to four or more ipsilateral
      axillary lymph nodes. Intravenous treatment, given at 14-day intervals, began
      with three cycles of doxorubicin 90 mg/m2, followed by three cycles of paclitaxel
      250 mg/m2, given as a 24-hour infusion, and, finally, three cycles of
      cyclophosphamide 3 g/m2. Selected patients received radiotherapy. The median
      number of positive lymph nodes was eight (range, four to 25), and the median
      tumor size was 3.0 cm (range, 0 to 11.0 cm). Granulocyte colony-stimulating
      factor support was given. Both hematologic and non-hematologic toxicity were
      substantial but manageable. Hospital admission was necessary in 62 (17%) of 369
      chemotherapy cycles in 29 patients (69%). As planned, the median intertreatment
      interval was 14 days through all nine cycles of therapy, and the median delivered
      dose intensity exceeded 98% for all three agents. The median follow-up from local
      control surgery in December 1994 was 448 days (range, 82 to 632 days). Three
      patients (7.2%) had disease relapses, one during the doxorubicin portion of
      treatment and two (4.9%) who had completed treatment with all three agents.
      Sequential dose-intensive therapy with doxorubicin/paclitaxel/cyclophosphamide
      has manageable toxicity and, with short follow-up, is a promising new regimen
      suitable for randomized testing.

PMID- 8643967
TI  - Phase I/II study of paclitaxel plus cisplatin as first-line chemotherapy for
      advanced non-small cell lung cancer: preliminary results.
AB  - From March 1993 to May 1994, 32 chemotherapy-naive patients with advanced non
      small cell lung cancer entered a phase I/II study to determine the maximum
      tolerated dose and the activity of the paclitaxel (Taxol; Bristol-Myers Squibb
      Company, Princeton, NJ)/cisplatin combination. The 21 men and 11 women had a
      median age of 59 years (range, 25 to 72 years) and a median performance status of
      1 (range, 0 to 2). Histologic types were adenocarcinoma (13 cases), squamous cell
      carcinoma (10), and large cell carcinoma (nine). Nine patients had stage IIIB
      disease and 23 had stage IV disease. The first four dose levels of paclitaxel
      were 135, 175, 200, and 225 mg/m2 given with a fixed cisplatin dose of 100 mg/m2;
      at level 5, paclitaxel 225 mg/m2 was again given, and the cisplatin dose was
      increased to 120 mg/m2. Cycles were given every 3 weeks. Paclitaxel was
      administered as a 3-hour infusion followed by cisplatin, with standard
      premedication and hyperhydration. The maximum tolerated dose for the first cycle
      was not reached. Grades 3 and 4 neutropenia occurred in 24% and 16% of cycles
      (two cases with fever), respectively. Grades 2 and 3 peripheral axonal
      neurotoxicity occurred in two and 16 patients, respectively; the neurotoxicity
      appeared to be dose dependent and cumulative after a median total paclitaxel dose
      of 1,300 mg/m2. Of the 29 patients evaluable for efficacy, 11 (38%) had a partial
      response; efficacy was superior at paclitaxel doses of at least 200 mg/m2, with
      eight (47%) of 17 evaluable patients responding at these levels. In conclusion,
      at these doses of paclitaxel and cisplatin, the dose-limiting neurologic toxicity
      is dose dependent and cumulative after a total paclitaxel dose of approximately
      1,300 mg/m2. This combination is highly active, with a total objective response
      rate of 38% and an objective response rate of 47% at paclitaxel doses of 200
      mg/m2 or higher. Further evaluation is warranted.

PMID- 8643968
TI  - A phase I/II trial of combination paclitaxel and carboplatin in advanced or
      metastatic non-small cell lung cancer: preliminary results of an ongoing study.
AB  - Because of paclitaxel's (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) high
      single-agent activity in non-small cell lung cancer we developed a study to
      determine the maximum tolerated dose and a dose suitable for outpatient phase
      II/III trials of paclitaxel combined with a fixed dose of carboplatin (area under
      the concentration-time curve of 6, Calvert formula). From October 1993 to
      November 1994, 41 patients were entered into this trial, including six at dose
      level I (paclitaxel 150 mg/m2), six at dose level 2 (paclitaxel 175 mg/m2), II at
      dose level 3 (paclitaxel 200 mg/m2), 13 at dose level 4 (paclitaxel 225 mg/m2),
      and five at dose level 5 (paclitaxel 250 mg/m2). Patient characteristics included
      27 men and 14 women with a median age of 64 years (age range, 46 to 81 years).
      The median Southwest Oncology Group performance status was I (range, 0 to 2).
      Nineteen patients had unresectable stage III and 22 had stage IV non-small cell
      lung cancer. Forty-one patients and 167 treatment courses were evaluable for
      toxicity. Hematologic toxicity was generally mild to moderate, not related to
      paclitaxel dose, and never dose limiting. Thrombocytopenia was remarkably mild,
      with only one episode of grade 3 toxicity (no grade 4). Arthralgias and
      cumulative sensory neuropathy were dose related and dose limiting. The maximum
      tolerated dose was defined at the 250 mg/m2 dose level with three of five
      patients achieving grade 3 (severe toxicity. The 225 mg/m2 dose level appears to
      be well tolerated, but accrual at this dose level is ongoing. This appears to be
      a highly active regimen, with objective responses in 20 (two complete responses
      and 18 partial responses) of 32 patients with objectively measurable disease for
      an overall response rate of 62.5%.

PMID- 8643969
TI  - Combined-modality therapy for advanced non-small cell lung cancer: paclitaxel and
      thoracic irradiation.
AB  - Despite advances in the modalities used to treat non-small cell lung cancer
      (NSCLC), the frequency of locoregional and distant relapses necessitates further
      enhancement of the therapeutic program. Paclitaxel (Taxol; Bristol-Myers Squibb
      Company, Princeton, NJ) has demonstrated clinical efficacy against NSCLC and in
      vitro studies support its role as a radiation potentiator at concentrations
      achievable in vivo. Thus, a phase I study of weekly paclitaxel and daily
      concurrent thoracic radiation was conducted in patients with advanced NSCLC to
      determine (1) the maximum tolerated dose of paclitaxel administered on an
      outpatient basis for 6 consecutive weeks with daily radiation and (2) the
      toxicities of the paclitaxel/radiation combination. Paclitaxel was administered
      as a 3-hour infusion, repeated weekly for 6 weeks with the usual premedication
      regimen for hypersensitivity prophylaxis. The starting dose of paclitaxel was 10
      mg/m2/wk, which was increased by 10 mg/m2 in successive cohorts of three new
      patients, as tolerated. Radiation therapy was delivered as 40 Gy in 20 fractions
      to the original volume with a boost of 20 Gy in 10 fractions to the primary
      tumor. Doses were escalated from 10 to 70 mg/m2/wk. Of the 23 patients evaluable
      for response, one had stage II NSCLC, four had stage IIIA, 17 had stage IIIB, and
      one had stage IV. Severe esophagitis (grade 4) occurred in two of the three
      patients treated at 70 mg/m2 and was dose limiting. One patient discontinued
      therapy due to hypersensitivity, two developed grade 3 neutropenia, and one
      developed radiation pneumonitis. With a median follow-up of 7 months, 15 of the
      23 patients remain alive. Four had a complete response and 13 had a partial
      response, for an overall response rate of 74% (95% confidence interval, 52% to
      90%). The schedule of weekly paclitaxel and daily thoracic radiation appears
      active in NSCLC and can be delivered safely in the outpatient setting. The
      principal dose-limiting toxicity is esophagitis, and the maximum tolerated dose
      of paclitaxel for this schedule is 60 mg/m2/wk. A phase II trial of weekly
      paclitaxel 60 mg/m2 and radiation has been initiated in patients with NSCLC.

PMID- 8643970
TI  - Paclitaxel in lung cancer: 1-hour infusions given alone or in combination
      chemotherapy.
AB  - Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 1-hour
      infusion potentially offers its recipients reduced toxicity, demonstrated
      efficacy, and greater ease of administration. To confirm this hypothesis, we
      undertook a phase I/II study of 1-hour, single-agent paclitaxel in 164 patients'
      refractory malignancies; 59 patients with recurrent or stage IV non-small cell
      lung cancer (NSCLC) participated in the study. Our objective was to compare two
      paclitaxel doses (135 and 200 mg/m2) and two 1-hour infusion schedules (1 hour in
      1 day, or 1 hour each day for 3 days, divided dose). Results from this study show
      that paclitaxel given over 1 hour possesses marked antitumor activity. In
      patients with NSCLC, the overall response rate was 25%, with a higher response
      rate among higher-dose recipients (31% v 12%). These promising results with
      single-agent paclitaxel prompted phase II trials of combination therapy
      incorporating the 1-hour paclitaxel infusion. Twenty-three patients with locally
      advanced, unresectable stage IIIA or IIIB NSCLC have been treated with 1-hour
      paclitaxel and cisplatin/etoposide plus radiation therapy. Three patients have
      had complete responses (CRs) and another five have had "near CRs," defined as
      only nonspecific abnormalities in previously irradiated areas on computed
      tomography. Five patients had partial responses. Although the median follow-up is
      only 9 months, it is encouraging that disease has recurred in only one of the
      eight patients with CR or near CR and that toxicity has been manageable. Another
      phase II trial is evaluating 1-hour paclitaxel, carboplatin, and extended
      schedule etoposide in patients with limited or extensive small cell lung cancer.
      Of the 22 patients now evaluable for response (median follow-up, 8 months), 10
      (six with limited and four with extensive small cell lung cancer) have achieved
      CRs and 11 have achieved partial remissions. The regimen is well tolerated. The
      final results of these and other phase II trials should help clarify optimal
      paclitaxel schedules and regimens for large-scale randomized trials in patients
      with lung cancer.

PMID- 8643972
TI  - Paclitaxel: current developmental approaches of the National Cancer Institute.
AB  - National Cancer Institute studies are addressing important issues in the
      development of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ),
      including optimal dose and schedule, the development of combination chemotherapy
      and multimodality regimens, and the evaluation of paclitaxel-containing therapy
      as front-line and adjuvant treatment. Phase III trials are ongoing in ovary,
      breast, lung, and head and neck cancers. Broad phase II testing of paclitaxel is
      nearing completion. Recent identification of paclitaxel activity in esophageal,
      bladder, germ cell, and endometrial cancers and in Kaposi's sarcoma associated
      with the human immunodeficiency virus has provided additional areas for
      investigation. Promising results from initial trials provide reasons to expect
      further advances as investigators around the world continue to evaluate this
      important new drug.

PMID- 8643971
TI  - A phase I/II study of paclitaxel plus cisplatin as first-line therapy for head
      and neck cancers: preliminary results.
AB  - Improved outcomes among patients with head and neck carcinomas require
      investigations of new drugs for induction therapy. Preliminary results of an
      Eastern Cooperative Oncology Group study of single-agent paclitaxel (Taxol;
      Bristol-Myers Squibb Company, Princeton, NJ) reported a 37% response rate in
      patients with head and neck cancer, and the paclitaxel/cisplatin combination has
      been used successfully and has significantly improved median response duration in
      ovarian cancer patients. We initiated a phase I/II trial to determine the
      response and toxicity of escalating paclitaxel doses combined with fixed-dose
      cisplatin with granulocyte colony-stimulating factor support in patients with
      untreated locally advanced inoperable head and neck carcinoma. To date, 23 men
      with a median age of 50 years and good performance status have entered the trial.
      Primary tumor sites were oropharynx, 10 patients; hypopharynx, four; larynx, two;
      oral cavity, three; unknown primary, two; and nasal cavity and parotid gland, one
      each. Of 20 patients evaluable for toxicity, four had stage III and 16 had stage
      IV disease. Treatment, given every 21 days for a maximum of three cycles,
      consisted of paclitaxel by 3-hour infusion followed the next day by a fixed dose
      of cisplatin (75 mg/m2). The dose levels incorporate escalating paclitaxel doses,
      and intrapatient escalations within a given dose level are permitted if toxicity
      permits. At the time of this writing, dose level 4 (260, 270, and 280 mg/m2) is
      being evaluated; three patients from this level are evaluable. With paclitaxel
      doses of 200 mg/m2 and higher, granulocyte colony-stimulating factor 5
      micrograms/kg/d is given (days 4 through 12). Of 18 patients evaluable for
      response, seven (39%) achieved a complete response and six (33%) achieved a
      partial response. Three patients had no change and disease progressed in two. The
      overall response rate is 72%. Eleven responding patients had subsequent
      surgery/radiotherapy or radical radiotherapy. Two pathologic complete responses
      were observed in patients who had achieved clinical complete responses. Alopecia,
      paresthesias, and arthralgias/myalgias have occurred frequently, but with one
      exception (a grade 3 myalgia) they have been grade 1 or 2. No dose-limiting
      hematologic toxicity has been seen. Paclitaxel/cisplatin is an effective first
      line regimen for locoregionally advanced head and neck cancer and continued study
      is warranted. Results thus far suggest no dose-response effect for paclitaxel
      doses above 200 mg/m2.

PMID- 8643974
TI  - Abortion from a crosscultural perspective: an introduction.

PMID- 8643973
TI  - Paclitaxel combined with carboplatin in the first-line treatment of advanced
      ovarian cancer.
AB  - In a phase I study to determine the maximum tolerated dose of paclitaxel (Taxol;
      Bristol-Myers Squibb Company, Princeton, NJ) given as a 3-hour infusion in
      combination with carboplatin administered every 21 days to women with advanced
      ovarian cancer, paclitaxel doses were escalated as follows: level 1, 135 mg/m2;
      level 2, 160 mg/m2; level 3, 185 mg/m2; and level 4,210 mg/m2. The fixed dose of
      carboplatin at levels 1 through 4 was given to achieve an area under the
      concentration-time curve (AUC) of 5 using the Calvert formula. In levels 5 and 6
      the carboplatin dose was targeted at AUCs of 6 and 7.5, respectively, combined
      with a fixed paclitaxel dose of 185 mg/m2. To date, 30 previously untreated
      patients, all with a good performance status (Eastern Cooperative Oncology Group
      0 to 2) have been entered into this ongoing study. The dose-limiting toxicity of
      the combination was myelosuppression (leukopenia, granulocytopenia, and
      thrombocytopenia). Neurotoxicity was largely moderate. So far, 14 patients are
      evaluable for response; of these, eight (57%) showed objective (complete or
      partial) response and disease stabilized in six patients. No patient had disease
      progression. We conclude that the combination of paclitaxel 185 mg/m2
      administered as a 3-hour infusion followed immediately by a 1-hour infusion of
      carboplatin at an AUC of 6 can be administered safely in a 21-day schedule in the
      outpatient setting. The recommended dose for phase III studies is paclitaxel 185
      mg/m2 and carboplatin AUC 6.

PMID- 8643975
TI  - The pregnancy that doesn't stay: the practice and perception of abortion by Ekiti
      Yoruba women.
AB  - Ekiti Yoruba village women in southwest Nigeria make use of traditional and
      'patent' medicines as abortifacients as well as D&Cs performed in urban centers
      to terminate unwanted pregnancies. This paper examines present day abortion
      practices and attitudes and relates them to traditional beliefs about conception,
      fetal development and infertility. These beliefs, along with factors of economy
      and access, help to explain the continued use of abortion as a form of birth
      control, despite the presence of other options. The paper concludes with a
      discussion of the current debate about legalizing abortion in Nigeria and a
      recommendation consonant with everyday village practice.

PMID- 8643976
TI  - Abortion traditions in rural Jamaica.
AB  - Abortion is not condoned in Jamaica. Its meaning is linked to the meanings of
      kinship and parenthood, which are expressed through procreation and involve
      altruism and the assumption of responsibility for the well-being of others.
      Abortion subverts these ideals but indigenous methods for it are known and are
      secretly used. The inconsistencies between abortion talk and abortion practice
      are examined, and the structural functions of abortion (and of its culturally
      constructed, ideological meaning) are discussed. The distinction--and the overlap
      -between abortion as such and menstrual regulation is explored. The use of the
      culturally constructed 'witchcraft baby' syndrome to justify abortion is also
      investigated. Traditional abortion techniques follow from (and can illuminate)
      general health practices, which focus on inducing the ejection of 'blockages' and
      toxins, and from ethnophysiological beliefs about procreation and reproductive
      health, which easily allow for menstrual delays not caused by conception. The
      latter understanding and the similarity between abortifacients, emmenagogues and
      general purgatives allows women flexibility in interpreting the meanings of their
      missed periods and the physical effects of the remedy.

PMID- 8643977
TI  - Abortion policy and practice in Greece.
AB  - Despite its illegality until recently, abortion is estimated to have been
      responsible for almost half of the sharp postwar decline in the Greek birth rate.
      This article examines abortion as a part of a Greek contraceptive culture which
      has taken shape during the postwar period both in response, and in resistance to,
      a variety of macro- and micropolitical institutions and forces. During much of
      this period, pronatalist policies and discourses of both state and church
      combined to foreclose most medical contraceptive alternatives. In contrast,
      illegal abortion was a relatively safe, medicalized procedure widely practiced by
      doctors. Even after being legalized in 1980, female medical contraceptive methods
      continue to be rejected by the great majority of Greek women, and abortion and
      male methods of birth control remain the principal means of controlling
      fertility. The article focuses on the specific abortion practices and meanings of
      three generations of married women living in the city of Rhodes, capital of the
      Dodecanese Province of Greece's Eastern Aegean, and explores the ways in which
      they have been shaped by, and reflect, local cultural understandings of the body,
      health, sexuality, morality, motherhood and childhood, as well as micropolitical
      relations within the family.

PMID- 8643978
TI  - Women's perspectives on abortion in Romania.
AB  - Romanian women have commonly used abortion (both legal and clandestine) to
      prevent unwanted births. We introduce this paper with a brief summary of the
      recent history of abortion in Romania, then we combine quantitative data from a
      previous report ([1] Johnson et al., Lancet 341, 875, 1993) of the research with
      women's own words about the following issues: their decisions to have an
      abortion, the impact of abortion restrictions under the Ceausescu government, and
      their needs and desires for improved reproductive health services. We also
      present gynaecologists' views of abortion restrictions and needs for improved
      family-planning services to make a compelling case for the need for safe, legal,
      comprehensive abortion care in Romania and elsewhere.

PMID- 8643979
TI  - Abortion in Turkey: a matter of state, family or individual decision.
AB  - This paper gives a historical, international and cultural outlook on the debate
      related to the 1982 legalization of abortion in the modern democratic republic of
      Turkey. A belief that the country is under-populated and subsequent pro-natalist
      concerns of the turn of the century seem to have strongly influenced the legal
      prohibition of abortion. The paper first discusses the widespread social practice
      and the permissive attitudes towards abortion in the late Ottoman Empire and in
      contemporary Turkey. The contrast between the above social situation and until
      recently the strict, non-permissive religious and secular attitudes are presented
      with a discussion of the effects of the westernization and secularization
      processes in the late Ottoman Empire. Moral concerns and judgements regarding
      abortion seem to have penetrated Ottoman society as part of the above processes
      beginning in the nineteenth century. The present day official religious
      interpretations seem to conform with the more conservative Islamic schools of
      thought rather than the more liberal Islamic interpretations. Furthermore, the
      1982 laws which legalize abortion until the eight week of pregnancy consider
      family planning to be a family issue and bring the restriction of making married
      women have their husband's permission before preceding with abortion. As such,
      the present legal platform opens to question the rationales and population
      control motives behind the law and the importance of who it is that can make the
      decision to proceed with abortion. Thus, in the last 70 years a historical and
      ideological progression can be discerned in the line of assuming first the state
      and then the family to have decision making legitimacy as regards reproductive
      choices. Today, the platform of radical discussion has shifted to evaluating the
      importance of individual women in making this reproductive choice. In this
      context, in conclusion, the paper discussed the rationale and the logic behind
      and the implications for gender power structures of the existing legal situation
      in Turkey.

PMID- 8643980
TI  - Abortion law and practice in China: an overview with comparisons to the United
      States.
AB  - This article utilizes legal documents, policy statements and ethnographic data to
      compare abortion law and practice in China and the United States. It outlines
      Chinese abortion law from ancient to modern times, identifies categories of
      reasons for aborting, and describes both folk remedies and the most common
      methods of modern medicine for inducing abortion. The contemporary incidence of
      abortion is discussed in the context of official family planning policy; evidence
      is presented to suggest that while modern methods are far safer than traditional
      remedies, the use of abortion as a major form of birth control has had an impact
      on women's health. The interference of the state in women's reproductive life is
      put in historical/cultural context and compared to U.S. views of women's
      reproductive rights. Differences in conception of abortion rights are attributed
      to contrasting historical relationships between the state and the individual and
      religiously and legally based theories of human rights, including fetal
      personhood and right to life.

PMID- 8643981
TI  - Alcohol use among American Indian adolescents: the role of culture in
      pathological drinking.
AB  - Over the last 20 years, the field of substance use among American Indian
      adolescents has come to be dominated by survey approaches that are unable to
      answer important questions about how the use of alcohol and drugs is
      conceptualized and meaningfully integrated in the lives of Indian teens. Without
      a model of adolescent alcohol use that incorporates culture, the field
      misapprehends the social and cultural grounding of both normal and pathological
      drinking, and cannot accurately differentiate between normal and pathological
      drinking. Traditionally, the field has relied upon either a biological model or a
      distress model, thus locating pathology in the biochemistry of ethanol ingestion
      or in psychopathological distress. However, findings from an ethnographic
      investigation of alcohol use among American Indian adolescents suggest that the
      criteria for distinguishing pathological drinking lie, instead, in the
      developmental and gender-specific expectations that derive from cultural values.
      Specifically, at a Northern Plains site, teen drinking is judged by whether
      drinking has begun to interfere with developmental tasks relating to the cultural
      values of courage, modesty, humor, generosity and family honor. We conclude with
      suggestions for clinicians and researchers that offer the potential to facilitate
      the incorporation of culture into research and practice in the field of American
      Indian adolescent alcohol use.

PMID- 8643982
TI  - Demarcation and transformation within homoeopathic knowledge. A strategy of
      professionalization.
AB  - Both the medically and non-medically qualified homoeopaths in Britain have
      engaged in a number of changes to the way that their knowledge is constructed and
      communicated. In this paper we describe these changes and link them to claims for
      legitimacy, status and authority in the health care market. The public
      presentation of homoeopathic knowledge claims are thus linked to a 'professional
      project'.

PMID- 8643983
TI  - Black/white differences in the relationship of maternal age to birthweight: a
      population-based test of the weathering hypothesis.
AB  - This study seeks to explore if early health deterioration ('weathering') among
      young adult African American women contributes to observed increases with
      maternal age in the black/white disparity in birth outcome. Theoretically,
      'weathering' is constructed as being a physical consequence of social inequality.
      Thus, we also examine whether African American mothers vary in their age
      trajectories of poor birth outcome with respect to social class. Black or white
      singleton first births to Michigan residents aged 15-34 in 1989 (N = 54,888
      births) are analyzed, using data drawn from linked birth and infant death
      certificates augmented with census-based economic information. We find among
      blacks, but not whites, advancing maternal age above 15 years is associated with
      increased odds of LBW and VLBW. Among blacks in low-income areas, the odds of LBW
      increase 3-fold, and of VLBW 4-fold, between maternal ages 15 and 34. The
      findings suggest that African American women, on average, and those residing in
      low-income areas, in particular, experience worsening health profiles between
      their teens and young adulthood, contributing to their increasing risk of LBW or
      VLBW with advancing maternal age and to the black-white gap in this risk. The
      findings suggest the importance of comprehensive prevention strategies to improve
      the health of socioeconomically disadvantaged African American women prior to
      pregnancy and the reduction of social inequalities that impact health.

PMID- 8643984
TI  - Psychological distress among caregivers to heart transplant recipients.
AB  - To test the hypothesis that family caregivers to heart transplant recipients may
      experience higher than average levels of distress during the period post
      transplant and explore the correlates of distress, 83 caregivers were interviewed
      3 times during the first year post-transplant and evaluated on predisposing and
      psychosocial characteristics. Mean distress was significantly elevated above
      community norms at initial assessment but subsided as the year progressed.
      Multiple regression analyses showed that: (a) employment status and caregivers'
      physical health were strong predictors of post-transplant distress while
      psychiatric history was not; (b) the burden of caregiving was associated with
      increased distress early post-transplant but not in later months; and (c)
      intrapersonal and social support resources early post-transplant were associated
      with distress both short-term and long-term. Interventions targeted at these
      environmental and personal factors may be important for minimizing negative
      effects of the transplant experience on family caregivers.

PMID- 8643985
TI  - Inconsistency and health state valuations.
AB  - The comparison of scaling methods used to value health states sometimes rests
      upon an analysis of aggregate scores. This analysis is usually undertaken once
      'inconsistent' respondents have been excluded from the data. However, it is
      important to be able to judge the extent to which respondents as a whole are
      logically consistent when assigning values to health states. The degree of
      inconsistency will depend on how the health states are described, how the
      questionnaire is administered and who the respondents are. This paper analyses
      the inconsistency rates from two studies in which valuations for EuroQol health
      states were elicited using the visual analogue scale (VAS) method. The studies
      differed in design and incorporated several different variants of the standard
      EuroQol questionnaire, thus providing an opportunity to examine the relative
      importance of the different factors that were thought to affect inconsistency
      rates. Our general conclusions are that inconsistency rates are higher for
      interviewer-based than for postal surveys, possibly due to response bias, and
      that inconsistency rates are positively related to age and negatively related to
      educational attainment.

PMID- 8643987
TI  - Social roles and physical health: the case of female disadvantage in poor
      countries.

PMID- 8643986
TI  - Gender differences in health: are things really as simple as they seem?
AB  - It is conventional wisdom in medical sociology and social epidemiology that in
      industrialized societies men die earlier than women, but that women have poorer
      health than men. A number of explanations for these differences have been
      postulated and tested (for example, different biological risks, acquired risks,
      reporting biases and experiences of health care). Using two recent British data
      sets we find that the pattern of sex differences in morbidity is more complicated
      than the conventional wisdom often suggests. The direction and magnitude of sex
      differences in health vary according to the particular symptom or condition in
      question and according to the phase of the life cycle. Female excess is only
      consistently found across the life span for psychological distress and is far
      less apparent, or reversed, for a number of physical symptoms and conditions.
      Detailed inspection of papers on gender differences published in the last decade
      reveals that our findings are not unique, but that a relatively undifferentiated
      model of consistent sex differences has nevertheless continued to predominate in
      the literature. We believe that the topic of gender differences in health
      warrants periodic re-examination.

PMID- 8643988
TI  - [The presence of fluid in the paranasal sinuses in comparison with other
      diagnostic signs of drowning].
AB  - In a group of 387 drowned subjects and 50 control subjects the author
      investigated the presence and amount of fluid in the paranasal sinuses: in the
      cavity of the sphenoid bone and in the right and left maxillary sinus in
      conjunction with other signs supporting the diagnosis of drowning (presence of
      Paltauf spots, pulmonary aqueous emphysema, fluid in the stomach, drop of
      chlorides, creatinine and urea in the left heart). Fluid in the paranasal sinuses
      was found in 289 (74.4%) of the drowned subjects and in one control subject (2%).

PMID- 8643989
TI  - [Risk factors and sudden death in infancy].
AB  - The author analyzed data obtained by means of questionnaires from 58 children who
      died of the diagnosis of SIDS in the Central Bohemian region. A total of 81 data
      were evaluated pertaining to pregnancy, delivery, case-history of the mother and
      child, living and conditions and the death. The assembled data were compared with
      data in the literature. The authors confirmed the multifactorial etiology of
      SIDS. The questionnaire used was recommended for nationwide investigations of
      sudden infant deaths.

PMID- 8643990
TI  - Coordinate suppression of myeloma-specific genes and expression of fibroblast
      specific genes in myeloma X fibroblast somatic cell hybrids.
AB  - In most instances, fusion of differentiated cell types with fibroblasts has
      resulted in the extinction of the differentiation-specific traits of the non
      fibroblast parental cell. To explore the genetic basis of this phenomenon, we
      have studied a series of somatic cell hybrids between mouse myeloma and
      fibroblasts. All the hybrids were adherent having a fibroblast-like phenotype.
      Molecular analysis revealed that plasma cell specific genes like the productively
      rearranged Ig genes, the J chain gene and genes for the cell surface markers CD20
      and PC1, were extinguished in the hybrids. In contrast, fibroblast specific genes
      like fibronectin, alpha 2(I) and III collagens, as well as the receptor for
      fibroblast growth factor (flg), were expressed. Extinction was not due to
      chromosomal loss or lack of the relevant genes. To learn about the mechanism(s)
      of this phenomenon we have looked for the presence of positive and negative
      transcription factors in our hybrids. Expression of the PU.1 transcription
      factor, a member of the Ets transcription factor family normally expressed in B
      cells and macrophages, was lost in the cell hybrids. Interestingly, we found that
      the B-cell-specific Oct-2 transcription factor was still expressed at somewhat
      variable levels in several of the hybrid cell lines. In contrast, expression of
      the recently identified octamer coactivator BOB.1/OBF.1 was extinguished in all
      cell hybrids. This supports a critical role of this transcriptional coactivator
      for B-cell-specific gene expression. In addition, the Id and HLH462 genes coding
      for proteins known to repress bHLH transcription factors by formation of
      heterodimers, were found to be expressed at increased levels in fibroblasts and
      in the hybrids, indicating that their increased levels might also contribute to
      the suppression of myeloma-specific genes. Our results show that in myeloma x
      fibroblast hybrids, the phenotype of the fibroblast is dominant. It is suggested
      that fibroblasts contain regulatory "master" genes that are responsible for
      activation of the fibroblast differentiation pathway and suppress differentiation
      programs of other cell types.

PMID- 8643991
TI  - Targeted retroviral gene transfer into the rat biliary tract.
AB  - The ability to induce proliferation by temporary duct ligation suggested an
      hypothesis that retrovirus-mediated gene transfer into cells of the biliary tract
      could be accomplished. The time course of histologic changes, incorporation of 3H
      thymidine and immunofluorescent staining with a monoclonal antibody to
      cytokeratin-19 (a marker for differentiated bile ducts) was studied in male
      Fischer F344 rats. A recombinant Gibbon ape leukemia virus (GALV), containing a
      gene encoding Escherichia coli beta-galactosidase was next introduced into 24 hr
      obstructed bile ducts. Gene transfer was maximal when virus was exposed to the
      obstructed duct for 12 hr (approximately 0.1%). The majority of X-gal positive
      cells were in cytokeratin-19 negative peribiliary tissues, which had the
      appearance of newly forming bile ducts. The data suggest that cells targeted by
      retroviral infection of the obstructed rat bile duct may be a precursor of
      mature, fully differentiated biliary epithelium.

PMID- 8643992
TI  - Elevated levels of homologous DNA recombination activity in the regenerating rat
      liver.
AB  - We have characterized homologous DNA recombination activity in nuclear protein
      extracts prepared from quiescent and regenerating rat livers. Activity measured
      in regenerating liver extracts was elevated approximately 35-fold above control,
      and its appearance closely mirrored the first wave of DNA synthesis, peaking 24
      hours after a regenerative stimulus, and returning fairly rapidly to basal
      levels. We also identified a strand-transferase protein of approximately 100 kDa
      whose presence in these extracts correlates with homologous recombination
      activity. Recent evidence suggests that mammalian somatic cells possess a
      recombinational DNA repair mechanism analogous to that described in the yeast
      Saccharomyces cerevisiae. Our results indicate that this recombinational repair
      process may be regulated in vivo by, or play a role in, progression through the
      cell division cycle.

PMID- 8643993
TI  - Coordinate extinction of melanocyte-specific gene expression in hybrid cells.
AB  - Whole cell hybrids and microcell hybrids between mouse fibroblasts and pigmented
      Syrian hamster melanoma cells were analyzed for coordinate regulation of
      melanocyte-specific gene products. Extinction of pigmentation was observed in
      whole-cell hybrids and in a microcell hybrid containing a single mouse chromosome
      (mouse chromosome 1). Analysis of melanocyte-specific transcripts using reverse
      transcription, combined with the polymerase chain reaction (RT-PCR), demonstrated
      that tyrosinase, TRP-1, TRP-2, and microphthalmia transcripts were all absent in
      unpigmented whole-cell hybrids and in the monochromosomal unpigmented microcell
      hybrid. A pigmented subclone of this microcell hybrid, however, re-expressed the
      tyrosinase, TRP-1, TRP-2, and microphthalmia genes. These data suggest that all
      of these genes are coordinately extinguished by a single fibroblast locus. Since
      the only fibroblast chromosome detected in the unpigmented microcell hybrid was
      mouse chromosome 1, these results also suggest that the extinguisher locus
      affecting the expression of the tyrosinase, TRP-1, TRP-2, and microphthalmia
      genes in hybrid cells is located on that mouse chromosome (or on a fragment of
      another chromosome present in the unpigmented monochromosomal microcell hybrid
      but undetected in our analyses). In contrast to the results with the melanocyte
      specific genes mentioned above, transcripts for the melanocortin 1 receptor gene
      (MC1R) were present in the monochromosomal unpigmented microcell hybrid (although
      absent in the whole-cell hybrids). This suggests that regulation of MC1R gene
      expression is distinct from regulation of the other melanocyte-specific genes.

PMID- 8643994
TI  - Complete set of eleven region-specific microdissection libraries for human
      chromosome 2.
AB  - The construction and characterization of 11 region-specific libraries for the
      entire human chromosome 2 have been completed, including four libraries for the
      short arm and six libraries for the long arm, plus a library for the centromere
      region. These libraries were constructed using the chromosome microdissection and
      microcloning technology. Eight libraries have been described previously. This
      paper presents the final three libraries: 2q21-q22 (designated 2Q5 library), 2q11
      q14 (2Q6). and 2p11.1-q11.1 (2CEN). The sizes of the dissected regions ranged
      between 20 and 30 Mb, with the centromere region of about 4 Mb. All these
      libraries are large, potentially comprising hundreds of thousands of recombinant
      microclones. Between 77% and 97% of the microclones were shown to derive from
      respective dissected regions. From 26 to 66 unique sequence microlones were
      isolated and characterized in detail for each library. The microclones have short
      inserts, ranging between 50 and 600 bp, with a mean of about 200 bp. The short
      inserts can be conveniently sequenced as STSs to provide high density probes for
      the dissected region. A plasmid sub-library containing at least 20,000
      microclones, and usually more, has been prepared from each library and deposited
      to ATCC for general distribution. The libraries have been used effectively in
      constructing high resolution physical maps and for contig assembly, as well as in
      positional cloning of disease genes assigned to the dissected region. Comparing
      to other chromosomes with detailed mapping information and densely populated
      probes, chromosome 2 remains largely under-exploited. The availability of a
      complete set of region-specific libraries and unique sequence microclones from
      the libraries should provide valuable resources for genome analysis, high
      resolution physical mapping, region-specific cDNA isolation, and positional
      cloning for chromosome 2.

PMID- 8643995
TI  - A cyclophilin gene-like sequence maps to human X-chromosome.
AB  - We isolated cDNA fragments encoded in an X-chromosome specific YAC from the locus
      DXS995 by using direct cDNA selection method. Several of the selected cDNA
      fragments were identical to various exons of cyclophilin A gene. Hybridization of
      the selected cyclophilin cDNA fragments to the target YAC, presence of these
      sequences in an X-chromosome specific phage library and absence of a cross
      hybridizing fragment in a cell line (XL-45) that contains deletions of the
      interval Xq21, demonstrates that a cyclophilin like sequence is present in the
      human X-chromosome.

PMID- 8643996
TI  - Mapping of the P2U purinergic receptor gene to human chromosome 11q 13.5-14.1.
AB  - We mapped a human P2U purinergic receptor gene to chromosome 11q13.5-14.1.
      Oligonucleotide primers complementary to a part of the human P2U purinergic
      receptor cDNA were used to amplify a region from genomic DNAs from a panel of
      mouse/human somatic cell hybrid cell lines, each containing a single human
      chromosome. A PCR product of the expected size (378 bp) resulted from a single
      hybrid cell line containing human chromosome 11. The gene was further localized
      to a region of chromosome 11 using a sub-chromosomal hybrid panel containing
      different segments of chromosome 11. Based on the specific PCR product obtained
      and its Southern hybridization to the P2U receptor cDNA, the human P2U receptor
      gene was localized to chromosome 11q13.5-14.1.

PMID- 8643997
TI  - Production of transmitochondrial mouse cell lines by cybrid rescue of rhodamine
      6G pre-treated L-cells.
AB  - Treatment of mouse LMTK- cells with the toxic mitochondrial dye rhodamine 6G (R
      6G) at 2.5 micrograms/ml for 7 days prevented cell growth while maintaining
      viability, with less than 10(-6) cells recovering to form colonies. Pre-treatment
      of LMTK- cells with R-6G was followed by fusion with enucleated mouse 501-1 cells
      harboring a homoplasmic point mutation in the mitochondrial DNA (mtDNA) 16S rRNA
      gene conferring chloramphenicol resistance (CAPR). Cybrids and any surviving
      unfused LMTK- cells were selected in BrdU with or without CAP and their mtDNAs
      screened for the presence of the CAPR marker. Approximately 1 colony per 2 x
      10(5) LMTK- cells appeared in the fusion plates selected both with and without
      CAP. Most clones investigated were confirmed to be cybrids by showing the
      presence of the generally homoplasmic CAPR mutation, whether or not CAP selection
      was used. Hence, R-6G pre-treatment permits construction of transmitochondrial
      cybrid cell lines carrying a variety of mtDNAs, without the need for rho 0 cell
      lines.

PMID- 8643998
TI  - Current perspectives on repeat hepatic resection for colorectal carcinoma: a
      review.
AB  - BACKGROUND: Recurrence occurs in 65% to 85% of patients after initial hepatectomy
      for metastases from colorectal cancer. Approximately one half of these have liver
      metastases, and in 20% to 30% only the liver is involved. Opportunity for
      resection is frequently limited because of diffuse liver disease or extrahepatic
      extension, and only 10% to 25% of these patients have conditions amenable to
      resection. This current review is focused on the rationale, indications, and
      results of resection of hepatic metastases from colorectal cancer. METHODS: The
      major series of liver resection were reviewed, and the cases of repeat resections
      were culled out. In addition to standard clinical parameters, the indications and
      timing after initial resection and the survival and subsequent recurrence after
      repeat resection were recorded. RESULTS: A comprehensive review of the 28 series
      showed that the mean interval between the first and second liver varied from 9 to
      33 months and was about 17.5 months in the two largest series. The median
      survival in series reporting 10 or more patients was 19 months (mean, 24 months),
      which is comparable to data in single resection series. In the large French
      Association series containing 1626 patients with single resections and 144
      patients with two resections, the 5-year survival was 25% and 16%, respectively.
      The recurrence rate after repeat resection is high (greater than 60%), and one
      half are in the liver. The prognostic factors favoring repeat resection are
      variable, but they include absence of extrahepatic extension of tumor and a
      complete resection of the liver metastases. CONCLUSIONS: Repeat hepatic liver
      resection for metastatic colorectal cancer in carefully selected patients appears
      warranted in view of reasonable survival expectations, which approach that of
      single liver resection. Risk of recurrence is high, however, suggesting the need
      for rigorous preoperative and intraoperative assessment and postoperative
      adjuvant therapy

PMID- 8643999
TI  - Transplantation of kidneys from expanded criteria donors.
AB  - BACKGROUND: The critical shortage of organs for transplantation has resulted in a
      controversial expansion of the criteria used to define a suitable cadaveric organ
      donor. The shortage of kidneys has a particularly hard impact on those patients
      on the waiting list who have uncommon major histocompatibility antigens or who
      are highly immunized. METHODS: To determine outcomes between patients receiving
      grafts from expanded criteria donors (ECDs) and others, a retrospective review of
      105 consecutive kidney transplantations performed at a single institution during
      a 3 1/2 year period was conducted. A total of 44 (41.9%) patients received
      kidneys from ECDs, 45 (42.9%) from conventional cadaveric donors, and 16 (15.2%)
      from live donors. All patients were treated by the same physicians and received
      either triple or quadruple sequential immunosuppressive therapy. In general, high
      risk recipients did not receive kidneys from ECDs. RESULTS: Actuarial graft
      survival, incidence of delayed function, length of stay, and hospital charges
      were not significantly different between the ECD and conventional cadaveric donor
      groups of recipients. A higher incidence of urinary complications occurred in the
      ECD group (p=0.03). This incidence was noted primarily in the recipients of
      kidneys from donors 5 years of age or younger. However, no allografts were lost
      as a result of urinary complications. ECD kidneys that were imported from outside
      the local catchment area accounted for approximately 25% of all cadaveric
      transplantations performed. CONCLUSIONS: With appropriate selection of organs
      from ECDs, acceptable results can be obtained. ECD organs can serve to partially
      alleviate the extreme organ shortage. These organs should be procured and made
      available to those centers willing to use them.

PMID- 8644000
TI  - Prospective study of wound complications in continuous infrainguinal incisions
      after lower limb arterial reconstruction: incidence, risk factors, and cost.
AB  - BACKGROUND: Wound complications after lower extremity arterial reconstruction can
      range from a minor lymphatic leak that causes minimal disability to a severe
      infection that jeopardizes the limb and life of the affected patient. This study
      was designed to define more clearly the incidence, severity, and the cost of
      these complications. METHODS: During a 1-year period the infrainguinal incisions
      of all patients undergoing lower limb arterial reconstruction were evaluated
      prospectively. One hundred fifty-six infrainguinal incisions were monitored
      serially for the presence of infection, hematoma, seroma, serous leak, necrosis,
      or wound dehiscence. The need for additional treatment or services related to
      these complications and the cost of these services were determined. RESULTS:
      Complications occurred in 10% of 77 infrainguinal incisions that were isolated to
      the groin (groin incisions) e.g., after aortobifemoral bypass, femoral
      endarterectomy). In only one of these patients was significant cost related to
      treatment of a complication. Complications occurred in 44% of 79 incisions used
      for femoral popliteal/tibial and pedal bypasses (distal incisions). In this
      latter group independent predictors of any complication were age (p=0.02) and
      obesity (p=0.05); predictors of in-hospital infection were preoperative evidence
      of venous stasis (p=0.01) and preoperative infection in the same extremity
      (p=0.08). Fifteen distal wound complications provided additional expense related
      to reoperation, extended hospitalization or rehospitalization, and rehabilitation
      or visiting nurse services, with a mean cost per patient undergoing
      reconstruction of $688. CONCLUSIONS: After lower limb arterial reconstruction,
      infrainguinal wound complications in isolated groin incisions produce minimal
      morbidity and cost, whereas complications in incisions after distal bypass are
      both frequent and associated with significant additional expense.

PMID- 8644001
TI  - Laparoscopic splenectomy in adults and children: experience with 31 patients.
AB  - BACKGROUND: Open surgery is the standard approach for splenectomy in hematologic
      disorders, but a few cases of successful laparoscopic splenectomy have been
      reported. METHODS: Thirty-one patients (18 adults, group 1; and 13 children,
      group 2) underwent laparoscopic splenectomy. Indications for surgery included
      idiopathic thrombocytopenic purpura (25 patients), congenital spherocytosis (4
      patients), and hemolytic anemia (2 patients). In 97% of the patients the diameter
      of the spleen was less than 15 cm. RESULTS: Laparoscopic splenectomy was
      successful in 94% of the patients; conversion to open surgery was mainly related
      to hemorrhage. Accessory spleen was found in 39% in group 1 and 8% in group 2.
      Two adults received intraoperative autotransfusion. Postoperative morbidity was
      minimal. The median postoperative stay was 3 days (range, 2 to 12 days) in group
      1 and 2 days (range, 2 to 5 days) in group 2. CONCLUSIONS: Laparoscopic
      splenectomy is safe in both adults and children. Adequate selection of patients
      (small-size spleen, splenic destruction on preoperative scanning of platelets),
      appropriate preparation in patients with idiopathic thrombocytopenic purpura
      (immunoglobulin G), and meticulous surgical technique (with routine opening of
      the gastrocolic ligament to search for accessory spleen) are key factors in
      obtaining the same long-term results as with open surgery.

PMID- 8644002
TI  - William T. Bovie and electrosurgery.
AB  - For thousands of years human beings have used heat in the form of cautery to
      treat trauma and disease. By the late nineteenth century, as technology advanced,
      heat could be produced by electric current. In 1920 William T. Bovie, an
      eccentric inventor with a doctorate in plant physiology, developed an innovative
      electrosurgical unit that Harvey Cushing, the founder of modern neurosurgery,
      introduced to clinical practice. The Bovine unit passes high frequency
      alternating current into the body allowing the current to cut or coagulate. After
      75 years this basic device remains a fundamental tool in the practice of surgery.

PMID- 8644003
TI  - Clinical significance of occult micrometastasis lymph nodes from patients with
      early gastric cancer who died of recurrence.
AB  - BACKGROUND: Even after curative resection of an early gastric cancer, some
      patients die of a recurrence. It is our view that patients with early gastric
      cancer who died of their disease had occult micrometastases in perigastric lymph
      nodes at the time of the original diagnosis. In an attempt to identify these
      micrometastases, lymph nodes dissected from early gastric cancer lesions were
      stained after operation with monoclonal antibody against cytokeratin, an
      essential constituent of the cytoskeleton of epithelial cells. METHODS: The 420
      dissected lymph nodes from 34 patients with node-negative early gastric cancer
      who died of a recurrence were examined for the presence of tumor cells. We used
      immunocytochemical techniques and an antiserum to epithelial membrane antigen.
      The monoclonal antibody CAM 5.2 recognizes cytokeratin polypeptides (human
      cytokeratin numbers 8 and 18) commonly present in epithelial cells.
      Clinicopathologic characteristics and prognosis were determined for patients with
      cytokeratin-positive cells in the lymph nodes. RESULTS. Of 420 lymph nodes, 15
      (3.6%) nodes and 23.5% (8 of 34) of the patients presented with cytokeratin
      positive cells at the time of primary operation. The presence of cytokeratin
      positivity was not related to various clinicopathologic factors. The histologic
      stage of eight cytokeratin-positive cases was upstaged by the group of
      cytokeratin-positive lymph nodes from stage I to three of stage II, four of stage
      III, and one of stage IV, hematogenous recurrences were common, and the prognosis
      was poorer. CONCLUSIONS: Immunohistochemical techniques aid in identifying
      micrometastatic disease in lymph nodes missed in routine hematoxylin-eosin
      staining. Cytokeratin staining of the dissected lymph nodes is recommended to
      precisely determine tumor stage and prognosis for patients with early gastric
      cancer.

PMID- 8644004
TI  - Sump syndrome complicating Roux-en-Y hepaticojejunostomy: case report and review
      of the literature.
AB  - Sump syndrome is a rare complication of biliary-enteric anastomosis. Classically,
      the distal bile duct becomes obstructed by gastrointestinal debris after
      choledochoduodenostomy, resulting in cholangitis or, less commonly pancreatitis.
      Obstruction of the biliary tree by gastrointestinal contents after Roux-en-Y
      choledochojejunostomy or hepaticojejunostomy has not been described in the
      English-language literature. This report details the diagnostic and operative
      management of the first patient with sump syndrome after hepaticojejunostomy. The
      presumed pathophysiology was reflux of vegetable matter up the efferent limb,
      resulting in hepatic duct obstruction and cholangitis. The patient ultimately
      required complex choledochoscopic drainage of the intrahepatic biliary tree and
      revision of the previous Roux-en-Y hepaticojejunostomy.

PMID- 8644005
TI  - Recurrent varicose veins: investigation of the pattern and extent of reflux with
      color flow duplex scanning.
AB  - BACKGROUND: This study was conducted to investigate with color flow duplex
      imaging the patterns and the extent of venous valvular incompetence in recurrent
      varicose vein disease. METHODS: One hundred thirty-four limbs of 123 unselected
      patients who arrived in the outpatient clinic with residual or recurrent varicose
      veins after undergoing an operation were included. Limbs with history of
      compression sclerotherapy before or after the operation were excluded. The long
      (LSV) and short saphenous vein (SSV) systems in all limbs were examined with
      color flow duplex imaging for detection of the sites and the extent of reflux.
      RESULTS: Various patterns of recurrent valvular reflux were seen in both the LSV
      and SSV systems. Reflux confined to saphenofemoral junction alone or associated
      with reflux in the LSV system was seen in 29% of the limbs. Reflux in the whole
      LSV system was very common after saphenofemoral junction ligation was performed
      (chi-squared test, p<0.01). Most of the limbs (53%) with recurrence in the LSV
      system had incompetent perforating veins. Incompetent perforators in the thigh
      were more common after ligation (23%) than stripping (10%), but this finding was
      not true in the calf. After saphenopopliteal junction ligation was performed, the
      more common pattern was the reflux in the SSV (75%), whereas after SSV stripping
      was performed, it was the reflux in the SSV tributaries (64%). CONCLUSIONS:
      Multiple patterns of reflux develop in recurrent varicose veins. Precise mapping
      of the reflux and identification of the possible causes are required to instigate
      appropriate treatment. Color flow duplex imaging is an efficient noninvasive
      diagnostic technique to identify venous reflux.

PMID- 8644006
TI  - Converting gallbladder absorption to secretion: the role of intracellular
      calcium.
AB  - BACKGROUND: Experimental cholelithiasis is associated with elevated biliary
      calcium concentration and altered gallbladder absorption. Recent studies showed
      that extracellular calcium ([Ca2+]ec) plays a role in regulating gallbladder ion
      transport. The extent to which intracellular calcium ([Ca2+]ic) mediates the
      changes in gallbladder ion transport is not clear. We hypothesize that [Ca2+]ic
      is an important regulator of gallbladder ion transport. METHODS: Prairie dog
      gallbladders were mounted in Ussing chambers, standard electrophysiologic
      parameters were recorded, and unidirectional Na+, Cl- and H2O fluxes were
      measured before and after mucosal exposure of 10-5 mol/L calcium ionophore A23187
      was performed. RESULTS: A23187 caused an increase in transepithelial short
      circuit current and potential difference and a decrease in transepithelial
      resistance. A23187 inhibited mucosa to serosa Cl- flux and stimulated serosa to
      mucosa Na+ flux, resulting in increased net Cl- secretion and decreased net Na+
      absorption. A23187 converted H2O from absorption to secretion. Transepithelial
      short-circuit current effect of A23187 was delayed by indomethacin pretreatment
      and was completely blunted by low bathing Ca2+. CONCLUSIONS: This is the first
      demonstration that increased [Ca2+]ic converts the gallbladder from its normal
      absorptive state to a secretory one. Furthermore [Ca2+]ic appears to regulate ion
      transport through mechanisms that are partially prostaglandin-dependent. Studies
      are necessitated to define possible links between gallbladder secretion of Cl-
      and H2O and mucus hypersecretion, a well-described phenomenon associated with
      cholesterol gallstone formation.

PMID- 8644007
TI  - Decrease in muscle glutamine, ribosomes, and the nitrogen losses are similar
      after laparoscopic compared with open cholecystectomy during the immediate
      postoperative period.
AB  - BACKGROUND: The purpose of the study was to compare the postoperative muscle
      amino acid pattern, the ribosome concentration and size distribution, and
      postoperative nitrogen balance in patients who underwent either laparoscopic or
      open cholecystectomy. METHODS: Patients who underwent cholecystectomy by means of
      either laparoscopy (n=8;LAP) or laparotomy (n=8;OPEN) were studied. The
      concentrations of amino acids, ribosomes, and polyribosomes, reflecting protein
      synthesis, were determined in skeletal muscle tissue before operation and on
      postoperative day 2. The cumulated nitrogen balance was determined. RESULTS.
      Decreases in muscle glutamine (26.7% +/- 8.4% in the LAP group and 30.3% and +/-
      4.5% in the OPEN group) and in polyribosomes (28.7% +/- 6.5% in the LAP group and
      23.6% +/- 8.5% in the OPEN group) were observed without differences between the
      groups (mean +/- SEM). The nitrogen losses were similar in both groups (15.2 +/
      1.6 gm in the LAP group and 15.5 +/- 1.2 gm in the OPEN group). CONCLUSION: A
      stress++ response with effects on amino acid and protein metabolism in muscle in
      present also after laparoscopic cholecystectomy. On postoperative day 2 this
      response is of similar magnitude after both the laparoscopic and the open
      procedures.

PMID- 8644008
TI  - Reduced expression of basic fibroblast growth factor and its receptor mRNAs and
      proteins in portal hypertensive esophageal mucosa: a mechanism responsible for
      muscularis mucosae thinning and variceal rupture.
AB  - BACKGROUND: Basic fibroblast growth factor (bFGF) enhances cell migration,
      proliferation, and tissue integrity. This especially pertinent to the smooth
      muscle cells in which it stimulates cell proliferation and promotes their growth.
      The aim of this study was to determine whether expression of bFGF and its
      receptors (FGFR-1 and -2) is altered in portal hypertensive esophageal mucosa,
      especially in the muscularis mucosal layer, which constitutes a physical barrier
      to variceal rupture. METHODS: Portal hypertension (PHT) was produced by staged
      portal vein ligation. In 30 PHT rats and 30 sham-operated controls 2 weeks after
      operation, specimens of lower esophagus were obtained for (1) quantitative
      histologic assessment including thickness of epithelium and muscularis mucosae;
      (2) immunostaining with specific antibodies against bFGF and its receptors 1 and
      2 (intensity of bFGF, FGFR-1 and FGFR-2 immunostaining in esophageal structures
      was measured with a video image system); and (3) expression of bFGF and FGFR-1
      and -2 mRNAs was assessed with reverse transcription-polymerase chain reaction.
      RESULTS: The esophageal muscularis mucosae and epithelium overlaying large
      submucosal veins in PHT rats significatly thinner than those in controls
      (muscularis mucosae, 28.3 +/- 1.4 versus 52.2 +/- 8.0 micrometer, respectively,
      p<0.05); epithelium, 39.0+/- 7.1 versus 49.3 +/- 1.9 micrometer, respectively,
      p<0.05). The immunostaining intensity of bFGF and FGFR-2 was significantly
      reduced in PHT rats (42.1 +/- 2.3 and 71.3 +/- 6.5 units, respectively) versus
      controls (49.5 +/- 5.6 and 78.6 +/- 5.7 units, respectively, p< 0.05).
      Expressions of bFGF and FGFR-2 mRNAs in PHT esophageal mucosa were significantly
      reduced versus controls by 30.8% and 30.3%, respectively (p < 0.01, p 0.05).
      CONCLUSIONS: (1) Esophageal mucosa of PHT rats has thinner muscularis mucosae and
      reduced bFGF and FGFR-2 mRNAs and proteins. (2) Because bFGF stimulates smooth
      muscle cell proliferation and their growth, our findings can explain thinning of
      esophageal muscularis mucosae in PHT rats, thus indicating a possible mechanism
      for rupture of varices in the esophagus.

PMID- 8644009
TI  - Should all hepatic arterial branches be reconstructed in living-related liver
      transplantation?
AB  - BACKGROUND: Because graft arteries are smaller and shorter in living-related
      liver transplantation (LRLT) than in whole or reduced-size liver transplantation
      from cadavers, arterial reconstruction is thought to be one of the critical
      points for success. METHODS: Thirty LRLT patients were classified into two
      groups: those in whom all graft hepatic arteries were reconstructed (group A),
      and those whom only had some were reconstructed (group B). In group A 17 patients
      had a single hepatic artery and three had two hepatic arteries. In group B the
      thickest one of several arteries was reconstructed, but the others were ligated
      after pulsatile back-bleeding from their cut stumps had been confirmed. The
      clinical results were compared between the two groups. RESULTS: Neither arterial
      thrombosis nor liver dysfunction related to the arterial blood supply was
      observed during the postoperative course. One case of bile leakage and two cases
      of bile duct stenosis occurred in group A. No significant difference was noted in
      the postoperative values of aspartate aminotransferase, alanine aminotransferase,
      and lactate dehydrogenase between the two groups. Overall patient and graft
      survival was 90%. CONCLUSIONS: Although several hepatic arteries may supply the
      potential allograft in LRLT, it is not always necessary to reconstruct all of
      them.

PMID- 8644010
TI  - Effects of intraoperative chemohyperthermia in patients with gastric cancer with
      peritoneal dissemination.
AB  - BACKGROUND: The most common cause of noncurative resection and recurrence is
      gastric cancer is peritoneal seeding. However, the results of treatment of
      peritoneal dissemination with chemotherapy have been poor with 5-year survival
      rates of 0%. METHODS: A new in vitro thermochemosensitivity test was performed on
      gastric cancer cells obtained from 19 surgically resected specimens by using
      tetrazolium-based colorimetric assay (MTT assay). A novel treatment of the
      intraoperative chemohyperthermia was undertaken in 83 patients with gastric
      cancer with peritoneal dissemination. After aggressive resection of primary
      tumor, lymph nodes, and peritoneal metastases, warmed saline solution containing
      mitomycin C 30 mg, etoposide 150 mg, and cisplatin 300 mg was introduced into the
      peritoneal cavity via a closed circuit continuous hyperthermic peritoneal
      perfusion (CHPP) for 60 minutes to keep the abdominal temperature at 42 degree to
      43 degrees C by means of a heat exchange mechanism. RESULTS: The in vitro
      thermochemosensitivity test that 43 degrees C enhanced the cytotoxin effects on
      gastric cancer cells under clinically achievable drug concentrations. During
      CHPP, drug concentrations of cisplatin, mitomycin C, and etoposide in the
      perfusate remained statistically higher than in the peripheral venous
      circulation. Among 43 evaluable patients with residual peritoneal seeding, eight
      (19%) and nine (21%) exhibited complete response and partial response,
      respectively. The overall 1- and 5-year survival rates were 43% and 11%,
      respectively. Patients who underwent complete resection survived significantly
      longer than those with residual disease, and those with complete response had a
      significantly better prognosis than did those with partial response, and
      nonresponders. One-year survival rates with complete response, partial response
      or nonresponders were 88%, 27% and 22%, respectively. Five patients survived
      longer than 5 years. CONCLUSIONS: Our triple treatment combining surgery and CHPP
      is an effective therapy for selected patients with gastric cancer with peritoneal
      dissemination.

PMID- 8644011
TI  - Insulin metabolism after relief of obstructive jaundice: intravenous glucose
      tolerance test with portal blood sampling.
AB  - BACKGROUND: Glucose intolerance and impaired insulin secretion are often
      associated with obstructive jaundice. Our objective was to determine whether such
      abnormalities would be ameliorated after jaundice was relieved by biliary
      drainage. METHODS: Twenty-four patients with hepatobiliary malignancy
      prospectively underwent intravenous glucose tolerance test with femoral and
      portal blood sampling, and the kinetics of insulin release were determined.
      Sixteen patients had obstructive jaundice (group A) that had been completely
      relieved by percutaneous transhepatic biliary drainage by the time of intravenous
      glucose tolerance testing, and eight patients exhibited no jaundice (group B).
      RESULTS: Integrated immunoreactive insulin (sigmaIRI, 10 muU min/ml; mean +/- SD)
      and integrated C-peptide (sigmaCPR, 10 ng min/ml) in the portal blood in group A
      were significantly lower than those values in group B (sigmaIRI: group A, 436.0
      +/- 260.6; group B, 714.3 +/-287.2; p< 0.01; sigmaCPR; group A, 26 +/- 10.1;
      group B 49.5 +/- 18.8; p<0.005). The hepatic insulin extraction ratio (portal
      femoral difference of sigmaIRI divided by portal sigmaIRI) in group A was
      significantly higher than that in group B (group A, 0.75 +/- 0.06; group B, 0.55
      +/- 0.05; p<0.001), whereas the hepatic CPR extraction ratio did not differ
      significantly between the two groups (group A, 0.37 +/- 0.10; group B, 0.39 +/-
      0.05). CONCLUSIONS: The impaired insulin secretion caused by obstructive jaundice
      is not fully reversed after percutaneous transhepatic biliary drainage. The high
      hepatic extraction ratio of insulin in patients who had been treated with
      percutaneous transhepatic biliary drainage may compensate for the impaired
      insulin secretion, although its mechanism is still unclear.

PMID- 8644012
TI  - Recurrent hepatitis C virus hepatitis in liver transplant recipients receiving
      tacrolimus: association with rejection and increased immunosuppression after
      transplantation.
AB  - BACKGROUND: Recurrent hepatitis C virus is associated with significant morbidity
      and mortality after liver transplantation. However, the risk factors for clinical
      recurrence including the role of rejection and immunosuppression have not been
      defined in patients receiving tacrolimus (FK506) as primary immunosuppression.
      METHODS: Sixty-six consecutive adult liver transplant recipients receiving
      tacrolimus as primary immunosuppression were monitored; 31 of 66 underwent
      transplantation for end-stage liver disease caused by hepatitis C virus. Median
      follow-up for the patients in the study was 3 1/2 years. Recurrent hepatitis C
      virus hepatitis determined on histopathologic evaluation developed in 58% (18 of
      31). A number of clinical variables including rejection and intensity of
      immunosuppression were assessed for patients with and without recurrence.
      RESULTS: Rejection episodes preceding recurrence were documented in 72% (13 of
      18) of patients with recurrence compared with 23% (3 of 13) in those without
      recurrence (p=0.007). A total of 33% (5 of 15) of patients with no rejection
      experienced recurrence versus 83% (5 of 6) with one episode of rejection (p=0.06)
      and 80% (8 of 10) with more than one episode of rejection (p=0.04). The mean
      number of steroid boluses for the treatment of rejection was higher for patients
      with recurrence (2.3 versus 0.77, p=0.01). Overall immunosuppression (as measured
      by steroids boluses, recycles, OKT3, and azathioprine) was significantly more
      intense for patients with recurrence (p=0.013). CONCLUSIONS: Greater rejection
      concurrent with increased immunosuppression was associated with a higher
      recurrence of hepatitis C in liver transplant recipients.

PMID- 8644013
TI  - Basic fibroblast growth factor mediates angiogenic activity in early surgical
      wounds.
AB  - BACKGROUND: Wound angiogenesis is believed to be initiated by the early rapid
      release of performed growth factors such as basic fibroblast growth factor
      (bFGF). However, neither the angiogenic environment of early surgical wounds nor
      the potential contribution of bFGF to early surgical wound angiogenesis has been
      investigated. METHODS: We collected surgical drain fluid (SDF) from closed
      suction drains 6 hours to 6 days after operation. SDF was tested for endothelial
      cell (EC) proliferative and chemotactic activity and for the capacity to
      stimulate angiogenesis in vivo in the rat corneal assay. bFGF levels of SDF were
      determined with enzyme-linked immunosorbent assay. Neutralizing antibody to bFGF
      was used to determine the contribution of bFGF to SDF activity. RESULTS: The EC
      proliferative activity of SDF was maximal on postoperative day 0 (POD 0, 390%
      that of normal serum) and then fell by 41% on POD 1 and to near serum levels
      thereafter. SDF from PODs 0 and 1 also showed marked EC chemotactic activity and
      stimulated rapid formation of new vessels without signs of inflammation when
      implanted into rat corneas. The temporal appearance of bFGF in these exudates
      showed a pattern similar to EC proliferative activity, peaking on POD at 854
      pg/ml and decreasing 80% by POD 2. Neutralizing antibody to bFGF decreased he
      proliferative activity of SDF from PODs 0 and 1 to near serum levels and
      substantially decreased the chemotactic and the in vivo neovascular response to
      SDFs. CONCLUSIONS: Surgical wounds are characterized by a rapid and early
      angiogenic environment that is mediated in part by bFGF, suggesting that tissue
      or platelet stores of bFGF may initiate wound repair.

PMID- 8644014
TI  - Methodologic standards in surgical trials.
AB  - BACKGROUND: Concerns have been raised that flaws in the design and analysis of
      trials will hinder the interpretation of their relevance to clinical practice.
      The objective of this study was to review the nature and methodologic standards
      of surgical trails published in 10 prestigious journals between January 1988 and
      December 1994. METHODS: We evaluated the demography and methodologic standards of
      364 trials. Each article was independently scrutinized by two assessors with
      documentation of the interassessor variation. RESULTS: Less than 50% of the
      trials made comment about an unbiased assessment of outcome, gave an adequate
      description of the randomization technique, or provided a prospective estimate of
      the sample size. Economic factors were declared in 6.5% of the trials. Only 2% of
      the trials attempted to measure the effect of an intervention on the quality of
      life patients. CONCLUSIONS: Readers should be cautious when interpreting the
      results of surgical trials.

PMID- 8644015
TI  - Observational studies as alternatives to randomized clinical trials in surgical
      clinical research.

PMID- 8644016
TI  - Bile duct carcinoma arising from the anastomotic site of hepaticojejunostomy
      after the excision of congenital biliary dilatation: a case report.

PMID- 8644017
TI  - Small bowel obstruction after laparoscopic cholecystectomy as a result of a
      Maydl's herniation of the small bowel through a trocar site.

PMID- 8644018
TI  - Basic surgical research.

PMID- 8644019
TI  - Use of somatostatin analog in the management of traumatic parotid fistula.

PMID- 8644020
TI  - [The problems in optimizing the delivery of general therapeutic care at the
      regional level during the transition to compulsory medical insurance].
AB  - The authors hold that perfection of local therapeutic service in present-day
      situation when insurance principles are introduced in medical care may be
      achieved through design of medico-economic standards of guaranteed minimum of
      medical aid for each citizen of Russian Federation. This approach allows accurate
      estimation of required personnel and equipment. The standards should not replace
      the principle of individual approach to each case.

PMID- 8644021
TI  - [Diabetes mellitus: its prevalence, relationship to the risk factors for IHD and
      prognostic importance (an epidemiological study)].
AB  - Sample examination of the population aged 25-64 basing on the disease history,
      fasting blood glucose test, glucose tolerance test, WHO criteria, diabetes
      mellitus was found in 6% of males and 6.9% of females. Only 2.7% of males and
      3.1% of females were aware of their disease. Glucose tolerance test discovered
      abnormal carbohydrate tolerance in 5.6% and 13.3% of male and female examinees,
      respectively. Thus, a total of 12.2% of males and 20.2% of females had various
      disorders of carbohydrate metabolism. Diabetes mellitus patients had often
      hypercholesterolemia, hypertriglyceridemia, obesity, hypertension, low 10-year
      survival.

PMID- 8644022
TI  - [The dynamics of the prevalence of IHD among men working by the field-watch
      method at an oil- and gas-producing complex in western Siberia].

PMID- 8644023
TI  - [The dynamics of the risk factors for IHD and the physical work capacity of the
      workers on locomotive teams based on the results of prospective observations].
AB  - The paper reports the results of a simultaneous study of muscular performance
      (MP) and main risk factors (RF) of ischemic heart disease (IHD) in 466 locomotive
      team members aged 30-49 free of IHD symptoms. A negative relationship has been
      established between MP and systolic, diastolic pressure, body mass. A 4-6-year
      follow-up of MP and IHD RF showed that MP improvement was associated with a trend
      to improvement in RF, while MP worsening entailed greater risk of IHD, especially
      in a group of 30-39-year-olds.

PMID- 8644024
TI  - [The clinico-genetic aspects of familial hypercholesterolemia and their applied
      significance].
AB  - Clinico-biochemical, genealogical evidence was compared to molecular-genetic
      findings on LDLP receptor gene in 4 families with a history of high blood
      cholesterol. It was found that members of the same family carrying the anomalous
      gene can demonstrate varying atherogenic shift in blood lipid fractions
      suggesting involvement of other endo- and exogenic factors. Molecular-genetic
      examination of subjects with family hypercholesterolemia discovered a family with
      structural derangement of the gene, two families with spot defects and a family
      in which the proband's hypercholesterolemia seemed unrelated to changes in the
      gene, but probably related to the gene controlling synthesis of apoB-protein.

PMID- 8644025
TI  - [New drug forms of molsidomine, Corvaton-forte and Corvaton-retard, and their
      antianginal efficacy in stenocardia patients].

PMID- 8644026
TI  - [The efficacy of emoxipin and neoton in unstable stenocardia].
AB  - 55 patients with unstable angina pectoris (group 1) received conventional
      treatment and neoton infusions (30 g/day for 3 days). Emoxipin was injected
      intramuscularly to 20 patients of group 2 (3 mg/kg for 20 days) and intravenously
      to 38 patients of group 3 (10 mg/kg). Control group consisted of 100 patients.
      Stabilization occurred in 89.2, 80 and 86.8% of group 1, 2 and 3 patients,
      respectively, versus 78% in controls. Holter ECG monitoring provided evidence on
      decline of myocardial ischemia for group 1 patients. Diene conjugates in group 1
      decreased by 37%, ceruloplasmin level was higher by 30% compared to controls.
      Respective indices for emoxipin reached 52 and 37%, respectively. It is concluded
      that emoxipin and neoton produced a beneficial effect on unstable angina pectoris
      through correction of lipid peroxidation.

PMID- 8644027
TI  - [The effect of the dietary correction of nutrition on rehabilitative efficacy in
      IHD patients after having had a myocardial infarct during dispensary
      observation].
AB  - Follow-up of 218 postmyocardial infarction males on treatment in a cardiological
      hospital revealed that additional diet correction improves clinical condition of
      the patients, reduces excessive body mass and elevated blood levels of total
      cholesterol, triglycerides, atherogenic lipoproteins. As a result, 94% of the
      patients resumed their jobs.

PMID- 8644028
TI  - [Arterial hypertension and purine metabolic disorder].

PMID- 8644029
TI  - [The use of the delayed-action form of korinfar in arterial hypertension,
      stenocardia and hypertrophic cardiomyopathy].
AB  - Corinfar-retard (CR) was tried in 146 patients, the acute test was performed in
      26 cases. The findings confirm antihypertensive activity of the drug, reduced
      frequency of sharp changes in blood pressure and of hypertensive crises, side
      effects, its ability to diminish platelet aggregation. As for coronary heart
      disease. CR is more beneficial in non-severe angina of effort, spontaneous
      angina, associated hypertension. In hypertrophic cardiomyopathy prolonged
      administration of CR resulted in moderate subjective response. A CR two-month
      course did not induce noticeable changes in serum lipids. Hypertensive subjects
      on the acute test improved some hemodynamic and diastolic parameters.

PMID- 8644031
TI  - [The diagnostic potentials of magnetocardiography in the combined examination of
      patients with cardiomyopathies].
AB  - Diagnostic potential of magnetocardiography (MCG) was elucidated in comparison to
      ECG and echo-CG in 8 patients with cardiomyopathy (CMP) versus 28 healthy males.
      Elements of normal MCG curve were characterized in relation to incidence rate.
      Changes in MCG curve were considered with regard to hypertrophy of basal
      interventricular septum. In left ventricular hypertrophy MCG showed shifts
      corresponding to the degree of ventricular dilation. MCG diagnostic opportunities
      are shown in detection of right ventricular hypertrophy in the presence of the
      right His bundle blockade in patients with dilated CMP.

PMID- 8644032
TI  - [Therapeutic "masks" of primary hypothyroidism].
AB  - Misdiagnosis of primary hypothyroidism may be due to its running under the mask
      of myocardiodystrophy, coronary heart disease, bacterial and allergic
      myocarditis, arterial hypertension. It may underlie edema or accompany malignancy
      (thyroid cancer, in particular). Accurate diagnosis is complicated by primary
      damage to one organ or system.

PMID- 8644030
TI  - [The clinical, hemodynamic and hormonal-metabolic effects of the calcium
      antagonist treatment of middle-aged and elderly patients with IHD at the
      polyclinic stage of rehabilitation].
AB  - 160 presenile and senile CHD patients received calcium antagonists nifedipine,
      verapamil, diltiazem. The highest antianginal effect occurred after a course of
      verapamil with special effect in those functionally compromised.
      Rheoencephalographic picture was dependent on the initial functional class of the
      patient and overall treatment efficacy. The response was associated with low
      hydrocortisone and thyroxine levels, high glucose tolerance and content of
      ionized calcium.

PMID- 8644033
TI  - [Monoclonal free light-chain immunoglobulins: their clinical interpretation].
AB  - 23 cases of free light chains (FLC) occurrence in the blood and/or urine in the
      absence of monoclonal gammopathy are reported. Of them 15 cases were attributed
      to renal diseases associated with deranged catabolism of low-molecular proteins
      including FLC. In the rest cases FLC hyperproduction in autoimmune diseases was
      suspected to cause FLC appearance. No correlation was found between the amounts
      of FLC, creatinine, beta 2-microglobulin, light chains, kappa/lambda proportions.

PMID- 8644034
TI  - [Endothelial antibodies in Sneddon's syndrome].
AB  - Endothelial antibodies (EAB) were determined by enzyme immunoassay in 39 patients
      with Sneddon syndrome. EAB were detected in 12 patients (31%). Antibodies to
      phospholipids occurred more frequently in EAB-positive patients. Clinically, EAB
      positive and EAB-negative patients were similar except renal syndrome which in
      the form of proteinuria was more frequent in EAB-positive subjects.

PMID- 8644036
TI  - [The international ethical requirements for medical research with human
      participation].

PMID- 8644035
TI  - [Isolated microhematuria as the manifestation of lupus nephritis].
AB  - The paper is concerned with lupus nephritis with marked microhematuria. The
      presence of severe morphological alterations in the kidneys, hematuria gravity
      correlation with that of SLE, positive effects of active immunosuppressive
      treatment allow one to consider hematuria as a separate clinical criterion of
      lupus nephritis activity. A case is reported of a female who had unusual clinical
      picture of the disease possibly due to high IgA in the blood and the presence of
      renal vasculitis.

PMID- 8644038
TI  - [The effect of smoking on the status of immunity and on antiprotease protection].

PMID- 8644037
TI  - [Cholelithiasis. New developments in prevention].

PMID- 8644039
TI  - [Antimalarial preparations in rheumatology: new prospects].

PMID- 8644040
TI  - [The effect of micronized phenofibrate on the lipoproteins of the blood plasma at
      different initial lipid levels].
AB  - Novel antihyperlipidemic micronized phenofibrate lipantil 200 M was tested for
      safety and efficacy (one 200 mg capsule a day for 3 months) in 27 patients having
      cholesterol level above 6.5 mmol/l. The effect emerged upon 1 month of
      administration and persisted till the end of the treatment. In combined
      hyperlipidemia triglycerides decreased by 45-60%, total cholesterol and LDL
      cholesterol by 10-12%. In isolated hyperlipidemia the latter two values appeared
      lower by 20-23 and 22-27%, respectively. After lipantil 200 M treatment HDL
      cholesterol went up by 9% in low baseline level (< 1 mmol/l) by 27%. No negative
      clinico-biochemical shifts were seen, while fibrinogen and uric acid reduced by
      16%, apoB by 23-30%. Lipantil 200 M proved active against hyperlipidemia and is
      recommended for clinical practice.

PMID- 8644041
TI  - [Methods for assessing the theoretical and practical training of students in a
      department of polyclinic therapy].

PMID- 8644042
TI  - [The general practice physician--myth or reality?].

PMID- 8644043
TI  - [The Systemic Vasculitis Symposium based on materials from the scientific
      conference of the Institute of Rheumatology of the Russian Academy of Medical
      Sciences].

PMID- 8644044
TI  - [Overweight--overestimated or underestimated health problem?].

PMID- 8644045
TI  - [Air bags--do they help?].

PMID- 8644046
TI  - [Chronic pain--a field to concentrate on].

PMID- 8644047
TI  - [Patients with cancer-related pain and other chronic pain. Priorities and
      assessment].
AB  - In a survey completed at our hospital, 519 doctors and nurses were asked how pain
      treatment was estimated whether it received priority, and to what degree
      patients' pain syndromes were assessed. A total of 473 responded to the
      questionnaire. In the study cancer-related pain and pain from causes other than
      cancer were assessed in separate population groups. The responders considered
      that the staff gave higher priority to patients with cancer-related pain, than to
      patients with other pain. There was a discrepancy between the physicians' and the
      nurses' answers to the question whether optimal pain relief was obtained. In the
      cancer pain group, 94% of the physicians and 78% of the nurses assumed that
      optimal pain relief was obtained fairly often or very often. The corresponding
      figures in the non-cancer pain group were 53% for the physicians and 35% for the
      nurses. Only 46% assumed that a planned pain assessment was done as a routine.
      Physicians and nurses alike experienced great inadequacy in their work with
      patients in pain. This was expressed more clearly in connection with pain not
      caused by cancer.

PMID- 8644048
TI  - [Chloroquine poisoning].
AB  - More travel abroad and changes in the prevalence of malaria have made chloroquine
      more widely prescribed for prophylaxis and treatment. Acute chloroquine poisoning
      is life threatening, involving high risk of death caused by cardiac arrest,
      arrhythmia and apnoea within a few hours of ingestion. Rapid absorption of the
      drug from the gastrointestinal tract, and high toxicity, produce the sudden
      clinical symptoms after overdose. We describe the case of a 16 year-old woman who
      ingested 1.95 grams of chloroquine base. After an initially short period of
      apnoea, she was successfully treated with mechanical ventilation and large doses
      of diazepam. Plasma chloroquine levels showed an initial peak of 6.7 mumol/l. The
      pharmacokinetics of the drug and its major metabolite, the clinical features of
      an overdose of chloroquine and the principles of treatment are discussed.

PMID- 8644049
TI  - [Theophylline poisoning--clinical course and treatment].
AB  - After about half a century of treatment of asthma and chronic obstructive
      pulmonary disease, theophylline still occupies a central position in the
      treatment of these conditions. Severe poisonings are rare and may occur as a
      result of chronic over-medication or acute self-poisoning. The clinical course
      depends not only on the amount taken and the peak serum concentration, but also
      on whether the intoxication is acute or chronic. The therapeutic range is narrow
      (55-110 mumol/l). Total body clearance of theophylline varies considerably
      between individuals, and drug interactions are common. These circumstances lead
      to relatively high risk of poisoning. Clinical features vary from moderate
      gastrointestinal discomfort, particularly nausea, tremor and tachycardia, to life
      threatening conditions affecting the cardiovascular and central nervous systems.
      Treatment is discussed in connection with a presentation of three case histories.

PMID- 8644050
TI  - [Granulocyte colony-stimulating factor in neutropenia secondary to lymphoid bone
      marrow infiltration].
AB  - In patients with low-grade lymphoid malignancy, severe neutropenia due to massive
      bone marrow infiltration of lymphocytes increases the risk of infection,
      especially after myelosuppressive chemotherapy. Three patients (two with chronic
      lymphocytic leukemia and one with follicular lymphoma) with massive bone marrow
      infiltration and neutropenia not caused by short-term effects of chemotherapy,
      were treated with G-CSF for five two-week periods, to find out if the neutropenia
      was reversible. All three patients initially responded to G-CSF with an increase
      of neutrophil counts into the normal range or above. In one patient, G-CSF
      administered after a subsequent course of myelosuppressive chemotherapy
      apparently prevented severe chemotherapy-induced neutropenia. Retreatment of a
      previous responder in a later, preterminal stage of the disease produced very
      little response in terms of neutrophil counts. G-CSF can increase peripheral
      blood neutrophil counts to normal levels in patients with severe neutropenia
      induced by lymphoid bone marrow infiltration.

PMID- 8644051
TI  - [Hepatic artery aneurysm. Diagnosis and treatment].
AB  - From 1990 until 1995, four patients were successfully treated for symptomatic
      aneurysm of the hepatic artery, with rupture in three of them. In two of the
      patients, the aneurysm was located in the common hepatic artery. In one patient
      it ruptured. Both aneurysms were resected. One patient also underwent vascular
      reconstruction. The other two aneurysms ruptured in the left and right hepatic
      artery respectively. The aneurysm in the right hepatic artery was treated by
      selective embolization. The aneurysm in the left hepatic artery was ligated, and
      the patient was subsequently reoperated on for septic necrosis of the left lobe
      of the liver.

PMID- 8644052
TI  - [Spontaneous retroperitoneal hemorrhage].
AB  - Spontaneous retroperitoneal haemorrhage is most frequently due to rupture of an
      abdominal aortic aneurysm. Pathology in other retroperitoneal organs, most often
      the kidney and the adrenal gland, may cause retroperitoneal haemorrhage.
      Spontaneous rupture of veins, especially the iliac vein, and haemorrhage
      secondary to anticoagulant therapy, are less common causes. The symptoms are
      variable and non-specific, but most often include acute abdominal pain,
      hypotension, peritoneal irritation and a palpable abdominal mass. The diagnosis
      is confirmed by ultrasonography, computerized tomography, and if relevant
      angiography or scintigraphy. We discuss three patients with spontaneous
      retroperitoneal haemorrhage, examine the clinical approach and the role of the
      various diagnostic aids, and consider how the various conditions should be dealt
      with.

PMID- 8644053
TI  - [Results after surgical treatment of abdominal aortic aneurysm].
AB  - During the period 1983-1993 altogether 403 patients were operated on for
      abdominal aortic aneurysm. The median age was 69.5 years. 246 were operated on
      electively whereas 58 had symptoms without rupture and 99 had ruptured aneurysm.
      The 30 day mortality in the three groups was 4.1, 12.0 and 28.3% respectively.
      The mortality in hospital was 4.5, 12.0 and 31.3% in the three groups
      respectively. Coronary artery disease dominated as cause of death in the group as
      a whole, whereas irreversible shock and complications secondary to haemorrhage
      were common in the group with ruptured aneurysm. There were no graft infections
      in this series, and only one superficial infection which healed without
      complications. Investigation and treatment of coronary artery disease might
      perhaps decrease the mortality rate in the elective group. These results form a
      basis against which the results of endovascular treatment should be compared.

PMID- 8644054
TI  - [Ambulatory surgery--preoperative examinations].
AB  - The increasing use of ambulatory surgery has led to greater focus on the
      rationale for preoperative screening tests. What pre-operative tests are selected
      depends on the patient's history and a clinical examination with the focus on
      general health. A preoperative ECG of patients older than 60 years of age is the
      only test which should be performed as a routine prior to ambulatory surgery.

PMID- 8644055
TI  - [Selection of patients for ambulatory surgery].
AB  - Operation by an ambulatory surgical unit is becoming much more common. Both more
      extensive surgical procedures and patients with significant diseases are now
      being scheduled for day surgery. This makes it necessary to establish systems by
      which to identify and evaluate patients at risk. The author discusses certain
      factors that must be considered when deciding whether a patient is suited for day
      surgery. Many ASA (American Society of Anesthesiologists) class 3 patients, and
      in the case of minor surgical interventions, even some class 4 patients, can
      safely be treated on a day-case basis in a well-planned ambulatory unit. In
      Norway today, there are large variations among hospitals as regards which
      procedures and which patients are accepted for day surgery.

PMID- 8644056
TI  - [Losartan and the LIFE-study. Antihypertensive treatment with AT1-receptor
      antagonist].
AB  - The renin-angiotensin system, through the effects of angiotensin II, may be
      involved in the pathogenesis of essential hypertension and associated left
      ventricular hypertrophy. Treatment with angiotensin-converting enzyme inhibition
      (ACEI) lowers blood pressure and reduces left ventricular hypertrophy. ACEI,
      however, may not completely inhibit the production of angiotensin II and its
      effects, and adverse effects like cough and rise in creatinine have been
      associated with ACEI and reduced degradation of bradykinin. The first selective
      antagonist of the angiotensin II-1 (AT1) receptor, losartan, has recently been
      approved. The LIFE study has been started, in which 8,300 hypertensive patients
      with left ventricular hypertrophy in Scandinavia and the USA will be randomized
      to blinded treatment with either atenolol or losartan to compare the effects on
      cardiovascular morbidity and mortality over a period of five years.

PMID- 8644057
TI  - [Cardiopulmonary resuscitation skills. A survey among health and rescue personnel
      outside hospital].
AB  - The aim of this study was to survey practical skills and theoretical knowledge in
      lifesaving first aid among health and rescue workers outside hospital. 45 police
      officers, 46 firemen, 57 nurses and 42 general practitioners participated.
      Unprepared, they were presented with a "patient" (resuscitation doll) without
      respiration or heart beat, and were asked to do what was necessary to revive the
      "patient". They were afterwards questioned about specific emergency medical
      situations, how they assessed their own achievement and when they last had
      training in cardiopulmonary resuscitation. Only 1% were able to perform
      satisfactory basic cardiopulmonary resuscitation of a cardiac arrest according to
      the accepted guidelines, and only 17% ventilated and compressed efficiently with
      a rhythm of 2:15 or 1:5. 50% believed they were efficient in lifesaving first
      aid. Those who had taken a course in first aid during the previous year achieved
      significantly better results than the rest. It is concluded that health and
      rescue workers outside hospital follow the European Resuscitation Council's
      guidelines for basic cardiopulmonary resuscitation to only a small degree, but
      that the situation can be improved by more regular training.

PMID- 8644058
TI  - [Costs of medical treatment of injuries in Norway].
AB  - The objective of this study was to estimate the cost of medical treatment of
      injuries in Norway. We analysed aggregated data from two sources, the National
      Hospital Discharge Register and the National Injury Register, in order to
      calculate such costs in 1994. Approximately 400,000 injuries treated in hospitals
      and emergency departments in 1994 cost NOK 1.7 billion in terms of medical
      treatment. Unintentional injuries accounted for 91%, self-inflicted injuries for
      3%, and injuries stemming from violence for 6% of the costs. Injuries requiring
      hospitalisation accounted for 71% of the total costs. Persons aged 65 years or
      more constituted 14% of the cases but accounted for 46% of the cost of treating
      unintentional injuries. Injuries at home or during leisure time accounted for 75%
      of the costs of the unintentional injuries, while traffic injuries accounted for
      7%, occupational injuries for 8%, and 10% of the costs could not be classified.
      Hip fractures alone accounted for 27% of the total costs. Traffic and
      occupational injuries remain important targets for prevention, but greater
      efforts are required to reduce risk of injuries in the home and during leisure
      time, injuries to elderly people, hip fractures, and injuries that stem from
      violence.

PMID- 8644059
TI  - [Health services for physicians--what do physicians wish for themselves?].

PMID- 8644060
TI  - [Health services for physicians--what do physicians wish for themselves?].

PMID- 8644061
TI  - [Treatment of hyperlipidemia. No official guidelines].

PMID- 8644062
TI  - [Status of ongoing controlled clinical trials of hypertension treatment].

PMID- 8644063
TI  - [Of what benefit for the patients and their parents is a stay at Geilomo
      pediatric hospital? An evaluation based on a questionnaire].

PMID- 8644065
TI  - [Abortion proclamation].

PMID- 8644066
TI  - [Undivided leadership, but divided responsibility].

PMID- 8644064
TI  - [What is the benefit for patients and their parents in a stay at the Geilomo
      pediatric hospital?].

PMID- 8644067
TI  - [Management of hospital outpatient clinics].

PMID- 8644068
TI  - [When does the occupational environment cause lung disease?].

PMID- 8644069
TI  - [Changed injury pattern and by that therapeutic routines].

PMID- 8644070
TI  - [Abdominal aortic aneurysms. A new therapeutic method].

PMID- 8644071
TI  - [Endovascular treatment of abdominal aortic aneurysms].
AB  - Eight patients, six men and two women (mean age 67.3 years) were treated for
      infrarenal abdominal aortic aneurysm by endovascular technique. A bifurcated
      graft (Mialhe Stentor, Min Tec, France) was used in all cases. The introducing
      system, with an 18 French diameter, is inserted through an arteriotomy in the
      common femoral artery. The proximal end of the main part of the graft is placed
      just distal to the renal arteries, and includes one graft limb, which is placed
      in the iliac artery on the ipsilateral side. The contralateral graft limb is
      introduced into a short limb of the main graft through a 10 French introducer,
      using Seldinger-technique, from the contralateral common femoral artery. All the
      implantations were successful from both a technical and a clinical point of view.
      All patients except one were mobilized on the first day after operation and
      received a normal diet. A thorough preoperative evaluation of the patient with
      regard to selection of the right size of the implant is necessary, and the
      implantation must be performed with great attention to technical details.

PMID- 8644072
TI  - [Virological diagnostics in acute encephalitis. Experience with nucleic acid
      detection and ratio examination during the period 1991-94].
AB  - In every single case of acute encephalitis it is important to confirm the
      clinical diagnosis by means of virological investigations. Previously,
      examination by brain biopsy was regarded as the gold standard for detecting the
      presence of virus or virus antigen in suspected cases of encephalitis caused by
      herpes simplex virus, but the extraction of the sample material requires
      experience, and is not without risk. In recent years, detection of herpes simplex
      DNA using the polymerase chain reaction is recommended as the method of choice
      during the acute state of the illness, followed by ratio determination, e.g. the
      relation between IgG antibodies in serum and cerebrospinal fluid during the
      reconvalescence period. Between 1991 and 1994, the clinical diagnosis of acute
      encephalitis was confirmed by laboratory investigations in 42 cases in our
      laboratory. Detection of viral DNA and subsequent ratio determination showed the
      encephalitis to have been caused by herpes simplex virus in 21 cases, and by
      varicella zoster virus in eight cases. Nucleic acid was detected in 21 cases, and
      16 patients showed pathological ratio values. These results show that the
      polymerase chain reaction is a valuable diagnostic tool during the first two
      weeks of the illness, whereas ratio determination is a better way of
      investigating samples taken after this period.

PMID- 8644073
TI  - [Diagnosis and follow-up in chronic myeloid leukemia. Detection and
      quantification of specific transcripts with the help of reverse transcriptase
      polymerase chain reaction].
AB  - The Philadelphia chromosome in cells of patients with chronic myeloid leukemia
      and acute lymphoblastic leukemia can be detected by reverse transcriptase
      polymerase chain reaction (RT-PCR). We have tested two new methods for this
      purpose. For diagnostic purposes, three different BCR-ABL translocations (b3a2,
      b2a2 and ela2) can be detected in a multiprimed, one step PCR reaction. By using
      a competitor DNA construct and a two-step, nested PCR reaction, a quantitative
      measure of the number of specific BCR-ABL transcripts can be estimated. We tested
      five patients with chronic myeloid leukemia. All of them showed positive BCR-ABL
      translocations in the diagnostic test. Patients with other myeloproliferative
      disorders, used as controls, were all negative. Quantitative measurements of
      specific BCR-ABL mRNA showed that as few as ten transcripts could be quantified
      in the assay. The analysis showed that coefficients of variation between 15% and
      30% were obtained for specific transcripts per micrograms RNA, whereas specific
      BCR-ABL per normal ABL showed a coefficient of variation of 10%. These new
      methods to detect BCR-ABL translocation by RT-PCR should provide easy and
      sensitive diagnosis, and possibilities of monitoring residual disease or relapse.

PMID- 8644074
TI  - [Colonic perforation during combined steroid and radiotherapy. Diagnosis and
      treatment].
AB  - Eight patients with colon perforations after combined treatment with radiotherapy
      and steroid medication are studied retrospectively. Sigmoid diverticuli
      perforated after a minimum of 5 days treatment. The main symptom was a varying
      degree of abdominal pain. Clinical parameters were of limited value. The most
      important single examination was plain abdominal x-ray, though this was not
      positive in all cases. Seven patients were operated on, one with simple suture,
      the rest with Hartmann's procedure. None developed postoperative peritonitis. One
      died from cerebral infarction. Four died within 38 days postoperatively after
      discharge from hospital. Abdominal symptoms during high dose steroid treatment
      may indicate perforation of the colon. Immediate operative intervention may have
      an uncomplicated postoperative course.

PMID- 8644075
TI  - [Meconium ileus-equivalent in adult patients with cystic fibrosis].
AB  - Gastrointestinal complications of cystic fibrosis are becoming more common
      because patients with cystic fibrosis are living longer. There are 227 cystic
      fibrosis patients in Norway today, almost half of whom are more than 18 years
      old. Meconiumileus-equivalent is a complication which increases with age. It is a
      term used to describe partial or complete intestinal obstruction occurring in
      patients with cystic fibrosis. It results from abnormally viscid mucofaeculent
      material in the terminal ileum and right proximal colon. Some patients may
      experience acute complete obstruction, but most of them suffer from chronic
      partial obstruction, with recurring colicly abdominal pain and some distension.
      Of 70 adult cystic fibrosis patients at Aker hospital over a seven year period,
      26% had symptoms and signs of this disorder. Conservative treatment is
      preferable, and surgery should be avoided.

PMID- 8644076
TI  - [Assessment of causal relationship in work-related pulmonary diseases. An
      epidemiological approach].
AB  - A competent assessment of causal relationships in the case of work-related lung
      disorders depends on correct diagnosis, a detailed occupational history and
      updated epidemiological knowledge about causal relationships, obtained from the
      literature. Assessments for purposes of compensation demand, in addition, an
      explicit choice of methods for calculating causes, before a meaningful attempt
      can be made to weight the various factors in and outside the working environment.
      If adequate epidemiological knowledge is available, the causal probability, based
      on the etiological fraction among the exposed persons (attributable risk) may be
      a useful tool for apportioning the different causal factors.

PMID- 8644077
TI  - [Principles for assessment and diagnosis of work-related pulmonary and pleural
      diseases].
AB  - Proposals for diagnostic methods and clinical evaluation of occupational lung and
      pleural diseases have been worked out by a Working Group appointed by the
      Norwegian Thoracic Society and the Norwegian Society of Occupational Medicine.
      The management of this group of diseases demands both an evaluation of
      occupational exposure and a specific pulmonary diagnosis. Recommendations were
      made especially for obstructive, interstitial, and malignant diseases.

PMID- 8644078
TI  - [Admissions and readmissions from a unit of ambulatory surgery. Experiences after
      2 411 surgical interventions].
AB  - Postoperative admissions to hospital from a hospital-based day-surgery unit were
      analysed over a period of 19 months. A total of 2,411 patients were surveyed. The
      admission rate within 24 hours of the operation was 1.5% (35 patients). Surgery,
      anaesthesia, pain and social reasons accounted for 37, 29, 20 and 14% of the
      admissions respectively. One patient was re-operated on. 24 patients (1%) were
      hospitalized later than 24 hours but within 30 days after surgery (mean 7.5
      days), and were called re-admissions. Surgery (75.6%), pain (12.6%) and
      anaesthetic reasons (8.4%) accounted for the re-admissions. 12 patients (50%)
      underwent surgery when re-admitted. The number of admissions (4.1%, p < 0.001)
      and re-admissions (2.2%; p < 0.005) was significantly higher among
      gasteroenterologic patients than among patients operated on within other
      specialties. The time taken for the operation and the time spent under
      anaesthesia were significantly longer (p < 0.001 in both cases) for patients
      submitted to hospitalisation, but neither admission nor readmission was
      associated with age, gender, or health prior to operation (ASA classification).

PMID- 8644079
TI  - [Effect of physical exercise in fibromyalgia].
AB  - The aim of the present study was to review and discuss the literature on exercise
      induced pain and physical fitness training in patients with fibromyalgia. Normal
      muscle metabolism during exercise and no muscle damage after physical activity
      are reported from recent studies. However, no rise in blood noradrenaline
      concentration during exercise was found in fibromyalgia patients as compared with
      a many-folded rise in healthy subjects. Exercise has been used in the treatment
      of fibromyalgia. Training has shown little benefit as regards pain, but has
      improved the physical fitness of the patients. Since pain may be exacerbated by
      physical activity, many patients become physically inactive, with possible
      development of reduced physical fitness. In the long run, fibromyalgia patients
      who exercise report less symptoms than sedentary patients do. Thus, exercise
      should be aimed at preventing physical inactivity and improving the patients'
      physical fitness.

PMID- 8644080
TI  - [Prostatic cancer in Oslo--a real decline?].
AB  - Incidence of prostate cancer has increased steadily in Norway since the cancer
      registration started in the 1950s. In Oslo, however, the figures show decreasing
      incidence since the 1970s, a trend not observed in any other region. These
      changes have occurred in the groups older than 70 years of age. The most
      important change is a marked decrease in the number of cases first diagnosed at
      autopsy, from 12.7% in 1957-61 to 3.8% in 1987-91. However, even after these
      cases are excluded, a slight downward trend in incidence still exists. The same
      tendencies are not observed for other forms of cancer. It seems as if the
      diagnostic intensity has become lower in Oslo than in the rest of the country.
      This pattern may be explained by a change of priority in diagnostics, owing to
      scarce resources, but other reasons, such as stabilization of the incidence of
      prostatic cancer, are also possible.

PMID- 8644081
TI  - [Sensitivity to acetylsalicylic acid].
AB  - Because of its ability of prevent platelet aggregation, the use of aspirin in
      Norway is rising abruptly, after some years of fairly low consumption. The author
      reviews of aspirin-sensitivity, including chronic rhinosinusitis, nasal polyposis
      and corticosteroid-dependent asthma. Non-steroidal anti-inflammatory drugs have
      widespread cross-reactions with aspirin, while azo-dyes and food preservatives
      may induce a similar chronic inflammation of the airways. Why some people develop
      aspirin-sensitivity is unknown. The basic biochemical mechanisms of aspirin
      sensitivity are discussed. Specific treatment based on desensitisation and
      development of leukotriene receptor antagonists may be rewarding in the future.
      Possible beneficial or adverse effects of life-long, low-dose use of aspirin on
      aspirin-sensitivity should be monitored.

PMID- 8644082
TI  - [Heparin as the cause of severe thrombosis].
AB  - Heparin-induced thrombocytopenia with thrombosis occurs in one out of about 2,000
      patients on heparin treatment for five days. The new thrombosis is often arterial
      and may carry a grave prognosis. If thrombocytopenia develops during heparin
      treatment, heparin must be discontinued immediately. Alternative antihrombotic
      medication should be considered. Organs is probably the best alternative.
      Vascular surgery can be considered. In order to reduce the risk of experiencing
      this serious complication, oral anticoagulation should be initiated rapidly after
      heparin therapy is started. Compared with standard heparin, low molecular weight
      heparin probably involves less risk of the patient developing thrombocytopenia
      and thrombosis.

PMID- 8644083
TI  - [Expert statement and assessment of medical impairment in work-related pulmonary
      disease].
AB  - The Norwegian Societies of Thoracic Medicine and Occupational Medicine
      established a working group to standardise diagnostic procedures and evaluation
      of work-related respiratory disorders. In cases of suspected work-related
      diseases the physician may be asked by the National Insurance Administration or
      an insurance company to make a statement which will be one of the documents used
      to decide the patient's right to compensation benefit. We discuss the role of the
      physician as an independent expert. This is different from his role as clinician.
      The statement should include a balanced presentation of information from
      different sources, including health and occupational history, and the employer's
      information about the work environment (quantitative and qualitative exposure
      data). The statement must also include the results of a clinical examination and
      an assessment of functional status based on objective tests. The paper contains
      recommendations for evaluation of permanent impairment in light of the present
      Norwegian laws and regulations.

PMID- 8644084
TI  - [Winter depression--more than biology? A search for light in the darkness].
AB  - Winter depression has been much discussed lately in the media as a new diagnostic
      entity. Research on the topic is anchored in a clear biological framework, with
      reference to concepts like biological rhythm, serotonergic disturbance and light
      treatment. The author regards this framework of understanding as too limited, and
      suggests a need to include psychological and psychodynamic aspects in the
      theoretical understanding of the disease. A hypothesis is proposed that "winter
      depression" may conceal other diagnostic entities in individuals with inherent
      psychological vulnerability. In such cases, psychotherapy would probably be the
      treatment of choice.

PMID- 8644085
TI  - [The health sector after introduction of an economic reform program].

PMID- 8644086
TI  - [Fashion, environment or mystery?].

PMID- 8644087
TI  - [Missing 66-year olds in Lubeck--or a page from the history of BCG vaccination].

PMID- 8644088
TI  - [The extent of ambulatory surgery].

PMID- 8644089
TI  - [Management of hospital outpatient clinics].

PMID- 8644090
TI  - [Knowledge, professional practice and health policy].

PMID- 8644091
TI  - [Sleep problems among the elderly--what is done and what should be done?].

PMID- 8644092
TI  - [Human errors--more frequent than supposed? Errare humanum est].

PMID- 8644093
TI  - [Accidental administration of 50 mg racemic adrenaline to a 2-year-old boy].
AB  - A two-year-old boy received by mistake 50 mg racemic adrenaline intravenously,
      corresponding to 1.8 mg kg-1 of L-adrenaline. Blood pressure increased to 160/105
      mm Hg, heart rate to 160 beats min-1 and pulmonary oedema developed over the next
      two hours. He was treated with nitroprusside, nitroglycerine and digitoxin, and
      was intubated and ventilated. After three hours a hypotensive phase occurred,
      probably due to down-regulation of the beta- and alpha-adrenoceptors. This
      recessitated infusions of very high concentrations of catecholamines for 72
      hours. Renal failure recessitated renal transplantation, after which the child
      made an uneventful recovery.

PMID- 8644094
TI  - [May the choice of antibiotics against gonorrhea be guided by anamnesis?].
AB  - Aminopenicillin with probenecid is the standard treatment for gonorrhoea in
      Norway. Nowadays, one fourth of the cases are caused by gonococci that produce
      betalactamase. Clinicians who have to treat gonorrhoea at the time of first
      presentation, while awaiting sensitivity testing in the laboratory, are reluctant
      to use non-standard treatment except when indicated. Is it possible to predict,
      on the basis of the patient history, which cases need non-standard treatment? A
      logistic model was fitted to data on a random half of cases of gonorrhoea
      reported in 1993 and 1994, and validated in the other half of the cases.
      Infection with betalactamase-producing strains was associated with patients born
      in Africa or Asia, with patients who had acquired the infection in these areas,
      and with residence in the Oslo area. Presence of at least one of these factors
      predicted 87% of the resistant cases, but 54% of patients would have received non
      standard treatment. Thus, all patients might as well receive treatment that cures
      betalactamase-producing strains.

PMID- 8644095
TI  - [Prevention of frequent cystitis in otherwise healthy women].
AB  - Three or more events of cystitis over a period of 12 months may indicate a need
      for prophylactic treatment. We evaluate the available literature on prophylactic
      treatments: change of life-style, behavioural therapy, and pharmacological
      options. We believe that many women can be treated by means of simple practical
      measures, with oestrogen, or with methenamine hippurate. Only few women need to
      be treated with antibiotics.

PMID- 8644096
TI  - [Drug-induced dystonia misinterpreted as hysteria].
AB  - Psychic distress is often expressed in the form of physical pain or disease, but
      the converse also occurs. Illnesses with an organic aetiology are sometimes
      misdiagnosed as psychogenic. We describe three patients who developed rare forms
      of acute drug-induced dystonia when treated with antipsychotic drugs. All three
      cases were initially misdiagnosed as "hysteria" because the patients had
      psychiatric illnesses and because the symptoms were bizarre and became worse when
      the patients became very anxious. Furthermore, if the patients were helped to
      relax the symptoms disappeared for a moment. One of the patients developed
      dystonia 24 hours after ingestion of 750 mg tetrabenazine in an attempt at
      suicide. Another patient who had HIV/AIDS developed severe dystonia after
      receiving only 2 mg haloperidol by mouth. The clinical presentation, treatment,
      and possible mechanisms of the pathophysiology of acute drug-induced dystonia are
      briefly reviewed.

PMID- 8644097
TI  - [Quality assurance in hip prosthesis surgery. New type hip prostheses, review of
      a 3-year material].
AB  - This article deals with the short-term results of prosthetic replacement of the
      hip joint. The investigation was carried out three years after the introduction
      of a new hip prosthesis - the ITH (" International Total Hip") prosthesis. Our
      results were analysed retrospectively, the primary goal being quality assessment
      of the results of our hip surgery. We found that the results of hip prosthetic
      surgery with the ITH-prosthesis were satisfying, although the frequency of
      complications was rather high: 185 implantations of the ITH-prosthesis gave 13
      cases of deep venous thrombosis; one case of deep infection and subsequent
      revision surgery; four cases of dislocation of the prosthesis, of which two cases
      have been subsequently revised; one case of perforation of the femur with later
      revision; and one case of permanent paralysis of the femoral nerve. The overall
      rate of revisions was 2.7%. The overall survival of the prosthesis according to
      Kaplan Meier was 97% after three years.

PMID- 8644098
TI  - [Postoperative treatment and follow-up].
AB  - In outpatient surgery the patient leaves the hospital after a short period of
      observation. The initial postoperative period requires observation of the same
      standard as for inpatients. However, the anaesthesia and surgical techniques used
      should prepare for fast recovery. The challenge is to handle high patient
      turnover in a safe manner. The main postoperative problems are pain,
      nausea/vomiting and psychomotor impairment. To be able to discharge the patients
      safety is crucial for the success of day surgery. Well trained nurses can judge
      when the patient is ready to go home, provided that strict guidelines are set up
      by the physicians in charge. All the patients given general anaesthesia, sedation
      or opioids should be together with a responsible adult person until the next day.
      Adequate information must be given concerning what to expect during the following
      days, and how to respond to complications. Every day surgery unit should have its
      own control system to detect any problems after the treatment.

PMID- 8644099
TI  - [Treatment of chronic insomnia. A recommendation with special emphasis on
      problems of the elderly].
AB  - Normal physiological changes in sleep occur with increasing age. Most healthy
      individuals do not perceive these changes in themselves as a health problem.
      Despite this, chronic insomnia is a common complaint, especially among the
      elderly. In addition to considerable subjective distress, the symptom of chronic
      insomnia is associated with increased morbidity and mortality. Thus, a diagnostic
      evaluation is an essential starting point for rational treatment. The author
      emphasizes the importance of a multidimensional approach to both diagnosis and
      treatment. Concentrating on symptom relief only is not enough. Documented
      treatment modalities are reviewed. There is a discrepancy between the current
      knowledge and the actual management of sleep disorders. It is concluded that
      several effective interventions are available. The prevailing nihilism when it
      comes to treating chronic insomnia is not justified.

PMID- 8644100
TI  - [Cognitive therapy of subjective somatic symptoms].
AB  - In this article we present a model for the interaction between physical,
      psychological and social factors in the production of subjective somatic
      complaints, which is the most common reason for visiting a doctor. Especially if
      the patient has subjective somatic symptoms for which there is no apparent
      organic reason it may be important to motivate the patient to examine all the
      different factors that contribute to the vicious circle he/she often enters into.
      The following elements of this circle are explained: Physical (symptoms, signs,
      findings), beliefs (thoughts, cognitive processes and cognitive schemas),
      feelings (emotions), behaviour (all we say and do) and the so-called X-factor,
      which represents everything we do not know. The model might help us in our
      relationship to the patients, and can be used both in connection with known
      somatic disease and with conditions with a multifactorial genesis, like
      somatoform disorders.

PMID- 8644101
TI  - [Brain abscess. A difficult diagnosis?].
AB  - It is vital to diagnose brain abscess early, but this can be intricate. Four
      cases of brain abscess are described, illustrating the diagnostic difficulties.
      One of the patients had multiple brain abscesses. Important aspects of brain
      abscess are discussed. Brain abscess should be suspected in cases of increasing
      intracranial pressure combined with focal neurological signs or epileptic
      seizures, even with no apparent signs of infection. The characteristic contrast
      enhancing ring lesion and surrounding oedema may be sufficient for diagnosis, but
      biopsy and bacteriological culture are often necessary. Epileptic seizures and
      various neurological sequelae are common, even if the abscess is treated
      immediately. Delay in diagnosis may lead to fatal outcome.

PMID- 8644102
TI  - [What does the primary care physician now about his deceased patients? A study of
      deaths in a group practice].
AB  - Information about the cause of death is regarded as crucial for quality
      improvement in medicine. Although patients often consult their general
      practitioner close to their death, he or she is seldom involved as the attending
      physician during the terminal stage of life, and is often not told about death
      and its causes. This study analyses the extent of knowledge among general
      practitioners about deaths and the causes of death among their patients. Over a
      46 month period, 8,627 patients had consulted a suburban group practice outside
      the city of Oslo, consisting of three general practitioners. 105 patients (0.3%)
      had died within the period. 40% of the deaths and 65% of the causes of death were
      unknown to the general practitioners. More than half of the patients died in the
      local hospital, and one fifth in a nursing home. The general practitioner issued
      only 7% of the death certificates. Information was lacking in particular on
      violent deaths and deaths among younger people. A routine should be established
      to provide general practitioners with information about the death of a patient,
      and its causes.

PMID- 8644103
TI  - [Ambulatory surgery and incentives].
AB  - Day surgery is more cost-effective than in-patient surgical treatment and, for
      certain categories of patients is also a better quality form of care. It can
      often replace the traditional surgical treatment of patients, i.e. an operation
      with hospitalisation. For this reason, day surgery should become a more common
      form of treatment, also in Norway. This makes it necessary to create incentives
      that will encourage it. This cannot be done without first developing methods for
      collecting data on this activity.

PMID- 8644104
TI  - [Folic acid deficiency, cancer and congenital abnormalities].

PMID- 8644105
TI  - [Health service for physicians--what do physicians want?].

PMID- 8644106
TI  - [Doping legislation].

PMID- 8644107
TI  - Accumulation of orally given cadmium in Long-Evans Cinnamon (LEC) rats with an
      inherently abnormal copper metabolism.
AB  - An inherent defect of biliary Cu excretion and subsequent Cu deposition in the
      liver have been found in Long-Evans Cinnamon (LEC) rats, which are promising
      models of Wilson disease. LEC and Fischer rats were given water containing Cd
      (CdCl2) at a level of 5 ppm for 30 days. Regardless of drinking Cd water, LEC
      rats showed a very high concentration of Cu (200 to 250 microgram/g) and Cu
      metallothionein (Cu-MT) (18 mg/g) in the liver. There was no difference of Cd
      accumulation in the liver between the two strains exposed to Cd (2.6 and 2.7
      microgram/g in the Fischer and LEC groups, respectively). However, the renal Cd
      concentration was slightly but significantly higher in LEC rats (3.5 microgram/g)
      than in Fischer rats (2.0 microgram/g). The ratio of renal Cd contents to the sum
      of renal and hepatic Cd contents was significantly higher in LEC rats (0.25) than
      in Fischer rats (0.15). The serum Cd concentration in Cd-treated LEC rats
      increased threefold compared to Cd-treated Fischer rats. It seems likely that Cd
      from the liver is transported into the kidney in the form of Cd, Cu-MT. There was
      no difference in uptake of Cd in the hepatic MT fraction between the two strains.
      Although biliary Cu excretion in LEC rats was significantly lower than that in
      Fischer rats, reduced excretion of Cd into bile was not found in LEC rats. The
      gross amounts of Cu and Cu-MT influenced the accumulation of Cd in the kidney
      rather than in the liver when Cd was given orally at a low level to LEC rats. Our
      results suggest tht Cu and Cd do not share the same sites of hepatobiliary
      excretion in rats, although the main route of their excretion is via bile.

PMID- 8644108
TI  - Erythrocyte enzymes catalyze 1-nitropyrene and 3-nitrofluoranthene
      nitroreduction.
AB  - Nitroarenes are environmental contaminants produced during incomplete combustion
      processes. Nitroreduction, the most important pathway of nitroarene toxification,
      occurs mainly in the liver and intestine. In the present study, we show that
      human red cells may also possess the metabolic competence to reduce 1-nitropyrene
      (NP) and 3-nitrofluoranthene (NF), the nitroarenes chosen as model compounds, to
      their corresponding amino derivatives, 1-aminopyrene (AP) and 3-aminofluoranthene
      (AF). The requirement of the cofactor couple NADH/FMN suggests that erythrocyte
      nitroreductase activity occurs via one electron transfer. The presence of oxygen
      strongly inhibited the haemolysate-catalyzed nitroarene reduction, whether
      measured as amine formation or nitroarene disappearance. Intermediate reactive
      species, that bind covalently to haemoglobin and/or other erythrocyte proteins,
      are formed during nitroreduction catalyzed by human haemolysate. In fact, the
      reduced metabolites AP and AF were released after mild acid hydrolysis of red
      cell proteins exposed to NP and NF, thus suggesting that sulphinamide adducts
      have been formed.

PMID- 8644109
TI  - Nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol in
      Fischer 344 rats: comparisons with 2- and 4-chloroaniline and 2- and 4
      aminophenol.
AB  - Nephrotoxicity occurs following intraperitoneal (i.p.) administration of 2
      chloroaniline or 4-chloroaniline hydrochloride to Fischer 344 rats, but the
      nephrotoxicant chemical species and mechanism of nephrotoxicity are unknown. The
      purpose of this study was to evaluate the in vivo and in vitro nephrotoxic
      potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol, metabolites of 4
      chloroaniline and 2-chloroaniline. A comparison was also made between the
      nephrotoxic potential of the aminochlorophenols and the corresponding
      aminophenols to examine the effect of adding a chloride group on the nephrotoxic
      potential of the animophenols. Male Fischer 344 rats (4/group) were given an i.p.
      injection of a chloroaniline or aminochlorophenol hydrochloride (1.5 mmol/kg),
      and aminophenol (1.0 or 1.5 mmol/kg), or vehicle, and renal function monitored at
      24 and 48 h. Both aminochlorophenols induced smaller and fewer renal effects that
      the parent chloroanilenes in vivo. Also, 4-aminophenol was markedly more potent
      as a nephrotoxicant that 4-amino-3-chlorophenol, while 2-aminophenol and 2-amino
      5-chlorophenol induced only mild change in renal function. In vitro, the phenolic
      compounds reduce p-aminohippurate accumulation by renal cortical slices at bath
      concentrations of 0.01 mM, while a bath concentration of 0.50 mM or greater was
      required for the chloroanilines. However, all compounds reduced
      tetraethylammonium accumulation at bath concentrations of 0.1-0.5 mM or greater.
      These results indicate that extrarenally-produced aminochlorophenol metabolites
      do not contribute to the mechanism of chloroaniline nephrotoxicity. Also, the
      reduced nephrotoxic potential of 4-amino-3-chlorophenol compared to 4-aminophenol
      could result from an altered ability of the aminochlorophenol to redox cycle or
      form conjugates.

PMID- 8644110
TI  - In vivo and in vitro toxicity of newly synthesized monofunctional sulfur mustard
      derivatives.
AB  - The toxicity of two new monofunctional sulfur mustard derivatives was tested. The
      compound (4-carboxybutyl 2-chloroethyl sulfide, CBCS; 10-carboxydecyl 2
      chloroethyl sulfide, CDCS) possess the 2-chloroethyl sulfide moiety present in
      mustard gas. Exposure of guinea pig skin to CBCS resulted in a dose-related
      ulcerative effect. CDCS exhibited similar pathological effects. Dimethylsulfoxide
      (DMSO) exacerbated CBCS toxicity. Regeneration and healing were prominent six
      days after application. Concentration-related effects were found in in vitro
      systems, using human SH-SY5Y neuroblastoma cells for acute toxicity and Y79
      retinoblastoma cells for colony forming assay. CBCS or derivatives may serve as
      models compounds for investigating the mechanism of action of alkylating agents.

PMID- 8644111
TI  - Interactions of metallothionein with murine lymphocytes: plasma membrane binding
      and proliferation.
AB  - Metallothionein (MT) is a thiol rich protein that has been well characterized for
      its ability to bind and sequester heavy metal cations, free radicals and other
      reactive toxicants. In addition to induction by these stressors, MT gene
      expression is upregulated by several cytokines of the acute phase response. In
      previous work, we have shown that MT can alter aspects of lymphocyte function. MT
      alone induces modest proliferation of unfractionated splenocytes and acts
      synergistically with T cell- and B cell-specific mitogens. In contrast, MT
      inhibits humoral responsiveness in vivo and reduces in vitro T cell responses to
      processed antigen. In this report, we describe the effects of MT on specific
      lymphocyte subpopulations in order to further characterize the mechanism of MT
      mediated alterations of immune activity. MT binds to the plasma membrane of both
      T and B lymphocytes, but, in the absence of a costimulatory agent, MT induces
      lymphoproliferation only in B cells. MT also enhances the capacity of naive B
      lymphocytes to differentiate into plasma cells. These results demonstrate
      differential immunomodulatory activities of MT and may explain some of the
      diverse immunoregulatory effects associated with exposure to environmental
      toxins.

PMID- 8644112
TI  - Further evaluation of the local lymph node assay in the final phase of an
      international collaborative trial.
AB  - The local lymph node assay (LLNA) is a method used for the prospective
      identification in mice of chemicals that have the potential to cause skin
      sensitization. We report here the results of the second and final phase of an
      international trial in which the performance of the assay has been evaluated
      using seven test materials in five independent laboratories. The additional
      chemicals examined here included compounds which are considered less potent
      allergens than some of those tested in the first phase of the investigation, and
      includes hexylcinnamic aldehyde (HCA), a chemical recommended by the Organization
      for Economic Cooperation and Development (OECD) as a positive control for skin
      sensitization studies. In each laboratory all skin sensitizing chemicals examined
      (2,4-dinitrochlorobenzene {DNCB}, HCA, oxazolone, isoeugenal and eugenol)
      elicited positive responses of comparable magnitude as judged by the derived
      lowest concentration of test chemical required to elicit a 3-fold or greater
      increase in the proliferative activity of draining lymph node cells compared with
      vehicle-treated controls. We observed that sodium lauryl sulphate, considered to
      be a non-sensitizing skin irritant, also induced a positive response in the
      assay. Para-aminobenzoic acid (pABA), a nonsensitizing chemical, was negative at
      all test concentrations in each laboratory. Some laboratories incorporated minor
      modifications into the standard assay procedure, including the evaluation of
      lymph nodes pooled from individual mice rather than treatment groups and the use
      of statistical analyses. The use of statistics did not markedly change the
      determination of the lowest concentration yielding a positive response. These
      data confirm that the local lymph node assay is robust and yields equivalent
      results when performed independently.

PMID- 8644113
TI  - Spinal motor neuron neuroaxonal spheroids in chronic aluminum neurotoxicity
      contain phosphatase-resistant high molecular weight neurofilament (NFH).
AB  - It has previously been shown that a single intracisternal inoculum of AlCl3 in
      young adult New Zealand white rabbits will induce a dose-dependent phosphatase
      resistance of high molecular weight neurofilament protein (NFH) that is
      proportionate to the extent of neurofilamentous inclusion formation (Strong and
      Jakowec, 1994). To determine if the potential for dissolution of aluminum-induced
      neurofilamentous inclusions was dependent on the degree of NFH phosphatase
      resistance, we have examined NFH phosphatase sensitivity in a reversible chronic
      model of aluminum neurotoxicity. Rabbits receiving repeated intracisternal
      inoculums of 100 microgram AlCl3 at 28 day intervals until day 267 develop spinal
      motor neuron perikaryal and neuroaxonal neurofilamentous aggregates in a
      stereotypic, dose-dependent fashion. In the rabbits receiving inoculums until day
      156 with survival until day 267 without further aluminum exposure, neuroaxonal
      spheroids remained prominent while perikaryal inclusions largely resolved.
      Immunoreactivity to a monoclonal antibody recognizing phosphorylated NFH (SMI 31)
      was abolished in perikaryal aggregates at each time interval by dephosphorylation
      with bovine alkaline phosphatase. However, neuroaxonal spheroids maintained their
      immunoreactivity. Using time-course dephosphorylation studies of spinal cord
      homogenates, we observed a significant reduction in the rate of dephosphorylation
      of NFH following 267 days of AlCl3 exposure (P < 0.05). These observations
      suggest that neuroaxonal spheroids contain phosphatase-resistant NFH isoforms and
      that the potential for resolution of intraneuronal neurofilamentous inclusions
      correlates with the susceptibility of NF within these inclusions to enzymatic
      dephosphorylation.

PMID- 8644115
TI  - Toxic effects of ethylene oxide residues on bovine embryos in vitro.
AB  - The potential of ethylene oxide (EtO) residues in exposed plastic tissue culture
      dishes to adversely affect bovine oocyte maturation, fertilization and subsequent
      embryonic development was monitored. In experiment 1, the effects of aeration
      time and aeration combined with washing of EtO-gassed culture dishes on the
      extent of residual toxicity were investigated. There was no cleavage in any
      treatment in which oocytes were matured and fertilized in dishes exposed to EtO.
      EtO residues caused functional degeneration of oocytes even when culture dishes
      were aerated for more than 12 days post EtO-exposure and repeatedly washed. In
      experiment 2, the residual toxicity of EtO gas on in vitro maturation (IVM), in
      vitro fertilization (IVF) and in vitro culture (IVC) were evaluated. Cleavage
      rate significantly decreased and post-cleavage development was retarded in ova
      maintained in dishes treated with EtO either during IVM or IVF. EtO residues may
      be more detrimental to spermatozoa than to oocytes which may have been the
      primary cause of fertilization failure during IVF.

PMID- 8644114
TI  - Toxic effects of hexane derivatives on cultured rat Schwann cells.
AB  - The cytotoxic effects of the following five hexane-related compounds were
      examined on Schwann cell DNA synthesis: 2,5-hexanedione (2,5-HD), 2-hexanol (2
      OH), 2-hexanone (MnBK), 2,5-dimethylfuran (DF) and gamma-valerolactone (VL).
      Schwann cells were isolated from the sciatic nerves of neonatal Sprague-Dawley
      rats and cultured. [(3)H]-thymidine incorporation into Schwann cell nuclei was
      measured by scintillation spectrometry and autoradiography when hexane
      derivatives were added to the culture medium. All of the hexane-related compounds
      suppressed [(3)H]-thymidine incorporation in a concentration-dependent manner. DF
      was the most cytotoxic for the inhibition of Schwann cell DNA synthesis among the
      compounds. The finding suggests that DF-mediated cytotoxicity should be taken
      into account as a possible additional mechanism of hexane intoxication,
      especially in the impairment of mitotic cells.

PMID- 8644116
TI  - Dose-related effect of aflatoxin B1 on liver drug metabolizing enzymes in rabbit.
AB  - The effects of chronic administration of aflatoxin B1 (AFB1) on liver drug
      metabolism enzymes were measured in New Zealand rabbits divided into three groups
      of 5 animals, each receiving over 5 days either arabic gum or AFB1 in arabic gum
      at a daily oral dose of 0.05 or 0.10 mg/kg. These treatments did not lead to any
      lethality in any of the treated groups, but the body weight gain was altered.
      Biochemical exploration of plasma components revealed a dose-dependent
      hepatotoxicity characterized by cytolysis and cholestasis. At 0.10 mg/kd/day of
      AFB1, significant decreases were observed in total liver microsomal cytochrome
      P450, several P450-dependent monooxygenase activities, all individual P450
      isoenzymes levels analysed by Western-blotting and glutathione S-transferase
      activities. By contrast, at 0.05 mg/kg/day of AFB1, even though total cytochrome
      P450 was decreased by 30%, only P450 1A1 and 3A6 isoenzymes, and aniline
      hydroxylation, pentoxyresorufin O-depentylation, aminopyrine, erythromycin,
      ethylmorphine and dimethylnitrosamine N-demethylations were affected. In the same
      animal group, the only glutathione S-transferase accepting CDNB (1-chloro-2,4
      dinitrobenzene) as substrate was decreased by 22%. UDP-glucuronyltransferase
      accepting p-nitrophenol as substrate was increased in both groups of animals (33
      62%). The mechanisms that could contribute to the observed changes in drug
      metabolizing enzymes are discussed.

PMID- 8644117
TI  - Dissociation of DDVP-induced DNA strand breaks from oxidative damage in isolated
      rat hepatocytes.
AB  - Dichlorvos (DDVP)-induced DNA single strand breaks were investigated in isolated
      rat hepatocytes. In a dose-response study in hepatocytes from PB-treated rats (80
      mg/kg i.p., for 3 days), 250 microM DDVP substantially reduced cellular non
      protein sulfhydryl (NPSH) content, but had no detectable effect on DNA. At 500
      microM, the increase in DNA single strand breaks was significant, with a slight
      increase in cellular lipid peroxidation. At doses over 1000 microM DDVP, cell
      death was accompanied with considerable lipid peroxidation, and DNA single strand
      breaks were evident. When the antioxidant N,N'-diphenyl-p-phenylene diamine
      (DPPD) was added or if the hepatocytes were incubated under air instead of 95%
      O2, lipid peroxidation and cell death were attenuated but DNA single strand
      breaks and reduction in NPSH content were not. On the other hand, ferrous iron
      induced DNA single strand breaks, lipid peroxidation, and depletion of NPSH
      content were all attenuated by DPPD or by incubating the cells under air. With
      respect to the subcellular lipid peroxidation, DDVP caused a significant increase
      mainly in the microsomal fraction, whereas ferrous iron caused rapid and
      substantial increases in mitochondrial, microsomal, and nuclear fractions. There
      were more DNA single strand breaks caused by N-nitrosodiethylamine (NDEA), which
      becomes genotoxic after microsomal metabolism, in hepatocytes from PB-treated
      rats than in those from control rats. The number of these breaks was reduced by
      adding the cytochrome P450 inhibitor metyrapone. On the other hand, the effect of
      DDVP on DNA was not affected by modification of the cytochrome P450 status. These
      results suggest that lipid peroxidation induced by DDVP in isolated rat
      hepatocytes plays a significant role in its cytotoxicity but not in its
      genotoxicity.

PMID- 8644118
TI  - N-actylcysteine protects Chinese hamster ovary (CHO) cells from lead-induced
      oxidative stress.
AB  - In vitro administration of lead acetate (PbA) to cultures of Chinese hamster
      ovary (CHO) cells had a concentration-dependent inhibitory effect on colony
      formation. Colony formation was returned to control levels in lead-treated
      cultures that were supplemented with 1 mM N-actylcysteine (NAC), a well
      documented synthetic antioxidant. In order to investigate the nature of NAC's
      protective effect, we measured L-gamma-glutamyl-L-cysteinylglycine (GSH),
      oxidized glutathione (GSSG), malondialdehyde (MDA) and catalase activity both in
      the presence and absence of NAC in lead-exposed CHO cells. Increases in both MDA
      levels (p < 0.05) and catalase activity (P < 0.05) were observed in cultures that
      received only PbA, but supplementation with NAC returned these measures to
      pretreatment levels. The ratio of GSH to GSSG increased in lead-exposed cells
      incubated in NAC-enhanced media, but declined in cultures treated with PbA only.
      Our results suggest that NAC can confer protection against lead-induced oxidative
      stress to CHO cells, possibly through the enhancement of the cell's own
      antioxidant defense mechanisms.

PMID- 8644119
TI  - Cyclosporin A-induced functional and morphological changes in pilocarpine treated
      rat submandibular glands.
AB  - The effects of long-term administration of Cyclosporin A (CSA), an
      immunosuppressive agent, on submandibular glands of male albino rats were
      investigated. Sialochemistry studies revealed a reduction of pilocarpine
      stimulated flow rates to 54% compared to the controls. Salivary Mg(2+) and K+
      were elevated and a marked decrease in total protein concentration was observed.
      Light and electron microscopic features of treated glands show marked changes at
      tissue level. An irregular pattern of the nucleus, mitochondrial alterations,
      reduction in the number of secretory granules and their aggregation, disturbances
      of cytoplasmic organelles, and isometric vacuolation were among the most striking
      findings. Our results show that CSA causes marked functional and morphological
      alterations in rat submandibular glands, which may be due to the drug's direct
      effects on the tissue.

PMID- 8644120
TI  - Inorganic tin -- a new selective inducer of the murine coumarin 7-hydroxylase
      (CYP2A5).
AB  - The coumarin 7-hydroxylase of mice (Coh, CYP2A5) is known to be highly
      selectively inducible by both a set of heavy metals such as cobalt, indium and
      cerium and a variety of organic nitrogen-containing heteroaromatic compounds such
      as 3-amino-1,2,4-triazole, pyrazine and pyrazole. The investigations presented
      reveal that inorganic divalent tin has to be included in the list of selective
      inducers. Pretreatment of NMRI-mice with 50 mg SnCl2/kg body weight, daily for 2
      days, increases the coumarin hydroxylation 40- and 20-fold in the kidney and
      liver, respectively. So far, the inducing potency of tin chloride is higher than
      that of the agents already known. The diagnostic inhibitor metyrapone strongly
      inhibits the coumarin model reaction. In the kidneys tin generates an almost pure
      fraction of a cytochrome P450 isozyme catalyzing the metabolism of coumarins, as
      inhibition experiments reveal.

PMID- 8644121
TI  - Toxicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344 rats and
      B6C3F(1) mice.
AB  - Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost
      exclusively in the production of polychloroprene (neoprene) elastomer. Because of
      its structural similarity to isoprene (2-methyl-1,3-butadiene) and to 1,3
      butadiene, a potent trans-species carcinogen, inhalation studies were performed
      on chloroprene to characterize its toxicological potential and to provide a basis
      for selecting exposure concentrations for chronic toxicity and carcinogenicity
      studies. Thirteen-week inhalation toxicology studies were conducted in male and
      female F344 rats and B6C3F(1) mice at exposure concentrations of 0, 5, 12, 32 or
      80 ppm (6 h/day; 5 days/week). A 200 ppm exposure group was also included for
      rats only, because a previous study showed that this concentration of chloroprene
      is lethal to mice. In mice, exposure to 80 ppm chloroprene caused a marginal
      decrease in body weight gain in males and epithelial hyperplasia of the
      forestomach in males and females. This lesion has been observed in mice exposed
      to isoprene or 1,3-butadiene. In rats, exposure to 80 ppm chloroprene or higher
      concentrations caused degeneration and metaplasia of the olfactory epithelium and
      exposure to 200 ppm caused anemia, hepatocellular necrosis and reduced sperm
      motility. These lesions have not been observed in rats exposed to isoprene or 1,3
      butadiene. The profile of toxic effects of chloroprene is considerably different
      from that of isoprene or 1,3-butadiene; this may be due to differences in
      exposure concentrations that were used in toxicology studies of these compounds
      and /or to the influence of the chlorine substitution on the toxicokinetics of
      these compounds, on their biotransformation, or on the reactivity of metabolic
      intermediates with tissue macromolecules.

PMID- 8644122
TI  - Potentiation of hypoxic injury in cultured rabbit hepatocytes by the
      quinoxalinone anxiolytic, panadiplon.
AB  - The quinoxalinone anxiolytic, panadiplon, produces hepatic metabolic inhibition
      (mitochondrial impairment), microvesicular steatosis and centrilobular necrosis
      in rabbits. Metabolic inhibition occurs in cultured hepatocytes without
      cytotoxicity, suggesting that hepatic injury is influenced by additional factors.
      The present experiments were conducted to determine if metabolic inhibition by
      panadiplon predisposed hepatocytes to hypoxic injury. Injury (cell death) was
      evaluated by lactate dehydrogenase (LDH) release from cells; ATP and glycogen
      levels were also evaluated. Under hypoxic conditions, control cultures showed a
      6.5-fold increase in LDH release compared to normoxic controls, with a coincident
      80% decrease in ATP and 50% decrease in glycogen levels. Under normoxic
      conditions 10 microgram/ml panadiplon treatment for 48 h reduced ATP and glycogen
      levels by 40% but did not cause an increase in LDH leakage. Cells treated with
      panadiplon, then exposed to hypoxia conditions, showed a significant level of
      injury compared to normoxic control cultures, and a further reduction in ATP. No
      additional decrease in glycogen ws observed. In an attempt to prevent panadiplon
      mediated injury, glycolytic substrates (dihydroxyacetone or pyruvate) were
      included during normoxic and hypoxic incubations. Both cotreatments reduced the
      level of LDH leakage produced by panadiplon during hypoxia. Cotreatment did not
      generally increase ATP or glycogen levels (compared to panadiplon treatment
      groups) during hypoxia, though individual experiments showed a slight increase in
      ATP levels. During normoxia both cotreatments with panadiplon resulted in
      significantly higher glycogen levels than in panadiplon cultures alone. These
      results suggest that cellular glycogen and subsequently ATP levels are reduced
      during panadiplon exposure, metabolically predisposing hepatocytes to hypoxic
      injury.

PMID- 8644123
TI  - Comparison of cephaloridine renal accumulation and urinary excretion between
      normoglycemic and diabetic animals.
AB  - The renal toxicity of cephaloridine is reduced in a streptozotocin diabetic rat
      model. This study tested the hypothesis that renal cortical cephaloridine
      accumulation was diminished in diabetic rats. The following studies also
      investigated whether renal excretion was enhanced in diabetic rats. Male Fischer
      344 rats were randomly divided into normoglycemic or diabetic groups. Diabetes
      was induced by injection (intraperitoneal, i.p.) of 35 mg/kg streptozotocin.
      Normoglycemic and diabetic rats were injected (i.p.) with 1500 mg/kg
      cephaloridine. Peak plasma cephaloridine levels were similar in both groups.
      Renal cortical accumulation was diminished (P < 0.05) in the diabetic group 1 and
      4 h after cephaloridine injection. Urinary cephaloridine excretion was enhanced
      (P < 0.05) in the diabetic group relative to the normoglycemic animals during the
      first 4 h after cephaloridine injection. Comparisons between normoglycemic and
      diabetic groups indicated renal cortical cephaloridine accumulation was lower in
      the diabetic group. These findings would support the hypothesis that reduced
      cephaloridine toxicity in diabetic animals was due to reduced renal cortical
      accumulation of the toxin. These data also demonstrate that cephaloridine
      excretion was enhanced in the diabetic group and may contribute to the diminished
      renal accumulation.

PMID- 8644124
TI  - P-glycoprotein involvement in cuticular penetration of [14C]thiodicarb in
      resistant tobacco budworms.
AB  - Pesticides have been shown to interact with the multidrug resistance protein
      associated with cancer chemotherapy, P-glycoprotein (P-gp). P-gp, therefore, has
      also been implicated in the development of pesticide resistance. The purpose of
      this study was to characterize the effect P-gp has on the accumulation of the
      carbamate pesticide, thiodicarb. For these studies, resistant tobacco budworm
      larvae, expressing four times the P-gp as susceptible larvae, were pretreated
      with the P-gp inhibitor, quinidine, and challenged topically with thiodicarb.
      Quinidine enhanced thiodicarb toxicity in a dose-dependent manner, with mortality
      in the presence of P-gp inhibition increased up to 33%. Quinidine treatment
      increased [14C]thiodicarb accumulation 2- to 3-fold as compared to thiodicarb
      treatment alone. This study suggests that P-gp contributes to quinidine synergism
      of thiodicarb toxicity and suggests that P-gp may be involved in cuticular
      resistance to pesticides.

PMID- 8644125
TI  - Decreased endurance to cold water swimming and delayed sexual maturity in the rat
      following neonatal lead exposure.
AB  - The effects of neonatal lead (Pb) exposure on ability to endure stress and on the
      onset of sexual maturity were investigated using rats. Sprague-Dawley dams (n =
      17/treatment) were treated with or without lead acetate (0.3%) in drinking water
      from parturition until postnatal day (PND) 21, at which time the pups were
      weaned. A set of sex-balanced pairs of pups (24 male and 24 females/treatment)
      from randomly selected control and Pb-treated dams was tested for cold water (4
      degrees C) swimming-endurance on PND 15, 21, 25 and 30. Lead treated-female pups
      showed significantly (P < 0.05) lower endurance on PND 21 and 30, while Pb
      treated males exhibited lower (P < 0.05) endurance on PND 21 compared to their
      respective controls. The results of this study indicate that neonatal exposure to
      Pb decreased cold water swimming-endurance. Neonatal exposure to either Pb or
      swimming stress delayed (P < 0.002) the onset of sexual maturity in both sexes.
      However, exposure to both treatments masked the effect of swimming stress on the
      onset of maturity in females but not in males.

PMID- 8644126
TI  - Reduction of the concentrations of prostaglandins E2 and F2alpha, and thromboxane
      B2 in cultured rat hepatocytes treated with the peroxisome proliferator
      ciprofibrate.
AB  - Several hypolipidemic drugs, plasticizers and other chemicals induce peroxisome
      proliferation and hepatic tumors in rodents, but the mechanism by which they
      induce tumors is not fully understood. Their carcinogenic activity may be related
      to alterations in gene expression, such as induction of peroxisomal beta
      oxidation enzymes or of the cytochrome P450 4A family. These enzymes metabolize
      lipids, including eicosanoids and their precursor fatty acids. Because
      eicosanoids likely play a role in the carcinogenic process, alterations in their
      concentration by xenobiotics may be important in their carcinogenic or promoting
      activities. In this study we used isolated hepatocytes to study if peroxisome
      proliferators alter the metabolism of prostaglandins (PG) and thromboxanes (Tx).
      Isolated rate hepatocytes were cultured for 4 days with 2 concentrations of
      ciprofibrate (CIP): 100 and 400 microM. Fatty acyl CoA oxidase activities of the
      100 and 400 microM CIP treatment groups at the end of the experiment were
      increased 5.3 and 9.6 times, respectively. TxB2 and PGF2alpha concentrations in
      cultures treated with CIP were significantly lower than the control at days 3 and
      4, whereas a lower concentration of PGE2 was seen at day 4 only. These studies
      show that PG and Tx concentrations in cultured hepatocytes are lowered by the
      peroxisome proliferator CIP.

PMID- 8644127
TI  - A comparative study of five nitro musk compounds for genotoxicity in the SOS
      chromotest and Salmonella mutagenicity.
AB  - Five nitro musk compounds widely used in cosmetics and detergents were examined
      for DNA-damaging and mutation-inducing properties. For this purpose two short
      time assays were used, the SOS chromotest and the Salmonella/mammalian microsome
      test. Musk ambrette showed mutagenicity in Salmonella typhimurium TA 100
      requiring metabolic activation by rat liver postmitochondrial supernatant (S9)
      but it lacked mutagenicity in the absence of S9 and genotoxicity in the SOS
      chromotest. Musk xylene, musk ketone, musk moskene and musk tibetene showed
      neither mutagenicity nor genotoxicity in the presence and absence of S9.

PMID- 8644128
TI  - Histopathological effects of garlic on liver and lung of rats.
AB  - The comparative toxic effects of oral and intraperitoneal administration of
      garlic extracts on lung and liver tissue of rats were studied. Administration of
      low doses of garlic (50 mg/kg) to rats either orally or intraperitoneally had
      little effect on lung and liver tissues as compared to control animals. In
      contrast, administration of high doses of garlic (500 mg/kg) resulted in profound
      changes in lung and liver tissues of rats. Intraperitoneal administration of the
      high dose of garlic was more damaging to lung and liver tissue of rats than oral
      administration.

PMID- 8644129
TI  - Sex-related differences in the effect of aluminum on calcium transport in the
      small intestine of the rat.
AB  - Everted sacs of distinct segments of small intestine from male and female rats
      were incubated with 2 microM of aluminum (Al). In duodenum, Al significantly
      diminished calcium flux (JCams) in cycling females (31%, P < 0.01) and in males
      (17%, P < 0.05). Incubation under anaerobic conditions nullified the inhibition
      of Al on JCams both in male and in female duodenal sacs. Jejunal and ileal JCams
      measured under aerobic conditions were not modified by the presence of Al in
      mucosal fluid compared to Al-free controls, neither in males nor in cycling
      females. In ovariectomized female rats treated with estrogen the studies of dose
      response curves showed that the sensitivity to the effect of Al on JCams was
      raised (the dose that produced half maximum response diminished) with increasing
      17 beta-estradiol serum levels, without changes in the maximum response. In
      castrated male rats injected with testosterone, the effect of Al on duodenal
      JCams was found to be independent of testosterone levels. In summary, our results
      demonstrated that the Al inhibition on duodenal JCams was influenced by sexual
      hormone levels in females but was independent of them in males.

PMID- 8644131
TI  - Transplant procurement management training in Argentina: courses, results, and
      implementation.

PMID- 8644132
TI  - Brain death epidemiology: the Madrid Study. Madrid Transplant Coordinators.

PMID- 8644130
TI  - Comparison of the effects of pyridine and its metabolites on rat liver and
      kidney.
AB  - In order to evaluate the possibility that the metabolism of pyridine may be
      important for its toxic actions, pyridine was compared with pyridine N-oxide, 2
      hydroxypyridine, 3-hydroxypyridine, 4-hydroxypyridine and pyridinium methyliodide
      in rats given equal molar doses of the chemicals i.p. Hepatoxicity was assessed
      by measuring serum sorbitol dehydrogenase, nephrotoxicity by determining
      increases in blood urea nitrogen and serum creatinine, and influence on
      xenobiotic metabolism by measuring changes in p-nitrophenol hydroxylase and
      ethoxyresorufin and benzyloxyresorufin dealkylase activities. After a single dose
      of 2.5 mmol/kg, pyridinium methyliodide was the only compound that was lethal
      whereas 2-hydroxypyridine was the only one that caused significant hepatoxicity.
      Pyridine, pyridine N-oxide, 3-hydroxypyridine and 4-hydroxypyridine were
      effective inducers of xenobiotic metabolism. Thus the metabolites of pyridine may
      play a role, either singly or collectively, in the actions of pyridine.

PMID- 8644133
TI  - Non-heart-beating donor program contributes 40% of kidneys for transplantation.

PMID- 8644134
TI  - Transplantation of kidneys from non-heart-beating donors: protocol, cardiac death
      diagnosis, and results.

PMID- 8644135
TI  - Organ donation: the "Spanish model".

PMID- 8644136
TI  - Graft conditioning of liver in non-heart-beating donors by an artificial heart
      and lung machine in situ.

PMID- 8644137
TI  - Factors affecting graft function in cadaveric renal transplantation from non
      heart-beating donors using a double balloon catheter.
AB  - Experiences in 145 cadaveric kidney transplantation from non-heart-beating donors
      showed that not only donor age and WIT but also recipient body weight and
      duration of hemodialysis dependency were the determining factors affecting
      posttransplant kidney function analyzed with the use of a stepwise logistic
      regression model. This suggests that the fluid burden on the graft provides an
      additional insult on the recovery of the grafts from ischemic injury.

PMID- 8644138
TI  - Effect of HLA mismatching and other donor factors on renal allograft survival:
      analysis of 12,287 UK and Republic of Ireland transplants. UKTSSA Users' Kidney
      Advisory Group.

PMID- 8644139
TI  - The United Network for Organ Sharing: 1984 to 1994.

PMID- 8644140
TI  - Influence of HLA matching on kidney allograft survival.

PMID- 8644141
TI  - Risk factors of preservation injury and prognostic value of reperfusion biopsy in
      outcome of liver transplantation.

PMID- 8644142
TI  - Role of thrombolytic therapy in renal transplantation.

PMID- 8644143
TI  - Characterization of complement-mediated liver damage and protection in control
      and transgenic mice for human complement blockers MCP and DAF.

PMID- 8644144
TI  - A study of pig kidneys to expand the organ pool.

PMID- 8644145
TI  - Information on relatives of organ and tissue donors. A multicenter regional
      study: factors for consent or refusal.

PMID- 8644146
TI  - Study of 303 families regarding organ donation.

PMID- 8644147
TI  - Relationship of hospital characteristics to organ donation performance.

PMID- 8644148
TI  - Impact of zonal retrieval arrangements in the United Kingdom: the donor
      coordinator's perspective.

PMID- 8644149
TI  - Contemporary ethical considerations related to organ transplantation.

PMID- 8644150
TI  - Organ commerce in South America.

PMID- 8644151
TI  - Influence of donor gender on patient mortality after heart transplantation.

PMID- 8644152
TI  - Multiple organ harvesting: evolution of surgical technique--personal experience.

PMID- 8644153
TI  - Evaluation of the 3.0 Ortho EIA assay in 385 consecutive cadaveric organ donors.

PMID- 8644154
TI  - Do African-Americans wait longer for a kidney because of HLA class I antibody
      specificities and panel-reactive antibody sensitization?

PMID- 8644155
TI  - The non-heart-beating donor.

PMID- 8644156
TI  - How beneficial is the reduction of edema formation by polyethylene glycol during
      cardioplegic arrest?

PMID- 8644157
TI  - Serum melatonin levels in brain-dead organ donors.

PMID- 8644158
TI  - Hemodynamic and metabolic disturbances observed in brain-dead organ donors.

PMID- 8644159
TI  - Medical causes of failure to obtain consent for organ retrieval from brain-dead
      donors.

PMID- 8644160
TI  - Factors that can affect cadaveric islet graft function include hemodynamic
      changes in the donor prior to organ harvest.

PMID- 8644161
TI  - New profile of cadaveric donors: what are the kidney donor limits?
AB  - The need for donor organs is increasing more rapidly than the number of organs
      available from present resources using today's techniques. While efforts to
      improve consent rates through education and various incentives should continue,
      and while recovery and utilization of kidneys from donors at the extremes of age
      can further improve, we believe that the greatest potential for future expansion
      of the donor resource lies in the non-heart-beating donor. The combination of
      effective in situ preservation and ex vivo pulsatile preservation allows donation
      to occur from uncontrolled asystolic donors and provides a mechanism for both
      evaluation and resuscitation of the recovered kidneys. This approach, if fully
      utilized, can double the number of kidneys available for transplantation.

PMID- 8644163
TI  - Expanding the donor pool with the use of en bloc pediatric kidneys in adult
      recipients.

PMID- 8644164
TI  - Organ donation in Spain: evolution of organ donor characteristics.

PMID- 8644162
TI  - Hypophysis-thyroid axis disturbances in human brain-dead donors.

PMID- 8644165
TI  - Organs retrieved and not used for transplantation.

PMID- 8644166
TI  - Hepatitis C virus infection in patients on hemodialysis and after renal
      transplantation in the area of Rijeka-Croatia.

PMID- 8644167
TI  - Expanding the donor pool in cardiac transplantation by accepting donor hearts >
      40 years.

PMID- 8644169
TI  - Bacterial infections transmitted from the donor: antibiotic prophylaxis in the
      donor.

PMID- 8644168
TI  - Transmission of toxoplasmosis by renal transplant: a report of four cases.

PMID- 8644170
TI  - Reasons for unused retrieved organs in the cadaveric organ donation program in
      Saudi Arabia.

PMID- 8644171
TI  - Effect of last donor creatininemia > 200 mumol/L on kidney graft function.

PMID- 8644172
TI  - Human T lymphotropic virus 1-2 positive antibodies in potential organ donors in
      France.

PMID- 8644173
TI  - Pediatric cadaveric donors in Rio Grande do Sul, Brazil.

PMID- 8644174
TI  - Kidney transplantation in elderly patients.

PMID- 8644175
TI  - Procurement of liver grafts by an artificial heart-lung machine using leukocyte
      depleted washed red blood cells in non-heart-beating donors.

PMID- 8644176
TI  - Non-heart-beating donors: one answer to the organ shortage.

PMID- 8644177
TI  - Histidine-tryptophan-ketoglutarate versus Euro-Collins for preservation of
      kidneys from non-heart-beating donors.

PMID- 8644178
TI  - Liver transplantation from non-heart-beating donors: liver procurement without in
      situ portal flush.

PMID- 8644179
TI  - A novel technique for successful transplantation of non-heart-beating cadaver
      organs.

PMID- 8644180
TI  - MAG-3 scintigraphy in renal transplantation from non-heart-beating donors.

PMID- 8644181
TI  - Risk factors for the outcome of cadaveric renal transplantation with non-heart
      beating donors.

PMID- 8644182
TI  - Cadaveric liver donors; what are the limits?
AB  - The current crisis in organ availability will only be solved by aggressive and
      innovative solutions. One approach, outlined here, is to more carefully assess
      current donors and determine how to safely "push the limits" of acceptable
      cadaveric liver donors. Our experience, as well as that of others, indicates that
      donors with these higher risk factors may be used in certain carefully defined
      situations. The key elements to an appropriate use of these donors are careful
      donor and recipient assessment, and avoiding the presence of multiple risk
      factors. These guidelines form a foundation for continuing assessment of methods
      to increase, in an incremental fashion, the number of cadaver livers successfully
      transplanted.

PMID- 8644184
TI  - Genetic engineering targeted to donor organs using adenoviral vector.

PMID- 8644183
TI  - Comparison of the effect of plasmapheresis using human albumin or dextran 40 on
      the survival of pig-to-dog renal xenografts.

PMID- 8644185
TI  - Tissue distribution of Gal alpha(1,3)Gal epitope in heart, kidney, and liver of
      pig and mouse.

PMID- 8644186
TI  - Streamlining the donor organ placement process: use of portable computers in the
      field.

PMID- 8644187
TI  - Allocation of kidneys to Afro-American patients is proportional to wait-list
      composition.

PMID- 8644188
TI  - Stratification and successful transplantation of patients awaiting ABO
      incompatible (A2 into B and O) transplantation by A-isoagglutinin-titer
      phenogroup.

PMID- 8644189
TI  - Taboo HLA mismatches in cadaveric renal transplantation: definition, analysis,
      and possible implications.

PMID- 8644190
TI  - Proposal for an International Registry and Depository of Hyperacute Rejection
      after kidney transplantation.

PMID- 8644191
TI  - Regional vs national renal sharing organizations: pros and cons.

PMID- 8644192
TI  - Abnormalities in cadaveric organ donation rhythms and characteristics.

PMID- 8644194
TI  - Contribution of nontransplant and small hospitals to organ procurement in Spain.

PMID- 8644193
TI  - Cadaveric organ sharing in the United States: 1988 through 1993.

PMID- 8644195
TI  - Evaluation of a regional cadaver donor kidney allocation policy.

PMID- 8644196
TI  - A regional program for expanding the donor pool: experience in Piedmont, Italy.

PMID- 8644197
TI  - The cadaveric organ donation program in Saudi Arabia: 10-year experience.

PMID- 8644198
TI  - Effectiveness of the organizational transplant model in Catalonia (OCATT):
      encouraging results of 1994.

PMID- 8644199
TI  - Organ procurement: experience from a southern Italian region.
AB  - The authors report their experience of organ procurement during the last 5 years
      to evaluate a program that began in 1988 to improve organ retrieval in Calabria.
      In this region only two donations were reported up to 1988, one each in 1980 and
      1985. Because of the large population on dialysis and the willingness of a group
      of surgeons and anesthesiologists, this program was undertaken in 1988 under the
      supervision of C.C.S.T. (Co-ordination of Centre and South Italy for
      Transplantation). This program was designed to act on two levels: to create a
      large group of people directly involved in health care (physicians and nurses)
      motivated in organ procurement and transplantation, and to diffuse the "culture"
      of organ donation among lay people. This was achieved by means of scientific
      meetings inside the hospital and with conventions and TV programs, supported by
      an Association of Volunteers, where ethical and scientific problems of organ
      donation and transplantation were discussed in simple language. Various meetings
      were also held with high school students. During these meetings a questionnaire
      was distributed among students. Results of this questionnaire show that the main
      obstacles to organ donation are the "unclear" concept of "brain death" and
      religious feelings, but after the concept of brain death was explained, a
      significant number of students showed a different attitude toward organ
      procurement and transplantation. Results of this program are extremely
      encouraging (23 organ donations during the last 3 years). We hope to improve our
      results in the near future, and we do believe that a further and significant
      increase to our preliminary good results could be achieved by the possibility of
      performing at least kidney transplantation in our institution.

PMID- 8644200
TI  - How informed is informed consent?

PMID- 8644201
TI  - Influence of tissue donation on the organ donation rate.

PMID- 8644202
TI  - Standards of practice for procurement coordinators in the United Kingdom.

PMID- 8644203
TI  - Evaluation of the U.K. super-urgent liver transplant scheme.

PMID- 8644205
TI  - The Saudi Center for Organ Transplantation: an ideal model for Arabic countries
      to improve treatment of end-stage organ failure.

PMID- 8644204
TI  - Management of data in tissue banking: the Ariane database software developed by
      the Assistance Publique-Hopitaux de Paris Tissue Bank.

PMID- 8644206
TI  - Multiorgan donation from brain-death cases in the Kingdom of Saudi Arabia.

PMID- 8644207
TI  - Improving retrieval rate by increasing ICU involvement in the cadaveric organ
      donation program in Saudi Arabia.

PMID- 8644208
TI  - Role of computers in coordination of renal care facilities: experience in the
      Kingdom of Saudi Arabia.

PMID- 8644209
TI  - Correlation between transplant-coordinator activities and donor availability: a
      retrospective region analysis.

PMID- 8644210
TI  - Transplant coordinators in Rio Grande do Sul, Brazil: analysis of 7 years'
      activities.

PMID- 8644211
TI  - Rapid exenteration for multiorgan harvesting: a new technique for the unstable
      donor.

PMID- 8644212
TI  - Organization of organ procurement in the public hospitals of Buenos Aires,
      Argentina.

PMID- 8644213
TI  - Study of the status and certification of transplant coordinators in Japan.

PMID- 8644214
TI  - Logistics and management for improvement of multiorgan procurement from potential
      brain-dead donors.

PMID- 8644216
TI  - Survival in lung transplantation.

PMID- 8644215
TI  - Cadaver organs: limitations and results.

PMID- 8644217
TI  - How presumed is presumed consent?
AB  - All things considered, one is tempted to answer the question in the title: How
      presumed is presumed consent? Not very, or not at all. It is evident that,
      regardless of the law, be it opting in or opting out, presumed consent or
      presumed nonconsent, the family is almost always consulted. The family has the
      preferential right of interpretation. Their interpretation of the attitude toward
      organ donation by the deceased is usually not contested, whether it is in
      agreement with or contrary to the stated (verbal or written) view of the
      deceased. This is understandable and proper; the sudden and unexpected death of a
      close relative is the start of the grieving process and, besides, relatives might
      take legal action if their opinion is not respected. Taken together, it can be
      argued that well-designed presumed consent legislation is the best system for
      many of the reasons stated. Foremost among these is that it offers a very good
      way to initiate consultations with the family. With due respect for any legal
      system, one does not discuss the legal aspects with the relatives. Since they are
      expected to honor the opinion of the deceased, there is reason for each of us to
      make our wishes regarding organ donation known to our relatives. It might relieve
      them of a difficult decision.

PMID- 8644218
TI  - Is the decreased number of renal transplants in Warsaw caused by a shortage of
      potential organ donors?: an analysis of hospital deaths in Warsaw in 1993.

PMID- 8644219
TI  - Delayed graft function as principal correlate of kidney allograft outcome in a
      single-center multivariate analysis.

PMID- 8644220
TI  - The causes of brain death in the cadaver organ donation program in the Kingdom of
      Saudi Arabia.

PMID- 8644221
TI  - Organ retrieval trends in southern Alberta, Canada.

PMID- 8644222
TI  - Organ sharing for shipped livers used as full-size, reduced, or split grafts.

PMID- 8644224
TI  - How can we best measure organ procurement performance?

PMID- 8644223
TI  - Outcome of patients admitted for severe coma in an intensive care unit.

PMID- 8644225
TI  - Pediatric renal transplantation: personal experience.

PMID- 8644226
TI  - Metabolic and functional effects of polyethylene glycol 20M and 2,3- butanedione
      monoxime during single flush or oxygenated microperfusion preservation:
      comparison with Plegisol.

PMID- 8644227
TI  - Cardioprotective effect of ischemic preconditioning with University of Wisconsin
      solution on rat heart preservation: what is the optimal duration of
      preconditioning ischemia?

PMID- 8644228
TI  - Reduced incidence of cardiac arrhythmias after orthotopic heart transplantation
      with direct bicaval anastomosis.

PMID- 8644229
TI  - A cooling jacket to reduce tubular damage during kidney transplantation:
      evaluation of a prototype in the pig model.

PMID- 8644230
TI  - Protection of rat kidney from ischemia reperfusion injury by oligotide.

PMID- 8644231
TI  - Presidential address: the Society for Organ Sharing.

PMID- 8644232
TI  - Anti-ischemic effect of oligotide treatment in rat kidney: comparison with the
      effect of nifedipine and isosorbide dinitrate.

PMID- 8644234
TI  - Storage by continuous hypothermic perfusion for kidney harvested from
      hemodynamically unstable donors.

PMID- 8644233
TI  - Pathogenesis of delayed kidney graft function: role of endothelin-1, thromboxane
      B2, and leukotriene B4.

PMID- 8644236
TI  - Kidney allocation: potential for improvements.

PMID- 8644235
TI  - Functional activity of isolated perfused kidney transplants after flush and 48
      hour cold storage.

PMID- 8644237
TI  - Influence of systemic cyclooxygenase inhibition with single-dose aspisol on
      kinetics of arachidonic acid metabolites in the venous effluate of transplanted
      kidney grafts in humans.

PMID- 8644238
TI  - Tissue thiamine and carnitine deficiency as a possible cause of acute tubular
      necrosis after renal transplantation.

PMID- 8644239
TI  - Protective effect of University of Wisconsin solution on lipid peroxidation of
      liver grafts in reperfusion injury.

PMID- 8644240
TI  - Leakage of superoxide radicals from mitochondrial electron transport system after
      cold ischemia in liver grafts.

PMID- 8644241
TI  - Modulation of mitochondrial ATP synthesis and lipid peroxidation by Kupffer cells
      in liver grafts.

PMID- 8644242
TI  - Role of neutrophils in lipid peroxidation at reperfusion in liver
      transplantation.

PMID- 8644243
TI  - Mitochondrial function in liver preservation at low temperatures.

PMID- 8644244
TI  - Measurement of the ratio of superoxide-scavenging activity in the graft in swine
      liver transplantation.

PMID- 8644245
TI  - Application of a vena cava allograft in split liver transplantation in pigs.

PMID- 8644246
TI  - Ameliorative effect of gabexate mesilate on the disturbed microcirculation
      following prolonged cold ischemia of the liver.

PMID- 8644247
TI  - Beneficial effects of pentoxifylline and propentofylline on preservation
      reperfusion injury in rat liver transplantation.

PMID- 8644248
TI  - Organ specificity of pancreas preservation compared with kidney and heart
      preservation.

PMID- 8644249
TI  - Combined method of mechanical chopper and automated two-step digestion technique
      for islet isolation from canine pancreas.

PMID- 8644250
TI  - Oligotide anti-ischemic effect is related to in vitro inhibition of leukocyte
      endothelial cell adhesion.

PMID- 8644251
TI  - Facing organ shortage, should we revisit organ allocation?

PMID- 8644252
TI  - Retrovirus-mediated human superoxide dismutase cDNA transfer to prevent ischemia
      reperfusion injury.

PMID- 8644253
TI  - Temperature dependence of proton buffering capacity of HTK, Euro-Collins, and UW
      solution.

PMID- 8644254
TI  - Method for cryopreserving human arteries: 1H NMR spectroscopy for measuring the
      kinetics of permeation and ice-forming tendency of cryoprotective agents.

PMID- 8644255
TI  - Cryopreservation of organs: NMR follow-up of cryoprotectant perfusion in rabbit
      kidneys.

PMID- 8644256
TI  - The feasibility of organ preservation at warmer temperatures.

PMID- 8644257
TI  - HEH: a "High Na+ -low K+" cold-storage solution--functional, metabolic, and
      histological study by the isolated perfused rat kidney technique.

PMID- 8644258
TI  - Improvement of brain-dead lung assessment based on the mechanical properties of
      the respiratory system.

PMID- 8644259
TI  - Liver transplantation: first clinical experience.

PMID- 8644260
TI  - Posttransplant serum creatinine area under the curve predicts renal allograft
      outcome.

PMID- 8644261
TI  - Histologic and ultrastructural analysis of myocardial biopsies from donor hearts
      before transplantation.

PMID- 8644262
TI  - Delayed graft function adversely affects one-year graft survival of cadaveric
      renal transplants.

PMID- 8644263
TI  - Should we revisit recipient selection?

PMID- 8644264
TI  - Evaluation of pancreas graft function by the measurement of pancreatic protein
      synthesis rate.

PMID- 8644265
TI  - Evaluating renal allograft function prospectively.

PMID- 8644266
TI  - Heterotopic rat heart transplant as an in vivo model for reperfusion in long term
      heart preservation with a modified UW solution.

PMID- 8644268
TI  - Experience of a mobile transplant coordinator nurse.

PMID- 8644267
TI  - Living kidney donor with splenic artery aneurysm.

PMID- 8644269
TI  - Role of physicians in an awareness campaign concerning organ sharing.

PMID- 8644270
TI  - Impact of the presumed consent law on kidney procurement in Latvia.

PMID- 8644271
TI  - Intraoperative renal biopsy and its relation to renal function at the end of the
      first year posttransplantation.

PMID- 8644272
TI  - Medical utility versus legal justice: a proposal for the ethical use of prisoner
      donated organs.

PMID- 8644273
TI  - Severe pulmonary arterial hypertension during the apnea test for brain death.

PMID- 8644274
TI  - Cadaveric-related kidney donation: three case studies.

PMID- 8644275
TI  - Cerebral angiography must have medicolegal value for brain death confirmation in
      France.

PMID- 8644276
TI  - The texture and content of living donor transplant laws and policies.

PMID- 8644277
TI  - Trends for successfully documented cases of brain death in intensive care units
      in Saudi Arabia.

PMID- 8644278
TI  - Trend of consents for donation by relatives of cadaveric donors in the Kingdom of
      Saudi Arabia.

PMID- 8644279
TI  - Ethical and legal aspects, and the history of organ transplantation in Turkey.

PMID- 8644280
TI  - Hypothesis of insufficient efforts in respect to organ donation in some European
      regions.

PMID- 8644281
TI  - Support for donor families: the need for a structure and psychiatric help.

PMID- 8644282
TI  - The causes of family refusal to consent for organ donation from a brain-death
      relative in Saudi Arabia.

PMID- 8644284
TI  - Inquiry "INSERM 1992": opposition to organ harvesting.

PMID- 8644283
TI  - Analysis of organ donation refusal.

PMID- 8644285
TI  - On accepting death: languages of access to organ sharing.

PMID- 8644286
TI  - Regional awareness campaign concerning organ sharing.

PMID- 8644288
TI  - European Donor Hospital Education Program.

PMID- 8644287
TI  - An assessment of the impact of the National Minority Organ Tissue Transplant
      Education Program.

PMID- 8644289
TI  - Comparison between three different antilymphocyte induction protocols in renal
      transplant recipients with delayed graft function.

PMID- 8644290
TI  - The clinical relevance of pretransplant recipient immunoresponsiveness in renal
      transplantation: impact on rejection.

PMID- 8644291
TI  - Role of indirect allorecognition in chronic rejection of human allografts.

PMID- 8644292
TI  - Development of organ procurement in reunion island.

PMID- 8644293
TI  - Transplantation and organ donation in Hospital de Especialidades CMN SXXI in
      Mexico City.

PMID- 8644294
TI  - Kidney transplantation activities in Turkey.

PMID- 8644295
TI  - Kidney transplantation at one center: 1-year results.

PMID- 8644296
TI  - Organ procurement in Israel: demographic and religious aspects.

PMID- 8644297
TI  - Results of renal transplantation in French South Pacific Territories.

PMID- 8644298
TI  - Xenotransplantation: a possible solution to the shortage of donor organs.

PMID- 8644299
TI  - The influence of donor factors on development of hypertension following cadaveric
      renal transplantation in nonhypertensive recipients.

PMID- 8644300
TI  - Criminal hazards of human organ traffic.

PMID- 8644301
TI  - Results of en bloc kidney transplantation with a new technique.

PMID- 8644302
TI  - Overview of the European Donor Hospital Education Program.

PMID- 8644303
TI  - Acceptance principles of living-related donors for kidney transplantation.

PMID- 8644304
TI  - New profile of cadaveric donors: what are the limits in heart?

PMID- 8644305
TI  - Living-related liver transplantation in children.

PMID- 8644306
TI  - Logistical aspects and procedures in split-liver transplantation.

PMID- 8644307
TI  - A summation of the Third International Congress of the Society for Organ Sharing.

PMID- 8644308
TI  - Report of the Third Banff Conference on Allograft Pathology (July 20-24, 1995) on
      classification and lesion scoring in renal allograft pathology.

PMID- 8644309
TI  - Prospects for extension of Banff schema concepts to interpretation of native
      kidney biopsies.

PMID- 8644310
TI  - Angiotensin II and endothelin-1 circulating and interstitial myocardial release
      following brain death.

PMID- 8644312
TI  - Liver allograft rejection: current status of classification and grading.

PMID- 8644311
TI  - The Banff schema four years later.

PMID- 8644313
TI  - The use of immunocytochemistry (LCA and LEU-7) in diagnosis of renal allograft
      rejection.

PMID- 8644314
TI  - Chronic liver transplant rejection: definition and diagnosis.

PMID- 8644315
TI  - Early transplant glomerulitis: glomerular size and ultrastructure.

PMID- 8644317
TI  - A perspective on the Revised Working Formulation for the grading of lung
      allograft rejection.

PMID- 8644316
TI  - Morphometric and immunohistochemical investigation of renal biopsies from
      patients with transplant ATN, native ATN, or acute graft rejection.

PMID- 8644318
TI  - Assessment of a new cardioplegic solution for long-term heart preservation:
      experimental study using 31P magnetic resonance spectroscopy and biochemical
      analyses.

PMID- 8644319
TI  - Glomerulosclerosis in kidney transplants: pathophysiologic mechanisms.

PMID- 8644320
TI  - CD45 isoforms and lymphocyte activation antigens in acute renal allograft
      rejection.

PMID- 8644321
TI  - Molecular activation markers in rejection diagnosis.

PMID- 8644322
TI  - The Banff classification of renal allograft pathology: where do we go from here?

PMID- 8644323
TI  - Improvement of lesion quantitation for the Banff schema for renal allograft
      rejection.
AB  - The Banff Working Formulation provides objective criteria for diagnosis and
      grading of acute rejection in renal allografts and should be a reliable tool in
      the hands of most pathologists. However, as with any such schema, improvement and
      refinement are both possible and desirable. Agreement should be enhanced by more
      careful definitions of morphologic criteria, a process which is already underway.
      In addition, immunostaining, even nonspecific staining for common leukocyte
      antigen, would be useful in particular for identifying and quantitating
      glomerular and tubulitis. More specific immunostains, eg, for effector cell
      populations, cytokines, and/or adhesion molecules will doubtless also be
      validated by ongoing and future studies, and be incorporated into this rejection
      assessment schema.

PMID- 8644324
TI  - Protocol core biopsy as intermediate efficacy end-point in chronic kidney
      allograft rejection.

PMID- 8644325
TI  - Effect of subclinical rejection on renal allograft histology and function at 6
      months.

PMID- 8644326
TI  - Allograft vascular disease: comparison of heart and other grafted organs.
AB  - A striking resemblance exists between the vasculopathy in several different
      allografts. The arteriopathy of epicardial coronary arteries is diffuse,
      involving proximal, distal, and small branch segments in a generally concentric
      pattern of intimal thickening. Smooth muscle cells in a lipid- and
      glycosaminoglycan-rich matrix are the predominant components of this expanded
      intima. Varying amounts of collagen are present, more being present late
      posttransplant. A superficial and, to a lesser degree, deep, bandlike infiltrate
      of T cells and macrophages is uniformly present, although it is somewhat more
      prominent in early lesions as compared to more severely narrowed arteries from
      longer-term, susceptible grafts. The media is likewise altered by areas of lipid
      and glycosaminoglycan deposition associated with smooth muscle cell loss and
      phenotypic modulation. The media is altered in an outside-to-inside direction,
      with percolation of adventitial leukocytes into the outer media. Virtually all of
      the coronary features are seen in the medium to large arteries of liver,
      pancreas, and kidney allografts. Chronic rejection in lung allografts is manifest
      by obliterative bronchiolitis; vascular changes, although architecturally
      similar, are somewhat less common and result in less-severe luminal narrowing.
      The role of allograft vasculopathy in chronic lung rejection is thus less
      certain. A finding perhaps unique to epicardial coronary arteries of heart
      allografts is the presence of eccentric lesions more typical of native
      atherosclerosis. Many of the latter grafts probably have preexistent, undetected
      donor disease. Sequential evaluation of vascular changes is limited in human
      biopsy material by their general absence in endomyocardial or core liver needle
      specimens. Fortunately, vascular changes can be detected in some renal and
      pancreas core needle biopsies, and these findings may provide an avenue for
      monitoring the effectiveness of immunosuppressive therapy, antiviral or lipid
      altering therapies, or modifications of smooth muscle cell proliferation and
      glycosaminoglycan deposition yet to be developed.

PMID- 8644327
TI  - Risk of chronic liver disease in HBsAG and/or anti-HCV-positive renal allograft
      recipients.

PMID- 8644328
TI  - The Banff schema for allograft pathology: the end of the beginning.

PMID- 8644329
TI  - Proliferation rate of cells in the interstitial infiltrate in acute kidney
      allograft rejection.

PMID- 8644330
TI  - Diagnosis and grading of liver allograft rejection: a European perspective.

PMID- 8644331
TI  - Diagnosis of chronic rejection using peritubular and glomerular capillary
      lesions.

PMID- 8644332
TI  - Histologic grading of pancreas acute allograft rejection in percutaneous needle
      biopsies.

PMID- 8644333
TI  - Clinical and immunological aspects of liver allograft rejection.

PMID- 8644334
TI  - Follow-up of patients with borderline changes in renal allograft biopsies:
      clinical outcome and evaluation of other histological features in addition to
      tubulitis.

PMID- 8644336
TI  - Modification of mitochondrial energy metabolism in brain dead organ donor.

PMID- 8644335
TI  - Adhesion molecules as markers of acute cellular rejection of renal allografts.

PMID- 8644337
TI  - Optimisation of donor organ usage with the extended application of split-liver,
      reduced size and living related liver transplantation: a 1-year experience.

PMID- 8644339
TI  - Anatomic basis and technique of procurement of subsegment III from living donors
      for liver transplantation.

PMID- 8644338
TI  - Left lobectomy of the donor: operation for larger recipients in living related
      liver transplantation.

PMID- 8644340
TI  - Anatomic basis of pig liver partition for experimental transplantation and
      perspective in xenotransplantation.

PMID- 8644341
TI  - Living unrelated renal transplantation affords optimal donor utilization.

PMID- 8644342
TI  - Living donor transplantation: single center experience.

PMID- 8644343
TI  - The selectin family is responsible for microcirculatory disturbances after cold
      ischemia and reperfusion of the liver.

PMID- 8644344
TI  - Histochemical analysis of tissue injury in human hepatic grafts: potential
      usefulness in graft assessment before implantation.

PMID- 8644345
TI  - Protective properties of anti-IFN alpha/beta antibodies in normothermic hepatic
      ischaemia in the rat.

PMID- 8644346
TI  - The use of hyaluronic acid uptake in the evaluation of reperfusion injury in cold
      stored rat livers.

PMID- 8644347
TI  - The HTK solution with nicorandil can improve cardiac function after simple cold
      storage.

PMID- 8644349
TI  - Effect of Na/K/2Cl transporter inhibition with piretanide on postischemic kidney
      function.

PMID- 8644348
TI  - Delayed graft function of cadaveric renal transplants is prevented by diltiazem.

PMID- 8644350
TI  - Impact of Lazaroid U74006F on ischemia and reperfusion injury of islets after
      transplantation in the rat.

PMID- 8644351
TI  - Comparative analysis of kidney preservation methods. Collaborative Transplant
      Study.

PMID- 8644352
TI  - Donor age greater than 50 years does not influence midterm results of heart
      transplantation.

PMID- 8644354
TI  - Use of extended donors in high-risk renal transplant recipients: a 2-year single
      center experience.

PMID- 8644353
TI  - Long-term evaluation of kidney donors.

PMID- 8644355
TI  - Integrated ways to improve cadaveric organ donation.

PMID- 8644356
TI  - Significant increase of organ procurement in Argentina, 1992-1994.

PMID- 8644357
TI  - Ultrasound guided percutaneous fine needle aspiration cytology of pancreas: a
      review of 61 cases.
AB  - The study includes 61 cases which were subjected to ultrasound (US) guided fine
      needle aspiration cytology (FNAC) to find out the utility of this technique in
      the diagnosis of pancreatic lesions. Age of the patients ranged from 23 to 85
      years with a median of 50 years. Male to female ratio was 36:25. One or more
      clinical diagnoses were offered in 16 and in 9 of these, the disease was related
      to pancreas. Subsequent to US, the lesions were localized to pancreas in 57 and
      the nature of pathology in the pancreatic lesion could be diagnosed in 31. By
      FNAC, 31 cases (50.8%) were diagnosed to have pancreatic malignancy which
      included adenocarcinoma (23 cases), papillary cystic tumour (1), muco-epidermoid
      carcinoma (1), acinic cell carcinoma (1), islet cell tumor (1), and non Hodgkin
      lymphoma (4). FNAC of liver in 2 cases and retroperitoneal lymph node in a case
      of pancreatic adenocarcinoma revealed metastasis. During follow up, 1 case of non
      Hodgkin's lymphoma showed CSF involvement. Three cases (4.9%) were suspected to
      have epithelial malignancy of which one was confirmed as an adenocarcinoma
      following surgery and histology. Four (6.6%) were benign lesions which included
      nonspecific inflammation (2 cases), tuberculous pancreatitis (1) and
      pseudopancreatic cyst (1). The remaining 23 cases (37.7%) had normal or
      inadequate cytology. Of these, FNAC of liver showed metastasis in 2 cases and one
      case each were diagnosed as adenocarcinoma and pseudopancreatic cyst respectively
      following surgery. None of the patients had any complication following FNAC. We
      recommend US guided FNAC to be routinely used for diagnosis of pancreatic lesion.

PMID- 8644358
TI  - A profile of nutritional practices and its cost in an intensive care in India.
AB  - In a retrospective study fifty patients admitted to a combined medical and
      surgical intensive care unit were surveyed to see the pattern of nutritional
      support. The routine practices of initial assessment and monitoring of the
      nutritional state, ordering and technique of feeding, routes of administration
      and complications were noted over a 3 week period. This gives an idea of the
      pattern of care and problems associated with nutritional support of the
      critically ill in this part of the world. The average cost of parenteral
      nutrition for three weeks was approximately Rs. 25,960 ($865 approx.) per
      patient.

PMID- 8644359
TI  - Malignant retrorectal teratoma presenting as an infected perianal sinus.
AB  - Retrorectal teratomas are rare tumours arising in the presacral space. We report
      a case of malignant retrorectal teratoma which presented as an infected perianal
      sinus. The patient was treated with abdominoperineal resection.

PMID- 8644360
TI  - Rapid reversal of manifestations of acquired zinc deficiency in alcoholic
      cirrhosis with diet therapy.
AB  - Features of acquired zinc deficiency syndrome occurred in an alcoholic cirrhotic
      during hospital stay while he was on parenteral nutrition. Rapid reversal of
      symptoms occurred with resumption of normal diet without additional zinc
      supplementation.

PMID- 8644361
TI  - Endoscopic retrieval of sharp sewing needles from duodenum--a new technique.

PMID- 8644362
TI  - Analysis of symptomatic patients after cholecystectomy: is the term post
      cholecystectomy syndrome an anachronism?
AB  - Of 171 patients who were followed-up prospectively for 2.8 years after
      cholecystectomy, 31 developed postcholecystectomy symptoms, 24 of them being mild
      to moderate and 7 severe. Symptomatic patients mostly had functioning gall
      bladders preoperatively and longer duration of symptoms prior to cholecystectomy.
      The causes of postcholecystectomy symptoms could be identified in all of them
      except 9 patients who were labelled as having "essential dyspepsia". The symptoms
      in the latter syndrome as well as in other conditions diagnosed in the
      symptomatic postcholecystectomy patients appeared unrelated to the absence of
      gallbladder. Hence, we feel the term postcholecystectomy syndrome is an
      anachronism and should be redefined.

PMID- 8644364
TI  - Genetics for clinicians.

PMID- 8644363
TI  - A comparative study of double contrast barium enema and colonoscopy for
      evaluation of rectal bleeding in children.
AB  - In pediatric age group, rectal bleeding is both common and distressing. Unlike in
      adults, very few studies comparing diagnostic efficacy of double contrast barium
      enema (DCBE) and Colonoscopy are available in children. A prospective study was
      performed to compare the diagnostic accuracy of high quality DCBE against
      colonoscopy in children with overt rectal bleeding. Fourty four children
      underwent flexible colonoscopy and DCBE independently. The final diagnosis was
      made after considering all investigations. Against this gold standard, the
      sensitivity and specificity of DCBE were 66.66% and 100% while that of
      colonoscopy 74.35% and 100% respectively. When assessing polypoidal lesions of
      colon, diagnostic yield of enema study was 86.20% as compared to 72.41% with
      colonoscopy. In colitis cases, the similar figures for enema and endoscopy were
      53.84% and 76.92% respectively. The observed differences were statistically
      insignificant. No significant preparation, premedication or procedure related
      complications were encountered. The study thus highlights the utility and
      complementary role of DCBE and colonoscopy for evaluation of children with rectal
      bleeding.

PMID- 8644365
TI  - Prolonging survival in inoperable pancreatic cancer with combination
      chemotherapy.

PMID- 8644366
TI  - Delayed stoma closure improves prognosis in colorectal cancers?

PMID- 8644367
TI  - Pediatric gastroenterology.

PMID- 8644368
TI  - Hepato-renal syndrome: pathogenesis and management.

PMID- 8644369
TI  - Multi drug resistant tuberculosis.
AB  - The prevalence of multi-drug resistant tuberculosis is increasing globally which
      has upset tuberculosis treatment and control programmes. The problem has been
      further complicated by co-infection with HIV virus. Treatment of multi drug
      resistant tuberculosis is difficult, expensive and requires long duration
      chemotherapy. The long term prognosis is poor with frequent relapses following
      cessation of treatment. Health care workers are at considerable risk of
      contacting the disease. New, potent and less toxic drugs are required for
      management of multi drug resistant strains. Directly observed therapy of
      tuberculosis seems to be promising but demands enormous resources. Finally
      strengthening of tuberculosis control programmes for prevention and control of
      tuberculosis is essential.

PMID- 8644370
TI  - Descriptive epidemiology of hereditary non-polyposis colorectal cancer.
AB  - Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is
      characterized by early occurrence of colorectal malignancies, localization of
      tumors in the proximal colon, frequency of multiple primaries (both synchronous
      and metachronous) and an autosomal dominant type of genetic transmission. HNPCC
      has been reported in many races and populations, including Japanese, Philipinos
      and American Indians. The frequency off the disease ranges between 1 and 5% of
      all colorectal malignancies. In northern Italy, the frequency of HNPCC has been
      estimated in the order of 2.8-3.0% of all registered cancers of the large bowel,
      while lower estimates have been recorded in southern regions. The identification
      of HNPCC remains difficult, mainly because the full-blown syndrome does not
      become manifest until several family members are affected with cancer. The recent
      identification of at least four genes responsible, when mutated, for the clinical
      spectrum of Lynch syndrome should be of considerable help in recognizing this
      type of tumors in the general population.

PMID- 8644371
TI  - Genetic epidemiology of colorectal cancer.
AB  - Starting from a survey of the studies on familial aggregation of colorectal
      cancer, we introduce the aims of genetic epidemiology. One of its main goals is
      to assess population frequency of cancer susceptibility genes and to determine
      the age-specific risks for carriers with respect to non-carriers. In section two,
      segregation analysis investigations are reviewed, and inferences on the relevance
      of genetic components of susceptibility to colorectal cancer are drawn. In
      section three, the HNPCC paradigm is discussed in the light of the Knudson model
      of tumorigenesis and recent advances of molecular research. In the last section
      we show an example of genotype/environment interaction in the etiology of a
      particular cancer and present a conceptual framework for studies on cancer
      genetic epidemiology in terms of attributable and relative risk.

PMID- 8644372
TI  - Pathologic features of hereditary non-polyposis colorectal cancer.
AB  - In hereditary non-polyposis colorectal cancer (HNPCC) patients, the cancer
      frequently arises in the proximal colon and is often multiple (synchronous or
      metachronous). Pathologic differences seem to exist between hereditary and
      sporadic large bowel cancer, but the data are not uniform. Many authors reported
      that the following histologic features are often present in HNPCC: 1) mucinous
      histotype, 2) poorly differentiated tumors, 3) presence of peritumoral
      lymphocytic infiltrate, with Crohn's-like lymphoid reaction. Such features have
      also been found in apparently sporadic colorectal cancer with, but not in
      sporadic colorectal cancer without DNA replication errors. Many studies have
      suggested that adenoma plays a main role in HNPCC carcinogenesis, and that the
      "adenoma-carcinoma sequence" may be the pathway to cancer in HNPCC as in sporadic
      colorectal cancer. Moreover, HNPCC adenomas show an early onset, villous
      component, high-grade dysplasia, and positivity for DNA replication errors more
      frequently than sporadic adenomas. Such data suggest that the adenoma-carcinoma
      sequence is accelerated in- HNPCC and that surveillance in these patients should
      therefore be strict to avoid cancer development.

PMID- 8644373
TI  - Clinical aspects and management of hereditary non-polyposis colorectal cancer
      (HNPCC).
AB  - Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomical dominant
      trasmitted disease phenotypically defined according to the "Amsterdam criteria"
      as follows: at least 3 affected relatives, one of whom first degree relative of
      other two, at least two successive generations affected. Important cardinal
      features are: 1) prevalent proximal location of cancers (above splenic flexure);
      2) multiple synchronous or methachronous large bowel cancers; 3) early age of
      onset (<50 years); 4) presence of extracolonic cancers (endometrium, stomach,
      urinary tract, skin). The treatment is essentially surgical and total colectomy
      with ileo-rectum anastomosis is already proposed as standard procedure with
      annual endoscopic examination of retained rectum. The screening of individuals at
      risk, so determined by the analysis of pedigree or the results of molecular
      tests, must be performed every 1-2 years by colonoscopy starting around the age
      of 25 years. In this review are described and analysed the spectrum of the
      disease with particular attention to the frequency and characteristics of
      extracolonic cancers. Moreover, the guidelines of the surveillance and screening
      are reported following the data of the literature and as proposed by the
      International Collaborative Group (ICG-HNPCC).

PMID- 8644374
TI  - Molecular genetics of hereditary non-polyposis colorectal cancer (HNPCC).
AB  - The story of the molecular genetics of HNPCC is one of astonishingly rapid
      achievements. In just 16 months, from May 1993 to September 1994, four different
      genes, namely hMSH2, hMLH1, hPMS1 and hPMS2 have been identified and demonstrated
      to be associated with the disease. Their cloning was facilitated by the finding
      that tumor cells in HNPCC patients display a hypermutability of DNA short tandem
      repeats (microsatellite instability). In fact, HNPCC associated genes are the
      human counterparts of genetic elements known to control the fidelity of DNA
      replication in lower organisms. So far, more than 50 germline mutations of hMSH2
      and hMLH1 genes have been reported in HNPCC kindreds. In addition, somatic
      mutations have been documented in hereditary as well as sporadic cancers.
      Unfortunately, the molecular diagnosis of HNPCC is hampered by the lack of
      mutational "hot spots" and of clearly defined genotype-phenotype correlations and
      different screening methods are to be employed for the analysis of affected and
      at-risk individuals.

PMID- 8644375
TI  - Genetic counseling in hereditary non-polyposis colorectal cancer.
AB  - Genetic counseling is a medical process aimed at providing information about
      disease risks for hereditary conditions. For adult-onset diseases, such as
      cancer, the main purpose consists in formulating probability estimates of disease
      appearance, along with details on preventive or follow-up measures. The process
      of genetic counseling has been substantially modified by the availability of
      molecular tests to identify mutant gene carriers. So far, 16 autosomal dominant
      genes associated with cancer susceptibility have been cloned. Four of these,
      which encode for components of the DNA mismatch repair machinery, have been
      implicated in hereditary non-polyposis colorectal cancer, one of the most common
      hereditary cancer syndromes. Genetic counseling and testing in hereditary non
      polyposis colorectal cancer is associated with several problems that are common
      to other hereditary conditions (psychologic consequences, confidentiality,
      genetic "discrimination", testing of minors, prenatal diagnosis) and peculiar to
      the specific condition (incomplete penetrance, genotypic and phenotypic
      heterogeneity, limits of currently available tests). For such reasons, genetic
      testing should be performed in qualified research laboratories and restricted to
      highly selected families. In this way, pilot studies, involving both clinicians
      and researchers, can be undertaken with the aim of providing comprehensive
      results, potentially applicable to other cancer-predisposing conditions.

PMID- 8644376
TI  - Personal freedom and genetic overdetermination.
AB  - We do not intend to specify definite proposals as regards the scientific
      responsibility of genetic practice. This field of predicting the development of a
      pathology in an individual and family history requires reflection on the
      perception of personal risk, of the importance and reassurance deriving from a
      personal history, and of the benefits sharing knowledge and care with the
      clinical and scientific world. We evaluate the possibility to expand a reflection
      on sign-possibility and sign-expression of disease that could develop a wider
      comparison with personal freedom when confronted by genetic, philosophical and
      historical determinations. A parallel and preliminary consideration is made of
      guidelines for diagnostic and therapeutic behavior.

PMID- 8644377
TI  - Genetic counselling: communication and psychosocial aspects.
AB  - The results of genetic research have a remarkable role in medicine progress. At
      the same time the issues of prevention, individual attitudes and behaviour have
      acquired more importance, not only in relation to the illness but also regarding
      one's health. For these reasons is important to consider this field of study and
      intervention as an area to face, not only from the medical point of view but also
      from ethical and psychological ones. If we agree on the importance of a global
      approach to this problem, psychosocial support, which is often considered a
      parallel intervention, becomes a component of genetic counselling: the focal
      point of the intervention becomes the person, and not only the problem. The
      literature of the last years is rich of studies that have deepened these themes.
      Some studies have been analysed and reported but it is not easy to individualise
      a common patrimony of knowledge. Some aspects as information, communication, risk
      perception and psychological consequences are presented and discussed in this
      paper.

PMID- 8644379
TI  - [What does the Forskningsrad (Research Council) promise?].

PMID- 8644378
TI  - Collection of Italian hereditary non-polyposis colorectal cancer (HNPCC)
      pedigrees.

PMID- 8644380
TI  - [Optic neuritis. A common first manifestation of multiple sclerosis].
AB  - Acute monosymptomatic optic neuritis (ON) may be regarded as a specific disease
      entity, or ON may be viewed as a first manifestation of multiple sclerosis (MS)
      representing one end of a continuum with fully developed clinically definite MS
      at the other end. To clarify this, the literature is reviewed, and the
      relationship between ON and MS is exemplified by examination of a cohort of 50
      untreated representative patients with relevant paraclinical tests at onset of
      monosymptomatic ON. MRI, neurophysiological examinations and CSF analyses are
      supplementary methods, which together provide evidence that monosymptomatic ON is
      usually an early manifestation of MS, both being associated with the HLA tissue
      type DR15. The frequent finding of unenhanced lesions on MRI probably signify
      that the disease process may start long before the symptoms of ON. CSF may not be
      representative of the pathological processes in the CNS. Bilateral ON is not
      particularly liable to herald MS. More attention should be paid to subtle visual
      disturbances, which may indicate a new attack. It is important that more
      sensitive evaluations than merely assessing visual acuity be performed in these
      patients.

PMID- 8644381
TI  - [Measurement of intestinal permeability].
AB  - The intestinal epithelium has the dual functions of being an absorptive organ and
      acting as a barrier to the permeation of potentially harmful compounds and
      organisms. The theory behind measurement of intestinal permeability in human
      studies as well as selected studies of intestinal permeability are presented.
      Intestinal permeability studies as diagnostic, prognostic, sequential and
      screening parameters are illuminated- and the importance of changed intestinal
      permeability in the pathogenesis and maintenance of disease is discussed.
      Measuring of intestinal permeability can be used as both a prognostic and
      diagnostic tool, and maybe also as a screening parameter. The method may in the
      future turn out to be an important tool in the management of various diseases.

PMID- 8644383
TI  - [Gouty arthritis in women. The clinical picture in 13 newly diagnosed cases].
AB  - The clinical characteristics and symptoms at the time of diagnosis in 13 women
      with crystal-proven gouty arthritis were reviewed in a retrospective study based
      on hospital records. Twelve patients were at the age of 60 or older (median 74
      years). Tophaceous gout occurred in four, oligo- or polyarticular involvement in
      seven. Six patients had actual symptoms for two months or more, only one of these
      seemed to have had previous acute gouty attacks. The arthritis occurred evenly in
      the upper and lower extremities. Ten (77%) were in diuretic treatment, 12 (92%)
      had diseases associated with hyperuricaemia. Only nine (69%) had serum urate
      concentrations over the upper limit of normal range (0.35 mmol/l).

PMID- 8644382
TI  - [Diagnostic imaging in suspected lumbar disk prolapse. A controlled comparison of
      myelography, CT and magnetic resonance imaging].
AB  - Eighty patients with monoradicular sciatica were examined by myelography,
      computed tomography (CT) and magnetic resonance imaging (MRI) and all had
      subsequent surgery. The images were evaluated by a decision-analytic regret
      function. The largest amount of diagnostic information was gained from CT
      followed by MRI and myelography. Myelography was not significantly informative.
      The results suggest that CT or MRI should be the first choice examination in
      patients with suspected lumbar disc herniation.

PMID- 8644384
TI  - [Prevalence and sex distribution of different forms of migraine].
AB  - The aim of this study was to provide prevalence and sex-ratio of subtypes of
      migraine diagnosed by neurological interview according to the criteria of the
      International Headache Society. In all, 3000 males and 1000 females aged 40 years
      were randomly selected from the Danish population. They received a mailed
      questionnaire regarding migraine. The questionnaire response rate was 87%. People
      with self-reported migraine and a random sample of those reporting no migraine
      were invited to a headache interview, and a physical and a neurological
      examination. Those not reacting to the invitation were interviewed by telephone.
      Participation in the interview was 87%. Kappa was 0.77 validating self-reported
      migraine in the questionnaire against the diagnosis of the clinical interview.
      Lifetime prevalences of migraine without aura, migraine with aura, migraine aura
      without headache, and migrainous disorder were 8%, 4%, 1% and 1% in males and
      16%, 7%, 3% and 2% in females. Overall lifetime prevalence of any type of
      migraine was 18%, 12% in males and 24% in females. This is lower than the sum of
      the prevalences since migraine diagnoses are not mutually exclusive. The
      male:female ratios of migraine without aura, migraine with aura, migraine aura
      without headache, and migrainous disorder were approximately 1:2.

PMID- 8644385
TI  - [Significance of fat distribution for metabolic risk factors in healthy males of
      normal weight].
AB  - A homogeneous group of non-obese men (n = 58), all 44 years old, were
      investigated in order to determine whether body fatness and especially abdominal
      fatness influence the metabolic risk profile in normal-weighted men. In addition,
      it was investigated which anthropometric measurements that were most closely
      associated with the risk profile. It was found that enhancement of total fatness,
      but particularly even a minor accumulation of the adipose tissue in the abdominal
      region in these otherwise non-obese men, was associated with a considerably
      adverse metabolic risk profile. Those risk factors that seemed to be most
      "sensitive" for abdominal fatness were HDL-cholesterol, the atherogenic index,
      triglyceride and fasting plasma insulin. The sagittal diameter (SD) seemed to be
      slightly better correlated to the risk profile than other anthropometric indices
      of abdominal fatness (e.g. WHR).

PMID- 8644386
TI  - [Unusual clinical picture of a rotator cuff lesion].
AB  - A case of a 76 year-old male admitted to hospital because of a fast-growing
      tumour over his right shoulder is described. Malignity was initially suspected,
      but examination showed that the tumour was a cyst overlying, and arising from,
      the acromioclavicular joint. Furthermore we found a complete lesion of the
      rotator cuff. Acromioclavicular joint cysts are a known but unusual presentation
      of complete rotator cuff lesions, and their treatment includes anterior
      acromioplasty, acromioclavicular arthroplasty, and repair of the rotator cuff.
      Isolated surgical cystectomy is without purpose, as the cyst is bound to
      reappear. Surgical treatment is only indicated if there is severe pain, and/or
      unacceptable cosmetic problems.

PMID- 8644387
TI  - [Glove-sock syndrome. A new disease entity].
AB  - Papular-purpuric "gloves and socks" syndrome (PPGSS) is a rare acute dermatosis
      characterized by pruritic erythematous and slightly papular lesions on the hands
      and feet in a "gloves and socks" distribution associated with oral aphtoid
      lesions and fever. It was first described in 1990 by Harms et al. Until now 17
      cases have been reported. In five of these cases an association with Parvovirus
      B19 (PB19) was observed, suggesting that PPGSS could be another manifestation of
      PB19 infection. Since PB19 cannot be shown in all the cases, this virus should be
      considered as one possible etiologic factor and other viruses may be responsible
      for this entity as well. A 42 year old Danish woman with PPGSS is described. This
      case could not be associated to primary PB19 infection.

PMID- 8644388
TI  - [Kimura's disease in a 25-year old man].
AB  - Kimura's disease is a chronic inflammatory condition of unknown etiology. It
      usually presents as a tumour-like swelling with a predilection for periauricular
      and submandibular regions. There are no systemic visceral manifestations except
      an association with nephrotic syndrome. The lesion is always benign, but may
      easily be mistaken for a malignant tumour. The diagnosis is made by biopsy. The
      treatment of choice is surgical removal. A distinction between Kimura's disease
      and angiolymphoid hyperplasia with eosinophilia (ALHE) is made. A case of
      Kimura's disease in a young Caucasian male is presented.

PMID- 8644389
TI  - [Kidney stones, diet and prevention].

PMID- 8644390
TI  - [Treatment of varices].

PMID- 8644392
TI  - [Old environmental problems and new challenges].

PMID- 8644391
TI  - [Treatment of heart failure--one more time].

PMID- 8644393
TI  - [Sex education and contraception information].

PMID- 8644394
TI  - [Exposure of children to lead from contaminated soil].
AB  - To assess lead exposure in infants from contaminated soil a review of
      epidemiological studies was performed. Seventeen studies fulfilled criteria of
      individual exposure measures and a relevant confounder control. In 10 of these a
      clear association between blood lead and lead in soil was demonstrated after
      control of confounders. With some reservations three additional studies indicated
      an effect. No effect on blood lead from soil exposure was found in four studies.
      Quantitative estimates of the contributions to blood lead from soil varied within
      a wide range. In the best designed study-a controlled intervention against
      contaminated soil-blood lead values declined a little more than 1 microgram/100
      ml per 1000 ppm. reduction of soil lead concentration. Oral exposure, probably by
      mouthing behaviour, was indicated by modification of the association between
      blood and soil lead from time spent outdoors, area with uncovered soil, age and
      mouthing behaviour in several studies. The conclusions from the review were that
      children's mouthing behaviour on lead contaminated soil may affect blood lead,
      but the contribution to overall lead exposure seems to be relatively small.
      Considering the limited margin of safety for lead exposure an intervention
      regimen for contaminated areas where infants have direct and continued contact
      with soil is suggested. Intervention in other places is unlikely to significantly
      reduce the lead burden of children. Simultaneously with intervention a programme
      for the evaluation of its effect is proposed.

PMID- 8644395
TI  - [Evaluation of sex education and contraception instruction at the contraception
      clinic in Odense].
AB  - The aim of the study was to evaluate 1 1/2 hours of lessons on contraception
      given to 9. and 10. grade students at the Contraception Clinic in Odense,
      Denmark. The lessons are a supplement to the traditional sexual education given
      at the school. The study included 148 pupils in the period from August 1991 to
      January 1992. The median age was 15 years for both girls and boys. The pupils
      answered two identical questionnaires; one just before the lessons were given and
      the other ten to 13 weeks after the visit to the clinic. The article presents the
      answers given about male and female sexual function, knowledge/own choice of
      contraception, pregnancy, abortion and HIV. The extra lessons improved the
      knowledge among the pupils, but there were still some boys with inadequate
      knowledge. The article gives suggestions for improving the teaching of
      contraception, such as having both male and female teachers. This would also
      emphasize that both sexes have a common responsibility. If the pupils answer a
      simple questionnaire before the lessons, it is possible to goal-direct the
      education to individual requirements. The pupils are introduced to the
      Contraception Clinic, where they easily can seek advice in the future.

PMID- 8644396
TI  - [Methodological problems of depression research].
AB  - Controlled clinical trials on the effect of the new antidepressive drugs are
      encumbered by a number of methodological weaknesses, one of which is lack of
      placebo control in many studies. The main problem in research into depression is,
      however, the overlooked issue of how to validate the diagnosis of depression. The
      agreed diagnostic inclusion criteria in these studies are the diagnostic criteria
      from the DSM-III or the ICD-10. These disease classifications are in accordance
      with what has been called the epidemiological disease model. The conclusions of
      all clinical trials are, however, based on the assumption of a different disease
      model, the bio-medical disease model. There has truly been a documented effect of
      these drugs in controlled clinical trials of groups of patients diagnosed with
      depression, but this conclusion is not stronger than the validity of the
      diagnosis of depression itself. The categorization of antidepressive drugs as
      drugs with antidepressive effect has a similar basis even if these drugs were
      introduced on the basis of a theory of the neurobiology of depression. It is
      therefore perhaps unclear what has really been documented in these studies. The
      time has come for a closer inspection of how to use the controlled clinical trial
      in the field of depression, as well as for a discussion and clarification of what
      we mean when we use the diagnosis of depression.

PMID- 8644397
TI  - [Prognostic value of interleukin-8 in AIDS-related Pneumocystis carinii
      pneumonia].
AB  - We evaluated the significance of interleukin-8 (IL-8) in Pneumocystis carinii
      pneumonia (PCP). Bronchoalveolar lavage (BAL) fluid and serum was prospectively
      collected in 76 consecutive HIV-infected patients with a primary episode of PCP,
      as well as in ten healthy control subjects. Patients were found to have elevated
      levels of IL-8 in BAL fluid compared to control subjects (p < 0.01). Nine
      patients died during the course of PCP. Non-survivors had significantly higher IL
      8 levels in BAL fluid than survivors (p < 0.05). Furthermore patients with levels
      of IL-8 in BAL greater then 90 pg/ml (i.e. greater than control subjects) had
      significantly worse vital prognosis (log rank test, p < 0.05). Thirteen patients
      required mechanical ventilation (MV), and these patients had significantly
      elevated levels of IL-8 compared with patients not requiring MV (p < 0.05). IN
      CONCLUSION: i) IL-8 in BAL fluid correlates to the clinical severity of the
      pneumonia, and ii) is a predictor of mortality and severe respiratory compromise.

PMID- 8644398
TI  - [Can magnetic resonance imaging differentiate between benign and malignant
      conditions in patients with skeletal or soft tissue tumors?].
AB  - The records of 437 patients referred preoperatively for magnetic resonance
      imaging (MRI) due to clinical or radiological suspicion of a bone or soft-tissue
      malignancy were examined retrospectively in order to evaluate how good MRI is at
      distinguishing malignant from benign lesions. The MR-examination tends to
      overestimate malignancy. In all cases, the preoperative MR-examination correctly
      identified all malignant tumours as malignant, but also estimated a number of
      benign lesions as malignant. Sensitivity, specificity and predictive value was
      100%, 71.2% and 76.4% respectively. In case of bursa/ganglion and pseudotumour,
      MR was able to correctly identify these lesions as benign. MR could not
      differentiate between the different types of sarcomas.

PMID- 8644399
TI  - [Intraoperative ultrasonography in colorectal cancer. A prospective, blind
      study].
AB  - This study was designed to compare diagnostic accuracies of measuring liver
      enzymes, preoperative ultrasonography, surgical examination, and intraoperative
      ultrasonography for detection of liver metastases from colorectal cancer. A blind
      prospective comparison between the diagnostic examinations mentioned above were
      performed in 295 consecutive patients with colorectal cancer. An experienced
      ultrasonologist performed the preoperative examinations and the results were not
      known to the other experienced ultrasonologist, who did the intraoperative
      examinations. The latter was also unaware of the findings by the surgeon. The
      presence of metastases was further assessed by ultrasonography three months
      postoperatively, as well as surgery and liver biopsy in some of the patients. The
      sensitivity of intraoperative ultrasonography (62/64) was significantly superior
      to that of surgical exploration (54/64), and that of preoperative ultrasonography
      (45/64). The lowest sensitivity was presented by liver enzymes. "Bilobar"
      metastases were detected in 42 of 46 patients by intraoperative ultrasonography,
      but in no more than 33 by the surgeon. Intraoperative ultrasonography
      demonstrated the highest specificity of all examinations. Intraoperative
      ultrasonography reduces the number of patients with liver metastases being
      subjected to superfluous or even harmful liver surgery and it may increase the
      number in whom liver surgery will prolong life.

PMID- 8644400
TI  - [Compression stockings as prevention of hypotension in Cesarean section during
      spinal anesthesia].
AB  - Inflatable splints and wrapping of the legs have been shown to be effective
      against hypotension during spinal anaesthesia for Caesarean section. The aim of
      this study was to investigate if compression stockings could have a similar
      effect. Thirty healthy mothers scheduled for elective Caesarean section were
      randomised to have either compression stockings or no stockings on before spinal
      anaesthesia. The stockings had a pressure effect of 54 mmHg. The women were
      preloaded with 20 ml isotonic NaCl one hour preoperatively. Hypotension was
      defined as either a decrease in systolic blood pressure to 80% of preoperative
      values or systolic blood pressure under 100 mmHg. Blood pressure was measured
      every second minute, and ephedrine 5 mg was given in the presence of hypotension.
      Two patients were excluded in the control group. There were no differences in
      demographic data, extension of blockade, and spinal injection to delivery time.
      Nine patients in the group with stockings had either no fall in blood pressure or
      a fall in blood pressure corrected with only 5 mg ephedrine. In the control group
      the corresponding number was four patients (p < 0.12). Ephedrine dose between
      zero and 20 minutes and total ephedrine dose was significantly lower in the group
      with stockings than in the control group (p < 0.038). Five patients in the
      control group experienced nausea, no patients in the study group had nausea (p <
      0.013). In conclusion, compression stockings stabilised the blood pressure during
      Caesarean section in spinal anaesthesia and led to a significant smaller need for
      ephedrine.

PMID- 8644401
TI  - [Hypersenitivity reaction in connection with radiographic examination using
      barium sulfate].
AB  - A case is reported where a 25-year-old man had a hypersensitivity reaction on two
      separate occasions 1 1/2 months apart following radiographic examination using a
      barium sulphate suspension as gastro-intestinal contrast medium. Possible factors
      contributing to the reaction are discussed.

PMID- 8644402
TI  - [Epidemiology of schizophrenia].

PMID- 8644403
TI  - [Literature lists and male breast cancer].

PMID- 8644404
TI  - [Risks of epidemics in Denmark].

PMID- 8644405
TI  - [Monitoring of narcotic use and abuse].

PMID- 8644406
TI  - [Drug abuse among new draftees].
AB  - The aim of the study was to investigate the pattern of the use of drugs among
      young conscripts by a test screening of their urine. The participants in the
      investigation also filled in a questionnaire about use of drugs. The urine
      samples from 916 young recruits were examined for cannabinoids and 429 were also
      examined for amphetamines, cocaine, opiates and benzodiazepines. We found 68
      (7.8%) positive tests for cannabis and a negligible number of positive tests for
      other drugs. The questionnaire showed a lower statement of use of drugs though
      3.3% stated a daily or weekly use of cannabis. Fifty-eight percent of the
      soldiers admitted that they had tried cannabis. Six percent had used other drugs.
      The consumption of alcohol is low during weekdays. We concluded that the
      conscripts did not constitute a population of drug abusers. We recommend that
      urine test screening (regular or spot test) should be incorporated in the future
      medical examination in the Danish Army to pinpoint personnel with a moderate use
      of cannabis.

PMID- 8644407
TI  - [Sarcoidosis in children. Clinical manifestations, epidemiology, treatment and
      prognosis].
AB  - Sarcoidosis is a granulomatous disease of unknown aetiology, which may affect
      various organs. The diagnosis is obtained by the demonstration of epytheloid cell
      granulomas in an affected organ. The incidence of sarcoidosis in Danish children
      less than 15 years of age is 0.22-0.27/100.000 children/year, corresponding to
      approximately three new cases in Denmark each year. The disease often takes an
      asymptomatic course. During the period 1980-1992, three cases of paediatric
      sarcoidosis were observed in Copenhagen Country. All three had pulmonary
      involvement, and one had severe hypercalcaemia. In children less than five years
      of age, the disease is characterized by involvement of lungs, lymph nodes and
      eyes. Treatment, which is symptomatic, consists of systemic steroids. Due to the
      risk of growth retardation, the indication for treatment should be carefully
      considered and steroids administered at the lowest effective dose. Due to the
      lack of follow-up studies, the long term prognosis is unclarified.

PMID- 8644408
TI  - [Infection with human immunodeficiency virus type 2--HIV-2].
AB  - The majority of patients with HIV-2 infection come from West Africa or have had
      sexual contact with a person from there, as HIV-2 is prevalent in this area. HIV
      2 is phylogenetically closer related to SIVsm and SIVmac than to HIV-1. HIV-2 is
      mainly transmitted by heterosexual contact, whereas the risk of mother-to-child
      infection is very low. Nine cases of HIV-2 infection have been diagnosed in
      Denmark. Out of these, seven are from West Africa and two have been infected in
      Denmark by individuals from West Africa.

PMID- 8644410
TI  - [Ultrasonically guided gastroscopically assisted percutaneous internal drainage
      of pancreatic pseudocysts].
AB  - Non-surgical procedures are increasingly being used for drainage of pancreatic
      pseudocysts. We describe the results of placement of a double pigtail
      cystogastric stent under ultrasonographic and gastroscopic guidance. The stent
      was placed in 22 of 25 pseudocysts. There was no mortality associated with the
      procedure and the total complication rate was 20%. The cysts resolved in all
      patients and 87% reported reduction of abdominal pain. The median stent-time was
      347 days and there were no cyst recurrences or complications during that time.
      After removal of the stent four out of 19 patients had recurrences. After
      placement of a second stent in these four patients there were no recurrences.
      Treatment with a cystogastric stent is comparable to surgical cystogastrostomy as
      regards to results and has fewer complications.

PMID- 8644409
TI  - [Survival time after the diagnosis of AIDS in the county of Funen].
AB  - Since the diagnosis of AIDS was first made, a lot of efforts have been made to
      improve survival. Different studies have found varied results, both
      geographically as well as over periods of time. During the period 1.1.1985 to
      31.12.1993 142 patients that were HIV-positive were seen in the geographically
      well defined area of Funen. During the period 1.1.1985 to 31.12.1990 the median
      time elapsed between the patient being found to be HIV-positive and the patient
      presenting with an AIDS-defining disease was found to be 8.8 years. In the period
      1.1.1991 to 31.12.1993 it was 2.6 years (95% CL 1,3-?). The AIDS defining
      diseases were Pneumocystis carinii pneumonia in 43% of the cases, and oesophageal
      candidiasis in 24%. The median survival time after being diagnosed with AIDS was
      2.0 years (95% CL 1,7-2,4). Heterosexual infection seems more pronounced in our
      material than for the country as a whole.

PMID- 8644411
TI  - [Percutaneous cysto-gastrostomy of chronic cysts in the pancreas. A nine-year
      clinical experience].
AB  - During the years 1984-1992 74 patients with chronic pancreatic cysts were treated
      with percutaneous cystogastrostomy. Forty-five patients (61%) were males, 29
      females (39%). Pain was the indication for treatment in all patients. The
      catheter was successfully placed at the first attempt in 68 patients (92%).
      Immediate complications occurred in four patients (5.5%); they have not occurred
      since 1986. Abscess formation was seen in eight patients (10.8%). One patient
      died four days after the procedure from a myocardial infarction (mortality rate:
      1.3%); no mortality has occurred since 1986. Pain disappeared or decreased in
      90%, gain of weight was seen in 80%. The mean observation time was 27 months
      (range: 0-108 months). This method is less traumatizing than an operation, and
      mortality and complication rates compare favourably with those seen after
      surgery; the results are at least as good.

PMID- 8644412
TI  - [An outbreak of Streptococcus pyogenes infections in institutions for the
      mentally retarded in Greater Copenhagen 1995].
AB  - The largest reported outbreak of infections due to Streptococcus pyogenes, M-type
      18, in recent years is described. Ninety persons at institutions for mentally
      retarded (73% residents) had infections due to the epidemic strain. Pharyngitis
      and scarlatina were the most common infections. Six patients died, five having a
      streptococcal toxic shock syndrome. During the outbreak an intensive surveillance
      was carried out together with improved infection control measures and prompt
      culturing of residents and employees before antimicrobial treatment. The primary
      outbreak was confined but a secondary outbreak could not be prevented. This was
      probably due to difficulties in implementing proper isolation precautions in this
      setting.

PMID- 8644414
TI  - [Nephrocalcinosis and urolithiasis as primary symptoms in Boeck's sarcoidosis].
AB  - Hypercalcaemia is one of the extra-pulmonary symptoms of sarcoidosis. We describe
      a case of acute and chronic renal failure due to urolithiasis and
      nephrocalcinosis probably caused by sunlight-induced hypercalcaemia in a patient
      with undiagnosed sarcoidosis. Attention must be given to excessive sun exposure
      and vitamin D intake in patients with sarcoidosis.

PMID- 8644415
TI  - [Single cell sorting of human hematopoietic stem cells--why, how and with what
      consequences?].

PMID- 8644413
TI  - [Metaphyseal chondrodysplasia as differential diagnosis to rickets].
AB  - Metaphyseal chondrodysplasias are a heterogeneous group of rare disorders, with
      flaring and irregularity of various metaphyses. The radiographic changes are
      similar to rickets, but calcium and phosphorus metabolism is normal. Other types
      are Schmid, Spahr, McKusick, Schwachman and Jansen, which can be separated by
      clinical, radiographic, genetic and biochemical criteria. We present a patient
      with metaphyseal chondrodysplasia, Schmid type, whose bone disorder was thought
      to be rickets and was treated as such.

PMID- 8644416
TI  - [Audiologic care].

PMID- 8644417
TI  - [Emotional side-effects of sleeping pills?].

PMID- 8644418
TI  - [Remember malaria].

PMID- 8644419
TI  - [Estrogen therapy after uterine cancer?].

PMID- 8644420
TI  - [Anagrelide. A selective inhibitor of thrombopoiesis].

PMID- 8644421
TI  - [Pantoprazole. A new acid pump inhibitor against peptic ulcer and reflux
      esophagitis].

PMID- 8644422
TI  - [Prenatal screening for abnormalities and chromosomal disorders].

PMID- 8644423
TI  - [Improved prenatal diagnostic possibilities for congenital abnormalities and
      chromosomal disorders. Advantages and disadvantages of screening and diagnostic
      methods].
AB  - Significant progress has taken place in recent years regarding prenatal screening
      and diagnosis of severe foetal malformations and chromosomal disorders. This
      review describes blood sample screening in 15-16 week of pregnancy compared with
      the other prenatal examinations such as amniocentesis and chorionic villus
      sampling. Serological screening of all pregnant women based on a blood sample
      taken at 15-16 weeks of pregnancy would lead to identification of about 70% of
      the screened women having to undergo a conclusive investigation i.e. either a
      thorough ultrasound examination or an amniocentesis. This is compared with the
      present Danish prenatal program, where invasive examinations are carried out in
      about 13% pregnant women without a high detection rate for malformations and
      chromosome disorders. The Danish National Health Board has recently published new
      guidelines where the blood test is primarily offered to pregnant women over 34
      years of age and not to all pregnant women as in many other countries.

PMID- 8644424
TI  - [Implementation of research results. Are physicians interested in reference
      programs?].
AB  - In a questionnaire we investigated whether 315 general practitioners (GPs), 79
      heads of departments of medicine and 20 heads of departments of neuromedicine
      were aware of new national guidelines for oral anticoagulation in atrial
      fibrillation issued by the Danish Society of Internal Medicine. The guidelines
      were only known to 22% of the GPs, 6% of the neurological consultants and 64% of
      the medical consultants, but nevertheless only 4-7% of the doctors did not want
      distribution of guidelines. Fifty-four percent of the GPs and 12% of the
      specialists preferred the Danish College of General Practitioners to in some way
      participate in the development of guidelines. Our study suggests that guidelines
      are met with a positive response, but to obtain optimal use a powerful
      implementation effort must be recommended.

PMID- 8644425
TI  - [Mammographic screening in the municipality of Copenhagen. Results of the first
      screening round].
AB  - The aim of the study was to evaluate the results from the prevalence round of the
      mammography screening programme in the Municipality of Copenhagen. All women who
      by 1 April 1991 were 50-69 years old, and who lived in the Municipality of
      Copenhagen, were during the period 1 April 1991-24 April 1993 offered a
      mammography. Those with suspect findings were recalled for further examination
      and possible biopsy. Women with breast cancer were offered treatment according to
      the standard national protocols (DBCCG). The participation rate was 71%
      (30,416/43,087). Among these 2043 (6.7%) were re-examined and 592 (1.9%)
      underwent surgical biopsy. Breast cancer was revealed in 359 (1.2%) women, of
      whom 88% had an invasive breast cancer. Prevalence of breast cancer increased
      significantly with increasing age. The positive predictive value for breast
      cancer among those re-examined was 18% and for those who had a surgical biopsy
      61%. Among women with an invasive breast cancer 41% had a tumour of 10 mm or
      less, 80% had negative lymph node status and 56% had breast conserving surgery.
      During the following 12 months 14 women with a normal mammogram at the screening
      round developed breast cancer giving a sensitivity of 96%. It is concluded that
      the first mammography screening in Denmark showed the highest breast cancer
      prevalence published so far. A possible explanation could be a high sensitivity
      of the screening method, indicated by a relatively high frequency of small
      cancers. The screening programme was fully comparable with international
      standards.

PMID- 8644426
TI  - [Treatment of primary breast cancer. Consequences of mammographic screening in
      the municipality of Copenhagen].
AB  - In order to analyse changes in the pattern of primary treatment of breast cancer
      after introduction of mammography screening in the Copenhagen municipal area
      every second year, retrospective analyses of data from the Danish Breast Cancer
      Cooperative Group were performed. Newly diagnosed patients with breast cancer of
      the age of 50-69 years from the Copenhagen municipal area (1040 patients) were
      compared to a similar group of patients from the rest of Denmark (7353 patients).
      Parameters such as tumour size, lymph node status, grade of anaplasia, frequency
      of breast preserving surgery and adjuvant treatment were analysed. Introduction
      of mammography screening resulted in almost a doubling of newly diagnosed
      patients with invasive breast cancer during the prevalence phase, and a
      significant increase in the number of patients with tumour size < or = 1 cm
      without metastases to the axillary nodes. The frequency of breast preserving
      surgery increased from 5 to 45% in the municipality of Copenhagen compared to 6
      to 19% in the rest of the country. Ratio between low-risk versus high-risk
      patients increased from 1.0 before screening to 2.7 in the following prevalence
      phase and 2.5 in the first year of the subsequent incidence phase, while the
      ratio in the rest of Denmark was the same throughout the whole study period. It
      can be concluded that the introduction of mammography screening resulted in
      significant changes in the treatment pattern of patients with primary breast
      cancer.

PMID- 8644427
TI  - [Adjuvant systemic chemotherapy in colon cancer].
AB  - The prognosis for patients with cancer of the colon is dubious. An intendedly
      curative colon resection is performed in two-thirds of these patients, but half
      of them will subsequently die from metastatic disease. Randomized trials of
      adjuvant therapy with fluorouracil in combination with levamisole or leucovorin
      have shown significant benefit in terms of increased disease-free survival and
      overall survival. In 1990 adjuvant treatment was recommended as routine therapy
      in high risk patients in USA. A number of European countries are routinely
      treating high risk patients with Dukes' C coloncarcinoma. The recommendations are
      based on results from several cooperative trials reviewed in this article.
      Treatment related toxicity accelerates with increasing age but was acceptable in
      the reviewed trials. Adjuvant therapy is widely accepted as an important
      supplement to surgery in high risk patients. A Conference on the results and
      experiences now available should take place in the near future in order to
      establish a national consensus on adjuvant chemotherapy in Denmark. Patients with
      resected Dukes' C coloncarcinoma should receive adjuvant chemotherapy including 5
      fluorouracil and leucovorin. Randomized trials are needed to establish the most
      effective regimens but "no-treatment" controls are no longer ethically
      acceptable.

PMID- 8644428
TI  - [Familial occurrence of Chlamydia pneumoniae infection].
AB  - The clinical courses of six patients involved in a family outbreak of Chlamydia
      pneumoniae respiratory tract infection are described. The diagnosis was
      established by use of culture, polymerase chain reaction and determination of
      species specific antibodies. The patients had mild influenza-like symptoms with
      sore throat, occluded eustachian tubes and long-lasting cough. All patients
      received recommended antibiotic treatment regimens. Two out of the six patients
      needed further antibiotic treatment to obtain clinical and microbiological cure.

PMID- 8644429
TI  - [Kernicterus in a full term infant].
AB  - This article describes a case history of a term infant who developed extreme
      hyperbilirubinaemia and neurological manifestations of kernicterus during the
      first postnatal week. Signs of haemolysis (AB0) were found, and in addition the
      infant suffered from hypernatremic dehydration. The current hypothesis for the
      development of kernicterus is described.

PMID- 8644430
TI  - [Insurance law coverage of patients and healthy persons in clinical trials].

PMID- 8644431
TI  - [Active management of labour--all roads lead to Rome].

PMID- 8644432
TI  - [The genetic basis of Wilson's and Menke's diseases].

PMID- 8644433
TI  - Evaluation of an ELISA for Mycobacterium bovis infection in badgers (Meles
      meles).
AB  - The performance of an indirect ELISA for diagnosing Mycobacterium bovis infection
      in live badgers was evaluated by examining blood samples collected from 1982
      badgers captured during statutory badger removal operations in south west
      England. The Validity of the test and the factors affecting the prevalence of
      infection are described. The sensitivity of the ELISA was 40.7 percent, its
      specificity was 94.3 percent, the predictive value of a positive test was 67.5%
      percent and the predictive value of a negative test was 84.6 percent. Its
      sensitivity was significantly higher in males and animals with gross lesions
      typical of tuberculosis. The sensitivity and positive predictive values were
      enhanced when the results were grouped by control operation. Variables of
      significance for prevalence were the county, the time of year, the age and sex of
      animal, and the time after the start of a control operation. The possible use of
      the ELISA as a screening test is discussed.

PMID- 8644434
TI  - Evaluation of the persistence of porcine reproductive and respiratory syndrome
      virus in pig carcases.
AB  - The presence of porcine reproductive and respiratory syndrome (PRRS) virus in pig
      meat was assessed in samples collected from experimentally infected pigs and from
      the carcases of pigs from infected herds at an abattoir. In the experimental
      study, pigs approximately six months old were inoculated with two isolates of
      PRRS virus and tissue samples were collected seven and 14 days after inoculation.
      At seven days, PRRS virus was recovered from lungs, tonsils, lymph nodes and
      muscle tissues, and viral antigens were detected by immunogold silver staining
      (IGSS) in formalin-fixed lungs, tonsils and scattered cells in muscle tissues.
      Neither PRRS virus nor antigens were detected in muscle tissue samples collected
      14 days after inoculation. In the abattoir pigs, attempts were made to isolate
      PRRS virus from a total of 44 samples of muscle tissue, collected as pools, from
      the carcases of 44 pigs originating from seropositive herds. No PRRS virus could
      be isolated on porcine alveolar macrophages from these 44 muscle tissue samples
      and no PRRS virus antigens could be detected by IGSS in the formalin-fixed tissue
      samples. Although the results of experimental infections indicated that PRRS
      virus may be recovered from muscle tissues early after infection with the virus,
      the presence of PRRS virus in muscle tissues from carcases of slaughter pigs
      previously exposed to the PRRS virus could not be demonstrated.

PMID- 8644435
TI  - Isolation of a parapoxvirus from a grey seal (Halichoerus grypus).
AB  - A grey seal (Halichoerus grypus) developed cutaneous pocks which progressed to
      involve the skin extensively, necessitating euthanasia. Macroscopically and
      histologically the lesions resembled previous descriptions of parapoxvirus
      infections of seals and virus particles were observed in preparations of a scab
      and a skin lesion. Suspensions of the scab and skin lesion were prepared and
      inoculated on to monolayer cultures of grey seal kidney cells. After 25 days in
      culture and three passages, cytopathic effects were observed and parapoxvirus
      particles were detected by electron microscopy in the supernatant fluid. Both
      isolates were adapted to cultures of fetal lamb muscle cells and shown to be
      antigenically related to orf virus.

PMID- 8644436
TI  - Inhibition of pseudocholinesterase activity in a 20-year-old gelding.
AB  - A 20-year-old Arab crossbred gelding was examined because it had apparently
      suffered an overstimulation of the parasympathetic nervous system for three
      hours. The clinical signs consisted of hypersalivation, profuse sweating, maximal
      miosis, fasciculation of the muscles and lateral recumbency in combination with
      continuous convulsions without diarrhoea. The horse's plasma pseudocholinesterase
      activity was approximately 10 per cent of normal. It responded well to 10 mg
      atropine and 50 mg diazepam administered intravenously.

PMID- 8644437
TI  - Abortion due to Neospora species in a dairy herd.

PMID- 8644438
TI  - Urinary protein/creatinine ratio in the evaluation of renal failure in canine
      leishmaniasis.

PMID- 8644439
TI  - Problems with the use of ear tags in sheep.

PMID- 8644440
TI  - Welfare of caged birds.

PMID- 8644442
TI  - Eggstraordinary?

PMID- 8644441
TI  - Docking of puppies' tails.

PMID- 8644443
TI  - Rape straw as a possible cause of neonatal goitre and weakly calves.

PMID- 8644444
TI  - Role of larval nematode infection in lamb diarrhoea.

PMID- 8644445
TI  - Resistance to diminazine aceturate by Trypanosoma congolense from cattle in the
      Zambezi Valley of Zimbabwe.
AB  - The susceptibility of 14 stocks of Trypanosoma congolense, recently isolated from
      cattle, to therapeutic doses of diminazene aceturate and to isometamidium
      chloride was assessed in laboratory mice. Eight isolates were readily susceptible
      to the normal therapeutic dose of diminazene, two were resistant to the drug at
      14 mg kg-1, and four were totally resistant at 28 mg kg-1. All the isolates were
      susceptible to isometamidium chloride at 0.5 mg kg-1. These observations
      highlight the need for regular evaluation of drugs used in the control of
      trypanosomosis.

PMID- 8644446
TI  - Dose titration of moxidectin oral gel against migrating Strongylus vulgaris and
      Parascaris equorum larvae in pony foals.
AB  - Moxidectin was tested for efficacy in ponies against experimental infections of
      56 day Strongylus vulgaris larvae and 11 day Parascaris equorum larvae. Three
      dosages of moxidectin were tested: 300 micrograms per kg live body weight, 400
      micrograms per kg, and 500 micrograms per kg, and the vehicle served as control.
      Ponies were first infected with 600 S. vulgaris third-stage larvae (L3) on
      Experiment Day 0 and then with 3000 embryonated P. equorum eggs on Day 45.
      Moxidectin treatments were administered on Day 56 and necropsy examinations were
      performed on Day 91. Strongylus vulgaris fourth-stage (L4) and fifth-stage (L5)
      larvae were recovered at necropsy from the control ponies, in dissections of the
      cranial mesenteric artery and its branches (L4 and L5), and recovered from
      nodules in the wall of the cecum and ventral colon (L5). Parascaris equorum
      larvae were recovered from the small intestine of control ponies. Moxidectin was
      highly efficacious against S. vulgaris L4 and L5 at all three doses tested (99.6
      100%), and appeared to be equally efficacious against P. equorum larvae (100%);
      however, control ponies had low levels of P. equorum infections compared to
      previous experimental infections performed using identical methods. This suggests
      that the prior S. vulgaris infection on Day 0 may have influenced the subsequent
      experimental P. equorum infection on Day 45 and contributed to the lower
      recovery.

PMID- 8644447
TI  - Monospecific nematode infections of donor calves with Cooperia punctata.
AB  - During a 25 year period, 48 calves from three states were raised helminth-free
      from birth and inoculated with Cooperia punctata. These calves served
      sequentially as donors of the parasite. The following aspects of the monospecific
      infection were of value in successful donor management and contributed to
      understanding the host-parasite relationship. Calves with no previous experience
      with C. punctata were the best hosts for establishing initial infections. Male
      Holstein calves were satisfactory donors of the parasite. Inoculation of calves 6
      24 weeks of age with 10,000-11,200 infective third-stage larvae (L3) over a 2 day
      period produced the desired donors. Occasional over-feeding of calves appeared to
      reduce the patent period. Superimposed infection was more likely when calves were
      still patent from previous infection, whereas reinfection was less likely after
      patency of the earlier infection had ended. Strong immunity eventually developed
      following oral administration of L3.

PMID- 8644448
TI  - A 4-year study on the effectiveness of alternate grazing of cattle and sheep in
      the control of bovine parasitic gastro-enteritis.
AB  - In many farming enterprises, animal management systems which could provide a
      practical and effective alternative to chemotherapy for the control of bovine
      helminthosis would be readily accepted. One system which has been proposed and
      shown to be effective in the short or medium term involves grazing different host
      species on a rotational basis. The study described here examined the effect of
      alternating cattle and sheep annually over an extended period of 4 years. Up to
      the second grazing season the system appeared to be successful, with a marked
      reduction in the cattle worm burdens. However, by the end of the study period the
      parasite burdens in calves grazed on the alternated pasture were equal to, or
      greater than, those of set-stocked control animals. It was thus clear that the
      alternate grazing strategy had failed. Data obtained from other parameters
      measured, i.e. faecal egg counts, pasture larval numbers and plasma pepsinogen
      levels, confirmed this observation.

PMID- 8644449
TI  - A study of the vaccinal value of various extracts of concealed antigens and
      salivary gland extracts against Ornithodoros erraticus and Ornithodoros moubata.
AB  - On pig farms, elimination of the argasid ticks acting as reservoirs and vectors
      for African swine fever greatly favours the eradication of this disease. The
      elimination of Ornithodoros erraticus involves many problems, most of which could
      be easily solved by the development of an anti-O. erraticus vaccine. With a view
      to developing this vaccine, we have tested the protective value of the immune
      response induced in swine by seven 'concealed' antigens and one soluble salivary
      gland extract. The latter extract was also prepared from Ornithodoros moubata
      specimens and tested against this tick. Our results indicate that the immune
      response elicited by the concealed antigens has no protective value against O.
      erraticus. The immune response induced by the salivary gland extracts against
      adults of O. erraticus and O. moubata was apparent in a reduced ingestion of
      blood (40-60%; P < 0.01) (except in males of O. erraticus) and in a significant
      decrease (40-60%; P < 0.01) in fecundity in 100% of the females of both species.
      The good results obtained with salivary antigens, which in situations of natural
      contact have no protective value, are attributed to the fact that when these
      antigens are injected with adjuvants, the immune system recognizes certain
      salivary components (probably those which enable the parasite to feed) which it
      does not recognize under natural conditions of exposure.

PMID- 8644450
TI  - Effect of combing time on cat flea (Ctenocephalides felis) recovery from dogs.
AB  - Combing the haircoat to count fleas has been used to determine the efficacy of
      insecticides against fleas on dogs, but no standardization of method has been
      reported. In this study, the effect of combing time on flea recovery from dogs
      was examined. Six beagle dogs were infested with 100 unfed, adult Ctenocephalides
      felis (Bouche) on each of three consecutive days. A crossover design, balanced
      for carryover effects, was used to evaluate flea removal rates from each dog by
      comb-counting for three different time intervals; i.e. 5, 10 and 15 min. Each dog
      was combed once at each time interval on a different day, over three consecutive
      days. The results showed that the majority of fleas were recovered in the first 5
      min of combing and there were no significant differences (P > or = 0.19) in the
      total number of fleas recovered between the 5, 10 or 15 min protocols. Moreover,
      the standard deviation and coefficient of variation increased with an increase in
      the amount of time spent combing, resulting in a decrease in precision for the
      longer protocols. Therefore, the comb time of 5 min provided a precise and
      accurate representation of the number of fleas present on an animal and could be
      useful as a standard measure of flea infestation levels in efficacy trials.

PMID- 8644451
TI  - Efficacy of six anthelmintics against luminal stages of Baylisascaris procyonis
      in naturally infected raccoons (Procyon lotor).
AB  - The efficacy of six anthelmintics against natural infections of Baylisascaris
      procyonis in raccoons (n = 7 per drug) was determined in a series of critical
      tests. The drugs were given via moist cat food as a single dose or once daily for
      three consecutive days. Raccoons treated with pyrantel embonate (1 x 20 mg base
      kg-1 bodyweight (bwt.)), ivermectin (1 x 1 mg kg-1 bwt.), moxidectin (1 x 1 mg kg
      1 bwt.), albendazole (3 x 50 mg kg-1 bwt.), fenbendazole (3 x 50 mg kg-1 bwt.) or
      flubendazole (3 x 22 mg kg-1 bwt.) expelled 1-198, 2-24, 2-14, 3-80, 2-70, or 2
      35 B. procyonis stages, respectively, within the faeces. No roundworm was
      detected in any raccoon at post mortem examinations 7 days after the end of
      treatment. These results suggest that any of the six anthelmintics can be used at
      the dose rates tested in a deworming programme for captive raccoons.

PMID- 8644452
TI  - Helminth parasites and hypobiosis of nematodes in N'Dama cattle during the dry
      season in The Gambia.
AB  - Three series of necropsies of cattle were performed, corresponding to early dry
      season, approximately 1 month after the last rains (November, n = 6), mid dry
      season (February, n = 6) and end dry season (April, n = 3). Eggs per gram of
      faeces (epg) were determined just before necropsy. Three trematodes (Fasciola
      gigantica, Schistosoma spp. and Paramphistomatids) and 11 nematodes were
      identified from cattle, with the prevalence rate varying from 6.7% to 100%.
      Haemonchus contortus was the most abundant nematode species, constituting from
      81% (February) to 34.8% (April) of the total nematode burden. The proportion of
      L4 (indicating hypobiosis) of H. contortus was 85-99%. During the dry season, 44
      67% of Oesophagostomum radiatum and 8-34% of Cooperia spp. population occurred as
      L4. There was no correlation between the number of worms found at necropsy and
      the epg. H. contortus survives almost exclusively as larvae in the abomasal
      mucosae, whereas Cooperia spp. and O. radiatum survive partly as larvae in the
      lumen, and also in nodules in the case of O. radiatum, and partly as
      hypometabolic adults with highly reduced fecundity. Trichostrongylus axei, T.
      colubriformis, Bunostomum phlebotomum, Strongyloides papillosus, Nematodirus spp.
      and Setaria labiatopapillosa occurred in small numbers.

PMID- 8644453
TI  - Outbreak of trypanosomosis due to Trypanosoma evansi in horses of Pantanal Mato
      grossense, Brazil.
AB  - This paper reports an outbreak of trypanosomosis due to Trypanosoma evansi in
      horses of the Pantanal Mato-grossense region of Brazil. Forty-eight horses died
      (51% mortality) and abortion in one mare was recorded. The clinical signs
      observed were fever, anemia, conjunctivitis, edema of the legs and lower parts of
      the body, progressive weakness, loss of condition, and loss of appetite. The
      diagnosis was confirmed by morphological and biometrical studies.

PMID- 8644454
TI  - Cryptosporidium parvum oocyst antigens recognized by sera from infected
      asymptomatic adult cattle.
AB  - Gel electrophoresis and Western blotting were used to investigate the recognition
      of Cryptosporidium parvum oocyst antigens by sera from asymptomatic C. parvum
      seropositive cattle with or without coccidian oocysts in their faeces (C. parvum
      or/and Eimeria spp.). Most sera from coprologically C. parvum-positive animals
      (71%) recognized fractions in the 17-20 kDa range; these fractions were not
      recognized by sera from coprologically negative animals. In addition, most sera
      with antibodies to C. parvum (whether from coprologically positive or negative
      animals) showed moderate or strong reaction with antigenic fractions in the 47
      49.5 kDa range (43%) and the 56.5-69 kDa range (80%).

PMID- 8644455
TI  - Determination of Toxoplasma gondii in organs of naturally infected cattle in
      costa rica--comment.

PMID- 8644456
TI  - Eimeria magna: pathogenicity, immunogenicity and selection of a precocious line.
AB  - A precocious line (PrEmag) of Eimeria magna in rabbits was obtained by selecting
      for early development of oocysts. The prepatent period was shortened by 46 h. The
      pathogenicity of PrEmag was substantially reduced and its reproductive potential
      was much lower (500 times) than that of the parent strain. Rabbits given 2500
      oocysts of PrEmag were almost totally protected against a challenge with the
      parent strain. As in other precocious lines of coccidia from the rabbit, PrEmag
      showed morphological anomalies of the sporulated oocysts. Each sporocyst
      harboured one large refractile body instead of the two smaller ones in the parent
      strain.

PMID- 8644457
TI  - Prevalence of specific anti-Cryptosporidium IgG, IgM and IgA antibodies in cat
      sera using an indirect immunofluorescence antibody test.
AB  - Sera from 258 healthy and sick domestic and feral cats were screened for specific
      anti-Cryptosporidium antibodies using an indirect immunofluorescence antibody
      test (IFA). Sera were positive for IgG, IgM and IgA antibodies in 192 (74%), 84
      (32%) and 67 (26%) samples, respectively. Antibody was not detected at dilutions
      of 1:10 and 1:20 or greater in any of eight specific pathogen-free kittens. IgM
      and IgA antibody classes were more prevalent in sick than in healthy domestic
      cats. The presence of IgM and/or IgA antibodies indicated early infection.
      However, these antibody classes were present in sera from cats either positive or
      negative for Cryptosporidium infection by faecal examination. Pronounced polar
      fluorescence was observed in the sporozoites in positive samples under
      fluorescence microscopy. The higher prevalence of specific anti-Cryptosporidium
      antibodies and the absence of Cryptosporidium oocysts in faecal samples from some
      IFA-positive animals suggests that detection of these antibodies in sera from
      cats could be helpful for the diagnosis of feline cryptosporidiosis.

PMID- 8644458
TI  - Trypanosoma congolense infection in sheep: ultrastructural changes in the skin
      prior to development of local skin reactions.
AB  - Events occurring in the skin of sheep prior to development of Trypanosoma
      congolense-induced local skin reactions (chancres) were studied using electron
      microscopy. Three days after infection, few trypanosomes were present in the
      dermal collagen. However, these parasites were more abundant 5 days after
      infection, and were also found in dermal lymphatics and in the connective tissue
      matrix between collagen bundles. Mast cells in the skin obtained 5 days after
      infection showed evidence of degranulation. These events may play a role during
      the induction phase of trypanosomal chancres.

PMID- 8644459
TI  - Immunization of pigs against Taenia solium cysticercosis: factors related to
      effective protection.
AB  - Fifty-six (56) pigs were immunized against Taenia solium cysticercosis with
      antigens from Taenia crassiceps metacestodes, in a variety of protocols, and then
      challenged orally with Taenia solium proglottids or eggs. Results of immunization
      (expressed as individual parasite loads) ranged from significant reduction of
      parasite loads (host protection) to clear increase (parasite facilitation) in
      apparent relation to the immunogen dose, adjuvant employed and genetic background
      of the pigs. In all trials, however, immunized pigs harboured more damaged
      cysticerci than controls, indicating that immunization does induce some
      restrictions to parasite these are eventually overwhelmed by other parasite
      promoting factors. Western blots in immunized-protected pigs indicated antigens
      of 242, 234, 118, 77, 55 and 45 kDa as possibly being involved in immunological
      protection.

PMID- 8644460
TI  - A comparison of the responses to repeated experimental infections with Haemonchus
      contortus among Scottish Blackface lambs.
AB  - Twenty helminth-naive Scottish Blackface lambs were given three infections with
      10,000 infective larvae of Haemonchus contortus at 8 week intervals. An
      additional six lambs served as uninfected controls and eight lambs were
      infectivity controls. The lambs were 7 months old at the start of the infection.
      Four of the 20 lambs developed severe haemonchosis and were put down during the
      experiment. The remaining 16 lambs plus uninfected controls were necropsied 8
      weeks after the third infection. The mean faecal egg count peaked 6-8 weeks after
      the first infection, gave a second smaller peak 6-8 weeks after the second
      infection but produced no peak after the third infection. Mean red blood cell
      counts fell rapidly during the first infection, then rose gradually during the
      second and third infections. The mean values suggested that two infections were
      sufficient to produce effective immunity in the sheep population but they masked
      considerable individual variation. Eleven animals appeared relatively resistant
      following the first infection, while two animals were relatively susceptible to
      even the third infection. The repeatability of mean faecal egg counts or mean red
      blood cell counts for each animal during the replicate infections were very high,
      because the rankings of the individual sheep remained remarkably stable. Faecal
      egg counts were very strongly correlated with red blood cell counts. Multiple
      regression analysis showed that four factors--faecal egg counts, red blood cell
      counts, weight and sex--accounted for essentially all of the observed variation
      in worm burdens among the lambs. Therefore, under these controlled experimental
      conditions, additional markers appear unnecessary for the detection of resistance
      status.

PMID- 8644461
TI  - Patterns of Cryptosporidium antigen and oocyst excretion in calves studied by
      reverse passive haemagglutination and light microscopy.
AB  - A reverse passive haemagglutination (RPH) assay incorporating a monoclonal
      antibody against Cryptosporidium parvum oocysts was used to follow
      Cryptosporidium coproantigen excretion by calves. RPH detected soluble antigen
      that passed 0.22 micron filters. Non-specific reactions that occurred in some
      samples were markedly reduced by heat treatment of the faecal specimens and were
      abolished by filtration after heat treatment. Results were compared with oocyst
      counts performed by microscopy of modified Ziehl-Neelsen (MZN) stained faecal
      smears. Five hundred and thirty-two daily specimens were examined from 30 calves.
      The mean age at which positive results for both oocysts and antigen was detected
      was 9 days (range 5-15 days), and excretion lasted for 5-11 days with some
      cycling of positive reactions in some calves. The occasional cycling to a
      negative reaction demonstrates a need to take samples from consecutive days to
      ensure diagnosis. Two hundred and ninety-one (54.7%) specimens were negative in
      both tests, 178 (33.5%) were positive in both, 14 (2.6%) were positive only by
      microscopy, and 49 (9.2%) were positive only by RPH. By these criteria the kappa
      coefficient of agreement between the tests was good (0.753). Compared with MZN,
      the sensitivity of RPH is 92.7%, specificity 85.6%, positive predictive value
      78.4% and negative predictive value 95.4%. The method is simple, objective, has
      ease of quality control, and either single samples or batches can be processed.

PMID- 8644462
TI  - Controlled efficacy study of the bioequivalence of Strongid C and generic
      pyrantel tartrate in horses.
AB  - The bioequivalence of Strongid C and generic pyrantel tartrate was determined in
      a controlled study using 30 horses with naturally acquired endoparasitic
      infections. Three horses were randomly allocated to each of ten replicates based
      on quantitative nematode and ascarid egg counts and fecal larvae culture results.
      Horses within each replicate were randomly assigned to one of three treatment
      groups. Horses in Treatment Group 1 received only oats; horses in Treatment Group
      2 received generic pyrantel tartrate pellets (2.65 mg pyrantel tartrate kg-1)
      mixed with oats; horses in Treatment Group 3 were fed Strongid C pellets (2.65 mg
      pyrantel tartrate kg-1) mixed with oats. Horses were treated daily for a 30 day
      continuous treatment period. At the termination of the study the horses were
      necropsied and endoparasites recovered, identified, and enumerated. In all
      instances, no significant difference (P > 0.05) in mean numbers of parasites
      recovered existed between horses treated with generic pyrantel tartrate and
      Strongid C. Numbers of gastrointestinal parasites recovered from horses treated
      with generic pyrantel tartrate or Strongid C were shown to be significantly
      different (P < 0.05) from numbers of gastrointestinal parasites recovered from
      non-treated controls for the large strongyles (Strongylus vulgaris, S. edentatus,
      and Triodontophorus spp.), small strongyles (Cyathostomum spp., Cylicocyclus
      spp., and Cylicostephanus spp.) and fourth-stage Parascaris equorum. Numbers of
      adult P. equorum recovered from horses treated with Strongid C were also
      significantly different (P < 0.05) from those from non-treated controls. Numbers
      of adult P. equorum recovered from horses treated with generic pyrantel tartrate
      were not significantly different (P = 0.0761) from those from non-treated
      controls. The determination of bioequivalence was based upon the 95% confidence
      interval of the difference between the mean number of parasites recovered from
      horses treated with generic pyrantel tartrate and the mean number of parasites
      recovered from horses treated with Strongid C. For all instances in which the
      numbers of parasites recovered from horses treated with either Strongid C or
      generic pyrantel tartrate were significantly different from the numbers of
      parasites recovered from non-treated controls, bioequivalence was demonstrated.

PMID- 8644463
TI  - [Computerized tomography of pericardial diseases].
AB  - Computed tomography (CT) was used to examine 114 patients with pericardial
      diseases. CT symptomatology of pericardial diseases are given in detail. CT
      defines the thickness and density of the pericardium and its content. To identify
      constrictive pericarditis, it provides additional information on the status of
      the vena cava, atria, ventricles and on pleural changes. The minimum pericardial
      amount of capsulated fluid that can be detected by CT is estimated to be 10 ml.
      Multipositional CT and functional CT (to breathe in and out) are indicated in the
      diagnosis of pericardial cysts.

PMID- 8644464
TI  - [Fixation of the endocardial electrode in cardiac pacing].
AB  - The late outcomes of continuous endocardial pacing surgery were studied in 34
      patients when various approaches were used to fix a proximal endocardial
      electrode. When fixed to a vein or its adjacent tissues, the electrode remained
      to be stable while raising hands. When fixed to the cephalic vein, this procedure
      was accompanied by the displacement of the endocardial electrode and the
      appearance of X-ray signs of electrode instability. The new procedure for fixing
      the proximal electrode contributes to the stability preservation of the
      intracardiac part of an endocardial electrode.

PMID- 8644465
TI  - [Possibilities of various diagnostic methods in the assessment of the state of
      axillary lymph nodes in breast cancer].
AB  - The incidence of axillary lymph nodal metastases in breast cancer is proportional
      to the size of a focus: To is 25 +/- 25%, T1-33 +/- 17%, T2-55 +/- 7%, T3-65 +/-
      11%, the choice of the optimum treatment regimen requires more accurate
      preoperative detection of metastatic lymph nodes. Ultrasound technique (its
      accuracy is 80%, sensitivity-88%) is of the most diagnostic value in the
      detection of metastatic lymph nodes. The absence of echographic signs supports
      the nonspecific nature of changes. Palpation is preferable in nonspecific
      axillary lymph nodal lesions. The status of axillary lymph nodes in breast cancer
      may be correctly assessed by comprehensive clinical and ultrasonic studies of the
      axillary area wherein, supplementing each other, each technique yield the maximum
      information.

PMID- 8644466
TI  - [Significance of computerized, magnetic resonance and ultrasound tomography in
      the diagnosis of spreading of pulmonary cancer to the mediastinum].
AB  - In 232 patients predominantly with the central type of lung cancer underwent
      echotomography (ET) (n = 16), CT (n = 142) and MRT (n = 55) in order to evaluate
      their possibilities in the diagnosis of the spread of a tumor process to the
      mediastinum and their impact on disease staging. The results of the techniques
      and the data of surgical interventions were compared: CT in 55 patients, CT in 70
      and MRT in 22. The sensitivity of each method was determined by 3 parameters: 1)
      detection of intrathoracic lymphadenopathy; 2) diseased mediastinal large
      vessels; and 3) cancer spread to the pleura, pericardium, heart, and chest.
      Routine tomography is of informative value in the diagnosis of metastases into a
      peritracheo-bronchial group of lymph nodes (its sensitivity, 66%), ET, for
      paravasal (91%), CT and MRT for any groups of mediastinal lymph nodes (89-100%).
      MRT and ET (with sensitivities of 80 and 100%, respectively) were the methods of
      choice in the assessment of vascular lesions. MRT and CT are the most potent in
      evaluating the pleura, pericardium, and chest. The application of new techniques
      allows the clinical disease stage to be changed in 520 patients. Only X-ray and
      bronchological studies of patients with suspected lung cancer are not sufficient.
      ET either CT or MPR should be supplemented.

PMID- 8644467
TI  - [Computed tomography diagnosis of extranodal manifestations in malignant non
      Hodgkin's lymphoma].
AB  - The data of computed tomography (CT) were used to study the semiotics of
      extranodal manifestations in 78 patients with varying malignancy non-Hodgkin's
      lymphomas. The most common lesions were found in the viscera: liver, spleen,
      peritoneum, omentum, pancreas, adrenals, mesentery. The CT pattern of these
      lesions is diverse, each site has its own specific features. Combining the
      clinical manifestations and CT signs of lesions to individual organs, recording
      the extent of lymphadenopathy will aid in establishing the diagnosis of non
      Hodgkin's lymphoma. A lesion detected in some organs located both above and below
      the diaphragm is a typical feature of high-grade malignancy.

PMID- 8644469
TI  - [Computed tomography in the diagnosis of major stomatological diseases].
AB  - The paper summarizes the results of an examination of 32 patients aged 19 to 70
      years who present with various dental diseases and maxillofacial soft injuries
      (chronic odontogenic maxillary osteomyelitis, osteoradionecrosis of the jaw,
      sinusitis, malignant and benign neoplasms of the jaw and perimaxillary soft
      tissues, facial injuries, etc.), by using computerized tomography (CT). It also
      describes a CT procedure, shows its potentialities in the diagnosis of major
      dental diseases and injuries to maxillofacial organs and tissues.

PMID- 8644468
TI  - [X-ray intravascular surgery in oncologic urology].
AB  - The outcomes of treatment with intravascular embolization/chemoembolization and
      regional chemotherapy were analyzed in 862 patients with tumors of the kidney (n
      = 568), urinary bladder (n = 232) and prostate (n = 62). In renal cancer, the
      five-year survival rates after mechanical embolization followed by nephrectomy
      were 51%, those after chemoembolization and surgery, 77%. In inoperable cases,
      they were 3 and 25%, respectively (p < 0.05). The findings with new procedures of
      iron drug embolization, followed by local hyperthermia, are much more promising.
      In 90% after regional arterial chemotherapy, symptoms (pain, dysuria, hemorrhage)
      of bladder cancer ceased. With embolization, successful hemostasis was performed
      in 80% of massive bleedings from the bladder tumor and significant reductions of
      blood loss were achieved after transurethral resection of prostatic
      carcinoma/adenoma. X-ray endovascular surgical techniques play an important role
      in the treatment of oncologic urological diseases.

PMID- 8644470
TI  - [Visipaque: a step on the way to an ideal contrast medium].
AB  - To study tolerance of two nonionic X-ray contrasting agents Omnipaque and the iso
      osmolar dimer Visipaque, changes in central hemodynamic, myocardial
      electrophysiological, renal nitrogen-excretory parameters were studied in 50
      patients undergoing coronary angiography and ventriculography. The two
      contrasting agents were found to provide slight negative side effects; however,
      Visipaque showed better subjective tolerance and less frequently caused adverse
      reactions and complications. The beneficial properties of Visipaque allows the
      authors to recommend that it should be used in angiographic studies in high-risk
      patients.

PMID- 8644471
TI  - [Computed tomography in x-ray-negative calculi of the ureter].

PMID- 8644472
TI  - [Fatal outcome after hepatic artery embolization in spontaneous arterioportal
      fistula in a patient with liver cirrhosis].

PMID- 8644473
TI  - [Regularity of replacement of x-ray intensifying screens].

PMID- 8644474
TI  - [Classical roentgenology and computerized tomography in the diagnosis of
      pituitary adenomas].
AB  - The potentialities of diagnosis of pituitary adenomas using radiation techniques
      are analyzed on the basis of a material comprising 456 cases with this
      abnormality. The potentialities of CT and classical X-ray diagnoses are compared
      and recommendations are given for specific cases when, despite CT, routine
      craniograms must be made. The involvement and contribution of CT in the diagnosis
      of pituitary adenomas are considered. The results from the application of a fixed
      and mobile CT mounts are presented. At the same time the possibilities of
      achieving a greater efficiency by employing its mobile mount by the author's
      protocol are emphasized.

PMID- 8644475
TI  - [Nomenclature and training system of specialists in roentgenography and
      radiotherapy in the USA].

PMID- 8644476
TI  - [Role of the Moscow Research Institute of Diagnosis and Surgery in the
      development of materials and equipment for Russian roentgenology and radiology].

PMID- 8644477
TI  - Stimulatory effect of low-power density He-Ne laser radiation on human
      fibroblasts in vitro.
AB  - Cultures of human embryonic fibroblasts in vitro were subjected to helium-neon
      laser single and double irradiation to investigate the influence of low-energy
      laser irradiation on fibroblast proliferation. Mean increase in the cell number
      values of irradiated cells were compared with increase values of non-irradiated
      control samples of fibroblasts. He-Ne laser was used as a coherent source of
      monochromatic radiation at 632.8 nm, and Petri-dishes with cultured fibroblasts
      were irradiated in way to receive radiation of energy doses of 0.5; 1; 1.5 and
      2J/cm2. Single He-Ne laser irradiation exhibited a significant stimulation effect
      on human fibroblast proliferation in cell-culture.

PMID- 8644478
TI  - [Diagnostic and prognostic significance of long latency reflexes, somatosensory
      evoked potentials and the blink reflex in cerebral ischemia].
AB  - In order to determine diagnostic and prognostic value of long latency reflexes,
      blink reflex and somatosensory evoked potentials in patients with ischemic brain
      disease (IBD), examinations were done in 32 patients of both sexes with IBD,
      average age 44-76 years. First examinations were performed within first week of
      the onset of IBD and in majority of patients repeated after 3 and 6 months.
      Changes of electrophysiological characteristics compared with the degree of IBD,
      clinical presentation, localization, extent of infarction zone (measured by CT)
      and functional recovery where analyzed. Electrophysiological changes were
      predominantly associated with amplitude of physiological response and were in
      correlation with the degree of IBD, localization and the extent of infarction
      zone. Latencies were prolonged only in case of subcortical ischemic lesions.
      Correlation between functional recovery and electrophysiological changes was
      present only within the structures responsible for certain components of
      electrophysiological responses and localization of ischemic lesion. In
      conclusion, electrophysiological examinations are of high diagnostic and
      predictive value in IBD.

PMID- 8644479
TI  - [Detection of the presence of the hepatitis C viral genome in immunoglobulin
      preparations using RT-PCR].
AB  - Contemporary methods of molecular genetics were used to investigate the presence
      of hereditary matter, i.e., virus hepatitis C genome in immunoglobulin
      preparations of the Institute for blood transfusion of the Republic of Serbia.
      ELISA test in immunoglobulin preparations indicated the presence of antibodies to
      an antigen of hepatitis C virus. After RNA isolation and reverse transcription
      (RT), double reaction of in vitro DNA amplification (PCR) was done using two
      pairs of oligonucleotide. After several repeated tests and positive control from
      blood of the diseased it was concluded that neither of 11 investigated
      immunoglobulin preparations contained the nucleic acid (RNA) of the HCV origin,
      that meant that all preparations could be used with no danger of virus hepatitis
      C infection. Regarding the current experience in relation to the use of PCR for
      testing of contamination by hepatitis C virus in preparations from human blood,
      that are used in the therapy of various conditions and diseases, it is
      recommendable to use this method due to its sensitivity and specificity.

PMID- 8644480
TI  - [The duration of surgical procedures as a factor in the development of
      postoperative osteomyelitis].
AB  - In the period from January 1st, 1969, to December 31st, 1988, 585 osteosyntheses
      of the closed bone fractures of lower limbs were performed at the Orthopedic
      department at the Military Hospital in Nis. At the same period 25 postoperative
      osteomyelitis were registered, i.e., 4.27%. The average duration of
      osteosynthesis in the tested group of patients was 84.6 minutes, and 54 minutes
      in control group. The difference of the average duration of osteosynthesis
      between groups was significant. The type and size of metal implants did not
      directly affect the evolution of postoperative bone infection unless the correct
      implantation was done and unless they were made of standardized leaguers.

PMID- 8644481
TI  - [Treatment of duodenal ulcer with famotidine and proglumide].
AB  - In an open study the clinical efficacy of famotidine 40 mg on a duodenal ulcer
      was compared to that of proglumide 1600 mg. The study included 106 patients with
      acute duodenal ulcer, divided into two groups: A-famotidine and B-proglumide.
      There were no significant differences between the groups in baseline
      characteristics. Due to different reasons nine patients were excluded from
      analysis. Duodenal ulcer diagnosis and healing were determined exclusively by
      endoscopy. Ulcer healing was observed after four weeks in 40/49 (81.6%) patients
      in group A and 35/48 (72.9%) patients in group B and in 46/49 (94%) and 40/48
      (83.3) after eight weeks, respectively. There were no statistically significant
      differences between the healing rates for both groups (p > 0.05). The reduction
      of ulcer related symptoms and antacid consumption was equal in both groups. No
      adverse effects were reported in the group A, but there were three patients with
      transient skin rush in the group B. Reported adverse effects were minor and did
      not merit exclusion from the study. It was concluded that the efficacy of
      famotidine 40 mg vs. proglumide 1600 mg was similar, although famotidine had
      proportionally better effect than proglumide. These findings supported the
      hypothesis that famotidine suppressed acid secretion stronger than proglumide.

PMID- 8644482
TI  - [Long-term home oxygen therapy].
AB  - The analysis of medical reports was done for 30 patients in five years period
      (1988-1992) who received long-term oxygen therapy in home environment. The
      average values of respiratory functions were: forced vital capacity-43.3%, forced
      expired volume in the first second-27,4%; partial oxygen pressure in the arterial
      blood at rest-51 mmHg (6.8% kPa); partial carbon dioxide pressure in arterial
      blood at rest-46.2 mmHg (6.43% kPa) and oxygen saturation of hemoglobin-84.6%.
      After introduction of the constant oxygen therapy with flow of 1 to 2 l/min the
      values of arterial blood gasses at rest were: PaO2: 74.5 mmHg (9.94 kPa), PaCO2:
      44.65 mmHg (6.22 kPa), the average value of SAT 93.4%. The average duration of
      oxygen therapy was 18 months; 11 patients died, with the average survival time
      under the oxygen therapy of 12.6 months. As the source of oxygen 18 patients used
      electric concentrator, and 12 of them the compressed gas in steel bottles.

PMID- 8644483
TI  - [Social support and family relations in Graves-Basedow disease].
AB  - An anamnestic study encompassed 100 new patients with Graves-Basedow's disease
      and 100 controls matched according to sex, and age (+/-2 years) and place of
      living (rural/urban). The patients were treated in an out-patient clinic of the
      Clinical Center of the Medical Faculty, Clinical hospital center "Zvezdara" in
      Belgrade and in Special institution "Zlatibor" on Zlatibor in the period from May
      1st, 1993 to November 1st, 1993. The aim of this study was to estimate the
      influence of family relationship and social support on the development of Graves
      Basedow's disease. The diseased more often lived in an environment of family
      disharmony (McNemar's test = 3.76; relative risk (RR) = 3.25; 95% confidence
      limits CL = 1.01-10.68; probability (p) = 0.049) while the controls more often
      described themselves as nostalgic persons (McNemar's test = 4.96; RR = 0.38; CL
      (95%) = 0.16-0.89; p = 0.026). The possibility to discuss their personal problems
      with their relatives and friends (t = 2.29; DF = 99; p = 0.024), the relatives'
      and friends' interest for their problems and their readiness to help (t = 2.29;
      DF = 99; p = 0.004) and possibility of the patients to ask for help in case of
      financial problems (t = 2.78; DF = 99; p = 0.007) were more often present in
      persons from the control group.

PMID- 8644484
TI  - [New findings on reactive oxidative materials and their role in biological
      systems].

PMID- 8644485
TI  - [Epidemiology of prostate cancer].

PMID- 8644487
TI  - [Massive neurocysticercosis].

PMID- 8644486
TI  - [Pseudoporphyria in patients with kidney disease on hemodialysis].

PMID- 8644488
TI  - [Ocular pseudomyasthenia].

PMID- 8644489
TI  - Regulation of asymmetry and polarity during the Caulobacter cell cycle.

PMID- 8644490
TI  - Structure and function of the ion channel model system annexin V.

PMID- 8644491
TI  - The unique C-terminal domain of RNA polymerase II and its role in transcription.

PMID- 8644492
TI  - Cytochrome c oxidase: chemistry of a molecular machine.
AB  - The plethora of proposed chemical models attempting to explain the proton pumping
      reactions catalyzed by the CcO complex, especially the number of recent models,
      makes it clear that the problem is far from solved. Although we have not
      discussed all of the models proposed to date, we have described some of the more
      detailed models in order to illustrate the theoretical concepts introduced at the
      beginning of this section on proton pumping as well as to illustrate the rich
      possibilities available for effecting proton pumping. It is clear that proton
      pumping is effected by conformational changes induced by oxidation/reduction of
      the various redox centers in the CcO complex. It is for this reason that the CcO
      complex is called a redox-linked proton pump. The conformational changes of the
      proton pump cycle are usually envisioned to be some sort of ligand-exchange
      reaction arising from unstable geometries upon oxidation/reduction of the various
      redox centers. However, simple geometrical rearrangements, as in the Babcock and
      Mitchell models are also possible. In any model, however, hydrogen bonds must be
      broken and reformed due to conformational changes that result from
      oxidation/reduction of the linkage site during enzyme turnover. Perhaps the most
      important point emphasized in this discussion, however, is the fact that proton
      pumping is a directed process and it is electron and proton gating mechanisms
      that drive the proton pump cycle in the forward direction. Since many of the
      models discussed above lack effective electron and/or proton gating, it is clear
      that the major difficulty in developing a viable chemical model is not
      formulating a cyclic set of protein conformational changes effecting proton
      pumping (redox linkage) but rather constructing the model with a set of physical
      constraints so that the proposed cycle proceeds efficiently as postulated. In our
      discussion of these models, we have not been too concerned about which electron
      of the catalytic cycle was entering the site of linkage, but merely whether an ET
      to the binuclear center played a role. However, redox linkage only occurs if ET
      to the activated binuclear center is coupled to the proton pump. Since all of the
      models of proton pumping presented here, with the exception of the Rousseau
      expanded model and the Wikstrom model, have a maximum stoichiometry of 1 H+/e-,
      they inadequately explain the 2 H+/e- ratio for the third and fourth electrons of
      the dioxygen reduction cycle (see Section V.B). One way of interpreting this
      shortfall of protons is that the remaining protons are pumped by an as yet
      undefined indirectly coupled mechanism. In this scenario, the site of linkage
      could be coupled to the pumping of one proton in a direct fashion and one proton
      in an indirect fashion for a given electron. For a long time, it was assumed that
      at least some elements of such an indirect mechanism reside in subunit III. While
      recent evidence argues against the involvement of subunit III in the proton pump,
      subunit III may still participate in a regulatory and/or structural capacity
      (Section II.E). Attention has now focused on subunits I and II in the search for
      residues intimately involved in the proton pump mechanism and/or as part of a
      proton channel. In particular, the role of some of the highly conserved residues
      of helix VIII of subunit I are currently being studied by site directed
      mutagenesis. In our opinion, any model that invokes heme alpha 3 or CuB as the
      site of linkage must propose a very effective means by which the presumedly fast
      uncoupling ET to the dioxygen intermediates is prevented. It is difficult to
      imagine that ET over the short distance from heme alpha 3 or CuB to the dioxygen
      intermediate requires more than 1 ns. In addition, we expect the conformational
      changes of the proton pump to require much more than 1 ns (see Section V.B).

PMID- 8644493
TI  - Silicone gels as adjuvants. Effects on humoral and cell-mediated immune
      responses.

PMID- 8644494
TI  - The blood-brain barrier in virus-induced demyelination.

PMID- 8644495
TI  - Idiotype manipulation in disease management.

PMID- 8644496
TI  - Intravenous immunoglobins (IVIGs) to prevent and treat infectious diseases.
AB  - The availability of IVIGs for the prevention and treatment of bacterial diseases
      has presented may challenges. While a role for prophylaxis against infection has
      been suggested for some conditions characterized by hypogammaglobulinemia (or
      physiologic hypogammaglobulinemia), it has been difficult to demonstrate a
      convincing effect when IVIG is used as treatment for infectious diseases. The
      development of IVIGs enriched in antibody against specific pathogens may yet show
      therapeutic efficacy, but cost effective strategies for generating such reagents
      must be defined.

PMID- 8644497
TI  - Glucans as immunological adjuvants.

PMID- 8644498
TI  - Qualitative and quantitative immune response to bacterial capsular
      polysaccharides and their conjugates in mouse and man.

PMID- 8644499
TI  - Autoimmune recognition of acetylcholine receptor and manipulation of the
      autoimmune responses by synthetic peptides.

PMID- 8644500
TI  - Amelioration of autoimmune reactions by antigen-induced apoptosis of T cells.
AB  - We have shown that T cells vigorously cycling in response to growth lymphokines
      are driven into apoptosis by potent TCR restimulation. This process, termed
      propriocidal regulation, appears to be a normal feedback inhibitory mechanism to
      prevent excessive T cell proliferation and lymphokine production. Exposure of T
      cells to repeated high dose antigen treatments creates the conditions just
      described by activating T cells, and stimulating the production of growth
      lymphokines and their receptors. High growth lymphokine levels induced by the
      large amount of antigen present, stimulate vigorous cycling. The continued
      presence of high antigen levels subjects the cycling T cells to strong TCR
      restimulation as they enter the vulnerable S phase, inducing apoptosis in T cells
      responsive to the administered antigen. Thus, simple, repetitive, intravenous
      administration of high dose antigen may be used to delete potentially destructive
      clones of T cells, resulting in a state of peripheral tolerance. This has obvious
      therapeutic potential in disorders where the elimination of pathogenic T cell
      clones could be beneficial. We have described in EAE, an animal model for MS,
      that high dose MBP therapy is effective in preventing CNS pathology and the onset
      of disease as well as reducing the severity of the clinical symptoms of
      established EAE. We are currently involved in expanding this approach to other
      animal models of autoimmunity and graft rejection, as well as refining the
      immunotherapy in the EAE model with the objective of developing a clinical
      therapy for human demyelinating disease.

PMID- 8644501
TI  - Band 3 and its peptides during aging, radiation exposure, and Alzheimer's
      disease: alterations and self-recognition.
AB  - An aging antigen, senescent cell antigen, resides on the 911 amino acid membrane
      protein band 3. It marks cells for removal by initiating specific IgG
      autoantibody binding. Band 3 is a ubiquitous membrane transport protein found in
      the plasma membrane of diverse cell types and tissues, and in nuclear,
      mitochondrial, and golgi membranes. Band 3 in tissues such as brain performs the
      same functions as it does in red blood cells forming senescent cell antigen.
      Oxidation is a mechanism for generating senescent cell antigen. The aging
      antigenic sites reside on human band 3 map residues 538-554, and 812-830.
      Carbohydrate moieties are not required for the antigenicity or recognition of
      senescent cell antigen. Anion transport site were mapped to residues 588-594, 822
      839, and 869-883. The aging vulnerable site which triggers the antigenic site and
      the transport sites of band 3 were mapped using overlapping synthetic peptides
      along the molecule. Naturally occurring autoantibodies to regions of band 3
      comprising both senescent cell antigen and B cells producing these antibodies
      were demonstrated in the sera of normal, healthy individuals. The presence of
      these antibodies tend to increase with age. Individuals with autoimmune diseases
      (rheumatoid arthritis and systemic lupus erythematosus) have increased antibodies
      to senescent cell antigen peptides. Radiation exposure results in an increase in
      antibodies to peptides 588-602 which lies in a transport region containing the
      aging vulnerable site. Band 3 ages as cells and tissues age. Our studies, to
      date, indicate, that the anion transport ability of band 3 decreases in brains
      and lymphocytes from old mice. This decreased transport ability precedes obvious
      structural changes such as band 3 degradation and generation of SCA, and is the
      earliest change thus far detected in band 3 function. Other changes include a
      decreased efficiency of anion transport (decreased Vmax) in spite of an increase
      in number of anion binding sites (increased Km), decreased glucose transport,
      increased phosphorylation, increased degradation to smaller fragments as detected
      by quantitative binding of antibodies to band 3 breakdown products and residue
      812-830, and binding of physiologic IgG autoantibodies in situ. The latter 3
      findings indicate that post-translational changes occur. In Alzheimer's Disease
      (AD), our results indicate that post-translational changes occur in band 3. These
      include decreased band 3 phosphorylation of a 25-28kD segment, increased
      degradation of band 3, alterations in band 3 recognized by antibodies, and
      decreased anion and glucose transport by blood cells. Serum autoantibodies were
      increased in AD patients compared to controls to band 3 peptide 822-839. This
      band 3 residue lies in an anion transport/binding region.

PMID- 8644502
TI  - Establishment of a mouse model of myasthenia gravis which mimics human myasthenia
      gravis pathogenesis for immune intervention.

PMID- 8644503
TI  - Analysis of MHC-specific peptide motifs. Applications in immunotherapy.
AB  - The structural features which underlie peptide binding to MHC molecules permit
      the binding of a diverse array of peptides. Polymorphic residues of class I, and
      to a lesser extent, class II molecules, determine the peptide selectivities
      associated with various allomorphs. The motifs which are described here and
      elsewhere in the literature mainly reflect peptide features which contribute to
      high affinity binding. While high affinity MHC binding is not an absolute
      prerequisite for the immunologic relevance of a peptide, motifs provide general
      guidelines for eliciting and characterizing cellular responses to epitopes
      presented by a given MHC allomorph or group of related allomorphs. The utility of
      motifs is underscored by emerging developments in the clinical application of
      peptides to elicit specific and effective cellular responses.

PMID- 8644504
TI  - Autoantibodies against peptide-defined epitopes of T-cell receptors in
      retrovirally infected humans and mice.
AB  - Autoantibodies directed against peptide-defined epitopes of T-cell receptors
      occur in the serum of healthy humans with the levels and isotypic expression
      dependent upon physiological changes (aging, pregnancy) or upon the development
      of autoimmune disease. We carried out investigations of autoantibodies against
      Tcr peptide-defined epitopes in retroviral infections of humans (HIV-1) and mice
      (LP-BM5 strain of murine leukemia virus) to determine whether infection with
      these agents disrupted the regulation of the production of these antibodies.
      Retroviral infection in humans resulted in increased levels of autoantibody
      production against putative immunoregulatory regions of the Tcr beta chain (V
      beta CDR1 and Fr3), a result reflecting a disruption of regulation. In addition,
      antigenic mimicry was observed with a cross-reaction shared between the common
      portion of the V3 neutralizing loop of the HIV-1 gp120 molecule and the joining
      segment of T-cell receptors (J beta). Infection of mice with the defective
      retrovirus resulted in the induction of antibodies directed particularly against
      V beta CDR1 peptide-defined determinants. Analysis of the virally induced
      response to a set of 8 CDR1 peptide epitopes indicated a selectivity to the
      process. It was possible to partially reverse aberrant cytokine changes
      correlated with the onset of murine MAIDS by administration of T-cell receptor
      peptides in saline. These results show that retroviral infection in humans and
      mice has a profound dysfunctional effect on the regulation of autoantibodies to T
      cell receptors. The function of these autoantibodies in the immunopathogenesis of
      acquired immunodeficiency remains to be determined.

PMID- 8644505
TI  - Characterization of autoantibodies directed against T cell receptors.
AB  - Recently it has been observed that administration of intravenous immunoglobulin
      (IVIG) can have profound effects on a wide variety of diseases related to the
      dysregulation of the immune system. The mechanisms which explain these activities
      are poorly understood. Human IVIG and various Cohn plasma fractions contain
      autoantibodies directed against T cell receptors (Tcr). Previous studies have
      shown that IVIG contains autoantibodies against T cell receptor peptides. In
      order to further our understanding of autoantibody specificities, a single chain
      Tcr (scTcr) was constructed by recombinant DNA techniques from the variable alpha
      and variable beta chains of the Jurkat cell line. Anti-Tcr autoantibodies were
      isolated from IVIG and Cohn fractions I + III using a scTcr affinity column. This
      scTcr affinity purified material reacted with the surfaces of T cells at 10
      micrograms/ml whereas non-purified IVIG did not. Sera from patients with
      rheumatoid arthritis (RA) as well as serum from patients with systemic lupus
      erythematosus (SLE) reacted with the scTcr at levels above that of normals.

PMID- 8644506
TI  - Copolymer adjuvants.

PMID- 8644508
TI  - Influence of the anterior chamber of the eye on T-cell production of
      extracellular antigen-specific proteins.

PMID- 8644507
TI  - Autoregulation of Tcr V region epitopes in autoimmune disease.
AB  - Normal individuals possess low levels of autoantibodies specific for certain
      peptide defined regions of T-cell receptor (Tcr) variable regions, particularly
      CDR1 and Fr3. These regions are predicted to be exposed on the surface of the
      native molecule and, by analogy and comparison with immunoglobulins, correspond
      to public idiotype determinants. The anti-Tcr idiotype antibodies appear to be
      ubiquitous and we propose that they play a role in the regulation of T-cell
      function. To delineate the parameters of expression of these antibodies, we
      characterized anti-Tcr antibody activity in normal individuals, in those
      suffering from the autoimmune diseases rheumatoid arthritis (RA) and systemic
      lupus erythematosus (SLE), and in patients with non-autoimmune arthritis
      (osteoarthritis) as a disease control. There were significant increases in
      autoantibody levels in the autoimmune patients. There was also variation in
      isotype and the particular variable regions recognized. IgM autoantibodies
      directed against a few peptide defined determinants were elevated in RA, whereas
      SLE patient sera showed high levels of IgG binding to a broad spectrum of Tcr
      peptides.

PMID- 8644509
TI  - The development and use of T cell receptor peptide vaccines.

PMID- 8644510
TI  - Evidence that immunosuppression is an intrinsic property of the alpha-fetoprotein
      molecule.
AB  - Among the proteins that comprise the albumin family, alpha-fetoprotein (AFP) is
      the only member which exhibits immunoregulatory properties. However, some
      investigations have argued that AFP-mediated immunosuppression is not an inherent
      property of the molecule itself, but is instead, hypothesized to be either a
      function of a low molecular weight inhibitor bound to AFP or to a post
      translational modification of the protein. AFP cannot be isolated from natural
      sources in quantities sufficient for the detailed biochemical and functional
      analyses required to resolve these issues. We have therefore produced recombinant
      forms of the protein (rAFP) by cloning the cDNA's for mouse and human AFP in both
      eukaryotic and prokaryotic expression systems. As described in this report, we
      were able to abundantly express rAFP's in bacterial, baculovirus and yeast
      expression systems. Recombinant proteins derived from each expression system were
      recognized by polyclonal and monoclonal anti-AFP antibodies as determined by
      immunoblot analysis. Pure recombinant protein samples, as characterized by
      polyacrylamide gel analyses, N-terminal sequencing and FPLC and HPLC
      chromatography, were evaluated for their immunoregulatory properties in murine
      and human in vitro immunological assays. The results of these studies establish
      that rAFP is functionally equivalent to natural fetal derived AFP molecules.
      Importantly, the data reported here demonstrate that AFP-mediated
      immunoregulation is an activity intrinsic to the molecule itself and cannot be
      attributed to either putative non-covalently bound moieties or to post
      translational modifications such as glycosylation and sialylation. These studies
      provide a basis for initiating detailed investigations into the potential
      clinical usefulness of AFP as an immunotherapeutic agent.

PMID- 8644511
TI  - Regulation of IL-4 and IL-5 secretion by histamine and PGE2.
AB  - This study was designed to study the effects of autacoids on IL-4 and IL-5
      secretion. IL-4 and IL-5 are secreted by TH2 cells. TH2 cells were generated by
      the culture of peripheral blood lymphocytes from atopic individuals in the
      presence of ragweed or dustmite antigen. The cloned TH2 lymphocytes were then
      stimulated with PMA (10 ng/ml) and alpha-CD3 (50 ng/ml) in the presence and
      absence of histamine (10(-4) - 10(-8)M) and PGE2 (10(-6) - 10(-8)M) for 48 hours.
      Other cAMP elevating agents were used as control. The supernatants were then
      assayed for the presence of IL-4 and IL-5 by ELISA. Both histamine and PGE2
      suppressed the secretion of IL-4 in a dose dependent manner. Other cAMP elevating
      agents did not affect IL-4 secretion. In contrast, histamine upregulated the
      secretion of IL-5, whereas the effects of PGE2 on IL-5 secretion were not
      conclusive. Chloride channels have been implicated in the secretory processes.
      The effects of a chloride channel blocker, DIDS, were studied on histamine
      induced suppression of IL-4 secretion. DIDS (10(-7) - 10(-12)M) abrogated the
      inhibitory effects of histamine on IL-4 secretion. The observations suggest that
      histamine may inhibit IL-4 secretion via activation of chloride channels.

PMID- 8644512
TI  - Immunoglobulin isotype modulation after administration of IL-12.
AB  - We have begun a series of experiments assessing the role of IL-12 in the humoral
      immune response. IL-12 is known to enhance cellular immunity causing a shift
      toward a Th1, as opposed to a Th2, response. IL-12 is also a potent stimulator of
      IFN-gamma production which, among other activities, modulates isotype expression
      particularly with respect to IgG2a. We have performed a series of experiments
      involving the concurrent dosing of mice with murine IL-12 and TNP-KLH followed by
      the monitoring of IgG1 and IgG2a anti-TNP responses and total IgG1 and IgG2a
      levels. Following administration of IL-12, specific anti-TNP titers showed an
      IgG2a increase while IgG1 responses were markedly lower than those exhibited by
      animals which did not receive IL-12. Total IgG1 levels in IL-12 treated mice
      remained at or near baseline while untreated mice demonstrated an increase in
      total IgG1 levels. In addition, lymph nodes from these mice were removed,
      stimulated with KLH and assayed for expression of murine IFN-gamma and IL-4.
      Murine IFN-gamma levels in supernatants obtained from IL-12 treated mice were
      elevated over those seen in untreated mice while IL-4 levels were suppressed.

PMID- 8644513
TI  - Substance P mediated stimulation of cytokine levels in cultured murine bone
      marrow stromal cells.
AB  - Substance P (SP) is a neuropeptide which has been reported to have
      immunomodulatory activity. Most studies on SP have been performed on cells of the
      peripheral immune system. More recently, SP has been reported to have stimulatory
      activity on human bone marrow cells in vitro, and this activity was dependent on
      the presence of an adherent layer of cells. The in vitro adherent layer
      represents the stromal cells of the marrow. In this study, we directly addressed
      the effect of SP on cultured bone marrow stromal cells. Since stromal cells play
      an important role in the regulation of hematopoiesis, interactions of
      neuropeptides such as SP with this cell population could lead to an alteration of
      stem cell development within the bone marrow. Previously we have shown that SP
      stimulates protein synthesis in this cell population with two waves of protein
      synthesis activation, after 2 hr and 48 hr of SP incubation. In this study, we
      asked whether levels of known stromal cell cytokines were altered in response to
      SP incubation. We assayed the levels of Interleukin-7 (IL-7) and Stem Cell Factor
      (SCF) associated with the stromal cell surface following 2 hr and 48 hr of SP
      incubation. Cells were stimulated with SP for 2 hr or 48 hr. Following SP
      incubation, cells were washed and the levels of cell associated cytokine was
      determined by ELISA. Following 2 hr of treatment, 0.1 nM of SP significantly
      increased (p = 0.05) the level of IL-7 as compared to untreated controls. After
      48 hr of treatment, 1, 10, and 100 nM SP significantly increased the levels of IL
      7 in this cell population. When SCF levels were assayed, SP at all concentrations
      tested was found to increase significantly the levels of SCF following 2 hr of
      incubation. Following 48 hr of incubation, 10 and 100 nM of SP significantly
      increased the levels of SCF. The ability of SP to affect cytokine levels varied
      with time. Following 2 hr of SP incubation, cytokine levels were enhanced at the
      lower end of the concentration range as compared to 48 hr of SP treatment. A 48
      hr incubation with SP yielded the highest levels of cytokine at the higher end of
      the concentration range. Taken together, the results of these studies suggest
      that SP has an immunoregulatory effect on bone marrow stromal cells leading to
      alteration in the production and/or secretion of regulatory cytokines such as IL
      7 and SCF.

PMID- 8644514
TI  - Malaria transmission-blocking immunity. Identification of epitopes and evaluation
      of immunogenicity.

PMID- 8644515
TI  - The effect of molecular weight and gel preparation on humoral adjuvancy of
      silicone oils and silicone gels.

PMID- 8644517
TI  - Liposomal vaccines.
AB  - Liposomes have been used therapeutically to deliver drugs to certain anatomical
      sites. The use of liposomes to deliver antigens, although not a new concept, has
      received less attention. At least two vaccines of nearly identical liposome base
      composition to our vaccines have been tested in humans. A malaria vaccine study
      showed that the liposomal preparation is quite safe: reaction profiles of
      volunteers receiving the vaccine demonstrated little reactivity and virtually no
      pyrogenicity (14). The concentration of MPLA in the vaccine was substantially
      higher (nearly 50,000 times) than the pyrogenic dose of free lipid A. The same
      vaccine, but different antigen (gp120, an HIV protein), was tested in volunteers
      and had the same lack of toxicity (27). In both studies, antibodies and cytotoxic
      cells specific for the respective antigens were produced. We have several subunit
      vaccines under development for infectious diseases (gram negative sepsis, fungal
      infections, protozoan infections), metabolic disorders (hypercholesterolemia,
      diabetic retinopathy, macular degeneration), and neoplastic diseases (multi-drug
      resistant cancer, primary and metastatic tumors, and angiogenic
      hyperproliferative disorders). In each case, one or more antigens were identified
      that might be useful in immunologic control of biologic proliferation (i.e.,
      pathogen or tumor growth, rise in serum cholesterol, growth of blood vessels). We
      anticipate that at least one of these vaccines will be ready for testing in
      humans in the next calendar year.

PMID- 8644516
TI  - Experimental feline Lyme borreliosis as a model for testing Borrelia burgdorferi
      vaccines.
AB  - The feline model investigated establishes that domestic cats may act as an animal
      model for evaluating the pathogenesis of Lyme borreliosis. Specifically this
      feline model demonstrates: First, that animals seroconvert following either
      needle injection of, or arthropod delivery of, Borrelia burgdorferi. Clinical
      findings obtained are consistent with those observed in human Lyme disease;
      histopathological observations are also consistent with those observed in human
      Lyme disease. Therefore, cats may also be used as a representative animal model
      for measuring immune protection against Lyme borreliosis. Specifically we are
      exploring the protective capacity of Borrelia burgdorferi antigenic compounds in
      cats, namely OspA, OspB, OspC, heat shock proteins, flagellar antigens and
      various protective immunological combinations.

PMID- 8644518
TI  - Protection strategies against botulinum toxin.

PMID- 8644519
TI  - Collagen arthritis in T cell receptor congenic mice. A unique approach to study
      the role of T cell receptor genotypes in autoimmune arthritis.

PMID- 8644520
TI  - [The principles of ophthalmological research].

PMID- 8644521
TI  - [Three-dimensional structures of the nonpigmented epithelium of the dog ciliary
      body--application of sodium hydroxide digestion to scanning electron microscopic
      observation of the ciliary epithelium].
AB  - The nonpigmented epithelium (NPE) of the dog ciliary body was three-dimensionally
      observed by scanning electron microscopy (SEM) using sodium hydroxide digestion.
      The inner limiting membrane of the NPE and the zonular fibers covering the NPE
      were completely dissolved in 6N sodium hydroxide for 10-15 minutes at 60 degrees
      C, although the surface structures of the plasma membrane were remarkably
      preserved despite the rather rigorous treatment. Thus, the entire surface of the
      NPE was exposed for SEM. The surface of the NPE at the anterior part of the pars
      plicata was flat, but many complex processes were observed in the surfaces of the
      NPE as lateral walls of the middle and posterior parts of the pars plicata, to
      which the zonular fibers had adhered. The processes were more prominent in the
      middle portion and gradually flattened near the posterior portion. Many pit-like
      structures and drumstick-like processes of the plasma membrane were localized at
      the apex of the ciliary process.

PMID- 8644522
TI  - [Studies on transcranial magnetic stimulation--characteristics of the magnetic
      coil].
AB  - I measured the characteristics of several different magnetic coils. In a round
      coil and a doughnut-shaped coil, induced voltages measured by a longitudinal
      probe and compound muscle action potentials (CMAPs) recorded from the abductor
      pollicis brevis showed two peak voltages in the former at a point halfway between
      the coil center and the outer edge, and in the center of the windings in the
      latter. On the other hand, in a double coil, the maximum induced voltage showed a
      peak at the center of the coil, and when the coil current was antidromically
      charged against the median nerve, the distribution of CMAPs was more focal. When
      the distance from the coil surface was disregarded, the maximum induced voltage
      spot in the double coil did not move. However, in the other coils, it moved
      closer to the outer edge. From these findings, it was confirmed that a double
      coil is the most suitable for focal stimuli. In conclusion, when using magnetic
      coils, the peak spot of various coils and the direction of the coil current
      against the target nerve are important.

PMID- 8644523
TI  - [Medical treatment for experimental retinal vein occlusion--thrombolytic effect
      of nasaruplase].
AB  - The anti-thrombolytic effect of urokinase (UK), nasaruplase, and argatroban was
      studied using an experimental rabbit model of retinal vein occlusion (RVO).
      Experimental RVO was induced by transadventitial thrombin instillation. Five or
      fourteen days after thrombin application, the rabbits were injected with gelatin
      fluorescein sodium and their eyeballs were enucleated for microscopic observation
      and flat preparation of the retina. Occlusion of retinal vessels was found to be
      less in number and distribution in the nasaruplase group than in the control
      group. On microscopic observation, the retinal arteries and veins of the
      nasaruplase group showed a vascular subendothelial space formation which
      suggested a process of thrombogenesis and thrombolysis in the space. The
      coefficiency of beraprost sodium, aspirin, and ozagrel hydrochloride to UK
      therapy was studied, but there was no significant difference between these groups
      and the control group with no after-treatment (the UK group). This result shows
      the effectiveness of nasaruplase for the thrombolytic therapy of RVO.

PMID- 8644524
TI  - [Evaluation of visual functions and ophthalmologists in future].

PMID- 8644525
TI  - [Effect of endothelin on ionic background in the optic nerve head of rabbits].
AB  - Endothelin-1 (ET-1) is thought to have some effect on the retinal circulation and
      its autoregulation. The disturbance of ET-1 secretion might contribute to the
      pathogenesis of retinochoroidal or optic nerve disease. In this study, to
      determine the effect of ET-1 on the optic nerve head, we observed the optic nerve
      with a transmission electron microscope and measured element contents in the axon
      and myelin of the optic nerve head by electron probe X-ray microanalysis. Albino
      rabbits were given an injection of 0.1 ml (10(-6)M) ET-1 into the middle of the
      vitreous of one eye (ETs) and 0.1 ml Opeguard-MA into the other eye (controls),
      and 2 hours after the injection changes in the optic disc were observed. In
      transmission electron microscopy (n = 3), axon polymorphism and myelin disorder
      were seen. The X-ray analysis of frozen sections (n = 5) revealed that with ET-1
      treatment Ca and Cl concentrations were increased in the axon, and K
      concentration was decreased significantly in both axon and myelin. These results
      suggest that the increase of intracellular Ca could elevate the activity of some
      proteases, which might then cause damage to the optic nerve.

PMID- 8644526
TI  - [Visual functional changes in idiopathic macular holes treated by vitrectomy].
AB  - We evaluated visual functional measurements, visual acuity, central retinal
      sensitivity in a Humphrey field analyzer, and binocular function in Stereotest,
      Amsler grid testing, of 51 idiopathic macular holes before and after vitrectomy.
      In 36 of 51 eyes (71%) where the macular hole was closed after vitrectomy, there
      were improvements in all visual functional measurements postoperatively. The eyes
      in which the macular hole was closed had significantly better visual acuity
      before vitrectomy than those in which the hole was not closed. In 16 of 51 eyes
      that had visual acuity of less than 20/200 preoperatively, central retinal
      sensitivity before vitrectomy was higher in the eyes where the macular hole was
      closed than in those in which it was not closed. These measurements are useful
      for evaluation of visual functional improvements after vitrectomy and can help to
      choose candidates for macular hole surgery.

PMID- 8644527
TI  - [Corneal thickness mapping with an ultrasound biomicroscope].
AB  - We developed a corneal thickness mapping system with ultrasound biomicroscopy
      (UBM). Perpendicular section ultrasonic echo images of cornea within a radius of
      2.5 mm from the center of the cornea in normal eyes were digitized and analyzed
      with a computer. Pachymetric maps were then represented by a color scale.
      Individual corneal thickness mapping will be necessary in refractive surgery and
      helpful in understanding pathologic states.

PMID- 8644528
TI  - [Effect of a nitric oxide donor on optic nerve head circulation].
AB  - Recently the endothelium-derived relaxing factor was proved to be nitric oxide
      (NO) and it has been found to play an important role in the regulation of local
      blood flow. In this paper, we studied the effect of S-nitroso-N-acetyl-DL
      penicillamine (SNAP), a NO donor, on the optic nerve head (ONH) circulation in
      rabbits, using a hydrogen gas clearance flowmeter etc. Intravitreal application
      of SNAP (20 nmol) increased the caliber of the retinal artery at the edge of the
      ONH 60 to 120 minutes later and capillary blood flow in the ONH 90 to 135 minutes
      later. A dose-response relation was found between 2 and 20 nmol. These changes
      were thought to be caused by NO produced from SNAP because they were inhibited by
      pretreatment with a NO trapping agent. Blood pressure and IOP were reduced 30 to
      45 minutes later and 60 to 120 minutes later, respectively. It was considered
      that intravitreal injection of SNAP first reduced both the resistance of the ONH
      blood vessels and the perfusion pressure in the ONH and that the latter then
      rose, followed by an increase of the capillary blood flow in the ONH.

PMID- 8644529
TI  - [Clinical and electrophysiological studies on posterior retinitis pigmentosa].
AB  - On the basis of fundus appearance and angiographic fundus pictures, 48 cases of
      posterior retinitis pigmentosa were divided into pericentral type (20 cases),
      perimacular type (21 cases), and macular type (7 cases). We compared the 3 groups
      clinically and electrophysiologically. Visual acuity and visual field were
      progressively deteriorated in half of the cases of pericentral type two years
      after the initial visit. The waveform of flash electroretinogram (ERG) was
      negative in the pericentral type, subnormal in the perimacular type, and normal
      in the macular type. These ERG findings suggest that the rod function was more
      severely damaged in the pericentral type than in the other types. Contrary to the
      ERG findings, the pattern-evoked cortical potential was normal in the pericentral
      type, and we assumed there is less damage of the foveal function in the
      pericentral type.

PMID- 8644531
TI  - [Role of the vitreous in central retinal vein occlusion].
AB  - To investigate the role of the vitreous in eyes with central retinal vein
      occlusion, especially in relation to neovascularization and macular edema, we
      conducted a retrospective chart review of the vitreous condition of 150 patients
      (150 eyes) with central retinal vein occlusion. Based on fluorescein angiography
      findings and color photographs, eyes with central retinal vein occlusion were
      classified as ischemic or nonischemic. In ischemic cases, retinal or optic disc
      neovascularization, or both, developed in eight (57%) of 14 eyes without complete
      posterior vitreous detachment at the final examination. The prevalence of
      neovascularization was significantly higher than in eyes with complete posterior
      vitreous detachment (0%, 0/43) at the final examination (p < 0.01). In
      nonischemic cases, the prevalence of no posterior vitreous detachment or partial
      posterior vitreous detachment with vitreomacular adhesion was significantly
      higher in eyes with macular edema (76%, 28/37) than in eyes without it (23%,
      13/56) at the final examination (p < 0.01). Complete posterior vitreous
      detachment may protect against retinal or optic disc neovascularization in eyes
      with severe central retinal vein occlusion. Vitreomacular adhesion may cause
      persistent macular edema in eyes with mild central retinal vein occlusion.

PMID- 8644530
TI  - [Effect of topical adrenergic agents on tissue circulation in human optic nerve
      head evaluated with a laser speckle microcirculation analyser].
AB  - The effects of a single instillation of 2% carteolol or 0.1% dipivefrine on the
      tissue circulation in the human optic nerve head (ONH) was studied using a laser
      speckle tissue circulation analyser in 12 healthy volunteers. In the first
      experiment, normalized blur (NB), a quantitative index of peripheral blood
      velocity, was measured every 0.125 sec in an area located in the temporal site of
      ONH free of visible surface vessels and averaged over 5 pulses (mean NB) in both
      eyes before, 1.5, 3, and 4.5 hours after a 30 microliters instillation of placebo
      to serve as a control. Intraocular pressure (IOP), blood pressure (BP), and pulse
      rate (PR) were also measured. In the second experiment, a 30 microliters drop of
      2% carteolol (n = 6) or 0.1% dipivefrine (n = 7) was instilled in one randomly
      chosen eye and the placebo for each drug in the other eye, and the above
      parameters were measured according to the same time schedule as in the first
      experiment in a double masked manner. After topical carteolol, carteolol
      concentration in the plasma (CC) was also measured. In the control experiments,
      none of the parameters showed any significant change. After topical carteolol,
      the IOP was significantly lower between 1.5 and 4.5 hrs in the carteolol-treated
      eyes and at 1.5 and 4.5 hrs in the fellow eyes as compared with that obtained in
      the control experiment. The mean NB was significantly higher at 3 hrs (23.1%) in
      carteolol-treated eyes, and at 3 hrs (17.2%) in the fellow eyes, as compared with
      that obtained in the control experiment (p < 0.05). BP and PR showed little
      change. The maximum CC at 3 hrs averaged 522 pg/ml. Thus a single instillation of
      carteolol may increase the tissue blood velocity in ONH in the human eye. After
      topical dipivefrine, the IOP was significantly lower at 4.5 hr in the dipivefrine
      treated eyes than that obtained in the control experiment (p < 0.05). Mean NB, BP
      and PR showed no significant change.

PMID- 8644532
TI  - [Evaluation of risk factors of interferon-associated retinopathy in patients with
      type C chronic active hepatitis].
AB  - The risk factors of retinopathy associated with administration of interferon have
      not been fully clarified. We prospectively examined the retinal condition in 50
      patients with type C chronic active hepatitis during alpha-interferon treatment.
      43 patients (86%) were shown to have retinopathy during the course of interferon
      treatment, and were divided into three groups. Grades I, II and III were patients
      having a single episode of transient retinopathy with soft exudate or hemorrhage
      (34%), frequent episodes of retinopathy (42%), and exacerbating retinopathy
      requiring change or cessation of interferon treatment (10%), respectively. The
      patients with grade II and III were found to have the first retinal changes
      within 8 weeks after initiation of the interferon therapy. Early onset of
      retinopathy and presence of systemic disease such as diabetes mellitus or
      hypertension were risk factors for serious retinopathy with statistical
      significance. The grades of retinopathy were also well correlated with dosage and
      duration of interferon treatment. These results suggest that careful fundus
      examination is required up to 8 weeks after initiation of interferon treatment,
      especially for the patients with risk factors such as early onset of retinopathy,
      presence of systemic diseases, and large dosages and long duration of interferon
      therapy, in order to prevent serious ocular complications.

PMID- 8644533
TI  - [Structure and magnetic resonance imaging of the fiber connection between
      Whitnall's ligament and the superior wall of the orbit].
AB  - To confirm the structure of the fiber connection between Whitnall's ligament and
      the superior wall of the orbit, we observed ten orbits of five Japanese cadavers
      by magnetic resonance imaging (MRI) and dissection. Our findings were as follows:
      MRI showed a well-circumscribed low-intensity signal at the fiber connection.
      Preaponeurotic fat was prominent, and the fibers originating from Whitnall's
      ligament were fused at the lower face of the capsule of the preaponeurotic fat in
      four cadavers. The fibers originating from the upper face of the fat were
      attached to the superior periorbit (minimum width, 15 mm). The fifth cadaver had
      little preaponeurotic fat and few fibers. These anatomic differences may be
      within the normal range of variation. We believe that the fibers support
      Whitnall's ligament and help to retract preaponeurotic fat during levator muscle
      contraction as the eye opens.

PMID- 8644534
TI  - [Cytomegalovirus retinitis and Pneumocystis carinii choroidopathy in a patient
      with AIDS].
AB  - A case of Pneumocystis carinii (P. carinii) choroidopathy is reported. The
      patient was a 17-year-old man with acquired immunodeficiency syndrome (AIDS) who
      developed bilateral, multifocal, yellow-white, round, flat choroidal lesions
      ranging in size from 1/8 to 1/6 of the disc diameter while undergoing treatment
      for cytomegalovirus retinitis. He had had P. carinii pneumonia 43 months
      previously, and received inhaled pentamidine as suppressive therapy. Over a 4
      week period of observation, the choroidal lesions appeared to enlarge slowly and
      increased in number in the posterior pole, with no clinical evidence of
      intraocular inflammation and retinal involvement. He was diagnosed as having P.
      carinii choroidopathy and treated with intravenous pentamidine. Three months
      after systemic pentamidine therapy was begun the choroidal lesions disappeared.
      Despite the fact that P. carinii choroidopathy is a rare opportunistic ocular
      infection, ophthalmic manifestations may be an important initial marker of
      extrapulmonary disseminated infection in some patients. Therefore we recommend
      ophthalmologic examinations in patients with AIDS who receive long-term
      aerosolized pentamidine prophylaxis for pneumonia.

PMID- 8644535
TI  - [Retinitis pigmentosa is selected for one of registered serious diseases by
      Japanese Ministry Health and Welfare].

PMID- 8644536
TI  - [Fluorophotometry of the animal eye].
AB  - We assessed the usefulness of the Fluorotron Master fitted with a small animal
      adapter. We also discuss the measurement conditions for the tupai, which is a
      promising experimental mammal. A good concentration for measurements with this
      instrument ranged from 0.5 x 10(-6) to 1.0 x 10(-6) g/ml. A suitable time for
      fluorophotometry of the tupai was 30 min. after injection of fluorescein-Na, and
      a suitable dose of the fluorescein-Na was 2 mg/kg. We could do ultrafiltration
      for measurement of the protein unbound fluorescein concentration from a minimal
      sample of the blood using a hematocrit tube, and thus could reduce the
      deleterious effects of blood sampling on the animal. This instrument is useful
      for the estimation of the blood-ocular barrier permeability of animal models.

PMID- 8644537
TI  - [Dielectric behavior of rat lens and changes due to cold cataract].
AB  - To correlate the formation of cold cataract with changes in the passive
      electrical properties of the lens, we measured impedances of isolated rat lenses
      in the frequency range from 100 Hz to 500 MHz. Temperature-dependent, reversible
      changes were confirmed in the dielectric behavior as well as in the histological
      characteristics. The impedance of lenses showed two separate peaks (i.e. P1 and
      P2) when expressed in terms of loss tangent. At a low temperature of 4 degrees C,
      cytoplasmic "aggregates" characteristic of the cold cataract were formed inside
      the fiber cells of young rats with concomitant decreases in P2 (the peak value at
      higher frequencies), whereas no remarkable changes occurred in the control group.
      These results indicate that the lowering of P2 may reflect functional changes in
      the lens fiber membrane, an augmented heterogeneity in cytoplasm and/or decreases
      of protein-bound water. We conclude that the P2 is a useful dielectric index for
      the assessment of the nuclear opacity. This is the first report on the
      application of dielectric techniques to lenses with nuclear cataract. We suggest
      that dielectric spectroscopy may be applicable to a quantitative evaluation of
      cataract, not only of the cortical type but also of the nuclear type.

PMID- 8644538
TI  - [Expression of basic fibroblast growth factor and its receptor in the process of
      wound healing of rat retina after laser photocoagulation].
AB  - We investigated the expression of mRNA of basic fibroblast growth factor (bFGF)
      and FGF receptor 1 in rat retina after laser photocoagulation using in situ
      hybridization method. Pigmented rats (Brown Norway strain) received weak
      photocoagulation by krypton laser (500 microns, 0.05 sec, 60 mW) in the posterior
      retina. On 1, 3, 5, 7, 14 days after laser photocoagulation, the rats were fixed
      by perfusion with phosphate-buffered 4% paraformaldehyde and the eyes were
      enucleated. The eyes were further fixed by immersion in the same fixative, then
      quickly frozen in liquid nitrogen and finally sectioned with a cryostat. In situ
      hybridization was performed on frozen sections with digoxigenin (DIG) labeled
      riboprobes synthesized from rat bFGF cDNA and FGF receptor 1 cDNA. In normal
      chorioretinal tissue, the signals of bFGF and FGF receptor 1 mRNA were seen in
      the ganglion cell layer and inner nuclear layer. On day 3 after photocoagulation,
      we observed expression of bFGF and FGF receptor 1 mRNA in the proliferating
      retinal pigment epithelial (RPE) cells and endothelial cells of choriocapillaris
      at the photocoagulated lesion. We also observed expression of bFGF mRNA in some
      macrophage-like cells. On day 14 after photocoagulation, these expressions had
      disappeared. Our results suggest that bFGF may be involved in the process of
      retinal wound healing after laser photocoagulation.

PMID- 8644539
TI  - [Effects of amosulalol hydrochloride on intraocular pressure and aqueous humor
      dynamics in the rabbit eye].
AB  - The effects of amosulalol, which blocks alpha 1 adrenoceptors selectively and
      beta receptors nonselectively almost to the same extent, on intraocular pressure
      (IOP) and aqueous humor dynamics were studied in pigmented rabbits.
      Administration of topical amosulalol (0.5%) resulted in a significant difference
      in IOP between the treated and the contralateral eyes from 0.5 to 6 hours, and
      the maximum IOP reduction, 6.0 +/- 0.4 mmHg (mean +/- standard error), was
      observed at 2 hours after administration. Aqueous humor dynamics measurements
      (mean +/- standard error) in the amosulalol (0.5%)-treated and the contralateral
      eyes revealed that total outflow facility determined by the two-level constant
      pressure perfusion method was not significantly different, 0.14 +/- 0.01 and 0.12
      +/- 0.01 microliter/min/mmHg, respectively; the aqueous flow measurements
      determined by fluorophotometry were 3.0 +/- 0.1 and 3.4 +/- 0.2 microliters/min,
      respectively (p < 0.05, -11%); the uveoscleral outflow measurements determined by
      the fluorescein isothiocyanate-dextran perfusion method were 0.53 +/- 0.04 and
      0.46 +/- 0.04 microliter/min, respectively (p < 0.05, +15%). In conclusion,
      amosulalol lowers the IOP by inhibiting aqueous production and increasing
      uveoscleral outflow.

PMID- 8644540
TI  - [Histochemical study of human lens capsule--immunohistochemical analysis of
      collagen].
AB  - We studied the presence of different types of collagen (I, III, IV, V) in 31
      human lens capsule specimens by use of enzyme labeled antibody (indirect method)
      and tried to quantify them by microspectrophotometry. We also quantified the
      total collagen content of lining layer and crust layer by microspectrophotometry
      in specimens stained by the van Gieson method. The presence of types I, III, IV
      and V collagen was demonstrated in the lens capsule and total collagen content in
      the lining layer was significantly richer than in the crust layer. Total collagen
      content tended to decrease with age over 60 and with the advance of lens opacity.
      Type V collagen increased more than type IV collagen after 60 years of age. These
      results suggest that the collagen in the lens capsule varies quantitatively and
      qualitatively with age and lens opacity.

PMID- 8644541
TI  - [Anterior uveitis with ankylosing spondylitis and HLA].
AB  - We investigated the relationship between anterior uveitis with ankylosing
      spondylitis (AS) and human leukocyte antigen (HLA) alleles. Forty patients were
      studied, 19 with anterior uveitis and 21 without it. No deviation in the
      frequencies of HLA-B27 antigen and related alleles were observed between the two
      groups of patients. Twelve cases (63.2%) with anterior uveitis had expressed HLA
      DR8 (DRB1 0803). On the other hand, only 1 case had expressed the same antigen
      and this difference was statistically significant (relative risk: 34.3 Pc <
      0.007) as we reported previously. We found HLA-DR8 was a candidate for
      susceptibility to anterior uveitis in AS.

PMID- 8644542
TI  - [Aging changes in conjunctiva visualized by fluorescein angiography and
      histopathology].
AB  - In order to investigate the aging changes of the conjunctiva, we examined
      fluorescein-positive areas by fluorescein angiography. The deposition of melanin
      in basal cells, the degranulation of mast cells, and the lumens of capillaries
      were examined by light microscopy in 35 cataractous eyes without diabetes or
      hypertension. The fluorescein leakage increased with aging. The number of basal
      cells with deposition of melanin granules and mast cells with degranulation
      correlated significantly with aging. On the other hand, the narrowing of
      capillary lumens in conjunctival stroma was not observed with aging. Based on the
      above results, we conclude that the weakness of the conjunctival vessels without
      the narrowing of capillary lumens might be caused by functional disorder of the
      endothelium and pericytes. The increase of deposition of melanin granules in
      basal cells may be caused by the breakdown of the metabolic pathway of melanin.
      Long-time mechanical stimuli and metabolic disorders of active substances may
      increase the degranulation of mast cells.

PMID- 8644543
TI  - [Changes in axial length after scleral buckling surgery].
AB  - The eye lengthens after scleral buckling surgery for retinal detachment. We
      investigated the changes in axial length and refraction after scleral buckling. A
      total of 89 eyes from 88 patients which were all scheduled to undergo scleral
      buckling were included in this study. The eyes were classified into four groups
      based on the type of buckling procedures:1 local buckling, 2 encircling, 3
      encircling with vitrectomy, and 4 encircling with local buckling. We examined the
      axial length of these eyes using ultrasonography, preoperatively and at 1, 3, and
      6 months postoperatively. The refractive changes were also examined. Depending on
      the type of scleral buckling procedure employed, the eyes in Groups 2, 3, and 4
      clearly lengthened, but those of Group 1 did not. The amount of axial lengthening
      in Groups 2, 3, and 4 was significantly greater than in Group 1 at 3 and 6 months
      after surgery. In the spherical equivalent, a myopic shift occurred in the eyes
      in Groups 2, 3, and 4, and this shift was significantly greater than in Group 1
      In addition, the correlation between the extent of axial lengthening and myopic
      shift was significant. In conclusion, the axial length increases with a myopic
      shift due to encircling, whereas local buckling changed the axial length only
      slightly.

PMID- 8644544
TI  - [Temporal modulation transfer function in normal-tension glaucoma patients].
AB  - In an attempt to detect patients in an early stage of glaucoma, a new screening
      test, the Flicker System, by which temporal modulation transfer function is
      evaluated, was performed in 64 normal-tension glaucoma patients and 65 normal
      eyes. The early stage of glaucoma, i.e., stage 0-1 of Aulhorn-Greve's
      classification, showed a significant decrease of the modulation in the range from
      20 to 45 Hz in comparison with normal eyes (p value < 0.05). The moderate stage
      of glaucoma of stages 2-3 also revealed significantly decreased values of the
      modulation in the range from 14 to 55 Hz. In the range from 25 to 45 Hz, the
      reduction of modulation in the glaucoma with diffuse visual defect was more
      profound than in glaucoma with localized or mixed defects. The results seem to be
      compatible with the presence of diffuse visual function deficit in glaucoma.

PMID- 8644545
TI  - [Usefulness of the prick test for anaphylactoid reaction in intravenous
      fluorescein administration].
AB  - We examined whether a prick test was a valuable method in comparison with an
      intradermal skin test for predicting an anaphylactoid reaction to intravenous
      injection of fluorescein solution. Fifteen hundred cases were tested. The number
      (rate) of positive reactions to the prick test with 10% and 1.0% fluorescein
      solution was 2 (0.1%) and 0 (0.0%), respectively. In contrast, positive reaction
      to the intradermal skin tests with 10% and 0.1% fluorescein solution was observed
      in 686 cases (45.7%) and 13 cases (0.9%), respectively. Fluorescein angiography
      (FAG) was performed in 1,499 of the 1,500 cases. Adverse reactions such as
      nausea, cough, cold sweat, urticaria, and shock were noted in 85 cases (5.7%).
      Typical anaphylactoid shock occurred in one case (0.07%), which was one of the
      two cases positive to the prick test with 10% fluorescein. In the other positive
      prick test case, FAG was cancelled because of the high probability of
      anaphylactoid shock. The results suggest that a prick test with 10% fluorescein
      solution can markedly cut down the false positive reactions and can be a useful
      test for the prospective diagnosis of anaphylactoid reactions to intravenous
      fluorescein administration.

PMID- 8644546
TI  - [Six cases of secondary keratoconus with Fleischer's ring pattern corneal
      epithelial iron ring].
AB  - We observed 6 cases of secondary keratoconus with Fleischer's ring pattern
      corneal epithelial iron ring. These 6 cases were 2 males and 4 females. The
      causes of secondary keratoconus were 2 cases of trachoma, 2 cases of trauma, 1
      case of keratitis, and 1 case of unknown origin. All showed thinning of the
      cornea and Fleischer's ring pattern corneal epithelial iron ring. After
      penetrating keratoplasty of 1 case, the button of the recipient showed the
      deposition of hemosiderin in the corneal epithelium stained blue by Prussian
      blue. At the same time we confirmed the existence of iron in the corneal
      epithelium by the X-ray ultimate analysis. Fleischer's ring is considered to be
      characteristic of keratoconus, but we have found that Fleischer's ring is also
      seen in secondary keratoconus in which the cornea becomes thinner secondarily for
      some reason.

PMID- 8644547
TI  - [A case of Vogt-Koyanagi-Harada disease associated with aortitis syndrome].
AB  - This in a case report of Vogt-Koyanagi-Harada disease associated with aortitis
      syndrome in a 44-year-old female. She was diagnosed as having aortitis syndrome
      twenty years ago, and has been treated with systemic corticosteroids. At the
      first ophthalmic examination, her visual acuity was 0.2 (n. c.) in the right eye
      and 0.4(0.5) in the left eye. Inflammatory cells in the anterior chamber of the
      left eye and bilateral serous retinal detachment were observed. Fluorescein
      angiography revealed subretinal pooling of fluorescein. In the systemic
      examination, pleocytosis of the cerebrospinal fluid and human leukocyte antigen
      (HLA) types DR2 and DR4 were also found. We diagnosed the condition as Harada's
      disease from these findings, and then applied systemic administration of
      corticosteroids. After the treatment, the bilateral serous retinal detachment
      immediately disappeared, and the visual acuity improved to (1.0). Vogt-Koyanagi
      Harada disease associated with aortitis syndrome is very rare, because it has
      never been reported previously. It is possible that there is some unknown common
      mechanism in these two diseases, but it is more probable that this case was
      simply coincidental.

PMID- 8644548
TI  - Transurethral microwave thermotherapy in the treatment of chronic abacterial
      prostatitis: a 2 years follow-up.
AB  - OBJECTIVE: Transurethral microwave thermotherapy (TUMT) is a minimally invasive,
      outpatient treatment, applied as a single session of 1-hour duration. SUBJECTS
      AND METHODS: A group of 11 patients with chronic abacterial prostatitis, who
      failed to respond to a variety of conventional treatments, underwent this therapy
      in our centre. RESULTS: The results after two years of follow-up are encouraging:
      88% remain free of symptoms. CONCLUSION: Thermotherapy seems to add a new
      alternative for this hard to manage disease.

PMID- 8644549
TI  - [Apropos of a case of nephrogenic adenoma in a urethral diverticulum in a woman].
AB  - A nephrogenic adenoma in a urethral diverticulum has been observed in a 32 years
      old black woman. The association of both of these abnormalities is relatively
      uncommon, however symptomatic and source of complications.

PMID- 8644550
TI  - [Calcification of the bladder wall following instillation of mitomycin C. Apropos
      of a case report].
AB  - Bladder wall calcification is a rare complication of intravesical therapy with
      mitomycin C. We report a new case and discuss the pathogenic mechanism of this
      complication.

PMID- 8644551
TI  - [Mucous prolapse of the urethra].
AB  - Urethral prolapse represent a rare cause of urological consultation. Frequent in
      older women, it also happens in under 10-year-old little girls with a racial
      predominance. For most cases, medical treatment and follow-up are sufficient, but
      failure of these or possible complications may necessitate a surgical correction.
      Circumferential excision and muco-mucous suture are effective treatments with
      very few complications. About four case-reports, we are reviewing here the
      literature and discussing etiopathogenic mechanisms and therapeutic options for
      this disease.

PMID- 8644552
TI  - Urethral metastasis from a rectal carcinoma.
AB  - A 67-year-old man presented with a tumour of the penis. Endoscopy revealed a
      bleeding tumour. Histological examination showed an adenocarcinoma; urethral
      metastasis of rectal carcinoma. As far as we know only 6 previous cases have been
      described.

PMID- 8644553
TI  - Carcinoma of the urachus.

PMID- 8644555
TI  - Biofeedback in the treatment of voiding disorders in childhood.
AB  - Voiding disorders are a common problem in pediatric urology. Biofeedback is a non
      invasive method in the treatment of voiding disorders in childhood. Biofeedback
      takes aim at the learning or relearning of influencing involuntary functions. We
      report about our preliminary results of biofeedback training in the treatment of
      the enuretic syndrome in children. Out of 26 children with pseudo-detrusor
      sphincter-dyssynergy 17 could be completely cured and 5 improved considerably.
      Out of 21 children with motor urgency 9 could be completely cured and 7 children
      improved. Biofeedback is a successful method to treat children with the enuretic
      syndrome.

PMID- 8644554
TI  - Uterine prolapse and urinary tract obstruction.
AB  - A case is presented of total uterine prolapse accompanied by moderate bilateral
      hydroureteronephrosis which was diagnosed after evaluation for fever of unknown
      origin.

PMID- 8644556
TI  - Operative experience in hypospadias surgery.
AB  - The authors report their experience of the last 50 hypospadias corrections. 30%
      of the cases were glandular hypospadias. The correction was made by the MAGPI
      procedure. Thirty per cent of the cases were coronal hypospadias. The Mathieu
      procedure (meatal-based flap) is compared with the meatallateral flap technique.
      Twenty-five per cent of the cases were several hypospadias with chordee. The
      procedures of the tubed-transversal-preputial flap, versus onlay-transversal
      preputial flap, are compared.

PMID- 8644557
TI  - Where do the new agents fit in hypertension management?

PMID- 8644558
TI  - In-line skating: play it safe.

PMID- 8644559
TI  - Issues associated with prenatal testing for fetal abnormalities.

PMID- 8644560
TI  - Use of 'normal' to describe penile appearance after circumcision.

PMID- 8644561
TI  - A simple form of meditation for use in clinical practice.

PMID- 8644562
TI  - Postpoliomyelitis pain treated with gabapentin.

PMID- 8644563
TI  - The colposcopic examination.
AB  - A well-organized and complete colposcopic examination is a vital component of the
      evaluation of a patient with an abnormal Papanicolaou smear. The properly
      administered colposcopic examination requires patient preparation, correct
      equipment and an experienced colposcopist. Under magnified illumination, the
      cervix is examined for abnormalities. Visualization of premalignant and malignant
      changes guides the colposcopist in the choice of cervical biopsy sites. The
      severity and extent of disease can then be histologically determined, and
      appropriate treatment initiated.

PMID- 8644564
TI  - Practical methods of preventing ankle injuries.
AB  - Each year ankle sprains account for a significant degree of disability and
      expense. Thus, it is important that family physicians become familiar with
      methods of preventing ankle sprains. Both internal and external methods prevent
      ankle injuries. Internal methods include improving flexibility, strength and
      proprioception; effective external methods of ankle protection include using
      athletic tape, lace-up stabilizers and semirigid orthoses.

PMID- 8644565
TI  - Intestinal protozoa.
AB  - Giardia is the best known cause of protozoal gastrointestinal disease in North
      America, producing significant but not life-threatening gastrointestinal distress
      and diarrhea. Although diagnosis of giardiasis may be challenging, treatment is
      usually successful. Entamoeba histolytica poses a rarer but far more difficult
      clinical challenge. Dysentery caused by E. histolytica may be the most feared
      intestinal protozoal infection, although Cryptosporidium parvum, Balantidium
      coli, Isospora belli, Sarcocystis species and other newly described protozoa also
      may cause diarrhea in healthy individuals and may result in intractable, life
      threatening illness in patients with acquired immunodeficiency syndrome or other
      immunosuppressive diseases. Certain protozoa once considered relatively
      unimportant, such as Cryptosporidium, are now recognized as significant causes of
      morbidity even in the United States, since transmission readily occurs through
      contaminated water.

PMID- 8644566
TI  - Corneal abrasions: diagnosis and management.
AB  - Corneal abrasions are characterized by sudden onset of eye pain, photophobia and
      tearing. The patient usually relates a history of recent eye trauma but may not
      recall an inciting event. The differential diagnosis includes direct mechanical
      injury, recurrent erosion syndrome, ultraviolet keratitis and infection. Most
      abrasions heal within 24 to 48 hours. Therapeutic modalities include cycloplegia
      and topical antibiotics. Other treatment methods include pressure patching,
      topical nonsteroidal anti-inflammatory drugs, bandage contact lenses, collagen
      shields, anterior stromal puncture and epithelial debridement.

PMID- 8644567
TI  - Optimizing enteral nutrition.
AB  - Adequate nutritional support is an important aspect of the care of all patients.
      Enteral nutritional support accesses the gastrointestinal tract and includes both
      oral supplementation and tube-feeding techniques. Enteral nutritional support
      should be considered when a patient has functioning intestines but cannot or will
      not eat. Most patients require a caloric intake of 25 to 35 kcal per kg per day.
      The choice of route of administration for tube feedings should be based primarily
      on the anticipated length of therapy and patient comfort. Three schedules for the
      initiation and delivery of tube feedings are presented in this article. Both
      nasogastric and percutaneous endoscopic gastrostomy tubes are associated with
      potential complications, including aspiration and gastrointestinal intolerance.
      Important parameters include the patient's weight and volume status, and periodic
      laboratory determinations of the patient's serum electrolytes and protein status.

PMID- 8644568
TI  - Middle lobe syndrome.
AB  - Middle lobe syndrome is defined as recurrent or chronic collapse of the middle
      lobe of the right lung. It occurs in all age groups and is divided into an
      obstructive type, with a demonstrable airway occlusion, and a nonobstructive
      type, with a patent right middle lobe bronchus apparent on bronchoscopy. Middle
      lobe collapse has specific radiographic findings. Malignancy is the most common
      cause of the obstructive type, and infections are the second leading etiology.
      The nonobstructive type is associated with inflammatory conditions and
      bronchiectasis. In all cases, treatment is directed at the underlying cause.

PMID- 8644569
TI  - Management of hypertension, Part II.
AB  - Although calcium channel blockers and angiotensin-converting enzyme (ACE)
      inhibitors are effective in lowering blood pressure, no long-term data show their
      effect on morbidity and mortality in hypertensive patients. They are suggested as
      alternative initial therapy in hypertensive patients. Short-acting calcium
      channel blockers are to be used with caution or not at all in the treatment of
      hypertension. Nonhydropyridine calcium channel blockers may reduce the incidence
      of second infarction but not congestive heart failure or mortality in patients
      with ischemic heart disease. The ACE inhibitors increase insulin sensitivity and
      decrease intraglomerular pressure. In combination with a diuretic, they are the
      preferred agents in the treatment of diabetic patients with hypertension,
      especially those with nephropathy. In both hypertensive and normotensive
      patients, ACE inhibitors reduce morbidity and mortality resulting from congestive
      heart failure in patients with poor left ventricular function who are also being
      treated with a diuretic and/or digitalis. They do not, however, reduce strokes or
      myocardial infarctions in hypertensive patients.

PMID- 8644570
TI  - Choosing the best medications.
AB  - Physicians can create their own personal formulary by rigorously selecting and
      regularly using one or two drugs for each clinical condition they commonly
      encounter. The primary and secondary medical literature provides the necessary
      information to create this formulary. Primary literature sources include peer
      reviewed articles of randomized, double-blind clinical trials that compare
      medications. Secondary information sources include Physicians' Desk Reference and
      Drug Facts and Comparisons, which summarize but do not recommend particular
      drugs. Other secondary sources, such as The Medical Letter on Drugs and
      Therapeutics and review articles in peer-reviewed journals, compare drug classes
      and make recommendations about the drug of choice. The main medication
      characteristics to compare are efficacy, safety, patient acceptability and cost.
      The most objective information on efficacy is obtained through large,
      methodologically sound clinical trials that evaluate meaningful clinical
      outcomes. Three safety criteria to review include adverse drug effects,
      interactions with other drugs and the extent of clinical experience with the
      medication. Factors that contribute to patient acceptability should also be taken
      into consideration.

PMID- 8644571
TI  - SAFE questions: overcoming barriers to the detection of domestic violence.
AB  - Although domestic violence is an important public health problem in this country,
      several barriers tend to hinder its detection by physicians. Physicians may lack
      knowledge about the subject, harbor attitudes that hinder detection or lack the
      necessary skills to address patients who are victims of domestic violence. The
      SAFE questions--which address the areas of safety, abuse, friends' and family's
      knowledge and emergency plans--can be used to identify affected patients. In
      addition, these questions provide the physician with a logical framework for
      counseling and intervention.

PMID- 8644573
TI  - Smoking cessation: information for specialists. Smoking Cessation Guideline
      Panel. Agency for Health Care Policy and Research.

PMID- 8644572
TI  - Dysthymic disorder: the chronic depression.
AB  - Dysthymic disorder is defined as chronic depression of a mild to moderate degree
      for at least two years' duration. The disorder tends to be underdiagnosed despite
      a prevalence of 5 to 15 percent in primary care settings. Both the diagnosis and
      treatment of dysthymic disorder may be complicated by a variety of comorbid
      psychiatric and medical conditions as well as chronic stressors. Treatment may be
      determined by the accompanying comorbid condition. Antidepressant drugs are
      moderately efficacious in the treatment of dysthymia, with selective serotonin
      reuptake inhibitors preferred over tricyclic antidepressants. However, patients
      may report oversensitivity to antidepressants, experience only partial remission
      with treatment and suffer relapses. Adjunctive support or psychodynamic
      psychotherapy should also be considered.

PMID- 8644574
TI  - Benign paroxysmal positional vertigo: the canalith repositioning procedure.
AB  - As much as 20 percent of patients presenting with dizziness may have benign
      paroxysmal positional vertigo. This condition, which may be caused by otoliths
      lodged in the semicircular canals of the ear, tends to be persistent or
      recurrent. Traditionally, it has been treated symptomatically with medication.
      The canalith repositioning procedure, a series of defined head positions, is
      designed to shift the location of the otoliths to afford relief from the nausea,
      vomiting and dizziness often experienced by patients with this disorder.

PMID- 8644575
TI  - Hemochromatosis: diagnosis and management.
AB  - Hemochromatosis is a disorder of iron metabolism that causes progressive damage
      to the liver, pancreas, heart and other organs. It is the most common autosomal
      recessive disorder among whites, and it occurs five times more frequently in
      males than in females. Manifestations include diabetes mellitus, hepatic
      dysfunction, congestive heart failure and other end-organ insufficiency. The
      presentation of hemochromatosis is often nonspecific, requiring the clinician to
      maintain a high index of suspicion. The diagnosis is suggested by abnormal iron
      studies, most notably an elevated serum ferritin level and/or transferrin
      saturation. Liver biopsy can confirm the diagnosis and document the presence of
      cirrhosis. The diagnosis is also supported by characteristic findings on a
      magnetic resonance imaging scan, and a diagnostic response to repeated phlebotomy
      (a hematocrit level that rapidly returns to normal). Phlebotomy treatments reduce
      the total body iron load, prevent continuing deposition of iron in the tissues,
      and prevent premature morbidity and mortality. Screening is recommended in
      affected families, and screening programs for wider populations are being
      evaluated.

PMID- 8644576
TI  - A critical look at ocular allergy drugs.
AB  - Topical ocular allergy drugs are indicated for the treatment of allergic
      conjunctivitis after more conservative measures have been employed.
      Antihistamines, vasoconstrictors, nonsteroidal anti-inflammatory drugs, mast cell
      stabilizers and corticosteroids are available. Levocabastine and ketorolac
      tromethamine are new drugs for the treatment of allergic conjunctivitis.
      Lodoxamide is currently indicated only for the treatment of vernal
      keratoconjunctivitis, although treatment efficacy has been demonstrated in
      patients with giant papillary conjunctivitis and atopic keratoconjunctivitis. As
      a general rule, topical ocular allergy drugs are well tolerated by most patients
      except for transient stinging and burning on instillation. Ocular steroids should
      be reserved for severe cases and should be prescribed by an ophthalmologist, who
      can monitor the patient for possible ocular side effects.

PMID- 8644577
TI  - Conditions of the nervous system. Recommended core educational guidelines for
      family practice residents. American Academy of Family Physicians.

PMID- 8644578
TI  - Urgent and emergent care. Recommended core educational guidelines for family
      practice residents. American Academy of Family Physicians.

PMID- 8644579
TI  - AAFP issues position paper on diagnostic obstetrics-gynecology ultrasonography by
      family physicians.

PMID- 8644580
TI  - American Urological Association releases guidelines for the management of
      localized prostate cancer.

PMID- 8644582
TI  - Periprocedural Doppler coronary blood flow predictors of myocardial perfusion
      abnormalities and cardiac events after successful coronary interventions.
AB  - Thirty-four consecutive patients had coronary flow velocity assessed under basal
      and hyperemic conditions in the proximal and distal coronary artery, followed by
      rest-stress technetium 99m sestamibi myocardial tomography within 3 months of
      successful coronary angioplasty. In spite of significant angiographic
      improvement, 29% of patients had a persistent reversible myocardial perfusion
      defect associated with a residual abnormality of the proximal-to-distal coronary
      average peak velocity ratio (p/d APV = 2.2 +/- 1.5 vs 1.1 +/- 0.6; p = 0.02).
      Patients with an abnormal p/d APV ratio (>1.7) had more numerous angioplasty-zone
      perfusion defects (4.2 +/- 3.3 vs 0.8 +/- 2.0; p = 0.005). Multivariable analysis
      of clinical, angiographic, coronary flow, and scintigraphic data demonstrated
      that the relative risk of cardiac events (n = 11) was greatest in patients with a
      reversible angioplasty-zone perfusion defect (relative risk, 5.5), poststenotic
      coronary flow reserve <2.0 (relative risk, 8.3) and p/d APV ratio >1.7 (relative
      risk, 6.2). Residual basal coronary flow-velocity abnormalities are significant
      physiologic correlates of stress-induced myocardial perfusion defects and are a
      prognostic covariable associated with future ischemic cardiac events.

PMID- 8644581
TI  - Nitric oxide production by coronary conductance and resistance vessels in
      hypercholesterolemia patients.
AB  - NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide (NO)
      synthesis, was used to investigate the effects of inhibition of NO synthesis on
      the coronary conductance and resistance vessels in hypercholesterolemic patients.
      Acetylcholine (3 and 30 micrograms/min) was administered to 10
      hypercholesterolemic and 10 control patients before and after L-NMMA (25
      micromol/min) infusion. Epicardial coronary diameter was measured by quantitative
      angiography, and coronary blood flow (CBF) was derived from Doppler flow-velocity
      and coronary diameter measurements. In hypercholesterolemic patients,
      acetylcholine-induced dilation of epicardial arteries was attenuated, and the
      percentage increase in CBF caused by acetylcholine was smaller than that in
      control patients. L-NMMA attenuated acetylcholine-induced dilation of epicardial
      arteries in control patients. L-NMMA had no effect on CBF responses to
      acetylcholine in both patient groups. L-NMMA significantly decreased the baseline
      coronary diameter and CBF in both groups. These results indicated that
      hypercholesterolemia impaired the acetylcholine-induced dilation of the
      conductance and resistance coronary vessels. This impairment in the conductance
      vessels was dependent on NO production; that of resistance vessels was not. The
      basal release of NO in conductance and resistance vessels was preserved in
      hypercholesterolemic patients.

PMID- 8644583
TI  - Optimized expansion of the Wallstent compared with the Palmaz-Schatz stent: on
      line observations with two- and three-dimensional intracoronary ultrasound after
      angiographic guidance.
AB  - Optimized stent expansion by high-pressure inflations of oversized balloons has
      initially been derived from experience obtained with the Palmaz-Schatz stent,
      whereas there is little experience with this strategy in the Wallstent. By using
      this approach with quantitative coronary angiographic guidance, 20 Wallstents and
      20 Palmaz-Schatz stents were implanted in 34 patients and consecutively examined
      by conventional two-dimensional (2D) intracoronary ultrasound (ICUS) and three
      dimensional (3D) ICUS on the basis of the application of a pattern recognition
      algorithm. Ultrasound criteria of adequate stent expansion were defined as a
      complete apposition of the stent to the vessel wall, a stent symmetry index (SSI
      = minimum/maximum lumen diameter) > or = O.7, and a stent-reference lumen area
      ratio (SRR = Minimum intrastent lumen area/Average of proximal and distal
      reference lumen area) > or = O.8. In all cases a smooth angiographic lumen and a
      negative diameter stenosis, on the basis of a distal reference, was achieved. For
      the Wallstents ICUS showed a higher SSI (2D, 0.95 +/- 0.04 vs 0.85 +/- 0.09; p <
      0.001; 3D, 0.90 +/- 0.09 vs 0.82 +/- 0.11, p < 0.05) and a lower SRR (2D, 0.66 +/
      0.12 vs 0.81 +/- 0.13, p < 0.005; 3D, 0.63 +/- 0.14 vs 0.74 +/- 0.15, p < 0.05)
      than for the Palmaz-Schatz stents. Ninety percent of failure in meeting these
      criteria resulted from a low SRR. The incidence of incomplete stent apposition
      (one in both stents) or SSI <0.7 was low and generally associated with an SRR
      <0.8. The Wallstents met the ICUS criteria less often (2D, 2(1O%) vs 10(50%), p <
      0.01; 3D, 3(15%) vs 9(45%), p < 0.05), were significantly longer (35.1 +/- 7.7 mm
      and 14.3 +/- 3.3 mm, p < 0.0001), and generally demonstrated a larger vessel
      tapering, measured as proximal minus distal ICUS reference lumen area (1.33 +/-
      2.91 mm2 vs 0.44 +/- 1.97 mm(2), not significant). Wallstents meeting the ICUS
      criteria, however, showed less vessel tapering (0.18 +/- 1.64 mm(2)). Thus
      optimized stent expansion was followed by excellent angiographic results for both
      Palmaz-Schatz and Wallstent. Although angiographic results and visual assessment
      of the ICUS examination suggested a good outcome, few Wallstents met the ICUS
      criteria in contrast to the Palmaz-Schatz stents. The low value of the SRR in the
      Wallstents is likely to be caused by vessel tapering, suggesting that this
      criterion may be unsuitable in assessing the adequacy of the expansion of
      relatively long stents such as the Wallstent.

PMID- 8644585
TI  - Myocardial perfusion abnormalities during low-dose dobutamine after coronary
      reperfusion can be demonstrated with intravenous perfluorocarbon-exposed
      sonicated dextrose albumin ultrasound contrast.
AB  - We measured background-subtracted peak myocardial videointensity (PMVI) in the
      left anterior descending and left circumflex perfusion zones in open-chest dogs
      after intravenous injection of perfluorocarbon-exposed sonicated dextrose albumin
      ultrasound contrast (PESDA) after reperfusion of a coronary occlusion. These
      measurements were repeated during low-dose dobutamine (LDD). The ratio of PMVI in
      the reperfused zone (RZ) compared with the adjacent normal zone (NZ) was measured
      at baseline and during LDD. Dogs with a >50% diameter residual stenosis were
      group I (n = 10), and those with <50% residual stenosis were group II (n = 13).
      Wall-thickening (WT) responses to LDD were not different between groups. Although
      the PMVI ratio (PMVI(RZ)/PMVI(NZ)) was the same in both groups at baseline, it
      decreased by >0.1 during LDD in 8 of 10 in group I compared with only 3 of 13 in
      group II dogs (p = 0.01). PMVI in the RZ increased by > or = 1.5 U in 12 of 13
      group II dogs during LDD, but only in 3 of 10 group I dogs. Therefore,
      intravenous PESDA can be combined with WT responses to define both myocardial
      function and flow after reperfusion.

PMID- 8644584
TI  - Randomized comparison of flexible versus nonflexible femoral sheaths on patient
      comfort after angioplasty.
AB  - Patients who undergo percutaneous transluminal coronary angioplasty (PTCA) by the
      femoral approach are usually required to lie flat in bed for 6 to 24 hours, which
      may result in significant discomfort. This study was performed to evaluate the
      safety and benefit of a flexible sheath that enables patients to sit at a 60
      degree angle while the sheath is in place in the femoral artery. Sixty patients
      were randomly assigned to receive either flexible or nonflexible sheaths before
      PTCA. Patients with flexible sheaths were allowed to sit at an angle of 60
      degrees after the procedure. Heparin management was the same in both groups.
      Frequency of calls to nurses for back pain was recorded for both groups. For
      analgesia, nalbuphine was administered in 2-mg increments. All sheaths were
      removed the day after the procedure. Femoral ultrasound was used to detect groin
      complications (hematoma, pseudoaneurysm, or arteriovenous fistula) and was
      performed in all patients. Baseline characteristics were similar in both groups.
      There were no differences in ease of sheath insertion or guide catheter movement
      through the sheaths. The arterial pressure waveform was not dampened in any of
      the flexible sheath patients while in the sitting position. Patients with
      flexible sheaths had fewer calls for back pain and required less nalbuphine than
      patients with nonflexible sheaths. Groin complications were similar in both
      groups. In conclusion, by allowing patients to sit up to an angle of 60 degrees,
      flexible sheaths have a beneficial effect in reducing back pain and the need for
      analgesics after PTCA.

PMID- 8644586
TI  - Low-dose dobutamine echocardiography and rest-redistribution thallium-201
      tomography in the assessment of spontaneous recovery of left ventricular function
      after recent myocardial infarction.
AB  - Spontaneous improvement of contraction and perfusion occurs after acute
      myocardial infarction. The relative merit of low-dose dobutamine stress
      echocardiography (LDDE) and rest-redistribution thallium scintigraphy (RR TI) in
      this setting has not been evaluated. We studied 30 patients at 7 +/- 3 days after
      acute myocardial infarction with LDDE (5 to 10 micrograms/kg/min) and RR TI
      single photon emission computed tomography. Viability was defined as improvement
      of wall thickening at LDDE in the presence of redistribution or a defect with
      uptake > or = 50% of peak activity at RR TI. Baseline echocardiography and RR TI
      were repeated after 3 months. In 112 dyssynergic segments, viability was detected
      in 60 (54%) by RR TI and in 39 (35%) by LDDE (p < 0.005). Spontaneous improvement
      of function was detected in 35 (31 %) segments. In the same regions, thallium
      uptake increased significantly. The sensitivity, specificity, and accuracy of
      LDDE for predicting late improvement of wall motion were 77%, 84%, and 82%,
      respectively. Those of RR TI were 77%, 57%, and 63%, respectively. Specificity
      and accuracy of LDDE were higher than RR TI (p < 0.005). We conclude that a
      myocardial viability pattern after acute myocardial infarction is more frequently
      detected by RR TI than by LDDE. Both techniques are equally sensitive, but LDDE
      is a more specific predictor of spontaneous recovery of regional left ventricular
      function.

PMID- 8644587
TI  - Defining the appropriate threshold of creatine kinase elevation after
      percutaneous coronary interventions.
AB  - The threshold of creatine kinase elevation after coronary interventions has been
      set at levels ranging in different studies from 2 to > 5 times the laboratory's
      upper limit of normal. This high variability is caused by the absence of any
      systematic evaluation of the prognostic implications of cardiac-enzyme elevation
      in this setting. This study was undertaken to evaluate the clinical, morphologic,
      and procedural correlates, and the long-term follow-up of two commonly used
      thresholds of creatine kinase (CK) elevation after successful percutaneous
      coronary interventions, in an attempt to define the level of postprocedural
      cardiac enzymes that correlates with adverse clinical outcome. We examined 4664
      consecutive patients who underwent successful coronary angioplasty or directional
      atherectomy at the Cleveland Clinic. Group I (4480 patients) had CK > or = 2
      times control levels after the procedure (i.e., < or = 360 IU/L). Group II (123
      patients) had a peak level between 361 and 900 IU/L, and group III (61 patients)
      had a peak level >900 IU/L with positive myocardial isoenzymes (CK-MB > 4%).
      Elevation of cardiac enzymes was associated with distinct clinical, morphologic,
      and procedural characteristics, including coronary embolism, recent infarction,
      transient in-laboratory closure, hemodynamic instability, vein graft procedures,
      and large dissections. Clinical follow-up was available in 4644 (99.6%) patients,
      with a mean follow-up of 36 +/- 22 months. Kaplan-Meier survival analysis
      adjusted with Cox proportional hazards regression model showed that cardiac
      enzyme elevation was an important correlate of cardiac death (risk ratio, 2.19; p
      < 0.0001). The groups with elevated cardiac enzymes had a higher incidence of
      cardiac death compared with group I (p < 0.0001). There was also a trend toward
      more cardiac hospitalizations in the same groups (p = 0.15). The incidence of
      cardiac death and cardiac hospitalization on follow-up was not different between
      groups II and III, This study shows that CK elevations between 2 and 5 times
      control values after successful coronary interventions are associated with an
      adverse long-term outcome. The findings suggest that an appropriate CK threshold
      that has prognostic implications would be twice the upper limit of normal.

PMID- 8644588
TI  - Rapid adaptation of myocardial calcium homeostasis to short episodes of ischemia
      in isolated rat hearts.
AB  - Short episodes of ischemia and reperfusion (ischemic preconditioning) have been
      shown to attenuate the detrimental rise in intracellular free Ca2+ ([Ca2+]i)
      caused by subsequent sustained ischemia. The purpose of this study was to
      investigate the detailed time course of [Ca2+]i during such short episodes of
      ischemia and reperfusion. [Ca2+]i was measured at a high time resolution by
      surface fluorometry and indo-1 in isolated perfused rat hearts during three
      episodes of 5 minutes of ischemia followed by 5 minutes of reperfusion. We found
      that the rise in systolic [Ca2+]i was significantly smaller during the second
      (191% +/- 67%) and third (194% +/- 75%) episodes of ischemia than during the
      first episode (289% +/- 75%, P < 0.05 vs both subsequent episodes). This
      attenuated rise in systolic [Ca2+]i was preserved during perfusion with low
      extracellular Na+ (105.5 mmol/L [Na+]o). During short episodes of ischemia and
      reperfusion, [Ca2+]i rises less during the second and third ischemic episode than
      during the first episode. Thus one transient ischemic stimulus led to a rapid
      adaptation of [Ca2+]i homeostasis to subsequent ischemic conditions. Such a rapid
      adaptation might be an important mechanism of the ischemic preconditioning
      phenomenon in protecting against ischemic injury.

PMID- 8644589
TI  - Temporal changes in regional end-diastolic wall thickness early after reperfusion
      in acute anterior myocardial infarction: relation to myocardial viability and
      vascular damage.
AB  - We investigated early temporal changes in end-diastolic wall thickness (EDWT) of
      the infarcted myocardium in 46 patients with reperfused anterior acute myocardial
      infarction in relation to myocardial viability. Two-dimensional echocardiography
      was performed on days 1 and 2 of acute myocardial infarction, and the EDWT of the
      anterior segment was measured in the short-axis view. Patients were divided into
      three groups on the basis of day 1 to day 2 ratio of EDWT: the ratio < or = 0.85
      as group A (n = 13), >0.85 but < or = 1.15 as group B (n = 23), and >1.15 as
      group C (n = 1 0). Left ventricular functional improvement was significantly
      better in group B than in groups A and C. Substantial size of "no reflow"
      phenomenon was observed only in groups A (n = 9, 69%) and C (n = 6, 60%). The
      frequency of transient ST re-elevation after reperfusion was the highest in group
      C (70%), and left ventricular expansion was observed at day 2 only in group A. We
      conclude that changes in the EDWT of the infarct segment early after reperfusion,
      either decreases or increases, are related to irreversibly damaged myocardium. A
      decrease in EDWT and concomitant ventricular expansion may be related to impaired
      myocardial perfusion. An increase in EDWT after reperfusion may be caused by
      accelerated myocardial and microvascular damage after reperfusion.

PMID- 8644590
TI  - Ventricular pacing threshold and refractoriness after defibrillation shocks in
      patients with implantable cardioverter-defibrillators.
AB  - The aim of this study was to examine the effect of ventricular fibrillation and a
      subsequent defibrillation shock on ventricular excitability and refractoriness in
      human beings. We studied 16 consecutive patients with implantable cardioverter
      defibrillators undergoing follow-up studies. The pre- and post-shock pacing
      threshold, ventricular effective refractory period, monophasic action potential
      duration, and serum catecholamine levels were measured. Compared with the
      baseline state, immediately after ventricular fibrillation, and a successful
      defibrillation shock: (1) the ventricular effective refractory period decreased
      from 251 +/- 24 ms to 222 +/- 30 ms (p < 0.01), (2) the monophasic action
      potential duration decreased from 210 +/- 16 ms to 179 +/- 23 ms (P < 0.01) at
      50% repolarization and from 274 +/- 24 ms to 240 +/- 26 ms (P< 0.01) at 90%
      repolarization, (3) the pacing threshold was not significantly altered and, (4)
      serum levels of epinephrine and norepinephrine were elevated. These results show
      that although ventricular fibrillation and subsequent defibrillation had no
      effect on the ventricular pacing threshold in human beings, it was associated
      with a decrease in post-shock monophasic action potential duration and
      ventricular effective refractory period, contrary to some previously reported
      findings.

PMID- 8644591
TI  - Factors associated with successful implantation of nonthoracotomy defibrillation
      lead systems.
AB  - Two hundred forty-three consecutive patients underwent attempted implantation of
      nonthoracotomy defibrillation lead (NTL) systems. The importance of clinical and
      lead-related factors were analyzed regarding their relation with implantation
      failure caused by an unacceptably high defibrillation threshold (DFT). Overall,
      33 (14%) of 243 patients failed NTL implantation. Patients undergoing attempted
      implantation of NTL systems with monophasic shock waveforms (monophasic group, n
      = 145) had an incidence of failed implantation of 22% (n = 32) versus an
      incidence of 1% (n = 1) among patients undergoing attempted implantation by using
      biphasic shock waveforms (biphasic group, n = 98; odds ratio, 26.9; p < 0.001).
      The incidence of success and simplicity of implantation of NTL systems was
      markedly improved in patients undergoing NTL implantation by using biphasic shock
      waveforms. Clinical factors could be used to stratify patients in the monophasic
      group for their risk of implantation failure. In the biphasic group, no clinical
      factor could be correlated with a low DFT with a fully endovascular system.

PMID- 8644592
TI  - Electrocardiographic abnormalities in patients receiving hemodialysis.
AB  - We assessed standard 12-lead and Holter electrocardiographic (ECG) abnormalities
      in maintenance hemodialysis (HD) patients. Of 221 outpatients receiving HD, 143
      (65%) had ECG abnormalities. Rates were higher in male, elderly, hypertensive,
      and diabetic patients than in female, younger, normotensive, and nondiabetic
      patients. The prevalence of ECG changes correlated inversely with HD duration.
      Serial ECGs were compared in 87 patients whose average HD duration was 7.5 +/-
      2.5 years. Thirty-four patients (39%) showed normal ECGs throughout, 27 (31%)
      relatively stable abnormalities, 22 (25%) worsening, and 4 (5%) reversion to
      normal. Age, hypertension, and diabetes are factors related to abnormal ECG
      findings. Among the 142 Holter recordings from 72 patients, 70 (97%) were
      basically in sinus rhythm, and 2 (3%) were in atrial fibrillation. The average
      frequency of supraventricular premature contractions (SVPCs) was 1597 +/- 9725
      per 24 hours, and that of ventricular premature contractions (VPCs), 556 +/-
      1415. VPCs were multifocal in 9%, in runs in 25%, and early in 1%. In 29 (40%) of
      recordings, VPCs appeared mainly during and for several hours after HD. ST-T
      changes were seen in 43 (60%). In 11, ST depression occurred during and a few
      hours after HD. Patients receiving HD showed diverse ECG abnormalities. Holter
      ECGs revealed a high incidence of arrhythmias and ST-T changes, which frequently
      appeared in relation to HD timing.

PMID- 8644593
TI  - Pulmonary embolism and deep venous thrombosis during pregnancy or oral
      contraceptive use: prevalence of factor V Leiden.
AB  - Activated protein C resistance caused by factor V Leiden mutation is the most
      common inherited cause of an underlying predisposition to pulmonary embolism (PE)
      and deep venous thrombosis (DVT). We studied the frequency of the factor V Leiden
      mutation in 50 women who had PE and/or DVT during or after pregnancy or during
      oral contraceptive use. Ten (20%; 95% CI 10% to 34%) of the 50 women were
      heterozygous for the mutation. First-trimester PE or DVT developed in 6 (60%; 95%
      CI, 26% to 88%) of the 10 women with the mutation compared with 3 (8%; 95% CI 2%
      to 20%) of 40 women without the mutation (p = 0.0009). These data indicate that
      the factor V Leiden mutation is an important risk factor for PE or DVT during
      pregnancy (especially the first trimester), after pregnancy, or during oral
      contraceptive use.

PMID- 8644594
TI  - Risk of catheter-related emboli in patients with atherosclerotic debris in the
      thoracic aorta.
AB  - The aim of this study was to evaluate the risk of performing cardiac
      catheterization or intraaortic balloon pump placement in patients with
      transesophageal echocardiographically detected atherosclerotic aortic debris.
      Cardiac catheterization was performed in 70 patients with atherosclerotic aortic
      debris (in 11 via the brachial approach and in 59 via the femoral approach) and
      in 71 control patients. An embolic event occurred in 10 (17%) of 59 patients with
      atherosclerotic aortic debris after femoral catheterization compared to 2 (3%) of
      71 control patients without atherosclerotic aortic debris (p = 0.01). None of the
      11 patients with atherosclerotic aortic debris who underwent brachial
      catheterization had an embolic event. An intraaortic balloon pump was placed in
      10 patients with atherosclerotic aortic debris and in 12 control patients. An
      embolic event related to placement of the intraaortic balloon pump occurred in 5
      (50%) of 10 patients with atherosclerotic aortic debris; no control patient had
      an embolic event (p = 0.02). Patients with mobile atherosclerotic aortic debris
      were at the highest risk for catheter-related embolism. The strongest clinical
      predictors of atherosclerotic aortic debris were advanced age and peripheral
      vascular disease. Transesophageal echocardiographic recognition of
      atherosclerotic aortic debris identifies patients at high risk of stroke or
      peripheral embolism after cardiac catheterization or intraaortic balloon pump
      placement. If the aortic debris is mobile, the risk is particularly high. When
      atherosclerotic aortic debris is detected, especially if the debris is mobile,
      substituting brachial for femoral catheterization and avoiding placement of an
      intraaortic balloon pump may reduce the risk of embolism.

PMID- 8644595
TI  - Follow-up of chronic thoracic aortic dissection: comparison of transesophageal
      echocardiography and magnetic resonance imaging.
AB  - Because survivors of thoracic aortic dissection require follow-up to detect
      prognostic factors such as intimal tears, persistent flow in the false lumen, and
      complications associated with grafts, we compared transesophageal
      echocardiography (TEE) with magnetic resonance imaging (MRI) prospectively in 14
      patients 1 year after their initial examination. Residual dissection was
      identified by both techniques in 11 patients. Flow and/or thrombus in the false
      lumen were detected by TEE in 10 (91 %) and 6 (55%) patients, respectively, and
      by MRI in 9 (82%) and 5 (45%), respectively (p = NS); more tears were detected by
      TEE (2.5 +/- 1.4 per patient vs 0.2 +/- 0.4; p < 0.005). Satisfactory delineation
      of a graft in the ascending aorta was noted in all 8 (100%) of the surgically
      treated patients by TEE compared with 4 (50%) by MRI (p < 0.005). The upper
      ascending aorta was visualized clearly in fewer patients by TEE than by MRI (7
      [50%] vs 13 [93%]; p < 0.05), as were the origins of the head and neck vessels
      (10 [71%] vs 13 [93%], p = NS). We conclude that TEE and MRI are both suitable
      techniques for the follow-up of patients with aortic dissection. TEE is more
      sensitive in identifying prognostic factors. MRI has a complementary role,
      particularly in visualization of the upper ascending aorta and the head and neck
      vessels.

PMID- 8644596
TI  - Aortopulmonary collateral vessels and prolonged pleural effusions after modified
      Fontan procedures.
AB  - Pleural effusions after the modified Fontan procedure are unpredictable, increase
      morbidity, and prolong hospital stay. To assess the relation between preoperative
      characteristics and postoperative pleural drainage, we performed a retrospective
      study of 71 patients who underwent Fontan procedures. Analyses revealed no
      significant relation between duration of effusion and age at Fontan, preoperative
      oxygen saturation, pulmonary artery pressure, ventricular end-diastolic pressure,
      type of Fontan, or prior cavopulmonary anastomosis. Patients with significant
      aortopulmonary collateral vessels evidenced by angiographic opacification of the
      pulmonary arteries or veins had more prolonged pleural drainage. The duration of
      the pleural drainage was significantly less in patients who had aortopulmonary
      collateral occlusion.

PMID- 8644597
TI  - Fontan palliation versus heart transplantation: a comparison of charges.
AB  - Surgical approaches to single-ventricle physiologic abnormalities have included
      Fontan palliation or transplantation. No cost expenditures have been published.
      This study compared expenditures between the Fontan procedure and heart
      transplantation. Between 1988 and 1992, records of 82 patients who underwent the
      Fontan procedure and 26 who underwent transplant were retrospectively reviewed.
      Charges for Fontan or transplant procedures were accrued from the date of
      surgical admission until discharge or patient death and included hospital,
      physician, and diagnostic laboratory charges. Additionally, the frequency and
      cost of postoperative hospital readmissions, outpatient evaluations, and
      diagnostic procedures were recorded for each patient. Estimated expenditures for
      each evaluated parameter were based on 1992 to 1993 dollar charges. The total
      expenditure (surgery plus yearly follow-up) for transplantation exceeded that for
      the Fontan procedure ($96,475 vs $29,730; p < 0.001). Although both groups had
      similar follow-up periods and mortality rates, the number of hospital
      readmissions and postoperative diagnostic tests was higher among transplant
      recipients. Within 1 postoperative year at least four high-risk patients who had
      undergone a Fontan procedure required listing for transplantation; the total
      costs of their combined procedures (approximately $80,000 + $3,000 to $5,000
      annual outpatient charges) was markedly greater than the cost of the Fontan
      procedure alone. Although the expenditure for heart transplantation far exceeds
      that for the Fontan procedure, Fontan palliation in high-risk patients is
      ultimately more costly and increases postoperative morbidity. In this subgroup,
      we recommend heart transplantation as the initial definitive procedure because it
      may increase long-term survival rates and minimize health care expenditures.

PMID- 8644598
TI  - Noninfective valvular masses: review of the literature with emphasis on imaging
      techniques and management.

PMID- 8644599
TI  - Probucol-associated tachyarrhythmic events and QT prolongation: importance of
      gender.
AB  - From published articles and adverse reactions reports filed with the FDA
      (available through the Freedom of Information Act), we analyzed occurrences of
      tachyarrhythmias and the magnitude of QTc prolongation associated with probucol
      therapy. Of 16 cases of tachyarrhythmic events reported in association with
      probucol, 15 (94%) occurred in women (p < 0.01 vs expected value of 58%).
      Tachyarrhythmias were specifically described as TdP in 11 (63%) cases, all women;
      additional potential contributory QT-prolonging factors (besides probucol) were
      not identifiable in 2 of the 11 cases. We also analyzed QTc responses in 359
      probucol-treated patients, all having baseline QTc < or = 0.44 sec1/2. At doses
      of 500 to 1000 mg/day, probucol-associated prolongation of QTc to values > or =
      0.45 sec1/2 was observed in 22% of women versus 7% of men (p < 0.001) and to
      values > or = 0.47 sec1/2 in 8% of women versus 2% of men (p < 0.03).
      Multivariate analysis identified baseline QTc (p < 0.0001) and female gender (p <
      0.03), but neither age nor dose, as significant independent predictors of QTc
      prolongation to > or = 0.45 sec1/2 with probucol. These findings have relevance
      to the clinical use of probucol, provide further evidence that women have a
      relatively greater predisposition to development of acquired long QT syndrome,
      and carry implications for the design of trials involving QT-prolonging drugs.

PMID- 8644600
TI  - Atherosclerosis: an update.
AB  - CHD remains the leading cause of death in most developed countries; therefore,
      elucidation of risk factors and associated mechanisms for atherosclerosis and
      development of CHD has been a high priority. Data from the Framingham Heart Study
      and other large-scale epidemiologic studies have identified major risk factors
      associated with CHD, demonstrating the adverse effects of increased total and LDL
      C levels and the protective effect of HDL-C. Other endogenous and exogenous risk
      factors have been identified and are discussed in this review. In addition, we
      address known mechanisms involved in the atherosclerotic process.

PMID- 8644601
TI  - Color-coded measures of myocardial velocity throughout the cardiac cycle by
      tissue Doppler imaging to quantify regional left ventricular function.
AB  - TDI is a new echocardiographic technique that calculates and displays color-coded
      myocardial velocity on-line. To determine the feasibility of endocardial velocity
      throughout the cardiac cycle as a means to quantify regional function, 20 normal
      subjects aged 30 +/- 5 years and 12 patients with heart disease aged 62 +/- 17
      years were studied with a prototype TDI system. TDI M-mode images were acquired
      by using a multicolored velocity map (display range, -30 to 30 mm/sec; temporal
      resolution, 90 Hz). Color-coded velocity data were then converted to numeric
      values off-line at 50 msec intervals. Posterior wall velocities throughout the
      cardiac cycle by TDI were closely correlated with velocity calculations from the
      first derivative of routine digitized M-mode tracings (group mean r = 0.88 +/-
      0.03, SEE = 7.0 +/- 1.1 mm/sec). Anteroseptal TDI color-coded systolic velocity
      occurred 164 +/- 84 msec from the onset of the electrocardiographic QRS compared
      with 203 +/- 33 msec in the posterior wall (P < 0.05) in normal subjects,
      consistent with normal electrical activation. Significant differences in systolic
      and diastolic posterior wall TDI velocity data were observed in patients with
      hypokinetic or akinetic segments assessed by independent routine study when
      compared with normal controls. Calculated systolic and early diastolic posterior
      wall TDI indexes correlated significantly with percentage of wall thickening. Of
      abnormal anteroseptal segments, TDI systolic time velocity integrals were
      significantly different than normal and correlated with percentage of wall
      thickening. TDI has potential to quantitatively assess regional left ventricular
      function.

PMID- 8644603
TI  - Coronary angioscopy confirms the presence of red thrombus in acute myocardial
      infarction after blunt chest trauma.

PMID- 8644602
TI  - Ventricular fibrillation after intravenous amiodarone in Wolff-Parkinson-White
      syndrome with atrial fibrillation.

PMID- 8644604
TI  - Coronary stenting for transplant coronary artery disease.

PMID- 8644605
TI  - Aortic dissection complicating coronary angioplasty in cystic medial necrosis.

PMID- 8644606
TI  - Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome
      progressing to ventricular dilation.

PMID- 8644607
TI  - Rapid identification of congenital heart disease by transmission of
      echocardiograms.

PMID- 8644608
TI  - Diagnosis and management of right atrial thrombus in heparin-induced
      thrombocytopenia and thrombosis syndrome with transesophageal echocardiography
      and thrombolytic therapy.

PMID- 8644609
TI  - Echocardiographic detection of severe prosthetic valvular cloth wear.

PMID- 8644610
TI  - Hibernating myocardium.

PMID- 8644612
TI  - Recurrent atrial fibrillation.

PMID- 8644611
TI  - Dobutamine stress echocardiography.

PMID- 8644613
TI  - Unstable angina.

PMID- 8644614
TI  - Radiation-induced cardiac disease.

PMID- 8644615
TI  - Radiation-induced cardiac disease.

PMID- 8644616
TI  - P-wave signal-averaged electrocardiography.

PMID- 8644617
TI  - Paradoxic embolism.

PMID- 8644618
TI  - Silent myocardial ischemia.

PMID- 8644619
TI  - Reperfusion in acute inferior myocardial infarction: could tailored therapy be
      based on precordial ST depression?

PMID- 8644620
TI  - Is there a role for thiamine supplementation in the management of heart failure?

PMID- 8644621
TI  - Drug therapy versus implantation of a cardiac defibrillator for the treatment of
      malignant arrhythmias in left ventricular dysfunction.

PMID- 8644622
TI  - Prevalence of coronary artery disease in obese versus lean men with angina
      pectoris and positive exercise stress test.
AB  - The present study assesses the extent of coronary artery disease in men with
      angina pectoris and definite signs of myocardial ischemia in relation to body
      mass index. Our results demonstrate that exercise-induced myocardial ischemia in
      the absence of coronary artery disease in men with angina pectoris is more (2.6
      fold) frequent in obese than in lean patients.

PMID- 8644623
TI  - Recurrence of neurocardiogenic syncope without pharmacologic interventions.
AB  - In 54 patients with positive tilt and who refused medical therapy, we observed a
      significant decrease in the frequency of syncopal spells after diagnosis and
      counseling. However, symptoms were reported at follow-up by 64.8% of the patients
      and were predicted by the frequency and total number of syncope episodes before
      upright tilt.

PMID- 8644624
TI  - Reverse use dependence of human ventricular repolarization by chronic oral
      sotalol in monophasic action potential recordings.
AB  - Reverse use dependence of action potential duration and effective refractory
      period by chronic oral sotalol was demonstrated by monophasic action potential
      recordings in the human ventricle. There were no changes of the QRS duration over
      the cycle length, indicating that sotalol had no sodium channel blocking effects.

PMID- 8644625
TI  - Lack of association between insertion/deletion polymorphism of the angiotensin
      converting enzyme gene and end-stage heart failure due to ischemic or idiopathic
      dilate cardiomyopathy in the Chinese.
AB  - Homozygosity for the deletion allele of the angiotensin-converting enzyme gene
      (DD) has been associated with a variety of cardiovascular diseases, including
      ischemic and idiopathic dilated cardiomyopathy, in Caucasians. In this study of
      104 Chinese patients with end-stage heart failure due to idiopathic dilated or
      ischemic cardiomyopathy, the DD genotype frequency was low (12% and 11%,
      respectively) and was not seen more often than in a control group of 183 subjects
      without cardiac disease (13%). Therefore, in the Chinese, the DD genotype is less
      common than in Caucasians and does not appear to be associated with the
      development of either ischemic or idiopathic dilated cardiomyopathy.

PMID- 8644626
TI  - Importance of case mix during training in interventional cardiology.
AB  - Adequate case mix is an important component of a physician's training in
      interventional cardiology. Physicians who seek competence in this area should
      have experience with patients who undergo interventional procedures for a variety
      of indications using a variety of techniques in a variety of situations. Future
      guidelines for physician training in interventional cardiology should address the
      issue of case mix.

PMID- 8644628
TI  - Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left
      Ventricular Dysfunction (SOLVD) Trials and Registry.
AB  - Diabetes is an independent predictor of morbidity and mortality in patients with
      symptomatic heart failure, patients with asymptomatic left ventricular
      dysfunction (defined as an ejection fraction of 35% or less), and in a broader
      registry population with less stringent entry criteria. Although the SOLVD Trials
      made a major clinical contribution by proving the value of enalapril, diabetes
      remains a significant predictor of outcome even after adjusting for treatment
      with enalapril.

PMID- 8644627
TI  - Results of radiofrequency catheter ablation for atrial flutter.
AB  - RF catheter ablation for symptomatic typical atrial flutter is associated with a
      high procedural success rate, but a second RF procedure may be required in up to
      one third of subjects, particularly those with right atrial enlargement. In those
      subjects with both established AF and flutter, RF ablation for atrial flutter may
      decrease the recurrence rate of AF. However, patients remain at risk for the
      development of newly documented AF, most likely secondary to the high incidence
      of underlying structural heart disease.

PMID- 8644629
TI  - High altitude-related neurocardiogenic syncope.
AB  - This report presents a well-documented link between vasodepressor syncope, a
      marked increase of LF/HF ratio response to orthostasis (sympathetic dominance),
      and the efficacy of beta blockers in preventing orthostatic symptoms and absence
      of tilt-induced syncope, with normalization of the LF/HF ratio response.

PMID- 8644630
TI  - Spasm of the gastroepiploic artery used for coronary artery bypass grafting.
AB  - The GEA, though similar to the internal mammary artery in size and flow
      characteristics, is different histologically as well as physiologically. When
      used as a free graft, the GEA is very vasospastic, which may influence its long
      term patency. When it is necessary to use the GEA as a conduit, it may be
      preferable to use it in situ rather than as a pedicle graft.

PMID- 8644631
TI  - Association of a mosaic chromosomal 22q11 deletion with hypoplastic left heart
      syndrome.
AB  - The atypical presentation of CATCH 22 raises several important concerns. First,
      in this patient, as in others, the heart defects were found in association with
      subtle facial abnormalities but with few of the other criteria normally seen in
      CATCH 22. This association alone may be sufficient to raise suspicion that an
      interstitial 22q11 deletion may be present. Second, the incidence of chromosome
      22 deletions in parents of children with a 22q11 deletion (25%) suggests that
      siblings or subsequent fetuses may also be at risk. Parents with subtle or
      unusual manifestations of CATCH 22 may be unaware of their potential carrier
      status. Finally, the recognition of chromosomal mosaicism in this patient may
      have been fortuitous, as cytogenetic studies of leukocytes from other individuals
      with a mosaic karyotype may sometimes fail to reveal a 22q11 deletion that is
      present in cardiac tissues. Molecular cytogenetic analysis of cardiac specimens
      that are removed during routine surgical procedures may be warranted in
      appropriate clinical situations.

PMID- 8644632
TI  - Segment changes detected by ambulatory electrocardiography after acute myocardial
      infarction.

PMID- 8644633
TI  - Short-coupled variant of torsades des pointes with normal QT interval and risk of
      sudden death.

PMID- 8644634
TI  - Conservative versus invasive strategy for non-Q-wave acute myocardial infarction.

PMID- 8644635
TI  - Noctural dosing of a novel delivery system of verapamil for systemic
      hypertension.

PMID- 8644636
TI  - Quantitation of shunt flow in atrial septal defects by contrast echocardiography.

PMID- 8644637
TI  - Comparison of the diagnostic potential of four echocardiographic stress tests
      shortly after acute myocardial infarction: submaximal exercise, transesophageal
      atrial pacing, dipyridamole, and dobutamine-atropine.
AB  - This study assessed and compared the diagnostic potential of submaximal exercise,
      transesophageal atrial pacing, dipyridamole, and dobutamine-atropine stress
      echocardiography tests shortly after acute myocardial infarction. In 121 study
      patients, 325 digital echocardiographic stress tests were attempted 10 to 11 days
      after acute myocardial infarction: 83 submaximal exercise tests, 121 high-dose
      dipyridamole echocardiography tests (DET), 69 transesophageal atrial pacing tests
      (< 150 beats/min), and 52 dobutamine tests, starting at 10 microgram/kg per
      minute, increasing stepwise to 40 microgram kg/min, and coadministering atropine
      in 12 patients (dobutamine-atropine stress echocardiography [DASE]). Results were
      correlated to a coronary artery diameter stenosis > or = 50% as determined by
      quantitative angiography. Feasibility to perform submaximal exercise
      echocardiography, atrial pacing echocardiography, DET, and DASE was 89%, 52%,
      98%, and 88%, respectively. Atrial pacing was not tolerated by 18 patients and
      refused by 6 (9%). Severe but not life-threatening side effects were hypotension
      in DET (2%) and tachyarrhythmias in DASE (6%). Test positivity in multivessel
      disease with submaximal exercise, DET, and DASE was 55%, 93%, and 90%,
      respectively, and in 1-vessel disease 47%, 65%, 71%, and for atrial pacing, 82%,
      respectively. We conclude that submaximal exercise has limited sensitivity and
      atrial pacing limited feasibility. The pharmacologic stressors provide a useful,
      safe diagnostic approach: DET with slightly lower sensitivity in 1-vessel disease
      and DASE with insignificantly less feasibility.

PMID- 8644638
TI  - Effect of delayed percutaneous transluminal coronary angioplasty of occluded
      coronary arteries after acute myocardial infarction.
AB  - Whether angioplasty of occluded vessels after myocardial infarction may have
      beneficial effects on left ventricular function remains unknown. Patients with a
      first myocardial infarction and thrombolytic therapy who had an occluded infarct
      related vessel at delayed coronary angiography were referred systematically for
      an elective coronary angioplasty performed between 3 and 4 weeks after the
      myocardial infarction. All patients underwent stress-redistribution-reinjection
      thallium-201 single-photon emission computed tomography for myocardial viability
      assessment. Prior angioplasty, a quantitative evaluation of global and regional
      left ventricular function, was performed. The study group consisted of 38
      patients (aged 57 +/- 10 years); 18 had anterior wall infarctions and 20 inferior
      wall infarctions, but before angioplasty 3 had a patent artery and were excluded.
      Angioplasty was successful in 30 patients. At follow-up 13 patients (43%) had an
      occluded coronary artery. In contrast with patients with an occluded coronary
      artery at follow-up, those with a patent coronary artery had no left ventricular
      enlargement and had an improvement in both left ventricular ejection fraction
      (from 48 +/- 9% to 52 +/- 9.8%, p = 0.002) and regional wall motion index (delta
      = +0.95 SD, p <0.01). In patients with a patent vessel at follow-up, there was a
      positive correlation between the number of myocardial viable segments and
      improvement of the infarct zone wall motion (r = 0.52; p = 0.035), and the number
      of necrotic segments at baseline was positively correlated to the 4-month changes
      in end-diastolic volume indexes (r = 0.6; p = 0.04). Thus, elective
      revascularization of occluded coronary arteries with viable myocardium after
      myocardial infarction improves left ventricular function and lessens remodeling
      if the artery remains patent during follow-up.

PMID- 8644639
TI  - Usefulness of redistribution images in viability detection after acute myocardial
      infarction.
AB  - We undertook this study to evaluate the importance of redistribution images in
      thallium 201 single-photon emission computed tomography (Tl-201 SPECT) assessment
      of myocardial viability after acute myocardial infarction. Stress-redistribution
      reinjection Tl-201 SPECT was performed in 55 consecutive patients with recent
      (within 1 month) acute myocardial infarction. The myocardium was divided into 16
      segments and activity assessed visually with a score from 0 to 3 on stress
      redistribution and stress-reinjection images. A defect was considered moderate if
      the stress score was 2 and severe if the stress score was 0 or 1. All moderate
      defects were considered viable, regardless of score on redistribution or
      reinjection images. Severe defects were considered viable if they were reversible
      (improvement of 1 score) on redistribution or reinjection images. Stress
      redistribution and stress-reinjection images were visually analyzed and compared
      in terms of viability classification. On visual analysis, 461 segments (52%) were
      abnormal. One hundred eleven stress defects were moderate; of these, 28 were
      reversible on reinjection images only and 15 on redistribution images only.
      However, all of these segments were viable, regardless of the analysis chosen. Of
      350 severe stress defects, 48 were reversible on reinjection and irreversible on
      redistribution images, and 4 were reversible on redistribution and irreversible
      on reinjection images. Therefore, in viability assessment, 48 segments were
      misclassified with stress-redistribution analysis, whereas only 4 segments were
      misclassified using stress-reinjection analysis. Although the usefulness of Tl
      201 reinjection imaging is confirmed, redistribution images seem to be of little
      interest in post-myocardial infarction viability assessment.

PMID- 8644640
TI  - Beat-to-beat QRS amplitude variability after acute myocardial infarction and
      coronary artery bypass grafting.
AB  - Ischemic myocardial injury has been demonstrated to be associated with increased
      beat-to-beat electrical variability of the depolarization phase. This can be
      quantified by electrocardiographic (ECG) signal variance analysis, a technique
      that has proven its diagnostic value in the detection of coronary artery disease
      (CAD). This study evaluates QRS amplitude variability during a 6-month follow-up
      period in 73 patients with acute myocardial infarction (AMI) and in 56 patients
      subjected to coronary artery bypass grafting (CABG). The beat-to-beat QRS
      amplitude variability was quantified with variance electrocardiography. The
      equipment allows computerized time domain analysis of high-fidelity ECG signals
      from 24 leads, and the detected electrical heterogeneity is then expressed as a
      nondimensional index ranging from 0 to 150, with values >90 being indicative of
      ischemic myocardial involvement. One week after AMI 55% of the patients presented
      with an abnormal QRS variability index >90. A significant (p <0.01) increase in
      the index values occurred during the follow-up period, but only in the patients
      with an initial index <70. In the CABG group 44% of the patients had a
      preoperative QRS variability index >90. The values increased (p <0.05) in all
      patients after surgery; the increase was transient in patients with an initial
      index <70 (p <0.01). The results demonstrate that the myocardial injury in
      patients with CAD is often associated with increased electrical variability of
      myocardial depolarization. The QRS amplitude variability index can be used as a
      marker of such an injury, and analysis of its changes in the course of ischemic
      cardiac events may provide new insights into the dynamics of ischemic heart
      disease and the myocardial healing process.

PMID- 8644641
TI  - Heart period variability in patients with variant angina.
AB  - To clarify how cardiac autonomic control is affected in variant angina, we
      analyzed heart period variability in 35 patients with variant angina and in 19
      control subjects. Patients with variant angina were divided into 1-vessel (group
      S, n = 17) and multivessel spasm groups (group M, n = 18) according to the
      site(s) of ST elevation on the electrocardiogram during attacks. The 24-hour
      Holter electrocardiogram recorded 6 +/- 3 days after the treatment with calcium
      antagonist was analyzed to avoid the possible influence of spontaneous attacks.
      In 5 group M patients, the electrocardiogram recorded 1 month after the treatment
      was also analyzed. There was no difference in the number of spontaneous attacks
      between groups S and M. The standard deviation of all normal RR intervals (SDNN)
      and the percentage of differences between adjacent normal RR intervals >50
      (pNN50) in variant angina were slightly but significantly lower than those in
      controls. There were no differences in other indexes between variant angina and
      controls. When the data were analyzed separately in groups S and M, averaged RR
      intervals (MN), SDNN, pNN50, high-frequency power, and low-frequency power in
      group M were significantly lower than those in group S and controls, and the
      ratio of low- to high-frequency power in group M was significantly higher than
      that in group S and controls. There was no difference in any index between group
      S and controls. All abnormal indexes in group M recovered to levels similar to
      those in controls 1 month after the treatment. In conclusion, depressed cardiac
      vagal control and sympathetic-dominant sympathovagal interaction were present in
      patients with variant angina, especially in those with multivessel spasm.

PMID- 8644642
TI  - Short-term hemodynamic, anti-ischemic, and antianginal effects of pirsidomine, a
      new sydnonimine.
AB  - Pirsidomine is a new sydnonimine compound in clinical development. As a prodrug,
      it is transformed into a nitric oxide-releasing metabolite in vivo. In animal
      tests there were no signs of tolerance with repeated administration. The short
      term effects of 10, 20, and 40 mg of the drug on pulmonary hemodynamics and
      ischemic parameters were examined at rest and during exercise in a double-blind,
      randomized, placebo-controlled study. The study included 48 patients with
      documented coronary artery disease and exercise-induced ST-segment depression.
      Compared with the baseline test, there was a reduction of diastolic pulmonary
      artery pressure with pirsidomine at rest (placebo: -0.4 +/- 0.5 mm Hg; 10 mg: -
      1.5 +/- 2.4 mm Hg; 20 mg: - 1.4 +/- 1.1 mm Hg; 40 mg: - 2.3 +/- 1.3 mm Hg [p <
      0.05 ]) and at the highest comparable workload (placebo: -2.8 +/- 1.9 mm Hg; 10
      mg: -7.3 +/- 6.8 mm Hg; 20 mg: -8.4 +/- 7.9 mm Hg [p <0.05]; 40 mg: -13.8 +/- 7.1
      mm Hg [p <0.05]). ST-segment depression decreased at the highest comparable
      workload (placebo: -0.33 +/- 0.49 mm; 10 mg: -1.33 +/- 1.37 mm [p <0.05]; 20 mg: 
      1.33 +/- 0.83 mm [p <0.05]; 40 mg: -1.96 +/- 0.86 mm [p <0.05]) and total
      exercise time increased (placebo: 15 +/- 48 s; 10 mg: 98 +/- 126 s; 20 mg: 165 +/
      251 s [p <0.05]; 40 mg: 155 +/- 174 s [p <0.05]). Of 40 patients who complained
      of angina pectoris symptoms in the baseline test, 15 became free of angina
      pectoris with pirsidomine. Compared with placebo, blood pressure, heart rate
      during exercise, and cardiac output during exercise showed no significant change.
      Plasma concentration response relations of the metabolite revealed concentrations
      that caused a half-maximum effect of 6 ng/ml, 13 ng/ml, 20 ng/ml, and 28 ng/ml in
      reduction of ST-segment depression, reduction of diastolic pulmonary artery
      pressure, relief of angina pectoris symptoms, and an increase in exercise
      duration, respectively. Thus, pirsidomine is an effective anti-ischemic and
      antianginal agent. A significant preload reduction was obtained with plasma
      metabolite concentrations lower than those necessary to achieve a satisfactory
      antianginal effect.

PMID- 8644643
TI  - Transient autonomic dysfunction precedes ST-segment depression in patients with
      syndrome X.
AB  - Increased sympathetic drive has been suggested to play a role in the pathogenesis
      of syndrome X (angina pectoris, positive exercise testing, and angiographically
      normal coronary arteries). Heart rate variability (HRV) studies have shown that
      patients with syndrome X have an imbalance in autonomic nervous system activity
      (sympathetic predominance). However, it is not known if transient ST-segment
      depression which occurs in syndrome X during daily activities is related to this
      autonomic nervous system dysfunction. This study investigates the relation
      between the response of the autonomic nervous system, as assessed by HRV
      analysis, and the occurrence of transient ST-segment depression during 24-hour
      ambulatory electrocardiographic monitoring in 23 patients (4 men and 19 women,
      mean age 55 +/- 6 years) with syndrome X. The frequency-domain variables of HRV
      low-frequency (0.04 to 0.15 Hz) and high-frequency (0.15 to 0.40 Hz) power were
      measured at 6-minute intervals during the 30 minutes preceding the onset of
      transient ST-segment depression. Fourteen patients (61%) had > or = 1 episode of
      ST-segment depression in the 24 hours, whereas the remaining 9 patients (39%) had
      no significant ST-segment change. HRV measures differed according to whether or
      not ST-segment depression was associated with increased heart rate. Episodes of
      ST-segment depression associated with increased heart rate were preceded by a
      reduction of high-frequency power and an increase in the low-frequency--high
      frequency ratio, whereas episodes of ST-segment depression not associated with
      increased heart rate showed no significant HRV changes. Low-frequency power
      remained unchanged irrespective of heart rate. Thus, in patients with syndrome X,
      a sympathovagal imbalance (sympathetic predominance due to vagal tone withdrawal)
      precedes episodes of ST-segment depression that are associated with an increased
      heart rate.

PMID- 8644644
TI  - Correlation of poststenotic hyperemic coronary flow velocity and pressure with
      abnormal stress myocardial perfusion imaging in coronary artery disease.
AB  - The functional significance of coronary stenoses is frequently determined by
      adjunctive noninvasive myocardial perfusion imaging. Poststenotic coronary flow
      velocity and pressure can be measured directly during routine cardiac
      catheterization. The aim of this study was to correlate poststenotic (distal)
      flow velocity and pressure with stress perfusion imaging in patients.
      Quantitative angiography, basal and hyperemic transstenotic coronary flow
      velocities, and pressure gradients were measured in 50 patients within 1 week of
      exercise (n = 29) or of pharmacologic (n = 21) stress perfusion imaging. Twenty
      two of 25 patients (88%) with reversible perfusion abnormalities had diminished
      distal coronary flow velocity reserves (CFVR) of < or = 2.0 x baseline, whereas
      22 of 25 (88%) with normal perfusion imaging studies had a normal distal CFVR of
      > 2.0 (p = 0.000 1). Thirteen of 25 patients (52%) with reversible perfusion
      abnormalities had transstenotic gradients > or = 20 mm Hg, whereas 20 of 25 (80%)
      with normal perfusion studies had gradients <20 mm Hg (p = 0.01). Quantitative
      angiography did not differentiate patients with normal versus abnormal myocardial
      perfusion imaging. Distal CFVR was correlated more significantly with myocardial
      perfusion imaging results (kappa = 0.76) than with pressure gradients (kappa =
      0.32). Exercise and pharmacologic stress myocardial perfusion imaging
      abnormalities reflect diminished post-stenotic coronary flow to a greater degree
      than transstenotic pressure gradients.

PMID- 8644645
TI  - Relation between contractile response of akinetic segments during dobutamine
      stress echocardiography and myocardial ischemia assessed by simultaneous thallium
      201 single-photon emission computed tomography.
AB  - There are no standard criteria for the diagnosis of myocardial ischemia in
      akinetic segments during dobutamine stress echocardiography (DSE). The aim of the
      study was to assess the relation between different responses of akinetic segments
      during DSE and ischemia assessed by thallium-201 single-photon emission computed
      tomography (SPECT). Dobutamine-atropine stress echocardiography with simultaneous
      stress-reinjection thallium-201 SPECT was performed in 67 patients with old
      myocardial infarction significant and coronary artery stenosis. Fourteen
      myocardial segments were matched for both DSE and SPECT. Ischemia on SPECT was
      defined as reversible thallium defects. In 257 akinetic segments, 4 patterns
      during DSE were identified: (1) biphasic response in 41 segments (16%), defined
      as improvement at low dose (5 to 10 microgram/kg/min) followed by worsening at
      high dose; (2) persistent akinesia in 155 segments (60%); (3) akinesia becoming
      dyskinesia in 39 segments (15%); and (4) sustained improvement in 22 segments
      (9%). Reversible thallium defects were detected in 21 segments (51%) in group 1,
      in 20 segments (13%) in group 2, none in group 3, and in 2 segments in group 4
      (9%). The prevalence of reversible defects in biphasic segments was higher
      compared with other patterns (p <0.00001 vs groups 2 and 3, p <0.005 vs group 4).
      The ischemic perfusion defect score was significantly higher in group 1 than
      group 2. The positive predictive value of biphasic response for reversible
      thallium defects was similar to that of stress-induced dyssynergia in normal
      segments at rest (51% vs 58%). It is concluded that of the various responses of
      akinetic segments to dobutamine infusion, the biphasic response is associated
      with the highest prevalence and greatest severity of ischemic on thallium SPECT.
      Observation of contractile response at both low- and high-dose DSE is a valuable
      approach for the diagnosis of myocardial ischemia in akinetic segments.

PMID- 8644646
TI  - Comparative efficacy of intravenous ibutilide versus procainamide for enhancing
      termination of atrial flutter by atrial overdrive pacing.
AB  - This study compares the influence of intravenous ibutilide, a class III
      antiarrhythmic agent, with procainamide, a class IA antiarrhythmic agent, and
      with placebo on its ability to terminate atrial flutter using rapid atrial
      pacing. Fifty-nine episodes of atrial flutter in 54 patients who failed to
      terminate with an intravenous infusion of ibutilide, procainamide, or placebo
      alone underwent attempts at pacing termination using a standard protocol of burst
      atrial overdrive pacing. Atrial flutter cycle length and atrial monophasic action
      potential duration recorded from the right atrium during atrial flutter were
      measured at baseline and following infusion of ibutilide, procainamide, or
      placebo. Both ibutilide and procainamide significantly enhanced (p <0.001) pacing
      induced termination of atrial flutter compared with placebo. Pacing converted 2
      of 11 patients (18%) who received placebo, 13 of 15 patients (87%) who received
      ibutilide, and 29 of 33 patients (88%) who received procainamide to sinus rhythm.
      Ibutilide and procainamide compared with placebo markedly reduced (p <0.001) the
      incidence of pacing-induced atrial fibrillation. The atrial flutter cycle length
      was prolonged significantly less (p <0.001), and the atrial monophasic action
      potential duration was increased significantly more (p <0.001) by ibutilide than
      by procainamide. Although the electrophysiologic changes induced by these
      antiarrhythmic agents contributed to facilitating pacing-induced termination,
      neither tachycardia cycle length nor action potential duration were useful
      predictors of the ability of pacing to terminate atrial flutter. In conclusion,
      despite differing electrophysiologic effects, the use of intravenous ibutilide or
      procainamide enhances the termination of atrial flutter by atrial overdrive
      pacing.

PMID- 8644647
TI  - Spectrum of electrophysiologic and electropharmacologic characteristics of
      verapamil-sensitive ventricular tachycardia in patients without structural heart
      disease.
AB  - Verapamil-sensitive ventricular tachycardia (VT) is a well-recognized clinical
      entity that some authorities believe may result from triggered activity. Despite
      its uniform response to verapamil, however, there is evidence that this uncommon
      form of VT may not be as homogeneous as first believed. Standard intracardiac
      electrophysiologic techniques were used to study verapamil-sensitive VT in 32
      patients (aged 38 years +/- 20 years) without evidence of structural heart
      disease. More than half of these patients (69%) exhibited VT with a right bundle
      branch block-type QRS pattern, with the remainder (31%) displaying VT with a left
      bundle branch block pattern. In 31% of the patients the VT could be induced by
      fixed-cycle length atrial pacing, whereas in 59% of patients fixed-cycle length
      ventricular pacing was necessary. A critical range of cycle lengths for VT
      induction was required in 66% of the patients. Ventricular tachycardia was
      initiated with single atrial premature extrastimuli in 16% of patients, single
      ventricular extrastimuli in 50% of patients, and double ventricular premature
      extrastimuli in 9% of patients. Ventricular tachycardia displaying cycle-length
      alternans was observed in 28% of patients. In only 19% of patients was it
      possible to entrain VT during pacing from the right ventricular apex.
      Isoproterenol infusion was required for tachycardia induction in 50% of patients,
      44% of whom had VT with a left bundle branch block QRS pattern, with the
      remaining 56% exhibiting VT with a right bundle branch block pattern. Beta
      adrenergic blockers suppressed 53% of verapamil-sensitive VT in patients tested,
      whereas adenosine terminated VT in 50% of patients, with 81% of these patients
      exhibiting either a left bundle branch block QRS pattern or isoproterenol
      dependence. Ventricular tachycardia exhibiting a left bundle branch block pattern
      was more likely to be isoproterenol dependent (p <0.05) and adenosine sensitive
      (p <0.001). However, verapamil-sensitive, catecholamine-dependent VT was no more
      likely to be adenosine sensitive than the catecholamine-independent form of the
      arrhythmia (p >0.5). Verapamil-sensitive VT exhibits properties expected of both
      a reentrant and triggered arrhythmia, and it is inconsistently dependent on both
      exogenous catecholamines for induction and intravenous adenosine for termination.
      Verapamil-sensitive VT encompasses a heterogeneous group of tachycardias that may
      result from multiple cellular electrophysiologic mechanisms.

PMID- 8644648
TI  - Prediction of the left ventricular mass from the electrocardiogram in systemic
      hypertension.
AB  - Although echocardiography provides a reliable method to determine left
      ventricular (LV) mass, it may not be available in all settings. Numerous
      electrocardiographic (ECG) criteria for the detection of LV hypertrophy have been
      developed, but few attempts have been made to predict the LV mass itself from the
      ECG. In a community-based survey program in the general population, 277 subjects
      were identified with untreated diastolic hypertension (diastolic blood pressure
      95 to 115 mm Hg, 3 occasions) or isolated systolic hypertension (diastolic blood
      pressure <95 mm Hg and systolic blood pressure 160 to 220 mm Hg, 3 occasions).
      All subjects underwent ECG and echocardiography on the same day. A multiple
      linear regression analysis was performed using a random training sample of the
      data set (n = 185). The independent variables included both ECG and non-ECG
      variables. The resulting model was used to predict the LV mass in the remainder
      of the data set, the validation sample (n = 92). Using sex, age, body surface
      area, the S-voltage in V1 and V4, and the duration of the terminal P in V1 as
      independent variables, the model explained 45% of the variance (r = 0.67) in the
      training sample and 42% (r = 0.65) in the validation sample. This result exceeded
      that of 2 existing ECG models for LV mass (r = 0.40 and 0.41). The correlations
      between LV mass and combinations of ECG variables used for the detection of LV
      hypertrophy, such as the Sokolow-Lyon Voltage (r = 0.03) and the Cornell Voltage
      (r = 0.31), were comparatively low. In settings where echocardiography is not
      available or is too expensive and time-consuming, prediction of the LV mass from
      the ECG may offer a valuable alternative.

PMID- 8644649
TI  - Mitral annular descent velocity by tissue Doppler echocardiography as an index of
      global left ventricular function.
AB  - Mitral annular descent has been described as an index of left ventricular (LV)
      systolic function, which is independent of endocardial definition.
      Echocardiographic tissue Doppler imaging is a new technique that calculates and
      displays color-coded cardiac tissue velocities on-line. To evaluate mitral
      annular descent velocity as a rapid index of global LV function, we performed
      tissue Doppler imaging studies in 55 patients, aged 56 +/-15 years, within 3
      hours of radionuclide ventriculographic ejection fraction. Tissue Doppler M-mode
      studies were obtained from each of 6 mitral annular sites, as follows:
      inferoseptal and lateral from apical 4-chamber views, anterior and inferior from
      apical 2-chamber views, and anteroseptal and posterior from apical long-axis
      views. Only 1 patient with severe mitral annular calcification was excluded. The
      group mean 6-site average peak mitral annular descent velocity was 5.5 +/- 1.9
      cm/s (range 2.4 to 10.5), and the group mean ejection fraction was 49 +/- 18%
      (range 17 to 80%). The 6-site average peak annular descent velocity correlated
      linearly with LV ejection fraction (r = 0.86, SEE = 1.02 cm/s): LV ejection
      fraction = 8.2 (average peak mitral annular descent velocity) + 3%. The 6-site
      peak mitral annular descent velocity average >5.4 cm/s was 88% sensitive and 97%
      specific for ejection fraction >50%. The peak mitral annular descent velocity
      from the apical 4-chamber view (average from inferoseptal and lateral sites)
      correlated most closely with the LV ejection fraction (r = 0.85) as an individual
      view. Peak mitral annular descent velocity by tissue Doppler imaging has the
      potential to estimate rapidly the global LV function.

PMID- 8644650
TI  - Mapping and radiofrequency ablation of intraatrial reentrant tachycardia after
      the Senning or Mustard procedure for transposition ofthe great arteries.
AB  - The Senning and Mustard procedures are often associated with the development of
      atrial tachyarrhythmias, which may be a cause of sudden death. We hypothesized
      that atrial surgery creates barriers to impulse propagation, establishing
      potential routes for atrial reentry, and that mapping combined with knowledge of
      the surgical anatomy could identify zones that are critical to the tachycardia to
      be targeted for radiofrequency catheter ablation. Patients underwent mapping to
      identify early sites of atrial activation that were related to anatomic or
      surgically created obstacles, with confirmation by pacing to demonstrate
      concealed entrainment. Radiofrequency lesions were placed to connect these
      obstacles, while observing for tachycardia termination. Thirteen tachycardias
      were attempted in 10 patients, 10 successfully. Three patients had 2 distinct
      tachycardias. Successful sites were in right atrial tissue, although in many, a
      retrograde approach to the pulmonary venous atrium was necessary. Ablation of the
      clinically documented tachycardia was successful in 9 of 10 patients. The most
      common successful site was the region of the coronary sinus mouth, approached
      antegrade or retrograde. Ablation of intraatrial reentrant tachycardias after the
      Senning or Mustard procedure is feasible using concealed entrainment mapping
      techniques, but requires a detailed knowledge of the individual surgical anatomy
      and the ability to approach the pulmonary venous atrium. Radiofrequency ablation
      offers significant advantages over other management modalities in this patient
      group.

PMID- 8644651
TI  - Causes of sudden unexpected cardiac death in the first two decades of life.
AB  - Sudden, unexpected cardiac death in the age group 1 to 21 years usually is due to
      myocarditis, hypertrophic cardiomyopathy, aortic valvar stenosis, and coronary
      arterial abnormalities. The hearts of 70 patients <21 years of age who died
      suddenly were reviewed. Twenty patients were <1 year of age and 50 were 1 to 21
      years old. The cardiac findings were compared with those in 68 age-matched
      controls with known cardiac disease who did not die suddenly. Significant cardiac
      abnormalities were present in 13 (65%) of the 20 infants; 10 (50%) had anomalies
      of the aortic origin of the coronary arteries. Among the 50 older patients,
      cardiac abnormalities were found in 40 (80%), among whom coronary arterial
      anomalies existed in 12 (24%). Anomalies of aortic origin more frequently
      involved the left main than the right coronary artery in both groups.

PMID- 8644652
TI  - Serum nifedipine concentrations and response of patients with pulmonary
      hypertension.
AB  - In patients with primary pulmonary hypertension who respond to nifedipine during
      acute drug testing, there is a significant linear correlation of serum nifedipine
      concentration with pulmonary artery pressure and resistance. Although most
      demonstrate an initial response at readily attainable nifedipine concentrations
      with conventional dosages, a subset of patients seem to display delayed or
      incomplete oral absorption; these results may facilitate the clinical use of
      nifedipine in patients with primary pulmonary hypertension.

PMID- 8644654
TI  - Heart rate variability in the early hours of an acute myocardial infarction.
AB  - The occurrence of an autonomic disturbance early in acute myocardial infarction
      (AMI) has been reported: signs of sympathetic activation were mainly observed in
      relation to an anterior localization, whereas signs of vagal overactivity were
      more frequent in inferior wall AMI. Information is limited in relation to the
      persistence of these alterations during the early hours of AMI. We studied 33
      patients with an AMI within 188 +/- 16 minutes from the onset of symptoms and 1
      week after hospital admission. From a 20-minute Holter recording, we computed
      with autoregressive methodology, time and frequency domain indexes of heart rate
      variability. At admission, patients with an anterior wall AMI exhibited a smaller
      RR variance (593 +/- 121 ms2) than did those with an inferior wall AMI (1,122 +/-
      191 ms2). In both groups the spectral profile was characterized by a predominant
      (73 +/- 4 and 61 +/- 4 normalized units) low frequency and by a small (13 +/- 2
      and 22 +/- 3 normalized units) high-frequency component, indicating the presence
      of a sympathetic excitation and of a diminished vagal modulation. Although signs
      of sympathetic activation were more evident in patients with anterior wall AMI,
      no evidence of a vagal hyperactivity was observed in patients with inferior wall
      AMI. In the latter group, we noticed 1 week after the acute event an increase in
      the low-frequency component, which reached the values observed in patients with
      anterior wall AMI. Thrombolysis did not affect heart rate variability parameters.
      Thus, this study suggests the presence of an autonomic disturbance characterized
      by signs of sympathetic excitation and of a reduced vagal modulation, which was
      more evident in patients with an anterior localization early after AMI.

PMID- 8644653
TI  - Troponin T as a marker for myocardial ischemia in patients undergoing major
      noncardiac surgery.
AB  - To assess the diagnostic performance of cardiac troponin T as a marker for
      myocardial injury in patients undergoing major noncardiac surgery, we
      prospectively collected preoperative and postoperative clinical data, including
      measurements for creatine kinase (CK), CK-MB, and troponin T for 1,175 patients
      undergoing major noncardiac surgery. Acute myocardial infarction was diagnosed in
      17 patients (1.4%) by a reviewer who was blinded to troponin T data and who used
      CK-MB and electrocardiographic criteria to define acute myocardial infarction.
      Other predischarge major cardiac complications were detected for another 17
      patients. Troponin T elevations (>0.1 ng/ml) occurred in 87% of patients with and
      in 16% of patients without myocardial infarction. Among patients without
      myocardial infarction, troponin T was elevated in 62% of patients with and in 15%
      of patients without major cardiac complications. Receiver-operating
      characteristic analysis indicated that troponin T had a performance for the
      diagnosis of acute myocardial infarction similar to CK-MB, and a significantly
      better correlation with other major cardiac complications in patients without
      definitive infarction. Future research should seek to determine the significance
      of troponin T elevations in patients without complications.

PMID- 8644655
TI  - Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric
      monoclonal antibody (abciximab) on acute and six-month outcomes after
      percutaneous transluminal coronary angioplasty for acute myocardial infarction.
      EPIC investigators.
AB  - Percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial
      infarction is an attractive alternative to thrombolysis, but is still limited by
      recurrent ischemia and restenosis. We determined whether adjunctive platelet
      glycoprotein IIb/IIIa receptor blockade improved outcomes in patients undergoing
      direct and rescue PTCA in the Evaluation of c7E3 for Prevention of Ischemic
      Complications (EPIC) trial. Of the 2,099 patients undergoing percutaneous
      intervention who randomly received chimeric 7E3 Fab (c7E3) as a bolus, a bolus
      and 12-hour infusion, or placebo, 42 underwent direct PTCA for acute myocardial
      infarction and 22 patients had rescue PTCA after failed thrombolysis. The primary
      composite end point comprised death, reinfarction, repeat intervention, or bypass
      surgery. Outcomes were assessed at 30 days and 6 months. Baseline characteristics
      were similar in direct and rescue PTCA patients. Pooling the 2 groups, c7E3 bolus
      and infusion reduced the primary composite end point by 83% (26.1% placebo vs
      4.5% c7E3 bolus and infusion, p = 0.06). No reinfarctions or repeat urgent
      interventions occurred in c7E3 bolus and infusion patients at 30 days, although
      there was a trend toward more deaths in c7E3-treated patients. Major bleeding was
      increased with c7E3 (24% vs 13%, p = 0.28). At 6 months, ischemic events were
      reduced from 47.8% with placebo to 4.5% with c7E3 bolus and infusion (p = 0.002),
      particularly reinfarction (p = 0.05) and repeat revascularization (p = 0.002). We
      conclude that adjunctive c7E3 therapy during direct and rescue PTCA decreased
      acute ischemic events and clinical restenosis in the EPIC trial. These data
      provide initial evidence of benefit for glycoprotein IIb/IIIa receptor blockade
      during PTCA for acute myocardial infarction.

PMID- 8644656
TI  - Influence of gender on short- and long-term mortality after acute myocardial
      infarction. TRACE study group.
AB  - The aim of this study was to assess differences in short- and long-term mortality
      between male and female patients with acute myocardial infarction (AMI). The
      study population consisted of 6,676 consecutive patients admitted alive with an
      enzyme-confirmed AMI to 27 Danish hospitals from 1990 to 1992. Five patients were
      excluded because of missing information. Female patients (n = 2,170) were on
      average 5 years older than male patients (n = 4,501, p <0.001), had lower body
      mass index, and more often had diabetes, hypertension, and congestive heart
      failure. Left ventricular systolic function was the same for men and women. Women
      received thrombolytic therapy less often. The 1-year mortality for female
      patients was 28 +/- 1% and for men 21 +/- 1% (p <0.001). The unadjusted risk
      ratio associated with male gender in a proportional-hazards model was 0.76 (95%
      confidence intervals [CI] 0.70 to 0.83). Adjustment for age removed the
      importance of gender, and the risk ratio associated with male gender was 1.06
      (95% CI 0.97 to 1.2, p = 0.2). An introduction of further variables in the model
      did not change this. Subdividing mortality into 6-day, 30-day, and late mortality
      demonstrated a significantly increased mortality in women in the short-term (6
      and 30 days), with a risk ratio in men of 0.58 (95% CI 0.42 to 0.81) and 0.80
      (95% CI 0.65 to 0.99), respectively. From day 30 onward there was an increased
      mortality in men with a risk ratio of 1.16 (95% CI 1.03 to 1.31, p = 0.01). Thus,
      women admitted alive to the hospital with an AMI have an increased long-term
      mortality that is explained by their older age. However, short-term mortality in
      women seems to increase independently of other risk factors, but is later
      followed by an increase in mortality in men.

PMID- 8644657
TI  - Prognostic significance of normal dobutamine-atropine stress sestamibi
      scintigraphy in women with chest pain.
AB  - To evaluate the prognostic value of normal dobutamine-atropine technetium-99m
      sestamibi single-photon emission computed tomography (SPECT) perfusion imaging in
      women with chest pain and inability to perform an adequate exercise test, 80
      women with a normal scintigram were followed up for 23 +/- 13 months. Mean age of
      the patients was 61 +/- 12 years. Nine patients (11%) had a low probability (<
      10%) of coronary artery disease, 43 (54%) had an intermediate probability (10% to
      80%) of disease, and 28 (35%) had a high probability (>80%) of disease (including
      19 patients with known coronary artery disease). During follow-up, no major
      cardiac events (cardiac death or nonfatal myocardial infarction) occurred. One
      patient with known coronary disease underwent coronary bypass surgery after 3
      months, and 1 patient with a 91% pretest likelihood of coronary disease underwent
      coronary angioplasty after 7 months. Thus, the overall incidence of (soft)
      cardiac events during the follow-up period was 2 of 80 patients, or 1.3%/year. It
      is concluded that normal dobutamine-atropine technetium-99m sestamibi SPECT
      perfusion imaging in women with chest pain implies an excellent prognosis, even
      in women with high pretest likelihood of coronary disease.

PMID- 8644658
TI  - Effects of prolonged sequential balloon inflations on results of coronary
      angioplasty.
AB  - In percutaneous transluminal coronary angioplasty (PTCA), prolonged balloon
      inflations using perfusion balloon catheters have shown a higher procedural
      success rate and fewer in-hospital complications than short balloon inflations.
      However, perfusion balloons have well-recognized limits for routine use. This
      study assessed the effects of a prolonged cumulative occlusion time obtained with
      sequential balloon inflations using a routine balloon catheter, applicable to all
      lesions, and compared these results with those obtained with standard short
      balloon inflations. Three hundred ten lesions (in 289 patients) were randomized
      to either standard (3 to 5 inflations < or = 1 minute each; n = 161) or prolonged
      (3 to 5 inflations of 3 to 5 minutes each; n = 149) balloon inflations.
      Angiographic success (residual stenosis <50% and no dissection > or = D1) was
      assessed at the end of this "protocol" phase. Further dilatation was performed if
      required ("adjunctive" phase). Systematic repeat catheterization was scheduled 4
      to 6 months later. Cumulative inflation time was 198 +/- 58 seconds in the
      "standard" group versus 782 +/- 303 seconds in the "prolonged" group. At the end
      of the protocol phase, the success rate was higher after prolonged than after
      standard dilatation (92% vs 80%; p <0.002), with less frequent dissections (14%
      vs 30%; p = 0.0009). At the end of the adjunctive phase, required for 12 patients
      in the prolonged group and 32 patients in the standard group (p = 0.003), results
      were comparable in the 2 groups and the restenosis rate was similar at 6 months.
      The prolonged cumulative occlusion time achieved with sequential balloon
      inflations using a routine balloon catheter improves the immediate results of
      PTCA. Repeat catheterization shows no effect of prolonged sequential inflations
      on the restenosis rate.

PMID- 8644659
TI  - Value of visual versus central quantitative measurements of angiographic success
      after percutaneous transluminal coronary angioplasty. NHLBI PTCA Registry
      Investigators.
AB  - This study examined the optimal angiographic definition for long-term success
      after angioplasty and compared visual and quantitative angiographic measurements
      in assessing outcome. The National Heart, Lung, and Blood Institutes-
      Percutaneous Transluminal Coronary Angioplasty Registry prospectively followed
      1,768 patients from 15 clinical centers. Symptom-free survival, defined as
      survival without angina, myocardial infarction, bypass surgery, or death,
      occurred in 59% of patients. In a subset of 393 patients, quantitative coronary
      angiography (QCA), done at a core angiographic laboratory, was compared with
      visual site readings. Although there was considerably more variability for visual
      readings, a site reading of a change in percent stenosis of >20% correlated
      highly with symptom-free survival (64.6% for patients who had all lesions
      successfully dilated, 48% for patients with partial success, and only 21% for
      patients without angiographic success; p < 0.001). Similar findings were seen for
      other angiographic definitions, but a change of > 20% was most discriminatory. In
      contrast, QCA readings had little or no predictive value. This study confirms
      that visual assessment of the immediate change in percent stenosis is predictive
      of a successful 1-year outcome. A change of greater than 20% is most
      discriminatory and should still be used to define angiographic success. QCA does
      not appear to be superior to visual assessment in predicting 1-year outcome.

PMID- 8644660
TI  - Heart rate variability in systemic hypertension.
AB  - Low heart rate (HR) variability is a risk factor for cardiac mortality in various
      patient populations, but it has not been well established whether patients with
      long-standing hypertension have abnormalities in the autonomic modulation of HR.
      Time and frequency domain measures of HR variability were compared in randomly
      selected, age-matched populations of 188 normotensive and 168 hypertensive males
      (mean age 50 +/- 6 years for both). The standard deviation of the RR intervals
      was lower in the hypertensive subjects than in the normotensive ones (52 +/- 19
      vs 59 +/- 20 mss; p <0.01), and the very low and low-frequency spectral
      components of HR variability analyzed as absolute units were reduced in the
      hypertensive patients relative to the normotensive controls (p <0.001 for both).
      Hypertensive subjects also had blunted changes of the normalized low- and high
      frequency components in response to an upright (sitting) posture (NS) as compared
      with normotensive subjects (p <0.001 for both). Multiple regression analysis
      showed the standard deviation of the RR intervals to be predicted most strongly
      by systolic blood pressure, both in the patients with hypertension (beta--0.20,
      p=0.01) and in the normotensive subjects (beta--0.28, p=0.0002). After adjustment
      for the baseline differences in blood pressure and body mass index, none of the
      absolute measures of the HR variability or the responses of the normalized units
      of HR variability to a change in the body posture differed between the
      hypertensive subjects and normotensive controls. These data show that long
      standing hypertension results in reduced overall HR variability and blunted
      autonomic responses to a change in body posture. Altered autonomic modulation of
      HR in hypertension is mainly due to elevated blood pressure and obesity in males
      with long-standing hypertension as compared with normotensive subjects.

PMID- 8644661
TI  - Rationale and design of the third vasodilator-heart failure trial (V-HeFT III):
      felodipine as adjunctive therapy to enalapril and loop diuretics with or without
      digoxin in chronic congestive heart failure. V-HeFT III investigators.
AB  - Therapy with angiotensin-converting enzyme inhibitors and nonselective
      vasodilators (hydralazine and isosorbide dinitrate) has become accepted treatment
      in patients with symptomatic, chronic congestive heart failure (CHF), and has
      been demonstrated in large clinical trials to ameliorate symptoms, improve
      exercise performance, and reduce cardiac mortality. Nevertheless, the management
      of patients with CHF remains a therapeutic challenge. The second Vasodilator
      Heart Failure Trial (V-HeFT II) showed that the average 2-year mortality with
      enalapril (18%) was significantly lower than that with hydralazine-isosorbide
      dinitrate (25%) but, somewhat surprisingly, the nonspecific vasodilators produced
      significantly more improvement in exercise performance and left ventricular
      function. Such data suggest that improvement in symptoms, hemodynamics, and
      survival may not be afforded by the use of a single class of vasodilator therapy,
      but might be optimized by the combined use of different agents. This report
      describes the rationale and design of V-HeFT III, a multicenter, prospective,
      randomized, double-blind, placebo-controlled trial comparing the effects of
      chronic oral extended-release felodipine (felodipine ER) 2.5 to 5 mg twice daily,
      when added to a stable regimen of enalapril and loop diuretics, with or without
      digoxin, on exercise performance, morbidity, and mortality in patients with New
      York Heart Association functional class II to III CHF followed for a minimum of
      12 weeks. Felodipine is a second-generation dihydropyridine calcium antagonist
      with a high degree of vascular selectivity which, in the doses used in this
      study, exerts its systemic arterial effect by decreasing peripheral vascular
      resistance without producing negative inotropic effects. The results of V-HeFT
      III may shed important light on the role of additive vasodilator therapy in the
      management of patients with CHF.

PMID- 8644662
TI  - Left atrial isomerism detected in fetal life.
AB  - Left and right atrial isomerism, comprising congenital heart defects with
      disturbances in normal left-right asymmetry, are phenotypically distinct after
      birth, although animal models suggest a common embryologic origin. We postulated
      that the prenatal phenotype may indeed be similar in both syndromes but that
      differential fetal loss is responsible for the distinct postnatal phenotypes.
      Distinctive fetal echocardiographic features of these syndromes have not been
      described in detail. We therefore sought markers of left atrial isomerism that
      could be recognized prenatally by echocardiography and compared our results with
      postnatal data to identify unique intrauterine features. We reviewed 10 cases at
      our center and 28 published cases of cardiac malformations with atrial isomerism
      detected by fetal echocardiography. Postnatal imaging and autopsies provided
      definitive diagnoses. Ninety-five percent of cases exhibited left atrial
      isomerism and formed the primary study population. Echocardiographic markers
      included a large azygos continuation of an interrupted inferior vena cava,
      atrioventricular block with structural heart disease, and viscerocardiac
      heterotaxy. At least 1 of these markers was seen in all of our center's cases.
      The incidences of most cardiac lesions detected prenatally were similar to those
      detected postnatally. However, although the incidences of atrioventricular septal
      defect and pulmonary outflow obstruction in live births were 50% and 45%,
      respectively, they were found much more frequently among stillbirths (80% each).
      In summary, we identified key fetal echocardiographic features highly sensitive
      for left atrial isomerism. Fetal loss selects against certain lesions such as
      atrioventricular septal defect. The spectrum of cardiac disease suggests a
      greater primitivity of the fetal heart than previously shown; the typical cardiac
      phenotypes are closer to right atrial isomerism than are their extrauterine
      presentations.

PMID- 8644663
TI  - Usefulness of banding of the pulmonary trunk with single ventricle physiology at
      risk for subaortic obstruction.
AB  - This study addresses the effects of early banding of the pulmonary trunk and
      subsequent management of subaortic obstruction on the attainment of acceptable
      pre-Fontan hemodynamics in patients with a single left ventricle and aorta
      arising from an outflow chamber. We report our experience with 26 patients seen
      at our institution between January 1984 and December 1994 with a diagnosis of
      double-inlet left ventricle or tricuspid atresia and transposed great arteries,
      who were initially managed with pulmonary artery banding in the first 6 months of
      life. Pulmonary artery band placement was performed at an age of 2.1 +/- 1.8
      months (mean +/- SD). Associated aortic arch abnormalities were present in 8
      patients (31%). There were 19 patients (73%) who underwent treatment with a Damus
      Kaye-Stansel procedure or ventricular septal defect (VSD) enlargement for a
      significant subaortic gradient or morphologically small VSD, alone or in
      conjunction with a Glenn or Fontan procedure. Eighteen of 26 patients (69%)
      underwent cardiac catheterization to assess their candidacy for the Fontan
      operation. Of this group, 16 were classified as low to moderate risk and 2 as
      high-risk Fontan candidates, based on hemodynamic criteria. The cumulative
      mortality for the entire cohort was 19%. Our results suggest that this high-risk
      group of patients can undergo effective pulmonary artery banding as an initial
      palliative step, with subsequent intervention for subaortic ob- struction when it
      is documented or highly suspected, and that acceptable pre-Fontan hemodynamic
      parameters can be achieved.

PMID- 8644664
TI  - Percutaneous catheter closure of the persistently patent ductus arteriosus in the
      adult.
AB  - The USCI patent ductus occluder has been shown to be an effective nonsurgical
      technique for closure of the persistently patent ductus in a primarily pediatric
      population. Its clinical impact in the adult has been reported only within small
      subgroups of larger pediatric studies or for a small population. This study was
      conducted to determine the feasibility, success rate, and complications of device
      closure for the persistently patent ductus arteriosus (PDA) in the adult. The
      population consisted of 55 patients (4 men and 51 women; mean age 38.8 +/- 15.0
      years) with follow-up of 2.2 +/- 2.1 years. All patients underwent
      echocardiography obtained as part of their follow-up assessment. The device was
      successfully placed in 54 patients, with 75% clinical and echocardiographic
      closure at the first follow-up assessment 2.4 +/- 2.6 months). One patient with
      initial clinical and echocardiographic evidence of closure was subsequently found
      to have an open ductus. Spontaneous closure (2 patients) or second implant (6
      patients) resulted in 86% closure at the most recent assessment. Thus, the
      percutaneous PDA double-umbrella occluder device is a feasible and effective
      technique for closing persistent PDA in the adult and will result in occlusion of
      the shunt in most patients without the need for thoracotomy.

PMID- 8644665
TI  - Accuracy of biplane long-axis left ventricular volume determined by cine magnetic
      resonance imaging in patients with regional and global dysfunction.
AB  - Left ventricular (LV) volumes and ejection fraction can be obtained by applying
      Simpson's rule to multiple short-axis tomographic planes. A simpler method for
      determining LV volumes using the area-length equation is widely accepted and
      requires less time to acquire and analyze. Its accuracy, however, is questionable
      in deformed or asymmetrically contracting ventricles. This study compares biplane
      long-axis to serial short-axis computed LV volumes obtained by cine gradient-echo
      magnetic resonance imaging (MRI) in 2 distinct patient populations: (1) patients
      with global LV dysfunction, and (2) patients with regional LV dysfunction. A
      total of 114 patients were studied using both methods. Among 37 patients with
      global LV dysfunction, there was no statistically significant difference between
      methods (long axis vs short axis) for determining LV end-diastolic volume (203 +/
      91 vs 201 +/- 90 ml), end-systolic volume (142 +/- 81 vs 141 +/- 82 ml), and
      ejection fraction (33 +/- 12 vs 33 +/- 13%). However, in the 77 patients with
      regional dysfunction, LV end-diastolic volume was statistically slightly higher
      when obtained using the long-axis approach (157 +/- 53 vs 152 +/- 51 ml;
      p=0.004). Otherwise, end-systolic volume (97 +/- 49 vs 95 +/- 49 ml) and ejection
      fraction (40 +/- 13 vs 40 +/- 13%) were similar (p=NS). The correlation between
      LV volumes and ejection fractions for both groups was excellent (r >0.91). Thus,
      in this study group, biplane long-axis and serial short-axis computed LV volumes
      and ejection fractions were similar in patients with global or regional LV
      dysfunction. In critically ill patients unable to complete a comprehensive MRI
      examination, the biplane long-axis-derived volumes provide adequate data.

PMID- 8644666
TI  - Intracoronary stenting without intravascular ultrasound guidance followed by
      antiplatelet therapy with aspirin alone in selected patients.
AB  - One hundred selected patients with 103 lesions were treated with the deployment
      of 117 Palmaz-Schatz stents without the use of intravascular ultrasound, followed
      by antiplatelet therapy with aspirin alone. Angiographic and clinical follow-up
      revealed 2 stent thromboses; 3 stents required redilation, and 3 patients
      required intervention for disease progression elsewhere, suggesting that this
      approach can be applied effectively in selected patients.

PMID- 8644667
TI  - Can angiographic findings predict which coronary patients will benefit from
      enhanced external counterpulsation?
AB  - Enhanced external counterpulsation is an effective treatment for chronic angina.
      Theoretical considerations predict greatest benefit in patients with at least 1
      patent conduit in this group of 50 patients (all of whom improved clinically).
      Improvement in radionuclide stress perfusion imaging was seen in 80% of treated
      patients and was inversely related to extent of coronary disease.

PMID- 8644668
TI  - Combined percutaneous carotid stenting and coronary angioplasty during acute
      ischemic neurologic and coronary syndromes.
AB  - This study demonstrates the feasibility of percutaneous carotid and coronary
      intervention in patients with unstable neurologic and coronary syndromes. Further
      study is warranted to determine the safety and long-term results in a large
      series of patients.

PMID- 8644669
TI  - Low-serum, high-density lipoprotein cholesterol concentration is an important
      coronary risk factor in Chinese patients with low serum levels of total
      cholesterol and triglyceride.
AB  - The significance of low-serum high-density lipoprotein concentrations (<35 mg/dl)
      with respect to coronary atherogenesis in Chinese patients with low levels of
      total serum cholesterol (<200 mg/dl) and triglycerides (<250 mg/dl) was assessed.
      Persons with such a lipid profile pattern were still at high risk, and high
      density lipoprotein. like smoking, appeared to be the most predictive independent
      coronary risk factor.

PMID- 8644670
TI  - In vivo validation of intravascular ultrasound length measurements using a
      motorized transducer pullback system.
AB  - Using sonoreflective endovascular targets of known length (stainless steel
      tubular slotted stents), we have validated in vivo the accuracy and
      reproducibility of intravascular ultrasound length measurements using a system
      incorporating motorized transducer pullback through a stationary imaging sheath.
      The correlation was r = 0.936, with a measurement error of only +/- 5.2%, minimal
      intraobserver variability, and variability of sequential measurements of only +/-
      4.8%.

PMID- 8644671
TI  - Absence of atherosclerotic lesions in the thoracic aorta indicates absence of
      significant coronary artery disease.
AB  - Atherosclerotic lesions may be readily visualized in the thoracic aorta using
      transesophageal echocardiography. The absence of aortic plaque in the thoracic
      aorta rules out significant coronary artery obstruction whereas the existence of
      the former appears to be a sensitive and specific predictor of the latter.

PMID- 8644673
TI  - Angiographic correlates of cardiac death and myocardial infarction complicating
      major nonthoracic vascular surgery.
AB  - In a case-control study of 63 patients undergoing major nonthoracic vascular
      surgery with prior cardiac catheterization, we found total coronary occlusion
      serving viable myocardium and "nonobstructive" lesions to be the most common
      proximate cause of perioperative myocardial infarction or death. The extent of
      coronary disease by several measures was significantly correlated with adverse
      outcome, and prior bypass surgery appeared to be protective.

PMID- 8644672
TI  - Elevation of the plasma histamine concentration in the coronary circulation in
      patients with variant angina.
AB  - In the present study plasma histamine was found to be elevated in the great
      cardiac vein in 8 of 11 patients with variant angina but in none of 8 control
      patients. Although further investigation is required to determine the exact cause
      and-effect relation between histamine release and provocation of spontaneous
      variant anginal attacks, the present study presents clinical evidence that
      histamine may well be related to episodes of variant angina as suggested in
      animal studies.

PMID- 8644674
TI  - Correlation of P-wave polarity with underlying electrophysiologic mechanisms of
      long RP' tachycardia.
AB  - Analysis of surface electrocardiograms from patients with long RP' tachycardia
      due to either atypical atrioventricular node reentrant tachycardia, permanent
      junctional reciprocating tachycardia, or low atrial tachycardia was performed.
      Although a negative P wave in the inferior leads is common to all 3 mechanisms,
      the results suggest that a positive or isoelectric P wave in electrocardiographic
      lead I strongly supports a diagnosis of atypical atrioventricular node reentrant
      tachycardia, whereas a negative or biphasic P wave in lead I argues against this
      mechanism.

PMID- 8644675
TI  - Electromechanical delay in the left atrium as a consequence of interatrial block.
AB  - Right and left atrial electromechanical intervals and onsets of active right and
      left ventricular filling were measured in patients with interatrial block and
      compared with control patients. Left atrial mechanical activity is significantly
      delayed by interatrial block.

PMID- 8644677
TI  - Iron supplementation during pregnancy: is it effective?

PMID- 8644676
TI  - Comparison of infective endocarditis in patients with and without previously
      recognized heart disease.
AB  - In a consecutive series of patients with infective endocarditis, we compared the
      charts of 123 nonaddicted patients without previously known heart disease with
      those of 174 patients with native valve disease. The 2 groups were similar in
      age, sex, clinical findings, and mortality rates, but infective endocarditis was
      more often located on the aortic valve, more often due to Streptococcus bovis and
      enterococci in patients without previously known heart disease.

PMID- 8644678
TI  - Evaluation of modified multicompartment models to calculate body composition in
      healthy males.
AB  - The purpose of this study was to develop flexible and accurate multicompartment
      equations to calculate body composition and compare the results with methods
      using common two-compartment equations. Twenty-two healthy male volunteers 22-59
      y of age were studied. Body volume was measured by underwater weighing (UWW) or
      with a skinfold caliper, bone mineral by dual-energy X-ray absorptiometry (DXA),
      and body water by bioelectrical impedance analysis (BIA). The percentage of water
      and bone mineral in fat-free mass (FFM) had a significant effect on the
      difference in percentage fat obtained by the two-compartment model compared with
      a four-compartment model. FFM density was negatively (r = -0.76, P < 0.001) and
      percentage water in FFM was positively correlated with age (r = 0.75, P < 0.001).
      The three-compartment model based on field-adapted methods (skinfold thickness +
      BIA) to calculate percentage body fat correlated significantly with the more
      complex four-compartment model (UWW + BIA + DXA; r = 0.95, P < 0.001). The
      advantages of three- and four-compartment equations are that they compensate for
      differences in body content of bone mineral and water.

PMID- 8644679
TI  - Total-body skeletal muscle mass: evaluation of 24-h urinary creatinine excretion
      by computerized axial tomography.
AB  - A classic body-composition method is estimation of total-body skeletal muscle
      mass (SM, in kg) from 24-h urinary creatinine excretion (in g). Two approaches of
      unknown validity have been used to calculate SM from creatinine: one assumes a
      constant ratio of SM to creatinine, the so-called creatinine equivalence (k), and
      that SM = k x creatinine; the other suggests a highly variable ratio of SM to
      creatinine and is based on regression equations of the form SM = b + a x
      creatinine. We explored these two extreme possibilities by measuring SM with
      whole-body computerized axial tomography and collecting urinary creatinine during
      meat-free dietary conditions in 12 healthy adult men. Prediction equations were
      developed in the men that fit these two models: SM = 21.8 x creatinine (SD and CV
      of the ratio of SM to creatinine: 1.3 kg and 6.0%, respectively) and SM = 18.9 x
      creatinine + 4.1 (r = 0.92, P = 2.55 x 10(-5), SEE = 1.89 kg). The validity of
      each model is reviewed in the context of theoretical aspects of creatine
      creatinine metabolism. This first investigation of the method of measuring
      urinary creatinine excretion to determine SM by using modern techniques raises
      important practical and basic questions related to SM prediction.

PMID- 8644680
TI  - Energy expenditure of urban Colombian women: a comparison of patterns and total
      daily expenditure by the heart rate and factorial methods.
AB  - The heart rate and factorial methods of measuring both total daily energy
      expenditure (TDEE) and the daily pattern of energy expenditure (EE) were compared
      in nonpregnant, nonlactating women aged 19-43 y living in urban conditions of
      economic deprivation. The methods were applied on each of 2 successive days.
      There were no significant differences between the 2 d by either method. Women who
      worked at their household chores at home (n = 29) and those who also worked for
      remuneration (at work) in various kinds of employment (n = 23) were compared. The
      factorial method gave values for TDEE and for the pattern of EE that were
      significantly lower than those obtained by the heart rate method. This was
      related to lower values for EE for certain activities obtained from the
      literature than for values measured in these subjects. Women at work had
      significantly higher values for both TDEE and for the pattern of EE than did
      those at home. The TDEE at home by the heart rate method was 8.83 +/- 1.94 MJ/d
      and at work was 9.99 +/- 1.91 MJ/d (P = 0.036); this difference disappeared when
      adjusted for body weight or fat-free mass. Physical activity levels were 1.83 +/-
      0.43 for women at home and 1.90 +/- 0.46 for women at work, which indicate
      moderate to heavy work. The factorial method should be used with measured EE
      values in the present subject population. The heart rate method can detect
      differences in TDEE and in the pattern of EE between women engaged in different
      activities and may offer an experimental approach to the study of the effects of
      daily variations in EE on nutritional energy intake.

PMID- 8644681
TI  - Low resting metabolic rate in subjects predisposed to obesity: a role for thyroid
      status.
AB  - A low resting metabolic rate (RMR) for a given body composition has been
      identified as a risk factor for weight gain and obesity, and has also been
      reported in formerly obese individuals with the genetic predisposition for
      obesity. The possible role of thyroid hormone in low RMR was studied in a large
      sample of postobese women. RMR was measured by indirect calorimetry in 28 weight
      stable postobese women with a family history of obesity (PO group) and in a
      control group of 28 nonobese women closely matched for age, fat mass, and fat
      free mass. RMR was 8% lower in the PO than in the control group [[symbol: see
      text]; 95% Cl:5856 (5520, 6214) compared with 6408 kJ/d (6096, 6768 kJ/d), P <
      0.02], and the group difference remained unchanged after fat-free mass and fat
      mass were adjusted for (552 kJ/d, P < 0.015). The PO group had lower plasma free
      triiodothyronine [2.4 (1.9, 3.0) compared with 3.4 pmol/L (2.9, 3.9 pmol/L), P <
      0.01], whereas plasma androstenedione only tended to be lower in the PO than in
      the control group. Adjustment for differences in androstenedione did not reduce
      the difference in RMR, whereas adjustment for differences in plasma free
      triiodothyronine eliminated the group difference (96 kJ/d, P = 0.59). The present
      study shows that RMR for a given body composition is lower among postobese than
      among matched never-obese control subjects. Statistically, the lower plasma free
      triiodothyronine concentrations of the postobese subjects could explain their
      lower RMRs, but it remains to be established whether these findings are causally
      related.

PMID- 8644682
TI  - Effects of weekly iron supplementation on pregnant Indonesian women are similar
      to those of daily supplementation.
AB  - The effect of daily rather than weekly iron supplementation was compared in women
      who were 8-24 wk pregnant. One group (n = 68) received 60 mg Fe/d, the second
      group (n = 71) received 120 mg Fe/wk, given at once. Supplementation lasted 11.3
      wk on average, depending on gestational date at entry, and was not supervised.
      Hemoglobin increased in both groups (P < 0.001); serum ferritin did not change
      significantly. There was no significant difference between groups for changes in
      hemoglobin and serum ferritin. In a subgroup of women with a hemoglobin
      concentration < 110 g/L at baseline (n = 45 daily; n = 54 weekly) no significant
      within-group changes occurred in serum ferritin, but the change in the daily
      group was 4.1 micrograms/L higher than in the weekly group (P = 0.049).
      Compliance, as indicated by two positive stool tests, was approximately equal to
      54.3% in the daily group and 62.2% in the weekly group. We conclude that for the
      complete sample of subjects, the treatment effect of daily compared with weekly
      supplementation was similar under conditions resembling a normal antenatal care
      program.

PMID- 8644683
TI  - Replacement of dietary fat with sucrose polyester: effects on energy intake and
      appetite control in nonobese males.
AB  - In previous experiments using the fat substitute sucrose polyester (SPE, or
      olestra), no compensatory response was observed on day 2 after experimental
      manipulations, which reduced the percentage of energy from fat to approximately
      equal to 30% from 40% on day 1. In the present study a more severe manipulation
      was made; the amount of energy from fat was reduced from 32% to 20% to determine
      whether such a reduction would provoke any physiologic or behavioral response.
      Subjects came to the unit for two, 2-d test sessions. Intake on day 1 was fixed:
      subjects were given meals containing either control fat (11319 kJ, 32% of energy
      as fat) or SPE (9561 kJ, 20% of energy as fat). On day 2, intake was ad libitum.
      On day 1 subjects rated themselves as more hungry while consuming the fat
      substituted meals than when consuming the control meals and they disclosed
      greater hunger in the end-of-day questionnaires. The effect of the manipulation
      was carried over into day 2. By the end of day 2, subjects had compensated for
      74% of the energy (fat) deficit caused by the previous day's manipulation. These
      results differ from those obtained when fat was reduced from 40% to 30% of
      energy; this more severe reduction reveals that a reduction in fat of this size
      can lead to a biobehavioral response. Together, these data suggest that people
      could change their diet to meet dietary guidelines; however, if a more severe
      reduction is attempted, adherence may be made more difficult by the strength of
      the compensatory response.

PMID- 8644684
TI  - Comparison of the effects of diets enriched in lauric, palmitic, or oleic acids
      on serum lipids and lipoproteins in healthy women and men.
AB  - The degree to which different saturated fatty acids exert their cholesterol
      raising effects is still unknown. Therefore, we studied the effect on serum
      lipids and lipoproteins of diets rich in lauric, palmitic, or oleic acids.
      Eighteen women and 14 men consumed in random order three experimental diets, each
      for 6 wk. The diets consisted of solid foods and contained 40% of energy as fat,
      of which 28% was supplied by the experimental fats. The fat high in lauric acid
      was a mixture of palm kernel oil (75%) and a high-oleic acid sunflower oil (25%);
      the fat high in palmitic acid consisted of dairy fat (55%), palmstearin (36%),
      and sunflower oil (9%); and the fat high in oleic acid consisted of dairy fat
      (37%) and sunflower oil (63%). The calculated nutrient composition was the same
      in each diet except for approximately equal to 8.5% of energy, which was provided
      by lauric, palmitic, or oleic acids. With the lauric acid diet the subjects'
      serum total cholesterol concentration increased by 0.22 mmol/L (P = 0.0121; 95%
      CI: 0.02, 0.41 mmol/L) as compared with the palmitic acid diet and by 0.48 mmol/L
      (P < 0.0001; 95% CI: 0.29, 0.67 mmol/L) compared with the oleic acid diet. Total
      cholesterol concentrations with the palmitic acid diet were 0.26 mmol/L (P =
      0.0012; 95% CI: 0.07, 0.46 mmol/L) higher than with the oleic acid diet. High
      density-lipoprotein (HDL)-cholesterol concentrations increased by 0.12 mmol/L (P
      = 0.006; 95% CI: 0.04, 0.20 mmol/L) with the lauric acid compared with the
      palmitic acid diet and by 0.14 mmol/L (P < 0.001; 95% CI: 0.07, 0.22 mmol/L)
      compared with the oleic acid diet. HDL-cholesterol concentrations with the
      palmitic acid and the oleic acid diet were the same. No effects were seen in
      serum triacylglycerol and lipoprotein(a) concentrations. We conclude that both
      lauric and palmitic acids are hypercholesterolemic compared with oleic acid.
      Lauric acid raises total cholesterol concentrations more than palmitic acid,
      which is partly due to a stronger rise in HDL cholesterol.

PMID- 8644685
TI  - Choline supplementation reduces urinary carnitine excretion in humans.
AB  - Two experiments were conducted to determine the effects of supplementary choline
      and/or pantothenate on the carnitine and lipid status of free-living humans.
      Analyses of carnitine and cholesterol fractions, triacylglycerols, and creatinine
      were determined in serum and/or urine. In experiment 1, adults receiving 13.5
      mmol choline plus 1.4 mmol pantothenate/d had a significant decline in urinary
      carnitine excretion and renal clearance with nonesterfied carnitine (NEC)
      declining the most dramatically, 84%. Additionally, serum NEC and total carnitine
      concentrations decreased significantly. No changes were observed in any of the
      serum lipids examined. In experiment 2, subjects took 0.20 mmol and 0.02 mmol/kg
      choline or pantothenate, respectively. Choline, but not pantothenate,
      supplementation significantly decreased urinary carnitine excretion, renal
      clearance, and fractional clearance of NEC. We conclude that supplementary
      choline maintained serum carnitine concentrations by conserving urinary
      carnitine. Moreover, these observations merit additional investigation to
      determine metabolic and functional consequences of choline and carnitine
      interactions in humans.

PMID- 8644686
TI  - Oral fat exposure alters postprandial lipid metabolism in humans.
AB  - Accumulating evidence indicates that oronasal sensory stimulation influences
      nutrient metabolism. This work examined the effects of oral exposure to dietary
      fat on postprandial plasma triacylglycerol (triglyceride) concentrations. Fifteen
      (six male, nine female) healthy adults were exposed to each of four treatments
      presented in random order. After ingestion of a 50-g load of safflower oil in
      capsules (to preclude oral exposure to the fat), they masticated and expectorated
      1) crackers with cream cheese, 2) crackers with nonfat cream cheese, 3) crackers
      alone, or 4) nothing. Blood samples were collected at baseline and 2, 4, and 6 h
      after load ingestion. Sensory discrimination tests were conducted with the cream
      cheese samples after these sessions. Oral exposure to the full-fat cream cheese
      led to a significantly greater area under the plasma triacylglycerol curve than
      did the other treatments (P < 0.05). The increment was attributable to both a
      significantly higher peak concentration and a more enduring elevation (P < 0.05).
      The oral stimuli were not ingested (so did not add to the load), subjects were
      not aware of the macronutrient composition of the cream cheese samples (thereby
      eliminating cognitive effects), and subjects could not distinguish between the
      cream cheese samples in sensory tests (minimizing a sensory influence).
      Consequently, these data suggest that there is a chemosensory or tactile
      mechanism in the oronasal region of humans for detecting some aspect of the
      chemical composition of dietary fat, or a component derived from or carried in
      fat, that elicits a change in postprandial lipid metabolism.

PMID- 8644687
TI  - Effect of butter compared with tallow consumption on postprandial oxidation of
      myristic and palmitic acids.
AB  - To assess the influence of dietary fat composition on rates of oxidation of
      dietary myristic (MA) and palmitic (PA) acids, eight healthy males consumed
      prepared solid-food diets for 11 d with 40% of total energy as fat. Fifty-five
      percent of the energy obtained in the form of fat was provided as butter or beef
      tallow. On days 8 and 11 of each diet cycle, 20 mg/kg body wt of either [1
      (13)C]MA or [1-(13)C]PA was ingested with breakfast. Hourly breath samples were
      collected over 9 h thereafter and 13CO2 enrichments were determined by using
      isotope-ratio mass spectrometry. The percentage of [13C]MA appearing in breath
      carbon dioxide over 9 h was more than twofold that of PA (P < 0.01). Diet fat
      composition did not influence the mean (+/- SEM) percentage 13C recovered over 9
      h from either labeled MA (7.1 +/- 1.0% compared with 8.6 +/- 0.9% for butter and
      tallow, respectively) or PA (3.3 +/- 0.7% compared with 3.0 +/- 0.9% for butter
      and tallow, respectively). However, net MA oxidation, calculated as the percent
      recovery of fatty acids in the meal, was greater (P < 0.05) after the butter (329
      +/- 45 mg) than after the tallow (212 +/- 25 mg) breakfast. In contrast, no
      difference was observed in net oxidation of dietary PA between butter (441 +/- 99
      mg) and tallow (348 +/- 95 mg) meals. In conclusion, there was no effect of
      varying the dietary content of MA and PA on fractional oxidation; consequently,
      net oxidation of these fatty acids was proportional to their concentration within
      the diet.

PMID- 8644688
TI  - Effect of n-3 polyunsaturated fatty acid intake on phospholipid fatty acid
      composition in plasma and erythrocytes.
AB  - To characterize the time course of plasma and red blood cell (RBC) changes after
      n-3 polyunsaturated fatty acid (PUFA) supplementation, 20 healthy male volunteers
      were randomly assigned to receive either four 1-g capsules of n-3 PUFA ethyl
      esters or four 1-g capsules of olive oil (as placebo) for a period of 4 mo,
      followed by a 3-mo washout period. Fatty acids of plasma and RBC phospholipid
      fractions were analyzed at 0, 2, and 4 mo of treatment and at 1, 2, and 3 mo of
      washout. During n-3 PUFA supplementation, accumulations of eicosapentaenoic
      (EPA), docosapentaenoic (DPA), and docosahexaenoic (DHA) acids were marked after
      2 mo with differences among different fractions of plasma and RBCs in further
      accumulation up to 4 mo. During the first and second months of the washout,
      slight differences were observed in changes of various fatty acids among
      different phospholipid fractions, but after 3 mo of washout, only minor
      alterations were still detectable with respect to pretreatment values. These data
      confirm the complex relations among different fatty acid pools after n-3 PUFA
      supplementation.

PMID- 8644689
TI  - Effect on serum lipids of monounsaturated oil and margarine in the diet of an
      Antarctic Expedition.
AB  - A 13-wk dietary intervention was carried out with 23 members of the 1991
      wintering party of an Australian National Antarctic Research Expedition. Canola
      margarine and canola cooking oil were substituted for usual dietary fats (butter,
      a margarine containing 28% saturated fat, a polyunsaturated margarine, and
      vegetable oil). Mean energy intake slowly decreased although body weight slowly
      increased during the 42-wk wintering-over period. During 13 wk of dietary
      substitution, mean total cholesterol and low-density-lipoprotein-cholesterol
      concentrations fell by 7.0% and 10.0%, respectively (P < 0.05, repeated-measures
      ANOVA). These changes were not found in a second wintering-over group that did
      not experience this dietary intervention. The data indicate that a relatively
      simple change to the food supply has the potential to produce significant
      beneficial changes in lipoprotein lipid profile.

PMID- 8644690
TI  - Chronic consumption of short-chain fructooligosaccharides by healthy subjects
      decreased basal hepatic glucose production but had no effect on insulin
      stimulated glucose metabolism.
AB  - We aimed to study the effects of chronic ingestion of short-chain
      fructooligosaccharides (FOS), an indigestible carbohydrate, on hepatic glucose
      production, insulin-mediated glucose metabolism, erythrocyte insulin binding, and
      blood lipids in healthy subjects. Twelve healthy volunteers received either 20 g
      FOS/d or sucrose for 4 wk in a double-blind crossover design. FOS did not modify
      fasting plasma glucose and insulin concentrations. Mean (+/- SEM) basal hepatic
      glucose production was lower after FOS than after sucrose consumption (2.18 +/-
      0.10 compared with 2.32 +/- 0.09 mg.kg-1, min-1, respectively; P < 0.02, paired
      Student's t test). However, neither insulin suppression of hepatic glucose
      production nor insulin stimulation of glucose uptake measured by hyperinsulinemic
      clamp was significantly different between the two dietary periods. Erythrocyte
      insulin binding was also comparable. Serum triacylglycerols, total and high
      density- lipoprotein cholesterol, apolipoproteins A-I and B, and lipoprotein(a)
      were not modified by FOS. To try to understand why FOS did not increase serum
      lipids, the in vitro production of short-chain fatty acids from FOS was evaluated
      by using human fecal inoculum and compared with that from lactulose, which was
      found to increase serum lipids. FOS produced an acetate-propionate ratio two
      times lower than that of lactulose. We conclude that 4 wk of 20 g FOS/d decreased
      basal hepatic glucose production but had no detectable effect on insulin
      stimulated glucose metabolism in healthy subjects. The colonic fermentation
      pattern of undigestible carbohydrates may be relevant to predicting their
      metabolic effects.

PMID- 8644691
TI  - Relation between dietary vitamin intake and resistance to insulin-mediated
      glucose disposal in healthy volunteers.
AB  - The relation between the self-reported intake of various dietary constituents and
      insulin-mediated glucose disposal was evaluated in 52 healthy volunteers. Insulin
      mediated glucose uptake was independently associated with degree of obesity
      (inversely) and estimates of level of physical activity (directly). An
      independent relation between increased intake of vitamin A and insulin action was
      shown, ie, the greater the intake of vitamin A, the more effective was insulin in
      stimulating glucose disposal. However, there was no independent relation noted
      between insulin-mediated glucose disposal and estimates of the intake of
      carbohydrate, protein, amount or kind of fat, fiber, or vitamins C and E.
      Furthermore, the 20 individuals with estimates of vitamin A consumption > 10 000
      IU/d had significantly lower plasma glucose (P < 0.01) and insulin (P < 0.05)
      responses to oral glucose, and insulin-mediated glucose disposal values that were
      higher (P < 0.005) than those of the 20 individuals whose estimated vitamin A
      intake was < 8000 IU/d. These results suggest that vitamin A intake, but not
      intakes of vitamin C and E, fiber, fat, or carbohydrate is associated with
      enhanced insulin-mediated glucose disposal.

PMID- 8644693
TI  - Chromium supplementation and resistance training: effects on body composition,
      strength, and trace element status of men.
AB  - The effects of 8 wk of daily chromium supplementation (3.3-3.5 mumol as chromium
      chloride or chromium picolinate) or placebo (0.1 mumol Cr) and weight training
      were examined in 36 men in a double-blind design. Strength, mesomorphy, fat-free
      mass, and muscle mass increased with resistance training independently of
      chromium supplementation (P < 0.0001). Protein, magnesium, zinc, copper, and iron
      intakes equalled or exceeded the recommended dietary allowance (RDA) or estimated
      safe and adequate daily dietary intake (ESADDI) during training and did not
      change significantly from pretraining intakes (P > 0.05). Chromium
      supplementation increased the serum chromium concentration and urinary chromium
      excretion without a difference as a result of the chemical form of chromium (P <
      0.05). Resistance training was associated with a significant decrease (P < 0.05)
      in serum ferritin, total-iron-binding capacity, transferrin saturation, the ratio
      of enzymatic to immunoreactive ceruloplasmin, and plasma copper, independently of
      chromium supplementation. However, transferrin saturation was decreased more with
      chromium picolinate supplementation (24%) than with chromium chloride or placebo
      (10-13%). Compared with pretraining values, urinary magnesium excretion increased
      (P < 0.05) and urinary zinc output tended to decrease during the first 4 wk of
      resistance training and then returned to baseline values for the final 4 wk,
      which suggests an adaptation in mineral excretion in response to weight training.
      These findings suggest that routine chromium supplementation has no beneficial
      effects on body- composition change or strength gain in men. Whether chromium
      supplementation of individuals with diminished chromium nutriture facilitates
      propitious changes in body structure and function remains to be determined.

PMID- 8644692
TI  - Magnesium balance in adolescent females consuming a low- or high-calcium diet.
AB  - Increasing emphasis is being placed on optimizing calcium intake during growth as
      a way to enhance peak bone mass. Although some studies in adults have shown that
      high calcium intake may negatively affect magnesium utilization, few data are
      available regarding the interaction of calcium and magnesium in healthy children.
      The purpose of our study was to measure the effect of calcium intake on magnesium
      balance in 26 adolescent girls (mean age 11.3 y) during a 14-d period. Subjects
      ate a controlled basal diet containing 667 mg Ca and 176 mg Mg. In addition to
      the basal diet, subjects were randomly assigned in a double-blind fashion to
      consume 1000 mg elemental Ca/d as calcium citrate malate or a placebo. Magnesium
      use did not differ between the low-calcium and high-calcium groups as measured by
      absorption (50% compared with 55%), urinary excretion (70 compared with 74 mg/d),
      and fecal excretion (88 compared with 79 mg/d). Accordingly, magnesium balance
      was not different in subjects consuming 667 or 1667 mg Ca/d and averaged 21 mg
      Mg/d for the whole study group. Magnesium balance was significantly correlated
      with magnesium intake (r = 0.511, P = 0.008) and magnesium absorption (r = 0.723,
      P < 0.001). Prediction intervals from the regression of magnesium balance on
      intake indicated that the current recommended dietary allowance of magnesium
      would result in magnesium balance > or = 8.5 mg/d in 95% of the girls. This value
      appears consistent with long-term accretion rates needed to account for the
      expansion of the total-body magnesium pool during growth. In summary, our
      observations support the adequacy of the current recommended dietary allowance
      for magnesium and indicate that alterations in magnesium utilization should not
      be anticipated in adolescent females consuming a high-calcium diet.

PMID- 8644695
TI  - Folate dose may mask small differences in folate metabolism.

PMID- 8644694
TI  - Risk factors for wasting and stunting among children in Metro Cebu, Philippines.
AB  - Risk factors for wasting and stunting were examined in a longitudinal study of 18
      544 children younger than 30 mo in Metro Cebu, Philippines. Measures of household
      demographic and socioeconomic characteristics, maternal characteristics and
      behavior, and child biological variables were analyzed cross-sectionally in six
      child age-residence strata by using logistic regression. Our results support
      biological and epidemiologic evidence that wasting and stunting represent
      different processes of malnutrition. They also indicate that the principal risk
      factors for stunting and wasting in infants < 6 mo of age were either maternal
      behaviors or child biological characteristics under maternal control, eg, breast
      feeding status and birth weight. After 6 mo of age, household socioeconomic
      characteristics emerged with behavioral and biological variables as important
      determinants of malnutrition, eg, father's education and presence of a television
      and/or radio. Household socioeconomic status influenced the risk of stunting
      earlier in rural than in urban barangays. Implications of the results for
      interventions are discussed.

PMID- 8644696
TI  - Visceral adiposity and lipid oxidation.

PMID- 8644697
TI  - The need to consider functional endpoints in defining nutrient requirements.

PMID- 8644698
TI  - Oxidative damage and defense.
AB  - Increased production of reactive oxygen species is a feature of most, if not all,
      human disease, including cardiovascular disease and cancer. Dietary antioxidants
      may be especially important in protecting against human diseases associated with
      free radical damage to cellular DNA, lipids, and proteins. Ascorbic acid is an
      effective water-soluble antioxidant, and epidemiologic studies suggest that
      increased ascorbate nutriture is associated with reduced risk of some
      degenerative diseases, especially cancer and eye cataracts. Population studies
      have also shown that high vitamin E intakes are associated with decreased risk of
      coronary heart disease, possibly as a result of inhibition of atherogenic forms
      of oxidized low-density lipoprotein. Recent data suggest that beta-carotene
      provides protection against lipid peroxidation in humans, as well as provitamin A
      activity. Yet, present data are not sufficient to quantitate micronutrient
      requirements needed to protect against oxidative damage. The antioxidant roles of
      many food constituents, such as polyphenols, have not been clarified. Most
      antioxidants can act as prooxidants under certain conditions, and more research
      is needed to determine the occurrence and importance of this in vivo. The few
      controlled intervention trials carried out so far have shown mixed results as to
      the potential of antioxidant supplements for reducing the incidence of chronic
      diseases. Definitive recommendations on antioxidant intakes for disease
      prevention must await evidence from controlled studies and intervention trials,
      some currently in progress. Overall, the present data suggest that protection
      against oxidative damage and related disease is best served by the variety of
      antioxidant substances found in fruit and vegetables.

PMID- 8644699
TI  - Fatty acid-related functions.
AB  - The first recommendations for specific nutrient quantities that must be obtained
      to support health were made by the US Department of Agriculture before 1939.
      Hazel Stiebeling was the leader of this effort and the scientific background was
      published in the Yearbook of Agriculture. The recommendations clearly stated that
      food must be available to provide the nutrients to support health. The science of
      nutrition in the United States is engaged in the most thorough review and
      reexamination of the recommended dietary allowances in at least a generation of
      nutrition scientists. There is a new awareness of nutrition complexity and the
      likelihood of identification of new essential nutrients. This meeting was devoted
      to the search for functional endpoints to reach quantitative estimates of dietary
      substances needed to support a function. Included in that concept is determining
      a range of individual needs and identifying factors that alter these needs. We
      give the rationale for endpoints of fatty acid metabolism related to platelets
      and the risk of thrombosis, give the rationale for the recommendation for a new
      nutrient, and show the necessity for including nutrient interaction in the
      determination of needs for two nutrients.

PMID- 8644700
TI  - Essential nutrients and immunologic functions.
AB  - Several indexes of immune response, including responses on delayed-type
      hypersensitivity skin tests, antibody production, lymphocyte proliferation,
      cytokine production, and numbers of the specific subgroups of white blood cells,
      are influenced by essential nutrient intake and may serve as functional tests for
      evaluating nutritional status. In certain segments of the population, such as
      elderly persons and smokers, activity of the immune indexes can be increased
      through dietary supplementation with micronutrients, and there may be a rationale
      to increase selected recommended dietary allowances for the general population.
      The activity of the immune system may also be enhanced with decreases in total
      fat intake or lessened with increases in total fat intake, particularly of the n
      3 type. Research to date, therefore, suggests that several dietary components,
      both essential and nonessential, can affect human immune response. The intake of
      these nutrients can be modulated to regulate the activity of the immune system.

PMID- 8644701
TI  - The role of nutrition in the development of normal cognition.
AB  - The goal of this section of the meeting was to review the relation between
      nutrition and cognition. The topics selected for discussion included generalized
      malnutrition, iodine deficiency, iron metabolism, and the relation of fatty acids
      to the development of the nervous system. Each subject is immense and demands a
      detailed exposition, but can be treated here only in brief form. However, these
      short essays should give some insight into the status of our current knowledge.

PMID- 8644702
TI  - Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern
      Sweden.
AB  - Nine different germ-line mutations in the BRCA1 breast and ovarian cancer
      susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by
      use of SSCP and heteroduplex analysis of all exons and flanking intron region and
      by a protein-truncation test for exon 11, followed by direct sequencing. All but
      one of the mutations are predicted to give rise to premature translation
      termination and include seven frameshift insertions or deletions, a nonsense
      mutation, and a splice acceptor site mutation. The remaining mutation is a
      missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish
      founding mutations were identified: the nucleotide 2595 deletion A was found in
      five families, the C 1806 T nonsense mutation in three families, the 3166
      insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two
      families. Analysis of the intragenic polymorphism D17S855 supports common origins
      of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were
      breast-ovarian cancer families, several of them with a predominant ovarian cancer
      phenotype. The set of 32 families in which no BRCA1 alterations were detected
      included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1
      region and loss of the wild-type chromosome in associated tumors. Other tumor
      types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas,
      skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a
      carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage
      contained ovarian cancer, as compared with only 6 of the remaining 31 families
      (P<.001). The present study confirms the involvement of BRCA1 in disease
      predisposition for a subset of hereditary breast cancer families often
      characterized by ovarian cancers.

PMID- 8644703
TI  - Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex
      heteroduplex analysis. UKCCCR Familial Ovarian Cancer Study Group.
AB  - Germ-line mutations of the BRCA1 gene are responsible for a substantial
      proportion of families with multiple cases of early-onset breast and/or ovarian
      cancer. Since the isolation of BRCA1 last year, >65 distinct mutations scattered
      throughout the coding region have been detected, making analysis of the gene time
      consuming and technically challenging. We have developed a multiplex heteroduplex
      analysis that is designed to analyze one-quarter of the coding sequence in a
      single-step screening procedure and that will detect approximately 50% of all
      BRCA1 mutations so far reported in breast/ovarian cancer families. We have used
      this technique to analyze BRCA1 in 162 families with a history of breast and/or
      ovarian cancer and identified 12 distinct mutations in 35 families.

PMID- 8644705
TI  - Prevalence and origin of de novo duplications in Charcot-Marie-Tooth disease type
      1A: first report of a de novo duplication with a maternal origin.
AB  - Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral
      neuropathy. Sporadic cases of CMT have been described since the earliest reports
      of the disease. The most frequent form of the disorder, CMT1A, is associated with
      a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the
      disease. In order to investigate the prevalence of de novo CMT1A duplications,
      this study examined 118 duplication-positive CMT1A families. In 10 of these
      families it was demonstrated that the disease had arisen as the result of a de
      novo mutation. By taking into account the ascertainment of families, it can be
      estimated that > or = 10% of autosomal dominant CMT1 families are due to de novo
      duplications. The CMT1A duplication is thought to be the product of unequal
      crossing over between parental chromosome 17 homologues during meiosis.
      Polymorphic markers from within the duplicated region were used to determine the
      parental origin of these de novo duplications in eight informative families.
      Seven were of paternal and one of maternal origin. This study represents the
      first report of a de novo duplication with a maternal origin and indicates that
      it is not a phenomenon associated solely with male meioses. Recombination
      fractions for the region duplicated in CMT1A are larger in females than in males.
      That suggests that oogenesis may be afforded greater protection from misalignment
      during synapsis, and/or that there may be lower activity of those factors or
      mechanisms that lead to unequal crossing over at the CMT1A locus.

PMID- 8644704
TI  - Molecular analysis of patients with beta-glucuronidase deficiency presenting as
      hydrops fetalis or as early mucopolysaccharidosis VII.
AB  - Although not all mucopolysaccharidosis type VII (MPS VII) neonates present with
      hydrops fetalis or with related symptoms, hydrops fetalis is a common form of
      presentation of this mucopolysaccharidosis. We used reverse-transcription-PCR
      SSCP and direct sequencing to screen for mutations in the human beta
      glucuronidase cDNA of 17 MPS VII patients with severe presentation of the
      disease. Mutations resulting in an unstable mRNA were detected in genomic DNA
      with direct sequencing of the PCR-amplified beta-glucuronidase exons. We found
      extensive genetic heterogeneity in MPS VII alleles: in addition to 6 or 12
      previously reported mutations (L176F, R216W, R357X, R382C, W507X, and W627C), we
      detected 14 undescribed mutations in the beta-glucuronidase coding region that
      produce MPS VII alleles (G136R, E150K, S312X, Y320S, Y320C, H351Y, R382H, R374C,
      R435P, R477W, G572D, Y508C, K606N and 1900 delta GA). The mutations in hydropic
      fetuses were widely scattered in the beta-glucuronidase gene. Analysis of three
      polymorphic sites of the mutant alleles (1766T/C, 1972C/T and a new 1091+27C/G
      polymorphism) allowed exclusion of identity by descent for some recurrent
      mutations. Three of four mutations introducing a premature translation stop codon
      were found to affect mRNA abundance and/or structure. Expression studies provided
      evidence for the causal relationship between each of the mutations found in MPS
      VII alleles and the enzyme deficiency, in that all mutations identified exhibited
      markedly reduced enzyme activity expressed in COS7 cells following transfection
      with the mutant cDNA.

PMID- 8644706
TI  - Discordant phenotype in siblings with X-linked agammaglobulinemia.
AB  - X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused
      by a defect in a B-cell-specific signaling molecule, Btk. There has been little
      concordance of phenotype with genotype in this disorder, and defects in Btk cause
      immunodeficiencies that range from mild impairment to complete inability to
      produce antibodies. The factors modifying the phenotype of XLA are not
      understood. The current study is the first description of two male siblings with
      identical T134 --> C mutations in the translation initiation ATG of Btk who have
      different clinical phenotypes. The proband lacks immunoglobulins and B cells and
      has recurrent infections, while the elder, affected brother has normal levels of
      IgG and IgM and very few infections. Both have undetectable levels of Btk kinase
      activity in circulating mononuclear cells. Complete sequencing of Btk gene
      transcripts in both brothers revealed no additional mutations to account for the
      discordant phenotypes. This description provides unequivocal evidence that the
      phenotype of XLA is influenced by factors additional to the Btk gene.

PMID- 8644707
TI  - Somatic mosaicism in a patient with neurofibromatosis type 1.
AB  - Using loss of heterozygosity analysis, a method designed to detect moderate to
      large gene deletions, we have identified a new-mutation neurofibromatosis type 1
      (NF1) patient who is somatically mosaic for a large maternally derived deletion
      in the NF1 gene region. The deletion extends at least from exon 4 near the 5' end
      of the gene to intron 39 near the 3' end. The gene-coding region is, therefore,
      mostly or entirely deleted, encompassing a loss of > or = 100 kb. We hypothesize
      that the deletion occurred at a relatively early developmental timepoint, since
      signs of NF1 in this patient are not confined to a specific body region, as seen
      in "segmental" NF, and since both mesodermally and ectodermally derived cells are
      affected. This report provides the first molecular evidence of somatic mosaicism
      in NF1 and, taken together with a recent report of germ-line mosaicism in NF1,
      adds credence to the concept that mosaicism plays an important role in phenotypic
      and genetic aspects of NF1 and may even be a relatively common phenomenon.

PMID- 8644708
TI  - FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer
      syndromes: evidence for missense changes, insertions, and a deletion due to
      alternative RNA splicing.
AB  - Fibroblast growth factor receptor 2 (FGFR2) mutations have been associated with
      the craniosynostotic conditions Crouzon, Jackson-Weiss, and Pfeiffer syndromes.
      Previously, mutations were described in the exons IIIa and IIIc, which form the
      extracellular, third immunoglobulin-like domain (IgIII) and adjacent linker
      regions, both of which are normally involved in ligand binding. For all three
      conditions, mutations were found in exon IIIc. Only in Crouzon syndrome were
      mutations identified in exon IIIa. In this study, 39 cases with one of these
      three conditions were screened for exon IIIa or IIIc mutations. Eleven mutations
      are reported in 17 unrelated cases. Mutations in exon IIIa are identified for not
      only Crouzon but also Jackson-Weiss and Pfeiffer syndromes. Four mutations in
      either exon IIIa or exon IIIc reported only in Crouzon syndrome are present also
      in one of the other two syndromes. Two insertions, one in exon IIIa in a Crouzon
      syndrome patient and the other in exon IIIc in a Pfeiffer syndrome patient, were
      observed. The latter mutation has the same alternative RNA splicing effect as a
      reported synonymous mutation for Crouzon syndrome. A missense mutation was
      detected in one Pfeiffer syndrome family in which two members had
      craniosynostosis without limb anomalies. The inter- and intrafamilial variability
      in expression of FGFR2 mutations suggests that these three syndromes, presumed to
      be clinically distinct, are instead representative of a spectrum of related
      craniosynostotic and digital disorders.

PMID- 8644709
TI  - Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation
      phenotype without alpha-thalassemia.
AB  - We have previously reported the isolation of a gene from Xq13 that codes for a
      putative regulator of transcription (XNP) and has now been shown to be the gene
      involved in the X-linked alpha-thalassemia with mental retardation (ATR-X)
      syndrome. The widespread expression and numerous domains present in the putative
      protein suggest that this gene could be involved in other phenotypes. The
      predominant expression of the gene in the developing brain, as well as its
      association with neuron differentiation, indicates that mutations of this gene
      might result in a mental retardation (MR) phenotype. In this paper we present a
      family with a splice junction mutation in XNP that results in the skipping of an
      exon and in the introduction of a stop codon in the middle of the XNP-coding
      sequence. Only the abnormal transcript is expressed in two first cousins
      presenting the classic ATR-X phenotype (with alpha-thalassemia and HbH
      inclusions). In a distant cousin presenting a similar dysmorphic MR phenotype but
      not having thalassemia, approximately 30% of the XNP transcripts are normal.
      These data demonstrate that the mode of action of the XNP gene product on globin
      expression is distinct from its mode of action in brain development and facial
      morphogenesis and suggest that other dysmorphic mental retardation phenotypes,
      such as Juberg-Marsidi or some sporadic cases of Coffin-Lowry, could be due to
      mutations in XNP.

PMID- 8644710
TI  - The age of human mutation: genealogical and linkage disequilibrium analysis of
      the CLN5 mutation in the Finnish population.
AB  - Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal
      recessive progressive encephalopathy of childhood enriched in the western part of
      Finland, with a local incidence of 1 in 1500. We recently assigned the locus for
      vLINCL, CLN5, to 13q21.1-q32. In the present study, the haplotype analysis of
      Finnish CLN5 chromosomes provides evidence that one single mutation causes vLINCL
      in the Finnish population. Eight microsatellite markers closely linked to the
      CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared
      haplotype analysis. One single haplotype formed by flanking markers D13S160 and
      D13S162 in strong linkage disequilibrium (P < .0001) was present in 81% of
      disease-bearing chromosomes. Allele 4 at the marker locus D13S162 was detected in
      94% of disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by
      virtue of its restricted geographical distribution, church records were used to
      identify the common ancestors for 18 vLINCL families diagnosed in Finland. The
      pedigrees of the vLINCL ancestors merged on many occasions, which also supports a
      single founder mutation that obviously happened 20 to 30 generations ago (i.e.,
      approximately 500 years ago) in this isolated population. Linkage disequilibrium
      was detected with seven markers covering an extended genetic distance of 11 cM,
      which further supports the young age of the CLN5 mutation. When the results of
      genealogical and linkage disequilibrium studies were combined, the CLN5 gene was
      predicted to lie approximately 200 - 400 kb (total range 30 - 1360 kb) from the
      closest marker D13S162.

PMID- 8644711
TI  - FMR1 in global populations.
AB  - Fragile X syndrome, a frequent form of inherited mental retardation, results from
      the unstable expansion of a cryptic CGG repeat within the 5' UTR region of the
      FMR1 gene. The CGG repeat is normally polymorphic in length, and the content is
      frequently interrupted by AGG triplets. These interruptions are believed to
      stabilize the repeat, and their absence, leading to long tracts of perfect CGG
      repeats, may give rise to predisposed alleles. In order to examine the stability
      of normal FMR1 alleles, the repeat length of 345 chromosomes from nine global
      populations was examined with the content also determined from 114 chromosomes as
      assessed by automated DNA sequencing. The FMR1 alleles, defined by the CGG
      repeat, as well as by the haplotypes of nearby polymorphic loci, were very
      heterogeneous, although the level of variation correlated with the age and/or
      genetic history of a particular population. Native American alleles, interrupted
      by three AGG repeats, exhibited marked stability over 7,000 years. However, in
      older African populations, parsimony analysis predicts the occasional loss of an
      AGG, leading to more perfect CGG repeats. These data therefore support the
      suggestion that AGG interruptions enhance the stability of the FMR1 repeat and
      indicate that the rare loss of these interruptions leads to alleles with longer
      perfect CGG-repeat tracts.

PMID- 8644713
TI  - High-resolution mapping of the gene for cystinosis, using combined biochemical
      and linkage analysis.
AB  - Infantile nephropathic cystinosis is an autosomal recessive disorder
      characterized biochemically by an abnormally high intracellular content of free
      cystine in different organs and tissues due to a transport defect of cystine
      through the lysosomal membrane. Affected children present with the Fanconi
      syndrome and usually develop progressive renal failure within the 1st decade of
      life. Measurement of free cystine in purified polymorphonuclear leukocytes
      provides an accurate method for diagnosis and detection of heterozygous carriers.
      In order to localize the gene locus for cystinosis we performed linkage analysis
      in 18 cystinosis families. However, since 17 of these were simplex families, we
      decided to include the phenotypes of the heterozygous carriers previously
      determined by their leukocyte cystine content in the linkage analysis. This
      approach allowed us to obtain highly significant results, confirming the
      localization of the cystinosis gene locus recently mapped to the short arm of
      chromosome 17 by the Cystinosis Collaborative Research Group. Crucial
      recombination events allowed us to refine the interval of the cystinosis gene to
      a genetic distance of 1 cM. No evidence of genetic heterogeneity was found. Our
      results demonstrate that the use of the previously determined phenotypes of
      heterozygous carriers in linkage analysis provides a reliable method for the
      investigation of simplex families in autosomal recessive traits.

PMID- 8644712
TI  - Linkage disequilibrium mapping places the gene causing familial Mediterranean
      fever close to D16S246.
AB  - This report presents refined genetic mapping data for the gene causing familial
      Mediterranean fever (FMF), a recessively inherited disorder of inflammation. We
      sampled 65 Jewish, Armenian, and Arab families and typed them for eight markers
      from chromosome 16p. Using a new algorithm that permits multipoint calculations
      for a dense map of markers in consanguineous families, we obtained a maximal LOD
      score of 49.2 at a location 1.6 cM centromeric to D16S246. A specific haplotype
      at D16S283-D16S94-D16S246 was found in 76% of Moroccan and 32% of non-Moroccan
      Jewish carrier chromosomes, but this haplotype was not overrepresented in
      Armenian or Arab FMF carriers. Moreover, the 2.5-kb allele at D16S246 was
      significantly associated with FMF in Moroccan and non-Moroccan Jews but not in
      Armenians or Arabs. Since the Moroccan Jewish community represents a relatively
      recently established and genetically isolated founder population, we analyzed the
      Moroccan linkage-disequilibrium data by using Luria-Delbruck formulas and
      simulations based on a Poisson branching process. These methods place the FMF
      susceptibility gene within 0.305 cM of D16S246 (2-LOD-unit range 0.02-0.64 cM).

PMID- 8644714
TI  - Isolation of a cosmid clone corresponding to an inv(21) breakpoint of a patient
      with transient abnormal myelopoiesis.
AB  - Transient abnormal myelopoiesis (TAM) is a leukemoid reaction occurring
      occasionally on Down syndrome (DS) newborn infants. It has been hypothesized that
      "disomic homozygosity" in 21-trisomic cells plays an important role in the
      genesis of TAM, and the putative TAM gene was suggested to be mapped at a 21q11
      region. We encountered a DS-associated TAM infant with a
      47,XY,inv(21)(q11.1q22.13),+inv(21)(q11.1q22.13) karyotype. On the basis of
      another presumption that in this patient the putative TAM gene is disrupted by
      the break, we tried to isolate a breakpoint DNA. FISH analysis with cosmid clones
      corresponding to various sequence-tagged-site (STS) markers mapped at around
      21q11.1-q11.2, we confirmed that the proximal breakpoint of the inv(21) was
      located between two STSs, G51E07 and D21S215, the latter locus being consistent
      with the previous tentative mapping. After construction of a cosmid contig
      encompassing between the two markers, we have isolated a cosmid clone
      corresponding to the proximal breakpoint of the inversion. This breakpoint was
      located near a previously identified duplicated region that is homologous to the
      sequence at 21q22.1. The isolated cosmid clone is useful for analysis of other
      TAM patients and for a search for a transcript at or flanking the breakpoint.

PMID- 8644715
TI  - Orofacial clefts, parental cigarette smoking, and transforming growth factor
      alpha gene variants.
AB  - Results of studies to determine whether women who smoke during early pregnancy
      are at increased risk of delivering infants with orofacial clefts have been
      mixed, and recently a gene-environment interaction between maternal smoking,
      transforming growth factor-alpha (TGFa), and clefting has been reported. Using a
      large population-based case-control study, we investigated whether parental
      periconceptional cigarette smoking was associated with an increased risk for
      having offspring with orofacial clefts. We also investigated the influence of
      genetic variation of the TGFa locus on the relation between smoking and clefting.
      Parental smoking information was obtained from telephone interviews with mothers
      of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734
      (78.2%) nonmalformed control infants. DNA was obtained from newborn screening
      blood spots and genotyped for the allelic variants of TGFa. We found that risks
      associated with maternal smoking were most elevated for isolated cleft lip with
      or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and
      for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked > or =20
      cigarettes/d. Analyses controlling for the potential influence of other variables
      did not reveal substantially different results. Clefting risks were even greater
      for infants with the TGFa allele previously associated with clefting whose
      mothers smoked > or =20 cigarettes/d. These risks for white infants ranged from 3
      fold to 11-fold across phenotypic groups. Paternal smoking was not associated
      with clefting among the offspring of nonsmoking mothers, and passive smoke
      exposures were associated with at most slightly increased risks. This study
      offers evidence that the risk for orofacial clefting in infants may be influenced
      by maternal smoke exposures alone as well as in combination (gene-environment
      interaction) with the presence of the uncommon TGFa allele.

PMID- 8644716
TI  - Heritability of human brain functioning as assessed by electroencephalography.
AB  - To study the genetic and environmental contributions to individual differences in
      CNS functioning, the electroencephalogram (EEG) was measured in 213 twin pairs
      age 16 years. EEG was measured in 91 MZ and 122 DZ twins. To quantify sex
      differences in the genetic architecture, EEG was measured in female and male same
      sex twins and in opposite-sex twins. EEG was recorded on 14 scalp positions
      during quiet resting with eyes closed. Spectral powers were calculated for four
      frequency bands: delta, theta, alpha, and beta. Twin correlations pointed toward
      high genetic influences for all these powers and scalp locations. Model fitting
      confirmed these findings; the largest part of the variance of the EEG is
      explained by additive genetic factors. The averaged heritabilites for the delta,
      theta, alpha and beta frequencies was 76%, 89%, 89%, and 86%, respectively.
      Multivariate analyses suggested that the same genes for EEG alpha rhythm were
      expressed in different brain areas in the left and right hemisphere. This study
      shows that brain functioning, as indexed by rhythmic brain-electrical activity,
      is one of the most heritable characteristics in humans.

PMID- 8644717
TI  - Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE
      genotypes among elderly African Americans, Caucasians, and Hispanics in New York
      City.
AB  - Apolipoprotein-E epsilon 4 (APOE-epsilon 4) has been consistently associated with
      Alzheimer disease (AD) and may be responsible for an earlier age at onset. We
      have previously reported a diminished association between APOE-epsilon 4 and AD
      in African Americans. Using a new method, which allows inclusion of censored
      information, we compared relative risks by APOE genotypes in an expanded
      collection of cases and controls from three ethnic groups in a New York
      community. The relative risk for AD associated with APOE-epsilon 4 homozygosity
      was increased in all ethnic groups (African American relative risk [RR]=3.0; 95%
      confidence interval [CI]=1.5-5.9; Caucasian RR=7.3, 95% CI=2.5-21.6; and Hispanic
      RR=2.5, 95% CI=1.1-5.7), compared with those with APOE-epsilon 3/epsilon 3
      genotypes. The risk was also increased for APOE-epsilon 4 heterozygous Caucasians
      (RR=2.9, 95% CI=1.7-5.1) and Hispanics (RR=1.6, 95% CI=1.1-2.3), but not for
      African Americans (RR=0.6, 95% Ci=0.4-0.9). The age distribution of the
      proportion of Caucasians and Hispanics without AD was consistently lower for APOE
      epsilon 4 homozygous and APOE-epsilon 4 heterozygous individuals than for those
      with other APOE genotypes. In African Americans this relationship was observed
      only in APOE-epsilon 4 homozygotes. These results confirm that APOE genotypes
      influence the RR of AD in Caucasians and Hispanics. Differences in risk among
      APOE-epsilon 4 heterozygote African Americans suggest that other genetic or
      environmental factors may modify the effect of APOE-epsilon 4 in some
      populations.

PMID- 8644718
TI  - Multilocus genetic determinants of LDL particle size in coronary artery disease
      families.
AB  - Recent interest in atherosclerosis has focused on the genetic determinants of low
      density lipoprotein (LDL) particle size, because of (i) the association of small
      dense LDL particles with a three-fold increased risk for coronary artery disease
      (CAD) and (ii) the recent report of linkage of the trait to the LDL receptor
      (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative
      pair analysis methods in CAD families, we tested for linkage of a gene or genes
      controlling LDL particle sizes with the genetic loci for the major
      apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed
      evidence for linkage to the LDL receptor locus (P=.008). For six candidate gene
      loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein
      lipase, and high-density lipoprotein-binding protein, no evidence for linkage was
      observed by sib-pair linkage analyses (P values ranged from .24 to .81). However,
      in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV
      locus (chromosome 11) (P=.06) and significant evidence for linkage of the
      cholesteryl ester transfer protein locus (chromosome 16) (P=.01) and the
      manganese superoxide dismutase locus (chromosome 6) (P=.001), thus indicating
      multilocus determination of this atherogenic trait.

PMID- 8644719
TI  - mtDNA control-region sequence variation suggests multiple independent origins of
      an "Asian-specific" 9-bp deletion in sub-Saharan Africans.
AB  - The intergenic COII/tRNA(Lys) 9-bp deletion in human mtDNA, which is found at
      varying frequencies in Asia, Southeast Asia, Polynesia, and the New World, was
      also found in 81 of 919 sub-Saharan Africans. Using mtDNA control-region sequence
      data from a subset of 41 individuals with the deletion, we identified 22 unique
      mtDNA types associated with the deletion in Africa. A comparison of the unique
      mtDNA types from sub-Saharan Africans and Asians with the 9-bp deletion revealed
      that sub-Saharan Africans and Asians have sequence profiles that differ in the
      locations and frequencies of variant sites. Both phylogenetic and mismatch
      distribution analysis suggest that 9-bp deletion arose independently in sub
      Saharan Africa and Asia and that the deletion has arisen more than once in
      Africa. Within Africa, the deletion was not found among Khoisan peoples and was
      rare to absent in western and southwestern African populations, but it did occur
      in Pygmy and Negroid populations from central Africa and in Malawi and southern
      African Bantu-speakers. The distribution of the 9-bp deletion in Africa suggests
      that the deletion could have arisen in central Africa and was then introduced to
      southern Africa via the recent "Bantu expansion."

PMID- 8644720
TI  - Mitochondrial D-loop "signatures" produced by low-stringency single specific
      primer PCR constitute a simple comparative human identity test.
AB  - We have developed a technique called "LSSP-PCR" (low-stringency single specific
      primer PCR) that detects single or multiple mutations in DNA. A purified DNA
      fragment is submitted to PCR by using a single primer specific for one of the
      extremities of the fragment, under conditions of very low stringency. The primer
      hybridizes specifically to its complementary extremity and nonspecifically to
      multiple sites within the fragment, in a sequence-dependent manner. A complex set
      of reaction products is thus created that, when separated by electrophoresis,
      constitutes a unique "gene signature." We here report the application of LSSP-PCR
      to the detection of sequence variation in the control (D-loop) region of human
      mtDNA, which is known to differ significantly between unrelated individuals. We
      prepared human DNA samples from blood and amplified a 1024-bp portion of the
      mtDNA control region, using primers L15996 and H408. The amplified mtDNA
      fragments were then reamplified under LSSP-PCR conditions by using L15996 or H408
      as drivers to produce complex signatures that always differed between unrelated
      individuals and yet were highly reproducible. In contrast, all mother-child pairs
      tested were identical, as expected from the matrilineal inheritance of mtDNA.
      Thus, the use of LSSP-PCR to produce D-loop signatures constitutes a powerful new
      technique for mtDNA-based comparative identity testing.

PMID- 8644721
TI  - Lack of interest by nonpregnant couples in population-based cystic fibrosis
      carrier screening.
AB  - We used signs and letters to offer free cystic fibrosis (CF) carrier screening to
      nonpregnant adults in stable relationships who visited numerous clinical and
      nonclinical sites in Nashville. A total of 179 individuals (<<1% of those
      eligible) elected to be tested. To understand this observation, we used
      questionnaires to assess individuals' attitudes about genetic testing in general
      and about CF carrier screening in particular (n=873). Participants expressed
      conflicting views about carrier screening. More than 90% of people thought that
      genetic testing should at least be available. Most respondents said that the
      views of their partners and physicians were important in their decision making,
      and most believed that these others favored genetic testing. Yet, more than two
      thirds indicated that such factors as insurability, being "at risk," what they
      would need to learn, abortion, and religious beliefs were important in their
      decision making, opinions that mitigated against genetic testing. In particular,
      one-third feared that carriers would lose their health insurance, one-quarter
      said that they would have been more interested had they been able to provide DNA
      by buccal swab rather than by finger stick, and less than one-sixth believed that
      genetic testing was meddling in God's plan. In the face of both the low level of
      use of free CF carrier screening by nonpregnant couples when it was not offered
      in person by health-care professionals and the wide variety of concerns
      demonstrated, we believe that clinicians should not routinely offer carrier
      screening to nonpregnant individuals who do not have a family history of CF.

PMID- 8644722
TI  - Advanced maternal age and the risk of Down syndrome characterized by the meiotic
      stage of chromosomal error: a population-based study.
AB  - The identification of DNA polymorphisms makes it possible to classify trisomy 21
      according to the parental origin and stage (meiosis I [MI], meiosis II [MII], or
      postzygotic mitotic) of the chromosomal error. Studying the effect of parental
      age on these subgroups could shed light on parental exposures and their timing.
      From 1989 through 1993, 170 infants with trisomy 21 and 267 randomly selected
      control infants were ascertained in a population-based, case-control study in
      metropolitan Atlanta. Blood samples for genetic studies were obtained from case
      infants and their parents. Using logistic regression, we independently examined
      the association between maternal and paternal age and subgroups of trisomy 21
      defined by parental origin and meiotic stage. The distribution of trisomy 21 by
      origin was 86% maternal (75% MI and 25% MII), 9% paternal (50% MI and 50% MII),
      and 5% mitotic. Compared with women <25 years of age, women > or = 40 years old
      had an odds ratio of 5.2 (95% confidence interval, 1.0-27.4) for maternal MI
      (MMI) errors and 51.4 (95% confidence interval, 2.3-999.0) for maternal MII
      (MMII) errors. Birth-prevalence rates for women > or = 40 years old were 4.2/1000
      births for MMI errors and 1.9/1000 for MMII errors. These results support an
      association between advanced maternal age and both MMI and MMII errors. The
      association with MI does not pinpoint the timing of the error; however, the
      association with MII implies that there is at least one maternal-age related
      mechanism acting around the time of conception.

PMID- 8644723
TI  - Prenatal diagnosis of 45,X/46,XX.

PMID- 8644724
TI  - Isolated case of mental retardation and ataxia due to a de novo mitochondrial
      T8993G mutation.

PMID- 8644726
TI  - Positive fragile X microsatellite associations point to a common mechanism of
      dynamic mutation evolution.

PMID- 8644725
TI  - High frequency of mutations in codon 98 of the peripheral myelin protein P0 gene
      in 20 French CMT1 patients.

PMID- 8644727
TI  - 1995 ASHG presidential address. The challenges and opportunities of times of
      change.

PMID- 8644728
TI  - Characterization of the factor VIII defect in 147 patients with sporadic
      hemophilia A: family studies indicate a mutation type-dependent sex ratio of
      mutation frequencies.
AB  - The clinical manifestation of hemophilia A is caused by a wide range of different
      mutations. In this study the factor VIII genes of 147 severe hemophilia A
      patients--all exclusively from sporadic families--were screened for mutations by
      use of the complete panel of modern DNA techniques. The pathogenous defect could
      be characterized in 126 patients (85.7 percent). Fifty-five patients (37.4
      percent) showed a F8A-gene inversion, 47 (32.0 percent) a point mutation, 14 (9.5
      percent) a small deletion, 8 (5.4 percent) a large deletion, and 2 (1.4 percent)
      a small insertion. Further, four (2.7 percent) mutations were localized but could
      not be sequenced yet. No mutation could be identified in 17 patients (11.6
      percent). Sixteen (10.9 percent) of the identified mutations occurred in the B
      domain. Four of these were located in an adenosine nucleotide stretch at codon
      1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9
      percent) of 76 patients, mothers, comprising 3 of 16 de novo mutations in the
      patients mothers. Investigation of family relatives allowed detection of a de
      novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families.
      On the basis of these data, the male:female ratio of mutation frequencies (k) was
      estimated as k = 3.6. By use of the quotients of mutation origin in maternal
      grandfather to patients mother or to maternal grandmother, k was directly
      estimated as k = 15 and k = 7.5, respectively. Considering each mutation type
      separately, we revealed a mutation type-specific sex ratio of mutation
      frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10
      fold-higher mutation rate in male germ cells, whereas deletions showed a >5-fold
      higher mutation rate in female germ cells. Consequently, and in accordance with
      the data of other diseases like Duchenne muscular dystrophy, our results indicate
      that at least for X-chromosomal disorders the male:female mutation rate of a
      disease is determined by its proportion of the different mutation types.

PMID- 8644729
TI  - Glycine substitutions in the triple-helical region of type VII collagen result in
      a spectrum of dystrophic epidermolysis bullosa phenotypes and patterns of
      inheritance.
AB  - The dystrophic forms of epidermolysis bullosa (DEB) are characterized by
      fragility of the skin and mucous membranes. DEB can be inherited in either an
      autosomal dominant or autosomal recessive pattern, and the spectrum of clinical
      severity is highly variable. The unifying diagnostic hallmark of DEB is
      abnormalities in the anchoring fibrils, which consist of type VII collagen, and,
      recently, mutations in the corresponding gene, COL7A1, have been disclosed in a
      number of families. In this study, we report six families with glycine
      substitution mutations in the triple-helical region of type VII collagen. Among
      the six families, two demonstrated a mild phenotype, and the inheritance of the
      mutation was consistent with the dominantly inherited form of DEB. In the four
      other families, the mutation was silent in the heterozygous state but, when
      present in the homozygous state, or combined with a second mutation, resulted in
      a recessively inherited DEB phenotype. Type VII collagen is, therefore, unique
      among the collagen genes, in that different glycine substitutions can be either
      silent in heterozygous individuals or result in a dominantly inherited DEB.
      Inspection of the locations of the glycine substitutions along the COL7A1
      polypeptide suggests that the consequences of these mutations, in terms of
      phenotype and pattern of inheritance, are position independent.

PMID- 8644730
TI  - Compound heterozygosity for COL7A1 mutations in twins with dystrophic
      epidermolysis bullosa: a recessive paternal deletion/insertion mutation and a
      dominant negative maternal glycine substitution result in a severe phenotype.
AB  - We have previously demonstrated genetic linkage between the type VII collagen
      gene (COL7A1) and the dominant (DDEB) and recessive (RDEB) forms of dystrophic
      epidermolysis bullosa (DEB) and have subsequently identified pathogenetic
      mutations in several families. Mutations in DDEB identified thus far are glycine
      substitutions in the collagenous domain of COL7A1, while the most severe forms of
      RDEB result from premature termination codon (PTC) mutations on both alleles. In
      this study, we performed mutation analysis in the COL7A1 gene in twins who
      displayed a severe DEB phenotype. Mutational analysis revealed a paternal 2-bp
      deletion/1-bp insertion in exon 56, designated 5103CC-->G, which results in a
      frameshift and downstream PTC. Analysis of the maternal COL7A1 allele revealed a
      glycine-to-arginine substitution in exon 91 (G2351R). Careful questioning of the
      mother revealed that she and her father had a history of shedding of toenails and
      occasional poorly healing erosions, consistent with a mild form of DDEB.
      Immunoprecipitation of type VII collagen from fibroblasts of the twins revealed a
      marked reduction in intracellular protein production, consistent with the drastic
      reduction in mRNA transcript from the paternal mutant allele, while the majority
      of polypeptides bearing the glycine substitution appeared to be degraded
      intracellularly. Thus, the severe RDEB phenotype in the probands results from
      compound heterozygosity for one glycine substitution and one PTC mutation in
      COL7A1.

PMID- 8644731
TI  - Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the
      most prevalent mutant allele associated with loss of catalytic activity in
      Caucasians.
AB  - The autosomal recessive trait of thiopurine S-methytransferase (TPMT) deficiency
      is associated with severe hematopoietic toxicity when patients are treated with
      standard doses of mercaptopurine, azathioprine, or thioguanine. To define the
      molecular mechanism of this genetic polymorphism, we cloned and characterized the
      cDNA of a TPMT-deficient patient, which revealed a novel mutant allele (TPMT*3)
      containing two nucleotide transitions (G460-->A and A719-->G) producing amino
      acid changes at codons 154 (Ala-->Thr) and 240 (Tyr--> Cys), differing from the
      rare mutant TPMT allele we previously identified (i.e., TPMT*2 with only G238-
      >C). Site-directed mutagenesis and heterologous expression established that
      either TPMT*3 mutation alone leads to a reduction in catalytic activity (G460-
      >A, ninefold reduction; A719-->G, 1.4-fold reduction), while the presence of both
      mutations leads to complete loss of activity. Using mutation specific PCR-RFLP
      analysis, the TPMT*3 allele was detected in genomic DNA from approximately 75
      percent of unrelated white subjects with heterozygous phenotypes, indicating that
      TPMT*3 is the most prevalent mutant allele associated with TPMT-deficiency in
      Caucasians.

PMID- 8644732
TI  - Genetic and biochemical impairment of mitochondrial complex I activity in a
      family with Leber hereditary optic neuropathy and hereditary spastic dystonia.
AB  - A rare form of Leber hereditary optic neuropathy (LHON) that is associated with
      hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy
      and ophthalmological lesions were present together in some family members,
      whereas only one type of abnormality was found in others. mtDNA mutations
      previously reported in LHON were not present. Sequence analysis of the protein
      coding mitochondrial genes revealed two previously unreported mtDNA mutations. A
      heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene
      resulted in the substitution of an isoleucine for valine at amino acid position
      312. A second mutation, a homoplasmic T-->A transition at nucleotide position
      14596 in the ND6 gene, resulted in the substitution of a methionine for the
      isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy
      revealed a severe complex I deficiency, providing a link between these unique
      mtDNA mutations and this rare, complex phenotype including Leber optic
      neuropathy.

PMID- 8644733
TI  - Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study
      of three families with hepatoerythropoietic porphyria.
AB  - A deficiency in uroporphyrinogen decarboxylase (UROD) enzyme activity, the fifth
      enzyme of the heme biosynthetic pathway, is found in patients with sporadic
      porphyria cutanea tarda (s-PCT), familial porphyria cutanea tarda (f-PCT), and
      hepatoerythropoietic porphyria (HEP). Subnormal UROD activity is due to mutations
      of the UROD gene in both f-PCT and HEP, but no mutations have been found in s
      PCT. Genetic analysis has determined that f-PCT is transmitted as an autosomal
      dominant trait. In contrast, HEP, a severe form of cutaneous porphyria, is
      transmitted as an autosomal recessive trait. HEP is characterized by a profound
      deficiency of UROD activity, and the disease is usually manifest in childhood. In
      this study, a strategy was designed to identify alleles responsible for the HEP
      phenotype in three unrelated families. Mutations of UROD were identified by
      direct sequencing of four amplified fragments that contained the entire coding
      sequence of the UROD gene. Two new missense mutations were observed at the
      homoallelic state: P62L (proline-to-leucine substitution at codon 62) in a
      Portuguese family and Y311C (tyrosine-to-cysteine substitution at codon 311) in
      an Italian family. A third mutation, G281E, was observed in a Spanish family.
      This mutation has been previously described in three families from Spain and one
      from Tunisia. In the Spanish family described in this report, a paternal uncle of
      the proband developed clinically overt PCT as an adult and proved to be
      heterozygous for the G281E mutation. Mutant cDNAs corresponding to the P62L and
      Y311C changes detected in these families were created by site-directed
      mutagenesis. Recombinant proteins proved to have subnormal enzyme activity, and
      the Y311C mutant was thermolabile.

PMID- 8644735
TI  - Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado
      Joseph disease: the mutant allele is preferentially transmitted in male meiosis.
AB  - Autosomal dominant dentatorubral-pallidoluysian atrophy (DRPLA) and Machado
      Joseph disease (MJD) are neurodegenerative disorders caused by CAG trinucleotide
      repeat expansions. An inverse correlation of age at onset with the length of the
      expanded CAG trinucleotide repeats has been demonstrated, and the
      intergenerational instability of the length of the CAG trinucleotide repeats,
      which is more prominent in paternal than in maternal transmissions, has been
      shown to underlie the basic mechanisms of anticipation in DRPLA and MJD. Our
      previous observations on DRPLA and MJD pedigrees, as well as a review of the
      literature, have suggested that the numbers of affected offspring exceed those of
      unaffected offspring, which is difficult to explain by the Mendelian principle of
      random segregation of alleles. In the present study, we analyzed the segregation
      patterns in 211 transmissions in 24 DRPLA pedigrees and 80 transmissions in 7 MJD
      pedigrees, with the diagnoses confirmed by molecular testing. Significant
      distortions in favor of transmission of the mutant alleles were found in male
      meiosis, where the mutant alleles were transmitted to 62% of all offspring in
      DRPLA (chi2 = 7.69; P<.01) and 73% in MJD (chi2 = 6.82; P<.01). The results were
      consistent with meiotic drive in DRPLA and MJD. Since more prominent meiotic
      instability of the length of the CAG trinucleotide repeats is observed in male
      meiosis than in female meiosis and meiotic drive is observed only in male
      meiosis, these results raise the possibility that a common molecular mechanism
      underlies the meiotic drive and the meiotic instability in male meiosis.

PMID- 8644734
TI  - Human homologue sequences to the Drosophila dishevelled segment-polarity gene are
      deleted in the DiGeorge syndrome.
AB  - DiGeorge syndrome (DGS) is a developmental defect of some of the neural crest
      derivatives. Most DGS patients show haploinsufficiency due to interstitial
      deletions of the proximal long arm of chromosome 22. Deletions of 22q11 have also
      been reported with patients with the velocardio-facial syndrome and familial
      conotruncal heart defects. It has been suggested that the wide phenotype spectrum
      associated with 22q11 monosomy is a consequence of contiguous-gene deletions. We
      report the isolation of human cDNAs homologous to the Drosophila dishevelled
      (dsh) segment-polarity gene. Sequences homologous to the 3' UTR of these
      transcripts (DVL-22) were positioned within the DGS critical region and were
      found to be deleted in DGS patients. Human DVL mRNAs are expressed in several
      fetal and adult tissues, including the thymus and, at high levels, the heart. Two
      transcripts, 3.2 and 5kb, were detected, in northern blot analysis, with
      different expression patterns in the surveyed tissues when different cDNAs were
      used. The isolated cDNAs exhibit high amino acid homology with the mouse and
      Xenopus Dvl-1 gene, the only other vertebrate dsh homologues so far isolated. The
      pivotal role of dsh in fly development suggests an analogous key function in
      vertebrate embryogenesis of its homologue genes. Since DGS may be due to
      perturbation of differentiation mechanisms at decisive embryological stages, a
      Dsh-like gene in the small-region overlap (SRO) might be a candidate for the
      pathogenesis of this disorder.

PMID- 8644736
TI  - Delineation of a contiguous gene syndrome with multiple exostoses, enlarged
      parietal foramina, craniofacial dysostosis, and mental retardation, caused by
      deletions in the short arm of chromosome 11.
AB  - A contiguous gene syndrome due to deletions of the proximal short arm of
      chromosome 11 is described in eight patients belonging to four families. The main
      clinical features are multiple exostoses, enlarged parietal foramina,
      craniofacial dysostosis, and mental retardation. The patients have cytogenetic
      and/or molecular deletions of chromosome 11p11-p13. These deletions are located
      between the centromere and D11S914 in a region of approximately 20cM. The present
      study confirms the presence of a multiple exostoses gene on chromosome 11p.
      Furthermore, it suggests that the gene for isolated foramina parietalie permagna
      and genes associated with craniofacial dysostosis and mental retardation reside
      in the same chromosomal region.

PMID- 8644737
TI  - The locus for a novel syndromic form of neuronal intestinal pseudoobstruction
      maps to Xq28.
AB  - The neuronal type of primary chronic idiopathic intestinal pseudoobstruction
      (CIIP) results from the developmental failure of enteric neurons to migrate or
      differentiate correctly. This leads to intestinal motility disorders, which are
      characterized by symptoms and signs of bowel obstruction in the absence of a
      mechanical obstacle. Most of these conditions are congenital, and among them some
      are inherited. One syndromic condition characterized by intestinal
      pseudoobstruction with morphological abnormalities of the argyrophil neurons in
      the myenteric plexus, associated with short small bowel, malrotation, and pyloric
      hypertrophy, has been previously described. We have studied a family affected by
      this disorder, in which the disease appeared to segregate as an X-linked
      recessive trait. In order to map the CIIP locus in this family, we performed
      linkage analysis in 26 family members by use of highly polymorphic microsatellite
      markers from the X chromosome. One of these markers, DXYS154, located in the
      distal part of Xq28, shows no recombination with a maximum lod score of 2.32.
      Multipoint analysis excluded linkage with markers spanning other regions of the X
      chromosome. Our results, integrated with the current genetic and physical map of
      Xq28, determine the order of loci as cen-DXS15-(CIIPX)-DXS1108/DXYS154-tel. This
      study establishes, for the first time, the mapping assignment of a neuropathic
      form of CIIP other than Hirschsprung disease.

PMID- 8644738
TI  - Frequent occurrence of BRCA2 linkage in Icelandic breast cancer families and
      segregation of a common BRCA2 haplotype.
AB  - Cloning of a breast cancer-predisposing gene (BRCA2) on chromosome 13Q12-14 has
      been reported recently. We analyzed seven large Icelandic breast cancer families
      with markers from the BRCA2 region. Five families showed strong evidence of
      linkage. The maximum two-point LOD scores for the five BRCA2-linked families
      ranged from 1.06 to 3.19. Haplotype analyses revealed a region with identical
      allele sizes between the families, suggesting that they have inherited the
      mutation from a common ancestor. Cancer types other than breast cancer occur in
      individuals, segregating the affected haplotype within these families. This
      suggests that mutations in the gene may also confer some risk of other
      malignancies in both males and females.

PMID- 8644739
TI  - Linkage of a gene for macular corneal dystrophy to chromosome 16.
AB  - Autosomal recessive macular corneal dystrophy (MCD) is a heterogeneous disorder
      leading to visual impairment. Sixteen American and Icelandic families (11 type I
      and 5 type II) were analyzed for linkage, by use of 208 polymorphic
      microsatellite markers. A significant maximum LOD score Zmax of 7.82 at a maximum
      recombination fraction (thetamax) of .06 was found with the 16q22 locus D16S518
      for MCD type I. In addition, a peak LOD score of 2.50 at a recombination fraction
      of .00 was obtained for the MCD type II families, by use of the identical marker.
      These findings raise the possibility that MCD type II may be due to the same
      genetic locus that is involved in MCD type I.

PMID- 8644740
TI  - An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p.
AB  - Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder
      characterized by ptosis, progressive weakness of the external eye muscles, and
      general muscle weakness. The patients have multiple deletions of mtDNA on
      Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or
      more respiratory-chain enzymes carrying mtDNA-encoded subunits. The pattern of
      inheritance indicates a nuclear gene defect predisposing to secondary mtDNA
      deletions. Recently, in one Finnish family, we assigned an adPEO locus to
      chromosome 10q 23.3-24.3 but also excluded linkage to this same locus in two
      Italian adPEO families with a phenotype closely resembling the Finnish one. We
      applied a random mapping approach to informative non-10q-linked Italian families
      to assign the second locus for adPEO and found strong evidence for linkage on
      chromosome 3p 14.1-21.2 in three Italian families, with a maximum two-point lod
      score of 4.62 at a recombination fraction of .0. However, in three additional
      families, linkage to the same chromosomal region was clearly absent, indicating
      further genetic complexity of the adPEO trait.

PMID- 8644741
TI  - Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q.
AB  - Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile
      polyps, colonic adenomas, and colorectal carcinomas. HMPS appears to be inherited
      in an autosomal dominant manner. Genetic linkage analysis has been performed on a
      large family with HMPS. Data did not support linkage to the APC locus or to any
      of the loci for hereditary nonpolyposis colorectal cancer. Evidence that the HMPS
      locus lies on chromosome 6q was, however, provided by significant two-point LOD
      scores for linkage between HMPS and the D6S283 locus. Analysis of recombinants
      and multipoint linkage analysis suggested that the HMPS locus lies in a 4-cM
      interval containing the D6S283 locus and flanked by markers D6S468 and D6S301.

PMID- 8644742
TI  - Familial cryptic translocation resulting in Angelman syndrome:implications for
      imprinting or location of the Angelman gene?
AB  - Angelman syndrome (AS) is associated with a loss of maternal genetic information,
      which typically occurs as a result of a deletion at 15q11-q13 or paternal
      uniparental disomy of chromosome 15. We report a patient with AS as a result of
      an unbalanced cryptic translocation whose breakpoint, at 15q11.2, falls within
      this region. The proband was diagnosed clinically as having Angelman syndrome,
      but without a detectable cytogenetic deletion, by using high-resolution G
      banding. FISH detected a deletion of D15S11 (IR4-3R), with an intact GABRB3
      locus. Subsequent studies of the proband's mother and sister detected a cryptic
      reciprocal translocation between chromosomes 14 and 15 with the breakpoint being
      between SNRPN and D15S10 (3- 21). The proband was found to have inherited an
      unbalanced form, being monosomic from 15pter through SNRPN and trisomic for
      14pter to 14q11.2. DNA methylation studies showed that the proband had a paternal
      only DNA methylation pattern at SNRPN, D15S63 (PW71), and ZNF127. The mother and
      unaffected sister, both having the balanced translocation, demonstrated normal
      DNA methylation patterns at all three loci. These data suggest that the gene for
      AS most likely lies proximal to D15S10, in contrast to the previously published
      position, although a less likely possibility is that the maternally inherited
      imprinting center acts in trans in the unaffected balanced translocation carrier
      sister.

PMID- 8644743
TI  - The same molecular mechanism at the maternal meiosis I produces mono- and
      dicentric 8p duplications.
AB  - We studied 16 cases of 8p duplications, with a karyotype 46,XX or XY,dup(8p),
      associated with mental retardation, facial dysmorphisms, and brain defects. We
      demonstrate that these 8p rearrangements can be either dicentric (6 cases) with
      the second centromere at the tip of the short arm or monocentric (10 cases). The
      distal 8p23 region, from D8S349 to the telomere, including the defensin 1 locus,
      is deleted in all the cases. The region spanning from D8S252 to D8S265, at the
      proximal 8p23 region, is present in single copy, and the remaining part of the
      abnormal 8 short arm is duplicated in the dicentric cases and partially
      duplicated in the monocentric ones. The distal edge of the duplication always
      spans up to D8S552 (8p23.1), while its proximal edge includes the centromere in
      the dicentric cases and varies from case to case in the monocentric ones. The
      analysis of DNA polymorphisms indicates that the rearrangement is consistently of
      maternal origin. In the deleted region, only paternal alleles were present in the
      patient. In the duplicated region, besides one paternal allele, some loci showed
      two different maternal alleles, while others, which were duplicated by FISH
      analysis, showed only one maternal allele. We hypothesize that, at maternal
      meiosis I, there was abnormal pairing of chromosomes 8 followed by anomalous
      crossover at the regions delimited by D8S552 and D8S35 and by D8S252 and D8S349,
      which presumably contain inverted repeated sequences. The resulting dicentric
      chromosome, 8qter-8p23.1(D8S552)::8p23.1-(D8S35)-8q ter, due to the presence of
      two centromeres, breaks at anaphase I, generating an inverted duplicated 8p,
      dicentric if the breakage occurs at the centromere or monocentric if it occurs
      between centromeres.

PMID- 8644744
TI  - Assessment of aneuploidy for chromosomes 8, 9, 13, 16, and 21 in human sperm by
      using primed in situ labeling technique.
AB  - The incidence of aneuploidy was estimated for chromosomes 8, 9, 13, 16, and 21 in
      mature human spermatozoa by primed in situ (PRINS) labeling technique. This
      method allows us to perform a chromosome-specific detection by in situ annealing
      of a centromeric specific primer. A dual color PRINS protocol was adapted to
      human sperm. The decondensation and the denaturation of sperm nuclei were
      simultaneously performed by 3-M NaOH treatment. Double labeling of spermatozoa
      was obtained in <2 h. A total of 96,292 sperm nuclei were analyzed by two
      independent observers. The estimates of disomy were 0.31% for chromosome 8, 0.28%
      for chromosome 9, 0.28% for chromosome 13, 0.26% for chromosome 16, and 0.32% for
      chromosome 21. These homogeneous findings suggest an equal distribution of
      aneuploidies among autosomal chromosomes in males.

PMID- 8644745
TI  - Gender difference in apolipoprotein E-associated risk for familial Alzheimer
      disease: a possible clue to the higher incidence of Alzheimer disease in women.
AB  - Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)
      epsilon4 allele. In late-onset familial AD, women have a significantly higher
      risk of developing the disease than do men. The aim of this study was to
      determine whether the gender difference in familial AD is a function of APOE
      genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival
      analysis was used to assess genotype-specific distributions of age at onset. Odds
      ratios were estimated by logistic regression with adjustment for age and by
      conditional logistic regression with stratification on families. All methods
      detected a significant gender difference for the epsilon4 heterozygous genotype.
      In women, epsilon4 heterozygotes had higher risk than those without epsilon4;
      there was no significant difference between epsilon4 heterozygotes and epsilon4
      homozygotes. In men, epsilon4 heterozygotes had lower risk than epsilon4
      homozygotes; there was not significant difference between epsilon4 heterozygotes
      and those without epsilon4. A direct comparison of epsilon4 heterozygous men and
      women revealed a significant twofold increased risk in women. We confirmed these
      results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at
      Indiana University Alzheimer Disease Center. These observations are consistent
      with the increased incidence of familial AD in women and may be a critical clue
      to the role of gender in the pathogenesis of AD.

PMID- 8644746
TI  - Inherited susceptibility determines the distribution of dense low-density
      lipoprotein subfraction profiles in familial combined hyperlipidemia.
AB  - Familial combined hyperlipidemia (FCH) is a heritable lipid disorder, in which
      dense low-density lipoprotein (LDL) subfraction profiles due to a predominance of
      small dense LDL particles are frequently observed. These small dense LDL
      particles are associated with cardiovascular disease. Using segregation analysis,
      we investigated to what extent these LDL subfraction profiles are genetically
      determined; also, the mode of inheritance was studied. Individual LDL subfraction
      profiles were determined by density gradient ultracentrifugation in 623
      individuals of 40 well-defined Dutch FCH families. The individual LDL subfraction
      profile was defined as a quantitative trait by the continuous variable K, a
      reliable estimate of the relative contribution of each LDL subfraction to the
      overall profile. Variation in parameter K due to age, sex, and hormonal status
      was taken into account by introducing liability classes. Segregation analysis was
      performed by fitting a series of class D regressive models, implemented in the
      Statistical Analysis for Genetic Epidemiology (SAGE) program, after which genetic
      models were compared using log-likelihood ratio tests. Our data show that 60% of
      the variability of parameter K could be explained by lipid and lipoprotein levels
      and that a major autosomal locus, recessively inherited, with a population
      frequency of .42 +/- .07, and an additional polygenic component of .25 best
      explained the clustering of atherogenic dense LDL subfraction profiles in these
      FCH families. Therefore, dense LDL subfraction profiles, associated with elevated
      lipid levels, appear to have a genetic basis in FCH.

PMID- 8644748
TI  - Mapping quantitative trait loci with extreme discordant sib pairs: sampling
      considerations.
AB  - Elsewhere we have proposed the use of extreme discordant sib pairs (EDSPs) for
      mapping quantitative trait loci in humans. Here we present sample sizes necessary
      to achieve a given level of power with this study design, as well as the number
      of sibs that need to be screened to obtain the required sample. Further, we
      present simple formulas for adjusting sample sizes to account for variable
      significance levels and power, as well as the density and informativeness of
      linkage markers in a multipoint sib-pair analysis. We conclude that with EDSPs,
      the most powerful study design, the smallest genetic effect detectable with a
      realistic sample size is approximately 10% of the variance of the trait.

PMID- 8644747
TI  - Cystic fibrosis heterozygote screening in 5,161 pregnant women.
AB  - A screening program for cystic fibrosis (CF) heterozygotes was conducted in a
      large HMO prenatal population, to evaluate the level of interest among eligible
      patients, the effectiveness of prescreening education, attitudes toward the
      screening process, psychological effects, and utilization of prenatal diagnosis
      and its outcomes. The heterozygote identification rate and frequency of specific
      CFTR mutations were also assessed. Identified carriers were offered genetic
      counseling and testing of male partners. Prenatal diagnosis was offered if both
      parents were identified as carriers. A total of 5,161 women underwent carrier
      testing; 947 others completed survey instruments only. The acceptance rate of
      screening was high (78%), and pretest education by videotape was generally
      effective. Adverse psychological effects were not reported. Participants
      generally found screening to be desirable and useful. Screening identified 142
      female heterozygotes, 109 couples in which the male partner was not a carrier,
      and 7 high-risk couples. The incidence of R117H mutations was much higher than
      expected. The number of identified carriers was much lower in Hispanics than in
      Caucasians. We conclude that large-scale prenatal screening for CF heterozygotes
      in the absence of a family history of CF is an acceptable method for identifying
      couples at risk for affected fetuses. Sufficient pretest education can be
      accomplished efficiently, test insensitivity is well accepted, adverse
      psychological events are not observed, and general patient satisfaction is high.

PMID- 8644749
TI  - A general statistical model for detecting complex-trait loci by using affected
      relative pairs in a genome search.
AB  - Scanning of the human genome by use of affected relative pairs and dense sets of
      highly polymorphic markers or by emerging techniques such as genomic mismatch
      scanning. (GMS) is making it possible to identify the genetic etiology of a
      disease through detection of susceptibility loci. We present a general
      statistical model and test to detect disease genes, using affected relative pairs
      and either markers or GMS technologies in a genome search. There are an exact
      test and large-sample normal approximation that control for the elevated
      probability of false detection of linkage in a genome search. The approach can be
      used to determine the sample size needed to obtain a prespecified power to detect
      a disease gene in the presence of etiologic heterogeneity for a single class or
      mixture of relative classes, with any number of markers, or clones, markers PIC
      values, or mapping function. The approach is used to examine differences in
      performance of markers and GMS technologies in a common statistical framework and
      to provide practical information for designing studies of complex traits.

PMID- 8644750
TI  - Association studies in consanguineous populations.
AB  - To study the genetic determinism of multifactorial diseases in large panmictic
      populations, a strategy consists in looking for an association with markers
      closely linked to candidate genes. A distribution of marker genotypes different
      in patients and controls may indicate that the candidate gene is involved in the
      disease. In panmictic populations, the power to detect the role of a candidate
      gene depends on the gametic disequilibrium with the marker locus. In
      consanguineous populations, we show that it depends on the inbreeding coefficient
      F as well. Inbreeding increases the power to detect the role of a recessive or
      quasi-recessive disease-susceptibility factor. The gain in power turns out to be
      greater for small values of the gametic disequilibrium. Moreover, even in the
      absence of gametic disequilibrium, the presence of inbreeding may allow to detect
      the role of a recessive factor. Ignoring inbreeding when it exists may lead to
      reject falsely a recessive model if the mode of inheritance is inferred on the
      distribution of genotypes among patients.

PMID- 8644751
TI  - Nonparametric simulation-based statistics for detecting linkage in general
      pedigrees.
AB  - We present here four nonparametric statistics for linkage analysis that test
      whether pairs of affected relatives share marker alleles more often than
      expected. These statistics are based on simulating the null distribution of a
      given statistic conditional on the unaffecteds' marker genotypes. Each statistic
      uses a different measure of marker sharing: the SimAPM statistic uses the
      simulation-based affected-pedigree-member measure based on identity-by-state
      (IBS) sharing. The SimKIN (kinship) measure is 1.0 for identity-by-descent (IBD)
      sharing, 0.0 for no IBD status sharing, and the kinship coefficient when the IBD
      status is ambiguous. The simulation-based IBD (SimIBD) statistic uses a recursive
      algorithm to determine the probability of two affecteds sharing a specific allele
      IBD. The SimISO statistic is identical to SimIBD, except that it also measures
      marker similarity between unaffected pairs. We evaluated our statistics on data
      simulated under different two-locus disease models, comparing our results to
      those obtained with several other nonparametric statistics. Use of IBD
      information produces dramatic increases in power over the SimAPM method, which
      uses only IBS information. The power of our best statistic in most cases meets or
      exceeds the power of the other nonparametric statistics. Furthermore, our
      statistics perform comparisons between all affected relative pairs within general
      pedigrees and are not restricted to sib pairs or nuclear families.

PMID- 8644752
TI  - Germ-line BRCA1 mutations in selected men with prostate cancer.

PMID- 8644753
TI  - The gene for Nijmegen breakage syndrome (V2) is not located on chromosome 11.

PMID- 8644754
TI  - Codon 219 polymorphism of PRNP in healthy Caucasians and Creutzfeldt-Jakob
      disease patients.

PMID- 8644755
TI  - CFTR gene variant IVS8-5T in disseminated bronchiectasis.

PMID- 8644757
TI  - Harry Harris (1919-94): in memoriam.

PMID- 8644756
TI  - Affecteds-only linkage methods are not a panacea.

PMID- 8644758
TI  - Diagnosis of Clostridium difficile--associated disease: patient selection and
      test perfection.

PMID- 8644759
TI  - Clinical prediction rules to optimize cytotoxin testing for Clostridium difficile
      in hospitalized patients with diarrhea.
AB  - BACKGROUND: Although routine testing of hospitalized patients with diarrhea for
      Clostridium difficile cytotoxin has been advocated as a high-yield procedure, the
      rationale for this practice has been questioned. To target a low-yield subgroup
      for whom routine testing could be deferred, we derived a clinical decision rule
      for predicting results of the C difficile cytotoxin assay in hospitalized adults
      with diarrhea. METHODS: We hypothesized a priori that two variables, antibiotic
      use (within 30 days prior to testing) and history of significant diarrhea (new
      onset of > 3 partially formed or watery stools per 24 hour period), would be
      highly predictive of cytotoxin results, and obtained these data on 480
      consecutive patients who underwent diagnostic testing for C difficile at a
      university hospital and affiliated Veterans Affairs medical center. For more
      detailed modelling, we recorded symptoms, signs, comorbidity, and other potential
      causes of diarrhea for 68 test positive patients (cases) and 265 randomly
      selected test negative patients (controls) within the study cohort. RESULTS: The
      overall prevalence of positive cytotoxin assays was 14%. Prior antibiotic therapy
      (OR = 9.0, 95% CI 2.1-38.4), significant diarrhea (OR = 2.2, 95% CI 1.1-4.7), and
      abdominal pain (OR = 1.9, 95% CI 0.96-3.7) were independent predictors of
      cytotoxin assay results. The model discriminated patients with positive and
      negative assays with a receiver operating characteristic (ROC) area of 0.68;
      observed and predicted probabilities of a positive cytotoxin assay were well
      correlated over the entire range of observed probabilities (r2 = 0.86). A
      decision rule (defined as positive if prior antibiotic use and either significant
      diarrhea or abdominal pain are present) demonstrated sensitivity and specificity
      of 86 and 45%. When applied to the entire dataset (N = 480), a simplified a
      priori rule, defined as positive if both prior antibiotic use and history of
      significant diarrhea are present, demonstrated sensitivity, specificity, positive
      and negative predictive value of 80, 45, 18 and 94%, respectively (6% of those
      predicted to be cytotoxin-negative actually tested positive). Use of this rule
      would have averted 39% of cytotoxin assays in our study population. CONCLUSIONS:
      Patients without prior antibiotic use and either significant diarrhea or
      abdominal pain are unlikely to have positive C difficile cytotoxin assay results,
      and may not routinely require cytotoxin testing.

PMID- 8644760
TI  - Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected
      patients.
AB  - OBJECTIVE: To assess the effectiveness of two regimens with allopurinol or
      pentavalent antimony as secondary prophylaxis for visceral leishmaniasis (VL) in
      human immunodeficiency virus (HIV)-infected patients. DESIGN: Retrospective,
      nonrandomized, open trial. SETTING: A 1,000-bed academic tertiary institutional
      hospital in Barcelona. PATIENTS: Forty-six individuals over 14 years old with HIV
      infection, who recovered from an episode of VL between January 1988 and February
      1995. INTERVENTIONS: Twenty patients did not receive any prophylaxis, nine
      received 300 mg/8 h of allopurinol, and 17 received 850 mg once-a-month of
      pentavalent antimony. Patients were followed-up every 3 months, and the endpoint
      of study was relapse of VL. RESULTS: Twenty-one patients had recurrent VL: 13 of
      20 in the control group (65%), 5 of 9 in the allopurinol group (56%), and 3 of 17
      in the antimonial group (18%). Kaplan-Meier estimates of the probability of
      remaining relapse-free at 12 months were 9% without prophylaxis (95% CI, 0-22%),
      21% with allopurinol (95% CI, 0-51%), and 93% with antimonials (95% CI, 82-100%)
      (P < 0.001). Multivariate analysis showed that the only significant variables
      related to relapsing course of VL were assignment to the antimonial group, and
      the fact that the patient had experienced a previous episode of VL. CONCLUSIONS:
      Pentavalent antimony given once a month is effective in the prevention of VL
      relapses in HIV-infected individuals. It is a low-cost treatment that proved to
      be well tolerated. Therefore, pentavalent antimony should be considered a
      suitable agent for secondary prophylaxis against VL.

PMID- 8644761
TI  - The clinical spectrum of early Lyme borreliosis in patients with culture
      confirmed erythema migrans.
AB  - BACKGROUND: The diagnosis of erythema migrans (EM), the characteristic rash of
      early Lyme borreliosis, is based primarily on its clinical appearance since it
      often occurs prior to the development of a specific antibody response. Other skin
      disorders, however, may be confused with EM. METHODS: Between June 1991 and
      September 1993, a prospective study was conducted at the Lyme Disease Diagnostic
      Center of the Westchester County Medical Center to isolate Borrelia burgdorferi
      systematically from patients with Em, and to characterize the clinical
      manifestations of patients with culture-documented infection. Skin biopsies
      and/or needle aspirates of the advancing margin of primary lesions, and blood
      specimens from adult patients were cultured for B burgdorferi in modified Barbour
      Stoenner-Kelly medium at 33 degrees C. RESULTS: B burgdorferi was recovered from
      79 patients (49 [62%] males) ranging in age from 16 to 76 years old (mean, 43 +/-
      14 years old). Maximum EM diameter (mean, 16 +/- 10 cm; range, 6-73 cm) was a
      function of EM duration (mean 6.7 +/- 6.4 days; range, 1-39 days) (correlation
      coefficient = 0.7; P < 0.001). Twenty (25%) patients had noted a tick bite at the
      site of the primary lesion a mean of 10 days (range, 1-27 days) before onset.
      Multiple EM lesions (range, 2-70) were present in 14 (18%) patients. Systemic
      symptoms were present at the time of culture in 54 patients (68%) including
      fatigue (54%), arthralgia (44%), myalgia (44%), headache, (42%), fever and/or
      chills (39%), stiff neck (35%), and anorexia (26%). Thirty-three patients (42%)
      had at least one objective finding on physical examination in addition to EM,
      including 18 (23%) with localized lymphadenopathy, 13 (16%) with fever (t > or =
      37.8 degrees C), seven (9%) with tender neck flexion, six (8%) with joint
      tenderness, and 1 each with joint swelling, nuchal rigidity, and facial nerve
      palsy. No patient had new electrocardiogram evidence of atrioventricular block.
      Liver function assays were abnormally elevated in 37% of patients. Thirty-four
      percent of patients were seropositive by enzyme-linked immunosorbent assay at
      presentation. Most others rapidly seroconverted so that 69 of 78 evaluable
      patients (88%) were seropositive at some point during the first month after
      diagnosis. CONCLUSIONS: We describe the largest group of culture-positive
      patients with EM from the United States to date. Although systemic symptoms were
      present in most patients, objective evidence of advanced disease was uncommon.
      Our patients with culture-confirmed EM were less sick than those described in the
      days before culture confirmation was possible. The ability to isolate B
      burgdorferi from lesional skin of large numbers of patients with EM should make
      culture-positive patients the standard by which to define manifestations of early
      Lyme borreliosis associated with this rash. Microbiologic documentation of Lyme
      borreliosis will help delineate the manifestations of this illness, and should
      form the framework for research directed at pathophysiology, diagnosis,
      treatment, and prevention.

PMID- 8644762
TI  - Nosocomial Staphylococcus aureus bacteremia among nasal carriers of methicillin
      resistant and methicillin-susceptible strains.
AB  - OBJECTIVES: To determine the relevance of nasal carriage of Staphylococcus
      aureus, either methicillin-sensitive (MSSA) or methicillin-resistant (MRSA), as a
      risk factor for the development of nosocomial S aureus bacteremia during an MRSA
      outbreak. PATIENTS AND METHODS: In this prospective cohort study, 488 patients
      admitted to an intensive care unit (ICU) during a 1-year period were screened
      with nasal swabs within 48 hours of admission and weekly thereafter in order to
      identify nasal S aureus carriage. Nasal staphylococcal carriers were observed
      until development of S aureus bacteremia, ICU discharge, or death. RESULTS: One
      hundred forty-seven (30.1%) of 488 patients were nasal S aureus carriers; 84
      patients (17.2%) harbored methicillin-sensitive S aureus; and 63 patients (12.9%)
      methicillin-resistant S aureus. Nosocomial S aureus bacteremia was diagnosed in
      38 (7.7%) of 488 patients. Rates of bacteremia were 24 (38%) of the MRSA
      carriers, eight (9.5%) of the MSSA carriers, and six (1.7%) of noncarriers. After
      adjusting for other predictors of bacteremia by means of a Cox proportional
      hazard regression model, the relative risk for S aureus bacteremia was 3.9 (95%
      confidence interval, 1.6-9.8; P = 0.002) for MRSA carriers compared with MSSA
      carriers. CONCLUSIONS: Among ICU patients, nasal carriers of S aureus are at
      higher risk for S aureus bacteremia than are noncarriers; in the setting of an
      MRSA outbreak, colonization by methicillin-resistant strains represents a greater
      risk than does colonization by MSSA and strongly predicts the occurrence of MRSA
      bacteremia.

PMID- 8644763
TI  - Behavioral differences and effects of cardiac rehabilitation in diabetic patients
      following cardiac events.
AB  - PURPOSE: To describe the incidence of depression and other behavioral disorders
      in diabetic coronary patients following major cardiac events and to assess the
      impact of cardiac rehabilitation. PATIENTS: 291 consecutive coronary patients (70
      with diabetes mellitus). METHODS: Patients were prospectively enrolled in
      comprehensive phase II cardiac rehabilitation 4 to 6 weeks following a major
      cardiac event. Depressive symptoms and other behavioral characteristics (anxiety,
      somatization, hostility), as well as parameters of quality of life, were assessed
      by validated questionnaires at entry and upon completion (12 weeks, 36 sessions)
      of cardiac rehabilitation. RESULTS: Diabetic patients made up 24% of the cohort
      and were more likely to be female (P = 0.08), hypertensive (P = 0.05), and obese
      (P = 0.08). Additionally, diabetic patients had a reduced exercise capacity (P =
      0.008), lower high-density lipoprotein cholesterol (P = 0.008), lower low-density
      lipoprotein cholesterol (P = 0.02), and increased triglyceride (P = 0.04) levels.
      Diabetic patients had a higher incidence of depression (26% versus 14%; P <
      0.03), demonstrated more symptoms of somatization (P < 0.06), and exhibited lower
      scores for components of quality of life. Following cardiac rehabilitation, the
      incidence of depression was reduced in diabetic patients by 67% (P = 0.01) and
      ultimately equaled the 9% prevalence found in the non-diabetic group.
      CONCLUSIONS: Diabetic coronary patients demonstrate a higher incidence of
      depression than non-diabetic patients following major cardiac events. In addition
      to improving traditional cardiac risk factors, cardiac rehabilitation reduces
      depression in this high-risk group.

PMID- 8644764
TI  - Redefining the incidence of clinically detectable atheroembolism.
AB  - BACKGROUND AND OBJECTIVES: Atheroembolism, caused by peripheral embolization of
      small cholesterol crystals that fracture off of ruptured atherosclerotic plaques
      in the major vessels, leads to multifocal ischemic lesions and progressive tissue
      loss. The end result is often ischemic injury in the skin, kidney, brain,
      myocardium, and intestine, but any organ distal to the culprit lesion may be
      affected. The precise incidence of this serious clinical syndrome has been
      difficult to ascertain from the available literature, but it appears to be much
      more common than has been assumed. The objective of the present study is to
      clarify the incidence of atheroembolism among inpatients in an acute hospital
      setting. PATIENTS AND METHODS: We surveyed inpatient nephrology consultations
      during a 7-month period from January through July 1994. From a pool of 402
      consultation charts, 99 were identified with two or more substantive risk factors
      for atheroembolism. The records of 85 of these patients were available for
      careful review. More than 300 additional patients were found to have ICD-9
      discharge codes for other vascular conditions, but we were unable to confirm that
      any of these were in fact cases of atheroembolism, since there is no specific ICD
      9 discharge code for this entity. In the 85 cases reviewed, a diagnosis of
      atheroembolism was made only if the patient had identifiable substantive risk
      factors, suggestive physical findings, and supporting laboratory results.
      RESULTS: Eleven of the 85 surveyed records documented strong evidence supporting
      a "probable" diagnosis of atheroembolism. Tissue was examined in 4 of these 11,
      resulting in definitive histologic confirmation in 3. Another 5 of the 85
      surveyed records were "suggestive" of atheroembolism. Altogether, atheroembolism
      was a likely diagnosis in a total of 16 cases during this 7-month period, or 1
      case in every 2 weeks. These cases comprised 19% of nephrology consultations in
      which 2 or more risk factors were present, or 4% or all nephrology consultations.
      The patients' records confirmed the serious implications of clinically detectable
      atheroembolism. Several patients underwent lower extremity amputation, nearly
      half required acute or chronic dialysis, and more than half died within several
      months of diagnosis CONCLUSIONS: The present study suggests that at least 4% of
      all inpatient nephrology consultations, representing approximately 5% to 10% of
      the acute renal failure encountered, involve clinically significant
      atheroembolism. Patients with atheroembolism appear at a rate of at least 1 case
      every 2 weeks. They often have identifiable substantive risk factors at initial
      consultation, and probably represent only the most severe cases of
      atheroembolism. In view of the serious implications of this basically untreatable
      syndrome, heightened awareness and preventive maneuvers in the population at risk
      are essential.

PMID- 8644766
TI  - Gender differences in heart rate before and after autonomic blockade: evidence
      against an intrinsic gender effect.
AB  - OBJECTIVES: To document gender differences in heart rate in healthy young adult
      men and women, and examine the degree to which autonomic tone and other variables
      may be associated with the gender differences in heart rate. DESIGNS: Cohort
      study. SETTINGS: Clinical Research Center of a tertiary care medical center.
      PATIENTS: A volunteer sample of 20 healthy men and 23 healthy women between ages
      21 and 39 years. INTERVENTIONS: Subjects were each studied three times: during
      the menstrual, follicular, and luteal phases of the menstrual cycle in women; and
      5 to 10 days apart in men. Electrocardiograms (ECGs) were obtained at baseline
      and following double autonomic blockade with propranolol 0.2 mg/kg and atropine
      0.04 mg/kg. Maximum exercise capacity was determined by bicycle ergometry. MAIN
      OUTCOME MEASURES: Sinus cycle length at baseline and following double autonomic
      blockade, before and after correction for confounding variables. RESULTS: Men had
      longer sinus cycle length both at baseline and after double autonomic blockade
      (971 +/- 88 ms versus 918 +/- 115 ms, P < 0.02, and 645 +/- 41 ms versus 594 +/-
      57 ms, P < 0.0001). Sinus cycle length in women was longer than during the
      menstrual than luteal phase but this difference could not account for the gender
      difference in sinus cycle length. Men also had a greater maximum exercise
      capacity than women (1295 +/- 167 kpm/min versus 857 +/- 227 kpm/min; P <
      0.0001). By analysis of covariance, maximum exercise capacity was the most
      significant predictor of sinus cycle length (P < 0.0003 at baseline, and P <
      0.001 post blockade) and gender did not have a significant effect. The
      relationship of maximum exercise capacity to sinus cycle length was blunted but
      not abolished by autonomic blockade. CONCLUSIONS: Sinus cycle length is longer in
      men than women. This difference appears to be associated with a gender difference
      in exercise capacity rather than intrinsic gender related properties of the sinus
      node or differences in autonomic tone. In addition, exercise induced bradycardia
      is mediated by both autonomic and nonautonomic factors in both genders.

PMID- 8644765
TI  - Natural history and risk factors for thrombosis in 360 patients with
      antiphospholipid antibodies: a four-year prospective study from the Italian
      Registry.
AB  - PURPOSE: To assess the natural history and risk factors for thrombosis in a large
      cohort of unselected patients with antiphospholipid antibodies. PATIENTS AND
      METHODS: Three hundred sixty consecutive patients (118 males, 242 females, median
      age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for
      diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G
      anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian
      institutions and prospectively observed for a median of 3.9 years (range 0.5 to
      5). Main endpoints were the occurrence of arterial or venous thrombosis, the
      outcome of pregnancies, and any severe complications leading to hospitalization
      or death. RESULTS: Thirty-four patients developed a thrombotic complication, with
      a total incidence of 2.5% patient-years. Multivariate logistic regression
      analysis identified two independent risk factors for thrombotic events: a
      previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer
      above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28
      pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse
      pregnancy outcomes were significantly more frequent in women with a history of
      miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12,
      17%) (P = 0.035). Four patients developed non-Hodgkin's lymphoma during the
      follow-up. Eighteen patients died. Vascular events and hematological malignancies
      represented the most frequent causes of death (n = 5 for each). CONCLUSIONS: The
      present study shows that: (a) previous thrombosis and ACA titer > 40 U are
      independent predictors of thrombosis; (b) history of miscarriage or vascular
      disease is significantly associated with adverse pregnancy outcome; (c)
      hematological malignancies can develop during follow-up in patients with
      antiphospholipid antibodies.

PMID- 8644767
TI  - Somatotrophinomas in multiple endocrine neoplasia type 1: a review of clinical
      phenotype and insulin-like growth factor-1 levels in a large multiple endocrine
      neoplasia type 1 kindred.
AB  - PURPOSE: Within the spectrum of pituitary disease in multiple endocrine neoplasia
      type 1 (MEN-1), widely disparate prevalence rates for somatotrophinomas have been
      described. Studies that combine multiple, small MEN-1 kindreds report pituitary
      disease in 60% to 65% of patients, somatotrophinomas accounting for 27% to 37% of
      total pituitary lesions. However, reports based on large MEN-1 family screening
      programs have produced lower prevalence rates for pituitary adenomas (9% to 40%),
      of which somatotrophinomas comprise up to 14%. We sought to determine the
      prevalence of both biochemical and clinically overt growth hormone (GH)
      hypersecretion in the largest reported MEN-1 genealogy, the Tasman 1 kindred.
      PATIENTS AND METHODS: The Tasman 1 MEN-1 kindred contains 165 members with
      established MEN-1. We reviewed the records of 124 MEN-1 patients for evidence of
      acromegaly or gigantism. To determine if clinical criteria underestimate the
      occurrence of biochemical GH hypersecretion, a subset of 33 patients was assessed
      for elevated levels of serum insulin-like growth factor-1 (IGF-1). RESULTS: No
      cases of acromegaly or gigantism were detected in the 124 patients reviewed. Of
      the 33 patients screened with IGF-1, 13 had previously diagnosed pituitary
      lesions--11 prolactinomas and 2 nonsecretory lesions. The IGF-1 levels were
      normal in all patients studied. There were no significant differences in mean IGF
      1 values between patients with and without pituitary lesions. CONCLUSIONS: This
      report represents the largest study of growth hormone secretion patterns thus far
      described in MEN-1. The apparent absence of somatotrophinomas in a kindred of
      this size is unexpected. These results support the existence of kindred-specific
      MEN-1 phenotypes. We conclude that the pathogenesis of GH-secreting adenomas in
      MEN-1 is influenced by secondary factors acting in synergy with the well
      documented primary MEN-1 gene defect on chromosome 11q13.

PMID- 8644768
TI  - A case-control study to assess possible triggers and cofactors in chronic fatigue
      syndrome.
AB  - PURPOSE: To assess possible triggers and cofactors for chronic fatigue syndrome
      (CFS) and to compare levels of selected cytokines between cases and an
      appropriately matched control group. PATIENTS AND METHODS: We conducted a case
      control study of 47 cases of CFS obtained through a regional CFS research program
      maintained at a tertiary care medical center. One age-, gender-, and neighborhood
      matched control was identified for each case through systematic community
      telephone sampling. Standardized questionnaires were administered to cases and
      controls. Sera were assayed for transforming growth factor-beta (TGF-beta),
      interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and antibody to
      Borrelia burgdorferi and Babesia microti. RESULTS: Cases were more likely to have
      exercised regularly before illness onset than controls (67% versus 40%; matched
      odds ratio (MOR) = 3.4; 95% CI = 1.2 to 11.8; P = 0.02). Female cases were more
      likely to be nulliparous prior to onset of CFS than controls (51% versus 31%; MOR
      = 8.0; 95% CI = 1.03 to 170; P = 0.05). History of other major factors, including
      silicone-gel breast implants (one female case and one female control), pre-morbid
      history of depression (15% of cases, 11% of controls) and history of allergies
      (66% of cases, 51% of controls) were similar for cases and controls. However,
      cases were more likely to have a diagnosis of depression subsequent to their
      diagnosis of CFS compared to a similar time frame for controls (MOR = undefined;
      95% CI lower bound = 2.5; P < 0.001). Positive antibody titers to B burgdorferi
      (one case and one control) and B microti (zero cases and two controls) were also
      similar. CONCLUSIONS: Further investigation into the role of prior routine
      exercise as a cofactor for CFS is warranted. This study supports the concurrence
      of CFS and depression, although pre-morbid history of depression was similar for
      both groups.

PMID- 8644770
TI  - Deterioration and death in a 30-year old male with AIDS.

PMID- 8644769
TI  - Chronic myelogenous leukemia: a review.
AB  - Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder with
      an initially chronic course lasting for 3-5 years. It eventually transforms into
      accelerated and blastic phases, which are generally fatal. CML was one of the
      first diseases in which a specific chromosomal abnormality was identified, a
      t(9;22)(q34;q11) or Philadelphia chromosome. CML had been traditionally treated
      with conventional chemotherapy with hydroxyurea or busulfan. Although these
      agents can achieve hematologic remissions in most patients, no evidence of
      sustained disappearance of the chromosomal abnormality was evident. Interferon
      alpha (IFN-alpha) has been able to achieve hematologic and cytogenic remissions
      in a significant number of patients, and recent studies show a survival advantage
      for patients treated with IFN-alpha compared with those treated with conventional
      chemotherapy. The results of these studies are discussed, and the reasons for
      discordance among different investigators analyzed in this review. Allogeneic
      bone marrow transplantation (BMT) may be curative in some patients with CML. The
      benefits and limitations of this approach in the treatment of CML are also
      discussed and the results of different alternatives compared. Other alternatives
      of therapy, including newer chemotherapeutic agents, combinations of IFN-alpha
      with other agents, and autologous BMT, are presented. The availability of very
      sensitive techniques for detection of the Philadelphia chromosome at the
      molecular level has allowed the detection of minimal residual disease. The
      information available on these measurements is also analyzed. Finally, we discuss
      the alternatives for patients with accelerated and blastic phase CML, as well as
      the clinical characteristics and prognosis for patients with Philadelphia
      chromosome-negative CML.

PMID- 8644771
TI  - Killing in the name of healing: the active role of the German medical profession
      during the Third Reich.

PMID- 8644772
TI  - Human immunodeficiency virus among the homeless in Miami: a new direction for the
      HIV epidemic.

PMID- 8644773
TI  - Agenesis of the diaphragm.

PMID- 8644774
TI  - Clinical profiles of patients with sarin poisoning after the Tokyo subway attack.

PMID- 8644775
TI  - Cortisol levels after single local steroid injection.

PMID- 8644776
TI  - Dialysis-related beta-2-microglobulin amyloidosis after long-term dialysis, and
      the effect of renal transplantation and cyclosporin therapy.

PMID- 8644778
TI  - Helicobacter pylori and ulcerogenesis.
AB  - The dictum "no acid-no ulcer" had, in the past, summarized the thinking
      concerning the pathogenesis of peptic ulcer disease. It is now recognized that
      infection with Helicobacter pylori is the major causal factor leading to both
      duodenal and gastric ulceration. Infection is associated with many of the acid
      secretory abnormalities that have traditionally characterized peptic ulcer
      disease; indeed, acid secretory physiology returns to normal following bacterial
      eradication. Since not all individuals infected with H. pylori develop ulcers,
      host susceptibility, bacterial virulence, and/or specific environmental factors
      must determine the response to infection and the ultimate clinical outcome. The
      relative importance of these factors and their complex interactions remain to be
      determined. H. pylori infection produces tissue damage indirectly because the
      organism does not directly invade gastroduodenal tissue. A variety of bacterial
      enzymes, toxins, and inflammatory mediators produced in response to bacterial
      colonization challenge the integrity of host mucosal defenses. In a susceptible
      host, breached defenses render epithelium more vulnerable to acid injury and
      ulcer development. Eradication of H. pylori leads to rapid ulcer healing and
      reversal of tissue injury, thereby obviating ulcer recurrence.

PMID- 8644777
TI  - Transmission and epidemiology of Helicobacter pylori.
AB  - Helicobacter pylori is one of the most common bacterial infections worldwide.
      However, the majority of those infected do not develop clinical manifestations of
      disease. This review discusses the epidemiology of the organism in terms of
      incidence and prevalence, the presumed means of transmission from person to
      person, and how typing of the organism has helped the epidemiologist. The
      epidemiology of disorders that are associated with H. pylori is also discussed.

PMID- 8644779
TI  - Defining Helicobacter pylori as a pathogen: strain heterogeneity and virulence.
AB  - Helicobacter pylori, the etiologic agent of gastritis and peptic ulceration, may
      infect the gastric mucosa of over half of the world's population. Despite the
      high infection rate, symptomatic disease beyond gastritis (characterized by
      gastric or duodenal ulcer) is noted in a small, but nevertheless significant,
      fraction of this population. What defines an H. pylori strain as a pathogen that
      can cause the more serious clinical manifestations? In addition to the more well
      recognized virulence determinants, such as urease, flagella, and vacuolating
      cytotoxin, evidence is emerging that the more virulent strains possess well
      defined segments of DNA. These "pathogenicity islands" include cytotoxin
      associated gene A and encode proteins involved in signal transduction events that
      may facilitate intimate attachment to host cells, cytoskeletal rearrangement via
      actin polymerization, and host cell protein phosphorylation.

PMID- 8644781
TI  - Testing for Helicobacter pylori in clinical practice.
AB  - It is now accepted that cure of Helicobacter pylori infection will result in
      healing of chronic active gastritis and will change the natural history of
      gastroduodenal ulcer disease. A variety of highly sensitive and specific
      diagnostic methods have been developed over the past few years to establish
      whether a patient is infected with this organism. The two major categories of
      diagnostic tests for H. pylori are invasive methods, which require endoscopy, and
      noninvasive tests in which endoscopy is not necessary. Invasive tests include
      rapid urease tests, histology, and culture. Noninvasive tests include various
      methods of antibody detection and carbon-labeled urea breath tests. This review
      describes the characteristics, appropriate uses, and comparative accuracy of the
      available diagnostic tests for detection of H. pylori. It offers suggestions on
      the test of choice to establish a patient's H. pylori infection status in
      different clinical settings.

PMID- 8644780
TI  - Clinical expressions of Helicobacter pylori infection.
AB  - Helicobacter pylori infection is very common both in the United States and
      internationally. However, clinical manifestations of this infection vary markedly
      among different individuals. Apart from gastritis, which may be asymptomatic,
      patients may develop peptic ulceration or a gastric neoplasm. However, these
      patients represent a minority of patients infected with H. pylori. This article
      aims to review the different possible consequences of H. pylori infection.

PMID- 8644782
TI  - Eradication of Helicobacter pylori infection.
AB  - Helicobacter pylori is probably the most common bacterial infection worldwide and
      the accepted cause of chronic active gastritis. It has a critical role in
      duodenal ulcer, where the prevalence of infection is 90-95%. There is a dramatic
      reduction in the rate of ulcer recurrence after successful eradication of the
      organism to about 4% per annum compared with up to 80% when the infection
      persists. What is true for duodenal ulcers is also true for patients with gastric
      ulcer who are infected with H. pylori. The risk of recurrent ulcer complications
      with bleeding is virtually abolished following successful eradication of H.
      pylori; in contrast, the risk of rebleeding is about 33% in patients still
      harboring the organism. The treatment of H. pylori infection in patients with
      confirmed peptic ulcer on first presentation or recurrence has been advocated by
      a Consensus Conference of the National Institutes of Health. The most evaluated
      regimens include dual therapy with a proton pump inhibitor and either amoxicillin
      or clarithromycin, and bismuth-based triple therapy with metronidazole and
      tetracycline. The use of a proton pump inhibitor-containing regimen offers the
      advantage of rapid symptom relief and the highest rates of duodenal ulcer
      healing. Moreover, combinations of a proton pump inhibitor and clarithromycin
      show more predictable and higher eradication rates than amoxicillin combinations.
      Newer triple therapies with a proton pump inhibitor plus two antibacterial agents
      given for 7-1O days are being increasingly described and may become the treatment
      of choice if initial results are confirmed. However, the optimum dosage regimen
      needs to be established. A new combination of ranitidine bismuth citrate and
      clarithromycin has also recently been shown to be effective. At this time it is
      reasonable to consider all patients with confirmed duodenal or gastric ulcer for
      eradication of H. pylori, and no patient should be considered for elective
      surgery without first being offered eradication therapy.

PMID- 8644784
TI  - The economics of eradicating Helicobacter pylori infection in duodenal ulcer
      disease.
AB  - Approximately 5 million people in the United States suffer from peptic ulcer
      disease, making this an important clinical problem. In addition to the huge costs
      associated with treatment, peptic ulcer disease also results in losses to
      industry as a result of loss of productivity. Infection with Helicobacter pylori
      is now accepted as the cause of duodenal ulcer in the majority of patients.
      Eradication of this infection leads to healing of the ulcer and prevents disease
      recurrence. A number of treatment regimens have been described for the
      eradication of H. pylori, but there is uncertainty regarding the optimum regimen
      to be used. Economic analyses allow an assessment of the probable costs
      associated with existing and new treatment strategies. In an era of increasing
      cost awareness, the results of such analyses are becoming increasingly important
      determinants of management strategies for the treatment of H. pylori infection.

PMID- 8644783
TI  - Helicobacter pylori and complicated ulcer disease.
AB  - Approximately 20-25% of patients with peptic ulcer disease develop complications-
      bleeding, perforation, or obstruction. Although the majority of patients with
      complicated ulcers are infected with Helicobacter pylori, the prevalence of
      infection appears to be lower in these patients compared with patients with
      uncomplicated ulcers. Among patients who present with a bleeding ulcer,
      approximately one-third will develop recurrent bleeding in the following 1-2
      years if left untreated after ulcer healing. A number of studies have shown that
      the recurrence of rebleeding is virtually abolished if patients receive H. pylori
      eradication therapy. In contrast, the rate of rebleeding in patients receiving
      maintenance antisecretory therapy is around 10%. Thus, H. pylori infection status
      must be determined in patients presenting with complicated ulcer disease and, if
      positive, eradication therapy initiated. Eradication should be documented at
      least 4 weeks after the end of therapy (by endoscopic biopsy or urea breath test)
      and maintenance antisecretory therapy discontinued if the infection is cured.

PMID- 8644786
TI  - Dementia at 700?

PMID- 8644785
TI  - Med errors: watch those labels.

PMID- 8644787
TI  - Pediatric tool adapts to elderly patients.

PMID- 8644788
TI  - Methadone patients in the hospital.

PMID- 8644789
TI  - Mismatch: when nurses rate patients' pain.

PMID- 8644790
TI  - Better topical anesthetic.

PMID- 8644791
TI  - Mastering emergency airway management.

PMID- 8644792
TI  - When a loved one is dying: families talk about nursing care.

PMID- 8644793
TI  - Tube feeding aspiration.

PMID- 8644794
TI  - Clinical snapshot: acute myocardial infarction.

PMID- 8644796
TI  - Seven ways to empower dying patients.

PMID- 8644795
TI  - Meeting the challenge of the older trauma patient.

PMID- 8644797
TI  - Commonly asked questions about chest tubes.

PMID- 8644798
TI  - Fear and informed consent.

PMID- 8644799
TI  - A dose of deception.

PMID- 8644800
TI  - The illusion of strategic planning.

PMID- 8644801
TI  - Nurses do matter.

PMID- 8644802
TI  - Prospective randomized trial of vitrectomy or observation for stage 2 macular
      holes. Vitrectomy for Macular Hole Study Group.
AB  - PURPOSE: To determine the risks and benefits of vitrectomy surgery in eyes with
      stage 2 macular holes. METHODS: A multicentered, controlled, randomized clinical
      trial was performed with participation of 16 community and university-based
      ophthalmology clinics. Thirty-six eyes with stage 2 macular holes and 12 months
      of follow-up were studied. Pars plana vitrectomy with separation of the posterior
      hyaloid membrane and intraocular injection of perfluoropropane (C3F8) was
      followed by postoperative face-down positioning for two weeks. This protocol was
      compared with observation alone. Outcome variables included anatomic closure of
      the macular hole, macular hole size, and four standardized measures of vision.
      RESULTS: At 12 months, 15 (71%) of 21 eyes randomly assigned to observation
      progressed to stages 3 or 4, compared with three (20%) of 15 eyes randomly
      assigned to surgery (P < .006). Compared with eyes randomly assigned to
      observation, eyes randomly assigned to surgery had significantly smaller hole
      diameters (P < .01) and significantly better visual acuity outcomes, as measured
      by the Word Reading (P = .02) and Potential Acuity Meter (P = .002) charts. No
      significant differences were found for the Early Treatment Diabetic Retinopathy
      Study chart and Contrast Sensitivity test. CONCLUSION: Compared with observation
      alone, surgical intervention in stage 2 macular holes resulted in a significantly
      lower incidence of hole enlargement and appeared to be associated with better
      outcome in some measures of visual acuity.

PMID- 8644803
TI  - Increased intraocular pressure after macular hole surgery.
AB  - PURPOSE: To determine the incidence and timing of increased intraocular pressure
      in eyes with an idiopathic macular hole treated with bovine transforming growth
      factor-beta 2 (TGF-beta 2) with different intraocular gas concentrations,
      recombinant TGF-beta 2, or placebo. METHODS: Intraocular pressure was measured
      preoperatively and two days, two weeks, six weeks, and three months
      postoperatively in two prospective studies of the treatment of idiopathic macular
      hole with vitrectomy. Group 1 consisted of 95 eyes treated with bovine TGF-beta
      2. Eyes in this group were treated with different concentrations of air and
      perfluoropropane (C3F8) intraocular gas bubbles. Fifteen eyes were treated with
      air, 15 eyes with 5% perfluoropropane, 15 eyes with 10% perfluoropropane, and 50
      eyes with 16% perfluoropropane. Group 2 consisted of 29 eyes treated with
      recombinant TGF-beta 2. Twenty-six eyes were treated with placebo in a double
      masked, randomized, placebo-controlled study evaluating recombinant TGF-beta 2
      with a 16% perfluoropropane intraocular gas bubble. RESULTS: At the two-week
      examination, the intraocular pressure in Group 1 eyes was > 30 mm Hg in four
      (26.7%) of 15 eyes treated with air, two (13.3%) of 15 eyes treated with 5%
      perfluoropropane, one (8.3%) of 12 eyes treated with 10% perfluoropropane, and
      nine (19.1%) of 47 eyes treated with 16% perfluoropropane. There was no
      statistically significant difference in the risk of increased intraocular
      pressure in eyes treated with short-, intermediate-, or long-duration gas
      tamponade using bovine TGF-beta 2. The intraocular pressure in Group 2 was > 30
      mm Hg at the two-week examination in 11 (39.3%) of 28 eyes receiving recombinant
      TGF-beta 2 compared with one (4.3%) of 23 eyes receiving a placebo (P = .006).
      CONCLUSIONS: Some eyes develop increased intraocular pressure after vitreous
      surgery for macular hole, and the increase occurs most frequently between two
      days and two weeks postoperatively. The risk of increased intraocular pressure is
      somewhat increased in eyes treated with bovine TGF-beta 2 but is markedly
      increased in eyes in which recombinant TGF-beta 2 is used as an adjunctive agent
      for macular hole surgery. Intraocular injection of growth factors produced by
      similar recombinant DNA techniques may result in potentially dangerous increased
      intraocular pressure several weeks after surgery. Impurities in the recombinant
      TGF-beta 2 may explain the relatively high risk of increased intraocular
      pressure.

PMID- 8644804
TI  - Autosomal dominant central areolar choroidal dystrophy caused by a mutation in
      codon 142 in the peripherin/RDS gene.
AB  - PURPOSE: Because several macular dystrophies are caused by mutations in the
      peripherin/RDS gene, we examined autosomal dominant and sporadic cases of central
      areolar choroidal dystrophy for mutations in the peripherin/RDS gene. METHODS:
      DNA sequence analysis of the peripherin/RDS gene was performed in four sporadic
      cases and in ten affected and nine unaffected individuals from seven families
      with autosomal dominant central areolar choroidal dystrophy. RESULTS: An Arg-142
      Trp mutation in the peripherin/RDS gene was found in ten affected family members
      in seven families. Among these, a 69-year-old man with the Arg-142-Trp mutation,
      who was unaffected six years before blood sample analysis, showed a parafoveal
      area of chorioretinal atrophy. The 65-year-old sister of this family had the Arg
      142-Trp mutation with no macular abnormalities, but she might still develop
      central areolar choroidal dystrophy at an older age. No mutation was found in the
      four sporadic cases. CONCLUSION: Autosomal dominant central areolar choroidal
      dystrophy, studied in seven families, is caused by an Arg-142-Trp mutation in the
      peripherin/RDS gene.

PMID- 8644805
TI  - Treatment of maculopathy associated with optic disk pit by sponge explant.
AB  - PURPOSE: To evaluate the anatomic and functional outcome in nine patients with
      optic disk pit maculopathy after the use of the macular buckling procedure.
      METHODS: In this prospective study, nine consecutive patients (five women and
      four men with a mean age of 28 years [range, 14 to 49 years] who had unilateral
      maculopathy associated with optic disk pit) were treated with macular buckling
      surgery. A scleral sponge of 7.5 x 5.5 mm was fixed at the posterior pole of the
      globe corresponding to the macula along the vertical axis of the 12-to-6 o'clock
      meridian. No additional treatment of any kind (laser, diathermy, or cryotherapy)
      was used. The correct positioning of the sponge during the operation was
      monitored by B-scan ultrasonography. Within the first week after surgery,
      indocyanine green angiography was performed to evaluate the choroidal
      circulation. During the same period, magnetic resonance imaging of the orbit was
      performed to determine the sponge position in relation to the optic nerve.
      RESULTS: In all nine eyes, complete disappearance of subretinal and intraretinal
      fluid in the macula and in the surrounding area was noted. The absorption of the
      macular fluid started immediately after the operation and was completed after
      five to six months. No further change of the appearance of the fundus was noted
      during the follow-up period, which ranged from 18 to 66 months (mean follow-up,
      42 months). Six eyes gained four or five lines of visual acuity, and two eyes
      improved by three lines. CONCLUSIONS: The macular scleral buckling procedure in
      optic disk pit maculopathy can yield favorable anatomic and functional results.

PMID- 8644806
TI  - Diagnosis and treatment of an ophthalmic artery occlusion during an intralesional
      injection of corticosteroid into an eyelid capillary hemangioma.
AB  - PURPOSE: To demonstrate the usefulness of simultaneous indirect ophthalmoscopy in
      the diagnosis and treatment of embolization of the ocular circulation during
      intralesional injection of corticosteroids into capillary hemangiomas. METHODS: A
      4-month-old infant had an ophthalmic artery occlusion during an intralesional
      injection of corticosteroids into a right upper eyelid capillary hemangioma. The
      injection was discontinued immediately and a paracentesis was performed.
      Fluorescein angiography was performed 20 minutes and three weeks after the
      ophthalmic artery occlusion. RESULTS: Fluorescein angiography after the
      paracentesis showed delayed retinal and choroidal filling and large areas of
      retinal and choroidal ischemia. Three weeks after treatment, the angiographic
      abnormalities had resolved, and the retinal and choroidal circulations were
      normal. Twenty-eight months after treatment, the visual acuity was 20/20 in each
      eye. CONCLUSION: Ophthalmic artery occlusion can occur during intralesional
      injection of corticosteroids into capillary hemangiomas. Simultaneous indirect
      ophthalmoscopy allows the surgeon to discontinue the injection and provide
      treatment to allow for the best possible visual outcome after this complication.

PMID- 8644807
TI  - Choroidal neovascularization secondary to Candida albicans chorioretinitis.
AB  - PURPOSE: To study the clinical histories and courses of six patients with
      choroidal neovascularization secondary to endogenous Candida albicans
      chorioretinitis. METHODS: The medical records, fundus photographs, and
      fluorescein angiograms of six patients who developed C. albicans chorioretinitis
      secondary to candidemia and who subsequently developed choroidal
      neovascularization in one or both eyes were reviewed. RESULTS: The six patients
      ranged in age from 18 to 79 years. Four were women and two men; all but one
      showed evidence of bilateral chorioretinal scarring secondary to C. albicans
      chorioretinitis. All patients had been treated successfully with systemic
      antifungal therapy (amphotericin B). Two weeks to two years after the
      chorioretinitis, choroidal neovascularization developed in one eye (four cases)
      or both eyes (two cases). The neovascularization on initial examination was
      subfoveal in four eyes, extrafoveal in three eyes, and juxtafoveal in one eye.
      Laser photocoagulation was used in four of the eight involved eyes. In these
      cases, the active choroidal neovascularization was brought under control. In one
      eye, the patient had submacular surgery for excision of the choroidal neovascular
      membrane. Final visual acuities ranged from 20/20 to 20/200 in treated eyes and
      from 20/50 to 20/400 in untreated eyes. CONCLUSION: Choroidal neovascularization
      is a potential cause of late visual loss in patients who have had C. albicans
      sepsis and endogenous C. albicans chorioretinitis. Eyes that have chorioretinal
      scarring from C. albicans chorioretinitis should be watched for the development
      of choroidal neovascularization. Laser photocoagulation or perhaps surgical
      excision of the neovascular complex may be of benefit in selected cases.

PMID- 8644808
TI  - Serologic and polymerase chain reaction analysis of intraocular fluids in the
      diagnosis of infectious uveitis.
AB  - PURPOSE: Infectious uveitis entities are usually rapidly progressive blinding
      diseases that can be prevented by prompt administration of specific antimicrobial
      therapy. With the aim of improving early diagnosis in patients with infectious
      uveitis, intraocular fluid samples from patients with sight-threatening posterior
      uveitis were investigated to determine the causative agent. METHODS: Thirty-eight
      patients with acquired immunodeficiency syndrome (AIDS) and retinitis, eight
      immunosuppressed patients with retinitis, 16 immunocompetent patients with acute
      retinal necrosis, and 22 immunocompetent patients with toxoplasmic
      retinochoroiditis were analyzed by polymerase chain reaction for the presence of
      herpesviruses and Toxoplasma gondii DNA and for local antibody production against
      these microorganisms. RESULTS: In patients with AIDS and retinitis, polymerase
      chain reaction was positive for cytomegalovirus DNA in 21 (91%) of the 23 ocular
      fluid samples obtained during active cytomegalovirus retinitis, whereas local
      antibody production analysis was negative in all cases. In acute retinal
      necrosis, varicella-zoster virus or herpes simplex virus could be established as
      the inciting agent in 81% of the cases, using the combination of both techniques.
      Polymerase chain reaction was positive in all samples obtained within two weeks
      after the onset of disease. Toxoplasma gondii DNA was detected in 4 of 13 samples
      (31%) from immuno-competent patients with active toxoplasmic retinochoroiditis;
      in each case, local antibody production was also detected. In contrast, no local
      antibody production was observed in two of three samples from transplant
      recipients that were positive for T. gondii DNA. All the control samples tested
      were negative for the above-mentioned tests. CONCLUSIONS: In patients with AIDS,
      polymerase chain reaction analysis is preferable above local antibody production
      in detecting the inciting agent of retinitis. In other cases, the combination of
      both techniques can make a valuable contribution to the diagnosis.

PMID- 8644809
TI  - Comparison of methods to evaluate the optic nerve head and nerve fiber layer for
      glaucomatous change.
AB  - PURPOSE: To compare the rates of optic nerve damage in early human glaucoma as
      measured by four methods to evaluate change in the optic nerve and nerve fiber
      layer. METHODS: Four techniques were used to detect progressive glaucomatous
      damage in a prospective, longitudinal study: (1) qualitative evaluation of
      stereoscopic color optic disk photographs, (2) qualitative evaluation of
      monochromatic nerve fiber layer photographs, (3) manual stereoplanimetric
      measurements of disk rim area, and (4) computerized measurement of peripapillary
      nerve fiber layer height. One eye of each patient with glaucoma or ocular
      hypertension was evaluated at the beginning and end of a follow-up period of not
      less than one year. The rates of structural change measured by these techniques
      and the rate of visual field change measured with threshold automated perimetry
      were determined. RESULTS: We followed up 193 patients for a mean (+/- S.D.) of
      3.3 +/- 1.0 years (range, one to six years). Twenty-nine (15%) of 193 eyes
      progressed by qualitative optic disk evaluation, 14 (7.2%) of 193 eyes progressed
      by qualitative nerve fiber layer evaluation, seven (3.6%) of 193 eyes progressed
      by stereoplanimetry, and 24 (13.2%) of 182 eyes progressed by measurement of
      nerve fiber layer height. Visual field deterioration was detected in 12 (5.2%) of
      193 patients and correlated best with qualitative optic disk and nerve fiber
      layer evaluations. Evaluation by stereoplanimetry and nerve fiber layer height
      measurement detected change in eyes with primarily diffuse structural damage, a
      pattern not well detected by qualitative methods. CONCLUSION: Both qualitative
      and quantitative methods of optic disk and nerve fiber layer evaluation
      contribute to the identification of progressive damage, depending on the stage of
      disease and the characteristics of optic nerve cupping.

PMID- 8644810
TI  - Height measurement of astigmatic test surfaces by a keratoscope that uses plane
      geometry surface reconstruction.
AB  - PURPOSE: To assess the accuracy with which the Keratron keratoscope (Optikon
      2000, Rome, Italy) measured astigmatic test surfaces by a profile reconstruction
      algorithm within a plane geometry model and to discriminate between error caused
      by the model and error caused by other factors. METHODS: Height was reported by
      the Keratron for eight surfaces with central astigmatism ranging from 4 to 16
      diopters. A three-dimensional ray tracing simulation produced theoretic reflected
      ring patterns on which the Keratron's reconstruction algorithm was performed. The
      Keratron's measurements were compared with the surfaces' formulas and the ray
      traced simulations. RESULTS: With a new mathematical filter for smoothing ring
      data, now part of the Keratron's software, maximum error was 0.47% of the total
      height and was usually less than 1% of local power for surfaces with 4 diopters
      of astigmatism. For surfaces with 16 diopters of astigmatism, maximum error was
      as high as 2.9% of total height and was usually less than 2.5% of local power.
      The reconstruction algorithm accounted for 40% and 70% of height error,
      respectively. CONCLUSIONS: The efficacy of keratoscopes cannot be assumed from
      their design theories but must be tested. Although plane geometry surface
      reconstruction contributed greatly to total height error, total error was so
      small that it is unlikely to affect clinical use.

PMID- 8644811
TI  - Improvement in subjective visual function and quality of life outcome measures
      after blepharoptosis surgery.
AB  - PURPOSE: To examine patients' subjective perception of visual function and health
      related quality of life as affected by blepharoptosis and the change in these
      perceptions after blepharoptosis surgery. METHODS: A 27-item questionnaire
      pertaining to vision-related activities and symptoms was used preoperatively to
      assess 50 consecutive patients (18 years old or older) with unilateral or
      bilateral acquired involutional blepharoptosis, and postoperatively six to eight
      weeks after blepharoptosis repair. RESULTS: Of the 24 items statistically
      analyzed, 16 items (67%) demonstrated significant improvement postoperatively (P
      < .05) among the unilateral cases and 18 items (75%) showed significant
      improvement postoperatively (P < .05) among the bilateral cases. The four
      activities that improved the most after surgery for both the unilateral and
      bilateral groups were the ability to perform fine manual work, hanging or
      reaching objects above eye level, watching television, and reading. CONCLUSIONS:
      Surgical repair of acquired involutional blepharoptosis resulted in significant
      improvement in several aspects of patients' subjective visual function and health
      related quality of life. These issues are important in determining both the
      indications for and outcome of blepharoptosis surgery.

PMID- 8644812
TI  - Sensory experiences with posterior vitreous detachment.

PMID- 8644813
TI  - Advances in neuroimaging of the visual pathways.
AB  - PURPOSE: To provide a practical review for the ophthalmologist of advances in
      neuroimaging of the visual pathways. METHODS: We reviewed recent advances in
      computed tomography, magnetic resonance imaging, and angiography that are
      applicable to visual pathways imaging. RESULTS: For detailed ocular imaging,
      computed tomography complements ocular sonography for imaging of calcification,
      trauma, and masses. Magnetic resonance imaging may be helpful for localization
      and characterization of ocular masses in the setting of hemorrhage. For orbital
      imaging, computed tomography is most appropriate in the evaluation of suspected
      thyroid ophthalmopathy, infection, and trauma; otherwise, either computed
      tomography or magnetic resonance imaging is useful for detection and
      characterization of abnormality. For disorders affecting the sellar,
      retrochiasmal, and brainstem pathways, magnetic resonance imaging is the study of
      choice, except for acute hemorrhage, for which noncontrast computed tomography is
      preferable. Although magnetic resonance angiography has a role in the elective
      evaluation of cerebrovascular disease, conventional angiography is the definitive
      study for suspected aneurysm and for surgical planning. CONCLUSIONS: A practical
      approach for selection of the most appropriate imaging modalities by the
      ophthalmologist is suggested on the basis of the anatomic location and type of
      disease suspected.

PMID- 8644814
TI  - Dislocation of the lens nucleus into the vitreous cavity after standard
      hydrodissection.
AB  - PURPOSE: Having encountered dislocation of the lens nucleus into the vitreous
      cavity immediately after continuous tear capsulorhexis and hydrodissection of the
      nucleus, we examined common features of eyes with this complication. METHODS: We
      reviewed consecutive cases of cataract extraction. RESULTS: The complication
      occurred in four of 10,126 eyes. All four eyes were in elderly patients and
      except for the patient whose contralateral eye had pseudoexfoliation syndrome,
      all eyes had an increased axial length. CONCLUSION: In elderly patients with eyes
      that have a long axial length or pseudoexfoliation, we recommend performing
      hydrodissection with extreme care and only when necessary.

PMID- 8644815
TI  - Bilateral simultaneous corneal graft rejection after influenza vaccination.
AB  - PURPOSE: To treat a patient with bilateral simultaneous corneal graft rejection
      after influenza vaccination. METHODS: The patient received topical,
      subconjunctival, and systemic corticosteroids. RESULTS: The corneal grafts
      cleared after administration of corticosteroids. CONCLUSION: Ophthalmologists
      should be aware of the possibility of corneal graft rejection after influenza
      vaccination.

PMID- 8644816
TI  - Corneoscleral laceration caused by air-bag trauma.
AB  - PURPOSE: To report a case of a corneoscleral laceration sustained as a direct
      result of inflation of a driver-side air bag. METHODS: A patient who sustained a
      severe ocular injury in a low-speed motor vehicle accident underwent clinical and
      radiologic examination and subsequent treatment. RESULTS: The left eye underwent
      primary repair of a complex corneoscleral laceration. Two weeks postoperatively,
      visual acuity in the left eye remained at bare hand motion. CONCLUSION: Although
      air-bag-related eye trauma may be relatively infrequent, the severity of the
      injuries incurred warrant research efforts to explore new air-bag designs that
      minimize the risk of ocular injury.

PMID- 8644817
TI  - Possible consequences of shaking hands with your patients with epidemic
      keratoconjunctivitis.
AB  - PURPOSE: We evaluated patients' hands as a possible vector for the spread of
      epidemic kerato-conjunctivitis. METHODS: The hands and conjunctivitis of 26
      patients with epidemic keratoconjunctivitis and the hands of 26 uninfected
      control patients were cultured for infectious adenovirus. RESULTS: In 12 (46%) of
      26 patients with epidemic keratoconjunctivitis, cultures from the hands were
      positive for adenovirus, whereas cultures from the hands of all uninfected
      control patients were negative. CONCLUSIONS: Simultaneous coinfection of
      patients' hands and eyes with adenovirus may contribute to office epidemics.
      Ophthalmologists and coworkers should not shake the hands of patients suspected
      of having epidemic keratoconjunctivitis unless properly gloved.

PMID- 8644819
TI  - Microsporidial keratoconjunctivitis caused by Septata intestinalis in a patient
      with acquired immunodeficiency syndrome.
AB  - PURPOSE: To examine and treat a patient with acquired immunodeficiency syndrome
      (AIDS) who had mildly hyperemic conjunctiva and epithelial keratopathy in both
      eyes. METHODS: The patient underwent conjunctival biopsy. The specimen was
      examined by transmission electron microscopy. RESULTS: Septata intestinalis was
      demonstrated to be the cause of keratoconjunctivitis in the patient. The
      keratoconjunctivitis resolved after three weeks of therapy with topical
      fumagillin. No organisms were seen on repeat conjunctival biopsy. CONCLUSIONS:
      Microsporidial keratoconjunctivitis in patients with AIDS can be caused by S.
      intestinalis. This condition appears to respond to topical fumagillin.

PMID- 8644818
TI  - Fluoroquinolones in the treatment of bacterial keratitis.
AB  - PURPOSE: We evaluated the potential role of three topical fluoroquinolones in the
      treatment of bacterial keratitis by means of a laboratory database. METHODS:
      Antibiotic susceptibilities were determined for 153 isolates from patients with
      bacterial keratitis. Results were analyzed for each fluoroquinolone individually
      and in combination with cefazolin. RESULTS: Predicted susceptibility to each
      cefazolin-fluoroquinolone combination (98.7%) was superior to that for single
      agent therapy with ofloxacin (88.2%), ciprofloxacin (82.3%), or norfloxacin
      (80.4%) (P = .0002). A cefazolin-fluoroquinolone combination (98.7%) was
      comparable to a cefazolin-gentamicin combination (97.4%). CONCLUSIONS:
      Combination therapy with cefazolin and a fluoroquinolone offers a reasonable
      alternative for the treatment of bacterial keratitis. Single-agent therapy with
      fluoroquinolones for vision-threatening bacterial keratitis is not advised.

PMID- 8644820
TI  - Bilateral tuberculous abscesses on the face (eyelids) of a child.
AB  - PURPOSE: To report a rare case of tuberculosis with facial abscess. METHODS: A 4
      1/2-year-old girl had an acute left upper eyelid abscess and a large, spherical
      tumescence involving the right upper eyelid, eyebrow, and forehead. The left
      upper eyelid abscess was drained, and the mass involving the right eyelid,
      eyebrow, and forehead was excised. RESULTS: Histopathologic and microbiologic
      examination established a human type of tuberculous mycobacterium as the cause of
      the bilateral facial lesions. CONCLUSION: Tuberculosis should be considered as a
      possible cause of abscess even when clinical features are not typical.

PMID- 8644821
TI  - Repair of Descemet's membrane detachment with the assistance of intraoperative
      ultrasound biomicroscopy.
AB  - PURPOSE: To evaluate the ability of ultrasound biomicroscopy to monitor the
      repair of large Descemet's membrane detachments. METHODS: Intraoperative
      ultrasound biomicroscopy was performed in two patients who had undergone previous
      unsuccessful surgical repair of large Descemet's membrane detachments. RESULTS:
      Ultrasound biomicroscopy visualized and located Descemet's membrane detachment
      and verified proper suture placement and membrane repositioning. CONCLUSIONS:
      Ultrasound biomicroscopy is a useful tool to guide surgical repair of Descemet's
      membrane detachments, particularly when hazy media prevent satisfactory
      visualization.

PMID- 8644822
TI  - Ultrasound biomicroscopic analysis of transient shallow anterior chamber in Vogt
      Koyanagi-Harada syndrome.
AB  - PURPOSE: To evaluate the mechanism of formation of the transient shallow anterior
      chamber in Vogt-Koyanagi-Harada syndrome. METHODS: Two patients with Vogt
      Koyanagi-Harada syndrome with shallow anterior chambers were examined with an
      ultrasound biomicroscope. RESULTS: A ciliochoroidal detachment, which was not
      obvious on ophthalmoscopic examination, was clearly demonstrated in both patients
      by ultra-sound biomicroscopy. The detachment disappeared after systemic
      corticosteroid therapy. CONCLUSION: The shallowing of the anterior chamber in two
      patients with Vogt-Koyanagi-Harada syndrome was caused by suprachoroidal effusion
      secondary to inflammation of the uvea.

PMID- 8644823
TI  - Spontaneous regression and successful laser prophylaxis in progressive outer
      retinal necrosis syndrome.
AB  - PURPOSE: To describe a case of progressive outer retinal necrosis syndrome that
      regressed spontaneously after discontinuation of all systemic antiviral
      medications with macular sparing after prophylactic laser photocoagulation of the
      posterior pole. METHODS: Prophylactic laser photocoagulation surrounding the
      posterior pole was performed in an attempt to spare the macula from detachment in
      a patient with progressive outer retinal necrosis. RESULTS: Progressive outer
      retinal necrosis regressed spontaneously without systemic antiviral medications.
      The posterior pole within the area of photocoagulation remained attached.
      CONCLUSIONS: Prophylactic laser treatment surrounding the posterior pole rather
      than peripheral retina may allow more time for formation of firm chorioretinal
      adhesions and protect the macula from detachment.

PMID- 8644824
TI  - Diagnosis of oculocutaneous albinism with molecular analysis.
AB  - PURPOSE: To use molecular analysis to diagnose oculocutaneous albinism in a
      patient with an atypical clinical presentation. METHODS: A 34-year-old woman with
      a history of strabismus and absent cutaneous pigment underwent comprehensive
      ophthalmic examination, visual-evoked potentials to detect altered optic
      decussation, and molecular analysis. RESULTS: Examination showed fine nystagmus,
      iris transillumination, foveal hypoplasia, and corrected visual acuity of 20/25
      in each eye. Misrouting of the retinostriate fibers was demonstrated with visual
      evoked potentials. Mutations in the tyrosinase gene established the diagnosis of
      oculocutaneous albinism 1 even though the patient had atypical clinical features.
      CONCLUSIONS: Molecular analysis can establish the diagnosis of oculocutaneous
      albinism 1 in the patient with atypical ocular features.

PMID- 8644825
TI  - Attempted autoenucleation.
AB  - PURPOSE: A 24-year-old man had visual acuity of no light perception in the left
      eye after attempted autoenucleation. METHODS: An urgent lateral canthotomy was
      performed, followed by treatment with high-dose intravenous corticosteroids.
      RESULTS: Visual acuity improved to L.E.: 20/30. Visual field testing disclosed
      recovery of the central visual field with persistent arcuate visual field
      defects. CONCLUSION: Visual acuity of no light perception after attempted
      autoenucleation does not preclude the return of good visual acuity.

PMID- 8644826
TI  - Essential thrombocythemia and central retinal vein occlusion with neovascular
      glaucoma.
AB  - PURPOSE: We report a case of unilateral central retinal vein occlusion resulting
      from essential thrombocythemia, a rare myeloproliferative disorder with
      abnormally increased platelet count. METHODS: A 59-year-old man had central
      retinal vein occlusion in the left eye as the initial sign of essential
      thrombocythemia. He later developed neovascular glaucoma and optic disk
      neovascularization. RESULTS: Laser panretinal photocoagulation,
      goniophotocoagulation, glaucoma medications, and control of the platelet count
      were effective treatment. CONCLUSIONS: Early thrombocythemia is associated with
      systemic and ocular thrombotic and embolic complications. Early diagnosis,
      recognition of ocular complications, and appropriate treatment were crucial in
      controlling central retinal vein occlusion and ocular neovascularization
      associated with essential thrombocythemia.

PMID- 8644827
TI  - Analysis of astigmatic keratotomy with a 5.0-mm optical clear zone.

PMID- 8644828
TI  - Causes of uveitis in the general practice of ophthalmology.

PMID- 8644829
TI  - Incidence of acute angle-closure glaucoma after pharmacologic mydriasis.

PMID- 8644830
TI  - Prevent Blindness America visual field screening study.

PMID- 8644831
TI  - A comparison of performance in added-purpose occupations and rote exercise for
      dynamic standing balance in persons with hemiplegia.
AB  - OBJECTIVES: Adding purpose to daily occupations to promote performance is a basic
      premise of occupational therapy. This study investigated the hypothesis that in
      persons with hemiplegia, two added-purpose occupations would elicit more exercise
      repetitions than a rote exercise. METHOD: In a counterbalanced order, 21 subjects
      with hemiplegia, aged 51 to 78 years, experienced all three conditions of a
      dynamic standing balance exercise that involved bending down, reaching, standing
      up, and extending the arm. One condition of added purpose involved the use of
      materials (small balls and target); a second added-purpose condition involved the
      subjects' imagination of the small balls. The third condition was the rote
      exercise without added purpose. RESULTS: A one-way analysis of variance for
      related measures indicated that the subjects performed significantly differently
      in each of the three conditions (p < .001). A Tukey multiple comparison test
      revealed that the subjects did significantly more exercise repetitions in the
      added-materials condition and in the imagery-based condition than in the rote
      exercise condition (p < .05). CONCLUSION: This study demonstrates how added
      purpose can enhance motor performance in persons with hemiplegia. Purpose may be
      effectively added to an exercise through the use of materials or imagery.

PMID- 8644832
TI  - Effects of a program on symmetrical posture in patients with hemiplegia: A single
      subject design.
AB  - OBJECTIVES: Asymmetrical posture during static stance has been identified as a
      common problem in persons with hemiplegia. This study examined the effect of an
      activity-based therapy regimen on symmetric weight bearing and midline position
      of center of gravity (COG) in three adult subjects with hemiplegia. METHOD: An
      ABAB single-subject design was used. The intervention program, including sanding
      in front of a standing table and play a bean bag game, was introduced for 30 min
      each day during each intervention phase. Quantitative measurements of the weight
      distribution and the midline position of COG were taken with the Balance Master
      System (version 2.20). RESULTS: Visual inspection and statistical analysis of the
      data revealed a significant improvement in symmetric weight distribution and
      midline position of COG. The study suggests that this program may be a promising
      alternative to a variety of postural rehabilitation programs for persons with
      hemiplegia. CONCLUSION: Insecurity caused by poor stabilization and abnormal
      reactions to body weight bearing in an antigravity position might contribute to
      asymmetric postures. Results of this study suggest that an activity-oriented
      program can be effective in helping the persons with hemiplegia achieve symmetric
      stances.

PMID- 8644834
TI  - Grip strength and finger dexterity across five styles of commercial wrist
      orthoses.
AB  - OBJECTIVE: Five styles of commercial static wrist extensor orthoses were compared
      to determine whether any style, or styles, afforded better power grip strength or
      finger dexterity. Because wrist extensor orthoses are intended for use during
      functional tasks, their influence on hand function is of great importance.
      METHOD: Twenty-three right-hand-dominant women without upper extremity
      dysfunction participated in this crossover study. Dominant-hand finger dexterity
      and power grip strength were evaluated while wearing each of five commercial
      orthoses-Kendall-Futuro #33 (Futuro), AliMed Freedom Long (AliMed Long), AliMed
      Freedom Short (AliMed Short), Smith & Nephew Rolyan D-Ring (Rolyan), and LMB
      Wrist Rest (LMB)--and while using the dominant hand without an orthosis (free
      hand). Finger dexterity was assessed with the unimanual subtest of the Purdue
      Pegboard. Grip strength was assessed with a Jamar hydraulic dynamometer. RESULTS:
      Four of the study orthoses (Futuro, AliMed Short, Rolyan, and LMB) afforded
      finger dexterity that did not differ significantly from that of the free hand.
      The AliMed Long orthosis slowed finger speed when compared with the speeds
      afforded by both the LMB orthosis and the free hand. The Rolyan orthosis
      permitted a power grip strength that was not significantly different from the
      free hand. The other four commercial orthoses reduced grip strength when compared
      with the strength observed when wearing a Rolyan orthosis and when gripping with
      a free hand. CONCLUSION: The five styles of commercial orthoses affect power grip
      and finger dexterity differently. When power grip or finger dexterity are
      priorities, differences among the orthoses furnish grounds for initial
      suggestions, although medical needs and patient preference should be the
      overriding factors in the final selection of an orthosis.

PMID- 8644833
TI  - Effects of a skiing experience on adolescents with limb deficiencies: an
      occupational adaptation perspective.
AB  - OBJECTIVE: Effects of a 6-day snow skiing trip on 14 adolescents with limb
      deficiencies were explored. The purpose was to determine whether components of
      mastery and self-esteem could be identified. METHOD: Participant observation data
      collection methods included videotape, interviews, daily progress notes by ski
      instructors, and a 1-month posttrip questionnaire. Data were analyzed for
      evidence of efficiency, effectiveness, and satisfaction to self and others
      (properties of relative mastery described in occupational adaptation.) Skier
      reports of positive effects were analyzed for indications of an impact on self
      esteem. Three occupational therapists who have extensive experience working with
      adolescents also reviewed videotapes and written information. RESULTS: The
      therapists acknowledged the presence of skill mastery as an important component
      of skiers' positive self-evaluation. They also commented that evidence of
      preexisting self-esteem and social aspects of the trip were as likely to produce
      positive effects as mastery of skiing. CONCLUSION: Research method considerations
      (use of participant observation for hypothesis testing) preclude definitive
      interpretation of a link between skill mastery and self-esteem. Short-term
      positive effects of the skiing experience reported by questionnaire were present
      1 month after the trip. Long-term effects should be studied.

PMID- 8644835
TI  - The meaning of sea kayaking for persons with spinal cord injuries.
AB  - OBJECTIVES: Research has described benefits of physical, athletic, and
      avocational activity on improving self-esteem, quality of life, and locus of
      control in persons with disabilities. The objective of this study was to identify
      meaningful components of the experience of sea kayaking as described by persons
      with spinal cord injury (SCI). METHOD: Three subjects with SCI who had
      participated in recreational kayaking were interviewed. Qualitative research
      methods included strategies from Guba's model for rigor in qualitative research,
      Spradley's interviewing guidelines, and Good's method of semantic network
      analysis. Three interviews of approximately 45 min in length were conducted with
      each subject. Initial interviews began with a single question: "Tell me about sea
      kayaking." Subsequent questions contained only concepts and terms used in the
      subjects' responses. RESULTS: The subjects valued the novelty, challenge, safety,
      sociability, and natural environment aspects of sea kayaking. Perceptions of the
      self as able in the eyes of others and the need for support in pursuit of outdoor
      leisure activities were themes that figured prominently in the subjects'
      discourse. CONCLUSION: Subjects' comments indicate that meaningful time use and
      the construction of an identity after injury are linked. This link has also been
      suggested in the rehabilitation literature. This information suggests the use of
      therapeutic intervention that supports a person's adjustment to an irreversible
      SCI.

PMID- 8644836
TI  - A pet therapy intervention with geriatric psychiatry inpatients.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of pet therapy
      on geriatric psychiatry inpatients. A demonstrable impact could lead to more
      widespread or targeted use of animal companionship programs for hospitalized
      older persons. METHOD: The study design was a randomized, parallel-group control
      treatment trial with pretreatment and posttreatment measures. Fifty-eight
      subjects with chronic age-related disabilities who were patients of the Wills Eye
      Hospital Geriatric Psychiatry Unit were assigned to a pet therapy intervention
      group or an exercise control group for 1 hr a day for 5 consecutive days. Every
      subject was blindly evaluated with the Multidimensional Observation Scale for
      Elderly Subjects (MOSES) before and after the intervention week. RESULTS: No
      significant differences in MOSES scores were found between or within groups
      before and after the interventions. There was a nonsignificant tendency for
      subjects who received the pet intervention to have less irritable behavior after
      treatment. However, women with dementia who received either pet therapy or
      exercise intervention had improved irritable behavior scores after treatment.
      CONCLUSION: This pilot study demonstrates the need for further research on animal
      assisted interventions with hospitalized elderly persons. Differential
      improvement in women with dementia also requires further investigation.

PMID- 8644837
TI  - Fine motor outcomes in preschool children who receive occupational therapy
      services.
AB  - OBJECTIVE: This study examined preschool children's acquisition of fine motor
      skills and functional performance when occupational therapy services are included
      as part of the educational program. It also investigated the relationships among
      fine motor skills and functional performance in self-care, mobility, and social
      function. METHOD: Twenty-six preschool children who received weekly occupational
      therapy were studied. Measurements of their in-hand manipulation, tool use, eye
      hand coordination, grasping strength, and functional performance in self-care,
      mobility, and social function were taken at the beginning and end of the school
      year. RESULTS: Raw and scaled scores showed significant improvements in all skill
      areas; standard scores showed slight improvement in eye-hand coordination and
      mobility function. Correlations of the motor skill tests with the functional
      performance scales using year-end data revealed significant correlations for in
      hand manipulation, eye-hand coordination, and grasping strength with self-care
      function and mobility. CONCLUSIONS: The results demonstrate the level of change
      that occurs in fine motor skill and self-care, mobility, and social function
      during the course of the school year for preschoolers with moderate fine motor
      delays. The relationships found in the year-end testing imply that performance in
      underlying fine motor skills as the focus of occupational therapy intervention is
      associated with self-care and mobility function.

PMID- 8644838
TI  - The effect of neuromuscular electrical stimulation in reducing tone.

PMID- 8644839
TI  - Mental health: An endangered occupational therapy specialty?

PMID- 8644840
TI  - Multiskilling: who, how, when, and why?

PMID- 8644841
TI  - Yerxa's criticisms of cross training are appropriate.

PMID- 8644842
TI  - The two faces of tumor suppressor p53.

PMID- 8644844
TI  - Reshaping the interstitium by platelet-derived growth factor. Implications for
      progressive renal disease.

PMID- 8644843
TI  - Cellular adhesion molecules. Newly identified mediators of angiogenesis.

PMID- 8644845
TI  - Tumor suppressor genes and related molecules in leiomyosarcoma.
AB  - Soft tissue sarcomas represent a heterogeneous group of mesenchymal malignancies,
      and the majority of the previous scientific studies that have analyzed the
      occurrence of cell cycle regulators aberrations within soft tissue sarcomas have
      dealt with broad categories of different tumors. As a consequence, data
      concerning single classes of sarcomas are very limited. The authors analyze
      herein a histologically homogeneous series of 23 cases of leiomyosarcoma of the
      deep soft tissue. The p53 pathway was studied by investigating the p53 gene and
      protein, MDM2 protein, and p21waf1 protein. The Rb-cyclin D pathway was analyzed
      by studying the Rb gene and protein, p16MTS1/INK4A gene and protein, cyclin
      D1Prad1/bcl1 and cyclin D3 proteins. Aberrations of the p53 pathway were observed
      in about 16 percent of cases and were limited to the p53 gene. Such a finding
      contrasts with the higher rates of p53/MDM2 abnormalities reported in other types
      of sarcomas such as liposarcoma. Interestingly, abnormalities involving the Rb
      cyclin D pathway were detected in about 90 percent of cases. The Rb-cyclin D
      pathway therefore emerges as the preferred target for molecular abnormalities in
      this subset of soft tissue sarcomas.

PMID- 8644846
TI  - Patterns of epidermal growth factor receptor amplification in malignant gliomas.
AB  - Amplification of the gene for epidermal growth factor receptor (EGFR) is a common
      finding in malignant gliomas. We found that 18 of 29 grade 3 and grade 4 gliomas
      had EGFR amplification when assayed using fluorescence in situ hybridization. The
      amplification pattern suggests that the amplicon is contained within double
      minute chromosomes in most cases. EGFR copy number can differ by 20-fold in
      amplified cells within a single case. Polysomy 7 occurs frequently in both EGFR
      amplified and -unamplified cells. More than one-third of the cases had < or = 10
      percent of cells with amplified EGFR, and it is likely that these cases would not
      have been identified by methods that do not examine DNA on a cell by cell basis.

PMID- 8644847
TI  - Immunihistochemical detection of Bcl-2 in AIDS-associated and classical Kaposi's
      sarcoma.
AB  - Kaposi's Sarcoma (KS) is an angioproliferative disease that is characterized by
      proliferation of spindle-shaped cells predominantly of vascular endothelial cell
      origin, neoangiogenesis, inflammatory cell infiltration, and edema. Although the
      lesions of classical KS and AIDS-associated KS (AIDS-KS) share common
      histological features, AIDS-KS occurs at a markedly higher frequency with a more
      aggressive clinical course. Immunohistochemical analyses of 26 evolutionarily
      staged AIDS-KS lesions derived from HIV-infected patients demonstrate significant
      cytoplasmic levels of Bcl-2, a protooncogene known to prolong cellular viability
      and to antagonize apoptosis. Bcl-2 expression increases as the pathological stage
      of KS advances. Immunohistochemical analyses of classical KS lesions demonstrate
      prevalent expression of Bcl-2 as well, indicating that upregulation of Bcl-2 may
      be important in the pathogenesis of both classical and AIDS-associated KS.
      Coexpression of Bcl-2 and factor VIII-related antigen in spindle-shaped cells
      present within KS lesions suggests that Bcl-2 is upregulated within the vascular
      endothelial spindle-shaped cells of KS. The consequences of upregulated Bcl-2
      expression within KS lesions may be prolonged spindle cell viability which, when
      coupled with dysregulated cellular proliferation due in part to synergistic
      activities of inflammatory and angiogenic cytokines and HIV-1 Tat protein, may
      result in the maintenance, growth, and progression of KS.

PMID- 8644848
TI  - Strong expression of kinase insert domain-containing receptor, a vascular
      permeability factor/vascular endothelial growth factor receptor in AIDS
      associated Kaposi's sarcoma and cutaneous angiosarcoma.
AB  - Vascular permeability factor (VPF), also known as vascular endothelial growth
      factor (VEGF), plays an important role in the angiogenesis associated with the
      growth of many human and animal tumors. VPF/VEGF stimulates endothelial cell
      growth and increases microvascular permeability by interacting with two
      endothelial cell tyrosine kinase receptors, KDR and flt-1. We studied 16 cases of
      AIDS-associated Kaposi's sarcoma (KS), 2 cases of cutaneous angiosarcoma, and 6
      cases of capillary hemangioma by in situ hybridization for expression of
      VPF/VEGF, KDR, and flt-1 mRNAs. We also performed immunohistochemical staining
      for VPF/VEGF protein in 15 cases. Tumor cells in KS and angiosarcoma strongly
      expressed KDR but not flt-1 mRNA. Endothelial cells in small stromal vessels in
      and around these tumors strongly expressed both KDR and flt-1 mRNAs. Tumor cells
      expressed VPF/VEGF mRNA strongly in only one case of KS, adjacent to an area of
      necrosis. This was also the only case in which the tumor cells stained
      substantially for VPF/VEGF protein. VPF/VEGF mRNA and protein were, however,
      strongly expressed by squamous epithelium in areas of hyperplasia and near areas
      of ulceration overlying tumors. VPF/VEGF mRNA was also expressed focally at lower
      levels by infiltrating inflammatory cells, probably macrophages. The strong
      expression of both KDR and flt-1 in small stromal vessels in and around tumors
      suggests that VPF/VEGF may be an important regulator of the edema and
      angiogenesis seen in these tumors. The strong expression of KDR by tumor cells in
      KS and angiosarcoma implies that VPF/VEGF may also have a direct effect on tumor
      cells. Tumor cells in four of six capillary hemangiomas strongly expressed both
      KDR and flt-1 mRNAs in contrast to the high level expression of only KDR observed
      in the malignant vascular tumors studied. Neither VPF/VEGF mRNA or protein were
      strongly expressed in capillary hemangiomas. VPF/VEGF and its receptors may play
      an important but as yet incompletely understood role in the pathogenesis of both
      benign and malignant vascular tumors.

PMID- 8644850
TI  - Monoallelic expression of the insulin-like growth factor-2 gene in ovarian
      cancer.
AB  - Genomic imprinting is defined as a gamete-specific modification causing
      differential expression of the two alleles of a gene in somatic cells and is
      becoming increasingly recognized as playing an important role in a number of
      human diseases including cancer. We have reported that the loss of the insulin
      like growth factor-2 (IGF2) gene imprinting results in the deregulation of both
      IGF2 alleles, which may contribute to the onset of Wilms tumor. It is important
      to see whether such abnormal genomic imprinting is implicated in the etiology of
      common adulthood cancers. In the present study we have examined the expression
      level and imprinting status of the IGF2 gene in human ovaries and ovarian
      cancers. We confirm that IGF2 is significantly expressed in ovaries and ovarian
      cancers. In normal ovaries, both surface epithelium and the ovary proper
      demonstrate monoallelic IGF2 expression. Among 27 tumors, all 11 heterozygous for
      the IGF2 locus show monoallelic IGF2 expression (2 of them are proven to be from
      the paternal allele). The data suggest that the increased IGF2 gene expression in
      ovarian cancer may be achieved by a mechanism other than loss of imprinting.

PMID- 8644849
TI  - Telomerase activity is commonly detected in hereditary nonpolyposis colorectal
      cancers.
AB  - Telomerase activity can be detected in most human cancers. These findings are
      consistent with the telomere hypothesis, which predicts telomerase expression
      after a number of mitotic divisions to prevent the progressive and catastrophic
      loss of telomeres. However, telomerase is not detected in a minority of
      colorectal cancers suggesting either alternative mechanisms of immortalization or
      that their telomeres have not yet shortened sufficiently to require telomerase
      activity. Colorectal cancers arising in patients with hereditary nonpolyposis
      colorectal cancer (HNPCC) were examined for telomerase activity because compared
      to sporadic tumors, HNPCC tumors are less likely to pass a telomere threshold as
      they occur in younger patients and exhibit "accelerated" progression, perhaps
      because of their characteristic mutator phenotypes and losses of mismatch repair.
      Primary, colorectal cancers, 13 in HNPCC patients, and 37 sporadic tumors (17
      with mutator phenotypes) were examined for telomerase activity by the TRAP
      (telomeric repeat amplification protocol) assay. The majority of colorectal
      cancers contained detectable telomerase activity regardless of underlying
      phenotype (77 percent of HNPCC; 81 percent of sporadic tumors, 88 percent with
      mutator phenotypes and 75 percent without mutator phenotypes). Therefore,
      telomerase expression appears to be commonly acquired in the progression of both
      mutator phenotype and sporadic colorectal cancers.

PMID- 8644851
TI  - Clonal analysis of focal nodular hyperplasia of the liver.
AB  - Recent evidence suggests that focal nodular hyperplasia of the liver (FNH) may
      represent a hyperplastic response to a vascular malformation, but the precise
      etiology remains unclear. We performed a clonal analysis of ten FNHs from nine
      patients by patterns of X chromosome inactivation. DNA isolated from paraffin
      embedded specimens was subjected to polymerase chain reaction amplification for a
      highly polymorphic region of the human androgen receptor gene (HUMARA).
      Predigestion of tumor DNA with the methylation-sensitive, restriction enzyme
      HpaII allowed for selective amplification of the methylated (inactivated) allele.
      Of the nine patients analyzed, seven were heterozygous for the HUMARA
      polymorphism and informative for analysis. One informative patient had two
      lesions, for a total of eight FNHS. Amplification of lesional DNA after HpaII
      digestion demonstrated clonality in six of the eight informative cases. Paired
      tissue samples from different lesional areas were available in four of the six
      FNHs with evidence of clonality. In three of the four cases, DNA extracted from
      the two tissue samples showed both evidence of clonality and an identical pattern
      of X chromosome inactivation. In the remaining case, one sample showed evidence
      of clonality whereas the other was nonclonal. Three hepatic adenomas from two
      informative patients were also analyzed for comparative purposes, all of which
      showed evidence of clonality after HpaII digestion. The current study illustrates
      that most cases of FNH show a uniform pattern of X chromosome inactivation
      consistent with clonality.

PMID- 8644852
TI  - Triple primer polymerase chain reaction. A new way to quantify truncated mRNA
      expression.
AB  - The most practical method to quantify mRNA expression within small tumor samples
      is reverse transcription (RT) followed by quantitative polymerase chain reaction
      (PCR). One approach, known as "competitive RT-PCR" allows absolute quantitation
      by reference to synthetic RNA standards but is time-consuming and requires
      multiple manipulations that limit its usefulness as a screening assay. We
      describe here a new approach to quantify truncated type mRNAs relative to the
      wild-type transcripts in small amounts of tissue. This technique, called RT
      triple primer-PCR, consists of coamplification of wild-type and truncated cDNAs
      using three primers in the PCR. To validate this approach, a truncated estrogen
      receptor variant (clone 4) was quantified relative to the wild-type estrogen
      receptor using plasmid preparations. The ratio of triple primer-PCR products
      obtained was directly related to the initial ratio of input cDNAs. RT-triple
      primer-PCR was then used to compare the relative expression of clone 4 mRNA in
      frozen sections of normal human breast tissue and human breast tumors with
      characteristics of good prognosis. The statistically significant difference (P =
      0.03) observed between normal and tumor tissues suggests that elevated expression
      of the clone 4 variant may be associated with early steps of tumorigenesis. This
      technique provides a useful alternative to already described quantitative RT-PCR
      techniques for the quantification of truncated mRNA within small amounts of
      biological material.

PMID- 8644853
TI  - Chemiluminescent in situ hybridization for the detection of cytomegalovirus DNA.
AB  - A chemiluminescent in situ hybridization assay that could combine the sensitivity
      of chemiluminescent substrates, the specificity of digoxigenin-labeled probes,
      and the spatial morphological resolution and localization of the signal of the in
      situ hybridization was developed for the detection of cytomegalovirus (CMV) DNA.
      CMV DNA in cultured CMV-infected cells and in different clinical samples (tissue
      sections and cellular smears) was detected using digoxigenin-labeled probes
      constructed in our laboratory that were immunoenzymatically visualized employing
      anti-digoxigenin Fab fragments labeled with alkaline phosphatase and the
      chemiluminescent adamantil-1,2-dioxetane phenyl phosphate substrate for alkaline
      phosphatase. The luminescent signal from the hybrid formation was detected,
      analyzed, and measured with a high performance, low light level imaging
      luminograph apparatus connected to an optical microscope and to a personal
      computer for quantitative image analysis. Increasing values of emitted photons
      per second per infected cell, corresponding to the presence of hybridized CMV
      DNA, could be found in infected cells fixed at various times after infection,
      following the CMV replication cycle. When the assay was performed on different
      clinical samples from patients with acute CMV infections, CMV DNA was detected in
      all positive samples tested, both in cellular samples and in frozen and paraffin
      embedded tissue sections, proving specific and sensitive. The chemiluminescent in
      situ hybridization assay developed in this work can be a useful tool for a
      sensitive and specific diagnosis of viral infection and can be easily adapted to
      detect and study any specific gene sequence inside the cells. The assay may also
      be promising for an estimation and quantification of nucleic acids present in
      tissue samples or cellular smears and for imaging gene expression in cells.

PMID- 8644854
TI  - Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53
      transgenic mice.
AB  - p53 tumor suppressor plays a vital role in the cellular responses to genotoxic
      stress. It is believed that p53 regulates the cell cycle by activating the G1
      checkpoint after exposure to agents like ionizing radiation, ultraviolet (UV)
      radiation, or genotoxic chemicals. Recently, it is conjectured that p53 may have
      additional functions in DNA repair and apoptosis. Previously, we demonstrated
      that p53-transgenic mice that carry mutant alleles of a p53 gene developed twice
      as many skin tumors as control mice after UV exposure. To elucidate the molecular
      mechanisms of mutant p53 in skin cancers, we studied DNA repair efficiency and
      the rate of apoptosis in murine keratinocytes after UV irradiation. In this
      report, we show that mutant p53-transgenic mouse skin has reduced repair of UV
      induced DNA damage in both in vivo and in vitro radioimmunoassays. In control
      mice, DNA repair is associated with increased amounts of wild-type P53 protein.
      Unexpectedly, mutant p53-transgenic mice had slightly increased apoptosis after
      UV irradiation, suggesting that the wild-type p53 protein in the cells still
      functions in inducing apoptosis, or that this cell death results from p53
      independent mechanisms. These results suggest that mutant p53 interferes with
      wild-type p53 in the repair of UV-induced DNA damage but not in apoptosis.

PMID- 8644855
TI  - Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral
      primitive neuroectodermal tumor? A report of four cases showing this transcript
      in a wider range of tumor types.
AB  - The presence of t(11;22)(q24;q12) is often considered diagnostic of Ewing sarcoma
      and peripheral primitive neuroectodermal tumor. We report four cases, all of
      which possessed this translocation as detected by reverse transcriptase
      polymerase chain reaction and confirmed by sequencing with or without fluorescent
      in situ hybridization, but none of which were Ewing sarcoma or peripheral
      primitive neuroectodermal tumor by histological criteria. Two were polyphenotypic
      tumors and two were mixed embryonal and alveolar rhabdomyosarcomas. Only one case
      was positive for MIC2 by immunohistochemistry and only in a rare cell. Two cases
      (one polyphenotypic tumor and one rhabdomyosarcoma) had double minute chromosomes
      with > 100 copies of the MDM2 gene. The presence of the t(11;22)(q24;ql2)
      translocation should probably not be considered diagnostic of Ewing sarcoma and
      peripheral primitive neuroectodermal tumor in the absence of supporting
      histological evidence. The presence of this translocation in Ewing sarcoma and
      peripheral primitive neuroectodermal tumor has been taken as evidence that these
      two tumors are related. Extending this relationship to include some
      polyphenotypic tumors and some rhabdomyosarcomas may not be justified unless
      additional evidence is gathered. Pathologists and oncologists will need to decide
      whether treatment regimens for tumors are better based on phenotype rather than
      genotype when these two profiles are seemingly in conflict.

PMID- 8644856
TI  - Expression of complement membrane regulators membrane cofactor protein (CD46),
      decay accelerating factor (CD55), and protectin (CD59) in human malignant
      gliomas.
AB  - Gliomas are malignant brain tumors, which, despite recent progress in surgical
      and radiological treatment, still have a poor prognosis. Since gliomas apparently
      resist immunological clearance mechanisms, we became interested in examining bow
      gliomas resist killing by the human complement system. The resistance of human
      cells to complement-mediated damage is, in large part, mediated by specific
      inhibitors of complement:membrane cofactor protein (CD46), decay-accelerating
      factor (CD55), and protectin (CD59). In the present study we examined the
      expression of complement regulators in 14 human glioma tumors and in 7 glioma
      cell lines (U251, U87, HS683, U373, U138, U118, and H2). Protectin was found to
      be strongly expressed by all glioma tumors and cell lines. Northern blotting
      analysis demonstrated the typical pattern of four to five protectin mRNAs in the
      glioma cells. Except for blood vessels, the expression of decay-accelerating
      factor was weak or absent in the tumors in situ, whereas in the cell lines its
      expression varied, ranging from negative to intermediate. Membrane cofactor
      protein was moderately expressed by all the cell lines but only weakly in the
      tumors. Cell-killing experiments demonstrated that the glioma cell lines were
      exceptionally resistant to C-mediated lysis. Five of the seven cell lines (U373,
      HS683, U118, U138, and H2) resisted complement lysis under conditions where most
      other cell lines were sensitive to killing. Neutralization experiments using
      specific monoclonal antibodies indicated that protectin was functionally the most
      important complement regulator in the glioma cells. The killing of the U87 and
      U251 cells could be significantly increased by a blocking anti-protectin
      monoclonal antibody, whereas for the other cell lines only moderate or no
      response was observed. The H2 cell line resisted killing by all antibodies and by
      complement. These results show that protectin is the most important complement
      regulator on human glioma cells. The exceptional complement resistance of some
      glioma cell lines suggests that they may utilize other, hitherto less well
      characterized, mechanisms to resist complement killing.

PMID- 8644857
TI  - SPARC is expressed by mesangial cells in experimental mesangial proliferative
      nephritis and inhibits platelet-derived-growth-factor-medicated mesangial cell
      proliferation in vitro.
AB  - Mesangial cell proliferation is a characteristic feature of many glomerular
      diseases and often precedes extracellular matrix expansion and
      glomerulosclerosis. This study provides the first evidence that SPARC (secreted
      protein acidic and rich in cysteine) could be an endogenous factor mediating
      resolution of experimental mesangial proliferative nephritis in the rat. SPARC is
      a platelet-derived-growth-factor-binding glycoprotein that inhibits proliferation
      of endothelial cells and fibroblasts. We now show that SPARC is synthesized by
      mesangial cells in culture and that SPARC mRNA levels are increased by platelet
      derived growth factor and basic fibroblast growth factor. Recombinant SPARC or
      the synthetic SPARC peptide 2.1 inhibited platelet-derived-growth-factor-induced
      mesangial cell DNA synthesis in vitro. In a model of experimental
      mesangioproliferative glomerulonephritis, SPARC mRNA was increased 5-fold by day
      7 and was identified in the mesangium by in situ hybridization. Similarly, SPARC
      was increased in glomerular mesangial cells and visceral epithelial cells by day
      5 and reached maximal expression levels by day 7. Mesangial cell proliferation
      increased by 36-fold on day 5 and decreased abruptly on day 7. Maximal expression
      of SPARC was correlated with the resolution of mesangial cell proliferation. We
      propose that SPARC functions in part as an endogenous inhibitor of platelet
      derived-growth-factor-mediated mesangial cell proliferation in glomerulonephritis
      and that it could account for the resolution of cellular proliferation in this
      disease.

PMID- 8644858
TI  - Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast
      formation and tubulointerstitial fibrosis.
AB  - Tubulointerstitial fibrosis correlates closely with renal function, although the
      mechanism regulating tubulointerstitial fibrogenesis remains poorly understood.
      Since platelet-derived growth factor (PDGF) is a growth factor for fibroblasts,
      we examined the effect of daily (for 7 days) PDGF-AA or PDGF-BB administration on
      renal tubulointerstitial architecture in rats. PDGF-AA administration at a dose
      of 5 mg/kg did not affect the renal tubulointerstitium. By comparison, PDGF-BB
      induced dose-dependent renal tubulointerstitial cell proliferation and fibrosis.
      At 5 mg/kg, PDGF-BB increased BrdU labeling in tubulointerstitial fibroblasts at
      24 hours (19-fold), which peaked at 72 hours (23-fold) with bromodeoxyuridine
      uptake returning to control values by 7 days. Tubulointerstitial proliferation
      was associated with the differentiation of these cells into myofibroblasts as
      evidenced by alpha-smooth muscle actin expression beginning on day 3. The
      expression of alpha-smooth muscle actin peaked on day 5 and had markedly declined
      by day 21. In addition, apoptotic cells were identified within the
      tubulointerstitium on day 3 and progressively increased through day 7, suggesting
      that the disappearance of myofibroblasts may have occurred through apoptosis.
      These changes were accompanied by increased expression of alpha 1 (III) collagen
      mRNA and interstitial accumulation of type III collagen within the renal cortex.
      By morphometric analysis, an approximately twofold increase in collagen III
      immunolabeling within the interstitial compartment was evident at 24 hours and
      peaked on days 5 to 7 (approximately fourfold). These data suggest that PDGF-BB
      may be an important mediator of tubulointerstitial hyperplasia and fibrosis.

PMID- 8644859
TI  - E-selectin is present in proliferating endothelial cells in human hemangiomas.
AB  - E-selectin, an endothelial-cell-specific leukocyte adhesion molecule, may also
      function in angiogenesis. To investigate its role in a noninflammatory angiogenic
      disease, E-selectin was analyzed by immunohistochemistry in specimens of
      proliferative phase and involutive phase hemangiomas. Hemangioma is an
      endothelial cell tumor of capillary blood vessels that grows rapidly during
      infancy and regresses spontaneously during childhood. E-selectin expression was
      high in proliferative phase specimens and was co-localized with dividing
      microvascular endothelial cells. Relative to the number of blood vessels, E
      selectin declined significantly in involutive phase specimens demonstrating that
      E-selectin correlates with angiogenesis in the tumors. E-selectin was not
      detected in quiescent endothelium but was co-localized in dividing microvascular
      endothelial cells in placenta and neonatal foreskin, two tissues with ongoing
      growth of microvessels. These in vivo studies support the hypothesis that E
      selectin functions in angiogenesis and suggest that E-selectin may be a marker
      for proliferating endothelium.

PMID- 8644860
TI  - Fibroblast growth factor receptor-1 expression is associated with neointimal
      formation in vitro.
AB  - Neointimal formation was studied in a porcine aortic organ culture model that
      exhibits intimal smooth muscle cell accumulation after a brief time in culture.
      This in vitro model is dependent upon an intact endothelium, as removal of the
      endothelium at the time of harvesting results in the failure to develop a
      neointima. We previously showed that conditioned media from intact cultures
      induce neointimal formation in denuded aortic explants, and we speculated that
      basic fibroblast growth factor was the endothelial-derived factor in conditioned
      media promoting neointimal formation. However, the concentration of basic
      fibroblast growth factor in conditioned media from both intact and denuded
      explants, measured by an enzyme-linked immunosorbent assay, was not significantly
      different and, in fact, steadily decreased over the first 7 days of culture.
      Furthermore, the amount and intensity of immunoreactive basic fibroblast growth
      factor in tissue sections, also similar in both groups, decreased over the same
      time course. Nonetheless, exogenous basic fibroblast growth factor (1 ng/ml)
      induced neointimal formation in intact explants but was unable to do so in
      denuded explants. Western blot analysis of intimal lysates prepared from both
      intact and denuded explants showed a time-dependent increase in fibroblast growth
      factor receptor-1 expression over the first 7 days of culture, with higher levels
      seen in intimal lysates from intact explants at each time point examined.
      Immunoreactive fibroblast growth factor receptor-1 was detected in both
      endothelial cells and intimal smooth muscle cells of intact explant sections.
      These data indicate that, in the presence of the endothelium, neointimal
      formation may in part be mediated by upregulation of fibroblast growth factor
      receptor-1 in the intimal cells of porcine aortic explants.

PMID- 8644861
TI  - Analysis of the tumor vasculature and metastatic behavior of xenografts of human
      melanoma cell lines transfected with vascular permeability factor.
AB  - Vascular permeability factor (VPF) is an important mediator of vascular
      development in tumors. Some human melanoma cell lines have a low VPF expression
      level in culture, but this level is upregulated when growing as a tumor in nude
      mice. Other melanoma lines have a constitutively high VPF expression. To compare
      the biological behavior of tumors with these two expression patterns, a human
      melanoma cell line with an inducible VPF expression was transfected with VPF
      expression constructs. In this way, several lines were obtained that
      constitutively produce either the soluble VPF121 or the matrix-associated VPF189
      variant at levels of 4 to 30 times the VPF level in mature tumors derived from
      the parental line. The recombinant VPF RNA, which lacks most of the 5' noncoding
      sequences present in the endogenous VPF mRNA, was much more efficiently
      translated than the endogenous messenger. Upon injection in nude mice, all VPF
      transfected lines developed tumors with aberrations in vascularization and in
      distribution of matrix components. In these tumors the blood vessels were
      hyperpermeable for an i.v. injected protein tracer. Transfection did not
      influence the in vitro growth rate of the cell lines, but the tumors from the VPF
      transfected lines had higher growth rates in vivo than tumors from the parental
      line or the vector-transfected line. Although the incidence of lung metastasis
      was similar in all lines, the number of metastases per affected lung was
      significantly increased in mice carrying VPF-transfectant tumors. We conclude
      that the pattern and the level of VPF expression in a tumor are important
      determinants of the architecture and functionality of the vascular bed, but that
      overexpression of VPF does not necessarily lead to an increase of microvascular
      density or metastatic spread. The role of VPF in melanoma progression is
      obviously complex and may be difficult to derive in its generality from a single
      experimental model.

PMID- 8644862
TI  - Presence of T cells and macrophages in inflammatory vitiligo skin parallels
      melanocyte disappearance.
AB  - Evidence for the involvement of cellular immunity in the etiopathogenesis of the
      hypopigmentary disorder vitiligo is provided by rare cases of inflammatory
      vitiligo. Nonlesional, perilesional, and lesional skin biopsies from three
      inflammatory vitiligo patients were immunohistochemically analyzed. The
      composition of inflammatory infiltrates present in perilesional skin was analyzed
      by antibodies to T cells (CD2, CD3, CD4, and CD8), Langerhans cells (CD1a), and
      macrophages (CD36 and CD68). The presence of activation markers on inflammatory
      cells was evaluated by analysis of HLA-DR, interleukin-2 receptor, and HECA452
      expression. The presence or absence of melanocytes was determined by the antibody
      NKI-beteb. Moreover, the abundance of matrix molecule tenascin was semi
      quantified using T2H5. Results indicate that within perilesional skin, epidermis
      infiltrating T cells exhibit an increased CD8/CD4 ratio and increased cutaneous
      lymphocyte antigen and interleukin-2 receptor expression. These cells are
      frequently juxtapositionally apposed to remaining melanocytes. In perilesional
      dermis, CD68+OKM5- macrophages were more numerous than in lesional or nonlesional
      skin. Keratinocytes as well as melanocytes consistently express major
      histocompatibility complex class II antigens along stretches of basal and
      suprabasal layers in perilesional epidermis. Moreover, inflammation is
      accompanied by increased tenascin content. Although these observations do not
      permit differentiation between the immune infiltrates being a result as opposed
      to the cause of the disease process, results presented in this study are very
      suggestive of involvement of local immune reactivity in melanocyte destruction.

PMID- 8644863
TI  - Interleukin-8 in Hodgkin's disease. Preferential expression by reactive cells and
      association with neutrophil density.
AB  - Hodgkin's disease (HD) shows rare neoplastic Hodgkin and Reed-Sternberg cells
      embedded in an abundant reactive infiltrate containing, among other cell types,
      neutrophilic granulocytes. Interleukin (IL)-8 is chemotactic for neutrophils. The
      expression of IL-8 was tested by in situ hybridization with 35S-labeled IL-8
      specific RNA probes on 38 cases of HD. Reactive lesions, non-Hodgkin's lymphomas
      of B and T phenotype, and Langerhans cell histiocytosis served as controls. IL-8
      expression was observed in Hodgkin and Reed-Sternberg cells in 3 of 33 cases of
      classical HD and in reactive cells in 20 of 33 HD cases as evidenced by combined
      isotopic in situ hybridization and immunohistology for the demonstration of cell
      type-characteristic antigens or enzyme histochemistry for chloroacetate esterase.
      IL-8-positive cells were more numerous in cases of nodular sclerosing HD as
      compared with the mixed cellularity histotype (P = 0.01). The number of IL-8
      positive cells and the density of neutrophils were positively correlated (P < 0.
      01). In 5 cases of lymphocyte-predominant HD, IL-8 expression was not displayed.
      Non-Hodgkin's lymphoma cases contained IL-8 transcripts only in 1 of 23 cases in
      sparse reactive cells. In 4 of 7 cases of Langerhans cell histiocytosis, IL-8
      specific signals were displayed in S100-negative cells. In conclusion, IL-8
      expression in HD is largely confined to reactive cells and associated with
      infiltration by neutrophils. Elaboration of other cytokines by Hodgkin and Reed
      Sternberg cells and reactive cells may explain the frequent expression of this
      cytokine in HD, particularly in the nodular sclerosing type.

PMID- 8644864
TI  - Tissue distribution of the multidrug resistance protein.
AB  - The human multidrug resistance protein (MRP) is a 190 kd membrane glycoprotein
      that can cause resistance of human tumor cells to various anticancer drugs, by
      extruding these drugs out of the cell. Three different monoclonal antibodies,
      directed against different domains of MRP, allowed us to determine the
      localization of MRP in a panel of normal human tissues and malignant tumors.
      Whereas in malignant tumors strong plasma membrane MRP staining was frequently
      observed, in normal human tissues MRP staining was predominantly cytoplasmatic.
      Here, MRP was detected in several types of epithelia, muscle cells, and
      macrophages. From the presence of MRP in many epithelia we infer that MRP, like
      MDR1 P-glycoprotein, may have an excretory function in protecting the organism
      against xenobiotics. Recent studies indicate a role for MRP as a carrier for
      transport of glutathione-conjugated endo- and xenobiotics. The presence of MRP in
      bronchiolar epithelium, heart muscle, and macrophages would agree with the
      glutathione S-conjugate carrier activity previously detected in these cells.
      Furthermore, in 46 of 119 untreated tumors from various histogenetic origins MRP
      staining was seen. In these tumors MRP may contribute to the intrinsic resistance
      against treatment with chemotherapeutic drugs.

PMID- 8644865
TI  - Altered liver acini induced in diabetic rats by portal vein islet isografts
      resemble preneoplastic hepatic foci in their enzymic pattern.
AB  - As demonstrated previously, liver acini draining the blood from intraportally
      transplanted pancreatic islets in streptozotocin-diabetic rats are altered in
      various respects. The hepatocytes in these acini store glycogen and/or fat, and
      they show an increase in proliferation as well as in apoptotic activity. Thus,
      they are phenotypically similar to carcinogen-induced preneoplastic liver foci
      (glycogen-storing foci and sometimes also mixed cell foci). By means of catalytic
      enzyme histochemistry or immunohistochemistry, we investigated the activity of
      key enzymes of alternative pathways of carbohydrate metabolism and some
      additional marker enzymes (well known from studies on preneoplastic hepatic foci)
      in the altered liver acini surrounding the islet isografts. In addition, the
      expression of glucose transporter proteins 1 and 2 (GLUT-1 and GLUT-2) were
      investigated immunohistochemically. The activities of hexokinase, pyruvate
      kinase, glyceraldehyde-3-phosphate dehydrogenase, and glucose-6-phosphate
      dehydrogenase were increased, whereas the activities of glycogen phosphorylase,
      adenylate cyclase, glucose-6-phosphatase, and membrane-bound adenosine
      triphosphatase were decreased in the altered liver acini. The expression of GLUT
      2 was also decreased. GLUT-1 and glutathione S-transferase placental form were
      not expressed, and the activities of glycogen synthase and gamma-glutamyl
      transferase remained unchanged. All changes of the enzyme activities were in line
      with the well known effects of insulin and resembled alterations characteristic
      of preneoplastic liver foci observed in different models of hepatocarcinogenesis.
      It remains to be clarified in long-term experiments whether or not these foci
      represent preneoplastic lesions and may proceed to neoplasia.

PMID- 8644866
TI  - Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's
      disease and hereditary cerebral hemorrhage associated with mutations in the
      amyloid precursor protein gene.
AB  - Amyloid (A beta) deposition was investigated in cases of Alzheimer's disease and
      hereditary cerebral hemorrhage with amyloidosis, Dutch type, due to mutations in
      the amyloid precursor protein (APP) gene using the end-specific monoclonal
      antibodies BA27 and BC05 that recognize A beta 40 or A beta 42(43), respectively.
      In cases of APP717 mutation the predominant A beta species within plaques
      terminate at A beta 42(43) with relatively little A beta 40 being present. The
      total amount of A beta deposited as A beta 42(43) is significantly greater than
      in sporadic Alzheimer's disease, consistent with the suggestion that this
      mutation might influence the processing of APP so as to produce more of the
      highly aggregatable form, A beta 1-42. In cases of APP670/671 mutation the major
      peptide in plaques is also A beta 42(43), although the proportion of plaques
      containing A beta 40, and the total A beta load is similar to that in sporadic
      Alzheimer's disease. As in sporadic Alzheimer's disease, the vascular amyloid in
      APP670/671 and APP717 and in cases of hereditary cerebral hemorrhage with
      amyloidosis, Dutch type is predominantly A beta 40 in this latter disorder,
      however, parenchymal deposits are exclusively A beta 42(43). Although the various
      APP mutations may influence the type, quantity, and location of A beta deposited,
      the predominant, and possibly the initial, species deposited in the brain
      parenchyma is A beta 42(43).

PMID- 8644867
TI  - Immunohistochemical localization of capsular polysaccharide antigen in the
      central nervous system cells in cryptococcal meningoencephalitis.
AB  - Cryptococcal meningoencephalitis (CME) is caused by the encapsulated fungus
      Cryptococcus neoformans (CN) and is a major cause of mortality and morbidity in
      patients with AIDS. The polysaccharide capsule of CN is important for virulence,
      and soluble polysaccharide has the potential to cause immune modulation. To
      better understand the interactions of central nervous system cells and
      cryptococcal capsular polysaccharide (CNPS) in the pathogenesis of human CME,
      postmortem brain tissue from 21 patients with CME (13 AIDS and 8 non-AIDS
      patients) was analyzed. Histopathology and distribution of tissue CNPS antigen
      were analyzed using monoclonal antibodies against CNPS in combination with cell
      type-specific markers (glial fibrillary acidic protein for astrocytes, Ricinus
      communis agglutinin (RCA)-l for macrophage/microglia and endothelial cells; UCHL
      1 for T cells, L26 for B cells). The CN cells showed discrete capsular
      immunoreactivity as expected; however, diffuse and particulate cellular and
      tissue staining for CNPS was detected in the brain parenchyma and the meninges in
      all cases. By quantitative analysis, the CNPS immunoreactive area ranged from 0.1
      to 88 percent of tissue cross sectional area, and tended to be higher in brains
      of AIDS (median values from two sections ranged from 1 to 57 percent; mean, 26
      percent) than in non-AIDS (0.1 to 40 percent; mean, 9.6 percent) patients. The
      proportion of CNPS immunoreactive area was positively correlated with the
      estimated number of CN. None (0/13) of the AIDS patients displayed significant
      inflammatory responses to CN, whereas most (7/8) non-AIDS patients showed
      granulomatous inflammatory responses. The phenotype of infiltrating lymphocytes
      was UCHL-1+/L26-/RC4-, thus consistent with activated T cells, both in AIDS and
      non-AIDS patients. Double immunolabeling studies revealed that tissue CNPS
      immunoreactivity was most often localized in macrophages and microglia, less
      frequently in reactive astrocytes and endothelial cells, but not in lymphocytes.
      This study demonstrates that CNPS can be detected not only in the serum and
      cerebrospinal fluid (CSF) of patients, but also in the affected tissue, most
      often localized in cells of mononuclear phagocyte system. Potential implications
      of these findings for the pathogenesis of CME are discussed.

PMID- 8644869
TI  - Cytoskeletal changes in podocytes associated with foot process effacement in
      Masugi nephritis.
AB  - Foot process effacement represents the most characteristic change in podocyte
      phenotype under a great variety of experimental as well as human
      glomerulopathies. It consists in simplification up to a total disappearance of an
      interdigitating foot process pattern. Finally, podocytes affix to the glomerular
      basement membrane by outspread epithelial sheets. Structural and
      immunocytochemical techniques were applied to analyze the cytoskeletal changes
      associated with foot process effacement in Masugi nephritis. Three days after
      injection of the anti-glomerular-basement-membrane serum an interdigitating foot
      process pattern was almost fully lost; more than 90 percent of the outer
      glomerular capillary surface were covered by expanded sheets of podocyte
      epithelium that contain a highly organized cytoskeleton adhering to the basal
      cell membrane. Structurally, this cytoskeleton consists of an interwoven network
      of microfilaments with regularly distributed dense bodies, which obviously serve
      as cross-linkers within this network. Immunocytochemically, the expression of
      actin, alpha-actinin, and pp44 (a specific podocyte protein normally associated
      with the cytoskeleton of foot processes) were increased in this structure; alpha
      actinin was especially prominent in the dense bodies. The results are consistent
      with the view that foot process effacement represents an adaptive change in cell
      shape including hypertrophy of the contractile apparatus, reinforcing the
      supportive role of podocytes. Several factors associated with increased
      distending forces to podocytes may underlie this phenotype change including loss
      of mesangial support, elevated glomerular pressures, and impairment of GBM
      substructure as well as of podocyte-GBM-contacts. Twenty-eight days after serum
      injection a remodeling of the foot process pattern was seen. It appears that this
      restitution depends on a preceding repair of mesangial support function to
      glomerular capillaries.

PMID- 8644868
TI  - Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus
      neoformans granulomas.
AB  - Rats, like humans, have extremely effective immune mechanisms for controlling
      pulmonary Cryptococcus neoformans infection. The mechanism(s) responsible for
      efficient immunity in rat experimental infection is unknown. Recently, induction
      of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) have been
      implicated as an important microbicidal mechanism by which activated macrophages
      effect cytotoxicity against microbes. In this report, we investigated the
      expression of iNOS in rat pulmonary cryptococcosis. Localization and regulation
      of NO production was studied by immunohistochemistry for iNOS in conjunction with
      immunohistochemistry for cell markers, cytokines, and cryptococcal capsular
      polysaccharide. iNOS immunoreactivity was detected in macrophages, neutrophils,
      vascular endothelium, and respiratory epithelium. Double-immunolabeling studies
      revealed that the most prominent iNOS immunoreactivity was localized to
      epithelioid macrophages (CD11b/c+) within granulomas; CD4+ and CD8+ T cells were
      numerous around granulomas but did not express iNOS. iNOS immunoreactivity was
      detected in a selective population of epithelioid macrophages within some
      granulomas but not others. iNOS- granulomas were identical to iNOS+ granulomas
      with respect to morphology and immunohistochemical profiles. Macrophage iNOS
      immunoreactivity was detected 1 week after infection in one out of four rats and
      was strongly expressed in all rats at 2 weeks (in up to 50 percent of the
      granulomas) but declined considerably by 25 days. iNOS expression coincided with
      granuloma formation and preceded a decrease in lung fungal burden, suggesting an
      anticryptococcal role for NO. By double labeling, cytokines that have been shown
      to promote (interferon-gamma, granulocyte/macrophage colony-stimulating factor)
      and inhibit (transforming growth factor-beta) macrophage iNOS expression were
      detected around iNOS+ granuloma. iNOS immunoreactivity was expressed in selected
      neutrophils (1 and 2 weeks) and endothelial cells (1 and 2 weeks and 25 days) in
      the inflamed lung. Airway iNOS immunoreactivity was limited to the luminal border
      of rare bronchiolar epithelial cells. iNOS immunoreactivity was not detected in
      uninfected rats. The present study provides the first evidence for association of
      iNOS expression with protective cellular responses to cryptococcal infection in
      vivo.

PMID- 8644871
TI  - All-trans retinoic acid reduces membrane fluidity of human dermal fibroblasts.
      Assessment by fluorescence redistribution after photobleaching.
AB  - All-trans retinoic acid (RA) preserves human dermal fibroblast viability and
      stimulates proliferation in vitro. These effects are mediated, at least in part,
      by reducing the extracellular Ca2+ requirement. The same concentrations of RA
      that reduce the extracellular Ca2+ requirement also interrupt movement of Ca 2+
      across the fibroblast plasma membrane. Based on these observations, we have
      examined the effects of RA on membrane properties that could influence Ca2+
      movement. Fibroblasts were labeled with 1-acyl-2-(N-4- nitrobenzo-2-oxa-1,3
      diazole)-amino-caproyl phosphatidyl-choline (a fluorescent phospholipid analogue)
      and examined for fluorescence redistribution after photobleaching (FRAP) with a
      pulse of intense light as a measure of membrane fluidity. Using this approach, we
      observed that membrane fluidity was higher when the cells were incubated in
      medium containing a low (sub-optimal) level of extracellular Ca2+ (0.15 mmol/L)
      than in a medium containing an optimal concentration (1.4 mmol/L). Treatment of
      the cells with 3 micromol/L RA reduced membrane fluidity of the cells under both
      high- and low-Ca2+ conditions. These findings demonstrate that RA has a direct
      effect on the plasma membrane of human dermal fibroblasts. This provides a
      possible mechanism for the previously identified inhibition of Ca2+ movement
      across the membrane of the same cells and for the previously identified
      protective effects against lysis under low-Ca2+ conditions.

PMID- 8644870
TI  - Role of CD 11/CD 18 in neutrophil emigration during acute and recurrent
      Pseudomonas aeruginosa-induced pneumonia in rabbits.
AB  - This study examined CD11/CD18-mediated adhesion in neutrophil emigration during
      acute and recurrent Pseudomonas aeruginosa-induced pneumonia. Neutrophil
      emigration during acute pneumonia was studied in anti-CD18 antibody or murine-IgG
      pretreated rabbits 4 hours after intrabronchial instillation of P. aeruginosa. To
      examine emigration in recurrent pneumonias, rabbits given P. aeruginosa on day 0
      received anti-CD18 antibody or IgG on day 7. A second instillate was placed
      either at the initial site or in a separate lobe, and emigration into alveolar
      spaces was quantitated morphometrically after 4 hours. The results show that
      CD11/CD18 was required for neutrophil emigration in acute pneumonias and in
      recurrent pneumonias that occurred at a site distant from the initial infection.
      However, when the recurrent pneumonia occurred in the previously inflamed site,
      CD11/CD18 was not required. When the same number of organisms were instilled on
      days 0 and 7, emigration was reduced to 15 to 20 percent of the number that
      migrated initially and only CD18-independent adhesion pathways were used.
      Increasing the concentration of organisms threefold increased emigration through
      both CD18-dependent and CD18-independent pathways. These data indicate that P.
      aeruginosa induces CD11/CD18-dependent emigration during acute pneumonia and
      recurrent pneumonia at previously uninflamed sites. However, adhesion pathways
      are altered in regions of chronic inflammation, and a greater proportion of
      neutrophil emigration occurs through CD11/CD18-independent pathways.

PMID- 8644872
TI  - Oral candidiasis, HIV, and saliva glucocorticoids.

PMID- 8644873
TI  - Structural adaptations for gliding in mammals with implications for locomotor
      behavior in paromomyids.
AB  - The gliding abilities of paromomyid plesiadapiforms are evaluated through a
      functional analysis of long bone morphology in a comparative sample of modern
      gliders and related nongliders. Relationships between body mass, long bone
      lengths, and long bone midshaft cross-sectional areas are explored. Theory
      suggests that gliders should have long humeri and femora to improve aspect ratio,
      and that larger gliders should have relatively longer limb bones than smaller
      gliders to minimize drag and patagial loading at greater body masses. Comparisons
      between extant taxa support these predictions: gliders have relatively longer
      humeri and femora than those of nongliders, and glider long bone lengths scale
      with positive allometry, while the scaling of nonglider long bones does not
      differ from isometry. Preliminary analysis of distal to proximal limb segment
      proportions further suggests that bone lengthening is, to some extent, related to
      patagial attachment site, although humeri and femora are relatively long in all
      of the gliders, regardless of attachment site. The proportions of paromomyids
      relative to those of extant mammals do not support a gliding interpretation for
      these fossils.

PMID- 8644874
TI  - Paleopediatrics: or when did human infants really become human?
AB  - Modern human children take about twice as long as their closest biological
      relative, the chimpanzee, to mature. One standard explanation for the evolution
      of "delayed maturation" at an early stage of human evolution is that it provided
      the time necessary for immature individuals to learn complex skills, most notably
      those relating to tool-making abilities. However, after comparing dental
      maturational profiles of early hominids from South Africa (who apparently did
      make and use stone tools) (Susman [1994] Science 265:1570-1573) to those of
      extant humans and chimpanzees, we find no evidence to document an association
      between "delayed maturation" and tool-making abilities in the early stages of
      human evolution. This also suggests that the assumed association between
      prolonged childhood dependency and other behaviors often associated with the
      advent of tool-making such as cooperative hunting, food sharing, home bases,
      sexual division of labor, etc., is also suspect. Instead, we must look for other,
      or additional, selective pressures for the evolution of "delayed maturation,"
      which may postdate the australopithecine radiation.

PMID- 8644875
TI  - A genetic study of 2,000-year-old human remains from Japan using mitochondrial
      DNA sequences.
AB  - We present nucleotide sequence data for mitochondrial DNA extracted from ancient
      human skeletons of the Yayoi era (ca. 2,000 BP) excavated from the Takuta
      Nishibun site in northern Kyushu of Japan. Nucleotide sequence diversity showed
      that the Yayoi people of the Takuta-Nishibun site were not a genetically
      homegeneous population. This site shows a diversity in the burial style.
      Phylogenetic analysis indicated a statistically significant correlation between
      burial style and the genetic background of the Takuta-Nishibun individuals, and
      revealed no discrete clusterig patterns for the Yayoi individuals, for early
      modern Ainu, or for the Jomon people.

PMID- 8644876
TI  - Work performance of Chinese cycle haulers: controlled field experiments in normal
      work conditions.
AB  - Forty-five male Chinese cycle haulers performed a controlled field experiment
      under mild winter conditions. The objective was to gain insight into factors that
      affect work performance. Each man hauled the same 481-kg load around a Beijing
      street course of 14.18 km. The experiment was a measured sample of the same work
      they do routinely, on the same roads, using similar human powered hauling cycles
      (modified only enough to carry observers and instruments). The course was
      completed at a mean speed of 10.4 kph and mean time of 84.2 min. While there was
      considerable variation in individual pace and in pace change during work, the
      haulers performed at relatively high output in reference to their capacities.
      Mean heart rate was 156.8 +/- 16.1 bpm, 83.9% of maximum. The men had average
      body build and were average in size for the general Chinese population (X stature
      = 169.7 cm) although they showed relatively high aerobic capacity (determined in
      laboratory tests). Performance levels during experiments appear to match habitual
      work patterns, and self-pacing emerged as a major behavioral finding of this
      research. Speed, a primary index of job performance, showed significant
      correlation to heart rate, VO2max, variation in windchill, self-reported health
      and other variables, with a multiple regression coefficient of 0.811. Similar
      patterns were seen for heart rate relative to speed, except that physical size,
      education, and other behavioral variables were also predictors.

PMID- 8644877
TI  - Bone remodeling rates and skeletal maturation in three archaeological skeletal
      populations.
AB  - Cortical bone remodeling rates for rib samples from three archaeological
      populations and a modern autopsy sample were determined using an algorithm
      developed by Frost (Frost [1987a] Calcif. Tissue Res. 3:211-237). When plotted
      against the relative antiquities for population samples, histomorphometric
      variables; i.e., activation frequency (mu rc), net bone formation (netVf,r,t),
      and mean annual bone formation rate (Vf,r,t), exhibit a concordant trend of
      increased cortical bone remodeling activity levels over time. Two intensive
      foraging populations, Windover and Gibson, are similar for all bone remodeling
      parameters and have the lowest remodeling activity levels among the samples. The
      more recent Ledders sample, which is reported to practice agricultural
      subsistence, is consistently intermediate between these and a modern autopsy
      sample. Although there appear to be differences in bone formation rates among the
      populations it is concluded that these differences cannot be attributed to
      differences in bone remodeling rates among the populations, but rather are
      reflecting different effective ages of adult compacta for their ribs. These
      findings suggest that the earlier populations, particularly Windsor and Gibson,
      appear to have reached skeletal maturity at an older age than observed for
      modern.

PMID- 8644878
TI  - Asymmetric vault modification in Hopi crania.
AB  - Cradleboarding was practiced by numerous prehistoric and historic populations,
      including the Hopi. In this group, one result of cradleboarding was bilateral or
      asymmetric flattening of the posterior occipital. We test whether cradleboarding
      had significant effects on the morphology of the cranial vault, cranial base, and
      face. Additionally, we examine associations between direction of flattening and
      asymmetric craniofacial growth. A skeletal sample of Hopi from the Old Walpi site
      includes both nonmodified (N = 43) and modified individuals (N = 39). Three
      dimensional coordinates of 53 landmarks were obtained using a diagraph. Thirty
      six landmarks were used to define nine finite elements in the cranial vault,
      cranial base, and face. Finite element scaling was used to compare average
      nonmodified individuals, with averages of bilaterally, right, and left modified
      individuals. The significance of variation among "treatment" groups was evaluated
      using a bootstrap test. Pearson product-moment correlations test the association
      of asymmetry with direction of modification. Hopi cradleboarding has a
      significant effect on growth of the cranial vault, but does not affect morphology
      of the cranial base or face. Bilateral flattening of the cranial vault leads to
      decreased length and increased width of the cranial vault. Flattening of the
      right or left cranial vault results in ipsilaterally decreased length and width
      coupled with a corresponding increased length and width on the contralateral side
      of the cranial vault. There is a significant correlation of size asymmetry with
      direction of modification in the cranial vault, but not with size or shape change
      in the cranial base or face.

PMID- 8644879
TI  - Matrilineal distribution of louse egg-handling techniques during grooming in free
      ranging Japanese macaques.
AB  - Grooming behavior of which the primary function appears to be the removal of lice
      on other (Tanaka and Takefushi [1993] Anthropological Science 101:187-193) was
      studied in Japanese maceques at Jigokudani Monkey Park, Japan, June 1990-July
      1993. Several louse egg-handling techniques used during grooming were identified
      (with differences in efficiency) in a free-ranging group. In the low-ranking
      maternal lineages, the distribution of these techniques is quite homogeneous,
      suggesting social transmission with goal emulation (one form of social learning)
      based on maternal kin. However, there is considerable variation in the high
      ranking matriline. The social system of dominance--the tendency of subordinates
      to groom more often than to be groomed--may result in oblique transmission of
      more effective techniques from low-ranking monkeys to some offspring of high
      ranking females.

PMID- 8644881
TI  - Learning to live with a trichotomy.

PMID- 8644880
TI  - Brief communication: earliest cranial surgery in North America.
AB  - The archaeological evidence of ancient cranial surgery is limited to cases of
      trepanation and cauterization. I report here on the only known case of cranial
      surgery in direct association with the osseous image of a non-trauma-induced soft
      tissue lesion (sinus pericranii). This case, from Alameda County, California
      (Late Middle Period, ca. 300-500 AD), is the earliest and only definitive
      evidence of invasive surgery from prehistoric North America. Because this
      individual presents the only bony evidence of cranial surgery other than
      trepanation or cauterization, it contributes substantially to our extremely
      limited understanding of medical practices in preliterate societies.

PMID- 8644882
TI  - The involucrin gene and hominoid relationships.

PMID- 8644883
TI  - When is ancient polymorphism a potential problem for molecular phylogenetics?

PMID- 8644884
TI  - Effects of memory demand and motivation on sustained attention in young and older
      adults.
AB  - In two experiments, young and older adults performed 60-min cognitive vigilance
      tests in which memory demands were equated for individual differences in digit
      span. In the first experiment, the effects of monetary reward on subjects'
      performance were assessed. The sustained attention of young and older adults who
      were both paid for their participation did not differ, and it did not decline
      during the vigil, but young adults who were not paid for their participation
      evidenced a significant vigilance decrement. In the second experiment, memory
      demands were increased and there was no mention of monetary reward for
      participation. The attention of young adults declined rapidly, but that of older
      adults did not evidence a vigilance decrement. Subjects' sustained attention is
      explained in terms of task characteristics and intrinsic and extrinsic
      motivational factors.

PMID- 8644885
TI  - Attention in direct and indirect memory tasks with short- and long-term probes.
AB  - In two experiments, college students verified the answers to addition problems as
      their primary task while simultaneously viewing a word or nonword. The degree of
      attention allocated to the verbal stimulus varied depending on the difficulty of
      the problem and the instructions given. After each problem, a test probe assessed
      either a direct test of recognition memory or an indirect test of repetition
      priming in lexical decision at lags of 0, 1, or 8 intervening trials. The degree
      of attention at encoding and lag strongly affected recognition sensitivity (d'),
      but only lag affected recognition latencies. The repetition-priming effect
      neither declined with lag nor varied with the degree of attention. The degree of
      attention at encoding thus affects direct and indirect test performance
      differentially, a finding consistent with the distinction between explicit and
      implicit systems of long-term memory.

PMID- 8644886
TI  - Synesthesia-like mappings of lightness, pitch, and melodic interval.
AB  - Synesthesia-like mappings between visual lightness and auditory pitch and between
      visual lightness and melodic interval were examined. When subjects rated how
      visual lightnesses and auditory pitches "fit together," lighter stimuli fit
      better with higher pitches, and darker stimuli fit better with lower pitches.
      These patterns were stronger against black than against white visual backgrounds;
      however, effects of visual background were eliminated when subjects had a large
      set of lightness levels from which to choose the visual lightness level that best
      fit a given auditory pitch or melodic interval. When subjects chose which visual
      lightness best fit or matched a melodic interval, lighter stimuli were chosen for
      ascending melodic intervals, and darker stimuli were chosen for descending
      melodic intervals. Larger melodic intervals produced more extreme (lighter or
      darker) choices. Auditory pitch exhibits meaningful synesthesia-like mappings
      with visual lightness when unidimensionally varied in frequency and when
      multidimensionally varied in interval size and direction.

PMID- 8644887
TI  - Attentional selection and word processing in Stroop and word search tasks: the
      role of selection for action.
AB  - The time course of visual word processing was investigated in two tasks differing
      in whether words were "selected for action" (Allport, 1989). Using identical
      displays in which a square color patch appeared at fixation with either 2, 4, or
      8 flanking words appearing at any of the 8 sides and corners, subjects performed
      either a Stroop color-naming task or a word search task requiring detection of a
      color name among the flanking words by either a manual presence/absence response
      (Experiment 1) or a vocal naming response (Experiment 2). The color-naming task
      produced Stroop effects indicating parallel word processing in multiword
      displays, whereas the word search task produced evidence consistent with serial,
      self-terminating search requiring allocation of spatial attention. The
      differences in word processing across tasks are reconciled using Allport's
      concept of selection for action and extended to neuropsychological evidence on
      attention.

PMID- 8644888
TI  - Pavlov's conceptualization of the dynamic stereotype in the theory of higher
      nervous activity.
AB  - David Joravsky (1989) alleges that Ivan Petrovich Pavlov's theory of higher
      nervous activity fails to explain "most forms of complex behavior" because
      establishment of second-order and third-order chains of conditional reflexes was
      not feasible. Yet, Pavlov (1951a), relying on experimental evidence, some of
      which is presented, held that the interaction of higher organisms with the
      external environment was based on the dynamic stereotype, that is, on the
      integration in the cortical hemispheres of neural traces coming from the external
      and internal environments. In its formulation in the 1930s, Pavlov's theory was
      dynamic, not associative. It postulated the synthesis of conditioned reflexes,
      not associative chains of conditioned reflexes.

PMID- 8644889
TI  - The third step: Freud, the feminists, and postmodernism.

PMID- 8644890
TI  - The consultant's role when the analyst terminates therapy.

PMID- 8644891
TI  - Consultation when the patient terminates an impaired treatment.

PMID- 8644892
TI  - The myth of the invulnerable self of adolescence.

PMID- 8644893
TI  - Psychology of Jesus.

PMID- 8644894
TI  - Psychology of Jesus.

PMID- 8644895
TI  - Tropical diseases: new peril, new promise.

PMID- 8644896
TI  - Assessment of the role of naturally acquired antibody levels to Plasmodium
      falciparum merozoite surface protein-1 in protecting Papua New Guinean children
      from malaria morbidity.
AB  - We investigated the prevalence and magnitude of naturally acquired humoral immune
      response to the major merozoite surface protein (MSP-1) in a malaria-endemic
      population in Papua New Guinea. A prospective longitudinal study in 0.5-15-year
      old children was conducted for one year to examine the relationship between
      acquired immune response to MSP-1 and subsequent susceptibility to clinical
      disease. The prevalence and concentration of antibodies to both N-(195A) and C
      terminal (BVp42) regions of MSP-1 as well as to the parasite-derived MSP-1
      increased with age, with the highest prevalence and concentration of antibodies
      being detected for the parasite-derived MSP-1 molecule and the C-terminal region
      of MSP-1. As malaria morbidity decreases with age, a significant negative
      correlation was observed between antibody levels to both 195A and BVp42 and the
      incidence rate of clinical malaria. When age and past exposure were corrected
      for, only antibody concentrations against BVp42 and to a lesser extent parasite
      derived MSP-1 were significantly associated with protection from clinical malaria
      and severe parasitemia. The reduction in the incidence rate of clinical malaria
      observed in individuals with high antibody concentration to MSP-1 may be due to
      antibodies directed against epitopes within the C-terminal region of MSP-1.

PMID- 8644897
TI  - Pattern of immunoglobulin isotype response to Plasmodium falciparum blood-stage
      antigens in individuals living in a holoendemic area of Senegal (Dielmo, west
      Africa).
AB  - Three cross-sectional studies were conducted in a representative cohort of
      individuals living continuously in an area holoendemic for malaria in Senegal.
      Plasma from 145 children and adults were tested. The pattern of antimalarial
      immunoglobulin class (IgM and IgG) and subclass (IgG1 to IgG4) antibody
      distribution was determined by enzyme-linked immunosorbent assay using a crude
      blood-stage antigen of Plasmodium falciparum-infected red blood cells. Adults had
      higher levels of specific antibodies than children, and IgM, IgG2, and IgG3
      accounted for the highest difference (2.9, 6.5, and 4.5 times, respectively).
      Differences in antibody levels were significant for IgG1 to IgG4 between the
      lowest and the highest transmission season. No particular isotype distribution
      pattern could be found associated with any given parasitemia level. The
      relationship between the optical density (OD) values of each isotype and the risk
      of clinical malaria attack was tested using a Poisson regression model. Only the
      IgG3 OD increases were found associated with a significantly reduced risk of
      malaria attack. These seroepidemiologic data suggest that whereas the total IgG
      specific activity is not indicative of any given level of protection against
      malaria, the level of IgG3 was significantly associated with the relative
      susceptibility to clinical P. falciparum malaria attacks.

PMID- 8644898
TI  - Acquired transmission-blocking immunity to Plasmodium vivax in a population of
      southern coastal Mexico.
AB  - Naturally acquired transmission-blocking immunity to Plasmodium vivax was studied
      in three groups of patients from the southern coast of Mexico: primary cases
      (Group A, 61% of the study population), secondary cases with the prior infection
      seven or more months earlier (Group B, 23%), and secondary cases with the
      previous malaria experience within six months of the present study (Group C,
      16%). Anopheles albimanus mosquitoes were fed with patients' infected blood cells
      in the presence of autologous or control serum, with or without heat
      inactivation. Patients from all three groups had transmission-blocking immunity,
      although the quality and quantity of this blocking activity was significantly
      higher in the two secondary patient groups (B and C). Only primary malaria cases
      produced transmission-enhancing activity (23% of the cases), which was dependent
      on heat-labile serum components. The levels of patient group transmission
      blocking immunity and mosquito infectivity were used to calculate the
      probabilities of a mosquito becoming infective after taking a blood meal from a
      P. vivax-infected patient from any one of the three groups. This probability was
      0.025, with Group A patients providing the major source of these infections (92%
      risk from Group A and 4% risk for Groups B and C).

PMID- 8644899
TI  - A novel pathway for Ca++ entry into Plasmodium falciparum-infected blood cells.
AB  - Growth of the human malaria parasite, Plasmodium falciparum, within the red blood
      cell (RBC) requires external Ca++ and is associated with a markedly elevated
      intracellular Ca++ concentration, [Ca++]i. We used 45Ca++ flux studies and patch
      clamp recordings to examine the mechanisms responsible for this increased
      [Ca++]i. The 45Ca++ flux studies indicated that net Ca++ entry into parasitized
      RBCs (PRBCs) is 18 times faster than into unparasitized ATPase that keeps the
      [Ca++]i of unparasitized RBCs exceedingly low. Acceleration of the preexisting
      Ca++ entry, ATPase that keeps the [Ca++] of unparasitized RBCs exceedingly low.
      Acceleration of the preexisting Ca++ entry, mediated by a divalent cation
      carrier, also cannot explain Ca++ accumulation in PRBCs: there are fundamental
      differences in substrate preference and in the effects of external Ca++ on 45Ca++
      efflux between unparasitized RBCs and PRBCs. Patch clamp of intact PRBC surface
      membranes revealed rare unitary channel openings not observed on unparasitized
      RBCs. With 80 mM of CaCl2 in the patch pipette, this channel carried inward
      current, suggesting Ca++ entry at a rate comparable with the observed 45Ca++
      flux. These data indicate that the malaria parasite induces a novel pathway in
      the host RBC membrane for Ca++ entry and suggest that this pathway is a Ca++
      permeable channel.

PMID- 8644900
TI  - Short report: regulation of inducible heat shock protein 70 genes in Leishmania
      chagasi.
AB  - Eukaryotic and prokaryotic cells undergo an increase in heat shock proteins,
      including hsp70, during exposure to environmental stress and during some
      developmental changes. In trypanosomatid protozoa such as Leishmania sp. that
      cycle between poikilothermic vectors and mammalian hosts, this heat shock
      response occurs at programmed times in the parasite's life cycle. The increase in
      heat shock proteins in mammalian cells is initiated by an increased rate of
      transcription, resulting in greater amounts of total hsp70 RNA and protein. In
      contrast, we found a dramatic increase in hsp70 RNA during growth of Leishmania
      chagasi promastigotes from logarithmic to stationary phase in liquid culture,
      which was not accompanied by an increased amount of hsp70 protein. Furthermore,
      there was a 1.8-fold increase in hsp70 protein induced by exposure of L. chagasi
      to superoxide, but this was not associated with an increase in hsp70 RNA. We
      conclude that in contrast to higher eukaryotes, the amount of hsp70 protein
      produced by Leishmania sp. is not regulated by the steady state level of total
      hsp70 RNA.

PMID- 8644901
TI  - Isolation and characterization of the tsetse thrombin inhibitor: a potent
      antithrombotic peptide from the saliva of Glossina morsitans morsitans.
AB  - A potent and specific inhibitor of the human coagulation protease thrombin was
      identified in salivary gland extracts of the tsetse fly, Glossina morsitans
      morsitans, an important vector of African trypanosomiasis. This low molecular
      weight peptide (MW = 3,530 Da as determined by laser desorption mass
      spectrometry) was purified using a combination of size-exclusion chromatography
      and reverse-phase, high-performance liquid chromatography, respectively. Amino
      terminal sequencing of the purified protein reveals no homology to any previously
      identified serine protease inhibitor or naturally occurring anticoagulant. The
      tsetse thrombin inhibitor (TTI) is a stoichiometric inhibitor of thrombin, with
      an apparent equilibrium dissociation inhibitory constant (Ki*) [corrected] of 584
      x 10(-15)M. In addition, it is also a potent inhibitor of thrombin-induced
      platelet aggregation. Like other hematophagous arthropods, tsetse flies appear to
      have evolved a novel protease inhibitor capable of antagonizing host hemostasis
      and facilitating blood feeding.

PMID- 8644902
TI  - Susceptibility of Culicoides variipennis sonorensis to infection by polymerase
      chain reaction-detectable bluetongue virus in cattle blood.
AB  - Cattle bloods containing only polymerase chain reaction (PCR)--detectable
      bluetongue-10 viral nucleic acid, but as determined by virus isolation
      techniques, not bluetongue-10 virus, were incapable of infecting
      intrathoracically inoculated Culicoides variipennis sonorensis. These insects
      also failed to transmit bluetongue-10 virus when fed on sheep. Cattle whose blood
      contain only PCR-detectable bluetongue viral nucleic acid, but no infectious
      virus, are unlikely to play a role in the epidemiology of bluetongue. The
      biological significance of PCR-based detection assays and their effect on animal
      health regulations on the international trade of livestock and livestock
      germplasm is discussed. Bluetongue virus infection provides a very useful model
      with which to study arthropod-transmitted RNA virus infections of humans and
      other animals.

PMID- 8644904
TI  - Identification of Onchocerca volvulus collagen as an antigen mainly recognized by
      antibodies in chronic hyper-reactive onchodermatitis (sowda).
AB  - An Onchocerca volvulus expression library was differentially screened to identify
      a molecular marker distinguishing sowda (lichenified onchodermatitis) from other
      onchocerciasis forms. One clone, PG3, was recognized by pooled sera from patients
      with sowda, but not by pooled sera from patients with generalized onchocerciasis;
      it was not recognized by sera from patients with lymphatic filariasis or other
      helminth infections. The DNA of PG3 hybridized strongly with O. volvulus Eco RI
      digested DNA, but not with DNA from Brugia spp., Trichinella spp., and humans. A
      weak reaction was observed with DNA from O. gibsoni and Acanthocheilonema viteae.
      The PG3 DNA sequence showed a high homology with both human and nematode
      collagens. Confirmation of the collagen-like nature of the sowda-specific PG3
      product was obtained by amino terminal sequencing of the PG3 expression product,
      as well as by demonstrating its susceptibility to collagenase digestion. The
      characteristic recognition of the O. volvulus collagen specified by clone PG3 was
      confirmed by measuring antibody levels to the expressed product in individual
      sowda and generalized onchocerciasis sera, respectively. Identification of a
      nematode collagen antigen mainly recognized in sowda patients raises the
      possibility that this extreme form of dermatitis might arise through cross
      reactivity between anti-O. volvulus collagen antibodies and human collagen.
      However, a relationship between the PG3 recognition by antibodies and the sowda
      pathogenesis could not be demonstrated.

PMID- 8644903
TI  - Nitric oxide production in murine leishmaniasis: correlation of progressive
      infection with increasing systemic synthesis of nitric oxide.
AB  - Previous studies have shown that nitric oxide (NO) production is a major effector
      mechanism in the control of Leishmania major infection in the BALB/c and C3H
      murine models. The susceptibility of mice correlates with intrinsic NO production
      after infection. We have previously shown that blocking of systemic NO production
      with oral N-Omega-monomethyl-L-arginine results in decreased NO and exacerbated
      infection. The C3H mice also synthesize markedly more NO than BALB/c mice shortly
      after initial infection. We now show that late in infection, as the lesion size
      is increasing, the BALB/c NO production actually exceeds that seen during the
      curative stages of the C3H infection. In addition, treatment with meglumine
      antimoniate, which ameliorates but does not cure the BALB/c mouse, results in
      decreased systemic parasite load with a concomitant decrease in NO production.
      These results imply that in vivo, systemically measured levels of NO may in some
      circumstances reflect ongoing parasitic load, and that NO production is not
      always correlated with a curative response.

PMID- 8644905
TI  - Schistosomiasis japonica and childhood nutritional status in northeastern Leyte,
      the Philippines: a randomized trial of praziquantel versus placebo.
AB  - The hypothesis that infection with Schistosoma japonicum causes decreased
      nutritional status was studied in a randomized trial among 170 males and females,
      mean (SD) age 11.4 (3.5) years, residing in an endemic region of northeastern
      Leyte, Philippines. The S. japonicum-infected children were randomized to receive
      praziquantel or placebo and followed-up six months after randomization. Stature,
      weight, triceps, subscapular, and calf skinfold thicknesses and their sum, and
      hemoglobin level were measured at baseline and follow-up. Schistosoma japonicum
      eggs were detected in Kato-Katz stool smears and the intensity of infection was
      assessed by quantitative egg count. Intensities of hookworm, ascaris, and
      trichuris infections were also measured. The six-month levels of the
      anthropometric measures and hemoglobin were adjusted for age and their baseline
      levels and then compared between the praziquantel and placebo groups. Treatment
      interactions were also analyzed by sex. Baseline anthropometric and hemoglobin
      levels and parasite infection intensities were the same in the two groups. At six
      months, the praziquantel group had significantly higher hemoglobin levels (P <
      0.001) and sum of skinfolds (P < 0.001) than the placebo group. Males had a
      significantly greater increase in hemoglobin levels with treatment than did
      females. The hemoglobin increase was not due to changes in hookworm intensity.
      The results show that schistosomiasis japonica caused decreased nutritional
      status in children and probably is partly responsible for the malnutrition and
      reduction in growth for age described in prior cross-sectional studies.

PMID- 8644906
TI  - Dengue-2 virus infection of human bone marrow: characterization of dengue-2
      antigen-positive stromal cells.
AB  - Dengue is often associated with neutropenia and thrombocytopenia, suggesting that
      cells of the bone marrow may be targets of dengue viral infections. In this study
      we infected long-term marrow cultures with dengue type-2 (DEN-2) virus and
      characterized the viral antigen-positive cells. Using immunofluorescence
      microscopy and immunohistochemical staining, we demonstrated two types of stromal
      cells that were positive for DEN-2 virus antigens. The first was a population of
      relatively small (approximately 25 microns) CD11b/CD18 (MAC-1)-positive cells.
      When stained with anti-DEN-2 polyclonal antibody, these cells showed viral
      antigen-positive inclusions and, when stained with anti-tubulin or anti-vimentin
      antibodies, they showed a diffuse pattern of fluorescence, consistent with mobile
      dendritic cells with phagocytic functions. The second population of DEN-2 antigen
      positive cells comprised a smaller proportion of the total cells. It was made up
      of larger cells (> 100 microns) that had a well-formed cytoskeletal system as
      demonstrated by intense staining with anti-actin, anti-tubulin, and anti-vimentin
      antibodies. When stained with anti-DEN-2 antibody, these cells showed a more
      diffuse pattern of fluorescence in the perinuclear and Golgi regions, consistent
      with ongoing virus replication. These large, strongly adherent cells were
      positive for nerve growth factor receptor, consistent with their identification
      as adventitial reticular cells. The molecule that mediates the virus interaction
      with susceptible cells has not previously been identified. Using plasma membrane
      proteins isolated from K562 cells, virus-binding studies suggest that an
      approximately 100-kD membrane protein may be involved in the initial virus-cell
      interaction.

PMID- 8644907
TI  - Narrow-mouthed water storage vessels and in situ chlorination in a Bolivian
      community: a simple method to improve drinking water quality.
AB  - Epidemiologic investigations of the Latin America cholera epidemic have
      repeatedly implicated untreated drinking water and water touched by hands during
      storage as important vehicles for disease transmission. To prevent such
      transmission, we provided a new narrow-mouthed, plastic, water storage vessel and
      5% calcium hypochlorite solution for home disinfection of stored water to a
      Bolivian Aymara Indian community at risk for cholera. We evaluated acceptance of
      this intervention and its effect on water quality. Each of 42 families in the
      study obtained water from a household well; fecal coliform bacteria were found in
      water from 39 (93%) of 42 wells and 33 (79%) of 42 usual water storage vessels.
      One group of families received the special vessels and chlorine (group A), a
      second received only the special vessels (group B), and a third served as a
      control group (group C). Water samples collected every three weeks from group A
      special vessels had lower geometric mean fecal coliform colony counts (P <
      0.0001) and lower geometric mean Escherichia coli colony counts (P < 0.0001) than
      water from group B or C vessels. Adequate levels of free chlorine persisted in
      these vessels for at least 5 hr. The special vessels and chlorine solution were
      well accepted and continued to be used for at least six months. Use of the vessel
      and chlorine solution produced drinking water from nonpotable sources that met
      World Health Organization standards for microbiologic quality.

PMID- 8644909
TI  - Human blood-feeding rates among sympatric sibling species of Anopheles
      quadrimaculatus mosquitoes in northern Florida.
AB  - We compared rates of feeding on human hosts for blood-engorged female Anopheles
      quadrimaculatus species A, B and C1 collected from daytime resting sites in
      Manatee Springs State Park, Levy County, Florida during 1992-1993. Quick-blot DNA
      probes were used to identify mosquito taxa and also the presence of human blood
      in the mosquito gut. In collections from a campground area, human blood-feeding
      rates differed significantly among mosquito species (10.7% [19 of 177], 0%, [0 of
      62], and 1.2%, [4 of 327]), respectively for species A, B and C1). In collections
      from a woodland site (1 km from the campground), 1.5% (2 of 129) of the species B
      females had fed on humans, whereas none of 19 species A or 159 species C1 females
      had done so. Of the three species in this study area, species A appears the most
      likely to be a biting pest of humans and a vector of human malaria.

PMID- 8644908
TI  - Ivermectin distribution and the cultural context of forest onchocerciasis in
      South Province, Cameroon.
AB  - This investigation examined the cultural context of forest onchocerciasis in
      several communities in the Dja-Lobo Division of southern Cameroon. The study
      sought to elucidate behaviors that would enhance or diminish health status
      relative to forest onchocerciasis and other filarial infections, and to make
      culturally sensitive and appropriate recommendations regarding the development of
      health education materials and the long-term sustainability of the ivermectin
      distribution program in Dja-Lobo. The study consisted of two sequential
      components; the first was a qualitative study of a few severely affected villages
      and the second was a quantitative study of 212 randomly selected heads of
      households from eight villages. The Boulou and Baka peoples in these communities
      defined general filariasis (minak) as small worms under the skin, identified
      flies as important transmitters of the illness, and indicated that blindness and
      other skin and ocular problems were a consequence of the illness. Illness of the
      Dja (referring to an illness found near the Dja River) was another illness that
      was closely linked to onchocerciasis; local people indicated it was transmitted
      by the black flies found near the Dja River, resulting in severe itching and
      leopard skin. These and other cultural-behavioral data on filariasis were used to
      implement a health education and distribution program.

PMID- 8644910
TI  - Postmortem diagnosis of autochthonous acute chagasic myocarditis by polymerase
      chain reaction amplification of a species-specific DNA sequence of Trypanosoma
      cruzi.
AB  - We report a fatal case of vector-transmitted acute Chagas' myocarditis in a seven
      month-old child in south Texas. This diagnosis was not suspected during the three
      days of hospitalization that preceded the child's death, which was caused by
      heart failure. A diagnosis of acute myocarditis, probably of viral origin, was
      listed as the cause of death after cardiac tissue was examined microscopically at
      autopsy. One year after the death of the patient, a diagnosis of Trypanosoma
      cruzi myocarditis, based solely on morphological grounds, was made after newly
      prepared slides of cardiac tissue were examined. Seven years later, we confirmed
      the diagnosis of T. cruzi infection by using the polymerase chain reaction to
      amplify a species-specific genomic repetitive DNA sequence of the parasite from
      fixed cardiac tissue.

PMID- 8644911
TI  - Use of weather data and remote sensing to predict the geographic and seasonal
      distribution of Phlebotomus papatasi in southwest Asia.
AB  - Sandfly fever and leishmaniasis were major causes of infectious disease morbidity
      among military personnel deployed to the Middle East during World War II.
      Recently, leishmaniasis has been reported in the United Nations Multinational
      Forces and Observers in the Sinai. Despite these indications of endemicity, no
      cases of sandfly fever and only 31 cases of leishmaniasis have been identified
      among U.S. veterans of the Persian Gulf War. The distribution in the Persian Gulf
      of the vector, Phlebotomus papatasi, is thought to be highly dependent on
      environmental conditions, especially temperature and relative humidity. A
      computer model was developed using the occurrence of P. papatasi as the dependent
      variable and weather data as the independent variables. The results of this model
      indicated that the greatest sand fly activity and thus the highest risk of
      sandfly fever and leishmania infections occurred during the spring/summer months
      before U.S. troops were deployed to the Persian Gulf. Because the weather model
      produced probability of occurrence information for locations of the weather
      stations only, normalized difference vegetation index (NDVI) levels from remotely
      sensed Advanced Very High Resolution Radiometer satellites were determined for
      each weather station. From the results of the frequency of NDVI levels by
      probability of occurrence, the range of NDVI levels for presence of the vector
      was determined. The computer then identified all pixels within the NDVI range
      indicated and produced a computer-generated map of the probable distribution of
      P. papatasi. The resulting map expanded the analysis to areas where there were no
      weather stations and from which no information was reported in the literature,
      identifying these areas as having either a high or low probability of vector
      occurrence.

PMID- 8644912
TI  - Circulating anodic antigen (CAA) levels in different age groups in a Zimbabwean
      rural community endemic for Schistosoma haematobium determined using the magnetic
      beads antigen-capture enzyme-linked immunoassay.
AB  - A simplified version of the magnetic bead antigen-capture enzyme-linked
      immunoassay (MBAC-EIA) was used to detect circulating anodic antigen (CAA) in
      individuals of different age groups with Schistosoma haematobium infection only
      in an endemic area of Zimbabwe. An overall positive correlation between S.
      haematobium egg excretion and CAA levels was demonstrated. The age profile for
      CAA levels was generally comparable with the age profile of S. haematobium
      prevalence and intensity of infection. The CAA levels were higher in younger (5
      14 years of age) individuals than in older (greater than 14 years of age) ones.
      Since the sensitivity of the MBAC-EIA in the diagnosis of S. haematobium
      infection was found to be 97%, CAA levels appear to be a useful indicator of worm
      burden in an endemic area.

PMID- 8644913
TI  - Critical examination of Aedes aegypti indices: correlations with abundance.
AB  - The following immature stage indices for Aedes (Stegomyia) aegypti surveillance
      were evaluated in four north Queensland, Australia towns with respect to their
      relationship to immature and adult female densities: Breteau, House, Container,
      Larval Density, Stegomyia (and modifications thereof), and a newly created Adult
      Productivity Index. Spearman's correlations of indices that considered larval or
      immature (larvae and pupae) numbers had a better relationship with immature
      abundance but this was not necessarily the case against adult abundance. To
      examine the robustness of the indices, data from 758 premises in Townsville,
      Charters Towers, Ravenswood, and Mingela were pooled and 30 random subsamples,
      each consisting of 50 premises were taken. After each subsample was taken, the
      premises selected were reintroduced into the original data bank of 758 premises,
      and therefore, were available for further selection, i.e., sampling with
      replacement. Indices were calculated for each of the 30 subsamples and the
      coefficients of variation of each index were estimated from these. The Breteau,
      Adult Productivity, House, and Adult density indices proved to have the smallest
      coefficients compared with index size. No alternate index was regarded as being
      superior to the Breteau, including the Adult Productivity Index measuring both
      container type frequency and immature density. For this reason and in view of the
      labor intensiveness of estimating immature indices that incorporate productivity,
      it is recommended that new and cost-effective methods of adult surveillance be
      pursued.

PMID- 8644914
TI  - An integrated strategy for structural characterization of the protein and
      carbohydrate components of monoclonal antibodies: application to anti-respiratory
      syncytial virus MAb.
AB  - The relatively rapid and extensive characterization of the amino acid sequence
      and site-specific carbohydrate structures of a recombinant, reshaped human
      monoclonal antibody directed against respiratory syncytial virus (RSHZ19) is
      presented. The integrated strategy used a combination of mass spectrometric and
      conventional methodologies. Liquid chromatography/electrospray mass spectrometry
      was used for peptide mapping and selective identification of glycopeptides, and
      Edman degradation and tandem mass spectrometry were used to define the sequences
      of selected peptides. Matrix-assisted laser desorption/ionization mass
      spectrometry provided the M(r) of the intact protein and was used to characterize
      endo- and exoglycosidase digests of isolated glycopeptides to identify the
      glycosylation-site peptide and define the structures of the carbohydrates at that
      site. These experiments verified 99.1% of the light- and 99.3% of the heavy-chain
      amino acid sequences. The N and C termini of both chains were confirmed, and the
      nature and extent of heterogeneity at the N and C termini of the heavy chain were
      determined. Oxidation of a specific methionine residue to the sulfoxide was
      demonstrated by sequencing the N-terminally blocked peptide by tandem MS.
      Carbohydrate was found exclusively at Asn296 of the heavy chain. There was no
      evidence for a nonglycosylated form of the molecule or for the presence of O
      linked carbohydrate. The qualitative distribution of glycoforms at this site was
      determined by MS of the isolated, tryptic glycopeptide and compared with results
      obtained by high-performance anion exchange chromatography and high-resolution
      gel permeation chromatography of oligosaccharides released by hydrazinolysis. The
      sequence and linkage of individual glycan species were determined using matrix
      assisted laser desorption/ionization MS to monitor the results of a series of
      controlled digestions with specific exoglycosidases. The set of glycoforms
      consists predominantly of biantennary, core fucosylated carbohydrates lacking
      sialic acid. The present study is one of the first to directly evaluate the
      quantitative as well as qualitative consistency of the MS methods with
      conventional methods for carbohydrate analysis.

PMID- 8644915
TI  - Monitoring of IgG antibody thermal stability by micellar electrokinetic capillary
      chromatography and matrix-assisted laser desorption/ionization mass spectrometry.
AB  - Monitoring the stability of immunoglobulin G (IgG) type antibodies is a crucial
      analytical issue spanning a wide variety of immunological/biotechnological
      studies, which includes the analysis of conjugated IgG's for drug delivery.
      Capillary electrophoresis (CE) has proven valuable for the analysis of proteins
      and has the potential to separate and detect native antibody components. An ideal
      complement to CE, which is capable of providing the desired detection specificity
      to provide species identification information, is matrix-assisted laser
      desorption/ionization mass spectrometry (MALDI-MS). Utilizing these two
      techniques we have developed an antibody examination procedure and monitored the
      degradation of an internalizing chimeric (human/mouse) monoclonal antibody
      (BR96). Electropherograms of the antibody after up to 166 h of thermal stress are
      presented; MALDI mass spectra of the stressed antibody were acquired at the same
      time points. At 166 h, the percentage of ionization carried by the intact
      antibody molecular ions M+, M2+, etc., had clearly decreased, while that due to
      additional ion species had significantly increased. Ions corresponding in mass to
      loss of one light chain, loss of an Fab arm to yield an Fab/c type fragment, and
      formation of separated heavy-chain and light-chain moieties were observed.
      Several of these fragments result from simple disulfide linkage disruption. In
      addition, species less in mass than common antibody subunits were also observed,
      demonstrating peptide as well as disulfide bond cleavage. The observation that a
      small number of well-defined species were formed during the study suggests that
      the cleavage induced by thermal stress is very site-specific within the IgG.

PMID- 8644916
TI  - Electrochemical detection of exocytosis at single rat melanotrophs.
AB  - Amperometry at a carbon fiber microelectrode was used to monitor secretion of
      peptide hormone from single melanotrophs of the intermediate lobe of the rat
      pituitary. The method is based on electrochemical oxidation of tryptophan and
      tyrosine residues of small proopiocortin-derived peptides secreted from these
      cells. For single-cell measurements, the electrode, which had a sensing diameter
      of approximately 9 microns and a total tip diameter of 30 microns, was positioned
      approximately 1 micron away from single melanotrophs. When cells were stimulated
      by application of 64 mM K+, a series of randomly occurring current spikes with an
      average area of 34 +/- 6 fC was observed. The current spikes were strongly
      dependent on the presence of Ca2+. Current spikes of nearly identical area and
      shape were also elicited by mechanical stimulation. Cyclic voltammograms obtained
      from cell releasates confirmed that the substance detected was a tryptophan- or
      tyrosine-containing peptide. On the basis of amperometric tests of the most
      abundant peptides in melanotrophs, it is concluded that the current spikes are
      due to detection of primarily alpha-melanocyte stimulating hormone. The spike
      area corresponds to 0.32 amol of alpha-melanocyte stimulating hormone. It is
      concluded that the current spikes represent detection of concentration pulses
      that are expected following exocytosis events.

PMID- 8644917
TI  - Analysis of high-mass biomolecules using electrostatic fields and matrix-assisted
      laser desorption/ionization in a Fourier transform mass spectrometer.
AB  - A new decelerating technique that places dc potentials on the orthogonal
      excitation and receiver plates as well as the rear trapping plate (conductance
      limit) of the source cell of a dual cubic cell has been applied to the standard
      matrix-assisted laser desorption/ionization Fourier transform mass spectrometry
      technique. When this five-plate trapping method is applied, high-mass ions with
      large translational kinetic energies can be trapped efficiently and detected.
      Using this approach, low-resolution spectra of carbonic anhydrase (MW = 29,000),
      egg albumin (MW = 45,000), and bovine albumin (MW = 66,000) have been obtained.
      Because the new decelerating method requires no modification to the existing
      cell, it is also possible to obtain high-resolution spectra for compounds with
      masses of ca. 14,000 Da and lower. Utilizing the five-plate trapping method, a
      bovine insulin spectrum with a resolving power of 20,000 was obtained. It is not
      yet possible to obtain higher resolution for the higher mass proteins. The
      reasons for this difficulty are currently being investigated.

PMID- 8644918
TI  - Detection of hypoglycemic drugs in human urine using micellar electrokinetic
      chromatography.
AB  - Micellar electrokinetic chromatography (MEKC) is evaluated as a potential
      analytical method for the separation and detection of a series of sulfonylurea
      drugs used in the treatment of hyperglycemia. These drugs are often
      surreptitiously abused, producing extremely low blood glucose levels and symptoms
      indistinguishable from those associated with an insulin-secreting tumor.
      Separation buffer containing 50 mM sodium dodecyl sulfate (SDS) was found to be
      adequate for the MEKC separation of the third generation drugs (glipizide and
      glyburide) but not the second generation drugs (acetohexamide chlorpropamide,
      tolazamide, and tolbutamide). At a pH of 8.5 in the presence of 20 mM borate/20
      mM phosphate and 150 mM SDS, all seven components were adequately resolved with
      an analysis time of 17 min. Altering the concentration of the buffering
      components to either 5 mM borate/5 mM phosphate or 40 mM borate alone reduced the
      analysis time to less than 10 min with no observable loss in resolution. A series
      of other micelle-forming surfactants were evaluated, and only sodium cholate
      provided an improvement over the SDS-based system. Optimal separation was
      obtained with 75 mM sodium cholate and led to complete analysis with baseline
      resolution of all seven components in less than 8 min. These conditions were
      shown to be adequate for the detection of the hypoglycemic drugs spiked into
      normal urine and in patients taking these drugs. The precision associated with
      nine consecutive injections of six samples (n = 54) was found to be acceptable
      with percent coefficient of variance for absolute migration times (MTabs) for all
      peaks averaging 0.89 with peak area and peak height being 8.49 and 8.26,
      respectively. The between-sample precision was found to average 0.92% for MTabs
      and 8.56% and 8.45%, respectively, for the relative peak area and peak height.
      With a detection limit for the drugs in urine (following extraction) in the 50
      ng/mL range, the potential exists for an MEKC-based assay for the detection of
      sulfonylurea drugs in urine.

PMID- 8644919
TI  - Ultra-high-speed DNA sequencing using capillary electrophoresis chips.
AB  - DNA sequencing has been performed on microfabricated capillary electrophoresis
      chips. DNA separations were achieved in 50 x 8 microns cross-section channels
      microfabricated in a 2 in. x 3 in. glass sandwich structure using a denaturing 9%
      T, 0% C polyacrylamide sieving medium. DNA sequencing fragment ladders were
      produced and fluorescently labeled using the recently developed energy transfer
      dye-labeled primers. Sequencing extension fragments were separated to
      approximately 433 bases in only 10 min using a one-color detection system and an
      effective separation distance of only 3.5 cm. Using a four-color labeling and
      detection format, DNA sequencing with 97% accuracy and single-base resolution to
      approximately 150 bases was achieved in only 540 s. A resolution of greater than
      0.5 was obtained out to 200 bases for both the one- and four-color separations.
      The prospects for enhancing the resolution and sensitivity of these chip
      separations are discussed. This work establishes the feasibility of high-speed,
      high-throughput DNA sequencing using capillary array electrophoresis chips.

PMID- 8644920
TI  - Analytical magnetapheresis of ferritin-labeled lymphocytes.
AB  - Analytical magnetapheresis is a technique for analyzing magnetic particles in
      suspension. The magnetically susceptible particles form a deposition pattern from
      the suspending medium under carefully controlled flow and magnetic field
      conditions. This technique was used to determine the effective magnetic
      volumetric susceptibility, delta chi, of human lymphocytes labeled with an iron
      rich protein, ferritin. Dynabeads M450, monodisperse polymeric beads doped with
      magnetite, of a diameter 4.5 microns, close to that of human lymphocytes, were
      used as a reference. The experiment showed an almost complete deposition of
      ferritin-labeled lymphocytes at an average flow velocity of 0.28 mm/s, a
      representative magnetic field of 1.67 T, and a magnetic field gradient of 2.57
      T/mm. The calculated delta chi was (2.92 +/- 0.24) x 10(-6)[SI] (ferritin-labeled
      lymphocytes), and the corresponding number of ferritin molecules per lymphocyte
      was (1.75 +/- 0.44) x 10(7). In comparison, an almost complete deposition of the
      Dynabeads was observed at a much higher average flow velocity, 15 mm/s, a much
      lower field, 0.164 T, and a much lower field gradient, 0.025 T/mm. These results
      corresponded to a much higher delta chi = 0.245[SI] (Dynabeads M450). These
      results offer important guidelines in evaluating the use of ferritin as a soluble
      magnetic cell label.

PMID- 8644921
TI  - Chromatography of proteins using polybutadiene-coated zirconia.
AB  - Polybutadiene-coated zirconia (PBD-ZrO2), when used as a stationary phase in
      conjunction with a mobile phase containing phosphates, constitutes a reversed
      phase/cation-exchange mixed-mode chromatographic system. The separation of
      proteins on this phase can be achieved only through the use of mobile phases
      containing the correct combination of phosphoric acid, displacing salt, and
      organic cosolvent. We found that excessive Coulombic interactions between
      proteins and the stationary phase impair the system performance for the
      separation of proteins. The effects of mobile phase conditions on the separation
      of proteins using phosphate-adsorbed PBD-ZrO2 are studied in this work. Factors
      such as the presence of a multivalent cation, mobile phase pH, phosphate
      concentration, and salt concentration can be manipulated to reduce the net
      negative charge on the surface and thereby improve the performance of the system
      toward the separation of proteins.

PMID- 8644922
TI  - Dual-analyte fiber-optic sensor for the simultaneous and continuous measurement
      of glucose and oxygen.
AB  - A fiber-optic sensor for the continuous and simultaneous determination of glucose
      and oxygen is described. The sensor is comprised of dual-analyte sensing sites in
      defined positions on the distal end of an imaging fiber (350 microns o.d.). Each
      sensing site is an individual polymer cone covalently attached to the activated
      fiber surface using localized photopolymerization. The oxygen sensor consists of
      a double-layer polymer cone. The inner polymer cone is a hydrophobic gas
      permeable copolymer containing an oxygen-sensitive ruthenium dye, and the outer
      layer is a poly(hydroxyethyl methacrylate) (HEMA) polymer. The glucose sensor is
      an oxygen sensor with a poly-HEMA outer layer containing immobilized glucose
      oxidase. The fluorescence images of both sensing sites are captured with a CCD
      camera, and the measured fluorescence intensities are related to analyte
      concentrations. Oxygen quenching data for both sensing sites fit a two-site Stern
      Volmer quenching model. The sensor has been used to simultaneously monitor
      independent changes in glucose and oxygen concentrations. Glucose calibration
      curves were obtained under varying oxygen tensions, and the detection limit is
      0.6 mM glucose. The effect of fluctuations in oxygen partial pressure on the
      glucose response can be used to calibrate the sensor. The sensor response time
      varies from 9 to 28 s, depending on the different thicknesses of the enzyme
      layer. The sensor maintains the same sensitivity for 2 days. Multiple glucose
      sensing sites with different enzymatic activities can be immobilized on the
      distal end of the fiber, affording control of the linear range.

PMID- 8644923
TI  - Dynamics of acrylodan-labeled bovine and human serum albumin sequestered within
      aerosol-OT reverse micelles.
AB  - We investigate the effects of hydration on acrylodan-labeled bovine and human
      serum albumin (BSA-Ac and HSA-Ac) in aerosol-OT (AOT) reverse micelles
      solubilized in n-heptane. Time-resolved fluorescence intensity decay experiments
      reveal a dipolar relaxation process surrounding the acrylodan cybotactic region.
      This process is best described by a two-term rate law wherein the average
      relaxation increases with increased hydration. However, the actual rate constants
      describing the relaxation process either remain unchanged or actually decrease
      with increased hydration. The results illustrate that the fractional contribution
      associated with the individual relaxation pathways causes the observed changes in
      relaxation dynamics. The recovered rotational reorientation dynamics of the
      acrylodan residue are also affected by the extent of protein hydration. As
      hydration is increased, the semiangle through which the acrylodan residue
      precesses increases by 10 degrees for both protein systems. Interestingly, the
      recovered semiangles for the native proteins equal those recovered at lower
      hydration when the proteins are sequestered within the AOT reverse micelle. These
      results demonstrate the importance of hydration on protein behavior in
      environments where water is limited (e.g., biosensor interfaces and sol--gel
      derived biocomposites).

PMID- 8644924
TI  - Exact mass determination for elemental analysis of ions produced by matrix
      assisted laser desorption.
AB  - The exact masses of bastadins, cyclic peptides from marine sponges Ianthella
      basta, are determined using matrix-assisted laser desorption ionization (MALDI)
      coupled to a Fourier transform mass spectrometer. Two known compounds were mixed
      with the unknown to serve as internal calibrants. The mass of the calibrants
      bracketed the mass of the unknown compound. With this method, exact masses were
      obtained to within 5 ppm for single determinations, and less than 3 ppm for
      multiple determinations, allowing the derivation of elemental composition. This
      method is viable for routinely obtaining the exact masses of new compounds with
      MALDI.

PMID- 8644925
TI  - Failure of 29Si NMR to detect increased blood silicon levels in silicone gel
      breast implant recipients.
AB  - We have compared directly the results of atomic absorption (AA) spectroscopy and
      a 29Si magic angle spinning (MAS) nuclear magnetic resonance (NMR) technique
      reported in the literature by Garrido et al. (Garrido, L.; et al. Magn. Reson.
      Med. 1994, 31, 328-330) for analyzing blood silicon levels in control patients
      versus patients with silicone gel breast implants. AA spectroscopy yielded blood
      silicon levels in the nanogram per milliliter range for control patients, while
      somewhat higher values were found in patients with implants. The 29Si MAS NMR
      technique applied to the identical blood samples was unable to detect silicon in
      any of the samples. Sensitivity calculations demonstrate that 29Si MAS NMR should
      not be expected to detect silicon at the levels determined by AA spectroscopy
      under the spectroscopic conditions employed and that the concentration of silicon
      containing compounds would need to 10(4) times the level detected by AA in order
      to be detected by this NMR method.

PMID- 8644926
TI  - Attomole-sensitivity electrospray source for large-molecule mass spectrometry.
AB  - Full mass spectra of high resolving power are obtained from 0.2 nL sample volumes
      of large (> 10 kDa) nucleotides and proteins using a new electrospray ionization
      (ESI) system combined with Fourier transform mass spectrometry. The ESI needles
      are fabricated by laser-heated pulling of fused-silica tubing (5-20 microns
      i.d.), followed by chemical etching and surface metalization. Total analyte
      loaded at the instrument of 8.6 fmol and 216 amol produces signal-to-noise ratios
      of 400:1 and 60:1, respectively, and resolving power of > 10(5) for full mass
      spectra, while the total amount of material consumed is approximately 150 and 10
      amol, respectively.

PMID- 8644927
TI  - The leukocytes of the roughtail gecko Cyrtopodion scabrum: a bright-field and
      phase-contrast study.
AB  - The morphology of the peripheral blood leukocytes of the roughtail gecko,
      Cyrtopodion scrabum, is carefully described in Wright-Giemsa and toluidine-blue
      stained blood films, and in the living condition by phase-contrast microscopy,
      using supravitally stained preparations. Mature eosinophils, basophils and small
      lymphocytes commonly occur in the blood, while monocytes are rarely seen. In
      addition, macrophages are occasionally encountered, but neutrophils cannot be
      observed. Developmental stages in eosinophil and basophil differentiation can be
      seen. This study serves as a basis for the cytochemical localization of
      substances within these blood cells.

PMID- 8644928
TI  - Anatomical, histological and functional specificities of the digestive tract in
      the male grasscutter (Thryonomys swinderianus, Temminck 1827).
AB  - Using standard methods, the study of topographic and descriptive anatomy, and
      histology, has led to the specification of some special features and their
      relationship to the function of the grasscutter digestive tract. These details
      include the development of dorsal excrescence on the tongue, lack of a true
      pylorus, and advanced disappearance of Brunner glands in the last third of the
      duodenum submucosa. More interesting is the size of the caecum, which fills 60%
      of the abdominal cavity, and the presence of large anal glands, making this
      animal an unusual rodent.

PMID- 8644929
TI  - [Functional magnetic resonance imaging (MRI) of hepatic ischemia in the rabbit.
      Contribution of a particulated contrast agent (AMI-25)].
AB  - A functional approach of the rabbit portal ischemia was performed on five New
      Zealand rabbits using magnetic-resonance (MR) imaging and an MR-specific contrast
      agent for the liver. The hepatic vascularization and the functionality of the
      phagocytosis cells were both studied with a single low dose of a unique contrast
      agent-superparamagnetic iron oxide particles (SPIOs). After a rapid i.v.
      injection of SPIOs, functional vessels and normally perfused liver parenchyma
      appeared with positive signal enhancement, whereas the ischemic area remained
      dark (cold spot). After the intravascular time period, the well-known negative
      enhancement induced by these particles on normal parenchyma was observed, with
      the difference of the ischemic liver, and could be related to the uptake of SPIOs
      by functional Kupffer cells.

PMID- 8644930
TI  - A juxtaposition between A-cells and D-cells in the chicken pancreatic islets
      following vagotomy.
AB  - Conventional electron microscopy and enzyme-cytochemistry were applied to
      elucidate the juxtaposition between the pancreatic D-cell and A-cell, 1-2 weeks
      after abdominal vagotomy in chickens. A pancreatic D-cell frequently encircled an
      A-cell. Around this juxtaposition, several D-cells, characterized by the
      occurrence of peculiar dense bodies, formed a cluster. Both the D-cell and the A
      cell juxtaposed with each other and had an irregularly shaped nucleus with
      several indentations. Exocytosis of secretory granules from D-cells encircling an
      A-cell was often observed in the capillary side, but no release of secretory
      granules from A-cells was detected, except on the capillary side. A few large
      dense bodies, resembling a multivesicular body, were observed in the A-cell
      cytoplasm, showed positive acid-phosphatase activity, and contained remnants of
      several types of cell organelles. They thus seemed to be secondary lysosomes. It
      is possible that the juxtaposition between the A-cell and the D-cell may be
      morphological evidence of the inhibitory action on the A-cell by the D-cell.

PMID- 8644931
TI  - [The spermathecal epithelium of the queen bee (Apis mellifera): morphology, age
      dependent changes and cell contacts].
AB  - The spermatheca of the honey bee queen is covered by a single-layered, uniform,
      polarised epithelium. The apical cell surface is greatly enlarged by protrusions
      and plasma membrane infoldings, the basal cell surface by numerous
      interdigitating, long, small processes. Cytoplasmic organelles are chiefly
      represented by mitochondria. Numerous microtubuli extend throughout the
      cytoplasm. Golgi and endoplasmic profiles are rare. The cells are subject to
      senile degeneration: with increasing age, a variety of cytoplasmic inclusions
      appear, among which are myelinated membranes, dense bodies and dense filamentous
      aggregates. The spermathecal epithelium does not seem to be involved in exocrine
      secretion related to nutrition of the long-term stored spermatozoa. The ultra
      structure points, however, to ion transport functions and to an engagement in the
      maintenance of an adequate physicochemical environment ensuring the viability of
      the spermatozoa. Cellular junctions are represented by luminal zonulae
      adherentes, focal cell-cell adhering junctions and hemiadhering junctions along
      the basal plasmalemma. Desmosomal contacts and cytoskeletal intermediate
      filaments are missing. Along the lateral plasmalemma, gap junctions and septate
      junctions are found.

PMID- 8644932
TI  - Anatomy of the sinus node of camels (Camelus dromedarius).
AB  - Anatomy of the sinus node was studied in six camel hearts (Camelus dromedarius)
      with serial histologic sectioning. The sinus node in this species of animal was
      located 0.5 mm beneath the epicardium, near the junction between the cranial vena
      cava and the right atrium at the sulcus terminalis. Its shape was elongated, bent
      oblong with 28.25 mm length, 5.75 mm width and 5.38 mm thickness. The maximum
      section area was 101.66 mm2. The central artery of the node originated from the
      circumflexus branch of the left coronary artery and, throughout its length in the
      substance of the sinus node, had an internal elastic membrane. Histologically,
      the sinus node of this animal contained a central artery and a framework of
      collagen fibres, which were distributed around the central artery. The nodal
      cells were irregularly organized around the central artery and two types, i.e.
      "p' cells and transitional cells were present. The "p' cells had a perinuclear
      clear zone but the transitional cells contained more myofibrils. The intercalated
      discs were not present. At the periphery of the sinus node there were many nerve
      fibres and a ganglion. The purkinje fibres were present within atrial myocardium,
      as well as within ventricular myocardium. The glycogen content of the sinus nodal
      cells was higher than that of the atrial myocardial cells.

PMID- 8644933
TI  - Quantitative histomorphology of liver growth in sheep at prenatal and postnatal
      stages.
AB  - This study was carried to determine quantitative histomorphologically on the
      development of the liver of sheep in prenatal and postnatal stages, and to prove
      the relationship between functional and structural differentiation of liver.
      There were more blood cells than hepatocytes, and haemotopoieisis was the primary
      function of the liver in the first half of gestation. As observed in the fetal
      stages bile ducts and Kiernan areas are formed from the 12th week. The distance
      between the two adjacent central veins was 401.2 = 20.8 micron in the fetuses and
      629.77 -/+ 34.7 micron in the lambs, while rising in the adult to 740 + 14.35
      micron. This increase was directly proportional to age. The average diameter of
      sheep hepatocyte and nuclei, and the ratio between the diameters of nuclei and
      their hepatic cells were compared according to the prenatal and postnatal stages,
      and the difference between these stages was found to be statistically significant
      (P < 0.05). This difference was sourced from adult sheep. The number of
      hepatocytes per unit area were 107.48 -/+ 6.63, 133.6 -/+ 7.01, 100.84 -/+ 6.63
      in the fetus, lamb and adult liver of sheep, respectively, and the differentia
      that earned statistical importance was sourced from the young stages. The number
      of ductus biliferi was 2.75 -/+ 0.47 in the fetuses, however, this had risen to
      5.8 -/+ 0.6 and 6.8 -/+ 0.37 respectively in the lambs and adult sheep. The
      portal lobule areas rose according to the age and were 0.17796 -/+ 0.00086 mm2
      and 2.022650 -/+ 0.0097 mm2 respectively in the lambs and adult sheep and the
      differentia between young and adult sheep was statistically important (P < 0.05).

PMID- 8644934
TI  - Anatomy and cholinergic innervation of the sinus paranalis in dogs.
AB  - Conventional methods have been used to study the general configuration of the
      wall of the Sinus paranalis in dogs. Apocrine tubular glands, elastic fibres and
      smooth-muscle fibres are the more significant elements of the wall, together with
      the epithelium and connective tissue. By means of the immunohistochemical method
      described in this paper, the results provide histochemical evidence for the
      presence of an AChE-positive reaction, and supposedly cholinergic nerve fibres in
      the wall of the dog anal sacs, mainly associated with subepithelial smooth
      muscle, vessels, and glands.

PMID- 8644935
TI  - [The blood vessel system of the large intestine of swine (Sus scrofa f.
      domestica)].
AB  - The circulatory system of the large intestine of 27 pigs was examined by means of
      corrosion anatomy (vascular casts), histology and electron microscopy. The
      results were as follows: The Aa. et Vv. breves et longae leave the mesenteric
      vessels and reach the wall of the intestine at the mesenteric margin. The short
      vessels enter the deeper layers of the wall, whereas the Aa. et Vv. longae, by
      taking a variable subserous course, reach the submucosa after penetrating the
      muscular layers. The tela submucosa contains an arterial and a venous vascular
      plexus. Where the submucosa is larger, there is a three-dimensional vascular
      network, a deep and superficial vascular plexus that are closely interconnected.
      The deep plexus is applied to the inner circular muscles, whereas the superficial
      plexus is adjacent to the muscularis mucosae. The deep arterial plexus receives
      its afflux from the Aa. breves et longae and provides part of the circular muscle
      layers with recurrent muscle branches. The vascularization of the mucosa is
      derived from the (superficial) submucosal plexus. The arteries that ascend the
      tunica mucosa ramify, in the form of a brush, into some arterioles. In the basal
      part of the mucosa, they turn into a periglandular capillary system, i.e. a
      network around each Lieberkuhn crypt. Close to the lumen, a polygonal
      subepithelial capillary system is formed. Below the epithelium of the mucosal
      surface, the capillaries turn into postcapillary venules. These are running
      vertically through the submucosa, with few inflowing side branches, and finally
      enter the submucosal plexus An intermuscular plexus is formed by anastomoses
      between the circular and the longitudinal muscular layers from the branches of
      the subserous-submucosal connections. This intermuscular plexus provides the
      capillaries for the tunica muscularis. The subepithelial capillaries are, above
      all, furnished with a so-called fenestrated endothelium, whereas the capillaries
      of the pericryptal mucosa mainly show a continuous endothelium. The latter
      contains multiple vesicles that can fuse to form transcytoplasmic channels. In
      the wall of the large intestine of the pig, there are no sure indications as to
      the existence of either arterio-venous anastomoses or haemodynamic regulatory
      structures.

PMID- 8644936
TI  - Morphological characteristics of the ileal Peyer's patches in the rhesus macaque:
      a histological and ultrastructural study.
AB  - Ileal Peyer's patches of rhesus macaques were investigated by light and electron
      microscopy (scanning-electron microscopy, transmission-electron microscopy). The
      results were compared with findings in other species. Differences were found
      concerning the shape of the dome area, the composition of the dome epithelium and
      the apical membrane of M cells: in the rhesus monkey, hemispherical domes bulge
      into the intestinal lumen. The dome epithelium is composed of three populations
      of gut epithelial cells; absorptive enterocytes as the predominant cell type;
      goblet cells; and M cells ("microfold bearing' or "membraneous' gut epithelial
      cells). The apical membrane of M cells forms irregular protrusions.

PMID- 8644937
TI  - The zygomatic branch of the auriculopalpebral nerve: can it be normally palpated
      in the live horse?
AB  - A detailed description is given of the methods to locate and palpate a
      subcutaneous part of the zygomatic branch of the auriculopalpebral nerve in 9 out
      of 10 adult horses examined. This permits the exact placing of local anaesthetic
      along the nerve branch at the described site, resulting in the akinesis of the m
      orbicularis oculi and the elimination of the blink reflex. This facilitates
      ophthalmologic examination and possible treatment of some eye conditions.

PMID- 8644938
TI  - [The anatomy of consciousness in domestic animals. Opening address of the 20th
      Congress of the EVVA in Zurich in memory of Eugen Seiferle].
AB  - All living organisms have a consciousness, not only humans. To seek to find
      humans' consciousness in animals is to seek wrongly. The question must be: "To
      what extent are prehuman and human consciousness comparable.' Animals have an
      instinctive sensational consciousness with a partial learning consciousness. It
      is a purely self-sustaining consciousness. In addition, humans have a spiritual
      thinking consciousness, which is predominantly a learning consciousness and is
      not a pure self-sustaining consciousness. Since human consciousness arose from
      animals' consciousness, that behaviour in animals which is similar to the thought
      process in human beings can only be based on sensations. Sensations of pain and
      fear are not very different in man and animal, because they also belong to the
      sensation consciousness in humans, but humans have the additional advantage of
      being able to think about them and to understand their cause and meaning. That is
      not possible in animals, therefore, animals have to be anaesthetized to protect
      them from pain. Seiferle recognized this clearly, and my consciousness theory
      reinforces Seiferle's view, i.e. that consciousness is the central force of the
      soul. Its afferent forces are perception and sensation; its efferent forces are
      will, feeling, and deed.

PMID- 8644939
TI  - The menstrual cycle and Raynaud's phenomenon.
AB  - Fluctuations in female sex hormones may be responsible for the high prevalence of
      Raynaud's phenomenon (RP) observed in premenopausal women. These hormones are
      known to act on central and peripheral thermoreceptors. In an attempt to
      establish whether cold sensitivity is altered during the menstrual cycle 50
      premenopausal women were investigated. Of these, 26 had primary RP and 24 acted
      as controls. Each subject was exposed to environmental heating and cooling at
      three stages of the menstrual cycle to coincide with peaks and troughs in hormone
      levels. These stages were menstruation, periovulation, and during the midluteal
      phase. Finger hemodynamics was assessed by means of venous occlusion strain gauge
      plethysmography and fingertip temperature. Core temperature was assessed with an
      oral thermocouple. The results show that cold sensitivity was altered during the
      menstrual cycle in both groups with the fastest finger rewarming pattern during
      menstruation. Moreover, a significant difference was observed in core temperature
      between the two groups during the midluteal phase. As a group, subjects with RP
      failed to show a significant rise in core temperature following ovulation. The
      authors conclude that the menstrual cycle is associated with changes in the
      effect of cold on digital blood flow.

PMID- 8644940
TI  - Identification of viable myocardium by nitrate echocardiography after myocardial
      infarction: comparison with planar thallium reinjection scintigraphy.
AB  - BACKGROUND: The aim of this study was to validate a new diagnostic tool, nitrate
      echocardiography (NE), for the identification of viable noncontracting myocardium
      in patients with a history of prior myocardial infarction (MI). Nitroglycerin
      (NTG) may be useful for this purpose for its peculiar pharmacodynamic action and
      may represent an option other than dobutamine echocardiography for the detection
      of hibernating segments in the presence of severely reduced coronary reserve.
      METHODS: Twenty selected patients (pts) with an old MI were studied with NE and
      planar thallium scintigraphy with reinjection. NE was performed by administering
      i.v. NTG starting at 0.4 mcg/kg/minute with equal increments every five minutes
      up to 2 mcg/kg/minute or to early interruption of the test (decrease of systolic
      blood pressure > or = 20% or improvement of previously akinetic segments). Left
      ventricular wall motion was analyzed by dividing the left ventricle (LV) into 16
      segments, and a wall motion score index (WMSI) was calculated. Thallium images
      were obtained at peak exercise, at four hours, and after reinjection. Myocardial
      viability was defined as an improvement in thallium uptake after reinjection in
      fixed defects. RESULTS: Basal echo demonstrated 74 akinetic segments; of these 21
      (28%, 11 pts) showed improved contractility during NTG infusion at a mean dose of
      0.87 +/-0.33 mcg/kg/minute. WMSI decreased from 1.69 +/- 0.29 to 1.46 +/- 0.31 (P
      = .001). The only hemodynamic response was a drop in systolic blood pressure (136
      mmHg to 124; P = .02). Thallium studies showed 29 segments with a four-hour
      reversible defect and 79 segments with a four-hour fixed defect; of the latter,
      14 regions demonstrated improvement in tracer uptake after reinjection (17.7%; 10
      pts). Nine pts had a positive echo and thallium study, while 8 showed no
      improvement either during NE or after thallium reinjection. Two pts had a false
      positive nitrate echocardiogram. Therefore, according to an echo/thallium study
      match, sensitivity, specificity, and accuracy are 90%, 80%, 85%, respectively.
      CONCLUSION: NE is a reliable and low-cost method for the detection of viable
      noncontracting myocardium in selected patients with CAD but needs further
      validation for widespread application.

PMID- 8644941
TI  - Outcome predictors of ultrafiltration in patients with refractory congestive
      heart failure and renal failure.
AB  - This study is an attempt to identify predictors of outcome from the use of
      ultrafiltration (UF) in patients with refractory congestive heart failure (CHF)
      and renal failure. The authors studied 30 patients in NYHA functional class IV in
      whom UF was utilized in the management of refractory CHF. Patients were
      retrospectively divided into two groups according to their outcome. Group A
      included 12 patients who improved and survived hospital admission, and group B
      included 18 patients who did not respond and died shortly after UF. Clinical,
      hemodynamic, and laboratory data before UF were fairly comparable between both
      groups. Renal function and hemodynamic parameters were compared and analyzed
      within the same group and between both groups before and after UF. The mean age
      in group A was sixty-three +/- thirteen years while in group B it was seventy +/-
      eleven years (P < 0.005). A mean of 9.6 liters of fluid were removed from group A
      and 3.2 liters from group B (P < 0.001). Group A showed greater reduction in the
      mean values of right atrial pressure (P < 0.005) and pulmonary capillary wedge
      pressure (P < 0.05) after UF. Additionally, group A showed a significant decrease
      in their blood urea nitrogen (P < 0.05) and serum creatinine values (P < 0.05),
      in contradistinction to group B patients who showed a major increase in those
      values after UF. There was no significant change in the mean values of cardiac
      index, systemic vascular resistance, and pulmonary vascular resistance after UF.
      These findings suggest that younger age groups, greater fluid removal, as well as
      significant decreases in blood urea nitrogen, serum creatinine, and right atrial
      and pulmonary wedge pressures after UF, are associated with favorable outcome.
      Conversely, older age groups, less fluid removal, and rising blood urea nitrogen
      and serum creatinine levels after UF were associated with poor outcome.

PMID- 8644942
TI  - Brain ischemia following bilateral carotid occlusion during development of
      hypertension in young spontaneously hypertensive rats--importance of morphologic
      changes of the arteries of the circle of Willis.
AB  - The present study was designed to examine the effect of morphologic changes of
      the arteries of the circle of Willis on cerebral blood flow (CBF) and metabolism
      in young spontaneously hypertensive rats (SHR). CBF in the parietal cortex was
      measured by the hydrogen clearance method before and during a one-hour bilateral
      carotid artery occlusion (BCO), and supratentorial brain metabolites were
      determined by standard enzymatic methods at a one-hour BCO. The internal
      diameters of the main arteries of the circle of Willis were estimated
      morphologically. With increase in age, systemic arterial pressure at rest was
      significantly raised, while cortical CBF tended to decrease and calculated
      cerebral vascular resistance increased. During BCO, CBF and supratentorial
      metabolism (adenosine triphosphate and lactate/pyruvate ratio) tended to be
      better preserved in two-month-old rats as compared with those in one- or three
      month-old rats. The internal diameter of the posterior communicating artery
      (PcomA) was significantly smaller in the one-month-old group than in the other
      groups, while the diameter of the internal carotid artery was significantly
      smaller in rats aged three months than those in rats aged one or two months. It
      is indicated that cortical CBF reduction and impairment of supratentorial
      metabolism following occlusion of carotid arteries, at least in part, depend on
      the morphologic changes of the arteries of the circle of Willis associated with
      age and development of hypertension in young SHR.

PMID- 8644943
TI  - Noninvasive evaluation of right ventricle systolic pressure during dynamic
      exercise by saline-enhanced Doppler echocardiography in progressive systemic
      sclerosis.
AB  - Progressive systemic sclerosis (PSS) is characterized in its first phases by
      vascular damage. Lungs are involved in two thirds of patients with initial
      progressive destruction of the capillary bed and consequent reduction of the
      functional reserve, which may lead to hypertension of the pulmonary circulation.
      For these reasons it is of great interest to have early information about the
      pressure of the pulmonary circulation, both at rest and during exercise, to
      follow the progression and the evolution of the illness independently from
      subjective symptoms. The aim of the study was to evaluate by a noninvasive
      method, saline-enhanced Doppler echocardiography, the behavior of the right
      ventricular systolic pressure in patients with PSS, at rest and during exercise,
      without clear instrumental or clinical signs of pulmonary involvement at rest.
      Nine patients (7 women and 2 men) with PSS, aged 55.7 +/- 8.7 years, and 9
      control subjects were evaluated. All patients had normal pulmonary pressure at
      rest and negative history for effort dyspnea. Subjects underwent Doppler
      echocardiographic examination at rest and during exercise. Right ventricular
      systolic pressure was evaluated by saline-enhanced Doppler technique, at rest and
      throughout exercise. At rest the right ventricular systolic pressure was normal
      in all patients and controls. At the end of exercise, in 4 patients, values were
      still normal (40.7 +/- 2.2 mmHg); in the others pathologic values were recorded
      (59.8 +/- 3.9 mmHg). In the control group values were always normal (35.6 +/- 4.6
      mmHg). In our study the saline-enhanced Doppler echocardiography has been
      demonstrated to be an important diagnostic tool for the noninvasive evaluation of
      right ventricular systolic pressure, both at rest and during exercise; it could
      be useful in monitoring the pulmonary vascular damage in patients with PSS.

PMID- 8644944
TI  - Comparative assessment of the effects of vasodilators on peripheral vascular
      reactivity in patients with systemic scleroderma and Raynaud's phenomenon: color
      Doppler flow imaging study.
AB  - The aim of the present study was assessment of peripheral vascular reactivity
      during cold test effects of different types of vasodilators on vascular
      resistance in patients with progressive systemic sclerosis and Raynaud's
      phenomenon with use of color Doppler flow imaging of upper extremity.

PMID- 8644945
TI  - Doppler echocardiographic assessment of normally functioning Starr-Edwards,
      carbomedics and Carpentier-Edwards valves in aortic position.
AB  - Doppler echocardiography was performed in 168 normally functioning aortic
      prostheses to determine acceptable pressure gradients across the commonly used
      valves and to establish the relationship between valve size and gradients. There
      were 82 Carbomedics (C), 63 Starr-Edwards (SE), and 23 Carpentier-Edwards (CE)
      valves. Peak and mean gradients across the prostheses were measured by use of the
      simplified Bernoulli equation. CarboMedics valve had a lower peak and mean
      gradient than Starr-Edwards and Carpentier-Edwards valve (P < 0.05 when compared
      with Starr-Edwards). The authors observed a weak inverse correlation between
      valve size and peak and mean gradients in CarboMedics and Carpentier-Edwards
      valves but not in the Starr-Edwards valve. For the CarboMedics valve the peak
      pressure gradient (PPG) was 26.1 +/- 8.2 mm Hg and the mean pressure gradient
      (MPG) was 14.7 +/- 5.1 mm Hg; in Starr-Edwards valve the PPG was 32.8 +/- 9.1 mm
      Hg and the MPG was 19.5 +/- 5.6 mm Hg; in the Carpentier-Edwards valve the PPG
      was 28.7 +/- 10.1 mm Hg and the MPG was 16.1 +/- 5.2 mm Hg when size was not
      specified. The CarboMedics valves were noted to have a better hemodynamic profile
      in comparison with Starr-Edwards and Carpentier-Edwards prostheses.

PMID- 8644946
TI  - The effect of low molecular weight heparin (fragmin) on myocardial neutrophil
      accumulation and infarct size in a rat model of myocardial infarction.
AB  - BACKGROUND: Heparin molecules possess immunomodulating properties, which are
      thought to complement their established antithrombotic activity. The purpose of
      this study was to evaluate whether the antiinflammatory properties of low
      molecular weight heparin (LMWH) can attenuate polymorphonuclear neutrophil
      accumulation and infarct size in a rat model of myocardial infarction. METHODS:
      Myocardial infarction was induced by ligating the left main coronary artery. LMWH
      (fragmin 500 anti-FXa u/kg) or vehicle (saline) were administered subcutaneously
      thirty minutes prior to coronary artery occlusion. Significant anticoagulant
      activity was attained with LMWH for more than eight hours. Twenty-four hours
      later, neutrophil accumulation and infarct size were determined by measuring left
      ventricular free wall myeloperoxidase and residual creatine kinase activity,
      respectively. RESULTS: As compared with rats administered vehicle,
      myeloperoxidase activity was insignificantly decreased in rats treated with LMWH
      (1.24 +/- 0.28 u/g vs 1.66 +/- 0.15 u/g, P = 0.16. Infarct size was also not
      significantly different between the groups (62.48 +/- 3.5% and 50.67 +/- 7.2% of
      left ventricular free wall with vehicle and LMWH, respectively, P = 0.1).
      CONCLUSION: The authors conclude that LMWH does not significantly reduce
      myocardial neutrophil accumulation and infarct size twenty-four hours after
      myocardial infarction in the rat.

PMID- 8644947
TI  - Asymmetric hypertrophic cardiomyopathy diagnosed by echocardiography and magnetic
      resonance imaging. Case reports.
AB  - The authors present 3 patients with asymmetric hypertrophic cardiomyopathy, which
      was diagnosed by echocardiography. Magnetic resonance imaging, however, proved
      superior in visualizing the cardiac anatomy of the left ventricle and enabled
      myocardial evaluation with determination of the location, severity, and extent of
      the abnormality. Magnetic resonance imaging can also differentiate unusual
      asymmetric hypertrophy from other pathologic states.

PMID- 8644948
TI  - An open-ended-pattern coronary circulation: demonstration of its potential "self
      cure" role in obstructive coronary artery disease. A case report.

PMID- 8644949
TI  - Pulmonary vascular sling responsible for esophageal and tracheal obstruction. A
      case report.
AB  - The disease of pulmonary vascular sling is a rare congenital condition. When it
      does occur it is often in conjunction with tracheal compression. The authors
      report herein a newborn with this anomaly presenting with a tracheal and
      esophageal compression.

PMID- 8644950
TI  - Paraumbilical vein aneurysm. Case reports.
AB  - Two cases of paraumbilical vein aneurysm are reported. The patients were
      diagnosed as having cirrhotic liver with portal hypertension. Angiography and
      contrast-enhanced computed tomography demonstrated a dilated paraumbilical vein
      arising from the left branch of the portal vein. Furthermore, localized
      dilatation of a paraumbilical vein was demonstrated. The focal aneurysmal
      dilatation of the dilatated paraumbilical vein is rare.

PMID- 8644951
TI  - Stenotic origin of an aberrant left subclavian artery from a right-sided aortic
      arch. A case report.
AB  - A patient with a right-sided aortic arch giving origin to an aberrant left
      subclavian artery with circumferential ostial stenosis is reported. This
      asymptomatic anomaly was discovered serendipitously during cerebral arteriography
      for subarachnoid hemorrhage. The embryologic origin of this anatomic variant is
      discussed, as are some practical implications relating to the angiographic
      technique of selective catheterization of branches of the aortic arch.

PMID- 8644952
TI  - Venous aneurysms.

PMID- 8644953
TI  - Feasibility of an emergency department-based, risk-targeted voluntary HIV
      screening program.
AB  - STUDY OBJECTIVE: To assess the feasibility and effectiveness of an emergency
      department-based, risk-targeted voluntary HIV screening program. METHODS: We
      prospectively enrolled consenting adult i.v. drug users (IDUs) not known to have
      HIV infection in the ED of a large inner-city hospital with a high rate of HIV
      infection among patients during a 10-week trial. Study patients were given
      confidential HIV pretest and risk-reduction counseling, with 10- to 14-day on
      site ED follow-up. Follow-up included posttest counseling, reinforcement of risk
      reduction practices, and a +10 incentive to cover transportation costs. HIV
      seropositive patients were referred to the hospital HIV clinic for further
      evaluation and treatment. RESULTS: Of 200 eligible IDUs, 168 (84%) consented to
      HIV testing. Of the 104 (62%) who returned for follow-up, 17 (16%) tested
      positive for HIV. Of these patients, 6 (35%) kept their initial hospital HIV
      clinic referral appointment, a rate consistent with the experience of the
      hospital HIV clinic. Of nine patients in whom CD4+ counts were performed at time
      of the visit, three (33%) had counts less than 200. At 3-month follow-up, 4 of 20
      active IDUs (20%) had reportedly ceased drug use because of the program. The
      complete program costs was an estimated $16,659, $99 per enrolled patient and
      $521 per HIV-positive patient. CONCLUSION: An ED-based, risk-targeted HIV
      screening program is feasible and over time could detect a significant number of
      asymptomatic HIV-infected individuals, including those who should receive
      antiretroviral therapy and prophylaxis for Pneumocystis carinii pneumonia therapy
      (CD4+ count less than 200). An additional benefit of ED-based HIV screening in
      high-prevalence EDs is the opportunity to conduct successful risk-reduction
      counseling in some high-risk individuals.

PMID- 8644954
TI  - Reliability of subjective fever in triage of adult patients.
AB  - STUDY OBJECTIVE: To determine whether a historical complaint of fever is
      predictive of fever on emergency department triage. METHODS: We prospectively
      questioned 651 ambulatory adult patients in a military tertiary care emergency
      department as to whether they had fever before oral temperature was taken. Fever
      was defined as a temperature of 38 degrees C (100.4 degrees F) or greater.
      RESULTS: Sensitivity and specificity were 84% (95% confidence interval [CI], 71%
      to 95%) and 83% (95% CI, 80% to 86%), respectively. The prevalence of objective
      fever was 6.4%, yielding positive and negative predictive values of 25% (95% CI,
      18% to 32%) and 99% (95% CI, 93% to 100%), respectively. Overall accuracy was 83%
      (95% CI, 80% to 86%). CONCLUSION: In this study, outpatients were fairly accurate
      in predicting fever. However, in an outpatient population with a low overall
      prevalence of objective fever, the predictive value of a complaint of fever
      representing an objective fever remained low. Therefore the complaint of
      subjective fever should be interpreted with caution when it is used to support a
      given diagnosis in an ambulatory care setting.

PMID- 8644955
TI  - Emergency department presentation and misdiagnosis of imported falciparum
      malaria.
AB  - STUDY OBJECTIVE: To review the travel history, clinical presentation, laboratory
      findings, diagnostic accuracy, management, and outcome of the largest reported
      series of emergency department patients with imported falciparum malaria in the
      United States. METHODS: This is a retrospective case series at large, inner-city
      medical center in Los Angeles. Twenty cases of falciparum malaria with initial
      medical evaluation in the ED were identified from the period 1979 through 1993.
      RESULTS: Fifteen male and 5 female patients were identified, with an age range of
      5 to 55 years. All had a recent history (within 2 months) of international travel
      in regions endemic for malaria. Most (85%) were recent immigrants or expatriates
      returning from a recent visit to their native country. The most common documented
      symptoms were fever (100%), chills (65%), vomiting (60%), anorexia (45%), and
      headache (45%). Tachycardia (85%) and hyperpyrexia (> 39 degrees C) (65%) were
      the most common presenting signs. Malaria was considered in the ED diagnoses in
      only 12 cases (60%). The specification of falciparum (malignant) malaria was
      established in only 2 cases (10%). Hepatitis and gastroenteritis were the most
      common misdiagnoses. Only four patients received antimalarial medication in the
      ED. There were no deaths, and complications were limited to thrombocytopenia and
      anemia. Two patients required transfusion. CONCLUSION: Imported falciparum
      malaria presenting to EDs in the United States is frequently misdiagnosed.
      Emergency physicians improve their ability to diagnose falciparum malaria by
      obtaining a thorough travel history on all patients with clinical features
      suggesting an infectious origin and considering this diagnosis in any patient
      with a history of travel to or migration from malaria-endemic areas.

PMID- 8644956
TI  - Effectiveness of emergency medical services for victims of out-of-hospital
      cardiac arrest: a metaanalysis.
AB  - STUDY OBJECTIVE: To determine the relative effectiveness of differences in
      response time interval, proportion of bystander CPR, and type and tier of
      emergency medical services (EMS) system on survival after out of hospital cardiac
      arrest. METHODS: We performed a comprehensive literature search, excluding EMS
      systems other than those of interest (systems of interest were those comprising
      one tier with providers of basic life support [BLS] or advanced life support
      [ALS] and those comprising two tiers with providers of BLS or BLS-defibrillation
      followed by ALS), patient population of fewer than 100 cardiac arrests, studies
      in which we could not determine the total number of arrests of presumed cardiac
      origin, and studies lacking data on survival to hospital discharge. Metaanalysis
      using generalized linear model with dispersion estimation for random effects was
      then performed. RESULTS: Increased survival to hospital discharge was
      significantly associated with tier (P < .01), response time interval (P < .01),
      and bystander CPR (P = .04). A significant interaction was detected between
      response time interval and bystander CPR (P = .02). For the studies analyzed,
      survival was 5.2% in a one-tier EMS system or 10.5% in a two-tier EMS system. A 1
      minute decrease in mean response time interval was associated with absolute
      increases in survival rates of .4% and .7% in a one-tier and two-tier EMS
      systems, respectively. CONCLUSION: Increased survival to hospital discharge may
      be associated with decreased response time interval and with the use of a two
      tier EMS system as opposed to a one-tier system. The data available for this
      analysis were suboptimal. Policymakers need more methodologically rigorous
      research to have more reliable and valid estimates of the effectiveness of
      different EMS systems.

PMID- 8644957
TI  - Cost-effectiveness analysis of potential improvements to emergency medical
      services for victims of out-of-hospital cardiac arrest.
AB  - STUDY OBJECTIVE: To measure the incremental cost-effectiveness of various
      improvements to emergency medical services (EMS) systems aimed at increasing
      survival after out-of-hospital cardiac arrest. METHODS: We performed cost
      effectiveness analysis based on (1) metaanalysis of effectiveness of the various
      EMS systems, (2) costing of each component of EMS systems, (3) modeling of the
      relationship between the proportion of cardiac arrest victims who receive CPR and
      the proportion of individuals trained, (4) modeling of the relationship between
      response time interval and the characteristics of the EMS system, (5) measurement
      of quality of life, and (6) decision analysis to combine the results of the first
      five components. RESULTS: The incremental cost-effectiveness ratio for a 48
      second improvement in mean response time in a one-tier EMS system yielded by the
      addition of more EMS providers was $368,000 per quality-adjusted life year
      (QALY). For improved response time in a two-tier EMS system by the addition of
      more basic life support (BLS)/BLS-defibrillator (BLS-D) providers to the first
      tier, the ratio was $53,000 per QALY with pump vehicles or $159,000 per QALY with
      ambulances. Change from a one-tier EMS to a two-tier EMS system by the addition
      of initial BLS/BLS-D providers in pump vehicles as the first tier was associated
      with a cost per QALY of $40,000. Change from one-tier EMS to two-tier EMS by the
      addition of initial BLS/BLS-D providers in ambulances as the first tier was
      associated with a cost per QALY of $94,000. CONCLUSION: The most attractive
      options in terms of incremental cost-effectiveness were improved response time in
      a two-tier EMS system or change from a one-tier to a two-tier EMS system. Future
      research should be directed toward identification of the costs of instituting the
      first tier of a two-tier EMS system and identification of cost-effective methods
      of improving response time.

PMID- 8644959
TI  - Efficacy of esophageal bougienage by emergency physicians in pediatric coin
      ingestion.
AB  - STUDY OBJECTIVE: To determine the efficacy and safety of bougienage performed by
      properly trained pediatric emergency medicine physicians to advance a recently
      ingested coin lodged in the esophagus into the stomach. METHODS: We carried out a
      prospective study of consecutive cases at two university-affiliated pediatric
      hospitals. Our subjects were 31 children, each with an ingested coin lodged in
      the esophagus, who met criteria for bougienage: a single coin ingested in the
      preceding 24 hours, radiographically localized in the esophagus; no history of
      esophageal disease, esophageal surgery, or foreign body removal; and no sign of
      respiratory compromise. The bougienage procedure involved a single pass of a
      Hurst bougie dilator from the mouth to the stomach with the unsedated patient
      sitting upright. RESULTS: In all cases, the coin was successfully advanced into
      the stomach with a single pass of the bougie dilator. No patient experienced an
      acute complication or delayed surgical complication related to the procedure. In
      one case the coin was vomited after the procedure and recovered without
      complications. Mild abdominal pain developed in two patients, who were
      reevaluated 2 weeks after the procedure. In each case the coin was present in the
      stomach and was removed endoscopically without subsequent complications.
      CONCLUSION: When used by trained emergency physicians, esophageal bougienage is a
      safe, effective, cost-containing treatment for dislodging and advancing ingested
      coins from the esophagus into the stomach that requires no sedation or general
      anesthesia.

PMID- 8644958
TI  - Utility of blood cultures in pediatric patients found to have pneumonia in the
      emergency department.
AB  - STUDY OBJECTIVE: To determine the prevalence of bacteremia in pediatric patients
      with radiographic evidence of pneumonia in whom blood cultures were obtained.
      METHODS: We carried out a retrospective review of the radiology log of a tertiary
      care children's hospital to identify patients with radiographic evidence of
      pneumonia seen between August 1991 and July 1992. These patients were cross
      referenced with the hospital laboratory information system, yielding results of
      any CBC or blood cultures. RESULTS: We found 939 patients with chest radiography
      findings consistent with pneumonia. Blood culturing was performed in 409 (44%).
      Eleven of these cultures (2.7%) grew pathogenic bacteria. Review of the medical
      records revealed no changes in clinical management made on the basis of the
      results of the blood cultures. CONCLUSION: Blood cultures are uncommonly positive
      in outpatients diagnosed with pneumonia.

PMID- 8644960
TI  - Empiric use of flumazenil in comatose patients: limited applicability of criteria
      to define low risk.
AB  - STUDY OBJECTIVE: To develop clinical rules for the safe and effective use of
      flumazenil in suspected benzodiazepine overdose. METHODS: We assembled a
      retrospective series of 35 consecutive comatose patients admitted between October
      1992 and July 1993 to a toxicologic ICU with the presumptive diagnosis of drug
      overdose. These patients were divided into two groups. Group A (low-risk)
      patients had a clinical picture compatible with uncomplicated benzodiazepine
      intoxication (calm, without abnormalities in pulse or blood pressure,
      lateralizing signs, hypertonia, hyperreflexia, or myoclonus) in the absence of
      predefined electrocardiographic or clinical signs of tricyclic antidepressant or
      other proconvulsant overdose, and absence of an available history of long-term
      benzodiazepine treatment or an underlying seizure disorder. Group B ("non-low
      risk") comprised all other patients. Efficacy of flumazenil was categorized as
      complete awakening (with normal level of alertness), partial awakening, or no
      change in alertness level. The safety of flumazenil was defined on the basis of
      the absence of seizures or death. RESULTS: In group A (n=4), flumazenil was
      associated with complete awakening in three patients and partial awakening in
      one. No seizures were observed. In group B (n=31), flumazenil was associated with
      complete awakening in 4 patients, partial awakening in 5, and no response in 22.
      In group B, five seizures occurred. CONCLUSION: Comatose patients with clinical
      or ECG criteria thought to contraindicate the use of flumazenil have a reasonably
      high risk of seizures after administration of this drug. Low-risk patients may be
      able to receive flumazenil safely, but they may be only a small portion of
      comatose patients with suspected overdose.

PMID- 8644961
TI  - Neuropsychologic and functional recovery from severe carbon monoxide poisoning
      without hyperbaric oxygen therapy.
AB  - STUDY OBJECTIVE: To test the hypothesis that neuropsychologic test results and
      functional outcome will be abnormal if hyperbaric oxygen (HBO) is not used in
      patients with severe carbon monoxide (CO) poisoning. METHODS: For a 1-year
      interval, we retrospectively identified all CO-poisoned patients who were
      comatose on presentation at a large, urban tertiary hospital and did not receive
      HBO therapy. Prospectively, 6 and 12 months after CO poisoning, we administered
      standardized questionnaires to assess functional outcome. At 6 months, we
      performed extensive neuropsychologic testing. RESULTS: All four patients
      exhibited normal performance on a neuropsychologic test battery at 6 months. The
      Folstein Mini-Mental Status Examination was normal in all patients. All patients
      had normal functional outcomes. CONCLUSION: Normal neuropsychologic and
      functional outcomes are possible after severe CO poisoning without the use of HBO
      therapy.

PMID- 8644962
TI  - Prevalence study of domestic violence victims in an emergency department.
AB  - STUDY OBJECTIVE: In 1992, a study of the prevalence and predictors of domestic
      violence victims among individuals who presented to a major public hospital
      emergency department was conducted to replicate a study conducted by the authors
      in the same setting 12 months previously. The second study aimed to investigate
      more accurately the presentation of current victims of domestic violence to the
      ED. METHODS: In a retrospective, cross-sectional study, a screening questionnaire
      was administered to participants to establish the prevalence of a history and
      current presentation of domestic violence problems among patients who presented
      to the ED of a major public hospital. The study group comprised a representative
      sample of 670 male and 553 female adults (older than 16 years) who presented to
      all sections of a public hospital ED during 53 randomly selected 8-hour nursing
      shifts over an 8-week period in 1992. RESULTS: The results of the second
      prevalence study confirmed those of the first study. Of the 1,223 respondents in
      the study, 15.5% disclosed a history of adult domestic violence (8.5% of men,
      23.9% of women). Women were at greater risk than men for abuse as adults (raw
      relative risk [RR], 3.27; 95% confidence interval [CI], 2.23 to 4.79; RR adjusted
      for age, history of child abuse, and country of birth, 4.13; CI, 2.86 to 5.95).
      Women were at greater risk than men for being doubly abused (as a child and as an
      adult)(raw RR, 2.17; CI, 1.33 to 3.53). The second prevalence study confirmed
      what had been indicated in the first study: that 2.0% of women who presented to
      the ED (11.6% of all women with a history of adult domestic violence) were
      current victims of domestic violence and that these women presented mainly
      between the hours of 5 pm and 8 am, when no social work services were available
      for referral of victims. CONCLUSION: These Australian studies support the
      findings of prevalence studies of domestic violence victims in ED in the United
      States. The prevalence and risk factors indicate the need for training of
      physicians and nurses in the ED about domestic violence and for provision of
      appropriate backup referral services such as after-hours social work services.

PMID- 8644963
TI  - Increasing emergency physician recognition of domestic violence.
AB  - STUDY OBJECTIVE: To determine whether recognition of domestic violence in the
      emergency department is affected by restructuring of the ED chart to include a
      specific question about domestic violence, to evaluate whether training
      concerning domestic violence further increases its recognition, and to develop a
      profile of women who present to the ED as a result of domestic violence. METHODS:
      We collected prospective data on all females aged 15 to 70 years who presented to
      an urban Level I trauma center during a 3-month period. Two keywords were used to
      define domestic violence: (1) mechanism (eg, kicked, hit, pushed) and (2)
      perpetrator (eg, current/former boyfriend, spouse). We used the first month to
      define the baseline number of domestic violence cases. We modified charts in the
      second and third months (intervention months) to include, "Is the patient a
      victim of domestic violence?" In addition, the third month included a 1-hour
      educational lecture on the identification of domestic violence in the ED.
      RESULTS: We identified 123 cases of domestic violence from a survey population of
      4,073: 25 (2.0%) in the baseline month, 49 (3.4%) in the chart-modification
      month, and 49 (3.6%) in the education month. The proportion of cases identified
      during the intervention months was 1.8 times higher than during the control month
      (relative risk [RR], 1.78; 95% confidence interval [CI], 1.15 to 2.75), but did
      not differ between each other (RR, 1.06; 95% CI, .72 to 1.57). Women identified
      as domestic violence cases ranged in age from 15 to 61 years (median, 28.5
      years). Most of the identified domestic violence patients presented with a triage
      classification of assault (54.5%), trauma (8.1%), or abdominal complaints (7.3%).
      Triage complaint differed for domestic violence and non-domestic violence cases
      (chi 2 = 830; P < .0001). Nearly one third of domestic violence patients (31.7%)
      presented between 11 PM and 6:59 AM, compared with 19.0% of non-domestic violence
      patients (chi 2 = 12.4; P = .005). CONCLUSION: Modification of the chart
      significantly increased the recognition rate of domestic violence. An education
      intervention did not significantly improve this rate. The profile of a woman
      presenting to the ED differs from those of other women with respect to chief
      complaint and time of presentation.

PMID- 8644964
TI  - Development and validation of an emergency department screening and referral
      protocol for victims of domestic violence.
AB  - STUDY OBJECTIVE: To describe the development, design, and validation of an
      emergency department protocol for the identification, documentation, and referral
      of victims of domestic violence. METHODS: We based protocol development and
      design on a departmental needs assessment. The validation component involved the
      screening of women 16 years and older treated in the ED during a 2-week period at
      both triage (stage 1) and nursing assessment (stage 2). Sensitivity and
      specificity of the triage screen were determined. RESULTS: The departmental needs
      assessment revealed several important limiting factors that motivated the design
      of the protocol. In response, the protocol design included a two-stage screening
      process, stage 1 taking place at triage and stage 2 as part of the nursing
      assessment. During the 2-week validation study, 595 women 16 years and older were
      treated in the ED, but complete two-stage screening data were obtained for only
      114 (19%). Of the patients who were appropriately screened, eight screened
      positive at stage 1 and two of the eight were confirmed at stage 2. Two
      additional cases were identified at stage 2 in whom violence had not been
      suspected at stage 1. Triage screen sensitivity was 50%, specificity 95%. Of the
      women properly screened at both stages, 3.5% were identified as victims of
      domestic violence. CONCLUSION: We identified many obstacles to implementation of
      an ED domestic violence screening and referral protocol, demonstrating that
      evaluation is imperative in determining actual clinical impact.

PMID- 8644965
TI  - Domestic violence: issues for health care providers.

PMID- 8644966
TI  - Domestic violence.

PMID- 8644967
TI  - Domestic violence: clues to victimization.

PMID- 8644969
TI  - Overcoming barriers to physician involvement in identifying and referring victims
      of domestic violence.

PMID- 8644968
TI  - Violence against women: response from clinicians.

PMID- 8644970
TI  - Blood culture in children with pneumonia.

PMID- 8644971
TI  - Cervical spine epidural abscess in a patient with no predisposing risk factors.
AB  - We report a case of cervical spine epidural abscess in a 50-year-old man with a 4
      day history of neck pain but no neurologic deficits or fever. The patient had no
      predisposing risk factors such as recent spinal surgery, trauma, instrumentation,
      distal site of infection, immunosuppression, diabetes, or i.v. drug abuse. A
      review of the literature follows.

PMID- 8644972
TI  - Acute renal toxicity after ingestion of Lava light liquid.
AB  - A 65-year-old man with a history of alcohol abuse and seizure disorder presented
      to the emergency department with altered mental status, increased anion gap
      acidosis, phenytoin toxicity, and acute kidney failure. The patient had ingested
      the liquid contents of a Lava light, which contained chlorinated paraffin,
      polyethylene glycol (molecular weight 200), kerosene, and micro-crystalline wax.
      Gas chromatography-mass spectrophotometry of the patient's blood produced results
      consistent with the same analysis of the Lava light contents. After 3 days of
      declining mental status and worsening kidney function, the patient required
      hemodialysis. After a prolonged hospitalization, the patient was discharged home
      with residual renal insufficiency. Although multifactorial, the associated renal
      toxicity was most probably related to the low molecular weight polyethylene
      glycol content of the lamp's liquid contents.

PMID- 8644973
TI  - Methemoglobinemia from perineal application of an anesthetic cream.
AB  - A 34-year-old woman presented with cyanosis and a methemoglobin level of 23.2%
      after perineal application of a topical anesthetic cream containing 20%
      benzocaine. Many commonly used products contain high levels of benzocaine, and
      their use can lead to life-threatening methemoglobin levels. This case reinforces
      the need for stricter guidelines for product use and warning labels to alert
      consumers to this potential side effect of topical benzocaine-containing products
      sold over the counter.

PMID- 8644974
TI  - Perceptions, deceptions, psychosis, and reflections.

PMID- 8644976
TI  - Mefloquine-induced psychosis.

PMID- 8644975
TI  - Fentanyl neurotoxicity.

PMID- 8644977
TI  - Reinventing the emergency department.

PMID- 8644978
TI  - Clinical policy for the initial approach to adolescents and adults presenting to
      the emergency department with a chief complaint of headache. American College of
      Emergency Physicians.

PMID- 8644979
TI  - Domestic violence: the role of emergency medical services personnel. American
      College of Emergency Physicians.

PMID- 8644980
TI  - Violence-free society. American College of Emergency Physicians.

PMID- 8644981
TI  - Guidelines of care for cruise ship medical facilities. American College of
      Emergency Physicians.

PMID- 8644982
TI  - Immunization of the adult patient in the emergency department. American College
      of Emergency Physicians.

PMID- 8644983
TI  - The long-term clinical course of acute deep venous thrombosis.
AB  - BACKGROUND: In patients who have symptomatic deep venous thrombosis, the long
      term risk for recurrent venous thromboembolism and the incidence and severity of
      post-thrombotic sequelae have not been well documented. OBJECTIVE: To determine
      the clinical course of patients during the 8 years after their first episode of
      symptomatic deep venous thrombosis. DESIGN: Prospective cohort study. SETTING:
      University outpatient thrombosis clinic. PATIENTS: 355 consecutive patients with
      a first episode of symptomatic deep venous thrombosis. MEASUREMENTS: Recurrent
      venous thromboembolism, the post-thrombotic syndrome, and death. Potential risk
      factors for these outcomes were also evaluated. RESULTS: The cumulative incidence
      of recurrent venous thromboembolism was 17.5% after 2 years of follow-up (95% CI,
      13.6% to 22.2%), 24.6% after 5 years (CI, 19.6% to 29.7%), and 30.3% after 8
      years (CI, 23.6% to 37.0%). The presence of cancer and of impaired coagulation
      inhibition increased the risk for recurrent venous thromboembolism (hazard
      ratios, 1.72 [CI, 1.31 to 2.25] and 1.44 [CI, 1.02 to 2.01], respectively). In
      contrast, surgery and recent trauma or fracture were associated with a decreased
      risk for recurrent venous thromboembolism (hazard ratios, 0.36 [CI, 0.21 to 0.62]
      and 0.51 [CI, 0.32 to 0.87], respectively). The cumulative incidence of the post
      thrombotic syndrome was 22.8% after 2 years (CI, 18.0% to 27.5%), 28.0% after 5
      years (CI, 22.7% to 33.3%), and 29.1% after 8 years (CI, 23.4% to 34.7%). The
      development of ipsilateral recurrent deep venous thrombosis was strongly
      associated with the risk for the post-thrombotic syndrome (hazard ratio, 6.4; CI,
      3.1 to 13.3). Survival after 8 years was 70.2% (CI, 64.7% to 75.6%). The presence
      of cancer increased the risk for death (hazard ratio, 8.1; CI, 3.6 to 18.1).
      CONCLUSION: Patients with symptomatic deep venous thrombosis, especially those
      without transient risk factors for deep venous thrombosis, have a high risk for
      recurrent venous thromboembolism that persists for many years. The post
      thrombotic syndrome occurs in almost one third of these patients and is strongly
      related to ipsilateral recurrent deep venous thrombosis. These findings challenge
      the widely adopted use of short-course anticoagulation therapy in patients with
      symptomatic deep venous thrombosis.

PMID- 8644984
TI  - Deletion polymorphism of the angiotensin I-converting enzyme gene is associated
      with increased plasma angiotensin-converting enzyme activity but not with
      increased risk for myocardial infarction and coronary artery disease.
AB  - BACKGROUND: Previous research has shown that the insertion/deletion (I/D)
      polymorphism of the angiotensin I-converting enzyme (ACE) gene is a major
      determinant of plasma ACE activity. It has been suggested that persons with the
      DD genotype (those who express, on average, the highest levels of circulating
      ACE) have an increased risk for myocardial infarction and coronary artery
      disease, particularly if they are otherwise at low risk. Subsequent studies,
      however, have not confirmed that ACE I/D gene polymorphism is a risk factor for
      coronary artery disease and myocardial infarction. OBJECTIVE: To investigate the
      association between the I/D polymorphism of the ACE gene and the risk for
      coronary artery disease and myocardial infarction in patients in whom coronary
      artery disease status was documented by angiography. DESIGN: Cross-sectional
      study. SETTING: University medical center. PATIENTS: 209 male case-patients with
      coronary artery disease and 92 male controls without coronary artery disease, as
      documented by coronary angiography. MEASUREMENTS: Assessment of the cardiac risk
      profile by questionnaire; classification of patients by the degree of coronary
      artery stenosis; levels of lipoproteins, apolipoproteins, and fibrinogen; and ACE
      I/D gene polymorphism assessed by polymerase chain reaction amplification.
      RESULTS: Plasma ACE activity was significantly associated with ACE I/D gene
      polymorphism. The ACE genotype was not associated with the presence of coronary
      artery disease or myocardial infarction. If a recessive effect of the D allele
      was assumed (DD compared with DI and II), the relative risk was 1.00 (95% CI,
      0.76 to 1.30) for coronary artery disease and 1.03 (CI, 0.77 to 1.38) for
      myocardial infarction. Results of analyses were also negative when a dominant
      effect of the D allele was assumed and when low-risk subgroups were examined. The
      established risk factors age and apolipoprotein B level emerged as the most
      important risk predictors in multivariate analyses, followed by diastolic blood
      pressure and fasting glucose levels. CONCLUSIONS: In an angiographically defined
      study sample, ACE I/D gene polymorphism was not associated with an increased risk
      for coronary artery disease or myocardial infarction, despite its effects on
      plasma ACE activity.

PMID- 8644985
TI  - Somatostatin receptor scintigraphy: its sensitivity compared with that of other
      imaging methods in detecting primary and metastatic gastrinomas. A prospective
      study.
AB  - OBJECTIVE: To compare the sensitivity of somatostatin receptor scintigraphy done
      using [111In-DTPA-DPhe1]octreotide with that of other imaging methods in the
      localization of gastrinomas in patients with the Zollinger-Ellison syndrome.
      DESIGN: Prospective study. SETTING: Referral-based clinical research center.
      PATIENTS: 80 consecutive patients with the Zollinger-Ellison syndrome.
      INTERVENTIONS: Conventional tumor localization studies (ultrasonography, computed
      tomography [CT], magnetic resonance imaging [MRI], selective angiography, and
      bone scanning) and somatostatin receptor scintigraphy done using [111In-DTPA
      DPhe1]octreotide with single-photon emission CT imaging at 4 and 24 hours.
      Patients with possible liver metastases had biopsies done for confirmation, and
      15 patients had exploratory laparotomies done to assess primary tumor
      localization. RESULTS: Extrahepatic gastrinomas or liver metastases were
      identified by ultrasonography in 19% of patients, by CT in 38% of patients, by
      MRI in 45% of patients, by angiography in 40% of patients, and by somatostatin
      receptor scintigraphy in 70% of patients. Somatostatin receptor scintigraphy was
      as sensitive as the other tests combined (59%), and when the results of all other
      tests were added to the somatostatin receptor scintigraphy results, tumors were
      localized in 75% of patients. Among patients with a possible primary tumor, the
      results of ultrasonography were positive in 9%, the results of CT were positive
      in 31%, the results of MRI were positive in 30%, the results of angiography were
      positive in 28%, and the results of somatostatin receptor scintigraphy were
      positive in 58%. Somatostatin receptor scintigraphy was as sensitive as all of
      the other imaging studies combined; when the results of scintigraphy were added
      to the results of the other studies, possible primary tumors were identified in
      68% of patients. In 24 patients who had histologically proven metastatic liver
      disease, sensitivities for the detection of any metastatic liver lesions were 46%
      for ultrasonography, 42% for CT, 71% for MRI, 62% for angiography, and 92% for
      somatostatin receptor scintigraphy. Somatostatin receptor scintigraphy was
      significantly better than all of the conventional imaging methods in the
      identification of gastrinomas later found at surgery (P = 0.004), but it still
      missed 20% of gastrinomas. CONCLUSIONS: Somatostatin receptor scintigraphy is the
      single most sensitive method for imaging either primary or metastatic liver
      lesions in patients with the Zollinger-Ellison syndrome. Because of its
      sensitivity, simplicity, and cost-effectiveness, it should be the first imaging
      method used in these patients. For patients with negative results on somatostatin
      receptor scintigraphy, guidelines about the use of other imaging studies are
      proposed.

PMID- 8644986
TI  - Nonsustained ventricular tachycardia in coronary artery disease: relation to
      inducible sustained ventricular tachycardia. MUSTT Investigators.
AB  - BACKGROUND: Many physicians believe that electrocardiographic characteristics of
      nonsustained ventricular tachycardia correlate with the risk for sudden death in
      survivors of myocardial infarction. Sustained ventricular tachycardia induced by
      programmed electrical stimulation has also been shown to predict sudden death.
      OBJECTIVE: To determine whether electrocardiographic characteristics of
      spontaneous nonsustained ventricular tachycardia can predict the inducibility of
      sustained ventricular tachycardia by programmed electrical stimulation in
      patients with coronary artery disease having abnormal ventricular function.
      DESIGN: Observational cohort study. SETTING: 70 clinical electrophysiology
      laboratories in the United States and Canada. PATIENTS: 1480 consecutive patients
      with coronary artery disease, left ventricular ejection fraction of 0.40 or less,
      and asymptomatic nonsustained ventricular tachycardia. INTERVENTION:
      Electrophysiologic study attempting to induce sustained monomorphic ventricular
      tachycardia. MEASUREMENTS: Daily frequency, duration, and cycle length of
      spontaneous episodes of nonsustained ventricular tachycardia, measured by
      standard electrocardiographic recordings. RESULTS: No statistically significant
      difference in the frequency or duration of spontaneous nonsustained ventricular
      tachycardia was seen between patients with and those without inducible sustained
      ventricular tachycardia. Rates of spontaneous tachycardia were slightly slower in
      patients with inducible ventricular tachycardia than in patients without
      inducible ventricular tachycardia (P = 0.047), but the difference was not
      clinically significant. CONCLUSION: Electrocardiographic characteristics of
      spontaneous nonsustained ventricular tachycardia do not predict which patients
      with coronary artery disease will have inducible sustained ventricular
      tachycardia.

PMID- 8644987
TI  - Update in cardiology.

PMID- 8644988
TI  - Anthracycline-induced cardiotoxicity.
AB  - PURPOSE: To review the current understanding of the clinical significance,
      detection, pathogenesis, and prevention of anthracycline-induced cardiotoxicity.
      DATA SOURCES: A MEDLINE search of the English-language medical literature and a
      manual search of the bibliographies of relevant articles, including abstracts
      from national cardiology meetings. STUDY SELECTION: Pertinent clinical and
      experimental studies addressing the clinical relevance, pathogenesis, detection,
      and prevention of anthracycline cardiotoxicity were selected from peer-reviewed
      journals without judgments about study design. A total of 137 original studies
      and 9 other articles were chosen. DATA EXTRACTION: Data quality and validity were
      assessed by each author independently. Statistical analysis of combined data was
      inappropriate given the differences in patient selection, testing, and follow-up
      in the available studies. DATA SYNTHESIS: Anthracycline-induced cardiotoxicity
      limits effective cancer chemotherapy by causing early cardiomyopathy, and it can
      produce late-onset ventricular dysfunction years after treatment has ceased.
      Detection of subclinical anthracycline-induced cardiomyopathy through resting
      left ventricular ejection fraction or echocardiographic fractional shortening is
      suboptimal. Conventional doses of anthracycline often lead to permanent
      myocardial damage and reduced functional reserve. Underlying pathogenetic
      mechanisms may include free-radical-mediated myocyte damage, adrenergic
      dysfunction, intracellular calcium overload, and the release of cardiotoxic
      cytokines. Dexrazoxane is the only cardioprotectant clinically approved for use
      against anthracyclines, and it was only recently introduced for selected patients
      with breast cancer who are receiving anthracycline therapy. CONCLUSIONS: A
      rapidly growing number of persons, including an alarming fraction of the 150 000
      or more adults in the United States who have survived childhood cancer, will have
      substantial morbidity and mortality because of anthracycline-related cardiac
      disease. The development of effective protection against anthracycline-induced
      cardiotoxicity will probably have a significant effect on the overall survival of
      these patients.

PMID- 8644989
TI  - Physician-run health plans and antitrust. American College of Physicians.
AB  - As the health care system changes and large managed care entities gain greater
      control in some markets, proponents of antitrust reform have expressed concern
      that physicians could lose their autonomy. To respond to this concern, the
      American College of Physicians has consistently argued that physicians should be
      allowed to establish their own health plans and networks to provide high-quality
      and cost-effective care. Moreover, the College has advocated utilization review
      reform and due process protections to empower physicians in their dealings with
      insurers. Under current antitrust law, as interpreted by the federal enforcement
      agencies, physicians already have the legal authority to form their own health
      plans and networks, and many state medical societies are sponsoring such plans.
      The law also allows physicians to operate the clinical components of a health
      plan, regardless of who owns it. Moreover, physicians can share information about
      quality, utilization, and, in some circumstances, fees. An examination of federal
      enforcement agency actions since the mid-1970s shows that physician networks have
      rarely been challenged. In light of market developments, however, the College has
      urged the federal antitrust agencies to analyze the effect of their current
      enforcement policies on physician activities and adopt a more flexible approach.
      Further monitoring and analysis of the changing health care marketplace are
      necessary to ensure that physicians are being treated fairly and to determine
      which factors spur or inhibit the development of physician-run health plans and
      networks.

PMID- 8644990
TI  - Mandated choice for organ donation: time to give it a try.
AB  - A severe shortage of organs greatly limits the ability to deliver the miracle of
      transplantation to people suffering from end-stage organ disease. Contributing to
      this shortage is a high rate of refusal among families who are asked for
      permission to remove organs from a recently deceased relative. Mandated choice
      offers an alternative to obtaining consent from the family by returning control
      to the individual. This plan would require all adults to record their wishes
      about posthumous organ donation and would consider those wishes binding. By
      moving the decision-making process to a relaxed setting and ensuring that a
      person's wishes would be honored, mandated choice would hopefully take advantage
      of favorable public attitudes toward donation and thereby facilitate organ
      procurement. Preliminary research suggests that public commitment to organ
      donation would increase under mandated choice. A pilot study of this promising
      proposal should be undertaken.

PMID- 8644992
TI  - Farewell to the "Shy-Drager syndrome".

PMID- 8644991
TI  - Who are the donors in organ donation? The family's perspective in mandated
      choice.
AB  - Evidence that families requested to permit organ donation refuse half the time
      has led to proposals for mandated choice. Under mandated choice, a person's
      donation wishes would be collected and retrieved at death, and requests to
      families would be avoided. There are both ethical and logistic problems with
      mandated choice. The view of the family should be respected in organ requests,
      even when patient wishes are known. Public sentiment against overriding family
      wishes could cause low rates of pro-donation registration. Caregivers have
      usually refused to take organs when families oppose donation. Logistic issues
      with mandated choice include the cost and complexity of maintaining a national
      database on donors and the enforcement of registration. No such database of
      adults currently exists, even for tax purposes. Two states that have mandated
      choice programs through departments of motor vehicles report relatively low
      number of pro-donation registrants compared with nondonors or undecided persons.
      Public education and voluntary donor identification hold more potential to
      increase donation.

PMID- 8644993
TI  - Three-year follow-up on effects of transdermal estrogen.

PMID- 8644994
TI  - Medical heuristics.

PMID- 8644995
TI  - Medical heuristics.

PMID- 8644996
TI  - The appropriateness of coronary artery bypass graft surgery in academic medical
      centers. Working Group of the Appropriateness Project of the Academic Medical
      Center Consortium.
AB  - OBJECTIVE: To compare the appropriateness of use of coronary artery bypass graft
      (CABG) surgery in Academic Medical Center Consortium hospitals as judged 1)
      according to criteria developed by an expert panel, 2) according to revisions of
      those criteria made by cardiac surgeons from the Academic Medical Center
      Consortium, and 3) by review of cases by the surgeons responsible for those
      cases. DESIGN: Retrospective, randomized medical record review. SETTING: 12
      Academic Medical Center Consortium hospitals. PATIENTS: Random sample of 1156
      patients who had had isolated CABG surgery in 1990. MAIN OUTCOME MEASURES: 1)
      Percentage of patients with indications for which CABG surgery was classified as
      appropriate, Inappropriate, or of uncertain appropriateness and 2) percentage of
      cases in which CABG surgery was judged inappropriate or uncertain for which
      ratings changed after local case review. RESULTS: Data were retrieved from
      medical records by trained abstractors using an explicit data collection
      instrument. Cases in which CABG surgery was judged to be inappropriate or
      uncertain were individually reviewed by the responsible surgeons. According to
      the expert panel ratings, 83% of the CABG operations (95% CI, 81% to 85%) were
      necessary, 9% (CI, 8% to 10%) were appropriate, 7% (CI, 5% to 8%) were uncertain,
      and 1.6% (CI, 0.6% to 2.5%) were inappropriate. These rates are almost identical
      to those found in a previous study that was done in New York State and that used
      the same criteria (in that study, 91% of operations were classified as necessary
      or appropriate, 7% were classified as uncertain, and 2.4% were classified as
      inappropriate). Rates of inappropriate procedures varied from 0% to 5% among the
      12 member hospitals (P = 0.02). The Academic Medical Center Consortium cardiac
      surgeons revised 568 (24%) of the indications used by the expert panel. However,
      because those revisions altered the appropriateness ratings in both directions
      and affected only 50 cases (4%), the net effect of the revisions was slight: The
      rate of inappropriate CABG surgery increased from 1.6% to 1.9%. Local review
      found that data collection errors had caused erroneous ratings in 12.5% of 64
      cases in which surgery had been classified as inappropriate or uncertain.
      CONCLUSIONS: The Academic Medical Center Consortium hospitals had low rates of
      inappropriate and uncertain use of CABG surgery, regardless of the criteria used
      for assessment. Even though surgeons from the Consortium revised the
      appropriateness ratings extensively, their revisions had a negligible effect on
      the overall assessment of appropriateness. However, because of potential data
      collection errors, appropriateness criteria should be used for individual case
      audits only if supplemented by subsequent physician review.

PMID- 8644997
TI  - Purification of the 11- and 5-kDa antibacterial polypeptides from guinea pig
      neutrophils.
AB  - It has been known that neutrophils contain various antimicrobial components in
      the granules, which contribute to the oxygen-independent host defense mechanism.
      In this study, we have isolated the two antimicrobial polypeptides from guinea
      pig neutrophil granules. Urea-SDS-PAGE analysis revealed that the molecular
      masses of the polypeptides were 11 and 5 kDa under nonreducing conditions. Under
      reducing conditions, the molecular mass of the 5-kDa polypeptide did not change,
      whereas the molecular mass of the 11-kDa polypeptide changed to about 5 kDa,
      suggesting that the 11-kDa polypeptide is a dimer composed of 5-kDa subunits
      joined with a disulfide bond. The amino acid composition and sequence data
      indicated that the 5-kDa subunit of the 11-kDa polypeptide contained 9 lysine, 8
      arginine, and 1 cysteine residues and that the 11-kDa polypeptide was a homodimer
      of G1LRKKFRKTRKRIQKLGRKIGKTGRKVWKAWREYGQIPYPCRI43 (4599 Da) joined with one
      disulfide bond. Amino acid sequence of the 11-kDa polypeptide showed partial
      homology (19-30%) to the active peptides of rabbit and human cationic
      antimicrobial proteins of 18 kDa (CAP18), suggesting the 11-kDa polypeptide might
      be a homologue of CAP18. In contrast, the amino acid analysis of the 5-kDa
      antibacterial polypeptide revealed that the polypeptide was composed of 41 amino
      acids (5007 Da) containing 7 lysine, 10 arginine, and 2 cystine residues.
      However, sequence analysis indicated that the N-terminus of the 5-kDa polypeptide
      was likely blocked. The 11- and 5-kDa polypeptides showed almost the same
      antibacterial activities; ED50 values were 30-35 nM against Escherichia coli and
      90-120 nM against Staphylococcus aureus, which were 4- to 20-fold lower than
      those of defensins. Furthermore, the 11- and 5-kDa polypeptide retained the
      antibacterial activities even at the physiological concentration of NaCl (0.15
      M), although the antibacterial activity of defensin was completely lost in the
      presence of NaCl.

PMID- 8644998
TI  - Modulation of protein kinase C-related signal transduction by 2,3,7,8
      tetrachlorodibenzo-p-dioxin exhibits cell cycle dependence.
AB  - The modulation of protein kinase C (PKC)-mediated protein phosphorylation in
      quiescent vascular smooth muscle cells (SMCs) by 2,3,7,8-tetrachlorodibenzo-p
      dioxin (TCDD) exhibits a discrete temporal pattern in which early reductions of
      kinase activity are followed by marked increases in activity. This profile may be
      accounted for by transcriptional- and/or cell cycle-related effects of TCDD. To
      test this hypothesis, experiments were conducted to examine the influence of TCDD
      on PKC activity during different phases of the cell cycle in vascular (aortic)
      SMCs. Increased PKC activity was observed in the cytosolic and particulate
      fractions of randomly cycling SMC cultures derived from female rats treated in
      vivo with 10 microgram/kg TCDD relative to corn oil. Treatment of cycling naive
      SMC cultures with TCDD (0.1 to 1000 nM) for 0.5 h caused a concentration
      dependent increase of particulate PKC activity and no changes in cytosolic
      counterparts. Extended challenge of SMCs with TCDD for 24 h increased PKC
      activity in both cellular fractions. Incubation of SMCs with various
      concentrations of fetal bovine serum for 72 h to differentially regulate cell
      cycling followed by challenge with 10 nM TCDD for 24 h reduced cytosolic and
      particulate PKC activity in quiescent cells, but enhanced activity in cycling
      cells. To determine if this serum-related profile was strictly dependent upon
      cell cycle-related events, SMCs were synchronized in the G0 phase and then pulsed
      with 10 nM TCDD during different phases of the cell cycle. Differential profiles
      were observed where reduced C-kinase activity occurred during the G0/G1
      transition followed by increases during G1/S and no changes during S. Western
      blot analysis confirmed the patterns of PKC activity observed during the G0/G1
      and G1/S transitions. PKCalpha, beta II, and delta isoforms were reduced during
      G0/G1, while only PKCbetaII and delta were increased during G1/S. These data show
      that modulation of PKC by TCDD in vascular SMCs exhibits cell cycle dependence
      and isoform specificity.

PMID- 8644999
TI  - Extracellular zinc ions induces mitogen-activated protein kinase activity and
      protein tyrosine phosphorylation in bombesin-sensitive Swiss 3T3 fibroblasts.
AB  - The growth factor-like effect of zinc in vitro and in vivo, which has long been
      recognized was investigated with respect to its mechanisms of action. Addition of
      zinc chloride to bombesin-sensitive Swiss 3T3 mouse fibroblasts induced a
      fourfold stimulation in the cytosolic myelin basic protein kinase activity. The
      response was dose- and time-dependent, with an ED50 of around 100 microM and a
      peak at 5 min. The kinase activity coeluted with p42 MAP kinase using
      chromatography on Mono-Q ion exchange. Intracellular loading of cells with the
      heavy metal chelator BTC-5N did not attenuate the response to zinc. The action of
      zinc was not suppressed by long-term pretreatment with 4-beta-phorbol dibutyrate
      (48 h). Addition of 0.3 mM vanadate alone did not increase the kinase activity,
      but prolonged the action of zinc when added simultaneously. Addition of zinc (0.3
      mM) or epidermal growth factor for 1 min resulted in a marked increase in
      tyrosine phosphorylation of proteins with apparent molecular weights of
      approximately 100, 105-120, 215, and 240 kDa in whole cell extracts.
      Immunoprecipitation against the p85 subunit of phosphatidylinositol 3-kinase
      resulted in the appearance of two phosphotyrosine-containing proteins, 100 and
      115 kDa, in extracts from cells treated with zinc or epidermal growth factor,
      indicating that the tyrosine phosphorylation was recognized by the corresponding
      SH2-domains. The present study demonstrates that extracellular zinc has the
      potential to partially mimic the action of growth factors on intracellular MAP
      kinase activation and protein tyrosine phosphorylation.

PMID- 8645000
TI  - The calcium sensor ruthenium red can act as a Fenton-type reagent.
AB  - Ruthenium red (RR), an ammoniated form of tris-ruthenium(III,IV,III) oxychloride,
      has been widely used in the micromolar range as a strong and specific inhibitor
      of in vitro and in vivo Ca(2+)-mediated biochemical processes without regard for
      its redox properties. We show here that in the presence of tert-butyl
      hydroperoxide (TBHP) and an electron source, either succinate-energized rat liver
      mitochondria or ascorbate, RR amplifies the generation of methyl radicals. The
      EPR spin trapping signal of the 5,5-dimethyl-1-pyrroline-N-oxide/methyl radical
      (DMPO/.CH3) adduct obtained from incubations of TBHP (1.5 mM) and mitochondria (5
      mg protein/ml) in an adequate medium increases upon addition of RR in a
      concentration-dependent fashion: sixfold at 10 microM RR. Respiring mitochondria
      can be replaced by ascorbate (1 mM), the characteristic EPR signal of the
      ascorbyl radical also being observed (aH = 0.18 mT). Spectrophotometric, cyclic
      voltammetric and spectroelectrochemical studies unequivocally show oxidation of
      RR(III,IV,III) (lambda max = 538 nm) to the ruthenium(IV,III,IV) species
      ("ruthenium brown," RB; lambda max = 464 nm) by TBHP, followed by its one
      electron back reduction to RR by the respiratory chain or ascorbate. The calcium
      chelator EGTA (1 mM) strongly binds and stabilizes the RR form, slowing down its
      recycling by TBHP and either ascorbate or the mitochondrial electron chain. These
      data clearly show that Ru(III) in the RR complex can reduce TBHP via a Fenton
      type reaction and thus must be considered when RR is used as a tool to study
      biological processes simultaneously involving Ca2+ ions and peroxides.

PMID- 8645001
TI  - Characterization of the n-alkane and fatty acid hydroxylating cytochrome P450
      forms 52A3 and 52A4.
AB  - Two enzymes, P450 52A3 (P450Cm1) and 52A4 (P450Cm2), the genes of which belong to
      the CYP52 multigene family occurring in the alkane-assimilating yeast Candida
      maltosa, have been characterized biochemically and compared in terms of their
      substrate specificities. For this purpose, both the p450 proteins and the
      corresponding C. maltosa NADPH-cytochrome P450 reductase were separately produced
      by expressing their cDNAs in Saccharomyces cerevisiae, purified, and
      reconstituted to active monooxygenase systems. Starting from microsomal fractions
      with a specific content of 0.75 nmol P450Cm1, 0.34 nmol P450Cm2, and 10.5 units
      reductase per milligram of protein, respectively, each individual recombinant
      protein was purified to homogeneity. P450 substrate difference spectra indicated
      strong type I spectral changes and high-affinity binding of n-hexadecane (Ks= 26
      micron) and n-octadecane (Ks = 27 microM) to P450Cm1, whereas preferential
      binding to P450Cm2 was observed using lauric acid (Ks = 127 microM) and myristic
      acid (Ks = 134 microM) as substrates. These substrate selectivities were further
      substantiated by kinetic parameters, determined for n-alkane and fatty acid
      hydroxylation in a reconstituted system, which was composed of the purified
      components and phospholipid, as well as in microsomes obtained after coexpressing
      each of the P450 proteins with the reductase. The highest catalytic activities
      within the reconstituted system were measured for n-hexadecane hydroxylation to 1
      hexadecanol by P450Cm1 (Vmax = 27 microM x min-1, Km = 54 microM) and oxidation
      of lauric acid to 16-hydroxylauric acid by P450Cm2 (Vmax = 30 microM x min-1, Km
      = 61 microM). We conclude that P450Cm1 and P450Cm2 exhibit overlapping but
      distinct substrate specificities due to different chain-length dependencies and
      preferences for either n-alkanes or fatty acids.

PMID- 8645002
TI  - Allosteric regulation of liver phosphorylase a: revisited under approximated
      physiological conditions.
AB  - Phosphorylase removes glucosyl units from the terminal branches of glycogen
      through phosphorolysis, forming glucose-1-P. It is present in two
      interconvertible forms, phosphorylase a and b. The a form is the active form and
      is rate limiting in glycogen degradation. The activities of phosphorylase a and
      of total phosphorylase as conventionally measured exceed the activities of
      glycogen synthase R (active form) and of total synthase by approximately 10- and
      20-fold. Thus, unless phosphorylase a is inhibited or compartmentalized or its
      substrates are exceedingly low in vivo, net glycogen synthesis could not occur.
      In addition, following an administered dose of glucose, phosphorylase a activity
      changes little when glycogen is being synthesized, is stable, or is being
      degraded, suggesting an important role for allosteric effectors in regulation.
      Therefore, we have determined the effect of potential modifiers of enzyme
      activity at estimated intracellular concentrations. Purified liver phosphorylase
      a was used. Activity was measured in the direction of glycogenolysis, at 37
      degrees C, pH 7.0, and under initial rate conditions. Both a Km and a near
      saturating concentration of inorganic phosphate (substrate) were used in the
      assays. A physiological concentration of AMP was saturating. It decreased the Km
      for Pi by approximately 50% and stimulated activity. ADP, ATP, and glucose
      inhibited activity. Fructose-1-P inhibited activity only at a high and
      nonphysiological concentration. Glucose-6-P and UDP-glucose were not significant
      inhibitors. Inhibition of activity by ADP was little affected by the addition of
      AMP. However, AMP partially abolished the inhibitory effect of ATP and completely
      abolished the inhibitory effect of glucose. When AMP, ADP, ATP, glucose-6-P, UDP
      glucose, glucose, and fructose-1-P were added together, the net effect was no
      change in phosphorylase a activity compared to the activity without any
      effectors. In addition, changes in glucose concentration did not affect activity.
      K glutamine modestly stimulated activity. Numerous other metabolites were tested
      and were without effect. The present data indicate that the known endogenous
      allosteric effectors cannot explain the smaller than expected in vivo
      phosphorylase a activity or the regulation of phosphorylase a activity.

PMID- 8645003
TI  - Aldose reductase is a major reductase for isocaproaldehyde, a product of side
      chain cleavage of cholesterol, in human and animal adrenal glands.
AB  - Isocaproaldehyde (4-methylpentanal) is a product of the side-chain cleavage of
      cholesterol, the first step of steroid biosynthesis. Here, we report the
      characterization of enzymes responsible for the oxidoreduction of
      isocaproaldehyde in human, monkey, dog, and rabbit adrenal glands. NADPH-linked
      isocaproaldehyde reductase activity in the adrenal extracts of the four species
      was much higher than the NADH-linked reductase and NAD(P)(+)-linked dehydrogenase
      activities and was potently inhibited by aldose reductase inhibitors. The major
      species of isocaproaldehyde reductase purified from the four mammalian adrenal
      glands were biochemically identical with aldose reductase, and exhibited Km
      values of 1 microM. The contents of aldose reductase in adrenal glands of the
      four mammals were relatively high, and its localization in canine adrenal cortex
      was immunohistochemically demonstrated. In addition, the purified aldose
      reductases and recombinant human aldose reductase reduced other alkanals and
      alkenals at low Km values of 2-61 microM, and their catalytic efficiencies were
      higher than that of human aldehyde reductase. Thus, aldose reductase acts not
      only as a major reductase for isocaproaldehyde formed from steroidogenesis but
      also as a scavenger of aldehydes derived from lipid peroxidation in mammalian
      adrenal glands.

PMID- 8645004
TI  - Endogenous 7-oxocholesterol is an enzymatic product: characterization of 7 alpha
      hydroxycholesterol dehydrogenase activity of hamster liver microsomes.
AB  - Previously, we described a new metabolite derived from endogenous cholesterol in
      the presence of hamster liver microsomal protein and NADPH (Song et al., 1991,
      Biochem. Pharmacol. 41, 1439-1447). Through gas chromatography/mass spectral
      analysis of the metabolite and its methoxime-3-dimethyl-t-butylsilyl ether
      derivative, this metabolite has been definitively identified as 7-oxocholesterol.
      Isotope incorporation experiments using molecular 18O2 demonstrated that no
      oxygen atoms from molecular oxygen were incorporated into the product, 7
      oxocholesterol, when 7 alpha-hydroxycholesterol was used as substrate. In
      contrast, one atom of 18O was incorporated into cholesterol from 18O2 during its
      metabolism to form 7 alpha-hydroxycholesterol. Formation of 7-oxocholesterol was
      dependent upon the presence of NADP+, 7 alpha-hydroxycholesterol, and hamster
      liver microsomes. This enzyme appears to be a membrane-bound protein and its
      activity was most abundant in liver microsomal fractions and to a lesser extent
      in mitochondrial fractions; little or no activity was observed in nuclei or
      cytosol. The enzyme activity was present in highest content in the livers of
      hamsters and was also observed in human and bovine liver microsomes, but not
      those of mouse, rabbit, or rat. The reaction was inhibited by 2'-AMP, but not by
      anti-NADPH:cytochrome-P450 oxidoreductase globulin, carbon monoxide, metyrapone,
      nor miconazole. In contrast to the previously characterized 3 beta-hydroxy-delta
      5-C27-steroid oxidoreductase activity, NAD+ did not serve as an effective
      cofactor for 7-oxocholesterol formation. The ability of NADPH to partially serve
      as a cofactor in this reaction was shown to be due to a high NADPH-oxidase
      activity of hamster liver microsomes, thereby providing sufficient NADP+ to serve
      as the oxidizing pyridine nucleotide for the reaction. These results document the
      existence of a non-P450, NADP(+)-dependent 7 alpha-hydroxycholesterol
      dehydrogenase in liver microsomes which catalyzes this reaction. The product, 7
      oxocholesterol, is produced enzymatically in the livers of hamsters and other
      mammals and may regulate bile acid metabolism or other processes due to its
      action as an oxysterol.

PMID- 8645005
TI  - Rate-determining steps in the biosynthesis of glycogen in COS cells.
AB  - Consistent with previous results, overexpression of rabbit skeletal muscle
      glycogen synthase in COS cells did not lead to overaccumulation of glycogen
      unless activating Ser-->Ala mutations were present at key regulatory
      phosphorylation sites 2 (Ser7) and 3a (Ser644) in the enzyme. In addition, we
      found that expression of glycogenin, glycogen branching enzyme, or UDP-glucose
      pyrophosphorylase alone in COS cells had no effect on the glycogen level.
      However, coexpression of the hyperactive 2,3a glycogen synthase mutant with
      either glycogenin or UDP-glucose pyrophosphorylase led to higher glycogen
      accumulation than that obtained from the expression of glycogen synthase alone.
      Coexpression of glycogenin with the 2,3a mutant of glycogen synthase led to the
      appearance of glycogenin with a lower molecular weight suggestive of reduced
      glucosylation. Increased glycogen synthesis may lead to competition between
      glycogenin and glycogen synthase for their common substrate UDP-glucose. In
      summary, we conclude that (i) glycogen synthase is a primary rate-limiting enzyme
      of glycogen biosynthesis in COS cells, (ii) that phosphorylation of glycogen
      synthase is regulatory for glycogen accumulation, and (iii) once glycogen
      synthase is activated, the reaction mediated by UDP-glucose pyrophosphorylase can
      become rate-determining.

PMID- 8645007
TI  - Further characterization of Escherichia coli alanyl-tRNA synthetase.
AB  - Selected physical and thermodynamic parameters for Escherichia coli alanyl-tRNA
      synthetase (AlaRS) have been determined primarily to assess the quaternary
      structure of this enzyme. The extinction coefficient (epsilon) at 280 nm was
      determined experimentally to be 0.71 ml mg-1 cm-1, and the partial specific
      volume (nu) was calculated from the amino acid composition to be 0.73 ml g-1.
      From viscosity experiments the intrinsic viscosity (eta) of AlaRS was
      extrapolated to be 3.4 ml g-1 and the degree of hydration (delta 1) estimated to
      be 0.67 gH2O g(-1)(AlaRS). Laser light-scattering studies indicated some
      heterogeneity; a radius of 6.3 nm was calculated for the major fraction with a
      diffusion coefficient (D20,W) of 3.89 x 10(-7) cm2 s-1. In 50 mM Hepes, pH 7.5,
      20 mM KCl, 2 mM 2-mercaptoethanol and at a protein concentration of 4.2 mg ml-1
      the sedimentation coefficient (S20,W) was 6.36 S; this value increased slightly
      when the protein concentration was decreased. The combination of S20,W and D20,W
      under these conditions yielded a molecular weight of approximately 186,000 Da,
      corresponding to a dimer. The S20,W was virtually independent of temperature in
      the range of 10-37 degrees C, while an Arrhenius plot of aminoacylation activity
      was biphasic. The isoelectric point was determined experimentally to be 4.9.
      Sedimentation equilibrium data were best fit to a decamer association complex in
      which dimeric AlaRS is the predominant species at 25 degrees C.

PMID- 8645006
TI  - Control of hemoglobin synthesis in erythroid differentiating K562 cells. I. Role
      of iron in erythroid cell heme synthesis.
AB  - K562 cells were used to investigate the factors that control hemoglobin (Hb)
      synthesis. Treatment with sodium butyrate enhanced Hb synthesis and glycophorin A
      expression. delta-Aminolevulinate synthase (ALAS) activity and Hb levels
      simultaneously increased to a similar extent and with a similar time course, and
      the increases were dependent on the concentration of diferric transferrin (FeTf)
      in the culture medium. Addition of exogenous delta-aminolevulinic acid (ALA)
      resulted in a dose-dependent increase in Hb content. Hb synthesis was inhibited
      50% after addition of succinylacetone (SA), a potent inhibitor of delta
      aminolevulinate dehydratase. These findings suggest that ALAS is a key enzyme in
      the eight steps of de novo heme synthesis and that iron, including FeTf, plays a
      central role in Hb synthesis through control of ALAS activity in erythroid
      differentiating cells. On the other hand, erythropoietin (EPO) treatment had no
      effect on Hb synthesis and slightly suppressed glycophorin A expression. Hemin
      enhanced Hb synthesis in the K562 cells but not glycophorin A expression. The
      addition of ALA, SA, or FeTf to hemin-treated cells caused no significant changes
      in Hb synthesis. Butyrate, EPO, and hemin acted on the K562 cells in different
      ways and caused different biochemical changes in the Hb synthesis process.

PMID- 8645008
TI  - Purification and characterization of a heterodimeric 23/20-kDa proteolytic
      fragment of bacterial glutathione transferase B1-1.
AB  - The proteolytic attack of bacterial glutathione S-transferase (GSTB1-1) by
      trypsin cleaves and inactivates the enzyme. The polypeptide portion of GSTB1-1
      encompassing the cleavage site (Lys35-Lys36) constitutes an exposed and flexible
      region of the GSTB1-1 G-site. By sequentially using a benzamidine-affinity
      chromatography and GSH-affinity column, a proteolyzed form of GSTB1-1 (23/20
      kDa), in which only one subunit has been cleaved has been purified and
      characterized. Gel filtration, sequence analysis of subunits separated by HPLC,
      and CD experiments indicate that the 23/20-kDa GSTB1-1 form is a dimer and
      maintains its secondary structure. In addition, kinetic determinations reveal
      that the proteolytic cleavage of one polypeptide chain inactivates one active
      site but does not influence the catalytic efficiency of the second one. Previous
      refolding studies on GSTB1-1 have shown that the formation of a correct dimer
      precedes the recovery of the full activity of the enzyme, indicating that the
      dimeric structure is essential for catalytic activity of GSTB1-1. Thus, although
      GSTB1-1 active sites are catalytically independent and, probably, mainly located
      on each monomer, interactions deriving from the dimeric arrangement of the
      molecule appear essential for maintaining each active site in a fully active
      conformation. The catalytic independence of the two active sites, as well as the
      importance of dimeric structure for catalytic activity, has already been
      established for other GSTs. Thus, despite the very low sequence identity and
      kinetic differences between bacterial and other distant members of the GST
      superfamily, the results reported here indicate that important properties of the
      GST active site are conserved.

PMID- 8645009
TI  - Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial
      electron transport.
AB  - Various authors have suggested that nitric oxide (.NO) exerts cytotoxic effects
      through the inhibition of cellular respiration. Indeed, in intact cells .NO
      inhibits glutamate-malate (complex I) as well as succinate (complex II)-supported
      mitochondrial electron transport, without affecting TMPD/ascorbate (complex IV)
      dependent respiration. However, experiments in our lab using isolated rat heart
      mitochondria indicated that authentic .NO inhibited electron transport mostly by
      reversible binding to the terminal oxidase, cytochrome a3, having a less
      significant effect on complex II- and no effect on complex I-electron transport
      components. The inhibitory action of .NO was more profound at lower oxygen
      tensions and resulted in differential spectra similar to that observed in
      dithionite-treated mitochondria. On the other hand, continuous fluxes of .NO plus
      superoxide (O.(2)(-)), which lead to formation of micromolar steady-state levels
      of peroxynitrite anion (ONOO-), caused a strong inhibition of complex I- and
      complex II-dependent mitochondrial oxygen consumption and significantly inhibited
      the activities of succinate dehydrogenase and ATPase, without affecting complex
      IV-dependent respiration and cytochrome c oxidase activity. In conclusion, even
      though nitric oxide can directly cause a transient inhibition of electron
      transport, the inhibition pattern of mitochondrial respiration observed in the
      presence of peroxynitrite is the one that closely resembles that found secondary
      to .NO interactions with intact cells and strongly points to peroxynitrite as the
      ultimate reactive intermediate accounting for nitric oxide-dependent inactivation
      of electron transport components and ATPase in living cells and tissues.

PMID- 8645010
TI  - Kinetic characterization of human immunodeficiency virus type 1 protease:
      determination of inhibitor rate constants during dynamic monomer-dimer
      interconversion.
AB  - A numerical method was applied to a system of differential rate equations
      describing the monomer-dimer-inhibitor (M-D-I) interaction involving human
      immunodeficiency virus type 1 protease and a peptidomimetic, competitive
      inhibitor. Two pairs of progress curves were obtained, one involving the M-D
      interaction and the other the M-D-I interaction. Each pair of reactions was
      designed to begin with extreme conditions and end at the identical equilibrium
      position. The results were compared with analytical (exact mathematical) methods
      reported previously. Good agreement between the two methods was observed at high-
      and low-salt conditions for the rates of monomer association and dimer
      dissociation. Not surprisingly, however, the major difference was observed in the
      analyses involving the M-D-I interaction, since analytical methods cannot account
      for dimer dissociation in the presence of inhibitor. While the estimates for the
      inhibitor off rate were comparable for high-salt conditions (where dimer
      dissociation is minimized), the analytical method underestimated this parameter
      for low-salt conditions by an order of magnitude, the consequence of mistaking
      inactive M for inactive DI.

PMID- 8645011
TI  - Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA
      reductase in rat liver.
AB  - A recent report, in which cultured tumor cells were used, identified farnesol as
      the nonsterol mevalonate-derived metabolite required for the accelerated
      degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (C. C.
      Correll, L. Ng, and P. A. Edwards, 1994, J. Biol. Chem. 269, 17390-17393). We
      examined this proposed linkage in animals by measuring hepatic farnesol levels
      and rates of HMG-CoA reductase degradation under conditions previously shown to
      alter the stability of the reductase. In normal rats, the hepatic farnesol level,
      quantified by high-pressure liquid chromatography, was 0.10 +/- 0.08 microgram/g
      and the half-life of HMG-CoA reductase was 2.5 h. Administration of
      mevalonolactone at 1 g/kg body wt to provide all nonsterol metabolites in
      addition to cholesterol increased farnesol levels 6-fold without significantly
      affecting the half-life of the reductase. Treatment of rats with zaragozic acid
      A, an inhibitor of squalene synthase, raised hepatic farnesol levels 10-fold and
      decreased the half-life of HMG-CoA reductase to 0.25 h. However, feeding
      lovastatin to rats did not lower hepatic farnesol levels despite a marked
      stabilization of HMB-CoA reductase protein. Moreover, intubation of rats with 500
      mg/kg body wt of farnesol failed to decrease the half-life of HMG-CoA reductase
      protein, alter the levels of enzyme activity, or change of the levels of
      immunoreactive protein despite an increase of 1000-fold in hepatic farnesol
      levels. These observations indicate that farnesol per se does not induce
      accelerated degradation of HMG-CoA reductase in rat liver.

PMID- 8645012
TI  - Compression of cartilage results in differential effects on biosynthetic pathways
      for aggrecan, link protein, and hyaluronan.
AB  - The differential effects of static compression and recovery from compression on
      biosynthesis and biosynthetic pathways of aggrecan, link protein, and hyaluronan
      were assessed. During compression, biosynthesis of aggrecan and link protein were
      inhibited to approximately 25 and approximately 40%, respectively, of free
      swelling control levels. In marked contrast, hyaluronan synthesis was unaffected
      by static compression. After release from 12-h 50% static compression, aggrecan
      synthesis remained inhibited for up to 2.5 days; however, link protein synthesis
      completely recovered to free-swelling control levels within 8 h after release.
      Hyaluronan synthesis remained at control levels after release of compression.
      During compression, aggrecan core protein pool size was decreased, whereas the
      rate of processing into the proteoglycan form remained essentially the same as in
      free swelling control tissue. Four hours after release from compression, aggrecan
      core protein pool size remained small and the rate of intracellular processing of
      aggrecan had become slower than that of free swelling control tissue. Due to the
      altered core-protein processing kinetics, fewer but longer chondroitin sulfate
      chains were added to the core proteins. Sulfation was not markedly altered. The
      differential effects of static compression and release on the biosynthesis of
      aggrecan, link protein, and hyaluronan are similar to the changes in the
      biosynthetic pathways that are affected in response to IL-1 treatment, suggesting
      that the response to static compression is not a general inhibition of cellular
      activity, but appears to be part of a specific transduction mechanism.

PMID- 8645014
TI  - [New direction of cancer hormonal therapy--concepts of this issue].

PMID- 8645013
TI  - [Breast cancer angiogenesis].
AB  - Recent clinical investigations have confirmed that angiogenesis is a basic
      property of solid tumors as well as proliferation, invasion and metastasis. In
      addition to the fundamental analysis of tumor angiogenesis in clinical tumors,
      the focus has been on clinical applications of tumor angiogenesis.
      Representatives are applications for prognostic indicators of primary breast
      tumor and for antiangiogenesis therapy. The clinical value of angiogenesis
      related factors as a tumor marker and diagnostic applications targeting newly
      developed vasculatures have been investigated. In this review, recent new
      findings on the clinical applications of tumor angiogenesis in human tumors,
      particularly breast cancer, will be summarized and discussed.

PMID- 8645016
TI  - [Hormone therapy of endometrial carcinoma].
AB  - Various hormone therapies for endometrial carcinoma have been reported in the
      literature using progestins, tamoxifen (anti-estrogen), danazol, Gn-RH etc. The
      response rates of these hormone therapies are reported to be approximately 30%,
      which is no longer superior to other types of treatment methods. On the other
      hand, endometrial carcinoma is considered to be one of hormone dependent tumors.
      Although sex steroid hormones play an important role in the mechanism of
      carcinogenesis and the progression of early and well-differentiated endometrial
      carcinoma, most of the advanced carcinomas treated by hormone therapy have
      transformed into hormone independent state. It is expected that endometrial
      hyperplasia and well-differentiated carcinoma especially in younger patients
      should be effective materials for hormone therapy.

PMID- 8645015
TI  - [Strategy of drug development for hormone-dependent tumor].
AB  - It is established that estrogen and androgen facilitate the proliferation of
      breast and prostate cancers. Hormonal therapy for these tumors using agents which
      inhibit hormone synthesis (inhibitors of aromatase and lyase) or bind hormone
      receptor have been used. However, some patients become resistant gradually during
      the hormonal therapy. Furthermore, QOL of patients was impaired by the side
      effects associated with the therapy, such as decreases in bone density, libido,
      and potency. The osteoporosis is a potential concern with the prolonged use of
      antiestrogen. The beneficial effect of estrogen receptor antagonist, tamoxifen on
      breast cancer has been established, but this agent may increase the proliferation
      of endometrium, which may increase the incidence of uterine cancer. Tamoxifen is
      a partial agonist, leading to the increase in transcriptional activity. Recently,
      ICI-164.384 is reported to be a pure antagonist and effective in tamoxifen
      refractory tumor. Hopefully, pure antiandrogen will be available in the near
      future. There are reports suggesting that several specific and tissue-specific
      factors are involved in transcriptional activity of sex steroid hormone
      receptors. It is likely that these factors are novel targets for drugs which have
      a high potency and organ-or tissue-selective antagonist of sex steroid hormone
      for the treatment of hormone-dependent cancers.

PMID- 8645017
TI  - [New developments in hormonal therapy for breast cancer].
AB  - Recently, new hormonal drugs such as aromatase inhibitor, LHRH and analogue and
      the derivative of tamoxifen have been introduced clinically into treatment of
      breast cancer. Combined therapies not only with a variety of hormonal drugs but
      with anti-cancer drugs are under consideration and superior results are expected.

PMID- 8645018
TI  - [New development of endocrine therapy in prostate cancer].
AB  - Indication and new agents for endocrine therapy in prostate cancer were outlined,
      and new development of endocrine therapy was reviewed in terms of total androgen
      blockade (TAB) for advanced disease and localized disease as neoadjuvant setting,
      and antiandrogen withdrawal syndrome. TAB is considered to be useful in the
      treatment of patients with advanced prostate cancer, particularly those with
      minimal disease and good performance status. Neoadjuvant TAB therapy before
      radical prostatectomy may decrease cancer positive surgical margins. However,
      long-term follow-up data are required to determine the impact on survival.
      Antiandrogen withdrawal seems to be therapeutically efficacious for patients with
      hormone-refractory prostate cancer, with a response rate of about 20%. Therefore,
      antiandrogen withdrawal should be tried before initiating therapy for hormone
      refractory prostate cancer.

PMID- 8645019
TI  - [An overview of clinical trials in endocrine therapy for cancer].
AB  - To obtain information for published clinical trials in endocrine therapy for
      cancer in Japan, a computerized literature search of MEDLINE, EMBASE and IGAKU
      CHUO-ZASSHI (CD-ROM) was done. We found four articles on randomized trials for
      prostate cancer and two for breast cancer. In order to obtain information for
      ongoing randomized phase III trials in endocrine therapy for cancer in the United
      States and Europe, a search of PDQ (Physician's Data Query) was done. In PDQ, 13
      active trials started after January 1990 in endocrine therapy for breast cancer
      and six active trials started after January 1990 in endocrine therapy for
      prostate cancer were registered. Out of 13 trials for breast cancer, projected
      sample sizes were over 1,000 in eight trials, and QOL was selected as an end
      point in six trials. Out of six trials for prostate cancer, projected sample
      sizes were over 500 in three trials, and QOL or sexual function was selected as
      an end point in three trials.

PMID- 8645020
TI  - [Early phase II study of BMS-181339 (paclitaxel) in patients with non-small cell
      lung cancer. BMS-181339 Non-Small Cell Lung Cancer Study Group].
AB  - We conducted a multi-institutional (11 facilities), early phase II study of BMS
      181339 (paclitaxel), a novel anti-cancer drug, for non-small cell lung cancer
      (NSCLC). The 150 mg/m2 dose of paclitaxel was given by intravenous infusion over
      24 hours every three weeks. When fifteen patients were accumulated, the interim
      review revealed that three of 15 eligible patients had a partial response for a
      response rate of 20%. The most common toxic effects were grade 3 or 4 leukopenia
      seen in 73.3% (11/15), and grade 4 neutropenia in 93.3% (14/15). One patient with
      neutropenia had suspected septic shock, which could be managed by G-CSF and
      antibiotics. No serious hypersensitivity reaction was seen with premedication of
      anti-allergic drugs, although mild allergic reactions such as skin rash and
      flush, were observed in 20.0% (3/15). Other adverse reactions, including
      alopecia, fever, arthralgia, myalgia and peripheral neuropathy, were mild in most
      cases. We conclude that it is relevant to proceed to a late phase II study for
      NSCLC.

PMID- 8645021
TI  - [Distributions of pyrimidine nucleoside phosphorylase (PyNPase) in tissues of
      benign and malignant mammary diseases--immunohistochemical observations].
AB  - Pyrimidine nucleoside phosphorylase (PyNPase) is considered to be important for
      producing antitumor function of 5'-DFUR or 5-FU inducing compounds, since this
      enzyme transforms 5'-DFUR into 5-FU and 5-FU into their activated forms.
      Additionally, PyNPase shows high activity in various malignant tumor tissues. In
      this investigation, the distributions of PyNPase were examined in the tissues of
      mastopathy, fibroadenoma, phyllodes tumor and mammary cancer using
      immunohistochemical procedures. The following results were obtained. In the
      tissues of mastopathy or fibroadenoma, immunoreactivity was generally very weak
      and only a few positive epithelial cells were observed. In the phyllodes tumor,
      immunoreactivity was also weak, but every epithelial cell showed positive
      immunoreactivity. On the contrary, apparent immunoreactivity was observed in the
      tissues of mammary cancer, and cancer cells revealed prominent immunoreactivity.

PMID- 8645023
TI  - [Comparative study of the combined effect of HCFU and dipyridamole (DP) in
      colorectal carcinoma--TS inhibition rate. Kinki Cooperative Study Group of
      Chemotherapy for Colorectal Carcinoma].
AB  - In the forty-seven medical centers in the Kinki district, a comparative trial was
      conducted to investigate the enhancement of the efficacy of HCEU due to
      dipyridamol (DP), which is a biochemical modulator in patients with colorectal
      cancer who have had a curative resection. The trial consisted of two comparative
      groups: one group (Group A) received HCFU only for five days before operation and
      for two years from the second week, and the other group (Group B) was given HCFU
      + DP for the same trial period as Group A. The total number of patients collected
      was 653 (Group A: 327 patients; Group B: 326 patients) during the two-year trial
      period from October, 1991. Thymidylate Synthetase (TS) activity in the primary
      lesions, which is an index of proximity effect, was measured, and the TS
      inhibition rate (TSIR) was calculated from the activities. The results showed
      that the TSIR in the primary lesions for the HCFU + DP group (Group B: 0.33) was
      significantly higher than that of the HCFU group (Group A: 0.27) (p = 0.0006).
      There was no increase in the side effects of HCFU due to combined administration
      with DP. From the above results, the therapy with HCFU + DP is expected to be
      useful for patients with colorectal cancer who have undergone curative resection.

PMID- 8645022
TI  - [Prospective randomized trial comparing 1/2 FAM (5-fluorouracil (5-FU) +
      adriamycin + mitomycin C) versus palliative therapy for the treatment of
      unresectable pancreatic and biliary tract carcinomas (the 2nd trial in non
      resectable patients). Japanese Study Group of Surgical Adjuvant Therapy for
      Carcinomas of the Pancreas and Biliary Tract].
AB  - The efficacy of 1/2 FAM, which consists of 5-fluorouracil (5-FU), adriamycin
      (ADM) and mitomycin C (MMC), was compared with that of palliative treatment in
      patients with unresectable pancreatic and biliary tract carcinomas in a
      multicenter randomized trial. The patients assigned to 1/2 FAM group were treated
      with 5-FU 200 mg/m2/day IV, ADM 15 mg/m2/day IV and MMC 5 mg/m2/day IV. These 3
      drugs were given concurrently as the initial dose within a week after palliative
      operation, and this regimen was repeated for at least 2 whole courses, at 4-week
      intervals before the next course of therapy. Those randomized to the control
      group were subjected to palliative treatment alone. Completely eligible for
      analysis were 42 cases of the 1/2 FAM group and 41 of the control group. There
      was no significant difference between the groups with respect to the overall and
      differentiated survival times according to the tumor sites and the clinical
      efficacy. As for the duration of 50% inhibition of tumor progression, a
      significantly better outcome was obtained in 1/2 FAM group. Tumor progression was
      most significantly inhibited in patients with gallbladder carcinoma. In 1/2 FAM
      group, tumor reduction was achieved in 1 CR and 2 PR patients. The most frequent
      adverse reaction was gastrointestinal manifestations, along with diarrhea and
      alopecia. 1/2 FAM did not contribute to the life prolongation, but inhibited the
      tumor progression for a significantly longer duration and, to a lesser extent,
      reduced the tumor size in unresectable pancreatic and biliary tract carcinomas.
      This regimen is suggested to be useful particularly in the treatment of the
      latter carcinoma.

PMID- 8645024
TI  - [Estimation of pathways of 5-fluorouracil anabolism in human cancer cells in
      vitro and in vivo].
AB  - Possible pathways of intracellular phosphorylation of 5-fluorouracil (5-FU) in
      human cancer cells were investigated in vitro and in vivo. We used two inhibitors
      which regulate the anabolism of 5-FU for the purpose of elucidation of its
      pathways; one is oxonic acid (Oxo), an inhibitor of orotate
      phosphoribosyltransferase (OPRTase), catalizing a formation of FUMP from 5-FU,
      and another is 2, 6-dihydroxypyridine (DP), an inhibitor of uracil
      ribosyltransferase which catalizes a conversion of 5-FU to 5-fluorouridine.
      Although the pathway of 5-FU phosphorylation in murine tumor cells was varied,
      about 80% of human cancer cells tested were found to utilize the first pathway in
      which 5-FU was converted to FUMP by OPRTase. Thus, the phosphorylation of 5-FU
      via the first pathway was markedly inhibited by Oxo in 4 strains of 5 gastric
      cancer cells, 7 of 8 colorectal cancer cells and 3 of 4 lung cancer cells. In
      xenografts of human gastric and colorectal adenocarcinoma in which 5-FU
      phosphorylation is regulated by Oxo in vitro, the production of 5
      fluoronucleotides and its incorporation into RNA after iv administration of 5-FU
      significantly decreased by co-administration of Oxo, suggesting that the nature
      of an anabolic pathway of 5-FU in the tumor cells in vitro reflects in vivo
      behavior. We also confirmed that the phosphoribosylpyrophosphate level in tumor
      cells was importantly related to determination of the metabolic pathway of 5-FU.
      These results would suggest that possible modulation of 5-FU lies on the
      augmentation of 5-FU efficacy.

PMID- 8645025
TI  - [Measurement of serum tissue polypeptide antigen (TPA) in patients with malignant
      tumor using prolifigen TPA-M "Daiichi" kit].
AB  - Serum tissue polypeptide antigen (TPA) was measured using a newly developed
      Prolifigen TPA-M "Daiichi" kit in 1,236 healthy subjects, 2,867 patients with
      malignant tumors, and 901 with benign diseases. Because 94.0% of healthy subjects
      had serum TPA under 70 U/l, the cut-off value was set at 70 U/l. Serum TPA was
      elevated in more than 50% of patients with head and neck cancer, lung cancer,
      liver cancer, gallbladder or bile duct cancer, pancreatic cancer, colorectal
      cancer, ovarian cancer, and prostate cancer. The overall positive rate in
      malignant tumors was 55.5%. Serum TPA was higher in advanced cancer than in
      earlier stage cancer, and decreased after the resection of the tumor. The false
      positive rate in benign diseases was 31.3%. ROC analysis revealed the usefulness
      of TPA as a tumor marker in many cancers. The correlation coefficient between TPA
      and CYFRA 21-1, and between TPA and TPSA, was 0.747 and 0.694, respectively. In
      conclusion, measurement of serum TPA using the new kit is useful in the
      management of patients with various malignant tumors.

PMID- 8645026
TI  - [The development of a new QOL Questionnaire on chemotherapy - induced emesis and
      vomiting--investigation of reliability and validity. Group for Investigation of
      QOL Questionnaire for Anti-Emetics Used in Cancer Chemotherapy. Joint Research
      Group for Tropisetron Double-Blind Comparative study].
AB  - A new questionnaire on QOL of patients with chemotherapy-induced emesis and
      vomiting was developed, and its reliability and validity were investigated in the
      present multi-center clinical trial. The questionnaire consisted of 15 items
      which included descriptive questions on appetite, feeling, sleep, mental fatigue,
      anxiety, pain, sputum, respiratory distress, nausea, vomiting, abdominal
      condition, daily life in a hospital and relationship with family, a linear
      analogue scale representing influence of nausea and vomiting on patient's life
      during 24 hours, and a face scale as the global scale. Data from 98 patients with
      cancer were analyzed by principal component analysis and correlation analysis.
      The results were summarized as follows: 1) Recollect rate was 78.1% and complete
      response rate was 86.0% in this QOL measurement. 2) A clear correlation was
      observed between appetite, feeling, nausea, vomiting and the physiological scale,
      between sleep, mental fatigue, anxiety, pain, abdominal condition and the
      psychological scale, between sputum, respiratory distress and the respiratory
      condition related scale, between daily life in hospital and the active scale,
      between relationship with family and the social relation scale. These results
      satisfied internal consistency. 3) As for test-retest reliability, the total
      score of 13 descriptive items between the day before and two days before the
      start of chemotherapy showed no significant difference. 4) The 13 items were
      grouped into physiological, the psychological, the respiratory condition related,
      the active and the social relation scales, and these scales belonged to a
      different dimension. 5) The linear analogue scale, the face scale and the total
      scores of 13 descriptive items correlated respectively with all of items except
      item of, relationship with family. 6) As for concurrent validity, vomiting
      frequency, severity of nausea and anorexia correlated with the physiological
      scale. Severity of nausea and anorexia also correlated with the psychological and
      active scales. 7) As a result of investigation of sensitivity, the total score of
      the 13 descriptive items, the linear analogue scale representing influence of
      nausea and vomiting on patient's life during 24 hours and the face scale revealed
      the poorest levels 2-3 days after chemotherapy but recovered thereafter. The
      aggravation of QOL of patients treated with chemotherapy was reduced in the anti
      emetic administration group compared with the placebo administration group. These
      results suggested that this new questionnaire developed for chemotherapy-induced
      emesis and vomiting had sufficient validity and reliability to reflect the
      effects of anti-emetic drug.

PMID- 8645028
TI  - [A case of common bile duct cancer responding to MMC leucovorin, 5-FU, and UFT
      combination chemotherapy and radiation].
AB  - A case of unresectable common bile duct cancer involving the portal vein and with
      Virchow lymph node metastasis was treated with MMC, Leucovorin, 5-FU and UFT
      combination chemotherapy as well as radiation. The case was a 71-year-old female
      who was admitted to the hospital with vomiting and anorexia. Abdominal US study
      showed obstructive jaundice. The PTCD tube was pierced to dilate the intrahepatic
      bile duct. Bile juice cytology was class V. Abdominal CT showed paraaortic lymph
      node metastasis. Angiography revealed portal vein invasion, and the diagnosis was
      unresectable common bile duct cancer. We started anticancer therapy and
      radiation. The anticancer therapy selected was MMC, LEUCOVORIN, 5-FU and UFT
      combination chemotherapy. After 2 cycles of the treatment, Virchow lymph node
      completely disappeared and the symptoms diminished. These combination therapies
      were effective for common bile duct cancer.

PMID- 8645027
TI  - [Effects of an anti-emetic tropisetron capsule on QOL of patients with delayed
      nausea and vomiting induced by cancer chemotherapy. Group for Investigation of
      QOL Questionnaire for Anti-Emetics used in Cancer Chemotherapy. Joint Research
      Group for Tropisetron Double-Blind Comparative Study].
AB  - We have reported our "new questionnaire of QOL (quality of life) in anti-emetic
      therapies during cancer chemotherapy" and demonstrated its reliability and
      validity. In the present study we investigated the utility of tropisetron
      capsules for delayed nausea and vomiting induced by cancer chemotherapies with
      CDDP single administration in a placebo-controlled double-blind comparative study
      using the questionnaire. The questionnaire was composed of the following scales:
      a physiological scale (appetite, feeling, vomiting, nausea), a psychological
      scale (sleep, mental fatigue, anxiety, pain, abdominal condition), a respiratory
      condition related scale (sputum, respiratory distress), an active scale (daily
      life in a hospital), a social relation scale (understanding of the family), a
      linear analogue scale for evaluation of the influence of nausea and vomiting in
      patient's life during 24 hours, and a face scale as the global scale. First, all
      patients were administered a preventive dose of tropisetron capsule on day 1 (the
      day of CDDP administration) and then allotted to once-daily oral administration
      of either a tropisetron (T group) or a placebo (P group) capsule during days 2 to
      5 by a double-blind method. Chronological changes of QOL during the study period
      were measured by the area under the curve (AUC) generally used for calculation of
      blood levels of drugs. The maximum fluctuation (Difmax) of QOL scores throughout
      the whole study period was also evaluated. The data were collected from 114
      cases, and 98 cases (51 in P group, 47 in T group) were analyzed. 1) The total
      score or 13 items (a modified linear analogue scale with 5 graduations), the face
      scale and linear analogue scale of T group were higher (better) than those of P
      group. 2) As for the total score of each scale, the physiological, psychological
      and active scales in the T group showed higher (better) levels than the P group.
      3) As for the AUC values, the T group was lower (better) than the P group in most
      items. In AUC of the total score of 13 items, the face scale, the physiological
      and the psychological scales, the T group was significantly superior to the P
      group. 4) AUC levels of each item belonged to the physiological and the
      psychological scales in the T group tended to be lower (better) than the P group,
      and "sleep" and "pain" in the psychological scale were significantly lower
      (better) in T group than P group. 5) In Difmax values, all scales except
      respiratory condition related scale showed lower levels (better) in T group and
      the total score of 13 items, the face scale and the physiological and
      psychological scales showed significantly lower levels than P group. 6) Difmax
      values in each item belonging to the physiological and psychological scales
      showed lower levels in the T group, while "appetite" and "vomiting" in the
      physiological scale and "sleep" in the psychological scale showed significantly
      lower levels (better) than those of the P group. 7) In the stratified analysis
      performed for patients without nausea and vomiting on the 1st day of
      chemotherapy, there was no significance in AUC levels of all items in both
      groups. In patients with nausea and vomiting on the 1st day, the total score of
      13 items, the face scale, the physiological and the psychological scales in the T
      group were significantly better than in the P group. 8) It was suggested that the
      anti-emetic efficacy of tropisetron for delayed nausea and vomiting might reduce
      the undesirable influence of chemotherapy on QOL, especially on the physiological
      and the psychological effects. These results suggested that this new
      questionnaire is applicable for evaluation of the utility of anti-emetics in
      patients in cancer chemotherapy, and that tropisetron capsules could reduce the
      decrease of QOL in delayed nausea and vomiting induced by chemotherapy.

PMID- 8645029
TI  - [Successful combination chemotherapy for a post-operative gastric cancer patient
      with multiple liver metastases and elevated CEA].
AB  - A 75-year-old male was admitted one year after surgery for advanced gastric
      cancer. He was diagnosed as having multiple liver metastases with elevated serum
      CEA level. Combination chemotherapy consisting of THP-ADM, MMC and 5'-DFUR was
      done in the outpatient clinic. As a result, both multiple metastatic liver tumors
      and serum CEA level showed a remarkable response.

PMID- 8645030
TI  - [Combination of intra-hepatic arterial infusion of low-dose cisplatin and oral
      administration of high-dose doxyfluridine for patients with liver metastases of
      gastric cancer].
AB  - Three cases of gastric cancer with multiple liver metastases were treated with
      low-dose CDDP and high-dose 5'-DFUR after surgery. The regimen was 20 mg CDDP
      intra-hepatic arterial infusion per week and 1,200 mg 5'-DFUR oral treatment per
      day. The liver metastases of two cases responded to this chemotherapy with a
      reduction of more than 90%, and two cases lived more than 2 years. All of them
      lived more than one year. This therapy had few side effects and was performed
      ambulatorily once per week, so patients were able to maintain their quality of
      life. This combination therapy may well assure a better prognosis for patients
      with liver metastases of gastric cancer.

PMID- 8645031
TI  - [Effectiveness of LH-RH agonist for bone metastases of breast cancer--report of a
      case].
AB  - A 44-year-old premenopausal woman with bone metastases of breast cancer was
      initially treated with systemic chemotherapy (CEF) and radiation therapy after
      standard mastectomy. However, progressive change of bone metastases with
      elevation of tumor markers (CEA, NCC-ST 439) was detected, so continuous
      administration of LH-RH agonist and combination chemotherapy (CEF) were
      conducted. Subsequently, complete objective regression was attained after 40
      weeks.

PMID- 8645032
TI  - [Highly effective preoperative intraarterial infusion chemotherapy with CDDP for
      progressive uterine corpus cancer with a Sister Mary Joseph's nodule].
AB  - A 57-year-old female patient complained of atypical genital bleeding and a
      noxious emanation from her navel. A histological examination of the uterine body
      and the navel area confirmed a diagnosis of adenocarcinoma. We diagnosed it as
      IVb stage of uterine corpus cancer with a Sister Mary Joseph's nodule. We
      selectively administered intraarterial injection chemotherapy (Cisplatin 120 mg,
      Pirarubicin 40 mg) in the uterus and navel area (three times, once every three
      weeks) prior to surgery. The isolated uterus showed that the cancerous tissue had
      been eradicated, and we judged the cancer to be grade 3 following
      histopathological effective grading standards. The metastasis exhibited extreme
      shrinkage, but affirmed changes in the tumor quality. Currently, the patient is
      receiving maintenance therapy of 600 mg of Hysron H, and 600 mg of UFT. There are
      no indications of recurrence, and the patient is progressing well.

PMID- 8645034
TI  - [Immunohistochemistry and activities of thymidine phosphorylase in the tissues of
      uterine cervical and endometrial carcinomas].

PMID- 8645033
TI  - [Biweekly cyclophosphamide, epirubicin, vincristine and prednisolone (CEOP)
      chemotherapy for the elderly patients with aggressive non-Hodgkin's lymphoma.
      Tochigi Malignant Lymphoma Study Group for the Elderly Patients].

PMID- 8645035
TI  - [Prognostic factors in ovarian epithelial cancer].
AB  - To data much has been reported concerning the prognostic factors in ovarian
      cancer. The factors may be summarized in accordance with their predictability and
      feasibility. The emphases are the most valuable clinical, histopathological,
      molecular biological and immunological factors.

PMID- 8645036
TI  - Loss of upper respiratory tract immunity with parenteral feeding.
AB  - OBJECTIVE: The authors examine the effect of route and type of nutrition on an
      established upper respiratory tract immunity and investigate potential mechanisms
      for increased pneumonia rates in critically injured patients fed parenterally.
      SUMMARY BACKGROUND DATA: The primary immunologic defense against many mucosal
      infections is IgA. Prior work shows that mice fed total parenteral nutrition
      (TPN) solutions either intravenously or intragastrically had small intestinal gut
      associated lymphoid tissue (GALT) atrophy along with decreased intestinal IgA
      compared with animals fed complex enteral diets. The small intestine is
      postulated to be the origin of most mucosal immunity, both intraintestinal and
      extraintestinal. The impact of diets affecting GALT, small intestine IgA, and
      upper respiratory tract immunity is studied. METHODS: Male Institute of Cancer
      Research mice underwent intranasal inoculation with a mouse-specific influenza
      virus to establish immunity. Three weeks later, the mice were randomized to chow,
      intragastric Nutren (Clintec, Chicago, IL), intravenous TPN, or intragastric TPN.
      After 5 days of feeding, mice were challenged with intranasal virus and killed at
      40 hours to determine viral shedding from the upper respiratory tract. RESULTS:
      Despite similar body weights, there was significant atrophy in the Peyer's patch
      cells from animals fed the TPN solution intravenously or intragastrically. There
      was no viral shedding in any animal fed via the gastrointestinal tract, whereas 5
      of 10 animals fed intravenous TPN had continued viral shedding. CONCLUSIONS: The
      IgA-dependent upper respiratory tract immunity was preserved with enteral feeding
      but not with intravenous feeding. Upper respiratory tract immunity is not
      dependent on intestinal GALT mass but is influenced by route of nutrition. The
      underlying mechanisms may explain the higher pneumonia rate in critically injured
      patients fed parenterally.

PMID- 8645037
TI  - Long-term follow-up after bilioenteric anastomosis for benign bile duct
      stricture.
AB  - OBJECTIVE: The authors provide a prospective evaluation of long-term results
      after bilioenteric anastomoses for benign biliary stricture. SUMMARY BACKGROUND
      DATA: With the advent of laparoscopic techniques, the frequency of bile duct
      injury after operation has increased. Reports on the operative management of
      these injuries have not provided long-term follow-up. Over a similar period,
      reports of both endoscopic and invasive radiographic methods as primary treatment
      for bile duct stricture have compared success rates to antiquated surgical
      reports. METHODS: A protocol whereby preoperative radiographic (e.g.,
      cholangiogram, computed tomographic scan, ultrasound), biochemical (e.g.,
      alkaline phosphatase, and total bilirubin), and clinical evaluation was combined
      with ongoing postoperative evaluation and follow-up at approximately 6-month
      intervals. A total of 111 patients were evaluated from 1985 to 1995. Patients
      were categorized in three groups: 1) those with postoperative injuries during
      open and laparoscopic gallbladder surgery (31 patients), 2) those undergoing
      operation for pain associated with chronic pancreatitis who have distal common
      bile duct stenoses (64 patients), and 3) those with nonchronic pancreatitis
      associated benign bile duct strictures (16 patients). RESULTS: Mean follow-up was
      60 months. Overall preoperative alkaline phosphatase was 640 units/L with a range
      of 280 to 1860 units/L. All patients had abnormally elevated alkaline
      phosphatase. Only 3 of 111 patients have had mild persistent elevation after
      operation. Clinical jaundice, present in 49 of 111 patients, was resolved
      uniformly by operative decompression. Total bilirubin was elevated abnormally in
      56 of 111 patients and also was uniformly corrected by operation. CONCLUSIONS:
      These data support the careful combined use of endoscopy, invasive radiology, and
      surgery in the management of benign strictures of the biliary tree. These data
      further suggest a success rate for surgical management that, over long-term
      follow-up, appears to exceed that found using alternative measures. Alternative
      methods should measure their success rates against success rates currently
      achieved by operative management.

PMID- 8645039
TI  - Liver transplantation in infants younger than 1 year of age.
AB  - OBJECTIVE: The authors report on experience with liver transplantation for
      infants younger than 1 year of age. SUMMARY BACKGROUND DATA: Over the last 15
      years, orthotopic liver transplant has become the only lifesaving procedure
      available for infants with end-stage liver disease. Many transplant centers
      initially required infants to reach a specific weight or age to minimize
      morbidity and mortality. Size-appropriate infant donors also were uncommon. As a
      result, many children, in the first few years of life, died of their disease. The
      availability of reduced-size cadaveric and living-related liver transplants has
      offered the ability to transplant the young infant with liver failure. METHODS:
      The authors instituted a program to aggressively transplant infants with liver
      failure in the first year of life using both cadaveric and living-related liver
      donors. RESULTS: Between June 1991 and January 1995, 13 infants were transplanted
      for rapidly progressive liver failure. Infant age ranged from 4 to 11 months
      (mean, 7.5 months). The cause of liver failure included biliary atresia (11),
      alpha 1-antitrypsin deficiency (1), and liver failure secondary to echovirus 7
      (1). The United Network for Organ Sharing status at the time of transplant ranged
      from status 4, intensive care unit bound (4 patients); status 3, hospitalized (4
      patients); or status 2, failing at home (5 patients). Six patients (46%) received
      cadaveric whole organ (2) or segmental transplants (4). Seven patients (54%)
      received left lateral segment living-related transplants from parental donors.
      After operation, patients received cyclosporine or FK506-based immunosuppression.
      Three patients (23%) required four retransplants (two cadaveric for primary
      nonfunction; one living-related for graft thrombosis in the face of fungal
      infection and bile leak). Postoperative complications included primary
      nonfunction (15%), rejection (85%), graft vascular thrombosis (15%, two of three
      revascularized successfully), bacterial and fungal infections (77%), and viral
      infections (46%). Epstein-Barr virus-associated lymphoproliferative developed in
      two patients (15%). Intestinal perforation requiring reoperation developed in two
      patients (15%). Bile leaks requiring reoperation or transhepatic stinting or both
      developed in three patients (23%). Two patients died in the perioperative period
      (< 1 month) from a combination of primary nonfunction or graft thrombosis and
      sepsis. Overall survival was 85%, ranging from 11.0 months to 4.5 years.
      CONCLUSIONS: Orthotopic liver transplantation in infants younger than 1 year of
      age poses significant challenges from technical and infectious complications.
      Despite these barriers, overall patient survival is comparable to that of older
      children and adults.

PMID- 8645038
TI  - The use of jejunal transplants to treat a genetic enzyme deficiency.
AB  - INTRODUCTION: The Gunn rat is an excellent animal model of Crigler-Najjar
      syndrome, type 1. The liver and small intestine synthesize no functional
      bilirubin uridine diphosphoglucuronosyl transferase and, consequently, the
      animals cannot conjugate bilirubin. In prior studies, the authors have shown that
      15- to 20-cm jejunal transplants from normal Wistar rats lowered but did not
      normalize serum bilirubin levels. Phenobarbital has been used to increase enzyme
      conjugation of bilirubin. HYPOTHESIS: Phenobarbital treatment of Gunn recipients
      of jejunal transplants from Wistar rats normalizes serum bilirubin levels.
      METHODS: Forty-three Gunn recipients of jejunal transplants from Wistar rats were
      divided into four groups: 1) heterotopically placed grafts (Thiry-Vella loops),
      saline-treated, n = 14; 2) heterotopically placed grafts, phenobarbital-treated
      (80 mg/kg/day), n = 17; 3) orthotopically placed (in intestinal continuity)
      grafts, saline-treated, n = 5; and 4) orthotopically placed grafts, phenobarbital
      treated, n = 7. Serum was collected before operation and weekly for 8 weeks for
      measurement of serum total, indirect, and direct bilirubin levels. Animals
      received cyclosporine, 5 micrograms/kg, daily intramuscularly. RESULTS:
      Phenobarbital significantly augmented the bilirubin-lowering effect of
      heterotopic jejunal transplants (group 2). Mean total serum bilirubin fell from
      9.14 +/- 0.01 to a nadir of 1.63 +/- 0.11 mg/dL at 6 weeks, after which time,
      levels began to rise toward baseline (as noted previously). Serum indirect
      bilirubin levels behaved in a similar fashion. Phenobarbital treatment
      "normalized" serum bilirubin levels in recipients of orthotopic Wistar jejunal
      grafts (group 4). Mean total serum bilirubin plummeted from 8.41 +/- 0.20 to 0.76
      +/- 0.15 mg/dL at 1 week, and levels remained within the normal range for the
      entire 8-week study period. Identical changes were observed for serum indirect
      bilirubin levels. CONCLUSIONS: The combination of phenobarbital treatment and
      orthotopic small bowel transplantation may be an appropriate therapeutic
      alternative to liver transplantation in the management of Crigler-Najjar
      syndrome, type 1.

PMID- 8645040
TI  - Quality of life after treatment for pancreatitis.
AB  - OBJECTIVE: The authors evaluated the morbidity, mortality, and quality of life
      after pancreatic debridement for necrosis and compared these values to those for
      quality of life after elective medical and surgical management for chronic
      pancreatitis. SUMMARY BACKGROUND DATA: Quality of life after pancreatic
      debridement for necrosis has received little attention. Although quality of life
      after other pancreatic surgery has been evaluated and is though to be good,
      management of patients with pancreatic necrosis can be labor intensive and
      require extraordinary resources. Therefore, further evaluation of the quality of
      life achieved after treatment is appropriate. METHODS: Forty patients (group 1)
      underwent operative debridement for necrosis between 1986 and 1994. Medical
      records of these patients were reviewed for morbidity, mortality, and in-hospital
      costs. Follow-up of quality of life was assessed by the Short Form-36 Health
      Survey. Patients in group 2 (n = 89) underwent medical management of chronic
      pancreatitis. Group 3 included 47 patients who underwent elective operations for
      ductal abnormalities. The Short Form-36 Health Surveys were administered to all
      three groups and compared statistically. RESULTS: Mortality and morbidity from
      pancreatic debridement was 18% and 77%, respectively. Quality-of-life evaluations
      in groups 1 through 3 and age-matched controls were statistically similar.
      CONCLUSIONS: Pancreatic debridement for necrosis requires intense application of
      resources and is associated with a high mortality and morbidity. Long-term follow
      up shows good quality of life for patients who survive this morbid disease. This
      study supports the continued aggressive approach to the management of pancreatic
      necrosis, given that long-term outcome about quality of life is good.

PMID- 8645041
TI  - A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux
      disease.
AB  - OBJECTIVE: The authors examined indications, evaluations, and outcomes after
      laparoscopic fundoplication in patients with gastroesophageal reflux through this
      single-institution study. SUMMARY OF BACKGROUND DATA: Laparoscopic fundoplication
      has been performed for less than 5 years, yet the early and intermediate results
      suggest that this operation is safe and equivalent in efficacy to open techniques
      of antireflux surgery. METHODS: Over a 4-year period, 300 patients underwent
      laparoscopic Nissen fundoplication (252) or laparoscopic Toupet fundoplication
      (48) for gastroesophageal reflux refractory to medical therapy or requiring daily
      therapy with omeprazole or high-dose H2 antagonists. Preoperative evaluation
      included symptom assessment, esophagogastroduodenoscopy, 24-hour pH evaluation,
      and esophageal motility study. Physiologic follow-up included 24-hour pH study
      and esophageal motility study performed 6 weeks and 1 to 3 years after operation.
      RESULTS: The most frequent indication for surgery was the presence of residual
      typical and atypical gastroesophageal reflux symptoms (64%) despite standard
      doses of proton pump inhibitors. At preoperative evaluation, 51% of patients had
      erosive esophagitis, stricture, or Barrett's metaplasia. Ninety-eight percent of
      patients had an abnormal 24-hour pH study. Seventeen percent had impaired
      esophageal motility and 2% had aperistalsis. There were four conversions to open
      fundoplication (adhesions, three; large liver, one). Intraoperative technical
      difficulties occurred in 19(6%) patients and were dealt with intraoperatively in
      all but 1 patient (bleeding from enlarged left liver lobe). Minor complications
      occurred in 6% and major complications in 2%. There was no mortality. Median
      follow-up was 17 months. One year after operation, heartburn was absent in 93%.
      Four percent took occasional H2 antagonists, and 3% were back on daily therapy.
      Atypical reflux symptoms (e.g., asthma, hoarseness, chest pain, or cough) were
      eliminated or improved in 87% and no better in 13%. Overall patient satisfaction
      was 97%. Four patients have subsequently undergone laparotomy for repair of
      gastric perforation (1 year after operation), severe dumping, "slipped" Nissen,
      and repair of acute paraesophageal herniation. Two patients had laparoscopic
      revision of herniated fundoplications. Results of follow-up 24-hour pH studies
      were normal in 91% of patients more than 1 year after operation. In patients with
      poor esophageal motility, esophageal body pressure improved 1 year after
      operation in 75% and worsened in 10%. CONCLUSIONS: Although long-term efficacy
      data are lacking, intermediate follow-up shows laparoscopic fundoplication to be
      safe and effective. A physiologic approach to evaluation and follow-up of
      patients with gastroesophageal disease allows the surgeon to tailor antireflux
      surgery to esophageal body function and follow the function of the fundoplication
      and esophagus after operation.

PMID- 8645042
TI  - Mammographically detected breast cancer. Benefits of stereotactic core versus
      wire localization biopsy.
AB  - OBJECTIVE: The authors evaluated the differences between stereotactic core needle
      biopsy (SCNBx) and needle localization surgical biopsy (NLBx) in cost and
      treatment course for patients with mammographically detected breast cancer.
      SUMMARY BACKGROUND DATA: Stereotactic core needle breast biopsy is a reproducible
      and reliable alternative to surgical biopsy for histologic diagnosis of
      mammographic lesions. METHODS: Records from 52 consecutive patients with invasive
      breast cancer diagnosed by SCNBx (n = 21) or NLBx (n = 31) over 2 years were
      reviewed. Episode-of-care costs were extracted from the Barnes Hospital billing
      system database. RESULTS: At the time of excision, surgical margins were
      statistically more frequently positive in patients treated with NLBx (55%) than
      patients treated with SCNBx (0%, p < 0.0001). Furthermore, patients in the NLBx
      group undergoing breast conservation surgery required re-excision more frequently
      (74%) than those in the SCNBx group (0%, p = 0.001). There were no complications
      in either group after the diagnostic procedure. All SCNBx results were correct in
      the diagnosis of invasive breast cancer. The median cost of SCNBx was
      approximately $1000 less than the median cost of NLBx. This cost difference was
      carried through the definitive procedure, whether it was breast conservation or
      mastectomy. CONCLUSIONS: This study shows the advantage of SCNBx to diagnose
      breast cancer and definitive operative care at a single procedure. The
      preoperative diagnosis of breast cancer eliminated positive operative margins and
      procedures to re-excise breast tissue. The use of SCNBx also saved approximately
      $1000 per patient compared with the use of NLBx. Our data suggest that SCNBx is
      the diagnostic procedure of choice for mammographically detected cancers.

PMID- 8645043
TI  - Management of gastric remnant carcinoma based on the results of a 15-year
      endoscopic screening program.
AB  - SUMMARY BACKGROUND DATA: Partial gastrectomy for benign peptic ulcer disease is
      associated with an increased risk of adenocarcinoma of the gastric remnant,
      especially in patients who are at least 15 years' postgastrectomy. Increasing
      evidence of mucosal dysplasia is noted on random gastric biopsy and may serve as
      a histologic marker in the identification of early cancer of the gastric stump.
      METHODS: From an initial group of 233 patients who underwent gastrectomy for
      benign peptic ulcer disease between 1960 and 1975, 163 patients began yearly
      flexible gastroscopy and random mucosal biopsy. Routine histologic studies
      identified either normal or dysplastic epithelium as well as adenocarcinoma. An
      average of eight biopsies were taken per endoscopic study. All endoscopic studies
      were performed by surgical residents under the supervision of one surgical
      attending. RESULTS: From July 1980 to June 1995, 145 patients completed annual
      gastroscopy and random biopsy. A total of 2287 endoscopic studies were performed.
      Fifteen patients were found to have severe dysplasia. Nine (60%) had associated
      microscopic evidence of adenocarcinoma. Four additional patients had macroscopic
      adenocarcinoma on endoscopic examination. All 13 patients with cancer were
      asymptomatic. Six patients continue surveillance who display moderate-to-severe
      dysplasia alone. The 13 patients with carcinoma underwent completion gastrectomy
      (R2 nodal dissection) with no evidence of cancer found beyond the gastric wall.
      These patients averaged 29 years since their original partial gastrectomy.
      OBJECTIVE: A prospective screening program for gastric remnant cancer was begun
      to assess the ability to discover early neoplastic changes on random biopsy and
      to make treatment decisions regarding the efficacy of completion gastrectomy
      after discovery of carcinoma. CONCLUSIONS: Aggressive annual screening using
      flexible endoscopy and multiple random biopsy may discover cancer in the gastric
      remnant and can lead to completion curative gastrectomy in asymptomatic people.
      Patients who are at least 20 years postpartial gastrectomy for benign disease
      should be considered for annual endoscopic surveillance.

PMID- 8645044
TI  - Long-term results of breast conservation therapy for breast cancer.
AB  - OBJECTIVE: This study was done to determine the long-term outcome of breast
      conservation therapy (BCT) for patients with early-stage breast cancer during a
      period of treatment evolution at a single institution. SUMMARY BACKGROUND DATA:
      Breast cancer treatment has evolved from extensive surgical extirpation of the
      breast to treatment options that conserve the breast. Prospective and
      retrospective studies have confirmed the efficacy of BCT and justify its use for
      many patients with early breast cancer, but there is no universally accepted
      consensus as to who benefits from more aggressive application of surgery or
      radiotherapy in BCT. Prognostic variables for breast cancer and information on
      factors that contribute to local recurrence help predict BCT results. Continued
      analysis of BCT still is necessary to improve patient outcome. METHODS: Eighty
      five patients treated with BCT (lumpectomy with adjuvant radiation therapy) at
      the Medical College of Virginia from 1980 to 1990 were identified.
      Clinicopathologic parameters and treatment details were analyzed for relationship
      to development of local recurrence, distant metastasis, and survival. Fisher's
      exact test was used for comparisons. Actuarial survival curves were plotted. The
      earlier treatment period (1980-1985) was compared with the later treatment period
      (1985-1990). RESULTS: Median follow-up was 5 years. Actuarial overall survival
      was 83% at 5 years (69% at 10 years), and 5-year distant metastasis-free survival
      was 79%. The 5-year actuarial local recurrence rate was 6.6% (crude rate 10.6%,
      9/85). Young patients (age < 40 years) were found to be at increased risk for
      local recurrence (24% < 40 years vs. 6% > or = 40 years, p < 0.05). Tumor margins
      < or = 3 mm were more frequently found, and lumpectomy site radiation boost was
      used increasingly from 1986 to 1990. Almost half of all local recurrences
      occurred after 5 years. CONCLUSIONS: Survival and local recurrence rates were
      comparable to other series. Young patients were found to be at increased risk for
      local recurrence. Negative microscopic margins, even when close, can provide low
      local recurrence rates when adjuvant radiation therapy is administered.

PMID- 8645045
TI  - Pancreaticoduodenectomy. Does it have a role in the palliation of pancreatic
      cancer?
AB  - OBJECTIVE: The authors define the role of palliative pancreaticoduodenectomy in
      patients with pancreatic carcinoma. BACKGROUND: Decreases in perioperative
      morbidity and mortality and improved long-term survival associated with
      pancreaticoduodenectomy for patients with pancreatic carcinoma have clearly
      established a role for this operation when performed with curative intent.
      However, most surgeons remain hesitant to perform pancreaticoduodenectomy unless
      surgical margins are widely clear, choosing rather to perform palliative biliary
      and gastric bypass. METHODS: A single-institution retrospective review was
      performed comparing the outcome of 64 consecutive patients undergoing
      pancreaticoduodenectomy for pancreatic carcinoma with gross or microscopic
      evidence of adenocarcinoma at the surgical resection margins, and 62 consecutive
      patients found to be unresectable at the time of laparotomy because of local
      invasion without evidence of metastatic disease (stage III). Combined biliary and
      gastric bypass were performed in 87% of patients not resected. RESULTS: The two
      groups were similar with respect to age, gender, race, and presenting symptoms.
      The hospital mortality rate was identical in both groups (1.6%). Fifty-eight
      percent of patients undergoing pancreaticoduodenectomy had an uncomplicated
      postoperative course compared with 68% of patients undergoing palliative bypass
      (not significant). The length of postoperative hospital stay after
      pancreaticoduodenectomy was 18.4 days, which was significantly longer (p < 0.05)
      than for patients undergoing palliative bypass (15.0 days). The overall actuarial
      survival (Kaplan-Meier) was improved significantly in patients undergoing
      pancreaticoduodenectomy (p < 0.02). Postoperative chemotherapy and radiation
      therapy improved survival in both groups. CONCLUSIONS: Pancreaticoduodenectomy
      can be performed with a similar perioperative morbidity and mortality and only a
      minimal increase in hospital stay when compared with traditional surgical
      palliation. Pancreaticoduodenectomy with postoperative chemotherapy and radiation
      therapy is associated with improved long-term survival when compared with
      patients treated with surgical bypass. These data support the role of palliative
      pancreaticoduodenectomy in patients with pancreatic carcinoma and with local
      residual disease.

PMID- 8645046
TI  - Visceral ischemia and organ dysfunction after thoracoabdominal aortic aneurysm
      repair. A clinical and cost analysis.
AB  - OBJECTIVE: Repair of thoracoabdominal aortic aneurysms (TAAAs) is associated with
      significant postoperative morbidity and mortality. Reperfusion of acutely
      ischemic abdominal viscera in animals leads to release of multiple factors that
      cause local and distant organ damage, and similar phenomena occurring in humans
      after TAAA repair could contribute to the high morbidity/mortality and cost
      associated with this procedure. METHODS: Twenty-nine patients undergoing elective
      TAAA repair were studied prospectively. Preoperative organ dysfunction and
      intraoperative risk factors (cross-clamp time, blood loss, operative time) were
      assessed and compared with postoperative organ dysfunction (defined as:
      pulmonary, positive pressure ventilation for > 7 days; renal, increase in serum
      creatinine > 2.0 mg/dL over baseline; hepatic, lactate dehydrogenase > 500
      international units and total bilirubin > 3.0 mg/dL or serum transaminase level >
      200 international units; hematopoietic, platelet count > 50 K or leukocyte count
      > 4.5 K, mortality, and costs. RESULTS: No relationship between preoperative
      organ dysfunction, blood loss, or operative time and postoperative organ
      dysfunction or mortality was seen; however, cross-clamp times > 40 minutes were
      associated with a significantly greater incidence of pulmonary (59%), renal
      (47%), hepatic (35%), and hematopoietic (47%) dysfunction. In addition, multiple
      organ dysfunction (> 2 organ systems) was more common after > 40 minutes of
      visceral ischemia and led to significantly greater overall hospital ($88,465 +
      $76,155 vs. $41,782 + $31,244) and intensive care unit ($26,726 + $28,256 vs.
      $11,234 + $12,146) costs (p < 0.01, Mann-Whitney U test). Mortality associated
      with leukopenia was 67% compared with 4% without leukopenia (p < 0.01).
      CONCLUSION: Increasing durations of acute visceral ischemia led to significant
      multiple organ dysfunction after TAAA repair. Methods of limiting visceral
      ischemia or the systemic effects of visceral ischemia may decrease both the
      morbidity and mortality and the overall hospital cost associated with this
      procedure.

PMID- 8645047
TI  - The role of surgeon-performed ultrasound in patients with possible cardiac
      wounds.
AB  - OBJECTIVE: The authors evaluate surgeon-performed ultrasound in determining the
      need for operation in patients with possible cardiac wounds. BACKGROUND DATA:
      Ultrasound quickly is becoming part of the surgeon's diagnostic armamentarium;
      however, its role for the patient with penetrating injury is less well-defined.
      Although accurate for the detection of hemopericardium, the lack of immediate
      availability of the cardiologist to perform the test may delay the diagnosis,
      adversely affecting patient outcome. To be an effective diagnostic test in trauma
      centers, ultrasound must be immediately available in the resuscitation area and
      performed and interpreted by surgeons. METHODS: Surgeons performed pericardial
      ultrasound examinations on patients with penetrating truncal wounds but no
      immediate indication for operation. The subcostal view detected hemopericardium,
      and patients with positive examinations underwent immediate operation by the same
      surgeon. Vital signs, base deficit, time from examination to operation, operative
      findings, treatment, and outcome were recorded. RESULTS: During 13 months, 247
      patients had surgeon-performed ultrasound. There were 236 true-negative and 10
      true-positive results, and no false-negative or false-positive results; however,
      the pericardial region could not be visualized in one patient. Sensitivity,
      specificity, and accuracy were 100%; mean examination time was 0.8 minute (246
      patients). Of the ten true-positive examinations, three were hypotensive. The
      mean time (8 patients) from ultrasound to operation was 12.1 minutes; all
      survived. Operative findings (site of cardiac wounds) were: left ventricle (4),
      right ventricle (3), right atrium (2), right atrium/superior vena cava (1), and
      right atrium/inferior vena cava (1). CONCLUSIONS: Surgeon-performed ultrasound is
      a rapid and accurate technique for diagnosing hemopericardium. Delay times from
      admission to operating room are minimized when the surgeon performs the
      ultrasound examination.

PMID- 8645048
TI  - Management of biliary tract stones in heart transplant patients.
AB  - OBJECTIVE: The authors report their experience with biliary tract stones in adult
      and pediatric heart transplant patients, and review the current literature
      relative to this problem. SUMMARY BACKGROUND DATA: Prior studies in adults have
      noted that heart transplant patients frequently have cholelithiasis, but offer no
      consensus about treatment strategy. Few studies exist for pediatric heart
      transplant patients. A higher rate of hemolysis and cyclosporine-induced changes
      in bile metabolism may contribute to lithogenesis in this population. METHODS: A
      chart review was conducted for 211 patients who had heart transplants between
      January 1988 and September 1994 to determine prevalence of biliary tract stones,
      management strategies used, and outcome. RESULTS: Of 175 long-term heart
      transplant survivors, 52 (29.7%) had stones detected: 32.8% of adults (47/143)
      and 15.6% of children (5/32). The majority of patients (31) were diagnosed 4
      months (mean) after transplantation; cholelithiasis developed in 10 of these
      patients (32%) within 11 months (median) after a negative ultrasound. Symptoms
      developed in 45% of patients. All patients underwent either elective (36) or
      urgent (6) cholecystectomy via an open (32) or laparoscopic (10) approach, or
      endoscopy for common bile duct stones (2). There were no deaths or complications
      during a follow-up period of up to 7 years. CONCLUSION: Heart transplant patients
      have a high prevalence of symptomatic biliary tract stone disease. They can be
      treated safely via an open or laparoscopic approach after transplantation. The
      authors recommend routine gallbladder ultrasound screening and elective
      cholecystectomy in the post-transplant period if stones are detected.

PMID- 8645049
TI  - Success and complications of pancreatic transplantation at one institution.
AB  - OBJECTIVE: The authors report the results and complications of the first 59
      pancreas transplantation procedures performed at one institution. SUMMARY
      BACKGROUND DATA: Pancreas transplantation is performed at relatively few centers.
      Results have improved in the past few years. METHODS: A retrospective review was
      completed of the results and complications after pancreas transplantation at one
      institution. Pancreas transplantation was indicated for patients with insulin
      dependent diabetes mellitus and who were younger than 50 years of age. The
      results were divided into era I (March 1987-December 1992) and era II (January
      1993-October 1995). RESULTS: Fifty-nine transplants were performed since March
      1987. There were 45 combined kidney/pancreas transplants and 13 pancreas
      transplants. Graft survival at 1 year was 57% for those in era I versus 79% in
      era II. Rejection occurred in 74% of the patients in era I and 48% in era II.
      Eighty-five percent of all rejection episodes in both eras were steroid resistant
      and required antibody therapy. Complications were not different from eras I and
      II. CONCLUSIONS: Pancreas transplantation is a successful procedure with a number
      of significant complications. Rejection episodes are most often steroid
      resistant.

PMID- 8645050
TI  - Repeat hepatic surgery for colorectal cancer metastasis to the liver.
AB  - OBJECTIVE: The authors addressed whether a repeat hepatic operation is warranted
      in patients with recurrent isolated hepatic metastases. Are the results as good
      after second operation as after first hepatic operation? SUMMARY BACKGROUND DATA:
      Five-year survival after initial hepatic operation for colorectal metastases is
      approximately 33%. Because available alternative methods of treatment provide
      inferior results, hepatic resection for isolated colorectal metastasis currently
      is well accepted as the best treatment option. However, the main cause of death
      after liver resection for colorectal metastasis is tumor recurrence. METHODS:
      Records of 95 patients undergoing initial hepatic operation and 10 patients
      undergoing repeat operation for isolated hepatic metastases were reviewed for
      operative morbidity and mortality, survival, disease-free survival, and pattern
      of failure. The literature on repeat hepatic resection for colorectal metastases
      was reviewed. RESULTS: The mean interval between the initial colon operation and
      first hepatic resection was 14 months. The mean interval between the first and
      second hepatic operation was 17 months. Operative mortality was 0%. At a mean
      follow-up of 33 +/- 27 months, survival in these ten patients was 100% at 1 year
      and 88% +/- 12% at 2 years. Disease-free survival at 1 and 3 years was 60% +/-
      16% and 45% +/- 17%, respectively. After second hepatic operation, recurrence has
      been identified in 60% of patients at a mean of 24 +/- 30 months (median 9
      months). Two of these ten patients had a third hepatic resection. Survival and
      disease-free survival for the 10 patients compared favorably with the 95 patients
      who underwent initial hepatic resection. CONCLUSIONS: Repeat hepatic operation
      for recurrent colorectal metastasis to the liver yields comparable results to
      first hepatic operations in terms of operative mortality and morbidity, survival,
      disease-free survival, and pattern of recurrence. This work helps to establish
      that repeat hepatic operation is the most successful form of treatment for
      isolated recurrent colorectal metastases.

PMID- 8645051
TI  - Beta-blockade lowers peripheral lipolysis in burn patients receiving growth
      hormone. Rate of hepatic very low density lipoprotein triglyceride secretion
      remains unchanged.
AB  - OBJECTIVE: The purpose of this study was to determine the effect of propranolol
      on peripheral lipolysis in massively burned children during treatment with
      recombinant human growth hormone (rhGH), and to ascertain whether decreased free
      fatty acid availability for re-esterification would alter the hepatic rate of
      secretion of triglycerides (TGs) bound to very low density lipoproteins (VLDLs).
      BACKGROUND: Fatty liver occurs in severely burned patients, often resulting in a
      twofold increase in liver size. This could be the result of an imbalance between
      increased provision of free fatty acids from peripheral lipolysis, coupled with
      no increase in fat oxidation, and insufficient rate of secretion of TGs from the
      liver. METHODS: In a cross-over study, six burned children were treated with
      either rhGH or rhGH plus propranolol. On the sixth day of treatment, isotopic
      tracer infusions were conducted to determine the rate of release of free fatty
      acid (Ra FFA) from peripheral tissue and the rate of secretion of VLDL-bound TGs
      by the liver. RESULTS: Exogenous rhGH increased Ra FFA in children with large
      third-degree burns. Propranolol decreased Ra FFA, but the rate of secretion of
      fatty acids in the form of VLDL-TG from the liver was maintained. Plasma FFA, as
      opposed to fatty acids newly synthesized in the liver, were the primary
      precursors for hepatic triglyceride synthesis. CONCLUSIONS: The administration of
      propranolol to burned children receiving rhGH is safe, has salutary
      cardiovascular effects, decreases the release of FFA from adipose tissue and
      increases the efficiency of the liver in secreting fatty acids as VLDL TGs.

PMID- 8645053
TI  - [Comparative study of methods of drying mycelial waste].
AB  - Two types of apparatus recommended for drying paste-like products, i.e. a
      continuous-belt film drier and a spouting-bed drier were tested to choose a
      process for drying mycelial waste. The laboratory studies with the use of the
      continuous-belt film drier confirmed that a dry moulded product with the moisture
      content of less than 5 to 6 per cent could be obtained in such an apparatus. In
      the laboratory and pilot plant studies with the use of the spouting-bed drier
      equipped with a specially constructed granulator the technological conditions of
      the drying were defined. The conditions provided stable hydrodynamic drying and
      obtaining of a dry product with the moisture content of 5 to 6 per cent.
      Preliminary dried and ground mycelial waste of the tetracycline and rifampicin
      manufacture is useful as a dry additive in the preparation of the paste with the
      required moisture content.

PMID- 8645052
TI  - Minimally invasive surgery for colorectal cancer. Initial follow-up.
AB  - OBJECTIVE: An analysis was performed to evaluate early patterns of recurrence and
      survival in patients undergoing laparoscopic-assisted colectomies for primary
      colorectal cancer. Thirty-nine patients are available with a minimum of 24 months
      postoperative follow-up. SUMMARY BACKGROUND DATA: The techniques and expected
      surgical outcomes for patients undergoing laparoscopically assisted colectomies
      are slowly being defined as these procedures become more common and more widely
      available. One of the areas of greatest concern is the use of laparoscopic
      assisted colectomy for the surgical treatment of patients with primary colorectal
      cancer. There are anecdotal reports in the literature describing both port site
      recurrence and wound recurrence in patients undergoing laparoscopic-assisted
      colectomies for colorectal cancer. This raises concerns about whether these
      recurrences are more common in patients undergoing laparoscopic procedures and
      whether overall survival is compromised. Wound recurrences and laparoscopic port
      site recurrences have been described with numerous other intra-abdominal tumors,
      but the precise incidence remains unknown. The authors reviewed data from 39
      patients to determine early patterns of recurrence and overall survival. METHODS:
      Two-hundred thirty-eight laparoscopic-assisted colectomies were performed by the
      Norfolk Surgical Group between June 1992 and September 1995. Thirty-nine of the
      patients who underwent resection for colorectal cancer between June 1992 and
      September 1993 currently are available for at least a 2-year follow-up.
      Preoperative evaluation included physical examination, liver function studies,
      carcinoembryonic antigen, chest x-ray, computed tomography scans, and endoscopies
      with biopsy. Postoperative follow-up data consisted of physical examination,
      liver function tests, CEA, chest X-ray, computed tomography scan of the abdomen,
      and endoscopy of the colon. No patients have been lost to follow-up. Survival
      rates and patterns of recurrence were compared between node-negative and node
      positive patients and compared with conventional data after open surgery.
      RESULTS: There were 22 men and 17 women ranging in age from 33 to 89 years. Mean
      follow-up was 30 months, with a range of 24 to 40 months. There were three
      patients with recurrence and nine deaths. Recurrence and tumor-related death
      rates, respectively, for each Dukes' stage were 0/1 and 0/1 for stage A, 0/7 and
      0/7 for stage B-1, 1/16 and 2/16 for stage B-2, 0/1 and 0/1 for stage C-1, and
      2/8 and 1/8 for Stage C-2. All six patients with Dukes' stage D disease died of
      metastatic colorectal cancer within 4 to 14 months of surgery. There were two
      patients with anastomotic recurrence. No unusual patterns of recurrent disease
      were noted, and there were no wound or port site recurrences. CONCLUSIONS: In
      this group of patients undergoing laparoscopic-assisted colectomies for primary
      colorectal malignancy, no adverse patterns of recurrence or decreased survival
      has been noted at 2-year follow-up when compared with standard open colorectal
      cancer surgery statistics. Prospective randomized studies with long-term follow
      up will be required to better define the potential benefits and adverse effects
      of laparoscopic surgery for colorectal malignancy.

PMID- 8645054
TI  - [Sensitivity of Yersinia pseudotuberculosis to pefloxacin].
AB  - Pefloxacin susceptibility of 27 Yersinia pseudo-tuberculosis isolates from the
      infected humans and animals (serovars 1a and 1b with different plasmid spectra)
      was studied by the method of two-fold serial dilutions in the liquid medium. The
      culture was incubated at a temperature of 37 degrees C for 48 hours. It was shown
      that all the isolates were highly susceptible to the antibiotic. The MIC was
      0.0625-1.0 microgram/ml and did not depend on the source of the strain isolation.

PMID- 8645055
TI  - [Effect of antibiotics on glucocorticoid receptor function].
AB  - The effects of penicillin G and cefazolin (cefamezin) on the function of the
      types II and III glucocorticoid receptors of the liver cytosol were studied on
      Wistar male rats weighing 180-200 g. The Scatchard and Lineweaver--Berk analysis
      showed that penicillin G and cefazolin (0.1-10.0 mM) induced a dose-dependent
      increase in the density of the type III glucocorticoid receptors and a decrease
      in the affinity of 3H-corticosterone with the type III glucocorticoid receptors.
      The activation of the function of the type III glucocorticoid receptor by
      penicillin G and cefazolin was not competitive. Penicillin G had no significant
      effect on the function of the type II glucocorticoid receptors. The increase in
      the density of the type II glucocorticoid receptors under the effect of cefazolin
      was dose-dependent though Ka and Kd did not significantly change. The results
      were indicative of the fact that penicillins and cephalosporins had a strong
      action on the most important regulatory system of homeostasis, i.e. the
      glucocorticoid function which is the decisive one in the pathogenesis of
      inflammation.

PMID- 8645056
TI  - [Effect of nitrogen-containing compounds on the biosynthesis of avermectins].
AB  - The influence of complex nitrogen-containing substrates (Difko yeast extract, EKD
      nutrient yeast extract, soy bean flour and cotton seed meal), ammonium salts and
      some amino acids (alanine, methionine, valine, isoleucine and threonine) on the
      biosynthesis of avermectins in the cultures of two mutants of Streptomyces
      avermitilis was studied. It was shown that an excess of the nitrogen compounds in
      the fermentation medium induced a decrease in the antibiotic biosynthesis and the
      relative content of the group B avermectins.

PMID- 8645057
TI  - [Ribonuclease stimulation of nonspecific factors of protection in experimental
      animals].
AB  - It was shown that a single intraperitoneal administration of Bacillus intermedius
      RNAse to rats stimulated the activity of lysozyme and blood serum complement. A
      single intraperitoneal administration of pancreatic RNAse, Bacillus intermedius
      RNAse and its derivative selectively inactivated by the histidine active centre
      stimulated the metabolic activation of neutrophils as was shown by their ability
      to reduce tetrazolium nitroblue to diphormazone. The efficiency of the neutrophil
      stimulation by the RNAses was comparable with that of the microbial vaccine and
      did not depend on the catalytic activity of the RNAses.

PMID- 8645058
TI  - [Dirithromycin in the treatment of infections of the lower respiratory tract].
AB  - Good results of the treatment of patients with lower respiratory tract infections
      with dirithromycin (Eli Lilly, USA), a new semisynthetic macrolide, were
      recorded. The trial included 15 patients: 6 with acute bronchitis (AB) and 9 with
      exacerbation of chronic bronchitis (AB) and 9 with exacerbation of chronic
      bronchitis (ECB). The antibiotic was administered orally in a single dose of 500
      mg once a day for 7 days. The treatment efficacy was estimated by the clinical
      results and laboratory findings. The sputum specimens were investigated
      bacteriologically with testing the microflora for the drug susceptibility by
      using the diffusion disks. 50 per cent of the patients with AB isolated
      Streptococcus viridans with low (the diameter of the growth inhibition zones < 16
      mm) and intermediate (16-17 mm) susceptibility to the antibiotic, 33.3 per cent
      of the patients isolated highly susceptible (19 mm) strains of Str. pneumonia and
      16.7 per cent of the patients isolated resistant (15 mm) strains of
      Staphylococcus epidermidis. Highly susceptible (17-19 mm) strains of Haemophilus
      influenzae and Str. viridans were isolated respectively from 55.5 and 45.5 per
      cent of the patients with ECB. In 4 patients with ECB a clinical improvement of
      the state was recorded. In the other patients with AB and ECB the recovery was
      stated. The bacteriological tests revealed a new pathogen in 2 patients with ECB
      and the failure of the treatment in another 2 patients with ECB. In all the other
      patients the pathogen was shown to be eradicated. In the patients isolating the
      new pathogen the symptomatic recovery was stated in the posttherapeutic period.
      Therefore, diritromycin proved to be efficient in 13 out of the 15 patients with
      lower respiratory tract infections. It should be noted that the drug tolerance
      was excellent. None of the patients showed any adverse reactions.

PMID- 8645059
TI  - [Effectiveness of pefloxacin in brucellosis].
AB  - The clinical efficacy of pefloxacin in the treatment of 51 and 19 patients with
      acute and subacute brucellosis respectively was studied. It was shown that in a
      dose of 400 mg twice a day for 15 days pefloxacin provided a rapid regression of
      the brucellosis clinical signs. By the efficacy it was not inferior to the
      combination of doxycycline and rifampicin used in the routine doses. Pefloxacin
      had no toxic action on the function of the liver, kidneys and hematopoietic
      system. The side effects were minimal. Pefloxacin did not suppress the immunity.
      By decreasing the activity of the brucellosis process it promoted normalization
      of the immunological indices.

PMID- 8645060
TI  - [The combined preparation ligentin in the treatment of inflammatory disease of
      the urogenital organs].
AB  - The actuality of the problem is conditioned by the persistence of residual
      inflammations in a significant number of the patients with urogenital infections
      after the completion of the etiotropic therapy. The main goal of the study was to
      develop a method for the treatment of post-gonorrheal and post-chlamydial
      colpitis, colpomycosis, endocervicitis and urethritis by local application of
      Ligenten, a gel containing gentamicin, ethonium and lidocaine (as an anesthetic).
      The trial included 28 females at the age of 20 to 58 years with residual
      inflammations in the urogenital organs after the completion of the antimicrobial
      therapy of the urogenital infections. The gel was applied locally as tamponade
      and/or irrigation of the urethra 1-2 times a day for 6 to 10 days. The results of
      the treatment showed that the residual inflammations were completely eliminated
      in 17 out of 26 patients, in 5 patients a significant improvement was stated and
      in 4 patients the treatment failed. The data indicated that Ligenten is useful in
      the complex treatment of urogenital infections as a local therapy of residual
      inflammations.

PMID- 8645061
TI  - [Antimicrobial peptides and resistance in animals].

PMID- 8645062
TI  - [Metabolites of tetracycline obtained during its irradiation with visible light
      or peroxidase oxidation. Their toxic properties in relation to hemoglobin].
AB  - It was indicated in the literature that when exposed to visible light
      tetracycline induced phototoxic effects with respect to heme-containing proteins.
      The present study showed that when tetracycline was exposed to visible light it
      formed metabolites due to the photochemical transformations, the metabolites
      formation being slightly affected by the anti-radical drugs such as L-histidine,
      mannitol, ethanol and catalase. The investigation of the conditions of the
      metabolites formation as a result of the photochemical transformations revealed a
      specific role of ascorbate in the process. The comparative analysis of the
      physico-chemical properties of the metabolites resulting from the tetracycline
      exposure to visible light or peroxidase oxidation provided a conclusion that the
      nature of the metabolites was the same. It was shown that the metabolites were
      equal in their phototoxic capacity for the damage of hemoglobin by inducing its
      oxidative degradation.

PMID- 8645063
TI  - Ploidy as a prognostic feature in colonic adenocarcinoma.
AB  - OBJECTIVE: To determine whether DNA content and cell-cycle kinetic
      characteristics in Dukes stage B colonic adenocarcinomas provide additional
      prognostic information in the context of clinicopathologic variables of known
      significance. DESIGN: Archival, paraffin-embedded tissue blocks from 210 Dukes B
      colonic adenocarcinomas were retrieved. After confirming stage, tumor cell nuclei
      were extracted, suspended, and stained. Cell nuclei from adjacent normal colon
      mucosa were used as controls. SETTING: University-based, tertiary cancer referral
      center. INTERVENTIONS: Samples obtained from tumors resected at our institution
      between 1965 and 1984 were analyzed by flow cytometry for DNA index (DI) and
      percentages of cells in synthesis (S) phase (%S) and in G2 and mitosis (M) phases
      (%G2M). The data were correlated with 5-year survival. Follow-up was complete in
      all patients to at least 5 years. RESULTS: Univariate analysis showed that the
      highest survival rates were associated with DI values near 1 and 2 (diploid and
      tetraploid tumors, P = .02) and the lowest %G2M values (tumors with fewer
      mitoses; P = .01). Five-year survival rates also differed significantly between
      patients with diploid (DI < 1.1) and those with aneuploid (1.1 < DI < 2) tumors
      (80% vs 64%, respectively; P = .02). Multivariate analysis revealed that race (P
      < .01), lymphatic or capillary microinvasion (P < .03), and ploidy (P < .05) were
      significantly associated with outcome. The influence of ploidy, race, and
      microinvasion on 5-year survival was estimated with logistic regression, and 8
      subgroups of patients emerged with 5-year survival probabilities ranging from 39%
      for black patients with aneuploid tumors and microinvasion to 88% for white
      patients with diploid tumors and no microinvasion. CONCLUSIONS: Tumor DNA content
      provides additional independent information that allows further refinement of our
      prognostic ability in patients with Dukes B colonic adenocarcinoma. This may aid
      in the identification of a cohort of patients who may potentially benefit from
      aggressive adjuvant therapy.

PMID- 8645064
TI  - Heller myotomy via minimal-access surgery. An evaluation of antireflux
      procedures.
AB  - BACKGROUND: Myotomy offers the best known cure for achalasia and can now be
      performed via minimal-access surgery. OBJECTIVE: To examine the questions of
      surgical approach for Heller myotomy and choice of fundoplication in the setting
      of minimal-access surgery. DESIGN: Thirty-nine patients with achalasia underwent
      Heller myotomy via either thoracoscopy or laparoscopy, with either a Dor or a
      Toupet fundoplication (Heller-Dor and Heller-Toupet procedures, respectively).
      Manometry, pH analysis, and clinical course were evaluated 3 to 9 months after
      surgery. Clinical course was reviewed at 11 to 46 months after surgery. SETTING:
      University hospitals. PATIENTS: Diagnosis of achalasia was based on history and
      physical examination, contrast radiography, stationary manometry, and 24-hour pH
      analysis. All patients participated in the clinical evaluations. Twenty-two
      patients consented to postoperative manometry and 18 to postoperative pH
      analysis. INTERVENTIONS: Thoracoscopic Heller-Dor procedures (n = 4),
      laparoscopic Heller-Dor procedures (n = 6), and laparoscopic Heller-Toupet
      procedures (n = 29). MAIN OUTCOME MEASURES: Hospital stay and recovery time were
      compared between thoracoscopic and laparoscopic groups. Decrease in the lower
      esophageal sphincter pressure, 24-hour esophageal pH, postoperative symptoms, and
      overall satisfaction were compared between the Dor and Toupet groups. RESULTS:
      Only 1 patient was dissatisfied with the experience. Patients undergoing
      thoracoscopy had a longer convalescence. No postoperative reflux was identified,
      although some patients complained of heartburnlike symptoms. Dysphagia and
      heartburn were more prevalent among patients with Dor fundoplication than among
      patients with Toupet fundoplication. CONCLUSIONS: Minimal-access myotomy is an
      excellent intervention for achalasia. The preferred approach is via laparoscopy.
      Our experience has led us to favor the Toupet over the Dor fundoplication after
      myotomy.

PMID- 8645065
TI  - Improved graft survival in cadaveric renal retransplantation by flow
      crossmatching.
AB  - OBJECTIVE: To evaluate the role of flow cytometry cross-matching on graft
      survival in patients undergoing cadaveric renal retransplantation compared with
      our conventional antihuman globulin cytotoxic crossmatch. DESIGN: In 1990, 6 of 7
      transplantation centers in 1 organ procurement organization service area began
      performing cadaveric renal retransplantation only if the flow T-cell IgG
      crossmatch was negative. During that period, 1 center continued to use only the
      antihuman globulin T-cell IgG crossmatch. Prior to 1990, all centers used only
      the antihuman globulin T-cell IgG crossmatch as their crossmatch selection
      criterion for retransplantation. Regraft survival was compared between those
      centers by crossmatch selection criteria. PATIENTS: Patient selection and
      immunosuppression decisions were made at the transplantation center. SETTING: All
      flow cytometry crossmatches for all 7 centers participating in the evaluation
      were performed at the Histocompatibility Laboratory of the Midwest Organ Bank
      Inc, Westwood, Kan. RESULTS: Graft survival is significantly better (P = .03
      [logrank test]) in regrafts when the flow crossmatch is used to select patients
      for transplantation. CONCLUSION: Flow crossmatching improves graft survival in
      cadaveric renal retransplantation by identifying a subset of patients with donor
      directed HLA class I antibodies that are not detectable by our conventional
      antihuman globulin crossmatch.

PMID- 8645066
TI  - Improved survival in children with esophageal perforation.
AB  - OBJECTIVE: To analyze the cause, location, signs and symptoms, presence of
      underlying disease, time interval to diagnosis, treatment, and morbidity and
      mortality in 24 children (19 boys and 5 girls) with esophageal perforation who
      were treated from 1975 to 1995. DESIGN: Data were collected retrospectively from
      hospital and office records. SETTING: A tertiary care children's hospital.
      RESULTS: The average age at diagnosis was 58 months (range, 1 day to 19 years).
      Fourteen children had underlying esophageal disease (atresia, n = 7 and
      gastroesophageal reflux, n = 7). Iatrogenic perforations occurred in 17 children:
      8 during dilatation, 5 during an antireflux procedure, 2 during endoscopy, and 2
      after passage of a feeding tube. Trauma was the cause of perforation in 6
      children. In 2 cases the cause was unknown. Perforation occurred in the thoracic
      esophagus in 12 cases, abdominal esophagus in 7, cervical esophagus in 5, and
      involved both the thoracic and abdominal esophagus in 1. Signs and symptoms
      included dysphagia (15 patients), dyspnea (14), fever (12), cyanosis (8),
      abdominal pain (6), chest pain (5), and subcutaneous emphysema (3). Management of
      esophageal perforation included nonoperative management (7 patients), drainage
      alone (1), primary closure (16), and resection and diversion (1). Two
      perforations occurred in 1 child. Complications occurred in 11 (44%) of the 25
      cases and were more common after delayed diagnosis (73%). The average hospital
      stay was 20 days. There was 1 death (4%) attributed to esophageal perforation.
      CONCLUSIONS: Morbidity and mortality are directly related to delays in diagnosis
      and therapy. Most cases of esophageal perforation in children can be closed
      primarily and the esophagus salvaged despite delayed presentation. The mortality
      rate in children with esophageal perforation (4%) is significantly less than that
      for adults (25%-50%).

PMID- 8645068
TI  - Blunt thoracic aortic trauma. A cost-utility approach for injury detection.
AB  - OBJECTIVE: To evaluate the influences of patient preference and treatment costs
      on the diagnostic approach to blunt aortic trauma. METHODS: Decision and cost
      utility analysis. DATA SOURCES: A MEDLINE search of all literature dealing with
      the diagnosis and management of blunt aortic injury was used to establish
      assumptions and assign baseline probability estimates. Utility assignments were
      made from published data and our own assignments. We obtained institution
      specific cost data. STUDY SELECTION: Only randomized, prospective trials that
      used aortography as the gold standard test were used to assign baseline accuracy
      of transesophageal echocardiography and dynamic chest computed tomography. Other
      baseline estimates were taken from class II and class III published data. DATA
      SYNTHESIS: A decision tree compared 4 diagnostic approaches for blunt chest
      trauma after an initial normal chest radiograph: observation with follow-up chest
      radiography, aortography, transesophageal echocardiography, and dynamic chest
      computed tomography. Utility (a quality-of-life measure) was assigned to ultimate
      health states to incorporate patient preference. Chest radiography and
      aortography had similar utility. Aortography gained 1 quality-adjusted life year
      for minimal cost. Transesophageal echocardiography and dynamic chest computed
      tomography lose quality-adjusted life-years at increased cost. No variable
      changed the relative cost-utility of the screening methods in 2-way sensitivity
      analyses. CONCLUSIONS: Aortography gains additional quality life at minimal cost
      when used as a screening method for all patients with blunt chest trauma
      regardless of the results of the initial chest radiograph. With a normal initial
      chest radiograph, transesophageal echocardiography and dynamic chest computed
      tomography are associated with increased cost and loss of quality-adjusted life.

PMID- 8645067
TI  - The Hartmann procedure. First choice or last resort in diverticular disease?
AB  - OBJECTIVE: To critique changing trends in the surgical management of diverticular
      disease. DESIGN: Case series. Two hundred twenty-seven consecutive patients
      required surgery for diverticular disease from 1988 to 1993. Patient records were
      reviewed retrospectively. Operative procedures included primary resection in all
      patients with either anastomosis, anastomosis with proximal ileostomy, or the
      Hartmann procedure. Morbidity, mortality, and length of stay were then compared
      with each operative procedure and stage of disease. Patients were categorized
      according to the following pathologic stages: stage 0, no inflammation; stage I,
      chronic inflammation; stage II, acute inflammation with or without
      microabscesses; stage III, pericolonic or mesenteric abscess; stage IV, pelvic
      abscess; and stage V, purulent or feculent peritonitis. SETTING: A university
      hospital and private affiliated hospitals in a large metropolitan area. MAIN
      OUTCOME MEASURES: Study outcome parameters included mortality, morbidity, length
      of hospital stay, and leak rates. These outcomes were then compared with
      different disease stages and treatments. RESULTS: Mean patient age was 66 years
      (range, 25-98 years). Male-female ratio was 84:143. Mean follow-up was 23 months
      (range, 1-132 months). There were 50 fistulas: 24 colovesical, 21 colovaginal, 3
      colocolonic, 1 coloenteric, and 1 colouterine. Surgery was categorized as
      elective for 196 patients (86%), urgent for 12 (5%), and emergent for 19 (8%).
      Primary resection was performed in all cases. Primary anastomosis was performed
      in 200 patients (88%), 183 without and 17 with proximal diversion. Twenty-seven
      patients (12%) underwent a Hartmann procedure with colostomy; 19 patients (70%)
      have since undergone colostomy closure. Morbidity occurred in 52 patients (23%),
      including 4 anastomotic leaks (2%). There were 3 perioperative deaths (1%). Mean
      length of initial hospital stay was 11 days (range, 4-59 days). Length of stay
      was 5 days (range, 4-7 days) for ileostomy closure (7% morbidity) and 13 days
      (range, 7-35 days) for the colostomy closure after the Hartmann procedure (33%
      morbidity). CONCLUSIONS: Primary resection is virtually always possible in
      complicated diverticular disease. Primary anastomosis, with or without proximal
      diversion, is safe for patients with no abscesses or localized abscesses and
      should be considered on an individual basis for patients with pelvic abscesses
      and peritonitis. Colostomy closure after the Hartmann procedure is associated
      with significant length of hospitalization and morbidity and leaves one third of
      patients with permanent stomas.

PMID- 8645069
TI  - Surgeons and trauma care. Results of a North American satisfaction survey.
AB  - OBJECTIVE: To examine job satisfaction among trauma surgeons. DESIGN: Cross
      sectional mail survey. SETTING: Hospital-based trauma care. PARTICIPANTS: Trauma
      surgeons in the United States and Canada. MAIN OUTCOME MEASURES: A 20-item Likert
      satisfaction questionnaire, three open-ended questions, and demographic data.
      RESULTS: Survey respondents were slightly dissatisfied with providing trauma
      care. The greatest sources of dissatisfaction were extrinsic, such as poor hours,
      low pay, and interference with a daily schedule. The major sources of
      satisfaction were personal, such as the challenging and rewarding nature of
      operative trauma care. Satisfaction was not statistically related to most aspects
      of the work environment or personal characteristics. CONCLUSIONS: Survey
      respondents strongly affirmed that operative trauma care was satisfying and that
      saving lives was challenging and rewarding. However, 40% of these respondents
      were seriously considering withdrawing from the trauma call roster.

PMID- 8645070
TI  - Feasibility of breast-conserving therapy for younger women with breast cancer.
AB  - OBJECTIVE: To determine if breast-conserving therapy (BCT) consisting of
      segmentectomy, axillary lymph node dissection, and postoperative irradiation is a
      feasible approach to breast cancer in younger women, whose breast tissue is dense
      and whose tumors can be difficult to detect and successfully excise. DESIGN AND
      PATIENTS: We studied BCT in 59 women 35 years old or younger (mean age, 31.7
      years) treated for breast cancer since 1982. Ninety percent of their cancers were
      palpable; 44% were not visible by mammography. Most (93%) had T1 or T2 lesions (<
      or = 5 cm). Invasive ductal carcinoma was the predominant histologic diagnosis
      (68%). RESULTS: Segmentectomy with axillary dissection was the initial operative
      procedure for 39 (66%) of the 59 patients; of these, 21 (54%) had microscopically
      positive segmentectomy margins. Nine patients (23%) with diffusely positive
      segmentectomy margins and four patients (13%) with local recurrences after BCT
      required conversion to mastectomy. Three patients (8%) underwent reexcision to
      achieve negative margins. The 39 patients required a total of 22 additional
      surgical procedures for local control. Thirty-three (56%) of the 59 patients
      underwent mastectomy during the mean 68-month follow-up period; 20 (34%)
      underwent mastectomy as the initial definitive treatment. Reasons for primary
      mastectomy included multifocality or multicentricity (35%), large tumor size
      (30%), patient preference (15%), and occult primary tumor (10%). During the same
      time period, 474 (64%) of 745 women older than 35 years underwent BCT as
      treatment of breast cancer. Two percent required conversion to mastectomy and 1%
      required repeated excision. Twenty-four patients (5%) required mastectomy for
      local recurrence after BCT. After excluding mastectomies performed because of
      patient preference, significantly fewer older women required mastectomy to
      achieve local control (21% vs 50%, P < .001). CONCLUSIONS: Breast-conserving
      therapy is significantly more difficult in younger women despite surgeon and
      patient commitment. Patients and physicians should be encouraged to consider BCT
      but should be aware of the potential difficulty in obtaining adequate local
      control and the possible need for additional operative procedures.

PMID- 8645071
TI  - Biliary-enteric anastomosis by means of a single layer of serosubmucosal sutures
      without T-tube drainage.
AB  - BACKGROUND: To lessen anastomotic stricture after biliary-enteric anastomosis, we
      developed a new biliary-enteric anastomosis that uses a single layer of
      interrupted serosubmucosal sutures without T-tube drainage. OBJECTIVE: To
      evaluate the safety and reliability of this new technique in a canine model of
      choledochoduodenostomy. METHODS: In 10 beagles, the common bile duct (2 to 3 mm
      in diameter) was ligated close to the duodenum with 3-0 polyglactin. On the fifth
      day after operation, the serum bilirubin level was elevated (137 to 205 mumol/L
      [8 to 12 mg/dL]) and the bile duct was dilated. The anastomosis between
      serosubmucosal layers of the dilated bile duct (8 to 10 mm in diameter) and
      duodenum was accomplished with interrupted sutures of 6-0 polyglactin with two
      needles. Stitches were inserted in the submucosal plane at the cut edge of the
      duct and duodenum to appose the mucosa accurately and to avoid accidental
      perforation of the entire thickness of the duct and duodenum. A T tube was not
      placed. RESULTS: There was no anastomotic leakage and the bilirubin level was
      normalized (14 to 17 mumol/L [0.8 to 1.0 mg/dL]) 7 days after operation for
      anastomosis. Histologic examination of specimens removed 6 or 12 months after
      operation showed good connective-tissue union and good mucosal continuity between
      the bile duct and the duodenum. There was no mucosal scarring and contracture or
      stricture formation. CONCLUSION: This new technique is simple and reliable and is
      recommended as an alternative method for restoring the continuity between the
      bile duct and intestinal tract after operation for obstructive jaundice caused by
      benign and malignant stricture of the bile duct.

PMID- 8645072
TI  - Prognosis in intra-abdominal infections. Multivariate analysis on 604 patients.
AB  - OBJECTIVES: To identify factors that influence mortality in patients who are
      affected by intra-abdominal infections (IAIs) and to make a comparison among
      three different scoring systems: the Acute Physiology and Chronic Health
      Evaluation (APACHE) II score, the sepsis score of Elebute and Stoner, and the
      Mannheim peritonitis index. DESIGN: Case series. SETTING: Both primary and
      referral hospital care. PATIENTS: The hospital records of 604 patients who
      consecutively underwent emergency operations for unequivocal IAIs, both
      spontaneous and postoperative, from 1981 to 1993, were retrospectively reviewed.
      Patients with IAIs that were related to peritoneal dialysis or infected ascites,
      those patients who were affected by primary peritonitis from a distant site, and
      those patients who underwent operations for acute appendicitis or acute
      cholecystitis without peritoneal contamination were excluded from the study.
      Univariate and multivariate analyses were used to calculate the prognostic
      significance of the following variables: age (< or = 70 vs > 70 years); sex; type
      (spontaneous vs postoperative) and extent (localized vs diffuse) of infection;
      preoperative serum levels of albumin, cholesterol, and hemoglobin; preoperative
      total lymphocyte count; amount of intraoperative blood loss; presence of
      preoperative organ impairment; the APACHE II score; the sepsis score of Elebute
      and Stoner; and the Mannheim peritonitis index. MAIN OUTCOME MEASURE: Death was
      the outcome variable that was studied. RESULTS: Multivariate logistic regression
      analysis showed that the APACHE II score, the Mannheim peritonitis index,
      hypoalbuminemia, hypocholesterolemia, and preoperative organ impairment were
      independent predictors of death. CONCLUSIONS: Results showed a significant
      dominance of host-related factors over the type and source of infection on the
      prognosis of patients with IAIs. Both the APACHE II score and the Mannheim
      peritonitis index correctly graded IAI severity and were strongly and
      independently associated with the outcome; however, the latter score has the
      advantage of being easier to calculate.

PMID- 8645073
TI  - Factors influencing outcome of surgery for primary aldosteronism.
AB  - OBJECTIVE: To identify factors that influence the outcome of surgery for primary
      aldosteronism. DESIGN: A retrospective clinical series, with a mean follow-up of
      106 months (range, 12-280 months), of 42 patients who underwent adrenalectomy for
      primary aldosteronism between the years 1970 and 1993. SETTING: All patients were
      operated on at the Boston University Medical Center Hospital. PATIENTS AND
      INTERVENTION: We reviewed the records of 22 women and 20 men, ranging in age from
      25 to 68 years, who underwent adrenalectomy for primary aldosteronism. Tests
      performed for preoperative classification of the adrenal pathological
      abnormalities included adrenal venous sampling, postural stimulation test,
      iodocholesterol I 131 scintigraphy, and computed tomography. MAIN OUTCOME
      MEASURES: The surgical outcome was classified as follows: response, normal blood
      pressure measurement (< 160/95 mm Hg) without medication; incomplete response,
      normal blood pressure measurement with medication or blood pressure measurement
      greater than 160/95 mm Hg despite antihypertensive treatment. RESULTS: Twenty
      five patients (60%) became normotensive following surgery. The following factors
      were associated with a complete response to adrenalectomy by univariate analysis:
      adenoma classification (odds ratio [OR] = 9.6, P = .002); preoperative response
      to spironolactone (OR = 8.3, P = .007); age younger than 44 years (OR = 6.2, P =
      .009); and duration of hypertension less than 5 years (OR = 5.1, P = .03).
      Response to spironolactone was predictive only in cases classified as adenoma (P
      = .004). Duration of hypertension showed a strong correlation with age (r =
      0.62). Using stepwise logistic regression, adenoma pathological classification,
      response to spironolactone, and duration of hypertension less than 5 years
      contributed independently to a predictive model. Micronodular hyperplasia alone
      was associated with incomplete response. The presence of coexisting micronodular
      hyperplasia in patients with adenoma did not affect the odds for a complete
      response. Computed tomography for preoperative diagnosis of adenoma showed the
      same level of accuracy (75%) as that for postural stimulation test and
      iodocholesterol scintigraphy, but less than that for adrenal venous sampling
      (91%). CONCLUSIONS: The study showed that the main determinants of a surgical
      cure of hypertension in primary aldosteronism were presence of adenoma and
      preoperative response to spironolactone. We favor computed tomography as the
      initial test to establish preoperative diagnosis of adenoma because of its
      reproducibility and high specifity.

PMID- 8645074
TI  - The dilemma of delayed cellulitis after breast conservation therapy.
AB  - OBJECTIVE: To determine the clinicopathologic characteristics of patients with
      breast cancers in whom delayed breast cellulitis developed after conservation
      therapy (lumpectomy, axillary dissection, and radiation). BACKGROUND: Breast
      cellulitis developing after conservation therapy represents a difficult
      diagnostic and management dilemma because determination of its origin may be
      necessary before further treatment decisions can be made. METHODS: In this
      retrospective evaluation of 184 sequential patients with breast cancers who
      underwent conservation therapy, 10 study patients (5%) in whom breast cellulitis
      developed 3 or more months after surgery were compared with the 174 patients in
      whom cellulitis did not develop. RESULTS: There was no significant difference in
      clinicopathologic characteristics of the study patients compared with control
      patients. The cellulitis resolved in 5 patients (50%) and persisted from 4 months
      to more than 1 year in 5 patients (50%). The cellulitis recurred in 1 patient who
      responded to repeated therapy. The 5 patients with persistent cellulitis
      underwent biopsies, and recurrent cancer was found in 1 patient. Recurrent cancer
      did not develop in the patients whose cellulitis resolved within 4 months with a
      minimum follow-up of 24 months. CONCLUSIONS: Delayed-onset cellulitis occurs in a
      small percentage of patients with breast cancers treated by conservation therapy.
      The cellulitis may take several weeks to clear, and/or it may recur or persist.
      If the condition persists after 4 months of therapy, a biopsy should be performed
      to rule out recurrent cancer.

PMID- 8645075
TI  - The role of a defective lower esophageal sphincter in the clinical outcome of
      treatment for gastroesophageal reflux disease.
AB  - OBJECTIVE: To evaluate the clinical role of a defective lower esophageal
      sphincter in the long-term outcome of medical and surgical treatment for
      gastroesophageal reflux disease. DESIGN: Nonrandomized control study (median
      follow-up, 33 months). SETTING: Referred care. PATIENTS: Fifty-five patients with
      gastroesophageal reflux disease were prospectively evaluated using a symptom
      questionnaire, upper endoscopy, esophageal manometry, and 24-hour pH monitoring.
      Patients were classified into three groups: (1) those with a manometrically
      defective lower esophageal sphincter, treated surgically; (2) those with a
      manometrically defective lower esophageal sphincter, treated medically; and (3)
      those with a manometrically normal lower esophageal sphincter, treated medically.
      INTERVENTION: Nissen antireflux procedure and medical therapy with H2-blockers
      and/or omeprazole. MAIN OUTCOME MEASURES: Symptomatic improvement after treatment
      and need for continuous medication. RESULTS: After therapy, symptoms improved
      significantly in all three groups (P < .05), but least in the patients who
      declined surgery. Among patients with a defective lower esophageal sphincter,
      medical therapy could be discontinued in 13 of 14 patients who had surgery
      compared with one of 14 who declined surgery. Of the 27 patients with a normal
      lower esophageal sphincter who were treated medically, medical therapy could be
      discontinued in 12. CONCLUSIONS: In patients with gastroesophageal reflux disease
      who have a defective lower esophageal sphincter, surgery can ensure durable
      symptom control. Patients with a defective sphincter who decline surgery are
      destined for lifelong therapy, whereas in approximately half of those with a
      normal sphincter, medical therapy can eventually be discontinued.

PMID- 8645076
TI  - Keratinocyte growth factor induces granulation tissue in ischemic dermal wounds.
      Importance of epithelial-mesenchymal cell interactions.
AB  - BACKGROUND: Keratinocyte growth factor acts specifically on epithelial cells and
      is presumed to play an important role in tissue repair. OBJECTIVE: To examine the
      wound-healing effects of keratinocyte growth factor under hypoxic conditions in
      vivo and in vitro. DESIGN AND INTERVENTIONS: Dermal ulcers were created in the
      ischemic ears of 40 anesthetized young female rabbits. Either recombinant
      keratinocyte growth factor (rKGF) or buffer was applied to each wound. Wounds
      were bisected and analyzed histologically at days 7 and 10 after wounds were
      created. For the in vitro study, normal keratinocytes were treated with rKGF (20
      ng/mL) and cultured under hypoxic (3.5% oxygen) conditions. The conditioned media
      were collected at 48 and 72 hours. MAIN OUTCOME MEASUREMENTS: The amount of
      epithelial growth and deposition of granulation tissue were measured in all
      wounds. The amount of transforming growth factor alpha in keratinocyte
      conditioned media was measured by using a sensitive radioimmunoassay. A
      proliferation assay of dermal fibroblasts, treated with conditioned media, was
      also performed under 3.5% oxygen culture conditions. RESULTS: The rKGF (range, 5
      40 micrograms per wound) that was applied significantly increased new epithelium
      by greater than 70% (P = .03) at days 7 and 10 after wounds were created. A
      significant increase in new granulation tissue formation (170%) was also observed
      in rKGF-treated wounds at day 10, at a dose of 40 micrograms per wound (P <
      .002). The amount of transforming growth factor alpha protein in the conditioned
      media that were treated with rKGF (20 ng/mL) increased by 26.8% and 171% at 48
      and 72 hours, respectively, over that of controls. The conditioned media from
      rKGF-treated keratinocytes, grown for 72 hours, resulted in a 51% increase in the
      proliferation of primary rabbit dermal fibroblasts. CONCLUSION: Keratinocyte
      growth factor enhances the wound-healing process of ischemic ulcers, indicating
      that epithelial-mesenchymal cell interactions are critical for the healing of
      wounds under ischemic conditions and possibly under normal conditions as well.

PMID- 8645077
TI  - Feasibility of photodynamic therapy using endogenous photosensitization for colon
      cancer.
AB  - A novel approach to photodynamic therapy (PDT) involves endogenous
      photosensitization by the oral administration of delta-aminolevulinic acid (ALA),
      a naturally occurring substance that is the precursor of protoporphyrin IX
      (PpIX). A 60-year-old man with adenocarcinoma of the sigmoid colon received ALA,
      60 mg/kg by mouth. Six hours later, when the plasma level of PpIX had peaked, the
      tumor was exposed locally to red light at 633 nm to activate PpIX. Endoscopy and
      biopsy findings subsequent to this treatment showed unequivocal visible changes
      and necrosis. Six months later, the patient again underwent successful treatment
      without adverse effects. This report suggests a role for PDT using endogenous
      photosensitization in certain circumstances involving adenocarcinoma of the large
      intestine.

PMID- 8645078
TI  - Captopril-associated "pseudocholangitis'. A case report and review of the
      literature.
AB  - Captopril, a competitive inhibitor of angiotensin-converting enzyme, is widely
      used in the treatment of hypertension and heart failure. Captopril is known to be
      associated with dermatologic, hematologic, and pulmonary adverse effects.
      However, hepatotoxicity is extremely rare. A patient with severe cholestatic
      jaundice induced by captopril is presented. On admission to the hospital, the
      patient was diagnosed and treated as having cholangitis. Review of the literature
      showed similar occurrences in other patients. Patients treated with captopril who
      develop "atypical cholangitis" should be suspected of having captopril-associated
      liver damage.

PMID- 8645079
TI  - Isolated limb perfusion of an irradiated foot with tumor necrosis factor,
      interferon, and melphalan.
AB  - A 57-year-old woman presented with the second recurrence of a high-grade
      malignant fibrous histiocytoma of the right foot, following previous local
      resection plus curative adjuvant radiotherapy. The first recurrence of the lesion
      was treated by isolated limb perfusion with cisplatin; the second recurrence was
      treated by isolated limb perfusion with tumor necrosis factor, interferon, and
      melphalan. The tumor and the area that had been irradiated showed a bluish color
      a few hours after tumor necrosis factor perfusion. Amputation of the right foot
      and leg below the knee had to be performed because of severe necrosis.

PMID- 8645080
TI  - Familial nonmedullary thyroid cancer: an emerging entity that warrants aggressive
      treatment.

PMID- 8645081
TI  - Antrectomy: a safe and effective bypass for unresectable pancreatic cancer.

PMID- 8645082
TI  - Axillary lymphadenectomy for breast cancer without axillary drainage.

PMID- 8645083
TI  - Detection of respiratory syncytial virus (RSV) antigen in the lungs of guinea
      pigs 6 weeks after experimental infection and despite of the production of
      neutralizing antibodies.
AB  - Infections with respiratory syncytial virus (RSV) are characterized by frequently
      occurring reinfections and are regarded to be responsible for bronchial
      hyperreactivity. In this report we describe a small-animal model suited to study
      RSV-induced pathogenesis and immune response. Guinea pigs are infected by
      inhalation of an RSV-aerosol. Lungs of infected animals show signs of a
      bronchiolitis at 7 days after the initial infection. Although neutralizing serum
      antibodies are synthesized viral proteins are still detectable at 6 weeks post
      infection. Therefore, the presence of neutralizing antibodies is obviously not
      sufficient for rapid clearance of persistent RSV-proteins from the lungs of
      infected guinea pigs.

PMID- 8645085
TI  - Characterization of nuclear localization of a hepatitis B virus precore protein
      derivative P22.
AB  - Both of hepatitis B virus core protein and a precore protein derivative, named
      P22, have been shown to localize in the nucleus. Although P22 has ten additional
      amino acid residues at its amino-terminus, both proteins contain the same nuclear
      localization signal. In order to understand the mechanism that regulates the
      activity of this signal, we have studied the nuclear localization of P22 and
      compared it with that of core protein. It was found that both cytosolic and
      nuclear fractions of P22 were phosphorylated but to a lesser extent when compared
      with cytosolic core protein. This distinction was likely attributed to different
      conformations between these two proteins since the density gradient analysis
      revealed a different particle formation for P22 in the cytosol. When expressed in
      Vero cells synchronized by serum deprivation, P22 remained in the cytosol during
      G0 and G1 phases, accumulated gradually in the nucleus during S phase, and
      largely localized in the nucleus when cells were confluent. On the other hand,
      the core protein was transported into the nucleus during mid-G1 phase, shuttled
      back to the cytosol in S phase and again accumulated in the nucleus when cells
      were confluent. Interestingly, when aphidicolin was used to arrest the cells in
      late G1 phase, both proteins were found to accumulate in the nuclei. These
      results indicated that although both P22 and core proteins possessed the same
      nuclear localization signal, the cellular regulation of their nuclear transport
      was not identical and might involve different molecular mechanisms.

PMID- 8645084
TI  - Immunosuppression induces transcription of murine cytomegalovirus glycoprotein H
      in the eye and at non-ocular sites.
AB  - In these studies, DNA PCR was used to identify sites of murine cytomegalovirus
      (MCMV) latency after inoculation of virus into the supraciliary space of the eye.
      Reverse transcription (RT) PCR for an immediate early gene and a late gene was
      used to identify putative sites of virus reactivation after methylprednisolone
      (steroid)-induced immunosuppression. Ten weeks after inoculation of 5 x 10(2) PFU
      of MCMV, BALB/c mice were immunosuppressed by intramuscular injection of steroid.
      Control mice were infected but not immunosuppressed. Two weeks after initiation
      of immunosuppression, mice were sacrificed. DNA and RNA extracted from
      homogenized tissues were amplified for immediate early gene 1 (IE1) and late
      gene, glycoprotein H (gH), DNA and mRNA by PCR and RT-PCR, respectively.
      Replicating virus was detected in homogenized ocular and non-ocular tissues by
      plaque assay. In the latently infected PBS-treated control group, viral DNA was
      detected in the inoculated eye and in several non-ocular tissues; IE1 mRNA was
      found in most of the DNA-positive tissues, while gH mRNA was amplified only in a
      few of the MCMV DNA-positive tissues from a single mouse. After
      immunosuppression, viral DNA and IE1 mRNA were detected at a higher frequency in
      various tissues of steroid-treated mice. gH mRNA was detected in a significantly
      higher number of the inoculated eyes, salivary glands and other non-ocular
      tissues of steroid-treated mice. After immunosuppression, low titers of
      infectious virus were recovered from the salivary glands of steroid-treated mice,
      but infectious virus was not recovered from the inoculated eye of either steroid
      treated of non-immunosuppressed mice. The DNA PCR results suggest that after
      inoculation of 5 x 10(2) PFU of MCMV into the supraciliary space of euthymic
      BALB/c mice, virus becomes latent in the inoculated eye, salivary gland and other
      extraocular tissues. The RT-PCR results suggest that latent MCMV can be
      reactivated in multiple tissues by immunosuppression.

PMID- 8645086
TI  - Heat shock induces HIV-1 replication in chronically infected promyelocyte cell
      line OM10.1.
AB  - A long period of clinical latency before development of symptoms is
      characteristic of human immunodeficiency virus type 1 (HIV-1) infection. OM10.1,
      a promyelocyte cell line latently infected with HIV-1, has been developed as a
      model for studying the mechanism of viral latency and the activation of virus
      expression. We found that this latently infected cell line with heat shock at 42
      degrees C for 2 h resulted in a high level of HIV-1 production without addition
      of any cytokines. The mechanism of activation was analyzed by using anti-TNF
      alpha antibody and various inhibitors. Although the TNF-alpha level in culture
      supernatants was below the sensitivity of an ELISA assay system, addition of anti
      TNF-alpha antibody in culture medium could partially suppress the heat shock
      induced HIV-1 production. Staurosporine (PKC inhibitor), pentoxifylline (NF-kappa
      B inhibitor), and Ro5-3335 (HIV-1 Tat inhibitor) also inhibited significantly the
      heat shock induced virus activation. In particular, staurosporine achieved
      approximately 90% inhibition of the HIV-1 antigen expression in heat shock
      treated OM10.1 at a non-toxic concentration. Although the mechanism of HIV-1
      activation with heat shock has not been fully elucidated yet, it is presumed PKC
      plays an important role in HIV-1 activation. Thus, the present observations will
      provide a further insight into the pathogenesis of HIV-1 infections.

PMID- 8645087
TI  - Human papillomavirus type 16 (HPV 16) E7 and major histocompatibility complex
      (MHC) class I and II expression in human keratinocytes in culture.
AB  - The low expression of major histocompatibility complex (MHC) class I antigens on
      human papillomavirus (HPV)-infected cervical carcinoma cells may be responsible
      for an insufficient cytotoxic T cell response against these cells. To investigate
      in vitro whether the HPV type 16 early gene product E7 influences cell surface
      expression of MHC class I and II molecules the HPV negative keratinocyte cell
      line HaCaT was either stably transfected with the E7 gene or infected with E7
      recombinant vaccinia viruses. No difference in MHC class I transcription was
      detected between E7-transfected and untransfected HaCaT cells. MHC class I cell
      surface expression as determined by FACS analysis was stronger in some of the
      transfectants and less intensive in others when compared to untransfected HaCaT
      cells. In wildtype as well as in E7-recombinant vaccinia virus infected HaCaT
      cells downregulation of MHC class I molecules on protein and transcriptional
      level was observed. The alterations in MHC class I expression were independent of
      the presence and amount of E7-specific transcripts. None of the transfectants or
      infected HaCaT cells had MHC class II molecules on their cell surface. Hence, our
      data did not show a correlation between HPV 16 E7 and MHC expression in vitro.

PMID- 8645088
TI  - West Nile virus neuroinvasion and encephalitis induced by macrophage depletion in
      mice.
AB  - The encephalitic West Nile virus and its nonneuroinvasive variant, WN-25, were
      used to study the effect of macrophage depletion on viral invasion of the central
      nervous system. The in vivo elimination of macrophages was achieved by use of
      liposome-encapsulated drug dichloromethylene diphosphonate. Depletion of
      macrophages had an exacerbating effect on the course of the viral infection,
      exhibited by higher and extended viremia and accelerated development of
      encephalitis and death. Using a low dose of West Nile virus (5 PFU/mouse), an
      increase in mortality (from 50% to 100%) due to macrophage depletion was
      demonstrated. Furthermore, the attenuated noninvasive variant WN-25 showed high
      and prolonged viremia in the macrophage depleted mice (approximately 5 log 10
      PFU/ml versus 2 in control mice), that allowed the penetration of the virus into
      the central nervous system. The mortality rate caused by the attenuated virus in
      the macrophage-depleted mice was 70-75%, as compared to complete survival in the
      control inoculated mice. These results indicate a significant role of macrophages
      in the non-specific immediate defence system of the organism in case of viral
      infection.

PMID- 8645089
TI  - Protection of rabbits against HTLV-II infection with a synthetic peptide
      corresponding to HTLV-II neutralization region.
AB  - Rabbit immune sera raised against synthetic peptides of the HTLV-II envelope gp46
      region were examined for HTLV-II neutralization ability by HTLV-vesicular
      stomatitis virus (VSV) pseudotype assay and syncytium inhibition assay. HTLV-II
      neutralization activity was detected in the sera against HTLV-II Env gp46, 80-103
      but not in those to HTLV-II Env gp46, 171-196. Three rabbits immunized with the
      synthetic peptide of HTLV-II Env gp46, 80-103 and three non-immunized rabbits
      were challenged with intravenous inoculation of an HTLV-II-producing human cell
      line (MOT, 1 x 10(7) cells). The non-immunized rabbits showed seroconversion for
      HTLV-II after 2 weeks and maintained persistent infection but the immunized
      rabbits were protected from HTLV-II infection. Nested or repeated polymerase
      chain reaction revealed the presence of HTLV-II provirus sequences in the non
      immunized rabbits but not in the immunized rabbits. These results suggest that
      peptide vaccination with a synthetic peptide corresponding to the HTLV-II
      neutralization region is useful for preventing HTLV-II infection.

PMID- 8645090
TI  - Pathogenicity and vaccine efficacy of a thymidine kinase-deficient mutant of
      feline herpesvirus type 1 in cats.
AB  - We constructed a recombinant feline herpesvirus type 1 (FHV-1) which was deleted
      in a defined region (450 bp) within the thymidine kinase (TK) gene (C7301dlTK)
      [Yokoyama et al. (1995) J Vet Med Sci 57: 709-714]. In this report, we carried
      out two experiments to assess the pathogenicity and vaccine efficacy of the
      recombinant C7301dlTK in cats. The first experiment showed that, following
      multiple inoculation of the recombinant C7301dlTK by intraocular, intranasal and
      oral routes, the virus was sufficiently attenuated in cats, although a high titer
      of the virus was recovered from target organs (eye, nose, and mouth). In the
      second experiment, two intramuscular vaccinations with the recombinant C7301dlTK
      protected cats to a significant degree against subsequent challenge with the
      parent FHV-1 strain C7301 at 4 weeks after the last vaccination. These results
      demonstrate that the recombinant C7301dlTK is effective as a live attenuated
      vaccine with a clear genetic marker.

PMID- 8645091
TI  - Equine gammaherpesvirus 2 (EHV2) is latent in B lymphocytes.
AB  - Peripheral blood leukocytes were collected from 5 Thoroughbred horses and
      examined for the presence of EHV2 in sub-populations of mononuclear cells.
      Peripheral blood mononuclear cells were separated on Percoll gradients and then
      enriched for plastic adherent cells (predominantly monocytes), surface
      immunoglobulin positive (sIg+) B lymphocytes and T lymphocytes, using panning
      techniques. The purity of each cell population was assessed by fluorescence
      activated cell scanning. In an infectious centre assay, each cell population was
      inoculated onto equine foetal kidney monolayer cell cultures which are fully
      permissive for the replication of EHV2. Only enrichment for sIg+ B lymphocytes
      resulted in a marked increase in the number of infectious centres, indicating
      that EHV2 is present in B lymphocytes. Freeze-thawing of sIg+ B lymphocytes,
      prior to inoculation onto EFK monolayer cell cultures, resulted in the complete
      abrogation of infectious centre formation, confirming that EHV2 is latent in B
      lymphocytes i.e., infectious free virus was not present in the cells. The number
      of EHV2 infected B lymphocytes varied considerably between horses from 4 to 780
      per 10(6) cells. Evidence was also obtained that direct cell to cell contact
      between the epithelial cells and sIg+ B lymphocytes was necessary for the
      production of infectious centres. The data indicate that EHV2, like other members
      of the Gammaherpesvirinae, is latent within B lymphocytes.

PMID- 8645092
TI  - Intra-nuclear localization of two envelope proteins, gB and gD, of herpes simplex
      virus.
AB  - The envelopes of herpes simplex virus (HSV) particles are acquired from the inner
      nuclear membrane (INM) of the infected cell and virus-coded glycoproteins are
      present in the envelope of mature virions. Our ultrastructural study examined the
      process of virus envelopment and the targeting of two major viral glycoproteins,
      gB and gD, to the INM in HSV-infected human embryonic fibroblasts. It was shown
      that envelopment and transport of virus particles from the nucleus is facilitated
      by the formation of a dynamic tubulo-reticulum arising from the INM. Capsids were
      assembled in the nucleus and collected within INM tubules which protruded into
      the perinuclear space and thence into the cisternae of the endoplasmic reticulum
      (ER). Envelopment occurred by constriction and fusion of the tubular channel
      walls, releasing enveloped virions into the ER. Transport to the cell surface
      took place in membrane-bound compartments and probably followed the normal
      secretory pathway through the Golgi apparatus. Immunogold probes, tagged with
      specific monoclonal antibodies, were used to localize gB and gD during the
      process of virus maturation. Cytoplasmic membranes were not labelled, but probes
      bound inside the nucleus, mainly at sites of virus assembly. Labelling occurred
      on the nucleoplasmic side of the INM which surrounded capsids in the process of
      envelopment, but not on the outside of that membrane, although characteristic gB
      glycoprotein spikes were labelled on the envelopes of extracellular virus
      particles and on virions in trans-Golgi transport vesicles just prior to their
      release from the infected cell. gB was not detected on the surface of enveloped
      virions in the perinuclear space, or the cisternae of the ER or cis-Golgi, which
      suggests that the specific epitope was masked during that stage of intracellular
      processing. gD probes bound to virion envelopes and also to the tegument region
      of some particles found in both perinuclear and extracellular sites. We postulate
      the precursor core proteins for both gB and gD are transported first to the
      nucleus, and then, together with maturing capsids, are targeted to the INM, and
      later inserted into viral envelopes at the site of budding. Post-translational
      glycosylation of envelope proteins could occur as virus particles exit the
      nucleus and travel through the ER and Golgi compartments.

PMID- 8645093
TI  - Influenza virus PB1 protein is the minimal and essential subunit of RNA
      polymerase.
AB  - RNA polymerase of influenza virus with the subunit structure PB1-PB2-PA is
      involved in both transcription and replication of the genome RNA. The RNA
      polymerase with transcription activity was reconstituted from three P proteins,
      which were separately isolated from insect cells infected with recombinant
      baculoviruses, each carrying cDNA for one P protein. Nuclear extracts of the
      insect cells infected with each of the recombinant baculoviruses or various
      combinations of these viruses were examined for transcription and replication
      activities. The nuclear extract of cells expressing all three P proteins
      catalyzed model template-directed RNA synthesis in the absence of primers (an
      indication of RNA replication), supporting the notion that the complete set of
      three P proteins is required for RNA replication. All the nuclear extracts
      containing the PB1 subunit, including the extract containing PB1 alone, were able
      to catalyze model template-directed dinucleotide-primed RNA synthesis (an
      indication of transcription). These observations not only confirm that the PB1
      protein is a catalytic subunit of influenza virus RNA polymerase, but also
      indicate that PB1 alone is able to catalyze RNA synthesis in the absence of PB2
      and PA subunits.

PMID- 8645094
TI  - Purification and coat protein gene sequence of a Montana RMV-like isolate of
      barley yellow dwarf virus.
AB  - A Montana barley yellow dwarf virus (BYDV) isolate, BYDV-RMV-MT, is serologically
      identical to the New York RMV type isolate (RMV-NY) but differs in aphid
      transmission phenotype. A purification procedure for BYDV-RMV-MT was developed
      and cDNAs encompassing the entire coat protein gene and a portion of the putative
      polymerase gene of both RMV-MT and RMV-NY were cloned and sequenced. Diameters of
      RMV-MT virions averaged 24.7 nm. Average virus yield was 4.2 mg/kg plant tissue.
      There was 81% sequence identity between the clones of MT and NY RMV isolates at
      the nucleotide level. At the amino acid level the polymerase genes were 91%
      identical to each other and 74% homologous with that of beet western yellow
      virus. The coat protein amino acid sequences of the two RMV isolates were only
      81% identical and, compared to other sequenced luteoviruses, both were most
      similar to cucurbit aphid-borne yellows virus.

PMID- 8645095
TI  - Retrieval of human cytomegalovirus glycoprotein B from the infected cell surface
      for virus envelopment.
AB  - Surface biotinylation of human cytomegalovirus (HCMV)-infected fibroblasts under
      pulse-chase conditions was used to define the cellular route of the dominant
      viral envelope glycoprotein gB into the cytoplasmic compartment of viral
      maturational envelopment. The results showed that a major fraction of gB was re
      internalized from the infected cell surface prior to incorporation into the viral
      envelope. Viral particles carrying biotinylated gB were subsequently released
      into the culture medium. Viral release appeared to be inhibited in the presence
      of gB-specific antibody or when infected cultures were incubated at room
      temperature, but was not reduced by inhibitors of cellular glycoprotein
      transport. To our knowledge this is the first report describing that HCMV gB is
      retrieved from the infected cell surface prior to viral envelopment.

PMID- 8645097
TI  - Human rotavirus VP4 contains strain-specific, serotype-specific and cross
      reactive neutralization sites.
AB  - The neutralization epitopes of human rotavirus VP4 were studied by using a panel
      of neutralization monoclonal antibodies previously shown to be strain-specific
      (RV-3:3), serotype-specific (RV-5:2, ST-3:3) or cross-reactive (F45:4). Antigenic
      variants of human rotaviruses RV-3, ST-3, RV-5 and F45 resistant to
      neutralization by the appropriate of VP4 specific monoclonal antibodies (RV-3:3,
      ST-3:3, RV-5:2 and F45:4 respectively) were selected. By nucleotide sequence
      analysis and single strand conformational polymorphism analysis of these
      variants, three sites of neutralization on VP5* and one site on VP8* were
      identified. At or near to the putative fusion region on VP5*, a strain-specific
      site (aa383), a serotype P1A-P2 cross-reactive site (aa392) and a serotype P2
      specific site (aa397) were found. On VP8*, a serotype P1B-specific site at aa148
      was detected. These results confirmed the importance of the putative fusion
      region in neutralization and have identified a new neutralization site in the
      hypervariable region of VP8* which is specific for serotype P1B human
      rotaviruses.

PMID- 8645096
TI  - Alteration of interleukin-1 alpha production and interleukin-1 alpha binding
      sites in mouse brain during rabies infection.
AB  - We have evaluated the effect of rabies virus infection on interleukin-1 alpha (IL
      1 alpha) production and its receptors in mouse brain. Study of virus
      dissemination in the central nervous system (CNS) showed a massive infection of
      main brain structures from day 4 post infection (p.i.) up to the agony stage on
      day 6 p.i. At the same time, IL-1 alpha concentrations increased in cortical and
      hippocampal homogenates, whereas no change was detected in serum. In non-infected
      mice, IL-1 alpha binding sites were observed in the dentate gyrus, the cortex,
      the choroid plexus, the meninges and the anterior pituitary. During rabies virus
      infection, a striking decrease in IL-1 alpha binding sites was observed on day 4
      p.i. with a complete disappearance on day 6 p.i., except in the pituitary gland
      where they remained at control level. In conclusion, concomitantly with the early
      rabid pathological signs, brain IL-1 alpha production and IL-1 alpha binding
      sites are specifically and significantly altered by brain viral proliferation.
      These results indicate that IL-1 alpha could be involved in the brain response to
      viral infection as a mediator and could participate in the genesis of the rabies
      pathogeny.

PMID- 8645098
TI  - Cross-reactive, serotype- and monotype-specific neutralization epitopes on VP7 of
      serotype G3 and G5 porcine rotavirus strains.
AB  - VP7 specific monoclonal antibodies raised against serotype G5 porcine rotavirus
      strains isolated in Venezuela showed either a serotype G5- or monotype-specific
      pattern of reactivity by neutralization against a panel of 53 group A rotavirus
      isolates representative of all established G serotypes. Monoclonal antibodies
      raised against two G3 porcine strains were either specific for a subset of
      porcine G3 strains or reactive with another subset of porcine G3 strains and with
      most G5 strains. Neither were reactive with G3 strains from other species.
      Analysis of neutralization resistant mutants selected with these monoclonal
      antibodies indicated that epitopes defined by cross-reactive, serotype- and
      monotype-specific monoclonal antibodies overlap functionally and that binding and
      neutralization by these antibodies depended on specific amino acid residues in
      the region A or C of VP7. Results indicate that a high degree of monotypic
      variation occurs among G5 and G3 porcine rotavirus strains and the existence of
      at least one common epitope shared by G5 and G3 porcine strains, in the major
      neutralization domain of these VP7s.

PMID- 8645099
TI  - Isolation of a human rotavirus containing a bovine rotavirus VP4 gene that
      suppresses replication of other rotaviruses in coinfected cells.
AB  - Bovine-human reassortant strains containing ten human rotavirus gene segments and
      segment 4, encoding VP4, of a bovine rotavirus were isolated from the stool of an
      infected Bangladeshi infant during cell culture adaptation. Two plaque purified
      variants of this reassortant, one making very large (429-L4) and the other tiny
      (429-S4) plaques, were further analyzed. The electropherotypes of these variants
      were identical except for slight mobility differences in segment 4. The predicted
      sequence of amino acids (aa) 16-280 in VP4 proteins revealed four differences
      between variants even in this limited region, so no single difference could be
      linked to plaque size. The small plaque variant S4 was phenotypically unstable
      and mutated to a large plaque-former within a single cell culture passage. The
      predicted sequence of aa 16-280 of a large plaque variant derived from S4
      revealed six changes, only one of which was common to that of the L4 strain, thus
      suggesting that multiple amino acid changes in VP4 may affect plaque size.
      Although the large plaque variant L4 grew faster and was released from cells more
      rapidly than S4, its replication and that of other rotaviruses tested (i.e. RRV,
      NCDV and Wa) was suppressed by S4 in coinfected cells. Using an RRV x S4
      reassortant containing only RRV segment 4, it was established that suppression
      was linked to the S4 VP4 protein. This suppression could not be associated with
      inhibition of viral adsorption and, therefore, appeared to occur following
      internalization. Thus, a new property of the rotavirus VP4 protein has been
      identified in a bovine-human rotavirus reas-sortant.

PMID- 8645100
TI  - Pathogenicity and phylogenetic evaluation of the variant Newcastle disease
      viruses termed "pigeon PMV-1 viruses" based on the nucleotide sequence of the
      fusion protein gene.
AB  - The nucleotide sequences of the entire F genes of two isolates of the pigeon PMV
      1 (PPMV-1) variant of Newcastle disease virus (NDV) were determined using RTPCR.
      The deduced amino acid sequences of the F0 protein showed four differences
      between isolate 760/83 which had been passaged 4 times in chickens and gave an
      intravenous pathogenicity index in chickens (IVPI) of 2.01 and isolate 1168/84
      which had received six passages in chickens and had an IVPI of 0.00. The F genes
      of virus from two passage levels of isolate 1447/84, 0 with IVPI value 0.00 and
      six with IVPI value 0.58, were partially sequenced to cover the areas of
      variation between 760/83 and 1168/84. The two passage levels of 1447/84 showed
      identical sequences in these areas which in turn were identical of those of
      760/83. It was concluded that the recorded differences in intravenous
      pathogenicity were unlikely to be associated with differences in the primary
      structure of the F0 protein. Phylogenetic comparisons of the F gene sequences of
      the two PPMV-1 viruses with those published for other NDV strains and isolates
      showed that the PPMV-1 viruses formed a new fourth lineage but were closely
      related to strain Warwick with which they presumably shared a common origin.

PMID- 8645101
TI  - Influenza infection in humans and pigs in southeastern China.
AB  - The three last pandemic strains of influenza A virus-Asian/57, Hong Kong/68 and
      Russian/77-are believed to have originated in China. The strains responsible for
      the 1957 and 1968 human pandemics were reassortants incorporating both human and
      avian influenza viruses, which may have arisen in pigs. We therefore undertook a
      population-based study in the Nanchang region of Central China to establish the
      prevalence, types and seasonal pattern of human influenza infection and to screen
      serum samples from animals and humans for evidence of interspecies transmission
      of influenza viruses. Two definite influenza seasons were demonstrated, one
      extending from November to March and the other July to September. The profile of
      antibodies to commonly circulating human influenza viruses was no different in
      Nanchang and neighboring rural communities than in Memphis, Tennessee, USA. In
      particular, Chinese women who raised pigs in their homes were no more likely to
      have been exposed to influenza virus than were subjects who seldom or never had
      contact with pigs. However, we did obtain evidence using isolated H7 protein in
      an enzyme-linked immunoabsorbent assay for infection of pig farmers by an avian
      H7 influenza virus suggesting that influenza. A viruses may have been transmitted
      directly from ducks to humans. The results of the serological survey also
      indicated that pigs in or near Nanchang were infected by human H1N1 and H3N2
      influenza viruses, but not with typical swine viruses. We found no serological
      evidence for H2 influenza viruses in humans after 1968.

PMID- 8645102
TI  - Evaluation of the thymidine kinase (tk) locus as an insertion site in the highly
      attenuated vaccinia MVA strain.
AB  - The highly attenuated 'modified vaccinia Ankara' (MVA) strain is a potential live
      vaccine vector. Insertional inactivation of the tk-gene resulted in viruses
      difficult to purify. Co-integration of a functional fowlpox virus tk-gene allowed
      easy generation of recombinants, indicating that the genetically stable tk-gene
      region is a suitable insertion site, if tk-gene activity is substituted.

PMID- 8645103
TI  - Rabies virus M protein expressed in Escherichia coli and its regulatory role in
      virion-associated transcriptase activity.
AB  - Rabies virus M protein was expressed in Escherichia coli in the form of a fusion
      protein with maltose binding protein (MBP) and purified by amylose affinity
      column chromatography after extraction. In order to investigate the possible
      regulatory role of M protein in viral transcription, an assay system for rabies
      virion-associated transcriptase activity was established by using the
      ribonucleoprotein (RNP) cores prepared from purified virions. Analysis of the
      products of the transcription assay system showed that the products are sensitive
      to RNase and are positive-strand RNA. Addition of the fusion protein to the
      system after cleavage with a proteinase Factor Xa (FXa), which cleaves the fusion
      protein into the M protein and MBP, resulted in an efficient and dose-dependent
      inhibition of the transcription. Furthermore, addition to the system of anti-M
      protein monoclonal antibody significantly restored the transcription. Control
      experiments with the same transcription assaying system using rabies virus
      nucleoprotein expressed as a fusion protein with MBP and cleaved with FXa did not
      result in an inhibition of the transcription. These results suggest that the M
      protein of rabies virus has the property to down-regulate virion-associated
      transcription.

PMID- 8645104
TI  - RNA binding properties of core protein of the flavivirus Kunjin.
AB  - Kunjin virus (KUN) C is a typical flavivirus core protein which is truncated in
      vivo to a mature form of 105 residues enriched in lysine and arginine. In order
      to study the possible association of KUN C with RNA in vitro, we prepared several
      recombinant C proteins with specific deletions, each fused at the amino-terminus
      to glutathione-S-transferase (GST) and expressed in E. coli. They were reacted
      with KUN RNA probes transcribed in vitro from cDNA representing the 5'
      untranslated region (5' UTR, 93 to 96 nucleotides), the 3' UTR (624 nucleotides),
      and the 5' UTR plus most of the C coding region (5' core, 440 nucleotides).
      Fusion protein C107 (incorporating mature C) bound strongly to all KUN RNA probes
      with apparent specificity, being completely resistant to inhibition by 800 mM
      NaCl, and to competition by a large excess of tRNA. In reactions with labelled
      KUN RNA probes putative binding sites were identified in the isolated amino
      terminal (32 residues) and carboxy-terminal (26 residues) basic amino acid
      domains; this binding was strongly competed by unlabelled KUN UTR probes but
      weakly or not at all by tRNA. These small domains probably acted co-operatively
      in binding of mature C to KUN RNA probes. The KUN RNA-core protein binding
      reactions are similar to those reported with other viral coat or capsid proteins
      and viral RNAs.

PMID- 8645105
TI  - Full-length genomic sequence of a hepatitis C virus genotype 2c isolate (BEBE1)
      and the 2c-specific PCR primers.
AB  - We sequenced the entire genome of an Italian isolate of hepatitis C virus: the
      first full-length sequence for the genotype 2c. We report hereby its
      characteristics and differential detection of 2c isolates using PCR.

PMID- 8645107
TI  - Epidemiology of symptomatic human rotaviruses in Bangalore and Mysore, India,
      from 1988 to 1994 as determined by electropherotype, subgroup and serotype
      analysis.
AB  - Epidemiology of symptomatic rotaviruses from Bangalore and Mysore in Southern
      India was investigated. While serotype G3 predominated throughout the 7-year
      study period from 1988 to 1994 in Bangalore, serotype G1 was more predominant
      than serotype G3 in Mysore during 1993 and 1994. Serotype G2 strains were either
      not detected or infrequently observed in both the cities. However, several
      strains with subgroup I and 'short' RNA pattern that exhibited high reactivity
      with typing MAbs specific for serotype 2 as well as other serotypes were detected
      throughout the period. Among the nonserotypeable strains from both cities,
      several exhibited dual subgroup (SGI + II) or subgroup I specificity and 'long'
      RNA pattern indicating their probable animal origin. Notably, a gradual, yet
      highly significant reduction in rotavirus gastroenteritis, from 45.3% in 1988 to
      1.8% during 1994, was observed in Bangalore in stark contrast to the consistently
      high (about 34%) incidence of asymptomatic infections among neonates by I321-like
      G10P11 type strains during the same period. Moreover, I321-like asymptomatic
      strains were not detected in children with diarrhea.

PMID- 8645108
TI  - Capsid protein of cucumber mosaic virus accumulates in the nuclei and at the
      periphery of the nucleoli in infected cells.
AB  - Tobacco leaves infected with two strains and their reciprocal RNA 3
      pseudorecombinants of cucumber mosaic virus (CMV) were examined by immunoelectron
      microscopy. In addition to the regular detection of CMV in the cytoplasm and
      vacuoles, immunogold-labelled viral proteins occurred commonly in the nuclei and
      at the periphery of impacted nucleoli in all four samples examined. However,
      viral protein was present only in the euchromatin region and rare in the
      heterochromatin region.

PMID- 8645106
TI  - Sequence comparison of the VP7 gene encoding the outer capsid glycoprotein among
      animal and human group C rotaviruses.
AB  - The nucleotide sequences of the outer capsid glycoprotein (VP7) genes from the
      Shintoku bovine and the HF and WH porcine group C rotaviruses were determined and
      compared with those of the published corresponding genes from the Cowden porcine
      and Ehime human group C rotaviruses. The VP7 genes of all 5 strains were 1063
      nucleotides in length and possess one open reading frame encoding a polypeptide
      of 332 amino acids. Comparative analysis of the deduced amino acid sequences
      indicated that 85.2-97.0% identity was observed for the VP7 of the serotypically
      related strains of group C rotaviruses (Cowden, WH and Ehime) whereas 69.9-74.7%
      identity was observed among the serotypically distinct strains (Shintoku; Cowden,
      WH and Ehime; and HF). At least 8 variable regions in the VP7 were recognized
      among serotypically distinct strains, and these locations were similar to those
      of the variable regions in the VP7 of group A rotaviruses.

PMID- 8645109
TI  - A new mumps virus lineage found in the 1995 mumps outbreak in western Switzerland
      identified by nucleotide sequence analysis of the SH gene.
AB  - We determined the nucleotide sequence of the SH gene its flanking regions over a
      range of 380 nucleotides for three distinct mumps virus (MUV) isolates. Two
      isolates from the 1992 mumps epidemic in Western Switzerland and one MUV isolated
      in 1995 in the same geographic area have been analyzed and compared to 16
      recently published SH nucleotide sequences and their presumed amino acid
      sequences. The nucleotide sequences from the 1992 MUV isolates were identical and
      closely related to two MUV strains from Eastern Switzerland and strains from the
      U.K. The MUV isolated in 1995 is clearly different from all other strains.

PMID- 8645110
TI  - Immunisation with DNA polynucleotides protects mice against lethal challenge with
      St. Louis encephalitis virus.
AB  - In vivo transfection by intramuscular injection with plasmids expressing the
      immunogenic proteins of microbial pathogens has considerable potential as a
      vaccination strategy against many pathogens of both man and animals. Here we
      report that weanling mice given a single intramuscular injection of 50 micrograms
      of a plasmid, pSLE1 expressing the St. Louis encephalitis virus (SLE) prM/E
      protein under the control of the cytomegalovirus immediate early protein promoter
      produced SLE-specific antibody and were protected against lethal challenge with
      the virulent virus. Polynucleotide vaccine technology provides a unique
      opportunity to produce vaccines against flavivirus diseases of low incidence
      cheaply and rapidly, and to produce multivalent vaccines such as would be
      required for immunisation against dengue virus disease.

PMID- 8645112
TI  - Detection of species specific epitopes of mouse and hamster prion proteins (PrPs)
      by anti-peptide antibodies.
AB  - Antisera to four synthetic peptides containing the substitutions between mouse
      and hamster prion proteins (PrPs) were produced in rabbits. The synthetic
      peptides used represent two mouse (Mo-I: residues 100-115 and Mo-V: residues 199
      208) and two hamster PrP subregion sequences (Ha-I: 101-116 and Ha-V: 200-209).
      All antisera reacted strongly with homologous peptides but either not at all or
      poorly with heterologous peptides in enzymelinked immunosorbent assay (ELISA).
      Antisera to Mo-I and Mo-V recognized mouse PrPSc but not hamster PrpSc in western
      blot analysis (WB) and ELISA. Antisera to Ha-I contain antibodies specific to
      hamster PrPSc. The results indicate that these regions of PrPSc constitute
      species-specific epitopes. In contrast to these antisera, the antiserum to Ha-V
      recognized neither hamster nor mouse PrPSc. In this study, we identified mouse
      subregion-V as a species-specific epitope.

PMID- 8645111
TI  - Kinetics of humoral immune response to the major structural proteins of the
      porcine reproductive and respiratory syndrome virus.
AB  - The kinetics of appearance of antibodies directed to the major structural
      proteins N, M and E of porcine reproductive and respiratory syndrome virus
      (PRRSV) was followed in pigs naturally- and experimentally-exposed to the virus.
      Specific IgM antibody titers were first detected by indirect immunofluorescence
      (IIF) at the end of the first week of PRRSV infection, peaked by day 14 to 21
      post-inoculation (p.i.), then rapidly decreased to undetectable levels by day 35
      to 42 p.i. On the other hand, specific IgG antibody titers peaked by day 21 to 28
      p.i. and remained unchanged to the end of the 6- or 9-week observation period; in
      addition, a persistent viremia was observed. Virus neutralizing (VN) antibody
      titers > 8 were not detected until 3 to 4 weeks p.i. Taken together, the results
      obtained by Western blotting analyses using purified virus and E. coli-expressed
      ORFs 5 to 7 gene products, suggested that antibodies directed against the
      envelope E protein appear by day 7 p.i., whereas antibodies directed against the
      nucleocapsid N and membrane M proteins can only be detected by the end of the
      second week p.i. No correlation could be demonstrated between VN and IIF antibody
      titers, viremia, and viral protein specificities of circulating antibodies at
      various times p.i.

PMID- 8645113
TI  - Comparative sequence analysis of the 5' noncoding region of classical swine fever
      virus strains from Europe, Asia, and America.
AB  - Polymerase chain reaction was utilized to determine the sequence of a 280 base
      pair fragment from cDNAs of the 5' noncoding region of 29 isolates of classical
      swine fever virus. Phylogenetic analysis of the sequences revealed low level
      genomic variation that correlated with the geographic origins of the isolates.

PMID- 8645114
TI  - Reminiscences of a virologist wandering in serendip.

PMID- 8645115
TI  - Cancer of the lung, pleura, larynx and pharynx in an area with an asbestos-cement
      plant.
AB  - Data on persons who died of cancer of the respiratory tract and pharynx in a
      Croatian coastal area with an asbestos-cement industry were collected and
      analysed for the period 1970-1990. Cancer mortality data were obtained from the
      Cancer Registry of Croatia. By the poll method, additional data on occupation,
      life style (smoking, alcohol drinking), length of residence in the area,
      educational level and cancer mortality among the relatives were obtained. The
      results of the investigation showed that the mortality rates for the lung, larynx
      and pharynx cancers, standardized according to age, were lower in the study area
      than expected (data for Croatia). Standardized mortality rates for mesothelioma
      were higher in the area under study for both sexes (except for women in the rural
      part of the area) than in Croatia. Within the study area the highest mortality
      rates for follow-up cancers were registered in the settlement where the asbestos
      cement plant was located. Some settlements in two municipalities within the area
      also had higher mortality rates caused by these tumours in comparison with the
      rest of the study area or Croatia as a whole. In the evaluation of the obtained
      findings possible uneven distribution of emissions from the asbestos-cement plant
      caused by prevailing wind and air stream direction were considered.

PMID- 8645116
TI  - Exposure evaluation is a crucial step for quantitative risk assessment of
      methomyl.
AB  - Methomyl, methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate is a carbamate
      insecticide with anticholinesterase activity. As a broad spectrum insecticide, it
      is one of the most frequently used pesticides in tangerine orchards in Thailand.
      Although methomyl is said to be rapidly eliminated from experimental animals (1)
      high incidence of acute poisonings was reported among patients occupationally
      exposed to a powder formulation of methomyl (2, 3). In this passive dosimetry
      study of tangerine growers, during mixing and overhead spraying of a 90% powder
      formulation of methomyl, ocular and nasal exposure was measured. Exposure data
      are discussed in terms of the "potentially absorbed" or "internal dose".

PMID- 8645117
TI  - Biomarkers of exposure to organic solvents from glues used in table tennis bats.
AB  - In nine samples of the glues used to glue rubber onto the table tennis bats,
      benzene, toluene, xylene, trichloroethene (TRI) and tetrachloroethene (TETRA)
      were determined by head-space gas chromatography. The analyses demonstrated the
      presence of benzene (1.8-4.8% (w/w)), toluene (0.32-33.90% (w/w)) and TRI (0.0006
      0.280% (w/w)) in seven samples and of toluene only (22.50-67.20% (w/w)) in two
      samples. Xylene and TETRA were not detected in any of the glue samples analysed.
      Benzene, toluene and TRI in blood, as a measure of body burden, were determined
      in four table tennis players (aged 11-14 years) and five volunteers (aged 26-38
      years). They were at the same level as in the general population. The aim of the
      study was to draw attention to the possibility of exposure to organic solvents
      from glues used in table tennis bats, particularly as it is very often a question
      of child exposure.

PMID- 8645118
TI  - Arterial hypertension in workers: prevalence, awareness, treatment, control and
      heart changes.
AB  - Hypertension prevalence, awareness of high blood pressure, its treatment and
      control were estimated in 1100 workers, between the ages 35 and 59. Hypertension
      was defined as blood pressure > or = 160/95 mm Hg. The incidence of hypertensive
      heart disease was also investigated. All hypertensive persons were taken M-mode
      and 2-dimensional echocardiograms, electrocardiogram and chest X-ray. The
      criteria for both sexes were Casale's ECG for left ventricular hypertrophy and
      echocardiographic left ventricular mass index of 120 g/m or greater. The
      prevalence of hypertension was 14%. The percentage of persons who were aware of
      hypertension but did not receive treatment was 66%; 28% were treated but were not
      adequately controlled for high blood pressure. Only 6% of hypertensive workers
      received treatment and had high blood pressure under control. The prevalence of
      heart changes among the hypertensive workers as determined by echocardiographic
      standards was 67%, by electrocardiographic standards 19% and chest X-ray
      standards 29%. Systolic blood pressure was significantly related to ventricular
      mass (r = 0.34; 0.26) and voltage of R in a VL + S in V3 (r = 0.28; 0.24) in all
      hypertensive subjects, irrespective of treatment. Our study showed a high
      prevalence of hypertensive heart disease, 100% awareness of disorder and a low
      rate of treatment and control.

PMID- 8645119
TI  - [Respiratory symptoms and ventilatory function of the lungs in wool textile
      industry workers].
AB  - Subjects in the study were 158 female wool textile workers and 87 control non
      exposed workers. Respiratory symptoms were assessed by means of a questionnaire.
      Ventilatory capacity was measured in wool workers by recording maximum expiratory
      flow-volume (MEFV) curves on Monday before and after the work shift. Forced vital
      capacity (FVC), one-second forced expiratory volume (FEV1) and flow rates at 50%
      and the last 25% of the vital capacity (FEF50, FEF25) were measured on MEFV
      curves. Significantly higher prevalences of all chronic respiratory symptoms were
      recorded in exposed than in control workers (P < 0.01). Exposure to wool dust
      caused significant across shift reductions of ventilatory capacity varying from
      2.0 to 9.1%. Those reductions were similar in textile workers exposed to wool for
      more than 10 years showed similar across shift reductions of ventilatory capacity
      tests as those with shorter exposure. Smokers and non-smokers had similar acute
      and chronic lung function changes. In a larger number of wool workers FEF50 and
      FEF25 were below 70% of predicted normal values. Bronchoprovocation testing with
      wool dust extract did not demonstrate correlation with respiratory impairment.
      Our data suggest that dust exposure in wool textile mills may be associated with
      the development of chronic respiratory symptoms and impaired lung function.

PMID- 8645120
TI  - The toxicity/essentiality of dietary minerals. A review on some micronutrients
      prepared in honor of the Award for Life Achievement to Doctor Krista Kostial.
AB  - Continued progress in the theory and practice of trace element analytical
      chemistry has made possible significant advances in investigating the role and
      fate of trace elements in biological systems. Public health commissions and
      environmental protection agencies have subsequently established requirements for
      intakes of and exposures to trace elements both from the nutritional (copper
      zinc) and from the toxicological (cadmium-mercury) perspectives. Some trace
      elements demonstrate the properties of both categories, and consequently give
      rise to questions about the toxicity of essential dietary minerals. Selenium and
      chromium are typical examples of this toxicity-essentiality paradox. The systemic
      intoxication by and/or nutritional importance of these elements are reviewed as
      are the criteria for assessing their toxicity and essentiality.

PMID- 8645121
TI  - [Importance of risk assessment in occupational medicine].
AB  - The principles of risk assessment and its relevance in the working environment
      are discussed. Occupational health protection is a complicated process comprising
      risk assessment, health monitoring and eventually treatment of irreversible
      health effects. Risk assessment consists of the following four steps: hazard
      identification, dose-response assessment, exposure assessment and risk
      characterization. Although established for environmental protection, risk
      assessment is also used in occupational hazard identification and determination
      of priorities and risk management in occupational health and safety. In Croatia,
      the methodology of risk assessment is still undeveloped. The paper emphasises the
      role of occupational health in risk assessment and in implementation of the
      results of this complex process in the working environment.

PMID- 8645122
TI  - [Scientific and technical publications of the Institute of Medical Research and
      Occupational Health 1988-1993].
AB  - The bibliographic output of the Institute over an eight-year period (1988-1993)
      was classified into nine categories: scientific papers published in journals
      covered by Current Contents, scientific papers covered by other secondary
      publications, scientific papers in journals not covered by non-selective
      secondary or tertiary publications, congress communications, congress abstracts,
      technical papers, chapters in books, books and theses. The number of the
      Institute's staff, their academic degrees and professions were also recorded. The
      ratio between the number of papers and the number of scientists was calculated
      and compared to the ratio in the previous years and in some other research
      institutions in the country. An increase was observed in the Institute production
      of scientific papers in international journals. The papers were published in
      journals covered by all seven Current Contents editions. Most papers were in
      journals which were covered by the Life Sciences edition of Current Contents.

PMID- 8645123
TI  - Is it necessary to use metabolic assist for multiorgan failure patients with left
      ventricular assist devices? No, it should be circulatory assist for splanchnic
      organs.

PMID- 8645125
TI  - Potential hazards of deionization systems used for water purification in
      hemodialysis.
AB  - This study was conducted to determine the efflux of specific ions, including
      fluoride, from a deionization (DI) water purification system (WPS) when the WPS
      was operated beyond exhaustion of the DI resin. Effluent from the DI WPS was
      monitored for resistivity, total dissolved solids, pH, and concentrations of
      silica, fluoride, potassium, and sodium. After 16,000 L of water was purified,
      the resistivity declined to 0.492 omega Ohm-cm, and silica was released from the
      DI WPS. Fluoride ions were released after an additional 8,000 L water was
      treated, and the resistivity fell to 0.07 omega Ohm-cm. The fluoride efflux
      reached a peak of 32 mg/L, 28 times greater than the original fluoride
      concentration in the city water. Sodium and potassium ions were released after
      approximately 26,000 and 32,000 L of water had been treated and reached peaks of
      76 and 47 mg/L, respectively. This study confirms that the minimum resistivity
      standard of 1 omega Ohm-cm for DI water used for hemodialysis should provide an
      adequate safety margin. Once resistivity fell to 1 omega Ohm-cm, more than 8,000
      L of water was treated before fluoride efflux occurred. Accordingly, hemodialysis
      centers should be attentive to the calculated capacity of their DI WPS and
      reliably monitor the resistivity to prevent patient illness related to exhaustion
      of DI resins.

PMID- 8645124
TI  - Biophysical studies on the correction of uremic human serum albumin binding
      defects by in vitro charcoal adsorption treatment.
AB  - Spectrofluorimetry, flow microcalorimetry, and differential scanning
      microcalorimetry (DSMC) were used to study the conformation, binding function,
      and ligand loading of uremic albumin obtained from the blood plasma of 2 end
      stage renal disease (ESRD) patients before and after charcoal plasma treatment at
      different pH values (3.0-9.0). The spectrofluorimetric patterns of conformational
      N-F transition at low pH (4.2-3.5) are practically identical for both samples of
      uremic human serum albumin (HSA) and control HSA from healthy donors. After the
      charcoal treatment at pH 3.0 and 4.0, the enthalpies of complexing on uremic HSA
      with bromsulfalein and sodium dodecylsulfate approach that of donor HSA. The
      binding affinity of uremic HSA for sodium octanoate, phenol red, and salicylic
      acid following low pH charcoal treatment even exceed those of donor HSA. At the
      same time the charcoal treatment of uremic plasma at neutral and alkaline pH does
      not notably improve the binding characteristics of isolated HSA. Adsorption at
      low pH values completely restores the tryptophan fluorescence spectrum position
      of uremic albumin and improves the thermodynamic characteristics of its melting
      process. Using DSMC data, it can nevertheless be concluded that some
      conformational changes or a certain amount of high-affinity bound endogenous
      ligands still remain after low pH uremic HSA purification. The latter conclusion
      requires additional improvements of adsorption treatment of uremic plasma.

PMID- 8645126
TI  - An immunohistochemical analysis of implanted woven Dacron and expanded
      polytetrafluoroethylene grafts in humans.
AB  - An immunohistochemical analysis was performed to clarify the healing process in
      implanted vascular grafts in human. Eight woven Dacron grafts and 6 expanded
      polytetrafluoroethylene grafts were obtained following redo surgery, limb
      amputation, and autopsy. The implantation periods ranged from 5 days to 148
      months. The antibodies used for the analysis were specific to alpha-actin (smooth
      muscle cells), macrophages, von Willebrand factor (endothelial cells), fibrin,
      elastin, collagen types 1-5, CD3 (T cells), and CD20 (B cells). At 5 and 24 days
      after implantation, thrombi containing red blood cells and fibrin covered the
      anastomotic lines and some of the luminal surfaces of the grafts. Macrophages
      were scattered throughout the thrombi. At 11-148 months after implantation,
      either a single layer of endothelial cells or a thin layer of fibrin covered the
      anastomotic segments of the grafts, and smooth muscle cells and collagen fiber
      were seen forming anastomotic intimal hyperplasia (AIH). The AIH in the grafts at
      94 and 148 months after implantation was almost the same thickness and length a
      that in the grafts at 11-36 months after implantation Apart from the anastomotic
      segments, a connective tissue matrix containing collagen fibers covered the
      luminal surfaces, and some thrombi were noted. Most of the collagen present was
      type 3, in addition to some type 1, 4, and 5 collagen. No type 2 collagen was
      noted. Some elastin was also detected in the AIH but not in the midportion of the
      grafts. Some macrophages and T cells were noted in the perigraft tissues.

PMID- 8645128
TI  - In vitro testing of artificial heart valves: comparison between Newtonian and non
      Newtonian fluids.
AB  - The in vitro testing of artificial heart valves is often performed with simple
      fluids like glycerol solutions. Blood, however, is a non-Newtonian fluid with a
      complex viscoelastic behavior, and different flow fields in comparable geometries
      may result. Therefore, we used different polymer solutions (Polyacrylamid,
      Xanthan gum) with blood-like rheological properties as well as various Newtonian
      fluids (water, glycerol solutions) in our heart valve test device. Hydrodynamic
      parameters of Bjork-Shiley heart valves with a tissue annulus diameter (TAD) of
      21-29 mm were investigated under aortic flow conditions. Major results can be
      summarized as follows. The mean systolic pressure differences depend on the model
      fluids tested. Closing time and closing volume are not influenced by the
      rheological behavior of fluids. These parameters depend on TAD and the pressure
      differences across the valve. In contrast, rheological behavior has a pronounced
      influence upon leakage flow and leakage volume, respectively. Results show
      furthermore that the apparent viscosity data as a function of shear rate are not
      sufficient to characterize the rheological fluid behavior relevant to
      hydrodynamic parameters of the heart valves investigated. Therefore, similarity
      in the yield curves of non-Newtonian test fluids mimicing blood is only a pre
      requisite for a suitable test fluid. More information about the viscous and
      elastic component of the fluid viscosity is required, especially in geometries
      where a complex flow field exists as in the case of leakage flow.

PMID- 8645127
TI  - The superiority of hollow fiber membrane over bubble oxygenator in a perfusion
      circuit for the evaluation of small caliber endothelialized arterial prostheses.
AB  - A perfusion circuit was constructed from a pneumatic ventricular assist device, 2
      compliance chambers, 4 small-diameter silicone tubes (ID 4 mm) simulating shear
      inducing vascular prostheses, and an oxygenator with a heat exchanger. A bubble
      oxygenator (in a BO circuit) and a hollow fiber membrane oxygenator (in an MO
      circuit) were studied. The circuits were perfused with 30% human serum containing
      culture medium for 7 days at 37 degrees C. The pH, Po2, PCo2, Na+, K+, Ca2+, Cl,
      glucose, and total protein concentrations remained the same in BO and MO circuits
      during the 7 days of perfusion. The differences between the values measured in
      the perfusion medium and in the medium maintained in the static conditions of
      cell culture were not significant. In the BO circuit, the amount of cholesterol
      and triglyceride concentrations decreased whereas the relative amounts of
      albumin, alpha 1, alpha 2, beta, and gamma globulins remained stable in the
      perfusion medium. The medium from the BO circuit did not promote the
      proliferation of cultured human saphenous vein endothelial cells. In the medium
      from the MO circuit, the cholesterol and triglyceride concentrations did not
      change with perfusion time; the proliferation rate and anticoagulant function of
      endothelial cells were maintained. The hollow fiber membrane oxygenator preserves
      the biological characteristics of the cell culture medium in a perfusion circuit.
      The MO circuit permits the performance of relevant studies on shear stress
      resistance and functional activity of human endothelial cells seeded onto
      vascular prostheses.

PMID- 8645129
TI  - Ex vivo phase 1 evaluation of the DeBakey/NASA axial flow ventricular assist
      device.
AB  - A small ventricular assist device intended for long-term implantation has been
      developed by a cooperative effort between the Baylor College of Medicine and the
      NASA/Johnson Space Center. To date, in vitro tests have been performed to address
      hemolysis and pump performance issues. In this Phase 1 study, we assessed the
      durability and atraumatic features aiming for 2 day implantation. Eight pumps
      were implanted in 2 calves as paracorporeal left ventricular assist devices. The
      pump running times ranged from 18 to 203 h (78.1 +/- 23.7; mean +/- SEM). All the
      pump implantations were terminated because of thrombus formation. Plasma-free
      hemoglobin levels were below 13.7 mg/dl, except for 1 case complicated by inflow
      cannula obstruction. The pump speed was maintained between 10,100 and 11,400 rpm.
      Pump outputs were from 3.6 to 5.2 L/min. The electrical power required by the
      system ranged between 9 and 12 W. Clinically there was no detectable organ
      dysfunction noted, and postmortem evaluation demonstrated no pump related adverse
      effects in either calf except for small kidney infarctions. Thrombus deposition
      was observed mainly at the hub portions and the flow straightener.

PMID- 8645130
TI  - Dialyzer reuse: interaction between dialyzer membrane, disinfectant (formalin),
      and blood during dialyzer reprocessing.
AB  - The growing practice of dialyzer reuse in recent years is mainly based on medical
      and economic considerations. However, adverse reactions such as immunohemolytic
      anemia due to anti-Nform antibody associated with dialyzer reuse have been
      reported. In this study, scanning electron microscopy and cytologic staining were
      used to evaluate the interaction between blood components and the reprocessed
      synthetic dialyzer membrane (polysulfone) after disinfectant (formaldehyde)
      treatment. The results showed that various blood components such as fibrin and
      blood cells still adhered to the dialyzer membrane after reprocessing. The study
      also demonstrated that the adhered denatured blood components could be detached
      by sonication and/or simulated hemodialysis and then gain access into the
      circulation. The re-entry of the denatured blood components to the patients
      exposed to reused dialyzers may result in an enhanced immunological response
      which may contribute to antibody formation (such as anti-Nform antibody) with a
      reused hemodialyzer.

PMID- 8645131
TI  - Functional stability of porcine hepatocyte spheroids in various culture systems
      under 100% porcine and human plasma conditions.
AB  - To select an immobilization method suitable for bioartificial liver (BAL) modules
      utilizing porcine hepatocyte spheroids, functional activities were compared in
      various systems in 100% porcine and human plasma together with a synthesized
      medium. The spheroids, continuously suspended in rotating dishes or entrapped in
      collagen (CN) gel, expressed approximately two times higher ammonium
      detoxification abilities over conventional monolayers during 8 days of direct
      contact with 100% human or porcine plasma with a standardized inoculum cell
      number. No significant deterioration was observed in the abilities as compared
      with that in a synthesized medium. Although the cell number gradually decreased
      in rotational culture, the abilities per cells remaining on Day 10 were two times
      higher than in the CN-gel entrapped spheroids in all the media examined,
      presumably due to the diffusion limitation by the gel. Thus, in utilizing porcine
      hepatocyte spheroids in BAL modules, immobilization allowing direct contact of
      spheroids with perfused patient plasma was concluded to be possible and suitable.

PMID- 8645132
TI  - Inhaled nitric oxide during extracorporeal membrane oxygenation for the treatment
      of severe persistent pulmonary hypertension of the newborn.
AB  - Inhaled nitric oxide (NO) as a complementary treatment was studied in 10 neonates
      during extracorporeal membrane oxygenation (ECMO) therapy of various persistent
      pulmonary hypertension of the newborn (PPHN)-associated diseases. At individually
      different levels of inhaled NO (20-80 ppm), the mean Pao2 increased by 59.7% in 6
      responders, but it remained unchanged in 4 nonresponders. Adverse side effects of
      the NO inhalation were tolerable. It was associated with a reversible decrease of
      the mean arterial blood pressure in 1 patient. During prolonged NO inhalation,
      the methemoglobin (met-Hb) level increased to 0.9-4.6% in 6 patients. Based on
      these preliminary results, we conclude that inhaled NO during ECMO can improve
      oxygenation in some PPHN patients. Further studies with control groups are needed
      to determine whether inhaled NO can shorten ECMO treatment or improve the rate of
      survival among PPHN patients.

PMID- 8645133
TI  - Long-term ventricular wall actuation: can and should it be systematically
      explored?
AB  - Hearts fail because myocardial power fails. Assist, support, or replacement
      devices fail, at least in part, because their blood-contacting surfaces fail.
      Mechanical repowering of a failing heart might circumvent these difficulties by
      preserving a largely healthy endocardium while correcting the basic deficit,
      power. Any serious consideration of doing this though must confront some
      difficult requirements. Effective indefinite support must be coupled with
      preservation or restoration of valve competence, coronary flow, rapid low
      impedance refilling and independent left and right pressures; the avoidance of
      wall coaptation; hardware that fits in the available space; and unless muscle
      powered, adaptability to a deliverable form of power. Despite earlier intense
      interest in acute mechanical devices and later empiric study of muscle wraps,
      little systematic methodical work has been done on elucidating and meeting these
      practical requirements. Concerted efforts toward developing research tools and
      techniques for their study and then finding mechanisms to meet them could well
      yield one or more effective modalities that circumvent a major obstacle to the
      indefinite mechanical treatment of heart failure.

PMID- 8645134
TI  - Regenerated cellulose-based hemodialyzers with immobilized proteins as potential
      devices for extracorporeal immunoadsorption procedures: an assessment of protein
      coupling capacity and in vitro dialysis performances.
AB  - The development of immunoadsorbents usable with whole blood should offer the
      potential for making significant improvements in extracorporeal immunoadsorption
      procedures. In contrast to traditional chromatographic media, these
      hemocompatible matrices could be used without requiring the previous step of the
      separation of blood cells and plasma. Conventional hemodialyzers seem to be
      particularly appropriate for such a purpose. This paper describes a feasibility
      study of the preparation of immunoaffinity supports, from regenerated cellulose
      (Cuprophan)-based dialyzers by cyanogen bromide activation and coupling of bovine
      serum albumin or human immunoglobin G, used as models for immunochemical ligands.
      Several parameters of the activation and coupling steps were studied in order to
      define the optimum preparation conditions. In addition, the preservation of the
      transport properties (clearance and ultrafiltration) of the modified
      hemodialyzers was evaluated in vitro to ensure that the device potentially could
      be used in future human therapeutic applications with no risk of massive removal
      of solutes and fluid from the blood. Results indicate that 150-300 mg of
      immunoglobulins can be immobilized per square meter of Cuprophan. Modified
      hemodialyzers show a slight decrease of their clearance values and a slight
      increase of their ultrafiltration coefficients, and thus they can be proposed as
      reliable carrier material for extracorporeal cleansing systems.

PMID- 8645135
TI  - Two mathematically defined expressive language structures in humans and
      chimpanzees.
AB  - Two expressive language structures have been identified mathematically in humans
      and chimpanzees. The first was found by measuring the waiting times between the
      invocation of new words or symbols, which consistently yielded individually
      characteristic rate constants and descending exponential curves that reflect a
      stochastically lawful Poisson process. The second was discovered by calculating
      the cumulative informational complexity (entropy) of word usage, which in all
      cases was a deterministically lawful logarithmic function of the number of words
      used to a given point in a communicative sequence. Individual and species
      differences in how this law is obeyed also characterized the sample. The results
      from the apes resembled those from the works of human poets like Shakespeare. The
      findings speak for deep, natural, unlearned expressive language structures in
      apes that are comparable to those seen in humans.

PMID- 8645136
TI  - pH-dependence of the dithiol-oxidizing activity of DsbA (a periplasmic protein
      thiol:disulphide oxidoreductase) and protein disulphide-isomerase: studies with a
      novel simple peptide substrate.
AB  - A decapeptide containing two cysteine residues at positions 3 and 8 has been
      designed for use in monitoring the disulphide bond-forming activity of
      thiol:disulphide oxidoreductases. The peptide contains a tryptophan residue
      adjacent to one of the cysteine residues and an arginine residue adjacent to the
      other. Oxidation of this dithiol peptide to the disulphide state is accompanied
      by a significant change in tryptophan fluorescence emission intensity. This
      fluorescence quenching was used as the basis for monitoring the disulphide bond
      forming activity of the enzymes protein disulphide-isomerase (PDI) and DsbA (a
      periplasmic protein thiol:disulphide oxidoreductase) in the pH range 4.0-7.5,
      where the rates of spontaneous or chemical oxidation are low. Reaction rates were
      found to be directly proportional to enzyme concentration, and more detailed
      analysis indicated that the rate-determining step in the overall process was the
      reoxidation of the reduced form of the enzyme by GSSG. The pH-dependence of the
      enzyme-catalysed reaction reflected primarily the pKa of the reactive cysteine
      residue at the active site of each enzyme. The data indicate a pKapp of 5.6 for
      bovine PDI and of 5.1 for Vibrio cholerae DsbA.

PMID- 8645137
TI  - Binding and internalization of extracellular type-I phospholipase A2 in uterine
      stromal cells.
AB  - The cellular uptake of extracellular type-I phospholipase A2 (PLA2) was
      investigated in rat uterine stromal cells (UIII) in culture, which were found to
      express the high-affinity binding site for mammalian type-I PLA2, with a measured
      KD of 6.4 nM, a Bmax of 0.1-1 pmol/mg of DNA at 4 degrees C, and a molecular mass
      of about 200 kDa. When UIII cells were treated with type-I PLA2 at 37 degrees C,
      the ligand specifically associated with the cells increased, reaching a plateau
      after 90 min of incubation, whose level was about 5-fold higher than that
      measured if cells were maintained at 4 degrees C. We could determine that the
      PLA2 was bound to plasma membrane receptors which were responsible for
      internalization of the ligand, and that the binding sites were still suitable for
      binding at the level of plasma membrane during UIII cell incubation at 37 degrees
      C. Proteolysis of internalized PLA2 could be clearly detected only after 90 min
      of UIII cell incubation with the ligand at 37 degrees C, and most of the
      intracellular PLA2 consisted of the apparently intact 14 kDa enzyme. By cross
      linking studies, we found that most of the internalized PLA2 was not associated
      with the receptor, supporting the conclusion that in our experimental system a
      single pool of membrane receptors for mammalian type-I PLA2 undergoes cycles of
      ligand binding, intracellular transfer and release of PLA2, followed by
      restoration of binding sites on the plasma membrane. We calculated that the rate
      of internalization of the ligand by one receptor molecule in UIII cells at 37
      degrees C is about three molecules of type-I PLA2 per h.

PMID- 8645138
TI  - Temporal sequence of metabolic and ionic events in glucose-stimulated clonal
      pancreatic beta-cells (HIT).
AB  - Stimulation of insulin release by glucose requires increased metabolism of
      glucose and a rise in cytosolic free Ca2+ in the pancreatic beta-cell. It is
      accompanied by increases in respiratory rate, pyridine and flavin nucleotide
      reduction state, intracellular pH and the ATP/ADP ratio. To test alternative
      proposals of the regulatory relationships among free Ca2+, mitochondrial
      metabolism and cellular energy state, we determined the temporal sequence of
      these metabolic and ionic changes following addition of glucose to clonal
      pancreatic beta-cells (HIT). Combined measurements of the native fluorescence of
      reduced pyridine nucleotides and oxidized flavin, intracellular pH, and free Ca2+
      were performed together with simultaneous measurement of O2 tension or removal of
      samples for assay of the ATP/ADP ratio. The initial changes were detected in
      three phases. First, decreases occurred in the ATP/ADP ratio (<3 s) and increases
      in pyridine (2 +/- 1 s) and flavin (2 +/- 1 s) nucleotide reduction. Next,
      increases in the O2 consumption rate (20 +/- 5 s), the ATP/ADP ratio (29 +/- 12
      s) and internal pH (48 +/- 5 s) were observed. Finally, cytosolic free Ca2+ rose
      (114 +/- 10 s). Maximal changes in the ATP/ADP ratio, O2 consumption and pyridine
      and flavin nucleotide fluorescence preceded the beginning of the Ca2+ change.
      These relationships are consistent with a model in which phosphorylation of
      glucose is the initial event which generates the signals that lead to an increase
      in respiration, a rise in the ATP/ADP ratio and finally influx of Ca2+. Our
      results indicate that Ca2+ does not function as the initiator of increased
      mitochondrial respiration.

PMID- 8645139
TI  - Interaction of proteolytic fragments of calmodulin with caldesmon and calponin.
AB  - Interaction of five tryptic fragments of calmodulin with caldesmon and calponin
      was analysed by native gel electrophoresis. In the presence of Ca2+ intact
      calmodulin interacts with caldesmon and calponin with apparent Kd values equal to
      0.23 and 1.3 microM respectively. The interaction was abolished in the absence of
      Ca2+. Two large tryptic fragments of calmodulin obtained in the presence of Ca2+
      (TR1C, residues 1-77, and TR2C, residues 78-148) interact with caldesmon with
      apparent Kd values of 11.9 and 4.6 microM. Affinity of TR2C to calponin (Kd 3.8
      microM) was comparable with that of native calmodulin and was much higher than
      the corresponding value for TR1C (Kd 41 microM). The short C-terminal tryptic
      peptide of calmodulin obtained in the presence of EGTA (TR3E, residues 107-148)
      interacts with caldesmon and calponin with Kd values of 23.9 and 12.1 microM,
      whereas the large N-terminal peptide TR1E (residues 1-106) interacts with both
      caldesmon and calponin with a very low affinity (Kd 60 microM). Thus although
      both N- and C-terminal domains of calmodulin are involved in the interaction with
      caldesmon and calponin, the C-terminal part of calmodulin (residues 78-148) is of
      special importance and has the highest contribution for caldesmon and calponin
      binding.

PMID- 8645140
TI  - Isolation of InsP4 and InsP6 binding proteins from human platelets: InsP4
      promotes Ca2+ efflux from inside-out plasma membrane vesicles containing 104 kDa
      GAP1IP4BP protein.
AB  - A low-density membrane fraction from human platelets contained the plasma
      membrane marker glycoprotein Ib (GpIb) and selective binding sites for InsP4 and
      InsP6. It was separated from the bulk of InsP3-receptor-containing membranes, but
      was heterogeneous, probably also containing surface-connected canalicular system
      and some lighter elements of the internal dense tubule system. After loading with
      calcium oxalate and re-centrifugation on Percoll gradients, this mixed fraction
      was subfractionated into light membranes containing all of the GpIb, high
      affinity InsP4 binding sites (KD = 18 nM) and phosphate-stimulated Ca2+ transport
      activity. InsP4 (EC50 0.6 microM), but not InsP3 or InsP6, released up to 35% of
      the accumulated Ca2+ from these vesicles, which were shown to be inside-out
      plasma membrane vesicles by a biotinylation labelling technique and selective
      removal of right-side-out plasma membrane vesicles with streptavidin-agarose.
      Most of the InsP4, and all of the InsP6, binding was present in the much denser
      calcium oxalate-loaded subfractions, which were free of GpIb. InsP6 binding
      activity was chromatographically purified as a 116 kDa protein (KD for InsP6 =
      5.9 nM), with an amino acid content and two internal peptide sequences identical
      to those of 116 kDa vinculin. A 104 kDa InsP4 binding protein (KD for InsP4 = 12
      nM), probably identical to GAP1IP4BP described by Cullen, Hsuan, Truong, Letcher,
      Jackson, Dawson and Irvine [(1995) Nature (London) 376, 527-530], was also
      isolated. This InsP4 receptor may mediate Ca2+ influx in platelets that occurs
      subsequent to receptor-stimulated production of InsP3 and unloading of internal
      Ca2+ stores.

PMID- 8645141
TI  - Focal adhesion kinase (p125FAK) and paxillin are substrates for sphingomyelinase
      induced tyrosine phosphorylation in Swiss 3T3 fibroblasts.
AB  - We examined the effect of sphingomyelinase on tyrosine phosphorylation of
      intracellular proteins in mouse Swiss 3T3 fibroblasts. Incubation of the cells
      with bacterial sphingomyelinase resulted in the elevation of tyrosine
      phosphorylation of multiple cellular proteins of 190, 130, 120, 97 and 70 kDa
      within minutes. The 120 and 70 kDa tyrosine-phosphorylated peptides were
      identified as p125 focal adhesion kinase (p125FAK) and paxillin respectively by
      the use of specific antibodies against the proteins. Tyrosine kinase activity
      associated with anti-p125FAK immunoprecipitate was stimulated by incubation of
      cells with sphingomyelinase. Cytochalasin D, which selectively disrupts the
      network of actin filaments, inhibited sphingomyelinase-induced tyrosine
      phosphorylation of p125FAK and elevation of tyrosine kinase activity in the anti
      p125FAK immunoprecipitates. Sphingomyelinase-induced phosphorylation of p125FAK
      was not inhibited by wortmannin, an inhibitor of phosphatidylinositol 3-kinase.
      This was in sharp contrast with a wortmannin-sensitive phosphorylation of p125FAK
      observed in platelet-derived growth factor (PGDF)-stimulated cells. Thus
      hydrolysis of sphingomyelin is considered to regulate the tyrosine kinase cascade
      including p125FAK and paxillin by a mechanism distinct from PDGF.

PMID- 8645143
TI  - Evidence for a role of conventional protein kinase-C alpha in the control of
      homotypic contacts and cell scattering of HT-29 human intestinal cells.
AB  - Incubation of HT-29 M6 cells with the phorbol ester phorbol 12-myristate 13
      acetate (PMA) induces cell scattering, loss of cellular contacts and inactivation
      of E-cadherin. We have investigated the involvement of different protein kinase C
      (PK-C) isoforms in these processes using specific activators. Thymeleatoxin, a
      derivative of mezerein that activates conventional PK-Cs (cPK-Cs) but not novel
      PK-Cs (nPK-Cs), promoted effects that were similar to those of PMA, i.e. at
      concentrations of 200 nM it induced scattering of HT-29 M6 colonies, loss of
      homotypic contacts and dissociation of E-cadherin from the cytoskeleton. Among
      the isoforms activated by this compound, only cPK-C alpha was detected in HT-29
      M6 cells by Western blot. The specificity of this compound with respect to the
      rest of the PK-C isoforms present in these cells was determined; thymeleatoxin
      induced, as did PMA, the translocation of cPK-C alpha from the cytosol to the
      membrane and the cytoskeleton, and its partial down-regulation. On the other
      hand, thymeleatoxin did not modify the cellular levels or localization of nPK-C
      epsilon or atypical PK-C zeta. "In vitro' assays also showed that thymeleatoxin
      did not activate nPK-C epsilon at the concentrations added to the cell cultures.
      These results indicate that thymeleatoxin is selective for cPK-C alpha over nPK-C
      epsilon and show a role for the former enzyme in the regulation of cell-cell
      contacts and the inactivation of E-cadherin in HT-29 M6 cells.

PMID- 8645142
TI  - Two different sialidases, KDN-sialidase and regular sialidase in the starfish
      Asterina pectinifera.
AB  - We have found the coexistence of two different sialidases in the entrails of the
      starfish Asterina pectinifera: a regular sialidase (RS), which cleaves sialic
      acid from sialoglycoconjugates, and a KDN-sialidase (KS) which releases the
      sialic acid analogue KDN (2-keto-3-deoxy-D-glycero-d-galacto-nononic acid) from
      KDN-containing glycoconjugates that are resistant to RS. The 6700-fold purified
      KS and 1300-fold purified RS were prepared to study the properties of these two
      sialidases. KS and RS from Asterina starfish differ in several properties other
      than glycon specificity, including molecular mass, isoelectric point (pI) and
      susceptibility to competitive and non-competitive inhibitors. KS has a molecular
      mass of 31 kDa and a pI of 8.3 while RS has a molecular mass of 128 kDa and a pI
      of about 4.8. 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (NeuAc2en), but not 2,3
      dehydro-2-deoxy-KDN (KDN2en), is a potent competitive inhibitor of RS (Ki
      approximately 0.007 mM); however, both NeuAc2en and KDN2en are moderate
      inhibitors of KS (K1 approximately 0.04 mM). Hg2+ is a potent non-competitive
      inhibitor of RS but not of KS. KS and RS were examined for their ability to
      hydrolyse KDN- and NeuAc-containing glycoconjugates. KS hydrolyses 4-methyl
      umbelliferyl-alpha-KDN (MU-KDN) 20 times faster than 4-methylumbelliferyl-alpha
      NeuAc (MU-NeuAc), while RS hydrolyses MU-NeuAc 88 times faster than MU-KDN at the
      pH optimum of 4.0 KS effectively hydrolyses KDN-GM3 (where GM3 is NeuAc alpha 2 -
      > 3Gal beta 1 --> 4Glc beta 1-1' Cer, and Cer is ceramide), KDN alpha 2 -->
      3lactose, KDN alpha 2 --> 6lactose, KDN alpha 2 --> 6N-acetylgalactosaminitol,
      KDN alpha 2 --> 6 (KDN alpha 2 --> 3)N-acetylgalactosaminitol and KDN alpha 2 -->
      6(GlcNAc beta 1 --> 3) N-acetylgalactosaminitol. However, under the same
      conditions, these KDN-containing glycoconjugates are refractory to RS.
      Conversely, GM3, NeuAc alpha 2 --> 3lactose and NeuAc alpha 2 --> 6lactose are
      effectively hydrolysed by RS but not by KS.

PMID- 8645145
TI  - Elder (Sambucus nigra L.)-fruit lectin (SNA-IV) occurs in monomeric, dimeric and
      oligomeric isoforms.

PMID- 8645144
TI  - Biosynthesis of the MUC2 mucin: evidence for a slow assembly of fully
      glycosylated units.
AB  - The human colonic cell line PC/AA was grown to near confluency over 24 days and
      labelled with [14C]proline and [3H]glucose over the last 48 h in culture. The
      cell layer was extracted with 6 M guanidinium chloride and the mature fully
      glycosylated mucins were isolated at a density of 1.45 g/ml by using density
      gradient centrifugation in CsCl/4 M guanidinium chloride. These mucins were
      identified as MUC2 with an anti-peptide antibody. The macromolecules were
      fragmented by reduction into two distinct populations of MUC2 subunits as
      assessed by agarose electrophoresis. The MUC2 mucin was polydisperse in length,
      ranging from 500 nm to many microns and its molecular-mass distribution, assessed
      by rate-zonal centrifugation, ranged from 5 x 10(6) to 40 x 10(6) Da. However,
      the metabolically labelled MUC2 mucins, though found throughout the whole
      distribution, were of much smaller average size. Since the entire distribution is
      not uniformly radiolabelled over 48 h, the formation of the largest species must
      be preceded by glycosylation and occur slowly, over several days, via the
      assembly of fully glycosylated units which are likely to be at least dimers
      [Asker, Baeckstrom, Axelsson, Carlstedt, and Hansson (1995) Biochem. J. 308, 873
      880].

PMID- 8645146
TI  - Inhibition of poly(ADP-ribose) formation by 4-hydroxynonenal in primary cultures
      of rabbit synovial fibroblasts.
AB  - The formation of poly(ADP-ribose) in primary cultures of rabbit synovial
      fibroblasts after treatment with active oxygen released by xanthine/xanthine
      oxidase is inhibited by addition of 1 and 10 microM 4-hydroxy-2,3-trans-nonenal
      (HNE). The endogenous formation of HNE by the xanthine/xanthine oxidase system is
      not responsible for the inhibitory effect of the aldehyde, owing to the low
      accumulation rate of the lipid peroxidation product in the system used. HNE is
      able to inhibit the isolated nuclear enzyme ADP-ribosyltransferase, as shown by
      an in vitro assay with an Ki of 4 mumol/litre. Therefore the molecular basis of
      HNE-mediated effects on cell proliferation, differentiation and transformation
      might be due to the inhibitory effect of poly(ADP-ribos)ylation.

PMID- 8645148
TI  - Structures of diphospho-myo-inositol pentakisphosphate and bisdiphospho-myo
      inositol tetrakisphosphate from Dictyostelium resolved by NMR analysis.
AB  - Diphospho-myo-inositol phosphates (PP-InsP5 and bis-PP-InsP4) were isolated from
      Dictyostelium in order to clarify the precise positional isomerism by two
      dimensional 1H/31P-NMR analysis. The diphosphorylated inositol phosphates are 4
      PP-Ins(1,2,3,5,6)P5 and 4,5-bis-PP-Ins(1,2,3,6)P4 or their corresponding
      enantiomers. The vicinal arrangement of the diphospho groups with its steric and
      electrostatic constraints possibly qualifies bis-PP-InsP4 as a metabolite with
      high phosphate-group-transfer potential in phosphotransferase reactions.

PMID- 8645147
TI  - Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5
      trisphosphate without subsequent activation.
AB  - Recent evidence has suggested that activation of phosphoinositide 3-kinase (PI 3
      kinase) is required for the activation of Akt-1 by growth factors and insulin.
      Here we demonstrate by two independent methods that Akt-1 from L6 myotubes binds
      to PtdIns(3,4,5)P3, PtdIns(3,4)P2 and PtdIns(4,5)P2 when presented against a
      background of phosphatidylserine (PtdSer) or a 1:1 mixture of PtdSer and
      phosphatidylcholine (PtdCho). No binding was observed with the lipids
      PtdIns(3,5)P2, PtdIns4P and PtdIns3P or background lipids. Activated,
      hyperphosphorylated forms of Akt-1 from insulin-stimulated L6 myotubes bound to
      PtdIns(3,4,5)P3 in a similar manner as inactive Akt-1. Quantitative analysis
      using surface plasmon resonance showed that the equilibrium association constant
      for the binding of Akt-1 to PtdIns(3,4,5)P3 was submicromolar and that
      PtdIns(3,4)P2 and PtdIns(4,5)P2 bound to Akt-1 with 3- and 6-fold lower
      affinities respectively. Interaction of Akt-1 with PtdIns(3,4,5)P3 did not
      activate the protein kinase activity, either before or after incubation with
      MgATP. A model is presented in which PtdIns(3,4,5)P3 may prime Akt-1 for
      activation by another protein kinase, perhaps by recruiting it to the plasma
      membrane.

PMID- 8645149
TI  - Nicotinic acid-adenine dinucleotide phosphate mobilizes Ca2+ from a thapsigargin
      insensitive pool.
AB  - Nicotinic acid-adenine dinucleotide phosphate (NAADP) is a novel intracellular
      Ca2+ releasing agent recently described in sea-urchin eggs and egg homogenates.
      Ca2+ release by NAADP is independent of that induced by either inositol
      trisphosphate (InsP3) or cyclic adenosine dinucleotide phosphate (cADPR). We now
      report that in sea urchin egg homogenates, NAADP releases Ca2+ from a Ca2+ pool
      that is distinct from those that are sensitive to InsP3 and cADPR. This organelle
      has distinct Ca2+ uptake characteristics: it is insensitive to thapsigargin and
      cyclopiazoic acid, but maintenance of the pool shows some requirement for ATP.
      Although the different Ca2+ pools have different characteristics, there appears
      to be some degree of overlap or cross-talk between the NAADP- and cADPR/InsP3
      sensitive Ca2+ pools. Ca(2+)-induced Ca2+ release is unlikely to account for the
      apparent overlap between stores, since NAADP-induced Ca2+ release, in contrast
      with that stimulated by cADPR, is not potentiated by bivalent cations.

PMID- 8645150
TI  - Purification and characterization of a recombinant human Theta-class glutathione
      transferase (GSTT2-2).
AB  - A cDNA encoding the human Theta-class glutathione transferase GSTT2-2 was
      expressed in Escherichia coli as a ubiquitin fusion protein. The co-translational
      removal of the ubiquitin by a cloned ubiquitin-specific protease, Ubp1, generates
      enzymically active GSTT2-2 without any additional N-terminal residues. The
      recombinant isoenzyme was purified to apparent homogeneity by DEAE anion
      exchange, gel filtration, dye ligand chromatography and high resolution anion
      exchange chromatography on Mono Q FPLC. The recombinant enzyme had significant
      activity with a range of substrates, including cumene hydroperoxide and 1
      menapthyl sulphate. The activity of GSTT2-2 with a range of secondary lipid
      peroxidation products such as the trans,trans-alka-2,4-dienals and trans-alk-2
      enals, as well as its glutathione peroxidase activity with organic
      hydroperoxides, suggest that it may play a significant role in protection against
      the products of lipid peroxidation.

PMID- 8645151
TI  - Processing of N3, a mammalian proteasome beta-type subunit.
AB  - Proteasome subunits are encoded by members of the same gene family and can be
      divided into two groups based on their similarity to the alpha and beta subunits
      of the simpler proteasome isolated from Thermoplasma acidophilum. RN3 is the beta
      type subunit, N3, of rat proteasomes which has been implicated in the
      peptidylglutamyl-peptide hydrolase activity of the proteinase complex. We have
      expressed recombinant RN3 protein in Escherichia coli in order to raise subunit
      specific polyclonal antibodies. Identification of the position of RN3 on two
      dimensional PAGE gels of purified rat liver proteasomes showed a single protein
      spot of molecular mass 24 kDa and of pI value of about 5. This protein has a free
      N-terminus, having undergone post-translational processing. After
      immunoprecipitation from [35S]methionine-labelled human embryo lung L-132 cells
      using anti-RN3 antibodies, two radiolabelled spots were observed on two
      dimensional PAGE gels, one corresponding to the mature N3, the other of molecular
      mass 28.5 kDa and pI value around 5, which was probably the unprocessed form of
      N3. However, the latter protein had a higher molecular mass (31 kDa) than was
      predicted from the sequence of previously cloned cDNA. Therefore rapid
      amplification of cDNA ends ("RACE') was carried out to determine the full
      sequence. The lack of detectable RN3 precursor in purified rat liver proteasomes
      suggests that the processing probably accompanies assembly of the complex. The
      half-life of the processing was determined to be 31 min in growing L-132 cells.
      The unprocessed form of N3 was not observed after immunoprecipitation of 35S
      labelled complexes with anti-proteasome antibodies. There was no evidence to
      suggest that unprocessed N3 is found in precursor complexes which have been
      implicated in the assembly of some other unprocessed beta-type subunits.
      Interestingly also, the site of cleavage of N3 (ITR decreases TQN) differs
      significantly from those of other processed animal beta-type proteasome subunits
      [(H/T)G decreases TT(T/L)], many of which resemble more closely the cleavage site
      of the Thermoplasma acidophilum beta subunit.

PMID- 8645152
TI  - Oxytocin receptor couples to the 80 kDa Gh alpha family protein in human
      myometrium.
AB  - One of the primary functions of the oxytocin receptor is to modulate
      intracellular calcium levels in myometrium. The oxytocin receptor has been
      purified and cloned. Although it has been suggested that oxytocin receptor
      couples with a GTP-binding regulatory protein (G-protein), the identity of this G
      protein remains unclear. To elucidate the mechanism of oxytocin receptor
      signalling, we used the oxytocin-receptor-G-protein ternary complex preparation
      from human myometrium, and evaluated oxytocin-mediated activation of
      [35S]guanosine 5'-[gamma-thio]triphosphate ([35S]GTP[S]) binding and [alpha
      32P]GTP photoaffinity labelling to a G-protein. Binding of [35S]GTP[S] and the
      intensity of the [alpha-32P]GTP photoaffinity labelled protein resulting from
      activation of the oxytocin receptor were significantly attenuated by the
      selective oxytocin antagonist, desGlyNH2d(CH2)5[Tyr(Me)2,Thr4]OVT. Furthermore,
      the molecular mass of the specific GTP-binding protein was approximately 80 kDa;
      homologous with the Gh alpha family, the new class of GTP-binding proteins first
      identified in rat liver that couples to the alpha 1B-adrenoceptor. Consistent
      with these observations, in co-immunoprecipitation and co-immunoadsorption of the
      oxytocin receptor in the ternary complex preparation by anti-Gh7 alpha antibody,
      the Gh alpha family protein tightly coupled to the oxytocin receptor. These
      findings demonstrate that oxytocin receptor couples with approximately 80 kDa Gh
      alpha in signal mediation.

PMID- 8645153
TI  - The role of residues glutamate-50 and phenylalanine-496 in Zymomonas mobilis
      pyruvate decarboxylase.
AB  - Several enzymes require thiamine diphosphate (ThDP) as an essential cofactor, and
      we have used one of these, pyruvate decarboxylase (PDC; EC 4.1.1.1) from
      Zymomonas mobilis, as a model for this group of enzymes. It is well suited for
      this purpose because of its stability, ease of purification, homotetrameric
      subunit structure and simple kinetic properties. Crystallographic analyses of
      three ThDP-dependent enzymes [Muller, Lindqvist, Furey, Schulz, Jordan and
      Schneider (1993) Structure 1, 95-103] have suggested that an invariant glutamate
      participates in catalysis. In order to evaluate the role of this residue,
      identified in PDC from Zymomonas mobilis as Glu-50, it has been altered to
      glutamine and aspartate by site-directed mutagenesis of the cloned gene. The
      mutant proteins were expressed in Escherichia coli. Here we demonstrate that
      substitution with aspartate yields an enzyme with 3% of the activity of the wild
      type, but with normal kinetics for pyruvate. Replacement of Glu-50 with glutamine
      yields an enzyme with only 0.5% of the catalytic activity of the wild-type
      enzyme. Each of these mutant enzymes has a decreased affinity for both ThDP and
      Mg2+. It has been reported that the binding of cofactors to apoPDC quenches the
      intrinsic tryptophan fluorescence [Diefenbach and Duggleby (1991) Biochem. J.
      276, 439-445] and we have identified the residue responsible as Trp-487
      [Diefenbach, Candy, Mattick and Duggleby (1992) FEBS Lett. 296, 95-98]. Although
      this residue is some distance from the cofactor binding site, it lies in the
      dimer interface, and the proposal has been put forward [Dyda, Furey, Swaminathan,
      Sax, Farrenkopf and Jordan (1993) Biochemistry 32, 6165-6170] that alteration of
      ring stacking with Phe-496 of the adjacent subunit is the mechanism of
      fluorescence quenching when cofactors bind. The closely related enzyme
      indolepyruvate decarboxylase (from Enterobacter cloacae) has a leucine residue at
      the position corresponding to Phe-496 but shows fluorescence quenching properties
      that are similar to those of PDC. This suggests that the fluorescence quenching
      is due to some perturbation of the local environment of Trp-487 rather than to a
      specific interaction with Phe-496. This latter hypothesis is supported by our
      data: mutation of this phenylalanine to leucine, isoleucine or histidine in PDC
      does not eliminate the fluorescence quenching upon addition of cofactors.

PMID- 8645154
TI  - Modulation of gelsolin-induced actin-filament severing by caldesmon and
      tropomyosin and the effect of these proteins on the actin activation of myosin
      Mg(2+)-ATPase activity.
AB  - We have investigated the cumulative effects of three smooth-muscle actin-binding
      proteins, gelsolin, caldesmon and tropomyosin, on actin activation of myosin
      Mg(2+)-ATPase activity under low-ionic-strength conditions. A combination of
      tropomyosin (at a stoicheiometric ratio to actin) and gelsolin (at a molar ratio
      to actin of up to 1:100) showed essentially additive stimulatory effects that
      were counteracted by caldesmon. Suppression of the gelsolin-induced activation of
      the ATPase by caldesmon was higher in the presence of tropomyosin although it was
      not complete even at stoicheiometric amounts of both proteins to actin. Since
      activation of actin-activated ATPase activity of myosin by gelsolin is related to
      its severing action, it is concluded that caldesmon and tropomyosin cannot fully
      protect actin filaments against the severing activity of gelsolin. Direct
      analysis of the actin-severing activity of gelsolin by a fluorimetric assay using
      pyrene-labelled actin confirmed this conclusion. Tropomyosin and caldesmon in
      saturating amounts relative to actin inhibited the activity of gelsolin by
      between 21 and 40% and 25 and 48% respectively, depending on the molar ratio of
      gelsolin to actin. The inhibitory effect was increased with a combination of both
      (up to 67%) although it was evident that even under these conditions the actin
      filaments were not fully protected from being severed by gelsolin. These findings
      were corroborated by electron-microscopic investigation of actin filaments with
      or without tropomyosin and caldesmon after the addition of gelsolin.

PMID- 8645156
TI  - Growth inhibition signalled through the interleukin-4/interleukin-13 receptor
      complex is associated with tyrosine phosphorylation of insulin receptor substrate
      1.
AB  - Induction of growth inhibition in human colorectal carcinoma cell lines by
      interleukin (IL)-4 and IL-13 was associated with the neophosphorylation of a 170
      kDa cellular protein, identified as insulin receptor substrate-1 (IRS-1) by
      immunoprecipitation. Tyrosine phosphorylation of IRS-I was also induced by
      insulin and insulin-like growth factor I. Sublines of colorectal carcinoma cells
      unresponsive to growth modulation by IL-4, IL-13 or insulin-like growth factor I
      induced growth did not phosphorylate IRS-1. A functional, multimeric IL-4
      receptor complex was present on all carcinoma cell lines with a subunit
      composition of 65 kDa, 75 kDa and the previously characterized 130 kDa band as
      demonstrated by affinity cross-link with 126I labelled IL-4. The 65 kDa subunit
      is novel whereas the 75 kDa band represents the common IL-2 receptor gama-chain
      the novel 65 kDa receptor was present as a double band and bound primarily 125I
      labelled IL-13. The present study demonstrates the involvement of a novel chain
      other than the gama-chain in the receptor complexes of IL-4 and IL-13 and and
      post-receptor tyrosine phosphorylation of IRS-1. The association of IRS-1 with
      growth inhibitory signals in carcinoma cells suggests a novel mechanism of tumour
      growth control.

PMID- 8645155
TI  - Site-directed mutagenesis of rat liver S-adenosylmethionine synthetase.
      Identification of a cysteine residue critical for the oligomeric state.
AB  - We have examined the functional importance of the cysteine residues of rat liver
      S-adenosylmethionine synthetase. For this purpose the ten cysteine residues of
      the molecule were changed to serines by site-directed mutagenesis. Ten
      recombinant enzyme mutants were obtained by using a bacterial expression system.
      The same level of expression was obtained for the wild type and mutants, but the
      ratio of S-adenosylmethionine synthetase between soluble and insoluble fractions
      differed for some of the mutant forms. The immunoreactivity against an anti-(rat
      liver S-adenosylmethionine synthetase) antibody was equivalent in all the cases.
      Effects on S-adenosylmethionine synthetase activities were also measured. Mutants
      C57S, C69S, C105S and C121S showed decreased relative specific activity of 68,
      85, 63 and 29%, respectively, compared with wild-type, whereas C312S resulted in
      an increase of 1.6-fold. Separation of tetramer and dimer forms for wild type and
      mutants was carried out by using phenyl-Sepharose columns. The dimer/tetramer
      ratio was calculated based on the activity and on the protein level estimated by
      immunoblotting. No monomeric forms of the enzyme were detected in any case.
      Comparison of dimer/tetramer ratios indicates the importance of cysteine-69
      (dimer/tetramer protein ratio of 88 versus 10.2 in the wild type) in maintaining
      the oligomeric state of rat liver S-adenosylmethionine synthetase. Moreover, all
      the mutations carried out of cysteine residues between cysteine-35 and cysteine
      105 altered the ratio between oligomeric forms.

PMID- 8645157
TI  - Rac GTPase interacts specifically with phosphatidylinositol 3-kinase.
AB  - The Rac GTP-binding proteins are members of the Rho family and regulate growth
      factor-stimulated actin assembly in a variety of cells. The formation of
      phosphorylated inositol lipids has been implicated in control of the processes
      initiating and regulating such actin polymerization. Associations of Rho family
      GTP-binding proteins with enzymes involved in lipid metabolism have been
      described. Here we demonstrate a direct and specific interaction of Rac proteins
      with phosphatidylinositol (PI) 3-kinase. This interaction is dependent upon Rac
      being in a GTP-bound state and requires an intact Rac effector domain. In
      contrast, direct binding of RhoA to PI 3-kinase could not be detected. Rac-GTP
      also bound to PI 3-kinase in Swiss 3T3 fibroblast and human neutrophil lysates,
      and increased PI 3-kinase activity became associated with Rac-GTP in platelet
      derived growth factor-stimulated cells. Interaction of Rac-GTP with PI 3-kinase
      in vitro stimulated the activity of the enzyme by 2-9-fold. A specific
      interaction of active Rac with PI 3-kinase might be important in regulation of
      the actin cytoskeleton.

PMID- 8645158
TI  - Transfer of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin from
      low- and high-density lipoprotein to human platelets.
AB  - Following a 1 h incubation of human platelets with low-density lipoprotein (LDL)
      labelled in the apoprotein fraction (125I-apoB) or in phospholipid fractions [14C
      labelled phosphatidylcholine (PC), phosphatidylethanolamine (PE) or sphingomyelin
      (SM)], the percentage of total 14C associated with the cells was about 3-fold
      higher than the percentage of 125I. Differences in temperature sensitivity also
      indicated differential interactions of phospholipids and apoprotein with
      platelets. In order to assess the amount of [14C]phospholipid transferred from
      LDL or high-density lipoprotein (HDL) to the cells, the quantity of bound
      lipoproteins was estimated by adding an excess of unlabelled lipoprotein, or by
      selectively degrading LDL- and HDL-associated [14C]PC and [14C]PE with
      phospholipase C. Incubation of platelets with LDL or HDL containing
      pyrenedecanoic acid-labelled PC or SM (py-PC, py-SM) increased pyrene monomer
      fluorescence, indicating incorporation of the phospholipids into platelets. With
      HDl as donor, incorporation of py-SM was greater than uptake of py-PC.
      Pretreating platelets with elastase dose-dependently inhibited uptake of py-SM
      and py-PC. Treatment of cells with phospholipase C indicated that the uptake of
      [14C]PC by platelets, and not the binding of lipoproteins to the cells, was
      partially inhibited by elastase. In conclusion, LDL and HDL rapidly deliver SM,
      PC and PE to platelets. Incorporation of LDL-derived phospholipids into platelets
      is unlikely to be mediated by endocytosis of lipoprotein particles. The uptake of
      the two choline-containing phospholipids appears to require the presence of
      specialized platelet membrane protein(s).

PMID- 8645159
TI  - Regulation of gene expression for translation initiation factor eIF-2 alpha:
      importance of the 3' untranslated region.
AB  - Gene expression of the alpha-subunit of eukaryotic initiation factor-2 (eIF-2
      alpha), involves transcriptional and post-transcriptional mechanisms. eIF-2 alpha
      is a single-copy gene expressing two mRNAs, 1.6 and 4.2 kb in size. Cloning and
      sequencing of the cDNA for the 4.2 kb mRNA revealed that it is the result of
      alternative polyadenylation site selection. Four polyadenylation sites were
      identified within the 3' untranslated region (UTR) of eIF-2 alpha, only two of
      which are normally utilized in human and mouse tissues. A functional role for the
      extended 3' UTR was assessed by comparing the translatability and stability of
      the 1.6 and 4.2 kb mRNAs. Both the 1.6 and 4.2 kb transcripts could be translated
      in vitro and were identified in vivo as being distributed on large polyribosomes.
      This indicates that both mRNAs are efficiently translated. Stability studies
      showed that in activated T-cells the 4.2 kb mRNA was more stable than the 1.6 kb
      mRNA. Polyadenylation site selection and mRNA stability differ for the two mRNAs
      of eIF-2 alpha. These activities might be modulated by sequence elements
      contained within the untranslated regions of the eIF-2 alpha gene.

PMID- 8645160
TI  - Identification of a new isoform of cell-cell adhesion molecule 105 (C-CAM), C
      CAM4: a secretory protein with only one Ig domain.
AB  - A series of Southern blot hybridization experiments using probes derived from
      different regions of the rat liver cell-cell adhesion molecule 105 (C-CAM) cDNA
      revealed the presence of a 9.6 kb EcoRI genomic fragment that seemed to encode a
      unique C-CAM isoform. An RNase protection study showed that this c-CAM transcript
      was expressed in placenta, spleen, lung and large intestine. In contrast, the
      other C-CAM isoforms, C-CAM1 and C-CAM2, are expressed in liver and small
      intestine. This result also suggests that the new isoform, which we named C-CAM4,
      was indeed encoded by a new C-CAM gene. A rat placenta cDNA library was then
      screened and the full-length cDNA coding for C-CAM4 was isolated. The deduced
      protein contained 142 amino acids and had a calculated molecular mass of 15 kDa.
      C-CAM4 was composed of a leader sequence and the first V-like Ig domain typical
      of C-CAM-family proteins. However, C-CAM4 lacked the C-like Ig domains, the
      transmembrane domain, and the cytoplasmic domain found in other C-CAM isoforms.
      Thus, C-CAM4 is different from the other known C-CAMs in that it is a secreted
      protein. We have previously shown that the first Ig domain of C-CAM1 is crucial
      for its adhesion function. The V-like Ig domain of C-CAM4 had 92% and 89%
      sequence identity with the corresponding regions of C-CAM1 and C-cam2
      respectively. Together these results suggest that C-CAM4 may play a role in
      regulating the function of other C-CAM family proteins.

PMID- 8645161
TI  - Molecular cloning, sequencing and expression of the cDNA of the mitochondrial
      form of phosphoenolpyruvate carboxykinase from human liver.
AB  - In human liver, phosphoenolpyruvate carboxykinase (PCK; EC 4.1.1.32) is about
      equally distributed between cytosol and mitochondria in contrast with rat liver
      in which it is essentially a cytosolic enzyme. Recently, the isolation of the
      gene and cDNA of the human cytosolic enzyme has been reported [Ting, Burgess,
      Chamberlian, Keith, Falls and Meisler (1993) Genomics 16, 698-706; Stoffel,
      Xiang, Espinosa, Cox, Le Beau and Bell (1993) Hum. Mol. Genet. 2, 1-4]. It was
      the goal of this investigation to isolate the cDNA of the human mitochondrial
      form of hepatic PCK. A human liver cDNA library was screened with a rat cytosolic
      PCK cDNA probe comprising sequences from exons 2 to 9. A cDNA clone was isolated
      which had overall a 68% DNA sequence and a 70% deduced amino acid sequence
      identity with the human cytosolic PCK cDNA. Without the flanking 270 bases (=90
      amino acids) each at the 5' and 3' end, the sequence identity was 73% on the DNA
      and 78% on the amino acid level. The isolated cDNA had an open reading frame of
      1920 bp; it was 54 bp (equivalent to 18 amino acids) longer than that of human or
      rat cytosolic PCK cDNA. The isolated cDNA was cloned into the eukaryotic
      expression vector pcDNAI and transfected into human embryonal kidney cells
      HEK293; PCK activity was increased by 3-fold in the mitochondria, which normally
      contain 70% of total PCK activity, but not in the cytosol. The isolated cDNA was
      also transfected into cultured rat hepatocytes; again, PCK activity was enhanced
      by about 40-fold in the mitochondria, which normally possess only 10% of total
      PCK activity, but not in the cytosol. In the rat hepatocytes only the endogenous
      cytosolic PCK and not the transfected mitochondrial PCK was induced 3-fold with
      glucagon. Comparison of the amino acid sequences deduced from the isolated cDNA
      with human and rat cytosolic PCK showed that the additional 18 amino acids were
      located at the N-terminus of the protein and probably constitute a mitochondrial
      targeting signal. Northern-blot analyses revealed the human mitochondrial PCK
      mRNA to be 2.25 kb long, about 0.6 kb shorter than the mRNA of the cytosolic PCK.
      Primer extension experiments showed that the 5'-untranslated region of
      mitochondrial PCK mRNA was 134 nucleotides in length.

PMID- 8645162
TI  - Betaglycan has multiple binding sites for transforming growth factor-beta 1.
AB  - The transforming growth factor-beta (TGF-beta) binding site in betaglycan, the
      type III TGF-beta receptor, has been variously assigned to the C-terminal half
      and N-terminal one-third of the extracellular domain. In this study, we show that
      there are at least two TGF-beta-binding sites in betaglycan. Bacterially
      expressed fragments bg 1,2 and bg3, which represent the N-terminal two-thirds and
      C-terminal one-third of betaglycan extracellular domain, both competed for the
      binding of 125I-TGF-beta to mink lung epithelial cells. 125I-bg1,2 bound to
      immobilized TGF-beta with an affinity about 4-fold higher than bg3 had. Both bg3
      and bg1,2 enhanced the bioactivity of TGF-beta. The whole ectodomain of
      betaglycan was more active than either bg3 or bg1,2 in the assays. The binding of
      125I-bg3 to TGF-beta was inhibited by bg1,2 and vice versa. The binding of 125I
      bg3 and 125I-bg1,2 to TGF-beta was also inhibited by the small decorin family of
      proteoglycans. These results indicate that there are at least two binding sites
      for TGF-beta in betaglycan and that these sites recognize the same or overlapping
      sites in TGF-beta.

PMID- 8645163
TI  - Chinese hamster fibroblasts overexpressing CuZn-superoxide dismutase undergo a
      global reduction in antioxidants and an increasing sensitivity of DNA to
      oxidative damage.
AB  - Transfection of a CuZn-superoxide dismutase (SOD) expression vector into V79
      Chinese hamster cells produced clones in which CuZn-SOD activities were 2.2-3.5
      fold higher than in the parental cells. An overall moderate reduction of
      glutathione peroxidase, glutathione reductase and glucose-6-phosphate
      dehydrogenase activities and of both GSSG and total glutathione levels was found.
      In one particular clone the catalase activity was also reduced. The pro-oxidant
      status established by the lower level of antioxidant defence rendered the SOD
      overexpressing cells more sensitive to the production of 8-oxo-2'-deoxyguanosine
      by hydrogen peroxide. The data are discussed in terms of a model resembling the
      bacterial sox RS system.

PMID- 8645164
TI  - Substrate specificity and kinetic parameters of GLUT3 in rat cerebellar granule
      neurons.
AB  - This study examines the apparent affinity, catalytic-centre activity ("turnover
      number') and stereospecificity of the neuronal glucose transporter GLUT3 in
      primary cultured cerebellar granule neurons. Using a novel variation of the 3-O
      [14C]methylglucose transport assay, by measuring zero-trans kinetics at 25
      degrees C, GLUT3 was determined to be a high-apparent-affinity, high-activity,
      glucose transporter with a K(m) of 2.87 +/- 0.23 mM (mean +/- S.E.M.) for 3-O
      methylglucose, a Vmax of 18.7 +/- 0.48 nmol/min per 10(6) cells, and cells, and a
      corresponding catalytic-centre activity of 853 s-1. Transport of 3-O
      methylglucose was competed by glucose, mannose, 2-deoxyglucose and galactose, but
      not by fructose. This methodology is compared with the more common 2
      [3H]deoxyglucose methodology and the [U-14C]-glucose transport method. The high
      affinity and transport activity of the neuronal glucose transporter GLUT3 appears
      to be an appropriate adaptation to meet the demands of neuronal metabolism at
      prevailing interstitial brain glucose concentrations (1-2 mM).

PMID- 8645166
TI  - Heat shock proteins and macrophage resistance to the toxic effects of nitric
      oxide.
AB  - Nitric oxide (NO) functions as a pathophysiological mediator in mammalian
      tissues. Activated macrophages produce NO as a non-specific immune response
      directed against invading bacteria or micro-organisms. The same macrophages that
      initiate the production of NO also can be toxically affected by NO. Incubation of
      RAW 264.7 macrophages with lipopolysaccharide (LPS) and/or interferon-gamma (INF
      gamma) induced the formation of NO by the activation of a cytokine-inducible NO
      synthase (NOS). The viability of these macrophages was inversely correlated with
      the formation of nitrite, a final NO-oxidation product measurable in the
      incubation medium. The addition of an NOS inhibitor, NG-monomethyl-L-arginine,
      diminished NO formation and preserved cell viability in a dose- and time
      dependent fashion. Treatment of macrophages with ten cycles of non-lethal doses
      of LPS and INF-gamma, each followed by subculturing of the surviving cells,
      resulted in cell resistance to the NO toxic insult induced by LPS and INF-gamma.
      These resistant macrophages showed a 2-fold increase in the expression of the
      constitutive heat shock protein (HSC 70) which is known to be involved in
      protecting cells against the action of various metabolic insults. Our results
      establish a link between cell resistance to the toxic effects of NO, and the
      expression of heat shock proteins in RAW 264.7 macrophages.

PMID- 8645165
TI  - Multiple cis-trans conformers of the prolactin receptor proline-rich motif (PRM)
      peptide detected by reverse-phase HPLC, CD and NMR spectroscopy.
AB  - An eight-amino-acid synthetic peptide (IIe1-Phe2-Pro3-Pro4-Val5-Pro6-Gly7-Pro8)
      corresponding to the conserved proline-rich motif (PRM) of the intracellular
      domain of the prolactin receptor (PRL-R) was studied by one- and two-dimensional
      (1D and 2D) proton NMR spectroscopy in water and DMSO in order to characterize
      its conformational dynamics. The purified PRL-R PRM peptide eluted as two
      partially resolved peaks in equilibrium on reverse-phase HPLC (RP-HPLC) at 20
      degrees C with a ratio of 60:40. At 30 degrees C, the two peaks coalesced into a
      single peak The two RP-HPLC peaks correspond to two peptide conformers resulting
      from the slow cis-trans isomerization of one of the four proline amide bonds.
      Although the peptide has only three amide (NH) protons, its ID NMR spectrum in
      water contains approximately 15 discernible NH region peaks, providing evidence
      for multiple conformers. The amide resonances were assigned on the basis of 2D
      COSY spectra, chemical shift values resonance splitting patterns and temperature
      coefficients. The cis:trans ratio for each proline in water, calculated from
      integrated intensities and/or peak heights of the appropriate resonances, were
      Phe2-Pro3 (35:65), Pro3-Pro4 (40:60), Val5-Pro6 (70:30), and Gly7-Pro8 (30:70).
      Temperature studies (25-70 degrees C) were used to semi-quantitatively estimate
      the rates of isomerization for the different prolines. In water, Pro8 undergoes
      rapid isomerization; Pro3 isomerizes at an intermediate rate; while Pro4 and Pro6
      both appear to isomerize very slowly since no coalescence of amide resonances was
      observed. In DMSO, only Pro4 displayed slow isomerization. Slow kinetics combined
      with a similar 60:40 ratio of conformers determined by RP-HPLC and NMR suggests
      that isomerization of the Pro3-Pro4 bond generates the two RP-HPLC peaks. Both
      proximal and distal proline isomerization effects were observed in NMR
      experiments. All of the 16 theoretical (24 = 16) proline configurations appear to
      exist in equilibrium in water The predominant (19%) conformation, trans3-trans4
      cis6-trans8, may reflect the configuration of the PRM prolines in the native PRL
      R. Isomerization of Pro6 from cis to trans generates an interaction between the
      peptide N-and C-termini, suggesting an overall pseudo-cyclic conformation. This
      all-trans proline configuration may play an important biochemical role in the
      function of cytokine/haematopoietin receptors. A model is proposed which suggests
      that isomerization of the PRM by an immunophilin such as the FK 506-binding
      protein (FKBP) serves as an on-off switch for cytokine receptor activation.

PMID- 8645167
TI  - New insights into the pathogenesis of copper toxicosis in Wilson's disease:
      evidence for copper incorporation and defective canalicular transport of
      caeruloplasmin.
AB  - Previous studies have suggested that copper is incompletely incorporated into
      caeruloplasmin, the major plasma form of copper-transporting protein, in the
      genetic copper toxic condition, Wilson's disease. In this paper we have
      investigated the role of copper and caeruloplasmin in the abnormal biliary copper
      transport and characterizes Wilson's disease. Using SDS/PAGE and Western
      blotting, we have demonstrated the presence of holocaeruloplasmin in liver
      samples from patients with Wilson's disease (abnormal biliary copper excretion)
      and in control patients (normal biliary copper excretion). The presence of
      holocaeruloplasmin was also confirmed by measurement of caeruloplasmin oxidase
      activity using staining with o'Dianisidine. In contrast with the findings in
      liver tissue, holocaeruloplasmin was absent from bile from patients with Wilson's
      disease, but as expected it was present in the bile from control subjects. We
      have also identified and partially characterized a 189-200 kDa protein from
      purified human biliary canalicular membranes which binds copper and possesses
      caeruloplasmin-like activity when probed with a specific human anti
      caeruloplasmin antibody. In conclusion, we have demonstrated that copper
      incorporation in caeruloplasmin is normal in patients with Wilson's disease
      contrary to previous reports. Secondly, we have shown that the defect in Wilson's
      disease appears to lie in the biliary canalicular excretion of holocaeruloplasmin
      resulting in its retention within the hepatocyte causing copper toxicosis.
      Finally we have identified and partially characterized a caeruloplasmin-binding
      protein from biliary canalicular membranes which may provide a link to the gene
      defect in Wilson's disease.

PMID- 8645168
TI  - A protein targeting signal that functions in polarized epithelial cells in vivo.
AB  - Eukaryotic membrane-associated polypeptides often contain a
      glycosylphosphatidylinositol (GPI) anchor that signals the attachment of GPI
      lipids to these proteins. The GPI anchor can function as a basolateral or apical
      targeting signal in mammalian cells cultured in vitro, although the function of
      the GPI anchor in vivo remains to be elucidated. In this study we have evaluated
      the effect of fusing a GPI anchor sequence to a prokaryotic reporter protein on
      the cellular location of the polypeptide in polarized epithelial cells of
      transgenic mice. The bacterial enzyme, when fused to a eukaryotic signal peptide,
      was secreted through the basolateral membrane of small-intestinal enterocytes;
      however, when the enzyme was lined to the GPI anchor sequence the polypeptide was
      redirected to the apical surface of the epithelial cells. These data provide the
      first direct evidence that the GPI anchor functions as an apical membrane protein
      sorting signal in polarized epithelial cells in vivo.

PMID- 8645169
TI  - Rat endothelin-converting enzyme-1 forms a dimer through Cys412 with a similar
      catalytic mechanism and a distinct substrate binding mechanism compared with
      neutral endopeptidase-24.11.
AB  - Endothelin-converting enzyme-1 (ECE-1) is involved in the conversion of big
      endothelins (big ETs) into endothelins (ETs) and shows sequence similarity with
      neutral endopeptidase-24.11 (NEP). Unlike NEP, ECE-1 exists as a disulphide
      linked dimer. Here we reveal that Cys412 is solely responsible for the
      dimerization of rat ECE-1. The C412S mutant enzyme, which existed as a monomer,
      showed no difference in glycosylation level, subcellular localization of
      clustering structure formation, but showed a higher K(m) and lower kcat for big
      ET-1 compared with the wild-type enzyme. These results indicate that dimerization
      of ECE-1 is preferential for effective conversion of big ETs into ETs. In
      addition, complete loss of activity in the mutants E592Q, E651Q and H716Q
      confirmed that these residues are responsible for catalytic activity, zinc
      binding and stabilization of the intermediate during the transition state
      respectively. In contrast, the catalytic properties of mutant enzymes containing
      a substitution at Arg129 or Glu752 were not markedly different from those of the
      wild-type enzyme, suggesting that these residues play only a minor role, if any,
      in substrate binding, in contrast with their role in NEP.

PMID- 8645170
TI  - Expression, purification and properties of lycopene cyclase from Erwinia
      uredovora.
AB  - Lycopene cyclase, an enzyme responsible for the formation of cyclic carotenoids
      from acyclic precursors has been purified to homogeneity in an active state. The
      Erwinia uredovora lycopene cyclase gene (crtY) was over-expressed in Escherichia
      coli. From this recombinant strain the enzyme was purified by immuno-affinity
      chromatography and its cyclization activity characterized as a two-step reaction
      in which both sides of the lycopene molecule are cyclized to beta-ionone rings
      with the monocyclic gamma-carotene as an intermediate. Furthermore, neurosporene
      as well as l-hydroxylycopene were cyclized to beta-zeacarotene and hydroxy-gamma
      carotene respectively. In contrast, neither 1,1'- dihydroxylycopene nor the tetra
      cis-prolycopene were accepted as substrates. The cofactors involved in the
      reaction were either NADH or NADPH. K(m) values were determined for lycopene and
      NADPH to be 1.8 microM and 2.5 mM respectively.

PMID- 8645172
TI  - Muscarinic m1 receptor-stimulated adenylate cyclase activity in Chinese hamster
      ovary cells is mediated by Gs alpha and is not a consequence of
      phosphoinositidase C activation.
AB  - The mechanism underlying muscarinic m1 receptor-mediated increases in adenosine
      3',5'-cyclic monophosphate (cAMP) was investigated in Chinese hamster ovary (CHO)
      cells expressing human recombinant m1 muscarinic receptors (CHO-ml cells).
      Stimulation of CHO-ml cells with carbachol resulted in marked accumulation of
      Ins(1,4,5)P3 and cAMP, in an atropine-sensitive manner, with EC50 values (log M)
      of -5.16 +/- 0.06 and -3.93 +/- 0.07 respectively. Basal and agonist-stimulated
      cAMP accumulation were unaffected by a 5 min pretreatment with l microM phorbol
      12,13-dibutyrate and were not attenuated by pertussis toxin (100 ng/ml, 20h).
      Agonist-stimulated cAMP accumulation was also observed in CHO-ml cell membranes
      incubated in a buffer containing 100 nM free Ca2+. Guanosine 5'- [gamma
      thio]triphosphate (10 microM) potentiated agonist-stimulated cAMP accumulation in
      CHO-ml cell membranes, implicating a G-protein involvement in this response. Co
      incubation of carbachol with forskolin (10 microM) produced a greater than
      additive accumulation of cAMP in CHO-ml cells. Furthermore, a C-terminal-directed
      anti-Gs alpha serum attenuated both carbachol-stimulated (in CHO-ml cell
      membranes) and isoprenaline-stimulated (in CHO-beta 2 cell membranes) cAMP
      accumulation with a similar dose-dependency. These results suggest that
      muscarinic agonist-stimulated cAMP accumulation in CHO-ml cells occurs via
      activation of Gs alpha and not as a consequence of phosphoinositidase C
      activation.

PMID- 8645171
TI  - Roles of insulin, guanosine 5'-[gamma-thio]triphosphate and phorbol 12-myristate
      13-acetate in signalling pathways of GLUT4 translocation.
AB  - Insulin, guanosine 5'-[gamma-thio]triphosphate (GTP[S] and phorbol 12-myristate
      13-acetate (PMA) trigger the translocation of Gl UT4 (type 4 glucose transporter;
      insulin-sensitive glucose transporter) from an intracellular pool to the cell
      surface. We have developed a highly sensitive and quantitative method to detect
      GLUT4 immunologically on the surface of intact 3T3-L1 adipocytes and Chinese
      hamster ovary (CHO) cells, using c-myc epitope-tagged GLUT4 (GLUT4myc). We
      examined the roles of insulin, GTP[S] and PMA in the signalling pathways of GLUT4
      translocation in the CHO cell system. Among small molecular GTP-binding proteins,
      ras, rab3D, rad and rho seem to be candidates as signal transmitters of insulin
      stimulated GLUT4 translocation. Overexpression of wild-type H-ras and the
      dominant negative mutant H-rass17N in our cell system respectively enhanced and
      blocked insulin-stimulated activation of mitogen-activated protein kinase, but
      did not affect insulin-stimulated GLUT4 translocation. Overexpression of rab3D or
      rad in the cells did not affect GLUT4 translocation triggered by insulin, GTP[S]
      or PMA. Treatment with Botulinum C3 exoenzyme, a specific inhibitor of rho, had
      no effect on GLUT4 translocation induced by insulin, GTP[S] or PMA. Therefore
      these small molecular GTP-binding proteins are not likely to be involved in GLUT4
      translocation. In addition, insulin, GTP[S] and PMA apparently stimulate GLUT4
      translocation through independent pathways.

PMID- 8645174
TI  - 1H-NMR characterization of L-tryptophan binding to TRAP, the trp RNA-binding
      attenuation protein of Bacillus subtilis.
AB  - A 1H-NMR study of the binding of L-tryptophan to the trp RNA-binding attenuation
      protein of Bacillus subtilis (TRAP), an ondecamer (91.6 kDa), has been
      implemented. The assignment of the aromatic indole ring proton resonances of the
      bound tryptophan ligand has been successfully carried out by two-dimensional
      chemical exchange experiments. The observation of only a single set of chemical
      shifts of the bound ligand demonstrates that the tryptophan binding site is
      identical in all the 11 subunits of the protein. Further, the large change in
      ligand chemical shifts suggests that the conformation of tryptophan ligand
      undergoes a significant rearrangement after complex formation with TRAP. This is
      further substantiated by the extensive ligand-induced chemical shift changes
      observed to the protein resonances and identification of several strong ligand
      protein intermolecular nuclear Overhauser effects. A correlation of these
      preliminary NMR data with the X-ray crystal structure of the TRAP-tryptophan
      complex also suggests, tentatively, that the observed changes to the NMR spectra
      of the protein might correspond to changes associated with residues surrounding
      the tryptophan binding pocket owing to complex formation.

PMID- 8645173
TI  - Oct-1 [corrected] and Oct-2 DNA-binding site specificity is regulated in vitro by
      different kinases.
AB  - The transcription factors Oct-1 and Oct-2 bind differentially to three octamer
      binding sequences corresponding to the octamer binding site from the H2B promoter
      [ATGCTAATAA], a simple TAATGARAT motif, found in herpes simplex virus IE4/5 genes
      [GCGGTAATGAGAT], and a perfect consensus overlapping octamer/TAATGARAT motif
      [ATGCTAATGAGAT]. By comparing the effects of protein kinase A, protein kinase C
      and casein kinase 2 in vitro on the binding of Oct-1 and Oct-2 to the three
      motifs, we show that the actions of these kinases regulate Oct-1 and Oct-2 DNA
      binding independently of each other in a binding-site-specific manner. Inhibition
      of cellular phosphatases also regulate Oct-1 and Oct-2 DNA binding in a binding
      site-specific manner. Both kinase and phosphatase activity are important for
      regulating the DNA binding activity of Oct-1 and Oct-2 because, in the presence
      of phosphatase inhibitors, protein kinase A attenuates the binding of both Oct-1
      and Oct-2 to the octamer binding site but enhances binding when phosphatase
      inhibitors are omitted. Thus the DNA specificity of Oct-1 and Oct-2 can be
      regulated in vitro by the action of different kinases.

PMID- 8645176
TI  - Probing the high-affinity site of beef heart cytochrome c oxidase by cross
      linking.
AB  - A covalent complex between cytochrome c oxidase and Saccharomyces cerevisiae iso
      1-cytochrome c (called caa3) has been prepared at low ionic strength. Subunit III
      Cys-115 of beef heart cytochrome c oxidase cross-links by disulphide bond
      formation to thionitrobenzoate-modified yeast cytochrome c, a derivative shown to
      bind into the high-affinity site for substrate [Fuller, Darley-Usmar and Capaldi
      (1981) Biochemistry 20, 7046-7053]. Stopped-flow experiments show that (1)
      covalently bound yeast cytochrome c cannot donate electrons to cytochrome
      oxidase, whereas oxidation of exogenously added cytochrome c and electron
      transfer to cytochrome a are only slightly affected; (2) the steady-state
      reduction levels of cytochrome c and cytochrome a in the covalent complex caa3
      are higher than those found in the native aa3 enzyme. However, (3) K(m) and Vmax
      values obtained from the non-linear Eadie-Hofstee plots are very similar in both
      caa3 and aa3. The results imply that cytochrome c bound to the high-affinity site
      is not in a configuration optimal for electron transfer.

PMID- 8645175
TI  - Tissue specific and androgen-regulated expression of human prostate-specific
      transglutaminase.
AB  - Transglutaminases (TGases) are calcium-dependent enzymes catalysing the post
      translational cross-linking of proteins. In the prostate at least two TGases are
      present, the ubiquitously expressed tissue-type TGase (TGC), and a prostate
      restricted TGase (TGP). This paper deals with the molecular cloning and
      characterization of the cDNA encoding the human prostate TGase (hTGP). For this
      purpose we have screened a human prostate cDNA library with a probe from the
      active-site region of TGC. The largest isolated cDNA contained an open reading
      frame encoding a protein of 684 amino acids with a predicted molecular mass of 77
      kDa as confirmed by in vitro transcription-translation and subsequent SDS/PAGE.
      The hTGP gene was tissue-specifically expressed in the prostate, yielding an mRNA
      of approx. 3.5 kb. Furthermore, a 3-fold androgen-induced upregulation of hTGP
      mRNA expression has been demonstrated in the recently developed human prostate
      cancer cell line, PC346C. Other well established human prostate cancer cell
      lines, LNCaP and PC-3, showed no detectable hTGP mRNA expression on a Northern
      bolt. The gene coding for prostate TGase was assigned to chromosome 3.

PMID- 8645177
TI  - The differential regulation of cyclic AMP by sphingomyelin-derived lipids and the
      modulation of sphingolipid-stimulated extracellular signal regulated kinase-2 in
      airway smooth muscle.
AB  - We report that sphingosine and short-chain ceramides activate adenylate cyclase
      and stimulate intracellular cyclic AMP formation in airway-smooth-muscle (ASM)
      cells. In each case, there is a conditional requirement for GTP-Gs alpha.
      Sphingosine utilizes a protein kinase C-dependent pathway to elicit activation of
      adenylate cyclase, whereas for short-chain ceramides the mechanism remains
      unidentified. In contrast, sphingosine phosphate inhibits Gs-stimulated cyclic
      AMP formation via a Gi-dependent mechanism. Therefore, the potential
      interconversion of sphingosine and sphingosine phosphate is a switch that can
      elicit reciprocal changes in cyclic AMP levels. This may have a significant
      impact upon the regulation of extracellular signal-regulated kinase (ERK) and c
      Jun N-terminal specific kinase (JNK) by sphingolipids and may help to explain how
      growth factors that utilize these second messengers evoke pleiotropic responses
      such as proliferation and cell survival. In this context, short-chain ceramides
      are poor stimulators of ERKs in ASM cells, and sphingosine is inactive, whereas
      both sphingolipids are powerful activators of the JNK module. Activated JNK
      catalyses N-terminal phosphorylation of c-Jun, a kinase cascade that programmes
      growth arrest. Therefore, in blocking ceramide-stimulated ERK-2 activity, cyclic
      AMP may allow the ceramide-dependent activation of JNK to programme cells to opt
      out of the cell cycle. In contrast, sphingosine phosphate activates ERK-2,
      potentiates growth-factor-stimulated DNA synthesis and fails to activate JNK,
      indicating that its sequential formation from ceramide and sphingosine may commit
      cells to DNA synthesis. ERK-2 can be activated by both cyclic AMP-sensitive c-Raf
      1 kinase-dependent and cyclic AMP-insensitive c-Raf-1 kinase-independent pathways
      in ASM cells. In this context, sphingosine phosphate activates ERK-2 exclusively
      via c-Raf-1 kinase. Sphingosine phosphate-stimulated ERK-2 activity is also
      abolished by pertussis toxin, indicating that c-Raf-1 kinase is activated via a
      Gi-dependent mechanism.

PMID- 8645178
TI  - Phosphorylation of a membrane-intercalated proteoglycan, syndecan-2, expressed in
      a stroma-inducing clone from a mouse Lewis lung carcinoma.
AB  - We previously reported that a mouse Lewis lung carcinoma-derived stroma-inducing
      clone, P29, highly expresses a syndecan-like proteoglycan exhibiting specific
      binding to fibronectin, a major constituent of the interstitial matrix formed by
      the induced stromal cells, via its heparan sulphate chains [Itano, Oguri,
      Nakanishi and Okayama (1993) J. Biochem. (Tokyo) 114, 862-873]. On metabolic
      labelling of the proteoglycan with [32P]Pi, followed by identification of the
      radiolabelled material using glycanases, almost all the isotope was found to have
      been incorporated into a core portion of molecular mass 48 kDa, which was
      generated by digestion with heparan sulphate lyase I plus chondroitin ABC lyase.
      Immunoblotting of the core protein with a monoclonal antibody, F58-6G12,
      demonstrated that the proteoglycan was mouse syndecan-2. CsCl-density-gradient
      centrifugation after mild treatment of liposome-intercalated 32P-labelled
      syndecan-2 with trypsin resulted in clear separation of the radioactivity into a
      bottom fraction containing all the glycosaminoglycans (accounting for 40% of the
      total radioactivity) and a top fraction containing liposome-associated peptides
      (60%). The former isotope was shown to be linked covalently to both heparan
      sulphate and chondroitin sulphate chains, probably at their bridge regions. The
      latter was mostly attributed to phosphoserine, the one and only phosphorylated
      amino acid released on acid hydrolysis of this proteoglycan, strongly suggesting
      that the phosphorylation occurs at a specific serine residue(s) in the
      cytoplasmic domain of the core protein.

PMID- 8645179
TI  - Purification, cloning and expression of dehydroascorbic acid-reducing activity
      from human neutrophils: identification as glutaredoxin.
AB  - Dehydroascorbic acid-reducing activity in normal human neutrophil lysates was
      characterized and identified by activity-based purification and measurement of
      newly synthesized ascorbate by HPLC. The initial reducing activity was non
      dialysable and could not be accounted for by the activity of glutathione as a
      reducing agent. The reducing activity was purified to homogeneity as an 11 kDa
      protein. The protein had a specific activity of 3 mumol/min per mg of protein and
      was glutathione dependent. Kinetic experiments showed that the protein had a K(m)
      for glutathione of 2.0 mM and a K(m) for dehydroascorbic acid of 250 microM.
      Dehydroascorbic acid reduction by the purified protein was pH dependent and was
      maximal at pH 7.5. Peptide fragments from the purified protein were analysed for
      amino acid sequence and the protein was identified as glutaredoxin. By using
      degenerate oligonucleotides based on the amino acid sequence, glutaredoxin was
      cloned from a human neutrophil library. Expressed purified glutaredoxin displayed
      reducing activity and kinetics that were indistinguishable from those of native
      purified enzyme. Several approaches indicated that glutaredoxin was responsible
      for the most of the protein-mediated dehydroascorbic acid reduction in lysates.
      From protein purification data, glutaredoxin was responsible for at least 47% of
      the initial reducing activity. Dehydroascorbic acid reduction was at least 5-fold
      greater in neutrophil lysates than in myeloid tumour cell lysates, and
      glutaredoxin was detected in normal neutrophil lysates but not in myeloid tumour
      cell lysates by Western blotting. Glutaredoxin inhibitors inhibited
      dehydroascorbic acid reduction in neutrophil lysates as much as 80%. These
      findings indicate that glutaredoxin plays a major role in dehydroascorbic acid
      reduction in normal human neutrophil lysates, and represent the first
      identification of dehydroascorbic acid reductase in human tissue by activity
      based purification.

PMID- 8645180
TI  - The serine protease granzyme A does not induce platelet aggregation but inhibits
      responses triggered by thrombin.
AB  - Granzyme A is a serine protease stored in cytoplasmic granules of cytotoxic and
      helper T lymphocytes. This protease seems to elicit thrombin receptor-mediated
      responses in neural cells, thereby triggering neurite retraction and reversal of
      astrocyte stellation. Here we report that granzyme A does not cause platelet
      aggregation even at concentrations that are more than two orders of magnitude
      higher than the EC50 for granzyme A in causing morphological changes in neural
      cells. However, granzyme A blocks thrombin-induced platelet aggregation in a dose
      dependent manner without affecting the response to either ADP or to the peptide
      agonist of the thrombin receptor SFLLRN that corresponds in sequence to the
      tethered ligand domain. The inability of granzyme A to cause aggregation and its
      inhibition of thrombin-induced aggregation were seen in platelets from man, rat
      and mouse. Granzyme A does not affect the catalytic activity of thrombin in
      cleaving a chromogenic substrate or the macromolecular substrate fibrinogen.
      However, granzyme A does seem to cleave the thrombin receptor on platelets to
      produce a weak Ca2+ signal and reduce the response to subsequent challenge with
      thrombin, but does not induce a signal in thrombin-stimulated platelets. It is
      proposed that granzyme A interacts with the thrombin receptor found on platelets
      in a manner that is insufficient to cause aggregation, but sufficient to compete
      with thrombin for the receptor. These results suggest that granzyme A cleaves the
      thrombin receptor at a rate that is insufficient to cause platelet aggregation
      but is sufficient to cause morphological changes in neural cells. Furthermore,
      these observations demonstrate that granzyme A release occurring during immune
      responses within blood vessels would not directly cause platelet aggregation.

PMID- 8645181
TI  - Degradation of pyrene-labelled phospholipids by lysosomal phospholipases in
      vitro. Dependence of degradation on the length and position of the labelled and
      unlabelled acyl chains.
AB  - The hydrolysis of pyrenylacyl phosphatidylcholines (PyrnPCs)(n indicates the
      number of aliphatic carbons in the pyrene-chain) by crude lysosomal
      phospholipases in vitro was investigated. PyrnPCs consist of several sets in
      which the length of the pyrene-labelled or the unlabelled acyl chain, linked to
      the sn-1 or sn-2 position, was systematically varied. Lysophosphatidylcholine and
      fatty acid were the only fluorescent breakdown products detected, thus indicating
      that PyrnPCs were degraded by A-type phospholipases and lysophospholipases. Of
      these, mainly A1-type phospholipases appear to be involved, as determined from
      the relative amounts of labelled fatty acid and lysolipid released from the
      positional isomers. Based on the effects of the length and position of the pyrene
      labelled and unlabelled chains it is suggested that (1) the lysosomal A-type
      phospholipases acting on PyrnPCs recognize the carboxy-terminal part of the lipid
      acyl chains and (2) the relevant part of the binding site is relatively narrow.
      Thus phospholipids with added bulk in the corresponding region, such as those
      that are peroxidized and polymerized, may not be good substrates for the
      lysosomal phospholipases mentioned. The impaired hydrolysis of the most
      hydrophobic PyrnPCs indicates that lysosomal phospholipases may not be able to
      penetrate significantly into the substrate interphase, but upward movement of the
      lipid may be required for efficient hydrolysis. Finally, the rate of hydrolysis
      of many pyrenyl derivatives was found to be comparable to that of a natural
      phosphatidylcholine species, both in micelles and in lipoprotein particles,
      indicating that these derivatives can be used as faithful reporters of lysosomal
      degradation of natural lipids in vivo and in vitro.

PMID- 8645182
TI  - Characterization of structural determinants and molecular mechanisms involved in
      pro-stromelysin-3 activation by 4-aminophenylmercuric acetate and furin-type
      convertases.
AB  - Stromelysin-3 (ST3) is a matrix metalloproteinase (MMP) which has been implicated
      in cancer progression and in a number of conditions involving tissue remodelling.
      In contrast to other MMPs which are secreted as zymogens requiring extracellular
      activation, ST3 is found in the extracellular space as a potentially active
      mature form, suggesting that the activation of the ST3 proform differs from that
      of other MMPs. We show in the present study that the ST3 proform is not
      autocatalytically processed in the presence of 4-aminophenylmercuric acetate
      (APMA). By using ST3/ST2 chimeras, we demonstrate that resistance to APMA is due
      to properties associated with both the ST3 pro- and catalytic domains. In
      agreement with the observation made by Pei and Weiss [Pei and Weiss (1995) Nature
      (London) 375, 244-247], we find that the requirement for activation of the ST3
      proform by the furin convertase is entirely contained within a stretch of 10
      amino acids located at the junction between the ST3 pro- and catalytic domains.
      Furin cleaves human and mouse ST3 equally well. However, PACE-4, a furin-like
      convertase, is much more efficient on the mouse enzyme, suggesting that ST3
      protein determinants other than the conserved Ala-Arg-Asn-Arg-Gln-Lys-Arg
      sequence preceding the furin cleavage site are implicated in PACE-4 action.
      Finally, we show that processing of the ST3 proform is inhibited by a furin
      inhibitor in human MCF7 breast cancer cells stably transfected to constitutively
      express a full-length human ST3 cDNA. Using brefeldin A, we demonstrate that, in
      these MCF7 cells, the 56 kDa precursor form of ST3 is post-translationally
      modified in the cis- or media-Golgi into a 62 kDa proform. Thereafter, its
      processing into the 47 kDa mature form occurs in the trans-Golgi network and is
      followed by secretion into the extracellular space.

PMID- 8645183
TI  - Chronic growth hormone treatment in normal rats reduces post-prandial skeletal
      muscle plasma membrane GLUT1 content, but not glucose transport or GLUT4
      expression and localization.
AB  - Whether skeletal muscle glucose transport system is impaired in the basal, post
      prandial state during chronic growth hormone treatment is unknown. The current
      study was designed to determine whether 4 weeks of human growth hormone (hGH)
      treatment (3.5 mg/kg per day) would impair glucose transport and/or the number of
      glucose transporters in plasma membrane vesicles isolated from hindlimb skeletal
      muscle of Sprague-Dawley rats under basal, post-prandial conditions. hGH
      treatment was shown to have no effect on glucose influx (Vmax or K(m)) determined
      under equilibrium exchange conditions in isolated plasma membrane vesicles.
      Plasma membrane glucose transporter number (Ro) measured by cytochalasin B
      binding was also unchanged by hGH treatment. Consequently, glucose transporter
      turnover number (Vmax/Ro), a measure of average glucose transporter intrinsic
      activity, was similar in hGH-treated and control rats. hGH did not change GLUT4
      protein content in whole muscle or in the plasma membrane, and muscle content of
      GLUT4 mRNA also was unchanged. In contrast, GLUT1 protein content in the plasma
      membrane fraction was significantly reduced by hGH treatment. This was associated
      with a modest, although not significant, decrease in muscle content of GLUT1
      mRNA. In conclusion, high-dose hGH treatment for 4 weeks did not alter post
      prandial skeletal muscle glucose transport activity. Neither the muscle level nor
      the intracellular localization of GLUT4 was changed by the hormone treatment. On
      the contrary, the basal post-prandial level of GLUT1 in the plasma membrane was
      reduced by hGH. The mRNA data suggest that this reduction might result from a
      decrease in the synthesis of GLUT1.

PMID- 8645184
TI  - Purification and characterization of cytosolic and microsomal cyclophilins from
      maize (Zea mays).
AB  - Methods for the purification and separation of peptidyl prolyl cis-trans
      isomerase (PPI) from cytosolic and microsomal fractions of etiolated maize are
      described. On SDS/PAGE, the purified preparations appears as single polypeptides
      with molecular masses of 17.5 kDa and 17.7 kDa respectively. Instead of using
      immobilized cyclosporin A derivatives as affinity adsorbents, our methods employ
      conventional techniques enabling purification of the proteins on a much larger
      scale than previously described. An antiserum raised against the cytosolic PPI
      recognizes polypeptides of similar molecular mass from a wide range of plant
      species on an immunoblot. There is virtually no recognition of the microsomal
      PPI. The cytosolic and microsomal PPIs are inhibited by cyclosporin A (Ki = 6 nM
      in both cases), indicating that they are cyclophilins. The cytosolic enzyme is
      inactivated by 5 mM N-ethylmaleimide and 2 mM phenylglyoxal. N-terminal
      sequencing of the microsomal PPI indicates a high level of sequence similarity
      with the N-terminal sequence of mature animal s-cyclophilin (cyclophilin B).

PMID- 8645185
TI  - Functional expression of rat GLUT 1 glucose transporter in Dictyostelium
      discoideum.
AB  - To facilitate expression of the rat GLUT 1 glucose transporter cDNA in
      Dictyostelium discoideum, we mutated the 5' end of the coding sequence such that
      the codons for the first ten amino acids conformed to preferred Dictyostelium
      codon usage. As determined by Western-blot analysis, a population of
      Dictyostelium transformed with the mutated cDNA expressed nonglycosylated GLUT 1
      protein. Cell lines expressing GLUT 1 transport radiolabelled 2-deoxy-D-glucose
      at a rate 6-10 times that of cell lines transformed with vector alone. The
      initial rate of inward transport of 2-deoxy-D-glucose was stimulated several-fold
      by the presence of unlabelled glucose in the Dictyostelium cytoplasm,
      exemplifying the trans-activation of GLUT 1 transport characteristic of GLUT 1
      present in erythrocyte membranes. The K(m) and Ki values for 2-deoxy-D-glucose, D
      glucose, D-mannose and D-galactose were 3.7 mM, 2.6 mM, 11 mM and 30 mM
      respectively, similar to the values for GLUT 1 expressed in mammalian cells. L
      Glucose and L-galactose, which are not transported by GLUT 1, do not inhibit
      uptake of 2-deoxy-D-glucose in Dictyostelium expressing GLUT 1. Thus, even though
      GLUT 1 expressed in Dictyostelium is not N-glycosylated, it transports hexoses
      normally; this is the first example of functional expression of a mammalian
      transport protein in this lower eukaryote.

PMID- 8645186
TI  - A novel structural class of K+-channel blocking toxin from the scorpion Pandinus
      imperator.
AB  - A novel peptide was purified and characterized from the venom of the scorpion
      Pandinus imperator. Analysis of its primary structure reveals that it belongs to
      a new structural class of K+-channel blocking peptide, composed of only 35 amino
      acids, but cross-linked by four disulphide bridges. It is 40, 43 and 46%
      identical to noxiustoxin, margatoxin and toxin 1 of Centruroides limpidus
      respectively. However, it is less similar (26 to 37% identity) to toxins from
      scorpions of the geni Leiurus, Androctonus and Buthus. The disulphide pairing was
      determined by sequencing heterodimers produced by mild enzymic hydrolysis. They
      are formed between Cys-4-Cys-25, Cys-10-Cys-30, Cys-14-Cys-32 and Cys-20-Cys-35.
      Three-dimensional modelling, using the parameters determined for charybdotoxin,
      showed that is it possible to accommodate the four disulphide bridges in the same
      general structure of the other K+-channel blocking peptides. The new peptide
      (Pil) blocks Shaker B K+ channels reversibly. It also displaces the binding of a
      known K+-channel blocker, [125I]noxiustoxin, from rat brain synaptosomal
      membranes with an IC50 of about 10 nM.

PMID- 8645187
TI  - Tight connection between choline transport and phosphatidylcholine synthesis in
      MDCK cells.
AB  - In MDCK cells, choline uptake, the first step in the CDP-choline pathway for the
      biosynthesis of choline-containing phospholipids and osmolytes, occurs via both a
      transport system highly specific for choline and a non-specific pathway. The
      specific choline carrier is present at the apical domain of cells grown on dishes
      and is sodium-independent. Growing the cells on a permeant support results in the
      preferential localization of the specific choline carrier at the basolateral
      domain. To characterize the relationships between the choline uptake sites and
      the synthesis of phosphatidylcholine, MDCK cells were incubated with [Me
      3H]choline and/or [Me-14C]choline for various times (up to 36 h) and the
      incorporation of label into phospholipids and water-soluble molecules was
      determined. For cells grown on dishes, addition of [Me-3H]choline at the apical
      side was followed by rapid incorporation of the label into the successive
      intermediates of the CDP-choline pathway. A comparable situation was found when
      growing the cells on a permeant support and adding the labelled choline at the
      basolateral side of the culture. On the other hand, radioactive choline added to
      the apical bath entered the CDP pathway to only a very low extent. Efflux
      experiments on cells loaded with choline from either the apical or the
      basolateral side demonstrate the existence of intracellular pools of choline.
      Addition of hemicholinium-3, an inhibitor of the specific choline carrier,
      markedly reduced the metabolism of choline taken up by the cells on the
      basolateral side but had no effect on that transported at the apical side. These
      results strongly suggest the existence of a tight connection between the entry of
      choline through the specific choline carrier and phosphatidylcholine synthesis in
      MDCK cells.

PMID- 8645188
TI  - Bovine inositol monophosphatase: enzyme-metal-ion interactions studied by pre
      equilibrium fluorescence spectroscopy.
AB  - Stopped-flow fluorescence spectroscopy has been used to determine the on-rate
      (kass) and the off-rate (kdiss) for the equilibrium between inositol
      monophosphatase and Mg2+ ions. The dissociation constant (Kd) for the equilibrium
      calculated from these constants suggests that the ions interact at site 1 on the
      enzyme with a Kd typically around 450 microM, close to values determined by
      equilibrium studies (270-300 microM). The affinity of this site on the wild-type
      enzyme for Mg2+ ions increases as the pH is increased. This is mediated almost
      entirely by change in the rate kdiss. A slow increase occurs in the fluorescence
      intensity of the pyrene-labelled enzyme after the initial, fast, increase in
      fluorescence caused by the binding of the Mg2+ ion. The rate of this change is
      independent of the concentration of the metal ion, implying that it may be a
      structural change in the enzyme-Mg2+ complex. Neither the fast nor the slow
      change in fluorescence intensity occurs when enzyme subjected to limited
      proteolysis by trypsin, which removes the N-terminal 36 residues, is mixed with
      Mg2+ ions. The data suggest that interaction with Mg2+ ions at a high-affinity
      site leads to a structural change in inositol monophosphatase. The data further
      confirm the importance of the presence of two metal ions in the
      structure/function of this enzyme, and show that the binding of the metal ions is
      not competitive with that of H+ ions and that the variation in Kd with pH is
      mediated almost totally by changes in kdiss.

PMID- 8645189
TI  - Marked alteration of proteoglycan metabolism in cholesterol-enriched human
      arterial smooth muscle cells.
AB  - To elucidate the correlation between vascular cholesterol metabolism and
      proteoglycan (PrGl) biosynthesis, we investigated PrGl synthesis in human aortic
      smooth muscle cells (SMCs) after cholesterol enrichment with cationized low
      density lipoproteins (LDL). Compared with normal SMCs, total PrGl synthesis by
      cholesterol-enriched cells decreased 2.4-fold (11874 +/- 530 d.p.m. per 10(5)
      cells compared with 4890 +/- 385 d.p.m. per 10(5) cells). This was the net result
      of a 6.9-fold reduction in medium PrGl (11000 +/- 490 d.p.m. per 10(5) cells
      compared with 1580 +/- 246 d.p.m. per 10(5) cells) and a 3.8-fold increase in
      cellular PrGl over controls (874 +/- 27 d.p.m. per 10(5) cells compared with 3310
      +/- 193 d.p.m. per 10(5) cells). Prior incubation of SMCs with native LDL had no
      effect on PrGl synthesis by these cells. The decrease in PrGl synthesis in
      cholesterol-enriched cells correlated with a 90% and 20% reduction in the steady
      state level of mRNA for biglycan and decorin respectively, and a virtual
      elimination of the steady-state level of mRNA for versican over controls. Despite
      the down-regulation of PrGl synthesis, cholesterol-loaded cells produced a 2-fold
      increase in a PrGl subfraction with high affinity for LDL. Compared with the
      corresponding PrGl subfraction from normal cells, that from the cholesterol
      enriched cells exhibited increased charge density and a higher molecular mass and
      contained relatively larger proportions of chondroitin 6-sulphate and dermatan
      sulphate. These results show that PrGl metabolism is dramatically altered in
      cholesterol-enriched human SMCs.

PMID- 8645191
TI  - Transcriptional induction of the human renin gene by cyclic AMP requires cyclic
      AMP response element-binding protein (CREB) and a factor binding a pituitary
      specific trans-acting factor (Pit-1) motif.
AB  - To delineate the cis-acting elements of the proximal promoter responsible for
      cyclic AMP (cAMP)-induced human renin gene transcription, 5'-flanking regions of
      the human renin gene were fused to a luciferase reporter gene and transfected in
      chorionic cells. Forskolin treatment induced the expression of luciferase by 2.4
      fold when the reporter plasmid contained the promoter region (-582 to + 16).
      Mutation or deletion of the cAMP response element (CRE) diminished (1.7-fold) but
      did not abolish cAMP-induced transcription, demonstrating that the (-582 to -145)
      region containing the CRE and the region (-145 to -38) containing a Pit-1
      (pituitary-specific trans-acting factor) site were both necessary for cAMP
      maximal induction. To study the molecular events mediating the cAMP induction,
      DNase I footprinting and electromobility shift assays (EMSAs) were performed with
      renin-producing chorionic cell and kidney cortex cell nuclear extracts, showing
      that the CRE-binding protein (CREB) interacts with the CRE and that tissue
      specific factors, distinct from Pit-1, specifically bind the renin Pit-1 motif.
      Taken together, these results demonstrate that the cAMP response of the human
      renin gene may involve CREB binding the CRE and tissue-specific factors,
      different from Pit-1, that interact with the Pit-1 response DNA elements.

PMID- 8645190
TI  - Collagen fibril formation.
AB  - Collagen is most abundant in animal tissues as very long fibrils with a
      characteristic axial periodic structure. The fibrils provide the major
      biomechanical scaffold for cell attachment and anchorage of macromolecules,
      allowing the shape and form of tissues to be defined and maintained. How the
      fibrils are formed from their monomeric precursors is the primary concern of this
      review. Collagen fibril formation is basically a self-assembly process (i.e. one
      which is to a large extent determined by the intrinsic properties of the collagen
      molecules themselves) but it is also sensitive to cell-mediated regulation,
      particularly in young or healing tissues. Recent attention has been focused on
      "early fibrils' or "fibril segments' of approximately 10 microns in length which
      appear to be intermediates in the formation of mature fibrils that can grow to be
      hundreds of micrometers in length. Data from several laboratories indicate that
      these early fibrils can be unipolar (with all molecules pointing in the same
      direction) or bipolar (in which the orientation of collagen molecules reverses at
      a single location along the fibril). The occurrence of such early fibrils has
      major implications for tissue morphogenesis and repair. In this article we review
      the current understanding of the origin of unipolar and bipolar fibrils, and how
      mature fibrils are assembled from early fibrils. We include preliminary evidence
      from invertebrates which suggests that the principles for bipolar fibril assembly
      were established at least 500 million years ago.

PMID- 8645193
TI  - Effect of substituent on the thermodynamics of D-glucopyranoside binding to
      concanavalin A, pea (Pisum sativum) lectin and lentil (Lens culinaris) lectin.
AB  - Titration calorimetry measurements of the binding of phenyl-alpha (alpha PhOGlu),
      3-methoxy (3MeOGlu), fluorodeoxy and deoxy derivatives of alpha-D-glucopyranose
      (Glu) to concanavalin A (conA), pea lectin and lentil lectin were performed at
      approx. 10 and 25 degrees C in 0.01 M dimethylglutaric acid/NaOH buffer, pH 6.9,
      containing 0.15 M NaCl and Mn2+ and Ca2+ ions. Apparently the 3-deoxy, 4-deoxy
      and 6-deoxy as well as the 4-fluorodeoxy and 6-fluorodeoxy derivatives of Glu do
      not bind to the lectins because no heat release was observed on the addition of
      aliquots of solutions of these derivatives to the lectin solutions. The binding
      enthalpies, delta H0b, and entropies, delta S0b, determined from the measurements
      were compared with the same thermodynamic binding parameters for Glu, D
      mannopyranoside and methyl-alpha- D-glucopyranoside (alpha MeOGlu). The binding
      reactions are enthalpically driven with little change in the heat capacity on
      binding, and exhibit enthalpy-entropy compensation. Differences between the
      thermodynamic binding parameters can be rationalized in terms of the interactions
      apparent in the known crystal structures of the methyl-alpha-D-mannopyranoside
      conA [Derewenda, Yariv, Helliwell, Kalb (Gilboa), Dodson, Papiz, Wan and Campbell
      (1989) EMBO J. 8, 2189-2193] and pea lectin-trimanno-pyranoside [Rini, Hardman,
      Einspahr, Suddath and Carber (1993) J. Biol. Chem. 268, 10126-10132] complexes.
      Increases in the entropy change on binding are observed for alpha MeOGlu binding
      to pea and lentil lectin, for alpha PhOGlu binding to conA and pea lectin, and
      for 3MeOGlu binding to pea lectin relative to the entropy change for Glu binding,
      and imply that the phenoxy and methoxy substituents provide additional
      hydrophobic interactions in the complex. Increases in the binding enthalpy
      relative to that of Glu are observed for deoxy and fluoro derivatives in the C-1
      and C-2 positions and imply that these substituents weaken the interaction with
      the surrounding water, thereby strengthening the interaction with the binding
      site.

PMID- 8645192
TI  - Cloning and expression of the gene encoding the Thermoanaerobacter ethanolicus
      39E secondary-alcohol dehydrogenase and biochemical characterization of the
      enzyme.
AB  - The adhB gene encoding Thermoanaerobacter ethanolicus 39E secondary-alcohol
      dehydrogenase (S-ADH) was cloned, sequenced and expressed in Escherichia coli.
      The 1056 bp gene encodes a homotetrameric recombinant enzyme consisting of 37.7
      kDa subunits. The purified recombinant enzyme is optimally active above 90
      degrees C with a half-life of approx. 1.7 h at 90 degrees C. An NADP(H)-dependent
      enzyme, the recombinant S-ADH has 1400-fold greater catalytic efficiency in
      propan-2-ol oxidation than in ethanol oxidation. The enzyme was inactivated by
      chemical modification with dithionitrobenzoate (DTNB) and diethylpyrocarbonate,
      indicating that Cys and His residues are involved in catalysis. Zinc was the only
      metal enhancing S-ADH reactivation after DTNB modification, implicating the
      involvement of bound zinc in catalysis. Arrhenius plots for the oxidation of
      propan-2-ol by the native and recombinant S-ADHs were linear from 25 to 90
      degrees C when the enzymes were incubated at 55 degrees C before assay.
      Discontinuities in the Arrhenius plots for propan-2-ol and ethanol oxidations
      were observed, however, when the enzymes were preincubated at 0 or 25 degrees C.
      The observed Arrhenius discontinuity therefore resulted from a temperature
      dependent, catalytically significant S-ADH structural change. Hydrophobic cluster
      analysis comparisons of both mesophilic and thermophilic S-ADH and primary-
      versus S-ADH amino acid sequences were performed. These comparisons predicted
      that specific proline residues might contribute to S-ADH thermostability and
      thermophilicity, and that the catalytic Zn ligands are different in primary
      alcohol dehydrogenases (two Cys and a His) and S-ADHs (Cys, His, and Asp).

PMID- 8645194
TI  - Sphingolipid metabolites differentially regulate extracellular signal-regulated
      kinase and stress-activated protein kinase cascades.
AB  - The mitogen-activated protein kinase (MAPK) signalling pathway serves to
      translocate information from activated plasma-membrane receptors to initiate
      nuclear transcriptional events. This cascade has recently been subdivided into
      two analogous pathways: the extracellular signal-regulated kinase (ERK) cascade,
      which preferentially signals mitogenesis, and the stress-activated protein kinase
      (SAPK) cascade, which is linked to growth arrest and/or cellular inflammation. In
      concurrent experiments utilizing rat glomerular mesangial cells (MCs), we
      demonstrate that growth factors or sphingosine activate ERK but not SAPK. In
      contrast, inflammatory cytokines or cell-permeable ceramide analogues activate
      SAPK but not ERK. Ceramide, but not sphingosine, induces interleukin-6 secretion,
      a marker of an inflamed phenotype. Moreover, ceramide can suppress growth factor-
      or sphingosine-induced ERK activation as well as proliferation. These studies
      implicate sphingolipid metabolites as opposing regulators of cell proliferation
      and inflammation through activation of separate kinase cascades.

PMID- 8645196
TI  - Organization of Ca2+ stores in myeloid cells: association of SERCA2b and the type
      1 inositol-1,4,5-trisphosphate receptor.
AB  - In this study, we have analysed the relationship between Ca2+ pumps and
      Ins(1,4,5)P3-sensitive Ca2+ channels in myeloid cells. To study whether
      sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA)-type Ca(2+)-ATPases are
      responsible for Ca2+ uptake into Ins(1,4,5)P3-sensitive Ca2+ stores, we used the
      three structurally unrelated inhibitors thapsigargin, 2,5-di-t-butylhydroquinone
      and cyclopiazonic acid. In HL-60 cells, all three compounds precluded formation
      of the phosphorylated intermediate of SERCA-type Ca(2+)-ATPases. They also
      decreased, in parallel, ATP-dependent Ca2+ accumulation and the amount of
      Ins(1,4,5)P3-releasable Ca2+. Immunoblotting with subtype-directed antibodies
      demonstrated that HL-60 cells contain the Ca2+ pump SERCA2 (subtype b), and the
      Ca(2+)-release-channel type-1 Ins(1,4,5)P3 receptor. In subcellular fractionation
      studies, SERCA2 and type-1 Ins(1,4,5)P3 receptor co-purified. Immunofluorescence
      studies demonstrated that both type-1 Ins(1,4,5)P3 receptor and SERCA2 were
      evenly distributed throughout the cell in moving neutrophils. During phagocytosis
      both proteins translocated to the periphagosomal space. Taken together, our
      results suggest that in myeloid cells (i) SERCA-type Ca(2+)-ATPases function as
      Ca2+ pumps of Ins(1,4,5)P3-sensitive Ca2+ stores, and (ii) SERCA2 and type-1
      Ins(1,4,5)P3 receptor reside either in the same or two tightly associated
      subcellular compartments.

PMID- 8645195
TI  - Heterologous expression, purification and characterization of rat class theta
      glutathione transferase T2-2.
AB  - Rat glutathione transferase (GST) T2-2 of class Theta (rGST T2-2), previously
      known as GST 12-12 and GST Yrs-Yrs, has been heterologously expressed in
      Escherichia coli XLI-Blue. The corresponding cDNA was isolated from a rat
      hepatoma cDNA library, ligated into and expressed from the plasmid pKK-D. The
      sequence is the same as that of the previously reported cDNA of GST Yrs-Yrs. The
      enzyme was purified using ion-exchange chromatography followed by affinity
      chromatography with immobilized ferric ions, and the yield was approx. 200 mg
      from a 1 litre bacterial culture. The availability of a stable recombinant rGST
      T2-2 has paved the way for a more accurate characterization of the enzyme. The
      functional properties of the recombinant rGST T2-2 differ significantly from
      those reported earlier for the enzyme isolated from rat tissues. These
      differences probably reflect the difficulties in obtaining fully active enzyme
      from sources where it occurs in relatively low concentrations, which has been the
      case in previous studies. 1-Chloro-2,4-dinitrobenzene, a substrate often used
      with GSTs of classes Alpha, Mu and Pi, is a substrate also for rGST T2-2, but the
      specific activity is relatively low. The Km value for glutathione was determined
      with four different electrophiles and was found to be in the range 0.3 mM-0.8 mM.
      The Km values for some electrophilic substrates were found to be in the
      micromolar range, which is low compared with those determined for GSTs of other
      classes. The highest catalytic efficiency was obtained with menaphthyl sulphate,
      which gave a Kcat/Km value of 2.3 x 10(6) s-1.M-1 and a rate enhancement over the
      uncatalysed reaction of 3 x 10(10).

PMID- 8645197
TI  - Subunit structure of vacuolar proton-pyrophosphatase as determined by radiation
      inactivation.
AB  - Vacuolar proton-pyrophosphatase (H(+)-PPase) of mung bean seedlings contains a
      single kind of polypeptide with a molecular mass of approx. 73 kDa. However, in
      this study, a molecular mass of approx. 140 kDa was obtained for the purified
      vacuolar H(+)-PPase by size-exclusion gel-filtration chromatography, suggesting
      that the solubilized form of this enzyme is a dimer. Radiation inactivation
      analysis of tonoplast vesicles yielded functional masses of 141.5 +/- 10.8 and
      158.4 +/- 19.5 kDa for PP1 hydrolysis activity and its supported proton
      translocation respectively. These results confirmed the in situ dimeric structure
      of the membrane-bound H(+)-PPase of plant vacuoles. Further target-size analysis
      showed that the functional unit of purified vacuolar H(+)-PPase was 71.1 +/- 6.7
      kDa, indicating that only one subunit of the purified dimeric complex would
      sufficiently display its enzymic reaction. Moreover, in the presence of
      valinomycin and KCl, the functional size of membrane-bound H(+)-PPase was
      decreased to approx. 63.4 +/- 6.3 kDa. A working model was proposed to elucidate
      the structure of native H(+)-PPase on vacuolar membrane as a functional dimer.
      Factors that would disturb the membrane, e.g. membrane solubilization and the
      addition of valinomycin and KCl, may induce an alteration in its enzyme
      structure, subsequently resulting in a different functional size.

PMID- 8645198
TI  - Localization of a putative second membrane association site in penicillin-binding
      protein 1B of Escherichia coli.
AB  - We have shown previously that the periplasmic domain of penicillin-binding
      protein 1B (PBP 1Bper; residues 90-844) from Escherichia coli is insoluble in the
      absence of detergents, and can be reconstituted into liposomes [Nicholas, Lamson
      and Schultz (1993) J. Biol. Chem. 268, 5632-5641]. These data suggested that
      native PBP 1B contains a membrane association site in addition to its N-terminal
      transmembrane anchor. We have studied the membrane topology of PBP 1B in greater
      detail by assessing detergent binding and solubility in the absence of detergents
      for PBP 1Bper and a set of proteolytic fragments of PBP 1B. PBP 1Bper was shown
      by three independent methods to bind to detergent micelles, which strongly
      suggests that the periplasmic domain interacts with the hydrophobic milieu of
      membrane bilayers. Digestion with high weight ratios of thrombin of purified PBP
      1B containing an engineered thrombin cleavage site on the periplasmic side of the
      transmembrane anchor generated four fragments in addition to PBP 1Bper that
      varied in size from 71 to 48 kDa. In contrast to PBP 1Bper, all fragments of 67
      kDa and smaller were eluted from a gel-filtration column in the absence of
      detergents and did not bind to detergent micelles. The N-terminal sequences of
      the four fragments were determined, allowing the cleavage sites to be located in
      the primary sequence of PBP 1B. These data localize the membrane association site
      of PBP 1B to a region comprising the first 163 amino acids of the periplasmic
      domain, which falls within the putative transglycosylase domain. Lipid
      modification does not appear to be the mechanism by which PBP 1Bper associates
      with membranes.

PMID- 8645199
TI  - Expression of ferredoxin-NADP+ reductase in heterocysts from Anabaena sp.
AB  - The expression of ferredoxin-NADP+ reductase (FNR) from Anabaena sp. PCC 7119 in
      heterocysts and vegetative cells has been quantified. Specific reductase activity
      in heterocysts was approximately 10 times higher than in vegetative cells,
      corresponding to the increased FNR protein content. This was confirmed by
      immunoquantification of the FNR protein from whole filaments of Anabaena sp. PCC
      7120 grown in media with and without combined nitrogen. Transcription of the petH
      gene was markedly enhanced in the absence of combined nitrogen. This suggests
      that the increased RNA level is mainly responsible for the up-regulation of FNR
      in heterocysts. As has been observed for nif genes, iron deficiency also
      increased transcription of petH. Characterization of the FNR purified from
      isolated heterocysts showed no detectable differences from the enzyme from
      vegetative cells. Although nitrogen stress was a key regulatory factor,
      localization of the petH gene in the genomic map of Anabaena PCC 7120 showed that
      this gene is not physically associated with the nif cluster.

PMID- 8645200
TI  - Lysophosphatidic acid stimulates glucose transport in Xenopus oocytes via a
      phosphatidylinositol 3'-kinase with distinct properties.
AB  - Lysophosphatidic acid (LPA) stimulated the transport of deoxyglucose into oocytes
      isolated from Xenopus laevis. This stimulation was accounted for entirely by an
      increase in the Vmax for transport. Various LPAs with different acyl groups in
      the sn-1 position and phosphatidic acid stimulated deoxyglucose (deGlc) transport
      in these cells with a rank order potency of 1-oleoyl-LPA > 1-palmitoyl-LPA >
      phosphatidic acid = 1-stearoyl-LPA > 1-myristoyl-LPA. The phosphatidylinositol 3'
      kinase inhibitor LY294002 completely blocked LPA-stimulated deoxyglucose uptake
      (IC50 approximately 2 microM). In marked contrast, wortmannin, which can
      completely block both insulin-like growth factor-I (IGF-I)-stimulated deGlc
      uptake in oocytes and phosphatidylinositol 3'-kinase activation at concentrations
      as low as 20 nM [Gould, Jess, Andrews, Herbst, Plevin and Gibbs (1994) J. Biol.
      Chem. 269, 26622-26625], was a relatively poor inhibitor of LPA-stimulated deGlc
      transport, even at concentrations as high as 100 nM. We further show that LPA
      stimulates phosphatidylinositol 3'-kinase activity(s) that can phosphorylate both
      phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate, and that this
      stimulation is inhibited by LY294002 but is relatively insensitive to wortmannin,
      again in marked contrast to IGF-I-stimulated phosphatidylinositol 3'-kinase
      activity. Antibodies against the p85 regulatory subunit of phosphatidylinositol
      3'-kinase or antiphosphotyrosine antibodies immunoprecipitated IGF-I-stimulated
      but not LPA-stimulated phosphatidylinositol 3'-kinase activity. We conclude that
      LPA stimulates glucose uptake in Xenopus oocytes by a mechanism that may involve
      activation of a form of phosphatidylinositol 3'-kinase that is distinguished from
      other isoforms by its resistance to wortmannin and by its substrate specificity.
      Since the LPA-activated form of phosphatidylinositol 3'-kinase is
      pharmacologically and immunologically distinct from that which is involved in IGF
      I-stimulated glucose transport in these cells, we suggest that distinct isoforms
      of this enzyme are able to function with the same biological effect, at least in
      the regulation of sugar transport.

PMID- 8645201
TI  - Transforming growth factor beta 1 inhibits mitogen-activated protein kinase
      induced by basic fibroblast growth factor in smooth muscle cells.
AB  - Stimulation of smooth muscle cells with basic fibroblast growth factor (bFGF)
      results in the activation of the mitogen-activated protein kinase (MAP kinase)
      cascade and leads to cell proliferation. We show that transforming growth factor
      beta 1 (TGF-beta 1), at concentrations that completely inhibited bFGF-induced
      mitogenic activity, decreased bFGF-induced MAP kinase activity. Under these
      conditions, tyrosine and threonine phosphorylations of MAP kinase were
      differentially affected depending on the time period of TGF-beta 1 pretreatment.
      After a short (30 min) TGF-beta 1 pretreatment, the bFGF-mediated increase in
      phosphorylation of p42mapk on threonine was inhibited, with no effect on the
      level of phosphotyrosine or decrease in the electrophoretic mobility of p42mapk.
      This suggests that TGF-beta 1 inhibited MAP kinase activity through the action of
      a serine/threonine phosphatase. In contrast, a longer TGF-beta 1 pretreatment (4
      h) partly inhibited the bFGF-induced MAP kinase mobility shift and correlated
      with the inhibition of phosphorylation on both threonine and tyrosine, suggesting
      that long-term TGF-beta 1 treatment prevented activation of the MAP kinase
      cascade or directly blocked MAP kinase. The ability of long-term (4 h) but not
      short-term (30 min) TGF-beta 1 pretreatment to inhibit MAP kinase activity was
      completely dependent on protein synthesis and suggests that TGF-beta 1 inhibits
      MAP kinase activity by two distinct mechanisms. These findings provide a
      molecular basis for the growth-inhibitory action TGF-beta 1 on bFGF-induced
      mitogenic activity.

PMID- 8645202
TI  - Thyroid-stimulating hormone rapidly stimulates inositol polyphosphate formation
      in FRTL-5 thyrocytes without activating phosphoinositidase C.
AB  - The thyroid-stimulating hormone (TSH) receptor is widely regarded as one of a
      limited number of G-protein-coupled receptors that activate both adenylate
      cyclase and phosphoinositidase C (PIC) via G-proteins, but the existing
      experimental evidence for TSH-stimulated PtdIns(4,5)P2 hydrolysis remains
      inconclusive. We have compared the effects of TSH and of ATP (acting via P2
      purinergic receptors) on the inositol lipids and polyphosphates of [2-3H]inositol
      labelled FRTL-5 rat thyroid cells. ATP initiated a rapid decrease in 3H-labelled
      PtdIns4P and PtdIns(4,5)P2, whereas TSH did not. Stimulation with ATP and, less
      consistently, with noradrenaline (acting via alpha-adrenergic receptors) provoked
      rapid formation of Ins(1,4,5)P3, Ins(1,3,4,5)P4, Ins(1,3,4)P3 and Ins(1,4)P2,
      confirming activation of PtdIns(4,5)P2 hydrolysis. No concentration of TSH
      provoked detectable accumulation of Ins(1,4,5)P3 or Ins(1,4)P2 during the first
      few minutes of stimulation. However, an InsP3 [with the chromatographic
      properties of Ins(1,3,4)P3] and two InsP4 isomers [neither of which was
      Ins(1,3,4,5)P4] accumulated quickly in TSH-stimulated cells. ATP immediately
      provoked a large increase in intracellular calcium concentration ([Ca2+]i) in
      Indo 1-AM-loaded cells. TSH provoked a small and delayed [Ca2+]i elevation in
      only some experiments. We therefore confirm that activation of P2-purinergic
      receptors and alpha 1-adrenergic receptors provokes PIC activation, an
      accumulation of Ins(1,4,5)P3 and its metabolites and rapid [Ca2+]i mobilization
      in FRTL-5 cells. By contrast, TSH provokes no rapid PIC-catalysed PtdIns(4,5)P2
      hydrolysis or immediate [Ca2+]i mobilization. These results fail to support the
      widespread view that the TSH receptor of FRTL-5 cells signals, in part, through
      PIC activation. Our results suggest that TSH activates another, still undefined,
      mechanism that causes accumulation of an InsP3 and two isomers of InsP4.

PMID- 8645203
TI  - Transient activation of mitochondrial translation regulates the expression of the
      mitochondrial genome during mammalian mitochondrial differentiation.
AB  - Regulation of the expression of the nuclear-encoded beta-subunit of H(+)-ATP
      synthase (beta-F1-ATPase) gene of oxidative phosphorylation during
      differentiation of liver mitochondria is mainly exerted at two post
      transcriptional levels affecting both the half-life [Izquierdo, Ricart,
      Ostronoff, Egea and Cuezva (1995) J. Biol. Chem. 270, 10342-10350] and
      translational efficiency [Luis, Izquierdo, Ostronoff, Salinas, Santaren and
      Cuezva (1993) J. Biol. Chem. 268, 1868-1875] of the transcript. Herein, we have
      studied the expression of the mitochondrial (mt) genome during differentiation of
      rat liver mitochondria in an effort to elucidate the mechanisms of nucleo
      mitochondrial cross-talk during biogenesis of the organelle. Estimation of the
      relative cellular representation of met-DNA in liver reveals a negligible
      increase in mt-DNA copy number during organelle differentiation. Concurrently,
      the lack of changes in transcription rates of the mt-DNA "in organello', as well
      as in steady-state levels of the mt-transcripts, suggests that organelle
      differentiation is not controlled by an increase in transcription of the mt
      genome. However, translation rates in isolated mitochondria revealed a transient
      2-fold increase immediately after birth. Interestingly, the transient activation
      of mitochondrial translation at this stage of liver development is dependent on
      the synthesis of proteins in cytoplasmic polyribosomes. These findings support
      the hypothesis that the expression of nuclear and mitochondrial genes during
      biogenesis of mammalian mitochondria is developmentally regulated by a post
      transcriptional mechanism that involves concerted translational control of both
      genomes.

PMID- 8645204
TI  - Differential distribution of ryanodine receptor type 3 (RyR3) gene product in
      mammalian skeletal muscles.
AB  - Activation of intracellular Ca(2+)-release channels/ryanodine receptors (RyRs) is
      a fundamental step in the regulation of muscle contraction. In mammalian skeletal
      muscle, Ca(2+)-release channels containing the type 1 isoform of RyR (RyR1) open
      to release Ca2+ from the sarcoplasmic reticulum (SR) upon stimulation by the
      voltage-activated dihydropyridine receptor on the T-tubule/plasma membrane. In
      addition to RyR1, low levels of the mRNA of the RyR3 isoform have been recently
      detected in mammalian skeletal muscles. Here we report data on the distribution
      of the RyR3 gene product in mammalian skeletal muscles. Western-blot analysis of
      SR of individual muscles indicated that, at variance with the even distribution
      of the RyR1 isoform, the RyR3 content varies among different muscles, with
      relatively higher amounts being detected in diaphragm and soleus, and lower
      levels in abdominal muscles and tibialis anterior. In these muscles RyR3 was
      localized in the terminal cisternae of the SR. No detectable levels of RyR3 were
      observed in the extensor digitorum longus. Preferential high content of RyR3 in
      the diaphragm muscle was observed in several mammalian species. In situ
      hybridization analysis demonstrated that RyR3 transcripts are not restricted to a
      specific subset of skeletal-muscle fibres. Differential utilization of the RyR3
      isoform in skeletal muscle may be relevant to the modulation of Ca2+ release with
      respect to specific muscle-contraction properties.

PMID- 8645205
TI  - Reversibility of biotin-binding by selective modification of tyrosine in avidin.
AB  - The tight interaction between the vitamin biotin and the protein avidin is so
      strong (Ka approximately 10(15) M-1) that conditions which are usually sufficient
      for protein denaturation fail to dissociate the avidin-biotin complex. In order
      to form a reversible interaction between the two biomolecules, we have modified
      the binding-site tyrosine by nitration, thus reducing the pKa of the phenol group
      which forms a crucial hydrogen bond with the ureido group of biotin. At
      relatively low pH values (4-5), the resultant modified forms of avidin bind
      biotin with a very high association constant ( > 10(9) M-1). The modified avidins
      are thus capable of supporting stable, long-term binding of biotin or
      biotinylated macro-molecules. The latter molecules can be detached by increasing
      the pH of the medium or by introduction of excess levels of biotin at neutral pH.
      These findings demonstrate the importance of a single hydrogen bond for strong
      biotin binding. The new derivatives of avidin should be useful for applications
      whereby a reversible interaction between the four biotin-binding sites and biotin
      is desired, thus increasing the versatility of the avidin-biotin system for
      biotechnological application.

PMID- 8645206
TI  - Translation of Ser16 and Thr17 phosphorylation of phospholamban into Ca 2+-pump
      stimulation.
AB  - Stimulation of cardiac sarcoplasmic reticulum Ca 2+-pump activity is achieved by
      phosphorylation of the oligomeric protein phospholamban at either Ser16 or Thr17.
      The altered mobility of phosphorylated forms of pentameric phospholamban has been
      utilized to demonstrate that the mechanisms of phosphorylation of the two sites
      differ. Phosphorylation of Ser16 by the AMP-dependent protein kinase proceeds via
      a random mechanism [Li, Wang and Colyer (1990) Biochemistry 29, 4535-4540],
      whereas phosphorylation of Thr17 by calmodulin-dependent protein kinase is shown
      here to proceed via a co-operative mechanism. This co-operative reaction
      mechanism was unaffected by the phosphorylation status of Ser16. These two
      mechanisms of phosphorylation generate very different phosphoprotein profiles
      depending on whether the Ser16 or Thr17 residue is phosphorylated. The
      translation of these patterns of phosphorylation into Ca 2+-pump function was
      reviewed using a fluorimetric Ca 2+-indicator dye, fluo-3, to measure Ca2+ uptake
      by cardiac sarcoplasmic reticulum vesicles. The rate of Ca2+ accumulation, which
      parallels Ca 2+-pump activity, was stimulated in proportion with the
      stoichiometry of phospholamban phosphorylation, irrespective of whether
      phosphorylation was on Ser16 or Thr17.

PMID- 8645207
TI  - Regulation of the mouse inducible-type nitric oxide synthase gene promoter by
      interferon-gamma, bacterial lipopolysaccharide and NG-monomethyl-L-arginine.
AB  - Cytokines and bacterial lipopolysaccharides (LPSs) stimulate nitric oxide
      production in macrophages by inducing transcription of the gene coding for the
      inducible isoform of nitric oxide synthase (iNOS). We have cloned the mouse iNOS
      gene promoter and analysed its structural features and its response to interferon
      gamma (IFN-gamma) and Escherichia coli LPS in RAW 264.7 mouse macrophage-like
      cells. Transcription of a recombinant reporter gene including the promoter and 4
      kb of its 5'-flanking DNA, linked to the bacterial chloramphenicol
      acetyltransferase (CAT) reporter gene, is stimulated by IFN-gamma and, more
      efficiently, by LPS upon transient transfection in RAW 264.7 cells. Two upstream
      DNA regions are required for maximal promoter activation of LPS: the first maps
      between positions -1541 and -775 and the other between -420 and -47, with respect
      to the major transcriptional start site of the iNOS gene. The upstream-most
      region also mediates promoter trans-activation by IFN-gamma. As reported earlier
      for transcription of the endogenous iNOS gene, combined stimulation of RAW 264.7
      cells with IFN-gamma and LPS results in lower activation of the transfected
      promoter, when compared with LPS alone. NG-Monomethyl-L-arginine, a competitive
      inhibitor of nitric oxide synthase activity, enhances iNOS gene mRNA induction
      and promoter activation by IFN-gamma and LPS, indicating that nitric oxide can
      influence negatively the reponsiveness of this gene to inducers. These results
      suggest the possibility of a negative regulatory feedback exerted by iNOS on the
      transcriptional activation of its own gene.

PMID- 8645209
TI  - A comparison of nitrophenyl esters and lactones as substrates of cytosolic
      aldehyde dehydrogenase.
AB  - 1. p-Nitrophenyl (PNP) acetate and propionate show a burst of p-nitrophenoxide
      release when their hydrolysis is catalysed by sheep liver cytosolic aldehyde
      dehydrogenase. This is not seen in the presence of NAD+ or NADH, implying a
      change in ratedetermining step. 2. 6-Nitrodihydrocoumarin (6-NDC) shows no burst
      of absorbance in the visible region. We propose that the pKa of the transient
      "reporter group' produced during the hydrolysis of this lactone is high (approx.
      10) and that the incipient covalently linked p-nitrophenoxide moiety is
      protonated immediately on formation. The small burst seen in the hydrolysis of 5
      nitro-2-coumaranone (5-NC) suggests that the pKa of its reporter group is about
      8.5. 3. NADH markedly enhances the steady-state rate with the lactones. 5-NC
      shows a large rapid burst of colour development in the presence of NADH; this
      implies that NADH decreases the pKa of the reporter group to 7-7.5. 4. In the
      presence of NAD+, 5-NC and 6-NDC give an unusual "negative burst' in the stopped
      flow traces. We propose that, under these circumstances, acylation of the enzyme
      is extremely fast and that the first event seen in the stopped-flow traces is
      protonation of the reporter group. NAD+ also greatly increases the steady-state
      rate. 5. With the lactones in the presence of NADH, the kcat value (nearly 6 s
      1), a measure of the deacylation rate, is compatible with the single-site model
      for dehydrogenase and esterase activities.

PMID- 8645208
TI  - Activation of hepatic acetyl-CoA carboxylase by glutamate and Mg2+ is mediated by
      protein phosphatase-2A.
AB  - The activation of hepatic acetyl-CoA carboxylase by Na(+)-cotransported amino
      acids such as glutamine has been attributed mainly to the stimulation of its
      dephosphorylation by accumulating dicarboxylic acids, e.g. glutamate. We report
      here on a hepatic species of protein phosphatase-2A that activates acetyl-CoA
      carboxylase in the presence of physiological concentrations of glutamate or Mg2+
      and, under these conditions, accounts for virtually all the hepatic acetyl-CoA
      carboxylase phosphatase activity. Glutamate also stimulated the dephosphorylation
      of a synthetic pentadecapeptide encompassing the Ser-79 phosphorylation site of
      rat acetyl-CoA carboxylase, but did not affect the dephosphorylation of other
      substrates such as phosphorylase. Conversely, protamine, which stimulated the
      dephosphorylation of phosphorylase, inhibited the activation of acetyl-CoA
      carboxylase. A comparison with various species of muscle protein phosphatase-2A
      showed that the stimulatory effects of glutamate and Mg2+ on the acetyl-CoA
      carboxylase phosphatase activity are largely mediated by the regulatory A
      subunit. Glutamate and Mg2+ emerge from our study as novel regulators of protein
      phosphatase-2A when acting on acetyl-CoA carboxylase.

PMID- 8645210
TI  - The nucleoside diphosphate kinase of human neutrophils.
AB  - Nucleoside diphosphate kinase (NDP kinase) catalyses the phosphate transfer
      between nucleoside triphosphates and nucleoside diphosphates. As formation of
      guanosine triphosphate could be dependent on ATP in neutrophils, the presence of
      NDP kinase was tested in these phagocytic cells. Both membrane and cytosolic
      fractions of human neutrophils were found to contain NDP kinase activity. The
      specific activity measured in the cytosol appeared 10-fold higher than in the
      membrane and was not modified when the cells were activated with phorbol 12
      myristate 13-acetate. Interestingly, stimulation with N-formylmethionyl
      leucylphenylalanine in the presence of cytochalasin B showed an increase in
      membrane NDP kinase activity together with the translocation of the enzyme from
      the cytosol to the membrane, suggesting a possible role of NDP kinase in
      regulating G-proteins as previously reported. In addition, activation with
      opsonized zymosan induced an increase in cytosolic activity, suggesting different
      regulation depending on the signal transduction pathway. The neutrophil enzyme
      consisted of two subunits of 21 kDa (NDPKA) and 18 kDa (NDPKB) again essentially
      present in the cytosol of the cell. Separation of proteins by two-dimensional
      PAGE demonstrated that each subunit consisted of at least four isoforms,
      indicating post translational modifications. A characteristic of this family of
      enzymes is the stability of the phosphorylated intermediate. In neutrophils, only
      one acidic isoform of each NDPKA and NDPKB was labelled in the presence of EDTA.
      In addition, non-denatured complexes were apparent between 91 and 130 kDa,
      suggesting a hexameric structure as was also proposed for NDP kinases from other
      eukaryotic cells. These complexes were found to differ in their isoelectric
      points, indicating the existence of various isoenzymes probably resulting from
      combination between several isoforms of each subunit.

PMID- 8645212
TI  - Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous
      polyamine formed by decarboxylation of arginine.
AB  - Agmatine, decarboxylated arginine, is a metabolic product of mammalian cells.
      Considering the close structural similarity between L-arginine and agmatine, we
      investigated the interaction of agmatine and nitric oxide synthases (NOSs), which
      use L-arginine to generate nitric oxide (NO) and citrulline. Brain, macrophages
      and endothelial cells were respectively used as sources for NOS isoforms I, II
      and III. Enzyme activity was measured by the production of nitrites or L
      citrulline. Agmatine was a competitive NOS inhibitor but not an NO precursor. Ki
      values were approx. 660 microM (NOS I), 220 microM (NOS II) and 7.5 mM (NOS III).
      Structurally related polyamines did not inhibit NOS activity. Agmatine,
      therefore, may be an endogenous regulator of NO production in mammals.

PMID- 8645211
TI  - Leukotriene D4-induced mobilization of intracellular Ca2+ in epithelial cells is
      critically dependent on activation of the small GTP-binding protein Rho.
AB  - We have previously shown that the leukotriene D4 (LTD4)-induced mobilization of
      intracellular Ca2+ in epithelial cells is mediated by a G-protein that is
      distinctly different from the pertussis toxin-sensitive G-protein that regulates
      the subsequent influx of Ca2+. In the present study, we attempted to gain further
      knowledge about the mechanisms involved in the LTD4-induced mobilization of
      intracellular Ca2+ in epithelial cells by investigating the effects of compactin,
      an inhibitor of the isoprenylation pathway, on this signalling event. In cells
      preincubated with 10 microM compactin for 48 h, the LTD4-induced mobilization of
      intracellular Ca2+ was reduced by 75% in comparison with control cells. This
      reduction was reversed by co-administration of mevalonate (1 mM). The effect of
      compactin occurred regardless of whether or not Ca2+ was present in the
      extracellular medium, suggesting that isoprenylation must occur before Ca2+ is
      released from intracellular stores. In accordance with this, we also found that
      both the LTD4-induced formation of inositol 1,4,5-trisphosphate and the LTD4
      induced phosphorylation of phospholipase C gamma 1 (PLC gamma 1) on tyrosine
      residues were significantly reduced in compactin-pretreated cells. These results
      open up the possibility that the activation of PLC gamma 1 is related to a
      molecule that is sensitive to impaired activity of the isoprenylation pathway,
      such as a small monomeric G-protein. This idea was supported by the observation
      that Clostridium botulinum C3 exoenzyme-induced inhibition of Rho proteins
      abolished the LTD4-induced intracellular mobilization of Ca2+. A regulatory role
      of Rho proteins in the LTD4-induced activation of PLC gamma 1 is unlikely to be
      indirectly mediated via an effect on the cytoskeleton, since cytochalasin D had
      no major effect on the LTD4-induced mobilization of Ca2+. Although the mechanism
      of interaction remains to be elucidated, the present findings indicate an
      important role of an isoprenylated protein such as Rho in the LTD4-induced Ca2+
      signal.

PMID- 8645213
TI  - prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory
      action of Bcl-2.
AB  - The novel lipid second messenger, ceramide, specifically induced poly(ADP-ribose)
      polymerase cleavage through activation of the protease prICE. Over-expression of
      Bcl-2 inhibited ceramide-induced poly(ADP-ribose) polymerase proteolysis and
      protected cells from ceramide-induced death. These data provide the first insight
      into the mechanism by which ceramide mediates apoptosis and suggest a mechanism
      by which Bel-2 protects from cell death.

PMID- 8645214
TI  - The catalase-peroxidase of Synechococcus PCC 7942: purification, nucleotide
      sequence analysis and expression in Escherichia coli.
AB  - Synechococcus PCC 7942, a cyanobacterium, possesses catalaseperoxidase as the
      sole hydrogen peroxide-scavenging system. The enzyme has been purified to
      electrophoretic homogenenity from the cells. The native enzyme had a molecular
      mass of 150 kDa and was composed of two identical subunits of molecular mass 79
      kDa. The apparent Km value of the catalase activity for H2O2 was 4.2 +/- 0.27 mM
      and the kcat value was 2.6 x 10(4) s-1. The enzyme contained high catalase
      activity and an appreciable peroxidase activity with o-dianisidine and
      pyrogallol. The catalase activity was not inhibited by 3-amino-1,2,4-triazole but
      by KCN and NaN3 (apparent Ki values 19.3 +/- 0.84 and 20.2 +/- 0.95 microM
      respectively). The enzyme showed an absorption spectrum of typical protohaem and
      contained one protohaem molecule per dimer. The gene encoding catalase-peroxidase
      was cloned from the chromosomal DNA of Synechococcus PCC 7942. A 2160 bp open
      reading frame (ORF), coding a catalase-peroxidase of 720 amino acid residues
      (approx. 79.9 kDa), was observed. The deduced amino acid sequence coincided with
      that of the N-terminus of the purified enzyme and showed a remarkable similarity
      to those of a family of catalase-peroxidases of prokaryotic cells. Escherichia
      coli BL21 (DE3)plysS, harbouring a recombinant plasmid containing the catalase
      peroxidase gene, produced a large amount of proteins that co-migrated on SDS/PAGE
      with the native enzyme. The recombinant enzyme showed the same ratio of catalase
      activity to peroxidase activity with o-dianisidine and the same Km for H2O2 as
      the native enzyme.

PMID- 8645215
TI  - Secretion of human intestinal angiotensin-converting enzyme and its association
      with the differentiation state of intestinal cells.
AB  - Human angiotensin I-converting enzyme (ACE) exists in intestinal epithelial cells
      as a membrane-bound (ACEm) and secretory glycoprotein (ACEsec). The
      electrophoretic mobilities of ACEsec and ACEm on SDS/polyacrylamide gels are
      similar; the N-deglycosylated ACEsec and ACEm, in contrast, display slight
      differences in their apparent molecular masses, indicating that the carbohydrate
      contents of ACEsec and ACEm are different. Moreover, ACEsec is solely N
      glycosylated whereas ACEm is N- and O-glycosylated, assessed by lectin binding
      studies. Spontaneous release of ACEsec is achieved by incubation of brush border
      membranes at 37 degrees C. Aprotinin, leupeptin and EDTA partly inhibit the
      generation of ACEsec, strongly suggesting that ACEsec is generated from ACEm by
      proteolytic cleavage. The expression levels of ACEsec in the intestine may be
      associated with the differentiation state of mucosal cells. Thus ACEsec is more
      abundant than ACEm in immature non-epithelial crypt cells of patients with
      coeliac disease. Well-differentiated epithelial cells, by contrast, contain
      predominantly ACEm. The variations in the proportions of cleaved ACEsec in
      differentiated and non-differentiated cells may be due to varying levels of the
      cleaving protease. Alternatively, because epithelial cell differentiation is
      accompanied by alterations in the levels of oligosaccharyltransferases, the
      results suggest a critical role for the glycosylation pattern of ACEm in its
      susceptibility to the putative cleaving protease.

PMID- 8645216
TI  - Molecular heterogeneity in the Major Urinary Proteins of the house mouse Mus
      musculus.
AB  - Major Urinary Proteins (MUPs) from different inbred strains of mouse have been
      analysed by high-resolution ion-exchange chromatography and mass spectrometry.
      MUPs from six strains were resolved chromatographically into four major protein
      peaks which characterized two distinct phenotypes, typified by the profiles
      obtained from the Balb/c and C57BL/6 inbred strains. A combination of ion
      exchange chromatography and electrospray ionization mass spectrometry analysis of
      the MUPs from each strain identified five proteins, only one of which was common
      to both strains. The charge and mass data, together with N-terminal sequence
      analyses, were correlated with the masses of the proteins inferred from published
      cDNA sequences. Several members of the family of MUP sequences differ in only
      four positions, and in some circumstances the substitutions elicit a minimal
      change in protein mass (Lys/Gln; Lys/Glu). Peptide mapping with endopeptidase Lys
      C, followed by matrix-assisted laser desorption ionization-time-of-flight mass
      spectrometry permitted identification of new MUPs that were correlated with
      partial cDNA sequence data. In the two strains there are at least 13 different
      MUPs, either observed or predicted, indicating the heterogeneity of expression of
      this group of proteins.

PMID- 8645217
TI  - S-adenosylmethionine decarboxylase gene expression in rat hepatoma cells:
      regulation by insulin and by inhibition of protein synthesis.
AB  - We have investigated expression of the S-adenosylmethionine decarboxylase
      (AdoMetDC) gene in H4-II-E rat hepatoma cells treated with growth factors
      (epidermal growth factor and transforming growth factor beta 1) and inducers
      (cAMP and insulin). Treatment with insulin caused a marked increase in both RNA
      level and enzyme activity. The stability of AdoMetDC mRNA was not altered by
      insulin treatment: the accumulation of mRNA in hepatoma cells therefore seems to
      be due to an increase in the transcription rate. Cycloheximide was found to be a
      strong inducer of AdoMetDC mRNA transcription and the effects of insulin and
      cycloheximide were additive, suggesting that they increase expression by separate
      mechanisms. Chloramphenicol acetyltransferase assays in rat hepatoma cells using
      5' flanking regions of different lengths revealed that the promoter region
      extending 337 bp upstream from the transcription start site contains elements
      involved in insulin response.

PMID- 8645218
TI  - Induction of cytochrome P-450 BM-3 (CYP 102) by non-steroidal anti-inflammatory
      drugs in Bacillus megaterium.
AB  - Bacillus megaterium contains a cytochrome P-450 fatty acid mono-oxygenase which
      is inducible with barbiturate drugs. We have demonstrated that this enzyme system
      is inducible with peroxisome proliferators. In mammals, peroxisome proliferators
      also induce mono-oxygenases in the CYP4A gene family. In this paper we
      demonstrate that the non-steroidal anti-inflammatory drugs ibuprofen, ketoprofen
      and indomethacin are potent inducers of fatty acid mono-oxygenase activity as
      well as of P-450BM-3 protein in B. megaterium. The levels of induction of P-450
      protein were 11.8-, 3.9- and 3.0-fold respectively. In addition, we demonstrate
      that these inducing agents interact with a transcriptional repressor, Bm3R1,
      which leads to its dissociation from its operator sequence. This provides a
      rational mechanism for the induction process. This is the first report which
      demonstrates that non-steroidal anti-inflammatory drugs can interact directly
      with a transcription factor to initiate gene expression, and further
      substantiates the structure-activity relationships that identify inducers of
      cytochrome P-450BM-3 and compounds that have the potential to act as peroxisome
      proliferators and induce CYP4A expression in mammals.

PMID- 8645219
TI  - Isolation of the murine S100 protein MRP14 (14 kDa migration-inhibitory-factor
      related protein) from activated spleen cells: characterization of post
      translational modifications and zinc binding.
AB  - MRP14 (macrophage migration-inhibitory factor-related protein of molecular mass
      14 kDa) is an S100 calcium binding protein constitutively expressed in human
      neutrophils which may be associated with cellular activation/inflammation. Murine
      MRP14 expression was up-regulated following concanavalin A activation of spleen
      cells, and the protein was isolated from conditioned medium in high yield
      (approx. 500 ng/ml). MRP14 had a mass of 12972 +/- 2 Da by electrospray
      ionization MS, whereas the theoretical mass derived from the cDNA sequence, after
      removal of the initiator Met, was 12918 Da, suggesting that the protein was post
      translationally modified. We identified four post-translational modifications of
      MRP14: removal of the N-terminal Met, N-terminal acetylation, disulphide bond
      formation between Cys79 and Cys90, and 1-methylation of His106; the calculated
      mass was then 12971.8 Da. Methylation of His106 was further characterized after
      incubation of spleen cells with L-[methyl-3H]Met during concanavalin A
      stimulation. Sequential analysis of a peptide (obtained by digestion with Lys C)
      containing methylated His indicated that > 80% of the label in the cycle
      corresponded to His106, suggesting that the methyl residue was transferred from S
      adenosyl-L-methionine. Comparison of the C18 reverse-phase HPLC retention times
      of phenylthiocarbamoyl derivatives of a hydrolysed digest peptide of MRP14 with
      those of standards confirmed methyl substitution on the 1-position of the
      imidazole ring. MRP14 bound more 85Zn2+ than the same amounts of the 10 kDa
      chemotactic protein (CP10) or S100 beta. Ca2+ decreased Zn2+ binding in S100 beta
      but it did not influence binding to MRP14, suggesting that the Zn2+ binding site
      was distinct from and independent of the two Ca2+ binding domains.

PMID- 8645220
TI  - Discovery of a novel protein modification: alpha-glycerophosphate is a
      substituent of meningococcal pilin.
AB  - Pili, which are filamentous protein structures on the surface of the meningitis
      causing organism Neisseria meningitidis, are known to be post-translationally
      modified with substituents that affect their mobility in SDS/PAGE and which might
      play a crucial role in adherence and bloodstream invasion. Tryptic digests of
      pili were analysed by fast atom bombardment and electrospray MS to identify
      putative modifications. Serine-93 was found to carry a novel modification of
      alpha-glycerophosphate. This is the first time that alpha-glycerophosphate has
      been observed as a substituent of a prokaryotic or eukaryotic protein.

PMID- 8645221
TI  - Isolation and characterization of vascular smooth muscle inositol 1,4,5
      trisphosphate receptor.
AB  - myo-Inositol 1,4,5-trisphosphate (InsP3) receptor of porcine aorta was purified
      to near homogeneity and its biochemical properties were compared with those of
      cerebellar InsP3 receptor of the same animal species. The aortic InsP3 receptor
      consisted of equal amounts of two polypeptides with slightly differing molecular
      masses of around 240 kDa and was found to possess a single population of InsP3
      binding site (Kd of 1.2 nM). The InsP3 receptor purified from porcine cerebellum
      was also comprised of two polypeptides. However, the molecular mass was slightly
      but definitely larger, being 250 kDa, and the amounts of the two polypeptides
      were not equal. The aortic InsP3 receptor cross-reacted with polyclonal antibody
      specific to type 1 InsP3 receptor as did the cerebellar InsP3 receptor. The
      aortic InsP3 receptor bound to calmodulin-Sepharose in a Ca(2+)-dependent manner,
      while the cerebellar InsP3 receptor did not. Reverse transcriptase-PCR analysis
      revealed two splicing variants of the type 1 InsP3 receptor in porcine aortic
      smooth muscle distinct from those of the type 1 InsP3 receptor of porcine
      cerebellum. The possible relevance of this difference to difference in calmodulin
      binding property was discussed.

PMID- 8645222
TI  - Transforming growth factor-beta type-II receptor signalling: intrinsic/associated
      casein kinase activity, receptor interactions and functional effects of blocking
      antibodies.
AB  - The transforming growth factor beta (TGF-beta) family of growth factors control
      proliferation, extracellular matrix synthesis and/ or differentiation in a wide
      variety of cells. However, the molecular mechanisms governing ligand binding,
      receptor oligomerization and signal transduction remain incompletely understood.
      In this study, we utilized a set of antibodies selective for the extracellular
      and intracellular domains of the TGF-beta type-II receptor as probes to
      investigate the intrinsic kinase activity of this receptor and its physical
      association in multimeric complexes with type-I and type-III receptors. The type
      II receptor immuno-precipitated from human osteosarcoma cells exhibited
      autophosphorylation and casein kinase activity that was markedly stimulated by
      polylysine yet was insensitive to heparin. Affinity cross-linking of 125I-TGF
      beta 1 ligand to cellular receptors followed by specific immunoprecipitation
      demonstrated that type-II receptors form stable complexes with both type-I and
      type-III receptors expressed on the surfaces of both human osteosarcoma cells and
      rabbit chondrocytes. Pretreatment of the cultured cells with an antibody directed
      against a distinct extracellular segment of the type-II receptor (anti-TGF-beta
      IIR-NT) effectively blocked the 125I-TGF-beta labelling of type-I receptors
      without preventing the affinity labelling of type-II or type-III receptors,
      indicating a selective disruption of the type-I/type-II hetero-oligomers. The
      anti-TGF-beta-IIR-NT antibodies also blocked the TGF-beta-dependent induction of
      the plasminogen activator inhibitor (PAI-1) promoter observed in mink lung
      epithelial cells. However, the same anti-TGF-beta-IIR-NT antibodies did not
      prevent the characteristic inhibition of cellular proliferation by TGF-beta 1, as
      determined by [3H]thymidine incorporation into DNA. The selective perturbation of
      PAI-1 promoter induction versus cell-cycle-negative regulation suggests that
      strategic disruption of TGF-beta type-I and -II receptor interactions can
      effectively alter specific cellular responses to TGF-beta signalling.

PMID- 8645223
TI  - KS-505a, an isoform-selective inhibitor of calmodulin-dependent cyclic nucleotide
      phosphodiesterase.
AB  - The effects of KS-505a, a novel microbial metabolite, on the activity of
      calmodulin-dependent cyclic nucleotide phosphodiesterase (CaM-PDE) were
      investigated. (1) KS-505a potently inhibited the purified 61 kDa isoenzyme of CaM
      PDE from bovine brain and required much higher doses to inhibit the purified 59
      kDa isoenzyme of CaM-PDE from bovine heart. The inhibition of both isoenzymes was
      observed only in the presence of calcium-activated calmodulin (Ca2+/CaM). The
      IC50 values for the 61 and 59 kDa isoenzymes were 0.17 and 13 microM respectively
      with 20 microM cAMP as a substrate. (2) Kinetic analysis indicated that the
      inhibitory mode of KS-505a for the 61 kDa isoenzyme was competitive with respect
      to Ca2+/CaM; the K1 for KS-505a was 0.089 microM. The inhibition was not
      competitive with respect to the substrates cAMP or cGMP. (3) KS-505a did not
      interfere with the interaction between Ca2+/CaM and n-phenyll-naphthylamine, a
      hydrophobic fluorescent probe, nor was it adsorbed to CaM-conjugated gels in the
      presence of Ca2+, thereby indicating that KS-505a does not bind to Ca2+/CaM. (4)
      Trypsin-activated 61 kDa isoenzyme, which lacked the Ca2+/CaM-binding domain, was
      not inhibited by KS-505a at less than micromolar concentrations. Taken together,
      these results suggest that KS-505a apparently bound to a site in the Ca2+/CaM
      binding domain of the 61 kDa isoenzyme and selectively inhibited Ca2+/CaM
      activated 61 kDa isoenzyme activity. (5) In rat hippocampal slices, KS-505a at 10
      micronM increased the intracellular cAMP concentration to approximately three
      times the basal level, whereas in rat striatal slices it had no effect on the
      cAMP concentration at concentrations of 1.0-10 microM, suggesting that each CaM
      PDE isoenzyme functions differentially in these regions. These results
      demonstrate that KS-505a is a highly potent selective inhibitor both in vitro and
      in vivo and distinguishes between subfamily members within the CaM-PDE family.

PMID- 8645224
TI  - Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma
      aminobutyraldehyde: purification, characterization, cloning and distribution.
AB  - Enzyme purification and characterization, cDNA cloning and Northern blot analysis
      were the techniques utilized during this investigation to determine the identity
      and occurrence of the aldehyde dehydrogenase that metabolizes gamma
      aminobutyraldehyde in adult human brain. The purification yielded one major
      protein which was active with gamma-aminobutyraldehyde. It had the physico
      chemical and kinetic properties of the human liver E3 isoenzyme of aldehyde
      dehydrogenase (EC 1.2.1.3), and also interacted with an anti-(liver E3 isoenzyme)
      antibody. Tryptic peptides derived from the purified brain protein matched the
      amino acid sequence of the liver E3 isoenzyme. Employing liver E3 cDNA, a human
      cerebellar cDNA library was screened and a 2.0 kb cDNA fragment was isolated. The
      cerebellar cDNA yielded a derived primary structure which differed from the liver
      E3 amino acid sequence by a single serine-to-cysteine substitution at position 88
      (position 84 in the liver sequence). Thus the gamma-amino-butyraldehyde
      metabolizing enzyme from human brain can be identified as E3', a variant of the
      E3 isoenzyme. The catalytic properties of the brain variant were
      indistinguishable from those of E3, and so the functional importance of this
      variant is at present unknown. The distribution of this enzyme in brain was
      investigated by Northern blot analysis, which demonstrated the presence of E3'
      mRNA in all regions of the human brain. mRNA levels were variable in the
      different brain areas, with the highest levels in the spinal cord and the lowest
      in the occipital pole.

PMID- 8645226
TI  - Casein kinase 2 inhibits the renaturation of complementary DNA strands mediated
      by p53 protein.
AB  - Considerable effort is currently being devoted to understand the functions of
      protein p53, a major regulator of cell proliferation. The protein p53 has been
      reported to catalyse the annealing of complementary DNA or RNA strands. We report
      that this activity is inhibited in the presence of the serine/threonine protein
      kinase CK2. It is shown that this inhibition can be explained by the occurrence
      of a high-affinity molecular association between p53 and CK2. The molecular
      complex involves an interaction between the C-terminal domain of p53 and the beta
      subunit of the oligomeric kinase. Accordingly, the isolated alpha subunit of the
      kinase was without effect. In addition, after phosphorylation by CK2,
      phosphorylated p53 lost its DNA annealing activity. Because the C-terminal domain
      of p53 is both involved in the association with CK2 and phosphorylated by it, our
      results suggest that either protein-protein interaction or phosphorylation of
      this domain might control the base pairing of complementary sequences promoted by
      p53 in processes related to DNA replication and repair.

PMID- 8645225
TI  - Function and membrane topology of wild-type and mutated cytochrome P-450c21.
AB  - We have studied membrane topology of cytochrome P-450c21 (P450c21) using the
      approaches of mutagenesis and protease digestion. P450c21 is located at the
      cytoplasm with an N-terminal hydrophobic domain integrated into microsomal
      membranes. When this hydrophobic domain was replaced by a secretory signal
      peptide, P450c21 was translocated into the lumen and lost enzymic activity. No
      other topogenic sequence was detected in the bulk of the P450c21 peptide. A
      mutant protein with Pro-30 replaced by Leu (L30) corresponding to the mutation
      found in the diseased state was created. L30 protein lost 90% of enzymic
      activity, while a double mutant (L30R32) with an additional Leu-32 to Arg
      mutation had slightly higher residual enzymic activity. Apart from lower
      activity, L30 was also present in the cell at a lower level than wild-type
      P450c21. This lower level is probably due to increased degradation, as L30 is
      synthesized at a normal rate. Both L30 and L30R32 proteins, however, were
      integrated into membranes normally. Therefore the Pro-30 --> Leu mutation did not
      affect membrane integration, but affected the abundance and enzymic activity of
      P450c21.

PMID- 8645227
TI  - Isoleucine 368 is involved in low-affinity binding of N6-modified cAMP analogues
      to site B of the regulatory subunit of cAMP-dependent protein kinase I.
AB  - The regulatory (R) subunit of cAMP-dependent protein kinase has a well-defined
      domain structure including the two in-tandem cAMP-binding sites that constitute
      the C-terminus of the protein. The N-terminal binding site (A) has a considerably
      higher affinity for analogues of cAMP that are substituted with bulky and
      hydrophobic substituents at the 6-amino group of the adenine ring compared to the
      affinity observed at the second site (B). On the basis of the crystal structure
      of the catabolite gene activator protein from Escherichia coli, molecular
      modelling of the binding domains suggested that a tyrosine (Y244) in site A could
      be involved in a high-affinity hydrophobic interaction, whereas a corresponding
      isoleucine (I368) in domain B could lead to steric hindrance in the binding of
      bulky N6-substituted analogues. Site-directed mutagenesis was used to construct
      mutations in Y244 and I368. Binding displacement experiments showed that
      replacing the tyrosine in site A with isoleucine (Y244I) did not affect the
      interaction of either N6-substituted or otherwise modified analogues with this
      site. However, replacing I368 with tyrosine (I368Y) led to a 3-4-fold increase in
      affinity for those N6-modified analogues that had a hydrophobic group attached
      directly or close to the 6-amino molecule. We conclude that I368 is involved in
      the molecular interaction between binding domain B and the 6-amino group of the
      adenine moiety of cAMP and that this residue is partly responsible for the
      reduced affinity of N6-substituted cAMP analogues for this site.

PMID- 8645228
TI  - Characterization of prenylcysteine methyltransferase in insulin-secreting cells.
AB  - Prenylcysteine carboxymethyltransferase, an enzyme involved in the post
      translational modification of many signalling proteins, was characterized in
      insulin-secreting INS-1 cells and normal rat pancreatic islets. The activity of
      this enzyme was monitored by the methylation of an artificial substrate (a
      prenylated cysteine analogue) with S-adenosy1[methyl-3H]methionine as methyl
      donor. More than 95% of the methyltransferase activity was associated with the
      membranes, and high-salt treatment only partially extracted the enzyme from the
      membranes. The highest specific activity was in the insulin-granule-enriched
      25000 g pellet obtained by differential centrifugation. However, a highly
      purified insulin-enriched fraction obtained by density centrifugation in Percoll
      did not exhibit methyltransferase activity. The analyses of marker enzymes for
      cellular organelles revealed that the methyltransferase was co-localized, with
      the plasma membrane and probably the endoplasmic reticulum, but not with the
      mitochondria or lysosomes. Guanosine 5'-[gamma-thio]-triphosphate failed to
      increase methyltransferase activity directly, although it promotes the
      methylation of GTP-binding proteins. Mastoparan, Ca2+, cAMP and the protein
      kinase C activator phorbol 12-myristate 13-acetate did not alter enzyme activity.
      In addition, methyltransferase activity was not stably modified by stimulation of
      intact cells using glucose or other agents. However, the carboxymethylation of
      certain low-molecular-mass G-proteins is increased by glucose stimulation;
      conversely, treatment of cells with N-acetyl-S-trans,trans-farnesyl-L-cysteine
      inhibited glucose- and forskolin-induced insulin secretion. These results suggest
      that the membrane-associated prenylcysteine carboxymethyltransferase may be
      constitutively active and that the methylation of target proteins in vivo is
      regulated by the access of these proteins to the methyltransferase, as well as by
      their active (GTP-liganded) configuration.

PMID- 8645229
TI  - Translocation of annexin I to plasma membranes and phagosomes in human
      neutrophils upon stimulation with opsonized zymosan: possible role in phagosome
      function.
AB  - Annexin I in the cytosol of resting neutrophils was translocated to the plasma
      membranes upon addition of opsonized zymosan (OZ). Maximum translocation could be
      detected 1 min after stimulation with OZ, and decreased thereafter. Subcellular
      fractionation studies demonstrated that annexin I could not be detected in the
      granule fractions in either resting or activated cells, but was found in
      association with the phagosome fraction. The marked translocation of annexin I
      was unique to OZ, since formyl-Met-Leu-Phe induced only slight translocation of
      annexin I to the plasma membranes, and phorbol 12-myristate 13-acetate had no
      effect at all. The mechanism regulating the translocation of annexin I is not
      clear. Annexin I is not phosphorylated in resting or stimulated cells. The
      correlation between the elevation in the intracellular calcium ion concentration
      ([Ca2+]i) and the degree of translocation of annexin I to the plasma membranes
      induced by the different stimuli, together with the inhibition of these processes
      by the addition of EGTA, indicate that the translocation of annexin I can
      probably be attributed to the rise in [Ca2+]i. However, this cannot be the sole
      mechanism since ionomycin, which caused an increase in [CA2+]i similar to that
      induced by OZ, was less efficient than OZ in inducing translocation of annexin I.
      The induction of annexin I translocation to the plasma membrane by OZ, which was
      the only agent that induced phagosome formation, and the detection of annexin I
      in the phagosome fraction, suggest that annexin I participates in phagosome
      function.

PMID- 8645230
TI  - Detection of isoform 4 of the plasma membrane calcium pump in human tissues by
      using isoform-specific monoclonal antibodies.
AB  - The epitope location and specificity of monoclonal antibodies JA9, 5F10 and JA3,
      raised against the human plasma membrane Ca2+ pump (hPMCA), were analysed by
      using synthetic peptides of the corresponding epitopes as well as the complete
      isoforms, hPMCA4b, hPMCA4a and hPMCA1b, expressed in COS-1 cells. The experiments
      with the peptides showed that JA9 reacted specifically with a region containing
      residues 51-75 of hPMCA4 (a or b), but not with the same region of isoforms 1, 2
      or 3. JA3 reacted with residues 1156-1180, a region unique to hPMCA4b. 5F10
      reacted in the region of residues 719-738, which is highly conserved in all PMCA
      isoforms. Indeed, 5F10 recognized all three isoforms expressed in COS-1 cells.
      JA9, in contrast, reacted with both variants a and b of hPMCA4 but not with
      hPMCA1, and JA3 recognized exclusively hPMCA4b. We used these antibodies to
      discern the distribution of hPMCA4a and hPMCA4b in human brain, heart, kidney and
      lung. In Western blots of human brain samples, we could identify both hPMCA4a and
      hPMCA4b. Heart tissue also showed isoform 4b, and probably 4a. In contrast,
      kidney and lung showed primarily hPMCA4b. In brain, overlapping bands that did
      not correspond to either variant of hPMCA4 were detected, and in kidney a band
      migrating in the same position as hPMCA1b was observed. The distribution of the a
      and b forms of hPMCA4 at the protein level, as analysed by these antibodies, is
      consistent with the available data about the abundance of mRNAs for the hPMCA
      isoforms. The presence of hPMCA4b in all the samples supports the proposed role
      of this isoenzyme as a constitutive form of the pump.

PMID- 8645231
TI  - Recombinant bovine conglutinin, lacking the N-terminal and collagenous domains,
      has less conglutination activity but is able to inhibit haemagglutination by
      influenza A virus.
AB  - Conglutinin is a bovine serum protein which was first described as a vertebrate
      lectin. This protein belongs to the family of C-type lectins. These lectins are
      composed of four characteristic domains: (1) an N-terminal cysteine-rich domain,
      (2) a collagen-like domain, (3) a neck domain and (4) a carbohydrate recognition
      domain (CRD). Recently lectins have been shown to function as immunoglobulin
      independent defence molecules due to a complement-mediated mechanism or
      opsonization. Our previous study showed that bovine conglutinin can inhibit
      haemagglutination by influenza A viruses and act by directly neutralizing them
      due to its lectin properties. In order to elucidate the biological role of the
      collagen-like domain, a recombinant partial conglutinin lacking this collagen
      like domain was produced in an Escherichia coli system and its biological
      activities were examined. A 497 bp sequence, consisting of a short collagen
      region (two repeats of G-X-Y amino acid sequences), the neck domain, and the CRD
      of conglutinin cDNA, was amplified by the reverse-transcriptase PCR technique.
      The cDNA was transferred to a bacterial expression vector system (pRSET-A) and
      stable transfectants with a high level of conglutinin production were obtained.
      SDS/PAGE and Western blotting analyses showed a recombinant fusion protein of 27
      kDa. Results of a cross-linking study and gel-filtration assay indicated that the
      recombinant conglutinin can form a trimeric structure and that it has sugar
      binding activity and specificity similar to that of native conglutinin. The
      recombinant conglutinin was also found to inhibit haemagglutination caused by
      influenza A virus as well as to possess less conglutination activity. These
      results suggest that in order for conglutinin to inhibit haemagglutination caused
      by the influenza virus, as well as to have sugar binding activity or to form
      trimers, it does not require the N-terminal and collagenous domains; however,
      they are essential for full conglutination activity.

PMID- 8645232
TI  - cDNA cloning and tissue-specific expression of the phosphatidylcholine transfer
      protein gene.
AB  - We have isolated a cDNA containing the complete coding sequence of bovine liver
      phosphatidylcholine transfer protein (PC-TP). The deduced amino acid sequence
      consists of 213 amino acid residues and is, except for a lysine instead of an
      arginine at position 167, identical to the sequence determined by Edman
      degradation [Akeroyd, Moonen, Westerman, Puyk and Wirtz (1981) Eur. J. Biochem.
      114, 385-391]. A cDNA encoding amino acid residues 41-214 of mouse lung PC-TP was
      also isolated. The predicted amino acid sequence was 90% similar (81% identical)
      to the corresponding sequence of bovine liver PC-TP, demonstrating that PC-TP is
      conserved among mammalian species. By Southern blot analysis, evidence was
      obtained for the presence of a single bovine PC-TP-encoding gene. The expression
      of the PC-TP gene was determined during mouse embryonic development and in adult
      mouse tissues using an RNase protection assay. PC-TP RNA was present in embryos
      at all stages of development as early as the embryonic stem cell, suggesting a
      role for PC-TP in cell growth and differentiation. Towards the end of embryonic
      development, just before term, high levels of PC-TP RNA were found in the liver.
      This level was even higher 7 days post-term. In addition to adult liver, high
      levels of PC-TP RNA were also found in kidney and testis. The prominent presence
      of PC-TP in developing and adult liver is compatible with its proposed role in
      bile formation.

PMID- 8645233
TI  - Pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica: molecular
      cloning, recombinant expression and inhibition by pyrophosphate analogues.
AB  - By using oligonucleotide primers derived from regions highly conserved in
      prokaryotic and eukaryotic phosphofructokinase sequences, a genomic DNA fragment
      was amplified and used to isolate cDNA and genomic clones coding for PPi
      dependent phosphofructokinase (PPi-PFK) of Entamoeba histolytica. The open
      reading frame consists of 1308 bp and the corresponding protein has a calculated
      molecular mass of 47.6 kDa. The N-terminal half of the protein shows 27-35%
      identity with PPi-PFKs or ATP-dependent phosphofructokinases (ATP-PFKs) of
      various eukaryotic and prokaryotic organisms. The amino acid residues that form
      the active site of the PPi-PFK from Propionibacterium freudenreichii and the
      allosteric ATP-PFK from Escherichia coli are conserved within the amoeba
      sequence. The PPi-PFK was recombinantly expressed by using a prokaryotic
      expression system. The purified recombinant protein was found to be enzymically
      active. The K(m) values for PPi and fructose 6-phosphate of the native and the
      recombinant PPi-PFKs were nearly identical. Various bisphosphonates (synthetic
      pyrophosphate analogues) were tested for their ability to inhibit PPi-PFK
      activity or amoebic growth. All bisphosphonates tested were competitive
      inhibitors for amoeba PPi-PFK activity. The best inhibitors were CGP 48048 and
      zoledronate, with Ki values of 50 microM. All bisphosphonates inhibited amoebic
      growth. One of them (risedronate) was inhibitory at a concentration of 10 microM.
      Bisphosphonates are therefore potential therapeutic agents for the treatment of
      amoebiasis.

PMID- 8645235
TI  - Biosynthesis of isoprenoids (carotenoids, sterols, prenyl side-chains of
      chlorophylls and plastoquinone) via a novel pyruvate/glyceraldehyde 3-phosphate
      non-mevalonate pathway in the green alga Scenedesmus obliquus.
AB  - Isoprenoid biosynthesis was investigated in the green alga Scenedesmus obliquus
      grown heterotrophically on 13C-labelled glucose and acetate. Several isoprenoid
      compounds were isolated and investigated by 13C-NMR spectroscopy. According to
      the 13C-labelling pattern indicated by the 13C-NMR spectra, the biosynthesis of
      all plastidic isoprenoids investigated (prenyl side-chains of chlorophylls and
      plastoquinone-9, and the carotenoids beta-carotene and lutein), as well as of the
      non-plastidic cytoplasmic sterols, does not proceed via the classical
      acetate/mevalonate pathway (which leads from acetyl-CoA via mevalonate to
      isopentenyl diphosphate), but via the novel glyceraldehyde 3-phosphate/pyruvate
      route recently detected in eubacteria. Formation of isopentenyl diphosphate
      involves the condensation of a C2 unit derived from pyruvate decarboxylation with
      glyceraldehyde 3-phosphate and a transposition yielding the branched C5 skeleton
      of isoprenic units.

PMID- 8645234
TI  - Coordinate activation of lysosomal, Ca 2+-activated and ATP-ubiquitin-dependent
      proteinases in the unweighted rat soleus muscle.
AB  - Nine days of hindlimb suspension resulted in atrophy (55%) and loss of protein
      (53%) in rat soleus muscle due to a marked elevation in protein breakdown (66%, P
      < 0.005). To define which proteolytic system(s) contributed to this increase,
      soleus muscles from unweighted rats were incubated in the presence of proteolytic
      inhibitors. An increase in lysosomal and Ca 2+-activated proteolysis (254%, P <
      0.05) occurred in the atrophying incubated muscles. In agreement with the
      measurements in vitro, cathepsin B, cathepsins B + L and m-calpain enzyme
      activities increased by 111%, 92% and 180% (P < 0.005) respectively in the
      atrophying muscles. Enhanced mRNA levels for these proteinases (P < 0.05 to P <
      0.001) paralleled the increased enzyme activities, suggesting a transcriptional
      regulation of these enzymes. However, the lysosomal and Ca 2+-dependent
      proteolytic pathways accounted for a minor part of total proteolysis in both
      control (9%) and unweighted rats (18%). Furthermore the inhibition of these
      pathways failed to suppress increased protein breakdown in unweighted muscle.
      Thus a non-lysosomal Ca 2+-independent proteolytic process essentially accounted
      for the increased proteolysis and subsequent muscle wasting. Increased mRNA
      levels for ubiquitin, the 14 kDa ubiquitin-conjugating enzyme E2 (involved in the
      ubiquitylation of protein substrates) and the C2 and C9 subunits of the 20 S
      proteasome (i.e. the proteolytic core of the 26 S proteasome that degrades
      ubiquitin conjugates) were observed in the atrophying muscles (P < 0.02 to P <
      0.001). Analysis of C9 mRNA in polyribosomes showed equal distribution into both
      translationally active and inactive mRNA pools, in either unweighted or control
      rats. These results suggest that increased ATP-ubiquitin-dependent proteolysis is
      most probably responsible for muscle wasting in the unweighted soleus muscle.

PMID- 8645236
TI  - Functional coupling of adenosine A2a receptor to inhibition of the mitogen
      activated protein kinase cascade in Chinese hamster ovary cells.
AB  - Activation of Gs-coupled receptors enhances the increase in cyclic AMP mediated
      by adenylate cyclases. As it has been shown that cyclic AMP inhibits the
      epidermal growth factor-activated mitogen-activated protein kinase (MAPK)
      signalling pathway, stimulation of Gs-coupled receptors may lead to the
      inhibition of MAPK activation. To investigate the effect of a Gs-coupled receptor
      on the MAPK cascade, we cloned the adenosine (Ado) A2a receptor from a guinea-pig
      leucocyte cDNA library, and established Chinese hamster ovary (CHO) cells stably
      expressing the receptor (CHOAdoA2R). The [3H]5'-N-ethylcarbamoyladenosine (NECA)
      binding characteristics (Kd = 91.0 +/- 5.4 nM, Bmax = 707 +/- 11 fmol/mg of
      protein, n = 3) and NECA-induced cyclic AMP production indicate that the cloned
      Ado A2a receptor was functionally expressed in the cells. In CHO cells, thrombin
      induced intracellular Ca2+ increase and MAPK activation through the intrinsic G
      coupled receptor. In CHOAdoA2R cells, NECA partially inhibited thrombin-elicited
      MAPK activation. When combining NECA-treatment with 1,2-bis-(o
      aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM)
      loading, a nearly complete inhibition of the MAPK activation occurred. Forskolin
      also partially inhibited the MAPK activation and synergized with BAPTA-AM,
      suggesting that partial inhibition of MAPK activation by NECA results from cyclic
      AMP production via Ado A2a receptor activation. The same synergism of MAPK
      inhibition between wortmannin and BAPTA-AM was observed, but not between
      wortmannin and NECA. These results suggest that cyclic AMP production through Ado
      A2a receptor inhibits thrombin-elicited MAPK activation by a Ca(2+)
      independent/wortmannin-sensitive pathway in CHO cells.

PMID- 8645237
TI  - Epidermal growth factor regulates adenylate cyclase activity via Gs and Gi1-2
      proteins in pancreatic acinar membranes.
AB  - In the present study, Western-blot and radioreceptor analyses have revealed the
      presence of the epidermal growth factor (EGF) receptor in pancreatic acinar
      membranes. Isolated pancreatic acinar membranes, which allow access of functional
      antibodies to individual components of the signal transduction cascade, were used
      to examine EGF-induced regulation of adenylate cyclase activity. Forskolin,
      vasoactive intestinal peptide (VIP) and to a smaller extent EGF increased cAMP
      production in pancreatic acinar membranes. Preincubation of the membranes with
      anti-GS alpha antibody abolished EGF- and VIP-induced cAMP production, but had no
      effect on forskolin-induced cAMP accumulation. In the presence of either VIP or
      forskolin, EGF inhibited the VIP- and forskolin-induced cAMP production with an
      IC50 of 5 nM. Anti-G alpha i1-2 protein antibody, but not anti-G alpha i3
      antibody, increased basal cAMP production, indicating that Gi proteins exert an
      inhibitory influence on basal adenylate cyclase activity. Anti-G alpha i1-2
      antibody, but not anti-G alpha i3 antibody, abolished the inhibitory effect of
      EGF on the forskolin- and VIP-induced cAMP accumulation. A peptide corresponding
      to the juxtamembrane region in the cytosolic domain of the rat EGF receptor
      increased cAMP production in pancreatic acinar membranes in an anti-G alpha s
      antibody-sensitive fashion, whereas the EGF receptor peptide did not mimic the
      inhibitory effect of the native EGF receptor. The tyrosine kinase inhibitors
      genistein and pp60v-src (137-157) inhibited both the stimulatory and the
      inhibitory effects of EGF on cAMP production. Thus the data of the present study
      show that EGF regulates adenylate cyclase via activation of Gs and Gi proteins by
      a tyrosine phosphorylation-dependent mechanism in pancreatic acinar membranes.
      This leads to stimulation of basal and inhibition of forskolin- and VIP-induced
      adenylate cyclase activity respectively.

PMID- 8645238
TI  - Thrombopoietin potentiates activation of human platelets in association with JAK2
      and TYK2 phosphorylation.
AB  - Thrombopoietin (TPO), also known as the c-mpl ligand, stimulates rapid tyrosine
      phosphorylation of multiple proteins in human platelets including the Janus
      family kinases JAK2 and TYK2. On its own, TPO has no effect on platelet
      aggregation and dense-granule secretion but induces a general potentiation of
      these responses by other stimuli. The most dramatic effect is observed against
      threshold concentrations of agonists for aggregation. Shape change or weak
      reversible aggregation induced by low concentrations of thrombin, collagen and
      the thromboxane mimetic, U46619, are converted into irreversible aggregation in
      the presence of TPO. A similar result is obtained in the presence of the ADP
      scavenger apyrase and cyclo-oxygenase inhibitor indomethacin. TPO also induces
      potentiation of dense-granule secretion measured through release of 5-hydroxy[3H]
      tryptamine. This effect is most striking against low concentrations of stimuli
      and is independent of aggregation as it is observed in the presence of chelation
      of extracellular Ca2+ with EGTA. TPO potentiates activation of phospholipase C
      and elevation of intracellular Ca2+, providing a molecular explanation for
      potentiation of functional responses. TPO may have an important physiological
      role in priming platelet activation in thrombocytopenia, an action that may help
      to compensate for the reduced platelet density.

PMID- 8645240
TI  - Homozygous expression of a missense mutation at nucleotide 385 in the FUT2 gene
      associates with the Le(a+b+) partial-secretor phenotype in an Indonesian family.
AB  - A new point mutation was found in the coding sequence of the secretor FUT2 gene.
      This missense mutation with an A-->T substitution at nucleotide 385 resulted in
      an amino acid change of Ile129 to Phe129. This mutation showed a clear genetic
      trait in an Indonesian pedigree and, when appearing in a homozygous form, it was
      associated with the red cell Le(a+b+) and salivary partial-secretor phenotype.
      This result suggests that the molecular basis for the Le(a+b+) and associated
      partial-secretor phenotype is caused by a partially inactivating amino acid
      change in the alpha(1,2)fucosyltransferase coded for by this new FUT2 allele.

PMID- 8645239
TI  - Association of nucleoside diphosphate kinase with pancreatic zymogen granules:
      effects of local GTP generation on granule membrane characteristics.
AB  - It is well established that both GTP-binding proteins and phosphoproteins are
      involved in the control of exocytosis in the exocrine pancreas. Exocytotic
      membrane fusion is stimulated by guanosine 5'-[gamma-thio]triphosphate, and the
      phosphorylation states of several proteins, including at least one on the zymogen
      granule membrane, are known to change during exocytosis. We show here that a
      nucleoside diphosphate kinase is associated with the cytoplasmic face of
      pancreatic zymogen granules. This enzyme behaves as a phosphoprotein of apparent
      molecular mass 21 kDa on SDS/polyacrylamide gels, and is able to produce GTP by
      using ATP to phosphorylate endogenous GDP. GTP production by nucleoside
      diphosphate kinase is stimulated by the wasp venom peptide mastoparan, both
      through a direct action on the enzyme and through its ability to increase the
      availability of endogenous GDP. Two effects of the GTP produced by nucleoside
      diphosphate kinase are demonstrated: phosphorylation of a 37 kDa zymogen granule
      protein on histidine residues, and stimulation of the fusion of zymogen granules
      with pancreatic plasma membranes in vitro. These results suggest that granule
      associated nucleoside diphosphate kinase is able to maintain local GTP
      concentrations, and raise the possibility that it might be involved in the
      control of exocytosis in the pancreatic acinar cell.

PMID- 8645241
TI  - Expression and regulation by serum of multiple FGF1 mRNA in normal transformed,
      and malignant human mammary epithelial cells.
AB  - In normal (NMEC), transformed (HBL-100) and malignant human mammary epithelial
      cells (MCF 7, BT-20, MDA-MB 231), we have examined the expression and the
      regulation by serum of FGF1 and FGF2 mRNA. FGF2 mRNA level was higher in NMEC and
      in a HBL-100 than in malignant cell lines (MDA-MB-231, BT-20). No FGF2 mRNA was
      detected in the malignant cell line, MCF-7. In contrast, the FGF1 mRNA was
      detected in all the mammary epithelial cells but at different levels. NMEC, HBL
      100 and MDA-MB231 cells expressed similar level of FGF1 and higher than that
      observed in BT-20 and MCF-7. In contrast to FGF2 which is only expressed in
      nonmalignant cells, no correlation between FGF1 mRNA expression and the phenotype
      of the cells was observed. We followed the expression of four FGF1 mRNA,
      heterogenous in their 5' untranslated regions. This study demonstrated that (i)
      the FGF1 mRNA 1.A was not expressed by mammary epithelial cells, (ii) the FGF1
      mRNA 1.B was only expressed in normal mammary epithelial cells and (iii) the
      transcripts 1.C and 1.D were expressed in normal and malignant cells with
      specific patterns. The expression of FGF1 mRNAs responded in a cell specific
      manner to serum starvation. The mRNA 1.A was only expressed in normal cells
      cultured in the absence of serum while 1.C was either up- or down-regulated by
      serum in transformed cells and the expression of 1.D was greater in presence of
      serum in all cell lines. These results show that the regulation of FGF1 mRNAs
      expression is cell specific and does not correlate with a tumorigenic or
      transformed cell phenotype.

PMID- 8645242
TI  - DSBC protein: a new member of the thioredoxin fold-containing family.
AB  - Prediction of the DsbC protein secondary structure has been performed using a
      novel prediction technique which is based on consideration of both local and long
      range interactions between amino acid residues. The C-terminal portion of the
      protein is shown to contain the thioredoxin folding motif. The N-terminal part
      represents a yet unknown structural domain.

PMID- 8645243
TI  - Inhibition of Borrelia burgdorferi-bound fibrinolytic enzymes by alpha2
      antiplasmin, PAI-1 and PAI-2.
AB  - Lyme disease is caused by Borrelia burgdorferi. Human plasminogen and urokinase
      type plasminogen activator bind to the surface of the spirochete where plasmin is
      generated. We have suggested that bound urokinase and plasminogen are utilized by
      the organism to disseminate. We tested whether the physiological inhibitors of
      urokinase, plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), could
      regulate the activity of spirochete-bound urokinase. The k(ass) of PAI-1 and PAI
      2 for bound urokinase were 1.3 x 10(6) M(-1)s(-1) and 6.9 x 10(4)M(-1)s(-1),
      respectively, whereas the k(ass) for free urokinase were 7.2 x 10(6) M(-1)s(-1)
      and 5.3 x 10(5) M(-1)s(-1), respectively. Plasmin associated with the spirochete
      was not inhibited by alpha2-antiplasmin. These results suggest that PAI-1, PAI-2
      and alpha2 antiplasmin would not be efficient regulators of fibrinolytic protease
      activity on the Borrelial surface and would not pose a barrier to utilization of
      these enzymes for dissemination in the human host.

PMID- 8645244
TI  - Identification of three separate binding sites on SHK toxin, a potent inhibitor
      of voltage-dependent potassium channels in human T-lymphocytes and rat brain.
AB  - Eighteen synthetic analogs of ShK toxin, a thirty-five residue K channel blocker
      derived from the sea anemone Stichodactyla helianthus, were prepared in order to
      identify functionally important residues. CD spectra of sixteen of the analogs
      were virtually identical with the spectrum of wild-type toxin, indicating that
      the conformations were not affected by the substitutions. A conserved residue,
      Lys22, is essential for ShK binding to rat brain K channels which are primarily
      of the Kv1.2 type. However, a cationic side chain at position 22 is not essential
      for binding to the human Jurkat T-lymphocyte Kv1.3 channel. While decreasing
      bulkiness at this position affected toxin affinity for the brain K channels,
      increasing bulkiness decreased toxin affinity for both brain and lymphocyte K
      channels. In contrast to the rat brain channels, ShK binding to Kv1.3 was
      sensitive to substitution at Lys9 and Arg11.

PMID- 8645245
TI  - Identification of a melanocyte-type promoter of the microphthalmia-associated
      transcription factor gene.
AB  - Microphthalmia-associated transcription factor (MITF), the human homolog of the
      mouse microphthalmia gene product, regulates melanocyte-specific transcription of
      the tyrosinase gene that codes for an essential enzyme in melanin biosynthesis.
      In this study, we have cloned and characterized the human genomic DNA segment
      containing a melanocyte-type exon and its 5'-flanking region of the MITF gene. A
      major transcriptional initiation site was assigned by primer extension and S1
      nuclease mapping analyses using melanoma RNA. Subsequently, the fusion genes,
      containing the identified 5'-flanking region upstream from the firefly luciferase
      gene, were constructed and were introduced into pigmented melanoma cells or HeLa
      cells which do not express MITF mRNA. Transient expression assays show that the
      5'-flanking region of 2.3 kb is able to confer preferential expression of a
      luciferase gene in pigment cells. These results establish that the MITF gene
      contains a melanocyte-specific promoter.

PMID- 8645246
TI  - Regional and cellular presenilin 1 gene expression in human and rat tissues.
AB  - Presenilin 1 (PSNL1) is a novel causative gene for early-onset familial
      Alzheimer's disease (EOFAD). We have examined the regional and cellular
      distribution of PSLN1 gene expression in normal human and rat tissues. In situ
      hybridization and Northern blot analysis showed that PSNL1 mRNA was ubiquitously
      expressed in many different organs. We also demonstrated that PSNL1 mRNA was
      expressed predominantly in the neuronal cells of the central nervous system, but
      only at low-level in glial cells. Furthermore, the distribution of PSNL1 mRNA in
      human and rodent brains was similar.

PMID- 8645247
TI  - Structure and regional distribution of nociceptin/orphanin FQ precursor.
AB  - We have cloned cDNA carrying the entire coding sequence of the precursor protein
      for nociceptin/orphanin FQ, a neuropeptide-ligand for an opioid-receptor like G
      protein coupled receptor. The deduced nociceptin/orphanin FQ precursor shows
      sequence similarity to the opioid peptide precursors and shares characteristic
      structural features particularly with preprodynorphin. In situ hybridization
      analysis of nociceptin precursor mRNA in the mouse central nervous system
      revealed that it is highly expressed in discrete neuronal sites with the pattern
      distinct from those of opioid peptides.

PMID- 8645248
TI  - The hemorrhagin catrocollastatin inhibits collagen-induced platelet aggregation
      by binding to collagen via its disintegrin-like domain.
AB  - Catrocollastatin, a 50 kDa snake venom protein purified from Crotalus atrox,
      specifically inhibits platelet-collagen adhesion and collagen-induced
      aggregation. Catrocollastatin is composed of an N-terminal domain, a
      metalloproteinase domain, a disintegrin-like domain and a cysteine-rich C
      terminal domain. The present studies show that catrocollastatin exerts its effect
      by binding to collagen. Based on the amino acid sequence and homology analysis, a
      cyclic oligopeptide corresponding to a conservative fragment containing the
      sequence SECD in the disintegrin-like domain has been synthesized. Like its
      protein parent, the synthetic peptide inhibits collagen-induced aggregation and
      possesses the ability to bind to collagen. This is the first snake venom protein
      with a disintegrin-like structure shown to bind to an integrin ligand matrix
      molecule instead of an integrin.

PMID- 8645249
TI  - Primary structure of alboaggregin-B purified from the venom of Trimeresurus
      albolabris.
AB  - The complete amino acid sequences of alpha and beta subunits of alboaggregin-beta
      are presented. The alpha and beta subunits were separated by reversed-phase HPLC
      after reduction and S-pyridylethylation, and their sequences were determined by
      analysis of peptides generated by enzymatic or chemical digestion. The alpha and
      beta subunits consist of 133 and 123 amino acid residues, respectively. The
      sequences are highly homologous to each other (41.4% identity) and also to those
      of the alpha and beta subunits of botrocetin (a von Willebrand factor modulator)
      and the A and B chains of factor IX/X binding protein from other snake venoms. It
      is also homologous to C-type lectins with a homodimeric structure, but it shows
      no lectin-like activity.

PMID- 8645250
TI  - Decreased ET(B) receptor expression in human metastatic melanoma cells.
AB  - In this study, we examined the endothelin (ET) receptor subtype involved in
      mitogenic signaling in human primary and metastatic melanoma cell lines. In a
      reverse transcriptase-polymerase chain reaction (RT-PCR) study, ET(B) mRNA
      expression in metastatic melanoma cells was decreased from that of primary
      melanoma. Only RPM-EP, a primary recurrent melanoma cell line, showed strong
      ET(A) mRNA expression. ET-1 and ET-3 stimulated DNA synthesis of primary and
      recurrent cutaneous melanoma cells in serum-deprived cultures. The growth
      response to ET-1 in metastatic melanoma cells was decreased from that in primary
      melanoma cells. [125I]-IRL-1620 binding to PM-WK, a primary melanoma cell line,
      was significantly blocked by excessive amounts of unlabeled BQ-788. [125I]-IRL
      1620 binding to metastatic melanoma cells was significantly decreased from that
      of primary melanoma cells. From these results, we conclude that the mitogenic
      effects of ET in human primary melanoma are mainly mediated through ET(B)
      receptors and that down-regulation of ET(B) receptors causes the decreased growth
      response of ET-1 in metastatic melanoma cells.

PMID- 8645251
TI  - Surface expression of CD63 antigen (AD1 antigen) in P815 mastocytoma cells by
      transfected IgE receptors.
AB  - The surface expression CD63 antigen in rat basophilic leukemia cells (RBL-2H3)
      was observed after antigen stimulation by confocal fluorescence microscopy. The
      surface expression of CD63 antigen reflected the degranulation in RBL-2H3 cells.
      Then, we did the same experiments in P815 mastocytoma cells with transfected IgE
      receptors. The expression was observed in P815 cells with normal IgE receptors,
      but not in P815 variant cells with IgE receptors which were missing a C-terminal
      cytoplasmic domain of beta or gamma subunit. In addition, the expression in P815
      cells with normal IgE receptors was mostly blocked by the pretreatment of
      herbimycin A. The results suggested that tyrosine phosphorylation of the C
      terminal cytoplasmic domains of beta and gamma subunits was essential for
      degranulation.

PMID- 8645252
TI  - An allel-specific abnormal transcript of the heat shock protein 70 gene in
      patients with major depression.
AB  - Stress-inducible 72-kDa heat shock proteins (HSP70) were encoded on genes in
      multiple chromosomes. The expression of mRNA transcribed from the gene (HSP70-1)
      on chromosome 6 was studied using reverse transcript polymerase chain reaction in
      peripheral blood mononuclear cells of patients with different diseases. The
      deletion of 29 bp occurred in 5' noncoding and subsequent 133 bp in coding
      sequences of HSP70 mRNA in patients with major depression (n = 18), while normal
      subjects (n = 10) and patients with schizophrenia (n = 5), essential hypertension
      (n = 3), rheumatoid arthritis (n = 7), and Graves' disease (n = 3) had normal
      mRNA. No such deletion occurred in genomic DNA and no protein was translated from
      deleted mRNA. The allel-specific abnormal transcript of the HSP70 gene on
      chromosome 6 thus may underlie the altered stress and/or immune response in major
      depression.

PMID- 8645253
TI  - In vivo measurements of ion transport in long-living CF mice.
AB  - The Cftr (Cystic Fibrosis Transmembrane Conductance Regulator) gene codes for an
      epithelial chloride (C1) channel essential for fluid secretion into the
      respiratory and gastrointestinal tract and from exocrine glands. Mice lacking
      CFTR function due to a disruption of Cftr exon 10 or exon 1 (Cftr (m1UNC/m1UNC)
      or Cftr(m1HSC/m1HFC) mice, respectively) generally suffer from severe
      gastrointestinal disease resulting in death shortly after birth or at the time of
      weaning. However, a subgroup of the Cftr(m1HSC/m1HSC) mice have been
      characterized which exhibit relatively mild intestinal pathology resulting in a
      noncompromised lifespan compared to the more severely affected Cftr(m1UNC/m1UNC)
      mice. We compared the ion transport capacity of the intestinal mucosa of the
      mildly and severely affected CF mice using the in vivo technique of rectal
      potential difference (PD) measurement and found that the net calcium-activated
      chloride conductance toward the lumen was much greater in the rectum of mildly
      affected mice than in the severely affected mice. Hence, the milder phenotype may
      be related to the expression of a factor which enhances the net calcium-activated
      chloride conductance into the lumen of the intestinal tract.

PMID- 8645254
TI  - Abundant expression of erythroid transcription factor P45 NF-E2 mRNA in human
      peripheral granurocytes.
AB  - Transcription factor NF-E2 is crucial for regulation of erythroid-specific gene
      expression. p45 subunit of NF-E2 contains a basic-leucine zipper domain and
      dimerizes with the small Maf family protein to form functional NF-E2 complex.
      While p45 expression was shown to be restricted to erythroid cells,
      megakaryocytes and mast cells in hematopoietic lineage, we found in this study
      that p45 mRNA is abundantly transcribed in the granulocyte fraction of human
      peripheral blood cells. As neutrophils occupy approximately 92% of the cells in
      granulocyte fraction of human peripheral blood cells. As neutrophils occupy
      approximately 92% of the cells in this fraction, the cells expressing p45 is most
      likely to be neutrophils. p45 mRNA is also expressed in HL-60 promyelocytes,
      albeit the expression level is much lower than that of the granulocyte fraction.
      HL-60 cells were found to express mafK mRNA, indicating the presence of genuine
      NF-E2 complex in the cells. Although p45 mRNA is transcribed from two different
      promoters, aNF-E2 promoter and fNF-E2 promoter, in erythroid and megakaryocytic
      lineage cells, p45 mRNA is transcribed only from aNF-E2 promoter. The expression
      of p45 megakaryocytic lineage cells, p45 mRNA is transcribed only from aNF-E2
      promoter. The expression of p45 mRNA in the neutrophils declined rapidly after
      transfer of the cells to in vitro culture and G-CSF could not sustain the
      expression from the down-regulation, suggesting the E2 may also participate in
      the regulation of neutrophil-specific gene expression.

PMID- 8645255
TI  - Identification of a novel isoform of estrogen receptor, a potential inhibitor of
      estrogen action, in vascular smooth muscle cells.
AB  - Clinical and experimental studies showed that estrogen has antiatherogenic
      effects. We previously demonstrated that the estrogen receptor (ER) mRNA and
      protein are expressed in vascular smooth muscle cells (VSMC) derived from rat
      aorta. Here, the expression of isoforms of the ER was examined in VSMC. Reverse
      transcriptase-polymerase chain reaction using specific primers for rat ER cDNA
      was performed from RNA of rat VSMC. This revealed the existence of ER cDNA that
      is shorter than the wild-type ER cDNA. Sequencing of the amplified products
      identified three isoforms of the ER and the wild-type ER. These ER mRNA isoforms
      lacked the region corresponding to exon 4, exon 4 and 5, and exon 3 and 4.
      Therefore, they were designated as ERdelta4 isoform, ERdelta4/5 isoform and
      ERdelta3/4 isoform, respectively. Chloramphenicol acetyltransferase assay was
      performed with these ER isoforms constructed into the expression vector and the
      reporter plasmid containing the estrogen responsive element. The assay showed
      that these ER isoforms lost estrogen-dependent transactivation activities and
      that ERdelta4/5 isoform has a inhibitory effect on normal estrogen action when it
      was cotransfected with the wild-type ER. These ER isoforms might be involved in
      the regulation of VSMC by estrogen.

PMID- 8645257
TI  - UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent
      kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene
      product in A549 human lung cancer cell line.
AB  - UCN-01 (7-hydroxyl-staurosporine), which was initially developed as a selective
      protein kinase C inhibitor, has an anti-tumor effect on several human cancer cell
      lines in vivo. In this study, we examined whether this compound has an inhibitory
      effect on cell cyclin-dependent kinases (cdks) in vitro and in vivo using A549
      human lung adenocarcinoma cell line. UCN-01 inhibited the retinoblastoma
      susceptibility gene product (pRB) kinase activity of three types of cdks (cdk 2,
      4 and 6) with 50% inhibitory concentration values of 42, 32, and 58 nM,
      respectively, in vitro. Moreover, the amount of phosphorylated pRB was reduced by
      UCN-01 at a concentration of 100 nM in the living cells. Flow cytometric analysis
      showed that UCN-01 inhibited cell cycle progression at G1 to S transition in A549
      cells at the concentration of 100 nM. These results suggest that inhibition of
      pRB phosphorylation by UCN-01 might lead to inhibition of the cell cycle and
      thereby contribute to antitumor activity of this compound.

PMID- 8645256
TI  - Formation of the enzyme complex in mitochondria is required for function of
      trifunctional beta-oxidation protein.
AB  - The first Japanese patient with mitochondrial trifunctional protein deficiency
      has been identified. The patient's alpha and beta-subunits were synthesized,
      transported into the mitochondria, and converted to the mature size, but rapidly
      disappeared. The newly synthesized mature alpha and beta-subunits in the control
      cells were incorporated into the enzyme complex, alpha4beta4, whereas those in
      the patient's cells were present as monomers. We propose that formation of the
      enzyme complex is required for stabilization of trifunctional protein.

PMID- 8645258
TI  - Molecular cloning and structural organization of the human inducible nitric oxide
      synthase gene (NOS2).
AB  - Previously, we reported the isolation and molecular cloning of human inducible
      nitric oxide synthase gene (NOS2) sequences from human chromosome 17 cosmid
      libraries. Here we describe the further characterization and sequencing of the
      NOS2 gene. The genomic structure of the NOS2 gene was determined from two
      overlapping cosmid clones, namely, pcos4A and pcos20. the NOS2 open reading frame
      is encoded by 27 exons, with translation initiation and termination in exon 2 and
      exon 27, respectively. These results differ from the previously reported
      organization of the iNOS gene, where 26 exons were reported for the genomic
      structure of NOS2.

PMID- 8645259
TI  - Genomic organization of the human bone morphogenetic protein-4 gene: molecular
      basis for multiple transcripts.
AB  - The structure of the human bone morphogenetic protein-4 (BMP-4) gene has been
      characterized from a genomic cosmid clone of about 38 kb. The transcriptional
      unit of the human BMP-4 gene is encoded by 5 exons and spans approximately 7 kb.
      The exon-intron organization of the human BMP-4 gene is similar to that of the
      mouse gene, with notable sequence differences in the 5' non-coding exons. The
      human BMP-4 gene has at least two functional promoters, which are used in a cell
      type specific manner. This observation is of fundamental relevance for
      understanding the specific role of BMP-4 in skeletal development and bone
      remodeling.

PMID- 8645260
TI  - Molecular characterization of seizure-related genes isolated by differential
      screening.
AB  - To isolate seizure-related genes, we applied differential screening technique to
      the cDNA library which constructed from primary cultured cerebral cortical cells
      treated with pentylenetetrazol (PTZ). Northern blotting analysis of mRNA levels
      in the cerebra after systemic administration of PTZ confirmed the results of
      differential screening procedure: 6 clones showed increased mRNA level and 3
      clones showed decreased expression with PTZ. Interestingly, 4 genes which were
      isolated by this technique were related to intracellular calcium action. They
      were cytosolic phospholipase A2, 78 kDa glucose regulated protein, SEZ-15 which
      has an EF hand motif and PTZ-17 that causes calcium current in Xenopus oocyte
      with PTZ application. These data and our previous results suggest that
      intracellular calcium may play an important role for seizure-related
      pathophysiological changes in neuronal cells.

PMID- 8645261
TI  - Lactacystin, an inhibitor of the proteasome, blocks the degradation of a mutant
      precursor of glycosylphosphatidylinositol-linked protein in a pre-Golgi
      compartment.
AB  - When transiently expressed in the COS-1 cell, a mutant chimeric protein with an
      uncleavable glycosylphosphatidylinositol (GPI) -anchor signal failed to be
      modified by GPI and undergoes rapid degradation in a pre-Golgi compartment. Among
      several protease inhibitors, 3,4-dichloroisocoumarin and N-acetyl-L-leucinyl-L
      leucinyl-L-norleucinal, potent inhibitors of the proteasome, strongly inhibited
      the degradation of the mutant protein. Furthermore, lactacystin, a highly
      specific inhibitor of the proteasome, was found to block the degradation. These
      results suggest that the pre-Golgi degradation pathway is functionally linked to
      the proteolytic system dependent on the proteasome, which hitherto was believed
      to play a role mostly in the cytoplasm and nucleus.

PMID- 8645262
TI  - Complementary DNA cloning and sequencing of rat enteropeptidase and tissue
      distribution of its mRNA.
AB  - A cDNA clone encoding enteropeptidase (EC 3.4.21.9), a key enzyme for the
      conversion of trypsinogen to trypsin, was isolated from a rat duodenal mucosa
      cDNA library. Sequences of the 3585 base pair clone predicted that
      enteropeptidase is synthesized as a single-chain precursor form,
      proenteropeptidase, consisting of 1058 amino acid residues with an internal
      signal sequence (51 residues) and is then processed into the mature enzyme
      consisting of three different peptide chains, i.e., mini, light and heavy chains,
      not the previously reported two-chain enzyme. The structure of enteropeptidase is
      relatively conserved among different species and the rat enteropeptidase is 24
      and 39 amino acids longer than the porcine and human ones, respectively. Northern
      blot analysis of rNAs from normal rat tissues revealed that the enteropeptidase
      mRNA of around 4.4 kb in size was expressed only in the duodenal mucosa, and high
      proteolytic activity of the enzyme was detected in the proximal small intestine.
      Additional analysis of the RNAs by RT-PCR revealed that a low level of the mRNA
      was also expressed in the other parts of the small intestine, i.e., jejunum and
      ileum. These results indicate that the biosynthesis of enteropeptidase takes
      place mainly in the proximal small intestine, the duodenum, and the importance of
      the region in the physiology of intestinal protein digestion regulated by the
      enzyme is suggested. Furthermore a faint signal of the mRNA was also detected in
      the stomach, colon and brain in which the existence of trypsin-like serine
      proteases were reported. The significance of the low level expression of the gene
      is unclear, but the potential peptide-processing function of the enzyme in these
      tissues is also suggested.

PMID- 8645263
TI  - Transcriptional repression activity of N-MYC protein requires phosphorylation by
      MAP kinase.
AB  - The transrepressing function of the N-myc protein is due to the distinct domains
      located at the N-terminus. In this report we introduced various point mutations
      around the myc boxes of the N-myc protein to examine whether the phosphorylation
      of the protein affected its transrepressing function. Serine (Ser) residues
      located at amino acid numbers 12, 31, 51, and 65 were changed to leucine or
      arginine, and the expression vectors of the mutant proteins were transfected to
      HeLa cells together with the luciferase gene linked to the MHC class I gene.
      Among the mutants, only the N(51)-myc carrying mutation at Ser(51), a target for
      mitogen-activated protein kinase (MAP kinase), lost the repression activity,
      while the other mutant proteins preserved it. Formation in vitro of the specific
      nucleoprotein complexes on the H2TF1/NFkappaB element, a major target for
      transrepression by N-myc protein, was interfered by the wild-type N-myc protein,
      but not by the Ser(51)-mutated protein. The results suggest that the
      phosphorylation of the N-myc protein at Ser(51) by MAP kinase is required for the
      transcriptional repression activity of the protein.

PMID- 8645264
TI  - Combining the technique of RNA fingerprinting and differential display to obtain
      differentially expressed mRNA.
AB  - We have modified recently developed methods of RNA fingerprinting and
      differential display based on arbitrarily primed PCR which can be used for
      detection and cloning of differentially expressed mRNAs. Our protocol requires
      only a single cDNA synthesis for each different RNA sample, in contrast to the
      multiple cDNA reactions required for differential display method, followed by
      selective amplification of cDNA sequence fraction by arbitrary and oligo(dT)
      primers. We have shown that the longer primers (25-29-mers) allow the use of
      optimal dNTP concentration and higher stringency PCR. Further improvements
      include using TaqStart antibody for hot start PCR and thermostable enzyme mixes
      suitable for long-distance PCR. Long-distance PCR enables the method to display
      bands of up to 2 kb and should result in a higher fidelity of PCR products to the
      original RNA template. When these improvements are combined the resulting method
      is highly reproducible, and more than 85% of the differentially expressed bands
      can be confirmed by Northern blot analysis.

PMID- 8645265
TI  - Apoptosis of human kidney 293 cells is promoted by polymerized cadmium
      metallothionein.
AB  - Transformed human kidney cells (293 cells) exposed to 12.5 to 37.5 microM CdCl(2)
      showed apoptosis as confirmed by characteristic electron microscopic features, a
      ladder on gel electrophoresis of extracted DNA, and fragmentation of nucleosomes
      as detected by enzyme linked immunosorbent assay (ELISA). Higher concentrations
      of Cd were less effective in inducing apoptosis. Furthermore, addition of the
      protein extract from the serum-free medium used for Cd-exposure promoted
      apoptosis exhibiting the same features as that after Cd-exposure. The apoptosis
      induced by the protein was dose-dependent. The molecular weight of the protein
      (Cd-protein) was shown to be 40 kDa by gel filtration. Two-dimensional
      electrophoresis revealed the Cd-protein as a single spot with a molecular weight
      of 6 kDa and pI of 4.5. Competitive ELISA showed that the Cd-protein reacted with
      anti-metallothionein antibody. The present findings suggest that apoptosis is
      induced not only by Cd itself but also by polymerized metallothionein molecules
      (MT) released from cells into the medium.

PMID- 8645266
TI  - NO-redox paradox: direct oxidation of alpha-tocopherol and alpha-tocopherol
      mediated oxidation of ascorbate.
AB  - Nitric-oxide (NO) can act as both a pro- or an antioxidant, yielding either
      cytotoxic or protective effects, respectively. The previously unrecognized redox
      interactions of NO with antioxidants, and not solely its well-known reactions
      with oxygen radicals, peroxyl radicals and transition metal centers, may be
      essential for its dual mechanisms in cells. Since the alpha-tocopherol/ascorbate
      redox cycle is central to antioxidant protection, we studied the direct effects
      of NO on alpha-tocopherol, ascorbate and combinations thereof in aqueous,
      micellar environments using ESR spectral and HPLC quantitative techniques. We
      found that NO does not directly oxidize ascorbate under anaerobic conditions.
      alpha-Tocopherol, however, in the presence of NO and under anaerobic conditions,
      was oxidized to the alpha-tocopheroxyl radical. Under conditions where NO
      oxidized alpha-tocopherol, the subsequent production of the alpha-tocopheroxyl
      radical depleted ascorbate, yielding the semidehydroascorbyl radical and
      regenerating alpha-tocopherol. Thus, NO interacts with the redox cycle involving
      alpha-tocopherol and ascorbate in a pro-oxidant manner.

PMID- 8645268
TI  - Glutamic acid residue 98 is critical for catalysis in pig kidney fructose-1,6
      bisphosphatase.
AB  - Site-specific mutagenesis has been used to replace Glu-98 with flutamine in pig
      kidney fructose-1,6-bisphosphatase (Fru-1,6-P(2)ase) in order to evaluate the
      role of this residue in catalysis. The combination of lower k(cat) and higher
      K(m) resulted in an approximately 12,000-fold reduction in the catalytic
      efficiency of the Glu-98-->Gln enzyme when compared to the wild-type enzyme. The
      affinity of the enzyme for Mg(2+) and for the allosteric inhibitor AMP was
      altered only slightly; however, cooperativity in the binding of both of these
      effectors was eliminated. In addition, AMP could not fully inhibit the Glu-98-
      >Gln enzyme. These data suggest a critical role for the carboxylate of Glu-98
      both as a general base in the reaction, and in the mechanism of allosteric
      inhibition of the enzyme by AMP.

PMID- 8645267
TI  - Analysis of heterophilic cell adhesion mediated by CD66b and CD66c using their
      soluble recombinant proteins.
AB  - The heterophilic cell adhesion mediated by CD66b (carcinoembryonic antigen (CEA)
      gene family member 6, CGM6) and CD66c (nonspecific cross-reacting antigen, NCA),
      both CEA family members expressed on neutrophils, was investigated using their
      soluble recombinant proteins prepared in silkworm larvae. The recombinant CD66b
      and CD66c immobilized on plastic bound CHO transfectants expressing CD66c and
      CD66b, respectively. Their deglycosylated forms retained the adhesion activity,
      suggesting that their carbohydrate portions are not prerequisite for the binding.
      This cell adhesion appeared to be mediated via interaction between the N domains
      of CD66b and CD66c, because CD66 antibodies recognizing their N domains inhibited
      the binding. Neutrophils, when activated, adhered to the immobilized CD66b and
      CD66c. In addition, the binding of primed neutrophils to the antigens induced
      superoxide anion release. The cell adhesion mediated by CD66b and CD66c may play
      a role in interaction between neutrophils or between neutrophils and epithelial
      cells expressing CD66c in vivo.

PMID- 8645269
TI  - A serotonin receptor gene (5HT1A) variant found in a Tourette's syndrome patient.
AB  - Serotonergic pathway disturbances have been implicated in neuropsychiatric
      disorders such as Tourette's syndrome (TS), substance abuse, and depression. In
      order to search for the presence of an association between these neuropsychiatric
      disorders and particular serotonin receptors isolated from these patients, we
      have started to analyze the structure of these receptor genes. We now report that
      a missense nucleotide change in the 5HT1A receptor gene produces a variant form
      of the 5HT1A receptor (Arg(219) to Leu) identified in DNA extracted from a TS
      patient. Also, in several DNA samples examined, both in controls and in the
      patients, we found a second missense nucleotide change which resulted in an amino
      acid change (Asn(417) to Lys) located in the carboxyl tail of the receptor.
      Several other polymorphic changes have been reported previously in the human
      5HT1A receptor and we have also confirmed these findings in our samples.

PMID- 8645270
TI  - Translocation of p190rho guanosine triphosphatase-activating protein from cytosol
      to the membrane in human neutrophils stimulated with different agonists.
AB  - In this paper, we investigated the subcellular distribution of p190rho guanosine
      triphosphatase-activating protein (p190 GAP) in human neutrophils stimulated with
      different agonists. The results show that in neutrophils treated with formyl
      methionyl-leucyl-phenylalanine (FMLP) (1) p190 GAP was translocated from the
      cytosol to the membranes; (2) the translocation of p190 GAP took place only at
      doses of FMLP that induced the translocation of rac 1 and rac 2 and the
      activation of the NADPH oxidase; and (3) the kinetic of translocation of p190 GAP
      paralleled that of rac 1 and rac 2. However, when the agonist was concanavalin A
      (ConA) or phorbol 12-myristate 13-acetate (PMA), rac 1 and rac 2, but not the
      p190 GAP, were translocated.

PMID- 8645271
TI  - Phosphorylation of phosphatase-1alpha in cells expressing v-src.
AB  - Phosphatase-1 (PP1) is phosphorylated "in vitro" by the tyrosine-kinases c-src, v
      src and v-abl. In the case of src, this induces enzyme inactivation. We
      investigated whether in NIH-3T3 cells expressing v-src (A4 cells) PP1 was
      phosphorylated on Tyr and inactivated. In mammalian cells, three PP1 isoforms are
      present: PP1alpha, PP1gamma1 and PP1delta. In A4 cells the three PP1 isoforms
      were all phosphorylated on Ser, but only PP1alpha was also phosphorylated on Tyr.
      A lower level of PP1 phosphorylation, and on Ser only, was found also in wild
      type NIH-3T3 cells. In A4 cells most of Tyr-phosphorylated PP1alpha was
      cytosolic. Also the PP1 activity was decreased in the cytosol of the A4 cells.
      Assay of the three immunoprecipitated PP1 isoforms indicated that only PP1alpha
      was inactivated. Altogether the data suggest that PP1alpha might be a target of v
      src "in vivo".

PMID- 8645272
TI  - Regulatory region with putA gene of proline dehydrogenase that links to the lum
      and the lux operons in Photobacterium leiognathi.
AB  - Nucleotide sequence of regulatory region (R & R) with putA gene (EMBL Accession
      No. U39227) from Photobacterium leiognathi PL741 has been determined, and the
      putA gene encoded amino acid sequence of proline dehydrogenase is deduced.
      Alignment and comparison of proline dehydrogenase of P. leiognathi with the
      proline dehydrogenase domain in the PutA protein of Escherichia coli and
      Salmonella typhimurium show that they are homologous. Nucleotide sequence reveals
      that regulatory region with the putA gene is linked to the lum and lux operons in
      genome; the gene order is <--putA--R & R(I)<--ter-lumQ-lumP-R & R-luxC-luxD-luxA
      luxB-luxE--> (R & R: regulatory region; ter:transcriptional terminator), whereas
      the R & R is the regulatory region for the lum and the lux operons, ter is the
      transcriptional terminator for the lum operon, and R & R(I) apparently is the
      regulatory region for the putA and related genes. Nucleotide sequence analysis
      illustrates the specific inverted repeat (SIR), cAMP-CRP consensus sequence,
      canonical -10/-35 promoter, putative operator and Shine-Dalgarno (SD) sequence on
      the regulatory region R & R(I) for the putA and related genes; it suggests that
      the putA and related genes are simply linked to the lum and the lux operons in
      genome, the regulatory region R & R(I) is independent for the putA and related
      genes.

PMID- 8645273
TI  - E. coli growth inhibition by a high copy number derivative of plasmid pBR322.
AB  - We have observed that plasmid pKH47, a pBR322-derivative containing a 100bp
      poly(dA)-poly(dT) insertion, causes growth inhibition of host E. coli cells
      harboring it. In this paper we show that this inhibitory effect is due to an
      increased copy number property of this plasmid, which is turn leads to an over
      expression of the plasmid-encoded tet gene. Our work also indicates that contrary
      to other pleiotropic effects caused by the tet gene product, which solely depend
      on the expression of the 5' end of the gene, growth inhibition requires an intact
      tet gene. In addition we present the isolation of an E. coli mutant that is
      refractive to the inhibitory effect of pKH47 and shares some properties with the
      parental bacteria containing plasmid pKH4.

PMID- 8645274
TI  - Autoradiographic localization of leptin binding in the choroid plexus of ob/ob
      and db/db mice.
AB  - The obese gene product, leptin, is synthesized in adipose tissue and is a
      circulating factor regulating body weight. To identify the location of leptin
      receptors in the brain we have performed an autoradiographic study of the binding
      of [(125)I]leptin to frozen sections of mouse brain. Dense specific binding of
      [(125)I]leptin was found only in the choroid plexus which is located in the
      dorsal part of the third ventricle and lateral ventricles. Specific binding of
      [(125)I]leptin was found the ob/ob and db/db mice. These findings further our
      understanding of the sites and mechanism of action of leptin on brain centers
      regulating body weight.

PMID- 8645275
TI  - Efficient synthesis of a 72-kDa mitochondrial polypeptide using the yeast Ty
      expression system.
AB  - Using the Ty system from yeast we report the efficient expression of a
      heterologous eukaryotic gene encoding a 72 kDa mitochondrial polypeptide. The
      pFM2IIBgIII expression vector was initially modified for this purpose by
      inserting the factor X(a) protease cleavage site. The TyA gene, which encodes the
      structural component of the yeast virus-like particles (VLPs), and the eukaryotic
      yst1 gene, encoding a 72 kDa mitochondrial tyrosyl-tRNA synthetase from the
      filamentous fungus Podospora anserina, were subsequently fused to the factor X(a)
      cleavage site. The resulting chimeric gene, in which the two polypeptide coding
      sequences are separated by the factor X(a) cleavage site, was expressed in yeast.
      High yield expression of this foreign protein, which was isolated from yeast
      transformants as hybrid TyVLPs, was verified after factor X(a) treatment by SDS
      polyacrylamide gel electrophoresis and antibody detection. The strategy presented
      here should be useful for expressing a wide variety of eukaryotic genes.

PMID- 8645276
TI  - Sulfhydryl redox modulates ATP-sensitive K+ channels in rabbit ventricular
      myocytes.
AB  - The properties of sulfhydryl redox modulation of the ATP-sensitive K+ K(ATP)
      channel have been examined in rabbit ventricular myocytes, using the patch-clamp
      technique. The sulfhydryl oxidizing agent 5.5'-dithio bis-(2-nitro-benzoic acid)
      (DTNB) induced an inhibition of the channel activity without change in the single
      channel conductance. DTNB had no effect on the inhibitory action by ATP. Analysis
      of the open and closed time distributions showed that DTNB decreased the life
      time of bursts and increased the interburst interval without changes in open and
      closed time distributions shorter than 5 ms. N-ethylmaleimide (NEM), a substance
      that reacts with sulfhydryl groups of cysteine residues in proteins, induced an
      irreversible closure of the channel. The results suggested that changes in the
      sulfhydryl redox also modulate K(ATP) channel activity of the K(ATP) channel in
      rabbit ventricular myocytes.

PMID- 8645277
TI  - Induction of apoptosis in HL-60 human promyelocytic leukemia cells by adenosine
      A(3) receptor agonists.
AB  - The effects of adenosine (ADO) analogs on cells of the human promyelocytic HL-60
      line were examined. ADO A(3) receptor agonists, N(6)-(3-iodobenzyl)adenosine-5'-N
      methylcarboxamide (IB-MECA, 30-60 microM) and 2-chloro-N(6)-(3
      iodobenzyl)adenosine-5'-N-methyluronamide (CI-IB-MECA, 10-30 microM) induced
      apoptotic cell death. In contrast, neither an A(1)/A(2) antagonist (XAC) nor
      other selective ADO receptor agonists (CPA, NECA and CGS21680) induced apoptosis
      at concentrations of <30 microM. Both IB-MECA and CI-IB-MECA significantly
      induced Ca(2+) release from intracellular Ca(2+) pools followed by Ca(2+) influx,
      suggesting the presence of phospholipase C-coupled ADO A(3) receptors on HL-60
      cells. This was further supported by the presence of mRNA of ADO A3 receptor in
      the cells. These results suggest that activation of ADO A(3) receptors is
      responsible for the ADO-induced apoptosis in HL-60 cells and could be of
      potential therapeutic value in the treatment of leukemia.

PMID- 8645278
TI  - Hepatitis C virus sequences encoding truncated core proteins detected in a
      hepatocellular carcinoma.
AB  - RNA was specifically extracted from tumor and peritumor tissue of a hepatitis C
      virus (HCV)-associated hepatocellular carcinoma after microdissection. RT-PCR
      products of the HCV 5'-noncoding (NC), core and nonstructural (NS)-5 gene were
      examined. Nucleotide sequences of the core region derived from the tumor tissue
      revealed deletions and mutations resulting in truncated proteins. Peritumor and
      serum HCV sequences were unaffected.

PMID- 8645279
TI  - Permeability of liver microsomal membranes to glucose.
AB  - The permeability of rat liver microsomes to glucose has been studied by using
      (14)C-labelled D-glucose and a light-scattering technique. 1) The microsomal
      intravesicular apparent isotope space for D-glucose (1mM; after 5 min incubation
      at 22 degrees C) was 2.34 microl/mg protein, i.e., approximately 72% of the
      apparent water space. 2) Efflux of [(14)C]D-glucose from microsomal vesicles pre
      loaded as in 1) and measured by rapid Millipore filtration after dilution (100
      fold) in a glucose-free medium revealed that 15 sec after dilution only 15% of
      intravesicular glucose was still retained by microsomes. 3) Osmotic behaviour of
      microsomes upon addition of D-glucose measured by a light-scattering technique
      revealed a glucose influx, saturable at [D-glucose] > 100 mM, and (partially)
      inhibited by pentamidine and cytochalasin B. Ascorbic acid, L-glucose and other
      monosaccharides and related compounds also permeated liver microsomes in a
      fashion similar to D-glucose. These data indicate the existence of a facilitative
      transport system(s) for glucose in the membrane of liver endoplasmic reticulum
      vesicles.

PMID- 8645280
TI  - The activity of plant-derived antiretroviral proteins MAP30 and GAP31 against
      herpes simplex virus in vitro.
AB  - We examined the effect on anti-HIV proteins MAP30 and GAP31, from Momordica
      charantia and Gelonium multiflorum, on the infection and replication of Herpes
      Simplex Viruses (HSV). Human lung WI-38 fibroblasts cultured in the presence of
      tenfold dilutions of MAP30 or GAP31 were exposed to HSV and viral yield was
      measured at 24-48 hours by ELISA. The effective concentrations for 50%
      inhibitions (EC50) were 0.1-0.2 microM for HSV-2, and 0.3-0.5 microM for HSV-1
      for MAP30 and GAP31, respectively. In comparison, the EC(50) for acyclovir (ACV),
      a commonly used anti-HSV drug, was 0.2 and 1.7 microM for HSV-2 and HSV-1,
      respectively. The cytotoxicity of all three antivirals was negligible and
      comparable. However, the antiherpetic activity of the plant proteins against
      acyclovir-resistant strains was two to three logs more potent than ACV. These
      results suggest that MAP30 and GAP31, previously shown to be active against HIV,
      may be useful for the therapy of herpesvirus infections.

PMID- 8645281
TI  - Assessment of the flavoprotein nature of the redox core of neutrophil NADPH
      oxidase.
AB  - The latent NADPH oxidase activity of purified cytochrome b(558) from rabbit
      peritoneal neutrophils was expressed in a cell-free system consisting of either
      gel-filtrated cytosol from resting neutrophils, or a mixture of the three
      cytosolic activation factors, namely p47, p67 and the G protein Rac1. The cell
      free system was supplemented with arachidonic acid and GTPgammaS. With gel
      filtrated cytosol, the oxidase activity was relatively high (22 moles O(2)(
      )/s/mole heme b in the absence of added FAD), and enhanced by less than one
      fourth upon addition of FAD. In contrast, with the purified cytosolic activation
      factors the rate of O(2)(-) production was low (8 moles O(2)(-)/s/mole heme b),
      and enhanced more than two-fold by a saturating concentration of FAD. The
      specificity of FAD was demonstrated by the lack of effect of FMN. FAD was
      determined together with heme b and the oxidase activity in eluates from a
      Sepharcryl column at the last step of the purification of cytochrome b(558). In
      the eluted fraction that contained both the maximal inducible oxidase activity
      and the highest amount of heme b, the molar amount of FAD was 20 times less than
      that of heme b. It is concluded that cytochrome b(558) is an NADPH-dependent
      flavocytochrome oxido-reductase (NADPH oxidase) in which one part of FAD is
      firmly bound and another, loosely attached. On the other hand, there may exist a
      parallel pathway of electron transfer from NADPH via distinct FAD
      dehydrogenase(s) to the heme b component of the NADPH oxidase.

PMID- 8645282
TI  - Internal motions in myosin head: effect of ADP and ATP.
AB  - Internal flexibility of myosin heads in glycerinated muscle fibres in the
      presence of MgADP plus orthovanadate and after addition of Ca-ATP was studied
      using an isothiocyanate-based spin label attached to the reactive sulfhydryl
      sites of myosin. The spin labels were immobilized on the microsecond time scale
      and exhibited significant orientational order in rigor. In AM+.ADP.V(i) state a
      smaller fraction of ordered population was found showing distinct orientation
      from rigor; the larger population of heads was in dynamically disordered state.
      This new ordered population of heads was detected even in contracting fibres.

PMID- 8645283
TI  - Pancreatic islet cells express BST-1, a CD38-like surface molecule having ADP
      ribosyl cyclase activity.
AB  - Cyclic ADP-ribose (cADPR), a well-known stimulator of ca(2+) release from the
      intracellular Ca(2+) pool, has recently emerged as a potential regulator of
      insulin secretion in pancreatic beta cells. As recently described, BST-1 is a
      glycosyl-phosphatidylinositol (GPI)-anchored surface molecule that exhibits
      homology with CD38 and Aplysia ADP-ribosyl cyclase. Like CD38, BST-1 has both ADP
      ribosyl cyclase and cADPR hydrolase activities. As a step toward elucidating the
      physiological role of cADPR in insulin secretion we examined whether BST-1 is
      expressed in pancreatic islet cells. Sensitive reverse transcription-polymerase
      chain reaction detected almost as abundant expression of BST-1 mRNA in pancreatic
      islets as CD38 mRNA. Immunohistochemical analyses utilizing mirror image sections
      revealed that BST-1 protein is expressed in a majority of the cells in pancreatic
      islets and that at least beta cells and, to an even greater extent, alpha cells
      express BST-1. These observations suggest the involvement of multiple enzymes in
      the regulation of cADPR concentrations in pancreatic islet cells.

PMID- 8645285
TI  - Mitochondrial DNA 3394 mutation in the NADH dehydrogenase subunit 1 associated
      with non-insulin-dependent diabetes mellitus.
AB  - Mitochondrial DNA (mtDNA) mutation is associated with a subtype of non-insulin
      dependent diabetes mellitus (NIDDM). We identified two homoplasmic mtDNA
      mutations at the positions of 3394 (T-C) and 3423 (G-T) in a NIDDM patient with
      clinical features of mitochondrial encephalopathy. The mtDNA 3394T-C mutation
      changed a conserved tyrosine to a histidine in NADH dehydrogenase subunit 1. The
      frequency of mtDNA 3994 T-C mutation was determined with Polymerase Chain
      Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) in general NIDDM
      patients and nondiabetic control subjects. The mutation was seen in 4.9% of NIDDM
      patients and 1.3% of nondiabetic controls. It is indicated that the mtDNA 3394 T
      C mutation is associated with NIDDM in Japan.

PMID- 8645284
TI  - Gene transfer to the retina of rat by liposome eye drops.
AB  - Gene delivery to the intraocular tissues of the retina is hampered by complicated
      surgical interventions to administer the gene. Here we showed that instillation
      as eye drops of an expression plasmid vector for beta-galactosidase gene carried
      by the specific kinds of liposomes could transfer the gene to the retinal
      ganglion cells of rat, without causing any inflammation. This non-surgical,
      convenient way for gene delivery to the retina would facilitate the development
      of treatment for various intraocular diseases.

PMID- 8645286
TI  - Beta-nerve growth factor as a mediator of the acute phase response in vivo.
AB  - Nerve growth factor (NGF) is increased during inflammation and stress. Stress
      induced increases in specific serum proteins, such as serum amyloid A (SAA) and
      serum triglyceride (TG) levels, are part of the acute phase response which is
      mediated by cytokines. We now report the effect of systemic administration of
      beta-NGF on levels of serum lipids and SAA. Beta-NGF induced a rapid and
      sustained increase in serum TG and free fatty acid (FFA) in a dose dependent
      manner, while decreasing serum cholesterol levels in rats. Additionally, beta-NGF
      increased hepatic mRNA levels and serum concentrations of SAA at 16 hours in
      mice. Thus, beta-NGF joins the list of cytokines and growth factors that can
      mediate the acute phase response.

PMID- 8645287
TI  - The fibril forming region of the beta-amyloid precursor differs from that of the
      amyloid A precursor in its interaction with lipids.
AB  - Since the amyloid A (AA) precursoir, serum amyloid A (apoSAA), has been shown to
      bind cholesterol (C) in the AA fibril forming region, we investigated the
      interaction of the beta-amyloid precursor protein (AbetaPP) and beta-amyloid
      (Abeta) peptide with C and phosphatidyl choline (PC) by measuring changes in
      binding to microtiter wells at physiological pH and ionic strength. While either
      C or PC inhibited AbetaPP binding to the same extent that C inhibited apoSAA
      binding, neither C nor PC had any effect on binding of the Abeta peptide,
      although antibodies to Abeta1-40 did block binding. The binding of (125)I-Abeta1
      40 and (125)I-AbetaPP was inhibited by apoE3 and apoE4, but not by either apoSAA
      or bovine serum albumin. Bound (125)I-AbetaPP was partially released into medium
      containing C, PC, apoE3, apoE4, or antibodies to AbetaPP. Our results indicate
      that AbetaPP but not Abeta peptide can be retained in solution in the presence of
      C and PC and suggest that this failure to interact with lipids may account for
      the greater insolubility of Abeta fibrils than AA fibrils.

PMID- 8645288
TI  - Mutation of an aspartate at position 63 in the human platelet-activating factor
      receptor augments binding affinity but abolishes G-protein-coupling and inositol
      phosphate production.
AB  - Platelet-activating factor is a potent phospholipid mediator which binds to a
      specific, high affinity receptor of the G protein-coupled receptor (GPCR) family.
      In the present report, we demonstrate that the highly conserved aspartate 63 is
      critical in G protein coupling of the PAF receptor: substitution of an asparagine
      for the aspartate 63 (D63N) abolished inositol phosphate production following
      agonist stimulation; moreover, binding isotherms of the D63N mutant were
      monophasic and unaffected by GTPgammaS. We also demonstrate that aspartate 63 is
      not involved in direct interaction with the agonist: the D63N mutant displayed a
      higher intrinsic affinity for PAF than the uncoupled WT receptor. Sodium
      decreased specific (3)H-PAF and antagonist (3)H-WEB2086 binding to the PAF
      receptor, but the aspartate 63 residue was not involved in this regulation,
      contrary to cognate aspartate residues in other GPCRs. Our data suggest that
      aspartate 63 in the PAF receptor may be involved in the structural requirement
      for G protein coupling to the receptor and may contribute to receptor affinity
      for the ligand.

PMID- 8645289
TI  - A formal discussion of the archival journal requirements for data deposition.

PMID- 8645290
TI  - Interleukin-6 enhances glucose transport in 3T3-L1 adipocytes.
AB  - To study the effect of interleukin-6 (IL-6) on glucose transport, 2-deoxy-D
      glucose (2-DOG) uptake in 3T3-L1 adipocytes after incubation with IL-6 was
      measured. IL-6 increased 2-DOG uptake maximally after 5 hours by 30 +/- 12%, with
      a half-maximal effect at an IL-6 concentration of approximately 800 U/mL. 3-O
      methylglucose uptake was stimulated in a similar way, indicating that IL-6
      enhanced glucose transport rather than phosphorylation. IL-6-induced glucose
      transport was additive to the effect of insulin. Addition of cycloheximide did
      not affect the stimulatory action of IL-6, although cycloheximide itself had
      profound effects on basal glucose transport. We conclude that IL-6 may enhance
      glucose uptake by increasing GLUT-1 intrinsic activity.

PMID- 8645291
TI  - Structural analysis of a biologically active echistatin analogue des(46-49)
      [Ala8,37]-echistatin gamma with three disulfide bonds by 2D-NMR and computer
      graphics.
AB  - An echistatin analogue, designated as des(46-49)-[Ala8,37]-echistatin gamma, was
      synthesized chemically by solid-phase peptide synthesis. The analogue was made by
      replacing Cys8 and Cys37 residues with two alanines and the deletion of C
      terminal peptide 46-49 of echistatin gamma, resulting in an artificial
      polypeptide of 45 amino acids with three disulfide bonds. In the platelet
      aggregation assay, the analogue exhibits almost the same activity as echistatin
      gamma, indicating that the linear sequence of des(46-49)-[Ala8,37]-echistatin
      gamma contains all of the primary-structure information that is required for
      proper folding of this synthetic polypeptide. The tertiary structure of the
      analogue, as determined from high-resolution nuclear magnetic resonance (NMR)
      coupled with dynamic simulated annealing, is very similar to that of echistatin
      alpha1 which differs from echistatin gamma by 8 residues. In particular the two
      important sites of the Arg-Gly-Asp (RGD) loop and the C-terminal Lys45, both of
      which show some degree of disorder, are maintained in similar spatial orientation
      and proximity as those in echistatin alpha 1 even without the constraint provided
      by the disulfide bond of the (Cys8-Cys37) pair. These results provide new
      insights in further defining distinct structural features of echistatin gamma,
      which are involved in supporting the active polypeptide conformation to achieve
      biological activity in the absence of one pair of disulfide bonds.

PMID- 8645292
TI  - Expression and functional characterization of a single chain Fv antibody directed
      against secretions involved in plant nematode infection process.
AB  - Expression in plants of antibodies directed against proteins essential for
      pathogenesis could provide an alternative approach to engineer new resistance
      traits into crops. Salivary secretions of the root-knot nematode Meloidogyne
      incognita are known to play a key role during this nematode infection process.
      From a hybridoma cell line producing an IgM monoclonal antibody specific to these
      secretions, we have constructed a synthetic gene that encodes an antigen-binding
      single-chain Fv protein (scFv). The scFv gene was created by polymerase chain
      reaction amplification of variable domain encoding regions from the IgM antibody.
      The cloned scFv was initially expressed in Escherichia coli as a 33-kDa protein
      which could be purified to near homogeneity by immobilized metal affinity
      chromatography. The produced scFv is fully functional since it shows the same
      specificity towards a crude extract of M. incognita infective larvae as the
      corresponding parental IgM. Transient expression assays with tobacco leaf
      protoplasts using different targeting signals resulted in a high intracellular
      accumulation of scFv, especially when fused to the tetrapeptide KDEL retention
      signal. Activity analysis and stability characterization of this scFv in tobacco
      protoplast represent the first step before plant transformation in order to test
      a new form of resistance to root-knot nematode in plants.

PMID- 8645293
TI  - Induction of protein disulfide isomerase mRNA by delta 12-prostaglandin J2.
AB  - Protein disulfide isomerase (PDI) catalyzes the correct protein disulfide
      formation and is a key regulator for protein folding. We examined the effect of
      delta 12-prostaglandin (PG) J2, a thiol-reactive stress PG, on the expression of
      the PDI gene. Delta 12-PGJ2 transiently induced the PDI mRNA in HeLa cells. Other
      stress inducers, tunicamycin, A23187, and heat shock, which caused an
      accumulation of unfolded proteins, also induced the PDI mRNA, indicating that the
      unfolded protein accumulation response induces PDI gene expression. Cycloheximide
      by itself strongly induced the PDI mRNA, but did not inhibit the effect of delta
      12-PGJ2, suggesting that the pathway of delta 12-PGJ2-induced PDI gene expression
      does not involve unfolded protein accumulation. On the other hand,
      dithiothreitol, a reducing agent, induced the PDI mRNA, and delta 12-PGJ2 did not
      exert additive induction. Thus, delta 12-PGJ2 induces PDI gene expression through
      a pathway independent of de novo protein synthesis.

PMID- 8645294
TI  - Ca2+-dependent interaction of calcyclin with membrane.
AB  - The presence of calcyclin in the microsomal fraction of Ehrlich ascites tumor
      cells was detected using polyclonal antibodies. Association of calcyclin with the
      microsomes depended on the presence of calcium ions in the buffer used for cell
      fractionation. The interaction of calcylcin with Ehrlich ascites tumor cells
      microsomes was confirmed in the in vitro conditions by cosedimentation assay
      using exogenous calcyclin. It was shown that phospholipids extracted from natural
      membranes and purified phosphatydylserine or phosphatydylcholine were not
      involved in the binding. Instead, several low molecular weight polypeptides in
      the Triton X-100 resistant membrane fraction were found to interact with
      calcyclin.

PMID- 8645295
TI  - Identification of novel DNA binding sites recognized by the transcription factor
      mPOU (POU6F1).
AB  - Transcription factors of the POU family recognize DNA through their POU domain
      which represents a bipartite DNA binding motif consisting of a POU specific
      domain and a POU homeobox. It is thought that both subdomains make specific
      contacts with DNA and participate in DNA binding. Here we identify novel DNA
      binding sites for the POU protein mPOU (POU6F1). The sites contain two TAAT
      motifs either as palindromes or as direct repeats. DNA binding is mediated
      through the POU homeobox only. Transactivation experiments revealed that mPOU per
      se showed no transcriptional activation but could act as a repressor of Oct2A
      mediated activation.

PMID- 8645297
TI  - Expression of heparin-binding EGF-like growth factor in rat liver injured by
      carbon tetrachloride or D-galactosamine.
AB  - We reported recently that heparin-binding EGF-like growth factor (HB-EGF), a
      member of the EGF family, is a new hepatotrophic factor for the regeneration of
      rat liver after partial hepatectomy. The current study examined changes in the
      amount of HB-EGF mRNA in liver injured by hepatotoxins. The level of HB-EGF mRNA
      was very low in normal rat liver, but increased markedly in the liver of rats
      injured by CCl4, showing two peaks, the first at 6 h and the second at 36 h.
      Western blot analysis showed that HB-EGF protein in the liver of CCl4-treated
      rats (at 6 h) was increased about 3.4-fold above normal. The level of HB-EGF mRNA
      also increased markedly in the liver of rats treated with D-galactosamine,
      showing a major peak at 18 h, and a smaller one at 6 h. These results indicate
      that HB-EGF may play a role in the regeneration of the liver following
      hepatotoxic injury.

PMID- 8645298
TI  - Scanning-deletion analysis of the extracellular domain of the TGF-beta receptor
      type II.
AB  - There are three main types of receptors for TGF-beta termed receptor type I, type
      II and type III. TGF-beta receptor type II has a crucial role in the cell's
      responsiveness to TGF-beta as it is mandatory for the TGF-beta binding to the
      signaling complex (receptor type I and type II). Here we have used a scanning
      deletion mutagenesis approach to determine the core binding domain of the
      extracellular domain of receptor type II that is required for interaction with
      TGF-beta. Deletions of three amino acids were systematically introduced at
      intervals of five amino acids in order to scan the N- and C-terminus of the
      extracellular domain of the receptor. We find that the N-terminal region which is
      devoid of cysteine residues is not critical for ligand binding. Similarly, the C
      terminal region, i.e., the amino acids flanking the transmembrane domain, are
      dispensable for binding. These results suggest that the central 100 amino acid
      span that is rich in cysteine residues is the core binding domain for TGF-beta.

PMID- 8645296
TI  - A new plasmid-encoded proteic killer gene system: cloning, sequencing, and
      analyzing hig locus of plasmid Rts1.
AB  - A new proteic killer gene system, hig, was identified on the plasmid Rts1. The
      hig locus consisting of a higA and higB is directly related to the temperature
      sensitive host cell growth conferred by Rts1. We proved that higB encoding
      presumably a 92-amino-acid polypeptide inhibited segregation of plasmid free
      cells, and higA encoding a 104-amino-acid polypeptide suppressed the higB
      function both in cis and in trans.

PMID- 8645299
TI  - Identification of mutant adeno-associated virus Rep proteins which are dominant
      negative for DNA helicase activity.
AB  - Adeno-associated virus type 2 (AAV) Rep proteins have been postulated to play a
      role in unwinding the 145-bp inverted terminal repeats during AAV DNA
      replication. Previous studies showed that AAV Rep78 and Rep68 could unwind a DNA
      partial duplex of 26 bp. In this work it is demonstrated that nuclear extracts of
      human 293 cells containing wild-type Rep68 can unwind partial DNA duplexes up to
      160 bp long. Mutant Rep proteins with either a histidine substituted for lysine
      340 or a deletion of methionine 225 had no detectable helicase activity and
      inhibited the helicase activity of wild-type Rep68 protein. This observation is
      consistent with the model that the functional form of the Rep proteins is a
      multimer.

PMID- 8645300
TI  - G protein-gated K+ channel (GIRK1) protein is expressed presynaptically in the
      paraventricular nucleus of the hypothalamus.
AB  - We prepared a specific antibody against GIRK1, the major subunit of the G protein
      gated K+ (KG) channel. Immunohistochemical study revealed that GIRK1
      immunoreactivity was detected in the presynaptic, but not in the postsynaptic,
      region in the paraventricular nucleus of the rat hypothalamus (PVN). Therefore,
      activation of the KG channel may underlie presynaptic inhibition of
      neurotransmitter release by various agonists, such as dopamine, noradrenaline,
      opioids, and histamine, in PVN.

PMID- 8645301
TI  - Inhibition of Cu2+-induced LDL oxidation by nitric oxide: a study using donors
      with different half-time of NO release.
AB  - The incubation of low density lipoproteins with Cu++ promotes oxidative
      modifications that make them atherogenic. Comparable alterations occur in vivo
      and are modulated by the generation of nitric oxide by endothelial cells or
      macrophages. Here we report that two donors (NOC-9 and NOC-18) with different
      half times of NO release (2.7 and >500 min, respectively) inhibit in vitro
      lipoprotein oxidation promoted by Cu++. Both donors increase the duration of the
      lag-phase and decrease the maximum rate of conjugated diene formation, prevent
      the loss of tryptophan in Apo B100, and decrease the formation of fluorescent
      adducts. The protective effect of NOC-9 was rapidly exhausted and its overall
      efficacy in preventing LDL oxidation was two orders of magnitude lower than that
      exhibited by NOC-18. These findings suggest that a continuous flux of NO
      generation, even at lower concentrations, is more efficient than considerably
      higher doses released as a burst in protecting both the lipid and the protein
      moiety of LDL from oxidation.

PMID- 8645302
TI  - Transient overexpression of human 15-lipoxygenase in aortic endothelial cells
      enhances tumor necrosis factor-induced vascular cell adhesion molecule-1 gene
      expression.
AB  - 15-lipoxygenase (15-LO) expression in artery wall cells has been demonstrated
      during the development of atherosclerosis in various animal models. We examined
      whether the expression of 15-LO in aortic endothelial cells affects the gene
      expression of the adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1).
      Transient transfection of human 15-LO cDNA into bovine aortic endothelial cells
      led to the expression of 15-LO protein and enzymatic activity. We studied the
      induction of VCAM-1 mRNA in these cells. 15-LO expressing cells showed no
      detectable levels of VCAM-1 message. However, when TNF was added to these cells
      there was a synergistic increase in VCAM-1 expression relative to cells that were
      transfected with control plasmid pcDNA I. Our data suggest that 15-LO expression
      in aortic endothelium may amplify the expression of VCAM-1 induced by
      inflammatory stimulus during atherogenesis.

PMID- 8645303
TI  - Expression of Retinoid X Receptor alpha is increased upon monocytic cell
      differentiation.
AB  - 1 alpha, 25-Dihydroxyvitamin D3 (VD) is a potent inducer of monocytic
      differentiation of both normal and leukemic cells. Its effects are mediated by
      its nuclear receptor (VDR). Efficient gene activation requires the
      heterodimerization of VDR with Retinoid X Receptors (RXR). In the present study
      using specific antibodies, we analyzed the expression of the RXR alpha protein in
      blood mononuclear cells from acute myeloid patients (AML) (10 cases) and from
      myelomonocytic cell lines arrested at different stages of differentiation. We
      observed that the RXR alpha expression increased during myelomonocytic
      differentiation, since the highest levels were found in AML samples and in
      myelomonocytic cell lines having the highest amounts of monocytic precursors. We
      also demonstrated that fresh leukemic cells, whatever their stage of
      differentiation, as well as myelomonocytic cell lines, respond to VD by an
      increase in RXR alpha levels. Combinations of all-trans retinoic acid (RA) and
      VD, in some cases, increased this effect. This response suggests the involvement
      of RXR alpha in monocytic differentiation upon VD treatment.

PMID- 8645304
TI  - An insect juvenile hormone-specific epoxide hydrolase is related to vertebrate
      microsomal epoxide hydrolases.
AB  - We describe the first cDNA sequence encoding a juvenile hormone-specific epoxide
      hydrolase from an insect. A full-length cDNA clone revealed a 462-amino-acid open
      reading frame encoding an amino acid sequence with 44% identity and 64%
      similarity to human microsomal epoxide hydrolase. All residues in the catalytic
      triad (residues Asp227-His428-Asp350 in the M. sexta protein) were present, as
      was the conserved Trp154 corresponding to the oxyanion hole. The surprising
      similarity of insect juvenile hormone epoxide hydrolase to vertebrate microsomal
      epoxide hydrolases, coupled with the ancient lineage of the epoxide hydrolases
      and haloalkane dehalogenases, suggests that this catabolic enzyme evolved from an
      original ubiquitous detoxication function to a more recent role in hormonal
      regulation.

PMID- 8645305
TI  - Site-directed mutagenesis of the conserved serine 138 of human placental NAD+
      dependent 15-hydroxyprostaglandin dehydrogenase to an alanine results in an
      inactive enzyme.
AB  - Human placental NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is
      a member of the short-chain dehydrogenase family of enzymes. It has been proposed
      that a highly conserved serine residue (corresponding to serine 138 of 15-PGDH)
      may be involved in the catalytic mechanism of many of these enzymes. Site
      directed mutagenesis was used to change serine 138 of NAD+-dependent 15
      hydroxyprostaglandin dehydrogenase to an alanine. The mutant protein was then
      expressed in E. coli. Western blot analysis indicated that the S138A mutant
      protein was expressed at levels similar to the wild type enzyme; however, the
      mutant protein was found to be inactive. These results support the proposed role
      of this highly conserved serine in enzyme activity.

PMID- 8645306
TI  - Differential effect of interleukin-4 and transforming growth factor beta 1 on
      expression of proto-oncogenes and autocrine insulin-like growth factor II in
      colorectal carcinoma cells.
AB  - We have compared the effect of interleukin-4 and transforming growth factor beta
      1 on proliferation and gene expression in two colorectal carcinoma cell lines,
      LS513 and LS1034. Transforming growth factor beta 1 was a potent inhibitor for
      both cells lines and virtually abolished de novo DNA synthesis. Interleukin-4
      inhibited thymidine incorporation up to 60 and 45%, respectively. While both
      cytokines exerted a comparable cyto-inhibitory activity they displayed
      differential effects on proto-oncogene expression. Transforming growth factor
      beta 1 markedly down-regulated c-myc in LS1034 but not in LS513 cells. In
      contrast, expression of c-fos was induced by interleukin-4 in LS513 but not in
      LS1034 cells. Interestingly, in agreement with their cyto-inhibitory activity
      both cytokines suppressed the expression of insulin-like growth factor II in
      LS1034, which is an autocrine growth factor for these cells.

PMID- 8645308
TI  - Role of extracellular matrix on colonic cancer cell migration and proliferation.
AB  - A simplified method to quantitatively analyze the migration and proliferation
      capacity of a colonic cancer cell line (SW837) in vitro was developed. The
      objective of this study was to evaluate the role of the extracellular matrix in
      colon cancer metastasis. We used this model to investigate the effects of the
      extracellular matrix components collagen type I and type IV, laminin, and
      fibronectin on the migration and the proliferation of cancer cells. Migration was
      fastest on laminin and slowest on collagen type I. Further, proliferation was
      highest on laminin of all extracellular matrices groups studied. Therefore, it is
      concluded that laminin had pronounced effects on migration and proliferation of
      SW837 cells. These findings suggest that the composition of the extracellular
      matrix plays an important role in the mechanism of metastasis of colon cancer
      cells.

PMID- 8645307
TI  - Novel bacterial rhodopsins from Haloarcula vallismortis.
AB  - New bacterial rhodopsins of the cruxrhodopsin (cR) tribe were identified in a
      type strain Haloarcula vallismortis. The genes encoding a bacteriorhodopsin-like
      ion pump (named cR-3), a halorhodopsin-like ion pump (chR-3) and a sensor
      rhodopsin (csR-3) were cloned and sequenced. Together with the data for vsRII
      (Seidel et al., Proc. Natl. Acad. Sci. USA 92, 3036-3040 (1995); cpR-3 in our
      notation), the primary structures of a set of four rhodopsins are now all known
      only in this species. They are separated by almost the same distances in
      homology, suggesting that they have derived from a single ancestral rhodopsin.
      The degree of conservation in the amino acid sequence of each helix showed that
      helices C and G are relatively well conserved in all rhodopsins, whereas helices
      DEF are conserved especially in sensor rhodopsin-I, possibly because these
      helices are needed for interaction with the transducer protein (Htr).

PMID- 8645309
TI  - Characterization of component-I gene of botulinum C2 toxin and PCR detection of
      its gene in clostridial species.
AB  - Botulinum C2 toxin is composed of two nonlinked protein components, component-I
      (light chain) and component-II (heavy chain). It is produced by Clostridium
      botulinum types C and D, and is thought to play a lethal pathogenic role. These
      biological activities of C2 toxin may be due to the ADP-ribosylation of non
      muscle actin by component-I of the toxin. We were able to isolate two overlapping
      gene fragments encoding component-I from the chromosomal DNA of Clostridium
      botulinum type C strain (C)-203U28, and determine the complete nucleotide
      sequence of component-I gene. The gene for component-I, bc21, consists of one
      open reading frame (ORF) encoding 431 amino acid residues (1293 nucleotides)
      without signaling peptide sequence. The molecular mass calculated from the
      deduced amino acid sequence was 49400.37 Da. Mono-ADP-ribosyltransferase activity
      was demonstrated in the lysate from E. coli transformed by the recombinant
      plasmid, pGEM-C2 encompassing whole component-I gene with its own promoter.

PMID- 8645310
TI  - Ca2+-dependent binding of calcyclin to muscle tropomyosin.
AB  - The interaction of calcyclin with tropomyosin and tropomyosin-actin was studied
      with fluorescence titrations and photo-reactive crosslinking experiments.
      Titrations of pyreneiodoacetamide-labeled tropomyosin alone or with actin showed
      binding of calcyclin to tropomyosin with muM dissociation constants when Ca2+ was
      present. UV irradiation of mixtures of calcyclin and gizzard beta beta
      tropomyosin labeled with benzophenone-iodoacetamide at Cys36, with or without
      actin, produced crosslinks between tropomyosin chains and calcyclin monomers only
      in the presence of Ca2+. These data provide direct evidence for a Ca+2-dependent
      tropomyosin-calcyclin interaction at or near Cys36 of tropomyosin and indicate
      that calcyclin binding to tropomyosin-actin does not cause tropomyosin
      dissociation.

PMID- 8645311
TI  - Effects of BMP-2, BMP-4, and BMP-6 on osteoblastic differentiation of bone marrow
      derived stromal cell lines, ST2 and MC3T3-G2/PA6.
AB  - The effects of bone morphogenetic protein-2 (BMP-2) on osteoblastic
      differentiation of bone marrow stromal cells were investigated using two bone
      marrow stromal cell lines, ST2 and MC3T3-G2/PA6 (PA6). BMP-2 stimulated ALP
      activity and induced parathyroid hormone (PTH)-dependent production of cAMP in
      both ST2 and PA6 cells, but these effects were more apparent in ST2 cells than in
      PA6 cells. BMP-2 induced the production of osteocalcin in ST2 cells, but not in
      PA6 cells. BMP-4 and BMP-6 stimulated ALP activity in ST2 cells, but the effect
      of BMP-6 was less marked than that of BMP-2 and BMP-4. BMP-4 induced PTH
      dependent cAMP production of cAMP in ST2 cells, but BMP-6 did not. When ST2 cells
      were transplanted into the peritoneal cavities of athymic mice with BMP-2 in
      diffusion chambers, these cells generated mineralized bone in the chambers. These
      results indicate that BMPs induce the differentiation of bone marrow stromal
      cells into osteoblasts. However, the effects differ among the BMPs and among the
      types of cell exposed to these proteins.

PMID- 8645312
TI  - Inhibition of Aspergillus serine proteinase by Streptomyces subtilisin inhibitor
      and high-level expression of this inhibitor in Pichia pastoris.
AB  - Aspergillus fumigatus encodes an extracellular serine proteinase of the
      subtilisin family that is thought to be involved in invasive aspergillus
      infection of immunocompromised patients. When the structure of proteinase K was
      used to model this Aspergillus serine proteinase, Streptomyces subtilisin
      inhibitor (SSI) was predicted to be capable of binding to the serine proteinase.
      SSI purified from S. albogriseolus inhibited the serine proteinase with Ki of 1 x
      10(-9)M. This value is higher than that for subtilisin probably because the
      serine proteinase lacks the S(4-6) site that interacts with the P(4-6) site of
      SSI. A high level expression for SSI, established in Pichia pastoris, yielded
      0.5g of SSI per liter of culture medium. The secreted product was easily purified
      to homogeneity and biochemically characterized. The recombinant SSI showed a Ki
      of 1.1 x 10(-9) and 1 x 10(-8) for the serine proteinases from A. fumigatus and
      A. flavus, respectively.

PMID- 8645313
TI  - Plasmid-mediated degradation of o-phthalate and salicylate by a Moraxella sp.
AB  - A Moraxella sp. strain VG45 capable of utilizing o-phthalate and salicylate as a
      sole source of carbon and energy was isolated. The degradation of o-phthalate
      occurs via phthalate 4,5-dioxygenase, 4,5-dihydro-4,5-dihydroxyphthalate
      dehydrogenase, 4,5-dihydroxyphthalate decarboxylase and protocatechuate 4,5
      dioxygenase. Salicylate is degraded via salicylate 5-hydroxylase, gentisate 1,2
      dioxygenase and then by a glutathione-independent maleylpyruvate hydrolase.
      Further, a plasmid of app. 60 kilobase pairs (kb) is involved in the degradation
      of the o-phthalate and salicylate and the enzymes of these two pathways are
      independently regulated in strain VG45.

PMID- 8645314
TI  - cDNA cloning of IX/X-BP, a heterogeneous two-chain anticoagulant protein from
      snake venom.
AB  - IX/X-bp is an anticoagulant protein isolated from the venom of the habu snake
      (Trimeresurus flavoviridis). It is a heterogeneous two-chain protein linked by an
      interchain S-S bond. We prepared a cDNA library from the venom gland of the habu
      snake in the vector pSPORT1. cDNA clones containing the coding sequences for IX/X
      bp were isolated and sequenced to determine the structure of the proprotein of
      IX/X-bp. All cDNA clones containing coding sequences of either chain of IX/X-bp
      consisted of the 5'-end noncoding bases, the first ATG codon, a typical signal
      peptide sequence that was immediately followed by mature protein sequence that
      corresponded to one of the chains, a stop codon, the 3'-end noncoding bases, a
      polyadenylation signal, and a poly(A)+ region. These data indicate that the gene
      for each chain of the two-chain protein is transcribed and translated separately.

PMID- 8645315
TI  - Mechanisms-regulated platelet spreading after initial platelet contact with
      collagen.
AB  - In static condition, 6F1, an anti-glycoprotein Ia/IIa monoclonal antibody, almost
      completely prevented initial platelet adhesion to fibrillar collagen, but
      markedly lost its action with prolonged incubation. The platelet adhesion and
      spreading at the later stage were prevented by adding the peptide GRGDS, aspirin,
      and apyrase, suggesting that after initial recognition of platelet glycoprotein
      Ia/IIa with collagen the activation of glycoprotein IIb/IIIa and the release of
      thromboxane A2/ADP would promote platelet spreading, thus strengthening the
      stability of adhesion. Both initial platelet adhesion and platelet spreading were
      prevented by cytochalasin B, an inhibitor of actin polymerization. In contrast,
      BAPTA (an intracellular Ca2+ chelator) only inhibited platelet spreading.
      Inhibition of protein kinase C or protein tyrosine kinase by staurosporine or
      genistein, respectively, had only little effect on platelet adhesion. These data
      suggest that actin polymerization and intracellular Ca2+ mobilization are
      involved in the regulation of platelet spreading after initial platelet contact
      with collagen.

PMID- 8645316
TI  - Fibronectin harbors anticell adhesive activity.
AB  - Effect of fibronectin (FN) fragment derived from the carboxyl-terminal heparin
      binding (Hep 2) domain on cell adhesion was studied. A 30-kDa Hep 2 fragment
      showed no significant effect on adhesion of Mardin Darbyn caine kidney (MDCK)
      cells to FN substrate, whereas after exposure to urea, the Hep 2 fragment
      suppressed the MDCK cell adhesion to FN in an incompetitive fashion. This anti
      cell adhesive Hep 2 fragment preferentially inhibited the RGD (Arg-Gly-Asp)
      dependent cell adhesion to FN. No significant binding of the Hep 2 fragment with
      FN was detected. Additionally, data of flow cytometry showed the presence of
      specific binding site for the Hep 2 fragment on MDCK cell surface. These results
      indicate that the Hep 2 domain of FN has a cryptic molecular region having the
      anti-cell adhesive activity that is probably transduced by a putative cell
      surface receptor.

PMID- 8645317
TI  - Gene expression of pancreatic glutamic acid decarboxylase in the nonobese
      diabetic mouse.
AB  - The 65 kDa isoform of glutamic acid decarboxylase (GAD 65) is an autoantigen
      implicated in type I diabetes. We have developed a quantitative PCR method to
      measure GAD 65 mRNA in the pancreas of nonobese diabetic (NOD) mice. Two other
      nonautoimmune mouse strains were used as controls. In all mice, pancreatic GAD 65
      expression declined with age. In 5-week-old NOD mice, a clear difference was
      detected between males and females. This sexual dimorphism may explain the
      absence of tolerance to GAD 65 in the NOD female which could contribute to
      autoimmune destruction of beta cells in the pancreas and subsequent development
      of diabetes.

PMID- 8645318
TI  - Differential activation of the murine laminin B1 gene promoter by RAR alpha, ROR
      alpha, and AP-1.
AB  - RAR alpha, ROR alpha and AP-1 activated the transcription of the murine laminin
      B1 gene promoter, which consists of three core elements. Cotransfection
      experiments showed that AP-1-activated transcription is further stimulated by RAR
      alpha, but not by ROR alpha. Additionally, it was demonstrated by promoter
      mutagenesis that all of the three core elements are required for transactivation
      by RAR alpha and ROR alpha, while any one of them is dispensable for AP-1
      activated transcription. These results suggest that the modes of transactivation
      of the laminin B1 promoter are different among the three transactivators.

PMID- 8645319
TI  - Inhibitory effect of tannic acid on human immunodeficiency virus promoter
      activity induced by 12-O-tetra decanoylphorbol-13-acetate in Jurkat T-cells.
AB  - We investigated the effect of tannic acid, a potent inhibitor of poly(ADP-ribose)
      glycohydrolase, on human viral gene transcription, by using chloramphenicol
      acetyl transferase (CAT) assay experiments transfecting Jurkat cells with CAT
      reporter constructs that contain the promoter region of human immunodeficiency
      virus (HIV) or of human T-cell leukemia virus type I (HTLV-1). The activity of
      HIV promoter induced by treatment with 12-O-tetradecanoylphorbol-13-acetate was
      suppressed by the addition of tannic acid. On the other hand, HTLV-1 promoter
      activity induced by the p40(tax) expression plasmid was not affected by tannic
      acid treatment. Deletion analysis of the HIV promoter revealed that a 30-bp
      element located immediately upstream of NF-kappa B motifs was responsible for the
      suppressive effect of tannic acid. This was supported by the observations that
      the negative effect of tannic acid was introduced to tannic acid-non-responsive
      thymidine kinase promoter by the insertion of this element 5'-upstream of the
      promoter.

PMID- 8645320
TI  - Establishment and characterization of transgenic mice expressing human platelet
      glycoprotein Ib alpha.
AB  - The platelet glycoprotein (GP) Ib/IX/V is a hetero-oligomeric receptor complex
      for von Willebrand factor (vWF) and mediates platelet adhesion and aggregation
      under high shear stress conditions. It is composed of alpha and beta chain of GP
      Ib, GP IX, AND and GP V. To establish transgenic mice carrying human GP Ib alpha,
      we injected into mouse zygotes a 6 kb DNA fragment containing human GP Ib alpha
      gene that included entire coding sequence and putative promoter region. One
      hundred and thirteen offsprings were screened, and only one was found to express
      human GP Ib alpha protein and has passed the human GP Ib alpha gene as well as
      the expression of the gene to next generation. The expression of human GP Ib
      alpha in transgenic mice was limited to platelets and megakaryocytes.
      Glycocalicin, a proteolytic fragment of human GP Ib alpha found in normal human
      plasma, was not detected in transgenic mouse plasma. Human vWF in the presence of
      ristocetin supported agglutination of transgenic mouse platelets, but not of
      control mouse platelets.

PMID- 8645321
TI  - The Na-K-Cl cotransporters in the rat cochlea: RT-PCR and partial sequence
      analysis.
AB  - Nonsensory epithelial cells of the mammalian cochlea contribute to the production
      of the endolymph. The presence as well as the function of the Na-K-Cl
      cotransporter has been suggested, but not yet been proved. To identify the Na-K
      Cl cotransporter isoforms expressed in the cochlea, mRNA was extracted from the
      cochlear lateral wall. After reverse transcription, resulting cDNA was amplified
      by polymerase chain reaction (PCR) with primers specific for Na-K-Cl
      cotransporter isoforms. In the rat cochlear lateral wall, mRNA homologous to the
      mouse bumetanide-sensitive Na-K-Cl cotransporter (mBSC2) was detected. These
      results suggest that the basolateral localization of the cotransporter in the
      marginal cell is involved in the secretory process of the endolymph.

PMID- 8645322
TI  - Evidence that the PTH receptor binding site on PTHrP(1-34) can hinge at
      Arg19/Arg20.
AB  - The structure of the biologically-active mutant of human parathyroid hormone
      related protein (residues 1-34) containing an Ala substituted for a His in
      position 9 reveals two segments of helix extending from Glu4 to Lys13 and from
      Phe22 to Ala34, with a reverse turn from Gln16 to Arg19. The C-terminal region
      contains the bulk of the PTH receptor binding site in an amphipathic helix and is
      capable of hinging at Arg19/Arg20. The region of the molecule containing full
      antagonist properties is thus confined to the C-terminal helix.

PMID- 8645323
TI  - Cloning, sequencing, and expression of equinatoxin II.
AB  - Equinatoxin II (EqtII), a basic protein of 179 amino acids lacking cysteine
      residues, is the most abundant cytolysin isolated from the sea anemone Actinia
      equina. Its mode of action is still poorly understood. In order to initiate
      further structure-function studies by protein engineering, cDNA library was
      prepared from the whole animal and hybridized with a PCR-derived probe, deduced
      from the EqtII primary structure. The longest positive clone of 899 bp was shown
      to encode a 214 residue precursor of EqtII. The mature protein region was
      amplified by PCR, cloned into a T7 RNA polymerase-based expression vector and
      expressed in Escherichia coli. Recombinant toxin was isolated by a simple, two
      step isolation procedure including separation on CM-cellulose and gel filtration
      using an FPLC system. Its biochemical properties and hemolytic activity were
      practically indistinguishable from those of native toxin.

PMID- 8645324
TI  - Site-related differences in G-protein alpha subunit expression during
      adipogenesis in vitro: possible key role for Gq/11 alpha in the control of
      preadipocyte differentiation.
AB  - G protein alpha subunits were compared by immunoblotting in preadipocytes and
      adipocytes from rat subcutaneous and epididymal adipose tissue at three steps of
      adipogenesis. The most striking difference concerned the Gq/11 alpha subunits
      whose expression decreased during preadipocyte differentiation in subcutaneous
      cells while it remained constant in epididymal cells. The PKC inhibitor CGP 41251
      increased glycerol 3-phosphate dehydrogenase activity (EC 1.1.1.8), a late marker
      of differentiation, in epididymal preadipocytes but not in subcutaneous cells.
      There was no difference in the proliferation capacities between subcutaneous and
      epididymal preadipocytes: in both cells, CGP 41251 led to the same decrease in
      [(3)H]thymidine incorporation and, at confluence, the amounts of Gq/11 alpha
      subunits were equivalent. No major site-related difference was found in the
      amounts of Gs and Gi alpha during adipogenesis. Thus, compared to epididymal
      preadipocytes, the higher capacity of subcutaneous preadipocyte to differentiate
      seems to be correlated with the decrease in Gq/11 alpha expression and the
      decreased Gq/11 mediated PKC activation.

PMID- 8645325
TI  - Rapid identification of a novel chondrocyte-specific gene by RNA differential
      display.
AB  - Differential display or RNA fingerprinting is a novel approach for the isolation
      of differentially expressed genes. Here we describe the application of the RNA
      differential display technique to the analysis of the genes expressed in chick
      embryonic sternal chondrocytes, fibroblasts and BrdU-treated chondrocytes, which
      dedifferentiate back to mesenchymal-like phenotype. Parallel display among the
      genetags allowed us to isolate seven clones with differential expression
      patterns. Nucleotide sequencing of one of these clones revealed that it is a
      novel developmentally regulated gene with no significant homology to those
      reported previously. An RT-PCR analysis, using primers derived from this novel
      clone, confirmed the presence of the corresponding RNA only in the untreated
      chondrocytes, and not in the BrdU-treated chondrocytes or fibroblasts. This
      confirmation of the expression pattern given by the differential display
      reinforces the reliability of this approach. These results indicate that the
      differential display analysis provides a rapid and effective way to identify
      novel differentially expressed genes during chondrogenesis.

PMID- 8645326
TI  - G-protein modulation of neuronal class E (alpha 1E) calcium channel expressed in
      GH3 cells.
AB  - GH3 cell lines stably expressing alpha 1E channel were established and the
      modulation of this channel by G-protein through membrane-delimited pathways was
      studied. Alpha 1E channel expressed in GH3 cells showed slowing of activation and
      reduction of current amplitude by the application of carbachol or somatostatin.
      Both of these effects caused by these agents were pertussis toxin (PTX) sensitive
      and voltage dependent. Dialysis of the cell interior with GTP gamma S mimicked
      the action of these externally applied neurotransmitters, indicating that the
      alpha 1E channel is modulated by the PTX sensitive G-protein(s) through the
      membrane-delimited pathway but not by the PTX insensitive pathway that has been
      observed in alpha 1A channel expressed in GH3 cells. Thus different types of
      neuronal Ca2+ channels can be modulated not only by a similar mechanism but also
      by a different mechanism conferring a multilateral regulation of Ca2+ entry
      through these channels.

PMID- 8645328
TI  - Breast cancer cells cultured in a system of new design presecrete an
      extracellular matrix and proliferate within it without cell-cell adhesion.
AB  - Breast cancer cells, MCF-7 line, when cultured in microporous, hydrophobic
      polymer tubes, presecrete ribbon shaped, gauze-like extracellular matrices within
      which they then reside and proliferate without observable cell-cell adhesion and
      can do so in the complete absence of serum supplement in the culture media. This
      cell functioning is attributed to the direct access of oxygen to the cell
      attachment site.

PMID- 8645327
TI  - Nectrisine is a potent inhibitor of alpha-glucosidases, demonstrating activities
      similarly at enzyme and cellular levels.
AB  - Nectrisine, discovered as an immunomodulator, was found to inhibit alpha
      glucosidase, alpha- and beta-mannosidases, beta-glucosidase and beta-N
      acetylglucosaminidase, in that order of inhibition strength. Beta-Galactosidase,
      alpha-fucosidase, and neuraminidase were insensitive to this antibiotic. Also
      sensitive was the trimming glucosidase I which participates in the first step of
      modifying N-glycosidic oligosaccharide. Nectrisine demonstrated an inhibitory
      effect at the cellular level as strong as expected based on its action at enzyme
      levels; castanospermine and 1-deoxynojirimycin did not. Nectrisine and
      castanospermine suppressed syncytium formation and hemolytic activity in
      Newcastle disease virus (NDV)-infected BHK cells, without blocking the synthesis
      and cell-surface expression of HANA glycoprotein of NDV.

PMID- 8645329
TI  - Spontaneous and evoked oscillations of cytosolic calcium in the freshly prepared
      ciliary epithelial bilayer of the rabbit eye.
AB  - Under confocal microscopy, calcium imaging of the isolated secretory ciliary
      epithelium, especially the inner layer, non-pigmented epithelium (NPE), revealed
      spontaneous calcium oscillations in multiple patterns. Oscillations induced by
      stimulation of the muscarinic receptor have an onset that coincides with
      synthesis and release of InsP3. Caffeine (5 mM) induced a calcium transient and
      blocked spontaneous and (0.1 mM) muscarine induced oscillations. Thapsigargin (1
      microM) prevented a muscarinic response. Muscarine and caffeine induced
      transients have significantly greater amplitude in NPE than in PE (outer layer,
      pigmented epithelium). Calcium transients and frequencies of spontaneous
      oscillations are greater in NPE than PE. In NPE muscarine induced oscillations
      are observed with higher frequencies than the spontaneous ones: gamma-0.24 +/-
      0.05Hz (8) versus 0.08 +/- 0.01Hz (18). These repetitive responses, spontaneous
      and receptor coupled, reflect intracellular coding of information. A calcium
      signal may contribute to the regulation of aqueous humor formation.

PMID- 8645330
TI  - Targeting the epidermal growth factor receptor for therapy of carcinomas.
AB  - As a group, the carcinomas represent a substantial proportion of all human
      malignancies, but, with relatively few exceptions, current treatments are
      ineffective. Modification of existing chemotherapeutic agents has not led to
      significant improvements in the survival of carcinoma patients, and development
      of new therapeutic strategies is imperative. It is now becoming apparent that
      activation of the epidermal growth factor receptor (EGF-R) has much wider
      implications than a straightforward stimulation of cell division. The pleiotropic
      effects of EGF-R signalling may influence tumour behaviour and the response of
      carcinomas to treatment; these are important considerations for the development
      of new therapies that aim to exploit the expression or modulate the function of
      the EGF-R in these tumours.

PMID- 8645331
TI  - Maintenance of hepatic glutathione homeostasis and prevention of acetaminophen
      induced cataract in mice by L-cysteine prodrugs.
AB  - Administration of acetaminophen (ACP, 3.0 mmol/kg, i.p.) to beta-naphthoflavone
      induced C57 BL/6 mice led to the formation of bilateral cataracts within 8 hr
      with a 71% incidence. The hepatic glutathione (GSH) levels were reduced 99% and
      lenticular GSH levels reduced 42% in cataractous mice. Cataract formation was
      completely prevented by the co-administration of the L-cysteine prodrugs 2(R, S)
      methylthiazolidine-4(R)-carboxylic acid (MTCA) and 2(R, S)-n-propylthiazolidine
      4(R)-carboxylic acid (PTCA) in two divided i.p. doses totaling 4.5 mmol/kg. 2-Oxo
      L-thiazolidine-4-carboxylic acid (OTCA) was nearly equipotent, yielding only one
      cataract in 16 mice, but D-ribose-L-cysteine (RibCys, 5/16) and N-acetyl-L
      cysteine (NAC, 9/14) were much less effective. Hepatic and lenticular GSH were
      maintained at near normal levels by MTCA, PTCA and OTCA. These results suggest
      that maintenance of adequate cellular GSH levels in the presence of ACP protects
      against cataract induction.

PMID- 8645332
TI  - Gender-differential liver plasma membrane affinities in hepatic
      tetrabromosulfonephthalein (TBS) uptake.
AB  - The sex difference in the hepatic uptake of tetrabromosulfonephthalein (TBS) was
      investigated in male and female rats in two different experimental models. In the
      intact animal, the initial plasma disappearance constant rate, the initial
      velocity of uptake, and the plasma clearance of TBS were significantly higher in
      females than in males. In sinusoidal liver plasma membrane vesicles, kinetic
      parameters of TBS uptake were investigated in both sexes. The Km was lower in
      females than in males (5.5 +/- 0.4 vs 17 +/- 4 microM, P < 0.05), whereas Vmax
      showed comparable values (544 +/- 15 vs 581 +/- 60 nmol TBS/min/mg protein, mean
      +/- SD, NS, females and males, respectively). Collectively, these data indicate
      that the sex difference in hepatic uptake of TBS is located at the sinusoidal
      liver plasma membrane and is due to a greater affinity of the electrogenic
      transport system(s) in females.

PMID- 8645333
TI  - N-acetylcysteine protects lymphocytes from nitrogen mustard-induced apoptosis.
AB  - The ability of the antioxidant N-acetylcysteine to prevent apoptosis induced in
      lymphocytes by nitrogen mustard (HN2) was investigated. HN2 caused a
      concentration-dependent induction of apoptosis on C3H murine spleen cells, as
      identified by two criteria: morphological features revealed by microscopical
      observations and DNA fragmentation visualized by the characteristic "ladder"
      pattern observed upon agarose gel electrophoresis, as well as by hypodiploid DNA
      containing cells revealed by the flow cytometric analysis of propidium iodide
      labelled cells. The antioxidant N-acetylcysteine (NAC) was found to markedly
      reduce the occurrence of HN2-induced apoptosis in these cells. This protective
      effect will still obtained when NAC was added 30 min after HN2. In contrast, the
      pretreatment of spleen cells with this antioxidant did not provide any
      significant protection. We also showed that lymphocytes protected by NAC are
      still able to respond to a mitogenic stimulation. To gain some insight into the
      mechanisms underlying the cytoprotective action of NAC against HN2, we tested
      whether or not poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30), a nuclear enzyme
      that participates in the triggering of apoptosis induced by alkylating agents, is
      involved. We report that 6(5H)-phenanthridinone, a potent PARP inhibitor, did not
      affect the ability of NAC to prevent HN2-induced apoptosis under our experimental
      conditions. Thus, the exact mechanism by which NAC protects lymphocytes from HN2
      cytotoxicity has yet to be determined.

PMID- 8645334
TI  - The two isoforms of the 90-kDalton nucleolus organizer region autoantigen
      (upstream binding factor) bind with different avidity to DNA modified by the
      antitumor drug cisplatin.
AB  - It has been previously described that some proteins containing HMG boxes are able
      to bind more strongly to DNA modified with cis-diamminedichloroplatinum (II)
      (cisplatin) than to unmodified DNA. In the present study, we analyzed the
      interaction of cisplatin-modified DNA with the human autoantigen NOR-90 (UBF), a
      transcription factor that contains several HMG boxes. Using autoantibodies
      against NOR-90 to perform ELISA and immunoprecipitation, it was confirmed that
      NOR-90 (UBF) was able to bind cisplatin-modified DNA more avidly than unmodified
      DNA or trans-diamminedichloroplatinum(II) (transplatin) modified DNA. Moreover,
      by Southwestern, we observed that the 97 kDalton isoform of NOR-90 (UBF1) was
      able to bind cisplatin-modified DNA more strongly than the 94 kDalton isoform
      (UBF2); binding of unmodified DNA or transplatin-modified DNA was not detected
      with either isoform. Sera containing autoantibodies against NOR-90 did not
      inhibit, but increased the binding of NOR-90 to cisplatin-modified DNA.

PMID- 8645335
TI  - Distinct responses of mouse hepatic CYP enzymes to corn oil and peroxisome
      proliferators.
AB  - We studied the response of male DBA/2N mouse liver monooxygenases to acute (one
      day) and subacute (7-day) exposure to clofibrate, gemfibrozil, and corn oil. The
      day following a single treatment with clofibrate (200 mg/kg), coumarin 7
      hydroxylase (COH) activity decreased significantly (by 70%) with a concomitant
      decrease in the CYP2A4/5 protein and mRNA levels. The 7-day treatment schedule
      also decreased COH activity by only by 30%, though the levels of CYP2A4/5 protein
      and mRNA were still low. Treatment 1 and 7-day with clofibrate decreased 7
      pentoxyresorufin O-dealkylase (PROD) activity by 40%. No changes were seen in
      testosterone 15 alpha-hydroxylase (T15 alpha OH) activity after 1 day of
      treatment with clofibrate but, after 7 days, it was decreased by 50%. Clofibrate
      treatment had no significant effects on testosterone 7 alpha-hydroxylase (T7
      alpha OH), 7-ethoxyresorufin O-deethylase (EROD), or benzphetamine N-demethylase
      (BZDM) activities. Gemfibrozil (200 mg/kg) did not alter COH activity or CYP2A4/5
      protein content after a single treatment, but a slight decrease was seen in the
      mRNA level. Treatment for 7 days significantly increased (2.5-fold) the activity
      and mRNA content but the amount of protein remained unchanged. Gemfibrozil
      enhanced (2-2.7-fold PROD and EROD (2-2.5-fold) activities by both treatments,
      whereas T15 alpha OH, T7 alpha OH, or BZDM activities were not significantly
      affected. Treatment with corn oil for 7 days significantly decreased (65%) COH
      activity and CYP2A4/5 protein and mRNA levels. PROD (55%) and T15 alpha OH (65%)
      activities were significantly decreased even after a single dose although
      injection for 7 days had no effect. Neither of the corn oil schedules had any
      marked effect on T7 alpha OH, EROD, or BZDM activities. These results
      demonstrate: 1. a decrease in the expression of CYP2A4/5 gene by clofibrate and
      corn oil; 2. substantial differences within the CYP2A subfamily in their
      responses to corn oil, clofibrate, and gemfibrozil; and 3. distinct responses of
      other xenobiotic metabolizing CYP subfamily enzymes to clofibrate and
      gemfibrozil.

PMID- 8645336
TI  - Pharmacological characterization of the cloned human 5-hydroxytryptamine
      transporter.
AB  - We performed an extensive pharmacological study of the 5-hydroxytryptamine (5-HT)
      transporter polypeptide cloned from human placenta. Transient expression of this
      630 amino acid polypeptide in HeLa cells led to saturable 5-HT uptake activity
      (Km = 858 nM). This 5-HT uptake was blocked by selective 5-HT inhibitors, such as
      citalopram, litoxetine, sertraline, and indalpine, with Ki values in the low
      nanomolar range, and it exhibited a pharmacological profile similar to that found
      in rat brain. [3H]Citalopram binding to membrane preparations of the transfected
      cells occurred to a single class of high-affinity binding sites (Kd = 5.3 nM) and
      was potently inhibited by selective 5-HT uptake inhibitors. The pharmacological
      profile of [3H]citalopram binding to these transfected cells showed a good
      correlation with that of [3H]paroxetine binding to the rat cerebral cortical 5-HT
      transporter (r = 0.79). These data confirm that the full pharmacological
      characteristics of the 5-HT transport system are conferred by the expression of
      the 630 amino acid human placental 5-HT transporter polypeptide. [3H]Citalopram
      should, therefore, provide a useful probe for more insights at a molecular level
      into this cloned 5-HT transport system.

PMID- 8645337
TI  - Inhibition of Na+/H+ exchanger activity by an alkyl-lysophospholipid analogue in
      a human breast cancer cell line.
AB  - The mechanisms by which ET-18-OCH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3 
      phosphocholine) and other analogues of alkyl-lysophospholipids exert their
      antineoplastic effects are not yet fully elucidated. Possible interference with
      mechanisms involving intracellular pH (pHi) regulation was examined by measuring
      the effect of ET-18-OCH3 on the activity of the Na+/H+ exchanger in the breast
      cancer-derived cell line MCF-7. When ET-18-OCH3 was added to culture medium at 10
      muM (determined as a noncytotoxic but cytostatic concentration), it led to an
      intracellular acidification (0.15 pH unit). It also decreased the rate of pHi
      recovery by Na+/H+ exchange following artificial acidification. Kinetic
      parameters of the exchange indicated that this was due to a decrease in the
      affinity of the exchanger for both transported ions, rather than to a decrease in
      the number of exchanger proteins in the membrane (same maximal efflux rate for
      treated and untreated cells). These results suggest that Na+/H+ exchanger
      inhibition and subsequent cytoplasmic acidification participate in the mode of
      action of ET-18-OCH3, and could be used for modulation of tumor-cell
      chemosensitivity or their subsequent commitment into programmed cell death.

PMID- 8645338
TI  - Changes in glucose-6-phosphate dehydrogenase and malic enzyme gene expression in
      acute hepatic injury induced by thioacetamide.
AB  - NADPH-generating enzymes, glucose-6-phosphate dehydrogenase (G6PDH), and malic
      enzyme (ME) were studied in rat liver when necrosis and regeneration were induced
      by a single sublethal dose of thioacetamide (6.6 mmol/kg). Both enzyme activities
      decreased sharply at 12-24 hr of treatment and increased thereafter. These
      biphasic changes are related to the sequential processes of liver injury and
      hepatocellular regeneration. Expression of mRNA for G6PDH decreased at 12 hr
      following thioacetamide injection and increased during liver regeneration,
      reaching its highest levels of expression at 48 hr (247% of the control),
      parallel to the peak of DNA synthesis. Expression of ME decreased at 12-24 hr and
      increased during the postnecrotic regenerating process, reaching only half of the
      control value at 96 hr. A relationship between mRNA G6PDH gene expression,
      oxidative stress (detected by the GSH/GSSG ratio and malondialdehyde (MDA)
      concentration), and DNA synthesis is proposed.

PMID- 8645339
TI  - Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate
      infusions during consolidation treatment of acute lymphoblastic leukemia.
AB  - 6-mercaptopurine (6MP) cytotoxicity is caused by thioguanine and
      methylthioinosine nucleotides. Thiopurine methylation occurs to a large extent in
      vivo and in vitro. In this reaction, S-adenosyl-L-methionine (AdoMet), produced
      from methionine and ATP, is converted into S-adenosyl-L-homocysteine (AdoHcy)
      which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine
      into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts,
      AdoMet: AdoHcy ratio and DNA methylation decrease after incubation with 6MP. The
      aim of the present study was to investigate the influence of high-dose 6MP on the
      methylation capacity in children with acute lymphoblastic leukemia. Five patients
      received 4 courses with high-dose intravenous MTX (5' g.m-2 in 24 hr) immediately
      followed by high-dose 6MP (1300 mg.m-2 in 24 hr). Five control patients received
      high-dose MTX and oral 6MP (25 mg.m -2 daily for 8 weeks). Leucovorin rescue was
      started at 36 hr in both groups. In the intravenous 6MP group, 6
      methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were
      detectable in plasma in concentrations of 0.3-2.6 muM (6MP steady state levels:
      11.6 muM). In red blood cells, mean methylthioinosine nucleotide levels were one
      third of those of ATP (13.1 nmol/10(8)). AdoHcy levels (10 pmol/10(8)) remained
      constant in both groups and AdoMet was not detectable ( < 20 pmol/10(8)). In both
      groups, plasma homocysteine increased and methionine decreased following
      administration of MTX. The delay in the recovery of methionine in the intravenous
      6MP group after MTX infusion is probably the result of an increased demand on
      methyl groups during 6MP infusion.

PMID- 8645340
TI  - Inactivation of mouse epidermal 12-lipoxygenase by anthralin--implications for
      the role of oxygen radicals.
AB  - In activation of 12-lipoxygenase (12-LO) in mouse epidermal homogenate by the
      antipsoriatic drug anthralin has been studied in detail. In view of the chemical
      instability of anthralin in a physiological buffer, the biological effects
      ascribed to the molecule itself may be related to some of its breakdown products.
      However, the inhibitory activity could not be attributed to the known stable
      oxidation product of anthralin, danthron, which did not decrease (12-LO activity.
      Addition of the antioxidants 2,6-di-tert-butyl-4-methylphenol (BHT) or beta
      carotene, or the hydroxyl radical scavenger sodium benzoate, protected against
      anthralin-mediated 12-LO inactivation, suggesting that pro-oxidant species
      derived from anthralin play a key role in the inhibitory action. Even though
      inhibitory effects of anthralin against catalase and superoxide dismutase (SOD)
      have been observed under the conditions applied in this study, these antioxidant
      enzymes also partially prevented the inhibition of 12-LO by anthralin when added
      to the incubation mixtures. Control experiments without anthralin revealed that
      the oxygen radical scavengers and antioxidant enzymes, themselves, did not
      appreciably influence epidermal 12-LO activity. A mechanism underlying the
      inactivation of epidermal 12-LO by anthralin is proposed, which involves active
      oxygen species formed during the auto-oxidation of the drug.

PMID- 8645341
TI  - Inhibition of proliferation but not erythroid differentiation of J2E cells by
      rapamycin.
AB  - During erythropoiesis, replication and maturation are tightly coupled processes.
      Here, we show that the immunosuppressant rapamycin inhibited basal- as well as
      erythropoietin-stimulated proliferation of the erythroid cell line J2E. In
      addition, it enhanced the antiproliferative effect of sodium butyrate. Although
      rapamycin suppressed erythroid cell division, it did not affect terminal
      differentiation induced by erythropoietin or sodium butyrate. The proliferative
      status of J2E cells correlated well with the activity of the ribosomal S6 kinase
      p70S6k, an enzyme effectively blocked by rapamycin. It was concluded from this
      study that erythroid maturation proceeded normally despite the rapamycin-induced
      inhibition of mitosis and of p70S6k activity. These data provide further evidence
      that separate signalling pathways for proliferation and differentiation exist in
      erythroid cells.

PMID- 8645342
TI  - Characterization of the in vivo inhibition of rat hepatic microsomal aldehyde
      dehydrogenase activity by metyrapone.
AB  - Microsomal aldehyde dehydrogenase (mALDH; EC 1.2.1.3) has been proposed to
      catalyze the oxidation of various aldehydic products of lipid peroxidation, but
      the regulation of the enzyme has not been characterized. Metyrapone
      administration (100 mg/kg, i.p.) produced a rapid decline in the rates of mALDH
      catalyzed decanal dehydrogenation; other xenobiotics were generally without
      effect. Thus, a 22% decrease in activity was detected 2 hr following metyrapone
      administration, and 52% of the activity remained at 6 hr. The decrease in
      microsomal decanal dehydrogenation was also dose-dependent with 70, 43, and 12%
      of the control activity remaining following pretreatment with 25, 100, and 250
      mg/kg metyrapone, respectively. This disease in microsomal decanal dehydrogenase
      activity occurred without a change in mALDH immunoreactive protein, and
      metyrapone did not inhibit the activity in vitro. The kinetic analysis revealed
      similar decreases in the maximal reaction velocities (Vmax) for both decanal and
      NAD in the metyrapone-treated group (200 +/- 10 and 190 +/- 20 nmol NADH
      produced/min/mg protein, respectively) compared with the untreated group (330 +/-
      10 and 350 +/- 20 nmol NADH produced/min/mg protein, respectively), but the
      Michaelis constants (Km) were unchanged. These data are consistent with the in
      vivo inactivation of a portion of the mALDH enzyme. A possible consequence of the
      in vivo inhibition of this enzyme by metyrapone could be the accumulation of
      toxic aldehydes in the vicinity of the microsomal membrane following lipid
      peroxidation.

PMID- 8645344
TI  - Modulation of binding characteristics of peripheral benzodiazepine receptors in
      vitamin A-deficient guinea pig lung.
AB  - Both vitamin A and peripheral benzodiazepine receptors (PBRs) are involved in the
      control of cell proliferation and differentiation. The objective of this study
      was to determine whether vitamin A deficiency causes any modulation in the
      binding characteristics of the PBRs. Forty-five weanling guinea pigs were divided
      into three groups (control, pair-fed control, and vitamin A-deficient). Vitamin A
      deficiency status was achieved after 90 days of feeding. It caused atelectasis,
      hyperplasia and metaplasia of alveolar epithelium, acute inflammation of the
      tracheobronchial tree, and a significant increase in the number of alveolar type
      II cells. In comparison to the control and pair-fed control groups, the lung of
      vitamin A-deficient animals had 40.6 and 42.8% less PBR density, respectively.
      There was no significant difference in the equilibrium dissociation constant (KD)
      of PBRs between the control and the pair-fed control groups, whereas the KD value
      was 77.7 and 60% higher in the vitamin A-deficient groups than in the control and
      the pair-fed control groups, respectively. Furthermore, vitamin A-deficiency
      caused a decrease in the binding capacity of PBRs in both nuclear and
      mitochondrial fractions. These results may suggest a close functional
      relationship between vitamin A and PBRs.

PMID- 8645343
TI  - Similarities and differences in the glucuronidation of estradiol and estrone by
      UDP-glucuronosyltransferase in liver microsomes from male and female rats.
AB  - In this study, we evaluated the effects of pH, in vitro inhibitors, in vivo
      enzyme inducers, age, and sex on the glucuronidation of estradiol and estrone by
      rat liver microsomes. Although the pH dependence curves for the glucuronidation
      of estradiol and estrone were similar, the pH dependence curves for these
      estrogens by liver microsomes from adult male rats were very different from those
      by liver microsomes from adult female rats. These results suggest that liver
      microsomes from adult male and have different estrogen glucuronosyltransferases.
      Liver microsomes from immature or adult female rats catalyzed the glucuronidation
      of estrone and estradiol more rapidly than liver microsomes from age-matched male
      rats. Intraperitoneal injection of sodium phenobarbital (75 mg/kg/day) or
      dexamethasone (75 mg/kg/day) into immature or adult male or female rats for 3-4
      days resulted in a 33-58% increase in liver microsomal glucuronosyltransferase
      activity for estradiol, but there was little or no stimulatory effect on
      glucuronosyltransferase activity for estrone. Treatment of immature or adult male
      or female rats with 3-methylcholanthrene (25 mg/kg/day) for 3-4 days did not
      stimulate liver microsomal glucuronosyltransferase activity for estradiol or
      estrone, but the glucuronidation of 4-nitrophenol was stimulated several-fold.
      The in vitro addition of testosterone had a strong inhibitory effect on the
      glucuronidation of estradiol and estrone by liver microsomes from both adult male
      and female rats, whereas the in vitro addition of 4-nitrophenol had a slightly
      greater inhibitory effect on the glucuronidation of estradiol and estrone by
      adult male liver microsomes than by adult female liver microsomes. In conclusion,
      our results suggest that male and female rat livers have different estrogen
      glucuronosyltransferases and that the glucuronidation of estradiol, estrone, and
      4-nitrophenol is catalyzed by different glucuronosyltransferases that are under
      different regulatory control.

PMID- 8645345
TI  - The effect of a thiadiazinone derived Ca2+ sensitizer on the responsiveness of
      Mg(2+)-ATPase to Ca2+ in myofibrils isolated from stunned and nonstunned porcine
      and human myocardium.
AB  - Previously, we showed, in an in situ porcine model, that the thiadiazinone
      derivative [+]EMD 60263, a putative Ca2+ sensitizer with minimal
      phosphodiesterase III inhibitory properties, increased contractility more
      profoundly in stunned than in nonstunned myocardium. The aim of the present
      investigation was to study the mechanism of action by determining the in vitro
      effects of [+]EMD 60263 on the Ca2+ responsiveness of the Mg(2+)-dependent
      ATPases of myofibrils and sarcoplasmic reticulum membrane vesicles, isolated from
      normal ventricle of swine and hypertrophic septum of cardiomyopathic patients.
      Contamination of the myofibrils with sarcoplasmic reticulum membranes was
      excluded by testing the effect of the sarcoplasmic reticulum Ca(2+)-pumping
      ATPase inhibitor thapsigargin. The plasma concentrations at which [+]EMD 60263
      exerted its inotropic effect in the in situ porcine model were found to be
      submicromolar. [+]EMD 60263 stimulated concentration-dependently (1-10 microM)
      the submaximally activated Mg(2+)-ATPases (at pCa 6.1) of pig heart myofibrils.
      [+]EMD 60263 (10 microM) shifted the pCa50 of porcine myofibrillar Ca(2+)
      stimulated, Mg(2+)-dependent ATPase from 6.00 +/- 0.05 to 6.67 +/- 0.05, whereas
      the [-]enantiomer EMD 60264 had no significant effect. Although the effect was
      much less at 1 and 3 microM, [+]EMD 60263 (10 microM) also stimulated maximal
      myofibrillar Mg(2+)-ATPase activity. The Hill coefficient, reflecting the
      steepness of the fitted pCa/Mg(2+)-ATPase curve at half-maximal activation, was
      not affected by [+]EMD 60263 (10 microM). [+]EMD 60263 (10 microM) had no effect
      on sarcoplasmic reticulum Ca(2+)-stimulated, Mg(2+)-dependent ATPase from swine
      heart. The thiadiazinone derivative [+]EMD 57033 (10 microM), but not its [
      ]enantiomer EMD 57439, had similar, although less potent, effects on pig heart
      myofibrillar Mg(2+)-ATPase activity as compared to [+]EMD 60263. [+]EMD 60263 (3
      microM) produced a significantly larger leftward shift of the pCa2+/Mg(2+)-ATPase
      activity curve of myofibrils isolated from the stunned compared to the adjacent
      nonstunned myocardium (Delta pCa50s caused by the presence of [+]EMD 60263
      amounted to +0.57 +/- 0.04 and +0.42 +/- 0.05, respectively) in the in situ
      porcine model. The effects of [+]EMD 60263 on myofibrillar Mg(2+)-ATPase of
      hypertrophic human heart were identical to those observed with porcine heart
      myofibrils. The results indicate that the positive inotropic action of [+]EMD
      60263 observed in the in situ porcine model of stunned myocardium may be
      primarily due to myofilament sensitization to Ca2+, and that this compound may
      have a similar action on diseased human myocardium.

PMID- 8645346
TI  - Retrovirus-mediated transfer of the human O6-methylguanine-DNA methyltransferase
      gene into a murine hematopoietic stem cell line and resistance to the toxic
      effects of certain alkylating agents.
AB  - O6-Methylguanine-DNA methyltransferase (MGMT) is an important DNA repair protein
      that plays a key role in cancer chemotherapy by alkylating agents such as
      carmustine (BCNU) and Dacarbazine (DTIC). Therapy by BCNU and DTIC is reduced by
      dose-limiting hematological toxicity as a result of low MGMT repair activity in
      bone marrow cells. In this study, we have constructed a Moloney murine leukemia
      virus retroviral vector containing the human mgmt gene. High-titer retrovirus
      producer cells lines have been generated. Retroviral-mediated transfer of the
      human mgmt gene into murine multi-potent hematopoietic stem cells, FDCP-1,
      resulted in the expression of a high level of MGMT activity. In comparison with
      the control cells that were transduced with the parent vector, the MGMT
      expressing clones were considerably more resistant to the cytotoxicity of the
      methylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine, N-nitroso-N
      methyl-urea, and temozolomide, as well as the chloroethylating agents 1-(2
      chloroethyl)-1-nitrosourea and BCNU. The protection provided by MGMT could be
      eliminated by the MGMT inactivator O6-benzylguanine. Thus, the principal lethal
      lesions produced by these alkylating agents in the murine hematopoietic stem
      cells and the MGMT deficiency in these cells can be complemented by retroviral
      mediated gene transduction.

PMID- 8645348
TI  - Effects of salvianolic acid A on oxygen radicals released by rat neutrophils and
      on neutrophil function.
AB  - Salvianolic acid A (Sai A) has demonstrated potent antioxidant activity in
      previous studies. In the present study, the effects of Sai A on oxygen radicals
      released by rat neutrophils and on neutrophil function were investigated.
      Superoxide anion assayed by the nitroblue tetrazolium test and hydrogen peroxide
      detected with redox of scopoletin were scavenged concentration dependently by Sai
      A in n-formyl-methionyl-leucylphenylalanine (fMLP)- and phorbol myristate acetate
      (PMA)-stimulated rat neutrophils. Hydroxyl radicals generated in PMA-stimulated
      neutrophils, measured by HPLC, also were scavenged significantly by Sai A,
      whereas Sai A showed no significant effects on chemotaxis toward fMLP and
      phagocytosis of latex beads by rat neutrophils. In addition, the intracellular
      free calcium and cyclic nucleotide levels of neutrophils, when stimulated by
      fMLP, were not affected by Sai A. These results suggest that Sai A could
      significantly scavenge oxygen radicals released by activated neutrophils without
      affecting their functional ability.

PMID- 8645347
TI  - Differential effects of phorbol ester on apoptosis in HL-60 promyelocytic
      leukemia cells.
AB  - The role of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate
      (PMA) in apoptosis of HL-60 cells was investigated. PMA inhibited DNA
      fragmentation induced by thapsigargin (TG) and 4-bromo-calcium ionophore (Br
      A23187). The inhibitory effect of PMA was concentration-related and was abolished
      by a specific PKC inhibitor, bisindolylmaleimide (GF109203X. In addition TG
      induced apoptosis was decreased in cells in which PKC activity was down-regulated
      by long-term pretreatment with PMA. These results indicate that PKC activation by
      PMA inhibits HL-60 cell apoptosis induced by TG and Br-A23187, and that this
      inhibition is not influenced by the down-regulation of PKC. However, PMA did not
      inhibit DNA fragmentation induced by 1-beta-D-arabinofuranosylcytosine (Ara-C)
      and cycloheximide. PMA suppressed TG- or Br-A23187. Our results indicate that PKC
      participates in the regulation of apoptosis only by some pathways. Down
      regulation of PKC is not responsible for the diverse effects of PKC activators on
      apoptosis. The effect of a PKC modulator on apoptosis is dependent upon
      interaction with individual apoptotic stimulus.

PMID- 8645349
TI  - Pharmacological and molecular characterization of the neurotensin receptor
      expressed in Sf9 cells.
AB  - The rat neurotensin receptor was expressed in Spodoptera frugiperda insect (Sf9)
      cells using infection with a recombinant baculovirus. Immunoblot experiments
      performed with an antibody raised against the C-terminus of the receptor showed
      major bands at 47 (corresponding to the unglycosylated receptor protein) and 50
      kDa, and minor bands at 65 and 36 kDa. The expressed receptor bound 125I
      neurotensin with high affinity, was coupled to endogenous G-proteins, and agonist
      induced inositol phosphate production was observed at early times after
      infection. These results show that the rat neurotensin receptor retains
      functional properties when expressed in the heterologous insect cell system.

PMID- 8645350
TI  - Skeletal muscle fiber distribution influences serum high-density lipoprotein
      cholesterol level.
AB  - Earlier we have shown a significant positive association between muscle fiber
      distribution, i.e. percentage of slow-twitch (ST) fibers in the vastus lateralis
      muscle, and serum high-density lipoprotein cholesterol (HDL-C) level. This
      association may be due to the fact that ST fibers have a high capacity for
      oxidative energy metabolism and a high number of surrounding capillaries. These
      fibers have a high capacity to metabolize fatty acids liberated by lipoprotein
      lipase (LPL) from triglyceride-rich lipoproteins. This in turn elevates serum HDL
      C levels. Thus, a high percentage of ST fibers (ST-%) may be one factor having a
      beneficial effect on serum HDL-C concentration. A high ST-% may also increase the
      likelihood that a person will become involved in an endurance type of physical
      activity, which further increases serum HDL-C concentration by increasing further
      LPL activity in the capillary bed of skeletal muscle. In this paper we present a
      hypothetical background of the role that ST fibers may have on serum lipid and
      lipoprotein profile.

PMID- 8645351
TI  - Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human
      hepatoma HepG2 cells.
AB  - It has been suggested previously that lipoprotein lipase may act as a ligand to
      enhance binding and uptake of lipoprotein particles. In the present study we have
      examined the capacity of bovine milk lipoprotein lipase to induce intracellular
      accumulation of triglyceride and cholesterol ester by VLDL (Sr 60-400) isolated
      from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent
      of its lipolytic activity. We have also attempted to elucidate the cellular
      receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in
      intracellular triglyceride and cholesterol ester were dependent on the presence
      of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride
      mass by 301% +/- 28% (P < 0.0005) and cholesterol ester mass by 176% +/- 12% (P <
      0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and
      cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus
      lipase could replace LPL and cause equivalent increases in intracellular
      triglyceride and cholesterol ester (472% +/- 61%(P < 0.005) and 202% +/- 25% (P <
      0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also
      caused equivalent increases (274% +/- 18%(P < 0.01) and 177% +/- 12% (P < 0.005)
      for triglyceride and cholesterol ester). LDL also caused increases in
      intracellular cholesterol ester (189% +/- 20%(P < 0.005)), although three times
      more LDL cholesterol had to be added to achieve the same effect. These LDL
      induced increases were effectively blocked by monoclonal antibodies directed
      against the B,E receptor binding domains of apo B (-97% +/- 13% (P < 0.0005) with
      anti-apo B 5E11 and -68% +/- 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E
      receptor antibodies (-77% +/- 7% (P < 0.01) antibody C7). These same antibodies
      had little effect on the HTg-VLDL+LPL-induced increases in cholesterol ester
      (+21%, +15% and -22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E
      antibodies also had no effect on LDL-mediated increases in intracellular
      cholesterol ester, but had a small and significant effect on VLDL-mediated
      increases in cholesterol ester. However, heparin, which interferes with cell
      surface proteoglycan interaction, was very effective at blocking HTg-VLDL
      mediated increases in cholesterol ester in the presence of LPL (-86% +/- 8% P <
      0.0005). Heparin was also effective in the presence of Rhizopus lipase (-79%) or
      lipolyzed re-isolated HTg-VLDL (-95%). These results suggest that lipoprotein
      lipase may enhance the uptake process beyond its role in lipolytic remodelling
      but does not appear to be an absolute requirement. In contrast, heparin had no
      effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which
      inhibits interaction with the low density lipoprotein receptor-related protein
      (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular
      cholesterol ester (-95% +/- 6%, P < 0.01). However, there was no effect of either
      heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell
      surface heparin sulphate may facilitate intracellular lipid acquisition by
      providing a stabilizing bridge with the lipoproteins and enhance uptake through
      receptor-mediated processes such as LRP.

PMID- 8645352
TI  - Distribution of cell replication and apoptosis in atherosclerotic plaques of
      cholesterol-fed rabbits.
AB  - In human atherosclerosis the development of a cell-poor lipid-rich core is an
      important feature of atheromatous plaque formation. The core is characterized by
      extracellular lipid deposition, cholesterol crystals and cell death and is
      situated in the deep layer of the plaque. The aim of the present study was to
      localize apoptotic cell death and cell replication in atherosclerotic plaques of
      cholesterol-fed rabbits in order to examine the hypothesis that core formation is
      a consequence of an imbalance between cell replication and apoptosis. New Zealand
      White male rabbits were fed a diet supplemented with 0.3% cholesterol for 16 (n =
      5) and 27 weeks (n = 9). Cell replication and cell types were demonstrated by
      immunohistochemistry and apoptotic cell death was demonstrated by DNA in situ end
      labeling (ISEL) and transmission electron microscopy. Quantification was done
      using a colour image analysis system. The plaques showed a clear distinction
      between a luminal layer composed of numerous lipid-rich foam cells of macrophage
      origin and a deep layer which was fibrous, containing extracellular lipid
      deposits and few smooth muscle cells. Cell replication (expressed as percentage
      of total number of nuclei) in the superficial layer was higher then in the deep
      layer at both 16 (5.1 +/- 1.8% vs. 1.2 +/- 0.8%) and 27 weeks (11.3 +/- 2.1% vs.
      4.4 +/- 1.0%). This was also the case for the total number of nuclei per 50000
      microns2 cross-sectional intimal area (numerical density): 235 +/- 13 vs. 147 +/-
      7 at 16 weeks and 130 +/- 10 vs. 89 +/- 11 at 27 weeks. Apoptotic cell death
      (expressed as percentage of total number of nuclei) was low and there was no
      difference between the superficial and the deep layers of the plaques (0.8% +/-
      0.2% vs. 0.4% +/- 0.2% at 16 weeks and 0.6 +/- 0.2% vs. 1.7% +/- 0.6% at 27
      weeks). Our results indicate that the control of cell number in superficial vs.
      deep regions of the plaque is mainly a consequence of differences in cell
      replication. This may be due to a gradient of endothelial and plasma-derived
      growth factors. Cells can disappear by apoptosis, albeit at a relatively low
      level, throughout the lesion. This process may contribute to the pronounced cell
      loss in more advanced human atherosclerotic plaques, setting the base for plaque
      rupture.

PMID- 8645353
TI  - Dose-response relationship between peripheral vascular disease and ingested
      inorganic arsenic among residents in blackfoot disease endemic villages in
      Taiwan.
AB  - The purpose of this study was to examine the correlation between previous arsenic
      exposure and peripheral vascular disease after stopping consumption of high
      arsenic artesian well water for more than two decades in blackfoot disease
      endemic villages in Taiwan. A total of 582 adults (263 men and 319 women, aged
      52.6 +/- 10.6 years) living in these villages underwent Doppler ultrasound
      measurement of systolic pressures on bilateral ankle (posterior tibial and dorsal
      pedal) and brachial arteries and estimation for long-term arsenic exposure. The
      diagnosis of peripheral vascular disease was based on an ankle-brachial index
      (the ratio between ankle and brachial systolic pressures) <0.90 on either side.
      Three indices of arsenic exposure were estimated: (1) duration of living in
      blackfoot disease endemic villages; (2) duration of artesian well water
      consumption; and (3) cumulative arsenic exposure in mg/l-years based on the
      detailed history of residential addresses and artesian well water consumption and
      the arsenic concentration in artesian well water. Multiple logistic regression
      analysis was used to assess the association between peripheral vascular disease
      and arsenic exposure. A dose-response relation was observed between the
      prevalence of peripheral vascular disease and the long-term arsenic exposure. The
      odds ratios (95% confidence intervals) after adjustment for age, sex, body mass
      index, cigarette smoking, serum cholesterol and triglyceride levels, diabetes
      mellitus and hypertension were 2.77 (0.84-9.14), and 4.28 (1.26-14.54) for those
      who had cumulative arsenic exposure of 0.1-19.9 and > or = 20.0 mg/l-years,
      respectively, compared with those who were not exposed. This study suggests a
      close relation between long-term arsenic exposure and peripheral vascular disease
      in blackfoot disease endemic villages in Taiwan after stopping consumption of
      artesian well water.

PMID- 8645354
TI  - Impaired mobilisation of cholesterol from stored cholesteryl esters in human (THP
      1) macrophages.
AB  - The formation of macrophage-derived foam cells is central to the development of
      fatty streaks within the arterial wall, and to the progression of
      atherosclerosis. The unregulated deposition of cholesteryl esters, as lipid
      droplets within the cytoplasm of these cells, is responsible for the formation of
      foam cells; this process is thought to be regulated by the balance between
      cholesterol esterification, by acyl CoA:cholesterol acyltransferase (ACAT), and
      hydrolysis, by neutral cholesteryl ester hydrolase (nCEH). This study examines
      the importance of the balance between these two enzymes in determining the efflux
      of cholesterol from human (THP-1) macrophages. The presence of modified
      lipoprotein, or of 25-hydroxycholesterol, markedly increased cholesterol
      esterification in these cells and these effects were potently inhibited by the
      presence of the ACAT inhibitor, 447C88. In the absence of HDL, an acceptor
      particle, there was little or no hydrolysis of the cholesteryl ester pool and no
      efflux of cholesterol to the extracellular milieu; addition of HDL led to a
      partial (36%) reduction in cholesteryl esters, an effect which was not enhanced
      by the inhibition of ACAT. This suggested that the stored cholesteryl esters in
      human (THP-1) macrophages, unlike those in mouse peritoneal macrophages, were
      relatively resistant to removal by efflux to HDL. Efflux of newly synthesised
      free cholesterol from these macrophages was increased by HDL in a saturable
      manner, suggesting that the lack of reduction of stored cholesteryl esters was
      due to impaired mobilisation of cholesteryl esters to free cholesterol via nCEH.
      Indeed, nCEH activity in these macrophages was much lower than in mouse
      peritoneal macrophages, and appeared to be down-regulated in the presence of 25
      hydroxycholesterol or modified lipoproteins; this loss of nCEH activity was
      prevented by the ACAT inhibitor 447C88. The efflux of stored cholesteryl esters
      from THP-1 macrophages therefore appears to be limited by the activity of nCEH.

PMID- 8645355
TI  - Platelet trans fatty acids in relation to angiographically assessed coronary
      artery disease.
AB  - Epidemiological and metabolic studies indicate that a higher intake of trans
      fatty acids (TFA) may be associated with increased risk of coronary heart disease
      (CHD). In a cross-sectional study of patients who underwent coronary angiography,
      the relationships between TFAs, measured in platelets, and the degree of coronary
      artery disease (CAD) were examined in 191 non-diabetic patients (134 men and 57
      women). The degree of CAD was quantified by using an angiographic scoring system
      developed to provide an estimate of the extent of coronary atherosclerosis: an
      "extent score'. The TFA composition of platelets, including palmitelaidic (16:1
      omega 7t), elaidic (18:1 omega 9t), trans-10-octadecaenoic acid (18:1 omega 8t),
      trans vaccenic (18:1 omega 7t), trans-12-octadecaenoic acid (18:1 omega 6t) and
      linoelaidic (18:2 omega 6tt) acids, was measured by using gas chromatography and
      quantified as a percentage of total fatty acids. After adjustment for established
      CHD risk indicators, including age, gender, cigarette smoking, hypertension and
      serum total cholesterol concentration, elaidic acid (P = 0.0300) and trans-10
      octadecaenoic acid (P = 0.0434) were positively associated with the extent score
      of CAD. The adjusted associations between other individual TFAs, including
      palmitelaidic acid (P = 0.1189), vaccenic acid (P = 0.7651), trans-12
      octadecaenoic acid (P = 0.0582) and linoelaidic acid (P = 0.8793), and the extent
      score were not significant. The results of this study, therefore, provide
      evidence for an association between particular platelet TFAs and the degree of
      CAD in the patient population studied.

PMID- 8645357
TI  - Postprandial cholesteryl ester transfer and high density lipoprotein composition
      in normotriglyceridemic non-insulin-dependent diabetic patients.
AB  - Altered postprandial HDL metabolism is a possible cause of defective reverse
      cholesterol transport and increased cardiovascular risk in diabetic patients with
      a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non
      insulin dependent diabetes mellitus (NIDDM) patients and seven controls received
      a 980 kcal meal containing 78 g lipids with 100 000 IU vitamin A. Chylomicron
      clearance was not different, but area under the curve (AUC) for retinyl palmitate
      in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02).
      LCAT activity increased postprandially to the same extent in both groups. In
      control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also
      increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL2-CE (r
      = -0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35%
      higher in the fasting state (P < 0.005), decreased postprandially yet HDL2-CE
      remained unchanged. Postprandial HDL3 of controls were enriched with phospholipid
      (PL) (30.3 +/- 2.6% at 6 h) with respect to fasting (25.6 +/- 2.5%, P < 0.01) and
      to NIDDM-HDL3 (25.8 +/- 1.7% at 6 h, P < 0.01). These results show that variation
      in plasma CETA has little impact on HDL2-CE in NIDDH subjects. They support the
      concept that, in controls, the combined enrichment of HDL3 with PL, increased
      LCAT and CETA create the conditions for stimulation of cell cholesterol efflux
      and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL3
      enrichment with PL and of the inverse trend of CETA, these conditions fail to
      occur, depriving the patients of a potentially efficient mechanism of
      unesterified cholesterol (UC) clearance, despite their strictly normal
      preprandial profile.

PMID- 8645356
TI  - Dietary non-tocopherol antioxidants present in extra virgin olive oil increase
      the resistance of low density lipoproteins to oxidation in rabbits.
AB  - Consumption of a range of dietary antioxidants may be beneficial in protecting
      low density lipoprotein (LDL) against oxidative modification, as studies have
      demonstrated that antioxidants other than vitamin E may also function against
      oxidation of LDL in vitro. In the present study, the effect of polyphenol
      antioxidants on the susceptibility of LDL to copper-mediated oxidation was
      investigated after feeding semi-purified diets to 3 groups of New Zealand white
      (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic
      acid. Dietary fatty acid compositions were identical. Oils with different
      polyphenol contents were used to provide the dietary source of oleic acid-refined
      olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil.
      Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in
      the extra virgin olive oil. Vitamin E was equalised in all diets. LDL
      oxidizability in vitro was determined by continuously monitoring the copper
      induced formation of conjugated dienes after 6 weeks of experimental diet
      feeding. The lag phase before demonstrable oxidation occurred was significantly
      increased in the high polyphenol, extra virgin olive oil group (P < 0.05) when
      compared with combined results from the low polyphenol group (refined olive oil
      and Trisun), even though the LDL vitamin E concentration in the high polyphenol
      group was significantly lower. The rate of conjugated diene formation was not
      influenced by the presence of dietary polyphenols. Results demonstrate that
      antioxidants, possibly phenolic compounds which are present only in extra virgin
      olive oil, may contribute to the endogenous antioxidant capacity of LDL,
      resulting in an increased resistance to oxidation as determined in vitro.

PMID- 8645358
TI  - The heparin-bound fraction of human lipoprotein-deficient serum inhibits
      endocytic uptake of oxidized low density lipoprotein by macrophages.
AB  - We recently demonstrated that bovine lactoferrin, a cationic whey protein from
      bovine milk, interacts with the negative charges of modified low density
      lipoproteins (modified LDL) such as acetylated LDL (acLDL) and oxidized LDL
      (oxLDL), which markedly interferes with their endocytic uptake by rat peritoneal
      macrophages (Kajikawa M, Ohta T, Takase M, Kawase K, Shimamura S, Matsuda I.
      Biochim Biophys Acta 1994;1213:82-90). In the present study, we examined whether
      human lipoprotein-deficient serum (LPDS) might contain protein(s) that could
      inhibit the endocytic uptake of oxLDL by mouse macrophages. We fractionated LPDS
      by heparin affinity chromatography and found that the cellular binding of oxLDL
      to mouse macrophages and subsequent endocytic uptake were inhibited by 50%-60%
      with the heparin-bound fraction, whereas the heparin-unbound fraction had no
      effect. Similar results were obtained in the experiments with acetylated LDL.
      Sephacryl S-300 gel-filtration chromatography of a mixture of oxLDL and the
      heparin-bound fraction revealed that a 150-kDa protein was associated with oxLDL.
      These results indicate that the electrostatic interaction of oxLDL with some
      component(s) of the heparin-bound fraction might interfere with the endocytic
      uptake of oxLDL by the macrophage scavenger receptor.

PMID- 8645359
TI  - Long-term probucol treatment results in regression of xanthomas, but in
      progression of coronary atherosclerosis in a heterozygous patient with familial
      hypercholesterolemia.
AB  - A 66-year-old male heterozygous familial hypercholesterolemia (FH) patient with
      significant coronary atherosclerosis has been treated by us with probucol (1000
      mg daily) for eight years. This treatment has produced significant reductions in
      the cholesterol levels of his serum, low density lipoprotein (LDL), and high
      density lipoprotein (HDL) from 237 +/- 20 mg/dl (mean +/- S.D.) to 156 +/- 15,
      from 175 +/- 8 to 111 +/- 16 mg/dl, and from 23 +/- 4 to 19 +/- 2 mg/dl,
      respectively. These reductions have been maintained for eight years. Serum
      triglyceride levels also decreased, from 220 +/- 54 to 146 +/- 36 md/dl. During
      this period, marked regression of xanthomas on the eyelids and finger extensor
      tendons was observed, while thickness of the Achilles tendons was reduced from
      21.0 mm to 13.0 mm. On other hand, effort-induced anginal symptoms requiring
      additional antianginal medication have been noticed, and angiographically
      demonstrated coronary atherosclerosis has progressed significantly during these
      eight years. These observations lead us to suggest that maintaining low levels of
      HDL cholesterol with probucol, even though resulting in satisfactory reduction of
      LDL cholesterol and marked regression of xanthomas, appears to be associated with
      the progression of atherosclerosis in the coronary arteries.

PMID- 8645360
TI  - Formaldehyde produced endogenously via deamination of methylamine. A potential
      risk factor for initiation of endothelial injury.
AB  - Methylamine can be converted by semicarbazide-sensitive amine oxidase (SSAO) to
      formaldehyde and hydrogen peroxide, which have been proven to be toxic towards
      cultured endothelial cells. We investigated whether or not these deaminated
      products from methylamine can exert potentially hazardous toxic effects in vivo.
      Long lasting residual radioactivity in different tissues was detected following
      administration of [14C]-methylamine in the mouse. Approximately 10% of the total
      administered radioactivity could even be detected 5 days after injection of [14C]
      methylamine. Eighty percent of the formation of irreversible adducts can be
      blocked by a highly selective SSAO inhibitor, (E)-2-(4-fluorophenethyl)-3
      fluoroallylamine hydrochloride (MDL-72974A). The residual radioactivity was
      primarily associated with the insoluble tissue components and the soluble
      macromolecules. Radioactively labelled macromolecules were fragmented following
      enzymatic proteolysis. Results suggest that the formaldehyde derived from
      methylamine interacts with proteins in vivo. In the streptozotocin-induced
      diabetic mice, both SSAO activity and the formation of residual radioactivity
      were found to be significantly increased in the kidney. Chronic administration of
      methylamine enhances blood prorenin level, which strongly suggests that
      uncontrolled deamination of methylamine may be a risk factor for initiation of
      endothelial injury, and subsequent genesis of atherosclerosis.

PMID- 8645361
TI  - Oxidized lipid-mediated alterations in proteoglycan metabolism in cultured
      pulmonary endothelial cells.
AB  - Compared to cholesterol or linoleic acid (18:2), oxidized lipids such as
      cholestan-3 beta, 5 alpha, 6 beta-triol (triol) and hydroperoxy linoleic acid
      (HPODE) markedly impair endothelial barrier function in culture [Hennig and
      Boissonneault, 1987; Hennig et al. 1986]. Because proteoglycans contribute to
      vascular permeability properties, the effects of cholesterol and 18:2 and their
      oxidation products, triol and HPODE, on endothelial proteoglycan metabolism were
      determined. While cholesterol was without effect, a concentration-dependent
      decrease in cellular proteoglycans (measured by 35S incorporation) was observed
      after exposure to triol. Compared to control cultures, cholesterol reduced mRNA
      levels for the proteoglycans, perlecan and biglycan. Triol had a similar effect
      on biglycan but not an perlecan mRNA levels. Compared to 18:2, 1,3 and 5 microM
      HPODE depressed cellular proteoglycans. Perlecan mRNA levels were reduced more by
      HPODE when compared to 18:2. Biglycan mRNA levels were reduced by 3 microM, but
      not by 5 microM HPODE. These data demonstrate that oxidized lipids such as triol
      and HPODE can decrease cellular proteoglycan metabolism in endothelial monolayers
      and alter mRNA levels of major specific proteoglycans in a concentration
      dependent manner. This may have implications in lipid-mediated disruption of
      endothelial barrier function and atherosclerosis.

PMID- 8645362
TI  - Apo B-containing lipoprotein particles in poorly controlled insulin-dependent
      diabetes.
AB  - The goal of this study was to compare the structural and biological
      characteristics of apolipoprotein (apo) B-100-containing particle subfractions
      isolated from poorly controlled diabetic patients with insulin-dependent diabetes
      (IDDM), and healthy controls matched for sex, age and body mass index (BMI).
      Different apo B-containing particles were isolated by sequential
      immunochromatography and were free of apo A-I, apo A-II, apo A-IV and apo(a).
      Particles lipoprotein (Lp) B/C-III contained apo B and apo C-III. They were free
      of apo E. Particles Lp B/E contained apo B and apo E. They were free of apo C
      III. Particles Lp B were devoided of apo C-III and apo E. All these particles
      could contain other known apolipoproteins not cited here, as for example apo C-II
      and/or apo C-I. The plasma levels of cholesterol, triglycerides, phospholipids,
      apo A-I, B-100, C-III, E, total Lp B/C-III, total Lp B/E were not different
      between patients and controls. The physico-chemical properties of Lp B/C-III and
      Lp B/E were similar in both groups. Only Lp B from patients exhibited some
      changes, an increase in the size and a decrease in the cholesterol and
      cholesteryl ester levels. The conformational properties of the lipoproteins were
      studied through their immunoreactivity against four different anti-apo B-100
      monoclonal antibodies (MAb) for which sequential epitopes have been located on
      the protein, and one MAb for which the epitope is conformationally expressed.
      Again, minor changes were observed between patients and controls, and only a
      slight decrease in the immunoreactivity of the epitope encompassing amino-acid
      residues 405 to 539 of Lp B and of the conformationally expressed epitope of Lp
      B/C-III were found in patients. Nevertheless, whatever these conformational
      and/or physico-chemical modifications may be, they were not sufficient to induce
      functional alterations in the binding of the particles from the patients to the
      LDL-receptor of HeLa cells. This study shows that IDDM is not associated with any
      significant abnormalities in the apo-containing lipoprotein particles. The
      excessive occurrence of coronary heart disease (CHD) and other atherosclerotic
      vascular disease in patients with IDDM must have other causes.

PMID- 8645363
TI  - Serum levels of the TGF-beta receptor are increased in atherosclerosis.
AB  - Murine monoclonal antibody E9 recognises a transforming growth factor (TGF) beta
      receptor, which is expressed in increased amounts by activated endothelial cells.
      In order to examine the biological role of this molecule in atherosclerosis, we
      have measured levels of the TGF-beta receptor alongside those of two other
      endothelial cell products (von Willebrand factor and soluble E-selectin) in the
      serum of 55 patients with atherosclerosis (29 with ischaemic heart disease and 26
      with peripheral vascular disease), and in a cohort of 26 age- and sex-matched
      asymptomatic controls. There were increased levels of the TGF-beta receptor (P =
      0.0079) and von Willebrand factor (P = 0.0001), but not soluble E-selection in
      patients' serum relative to the controls. In multivariate analysis of the
      endothelial cell products against total cholesterol, high density lipoprotein
      cholesterol and low density lipoprotein cholesterol, triglycerides, systolic and
      diastolic blood pressures, age, sex and smoking, both the TGF-beta receptor and
      von Willebrand factor correlated with total cholesterol (Spearman's r = 0.37 and
      r = 0.35, respectively, both P < 0.001). Lack of a correlation with a coarse
      endothelial damage marker von Willebrand factor or soluble E-selectin (produced
      by immunologically stimulated endothelial cells) implies other mechanisms are
      responsible for increased levels of the TGF-beta receptor in serum of patients
      with atherosclerosis.

PMID- 8645364
TI  - An essential role for platelet-derived growth factor in neointima formation in
      human saphenous vein in vitro.
AB  - The role of platelet-derived growth factor (PDGF), a potent vascular smooth
      muscle cells (SMC) mitogen and chemoattractant, was investigated during neointima
      formation in human saphenous vein organ culture. PDGFA and B messenger
      ribonucleic acid (mRNA) expression was detected by RNase protection assay and in
      situ hybridisation and PDGF protein by immunocytochemistry. The expression of
      PDGFA and B mRNA was low in veins before culture while PDGF protein was detected
      in all cell types. A neointima consisting of densely packed SMC developed after
      14 days of culture. The dense packing and high expression of PDGFA and B mRNA in
      neointimal SMC led to higher PDGF protein concentrations in the neointima, the
      role of which was examined by culturing with neutralising anti-(human PDGF)
      antibodies. The anti-PDGF antibodies significantly reduced neointimal thickness
      by approximately 66% and the number of neointimal cells by approximately 50%,
      without affecting neointimal or medial proliferation indices or cell viability.
      These results suggest that PDGF played an essential role in SMC migration into
      the neointima in human saphenous vein.

PMID- 8645365
TI  - Lack of effect of oral N-acetylcysteine on the acute dialysis-related lowering of
      total plasma homocysteine in hemodialysis patients.
AB  - Hyperhomocysteinemia refractory to standard B-vitamin supplementation treatment
      persists in > or = 75% of maintenance dialysis patients, potentially increasing
      their risk for atherothrombotic sequelae. We examined whether predialysis
      administration of oral N-acetylcysteine (NAC), which acutely increases the non
      protein bound, dialyzable fraction of plasma homocysteine, might augment the
      homocysteine-lowering effect of dialysis therapy. Predialysis and postdialysis
      total plasma homocysteine levels were determined on a control day, and on a day
      in which oral NAC (1200 mg) was administered predialysis in n = 11 maintenance
      hemodialysis patients. Although NAC treatment had no significant effect on
      hemodialysis removal of plasma homocysteine (P = 0.594), we observed a 16%
      reduction (P = 0.033) in non-fasting prehemodialysis total plasma homocysteine on
      the NAC treatment vs. non-treatment day. Longer term, placebo-controlled
      confirmation of this finding will be required to evaluate the possible chronic
      homocysteine-lowering efficacy of NAC treatment in hemodialysis patients.

PMID- 8645366
TI  - Trans fatty acids in hardened vegetable oils.

PMID- 8645367
TI  - High-resolution mapping of the frequency of lipid deposits in thoracic aortae
      from cholesterol-fed and heritable hyperlipidaemic rabbits.

PMID- 8645368
TI  - Relation between risk factors and cardiovascular complications in patients with
      peripheral vascular disease. Results from the A.D.E.P. study.
AB  - The relationship between risk factors and the onset of cardiovascular events was
      analyzed in patients suffering from peripheral obstructive arterial disease. One
      thousand and eleven patients were recruited in 120 Italian centers and
      participated in a clinical trial on picotamide (A.D.E.P. study), whose results
      have been previously reported. Patients were followed-up for 18 months and
      cardiovascular events were recorded. Hypertension (35%), smoking (34%), and
      diabetes (19%) were the most common risk factors at baseline. During the follow
      up period, 246 patients (11.7%) had a cardiovascular event, mainly affecting
      cerebral, cardiac or peripheral circulation. Thirty-five of these events (14.2%)
      were fatal. A logistic regression analysis showed in general that hypertension
      (odds ratio 1.48), an ankle arm pressure ratio lower than 0.8 (odds ratio 1.42),
      smoking (odds ratio 1.43), previous vascular surgery (odds ratio 1.35), high
      white blood cell (WBC) count (odds ratio 1.15 for a difference of 2.0 x 10(9)
      WBC/1) and plasma fibrinogen (odds ratio 1.16 for a difference of 1.05 g/l) were
      significantly associated with a higher incidence of cardiovascular events. In
      particular, deaths of any origin were more frequent in patients with an ankle/arm
      pressure ratio below 0.8. High plasma fibrinogen increased the risk of
      cerebrovascular events, hypertension or coronary heart events and, to a less
      evident extent, peripheral vascular complications and cerebrovascular events. A
      history of vascular surgery increased the risk of peripheral vascular
      complications. Both smoking and a high WBC count showed to be borderline
      significant risk factors for coronary heart events and the former also for
      peripheral vascular complications. In male patients (84%), ankle/arm pressure
      ratio lower than 0.8, high fibrinogen and hypertension were the most important
      factors for cardiovascular events. This study helps to identify some categories
      at higher risk of cardiovascular events among patients with peripheral
      obstructive arterial disease; this finding is useful to plan future trials to
      decrease the frequency of such complications.

PMID- 8645369
TI  - Apolipoprotein B (apo B) signal peptide length polymorphisms are associated with
      apo B, low density lipoprotein cholesterol, and glucose levels in Mexican
      Americans.
AB  - We investigated the effects of apolipoprotein (apo) B signal peptide length
      polymorphisms on low density lipoprotein cholesterol (LDL-C), apo B, and post
      challenge (2 h) glucose levels in 686 Mexican Americans from 34 families. The
      most common allele encoded an apo B signal peptide of 27 amino acids (ins; SP
      27), the next most frequent allele encoded a 24 amino acid signal peptide (del;
      SP-24), and the rarest allele encoded a 29 amino acid signal peptide (ins; SP-29)
      that has been found only in Mexican Americans. Homozygotes for the SP-24 allele
      had significantly higher mean levels of apo B. LDL-C, and 2-h glucose than SP-27
      homozygotes, and SP-27/SP-24 heterozygotes had intermediate levels (P = 0.01 for
      apo B, P < 0.001 for LDL-C, and P = 0.04 for 2-h glucose). Heterozygotes for the
      SP-29 allele had higher apo B and LDL-C levels compared to homozygotes for the SP
      27 or SP-24 alleles. Apo B signal peptide length polymorphism accounted for 4.2%,
      3.5%, and 3.0% of the residual variation in LDL-C, apo B, and 2-h glucose levels,
      respectively, among the Mexican American families.

PMID- 8645370
TI  - Relation of serum elastase activity to ultrasonographically assessed carotid
      artery wall lesions and cardiovascular risk factors. The EVA study.
AB  - The potential interest of serum elastase activity (SEA) as a marker of vascular
      aging and atherosclerosis was studied as part of an epidemiological study on
      vascular and cognitive aging (EVA Study). SEA was measured in 555 men and 774
      women aged 59-71 years with a synthetic substrate, suc(ala)3pNA, according to a
      modified enzyme-linked immunosorbant assay (ELISA)-type procedure. The
      distribution of SEA-values was skewed to the right in men and women, the mean
      value was 0.52 +/- 0.55 U/ml in males and 0.43 +/- 0.52 U/ml for females. This
      difference could be entirely explained by alcohol consumption. SEA increased
      strongly with alcohol consumption in males and females. It was also positively
      and significantly correlated with body mass index (BMI) and systolic blood
      pressure (SBP). SEA significantly decreased with age in men and was not
      influenced by smoking in either sex. SEA was significantly increased in diabetic
      men compared with non-diabetics and a similar trend, although not significant,
      was observed in women. When both sexes were combined, the association between
      diabetes and SEA was independent of other clinical risk factors. No significant
      associations were observed with intima-media thickness or atherosclerotic plaques
      assessed by B-mode carotid ultrasonography. Among biological risk factors,
      triglycerides (in both sexes) and glucose (in men) appeared the strongest
      correlates of increase in SEA. In multivariate analysis, independent determinants
      of an increased SEA were age, alcohol consumption, triglycerides and glucose in
      men, and alcohol consumption and triglycerides in women.

PMID- 8645371
TI  - The Trp23-Stop and Trp66-Gly mutations in the LDL receptor gene: common causes of
      familial hypercholesterolemia in Denmark.
AB  - Mutations in the gene for the low density lipoprotein (LDL) receptor cause the
      autosomal dominant disease familial hypercholesterolemia (FH), the prevalence of
      which is about 0.2% in most populations. By PCR-SSCP analysis and direct
      sequencing, we identified the receptor-negative Trp23-Stop LDL receptor mutation
      (FH Cincinnati-5) in 10 of 63 FH probands and the receptor-defective Trp66-Gly
      LDL receptor mutation (FH French Canadian-4) in another 10 of the 63 FH probands.
      These two mutations thus account for 30% of diagnosed FH families in Denmark.
      Comparison of the mean lipid concentrations (unadjusted and adjusted for age),
      including serum total cholesterol and LDL-cholesterol, showed no significant
      differences between the two groups of FH heterozygote probands (cholesterol: 10.7
      mmol/l vs. 10.7 mmol/l) and between the probands and 16 and 22 non-proband family
      members with the Trp23-stop (cholesterol: 10.1 mmol/l) ad Trp66-Gly (cholesterol:
      10.7 mmol/l) mutations, respectively.

PMID- 8645372
TI  - Apolipoprotein E polymorphism in middle-aged Belgian men: phenotype distribution
      and relation to serum lipids and lipoproteins.
AB  - Apo E phenotype was determined in 760 Belgian men, aged 35 to 59 years. Serum
      lipids and lipoproteins were related to the apo E polymorphism in 734
      participants. By comparison with the most frequent apo E3/3 phenotype, the
      presence of the epsilon2 allele was associated with a lower serum total and non
      HDL cholesterol, and with a lower apo B and a higher HDL cholesterol,
      independently of age, lifestyle factors and apo E concentration. In contrast, the
      presence of the epsilon4 allele was associated with a higher serum total and non
      HDL cholesterol, and with a lower HDL cholesterol and a lower apo AI. The apo E
      phenotype explained 17.4% of the variance in apo E concentration; the proportion
      of the variance in total cholesterol, HDL cholesterol, apo AI and apo B levels
      explained by the apo E polymorphism was low but statistically significant. Among
      the lifestyle factors, waist to hip ratio was the only variable significantly
      associated with apo E concentration. The data suggest that besides the well
      documented increasing effect on non-HDL cholesterol, the epsilon4 allele could
      further predispose to coronary heart disease through a decreasing effect on HDL
      while the epsilon2 allele could exert a protective influence through both a
      decreasing effect on non-HDL cholesterol and an increasing effect on HDL
      cholesterol.

PMID- 8645373
TI  - Hypercoagulability and high lipoprotein(a) levels in patients with type II
      diabetes mellitus.
AB  - Diabetes mellitus is associated with disturbances in hemostasis that could
      contribute to the development of diabetic vascular disease. We investigated the
      changes in parameters of blood coagulation and the fibrinolytic system and in
      plasma levels of lipoprotein(a)(Lp(a)) in 124 patients with type II diabetes
      mellitus and 44 healthy control subjects matched for age and body mass index
      (BMI) to determine whether hemostatic disturbances may lead to increased
      cardiovascular mortality. Median levels of fibrinogen (P < 0.0001), thrombin
      antithrombin III complex (TAT) (P < 0.005), and plasminogen activator inhibitor-1
      (PAI-1) activity (P < 0.05) in plasma were significantly elevated in diabetic
      patients compared with controls. The median concentration of Lp(a) was
      significantly higher in diabetic patients than in normal controls (18.2 vs. 12.6
      mg/dl. P < 0.0005). Lp(a) levels tended to be elevated in patients with a
      prolonged history of diabetes. There was no evidence that Lp(a) levels were
      affected by metabolic control or by type of treatment. Twenty-two diabetics with
      coronary heart disease (CHD) had significantly higher levels of fibrinogen (P <
      0.05), TAT (P < 0.05), and Lp(a) (24.7 vs. 13.7 mg/dl, P < 0.01) than the 51
      patients without diabetic angiopathy. Our data indicate that impaired hemostatic
      balance in diabetes may cause hypercoagulability and may thus contribute to the
      increased cardiovascular mortality in diabetes.

PMID- 8645374
TI  - CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy
      Japanese.
AB  - Cholesteryl ester transfer protein (CETP) is one of the factors that regulate
      plasma levels of HDL-cholesterol. To identify the factors that may regulate CETP
      activity, and to determine to what extent CETP is correlated with physiologic
      concentrations of lipoprotein, we performed an epidemiologic study in 586 healthy
      volunteers (317 males and 269 females mean age 52.2 +/- 10.9 years). CETP
      activity in these subjects was 192.96 +/- 48.73 (mean +/- S.D.) nmol/ml/h and
      distributed to a wide range (60-450 nmol/ml/h). Using multiple regression
      analysis, we found significant positive correlations between CETP activity and
      LDL-cholesterol (P < 0.03), apolipoprotein (apo) E (P < 0.005) and LCAT activity
      (P < 0.001). CETP activities showed significant negative correlation with apo A-I
      (P < 0.03). However, CETP activity showed no significant correlation either with
      HDL cholesterol or with apo B. One-way layout analysis of variance showed that
      alcohol drinking and cigarette smoking significantly reduced CETP activity, but
      there was no significant association between CETP activity and body mass index.
      Although CETP activities were significantly higher in females than in males (P <
      0.001), multiple regression analysis showed no correlation between CETP activity
      and age in either the males or the females. Our results suggest that CETP
      activity regulates the concentration of apo A-I and LDL-cholesterol, and that
      such activity may be influenced by gender, alcohol consumption and cigarette
      smoking.

PMID- 8645375
TI  - A novel single base deletion in the LDLR gene (211delG): Effect on serum lipid
      profiles and the influence of other genetic polymorphisms in the ACE, APOE and
      APOB genes.
AB  - A single base deletion (211delG) in the low density lipoprotein receptor (LDLR)
      gene was shown to cause familial hypercholesterolaemia (FH) in a large family
      from Northern Ireland. Twenty-four of 52 family members tested had this mutation,
      13 of which were newly diagnosed. Mutation-positive individuals had significantly
      higher mean total-cholesterol (TC) and LDL-cholesterol (LDL-C) than those without
      211delG. LDL-C was a more accurate indicator of disease status than TC. When TC
      levels alone were considered, in individuals over 16 years, a false negative rate
      (TC < 7.5 mmol/l) of 40% was found; however this fell to 13% based on inclusion
      of LDL-C levels. Individuals with coronary artery disease (CAD) had significantly
      higher TC levels than those without CAD and tended to have tendinous xanthomas
      (TX) and corneal arcus (CA). Generic polymorphisms in the angiotensin converting
      enzyme (ACE) and apolipoprotein (apo) B genes did not appear to be associated
      with lipid levels or with the clinical severity of the disease; however, the apo
      E epsilon4 allele did show a lipid-raising effect in individuals with the
      mutation.

PMID- 8645376
TI  - Effects of lipoprotein(a) and low density lipoprotein on growth of mitogen
      stimulated human umbilical vein endothelial cells.
AB  - We investigated the effects of lipoprotein(a) (Lp(a)) and low density lipoprotein
      (LDL) on proliferation of human umbilical vein endothelial cells (HUVECs). Both
      Lp(a) and LDL stimulated the growth of HUVECs synergistically with basic
      fibroblast growth factor and insulin in a dose-dependent manner. The potency of
      Lp(a) to promote the cell proliferation was 40% less than that of LDL. Addition
      of anti-transforming growth factor-beta 1 neutralizing antibody into the medium
      could not diminish the difference of HUVECs proliferation by Lp(a) and LDL.
      However, addition of anti-LDL receptor antibody suppressed HUVECs proliferation
      to the same level and sequestered the difference by the two lipoproteins.
      Moreover, cholesteryl ester content incubated with Lp(a) was 50% less than that
      with LDL. These results suggest that Lp(a) has less effect on HUVECs
      proliferation and cholesterol delivery to the cells than LDL. Therefore, Lp(a)
      may play a role as an atherogenic lipoprotein by delaying the repair of
      endothelium after injury.

PMID- 8645377
TI  - Cardiovascular effects of cocaine in neonates exposed prenatally.
AB  - This blinded cross-sectional study was to determine whether chronic cocaine
      exposure in utero produces abnormalities in left ventricular function (shortening
      fraction), heart rate, rhythm, and conduction in term neonates. Three groups of
      neonates were evaluated by two-dimensional echo Doppler and 24 hour Holter
      monitor, with studies initiated in the first 24 hours of life. Group A (n = 32)
      neonates had a positive history of chronic maternal cocaine use in pregnancy
      (MCU+) and a positive neonatal urine cocaine test (NUC+). Group B (n = 23)
      neonates were MCU+ but NUC-. Group C (n = 32) neonates were MCU- and NUC-.
      Measured parameters were compared statistically by analysis of variance. p < 0.05
      was regarded as significant. Echocardiography showed no significant difference
      between groups A, B, and C for left ventricular shortening fraction. Holter
      monitor likewise revealed no significant difference between groups in minimal,
      maximal, and average heart rate, or in the incidence of supraventricular and
      ventricular arrhythmias greater than 20 beats/h in the 24-hour period. None of
      the patients had atrioventricular or bundle branch block. It is possible that the
      developmental state of the newborn heart makes it less responsive to the adverse
      effects of cocaine.

PMID- 8645378
TI  - Effect of dehydroepiandrosterone sulfate on maternal cardiac function in term
      pregnancy.
AB  - To search for possible effect of dehydroepiandrosterone sulfate (DHAS) on
      maternal cardiac function in term pregnancy, impedance cardiographic assessments
      were made on 15 normal full-term pregnant women before and 5, 10, 15, 20, 25, and
      30 minutes after the administration of a 200 mg intravenous dose of DHAS in 20 mL
      of 5% dextrose. The cardiac output, stroke volume, heart rate, and mean arterial
      pressure were recorded. Maternal cardiac output increased from baseline by 20% (p
      < 0.05) after 15 minutes and the mean increase in stroke volume was 25% (p <
      0.05) after 15 minutes. No change was found in heart rate or mean arterial blood
      pressure. DHAS induces a significant increase in both maternal stroke volume and
      cardiac output without change in heart rate or mean arterial pressure, which
      suggests a possible increase in cardiac contractility in term pregnancy.

PMID- 8645379
TI  - Doppler echocardiographic findings of indomethacin-induced occlusion of the fetal
      ductus arteriosus.
AB  - We present an unusual case of indomethacin-induced occlusion of the fetal ductus
      arteriosus, which occurred in one of twins. In fetal echocardiography, the
      characteristic findings, a to and fro regurgitation pattern at pulmonary valve
      and postvalvular dilation of the main pulmonary artery, were obtained in addition
      to right ventricular dilation and hypertrophy, tricuspid regurgitation, right
      atrium dilation, and pericardial effusion. This fetus developed fetal distress
      and was delivered by an emergency cesarean section at 35 weeks' gestation. We
      suggest that these fetal echocardiographic findings may be the end-stage signs of
      the fetal ductal occlusion as well as the signs for emergent delivery.

PMID- 8645380
TI  - Pregnancy and warm autoantibodies: a case report.
AB  - The presence of the maternal warm antibody in pregnancy should not be ignored. As
      there is risk of both maternal and fetal anemia, both patients need to be
      followed for the development of such. Serial complete blood counts in the mother
      and treatment if significant fetal anemia develops should be considered. Serial
      amniocentesis and nonstress testing should be part of any management plan in the
      presence of a maternal warm antibody.

PMID- 8645381
TI  - Surgery for pancreatic tumors during pregnancy: a case report and review of the
      literature.
AB  - Seven cases of surgery of pancreatic tumors during pregnancy have been reported
      in the literature. Six of the cases resulted in live term births. The patient
      discussed herein, a 37-year-old para 2-0-0-2 white female, had surgery for the
      removal of a pancreatic mass at 20 2/7 weeks' gestation. No intraoperative
      complications occurred, and both mother and fetus appeared to have done well. The
      postoperative course was complicated by pseudomembranous enterocolitis caused by
      C. difficile, which was treated with antibiotics. Despite treatment, diarrhea
      continued, and the patient was readmitted to the hospital for hydration and
      further antibiotics at 27 weeks. Three days after admission, the fetus was noted
      to have poor biophysical testing and a caesarean delivery was performed. The
      infant was found to have a large intracerebral hemorrhage, which most likely
      occurred antenatally, and life support was discontinued shortly after birth. We
      conclude from this that surgery for a pancreatic mass in pregnancy should be
      approached cautiously, and the risk to both the mother and fetus should be
      considered.

PMID- 8645383
TI  - Cryptococcal meningitis in pregnancy.
AB  - The case of an 18-year-old pregnant woman with cryptococcal meningitis treated
      with amphotericin B and flucytosine since the third trimester of pregnancy is
      reported. She delivered a normal baby. The maternal outcome was favorable. There
      is no evidence of congenital infection in the newborn.

PMID- 8645382
TI  - Advantages of larger volume, less frequent intrauterine red blood cell
      transfusions for maternal red cell alloimmunization.
AB  - Larger volume intravascular transfusions to manage severe maternal red cell
      alloimmunization in pregnancy may prolong the interval between procedures without
      increasing maternal, fetal, or neonatal complications. A retrospective cohort
      study compared the management and outcome of 19 patients with severe red cell
      alloimmunization managed at two facilities with different intravascular
      transfusion protocols. The volume of blood transfused, pre- and post-transfusion
      fetal hematocrit, and interval (days) between intravascular transfusions were
      compared. The respective maternal, fetal, and neonatal results were compared. The
      red blood cell volume transfused per procedure and the post- but not pre
      transfusion fetal hematocrits were higher at New York Hospital than at
      Westchester County Medical Center. The interval between transfusions at New York
      Hospital (25.2 +/- 8.65 days) was longer than at Westchester County Medical
      Center (13.5 +/- 6.0 days, p < 0.0001). Although larger volume transfusion was
      occasionally associated with transient fetal bradycardia, all red blood cell
      transfusions were completed without complication. The adverse outcomes,
      complication rates, and neonatal outcomes were otherwise similar in both
      management protocols. It is possible to significantly increase the interval
      between intravascular transfusions with larger transfusion volumes for the
      management of severe maternal red cell alloimmunization without undue risk. The
      overall risk for the fetus and mother may be reduced by performing fewer
      transfusions and avoiding additional blood product exposures.

PMID- 8645384
TI  - Evaluation of noise in the neonatal intensive care unit.
AB  - This study evaluated the noise level inside the incubators in a neonatal
      intensive care unit and identified its sources in order to attempt to reduce it.
      Although noise is not a proven risk factor as far as the sensory integrity of
      newborns is concerned, it is certainly an important cause of stress to them and a
      source of serious and dangerous changes in their behavioral and physiologic
      states. Noise recorded inside the incubators had two components. The first was
      background noise from the incubator motors, which varied from 74.2 to 79.9 dB,
      and was similar to environmental noise. The second source was impulsive events
      beyond 80 dB. These events were the result of voluntary and involuntary contact
      with the incubators' Plexiglas surface or to the abrupt opening and closing of
      their access ports. Considering its decibel levels and frequency, this latter
      component is undoubtedly an important source of stress to newborns. Moreover,
      these data reveal the need to train health care personnel on how to reduce such
      noise by taking more care in the handling of infants.

PMID- 8645385
TI  - An association between fetal parvovirus B19 infection and fetal anomalies: a
      report of two cases.
AB  - The association between fetal parvovirus B19 infection and hydrops was first
      reported in 1984. The virus has a predilection for the erythroid cell line, which
      in the fetus may produce anemia. Recent cases of parvovirus infection in other
      fetal cell lines have raised concern that the infection may induce fetal
      anomalies in rare cases. We report two pregnancies complicated by parvovirus B19
      infection. In each instance the patient had normal second trimester ultrasounds
      but subsequently developed fetal abnormalities--disruptions of normal structure.
      One infant has myocardial infarction, splenic calcifications, and mild
      hydrocephalus. The other had moderate hydrocephalus with central nervous system
      scarring. There are two possible mechanisms in which parvovirus may induce fetal
      anomalies. Both direct infection of fetal organs and vascular inflammation have
      been documented in association with B19 parvovirus. Although fetal abnormalities
      associated with parvovirus are rare, continued study of this organism may
      indicate a greater pathologic potential than is now thought.

PMID- 8645386
TI  - High incidence of cranial ultrasound abnormalities in full-term infants with
      congenital heart disease.
AB  - The objective of this retrospective study was to determine the incidence and
      types of cranial ultrasound abnormalities in full-term infants with congenital
      heart disease (CHD). We reviewed the cranial ultrasound scans of 49 full-term
      infants with CHD and compared them to 42 healthy full-term control infants. The
      relationship of each abnormality with the type of CHD, the presence of cyanosis,
      and cardiac catheterization and cardiac surgery were examined. We found that
      infants with CHD had a higher incidence of cranial ultrasound abnormalities than
      control infants (59% versus 14%; p < 0.001). Cerebral atrophy and linear
      echodensities in the basal ganglia and thalamus were the most common sonographic
      findings in infants with CHD, particularly in those with coarctation of the aorta
      or ventricular septal defect. Intraventricular hemorrhage occurred more often in
      infants with acryanotic CHD than in those with cyanotic CHD. Cardiac
      catheterization and cardiac surgery had no significant effects on cranial
      ultrasound findings. We conclude that cranial ultrasound abnormalities are very
      frequent in full-term infants with CHD. These findings emphasize the importance
      of cranial ultrasonography and long-term neurodevelopmental follow-up of infants
      with CHD.

PMID- 8645387
TI  - Trial of beclomethasone dipropionate by metered-dose inhaler in ventilator
      dependent neonates less than 1500 grams.
AB  - Beclomethasone dipropionate administered by metered-dose inhaler to ventilated
      infants with early chronic lung disease was evaluated in a double-blind, placebo
      controlled study to determine the feasibility and safety of administration.
      Patients selected for study were less than 1500 g birthweight, had previous
      radiographic evidence of respiratory distress syndrome with early changes of
      bronchopulmonary dysplasia (BPD), were greater than 2 weeks of age, and had
      failed attempts at extubation. The metered-dose inhaler was connected to the
      respirator circuit by an in-line spacer device and either saline placebo or
      beclomethasone was delivered for 7 days or until extubated. Beclomethasone was
      delivered in a dose calculated to be approximately 1 mg/kg/day in three divided
      doses. Nineteen infants were enrolled. Nine received placebo and 10 received
      beclomethasone. No adverse effects on blood pressure, heart rate, respiratory
      rate, ventilator settings, concentration or duration of oxygen therapy, incidence
      of retinopathy of prematurity (ROP) or infections, blood glucose, daily weight,
      or serum cortisol levels before and after adrenal stimulation tests were observed
      in the beclomethasone group compared with the placebo group. One infant in the
      placebo and six infants in the steroid group were extubated during the study
      period (p = 0.03). These data indicate that beclomethasone dipropionate may be
      administered safely to intubated neonates without adverse effects of
      hypertension, hyperglycemia, diminished weight gain, or adrenal suppression
      frequently seen with systemic steroid administration. Beclomethasone may enhance
      extubation in infants with early BPD, however, further data are required to
      substantiate this preliminary observation.

PMID- 8645388
TI  - Fetal myocardial calcification associated with maternal cocaine use.

PMID- 8645389
TI  - Examining the NRMP algorithm. National Resident Matching Program.

PMID- 8645390
TI  - Leadership strategies for GME.

PMID- 8645391
TI  - MD-PhD curricula.

PMID- 8645392
TI  - Academic medicine is ill: diagnosis and prognosis.

PMID- 8645393
TI  - Improving productivity: the ongoing experience of an academic Department of
      Medicine.
AB  - Beginning in 1991-92, the Department of Medicine at The University of Alabama
      (UAB) changed its practices for allocating funds made available through the
      dean's office and for handling professional practice revenues. The specific goals
      of this new "plan for responsibility-center management" were--and remain--(1) to
      increase financial flexibility so the chair can reward productivity, strengthen
      existing programs, and better respond to departmental and institutional needs and
      opportunities; (2) to encourage the UAB tradition of responsible entrepreneurism
      at the levels of division directors and individual faculty; (3) to increase
      extramurally funded program-building at the division level; and (4) to relate the
      costs of practice directly to total patient care revenues. The plan's intent is
      to provide rewards, incentives, and recognition for the contributions of
      individual faculty. The author describes in detail the operation of the plan and
      the traditions and assumptions underlying it (e.g., the first requirement is to
      have good employees), and evaluates its effects, strengths, and weaknesses after
      three full fiscal years. He explains how the plan was introduced and implemented,
      documents the outstanding gains in the department's financial resources, both
      short- and long-term, and describes past and ongoing difficulties (for example,
      the effect of historic UAB decisions regarding the funding of graduate medical
      education, the extreme decentralization of clinic operations and patient care
      billing activities, and the question of how fast the shift to capitated managed
      care will be). He concludes that the plan appears to be a successful effort at
      broadly-based productivity enhancement, but that evaluation is ongoing.

PMID- 8645394
TI  - How one academic health center is successfully facing the future.
AB  - The author maintains that the academic health centers (AHCs) that successfully
      weather the current vast changes in the health care environment will be stronger
      institutions. But to survive and prosper in the future, AHCs must come to terms
      with their entrenched cultures and create new forms of organization that are more
      flexible, more adaptive, and more agile. Even though each center confronts unique
      circumstances requiring unique solutions the author describes the changes made
      during the last six years at his center--the Allegheny Health, Education and
      Research Foundation (AHERF), in Pittsburgh, Pennsylvania--to show how one AHC is
      successfully facing change. The central problem facing AHERF (and all AHCs) is
      that revenues from all traditional sources are declining significantly. AHERF is
      dealing with the problem in part by actively seeking philanthropic and public
      funding for research and education. But such funding cannot be relied upon, and
      for AHERF to stay true to its mission, it must practice the "Three Rs" of modern
      academic medicine. First, the center is cultivating a more responsive
      organization. The author describes the organizational structure of the center;
      the emphasis on providing an environment that unleashes the creativity and
      productive potential of each employee and fosters teamwork; goals, objectives,
      and incentives; the way decisions are made; and the way revenue is allocated.
      Second, productivity must be improved through re-engineering. For example, AHERF
      oversaw the consolidation of two medical schools into one. The author describes
      the organizational changes that made the management of the resulting institution
      possible and cost-effective, and discusses changes in workflow, support
      functions, the use of information systems, and innovative supplier arrangements.
      Third, the revenue base must be secured. The author describes four of the main
      ways this is being done (e.g., the expansion of the center's large network of
      primary care physicians). The author provides a variety of statistics of AHERF's
      successes so far (e.g., patient revenues have gone from $500 million in 1989 to
      $1.3 billion in 1994). He concludes by emphasizing that AHCs cannot wait for
      outside help but must take their futures into their own hands, beginning now.

PMID- 8645395
TI  - A way to approach the strategic decisions facing academic health centers.
AB  - Rapid changes taking place in the various markets served by academic health
      centers (AHCs) are forcing these institutions to make difficult strategic
      decisions that may change AHCs' historic priorities. The authors present an
      approach that can help AHCs visualize possible new configurations of their
      traditional services of research, education, and clinical care. This approach is
      based on successful strategic management methods from the private sector and
      involves a three-dimensional "topography of services" encompassing all possible
      configurations of AHCs' services. From among the many possible configurations,
      the authors discuss three in detail. The historic one, which they call the
      traditional model, is characteristic of AHCs that give high priority to
      biomedical and clinical research, have broad medical education activities, and
      deliver comprehensive, high-quality clinical care. In the future, this
      configuration will be rare, and two others are likely to predominate. First is
      the "revised" traditional model, which would offer "boutique" clinical services,
      biomedical research, and medical education for MD-PhD students, residents, and
      fellows seeking tertiary care or academic careers. The patient care required for
      undergraduate medical education and clinical research would be provided by
      partnerships with community-based providers. Second is the academic services
      model, which would focus on competitive primary and secondary clinical services,
      health services and operations research, and primary care medical education. The
      authors discuss the implications of these models for AHCs' organizational
      structures and faculty incentives. They conclude that the clarity with which
      AHCs' strategic decisions are made and communicated to faculties and the
      incentive systems that are selected to motivate faculty and to provide the
      selected services may ultimately determine which institutions survive.

PMID- 8645396
TI  - Time to return medical schools to their primary purpose: education.
AB  - The author maintains that the quality of medical education has been dropping for
      the last few decades as medical schools become less and less focused on their
      primary purpose of training physicians. Until the years immediately following
      World War II, the administration of the medical school was carried out by a small
      staff headed by a dean whose role was to provide leadership in educational
      matters. Academic departments managed the educational program, and the faculty
      were expected to be teachers and to participate in educational planning,
      preparation of teaching materials, advising of students, assessment of students'
      performances, admission, and all other tasks associated with having a teaching
      position. Today, the administration of a typical school includes any number of
      assistants to the dean and a wide variety of other staff dealing not only with
      educational functions but with grant management, public relations, fund-raising,
      personnel policy, budgeting, and an enormous and complex parallel structure
      designed to manage clinical practice and to respond to market pressures. The role
      of faculty has also changed greatly; faculty are expected to be researchers and
      clinicians first, and teaching is usually shortchanged. The author explains why
      he believes these changes have come about; for example, the strong federal
      support of research after World War II, which encouraged a growing dependence of
      medical schools on research grants and consequently raised in importance those
      faculty who could obtain such grants. He concludes with common-sense proposals
      for reform (such as having the education of medical students in the hands of a
      small number of faculty whose prime responsibility is teaching), but admits that
      there are fundamental barriers to such reforms, especially vested interests and
      resistance to change. In the end, change will come only when those in power
      recognize that medical schools must be returned to their primary role of training
      physicians.

PMID- 8645397
TI  - Teaching clinical reasoning to second-year medical students.
AB  - In most U.S. medical schools, students begin clinical clerkships during their
      third year. They are expected to arrive prepared with the skills necessary to
      participate in patient-care activities, including data gathering, care
      coordination, and diagnostic reasoning. However, most students' training may
      inadequately prepare them to be proficient in diagnostic reasoning, and little
      time is available in the third year to develop these skills. Because of this
      inadequate preparation, students may become frustrated with many aspects of their
      clerkships. This paper describes a series of exercises developed by the author
      and implemented in this three years as a clinical tutor for second-year medical
      students in an introduction to clinical medicine course. The exercises are
      designed to accelerate the student's understanding of diagnostic reasoning,
      thereby better preparing them for the requirements of the third-year clerkship.
      The author describes how he uses this teaching approach and discusses in detail
      the method's central components. He notes that the six students he has worked
      with from 1993 to the present have responded very positively, and that further
      research is needed to explore possible long-term benefits of this teaching
      method.

PMID- 8645398
TI  - Reaping the benefits of medical information systems.
AB  - Increasingly, external forces affect and constrain physicians' clinical decision
      making and consequently their practice of medicine. Physicians are expected to
      achieve optimal patient outcomes at the lowest possible cost, which requires that
      they have quick and convenient access to comprehensive clinical information from
      different sources. Considerable experience to date has shown that computers can
      improve physicians' problem solving and decision making by presenting pertinent
      data, information, and knowledge when it is needed, where it is needed, and in an
      appropriate format. The authors advocate the use of medical information systems
      in the daily practice of medicine. They identify critical information-related
      issues affecting clinicians, provide a brief overview of computer applications in
      medical care, and discuss studies that indicate how medical information systems
      can assist physicians in the delivery of cost-effective, high-quality care.
      Finally they discuss how individual institutions can best reap the benefits of
      medical information systems.

PMID- 8645399
TI  - Case history. Complete nervous exhaustion.

PMID- 8645400
TI  - Time to catch a favorable tide.

PMID- 8645401
TI  - Clinical research 1996: stirrings from the academic health centers.

PMID- 8645402
TI  - Feasibility of hospital-based use of peer ratings to evaluate the performances of
      practicing physicians.
AB  - PURPOSE: To address the feasibility of obtaining reliable evaluations of
      individual physicians from peer ratings undertaken at diverse hospitals. METHOD:
      Eleven hospitals in diverse locations in the United States were recruited to
      participate. With the aid of the hospitals' medical directors, up to 40 board
      certified internists with admitting privileges were recruited per hospital.
      Participating physicians provided demographic data about themselves and nominated
      physician-associates to do peer ratings. Between April 1993 and January 1994, the
      physicians were rated by their peers, who received a single mailing with no
      follow-up. The raters used a nine-point Likert scale for 11 cognitive and
      noncognitive categories. Administrative procedures were coordinated from the
      American Board of Internal Medicine. Chi-square, Student's t-test, and factor
      analysis using varimax rotation were used to analyze the results. RESULTS: Of the
      4,139 questionnaires that were mailed to peer raters, 3,005 (73%) were returned.
      Of the 228 physicians who were rated, 187 received ten or more usable ratings,
      which were used for further analysis. The findings confirmed the results of
      previous research. The highest mean rating was for the category of integrity, and
      the lowest was for the category of psychosocial aspects of care. Ten to 11
      responses per physician were necessary to achieve a generalizability coefficient
      of .7. Nearly 90% of the variance in the ratings was accounted for by two
      factors, one representing cognitive and clinical management skills and the other,
      humanistic qualities. For 16 physicians (9%), the ratngs of overall clinical
      skills were less than 7 on a scale from 1 (low) to 9 (high); their ratings for
      all individual cognitive and noncognitive categories were below the ratings of
      the other physicians. CONCLUSION: The peer raters' response rate and the analysis
      of the ratings suggest that the rating process is acceptable to physicians and
      that it is feasible to obtain reliable, multidimensional peer evaluations of
      individual physicians practicing in diverse clinical settings.

PMID- 8645403
TI  - Preclinical course-evaluation methods at U.S. and Canadian medical schools.
AB  - BACKGROUND: Despite the apparent prevalence of the use of course evaluations by
      medical schools, course and curriculum evaluation have gone relatively unnoticed
      in the medical education literature. METHOD: In the fall of 1993, a 17-item
      questionnaire was mailed to all 141 U.S. and Canadian medical schools to elicit
      information concerning any course-evaluation systems in place in the schools'
      preclinical curricula. RESULTS: A total of 101 schools (72%) returned usable
      questionnaires. Of these, 79 reported having a centralized course-evaluation
      system and 56 used oversight committees consisting of administrators, faculty,
      and students. Beyond the use of written questionnaires (reported by 100 schools),
      course-evaluation practices varied widely. Eighteen schools reported that
      questionnaire content was the same across courses, while 56 used a common core of
      items with modifications for specific courses. The frequency and timing of
      questionnaire distribution varied from once at the final examination to weekly
      during the course. Summarized course-evaluation results were made available to
      departments (91 schools), the oversight committee (50 schools), the
      administration (47 schools), and students (13 schools). The feature most
      frequently cited as being a positive aspect of the course-evaluation process was
      student involvement (23 schools). Most frequently cited as areas of concern were
      low response rates to questionnaires (20 schools) and the need for simpler, more
      reliable methods of data collection (13 schools). Seventy schools reported
      specific types of changes that had resulted from course evaluation. CONCLUSION:
      The results confirm that course evaluation via student questionnaires is
      ubiquitous in North American medical schools. Most schools used centralized
      systems, but individual schools had developed their own combinations of technique
      and organization. This lack of uniformity may be due to the sensitivity of
      evaluation processes to local contexts, but it may also be due to the lack of
      literature on the subject.

PMID- 8645404
TI  - Adequacy of training in preventive medicine and public health: a national survey
      of residency graduates.
AB  - PURPOSE: To evaluate training in general preventive medicine and public health,
      determining which experiences and institutional sponsors best prepare residents
      for practice and where improvements are most needed. METHOD: A 1991 survey of the
      1,070 graduates of preventive medicine residencies from 1979 through 1989 asked
      the graduates to measure the adequacy of their training in preventive medicine
      topic areas by using a Likert-type scale of 1 (poor) to 4 (excellent). Adequacy
      was analyzed for variation against practice emphasis during training, training
      program sponsor, and other variables. The statistical methods included Student's
      t-test, analysis of variance and linear regression. RESULTS: A total of 797
      graduates (74.5%) responded. The overall mean ratings of adequacy of training
      were 3.1 (SD, 0.9) for epidemiology, 2.5 (SD, 1.0) for clinical preventive
      medicine, 2.4 (SD, 0.9) for environmental health, 2.3 (SD, 0.9) for health
      administration, 2.3 (SD, 0.9) for health education and behavioral sciences, and
      2.2 (SD, 0.9) for occupational medicine. Training was rated highest for topics
      emphasized during practice experiences. Adequacy varied by type of institution
      sponsoring the residency. Women rated their training as being less adequate than
      did men in all areas except clinical preventive medicine. The graduates tended
      ultimately to practice in topic areas emphasized during training. CONCLUSION: The
      graduates' ratings suggest that improvements are most needed in health
      administration, environment health, health education, and occupational medicine.
      Potential improvement strategies include highly focused practice experiences and
      increased emphasis on training in actual practice settings and community sites.

PMID- 8645405
TI  - Are international medical graduates a factor in residency program selection? A
      survey of fourth-year medical students.
AB  - PURPOSE: To examine whether the proportions of international medical graduates
      (IMGs) enrolled in certain residency programs would affect students' selection of
      those programs during the match, and to determine the importance of this factor
      relative to other established program-selection factors. METHOD: A sample of 702
      fourth-year students at 18 geographically diverse U.S. medical schools during
      March and April of 1994 were mailed a confidential survey asking them to rank and
      rate hypothetical programs and to rate the importance of selected characteristics
      in their rankings of programs during the match. The students were asked to rank
      five hypothetical programs described by nine characteristics. One-third of the
      students received additional information about the programs' reputations; another
      third, information about the percentages of IMGs in the programs. The control
      group received no information about these two characteristics. Comparisons of the
      mean rankings and ratings of the five programs between the control and
      intervention groups were made using the Mann-Wilcoxon rank-comparison statistical
      test. RESULTS: The response rate was 44%, with 291 survey forms returned
      completed (45 were returned due to no forwarding address). When the rankings and
      ratings of the control and intervention groups were compared, the programs with
      higher numbers of IMGs worsened significantly in rank and rating (p < .001 for
      both), whereas the programs with better reputations improved in rank (p < .001)
      and rating (p < .005). CONCLUSION: The results suggest that the proportion of
      IMGs in a residency program is a significant factor in program selection and is
      as important as previously established factors such as program reputation.
      Students, however, do not acknowledge the importance of this factor. Program
      directors and governing bodies may want to consider these findings when
      evaluating the impact and distribution of IMGs in U.S. training programs.

PMID- 8645406
TI  - Monitoring students' clinical experiences during a third-year family medicine
      clerkship.
AB  - PURPOSE: To demonstrate the importance of monitoring the clinical experiences and
      types of supervision that students receive in physicians' offices, in order to
      ensure quality control during a required clerkship. METHOD: In a documentation
      system introduced in 1991-92, third-year students in the family medicine
      clerkship at the University of North Carolina at Chapel Hill School of Medicine
      were asked to complete an optical scan card for every patient they saw. The card
      information consisted of demographic data, patient continuity, medical problems,
      types of histories and physical examinations, patient education issues, primary
      care procedures, and type of supervision. The data were collected from 293
      students placed in 63 practices from December 1991 through November 1993.
      RESULTS: Hypertension, health maintenance, and upper respiratory infection were
      the most frequently recorded medical problems. Although the students obtained
      adequate experience performing focused histories and physicals, their experiences
      with certain physical examinations (breast, rectal, and genital) were
      inconsistent. Patterns of supervision by the preceptors varied among practices.
      CONCLUSION: Although the validity of the data has not been assessed, previous
      literature and other information indicate that the documentation system
      successfully described the students' clinical experiences. The benefits of
      implementing such a monitoring system include highlighting the students' lack of
      certain experiences and making comparisons across sites in order to encourage
      change among preceptors.

PMID- 8645407
TI  - Exploratory factor analysis of students' ratings of a problem-based learning
      curriculum.
AB  - PURPOSE: To identify the factor structure underlying medical students' initial
      experience with a problem-based learning (PBL) curriculum and to examine the
      stability of this structure as students acquire further experience with PBL.
      METHOD: The PBL curriculum at the Michigan State University College of Human
      Medicine begins in the students' second year and is divided into 11 domains. In
      1992-93 students were asked to evaluate their learning experiences in the first
      and last domains of their first PBL semester, by using a five-point Likert scale
      to rate 19 items. Principal-components analysis and varimax rotation were used to
      identify the factors underlying the students' ratings. RESULTS: Ratings of the
      first and last domains were available from 101 and 71 students, respectively.
      Analysis yielded four meaningful factors: learning materials, small-group
      process, tutor effectiveness, and academic support. These four factors shifted in
      relative importance as the students progressed through the curriculum: for the
      first domain, tutor effectiveness accounted for the highest percentage of
      variance in the data; for the last domain, this factor ranked third, after
      learning materials and small group process. Internal reliabilities for the
      ratings of the last domain of the semester were higher and more consistent,
      ranging from .92 to .97. CONCLUSION: The students' initial dependence on the
      tutor progressed to an emphasis on learning resources. This shift is congruent
      with the theoretical model of the dynamics of PBL. The results suggest that the
      survey instrument provides a reliable measure of the multidimensional constructs
      underlying students' experience with PBL.

PMID- 8645408
TI  - Administering the American Board of Pediatrics in-training examination in a
      European pediatrics residency.

PMID- 8645409
TI  - Responses of U.S. clerkship directors about the organization of their clerkships
      in pediatrics.

PMID- 8645410
TI  - Effectiveness of commitment contracts in continuing medical education.

PMID- 8645411
TI  - Effect of debt on U.S. medical school graduates' preferences for family medicine,
      general internal medicine, and general pediatrics.
AB  - The authors assess the importance of educational debt in graduates' primary care
      specialty choices, and the variety of mechanisms through which debt may influence
      career decisions. Logistic regression models were used to identify significant
      predictors of the primary care specialty choices made by the 1991 and 1992
      graduates of U.S. medical schools. These predictors were debt itself; other
      financial indicators; certain medical school characteristics; certain practice
      location plans; certain demographic factors; aspects of academic performance; and
      students' predisposition to a primary care specialty. Data for this study were
      gathered from a variety of sources at the Association of American Medical
      Colleges and from the Health Education Assistance Loans program. Both direct and
      indirect effects of debt were identified under specific conditions. The study
      revealed complex relationships between debt and the other predictors identified.
      For example, debt operated in relation to the levels of the graduates' expected
      incomes; debt from subsidized loan sources was significant for women who chose
      general internal medicine; debt was important in choices of family practice; and
      debt by itself was significant for those planning to practice in the West and who
      chose general internal medicine. Also, seemingly opposing effects of debt
      occurred. For example, in the family practice model used in this study, the
      threshold effect of debt was positive, while the linear effect of debt above the
      threshold was negative. Such vriations help explain the conflicting findings of
      some past research. These and other findings prompt the authors to state that
      when investigating the effects of debt, it is not fruitful to ask what the effect
      of the debt is on all three primary care fields as a group. It is more
      appropriate to ask several questions, such as: under what conditions does debt
      influence specialty plans? Among which groups of students does debt have an
      impact on specialty plans? Are all of the primary care specialties similarly
      affected by the issues surrounding debt? Does the effect of debt change over
      time? The authors conclude by indicating possible policy implications of their
      findings.

PMID- 8645412
TI  - Analysis of heparin origin by HPLC quantitation of disaccharide components.
AB  - A simple method was developed to analyze by high performance liquid
      chromatography unsaturated disaccharide isomers, derived from heparin by
      enzymatic digestion. This method was successfully exploited in the investigation
      of heparin origin. The percent amount of 6-sulphated disaccharides in the heparin
      extracted from porcine mucosa was found to be higher than that contained in the
      heparin extracted from bovine mucosa. The differences in the contents of the
      disaccharides obtained by enzymatic beta-elimination cleavage of heparin were
      confirmed by 13C-NMR measures of heparin in toto. The processes for extracting
      and purifying heparin may, however, modify the sulphation pattern of heparin. The
      structure of the latter seems to depend on the species owing to the specificity
      of the biosynthesis.

PMID- 8645413
TI  - Acid derivatives of benzisothiazole-1,1-dioxide as inhibitors of rat lens aldose
      reductase.
AB  - A number of 6-substituted 1, 2-benzisothiazole-1, 1-dioxide alkanoic acids were
      synthesized and evaluated for crude rat lens aldose reductase inhibitory
      activity. The inhibitory potency of the acetic (6a, 10a), propionic (6b, 10b,
      11b), and isopropionic (6c, 10c, 11c) derivatives was very similar and generally
      lower than that of the reference compound, Sorbinil. The presence of an acyl
      moiety on the amino group in position 6, as in the acetic and propionic
      derivatives 14a-f and 15a, b, respectively, resulted in a significant increase in
      activity. A good potency was shown by compounds 14g and 15g, in which a second
      carboxylic function is present on the 6-acylamino group. Also the open products
      16, which contain the phenylsulfonyl fragment found in several known inhibitors
      of aldose reductase, were obtained and tested in the rat lens assay.

PMID- 8645414
TI  - Synthesis and in vitro antitumor activity evaluation of 9-substituted 1,2,3,4
      tetrahydrocarbazoles.
AB  - A series of 9-acetamido-1,2,3,4-tetrahydrocarbazoles (2) and 9
      (aminoalkyloxyethyl)-1,2,3,4-tetrahydrocarbazoles (4) were prepared and tested
      for their in vitro antitumor activity. Compounds 4 are highly cytotoxic in almost
      all subpanel cell lines when tested at 10(-4) M, but showed a weak activity at
      the lowest concentrations employed.

PMID- 8645415
TI  - 2-Diazopyrroles: synthesis and antileukemic activity.
AB  - The title compounds were synthesised in preparative yields by diazotization of
      the corresponding 2-aminopyrroles. In preliminary screening tests as antileukemic
      agents they showed modest activity against the murine and human leukemic cell
      lines FLC and K562S and their multidrug-resistant daunorubicin selected sublines.

PMID- 8645416
TI  - Anti-HIV agents. IV. Synthesis and in vitro anti-HIV activity of novel 1-(2,6
      difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazoles.

PMID- 8645417
TI  - Synthesis and antimicrobial activity of 7 beta-(S)- and 7 beta-[(R)-3
      (methyleneaminoxy)-2-methylpropionamido]substituted cephalosporanic acid
      derivatives.
AB  - Some 7-amino cephalosporanic acid derivatives substituted on the C(7) nitrogen
      with (S)-and (R)-3-(methyleneaminoxy)-2-methylpropionyl groups were synthesised
      and tested in vitro for their antimicrobial activity against Gram-positive and
      Gram-negative bacteria. Some of the new compounds showed a modest activity
      directed only against Gram-positive microorganisms.

PMID- 8645418
TI  - Fungicidal activity of arylfurylketoximes.
AB  - A series of arylfurylketoximes and their O-ethyl ethers and O-esters were
      prepared and evaluated for their fungicidal phytoiatric activity, in vitro and in
      vivo. The biological results show that the O-acetyderivatives and the free oximes
      present a very good activity.

PMID- 8645419
TI  - 1,2,3-Triazolo[5,4-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: a new class of
      A2A adenosine receptor antagonists.

PMID- 8645420
TI  - [Assay of IgE specific to dog epithelia by the Pharmacia CAP RAST technique:
      comparison of the two CAP RAST e2 and e5].
AB  - We present a comparative study of measurement of dog-epithelium-specific IgE by
      two Pharmacia CAP Rast techniques e2 and e5. For both measurements the technique
      is identical, but the allergen extracts are different: e2 = dachshund extract
      whilst e5 = a mixture of squames of german shepherd and poodle. We show that the
      e5-specific IgE seems to be more sensitive than the e2-specific IgE.

PMID- 8645421
TI  - Bronchial inhalation challenge procedures with allergens and other
      bronchoconstrictor substances.
AB  - Antigen inhalation challenges nowadays are most commonly used as an investigative
      tool to better understand the pathophysiology of asthma and possible blocking
      effects of immunotherapy. However, they also serve to better define the role of
      specific allergens in asthma, and as a possible substitution for skin tests when
      they cannot be performed. Of particular interest in the literature has been the
      late asthmatic response and the increase in so-called nonspecific reactivity that
      follows. When a new pharmaceutical agent is studied, its ability to block both
      the late phase and subsequent hyperreactivity is presumptive evidence for
      effectiveness. The more commonly employed challenges with bronchoconstrictive
      substances, such as methacholine and histamine, have been used to assess atypical
      asthma, better define occupational asthma and a way to quantitate hyperreactive
      airways disease. Other bronchoconstrictive agents that have been employed include
      acetylcholine, carbamylcholine, serotonin, prostaglandins and leukotrienes. Since
      any bronchoconstrictor agent has a potential for making a patient uncomfortable
      due to the induced bronchoconstriction, necessary equipment for anaphylaxis
      should be available and trained personnel should be aware of possible adverse
      reactions which can occur uncommonly.

PMID- 8645422
TI  - [How to diagnose food allergy or the importance of the underestimation of food
      allergy].
AB  - Food allergy has an origin of extra-digestive and/or digestive origin. Diagnosis
      includes the measurements of total and specific IgE, but especially an
      elimination test for at least a month, followed by re-introduction of the foods.
      Finally, the assistance is needed of a provocation test against placebo, under
      control of mediators of anaphylaxis, plasma histamine, tryptase, urinary methyl
      histamine. Treatment should include, apart from substitution of the food where
      necessary, the possibility of acceptance of the food under sodium cromoglycate
      (Nalcron 100 mg or Intercron 100 mg). This development is very desirable.
      Depending on the subject, and in a time that is difficult to evaluate, there may
      develop an immunological tolerance to the food.

PMID- 8645423
TI  - Effects of lodoxamide (LOD), disodium cromoglycate (DSCG) and N-acetyl-aspartyl
      glutamate sodium salt (NAAGA) on ocular active anaphylaxis.
AB  - LOD, DSCG and NAAGA eye-drops were evaluated on experimentally-induced ocular
      active anaphylaxis in guinea pigs. Twelve animals per group were sensitized with
      egg albumin i.p. and challenged on the surface of the eye 14 days later. Two days
      before challenge, animals were treated with LOD, DSCG or NAAGA 4 times a day.
      Permeability indexes were calculated after intracardiac injection of Evans Blue.
      No effect on ocular active anaphylaxis was found with LOD nor with DSCG. NAAGA
      was able to significantly reduce blood-eye permeability indexes.

PMID- 8645424
TI  - p53 transactivation through various p53-responsive elements.
AB  - p53 is a nuclear phosphoprotein whose function is classified as tumor
      suppression. Studies have shown that p53 functions by binding to p53 DNA
      recognition sequences and regulates transcription of growth-regulatory genes.
      Various p53 recognition sequences have recently been identified. pOST2 contained
      two copies of a palindromic high-affinity DNA-binding sequence for p53; the other
      p53 recognition sequences included p53-binding fragments found in the human
      ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase
      promoter (pMCK). The purpose of this study was to compare the abilities of
      various p53 recognition sequences to mediate transcription in the presence of
      endogenously produced wild-type (wt) or mutant p53. Three p53-responsive
      chloramphenicol acetyltransferase (CAT) reporter constructs (pOST2, pRGC, and
      pMCK) that contain one or two copies of p53 recognition sequences upstream of a
      herpes thymidine kinase (TK) promoter and CAT reporter cDNA were constructed.
      Either a p53-responsive gene or a control reporter gene was transfected into
      human carcinoma cell lines (having various p53 mutations) either with or without
      a wt or mutant p53 expression vector. CAT activity was assayed to measure
      transactivation through the various p53-responsive elements. We showed that pOST2
      had a greater ability to mediate transactivation by p53 than either pRGC or pMCK.
      p53 with a mutation at either codon 175 or 248 was unable to transactivate a
      reporter gene with pOST2, pRGC, or pMCK. We found it interesting that pOST2, but
      not pRGC or pMCK, was able to mediate transactivation in cell lines that produce
      codon 273-mutant p53. These findings suggest that various sensitivities of the
      different p53-responsive elements to specific mutant and wt p53s may be an
      important factor in the role of p53 as a transcriptional activator both under
      normal physiological conditions and during carcinogenesis.

PMID- 8645426
TI  - High-fat diet blocks the inhibition of skin carcinogenesis and reductions in
      protein kinase C by moderate energy restriction.
AB  - The aim of this investigation was to determine the impact of dietary energy
      restriction (ER) with control (C) and high-fat (HF) diets on two-stage skin
      carcinogenesis and on the expression of specific isoforms of protein kinase C
      (PKC). Skin carcinogenesis was initiated on SENCAR mice with 10 nmol of 7,12
      dimethylbenz[a]anthracene (DMBA) in 0.2 mL of acetone and then promoted with
      twice weekly treatments of 3.2 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA)
      in 0.2 mL of acetone for 18 wk. The experimental diets fed during TPA treatment
      and for 10 wk after the last TPA treatment were formulated with C (10% calories
      from fat) and HF (42% calories from fat) levels for freely fed groups. These
      diets were restricted by 20% (20% ER/C and 20% ER/HF) and by 40% (40% ER/C and
      40% ER/HF). Papilloma incidence was reduced in the mice fed the 20% ER/C, 40%
      ER/C, and 40% ER/HF diets in comparison with the C, HF, and 20% ER/HF groups.
      Carcinoma incidence was also reduced in these groups. PKC alpha and zeta were
      assessed by western blot analysis in the epidermises of mice pre-fed the six
      diets for 8-10 wk (without DMBA or TPA treatment). PKC alpha was reduced in the
      particulate fraction by 32-44% in the 20% ER/C, 40% ER/C, and 40% ER/HF groups (P
      < 0.005). PKC zeta was reduced by 24-31% in the cytosol of mice fed the 20% ER/C
      diet and in the particulate fraction of mice fed the 40% ER/C diet (P < 0.05).
      The HF diet was able to block the inhibition of skin carcinogenesis and the
      reduction in the expression of PKC in the epidermis by 20% ER but not by 40% ER.

PMID- 8645425
TI  - Influence of human papillomavirus type 16 gene expression on in vitro
      differentiation of the human teratocarcinoma cell line 2102Ep.
AB  - Human papillomaviruses (HPVs) are known to infect human keratinocytes and cause
      alterations in epithelial differentiation. We showed in this study that
      expression of the HPV-16 genome was able to interfere with the in vitro
      differentiation of a human simple-epithelial cell type, the 2102Ep
      teratocarcinoma cell line. Stable HPV-16 genome-expressing 2102Ep cell lines were
      generated, and subsequent alterations in differentiation were analyzed in
      comparison with parental 2102Ep cells. We found that in 2102Ep cells phorbol
      ester-induced differentiation led to changes in the expression of SSEA antigens,
      whereas in HPV-transfected cell lines only minor changes were observed.

PMID- 8645427
TI  - Use of transgenic animals in carcinogenesis studies.

PMID- 8645428
TI  - Enhancement of tumor growth by drugs with some common molecular actions.
AB  - A group of structurally related drugs representing diverse therapeutic classes
      share, among a number of pharmacological properties, enhancement of tumor growth
      in several rodent models of malignancy. One common action, the inhibition of
      histamine binding to and catalytic activity of cytochrome P450 monooxygenases, is
      highly correlated with potency to enhance tumor growth. Among members of this
      drug ensemble, the antiestrogen tamoxifen has been shown in controlled clinical
      studies to increase the incidence of uterine and gastrointestinal cancer and to
      accelerate the course of gastric cancer, and the tamoxifen analogue clomiphene
      has been linked to neuroblastoma and the tricyclic group of antidepressants to
      ovarian cancer. The determination of drug affinities for protein modulators of
      cell growth, proliferation, and transformation suggests a strategy for
      identifying at least some classes of chemicals that impart oncologic risks to
      humans.

PMID- 8645429
TI  - Effects of mutationally activated Ha-ras on c-fos expression kinetics in rat
      tracheal epithelial cells.
AB  - The rat tracheal implant model was used to characterize the role of activated Ha
      ras in the neoplastic progression of heterogeneous rat tracheal epithelial (RTE)
      cell populations. An activated Ha-ras-containing cell line, RTE 2-2, and its
      subclone, RTE 2-2n, which possesses only Ha-ras proto-oncogene alleles, were
      studied to determine whether activated ras could interact with the downstream
      signal transduction targets fos and myc and alter their cell-cycle-dependent
      expression in vitro. Transformed RTE cell lines with activated Ha-ras displayed
      earlier fos expression, with a peak at 15 min after serum stimulation. These cell
      lines also displayed a more accelerated loss of fos mRNA than seen in cells
      without activated Ha-ras. The effects on fos expression kinetics were seen only
      in cell lines with activated ras and were not related to the transformed
      phenotype of the cells. No change in myc expression kinetics were observed in any
      RTE cell line. These results suggest that mutations in ras can lead to
      alterations in nuclear components of the ras signaling pathway at the level of
      gene transcription.

PMID- 8645430
TI  - Loss of heterozygosity on chromosomes 1, 11, 12, and 14 in hybrid mouse lung
      adenocarcinomas.
AB  - An allelotype analysis of lung tumors in mouse hybrids was conducted to identify
      common regions of allelic loss. By using 50 informative genetic markers, the
      autosomes of 36 (A/J x C3H/HeJ) F1 adenocarcinomas were examined. Additional
      adenocarcinomas from as many as 72 (C3H/HeJ x A/J) F1 and 15 (BALB/cJ x DBA/2J)
      F1 hybrids also were analyzed for DNA loss at some of the loci. Loss of
      heterozygosity (LOH) was observed at multiple loci and occurred with the most
      regularity at markers on chromosomes 12 (28%), 14 (28%), 11 (21%), and 1 (20%).
      The frequency of LOH was not greater than 11% on any of the other chromosomes.
      Chromosomes 11 and 14 often displayed allelic loss at markers located near the
      p53 and retinoblastoma tumor suppressor loci, respectively. LOH at markers on
      chromosomes 12 and 14 was associated with tumors having overall frequencies of
      allelic loss that exceeded the median value. Losses on chromosomes 1, 11, 12, and
      14 also showed a significant association with the adenocarcinoma stage of mouse
      lung tumorigenesis, suggesting that the inactivation of tumor suppressor loci on
      these chromosomes may participate in the progression of these tumors.

PMID- 8645431
TI  - Alteration of c-fos gene methylation in human gliomas.
AB  - In an attempt to find a common DNA alteration occurring in human glioma, we
      examined DNA methylation in 34 gliomas of various pathological grades and
      compared them with those in normal cerebral subcortex DNA. The total methylated
      cytosine levels in the genome did not differ appreciably between the tumors and
      the normal tissues; however, the degree of DNA methylation in several proto
      oncogenes and suppressor oncogenes showed some alterations. Among them, the c-fos
      gene demonstrated deviation from that of normal tissues in all cases examined,
      suggesting that the alteration of c-fos gene methylation plays a role in the
      early steps of human glioma development.

PMID- 8645432
TI  - Spectral analysis during fatigue. Surface and fine wire electrode comparison.
AB  - Fine wire (FW) intramuscular electrodes and spectral analysis have not previously
      been used to quantify metabolic muscle fatigue in deep muscles not accessible
      with surface electrodes. This study compares initial median frequency (IMF) and
      decline in median frequency with fatigue (SLOPE) using surface and FW electrodes.
      Eighteen men performed isometric biceps contractions for 100 s. Electromyographic
      signals were collected using FW and surface electrodes. The recordings of SLOPE
      was greater with FW (-0.44 v -0.23 %IMF/s) and IMF was higher (195 v 69 Hz).
      Intrasession reliability for slope was better with FW electrode (intraclass
      correlation coefficient (ICC) = 0.74; P<0.0001) than with the surface electrode
      (ICC = 0.43; P = 0.006), but intersession reliability was best with the surface
      electrode (ICC = 0.50; P = 0.03). Spectral analysis using FW electrodes provides
      earlier detection of muscle fatigue and can be used in deep muscles, but the
      reliability must be improved before clinical application.

PMID- 8645433
TI  - Are you a fraud? Am I a fraud? Is PM&R a fraud?

PMID- 8645435
TI  - Effects of functional electrical stimulation-induced lower extremity cycling on
      bone density of spinal cord-injured patients.
AB  - Spinal cord-injured (SCI) patients are at increased risk for fractures secondary
      to neurogenic osteoporosis. Earlier research claimed physical conditioning
      resulted in a decreased incidence or reversal of neurogenic osteoporosis. This
      study evaluated the effects of functional electrical stimulation-induced lower
      extremity cycling (FESILEC) on the bone densities of SCI patients using dual
      energy x/ray absorptiometry (DEXA). The study consisted of 12 healthy male SCI
      patients, aged 23 to 46 (x +/- SD, 34 +/- 6) yr. The patients were post
      traumatic, complete, spastic SCI; time postinjury ranged from 2 to 19 (9.7 +/-
      5.1) yr. Patients participated in a three-phase training program. Phase 1
      consisted of quadriceps strengthening. Phase 2 consisted of progressive
      sequential stimulation of quadriceps, hamstrings, and gluteal muscles, achieving
      a rhythmical pedaling motion on the REGYS I ergometer. Phase 3a consisted of 30
      min FESILEC sessions. DEXAs were done at baseline and at completion of Phase 3a
      and Phase 3b. Bone densities were done of the lumbar spine levels 2-4 (L2-4),
      bilateral trochanters (T), Ward's triangles (WT) and femoral necks (FN). Baseline
      bone density indicated no difference between L2-4 of ambulatory males and SCI
      males. Baseline values obtained for T, WT, and FN were, respectively, 71, 82, and
      79% of ambulatory values. Results after completion of the Phase 3a training
      program indicated no statistically significant difference compared with baseline
      values. There was, however, a positive trend in the lumbar spine post-Phase 3a
      (L2-4, P=0.056). Eight patients continued the exercise program, using a
      combination of upper and lower extremity cycling (Phase 3b) for a longer period
      of time (25 +/- 9 wk). DEXAs done after Phase 3b indicated no change relative to
      baseline data or data post-Phase 3a. In conclusion, although FESILEC did not
      significantly increase bone density in the hip parameters of chronic SCI
      patients, a positive trend was observed in the lumbar spine. Further research
      with acute intervention, such as FESILEC during the first few months post-SCI, is
      warranted to further evaluate a treatment regimen to prevent or reduce neurogenic
      osteopenia.

PMID- 8645434
TI  - Systematic strength training as a model of therapeutic intervention. A controlled
      trial in postmenopausal women with osteopenia.
AB  - Physical exercise is often recommended as a therapeutic tool to combat pre- and
      postmenopausal loss of bone density. However, the relationship between training
      dosage (intensity, duration, frequency) and the effect on bone density still is
      undergoing discussion. Furthermore, the exercise quantification programs are
      often described so inadequately that they are neither quantitatively nor
      qualitatively reproducible. The aim of this investigation was to determine
      whether a clearly defined training of muscle strength, under defined safety
      aspects, performed only twice weekly, can counteract bone density loss in women
      with postmenopausal osteopenia. Data from 16 women in the training group (age,
      63.6 +/- 6.2 yr) and 15 women in the control group (age, 67.4 +/-9.7 yr), of
      comparable height and weight, were evaluated. Strength training was performed for
      6 mo as continually adapted strength training, providing an intensity of about
      70% of each test person's one repetition maximum. Bone mineral density of lumbar
      vertebrae 2 to 4 and the femoral neck was measured by dual-energy x-ray
      absorptiometry. Maximum performance in watts and parameters of hemodynamics were
      controlled with a bicycle ergometer test to maximal effort. In addition,
      metabolic data were assessed. In the lumbar spine and femoral neck, the training
      group showed no significant changes, whereas the control group demonstrated a
      significant loss of bone mineral density, especially in the femoral neck
      (P<0.05). The strength increase was highly significant in all exercised muscle
      groups, rising to about 70% above the pretraining status (P<0.001). Heart rate
      and blood pressure data indicated a slight economization, metabolism was not
      significantly influenced. Based on these findings, we conclude that continually
      adapted strength training is an effective, safe, reproducible, and adaptable
      method of therapeutic strength training, following only two exercise sessions per
      week.

PMID- 8645436
TI  - A tool to assess biomechanical gait efficiency; a preliminary clinical study.
AB  - A goal of many physiatric interventions is to improve biomechanical walking
      efficiency. Thus, a tool that helps assess this efficiency, independent of
      cardiac, pulmonary, psychologic, or other nonbiomechanical factors, would be
      useful. Currently used methods to measure efficiency, including comfortable
      walking speed, are not specific to biomechanical variables. A potential tool, the
      biomechanical efficiency quotient (BEQ), which uses three variables--average
      stride length, vertical displacement of the trunk during walking, and sacral
      height during standing--is proposed and preliminarily tested. This quotient is
      based on Saunders, Inman, and Eberhart's theories and on a prior study in able
      bodied subjects. The BEQ was computed in 20 consecutive patients with
      neurologically based gait disability referred for gait laboratory evaluation who
      subjectively reported that one or two ankle-foot-orthoses (AFOs) reduced the
      effort necessary to walk. The quotient was calculated with and without the AFO(s)
      by dividing the average vertical displacement of the sacrum, which was measured
      with an optoelectronic system, and by a predicted displacement, which was based
      on the patient's sacral height and average stride length. The mean BEQ with the
      AFO(s) (6.3 +/- 4.4) was significantly less than the mean BEQ without the AFO(s)
      (9.7 +/- 7.1); P = 0.005. Furthermore, the BEQ was less with the AFO(s) compared
      with trials without the AFO(s) in all subjects. Percent change in BEQ with the
      AFO(s) (26.8 +/- 19.6) correlated with percent change in comfortable walking
      velocity (24.8 +/- 31.8), r = 0.73, P<0.001, across all subjects. The BEQ may be
      useful in specifically assessing the effect on biomechanical efficiency of
      physiatric interventions, despite variable nonbiomechnical factors. An instrument
      to measure vertical trunk displacement during walking outside of the gait
      laboratory would be extremely useful for further necessary longitudinal studies.

PMID- 8645437
TI  - Posterior interosseous nerve conduction. A new method of evaluation.
AB  - Posterior interosseous nerve conduction was studied by a new method consisting of
      two different techniques in 40 controls. The motor latency of the brachioradialis
      and extensor carpi ulnaris was compared after stimulation of the radial nerve,
      either at the axilla or above the elbow. The nerve branches of the
      brachioradialis never cross the radial tunnel, whereas those of the extensor
      carpi ulnaris always cross the radial tunnel. The recording was performed with a
      coaxial needle electrode after percutaneous axillary stimulation and with surface
      electrodes after near-the-nerve elbow stimulation. The mean
      brachioradialis/extensor carpi ulnaris latency difference was 1.3 ms and
      represented the posterior interosseous nerve conduction in the radial tunnel.
      Identical values were obtained with both techniques, but the inter- and
      intraindividual variability was less marked with the elbow technique. Overall,
      the right/left comparison provided the best diagnostic data because of a normal
      range limited to only 0.4 ms after elbow stimulation.

PMID- 8645438
TI  - Effect of cognitive impairment on rehabilitation outcome.
AB  - Previous studies examining the relationship between cognition and ability to
      benefit from inpatient rehabilitation have found cognitive dysfunction to be
      associated with a poor rehabilitation outcome. To examine whether cognitive
      dysfunction precluded effective rehabilitation, 52 consecutive admissions to a
      geriatric rehabilitation unit were assigned Mini Mental State Examination (MMSE)
      scores. Functional gains were assessed by the change in Functional Independence
      Measure (FIM) score from admission to discharge. Neither MMSE score alone nor in
      combination with age was significantly associated with change in FIM (r = 0.10; R
      = 0.25; P< 0.18). MMSE score alone and in combination with age was correlated
      with functional status on admission (r = 0.58; R = 0.58; P< 0.0001) and discharge
      (r = 0.49; R = 0.51; P< 0.0004). Patients evidenced a similar increase in
      functional status regardless of cognitive ability, but cognitively impaired
      individuals entered the inpatient unit with a lower functional status, and their
      level of function at discharge was also impaired relative to cognitively intact
      cohorts. Low MMSE scores were associated with a greater likelihood of nursing
      home placement, but a considerable percentage (38%) of individuals with severe
      cognitive impairment and the majority of individuals with mild to moderate
      cognitive impairment returned home following discharge. These findings suggest
      that geriatric patients with cognitive dysfunction should be considered for
      admission to rehabilitation programs if functional gains will affect quality of
      life or disposition.

PMID- 8645439
TI  - Potential drug interactions in a physical medicine and rehabilitation clinic.
AB  - Potentially preventable adverse drug-drug interactions increase morbidity and
      financial costs to hospitals and third party payers. This study's purpose is to
      document the prevalence of potential drug-drug interactions (PDDI) in patients
      referred to a Physical Medicine and Rehabilitation (PM&R) clinic, to identify
      risk factors associated with PDDI, and to evaluate physicians' ability to
      correctly identify these PDDI. Current medication lists were obtained by
      questionnaire and confirmed by chart review for 121 consecutive new patients. The
      physician-identified PDDI were compared with computer-identified PDDI. Twenty
      seven patients (22%; 95% confidence interval, 15-31%) had PDDI. PDDI were
      associated with number of medications (P = 0.0011) and PM&R subspecialty clinic
      (P = 0.012). Twenty-nine of the 46 computer-identified interactions (63%) were
      not identified by the physicians, and the physicians falsely identified 28 other
      drug combinations as PDDI. Potential drug-drug interactions occur at high rates
      in PM&R outpatient populations, and physicians are inadequately prepared to
      identify these PDDI.

PMID- 8645440
TI  - Low-intensity, alternate-day exercise improves muscle performance without
      apparent adverse effect in postpolio patients.
AB  - The purpose of this study was to examine the effect of a low-intensity, alternate
      day, 12 wk quadriceps muscle-strengthening exercise program on muscle strength
      and muscle and motor unit integrity in 12 postpolio patients. Patients performed
      six to ten repetitions of a 5-s duration knee extension exercise with ankle
      weights. After completing six repetitions, patients rated the perceived exertion
      (RPE) in the exercised muscle. The patient continued repetitions until RPE was
      >/= 17 or ten repetitions were performed. The weight was increased the next
      exercise day whenever the RPE was < 17 after ten repetitions. Before and after
      the training program, median macroamplitude as well as jitter and blocking were
      determined electromyographically (EMG), serum creatine kinase (CK) was measured,
      and quadriceps muscle strength was assessed. The ankle weight lifted after 2 wk
      of training and at the end of the program were also recorded. Although the ankle
      weight lifted at the end of the program significantly (P < 0.05) increased from a
      mean +/- SD of 7.1 +/- 2.7 to 11.2 +/- 4.7 kg, the dynametrically determined
      muscle strength measures did not significantly (P > 0.05) increase. The EMG and
      the serum CK variables also did not significantly (P >0.05) change as a result of
      the exercise program. We conclude that performance was improved, as demonstrated
      by an increase in the amount of weight the patients lifted in the exercise
      program. No evidence was found to show that this program adversely affected the
      motor units or the muscle as the EMG and CK did not change.

PMID- 8645441
TI  - Successful treatment of post-traumatic narcolepsy with methylphenidate: a case
      report.
AB  - Narcolepsy is a rare sequela of brain injury. We report the case of a 27-yr-old
      male with post-traumatic narcolepsy who was successfully treated with
      methylphenidate. This patient sustained moderate brain injury from a motorcycle
      accident. Subsequently, he manifested the classic tetrad of narcolepsy:
      cataplexy, excessive daytime sleepiness, sleep paralysis, and hypnogogic
      hallucinations. There was no premorbid seizure or sleep disorder. There was no
      family history of sleep disorders. Polysomnography and Multiple Sleep Latency
      Test confirmed the diagnosis of narcolepsy. Sleep latency (time to sleep onset),
      rapid eye movement sleep latency (time from sleep onset to rapid eye movement
      sleep onset), and mean multiple sleep latency were all pathologically shortened
      (2.5, 66, and 1.2 min, respectively). Twenty-four hour electroencephalographic
      monitoring and magnetic resonance imaging of the brain were normal, as were serum
      chemistries. Treatment with caffeine was unsuccessful. He was then started on
      methylphenidate, 10 mg twice daily, which was increased to 30 mg twice daily over
      a 4-mo period. Cataplexy and excessive daytime sleepiness started to improve 1 mo
      after adjustments in methylphenidate dosing. Six months after the initiation of
      methylphenidate therapy, the patient is completely asymptomatic.

PMID- 8645442
TI  - Footwear: the hidden component in sporting injuries? A commentary.

PMID- 8645443
TI  - Functional gain and length of stay for major rehabilitation impairment
      categories. Patterns revealed by function related groups.
AB  - This study evaluates the relationship of functional severity to patterns of
      functional gain and length of stay (LOS) for patients discharged from medical
      rehabilitation. It further compares differences in patterns between summed and
      Rasch transformed subscales of the Functional Independence Measure (FIM). Two
      different schemes of the FIM-Function Related Groups (FIM-FRGs) are used to
      define groups of patients who present with similar degrees of functional
      severity. The first scheme was developed using summed admission motor and
      cognitive FIM subscores (FIM-FRGs). The second scheme was developed by
      transforming these same motor and cognitive FIM subscores into logits (Logit FIM
      FRGs), thus making FIM scores more equal-interval. The study included 32,494
      patients who were discharged from 123 facilities that submitted data to the
      Uniform Data System for Medical Rehabilitation (UDSMR) and involved the separate
      evaluation of 18 different rehabilitation impairment categories. Motor FIM gain
      was calculated for each FRG in both schemes as the patient's discharge motor FIM
      score minus the admission motor FIM score. There were four patterns of motor FIM
      gain and two patterns of LOS across rehabilitation impairment. The most common
      pattern in both schemes was linear trend, for which median gains and LOS were
      highest for patients in the most disabled FRGs and lowest for patients in the
      least disabled FRGs. Gain patterns differed across impairment and across the two
      schemes. The motor FIM gain distributions provide clinicians with a range of
      typical functional outcomes for patients admitted to medical rehabilitation. This
      descriptive approach provides clinicians and administrators with a simple way to
      compare the motor FIM gain and LOS patterns of patients teated in local
      facilities with broad-based norms. This sample includes about one-quarter of
      rehabilitation facilities nationwide, thus representing population standards for
      facilities participating in the UDSMR. Suggestions are made on how to use these
      norms most appropriately for both facility and patient comparison.

PMID- 8645445
TI  - Commercial implications of the Human Genome Project.

PMID- 8645444
TI  - Functional outcome and comorbidity indexes in the rehabilitation of the traumatic
      versus the vascular unilateral lower limb amputee.
AB  - This study compared the Functional Independence Measure (FIM) scores of traumatic
      (n=12) and vascular (n=12) unilateral lower limb amputees at admission and
      discharge from a rehabilitation facility. FIM scores that were measured were
      amputation FIM subscores and total FIM scores. Comorbidity indexes were developed
      to weight the stump condition and comorbidities seen in both groups. The vascular
      group was significantly (P<0.01) greater stump comorbidity, but there was no
      significant difference with respect to length of stay, medical comorbidity score,
      and amputation and total FIM scores both at admission and discharge between the
      two groups. Medical comorbidity was significantly (P<0.05) correlated with
      amputation and total FIM scores at discharge for traumatic amputees with r = 
      0.64 and r = -0.66, respectively. Stump comorbidity was significantly (P<0.05)
      correlated with total FIM at discharge with r = -0.64 for vascular amputees.
      Medical comorbidity was a good predictor of discharge FIM scores for traumatic
      amputees, whereas stump comorbidity predicted discharge FIM scores for vascular
      amputees, although not as well. In conclusion, inpatient traumatic amputees may
      be younger than vascular amputees, but traumatic amputees may not necessarily be
      healthier or do better functionally at discharge than vascular amputees.

PMID- 8645446
TI  - The promise of gene quantification.

PMID- 8645447
TI  - Phosphorothioate antisense oligodeoxynucleotides: questions of specificity.

PMID- 8645448
TI  - Controlling IGF-receptor function: a possible strategy for tumor therapy.
AB  - The insulin-like growth factor-1 receptor (IGF-IR) is one of several growth
      factor receptors that regulate the proliferation of mammalian cells. However, its
      ubiquitousness and certain unique aspects of its function make IGF-IR an ideal
      target for therapeutic interventions against abnormal growth, with very little
      effect on normal cells.

PMID- 8645449
TI  - Macromolecular versus small-molecule therapeutics: drug discovery, development
      and clinical considerations.
AB  - Recent advances in biomedical science in general, and molecular biology in
      particular, have provided a greater understanding of pathogenesis at the
      molecular and (sub)cellular level. In turn, this has stimulated the development
      of macromolecular, mechanism-based therapeutic agents, ranging from recombinant
      proteins, to oligonucleotides, to genes/gene fragments. The factors essential for
      the successful development of this new class of therapeutic agents are not
      necessarily the same as those for the development of conventional small organic
      molecules. This review mentions several issues relating to the development of
      macromolecular drugs, and emphasizes the key issue of drug transport and
      delivery.

PMID- 8645450
TI  - Engineering challenges in cell-encapsulation technology.
AB  - The use of implantable immunoisolation devices, in which the tissue is protected
      from immune rejection by enclosure within a semipermeable membrane or
      encapsulant, is one approach in the development of cell therapies. However,
      further research is required in the areas of: tissue supply from primary or cell
      culture sources; maintenance of cell viability and function, its relationship to
      device design, and the role of, and factors affecting, oxygen-supply limitations;
      and, protection from immune rejection, especially in view of the mechanisms
      thought to operate in the presence of a semipermeable membrane, the properties of
      that membrane, and the implications for biology and device design.

PMID- 8645451
TI  - Immunoprotection of therapeutic cell transplants by encapsulation.
AB  - The inflammatory response to an allogeneic or xenogeneic tissue transplant by the
      recipient is complex and includes both the specific immune response, and the non
      specific response resulting from damage during implantation, ischaemic
      reperfusion injury and partial necrosis of the transplanted tissue.
      Transplantation of allogeneic or xenogeneic tissue within a biomembrane requires
      that the biomembrane be biologically inert, and that the mean pore size is
      adequate to allow the passage of oxygen and nutrition of the enclosed tissues,
      egress of the desired hormone or growth factor, while protecting the enclosed
      tissue from both the specific and non-specific responses of the host.

PMID- 8645452
TI  - Islet amyloid in type 2 (non-insulin-dependent) diabetes.
AB  - Amyloid deposits are found in pancreatic islets of 90% of type 2 (non-insulin
      dependent) diabetic subjects at postmortem. Islet amyloid is formed from islet
      amyloid polypeptide (IAPP). IAPP is a 37 amino acid peptide which is a normal
      constituent of beta cells and is co-secreted with insulin in animals and in man.
      The causative factors for fibrillogenesis of IAPP are unclear, but could be
      related to the sequence of IAPP and abnormal production of the peptide. The lack
      of islet amyloid in rodent models of diabetes is due to proline substitutions in
      the amyloidogenic region of IAPP. Amyloid fibrils are deposited between beta
      cells and islet capillaries: fibrils in invaginations of the plasma membrane may
      interfere with membrane signalling and insulin release. Amyloid fibrils are
      formed within 2 days in culture in islets isolated from transgenic mice
      expressing the gene for human IAPP, but not in vivo. Overexpression and decreased
      clearance of human IAPP from islet spaces may be important factors. Progressive
      deposition of IAPP fibrils combined with the associated reduction in the insulin
      secreting beta cells is likely to contribute to deterioration of islet function
      in the course of type 2 diabetes.

PMID- 8645453
TI  - Increase in mucosal and connective tissue-type mast cells in the stomach with
      acetic acid-induced ulcer in rat.
AB  - Gastric ulcers were induced in rats by acetic acid treatment, and the mast cell
      kinetics in the lesions were studied. Within 24 h, mast cells had disappeared
      from the treated site and from the marginal zone, corresponding to the area of
      severe tissue injury. Regenerating epithelium appeared at day 10, and the lesion
      had healed by day 30. In this healing process, the number of mast cells was
      significantly increased, and their density in the regenerating mucosa, marginal
      mucosa, and marginal muscularis propria was 3.2 1.8, and 7.5-fold the control
      level, respectively. The increase in the number of mast cells was preceded by an
      increase in the percentage of S-phase mast cells. Mast cells in the mucosa were
      Alcian blue (AB)+/safranin (S)- and rat mast cell protease (RMCP) I-/II+,
      consistent with the features of mucosal mast cells throughout the observation
      period. On the other hand, most mast cells in the muscularis propria exhibited
      AB+/S+ and RMCP I+/II+ in the early period of ulcer healing. The latter feature
      was changed to RMCP I+/II- on day 30, indicating that immature CTMC appeared and
      then developed into mature CTMC during the ulcer healing. The significant change
      in the number of mast cells suggests that mast cells play an important role in
      the development and healing of gastric ulcers.

PMID- 8645454
TI  - T-cell recognition of beta-cell autoantigens in insulin-dependent diabetes
      mellitus.
AB  - Autoimmune T cells reactive to beta-cell autoantigens are generally believed to
      play an essential role in the immune-mediated selective pancreatic islet beta
      cell destruction process leading to insulin-dependent diabetes mellitus (IDDM).
      Many of the supportive data have been obtained from animal models of this
      disease, but often these data remain to be validated in human IDDM, including the
      nature of the responsible autoreactive T cells and their targets on the beta
      cells. In the last few years, however, considerable progress has been made, and
      several candidate autoantigens have been identified. Diabetogenic T-cell clones
      have been isolated and characterized in animal models, but for the majority of
      these clones, the target autoantigen is unknown. In humans, the first islet
      autoantigens recognized by autoreactive T cells have been defined. This opens the
      way to designing immunointerventive strategies selective for these T cells and
      their candidate target antigens, in an attempt to prevent the onset of IDDM. In
      this review, we described the significance of T lymphocytes for the pathogenic
      process leading to type 1 diabetes and our studies showing (auto)immune responses
      by beta-cell-reactive T lymphocytes of newly diagnosed patients.

PMID- 8645455
TI  - Human papillomavirus infection in cervical biopsies from Norwegian gynecological
      in-patients.
AB  - Polymerase chain reaction (PCR) and Southern blotting were used to assess the
      prevalence of HPV in cervical biopsies of 100 women who were treated at the
      gynecology department of Telemark Central Hospital for non-cancerous conditions.
      Nine (9%) of the biopsies were HPV positive. Four (4%) were of HPV type 18, one
      (1%) was HPV11 positive, and four contained different unrecognized HPV types
      (HPVX). HPV16 was not detected.

PMID- 8645456
TI  - Interrelations of clinicopathologic variables and their prognostic value in
      colorectal adenocarcinoma.
AB  - We analyzed the interrelations of sex, age, tumor site, Dukes' stage, growth
      pattern and differentiation, and their prognostic value in 293 patients with
      primary colorectal adenocarcinoma. Simultaneously, growth pattern,
      differentiation, DNA and S-phase fraction (SPF) in paired primary tumors and
      lymph node metastases from 97 colorectal cancer patients were compared. The
      results revealed that poorly differentiated and mucinous tumors, as against
      well/moderately differentiated tumors, were frequently located in the proximal
      colon, and their frequencies were increased as Dukes' stage advanced (p=0.03).
      Tumor differentiation was usually identical in primaries and corresponding
      metastases (p=0.002), but this was not true of tumor growth pattern, DNA ploidy
      or SPF. In multivariate survival analyses, Dukes' stage provided strongly
      prognostic information (p<0.001) and mucinous tumors tended to predict worse
      survival (p=0.08).

PMID- 8645457
TI  - The adherence of oral isolates of Enterobacteriaceae to HeLa cells. An in vitro
      method using image analysis.
AB  - An in vitro model and an image analysis were designed to improve on existing
      quantification methods in the assessment of the adherence of Enterobacteriaceae
      to human epithelial cell monolayers. Adherence to HeLa cell monolayers of three
      oral isolates and one type strain from each of four species of Enterobacteriaceae
      over two incubation time periods was examined. Correction for actual cell area
      and a cube root transformation of the data to stabilize variance were applied.
      While behaviour varied between strains within species, E. cloacae was the most,
      and K. pneumoniae the least, adherent species irrespective of the incubation
      period. Increasing the incubation period from 30 min to 60 min resulted in
      greater adherence for E. cloacae, E. coli, and C. freundii, but not K. pneumoniae
      strains. The method permits the reliable measurement and valid analysis of the
      adherence of Enterobacteriaceae to cultured epithelial cell monolayers.

PMID- 8645458
TI  - Altered expression of CA-125 in breast carcinomas.
AB  - CA-125 is a high molecular weight glycoprotein that is best known as a tumour
      marker for ovarian carcinoma but has been found to be present on various
      epithelial surfaces including normal tissues. Elevated serum levels of CA-125
      have been described in malignancies other than ovarian carcinoma as well as in
      inflammatory conditions. The expression of CA-125 was studied in paraffin
      embedded tissue from 48 mammary carcinomas and 11 samples of normal mammary gland
      using two monoclonal antibodies, M2 and M11. CA-125 was detected in all normal
      tissue samples and 64% of the breast carcinomas. Eight of the thirty CA-125
      positive carcinomas reacted with only one of the antibodies, indicating molecular
      change. In normal mammary tissue, CA-125 was seen on apical surfaces and in
      ductal contents, whilst the majority of the carcinomas (90%) expressed CA-125 in
      cytoplasmic granules, often showing membranous staining as well. In 16 samples of
      lymph node metastases CA-125 expression was similar to that seen in the primary
      tumour. Elevated serum levels of CA-125 were detected in only 3 out of 41 samples
      available from this patient group. No significant associations were detected with
      various clinical parameters. We conclude that CA-125 is normally expressed in the
      mammary gland and that the expression is frequently altered and sometimes absent
      in mammary carcinoma, possibly reflecting the loss of cellular polarity.
      Measuring serum levels of CA-125 is not relevant in breast carcinoma patients
      since one third of breast carcinomas were CA-125 negative and even patients with
      strongly CA-125-positive tumors had undetectable CA-125 serum levels.

PMID- 8645459
TI  - Immunological properties of meningococcal lipopolysaccharide from serogroups A, B
      & C.
AB  - The aim of the study was to measure and compare the oxidative burst, chemotaxis
      and cytokine production of human white blood cells, stimulated with meningococcal
      lipopolysaccharides (LPS) extracted from three different serogroups (A, B and C)
      of Neisseria meningitidis, and to evaluate whether convalescent sera from
      patients with meningococcal disease could modify cell stimulation of LPS. All
      three preparations of LPS from groups A, B and C were tested using the Limulus
      amoebocyte lysate assay (LAL), and the KDO concentrations of the LPS extracts
      were measured. Equivalent amounts of biologically active LPS, judged by LAL, and
      LPS with the same KDO concentration were assayed. IL-1alpha, IL-1beta, IL-6 and
      TNF-alpha production was stimulated by all three LPS preparations. All three
      preparations stimulated oxidative burst in monocytes (MNC). Only group A LPS
      stimulated neutrophil chemotaxis, while none of the three LPS stimulated
      superoxide production. Pooled convalescent sera from five patients with
      meningococcal disease suppressed the activity of neutrophils stimulated with LPS
      from groups B and C (p<0.05, Mann-Whitney U-test).

PMID- 8645460
TI  - Basophil-bound IgE and serum IgE directed against Haemophilus influenzae and
      Streptococcus pneumoniae in patients with chronic bronchitis during acute
      exacerbations.
AB  - The investigation includes 12 patients hospitalized with acute exacerbations of
      chronic bronchitis (CB) and infected in the lower respiratory tract with
      Haemophilus influenzae (HI) or Streptococcus pneumoniae (SP). Eight patients were
      infected the HI, three with SP, and one patient with both species. Basophil-bound
      IgE and serum IgE directed against these species were examined using the
      patients' own bacterial isolates. All patients showed IgE-mediated histamine
      release when their peripheral leukocytes were incubated in vitro with the
      infecting species, indicating basophil-bound IgE directed against their own
      bacterium. No IgE-mediated response was obtained in the control group of 12
      healthy individuals. Bacteria-specific IgE in serum was demonstrated by
      immunofluorescence assay and further verified by passive sensitization. There was
      a positive serum titre in seven of nine patients housing HI and in all SP
      infected patients but not in the control group. No synchronism was found between
      a positive response in the histamine release test and the immunofluorescence
      assay by parallel testing during the test period. This may be due to a time delay
      between production of serum IgE and its fixation to the cell surface. The results
      indicate a potential for a bacteria-specific IgE-mediated immune response in CB.
      Thus, by triggering mediator release, bacteria may be involved in the
      pathogenesis of exacerbations in CB.

PMID- 8645461
TI  - Prevalence of human papillomavirus in cervical scrapes, as analyzed by PCR, in a
      population-based sample of women with and without cervical dysplasia.
AB  - HPV is suspected of being a major cause of cancer of the uterine cervix. To
      understand the risk of disease in the general population of women, it is
      important to estimate the prevalence of HPV infection in a random population
      based sample of women without disease. In this study, a total of 231 randomly
      selected women without dysplasia (controls) were examined, and compared with 103
      women with histologically confirmed CIN II-III (patients). The prevalence of HPV
      DNA in cervical scrapes was determined by general nested PCR, which was expected
      to detect any relevant HPV type commonly found in cervical samples. The nested
      positive samples were typed with type-specific PCR. In the general nested PCR,
      15% of the controls were positive, compared to 91% of the patients. In the
      population-based sample, 2.2% had HPV types 6 and 11 and 10% had types 16, 18,
      31, and 33. In both groups, HPV DNA was observed less frequently in women above
      than below the age of 30. The results are among the few population-based figures
      on the prevalence of HPV in women, and provide a baseline for understanding the
      risk of developing cancer of the uterine cervix, and determining the proportion
      of women to be included in intervention studies.

PMID- 8645462
TI  - Comparison of haemolytic activity between Fusobacterium necrophorum subsp.
      necrophorum and Fusobacterium necrophorum subsp. funduliforme in vitro and in
      vivo.
AB  - Haemolytic activity of two subspecies of Fusobacterium necrophorum was compared
      in vitro and in vivo. F. necrophorum subsp. necrophorum (Fnn) showed a stronger
      activity than F. necrophorum subsp. funduliforme (Fnf) in vitro. Haemolytic
      activity of Fnn and Fnf was 57.97%+/-1.90 and 17.33%+/-1.44, respectively,
      compared to complete haemolysis by distilled water. In the mice injected with
      Fnn, haemolysin was detected in the liver at a titre of from 1 : 16 to 1 : 128,
      and Fnn was recovered from all mice at a viable bacterial count of 10(5) to 10(6)
      cells per gram liver tissue. In the mice injected with Fnf, haemolysin titre was
      <1 : 2 to 1 : 32. No liver abscess was formed. The viable count of recovered
      bacteria was 10(3) to 10(5) cells per gram, except for two mice in which no Fnf
      was detected. The results suggest that haemolysin might be a virulence factor in
      this species.

PMID- 8645463
TI  - Diagnosis of systemic mycoses by specific immunohistochemical tests.
AB  - Immunohistochemistry has proved to be a powerful tool for the accurate diagnosis
      of a number of important mycoses in humans and animals, such as aspergillosis,
      candidosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis
      capsulati and duboisii, paracoccidioidomycosis, fusariosis, pseudallescheriosis
      (scedosporiosis), sporotrichosis, trichosporonosis, penicilliosis, and
      zygomycosis (mucormycosis). These techniques are also applicable to
      pneumocystosis and to non-mycotic infections caused by algae such as
      protothecosis. Apart from the specificity of immunohistochemistry, the
      application of fluorochromes is highly effective for the localization of typical
      or atypical fungal elements in lesions with only few organisms present.
      Occasionally, a dual aetiology of fungal infections may be suspected on the basis
      of morphological study, and dual staining techniques have the capacity for
      resolving this question by simultaneous and differential staining of two fungal
      species present in a tissue specimen.

PMID- 8645464
TI  - Effects of heparin and aminoguanidine on glomerular basement membrane thickening
      in diabetic rats.
AB  - The effects of heparin and aminoguanidine on glomerular basement membrane
      thickening were studied in streptozotocin diabetic Sprague-Dawley rats. A placebo
      treated group and a non-diabetic group served as controls. All diabetic rats
      remained severely hyperglycaemic (23 mmol/l) throughout the 8-month study period.
      At the end of this time relative kidney weight was significantly increased in
      diabetic control rats (4.9 +/- 0.5 g/kg b.w.) compared with non-diabetic rats
      (3.3 +/- 0.3 g/kg). This increase was not affected by the intervention
      treatments. Glomerular basement membrane thickness increased 32% in diabetic
      control rats (240 +/- 24 nm) compared with non-diabetic rats (182 +/- 20 nm).
      This increase was prevented by s.c. treatment with both unfractionated and low
      molecular weight heparins, while basement membrane thickness was the same in
      animals treated with oral heparins and aminoguanidine and untreated diabetic
      rats. Macroscopic malignant kidney tumours were seen in three aminoguanidine
      treated rats. In conclusion, subcutaneously administered heparin prevents
      diabetes-induced glomerular basement membrane thickening.

PMID- 8645465
TI  - Lipofuscin formation in cultured retinal pigment epithelial cells exposed to
      photoreceptor outer segment material under different oxygen concentrations.
AB  - Lipofuscin accumulates in the course of time in the acidic vacuolar apparatus of
      retinal pigment epithelial (RPE) cells and may influence their metabolic
      functions. In order to study the effect of oxidative stress on lipofuscin
      accumulation, rabbit RPE cell cultures were kept at an ambient oxygen
      concentration of either 8% or 40%. To simulate the normal phagocytic function of
      RPE cells, bovine photoreceptor outer segments (POS) were added daily. The
      lipofuscin-specific autofluorescence was measured after 1, 2 and 3 weeks. RPE
      cells cultured under normobaric hyperoxic conditions (40% oxygen) showed
      significantly higher levels of lipofuscin-like autofluorescence than those kept
      under normobaric and probably normoxic conditions (8% oxygen) after 1 (p =
      0.0050), 2 (p = 0.0001) as well as 3 (p = 0.0077) weeks. At both oxygen
      concentrations, the lipofuscin accumulation level was increased after 2 weeks of
      POS exposure (40% p = 0.0001; 8% p = 0.0037) and even further after 3 weeks (40%
      p = 0.0541; 8% p = 0.0377). The results suggest an involvement of oxidative
      mechanisms in the formation of lipofuscin from phagocytized POS by RPE cells. The
      autofluorescence of control cells, not exposed to POS, was significantly (40%: 1
      week p = 0.0011, 2 weeks p = < 0.0001, 3 weeks p = 0.0001; 8%: 1 week p = 0.0036,
      2 weeks p = 0.0063, 3 weeks p = 0.0066) lower than that of the POS-fed cells. The
      autofluorescence increased significantly (40% p = 0.0059; 8% p = 0.0034) between
      week 1 and week 3 in the control cells. This finding may reflect a contribution
      to lipofuscin formation by autophagocytized intracellular material. The present
      model seems to be useful for further studies on the mechanisms behind
      lipofuscinogenesis of RPE cells as well as the possible effects of lipofuscin
      accumulation on cell functions and viability.

PMID- 8645466
TI  - Formation of lipofuscin in cultured retinal pigment epithelial cells exposed to
      pre-oxidized photoreceptor outer segments.
AB  - Accumulation of lipofuscin in the retinal pigment epithelium (RPE) with
      increasing age may affect essential supportive functions for the photoreceptors.
      Earlier, we described a model system for the study of lipofuscinogenesis in RPE
      cell cultures and showed that mild oxidative stress enhances lipofuscin formation
      from phagocytized photoreceptor outer segments (POS). In the present study,
      bovine POS were photo-oxidized, and turned into a lipofuscin-like material, by
      irradiation with UV light. Transmission electron microscopy of irradiated POS
      showed loss of the normal stacks of the disk membranes with conversion into an
      amorphous osmiophilic electron-dense mass. The formation of thiobarbituric acid
      reactive substances (TBARS), estimated during the irradiation process, indicated
      lipid peroxidation. Irradiated POS also showed a strong granular yellow
      autofluorescence. RPE cell cultures, kept at 21% ambient oxygen, were fed daily
      for 3, 5 or 7 days with either (i) UV-peroxidized POS, (ii) native POS or (iii)
      culture medium only. RPE cells fed irradiated POS showed significantly higher
      levels of lipofuscin-specific autofluorescence compared to cells exposed to
      native POS after 3 days (p = 0.0056), 5 days (p = 0.0037) and 7 days (p =
      0.0020), and to the non-exposed control cells (3 days: p = 0.005, 5 days: p =
      0.0037, 7 days: p = 0.0094). The lipofuscin content of cells exposed to
      irradiated POS increased significantly between days 3 and 7 (p = 0.0335).
      Ultrastructural studies showed much more numerous and larger lipofuscin-like
      inclusions in RPE cells fed irradiated POS compared to cells exposed to native
      POS. In the control cells, lipofuscin-like granules were small and sparse. It
      appears that exposing RPE cells to previously peroxidized POS, thus artificially
      converted to lipofuscin and obviously not digestible by the lysosomal enzymes,
      accelerates the formation of severely lipofuscin-loaded cells. The results will
      be useful for further studies of possible harmful effects of lipofuscin in
      heavily loaded RPE cells.

PMID- 8645467
TI  - Resistance of Streptococcus sanguis biofilms to antimicrobial agents.
AB  - Bacteria living in biofilms as dental plaque on tooth surfaces are generally more
      resistant to antimicrobial agents than bacteria in batch culture normally used
      for in vitro susceptibility testing. In order to compare the resistance of free
      living and surface-grown oral bacteria, the MIC of Streptococcus sanguis 804 and
      ATCC 10556 to amoxicillin, doxycycline and chlorhexidine was determined by a
      broth dilution method. Subsequently, S. sanguis biofilms established in an in
      vitro flow model were perfused with the antimicrobial agents for 48 h at
      concentrations equal to and up to 500 times the MIC, and biofilm cell number was
      determined during this period. The antibiotics at the MIC did not affect the cell
      number of S. sanguis biofilms compared to the starting point, and only after 48 h
      at 500 times the MIC were the biofilm bacteria eliminated. At intermediate
      concentrations biofilm cell number gradually decreased. Chlorhexidine also
      gradually reduced biofilm cell number, but was inhibitory at concentrations
      closer to the MIC than was the case for the antibiotics. Thus S. sanguis in
      biofilms survived up to 500 times the MIC found in batch culture for up to 48 h.

PMID- 8645468
TI  - Interferon-gamma increases inositol phosphate formation and cellular calcium ion
      concentration independent of ICAM-1 antigen enhancement in renal tubular cells.
AB  - In the present study, we investigated the effect of interferon-gamma (IFN-gamma)
      on cellular inositol phosphate formation and cellular calcium ion concentration
      [Ca2+]i in human renal proximal tubular (HRPT) cells. We also examined the
      possible role of the inositol phosphate-Ca2+ signalling pathway during IFN-gamma
      induced intercellular adhesion molecule-1 (ICAM-1) antigen expression. IFN-gamma
      caused an increase in the formation of inositol 1-monophosphate (Ins 1-P),
      inositol 1,4-bisphosphate (Ins 1,4-P2), inositol 1,4,5-trisphosphate (Ins 1,4,5
      P3) and inositol 1,3,4,5-tetrakisphosphate (Ins 1,3,4,5-P4). A rapid time
      dependent rise in [Ca2+]i was observed upon IFN-gamma stimulation, with maximal
      levels reached after 1 min. A lower rise in [Ca2+]i was observed when cells were
      stimulated in Ca2+-free medium. This correlated with the generation of Ins 1,4,5
      P3 by IFN-gamma, a well-known secondary messenger capable of releasing Ca2+ from
      intracellular stores. The induction of ICAM-1 antigen expression was enhanced by
      IFN-gamma, 4-bromocalcium ionophore A23187 (Bromo-A23187), and their
      combinations. However, the calcium antagonist diltiazem and calcium chelator EGTA
      had no effect on IFN-gamma antigen induction. In conclusion, our data suggest
      that IFN-gamma stimulation of HRPT cells results in the cleavage of
      phosphatidylinositol bisphosphate by phospholipase C, generating inositol
      phosphates, of which Ins 1,4,5-P3 probably releases Ca2+ from intracellular
      stores. A further increase in [Ca2+]i upon IFN-gamma stimulation results from
      influx of extracellular Ca2+. IFN-gamma signal transduction in HRPT cells may not
      be limited to the inositol phosphate-Ca2+ pathway since IFN-gamma-induced ICAM-1
      antigen expression was unaffected by calcium antagonist/chelator.

PMID- 8645469
TI  - Vascular expression of glucose transporter in and around hematogenous metastases
      of the human brain. Immunohistochemical observations.
AB  - The expression of the glucose transporter protein, GLUT 1, in endothelial cells
      of microvessels within and around hematogenous metastases of the human brain was
      investigated by immunohistochemistry using a polyclonal antibody raised against
      the carboxyl terminus of the transporter molecule. The metastases were obtained
      from 18 autopsy cases with pulmonary carcinomas. Endothelial cells of controls
      without evidence of brain pathology showed a strong immunoreactivity, indicating
      that the antigenic sites of the glucose transporter remained in the postmortem
      material. The endothelial cells of microvessels around the metastases did not
      show any changes with regard to expression of the glucose transporter. However,
      in 14 of the 18 tumor cases, microvessels located in the metastases did not
      express the transporter. Our results indicate that in human cases of brain
      metastases functional changes with regard to glucose transport occur within the
      metastases rather than in the peritumoral region.

PMID- 8645470
TI  - Antibiotic resistance mechanisms in Salmonella species causing bacteraemia in
      Malawi and Kenya.
AB  - In two studies on the causative agents of bacteraemia in Malawi and Kenya, 33
      Salmonella strains were isolated. Fourteen strains of Salmonella typhimurium and
      Salmonella enteritidis were found to exhibit resistance to amoxicillin,
      amoxicillin/clavulanic acid and cotrimoxazole as well as decreased susceptibility
      to a range of aminoglycosides. The resistant strains were studied to establish
      their resistance mechanisms. Beta-lactamase co-focusing with TEM-1 was present in
      12 strains. In two strains, both S. typhimurium from Kenya, an OXA-1 beta
      lactamase was detected. The aminoglycoside-modifying enzyme ANT(2") was found in
      10 strains. The presence of the encoding genes was confirmed by PCR. For
      comparison, susceptibility records of 73 Salmonella strains isolated during the
      past 14 years in our hospital were studied retrospectively. Only one of these
      strains was resistant to amoxicillin. This resistance was acquired during
      therapy.

PMID- 8645471
TI  - The antibody response after immunization with pneumococcal polysaccharide vaccine
      in splenectomized mice: the effect of re-immunization with pneumococcal antigens.
AB  - Splenectomized individuals are at increased risk of acquiring fulminant
      pneumococcal infections. In an experimental mouse model, we have studied how
      removal of the spleen influences the anti-pneumococcal antibody response to s.c.
      primary immunization with a 23-valent pneumococcal polysaccharide vaccine and to
      re-immunization 5 months later. In splenectomized BALB/c mice the antibody
      response to serotypes 1, 4, 7F, and 19F was reduced both after the first and
      after the second immunization, compared to that in normal mice. In contrast,
      splenectomized and normal CBA/J mice produced similar antibody levels to
      serotypes 1 and 4 after the second immunization, although the response to these
      serotypes was reduced in splenectomized mice after the first immunization. After
      i.v. injection with heat-killed pneumococci serotype 4, splenectomized BALB/c
      mice that had been immunized 5 months earlier with 23-valent vaccine were able to
      mount higher antibody levels which were reached earlier than in unprimed
      splenectomized mice. However, normal mice that had been vaccinated 5 months
      earlier had the highest antibody levels after immunization with pneumococci. Our
      results indicate that although splenectomized mice generally do not reach as high
      antibody levels as are seen in normal mice after pneumococcal immunization, they
      benefit from previous immunization with regard to antibody levels when given a
      second antigen challenge.

PMID- 8645472
TI  - Multiple serovars of Mycobacterium avium complex in patients with AIDS.
AB  - Mycobacterium avium complex (MAC) was isolated and serotyped from 127 samples
      from 43 HIV-infected patients with disseminated disease in Sweden. Thirteen
      different serovars were observed. Serovar 6 was the most common, followed by 4, 9
      and 11. Serovar 8 was rare. In 22 of the patients the same serovar was found in
      blood and at other sites. Clinical symptoms and outcome were compared in patients
      with different serovars. Analysis of patient records revealed no association
      between clinical picture and any specific serovar. The median survival time after
      MAC infection was 7 months. Somewhat shorter survival was observed in patients
      with serovar 4 than in those with serovar 6.

PMID- 8645473
TI  - [Neurocardiogenic syncope: its pathogenesis, diagnosis and treatment].
AB  - Neurocardiogenic syncope seems to be the most common cause of syncope. It is
      believed to be triggered by paradoxical autonomic reflexes, beginning in the
      ventricular mechanoreceptors of the heart, modulated by the brain stem and
      terminating in the autonomic efferent pathways (parasympathetic stimulation with
      bradycardia or asystole and sympathetic inhibition with severe hypotension). Tilt
      test has been used recently, as a safety and effective tool to identify subjects
      prone to syncope. Although the pathophysiology of this syndrome is not completely
      understood, pharmacological therapeutics seems very effective in resolving
      symptoms.

PMID- 8645474
TI  - [The radiofrequency catheter ablation of occult accessory atrioventricular
      pathways].
AB  - OBJECTIVE: The aim of this study was to evaluate our results of radiofrequency
      catheter ablation (RFCA) of concealed accessory atrioventricular pathways (CP).
      PATIENT SELECTION: We treated with RFCA 19 patients, with 21 CP, 10 men and 9
      women, mean age 37 +/- 16 years, with supraventricular tachycardia (SVT) and
      absence of ventricular pre-excitation in the electrocardiogram (ECG). These
      patients comprised 50% of the patients who underwent RFCA for SVT and had no
      ventricular pre-excitation in the ECG. The diagnosis of CP was made by
      electrophysiologic study, based on the demonstration of a pathway capable of
      retrograde conduction only. METHODS: The RFCA was performed without
      antiarrhythmic drugs in the same session of the electrophysiologic diagnosis. The
      location of the CP site was obtained by catheter mapping, looking for the
      earliest atrial retrograde activation during tachycardia or ventricular pacing.
      RESULTS: The CP had a right-sided location in only 2 patients who had an
      incessant form of SVT, the CP in these patients exhibit decremental conduction-
      permanent junctional reciprocating tachycardia. In the other patients the CP was
      left-sided, lateral in 11 patients, posterior in 3, postero-septal in 3 and
      medial septal in one patient. In 9 patients there was a simultaneous ventricular
      activation in the his bundle electrogram and in the electrogram of the ablation
      site, suggesting partial anterograde penetration of the stimuli on the accessory
      pathway. Success criteria were achieved in 18 patients (95%) corresponding to 20
      CP. CONCLUSIONS: The prevalence of CP in the presence of SVT without ventricular
      pre-excitation is high, almost all left-sided. The CP displays eccentric atrial
      activation during SVT. It is possible that CP are capable of partial anterograde
      conduction as well. The success rate of RFCA is high.

PMID- 8645475
TI  - [The radiofrequency catheter ablation of ventricular tachycardia].
AB  - OBJECTIVE: The aim of this study was to evaluate our results of radiofrequency
      catheter ablation (RFCA) of ventricular tachycardia. PATIENT SELECTION: We
      treated with RFCA nine patients, six male and three female, mean age 36 +/- 12
      years with ventricular tachycardia (VT), who fulfilled the following criteria; 1)
      recurrent VT; 2) resistant fo medical therapy despite the use of more than one
      antiarrhythmic drug; 3) inducible by programmed ventricular stimulation; 4)
      hemodynamically well tolerated. The VT etiology was coronary artery disease (CAD)
      in three patients, dilated cardiomyopathy in one, right ventricular dysplasia in
      one and it was idiopathic in four (being fascicular in three and
      catecholaminergic right ventricular outflow tract VT in one). METHODS: The RFCA
      was performed under antiarrhythmic medication. The adequate ablation site was
      obtained by mapping of the VT, looking for the earliest ventricular activation,
      identification of isolated mid-diastolic potentials during sinus rhythm or
      presystolic during VT, good pace mapping (at least 10 of the 12 standard ECG
      leads), and high frequency short duration spikes, the so called P potentials in
      fascicular VT. Primary success achieved when occurred termination of VT during
      application of RF energy and/or VT was no longer inducible by programmed
      stimulation with the same stimulation protocol. RESULTS: Global primary success
      rate was 89%, being 100% in idiopathic VT, and 80% in VT associated with
      structural heart disease. In a follow-up period of 12 +/- 14 months all patients
      were alive, 75% free of VT in the idiopathic VT group; and 50% in patients with
      structural heart disease. One of these patients underwent cardioverter
      defibrillator implantation to treat a fast VT with a new morphology not treated
      by ablation, and the other two had VT modification with a significant reduction
      in the number of episodes. CONCLUSIONS: Radiofrequency catheter ablation of VT
      has shown a good success rate, and it is a valuable alternative in patients with
      hemodynamically tolerable VT, refractory to drug treatment, highly symptomatic
      and without surgical indication. In cases of idiopathic VT we had a high rate
      success and we think that RFCA will probably become the primary indication in
      symptomatic patients.

PMID- 8645476
TI  - [Pharmacological stimulation with dipyridamole in thallium-201 myocardial
      perfusion scintigraphy: a study of the secondary effects].
AB  - To evaluate the safety of intravenous dipyridamole thallium-201 imaging as an
      alternative to exercise thallium imaging in the evaluation of coronary artery
      disease, clinical data from 140 patients were retrospectively analyzed. Adverse
      effects were experienced by 39 patients (27.9%) with a total number of 52
      effects: chest pain (23), dizziness (13), headache (7), nausea (7), dyspnea (2).
      All patients presented complete relief of symptoms. In 15 patients administration
      of aminophylline was necessary. Major effects (fatal and non fatal myocardial
      infarction and acute bronchospasm) were not registered. Vital sign data change
      observed after infusion of dipyridamole was: decreased blood pressure and
      increased pulse rate. Patient's age and incidence of coronary artery disease did
      not differ significantly in the subgroup of patients with adverse effects versus
      the group of patients without it.

PMID- 8645477
TI  - [The maximum heart rate in the exercise test: the 220-age formula or Sheffield's
      table?].
AB  - OBJECTIVE: To determine in the maximum cardiac rate in exercise test of
      apparently healthy individuals may be more properly estimated through 220-age
      formula (Astrand) or the Sheffield table. DESIGN: Retrospective analysis of
      clinical history and exercises test of apparently healthy individuals submitted
      to cardiac check-up. PARTICIPANTS: Sequential sampling of 170 healthy individuals
      submitted to cardiac check-up between April 1988 and September 1992. MATERIAL AND
      METHODS: Comparison of maximum cardiac rate of individuals studied by the
      protocols of Bruce and modified Bruce, in interrupted exercise test by fatigue,
      and with the estimated values by the formulae: 220-age versus Sheffield table.
      RESULTS: The maximum cardiac heart rate is similar with both protocols. This
      parameter in normal individuals is better predicted by the 220-age formula.
      CONCLUSIONS: The theoretic maximum cardiac heart rate determined by 220-age
      formula should be recommended for a healthy, and for this reason the Sheffield
      table has been excluded from our clinical practice.

PMID- 8645478
TI  - [Traumatic aortic valve insufficiency].
AB  - The traumatic aortic valvular insufficiency (TAVI), through less frequent after a
      non-penetrating thoracic traumatism, is a serious entity with a very reserved
      prognosis. So it must be suspected in every patients with signs or symptoms of de
      novo heart failure post-traumatism. The transthoracic echocardiography and
      eventually transesophageal echocardiography have a fundamental role in the
      confirmation of the diagnosis. The clinical picture of traumatic aortic
      regurgitation is quickly evolutionary and the non efficacy of medical therapy has
      placed the valvular substitution surgery as the best succeeded treatment. With
      the advent of the aortic valve repairing surgery some TAVI cases has been
      submitted to this procedure. Nevertheless, the development of residual aortic
      regurgitation in these situations, usually requiring later valvular replacement
      surgery, make the aortic valvuloplasty a controversial surgical technique. The AA
      describe a recent clinical case of aortic regurgitation after a non-penetrant
      thoracic traumatism, discussing the aspects connected with physiopathology,
      diagnosis and therapy. The singularity of this case was based on the fact that
      the initial clinical diagnosis had been prejudiced by the context of a
      polytraumatism and there had been a time free of symptoms between the traumatism
      and the beginning of the symptomatology of left ventricular failure. Even though
      the identification of the problem allowed an intensive treatment of this serious
      situation that ended with the replacement of the aortic valve by mechanical
      aortic prosthesis, with the patient's total recovery.

PMID- 8645479
TI  - [Sessions of a cardiac rehabilitation program in coronary disease--the hospital
      phase (phase I)].
AB  - Cardiac rehabilitation is nowadays an integral part of global treatment of the
      coronary disease. It has the goals to restore a cardiac patient to the maximum
      level of physical, mental and social condition, so that to achieve the best
      possible sociofamilial reintegration, and of secondary prevention. The cardiac
      rehabilitation programs integrate three major components: physical exercise, risk
      factor control and psychosocial intervention. They start during the period of
      hospitalization (Phase I), after medical stabilization. In this initial phase the
      aims are: risk factor education and motivation for healthier life-styles,
      psychological support, and physical training for early ambulation and self-care,
      for preventing the deleterious physiological effects of immobilization and for
      progressive reconditioning.

PMID- 8645480
TI  - [1995, the centenary year of the birth of Prof. Fernando Fonseca].

PMID- 8645481
TI  - [Reorganization of the Bylaws and Regulations of the Portuguese Society of
      Cardiology].

PMID- 8645482
TI  - [Radiological criteria for laryngeal tumors and cervical metastases].
AB  - Radiological techniques are important for studying the extension of laryngeal
      tumors. CT and MRI yield high-quality images with few artifacts that can be
      studied quickly. We reviewed the fundamental criteria for radiologic study of
      these tumors by ear, nose, and throat specialists on the basis of our personal
      experience and the literature.

PMID- 8645484
TI  - [Myringoplasty: onlay vs. underlay. Review of 460 cases].
AB  - A retrospective review was made of 460 myringoplasties performed in our
      department from 1984 to 1990. In 80%, the perforation closed successfully. There
      were no differences in site, size, cause, or previous operations. Results were
      statistically better with the onlay technique than with the underlay technique,
      particularly in large perforations. Poorer results were obtained in younger
      patients, a difference that almost reached statistical significance. Hearing
      improved in 64% of patients with closed perforations and hearing deteriorated in
      29% (2.1% complete hearing loss).

PMID- 8645483
TI  - [Criteria for assessing functional results in middle ear surgery].
AB  - INTRODUCTION AND OBJECTIVES: Comparison of reports of the functional results of
      middle-ear surgery is difficult because there are no standardized criteria, such
      as; auditory activity, histology, evaluation of functional results, follow-up
      period, etc. Moreover, surgeons and patients often disagree over the results
      obtained. The functional results obtained in 246 middle-ear operations performed
      in our department for postotorrhea sequelae were analyzed. MATERIAL AND METHOD:
      Using the SMYTH and PATTERSON criteria, benefits were analyzed in 246 patients
      for whom functional results were available. RESULTS: Benefits were analyzed by
      type of surgery, type of ossiculoplasty, presence or absence of stapedial
      superstructure, and subjective patient assessment. DISCUSSION AND CONCLUSIONS:
      Results were analyzed as surgical evaluation of functional outcome in relation to
      subjective patient assessment. Guidelines for standardizing criteria for the
      functional evaluation of middle-ear surgery are proposed.

PMID- 8645485
TI  - [Human leukocyte antigen and otosclerosis].
AB  - Fifty patients (32 women, 18 men) who underwent stapedectomy [FISCH, V. (1),
      1982] for otosclerosis were studied. Histo-compatibility antigens were typed in
      all patients using the microlymphocytic test to determine antigens of the HLA
      system loci A and B. Statistical comparison of results with those obtained in a
      control group of 339 persons without otosclerosis showed that otosclerosis has a
      genetic HLA-related component.

PMID- 8645486
TI  - [EOG findings in patients with multiple sclerosis].
AB  - Electroculography (EOG) is useful in the diagnosis of multiple sclerosis (MS), a
      common disorder. We reviewed the EOG recordings of 192 patients with MS (98
      definite, 29 probable, 65 possible diagnoses) to evaluate spontaneous nystagmus,
      rotation tests, positional tests, vestibulo-ocular reflex visual suppression
      (VOR), optokinetic nystagmus, saccades and pursuit tracking. The most frequent
      findings were abnormalities in the pursuit tracking, saccade dysmetria and
      vestibulo-ocular reflex suppression disorders. Results are discussed and the
      literature is reviewed.

PMID- 8645488
TI  - [The study of survival in the glottic cancer].
AB  - The survival rate for glottic carcinoma was analyzed in the cases treated in our
      service in 1978-88. All cases had a minimum of 5 years of follow-up. Clinical
      manifestations, tumor site, TNM and pTNM stages, histopathologic type, treatment,
      and five-year survival and recurrence rates were studied.

PMID- 8645487
TI  - [Clinico-histological scale for identifying preinvasive lesions of the larynx].
AB  - Preinvasive laryngeal lesions progress to infiltrating carcinoma in 7-15% of
      cases. Clinical manifestations and histological findings are not reliably
      predictive of progression. Quantitative cytometry improves predictive
      effectiveness, but is not a routine procedure. A clinico-histological scale
      consisting of 13 variables which were combined and used prospectively had a
      predictive value of 0.8 sensitivity and 0.9 specificity for progression of
      preinvasive laryngeal lesions.

PMID- 8645489
TI  - [Cervical dissection in laryngeal cancer: our experience of 15 years].
AB  - A retrospective study was made of surgery with cervical dissection in 640
      patients with laryngeal carcinoma treated from 1976 to 1991. Cervical dissection
      was carried out in 386 of 640 patients with laryngeal carcinoma treated
      surgically. Of a total of 496 cervical dissections performed, there were 173
      unilateral functional, 88 bilateral functional, 67 unilateral block, 13 bilateral
      block, and 27 bilateral block dissections with contralateral functional
      dissection. The relations between tumor stage (T) and nodal involvement (N), type
      of dissection and T, type of dissection and N, laryngeal surgery and neck
      dissection, clinical and histological N, N+ and histologic type, extracapsular
      spread, number of recurrences, and their relation with T and N, and the relation
      between N+ and type of neck dissection were studied.

PMID- 8645490
TI  - [Lip biopsy of minor salivary glands in Sjogren's syndrome: histological findings
      and clinico-pathological correlations].
AB  - Thirty-seven lip biopsies of minor salivary glands from patients with suspected
      Sjogren syndrome (SS) and no other known disease were studied. Two cases were
      excluded for not meeting disease criteria (one had histologic findings of
      sarcoidosis). Of 35 SS cases, 4 were considered secondary to associated disease.
      In 24 cases the Daniels technique was used and in 11, an elliptical excision. In
      3 elliptical excisions (27.3%) the biopsy did not contain glands (p = 0.002
      compared with the Daniels technique). The mean number of glands per biopsy was
      7.7 (2-16) with the Daniels technique and 5 (0-15) by elliptical excision (no
      significant difference). Focal lymphoid sialoadenitis was present in all 32 gland
      bearing specimens. Multiple inflammatory foci were found in 28 (87.5%), 8(25%) of
      which had a diffuse infiltrate. SS presented more frequently as xerostomy in
      patients with diffuse infiltrate (p = 0.09). In 11 lip biopsies from controls
      with other diseases of the oral cavity, 7 (63.6%) showed changes suggestive of
      SS.

PMID- 8645491
TI  - [The descriptive study of primary care in otorhinolaryngology].
AB  - A descriptive study was made of medical and surgical activity over a six-month
      period in an outpatient ENT clinic of Valladolid, Spain, serving a health
      district of 142,779 persons. Age, sex, type of consultation, symptoms,
      complementary studies, diagnosis, check-up, and surgical treatment were analyzed
      and correlated in 1170 patients.

PMID- 8645492
TI  - [Tuberculous otitis media: a case report].
AB  - Tuberculosis is endemic in Spain and the primary site is pulmonary in 70% of
      cases. Extrapulmonary foci have increased in frequency and the incidence of
      tuberculous middle otitis, which often is difficult to diagnose, is about 0.04%.
      A case of chronic tuberculous middle otitis is reported.

PMID- 8645493
TI  - [Intralesional treatment of cutaneous leishmaniasis: a report of two cases].
AB  - Two clinical cases of cutaneous leishmaniasis of the outer ear in children are
      reported. The patients were treated successfully with a single intralesional
      injection of N-methylglucamine antimonate (Glucantime). Aetiopathogenesis,
      epidemiology, clinical manifestations, diagnosis, and treatment of cutaneous
      leishmaniasis are discussed.

PMID- 8645494
TI  - [Paranasal sinus pleomorphic adenoma].
AB  - Pleomorphic adenomas with atypical facial presentation, specifically, in the
      nasal sinus region, were studied. A patient who presented with malignant tumor of
      the nasal sinus was diagnosed as pleomorphic adenoma after histologic
      misdiagnosis. The surgical technique and outcome at one year are described.

PMID- 8645495
TI  - [Undifferentiated carcinoma, or lymphoepithelioma, of the base of the tongue].
AB  - The histologic features of undifferentiated carcinoma of the base of the tongue
      and lymphoepithelioma, or lymphoepithelial carcinoma, of the nasopharynx are
      identical and can be considered synonymous. The frequency of undifferentiated
      nasopharyngeal carcinoma (lymphoepithelioma) located on the base of the tongue is
      discussed because undifferentiated carcinoma of the base of the tongue is
      considered to be the same tumor.

PMID- 8645496
TI  - [Cervical synovial sarcoma: a case report].
AB  - Synovial sarcomas of the head and neck are rare, fewer than 80 cases having been
      reported in the literature. A synovial sarcoma of cervical soft tissues presented
      as a lateral mass in a 51-year-old male and was treated by cervical dissection
      and radiotherapy. After 24 months the patient is recurrence-free. The histology
      and origin of synovial sarcomas is discussed.

PMID- 8645497
TI  - [Neurilemmoma of the ansa cervicalis: a case report].
AB  - Neurilemmomas are relatively rare tumors derived from Schwann cells that may
      occur anywhere in the body. Many are encapsulated and they are more frequent in
      adults. A neurilemmoma of the ansa cervicalis, an unusual site, in a young
      patient is reported. Thyroid malignancy was suspected initially.

PMID- 8645498
TI  - [Reconstructive techniques in cutaneous defects of the nasal tip].
AB  - Many techniques are used for repairing nasal tip defects. Our own guidelines are
      reviewed: Small defects often can be closed directly. Lesions of the nasal tip
      over 0.5 cm in diameter usually require a skin graft or flap. Postauricular,
      preauricular, and nasolabial full-thickness skin grafts may produce noticeable
      color or contour differences. The type of local skin flap used depends on defect
      size: Local rotation-transposition flaps or the nasalis myocutaneous sliding flap
      described by Rybka are used for defects 2 cm or less in diameter. Rieger and de
      Marchac frontonasal flaps are used for defects 2-3.5 cm in diameter. Forehead
      flaps are used for defects of 3.5 cm or more. We prefer Rybka's flap for nasal
      tip defects less of 2 cm because it has cosmetic advantages: incisions do not
      deform natural cutaneous crease lines and chronic edema and "dog ears" secondary
      to rotation-transposition pedicle flaps are avoided. For more extensive defects,
      we prefer frontonasal or forehead flaps.

PMID- 8645499
TI  - [The effect of the design and the direction of cutaneous flaps in the phenomenon
      of delay: an experimental study on rabbits].
AB  - The effectiveness of two-stage surgery was studied in several skin-flap models in
      rabbits. The first group (n = 8) of 7 cm x 2 cm skin flaps perpendicular to major
      regional blood vessels became necrotic after the first stage of surgery. In the
      second group (n = 16) of 4 cm x 2 cm skin flaps, survival was no better in the
      two-stage group (n = 8) than in controls (n = 8). In the third group (n = 32) of
      7 cm x 2 cm skin flaps parallel to major blood vessels, survival was better (p <
      0.001) in the two-stage subgroup (n = 16). We conclude that effective two-stage
      skin-flap surgery requires the use of narrow skin flaps that are parallel to
      major blood vessels.

PMID- 8645500
TI  - Liver slice culture for assessing hepatotoxicity of freshwater cyanobacteria.
AB  - 1. A modified mouse liver slice culture technique was established and the
      viability of the system was assessed on the basis of leakage of cytosolic enzymes
      viz. lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine
      aminotransferase (ALT), aspartic aminotransferase (AST) and slice histology. 2.
      This system was employed for toxicity screening of five algal species of Indian
      origin on the basis of the EC50 for LDH leakage (dose of cyanobacteria resulting
      in leakage of 50% of enzyme) of a known toxic cyanobacterial strain Microcystis
      aeruginosa (PCC 7820). On the basis of both in vitro and in vivo toxicity none of
      the five species screened exhibited toxicity. 3. The toxicity of PCC 7820 was
      compared with a purified cyanobacterial hepatotoxin, Microcystin-LR. Various
      biochemical indices and histological changes confirm the hepatotoxic nature of
      the toxins. 4. The toxins did not induce glutathione-mediated lipid peroxidation
      but they did cause significant mitochondrial damage based on an MTT assay. 5. The
      study illustrates the utility of this in vitro system in identifying naturally
      occurring toxic cyanobacteria, particularly hepatotoxic species.

PMID- 8645501
TI  - Nasal lavage as tool for health effect assessment of photochemical air pollution.
AB  - It is widely accepted that humans exposed to known concentrations of ozone under
      controlled conditions exhibit reversible changes that affect the large and small
      airways as well as the alveolar region of the lung. Among the reversible changes,
      the induction of inflammatory responses in the lung are of major concern. Many of
      the cell types found in the lining of the nasopharyngeal region are similar to
      cells of the tracheal and bronchial lining. therefore, it has been suggested that
      the cellular responses in the nose to toxicants are likely to be similar to the
      lower airway at the same dose of the agent. If these pollutants are respiratory
      irritants, capable of causing cellular damage, effects may therefore be detected
      in the nasal passage. Experimental studies have shown that the inflammatory
      response in the nose may be predictive for the situation in the lung. In this
      paper we described the results of a feasibility study on the use of nasal lavage
      for epidemiological studies. Nasal lavages were performed in 12 volunteers, 5-7
      times per volunteer during 2 months. Polymorph nuclear leukocytes (PMN's), immune
      mediators and markers for exudation were monitored in the nasal lavage (NAL). It
      was found that the procedure of the nasal lavage technique was minimally
      invasive, very well tolerated and no adverse side effect were observed. The
      leukocytes, the proteins myeloperoxidase (MPO), eosinophil cationic proteins
      myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8)
      were detectable in NAL of most volunteers, while tryptase IgE and IL-6 were not
      detectable. Exudation markers albumin, urea and uric acid were also detectable.
      The coefficient of variance (CV) values of the various cells and mediators varied
      between 13% and 137%. It was calculated that, except for the number of leukocytes
      and the concentration of ECP, it should be possible to detect ozone effects with
      a study-protocol of 6 repeated measurements among 35 children and an assumed 26%
      increase in cells or mediators per 100 micrograms O3 per m3. To measure increase
      in leukocytes number or in ECP concentration more children are needed. In
      conclusion, this pilot study has shown that it is possible to measure relevant
      biomarkers in NAL, and that these assays can be easily incorporated in
      epidemiological studies.

PMID- 8645502
TI  - Reduced survival after isoprenaline/dopamine in d,l-propranolol intoxicated rats.
AB  - 1. Respiratory and cardiovascular failure are principle toxic effects of beta
      blocker overdose. Respiratory arrest is the primary cause of death in beta
      blocker intoxicated rats. 2. The effect of beta-adrenoceptor agonists on
      respiratory and cardiovascular failure in beta-blocker overdose was investigated
      in a model of acute d,l-propranolol (30 mg kg-1 h-1) intoxication in
      spontaneously breathing rats. 3. Neither the aselective, hydrophilic beta-agonist
      isoprenaline (10, 25, 50 micrograms kg-1 min-1), nor the beta 1-selective,
      lipophilic beta-agonist flerobuterol (1, 3, 10 microgram kg-1 min-1) and the beta
      2-selective, lipophilic beta-agonist clenbuterol (10, 25, 50 micrograms kg-1 min
      1) had any beneficial effect on cardiovascular and respiratory variables or
      survival time in d,l-propranolol intoxicated spontaneously breathing rats. 4.
      Isoprenaline (10 micrograms kg-1 min-1) had no favourable effect on haemodynamic
      and respiratory variables in artificially ventilated d,l-propranolol intoxicated
      rats either. 5. Addition of dopamine to isoprenaline resulted in a significant
      reduction of survival time, primarily caused by a decreased in mean arterial
      blood pressure, in artificially ventilated d,l-propranolol intoxicated rats.
      Addition of glucagon to isoprenaline did not affect survival time. 6. Artificial
      ventilation is the most important supportive measure in d,l-propranolol
      intoxication in the rat.

PMID- 8645504
TI  - Establishment of a new human cell line, LI90, exhibiting characteristics of
      hepatic Ito (fat-storing) cells.

PMID- 8645503
TI  - Effect of short-term dietary administration of eugenol in humans.
AB  - 1. In order to study the antigenotoxic potential of eugenol in humans, ten
      healthy non-smoking males ingested a daily amount of 150 mg eugenol or the
      placebo for seven consecutive days. After a washout period of one week, groups
      ingesting eugenol or the placebo were crossed and received the other treatment
      for seven consecutive days. 2. On days 8 and 22 blood samples were taken for the
      assessment of standard clinical biochemical parameters. To study the possible
      antigenotoxic effect of eugenol, on day 8 and 22 blood samples were collected and
      exposed in vitro to the established genotoxic agents mitomycin C and vinblastine.
      After exposure the percentage of cells with chromosome aberrations and
      micronuclei was determined in cultured white blood cells. On days 8 and 22
      paracetamol (500 mg p.o.) was administered as test substance to measure phase-II
      biotransformation capacity. Glutathione-S-transferase (GST) activities were
      determined in erythrocytes and blood plasma. 3. No significant differences in the
      clinical biochemical parameters were detected between the eugenol-period and the
      placebo-period, indicating that daily administration of 150 mg eugenol for 7 days
      has no toxic affects. 4. No significant differences on the cytogenetic parameters
      were found after ingestion of eugenol. Thus, there are no indications for an
      antigenotoxic potential of eugenol in humans, consuming daily 150 mg eugenol for
      7 days. 5. A significant reduction in alpha-class GSTs in plasma (P < 0.05), but
      not in the other measured biotransformation parameters, was found in volunteers
      during the eugenol-periods as compared to the placebo-period. This may either
      reflect GST-inhibition by eugenol or protection against background damage of
      liver cells by eugenol.

PMID- 8645505
TI  - Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding
      Ah receptor.

PMID- 8645506
TI  - Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4
      trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4
      methanesulfonylbenzoyl)-cyclohexane-1,3-dione.

PMID- 8645507
TI  - Forced evolution of glutathione S-transferase to create a more efficient drug
      detoxication enzyme.

PMID- 8645508
TI  - Quantitative risk assessment and the limitations of the linearized multistage
      model.
AB  - 1. Quantifying carcinogenic risk is an important objective for assisting in the
      assessment and management of risks from chemical exposure. The most widely used
      of the many mathematical models proposed for extrapolation of carcinogenicity
      data from animal studies to low dose human exposures is the linearized multistage
      (LMS) model. This has, in effect, become the default approach for much of
      Quantitative Risk Assessment (QRA). The practical properties of this model have
      been investigated. 2. Analysis of stimulated data using the LMS model showed (i)
      that the Maximum Likelihood Estimate (MLE) of the low dose slope, q1, was
      unstable and extremely sensitive to small changes in the data; (ii) the 95% Upper
      Confidence Limit (UCL) estimate, q1*, preferred by the US Environmental
      Protection Agency (EPA) was insensitive with only small changes in values being
      obtained for large changes in the data; (iii) data sets where there was no
      statistical significance could give risk estimates similar to those obtained from
      data sets with clear dose-related effects; (iv) the size of the values of the
      Virtually Safe Dose (VSD) obtained did not necessarily relate to the biological
      interpretation of the data sets; (v) the value of q1* obtained was closely
      related to the top dose used in the study. 3. Limitations of the LMS model were
      illustrated by examples of its use in assessing the carcinogenicity of 2, 3, 7, 8
      TCDD leading to the conclusion that the existing models are not suitable for
      routine use in the estimation of the risk from chemical carcinogens. The use of
      the LMS model has been justified in part by its original derivation from a
      mathematical model based upon a multistage model of carcinogenesis. However,
      estimates of the parameters of the model used to provide estimates of low dose
      risk to humans have no direct relationship to specific biological event in
      carcinogenesis. Further developments in mathematical models and increased
      understanding of the biological events underlying the carcinogenesis will lead to
      more biologically plausible QRA methods which would then justify serious
      consideration of QRA by regulatory authorities throughout the world.

PMID- 8645509
TI  - [Reoperation after failure of gastroesophageal reflux surgery].
AB  - We present 28 patients who underwent surgery after failed procedures due to
      gastroesophageal reflux with an asymptomatic period over 2.6 years. The most
      frequent complications resulted in recurrent reflux (86%) and peptic strictures
      (36%). An abdominal approach was used on all the patients. Reoperation, using the
      Collis-Nissen gastroplasty (19 cases), Nissen 360 degrees (3 cases), duodenal
      diversion with Roux-en-Y (3 cases) and Angelchick prothesis (3 cases) gave
      excellent or good results in 84% of the patients and poor in 4 cases. There was
      one operative death. All patients were referred for 24 hour pH-monitoring.
      Sphincter pressure and length of the distal esophageal sphincter were
      significantly increased over the preoperative values. Our results suggest that
      the Collis Nissen procedure is a suitable form of treatment for complicated forms
      of peptic esophagitis after the failed antireflux operations.

PMID- 8645510
TI  - [What factors influence healing of duodenal ulcer when Helicobacter pylori
      eradication treatment is used?].
AB  - AIM: To study the influence of various factors on duodenal ulcer healing,
      specially the success or failure of Helicobacter pylori eradication. METHODS: One
      hundred and nine patients with duodenal ulcer and H. pylori infection were
      studied. At endoscopy biopsies were obtained from the gastric antrum and body,
      and processed by microbiological (Gram stain and culture) and histological
      methods (haematoxylin-eosin); also, a 13C breath test was performed. A
      <<classical >> triple therapy (bismuth, tetracycline, metronidazole) or
      omeprazole plus amoxicillin was administered. Endoscopy and breath test were
      repeated one month after completing therapy. Eradication was defined as the
      absence of H. pylori by all diagnostic methods. RESULTS: H. pylori eradication
      was achieved in 60 patients (55%). In the multivariate analysis H. pylori
      eradication was the only variable which correlated with ulcer healing (regr.
      coef. = 2.4; OR = 10.6). Additional variables (age, sex, smoking, time of
      evolution, ulcer size, and type of therapy) were not significantly correlated.
      Ulcer healing was achieved in 92% of patients after H. pylori eradication, and in
      51% of therapy failures (p < 0.001). CONCLUSION: H. pylori eradication
      accelerates ulcer healing, which represents an additional argument for employing
      eradicating therapy in patients with duodenal ulcer disease.

PMID- 8645512
TI  - [Evaluation of intravenous ranitidine and omeprazole effect on the 24-hour
      gastric ph-metry in duodenal ulcer hemorrhage].
AB  - BACKGROUND: The pharmacotherapy of bleeding peptic ulcer is directed to improve
      the environment of the bleeding point by keeping the gastric pH above the
      proteolytic range for pepsin. OBJECTIVE: To evaluate the best pharmacological
      approach to inhibit gastric acid secretion with current antisecretory drugs in
      patients with bleeding duodenal ulcers. METHODS: Forty-seven patients with
      bleeding duodenal ulcers were randomized to receive I.V.: I) Omeprazole: an
      initial bolus of 80 mg + perfusion of 3.3 mg/h; II) Omeprazole: an initial bolus
      of 80 mg + 40 mg/12 h; III) Omeprazole: 40 mg/8 h; IV) Ranitidine: perfusion of
      12.5 mg/h; V) Ranitidine: 50 mg/4 h. Gastric acidity was measured and recorded by
      24 h gastric pH monitoring. RESULTS: All types of treatment with omeprazole were
      superior to either continuous perfusion or intermittent bolus of ranitidine in
      increasing the pH for 24 h and reducing the % of time the gastric pH was below 4
      and 6, and the number of time the gastric pH was below 4 for more than 5 min.
      There were no statistical differences between the different regimens of
      omeprazole, but continuous perfusion of ranitidine was superior to intermittent
      ranitidine bolus. CONCLUSIONS: Parenteral omeprazole is better than parenteral
      ranitidine in keeping the intragastric pH above the proteolytic range for pepsin
      in patients with bleeding duodenal ulcers.

PMID- 8645511
TI  - [Comparison of 2 treatment strategies with prednisone and interferon in chronic
      hepatitis B].
AB  - Twenty patients with chronic B hepatitis and viral replication were included in a
      randomized study comparing the efficacy of sequential treatment with prednisone
      for 6 weeks followed by alpha-2a interferon (IFN) for 6 months (group A, 9
      cases), versus concomitant administration of both drugs (group B, 11 cases).
      There were no significant differences between the two groups regarding age, sex,
      AST, ALT, DNA-VHB values, index of histological activity or type of underlying
      chronic hepatitis. Two patients from each group were excluded. The mean follow-up
      of the patients was 22.2 months. In group A, four responses were achieved
      (57.1%), of which 2 were complete and 2 partial. The overall response rate in
      group B was 77.7% (7 cases), 6 of them were complete responses (66.7%). Among
      HBsAg-positive patients from group B, one seroconverted to anti-HBs. A total of 7
      patients with anti-HBe were included in the study. Two belonged to group A, in
      which a partial response was achieved, and another 5 were in group B, with 4
      reaching a complete response and one reaching a partial response. There were no
      statistical differences with regards to the type of response in both groups. The
      AST, ALT values, as well as the pre-treatment levels of DNA-VHB, showed a
      significant statistical association with the response (p < 0.05). In all patients
      responding to treatment a histological improvement was observed that became even
      more evident in the biopsy performed 12 months after IFN withdrawal. In
      conclusion, concomitant therapy with prednisone and IFN is as effective as
      sequential therapy in the treatment of chronic B hepatitis. The results achieved
      with concomitant therapy suggest that new controlled trials are need to establish
      if this therapeutic schedule is the elective treatment in chronic B hepatitis.

PMID- 8645513
TI  - [Study of arterial blood gases in liver cirrhosis with and without ascites].
AB  - OBJECTIVE: The study of the disturbances of arterial gases and the changes in the
      arterial pH which are present in patients with liver cirrhosis and ascites and
      their modification after the disappearance of ascites by treatment. EXPERIMENTAL
      DESIGN: Open study,with protocol and prospective, to evaluate the changes in
      measurement of the arterial gases and acid-base, parameters in matching groups of
      patients. PATIENTS: We include 24 patients, 15 males and 9 females, without
      preliminary or cardio-respiratory pathology age range between 37 and 77 years,
      average of 56.8 years, all of them diagnosed of liver cirrhosis of different
      etiologies and with important ascites. All of them finished the study. RESULTS:
      In patients with liver cirrhosis and ascites a fall in the PaO2 and in the PaCO2
      was demonstrated the pH in the upper limit of the normality compatible with
      hypoxemia and respiratory alkalosis. After the disappearance of the ascites, a
      significant improvement in the PaO2 (p < 0.05), without any changes in the PaCO2
      and pH values was apparent. CONCLUSIONS: In patients with liver cirrhosis, with
      or without ascites, hyperventilation is present, that can be multifactorial in
      origin, but which really has an unknown cause. We have found no relationship with
      the circulating levels of progesterone.

PMID- 8645514
TI  - [C13 urea breath test in the diagnosis of Helicobacter pylori infection in the
      gastric mucosa. Validation of the method].
AB  - Helicobacter pylori has been implicated as an agent in the pathogenesis of antral
      gastritis, gastric and duodenal ulcer and probably in gastric cancer. The C13
      urea breath test is a diagnostic method quick to perform, sensitive, reliable and
      non invasive. It is based on the presence of Helicobacter pylori urease activity,
      which permits to detect it in the infected mucosa. A substrate (urea) labelled
      with Carbon 13 is administered to the patient and exhaled breath is collected to
      detect the possible catabolism product (CO2 labelled with C13). In the European
      protocol, patients in fasting condition are given a test meal to delay gastric
      emptying and five minutes later a solution which contents 100 mg of C13 labelled
      urea. Breath samples are collected before and 30 minutes after urea was given. In
      our first year of experience, 363 patients with Helicobacter pylori infection
      detected by histology or urease were studied by C13 urea breath test, with a
      sensitivity and specificity of 95 and 96%. False negatives may occur if the test
      is used after antibiotics and other antiulcer drugs. Its main indication is to
      monitor eradication therapy after treatment. Its possible use as a quantitative
      test still remains unclear.

PMID- 8645515
TI  - [Laparoscopic surgery in the treatment of complicated gastroesophageal reflux].
AB  - Laparoscopic antireflux surgery has quickly developed since Bernard Dallemagne
      carried out the first laparoscopic fundoplication in 1991. However, only
      preliminary results from institutional series are available. The authors review
      the indications for laparoscopic antireflux surgery. In addition, technical
      aspects of several reported laparoscopic antireflux procedures are evaluated.
      Data from institutional series show that morbidity and mortality rates after
      laparoscopic antireflux surgery are similar to those reported for open surgery,
      with a perioperative morbidity rate ranging between 4% and 26% and a mortality
      rate under 0.6%. Endoscopic dilation for postoperative dysphagia is required in
      7%-11% of the cases. In summary, preliminary data show that laparoscopic
      antireflux surgery may play a predominant role in the treatment of complicated
      gastroesophageal reflux. Meanwhile, controlled trials with open surgery and
      medical therapy should be done before the laparoscopic approach is generalized.

PMID- 8645517
TI  - [Dysphagia as an unusual form of presentation of malignant pleural mesothelioma].
AB  - Dysphagia is an unusual presenting symptom as of extradigestive tumors. Malignant
      mesothelioma, is a rare tumor localized in the pleural cavity in 80% of all cases
      and it rarely appears with dysphagia as first symptom. We describe the case of a
      74-year-old woman admitted with progressive dysphagia for solid and liquid food,
      atypical epigastric pain, with in conclusive endoscopic and radiologic studies.
      Nuclear Magnetic Resonance established the diagnostic suspicion of malignant
      mesothelioma which was confirmed by the histologic study of a biopsy taken by
      thoracotomy. We think of interest to report this case of paraesophageal
      mesothelioma because of its unusual localization and presentation.

PMID- 8645516
TI  - [Association of porphyria cutanea tarda and hepatitis C virus].
AB  - Porphyria cutanea tarda (PCT) is caused by reduced activity of hepatic
      uroporphyrinogen decarboxylase. However extrinsic factors such as alcohol abuse
      and drug intake are required for the clinical manifestation of the disease.
      Hepatitis C virus antibodies have been detected in a high percentage of patients
      with PCT. Hepatitis C virus is probably the main pathogenetic factor of liver
      damage in patients with PCT. AIM: To study the association between hepatitis C
      virus and PCT in our patients with PCT. MATERIAL AND METHODS: We have
      investigated six patients diagnosed of PCT in order to detect the presence of
      hepatitis C virus and other possible causes of the disease. RESULTS: We have
      found that 66% of our patients had hepatitis C virus antibodies, 50% ethanol
      abuse, of which 2/3 presented hepatitis C virus antibodies, and one case of HIV.

PMID- 8645519
TI  - [Low digestive hemorrhage caused by amebic colitis].
AB  - Amebiasis is an infectious disease produced by Entamoeba histolytica, which has
      invasion capacity of the colon mucosa. It has different clinical forms, varying
      from the asymptomatic carrier state to severe, although not frequent, fulminant
      or necrotizing colitis, with an important necrosis of the colon mucosa.
      Perforation or intestinal bleeding are possible. We report one case of patient
      who had a history of recent travel to India. Was admitted with a clinical picture
      of abdominal pain, diarrhea and fever. Initially he received treatment with
      Metronidazole and steroids, because of doubts in the endoscopy diagnosis of
      Crohn's Disease versus Amebic Colitis. The patient developed a fulminant colitis,
      that required emergency surgery because of lower intestinal massive bleeding.
      During the operation perforations of the caecum and rectum were found. We
      performed a total colectomy with ileostomy and closing of the stump rectal. Six
      months later a second operation was made for the reconstruction of the intestinal
      continuity by an ileal pouch and rectal anastomosis.

PMID- 8645520
TI  - [Zieve's syndrome. A case report].
AB  - We report a case of Zieve's Syndrome that developed after an important alcohol
      consumption in a 32-yr-old female patient. She was admitted to the hospital with
      anorexia, asthenia and jaundice. Physical examination showed liver stigmata and
      hepatomegaly. Laboratory tests demonstrated increased aminotransferase levels,
      hyperbilirubinemia, hyperlipidemia and normocytic and normochromic anemia with
      dianocytes in peripheral blood smear. Ultrasonography showed a hyperechoic liver
      and a liver biopsy showed acute and chronic alcoholic liver disease. Clinical
      evolution was satisfactory and the therapy consisted of blood transfusion,
      parenteral fluids, B-complex vitamin and a fatty free diet. Jaundice,
      hyperlipidemia and haemolytic anemia define Zieve's Syndrome (Z.S.) There is a
      pathogenetic relationship among the clinical and biological phenomena in this
      syndrome, whose starter is an acute alcohol intake. Haemolysis is the distinctive
      feature with respect to the classical acute alcoholic hepatitis, and it is due to
      erythrocyte's metabolic and osmotic instability in relation to lipids
      abnormalities. Its clinical resolution precedes the normalization of serum lipids
      levels. Therapy is similar to that for acute alcoholic hepatitis although
      sometimes the anemia requires blood transfusion.

PMID- 8645518
TI  - [Sarcoidosis simulating carcinoma of the head of pancreas].
AB  - Sarcoidosis is a granulomatous disease of unknown origin with a variable clinical
      presentation. Although involvement of every organ has been described, the
      pulmonary system is most frequently involved. Isolated extrapulmonary disease is
      rare. Hepatic manifestations include granulomatous hepatitis and hilar
      lymphadenopathy. We describe a case of sarcoidosis initially presenting as
      extrahepatic jaundice.

PMID- 8645521
TI  - [Spontaneous splenic rupture in infectious mononucleosis].

PMID- 8645522
TI  - [Do diagnostic laparoscopy and the use of drains favor the appearance of
      cutaneous metastases after oncological surgery?].

PMID- 8645523
TI  - [Primary torsion of great epiploon].

PMID- 8645524
TI  - [Dissection of the epiaortic vessels: an emergency pathology as the cause of
      focal cerebral ischemia. The evaluation of a case load of 7 patients].
AB  - Dissection of the epiaortic vessels is an emerging cause of focal cerebral
      ischemia, especially in young patients. Non-invasive diagnostic devices
      (ultrasound, nuclear magnetic resonance) have greatly improved the ability to
      suspect and identify it. We report our clinical experience with 5 patients
      affected by carotid artery dissection and 2 patients affected by vertebral artery
      dissection. Vessel dissection generally occurred spontaneously; it was preceded
      by head or cervical trauma in 2 cases. Arterial hypertension was commonly
      associated, and headache was always present together with other focal
      neurological signs. Clinical suspicion was confirmed by ultrasound duplex
      scanning: although never conclusive, it always showed typical Doppler patterns.
      Nuclear magnetic resonance has become an acknowledged means of definitive
      diagnosis although angiography remains the gold standard. In any case, diagnosis
      requires clinical suspicion and the accurate correlation of clinical data and
      instrumental results. Therapy consisted in anticoagulant and antiplatelet drugs.
      The clinical course of our patients was favorable in all cases, and no
      recurrences were recorded.

PMID- 8645525
TI  - [Arg506 --> Gln mutation of coagulation factor V (factor V Leiden) and transient
      cerebral ischemia at a young age in 3 members of the same family].
AB  - The Arg506 --> Gln coagulation factor V mutation (factor V Leiden) is the most
      frequent inherited abnormality of blood coagulation which predisposes to venous
      thromboembolism. Its association with an increased risk of arterial thrombosis is
      uncertain. We describe 3 members of the same family (a woman and her 2 children)
      who were heterozygous for the Arg506 --> Gln mutation and who presented cerebral
      transient ischemic attacks (TIA) at a young age. The patients (with the exception
      of one smoker) had no risk factors for TIA and no abnormality of the coagulation
      system other than the Arg506 --> Gln mutation. The observation of the mutation
      and TIA in 3 members of the same family may suggest the hypothesis of an
      association between the mutation and arterial thrombosis. This hypothesis must be
      interpreted with caution, due to the absence of objective instrumental findings
      in patients with TIA and to the high prevalence of the Arg506 --> Gln mutation in
      the general population.

PMID- 8645526
TI  - [Ischemic stroke associated with atrial fibrillation: the demographic and
      clinical characteristics and 30-day mortality in a hospital stroke registry. The
      European Community Stroke Project, Florence Unit].
AB  - The importance of atrial fibrillation (AF) as a risk factor for stroke is well
      known. The role of AF as a prognostic indicator of outcome in the acute phase of
      stroke has been less thoroughly investigated. We considered the 635 patients
      admitted over a 1-year period to two general hospitals in the area of Florence
      (Italy), in order to examine the demographic and clinical characteristics, risk
      factors of the patients presenting with stroke and AF, and to evaluate their post
      stroke mortality rate. Of the 447 patients diagnosed as affected by ischemic
      stroke, 103 (23.05%) had AF. These patients were older, more often female, and
      had fewer risk factors for factors for atherosclerosis than patients without AF.
      The risk of death at 30 days after stroke was about double in patients with AF as
      compared to those without AF after control by Cox regression analysis for the
      effect of the other prognostic indicators of mortality. Demographic variations
      anticipated for the future in our country (progressive ageing of the population)
      would lead us to predict a proportional increase of these forms in the coming
      decades. Therapeutic measures of proven effectiveness for primary prevention of
      stroke in patients with AF seem to be taken to an extremely limited degree in
      Italy. Our data could thus serve as a stimulus to the reconsideration of
      therapeutic guidelines and may be useful for the establishment of health care
      policy orientations.

PMID- 8645527
TI  - Systolic and diastolic cardiac function in acromegaly. An echocardiographic
      study.
AB  - The aim of this study was to establish the existence of primary acromegalic
      cardiomyopathy different from the cardiovascular complications often associated
      with acromegaly. Thirty-four acromegalic patients, referred to our non-invasive
      laboratory and divided into two groups on the basis of the presence of
      hypertension, underwent echocardiographic studies. A control group of 34 subjects
      individually matched with the patients for age, sex, and blood pressure values
      was also studied. To evaluate cardiac function during exercise, the normotensive
      acromegalics, the control group, and a group of 9 athletes with left ventricular
      mass comparable to that of the acromegalic subjects underwent a handgrip test.
      Cardiac mass was increased in all patients; hypertensive patients had a greater
      increase than normotensive patients (144.9 +/- 38 vs 120.9 +/- 20.8 g/m, p <
      0.02). Systolic wall stress and percent fractional shortening, although similar
      to the values confirmed in controls, were modified in the hypertensive patients
      (wall stress 77.5 +/- 9.3 vs 60.8 +/- 9.4 dyne/cm2, p < 0.01). In all patients,
      diastolic function at rest was similar to that in controls, although the
      hypertensive patients had deteriorated diastolic function (E peak 56.9 +/- 12.4
      vs 71 +/- 15 cm/s, p < 0.01; A peak 70.4 +/- 21.1 vs 52.3 +/- 16.4 cm/s, p <
      0.03; E/A ratio 0.89 +/- 0.37 vs 1.38 +/- 0.35, p < 0.02). During handgrip
      testing, wall stress in both the normotensive acromegalics and the control
      subjects increased but remained unchanged in the athlete group; percent
      fractional shortening decreased in all patients and controls but increased
      slightly in the athlete group. In conclusion, cardiac hypertrophy caused by GH
      hyperincretion does not improve acromegalic heart activity: diastolic function,
      although normal at rest, appears deficient during isometric exercise.

PMID- 8645528
TI  - [Ischemic stroke in the young adult].
AB  - Ischemic stroke is uncommon in young adults, and its etiologies and prognosis are
      different from those verified in the cerebrovascular disease of old age.
      Atherosclerosis is the main cause of stroke in the elderly, while emboligenous
      cardiopathy is one of the main mechanism underlying this pathology in young
      adults. Other etiologies include atherosclerosis, coagulopathies, vasculitides,
      arterial dissection and migraine. Ischemic stroke in young adults must thus be
      studied with a different protocol from that used for the elderly.

PMID- 8645529
TI  - [The feasibility and current limits in the prevention of diabetic nephropathy].
AB  - Diabetic nephropathy is the leading cause of uremia in Italy and other
      industrialized countries: once diabetic nephropathy commences, it advances slowly
      but inexorably to uremia. Prevention begins with strict control of blood sugar to
      inhibit or normalize glomerular hyperfiltration, and control of blood pressure to
      prevent glomerular hypertension and decrease microalbuminuria. Pharmacological
      measures include ACE-inhibitors and calcium channel blockers, alone or in
      combination, to reduce proteinuria and preserve renal function. It is believed
      that some classes of anti-hypertensive drugs have a direct pharmacological
      depressive effect on cell growth factors that lead to mesangial sclerosis: ACE
      inhibitors would thus depress angiotensin II, and the calcium channel blockers
      would inhibit the increase in intracellular calcium of the mesangial cells which
      increases gene expression of early growth. Dietary sodium restriction seems to
      correct the expansion of the sodium pool and related volemic expansion
      hypertension. A protein-poor diet limits the precapillary glomerular
      vasodilatation resulting from protein-induced hyperaminoacidemia. The earlier
      dietetic and pharmacological measures are taken, the more effective they become:
      while they cannot arrest diabetic nephropathy once it has commenced, they are
      able to delay evolution of the disease to uremia.

PMID- 8645530
TI  - [The L-arginine/nitric oxide metabolic pathway. Its physiopathology and clinical
      implications].
AB  - The L-arginine/nitric oxide (NO) pathway plays a key role in a number of
      biological processes within most organs and systems. Increasing attention has
      been addressed to its involvement in the pathogenesis of various human diseases.
      In this review we examine the enzymology of different NO-synthase isoforms, the
      major NO detection techniques as well as the possible clinical and
      pharmacological implications of this new metabolic pathway.

PMID- 8645531
TI  - [A new cause of thrombophilia].

PMID- 8645532
TI  - [Systemic mastocytosis: a review of the literature and of the cases in Reggio
      Emilia from 1986 to 1994].
AB  - Systemic mastocytosis is a rare pathology that can affect most systems of the
      human organism. Although diagnosis is often fortuitous and prognosis good in a
      very high percentage of cases, it can sometimes present in extremely severe and
      occasionally fatal forms. With the aid of the available literature, we discuss
      the most recent classifications, clinical features and diagnostic and therapeutic
      approaches to this disease. We then do an epidemiological review of the cases
      reported in Reggio Emilia over the past 9 years. Due to the lack of symptoms of
      this pathology, its reported incidence of about 0.3 new cases per 100,000
      inhabitants per year is obviously underestimated. Drug therapy is purely
      symptomatic and does not affect its clinical evolution.

PMID- 8645533
TI  - [Physical exercise and increase in arterial pressure and temperature in a female
      heterozygote for anhidrotic ectodermal dysplasia].
AB  - A 51-year-old woman suffered from an increase in body temperature from 37 degrees
      to 38.4 degrees C after physical exercise. She did not sweat. The patient also
      had labile hypertension with maximum values reaching 210/130 mmHg. Tests were
      carried out to explore the possibility of a link between the increase in body
      temperature and her hypertension. Evaluation of the patient's blood pressure and
      temperature changes after exercise and after environmental modification suggests
      a pathogenetic link between hyperthermia and hypertension.

PMID- 8645534
TI  - [Praise for the clinic. The contribution of clinical medicine to the philosophy
      of science].

PMID- 8645535
TI  - [Stroke in the young: a diagnostic protocol].
AB  - This study attempts to propose guidelines for diagnostic procedures in young
      adults with focal cerebral ischemia. Our data indicate that the most common
      etiologies are atherothrombosis (primarily in 40-47-year-old subjects), and
      cardioembolism (more prevalent in subjects under 30 years old). Autoimmune
      conditions were observed in 12.6%, and arterial dissections in 11% of our
      patients. Despite extensive diagnostic studies, we were unable to determine the
      etiology of the cerebral ischemic event in 10% of our patients.

PMID- 8645536
TI  - [Radioimmunoguided surgery: its current status and outlook].

PMID- 8645537
TI  - Thoracic desmoid tumors: a rare evolution of rib fracture. Etiopathogenesis and
      therapeutic considerations.
AB  - The Authors report a case of thoracic desmoid tumor. The strict correlation
      between a previous chest injury and the site of desmoid tumor in this patient
      seems to strengthen the possible etiological role of trauma, as already
      suggested.

PMID- 8645538
TI  - [Septic complications in emergency surgery: our experience and a review of the
      literature].
AB  - Surgical infections represent one of the main causes of postoperative morbidity
      and mortality, especially in emergency surgery, with negative consequences on
      health costs. The Authors examined 2002 cases of emergency admission for surgical
      pathologies at the I Surgical Department of the University of Rome ?La Sapienza?
      from 1987 to 1992. Overall septic complications were 13,7%, with a mortality rate
      of 1,2%. The Authors underline the lack in Italy of either an accurate system for
      monitoring septic complications or a useful method for data collection. At last
      the attention is focused on the main causes of septic complications, their
      diagnosis and treatment.

PMID- 8645539
TI  - [Endometriosis of the abdominal wall. A report of a case secondary to cesarean
      section].
AB  - The Authors report a case of endometriosis of the surgical scar following
      caesarean section. The patient, arrived at surgical observation for a doubtful
      foreign body granuloma, underwent a diagnostic biopsy of the lesion. Histological
      examination confirmed the endometriosis nature of the lesion. Before surgical
      removal, adjuvant therapy based on GnRH analog was performed with the aim to
      reduce the volume of the lesion. After removal a cycle of therapy with GnRH
      analog was performed in oder to exclude possible residual pathologic microscopic
      lesions.

PMID- 8645540
TI  - [Digestive hemorrhage in a patient with multiple neurofibromatosis].
AB  - Neurofibromatosis is an autosomal dominant trait with variable expressivity
      clinically defined by the coexistence of multiple cafe au lait spots,
      subcutaneous neurofibromas and Lisch nodules. Hemorrhage from intestinal
      neurofibromas or related tumors may be life-threatening because often
      inaccessible and therefore difficult to locate. The Authors report a case of
      gastrointestinal hemorrhage in a 68 year old patient with neurofibromatosis who
      had an episode of melena from duodenal ulcer endoscopically detected 5 years
      earlier. Endoscopy failed to discover the site of bleeding; this was successfully
      demonstrated by angiography: superior mesenteric arteriography disclosed 32
      hypervascular masses supplied by a digiunal branch and by the oleo-colic artery.
      Because of continuing hemorrhage the patient was submitted to surgery. The
      exploration demonstrated ulcerated neurofibromatous neoplasms at the level of the
      digiunum and terminal ileum, with a Meckel's diverticulum and gallbladder stones.
      Intestinal resection, right emicolectomy, Meckel's diverticulum resection and
      colecystectomy were performed. Review of the literature demonstrates angiography
      is the most reliable imaging modality for detecting such tumors.

PMID- 8645541
TI  - [Hemidiaphragmatic reconstruction: the evaluation of 3 clinical cases].
AB  - The Authors after a review of the embriology, physiology and pathophysiology of
      diaphragm, report three cases of congenital or acquired diaphragmatical hernias.
      They discuss advantages and disadvantages of different surgical techniques on the
      basis of their technical experience as well as results obtained.

PMID- 8645542
TI  - [Phyllodes breast tumors: apropos 2 cases].
AB  - The observation of two cases of phyllode tumors of the breast, one benign and the
      other malignant, brought the Authors to focus the fundamental aspects of these
      neoplasias. The histologic coexistence of both epithelial and connectival
      components, a relative unpredictable clinical evolution, the high frequency of
      recurrences, the stromal hyperproduction and modifications as expression of
      malignancy, and the need for large excisions are the fundamental characteristics
      of these tumors, which are considered transitional forms between benignity and
      malignancy.

PMID- 8645543
TI  - [Diverticula of the small intestine: the authors' own experience].
AB  - The Authors report the experience acquired in the management of small bowel
      diverticula at the Emergency Surgical Department of the University of Bari, from
      1987 to 1993. After a brief illustration of the few cases observed, the Authors
      discuss the problems of this rare pathology, which as all types of bowel
      diverticula, is diagnosed with difficulty. In fact, only in case of
      complications, with a specific check-up, the lesions may be discovered. Although
      rarely, emergency surgery may be needed when complications such as bleeding or
      occlusion occur. Usually the treatment of minor complications (dyspepsia, gripes,
      steatorrhoea, constipation and diarrhoea) consists of dietetic indications and
      symptomatic drugs.

PMID- 8645544
TI  - [Total thyroidectomy in the treatment of multinodular toxic goiter].
AB  - The Authors report their experience in the management of 201 patients with
      multinodular toxic goiter (MTG): 122 (60.7%) underwent subtotal thyroidectomy
      (STT), while 79 (39.3%) underwent total thyroidectomy (TT). Through a
      retrospective study the patients were stratified into two groups according to the
      type of operation (TT or STT). Overall, neither operative mortality nor recurrent
      nerve damage were encountered. Permanent hypocalcemia was observed in 7 patients
      (5.7%) who underwent STT and in 6 patients (7.5%) who underwent TT (p=N.S.),
      while transitory hypocalcemia was observed in 12 cases (9.8%) in group I and 11
      cases (13.9%) in group II (p=N.S.). All patients were followed every 4 months for
      the first year and every 6 months thereafter. Average and median follow-up period
      were, respectively, 72 and 74 months. The Authors conclude that total
      thyroidectomy is the surgical treatment of choice in multinodular toxic goiter
      (MTG). A thorough anatomical-surgical evaluation is essential in order to prevent
      the complications characteristic of this type of surgery (inferior laryngeal
      nerve injury and hypoparathyroidism).

PMID- 8645545
TI  - [Male infertility due to varicocele: their diagnosis and treatment. Our
      experience].
AB  - The Authors have examined, over a period of two years, 110 patients presenting
      with varicocele and infertility. Varicocele has an incidence of 40% in male
      sterility, causing oligozoospermia and asthenospermia. Patients first underwent
      non-invasive tests such as Doppler and echo-Doppler tests. According to the
      Authors experience, Doppler speedometry is decisive for the diagnosis of both
      idiopathic and subclinical varicocele, for the post-operative control of
      microsurgical anastomosis, and for the intra-operative detection of accessory
      spermatic veins. The surgical technique used by the Authors is the modified
      Palomo technique, but other techniques are investigated as well. Post-operative
      results, concerning both spermiogram and relapses are also evaluated.

PMID- 8645546
TI  - [Indications for the use of a skin-stretching device].
AB  - In the management of surgical or traumatic skin loss the Authors consider an
      alternative method which involves the use of a tool called skin stretching
      device. The latter seems easy to apply, atraumatic and the least troublesome for
      the isolation and detaching of tissues employed in skin repair.

PMID- 8645547
TI  - Dengue and dengue haemorrhagic fever. 1990-1994.

PMID- 8645548
TI  - Zoonoses control. WHO consultation on intradermal application of human rabies
      vaccines.

PMID- 8645549
TI  - The two Hammarstens and nucleic acids.

PMID- 8645550
TI  - Gustaf Retzius and spermatology.

PMID- 8645551
TI  - A polar development. The Runnstrom tradition in Swedish developmental biology.

PMID- 8645552
TI  - Developmental biology in Lund from a zoological perspective.

PMID- 8645553
TI  - Swedish contributions to the understanding of amphibian embryogenesis --a
      phenomenon of the past?

PMID- 8645554
TI  - Cell movements in neurogenesis. An interview with Professor Carl-Olof Jacobson.
      Interview by Ted Edendal.

PMID- 8645555
TI  - B-cell neoplasia in a developmental framework.

PMID- 8645556
TI  - Expression of a large number of novel testis-specific genes during
      spermatogenesis coincides with the functional reorganization of the male germ
      cell.
AB  - Structural and functional changes, essential for the formation of mature male
      germ cells, are known to take place at specific stages of the mammalian
      spermatogenic process. To identify novel genes that are involved in this
      developmental process, we have initiated a large-scale cDNA sequencing project
      (Hoog+, Nucleic Acids Res. 19: 93-98, 1991; Starborg et al., Mol. Reprod. Dev.
      33: 243-251, 1992; Yuan et al., Biol. Reprod., 1995). Five-hundred and forty
      cDNAs have been isolated from testicular cDNA libraries and partially sequenced,
      355 of which were found to represent genes previously not described in the
      literature. In addition, a number of cDNAs was found to be related to genes
      previously identified only in lower eukaryotes, suggesting that these murine
      genes encode functions that are evolutionary conserved. One of these murine cDNAs
      was related to the Aspergillus nidulans BimE gene, a putative cell cycle
      checkpoint regulator (Starborg et al., J. Biol. Chem., 1994). Southern blot
      analysis revealed that the murine BimE-related gene is strongly conserved in
      mammals. RNA blotting experiments of 361 novel murine cDNAs have identified 52
      cDNAs that are expressed only during spermatogenesis, 36 of which are expressed
      only in spermatids, and 16 cDNAs that are expressed in both spermatocytes and
      spermatids. A survey of the literature revealed 40 mammalian genes that have
      previously been shown to be expressed mainly during spermatogenesis, and together
      with our results, they define three dominating temporal patterns of gene
      expression during spermatogenesis, each pattern coinciding with known functional
      or structural changes occurring during this differentiation process.

PMID- 8645557
TI  - Sex differentiation -- gonadogenesis and novel genes.
AB  - During embryogenesis, most organ rudiments differentiate into only one type of
      organ and functional mutations are normally lethal for the embryo. However, the
      indifferent gonad has two options, to form either a testis or an ovary, and
      mutations of this tissue usually produce sex reversal or sterility which is not
      lethal for the individual. Therefore, gonadal development serves as an excellent
      model system for investigating questions of cell fate and organogenesis. The
      studies of human patients showing different types of sex reversal, in combination
      with the use of transgenic mice and/or gene targeting disruption, have led to the
      isolation of several genes important for sex development. These include SRY/Sry,
      encoding the testis-determining factor, Ftz-F1 encoding steroidogenic factor 1
      (SF-1) and Wilms' tumor gene (WT-1). However, the mammalian sex differentiation
      pathway requires the function of a number of additional genes which we are now
      trying to identify with the help of mRNA differential display technique.

PMID- 8645558
TI  - DNA methylation and polyamines in embryonic development and cancer.
AB  - Mammalian DNA contains relatively large amounts of a modified base, 5-methyl
      cytosine (m5C). Methylation of cytosine is catalyzed by DNA(cytosine
      5)methyltransferase (DNA MTase). DNA methylation seems to play an important role
      in the regulation of gene expression during development. Thus, m5C may inhibit
      transcription by preventing the binding of transcription factors and/or by
      altering chromatin structure. The DNA methylation patterns of the male and female
      pronuclei are erased in the morula and early blastula, and when the blastocyst
      forms, most of the DNA has become demethylated. Following implantation, however,
      there is a surge of de novo methylation affecting the entire genome, and already
      by gastrulation DNA is methylated to an extent characteristic of that of the
      adult animal. During subsequent development, tissue-specific genes undergo
      programmed demethylation, which may cause their activation. Site-directed
      mutagenesis of the DNA MTase gene, has recently shown that DNA methylation is
      absolutely required for normal development of the early mouse embryo. DNA
      methylation and polyamine synthesis depend on a common substrate, S
      adenosylmethionine (AdoMet). As a consequence, changes in cellular polyamine
      levels may affect the degree of DNA methylation. When the first step in the
      polyamine biosynthetic pathway is blocked, F9 teratocarcinoma stem cells
      accumulate large amounts of decarboxylated AdoMet, the aminopropyl group donor in
      polyamine synthesis, and go through terminal differentiation into parietal
      endoderm cells. The accumulation of decarboxylated AdoMet is a direct consequence
      of the polyamine-depleted state of the cell. Although the decarboxylated AdoMet
      molecule contains a methyl group, it does not act as a methyl group donor in DNA
      methylation. Instead it acts as a competitive inhibitor of DNA MTase. A
      consequence of polyamine depletion is therefore genome-wide loss of DNA
      methylation due to insufficient maintenance methylation during successive rounds
      of DNA replication. Our recent finding that prevention of the accumulation of
      decarboxylated AdoMet counteracts the differentiative effect lends further
      support to the hypothesis proposed.

PMID- 8645559
TI  - Growth factors and apoptosis in development. The role of insulin like growth
      factor I and TGFbeta1 in regulating cell growth and cell death in a human
      teratocarcinoma derived cell line.
AB  - The balance between different cell populations in the developing organism is
      controlled by regulating the rates of multiplication, differentiation or death of
      its constituent cells. The human teratocarcinoma derived cell line Tera 2, which
      in several aspects mirrors early embryonic cells, can be induced to undergo
      programmed cell death (apoptosis) by depriving cell cultures of serum. This study
      demonstrates that this process can be reversed by replacing serum with
      physiological concentrations of insulin like growth factor I (IGF I). As a
      result, IGF I enhances the rate of Tera 2 cell proliferation in serum free
      medium. In contrast, Transforming Growth Factor beta1 did not exert any effect on
      growth or apoptosis in Tera 2 cells. The results indicate that one effect of
      growth factors on pluripotential cells is to regulate the balance between cell
      proliferation and cell death.

PMID- 8645560
TI  - The Drosophila Stock Centers and their implications for developmental biology.
AB  - Mutations are central to functional analyses of genes and their products. In
      vertebrates, gene clones may be readily available, but there is often a lack of
      mutations. In Drosophila melanogaster, which has been used in genetic research
      for almost a decade, mutations defining thousands of genes have been isolated.
      Much of the basic genetic knowledge available today has been obtained from
      fundamental experiments done on the fruitfly. This year's Nobel laureates in
      physiology and medicine, E.B. Lewis, C. Nusslein-Volhard and E. Wieschaus, were
      rewarded for their important contributions to our understanding of the genetic
      control of early embryonic development where they used Drosophila melanogaster as
      a model system. Such experiments often result in huge numbers of mutant strains
      that should be maintained to aid in the localization and functional analyses of
      new genes in the future. For this reason Drosophila Stock Centers have been
      established in Europe and North America. Japan is also planning to build an Asian
      Drosophila Stock Center. The objectives of Drosophila Stock Centers are to
      maintain strains with well characterized mutations, check their constitution and
      distribute strains together with information about their genetic defects to
      research groups around the world. The European Commission has recently
      acknowledged the importance of stock centers as part of the biological research
      infrastructure by supporting the European Drosophila Stock Centre in Umea.

PMID- 8645561
TI  - Notch-related genes in animal development.
AB  - The Drosophila melanogaster gene Notch is central to many cell differentiation
      events during development. It encodes a large transmembrane signal receptor
      protein that acts in a poorly understood mechanism of communication affecting the
      choice of alternative differentiation fates by cells in close proximity. Genes
      with homology to Notch have been isolated from the nematode Caenorhabditis
      elegans and a number laboratories, including our own, have isolated multiple
      vertebrate Notch homologs. In this article we briefly outline the current state
      of research on Notch and our contribution to it. First, we examine the structure
      of Notch-related proteins. We then examine the requirements for Notch activity in
      the development of different organisms and how genetic and transgenic studies are
      helping us to understand the mechanism(s) by which these proteins function. We
      present models for the action of Notch receptors during signal transduction and
      for the interaction of multiple vertebrate Notch receptors. Finally, we discuss
      current ideas about the role played by Notch in differentiation and cell-cell
      communication.

PMID- 8645562
TI  - Structure and function of basement membranes.
AB  - The importance of basement membranes in development and adult tissue function has
      been inferred from a number of observations. Cells migrate along basement
      membranes during development, basement membranes are required for the
      polarization of cells in both the embryo and the adult, and basement membranes
      serve as substrates for cell adhesion and migration during wound healing and
      nerve regeneration. The importance of basement membranes in adult tissue function
      has been directly demonstrated by the genetic diseases caused by mutations in the
      genes for structural basement membrane components. Examples of such diseases are
      Alport syndrome and junctional epidermolysis bullosa. Recently, defects in the
      major laminin variant in muscle, merosin, has been shown to be correlated with
      muscular dystrophies in man and animals. We are using the dystrophic mutant mouse
      dy, which lacks laminin-2, to analyze the function of laminin-2 in different
      tissues. Studies of laminin defects in animals and humans are expected to give
      new information on the function of basement membrane in general and on laminin in
      particular. Such information may give directions for future diagnosis and
      treatment of diseases involving basement membranes.

PMID- 8645563
TI  - IPF1, a homeodomain protein with a dual function in pancreas development.
AB  - Insulin promoter factor 1 (IPF1), is a homeodomain protein which, in the adult
      mouse pancreas, is selectively expressed in beta-cells, and which binds to, and
      transactivates, the insulin promoter via the P1 element. In mouse embryos, IPF1
      expression is initiated when the foregut endoderm commits to a pancreatic fate,
      i.e. prior to both morphogenesis and hormone specific gene expression. At later
      stages of development the expression is restricted to the dorsal and ventral
      walls of the primitive foregut at the positions where the pancreases will form.
      Mice homozygous for a targeted mutation in the Ipf1 gene selectively lack the
      pancreas. The mutant pups develop to term and are born alive, but die after a few
      days. The gastrointestinal tract with its associated organs show no obvious
      malformations. No pancreatic tissue and no ectopic expression of insulin or
      pancreatic amylase could be detected in this region in mutant neonates or
      embryos. These findings demonstrate that IPF1 is needed for the formation of the
      pancreas, and suggest that IPF1 acts to determine the fate of common pancreatic
      precursor cells and/or to regulate their propagation. The lack of a pancreas in
      the Ipf1-deficient mutants, the pattern of IPF1 expression and its ability to
      stimulate insulin gene transcription, strongly suggest that IPF1 functions both
      in the early specification of the primitive gut to a pancreatic fate and in the
      maturation of the pancreatic beta-cell.

PMID- 8645564
TI  - Studies on the physiological role of brain-derived neurotrophic factor and
      neurotrophin-3 in knockout mice.
AB  - Brain-derived neurotrophic factor and neurotrophin-3 deficient mice were
      generated by gene targeting. The analysis of these mice has led to the
      characterization of their role in the survival of neurons in the peripheral
      nervous system. NT-3 deficient mice displayed severe movement defects and most
      died shortly after birth. The mutation causes loss of substantial portions of
      cranial and spinal peripheral sensory and sympathetic neurons. Significantly,
      spinal proprioceptive afferents and their peripheral sense organs (muscle
      spindles and Golgi tendon organs) were completely absent in homozygous mutant
      mice. BDNF deficient mice displayed deficiencies in coordination and balance.
      Excessive loss of neurons was detected in most of the peripheral sensory ganglia
      examined, but the survival of sympathetic neurons was not affected. The most
      marked reduction of neurons was observed in the vestibular ganglion, leading to a
      loss of innervation of the sensory epithelia of the vestibular compartments of
      the inner ear.

PMID- 8645565
TI  - Sonic hedgehog: a common signal for ventral patterning along the rostrocaudal
      axis of the neural tube.
AB  - The vertebrate hedgehog-related gene, sonic hedgehog, is expressed in ventral
      domains along the entire rostrocaudal length of the neural tube, including the
      forebrain. Shh induces the differentiation of ventral neuronal cell types in
      explants derived from prospective forebrain regions of the neural plate. Neurons
      induced in explants derived from diencephalic and telencephalic levels of the
      neural plate express the LIM homeodomain protein Islet-1, but these neurons
      possess distinct identities that match those of the ventral neurons normally
      generated in these two subdivisions of the forebrain. These results, together
      with other studies of neuronal differentiation at caudal levels of the neural
      tube, suggest that a single inducing molecule, Shh, mediates the induction of
      distinct ventral neuronal cell types along the entire rostrocaudal extent of the
      embryonic central nervous system.

PMID- 8645566
TI  - Role of platelet-derived growth factors in mouse development.
AB  - The current understanding of platelet-derived growth factor (PDGF) physiological
      functions in vivo is discussed in the context of mouse development. In
      particular, the review focuses on recent experiments in which genetic approaches
      have been applied in order to mutate the PDGF and PDGF receptor genes in the
      mouse. Thus, the PDGF-B and PDGF beta receptor (PDGFRb) genes were recently
      inactivated by homologous recombination in embryonic stem cells. Their phenotypes
      are highly similar, displaying cardiovascular, hematological and renal defects.
      The latter is particularly interesting since it consists of a specific cellular
      defect: the complete loss of kidnety glomerular mesangial cells. As such, the
      phenotype not only sheds light on the developmental importance of PDGF-B-PDGFRb
      interactions, but also reveals information about the function of mesangial cells.
      Based on detailed morphological studies of mutant glomeruli and the absence of
      urine collection in the urinary bladder, I propose that the mesangial cells
      function as interior "filter holders", the "filter" consisting of the glomerular
      basement membrane and associated cell types. The filter holder model would
      predict that glomerular filtration is critically dependent on an interior
      structural support of the filter, which is normally provided by the mesangial
      cells and the mesangial matrix. In addition to the mutants generated by gene
      targeting, the mouse patch mutation is discussed. This deletion encompasses the
      PDGFRa locus. The last part of the review focuses on the problems encountered
      when interpreting gene knockout phenotypes in the physiological functions of gene
      products.

PMID- 8645567
TI  - Norepinephrine as a morphogen?: its unique interaction with brown adipose tissue.
AB  - Norepinephrine is normally considered a neurotransmitter mediating acute
      metabolic effects in target cells. However, analysis of the regulation of the
      recruitment process in brown adipose tissue has indicated that norepinephrine may
      interact with this tissue in such a way that it could be considered a morphogen
      for this tissue. Besides stimulating the acute thermogenic processes,
      norepinephrine can induce the expression of tissue-specific proteins such as the
      uncoupling protein, induce expression of non-tissue specific proteins necessary
      of the thermogenic processes (e.g. lipoprotein lipase) and repress the expression
      of non-essential proteins (e.g. subunit c of the ATP-synthase). Upon chronic
      adrenergic stimulation, the general differentiation state of the tissue is
      advanced, indicating that the expression of factors with a more general effect on
      brown adipocyte differentiation is also under adrenergic control. It may even be
      discussed that norepinephrine may be involved early in the embryonal
      determination process directing cell clones into this line. The molecular basis
      for these effects of norepinephrine are only poorly known at present, but
      adrenergic effects on the expression level of many transcription factors, such as
      C/EBPalpha, C/EBPbeta, and PPARgamma 2, have been noted. These collective
      recruitment effects of norepinephrine are well suited to allow the tissue to grow
      or atrophy in response to the physiological needs of the organism.

PMID- 8645568
TI  - Situs inversus and ciliary abnormalities. What is the connection?
AB  - The finding of men with living but immotile sperm tails has initiated a search
      for the cause of the disorder. The sperm tails were found to lack dynein arms or
      to have some other ultrastructurally visible defect and the cilia were found to
      have the same defects. The disorder was hence named the immotile-cilia syndrome.
      Two more groups with the same clinical symptoms were later found, characterized
      by ciliary dysmotility or ciliary aplasia. In each group there are several
      subgroups. Many of the affected persons have situs inversus totalis; in some
      subgroups the incidence of situs inversus is probably 50%; there is, thus, a
      random determination of visceral asymmetry. Five hypotheses have been forwarded
      that attempt to explain the connection between ciliary defects and loss of
      laterality control. Support for, or evidence against, these five hypotheses have
      been sought in some animal models of the syndrome. Whereas immotile-cilia
      syndrome in dogs and pigs is very similar to the human one, an animal model in
      the rat differs from the human syndrome in that mainly the males are affected.
      Two animal models in the mouse differ in that one has ciliary defects but no
      increased incidence of situs inversus and the other has a random determination of
      visceral laterality and no ciliary defects. The connection between ciliary
      defects and random determination of laterality remains enigmatic.

PMID- 8645569
TI  - Extracellular matrix and its receptors during development.
AB  - Extracellular matrix (ECM) components are essential for morphogenesis of
      virtually all tissues. The ECM interacts with the cell surface by binding to
      specific receptors. The first family of receptors for the ECM that was identified
      was the integrin family. Integrins are composed of an alpha and a beta-chain,
      both of which are single pass transmembrane proteins. In muscle cells the
      dystroglycan complex forms another important receptor system for ECM. It is a
      complex composed of many proteins. Recent studies have shown that dystroglycan is
      expressed by embryonic epithelial cells as well. The nature of constituents of
      the dystroglycan complex is well known for muscle, whereas the detailed
      composition of the dystroglycan complex in embryonic epithelium is not yet well
      known. We here review the evidence that binding of ECM to integrins and the
      dystroglycan complex could be essential for muscle and epithelial cell
      development and function. It is likely that integrins and the dystroglycan
      complex have distinct roles during development. It will be an interesting task to
      study the signal transduction pathways elicited by the interactions between ECM
      and the two receptor systems during muscle and epithelial morphogenesis.

PMID- 8645571
TI  - Normal development and neoplasia: the imprinting connection.
AB  - The observation that a number of autosomal genes are expressed in a parent of
      origin-dependent monoallelic manner has fuelled a frantic research effort into
      the underlying mechanisms and biological functions of this phenomenon, termed
      genomic or parental imprinting. The level of intrigue associated with this
      subject has been heightened by the discovery that the "transcriptional phenotype"
      of some imprinted genes shows developmental and tissue-specific variation, and
      that some imprinted genes are expressed biallelically in tumors. Here we describe
      some further examples of variation in the allele-specific transcription of an
      imprinted gene, human IGF2. Analysis of different sub-clones of an established
      tumor cell line (Jeg-3) revealed examples of both a switch from monoallelic to
      biallelic expression, as well as monoallelic expression from the opposite
      parental allele. Examination of IGF2 expression in adult human liver clearly
      demonstrated that the functional imprinting is manifested in a promoter-specific
      manner. The P1 promoter produced biallelically derived transcripts, whereas the
      remaining three promoters were utilized in a complex pattern of mono- and
      biallelic expression which varied from sample to sample. These observations
      emphasize the need to re-examine the imprinting phenomenon and its plasticity in
      terms of the cis elements and trans-acting factors involved in the
      transcriptional regulation of these genes both in the normal and pathological
      contexts.

PMID- 8645570
TI  - Neurotrophins and their receptors in chicken neuronal development.
AB  - A review on current studies of chicken neurotrophins and their receptors is
      given. Chicken NGF, BDNF and NT-3 have been cloned and sequences have been used
      to synthesize oligonucleotides for specific localization of expression during
      development. Also, chicken TrkA, TrkB and TrkC have been cloned, sequenced and
      studied by in situ hybridization. Recombinant NT-3 was applied to chicken ganglia
      at different developmental stages to examine acquirement of responsiveness to NT
      3 compared to NGF. Phylogenetic analyses of the chicken neurotrophins and Trk
      receptors were carried out based on parsimony. Finally, some data on apoptosis in
      chicken embryo sympathetic ganglia are presented.

PMID- 8645572
TI  - Measuring symptomatic benefit and quality of life in paediatric oncology.

PMID- 8645573
TI  - Recent insights into the pathogenesis of Kaposi's sarcoma.

PMID- 8645574
TI  - Altered biodistribution of an antibody--enzyme conjugate modified with
      polyethylene glycol.
AB  - Polyethylene glycol modification of the antibody--enzyme conjugate, F(ab')2-A5B7
      CPG2, extends its duration in the circulation of nude mice bearing human colonic
      cancer xenografts (LS174T). Increased concentration of modified conjugate is
      achieved in the tumour, but residual non-specific enzyme concentrations in normal
      tissue and blood demonstrate the fundamental requirement to remove or inactivate
      non-specifically held enzyme in this system.

PMID- 8645575
TI  - The chronic administration of drugs that inhibit the regulation of intracellular
      pH: in vitro and anti-tumour effects.
AB  - Mean values of extracellular pH (pHe) in tumours tend to be about 0.5 pH units
      lower than in normal tissues, whereas values of intracellular pH (pHi) in tumours
      and normal tissues are similar. Previous studies have shown that drugs that
      acidify cells at lower pHe such as nigericin, used alone or with agents that
      inhibit the regulation of pHi, have toxicity to cultured cells at pHe < 6.5 in
      short-term exposure; these agents also lead to modest anti-tumour effects in mice
      when given acutely. To evaluate the long-term effects of these drugs at levels of
      pHe that might occur commonly in tumours, we exposed cells for up to 72h at pHe
      6.8 or 7.2 in vitro. Nigericin (0.033 microM) caused time-dependent cell killing
      of murine KHT and EMT-6 cells at pHe 6.8 (but not at pHe 7.2) with a surviving
      fraction approximately 5 x 10(-3) after 72 h exposure. Cell killing was increased
      in the presence of 4,4-diisothiocyanstilbene 2,2-disulphonic acid (DIDS), an
      inhibitor of Na+-dependent HCO3-/CI- exchange, and to a lesser extent in the
      presence of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), an inhibitor of Na+/H+
      exchange. Cell killing was exquisitely sensitive to the level of pHe. Osmotic
      pumps were used to obtain a 72 h continuous infusion of nigericin in mice; this
      led to dose-dependent killing of cells in KHT tumours with surviving fraction of
      approximately 0.1 at maximum tolerated doses. Hydralazine, which may cause tumour
      hypoxia and lower pHi as well as pHe, caused cytotoxity when given alone by
      chronic infusion, and enhanced the cytotoxicity due to nigericin. The addition of
      DIDS and/or EIPA (using two pumps) further enhanced anti-tumour toxicity, with a
      surviving fraction of approximately 0.002 at tolerated doses of the four drugs
      used to treat KHT tumours. The experiments demonstrate the activity of drugs that
      inhibit the regulation of pHi against murine tumours when delivered by chronic
      infusion.

PMID- 8645576
TI  - Photodynamic treatment of human endothelial cells promotes the adherence of
      neutrophils in vitro.
AB  - The effects of photodynamic treatment (PDT) on venules include vascular leakage
      accompanied by oedema formation, vasoconstriction and blood flow stasis. The goal
      of this study was to gain insight into the mechanism underlying these vascular
      events by studying one of the earliest observations after PDT, granulocyte
      adhesion, in an in vitro model. For this purpose human umbilical vein endothelial
      cells (HUVECs) preincubated with Photofrin II (PII) were illuminated with red
      light and incubated with neutrophils. PDT led to a dramatic change in the
      morphology of the endothelial cells. Clearly, neutrophils adhered to the
      subendothelial matrix and their adherence coincided with an increase in the
      percentage of exposed subendothelial matrix by the gradual contraction of
      endothelial cells. Furthermore, the increase in adherence was dependent on drug
      dose, illumination time and the time delay after PDT. The neutrophil adherence
      could be inhibited by anti-beta2-integrin antibodies, which suggests that the
      alphaL-, alphaM- or alphaX-beta2 receptors of the neutrophil mediated this
      phenomenon. At 4 degrees C or by preincubation of the neutrophils with
      staurosporin, their adherence to the subendothelial matrix exposed by PDT of
      endothelial cells could be prevented. Apparently, activation of the beta2
      integrin receptor by interaction with the subendothelial matrix is necessary for
      the increased binding of neutrophils. Taken together, these in vitro findings
      suggest that the PDT-induced contraction of the endothelial cells permits
      neutrophil adherence to the subendothelial matrix. It is conceivable that a
      similar mechanism contributes to the initial adherence of granulocytes to the
      vessel wall as observed after PDT in vivo.

PMID- 8645577
TI  - Growth-inhibitory effects of vitamin D analogues and retinoids on human
      pancreatic cancer cells.
AB  - Retinoids and vitamin D are important factors that regulate cellular growth and
      differentiation. An additive growth-inhibitory effect of retinoids and vitamin D
      analogues has been demonstrated for human myeloma, leukaemic and breast cancer
      cells. We set out to study the effects of the vitamin D analogue EB1089 and the
      retinoids all-trans- and 9-cis-retinoic acid on the human pancreatic
      adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic
      carcinoma cell line Hs766T. The cell lines investigated expressed vitamin D
      receptor, retinoic acid receptor (RAR)-alpha and gamma as determined by
      polymerase chain reaction after reverse transcription. RAR-beta was expressed
      only in Hs766T cells. Addition of all-trans-retinoic acid increased the amount of
      RAR-alpha mRNA in the three cell lines and induced RAR-beta mRNA in Capan 1 and
      Capan 2 cells. All-trans-retinoic acid at a concentration of 10 nM inhibited the
      growth of Capan 1 and Capan 2 cells by 40% relative to controls. 9-cis-Retinoic
      acid was less effective. Neither all-trans-retinoic acid nor 9-cis-retinoic acid
      affected the growth of Hs766T cells. EB1089, if added alone to the cells, did not
      significantly inhibit growth. However, the combination of 1 nM EB1089 with 10 nM
      all-trans-retinoic acid exerted a growth-inhibitory effect of 90% in Capan 1
      cells and of 70% in Capan 2 cells. Our data suggest that vitamin D analogues
      together with retinoids inhibit the growth of human pancreatic cancer cells.
      However, in vivo studies are necessary to examine the potential use of retinoids
      and vitamin D analogues on pancreatic cancer.

PMID- 8645578
TI  - Expression of Mad, an antagonist of Myc oncoprotein function, in differentiating
      keratinocytes during tumorigenesis of the skin.
AB  - The Myc oncoprotein is associated with cell proliferation and is often down
      regulated during cell differentiation. The related Mad transcription factor,
      which antagonises Myc activity, is highly expressed in epidermal keratinocytes.
      Mad also inhibits cell proliferation in vitro. To study Mad expression in
      keratinocyte proliferation and differentiation, we have analysed Mad RNA
      expression in regenerating and hyperproliferative epidermal lesions and epidermal
      tumours of varying degrees of differentiation using the RNA in situ hybridisation
      and RNAase protection techniques. Mad was strongly expressed in differentiating
      suprabasal keratinocytes in healing dermal wounds and in benign
      hyperproliferative conditions, but also in squamous cell carcinomas, in which the
      keratinocytes retain their differentiation potential. However, Mad expression was
      lost in palisading basal carcinoma cells and poorly differentiated squamous cell
      carcinomas, which lacked the epithelial differentiation marker syndecan-1. We
      therefore suggest that Mad expression is closely associated with epithelial cell
      differentiation, and that this association is retained in epithelial tumours of
      the skin.

PMID- 8645579
TI  - Defective interleukin six expression and responsiveness in human mammary cells
      transformed by an adeno 5/SV40 hybrid virus.
AB  - Mammary epithelial cells (MECs) were isolated and cultured from mammary glands of
      healthy women undergoing reduction mammoplasty. Normal MECs were infected with
      the transforming hybrid virus adeno-5/SV40. Two transformed epithelial cell
      lines, M1 and M2, were obtained, characterised phenotypically and studied for the
      production of and the response to cytokines and growth regulators. In both cell
      lines, expression of the SV40 large T antigen was associated with loss of
      interleukin 6 (IL-6) production and responsiveness as well as with down
      regulation of IL-8 and transforming growth factor (TGF)-alpha production. Both M1
      and M2 cell lines were capable of forming colonies in semisolid media, but upon
      injection into severe combined immunodeficient (SCID) mice only M2 cells were
      tumorigenic. DNA synthesis in M1 cells was partially inhibited by serum or TNF
      alpha and weakly stimulated by hydrocortisone (HC) and IL-8. In contrast, M2
      cells were totally unresponsive to a variety of growth regulators. Both lines
      overexpressed the p53 protein at levels about 20-fold higher than those observed
      in primary MEC cultures, but no mutations of the p53 gene could be detected. The
      date confirm the view that the expression in human mammary cells of different
      oncogenes - including the SV40 T antigen - is frequently associated with
      alterations of cytokine production and responsiveness.

PMID- 8645580
TI  - In vitro and in vivo anti-tumour effects of a humanised monoclonal antibody
      against c-erbB-2 product.
AB  - The c-erbB-2 product is thought to be a unique and useful target for antibody
      therapy of cancers overexpressing the c-erbB-2 gene. In vitro and in vivo anti
      tumour effects of a humanised antibody against the extracellular domain of the c
      erbB-2 gene product, rhu4D5, were examined. Rhu4D5 was less effective than its
      murine counterpart, mu4D5, for the direct antiproliferative activity against the
      c-erbB-2-overexpressing SK-BR-3 cell line. In vivo treatment of severe combined
      immunodeficient (SCID) mice carrying the c-erbB-2-overexpressing 4-1ST human
      gastric carcinoma xenograft with 4hu4D5 revealed that the recombinant protein had
      potent anti-tumour activity. Furthermore, cytotoxicity of human peripheral blood
      mononuclear cells against 4-1ST was significantly augmented with rhu4D5, but not
      with mu4D5. These results indicate that rhu4D5 might perform better in patients
      than predicted from preclinical studies.

PMID- 8645581
TI  - Monoclonal antibody against the fusion junction of a deletion-mutant epidermal
      growth factor receptor.
AB  - A mouse monoclonal antibody (IgG2b), 3C10, was produced against the truncated
      epidermal growth factor receptor (EGFR), encoded by the (type III) in-frame
      deletion mutation of 801 nucleotides of EGFR affecting the external domain, known
      to be expressed in some human glioblastoma. As this mutation newly generates a
      glycine residue at the fusion point, a 14 amino acid peptide around the fusion
      junction including this glycine was chemically synthesised and used for
      immunisation of (B6 x DBA/2) F1 mice. Flow cytometric analysis showed 3C10
      antibody staining of a mouse NIH/3T3 transfectant (ERM5) with the type III EGFR
      deletion-mutant gene, but not one with wild-type EGFR. The antibody
      immunoprecipitated the truncated EGFR protein with a molecular mass of
      approximately 140 kDa from ERM5 cells. Immunostaining of glioblastomas revealed
      binding in the case with the type III EGFR mutation, the five other specimens
      without the mutation being negative despite overexpression of EGFR in some cases.

PMID- 8645582
TI  - Effect of transfection of a Drosophila topoisomerase II gene into a human brain
      tumour cell line intrinsically resistant to etoposide.
AB  - The human brain tumour cell line HBT20 is intrinsically resistant to etoposide
      and does not express mdr-1 mRNA. These studies were conducted to determine
      whether transfecting a Drosophila (D) topoisomerase II (topo II) gene into HBT20
      cells could increase their sensitivity to etoposide. A D-topo II construct in a
      pMAMneo vector under the control of a mouse mammary tumour virus (MMTV) promoter
      was transfected into HBT20 cells. The gene is inducible by dexamethasone (Dex).
      The growth rate of the transfected cells and percentage of the cells in G1, S and
      G2M was no different than the parental cells. Survival after etoposide exposure
      (10 microM x 2 h) was measured by colony formation. Parental cells and cells
      transfected by pMAMneo vector alone showed no enhanced etoposide sensitivity
      after 24 h of Dex stimulation. By contrast, D-topo II transfected cells were
      sensitised 3-fold when etoposide treatment was preceded by 24 h Dex stimulation.
      Northern blotting and Western blotting confirmed that Dex had induced D-topo II
      expression in the sensitised cells. However, in D-topo II-transfected cells
      increasing the duration of Dex stimulation to 48 h eliminated the sensitisation
      to etoposide although increased MMTV promoter activity and expression of the D
      topo II gene persisted. Measurement of endogenous human topo-II mRNA and protein
      revealed a decrease after Dex exposure of greater than 24 h. At these distal
      times, the total cellular topo II levels (endogenous + exogenous) may be
      decreased, which may explain why increased sensitivity to etoposide could no
      longer be demonstrated. This model suggests that D-topo II gene transfection can
      sensitise de novo resistant HBT20 cells to etoposide but that the time frame of
      that sensitisation is limited.

PMID- 8645583
TI  - A non-random deletion in the p53 gene in oral squamous cell carcinoma.
AB  - In a retrospective study of the mutational spectrum of the p53 gene in oral
      squamous cell carcinoma, 80 primary tumours diagnosed in 1980-90 were included.
      Using polymerase chain reaction/single strand conformation polymorphism
      (PCR/SSCP) analysis 47 mutations were found distributed in 39 of the tumours
      (49%). Unexpectedly, the majority of the mutations (29/47; 62%) were found in
      exon 8, and at sequencing 17 of them showed a 14 bp deletion in codons 287-292,
      causing formation of a stop codon and accordingly a truncated protein lacking the
      C-terminal. The majority of the patients with the 14 bp deletion were women
      (13/17), and it seemed as though certain potential risk factors for carcinoma of
      the head and neck were less common in this group.

PMID- 8645584
TI  - Intraperitoneal photodynamic therapy of the rat CC531 adenocarcinoma.
AB  - The goal of this study was to investigate the efficacy of photodynamic therapy
      (PDT) of a single tumour growing intraperitoneally. For this purpose the CC531
      colon carcinoma, implanted in an intraperitoneal fat pad of Wag/RijA rats, was
      treated with intraperitoneal photodynamic therapy (IPPDT) using Photofrin as the
      photosensitiser. Two illumination techniques have been compared. An invasive
      illumination technique using Perspex blocks to illuminate 30 cm2 of the lower
      abdomen gave a significant delay in tumour growth with 25 J cm-2 applied 1 day
      after Photofrin. A minimally invasive illumination technique using a balloon
      catheter to illuminate 14 cm2 resulted in an equivalent growth delay with 75 J cm
      2. The route of administration of the photosensitiser did not influence regrowth
      times of the tumour. Mitomycin C (MMC), a bioreductive agent, was used to exploit
      the known PDT-induced hypoxia. The combination of IPPDT with MMC resulted in an
      increased tumoricidal effect. In conclusion, IPPDT led to a significant growth
      delay for a single tumour implanted intraperitoneally and repetition of the PDT
      treatment was possible using a minimally invasive illumination technique.
      Repeated treatments resulted in increased tumour response.

PMID- 8645585
TI  - Microsatellite instability in early sporadic breast cancer.
AB  - We have studied the incidence of microsatellite instability at three
      trinucleotide repeats and seven dinucleotide repeats from five chromosomal
      regions, in a group of 30 mammographically detected 'early' invasive breast
      cancers and correlated its occurrence with clinicopathological parameters. The
      myotonic dystrophy (DM-1) trinucleotide repeat was analysed in 48 additional
      cases. In 4 out of 78 (5%) paired tumour-normal DNA samples we found evidence of
      somatic microsatellite instability at DM-1: a novel allele of a different size
      was seen in the tumour DNA which was not present in the normal DNA sample. All
      four tumours that showed evidence of instability were from the core group of 30
      cases (13%) and were well or moderately differentiated, oestrogen receptor
      positive, infiltrating ductal carcinomas. Two of these tumours were unstable at
      nine of ten loci studied, both trinucleotide and dinucleotide repeats. DNA
      prepared from different normal tissues showed no evidence of instability, for all
      four instability cases. These data indicate that microsatellite instability is
      specific to the tumour DNA and is an early event in the genesis of some sporadic
      breast cancers.

PMID- 8645586
TI  - WAF1/CIP1 structural abnormalities do not contribute to cell cycle deregulation
      in ovarian cancer.
AB  - Mutations in the WAF1/CIP1 gene were not found in 36 ovarian carcinomas,
      including tumours with loss of heterozygosity at the WAF1/CIP1 locus and/or
      lacking p53 mutations. In addition, no association was demonstrable between a
      polymorphism in a conserved region of the WAF1/CIP1 gene and ovarian carcinoma.

PMID- 8645588
TI  - Mathematical modelling of tumour response in primary breast cancer.
AB  - Although breast cancer is perceived to be relatively chemosensitive, cytotoxic
      drug therapy only leads to cure in the adjuvant setting. In advanced disease,
      primary resistance and inadequate cell kill may be important in determining the
      lack of a durable response to cytotoxics, but for an individual patient's tumour
      there is no consistent way of determining the importance of these two factors. An
      adaptation of Skipper's log cell kill model of tumour response to chemotherapy
      was applied to serial tumour measurements of 46 locally advanced primary breast
      carcinomas undergoing neoadjuvant chemotherapy. Assuming a log-normal
      distribution of errors in the clinically measured volumes, the model produced,
      for each tumour separately, in vivo estimates of proportional cell kill, initial
      resistance and tumour doubling times during therapy. After 4 weeks' treatment,
      these data could then be used to predict subsequent tumour volumes with good
      accuracy. In addition, for the 13 tumours that became operable after the
      neoadjuvant chemotherapy, there was a significant association between the final
      volume as predicted by the model and the final pathological volume (P < 0.05).
      This approach could be usefully employed to determine those tumours that are
      primarily resistant to the treatment regimen, permitting changes of therapy to
      more effective drugs at a time when the tumour is clinically responding but
      destined to progress.

PMID- 8645587
TI  - Comparative analysis of the expression patterns of metalloproteinases and their
      inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary
      carcinomas and malignant non-Hodgkin's lymphomas in humans.
AB  - Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of
      metalloproteinases, TIMPs) play essential roles in the remodelling of the
      extracellular matrix (ECM). Results of in vivo and in vitro studies suggest that
      the balance between MMPs and TIMPs is altered in neoplasia, contributing to the
      invasive and metastatic properties of malignant tumours. In this study we have
      analysed the expression of five MMP genes and TIMP-1 and TIMP-2 in 37 benign and
      malignant lesions of human breast using Northern blot analysis. MMP-9 (92 kDa
      gelatinase) and MMP-11 (stromelysin 3) were most consistently expressed by
      carcinomas. Based on detection of either MMP-9 or MMP-11 mRNAs, we were able to
      distinguish between malignant and benign disease with a predictive accuracy of
      90% with 94% sensitivity and 85% specificity. Subsequently, these results were
      compared with results for carcinomas of colon and lung and malignant non
      Hodgkin's lymphomas (NHL). Elevated MMP-9 and TIMP-1 expression was observed in
      all four systems. MMP-11 characterised all carcinomas as well as carcinomas in
      situ but was not detectable in NHL. Our data therefore argue that there are
      remarkably similar patterns of specific functions involved in ECM remodelling
      that correlate with malignancy in different human tumours of different
      histogenesis. However, MMP-11 expression is a characteristic of tumours of
      epithelial origin that is not found in lymphoid neoplasia. Thus it suggests that
      MMP-11 may play a regulatory role in the invasion and metastasis of carcinomas.

PMID- 8645589
TI  - Waning sexual function--the most important disease-specific distress for patients
      with prostate cancer.
AB  - The objective was to investigate how prostate cancer and its treatment affects
      sexual, urinary and bowel functions and to what extent eventual complications
      cause distress. A questionnaire was sent to 431 men aged 50-80 years with
      prostate cancer diagnosed in 1992 in the Stockholm area (Sweden) and 435 randomly
      selected men with a similar age distribution. Sexual function, as compared with
      their youth, was diminished in a majority of all men. The prostate cancer
      patients were, however, more likely to report low frequency and/or intensity in
      all aspects of sexual function. A majority of the men were distressed by a waning
      sexual capacity. The proportion of men with prostate cancer who were severely
      distressed owing to a decline in sexual function was larger than in the reference
      group. The willingness to trade off an intact sexual function for long-term
      survival varied considerably among the men in the reference group. Urinary and
      bowel symptoms were less common than a waning sexual function in both groups, and
      few appeared to be severely distressed by urinary or bowel symptoms. A decline in
      sexual functions was the most common cause of disease-specific distress in men
      with prostate cancer.

PMID- 8645590
TI  - Anxiety in women "at risk' of developing breast cancer.
AB  - Do family history clinics offering counselling, surveillance and preventative
      programmes alleviate or exacerbate anxiety in women at a high risk of developing
      breast cancer? In this study risk perceptions and anxiety of 99 'at risk' women
      participating in the Tamoxifen Prevention Trial were compared with those of 87
      'at risk' women not attending any specialist clinic who were recruited from the
      National Breast Screening Programme (NBSP). Most anxiety was found in NBSP women
      with a family history. Women attending the family history clinic and
      participating in the trial had anxiety scores comparable with 86 women recruited
      from the NBSP who did not have a family history. We conclude that such specialist
      clinics do not see a selected group of the most anxious 'at risk' women nor does
      participation in tamoxifen prevention programmes appear to increase anxiety.

PMID- 8645591
TI  - A feasibility study of accelerated polychemotherapy with cisplatin,
      epidoxorubicin and cyclophosphamide (PEC) in advanced ovarian cancer.
AB  - We have evaluated the feasibility of an increase in dose intensity of the
      cisplatin, epidoxorubicin and cyclophosphamide (PEC) regimen, with granulocyte
      colony-stimulating factor (G-CSF) support, in 22 patients with advanced ovarian
      cancer. Twenty-one patients (95.4%) received six cycles of treatment: of these,
      13 (61.9%) were also able to repeat cycles every 14 days as planned. Marrow
      toxicity was similar to that observed during conventional treatments. No severe
      mucositis or thrombocytopenia was observed. A clinical complete response was
      observed in 9 out of 16 evaluable patients (56.2%).

PMID- 8645592
TI  - A pilot study on risk factors and p53 gene expression in colorectal cancer.
AB  - Of 311 colorectal cancers diagnosed in 1984-86 in the county of Ostergotland,
      Sweden, 179 were included in a case-control study, and, of these, 70 were
      investigated using immunohistochemical staining for p53 gene mutations. Alcohol
      use as well as medication with hydralazine-containing antihypertensive drugs, but
      not heredity were associated with p53 staining. The study is offered to
      illustrate the possible value of investigating molecularly defined tumour
      subtypes in relation to specific risk factors.

PMID- 8645594
TI  - A computerised cancer registration network in the Veneto region, north-east of
      Italy: a pilot study.
AB  - A cancer registration network based on computerised coded diagnoses has been
      tested in the Veneto region, north-east Italy, with the goal of estimating cancer
      incidence during 1987-89. The results of the pilot study based on a population of
      1,449,513 (33.1% of the total population of the region) indicate that the
      computer-assisted system successfully ascertained 61.3% of the cases. The quality
      indices appear to be close to those from other cancer registries in Europe. The
      increasing availability of computerised coded information from hospitals,
      pathology departments and death certificates can provide an important
      contribution to cancer registration, thus reducing the amount of manual work and
      consequently allowing cancer registration on larger populations at reduced costs.

PMID- 8645593
TI  - Oral contraceptives, hormone replacement therapy and the risk of colorectal
      cancer.
AB  - The relationship between oral contraceptives (OCs), menopausal hormone
      replacement therapy (HRT) and the risk of colorectal cancer was investigated in a
      case-control study conducted in northern Italy between 1985 and 1992 on 709 women
      with incident colorectal cancer and 992 controls admitted to hospital for a wide
      spectrum of acute, non-neoplastic, non-digestive tract, non-hormone-related
      disorders. A reduced risk of colorectal cancer was observed in women who had ever
      used OCs [multivariate odds ratio (OR) = 0.58; 95% confidence interval (CI): 0.36
      0.92]. The OR was 0.52 (95% CI 0.27-1.02) for use over 2 years. For women ever
      using HRT, the multivariate OR was 0.40 (95% CI 0.25-0.66). The risk was
      inversely related to duration of use, with ORs of 0.46 for 2 years or less and
      0.25 for more than 2 years of use. No consistent pattern of trends was observed
      with time since first or last use. This study provides further evidence that OC
      and HRT do not increase, and possibly decrease, the risk of colorectal cancer.
      These results, if confirmed, would have important implications for the ultimate
      risk-benefit assessment of female hormone preparations.

PMID- 8645595
TI  - The multicentre south European study 'Helios'. I: Skin characteristics and
      sunburns in basal cell and squamous cell carcinomas of the skin.
AB  - The aim of this study was to investigate constitutional and environmental
      determinants of non-melanocytic skin cancer among different populations from
      south Europe. Between 1989 and 1993 we interviewed incident cases and a random
      population sample of controls from five centres where a cancer registry was
      operating, whereas we selected a sample of hospital-based cases and controls from
      three other centres. Controls were stratified according to the age and sex
      distribution of cases. In all, 1549 cases of basal cell carcinoma (BCC), 228 of
      squamous cell carcinoma (SCC) and 1795 controls were interviewed. Both cancers
      affected primarily sun-exposed sites such as face, head and neck, but the
      prevalence of BCC on the trunk was higher than for SCC. Pigmentary traits such as
      hair and eye colour as well as tendency to sunburn were strong and independent
      indicators of risk for both BCC and SCC. In SCC, adjusted odds ratios (ORs)
      ranged from 1.6 for fair hair colour to 12.5 for red hair. Light-blonde hair
      entailed a risk of about 2 for BCC. Pale eye colour was associated with a risk of
      1.8 for SCC and 1.4 for BCC. Subjects who always burn and never tan showed an
      adjusted OR of 2.7 for BCC and 2.0 for SCC. A history of sunburns and a young age
      at first sunburn were associated with an increased risk for BCC only (OR 1.7).
      Pigmentary traits and sun sensitivity of the skin confirmed their role as risk
      indicators. The effect of sunburns, as an indicator of both exposure and sun
      sensitivity of the skin, is less clear. Nevertheless, its association with BCC
      suggests, by analogy with melanoma, a relationship with intense sun exposure.
      Conversely, SCC would require prolonged exposure to sunlight.

PMID- 8645596
TI  - The multicentre south European study 'Helios'. II: Different sun exposure
      patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.
AB  - The role of sun exposure in development of basal cell and squamous cell
      carcinomas among different populations from south Europe was investigated.
      Between 1989 and 1993 we interviewed incident cases and a random population
      sample of controls from five centres where a cancer registry was operating,
      whereas we selected a sample of hospital-based cases and controls from the other
      three centres. We gathered information on life-long exposure to sunlight during
      different activities. Results are analysed for 1549 basal cell carcinoma (BCC)
      cases and 228 squamous cell carcinoma (SCC) cases compared with 1795 controls. We
      observed a statistically significant increase of risk of SCC with increasing sun
      exposure beyond a threshold of 70,000 cumulated hours of exposure in a lifetime.
      Sun exposures during work and holidays were, however, inversely correlated. Odds
      ratios (ORs) of SCC were up to eight or nine times the reference for the highest
      exposures (200,000 cumulated hours or more). BCC exhibited a 2-fold increase of
      risk for lower exposure (8000-10,000 cumulated hours in a lifetime) with a
      plateau and a slight decrease of risk for the highest exposures (100,000
      cumulated hours or more). Outdoor work showed a significantly increased risk of
      SCC (OR 1.6 for more than 54,000 cumulated hours of exposure in a lifetime),
      whereas recreational activities such as sun exposure during holidays at the beach
      (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) or during
      water sports (OR 1.6 for more than 2600 cumulated hours of exposure in a
      lifetime) were associated with an increased risk of BCC. Risk patterns were
      different in poor or good tanners with a significant risk trend for good tanners,
      whereas poor tanners were on a plateau of increased risk at any level of
      exposure. Solar radiation is associated with a risk of BCC even for relatively
      short periods of exposure such as during holidays and sports, whereas SCC
      develops later if exposure continues. The skin's ability to tan modulates the
      risk of BCC; subjects who tan poorly have a steady risk increase, whereas people
      who tan easily develop cancer only after prolonged exposures.

PMID- 8645597
TI  - Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural
      precursors.
AB  - The mammalian POU-domain factor Brn-3.0 (Brn-3, Brn-3a) is a member of the POU-IV
      class of transcription factors which resemble the C. elegans factor unc-86 in
      structure, DNA-binding properties and expression in subsets of sensory neurons.
      Using specific antisera, we have explored the expression of Brn-3.0 in the early
      development of the mouse nervous system. Brn-3.0 expression begins at embryonic
      day 8.5 (E8.5) in a specific set of midbrain tectal neurons whose time and place
      of appearance are consistent with the earliest CNS neurons previously identified
      using non-specific markers of neural differentiation. By E9.5, Brn-3.0
      immunoreactivity also identifies early CNS neurons in the hindbrain and spinal
      cord. In the peripheral sensory ganglia, Brn-3.0 expression is first observed at
      E9.0 in migrating precursors of the trigeminal ganglion, followed by the other
      sensory cranial and dorsal root ganglia, in a rostral to caudal sequence. Double
      label immunofluorescence with Brn-3.0 and the markers of cell division PCNA and
      BrdU demonstrate that Brn-3.0 is restricted to the post-mitotic phase of CNS
      development. In the sensory cranial and dorsal root ganglia, however, Brn-3.0 is
      expressed in dividing neural precursors, suggesting that the nature or timing of
      developmental events controlled by Brn-3.0 are distinct in the CNS and peripheral
      neurons. Restriction of Brn-3.0 expression to post-mitotic CNS neurons
      demonstrates that Brn-3.0 is not required for neurogenesis or patterning of the
      neuroepithelium in the CNS, but suggests a role in specification of mature
      neuronal phenotypes.

PMID- 8645598
TI  - A role for intermediate filaments in the establishment of the primitive epithelia
      during mammalian embryogenesis.
AB  - Investigations of the cytoskeleton in mammalian eggs and embryos have revealed
      the existence of an unusual array of crosslinked intermediate filaments composed
      of cytokeratins 5, 6, 16, and 'Z' that are referred to as cytoskeletal sheets. We
      have been investigating the function of these cytoskeletal sheets during
      embryogenesis. In this investigation we report the rapid appearance of extensive
      arrays of tonofilaments extending across blastomeres and in association with
      intercellular desmosomal junctions appearing at the time the embryo hatches from
      its zona pellucida, through the time of implantation of the embryo into the
      uterine wall. Just prior to the time of gastrulation these tonofilaments
      disappear. Electron microscopy and immunoconfocal microscopy demonstrate that the
      tonofilaments are composed of cytokeratins characteristic of the type found
      earlier in development, that is types 5 and 6; whereas, cytokeratin type 8 which
      has been shown to be synthesized in blastocysts is localized primarily at
      perinuclear regions. Cytokeratins 8 and 18 are synthesized to about the same
      extent as actin at the time the tonofilaments appear whereas the synthesis of
      cytokeratins 5 and 6 is greatly reduced. Our results suggest that cytokeratins 5
      and 6 in the tonofilaments may arise from the stored form of cytokeratins in the
      cytoskeletal sheets. Consequently, our results suggest that the sheets may serve
      as a maternal reserve of cytokeratin employed by the embryo at the time of
      implantation to form extensive arrays of tonofilaments in the embryo that likely
      provide structural integrity to the embryo as it is subjected to mechanical
      stress during invasion and implantation into the uterine wall.

PMID- 8645599
TI  - Targeted ribozymes reveal a conserved function of the Drosophila paired gene in
      sensory organ development.
AB  - The Drosophila paired (prd) gene, the founding member of the PAX gene family, is
      required for normal embryonic segmentation and is re-expressed later in
      development in the head and developing CNS. As for most embryonically active
      genes, global defects resulting from loss of early prd function obscure an
      analysis of the role of later expression phases. We used inducible targeted
      ribozymes to functionally 'knock-out' prd at late stages. When prd protein levels
      in the head are reduced in this fashion, the maxillary chemosensory ventral
      organs fail to develop and dorsal-lateral cirri rows are disrupted. These studies
      reveal a role for prd in sensory organ development that appears to be conserved
      in PAX genes throughout the animal kingdom.

PMID- 8645600
TI  - Expression of ret in the chicken embryo suggests roles in regionalisation of the
      vagal neural tube and somites and in development of multiple neural crest and
      placodal lineages.
AB  - In a screen for receptor tyrosine kinase genes regionally expressed in the
      developing hindbrain, we cloned and characterised the chicken ret gene. Data
      derived from studies of congenital human disease and from disruption of murine
      ret have demonstrated roles for ret in development of the kidney and enteric
      nervous system; the latter has been most well-studied in the avian embryo. In
      agreement with studies of the mouse embryo, we find expression of ret in both the
      intermediate mesoderm and the enteric nervous system. However, we additionally
      detect transcripts specifically in the vagal neural tube prior to the migration
      of enteric crest precursors, suggesting a possible earlier function in
      regionalisation of the neural tube and vagal neural crest. This spatial
      restriction in the neural tube is modulated by retinoic acid, but is not
      coordinately regulated with RAR-beta which shares a common anterior limit of
      expression with ret in normal embryos. Widespread expression of ret in placodal
      and neural crest derivatives raises the possibility of other roles in the
      development of the peripheral nervous system. In addition, ret may function in
      the spatial organisation of the epithelial somite, where it might play a role in
      the specification of anterior dermamyotome.

PMID- 8645601
TI  - Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related
      to the Drosophila lady bird genes.
AB  - We have cloned two novel homeobox genes which are the mouse (Lbx1) and human
      (LBX1) homologs of the Drosophila lady bird genes. They are highly related not
      only within the coding region but also in 5' and 3' untranslated regions. Several
      amino acid residues inside and around the homeodomain, have been conserved
      between the mammalian Lbx genes and their Drosophila counterparts. The mouse Lbx1
      gene is located on chromosome 19 (region D) and the human LBX1 gene maps to the
      related q24 region of chromosome 10, known as a breakpoint region in
      translocations t(7;10) and t(10;14) involved in T-cell leukemias. Thus, LBX1 and
      the protooncogene HOX11 map to a common chromosomal region, as do their
      Drosophila counterparts, the lady bird and 93Bal genes. The mouse Lbx1 gene is
      specifically expressed during embryogenesis. From 10.5 days of gestation, Lbx1
      expression is detected in the central nervous system and some developing muscles.
      In the CNS, Lbx1 transcripts are expressed in the dorsal part of the mantle layer
      of the spinal cord and hindbrain, up to a sharp boundary within the developing
      metencephalon. Thus, Lbx1 may be inolved in spinal cord and hindbrain
      differentiation and/or patterning, and its restricted expression pattern could
      depend upon evolutionarily conserved inductive signals involving some mammalian
      Wnt and Pax genes, as is the case for Drosophila lady bird genes and wingless or
      gooseberry.

PMID- 8645602
TI  - Complementary and combinatorial patterns of Notch gene family expression during
      early mouse development.
AB  - The Drosophila Notch gene encodes a transmembrane receptor involved in the
      regulation of cell fate. It exerts its effect by lateral specification, inductive
      signaling and is also important for cell adhesion and axonal pathfinding. In this
      report we analyse the expression of the three mammalian Notch homologues during
      early mouse development by in situ hybridization. The Notch 1, 2 and 3 genes show
      dynamic and complex expression patterns, in particular during gastrulation and
      somitogenesis and in early nervous system formation. During gastrulation, the
      Notch genes are expressed in non-overlapping, successive patterns. Notch 3 is
      widely expressed in both ectoderm and mesoderm. Notch 2 is then expressed in the
      node, notochord and neural groove while Notch 1 becomes highly expressed in
      presomitic mesoderm. As somitogenesis begins, Notch 2 expression is activated in
      newly forming somites while Notch 3 is activated in mature somites. Various
      neural crest cell populations and ectodermal placode cells can be defined by
      expression of specific combinations of Notch genes. All three Notch genes are
      expressed within cells of the dorsal neural tube at E9.5, although neural crest
      cells that have begun migrating all show distinct patterns of Notch expression.
      Finally, Notch 1 expression is observed not only in placodes, but also in cells
      migrating from placodes to the site of the ganglia anlagen. This expression
      pattern may be analogous to Notch expression in the peripheral nervous system of
      Drosophila, suggesting that mammalian Notch genes may also be involved in axonal
      pathfinding.

PMID- 8645603
TI  - TLE expression correlates with mouse embryonic segmentation, neurogenesis, and
      epithelial determination.
AB  - The TLE proteins are the mammalian homologues of Groucho, a member of the
      Drosophila Notch signaling pathway. Notch signaling controls the differentiation
      of a variety of tissues in invertebrates and vertebrates. We are investigating
      the role of the TLE genes during mammalian development. We show that TLE 1 and
      TLE 3 are expressed during a number of cell-determination events, including
      embryonic segmentation, central and peripheral neurogenesis, and epithelial
      differentiation. This expression pattern is in agreement with the involvement of
      Groucho in similar fate choices in Drosophila and suggests that Groucho and TLE
      proteins perform similar developmental roles. Our results also show that TLE
      genes are co-expressed during a variety of cell-fate choices with several
      vertebrate homologues of genes implicated in the Drosophila Notch cascade,
      suggesting a role for the TLE proteins in mammalian Notch signaling.

PMID- 8645604
TI  - Expression of bone morphogenetic protein-4 (BMP-4), bone morphogenetic protein-7
      (BMP-7), fibroblast growth factor-8 (FGF-8) and sonic hedgehog (SHH) during
      branchial arch development in the chick.
AB  - Expression of Fgf-8, Bmp-4, Bmp-7, and shh in the branchial arches of the chick
      embryo is examined by in situ hybridization. Fgf-8 expression is initially broad
      and diffuse, becoming more tightly restricted, particularly in the epithelium of
      the posterior ectodermal margin (PEM) of the 2nd branchial arch. Bmp-7
      transcripts, first seen at stage 12 in discrete regions corresponding to the
      developing branchial clefts, are later detected in both clefts and arches,
      including the PEM of the 2nd arch while Bmp-4 transcripts are detected at stage
      18 in the distal tips of the arches. Shh expression remains localized,
      overlapping with both Bmp-7 and Fgf-8 in the PEM of the 2nd arch at stages 16 and
      18. Based on these data, a model is proposed for the role of these signalling
      molecules in branchial arch development.

PMID- 8645605
TI  - New neuroblast markers and the origin of the aCC/pCC neurons in the Drosophila
      central nervous system.
AB  - Drosophila is an ideal system for identifying genes that control central nervous
      system (CNS) development. Particularly useful tools include molecular markers for
      subsets of neural precursors (neuroblasts) and the simple expression pattern of
      the even-skipped (eve) gene in a subset of neurons. Here we provide additional
      molecular markers for identified neuroblasts, including several with near single
      cell specificity. In addition, we use these new markers to trace the development
      of several eve+ neurons. Our results shows that the eve+ aCC/pCC neurons develop
      from a different neuroblast than previously thought, and have led us to assign
      new names for several neuroblasts. These results are supported by DiI cell
      lineage analysis of neuroblasts identified in vivo.

PMID- 8645606
TI  - Induction of anteroposterior neural pattern in Xenopus: evidence for a
      quantitative mechanism.
AB  - The developing vertebrate nervous system arises from ectoderm in response to
      inductive signals from the dorsal mesoderm, or Spemann organizer. It displays
      pronounced anteroposterior (AP) pattern, but the mechanism that generates this
      pattern is poorly understood. We demonstrate that the inducing ability of dorsal
      mesoderm is regionalized along the AP axis at the early gastrula stage, using the
      homeodomain-encoding genes Xanf-2 and en-2 as markers of anterior and mid-neural
      pattern, respectively. In addition, we show that changing the size ratio of
      posterior dorsal mesoderm to responding ectoderm affects the type of AP pattern
      induced. A low ratio leads to induction of anterior neural pattern, while a high
      ratio leads to expression of only mid-neural pattern. These and other results
      indicate that a quantitative mechanism specifies AP neural pattern.

PMID- 8645608
TI  - Kinetic analysis of steroid 5alpha-reductase activity at neutral pH in benign
      prostatic hyperplastic tissue: evidence for type I isozyme activity in the human
      prostate.
AB  - In human benign prostatic hyperplastic (BPH) tissue homogenates 5alpha-reduction
      of testosterone was examined at neutral pH. As Lineweaver-Burk and Eadie
      Scatchard plots of estimated initial velocities against a wide range of substrate
      concentrations of 2 nM to 3.2 microM were non-linear, the existence of two 5alpha
      reductase isozymes in this tissue was surmised. Indeed, enzyme parameters at pH
      7.0 suggested the presence of two isozymes with affinity constants of 1995 and
      11.8 nM, characteristic of the well established human steroid 5alpha-reductase
      isozymes type I and II, respectively. The physiological roles of these isozyme
      activities remain puzzling. The specific activities, Vmax, of these subtypes
      indicated an approx. 6-fold higher maximum velocity of type I than of type II
      5alpha-reductase in the human hyperplastic prostate at this pH. In contrast, the
      efficiency ratios, Vmax/Km, demonstrated that the type II isozyme had a nearly 27
      times higher potential in vivo activity than the type I isozyme, and is therefore
      most probably quantitatively responsible for dihydrotestosterone formation at
      physiological testosterone levels in this tissue at neutral pH. This is the first
      full paper on type I 5alpha-reductase activity in human BPH tissue.

PMID- 8645607
TI  - Dual regulation of the epidermal growth factor family of growth factors in breast
      cancer by sex steroids and protein kinase C.
AB  - There has been increased interest in the last few years in seeking a better
      understanding of the local regulation of polypeptide growth factors by systemic
      hormones, such as sex steroids and by polypeptide hormones. Growth factors and
      systemic hormones play pivotal roles in hormone-regulated cancers such as breast
      cancer. In this review, we discuss the regulation of members of the epidermal
      growth factor (EGF) family by sex steroids and by regulators of the polypeptide
      hormone signal transduction enzyme termed protein kinase C (PKC). Regulation of
      the EGF family of genes will be discussed as a model system to evaluate
      interactions between these two important types of regulatory pathways in breast
      cancer.

PMID- 8645609
TI  - Regulation of corticosteroid-binding globulin synthesis by 1alpha,25-dihyroxy
      vitamin D3 (calcitriol), 9-cis-retinoic acid and triiodothyronine in cultured rat
      fetal hepatocytes.
AB  - Evidence regarding the nature of the regulatory factors which directly act upon
      liver cells and extra-hepatic tissues to alter CBG synthesis is scarce. The
      present study used cultured rat fetal hepatocytes to investigate the involvement
      and possible interplay in this process of several members of the nuclear
      receptors superfamily: vitamin D (VDR), retinoic acids (RAR/RXR) and thyroid
      hormones (TR). Treatment of cells with 1alpha,25-(OH)2D3 (1,25-D) elicited a dose
      dependent inhibition of basal CBG concentration in culture medium. Maximum
      inhibition to about 15% of control level was achieved with 0.1-1.0 nM, with an
      IC50 of 3.8 x 10(-12) M and with no significant change in binding affinity.
      Differential activation of RAR and RXR with either 9-cis-retinoic acid (9-cis-RA)
      or the RAR-selective synthetic retinoid TTNPB revealed that high doses of both
      drugs diminished CBG expression, though the former proved about 10-times more
      potent than the latter in this regard. Amplification by triiodothyronine (T3) of
      CBG synthesis failed to block the inhibitory effects of either 1,25-D or
      retinoids, as revealed by both binding capacity and mRNA measurements. Relative
      to CBG, 1,25-D similarly depressed the synthesis of alpha-fetoprotein (AFP),
      while on the contrary, retinoids and T3 were shown to cause opposite effects, as
      9-cis-RA and TTNPB elevated and T3 decreased AFP expression. The present findings
      identify for the first time ligands of VDR and RAR/RXR as powerful negative
      regulators of both basal and T3-stimulated CBG biosynthesis in fetal hepatocytes
      and suggest lack of a functional interplay between TR and VR or RAR/RXR in these
      processes.

PMID- 8645610
TI  - Metabolism of the cell differentiating agent 1alpha,25(OH)2-16-ene-23-yne vitamin
      D3 by leukemic cells.
AB  - The metabolism of 1alpha,25(OH)2D3 and 1alpha,25(OH)2-l6-ene-23-yne-D3 is
      examined by in vitro incubation of the steroid hormones with WEHI-3 myeloid
      leukemia cells. Two experimental systems were used to evaluate the metabolism of
      each compound: (a) a double label incubation was performed to determine both the
      propensity for metabolism of each analog and the in vitro half-life of the
      analogs; and (b) separate single label incubations were performed to determine
      the metabolite profile derived from each of the analogs. The double label WEHI-3
      cell incubation with 25 nM [23,24(3)H]1alpha,25(OH)2D3 and 25 nM
      [25(14)C]1alpha,25(OH)2-16-ene-23-yne-D3 produced a single comigrating metabolite
      of higher polarity from each of the parent compounds in a gradient HPLC
      chromatogram. The half-life of each analog determined from this in vitro
      incubation was 6.9 and 6.7 h for 1alpha,25(OH)2D3 and 1alpha,25(OH)2-16-ene-23
      yne-D3, respectively. Individual incubations of 1alpha,25(OH)2D3 yielded a
      metabolite that comigrates with 1alpha,24,25(OH)2D3 standard in each of three
      independent HPLC separations. Individual incubations with [25(14)C]1alpha,25(OH)2
      16-ene-23-yne-D3 generated multiple metabolites, which are resistant to
      degradation as evaluated by intermediate build-up, are of increasing polarity and
      do not comigrate with the 1alpha,24,25(OH)3D3 standard. From these studies it is
      determined that 1alpha,25(OH)2-l6-ene-23-yne-D3 is metabolized differently but
      not preferentially compared to 1,25(OH)2D3 in myelogenous leukemia cells.

PMID- 8645611
TI  - The hamster adrenal cytochrome P450C11 has equipotent 11beta-hydroxylase and 19
      hydroxylase activities, but no aldosterone synthase activity.
AB  - We have isolated a hamster adrenal P45OC11 cDNA which shared 90 and 84% homology,
      respectively, with the nucleotide sequence and the amino acid sequence of the
      hamster adrenal P450aldo. Both P450C11 and P450aldo cDNA coding sequences were
      inserted in the plasmid pBluescript SK, transcribed and then translated using a
      rabbit reticulocyte system in the presence of [35S]methionine. The reaction
      products were immunoprecipitated with an anti-bovine P450C11 antibody for P450C11
      and with an anti-hamster P450aldo for P450aldo. Immunoprecipitated proteins were
      analyzed by polyacrylamide gel electrophoresis. A single 35S-labeled protein band
      was detected for P450C11 and for P450aldo, respectively. P450C11 and P450aldo
      cDNAs were then both inserted into the expression vector pCMV5 containing a viral
      sequence specific for the attachment of ribosomes to mRNA. These constructions
      were transfected in COS-1 cells. 24 h after transfection, the presence of P450C11
      and P450aldo mRNAs was determined by Northern blot analysis. In a time study
      experiment we found that P450C11 transformed the labeled-steroid into
      [14C]corticosterone, [14C]19-OH-deoxycorticosterone and [14C]18-OH
      deoxycorticosterone in ratios of 1:1.11:0.07, after 2 h of incubation; no
      [14C]aldosterone could be detected. Cells transfected with plasmids harboring the
      P450aldo cDNA transformed [14C]deoxycorticosterone to [14C]corticosterone,
      [14C]aldosterone, [14C]18-OH-corticosterone, [14C]18-OH-deoxycorticosterone,
      [14C]19-OH-deoxycorticosterone and [14C]11-dehydrocorticosterone in ratios of
      1:0.25:0.45:0.04:0.04:0.04 after 12 h of incubation. These results indicate that
      one P450 catalyzes the ultimate step of glucocorticoid formation and a separate
      P450 is involved in the final steps of aldosterone formation in hamster adrenals.
      The capacity of the hamster adrenal P450C11 to hydroxylate at positions 11beta
      and 19 in nearly equal ratio makes this animal an excellent model to study the
      mechanism of synthesis and inhibition of 19-OH-deoxycorticosterone, the precursor
      of 19-nor-deoxycorticosterone, a very potent mineralocorticoid involved in the
      development of essential hypertension.

PMID- 8645612
TI  - Expression of inositol 1,4,5-trisphosphate receptors in rat adrenocortical zones.
AB  - Previously we demonstrated the presence of InsP3R-I, -II and -III subtypes in the
      zona glomerulosa. Now we have examined the expression of different subtypes of
      inositol 1,4,5-trisphosphate receptor (InsP3R) in the inner zones of rat adrenal
      cortex. RNA extracted from decapsulated adrenal tissue (zonae fasciculata
      reticularis and the medulla) or from fasciculata-reticularis cells was reverse
      transcribed. Subsequent polymerase chain reaction revealed the presence of InsP3R
      I, -II and -III subtypes in decapsulated tissue but failed to demonstrate the
      expression of any known subtypes of InsP3R in fasciculata-reticularis cells.
      Accordingly, InsP3 receptors expressed in the decapsulated tissue are of
      medullary origin.

PMID- 8645613
TI  - Specific inhibition of the last steps of aldosterone biosynthesis by 18
      vinylprogesterone in bovine adrenocortical cells.
AB  - 18-Vinylprogesterone (18-VP), designed for mechanism-based specific inhibition of
      the last steps of the aldosterone biosynthesis, was used to characterize the
      mechanism of the 11 - and 18-hydroxylase activities of bovine cytochrome
      P450(11beta). In the present work, its action was studied by observations on a
      primary culture of bovine adrenocortical cells. First, we investigated the
      effects of 18-VP on the different enzymatic steps of the biosynthesis of cortisol
      and aldosterone. The production of cortisol, baseline or hormone-stimulated (ACTH
      or AII), was inhibited by 18-VP in a dose-dependent manner with a maximal
      inhibition at 5 microM. Supply of different exogenous substrates to support
      steroidogenesis revealed an inhibition of the last step of cortisol or
      corticosterone biosynthesis. We then used specific blockers to measure individual
      activities and conclude that 11beta-hydroxylation was the only enzymatic activity
      affected. Aldosterone, as well as 18-hydroxycorticosterone, was also measured
      following addition of corticosterone. The 18-hydroxylation of corticosterone was
      inhibited by 18-VP, with 50% inhibition occurring at 0.04 microM compared with
      the 50% inhibition value of 0.3 microM obtained for 11-hydroxylation.
      Surprisingly, 18-ethynyl-progesterone (18-EP), which has a structure very similar
      to 18-VP, only weakly inhibits 11beta-hydroxylation. The inhibition of
      aldosterone formation was also much lower with 18-EP than with 18-VP. These
      studies demonstrate that 18-VP inhibits only the later steps of aldosterone
      biosynthesis and more specifically 18- than 11-hydroxylation activity.

PMID- 8645614
TI  - The hormone responsive region of mouse mammary tumor virus positions a nucleosome
      and precludes access of nuclear factor I to the promoter.
AB  - The mouse mammary tumor virus (MMTV) promoter is transcriptionally silent prior
      to hormonal induction, partly because its organization into phased nucleosomes
      precludes access of transcription factors to their cognate sites. A T47D-derived
      cell line carrying a single integrated copy of the MMTV promoter exhibited a
      positioned nucleosome, which prevented binding of nuclear factor I (NFI). To
      study the molecular mechanisms controlling promoter accessibility we have made
      use of a strong chimeric transactivator, NFI-VP16, composed of NFI linked to the
      transactivation function of VP16. T47D cells transiently transfected with an MMTV
      CAT reporter show little transcription even after cotransfection of an expression
      vector for NFI-VP16. However, a truncated MMTV promoter, lacking the hormone
      regulatory region (HRR) was transactivated by cotransfected NFI-VP16. The
      repressive effect of the HRR was not due to binding of a sequence-specific
      transcriptional repressor, and was evident with the DEAE-Dextran transfection
      procedure but not with the calcium phosphate technique. A similar behavior was
      observed in Saccharomyces cerevisiae carrying wild type or truncated MMTV-lacZ
      reporters and expressing NFI-VP16. Reconstitution experiments suggest that the
      promoter lacking the HHR generates less stable nucleosomes, a fraction of which
      contain a more accessible NFI site. Recombinant NFI binds to nucleosomes
      assembled on this truncated promoter but not to nucleosomes encompassing the HRR.
      These results are compatible with the notion that transiently transfected MMTV
      promoters behave like their stably integrated counterparts, in that the HRR
      drives positioning of a nucleosome and mediates transcriptional repression by
      preventing access of NFI to its cognate site.

PMID- 8645615
TI  - Quantitative flow cytometry reveals a hierarchy of glucocorticoid effect on cell
      surface mouse mammary tumor virus gp52.
AB  - A flow cytometry protocol with CM mouse mammary tumor cells (Mm5mt/C1) was
      utilized to provide a fluorescence measurement of hormone-mediated changes in
      mouse mammary tumor virus (MMTV) cell surface envelope glycoprotein (gp52 CSA).
      Standards permitted gp52-specific fluorescence intensity to be measured as
      molecules of equivalent soluble fluorescein (MESF). The feasibility of using MESF
      determinations to reflect hormone-modulated changes in continuously infected
      cells was tested. A panel of five glucocorticoids having differing affinity for
      the glucocorticoid receptor were tested in 60 h treatments at dosages ranging
      from 10(-6) M to 10(-8) M. Determinations of MESF, as a measure of gp52 CSA, were
      highest with 10(-6) M treatments (36.7-44.5 x 10(-6) MESF). At lower dosages,
      MESF determinations were lower but showed a clear hierarchy of glucocorticoid
      effect. At 10(-8) M treatments, determinations of MESF x 10(-6) demonstrated the
      following glucocorticoid hierarchy: triamcinolone acetonide (TA) (33.7 +/- 1.6) >
      dexamethasone (DEX) (26.1 +/- 1.7) > prednisolone (8.0 +/- 0.3) > triamcinolone
      (6.6 +/- 0.4) > hydrocortisone (6.4 +/- 0.4) > control (2.4 +/- 0.1). The MESF
      derived respective fold increases over control for this hierarchy were: 13.87,
      10.74, 3.31, 2.71, and 2.65. The ability of TA to enhance gp52 CSA was 1.3-fold
      greater than DEX. 10-fold higher levels of steroid controls did not significantly
      elevate MESF levels. Findings argue that dosage, duration of treatment and
      relative affinity of glucocorticoids for receptor are reflected in MESF
      determinations of changing gp52 levels. Therefore, this new measure of effect may
      be useful in studying hormonal influence on viral and cellular regulatory systems
      in chronically infected cells.

PMID- 8645616
TI  - Putative steroid binding domain of the human mineralocorticoid receptor,
      expressed in E. coli in the presence of heat shock proteins shows typical native
      receptor characteristics.
AB  - Domain E, considered as the putative hormone binding domain (HBD) of the human
      mineralocorticoid receptor (hMR) was expressed in Escherichia coli as a fusion
      protein with either maltose binding protein (MBP) or glutathione S-transferase
      (GST). These bacterially-produced MR constructs had no steroid binding activity
      per se. In fact, heat shock protein association (hsp) is required for high
      affinity ligand-binding of the MR. After incubation of purified MBP- or GST-HBD
      with rabbit reticulocyte lysate, known to be rich in heat shock proteins, we
      obtained saturable binding of [3H]aldosterone. The Kd value for aldosterone was
      0.3 nM and the Bmax = 32 pmol/mg. Hormone binding specificity was assessed by
      competition studies with various steroid ligands. Sucrose gradient assays
      performed with [3H]aldosterone-MBP-HBD revealed complex sedimenting at 8.3S and
      4.9S with [3H]progesterone-MBP-HBD. Western-blot analysis of the sedimentation
      peak showed the concomitant presence of MBP-HBD by a monoclonal anti-MBP
      antibody, and hsp90 by a monoclonal anti-hsp antibody. Moreover, following
      incubation with the anti-rabbit hsp90 monoclonal antibody the sedimenting
      gradient showed a 10.4S sedimenting complex. These analyses demonstrated that the
      [3H]aldosterone-MBP-HBD complex is at least associated with hsp90 in reticulocyte
      lysate and that the HBD of hMR is sufficient to bind hsp90. Deletions of a
      relatively short amino- (729-766) or carboxy-terminal (940-984) region of the HBD
      fragment eliminated all steroid-binding properties. Overall, these results
      indicate that the integrity of domain E is necessary and sufficient to bind
      steroid ligands, agonists or antagonists, with characteristics similar to the
      entire native MR.

PMID- 8645617
TI  - Dissociation of 4-hydroxytamoxifen, but not estradiol or tamoxifen aziridine,
      from the estrogen receptor as the receptor binds estrogen response element DNA.
AB  - Estradiol-liganded estrogen receptor (E2-ER) binds EREs with a stoichiometry of
      one E2-ER dimer per estrogen response element (ERE). In contrast, although 4
      hydroxytamoxifen (4-OHT)-liganded ER (4-OHT-ER) binds EREs with high affinity,
      its saturation ERE binding capacity is consistently half that of E2-ER, giving an
      apparent stoichiometry of one 4-OHT-ER monomer per ERE. Here we show that one
      molecule of 4-OHT ligand dissociates from the ER dimer apparently during the
      process of binding to DNA. Under equilibrium conditions, the type I antiestrogen
      tamoxifen aziridine (TAz), covalently attached to ER (TAz-ER), binds a single ERE
      with high affinity (Kd = 0.27 nM), comparable to that of E2-ER and 4-OHT-ER. In
      contrast to 4-OHT-ER, the ERE binding stoichiometry of TAz-ER was identical to
      that of E2-ER: one dimeric receptor per ERE. By measuring [3H]ligand that was
      initially bound to ER, a significant loss of [3H]4-OHT from ER was detected after
      ERE binding, whereas all [3H]E2 or [3H]TAz remained ER-bound. These results
      confirm that one molecule of 4-OHT ligand dissociates from the ER dimer as a
      consequence of ERE binding. Binding of 4-OHT and TAz are likely to induce a
      conformation in ER dimers that alters their capacity for gene activation. Upon ER
      binding to DNA, this conformation reveals itself by allowing 4-OHT dissociation,
      and predictably would allow TAz dissociation were it not bound covalently.

PMID- 8645618
TI  - New insights in the molecular mechanism of progestin-induced proliferation of
      mammary epithelium: induction of the local biosynthesis of growth hormone (GH) in
      the mammary glands of dogs, cats and humans.
AB  - In contrast to the protective, anti-proliferative, action of progestins on the
      development of endometrium cancer, progestins may have local stimulatory and
      inhibitory effects on the proliferation of mammary epithelium. Until now there
      was no final molecular explanation of this discrepancy. Prolonged treatment of
      dogs with depot medroxyprogesterone acetate (DPMA) or with proligestone (PROL)
      results in enhanced plasma concentrations of growth hormone (GH), insulin-like
      growth factor (IGF)-I, IGF-II and IGF-binding proteins, together with the
      development of benign mammary tumours. The stimulated plasma GH levels do not
      have the typical pulsatile secretion pattern, and are not sensitive to
      stimulation with GHRH or to inhibition with somatostatin. The autonomous
      secretion can be inhibited by the anti-progestin RUU-486. The source of progestin
      induced plasma GH levels has been demonstrated to be the canine mammary gland
      where progestins induce the expression of the gene encoding GH. The expression of
      the GH gene is restricted to focal areas of hyperplastic epithelium as shown by
      immunohistochemistry, and is predominantly located in single positive epithelial
      cells with an intermediate position between luminal- and myo-epithelium.
      Progestin-induced fibroadenomatous changes in the mammary gland of cats are also
      associated with locally enhanced GH expression. In both normal, benign and
      malignant mammary tumours of humans GH mRNA expression has been demonstrated by
      RT-PCR. The presence of GH mRNA is associated with the presence of immunoreactive
      GH as shown by immunohistochemistry. Sequence analysis revealed 100% homology to
      the pituitary expressed GH gene. In malignant mammary tumours of humans and dogs
      GH expression is also found in specimens negative for progesterone receptors as
      measured by ligand binding. It is concluded that the gene encoding GH is
      expressed in the mammary gland of a variety of species, including man. This
      appears to represent a contribution to the molecular explanation of the action of
      progestins on proliferation of mammary epithelium. It needs, however, to be
      proven whether this local biosynthesis of GH in the mammary gland is the cause of
      the local stimulatory effect of progestins on the proliferation of mammary
      epithelium.

PMID- 8645619
TI  - Imidazole derivatives of pyrrolidonic and piperidonic as potential inhibitors of
      human placental aromatase in vitro.
AB  - Inhibitory activities towards human Placental aromatase of novel pyrrolidinone
      and piperidinone drugs were investigated and compared with those of
      aminoglutethimide (AG) in vitro. All compounds showing a stronger inhibitory
      effect than this of AG had the following common structural feature: an imidazole
      side-chain in C-3 position, with a substituted or non-substituted aromatic ring
      in the C-2 position and an aliphatic chain (n-butyl or n-octyl) or a phenyl
      moiety on the nitrogen of the pyrrolidone or piperidone ring. When the C-3 side
      chain did not bear any imidazole ring, no activity was observed. Respective Ki
      values for the competitive inhibition exerted by the more potent inhibitors 10,
      11, 13 and 21 with androstenedione as substrate were 19.2, 20.3, 16.8 and 15.4
      microM, respectively (Ki AG= 77.0 microM).

PMID- 8645620
TI  - Heteroatom-substituted analogues of the active-site directed inhibitor estra
      1,3,5(10)-trien-17-one-3-sulphamate inhibit estrone sulphatase by a different
      mechanism.
AB  - Estrogens have a pivotal role in the growth and development of hormone-dependent
      breast cancers. In postmenopausal women, the hydrolysis of the conjugate estrone
      sulphate (E1S) to estrone (E1) by the enzyme estrone sulphatase is the major
      source of breast tumour estrogen. Inhibitors of estrone sulphatase should
      therefore have considerable therapeutic potential for the treatment of hormone
      dependent tumours of the breast, either as the sole agent or in conjunction with
      aromatase inhibitors. Several inhibitors of estrone sulphatase have now been
      developed of which estra-1,3,5(10)-trien-17-one-3-sulphamate (EMATE) is the most
      potent and also inhibits the enzyme in a time- and concentration-dependent
      manner, showing that it acts as an irreversible inhibitor. Analogues of EMATE in
      which the 3-O-atom is replaced by other heteroatoms (S and N) were synthesized
      and tested for inhibition against estrone sulphatase. 4-Methoxyphenylsulphamide
      (1), 4-chlorothiophenyl-S-(N,N-dimethyl)sulphamate (2), estra-1,3,5(10)-trien-17
      one-3-sulphamide (3), estra-1,3,5(10)-trien-17-one-3-S-sulphamate (4) and estra
      1,3,5(10)-trien-17-one-3-S-(N,N-dimethyl)sulphamate (5) were found to inhibit
      estrone sulphatase weakly, but none of these compounds appears to behave as a
      time-dependent inhibitor. A model of the mechanism of enzyme inhibition by EMATE
      is proposed and we conclude that the sulphamate bridging oxygen atom of EMATE is
      essential for active site-directed inhibition of estrone sulphatase.

PMID- 8645621
TI  - In vitro studies of the subtypes of endothelin (ET) receptors present in the rat
      testis, and of their involvement in the secretory response of Leydig cells to ET
      1.
AB  - The distribution of the endothelin (ET)-receptor subtypes ET(A) and ET(B) in the
      rat testis and their involvement in the secretory response of Leydig cells to ET
      1 have been investigated by the use of specific ligands. Autoradiography showed
      that [125I]ET-1 binding was intense in the interstitial area of the testis,
      containing Leydig cells, and virtually absent in the walls of seminiferous
      tubules. Labelling was almost completely displaced by BQ-123, a selective ETA
      receptor antagonist, while sarafotoxin-6C and BQ-788, two specific ET(B) ligands,
      were ineffective. ET-1 concentration-dependently enhanced testosterone secretion
      of dispersed rat Leydig cells, and the response was suppressed by BQ-123, but not
      by BQ-788. Both antagonists per se did not affect either basal and hCG stimulated
      secretion of Leydig cells. Taken together our findings indicate that rat Leydig
      cells are mainly, provided with ETA, and that this ET-receptor subtype mediates
      their secretory response to ET-1.

PMID- 8645622
TI  - Kinetic analysis of rat steroid 5alpha-reductase activity in prostate and
      epididymis homogenates at neutral pH: evidence for type I activity in epididymis.
AB  - Immunocytochemical studies and mRNA measurements have shown that the rat
      epididymis--like the rat prostate--expresses both rat steroid 5alpha-reductase
      isozymes, i.e. type I and II. So far, enzyme activity measurements in rat
      epididymis homogenates, however, do not support the presence of type I 5alpha
      reductase activity. Incubating homogenates of both tissues with a wide range of
      substrate concentrations, we were able to detect activity of both isozymes in rat
      prostate and epididymis tissues at neutral pH. In rat prostate the amount of type
      I activity, as measured by the Vmax at pH 7.0, exceeds that of type II 5alpha
      reductase 50-fold. The efficiency ratio, Vmax/Km, of the type I isozyme accounts
      for 25% of the total in vivo potential activity. A possible anabolic role for the
      type I isozyme in rat prostate was thus surmised. In rat epididymis the Vmax of
      type I and type II 5alpha-reductase at pH 7.0 were similar. Comparison of the
      efficiency ratio Vmax/Km of either isozyme in the rat epididymis, however,
      suggested that the type II isozyme would play the major role in the 5alpha
      reduction of testosterone at physiological concentrations and at neutral pH. The
      specific localization of the isozymes should be considered to allow for correct
      quantification of their in vivo contribution to dihydrotestosterone formation.

PMID- 8645624
TI  - Dexamethasone decreases the expression of retinoic acid receptors (RARs) in rat
      liver.
AB  - Although adrenalectomy was without effect on the expression of retinoic acid (RA)
      receptors (RARs), administration of the glucocorticoid analog dexamethasone (Dex)
      to both control and adrenalectomized rats reduced the expression of these
      receptors in rat liver. This effect can be mainly attributed to the action of Dex
      on 4-hydroxylation of RA. Dex, by enhancing 4-hydroxylation of RA, reduces its
      intracellular concentration thereby leading to a decreased expression of RARs,
      since RARbeta, the main type of RARs in liver, are known to be up-regulated by
      RA.

PMID- 8645623
TI  - Kinetic analysis of the interaction of human estrogen receptor with an estrogen
      response element.
AB  - The kinetics of the interaction between recombinant human estrogen receptor and
      chicken vitellogenin gene II estrogen response element (ERE) were determined by
      ERE-Sepharose chromatography. The association constant of the interaction between
      the ERE and the human estrogen receptor was dependent on receptor concentration,
      estradiol binding and temperature. The highest association constant (80-100 x
      10(6)M-1) was measured for the estradiol-bound receptor prepared at 25 degrees C
      and at concentrations higher than 7 nM. At high receptor concentrations (>7 nM)
      the binding mechanism of estradiol to the receptor was positive cooperative,
      indicating receptor homodimerization. At lower concentrations the binding
      mechanism was partially cooperative and the association constant of the liganded
      receptor was significantly lower. The binding mechanism at 4 degrees C was
      cooperative as well, and the association constants were similarly dependent upon
      receptor concentration, but were 50% lower than the receptor prepared at 25
      degrees C. The association constant of the unliganded receptor was 4- to 5-fold
      lower than that of the liganded receptor at 25 degrees C. These data suggest that
      in addition to estradiol-induced conformational changes in the receptor, the
      receptor dimers are subjected to temperature-dependent changes, which further
      increase their affinity for an ERE.

PMID- 8645625
TI  - Influence of droloxifene on plasma levels of insulin-like growth factor (IGF)-I,
      Pro-IGF-IIE, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3 in
      breast cancer patients.
AB  - The influence of the novel anti-estrogen droloxifene on the insulin-like growth
      factor (IGF) system in plasma was studied in two groups of breast cancer patients
      receiving droloxifene 40 mg o.d. (group 1, n = 6) or 100 mg o.d. (group 2, n =
      7). Fasting blood samples were obtained from all patients before treatment and
      after 3 months (group 1) or 6 months (group 2) on droloxifene treatment, except
      for two patients in group 2 from whom the second sample was obtained following 2
      months on treatment when the drug was to be terminated due to progressive
      disease. Insulin-like growth factor (IGF)-I, insulin-like growth factor binding
      protein (IGFBP)-1, IGFBP-3 and pro-IGF-IIE (IGF-IIE) were measured by
      radioimmunoassay. In patients in group 1, plasma lGF-I levels decreased by a mean
      value of 20% (P < 0.05) on treatment with droloxifene, while IGFBP-1 increased by
      a mean value of 45% (P > 0.1). In group 2 we observed a 42% decrease in IGF-I
      during treatment (P < 0.025), while the level of IGFBP-1 increased by a mean
      value of 70% (P < 0.025). No significant effect on IGF-IIE or IGFBP-3 was noted
      in any of the groups. The change in plasma lGF-I and IGFBP-1 observed during
      treatment with droloxifene resembles what is found in patients treated with
      tamoxifen. As IGF-I is a potent mitogen for breast cancer cells in vitro, a
      decrease in the plasma level of this growth factor with an increase in the
      concentration of IGFBP-1 may contribute to the anti-tumour effects of
      droloxifene.

PMID- 8645626
TI  - Expression of fibroblast growth factor-8 in adult rat tissues and human prostate
      carcinoma cells.
AB  - Androgens are essential for normal prostatic and testicular function. However,
      paracrine and/or autocrine actions of a number of growth factors have been
      implicated in the function of these tissues. A recent addition to the fibroblast
      growth factor family, the so called androgen-induced growth factor (AIGF) or
      fibroblast growth factor-8 (FGF-8), has been proposed to be under strict androgen
      regulation and induction in the mouse mammary carcinoma cell line SC3. FGF-8,
      therefore, may have a local role in the prostate, which is known to be an
      androgen-responsive organ. This study reports, for the first time, the presence
      of FGF-8 mRNA in normal adult rat tissues (heart, brain, lung, kidney, testis,
      prostate and ovary), using an optimised reverse transcription and nested
      polymerase chain reaction (RT-PCR) procedure, although androgen-dependent FGF-8
      expression was not demonstrated in these adult tissues. Consistent with the
      oncogenic characteristics of FGF-8, the corresponding mRNA was detected in the
      human prostate tumour cell lines LNCaP and DU145. Because the DU145 cell line is
      known to be androgen-independent, and the expression of FGF-8 mRNA in cultured
      LNCaP cells also occurred in the absence of exogenous androgens, it can be
      concluded that the expression of FGF-8 mRNA in these human cell lines, in the rat
      prostate and in other rat tissues is not under the regulation of androgens as
      hitherto proposed.

PMID- 8645627
TI  - Molecular cloning and nucleotide sequences of cDNA clones of sheep and goat
      adrenocortical cytochromes P450scc (CYP11A1).
AB  - We isolated cDNA clones of the mRNAs for cytochromes P450scc (CYP11A1) from sheep
      and goat adrenocortices using the RT-PCR method. We determined the complete
      nucleotide sequences of the coding and 3'-flanking regions of these cDNA clones.
      The results confirmed the amino terminal sequence of the sheep cytochrome P450scc
      reported previously [Miyatake et al., Biochim. Biophys. Acta 1215,176-182
      (1994)]. On the basis of comparison of the deduced amino acid sequences of
      various animals and rainbow trout cytochromes P450scc, and other mitochondrial
      cytochrome P450 isozymes, we discussed the substrate-associated and adreno
      ferredoxin-binding region of cytochrome P450scc.

PMID- 8645628
TI  - CGP 53153: a new potent inhibitor of 5alpha-reductase.
AB  - CGP 53153 (N-2-(cyano-2-propyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carb
      oxamide) is a steroidal inhibitor of 5alpha-reductase, the enzyme which effects
      the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). In vitro,
      CGP 53153 competitively inhibited rat microsomal 5alpha-reductase from prostate
      by 50% (IC50) at a concentration of 36nM compared to the reference compound
      finasteride which inhibited 5alpha-reductase with an IC50 of 11 nM in the same
      system. In vivo, inhibition of 5alpha-reductase activity was characterized in
      three different test systems. Inhibition of 5alpha-reductase activity was first
      assessed in a standard test designed to compare directly the potency of different
      5alpha-reductase inhibitors. This test assesses potency through the inhibition of
      prostate growth in juvenile castrate male rats treated with a standard dose of T
      propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor administered orally
      at various doses for 4 days. CGP 53153 and finasteride significantly reduced T
      propionate-mediated prostate growth by about 25% (ED25) compared to T-propionate
      treated controls at oral doses of 0.01 and 0.1 mg/kg, respectively. Second, the
      effects on prostate weight were studied in normal adult male rats treated orally
      once daily for 14 days with 1, 3 and 10 mg/kg CGP 53153 and with 10 mg/kg
      finasteride. CGP 53153 significantly reduced prostate weight at 3 and 10 mg/kg by
      31% and 37%, respectively, compared to vehicle-treated controls, whereas the dose
      of 10 mg/kg finasteride did not significantly reduce prostate weight. Third, the
      effects on prostate volume were studied in normal 6-9-year-old male dogs treated
      orally once daily with 5 mg/kg CGP 53153 and with 5 mg/kg finasteride for 12
      weeks. Prostate volume was monitored with magnetic resonance imaging every 2
      weeks beginning 6 weeks before start of the treatment with 5alpha-reductase
      inhibitors and ending after a recovery period of 8 weeks after termination of
      treatment. Treatment for 12 weeks with both CGP 53153 and finasteride was equally
      effective in reducing prostate volume by more than 70% in individual dogs. Anti
      androgenic potency of CGP 53153 and finasteride was assessed in juvenile castrate
      male rats treated with DHT-propionate (1 mg/kg, s.c.) and a 5alpha-reductase
      inhibitor (p.o.) for 4 days. Neither CGP 53153 nor finasteride given at a dose of
      10 mg/kg had any significant effect on DHT-propionate-mediated prostate growth,
      whereas the reference anti-androgen flutamide given at a dose of 10 mg/kg reduced
      prostate weight to levels comparable to those seen in untreated castrate animals.
      For CGP 53153, the dose of 10 mg/kg is 1000-fold higher than the ED25 for 5alpha
      reductase inhibition in vivo. In conclusion, both CGP 53153 and finasteride are
      potent inhibitors of the rat 5alpha-reductase enzyme system in vitro without
      showing any anti-androgenic effects in vivo. Both CGP 53153 and finasteride were
      equally potent in reducing prostate volume in aged male dogs, whereas in rats,
      CGP 53153 is up to 10 times more potent than finasteride in reducing prostate
      weight as shown in two different rat models.

PMID- 8645629
TI  - Enhancement of antiproliferative activity of 1alpha,25-dihydroxyvitamin D3
      (analogs) by cytochrome P450 enzyme inhibitors is compound- and cell-type
      specific.
AB  - Ketoconazole (keto) or liarozole (liaro), inhibitors of the cytochrome P450
      enzymes that mediate vitamin D and A hydroxylations, could potentiate the
      antiproliferative effects of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] and
      its analogs. Proliferation of MCF-7 and T47-D human breast cancer cells, MG-63
      human osteosarcoma cells and HL-60 human promyeloid leukemia cells was
      concentration dependently inhibited by 1alpha,25(OH)2D3. The vitamin D analogs KH
      1060 [20-epi-22-oxa-24,26,27-trihomo-1alpha,25(OH)2D3], RO 23-6010 [16-ene-23-yne
      26-trifluoro-1,25(OH)2D2D3], ZXY 835 [20-epi-23-yne-25,26-epoxy-1alpha(OH)D3],
      and CD 99 [11alpha-methyl-1alpha,25(OH)2D3] were 150-,58-,16- and 7-fold more
      potent than 1alpha,25(OH)2D3 in inhibiting the proliferation of MCF-7 cells,
      respectively. A similar rank order of potency was observed in other cell lines.
      The antiproliferative effects of the vitamin D hormone and analogs was enhanced
      in MCF-7 cells when coincubated with 1 microM keto (7-, 10-, 5-, 25- and 1.3-fold
      more potent than in the absence of keto), respectively. The antiproliferative
      effect was less enhanced when 1alpha,25(OH)2D3 or its analogs KH 1060, ZXY 835
      and RO 23-6010 were combined with liaro (3-, 7-, 2- and 3-fold, respectively).
      Keto and liaro did not markedly potentiate the activity of 1alpha,25(OH)2D3 or
      its analogs in MG-63 or HL-60 cells. These results suggest that differences in
      cellular metabolism can at least partially explain the different potency of
      vitamin D analogs. Moreover, the metabolism of vitamin D analogs is cell-type
      specific.

PMID- 8645630
TI  - Estrogenic and antiestrogenic regulation of the half-life of covalently labeled
      estrogen receptor in MCF-7 breast cancer cells.
AB  - Effect of estrogens and antiestrogens (AEs) on estrogen receptor (ER) half-life
      was analyzed in MCF-7 cells by assessing its progressive disappearance after
      covalent labeling in situ with [3H]tamoxifen aziridine ([3H]TAZ). Cells were
      incubated for 1 h with 20 nM [3H]TAZ either in the absence or presence of a 500
      fold excess of unlabeled estradiol (E2) (non-specific binding). The entire ER
      population was labeled by this method as established by subsequent incubation of
      the cells with [125I]E2. [3H]TAZ labeled cells were maintained in culture for
      additional 5 h in the absence (control) or presence of increasing amounts (0.1 nM
      - 1 microM) of either a given estrogen (E2, estrone, diethylstilbestrol,
      bisphenol), a pure AE (RU 58 668, ICI 164 384) or an AE with residual estrogenic
      activity (RU 39 411, 4-hydroxytamoxifen, keoxifene). The progressive
      disappearance of nuclear and cytosolic [3H]TAZ-ER complex during 5 h incubation
      were assessed by their immunoprecipitation with anti-ER monoclonal antibody (H
      222) followed by scintillation counting or SDS-PAGE and fluorography. Fading of
      labeled receptors was extremely slow (approximately 10% loss after 6 h) in
      absence of any hormone/antihormone indicating a long half-life of the [3H]TAZ-ER
      complex. Addition of estrogens as well as pure AEs led to a dramatic reduction of
      the half-life while AEs with residual estrogenic activity were extremely less
      efficient in this regard providing an explanation for the ability of latter
      compounds to up-regulate the receptor since they do not affect ER mRNA synthesis
      and stability. Receptor disappearance induced by estrogens was closely related to
      their binding affinity for ER. Newly synthesized ER emerged during the treatment
      with hormones or antihormones seems to be implicated in the phenomenon since
      [3H]TAZ was covalently bound and could, therefore, not be displaced by these
      compounds. Induction of synthesis of a short half-life peptide(s) with
      degradative activity was demonstrated by addition of cycloheximide or puromycine
      (both at 50 microM) which completely blocked ER disappearance. The fact that no
      cleavage products of ER were detected by SDS-PAGE suggested a lysosomial
      hydrolysis. Hence, hormonal modulation of only a part of ERs may down-regulate
      their total population until it reaches the steady-state level.

PMID- 8645631
TI  - Effects of flavonoids on aromatase activity, an in vitro study.
AB  - In the study, the inhibitory effect of flavonoids, including isoflavonic
      phytoestrogens, on the ovarian aromatase enzyme complex from the rainbow trout,
      Oncorhynchus mykiss, was assessed in vitro. Some of the compounds tested on fish
      were also tested on human placental aromatase activity as a comparison between
      the two sources of enzyme. It was found that flavone, dl-aminoglutethimide,
      apigenin, quercetin, 7,4'- dihydroxyflavone, alpha-naphthoflavone and equol were
      potent inhibitors of the ovarian aromatase activity in rainbow trout. Relative
      potencies (RP) of these compounds compared to flavone (assigned an effect of 1)
      were, respectively, 19.0, 8.7, 5.3, 3.7, 3.2 and 0.9. Two other phytoestrogens,
      namely biochanin A and genistein, slightly inhibited aromatase activity. Finally,
      7-hydroxyflavone, formononetin, daidzein, coumestrol, chrysin, flavanone and
      estradiol-17beta did not inhibit ovarian aromatase activity at doses up to 1000
      microM. Experiments on human placental aromatase showed inhibitory effects of dl
      aminoglutethimide, flavone, flavanone and equol with RP values of 2.8. 1, 1.5 and
      0.4, respectively. These results are in accordance with previous studies. The
      influence of the experimental procedure on IC50 values and RP is discussed.

PMID- 8645632
TI  - Evidence for a role of glucuronosyltransferase in the regulation of androgen
      action in the human prostatic cancer cell line LNCaP.
AB  - Androgens play an important role in the regulation of cell growth and specific
      protein synthesis in hormone-sensitive prostatic cancer. In this study, we have
      investigated the metabolism of androgens in LNCaP cells from low passage (LP) and
      high passage (HP) cultures which were previously shown to possess differential
      androgen responsiveness. When treated with dihydrotestosterone (DHT), cells
      showed the characteristic biphasic response of cell proliferation with an ED50 of
      1 nM for both the LP and HP cells, but the maximal proliferative response was
      different with values of 2.65- and 4.29-fold over basal for LP and HP cells,
      respectively. Metabolism studies indicated no difference in 5alpha-reductase
      activity between LP and HP cells, while 3alpha-, 3beta- and 17beta-hydroxysteroid
      dehydrogenase activities were significantly higher in LP cultures. The formation
      of steroid glucuronides (-G), namely DHT-G, was higher in LP than in HP cells
      with values of 2.16 and 1.31 pmol of glucuronides formed/microgram DNA/3 h,
      respectively. Northern blot analysis with a UGT21B15 cDNA probe identified two
      bands corresponding to two or more UGT transcripts in both LNCaP cells and more
      transcript was observed in LP than in HP cells. Taken together these results
      indicate that DHT is deactivated more rapidly in the LP cells, which may explain
      in part the lower proliferative response to androgens of LP cells compared with
      HP cells.

PMID- 8645633
TI  - The possible involvement of LH/hCG induced mitochondrial proteins in the
      regulation of steroidogenesis in bovine luteal cells.
AB  - In previous studies we described the synthesis of three mitochondrial proteins
      (A, B and C) in response to acute in vitro stimulation by lutropin of small
      bovine luteal cells. Protein A had a molecular weight of 28 kDa and an
      isoelectric point (pI) of 6.7. Proteins B and C had a molecular mass of 27 kDa
      and pI of 6.2 and 6.4, respectively. The appearance of these proteins was
      prevented by 100 microM cycloheximide. In the present study, we have shown that
      the time course of synthesis of protein A and its hCG dose-response closely
      parallel the increase in progesterone production. The induction by hCG of protein
      A was already observed after a 5 min incubation. Pulse chase experiments by
      addition of excess unlabelled methionine after prelabelling with [35S]methionine
      indicated that its half-life was approximately 15-20 min. Study of 32P labelled
      phosphate incorporation into individual proteins and treatment by alkaline
      phosphatase of [35S]methionine-labelled proteins demonstrated that none of the
      three proteins A, B or C was a phosphoprotein. Localization of protein A in
      mitochondria, at the site of the rate limiting step in steroidogenesis, and the
      high degree of correlation between its 35S labelling and progesterone production
      argue in favour of its involvement in the acute regulation of steroidogenesis.

PMID- 8645634
TI  - Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma
      cells.
AB  - Nuclear translocation of activated glucocorticoid receptors (GRs) is a necessary
      step in the signal transduction by these GC hormones. Although in vitro
      activation of GRs can occur in the absence of a functional ligand, it is
      generally assumed that binding of a cognate hormone is required for activation of
      the intracellular GR. By indirect immunocytochemistry and Western-blot analysis,
      it was found that, in spontaneously aggregated human lymphoma DoHH2 cells,
      hormone-free GRs are located in the nucleus. Disruption of the aggregates
      redistributed GRs to a predominantly cytosolic location. Upon spontaneous re
      aggregation the GR again became localized to the nucleus. Intracellular cross
      linking of the heteromeric receptor complex was applied to investigate the
      protein composition of cytoplasmic and nuclear receptors. Untransformed,
      cytosolic GRs could be demonstrated by [3H]dexamethasone binding capacity and
      hsp90 co-immunoprecipitation, whereas absence of these characteristics suggested
      an activated conformation of the nuclear GRs. These observations suggest that
      cell-cell interactions are capable of transforming GRs in the absence of a
      ligand.

PMID- 8645635
TI  - Hormone-binding and solubility properties of fusion proteins containing the
      ligand-binding domain of the human androgen receptor.
AB  - The ligand-binding properties of the human androgen receptor (AR) reside in the
      carboxy terminus of the receptor and are retained in fusion proteins encoding
      this domain. Despite a wealth of information pertaining to the importance of
      specific amino acid residues in the binding of ligands, the precise amino
      terminal boundary of this domain has not been determined for the androgen
      receptor. The current studies focused on the expression of a series of AR fusion
      proteins in bacteria. These experiments demonstrate that specific androgen
      binding is detected in a fusion protein encoding amino acid residues 675-917,
      although this binding is of lower affinity than that observed for the native AR.
      Inclusion of an additional segment (residues 622-675) restores the capacity of
      the hormone-binding domain to bind mibolerone with high affinity. Detailed
      studies of the ligand-binding properties and solubility of one AR fusion protein
      (625-917) indicate that although the levels of ligand binding and soluble
      receptor fusion protein usually vary in parallel, this is not true at all time
      points and the proportion of soluble AR fusion that is able to bind hormone is
      highest when the levels of soluble AR fusion protein are lowest. This
      observation, coupled with the changes in the quantity of soluble and insoluble
      fusion protein occurring at different times following induction at 12 degrees C,
      22 degrees C, and 37 degrees C, suggests that the saturation of one or more steps
      is required for folding of the AR hormone-binding domain to a conformation that
      is both soluble and competent to bind hormone under conditions of high-level
      expression. Analysis of the solubility of six different fusion proteins
      containing different portions of the AR hormone-binding domain suggests that a
      discrete segment of this domain is not responsible for its synthesis as
      predominantly insoluble aggregates in bacteria when expressed at high levels.

PMID- 8645636
TI  - Obstetrics and gynaecology in the developing world.

PMID- 8645637
TI  - Treatment of large uterine fibroids.

PMID- 8645638
TI  - The need for systematic reviews in the treatment of menstrual disorders--another
      Cochrane collaborative review group is born.

PMID- 8645639
TI  - Routine obstetric ultrasound examinations in South Africa: cost and effect on
      perinatal outcome--a prospective randomised controlled trial.
AB  - OBJECTIVE: To compare routine midtrimester with selective obstetric
      ultrasonography concerning the Health Service cost and the effect on perinatal
      outcome. DESIGN: A randomised controlled trial. SETTING: Urban area served by
      Tygerberg Hospital, a tertiary referral centre in South Africa. PARTICIPANTS:
      Pregnant patients without risk factors for congenital anomalies referred for
      ultrasonography between 18 and 24 weeks of gestation. INTERVENTION: Between 18
      and 24 weeks, a level one ultrasound examination was performed on study patients
      only. Except for the routine scan, both groups received the same antenatal care
      and could be referred later for additional scans as judged by their clinicians.
      MAIN OUTCOME MEASURES: Overall adverse perinatal outcome and use of antenatal and
      neonatal services. RESULTS: The groups did not differ significantly in their use
      of antenatal and neonatal services except for a greater number of ultrasound
      scans in the study group. More suspected postdate pregnancies occurred in control
      patients, as well as more amniocenteses for confirmation of lung maturity. More
      babies of low birthweight were born in the study group. The incidence of overall
      or major adverse perinatal outcome was comparable. Routine ultrasonography was
      accompanied by a considerable increase in costs. CONCLUSION: Selective use of
      obstetric ultrasonography did not increase the use of antenatal and neonatal
      services. Not routinely performing ultrasonography has led to considerable Health
      Service savings without increasing the risk for adverse perinatal outcome. It
      saved 75% of selected patients a referral to an ultrasound unit. Specific
      problems related to inaccurate gestational age determination need to be
      addressed.

PMID- 8645640
TI  - A comparative study of caesarean deliveries by assistant medical officers and
      obstetricians in Mozambique.
AB  - OBJECTIVE: To evaluate the outcome of caesarean delivery performed by assistant
      medical officers and specialists in obstetrics and gynaecology with particular
      attention to post-operative complications. DESIGN: We performed a nonrandomised
      analysis of 2071 consecutive caesarean deliveries at Maputo Central Hospital. Of
      these, 958 (46.3%) were performed by assistant medical officers (medical
      assistants trained for surgery) and the rest (53.7%) by specialists in obstetrics
      and gynaecology. The age and parity distributions of women in the two groups were
      almost identical. SETTING: University Hospital in Maputo, covering all emergency
      obstetrics with about 48,000 deliveries per year. POPULATION: Two thousand and
      seventy-one consecutive caesarean deliveries. MAIN OUTCOME MEASURES: Post
      operative complications and the duration of post-operative hospital stay.
      RESULTS: There were no differences in the indications for caesarean delivery. The
      surgical interventions associated with caesarean delivery did not differ in the
      two groups. The only significant difference was in the group of superficial wound
      separation due to haematoma, which was slightly more common (0.35% vs 0.05%) in
      the group operated on by assistant medical officers (Odds Ratio 2.2; 95%
      Confidence Interval 1.3-3.9). CONCLUSION: Training selected medical assistants to
      perform caesarean delivery, even on women in poor general condition, is justified
      in settings in which doctors are scarce.

PMID- 8645641
TI  - Randomised evaluation of a prototype suction fetal scalp electrode.
AB  - OBJECTIVE: To compare the performance and acceptability of a prototype suction
      fetal scalp electrode with that of a double helix spiral electrode. SETTING: An
      urban academic hospital in Johannesburg, South Africa. DESIGN: Randomised, by
      means of sealed opaque envelopes opened consecutively. PARTICIPANTS: One hundred
      women in active labour with an indication for direct fetal heart rate monitoring.
      INTERVENTION: Application of a fetal scalp electrode to the presenting part.
      OUTCOME MEASURES: Performance of the electrodes with respect to application
      success, detachment, quality of the tracings, scalp trauma and women's
      preferences. RESULTS: Application of the suction electrode was unsuccessful in
      15/50 (30%) compared to 1/50 (2%) with the spiral electrode. Detachment rates
      were similar. There were more tracings of average quality with the suction
      electrode (nine versus four). There were three instances of scalp bleeding at
      delivery with the spiral electrode. The suction electrode was preferred by more
      women and its application caused somewhat less discomfort. CONCLUSIONS: The lower
      rate of successful application with the suction electrode needs to be weighed
      against the advantage of avoiding fetal scalp penetration. In particular, women's
      concerns about pain or harm to the baby from needle electrodes, the theoretical
      risk of viral transmission, and the risk of serious scalp infection must be
      considered. These factors favour the use of a suction electrode when direct fetal
      heart rate monitoring is required. Needle electrodes should be considered when
      suction electrode application is unsuccessful. Correction of practical problems
      experienced with the prototype suction electrodes used in this study may result
      in improved success rates.

PMID- 8645642
TI  - The haemodynamic and respiratory effects of intravenous nimodipine used in the
      treatment of eclampsia.
AB  - OBJECTIVE: To establish the antihypertensive properties of intravenous nimodipine
      used to treat eclamptic patients. To assess the effects of intravenous nimodipine
      on oxygen delivery and consumption. DESIGN: A prospective observational study.
      SETTING: The Maternity Centre Obstetric Intensive Care Unit, Groote Schuur
      Hospital. PARTICIPANTS: Four unselected patients presenting with proteinuric
      hypertension and seizures. METHODS: Haemodynamic observations were obtained by a
      radial artery catheter and right heart catheterisation with a pulmonary artery
      flow directed thermodilution catheter. Observations were obtained prior to and
      after the administration of nimodipine. RESULTS: A significant reduction in mean
      arterial pressure occurred in all patients after administration of nimodipine.
      This was due to a significant reduction in systemic vascular resistance. Neither
      oxygen delivery to the tissues nor peripheral oxygen consumption changed
      significantly during nimodipine infusion. No adverse effects related to the use
      of nimodipine were documented. CONCLUSIONS: Nimodipine is an effective
      vasodilator. There may be a role for nimodipine as a single agent for the
      management of eclampsia.

PMID- 8645643
TI  - Cardiac abnormalities in pulmonary oedema associated with hypertensive crises in
      pregnancy.
AB  - OBJECTIVE: To describe the cardiac abnormalities by two-dimensional and Doppler
      echocardiography (echo-Doppler) in hypertensive crises in pregnancy (HCP)
      complicated by pulmonary oedema and identify pathogenic factors. DESIGN: A
      prospective observational study. SETTING: King Edward VIII Hospital, Durban,
      South Africa. PARTICIPANTS: Sixteen patients with HCP complicated by pulmonary
      oedema over a six-month period. Two control groups, 55 patients with HCP alone
      and 16 with normotensive pregnancies, were also studied. RESULTS:
      Echocardiography diagnosed impaired left ventricular systolic function in 4 of 16
      (25%) patients with HCP and pulmonary oedema. In the remaining 12 patients with
      preserved systolic function, left ventricular diastolic filling abnormalities
      were demonstrated in a significant proportion compared to control hypertensive
      and normotensive groups. Fifteen of 16 (94%) study patients presented with
      pulmonary oedema antepartum; in seven of these patients, the use of dexamethasone
      to enhance fetal lung maturity appeared to be a contributing factor in
      precipitating pulmonary oedema. CONCLUSION: This study demonstrates the value of
      echo-Doppler to diagnose structural and functional cardiac abnormalities in HCP
      complicated by pulmonary oedema. The potential role of left ventricular diastolic
      filling abnormalities in the pathogenesis of pulmonary oedema complicating HCP is
      discussed.

PMID- 8645644
TI  - Effects of fish oil supplementation in late pregnancy on blood pressure: a
      randomised controlled trial.
AB  - OBJECTIVE: To study the effect of fish oil supplementation on blood pressure
      during the third trimester of pregnancy. DESIGN: In the 30th week of pregnancy
      533 healthy women were randomly assigned in a ratio 2:1:1 to receive fish oil
      (2.7 g/day n-3 fatty acids (Pikasol)), or a control regimen of either olive oil
      or no oil supplementation. MAIN OUTCOME MEASURES: Blood pressure measured with an
      automatic device (Dinamap 1846 SX, Criticon) at baseline and in weeks 33, 37, 39
      and subsequently weekly until delivery. RESULTS: Mean blood pressure increased
      during the third trimester, and this was not influenced by group assignment. No
      significant effects on either systolic or diastolic blood pressure were seen in
      the fish oil group compared to the control groups. The proportions of women with
      a systolic blood pressure above 140 mmHg or a diastolic blood pressure above 90
      mmHg were not significantly different in the fish oil group compared with the
      control groups, although the proportion of women with diastolic above 90 mmHg
      tended to be lower in the fish oil group compared with the olive oil group. The
      corresponding relative risk was RR = 0.48 (95% CI 0.22-1.06; P = 0.07).
      CONCLUSION: 2.7 g/day of marine n-3 fatty acids provided in the third trimester
      of normal pregnancy showed no effect on blood pressure.

PMID- 8645645
TI  - Trends and variations in use of antenatal corticosteroids to prevent neonatal
      respiratory distress syndrome: recommendations for national and international
      comparative audit. Scottish Neonatal Consultants' Collaborative Study Group,
      International Neonatal Network.
AB  - OBJECTIVES: In 1990 a meta-analysis of randomised trials showed 70% lower
      mortality after antenatal corticosteroid therapy for 24 h or more for infants
      born before 31 weeks gestation. We investigated whether antenatal corticosteroid
      therapy has increased in these infants since 1990 and studied variations in use
      by hospital of birth. DESIGN: Retrospective cohort study in 1601 infants in nine
      neonatal units. SUBJECTS: Neonatal admissions before 31 weeks of gestation from
      January 1988 to October 1993. MEASURE OF OUTCOME: Corticosteroids administered
      for 24 h or more before delivery. RESULTS: Data were obtained in 1579 (99%)
      infants. The proportion (range) in each hospital whose mothers had antenatal
      corticosteroids for 24 h or more was 16% (0-43) in 1988-89 and 29% (0-36) in 1990
      93 (P < 0.001). In post hoc analyses, 65/347 (20%) births in district hospitals
      had treatment for 24 h or more compared with 354/1254 (28%) in teaching hospitals
      (P = 0.001). CONCLUSIONS: Antenatal corticosteroid therapy increased but varied
      by hospital of birth. This may reflect varying performance, or bias from
      reporting, selection or referral. Ideally, corticosteroid therapy should be
      compared in women at risk of preterm delivery, but standardising risk or
      indications for delivery between hospitals and accurate ascertainment presents
      major difficulties. To minimise selection or referral bias, hospitals should
      publish, for all mothers delivering between 24 and 33 weeks and 6 days gestation
      48 h or more after admission, the proportions treated 1. for 24 h or more
      (target: > 70%), or 2. at all (target: > 90%).

PMID- 8645646
TI  - Central and peripheral haemodynamic changes in post-term fetuses: correlation
      with oligohydramnios and abnormal fetal heart rate pattern.
AB  - OBJECTIVE: To assess the hypothesis that the occurrence of oligohydramnios and
      abnormal fetal heart rate (FHR) pattern in post-term fetuses is associated with
      impaired fetal cardiac function. DESIGN: A cross sectional study was performed on
      post-term and term fetuses. Fetal tests included a computerised analysis of the
      FHR, a biophysical profile and Doppler studies of the abdominal aorta, umbilical
      artery, middle cerebral artery and the fetal heart. Pulsatility index (PI) was
      calculated from the abdominal aorta, umbilical and middle cerebral artery flow
      velocity waveforms. Peak velocity, velocity time integral (VTI), E:A ratio, and
      heart rate (HR) were calculated from the flow velocity waveforms obtained from
      the aortic and pulmonic outflow, and from the mitral and tricuspid valves.
      SETTING: Maternal fetal laboratory, Department of Obstetrics. SAMPLE: One hundred
      and twenty post-term and 42 term fetuses. RESULTS: Only the tricuspid E:A ratio
      was significantly higher (P < 0.05) in post-term fetuses with a normal amniotic
      fluid index compared with term fetuses. Post-term fetuses with an abnormal
      amniotic fluid index had a significantly lower aortic peak velocity (P < 0.01),
      aortic VTI x HR (P < 0.01), and mitral VTI x HR (P < 0.05) compared with post
      term fetuses with a normal amniotic fluid index or compared with term fetuses.
      Post-term fetuses with reduced FHR variation had a significantly lower aortic
      peak velocity (P < 0.01), pulmonic peak velocity (P < 0.05), aortic VTI x HR (P <
      0.01), pulmonic VTI x HR (P < 0.05) and a significantly lower mitral VTI x HR (P
      < 0.05) when compared with post-term fetuses with normal FHR variation. Similar
      results were obtained in comparing fetuses with normal and adverse perinatal
      outcome. CONCLUSION: The occurrence of oligohydramnios and abnormal FHR pattern
      in post-term fetuses appears to be associated with impaired fetal cardiac
      function. This finding should allow further investigations of post-term fetuses.

PMID- 8645647
TI  - Erythrocyte ion and water balance and membrane potential in the puerperium of
      normal pregnancy.
AB  - OBJECTIVE: To examine the balance of erythrocyte ions and water during the rapid
      changes in plasma osmolality in the early puerperium, and during the subsequent
      period of sustained readjustment. DESIGN: A serial study from the third trimester
      of pregnancy to 20 weeks after delivery. PARTICIPANTS: Thirty-five primiparous
      women who had experienced no antenatal complications. MAIN OUTCOME MEASURES:
      Plasma osmolality, erythrocyte hydration, potassium, chloride and sodium were
      measured and nondiffusible ion content and erythrocyte membrane potential
      calculated. Plasma sodium, potassium and chloride were also measured. RESULTS:
      During the first week after delivery plasma osmolality increased (280 (SEM 0.52)
      289 (SEM 0.64) mosmol/kg; P < 0.001) but erythrocyte hydration did not decrease
      (2.060 (SEM 0.018)-2.067 (SEM 0.021) 1/kg dry cells) because of an increase in
      total cell osmole content (577 (SEM 5.31)-597 (SEM 6.15) mosmol/kg dry cells; P =
      0.001). This increase included nondiffusible anions, chloride and potassium.
      These changes in ionic balance did not affect membrane potential. After the first
      week of the puerperium and up to the 20th week, plasma osmolality was stable but
      erythrocyte osmole content and hydration both decreased. This was due to a
      decrease in nondiffusible anions and potassium with a smaller increase in
      chloride leading to a decrease in membrane potential (-14.31 (SEM 0.34)mV to 
      12.66 (SEM 0.28)mV; P < 0.001). CONCLUSIONS: A rapid increase in intracellular
      osmoles can occur in the mature erythrocyte and probably precedes the decrease in
      plasma osmolality in the puerperium. Changes in erythrocyte homeostasis in the
      first week of the puerperium can be accounted for by alterations in nondiffusible
      anions. After the first week of the puerperium it appears that the functional
      organisation of the membrane is changing.

PMID- 8645648
TI  - Antenatal diagnosis of congenital toxoplasmosis: evaluation of the biological
      parameters in a cohort of 286 patients.
AB  - OBJECTIVE: To evaluate the biological parameters obtained by cordocentesis and
      amniocentesis in the antenatal diagnosis of congenital toxoplasmosis. DESIGN:
      Nine-year retrospective study. SETTING: Parasitology Laboratory, Department of
      Obstetrics and Gynaecology and Department of Paediatrics, Centre Hospitalo
      Universitaire, Montpellier, France. PARTICIPANTS: Two hundred and eighty-six
      pregnant women infected with toxoplasmosis between 7 and 34 weeks of gestation.
      METHODS: Detection of abnormalities by ultrasound examination. Detection in fetal
      blood of Toxoplasma, of specific IgM and IgA and of nonspecific biological
      markers. Detection in amniotic fluid of Toxoplasma. RESULTS: Out of 286 antenatal
      diagnoses, 211 were negative (1st group), 40 were positive (2nd group) and led to
      8 medical abortions, and 35 were uncertain (3rd group). In the 1st and 3rd groups
      respectively, 7 (3.3%) and 5 (14.3%) cases of congenital toxoplasmosis were
      observed. Overall, 52 cases of congenital toxoplasmosis were detected: 12 were
      clinically apparent, 36 subclinical (of which 12 were in groups 1 and 3) and 4
      were lost to follow up. CONCLUSION: There is substantial importance in making the
      diagnosis of toxoplasmosis antenatally in order to limit the number of medical
      abortions. In our series, the most accurate predictor was the detection of the
      fetal antibody response (specific IgM and IgA) to Toxoplasma.

PMID- 8645649
TI  - Irrigating fluid absorption from the intact uterus.
AB  - OBJECTIVE: Absorption of irrigating fluid may occur through severed blood vessels
      during endometrial resection. We studied whether irrigating fluid can also be
      absorbed through the undamaged uterus. PARTICIPANTS: We studied 25 women, aged 28
      46 years (mean 38 years), who underwent elective laparoscopic sterilisation under
      general anaesthesia. INTERVENTIONS: In 15 women blue-stained irrigating fluid
      containing glycine 1.5% and ethanol 1% was applied to the uterine cavity under
      increasing pressure. Laparoscopy was employed to see when fluid emerged from the
      Fallopian tubes. Another 10 women had their Fallopian tubes clamped before the
      fluid pressure was raised, and systemic absorption was detected by measuring the
      serum glycine concentration. RESULTS: Passage of fluid through the Fallopian
      tubes occurred in 14 of the 15 patients at a uteroabdominal pressure gradient of
      40 mmHg (n = 4), 80 mmHg (n = 4), 120 mmHg (n = 3), and 160 mmHg (n = 3),
      respectively. The fluid passage rate ranged between 0.5 and 13 (mean 6.4) ml min
      1. Of the women with clamped Fallopian tubes, 8 of 10 showed an increase in the
      serum glycine level of 60% at a pressure gradient of 160 mmHg, and of 120% at 200
      mmHg. CONCLUSIONS: Uterotubal and transendometrial passage of small to moderate
      amounts of irrigating solution occurred frequently at the intrauterine fluid
      pressures normally used during endometrial resection.

PMID- 8645650
TI  - Treatment with a gonadotrophin releasing hormone agonist before endometrial
      resection: a multicentre, randomised controlled trial.
AB  - OBJECTIVES: To ascertain whether treatment with a gonadotrophin releasing hormone
      agonist before endometrial resection reduces absorption of distension fluid and
      operating time and facilitates the procedure. DESIGN: A multicentre, prospective,
      randomised controlled study. PARTICIPANTS: Seventy-one premenopausal women with
      established menorrhagia. INTERVENTIONS: Eight weeks of goserelin depot treatment
      before endometrial resection of immediate surgery in the early proliferative
      phase of the cycle. MAIN OUTCOME MEASURES: Irrigation fluid deficit, operating
      time and degree or difficulty of the procedure. RESULTS: After randomisation
      eight women withdrew from the study, leaving 33 women in the goserelin arm and 30
      in the immediate surgery arm. Mean (SD) operating time was 15.1 (9.0) min in the
      goserelin group versus 16.9 (9.5) min in the controls; mean difference + 1.8 min,
      95% CI, -2.9 to + 6.4. Mean (SD) distension medium deficit was, respectively, 422
      (287) ml versus 564 (291 ml); mean difference + 142 ml, 95% CI -4 to + 288. The
      goserelin effect was restricted to the 29 women with adenomyosis as the mean (SD)
      fluid deficit was considerably less in the 19 treated women than in the 10
      controls (299 (206) ml versus 597 (135) ml; mean difference + 298 ml, 95% CI +
      149 to + 447). The surgeons classified the intraoperative difficulties as none in
      6, minimal in 20, moderate in 7, and severe in no cases in the goserelin group;
      corresponding figures in the group without pretreatment were 2, 14, 13, and 1.
      CONCLUSIONS: Goserelin administration before endometrial resection may reduce
      absorption of fluid at surgery in women with adenomyosis and may facilitate
      intrauterine operating conditions.

PMID- 8645651
TI  - No change in sexual activity during preconceptional multivitamin supplementation.
AB  - OBJECTIVE: To study sexual activity related to preconceptional multivitamin
      supplementation. DESIGN: The rate of sexual activity (weekly sexual intercourse
      number) was compared before and during multivitamin supplementation and between
      women with multivitamin and placebo-like trace element supplementation. SETTING:
      The Hungarian randomised double blind controlled trial of periconceptional
      multivitamin supplementation. PARTICIPANTS: Six hundred and eighty-seven women
      with multivitamin and 655 women with trace element supplementation in the
      preconceptional period. RESULTS: There was no difference in the rate of sexual
      activity between the multivitamin and the trace element groups. CONCLUSION:
      Multivitamins do not increase sexual activity.

PMID- 8645652
TI  - The threadless copper intrauterine contraceptive device: analysis of the first
      150 women-years.

PMID- 8645653
TI  - Maternal urinary free beta-subunit of human chorionic gonadotrophin: creatinine
      ratios and fetal chromosomal abnormalities in the second trimester of pregnancy.

PMID- 8645654
TI  - The impact of maternal age on the cost effectiveness of Down's syndrome
      screening.

PMID- 8645655
TI  - Myolysis of a cervical fibroid with an Nd:YAG laser.

PMID- 8645656
TI  - Lack of evidence for a circadian rhythm of JGFBP-1 in the mother and fetus during
      labour.

PMID- 8645657
TI  - Transabdominal cervicoisthmic cerclage in the management of recurrent second
      trimester miscarriage and preterm delivery.

PMID- 8645658
TI  - A comprehensive one-stop menstrual problem clinic for the diagnosis and
      management of abnormal uterine bleeding.

PMID- 8645659
TI  - The surgical management of idiopathic facial pain produces intractable iatrogenic
      pain?

PMID- 8645660
TI  - Sub total unilateral oculomotor nerve palsy in a Le Fort I osteotomy.
AB  - A 35-year-old man developed a pupil sparing palsy of the oculomotor nerve after a
      standard Le Fort I osteotomy during which there had been more bleeding than
      usual. No definite cause was found but we suggest that it was caused by ischaemia
      of the nerve secondary to local injury by haematoma or instrumentation. The
      anatomical basis for this is discussed.

PMID- 8645661
TI  - Facial asymmetry with severe unilateral hypoplasia of the muscles of mastication:
      a report of clinical and electromyographic findings.
AB  - Mild degrees of asymmetry of the human body have been recognised both by
      classical sculptors and more recently by anatomists as both normal and widely
      occurring. Morphologic asymmetries of the face of a more severe nature are,
      however, quite rare. When such deformities occur, both the hard and soft tissues
      may be involved and the abnormality may be acquired as a result of trauma,
      infection, neoplasia or surgery or be of a developmental origin as in the
      syndromes affecting the first pharyngeal arch. Developmental asymmetries of the
      jaws may also arise as a result of unilateral disruption of mandibular
      development during the time of normal facial growth leading to hemiretrognathism.
      Severe hypoplasia of the muscles of mastication on one side only has not
      previously been reported.

PMID- 8645662
TI  - Evaluation of different doses of soluble ibuprofen and ibuprofen tablets in
      postoperative dental pain.
AB  - The object of the study was to assess the comparative efficacy of three single
      doses (200, 400, 600 mg) of soluble ibuprofen and ibuprofen tablets after third
      molar surgery in 148 patients and aged 18-40 years. Outcome was measured by
      overall assessment of pain (AUC360) assessed from serial visual analogue scales,
      the number of patients taking additional analgesic and by overall assessment of
      medication evaluated on a five-point categorical scale. Over the 6-hour
      investigation period all the ibuprofen treatments with the exception of ibuprofen
      tablets 200 mg resulted in significantly less pain (p < 0.05) than placebo
      treatment. A large number of patients required additional analgesia during the
      investigation period, but the time to taking it was significantly earlier in the
      placebo group. No significant dose response (p > 0.05) was observed for either
      ibuprofen preparations assessed by the outcome variable of overall pain
      experience (AUC360) or time to additional analgesia. There was no significant
      difference in pain scores or time to taking additional analgesics between the
      respective doses of soluble and tablet formulations of ibuprofen. Both soluble
      and tablet formulations of ibuprofen provide effective pain control in the early
      postoperative period after removal of impacted third molars. There is little
      analgesic advantage in increasing the dose to 600 mg and only minimal benefit
      from using a soluble formulation of the drug.

PMID- 8645663
TI  - Ulcerative eosinophilic granuloma: a report of five new cases.
AB  - Five new cases of ulcerative eosinophilic granuloma were diagnosed at the
      Massachusetts General Hospital between 1982 and 1993. In all cases the site was
      the tongue. They were unifocal, did not recur, and had a benign course. This
      report illustrates their benign nature despite the occasional aggressive
      presentation, and outlines possible aetiology.

PMID- 8645664
TI  - 3D computer data capture and imaging applied to the face and jaws.
AB  - There have been few attempts in the past at 3D computer modelling of facial
      deformity because of the difficulties with generating accurate three-dimensional
      data and subsequent image regeneration and manipulation. We report the
      application of computer aided engineering techniques to the study of jaw
      deformity. The construction of a 3D image of the mandible using a Ferranti co
      ordinate measuring machine for data capture and the 'DUCT5' surface modelling
      programme for image regeneration is described. The potential application of this
      work will be discussed.

PMID- 8645665
TI  - Cervical tuberculosis.

PMID- 8645666
TI  - Maxillectomy to reconstruct or obturate--results of a UK survey of oral and
      maxillofacial surgeons.

PMID- 8645667
TI  - Surgery by numbers?

PMID- 8645668
TI  - Surgery by numbers?

PMID- 8645669
TI  - Necrotizing sialometaplasia coincident with ipsilateral infarcted antral polyps.

PMID- 8645670
TI  - Obstructive sialadenitis.

PMID- 8645671
TI  - Verrucous carcinoma of the maxillary antrum.

PMID- 8645672
TI  - Management of an unusual tongue injury.

PMID- 8645673
TI  - Carcinoma colon with mandible and liver metastases.

PMID- 8645674
TI  - Specialty centralisation.

PMID- 8645675
TI  - A case report of metachronous salivary gland neoplasia.

PMID- 8645676
TI  - The free revascularized rectus abdominis myocutaneous flap for the repair of
      tumour related defects in the head and neck area.
AB  - The present work reviews a series of 11 consecutive patients who have received
      free revascularized rectus abdominis myocutaneous flaps for primary
      reconstruction of soft tissues after ablative tumour surgery in the head and neck
      area. In 10 patients, a total or subtotal glossectomy had been performed and the
      flap was used to replace the resected tongue volume. In 5 of these cases,
      extensive perforating defects had resulted after additional resection of large
      portions of the chin and the cheek. Mandibular continuity was restored by a metal
      plate and the flap was divided into an intraoral and extraoral portion in these
      patients. In one patient, the flap had been used for closure of a full thickness
      defect of the calvarium. 9 of the 11 flaps healed uneventfully. In one case, a
      partial flap loss was encountered after thrombosis of the venous pedicle due to
      compression as a result of an unfavourable defect anatomy and flap positioning.
      Primary closure of the abdominal wall was achieved in all cases. A subcutaneous
      hematoma occurred at the donor site in one patient. According to our present
      experience, the rectus abdominis free flap may serve as an alternative to the
      frequently employed latissimus dorsi flap in maxillofacial reconstructions while
      it offers the possibility for flap elevation simultaneously to the surgical
      procedures in the head and neck area.

PMID- 8645677
TI  - A comparative study of the efficacy of fluconazole and amphotericin B in the
      treatment of oropharyngeal candidosis in patients undergoing radiotherapy for
      head and neck tumours.
AB  - Radiotherapy given during treatment of oral and pharyngeal malignancy is
      frequently associated with colonization of the oral mucosa by Candida species.
      Treatment of these infections has included topical and systemic agents. In the
      present study 73 patients with oropharyngeal candidosis were treated with either
      amphotericin B (10 mg lozenges, four times daily for 14 days, 36 patients) or
      fluconazole (50 mg daily for 7 days, 37 patients). The yeasts most frequently
      isolated were C albicans and C glabrata. Clinical signs and symptoms showed
      improvement at end of treatment in 72% of patients who received amphotericin B
      compared with 92% of patients who received fluconazole. Mycological cure at end
      of treatment was achieved in 31% of the amphotericin B group and 46% of patients
      who received fluconazole. For both treatments the cure rate was less in denture
      wearers than in non denture wearers.

PMID- 8645678
TI  - Full-thickness reconstruction of cheek defect involving oral commissure with
      forearm tendinocutaneous flap.
AB  - An 82-year-old man underwent full-thickness reconstruction of the cheek for a
      defect of the oral commissure resulting from a T3N1M0 squamous cell carcinoma. He
      had previously had both radiotherapy and chemotherapy. A tendinocutaneous flap
      from the forearm incorporating palmaris longus was used for static
      reconstruction. The vermilion was then reconstructed with rotation flaps from the
      contralateral vermilion. Oral function was restored, and he had no problems with
      drooling or speech.

PMID- 8645679
TI  - Management of potentially malignant oral mucosal lesions by consultant UK oral
      and maxillofacial surgeons.
AB  - This paper describes the results of a recent survey carried out under the
      auspices of the Professional Education and Evaluation Subgroup of the UK Working
      Group on Screening for Oral Cancer and Precancer. The aim of this survey was to
      assimilate information regarding currently used management options of potentially
      malignant oral lesions as a basis from which to rationalise our future approach
      to their management. The survey has confirmed that variation exists among oral
      and maxillofacial consultants in their approaches and a more formal approach to
      management may therefore be indicated.

PMID- 8645680
TI  - The role of angiogenesis in the spread of oral squamous cell carcinoma.
AB  - Microvessels were counted in 41 primary oral squamous cell carcinomas using JC70
      antibody to PECAM (CD31). The counts were compared with clinical and pathological
      indicators of tumour behaviour including lymph node status, tumour stage, type of
      histological differentiation, size and velocity of tumour growth. Tumour
      microvessel counts correlated with lymph node metastasis (p < 0.001). This
      association was independent of tumour size, velocity and type of histological
      differentiation and when all the variables were analysed by multivariate analysis
      only vascular count showed a significant association with lymph node metastasis.

PMID- 8645681
TI  - The maxillofacial surgeon and cranial base surgery.
AB  - The paper reviews the role of the maxillofacial surgeon, surgical approaches and
      osteotomies available to allow comprehensive access to cranial base tumours.
      Maxillo facial reconstruction using free vascularised flaps to rehabilitate the
      patients is highlighted. Such reconstruction may also require vascularised bone
      grafts. The range of microvascular free tissue transfer in cranial base surgery
      is discussed. The need not to merely reconstruct but to rehabilitate the patient
      is stressed. The benefits of the latest imaging and navigation systems are
      outlined.

PMID- 8645682
TI  - An audit of Bjork flap tracheostomies in head and neck plastic surgery.
AB  - Patients undergoing head and neck surgery for malignancy especially resection of
      parts of the upper aerodigestive tracts need a secure airway intra- and
      postoperatively. A tracheostomy is an effective method of achieving this
      objective. In our unit the Bjork flap technique1 has been the preferred type of
      tracheostomy. Ninety-five consecutive Bjork flap tracheostomies performed by one
      surgeon preceding major head and neck resection for malignancy in patients aged
      17-79 years (median = 61 years) were retrospectively evaluated. The technique was
      quick and provided a secure airway. The tracheostomy tubes were left in situ for
      a median of 5 days (range 1-17 days). After extubation subsequent stoma closure
      was uneventful, 60% healing within 1 week. No patient developed tracheal fistula,
      clinical tracheal stenosis or cosmetically unacceptable scarring. There was no
      tracheostomy-related mortality. It is concluded that the Bjork flap tracheostomy
      technique can be safely used in head and neck cancer surgery in adults.

PMID- 8645683
TI  - The galeo pericranial flap in oropharyngeal reconstruction.
AB  - Flap reconstruction of the oropharyngeal region using a galeo pericranial flap
      was performed in 26 patients. This paper describes the anatomy, technique and
      discusses the outcome of the surgery showing that all flaps but one had good long
      term vascularity. Good access to all areas of the oropharynx was possible, the
      flap length was up to 20 cm and width up to 15 cm. Complications were minimal but
      included a tendency to form intra oral fibrous bands, patchy alopecia of the
      composite using outer plate of calvarium. The galeo pericranial flap is a
      valuable technique and can be used successfully in suitable cases.

PMID- 8645684
TI  - Ultrastructural analysis of the adjacent epithelium of oral squamous cell
      carcinoma.
AB  - Fifteen biopsies of the immediate adjacent epithelium of oral squamous cell
      carcinoma were examined under light and electron microscopy. Light microscopic
      examination of one micron thick sections revealed that the majority of lesions
      (67%) had hyperplastic or mildly dysplastic epithelium while the remaining (33%)
      had moderate to severe dysplasia. Ultrastructural observations showed that all
      these lesions had subcellular alterations similar to those seen in frank
      malignant oral tissue, particularly in the lower half of the epithelium.
      Important ultrastructural changes observed included bizarre nuclei of basal and
      lower spinal cells, enlarged and multiple nucleoli, presence of interchromatin
      and perichromatin granules, loss of desmosomes and marked spongiosis as well as
      disturbed cellular maturation sequences in the keratinocytes evidenced by
      abnormal and irregular distribution of maturation markers such as keratohyalin
      granules and tonofilaments. The present study thus shows the value of electron
      microscopy in the detection of malignant changes in the adjacent epithelium of
      oral squamous cell carcinoma.

PMID- 8645685
TI  - The use of immediate frozen autogenous mandible, for benign tumour mandibular
      reconstruction.
AB  - Reimplantation of frozen autogenous lesioned mandible was performed in 31
      patients with mandibular bone cysts and tumours. 26 reimplanted grafts survived
      without complications following surgery. Two cases had postoperative infections
      which were resolved following appropriate antibiotic treatment. Three grafts were
      removed due to the severe infection and wound dehiscence. The follow-up from 6
      months to 4 years showed that there was no recurrence of the primary lesion in
      the 28 successful cases. Satisfactory facial contour after surgery was achieved
      in 19 patients, while other patients showed relatively mild facial disfigurement.
      The inferior alveolar nerve was repaired in 4 cases and a functional evaluation
      was made using an acupuncture pressure tester.

PMID- 8645686
TI  - Non-union of mandibulotomy sites following irradiation for squamous cell
      carcinoma of the oral cavity.
AB  - Mandibulotomy improves surgical access to the oral cavity for the resection of
      tumours. Non-union of the mandibulotomy due to osteoradionecrosis has been
      observed in five patients with oral squamous cell carcinoma, all of whom had
      radiotherapy either as the primary modality of treatment or for tumour
      recurrence. This paper reports this series of patients, discusses their
      management and highlights the risk factors for the development of
      osteoradionecrosis.

PMID- 8645687
TI  - Use of photodynamic therapy for the treatment of squamous cell carcinoma of the
      soft palate.
AB  - A 53-year-old white woman presented with a 5-month history of throat pain. The
      soft palate was biopsied and histological examination confirmed the diagnosis of
      infiltrating squamous cell carcinoma. She refused surgery and radiotherapy and
      was therefore offered photodynamic therapy which she accepted. She was treated
      with 20 J/cm2 at 100 m W/cm2 over a 3 cm area. She was discharged three days
      later having made an uncomplicated recovery, though substantial analgesia was
      required. Healing was complete after 2 months, with no loss of palatal function
      and at most recent follow-up (16 months) there was no sign of residual disease
      and she remained well.

PMID- 8645688
TI  - Mandibular invasion by squamous cell carcinoma: a computed tomographic and
      histological study.
AB  - Our knowledge of the entry and spread of oral cell carcinoma (SCC) into the
      mandible is increasing, making an impact on surgical planning. Fourteen resection
      specimens of mandibular bone and adjacent SCC were radiographically (CT) and
      histologically investigated. In six cases there was no involvement of mandibular
      bone; a continuous periosteal layer separated the tumour from bone. The remaining
      eight specimens showed bony involvement with good correlation between
      corresponding CT and histological slices in the five edentate cases. The site of
      entry of the tumour into the bone was usually through the alveolar crest with
      additional spread through the lingual cortex in tumours that lay lingual to the
      mandible. Although limited, our data shows that the main site of entry of SCC is
      through the alveolar crest. It also highlights the usefulness of CT in the
      identification of bone involvement in edentate cases. This information may assist
      in the planning of operations to preserve as much bone as is consistent with
      complete excision of the tumour.

PMID- 8645689
TI  - Labial sensory function following sagittal split osteotomy.
AB  - A retrospective assessment of labial sensory function following sagittal split
      osteotomy was undertaken by a combination of record analysis, postal
      questionnaire and objective sensory testing. Case records for 90 sides operated
      upon by a single consultant surgeon between 1979 and 1992 identified a prevalence
      of persisting sensory changed at 2 years of 6.7%. A higher incidence of sensory
      change was seen in patients treated with intermaxillary fixation/upper border
      wires than those managed with buccal monocortical miniplates. Postal
      questionnaire returns for 67 consultant operated sides identified a higher
      incidence of sensory change than recorded in the notes. 5.9% had long term
      persisting anaesthesia. Another 28% had more variable subtle sensory impairment.
      A similar relation to method of fixation was seen. An association between
      duration of temporary sensory change and magnitude of forward mandibular advance
      was noted. Objective sensory testing validated the subjectively reported sensory
      status but also identified many patients self-assessed as normal had some
      undetected sensory impairment. Possible mechanisms for the above findings and
      implications for clinical practice are presented.

PMID- 8645690
TI  - The functional palatorrhaphy in the treatment of obstructive sleep apnoea.
AB  - We have developed a new operation for the surgical treatment of obstructive sleep
      apnoea, which we called functional palatorrhaphy. This preserves the posterior
      border of the soft palate and allows a controlled repair of the aponeurosis of
      the soft palate muscle. We combine the palatorrhaphy with a standard or a
      modified chin osteotomy with advancement of the base of tongue. In our first five
      treated and re-evaluated patients with severe obstructive sleep apnoea syndrome,
      who did not respond to conservative treatment, the operation was successful. All
      patients but one were considerably improved or cured of their symptoms.

PMID- 8645691
TI  - The mental nerve blink reflex in the diagnosis of lesions of the inferior
      alveolar nerve following orthognathic surgery of the mandible.
AB  - The purpose of this study was to evaluate the diagnostic value of a new
      modification of the blink reflex test with stimulation of the distribution of the
      mental nerve in iatrogenic lesions of the inferior alveolar nerve. The test was
      performed on 23 patients undergoing orthognathic surgery of the mandible, most of
      them (20) with bilateral sagittal split osteotomies. The function of the inferior
      alveolar nerve was studied preoperatively, and 2 weeks, 2 months, 6 months and 1
      year postoperatively with both mental nerve blink reflex test and clinical
      neurosensory testing. The objective electrophysiological test proved to be useful
      in the diagnosis and follow-up of sensory impairment of the inferior alveolar
      nerve. The results of the mental nerve blink reflex test and clinical
      neurosensory testing were closely related. The results of the two tests did not
      differ statistically significantly in the two first postoperative examinations.
      The positive predictive value of the mental nerve blink reflex test was better
      than that of clinical neurosensory testing: an initially abnormal reflex response
      predicted persistent subjective sensory symptoms after one year more reliably
      than did altered sensation at the first two examinations. Irrespective of the
      possible coexistent sensory symptoms and signs, a normal mental nerve blink
      reflex within 2 months after operation also predicted a reasonably good sensory
      recovery at 1 year.

PMID- 8645692
TI  - A study on the efficacy of late lingual nerve repair.
AB  - The level of sensory recovery was studied in 13 consecutive patients who had
      undergone lingual nerve repair after a delay of 7-32 (mean 16) months since the
      initial injury. In all patients the damaged segment of nerve was excised and the
      cut ends directly apposed by 6-10 (mean 7) epineurial sutures. The final outcome
      was assessed 12-24 months after repair. Preoperatively none of the patients could
      detect light touch stimuli in the denervated area, whereas 10 patients could
      detect some stimuli after repair. Pin-prick was detected in 6 preoperatively and
      in some areas by all 13 patients after repair. Two-point discrimination
      thresholds decreased after repair in 10 patients and in four of these became the
      same as on the uninjured side. Gustatory stimuli showed that there had been some
      return of taste sensation in 6 patients, and there were responses to
      electrogustometry in 12 patients. The patients' subjective assessment of the
      value of repair (scale 0-10) ranged from 0-10 (median 7). These results show that
      most patients undergo significant and worthwhile recovery after late lingual
      nerve repair.

PMID- 8645693
TI  - The nature of uncoupling by n-hexane, 1-hexanethiol and 1-hexanol in rat liver
      mitochondria.
AB  - We have analyzed the effects of n-hexane, 1-hexanethiol, and 1-hexanol on the
      coupled respiration of rat liver mitochondria. Incubation of mitochondria with n
      hexane, 1-hexanethiol and 1-hexanol resulted in a stimulation, at low
      concentrations, and an inhibition, at high concentrations, of the state 4
      mitochondrial respiration. Three criteria, all based on the comparison with the
      effect of DNP, have been used to establish whether the stimulation of
      respiration, at low concentrations of n-hexane, 1-hexanethiol, and 1-hexanol,
      depends on protonophoric mechanisms. First, the quantitative relationship between
      the extents of respiratory stimulation and membrane potential depression: a
      strong decrease of membrane potential was induced by increasing concentrations of
      DNP and a negligible depression by increasing concentrations of n-hexane or 1
      hexanethiol. Only a slight decrease was induced by 1-hexanol. Second, the
      quantitative relationship between the extents of respiratory stimulation and of
      proton conductance increase: at equivalent rates of respiration, the enhancement
      of the proton conductance induced by DNP was very marked, by n-hexane and 1
      hexanethiol practically negligible, and by 1-hexanol much smaller than that
      induced by DNP. Third, in titrations with redox inhibitors of the proton pumps,
      the pattern of the relationship between proton pump conductance and membrane
      potential was markedly different from protonophoric and non-protonophoric
      uncouplers: almost linear in the case of DNP, highly non-linear in the case of n
      hexane, 1-hexanethiol and 1-hexanol. These three criteria support the view that n
      hexane, 1-hexanethiol, and partially 1-hexanol, uncouple mitochondrial
      respiration by a non-protonophoric mechanism.

PMID- 8645695
TI  - The in vitro kinetics of mitochondrial and cytosolic creatine kinase determined
      by saturation transfer 31P-NMR.
AB  - Michaelis- and dissociation constants of sarcomeric mitochondrial creatine kinase
      (Mi(b)-CK) in solution were determined by enzyme assay and compared to those of
      cytosolic MM-CK under identical conditions at pH 7.4 and 25 degrees C. Saturation
      transfer 31P-NMR was used to determine the steady state fluxes mediated by Mi-CK
      and MM-CK in solution. The NMR detected fluxes of both Mi-CK and MM-CK exhibited,
      as expected, a linear dependence on Vmax (Vmax range 0-9 mM.s-1). Interestingly,
      the oligomeric state of Mi-CK, with the Mi-CK octamer/dimer ratio ranging from 2
      to 9, did not have a significant effect on the flux/Vmax ratio. Furthermore, the
      flux/Vmax ratio of Mi-CK was twice as high as that of MM-CK under similar
      conditions (flux/Vmax for Mi-CK was 0.31 and for MM-CK was 0.15). This difference
      was primarily due to a 4-fold higher apparent affinity for MgADP of Mi-CK
      compared to MM-CK (K(m)(MgADP) = 22 +/- 9 microM and 80 +/- 17 microM, resp.).
      The NMR observed fluxes were in agreement with the fluxes as calculated from the
      rate equation, using the appropriate metabolite concentrations and the kinetic
      constants from the spectrophotometric assays. Thus we conclude, that Mi-CK and MM
      CK, when in solution, catalyse an exchange-reaction, the flux of which is fully
      observable by saturation transfer 31P-NMR.

PMID- 8645694
TI  - Plant glyoxysomal but not mitochondrial malate dehydrogenase can fold without
      chaperone assistance.
AB  - Glyoxysomal (gMDH) and mitochondrial malate dehydrogenase (mMDH) from watermelon
      are synthesized as higher molecular weight precursor proteins. By overexpressing
      the precursor forms as well as the mature subunits with a histidine arm at the
      carboxy-terminus, it has been possible to purify relatively large amounts
      especially of the glyoxysomal precursor protein for studies of their refolding
      capacities after denaturation with guanidinium hydrochloride, heat or low pH.
      Glyoxysomal MDH and its precursor is capable of its spontaneous folding over a
      wide range of temperature conditions. Refolding can be enhanced by inclusion of
      BSA and ATP as stabilisers in the folding buffer. The N-terminal transit peptide
      of gMDH facilitates folding, but does not function as an intramolecular chaperon.
      Chemically denatured mitochondrial MDH requires chaperones for refolding.
      GroEL/GroES/ATP increase the yield and rate of watermelon mMDH folding
      dramatically while GroEL and Mg-ATP alone are not sufficient to provide folding
      assistance similar to the results with hydrophobic mammalian mMDH. The watermelon
      glyoxysomal MDH interacts with GroEL-like hydrophilic mammalian cytoplasmic MDH,
      a binding which has to be released by Mg-ATP before spontaneous folding can
      ensue. Interestingly, watermelon mMDH exhibited a much higher heat stability than
      gMDH or mammalian mMDH in the presence of BSA/ATP as well as GroEL/GroES/ATP. The
      differences between glyoxysomal and chaperone-assisted mitochondrial folding
      patterns are discussed.

PMID- 8645696
TI  - Interactions of the F1-ATPase subunits from Escherichia coli detected by the
      yeast two-hybrid system.
AB  - Subunit interactions among the F1-ATPase subunits were studied by the yeast two
      hybrid system. Various pairwise combinations of genes encoding alpha, beta,
      gamma, delta and epsilon subunits of Escherichia coli H+-ATPase fused to the DNA
      binding or activation domain of the yeast GAL4 gene were introduced into yeast
      and expression of a reporter gene encoding beta-galactosidase was detected.
      Combinations of the alpha and beta subunit genes, and of the epsilon and gamma
      subunit genes showed high levels of reporter gene expression, while those of
      alpha and delta, beta and delta, gamma and delta, and delta and epsilon
      demonstrated weak but significant reporter gene expression. However, combinations
      of alpha and gamma, beta and gamma, alpha and epsilon, and beta and epsilon did
      not induce reporter expression. None of the fused genes alone induced reporter
      gene expression. These results suggested that specific and strong interactions
      between the alpha and beta, gamma and epsilon, and weak interactions between the
      alpha and delta, beta and delta, and gamma and delta subunits occurred in yeast
      cells in the two-hybrid system. Effects of previously identified mutant beta
      subunits with Leu-40 to Pro. Glu-41 to Lys or Pro-332 to Gln substitutions which
      caused defects in molecular assembly of F1-ATPase were analyzed with regard to
      alpha-beta interactions. No interaction of the alpha and beta subunits was
      observed in this system using the beta subunit with mutation of Pro-332 to Gln.
      However, for the other two mutations, alpha-beta interactions were observed. This
      system may be useful for isolating mutants which have defects in interaction of
      F1-ATPase subunits.

PMID- 8645697
TI  - Axial heme ligation in the cytochrome bc1 complexes of mitochondrial and
      photosynthetic membranes. A near-infrared magnetic circular dichroism and
      electron paramagnetic resonance study.
AB  - The combination of EPR and low-temperature near-IR magnetic circular dichroism
      spectroscopies have been used to investigate the axial ligation of the
      cytochromes in the cytochrome bc1 complexes from bovine heart mitochondria,
      Rhodobacter capsulatus, Rhodobacter sphaeroides, and Rhodospirillum rubrum, and
      the purified cytochromes c1 from bovine heart mitochondria, Rb. capsulatus and
      Rb. sphaeroides. The possibility of axial ligation of cytochrome c1 by the amino
      terminus of the polypeptide was also assessed by acetylating the N-terminus of
      Rb. capsulatus cytochrome c1 and comparing the properties of the acetylated and
      unmodified samples. The results are consistent with bis-histidine axial ligation
      for the high- and low-potential b-type cytochromes and histidine/methionine axial
      ligation for the c1-type cytochrome in the intact cytochrome bc1 complexes.
      Purified samples of cytochrome c1 are mixtures of two forms, one with
      histidine/methionine and the other with bis-histidine axial ligation. The form
      with bis-histidine axial ligation is also assembled in the M183L mutant of the
      Rb. capsulatus cyt bc1 complex in which the methionine residue coordinating cyt
      c1 is replaced by a leucine. The bis-histidine form appears to be an artifact of
      dissociation of cytochrome c1 from the cytochrome bc1 complex and is greatly
      enhanced particularly in the bacterial cytochromes c1 by sample handling and the
      addition of 50% (v/v) ethylene glycol or glycerol.

PMID- 8645698
TI  - Cloning and sequencing of trehalose synthase gene from Pimelobacter sp. R48.
AB  - The gene encoding trehalose synthase (catalyzing the conversion of maltose into
      alpha, alpha-trehalose by intramolecular transglucosylation) was cloned from
      Pimelobacter sp. R48. Sequence analysis revealed a 1719-bp synthase gene and a
      573-residue amino-acid sequence. The 220 N-terminal residues were homologous to
      those of maltases from Saccharomyces carlsbergensis and Aedes aegypti.

PMID- 8645699
TI  - Differential expression and secretion of gelatinases and tissue inhibitor of
      metalloproteinase-1 during neutrophil adhesion.
AB  - Transmigrating neutrophils secrete a 92 kDa gelatinase (MMP-9) in order to
      degrade type IV endothelial basement membrane collagen. A model system for
      neutrophil adhesion combining a short pre-adhesion time (30 min) in plastic or
      endothelium-coated wells, medium removal and addition of soluble stimuli (fMLP,
      TNF alpha), enabled us to induce the release of a basal level of gelatinase
      activity (> 12% total cell content) from tertiary granules, while the release of
      vitamin B12 binding protein from specific granules was limited to 4% total cell
      content. Neutrophil gelatinase activity in unfractionated supernatants from
      endothelium-coated wells was significantly reduced (P < 0.01) compared to levels
      obtained on plastic supports, even after TNF alpha treatment or when cell
      populations were physically separated by trans-well inserts. In contrast, gelatin
      zymograms of supernatants from plastic and endothelium-coated wells remained
      similar. These findings suggest that MMP-9 is equally secreted but differentially
      inhibited by the tissue inhibitor of metalloproteinase-1 originating from the
      neutrophils. MMP-9 RT-PCR from neutrophils, assessed after up to one hour
      adhesion on plastic, yielded a single 270 bp fragment which was almost
      undetectable in the endothelial RT-PCR counterpart, whereas the TIMP-1 PCR
      product was apparent in both cell types. Furthermore, neutrophil adhesion on
      endothelial cells and TNF alpha activation for one hour induced the disappearance
      of MMP-9 cDNA without changes in TIMP-1 and beta-actin PCR products. These
      results suggest the existence of a dual down-regulation during neutrophil
      endothelial interaction, both at the level of secreted MMP-9 activity and of MMP
      9 gene transcription.

PMID- 8645700
TI  - Induction of heme oxygenase-1 in LMH cells. Comparison of LMH cells to primary
      cultures of chick embryo liver cells.
AB  - Heme oxygenase catalyzes the degradation of heme into biliverdin, carbon
      monoxide, and iron. Two forms of this enzyme, heme oxygenase-1 and -2, have been
      identified; only heme oxygenase-1 is subject to induction by heme, metal ions,
      and other chemical and physical perturbations (e.g. drugs, oxidants, and heat
      shock). Primary chick embryo liver cells are widely used for the study of heme
      metabolism because of their ease of preparation, low cost, and high degree of
      similarity to human heme metabolism. Nonetheless, this system has some
      limitations: new cultures must be prepared every week; the resulting cell
      populations are non-homogeneous; and cells are short-lived, limiting the feasible
      duration of time course and transfection studies. LMH cells are the first chicken
      hepatoma cell line to be established. The aim of this study was to characterize
      the regulation of heme oxygenase-1 in LMH cells, and to compare this regulation
      to that previously described in primary chick embryo liver cells. The induction
      of heme oxygenase-1 was assessed by measuring changes in mRNA levels or enzyme
      activities in response to several treatments, including heme, heavy metals,
      sodium arsenite, and heat shock, which have been shown to increase the expression
      of heme oxygenase. Similarities were observed with respect to regulation of heme
      oxygenase-1 expression in primary hepatocytes and LMH cells. We report the first
      measurable heat shock response of heme oxygenase-1 in CELC or LMH cells; and show
      that LMH cells are a useful model for the study of heme oxygenase-1 regulation.

PMID- 8645701
TI  - Specific ADP-ribose pyrophosphatase from Artemia cysts and rat liver: effects of
      nitroprusside, fluoride and ionic strength.
AB  - One specific ADP-ribose pyrophosphatase (ADPRibase) has been identified in
      Artemia cysts, following a protocol that in rat liver allows the identification
      of three ADPRibases. Artemia ADPRibase resulted similar, but not identical, to
      rat liver ADPRibase-I with respect to known and novel properties disclosed in
      this work. In the presence of Mg2+, Artemia ADPRibase was highly specific for ADP
      ribose and showed a low, 0.7 microM Km. Preincubation with the nitric oxide donor
      nitroprusside and dithiothreitol, elicited dose- and time-dependent, severalfold
      increase of Km and decrease of Vmax. At saturating ADP-ribose concentrations,
      fluoride was a strong inhibitor (IC50 approximately equal to 10-20 microM),
      whereas bringing ionic strength to 0.3-1.3 mol/l doubled the activity measured at
      lower or higher strengths. The novel fluoride and ionic strength effects were
      studied also with rat liver ADPRibase-I. Differences between the Artemia enzyme
      and ADPRibase-I concerned molecular weight (31,000 versus 38,500, respectively),
      Mn2+ ability to substitute for Mg2+ as the activating cation (better for the rat
      enzyme), and Vmax decrease by nitroprusside (not seen with the rat enzyme). The
      results are discussed in relation with the role of specific ADPRibases as
      protective factors limiting free ADP-ribose accumulation and protein glycation,
      and as targets for cytotoxic agents.

PMID- 8645702
TI  - Proteoglycans and glycosaminoglycans synthesized in vitro by mesangial cells from
      normal and diabetic rats.
AB  - In the renal glomerulus, two extracellular matrices have been identified, the
      glomerular basement membrane and the mesangial matrix. Accumulation of glomerular
      extracellular matrix is a conspicuous feature of most forms of progressive
      glomerular disease, including diabetic nephropathy. Since proteoglycans are
      prominent components of the extracellular matrix, we examined the
      glycosaminoglycans and proteoglycans synthesized in vitro by mesangial cells from
      normal and diabetic rats. A mixture of dermatan sulfate and heparan sulfate was
      recovered. Dermatan sulfate was the predominant glycosaminoglycan synthesized and
      most of it was released to the culture medium, in contrast to heparan sulfate
      which was found to be cell associated to a higher degree. The dermatan sulfate
      chains are composed by D-glucuronic and L-iduronic acid-containing disaccharides
      and are highly sulfated. Mesangial cells from diabetic rats produce much more
      glycosaminoglycans than mesangial cells from normal rats, especially dermatan
      sulfate and this increase was proportional to the duration of diabetes. In
      contrast, exposure of mesangial cell from normal rats to elevated glucose did not
      lead to any changes in glycosaminoglycan synthesis, indicating that this short
      term culture conditions may not adequately simulate diabetes mellitus. Other
      factors related to diabetes environment may be responsible for the observed
      alterations. The dermatan sulfate was secreted to the medium as proteoglycan. Two
      dermatan sulfate proteoglycans were identified, with molecular weights of 120 and
      85 kDa respectively. The proteoglycan core protein M(r) was 45 kDa and the
      dermatan sulfate chains were 35 kDa. It is possible that the two proteoglycans
      represent two populations, one with two dermatan sulfate side chains (120 kDa)
      and the other with only one side chain (85 kDa), presumably fitting in the
      decorin/biglycan family of small proteoglycans.

PMID- 8645704
TI  - Purification and characterization of virus-like particles and pentamers produced
      by the expression of SV40 capsid proteins in insect cells.
AB  - Three capsid proteins of SV40 (VP1, VP2, and VP3) were expressed in insect cells
      using recombinant baculoviruses. When the VP1 capsid protein was expressed alone
      or co-expressed with VP2 and VP3, virus-like particles (VLP) were produced. In
      the latter case, the minor capsid proteins, VP2 and VP3, were incorporated into
      the VLP. VLPs with and without VP2 and VP3, and the wild type SV40 virions were
      indistinguishable under electron microscope. The sedimentation coefficient,
      S20,w' obtained for the VLP consisting of VP1 alone (VP1-VLP) was 170 S, and that
      for the VLP consisting of all of the capsid proteins (VP1/2/3-VLP) was 174 S.
      Treatment of the VP1-VLP with a calcium ion chelating agent and a reducing agent
      caused dissociation of the VP1-VLP. The dissociated and purified VP1 proteins
      were identified as pentamers of VP1 based on the molecular weight determination
      by sedimentation equilibrium. The pentamers were shown to possess the ability to
      re-assemble into VLP which had the S20,w of 141S. The results are discussed in
      relation to the morphogenesis of SV40.

PMID- 8645703
TI  - Cathepsin B activity in normal human osteoblast-like cells and human osteoblastic
      osteosarcoma cells (MG-63): regulation by interleukin-1 beta and parathyroid
      hormone.
AB  - Cathepsin B activity and its regulation by interleukin 1 beta (IL-1 beta) and
      parathyroid hormone (PTH) was investigated in normal human osteoblast-like cells
      (hOB) and in the human osteoblastic osteosarcoma cell line MG-63. Cathepsin B
      activity was measured using a fluorescent synthetic substrate, 7-N
      benzyloxycarbonyl-L-arginyl-L-arginylamide-4-methylcoumarin, and its specificity
      was checked with E-64, a specific inhibitor of cysteine proteinases and CA074, a
      specific inhibitor of the enzyme. Cathepsin B activity was detected in crude
      extracts of cell monolayers and in conditioned media. In both cell types, basal
      activity was detected essentially in cell extracts, since in media only
      approximately 1.2% (hOB) and approximately 6% (MG-63) of the total activity was
      released. IL-1 beta (1-100 U/ml) and PTH (10(-9) M-10(-6) M) significantly
      stimulated cathepsin B activity in cell extracts and in conditioned media. In
      both cell types, the increase in proteolytic activity appeared to require RNA and
      protein synthesis after adding IL-1 beta or PTH. Using the above substrate, we
      also evaluated some biochemical properties of the enzyme, and its pH-stability
      and pH-optimum. In both cell types, intracellular cathepsin B activity was not
      resistant to neutral or slightly alkaline pH, whereas extracellular cathepsin B
      activity was stable. This study provides evidence that osteoblast-like cells
      produce and secrete active cathepsin B. The production and secretion was
      stimulated by IL-1 beta and PTH. The physiological role of cathepsin B produced
      by osteoblasts and stimulated by the bone resorbing agents remains to be
      elucidated. Since extracellular activity is stable under relatively physiological
      conditions, it is possible that the extracellular as well as intracellular form
      of the enzyme may play a role in matrix turnover.

PMID- 8645705
TI  - The sarcoplasmic reticulum calcium pump is functionally altered in dystrophic
      muscle.
AB  - In Duchenne muscular dystrophy, muscle cells, which lack the protein dystrophin,
      have been reported to have elevated resting intracellular calcium levels. It has
      also been noted that, compared to normal muscle, intracellular [Ca2+] in
      dystrophic muscle returns more slowly to its resting level following contractile
      stimulation. Consistent with this, it has been suggested that dystrophin is
      directly involved in the regulation of Ca2+ influx. A secondary alteration in the
      sarcoplasmic reticulum Ca2+ pump, however, could also contribute to, or be
      responsible for, the abnormal Ca2+ handling seen. To determine whether the Ca2+
      pump is functionally altered in dystrophic muscle, we examined Ca2+ uptake by
      vesicles derived from skeletal muscle sarcoplasmic reticulum of normal and
      dystrophic (mdx) mice. The Hill coefficient and the Ca2+ sensitivity of the Ca2+-
      ATPase were the same in both cases. The maximum velocity of Ca2+ uptake, however,
      normalized to the ATPase content of the vesicles, was less for mdx muscle.

PMID- 8645706
TI  - Hydrogen peroxide increases Na+/K(+)-ATPase function in alveolar type II cells.
AB  - We have studied the regulation of Na+/K(+)-ATPase function in alveolar type II
      cells submitted to oxidative stress. Alveolar type II cells were isolated from
      Sprague Dawley rats and suspended in Dulbecco's modified Eagle's medium. 500 muM
      xanthine plus 0.5 or 5 mU/ml xanthine oxidase (group 1 and 2, respectively) were
      added to the cell suspensions. Following various exposure times the reaction was
      stopped by adding allopurinol and cells were processed to assay H2O2 steady state
      concentrations, enzymatic activity of catalase and Na+/K(+)-ATPase function.
      Hydrogen peroxide production by the xanthine-xanthine oxidase system reached
      maximal values at 30 min of incubation in both groups. H2O2 steady state
      concentration increased 2- and 10-fold, respectively. Catalase activity was not
      changed after slight oxidative stress (group 1) but decreased in severe oxidative
      stress (group 2). Decreases in the Na+/K(+)-ATPase activity (10 and 60% for
      groups 1 and 2) were found during the first hour of exposure coinciding with the
      peak in H2O2 steady state concentration. This early inactivation was followed by
      progressive increases in the activity up to 70% over the control value in group
      1, and to the control value in group 2. [3H]Ouabain binding studies showed that
      the increase in Na+/K(+)-ATPase activity after oxidative stress was due to an
      increase in the number of phosphorylated pump molecules in the plasma membrane of
      alveolar type II cells.

PMID- 8645707
TI  - Evidence for a glycosylinositolphospholipid-anchored alkaline phosphatase in the
      aquatic plant Spirodela oligorrhiza.
AB  - Glycosylphosphatidylinositol (GPI)-anchored proteins occur widely, perhaps
      universally, on the surface of animal cells, where they perform a variety of
      important functions. However, the existence of GPI-anchored proteins on plant
      cells has never been established. Evidence is presented in this communication for
      the occurrence of a 50 kDa GPI-anchored alkaline phosphatase (AP) induced in the
      duckweed Spirodela oligorrhiza by phosphate deprivation. Triton X-114
      partitioning of the Spirodela proteins yielded two forms of AP activity. The
      detergent-associated form was labeled prominently by [3H]ethanolamine,
      [3H]myristic acid and [3H]palmitic acid. This amphiphilic form of AP, like
      authentic GPI-anchored AP from mammals, was clearly resolved from the remaining,
      water-soluble AP activity by two types of incompletely-denaturing polyacrylamide
      gel electrophoresis. Lipid covalently bound to the solvent-delipidated
      amphiphilic AP was resistant to cleavage by phosphatidylinositol-specific
      phospholipase C. Strong acid or alkaline hydrolysis of the 3H-fatty acid-labeled
      amphiphilic AP yielded radioactive fatty acids and a radioactive lipid
      tentatively identified as a long chain base. The more abundant water-soluble AP
      was also radioactive in plants incubated with [3H]ethanolamine and was labeled to
      a lesser extent by 3H-fatty acids. The water-soluble AP, unlike its amphiphilic
      counterpart, could be freed of all fatty acid radioactivity by mild alkaline
      hydrolysis, indicating the continued presence of an ester-linked fatty acid. All
      evidence supports the conclusion that Spirodela AP is synthesized as an
      amphiphilic protein with a ceramide-containing GPI anchor.

PMID- 8645708
TI  - Minimum structural requirement for an inhalational anesthetic binding site on a
      protein target.
AB  - The present study makes use of direct photoaffinity labeling and fluorescence and
      circular dichroism spectroscopy to examine the interaction of the inhalational
      anesthetic halothane with the uncharged alpha-helical form of poly(L-lysine) over
      a range of chain lengths. Halothane bound specifically to long chain homopolymers
      (190 to 1060 residues), reaching a stable stoichiometry of 1 halothane to 160
      lysine residues in polymers longer than 300 residues. Halothane bound only non
      specifically to an alpha-helical 30 residue polymer and to all of the polymers in
      their charged, random coil form. The data suggest that halothane binding is a
      function of supersecondary structure whereby intramolecular helix-helix clusters
      form in the longer polymers, resulting in the creation of confined hydrophobic
      domains. Circular dichroism spectroscopy cannot demonstrate changes in poly(L
      lysine) secondary structure at any chain length with up to 12 mM halothane,
      suggesting that extensive hydrogen bond disruption by the anesthetic does not
      occur.

PMID- 8645709
TI  - Molecular characterization of Euglena ascorbate peroxidase using monoclonal
      antibody.
AB  - Ascorbate peroxidase (EC 1.11.1.11) has been purified to electrophoretic
      homogeneity from Euglena gracilis Z. The enzyme showed a molecular mass of 58 kDa
      on SDS-PAGE and gel filtration, indicating that Euglena ascorbate peroxidase
      exists as a monomeric form. The substrate specificity for an electron donor and
      the stability of the purified enzyme were similar to those of cytosolic isozymes
      from higher plants. One of the characteristic properties was that Euglena
      ascorbate peroxidase reduces organic hydroperoxides as well as hydrogen peroxide.
      The N-terminal amino-acid sequence showed no significant similarity to any other
      ascorbate peroxidase from higher plants. However, the sequence of the peptides
      from the purified enzyme exhibited a high degree of homology to sequences of
      cytosolic and chloroplastic ascorbate peroxidases. Monoclonal antibodies against
      the purified Euglena ascorbate peroxidase were prepared. Two monoclonal
      antibodies (EAP1 and EAP2) showed high homology to cytosolic ascorbate
      peroxidases of higher plants, as judged by Western blot analysis. The EAP1 was
      also specific for chloroplastic ascorbate peroxidase from spinach. These findings
      indicate that Euglena ascorbate peroxidase exists in highly homologous regions
      with the ascorbate peroxidases of higher plants.

PMID- 8645710
TI  - Dipeptide-derived diphenyl phosphonate esters: mechanism-based inhibitors of
      dipeptidyl peptidase IV.
AB  - A number of dipeptide diphenyl phosphonate esters were studied as inhibitors of
      dipeptidyl peptidase IV, focusing on the role of the P2 residue in the
      inactivation process. The active compounds were slow irreversible inhibitors of
      the catalytic activity of the enzyme. With proline (or alanine) in the P1
      position, the rate constants of inactivation correlated with the acylation rate
      constants reported for homologous dipeptide derived substrates. The kinetic data
      indicate that the mechanism of inhibition consists of the formation of a fairly
      weak initial complex, followed by a slow irreversible inactivation step. This
      indicates that, as in the case of trypsin-like proteinases, dipeptide diphenyl
      phosphonate esters form a covalent adduct with the catalytic site of DPP IV, even
      though this enzyme belongs to a completely distinct class of serine peptidases.
      Enantioselectivity and secondary specificity further support the evidence that
      diphenyl phosphonate esters are mechanism-based inhibitors. The dipeptide
      diphenyl phosphonate esters had a half-life of 3-10 h at 37 degrees C in Tris
      buffer. The inhibitors were degraded in human plasma, depending on the type of
      amino-terminal amino acid. The compound with proline in the P2 position was the
      most resistant to degradation in plasma. Due to their stability and the
      irreversible nature of the inhibition, the diphenyl phosphonate esters promise to
      be useful tools in the continuing investigation of the physiological function of
      dipeptidyl peptidase IV.

PMID- 8645711
TI  - Strength and lifetime of the bond between actin and skeletal muscle alpha-actinin
      studied with an optical trapping technique.
AB  - The force required to break the bond between skeletal muscle actin and alpha
      actinin (unbinding force) was measured at the level of individual molecules with
      an optical trapping technique. An actin filament, to the barbed-end of which was
      attached a gelsolin-coated polystyrene bead, was bound to alpha-actinin molecules
      adsorbed to a nitrocellulose-coated glass surface (approximately equal to 1 alpha
      actinin molecule per 1 micron actin filament). The filament-bound bead was held
      by the optical trap and the force was applied to break the bond by pulling the
      bead. The unbinding force ranged from 1.4 to 44 pN. The average magnitude of the
      force was approximately equal to 18 pN. As the probability of the bond breakage
      has been suggested to be governed by the magnitude of the external force, the
      relationship was studied between the magnitude of the unbinding force and the
      time required to break the bond (unbinding time). The unbinding time ranged from
      approximately equal to 0.1 to approximately equal to 20 seconds, and tended to
      become shorter as the unbinding force became larger. The unbinding time seemed to
      be classifiable into two major groups: one group having a time value of 1 sec or
      less and the other having a time value ranging from several to 20 seconds. This
      suggests the existence of at least two classes of the actin-actinin bonds.

PMID- 8645712
TI  - Regulation of folate-dependent enzyme levels in Aspergillus nidulans: studies
      with regulatory mutants.
AB  - The synthesis of folate-dependent enzymes in Aspergillus nidulans appears to be
      regulated by intracellular pools of homocysteine and methionine. The results are
      consistent with the view that homocysteine acts as an inducer and methionine as a
      corepressor, but the molecular mechanism of the regulation is still unknown.
      Methionine-requiring mutants, metH2 and metD10, apparently allelic, show
      deregulation of folate-dependent enzymes. Most characteristic of the mutants is a
      repressed level of folylpolyglutamate synthetase. New mutations suppressing the
      metH2 lesion which render folate enzymes insensitive to methionine-mediated
      repression have been isolated. These mutations are likely to identify new
      regulatory genes in folate metabolism.

PMID- 8645713
TI  - Fluorescence emission properties of 8-azapurines and their nucleosides, and
      application to the kinetics of the reverse synthetic reaction of purine
      nucleoside phosphorylase.
AB  - An extensive study has been made of the fluorescence emission properties of the
      neutral and ionic forms in aqueous medium of the azapurine nucleosides, 8
      azaadenosine (8-azaAdo), 8-azainosine (8-azaIno), 8-azaguanosine (8-azaGuo), and
      their aglycons. The fluorescence of 8-azaGuo at pH 7 originates from its anionic
      species (pKa = 8.05, phi= 0.55), as is also the case for 8-azaIno (pKa = 8.0, phi
      = 0.02), whereas 8-azaAdo is a strong emitter (phi = 0.06) as the neutral
      species. By contrast the corresponding free 8-azapurines are only weakly
      fluorescent in aqueous medium, with the exception of 8-azaguanine (8-azaG).
      Examination of the emission properties of N-substituted 8-azaguanines
      demonstrated that the observed blue emission of the neutral form of 8-azaG (phi =
      0.05 to 0.33, dependent on lambda exc) originates from a minor tautomer of the
      compound, the N(8)-H form, present to the extent of 10-15%; while the principal
      N(9)-H tautomer is virtually nonfluorescent. The 8-azapurines are substrates of
      purine nucleoside phosphorylase (PNP), leading to their irreversible conversion
      to the corresponding nucleosides in the synthetic pathway of this enzyme. The
      fluorescent properties of these compounds, together with spectrophotometric
      methods, were applied to determine the basic kinetic parameters for synthesis of
      8-azapurine nucleosides by PNP from mammalian (calf spleen) and bacterial
      (Escherichia coli) sources. The fluorimetric method was also used to determine
      the kinetic parameters for the second substrate, alpha-D-ribose 1-phosphate, and
      for the analytical titration of the latter in solution. The pH optimum of the
      reverse synthetic PNP reaction with 8-azapurines as substrates is below pH 7, due
      to their enhanced acidity in comparison with natural purines. The 8-azapurine
      nucleosides, but not their aglycons, are reasonably good inhibitors of
      phosphorolysis of Ino and Guo by E. coli PNP. The most effective is 8-azaIno (Ki
      approximately 20 microM), also the only one to inhibit phosphorolysis by the calf
      spleen enzyme (Ki approximately 40 microM). The nature of this inhibition is
      apparently uncompetitive.

PMID- 8645714
TI  - Characterisation of an acid trehalase of Saccharomyces cerevisiae present in
      trehalase-sucrase aggregate.
AB  - An acid trehalase-sucrase aggregate was purified (by 780-fold) from Saccharomyces
      cerevisiae, following conventional protein purification techniques, to an
      apparent yield of 18.5%. The aggregate was electrophoretically homogeneous but
      contained 175, 90, 68, 60, 40 molar mass (kDa) bands on SDS-electrophoresis. The
      purified aggregate had a specific activity (acid trehalase) of 22 U/mg; a Km
      value of 5.0 mM but contained 3-times more sucrase activity. Only sucrose and
      trehalose were hydrolysed by this aggregate and both activities were inhibited by
      acetate or phosphate. Temperature and pH optima for trehalose hydrolysis appeared
      to be 40-45 degrees C and 5.0, respectively. The purified aggregate appeared to
      be disaggregating spontaneously resulting in inactivation of both enzymes, which
      was enhanced either at pH 3.5 or at pH 7.0. Separation of acid trehalase from the
      aggregate by hydrophobic interaction chromatography resulted in inactivation.
      Rechromatography (HPGPLC) of the purified aggregate also gave disaggregation as
      well as inactivation of both enzymes. Disaggregated acid trehalase and sucrase
      contained 20-fold and 13-fold lower specific activities, respectively, and
      appeared to be unstable. Based on these observations we suggest that acid
      trehalase is stabilised by aggregation with sucrase.

PMID- 8645715
TI  - Purification and identification of allergenic alpha (2u)-globulin species of rat
      urine.
AB  - Amino-acid compositional and sequence analyses as well as mass spectrometric
      determinations of purified rat urine proteins, previously termed prealbumin and
      alpha(2)-euglobulin, have revealed a high homology between the two forms which
      have now been identified as alpha(2)-globulin species. The "prealbumin' fraction
      was found to correspond to alpha(2u)-globulin originating from salivary gland and
      the 'alpha(2)-euglobulin' fraction was identical with the major urinary protein
      (MUP) or alpha(2u)-globulin. The results indicate that the two major protein
      fractions of rat urine constitute different forms of the same parent protein,
      alpha(2u)-globulin, having no amino-acid sequence resemblance to prealbumin
      (transthyretin) of rat serum.

PMID- 8645716
TI  - Purification and characterization of Artemia 2',3'-cyclic nucleotide 3'
      phosphodiesterase.
AB  - This paper describes the purification and properties of a 2',3'-cyclic nucleotide
      3'-phosphodiesterase which hydrolyzes nucleoside 2',3'-cyclic monophosphates to
      nucleoside 2'-phosphates. The enzyme is present in encysted gastrulae of Artemia
      and its specific activity greatly increases during larval development. The
      purified enzyme has a molecular weight of around 55 000 as estimated by gel
      filtration, does not require metals for activity, is inhibited by Zn2+ and
      inactivated by Cu2+ and has a pH optimum at around neutrality. Based on the
      relative values of V(max)/Km, the specificity of the phosphodiesterase toward the
      four 2',3'-cyclic nucleotides is Guo-2',3'-P > Ado-2',3'-P > Cyd-2',3'-P > Urd
      2',3'-P = 45:36:20:7. The enzyme from Artemia gastrulae is competitively
      inhibited by the four nucleosides 2'-phosphates (Ki values around 1 mM) while the
      enzyme from larvae is only inhibited by the purine nucleotides. The
      phosphodiesterase characterized in this work is more similar in substrate
      specificity to the 2',3'-cyclic nucleotide 3'-phosphodiesterase from the
      mammalian nervous system than to the plant enzyme. The functional relationship of
      this enzyme with the Artemia ribonuclease VI is discussed.

PMID- 8645717
TI  - Hyperosmotic exposure alters total taurine quantity and cellular transport in rat
      astrocyte cultures.
AB  - Taurine content and cellular taurine transport were characterized in astrocytes
      from rat cerebral cortex after growth in isoosmotic or hyperosmotic culture
      conditions to investigate mechanisms of taurine accumulation during conditions of
      increased osmolality. Total taurine content of the culture dishes was
      significantly (P < 0.05) elevated after 8, 24, and 48 h of hyperosmotic exposure
      compared to cultures grown for the same period in isoosmotic (300 mOsm, control)
      conditions. Hyperosmotic medium elevated intracellular taurine (nmol/mg protein)
      levels by 29-108% over control cultures. Significant (P < 0.02) increases in
      carrier-mediated taurine uptake rates were observed in astrocytes exposed to 350,
      400, and 450 mOsm culture medium for 24 h compared to control cultures at the
      same time point. The increase in uptake rate decreased to control values by 48 h
      in 450 mOsm treated cultures. The carrier-mediated transport binding constant for
      taurine uptake, Km, was not altered at any time after hyperosmotic treatment.
      Maximal velocity of uptake, V(max), increased by 70% and 36% after 24 h growth in
      400 and 450 mOsm culture medium, respectively, compared to control cells at the
      same time. After 48 h of hyperosmotic exposure, V(max) returned to control
      values. The diffusional transport rate for taurine efflux, Kdiff, was not
      affected by hyperosmotic exposure at any time point. Taurine release rates were
      increased by over two-fold during the first 8 h of exposure to 450 mOsm medium
      compared with cells grown in control conditions. After 24 and 48 h hyperosmotic
      exposure, release rates decreased to 44-72% of the release from control cultures.
      These data indicate at least three mechanisms contribute to taurine accumulation
      in cultured cerebral astrocytes exposed to hyperosmotic conditions. These
      mechanisms are (i) an increased rate of taurine uptake from the extracellular
      space within 24 h, (ii) a decrease in net taurine efflux by 48 h, and (iii) an
      enhanced rate of taurine synthesis.

PMID- 8645718
TI  - Dipeptidyl peptidase II from porcine seminal plasma: purification,
      characterization, and its homology to granzymes, cytotoxic cell proteinases (CCP
      1-4).
AB  - Dipeptidyl peptidase II (DPP II) was purified to homogeneity from porcine seminal
      plasma by polyacrylamide gel electrophoresis (PAGE). The molecular weight of the
      purified enzyme was calculated to be approx. 185,000 and 200,000 on Superdex 200
      column chromatography and non-denatured PAGE, respectively, and to be 58,000 and
      61,000 on SDS-PAGE in the absence and presence of beta-mercaptoethanol (beta-ME),
      respectively. These findings suggested that the enzyme is composed of three
      identical subunits. The enzyme rapidly hydrolyzed the substrates Lys-Ala-MCA and
      Gly-Pro-MCA at acidic pH. The Km and V(max) values of DPP II at optimal pH (pH
      6.0) were 1330 microM and 2.9 mumol/mg per min for Gly-Pro-MCA, and 360 microM
      and 1.43 mumol/mg per min for Lys-Ala-MCA, respectively. It was strongly
      inhibited by diisopropylphosphofluoride (DFP), and moderately by 4-(2
      aminoethyl)benzenesulfonyl fluoride (AEBSF). These findings suggest that DPP II
      is a serine peptidase. Furthermore, the enzyme activity was also strongly
      inhibited by copper ions. The amino-acid sequence of the first 41 residues of the
      enzyme was determined as Ala1-Ser-Pro-Pro-Glu-Pro-Gly-Phe-Arg- Glu10-Val-Tyr-Phe
      Glu-Gln-Leu-Leu-Asp-His-Phe20-Asn-Phe-Glu- Arg-Phe- Gly-Lys-Lys-Thr-Phe30-Arg-Gln
      Arg-Phe-Leu-Val-Ser-Asp-Lys-Phe40 -Trp. This sequence showed homology (11.6
      30.2%) to the N-terminal amino-acid sequences of cytotoxic cell proteinases (CCP
      1-4), granzymes. Other properties of DPP II including pH optimum, pH stability,
      and heat stability were characterized.

PMID- 8645719
TI  - Retinol-binding protein secretion from the liver of N-(4-hydroxyphenyl)
      retinamide-treated rats.
AB  - N-(4-Hydroxyphenyl)retinamide (HPR; Fenretinide), a synthetic retinoid possessing
      antitumor activity, depresses plasma retinol and retinol-binding protein (RBP)
      concentrations. In study 1, the ability of retinol or HPR to induce RBP secretion
      from the livers of vitamin A-deficient rats was compared. A large apoRBP pool
      accumulated in the liver rough microsomes of these rats. Following retinol
      repletion, 80% of the accumulated RBP was rapidly secreted into the plasma. In
      contrast, HPR treatment only induced two-thirds of the RBP secretion observed
      with retinol. Prior colchicine treatment caused a large RBP accumulation in the
      Golgi-enriched fraction following retinol repletion. HPR plus colchicine
      treatment produced significantly less accumulation of RBP in the Golgi-enriched
      fraction than did retinol. In study 2, HPR treatment of vitamin A-adequate rats
      caused RBP to accumulate in the liver rough microsomes. When vitamin A-adequate
      rats were treated with colchicine, the concentration of RBP in the Golgi-enriched
      fraction increased 2.9-fold. However, significantly less RBP accumulated in the
      Golgi following HPR treatment. These studies demonstrate that HPR will induce
      liver RBP secretion, but to a lesser degree than retinol. Further, more RBP
      remained in the rough microsomes of HPR treated, vitamin A-adequate rats,
      indicating that HPR depressed the amount of RBP secreted.

PMID- 8645720
TI  - Magnesium activated adenosine formation in intact perfused heart: predominance of
      ecto 5'-nucleotidase during hypermagnesemia.
AB  - Magnesium ion is an allosteric effector of 5'-nucleotidase and thus activates
      adenosine production from AMP. Two distinct 5'-nucleotidase systems, the membrane
      bound ecto and the soluble cytosolic isoforms, exist in mammalian myocardium. The
      aim of this study was to delineate the contributions of the ecto vs. cytosolic
      isoforms to Mg2+-stimulated cardiac purine nucleoside formation and release.
      Isolated guinea pig hearts were retrogradely perfused at their physiological
      aortic pressure with Krebs-Henseleit bicarbonate buffer fortified with 10 mM
      glucose. AMP and the adenylate degradatives adenosine and inosine were measured
      in coronary venous effluent and in epicardial transudate, which was sampled to
      estimate concentrations of adenylate degradatives in the interstitium. When
      perfusate Mg2+ was increased from 0.6 to 6 mM, coronary vascular resistance and
      spontaneous heart rate fell, and steady-state coronary venous release of
      adenosine + inosine rose severalfold. Cytosolic free magnesium, as estimated by
      31P-NMR after 15 min of perfusion with 6 mM Mg2+ or from chemically measured
      indicator metabolites after 30 min, rose 60 and 144% respectively (P < 0.05).
      Excess Mg2+ stimulated purine nucleoside release nearly threefold in coronary
      venous effluent and four- to sevenfold in epicardial transudate. 50 microM,
      alpha,beta-methylene adenosine 5'-diphosphate (AOPCP), a selective inhibitor of
      ecto 5'-nucleotidase, elevated interstitial AMP concentration tenfold, did not
      attenuate basal nucleoside release, but completely inhibited Mg2+-stimulated
      coronary venous purine nucleoside release and blunted Mg2+-stimulated
      interstitial purine nucleoside formation by 69%. During perfusion with exogenous
      1 microM [8-14C]AMP, excess perfusate MgCl2 increased [14C]adenosine release by
      63% in coronary effluent and 133% in epicardial transudate. AOPCP decreased
      baseline [14C]adenosine release in coronary effluent and epicardial transudate by
      85-90%, caused equilibration of arterial and epicardial AMP, and attenuated MgCl2
      activation of p[14C]adenosine formation by approx. 75%, in both the vascular and
      interstitial compartments. Intramyocytic concentrations of allosteric regulators
      of the cytosolic 5'-nucleotidases were evaluated in stop-frozen myocardium.
      Excess magnesium did not appreciably alter intracellular pH and ATP
      concentration, but lowered free cytosolic ADP and AMP concentrations by 50 and
      70%, respectively. A simplified model of compartmentalized adenosine metabolism
      is proposed in which magnesium ion-activated cardiac purine release originates
      predominantly from the ecto 5'-nucleotidase; magnesium ion stimulation of
      metabolic flux through the cytosolic isoforms was constrained by concomitant
      reductions in intracellular AMP substrate and allosteric activator ADP. Magnesium
      ion-enhanced adenosine formation by 5'-nucleotidase could contribute to the known
      cardioprotective effects of this clinically used cation.

PMID- 8645721
TI  - Purification and properties of L(-)-carnitine dehydrogenase from Agrobacterium
      sp.
AB  - L(-)-Carnitine:NAD+ oxidoreductase, EC 1.1.1.108, from Agrobacterium sp.
      catalyzes the oxidation of L(-)-carnitine to 3-dehydrocarnitine as initial step
      of L(-)-carnitine degradation. The enzyme was purified 76-fold by four
      chromatographic steps. A high substrate specificity for L(-)-carnitine and NAD+
      was observed. The molecular mass of the native enzyme is 114 kDa and it consists
      of two identical subunits as determined by sodium dodecyl sulfate polyacrylamide
      gel electrophoresis. The isoelectric point was found to be 5.2-5.4. The optimum
      temperature is 45 degrees C and the optimum pH for the oxidation and the
      reduction reaction are 9.5 and 5.5-6.5, respectively. Kinetic parameters and
      amino-terminal sequence were determined. The oxidation reaction is inhibited by
      D(+)-carnitine, trimethylamine, several metal ions and
      cetyltrimethylammoniumbromide (CTAB).

PMID- 8645722
TI  - Purification and characterisation of swine serum proteinase which hydrolyses
      epidermal inhibitory pentapeptide.
AB  - In this paper we describe the purification to molecular homogeneity of the enzyme
      that cleaves the synthetic epidermal mitosis-inhibiting pentapeptide (pyroGlu-Glu
      Asp-Ser-Gly; EPP) from swine serum. Biochemical characterisation of the enzyme
      shows a glycoprotein with apparent molecular mass of 200 kDa. The Km and Kcat
      values for EPP hydrolysis are 0.624 mM and 694 s-1, respectively. Use of
      proteinase inhibitors shows the enzyme's metalloendopeptidase character.
      Moreover, captopril and lisinopril prevent the cleavage of EPP. The N-terminal
      amino-acid sequence of the purified protein corresponds to the N-terminal amino
      acid sequence of swine kidney angiotensin-converting enzyme, a dipeptidyl
      carboxypeptidase (EC 3.4.15.1).

PMID- 8645723
TI  - In vitro inhibition of Ca2+/calmodulin-dependent kinase II activity by melatonin.
AB  - Recent evidence suggests that a melatonin (MEL) mechanism of action may be
      through modulation of Ca2+-activated calmodulin (CaM). MEL binds to CaM with a
      high affinity, and has been shown to act as a CaM antagonist. Among the CaM
      dependent enzymes, Ca2+/Calmodulin-dependent protein kinase II (CaM-kinase II) is
      a particularly abundant enzyme in the nervous system. In the brain it
      phosphorylates a broad spectrum of substrates, thus modulating important neuronal
      functions. We describe the MEL effect on CaM-kinase II activity in vitro. CaM
      kinase II was purified from rat brain by column chromatography, and identified by
      Western immunoblotting. CaM-kinase II activity was assessed in the presence of
      Ca2+/CaM by the kinase's ability to phosphorylate the synthetic substrate syntide
      2 and by enzyme autophosphorylation. MEL inhibited CaM-kinase II activity, and
      enzyme autophosphorylation. Inhibition of the enzyme by 10(-9) M MEL was nearly
      of 30%. Trifluoperazine (10 microM), W7 (10 microM), and compound 48/80 (30
      micrograms/ml), inhibited CaM-kinase II activity by 40%, 42%, and 93%,
      respectively. Both EGTA (5 mM) and MEL (10(-5) M) abolished autophosphorylation.
      The effect of MEL on CaM-kinase II activity was specific, since neither
      serotonin, N-acetylserotonin, nor 6-hydroxymelatonin inhibited its activity. Our
      results support the hypothesis that MEL acts as a CaM antagonist and cellular
      functions may be rhythmically regulated by MEL modulation of CaM-dependent
      protein phosphorylation.

PMID- 8645724
TI  - Stimulation of rat liver AMP-activated protein kinase by AMP analogues.
AB  - Stimulation of AMP-activated kinase (AMP-PK) by ZMP (5-amino-4
      imidazolecarboxamide ribotide, AICAR), formed by adenosine kinase upon addition
      of AICAriboside to isolated rat hepatocytes, results in inhibition of fatty acid
      and cholesterol synthesis by inactivation of acetyl-CoA carboxylase and 3-hydroxy
      3-methylglutaryl-CoA reductase, respectively (Henin et al. (1995) FASEB J. 9, 541
      546). The effects of ZMP and other AMP analogues have now been compared with
      those of AMP on AMP-PK purified from rat liver. ZMP stimulated AMP-PK to the same
      maximal extent as AMP (about 10-fold). ZMP had less affinity for AMP-PK than AMP,
      but this affinity was similarly influenced by ATP: half-maximal effects,
      requiring 0.4 mM AMP or 5 mM ZMP at 3 mM ATP, were obtained with 9 microM AMP or
      0.4 mM ZMP at 0.2 mM ATP. The kinetic parameters of AMP-PK for the SAMS peptide
      and for ATP were influenced in the same way by ZMP and AMP. Stimulation of AMP-PK
      by ZMP was additive with AMP, up to when maximal stimulation was obtained. Taken
      together, these results indicate that ZMP binds to the same site as AMP on AMP
      PK. Tubercidin 5'-monophosphate, 2'-deoxy-AMP and Ara-AMP stimulated AMP-PK, but
      N6-methyl-AMP, 1,N6-etheno-AMP, 6-mercaptopurine riboside 5'-monophosphate,
      adenylosuccinate and succinyl-AICAR were ineffective, suggesting that a free 6
      NH2 group may be important for binding of effectors to AMP-PK.

PMID- 8645725
TI  - Effect of chaotropic denaturant on the binding of 1-anilino-8-naphthalene
      sulfonic acid to proteins.
AB  - 1-Anilino-8-naphthalene sulfonic acid (ANS), a hydrophobic dye, is widely used to
      monitor conformational changes occurring in proteins during their
      folding/unfolding. Using cardiotoxin III (whose conformation remains unperturbed
      even in 6 M urea) from the Taiwan Cobra (Naja naja atra) venom, it is
      demonstrated that chaotropic denaturant such as urea directly competes with the
      interaction between ANS and the protein. The results presented in this report, in
      our opinion, has significant implication(s) in the area of protein folding,
      arising out of ANS binding experiments.

PMID- 8645726
TI  - Cloning, characterization and functional analysis of groEL-like gene from
      thermophilic cyanobacterium Synechococcus vulcanus, which does not form an operon
      with groES.
AB  - A gene encoding 57 102 Da polypeptide homologous to groEL of Escherichia coli but
      accompanying no groES, has been cloned and sequenced from a thermophilic
      cyanobacterium, Synechococcus vulcanus. The amount of the gene transcript
      increased several folds by heat shock. The gene was expressed as a minor
      component of two types of HSP60, and designated as groEL2. Although expressed and
      induced well upon heat shock treatment in the E. coli, introduction of the cloned
      groEL2 gene of S. vulcanus into an E. coli groEL-less mutant did not result in
      the complementation of heat sensitivity.

PMID- 8645727
TI  - Molecular cloning of dimethyl sulfoxide reductase from Rhodobacter sphaeroides.
AB  - The dsrA gene encoding the molybdoenzyme dimethyl sulfoxide reductase was
      isolated by screening phagemid libraries containing restriction fragments of
      Rhodobacter sphaeroides f. sp. denitrificans genomic DNA with a pool of
      degenerate oligonucleotides. The encoded 822 amino-acid protein includes a 42
      amino-acid periplasmic signal sequence that is cleaved during activation of the
      enzyme. Both forms of the protein were heterologously expressed in inactive
      states in E. coli and identified by Western blot analysis.

PMID- 8645728
TI  - The detection of kinetic intermediates during the unfolding of lipoxygenase-1 by
      urea or guanidine hydrochloride.
AB  - The unfolding of lipoxygenase-1 by urea and guanidine hydrochloride has been
      followed at the optimum pH of enzyme activity. The unfolding of lipoxygenase-1 by
      urea or guanidine hydrochloride was characterized by equilibrium transition
      curves for different parameters like (i) enzyme activity, (ii) change in
      ellipticity values at 222 nm, and (iii) relative fluorescence intensity at 332 nm
      could not be superimposed. The transition curves displayed more than one plateau
      region suggesting the presence of stable intermediates during unfolding. At urea
      concentrations less than 1 M there was no significant loss in activity although
      loss in secondary structure was approximately 20%. At 4.0 M urea concentration
      there was complete loss of activity with a midpoint concentration of 2.5 M urea.
      The loss in secondary structure was biphasic. The first transition had a midpoint
      concentration of 1.2 M, while the second transition which was complete at 8.0 M
      urea had a midpoint concentration of 3.5 M urea. The changes in relative
      fluorescence intensity and shift in emission maximum were complete at 8.0 M urea.
      The Stern-Volmer constant for acrylamide and potassium iodide did not change at
      urea concentrations less than 4 M and then at higher concentrations increased.
      The reactivity of sulfhydryl groups to Ellman's reagent increased during the
      course of unfolding. The kinetics of unfolding supported the presence of stable
      intermediates during unfolding. The unfolding was irreversible and complex
      because of the multidomain nature. The apparent irreversibility could be related
      to aggregation during unfolding which precluded the determination of
      thermodynamic parameters.

PMID- 8645729
TI  - FTIR studies of recombinant human granulocyte-macrophage colony-stimulating
      factor in aqueous solutions: secondary structure, disulfide reduction and thermal
      behavior.
AB  - Fourier transform infrared spectroscopy (FTIR) has been used to investigate the
      secondary structure, disulfide reduction and thermal behavior of recombinant
      human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in aqueous
      solutions. The contributions of amino-acid side-chain groups to the amide I bands
      of rhGM-CSF in H2O and in D2O solutions were carefully scrutinized, as 40% of the
      total 127 amino-acid residues of rhGM-CSF is side-chain absorptive (asparagine,
      glutamine, etc.). The FTIR results indicated that rhGM-CSF is composed of 46%
      alpha-helix, 7% beta-sheet, 23% turn and 24% loop/irregular structures which are
      in good agreement with the X-ray diffractional data. Reduction of rhGM-CSF with
      dithiothreitol caused apparent unfolding of the native conformation followed by
      the time-dependent increase of beta-aggregation bands which arose at 1622 and
      1693 cm(-1) in H2O, 1613 and 1684 cm(-1) in D2O solutions. The result also showed
      that tertiary structure can change independently of the secondary structure.
      Thermal denaturation of rhGM-CSF took place at 55 to 70 degrees C and the
      denatured protein adopted an irregular structure as revealed by the FTIR spectra.
      The thermal denaturation did not show the formation of intermolecular beta
      aggregates which is typical of most thermal denatured proteins. Moreover, it is
      partly reversible, indicating a special thermal stability of rhGM-CSF.

PMID- 8645730
TI  - Synthesis of alpha-helix-forming peptides by gene engineering methods and their
      characterization by circular dichroism spectra measurements.
AB  - Two kinds of peptides which were considered to form alpha-helices were designed
      and characterized. One was "alpha(3)-peptide' with 21 residues comprising three
      repeats of the seven-residue sequence Leu-Glu-Thr-Leu-Ala-Lys-Ala. This peptide
      appeared to be amphipathic due to a hydrophobic surface of Leu residues and a
      hydrophilic surface of Lys and Glu residues, thus forming a bundle structure. The
      other was "alpha(3)-GPRRG-alpha(3) peptide' with 47 residues in which two
      alpha(3)-peptides were connected by the five-residue sequence Gly-Pro-Arg-Arg
      Gly. The genes encoding these peptides were fused to the adenylate kinase gene
      via a methionine codon. The resulting fused protein was expressed as an inclusion
      body, and the peptides were purified after cleavage with BrCN. The stability of
      the peptides in various buffers was then examined by measuring their circular
      dichroism spectra. The alpha(3)-peptide showed concentration-dependent
      stabilization of the alpha-helix. Sedimentation equilibrium ultracentrifugation
      indicated that it formed a bundle structure composed of four polypeptide chains,
      and a dimer intermediate during oligomerization was also detected by analytical
      gel-filtration. The stability of the alpha(3)-peptide was decreased by shifting
      the pH to 2 or 12, due to electrostatic repulsion of charged residues. Thus, the
      alpha(3)-peptide was stabilized by increasing the ionic strength, particularly in
      acidic or alkaline buffer, through the masking of the repulsion by high salt
      concentration. In buffer of neutral pH and a high salt concentration, the
      alpha(3)-peptide at high concentration formed visible aggregates, due possibly to
      the exposed hydrophobic surfaces of the alpha-helical bundles. On the other hand,
      alpha(3)-GPRRG-alpha(3) peptide did not show concentration-dependent reversible
      dissociation and association. It was shown to exist as a trimer even at low
      concentration, indicating very tight association of the alpha(3)-GPRRG-alpha(3)
      peptide. In contrast to the alpha(3)-peptide, the alpha(3)-GPRRG-alpha(3) peptide
      was very stable at various pH values and salt concentrations. This seemed to be
      due to increased hydrophobic interactions resulting from the increase in the
      number of seven-residue repeats from three to six, even though each group of
      three repeats was separated by a five-residue sequence.

PMID- 8645731
TI  - A homology model of the Id-3 helix-loop-helix domain as a basis for structure
      function predictions.
AB  - The function of the dominant negative Id (inhibitor of differentiation) helix
      loop-helix (HLH) proteins is to dimerize with, and prevent the DNA binding of
      basic HLH (bHLH) transcription factors. A three-dimensional homology model was
      constructed for the HLH domain of human Id3 based on the X-ray crystal structures
      of the E47, MyoD, and Max bHLH proteins. The model showed that, in contrast to
      bHLH proteins, Id proteins appear able to dimerize without DNA stabilization
      because of better packing of the hydrophobic core, and the absence of
      destabilizing polar loop residues and of repulsive positive charges in the
      monomer interface at the base of the four alpha-helix bundle. This prediction was
      tested by in vitro protein-binding experiments, which showed that Id3 did indeed
      self-associate. It also showed that the inability of Id proteins to bind DNA
      arises from the non-basic, poorly defined, random coil structure of the region
      corresponding to that responsible for bHLH DNA-binding. A model of the Id1
      protein was constructed and revealed a potential site of charge-charge repulsion
      in the hypothetical homodimer interface that may explain its observed inability
      to form homodimers.

PMID- 8645732
TI  - Interactions of Escherichia coli tryptophanase with quasisubstrates and
      monovalent cations studied by the circular dichroism and fluorescence methods.
AB  - The reaction of tryptophanase and its W330F and W248F mutant forms with quasi
      substrates forming an external pyridoxal phosphate aldimine or quinonoid is
      accompanied by the appearance of a positive circular dichroism (CD) peak at 290
      nm. The peak seems to arise from a Tyr residue undergoing reorientation during
      the reaction. The peak does not appear upon formation of non-covalent Michaelis
      complexes of the enzyme with quasi-substrates such as indolepropionate, beta
      phenyllactate and alpha-methylphenylalanine. The non-covalent complexes and
      external aldimines exhibit similar absorption spectra but can be distinguished by
      their CD and by the intensity of their fluorescence. Formation of the non
      covalent complexes leads to an increase in positive CD at 420 nm while formation
      of the external aldimines leads to disappearance of the positive CD at 420 nm and
      its replacement by negative CD; it also leads to strong quenching of the coenzyme
      fluorescence at 500 nm. The quantum yield of fluorescence of the external
      aldimines is 6-times lower than that of the internal aldimine. Activating cations
      (K+, NH4+) strongly diminish the intensity of a negative protein CD band at 275
      nm. From a comparison of the intensity of this band in the spectra of the wild
      type holo- and apoenzyme and in the tryptophan mutants, it was deduced that the
      band belongs to a Tyr residue, which may be a part of the cation-binding site or
      located in its immediate vicinity.

PMID- 8645733
TI  - Purification and properties of D-aspartate oxidase from Cryptococcus humicolus
      UJ1.
AB  - D-Aspartate oxidase (EC 1.4.3.1), which is highly specific to D-aspartate, was
      inducibly produced by a yeast strain which was isolated from soil and identified
      as Cryptococcus humicolus UJ1. The enzyme was purified to homogeneity as
      indicated on SDS-polyacrylamide gel electrophoresis. The molecular mass of the
      monomer subunit was determined to be 40 kDa. The native enzyme was suggested to
      be a homotetramer by its behavior on gel filtration. The enzyme was shown to be a
      flavoprotein by its absorption spectral properties, and the flavin was found to
      be tightly, but not covalently, bound FAD. The purified preparation had a
      specific activity of 76.1 mumol/min per mg protein with D-aspartate as substrate.
      Optimum pH was 7.5 and optimum temperature was around 35 degrees C. D-Glutamate
      was a very poor substrate for the enzyme. N-Methyl-D-aspartate was better than D
      glutamate as substrate but markedly poorer than D-aspartate. Malonate was the
      most effective competitive inhibitor of the compounds tested. The N-terminal
      amino-acid sequence of the enzyme showed a significant homology with those of D
      aspartate oxidases from beef kidney and Octopus vulgaris and those of D-amino
      acid oxidases from various sources.

PMID- 8645734
TI  - Halolysin R4, a serine proteinase from the halophilic archaeon Haloferax
      mediterranei; gene cloning, expression and structural studies.
AB  - A gene encoding a halophilic serine proteinase, halolysin R4, from a halophilic
      archaeon Haloferax mediterranei strain R4 was cloned, its nucleotide sequence
      determined, and expressed in Haloferax volcanii WFD11. The deduced amino-acid
      sequence (403 aa in length) showed the highest similarity to halolysin 172P1,
      produced by another halophilic archaeon, strain 172P1 (now designated as
      Natrialba asiatica). Both halolysins belong to the thermitase branch of class I
      subtilases, but show long C-terminal extensions of 117 and 123 amino acids,
      respectively. Removal of this "tail' region from halolysin R4 abolished
      proteinase activity, indicating it provides an essential (but as yet unknown)
      function. Substitution of the two cysteine residues in the C-terminal extension
      with serine decreased enzyme stability in hypotonic solutions, possibly owing to
      disruption of potential disulfide bonds or perturbation of calcium binding
      site(s).

PMID- 8645735
TI  - A correlation between thermal stability and structural features of staphylokinase
      and selected mutants: a Fourier-transform infrared study.
AB  - Variants of recombinant staphylokinase (Sak) were investigated by Fourier
      transform infrared spectroscopy: Sak (wild type), Sak-M26A, Sak-M26L, and Sak
      G34S/R36G/R43H (Sak-B). Estimation of the secondary structure and hydrogen
      deuterium exchange experiments revealed the existence of fast-exchanging and
      strongly solvent-exposed fractions of the helical structures in the two samples
      Sak and Sak-M26L. These two samples are also thermally less stable with unfolding
      transition temperatures of 43.7 degrees C (Sak) and 43.5 degrees C (Sak-M26L),
      respectively. On contrast, Sak-M26A and Sak-G34S/R36G/R43H have a slower hydrogen
      deuterium exchange, have a smaller solvent-exposed portion of the helical part,
      and are more resistant against thermal unfolding; the transition temperatures are
      51.7 degrees C and 59.3 degrees C, respectively. The secondary structure analysis
      was performed by two different approaches, by curve-fitting after band narrowing
      and by pattern recognition (factor analysis) based upon reference spectra of
      proteins with known crystal structure. Within the limits of the used methods, we
      are unable to detect significant differences in the secondary structure of the
      four variants of Sak. According to the results of the factor analysis, the
      portions of secondary structure elements were obtained to 16-20% alpha-helix, 28
      30% beta-sheet, 23-27% turns, 28-30% irregular (random) and other structure. The
      sharp differences in the specific plasminogen-activating capacity (Sak, Sak
      G34S/R36G/R43H and Sak-M26L are fully active, but Sak-M26A does not form a stable
      complex with plasminogen) are not reflected in the structural features revealed
      by the infrared spectra of this study.

PMID- 8645736
TI  - Characteristics of 45Ca2+ release induced by quinolidomicin A1, a 60-membered
      macrolide from skeletal muscle sarcoplasmic reticulum.
AB  - Quinolidomicin A1, a 60-membered macrolide purified from an actinomycete
      Micromonospora sp. markedly induced 45Ca2+ release from the heavy fraction of
      skeletal muscle sarcoplasmic reticulum (HSR), but induced only slightly from the
      light fraction of sarcoplasmic reticulum (LSR), showing a lack of the
      ionophoretic activity even at a high concentration (300 microM). This was also
      confirmed by measuring the 45Ca2+ transport activity of quinolidomicin A1 across
      an organic solvent barrier. Quinolidomicin A1 (3-300 microM) increased 45Ca2+
      release from HSR with an EC50 value of approx. 20 microM. The potency of
      quinolidomicin A1 was approx. 100-fold higher than that of caffeine. The bell
      shaped profile of Ca2+ dependence for quinolidomicin A1 was different from that
      for caffeine. Blockers of Ca2+ release channels such as Mg2+ (10 mM), procaine
      (10 mM) and ruthenium red (10 microM) partially blocked quinolidomicin A1 (30
      microM)-induced 45Ca2+ release from HSR. At 0 degrees C, quinolidomicin A1
      induced 45Ca2+ release was ascertained not to be due to the inhibition of Ca2+
      ATPase by the ATPase assay. Quinolidomicin A1 potentiated [3H]ryanodine binding
      to HSR with a decrease in KD but without a change in Bmax. These results suggest
      that quinolidomicin A1-induced Ca2+ release from HSR is consisted of two
      components, which are both sensitive and insensitive to blockers of Ca2+ release
      channels, and that the former component is associated with the ryanodine
      receptor.

PMID- 8645737
TI  - Comparison of isotope exchange, H2 evolution, and H2 oxidation activities of
      Azotobacter vinelandii hydrogenase.
AB  - Azotobacter vinelandii hydrogenase was purified aerobically with a 35% yield. The
      purified enzyme catalyzed H2 oxidation at much greater velocity than H2
      evolution. There was a large difference in activation energy for the two
      reactions. EA was 10 kcal/mol for H2 oxidation and 22 kcal/mol for evolution.
      This difference in activation energies between the two reactions means that the
      ratio of oxidation velocity to evolution velocity drops from 70 at 33 degrees C
      to 8 at 48 degrees C. With D2 and H2O as substrates, both membranes and purified
      enzyme produced only H2 and no HD in the isotope exchange reaction. The velocity
      of isotope exchange was equal to the velocity of H2 evolution from reduced methyl
      viologen, indicating that the two reactions share the same rate-limiting step. D2
      and H2 inhibited H2 evolution, but D2 did not inhibit isotope exchange. We
      conclude that H2 and D2 do not inhibit H2 evolution by competing with H+ for the
      active site of the reduced enzyme. The Km for D2 in isotope exchange is 40-times
      greater than its Km in D2 oxidation. The difference in Km cannot be accounted for
      by differences in kcat. We propose that redox environment regulates hydrogenase's
      affinity for D2 (and likely H2 as well).

PMID- 8645738
TI  - Synergistic action of ADP and 2,3-bisphosphoglycerate on the modulation of
      cytosolic 5'-nucleotidase.
AB  - Cytosolic 5'-nucleotidase, acting preferentially on IMP, GMP and their
      deoxyderivatives, can also behave as a phosphotransferase, operating a transfer
      of phosphate from a nucleoside monophosphate donor to a nucleoside acceptor
      which, besides a natural nucleoside, can be also an analog. The enzyme activity
      is stimulated by ADP, ATP and 2,3-bisphosphoglycerate (BPG). The concentration of
      effector required to attain half maximal activation (A0.5) for the
      bisphosphorylated compound is in the millimolar range, so that BPG seems to act
      as a physiological activator of 5'-nucleotidase only in erythrocytes. However,
      the combination of BPG and ADP brings about a significant increase of their
      respective affinity for the enzyme, lowering their A0.5 values approx. 4-times.
      The observation that BPG favors the phosphotransferase more than the hydrolase
      activity of 5'-nucleotidase stands for a key role of this metabolite in the
      regulation of the processes of activation of purine pro-drugs, in which this
      enzyme is involved.

PMID- 8645739
TI  - The pressure-dependence of two beta-glucosidases with respect to their
      thermostability.
AB  - A comparative study of temperature and pressure effects were carried out by using
      two homologous enzymes exhibiting different thermostability and oligomery: almond
      beta-glucosidase and Sulfolobus solfataricus beta-glucosidase. Both the activity
      and stability were studied using an in-house built bioreactor allowing injection,
      stirring, sampling and on-line spectrophometric monitoring with retention of
      pressure up to 2.5 kbar and temperature control possible up to 150 degrees C.
      Almond beta-glucosidase, the most pressure sensitive enzyme of the two was
      continuously affected by pressure up to 1.5 kbar. Activation volume changes
      revealed that the inactivation of almond beta-glucosidase was due to both
      catalytic step inactivation and enzyme-substrate binding inactivation. Structural
      modifications generated by pressure, related to a loss of activity did not affect
      the global conformation of almond beta-glucosidase, after depressurization. In
      contrast, Sulfolobus solfataricus beta-glucosidase was a highly barostable
      enzyme. It maintained a half-life of 91 h at 60 degrees C and 2.5 kbar. Moreover,
      this enzyme appeared to be activated by pressure between atmospheric pressure and
      2.5 kbar with a maximal activity at 1.25 kbar. However, this enzyme still
      displayed the best catalytic efficiency at atmospheric pressure because of a Km
      value drastically increased by pressure. Activation volume changes indicated that
      the hydrolysis reaction catalysed by Sulfolobus solfataricus beta-glucosidase,
      was alternatively favoured and disfavoured by pressure due to the catalytic step
      activation or inactivation associated with the enzyme-substrate binding step
      being continuously inactivated by pressure.

PMID- 8645740
TI  - Rapid purification of a chloroplast nucleoside diphosphate kinase using CoA
      affinity chromatography.
AB  - An 18 kDa protein from spinach chloroplasts was purified in one step to
      homogeneity using CoA-affinity chromatography. Its N-terminal sequence was
      identical to spinach nucleoside diphosphate kinase II (NDPK II). The kinase was
      isolated as a approximately 100 kDa complex. Immunoblotting detected NDPKII in
      plastids from leaves, roots, seeds and male flowers. NDPK I, an isoform of NDPK
      II, was not found in chloroplast soluble extracts, whereas NDPK III was present.

PMID- 8645742
TI  - Storage of noncryopreserved periphered blood stem cells for transplantation.
AB  - Mobilized peripheral blood stem cells (PBSC) were collected in autologous plasma
      and acid-citrate-dextrose formula A (ACD-A) by leukaphereses using the CS3000
      cell separator (Baxter) and stored at 4 degrees C in a refrigerator for 8 days.
      We have looked at the viability of the nucleated cells with the trypan blue test
      and the proliferation and differentiation capacity using a standardized
      progenitor cell cloning assay. The changes in viability, granulocyte-macrophage
      colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed
      lineage colony-forming units (CFU-GEMM) were determined daily during the storage
      period. Viability was 90.8% (SD 8%) at day 0 and declined to a mean of 69.5% (SD
      15.5%) at day 8. CFU-GM decreased to 47% (SD 28.7%), CFU-GEMM to 48% (SD 42.2%),
      and BFU-E to 40.1% (SD 18.4%) after 6 days. After 5 days of storage the mean
      viability was 79.7% (SD 17.8%), whereas the mean CFU-GM were 65.3% (SD 28.4%) the
      mean CFU-GEMM were 61.8% (SD 30.4%) and the mean BFU-E were 55.1% (SD 18.2%). At
      day 4 viability was still 82.5% (SD 17.0%), recovery of CFU-GM was 78.5% (SD
      28.8%), recovery of CFU-GEMM was 70.7% (SD 40.4%) and recovery of BFU-E was 65.0%
      (SD 17.5%). These data show, that PBSC can be stored safely over at least 5 days
      at 4 degrees C while the patient receives high-dose chemotherapy.

PMID- 8645741
TI  - Cytogenetic findings in 175 patients indicate that items of the Kiel
      classification should not be disregarded in the REAL classification of lymphoid
      neoplasms.
AB  - Cytogenetics have proved to be a valuable tool for classifying systemic lymphatic
      neoplasms, as this technique allows different stem line aberrations and clonal
      developments to be distinguished. This study was designed to analyze how far
      groups defined according to common cytogenetic features correlated with their
      position in either the Kiel (KC) or the REAL classification. Cytogenetic analyses
      were performed on material from 175 patients with lymphoid neoplasms (LN).
      Samples were prepared from peripheral blood and bone marrow in acute
      lymphoblastic leukemia (ALL), from bone marrow in multiple myeloma (MM), and from
      lymph node biopsies in lymphomas. The results of this study support the inclusion
      of ALL, MM, and extranodal lymphomas into a comprehensive classification, because
      their chromosomal aberrations were always characteristic for LN. From the
      cytogenetic point of view, a subgroup of ALL appears as a leukemic manifestation
      of lymphoblastic lymphoma. MM have structural aberrations of chromosomes 1, 11,
      and 14 and secondary aberrations of chromosomes 3, 6, 7, 12, 13, and 18, all of
      which are characteristic for lymphatic disease. The groups with follicle center
      cell lymphoma and mantle cell lymphoma correlate well with our results both in
      the low-grade subtype and in the blastic variant type, the majority of cases
      demonstrating t(14; 18) and its variants and t(11; 14), respectively. In
      contrast, the group of diffuse large B-cell (DLB) lymphomas proved to be
      heterogeneous on the basis of our cytogenetic results. Accordingly, we would
      suggest keeping the immunoblastic lymphoma (IB) subtype defined by the KC. IB
      demonstrates no stem line aberration in common with any other group and seems to
      be characterized by stem line aberrations involving chromosomes 3 and 6. As some
      DLB lymphomas have a t(14;18) or variant translocations involving chromosome 18,
      they should either be separated as a subgroup or included into the group of
      follicle center lymphomas.

PMID- 8645744
TI  - Development of plasma cell tumors during treatment of multiple myeloma.
AB  - Plasma cell tumors (plasmacytomas-PCT) of the bone, or extramedullary PCT, may be
      diagnosed in patients with or without the diagnostic criteria for systemic
      multiple myeloma (MM). The reason for the local development of these tumors is
      not clear. Recent reports emphasize the contribution of CT and MRI in the
      detection of bone lesions and their expansion into the soft tissues. We report
      the development of PCT in nine patients with MM under maintenance treatment with
      alpha-IFN, of whom six had no evidence of systemic relapse and three had
      indications of early relapse. The PCT were located in the pelvis (4), thoracic
      (3), cervical (1), and lumbar (2) spine and in 8/9 cases were not demonstrable on
      plain X-rays. These observations suggest that frequent screening with advanced
      imaging techniques may detect local disease expansion in asymptomatic patients.
      Early application of radiochemotherapy may improve prognosis.

PMID- 8645743
TI  - LW/SO cell line: a tool for studying the phenotypical characterization and
      commitment of hematopoietic stem cells.
AB  - We report our observations with the cell line LW/SO, which was recently derived
      from the bone marrow of a patient with acute myeloid leukemia. Based on the
      morphological and histochemical examination, the leukemic cells were classified
      primarily as FAB type M4. However, 2 years later, in relapse, the cells changed
      their morphology and were hence specified as FAB type M2 (slightly positive for
      acid phosphatase and Sudan black). The cells established have now been in culture
      for approximately 11 months and display nearly 100% CD4/5/7/15/25/71/120a,b at
      varying densities. Some of them spontaneously and reversibly become either CD34 +
      /38- or CD34 - /38+, yet the majority of the cells remain negative for both. All
      attempts to separate the cells with a distinct phenotype by limiting dilution or
      sorting through a flow cytometer failed repeatedly. The subsets, enriched up to
      98% (regardless of their primary immunophenotype CD34 - / 38-, CD34 + /38-, or
      CD34 - /38+), soon displayed a phenotypical constellation similar to that before
      sorting. The ratio of CD34- to CD34+ seems to be influenced by the cell density:
      The greater the cell-to-cell contact, the lower the percentage of CD34-expressing
      cells. Some of the cells apparently differentiate into T-cell phenotype and
      acquire CD3 and T-cell receptor (TCR) alpha/beta molecules. While the quantity of
      CD34-expressing cells significantly increased in the presence of dexamethasone
      (10(-7) M), and some of them additionally acquired CD33 antigen, the percentage
      of CD3-positive cells was enhanced by adding 1% DMSO in medium. In contrast,
      cytokines such as IL-1, IL-2, IL-3, IL-4, IL-6, G-CSF, GM-CSF, or SCF (c-kit
      ligand) altered neither the proliferation capacity nor the phenotypical
      constellation of LW/SO cells (each tested alone). Although normal karyotype was
      obtained from the bone marrow cells, the LW/SO cells revealed a homogeneous
      chromosomal composition of 45, X, -X, der(9) inv(9) (p12q13) del(9) (p22?). These
      data suggested that LW/SO cells might be the leukemic counterpart of putative pre
      CD34-positive progenitors. In order to substantiate this assumption, we analyzed
      the expression of other so-called T-cell markers on CD34+ cells from peripheral
      blood stem cell aphereses of five patients who later underwent high-dose
      chemotherapy and subsequent stem cell retransfusion. These data clearly revealed
      that a considerable amount of CD34+ hematopoietic progenitors co-express
      CD2/4/(5)/(7)/25 at an early stage of differentiation, and support the notion
      that CD34-negative LW/SO cells with the surface markers CD4/5/7/25 are probably
      phenotypical representatives of pluripotent stem cell. Hence, not all CD34
      negative populations with so-called T-cell surface markers should be considered T
      cells; some may constitute the ancestor of CD34 antigen-expressing progenitors.

PMID- 8645746
TI  - Intensive induction and consolidation chemotherapy in a young woman with acute
      myeloid leukemia and severe chronic renal failure.

PMID- 8645747
TI  - Reversible metastatic pulmonary calcification in a patient with multiple myeloma.
AB  - A-52-year-old patient presented with a 2-year history of multiple myeloma,
      recurrent episodes of hypercalcemia, and extensive bone involvement. She
      developed pulmonary infiltrates, initially misdiagnosed as interstitial
      pneumonia. High-resolution computed tomography and bone scintiscanning indicated
      pulmonary calcification, which was confirmed by a transbronchial biopsy.
      Cytostatic treatment of multiple myeloma in combination with repetitive i.v.
      administration of bisphosphonates over a period of 6 months led to a significant
      improvement of clinical symptoms. Regression of pulmonary infiltrates was
      demonstrated by chest radiograph and computed tomography. There are only a few
      reports on pulmonary calcification in patients with multiple myeloma; the
      condition was associated mostly with progressive disease, kidney failure, adult
      respiratory distress syndrome and bad prognosis. In our patient isolated
      calcification of the lungs without involvement of other organ systems was
      successfully treated. These findings suggest that interstitial pulmonary
      calcinosis in multiple myeloma can be reversed by normalization of serum calcium
      levels using bisphosphonates combined with cytostatic treatment.

PMID- 8645745
TI  - Antibodies to factor VIII in plasma of patients with hemophilia A and normal
      subjects.
AB  - Non-neutralizing factor VIII (FVIII) antibodies (FVIII-Ab) in hemophilia A may be
      associated with an abnormal clinical response to FVIII concentrates. Patients
      with FVIII inhibitors may develop noncoagulation FVIII-Ab after the induction of
      immunotolerance. Natural FVIII-Ab may be detected in the plasma of some healthy
      subjects. The aim of this study was to analyze the presence of FVIII-Ab in the
      plasma of 53 normal blood donors and 124 patients with hemophilia A (18 patients
      had a previous history of FVIII inhibitor, but only 12 had inhibitor at the
      moment this study was performed). FVIIII inhibitor was measured using the
      Bethesda method. FVIII-Ab were analyzed by a specific ELISA assay using purified
      FVIII from a monoclonal concentrate and a standard plasma containing 26 Bethesda
      units (BU) of FVIII inhibitor. Purified FVIII was used to coat wells of a
      microtiter plate and was incubated with dilutions of plasma to be tested. Bound
      human IgG FVIII-Ab were detected by incubation with polyclonal sheep anti.human
      IgG alkaline phosphatase conjugate, and the OD405 was quantitated. A linear fit
      was obtained (by plotting FVIII-Ab positivity [OD 405nm] versus BU titer) when
      serial dilutions of this standard inhibitor plasma, containing titers of 0.5 BU
      or higher, were used. Four different levels of FVIII-Ab positivity [OD 405nm]
      were distinguished in this assay: Negative levels (-) were obtained with
      dilutions of the standard inhibitor containing < 0.5 BU. Mild levels (+) were
      obtained with dilutions of 0.5-5 BU. Moderate levels (+2) were obtained for
      dilutions ranging from 5-25 BU. Maximum positivity (+3) was obtained for
      dilutions of titers > 25 BU. FVIII-Ab positivity was detected in eight of the
      normal subjects (15%): three were found to be moderately positive (+2) and five
      mildly positive (+). No inhibitory activity was detectable when whole plasma was
      used. All the hemophilic patients with a presence of FVIII inhibitor at the time
      of the study were found to be positive for FVIII-Ab. In addition, the level of
      positivity correlated with the corresponding BU. Four of the six patients who had
      a history of inhibitory were negative and two positive. Twenty additional
      patients (16.12%) in whom no inhibitory activity was detected were found to be
      positive for FVIII-Ab: 16 + and four +2. The mean age of patients with FVII-Ab
      positivity was significantly higher than that of patients of the FVIII-Ab
      negative group (p < 0.005). In conclusion, FVIII-Ab positivity in patients with
      hemophilia A was 17.7% higher than the level of positivity detected by an
      inhibitory assay. We propose that this method for FVIII-Ab analysis could be used
      for patients with hemophilia A, at least to complement the functional inhibitor
      assay. FVIII recovery or half-life should be assessed in patients who test
      positive for FVIII-Ab and who show no evidence of inhibitor.

PMID- 8645748
TI  - Miliary tuberculosis in a patient with Epstein-Barr virus-associated
      angioimmunoblastic lymphadenopathy.
AB  - A 74-year-old woman developed angioimmunoblastic lymphadenopathy (AILD) with
      involvement of intra-abdominal and retroperitoneal lymph nodes. Southern blot
      analysis showed germline configuration of the JH genes and an oligoclonal pattern
      of the TcR beta genes. The immunoblasts were of B-cell phenotype and often
      expressed the CD30 antigen and the latent membrane protein 1 (LMP1) oncogene. Six
      nonsilent point mutations were identified near the 3' end of the LMP1 gene,
      leading to a cluster of six amino acid changes within a protein domain needed for
      maximal NF-kappa B stimulation. After a clinical remission of 8 months the
      patient relapsed with generalized lymphadenopathy and died secondary to
      tuberculosis. The oligoclonal rearrangements of the TcR beta genes may reflect an
      unsuccessful cellular immune response to Mycobacterium tuberculosis or an HLA
      restricted T-cell response to B-immunoblasts expressing mutated viral antigens. A
      positive percutaneous tuberculin test observed 6 months prior to the onset of
      AILD is in favor of the first possibility.

PMID- 8645749
TI  - Transformation of severe aplastic anemia into acute myeloblastic leukemia with
      monosomy 7.
AB  - A cytogenetically normal man with severe aplastic anemia was treated with
      granulocyte colonystimulating factor (G-CSF), erythropoietin (EPO), cyclosporin
      A, anti-thymocyte globulin, and interleukin-6 (IL-6), which resulted in a gradual
      improvement in his neutrophil count and hemoglobin level. After 2 years of the
      therapy, monosomy 7 was detected during cytogenetic analysis of his bone marrow,
      which evolved during a period of 5 months into acute myeloblastic leukemia. An in
      vitro proliferation assay of cytokine responses showed that leukemic blasts were
      sensitive only to G-CSF, and not to EPO or IL-6. Although allogeneic bone marrow
      transplantation from an HLA-matched unrelated donor was carried out in the non
      remission stage, the patient died of systemic fungal infection on day 25, without
      any evidence of hematological engraftment. As long-term use of cytokines and
      immunomo-suppressants in patients with severe aplastic anemia may induce or
      hasten the onset of a malignant transformation, careful attention must be paid to
      clonal evolution. Due to the poor prognosis of secondary myelodysplasia and
      leukemia, allogeneic bone marrow transplantation for such patients must be
      carried out early in the course of the disease.

PMID- 8645750
TI  - Detection of sheep-associated malignant catarrhal fever virus antibodies by
      complement fixation tests.
AB  - Some serological diagnosis methods and examinations for detection of antibodies
      to sheep-associated malignant catarrhal fever (MCF) infection were investigated.
      The wildebeest-associated MCF virus strain WC11 propagated on fetal bovine
      thyroid cell cultures was used as an antigen. Antibodies were detected by
      complement fixation (CF) tests in cattle pathologically diagnosed as having sheep
      associated MCF, as well as in cattle experimentally infected with MCF virus
      strain WC11. However, immunodiffusion precipitation was only detected in cattle
      infected with MCF virus strain WC11. The results of serological investigation by
      CF tests indicated that 64.3% of sheep possessed antibodies to MCF virus in the
      Hokkaido district of Japan and all serum samples which contained CF antibody
      titers greater than 1:4 had antibody titers larger than 1:8 in indirect
      immunofluorescence tests. The CF test we demonstrated here is available to
      quantitatively detect MCF virus antibody titers in epidemiological surveys.

PMID- 8645751
TI  - Development of the Bowman's and Jacobson's glands in the Japanese reddish frog,
      Rana japonica.
AB  - The olfactory organs are equipped with their own associated glands, Bowman's
      glands (BG) of the olfactory epithelium (OE), and Jacobson's glands (JG) of the
      vomeronasal organ (VNO). Histology and ultrastructure of these glands in the
      adult were investigated in the Japanese reddish frog, Rana japonica, along with
      their development from hatching to the end of metamorphosis. In the adult, BG
      cells contained large, electron-opaque secretory granules, intensely PAS-positive
      by light microscopy, while JG cells contained middle-sized secretory granules
      with moderate electron density, only faintly PAS-positive. Embryologically, BG
      appeared within the OE at 44 days after hatch, increased in number and were
      situated in the lamina propria under the OE at 52 days after hatch. BG cells
      contained large, electron-opaque granules, and well-developed rER at this time.
      While, JG appeared much earlier than BG. The VNO appeared as a concave of the
      ventral part of the OE at 4 days after hatch, and JG appeared under the VNO at 10
      days after hatch. JG cells contained well-developed rER at 12 days after hatch.
      Secretory granules appeared in a small number in JG at 24 days after hatch, and
      increased thereafter. These findings suggest that JG may take part in secretion
      earlier than BG in ontogeny.

PMID- 8645752
TI  - Cytopathic effect inhibition assay for canine interferon activity.
AB  - Conditions for cytopathic effect (CPE) inhibition assay of canine interferon
      (IFN) activity in Madin-Darby canine kidney (MDCK) cells and in canine tumor cell
      line A72 was investigated using the New Jersey strain of vesicular stomatitis
      virus (VSV). The culture supernatant from canine splenocytes stimulated with
      ultraviolet-irradiated Newcastle disease viruses was used as reference IFN. MDCK
      cells were resistant for growth of VSV when the cells were confluent. Full CPE
      was observed only in a sparsely growing culture. Canine IFN activity could be
      assayed on less than 10(4) MDCK cells/well of a 96-well microplate, and more than
      10(5) TCID50/ml of VSV was required. In A72 cells, VSV growth was not as
      dependent on cell density as in MDCK cells, requiring 10(3) TCID50/ml of VSV.
      MDCK-VSV system showed a higher IFN sensitivity than A72-VSV, whereas
      reproducibility was higher for the latter than the former. Based on these
      findings, A72-VSV system for canine IFN assay is recommended for practical use
      due to its easy handling characteristics.

PMID- 8645753
TI  - Ultrastructural and morphometrical studies on the endothelial cells of arteries
      supplying the abdomino-inguinal mammary gland of rats during the reproductive
      cycle.
AB  - The ultrastructure of the endothelial cells of the deep circumflex iliac and
      caudal superficial epigastric arteries supplying the abdomino-inguinal mammary
      gland of female Wistar rats was studied throughout the reproductive cycle with an
      electron microscope and image analyzer and compared with that of mammary gland
      capillaries. The subendothelial space of the arteries was broader at the virgin
      and post-weaning stages but narrower in pregnancy and lactation. In some rats,
      the endothelial cells of the arteries radiated some blunt processes into the
      media through fenestrations in the internal elastic lamina. The density of
      pinocytotic vesicles (PV) in the arteries (number of PV per micron2 of
      endothelial cytoplasm) significantly increased during pregnancy and reached its
      maximum value during lactation, then subsequently decreased during the post
      weaning stage. The mammary gland capillaries showed the maximum changes of PV
      during pregnancy and lactation, with twofold and fourfold increases during the
      respective periods. The density of mitochondria increased significantly in the
      capillaries during pregnancy and lactation. The length of the marginal folds and
      microvillous processes increased significantly during lactation in both the
      arteries and capillaries, and especially, increased twofold in the mammary gland
      capillaries. It is assumed that the ultrastructural changes of the endothelial
      cells of the arteries and capillaries are closely associated during reproductive
      cycle with the functional demand of the mammary glands.

PMID- 8645754
TI  - Spontaneous vascular mineralization in the brain of horses.
AB  - Cerebral vascular mineralization was found in 12 (60%) of 20 3- to 10-year-old
      healthy horses collected at an abattoir. It was variable in degree and occurred
      mostly in the pallidal arteries showing two types of lesions; small globoid
      bodies along capillaries, and amorphous deposits in the wall of arterioles, small
      or medium-sized arteries and veins. Both types were strongly positive for
      periodic acid-Schiff reaction, and weakly positive for von Kossa's and Berlin
      blue stains. Elemental analysis of the deposit revealed the presence of large
      amounts of aluminum, moderate amounts of phosphorus, zinc, calcium and iron, and
      a small amount of sodium.

PMID- 8645755
TI  - Longitudinal distribution of pulmonary vascular compliance in dogs.
AB  - The longitudinal distribution of pulmonary vascular compliance was evaluated in
      isolated canine lung lobes using arterial-(AO), venous-(VO), and double-occlusion
      (DO) techniques. Total vascular compliance (Ctau) was separated into pulmonary
      arterial (Ca) and venous compliance (Cv) in lumped model of pulmonary
      circulation. Under constant pulmonary venous pressure (Pv) at 5 mmHg, blood
      inflow to the lobe (Q) was gradually increased by changing pulmonary arterial
      pressure (Pa) from 10 to 22 mmHg at 4 mmHg ranges. Changes in vascular blood
      volume (deltaV) with each increment in Q were determined by decreased reservoir
      blood volume of perfusion system. DO was performed at each level of Q and
      allowing all vascular pressures to equilibrate at the same static pressure (Ps),
      which was equal to the compliance-weighted average pressure in the circulation.
      Ctau was obtained from the slope of the relationship between Ps and deltaV. When
      Pa and Pv were 14 and 5 mmHg, AO, VO, and DO were performed to measure pressures
      at Ca (Pca) and Cv (Pcv) and Ps. The arterial-to-venous compliance ratio (Ca/Cv)
      was evaluated using Pca, Pcv, and Ps measurements. Ctau was 0.113 +/- 0.012
      ml/kg/mmHg. Ca/Cv was 0.30. Ca and Cv were 0.026 +/- 0.013 and 0.087 +/- 0.007
      ml/kg/mmHg, respectively. These data demonstrated the usefulness of AO, VO, and
      DO techniques in evaluating the longitudinal distribution of compliance in canine
      pulmonary vasculature.

PMID- 8645756
TI  - Purification and characterization of cell growth factor in bovine colostrum.
AB  - Bovine colostrum has growth factor activity for stimulating DNA synthesis in calf
      kidney epithelial cells (CKT-1), Madincanine kidney epithelial cells (MDCK) and
      rat L6 myoblasts (L6), of which the DNA stimulation level and the activity change
      with the time elapsed after the birth of a calf varied with their respective
      cells. The growth factor activity of colostrum for CKT-1 was stable regardless of
      the collection time of colostrum, and it was purified about 3,650-fold in an
      overall yield of 1.2% from colostrum obtained 30 min after the birth of a calf.
      The purified growth factor had a molecular weight (MW) of 5,000 and an
      isoelectric point of pH 9.7, and the amino acid composition was: Asx5, Thr2,
      Ser4, Glx14, Pro2, Gly4, Ala4, Val2, Ile, Leu2, Tyr, Phe, Lys, His and Arg. The
      stimulated DNA synthesis in CKT-1 and L6 by the addition of purified growth
      factor at a final concentration of 16ng/ml was as the same extent as calf serum
      at a final concentration of 1.52 mg/ml, and the relative activity for CKT-1 was
      even greater than that for L6.

PMID- 8645757
TI  - Effect of M-711 on experimental asthma in rats.
AB  - We experimentally demonstrated the anti-asthmatic effects of M-711, the dry
      extract of a Chinese herb medicine called Mokuboi-to, using the rat model of
      allergic asthma. Allergic asthma was induced by the antigen-antibody reaction in
      the rats and they showed anaphylactic symptoms accompanied with hypotension and
      depression of respiratory function. More than 20 mg/kg body weight of M-711 was
      effective in relieving the asthmatic symptoms like methylephedrine. It could
      lessened the suppress of respiration and provided a good improvement. It also
      reduced a drop of the blood pressure and improved it quickly. Its ingredients
      alone were much less effective than M-711 as the total. Those data suggested that
      M-711 was effective for alleviating allergic asthma in the present study and that
      its action was provided by interaction of all ingredient raw herbs of M-711.

PMID- 8645758
TI  - Growth inhibitory effects of bovine lactoferrin to Toxoplasma gondii parasites in
      murine somatic cells.
AB  - Lactoferrin (LF) is known to have broad spectrum antimicrobial properties. In
      regards to its defense mechanism against parasitic infection, it has shown
      phagocytic activity in the destruction of amastigotes, an intracellular parasitic
      form of Trypanosoma cruzi in macrophages. The effect of bovine lactoferrin on the
      intracellular growth Toxoplasma gondii parasites was examined in murine
      macrophage and embryonal cells. Co-cultures of host cells with the parasites were
      supplemented with either lactoferrin, apo-lactoferrin, holo-lactoferrin or
      transferrin in the culture media for varying periods. The growth activity of
      intracellular parasites in the host cells was determined by the measurement of
      selective incorporation of 3H-uracil. Supplement of lactoferrin had no effect on
      the penetration activity of the parasites, while development of intracellular
      parasites was inhibited linearly in concentration of lactoferrin. Supplement of
      apo-lactoferrin and holo-lactoferrin, but not transferrin showed similar effects.
      These suggest that lactoferrin induces the inhibitory effects on the development
      of intracellular parasites. Pretreatment of lactoferrin to the macrophages,
      however, did not show any inhibitory effects. Whereas, mouse embryonal cells
      preincubated with lactoferrin suppressed the intracellular growth. Thus, the
      action of lactoferrin to macrophages would be different from that of mouse
      embryonal cells.

PMID- 8645759
TI  - Pathology of bovine abortion and newborn calf death caused by dual infection with
      Chlamydia psittaci and infectious bovine rhinotracheitis virus.
AB  - Nine aborted fetuses and one newborn calf, diagnosed as Chlamydia psittaci (C.
      psittaci) infection, were pathologically examined. The characteristic lesions in
      the liver were focal necrosis in 9 aborted fetuses and granulomatous necrotic
      foci in the newborn calf. Moderate numbers of intranuclear inclusion bodies were
      found in necrotic foci of the liver, spleen, thymus, lymph nodes, adrenal gland,
      kidney, lung and forestomach. Immunohistologically, a small number of C. psittaci
      antigens was demonstrated in necrotic foci of the liver and correlated with
      distribution of elementary bodies. Moderate numbers of infectious bovine
      rhinotracheitis (IBR) virus antigens were also detected in degenerating and
      necrotizing parenchymal cells in various organs and correlated with distribution
      of intranuclear inclusion bodies. Thus, these aborted bovine fetuses and newborn
      calf were interpreted as being dually infected with C. psittaci and IBR virus
      during pregnancy.

PMID- 8645760
TI  - Development of the olfactory epithelium and vomeronasal organ in the Japanese
      reddish frog, Rana japonica.
AB  - Histological and ultrastructural development of the olfactory epithelium (OE) and
      vomeronasal organ (VNO) was investigated in the Japanese reddish frog, Rana
      japonica. Tadpoles, from hatching to the end of metamorphosis, and adult frogs
      were examined. In the adult, olfactory cells of the OE were equipped with
      olfactory vesicles with long cilia, but supporting cells with microvilli. The
      supporting cells of the OE contained secretory granules, PAS-positive by light
      microscopy, in their apical cytoplasm. On the contrary, sensory cells of the VNO
      were equipped with microvilli, and supporting cells of the VNO were equipped with
      cilia, but without secretory granules. Embryologically, the olfactory cells were
      indistinguishable from the supporting cells in the olfactory placode (primitive
      OE) lining the nasal pit, at hatch. The VNO appeared as a concave of the ventral
      part of the OE at 4 days after hatch. At the time, the olfactory and supporting
      cells of the OE became distinguishable from each other. Secretory granules were
      formed in the supporting cells of the OE at 36 days after hatch, and the OE was
      similar in fine structure to that in the adult. While, the VNO remained immature
      at 24-36 days after hatch, and did not complete its ultrastructural development
      at 60 days after hatch, the end of metamorphosis. These findings suggest that the
      OE may take part in the olfaction earlier than the VNO in ontogeny.

PMID- 8645761
TI  - Western blotting using recombinant Hantaan virus nucleocapsid protein expressed
      in silkworm as a serological confirmation of hantavirus infection in human sera.
AB  - Recombinant Hantaan virus nucleocapsid protein expressed in silkworm larvae was
      applied as a serological diagnostic antigen in Western blots (WB) of human sera.
      The sensitivity of this method was similar to that of the IFA test. Hemorrhagic
      fever with renal syndrome (HFRS) and nephropathia epidemica diagnosed by their
      cross-reactivity in WB. The specificity of this method was higher than that of
      IFA test because the background was low. Sera that exhibited high background
      staining in the IFA test were readily diagnosed with this method. We recommended
      WB using recombinant Hantaan virus nucleocapsid antigen as a confirmatory
      procedure for the serodiagnosis of hantavirus.

PMID- 8645762
TI  - Effects of vitamin D3 injection on activity of thyroid parafollicular cells in
      pregnant rats.
AB  - Effects of vitamin D3 (VD3) injection on the activity of thyroid parafollicular
      cells (C cells) and calcium (Ca) metabolism were examined in rats of non-(NP),
      middle (MP) and late pregnancy (LP). At 3 days after injection, the average area
      of a C cell was significantly wider (P<0.01) in the VD3 groups than that in their
      control groups in NP, MP, and LP. On the otherhand, the plasma ca concentration
      in the VD3 groups decreased significantly (P<0.05) in comparison with that in
      their control groups in NP and LP, and tended to decrease in MP. These results
      suggest that injection of VD3 may accelerate the activity of C cells, which may
      result in the decrease of plasma Ca concentration in both non-pregnant and
      pregnant rats.

PMID- 8645763
TI  - Recent characterization of Salmonella strains isolated from chickens in Zambia.
AB  - Among the 23 Salmonella strains isolated from 21 diseased chicken and 2
      embryonated eggs in 6 poultry farms near Lusaka City in Zambia, serovars
      identified were S. Gallinarum (11 strains), S. Agona (7 strains), S. Alamo (1
      strain), S. Infantis (1 strain), S. Virginia (1 strain), S. Haifa (1 strain), and
      S. Dublin (1 strain). S Gallinarum was detected at the highest incidence and from
      all the poultry farms. Fourteen serovars have been reported for the chickens in
      Zambia so far. Three serovars (S. Alamo, S. Haifa, S. Virginia) were newly
      identified in this study.

PMID- 8645764
TI  - Dystrophy of the diaphragmatic muscles in Holstein-Friesian steers.
AB  - Diaphragmatic muscles in two slaughtered Holstein-Friesian revealed slightly pale
      color, swelling, and stiffness on palpation. Histologically the muscle fibers
      showed internal nuclei, fiber-splitting, variation in diameter, central core-like
      structures, sarcoplasmic masses, and vacuolar degeneration. These lesions were
      the same as those in dystrophy of the diaphragmatic muscles in Holstein-Friesian
      cows. It was demonstrated that muscular dystrophy of the diaphragm in Holstein
      Friesian cattle occurred also in males, probably by inheriting an autosomal
      recessive trait.

PMID- 8645765
TI  - Isolation of Bartonella henselae from domestic cats in Japan.
AB  - During the period from January to March 1995, the authors first isolated
      Bartonella henselae from the blood of three (9.1%) of 33 domestic cats in Japan.
      The three cats were a 1.5-year male pet cat-old with urinary retention, and 6
      year-old female pound and age-unknown female pet cats with no abnormalities. The
      blood was taken in a lysis-centrifugation tube (Wampole Isolator tube) and
      cultured on 5% rabbit-blood heart infusion agar plates at 35 degrees C in the 5%
      CO2 atmosphere. Visible tiny rough colonies developed 14 days after incubation.
      The isolates showed Gram-negative and pleomorphic rods in microscopic
      observation. The DNA extracted from the isolates was amplified by PCR using two
      primers, which were specific for the rikettsial citrate synthase gene. The
      isolates were identified as B. henselae from the patterns of digestion with TaqI
      and HhaI of the amplified gene. It was confirmed that cats in Japan harbored B.
      henselae in their blood, and that cats play a significant role as the reservoir
      of the organism.

PMID- 8645766
TI  - Phagocytosis of splenetic neutrophils of mice enhanced by orally administered
      peptidoglycan from Bifidobacterium thermophilum.
AB  - A preparation of peptidoglycan (PG) of swine Bifidobacterium thermophilum was
      orally administered to SPF-BALB/C and ICR mice and its effect on phagocytosis
      splenetic neutrophils from PG administered mice was measured by chemiluminescent
      response (CL) and fluorometric analysis and the result was compared with that of
      non-treated mice. PG stimulated phagocytosis of neutrophils in a dose-dependent
      manner, whereas dosage exceeding the optimum concentration (500 microgram)
      inhibited phagocytosis. The maximum effect on phagocytosis of neutrophils was
      observed at 3 days after administration of PG 500 microgram. The result of
      fluorometric analysis was almost similar to that of CL. These results indicate
      that orally administered PG enhances the activity of the phagocytosis of
      splenetic neutrophils from mice.

PMID- 8645767
TI  - Growth ability and immunological properties of Erysipelothrix rhusiopathiae
      serotype 2.
AB  - Five field strains of Erysipelothrix rhusiopathiae belonging to serotype 2 were
      compared for their growth ability, immunogenicity in mice, SDS-PAGE profile of
      cell surface proteins and their immunoblotting patterns. Strain Tama-96 showed
      the most stable growth in Feist medium and tryptose phosphate broth with Tween 80
      (TPB), and its immunogenicity was highest in a mouse protection test using the
      inactivated vaccines prepared from 20-h TPB culture. The 50% mouse protective
      dose of the vaccine was only 12 microliter. SDS-PAGE and immunoblotting patterns
      of the proteins were similar among the strains in general and indicated that 66
      to 64 kDa protein antigens were dominant.

PMID- 8645768
TI  - Advances in brain metabolism research: toward a moving picture of neural
      activity.

PMID- 8645769
TI  - Cognitive and motor impairments are related to gray matter volume deficits in
      schizophrenia.
AB  - This study examined whether the neuropsychological deficits observed in patients
      with schizophrenia were related to cortical gray matter volume deficits in these
      patients. All subjects were men and included 34 patients with DSM-III-R
      Schizophrenia and 47 age-matched healthy controls. Subjects received a battery of
      21 tests, assessing four different functional domains: executive functions, short
      term memory and production, declarative memory, and motor ability. MRI volumes
      were corrected for normal variation in head size and age, and neuropsychological
      test scores were corrected for normal variation in age. The schizophrenic group
      had significantly smaller cortical gray matter volumes (p < .05) and lower test
      scores in all functional domain than the control group (p = .0001). Within the
      schizophrenic group, lower scores in each domain were significantly correlated
      with smaller total cortical gray matter volumes; however, no predictable
      relationships were observed between neuropsychological test performance and the
      volumes of specific cortical regions.

PMID- 8645770
TI  - Impaired motor skill learning in schizophrenia: implications for corticostriatal
      dysfunction.
AB  - We assessed skill learning in young and older schizophrenic patients using the
      rotary pursuit task. Schizophrenic patients displayed impaired learning on this
      task compared with normal control subjects, but older patients were not more
      impaired than young ones. The patients' rotary pursuit learning was not
      correlated to the severity of abnormal movements or to their treatment with
      medication, but it was associated to conceptual abilities assessed on the
      Dementia Rating Scale (Mattis 1988). An impairment in acquiring motor procedures
      in this task might reflect neuropsychological deficits associated with
      corticostriatal pathology.

PMID- 8645771
TI  - Gender differences in neuroleptic nonresponsive clozapine-treated schizophrenics.
AB  - Gender differences in neuroleptic-refractory chronic schizophrenic disorder
      patients were examined to determine whether a superior or equivalent
      antipsychotic response in women vs. men existed similar to that of the general
      schizophrenic population. Sixty-nine DSM-III schizophrenic patients (47 males and
      22 females) were treated with clozapine using a standardized medication regime.
      The gender differences in these neuroleptic-nonresponsive chronic schizophrenic
      disorder patients differed from those previously observed in the general
      schizophrenic population in that an equivalent antipsychotic treatment response
      in females versus males was not found. These treatment-refractory women appear to
      be a severely ill subgroup of female schizophrenics with distinct onset of
      illness, course and treatment response characteristics.

PMID- 8645772
TI  - Autonomic characteristics of generalized anxiety disorder and worry.
AB  - Autonomic characteristics of generalized anxiety disorder (GAD) and worry were
      examined using measures of heart period variability. The cardiorespiratory
      responses of 34 GAD clients and 32 nonanxious control subjects were recorded
      during resting baseline, relaxation, and worry periods. Results indicated
      differences between GAD subjects and controls as well as among baseline,
      relaxation, and worry periods. GAD clients exhibited shorter cardiac interbeat
      intervals (IBIs) and lower high frequency spectral power across all task
      conditions. Relative to baseline and relaxation conditions, worry was associated
      with (1) shorter IBIs, (2) smaller mean successive differences (MSD) of the
      cardiac IBIs, and (3) lower high frequency spectral power. These findings suggest
      that GAD and its cardinal feature (worry), are associated with lower cardiac
      vagal control. The findings of the present study provide evidence for the utility
      of further exploration of the role of autonomic nervous system activity in GAD.

PMID- 8645773
TI  - Corticotropin-releasing hormone challenge in prepubertal major depression.
AB  - This study investigates cortisol and ACTH (corticotropin) responses to an
      infusion of human CRH (corticotropin-releasing hormone) in prepubertal children
      with major depressive disorder (MDD). Following a period of 24 hours of
      adaptation to the laboratory environment with an intravenous catheter in place,
      34 children with MDD and 22 healthy controls received 1 microgram/kg of human CRH
      at 5:00 PM. Blood samples for cortisol and ACTH were measured at baseline and
      post-CRH. Overall, there were no significant differences between the MDD and the
      normal controls in baseline or post CRH stimulation values of either cortisol or
      ACTH. Melancholic (n = 4) patients had significantly higher baseline cortisol
      levels than nonmelancholic (n = 24) patients. Compared with the outpatients and
      the nonmelancholics, the inpatients (n = 10) and the melancholics showed
      significantly lower total ACTH secretion (effect size: 0.9 and 1.4, respectively)
      after CRH infusion. These results are consistent with a broad literature
      suggesting that the HPA axis abnormalities occur less frequently in early-onset
      depression than reported in adult studies. The pattern of results in the
      subgroups of inpatients and in melancholic children, however, raise questions
      about possible continuities with adult studies.

PMID- 8645775
TI  - Prolactin and cortisol responses to fenfluramine challenge in mania.
AB  - Prolactin and cortisol responses to fenfluramine (60 mg PO) challenge were
      examined in 20 subjects (10 manic patients and 10 age- and gender-matched healthy
      controls) to ascertain the "net" central serotonin (5-HT) activity in mania.
      There was no difference in baseline prolactin or cortisol levels between manic
      patients and healthy controls. Similarly, neither prolactin nor cortisol response
      to fenfluramine was different in manic patients compared to controls. There was
      also no correlation between severity of symptoms in manic patients and prolactin
      or cortisol response to fenfluramine challenge. The results do not support the
      possibility that net central 5-HT activity is altered in mania.

PMID- 8645774
TI  - Plasma GABA predicts acute response to divalproex in mania.
AB  - Bipolar I, manic phase inpatients were treated with divalproex sodium, lithium,
      or placebo in a previously reported parallel group multicenter, double-blind,
      randomized, controlled acute phase treatment trial. Plasma concentrations of
      gamma aminobutyric acid (GABA) were measured before and after treatment. Higher
      pretreatment plasma GABA levels were significantly (p = .04) related to a better
      clinical response to divalproex (n = 19). Pretreatment plasma GABA levels did not
      correlate with response to either lithium (n = 13) or placebo (n = 31). Following
      treatment with divalproex sodium, plasma GABA levels decreased significantly (p <
      .05), compared to placebo. Pretreatment plasma GABA levels were not related to
      overall severity of manic symptoms. Plasma GABA may predict response to
      pharmacologic agents acting on the GABA system.

PMID- 8645776
TI  - Developmental and genetic influences on the P50 sensory gating phenotype.
AB  - Evoked potentials to pairs of click stimuli were recorded from 127 subjects
      ranging in age from 10 to 39 years to examine the developmental course of
      auditory sensory gating. The ratio of the amplitude of the second response to
      that of the first provides a quantitative measure of auditory sensory gating.
      Contrary to earlier results, the distribution of P50 ratios was unchanged between
      children and younger adolescents (10-14 years), older adolescents (15-19 years),
      and adults (20-29 and 30-39 years). Included in the sample were 39 adolescent
      twins, allowing assessment for possible genetic effects underlying the P50
      sensory gating phenotype, by comparison of the similarity of the measure in
      monozygotic and same-sex dizygotic twin pairs. The monozygotic twins had
      significantly higher similarity for the P50 ratio within each twin pair than the
      dizygotic twins. These results are consistent with the presence of genetic
      influences on the P50 sensory gating phenotype.

PMID- 8645777
TI  - Symptoms in neuroleptic-naive, first-episode schizophrenia: response to
      risperidone.

PMID- 8645778
TI  - Cerebrospinal fluid monoamine metabolites and atmospheric pressure.

PMID- 8645779
TI  - The D2 dopamine receptor gene, addiction, and personality: clinical correlates in
      cocaine abusers.

PMID- 8645780
TI  - Closed head injury patients with mild cognitive complaints without neurological
      or psychiatric findings have abnormal visual P300 latencies.

PMID- 8645781
TI  - Psychosocial characteristics of psychiatric inpatients with reproductive losses.
AB  - Rising fertility rates among the severely and persistently mentally ill require a
      better understanding of the family planning needs of this population. In the
      present study, 82 women hospitalized for major psychiatric disorders were divided
      into three groups: abortion (n = 22), relinquishment (n = 28), and no children (n
      = 32). Statistical analyses of demographic, diagnostic, and birth control data
      showed that those who aborted or relinquished custody of their children were
      likely to come from ethnic minority populations and have a history of substance
      abuse. More than 70 percent of the women who had abortions reported sexual and/or
      physical assaults as either children or adults. Only 34 percent of all
      participants indicated that they used contraceptives. Increased awareness of
      reproductive histories and family planning needs of women with major psychiatric
      disorders is suggested.

PMID- 8645782
TI  - Obese children should be screened for hypercholesterolemia.
AB  - Screening only those with a positive family history misses many children with
      hypercholesterolemia. This study investigated whether sensitivity improved by
      adding obesity as a criterion when screening children for cholesterol. During a
      two-year period screenings were conducted on 506 inner-city subjects aged 5-19.
      Demographic, clinical, and dietary information was also recorded. Mean age of
      participants was 11 +/- 4 years; 52 percent were female, 53 percent black, 39
      percent Hispanic, and 8 percent other. Mean cholesterol level was 4.14 mmol/l
      (160 mg/dl). In multivariate analysis obesity was an independent risk factor for
      hypercholesterolemia, F = 13.14, p < 0.001. The sensitivity of obesity as a
      screening tool for hypercholesterolemia was better than that for positive family
      history (42 vs. 24 percent, respectively). Combining the two improved the
      sensitivity to 49 percent. The authors recommend expanding the indications for
      screening children to include obesity, in addition to positive family history of
      hypercholesterolemia or premature cardiovascular disease.

PMID- 8645783
TI  - Children first: the need to reform financing of health care services for
      children.
AB  - Many children in the United States live in poverty, lack health insurance, and
      receive inadequate health care. Current methods of financing health care fail to
      adequately provide for the needs of children. On the basis of the moral
      principles of beneficence and justice, adult members of society have a duty to
      assure that all children receive at least a basic level of health care. Any
      reorganized health care system should assure health care coverage for all
      children, health insurance plans must guarantee access and adequate coverage for
      important medical needs of children, and out-of-pocket expenditures must not
      discourage the use of effective health care for children.

PMID- 8645784
TI  - The impact of housing status on health care utilization among persons with HIV
      disease.
AB  - This study sought to identify the prevalence of unstable housing situations, and
      for whom they occurred, and to examine differences in health care utilization by
      housing status. Housing status and inpatient and outpatient health care
      utilization of 1,851 HIV-infected individuals was ascertained through interviews.
      Nine percent of respondents were in unstable housing situations. Unstable housing
      was associated with significantly lower functional status. The unstably housed
      were more likely to visit an emergency room (p < 0.05) and had fewer ambulatory
      visits than persons with stable housing (p < 0.03). They incurred nearly five
      more hospital days and their average hospitalization was approximately 1.5 days
      longer than the stably housed, although these differences were not significant.
      Utilization of ambulatory care is lower among unstably housed persons with HIV
      disease, which may have led to their increased reliance upon emergency rooms and
      hospitals. Helping HIV-infected individuals maintain adequate housing could
      reverse this pattern.

PMID- 8645785
TI  - Coping with the cost of prescription drugs.
AB  - African Americans have higher rates of nonprescription drug utilization than
      white Americans, but lower rates of prescription drug use. In light of this
      discrepancy, this study examines 281 lower income African American households in
      the rural South for access to prescription drugs and coping strategies when
      households cannot afford prescription drugs. About half of the households could
      not always afford needed prescriptions, and ability to pay was related positively
      to Medicaid coverage. Households that could not afford prescriptions employed
      five strategies: (1) prioritizing, (2) financing, (3) rationing, (4)
      substituting, and (5) postponing. Financing, postponing, and rationing were cited
      most frequently. The impact of culture and areas for future research are
      discussed.

PMID- 8645786
TI  - Mycobacterium kansasii bacteremia in patients infected with human
      immunodeficiency virus.
AB  - In a retrospective review of microbiology records at the George Washington
      University Hospital from 1980 through 1990, Mycobacterium kansasii bacteremia was
      identified in 10 patients; this finding represented 4.5% of nontuberculous
      mycobacterial blood cultures. M. kansasii was isolated from respiratory specimens
      from all 10 patients, and pulmonary parenchymal changes were noted in five
      patients. The median survival time was 14 weeks; however, only five patients
      received therapy with two or more drugs active against M. kansasii.

PMID- 8645787
TI  - Bartonella henselae endocarditis in an immunocompetent adult.
AB  - We describe a case of aggressive Bartonella henselae endocarditis in an
      immunocompetent man who owned a cat. Aortic valve replacement was required, and
      his infection was diagnosed by histology, serology, and polymerase chain reaction
      analysis. The manifestations of his disease included mediastinal lymphadenopathy,
      glomerulonephritis, myocarditis, and a petechial rash; the unusual finding of a
      positive titer of c-antineutrophil cytoplasmic antibodies was noted. Serological
      titers were markedly elevated for > 1 year despite clinical improvement.

PMID- 8645788
TI  - Effect of rifabutin on the pharmacokinetics of zidovudine in patients infected
      with human immunodeficiency virus.
AB  - We investigated the effects of rifabutin (300 mg daily administered for 7 or 14
      days) on the pharmacokinetics of zidovudine in nine patients who were infected
      with human immunodeficiency virus (HIV). Serial blood and urine samples were
      collected over a 6-hour period on each day that the pharmacokinetics of
      zidovudine were studied. Pharmacokinetic parameters were determined for
      zidovudine and its glucuronide metabolite and compared with use of analysis of
      variance (ANOVA) appropriate for a repeated-measures design. Except for a
      statistically significant decrease (28%) in the terminal half-life of zidovudine
      from 1.5 to 1.1 hours (P = .005) after coadministration of both agents for 14
      days, concurrent administration of rifabutin for 7 or 14 days had no
      statistically significant effects on zidovudine plasma and urine pharmacokinetic
      parameters (the difference among treatment means was < 25%). Treatment with
      rifabutin is unlikely to influence the effectiveness of treating HIV-infected
      patients with zidovudine because of any pharmacokinetic interaction between these
      drugs.

PMID- 8645789
TI  - Evaluation of the response of human humoral antibodies to Salmonella typhi
      lipopolysaccharide in an area of endemic typhoid fever.
AB  - Because of the limited value of Widal's test in the diagnosis of typhoid fever in
      areas of endemicity, individual serum levels of IgM, IgA, IgG, and IgG subclass
      antibodies to Salmonella typhi lipopolysaccharide were evaluated in samples
      collected in Egypt. The study involved 106 febrile patients, including 40
      patients for whom cultures were positive for S. typhi and 66 patients for whom
      diseases other than typhoid were diagnosed. Multivariate regression modeling
      revealed that detection of the combination of IgA, IgG, and IgG2 correlated best,
      although not perfectly (adjusted r(2) = 68), with a positive culture; the
      sensitivity and specificity of testing for IgA, IgG, and IgG2 (i.e., all three
      tests positive vs. all three tests negative) were 91.7% and 98.1%, respectively.
      These results suggested that testing for IgA, IgG, and IgG2 in combination is of
      diagnostic value for S. typhi infection.

PMID- 8645790
TI  - Infections in patients with chronic adult T-cell leukemia/lymphoma: case report
      and review.
AB  - Adult T-cell leukemia/lymphoma (ATLL) is caused by the human T-cell lymphotropic
      virus type I (HTLV-I). ATLL is classified into the smoldering, chronic, lymphoma,
      and acute subtypes. We describe a North American woman with chronic ATLL who
      presented with pneumonia caused by Pneumocystis carinii, Cryptococcus neoformans,
      Mycoplasma pneumoniae, and Mycobacterium avium complex. Although opportunistic
      infections have been documented in patients with ATLL, there are few case reports
      detailing infectious complications in patients with chronic ATLL.

PMID- 8645791
TI  - Direct sequence analysis of human herpesvirus 6 (HHV-6) sequences from infants
      and comparison of HHV-6 sequences from mother/infant pairs.
AB  - Direct sequence analysis of polymerase chain reaction-amplified DNA fragments
      from the large tegument protein (LTP) gene of human herpesvirus 6 (HHV-6) was
      performed with use of uncultured peripheral blood mononuclear cells (PBMCs) from
      four mother/infant pairs. In two cases, LTP gene sequences were identical in
      paired mother/infant specimens, thus suggesting that mother-to-infant
      transmission of HHV-6 may have occurred. The genetic stability of HHV-6 strains
      was confirmed by the fact that there was no difference between amplified DNA
      fragments from sequential PBMC samples from two of two infants analyzed. In
      contrast, a change in the amplified viral strain was detected in an infant who
      had reinfection with HHV-6 variant B (HHV-6B). Furthermore, HHV-6B strains
      concurrently amplified from saliva and PBMCs from an adult were found to be
      different. The data suggest that HHV-6 may be frequently transmitted from mother
      to-infant and that reinfection with HHV-6B may occur.

PMID- 8645792
TI  - Rheumatic pneumonia: reappearance of a previously recognized complication of
      acute rheumatic fever.
AB  - The clinical diagnosis of acute rheumatic fever (ARF) may be challenging;
      however, a constellation of signs including new valvular insufficiency,
      cardiomegaly, and heart failure should readily prompt consideration of the
      diagnosis of rheumatic carditis. In addition, pulmonary findings are compatible
      with ARF, as associated pulmonary involvement may represent rheumatic pneumonia.
      We report the case of a young man with ARF and rheumatic pneumonia, a previously
      described but rare complication of ARF.

PMID- 8645793
TI  - Meningococcal endocarditis presenting as cellulitis.
AB  - We report the case of a patient with mixed connective tissue disease who
      presented with two very unusual manifestations of meningococcal disease,
      cellulitis and endocarditis, concurrently. We also review the literature
      concerning Neisseria meningitidis as a causative agent of cellulitis or
      endocarditis. While meningococcal endocarditis or cellulitis is very rare,
      autoimmune disease predisposes patients to meningococcal infection. Therefore,
      unusual infections with this organism should be considered in the differential
      diagnosis of fever and rash in patients with connective tissue diseases.

PMID- 8645794
TI  - Prospective comparison of methods for the early prediction of treatment failure
      in patients with falciparum malaria.
AB  - The prompt identification of patients with falciparum malaria who are at risk of
      late therapeutic failure could help clinicians avoid the dangers of missed or
      delayed retreatment. Different methods for predicting late recrudescence were
      compared for 52 patients whose parasitemia initially cleared after treatment with
      either halofantrine or quinine. Parasites reappeared in the peripheral
      circulation of six individuals 17 to 28 days after the initiation of therapy.
      Transient rises in parasite counts on thick blood films were accurate (91%
      specific and 100% sensitive) and prompt indicators of eventual recrudescence. All
      six therapeutic failures had been predicted by the third day (mean time [+/-
      SEM], 51.5 +/- 3.6 hours) after initiation of treatment. Parasite clearance time,
      fever clearance time, rRNA probe, and the polymerase chain reaction had less
      practical prognostic value. Serial thick-film parasite counts are a simple,
      cheap, rapid, and reliable method for identifying patients at high risk of
      recrudescence.

PMID- 8645795
TI  - Hemophagocytosis: a complication of acute Q fever in a child.
AB  - We describe an 11-year-old boy with acute Q fever complicated by
      hemophagocytosis. In addition to pancytopenia, the boy presented with
      hyponatremia, hypofibrinogenemia, and changes in lipid metabolism. Examination of
      a bone marrow aspirate revealed striking hemophagocytosis. All of the
      pathological changes were caused by an activated macrophage system. We also
      discuss the possible role that pathogenetic mechanisms play in these changes.

PMID- 8645796
TI  - Stenotrophomonas maltophilia: an unusual cause of biliary sepsis.
AB  - We report three cases of cholangitis caused by Stenotrophomonas maltophilia and
      review two other cases reported in the literature. All five episodes occurred in
      patients with hepatobiliary malignancy complicated by biliary tract obstruction.
      All five episodes occurred in patients with hepatobiliary malignancy complicated
      by biliary tract obstruction. All patients had undergone biliary tract
      instrumentation. Before infection developed, four of the five patients had
      received therapy with antibiotics that do not have in vitro activity against this
      organism. Four patients responded to appropriate antibiotic therapy and biliary
      tract decompression, whereas the fifth patient, who had persistent biliary
      obstruction, did not respond to appropriate antibiotic therapy.

PMID- 8645797
TI  - Herpes zoster as the initial presentation of human immunodeficiency virus type 1
      infection in Kenya.
AB  - We conducted a prospective observational study to determine the clinical
      features, the degree of immunosuppression, and the prevalence of human
      immunodeficiency virus type 1 (HIV-1) infection associated with herpes zoster in
      Kenya. The study included 196 HIV-1 positive individuals and 34 HIV-1 negative
      individuals between the ages of 16 and 50 years who presented to a referral
      clinic in Nairobi. Comparison of the clinical characteristics in the two groups
      found that the duration of illness in the HIV-1-positive group was longer (32 vs.
      22 days; P < .001) and that the HIV-1-positive group was more likely to have
      generalized lymphadenopathy (74% vs. 3%; OR: 12.2; 95% CI: 1.6, 91.7), severe
      pain (69% vs. 39%; OR: 3.6; 95% CI; 1.7, 7.6), bacterial superinfection (15% vs.
      6%; OR: 5.7; 95% CI: 1.3, 25.0), and more than one affected dermatome (38% vs.
      18%; OR: 2.8; 95% CI: 1.1, 8.0). Dermatomal distribution of the lesions was
      similar in the two groups, except for cranial lesions, which occurred exclusively
      in the HIV-1-positive group. The mean CD4 T lymphocyte count at presentation was
      333/mm(3) in the HIV-1-positive group and 777/mm(3) in the HIV-1-negative group
      (P < .001). Herpes zoster is often recognized as the initial HIV-1-related
      illness in Kenya despite the fact that patients have moderate to severe
      depression of CD4 cell counts at presentation. Although the clinical features of
      herpes zoster may be more severe in HIV-1-positive individuals, recovery is
      generally complete and uncomplicated.

PMID- 8645798
TI  - Stevens-Johnson syndrome induced by treatment with acyclovir.

PMID- 8645799
TI  - Moraxella nonliquefaciens septic arthritis in a patient undergoing hemodialysis.

PMID- 8645801
TI  - Nocardia asteroides as a cause of sphenoidal sinusitis: case report.

PMID- 8645800
TI  - Parainfluenza virus respiratory infection after heart transplantation: successful
      treatment with ribavirin.

PMID- 8645802
TI  - Group B streptococcal meningitis in a pregnant woman before the onset of labor.

PMID- 8645803
TI  - Central venous catheter infection due to Ustilago species.

PMID- 8645804
TI  - Acute gastroenteritis caused by Vibrio alginolyticus in an immunocompetent
      patient.

PMID- 8645805
TI  - Efficacy of azithromycin for typhoid fever.

PMID- 8645806
TI  - Strongyloides stercoralis infection in a chronically institutionalized patient
      with schizophrenia and dementia.

PMID- 8645807
TI  - Life-threatening neutropenia secondary to piperacillin/tazobactam therapy.

PMID- 8645808
TI  - Serum ferritin levels correlate with disease activity in patients with AIDS and
      disseminated histoplasmosis.

PMID- 8645809
TI  - Psoas pyomyositis as a late complication of typhoid fever.

PMID- 8645810
TI  - Clarithromycin-induced digoxin toxicity in a patient with AIDS.

PMID- 8645811
TI  - Morganella morganii pericarditis after resolvent splenectomy for immune
      pancytopenia following allogeneic bone marrow transplantation for acute
      lymphoblastic leukemia.

PMID- 8645812
TI  - Aseptic meningitis caused by parvovirus B19.

PMID- 8645813
TI  - False-positive Histoplasma antigen test in a patient with pulmonary
      blastomycosis.

PMID- 8645814
TI  - Recurrent Helicobacter cinaedi bacteremia in a patient infected with human
      immunodeficiency virus: case report.

PMID- 8645815
TI  - Rhabdomyolysis associated with Ehrlichia chaffeensis infection.

PMID- 8645816
TI  - A case of typhoid fever complicated by unexpected diffuse cerebral edema.

PMID- 8645817
TI  - Successful management of a serious group A streptococcal infection during the
      third trimester of pregnancy.

PMID- 8645818
TI  - Severe measles pneumonitis in adults.

PMID- 8645819
TI  - Bronchoesophageal fistula due to multidrug-resistant tuberculosis in a patient
      infected with human immunodeficiency virus.

PMID- 8645820
TI  - Delayed development of tuberculous bronchoesophageal fistulas in a patient with
      AIDS necessitates endoscopic surgery.

PMID- 8645821
TI  - Cervical suppurative lymphadenitis due to Yersinia pseudotuberculosis.

PMID- 8645822
TI  - Cat-scratch disease, Bartonella henselae, and the usefulness of routine
      serological testing for Afipia felis.

PMID- 8645823
TI  - Splenic abscess due to Salmonella heidelberg.

PMID- 8645824
TI  - Drug susceptibility of Mycobacterium tuberculosis isolates from a cohort of
      Haitian migrants evaluated in 1994.

PMID- 8645825
TI  - Fatal Scedosporium prolificans (S. inflatum) fungemia following allogeneic bone
      marrow transplantation: report of a case in the United States.

PMID- 8645826
TI  - Use of itraconazole for treating subcutaneous phaeohyphomycosis caused by
      Exophiala jeanselmei.

PMID- 8645827
TI  - Treatment of otitis media.

PMID- 8645828
TI  - Cystic fibrosis: pathogenesis, pulmonary infection, and treatment.

PMID- 8645829
TI  - Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107
      cases.
AB  - The etiologic and clinical features of cholecystisis in infection due to human
      immunodeficiency virus (HIV) were studies retrospectively. The charts and
      histopathologic specimens of 136 HIV-infected patients who underwent
      cholecystectomy between February 1987 and May 1993 at a large tertiary care
      center were reviewed. Opportunistic pathogens infecting the 107 patients with
      AIDS included microsporidia (eight cases-- Enterocytozoon bieneusi in six and
      Septata intestinalis in two); cytomegalovirus alone (six cases); Cryptosporidium
      alone (eight cases); cytomegalovirus plus Cryptosporidum (15 cases); and
      Pneumocystis carinii and Isospora belli (one case each). In addition,
      histopathologic changes characteristic of Kaposi's sarcoma were seen in one case.
      Thirty-eight patients with AIDS had acalculous cholecystitis for which no
      etiologic agent was found. Twenty-eight AIDS patients had cholelithiasis, six
      with coexistent opportunistic gallbladder infection. In the 107 AIDS patients, no
      specific symptom was found to be predictive of opportunistic infection of the
      gallbladder, but such infection was significantly associated with an abnormal
      abdominal ultrasound (P = .017) and with nonvisualization of the gallbladder by
      radionucleotide biliary scan (P < .001).

PMID- 8645830
TI  - Photo quiz. Murine typhus (Rickettsia typhi)

PMID- 8645831
TI  - Pertussis in German adults.
AB  - In a large pertussis vaccine efficacy trial in Germany, vaccinees and/or their
      family members were seen if a cough illness of >14 days was reported. Evidence of
      recent Bordetella pertussis infection included a positive culture and/or
      polymerase chain reaction (PCR) and/or significant antibody values in
      agglutination and/or ELISA assay. From July 1991 through February 1994, 246
      adults were evaluated and 64 had evidence of B. pertussis infection; of these,
      38% had whooping, 26% had a history of previous pertussis, and 48% were the
      primary cases in a family. The 64 adult cases suggest an adult attack rate in
      this population of 133 per 100,000 population per year. Since pertussis has been
      endemic and epidemic in Germany during the last 2 decades, it would seem likely
      that few persons would escape B. pertussis infections during childhood. In this
      regard, none of the serological controls lacked antibody to all four B. pertussis
      antigens (lymphocytosis-promoting factor, filamentous hemagglutinin, pertactin,
      and fimbriae-2). Thus, serological evidence of past infection may not indicate
      protection, and the widely held belief that individuals who have had infections
      with B. pertussis have lifelong clinical immunity to this disease is probably
      wrong.

PMID- 8645832
TI  - Trends in human immunodeficiency virus (HIV) infection among a patient population
      of an inner-city emergency department: implications for emergency department
      based screening programs for HIV infection.
AB  - Personnel of inner-city emergency departments (EDs), which are frequently the
      only source of medical care for many patients, may be in a unique position to
      detect human immunodeficiency virus (HIV) infection earlier than personnel at
      other recommended screening sites. To assist development of ED-based screening
      strategies for HIV infection, we undertook a serosurvey of HIV infection in adult
      patients attending an ED during a 6-week period in 1992 using an identity
      unlinked technique and compared our findings with data collected similarly in
      1988. Of 1,606 patients, 183 (11.4%) were HIV-positive, compared with 6.0% in
      1988. Seroprevalence rates of HIV infection among patients only at risk of
      heterosexual transmission increased more than fourfold (7% to 30.3%). CD4+ cell
      counts were higher in those patients with undiagnosed HIV infection than in those
      with known HIV infection. Targeting minority patients aged 25-44 years,
      intravenous drug users, and those patients at heterosexual risk would have
      identified 87% of patients with new HIV infection, while requiring screening of
      41% of the study sample. Targeted voluntary screening programs in certain EDs
      would likely detect significant numbers of new early HIV infections.

PMID- 8645834
TI  - Candida-associated diarrhea: a syndrome in search of credibility.
AB  - Candida species have been often considered but infrequently documented as a
      credible cause of diarrhea. Evaluations of the colon in patients who have
      diarrhea and for whom Candida organisms have been isolated from stool have not
      shown invasive fungal lesions, and the mechanisms by which Candida species may
      induce diarrhea remain undefined. However, symptoms ascribed to Candida
      associated diarrhea in the literature include prolonged secretory diarrhea with
      abdominal pain and cramping but without blood, mucus, fever, nausea, or vomiting.
      A critical review literature review showed a strong between the abatement of
      diarrheal symptoms in patients for whom a significant growth of Candida was found
      in their stools and treatment with specific topical antifungal agents. Most of
      the patients had received antibacterial therapy before the onset of symptoms. On
      the basis of these data, we conclude that Candida species may cause diarrhea in
      selective clinical settings.

PMID- 8645833
TI  - Intrapartum prophylaxis with ceftriaxone decreases rates of bacterial
      colonization and early-onset infection in newborns.
AB  - Because of high rates of neonatal gram-negative sepsis in many Latin American
      countries, we prospectively enrolled 784 high-risk pregnant women in a study
      designed to evaluate the effect of a single 1-g dose of ceftriaxone (n = 390) vs.
      that of no antibiotic prophylaxis (n = 394) on oral, rectal, and umbilical
      colonization and fatality rates among newborn infants. The mean ceftriaxone
      concentration in cord blood samples was 26 microgram/mL (range, 9-40
      microgram/mL). Compared with infants of untreated mothers, children born to women
      who were given ceftriaxone were colonized at a lesser rate by gram-negative
      bacilli (54% vs. 35%; P < .001) and by group B streptococci (54% vs. 21%; P =
      .03) and endured significantly fewer sepsis-like illnesses in the first 5 days of
      life (8.1% vs. 3.1%; P = .004). There was also a tendency for them to have fewer
      episodes of culture-proven early-onset sepsis (2.8% vs. 0.5%; P = .06). Sepsis
      related case-fatality rates (0.8% and 0.3%, respectively) were not significantly
      different. Although intrapartum administration of a single dose of ceftriaxone to
      high-risk mothers could be a safe and potentially useful strategy for reducing
      early-onset neonatal infections, additional information is required before this
      approach can be recommended for routine prophylaxis.

PMID- 8645835
TI  - Diagnostic utility of thoracentesis for neutropenic children with cancer.
AB  - Thoracentesis is a procedure often performed in children with pleural effusions
      to assist in diagnosis and management. Its safety and utility for
      immunocompromised patients with neutropenia (absolute neutrophil count, <1,500
      polymorphonuclear leukocytes and band forms per microL) is unclear. We reviewed
      our experience over a 10-year period to evaluate the role of thoracentesis for
      neutropenic children with cancer who had pulmonary effusions of presumed
      infectious etiology. Twenty-two patients were identified, and 18 had absolute
      neutrophil counts of < or = 500/microL. Empirical antibiotics had been
      administered to 95% of these patients and antifungal agents to 72%. Two patients'
      cultures were positive for fungal organisms: Aspergillus terreus in one case and
      Candida albicans in the other. Both of these patients had been receiving
      antifungal therapy. Therapy was altered for these two patients plus one
      additional patient in whose pleural fluid tumor cells were unexpectedly found.
      Eight of the remaining 19 patients underwent another diagnostic procedure,
      yielding five additional diagnoses. In conclusion, thoracentesis is safe and
      should be considered as a diagnostic test for febrile neutropenic patients with
      pulmonary effusions of presumed infectious etiology, although more invasive tests
      may be warranted.

PMID- 8645836
TI  - Use of the polymerase chain reaction and DNA sequencing for detection of
      Bartonella quintana in the aortic valve of a patient with culture-negative
      infective endocarditis.
AB  - We used the polymerase chain reaction (PCR) and broad-range bacterial primers,
      combined with DNA sequencing, to identify Bartonella quintana as the etiologic
      agent in a case of culture-negative infective endocarditis; all blood cultures,
      as well as the bacterial cultures of the resected aortic valve and vegetations,
      remained negative. PCR was used to amplify bacterial 16S rDNA from a template
      prepared from the aortic valve vegetation. The amplified 16S rDNA produced a
      nucleotide sequence that was 99.79% identical to the B. quintana rDNA sequence.
      The patient had a highly elevated level of serum antibodies to Bartonella antigen
      (1:8,192).

PMID- 8645837
TI  - Opportunistic candidiasis: an epidemic of the 1980s.
AB  - Hospital discharge data from 1980 to 1989 from the National Center for Health
      Statistics, National Hospital Discharge Survey (NHDH), and two commercially
      generated hospital discharge data sources (PAS and McAuto) were analyzed to
      document nationally the increased rate of opportunistic candidal infections among
      hospitalized patients in the 1980s and to identify the major risk factors.
      National projections were made by year. Age-, sex-, race-, and disease-specific
      denominators were generated from NHDS data. ICD-9-CM codes derived from discharge
      diagnoses were used to identify patients with oropharyngeal candidiasis,
      disseminated candidiasis, human immunodeficiency virus (HIV) infection/AIDS, or
      malignancies and transplants. Between 1980 and 1989, rates of oropharyngeal
      candidiasis increased 4.7 times (from 0.34 to 1.6 cases per 1,000 admissions per
      year), and the number of deaths among patients with oropharyngeal candidiasis
      increased fivefold. Although the highest rates were among pediatric patients (3
      cases per 1,000 pediatric admissions), the greatest rate increases were among 15-
      to 44-year-old patients (13-fold) and males (fivefold). Between 1983 and 1989,
      the rates of oropharyngeal candidiasis among patients with HIV infections/AIDS
      rose more than 22 times (from 0.02 to 0.45 case per 1,000 admissions; NHDS data).
      Over the whole decade, the rates of disseminated candidiasis increased 11 times
      (from 0.013 to 0.15 case per 1,000 admissions). Between 1985 and 1989, the rate
      of this complication among patients with HIV infection/AIDS increased 10-fold,
      compared with only a twofold rate increase among patients with malignancies or
      transplants. The rate of debilitating and life-threatening candidiasis among
      hospitalized patients increased considerably over the 1980s. This rate increase
      was significant among patients with HIV infection/AIDS and patients undergoing
      transplantation or immunosuppressive therapy for malignancies.

PMID- 8645838
TI  - Evaluation of the Duke criteria versus the Beth Israel criteria for the diagnosis
      of infective endocarditis.
AB  - New diagnostic criteria for infective endocarditis (IE) have been proposed by the
      Duke University Endocarditis Service (Durham, NC) to update the widely used Beth
      Israel (Boston) criteria. We compared the Duke criteria with the Beth Israel
      criteria in a series of 115 consecutive patients with suspected IE who were
      hospitalized in a referral center. The diagnosis of IE was histologically and/or
      bacteriologically confirmed for 27 operated patients. If surgery had not been
      performed on these 27 patients, 22 vs. 12 would have been classified as having
      ?clinically definite? and ?probable? IE by the Duke vs. the Beth Israel criteria,
      respectively, whereas 0 vs. 5 would have been ?rejected? by the Duke vs. the Beth
      Israel criteria, respectively. The improvement in sensitivity of the criteria
      from 44% (Beth Israel) to 82% (Duke) was statistically significant (P < .01). We
      confirm that the Duke criteria improve the sensitivity of diagnosis of IE. The
      specificity of these criteria should be further evaluated.

PMID- 8645839
TI  - Human granulocytic ehrlichiosis in Connecticut: report of a fatal case.
AB  - We report a case of granulocytic ehrlichiosis in a 71-year-old man who presented
      with an acute febrile illness and subsequently developed multisystem organ
      dysfunction and sudden severe anemia with thrombocytopenia requiring intensive
      care, mechanical ventilation, hemodialysis, and transfusions. The diagnosis was
      suspected on the fifth hospital day after a peripheral blood smear was examined;
      intracytoplasmic inclusion bodies were present in granulocytes only. Results of
      serological tests of acute and convalescent sera confirmed the diagnosis of
      granulocytic ehrlichiosis. We discuss the features of this case that were similar
      to those of published case reports as well as the course and outcome of
      treatment. This, to our knowledge, represents to first documented case of human
      granulocytic ehrlichiosis to occur outside the Upper Midwest. Because of the
      possible epidemiological association of Ehrlichia species with the deer tick
      Ixodes scapularis (dammini), this case raises additional concern for clinicians
      and patients in regions where Lyme disease is endemic.

PMID- 8645840
TI  - Molecular epidemiology of an SHV-5 extended-spectrum beta-lactamase in
      enterobacteriaceae isolated from infants in a neonatal intensive care unit.
AB  - Klebsiella oxytoca that produced extended-spectrum beta-lactamase (ESBL) and were
      resistant to ceftazidime were isolated from infants in a neonatal intensive care
      unit (NICU). During a 30-week period, 3 infants developed infections and an
      additional 60 infants were colonized with these bacteria. The molecular typing
      data suggested transmission of a single strain of ceftazidime-resistant K.
      oxytoca among 48 of the 63 infants. The ESBL of 46 of the 48 similar isolates, 14
      of the remaining 15 isolates, and 6 other Enterobacteriaceae appeared to be
      associated with a conjugative plasmid of approximately 85 kb. The ESBL gene was
      cloned, and DNA sequencing confirmed that the ESBL was an SHV-5. Hybridization
      data suggested that the SHV-5 gene was transmitted to other Enterobacteriaceae in
      vivo. The spread of the ESBL was reduced through adherence to infection control
      practices.

PMID- 8645841
TI  - Concentrations of interferon gamma, tumor necrosis factor alpha, and interleukin
      1 beta in the cerebrospinal fluid of children treated for tuberculous meningitis.
AB  - Concentrations of interferon gamma (IFN-gamma) in the lumbar cerebrospinal fluid
      (CSF) of 30 children (mean age, 27 months) being treated for stage III (16
      children) and stage II (14 children) tuberculosis meningitis (TBM) were
      determined by ELISA. Nine children with stage III TBM and six with stage II TBM
      received prednisone (4 mg/kg). Concentrations of IFN-gamma in 73 CSF specimens
      (18 from the first week of therapy, 20 from the second, 19 from the third, and 16
      from the fourth) were determined. The mean concentrations were 780 pg/mL in the
      first week of therapy and 554 pg/mL, 529 pg/mL, and 269 pg/mL in the second,
      third, and fourth weeks, respectively. Tumor necrosis factor alpha (TNF-alpha)
      and interleukin-1beta (IL-1beta) concentrations in 56 specimens from 23 of these
      same children were determined by ELISA. The mean CSF TNF-alpha concentration in
      12 specimens obtained during the first week of therapy was 17 pg/mL, and the mean
      was 11 pg/mL during each of the subsequent weeks (14 specimens were evaluated in
      the second week and 15 specimens in the third and fourth weeks of therapy). Mean
      IL-1beta concentrations in these same groups of specimens were 52 pg/mL, 43
      pg/mL, 42 pg/mL, and 18 pg/mL. No correlation could be shown between cytokine
      concentration and stage of disease, and no differences existed between those who
      did and those who did not receive prednisone. A significant decline in IL-1beta
      concentrations was shown during the 4-week period, but none in TNF-alpha or IFN
      gamma concentrations was noted. Persistently high CSF INF-gamma concentrations in
      cases of TBM (as in cases of aseptic meningitis but not bacterial meningitis) at
      the time of diagnosis suggest an immune response fundamentally different from
      that in bacterial meningitis.

PMID- 8645842
TI  - Factors associated with changes in the use of antiretroviral therapy by a cohort
      of homosexual men infected with human immunodeficiency virus type 1.
AB  - Changes in the use of antiretroviral drugs and factors associated with changes
      from monotherapy with zidovudine (ZDV) to other regimens were quantified in the
      Multicenter AIDS Cohort Study. Participants who had been receiving monotherapy
      with ZDV were categorized as (1) discontinuing ZDV monotherapy; (2) switching to
      disanosine (ddI), zalcitabine (ddC), or stavudine (d4T) monotherapy; (3)
      switching to combination therapy (ZDV with ddI, ddC, or d4T); or (4) continuing
      ZDV monotherapy. From 1990 to 1994, the percentage of participants using ZDV
      monotherapy decreased from 27% to 17% (among participants without AIDS) and from
      60% to 17% (among those with AIDS). At the same time, the proportion of
      participants using combination therapy increased from zero to 8% (no AIDS) and
      from 8% to 26% (AIDS). Polychotomous logistic regression methods were used to
      identify the factors predicting changes from ZDV monotherapy. Among participants
      without AIDS, indicators of drug failure (such as a lower CD4 lymphocyte count or
      symptoms of human immunodeficiency virus type 1 infection) were predictive of the
      initiation of combination therapy, while among patients with AIDS they were
      predictive of a switch to an alternative monotherapy. A decrease in hemoglobin
      levels, a marker of ZDV toxicity, was predictive for all patients of a switch to
      other monotherapy. These data show that clinicians and patients are opting for
      more aggressive antiretroviral regiments and that changes in CD4 lymphocyte count
      and in the status of symptoms remain the primary guides for changes in therapy.

PMID- 8645843
TI  - Hydatid cysts of the brain.
AB  - Intracranial hydatid cysts, although still rare, are being seen with increasing
      frequency. We report 12 cases of intracerebral hydatid cysts diagnosed with the
      use of computed tomography. We also review the methods recently available for
      diagnosis and therapy of this disease. Excellent therapeutic results can be
      achieved through surgical removal of the hydatid cyst; however, it is important
      to avoid rupturing the cyst.

PMID- 8645844
TI  - Bacteremia/septicemia due to Aerococcus-like organisms: report of seventeen
      cases. Danish ALO Study Group.
AB  - Some Aerococcus-like organisms (ALOs) have recently been described in Denmark.
      The bacteria were originally isolated from the urine of elderly patients with
      urinary tract infections. Since 1987, we have identified 17 cases of
      bacteremia/septicemia in which ALOs have been isolated in pure culture of blood;
      we report the data from these cases. Six of the patients presented with
      endocarditis, eight presented with urosepticemia, and three presented with
      septicemia. In all but one of the reports, the urinary tract was suspected as the
      focus of infection, and ALOs were isolated from the urine of nine patients. All
      but one patient had predisposing illnesses; these were predominantly of urinary
      or cardiac origin. Five patients died of their infection, two survived the
      infection but eventually died during hospitalization, and 10 recovered. All of
      the patients received adequate antimicrobial therapy.

PMID- 8645845
TI  - Incidence, capsular types, and antibiotic susceptibility of invasive
      Streptococcus pneumoniae in Sweden.
AB  - The number of reported cases of invasive pneumococcal infections in Sweden
      increased more than threefold from 1988 through 1992. We studied the capsular
      types and the antibiotic susceptibility of 619 pneumococcal strains isolated from
      blood or CSF at 18 Swedish microbiological laboratories in 1987 and in 1992.
      These strains belonged to 35 of the 84 recognized capsular types. We noted a
      remarkable increase in the prevalence of invasive infections with type 14 from
      1987 (8.2%) to 1992 (18%) (P = .001), which correspond to a sevenfold increase in
      absolute numbers. The most prominent increase in infections was seen among
      elderly people; in 1992, type 14 accounted for 22.5% of the isolates from
      infected persons who were >64 years of age. The majority of the strains were
      susceptible to all antibiotics tested. However, there was a significant increase
      in trimethoprim-sulfamethoxazole resistance from 1.4% in 1987 to 7.1% in 1992.
      Nine multiresistant isolates (1.5%) were found.

PMID- 8645847
TI  - Oral fluconazole versus amphotericin B bladder irrigation for treatment of
      candidal funguria.
AB  - A randomized trial was conducted to compare amphotericin B bladder irrigation
      (AmBBI) with oral fluconazole in terms of efficacy and safety in the treatment of
      candidal funguria. Fifty-three patients with two consecutive positive funal
      cultures of urine were randomized to undergo AmBBI (50 mg/L over 24 hours or 50
      mg/L for 7 days) or to receive fluconazole (200 mg/d for 7 days). Urinary
      catheters were changed upon entry into the study and following therapy. Blood and
      urine specimens were obtained throughout the study. Candida albicans was the
      species isolated most frequently from urine cultures. Eradication rates for
      funguria at 24 hours and 5-9 days after therapy were 82.4% and 75%, respectively,
      with the 7-day AmBBI regimen; and 83.3% and 76.9%, respectively, with
      fluconazole. There were no differences in the posttherapy eradication rates
      between the regimens at 24 hours (P = .597) and at 5-9 days (P = .66). Candida
      glabrata was the predominant organism recovered from patients in the fluconazole
      group 5-9 days after the completion of therapy. Adverse events were limited to
      bladder fullness in a patient who underwent AmBBI and hypoglycemia in a patient
      who received concomitant therapy with fluconazole and glyburide. AmBBI (once or
      for 7 days) and fluconazole appear to be equally efficacious in the treatment of
      candidal funguria.

PMID- 8645846
TI  - Bartonella (Rochalimaea) antibodies, dementia, and cat ownership among men
      infected with human immunodeficiency virus.
AB  - To determine the association between recent human immunodeficiency virus (HIV)
      associated dementia and serum antibodies to Bartonella (Rochalimaea) henselae, we
      performed a nested case control study within the Multicenter AIDS Cohort Study in
      Los Angeles. We measured serum IgG and IgM antibodies to B. henselae with use of
      enzyme immunoassay in 369 HIV-seropositive and HIV-seronegative participants with
      and without recent neuropsychological deterioration. Data on pet ownership were
      also collected. IgM antibodies to B. henselae were strongly associated with
      neuropsychological decline or dementia (OR = 6.6;95% CI = 1.4-31.9;P = .02).
      Those participants with IgM antibodies to B. henselae were 1.7 times more likely
      to develop HIV-associated dementia (HAD) or neuropsychological decline over the
      next 5 years. At least 4% of the new cases of HAD and neuropsychological decline
      were due to bartonella infection. Cat ownership was associated with the presence
      of IgM antibodies to B. henselae (OR = 6.4;95% CI = 1.3-30.8;p = .02) and with
      neuropsychological decline and dementia (OR = 2.4;95% CI = 1.2-5.1;P = .02). This
      finding suggests that some cases of HAD and neuropsychological decline are
      associated with potentially treatable B. henselae infections.

PMID- 8645848
TI  - Infant mortality and maternal vitamin A deficiency during human immunodeficiency
      virus infection.
AB  - The maternal factors that contribute to high mortality rates among infants born
      to women with human immunodeficiency virus (HIV) are unclear. We followed 474 HIV
      infected mothers and their infants in Malawi from pregnancy through the infants'
      12th month of life. Of the 474 HIV-infected pregnant women, 300 (63.3%) were
      deficient in vitamin A (serum level of vitamin A, <1.05 micromol/L). Mean serum
      vitamin A levels among mothers whose infants died were 0.78 +/- 0.03 micromol/L
      compared with 1.02 +/- 0.02 micromol/L among mothers whose infants had survived
      for the first 12 months of life (P <.0001). The overall infant mortality rate was
      28.7%. We divided HIV-positive mothers into six groups according to serum vitamin
      A levels (micromol/L) as follows: group 1, <0.35; group 2, between 0.35 and 0.70;
      group 3, between 0.70 and 1.05; group 4, between 1.05 and 1.40; group 5, between
      1.40 and 1.75; and group 6, >1.75. Infant mortality rates for each group were
      93.3%, 41.6%, 23.4%, 18.5%, 17.7%, and 14.2%, respectively (P < .0001). Maternal
      vitamin A deficiency during HIV infection may contribute to increased infant
      mortality.

PMID- 8645849
TI  - Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was
      receiving zidovudine.
AB  - Massive steatosis has recently been described among a few human immunodeficiency
      virus-seropositive patients who were receiving antiretroviral therapy. Although
      clinical and light-microscopic pathological findings were carefully described, no
      ultrastructural studies of the liver were performed in these cases. We report the
      light-microscopic and ultrastructural findings at autopsy of a 35-year-old woman
      with AIDS who developed severe lactic acidosis and hepatic failure. The patient
      had been receiving standard doses of zidovudine for 5 months when she was
      hospitalized because of the rapid onset of abdominal pain, nausea, and vomiting.
      The most significant findings at autopsy were massive hepatomegaly and steatosis.
      Ultrastructural examination of the liver and skeletal muscle showed slightly
      enlarged mitochondria in the liver but no mitochondrial changes in the skeletal
      muscle. The pathogenesis of mitochondrial toxicity associated with antiviral
      therapies is briefly discussed.

PMID- 8645850
TI  - Could nonsteroidal antiinflammatory drugs (NSAIDs) enhance the progression of
      bacterial infections to toxic shock syndrome?
AB  - Anecdotal reports suggest an association between the use of nonsteroidal
      antiinflammatory drugs (NSAIDs) and the progression of invasive group A
      streptococcal infections to shock and multiorgan failure. There is a biochemical
      rationale that could support this theory. Though NSAIDs are frequently used to
      relieve pain or reduce fever, they also attenuate granulocyte functions such as
      chemotaxis, phagocytosis, and bacterial killing. In addition, findings in recent
      studies involving human volunteers injected with endotoxin suggest that
      pretreatment with NSAIDs enhances production of tumor necrosis factor, which
      leads to higher blood levels of this cytokine, probably by preventing feedback
      inhibition by prostaglandin E2. Thus, NSAIDs may contribute to the sudden onset
      of shock, organ failure, and aggressive infection by inhibiting neutrophil
      function, augmenting cytokine production, and attenuating the cardinal
      manifestations of inflammation.

PMID- 8645851
TI  - Old and new therapies for sporotrichosis.
AB  - The old therapies for sporotrichosis--saturated solution of potassium iodide
      (SSKI) and amphotericin B--have largely been supplanted by itraconazole
      treatment. Although SSKI is effective for the treatment of lymphocutaneous
      sporotrichosis, it is difficult to administer and is frequently associated with
      side effects; response rates of >90% are associated with itraconazole therapy for
      lymphocutaneous sporotrichosis. Patients with osteoarticular sporotrichosis
      rarely have systemic symptoms and can be effectively treated with a prolonged
      course of itraconazole, thus obviating the need for intravenous amphotericin B
      therapy with its associated toxic effects. Pulmonary sporotrichosis in patients
      infected with human immunodeficiency virus continue to be difficult therapeutic
      problems, but itraconazole appears to be at least as effective as amphotericin B
      as treatment for these forms of sporotrichosis.

PMID- 8645852
TI  - Chronic varicella-zoster virus myelitis without cutaneous eruption in a patient
      with AIDS: report of a fatal case.
AB  - We describe a fatal case of varicella-zoster virus myelitis that was preceded by
      neurological symptoms for 10 months in a patient with human immunodeficiency
      virus infection and an extremely low CD4 cell count (20/microL). The patient was
      also receiving chronic acylovir therapy for suppression of herpes complex.
      Despite chronic unilateral periauricular and facial pain, which was later
      accompanied by upper- and lower-extremity weakness, a cutaneous eruption never
      developed. It is hypothesized that a blunted inflammatory response in the spinal
      cord--possibly related to a very low CD4 cell count--and long-term acylovir
      administration might have contributed to the atypical manifestation might have
      contributed to the atypical manifestation of varicella-zoster virus-related
      neurological disease in this immunocompromised patient.

PMID- 8645853
TI  - Herpes zoster in patients with human immunodeficiency virus infection--an ever
      expanding spectrum of disease.

PMID- 8645854
TI  - Development of human T-cell lymphotropic virus type I-associated adult T-cell
      leukemia/lymphoma during immunosuppressive treatment following renal
      transplantation.
AB  - Although it is recognized that there is an increased incidence of
      lymphoproliferative disorders among patients who have received immunosuppressive
      therapy following transportation, there have been few reports of adult T-cell
      leukemia/lymphoma (ATLL) developing in previously asymptomatic carriers of human
      T-cell lymphotropic virus type I (HTLV-I) who have undergone transplantation. We
      describe the development of such a tumor in a man who was HTLV-I-positive and
      received immunosuppressive treatment following renal transplantation. As the
      number of individuals in ethnic groups at risk for organ transplantation
      increases, it would seem prudent to screen such individuals for carriage of HTLV
      I before transplantation and to follow them prospectively to confirm if
      transplantation and immunosuppression predispose to the development of ATLL.

PMID- 8645855
TI  - Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study
      Group and the Candidemia Study Group.
AB  - During a comparative trial of amphotericin B vs. fluconazole for treatment of
      candidemia in nonneutropenic patients, data on the management of intravascular
      catheters were collected. Complete records were available for 91% of the 206
      study patients. For the subset of patients with a catheter in place at the time
      of their first positive blood culture, removal and replacement of all
      intravascular catheters without exchange over a guidewire from a preexisting line
      on or before the first day the study drug was administered were associated with a
      reduction in the subsequent mean duration (+/- SE) of candidemia, from 5.6 +/ 
      0.8 days to 2.6 +/- 0.5 days (P < .001).

PMID- 8645856
TI  - Relapse of catheter-related Flavobacterium meningosepticum bacteremia
      demonstrated by DNA macrorestriction analysis.
AB  - A 6-year-old boy with non-Hodgkin's lymphoma presented because of recurrent
      episodes (on 13 September 1993 and 12 January 1994) of possibly catheter-related
      bacteremia. The strains isolated during both episodes and seven epidemiologically
      unrelated control strains were typed by pulsed-field gel electrophoresis (PFGE)
      of chromosomal DNA. The similarity of the PFGE patterns of the two isolates
      suggests that both episodes of bacteremia were caused by the same strain. The
      antimicrobial susceptibility of the nine strains was tested against 32
      antimicrobial agents. The antimicrobial susceptibility patterns of the two
      isolates from the referred case were identical and differed from those of other
      clinical isolates. The best in vitro activity (associated with 100%
      susceptibility) was demonstrated by ofloxacin, clinafloxacin, minocycline, and
      rifampin.

PMID- 8645857
TI  - Ionic conductivity, transference numbers, composition and mobility of ions in
      cross-linked lysozyme crystals.
AB  - Micromethods for measurements of electric conductivity, transference numbers and
      concentrations of inorganic ions within immobilized protein crystals have been
      developed and applied to study tetragonal lysozyme crystals cross-linked with
      glutaraldehyde. Donnan equilibria and mobilities of ions in this crystal were
      calculated using the data of these methods and the data of crystal pH titration.
      Taken together these results characterize the lysozyme crystal as an ion
      exchanger whose electrical properties and ion composition differ greatly from
      those of the external solution. Although anions transfer most of the current in
      the crystals, anion mobility is considerably lower than that of cations. Mobility
      of all ions in the crystal is considerably lower than in solution (3.5-50 times
      for cations and 120-330 times for anions) and depends on steric restrictions and
      charges of both ions and lysozyme molecules. Similar features in behavior of
      crystalline and biological channels are discussed.

PMID- 8645858
TI  - [Acute diagnosis of thoracic injuries of therapeutic relevance in severely
      injured and polytraumatized patients].
AB  - PURPOSE: To determine the value of supine chest radiography in comparison to
      orientating chest CT in the initial diagnostic evaluation of severely
      polytraumatised patients. MATERIAL AND METHODS: 303 patients with primary
      indication for a cranial CT following trauma were investigated between 1988 and
      1993. After performing the cranial CT all patients underwent a chest CT with an
      average of 6 CT slices without changing the position of the patient and with a
      median scan time of 4 minutes. The results of the chest CT were correlated with
      the findings of the supine chest radiography in regard to therapeutically
      relevant pathological changes. RESULTS: The sensitivity in detection of
      pneumothorax in supine chest radiography was 53% versus 97% in CT, atelectasis
      20% versus 94%, lung contusion 79% versus 99%, haemotothorax 62% versus 97%. More
      fractures were found conventionally (sensitivity 94%) than by chest CT
      (sensitivity 44%). CONCLUSION: Supine chest radiography of polytraumatised
      patients is clearly inferior to orientating chest CT in demonstrating
      posttraumatic lesions; obtaining therapeutically relevant information justifies
      the additionally needed small amount of time.

PMID- 8645859
TI  - [Digital luminescence radiography in comparison with the conventional film-screen
      technique in diagnosis of fractures].
AB  - PURPOSE: The accuracy of digital luminescence radiography was compared with that
      of conventional film/screen techniques, using animal preparations and clinical
      examinations. MATERIAL AND METHOD: Fine fissures were made in 8 animal bones and
      these were examined radiologically. The digital examinations were carried out
      with and without edge enhancement. 208 patients were examined in a similar way.
      Film quality and assessment of the fractures were evaluated quantitatively.
      RESULTS: In no instance did either of the digital methods provide inferior
      quality when compared with conventional films. ROC analysis for evaluation of
      fractures in patients, using an experienced radiologist, showed no significant
      difference between the various methods (ROC areas: conventional 0.947, digital
      0.958, digital with edge enhancement 0.943). With a less experienced observer
      there were significant advantages for both digital methods (ROC areas: 0.851,
      0.886, 0.908). CONCLUSION: Our investigation has proved that fractures which are
      difficult to see can be reliably demonstrated by digital luminescence
      radiography.

PMID- 8645860
TI  - [Gastrointestinal diagnosis with hydrosonography and hydro-CT. 1: Stomach
      carcinoma].
AB  - PURPOSE: Hydrosonography (HUS) and hydro-CT (HCT) were evaluated for diagnostic
      accuracy and staging efficiency of gastric carcinomas. MATERIAL AND METHODS: 68
      patients suspected for gastric carcinoma were examined. At HUS the gastric wall
      is distended by water, the tumour is localised and enlarged to judge the depth of
      infiltration. At HCT the stomach is filled with water and after paralysis of the
      gut a spiral-CT optimised for parenchymal and vessel contrast is performed.
      Gastric carcinomas were classified according to the TNM-system and
      histopathological correlation was achieved. RESULTS: The number of
      normal/pathologic examinations was 10/30 (HUS) and 9/31 (HCT), the detection rate
      of gastric tumours was 77% (HUS) and 94% (HCT). The T-stage was correctly
      determined in 27% (HUS) and 55% (HCT), the N-stage in 65% and 45% and the M-stage
      in 81% and 73% of all cases, respectively. CONCLUSION: HCT is a reliable
      screening method for gastric tumors. Staging of gastric carcinomas, however, is
      not improved. Tumour extension beyond the wall and metastases can be assessed by
      a single examination.

PMID- 8645861
TI  - [Ductal carcinoma in situ in dynamic MR-mammography at 1.5 T].
AB  - PURPOSE: To define the value of contrast-enhanced MR mammography in ductal
      carcinoma in situ (DCIS). MATERIAL AND METHODS: In a group of 35 patients with
      DCIS, the results of MR imaging were compared to histopathology and
      immunohistochemistry in a retrospective study. RESULTS: In 35 patients with DCIS,
      a signal enhancement was found in 25 cases (72%). In 15 of these cases, the
      signal time curve was typical for malignancy. The other 10 patients had non
      specific signal curves. Six of 35 patients (11%) had no enhancement within the
      tumour region. Four of 35 patients (11%) had bilateral diffuse signal increase,
      and regions of DCIS could not be identified clearly. Three DCIS were visualised
      exclusively by MR mammography. The configuration of signal enhancement was sharp
      (32%), unsharp (48%) or dendritic (20%). DCIS of the comedo type showed a
      significantly higher enhancement than the non-comedo type. A significant
      correlation between the grade of vascularisation in immunohistochemistry and
      signal enhancement in MR mammography could not be demonstrated. CONCLUSION:
      Dynamic MR mammography does not reliably visualise DCIS.

PMID- 8645862
TI  - [Initial experiences with MR-mammography in after-care following surgical flap
      treatment of breast carcinoma].
AB  - PURPOSE: To demonstrate typical MR mammographic findings after plastic surgery of
      breast cancer. PATIENTS AND METHODS: Postoperative (7-38 months, median 13) MR
      mammographic examinations of 25 patients operated for breast cancer (11
      latissimus dorsi-flaps (LAT), 14 rectus abdominis myocutaneous-flaps (TRAM)),
      were reevaluated. The examinations were performed with a breast coil at 1 T. The
      sequences applied were a fat-suppressed 2-D turbo IR-sequence proton-weighted and
      a T1-weighted FLASH 3-D sequence as dynamic series. RESULTS: Scars between the
      myocutaneous flap and the remaining breast tissue always appeared in form of a
      ligament or septum. Signal and perfusion characteristics of scar tissue and
      muscle stalk in this investigation were clearly different from those of tumour.
      One tumour recurrence and one fat necrosis was found and rectified by biopsy.
      CONCLUSION: MR mammography is a very valuable diagnostic method for postoperative
      evaluation of myocutaneous flap-based therapy of breast cancer.

PMID- 8645863
TI  - [Detectability of focal liver lesions: comparison of MRI at 1.5 T and dynamic
      spiral CT].
AB  - PURPOSE: To compare dynamic spiral CT with MR imaging in the detectability of
      focal liver lesions. MATERIAL AND METHODS: Thirty-one patients with 62 focal
      liver lesions (27 benign) were evaluated retrospectively. Dynamic spiral CT scans
      were compared with T1- and T2- weighted spin-echo (SE) sequences and in part with
      multi slice 2-D-FLASH and single-shot slice-selective inversion recovery Turbo
      FLASH sequences at 1.5 T. RESULTS: Dynamic spiral CT detected 89% of all lesions
      and was superior to each sequence alone (56-70%), and also to MRI overall (79%)
      regardless of lesion size, localization, and histology. However, statistical
      significance (p < 0.05) was only found for the differences between CT and the T1
      weighted SE sequence. CONCLUSION: Compared to conventional SE and GE MR imaging
      sequences, dynamic spiral CT scanning seems to be more effective in the detection
      of focal liver lesions.

PMID- 8645864
TI  - [Magnetic resonance angiography of the carotid artery: effect of short and ultra
      short echo times].
AB  - PURPOSE: To evaluate the influence of short and ultrashort echo times (TE) on the
      magnetic resonance (MR) signal in the carotid sinus and in carotid artery
      stenoses. MATERIAL AND METHODS: High resolution gradient-echo sequences without
      and with flow compensation using TE's ranging from 1.5 to 8.0 ms were compared on
      phantoms, eight healthy volunteers, and 10 patients with moderate and severe
      carotid artery stenoses. RESULTS: MR sequences with shortest TE's provided the
      best visualisation of stenotic regions in the carotid sinus and demonstrated a
      substantial reduction of signal loss due to spin dephasing in both phantom and
      patient studies. This was made possible using an improved gradient system with
      higher gradient strengths and shorter rise times with lower acquisition
      bandwidths and better signal-to-noise ratio. CONCLUSION: MR sequences with short
      and ultrashort TE's enable a better definition of the stenotic region and
      therefore guide adequate therapeutic decisions.

PMID- 8645865
TI  - [The meningeal sign: a new appraisal].
AB  - PURPOSE: To evaluate the occurrence of the meningeal sign in meningiomas and
      metastases. MATERIAL AND METHODS: We studied 20 patients with meningiomas and 17
      patients with cerebral metastases adjacent to the dura. MRI studies (Siemens,
      Magnetom 1,5) included axial T1-weighted and T2-weighted unenhanced as well as
      gadolinium-DTPA enhanced T1-weighted (axial, coronal, sagittal) SE imaging. In
      all patients the tumours were resected with the attached dura mater.
      Histopathological examinations were done, which corresponded to the area of
      marked enhancement by gadolinium-DTPA. There was no correlation between the
      occurrence of the meningeal sign and the histopathological examinations. RESULTS:
      In 20 patients with meningiomas adjacent to the dura we found the meningeal sign
      in 11 cases. Histologically we observed an increase of collagen fibres and
      fibrocytes. In 5 of 17 cases with superficial cerebral metastases the meningeal
      sign was seen, histologically as dura infiltrations and microbleedings.
      CONCLUSION: The meningeal sign is not specific for meningiomas and can be
      observed in a wide variety of pathological entities.

PMID- 8645866
TI  - [The value of 3-phase skeletal scintigraphy for early diagnosis of Sudeck
      disease].
AB  - PURPOSE: In a prospective study the value of the three-phase bone scintigraphy in
      the early diagnosis of Sudeck's atrophy was analysed. MATERIAL AND METHODS: 137
      patients with the clinical suspicion on Sudeck's atrophy in stage I were
      examined. By means of the clinical course and additional examinations (block
      response), pain experts confirmed the diagnosis separately. RESULTS: With the
      findings of hyperperfusion of all 5 phalanges, homogeneous hyperaemia of the
      affected hand or the foot and periarticular increased uptake of the whole
      extremity a reliable diagnosis of Sudeck's atrophy was possible. The sensitivity
      was 95.9%, the specificity 100%. With bone scintigraphy Sudeck's atrophy could be
      clearly differentiated from an inactivity atrophy. CONCLUSION: Three-phase bone
      scintigraphy is an excellent tool for the objective diagnosis of Sudeck's atrophy
      in stage I.

PMID- 8645867
TI  - [Endovascular balloon occlusion test of the internal carotid artery with
      increased hemodynamic monitoring for determination of circulatory reserve before
      planned carotid occlusion].
AB  - PURPOSE: To evaluate stroke risk assessment of balloon test occlusion of the
      internal carotid artery (ICA) with enlarged haemodynamic monitoring prior to
      permanent ICA occlusion. MATERIAL AND METHODS: 24 patients with cervical
      metastasis (n = 18), cavernous meningiomas (n = 3) or inoperable cavernous
      aneurysms (n = 3) were examined. The test occlusion was monitored by EEG,
      neurological examinations and transcranial Doppler sonography of the ipsilateral
      middle cerebral artery with evaluation of the cerebrovascular reserve capacity.
      Additionally 99mTc-HMPAO-SPECT imaging was added showing the perfusion during
      test occlusion. RESULTS: In one (4%) patient the test occlusion had to be
      interrupted previously due to an acute neurological deficit. This patient and two
      (8%) patients with highly pathological test results in SPECT and TCD were
      excluded from permanent carotid occlusion. In 6 (25%) patients quantitative TCD
      monitoring could improve the stroke risk assessment by differentiating the
      patients in a low and high risk group. 6 (25%) patients were definitely occluded
      without haemodynamic complications, but two patients suffered from embolic
      infarctions which cannot be predicted by this procedure. CONCLUSIONS: The
      multimodal balloon test occlusion with enlarged haemodynamic monitoring allows
      haemodynamic stroke risk assessment prior to permanent occlusion of the ICA.

PMID- 8645868
TI  - [Determining the effectiveness of percutaneous cava filters: experimental
      studies].
AB  - PURPOSE: In vitro clot-trapping capacity of 16 different caval filters should be
      evaluated under varying experimental conditions. MATERIAL AND METHODS: In a flow
      model simulating in vivo conditions (soft latex tube, dextran solution at 37
      degrees C, pulsatile flow at a mean rate of 3 1/min) the efficiency of 16 caval
      filters was evaluated in horizontal and vertical position by using 640 or 1280
      clots/filter (8 sizes). Non-self centering filters were tested in centric and in
      tilted position. RESULTS: Efficiency of optimally centered caval filters varied
      between 97.8 and 69.4%. The largest thrombi were captured by all optimal centered
      filters. A change from vertical to horizontal position of the flow model resulted
      in a variation of filter efficiency by about 4.8%. Efficiency of non-self
      centering filters decreased significantly when placed in a tilted position (mean
      decrease 15.5%; range 2.7%-37.7%) resulting in a deterioration of the capture
      rate by as much as 43.2%. CONCLUSION: Under optimal study conditions efficiency
      of all evaluated caval filters was high. Tilting of caval filters resulted in a
      significant efficiency decrease.

PMID- 8645869
TI  - [MR imaging of a patient positioning-induced compartment syndrome of both lower
      legs after surgery in dorsal surgical position].

PMID- 8645871
TI  - [Magnetic resonance tomography diagnosis of subungual glomus tumor--a case
      report].

PMID- 8645870
TI  - [Rupture of a liver cell carcinoma after chemoembolization].

PMID- 8645872
TI  - [Annular pancreas--congenital anomaly as the cause of chronic calcifying
      pancreatitis in a 73-year-old patient].

PMID- 8645873
TI  - [Thrombosed anastomotic aneurysm of the vena saphena parva].

PMID- 8645874
TI  - [Rupture of a renal artery aneurysm in polyarteritis nodosa: evaluation by DSA
      and comparison with MR angiography].

PMID- 8645875
TI  - Sodium nitroprusside-induced apoptotic cellular death via production of hydrogen
      peroxide in murine neuroblastoma N1E-115 cells.
AB  - Sodium nitroprusside is widely used in pharmacological studies as a potent
      vasodilator or a nitric oxide donor. The mechanisms of cellular death induced by
      sodium nitroprusside were investigated in murine neuroblastoma N1E-115 cells.
      Sodium nitroprusside reduced the cellular viability, and the DNA extracted from
      treated cells showed a ladder-like intranucleosomal fragmentation pattern, which
      is an indication of apoptosis. The DNA fragmentations were also visualized by in
      situ nick translation. The cellular death was attenuated by cycloheximide,
      indicating that ongoing protein synthesis was essential for the initiation of the
      degenerative response. However, other nitric oxide donors did not decrease the
      cellular viability. The nitric oxide scavenger, hemoglobin, had no effect on
      sodium nitroprusside-induced cellular death. Furthermore, sodium cyanide, which
      is formed by the metabolism of sodium nitroprusside, did not cause cellular
      death. On the other hand, hydrogen peroxide, another product of sodium
      nitroprusside metabolism, reduced the cellular viability and induced DNA
      fragmentation. In addition, the cell damage induced by sodium nitroprusside was
      enhanced by a medium without fetal bovine serum. In conclusion, we proposed that
      hydrogen peroxide is the important toxic species for induction of apoptosis in
      N1E-115 cells exposed to sodium nitroprusside.

PMID- 8645876
TI  - A nitric oxide-sensitive electrode: requirement of lower oxygen concentration for
      detecting nitric oxide from the tissue.
AB  - In order to directly detect nitric oxide (NO) liberated from isolated tissue, a
      practical and convenient method using a nitric oxide-sensitive electrode is
      described. To avoid the nonselective signal caused by ionic substances, the
      electrode was covered with three layers but remains permeable for gaseous
      substances. In a solution bubbled with 20% oxygen (pO2, approximately 150 mm Hg),
      administration of S-nitroso-N-acetyl-d, l-penicillamine (SNAP) at concentrations
      greater than 10(-7) mol/L elicited an electrode response. Based on a comparison
      with the chemical determination of NO released from SNAP, the electrode may be
      able to detect nitric oxide around nmol/L. At least 30 nmol NO per liter in
      anoxic conditions was reported to be detected by this electrode (Matsui, 1995).
      In a specially designed small chamber, the electrode was attached on the surface
      of endothelial side of the isolated aorta of the guinea pig. When carbachol was
      added to the chamber, the electrode responded when the solution was bubbled with
      20% but not with 40% or 95% of oxygen, suggesting a much faster decomposition of
      nitric oxide in the presence of higher concentrations of oxygen. The electrode
      response to carbachol was abolished in the presence of NG-monomethyl-L-arginine
      or nitro arginine. These results suggest that the electrode method described in
      this manuscript is suitable for detecting nitric oxide liberated from isolated
      tissues when comparatively low oxygen levels are present in the physiological
      salt solution.

PMID- 8645877
TI  - Increasing-current electroshock seizure test: a new method for assessment of anti
      and pro-convulsant activities of drugs in mice.
AB  - We developed the increasing-current electroshock seizure (ICES) test, a new
      method for assessment of anti- and pro-convulsant activities of drugs in mice. In
      this method, a single train of pulses (square wave, 5 msec, 20 Hz) of linearly
      increasing intensity from 5 to 30 mA (increment of 0.1 mA/0.1 sec, i.e., 5-30 mA
      in 25 sec) was applied via ear electrodes. The current at which tonic hindlimb
      extension occurred was recorded as the seizure threshold. Thus, this method
      allows determination of the seizure threshold current for individual animals.
      Carbamazepine, phenytoin, valproate, phenobarbital, diazepam, and morphine all
      increased the seizure threshold current in a dose-dependent manner, whereas
      ethosuximide was not effective. The seizure threshold current decreased after
      treatment with reserpine, chlorpromazine, aminophylline, strychnine,
      pentylenetetrazol, bicuculline, picrotoxin, and ethyl-beta-carboline-3
      carboxylate (beta-CCE). These results indicate that the ICES test, like the
      maximal electroshock seizure test, is a model of grand mal-type seizure and is
      useful for evaluation of both the anti- and pro-convulsant activities of drugs.

PMID- 8645879
TI  - Determination of half-life for mRNA expressed in few copies and with short life.
AB  - Determination of stability of mRNA expressed in low abundance and with short life
      requires a sensitive method for detection and an accurate measurement of mRNA
      level. The method described here meets both of these criteria. An uniformly
      labeled single-stranded probe with high specific activity was used for the
      increased sensitivity in detection and quantitation of mRNA. The levels of mRNA
      were normalized with an invariant mRNA specie with longer half-life under the
      same experimental conditions in the same cells. These modifications may be
      helpful for situations where measurement of mRNA half-life for short-lived few
      copies of mRNA is necessary.

PMID- 8645878
TI  - A ferret model of electrical-induction of arterial thrombosis that is sensitive
      to aspirin.
AB  - An experimental model of acute thrombosis was developed in pentobarbital-
      anesthetized ferrets. A 10-min anodal electrical stimulation of 1 mA was
      delivered to the external surface of the carotid artery while measuring carotid
      blood flow (CBF). This produced an occlusive thrombus in all vehicle-treated
      ferrets within 41 +/- 3 min with an average weight of 8 +/- 1 mg (n = 7). These
      thrombi were enriched in both platelets and fibrin and were adherent at the site
      of transmural vascular injury as determined by light and electron microscopy. To
      determine the model's sensitivity to antiplatelet drugs, aspirin or a thromboxane
      (TxA2) receptor antagonist (ifetroban) were administered 15 min before electrical
      stimulation. Thrombus weight was reduced 58% by aspirin (10 mg/kg, i.v.) and 74%
      by ifetroban (1 mg/kg + 1 mg/kg per hr, i.v.). Both drugs also improved CBF and
      decreased vascular occlusion. Ferrets were more sensitive than rats to aspirin's
      inhibition of collagen-induced platelet aggregation as determined ex vivo in
      whole blood. Separate in vitro platelet aggregation studies revealed species
      differences in reactivity to U-46619 (TxA2 receptor agonist) and collagen in the
      order of human > ferret > rat, with relatively lesser variations in ADP
      responses. These studies identify the ferret as a useful species for evaluating
      antithrombotic drugs in a model in which aspirin is efficacious.

PMID- 8645880
TI  - Continuous monitoring of mitochondrial membrane potential in hepatocyte cell
      suspensions.
AB  - We report a simple fluorometric method for the continuous monitoring of
      mitochondrial membrane potential and cell viability in suspensions of hepatocytes
      exposed in vitro to cytotoxic agents. Suspensions of freshly isolated hepatocytes
      (10(6) cells/mL) preloaded with rhodamine 123 (Rh 123, 100 mumol/L) are
      transferred to a thermostatically controlled mixed cuvette to which the desired
      cytotoxic agent is added. Rh 123 is a cationic fluorophore that is actively
      accumulated by cells in direct proportion to the mitochondrial membrane
      potential. Cell viability was estimated by monitoring propidium iodide (PI)
      fluorescence. Exposure of cell suspensions to the mitochondrial uncoupling agent
      FCCP caused an immediate and titratable increase in Rh 123 fluorescence.
      Subsequent treatment with digitonin did not change Rh 123 fluorescence,
      suggeseting that Rh 123 equilibrates rapidly across the intact cell membrane.
      Likewise, treatment of hepatocyte suspensions with inhibitors of mitochondrial
      respiration (rotenone, cyanide, or menadione) caused an immediate increase in Rh
      123 fluorescence. This was accompanied by a progressive increase in PI
      fluorescence, suggesting a causal relationship between mitochondrial
      depolarization and cell injury. In contrast, 1,4-benzoquinone caused a time
      dependent and linear increase in PI fluorescence that paralleled changes in Rh
      123 fluorescence. Comparing the time courses for changes in PI and Rh 123
      fluorescence suggests that for benzoquinone, the depolarization of the
      mitochondria is a consequence rather than a cause of the cell injury. This
      modified procedure provides a simple and specific technique for continuously
      monitoring mitochondrial membrane potential and cell viability in suspensions of
      freshly isolated hepatocytes. The advantage is that there is no need to separate
      cells from the incubation medium, making it possible to record real-time changes
      in mitochondrial membrane potential and cell viability throughout the in vitro
      exposure period.

PMID- 8645881
TI  - Use of ganglionic blockers to assess neurogenic pressor activity in conscious
      rats.
AB  - The present study was conducted to develop a standardized ganglionic blockade
      protocol to assess neurogenic pressor activity in conscious rats. Rats were
      instrumented with arterial and venous catheters for measurement of arterial
      pressure and heart rate and for administration of three different ganglionic
      blockers (trimethaphan, hexamethonium, and chlorisondamine). To investigate the
      role of the pressor hormones angiotensin II (AII) and arginine vasopressin (AVP)
      in modulating the cardiovascular responses to ganglionic blockade, we also
      administered ganglionic blockers to rats pretreated with AVP and AII receptor
      antagonists. The peak depressor responses to trimethaphan (20 mg/kg; -45 +/- 2 mm
      Hg), hexamethonium (20 mg/kg; -44 +/- 2 mm Hg), and chlorisondamine (2.5 mg/kg; 
      47 +/- 3 mm Hg) were not different from each other. With trimethaphan, there was
      a significantly enhanced peak depressor response after blockade of AT1/V1
      receptors (-45 +/- 2 vs -59 +/- 2 mm Hg). No significant differences were
      observed for hexamethonium or chlorisondamine after hormonal blockade (-44 +/- 2
      vs. -46 +/- 3 and -47 +/- 3 vs -48 +/- 4 mm Hg, respectively). These observations
      suggest that, for hexamethonium and chlorisondamine, the peak depressor response
      to ganglionic blockade is a consistent measure of neurogenic pressor activity in
      the conscious rat. This response is not influenced by circulating AII or AVP. On
      the other hand, trimethaphan should be used carefully due to its complex
      interactions with other systems, particularly under conditions in which AVP or
      AII may be altered.

PMID- 8645882
TI  - Changes in calcium transient and left ventricular function during positive
      inotropic stimulation and myocardial ischemia in indo-1-loaded beating guinea pig
      heart.
AB  - To elucidate the issues such as excitation-contraction coupling and myocardial
      ischemia, it is necessary to measure intracellular free Ca2+ concentration and
      mechanical function of hearts perfused via the normal arterial circulation. For
      this purpose, we simultaneously measured Ca(2+)-dependent indo-1 fluorescence and
      left ventricular (LV) pressure on a beat-to-beat basis in Langendorff guinea-pig
      hearts, and investigated the changes in Ca2+ transient and LV function during
      inotropic stimulation and myocardial ischemia. The indo-1 fluoresence ratio and
      LV developed pressure increased the perfusate [Ca2+] increased from 1.6 to 3.2
      mmol/L, and there was a good correlation between Ca2+ transient and LV
      contractility. Digoxin (10(-6) mol/L) and milrinone (10(-5) mol/L) increased LV
      contractility with a concomitant increase in Ca2+ transient, and the relative
      increase of Ca2+ transient produced by milrinone was much more than that by
      digoxin. The reduction of coronary perfusion pressure from 80 to 40 mm Hg
      decreased LV contractility with an increase in indo-1 fluorescence ratio. These
      results suggest that Ca2+ responsiveness of contractile apparatus declines during
      inotropic stimulation by milrinone and during myocardial ischemia. Thus, this
      experimental technique is useful to investigate the interrelation of Ca2-
      regulation and LV function during a variety of pharmacological and physiologic
      perturbations.

PMID- 8645883
TI  - Methylprednisolone and cortisol metabolism during the early post-renal transplant
      period.
AB  - Despite the widespread use of methylprednisolone and the well-appreciated effects
      of this drug on HPA suppression, little data is available which describes
      individual patient exposure to both methylprednisolone and cortisol following
      renal allograft placement. The clinical utilization of methylprednisolone during
      the early post-transplant period is based upon standardized dosing protocols that
      do not consider factors which may influence the pharmacokinetics of this drug
      during the post-transplant period. Therefore, this study was designed to examine
      the pharmacokinetics of methylprednisolone (mean dose: 28 mg) and cortisol
      pharmacodynamics in 9 renal transplant recipients (4 females; 5 males) who were
      studied during the early post-transplant period (5 to 12 days after surgery). All
      patients (mean serum creatinine: 1.4 +/- 0.3 mg/dl) had serial blood samples
      collected over a 12- to 24-hour period (depending upon the dosing schedule) which
      were analyzed concurrently for methylprednisolone and cortisol. A three-fold
      variation in drug clearance ranging from 174 to 638 ml/h/kg with a range in the
      volume of distribution of 0.83 to 2.24 l/kg and resultant half-lives ranging from
      1.20 to 3.02 hours was noted. The cortisol response was quantitated by a 12-hour
      cortisol area under the curve (C-AUC12) to examine the interpatient cortisol
      patterns during the early post-transplant period. C-AUC12 ranged from 44.0 to 636
      ng.h/ml. Significant correlations were noted between the cortisol plasma
      concentration at 12 hours and methylprednisolone clearance and area under the
      concentration versus time curve (AUC). Interpatient variability in the
      disposition of methylprednisolone and cortisol response noted during the early
      post-transplant period contradict the clinical assumptions which underlie the
      fixed dosing protocols currently utilized for methylprednisolone.

PMID- 8645884
TI  - Homing of CD4+CD56+ T lymphocytes into kidney allografts during tubular necrosis
      or rejection.
AB  - The association between acute rejection, acute tubular necrosis, good function
      and relative infiltration of CD56 subsets of both CD8+ and CD4+ T cells was
      examined on 67 samples of graft infiltrating cells (GIC) and corresponding
      peripheral blood lymphocytes (PBL) obtained from renal allograft recipients.
      Quantification of cell subset profiles was determined by two-color flow
      cytometry. While a high proportion of CD4+CD56+ GIC was detected when both renal
      dysfunction and graft cytopathology (acute tubular necrosis or acute rejection)
      were present, this cell subset was undetectable in peripheral blood. In contrast
      the CD8+CD56+ T-cell subset was not discriminatory. The presence of CD4+CD56+
      cells among freshly-isolated lymphocytes from renal allografts supports the idea
      that the local environment is involved in the selection of this subset, thus
      participating in the amplification of the immune-response. In addition, a homing
      of this T-cell subset into the transplanted organ may constitute an early sign of
      graft immunopathology.

PMID- 8645885
TI  - Monitoring of allograft recipients for the development of HLA-specific
      antibodies: elimination of OKT3 as a complicating factor.
AB  - In this report we demonstrate that the use of immunoabsorbent beads to remove the
      OKT3 monoclonal antibody (MoAb) from the sera of transplant recipients is
      necessary in order to avoid the false positive reactivity in panel reactive
      antibody (PRA) assay. We have shown that the presence of OKT3 MoAb in patient's
      sera can give a positive reactivity in PRA, which may be interpreted as antibody
      development. Rabbit antimouse immunoglobulin covalently linked to sepharose can
      effectively remove the OKT3 MoAb from patients sera, but has no effect on anti
      HLA antibodies. The absorbance of OKT3 MoAb, therefore, is necessary to obtain
      accurate results in respect to humoral rejection, which may lead to mismanagement
      of patients.

PMID- 8645887
TI  - Effect of cyclosporine on renal function in kidney transplant recipients: a 12
      year follow-up.
AB  - Nephrotoxicity remains a concern for patients on long-term cyclosporine. We have
      previously reported on renal function in a cohort of kidney transplant recipients
      followed up to 10 years posttransplant. The current study extends the analysis to
      12 years. We find no evidence of cyclosporine-induced renal failure.

PMID- 8645886
TI  - Allogeneic microchimerism and donor antigen-specific hyporeactivity in lung
      transplant recipients.
AB  - The identification of peripheral donor cells in solid organ transplant recipients
      has led to speculation as to the tolerogenic role of circulating donor cells.
      Also being debated is the possible significance of persistent donor alloantigen
      presenting cells in inducing and maintaining an alloantigen-specific unresponsive
      state. Previously, we showed that donor antigen-specific hyporeactivity is a
      useful marker for identifying kidney, lung, or heart recipients at low risk for
      immunologic complications; we found donor antigen-specific hyporeactivity in 25%
      of kidney, 35% of lung, and 22% of heart recipients. All 3 hyporeactive subgroups
      experienced fewer late (> 3 months) rejection episodes and a lower incidence of
      chronic rejection. The purpose of the current study was to determine whether
      peripheral blood microchimerism correlates with the development of donor antigen
      specific hyporeactivity and affects clinical outcome. We correlated the detection
      of microchimerism with in vitro proliferative response to donor antigen in 19
      lung recipients who were > or = 12 months posttransplant. Allogeneic peripheral
      blood microchimerism was studied with a PCR-based limiting detection assay using
      HLA-DR sequence-specific primers. We detected microchimerism in 47% (9 of 19) of
      the lung recipients tested. All recipients who were donor antigen-specific
      hyporesponsive had microchimerism, and all recipients without detectable
      microchimerism were responsive to donor antigen. However, not all recipients with
      microchimerism developed donor antigen-specific hyporeactivity. Further, none of
      the hyporesponsive recipients has been diagnosed with obliterative bronchiolitis
      (OB). In contrast, 2 of the 4 with microchimerism who were responsive to donor
      antigen have been diagnosed with OB, as have 5 of the 10 who were negative for
      both hyporeactivity and microchimerism. Thus, long-term graft outcome may
      correlate more closely with donor antigen-specific hyporeactivity than with
      microchimerism.

PMID- 8645888
TI  - Behavioral distress, fear, and pain among children hospitalized for bone marrow
      transplantation.
AB  - This study assessed the extent of behavioral distress, fear, and pain of 10
      children hospitalized for bone marrow transplantation. Parents and nurses
      completed bi-daily ratings of the child's level of behavioral distress, fear, and
      pain, while children completed bi-daily ratings of their fear and pain. Analyses
      showed high parent-nurse agreement on ratings of children's behavioral distress,
      but generally low interrespondent agreement on ratings of children's fear and
      pain. Results also indicated significant changes over time for ratings of
      children's fear and pain, but not for ratings of behavioral distress.

PMID- 8645889
TI  - The utility of retroperitoneal kidney placement in simultaneous kidney pancreas
      transplantation.
AB  - Simultaneous kidney-pancreas (SPK) transplantation has become an accepted
      therapeutic modality for patients with Type I diabetes mellitus-mediated end
      stage renal disease (ESRD). However, the intraperitoneal placement of the renal
      allograft may pose technical problems when attempting percutaneous biopsy or
      Doppler ultrasound examination. Recently, the Stanford University Transplant
      Center adopted the technique of retroperitoneal placement of the renal allograft
      with intraperitoneal placement of the pancreas allograft (RETRO). From August
      1993 to August 1994, a total of 12 patients underwent SPK with this new
      technique. Twelve patients who had received SPK with the standard technique
      served as historical controls (INTRA). Demographic data, follow-up, operative
      time, creatinine and amylase on discharge, length of stay, intraoperative fluid
      requirements, rejection episodes, thrombotic complications, infections, and
      number of open and closed renal biopsies were compared between the two groups.
      Average length of follow-up was greater in the INTRA group (29.3 +/- 1.7 vs. 15.9
      +/- 1.1 months). In addition, the RETRO group had significantly fewer open renal
      biopsies (1/15) in comparison to the INTRA group (7/12) (p < 0.001). The two
      groups otherwise did not differ in any of the parameters studied. We conclude
      that retroperitoneal kidney and intraperitoneal pancreas allograft placement is
      associated with a significantly decreased requirement for open renal biopsy with
      its associated operating room and anesthetic costs. In addition, the option of
      transcystoscopic or percutaneous needle biopsy of the pancreas allograft is
      preserved. This technique should be considered as an alternative to
      intraperitoneal placement of both the pancreas and renal allografts.

PMID- 8645890
TI  - Cardiovascular complications following liver transplantation.
AB  - BACKGROUND: As the indications for liver transplantation broaden to include older
      and more critically ill patients, the likelihood of encountering unsuspected
      cardiovascular disease increases. PURPOSE: This study examined the frequency,
      type, and subsequent outcome of intra- and postoperative cardiovascular
      complications that occurred during the first 6 months following liver
      transplantation. METHODS: The records of 146 consecutive patients who underwent
      primary liver transplantation were reviewed retrospectively to determine the
      occurrence of major (myocardial infarction or reversible ischemia, pulmonary
      edema, cardiogenic shock, symptomatic rhythm disturbances, or pulmonary embolism)
      and minor (transient hypertension, hypotension, atrial or ventricular premature
      beats) cardiac events. The relation between such events and actuarial patient
      survival was evaluated. Stepwise logistic regression analysis was also employed
      to identify those pre-operative variables that predicted an increased risk of
      postoperative events or mortality. RESULTS: Cardiac events directly caused or
      contributed to 4 deaths (2.7%). Ventricular tachycardia/fibrillation was the most
      frequent intra-operative cardiac complication (3.4%); transient hypotension (post
      reperfusion syndrome) was the most common minor event (20%). Thirty-four
      recipients (23%) developed a major postoperative cardiac complication including
      pulmonary edema (9%), myocardial ischemia or infarction (5.4%), new dilated
      cardiomyopathy (3.4%), and ventricular tachycardia (2.7%). Pre-existing cardiac
      disease and older age (mean age 49 +/- 8 years) at transplantation were the only
      independent predictors of a major complication. Major cardiac events did not
      affect 6 month survival but were associated with a lower 5-year survival rate
      (event: 32% vs event-free: 52%; p = 0.04). The frequency of major intraoperative
      (21% vs 2%; p = 0.0005) and postoperative (57% vs 17%; p = 0.0001) cardiac
      complications was significantly higher for recipients with known heart disease
      (Group A) compared with those without pre-existing heart disease (Group B). Five
      year survival in Group A patients was 36% versus 50% for Group B patients; p =
      0.45. CONCLUSION: One or more cardiovascular complications occurred in over 70%
      of liver transplant recipients. Major events were associated with a lower
      likelihood of long-term survival. Older patients, particularly those with pre
      existing but compensated heart disease, are at greatest risk for a major cardiac
      event and may require more extensive pre-operative risk assessment.

PMID- 8645891
TI  - Immunologic monitoring of OKT3 induction therapy in cardiac allograft recipients.
AB  - OKT3 induction therapy was monitored in 31 cardiac allograft recipients during
      the 1st year posttransplant. Serum level of OKT3, anti-OKT3 antibodies, and
      interleukin-2 (IL-2) were monitored during the first 2 months posttransplant.
      These values were retrospectively correlated with allograft rejection episodes
      which occurred during the 1st year posttransplant and allograft survival rates
      over a 3-year observation period. We found that OKT3 induction therapy (10-14
      days) was not associated with the development of anti-OKT3 antibodies manifest by
      dropping OKT3 levels during OKT3 therapy, and is not associated with the
      development of vascular rejection in our patient population. Patients with high
      titer ant-OKT3 antibodies, erratic serum OKT3 levels, and/or high serum IL-2
      levels (> or = 5 ng/ml) during the first 2 months posttransplant showed a higher
      incidence of allograft rejection (predominantly cellular rejection) during the
      1st year posttransplant and showed lower allograft survival rates. We also showed
      that a concomitant elevation of serum IL-2 levels was found in patients who
      developed anti-OKT3 antibodies. CD3+ T-cell levels were not predictive of
      inefficacy of OKT3 therapy. We conclude that immunologic monitoring of serum
      OKT3, anti-OKT3 antibody, and possibly serum IL-2 levels is critical for
      identification of patients who develop early, OKT3-resistant rejection episodes
      and for the identification of patients who may be more susceptible to allograft
      rejection and decreased allograft survival long after completion of OKT3 therapy.

PMID- 8645892
TI  - Effect of 1-28 alpha-h atrial natriuretic peptide on acute renal failure in
      cadaveric renal transplantation.
AB  - The efficacy and safety of (1-28) alpha-human ANP in preventing acute tubular
      necrosis (ATN) in cadaveric renal transplantation was tested by comparing ANP
      infusion with a maximal hydration (MH) regimen which we previously reported as
      effective in lowering the incidence of ATN (1, 2). Since the production of
      endogenous ANP increases with volume overloading (3), we hypothesized that
      increased endogenous ANP production may contribute to the beneficial effects of
      MH in renal transplant recipients. We thus conducted an open randomized study
      comparing the effect on early renal allograft function of MH (control group)
      versus moderate hydration plus ANP infusion (ANP group). Forty patients were
      blindly paired in two groups of 20 according to the duration of cold ischemia
      time (mean +/- 2 h). The demographic characteristics of donors and recipients
      were similar. Using a Swan-Ganz catheter, hemodynamic parameters were monitored
      for 4 h after transplantation. The group receiving ANP and moderate hydration was
      perfused to a mean pulmonary arterial pressure (PAP) of < or = 20 mmHg. The PAP
      in patients receiving MH was driven to > or = 25 mmHg. In the ANP group, a bolus
      of 100 micrograms of ANP was infused into the graft's renal artery at the time of
      unclamping, followed by 24 h of continuous intravenous infusion at 0.03
      microgram/kg/min. Thereafter, the patients received ANP at a rate of 0.01
      microgram/kg/min until the serum creatinine reached < 2 mg/dl. As a consequence
      of the hydration regimen, the PAP at unclamping was lower in the ANP group than
      in the control group; 20 +/- 3 and 26 +/- 4 mmHg, respectively (p < 0.05). The
      ANP plasma levels were significantly higher during the first 3 d in the ANP group
      (p < 0.001). The median recovery rate of renal function was similar in both
      groups. No patients in the ANP group experienced ATN while 4 patients (20%) in
      the control group did (p = 0.125). The need for hemodialysis was markedly reduced
      in the ANP group compared to the control group (1 ANP-treated patient required
      dialysis once whereas 5 patients from the control group underwent dialysis a
      total of 26 times; p = 0.068). ANP administration was well-tolerated and no
      hypotensive episodes were reported. This preliminary study suggests that ANP
      infusion is at least as effective as maximal hydration in preventing ATN and
      represents an efficient alternative for transplantation centers which do not use
      maximal hydration as a standard regimen in managing kidney allograft recipients.

PMID- 8645894
TI  - "Marginal quality" donor livers: not so marginal.

PMID- 8645893
TI  - Use of immune globulin to prevent symptomatic cytomegalovirus disease in
      transplant recipients--a meta-analysis.

PMID- 8645895
TI  - [Differences in application and granting benefits for severely disabled patients
      before and after introduction of new benefits within the scope of the public
      health reform law].
AB  - Constituting part of the health reform in Germany ("Bundesgesundheits
      Reformgesetz"), an extension of health insurance benefits for severely disabled
      persons was introduced in 1991. The assessment of eligibility for benefits is
      based on standardised medical examinations. Examinations performed in the state
      of Baden-Wurttemberg in 1990 (n = 6401) were compared with a 20% random sample of
      those performed in 1991 (n = 7563) in order to analyse eventual changes in
      acceptance rates of applications. Acceptance rates decreased from 87.9% in 1990
      to 70.8% in 1991. The difference could not be explained by differences in age,
      sex, medical diagnosis or dependence on help in daily activities. This suggests
      that acceptance criteria were less restrictive before introduction of the
      extension of benefits.

PMID- 8645896
TI  - [Interdisciplinary cooperation in primary care of elderly patients--results of
      results with consequences for general practice].
AB  - In the networking of health care provision for the elderly the inclusion of the
      general practitioner is considered to be lacking, although the
      "Gesundheitsreformgesetz" (GRG) demands that the GP should act as a coordinator
      (Section 73 of German social welfare legislation). The views of GPs on already
      existing cooperation and on barriers to such cooperation in a selected district
      of Hamburg were examined by means of guided interviews. With the help of the
      agents in the region the building blocks for promoting cooperation were then
      developed in the district. A significant precondition for this was to make sure
      that the available local services on offer in respect of health promotion and
      health care provision are utilised by means of a data bank and a directory. On
      this basis the potential cooperation partners were identified and a local work
      circle comprising representatives of the most important health and social
      services was set up. From this a quality circle which was interdisciplinary and
      also consisted of members from all relevant fields was established, together with
      a working group on the development of a community based advice centre for the
      elderly.

PMID- 8645897
TI  - [Evaluation of anamnestic data of cancer patients (comprehensiveness of the
      "Oldenburg Anamnesis Questionnaire")].
AB  - An evaluation of case history data of cancer patients is presented. These data
      were recorded by means of a case history form in the cancer registry of Weser-Ems
      between 1988 and 1993 in the Weser-Ems region (Lower Saxony). Completeness and
      rate of errors were the quality criteria. The completeness was insufficient (23
      92%), whereas the rate of errors was low (1%). In the course of years the
      completeness of the clinically relevant items increased, probably because the
      form had to be completed by the physician. About 99% of the cancer patients were
      of German nationality. The cause of registration was mainly the appearance of
      symptoms or a pathological finding while investigating for another reason. In
      respect of correlations between anamnestic data and carcinomas smoking or/and
      alcohol-abusus were significant. There was an association in men between these
      factors and carcinomas of the oropharynx and oesophagus, respectively of the
      lung; 85 resp. 75% of the men with theses carcinomas had smoked excersively
      and/or had abused alcohol. Data concerning the profession of the patients were
      irrelevant. Gynaecological ananestic data did not yield any new knowledge, which
      is why these and other items may be ignored. This resulted in a new anamnestic
      and patient questionnaire sheet were drawn up. These are now being tested in the
      Weser-Ems region since October 1995.

PMID- 8645899
TI  - [Prevention during building construction against electromagnetic fields caused by
      high voltage electric lines--principles and risk evaluation].
AB  - A growing body of evidence by new risk assessments concerning permanent exposure
      to low level, extremely low frequency electric and magnetic fields shows, a
      moderate long-term risk. This possible long-term risk makes it necessary to think
      about prudent avoidance in city planning. There is no Federal German legislation
      to make prevention mandatory. The risk assessments are based on epidemiological
      investigations of a relationship between residential locations of children in the
      vicinity of power lines and incidence of leukemia. The study design of recent
      studies has been essentially optimised compared to previous ones. The
      investigations have been carried out independently. The overall conclusion is
      more in favour of a relationship than against it. In Hamburg a preventive
      practice was established several years ago. Safe distances between power lines
      and new apartment houses are taken into account. Other concepts of avoidance are
      presented. These may be guided by values of magnetic fields or can be expressed
      by security distances, as can be shown by international examples.

PMID- 8645898
TI  - [A leukemia cluster in the Pinneberg district. Results of an incidence study by
      the epidemiologic task force of the Schleswig-Holstein Medical Association].
AB  - After regional media had reported in early 1995 of multiple leukaemia cases in a
      small community in the state of Schleswig-Holstein, an "Epidemiological Task
      Force" was asked to review the existing evidence for a possible cluster. The Task
      Force is a small group appointed in 1994 by the regional Medical Association and
      the state's ministry of social affairs. It includes five professionals from the
      fields of environmental toxicology and hygiene, Public Health, epidemiology and
      cancer pathology. In agreement with the local Public Health administration and
      the ministry the Task Force organized a retrospective screening of all incident
      leukaemia, lymphoma and myeloma cases (ICD-9 codes 200-208) within a (5-10 km)
      around the small community (population on December 31st 1993: 72000) that had
      occurred after January 1st 1990. Any practising physician (response rate 78%),
      hospital (100 %), oncological centre (100%), and tumour registry (100%) serving
      the region were asked to notify all relevant cases to the Task Force.
      Additionally spontaneous case reports were elicited, and all death certificates
      from the a.m. time period were screened for by two Public Health administrations.
      We identified 202 single cases for further analysis. Comparative data for the
      entire region and single communities came from two cancer registries, the Danish
      and that of the state of Saarland/FRG, and allowed for calculating the expected
      number of cases by indirect standardisation. While Hodgkin's lymphomas and
      myelomas were (insignificantly) less frequent than expected, an excess of non
      Hodgkin's lymphomas and leukaemias (all types combined) was observed.
      Standardised incidence ratios for the whole region varied between 1.54 and 1.68
      with significant and consistent increases only for the group of leukaemias among
      adults (aged 15+). All results were reported to both the public and
      administrative/professional bodies together with specific recommendations. The
      reactions showed a good acceptance of the Task Force and its work.

PMID- 8645900
TI  - [Results from an epidemiologic study program of meningitis/encephalitis in
      Berlin, I: 1 January 1992-31 March 1994].
AB  - Although four types of meningitis/encephalitis must be reported by the Federal
      Communicable Disease Act since 1980, the incidence of etiologically not
      identified cases is constant over the years. We report on the first results in
      1097 patients with meningitis who were examined by microbiological methods. These
      examinations were free of charge for the clinics in Berlin.

PMID- 8645901
TI  - [Oral disease epidemiologic illness indices and oral health measures--traditional
      concepts are supplemented by new socio-dental indicators].
AB  - The article describes various of the commonly used measures for oral health and
      disease. Their disadvantages and shortcomings are discussed, and alternative
      approaches are presented. It is argued that the "classical" clinical indices
      reflect only parts of a holistic understanding of oral health. They should be
      supplemented by psycho-social measures, so-called socio-dental indicators, which
      can be applied in epidemiological surveys as well as in the evaluation of
      preventive programmes.

PMID- 8645902
TI  - [Ring trials in expert assessment--a practicable procedure for quality
      assurance?].
AB  - An intercomparison programme for expert assessment was carried out as part of
      quality assurance for the public health departments in Bavaria. A file
      documenting medical diagnoses and reports of a patient was presented to medical
      doctors in a district of Bavaria and in the Academy for Public Health Services in
      Munich for assessment. The participation was voluntary and anonymous. The case
      presented was an obese man who wanted to become a civil servant. The doctors were
      asked to give an expert assessment of his health. Four criteria were used to
      evaluate the assessments: the assessment, its conclusiveness, the documentation
      and the epicrisis. 54 out of 100 doctors asked participated. On average all
      criteria were adequately fulfilled. This paper discusses the advantages and
      disadvantages of an intercomparison programme for expert assessments in the field
      of social medicine. Our results show that an intercomparison programme for expert
      assessments could form part of quality assurance.

PMID- 8645903
TI  - [Results of expert assessment of disability with reference to selected diagnostic
      groups by the Medical Service of Hospital Insurance].
AB  - A topical survey is given by the documentation of the examination for the
      statutory nursing care insurance. The first part of the report contains the
      complete tabulated results of the Federal Republic of Germany. Furthermore a
      graphical comparison of selected groups of diagnoses like psychiatric disorders
      has been statistically evaluated and is commented upon.

PMID- 8645904
TI  - Carbon-catalyzed oxidative coupling of phenolic compounds.

PMID- 8645905
TI  - Pentachlorophenol levels in human urine.

PMID- 8645906
TI  - Migration of some toxic metals from crayons and water colors.

PMID- 8645907
TI  - Comparison of personal and area sampling strategies in assessing workers'
      exposure to vinyl chloride monomer.

PMID- 8645908
TI  - Impact on blood lead in children and adults following relocation from their
      source of exposure and contribution of skeletal tissue to blood lead.

PMID- 8645910
TI  - Recovery of trace organic chemicals from a large mass of water using a newly
      developed liquid-liquid continuous extractor.

PMID- 8645909
TI  - Organochlorine pesticide residues in cow's milk in Uganda.

PMID- 8645911
TI  - Photodegradation of Aroclor 1254 using simulated sunlight and various
      sensitizers.

PMID- 8645912
TI  - Photodegradation of 2,2',5,5'-tetrachlorobiphenyl in hexane.

PMID- 8645913
TI  - Adsorption/desorption and mobility of carbofuran in soil samples from Kenya.

PMID- 8645914
TI  - Distribution and dissipation of carbofuran in a paddy field in the Kano plains of
      Kenya.

PMID- 8645915
TI  - Fungicide procymidone residue in agriculture land.

PMID- 8645916
TI  - Adjusting hydration water volume to decrease preparation time in seed germination
      studies.

PMID- 8645917
TI  - Variation of brain and serum cholinesterase activity with age in wild small
      mammals.

PMID- 8645918
TI  - Northern bobwhite egg hatchability and chick immunocompetence following a field
      application of diazinon.

PMID- 8645919
TI  - Evaluation of technical HCH residues in differentiating rat intestinal epithelial
      cells.

PMID- 8645920
TI  - Comparative split dose effects of selenate and selenomethionine on erythropoiesis
      of mice.

PMID- 8645921
TI  - Bismuth induces metallothionein but does not protect against cadmium cytotoxicity
      in cultured vascular endothelial cells.

PMID- 8645923
TI  - Structure-toxicity relationships for aliphatic isothiocyanates to Tetrahymena
      pyriformis.

PMID- 8645922
TI  - Acetyl tributyl citrate and dibutyl sebacate inhibit the growth of cultured
      mammalian cells.

PMID- 8645924
TI  - Estimating safe concentrations of fluoride for three species of Nearctic
      freshwater invertebrates: multifactor probit analysis.

PMID- 8645925
TI  - Lead induced thyroid dysfunction and lipid peroxidation in the fish Clarias
      batrachus with special reference to hepatic type I-5'-monodeiodinase activity.

PMID- 8645926
TI  - Vertebral deformity susceptibilities of marine fishes exposed to herbicide.

PMID- 8645927
TI  - Stage-dependent uptake of cadmium by Bufo arenarum embryos.

PMID- 8645928
TI  - Uptake and elimination of cadmium by Japanese eel, Anguilla japonica, at various
      temperatures.

PMID- 8645929
TI  - Effects of metals on alpha-amylase activity in the digestive gland of the green
      mussel, Perna viridis L.

PMID- 8645931
TI  - Evaluation of an improved ileus monitoring system for intestinal motility.
AB  - To observe the recovery of normal intestinal movement and the effects of
      peristalsis-promoting agents in patients with intestinal obstruction, an ileus
      monitoring system using the balloon method was simultaneously compared with that
      using the infusion method in 24 patients. To initiate the balloon ileus
      monitoring system, measurement was started at a setting of 0 after connecting a
      transducer to the balloon inflation channel of a decompression tube. The
      recording sensitivity was 20 mmHg/cm, and the speed of recording was 5 mm/min.
      The sensitivity of the infusion method was found to be 0.70 +/- 0.17 times that
      of the balloon method, and therefore the balloon method was considered to be more
      accurate. The findings of this study show how useful this ileus monitoring system
      is for observing the motility of intestinal obstruction.

PMID- 8645930
TI  - Decreased expression of DCC mRNA in gastric and colorectal cancer.
AB  - The deleted-in-colorectal-cancer (DCC) gene, located on chromosome 18q 21.3, is
      considered to be a tumor suppressor gene related to cellular adhesion receptors.
      A loss of heterozygosity (LOH) on chromosome 18q is frequently observed in
      adenomatous polyposis coli, as well as in sporadic colon carcinoma and its liver
      metastatic loci. In this study, we investigated the expression of DCC mRNA in the
      resected specimens of 38 gastric cancers and 28 colorectal cancers by a reverse
      transcription-polymerase chain reaction method. In the gastric cancer patients,
      the mean expression level of DCC mRNA in the tumors was significantly lower than
      that in normal tissues (p = 0.009), but no difference was observed in the
      colorectal cancer patients. DCC mRNA expression was decreased in 15 gastric
      cancers (40%) and 10 colorectal cancers (36%), and there was a significant
      correlation between the decreased expression of DCC mRNA and nodal metastasis in
      colorectal cancer (chi 2 = 7.049, DF = 1, P = 0.0079). Two of four gastric cancer
      patients and none of seven colorectal cancer patients whose cancers were confined
      to the muscularis propria without metastasis showed decreased expression of DCC
      mRNA. These findings demonstrate that decreased expression of DCC mRNA may occur
      at an early stage in gastric cancer and at a late stage in colorectal cancer and
      that this decreased expression correlates with the potential to develop nodal
      metastasis.

PMID- 8645932
TI  - Preoperative disseminated intravascular coagulation (DIC) associated with aortic
      aneurysm--does it need to be corrected before surgery?
AB  - Disseminated intravascular coagulation (DIC) is one of the complications
      accompanying aortic aneurysm. We herein report four patients with aortic aneurysm
      who had DIC preoperatively. In all four cases, DIC was corrected immediately
      after surgery; however, in two cases, DIC could not be corrected preoperatively.
      This prompted us to reconsider the importance of correcting DIC before surgery.
      Of the four cases reported in this paper, DIC existed even at the time of surgery
      in two cases, in spite of meticulous treatment with heparin and/or protease
      inhibitor; however, the DIC could be removed postoperatively even in these two
      cases. Surgeons should not waste time with intensive DIC treatment
      preoperatively. If the DIC cannot be corrected within more than 2 weeks of
      meticulous treatment, surgeons should then perform surgery on the patient. In
      addition, it is also essential to ensure that the DIC is due to the aneurysm
      itself and that no other disease processes have been overlooked.

PMID- 8645934
TI  - Doppler ultrasonographic evaluation of hepatic circulation in patients following
      Kasai's operation for biliary atresia.
AB  - The hepatic circulation of eight children who underwent Kasai's operation for
      biliary atresia was serially evaluated by Doppler ultrasonography (US). A total
      of 36 examinations were performed to evaluate the maximal velocities (mvs) of the
      main portal vein (MPV), splenic vein (SV), and hepatic artery (HA), and to
      analyze the spectral waveform and the directions of flow. The mean mvs-MPV in
      four patients for whom adequate biliary diversion had been achieved and whose
      serum bilirubin had fallen to within the normal range (group A), was 19.8 +/- 7.5
      cm/s. Their MPV waveforms were constant, with blood flowing toward the liver,
      while their mean mvs-SV was 12.1 +/- 5.8 cm/s. In two other patients with
      apparent hypersplenism, but whose serum bilirubin levels had fallen to nearly
      normal (group B), the mean mvs-MPV was 20.7 +/- 10.4 cm/s and the mvs-SV was 22.4
      +/- 10.4 cm/s. In contrast, the mvs-MPV in the two remaining patients, whose
      serum bilirubin levels had either not fallen to within the normal range, or had
      fallen initially but increased due to recurrent cholangitis (group C), was 14.2
      +/- 9.1 cm/s. In these patients, the waveforms were unstable, the MPV flows were
      occasionally hepatofugal, and their mean mvs-SV was 18.0 +/- 5.8 cm/s. The mvs-HA
      were markedly increased in the latter four patients, whose clinical condition had
      also deteriorated. These observations led to the conclusion that hepatic
      circulation evaluated by serial Doppler US provides important information about
      liver status in children who have undergone Kasai's operation for biliary
      atresia.

PMID- 8645933
TI  - Clinicopathological study of clear-cell tumors of the thyroid: an evaluation of
      22 cases.
AB  - Twenty-two cases of partial or wholly composed clear-cell thyroid tumors were
      reviewed to differentiate between a primary nodule and metastatic clear-cell
      renal carcinoma in the thyroid. Pathological reevaluation of HE-stained
      specimens, immunohistochemical observation using anti-thyroglobulin (TG)
      antibody, and periodic acid-Schiff (PAS) staining were performed. The
      pathological characteristics in metastases from the kidney have a greater
      tendency to demonstrate a strikingly clear cytoplasm with small nuclei, rich
      vascularization, and a trabecular arrangement of tumor cells than do primary
      thyroid cases. The immunohistochemical TG staining in conjunction with PAS
      staining for the recognition of follicular colloid could provide much more
      reliable information of primary cases compared to that using TG staining alone.
      Clinically, in primary cases, the female:male ratio is substantially higher while
      the mean age is lower than in metastatic cases reflecting differentiated thyroid
      carcinoma. In conclusion, immunohistochemical staining for TG with PAS staining
      for the recognition of follicular colloid proved to be the most sensitive method
      for identifying primary clear cell thyroid tumors. In addition, a careful
      assessment of past and/or present kidney disorders to rule out metastatic renal
      cell carcinoma is advisable. Age, gender, and physiological findings are also
      informative when differentiating between them.

PMID- 8645935
TI  - The effect of pancreatopeptidase E (elastase) on anastomotic intimal thickness in
      two types of vascular prosthesis.
AB  - To determine the effects of pancreatopeptidase E (elastase) on anastomotic
      intimal thickness in vascular prostheses, expanded polytetrafluoroethylene
      (ePTFE) and Dacron grafts were implanted in the infrarenal aortas of 28 adult
      mongrel dogs, divided into four groups of seven dogs each according to the type
      of graft used and whether or not elastase was given. Thus, group E received ePTFE
      grafts without elastase; group D received Dacron grafts without elastase; group E
      + Ela received ePTFE grafts with concomitant oral elastase, 8 mg/kg per day; and
      group D + Ela received Dacron grafts with elastase given at the same dosage as in
      group E + Ela. Each graft was harvested 4 months following surgery for histologic
      examination. It was clearly observed that elastase suppressed intimal growth at
      the proximal and distal anastomoses in the ePTFE grafts (P < 0.05), but not in
      the Dacron grafts. Furthermore, when we measured the smooth muscle cell percent
      extinction (%E) on microspectrophotometry in the intima within 2 mm of the
      proximal and distal anastomoses, it was found that elastase reduced intimal
      smooth muscle proliferation at the anastomosis of the ePTFE grafts, but not the
      Dacron grafts (P < 0.05). These data suggest that elastase suppresses intimal
      growth by inhibiting smooth muscle cell migration and proliferation in the
      vascular prostheses of low but not of high porosity.

PMID- 8645936
TI  - Carcinoma of the fourth part of the duodenum: report of a case.
AB  - Primary carcinoma of the duodenum is rare, accounting for only 0.35% of all
      gastrointestinal carcinomas, and carcinoma of the fourth part of the duodenum
      constitutes approximately 10% of duodenal carcinomas. Since the predominant
      symptoms of tumors in this part of duodenum are related to upper intestinal
      obstruction, the diagnosis is usually made late. We report the case of a 66-year
      old man who presented with anemia, weight loss, and upper intestinal obstruction,
      and was found to have advanced primary carcinoma of the fourth part of the
      duodenum by upper gastrointestinal series and computed tomography (CT). A review
      of the literature indicates that survival, which is related to nodal status, the
      grade of the tumor, and surgical results, seems to be longer in patients with
      carcinoma in this part of the duodenum compared to those with carcinomas in other
      parts of the duodenum. Moreover, segmentary resection has been reported to
      achieve a favorable outcome.

PMID- 8645937
TI  - Synchronous double cancers of the remnant stomach and pancreas: report of a case.
AB  - We present here in the case of a 75-year-old man who developed synchronous double
      cancers of the remnant stomach and pancreas 12 years after undergoing distal
      gastrectomy for gastric carcinoma. The patient was referred to our hospital in
      March, 1993, with a provisional diagnosis of carcinoma of the remnant stomach.
      Laboratory data on admission showed an abnormal level of CA19-9 (116.1 U/ml) and
      positive occult blood in the stools. An upper gastrointestinal series and
      gastroendoscopy demonstrated an ulcerative polypoid tumor in the gastric stump
      proximal to the gastroduo-denostomy anastomosis, and a biopsy confirmed the
      findings of mucinous adenocarcinoma. Abdominal computed tomography (CT) scan
      revealed a low-density nodule anterior to the abdominal aorta, suggestive of a
      nodal metastasis. A laparotomy was performed which also disclosed a low-density
      mass located within the head of the pancreas. The patient was subsequently
      diagnosed as having double carcinomas of the remnant stomach and pancreas, and
      total gastrectomy and pancreatoduodenectomy were carried out. The histologic
      sections from the remnant stomach showed mucinous adenocarcinoma, whereas those
      from the pancreas showed tubular adenocarcinoma. Double carcinomas in this
      association are extremely rare and this case may in fact be the first observation
      of synchronous double cancers of the remnant stomach and pancreas.

PMID- 8645938
TI  - Lymphoepithelial cyst of the pancreas: a preoperatively diagnosed case based on
      an aspiration biopsy.
AB  - This paper reports an extremely rare case of lymphoepithelial cyst of the
      pancreas. The patient, a 58-year-old man with no subjective symptoms, was found
      to have a pancreatic tumor during a physical examination. He visited our clinic
      and was admitted for a follow-up examination. Based on the ultrasonographic
      findings, superselective angiography, and aspiration biopsy, an epidermoid cyst
      was diagnosed. Enucleation was easily performed. Macroscopically, this cyst
      resembled an atheroma. Histologically, the cavity of the cyst was lined with a
      squamous epithelium with a nucleated layer and below that, lymphatic tissue. No
      malignancy was found. Tumors of the pancreas with a squamous epithelial covering
      are extremely rare; only a few such cases have been reported in the literature.
      As of 1991, only 12 cases, including the present case, had been reported. With
      the advances in diagnostic techniques, the detection of pancreatic tumors is
      expected to improve. This paper reports a case in which the use of an aspiration
      biopsy and superselective angiography proved to be useful in making an accurate
      diagnosis.

PMID- 8645939
TI  - Carcinoid tumor of the gallbladder: report of a case.
AB  - We report herein the rare case of a 40-year-old woman with a 10-year history of
      dull abdominal pain, in whom a carcinoid tumor of the gallbladder was confirmed
      by postoperative histological findings. A review of the world literature revealed
      that only 22 other such cases have been documented, all of which were diagnosed
      by incidental findings at the time of surgery or at post mortem. Although these
      patients may present with liver metastasis, rarely do they manifest with features
      of a carcinoid syndrome. The rarity of this entity prompted us to present our
      patient's case report, followed by a brief review of the literature on the
      previous 22 cases.

PMID- 8645940
TI  - Carcinoma of the cystic duct protruding into the common bile duct: report of a
      case.
AB  - We report herein the case of 65-year-old man in whom a diagnosis of primary
      carcinoma of the cystic duct was made on the basis of Farrar's criteria. The
      patient was admitted with upper abdominal pain, and although there was no
      evidence of jaundice or a palpable mass, there was tenderness in his right upper
      quadrant. Carcinoma of the cystic duct was suspected on the basis of computed
      tomography and magnetic resonance imaging findings. Cholecystectomy with
      resection of the bile duct and lymph node resection was performed, and
      percutaneous transhepatic cholangiography revealed a filling defect in the common
      bile duct (CBD). The tumor was found to have arisen from the cystic duct and
      demonstrated papillary growth into the CBD intraluminally through the orifice of
      the cystic duct. Microscopically, the tumor was identified as papillary
      adenocarcinoma with invasion limited to the subserosal layer of the cystic duct.
      There were no signs of nodal metastasis.

PMID- 8645941
TI  - Synchronous growth of triple lung cancer.
AB  - The case of a 75-year-old man with three synchronous carcinomas of the lung
      (large cell carcinoma, adenocarcinoma, and small cell carcinoma) is reported.
      This is the eighth well-documented case report in the literature; however, our
      case is the first to be reported with the newly described histological
      combination.

PMID- 8645942
TI  - Endobronchial leiomyoma: report of a case treated by bronchoplasty and a review
      of the literature.
AB  - Endobronchial leiomyoma is extremely rare. Most endobronchial leiomyomas reported
      in the literature have been resected by either lobectomy or pneumonectomy. We
      herein report a case treated by sleeve bronchoplasty without pulmonary resection.
      A 42-year-old woman was admitted to our hospital complaining of hemoptysis.
      Bronchoscopy revealed a lobulated tumor arising from the medial wall of the right
      main stem bronchus. A sleeve resection of the right main bronchus including the
      tumor and end-to-end anastomosis was performed. The histological diagnosis of the
      resected specimen was leiomyoma with no evidence of malignancy. The importance of
      early diagnosis and appropriate surgical treatment to preserve pulmonary function
      are emphasized. Similar cases of an endobronchial type of pulmonary leiomyoma
      reported in the literature are also reviewed.

PMID- 8645943
TI  - The effect of thymectomy on myasthenia gravis, thrombocytopenia, and
      granulocytopenia associated with thymoma: report of a case.
AB  - We report the case of a 47-year-old woman with thymoma who developed myasthenia
      gravis, thrombocytopenia, and granulocytopenia, simultaneously, the concurrent
      association of these four disorders being extremely rare. Thymectomy was
      performed, and, during the post-thymectomy course, there were surprising findings
      concerning the recovery of not only the myasthenia gravis but also of the
      hematologic disorders. Immediately after thymectomy, the myasthenic symptoms
      completely disappeared, and the granulocyte and platelet counts recovered to
      within the normal range within a few days. The laboratory data revealed no
      difference between pre- and post-thymectomy in the release of cytokines (tumor
      necrosis factor; TNF, interleukin; IL-2, and IL-6), anti-acetylcholine receptor
      antibody, or platelet-associated IgG. On the other hand, the serum level of anti
      neutrophil cytoplasmic antibody (p-ANCA), against the myeloperoxidase of the
      granulocytes was dramatically decreased, after thymectomy, showing a significant
      correlation with the granulocyte count. According to our survey of the
      literature, this is the first report to show that the removal of a thymoma led to
      the dramatic resolution not only of myasthenia gravis but also of other
      associated diseases. It is possible that p-ANCA may be regulated by thymoma, thus
      causing severe granulocytopenia.

PMID- 8645944
TI  - Radiographic diagnosis and surgical repair of a sciatic hernia: report of a case.
AB  - We report the case of a 44-year-old woman who presented with a reducible painless
      swelling in her left buttock. The mass was preoperatively diagnosed as a sciatic
      hernia by herniography, which showed the peritoneal sac through the sciatic
      foramen, and by enterography, intravenous pyelography, and cystography, which
      demonstrated that the small intestine and urinary bladder had herniated into the
      sac. The diagnosis and management of this patient are described, followed by a
      review of the literature on sciatic hernias.

PMID- 8645946
TI  - Celiac disease and insulin-dependent diabetes mellitus--no proof for a causal
      association.

PMID- 8645945
TI  - The use of cyanoacrylate tissue adhesive in high-risk intestinal anastomoses.
AB  - The success of every intestinal surgical procedure primarily depends on correct
      technical execution of the intestinal sutures. Despite the continuing
      improvements in intestinal synthesis techniques and the introduction of
      mechanical staplers, the risk of anastomotic dehiscence remains a major concern.
      For high-risk anastomoses, defined as those performed under critical conditions,
      n-butyl-2-cyanoacrylate tissue adhesive allows for quick sealing of the two
      stumps and supports the physiological wound-healing process. Furthermore, no
      experimental or clinical studies have shown that this glue has any carcinogenic
      or mutagenic properties. Thus, we believe that n-butyl-2-cyanoacrylate will be
      extremely useful for intestinal anastomoses with a high risk of dehiscence.

PMID- 8645947
TI  - Quality of life among young adults born with very low birthweights.
AB  - Quality of life (QoL) was assessed in 85 young adults, born in 1971-1974 with
      birthweights < 1500 g (VLBW) and admitted to the neonatal intensive care unit of
      the State University Hospital in Copenhagen, Denmark. Their QoL was compared to
      that of 85 subjects with birthweights > 2500 g (NBW) born in the same period at
      the State University Hospital. The subjects were interviewed by telephone on the
      basis of the well-defined theories on QoL by Anton Aggernaes. Quality of life was
      assessed both in objective terms and as judged by the interviewed person.
      Subjects born with VLBWs and free of handicaps had QoL scores (both objective and
      subjective) fully comparable with the NBW group. VLBW subjects reporting various
      physical and mental handicaps had objective as well as subjective QoL scores
      significantly lower than the NBW group.

PMID- 8645948
TI  - Age-related decrease in plasma levels of gastrin, cholecystokinin and
      somatostatin.
AB  - Newborn babies have higher concentrations of gastrointestinal hormones than
      adults. The aim of the present study was to investigate the relationship between
      age and plasma levels of the three peptides gastrin, cholecystokinin and
      somatostatin in healthy children aged 1-15 years. Gastrin, cholecystokinin and
      somatostatin concentrations were twice as high at 1-2 years of age compared with
      children older than 10 years. Significant negative correlations between age and
      hormone concentrations were established. It is suggested that these age-dependent
      differences are related to the growth rate and relative energy consumption during
      the early years of life.

PMID- 8645949
TI  - Influence of two infant formulas and human milk on the development of the faecal
      flora in newborn infants.
AB  - The establishment of the faecal flora of 39 full-term infants fed exclusively on
      breast milk (n = 20) or with two different modern adapted cow's milk formulas (n
      = 19) was studied during the first 3 months of life. One formula investigated was
      based on 100% bovine casein as the protein source whereas the other formula
      contained bovine milk proteins with a whey/casein ratio of 60:40. A faecal flora
      rich in bifidobacteria was found in all study groups; the growth of putrefactive
      bacteria (especially Bacteroides spp.), however, was limited. In formula-fed
      infants, significantly higher bacterial counts of enterococci and clostridia were
      detected compared to breast milk-fed infants. Similarities and differences due to
      the feeding regimen were particularly reflected in the pattern of the anaerobic
      bacterial species. Bifidobacterium bifidum, B. infantis and B. breve constituted
      the majority of the bifidobacterial flora independent of the type of milk
      feeding. Other bifidobacterial species such as B. longum, B. adolescentis, B.
      parabifidum and B. pseudo-catenulatum were detected in high numbers and at low
      frequencies in breastfed infants. The latter three were observed in infants fed
      the whey/casein formula as well. It seems that infants fed a casein formula
      develop a faecal flora more like that of breastfed infants concerning
      Lactobacillus spp. (especially L. fermentum and L. brevis).

PMID- 8645950
TI  - Impact of chronic undernutrition on higher mental functions in Indian boys aged
      10-12 years.
AB  - Undernourished rural children 10-12 years of age demonstrated the following, when
      compared to normal nourished children: (i) a relative deficit of memory quotients
      assessed by the Wechsler memory scale; (ii) lower scores for abilities related to
      personal and current information, orientation, mental control, logical memory,
      digit span, visual reproduction and associative learning; (iii) impaired set
      formation and flexibility in attention as assessed by the card sorting test; and
      (iv) impairment in conditional learning on maze and conditional associative
      learning tests. The performance on the finger dexterity test for fine motor
      coordination was not affected in undernourished children.

PMID- 8645951
TI  - Sexual maturation in East German girls.
AB  - According to the internationally accepted classification (Tanner, 1962; van
      Wieringen, 1971), sexual maturation was investigated in 8703 healthy East German
      girls by means of the status quo method and probit regression analysis. The
      third, 50th and 97th centiles were calculated for the development of breasts,
      axillary and pubic hair, and the shape of the hips. The findings were compared
      with those of recent studies from different European countries. Special attention
      was paid to the stages at the beginning and at the end of sexual maturation, e.g.
      B2/B5, AH2/AH3, etc.

PMID- 8645953
TI  - Low sodium levels in serum are associated with subsequent febrile seizures.
AB  - Fever plays an important role in causing disturbances in fluid and electrolyte
      balance. Hyponatraemia has been thought to enhance the susceptibility to seizures
      associated with febrile illnesses in childhood. We have studied serum electrolyte
      levels in children with simple and complicated febrile convulsions. Sodium levels
      were lower in those children with complicated convulsions in comparison with
      those having simple convulsions (136.07 +/- 3.06 mmoll-1, mean +/- SD, n = 42,
      and 137.62 +/- 2.63 mmoll-1, n = 71, respectively; p < 0.01, Student's t-test).
      The sodium concentrations were lowest in children with repeated seizures (134.20
      +/- 2.30 mmoll-1, n = 15) compared with children having simple (p < 0.01, ANOVA,
      Duncan's test) or other complicated types of febrile convulsions: focal seizures
      (137.08 +/- 3.82 mmoll-1, n = 12, p < 0.01), seizures lasting longer than 15
      minutes (138.00 +/- 2.45 mmoll-1, n = 5, p < 0.05) and children over 5 years
      (136.70 +/- 2.06 mmoll-1, n = 10, p < 0.05). Serum potassium levels showed no
      statistically significant differences between the patient groups. Our results
      show that hyponatraemia may increase the risk for multiple convulsions during the
      same febrile illness.

PMID- 8645952
TI  - Autopsies of sudden infant death syndrome--classification and epidemiology.
AB  - An enquiry into sudden infant death syndrome (SIDS) in 1987 furnished us with
      detailed epidemiological data for 281 cases that underwent a thorough post-mortem
      examination. This analysis uses these data to evaluate the role the autopsy plays
      in explaining sudden death. The cases were classified into three diagnostic
      groups: explained causes of death (group 1), unexplained deaths with anomalies
      (group 2), and no anomaly (group 3). These 281 cases show the three essential
      features that characterize SIDS: over-representation of males, increased deaths
      during the second and third months of life, and increased deaths during winter.
      The autopsy examination revealed that many of these deaths had a medical
      explanation. Almost half were assigned to group 1. At the time of autopsy, no
      precise pathology could be diagnosed for 147 deaths; of these, 140 showed
      histological anomalies. There were only seven sudden deaths for which no abnormal
      sign was evident at the autopsy. These results are compared with those of similar
      studies and discussed in connection with three factors: the initial selection of
      cases, the nature and degree of the investigations, and the possible
      interpretations of the symptoms uncovered.

PMID- 8645954
TI  - The role of small bowel radiology in the diagnosis and management of Crohn's
      disease.
AB  - A total of 50 children with Crohn's disease were examined by barium follow
      through and colonoscopy with ileoscopy, to determine the value of small bowel
      radiology. Of these children, 40 (80%) had evidence of small bowel Crohn's
      disease on ileoscopy and/or barium follow-through. Twenty-two (44%) had disease
      confined to the terminal ileum. Radiology diagnosed disease proximal to the
      terminal ileum in 18 cases (36%), including 5 children in whom the terminal ileum
      was normal. Ileoscopy was not possible in nine patients (18%), six of whom had
      small bowel disease on barium follow-through. Colonic involvement, demonstrated
      in 34 (68%), was the sole site of disease in 6 (12%). Fifteen (30%) children had
      surgery, which in six (12%) was determined by the radiological findings of
      complicated small bowel disease. As the terminal ileum may be uninvolved in the
      presence of proximal ileal disease, normal ileoscopy does not exclude small bowel
      Crohn's disease. Small bowel radiology remains necessary to assess the full
      extent of Crohn's disease in children.

PMID- 8645955
TI  - Diagnostic value of chest radiography and electrocardiography in the evaluation
      of asymptomatic children with a cardiac murmur.
AB  - We investigated the diagnostic value of the chest radiograph and ECG in the
      evaluation of whether asymptomatic children with a cardiac murmur had a heart
      disease as defined by echocardiography. One hundred children aged 1 month to 15
      years (median 30.1 months) were included. After physical examination, a tentative
      diagnosis was made: 53 children had no heart disease, 24 had a probable heart
      disease and 23 children were thought to have heart disease on the basis of
      clinical assessment alone. After information from chest radiography and
      electrocardiography was obtained, the diagnoses were re-evaluated. This resulted
      in a change of the tentative diagnosis in three children. However, the diagnosis
      in relation to the definite diagnosis by colour Doppler echocardiography was not
      changed to the correct diagnosis in any of these cases. In 24 cases, radiography
      suggested the presence of heart disease; however, only 10 of these had heart
      abnormalities on the colour Doppler echocardiogram (CDE). Three children had an
      abnormal ECG; all of these had abnormalities on the CDE, but they were already
      diagnosed as having heart disease by physical examination. We conclude that chest
      radiography and electrocardiography is of no help in the discrimination between
      heart disease and no heart disease in asymptomatic children referred for a
      cardiac murmur.

PMID- 8645956
TI  - Primary empty sella: differences and similarities between children and adults.
AB  - To identify possible differences between empty sella in children and adults we
      studied 43 subjects (age 13.6 +/- 5.4 years, range 4.1-27 years) with
      hypothalamic-pituitary disorders and empty sella at magnetic resonance imaging.
      Pituitary function, presence of non-endocrine symptoms, perinatal history, sellar
      volume, pituitary height, midline or intrasellar anatomical abnormalities were
      evaluated. Twenty subjects had isolated growth hormone deficiency, 17 multiple
      pituitary hormone deficiency and 6 puberty disorders (3 precocious puberty, 2
      idiopathic delayed puberty, 1 Kallmann syndrome). The group with multiple
      pituitary hormone deficiency had a higher percentage of subjects with complete
      empty sella, i.e. pituitary height < 2 mm (p = 0.016), or intrasellar anatomical
      abnormalities (p = 0.0002) than the other groups. The subjects with puberty
      disorders had a mean sellar volume higher than the other groups (p < 0.05). Apart
      from pituitary dysfunction, symptoms of the empty sella syndrome were infrequent
      (9.3% of cases) in our subjects. The age of our subjects, the frequent
      association between empty sella and pituitary dwarfism and the non-enlarged
      sellae suggest a different aetiology, perhaps congenital, for empty sella in our
      subjects. As in adults, empty sella may be associated with both pituitary hypo-
      and hyperfunction.

PMID- 8645957
TI  - Prevalence, genetics and clinical presentation of chronic granulomatous disease
      in Sweden.
AB  - To estimate the prevalence of chronic granulomatous disease (CGD) in Sweden, an
      inquiry asking for known and possible CGD cases was mailed to paediatric,
      internal medicine and infectious disease departments all over Sweden. The
      detected patients were characterized as to genetics and the clinical
      presentation. Twenty-one patients (belonging to 16 different families) were
      found, corresponding to a prevalence of approximately 1/450,000 individuals. The
      patients with X-linked disease, lacking a functional gp91phox protein (n = 12),
      comprised 57% and 43% of the patients had an autosomal recessive (AR) disease
      lacking p47phox (n = 7) or p67phox (n = 1), respectively. All unrelated patients
      with X-linked disease displayed different gene abnormalities such as point
      mutations predicting nonsense (n = 3), missense (n = 1) or splice site mutations
      (n = 2), but also a total deletion and a unique 40 base pair duplicature
      insertion. The patients with p47phox-deficiency showed a GT deletion at a GTGT
      tandem repeat, and the p67phox-deficient patient displayed a heterozygous in
      frame deletion of AAG combined with a large deletion in the other allele. Three
      patients died during the study period, two from pseudomonas cepacia infections.
      Patients with X-linked disease had more frequent infections (mean of 1.7 per
      year), than the patients with AR inheritance (0.5 infections per year). The most
      common infections were dermal abscesses (n = 111), followed by lymphadenitis (n =
      82) and pneumonias (n = 73). Inflammatory bowel disease-like symptoms, mimicking
      Crohn's disease of the colon, was seen in three CGD patients.

PMID- 8645958
TI  - Psychological long-term coping with experience of disease and treatment in
      childhood cancer survivors.
AB  - Childhood cancer, although cured, may have long-term psychological consequences
      for the adult survivor. The outcome of patients' coping with the illness and
      treatment experience was assessed in relation to a theoretical model describing
      optimal long-term coping with a potential psychic trauma of this nature. Thirty
      young adult childhood cancer survivors were studied. The average age at diagnosis
      was 8 years, and at evaluation 22 years. The average time since diagnosis was 13
      years. The evaluations of coping were carried out independently by two
      psychologists, who rated material from semistructured in-depth interviews. By
      statistical cluster analysis three clusters were produced that could be
      interpreted as exhibiting "good," "intermediate" and "poor" coping, containing
      40, 33, and 27%, respectively, of the total group. Overall cluster differences
      were statistically significant. Profile analysis revealed statistical stability
      and internal homogeneity in the good coping cluster and the poor coping cluster.

PMID- 8645959
TI  - Procedural pain in a paediatric surgical emergency unit.
AB  - Pain induced by various types of procedures was assessed in the Paediatric
      Surgical Emergency Department at St Goran's Children's Hospital in Stockholm.
      Assessments of pain were obtained from the nurse, the parent, and children over
      10 years of age by means of a visual analogue scale. In children aged 3-9 years,
      the Smiley Five-Face Scale was used. The nurse and the parent also answered
      questionnaires about analgesic medication, the child's behaviour, and the
      parent's overall opinion of the pain management, etc. Irrigation of the glans
      penis because of balanitis, treatment of fractures and paronychia were considered
      to be the most painful procedures. Forty-four per cent of the children cried
      during the procedure and 16% fought against being restrained. In 24% of the
      cases, the child was judged to be in a state of "panic". In conclusion, we
      believe that the pain induced by procedures in the emergency rooms is
      unacceptably high. Children estimate higher pain scores than parents and nurses
      do. There was a poor correlation between the parent's and child's estimates of
      pain. Parents are not well informed about the possibilities for pain treatment.
      Infants and children attending emergency rooms must also benefit from recent
      advances in the treatment of pain.

PMID- 8645960
TI  - Cerebral and ventilatory depression during hypoxia in anaesthetized newborn
      guinea-pigs.
AB  - The effects of hypoxia on ventilation and cerebral activity were studied in
      urethane-anaesthetized newborn guinea-pigs. Ventilation was measured by a
      pneumotachograph, and cerebral activity by a cerebral function monitor (CFM). All
      animals were subjected to either 9% O2 or 6% O2 in N2 for 10 minutes or until
      apnoea occurred. Hypoxia produced a biphasic response in ventilation, that is, an
      increase followed by a decrease. The initial increase was attributed to the
      elevation of the respiratory rate, whereas the tidal volume showed a pure
      decline. The respiratory rate reached its peak at 3 minutes of hypoxia (170 +/-
      12% during 9% O2 and 169 +/- 12% during 6% O2). Cerebral activity during both 9
      and 6% O2 breathing showed a small increase followed by a decrease. In the group
      subjected to 9% O2 the maximum CFM activity increased to 114 +/- 8% of the
      control level and the minimum activity increased to 113 +/- 7%, while in the
      group subjected to 6% O2 the maximum CFM activity increased to 104 +/- 5% and the
      minimum CFM activity to 101 +/- 3%. The depression of CFM activity was more
      pronounced with 6% O2 than with 9% O2. Regression analysis showed a linear
      correlation between ventilation and cerebral activity during both 9 and 6% O2
      breathing. The results suggest that hypoxic ventilatory depression may be the
      consequence of cerebral depression produced by acute severe hypoxia.

PMID- 8645961
TI  - Postnatal development of the cerebral blood flow velocity response to changes in
      CO2 and mean arterial blood pressure in the piglet.
AB  - Cerebral blood flow velocity was studied during changes (haemorrhage) in mean
      arterial blood pressure or P(a)CO2 in 56 (aged 0-26 days) anaesthetized and
      ventilated piglets. The CO2 reactivity increased with age from 6.5% kPa-1 (< 1
      day) to adult levels of 25% kPa-1 for piglets over 4 days old. The mean arterial
      blood pressure reactivity was reduced from 1.3% mmHg-1 (< 1 day old) to 0.0%/mmHg
      (> 4 days old). The reactivities were similar with two different anesthetics:
      chloralose/urethane or pentobarbital. To validate the cerebral blood flow
      velocity data, both electromagnetic flow and precerebral Doppler ultrasound
      velocity were recorded from the same common carotid artery with extracranial
      branches tied off. There were no differences between the results with these two
      methods nor between these results and those obtained when the cerebral blood flow
      velocities were recorded from an intracerebral artery and the electromagnetic
      flowmeter recorded from the carotid artery. The vessel diameter appears stable
      during these interventions. In conclusion, the autoregulatory response and the
      reaction to P(a)CO2 appear poorly developed in the newborn piglet, but rapidly
      mature during the first 4 days of life.

PMID- 8645962
TI  - Erythrocyte cupric/zinc superoxide dismutase exhibits reduced activity in preterm
      and low-birthweight infants at birth.
AB  - In a comparative study in term, preterm and low-birthweight infants, the mean
      activity and standard error of the mean for copper/zinc superoxide dismutase
      (Cu/Zn SOD) in cord erythrocytes from five term small for gestational age infants
      was 0.94 +/- 0.10 SOD units (mg protein)-1. This value was significantly lower
      than the activity (2.34 +/- 0.24) in nine term, appropriate for gestational age
      (AGA) babies (p < 0.005). In 15 preterm (AGA) infants, the activity at birth
      (1.05 +/- 0.07 SOD units (mg protein)-1) was also significantly lower (p < 0.001)
      relative to term AGA babies. An increased level of activity (1.59 +/- 0.09) was
      detected in the red cells of eight preterm AGA infants on their expected date of
      delivery compared with (0.87 +/- 0.06) at birth (p < 0.001). However, the
      activity (1.59 +/- 0.09) was still lower than that detected in term AGA babies
      (2.34 +/- 0.24; p < 0.02). Similar findings were obtained when enzymatic activity
      was expressed in units per millilitre of packed erythrocytes. The low activity of
      Cu/Zn SOD in preterm and low-birthweight babies may render them susceptible to
      diseases associated with membrane lipid peroxidation.

PMID- 8645963
TI  - Use of enalapril in neonatal hypertension.
AB  - Treatment of hypertension with enalapril in a preterm infant is described.
      Enalapril is a new converting enzyme blocker with a longer plasma half-life and
      less side effects than captopril. Oral administration of enalapril 0.1 mg/kg
      caused severe hypotension and renal failure in a preterm infant. We recommend an
      oral starting dose of 0.01 mg/kg in preterm infants and extremely close
      monitoring of infants receiving the first dose of enalapril.

PMID- 8645965
TI  - Coeliac disease and insulin-dependent diabetes mellitus: a causal association?

PMID- 8645964
TI  - Intranasal versus intravenous administration of midazolam to children undergoing
      small bowel biopsy.
AB  - Sixty-three children under the age of 9 years were randomized to receive
      intravenous (group A, n = 33) or intranasal (group B, n = 30) midazolam as
      sedation for small bowel biopsy. Mean doses of midazolam given to produce
      adequate sedation were 0.31 mg (kg body weight)-1 in group A and 0.34 mg (kg body
      weight)-1 in group B (NS). Four children in group A and 10 children in group B
      required additional doses to maintain adequate sedation throughout the biopsy
      procedure (p < 0.05). There was no significant difference between the groups
      regarding the median procedure time (7 min in group A, 8.5 min in group B) or
      median fluoroscopy time (5 s in group A, 4 s in group B). All children in group B
      showed signs of discomfort from the nose when given midazolam intranasally. In
      conclusion, this study indicates that intravenous administration of midazolam is
      preferable to the intranasal route.

PMID- 8645966
TI  - Peripheral blood gamma delta T cells in human listeriosis.
AB  - A phenotypical analysis carried out by direct immunofluorescence and two-colour
      cytofluorometry showed that the number of lymphocytes bearing the gamma delta T
      cell receptor heterodimer was increased in the blood of eight children with
      Listeria monocytogenes infection, mainly due to an expansion of cells identified
      by monoclonal antibodies which recognize V delta 2 gene products. These findings
      are further evidence that gamma delta T cells are in some way involved in the
      immune response directed against human intracellular pathogens.

PMID- 8645967
TI  - Congenital anomalies in two infants born after gestational gamma-globulin
      prophylaxis.
AB  - The offspring of two women given prophylactic gamma-globulin 50 and 54 days after
      their last menstrual periods had congenital duodenal stenosis and a
      paraoesophageal hiatus hernia, respectively. The possibility that gamma-globulin
      may have contributed to these malformations is discussed.

PMID- 8645968
TI  - Iatrogenic radiant heat burns in severely asphyxic newborns.
AB  - We report two cases of newborns who developed second-degree burns following
      resuscitation under infra-red heating lamps. Both infants were asphyxic and
      suffered from insufficient peripheral circulation which, combined with the long
      duration of the exposure to the light, contributed to the development of the
      lesions. Both infants died shortly after birth for reasons other than the burns.

PMID- 8645969
TI  - Postnatal resolution of non-chylous primary fetal hydrothorax.
AB  - We describe two cases of non-chylous primary fetal hydrothorax not associated
      with hydrops or associated malformations. Repeated ultrasonographic examinations,
      to detect development of hydrops or progression of intrapleural effusion, were
      used to evaluate the need for intrauterine thoracocentesis and to decide the
      optimal time for delivery. Both infants did well after postnatal evacuation of
      the intrapleural fluid. Pre- and postnatal investigation to find the
      pathophysiological mechanism leading to hydrothorax were negative. We conclude,
      in agreement with previous work, that primary fetal hydrothorax is generally
      associated with a favourable outcome.

PMID- 8645970
TI  - Coincidental cases of primary sclerosing cholangitis and biliary atresia in
      siblings?
AB  - Familial cases of primary sclerosing cholangitis or biliary atresia have been
      reported, although genetic influences and immunopathological abnormalities in
      these diseases are considered to be obscure. We report a case of primary
      sclerosing cholangitis and biliary atresia in siblings with the observation of
      HLA-DR antigen expression in the abnormal bile duct epithelial cells.

PMID- 8645971
TI  - Diffuse juvenile non-adenomatous polyposis: a rare cause of severe
      hypoalbuminaemia in childhood.
AB  - Hypoalbuminaemia is a well-recognized complication of juvenile polyposis, which
      is often not clinically apparent. We describe a child with diffuse colonic non
      adenomatous polyposis who presented with generalized oedema and severe
      hypoalbuminaemia. The site of the protein loss was the polyps, and the problem
      resolved after colectomy. This is a case of unusually severe hypoalbuminaemia
      complicating juvenile polyposis.

PMID- 8645972
TI  - Association of leukocyte surface receptors with protein kinases.
AB  - Signalling through most leukocyte surface receptors is based on ligation-induced
      activation of the protein tyrosine kinases associated with the receptors'
      intracellular domains. The activated kinases phosphorylate specific cytoplasmic
      proteins involved in propagation of the signalling cascade which leads to
      ultimate cellular responses such as induction of gene transcription followed by
      proliferation, apoptosis, and execution of various effector functions. Some
      receptors possess intracellular domains with intrinsic kinase activity (e.g.
      insulin receptor; transforming growth factor receptor). Many leukocyte surface
      receptors (e.g. T-cell receptor, B-cell receptor, Fc receptors) are noncovalently
      associated with cytoplasmic protein tyrosine kinases of the Src family. Most
      cytokine receptors are associated with protein tyrosine kinases of the Jak family
      which phosphorylate and thereby activate transcription factors of the STAT
      family. Receptors anchored in the membrane via a glycolipid
      (glycosylphosphatidylinositol) moiety are linked to intracellular kinases within
      membrane microdomains of specific lipid composition which may include so far
      poorly known transmembrane linker proteins. A number of diseases have been
      identified which are caused by defective or dysregulated receptor-linked protein
      kinases or by defects in the receptor-kinase interaction. Therefore receptor
      associated kinases may be potential targets for therapeutic intervention.

PMID- 8645974
TI  - CD23 expression in activated human T cells is enhanced by interleukin-7.
AB  - Despite evidence for the expression of the low-affinity Fc receptor for IgE (Fc
      epsilon RII/CD23) in several pathological conditions, the role played by CD23 in
      normal human T cells is still unclear. We studied the effect of a stomal-derived
      cytokine, interleukin (IL-7), on the expression of CD23 in human T cells
      stimulated with 10 micrograms/ml phytohemagglutinin (PHA). The results
      demonstrate that IL-7 did not induce CD23 expression in the resting T cells.
      However, PHA-induced CD23 expression was enhanced by costimulation with IL-7
      (1,000 U/ml). Cytofluorometric analysis revealed that CD23 expression in
      activated T cells was enhanced by the addition of IL-7 (from 2% to 18%). It was
      also observed that the effect of IL-7 on CD23 expression is exclusively on CD4+ T
      cells. The enhanced expression of CD23 was blocked by an anti-IL-7 monoclonal
      antibody (mAb), but not by IL-2 and IL-4 mAbs. This suggests that IL-7 is a
      potent regulatory cytokine capable of acting independently of IL-2 and IL-4 in
      the expression of CD23. Northern blot analysis showed an increase in CD23 mRNA
      when activated T cells were cultured in the presence of IL-7. A significant
      increase in receptor numbers on activated T cells was detected by Scatchard
      analysis when IL-7 was added to the cell cultures. The induction of CD23
      expression by IL-1, IL-3, IL-4, IL-5, IL-6, interferon-8 and OKT3 on PHA
      activated T cells was not of the same magnitude as observed in the presence of IL
      7. These results demonstrate a selective induction of CD23 expression on
      activated human T cells cultured in the presence of IL-7. These data indicate
      that the stromal-derived growth factor points to an important role of CD23 in the
      regulatory network of the immune response.

PMID- 8645973
TI  - Role of mast cells, basophils and their mediators in adverse reactions to general
      anesthetics and radiocontrast media.
AB  - General anesthetics and radiocontrast media (RCM) can cause anaphylactic or
      anaphylactoid reactions. These are usually underdiagnosed and underreported, but
      their incidence is apparently rising. Their pathogenesis is complex and not
      completely understood, but the release of vasoactive mediators from basophils and
      mast cells plays a central role. The recent development of in vitro techniques to
      study the release of preformed (histamine and tryptase) and de novo synthesized
      mediators (PGD2, LTC4, and PAF) from purified basophils and mast cells has made
      it possible to quantify the mediator-releasing activity of anesthetics such as
      muscle relaxants, general anesthetics, opioids, and benzodiazepines and RCM on
      human basophils and mast cells isolated from lung, skin and heart tissues. The
      majority of general anesthetics and RCM tested induced only the release of
      preformed mediators (histamine and tryptase), not of the de novo synthesized
      eicosanoids. There was wide variability in the response of basophils and mast
      cells from different donors to the same drug or RCM, presumably due to the
      releasability parameter. Hyperosmolality is probably not the only factor
      responsible for basophil and mast cell activation by RCM. The in vitro release of
      histamine induced by anesthetic drugs and RCM was correlated with the release of
      tryptase. Given the longer half-life of tryptase than histamine in plasma,
      measurements of plasma tryptase may become a useful diagnostic tool for
      identifying adverse reactions to anesthetics and RCM.

PMID- 8645975
TI  - Disproportional distribution of isotype and non-isotype-specific IgG subclass
      anti-IgE autoantibodies in human cord serum.
AB  - The levels of naturally occurring IgG and IgG subclass anti-IgE autoantibodies (a
      E Ab) were studied in 71 randomly collected cord sera with ELISA using solid
      phase IgE-DES myeloma protein. IgG a-E Ab were present in all cord sera, and the
      range was 300-fold (1.8-540 arbitrary units/ML; median = 11.8). However, this
      activity is the sum of two major types of a-E Ab that we refer to as isotype
      specific (IS) and non-isotype-specific (NIS) because they react with E-chain
      specific and myeloma-restricted epitopes, respectively. These two types of a-E Ab
      were distinguished in IgG subclass a-E Ab inhibition ELISA for all samples using
      unheated IgE-PS and heated IgE-DES as inhibitors. IS and NIS a-E Ab were found
      among all four IgG subclasses though with different prevalences. No significant
      influence of gender was observed. Comparisons within each subclass indicate that
      NIS a-E Ab were more common than IS a-E Ab for the IgG1 (p < 0.00005), IgG2 (p =
      0.07) and IgG3 (p < 0.005) subclasses while the reverse was true for IgG4 (p <
      0.00005). In fact, only a minor part of the IgG1 (7%), IgG2 (13%) and IgG3 (9%) a
      E Ab activity towards IgE-DES was IS while for IgG4 it was a major part (82%).
      Attempts to quantify IS and NIS IgG subclass a-E Ab using chimeric IgG subclass
      antihapten Ab suggested that the pool of IgG a-E Ab against IgE-DES was dominated
      by NIS a-E Ab particularly of the IgG1 subclass. The 75 percentiles for NIS IgG1,
      IgG2, IgG3 and IgG4 a-E Ab were 24, < 2, 2.1 and 0.27 ng/ml, respectively,
      whereas the corresponding figures for IS a-E Ab were 7, < 2, < 2 and 0.90 ng/ml.
      The findings raise questions on the definition of a-E Ab and suggest that caution
      should be exercised in the interpretation of any a-E Ab results that are detected
      with IgE myeloma proteins. The potentially more interesting IS a-E Ab may be
      overshadowed by the bulk of ubiquitous NIS a-E Ab and background. Consequently,
      discriminatory assays are necessary if the physiological implication of naturally
      occurring IS IgG subclass a-E Ab is to be elucidated and these considerations are
      not limited to studies of cord serum.

PMID- 8645976
TI  - Cloning Aspergillus fumigatus allergens by the pJuFo filamentous phage display
      system.
AB  - A cDNA library from Aspergillus fumigatus has been displayed on the surface of
      filamentous phage M13 and screened for gene products binding to human serum IgE.
      The physical linkage of cDNA gene products to the genetic information required
      for their production, achieved by exploiting the high-affinity interaction of the
      Jun and Fos leucine zippers, allows rapid and easier screening of large libraries
      in semifluid systems. The pJuFo cloning vector is designed to display proteins on
      the surface of phage and allows selective isolation of genes by gene product
      ligand interaction. Thus the system is applicable to clone cDNA that encodes
      proteins for which a ligand is available. Herein we show that phage expressing
      IgE binding proteins from A. fumigatus can be enriched and separated from
      nonspecific phage by using serum IgE from A. fumigatus-allergic individuals
      coated to plastic dishes. Subsequently, the proteins can be produced in high
      amounts in Escherichia coli and purified for usage in allergy testing.

PMID- 8645977
TI  - Immunoblot analysis of IgE and IgG binding antigens in extracts of mosquitos
      Aedes vexans, Culex tarsalis and Culiseta inornata.
AB  - Extracts of one globally distributed mosquito species (Aedes vexans) and two
      North American species (Culex tarsalis and Culiseta inornata) were prepared from
      heads and thoraxes. Proteins of the three extracts were separated by 12% SDS-PAGE
      and transferred to nitrocellulose membranes for immunoblotting. Immunoblotting
      was completed by sequential incubations of the membranes with a pooled human
      serum from subjects allergic to mosquito bites, monoclonal antibodies to human
      IgE or IgG, and goat antimouse IgG conjugate. Twelve to sixteen antigens with
      molecular masses ranging from 18.5 to 160 kDa were found in each extract. Nine
      antigens were shared by 3 species and 6 were shared by 2 species. Only 3 were
      species-unique. Most antigens bound to both IgE and IgG antibodies. IgE and IgG
      antibodies against A. vexans were studied by immunoblotting using individual
      serum from subjects with or without skin reactions to A. vexans bites. All 3
      subjects with severe skin reactions had strong IgE and IgG antibodies to 32.5,
      40, and 50 kDa proteins. The patterns and magnitudes of IgE and IgG antibodies to
      the antigens varied among individuals. Very faint IgE antibodies to these
      antigens were found in the 2 subjects with no skin reactions, suggesting that IgE
      plays a role in the development of mosquito allergy.

PMID- 8645978
TI  - Cetirizine exerts anti-inflammatory effects on human neutrophils.
AB  - Leukotrienes are potent lipid mediators involved in acute and chronic
      inflammatory processes and allergic inflammation. Cetirizine is an H1-receptor
      antagonist used in the treatment of allergic symptoms. We analyzed the effect of
      cetirizine on the formation of leukotriene B4 (LTB4) after stimulation of human
      peripheral blood neutrophils. The inflammatory mediators were analyzed after
      cellular activation with different stimuli: the Ca ionophore A23187, which
      bypasses membranous signal transduction elements; the bacterial peptide formyl
      methionine-leucyl-phenylalanine (fMLP), which activates cells by binding to a GTP
      protein (G-protein)-coupled receptor, and with sodium fluoride (NaF), which
      directly activates G-proteins. After cellular preincubation with cetirizine, the
      amounts of LTB4 generated from neutrophil granulocytes decreased significantly
      when the cells were subsequently stimulated with either fMLP or NaF, in contrast
      to stimulations with the Ca ionophore. The data provide evidence that cetirizine
      exerts anti-inflammatory effects apart from H1 antagonism.

PMID- 8645979
TI  - KW-4679, an antiallergic drug, inhibits the production of inflammatory lipids in
      human polymorphonuclear leukocytes and guinea pig eosinophils.
AB  - The effects of (Z)-11-[(3-dimethylamino)propylidene]-6,11-dihydrodibenz
      [b.e.]oxepin-2-acetic acid monohydrochloride (KW-4679), an orally active
      antiallergic drug, on the production of platelet-activating factor (PAF),
      leukotriene (LT) and thromboxane (TX) induced by Ca2+ ionophore A23187 were
      examined. KW-4679 at 10 microM reduced the amount of cell-associated PAF by 52.8%
      in human polymorphonuclear leukocytes (PMNs). KW-4679 (1-100 microM) also
      inhibited the release of both LTB4 and TXB2, a stable metabolite of TXA2, by
      human PMNs in a concentration-dependent manner, but did not influence the release
      of beta-glucuronidase. The 50% inhibitory concentration (IC50) values for LTB4
      and TXB2 release were 5.9 and 6.0 microM, respectively. In guinea pig
      eosinophils, KW-4679 inhibited the release of peptide LTs at a concentration
      higher than 10 microM (IC50 = 66.9 microM). KW-4679 failed to inhibit PAF
      acetyltransferase, 5-lipoxygenase and TX synthase, but inhibited the arachidonic
      acid release by human PMNs in a concentration-dependent manner in a similar
      concentration as that inhibiting production or release of lipid mediators (IC50 =
      19.5 microM). These results indicate that KW-4679 suppresses LTs and TX release
      and PAF formation by reducing arachidonic acid release from phospholipids,
      probably through interference with phospholipase A2. The inhibitory action of KW
      4679 on PAF, LT and TX production is a beneficial effect of an antiallergic drug.

PMID- 8645980
TI  - Effects of KW-4679, a new orally active antiallergic drug, on antigen-induced
      bronchial hyperresponsiveness, airway inflammation and immediate and late
      asthmatic responses in guinea pigs.
AB  - We investigated the effects of KW-4679, an antiallergic drug, on the development
      of bronchial hyperresponsiveness, airway inflammation and early and late
      asthmatic responses following aerosol antigen challenge in guinea pigs actively
      sensitized by the inhalation of aerosolized ovalbumin. Pretreatment with KW-4679
      (10 mg/kg, p.o.) 1 h before antigen challenge prevented the development of
      bronchial hyperresponsiveness to inhaled methacholine. Examination of the
      bronchoalveolar lavage fluid 24 h after antigen challenge revealed the inhibitory
      effect of KW-4679 on the infiltration of eosinophils into the airway. Treatment
      with KW-4679 significantly inhibited both the immediate and late asthmatic
      responses. These results indicate that KW-4679 could be useful in the treatment
      of allergic diseases such as bronchial asthma.

PMID- 8645981
TI  - Wine and headache.
AB  - Headache can be induced by histamine in wine in patients suffering from histamine
      intolerance, a disease characterized by impaired histamine degradation based on
      reduced diamine oxidase activity or a lack of the enzyme. Diamine oxidase is
      localized in the jejunal mucosa and is the most important enzyme metabolising
      histamine. It is competitively inhibited by alcohol and numerous drugs. In
      preliminary investigations, assessment of diamine oxidase levels gave decreased
      activity (0.03 nKat/l) in patients with histamine intolerance compared to healthy
      controls (0.07 nKat/l). In pregnancy, diamine oxidase levels are known to be
      about 500-fold elevated, giving mean levels of 25.0 nKat/l. Other biogenic amines
      such as phenylethylamine or serotonin may be causative for wine/food-induced
      headache. In experimental models, headache has been induced by histamine infusion
      as well as red wine provocation. Histamine-induced headache is a vascular
      headache likely to be caused by nitric oxide which probably represents a key
      molecule in vascular headaches. A histamine-free diet is the treatment of choice
      for patients with histamine intolerance and chronic headache. To start treatment,
      an antihistamine (H1 blocker) for 14 days as well as a histamine-free diet for at
      least 4 weeks are recommended. Clinical improvement to the diet as well as in
      vitro tests for plasma histamine and diamine oxidase in the serum as well as
      vitamin B6 levels have to confirm the diagnosis. As supportive treatment, a
      vitamin B6 (pyridoxal phosphate) substitution appears useful in histamine
      intolerant patients as pyridoxal phosphate seems to be crucial for diamine
      oxidase activity. Histamine intolerance, based on reduced diamine oxidase
      activity or a lack in the enzyme is causative for wine/food-induced chronic
      headache. According to the localization of diamine oxidase in the jejunal mucosa,
      histamine intolerance is primarily a disease of intestinal origin. A histamine
      free diet is the treatment of choice in histamine-intolerant patients suffering
      from chronic headache. In addition, it is also important to avoid diamine-oxidase
      blocking drugs and alcohol which act as inhibitors of diamine oxidase. As
      avoidance of histamine-rich food is simple, inexpensive and harmless treatment,
      histamine-containing food such as cheese and alcoholic beverages should be
      labeled.

PMID- 8645982
TI  - Development of allergy to laboratory animals is associated with particular Gm and
      HLA genes.
AB  - To find out whether IgG genes are involved in atopy we studied 26 of 101
      laboratory technicians who had developed laboratory animal allergy (LAA). The
      genes for the constant region of the heavy chains of IgG subclasses were analyzed
      by serum Gm allotypes, representing products on allelic level of the IGHCG1,
      IGHCG2 and IGHCG3 on chromosome 14q32. There was a significantly increased
      frequency of the GM(f,f;n,n;b,b) genotype (57.7 instead of 22.3%, p < 0.001)
      representing IgG1, IgG2 and IgG3 molecules and in particular increased frequency
      of Gm genotypes with the homozygous expression of G2m (n,n) (69.2 instead of
      27.4%, p < 0.001) and of the Gm(f,n,b) haplotype (75 instead of 44.8%, p < 0.001)
      compared to a normal Caucasian population. An increased HLA-DR4 content of the
      LAA group (61.5 instead of 33.7%, p < 0.01) was further investigated for Gm
      allotypes. Among 16 HLA-DR4 LAA individuals, the Gm(f,f;n,n;b,b) genotype (56.3
      instead of 22.3%, p < 0.01) and the Gm genotypes with the homozygous expression
      G2m(n,n) (62.6 instead of 27.4%, p < 0.01) dominated. However, the HLA-DR4
      frequency among Gm(f,f;n,n;b,b) of LAA patients did not deviate from the
      frequency of healthy individuals of the same Gm genotype. The increased frequency
      of HLA-DR4 antigen in LAA patients might be due to its association to the
      Gm(f,f;n,n;b,b) genotype. This study supports the following concept: the
      susceptibility of developing LAA is associated with Gm allotypes Glm(f) expressed
      from IGHCG1, G2m(n) from IGHCG2 and G3m(b) from IGHCG3 on both alleles situated
      close to IGHCE on chromosome 14q32. The association of LAA to Gm allotypes
      [Gm(f,f;n,n;b,b)] expressed from chromosome 14q32 and of HLA class II antigens
      (HLA-DR4) expressed from chromosome 6p21.3 further confirms the polygenic
      inheritance of the immune response in atopy.

PMID- 8645983
TI  - Protective effect of heparin on immunologically induced tracheal smooth muscle
      contraction in vitro.
AB  - Our previous studies have shown that heparin, a competitive inhibitor of inositol
      triphosphate receptors, inhibits airway anaphylaxis in vivo. In the present
      study, we tested the hypothesis that heparin blocks immunologically induced
      tracheal smooth muscle (TSM) contraction in vitro. TSM was obtained from sheep
      allergic to Ascaris suum antigen, and was suspended in an organ bath containing
      oxygenated (95% O2, 5% CO2) Krebs-Henseleit buffer at 39 degrees C. After an
      equilibration period, the tissues were treated with heparin dissolved in 10
      microliters DMSO, at concentrations of 1, 10, or 100 U/ml (final concentration in
      the bath). Two types of controls were used: vehicle (10 microliters DMSO)-treated
      tissues and tissues treated with the anti-asthmatic nedocromil sodium (10(-5) M).
      After 30 min pretreatment, tissues were challenged with 10, 30 and 100
      microliters of antigen. Contractions induced by antigen were expressed as
      percentage of the contraction elicited by the maximum effective concentration of
      acetylcholine (ACh, 10(-2) M). Antigen produced dose-dependent increases in
      tension, which were blocked by heparin and nedocromil sodium; maximal inhibition
      was 43 and 52%, respectively. Neither heparin nor nedocromil sodium affected the
      dose-response curve or the maximum response to Ach. The addition of the heparin
      preservative (benzyl alcohol) did not reverse ACh-induced contractions, or
      inhibit antigen-induced contractile responses. These results suggest that heparin
      blocks immunologically induced TSM contraction, without affecting the contractile
      response to the airway smooth muscle agonist, ACh. This action of heparin is
      similar to that of the anti-asthmatic nedocromil sodium and may be related to
      inhibition of mast cell mediator release.

PMID- 8645984
TI  - Concentrations of myeloperoxidase in nasal secretions of atopic patients after
      nasal allergen challenge and during natural allergen exposure.
AB  - A quantitative determination of myeloperoxidase (MPO) concentration was performed
      in the nasal secretions of atopic patients (challenged group, n = 17) after nasal
      allergen challenge outside the pollen season, and of patients with ongoing
      seasonal (seasonal group, n = 40) and with perennial (perennial group, n = 30)
      allergic rhinitis. The concentrations of MPO obtained from 10 nonallergic healthy
      volunteers (control group) were used as a normal control. Results showed that
      there was no statistical difference between the normal controls (median: 2.0
      micrograms/g) and the atopic patients (median: 1.7 micrograms/g) outside the
      pollen season. After nasal allergen challenge (challenged group), there was no
      significant difference of MPO at 5 min (median: 1.0 microgram/G), 8 h (median:
      1.7 micrograms/g), and 24 h (median: 3.1 micrograms/g) after challenge as
      compared to the baseline values. Also, there was no significant difference
      between patients with ongoing seasonal (median: 1.3 micrograms/g) or perennial
      (median: 1.8 micrograms/g) rhinitis, and atopic patients outside the pollen
      season. In conclusion, this study showed that MPO is not locally elaborated in
      measurable quantities in nasal secretions after nasal allergen challenge and
      during natural allergen exposure. Further studies will be needed to elucidate the
      role of neutrophils in the pathophysiological processes of allergic rhinitis.

PMID- 8645985
TI  - Allergic rhinitis to thuja pollen.
AB  - Allergy to pollen of Cupressaceae has been linked to pollens of Cupressus,
      Juniper and Cryptomeria. The authors report 2 cases of rhinitis and
      conjunctivitis induced by thuja, another member of the Cupressaceae family.
      Monosensitization to thuja pollen has been identified as the causal agent: (1) of
      a long-standing springtime rhinitis in 1 patient with negative skin tests and
      specific IgE titers to the main inhalants (specificity of the prick test and
      nasal provocation with the thuja extract was confirmed by a positive RAST) and
      (2) in a 2nd patient without former history of allergy, who consulted for
      conjunctivitis following acquisition of a dog; the standard battery of skin
      tests, and Phadiotop were all negative. After controls, only the thuja extract
      gave significant skin test response. The level of total IgE was low, and RAST was
      negative. Sensitization and pollen provocation were produced by the intermediary
      of the dog, carrying thuja pollens on its fur. The immunoprint and the crossed
      radioimmunoelectrophoresis revealed common antigenicity between cypress and thuja
      extracts.

PMID- 8645986
TI  - Increased antibody titers against mycobacterial heat-shock protein 65 in patients
      with vasculitis and arteriosclerosis.
AB  - Heat shock proteins (HSPs) are a group of highly conserved proteins that show
      extensive homology at the DNA and protein level among bacterial and mammalian
      species. Furthermore, bacterial HSPs induce specific cellular and humoral immune
      responses in mammals. Cross-reacting antibodies may therefore be induced in
      chronic infections. Recently, it has been claimed that patients with
      arteriosclerosis (AS) of the carotid arteries have significantly elevated
      antibody titers to mycobacterial HSPs. In this study, we extended the spectrum of
      vascular diseases and analyzed sera from patients with systemic vasculitis and
      systemic lupus erythematosus (SLE) for the presence of anti-HSP antibodies. Anti
      HSP antibodies, tested in an ELISA with recombinant mycobacterial HSP 65, were
      significantly elevated in patients with vasculitis (n = 56; p < 0.01) and AS (n =
      29; p < 0.0001), but only marginally in patients with SLE (n = 22; p > 0.05)
      compared to healthy controls (n = 90). These findings further support the concept
      of infection-induced immune reactions playing a pathogenic role in the
      development of both AS and vasculitis.

PMID- 8645987
TI  - Production and modulation of T-cell cytokines in atopic allergy.
AB  - Atopic allergy is associated with allergen-specific CD4+ T cells showing a bias
      to production of the type-2 cytokines interleukin (IL)-4 and IL-5. There are
      indications that this bias is also evident in atopic T-helper (Th) cells with
      other antigen specificities. The balance between the production of type-1 and
      type-2 cytokines is influenced by various factors present in the microenvironment
      of the Th cells during their activation. Factors of special interest are antigen
      presenting cell-derived IL-12 and prostaglandin E2, skewing to type-1 and type-2
      cytokine production, respectively. The production of IL-12 and prostaglandin E2
      is induced by the interaction between CD40 and CD40 ligand expressed by Th cells,
      and by biologically active agents such as micro-organisms or their products. The
      IL-12/prostaglandin E2 production ratio depends on the antigen-presenting cell
      type, the type of stimulus and the presence of certain cytokines. Other Th
      cytokine-skewing factors are autocrine or paracrine IFN-gamma and IL-4. In fact,
      the type-1/type-2 cytokine production balance in Th cells is under the control of
      various soluble products that act in a complex network of type-1 (e.g. IL-12, IFN
      gamma) or type-2 (e.g. IL-4, IL-10 and prostaglandin E2) factors and are produced
      by Th cells and their accessory antigen-presenting or bystander cells. The levels
      of these factors may further be determined by gene polymorphisms or aberrant
      hormone levels. Despite the growing knowledge of the regulation of Th-cell
      cytokine production, the etiology of biased cytokine production in atopic
      allergic individuals is still enigmatic.

PMID- 8645988
TI  - Regulation of mRNA levels of TNF-alpha and the alpha chain of the high-affinity
      receptor for IgE in mast cells by IFN-gamma and alpha/beta.
AB  - Rat mast cell lines (hybrid rat mast cells, HRMC, and rat cultured mast cells,
      RCMC) and mast cells from the rat body cavity were used to test the hypothesis
      that IFN-alpha/beta and IFN-gamma inhibit tumor necrosis factor alpha (TNF-alpha)
      mediated cytotoxicity by depressing the steady-state levels of mRNA for TNF
      alpha. In vitro treatment of mast cells with IFN-gamma and IFN-alpha/beta
      depressed mRNA levels. By contrast, IFN pretreatment of mast cell lines induced
      an increase in levels of mRNA for the IFN-inducible gene, 2'5'-oligoadenylate
      synthetase and also for high-affinity IgE-receptor-alpha. The IFN-mediated
      regulation of mast cells may be an important mechanism in the control of
      inflammatory pathways characterized by Th1- and Th2-type responses.

PMID- 8645989
TI  - Specific high affinity binding of platelet activating factor to intact human
      blood neutrophils and eosinophils.
AB  - Neutrophils and eosinophils are involved in various inflammatory reactions such
      as leukocyte migration, adherence and phagocytosis. A regulation of platelet
      activating factor (PAF) receptors in intact human blood neutrophils and
      eosinophils is clinically important. Intact human blood neutrophils and
      eosinophils prepared under sterile conditions specifically bound [3H]PAF in the
      presence of fatty acid-free serum albumin (0.25% BSA). Excess unlabeled PAF (500
      nM) or the specific PAF receptor antagonist WEB 2086 (1 microM) inhibited the
      [3H]PAF binding. PAF receptors on the surface of intact blood neutrophils and
      eosinophils had high affinity Kd values of 0.55 and 2.3 nM at 4 degrees C. The
      Bmax values were 200 fmol/2.5 x 10(6) neutrophils and 26 fmol/2.5 x 10(5)
      eosinophils. PAF receptors on the outer plasma membranes were functionally
      relevant as high dose PAF displaced WEB 2086 after 3 min preincubation mediating
      maximal cytosolic [Ca2+]i flux. High doses of PAF or phorbol myristate acetate
      (PMA) downregulated neutrophils and a low dose PAF decreased the specific [3H]PAF
      binding to eosinophils determined with WEB 2086 at 20 degrees C. Only neutrophils
      were significantly upregulated by low dose PAF (5 nM), lyso PAF or low dose PMA
      (1 nM). Up- and downregulation by PAF itself of neutrophil and eosinophil PAF
      receptors might explain their desensitization and some clinical controversy
      concerning the role of PAF in inflammatory and allergic diseases. The latter
      hypothesis would lead to a novel combination of antagonists against PAF receptors
      and PAF production.

PMID- 8645990
TI  - Isolation and characterization of porcine cationic eosinophil granule proteins.
AB  - The allergic pig can be used as a large-animal model for studies of allergic
      reactions in the airways and the role of eosinophils in such reactions. To
      measure the activation of eosinophils, the release of eosinophil-derived cationic
      proteins can be used. The purpose of this study was to isolate and characterize
      cationic proteins derived from porcine eosinophils. Pigs were infested with live
      Ascaris suum eggs to induce eosinophilia (greater than or = 40% of leukocytes).
      Blood was collected and leukocytes were prepared by dextran sedimentation.
      Granules were obtained from the homogenized leukocytes by ultracentrifugation and
      cationic proteins were extracted and separated by gel filtration, cation exchange
      and zinc affinity chromatography. Using these methods, three cationic proteins
      were isolated from pig granulocytes, two of which were shown to originate from
      the eosinophil. The proteins were characterized according to molecular weight,
      amino acid composition, N-terminal sequence, isoelectric point, peroxidase and
      ribonuclease activity and antigenicity. One eosinophil protein was identified as
      eosinophil peroxidase and the other showed great similarities with human
      eosinophil cationic protein. The third protein was not specific for eosinophils,
      and had no obvious equivalent in human granulocytes. The eosinophil-derived
      proteins may be useful in the studies of eosinophil activation, e.g. in late
      phase asthmatic reactions, where the pig represents a new candidate model for
      large-animal allergy research.

PMID- 8645991
TI  - Structure and function of IgE myeloma protein VL from an atopic patient.
AB  - In a woman suffering from IgE myeloma, hay fever and polyvalent respiratory and
      skin allergy the IgE monoclonal protein VL was isolated and investigated with
      respect to structural and functional properties. The amino acid sequence of 22
      isolated peptides--especially of the biologically significant C2-C3 part-
      corresponded with that originally described by Bennich et al. (Immunol Rev
      1978;41:3-23; Prog Immunol 1974;13:49-58). However, in mass spectrometry the
      sugar residues on ASN 99 (219) and 252 (371) were deficient in sialic acids. The
      native IgE VL protein precipitated with high intensity all mannose-specific
      lectins as concanavalin A (Con A) and was able to release histamine after
      triggering by these lectins. The same lectins also elicited more histamine
      release and more positive skin reactions in atopic than in healthy persons. In
      sera from atopic patients the binding of IgE on Con A Sepharose 4B column was
      stronger than in normal persons. It is suggested that changes in the IgE
      glycosylation state may contribute to IgE-mediated pictures of clinical allergy
      by the nonimmunological pathway.

PMID- 8645992
TI  - Cross-reactivity and molecular mass of the epsilon chains of the IgE antibodies
      in dogs, humans, rats, and mice.
AB  - We report the cross-reactivities and comparative molecular masses of the IgE
      epsilon chains in humans, rats, mice, and dogs. Monoclonal human, rat, and mouse
      IgE, and our purified polyclonal dog IgE were used in the study. IgE of the 4
      species, separated by SDS-PAGE, were analyzed by immunoblotting with polyclonal
      and monoclonal antihuman IgE, polyclonal and monoclonal antimouse IgE, monoclonal
      antirat IgE, and polyclonal antidog IgE antibodies. The polyclonal antihuman and
      polyclonal antimouse IgE cross-reacted with the IgE of the other 3 species, while
      their monoclonal forms cross-reacted with dog IgE only. Polyclonal antidog IgE
      cross-reacted with human and mouse IgE, while the monoclonal antirat IgE did not
      cross-react with any other species. "Reverse' passive cutaneous anaphylaxis in
      ragweed-sensitized dogs revealed that polyclonal antihuman and polyclonal
      antimouse IgE were able to elicit positive skin responses, and monoclonal
      antihuman, antirat, and antimouse IgE antibodies were not. The molecular masses
      of the epsilon chains were 77 kDa for mice, 75 kDa for rats and dogs, and 70 kDa
      for humans.

PMID- 8645993
TI  - Comparison of the IgE titers to bovine colostral G immunoglobulins and their
      F(ab')2 fragments in sera of patients allergic to milk.
AB  - Colostral G immunoglobulins (IgGs) are described in many recent studies as having
      a beneficial effect for the treatment of viral, bacterial and parasitic diarrhea
      in animals and humans. The specific IgE titers to bovine colostral IgG, to bovine
      serum IgG, and to F(ab')2 fragments of IgG were immunoenzymatically quantified in
      sera of patients allergic to milk, to statistically evaluate and compare their
      relative immunoreactivity towards these purified antigens. The results clearly
      indicated that 36% of the population tested was potentially allergic to colostral
      IgG, and serum IgG globally elicited significantly lower IgE titers. The F(ab')2
      fragments lead to a significantly decreased immunoreactivity as compared to
      colostral IgG. This study shows the interesting use of peptic hydrolysis of IgG
      in producing fragments with preserved therapeutic immunoactivity and reduced
      potential allergenicity.

PMID- 8645995
TI  - Cross-reactivity between Aspergillus fumigatus and Penicillium.
AB  - Rabbit anti-Aspergillus fumigatus, rabbit anti-Penicillium and sera from patients
      with precipitating antibodies against A. fumigatus or Penicillium were analyzed
      by means of inhibition experiments in ELISA (IgG) and (or) immunoblot analysis
      (IgG). Sera from healthy donors were also analyzed in ELISA inhibition and sera
      from patients with allergic bronchopulmonary aspergillosis (ABPA) in RAST (IgE)
      inhibition. Most sera from patients with precipitins against Penicillium gave
      anti-A. fumigatus ELISA titers in the same range as sera from patients with
      aspergillosis. Anti-Penicillium IgG reacted with several A. fumigatus antigens
      with molecular weights between 28 and 130 kD. This reaction could be inhibited by
      the carbohydrate fraction of A. fumigatus and by extracts of related fungi. The
      binding to Penicillium of IgE antibodies in sera from patients with ABPA could be
      inhibited by A. fumigatus almost as effectively as by Penicillium. The binding of
      these antibodies to A. fumigatus was only slightly affected by Penicillium
      antigens. The presence of IgG antibodies that cross-react with A. fumigatus may
      strongly affect the immunoblot patterns and ELISA results obtained with sera from
      patients with aspergillosis. Penicillium spp. probably belong to the major
      stimuli which induce the synthesis of so-called naturally occurring antibodies to
      A. fumigatus.

PMID- 8645994
TI  - Sustained decrease of serum total IgE in cardiac transplant recipients.
AB  - A steady decrease in serum IgE was noted in cardiac transplant recipients
      receiving a combination of cyclosporin A and prednisolone for immunosuppressive
      therapy. The average time period for the demonstration of a 50% decrease in serum
      IgE levels was calculated to be 40 +/- 16 days in 19 patients.

PMID- 8645997
TI  - Tissue levels of histamine, PAF-acether and lysopaf-acether in carrageenan
      induced granuloma in rats.
AB  - The tissue concentrations of several inflammatory mediators were determined from
      day 0 to day 60 in granuloma induced in rats (n = 105) by injection of
      carrageenan in the fascia of the latissimus dorsi muscle. Noncollagen proteins
      (NCP) and the number of polymorphonuclear leukocytes (PMN) and mast cells were
      also assessed. In comparison with the tissue at time 0, we noted in the inflamed
      tissue (at 4 h) an increase in total proteins (4.0 +/- 3.0 vs. 84 +/- 12.0%, mean
      +/- SEM) and PMN (0.0 +/- 0.0 vs. 43.3 +/- 13.4%), and a fall in histamine
      concentration (from 30.0 +/- 9.0 to 9.0 +/- 4.0 ng/ml). A partial disappearance
      of mast cells and an increase of PAF-acether (PAF) levels (1.0 +/- 1.0 vs. 30.0
      +/- 22.0 ng/ml) was noted at 16 h, whereas lysopaf remained unchanged (3.7 +/-
      4.0 vs. 3.5 +/- 1.0 ng/ml). During evolution towards chronic inflammation (day 10
      60), NCP decreased, PMN disappeared and mast cells reappeared; the histamine
      level rose to 11.0 +/- 2.0 mg/ml, thus not reaching back baseline values. Lysopaf
      rose to 7.1 +/- 12.2 ng/ml and PAF levels increased further to reach 240.0 +/-
      153.0 ng/ml at day 10. This study suggests that PAF may contribute to the acute
      phase of an inflammatory state such as the carrageenan-induced granuloma and that
      it is also present during the chronic process.

PMID- 8645996
TI  - In vivo interleukin-4 regulation of antibody responses in euthymic and athymic
      mice to a T-independent antigen (hydroxyethyl starch).
AB  - The aim of this work was to analyze the implication of IL-4 in the antibody
      response induced in vivo after immunization with a class II T-cell-independent
      (TI) antigen. IL-4 suppression, through administration of a rat monoclonal
      antibody antimurine IL-4 (11B11), in euthymic BALB/c mice during the course of
      immunization with the DNP-coupled hydroxyethyl starch (TI antigen), inhibited the
      production of anti-DNP IgG1 antibodies, potentiated the synthesis of IgG2a and
      had no effect on the other isotypes (IgM, IgG2b and IgG3). After IL-4 treatment
      of athymic BALB/c mice in the same conditions, although the IgG2a production was
      not increased, the IgG1 synthesis was significantly decreased, as was observed in
      euthymic mice. These results demonstrate that cytokine IL-4 plays an active role
      in vivo in the regulation of antibody response after immunization by a T-cell
      independent antigen, in normal as well as in nude mice. The origin of IL-4 in
      these animals and especially in those athymic mice remains to be determined.

PMID- 8645998
TI  - A guinea pig model of hypersensitivity to allergenic fractions of natural rubber
      latex.
AB  - Allergy to natural rubber latex is a growing medical problem with life
      threatening aspects. The aim of this study was to learn if guinea pigs could
      serve as a suitable model for immediate-type hypersensitivity to latex. Guinea
      pigs were immunized either with whole non-ammoniated latex extract, or with one
      of nine SDS-PAGE-separated components. Other animals were injected with
      electroeluted latex components localized on gel at 14, 24 and a cluster around 45
      kD. Before and after immunization, sera from the animals were examined by ELISA,
      immunoblots, passive cutaneous anaphylaxis (PCA) and passive systemic
      anaphylaxis. Latex-specific antibodies were detected by ELISA and immunoblots in
      sera from all immunized animals. PCA assays showed that the guinea pigs had
      homocytotropic antibodies dilutable to 1:250. PCA was abolished when sera from
      animals immunized with allergens in alum were heated at 56 degrees C for 30 min
      indicating the antibodies were of the E isotype. Passive systemic anaphylaxis was
      induced in 4 of 10 guinea pigs. The results show that guinea pigs are capable of
      making antibodies to latex protein components that mediate dermal and systemic
      anaphylaxis, paralleling the spectrum of clinical and laboratory findings of
      humans with immediate-type clinical latex hypersensitivity.

PMID- 8646000
TI  - Pathogenesis of spongiform encephalopathies: an update.
AB  - In the last 40 years, the pathogenesis of transmissible spongiform
      encephalopathies of humans and animals have been the subject of exciting
      discoveries and also of passionate controversies. Although the human forms of
      these diseases are rare, the recent epidemics of bovine spongiform encephalopathy
      has most dramatically raised the issue of the transmissibility from affected
      animals to humans. This review summarizes some current hypotheses on the nature
      of the infectious agent causing these diseases, and on the pathogenetic pathways
      which produce histologically detectable damage to the central nervous system. The
      main focus is on the use of transgenic and knockout mice which, combined with
      organ transplantation and bone marrow reconstitution techniques, have provided
      powerful tools for dissecting the pathogenesis of these diseases.

PMID- 8645999
TI  - Homozygous C2 deficiency: association with defective alternative pathway function
      and immunoglobulin deficiency.
AB  - Deficiency in the second component of complement (C2) is the most common
      homozygous complement deficiency. While approximately half of the affected
      individuals are apparently healthy, C2 deficiency may be associated with
      autoimmune diseases and rarely increased susceptibility to infection. We report 5
      patients who had homozygous type I C2 deficiency in two families. Three of them
      suffered from frequent infections. These symptomatic patients had additional risk
      factors; the index cases in the first and the second family had IgG2 deficiency
      and IgA deficiency, respectively, and alternative complement pathway hemolytic
      activity was also low in both of them and in the sibling of the first index case.
      These results emphasize the probable role of other immunologic defects in the
      clinical presentation of C2 deficiency.

PMID- 8646001
TI  - -Coexistence of neural proliferations with early epithelial neoplasias and benign
      ectopias of the uterine cervix-.
AB  - OBJECTIVE: The study wanted to test the hypothesis that stromal systems can
      influence the development of the epithelium. METHOD: The stroma of specimens
      obtained by conizations of the cervix was histologically investigated. RESULTS:
      Neural proliferations such as neuromas, neurofibromas and vascular
      neurofibromatoses were found. They were common in the presence of epithelial
      lesions. CONCLUSION: Thus, the frequency of neural proliferations correlated with
      the nature of the epithelial abnormality. This association argues against the
      conventional concept that the growth of cervical intraepithelial neoplasias is
      absolutely autonomous.

PMID- 8646002
TI  - -Effect of endogenous opioids on adrenal cortex activity in women with
      hypothalamic amenorrhea-.
AB  - OBJECTIVE: Within an ovulation induction study, we investigated the activity and
      reactivity of the hypothalamic-pituitary-adrenal axis in women suffering from
      hypothalamic amenorrhea by using naloxone. METHODS: The central opioid receptors
      were blocked by means of a naloxone bolus injection of 4 mg i.v. daily. RESULTS:
      Before and after receptor blockade, the cortisol secretion showed diverse results
      independently from the hypothalamic opioid tone. The cortisol levels were not
      elevated. Also, the basal secretion of cortisol and DHEAS was nonspecific among
      the various responder groups. CONCLUSION: It seems that there is no close
      relationship between central opioid tone and adrenal function in hypothalamic
      amenorrhea.

PMID- 8646003
TI  - -Assessment of the prevalence of pre- and perimenstrual symptoms in female
      personnel of a university clinic-.
AB  - OBJECTIVE: This retrospective inquiry was designed to clarify the associations
      between the premenstrual syndrome (PMS) and premenstrual symptoms and personal
      and demographic data. METHODS: The entire female staff of our University
      Hospitals (1,535 women) were asked to fill in a questionnaire on 29 physical and
      psychical symptoms. 491 answers (32.7%) of women with regular menstruations were
      evaluated. RESULTS: PMS was diagnosed in 7.7% (p = 0.0006) and premenstrual
      symptoms in 42.4% (p = 0.021). The symptoms were significantly influenced by age
      (p = 0.0049) and use of oral contraceptives (OC, p = 0.047), but not by the
      duration of use and parity. CONCLUSION: The woman's social and familial
      background has a considerable impact on the occurrence and severity of
      premenstrual symptoms. The significant positive effect of some OCs on PMS may be
      of therapeutic use.

PMID- 8646004
TI  - -Inguinal irradiation versus no lymph node therapy in small vulvar carcinoma with
      clinically negative lymph nodes (T1, NO-1)-.
AB  - OBJECTIVE: The objective of this retrospective study was to determine if groin
      radiation was superior to no therapy in patients with small vulvar cancer with
      not palpable or not suspicious inguinal lymph nodes (T1, N0-N1). METHODS: From
      1974 to 1990, 135 patients with invasive T1, NO-1 vulvar cancer underwent radical
      vulvectomy with hot knife, groin nodes were left in situ. In 65 patients
      vulvectomy was followed by inguinofemoral irradiation: 70 patients had none.
      There were more cases with clitoris carcinoma (p < 0.04) in the group with groin
      irradiation but no other significant difference in prognostic factors was found.
      RESULTS: The actuarial 5-year survival was 93.7% with groin irradiation versus
      92.4% without lymph node therapy. Inguinal relapses occurred in only 4.6% of
      cases with groin irradiation versus 10% without lymph node treatment (n.s.).
      CONCLUSIONS: Radiation therapy to the groin seems to reduce groin relapses in
      early vulvar cancer.

PMID- 8646005
TI  - -Glucose, insulin and C-peptide kinetics during tocolysis with oral fenoterol-.
AB  - OBJECTIVE: The effect of oral fenoterol therapy (40 mg/day) on the kinetics of
      glucose, insulin and C-peptide during an oral glucose tolerance test (oGTT; 100 g
      glucose) was investigated in the third trimester. METHODS: 54 patients without
      tocolytic therapy (25 with a pathologic oGTT) were compared with 36 patients who
      received tocolytic therapy (18 patients with a pathologic oGTT). RESULTS: The
      patients with a normal or pathologic oGTT and with or without tocolytic therapy
      showed no significant differences in respect of the concentrations of glucose,
      insulin and C-peptide. During tocolytic therapy, an early increase in insulin was
      observed as well as slightly elevated C-peptide concentrations and a decreased C
      peptide/insulin quotient.

PMID- 8646006
TI  - [Intravesical electrostimulation for treatment of bladder dysfunction. Initial
      experiences after gynecological operations].
AB  - OBJECTIVE: We investigated the role of intravesical electrical stimulation in the
      treatment of voiding dysfunctions following major gynecologic surgery. METHODS:
      19 female patients with sensory and/or motor voiding dysfunction following
      gynecologic operations underwent intravesical electrostimulation after failure of
      traditional treatments. Before and after therapy, urodynamic examinations were
      performed. The follow-up was 6-24 months. RESULTS: All cases of sensory bladder
      dysfunction were cured. Volumes of residual urine significantly decreased (mean
      274 vs. 53 ml: p = 0.0003) and maximum detrusor pressure increased (mean 6 vs. 27
      cm H20; p = 0.0007). An early start of therapy (within 6 weeks after surgery)
      resulted in a better outcome. CONCLUSIONS: Intravesical electrical stimulation
      was effective in the treatment of sensory and motor voiding dysfunctions
      following major gynecologic surgery.

PMID- 8646007
TI  - -Chronic tubo-ovarian abscess with vaginal fistula after vaginal hysterectomy:
      combined laparoscopic-vaginal therapy-.
AB  - A chronic tuboovarian abscess with vaginal fistula occurring after vaginal
      hysterectomy was removed laparoscopically. The fistula was closed by a combined
      laparoscopic-vaginal procedure. A complete cure was achieved without
      complications.

PMID- 8646008
TI  - -Educational promotion in the Netherlands-.
AB  - Dutch medical students graduate from medical school with the title 'doctorandus',
      the Latin term implying that he or she is now qualified to pursue further studies
      that will eventually lead to a doctorate. The Dutch system of an academic career
      leading to a PhD-type doctorate is explained and compared with the German system,
      leading to a 'Habilitation'. The author recounts how a long research fellowship
      at Erasmus University Rotterdam eventually resulted in the successful defence of
      his thesis 'The early human fetal ductus arteriosus' and the award of a doctorate
      from that institution.

PMID- 8646009
TI  - -New toxoplasmosis infections in Steiermark-.

PMID- 8646010
TI  - [Serologic and genomic research by PCR of hepatitis C virus in different
      populations in Lome (Togo)].
AB  - An epidemiological survey carried out on several groups at University Hospital of
      Lome showed that the prevalence of anti-HCV antibodies is 3.3 % among blood
      donors, 1.3 % in STD positive subjects and 6.1 % in hospitalized patients. The
      disparity of the HCV seropositivity rate was not statistically significant among
      HIV-infected and non-infected subjects (6.9 % vs 3.3 % respectively). The HCV RNA
      was most frequently recovered from patients, whose serological pattern was
      confirmed but also from 30 % of subjects, for whom the HCV serology was proved.
      This shows the limits of serological tests in Africa.

PMID- 8646011
TI  - [Prevalence of serum markers of hepatitis B and C in blood donors and pregnant
      women in Algeria].
AB  - Serologic markers of hepatitis B (AgHBs, anti-HBc) and hepatitis C (anti-HCV) are
      investigated in 1,112 apparently healthy blood donors and 715 pregnant women in
      Algeria. Data of this study have shown a low prevalence of HCV and confirm that
      this country belongs to the middle endemic area for HBV. Indeed the anti-HCV were
      detected in 0.18 % of blood donors and 0.19 % of pregnant women. The AgHBs were
      observed in 3.6 % of blood donors and 1.6 % of pregnant women, anti-HBc
      antibodies were found in 13 % of blood donors and 11.1 % of pregnant women.

PMID- 8646012
TI  - [A case of disseminated Encephalitozoon intestinalis microsporidiosis in an AIDS
      patient in Nimes].
AB  - The pathogene's role importance of the microsporidia in nature is considerable.
      The human being, easily in contact, presents clinical manifestations only with
      some of them and in a very occasional manner. The increased frequency of the
      immunodepression has permitted to describe recently a new protozoon,
      Encephalitozoon intestinalis (alias Septata intestinalis) of the family of the
      Glugeidae and the human illness of which it is the agent. This parasitose is
      interesting to be presented because of its rarity and its circulation to organs
      far from one another. The diagnostic has been done thanks to the only optic
      microscope and confirmed from its visible efficacity of one cure of albendazole.
      The pyrimethamine could present a relative efficiency on a relapse of the
      sinusitis.

PMID- 8646013
TI  - [ORL manifestations observed in AIDS. Apropos of 65 cases].
AB  - We realized a clinical study in 65 patients with acquired immunodeficiency
      syndrome, aged from 3 to 62 years old (mean, 34 years) (34 males and 31 females)
      interned or showed in consultations at the hospital Gabriel Toure in Bamako, Mali
      (departments of ENT diseases and of internal medicine), in order to analyse and
      to state precisely different otorhinolaryngologic manifestations in AIDS.
      Oropharyngeal candidiasis was the most prevalent otorhinolaryngologic
      manifestation (57 %). Other less common lesions were suppurative otitis media (29
      %), atrophic pharyngitis (18,5 %), sinusitis (11 %), Kaposi's sarcoma (5 %)
      localized above all on the palate: they are however a frequent sign of infection
      by HIV. The manifestations merit a particular attention by otorhinolaryngologist
      because, although they have few influence on the general evolution of the
      disease, they appear as additional manifestations of infectious risks in AIDS
      patients.

PMID- 8646014
TI  - [Maxillary fissure cysts in Senegal. Analysis of a series of 14 cases].
AB  - The fissurary cyst is an non-odontogene and epithelial cyst. Their frequency in
      Senegal compared to the epidemiological records in European countries had led the
      authors to carry out a study. Around 14 fissurary cysts have been recorded in a
      seven year period. The teeth affected by the tumour could be saved in case of an
      early diagnosis.

PMID- 8646015
TI  - [Cerebral malaria in the child. A study of 11 cases with good prognosis at CHU of
      Yaounde, Cameroon].
AB  - From January to December 1993, 11 cases of cerebral malaria out of a total of 106
      cases of malaria were admitted in the paediatric unit of the Yaounde University
      Teaching Hospital. These 11 patients were comprised of 6 boys and 5 girls aged 6
      months to 10 years with a mean of 4.24 years. Convulsions and coma were the main
      clinical manifestation in 9 and 11 patients respectively. 10 patients had fever
      with 1 case of hyperpyrexia, whereas splenomegaly was noted in 6 patients and
      hepatomegaly in 2. Parasitemia was between 0.02 and 4 %. Chemoprophylaxis was
      irregular in 2 patients and absent in 9. The average hospital stay was 5.5 days
      and no death was noted in our series.

PMID- 8646016
TI  - [Benign maxillary tumors. Epulis in Senegal].
AB  - The epulis is a hyperplasic tumour restricted to the gum. It is the most widely
      spread tumour among the benin gum tumours. It has various etiologies. The authors
      emphasize the epidemiological and clinical aspects of 96 cases. Four types of
      epulis are observed, the most common type being the acquired epulis. On an
      etiological level, the factor related to oral hygiene is the most criticized.
      Their frequency in the oral pathology should lead the dental surgeon to master
      his treatment.

PMID- 8646017
TI  - [Bilateral choanal atresia in the newborn. Recommended management apropos of 1
      case observed in Lome, Togo].
AB  - The bilateral choanal atresia is a neonatal emergency. Its diagnosis is easily
      evoked when faced with a respiratory distress and cyanosis. It is quickly
      confirmed by a nasal optic endoscopy or when a nasopharyngeal aspiration catheter
      is held up by an obstacle. Putting a pharyngeal Mayo's cannula is an urgent
      gesture. The treatment uses transnasal perforation of the septum followed for two
      months with frequent aspirations.

PMID- 8646018
TI  - [Apropos of three cases of Turner's syndrome].
AB  - The authors report 3 cases of Turner's syndrome. These rare observations in
      Africans are the opportunity to give clinical and cytogenetic characteristics of
      Turner's syndrome. The importance of molecular biology in this disease is
      emphasized. All this because consensus about diagnostic and therapeutic
      recommendations are projected.

PMID- 8646019
TI  - [Salmonella isolated from food products of animal origin between 1989 and 1993 in
      the town of Tunis].
AB  - Among 260 strains of the genus Salmonella isolated by the "laboratoire de la
      municipalite de Tunis" from red meats or poultry sampled from public stores or
      slaughterhouse in Tunis township between 1989 and 1993, S. Agona, S. Enteritidis
      and S. Corvallis are the most frequent serovars. S. Agona is more frequent in
      food from bovine and equine origin, S. Enteritidis in poultry (phage type 35,
      "french classification", being more frequent). S. Corvallis ("new" serovar in
      Tunisia) is rather proceeding from turkeys.

PMID- 8646020
TI  - [Methicillin resistant Staphylococcus aureus. Decrease of incidence in a medical
      resuscitation unit at CHU Charles-Nicolle in Tunis].
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in
      hospitals. Between 1985 to 1988, there has been an increase in the number of MRSA
      (92 %) caused by an epidemic emergency in medical care unit of our hospital.
      Infections control measures allowed to stop these outbreaks (20 % MRSA in 1990).
      But incidence of MRSA persist to decrease without supplement control measures and
      in 1994, only 7 % of Staphylococcus aureus strains are MRSA.

PMID- 8646022
TI  - [First paleoparasitologic approach of the neolithic site in Chalain (Jura,
      France)].
AB  - On the neolithic site of Chalain, the analysis of 12 human coprolites and of 10
      sediment samples rich in organic matters has revealed the presence of many well
      preserved eggs of Helminths: eggs of Trichuris/Capillaria, Fasciola hepatica and
      Diphyllobothrium sp. The interest of palaeoparasitological analysis in
      Archaeology and the impact of taphonomical process on the parasitological
      material are discussed.

PMID- 8646021
TI  - [Evaluation of the impact of iron treatment. Interference of malaria].
AB  - In Togo, where malaria occurs all the year, 151 children, from 6 months to 3
      years old, were distributed in 2 groups, one of which received an iron
      supplementation during three months, and the other a placebo during the same
      time. At the end of the trial, no significant difference was observed between the
      two groups. However, taking into account malaria infection at the end of the
      trial, children who received iron supplementation and who were free of malaria
      infection showed improvement of their haematological status when compared to
      children receiving placebo and also free of malaria infection. Authors presumed
      that iron supplementation was masked by malaria when they evaluated effect of
      iron supplementation on anaemia.

PMID- 8646023
TI  - [Therapeutic options in locally advanced breast cancers].
AB  - The authors are showing their experience on 394 locally advanced breast cancer in
      the last 10 years. In this trial were included the tumours larger than 5 cm,
      multiple tumours, tumours invading the skin or the thoracic wall with invaded or
      fixed axillary or supraclavicular nodes and acute carcinomatous mastitis. The
      optional therapeutic schedule was modified upon the stage. It consisted in pre-
      or postoperative radiotherapy, polychemotherapy or polychemo- or radiotherapy
      alone, associated with nonspecific immunotherapy and hormonotherapy. In patients
      with complex treatment the survival rate was 45.4% at 5 years and 12.3% at 10
      years. The authors highlight the importance of the surgical treatment which offer
      a big potential in the context of the complex treatment.

PMID- 8646024
TI  - [Paget's disease of breast--a special form of breast cancer].
AB  - The incidence of Paget's disease of the breasts (15 cases) among 701 operated
      breast cancer was 2.1%. All studied cases were women. Over two-thirds of the
      patients were at menopause at the time of diagnosis. The interval between the
      clinical onset of disease and the histological diagnosis was approximately of
      21.4 month. The clinical diagnosis was based on the presence of the
      characteristic erythemato-squamous lesion. In five cases a palpable mass was
      found. We registered one case of bilateral metachronous Paget's disease. Four
      patients had axillary lymphadenopathy: three of them presented with palpable
      mass. Mammography, cytology and histological examination from biopsy were the
      principal means of diagnosis. There were 10 women in stage, two women in stage
      II, and three women in stage III. The surgical treatment was the major component
      of treatment. The best prognosis was registered in the cases without a palpable
      mass in the breast and axillary lymphadenopathy with 5-year survival in four of
      five cases.

PMID- 8646025
TI  - [Laparoscopic cholecystectomy in acute cholecystitis].
AB  - Contrary to earlier opinions, the laparoscopic cholecystectomy (LC) is not a
      contraindication in the acute cholecystitis. The most important parameter in
      determining the feasibility of attempting laparoscopic cholecystectomy in the
      setting of acute inflammation appears to be the experience of the surgeon. 59
      cases with LC are analyzed: 50 LC and 9 conversion. The operations were more
      difficult and lasted longer. The patients appeared to be at a greater
      intraoperative risk and the conversion rate was also higher. Neither lesions of
      the common bile duct nor deaths were recorded. The advantages of the method (the
      hospital stay was reduced, less postoperative pain, and early return to normal
      activities) should not make the surgeon disregard the risks and stubbornly employ
      LC in acute cholecystitis.

PMID- 8646026
TI  - [Laparoscopic cholecystectomy: its risks and limits. An analysis of a group of
      2546 patients operated on at the Clinica Chirurgie III in Cluj].

PMID- 8646027
TI  - [Primary solid tumors of the mesentery].
AB  - The interest for the primary solid tumors of the mesentery (TSPM) is justified by
      the difficulties of preoperative diagnosis and surgical treatment of these
      unusual lesions. We analyzed 68 TSPM operated in the Department of General
      Surgery of Fundeni Hospital between 1960-1993. In the study were included only
      the lymphoma presented as mesenteric masses (n = 17); the enlarged mesenteric
      lymph nodes were excluded. The most common malignant tumor was the fibroma (n =
      8) and lipoma (n = 10). In the resection of mesenteric tumors exposure of the
      superior mesenteric vessels is important. The relation between tumoral and
      superior mesenteric vessels is the necessary criterion of resectability: in 41
      cases from 43 unresectable lesions the reason of unresectability was the invasion
      of the superior mesenteric vein and artery; in only two cases the reason was the
      presence of liver metastases. The resectability was not influenced by the
      multiplicity of the lesions: in all cases with multiple mesenteric tumors (6
      patients) the resection was performed. The distant metastases of TSPM are rare;
      on the contrary, the local invasion is common.

PMID- 8646028
TI  - [Pancreatic injuries].

PMID- 8646029
TI  - [Surgically treated malignant melanoma. The long-term results].
AB  - It is presented the case of a 37-year-old man with diagnosis of junctional nevus
      malignant with aspect of nodular melanotic melanoma level V Clark with regional
      lymph node invasion who would be classified as III stage in T.N.M.
      classification. Remark on importance for diagnosis of malignancy the history of
      recently modification of congenital tumor and the local examination. Also, on
      remark the favourable evolution after an oncologic surgical treatment--wide
      surgical excision of lesion completely (in condition of negatives histopathologic
      tumor markers of prognostic) with prophylactic regional lymphadenectomy with
      curative intention. The excellent result 7 years after the surgical treatment
      determined us to present this case.

PMID- 8646031
TI  - The problems of fundholding.

PMID- 8646030
TI  - [Therapeutic strategy in breast cancer].
AB  - The authors present the actual concepts of the therapeutic strategy for the
      breast cancer. The choice of the optimal protocol treatment is based on a
      complete and correct pretherapeutic evaluation. This implies the staging using
      TNM/ UICC/ 1987 system (explained in the text) and the definition of the
      prognostic factors: axillary lymph node involvement, other pathological patterns,
      the situation of the hormonal receptors and the cell proliferation index. For the
      stages I-II the strategy of the treatment include: modified radical mastectomy,
      postoperative irradiation in well defined cases and the adjuvant systemic
      treatment using chemotherapy and hormonal therapy. The laparoscopic ovariectomy
      is a safe and simple technique. For the local advanced cancer (IIIA and IIIB) the
      treatment begins with a systemic aggressive approach, the surgery being applied
      following the tumoral regression. In the stage IV the complex palliative
      treatment is indicated.

PMID- 8646032
TI  - Chronic neurological effects of organophosphate pesticides.

PMID- 8646033
TI  - Bovine spongiform encephalopathy: its wider meaning for population health.

PMID- 8646034
TI  - The GMC, racism, and complaints against doctors.

PMID- 8646035
TI  - Naming of drugs: pass the epinephrine, please.

PMID- 8646036
TI  - Air pollution in homes.

PMID- 8646037
TI  - US approves HIV "home test".

PMID- 8646038
TI  - India cracks down on traditional drugs advertisements.

PMID- 8646039
TI  - IVF could be offered to older women in The Netherlands.

PMID- 8646040
TI  - Russians' health declines.

PMID- 8646041
TI  - More homes at risk from radon.

PMID- 8646042
TI  - Cost effectiveness of screening for and eradication of Helicobacter pylori in
      management of dyspeptic patients under 45 years of age.
AB  - OBJECTIVE: To assess the cost effectiveness of screening for and eradicating
      Helicobacter pylori in patients under 45 years of age presenting with dyspepsia.
      DESIGN: A decision analytic model composed of a decision tree to represent the
      epidemiology of dyspepsia and a Markov process to model the outcomes of
      treatment. PATIENTS: Patients under the age of 45 years presenting to their
      general practitioner with (peptic type) dyspepsia. INTERVENTIONS: Conventional
      empirical treatment with healing and maintenance doses of cimetidine v
      eradication treatment solely in patients with confirmed peptic ulcer; and
      conventional empirical treatment for all dyspeptic patients compared with the use
      of a serology test to identify patients with H pylori, who then receive endoscopy
      to investigate the presence of peptic ulcer disease and, when disease is found,
      are given eradication treatment with a breath test to confirm successful
      eradication. MAIN OUTCOME MEASURES: Expected cumulative costs over a period of 10
      years. The proportion of time patients spend without a recurrent ulcer. RESULTS:
      After receiving eradication treatment, patients with confirmed ulcer spend an
      average of 99% of their time free from recurrent ulcer disease compared with 95%
      after treatment with cimetidine. Eradication treatment costs less than that with
      cimetidine. When the initial cost of identifying appropriate patients to receive
      eradication treatment is added to the analysis, however, these cost savings take
      almost eight years to accrue. CONCLUSIONS: Enthusiasm for introducing testing for
      and eradication of H pylori for dyspeptic patients in general practice should be
      tempered by an awareness that cost savings may take many years to realise.

PMID- 8646043
TI  - Prevalence of child sexual abuse among adolescents in Geneva: results of a cross
      sectional survey.
AB  - OBJECTIVE: To measure the cumulative prevalence of child sexual abuse in a
      representative sample of the adolescent population of Geneva. DESIGN: Cross
      sectional survey with an anonymous self administered questionnaire centred on a
      factual description of sexual activities. SETTING: 68 classes (17 schools)
      randomly selected from the 201 ninth grade classes of the public school system in
      Geneva. SUBJECTS: 1193 adolescents aged 13-17 years, of whom 1116 (93.5%; 568
      girls, 548 boys) consented to the study and returned completed questionnaires.
      RESULTS: 192 (33.8%) girls and 60 (10.9%) boys reported having experienced at
      least one sexually abusive event. The prevalence of abuse involving physical
      contact was 20.4% (116 cases) among girls and 3.3% (18) among boys. The
      prevalence of abuse involving some form of penetration was 5.6% (32 cases) among
      girls and 1.1% (six) among boys. One third of the abused adolescents had
      experienced more than one abusive event and 46.5% (92/198) had experienced the
      first event before age 12. Abuse by a family member was reported by 20.5%
      (36/176) of abused girls and 6.3% (3/48) of abused boys. Abusers were known to
      victims in two thirds of cases. Ninety per cent of abusers were male and 35.3%
      (71/201) came from the victim's peer group. Over 80% of participants found the
      questionnaire interesting, clearly formulated, and useful. CONCLUSIONS: Child
      sexual abuse is a universal social phenomenon. Adolescents themselves can
      contribute to research and so help in the search for more efficient prevention
      and intervention strategies.

PMID- 8646044
TI  - Comparison of case fatality in south Asian and white patients after acute
      myocardial infarction: observational study.
AB  - OBJECTIVE: To compare mortality in south Asian (Indian, Pakistani, and
      Bangladeshi) and white patients in the six months after hospital admission for
      acute myocardial infarction. DESIGN: Observational study. SETTING: District
      general hospital in east London. PATIENTS: 149 south Asian and 313 white patients
      aged < 65 years admitted to the coronary care unit with acute myocardial
      infarction from 1 December 1988 to 31 December 1992. MAIN OUTCOME MEASURE: All
      cause mortality in the first six months after myocardial infarction. RESULTS: The
      admission rate in the south Asians was estimated to be 2.04 times that in the
      white patients. Most aspects of treatment were similar in the two groups, except
      that a higher proportion of the south Asians received thrombolytic drugs (81.2% v
      73.8%). After adjustment for age, sex, previous myocardial infarction, and
      treatment with thrombolysis or aspirin, or both, the south Asians had a poorer
      survival over the six months from myocardial infarction (hazard ratio 2.02 (95%
      confidence interval 1.14 to 3.56), P = 0.018), but a substantially higher
      proportion were diabetic (38% v 11%, P < 0.001), and additional adjustment for
      diabetes removed much of their excess risk (adjusted hazard ratio 1.26 (0.68 to
      2.33), P = 0.47). CONCLUSION: South Asian patients had a higher risk of admission
      with myocardial infarction and a higher risk of death over the ensuing six months
      than the white patients. The higher case fatality among the south Asians, largely
      attributable to diabetes, may contribute to the increased risk of death from
      coronary heart disease in south Asians living in Britain.

PMID- 8646046
TI  - Prospective study of hepatitis B vaccination in patients with chronic hepatitis
      C.

PMID- 8646045
TI  - Radiology services for remote communities: cost minimisation study of
      telemedicine.
AB  - OBJECTIVES: To determine the social costs of providing a rural population with
      radiology services under three different systems: the existing system (a small x
      ray unit at the remote site and all other examinations at the nearest radiology
      department (the host site)); a teleradiology system (most examinations at the
      remote site and more advanced examinations at the host site); and all
      examinations at the host site. DESIGN: Cost minimisation study. SETTING: Primary
      health care in a remote community in Norway. SUBJECTS: A randomly selected sample
      (n = 597) of all patients (n = 1793) having radiological examinations in 1993.
      MAIN OUTCOME MEASURES: Annual direct medical costs, direct non-medical (travel)
      costs, and indirect costs (lost production) of the three options. RESULTS: After
      exclusion of costs common to the three systems the direct medical, direct non
      medical, and indirect costs of the three options were, respectively, 9000 pounds,
      51,000 pounds, and 31,500 pounds (total 91,500 pounds) for the existing system;
      108,000 pounds, 2,000 pounds, and 13,500 pounds (total 123,500 pounds) for the
      teleradiology option; and 0 pounds, 75,000 pounds, and 42,000 pounds (117,000
      pounds in total) for the "all at host" option. Sensitivity analyses indicated
      that the existing system is the least costly option except when lost leisure is
      valued as highly as lost production. CONCLUSION: The teleradiology option did not
      seem to be cost saving in the study community. Such systems, however, may be
      justified on the grounds of equity of access and quality of care.

PMID- 8646047
TI  - Specificity of pH and osmolality of early morning urine sample in assessing
      distal renal tubular function in children: results in healthy children.

PMID- 8646048
TI  - Determining the approximate area of a burn: an inconsistency investigated and re
      evaluated.

PMID- 8646049
TI  - Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled
      study.

PMID- 8646051
TI  - Trends in staffing an academic department of surgery in a tropical hospital:
      past, present, and future?
AB  - OBJECTIVE: To evaluate the effect of staff mobility on student teaching, the
      training of young surgeons, and the volume of research in an academic department
      of surgery of a tropical teaching hospital. DESIGN: Retrospective study of
      academic staffing in the department of surgery of the Ahmadu Bello University
      Teaching Hospital between 1975 and 1993. SETTING: Zaria, Nigeria. SUBJECTS: 42
      academic staff, 1190 medical students, and 110 registrars (trainee surgeons).
      MAIN OUTCOME MEASURES: Number of academic staff in post, medical students, and
      registrars; number of research papers in latter years of the study. RESULTS: In
      19 years, 42 academic staff worked for varying periods (1-15 years) in the
      university department of surgery in Zaria. These included six professors, 12
      senior lecturers, and 24 lecturers. Although staff numbers diminished, numbers of
      students and registrars increased year by year. Average number of publications
      dropped from a peak of 14.4 to 7.4 a year. CONCLUSION: Staffing of the department
      has fallen steadily over the years and has adversely affected the department's
      primary responsibility of teaching students and training young surgeons.

PMID- 8646050
TI  - Cost effectiveness of treating primary care patients in accident and emergency: a
      comparison between general practitioners, senior house officers, and registrars.
AB  - OBJECTIVES: To compare outcome and costs of general practitioners, senior house
      officers, and registrars treating patients who attended accident and emergency
      department with problems assessed at triage as being of primary care type.
      DESIGN: Prospective intervention study which was later costed. SETTING: Inner
      city accident and emergency department in south east London. SUBJECTS: 4641
      patients presenting with primary care problems: 1702 were seen by general
      practitioners, 2382 by senior house officers, and 557 by registrars. MAIN OUTCOME
      MEASURES: Satisfaction and outcome assessed in subsample of 565 patients 7-10
      days after hospital attendance and aggregate costs of hospital care provided.
      RESULTS: Most patients expressed high levels of satisfaction with clinical
      assessment (430/562 (77%)), treatment (418/557 (75%)), and consulting doctor's
      manner (434/492 (88%)). Patients' reported outcome and use of general practice in
      7-10 days after attendance were similar: 206/241 (85%), 224/263 (85%), and 52/59
      (88%) of those seen by general practitioners, senior house officers, and
      registrars respectively were fully recovered or improving (chi2 = 0.35, P =
      0.840), while 48/240 (20%), 48/268 (18%), and 12/57 (21%) respectively consulted
      a general practitioner or practice nurse (chi2 = 0.51, P = 0.774). Excluding
      costs of admissions, the average costs per case were 19.30 pounds, 17.97 pounds,
      and 11.70 pounds for senior house officers, registrars, and general practitioners
      respectively. With cost of admissions included, these costs were 58.25 pounds,
      44.68 pounds, and 32.30 pounds respectively. CONCLUSION: Management of patients
      with primary care needs in accident and emergency department by general
      practitioners reduced costs with no apparent detrimental effect on outcome. These
      results support new role for general practitioners.

PMID- 8646052
TI  - Screening asymptomatic people at high risk for hepatitis C. The case for.

PMID- 8646053
TI  - Screening asymptomatic people at high risk for hepatitis C. The case against.

PMID- 8646055
TI  - ABC of urology. Urological trauma and bladder reconstruction.

PMID- 8646054
TI  - Paradoxical embolism in a young woman.

PMID- 8646056
TI  - Shortage of organs for transplantation. Editorial's comments on report were
      selective.

PMID- 8646057
TI  - Shortage of organs for transplantation. Human organs will remain superior to
      porcine organs.

PMID- 8646058
TI  - Shortage of organs for transplantation. Living donors should be used more often.

PMID- 8646059
TI  - Half of physicians are unaware of surveillance system for Creutzfeldt-Jakob
      disease.

PMID- 8646060
TI  - Shortage of organs for transplantation. Donation by living donors is effective
      for recipient and safe for donor.

PMID- 8646061
TI  - Shortage of organs for transplantation. Transplant coordinators need more money
      for education.

PMID- 8646062
TI  - Diagnosing testicular torsion. Isotope scanning is useful.

PMID- 8646063
TI  - Cerebral oedema after ingestion of MDMA ("ecstasy") and unrestricted intake of
      water.

PMID- 8646064
TI  - Don't count on urinary white cells to diagnose childhood urinary tract infection.

PMID- 8646065
TI  - Managing patients with an absent or dysfunctional spleen. Guidelines should
      highlight risk of Salmonella infection in sickle cell disease.

PMID- 8646066
TI  - Managing patients with an absent or dysfunctional spleen. Patients expect
      splenectomy in rural Zaire.

PMID- 8646067
TI  - Managing patients with an absent or dysfunctional spleen. Data linkage is useful
      in setting up a register.

PMID- 8646068
TI  - Managing patients with an absent or dysfunctional spleen. Uncertainty exists over
      frequency of blood tests to test antipneumococcal immunity.

PMID- 8646069
TI  - Managing patients with an absent or dysfunctional spleen. Under half of doctors
      know that antibiotic prophylaxis should be life long.

PMID- 8646070
TI  - Managing patients with an absent or dysfunctional spleen. Is there evidence to
      show that daily antibiotic treatment is best?

PMID- 8646071
TI  - Managing patients with an absent or dysfunctional spleen. Guidelines do not
      discuss resistance to antibiotics among pneumococci.

PMID- 8646072
TI  - Testing to check success of treatment to eradicate H pylori. Patients' wellbeing
      should not be risked for marginal cost savings.

PMID- 8646073
TI  - Screening for diabetic retinopathy.

PMID- 8646074
TI  - Testing to check success of treatment to eradicate H pylori. Routine retesting is
      necessary.

PMID- 8646076
TI  - HIV antibody test should be a routine investigation for undiagnosed pneumonia.

PMID- 8646077
TI  - The melanoma epidemic. Figures have risen by over 150% over 10 years.

PMID- 8646075
TI  - The melanoma epidemic. Excess exposure to ultraviolet light is established as
      major risk factor.

PMID- 8646078
TI  - Torture should not be trivialised.

PMID- 8646079
TI  - From black bag to black box: will computers improve the NHS?

PMID- 8646080
TI  - Going home.

PMID- 8646081
TI  - Mortality among second generation Irish in England and Wales.

PMID- 8646082
TI  - Does Britain need an academy of medicine?

PMID- 8646083
TI  - Laparoscopic cholecystectomy: the other side of the coin.

PMID- 8646085
TI  - Aid agencies need more self regulation.

PMID- 8646084
TI  - New hope for WHO?

PMID- 8646086
TI  - Amnesty highlights doctors' duty to report torture.

PMID- 8646087
TI  - Australian doctors put in firing line.

PMID- 8646088
TI  - US gene discovery leads to patent war.

PMID- 8646089
TI  - Herbal stimulant causes US deaths.

PMID- 8646090
TI  - Cocaine blamed for infants' emotional problems.

PMID- 8646091
TI  - New BUPA scheme hits NHS patients.

PMID- 8646092
TI  - Bigger tobacco companies offer a deal on adolescent smokers.

PMID- 8646093
TI  - Seasonality and the sudden infant death syndrome during 1987-9 and 1991-3 in
      Australia and Britain.
AB  - OBJECTIVE: To determine whether seasonality of the sudden infant death syndrome
      persists now that rates have fallen, mostly after widespread adoption of the
      "face upwards" sleeping position. DESIGN: Monthly data on the sudden infant death
      syndrome during 1987-9 were compared for seasonality with those of 1991-3; rates
      were studied as deaths per 1000 live births. SETTING: Australia and Britain
      (England, Wales, and Scotland). SUBJECTS: Infants under 1 year dying of the
      syndrome (2401 for Australia and 6630 for Britain). MAIN OUTCOME MEASURE: Extent
      of seasonal variation (amplitude) was established by cosinor analysis; amplitudes
      for the earlier and later years were compared. RESULTS: The rate fell in every
      month, and, though it did so relatively more in winter than summer, seasonality
      remained a distinctive feature. In the comparison of amplitudes the ratio between
      the earlier and later years was 1.4 in both Australia and Britain. Some
      differences between the hemispheres were noted. CONCLUSIONS: Seasonality of the
      sudden infant death syndrome remains to be explained and continues to be an
      important aetiological lead. Studies from other countries are needed.

PMID- 8646094
TI  - Long term backache after childbirth: prospective search for causative factors.
AB  - OBJECTIVES: To assess in a prospective randomised study the association between
      motor block resulting from high and low dose epidural infusions of bupivacaine in
      labour and the incidence of long term backache after childbirth, and to compare
      the incidence of backache in women not receiving epidural analgesia. DESIGN:
      Women requesting epidural analgesia in labour between October 1991 and March 1994
      were randomised to receive infusions of either bupivacaine alone or low dose
      bupivacaine with opioid. Data were collected during labour and the immediate
      postpartum period from these women and from women recruited at random over the
      same time from those who had laboured without epidural analgesia. A postal
      questionnaire about symptoms was sent three months after childbirth to all women.
      Further data were collected one year after childbirth from those who had reported
      new backache at three months. SETTING: St Thomas's Hospital, London. SUBJECTS:
      599 women were recruited, of whom 450 (75%) replied to a follow up questionnaire.
      RESULTS: 152 women (33.8% of responders) reported backache lasting three months
      after delivery and, of these, 33 (7.3%) had not previously suffered with
      backache. There were no significant differences between the treatment groups in
      the incidence of postnatal backache overall or of new backache or any symptoms
      after childbirth. Among all demographic, obstetric, and epidural variables
      examined the only factors significantly associated with backache after childbirth
      were backache before and during pregnancy. CONCLUSIONS: The incidence of new long
      term backache was not significantly increased in women who received epidural
      analgesia in labour. Motor block resulting from epidural local anaesthetic
      administration was not a significant factor in the development of backache.

PMID- 8646095
TI  - Patterns of mortality in second generation Irish living in England and Wales:
      longitudinal study.
AB  - OBJECTIVE: To examine the mortality of second generation Irish living in England
      and Wales. DESIGN: Longitudinal study of 1% of the population of England and
      Wales (longitudinal study by the Office of Population Censuses and Surveys (now
      the Office for National Statistics)) followed up from 1971 to 1989. SUBJECTS:
      3075 men and 3233 women aged 15 and over in 1971. MAIN OUTCOME MEASURES: Age and
      sex specific standardised mortality ratios for all causes, cancers, coronary
      heart disease, cerebrovascular diseases, respiratory diseases, and injuries and
      poisonings. Deaths were also analysed by socioeconomic indicators. RESULTS: 786
      deaths were traced to men and 762 to women. At working ages (men, aged 15-64;
      women, 15-59) the mortality of men (standardised mortality ratio 126) and women
      (129) was significantly higher than that of all men and all women. At ages 15-44,
      relative disadvantages were even greater both for men (145) and for women (164).
      Mortality was raised for most major causes of death. Significant excess mortality
      from cancers was seen for men of working age (132) and for women aged 60 and over
      (122). At working ages mortality of the second generation Irish in every social
      class and in the categories of car access and housing tenure was higher than that
      of all men and all women in the corresponding categories. Adjusting for these
      socioeconomic indicators did not explain the excess mortality. CONCLUSION:
      Mortality of second generation Irish men and women was higher than that of all
      men and all women and for most major causes of death. While socioeconomic factors
      remain important, cultural and lifestyle factors are likely to contribute to this
      adverse mortality.

PMID- 8646096
TI  - Growth in utero and cognitive function in adult life: follow up study of people
      born between 1920 and 1943.
AB  - OBJECTIVES: To examine the relation between fetal growth and cognitive function
      in adult life. DESIGN: A follow up study of men and women whose birth weights and
      other measurements of body size had been recorded at birth. SETTING:
      Hertfordshire, Preston, and Sheffield. SUBJECTS: 1576 men and women born in
      Hertfordshire, Sheffield, or Preston between 1920 and 1943. MAIN OUTCOME
      MEASURES: Intelligence quotient as measured by the AH4 test and amount of decline
      in cognitive function with age as estimated by the difference between score on
      the Mill Hill vocabulary test and score on the AH4 test. RESULTS: Score on the
      intelligence test was higher in people who had a large biparietal head diameter
      at birth, but it was not related to any other measure of body size or
      proportions. No association was found between decline in cognitive function and
      any measure of size or proportions at birth. CONCLUSION: Impaired fetal growth
      was not associated with poorer cognitive performance in adult life. Adaptations
      made by the fetus in response to conditions that retard its growth seem to be
      largely successful in maintaining brain development.

PMID- 8646097
TI  - Perioperative myocardial infarction in peripheral vascular surgery.

PMID- 8646098
TI  - Risk factors for sudden infant death syndrome: further change in 1992-3.

PMID- 8646099
TI  - The extent of the two tier service for fundholders.
AB  - OBJECTIVE: To examine possible differential changes in outpatient referrals to
      orthopaedic clinics, attendances, and waiting times between fundholding and non
      fundholding general practitioners. DESIGN: Observational controlled study of
      referrals by general practitioners to orthopaedic outpatients between April 1991
      and March 1995. SETTING: District health authority in south-west England.
      SUBJECTS: 10 fundholding practices with 108,300 registered patients; 22 control
      practices with 159,900 registered patients. MAIN OUTCOME MEASURES: Changes in age
      standardised referral and outpatient attendance ratios for the year before and
      the two years after achieving fundholder status; changes in outpatient waiting
      times. RESULTS: In the year before achieving fundholding status both groups were
      referring more patients than were being seen. Two years later, referral and
      attendance ratios had increased by 13% and 36% respectively for fundholders and
      32% and 59% for controls, and both groups were referring fewer patients than were
      being seen. Attendances represented 112% of referrals for fundholders and 104%
      for controls. In 1991-2, a similar proportion of patients in the two groups was
      seen within three months of referral. The two hospitals that set up specific
      clinics exclusively for fundholders showed faster access for patients of
      fundholders by 1993-4, as did a third hospital without such clinics by 1994-5.
      CONCLUSIONS: Fundholders increased their orthopaedic referrals less than did
      controls and achieved a better balance between outpatient appointments and
      referrals. Their patients were likely to be seen more quickly, particularly if
      the hospital provided special clinics exclusively for fundholders. Lack of case
      mix information makes it impossible to judge whether these differences benefit or
      disadvantage patients.

PMID- 8646100
TI  - Responding to out of hours requests for visits: a survey of general practitioner
      opinion.

PMID- 8646101
TI  - Callosities, corns, and calluses.
AB  - Inappropriate shoes, abnormal foot mechanics, and high levels of activity produce
      pressure and friction that lead to corns and calluses. Most lesions can be
      managed conservatively by proper footwear, orthoses, and, if necessary, regular
      paring. The lesions usually disappear when the causative mechanical forces are
      removed. Surgery is rarely indicated and should be specifically aimed at
      correcting the abnormal mechanical stresses.

PMID- 8646102
TI  - What value do computers provide to NHS hospitals?
AB  - As the NHS spends around pond 220 million a year on information technology for
      use by acute hospitals that are hard pressed for resources, it is reasonable to
      ask what value is provided. A review of rigorous scientific evidence for the
      value of information technology to NHS hospitals found that published evidence is
      scarce and far from conclusive. Information technology in NHS hospitals needs
      further assessment so that future decisions on such necessary and important
      investments are based on clear, well documented experience and research.

PMID- 8646103
TI  - Prison rights: mandatory drugs tests and performance indicators for prisons.
AB  - Mandatory drugs testing of prisoners applies throughout England and Wales. Data
      from the 1995 pilot study in eight prisons show that the proportion testing
      positive for opiates or benzodiazepines rose from 4.1% to 7.4% between the first
      and second phase of random testing and that there was a 20% increase over 1993-4
      in the provisional total of assaults for 1995. Interpretation of these data is
      difficult, but this is no excuse for prevarication over the danger that this
      policy may induce inmates to switch from cannabis (which has a negligible public
      health risk) to injectable class A drugs (a serious public health risk) in
      prison. The performance indicators for misuse of drugs that are based on the
      random mandatory drugs testing programme lack relevant covariate information
      about the individuals tested and are not reliable or timely for individual
      prisons.

PMID- 8646104
TI  - Adjuvant treatment for colorectal cancer. Reducing avoidable delays in
      establishing the diagnosis is also important.

PMID- 8646105
TI  - Adjuvant treatment for colorectal cancer. Concerns about chemotherapy are
      legitimate.

PMID- 8646106
TI  - Getting urgent information to doctors.

PMID- 8646107
TI  - Health link between countries should be global.

PMID- 8646108
TI  - One stop shopping for global health information.

PMID- 8646109
TI  - Monitoring the frequency of side effects of drugs. Reasons for stopping drugs
      could be recorded in general practice.

PMID- 8646110
TI  - Monitoring the frequency of side effects of drugs. Data from several sources are
      needed to show numbers taking drugs.

PMID- 8646111
TI  - Teenage sex. Trend towards earlier menarche stopped 30 years ago.

PMID- 8646112
TI  - Teenage sex. Image of various providers of sexual health care varies.

PMID- 8646113
TI  - Teenage sex. Teenagers can be helped to behave responsibly.

PMID- 8646114
TI  - Screening to prevent renal failure in diabetic patients. Study's assumptions are
      unwarranted.

PMID- 8646115
TI  - Doctors should check datasheets.

PMID- 8646116
TI  - Treat patients with kindness during magnetic resonance imaging.

PMID- 8646117
TI  - The nature of general practice. General practitioners are best placed to decide
      priorities.

PMID- 8646118
TI  - The nature of general practice. Favouring a mythological traditional orthodoxy is
      absurd.

PMID- 8646119
TI  - The nature of general practice. General practitioners are not as beleaguered as
      they were.

PMID- 8646120
TI  - The nature of general practice. Service is abused because it is perceived as
      being free.

PMID- 8646121
TI  - The nature of general practice. Nostalgia doesn't help recruitment.

PMID- 8646122
TI  - Myocardial infarction at work cannot be regarded as an accident.

PMID- 8646123
TI  - Redefining authorship. Drug industry is increasingly allowing employees to be
      named as authors.

PMID- 8646124
TI  - Redefining authorship. Relative contribution should be given after each author's
      name.

PMID- 8646125
TI  - The nature of general practice. Patient centred model of practice is unsuited to
      reforms.

PMID- 8646126
TI  - Promoting clinical effectiveness.

PMID- 8646127
TI  - Regulating complementary medicine.

PMID- 8646128
TI  - Ecstasy and neurodegeneration.

PMID- 8646129
TI  - Pharmaceutical representatives.

PMID- 8646131
TI  - Childhood bereavement.

PMID- 8646130
TI  - Designing a vaccine for tuberculosis.

PMID- 8646132
TI  - Common pollutants may harm fetuses.

PMID- 8646133
TI  - US pesticide use reaches new record.

PMID- 8646135
TI  - Germany fears more deaths from E coli outbreak.

PMID- 8646134
TI  - High levels of substandard care in maternal deaths.

PMID- 8646136
TI  - UK government proposes changes to primary care.

PMID- 8646137
TI  - Teenage smokers fail to recognise health risks.

PMID- 8646138
TI  - Definition of "authorship" may be changed.

PMID- 8646139
TI  - When MPs chicken out over beef.

PMID- 8646140
TI  - Effect of correcting outcome data for case mix: an example from stroke medicine.
AB  - OBJECTIVE: To show the influence of variations in case mix on clinical outcome
      indicators for patients admitted to hospital with acute stroke. DESIGN: "Before
      and after" cohort study, with prospective, consecutive identification of patients
      and prospective follow up; multiple logistic regression analyses to correct for
      case mix variations. SETTING: University teaching hospital. SUBJECTS: 216
      patients with stroke identified before the introduction of an organised stroke
      service, and 252 patients with stroke identified after its introduction. MAIN
      OUTCOME MEASURES: Case fatality at 30 days and 12 months; for survivors at 12
      months, proportions of patients who were independent (according to the Oxford
      handicap scale) and of those living at home. RESULTS: Crude outcome data
      suggested that patients in the cohort identified after the introduction of the
      stroke service were significantly more likely to be alive, independent, and
      living at home than patients managed before the stroke service. After adjustment
      for age and sex these "improvements" were less impressive but still significant.
      After adjustment for many other possible prognostic indicators, however, the
      differences between the two groups for all four outcomes were non-significant,
      suggesting that the "improvements" may have been entirely due to differences in
      case mix between the two cohorts, rather than the new stroke service.
      CONCLUSIONS: Variations in case mix have a crucial influence on the
      interpretation of outcome data, and this is particularly important in non
      randomised comparative studies. Such studies, comparing performance within and
      between different provider units, are likely to become increasingly common in the
      new reformed NHS. To allow meaningful interpretation, these studies must try to
      correct for case mix.

PMID- 8646141
TI  - Psychological complications after stillbirth--influence of memories and immediate
      management: population based study.
AB  - OBJECTIVE: To identify factors that may predict long term psychological
      complications among women who have had a stillborn child. DESIGN: Nationwide
      population based study using epidemiological methods. SUBJECTS: 380 subjects and
      379 controls who had had a stillborn or non-deformed live child in Sweden in
      1991. RESULTS: Information was provided by 636 (84%) women. The ratio (95%
      confidence interval) of proportions of women with symptoms related to anxiety
      above the 90th centile for women who had had a stillborn child compared with
      those who had not was 2.1 (1.2 to 3.9). An interval of 25 hours or more from the
      diagnosis of death in utero to the start of delivery gave a ratio of 4.8 (1.5 to
      15.9). The ratio was 2.3 (1.1 to 5.3) for not seeing the child as long as the
      mother had wished and 3.1 (1.6 to 6.0) for no possession of a token of
      remembrance. CONCLUSION: It is advisable to induce the delivery as soon as
      feasible after the diagnosis of death in utero. A calm environment for the woman
      to spend as much time as she wants with her stillborn child is beneficial, and
      tokens of remembrance should be collected.

PMID- 8646142
TI  - Does suppressing luteinising hormone secretion reduce the miscarriage rate?
      Results of a randomised controlled trial.
AB  - OBJECTIVE: To determine whether prepregnancy pituitary suppression of luteinising
      hormone secretion with a luteinising hormone releasing hormone analogue improves
      the outcome of pregnancy in ovulatory women with a history of recurrent
      miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone.
      DESIGN: Randomised controlled trial. SETTING: Specialist recurrent miscarriage
      clinic. SUBJECTS: 106 women with a history of three or more consecutive first
      trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising
      hormone. INTERVENTIONS: Women were randomised before conception to receive
      pituitary suppression with a luteinising hormone releasing hormone analogue
      followed by low dose ovulation induction and luteal phase progesterone (group 1)
      or were allowed to ovulate spontaneously and then given luteal phase progesterone
      alone or luteal phase placebo alone (group 2). No drugs were prescribed in
      pregnancy. MAIN OUTCOME MEASURES: Conception and live birth rates over six
      cycles. RESULTS: Conception rates in the pituitary suppression and luteal phase
      support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live
      birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal
      phase support group there was no difference in the outcome of pregnancy between
      women given progesterone and those given placebo pessaries. Live birth rates from
      an intention to treat analysis were 52% (26/50 pregnancies) in the group given
      pituitary suppression and 63% (35/56) in the controls (NS). CONCLUSIONS:
      Prepregnancy suppression of high luteinising hormone concentrations in ovulatory
      women with recurrent miscarriage and hypersecretion of luteinising hormone does
      not improve the outcome of pregnancy. The outcome of pregnancy without pituitary
      suppression is excellent.

PMID- 8646144
TI  - Certification of cause of death in patients dying soon after proximal femoral
      fracture.

PMID- 8646143
TI  - Topical treatment of erectile dysfunction: randomised double blind placebo
      controlled trial of cream containing aminophylline, isosorbide dinitrate, and co
      dergocrine mesylate.
AB  - OBJECTIVE: To examine the effectiveness in treating impotence to topically
      applied cream containing three vasodilators--aminophylline, isosorbide dinitrate,
      and co-dergocrine mesylate--which act by different mechanisms. DESIGN: Randomised
      double blinded placebo controlled crossover trial over two weeks. SUBJECTS: 36
      men with erectile dysfunction randomly allocated to two equal groups.
      INTERVENTIONS: Active cream containing aminophylline 3%, isosorbide dinitrate
      0.25%, and co-dergocrine mesylate 0.05% for one week and placebo for another.
      MAIN OUTCOME MEASURES: Patients' reported experience of penile responses and side
      effects of treatment in questionnaires. Penile tumescence and arterial flow in
      the laboratory. RESULTS: 21 patients reported full erection and satisfactory
      intercourse with the active cream. Three men reported full erection and
      satisfactory intercourse with either cream. The active cream was more effective
      in psychogenic than organic impotence (eight out of nine men with psychogenic
      impotence achieved a full erection upsilon four out of eight with neurogenic
      impotence and two out of seven with arterial insufficiency). No major side
      effects were reported. In the laboratory the active cream increased penile
      arterial flow (0.19 (SD 0.08) m/s upsilon 0.02 (0.15) m/s with placebo) and
      induced tumescence in 24 patients. CONCLUSIONS: Topical treatment with a cream
      containing three different vasodilators might be considered before intracavernous
      injection of vasoactive agents, particularly in psychogenic impotence.

PMID- 8646145
TI  - Audit study of next of kin's satisfaction with clinical necropsy service.

PMID- 8646146
TI  - Collecting morbidity data in general practice: the Somerset morbidity project.
AB  - OBJECTIVE: To collect a valid, complete, continuous, and representative database
      of morbidity presenting to primary care and to use the data to help commission
      services on the basis of local need and effectiveness. SETTING: Computerised
      general practices in Somerset. METHODS: Participating general practices were
      selected to be representative of the district health authority population for
      general practice and population characteristics. All conditions presented at face
      to face consultations were assigned a Read code and episode type and the data
      were regularly validated. Data were sent by modem from the practices via a third
      party to the health authority each week. MAIN OUTCOME MEASURES: Proportion of
      consultations coded and accuracy of coding. RESULTS: 11 practices agreed to
      participate. Validations for completeness during April 1994 to March 1995
      revealed that 96.4% of the records were coded; 94% of the 1090 records validated
      had appropriate episode types and 87% appropriate Read codes. The results have
      been used to help formulate the health authority's purchasing plans and have
      enabled a change in the local contracts for surgery for glue ear. CONCLUSIONS:
      The project has shown the feasibility of establishing a network of practices
      recording and reporting the morbidity seen in primary care. Early indications are
      that the data can be useful in evidence based purchasing.

PMID- 8646148
TI  - Lessons from international experience in controlling pharmaceutical expenditure.
      II: Influencing doctors.
AB  - This is the second of three papers that review international policies to control
      spending on drugs and to improve the efficiency of drug use. This paper reviews
      policies influencing doctors' prescribing of drugs--particularly the use of
      budgetary restrictions, information and feedback, and guidelines--and evaluates
      the impact of these policies. Studies evaluating incentive systems are limited,
      but evidence suggests that providing information on its own will not lead to
      substantial changes in practice and that more active strategies should be
      evaluated.

PMID- 8646147
TI  - The pneumococcal problem.

PMID- 8646149
TI  - The Asbury draft policy on ethical use of resources.
AB  - The general practice partners invited two medical ethicists (RC and TH) to meet
      them to develop the document. The partners met RC and TH for one and a half hours
      on eight occasions over one year and met without them on eight further occasions.
      The entire general practice also had an all day session to discuss in detail an
      advanced version of the draft. The developmental process was of great value to
      the partnership and has led to appreciable change in individuals' views. The
      draft policy presented here is intended to start the ball rolling, so that proper
      guidelines will be developed at whatever level in the NHS is most appropriate.
      Comments and feedback are welcomed.

PMID- 8646150
TI  - Secondary prevention of meningococcal disease. Ceftriaxone or ciprofloxacin
      should be considered as first line prophylaxis.

PMID- 8646151
TI  - Secondary prevention of meningococcal disease. Penicillin is not recommended in
      British guidelines.

PMID- 8646152
TI  - Secondary prevention of meningococcal disease. No evidence exists to support use
      of penicillin.

PMID- 8646153
TI  - Secondary prevention of meningococcal disease. British guidelines should have
      been considered.

PMID- 8646154
TI  - Secondary prevention of meningococcal disease. Cases are "unavoidably
      unpredictable".

PMID- 8646155
TI  - Admissions due to overdoses of aromatic analgesics have increased in Scotland.

PMID- 8646156
TI  - Children with an avulsed tooth may need antibiotic prophylaxis against bacterial
      endocarditis.

PMID- 8646157
TI  - GPs often fail to give early parenteral benzylpenicillin in suspected
      meningococcal infection.

PMID- 8646158
TI  - Advance directives are compatible with good medical practice.

PMID- 8646159
TI  - Coffee intake and death from coronary heart disease. Coffee drinking was compared
      with tea drinking in monozygotic twins in 18th century.

PMID- 8646160
TI  - Coffee intake and death from coronary heart disease. Coffee may have both short
      and long term effects.

PMID- 8646161
TI  - Care management. Care programme approach constitutes good management.

PMID- 8646162
TI  - Care management. Administrative demands of care programme approach.

PMID- 8646163
TI  - Care management. Case management confers substantial benefits.

PMID- 8646164
TI  - Continuing transmission of sexually transmitted diseases among patients infected
      with HIV. Qualitative study gave different results.

PMID- 8646165
TI  - Continuing transmission of sexually transmitted diseases among patients infected
      with HIV. HIV infection must be destigmatised.

PMID- 8646166
TI  - Continuing transmission of sexually transmitted diseases among patients infected
      with HIV. Several reasons exist for failure of health education message.

PMID- 8646167
TI  - Continuing transmission of sexually transmitted diseases among patients infected
      with HIV. Sexual behaviour of homosexual men with and without HIV infection
      differs.

PMID- 8646168
TI  - Continuing transmission of sexually transmitted diseases among patients infected
      with HIV. Different diseases indicate different risks of transmission of HIV.

PMID- 8646169
TI  - Junior doctors should get "additional duty miles".

PMID- 8646170
TI  - Managing HIV disease without Delta.

PMID- 8646171
TI  - Non-sexual transmission of human papillomavirus.

PMID- 8646172
TI  - Retinal hemodynamics during increased intraocular pressure.
AB  - The pathogenesis of primary chronic open-angle glaucoma (POAG) remains uncertain.
      It has been proposed that some of these patients may present with a deficiency in
      retinal hemodynamic autoregulation. It is also thought that visual field loss in
      POAG could be related to poor retinal perfusion. The present study was undertaken
      to evaluate the capacity of retinal autoregulation to maintain constant retinal
      circulation despite an acute rise in intraocular pressure (IOP). A total of 22
      healthy subjects were recruited to this study. Retinal hemodynamics were assessed
      by digital video fluorescein angiograms using a scanning laser ophthalmoscope at
      normal (13.8 +/- 1.5 mmHg) and increased IOP (33.8 +/- 3.4 mmHg). Suction cups
      were used for raising the IOPs. The angiograms were performed at baseline and
      after 1 min of increased IOP. To quantify retinal hemodynamics the arm-retina
      time (ART) and arteriovenous passage time (AVP) were evaluated. The ART increased
      significantly from 9.4 +/- 1.8 to 11.8 +/- 2.2 s (P < 0.05) during elevated IOP,
      and the AVP was significantly prolonged from 1.6 +/- 0.4 to 3.0 +/- 0.8 s (P <
      0.01) with IOP elevation as well. The increase in ART and AVP indicates an
      insufficiency of retinal autoregulation after an acute rise in IOP, even in
      healthy subjects. It appears that IOP values of > or = 30 mmHg may be detrimental
      to retinal perfusion in normals as well as in patients with POAG, who may have
      compromised retinal perfusion to begin with.

PMID- 8646173
TI  - Neuroborreliosis with retinal pigment epithelium detachments.
AB  - Borreliosis or Lyme disease, a tick-borne infection with the spirochete Borrelia
      burgdorferi, can cause various ocular and neurological symptoms. A 41-year-old
      man had been repeatedly bitten by ticks in June 1992; 6 months later, the patient
      complained of blurred vision in both eyes of 1-week duration, bifrontal headache
      that was more pronounced on the right side, and neck pain that had appeared
      months earlier and was becoming more severe. On ophthalmoscopy, clover-shaped
      retinal pigment epithelium detachments around the optic disc were observed in
      both eyes. The patient's visual acuity was reduced to 0.5 in his left eye. Liquor
      cells and total protein were significantly increased; however, a hemagglutination
      inhibition test revealed only moderately increased immunoglobulin values. After 2
      weeks of daily application of 4 g ceftriaxone disodium, ophthalmological and
      neurological symptoms disappeared. Even though the immunoglobulin values remained
      unchanged, neuroborreliosis with involvement of the retinal pigment epithelium
      was the most probable diagnosis, considering the history of tick bites and
      headache. The authors assume that the tissue around the optic nerve head, which
      does not have an effective blood-brain barrier, allowed the spirochetes to spread
      from the central nervous system into the subpigment-epithelium space, thus
      causing the observed parapapillary pigment epithelium detachments.

PMID- 8646174
TI  - Pattern, flicker, and flash electroretinography in human immunodeficiency virus
      infection: a longitudinal study.
AB  - To study electroretinographic (ERG) changes in the course of human
      immunodeficiency virus (HIV) disease, 42 eyes without retinitis were examined
      twice or more. During 9.6 months of mean observation time the visual acuity did
      not change. We found progressive functional impairment for the first, second, and
      third neurons of the visual pathway: the pattern-ERG amplitude (retinal ganglion
      cell function) decreased by 11%, the b-wave amplitude (bipolars mediated by
      Muller cells) decreased by 13%, and the a-wave amplitude (dominated by rods)
      diminished by 21%. The flicker amplitude (dominated by cones) decreased by 20%.
      All of the latter four changes were significant (P < 0.02). Damage to the retina
      in HIV infection cannot solely be explained by visible changes in HIV
      retinopathy.

PMID- 8646175
TI  - Falsely nonrecordable flash visual evoked cortical potentials in a diabetic eye
      with severe vitreous hemorrhage.
AB  - The examination of visual evoked cortical potentials (VECPs) prior to vitrectomy
      has been proposed for selection of patients with good chances for a favorable
      outcome following surgery. A missing single flash VECP has been considered a
      contraindication for further surgical treatment. A 64-year-old woman with
      proliferative diabetic retinopathy suffered from an intensive vitreous hemorrhage
      in one eye. Preoperatively, the flash VECP was nonrecordable. Intraoperatively, a
      dense vitreous hemorrhage and retrohyaloidal blood was found. The retina was
      attached. Postoperatively, the flash VECP was similar in both eyes with normal
      latencies. The visual acuity improved from light perception to 0.05. Severe
      vitreous hemorrhage may interfere with preoperative VECP recordings. A
      nonrecordable VECP has to be judged cautiously so as to prevent false-negative
      responses in eyes that could regain vision following vitrectomy and removal of
      the hemorrhage.

PMID- 8646176
TI  - Pattern electroretinogram and computerized optic nerve-head analysis in ocular
      hypertension--interim results after 2.5 years.
AB  - Evidence exists that both the pattern electroretinogram (PERG) as a parameter of
      ganglion-cell function and computerized morphometric disc analysis (ONHA) predict
      subsequent glaucomatous visual field defects in ocular hypertensive eyes. Since
      November 1991 we have conducted a prospective longitudinal study to evaluate the
      suitability of PERG and ONHA for detecting incipient glaucoma damage. Inclusion
      criteria were: an intraocular pressure of > or = 25 mmHG (at least two
      measurements taken on different days) or, in eyes with additional risk factors, >
      or = 23 mmHG; a normal Octopus visual field (mean defect < or = 2 dB, no local
      defect); and no definite glaucomatous disc cupping. After a mean follow-up period
      of 14.6 +/- 8.8 (range 1-33) months and with a mean intraocular pressure of 24.4
      (range 18-42) mmHg, none of the 66 patients (115 eyes) converted to glaucoma.
      Furthermore, PERG and ONHA do not agree in their estimation of the glaucoma risk
      at this stage.

PMID- 8646177
TI  - Keratoplasty in newborns with Peters' anomaly.
AB  - Severe Peters' anomaly with dense corneal opacities leads to blindness of the
      affected eye unless perforating keratoplasty is attempted. The optimal timing of
      this procedure has yet to be established. We performed keratoplasty early after
      birth in an attempt to optimally treat amblyopia. In eight eyes of five newborns
      with severe Peters' anomaly a first keratoplasty was performed at an average age
      of 54 days. A first control was done under general anesthesia 3 weeks thereafter,
      with subsequent controls being carried out according to the clinical course.
      Immunosuppressive therapy mostly consisted of topical steroid eye drops only. In
      two rekeratoplasty cases, systemic cyclosporin A was given in addition. Apart
      from the eight primary keratoplasties, three repeat keratoplasties, two
      lentectomies, and numerous glaucoma operations had to be performed. The average
      follow-up period was 46 months. As compared with the excellent results reported
      for penetrating keratoplasty in adults, the results obtained in this special
      group of newborns remain very poor. The observation of four eyes with a clear or
      partially clear graft and useful ambulatory vision might suggest a success rate
      of 50%. However, especially secondary glaucoma seems to be the limiting
      prognostic factor in the long run. At present, two of the four eyes continue to
      show uncontrolled intraocular pressure despite multiple surgical interventions,
      and their prognosis is poor. The performance of perforating keratoplasty in
      patients with Peters' anomaly early after birth is associated with a multitude of
      problems, especially glaucoma, and currently grafts can rarely be kept clear for
      an extended period. We would therefore conclude that it might be wise to postpone
      surgery until the patient is about 1 year old, in the hope that the overall
      chance for graft survival might be better at that point, even though persistent
      amblyopia might be quite severe and limit the functional success.

PMID- 8646178
TI  - The relative importance of risk factors used to define high-risk keratoplasty.
AB  - The risk factors commonly used to classify high-risk keratoplasty were studied to
      determine their relative importance. Survival analysis of a single-surgeon series
      of 702 grafts was performed using both univariate and multivariate analysis, with
      graft failure from rejection being the end point. The number of previously
      rejected grafts, the number of vascularized recipient corneal quadrants, the
      number of recipient stromal vessels, and the original diagnosis were highly
      significant factors for survival (P = 0.0001). Diseases usually associated with
      avascular corneas, such as keratoconus, fared best, whereas diseases causing
      vascularization had a poor diagnosis. Old interstitial keratitis had a good
      prognosis, indicating that ghost vessels are not a risk factor. Although a
      previously rejected graft was a significant risk factor, this was only true in
      vascularized recipients. There was no significant difference in survival between
      repeat grafts into avascular corneas and first-time grafts into avascular
      corneas, indicating that it is the vascularization associated with rejection that
      confers the increased risk. Multivariate analysis indicated that the number of
      vascularized quadrants (P = < 0.0001), the number of vessels (P = < 0.0001), and
      a previously rejected graft (P = 0.0002) were risk factors for graft survival but
      that patient age was not a significant risk factor (P = 0.9). Three distinct
      survival groupings were evident, namely, avascular corneas, corneas with 1-2
      quadrants or 1-15 vessels, and corneas with 3+ quadrants of vascularization or
      16+ vessels. This would seem a reasonable basis for classifying recipient corneas
      into low-, intermediate- and high-risk cases.

PMID- 8646179
TI  - Objective measurement of contrast sensitivity and visual acuity with the steady
      state visual evoked potential.
AB  - Since the appearance of Campbell and Maffei's and Harter and White's reports it
      has been well established that the visual evoked potential (VEP) can be used to
      predict psychophysical contrast sensitivity and visual acuity and is thus suited
      as an objective technique to assess these fundamental aspects of vision.
      Nevertheless, the technique has not become a standard diagnostic tool, being too
      time-consuming to apply and suffering from variable reliability under
      pathological visual conditions. In addition, there are problems of reliability in
      normal subjects. By using an unconventional stimulus--temporally sinusoidal 16-Hz
      on-off modulation of sinewave gratings--we demonstrated that these problems can
      be alleviated in normal subjects. This stimulus avoids the low signals in the
      visible range that frequently occur with conventional pattern-reversal stimuli,
      it leads to high correspondence between normal observers, and it is much faster
      to apply than are transient VEPs. Initial applications of this stimulus to
      amblyopes yielded promising results. The steady-state VEP could consequently turn
      into a viable diagnostic procedure in disturbances of visual contrast perception.

PMID- 8646180
TI  - Two new stereotests for long distance: examination of stereopsis with regard to
      the permission of driving.
AB  - Two differently constructed stereotests for a distance of 4 m are presented
      (tests A and B), which are based on the three-rod method of Helmholtz. In both
      tests, eight test objects are offered simultaneously, one of them being displaced
      toward the subject to a certain extent (100-10 s of arc). In test A the subject
      sees the eight test objects through eight holes, whereas in test B the test
      objects are seen directly. Each disparity is offered eight times. The threshold
      is defined as five of eight answers being correct. A total of 51 subjects without
      strabismus and with normal stereopsis in conventional tests achieved a mean
      stereo-acuity of 30 s of arc in test A and 10 s of arc in test B. The same
      subjects with one eye occluded and 49 patients with severe binocular defects
      reached chance scores only in test A, whereas in test B the success rate was
      improved slightly by monocular clues (P = 1/5). In examining stereopsis with
      regard to driving licenses, only tests for long distance should be used. Both new
      stereotests differentiate between normal and pathological candidates with high
      specificity and sensitivity.

PMID- 8646181
TI  - Indocyanine green videoangiography of malignant melanomas of the choroid using
      the scanning laser ophthalmoscope.
AB  - The diagnostic value of fluorescein angiography (FA) in the evaluation of small
      suspected choroidal melanomas is limited. Indocyanine green videoangiography
      (ICGV) has overcome some of the problems of FA in the imaging of normal and
      abnormal choroidal vessels. This study was performed to reveal the role of ICGV
      in the detection of the intrinsic tumor vasculature of choroidal malignant
      melanomas. A total of 24 patients with posterior-segment malignant melanoma
      underwent FA and ICGV using the scanning laser ophthalmoscope. All patients were
      grouped into 1 of 2 categories, depending on the tumor elevation: group I 10
      patients with lesions elevated to < 4 mm, and group II 14 patients with lesions
      measuring > 4 and < 8 mm in height. On early frames of the ICGV the borders of
      the tumors were better demarcated from the background and the tumors appeared
      larger in the basal dimension than with FA or clinical examination. ICGV was
      superior to standard FA in imaging intrinsic tumor vasculature. Abnormal
      vasculature features included different caliber size, tortuosities, corkscrew
      loops, irregular ramifications, and irregular staining of the vessel walls. These
      intrinsic tumor vessels were identified in 6 of 10 patients from group I and in
      12 of 14 patients from group II. ICGV appears to add some information in the
      diagnosis and documentation of tumor growth. It may allow detection of pathologic
      tumor vessels that cannot be detected by standard FA. The borders of the tumor
      are better demarcated against the background by ICGV than by FA or clinical
      examination.

PMID- 8646182
TI  - Severe congenital lagophthalmos with tarsal aplasia.
AB  - Congenital elongation of the palpebral fissure associated with large eyelids was
      named euryblepharon after Desmarres in 1854. In some cases the length of the
      lower lid margin exceeded that of the upper lid margin by more than 3 mm. The
      lids are lax and the elongated lid margin of the lower lid is only partially in
      contact with the globe. In marked cases of euryblepharon there may be an
      additional minor vertical shortening of the upper lid. However, the abnormalities
      described by Desmarres did not produce severe kerato-conjunctival xerosis. We
      speculate that euryblepharon as originally described is merely a mild
      manifestation of congenital lagophthalmos. More severe forms show additional
      malformations, leading to pronounced insufficiency of lid closure. We report on
      four patients with severe congenital lagophthalmos. The appearance differs from
      that of euryblepharon by the following details: (a) a symmetrical congenital
      retraction of both the lower and the upper lid margins; (b) a marked vertical
      shortening of the lids (case 1 was referred for bilateral descemetoceles); (c)
      tarsal aplasia; and (d) severe kerato-conjunctival xerosis after insufficient
      surgical treatment, leading to different degrees of disability. The surgical
      approach involved bilateral shortening of the lid margins and free
      transplantation of retroauricular skin. Stabilization of the lax lower lid margin
      was achieved by lyodura strips applied with medium tension and in contact with
      the lid margin. At 5 years after the first operation a petty horizontal
      shortening of the lower lids was necessary because of circumscribed trichiasis.
      The dura strip remained present. The long-term result as evaluated at more than 8
      years following the first operation was very satisfactory.

PMID- 8646183
TI  - [The secondary prevention of coronary disease].

PMID- 8646184
TI  - Hypertrophic cardiomyopathy in old agers. Definitions and general considerations.
AB  - Hypertrophic cardiomyopathy (HCM), a primary heart disease, in most of the cases
      genetically transmitted, characterized by hypertrophy, often asymmetric, of the
      left ventricle (LV), presents certain peculiarities in old agers. The shape of
      the LV in old agers, is characterized by aorto-septal angulation, by the frequent
      presence of a septal bulge and the calcification of the posterior mitral ring
      which contributes to the narrowing of the LV ejection tract by the anterior
      displacement of the mitral valve. Thus, HCM in old agers can also have an
      acquired component associated with the mild changes of aging, which in certain
      conditions can lead to the appearance of some peculiar forms of disease.

PMID- 8646185
TI  - Liposomes: presentation and actual applicative trends in medicine.
AB  - In this paper the main aspects of characterization, handling and applications of
      liposomes are presented. In the last 25 years much attention has been focused to
      liposomal systems for optimization of the drug targeting. Several pathways to
      optimize the drug action of liposomes in various situations as cancer, microbial
      therapy, vaccines, oral therapy and diagnosis were tested. Certain applications
      of liposomes especially those implying the phagocytic cells sustain a real
      interest for industrial applications.

PMID- 8646186
TI  - Duodenal ulcer and infection with Helicobacter pylori.
AB  - The incidence of gastritis with Helicobacter pylori (HP) was studied in 225
      patients with active duodenal ulcer diagnosed endoscopically. The infection was
      diagnosed by the urease test and in some cases by histopathological examination.
      Infection with Helicobacter pylori was detected in 55% of the patients, a
      proportion much smaller than the one generally reported in the literature, a
      rather surprising fact for our sanitary conditions. This might mean that in our
      country unlike the west-European countries other pathogenetic factors could be
      more important than HP.

PMID- 8646187
TI  - The prognostic significance of arterial blood pressure in liver cirrhosis.
AB  - A decrease of the blood pressure (BP) due to the changes in the regulatory
      mechanisms of blood pressures homeostasis is frequently observed in cirrhosis.
      The present work studied the blood pressure profile of the cirrhotic patients and
      estimated the influence it might have on the survival prognosis at one year. A
      lower mean blood pressure: 8.25 +/- 1.5 cm Hg is observed versus a control group:
      9.8 + 2.0 cm Hg (p < 0.001). The decrease is due to the patients with severe
      liver impairment (Child class C). The survival is poor in cirrhosis with
      hypotension (systolic blood pressure < 9 cm Hg): 75 +/- 10%, than in patients
      with systolic blood pressure between 9 and 11 cm Hg (survival rate 91 +/- 6%) and
      patients with systolic blood pressure over 11 cm Hg (survival rate 88 +/- 6%) (p
      < 0.001).

PMID- 8646188
TI  - The effect of slow-release nifedipine on ST-segment depression induced by effort
      test. Correlations with serum levels.
AB  - To study the anti-ischemic effect of slow-release nifedipine ten patients with
      stable angina pectoris and a positive effort test were selected. Nifedipinemia
      was measured by a gas chromatographic method. At the peak level of effort
      intensity slow-release nifedipine significantly decreased the mean ST-segment
      depression (p < 0.05) and the ischemic score (p < 0.01) when compared to the
      control effort test, without decreasing the double product. Nifedipine induced no
      more tachycardia additional to that produced by effort. At the beginning of the
      effort test the level of nifedipine (15.9 +/- 2.51 ng/ml) was superior to the
      value considered as minimal effective and was positively correlated with the
      ischemic score (r = 0.67; p < 0.05). A worsening of ischemia was noted in 2
      patients probably due to a steal phenomenon.

PMID- 8646189
TI  - Transcatheter radiofrequency ablation of atrioventricular by-pass tracts--a
      definitive cure of Wolff-Parkinson White syndrome.
AB  - Patients with an accessory atrioventricular pathway (AAVP) may have to face
      either life-threatening arrhythmias or life-long antiarrhythmic drug treatment
      with the associated expense and morbidity, to which some may be refractory. The
      actual refinement of radiofrequency (RF) ablation technique has dramatically
      changed the management of these patients. The aim of this study is to describe
      the results of transcatheter RF ablation of AAVP in 29 consecutive patients with
      recurrent and/or drug refractory tachyarrhythmias mediated by AAVP. After an
      approximate localization of the AAVP according to Arruda et al. ECG algorithm,
      the precise identification of the site of AAVP was attempted. This was
      accomplished by mapping the mitral and tricuspid annuli. The tricuspid annulus
      was mapped directly using deflectable multielectrode catheters and the mitral
      annulus was mapped by means of a multielectrode catheter inserted in the coronary
      sinus. For finer localization we looked for AAVP activation potentials recorded
      from the ablation catheter. Mapping evaluation was made by means of BARD LAB
      SYSTEM 24 EP laboratory: 14 patients had left free-wall AAVP, 11 patients had
      posteroseptal AAVP and 4-midseptal AAVP. RF energy was delivered (30-40 W for 30
      sec) by an Osypka HAT 200 S generator. The procedure lasted a mean 150 min and
      the maximum number of applications in successful sessions was 9. Twenty patients
      out of 29 (68.97%) were successfully ablated: 10 in the left free-wall group
      (71.43%), 7 in the posteroseptal group (63.64%) and 3 in the mid-septal group
      (75%). These lower figures are explained by the inclusion of the "learning curve"
      patients. For the patients of the last period the success percentage was of 90.
      The single complication was an arterial embolization during an arterial approach
      for ablation. After a mean 206-day follow-up no return of accessory pathway
      conduction was noticed. CONCLUSION: Transcatheter RF ablation of AAVP is a safe
      and effective therapeutic modality in selected patients.

PMID- 8646190
TI  - The correlation between Doppler data and effort capacity in mitral stenosis.
AB  - The data concerning the relation between mitral valve area (MVA), estimated
      invasively or by 2 D-echo and effort capacity in mitral stenosis (MS) are still
      controversial. Consequently we have studied the same relation, using the Doppler
      indices. METHODS: 19 patients with MS were submitted to a Doppler examination-
      MVA, pressure half time (PHT), mean pressure gradient (MPG)--and to a symptoms
      limited exercise testing on cycloergometer--effort intensity (Watts, METs)
      functional aerobic impairment (FAI), myocardial aerobic impairment (MAI). The "r"
      correlation index between these parameters was calculated. The results show no
      significant correlation between Doppler estimated severity of mitral stenosis and
      the effort capacity of the patients, even if a weak negative correlation ("r" = -
      0.32) is noted between effort intensity and MPG and a weak positive correlation
      ("r" = + 0.41) between FAI and PHT. The conclusion is that effort capacity of
      patients with mitral stenosis cannot predict the severity of the disease which is
      to be established through other methods.

PMID- 8646191
TI  - The effect of handgrip upon Doppler data in mitral stenosis.
AB  - The usefulness of physical rehabilitation in patients with valvular heart disease
      is now well established. But, mainly in mitral stenosis, the isometric exercises
      are under question, because of the risk of sudden rise in capillary pulmonary
      pressure. In order to clarify this aspect we have studied the effect of isometric
      exercise upon Doppler data in mitral stenosis. METHODS: in 25 patients with
      mitral stenosis the Doppler indices of severity-mitral valve area (MVA), pressure
      half time (PHT), maximal velocity (MxV), mean pressure gradient (MPG)-were
      determined before and after 3-4 minutes of handgrip performed with a dynamometer
      at 30% of the maximal voluntary contraction (MVC). There are no significant
      differences of Doppler parameters before and during handgrip: MVA (1.56 +/-
      0.30/1.49 +/- 0.53 cm2), PHT (171 +/- 72/150 +/- 58 ms) MPG (7.07 +/- 2.61/7.21
      +/- 1.8 mmHg), MxV (2.186 +/- 0.79/2.276 +/- 0.73 m/s). The results suggest that
      mild isometric exercise does not alter hemodynamic parameters in mitral stenosis.
      Consequently isometric exercise can be included in physical programmes of
      rehabilitation for this category of patients.

PMID- 8646192
TI  - Postextrasystolic changes in ventricular depolarization (electrocardiographic
      observations).
AB  - Postextrasystolic changes in ventricular depolarization were found in patients
      with coronary artery disease in two situations: a) after a compensatory
      postextrasystolic pause and, b) after an interpolated ventricular beat. The
      explanation and the underlying conditions of this phenomenon are discussed. In
      our opinion the postextrasystolic change may be a silent myocardial ischemia.

PMID- 8646194
TI  - High-dose cytotoxic therapy with autologous bone marrow or peripheral blood
      progenitor cell transplantation in malignant lymphomas.
AB  - The present paper is an attempt to assess the efficiency of high-dose cytotoxic
      therapy followed by autologous bone marrow or peripheral progenitor cell rescue
      with hematopoietic growth factor support given in a group of 27 patients (16 men,
      11 women) at the Department of Hematology of the Mont Godinne University Clinics,
      mainly in the same interval 1990-1994. The reasons for introducing such a therapy
      in these patients (6 with Hodgkin's disease, 14 with intermediate or high grade,
      aggressive non Hodgkin lymphomas and 7 with low grade follicular non Hodgkin
      lymphomas) were relapse of disease after conventional therapy (11 cases),
      resistance to initial therapy (5 patients) or because of histologically proven
      transformation to a more aggressive form (one case); in 10 patients with
      extended, poor prognosis forms, the procedure was used as part of the first line
      therapy. The conditioning high dose chemotherapy was given according to various
      regimens, most of them containing Cyclophosphamide, BCNU and Etoposide, with or
      without total body irradiation. In 14 patients, bone marrow (BM) graft was used,
      while peripheral blood progenitor cells (PBPC) were infused in the remaining 13
      patients. The number of infused granulocyte-macrophage colony forming units (CFU
      GM) ranged between 7,650 and 3,900,000/kg, with a mean value of 461,000/kg. The
      median time intervals required to reach an absolute neutrophil count >
      500/microliter, a platelet count > 50,000/microliter and a hematocrit > 30% were
      13 days, 20 days and 23 days respectively. Growth factors (GM-CSF and G-CSF) and
      PBPC use shortened the time for neutrophil recovery as well as neutropenia
      related complications. No procedure-related death was observed and complete
      remission was achieved in 22 cases (81.4%); after a mean follow-up of 32.6
      months, 14 patients (55.5%) are alive and free of disease, while in 7 patients
      (31% of the complete responders) relapse occurred at an average time interval of
      8.2 months since the procedure.

PMID- 8646193
TI  - Augmentation of CD8 and CD4 lymphocytes subsets in AIDS infected children after
      treatment with a non-toxic chelating agents compound--Rodilemid.
AB  - Twelve children were included into the protocol, 5 in March 1989 and 7 in April
      1993. All of them were HIV 1 positive and had diarrhoea, important adenopathy and
      opportunistic infections. Seven out of 12 patients had an immunological
      monitoring. One out of 12 children with B hepatitis died with liver cirrhosis.
      Eleven children had a clear improvement in their clinical course, during the
      treatment. Five out of 7 patients had a significant increase of the CD4
      lymphocytes at 4 and 7 months follow-up. Four patients had an important and
      significant increase of the CD8 count at 4 months and 6 out of 7 patients at 7
      months. Interestingly, in 4 out of 7 patients after 7 months treatment we
      observed higher than normal value of the CD8 count. Variations observed for CD8
      population compared to CD4 were more important.

PMID- 8646195
TI  - Sensitivity to augmentin and cephalosporines of some bacterial strains isolated
      from hospitalized patients.
AB  - The study allowed the determination of the degree of antibacterial efficiency of
      three antimicrobial agents belonging to the betalactamine family namely
      cefuroxime (IInd generation), ceftazidime (IIIrd generation) and augmentin.
      Likewise the relationship bacterial species-antibiotic could be established. It
      was found that the pathogenic staphylococcus strains were very sensitive to
      cefuroxime (92.1%) and equally sensitive to ceftazidime and augmentin (61.0%).
      The enterococci were 100% sensitive to augmentin and 100% resistant to both
      cephalosporines. The enterobacteriaceae presented a higher percentage of
      sensitive strains to cephalosporines than to augmentin 89.6% of the E. coli
      strains were sensitive to ceftazidime, 77.9% to cefuroxime and 27.3% to
      augmentin. Klebsiella was sensitive in 68.2%, 45.14% and 13.6% of the cases to
      ceftazidime, cefuroxime and respectively augmentin. Proteus presented 64.7%
      strains sensitive to ceftazidime, 35.3% sensitive to cefuroxime and 29.3%
      sensitive to augmentin. All the enterobacter strains proved resistant to the
      three antibiotics studied.

PMID- 8646196
TI  - Effect of hemodialysis on lipid peroxidation and antioxidant system in patients
      with chronic renal failure.
AB  - Plasma and blood lipid peroxidation, activity of erythrocyte superoxide dismutase
      (SOD), and serum antioxidant activity (AOA) in uremic patients were examined
      before and 15 and 30 minutes after the start of dialysis. Hemodialysis was found
      to produce increased lipid peroxidation in plasma and blood and a simultaneous
      decrease of SOD activity. The extracellular antioxidant systems were evaluated by
      the assay of ceruloplasmin level, which did not modify significantly during the
      dialysis. Our data indicate that the time since the start of dialysis is an
      important, but not unique factor, influencing possible oxidative damage during
      hemodialysis.

PMID- 8646197
TI  - Study of lung antibodies in patients with silicosis.
AB  - The presence of lung antibodies was determined in a group of 68 patients with
      silicosis in various stages of evolution and in a control group of 35 healthy
      subjects, by the standard indirect immunofluorescent technique with fluorescent
      conjugate anti human gammaglobulin and monospecific fluorescent conjugates anti
      human IgG, IgA and IgM. In the group of patients investigated, lung antibodies
      were detected by means of fluorescent conjugate anti human gammaglobulin, in 47
      cases of the 68 examined. As regards the investigations using monospecific
      fluorescent conjugates it was observed that all the 47 patients presented lung
      antibodies of the IgG class, 32 presented lung antibodies of the IgA class and 15
      presented lung antibodies of the IgM class. The presence of lung antibodies in
      silicotic patients suggests the participation of acquired humoral immunity in the
      pathogeny of disease without, however, being directly responsible for the
      evolution of disease. The association of silicosis with various other autoimmune
      diseases pleads for the existence of an immune component in the evolution of this
      pneumoconiosis.

PMID- 8646198
TI  - Apolipoproteins AI and B and plasma lipid values in well-treated diabetic
      patients from Romania.
AB  - This review is aiming to study the values of apolipoprotein AI and B and plasma
      lipid levels (total cholesterol, HDL cholesterol, LDL cholesterol and
      triglyceride) in well-treated diabetic patients, and their possible relationship
      with hemoglobin A1, body mass index and insulin levels. The study groups were 26
      insulin-dependent diabetic (IDDM) patients, 30 non-insulin-dependent diabetic
      (NIDDM) subjects and 20 non diabetic subjects (controls). Apolipoprotein AI
      concentrations were similar in the three groups, but apolipoprotein B values and
      apo B/apo AI ratio were significantly higher in IDDM as related to NIDDM patients
      (p < 0.001) and to non-diabetic subjects (p < 0.001). We were not able to find
      significant differences concerning plasma lipid values between the three groups.
      We found a weak correlation between apo B and hemoglobin AI in IDDM (r = 0.45;
      0.02 < p < 0.05), but not in NIDDM patients. Body mass index was not related to
      the values of apolipoproteins AI and B. We found a positive but weak correlation
      between insulin levels and triglyceride (r = 0.42), and an inverse one with HDL
      cholesterol (r = 0.57; 0.02 < p < 0.05) in non-diabetic subjects only, while in
      NIDDM patients these associations were even less significant. Plasma insulin
      values strongly correlate to body mass index in both NIDDM (r = 0.64; p < 0.001)
      and in control subjects (r = 0.73; 0.001 < p < 0.001).

PMID- 8646199
TI  - Effect of laser therapy on experimental inflammation in rats.
AB  - A favorable effect of laser therapy in rheumatic diseases was demonstrated in a
      previous paper [9] but it was not possible to estimate whether this benefit was
      due to an antiinflammatory, analgesic or decontracturant effect. In this work the
      effect of laser therapy was tested on an experimental inflammation in rats. Laser
      irradiation reduced the volume of the inflammation during 6 days of treatment
      more than 85% and prevented the appearance of necrosis. In the control group, the
      reduction of inflammation was of only 22.86%, the difference vs. the treated
      group being significant for p = 0.00009, and eight rats of the ten developed
      local necrosis.

PMID- 8646200
TI  - Complications of distal first metatarsal osteotomies.
AB  - Many surgical procedures have been described for the correction of hallux valgus
      and hallux limitus deformities. Distal first metatarsal osteotomies have been
      advocated since the turn of the century, and have been modified and improved
      since that time. Various complications have been associated with distal
      osteotomies, but there is infrequent reference to the normal changes in joint
      function, foot biomechanics, and forefoot pressures after surgery. The following
      literature review addresses the postoperative effects of decreased first
      metatarsophalangeal joint motion, shortening of the first metatarsal, dorsal
      displacement of the capital fragment, and transfer metatarsalgia on foot
      function.

PMID- 8646201
TI  - Schwannoma of the superficial peroneal nerve presenting as web space pain.
AB  - A 55-year-old male presented complaining of pain at his right fourth toe and
      dorsal fourth web space. Physical examination findings pointed to a lesion
      affecting the superficial peroneal nerve. A schwannoma of the superficial
      peroneal nerve was subsequently excised, relieving the patient's symptoms. In the
      differential diagnosis of nontraumatic and/or nonarthritic toe and foot pain,
      benign tumors, including schwannomas of the tibial and peroneal nerves, should be
      considered.

PMID- 8646202
TI  - Resection arthroplasty of the forefoot in rheumatoid arthritis cases.
AB  - Resection arthroplasty of the forefoot was performed in 30 patients (48 feet)
      with rheumatoid arthritis. A Keller/Clayton procedure yielded good results,
      whereas a less radical operation (Hybbinette) created poor results. Reoperation
      following failed Hybbinette operations was possible.

PMID- 8646203
TI  - Retrospective study of the use of a plantar transverse incision versus a dorsal
      incision for excision of neuroma.
AB  - The authors present a retrospective study comparing the results and complications
      of dorsal incision versus plantar transverse incision for excision of neuroma.
      The authors found several advantages using the plantar transverse incision. These
      included improved exposure and access to the neuroma, and no incidence of
      amputation neuromas postoperatively.

PMID- 8646204
TI  - Giant cell tumor of tendon sheath.
AB  - The authors present two case studies of giant cell tumor of tendon sheath. This
      uncommon lesion of the lower extremity is presented in these two cases in
      correlation with clinical, radiographic, and intraoperative findings. After the
      pathologic diagnosis was made, the patient in the first case decided not to have
      the tumor resected. This patient's postoperative course continues uneventfully
      without expansion of the tumor. In the second case, a local recurrence was noted
      13 months after en bloc resection. A review of the literature shows that
      treatment modalities for such lesions range from marginal excision to radiation
      therapy. The authors wish to emphasize the high risk of local recurrence of these
      tumors. Early marginal resection is the treatment of choice.

PMID- 8646206
TI  - Triplane fractures of the distal tibia.
AB  - Triplane fractures of the distal tibia are relatively rare and usually occur
      during adolescence. A classification of the various types of triplane fractures,
      based on a survey of the literature and the material in this study, is presented.
      The authors' treatment principles are discussed and the results of a consecutive
      group of 20 patients, including long-term follow-up (median 6 1/12 years) are
      described.

PMID- 8646205
TI  - Hematogenous osteomyelitis of the calcaneus in children: surgical treatment and
      use of implanted antibiotic beads.
AB  - Hematogenous osteomyelitis is a relatively uncommon disorder that may prove
      elusive to early diagnosis and treatment. Metaphyseal long bones are commonly
      involved and the calcaneus is rarely affected. A high index of suspicion should
      be maintained regarding the pediatric patient with pain out of proportion to a
      minor injury. Delay in the diagnosis of hematogenous osteomyelitis in the
      pediatric patient can result in irreversible growth disturbances and devastating
      sequelae. The authors present a typical case history with an unusual
      postoperative course and a review of the clinical aspects and surgical treatment
      of hematogenous calcaneal osteomyelitis in a child.

PMID- 8646207
TI  - Entrapment neuropathy of the deep peroneal nerve associated with the extensor
      hallucis brevis.
AB  - The authors report a case of entrapment neuropathy of the deep peroneal nerve
      associated with the extensor hallucis brevis. This entrapment neuropathy was
      found distal to the inferior retinaculum that causes the anterior tarsal tunnel
      syndrome. Surgical decompression of the deep peroneal nerve that was entrapped by
      the extensor hallucis brevis relieved the symptoms. This condition, like the
      anterior tarsal tunnel syndrome, deserves attention.

PMID- 8646208
TI  - Methicillin-resistant coagulase-negative staphylococcal osteomyelitis and its
      relationship to broad-spectrum oral antibiosis in a predominantly diabetic
      population.
AB  - Awareness of the virulence of coagulase-negative Staphylococci, previously
      regarded as saprophytes with minimal pathogenicity, has steadily increased.
      Eighty-seven individual patients diagnosed with acute osteomyelitis, as confirmed
      by microbiologic and pathologic analysis, were included in this study. Of these
      patients, 82% (71/87) were known to have diabetes mellitus. The prevalence of
      coagulase negative Staphylococcus was 40% (35/87) in deep bone cultures, 63%
      (22/35) of which were methicillin resistant. When the coagulase negative
      Staphylococcus group was assessed for prior long-term (> 2 week) oral antibiotic
      treatment with ciprofloxacin, it was found that 54% (12/22) of the methicillin
      resistant coagulase-negative Staphylococcal infected patients had received such
      treatment, compared with 15% (2/13) of patients with methicillin-sensitive
      coagulase-negative Staphylococcal osteomyelitis (p < 0.034). When the group was
      analyzed for prior long-term antibiotic treatment with amoxicillin/clavulanate,
      23% (5/22) of the methicillin-resistant patients had received oral
      amoxicillin/clavulanate, compared with 23% (3/13) of patients with methicillin
      sensitive coagulase-negative Staphylococcal osteomyelitis (p > 0.05). Prevalence
      of polymicrobial infections, which constituted 29% (25/87) of all individual
      patients, was also analyzed. Of those patients with coagulase-negative isolates,
      29% (10/35) were polymicrobial (p > 0.05). The results from this study suggest
      that infections of bone caused by coagulase-negative Staphylococci are associated
      with a high prevalence of methicillin resistance. This study also raises the
      question of whether injudicious prolonged use of ciprofloxacin may, in fact,
      promote proliferation of resistant organism strains.

PMID- 8646209
TI  - Buried Kirschner wire fixation in digital fusion.
AB  - There have been many methods utilized to fixate the proximal interphalangeal
      joints of the lesser digits for osseous fusion. The authors present a clinical
      retrospective review of a new alternative of buried Kirschner wire fixation. A
      review of forty-six Kirschner wires (30 cases) is presented.

PMID- 8646210
TI  - The use of a transyndesmotic bolt in the treatment of tibiofibular diastasis: two
      case studies.
AB  - The authors present a brief overview of tibiofibular diastasis and the mechanisms
      of injury associated with it. This type of injury is frequently misdiagnosed or
      improperly treated. Two case studies are presented with specific emphasis placed
      on the use of a transyndesmotic bolt in the reduction of the tibiofibular
      diastasis. The authors have found this to be more beneficial in the treatment of
      this condition, as opposed to the traditional use of a transmalleolar screw.

PMID- 8646211
TI  - Pedal polydactyly: an overview with case report.
AB  - Polydactyly is a fairly common congenital condition of the foot, and is
      characterized by supernumerary digits and/or metatarsals. It may be an isolated
      condition or part of a congenital syndrome. Polydactyly is generally classified
      into three major groups: medial ray (preaxial), central ray, and lateral ray
      (postaxial). A review of polydactyly and an unusual case report of central ray
      involvement and its surgical correction are presented.

PMID- 8646212
TI  - Patterns of muscle atrophy in the lower limbs in patients with Charcot-Marie
      Tooth disease as measured by magnetic resonance imaging.
AB  - Intrinsic atrophy of the calf musculature is a common finding in Charcot-Marie
      Tooth disease. Peroneal nerve atrophy leading to weakness in the anterior and
      lateral compartments is the most common clinical pattern, but considerable
      variability exists in the pattern of atrophy. Magnetic resonance imaging offers a
      valuable method for identifying the distribution and symmetry of muscle
      degeneration. Twenty-three patients with Charcot-Marie-Tooth disease had axial T
      1 magnetic resonance images obtained at proximal, middle and distal calf muscle
      locations. Areas of fatty infiltration and muscle atrophy were measured in the
      four calf muscle compartments. The worst areas of involvement, on a scale of one
      to four, with four being worst, were in the lateral compartment in the mid calf
      (mean, 2.5) and in the anterior, posterior and lateral compartments of the distal
      calf (2.6, 2.8 and 2.5). Comparing right and left legs showed that there was
      visible asymmetry, which was not statistically significant. There was
      considerable variation in the pattern of involvement from patient to patient. The
      fact that all four calf muscle compartments may be involved asymmetrically and in
      varying degrees is important for treatment planning, including surgery. Not all
      patients have the classic symmetrical peroneal pattern of denervation.

PMID- 8646213
TI  - Internal fixation of distal fibula fractures: a case presentation demonstrating a
      unique technique for a severely comminuted fibula.
AB  - The laterally comminuted fracture-dislocation of the ankle can be associated with
      devastating consequences. Previously described surgical as well as nonsurgical
      treatment results have been disappointing. Accurate anatomical reduction and
      rigid fracture stabilization of a comminuted fibula can be extremely difficult.
      This manuscript presents some of the more common methods of comminuted fibular
      fracture fixation described in the literature. A case report demonstrates
      successful anatomical stabilization of a comminuted fibula, utilizing a method
      for internal fibular fixation which has been previously employed, but has not
      been advocated, in the literature. Clinical and radiographic results at 12 and 20
      months post-injury are promising.

PMID- 8646214
TI  - Anatomical variation of the tibial plafond: the anteromedial tibial notch.

PMID- 8646215
TI  - Primary repair of lateral collateral ligaments of the ankle utilizing the Mini
      Statak device.

PMID- 8646216
TI  - Wagdy's technique for treatment of hallux valgus by double-V osteotomy.

PMID- 8646217
TI  - Talar fracture/dislocation in the adolescent patient.

PMID- 8646218
TI  - Lupus and poly (ADP-ribose)

PMID- 8646219
TI  - Occasional series: lupus around the world systemic lupus erythematosus research
      in the Asia-Pacific region: a co-ordinated and co-operative approach.
AB  - Research on SLE in the Asia-Pacific region is presently conducted separately in
      various centres. A co-ordinated and co-operative approach is advocated for a long
      term, prospective study on lupus patients in this region. A pilot study involving
      Beijing, Shanghai and Singapore has been initiated with the intention of
      expanding it to a larger study, involving up to 1000 newly diagnosed lupus
      patients who will be followed up for 10 years. The study design and term
      definitions are patterned after that of the Euro-Lupus project so as to allow for
      meaningful comparisons. The protocol was discussed, pretested and revised before
      arriving at the final version to be used. The principal co-ordinators met and
      discussed with all pioneer participating rheumatologists to ensure common
      understanding of definitions and standardisation of laboratory procedures.
      Preliminary results are expected to be presented in about six months' time
      together with an invitation for more rheumatologists to participate in the
      project.

PMID- 8646220
TI  - Biochemical characterization of ADP-ribose polymer metabolism in SLE.
AB  - The metabolism of poly(ADP-ribose) in peripheral blood mononuclear (PBM) cells
      was studied in 13 patients with systemic lupus erythematosus (SLE) and in 12 age
      and sex matched controls. Poly(ADP-ribose) polymerase activity was measured as
      the net accumulation of ADP-ribose polymers during the conversion of 32P-NAD to
      poly(ADP-ribose) in PBM cells in vitro.  The control population showed a mean
      activity of 418 +/- 91(s.d.)pmol ADP-ribose/10 min/10(6) cells.  The SLE
      population was more heterogeneous and showed a lower mean of 225 +/-
      147(s.d.)pmol ADP-ribose/10 min/10(6) cells.  The mechanism of decreased ADP
      ribose polymer accumulation was investigated. Measurements of turnover of the ADP
      ribose polymers and its substrate, NAD+, showed that diminished ADP-ribose
      polymer accumulation in SLE subjects resulted from decreased poly(ADP-ribose)
      synthesis and not from altered rates of polymer turnover or NAD utilization.
      Western blot analyses of enzyme protein levels, kinetic studies of poly(ADP
      ribose) polymerase activity and analyses of polymer size distribution suggested
      that the mechanisms of poly(ADP-ribose) synthesis in SLE cells is not altered but
      that the number of active poly(ADP-ribose) polymerase molecules is reduced.

PMID- 8646221
TI  - Fluctuations of antibody to ribosomal P proteins correlate with appearance and
      remission of nephritis in SLE.
AB  - Antibodies to ribosomal P proteins are found in widely variable proportions (up
      to 42%) of patients with SLE depending on the ethnic background of the patient
      population. Neuropsychiatric disease was first recognized to have increased
      prevalence with anti-P and more recently liver and renal disease.  We describe
      four patients with SLE and circumscribed episodes of nephritis of relatively
      short duration.  In two patients, antibodies to ribosomal P protein were the only
      specificity detected at the time of appearance of active nephritis; and in the
      other two patients, the appearance and disappearance of anti-ribosomal P was
      simultaneously found with similar fluctuations in anti-dsDNA titers.  Anti
      ribosomal P antibodies were measured by Western blot and a P peptide-specific
      ELISA. These data raise the possibility for a pathogenic role for anti-ribosomal
      P antibodies in lupus nephritis.

PMID- 8646222
TI  - Prolactin levels and antinuclear antibody profiles in women tested for connective
      tissue disease.
AB  - Hyperprolactinemia has been reported in some patients with active systemic lupus
      erythematosus (SLE).  To determine if there was an association between selected
      autoantibodies and hyperprolactinemia, we assayed prolactin concentrations in
      sera from women submitted to a reference antinuclear antibody laboratory. 
      Autoantibody-positive samples were separated into groups that contained
      antibodies to double-stranded DNA (anti-DNA), antibodies to SSA/Ro (anti-SSA/Ro),
      or antibodies to both SSA/Ro and SSB/La (anti-SSA/Ro-SSB/La).  Results were
      compared with autoantibody-negative sera from age-matched women, submitted to the
      same laboratory.  We also compared the study groups with a separate cohort of 84
      healthy women who were not referred for autoantibody testing. Elevated prolactin
      levels were clustered in 20% of sera from anti-DNA-positive women < or = 50 years
      of age.  Twenty-one percent of anti-SSA/Ro-SSB/La-positive women < 50 years of
      age were hyperprolactinemic.  Four of the 15 hyperprolactinemic women identified
      in this survey had no known cause of elevated prolactin.  In the other 11
      individuals secondary causes such as hypothyroidism, pregnancy, chronic renal
      failure, and medications may have accounted for high serum prolactin values.  We
      also examined sera by Western blot, to determine if immunoblot patterns were
      associated with elevated serum prolactin concentrations.  The hyperprolactinemic
      sera yielded novel bands migrating at 70 kd, 32 kd, and 16.5 kd. This study
      confirmed the reported associations of hyperprolactinemia with SLE and Sjogren's
      syndrome.  Multiple factors appeared to contribute to elevated serum prolactin
      levels in women with connective tissue diseases, and the presence of
      hyperprolactinemia was related to unique findings on immunoblot analysis.

PMID- 8646224
TI  - Will some day PAPS fade into SLE?

PMID- 8646223
TI  - Respiratory function in systemic lupus erythematosus: relation with activity and
      severity.
AB  - The objective of this study was to examine the relation between respiratory
      function tests, disease activity and disease severity in ambulatory patients with
      systemic lupus erythematosus (SLE) who did not present with overt respiratory
      problems. Lung volumes, maximal expiratory flows at 50% and 25% of vital capacity
      (MEF50 and MEF25), bronchial threshold to methacholine (PD15FEV1), transfer
      factor CO (KCO) were measured in 24 consecutive SLE outpatients (22 women, age 41
      +/- 14.8 years) and in 24 healthy controls matched for age and sex. In SLE
      patients alveolar-arterial oxygen gradient (AaO2) was also measured. Disease
      activity was assessed by European Consensus Lupus Activity Measurement (ECLAM)
      scoring system and disease severity by Lupus Severity of Disease Index. In
      comparison to controls SLE patients showed a significant decrease of total lung
      capacity (TLC) (91.7 +/- 16.5 vs 102.7 +/- 12.9% predicted, P < 0.01), MEF25
      (58.4 +/- 25.2 vs 73.5 +/- 19.5% predicted, P < 0.005) PD15FEV1 (2164 +/- 1122 vs
      4230 +/- 1014 micrograms methacholine, P < 0.0001) and KCO (77.1 +/- 20.5 vs 96.3
      +/- 12.4% predicted, P < 0.001). AaO2 (mean value 13.2 +/- 8.4) was abnormally
      high (> 20 mmHg) in 12 patients. The ECLAM score of activity was inversely
      related with KCO (r = 0.48, P < 0.02). The severity index was significantly
      related with FEV1/VC ratio (r = 0.43, P < 0.05), MEF50 (r = 0.51, P < 0.01),
      MEF25 (r = 0.40, P < 0.05) and PD15FEV1 (r = 0.51, P < 0.01). In eight patients,
      evaluated also after treatment intensification, there was a significant increase
      in KCO (from 71.8 +/- 24.7 to 84.9 +/- 22.3% predicted, P < 0.01) along with a
      decrease in ECLAM score (from 3.0 +/- 1.34 to 0.69 +/- 0.75, P < 0.01). The
      relation between disease activity and KCO suggests a relation between systemic
      and alveolar inflammation whereas the relation between severity index, airway
      patency and reactivity indices suggests a cumulative damage to the airways in SLE
      patients, even in the absence of overt respiratory manifestations.

PMID- 8646225
TI  - Heart rate variability in patients with systemic lupus erythematosus.
AB  - As patients with systemic lupus erythematosus (SLE) survive their episodes of
      disease activity, increasing morbidity is shown to be related to chronic
      cardiovascular complications. The objective of this study was to assess the
      cardiac parasympathetic autonomic functional status, as reflected by heart rate
      variability, in SLE patients with and without corticosteroid treatment.  A cross
      sectional study of SLE patients attending the Arthritis Clinic was done, using
      age and gender-matched controls.  Thirty-four female patients, age 39 +/- 11,
      were entered, 20 of whom were receiving steroids at the time of study.  Time and
      frequency domain heart rate variability indices were significantly reduced in the
      SLE groups with and without corticosteroid therapy, as compared to controls.  The
      indices were not, however, significantly different in the two SLE groups.

PMID- 8646226
TI  - Heart rate variability and cardiac autonomic function in systemic lupus
      erythematosus.
AB  - The cardiac autonomic function was evaluated in 23 patients with Systemic Lupus
      Erythematosus (SLE) without clinical expression of dysautonomia and in 14 healthy
      volunteer subjects as a control group, by analysis of Heart Rate Variability
      (HRV) from 24h ambulatory electrocardiography. All the patients were taking
      corticosteroids and 10 of them also Ciclosporin A (CsA). The following parameters
      of HRV were performed: Time domain: standard deviation of the RR intervals
      average (SDNN) and percentage of RR adjacent intervals differing from each other
      more than 50 msec (pNN50). Frequency domain: low frequencies (LF) and high
      frequencies (HF). Significant lower values were detected in SLE patients vs
      controls: SDNN = 69.40 vs 127.72; pNN50 = 16.44 vs 25.95; LF = 8.34 vs 34.97; HF
      = 3.21 vs 12.18. The incidence of autonomic dysfunction in our SLE population
      evaluated by considering intervals of normality is approximately 78% for SDNN;
      17% for pNN50; 91% for LF and, finally, 56% for HF. The analysis of HRV may be a
      valuable technique in the study of the incidence of dysautonomia for these
      patients.

PMID- 8646227
TI  - Valvular heart disease in primary antiphospholipid syndrome (PAPS): clinical and
      morphological findings.
AB  - PURPOSE: To describe clinically and pathologically the valvular lesion of the
      primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: We studied six
      patients with PAPS and valvulopathy. Four of them died and had autopsy and two
      had valvular replacement. The study comprised 18 heart valves, 16 from autopsy
      and two, one mitral and one aortic, resected at surgery. RESULTS: Murmurs and
      echocardiographic findings kept correlation with gross pathology. Abnormalities
      were found in one or more valves in all patients including two of five aortic,
      two of five mitral, one of four pulmonary and two of four tricuspid. Co-existence
      of new and old lesions was observed. Pathologic findings included intravalvular
      thrombosis with focal necrosis, and hemorrhage, vascular proliferation, mild
      histiocytic/fibroblastic infiltration, laminated and verrucous fibrin deposits,
      laminated and/or nodular fibrosis, and focal calcification. CONCLUSION: The PAPS
      valvular lesion consists mainly of superficial or intravalvular fibrin deposits
      and its subsequent organization: vascular proliferation, fibroblast influx,
      fibrosis and calcification. This results in valve thickening, fusion and rigidity
      leading to functional abnormalities. Inflammation is not a prominent feature of
      this lesion.

PMID- 8646228
TI  - The antiphospholipid syndrome and SLE: is there a clue in the link between
      complement and coagulation?
AB  - The heterogenous immunoglobulins known as antiphospholipid antibodies (APLA) or
      lupus "anticoagulants" (LA) are prevalent in lupus patients and have been
      implicated in life-threatening thromboembolic events. Unfortunately, observing
      the presence of these antibodies in an individual does not predict the likelihood
      of an event nor does it predict when it may occur. A pathogenic role for these
      antibodies is supported by the observation that high titers and IgG isotype
      confer an increased risk of thromboembolism. Additionally, numerous reports
      indicate that isolated patient antibodies interfere with various elements of the
      coagulation cascade. Nevertheless, attempts to correlate specific antibody
      characteristics with the future likelihood of a hypercoagulable event in an
      individual patient have been unsuccessful to date. Given such uncertainty
      combined with the potential complications of anticoagulant medications, patients
      are generally not treated until significant morbidity has occurred. Finally,
      because of the apparent high rate of reoccurrence most patients must remain on
      anticoagulant therapy indefinitely, regardless of need.

PMID- 8646230
TI  - The significance of anticardiolipin antibodies in patients with lupus nephritis.
AB  - The objective of this study was to determine whether anticardiolipin antibodies
      (ACL) in SLE patients are associated with a specific pattern of lupus nephritis
      and/or with renal microvascular changes. Patients with SLE, followed
      prospectively between June 1991-May 1994 at The Wellesley Hospital Lupus Clinic,
      who underwent a renal biopsy were included. The ACL was measured by the ELISA
      according to international standardized method. Renal biopsy morphology was
      assessed using the WHO criteria for the classification of lupus nephritis. Renal
      vascular changes included glomerular hyaline thrombi, intimal fibrosis and
      intraluminal thrombi of renal arterioles. There were 23 SLE patients. The mean
      age at diagnosis of SLE was 28.2 years and the mean disease duration was 6.3
      years. Of these 10 (43%) had high levels of ACL. No difference in the frequency
      of severe nephritis (Class III and IV) was identified amongst patients with and
      without ACL. Mesangial nephritis was more common in patients with ACL 40% vs 0, p
      = 0.02). Glomerular hyaline thrombi occurred in 3 (13%) patients. None of them
      had positive ACL. Renal vascular lesions included intimal proliferation in 4 (ACL
      + , 1) occluded lumens by thrombi in 2 (ACL + 1). Our data indicate that the
      development of glomerular and/or microvascular changes is not related to the
      presence of ACL.

PMID- 8646229
TI  - Systemic lupus erythematosus after heavy exposure to quartz dust in uranium
      mines: clinical and serological characteristics.
AB  - Epidemiological, clinical and serological data of uranium miners with symptoms of
      connective tissue diseases (CTD) were collected during the control examinations
      for occupational lung diseases since 1975. Twenty eight definite (four or more
      ARA criteria) and 15 probable (2-3 ARA criteria) SLE were diagnosed. The
      estimated prevalence among heavily silica exposed uranium miners was up to 93 in
      100,000. The only significant differences to nonexposed SLE patients were
      decreased frequency of arthritis and photosensitivity and the absence of anti-Sm
      and anti-U1-RNP antibodies. ANA were found in all definite SLE patients examined
      with the following specificities: anti-dsDNA (in 44.4%), & anti-Ro/SSA (in 55.6%,
      four cases together with anti-dsDNA) and anti-La/SSB (in 22.2%). The autoantibody
      profiles of patients with probable SLE were similar, but with a lower frequency
      of ANA, anti-dsDNA and anti-Ro/SSA. Middle to high-titred autoantibodies to
      dsDNA, Ro/SSA and La/SSB were detected in 3.2% uranium miners with no (N = 1229)
      and in 20.6% with some symptoms (one ARA criterion and/or two or more of other
      CTD typical symptoms, N = 68) of CTD development. We conclude, that the strong
      exposure to dust with a high content of silica may predispose to or initiate the
      development of SLE. The detection of SLE-typical antibodies in quartz dust
      exposed miners may indicate a higher risk for the development of systemic
      autoimmune disease.

PMID- 8646231
TI  - Mononeuritis multiplex in systemic lupus erythematosus: response to pulse
      intravenous cyclophosphamide.
AB  - Severe mononeuritis multiplex in systemic lupus erythematosus (SLE) is quite rare
      and almost always accompanied by evidence of active disease in other organs,
      although occasionally it may be the presenting feature of the disease. We
      describe here two patients with SLE who presented a severe mononeuritis multiplex
      secondary to a necrotizing vasculitis which respond successfully to therapy with
      intravenous cyclophosphamide, and review the literature of similar cases.

PMID- 8646232
TI  - Primary antiphospholipid syndrome evolving into systemic lupus erythematosus.
AB  - A young woman had a history of spontaneous venous thromboembolic disease which
      recurred on several occasions after cessation of treatment with oral
      anticoagulants. The presence of antiphospholipid antibodies (lupus anticoagulant
      and a high titre of lgG class anticardiolipin antibodies) in the absence of other
      clinical and serological features of systemic lupus erythematosus (SLE) confirmed
      a diagnosis of primary antiphospholipid syndrome (PAPS). Antinuclear antibodies
      (ANA) were positive (1:1280; speckled pattern). Twelve years after the first
      thrombotic episode she fulfilled criteria for the classification of SLE
      (antinuclear antibodies, platelet count < 100 x 10(9)/l, anti-dsDNA antibodies,
      Coombs' positive haemolytic anaemia). She suffered a myocardial infarction while
      adequately anticoagulated and developed polyarthritis and immune complex-mediated
      nephritis over the next 3 years. This case history supports suggestions made by
      others that a strongly positive ANA test in a patient diagnosed with PAPS may be
      a harbinger for the development of SLE. Such evolution can take place over more
      than 10 years.

PMID- 8646233
TI  - Correction of severe thrombocytopenia with chloroquine in the primary
      antiphospholipid syndrome.
AB  - We describe a patient with Primary Antiphospholipid Syndrome (PAPS) and severe
      thrombocytopenia with bleeding, in whom treatment with high dose steroids failed
      to maintain a sustained level of platelets following an initial short lived
      response.  After several unsuccessful attempts with Danazol and aspirin combined
      with low dose steroids, the platelets count rose following the administration of
      chloroquine and low dose steroids and remained in the normal range even when
      steroids were tapered.

PMID- 8646234
TI  - Use of hyperbaric oxygen in rheumatic diseases.

PMID- 8646236
TI  - The ileal neobladder--updated experience with 306 patients.
AB  - From April 1986 through May 1995, 306 men with primary urothelial carcinoma
      underwent radical cystoprostatectomy and orthotopic bladder substitution via the
      ileal neobladder. Altogether, 7.5% of the patients suffered general early
      complications, including thrombosis, embolism, wound infection, and pneumonia.
      Specific early complications directly related to formation of the neobladder and
      requiring surgery included ileus (4%), abscess drainage (2%), and leakage of the
      ileal anastomosis (0.5%). The early reoperation rate was 6.5%. Early
      complications that required temporary percutaneous drainage were lymphocele
      formation (3%) or ureteral obstruction (6%). In all, 9% of our patients required
      prolonged catheter drainage for leakage of the ileouretheral anastomosis. Late
      complications requiring reoperation were ileus (2%), abscess drainage (1%),
      neobladder fistula to the colon (1.5%), ureteral reimplantation because of
      obstruction (3.6%), and nephrectomy for hydronephrosis (1%). A transurethral
      incision of the ileouretheral anastomosis was necessary in 7% of cases.
      Continence was separately addressed by sending each patient and his home
      physician a detailed questionnaire: Using our criteria (no diapers, no
      awakenings) the night and day continence rate increased from 67% at 6 months, to
      72% at 1 year to 85% at 2 years, finally reacting 90% after 4 years. In part II
      of this presentation we address the question as to whether the option of
      orthotopic bladder replacement has any impact on the patient's and physician's
      decision toward earlier cystectomy. We compared our ileal neobladder cohort with
      a group of 137 patients that had been operated on during the same time span by
      the same group of surgeons. There was no negative selection with regard of the
      tumor stage of our patients. However, as compared with the conduit group, the
      neobladder cohort had a significantly improved survival rate. This phenomenon is
      explainable by the significantly lower number of previous transurethral
      resections of the bladder (TUR-Bs) performed in the neobladder group. The time
      span between primary diagnosis and cystectomy was 10 months in the neobladder
      group as compared with 18 months in the conduit patients. These data reinforce
      our belief that orthotopic bladder replacement using the ileal neobladder yields
      an extraordinary functional result that can be accomplished with a high degree of
      patient satisfaction and minimal complication. The availability of orthotopic
      bladder replacement does indeed stimulate the physicians and patients decision
      toward earlier cystectomy.

PMID- 8646237
TI  - Update on the Camey II procedure.
AB  - Between January 1987 and January 1991, 110 detubularized U-shaped
      ileocystoplasties (Camey II) following radical cystectomy were carried out in our
      Department of Urology (CMC Foch Suresnes, France). Our first evaluation of this
      procedure was carried out in 1989 and reviewed initial 57 patients operated on.
      These data were compared with those of the Camey I operation. The improvement in
      neobladder capacity as well as nighttime urinary control achieved by the
      detubularization required in the Camey II operation was obvious. In this article
      we review the first 110 patients treated by Camey II bladder replacement
      following cystectomy.

PMID- 8646235
TI  - The use of neobladders in women undergoing cystectomy for transitional-cell
      cancer.
AB  - Recent studies have provided us with new insights into the natural history of
      female bladder cancer as well as the behavior of the isolated urethra after
      cystectomy. Based on more than 16 years of experience with orthotopic lower
      urinary tract reconstruction to the urethra in men, a similar approach was
      attempted in women with transitional-cell cancer of the bladder. Refinements in
      the technique of cystectomy and subsequent intestinourethral anastomosis based on
      anatomical, histological, and clinical studies are described that should improve
      postoperative results in women undergoing anterior exenteration and creation of
      an orthotopic neobladder to the urethra. Our findings in a series of 11 patients
      are presented and compared with data from other institutions. Improved
      postoperative continence and micturition without compromise of the oncological
      outcome may be a result of preservation of the entire lateral vaginal walls,
      nerve-sparing dissection of the bladder neck and proximal urethra, removal of 1
      cm of proximal urethra en bloc with the cystectomy specimen, and a J-omentum flap
      or an additional attachment of the anastomosed intestinal pouch to surrounding
      pelvic structures. Taken together, our average of 90% daytime and 73% nighttime
      continence, 90% spontaneous residual-free micturition, and 100% patient
      satisfaction without compromise of the surgical oncological outcome seems to
      justify the creation of an orthotopic neobladder in selected women with bladder
      cancer.

PMID- 8646238
TI  - Summary of 10 years' experience with an ileal low-pressure bladder substitute
      combined with an afferent tubular isoperistaltic segment.
AB  - We report on 10 years of experience with an ileal low-pressure bladder substitute
      combined with an afferent tubular segment following cystectomy in 100 consecutive
      men. The median follow-up period was 30 months (range 3-108 months), with a 2.5
      year minimum in survivors. A total of 42 patients died, 33 of these dying of
      bladder cancer. The early complication rate was 11%, including 2 deaths due to
      postoperative sepsis. In all, 14 patients required reoperation for late
      complications. The reservoir's median functional capacity increased to 500 ml at
      12 months and was paralleled by improving continence: 92% by day (after 1 year)
      and 80% by night (after 2 years). Four ureteric strictures occurred. No
      coordinated, isolated pressure rise developed in the reservoir during voiding,
      which was accomplished by pelvic floor relaxation with abdominal straining, if
      necessary. Raised intraabdominal pressure acted equally on the reservoir and
      ureters, preventing reflux during voiding. This technique is straightforward,
      allows radical cancer surgery, and protects the upper tract. The favorable
      functional results are comparable with those achieved by similar techniques, but
      meticulous follow-up is essential.

PMID- 8646239
TI  - Incidence of urethral tumor involvement in 910 men with bladder cancer.
AB  - Urethral tumor involvement was examined in 910 patients treated for bladder
      cancer at a single institution over a period of 25 years. The overall incidence
      in 2,052 primary and recurrent bladder-tumor events was 6.1%. Risk factors for
      urethral tumor occurrence are tumors at the bladder neck and recurrent multifocal
      tumors. Carcinoma in situ (CIS) of the bladder not involving the bladder neck and
      muscle-invasive tumors with or without lymph-node involvement are not
      significantly correlated with urethral cancer. Patients at risk for urethral
      tumors as outlined should be worked up very carefully (multiple urethral biopsies
      and/or urethral brushings, frozen section of the membranous urethra) before they
      are considered for an orthotopic neobladder. Altogether, 17 of 89 patients had 1
      6 urethral tumor recurrences. The majority of urethral tumors were treated with a
      single conservative treatment session and did not recur thereafter. A
      conservative approach toward superficial urethral tumor recurrences in patients
      with an orthotopic neobladder to the urethra may therefore be feasible.

PMID- 8646241
TI  - The prosthetic bladder.
AB  - Bladder reconstruction may be required in a variety of pathological conditions,
      including bladder cancer, irradiation cystitis, interstitial cystitis,
      tuberculosis, and various congenital anomalies. Currently, bladder reconstruction
      is done with an autogenous bowel segment. Use of a total prosthetic bladder as an
      intracorporeal urinary reservoir has been an elusive goal for many decades. Many
      investigational and a few clinical trials have been performed in an attempt to
      develop a near-normal bladder prosthesis utilizing alloplastic materials. To date
      the ideal prosthetic bladder has not been developed. However, cumulative
      experimental studies suggest that many, perhaps all, of the ideal functional
      characteristics of a total prosthetic bladder are possible. Basically, two
      different alloplastic models have been investigated.

PMID- 8646240
TI  - Orthotopic urinary diversion: the Kock ileal neobladder.
AB  - Orthotopic urinary diversion via the Kock ileal neobladder is the preferred form
      of bladder reconstruction in men and, now, in women undergoing cystectomy at the
      University of Southern California. Through June of 1993, 266 men were diverted in
      this fashion. There were 3 perioperative mortalities (1.1%); early complications
      occurred in 47 men (17.7%), whereas 35 (15.0%) experienced late complications.
      Approximately 85% of the men enjoy good or satisfactory continence day and night,
      with a large majority having a normal voiding pattern. Through May of 1993, 14
      women were similarly diverted; 2 patients (14.2%) experienced early
      complications, whereas 1 patient (7.1%) had a late complication. The continence
      and voiding pattern appear to be even better in this small group of women as
      compared with the men. Orthotopic Kock continent urinary diversion yields an
      extraordinary functional result that can be accomplished with minimal
      complication and high patient satisfaction.

PMID- 8646243
TI  - Leiomyosarcoma of the spermatic cord: report of two cases and review of the
      literature.
AB  - Two cases of spermatic cord leiomyosarcoma are described. Preoperative ultrasound
      disclosed a paratesticular tumor. Inguinal orchiectomy was performed; there was
      no adjuvant treatment. Currently there is no evidence of disease after 12 and 24
      months of follow-up. The literature on this rare condition is reviewed.

PMID- 8646244
TI  - Low-molecular-weight inhibitor of in vitro fibroblast colony formation from human
      urine.
AB  - The role of urinary toxins in interstitial cystitis (IC) has been suggested. This
      report describes the partial purification of a substance from human urine that
      inhibited in vitro colony formation by mouse fibroblasts. Urine samples from 15
      women with IC and 17 healthy women serving as volunteers were fractioned by
      ultrafiltration and chromatography methods and tested by the inhibition of Swiss
      3T3 fibroblast colony formation. The fibroblasts were cultured at low density
      with varying concentrations of whole or fractioned urine. Colonies were counted
      at 10 days. Colony formation was reduced by incubation with whole urine,
      ultrafiltrate, and nonadsorbed C18 fractions. Inhibition of colony formation by
      urine from healthy volunteers or women with IC was not significantly different.
      In vitro colony formation by Swiss 3T3 cells was inhibited by a component of
      human urine. The toxicity of urine from IC patients was not different from that
      of urine from healthy controls.

PMID- 8646245
TI  - The use of orthotopic neobladders in women undergoing cystectomy for pelvic
      malignancy.
AB  - Since June 1990, 21 women aged from 31 to 78 years (mean, 62 years) have
      undergone lower urinary tract reconstruction by means of an orthotopic Kock ileal
      reservoir following cystectomy. The indication for cystectomy included 15
      patients with transitional-cell carcinoma of the bladder, 2 patients with urachal
      adenocarcinoma, 1 patient with cervical carcinoma, 1 patient with a mesenchymal
      tumor of endometrial origin, 1 patient with interstitial cystitis, and 1 patient
      with a fibrotic irradiated bladder. A total of four complications (two early and
      two late) have occurred in this group of patients. Excellent continence has been
      achieved during the day and night in 95% and 89% of the patients, respectively.
      In all, 16 of 20 patients void volitionally per urethra without a residual urine
      volume, whereas 4 patients require intermittent catheterization to empty the
      neobladder. All patients are completely satisfied. One patient died of metastatic
      transitional-cell carcinoma without a pelvic recurrence. Of the remaining 20
      patients, 18 are currently alive without evidence of recurrent disease. Tumor
      recurrence has occurred in two patients: one patient with an extensive
      mesenchymal tumor developed a sigmoid recurrence necessitating conversion to a
      continent cutaneous diversion, and one patient developed a right iliac
      recurrence. This initial experience with lower urinary tract reconstruction in
      women has yielded extraordinary results, and we feel that the option of
      orthotopic reconstruction following cystectomy can safely be offered to selected
      female patients.

PMID- 8646242
TI  - Prostate-specific antigen density--a reliable parameter for the detection of
      prostate cancer?
AB  - We compared the prostate-specific antigen density (PSAD) in clinically and
      surgically staged patients with specimen-confined prostate cancer (n = 57) and in
      patients with benign hyperplasia (n = 69), who underwent transvesical
      adenomectomy. The PSAD was calculated from the preoperative PSA level and the
      specimen volume. The prostate volume was determined by dividing the prostate
      weight by the specific gravity of the tissue. The mean tissue values used for
      PSAD calculation were 51.9 g in men with prostate cancer (PCA) and 62.9 g in men
      with benign prostatic hyperplasia (BPH). The PSAD values showed significant
      differences (BPH 0.19 versus PCA 0.37, P = 0.029). Receiver operator
      characteristic (ROC) curves demonstrated the best cutoff value to be 0.15, with
      the sensitivity being 58%; the specificity, 51% and the positive predictive value
      of PCA, 49%. At a serum PSA level below 10ng/ml, the best cutoff value was 0.1
      and the positive predictive value was 51%. The PSAD results we calculated from an
      accurate prostate volume (surgical estimate) show that PSAD is not a significant
      predictor of prostate cancer.

PMID- 8646246
TI  - Sex and age specific assessment of genetic and environmental influences on body
      mass index in twins.
AB  - OBJECTIVE: To assess, by use of a population based twin register, if there are
      sex and age differences in genetic and environmental influences on inter
      individual variation in BMI among middle-aged and elderly subjects. DESIGN: Twin
      study. SUBJECTS: 1233 like-sex Danish twin pairs (213 MZ male, 322 DZ male, 280
      MZ female, 418 DZ female pairs, age: 46-76 years, BMI: 15-45 kg/m2).
      MEASUREMENTS: Self-reported height and weight. METHODS: Proportions of variance
      due to genetic and environmental factors were estimated from variance-covariance
      matrices using the structural equation model approach. RESULTS: The most
      parsimonious explanation of the data was provided by a model that included
      additive genetic and non-shared environmental factors with the latter fixed to be
      equal across sex and age. The heritability of BMI was estimated to be 0.46 for
      males aged 46-59 years, 0.61 for males aged 60-76 years, 0.77 for females aged 46
      59 years and 0.75 for females aged 60-76 years. CONCLUSION: As in earlier
      studies, the present one showed a high heritability of BMI throughout adult life,
      with genetic influences being mainly additive and environmental influences being
      non-shared, without evidence for major impact of genetic dominance or shared
      environment. Most twin, family and adoption studies do not suggest important sex
      or age differences in magnitude of genetic effects, but we found that females had
      greater heritability than males, and that heritability in males increased by age.

PMID- 8646247
TI  - Trends in body mass index and obesity among adults in Finland from 1972 to 1992.
AB  - OBJECTIVE: To investigate trends in body mass index (BMI) and prevalence of
      obesity in different areas and educational groups in Finland. DESIGN:
      Cardiovascular risk factor surveys carried out at five-year intervals among men
      and women aged 30 to 59 years from 1972 to 1992. MEASUREMENTS: Body mass index
      and educational level have been measured in each survey. RESULTS: BMI increased
      in men over 40 years of age until 1987 and then levelled off. BMI decreased in
      women in all age groups until 1982 and then levelled off. Even though all men
      have become heavier, the change has been smallest in the highest educated group.
      This difference is even more pronounced in women. The prevalence of obesity (BMI
      over 30 kg2) was 19% in men and 18% in women in 1992. The prevalence of
      overweight (BMI over 25 kg/m2) was 63% in men and 49% in women. The prevalence of
      obesity among men with the lowest educational level was 27% and in women 26%.
      CONCLUSION: The differences in BMI between educational groups have become wider
      in both genders during 1972-1992.

PMID- 8646248
TI  - Biological maturation and the distribution of subcutaneous fat from adolescence
      into adulthood: the Amsterdam Growth and Health Study.
AB  - OBJECTIVE: To analyze differences in the development of a trunk-oriented fat
      distribution pattern between 13 and 27 years of age in individuals who either
      matured rapidly or slowly in adolescence. DESIGN: Longitudinal, observational,
      four annual measurements between 1977 and 1980 and additional measurements in
      1985 and 1991. SUBJECTS: 79 boys, 98 girls, health Caucasian schoolchildren,
      classified as rapidly, normally or slowly maturing. MEASUREMENTS: biceps,
      triceps, subscapular, suprailiac skinfolds resulting in two skinfold ratios, body
      mass index, skeletal age, peak height velocity (for boys only), age at menarche.
      RESULTS: No statistically significant differences were found between rapidly and
      slowly maturing boys and girls, based on the skeletal age or the peak height
      velocity. Girls with a relatively early menarche showed significant higher mean
      skinfold ratios between 13 and 27 years of age than girls with a relatively late
      menarche. CONCLUSION: Skeletal maturation of boys and girls and peak height
      velocity (only measured in boys) are not associated with a trunk-oriented fat
      distribution pattern between 13 and 27 years of age. Only a relatively early
      menarche in girls seems to be associated with a trunk-oriented fat distribution
      pattern from adolescence into adulthood.

PMID- 8646249
TI  - Effects of free fatty acids on the metabolic response to oral fructose in lean
      healthy humans.
AB  - OBJECTIVE: To study the effects of an experimental increase in plasma FFA
      concentration on fructose to glucose conversion, total hepatic glucose output and
      glycaemic response to oral fructose. SUBJECTS: Six healthy subjects (three men,
      three women; age: 24.3 +/- 2.3 years; BMI: 21.6 +/- 0.8 kg/m2). DESIGN: Each
      subject absorbed 0.5 g/kg of 13C-enriched fructose and randomly received either a
      triglyceride-heparin infusion or saline. MEASUREMENTS: Total hepatic glucose
      output was traced with 6,6-2H2-glucose. Appearance in plasma of glucose
      synthesized from fructose was calculated from the isotopic enrichment in 13C of
      plasma glucose. Substrates oxidation was assessed with indirect calorimetry.
      RESULTS: The triglycerides-heparin infusion increased FFA concentration before
      fructose as compared to saline (1086 +/- 40 vs 451 +/- 67 microM; p < 0.001) and
      lipid oxidation was 15% and 70% increased before and during fructose,
      respectively as compared to saline. Total hepatic glucose output, plasma
      appearance of glucose synthesized from fructose and glycaemic response were not
      affected. Glycogen storage over the first 3 h following fructose was increased
      (6.2 +/- 2.1 g vs 0.3 +/- 2.1 g; p < 0.01). CONCLUSION: Triglycerides-heparin
      infusion did not stimulate plasma glucose appearance from fructose. Liver glucose
      6-phosphate could have been produced in excess and diverted towards glycogen
      synthesis.

PMID- 8646250
TI  - Incidence, increasing prevalence, and predictors of change in obesity and fat
      distribution over 5 years in the rapidly developing population of Mauritius.
AB  - OBJECTIVE: To investigate the incidence and trends in prevalence of obesity and
      adverse fat distribution in Mauritius over 5 years. DESIGN: Prevalence studies
      were conducted in 1987 and 1992, incidence was estimated in a sub-sample of
      subjects attending on both occasions. SUBJECTS: 5021 Indian, Creole and Chinese
      Mauritian adults aged 25-74 were examined in 1987, in 1992 5111 subjects were
      examined, of whom 3667 had data from 1987. MEASUREMENTS: Body mass index (BMI),
      waist-hip ratio (WHR) and 75g oral glucose tolerance test. Questionnaire data
      were collected on parity, physical activity, smoking, education and income.
      RESULTS: The prevalence of 'overweight or obesity' (BMI > 25 kg/m2) increased
      from 26.1% to 35.7% in men and from 37.9% to 47.7% in women. The prevalence of
      abdominal obesity (WHR > 85 percentile in 1987 for each sex) also increased. The
      cumulative incidence of overweight or obesity in men ranged from 10.8% in Chinese
      to 18.2% in Creoles, and in women from 16.1% to 27.5% in Chinese and Creoles,
      respectively. The incidence of abdominal obesity exceeded 20% in Indian men and
      Indian and Creole women. Increases in BMI were predicted by younger age,
      leanness, non-diabetic glucose tolerance, smoking cessation (men) and multiparity
      and lower baseline income (women). Increases in WHR were predicted by ethnicity
      and BMI in men, and by glucose tolerance and BMI in women. CONCLUSION: The
      increases in obesity observed in this study occurred despite concurrent national
      programs promoting a healthy diet and increased physical activity. This
      highlights the difficulty of reversing the adverse effects of lifestyle change in
      rapidly modernising populations.

PMID- 8646251
TI  - Long-term effect of dexfenfluramine on amino acid profiles and food selection in
      obese patients during weight loss.
AB  - In depressive disorders an association between basal pre-treatment plasma ratios
      of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids (LNAA)
      and the clinical efficacy of serotonergic acting drugs have been established. In
      order to clarify whether a similar relation exists in obesity and to elucidate
      the long-term effect of dexfenfluramine (dF) on plasma amino acid profiles and
      macronutrient selection, we examined 29 obese patients participating in a 12
      months double-blind weight loss trial with either dexfenfluramine (dF) (30
      mg/day) or placebo (PL) in conjunction with 4.2-5.0 MJ/d diet. Maximum weight
      loss was obtained after 6 months (dF 12.8 +/- 5.4 kg; PL 13.8 +/- 9.2 kg, x +/-
      s.d., ns). Plasma Trp/LNAA and Tyr/LNAA were found to be lower than in normal
      weight controls and were further reduced during treatment (p < 0.05), but without
      differences between dF and PL groups. Macronutrient selection was not affected by
      the dF treatment. In the placebo group weight loss was associated with a high pre
      treatment energy intake and a high carbohydrate-protein ratio (p < 0.05). A
      decrease in dietary fat and increase in protein intake (%) and age was found to
      explain 82% of the variation in weight loss (p < 0.0005), whereas no correlation
      could be shown in the dF group. Pre-treatment plasma Trp/LNAA or Tyr/LNAA and
      weight loss were not correlated. In conclusion, neither food selection nor basal
      plasma amino acid profiles were predictors of weight loss during long-term
      treatment with dF as an adjuvant to energy restriction, and they were not
      affected by the drug treatment.

PMID- 8646252
TI  - The effects of weight loss on insulin sensitivity, skeletal muscle composition
      and capillary density in obese non-diabetic subjects.
AB  - OBJECTIVE: To investigate whether the improvement in insulin resistance by weight
      loss is associated with changes in skeletal muscle fiber composition or capillary
      density. DESIGN: Longitudinal, clinical intervention study of a 2.1 MJ diet daily
      for 3 weeks and 3.4 MJ diet daily for 9 weeks. SUBJECTS: Seven obese (age: 41-59
      y, five men, BMI > 34 kg/m2) non-diabetic subjects. MEASUREMENTS: Insulin action
      was measured by the euglycaemic hyperinsulinaemic clamp before and after 3 and 12
      weeks of the very low calorie diet. In addition, the skeletal muscle biopsies
      were taken before and after the 12 weeks. RESULTS: During the 12 weeks, the
      subjects lost about 16% of body weight. The weight loss was accompanied by a
      nearly two-fold increase in total body glucose disposal rate (GDR; baseline vs 12
      weeks: 842 +/- 91 vs 1505 +/- 242 mu mol/m2/min; p < 0.05). Most marked
      improvement was observed in non-oxidative component of GDR, which increased 2.7
      fold as compared to baseline (292 +/- 113 vs 788 +/- 231 mu mol/m2/min; p <
      0.05). However, no significant change in proportion of type II fibers as well as
      in skeletal muscle capillary density occurred during the study. CONCLUSION: In
      obese non-diabetic subjects the improvement in insulin sensitivity induced by
      weight loss was not accompanied by marked changes in skeletal muscle fiber
      composition or capillary density. However, due to small number of subjects
      studied, the role of structural changes in the muscle fiber composition cannot be
      entirely ruled out.

PMID- 8646254
TI  - Fat intake and adiposity in 8 to 11-year-old obese children.
AB  - OBJECTIVE: To investigate the relationships between diet composition, body
      composition, and macronutrient oxidation at rest in obese and non-obese children.
      DESIGN: Cross-sectional study on fat intake, adiposity and postabsorptive
      macronutrients oxidation rates. SUBJECTS: 82 prepubertal (age: 9.1 +/- 1.1 y)
      children, 30 obese (FM = 32.6 +/- 6.1%) and 52 non-obese (FM = 15.6 +/- 5.1%).
      MEASUREMENTS: Subcutaneous skinfold thickness for body composition, diet history
      for energy and nutrient intake, indirect calorimetry for resting metabolic rate
      (RMR) and RQ measurement. RESULTS: Energy intake (EI) was comparable in obese and
      non-obese children. Adjusted for RMR by ANCOVA, using RMR as the covariate, EI
      was significantly lower in obese than in non-obese children indicating either a
      blunted physical activity or a systematic underestimation of EI. Protein and
      carbohydrate intakes expressed as a percentage of total energy intake (%EI) were
      not significantly different in the two groups. Lipid intake (%EI) was slightly
      but significantly higher in the obese than in the non-obese group either
      unadjusted or adjusted for RMR by ANCOVA. The postabsorptive RQ was significantly
      lower in obese than in non-obese children. In the total group, %FM was weakly but
      significantly correlated to lipid intake (%EI). CONCLUSION: Obese prepubertal
      children have a higher relative fat intake than non-obese children and their FM
      is associated with this factor. The lower postabsorptive RQ of obese children may
      indicate a compensatory mechanism to achieve fat equilibrium by enhanced fat
      oxidation.

PMID- 8646253
TI  - Determinants of postprandial appetite sensations: macronutrient intake and
      glucose metabolism.
AB  - BACKGROUND: According to the glucostatic theory and the macronutrient balance
      concept, blood glucose and liver glycogen concentrations are important mediators
      of hunger and satiety. Results from acute postprandial studies are, however,
      still conflicting. OBJECTIVE: To investigate the associations between appetite
      sensations on the one hand and macronutrient intake and measures of glucose
      metabolism on the other hand. METHODS: Six group-means from three different
      studies (a total of 64 test meals) were tested in linear regression analyses.
      RESULTS: Positive correlations were found between delta-mean postprandial satiety
      and serving weight (r = 0.84, p < 0.05), and carbohydrate content (g) (r = 0.86,
      p < 0.05) of the meals. Furthermore, delta-mean satiety correlated to delta-AUC
      for plasma glucose (r = 0.92, p < 0.01), lactate (r = 0.98, p < 0.001), insulin
      (r = 0.95, p< 0.01), noradrenaline (r = 0.97, p < 0.01), gastric inhibitory
      polypeptide (r = 0.93), p < 0.01) and net carbohydrate oxidation (r = 0.86, p <
      0.05). CONCLUSION: Total serving weight and carbohydrate content of the meals as
      well as postprandial glucose metabolism seem to be involved in the changes of
      postprandial hunger and satiety sensations after a meal. Due to the covariation
      between the single variables it is not possible, however, to distinguish between
      the different factors involved.

PMID- 8646255
TI  - Modulation by glucose of insulin secretion and glucose phosphorylating activity
      in cultured pancreatic islets from obese (fa/fa) Zucker rats.
AB  - OBJECTIVE: In normal B-cells, glucokinase activity is regulated by glucose. We
      hypothesized that chronic exposure to low or high glucose levels would regulate
      glucokinase function and insulin secretion differently in islets of fa/fa
      compared with lean rats. SUBJECTS, DESIGN, and MEASUREMENTS: Islets isolated from
      lean and fa/fa rats (8-12 wk old) were cultured for 1-7 days in low (3.3 mM),
      moderate (12.5 mM) or supraphysiological (25.0 mM) glucose-supplemented medium.
      Sensitivity to glucose of hexokinase, glucokinase (by enzyme assay and kinetic
      analysis), and the insulin response (by radioimmunoassay) were assessed in each
      group of islets. RESULTS: Islets of fa/fa rats cultured in 12.5 mM glucose for 1
      7 days demonstrated a left-shift in both the EC50 of the insulin response and the
      Km of glucokinase to glucose. The glucokinase Vmax of fa/fa rat islets was lower
      under all conditions tested, thereby limiting the potential increase in insulin
      secretion. When cultured in 3.3 mM glucose for 1-7 days, fa/fa rat islets
      retained responsiveness to glucose longer and the estimated EC50 for glucose
      actually declined. However, the glucokinase Km for glucose increased three-fold
      in both phenotypes cultured in low glucose. Lean and fa/fa rat islets cultured in
      25.0 mM glucose demonstrated a paradoxical hypersecretion of insulin to basal
      glucose concentrations and desensitization to stimulation by high concentrations
      of glucose. Islets from fa/fa rats were more easily desensitized, with
      significant effects in 25.0 mM glucose by 3 days compared with 7 days for the
      lean rat islets. Culture in high glucose erased the phenotype differences in
      glucokinase Km that were observed in 12.5 mM glucose cultured islets.
      CONCLUSIONS: Differences in fa/fa rat islet glucokinase were observed only at
      moderate, near physiological glucose conditions. Glucokinase activity was
      similarly affected by low or high glucose in the two phenotypes, although
      differences in insulin secretion pattern were still detected, leading to the
      conclusion that factors other than glucokinase contribute to altered insulin
      secretion in the fa/fa rat. Further study of the glucose desensitization
      phenomenon in fa/fa rat islets might help unravel the factors that increase
      susceptibility to development of diabetes mellitus in some phenotypes.

PMID- 8646256
TI  - Alpha 2A-adrenergic regulation of cyclic AMP accumulation and lipolysis in human
      omental and subcutaneous adipocytes.
AB  - OBJECTIVE: To characterize differences in alpha 2-adrenergic regulation between
      subcutaneous and omental adipocytes which could offer a possibility of
      pharmacological intervention in the metabolic syndrome. DESIGN: Both subcutaneous
      and omental adipocytes were isolated from 32 patients. Adipocytes were incubated
      in the presence of adrenoceptor agonists, and cyclic AMP and glycerol levels were
      measured. alpha 2-Adrenoceptors of isolated plasma membranes were characterized.
      RESULTS: Adrenaline increased cyclic AMP levels about two-fold in omental
      adipocytes but had almost no effect in subcutaneous fat cells. The inhibition of
      cyclic AMP accumulation and glycerol release by UK-14304 and dexmedetomidine was
      less pronounced in omental adipocytes. The maximal effect of isoprenaline on
      cyclic AMP levels and glycerol release was similar at the two sites. The
      subcutaneous and omental alpha-adrenoceptors had similar affinities to 3H
      RX821002 and showed characteristics of the alpha 2A subtype. The receptor
      densities were 220 +/- 21 and 460 +/- 84 fmol/mg of protein (means +/- s.e.m.) in
      omental and subcutaneous membranes, respectively. CONCLUSION: Inhibition of
      cyclic AMP accumulation and lipolysis by alpha 2A-adrenoceptors is less
      pronounced in omental than subcutaneous adipocytes which could be due to
      differences in receptor number. These differences in alpha 2A-adrenergic
      regulation could be of value in the treatment of the metabolic syndrome.

PMID- 8646257
TI  - Post-prandial thermogenesis with ephedrine, caffeine and aspirin in lean, pre
      disposed obese and obese women.
AB  - OBJECTIVE: To determine whether or not aspirin further potentiates the greater
      post-prandial thermogenesis induced by ephedrine with caffeine. DESIGN:
      Determination of the acute metabolic rate response to the following treatments:
      1050 kJ liquid meal (M); meal plus ephedrine (30 mg) and caffeine (100 mg) (MEC)
      or meal plus ephedrine, caffeine and aspirin (300 mg) (MECA). SUBJECTS: Lean, pre
      disposed obese and obese women (n = 10 each group). MEASUREMENTS: Pre- and post
      treatment metabolic rate determinations via indirect calorimetry. Post-treatment
      measurements made at 20 min intervals for a total of 160 min. RESULTS: In all
      groups, metabolic rate increased significantly more following the MEC or MECA,
      compared to the meal only (p < 0.05). The obese group had a significantly greater
      absolute increase in metabolic rate following the MECA and MEC compared to both
      the lean and pre-disposed obese groups (p < 0.05). Metabolic rate remained
      elevated at the end of the 160 min following all treatments. CONCLUSION: Aspirin
      does not further potentiate the acute thermic effect of ephedrine and caffeine
      with a meal. However, the full thermogenic response was not measured and longer
      duration studies are necessary to confirm these results.

PMID- 8646259
TI  - Obesity and behaviour change: matching problems to practice.

PMID- 8646258
TI  - Glycogen phosphorylase activity and glycogen concentration in muscle of normal to
      overtly diabetic rhesus monkeys.
AB  - The effect of insulin to increase the activity of glycogen synthase (GS) in
      muscle has been well documented, however, the effect of in vivo insulin to
      inactivate glycogen phosphorylase (GP) has not been previously shown. To
      determine the effects of insulin on glycogenolysis in rhesus monkeys, GP and
      glycogen were determined in muscle samples obtained under basal fasting and
      insulin-stimulated conditions during a euglycemic hyperinsulinemic clamp in a
      group of 27 monkeys ranging from normal to overtly diabetic (NIDDM) and compared
      to GS activity previously examined. The diabetic monkeys had lower basal and
      insulin-stimulated glycogen concentrations compared to the normal and
      hyperinsulinemic monkeys (p < 0.05). The response of GP activity ratio (AR) to
      insulin (delta) was inversely correlated to delta GS fractional velocity (fv) (r
      = -0.57, p < 0.002) in all of the monkeys. The AR of GP was inversely correlated
      to the fv of GS measured under insulin-stimulated conditions (r = -0.60, p <
      0.05) in the 11 normal monkeys. In the normal group, the range in response of GS
      to insulin (delta GSfv) was previously shown to be 3-22%, with n = 6 < 11% ('low
      normals') and n = 5 > 11% ('high normals'). In the present study, the low normals
      were shown to have (1) higher delta GP independent activity and delta GP total
      activity compared to the high normals and hyperinsulinemic monkeys (p less than
      or equal to 0.05), (2) higher insulin-stimulated GP independent activity and GP
      total activity compared to the other three groups (p < 0.05), (3) higher insulin
      stimulated GP activity ratio compared to the high normals and hyperinsulinemic
      monkeys (p < 0.05), (4) and lower whole-body insulin-mediated glucose disposal
      rates compared to the high normals (p < 0.05). We conclude that NIDDM is
      accompanied by low glycogen content in the muscle, and that some clinically
      normal monkeys have an alteration in insulin action on muscle GS, GP, and whole
      body glucose disposal rates that may precede the development of hyperinsulinemia.

PMID- 8646260
TI  - Family-based behavioural intervention for obese children.
AB  - The family environment can contribute to the development of obesity. Parenting
      styles may influence the development of food preferences and the ability of a
      child to regulate intake. Parents and other family members arrange a common,
      shared environment that may be conducive to overeating or a sedentary lifestyle.
      Family members serve as models, and reinforce and support the acquisition and
      maintenance of eating and exercise behaviours. Family-based interventions are
      needed to modify these variables in treating obese children. We have made
      significant progress in developing interventions that target obese 8-12 year-old
      children, completing four 10-year follow-up studies that provide support for two
      factors that are useful in childhood obesity treatment. First, our research
      suggests that the direct involvement of at least one parent as an active
      participant in the weight loss process improves short- and long-term weight
      regulation. Second, our research suggests that increasing activity is important
      for maintenance of long-term weight control. Correlational analyses on the 10
      year database suggest that family and friend support for behaviour change are
      related to long-term outcome. Family-based obesity treatment provides
      interventions for both children and their parents, but children benefit more from
      treatment than their parents. These positive results provide an encouraging basis
      for optimism that further development of interventions, based on newer research
      on family processes and behaviour changes, can be useful in treating childhood
      obesity.

PMID- 8646261
TI  - Behaviour change in practice: targeting individuals.
AB  - This paper describes the emergence of motivational interviewing in the addictions
      field, and the development of broader negotiating methods for use in medical
      consultations about behaviour change. It is argued that much of this material
      should be relevant to the treatment of obesity in brief medical consultations. It
      should be possible to encourage patients to be much more active in the
      consultation, and for practitioners to avoid some of the pitfalls of ineffective
      advice-giving. Four potentially relevant clinical strategies are described.

PMID- 8646262
TI  - Behaviour change in practice: group approaches.
AB  - Preliminary research in the treatment of obesity suggests that group
      interventions may be at least as effective as individual interventions,
      presumably due to the social support created among individuals in the group.
      Given that a cost-effectiveness analysis may favor groups, further research is
      necessary on how the benefits of group process can be maximized.

PMID- 8646263
TI  - Behaviour change in practice: population strategies.

PMID- 8646264
TI  - New perspectives on dietary and behavioural treatments for obesity.

PMID- 8646265
TI  - Glycogen levels and obesity.
AB  - The degree of replenishment of the body's glycogen stores influences the
      contribution made by glucose and free fatty acids to the fuel mixed oxidized. The
      expansion of the adipose tissue mass required to promote fat oxidation to rates
      commensurate on average with fat intake is therefore influenced not only by the
      diet's fat content, but by glycogen levels as well. It seems possible that recent
      changes in the food supply and a further decline in physical activity could have
      led to some increase in the range within which glycogen levels are habitually
      maintained, and that this could be a cause for the recent increase in the
      incidence of obesity noted in many countries.

PMID- 8646267
TI  - Importance of energy density and macronutrients in the regulation of energy
      intake.

PMID- 8646266
TI  - Effect of sucrose and sweeteners on appetite and energy intake.
AB  - The effect of sweetness on appetite control has become important for two reasons.
      First, the problem of unwanted overconsumption associated with the tendency to
      gain weight. Second, the desire to lose weight by dieting. Two questions arise:
      does sweetness (with or without energy) contribute to over-consumption?, and does
      the replacement of a high energy sweetener (such as sucrose) with an artificial
      sweetener (such as saccharine or aspartame) lead to weight loss? How do these
      issues relate to processes involved in weight maintenance?

PMID- 8646268
TI  - Manipulating carbohydrate content and sources in obesity prone subjects: effect
      on energy expenditure and macronutrient balance.

PMID- 8646269
TI  - Intake of sugars in relation to fatness and micronutrient adequacy.
AB  - Dietary sugars have frequently been linked with excess body weight and poor
      quality diets. A review of the recent research in this area reveals no basis for
      a causative association between sugar intake and obesity. Rather, a diet which
      contains a high percentage of energy from carbohydrate (starch and sugars) may
      assist in weight loss if the proportion of energy from fat is low. Nutrient
      inadequacies tend to occur in susceptible groups (generally women and children)
      who have a low total energy intake, and this is compounded by a relatively high
      contribution from sugars. For general populations with an adequate caloric intake
      nutrient adequacy can be achieved across a wide range of dietary sugar (4-20%
      energy). In this respect, intakes at either extreme are sub-optimal.

PMID- 8646270
TI  - Self-poisonings with antidepressants and other psychotropics in an urban area of
      Sweden.
AB  - As part of a WHO project on parasuicide, the medications used for self-poisoning
      in the Stockholm area were studied. The prescribing rates of the medications were
      estimated from an independent survey of prescriptions. Anxiolytics, hypnotics,
      and analgesics were the drugs most commonly used for parasuicide. Related to
      prescribing rates, antipsychotics and anxiolytics represented an increased risk
      for parasuicide compared to the average for psychotropics. Analgesics, on the
      other hand, showed a lower risk for parasuicide. The low number of self
      poisonings with antidepressants may reflect that suicidal individuals are seldom
      prescribed antidepressants and/or that antidepressants actually prevent suicidal
      acts. As we have shown earlier for completed suicides, underprescribing and
      therapeutic failure seem to be greater problems with antidepressants than their
      use for self-poisoning.

PMID- 8646271
TI  - Assessment of changes in both weight and frequency of use of medications for the
      treatment of gastrointestinal symptoms among clozapine-treated patients.
AB  - Clozapine has an unusual profile of adverse effects; among them, gastrointestinal
      (GI) side effects are important management concerns. The charts of patients in a
      state hospital who received clozapine for at least 3 months were reviewed. We
      compared the pre- and post-clozapine weights and changes in frequency and
      intensity of use of drugs prescribed for gastrointestinal symptoms for each
      subject (n = 99). There were statistically significant increases in the use of
      antacids (p < 0.02) and both bulk and non-bulk laxatives (p < 0.05, p < 0.03).
      Seventy-three percent of patients gained weight, of whom 27% gained over 10% body
      weight. This study confirms clozapine's association with weight gain,
      constipation, and upper GI symptoms. The literature concerning weight gain, and
      the mechanisms underlying GI adverse effects were reviewed.

PMID- 8646272
TI  - The Mania Rating Scale (MRS): further reliability and validity studies with
      children.
AB  - Empirical studies of prepubertal mania are scarce and are limited by a lack of
      assessment instruments. This study extended previous research on the Mania Rating
      Scale (MRS) in children. Psychometric properties of the MRS were examined in
      three new groups of prepubertal subjects: (1) 10 inpatients with bipolar
      disorder, (2) 10 inpatients with attention deficit hyperactivity disorder (ADHD),
      and (3) 10 outpatients with ADHD. Subjects were administered the MRS and other
      standard depression and hyperactivity measures. The MRS had adequate internal
      consistency (alpha = .80), convergent validity (r = .83, p < .0001), and
      divergent validity (no significant correlations with depression and hyperactivity
      ratings). Items assessing "classic" manic symptoms (e.g., elevated mood,
      increased sexual interest, pressured speech, racing thoughts) effectively
      discriminated the bipolar group from both comparison groups, while items
      assessing increased activity level and irritability did not. Results suggest that
      the MRS can be used with children.

PMID- 8646273
TI  - Acute lymphocytic leukemia and psychosis: treatment with electroconvulsive
      therapy.
AB  - This paper reports the coocurrence of paranoid psychosis and acute lymphocytic
      leukemia in a 16-year-old African-American male. Subsequently, he developed a
      neuroleptic malignant-like syndrome and several other ill-defined complications
      of antipsychotic therapy, which presented difficult management problems for the
      medical and psychiatric staff caring for him. Definitive treatment for his
      psychiatric disorder (ECT) involved possible interactions with his cancer
      chemotherapy regimen that were not clearly defined.

PMID- 8646274
TI  - Delirium associated with clozapine and benzodiazepine combinations.
AB  - Delirium has many organic causes, one of which is the combination of medications.
      This is sometimes difficult to differentiate in the psychotic individual. To our
      knowledge there are no published cases of delirium definitively established by
      "rechallenge" with a combination of clozapine and benzodiazepines. Lorazepam was
      given for agitation in two individuals on clozapine. Because of either the short
      half-life, or the lack of knowledge about this interaction, multiple doses were
      given. Clonazepam was given to a third individual. Two of the reported
      individuals developed a delirium associated with the administration and onset of
      lorazepam. These patients had received both lorazepam and clozapine singularly in
      the past without the adverse effects seen with the combination. Both patients
      were rechallenged with second doses of lorazepam, when they again developed a
      delirium. In one case the patient was admitted on clonazepam and then started on
      clozapine. A delirium developed at a clozapine dose of 150 mg/day; she was not
      rechallenged. In all three cases the patients' sensorium cleared when
      benzodiazepines were discontinued. The combination of benzodiazepines and
      clozapine should be avoided if possible, and if they are used in combination, it
      should be with great caution.

PMID- 8646275
TI  - Augmentation with buspirone: a review.
AB  - Buspirone, an azaspirone serotonin (5-HT) 1A partial agonist, has been approved
      by the FDA as an anxiolytic. It has been tested for use in depression, panic
      disorder, obsessive-compulsive disorder, and schizophrenia as well. Several
      trials have indicated that it may prove to be a useful agent for augmentation of
      other psychotropic medications in these disorders. We review the literature
      supporting the potential use of buspirone as an augmenting agent.

PMID- 8646276
TI  - Cautions in the clozapine-to-risperidone switch.

PMID- 8646277
TI  - Brain temperature and hippocampal function.
AB  - Even though homeothermic animals regulate the body temperature, fluctuations up
      to 2-3 degrees C may occur during physiological conditions. In many species,
      including the rat, a similar variation can be measured in the brain temperature.
      Such changes are expressed throughout the brain with a preserved gradient between
      the warmer basal and cooler dorsal parts. In spite of these recordable
      physiological changes, spatial learning is quite robust, in that it occurs at
      brain temperatures between 30 and 39 degrees C. Even drastic cooling (to below 15
      degrees C) fails to affect consolidation or storage of information when the
      animal is tested after rewarming. The physiological temperature fluctuations have
      significant consequences for electrophysiological responses in the brain. Various
      bioelectrical signals are more sensitive during warming, axonal conduction is
      speeded up, and stimulus-elicited transmitter release becomes faster and more
      synchronized. Action potentials have shorter rise and decay times in warm
      conditions, and the amplitude becomes slightly smaller. Population responses are
      differently affected by these changes. Dentate field potentials in response to
      stimulation of perforant-path fibers appear with shorter latency in warm
      conditions, and the rate of rise in the field EPSP is increased. Paradoxically,
      the amplitude of the population spike is reduced. This is due to a combination of
      reduced amplitude of individual action potentials and reduced efficiency of the
      summation of groups of action potentials. Due to the large effects of temperature
      on hippocampal field potentials, it is mandatory that brain temperature changes
      are monitored and/or controlled whenever such responses are recorded in freely
      moving and anesthetized animals.

PMID- 8646278
TI  - Comparative studies of food-storing, memory, and the hippocampal formation in
      parids.
AB  - Birds which scatter-hoard large numbers of food items such as marsh tits, Parus
      palustris, use memory to retrieve their caches and have an enlarged hippocampal
      formation relative to the rest of the telencephalon compared with species that
      store little or no food. Preliminary observations suggested that captive blue
      tits, P. caeruleus, may store small quantities of food albeit in limited amounts.
      This experiment compared food-storing intensity, memory for cache sites, and
      relative hippocampal formation in marsh tits and blue tits. Comparisons were made
      both within species, by comparing wild-caught adults and hand-raised juvenile
      blue tits that store and those that do not, and between closely related species,
      by comparing food-storing adult wild-caught blue tits and juvenile hand-raised
      blue tits with adult wild-caught marsh tits. Food-storing blue tits stored fewer
      seeds than did marsh tits, and they had a less accurate memory for cache sites
      and a smaller absolute and relative hippocampal formation than did marsh tits.
      For further analysis, the hippocampal volume was divided into a rostral (front)
      portion and a caudal (rear) portion, separated by the first appearance of the
      anterior commissure. Marsh tits had both larger rostral and caudal portions than
      did blue tits, but the species difference in hippocampal volume was greater for
      the rostral than for the caudal portion. In blue tits, wild-caught adults had
      significantly larger absolute and relative hippocampal volumes than did hand
      raised juveniles, but there was no difference in the proportion of rostral to
      caudal portions, irrespective of whether they had stored and retrieved food.
      Although food-storing blue tits did not differ from non-storing blue tits in
      total absolute or relative hippocampal volume, they had larger rostral portions
      of the hippocampal formation and small caudal portions. Possible reasons for this
      are discussed.

PMID- 8646279
TI  - Topographically specific hippocampal projections target functionally distinct
      prefrontal areas in the rhesus monkey.
AB  - The sources of ipsilateral projections from the hippocampal formation, the
      presubiculum, area 29a-c, and parasubiculum to medial, orbital, and lateral
      prefrontal cortices were studied with retrograde tracers in 27 rhesus monkeys.
      Labeled neurons within the hippocampal formation (CA1, CA1', prosubiculum, and
      subiculum) were found rostrally, although some were noted throughout the entire
      rostrocaudal extent of the hippocampal formation. Most labeled neurons in the
      hippocampal formation projected to medial prefrontal cortices, followed by
      orbital areas. In addition, there were differences in the topography of afferent
      neurons projecting to medial when compared with orbital cortices. Labeled neurons
      innervating medial cortices were found mainly in the CA1' and CA1 fields
      rostrally, but originated in the subicular fields caudally. In contrast, labeled
      neurons which innervated orbital cortices were considerably more focal, emanating
      from the same relative position within a field throughout the rostrocaudal extent
      of the hippocampal formation. In marked contrast to the pattern of projection to
      medial and orbital prefrontal cortices, lateral prefrontal areas received
      projections from only a few labeled neurons found mostly in the subicular fields.
      Lateral prefrontal cortices received the most robust projections from the
      presubiculum and the supracallosal area 29a-c. Orbital, and to a lesser extent
      medial, prefrontal areas received projections from a smaller but significant
      number of neurons from the presubiculum and area 29a-c. Only a few labeled
      neurons were found in the parasubiculum, and most projected to medial prefrontal
      areas. The results suggest that functionally distinct prefrontal cortices receive
      projections from different components of the hippocampal region. Medial and
      orbital prefrontal cortices may have a role in long-term mnemonic processes
      similar to those associated with the hippocampal formation with which they are
      linked. Moreover, the preponderance of projection neurons from the hippocampal
      formation innervating medial when compared with orbital prefrontal areas followed
      the opposite trend from what we had observed previously for the amygdala (Barbas
      and De Olmos [1990] (J Comp Neurol 301:1-23). Thus, the hippocampal formation,
      associated with mnemonic processes, targets predominantly medial prefrontal
      cortices, whereas the amygdala, associated with emotional aspects of memory,
      issues robust projections to orbital limbic cortices. Lateral prefrontal cortices
      receive robust projections from the presubiculum and area 29a-c and sparse
      projections from the hippocampal formation. These findings are consistent with
      the idea that the role of lateral prefrontal cortices in memory is distinct from
      that of either medial or orbital cortices. The results suggest that signals from
      functionally distinct limbic structures to some extent follow parallel pathways
      to functionally distinct prefrontal cortices.

PMID- 8646280
TI  - Contribution of synapses in the medial supramammillary nucleus to the frequency
      of hippocampal theta rhythm in freely moving rats.
AB  - We have previously shown that in urethane-anesthetized rats the frequency of
      rhythmical slow activity in the hippocampus ("theta") is controlled by the medial
      supramammillary nucleus (SuM). In particular, injections of procaine into SuM in
      urethane-anesthetized animals reduce the frequency of theta. However, it has been
      reported that, in freely moving animals, lesions of SuM do not affect theta. The
      present experiments were designed to resolve this anomaly. Injections of procaine
      or chlordiazepoxide into SuM in urethane-anesthetized animals reduced the
      frequency of theta elicited by reticular stimulation. Mapping showed that
      procaine injections in freely moving animals were effective in the same locations
      as under urethane anesthesia. Injections of chlordiazepoxide were effective in a
      more restricted area than procaine, consistent with an action on synapses in SuM
      and sparing fibers afferent to SuM. Analysis of the functional spread indicated
      an effective radius of diffusion of the drugs of 500 microns. With optimal
      placements, this implied an action on at least 80% of SuM. However, in contrast
      to the results under urethane, the maximal frequency reductions obtained were
      less than 50% of the theoretical maximum. In a number of animals receiving
      repeated injections into SuM, lesions developed which encompassed the whole of
      SuM. As previously reported, theta was largely intact in SuM-lesioned animals.
      However, the frequency of theta produced by reticular stimulation was reduced
      after lesion by approximately the same amount as by procaine injections before
      lesion. These results suggest that in freely moving animals SuM is only one of
      two or more nuclei which jointly control the frequency of reticular-elicited
      theta.

PMID- 8646281
TI  - Selective damage to the hippocampal region blocks long-term retention of a
      natural and nonspatial stimulus-stimulus association.
AB  - Normal rats rapidly acquire and remember associations between nonspatial stimuli
      as expressed in the social transmission of food preferences. In the present
      study, rats with selective neurotoxic lesions including all subdivisions of the
      hippocampal region (hippocampus proper, dentate gyrus, and subiculum) normally
      acquired and briefly retained the food odor association as demonstrated by intact
      memory immediately after social training. However, long-term memory in these
      animals was severely impaired in contrast to strong 24-h retention by intact
      rats. More selective lesions to the hippocampus proper plus dentate gyrus alone,
      or the subiculum alone had no effect on memory at either test interval. These
      findings indicate that the hippocampal region is required for long-term retention
      of a nonspatial form of natural memory.

PMID- 8646282
TI  - Electrophysiological effects of Mu-selective opioids on hilar neurons in the
      hippocampus in vivo.
AB  - Although mu-selective opioids have been shown to produce dramatic effects on
      neurons within the CA1 and dentate regions of the rat hippocampus, little is
      known regarding their effects on neurons within the hilus, a region of potential
      importance in several disease states. We studied the neurophysiologic responses
      of hilar neurons recorded extracellularly to electrophoretic [D-Ala2, NMe-Phe4,
      Gly-ol]-enkephalin (DAMGO) and systemic morphine (MS) in anesthetized rats. We
      found that hilar cells could be readily divided into two categories, based on
      their pattern of spontaneous activity and response to perforant path stimulation.
      Cells that discharged in a bursting-type pattern formed a homogeneous group
      electrophysiologically. The response of these cells to opioids was dependent on
      route of administration, with the spontaneous activity of all cells tested
      increasing following electrophoretically administered DAMGO, and remaining
      unchanged in response to systemic MS. Cells that discharged in a non-bursting
      pattern showed some electrophysiologic variation, as well as some differential
      response to opioids. However, the spontaneous activity in the majority of non
      bursting cells increased following electrophoretic administration of DAMGO. In
      these cells, MS produced similar, although usually less dramatic, effects.
      Comparison with intracellular data suggests that the bursting cells in our study
      correlate most closely with hilar "mossy cells," while the non-bursting action
      potentials were recorded from other cells, primarily putative interneurons. We
      conclude that mu-selective opioids produce excitation of mossy cells, probably
      through an indirect mechanism, with the primary site of action occurring on cells
      in the granule cell layer. This regional excitation may help to mediate the
      effects of locally administered mu-selective opioids within the dentate gyrus.

PMID- 8646283
TI  - Place cells recorded in the parasubiculum of freely moving rats.
AB  - Previous studies have identified neurons in the hippocampus, subiculum, and
      entorhinal cortex which discharge as a function of the animal's location in the
      environment. In contrast, neurons in the postsubiculum and anterior thalamic
      nucleus discharge as a function of the animal's head direction in the horizontal
      plane, independent of its behavior and location in the environment. Because the
      parasubiculum (PaS) has extensive connections, either directly or indirectly,
      with these structures, it is centrally located to influence the neuronal activity
      in these areas. This study was therefore designed to determine the types of
      behavioral and spatial correlates in neurons from the PaS. Single unit recordings
      were conducted in the PaS of freely moving rats trained to retrieve food pellets
      thrown randomly into a cylindrical apparatus. A total of 10.3% of the cells were
      classified as place cells because they discharged in relation to the animal's
      location in the cylinder. A large percentage of cells (41.4%) were classified as
      theta cells. The remaining cells had nondiscernable behavioral correlates.
      Quantitative analysis of the firing rate maps for the place cells showed they had
      higher levels of background activity and contained larger firing fields than
      values reported previously for hippocampal place cells. Directional analysis
      showed that only three out of 16 cells contained a secondary directional
      correlate; the firing rate for the remaining cells was not affected by the
      animal's directional heading within the firing field. A time shift analysis,
      which shifted the spike time series relative to the animal location series, was
      conducted to determine whether the quality of the location-specific firing could
      be improved. The time shifts for three different spatial parameters were optimal
      when cell discharge led the animal's position. Furthermore, the optimal time
      shifts for two of these parameters (firing area and information content) were
      less than the optimal shift reported for hippocampal place cells and suggested
      that PaS cell discharge lagged behind hippocampal place cell activity. Rotation
      of the cue card with the animal out of view led to near equal rotation of the
      firing field when the animal was returned to the apparatus. These results
      indicate that a small population of cells in the PaS encode the animal's location
      in its environment, although the representation of space encoded by these cells
      is different from the type of representation encoded by hippocampal place cells.

PMID- 8646284
TI  - Hypothalamic tissue stimulates hippocampal pyramidal neuron survival during
      development: evidence from intraocular double transplants.
AB  - The present study was undertaken to evaluate innervation and possible growth
      promotion by posterior hypothalamic tissue on different areas that are, or are
      not, interactive with this brain region during development. Posterolateral
      hypothalamus was dissected from embryonic day 17 rat fetuses, and inserted into
      the anterior chamber of the eye of adult rat hosts. Two weeks postgrafting, a
      second transplant consisting of either fetal hippocampal, cerebellar, or lung
      tissue was placed adjacent to the first graft. Growth of the intraocular double
      transplants was monitored weekly by measurements through the cornea. Fetal
      hippocampal tissue grew significantly larger when placed together with a
      hypothalamic graft, as compared to single hippocampal transplants. Cerebellar or
      lung tissue growth was not stimulated by a hypothalamic cograft. Pyramidal neuron
      cell counts demonstrated a significantly higher final number of these neurons in
      growth-stimulated hippocampal grafts, as compared to non-stimulated single
      hippocampal grafts. Immunohistochemistry with antibodies directed against
      histamine or histidine decarboxylase revealed that hippocampal transplants
      received the most dense histaminergic innervation. Cerebellar transplants
      contained occasional histaminergic neurites, and lung tissue never exhibited any
      histaminergic innervation from the adjacent hypothalamic graft. Taken together,
      these results demonstrate a growth-promoting effect of posterior hypothalamic
      tissue on developing hippocampal tissue, as well as target specificity of
      histaminergic innervation patterns.

PMID- 8646285
TI  - Similarities vs. differences in place learning and circadian activity in rats
      after fimbria-fornix section or ibotenate removal of hippocampal cells.
AB  - Damage to either the fimbria-fornix or to the hippocampus can produce a deficit
      in spatial behavior and change in locomotor activity but the extent to which the
      two kinds of damage are comparable is not known. Here we contrasted the effects
      of cathodal sections of the fimbria-fornix with ibotenic acid lesions of the
      cells of the hippocampus (Ammon's horn and the dentate gyrus) on place learning
      in a swimming pool and on circadian activity. Rats in both ablation groups were
      impaired relative to control rats in learning a single place response but they
      did acquire the response as measured by swim latencies, errors, and by enhanced
      searching on probe trials. They were also more active than the control group on
      the test of activity. Nevertheless, the fimbria-fornix group was initially more
      impaired on learning and was more active than the hippocampal group. Analysis of
      the strategies used in learning indicated that the lesion groups were very
      similar to each other but different from the control group especially in that at
      asymptotic performance, rats in both lesion groups made rather tight loops as
      they swam toward the platform. This strategy likely contributed to the greater
      proportion of time they spent swimming in the correct quadrant on the subsequent
      probe trial. These findings confirm that rats with fimbria-fornix or hippocampal
      damage display impairments in place learning and are hyperactive but also show
      that there are lesion differences. The results are discussed with respect to the
      relative effectiveness of the lesions and the possibility that fibers in the
      fimbria-fornix may mediate some functions that are not attributable to the
      hippocampus.

PMID- 8646286
TI  - Relational features of acetylcholine, noradrenaline, serotonin and GABA axon
      terminals in the stratum radiatum of adult rat hippocampus (CA1).
AB  - In a well-defined sector of adult rat hippocampus (CA1, stratum radiatum), the
      ultrastructural features of acetylcholine (ACh), noradrenaline (NA), serotonin (5
      HT) and GABA axon terminals (varicosities) were compared by electron microscopy
      after immunostaining with antibodies against choline acetyltransferase, NA, 5-HT
      and glutamic acid decarboxylase. Approximately 100 sectional profiles of each
      type were analyzed for size, presence of a synaptic membrane specialization
      (synaptic incidence) and composition of the microenvironment. An equivalent
      number of immunonegative varicosity profiles selected at random from the same
      micrographs were similarly examined. ACh, NA and 5-HT varicosity profiles were of
      comparable size, and significantly smaller than GABA profiles. They exhibited a
      low frequency of junctional specialization, amounting to 7%, 15% and 21%,
      respectively, when extrapolated to the whole volume of these terminals. In
      contrast, GABA varicosities appeared entirely synaptic. The ACh, NA and 5-HT
      varicosities also differed from their GABA counterparts in being juxtaposed to a
      greater number of unlabeled axonal varicosities and a lower number of dendritic
      branches. In addition, the microenvironment of immunostained terminals showed a
      much lower number of dendritic spines than that of immunonegative varicosities.
      This latter finding was viewed as another indication that predominantly asynaptic
      varicosities do not maintain particular relationships with their immediate
      surround. It was also concluded that volume transmission represents a major mode
      of transmission for ACh, NA and 5-HT in adult rat hippocampus, thus contributing
      to the properties and functions assigned to these transmitters in this part of
      brain.

PMID- 8646287
TI  - Blood transfusion in beta thalassaemia major.
AB  - Conventional treatment of beta thalassaemia major is based on regular blood
      transfusion from early childhood. Maximum effectiveness of transfusion therapy
      depends on the following. (1) Availability of safe blood. Donation programmes
      should aim at retaining repeat donors, who carry decreased risk of transmitting
      blood-borne infections. Donors should be screened with laboratory tests performed
      to the highest possible standard of quality. Selection of safe donors can be
      improved by the adoption of questionnaires containing direct questions on risk
      factors for transfusion transmissible infections. (2) Use of good quality red
      blood cells, which should be leucodepleted, preferably by filtration, that can be
      carried out at the bedside. (3) Regular evaluation of blood transfusion indices,
      including mean level of haemoglobin maintained, annual blood requirement, daily
      haemoglobin fall, mean transfusion interval, transfusion reaction rate. This can
      be assisted by the use of a computerized patient record. (4) Maintenance of a
      permanent record of the patient's blood group genotype (including at least Rh,
      Kell, Kidd and Duffy systems) and any red cell antibodies that develop. This is
      mandatory to ensure optimal survival of transfused red cells. (5) Continuous
      monitoring of transfusion transmissible infections. (6) Vaccination against
      hepatitis B of all suitable patients. (7) Intensive iron chelation. This should
      be done by regular subcutaneous administration of desferrioxamine B. Oral
      chelators, which are currently under laboratory and clinical evaluation, are not
      yet available for general use.

PMID- 8646288
TI  - Feasibility and usefulness of an efficient anti-HBc screening programme in blood
      donors.
AB  - Post-transfusion hepatitis B remains a risk for recipients of hepatitis B surface
      antigen (HBsAg) screened blood. Anti-hepatitis B core antibody (anti-HBc)
      screening may help reduce this risk. To evaluate its usefulness, 9,238 East
      Anglian blood donors were screened for anti-HBc. Those with isolated anti-HBc
      were identified with two confirmatory anti-HBc and anti-HB surface antibody (anti
      HBs) assays. The prevalence of anti-HBc reactions in screening and confirmatory
      assays was 1.29% and 0.35%, respectively. The level of reactivity was
      significantly higher when two anti-HBc assays gave concordant results or, being
      concordant, were anti-HBs positive. All isolated anti-HBc-positive units (0.04%)
      were negative for additional HBV markers including DNA tested with nested
      polymerase chain reaction (PCR). A 0.31% prevalence of past HBV infection was
      found in this population, all carrying both anti-HBc and anti-HBs antibody, most
      above the protective level (0.1 IU/ml). The proposed screening schemes would
      limit the number of deferred donors and discarded units and keep the testing time
      within the remit of routine blood banking practices for an additional cost of
      approximately 1 pound per unit. However, no evidence was found in this donor
      population to suggest that anti-HBc screening would significantly reduce the
      incidence of post-transfusion hepatitis B.

PMID- 8646289
TI  - AIDS awareness in blood donors in north India.
AB  - Prevention of AIDS can only be achieved by a successful public awareness
      programme. This study was carried out to establish the level of awareness of AIDS
      and HIV infection through blood transfusion among Indian blood donors of various
      socioeconomic groups. A questionnaire consisting of 20 questions pertaining to
      various aspects of AIDS and HIV infection was circulated to 1012 voluntary blood
      donors. The responses were categorized as good, average and poor knowledge
      according to the number of correct responses. The majority of the donors were
      males (93.5%), married (69.7%) and belonged to the Hindu community. Of the
      donors, 44.4% were educated, 49.9% were highly educated and 5.8% were illiterate.
      Overall, only 205 (20.3%) showed good awareness of AIDS and the majority of these
      168 (16.6%) were highly educated. Approximately 80% of our population did not
      have sufficient knowledge about AIDS or the danger of contracting as well as
      disseminating this disease in the community. One hundred and ninety-one (18.9%)
      donors were in the higher income group and only 13 of them showed good awareness.
      Most of the donors, 384 (38.0%), were government white collar workers and
      belonged to the middle income group. In this group 154 had good awareness. The
      majority of donors with good awareness (176 out of 205) preferred to receive HIV
      tested banked blood or blood from their own relatives during emergencies. None of
      the blood donors had any knowledge of autologous blood donations. This study
      showed that awareness of AIDS was not satisfactory in Indian society. More
      intensive public awareness campaigns by the Government with the help of Non
      Governmental Organizations is required in India to prevent an explosive AIDS
      situation in the near future.

PMID- 8646290
TI  - Relationship of serum alanine aminotransferase (ALT) to body mass index (BMI) in
      blood donors: the need to correct ALT for BMI in blood donor screening.
AB  - A study was carried out on 1,028 voluntary blood donors to see how body mass
      index (BMI) correlated with the serum alanine amino transferase (ALT) activity.
      The mean ALT (U/l) values were 19.35, 27.63, 40.79 and 54.41 in the four BMI
      categories of < or = 20, 20.1-25, 25.1-30 and > 30, respectively. This study
      showed that the mean serum ALT level of obese subjects (BMI > 30 kg/m2), compared
      with the two categories of normal subjects (i.e. BMI < or = 20 and BMI = 20.1-25
      kg/m2), was increased by 2.8 and 1.96 times, respectively. Compared with the BMI
      group < or = 20, there was a gradual per cent increase in the mean serum ALT in
      the three different BMI groups: 20.1-25 (+133%), 25.1-30 (+196%) and > 30 kg/m2
      (+280%). This indicates the need to correct ALT values for BMI for blood donor
      screening, instead of using actual ALT values.

PMID- 8646291
TI  - Screening for IgA deficiency on the Olympus PK7100 by haemagglutination
      inhibition.
AB  - Severe or life-threatening anaphylactic reactions during blood transfusion to
      patients with anti-IgA, though infrequent, can be avoided by transfusing blood
      products prepared from IgA deficient donors. This report describes the
      development and use a passive haemagglutination assay adapted for use on the
      Olympus PK7100 blood group analyser. Donor plasma samples identified as being
      presumptive IgA deficient were further screened by a manual passive
      haemagglutination inhibition technique and finally confirmed by means of a
      quantitative enzyme-linked immunosorbent assay. Of 5723 donors tested
      simultaneously for IgA deficiency, blood grouping and red cell antibody
      screening, six (1 in 954) were confirmed as IgA deficient (i.e. < 100 ng/ml of
      IgA). The test is simple and cost effective and can be used to establish a
      database of IgA-deficient donors.

PMID- 8646292
TI  - Monocyte monolayer assay (MMA) reactivity of alloantibodies reacting by the
      manual polybrene technique but not by an antiglobulin test.
AB  - The manual polybrene technique (MP) has been shown to be useful in pretransfusion
      testing as a rapid method capable of detecting a wide range of red cell
      antibodies. The clinical significance of alloantibodies reacting by the MP but
      not by an antiglobulin test (MP+/AGT-) has not been determined. The monocyte
      monolayer assay (MMA) is an established in vitro technique for assessing the
      likely clinical significance of red cell antibodies. This was used to examine 21
      MP+/AGT- alloantibodies and 41 alloantibodies reacting by a LISS antiglobulin
      method (LISS-AGT). Two of the 21 MP+/AGT- antibodies (9.5%) produced positive
      results by the MMA compared with 26/41 (63.4%) of LISS-AGT-reactive antibodies.
      The incidence of positive reactivity of the latter antibodies in the MMA was
      similar between those that were reactive and nonreactive by the MP. These results
      suggest that antibodies reacting by MP and not by an antiglobulin test are less
      likely to be clinically significant.

PMID- 8646293
TI  - Human platelet antigen-2 and -3 genotyping by PCR-SSP.
AB  - Allele-specific PCR using sequence specific primers (PCR-SSP) is a simple and
      reliable technique to detect point mutations in genes. We have developed a PCR
      SSP to enable the detection of a C-T mutation at position 482 of the GPIb gene
      and a T-G mutation at position 13,962 in exon 26 of the GPIIb gene. These point
      mutations are at the basis of the HPA alloantigens 2a, 2b and 3a, 3b
      respectively. One primer of each primer set has a 3' nucleotide complementary to
      the DNA sequence coding for one allele. PCR product is only produced when the
      corresponding DNA is present and thus the genotype is determined by the presence
      or absence of a band in agarose electrophoresis of PCR products. A second set of
      primers in the same reaction yields a product regardless of the HPA genotype to
      control the efficiency of the PCR amplification. The HPA-2 and -3 genotypes
      determined in this way were in strict concordance with those established by
      conventional genotyping using PCR followed by restriction enzyme digestion (PCR
      ASRA). PCR-SSP is a rapid and reliable technique that can be used for the
      determination of alleles which code for platelet alloantigens.

PMID- 8646294
TI  - A pharmacokinetic study of an ion-exchange solvent-detergent-treated high-purity
      factor VIII concentrate. Haemophilia Directors for Scotland and Northern Ireland.
AB  - An ion-exchange chromatography purified factor VIII concentrate (Liberate) that
      had undergone a solvent-detergent viral inactivation treatment was compared with
      an intermediate-purity concentrate (Z8), which was terminally heated at 80
      degrees C for 72 h, in 15 haemophilia A patients in a blinded crossover
      pharmacokinetic study. Both products achieved a peak level close to that
      predicted (100 IU/dl for Liberate and 103 IU/dl for Z8) and there were no
      significant differences in the recoveries achieved nor of any of the other
      pharmacokinetic parameters. We conclude that the pharmacokinetic properties of
      factor VIII:C, following solvent-detergent treatment and ion-exchange
      chromatography, are equivalent to those of the lower purity terminally heat
      treated product (Z8), and it is therefore likely to be a clinically efficacious
      concentrate.

PMID- 8646295
TI  - In-line filtration of platelet concentrates obtained with the Omnix blood cell
      separator.
AB  - The quality of platelet concentrates (PC) obtained with the blood cell separator
      Omnix was investigated before and after in-line filtration. PC were filtered 2h
      (protocol A) and 4 h (protocol B) after the termination of apheresis. Platelet
      (PLT) yield after filtration was similar in both protocols (median 3.7 vs. 3.4 x
      10(11)). Median white blood cell (WBC) contamination after leucocyte depletion
      was 0.07 x 10(6) (range 0.02-3.27 x 10(6)) in protocol A and 0.06 x 10(6) (range
      0.02-2.1 x 10(6)) in protocol B. Glucose, lactate, lactate dehydrogenase,
      morphology score and pH value were not statistically different before and after
      filtration in both protocols. We conclude that in-line filtration results in
      sufficient leucocyte depletion of the PC. The prefiltration storage time did not
      influence the studied parameters of product quality.

PMID- 8646296
TI  - Determination of the number of Epstein-Barr virus genomes in whole blood and red
      cell concentrates.
AB  - The risk of Epstein-Barr virus (EBV) infection after blood transfusion has been
      controversially discussed. Little is known about EBV transmission via buffy-coat
      depleted red cell concentrates (RCC). In this study, we determined the number of
      EBV genomes in RCC of EBV-seropositive donors in comparison to whole blood. RCC
      were prepared from whole blood donations by using the 'top and bottom system'.
      Leucocyte content was significantly reduced in RCC in comparison to whole blood
      (0.47 x 10(9) vs. 2.3 x 10(9) per unit; P < 0.001). As B cells are expected to
      harbour EBV genomes, we analysed the number of B lymphocytes in both types of
      blood products. There was a significant reduction of B cell content from a median
      value of 90 x 10(6) in whole blood to 0.2 x 10(6) in RCCs (P < 0.001). The number
      of EBV genomes was estimated at a median value of seven from 10(6) B cells in the
      peripheral blood of healthy, EBV-seropositive blood donors by means of a
      polymerase chain reaction (PCR) assay. By calculation, one unit of RCC may
      contain an average of one to two EBV genomes, in contrast to a whole blood unit,
      which is likely to harbour an average of 600 to 700 EBV genomes. It is concluded
      that the use of leucocyte depletion systems significantly reduces the number of
      EBV genomes in erythrocyte concentrates. Thus, leucocyte reduced blood products
      appear to minimize the risk of EBV infection.

PMID- 8646297
TI  - Infectious disease markers in homologous blood and 'selected' autologous blood
      suitable for homologous use.

PMID- 8646298
TI  - Monoclonal anti-D specificity and Rh structure.

PMID- 8646299
TI  - Making a performance improvement plan work.
AB  - BACKGROUND: A carefully crafted organizational performance improvement (PI) plan
      can guide implementation and demonstrate that the organization is serious about
      continuously improving its processes and patient care outcomes. A good plan
      provides an overview of both the processes that are used to achieve PI and the
      expected outcomes. This article describes the process by which St John's Regional
      Medical Center (Joplin, Mo) developed and implemented its P1 plan. DEVELOPING THE
      PI PLAN: The first task is to define the desired PI program elements, such as use
      of teams and teamwork, measurement and monitoring systems, resource management
      tools, work redesign and reengineering, and customer-focused care. Then cultural
      changes to support the PI system need to be identified; the plan should include
      specific strategies to avoid or overcome any possible stumbling blocks. THE PI
      PLAN IN ACTION: As an example of customer-focused improvement, intensive care
      unit nurses formed a team to address customer complaints about waiting room
      policies and physical facilities. An open visiting policy was initiated, pagers
      for family members of patients were provided, and the waiting room was made more
      comfortable. Use of resource management tools is illustrated by the development
      of algorithms and pathways to address variation in care provided to patients with
      complicated and uncomplicated acute myocardial infarction. LESSONS LEARNED:
      Expectations for involvement from the top should be set, holding managers and
      employees accountable for participating appropriately; hospital departments and
      the medical staff should be integrated as soon as possible; and bureaucratic
      requirements should be kept to a minimum.

PMID- 8646300
TI  - Involving physicians in clinical pathways: an example for perioperative knee
      arthroplasty.
AB  - BACKGROUND: At Stanford University Hospital, attempts to improve the case
      management program led to the development of clinical paths, a multidisciplinary
      case management tool. Successful design and implementation of clinical paths
      depend on physician leadership. However, since physicians are trained to function
      independently and to treat each clinical problem as unique, they tend to resist
      attempts to have them follow clinical paths. Strategies to get physicians who
      perform the same clinical procedure to agree with each other on a sequence of
      common interventions had to be developed. Clinical paths define the expected
      processes of care and therefore allow for the introduction of continuous quality
      improvement (CQI) into the clinical arena. A structure had to be developed for
      the effective use of pathways in a CQI framework, and physicians had to be
      encouraged to function as CQI leaders. EXAMPLE: Description of the design of a
      perioperative knee arthroplasty pathway demonstrates the steps needed for
      successful physician involvement in pathway design and its integration into
      clinical CQI. CONCLUSIONS: With sensitive facilitation, physicians can become
      productive leaders of the design of clinical paths, and when they learn the
      benefits of improved efficiency, outcomes, and costs their involvement becomes
      self-sustaining. A quality improvement group led by physicians to develop the
      pathway after implementation can mark the beginning of clinical CQI
      implementation.

PMID- 8646301
TI  - Measuring outcomes in psychiatry: an inpatient model.
AB  - BACKGROUND: This article describes a system for measuring outcomes recently
      implemented in the department of psychiatry of Baptist Memorial Hospital, a 78
      bed inpatient and day treatment unit that represents one service line of a large,
      urban teaching hospital in Memphis. In June 1993 Baptist Hospital began a 15
      month pilot test of PsychSentinel, a measurement tool developed by researchers in
      the Department of Community Medicine at the University of Connecticut. The
      hospital identified the following four primary goals for this pilot project:
      provide data for internal hospital program evaluation, provide data for external
      marketing in a managed care environment, satisfy requirements of the Joint
      Commission on Accreditation of Health Care Organizations, and generate studies
      that add to the literature in psychiatry and psychology. DESCRIPTION OF MEASURE:
      PsychSentinel is based on the standardized diagnostic criteria in the Diagnostic
      and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). The outcome
      measure assesses the change in the number of symptoms of psychopathology that
      occurs between admission and discharge from the hospital. Included in the
      nonproprietary system are risk adjustment factors, as well as access to a
      national reference database for comparative analysis purposes. Data collection
      can be done by trained ancillary staff members, with as much or as little direct
      physician involvement as desired. The system has proven to be both time effective
      and cost effective, and it provides important outcome information both at the
      program level and at the clinician level. RESULTS: After the pilot test, the
      staff at Baptist Memorial Hospital determined that the system met all initial
      objectives identified and recently adopted the system as an ongoing measure of
      quality patient care in the department of psychiatry.

PMID- 8646302
TI  - The New York State Task Force on Clinical Guidelines and Medical Technology
      Assessment.

PMID- 8646303
TI  - Practice guidelines: at the interface of medicine and law.

PMID- 8646304
TI  - Critical care medicine: opportunities and strategies for improvement.
AB  - BACKGROUND: Like other areas of health care, critical care faces increasing
      pressure to improve the quality while reducing the cost of care. Strategies drawn
      from the literature and the authors' experiences are presented. STRATEGIES AND
      OPPORTUNITIES FOR IMPROVEMENTS: Ten process- or structure-related areas are
      targeted as strategically important focuses of improvement: (1) restructuring
      administrative lines to better suit key processes; (2) physician leadership in
      critical care units; (3) management training for critical care managers; (4)
      triage; (5) multidisciplinary critical care; (6) standardization of care; (7)
      developing alternatives to critical care units; (8) timeliness of care delivery;
      (9) appropriate use of critical care resources; and (10) tracking quality
      improvement. TIMELINESS OF CARE DELIVERY: Whatever the root cause(s) of
      unnecessary delays, the result is inefficient use of critical care resources-and
      ultimately either a need for more resources or longer wait times. Innovations
      designed to reduce wait times and waste, such as the establishment of a
      microchemistry stat laboratory, may prove valuable. APPROPRIATE USE OF CRITICAL
      CARE RESOURCES: Possible strategies for the appropriate use of critical care
      resources include better selection of well-informed patients who undergo
      procedures. Reduction in variation among physicians and organizations in
      providing therapies will also likely lead to a reduction in some high-risk
      procedures offering little or no benefit, and therefore a reduction in need for
      critical care services. Better preparation of patients and families should also
      make end-of-life decisions easier when questions of "futility" arise. Better
      information on outcomes and cost-effectiveness and consensus on withdrawal of
      critical care treatments represent two additional strategies.

PMID- 8646305
TI  - The impact of the vaccine for children's program on child immunization delivery.
      A policy analysis.
AB  - The Vaccine for Children (VFC) program was proposed as part of President
      Clinton's 1993 Childhood Immunization Initiative. It is a federal vaccine
      financing program that pays for and distributes free vaccine to providers serving
      4 classes of children: (1) Medicaid insured, (2) uninsured, (3) children with
      private insurance that does not cover immunizations, and (4) American Indian and
      Alaskan Native children. Despite support from major professional organizations,
      the VFC program has come under intense criticism, with critics arguing that the
      cost of vaccines is not a major barrier to immunization receipt. In this article,
      we analyze how the VFC program will influence the receipt of immunizations by
      children under different child health care delivery and financing systems. We
      conclude that the impact of VFC on access to immunizations will be uneven;
      however, VFC could significantly improve access to immunizations for the over one
      third of US children who are either uninsured or covered under Medicaid fee for
      service. With further augmentations and refinements, VFC could be fashioned to
      overcome significant and persistent barriers to the timely delivery of
      immunizations in our disjointed child health financing and delivery systems.

PMID- 8646306
TI  - Pediatric firearm-related fatalities. Not just an urban problem.
AB  - OBJECTIVE: To examine medical and demographic factors associated with the firearm
      related deaths among children in Kentucky. DESIGN: Retrospective review and
      multiple regression analysis. DATA SOURCE: All firearm-related deaths among
      children younger than 20 years reported to the Kentucky Office of Vital
      Statistics, Frankfort, from 1988 to 1993. INTERVENTIONS: None. MEASUREMENTS AND
      MAIN RESULTS: All 320 pediatric firearm-related deaths that occurred in Kentucky
      from 1988 to 1993 were analyzed. Death rates were calculated for each county in
      the state. While the overall death rate from firearms was not significantly
      different between African-American and white children (relative risk [RR], 1.39;
      95% confidence interval [CI], 0.98-1.98), the pattern of the types of events was
      markedly different. African American children were much more likely to have been
      involved in a homicide; suicides were more frequent in white children. Multiple
      Poisson regression analysis, controlling for age, race, and gender, identified
      only 1 variable that was significantly associated with deaths due to firearms.
      Children in rural Kentucky were at significantly more risk for a firearm-related
      death than children in urban areas (RR, 1.26; 95% CI, 1.01-1.62) even after
      controlling for medical system variables (availability of a hospital with 24-hour
      emergency services, availability of prehospital advanced life support, and
      availability of 911 service). CONCLUSIONS: Children in rural areas of Kentucky
      are at an increased risk for firearm-related mortality. Prevention and
      intervention programs that focus only on urban areas may not produce optimum
      results in the Kentucky setting. Further research is needed to determine factors
      that are important in rural areas so that interventions specific to them can be
      planned.

PMID- 8646308
TI  - Hospital-based evaluation of programs to prevent perinatal hepatitis B virus
      transmission.
AB  - OBJECTIVE: To evaluate the frequency of hepatitis B surface antigen (HBsAg)
      screening of pregnant women in the United States and factors associated with the
      lack of screening. DESIGN: A random sample of 200 hospitals with 100 or more
      births per year was surveyed with regard to policy and practices. Each hospital
      was also asked to provide maternal screening and infant follow-up data for the
      first 25 infants who were born on or after March 1, 1993. RESULTS: Of 183
      participating hospitals, 137 (75%) had maternal HBsAg screening policies, and 102
      (56%) had standing orders for HBsAg testing of pregnant women who were admitted
      without prior screening. Hospitals that were located in states with laws that
      required maternal HBsAg screening were more likely to have a written screening
      policy (prevalence ratio [PR], 1.7; 95% confidence interval [CI], 1.2-2.4) and a
      standing order (PR, 1.7; 95% CI, 1.4-2.2). A lack of screening was related to
      delivery in hospitals without screening policies (PR, 3.4; 95% CI, 1.3-8.9) or
      standing orders (PR, 2.8; 95% CI, 1.2-6.2), and to the infant's provider being a
      family practitioner (PR, 1.7; 95% CI, 1.1-2.7). Among the 3982 infants for whom
      data were available, 3342 (84%) were born to mothers who had undergone screening
      for HBsAg. CONCLUSIONS: These findings suggest that hospitals should develop
      specific policies for HBsAg screening, states should enact laws that require
      maternal screening, and additional education of health care providers is needed
      with regard to the screening of all pregnant women for HBsAg.

PMID- 8646307
TI  - Age at onset of puberty following high-dose central nervous system radiation
      therapy.
AB  - OBJECTIVE: To determine if a relationship exists between age at irradiation, sex
      of the patient, and age at onset of puberty and pubarche in children treated with
      high-dose radiation to the central nervous system. DESIGN: Case series. SETTING:
      Tertiary care institutional practices and clinics. PATIENTS: Thirty-six children
      treated with high-dose irradiation (hypothalamic pituitary dose, 30-72 Gy) by
      conventional (n = 29) or hyperfractionated (n = 7) schedules. Girls were treated
      before age 8 years and boys before age 9 years. Twenty-six of the 36 children
      also received chemotherapy. All tumors were distant from the hypothalamic
      pituitary region. MAIN OUTCOME MEASURE: Age at onset of puberty and pubarche.
      RESULTS: In girls, the median age at onset of puberty was 9.3 years vs 10.9 years
      for controls (P < .01); pubarche occurred at 9.4 years vs 11.2 years for controls
      (P < .01). In boys, the median age at onset of puberty--genital II--was 11.0
      years vs 11.5 years for controls (P = .30); pubarche occurred at a median age of
      10.5 years vs 12 years for controls (P = .25). A censored-data normal linear
      regression model was used to account for children (n = 6) who had not reached
      puberty. Age at diagnosis (P < .01) and sex (P = .01) were significant predictors
      of age at onset of puberty. Body mass index SD score (z score) was inversely
      related to age at onset of puberty (r = -0.77) and was greater at onset of
      puberty in girls than in boys. CONCLUSION: In children who have received high
      dose cranial radiation therapy, a significant positive correlation exists between
      age at diagnosis and age at onset of puberty in boys and girls.

PMID- 8646309
TI  - The utility of IgA antibody to human immunodeficiency virus type 1 in early
      diagnosis of vertically transmitted infection. National Institute of Allergy and
      Infectious Diseases and National Institute of Child Health and Human Development
      Women and Infants Transmission Study Group.
AB  - OBJECTIVE: To determine the sensitivity and specificity of anti-human
      immunodeficiency virus (HIV) IgA in identifying infected infants at or before 6
      months of age among the offspring of HIV-infected mothers. DESIGN: Prospective
      comparison of anti-HIV IgA measurement performed in 2 different laboratories by 2
      different methods with the criterion standard of blood culture. SETTING: Five
      centers in the United States and Puerto Rico. PATIENTS: Population-based sample
      of 156 infants of HIV-infected mothers in the Women and Infants Transmission
      Study. MAIN OUTCOME MEASURES: Results of anti-HIV IgA test in relation to the
      infection status of the infants as measured by blood culture. RESULTS: Six-month
      plasma or serum samples were first tested in the 2 laboratories. The sensitivity
      and specificity of anti-HIV IgA in detecting infected infants at this age by
      laboratories 1 and 2 were 69% and 63% and 100% and 99%, respectively. A look-back
      study of samples obtained at birth, 1, 2, and 4 months was then performed on all
      infected children and a matched set of uninfected children. The performance of
      the test at birth was unsatisfactory in both laboratories (sensitivity 44% and
      33%, specificity 43% and 60%), whether peripheral or cord blood was examined. At
      1, 2, and 4 months, the sensitivity of the test was lower than at 6 months, but
      specificity was high. A modest correlation of absent anti-HIV IgA antibody and
      low percentage of CD4 cells in peripheral blood was seen at 6 months of age.
      CONCLUSIONS: The anti-HIV IgA test has moderate sensitivity and high specificity
      for the diagnosis of HIV infection at 6 months of age in the offspring of
      infected mothers.

PMID- 8646310
TI  - The role of community health centers in providing preventive care to adolescents.
AB  - OBJECTIVES: To (1) compare preventive health visits by poor and nonpoor
      adolescents, (2) describe adolescent users of community health centers (CHCs),
      (3) investigate adolescent preventive visits to CHCs, and (4) determine factors
      independently associated with timely preventive visits. DESIGN: Analysis of the
      nationally representative sample of 6635 adolescents aged 11 to 17 years in the
      Child Health Supplement to the 1988 National Health Interview Survey. RESULTS:
      Overall, 4% of US adolescents used CHCs for routine health care, and the
      percentage was higher for poor compared with nonpoor adolescents (11% vs 3%, P <
      .01). Although CHC users were more likely to be poor (41% vs 10%, P < .001),
      uninsured (23% vs 10%, P < .001), and to have behavior (16% vs 9%, P = .02) and
      school problems (56% vs 43%, P < .001), they were as likely to have had timely
      preventive visits (83% vs 81%, P = .61) as adolescents who used private
      practices. Using logistic regression, timely adolescent preventive visits were
      independently associated with having a source for routine care (odds ratio, 4.1;
      95% confidence interval, 3.3-5.2), a chronic health condition (odds ratio, 1.2;
      95% confidence interval, 1.0-1.5), and the use of seat belts all or most of the
      time (odds ratio, 1.4; 95% confidence interval, 1.2-1.6), but no independent
      association was observed between poverty status and timely preventive visits.
      CONCLUSIONS: Community health centers are an important source of preventive care
      for impoverished adolescents. Although those who use CHCs have greater
      psychosocial problems, they seek preventive care as regularly as those using
      private practices. Thus, periodic comprehensive visits may be an effective
      strategy for CHCs to provide preventive services to adolescents.

PMID- 8646311
TI  - Disparities in clinical laboratory performance for blood lead analysis.
AB  - OBJECTIVE: To evaluate the validity of blood lead analysis for clinical
      specimens. DESIGN: We submitted blood lead samples with a known lead
      concentration, in a blinded fashion, as clinical specimens to 18 laboratories.
      These laboratories were surveyed for the following characteristics that were
      hypothesized to be related to assay validity: laboratory ownership (state vs
      private), participation in the Centers for Disease Control Blood Lead Proficiency
      Program, assay method, and price. Each laboratory received 6 specimens with an
      actual blood lead (ABPb) concentration of 0.43 mumol/L (9 micrograms/dL) and 3
      additional specimens--each with an ABPb concentration of 0.33, 0.89, and 1.59
      mumol/L (6.9, 18.4, and 32.9 micrograms/dL, respectively). OUTCOME MEASURES:
      Misclassification error rates for reporting an elevation ( > or = 0.48 mumol/L [
      > or = 10 micrograms/dL) in the blood lead concentration, the within-laboratory
      mean and coefficient of variation (CV) (for multiple specimens with an ABPb
      concentration of 0.43 mumol/L [9 micrograms/dL]), and the adjusted odds of a
      reported blood lead concentration differing from those of an ABPb concentration
      by more than 0.14 mumol/L (3 micrograms/dL). RESULTS: Blood lead results were
      obtained for 157 of 162 submissions. One laboratory reported all blood lead
      specimens as "below 0.48 mumol/L (10 micrograms/dL)." Two (11%) of 18 specimens
      with an ABPb concentration of 0.89 mumol/L (18.4 micrograms/dL) and 1 (6%) of 17
      with an ABPb concentration of 1.59 mumol/L (32.9 micrograms/dL) were classified
      as below 0.48 mumol/L (10 micrograms/dL); 2 (11%) of 18 with an ABPb
      concentration of 0.33 mumol/L (6.9 micrograms/dL) and 44 (42%) of 104 with an
      ABPb concentration of 0.43 mumol/L (9 micrograms/dL) were classified as 0.48
      mumol/L or greater ( > or = 10 micrograms/dL). For specimens with an ABPb
      concentration of 0.43 mumol/L (9 micrograms/dL), the within-laboratory mean
      ranged from 0.23 to 0.52 mumol/L (4.8-10.7 micrograms/dL); the CV ranged from 3%
      to 37%. Laboratories that used anodic stripping voltammetry were 6.3 (95%
      confidence interval, 1.4-28.6) times more likely to report a specimen that
      differed from the ABPb concentration by more than 0.14 mumol/L (3 micrograms/dL)
      than those that used atomic absorption methods. No other laboratory
      characteristic predicted discordance between the reported blood lead and ABPb
      concentrations. CONCLUSIONS: This study documents wide variation in the validity
      of the blood lead measurement among clinical laboratories. While the performance
      of some laboratories far exceeded the criteria of the Centers for Disease Control
      Blood Lead Proficiency Program, others made large errors that could have resulted
      in the false-negative misclassification of children with significant lead
      exposure. Given these differences, the purchasers of laboratory services may
      require access to laboratory proficiency data to make rational choices among
      clinical laboratories. Further study of laboratory performance on clinical
      specimens is required to determine if order-of-magnitude errors occur with
      sufficient frequency to warrant routine submission of blinded quality control
      specimens by proficiency programs and to determine the cause of the poor
      performance of laboratories that used the anodic stripping voltammetry
      methodology.

PMID- 8646312
TI  - Health care of children and adults with acquired immunodeficiency syndrome. A
      population-based analysis.
AB  - OBJECTIVES: To compare the use of medical services by pediatric and adult
      patients with acquired immunodeficiency syndrome (AIDS) in the 6 months before
      and after the diagnosis of AIDS when demand for care is often high and to study
      the influence of human immunodeficiency virus specialty care on survival of
      pediatric patients. DESIGN: Retrospective analysis of Medicaid files. SETTING:
      New York State Medicaid Program. PATIENTS: A cohort identified as having AIDS
      from 1985 through 1990 and enrolled on Medicaid from birth or 1 year or more
      before diagnosis. Because of differing prognoses, 3 groups were studied by age at
      the time that AIDS was diagnosed: infants younger than 6 months, children aged 6
      months to 12 years, and adults aged 13 to 60 years. MAIN OUTCOME MEASURES:
      Frequencies of any service use and, among users, monthly rates of services. From
      Cox proportional hazards models, the adjusted hazard of death for human
      immunodeficiency virus specialty ambulatory care. RESULTS: Nearly all infants (n
      = 122) were hospitalized before and after the diagnosis of AIDS was made--the
      most of all groups. After diagnosis, only 81% of older children (n = 612) were
      hospitalized vs 93% of infants and 90% of adults (n = 5602). Hospitalized
      children had a median of only 3.3 inpatient days per month vs 12.3 and 7.8
      inpatient days for infants and adults, respectively. Of older children, 45% used
      the emergency department vs 33% of adults. Human immunodeficiency virus specialty
      care for infants and children was associated with a 40% lower risk of death after
      the diagnosis of AIDS. CONCLUSIONS: In this AIDS cohort, infants had the greatest
      use of inpatient care, and older children used the emergency department more than
      adults. The finding of improved survival for infants and children with human
      immunodeficiency virus specialty care warrants further study in more recent
      years.

PMID- 8646313
TI  - Pituitary enlargement on magnetic resonance imaging in congenital hypothyroidism.
AB  - OBJECTIVE: To assess pretreatment and posttreatment pituitary gland size by
      magnetic resonance imaging in children with subtle or overt signs of long
      standing hypothyroidism. DESIGN: Etiologic diagnosis of hypothyroidism was
      confirmed by thyrotropin, triiodothyronine, and thyroxine assays; thyroid
      antibody tests; and radionuclide thyroid scan. Repeated magnetic resonance
      imaging was obtained after 6 to 12 months of therapy with levothyroxine sodium to
      restore a euthyroid state. SETTING: Endocrine service at a hospital for children
      in Bombay, India. PATIENTS: Ten children whose mean (+/-SD) chronologic age, bone
      age, and duration of symptoms were 11.39 +/- 1.81, 3.78 +/- 2.05, and 6.95 +/-
      2.91 years, respectively. One patient was seen for acute neurologic symptoms
      suggesting a suprasellar lesion. RESULTS: Magnetic resonance imaging showed
      homogeneous diffuse enlargement of the pituitary gland in all patients. The
      superior margin of the gland was flat in five patients and convex in the rest,
      with suprasellar extension and partial or complete obliteration of the
      infundibulum in three and mild compression of optic chiasma in two, thus
      mimicking a sellar or suprasellar tumor. Pretreatment pituitary mean (+/-SD)
      vertical height in the coronal plane was 10.02 +/- 2.24 mm, with a posttreatment
      regression to 4.93 +/- 1.11 mm (P < .001, Student's t test) and restoration of
      clinical and hormonal euthyroid status. CONCLUSION: Awareness of pituitary
      enlargement and the rare occurrence of neurologic symptoms and chiasmal syndrome
      are important in children with longstanding congenital hypothyroidism.

PMID- 8646314
TI  - Computer instruction in learning concepts of streptococcal pharyngitis.
AB  - OBJECTIVE: To evaluate a computer-assisted instruction unit covering the basic
      concepts of streptococcal pharyngitis for effectiveness as a learning tool.
      DESIGN: Randomized control trial. SETTING: A medical school associated with a
      tertiary care hospital. PARTICIPANTS: Third-year medical students on a pediatric
      clerkship from December 1, 1992, to October 31, 1993. INTERVENTION: Students were
      randomized into a study or a control group and given a pretest on streptococcal
      pharyngitis. The study group then completed the computer-assisted instruction
      unit. No attempt was made to distinguish among the clinical experiences of the
      two groups during the next 4 weeks, after which a second test on streptococcal
      pharyngitis was given to both groups. MAIN OUTCOME MEASURES: Outcome was measured
      by scores (percentage correct) from tests given at day 1 and week 4 of the
      clerkship. RESULTS: The posttest scores of the study group increased by an
      average of 12.1 above the pretest scores, but the scores of the control group
      were only 3.4 points higher. The difference between these increases is
      statistically significant (P < .01, Student's t test). CONCLUSION: Short, well
      designed computer-assisted instruction units can be effective tools in medical
      education.

PMID- 8646315
TI  - Pediatric resident training in a school environment. A prescription for learning.
AB  - OBJECTIVE: To describe our experience with developing, implementing, and
      evaluating the educational effect of a school health experience for pediatric
      residents. DESIGN: Descriptive. SETTING: University-based pediatric residency
      program and five public elementary and middle schools in surrounding communities.
      PARTICIPANTS: Eleven pediatric residents. INTERVENTION: A school health
      experience for pediatric residents was developed in response to the report of the
      American Academy of Pediatrics Task Force on Pediatric Education and the new
      training recommendations of the Residency Review Committee of the American
      Council for Graduate Medical Education. Residents spent 3 weeks in the schools
      engaged in teaching and observational activities. MAIN OUTCOME MEASURES:
      Questionnaires of residents' attitudes and knowledge, structured resident
      interviews, and teacher questionnaires. RESULTS: Positive effect on resident's
      knowledge of school structure, child development, communication with children,
      school-related problems, and special education. Positive effects on resident's
      attitudes about teamwork between teachers and pediatricians and roles of
      pediatricians in schools. Teacher feedback showed acceptance by the school
      community. CONCLUSIONS: Pediatric residents benefit from exposure to children in
      school settings. Schools provide an opportunity to observe normal childhood
      development and behavior in a more natural setting than that provided in the
      hospital.

PMID- 8646316
TI  - Teaching communication skills. An essential part of residency training.
AB  - OBJECTIVE: To design a structured curriculum concerning issues of communication
      with patients and families for use during training of pediatric residents.
      BACKGROUND: The stimulus for this initiative arose from residents perceived need
      for such a program and the realization that a structured approach to
      communication techniques did not currently exist in our residency and, in fact,
      in many undergraduate and graduate medical education curricula. METHODS: Our
      program was designed to address complex and difficult areas in physician-patient
      interaction, including how to deliver "bad news," deal with hostile parents, and
      speak to children about serious illness; the psychosocial aspects of death and
      dying were also covered in the program. Various teaching techniques were used. We
      attempted to assess residents' response and alteration in behavior consequent to
      the program. RESULTS: The program was successfully incorporated into the training
      of our residents and was carried out by using existent personnel; minimal expense
      was incurred. The residents thought the course was valuable and effective,
      although no statistically significant change in the communication skills of
      residents could be demonstrated. CONCLUSIONS: The area of physician-patient
      communication can be taught in a structured fashion during residency. Programs
      should be devised to meet the changing needs of training during residency and
      should incorporate the unique strengths of individual institutions.

PMID- 8646317
TI  - Radiological case of the month. Ectopic ossification and calcification in
      pseudohypoparathyroidism and pseudopseudohypoparathyroidism.

PMID- 8646318
TI  - Picture of the month. Roberts-SC phocomelia syndrome.

PMID- 8646319
TI  - Pathological case of the month. Centronuclear (myotubular) myopathy.

PMID- 8646320
TI  - An unusual presentation of erythema toxicum scrotal pustules present at birth.

PMID- 8646321
TI  - Marital status of Down syndrome parents.

PMID- 8646322
TI  - White forelock could be early sign of tuberous sclerosis.

PMID- 8646323
TI  - The association of vision-threatening ocular injury with infant walker use.

PMID- 8646324
TI  - Influenza A vaccine and the incidence of otitis media.

PMID- 8646325
TI  - Neonatal morbidity of abdominal and vaginal deliveries after uncomplicated
      pregnancies.

PMID- 8646326
TI  - Determination of alternariol and alternariol methyl ether in apple juice using
      solid-phase extraction and high performance liquid chromatography.
AB  - The present work describes a new method for determination of alternariol (AOH)
      and alternariol methyl ether (AME) in apple juice using solid-phase extraction
      (SPE) columns for extraction and cleanup of samples for high-performance liquid
      chromatography (HPLC). Chromatograms of spiked samples show that both toxins can
      be easily detected without interferences, and good recoveries for AOH (82.8 +/-
      7.4%) and AME (91.9 +/- 6.1%) with detection limits as low as 1.6 and 0.7
      micrograms/l, respectively, were obtained.

PMID- 8646327
TI  - Facile liquid chromatographic enantioresolution of native amino acids and
      peptides using a teicoplanin chiral stationary phase.
AB  - The glycopeptide antibiotic teicoplanin is shown to be a highly effective
      stationary phase chiral selector for the resolution of underivatized amino-acid
      and imino-acid enantiomers. Fifty four of these compounds (including all chiral
      protein amino acids) as well as a number of dipeptides were resolved. Hydro
      organic mobile phases are used and no buffers or added salts are needed in most
      cases. Hence the purified analytes are easily isolated in pure form, if needed,
      by evaporating of the solvent. The effect of pH, organic modifier type and amount
      are discussed. The enantioselective separation mechanism is examined using both
      molecular modeling and retention data. The strongest stereoselective interaction
      is for carboxy-terminated D-amino-acids. In case of peptides, it is not necessary
      for these to be a D-, D-, terminal sequence for strong interactions. In some
      cases, including Ala-Ala, the L-, D-, terminal sequence showed greater
      interaction with the teicoplanin chiral stationary phase.

PMID- 8646328
TI  - Affinity purification of phospholipase A2 on immobilized artificial membranes
      containing and lacking the glycerol backbone.
AB  - Immobilized artificial membranes (IAMs) are chromatography surfaces containing
      monolayers of phospholipid ligands. etherIAM.PCC10/C3 contains the glycerol
      backbone whereas delta GIAM.PCC10/C3 lacks the glycerol backbone. Affinity
      purification of PLA2 on these IAM surfaces demonstrated that the surface
      structural differences were not important for phospholipase A2 (PLA2) binding.
      This suggests that the chromatographically important binding event involves the
      PLA2 surface and the monolayer of polar choline headgroups on the IAM surface.
      After sample loading, short-chain alkylsulfonates were used as low eluotropic
      strength detergents to remove contaminating proteins, and PLA2 were eluted with
      CH3CN (30%). Octyllysophosphatidylcholine (0.5%) can replace CH3CN to elute PLA2
      from IAM surfaces. The PLA2 purity after IAM chromatography depends on the
      protein loading; analytical-scale loadings (0.8 mg protein/g IAM) resulted in a
      PLA2 purity of ca. 70% based on densitometric scans of proteins in polyacrylamide
      gels after electrophoresis. Preparative loadings of 3.21 mg protein/g IAM
      resulted in 48% PLA2 purity. Purification of PLA2 to electrophoretic homogeneity
      was achieved using an IAM column followed by a strong anion-exchange column.
      These results suggests that IAMs may be used to develop purification methods for
      PLA2 enzymes obtained from diverse biological specimens.

PMID- 8646329
TI  - High-performance liquid chromatographic determination of the biologically active
      principle hypericin in phytotherapeutic vegetable extracts and alcoholic
      beverages.
AB  - Hypericin was determined using an RP C18 (3 microns) column 8.3 x 0.4 cm I.D.),
      thermostated at 50 degrees C. The separation was achieved with programmed elution
      using phosphate buffer (pH 7)-methanol (3:7) and watermethanol (3:7) as eluents.
      Fluorimetric detection was carried out with excitation at 470 nm and emission at
      590 nm. The analytical sample was prepared by simple dilution in methanol of the
      phytotherapeutic extract or of the alcoholic beverage. Hypericin can be rapidly
      and accurately determined at concentrations down to 0.1 mg/kg without any
      interferences.

PMID- 8646330
TI  - Solid-phase extraction for the selective isolation of polycyclic aromatic
      hydrocarbons, azaarenes and heterocyclic aromatic amines in charcoal-grilled
      meat.
AB  - A method for the simultaneous analysis of 12 mutagenic and/or carcinogenic
      compounds is described; these substances belong to three different chemical
      groups: polycyclic aromatic hydrocarbons (PAHs), azaarenes, i.e., nitrogen
      containing polycyclic aromatic hydrocarbons (PANHs), and heterocyclic aromatic
      amines (HAAs). The selective enrichment procedure includes coupling of solid
      phase extraction (SPE) steps using diatomaceous earth, propylsulfonic acid,
      silica gel and octadecylsilane columns. The eluted fractions were analysed by
      high-performance liquid chromatography with UV and electrochemical detection.
      Levels measured were estimated to be 4-19 ng g-1. Peak confirmation was carried
      out by GC-MS for both PAHs and PANHs, and by LC with a photodiode array detector
      for HAAs. The method was applied to the analysis of charcoal-grilled meat and was
      judged to be generally applicable for detection of these mutagens at the ppb
      level in processed foods.

PMID- 8646331
TI  - Dynamic modeling of electrophoretically mediated microanalysis.
AB  - A dynamic model is presented for simulation of reaction-based chemical analysis
      of enzymes and substrates in capillary electrophoretic systems by the methodology
      of electrophoretically mediated microanalysis (EMMA). The mathematical model
      utilizes mass balance expressions describing the time-dependent effects of
      electromigration, chemical reaction, and diffusional band broadening upon the
      concentration profiles of the various reagent and product species. The model is
      implemented in an iterative computer program in which the capillary is segmented
      into arrays of bins storing the concentration profiles of each of the chemical
      species. During each time increment, the effects of electrophoresis, reaction
      kinetics, and diffusion are calculated, and the concentrations stored in the
      arrays are updated. The flexibility of the model to accommodate various initial
      capillary conditions, sample introduction methods, and voltage programming allows
      diverse EMMA analyses to be simulated. The simulated results are shown to be in
      good qualitative agreement with experimental data for zonal injection and moving
      boundary EMMA determinations of leucine aminopeptidase as well as an EMMA
      analysis of ethanol.

PMID- 8646332
TI  - Analysis of ligase chain reaction products amplified in a silicon-glass chip
      using capillary electrophoresis.
AB  - Ligase chain reaction (LCR) is a useful molecular technique for detecting known
      point mutations. We report the first example of the use of a disposable silicon
      glass micro-chip for LCR and the first application of capillary electrophoresis
      (CE) to analyze samples amplified by LCR in a chip. Silicon-glass chips were
      manufactured using conventional photolithography and anodic bonding. The chips
      provide three distinct advantages for LCR: excellent thermal conductivity, a
      micro reaction volume ( < 10 microliters), and reproducible, low-cost
      manufacturing. Investigation and quantitation of amplification efficiency of LCR
      in a chip or in a tube requires an analytical technique that is faster and more
      convenient than the conventional slab gel methods. Slab gel electrophoresis uses
      relatively large amounts of sample and is labor-intensive and time-consuming, and
      thus is unsuitable for the separation and detection of LCR products. In contrast
      CE requires sample volume (original LCR products) of less than 1 microliter and
      is therefore well-suited to analysis of the micro-volume reaction mixture from
      chips. We combined CE with a sensitive laser induced fluorescence (LIF) detection
      system for the rapid separation and quantitative detection of LCR products
      amplified from the lacI gene in a silicon-glass chip. Comparative studies were
      made with LCR between tubes and silicon-glass chips. CE-LIF analysis is ideally
      suited to examination of micro-LCR amplification with high throughput. The
      technologies may find medical uses in disease diagnosis and research.

PMID- 8646333
TI  - Application of high-performance liquid chromatograph-electrospray ionization mass
      spectrometry and matrix-assisted laser-desorption ionization time-of-flight mass
      spectrometry in combination with selective enzymatic modifications in the
      characterization of glycosylation patterns in single-chain plasminogen activator.
AB  - The application of high-performance liquid chromatography (HPLC), electrospray
      ionization mass spectrometry (ESI-MS) and matrix-assisted laser-desorption
      ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective
      enzymatic deglycosylation treatments is demonstrated in the analysis of
      glycosylation patterns in recombinant Desmodus salivary plasminogen activator, a
      heterogeneous glycoprotein. The sample was initially digested with a proteolytic
      enzyme (endoproteinase Lys-C) and then further treated with either PNGase F to
      remove N-linked carbohydrates or a combination of neuraminidase and O-glycosidase
      to remove sialic acid and O-linked carbohydrates. By comparison of the LC-ESI-MS
      peptide maps for the fully glycosylated and deglycosylated samples, it was
      possible to unambiguously identify the sites of N-linked glycosylation as well a
      number of N-linked glycopeptides. The O-link glycopeptides, which are present at
      low level ( < 1%), were not detected prior to the deglycosylation, nor could
      changes in peptide elution in the map following deglycosylation be correlated
      with potential O-linked glycosylation sites.

PMID- 8646334
TI  - Preparative separation of pyrrolizidine alkaloids by high-speed counter-current
      chromatography.
AB  - We have applied a high-speed counter-current chromatography (CCC) technique to
      the separation and purification of pyrrolizidine alkaloids from Amsinckia
      tessellata, Symphytum spp., Trichodesma incanum (Boraginaceae), and Senecio
      douglasii var. longilobus (Asteraceae). Alkaloidal fractions were separated in a
      solvent system composed of a chloroform mobile phase and 0.2 M potassium
      phosphate buffer, of an optimum pH, as the stationary phase. Up to 800 mg of
      sample could be successfully separated in a single run, with excellent resolution
      of alkaloids. Lycopsamine and several of its acetylated derivatives were resolved
      from alkaloidal fractions of Amsinckia and Symphytum. However, diastereomeric
      pairs such as 7-acetyl-lycopsamine and 7-acetyl-intermedine, could not be
      separated. The presence of diastereoisomers was determined by gas chromatography
      mass spectrometry. Trichodesma contained predominantly trichodesmine, which was
      resolved from a small quantity of incanine. we report the electron impact mass
      spectrum of incanine for the first time. Resolving power of CCC was sufficient to
      separate the closely related alkaloids senecionine and seneciphylline from
      Senecio, in addition to florosenine and retrorsine, Pyrrolizidine alkaloid
      compositions of the four species, determined by mass spectral techniques, were
      consistent with literature, except for the lack of riddelliine and the presence
      of the otonecine-based florosenine in Senecio douglasii var. longilobus.

PMID- 8646335
TI  - [Topical transfusion seminars of the National Institute of Blood Transfusion,
      October 26-27, 1995].

PMID- 8646336
TI  - Comments on the physics and chemistry of trehalose as a storage medium for
      hemoglobin-based blood substitutes: "from Kramers Theory to the Battlefield".
AB  - A glass of the naturally-occurring sugar trehalose may be a suitable medium for
      the storage of hemoglobin-based blood substitutes. Trehalose has many or possibly
      all of the properties required for this purpose, including solubilization of
      hemoglobin to a very high concentration, lack of toxicity, slowing of oxidation
      to the non-oxygen binding methemoglobin, stability at room temperature and above,
      and ease of transport. It should also be possible to prepare hemoglobin extremely
      rapidly for injection into the circulation in situations where blood replacement
      is required immediately, as in a domestic emergency room or on the battlefield.
      These practical considerations are briefly discussed, as well as the theoretical
      reasons for slowing of chemical reactions in the glassy state.

PMID- 8646337
TI  - Survival of lyophilized and reconstituted human red blood cells in vivo.
AB  - To assess the viability of human red blood cells that have been lyophilized and
      reconstituted to the hydrated state, we phlebotomized a unit of whole blood from
      six healthy male volunteers. Their packed red blood cells were lyophilized at -40
      degrees C and stored at 4 degrees C. Upon rehydration, recovery of erythrocytes
      was 85.2 +/- 2.79%. Aliquots of 20 ml were labeled with 51Cr and re-infused into
      the original donors for red cell survival studies. The red cells retained ABO and
      Rh identity upon rehydration. There were no adverse clinical affects of re
      infusion. The half time of 51Cr disappearance from the circulation was 31 +/-
      8.19 days, and there was no evidence of significant splenic sequestration on the
      day of reinfusion. Red cell indices of the rehydrated erythrocytes were normal,
      oxyhemoglobin content was 98.58 +/- 1.46%, and P50 was 27.25 +/- 1.84 mmHg.
      Although deformability was slightly decreased, the osmotic fragility and
      filterability of the red cells were normal. These data demonstrate that human
      erythrocytes can be lyophilized and reconstituted to the hydrated state and
      survive normally in the circulation. Metabolic, osmotic, hematological and
      rheological function remains intact.

PMID- 8646338
TI  - The role of hemoglobin based blood substitutes in transfusion medicine.
AB  - A cell-free oxygen transporting blood substitute would obviate many of the
      current concerns about conventional red cell transfusion therapy. Moreover, a
      stable oxygen-carrying solution could have benefits and applications not possible
      with red cell transfusions, such as the treatment of acute hypovolemic shock in
      acute care settings, the treatment of patients such as Jehovah's Witnesses who
      refuse blood transfusions, the priming of blood oxygenation pumps, ex vivo organ
      perfusion prior to transplantation, and in vivo perfusion in order to enhance
      sensitivity to radiation therapy. Among potential blood substitutes that
      transport oxygen, attention has focused on perfluorocarbons and a variety of
      hemoglobin preparations, either in free solution or encapsulated into lipid
      vesicles. In the design and production of hemoglobin solutions the following
      criteria must be met: low toxicity and antigenicity; efficacy as a plasma
      expander; prolonged survival in the circulation; adequate oxygen carrying
      capability and efficient oxygen unloading to tissues; long shelf life. Extensive
      preclinical testing and recent clinical trials have been performed on human and
      bovine hemoglobin chemically crosslinked to present rapid leakage of hemoglobin
      through the kidneys. Bovine hemoglobin has intrinsically low oxygen affinity
      simulating that of human hemoglobin in red cells. An alternative and attractive
      strategy is the production of human hemoglobin in E. Coli, thus enabling
      appropriate genetic mutations to optimize function. These include creation of
      peptide linkers to enhance plasma survival and amino acid replacements that
      permit a finely regulated lowering of oxygen affinity.

PMID- 8646339
TI  - [Expression of recombinant human hemoglobin in plants].
AB  - Human utilization of recombinant proteins of therapeutical interest, as
      hemoglobin, implies that the transgenic host allows a low cost production of the
      active proteins with minimal risks of pathogen contamination. In this regard, the
      use of transgenic plants could be of great interest. In particular, the systems
      based on plants could be one of the most economical transgenic system, compared
      with the others, because biomass obtention in fields is not expensive.

PMID- 8646340
TI  - [Conception and development of a new generation of oxygen carriers].

PMID- 8646341
TI  - [Pulsed Doppler ultrasonography to measure the vasoactive effects of hemoglobin
      dextran 10-benzene-tetracarboxylate, a potential erythrocyte substitute].
AB  - The effects of Dextran-Benzene-Tetracarboxylate-Hemoglobin (Dex-BTC-Hb), a
      chemically-modified hemoglobin-based oxygen carrier, on the vascular tone were
      compared to those of standard solutions, i.e. the animal's own blood and a 50
      milligrams albumin solution, by measuring the carotid blood flow velocity, the
      mean arterial pressure, the heart rate and respiratory frequency, in anesthetized
      Hartley guinea pigs after a hemorragic shock. Stroma-free hemoglobin induced 40%
      hypertension and a 110% rise in blood flow velocity immediately after injection.
      The velocity was still increased 38%, 3 hours after injection. The calculations
      of the vascular resistances showed an increase in carotid vascular tone. Dex-BTC
      Hb brought about 35% hypertension for two hours with no significant modifications
      of the vascular tone. These effects are similar to those of the albumin solution.
      These results indicate that, unlike stroma-free hemoglobin, Dex-BTC-Hb does not
      significantly affect the vascular tone, probably because of its slight
      interaction with the factors that regulate vascular tone.

PMID- 8646342
TI  - [Recombinant human hemoglobin with low oxygen affinity: additional effects of two
      mutations].
AB  - The search for human Hb variants exhibiting a low oxygen affinity without
      requiring 2,3-diphosphoglycerate, together with a low oxygation rate, is of an
      increased interest in the view of producing an artificial oxygen carrier. We have
      synthesized the recombinant Hb beta 41Phe-->Tyr (rHb beta F41Y) which exhibits a
      low oxygen affinity due to the stabilization of the deoxy state of tetrameric Hb
      [1]. Interestingly, the autooxydation rate for this mutant is similar to that for
      Hb A. We have associated the mutation beta F41Y with the naturally occurring beta
      82Lys-->Asp substitution (Hb Providence) known to be responsible for a low oxygen
      affinity [2]. The second-site mutation further decreases the oxygen affinity of
      the rHb beta F41Y. The effects of the beta F41Y and K82D mutations are additive,
      resulting in a four fold decrease in oxygen affinity of the artificial mutant Hb
      beta F41Y-K82D, compared to Hb A. In spite of the marked decrease in oxygen
      affinity, the autooxydation rate is 2- to 3 fold larger than that of Hb A. These
      data show that it is possible to adjust the oxygen binding properties of human Hb
      by using protein engineering methods. Because of the low oxygen affinity
      coexisting with a moderately increased autooxydation rate, this variant is a good
      candidate for the development of a Hb-based oxygen carrier.

PMID- 8646343
TI  - [Transfer of functional properties from bovine hemoglobin to human hemoglobin].
AB  - Bovine hemoglobin (Hb) has been proposed as a potential blood substitute because
      of its low intrinsic oxygen affinity in the absence of chloride anions and 2,3
      diphosphoglycerate. The use of bovine blood as a source of Hb does not eliminate
      the risks of viral infections. Biotechnology techniques allow to produce modified
      recombinant Hbs. We have engineered human Hb mutants with the aim of mimicking
      the functional properties of bovine Hb. The argument for this work resides in the
      crystallographic studies and in the comparison of human and bovine beta globin
      sequences. The mutant recombinant Hbs exhibit the heterotropic effects of bovine
      Hb do not exhibit the low intrinsic oxygen affinity of bovine Hb.

PMID- 8646344
TI  - Oxygen delivery and autoxidation of hemoglobin.
AB  - Hemoglobin can be considered to exist in active and inactive states. When the
      iron atom is in the ferrous form, the protein is active and can bind oxygen
      reversibly; high and low affinity substates account for the cooperativity of
      ligand binding. However, like bulk metal, the iron can rust. The oxidation to the
      ferric form (metHb) leads to an inactive protein. The oxidation rate will
      therefore limit the useful lifetime of oxygen transporters; this is especially
      critical for cell free Hb solutions. This problem is compounded by the fact that
      Hb is a tetramer. A single oxidized heme effects the other three subunits within
      the same tetramer. The statistics are different from those for a monomeric
      system. For example, a random distribution of 20% ferric iron would imply 58% of
      the tetramers with at least one oxidized subunit. The oxidized subunits remain
      liganded (with water or OH) and will change the oxygenation curve for the
      neighbouring subunits. Since the tetramer will no longer make a full transition
      to the deoxy state, the oxygenation curves are shifted towards higher affinities.
      Thus the oxygen delivery will decrease for two reasons: the direct loss of active
      hemes, and the secondary influence on the remaining ferrous subunits. Control of
      the oxidation rate is also complicated by the intercorrelation of parameters. The
      rate is globally correlated with the oxygen affinity; it is also increased for
      hemoglobin dimers relative to tetramers. One must therefore accept a compromise
      of these parameters, in order to obtain a useful transporter.

PMID- 8646345
TI  - Repeat isolated limb perfusion with melphalan for recurrent melanoma of the
      limbs.
AB  - BACKGROUND: Melanoma recurring locoregionally after isolated limb perfusion (ILP)
      constitutes a therapeutic dilemma. Major amputation is a deterrent option for
      local control and palliation in these patients who have a rather poor prognosis.
      Little is known about the feasibility and efficacy of repeat ILP in these
      situations. STUDY DESIGN: From 1978 to 1993, 28 patients with recurrent melanoma
      after ILP were retreated with various ILP procedures using melphalan. Eighteen
      patients underwent reperfusion by a single and four by a multiple normothermic
      schedule. Hyperthermia was applied in six repeat ILP procedures. RESULTS: A
      complete remission was achieved in 14 (74 percent) of 19 patients with measurable
      disease, with a median limb recurrence-free interval of 11 months. A partial
      remission was obtained in one patient (5 percent). Two patients had no change of
      disease and two patients had progressive disease. In the remaining nine patients,
      all macroscopic tumor tissue was excised before or during the repeat ILP
      procedure. The median limb recurrence-free interval of these nine patients was 15
      months. After a median follow-up period of 30 months after repeat ILP, seven (25
      percent) of the 28 total patients were alive without disease. Acute regional
      tissue toxicity was more severe after repeat ILP than after the first procedure
      (p < 0.05). Long-term regional morbidity occurred in 11 percent of the patients.
      CONCLUSIONS: A high complete remission rate can be obtained with repeat ILP using
      melphalan. However, the high limb recurrence rate and relatively short limb
      recurrence-free interval need improvement. Increased acute regional toxicity
      after repeat ILP can be explained by the use of more intensive schedules.

PMID- 8646346
TI  - Acetylcholine-induced calcium signaling associated with muscarinic receptor
      activation in cultured myenteric neurons.
AB  - BACKGROUND: Within the enteric nervous system, acetylcholine (ACh) is an
      important neurotransmitter. Experimental evidence has suggested that in myenteric
      neurons, calcium plays a key role in the coupling of cholinergic receptors to
      secretory responses. STUDY DESIGN: We investigated the effects of ACh on
      intracellular calcium concentration ([Ca2+]i) in individual myenteric neurons
      using fura-2 microspectrofluorometry. RESULTS: Resting [Ca2+]i in myenteric
      neurons was 62.5 +/- 3 nM. Acetylcholine produced dose-dependent increases in
      [Ca2+]i in myenteric neurons. As the concentration of ACh was increased from 0.1
      to 100 microM, both the peak [Ca2+]i response as well as the percentage of
      responding neurons progressively increased, with a maximal effect at 100 microM
      (347 +/- 31 nM, 95 percent of neurons). The effect of ACh was not sensitive to
      pertussis toxin (100 ng/mL). Calcium ion (Ca2+) responses to ACh were abolished
      by removal of extracellular Ca2+ as well as exposure to nifedipine (10 microM).
      Characterization of the specific muscarinic subtype(s) involved in ACh-mediated
      Ca2+ transients was performed using the specific antagonists pirenzepine (M1),
      gallamine (M2), and 4-DAMP (M3). Pirenzepine (1 microM) blocked increases in
      [Ca2+]i induced by ACh; gallamine (1 microM) and 4-DAMP (1 microM) had no
      significant effect. Intracellular Ca2+ responses to ACh were not affected by
      incubation with the phorbol ester tetradecanoylphorbol-13-acetate (1 microM).
      CONCLUSIONS: These findings suggest that ACh induces increases in [Ca2+]i in
      myenteric neurons by promoting influx of extracellular Ca2+ through L-type
      voltage-dependent Ca2+ channels by activation of the M1 muscarinic receptor
      subtype. The Ca2+ response does not appear to involve a pertussis toxin-sensitive
      G protein.

PMID- 8646347
TI  - Argyrophilic nucleolar organizer region in endoscopically obtained biopsy tissue:
      a useful predictor of nodal metastasis and prognosis in carcinoma of the stomach.
AB  - BACKGROUND: Argyrophilic nucleolar organizer region (AgNOR) staining is a simple
      and economical technique for investigating proliferative activity. We examined
      AgNOR measured in biopsy specimens of carcinoma of the stomach in humans. STUDY
      DESIGN: Argyrophilic nucleolar organizer region staining was done on 76 biopsy
      specimens and corresponding resected cancer tissues. All estimations were made at
      the invasive tumor margin. RESULTS: Of the 76 cases, intratumoral heterogeneity
      of AgNOR count (more than 1.0 difference) between superficial and deep layers was
      recognized in six (7.9 percent) cases, all of which were advanced. In biopsy
      specimens, the AgNOR count ranged from 1.68 to 7.74 (mean, 3.79). A significant
      correlation was found between AgNOR counts of biopsied materials and those of
      resected specimens, both in early and advanced cases. Tumors with a high AgNOR
      count (greater than or equal to 3.79) were more likely to be of a larger size (p
      < 0.01), to have metastasized to lymph nodes (p < 0.01), and to be associated
      with a lower survival rate (p < 0.05) compared to tumors with low AgNOR counts.
      CONCLUSIONS: Estimating the AgNOR count in endoscopically biopsied specimens at
      the margin of invasive gastric carcinoma is useful for assessing nodal metastasis
      and clinical prognosis. These preoperative estimates may aid in tailoring the
      operative procedure and administrating adjuvant therapy.

PMID- 8646348
TI  - Cost-effective management of complicated choledocholithiasis: laparoscopic
      transcystic duct exploration or endoscopic sphincterotomy.
AB  - BACKGROUND: In the United States of America, approximately 700,000 patients
      undergo laparoscopic cholecystectomy (LC) each year and at least 10 percent of
      these patients will have common bile duct stones (CBDS). The purpose of this
      study was to evaluate patients with choledocholithiasis and compare the economic
      and clinical results obtained by LC with endoscopic sphincterotomy (ES) with
      those of LC with laparoscopic transcystic common bile duct exploration (LTCBDE).
      STUDY DESIGN: From June 1991 to September 1994 patients undergoing LC plus LTCBDE
      and those undergoing LC plus ES at a single institution were compared where cost
      data were available. Of the 76 patients with choledocholithiasis, 59 patients
      underwent LC plus LTCBDE (group 1) and 17 patients underwent LC plus ES (group
      2). A subset of group 1 patients undergoing urgent LC plus LTCBDE (group 3) for
      cholecystitis, cholangitis, or pancreatitis plus laparoscopy were examined
      separately. RESULTS: Laparoscopic cholecystectomy plus LTCBDE, whether including
      all-comers (group 1) or just urgent cases (group 3), was associated with a
      significantly decreased length of hospital stay (6.1 and 6.9 days, respectively,
      compared with group 2, 12.4 days) (p < 0.001). The morbidity of patients in group
      1 was also markedly lower than for patients in group 2; 12 percent compared with
      41 percent, respectively. Patients in group 1 had a significantly decreased cost
      of hospitalization (+13,151), when compared with patients in group 2 (+18,712) (p
      = 0.05). This difference is even more pronounced when professional fee
      reimbursement is considered. The cost of treatment for patients in group 1 was
      +14,732 compared with +21,125 for patients in group 2 (p < 0.05). The total
      hospital cost for patients in group 3 was only +13,564 compared with +18,712 for
      patients in group 2. When professional reimbursement was considered, the cost was
      +15,150 for patients in group 3 compared with +21,125 for patients in group 2.
      CONCLUSIONS: Patients undergoing LC plus LTCBDE for CBDS, whether urgently or
      electively, have markedly decreased morbidity rates, length of hospital stay, and
      costs when compared with patients undergoing LC plus ES.

PMID- 8646349
TI  - Male and female sexual and urinary function after total mesorectal excision with
      autonomic nerve preservation for carcinoma of the rectum.
AB  - BACKGROUND: We performed a study to assess sexual and urinary function after
      total mesorectal excision with autonomic nerve preservation for primary carcinoma
      of the rectum. STUDY DESIGN: We studied retrospectively postoperative sexual and
      urinary function in 136 (78 percent) of 175 eligible patients (82 males and 54
      females) who responded to a standardized questionnaire. RESULTS: The ability to
      engage in intercourse was maintained by 86 percent of the patients younger than
      60 years of age, and by 67 percent of patients 60 years and older. Eighty-seven
      percent of male patients maintained their ability to achieve orgasm. The type of
      surgery (abdominoperineal resection compared to low anterior resection), and age
      equal to or greater than 60 years were significantly associated with male sexual
      dysfunction. Of the female patients, 85 percent were able to experience arousal
      with vaginal lubrication and 91 percent could achieve orgasm. The majority of
      patients had few or no complaints related to urinary function. Serious urinary
      dysfunction such as neurogenic bladder was not encountered. CONCLUSIONS:
      Autonomic nerve preservation in association with total mesorectal excision
      reduces the operative morbidity rate and is successful in minimizing sexual and
      urinary dysfunction in the operative treatment of patients with carcinoma of the
      rectum.

PMID- 8646350
TI  - Correlation between early recurrence and reoperation after ileocolonic resection
      in Crohn's disease: a prospective study.
AB  - BACKGROUND: The medical and surgical treatment of patients with Crohn's disease
      is directed at reducing symptoms and postponing recurrence. In the determination
      of high-risk groups for surgical recurrence after ileocolonic resection, the role
      of early endoscopic evaluation is unclear. STUDY DESIGN: We investigated the
      relationship between early recurrence detected endoscopically and recurrence
      detected by operation in a prospective study of 60 patients, who underwent
      ileocolonic resection for Crohn's disease. RESULTS: Recurrence detected
      endoscopically was found in 44 patients (73 percent) according to definition I
      (presence of any lesion detected endoscopically that was compatible with Crohn's
      disease) and in 21 patients (35 percent) according to definition II (five or more
      aphthous lesions present in the neoterminal ileum or at the anastomotic site, or
      25 percent or more of the intestinal circumference inflamed). Recurrence detected
      surgically was found in 14 patients (23 percent). No correlation between early
      recurrence detected endoscopically and recurrence detected surgically was
      evident. CONCLUSIONS: Early recurrence detected endoscopically did not predict
      recurrence detected surgically.

PMID- 8646351
TI  - Efficacy of an intraperitoneal antibiotic to reduce the incidence of infection in
      the trauma patient: a prospective, randomized study.
AB  - BACKGROUND: Antibiotic therapy in patients with blunt trauma remains an area of
      investigation. This study was undertaken in trauma patients evaluated with
      diagnostic peritoneal lavage to determine the effect of an intraperitoneal
      antibiotic on the following factors: infectious complications, length of hospital
      stay, and mortality. METHODS: A prospective, randomized double-blinded study
      compared using either 500 mg of intraperitoneal kanamycin or a saline control in
      69 adult trauma patients requiring diagnostic peritoneal lavage was conducted
      over a 24-month period. Advanced trauma life support indications for performing
      diagnostic peritoneal lavage were used. Patients were randomized to receive 50 mL
      of solution intraperitoneally through a lavage catheter and were evaluated for
      all septic complications, length of hospital stay, and outcome. RESULTS: Over a
      24-month period, 40 patients received kanamycin, and 29 patients received a
      placebo. Of patients receiving kanamycin, 27.5 percent experienced infectious
      complications compared to 65.5 percent of the control patients (p = 0.001, chi
      square analysis). The average length of stay in the intensive care unit was 4.18
      days in the kanamycin group and 6.96 days in the control group (p = 0.04, chi
      square analysis). The average length of stay was 12.32 days for patients
      receiving kanamycin and 17.36 days for the control group (p = 0.03, chi-square
      analysis). The mortality rate for each group was 13 percent. CONCLUSIONS:
      Intraperitoneal kanamycin given to trauma patients requiring diagnostic
      peritoneal lavage within the first three hours following injury reduces the
      incidence of infectious complications and shortens intensive care unit and
      hospital stay.

PMID- 8646353
TI  - The surgeon as a leader in cancer care: lessons learned from the study of soft
      tissue sarcoma.

PMID- 8646352
TI  - Long-term hepatic regeneration and function in infants and children following
      liver resection.
AB  - BACKGROUND: Hepatic regeneration and function after resection has been evaluated
      in adults, but long-term quantitative assessment has not been performed in
      children. Semiquantitative short-term evaluations, including radioisotope scans,
      have suggested that hepatic regeneration occurs quickly in children, but the
      effect of chemotherapy on hepatic regeneration has not been evaluated. Treating
      hepatoblastoma in children increasingly includes chemotherapy before resection,
      hence evaluating regeneration is critical. STUDY DESIGN: A retrospective
      evaluation was done of ten children older than one year following anatomic
      hepatic resection for benign or malignant tumors. Three components were
      evaluated. First, hepatic function was evaluated by a series of tests of
      synthetic function. Second, the metabolic function of the liver was evaluated by
      measuring the hepatic conversion of lidocaine to its breakdown product,
      monoethylglycinexylidide (MEGX). Third, hepatic volume was assessed by magnetic
      resonance imaging scan. RESULTS: All children were clinically well at the time of
      evaluation. Results of tests of synthetic function were essentially normal in all
      patients. Serum ammonia levels were mildly elevated in six patients.
      Hepatocellular enzymes were mildly elevated in several children, and the alkaline
      phosphatase level was mildly elevated in three. A lidocaine infusion study
      demonstrated normal levels of MEGX in all of the children except one with
      positive hepatitis C serology. Studies demonstrated that hepatic volumes were
      below but near the expected levels in most children. Sequential studies in six
      children demonstrated progressive growth of the livers. No adverse effect on
      hepatic size was noted in the children who received chemotherapy. CONCLUSIONS:
      The cohort of children had adequate regeneration and function of the liver
      following hepatic resection. No adverse effect of perioperative chemotherapy
      could be identified.

PMID- 8646355
TI  - Physician liability under managed care.

PMID- 8646354
TI  - Computerized vectorcardiography for improved perioperative cardiac monitoring in
      vascular surgery.
AB  - BACKGROUND: Postoperative cardiac complications occur frequently after noncardiac
      operations in high-risk patients. Routine cardiac monitoring is usually done by
      electrocardiographic (ECG) methods. The present analysis shows that computerized
      vectorcardiography (VCG) is superior to traditional ECG monitoring in predicting
      postoperative cardiac complications. STUDY DESIGN: Thirty-eight patients
      scheduled for abdominal aortic operations were monitored intraoperatively and for
      48 hours postoperatively using VCG. These data were analyzed in a blinded
      fashion, and compared to cardiac outcome and regularly calculated 12-lead ECGs.
      RESULTS: Thirteen patients suffered from cardiac events: myocardial infarction (n
      = 3), cardiac death (n = 1), recurrent myocardial ischemia (n = 1), arrhythmias
      (n = 2), congestive heart failure (n = 2), and arrhythmias combined with
      congestive heart failure (n = 4). Thirty of 38 patients had ischemia recorded on
      their VCG, including all 13 patients with cardiac events. Only seven of the 13
      patients had ischemic changes on the V5-lead alone and ten on the three leads II,
      V4, V5, yielding a sensitivity of 54 percent (V5), 77 percent (II, V4, V5) and
      100 percent (VCG). Signs of ischemia appeared 400 +/- 690 (mean plus or minus
      standard deviation) minutes earlier (median 78 minutes, with a range of zero to
      2,284 minutes), and never later on the VCG compared to the three leads II, V4,
      V5. CONCLUSIONS: Vectorcardiography in this risk group shows increased
      sensitivity in predicting perioperative cardiac complications and earlier
      ischemia detection than the most sensitive scalar leads. Vectorcardiography
      substantially improves the possibility of earlier intervention, potentially
      reducing the incidence of postoperative cardiac complications.

PMID- 8646356
TI  - Effective therapy: repeat limb perfusion for recurrent melanoma.

PMID- 8646357
TI  - Occlusion of vessels with posterior plaques.

PMID- 8646358
TI  - A method to trim multilayered polytetrafluoroethylene grafts.

PMID- 8646359
TI  - An easy technique for inferior vena cava control in pediatric liver
      transplantation.

PMID- 8646360
TI  - A new technique for pancreatojejunostomy.

PMID- 8646361
TI  - Improving the technique of performing a pancreaticoenterostomy and
      pancreatoduodenectomy.

PMID- 8646362
TI  - Cardiac tamponade caused by central venous catheter perforation of the heart: a
      preventable complication.

PMID- 8646363
TI  - Recommendations for the reporting of urinary bladder specimens containing bladder
      neoplasms. Association of Directors of Anatomic and Surgical Pathology.
AB  - The Association of Directors of Anatomic and Surgical Pathology have developed
      recommendations for the surgical pathology report for common malignant tumors.
      The recommendations for carcinomas of the urinary bladder are reported herein.

PMID- 8646364
TI  - Nasal biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis.
      Significance of palisading granuloma and leukocytoclastic vasculitis.
AB  - The diagnostic value of the nasal biopsy in the early diagnosis of Wegener's
      granulomatosis and its value in prognosis were examined in 11 patients with a
      clinicopathological diagnosis of the disease. The vascular lesions found included
      microabscess in the vascular walls in 82%, leukocytoclastic capillaritis in 73%,
      fibrinoid necrosis of blood vessels in 45%, leukocytoclastic endovasculitis in
      27%, and palisading granuloma in vascular wall in 9% of cases. The extravascular
      lesions included palisading granuloma in all cases, microabscess in 91%, and
      diffuse granulomatous tissues in 82%. Palisading microgranuloma (82%) was more
      frequent than palisading macrogranuloma (45%). After therapy, complete remission
      occurred in 8 patients, but 3 patients died of sepsis, diffuse pulmonary
      haemorrhage, and cerebral haemorrhage. Comparison of the frequency of each
      finding in the nasal biopsy specimens between patients who achieved remission and
      those who died showed that leukocytoclastic vasculitis was found more commonly in
      fatal cases, and leukocytoclastic endovasculitis was observed only in fatal
      cases. Palisading granuloma as a vascular or extravascular lesion is the primary
      and most important finding in a histopathological diagnosis of Wegener's
      granulomatosis, microabscess in vascular walls is a secondary but the next most
      important finding, and leukocytoclastic vasculitis heralds dissemination of the
      disease and poor prognosis. It requires aggressive therapy.

PMID- 8646365
TI  - Expression of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular
      cell adhesion molecule (VCAM)-1 in non-small-cell lung carcinoma.
AB  - Vascular cell adhesion molecules (VCAM) play an important part in the regulation
      of inflammation and are considered to be important in the process of malignant
      tumour growth. The present study describes the immunohistochemical staining
      patterns of E-selectin, intercellular adhesion molecule (ICAM)-1 and VCAM-1 on
      endothelial cells of the vessels in tumour stroma and other cell types in non
      small-cell lung carcinoma (NSCLC; n = 43) in association with inflammatory cells.
      Expression of E-selectin was dominant on endothelial cells in the stromal areas
      of the tumour, especially at the borders, and was confined to endothelial cells.
      Moderate to strong staining for ICAM-1 was demonstrated on endothelial cell
      irrespective of size or localization of the vessels. Compared with ICAM-1, fewer
      vessels were positive for VCAM-1, and stained with lesser intensity. ICAM-1
      expression was demonstrated on NSCLC cells, the basal cells of bronchial
      epithelium, type II pneumocytes, lymphocytes and fibroblasts. VCAM-1 was clearly
      expressed on NSCLC cells in 4 of the 43 cases and on lymphocytes and fibroblasts.
      The staining patterns observed on endothelial cells support the idea of an active
      status of NSCLC vessels. This phenotypic pattern looks similar to the vascular
      component of inflammation. The presence of ICAM-1 and VCAM-1 on NSCLC cells
      suggests a functional role in the process of chemotaxis for tumour cells.

PMID- 8646366
TI  - MT-MMP expression and localisation in human lung and breast cancers.
AB  - Thirteen primary pulmonary squamous cell carcinomas, 4 specimens of normal lung
      from around tumours, 4 benign proliferations of the mammary gland and 16 breast
      carcinomas were analysed by in situ hybridisation. Northern blot and
      immunohistochemistry for the expression of a recently described metalloproteinase
      (MMP), the MT-MMP (membrane-type matrix metalloproteinase). This MT-MMP can
      activate gelatinase A, involved in the degradation of basement membranes. In situ
      hybridisation revealed MT-MMP transcripts distributed in both tumour and stromal
      cells in squamous cell lung cancers, whereas these mRNAs were principally
      detected in stromal cells in close contact to tumour clusters in breast
      carcinomas and in lung adenocarcinomas. Northern blot analysis showed a parallel
      expression of MT-MMP and gelatinase A transcripts in both lung and breast
      cancers. Immunohistochemistry displayed a more extensive distribution of MT-MMP
      in pulmonary and mammary carcinomas with numerous labelled preinvasive and
      infiltrating cancer cells and stromal cells near the tumour cells. The large
      degree of expression of MT-MMP in these cancers indicates a potential role of
      this enzyme in tumour progression. The finding of MT-MMP transcripts in stromal
      cells in the vicinity of lung and breast tumour cells emphasises the cooperation
      between these cells and cancer cells for the expression of MT-MMP and in tumour
      invasion in vivo.

PMID- 8646367
TI  - Increased matrix metalloproteinases as possible cause of osseoarticular tissue
      destruction in long-term haemodialysis and beta 2-microglobulin amyloidosis.
AB  - Immunolocalization of matrix metalloproteinases (MMPs) and tissue inhibitors of
      matrix metalloproteinases (TIMPs) in periarticular tissues of beta 2
      microglobulin amyloidosis patients was investigated. MMP-1 (interstitial
      collagenase) the most strongly expressed of the MMPs, was localized in the
      synovial lining cells, mesenchymal cells in granulation tissue and nodular
      amyloid deposits, and chondrocytes within areas of cartilage erosion. Expression
      of MMP-1 was correlated with the degree of macrophage infiltration and synovial
      cell hyperplasia, but it was not correlated with the degree of amyloid deposition
      or haemodialysis period. Expression of MMP-1 appeared more intense than that of
      TIMP-1 and TIMP-2 in highly inflammatory cases. MMP-2 was mildly expressed in the
      interstitial fibroblasts and MMP-3 was faintly stained in the extracellular
      matrix of the synovial membrane. MMP-9 (gelatinase B) was found to be strongly
      positive in the osteoclasts which increased in the progressing osteolytic lesion
      from the destructive arthropathy. These results suggest involvement of MMPs in
      inflammation with an imbalance between expression of MMPs and TIMPs being closely
      related to pathogenesis of the destructive arthropathy.

PMID- 8646368
TI  - Comparison of benign and malignant endometrial lesions for their p53 state, using
      immunohistochemistry and temperature-gradient gel electrophoresis.
AB  - The aim of this study was to evaluate the presence and distribution of p53
      alterations in pure endometrioid adenocarcinomas (n = 120) of different grades
      and stages, as opposed to normal endometrium (n = 13) and various risk groups of
      hyperplasia (n = 39). All samples were initially analysed by immunohistochemistry
      with the monoclonal antibody Ab-6. Normal endometria were negative. With
      increasing degrees of malignancy, the number of cases with p53 accumulation rose
      and ranged from 9% to 18% in hyperplasia, through 25% in low-grade carcinomas
      (G1), to 69% in high-grade carcinomas (G3). This increase was also seen when
      comparing tumours by stage. Of carcinomas in stage IA, only 17% showed p53
      immunostaining, in contrast with 72% in stage IC. Of this material, 34 carcinomas
      and 8 hyperplasias were analysed for p53 mutations in exons 5-8 by means of
      polymerase chain reaction and temperature-gradient gel electrophoresis (TGGE). In
      none of 5 hyperplasia and 6 of 12 carcinomas showing p53 accumulation by
      immunohistochemistry, p53 mutations were detected by TGGE. In contrast, 4 of 22
      carcinomas harboured mutant p53 but were negative by immunohistochemistry.
      Immunohistochemical and molecular investigations revealed that p53 alterations
      are related to the standard prognostic markers of endometrial cancer, i.e.
      grading and staging. TGGE, an indirect screening procedure for p53 mutations, is
      used to detect the type of p53 alteration and may provide additional insight into
      the complex figure of p53 abnormalities in the development and progression of
      malignant endometrial lesions.

PMID- 8646369
TI  - Acute tubulointerstitial nephritis: phenotype of infiltrating cells and
      prognostic impact of tubulitis.
AB  - The prognostic impact of tubulitis and the phenotype of the infiltrating cells in
      the tubules were studied in ten percutaneous renal biopsies from six patients
      with acute tubulointerstitial nephritis (ATIN). The inflammatory cell subsets in
      the tubules and interstitium (CD3+, CD4+, CD8+, CD20+, CD45RO+, CD56+, CD57+,
      CD68+ and TIA-1+ cells), the expression of vimentin and the proliferation
      associated antigen Ki-67 by cortical tubular cells, and the grade of tubulitis,
      interstitial infiltration and fibrosis were analysed. Cytotoxic injury to tubular
      cells in the vicinity of tubular-wall-localized lymphocytes was studied
      ultrastructurally. ATIN was drug-induced in three patients, related to Legionella
      infection in two and idiopathic in one patient. Four patients recovered, one with
      reduced renal function. Two patients developed end-stage renal disease. CD8+ and
      CD4+ lymphocytes, and a smaller number of macrophages, infiltrated the tubules.
      The predominant lymphocyte subset in the tubules was the same as in the
      interstitium. Cytotoxic injury to tubular cells was not seen electron
      microscopically. The tubular cells exhibited increased proliferative activity and
      expressed vimentin, indicating non-specific tubular damage. The cell subset, the
      severity of tubulitis, and the tubular expression of vimentin were not related to
      outcome. The main prognostic factor was the severity of the interstitial
      fibrosis. Tubulitis in ATIN may be a harmless non-immune reaction, mediated by
      tubular expression of cytokines, together with adhesion and other molecules.

PMID- 8646370
TI  - Interphase cytogenetics on paraffin sections of paediatric extragonadal yolk sac
      tumours.
AB  - Germ cell tumours in children are more often extragonadal than in adults and the
      most frequent type is the yolk sac tumour. Limited cytogenetic data exist on
      extragonadal yolk sac tumours in children. We applied in situ hybridization (ISH)
      to interphase cell nuclei of four paediatric extragonadal pure yolk sac tumours
      and one yolk sac tumour component of a mixed germ cell tumour using paraffin
      embedded tissue sections. The panel of chromosome-specific DNA probes was
      selected on the basis of their relevance in adult germ cell tumours and consisted
      of five DNA probes specific for the (peri)centromeric regions of chromosomes 1,
      8, 12, and/or 17, X and/or one DNA probe specific for the subtelomeric region of
      chromosome 1 (p36.3). Only one tumour failed to show numerical and structural
      chromosome aberrations with the DNA probes used. The other four had an increased
      incidence of numerical chromosome aberrations with an over-representation of at
      least one chromosome. The DNA indices determined in the paraffin-embedded tumour
      material correlated well with the in situ hybridization findings. In only a few
      cases were chromosomes over-represented, when compared with the corresponding DNA
      indices. Recently, we have shown that the short arm of chromosome 1 is a non
      random site of deletion in paediatric gonadal pure yolk sac tumours. The
      occurrence of similar deletions in one extragonadal pure yolk sac tumour and in
      one yolk sac tumour component, in conjunction with two further ISH reports,
      suggests that the loss of gene(s) in this region is an important event in the
      pathogenesis of paediatric malignant germ cell tumours of nearly all sites.

PMID- 8646372
TI  - Asthma: The important questions, part 3. Report of a workshop. Paros, Greece,
      June 1995.

PMID- 8646371
TI  - Nature and origin of the neointima in whole vessel wall organ culture of the
      human saphenous vein.
AB  - Intimal proliferation is a characteristic feature of arteriosclerosis. Whole
      vessel wall organ culture systems have been developed to study the early stages
      of neointima formation. We have cultured a large number of explants of human
      saphenous vein specimens for several weeks, and have identified the nature of the
      cells in the newly formed intima by a panel of monoclonal antibodies recognizing
      endothelial cells (von Willebrand factor, platelet endothelial cell adhesion
      molecule-1 and EN-4 antigen), smooth muscle cells (monoclonal antibodies HHF35
      and CGA-7) and fibroblasts (5B5 antibody). In addition we determined the uptake
      of fluorescently labelled acetylated low density lipoprotein by the surface cells
      of the explants. We found that an apparent neointima was formed in the vein organ
      system, the cells of which were predominantly smooth muscle cells and originated
      from the cut edges and from the adventitia of the vein segment. The endothelial
      cells originally lining the luminal surface of the vessel segments became
      overgrown by these cells. They remained at the base of the newly formed neointima
      and a number of them reorganized into capillary-like structures. Our data suggest
      that explant culture of saphenous vein does not reflect the classical concept of
      neointima formation, in which intimal smooth muscle cells migrate through the
      internal elastic lamina and accumulate in the intima. Although it has this
      limitation, the model may serve well to study specific aspects of cell migration,
      smooth muscle cell differentiation and angiogenesis, and may reflect aspects of
      intimal thickening at surgical suture sites.

PMID- 8646373
TI  - The inflammatory response.

PMID- 8646374
TI  - Extracellular matrix.

PMID- 8646375
TI  - Airway behavior and its regulation: how do structural changes affect airway
      behavior?

PMID- 8646376
TI  - Can airway function be predicted?

PMID- 8646377
TI  - Role of airway smooth muscle.

PMID- 8646378
TI  - How does inflammation cause symptoms?

PMID- 8646379
TI  - Why does asthma become persistent?

PMID- 8646380
TI  - Is occupational asthma a relevant model?

PMID- 8646381
TI  - What are the prospects for immunization?

PMID- 8646383
TI  - Can steroids cause asthma to remit?

PMID- 8646382
TI  - How do steroids work?

PMID- 8646384
TI  - What is the role of nerves in chronic asthma and symptoms?

PMID- 8646385
TI  - Epithelial cells: barrier functions and shedding-restitution mechanisms.

PMID- 8646386
TI  - Introducing an acute pain service.
AB  - This article introduces the concept of an acute pain service (APS). It describes
      the initial steps needed in setting up such a service, the key areas that an APS
      focuses on and ways in which an APS might later expand.

PMID- 8646387
TI  - The eye in systemic disease.
AB  - All systemic diseases can affect the eye. This article discusses the clinical
      changes in the eye within traditional disease categories. Emphasis is placed on
      the most common disorders, those in which specific eye findings assist in
      diagnosis and those where involvement of the eye requires urgent referral to an
      ophthalmologist.

PMID- 8646388
TI  - An introduction to the principles and safety of electrosurgery.
AB  - With the advent of minimal access surgery, the use of different energy sources
      has made a tremendous contribution to the treatment modalities in many
      gynaecological disorders. The trainee must be clear in the understanding of not
      only the application of energy sources, but also the principles behind their use.
      This article has thus been written to provide insight into avoiding patient
      injury as well as safety of use.

PMID- 8646389
TI  - Basic principles of permanent cardiac pacing.

PMID- 8646390
TI  - The implantable cardiac defibrillator.

PMID- 8646391
TI  - Telemedicine: if it is the answer, then what are the questions?

PMID- 8646392
TI  - Advances in pacing.

PMID- 8646393
TI  - Advances in catheter ablation.

PMID- 8646394
TI  - Anaesthesia for the insertion of a catheter for peritoneal dialysis.

PMID- 8646395
TI  - Kidney transplantation from asystolic donors.
AB  - The growing shortage of donor organs continues to be an important limiting factor
      in renal transplantation and there has been renewed interest in non-heart-beating
      donors. Despite prolonged warm ischaemic periods, transplanted kidneys from
      asystolic donors have been shown to have good short-term results in terms of
      graft survival and renal function. Longer term results are awaited with interest.

PMID- 8646396
TI  - Major depression in children and adolescents.
AB  - Major depressive disorder (MDD) in young people is relatively common, disabling
      and recurrent, involving a substantial level of morbidity and mortality, mainly
      through suicide. Although much remains to be learned, an impressive body of
      knowledge has accumulated over the previous decade regarding the epidemiology,
      clinical features, management and outcome of MDD.

PMID- 8646397
TI  - Contrast agents in ultrasound.

PMID- 8646398
TI  - Litigation in anaesthesia.
AB  - Doctors in this country are more likely now than ever before to be involved in a
      legal action. This article discusses some recent cases involving anaesthetists to
      illustrate the difficulties facing both sides in our current legal system.

PMID- 8646399
TI  - Tension pneumocephalus: a case following petrousectomy.

PMID- 8646400
TI  - Income generation in the NHS: opportunity or myth?
AB  - Income generation through private practice is back on the agenda for NHS trusts.
      Is this in order to benefit patients or to allow the private sector to subsidize
      NHS care? If you are involved in private practice within your hospital, how
      should it be organised in order to ensure that your wishes are followed when it
      comes to using the profits?

PMID- 8646401
TI  - Kawasaki disease.
AB  - Kawasaki disease is an acute vasculitis of small- and medium-sized blood vessels
      which was first described by Dr Tomisaku Kawasaki in 1967. Involvement of the
      coronary arteries is common and may be life threatening or cause long-term
      cardiovascular complications.

PMID- 8646403
TI  - Inhibitors of the cytochrome P450-mono-oxygenase and endothelium-dependent
      hyperpolarizations in the guinea-pig isolated carotid artery.
AB  - 1. Transmembrane potentials were recorded from isolated carotid arteries of the
      guinea-pig superfused with modified Krebs-Ringer bicarbonate solution. Smooth
      muscle cells were impaled with sharp intracellular microelectrodes. 2.
      Acetylcholine (1 microM) induced an endothelium-dependent hyperpolarization (14.3
      +/- 2.8 mV, n = 6) which was not affected (15.1 +/- 1.1 mV, n = 35) by inhibitors
      of cyclo-oxygenase (indomethacin, 5 microM) and nitric oxide synthase (N omega
      nitro-L-arginine: L-NOARG, 100 microM). 3. The hyperpolarization produced by
      acetylcholine was abolished in the presence of elevated potassium (35 mM) in the
      superfusing physiological saline solution. 4. The acetylcholine-induced
      hyperpolarization was not affected by the inhibitors of cytochrome P450 mono
      oxygenases, SKF525a (10 and 100 microM, 13.9 +/ 2.2 and 15.3 +/- 4.6 mV),
      metyrapone (100 microM, 13.1 +/- 1.9 mV), clotrimazole (100 microM, 13.5 +/- 2.7
      mV), 17-octadecynoic acid (5 microM, 16.5 +/- 1.9 mV), methoxsalen (10 microM,
      15.3 +/- 1.6 mV), the inhibitor of phospholipase A2 quinacrine (10 microM 12.8 +/
      2.5 mV) and the non specific lipoxygenases/cyclo-oxygenases/cytochrome P450
      inhibitor, eicosatetraynoic acid (50 microM, 15.0 +/- 2.2 mV). However, the
      muscarinic antagonist, atropine (100 nM), abolished the hyperpolarization. 5.
      These results suggest that in guinea-pig carotid artery, the metabolism of
      arachidonic acid, either through cyclo-oxygenase, lipoxygenase or cytochrome p450
      mono-oxygenase, is not involved in acetylcholine-induced endothelium-dependent
      hyperpolarizations.

PMID- 8646404
TI  - Infiltration of neutrophils by intrapleural injection of tumour necrosis factor,
      interleukin-1, and interleukin-8 in rats, and its modification by actinomycin D.
AB  - 1. To assess in vivo chemotactic activity of tumour necrosis factor (TNF),
      interleukin-1 (IL-1), IL-8, and cytokine-induced neutrophil chemoattractant
      (CINC), we injected these cytokines into the pleural cavity of rats. 2. CINC (0.1
      1 microgram) and recombinant human IL-8 (rhIL-8, 0.2-5 micrograms) caused
      neutrophil infiltration into the rat pleural cavity in a dose-dependent fashion,
      peaking at 3 h. The number of leukocytes in the peripheral blood did not change
      significantly. 3. RhTNF alpha and rhIL-1 alpha also induced neutrophil
      accumulation. The dose response curves of rhTNF alpha (0.67 ng-6.7 micrograms)
      and rhIL-1 alpha (0.45 ng-4.5 micrograms) at 3 h were bell shaped. On the other
      hand, unlike CINC and rhIL-8, rhTNF alpha and rhIL-1 alpha caused transient
      marked leukopenia at 3 h in a simple dose-dependent fashion. 4. Concomitant
      injection of actinomycin D dose-dependently and completely at 10 micrograms
      inhibited neutrophil infiltration induced by rhTNF alpha (0.67 microgram) and
      rhIL-1 alpha (0.45 microgram) at 3 h. However, that induced by CINC or rhIL-8 was
      not affected by actinomycin D. 5. Peaking at 1 h, CINC production in the pleural
      cavity was found after intrapleural injection of rhTNF alpha (0.67 microgram) or
      rhIL-1 alpha (0.45 microgram), but not after that of rhIL-8 (5 micrograms). The
      CINC production induced by rhTNF alpha or rhIL-1 alpha and the neutrophil
      infiltration was suppressed by concomitant injection of actinomycin D (1 and 10
      micrograms). 6. These results indicate that CINC and IL-8 themselves are direct
      chemoattractants for neutrophils, whereas TNF and IL-1 induce neutrophil
      infiltration indirectly via newly synthesized mRNA for chemotactic protein
      including CINC, which may be involved in neutrophil emigration at local
      inflammatory sites in rats.

PMID- 8646405
TI  - Acetyl-11-keto-beta-boswellic acid (AKBA): structure requirements for binding and
      5-lipoxygenase inhibitory activity.
AB  - 1. 5-Lipoxygenase (5-LOX) products from endogenous arachidonic acid in ionophore
      stimulated peritoneal polymorphonuclear leukocytes (PMNL) and from exogenous
      substrate (20 microM) in 105,000 g supernatants were measured. 2. The effects of
      natural pentacyclic triterpenes and their derivatives on 5-LOX activity were
      compared with the inhibitory action of acetyl-11-keto-beta-boswellic acid (AKBA),
      which has been previously shown to inhibit the 5-LOX by a selective, enzyme
      directed, non-redox and non-competitive mechanism. 3. The 5-LOX inhibitory
      potency of AKBA was only slightly diminished by deacetylation of the acetoxy
      group or reduction of the carboxyl function to alcohol in intact cells (IC50 =
      1.5 vs. 3 and 4.5 microM, respectively) and in the cell-free system (8 vs. 20 and
      45 microM). 4. beta-Boswellic acid (beta-BA), lacking the 11-keto function,
      inhibited 5-LOX only partially and incompletely, whereas the corresponding
      alcohol from beta-BA, as well as amyrin, acetyl-11-keto-amyrin, 11-keto-beta
      boswellic acid methyl ester had no 5-LOX inhibitory activity up to 50 microM in
      either system. 5. beta-BA only partially prevented the AKBA-induced 5-LOX
      inhibition, whereas the non-inhibitory compounds, amyrin and acetyl-11-keto
      amyrin, almost totally antagonized the AKBA effect and shifted the concentration
      inhibition curve for the incomplete inhibitor beta-BA to the right. In contrast,
      the non-inhibitory 11-keto-beta-BA methyl ester exerted no antagonizing effect.
      6. The results demonstrate that the pentacyclic triterpene ring system is crucial
      for binding to the highly selective effector site, whereas functional groups
      (especially the 11-keto function in addition to a hydrophilic group on C4 of ring
      A) are essential for 5-LOX inhibitory activity.

PMID- 8646402
TI  - Release of [3H]-noradrenaline from rat hippocampal synaptosomes by nicotine:
      mediation by different nicotinic receptor subtypes from striatal [3H]-dopamine
      release.
AB  - 1. The aim of the present experiment was to characterize nicotine-evoked [3H]
      noradrenaline ([3H]-NA) release from rat superfused hippocampal synaptosomes,
      using striatal [3H]-dopamine release for comparison. 2. (-)-Nicotine, cytisine,
      DMPP and acetylcholine (ACh) (with esterase inhibitor and muscarinic receptor
      blocker) increased NA release in a concentration-dependent manner (EC50 6.5
      microM, 8.2 microM, 9.3 microM, and 27 microM, respectively) with similar
      efficacy. 3. Nicotine released striatal dopamine more potently than hippocampal
      NA (EC50 0.16 microM vs. 6.5 microM). (+)-Anatoxin-a also increased dopamine more
      potently than NA (EC50 0.05 microM vs. 0.39 microM), and maximal effects were
      similar to those of nicotine. Isoarecolone (10-320 microM) released dopamine more
      effectively than NA but a maximal effect was not reached. (-)-Lobeline (10-320
      microM) evoked dopamine release, but the effect was large and delayed with
      respect to nicotine; NA release was not increased but rather depressed at high
      concentrations of lobeline. High K+ (10 mM) released and NA to similar extents.
      4. Addition of the 5-hydroxytryptamine (5-HT) reuptake blocker, citalopram (1
      microM) to hippocampal synaptosomes affected neither basal NA release nor
      nicotine-evoked release. 5. The nicotinic antagonist, mecamylamine (10 microM),
      virtually abolished NA and dopamine release evoked by high concentrations of
      nicotine, ACh, cytisine, isoarecolone, and anatoxin-a. Although NA release evoked
      by DMPP (100 microM) was entirely mecamylamine-sensitive, DMPP-evoked dopamine
      release was only partially blocked. Dopamine release evoked by lobeline (320
      microM) was completely mecamylamine-insensitive. 6. The nicotinic antagonists
      dihydro-beta-erythroidine and methyllycaconitine inhibited nicotine-evoked
      dopamine release approximately 30 fold more potently than NA release. In
      contrast, the antagonist chlorisondamine, displayed a reverse sensitivity,
      whereas trimetaphan and mecamylamine did not preferentially block either
      response. None of these antagonists, given at a high concentration, significantly
      altered release evoked by high K+. 7. Blockade of nicotine-evoked transmitter
      release by methyllycaconitine and dihydro-beta-erythroidine was surmounted by a
      high concentration of nicotine (100 microM), but blockade by mecamylamine,
      chlorisondamine, and trimetaphan was insurmountable. 8. Nicotine-evoked NA
      release was unaffected by tetrodotoxin, whereas veratridine-evoked NA release was
      virtually abolished. 9. We conclude that presynaptic nicotinic receptors
      associated with striatal dopamine and hippocampal NA terminals differ
      pharmacologically. In situ hybridization studies suggest that nigrostriatal
      dopaminergic neurones express mainly alpha 4, alpha 5, and beta 2 nicotinic
      cholinoceptor subunits, whereas hippocampal-projecting noradrenaline (NA)
      neurones express alpha 3, beta 2 and beta 4 subunits. Pharmacological comparisons
      of recombinant receptors suggest that release of hippocampal NA may be modulated
      by receptors containing alpha 3 and beta 4 subunits.

PMID- 8646406
TI  - Spontaneous rearrangement of aminoalkylisothioureas into mercaptoalkylguanidines,
      a novel class of nitric oxide synthase inhibitors with selectivity towards the
      inducible isoform.
AB  - 1. The generation of nitric oxide (NO) from L-arginine by NO synthases (NOS) can
      be inhibited by guanidines, amidines and S-alkylisothioureas. Unlike most L
      arginine based inhibitors, however, some guanidines and S-alkylisothioureas, in
      particular aminoethylisothiourea (AETU), show selectivity towards the inducible
      isoform (iNOS) over the constitutive isoforms (endothelial, ecNOS and brain
      isoform, bNOS) and so may be of therapeutic benefit. In the present study we have
      investigated the effects of AETU and other aminoalkylisothioureas on the
      activities of iNOS, ecNOS and bNOS. 2. AETU, aminopropylisothiourea (APTU) and
      their derivatives containing alkyl substituents on one of the amidino nitrogens,
      potently inhibit nitrite formation by immunostimulated J774 macrophages (a model
      of iNOS activity) with EC50 values ranging from 6-30 microM (EC50 values for NG
      methyl-L-arginine (L-NMA) and NG-nitro-L-arginine were 159 and > 1000 microM,
      respectively). The inhibitory effects of these aminoalkylisothioureas (AATUs)
      were attentuated by L-arginine in the incubation medium, indicating that these
      agents may complete with L-arginine for its binding site on NOS. 3. The above
      AATUs undergo chemical conversion in neutral or basic solution (pH 7 or above) as
      indicated by (1) the disappearance of AATUs from solution as measured by
      h.p.l.c., (2) the generation of free thiols not previously present and (3) the
      isolation of species (as picrate and flavianate salts) from neutral or basic
      solutions of AATUs that are different from those obtained from acid solutions. 4.
      Mercaptoalkylguanidines (MAGs) were prepared and shown to be potent inhibitors of
      iNOS activity with EC50s comparable to those of their isomeric AATUs. 5. These
      findings suggest that certain AATUs exert their potent inhibitory effects through
      intramolecular rearrangement to mercaptoalkylguanidines (MAGs) at physiological
      pH. Those AATUs not capable of such rearrangement do not exhibit the same degree
      of inhibition of iNOS. 6. In contrast to their potent effects on iNOS, some AATUs
      and MAGs were 20-100 times weaker than NG-methyl-L-arginine and NG-nitro-L
      arginine as inhibitors of ecNOS as assessed by their effects on the conversion of
      L-arginine to L-citrulline in homogenates of bovine endothelial cells and by
      their pressor effects in anaesthetized rats. Thus mercaptoalkylguanidines
      represent a new class of NOS inhibitors with preference towards iNOS. 7. AETU and
      mercaptoethylguanidine (MEG), when given as infusions, gave slight decreases in
      MAP in control rats. However, infusions of AETU or MEG to endotoxin-treated rats
      caused an increase in MAP and restored 80% of the endotoxin-induced fall in MAP.
      8. High doses of MEG (30-60 mg kg-1) caused a decrease in MAP of normal rats.
      This depressor effect may be a consequence of the in vivo oxidation of MEG to the
      disulphide, guanidinoethyldisulphide (GED), which caused pronounced, transient
      hypotensive responses in anaesthetized rats and caused endothelium-independent
      vasodilator responses in precontracted rat aortic rings in vitro. 9. In some
      cases, slight differences were observed in the activities of AATUs and the
      corresponding MAGs. These may be explained by the formation of other species from
      AATUs in physiological media. For example, AETU can give rise to small amounts of
      the potent ecNOS inhibitor, 2-aminothiazoline, in addition to MEG. This may
      account for the differences in the in vitro and in vivo effects of AETU and MEG.
      10. In conclusion, the in vitro and in vivo effects of AETU and related
      aminoalkylisothioureas can be explained in terms of their intramolecular
      rearrangement to generate mercaptoalkylguanidines, a novel class of selective
      inhibitors of iNOS.

PMID- 8646407
TI  - Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic
      and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat.
AB  - 1. The aims of this study were to compare in the rat isolated perfused lung
      preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on
      the hypoxic pulmonary pressure response with or without hypercapnic acidosis and
      to investigate the possible involvement of K channels and EDRF in these effects.
      2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 +
      5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt
      solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce
      hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG
      nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM)
      were used to block KATP channels, KCa channels, EDRF synthesis and guanylate
      cyclase, respectively. 3. Hypoxic pressure response was significantly increased
      by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene
      blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast
      none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4.
      Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic
      pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more
      potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil
      and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast,
      glibenclamide inhibited the relaxant effects of the three drugs during hypoxia +
      hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during
      normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene
      blue inhibited partially the dilator response to pinacidil but did not modify the
      effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat
      isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not
      hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa
      channels are not involved in either case. Nicorandil and pinacidil dilate
      pulmonary vessels mainly through KATP channels but the effects of pinacidil may
      also involve an additional mechanism of action through KCa channels. Finally it
      is suggested that nitroglycerin may partly exert its relaxant effects through
      KATP channels.

PMID- 8646409
TI  - Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with
      imidazenil in rats.
AB  - 1. Development of anticonvulsant tolerance and benzodiazepine (BZD) receptor down
      regulation has been reported to occur upon chronic administration of conventional
      BZDs. We compared the effect of chronic treatment with imidazenil, a new BZD
      partial agonist, and diazepam in rats. 2. After acute administration, imidazenil
      was more potent though less effective than diazepam in protecting from
      bicuculline-induced seizure. The time-course analysis of two peak equieffective
      doses of imidazenil (2.5 mumol kg-1 p.o.) and diazepam (35 mumol kg-1, p.o.)
      showed a longer lasting action of the former drug. 3. The anticonvulsant efficacy
      of diazepam (35 mumol kg-1, p.o.) was reduced in rats given chronic diazepam (35
      mumol kg-1 p.o., 3 times a day for 8-15 days). No tolerance to imidazenil (2.5
      mumol kg-1, p.o.) was apparent after 130-day administration with imidazenil (2.5
      mumol kg-1, p.o., 3 times a day). 4. Plasma levels of imidazenil and diazepam,
      assessed 30 min after administration, were not changed in chronically treated
      animals. 5. In rats made tolerant to diazepam, the maximum number of [3H]
      flumazenil binding sites were reduced in both cerebral cortex (-36%) and
      cerebellum (-42%). No changes in [3H]-flumazenil binding were found in chronic
      imidazenil-treated rats. 6. Specific [3H]-flumazenil binding in vivo was
      decreased in the forebrain of chronic diazepam- but not of chronic imidazenil
      treated animals. 7. These data indicate that imidazenil possesses a very low
      tolerance potential to its anticonvulsant activity and does not affect BZD
      receptor density even after prolonged administration.

PMID- 8646408
TI  - Differences in the operational characteristics of the human recombinant
      somatostatin receptor types, sst1 and sst2, in mouse fibroblast (Ltk-) cells.
AB  - 1. The human recombinant somatostatin (SRIF) receptors, sst1 and sst2, have been
      stably expressed in mouse fibroblast (Ltk-) cells. Two stable clones, LSSR 1/20
      and LSSR 11/13, expressing sst1 and sst2 receptors, respectively, have been used
      to characterize these receptor types using radioligand binding assays as well as
      measurements of changes in extracellular acidification rates using
      microphysiometry. 2. [125I]-[Tyr11]-SRIF bound to sst1 and sst2 receptors
      expressed in Ltk- cells with high affinity, Kd values being 1.52 nM, and 0.23 nM
      respectively. 3. In Ltk- cells expressing sst1 receptors, SRIF, SRIF-28, [D-Trp8]
      SRIF and CGP 23996 all displaced [125I]-[Tyr11]-SRIF binding with high potency
      (IC50 values of 0.43 - 1.27 nM) whilst seglitide, BIM-23027, BIM-23056 and L
      362855 were either weak inhibitors of binding or were ineffective. 4. In contrast
      MK-678 (seglitide) and BIM-23027 were the most potent inhibitors of [125I]
      [Tyr11]-SRIF binding in Ltk- cells expressing sst2 receptors with IC50 values of
      0.014 and 0.035 nM, respectively. 5. SRIF and a number of SRIF agonists,
      including seglitide and BIM-23027, caused concentration-dependent increases in
      extracellular acidification rates in Ltk- cells expressing sst2 receptors but not
      in Ltk- cells expressing sst1 receptors. The maximum increase in acidification
      rate produced by SRIF was 11.3 +/- 0.7% above baseline (0.1-0.28 pH unit min-1).
      The relative potencies of the SRIF agonists examined in causing increases in
      extracellular acidification rates in Ltk- cells expressing sst2 receptors
      correlated well with their relative potencies in inhibiting [125I]-[Tyr11] -SRIF
      binding (r = 0.94). 6. The increase in extracellular acidification produced by
      SRIF was markedly inhibited by pretreatment of cells with pertussis toxin (100 ng
      ml-1) indicating the involvement of pertussis toxin-sensitive G proteins. 7. SRIF
      (1 microM) had no effect on basal cyclic AMP levels in Ltk- cells expressing sst1
      or sst2 receptors nor did it inhibit forskolin stimulated increases in cyclic AMP
      levels in either cell type. 8. The results from the present study describe the
      operational characteristics of human sst2 receptors expressed in Ltk- cells where
      receptor activation causes increases in extracellular acidification rates. This
      receptor is coupled to a pertussis toxin-sensitive G protein. In contrast,
      activation of sst1 receptors, at a similar transfection density, did not cause
      increases in extracellular acidification rates.

PMID- 8646410
TI  - Inhibition of vagally mediated gastric acid secretion by activation of central
      prostanoid EP3 receptors in urethane-anaesthetized rats.
AB  - 1. We studied the effects of intracerebroventricular (i.c.v.) administration of
      prostanoid EP receptor ligands on vagally stimulated gastric acid secretion in
      rats anaesthetized with urethane. 2. Administration of misoprostol (EP3/EP2
      receptor agonist) and sulprostone (EP3/EP1 receptor agonist) reduced vagally
      mediated gastric acid secretion in a dose-dependent manner (0.1, 0.3 and 1.0 nmol
      per animal). Butaprost (EP2 receptor agonist) (0.3 and 3.0 nmol per animal) was
      without effect. 17-Phenyl-omega- trinor PGE2 (EP1/EP3 receptor agonist)
      attenuated vagally mediated gastric acid secretion only at its highest dose (1.0
      nmol per animal); this antisecretory effect was not prevented by pretreatment
      with SC-19220 (selective EP1 receptor antagonist) (20 nmol per animal, i.c.v.).
      3. The potency of these test agents in attenuation of vagally mediated gastric
      acid secretion was as follows: misoprostol > or = sulprostone > > 17-phenyl-omega
      trinor PGE2 > > > butaprost. These results suggest that activation of central
      prostanoid EP3 receptors induces inhibition of vagally mediated gastric acid
      secretion in rats.

PMID- 8646411
TI  - A receptor autoradiographic and in situ hybridization analysis of the
      distribution of the 5-ht7 receptor in rat brain.
AB  - 1. Receptor autoradiography and in situ hybridization histochemistry have been
      used to delineate the distribution of the 5-ht7 receptor and its mRNA in rat
      brain. Receptor autoradiographic studies were performed using [3H]-5
      carboxamidotryptamine (5-CT) as the radioligand. The binding characteristics of
      the masking compounds were determined in Cos-7 cells transfected with a panel of
      5-HT receptor subtype cDNAs, including the rat 5-ht7 cDNA. In situ hybridization
      studies were carried out with 35S-labelled oligonucleotide probes to the rat 5
      ht7 mRNA. 2. Specific binding of [3H]-5-CT was observed in many areas of the rat
      brain. Following co-incubation with 1 microM ergotamine, this binding was
      completely eliminated. After addition of the masking ligands, [3H]-5-CT binding
      remained in layers 1-3 of cortex, septum, globus pallidus, thalamus,
      hypothalamus, centromedial amygdala, substantia nigra, periaquaductal gray, and
      superior colliculus. Addition of the antagonist, methiothepin, to the incubation
      regimen eliminated most of the remaining [3H]-5-CT binding in the brain, with the
      exception of the globus pallidus and substantia nigra. 3. The 5-ht7 mRNA was
      discretely localized in rat brain. The most intense hybridization signals were
      observed over the thalamus, the anterior hippocampal rudiment, and over the CA3
      region of the hippocampus. Other regions containing hybridization signals
      included the septum, the hypothalamus, the centromedial amygdala and the
      periaquaductal gray. The regions exhibiting a modest receptor binding signal
      after methiothepin incubation, the globus pallidus and the substantia nigra,
      contained no 5-ht7 hybridization signals, suggesting a non-5-ht7 subtype in these
      two related structures. 4. The distribution of the 5-ht7 receptor and its mRNA is
      suggestive of multiple roles for this novel 5-HT receptor, within several brain
      systems. The limbic system (centromedial amygdala, anterior hippocampal rudiment,
      hypothalamus) is particularly well-represented, indicating a potential role for
      the 5-ht7 receptor in affective processes.

PMID- 8646412
TI  - Augmentation by eosinophils of gelatinase activity in the airway mucosa:
      comparative effects as a putative mediator of epithelial injury.
AB  - 1. We have studied the release of gelatin-degrading enzymes from isolated sheets
      of bronchial mucosa in the presence and absence of eosinophils. 2. Isolated
      sheets of bovine bronchial mucosa released gelatin-degrading activity in similar
      amounts from both the apical and basolateral aspects of the tissue. Gelatinolytic
      activity could not be increased by treatment of the mucosal sheets with calcium
      ionophore, A23187. 3. The activity of the released gelatinases could be inhibited
      by chelation of divalent cations or by the matrix metalloproteinase inhibitors,
      BB-94 and BB-250. However, inhibitors of serine proteinases, or of cysteine
      proteinases were without effect. In zymography, major bands of gelatin-degrading
      activity consistent with gelatinases A and B were identified. 4. Addition of
      guinea-pig eosinophils to the basolateral aspect of bronchial mucosa for 60 min
      resulted in an increase in the gelatinolytic activity of the conditioned medium,
      irrespective of whether the eosinophils were stimulated with ionophore A23187 or
      not. However, only ionophore-stimulated eosinophils reacted to produce sufficient
      tissue damage to increase the transepithelial flux of serum albumin. 5. Purified
      eosinophils were a poor source of gelatinolytic activity, indicating that when
      interacting with the bronchial mucosa their effect is to increase the apparent
      release and/or activation of gelatinases derived from the airway mucosa. 6. After
      organomercurial activation, recombinant human progelatinase A increased the
      permeability of the bronchial mucosa to mannitol. However, the activity of enzyme
      and duration of exposure required to do this were greater than the amounts of
      gelatinase activity detected during eosinophil-mediated injury. Sheets of airway
      mucosa were also resistant to injury evoked by high concentrations of hydrogen
      peroxide or plasmin. 7. Collectively, these results suggest that if gelatinases
      are involved in eosinophil-mediated injury and repair of the bronchial mucosa,
      they require other mediators to act in concert to bring about outright epithelial
      cell detachment. This does not preclude the possibility that gelatinases are
      crucial in rendering the airway mucosa hyperfragile.

PMID- 8646414
TI  - Development of hyperthermia following intracerebroventricular administration of
      endotoxin in the rat: effect of kinin B1 and B2 receptor antagonists.
AB  - 1. E. coli lipopolysaccharide (LPS) produced a dose-dependent (dose range: 0.02
      150 micrograms) increase in rat core temperature that was maximal 6 h after
      intracerebroventricular (i.c.v.) administration. LPS (200 ng) increased core
      temperature by 1.0 +/- 0.2 degrees C, 6 h following administration, as compared
      to vehicle-treated controls (-0.2 +/- 0.2 degrees C). 2. LPS-induced (200 ng)
      hyperthermia was prevented by co-administration of the bradykinin (BK) B2
      receptor antagonist, Hoe 140 (10 and 30 pmol, i.c.v.) or by indomethacin (10
      nmol, i.c.v.). 3. Systemic administration of Hoe 140 at doses up to 1 mumol kg-1,
      s.c., did not attenuate LPS-induced (200 ng, i.c.v.) hyperthermia. However, LPS
      hyperthermia was significantly reduced by systemic administration of indomethacin
      (1 mumol kg-1, i.v.). 4. Co-administration of the selective B1 receptor
      antagonists, [des-Arg9, Leu8]BK (0.1 - 1 nmol, i.c.v.) or [des-Arg10] Hoe 140
      (0.1 - 1 nmol, i.c.v.), did not prevent LPS-induced hyperthermia. 5. It is
      concluded that the development of hyperthermia following central administration
      of endotoxin requires activation of central, but not peripheral bradykinin B2
      receptors. The formation of kinins within the CNS may be an important initial
      component of CNS inflammation following infection.

PMID- 8646413
TI  - Characterization of metabotropic glutamate receptor-mediated facilitation of N
      methyl-D-aspartate depolarization of neocortical neurones.
AB  - 1. Facilitation of the N-methyl-D-aspartate (NMDA) receptor-mediated
      depolarization of cortical neurones induced by metabotropic glutamate receptor
      (mGluR) agonists in the presence of tetrodotoxin has been examined by use of
      grease-gap recording. 2. Quisqualate (1-2 microM) and 10 to 100 microM 1S,3R-I
      aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) facilitated the NMDA-, but
      not the kainate-induced depolarization with an EC50 of 16 microM for 1S,3R-ACPD.
      The facilitation induced by quisqualate was reduced, but not blocked, by 4 microM
      6-cyano-7-nitroquinoxaline-2,3-dione. 3. D,L-2-Amino-3-phosphonopropionic acid
      and D,L-2-amino-4-phosphonobutyric acid antagonized the 1S,3R-ACPD facilitation
      in a non-competitive manner with IC50 values of 0.24 microM and 4.4 microM
      respectively. 4. Homologous desensitization of the 1S,3R-ACPD induced
      facilitation was not observed. The facilitation was not altered by 10 nM
      staurosporine or 3 microM phorbol diacetate. 5. Substitution of 20 microM 8-bromo
      cyclic adenosine monophosphate, 20 microM 8-bromo-cyclic guanosine monophosphate,
      or 10 microM arachidonic acid for 1S,3R-ACPD did not induce facilitation of the
      NMDA response. However, the 1S,3R-ACPD facilitation was potentiated by 10 mM myo
      inositol and exhibited heterologous desensitization following exposure to 100
      microM 5-hydroxytryptamine. 6. The 1S,3R-ACPD-induced facilitation persisted in
      both 10 microM nifedipine and nominally Ca(2+)-free medium and was only gradually
      eliminated following addition of 100 microM bis-(-o-aminophenoxy)-ethane-N,N,N,N
      tetraacetic acid in Ca(2+)-free medium. Facilitation of the NMDA response induced
      by carbachol, but not phenylephrine, was also observed in nominally Ca(2+)-free
      medium. Perfusing 50 microM bis-(-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid
      aminoethoxy eliminated the 1S,3R-ACPD facilitation. 7. These experiments have
      shown that mGluR agonists selectively facilitate the NMDA depolarization of
      cortical wedges, most likely by activating one or more mGluR subtypes that couple
      to phospholipase C. We conclude the facilitation results from a Ca(2+)-sensitive
      mechanism dependent on activation of phospholipase C and release of internal
      Ca2+. The facilitation is not contingent on activation of protein kinase C or
      entry of Ca2+ through nifedipine-sensitive Ca2+ channels.

PMID- 8646415
TI  - Effects of memantine and MK-801 on NMDA-induced currents in cultured neurones and
      on synaptic transmission and LTP in area CA1 of rat hippocampal slices.
AB  - The effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor
      antagonists, memantine (1-amino-3,5-dimethyladamantane) and MK-801 ((+)-5-methyl
      10,11-dihydro-5H-dibenzocyclo-hepten-5,10-imin e maleate) were compared on
      synaptic transmission and long-term potentiation (LTP) in hippocampal slices and
      on NMDA-induced currents in cultured superior collicular neurones. 2. Memantine
      (10-100 microM) reversibly reduced, but did not abolish, NMDA receptor-mediated
      secondary population spikes recorded in area CA1 of hippocampal slices bathed in
      Mg(2+)-free artificial cerebrospinal fluid. 3. Memantine (100 microM) antagonized
      NMDA receptor-mediated excitatory postsynaptic currents recorded in area CA1 in a
      strongly voltage-dependent manner i.e. depressed to 11 +/- 4% of control at -35
      mV and 95 +/- 5% of control at +40 mV (n = 9), with no apparent effect on
      response kinetics. 4. The effects of MK-801 and memantine on the induction of LTP
      were assessed after prolonged pre-incubations with these antagonists. When
      present for 6.6 +/- 0.4 h prior to tetanic stimulation, memantine blocked the
      induction of LTP with an IC50 of 11.6 +/- 0.53 microM. By comparison, similar
      long pre-incubations with MK-801 (6.4 +/- 0.4 h) blocked the induction of LTP
      with an IC50 of 0.13 +/- 0.02 microM. 5. Memantine and MK-801 reduced NMDA
      induced currents in cultured superior colliculus neurones recorded at -70 mV with
      IC50s of 2.2 +/- 0.2 microM and 0.14 +/- 0.04 microM respectively. The effects of
      memantine were highly voltage-dependent and behaved as though the affinity
      decreased epsilon fold per 50 mV of depolarization (apparent delta = 0.71). In
      contrast, under the conditions used, MK-801 appeared to be much less voltage
      dependent i.e. affinity decreased epsilon fold per 329 mV of depolarization
      (apparent delta = 0.15). 6. Depolarizing steps from -70 mV to +50 mV in the
      continuous presence of memantine (10 microM) caused a rapid relief of blockade of
      NMDA-induced currents from 83.7 +/- 1.9% to 21.8 +/- 1.8% (n = 5). This relief
      was best fitted by a double exponential function (17.2 +/- 11.7 and 698 +/- 204
      ms), the faster component of which was most pronounced. 7. In conclusion, whereas
      MK-801 is equipotent in blocking NMDA-induced currents (at - 70 mV) and the
      induction of LTP, memantine is relatively less potent in blocking the induction
      of LTP. This is due to its rapid relief of blockade upon depolarization; a
      property which might explain its promising clinical profile in the treatment of
      chronic neurodegenerative diseases.

PMID- 8646416
TI  - Effects of PPADS and suramin on contractions and cytoplasmic Ca2+ changes evoked
      by AP4A, ATP and alpha, beta-methylene ATP in guinea-pig urinary bladder.
AB  - 1. The contraction and intracellular Ca2+ change evoked by diadenosine
      tetraphosphate (AP4A) were studied in the outer longitudinal muscle of the guinea
      pig urinary bladder and compared with those evoked by ATP and alpha, beta
      methylene ATP (a P2-purinoceptor agonist). 2. AP4A, ATP and alpha, beta-methylene
      ATP produced concentration-dependent transient contractions. These contractions
      were inhibited by PPADS (pyridoralphosphate-6-azophenyl- 2'-4'-disulphonic acid),
      0.3- 30 microM, a P2x-purinoceptor antagonist, and suramin, 1-300 microM, a P2
      purinoceptor antagonist in a concentration-dependent manner. From Schild plot
      analysis, the apparent pA2 values for PPADS for contractions evoked by AP4A, ATP
      and alpha, beta-methylene ATP were 6.86, 6.56, 6.74, and those for suramin were
      6.01, 4.59 and 5.12, respectively; the Schild slopes for PPADS were 1.07, 1.14
      and 1.06, and, those for suramin 0.75, 1.05 and 1.16, respectively. 3. AP4A (10
      microM) and ATP (100 microM) failed to elicit any contraction of the tissue after
      a desensitization produced by repeated application of alpha, beta-methylene ATP
      (1 microM). 4. In fluorescence experiments with fura-2, the increases in [Ca2+]i
      and contraction evoked by AP4A were suppressed by suramin and nifedipine, an L
      type Ca2+ channel blocker. 5. These findings suggest that P2x-purinoceptors,
      which are more sensitive to PPADS than suramin, exist on the outer longitudinal
      muscles of guinea-pig urinary bladder, and that the AP4A-evoked contraction
      results from Ca2+ influx.

PMID- 8646417
TI  - Comparison of guinea-pig, bovine and rat alpha 1-adrenoceptor subtypes.
AB  - 1. To elucidate a possible role of species differences in the classification of
      alpha 1-adrenoceptor subtypes, we have characterized the alpha 1-adrenoceptors in
      guinea-pig spleen, kidney and cerebral cortex and in bovine cerebral cortex using
      concentration-dependent alkylation by chloroethylclonidine and competitive
      binding with 5-methlurapidil, methoxamine, (+)-niguldipine, noradrenaline,
      oxymetazoline, phentolamine, SDZ NVI-085, tamsulosin and (+)-tamsulosin. Rat
      liver alpha 1B-adrenoceptors were studied for comparison. Chloroethylclonidine
      sensitivity and (+)-niguldipine affinity were also compared at cloned rat and
      bovine alpha 1a-adrenoceptors. 2. Chloroethylclonidine concentration-dependently
      inactivated alpha 1-adrenoceptors in all five tissues. While chloroethylclonidine
      inactivated almost all alpha 1-adrenoceptors in rat liver and guinea-pig kidney
      and brain, 20-30% of alpha 1-adrenoceptors in guinea-pig spleen and bovine brain
      were resistant to alkylation by 10 microM chloroethylclonidine. With regard to
      concentration-dependency guinea-pig kidney and brain were approximately 10 fold
      less sensitive than guinea-pig spleen or rat liver. 3. In rat liver, all drugs
      tested competed for [3H]-prazosin binding with steep and monophasic curves. Drug
      affinities were relatively low and resembled most closely those of cloned rat
      alpha 1b-adrenoceptors. 4. In guinea-pig spleen, all drugs tested competed for
      [3H]-prazosin binding with steep and monophasic curves. Drug affinities were
      relatively low and resembled most closely those of cloned rat alpha 1b
      adrenoceptors. 5. In guinea-pig kidney most drugs tested competed for [3H]
      prazosin binding with steep and monophasic curves and had relatively low drug
      affinities close to those of cloned rat alpha 1b- and alpha 1d-adrenoceptors.
      However, noradrenaline and tamsulosin had consistently biphasic competition
      curves recognizing 36-39% high and 61-64% low affinity sites. 6. In guinea-pig
      cerebral cortex, all drugs tested competed for [3H]-prazosin binding with shallow
      and biphasic curves. While most drugs recognized approximately 25% high affinity
      sites, tamsulosin and noradrenaline recognized approximately 50% high affinity
      sites. Drug affinities at the high and low affinity sites except those for
      tamsulosin and noradrenaline resembled those at cloned alpha 1a- and alpha 1b
      adrenoceptors, respectively. 7. In bovine cerebral cortex all drugs tested except
      for noradrenaline competed for [3H]-prazosin binding with shallow and biphasic
      curves. All drugs recognized approximately 70% high affinity sites. Drug
      affinities at the high and low affinity sites resembled those at cloned alpha 1a-
      and alpha 1b-adrenoceptors, respectively. Noradrenaline competition curves in
      bovine cerebral cortex were steep and monophasic. 8. When cloned rat and bovine
      alpha 1a-adrenoceptors transiently expressed in COS cells were studied in a
      direct side-by-side comparison, both species homologues had similar
      chloroethylclonidine-sensitivity and (+)-niguldipine affinity. 9. We conclude
      that properties of bovine alpha 1A- and alpha 1B-adrenoceptors are very similar
      to those of other species such as rat. alpha 1-Adrenoceptor subtypes in guinea
      pigs resemble alpha 1A- and alpha 1B-adrenoceptors in other species but
      chloroethylclonidine sensitivity and competition binding profiles of
      noradrenaline and tamsulosin are not compatible with previously established alpha
      1-adrenoceptor subtype classification.

PMID- 8646418
TI  - Atypical responses of rat ileum to pindolol, cyanopindolol and iodocyanopindolol.
AB  - 1. Pindolol, cyanopindolol (CYP) and iodocyanopindolol (IodoCYP) have been
      reported to act either as antagonists, agonists or partial agonists at the beta 3
      adrenoceptor in different preparations. A comprehensive investigation has not yet
      been described with these compounds tested in one tissue from one species. This
      study was conducted to delineate the pharmacological effects of pindolol, CYP and
      IodoCYP and to provide data on their affinities at the predominant beta
      adrenoceptor in rat ileum. 2. The beta-adrenoceptors present in rat ileum were
      characterized in the presence of CGP 20712A and ICI 118 551, atropine and
      corticosterone, with (-)-isoprenaline used as an agonist. The role of the beta 1
      and beta 2-adrenoceptors was determined by the omission of either CGP 20712A, ICI
      118 551, or both, from the buffers. Conversely, the effectiveness of the beta 1-
      and beta 2-adrenoceptor blockade was examined by use of the beta 1-adrenoceptor
      selective agonist, RO 363 and the beta 2-adrenoceptor-selective agonist,
      salbutamol. 3. There was no evidence for the presence of functional beta 1
      adrenoceptors, and no strong evidence that beta 2-adrenoceptor stimulation
      contributed to the relaxant effects of (-)-isoprenaline. (-)-Phenylephrine did
      not produce relaxation of the tissue and 5-hydroxytryptamine produced
      contraction. 4. The beta 3-adrenoceptor-selective agonist, BRL 37344 and (-)
      isoprenaline were potent full agonists (pD2 8.35 +/- 0.04 and 7.76 +/- 0.14
      respectively), whereas ICI D7114 was less potent (pseudo pD2 6.92 +/- 0.15).
      These results indicate that the predominant functional beta-adrenoceptors in rat
      ileum are beta 3-adrenoceptors. 5. Partial agonist effects were produced by CYP
      (pD2 5.28 +/- 0.26) and IodoCYP (pD2 7.0 +/- 0.26), but not pindolol. All three
      compounds antagonized the effects of (-)-isoprenaline with pKb values of 6.68 +/-
      0.10, 7.59 +/- 0.07 and 7.59 +/- 0.11 for pindolol, CYP and IodoCYP respectively.
      Likewise, CYP and IodoCYP antagonized the effects of BRL 37344 with pKb values of
      7.20 +/- 0.22 and 7.21 +/- 0.14 respectively. This study provides the first
      functional data on the effects of IodoCYP, the ligand with the highest known
      affinity for the beta 3-adrenoceptor, at the characterized rat ileum beta 3
      adrenoceptor. 6. In conclusion, whereas pKb values suggest that CYP and IodoCYP
      have a similar affinity for the beta 3-adrenoceptor in rat ileum, the higher
      potency of IodoCYP suggests that it promotes a greater coupling efficiency, or
      that its partial agonist effects are produced through a site other than the beta
      3-adrenoceptor. The similar pKb values for CYP and IodoCYP at the beta 3
      adrenoceptor contrast with their order of known affinities at the beta 1- and
      beta 2-adrenoceptors, where IodoCYP is far more potent than CYP. This provides
      evidence of further differences in the characteristics of the beta 3
      adrenoceptors compared to the beta 1- and beta 2-adrenoceptors. Finally, the
      utility of IodoCYP as a beta 3-adrenoceptor antagonist would appear to be limited
      because of the greater magnitude of partial agonist effects that it produces.

PMID- 8646419
TI  - Nitric oxide synthase activity and non-adrenergic non-cholinergic relaxation in
      the rat gastric fundus.
AB  - 1. In the presence of atropine (1 microM) and guanethidine (5 microM), electrical
      field stimulation (EFS, 120 mA, 1 ms, 0.5-16.0 Hz, trains of 2 min) induced
      frequency-dependent relaxations of 5-hydroxytryptamine (3 microM)-precontracted
      longitudinal muscle strips from the rat gastric fundus. 2. L-Citrulline
      concentrations were measured in the incubation medium of precontracted strips
      before and after EFS to investigate nitric-oxide (NO) synthase activity and its
      possible relation to non-adrenergic non-cholinergic (NANC) relaxation. 3. Basal
      NO synthase activity was reflected by the finding of prestimulation levels of L
      citrulline of approximately 30 nM. These levels were unaffected by tetrodotoxin
      (3 microM) and NG-nitro-D-arginine methyl ester (D-NAME, 100 microM), slightly
      reduced by a calcium-free medium and halved by NG-nitro-L-arginine methyl ester
      (L-NAME, 100 microM). 4. EFS evoked significant, frequency-dependent increases in
      bath levels of L-citrulline at all frequencies tested. The increases evoked by 16
      Hz EFS were abolished by tetrodotoxin (3 microM), a calcium-free medium and L
      NAME (100 microM) but not by D-NAME (100 microM). 5. L-NAME (0.1 microM-1.0 mM)
      produced significant reduction of 4-Hz EFS-induced L-citrulline production (100%
      inhibition at 10 microM), but had less marked effects on basal production
      (approximately 50% reduction at 100 microM) and 4-Hz EFS-induced NANC relaxation
      (approximately 50% reduction at 1 mM). 6. L-Arginine (1 mM), but not D-arginine
      (1 mM), increased basal L-citrulline levels and reversed the inhibitory effect of
      L-NAME (10 microM). 7. These findings represent clear biochemical evidence of
      both basal and EFS-stimulated NO synthase activity in the rat gastric fundus.

PMID- 8646420
TI  - Involvement of central 5-HT1A receptors in the reflex activation of pulmonary
      vagal motoneurones by inhaled capsaicin in anaesthetized cats.
AB  - 1. The aim of the present experiments was to determine whether 5-HT1A receptors
      play a role in the control of the reflex activation of pulmonary vagal
      motoneurones. This was carried out by investigating the effects of intracisternal
      injections (i.c.) of the 5-HT1A receptor ligands, 8-OH-DPAT (50 micrograms kg-1),
      buspirone (200 micrograms kg-1), WAY-100635 (100 micrograms kg-1), methiothepin
      (200 micrograms kg-1) and (-)-pindolol (100 micrograms kg-1) and the 5-HT2
      receptor antagonist, cinanserin (200 micrograms kg-1), on the reflex
      bronchoconstriction evoked by inhaled capsaicin aerosol in alpha-chloralose
      anaesthetized, neuromuscularly blocked and artificially ventilated cats.
      Recordings were made of heart rate, blood pressure and upper tracheal pressure.
      2. Central application of all the 5-HT1A receptor antagonists (methiothepin, WAY
      100635 and (-)-pindolol) attenuated the reflex bronchoconstriction in the upper
      trachea. However, the same dose of WAY-100635 given i.v. had no effect on this
      reflex bronchoconstriction. The 5-HT1A receptor agonist, 8-OH-DPAT (50 micrograms
      kg-1) given i.c., potentiated the capsaicin-evoked reflex bronchoconstriction,
      whereas buspirone (200 micrograms kg-1) i.c. had no effect. The 5-HT2 receptor
      antagonist, cinanserin (200 micrograms kg-1) also had no effect. 3. It is
      concluded that the reflex excitation of pulmonary vagal motoneurones by inhaled
      capsaicin in alpha-chloralose anaesthetized cats involves the activation of
      central 5-HT1A receptors.

PMID- 8646422
TI  - Influence of regional differences in ETA and ETB receptor subtype proportions on
      endothelin-1-induced contractions in porcine isolated trachea and bronchus.
AB  - 1. Quantitative autoradiographic studies were conducted to determine the
      distributions and densities of ETA and ETB binding site subtypes in porcine
      tracheal and bronchial smooth muscle. In addition, the roles of ETA and ETB
      receptors in endothelin-1-mediated contraction of these tissues were assessed. 2.
      Quantitative autoradiographic studies revealed that both ETA and ETB binding
      sites for [125I]-endothelin-1 were present in both bronchial and tracheal airway
      smooth muscle. However, the proportions of these sites were markedly different at
      these two levels within the respiratory tract. In tracheal smooth muscle, the
      proportions of ETA and ETB sites were 30 +/- 1% and 70 +/- 1% respectively,
      whereas in bronchial smooth muscle, these proportions were virtually reversed,
      being 73 +/- 2% and 32 +/- 8% respectively. 3. Endothelin-1 induced concentration
      dependent contraction of porcine tracheal and bronchial airway smooth muscle.
      Endothelin-1 had similar potency (concentration producing 30% of the maximum
      carbachol contraction, Cmax) in trachea (22 nM; 95% confidence limits (c.l.), 9
      55 nM; n = 9) and bronchus (22 nM; c.l., 9-55 nM; n = 6). Endothelin-1 also
      produced comparable maximal contractions in trachea (59 +/- 5% Cmax; n = 9) and
      bronchus (65 +/- 4% Cmax, n = 6). 4. In trachea, endothelin-1 induced
      contractions were not significantly inhibited by either the ETA receptor
      selective antagonist, BQ-123 (3 microM) or the ETB receptor-selective antagonist,
      BQ-788 (1 microM). However, in the combined presence of BQ-123 and BQ-788, the
      concentration-effect curve to endothelin-1 was shifted to the right by 3.7 fold
      (n = 8; P = 0.01). 5. In bronchus, concentration-effect curves to endothelin-1
      were shifted to the right by BQ-123 (3 microM; 4.3 fold; P < 0.05), but not by BQ
      788 (1 microM). In the presence of both antagonists, concentration-effect curves
      to endothelin-1 were shifted by at least 6.7 fold (n = 6; P = 0.01). 6.
      Sarafotoxin S6c induced contraction in both tissue types, although the maximum
      contraction was greater in trachea (53 +/- 7% Cmax; n = 6) than in bronchus (21
      +/- 5% Cmax; n = 6). BQ-788 (1 microM) markedly reduced sarafotoxin S6c potency
      in both trachea and bronchus (e.g. by 50 fold in trachea; c.l., 14-180; n = 6; P
      < 0.05). 7. These data demonstrate that the proportions of functional endothelin
      receptor subtypes mediating contraction of airway smooth muscle to endothelin-1,
      vary significantly at different levels in the porcine respiratory tract.

PMID- 8646421
TI  - The distribution and density of receptor subtypes for endothelin-1 in peripheral
      lung of the rat, guinea-pig and pig.
AB  - 1. Quantitative autoradiographic studies were conducted to determine the
      distributions and densities of endothelin-A (ETA) and ETB receptor subtypes in
      peripheral lung alveolar wall tissue of the rat, guinea-pig and pig, with a view
      to assessing the potential suitability of these tissues as models for
      investigations of ET receptor function in human alveolar tissue. 2. High levels
      of specific [125I]-ET-1 binding were detected in peripheral lung components from
      all three species tested. In mature porcine alveolar wall tissue, specific
      binding increased in a time-dependent manner to a plateau, consistent with the
      previously described pseudo-irreversible binding of this ligand to a finite
      population of specific binding sites. 3. [125I]-ET-1 was associated specifically
      with both ETA and ETB binding site subtypes in alveolar wall tissue of foetal pig
      lung as early as 36 days gestation, raising the possibility of a functional role
      for ET-1 in lung development. In addition, both ETA and ETB binding site subtypes
      were detected in alveolar wall tissue and in peripheral airway smooth muscle of
      mature lung parenchyma from all three species. However, the binding subtype
      proportions differed in these tissues. For example, in porcine peripheral
      bronchial smooth muscle, ETA sites apparently predominated, whereas ETB sites
      constituted the major subtype detected in alveolar wall in this species. These
      data suggest significant shifts in ET receptor subtype expression at different
      levels in the respiratory tract. 4. ET binding site subtype proportions in the
      alveolar wall also differed markedly between species. In rat lung alveoli, ETA
      and ETB sites were detected in similar proportions (52 +/- 3% and 43 +/- 5%
      respectively). In contrast, in guinea-pig peripheral lung, ETB binding sites
      clearly predominated, constituting approximately 80% of total specific binding,
      with ETA sites accounting for only 12%. Porcine alveolar wall tissue also
      contained a mixture of these ET receptor subtypes, with ETA and ETB binding
      comprising 23 +/- 3% and 65 +/- 1% respectively of the total population of
      specific binding sites detected. These latter proportions are similar to values
      previously obtained in human peripheral lung tissue, suggesting that porcine lung
      might be a useful model of the human peripheral lung in subsequent studies of the
      functions of these pulmonary ET receptor subtypes.

PMID- 8646423
TI  - Neurochemical and behavioural interactions between ibogaine and nicotine in the
      rat.
AB  - 1. In vivo brain microdialysis has been employed to investigate the effects of
      ibogaine on nicotine-induced changes in dopamine overflow in the nucleus
      accumbens (NAc) of freely moving rats. The effects of the compound on locomotor
      responses to nicotine and behaviour in the elevated plus-maze were also examined.
      2. No changes were observed in the dopamine overflow or the locomotor activity of
      the animals following the administration of ibogaine (40 mg kg-1, i.p.). However,
      ibogaine, administered 22 h earlier, significantly (P < 0.01) attenuated the
      increase in dopamine overflow but not the hyperlocomotion, evoked by nicotine. 3.
      In the elevated plus-maze test, significant reductions in the open:total runway
      entries in both saline-treated controls (P < 0.05) and nicotine-treated (P <
      0.01) rats were obtained when the animals were tested 22 h after pretreatment
      with ibogaine (40 mg kg-1, i.p.). The total activity was significantly (P < 0.01)
      greater in the nicotine-treated rats but this response was not affected by
      ibogaine pretreatment. 4. Administration of ibogaine was associated with
      reductions in the tissue levels of 5-hydroxyindoleacetic acid (5-HIAA) in the NAc
      (P < 0.01) and striatum (P < 0.05) and an increase in the level of this
      metabolite in the medial prefrontal cortex (mPFC) (P < 0.01) while the levels of
      dopamine and 5-hydroxytryptamine (5-HT) in the mPFC were reduced (P < 0.05). The
      DOPAC/dopamine (P < 0.05) and 5-HIAA/5-HT (P < 0.01) ratios were significantly
      increased in the mPFC for at least 7 days after a single treatment with ibogaine.
      5. Ibogaine attenuates the nicotine-induced increases in dopamine overflow in the
      NAc and may, therefore, inhibit the rewarding effects of this drug. However, the
      long lasting anxiogenesis induced by ibogaine warrant further investigation
      before its use could be recommended for smokers.

PMID- 8646424
TI  - Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig
      behaviour and dorsal raphe 5-HT neurone firing.
AB  - 1. The effects of 5-HT1A antagonists on guinea-pig behaviour and dorsal raphe
      neuronal activity were investigated. 2. WAY100135 (10 mg kg-1, s.c.) and
      WAY100635 (1 mg kg-1, s.c.) significantly reduced the behaviours induced by 8
      hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-1, s.c.) indicative of
      post-synaptic 5-HT1A receptor antagonism. WAY100635 (10 mg kg-1, s.c.) alone
      induced ear twitches, which were antagonized by ketanserin (1 mg kg-1, s.c.), but
      no other overt behaviours. 3. WAY100635 (0.125 mg kg-1, i.v.) produced a right
      ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100
      micrograms kg-1, i.v.) but did not affect the maximum inhibition induced by 8
      OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5
      HT1A somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig.
      WAY100635 also produced a dose-related increase in the basal firing of 5-HT
      neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe
      neurones previously inhibited by 8-OHDPAT (10 micrograms kg-1, i.v.). 4. The
      results indicate that WAY100635 is a competitive 5-HT1A antagonist in the guinea
      pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it
      blocks a 5-HT1A receptor-mediated inhibitory tone acting on guinea-pig 5-HT
      neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated
      behaviours.

PMID- 8646425
TI  - Effect of NG-nitro-L-arginine methylester (L-NAME) on functional and biochemical
      alpha 1-adrenoceptor-mediated responses in rat blood vessels.
AB  - 1. The modulation by NG-nitro-L-arginine methylester (L-NAME) of alpha 1
      adrenoceptor-mediated contraction was investigated on isolated segments of rat
      tail artery and aorta. The influence of L-NAME on inositol phosphates
      accumulation by alpha 1-adrenoceptor agonists was also investigated to elucidate
      the intracellular mechanism responsible for this modulation. 2. In aorta but not
      in tail artery L-NAME (30 microM) enhanced the sensitivity (3.3 times) and the
      maximum contraction (Emax) induced by the full agonist, phenylephrine. 3. St-587,
      a partial alpha 1-adrenoceptor agonist, behaved as a weak agonist in the aorta
      (22.2% of phenylephrine Emax). However, when the same agonist was studied in tail
      artery rings a maximum contraction that was 78.4% of the phenylephrine induced
      Emax was reached. 4. L-NAME increased (3.3 times) the Emax for St-587 contraction
      in the aorta but not in the tail artery. Sensitivity to St-587 was slightly but
      significantly (P < 0.001) enhanced (1.9 times) by L-NAME in tail artery segments.
      5. Contractile responses to phenylephrine after partial alkylation with
      phenoxybenzamine were analyzed by the nested hyperbolic null method. To elicit
      50% of Emax for contraction only 1.1% of the receptors in the tail artery and 21%
      of the receptors in the aorta need to be occupied. These results indicate a
      higher receptor reserve for the tail artery than the aorta. 6. In the tail artery
      but not in the aorta, St-587 activates phosphoinositide turnover. The presence of
      L-NAME was without effect on inositol phosphates accumulation induced by this
      partial alpha 1-adrenoceptor agonist. 7. The maximum contraction induced by
      phenylephrine, after partial alpha-adrenoceptor alkylation, was enhanced by L
      NAME in tail artery rings. However, the NO synthase inhibitor was unable to
      modify the phenylephrine-induced accumulation of inositol phosphates in the
      presence of phenoxybenzamine. 8. These results indicate that the differences in
      St-587-induced contraction and the modulation by L-NAME of alpha 1-adrenoceptor
      mediated contraction observed between the tail artery and aorta are associated
      with differences in receptor reserve. In addition, our biochemical studies
      indicate that the potentiating effect of L-NAME is independent of intracellular
      calcium release via phosphatidylinositol turnover.

PMID- 8646427
TI  - Methotrexate in rheumatoid arthritis: toxicity issues.

PMID- 8646426
TI  - Comparative effects of PACAP and VIP on pancreatic endocrine secretions and
      vascular resistance in rat.
AB  - 1. The effects of pituitary adenylate cyclase-activating polypeptide (PACAP),
      vasoactive intestinal peptide (VIP) and secretin on pancreatic endocrine
      secretions and vascular resistance were investigated and compared in the isolated
      perfused pancreas of the rat. The PACAP/VIP receptor types involved have been
      characterized. 2. On insulin secretion, in the range 10(-11) to 10(-8) M, PACAP
      and VIP elicited a concentration-dependent biphasic response from pancreas
      perfused with 8.3 mM glucose; the peptides were equipotent. In contrast, secretin
      was ineffective in the range 10(-11) to 10(-9) M; at 10(-8) and 10(-7) M, it
      induced only low and transient insulin responses. On the other hand, the peptides
      did not modify the basal insulin release in the presence of a non stimulating
      glucose concentration (2.8 mM). 3. On glucagon secretion, PACAP and VIP (10(-11)
      to 10(-8) M) but also secretin (10(-9) to 10(-7) M) caused a concentration
      dependent peak shaped response from pancreas perfused with 2.8 mM glucose; PACAP
      and VIP were equipotent and 20 times more potent then secretin. On the other
      hand, the peptides did not affect the glucagon release in the presence of 8.3 mM
      glucose. 4. On pancreatic vessels, in the range 10(-11) to 10(-9) M, the three
      peptides were equipotent in inducing a concentration-dependent sustained increase
      in pancreatic flow rate. On the other hand, at the high concentration of 10(-7) M
      PACAP but not VIP provoked a transient decrease of flow rate. 5. This study
      provides evidence for PACAP/VIP type II receptors mediating insulin and glucagon
      secretion as well as vasodilatation in rat pancreas. In addition, the different
      efficacies of secretin suggest that these effects are mediated by different
      PACAP/VIP type II receptor subtypes.

PMID- 8646428
TI  - Why does an inflammation in the joint hurt?

PMID- 8646429
TI  - Increased expression of the Ed-B-containing fibronectin (an embryonic isoform of
      fibronectin) in human osteoarthritic cartilage.
AB  - Fibronectin is non-collagenous protein which accumulates in osteoarthritic
      cartilage. The presence of fibronectin and its specific isoform containing the B
      sequence, Ed-B fibronectin (B.Fn), was studied in normal and osteoarthritic human
      cartilage using immunohistochemical and biochemical assays, with a specific
      monoclonal antibody. Results showed substantial amounts of B.Fn in osteoarthritic
      cartilage, especially in the superficial and middle layers. Western blot analysis
      confirmed the presence of B.Fn with a molecular mass of 220 and 55 kDa. In
      contrast, in normal cartilage, expression of B.Fn was extremely low. In
      conclusion, the expression of a specific isoform of fibronectin during the
      osteoarthritic process suggests that this isoform might have specific functions
      in extracellular matrix remodelling.

PMID- 8646430
TI  - Difference in expression of the plasminogen activation system in synovial tissue
      of patients with rheumatoid arthritis and osteoarthritis.
AB  - Proteolytic joint destruction in inflammatory and non-inflammatory arthropathy is
      believed to be mediated, at least in part, by the plasminogen activation (PA)
      system. To further investigate possible involvement of the PA system, we
      quantified immunoreactive urokinase-type plasminogen activator (u-PA), tissue
      type plasminogen activator (t-PA), both plasminogen activator inhibitors (PAI-1
      and PAI-2) and u-PA-receptor (u-PAR) in synovial tissue extracts of 14 patients
      with rheumatoid arthritis (RA) and 12 with osteoarthritis (OA). u-PA, PAI-1, PAI
      2 and u-PAR concentrations were significantly higher in RA than in OA patients. t
      PA antigen levels were significantly lower in RA than in OA synovial tissue
      extracts. Immunohistochemistry was performed to compare the distribution and
      staining intensity of these components in samples of RA and OA synovial tissue.
      Intense immunostaining of u-PA, u-PAR, PAI-1 and, to a lesser degree, PAI-2 was
      observed predominantly in the synovial lining of RA patients. In OA patients, u
      PA, PAI-1, PAI-2 and u-PAR were barely detectable. t-PA immunostaining was
      restricted to the endothelial side of vascular walls in both groups. We conclude
      that the observed increase of u-PA, u-PAR and PAI expression, distributed mainly
      in the synovial lining area of proliferative and invasively growing synovial
      tissue in RA patients, supports a pathogenic role for the PA system in
      destructive arthritis. Depressed t-PA-mediated plasminogen activation might
      contribute to delayed intra-articular fibrin removal.

PMID- 8646431
TI  - Monocyte activity in Behcet's disease.
AB  - Monocytes obtained from patients with Behcet's disease (BD) were examined for
      differentiation markers (expression of CD14 and antigens reacting with monoclonal
      antibodies 25F9 and G16/1) and for expression of selected adhesion molecules.
      There was significantly raised expression of the CD14 molecule, and increased
      staining with 25F9 and G16/1 antibodies in monocytes obtained from patients with
      BD. A monocyte activation marker, soluble CD14, was also found to be raised in
      patients' serum compared with normal serum (8.1 +/- 9.2 vs 1.4 +/- 0.7
      micrograms/ml). Furthermore, BD patients' monocyte culture supernatants caused
      significantly increased adhesion of normal neutrophils to endothelial cell
      monolayers in vitro. All these findings show that BD patients' monocytes are
      active in vivo and produce a number of pro-inflammatory cytokines which may play
      a role in the chronic inflammation found in these patients.

PMID- 8646432
TI  - Expression of the multidrug resistance glycoprotein 170 in the peripheral blood
      lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes
      expressing glycoprotein 170 is increased in patients treated with prednisolone.
AB  - The objective was to evaluate the expression of the multidrug resistance P
      glycoprotein (P-gp) in peripheral blood lymphocytes (PBL) of patients with
      rheumatoid arthritis (RA). PBL from 68 RA patients and 44 controls were
      evaluated. RA patients had a mean disease duration of 10.7 yr, with a mean number
      of past resistances to DMARDs of 0.82, and were treated with NSAIDs (n = 34),
      DMARDs (n = 25) and prednisolone (n = 40). Fluorescence flow cytometry was used
      to assess P-gp membrane expression on PBL. In the RA group, the percentage of PBL
      expressing P-gp was higher in patients treated with prednisolone than in other
      patients [mean +/- S.D.: 10.7 +/- 15.8% vs 3.3 +/- 7.6%, P < 0.03, Student] and
      was not related to other therapies, age, sex, RA duration, number of past
      resistances to DMARDs, activity, ESR, CRP. The percentage of PBL expressing P-gp
      did not differ in RA and control groups, but was higher in the prednisolone
      treated RA patients than in controls. Prednisolone could induce a rise in the
      percentage of PBL expressing P-gp. On the contrary, patients with a high
      percentage of PBL expressing P-gp could be more resistant to DMARDs and need
      prednisolone earlier. Further studies are needed to address this question and to
      evaluate the potential implication of P-gp in drug resistance in RA.

PMID- 8646433
TI  - Endogenous opioid tone in patients with rheumatoid arthritis.
AB  - We have previously shown that there is deficient hypothalamic-pituitary-adrenal
      (HPA) responsiveness in rheumatoid arthritis (RA) patients. The basis for this
      deficient response is not known. The purpose of the project was to investigate
      whether the defective HPA response in RA patients is the result of increased
      endogenous opioid tone secondary to chronic pain which can suppress
      corticotrophin-releasing hormone (CRH) production. We conducted a double-blind
      placebo-controlled cross-over trial to study the effect of the opiate antagonist,
      naloxone, on psychometric function together with plasma adrenocorticotrophic
      hormone (ACTH), cortisol and prolactin. Seven RA patients with active and
      established disease and eight healthy controls were studied. Each received either
      a bolus i.v. infusion of 20 mg naloxone or normal saline. After at least 72 h,
      they received naloxone if they had previously received normal saline or vice
      versa. The pain score was statistically significantly higher at baseline in the
      RA group compared with controls (5.7 +/- 3.25 vs 0.35 +/- 0.21, P < 0.001). No
      difference was found in the other psychometric assessments throughout the study.
      Patients receiving normal saline did not show any significant change in cortisol
      or ACTH. Cortisol and ACTH showed a sharp and significant rise after naloxone
      treatment in both RA and normal subjects (P < 0.001 and P < 0.01), but no
      difference was observed between the two groups. The mean prolactin level showed
      no significant change in both groups after any treatment. We conclude that
      endogenous opioid tone does not appear to be a major contributor to the HPA
      defect in RA. However, the number of patients studied was small and this result
      will require confirmation from larger trials.

PMID- 8646434
TI  - Occurrence of pulmonary complications during methotrexate therapy in rheumatoid
      arthritis.
AB  - Treatment with methotrexate (MTX) in rheumatoid arthritis (RA) can lead to severe
      side-effects, especially pulmonary and haematological complications. The aim of
      this retrospective study was to evaluate, during a 6 yr period, the prevalence
      and severity of bronchopulmonary side-effects in RA patients treated with MTX. A
      cohort of 130 RA in-patients (106 women, 24 men) treated with MTX was studied for
      the occurrence of respiratory adverse events. Adverse bronchopulmonary side
      effects were observed in 12 patients (two men, 10 women), with a mean disease
      duration of 15 yr. Only three patients had previously suffered from pulmonary
      disease. MTX treatment duration was between 1 month and 4.5 yr. The diagnosis was
      that of hypersensitivity pneumonitis (HSP) in four cases, non-HSP pneumonitis in
      five patients with one case of Pneumocystis carinii infection, and bronchitis in
      three cases. The initial respiratory symptoms were not discriminatory between the
      different conditions. Risk factors were not identified for the occurrence of HSP.
      HSP always occurred in the first 5 months of treatment. Two patients with HSP
      died, and another patient with opportunistic infection underwent tracheostomy.
      HSP represents a potentially lethal side-effect in RA patients treated with MTX.
      Improved education of patients and physicians should certainly lead to a
      reduction of both the prevalence and severity of pulmonary side-effects during
      MTX therapy in RA.

PMID- 8646435
TI  - Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: a
      longitudinal study.
AB  - Lung volumes and gas exchange were investigated prospectively in 96 patients with
      rheumatoid arthritis selected without regard to pulmonary disorders and treated
      with i.m. methotrexate (MTX) injections [mean weekly dose 13.0 mg (5th-95th
      percentile (5-95 PC) 7.6-20.8)]. Individual changes over time during MTX
      treatment [mean duration 2.9 yr (5-95 PC 0.4-5.3)] were assessed by regression
      analyses in each individual. Forced vital capacity (FVC) remained stable in the
      majority of patients [mean annual change +0.8% (5-95 PC -8.1 to +14.0) of
      calculated normal value]. In addition, transfer factor using the indicator gas CO
      (TL,CO) was unaltered in most patients [mean annual change -2.1% (5-95 PC -16.2
      to +11.8) of predicted value]. However, there were significant decreases in the
      forced expiratory volume in 1 s (FEV1) before and after inhalation of 0.2 mg
      salbutamol [mean annual change -0.8% (5-95 PC -8.4 to +3.2) and -1.3% (5-95 PC 
      7.8 to +3.9) of the FVC measured, respectively]. In addition, there were
      significant increases in alveolar-arterial Po2 gradients (P(A-a),O2) at rest and
      after exercise [mean annual change +1.7 mmHg (5-95 PC -5.2 to +12.2) and +1.8
      mmHg (5-95 PC -3.5 to 9.0), respectively]. Nevertheless, the amounts were small
      in view of the reliability of the methods applied and reflect, at least in part,
      the normal process of ageing. The annual change in FEV1/FVC was negatively
      correlated with FEV1/FVC at baseline (Rs = -0.46, P < 0.001). The annual change
      in TL,CO was also negatively correlated with TL,CO at baseline (Rs = -0.31, P =
      0.028). No other risk factors for deterioration of lung volumes or gas exchange
      were found, including mean weekly MTX dose, age, gender, smoking, presence of
      rheumatoid factor and pulmonary function at baseline. We conclude that MTX has no
      major effect on pulmonary function in the majority of patients and that there is
      no evidence that patients with pre-existing pulmonary disease are at increased
      risk for further deterioration of lung function.

PMID- 8646437
TI  - Reversible ovulatory failure associated with the development of luteinized
      unruptured follicles in women with inflammatory arthritis taking non-steroidal
      anti-inflammatory drugs.
AB  - The case histories of three young women with ankylosing spondylitis, rheumatoid
      arthritis and a seronegative inflammatory polyarthritis undergoing investigations
      for infertility are presented. In each, non-steroidal anti-inflammatory drug
      (NSAID) therapy was associated with the recurrent development of luteinized
      unruptured ovarian follicles and normal ovulation following drug withdrawal. It
      is suggested that NSAID therapy may be an important and frequently overlooked
      cause of anovulation and infertility.

PMID- 8646436
TI  - Effect of age on the efficacy and tolerance of methotrexate in rheumatoid
      arthritis.
AB  - The objective of this study was to assess the influence of age on the efficacy
      and toxicity of methotrexate in rheumatoid arthritis. Four hundred and sixty-nine
      patients were separated according to the age of onset of methotrexate treatment:
      before 65 yr (group 1, n = 416) and after 65 yr (group 2, n = 53). No difference
      was found in the evolution of clinical and biological parameters between the two
      groups. The number of patients in remission at the end of the study was equal.
      The frequency and type of side-effects were similar. No significant difference
      was found in the frequency and reasons for methotrexate withdrawal. We noted a
      trend towards lower therapeutic maintenance of methotrexate when prescribed after
      the age of 65 yr (P = 0.07, actuarial method). In conclusion, the age at
      initiation of methotrexate treatment probably did not influence its efficacy and
      toxicity in rheumatoid arthritis.

PMID- 8646438
TI  - Arthroscopic synovectomy in rheumatoid and psoriatic knee joint synovitis: long
      term outcome.
AB  - A long-term prospective study was performed to evaluate the safety and long-term
      outcome of surgical arthroscopy (AS) for persistent rheumatoid (RA) and psoriatic
      (PsA) knee joint synovitis (KJS). Local signs of joint inflammation (tenderness,
      swelling, "ballottement') and range of motion (ROM) were scored and the sum,
      taken as a global outcome measure, was recorded in 17 RA and 18 PsA knees, both
      before and at follow-up periods of 2, 6, 12, 24 and 36 months after surgical AS
      (knee joint synovectomy; meniscal curettage, cartilage shaving or chondrectomy,
      according to the degree of cartilage damage). A survival analysis (Kaplan-Meier)
      of the long-term outcome of surgical AS treatment and of the predictive value of
      clinical parameters of knee joint involvement was also performed. No intra- or
      post-operative morbidity, pain worsening or loss of joint motion was observed and
      all patients were discharged within 48 h. Comparison of the parameters of knee
      joint evaluation showed a significant reduction of the signs of joint
      inflammation and a significant increase in the ROM in all follow-up periods. At
      36 months, the survival curves showed a 61.2% cumulative probability of clinical
      remission and 72.8% of definite improvement. No significant differences in the
      prognostic importance of RA, compared to PsA diagnosis, were observed, although
      higher percentages of PsA compared to RA knees (86.3% and 45.7% respectively)
      reached the end point of clinical remission at 36 months. KJS duration,
      radiographic severity and cartilage damage were not predictors of poor long-term
      outcome of AS synovectomy. Surgical AS treatment for PsA knees with more advanced
      cartilage damage gave a better long-term outcome. A total of 50.7% of operated
      knees reached the end point of a KJS relapse at 36 months, the majority (82%)
      within the initial 18 months of follow-up. Our study indicates that AS
      synovectomy is a safe procedure requiring short hospitalization which, in
      combination with second-line medical treatment, can reduce local inflammation in
      RA and PsA KJS, and preserve knee joint ROM for up to 3 yr.

PMID- 8646439
TI  - 'Seronegative' Sjogren's syndrome manifested as a subset of chronic fatigue
      syndrome.
AB  - We determined the extent to which chronic fatigue syndrome (CFS) patients with
      sicca symptoms fulfil the diagnostic criteria for Sjogren's syndrome (SS). Three
      sets of diagnostic criteria for SS, formulated by the Japanese, Europeans and
      Fox, were used. One-third of the CFS patients with sicca symptoms fulfilled the
      diagnostic criteria for SS. However, they were 'seronegative', differing from the
      ordinary primary SS.

PMID- 8646441
TI  - Changing patterns of rheumatology manpower and practice in the UK in the 1990s.
AB  - This paper reports the results of two surveys of all UK rheumatologists conducted
      in 1993 and 1995. Results are presented by regional health authority and by
      country. During the 2 yr, there has been a rise in the number of consultants, but
      a fall in the proportion doing rheumatology combined with rehabilitation.
      Consultants are working harder-doing more clinics and seeing more patients.
      Regional disparities in service provision persist, but are slowly diminishing. On
      the whole, the south of the country is better provided with consultants, but has
      fewer in-patient facilities, while the reverse is true in the north.

PMID- 8646440
TI  - A randomized clinical trial of in-patient multidisciplinary treatment versus
      routine out-patient care in active rheumatoid arthritis.
AB  - The aim of the present study was to compare the effects of in-patient
      multidisciplinary treatment with standard out-patient care in patients with
      active rheumatoid arthritis (RA). Eighty patients with active RA were randomized
      to receive 11 days of in-patient multidisciplinary treatment followed by standard
      out-patient care (n = 39), or to standard out-patient care only (n = 41).
      Patients were assessed at baseline, and after 2, 4, 12 and 52 weeks. In the in
      patients, the improvement in variables of disease activity (weeks 2 and 4) and
      emotional status (weeks 4 and 12) was greater when compared with the out-patients
      (P < 0.05). The improvement in laboratory and functional measures did not differ
      between the groups. In the in-patient group, the percentage of patients
      responding to the American College of Rheumatology criteria for improvement was
      significantly greater at any time point during follow-up than in the out-patient
      group. A short period of in-patient multidisciplinary treatment for active RA has
      a direct beneficial effect on disease activity and emotional status with the
      favourable effect on disease activity remaining after 52 weeks.

PMID- 8646442
TI  - Current trends in Finnish rheumatology.

PMID- 8646443
TI  - Search for infective agents in undifferentiated oligoarthritis in Papua New
      Guinea.

PMID- 8646444
TI  - Combination therapy with sulphasalazine and azathioprine.

PMID- 8646445
TI  - Health economics as an aspect of health outcome: basic principles and application
      in rheumatoid arthritis.

PMID- 8646446
TI  - Parvovirus B19 in rheumatoid arthritis: comment on the article by Kerr et al.

PMID- 8646447
TI  - A case of Zieve's syndrome presenting with myalgia: not to be confused with
      polymyalgia rheumatica.

PMID- 8646448
TI  - Polymyalgia rheumatica as the rheumatological manifestation of myelodysplastic
      syndrome in a Chinese patient.

PMID- 8646449
TI  - [Prognostication of disability caused by occupational diseases].
AB  - The article shows that prophylaxis of occupational disability depends on many
      official departments. Priority in prophylaxis of occupational disability should
      include safe work conditions. Better medical prophylaxis of occupational diseases
      necessitates creation of occupational medical service in Russia. Examination of
      ability to work and rational placement of the disabled people could be
      effectively performed with establishment of special commissions including medical
      experts and occupational officials. Planning, forecasting and control of
      disability prophylaxis require objective and complete information on variety of
      subjects--creation of universal informational service based on up-to-date
      computers. That could consider all influencing factors and apply mathematical
      models to forecasting of primary occupational disability and contingent of the
      disabled people.

PMID- 8646450
TI  - [State of peripheral blood of technical personnel exposed to constant magnetic
      fields].
AB  - The authors demonstrated that workers servicing calutrons (electromagnetic
      isotope separators) are exposed to direct-current field with high magnetic flux
      density (the values near the circuit reaching 0.175 T). The examinees with longer
      length of service (and exposure to the magnetic fields) tended to have more
      structural disorders in peripheral leukocytes.

PMID- 8646451
TI  - [Effects of an impulse magnetic field on lipid peroxidation and the antioxidant
      system of the testes in animal experiments].
AB  - The study covered influence of impulse magnetic field on lipid peroxidation and
      antioxidant defence in seminal tissue of rats. Monthly exposure to the impulse
      magnetic field (intensity of 30 kA/m; impulse frequency of 2.5 and 25 kHz)
      activated initial, intermediate and final stages of lipid peroxidation, increased
      non-enzymatic (ascorbic acid) defence systems and depressed the enzymatic
      (glutathione peroxidase, catalase) ones. The aftereffects included changes in the
      lipid peroxidation and in levels of antioxidant factors in the seminal tissue.

PMID- 8646452
TI  - [Mortality of personnel operating electric power objects with 500 kV voltage].
AB  - The retrospective cohort study covered causes and mortality levels among the
      staffers working at 6 objects of power supply line (voltage of 500 kV) in
      Vladimir, Gorky, Rjazan, Ulyanovsk and Lipetsk regions. The mortality in general
      and concerning specific causes demonstrated no increase in connection with
      exposure to industrial electromagnetic fields. The relative risk of mortality
      with leukemia appeared to be insignificantly higher.

PMID- 8646453
TI  - [A method of rapid evaluation of conditions of verbal communication in noisy
      industrial surroundings].
AB  - The article deals with creation of an express method using nomograms to evaluate
      conditions of verbal communication in noisy industrial compartments. Experimental
      creation of the nomogram requires alternate impulsive and constant noise. The
      method enables to forecast results of verbal understanding in noisy industrial
      conditions.

PMID- 8646454
TI  - [Several functional and diagnostic criteria in the evaluation of the state of the
      neuromuscular function of arms of workers exposed to the effects of local
      vibration].
AB  - The authors studied neuromuscular apparatus of hands in workers subjected to
      local vibration and in patients having vibration disease (VB). If compared to
      apparently healthy individuals both exposed to vibration or not, the VB patients
      proved lower muscular durability (MD) of hands, higher oxyproline excretion (OB)
      and greater MD/OB ratio. The studied parameters (MD, OB, MD/OB) in the VB
      patients turned out to be similar in the VB patients and the healthy examinees
      having initially low MD (under 29 s). The suggested criteria were recommended for
      early diagnosis of neuromuscular disturbances in hands and for occupational
      selection.

PMID- 8646455
TI  - [Effects of piracetam on occupationally significant functions of patients with
      arterial hypertension working under conditions of psychoemotional stress].
AB  - The study covered influence of Piracetam on occupationally important functions of
      memory and attention in hypertensive patients exposed to psychoemotional stress
      at work. The medicine appeared to improve psychic state, mental performance and
      the occupationally important function of memory, causing no effects on the
      attention. Besides hypotensive effect the medicine resulted in better clinical
      and physiologic parameters and increased physical performance.

PMID- 8646456
TI  - [Genetic screening for risk factors in the development of respiratory diseases
      caused by fiberglass dust].
AB  - The article represents results of genetic screening among workers engaged into
      fiber glass production. Propensity and resistance to occupational pulmonary
      diseases were believed to depend on genotype. Applied methods of genetic
      screening enabled to improve primary prophylaxis of respiratory diseases.

PMID- 8646457
TI  - [Effects of antioxidant state on individual susceptibility to silicosis (an
      experimental study)].
AB  - The authors proved that animals having higher natural antioxidant activity and
      lower intensity of lipid peroxidation are more resistant to fibrogenic effects of
      quartz. The peritoneal macrophages obtained from those animals show higher
      resistance to quartz exposure "in vitro". Parameters characterizing antioxidant
      system should be included into a group of indexes describing propensity to
      silicosis.

PMID- 8646458
TI  - [Antimicrobial means for individual protection used by medical personnel in
      emergency situations].
AB  - For protection of medical staff from infections during emergencies, the authors
      recommend individual antimicrobial means--medical gowns and special suits
      protecting skin against extremely dangerous causal agents, surgical masks and
      individual means with autonomous air supply for lower intake of bacteria.

PMID- 8646459
TI  - [Lipid peroxidation and antioxidant system in neurovascular disorders among
      poultry farm workers].
AB  - The article represents materials describing examination of 540 workers engaged
      into mass poultry farming and characterizing the risk factors of neurovascular
      disorders. The authors identified the disorders' peculiarities of prevalence and
      pathogenetic mechanisms associated with lipid peroxidation and activity of
      antioxidant defence system.

PMID- 8646460
TI  - [Specific source of the entry of polluting substances into living
      accommodations].
AB  - The article considers a specific source of pollutants entering living
      compartments. Carrying pollutants on clothes, shoes, hair, the workers could
      result in intensive pollution of the living area. Increased accumulation of the
      pollutants occur therefore in the family members and cause various illnesses.

PMID- 8646461
TI  - [Morphometric parameters of peripheral blood erythrocytes in patients with
      vibration disease].

PMID- 8646462
TI  - [Characteristics of the state of the autonomic nervous system in miners with heat
      injuries].

PMID- 8646463
TI  - [Changes in the functional state of the visual analyzer during work at video
      display terminals of graphic images].
AB  - The examination covered female operators of sewing pickup, engaged into the work
      at video-displays. The total work load appeared to equal 77.6% and the work at
      video-display--75.2% of the shift time. Functional state of the vision
      demonstrated a decrease even after 2 hrs of the work, then stabilized by midpoint
      of the shift and afterwards lowered by 10-12 hrs of the work. Those objective
      changes correlated with the sensation of orbital discomfort. The findings served
      as a base for prophylaxis to restore the performance during the regulated breaks.

PMID- 8646464
TI  - [Chromatic lighting and parametric indicators in the short-sighted subjected to
      visual strain].
AB  - Stability of achromatic vision in regular and chromatic (590 nm) light was
      examined in 10 myopic (1.0-4.0 diopters) patients. The parameters for chromatic
      light were better than for the regular one, especially after the visual load of
      correction by means of Landolt rings for half an hour.

PMID- 8646465
TI  - Local anesthetics.
AB  - BACKGROUND: Dermatology is dependent upon the effects of local anesthetics for
      diagnostic and therapeutic interventions. A working knowledge of the drugs'
      actions and interactions is necessary for anyone aspiring to optimize the
      benefits derived from the use of local anesthetic agents. OBJECTIVE: This article
      reviews nerve physiology, pharmacology, classification of local anesthetics,
      adverse reactions (toxic, drug, allergic), local anesthetic use in pregnancy,
      alternatives to the "-caine" anesthetics, methods for reducing the pain of
      infiltration, and new agents under development. CONCLUSION: Local anesthetics are
      safe and effective. With the understanding of the actions and interactions of
      this class of drugs, maximum patient safety and satisfaction can be achieved.

PMID- 8646466
TI  - Hydrogen peroxide inhibits human keratinocyte migration.
AB  - BACKGROUND: Reepithelialization is an important component of wound healing. In
      the first 48 hours keratinocyte migration and proliferation are important events
      in this process. Although the literature agrees that the risk/benefit of
      antiseptics has not been established, hydrogen peroxide is still commonly used in
      the management of acute and chronic wounds. OBJECTIVE: The purpose of this study
      was to evaluate the effect of hydrogen peroxide on human keratinocyte migration
      and proliferative potential. METHODS: The viability and proliferative potential
      of human keratinocytes in the presence of hydrogen peroxide was assessed by
      trypan blue exclusion, cell morphology, substratum attachment, and thymidine
      incorporation. Using concentrations of hydrogen peroxide that do not affect
      keratinocyte viability, keratinocyte migration was evaluated by a standard
      motility assay. RESULTS: Hydrogen peroxide in concentrations < or = 700 microM
      was found to have no effect on keratinocyte viability. At these low
      concentrations, however, hydrogen peroxide had a profound inhibitory effect upon
      keratinocyte migration on extracellular matrix and decreased the proliferative
      potential of the cells in a concentration-dependent fashion. CONCLUSION: Hydrogen
      peroxide, in very low concentrations (1000-fold less than the "everyday use"
      dilution) inhibits keratinocyte migration and proliferation.

PMID- 8646467
TI  - Dermatofibrosarcoma protuberans treated with Mohs micrographic surgery: cure
      rates and surgical margins.
AB  - BACKGROUND: Dermatofibrosarcoma protuberans is an uncommon malignant tumor of the
      skin with a frequent tendency to recur after standard surgical excision. This
      study assesses the degree of subclinical tumor extension and evaluates the cure
      rate and tissue conservation abilities of Mohs micrographic surgery. METHODS:
      Twenty-four patients with dermatofibrosarcoma protuberans underwent Mohs
      micrographic surgery. Surgical margins and clinical outcome were evaluated and
      compared with the results of standard surgical treatment in the medical
      literature. RESULTS: Twenty-six Mohs micrographic surgical procedures were
      performed on 24 patients. Eighty-five percent of the procedures were
      microscopically cleared with 2.5-cm margins, 69% with 2.0-cm margins, 50% with
      1.5-cm margins, and 35% with 1.0-cm margins. Two tumors would have been
      inadequately excised if standard 3-cm had been used. The assessment of tissue
      conservation revealed a mean of 43.0 cm(2) of tissue spared in a subset of seven
      tumors in functionally or cosmetically critical locations. Two tumors were
      recurrent following MMS and are detailed as case reports. CONCLUSION: The
      variability of subclinical tumor extension in dermatofibrosarcoma protuberans is
      confirmed. The ability of Mohs micrographic surgery to minimize surgical margins,
      preserve cosmetically and functionally vital tissue, and yield high cure rates is
      confirmed.

PMID- 8646468
TI  - Duplicitous growth of infiltrative basal cell carcinoma: Analysis of clinically
      undetected tumor extent in a paired case-control study.
AB  - BACKGROUND: Many clinicians believe infiltrative basal cell carcinoma (BCC) is a
      more difficult tumor to eradicate than nodular BCC because the growth of
      infiltrative BCC is not easy to detect clinically. However, data supporting this
      observation are largely anecdotal. OBJECTIVE: Our purpose was to show that
      infiltrative BCC have wider and deeper tumor extensions than nodular BCC of
      similar clinical size. METHODS: In this retrospective study, 139 cases of
      infiltrative BCC excised by Mohs micrographic surgery (MMS) were matched to a
      control group of 139 cases of nodular BCC similarly excised. They were paired by
      site, size, number of recurrences, age, gender, and previous treatment type. The
      cases were selected and paired by computer from 1197 consecutive BCC (primary and
      recurrent) referred for MMS over a 5-year period. MMS technique allowed us to
      quantitate the extent of tumor spread using three measurements: the number of
      surgical stages required for complete removal of tumor, the width of tissue
      required to remove subclinical extension of tumor, and the depth of defect at
      completion of MMS. RESULTS: Analysis showed the infiltrative BCC was more
      difficult to detect and to eradicate than the nodular BCC. The number of surgical
      stages required for complete removal of tumor, the width of tissue required to
      remove subclinical extension of tumor, and the depth of defect at completion of
      MMS were all greater with infiltrative BCC when compared with nodular BCC
      regardless of whether cases were primary or recurrent. These differences were all
      statistically significant. CONCLUSION: Infiltrative BCC can be significantly more
      destructive than nodular BCC because tumor extension is difficult to detect
      clinically. Clinicians should treat infiltrative BCC with its potential for
      convert invasion in mind.

PMID- 8646469
TI  - Caomparison of two high-energy, pulsed carbon dioxide lasers in the treatment of
      periorbital rhytides.
AB  - BACKGROUND: Carbon dioxide (CO2) laser technology has expanded over the past 20
      years from the production of precise excisional and cutting instruments to the
      recent development of high-energy, pulsed systems that allow for controlled
      tissue vaporization. These newest lasers permit removal of thin layers of skin
      with minimal damage to normal adjacent skin structures. The precise and
      reproducible nature of tissue destruction has led to a resurgence of interest in
      cutaneous resurfacing. OBJECTIVE: To compare the clinical effectiveness, side
      effect profile, and postoperative course of two different high-energy, pulsed CO2
      lasers (ultrapulse and surgipulse) in the treatment of periorbital rhytides.
      METHODS: Ten patients with moderate to severe periorbital rhytides received laser
      treatment using the surgipulse CO2 laser on one side and the ultrapulse CO2 laser
      on the opposite periorbital region. Equivalent laser parameters and treatment
      conditions were used with both systems. Sequential clinical analyses were
      performed independently by two blinded assessors. In addition, optical
      profilometry measurements of silicone rubber skin surface casts were obtained
      before and after laser irradiation to determine skin texture changes. RESULTS:
      There was a 63% average clinical improvement of periorbital rhytides following
      surgipulse laser treatment and a mean improvement of 82% after ultrapulse laser
      irradiation. Skin surface texture in all laser-treated rhytides approximated
      those found in normal skin. An increased number of laser passes were required
      using the surgipulse system to effect the same clinical endpoints as the
      ultrapulse system. CONCLUSION: While both the surgipulse and ultrapulse high
      energy CO2 laser systems can effectively improve periorbital rhytides, the
      ultrapulse system provides a slightly enhanced clinical response with fewer
      passes, presumably due to improved tissue vaporization.

PMID- 8646470
TI  - An intraoperative skin-stretching device to close wounds in Mohs defects.
AB  - BACKGROUND: A skin-stretching device takes advantage of the viscoelastic
      properties of the skin by exerting incremental traction to aid in closing complex
      wounds. OBJECTIVE: To evaluate the effectiveness of a skin-stretching device and
      determine the cosmetic results available when this device is used in Mohs
      surgery. METHODS: We applied a skin-stretching device to seven patients, each of
      whom had a large, complex wound defect following Mohs surgery. All of the
      patients had basal cell carcinomas. In one patient the carcinoma was on an upper
      extremity, and in the others the carcinoma was located on broad facial surfaces,
      including the temple and forehead. RESULTS: Complete primary closure was
      accomplished in six patients. A maximum of three cycles of tissue stretching were
      applied during the period of tissue processing between Mohs layers. In one
      patient the defect was reduced in size by more than 75%, with final healing by
      secondary intention. In two patients minor complications developed: focal wound
      dehiscence occurred in one patient and in the second patient, an inconsequential
      hypertropic scar developed. In both cases, the problems resolved with acceptable
      cosmetic results. The remaining patients experienced no complications and the
      cosmetic results were excellent. CONCLUSION: The skin-stretching device
      accomplishes effective primary closure of large skin defects by dramatically
      reducing the size of the defect. It allows a simpler closure where a full
      thickness graft or local flap would have otherwise been utilized. The device is
      convenient to use with minimal complications, reduces operative time, and aids
      greatly in preserving tissue integrity.

PMID- 8646471
TI  - An evaluation of the copper-bromide laser for treating telangiectasia.
AB  - BACKGROUND: Copper bromide lasers, producing pulsed yellow and green light, have
      been developed for treating cutaneous lesions. OBJECTIVE: A clinical trial was
      conducted to evaluate the role of this laser, using its yellow wavelength, to
      treat benign vascular ectasia and establish some clinical guidelines for therapy.
      METHODS: Twenty-three informed consenting adults with facial telangiectasia,
      spider angiomas, or vascular nevi on the head, neck, or upper chest were treated
      with the laser. Assessment of results was performed by: blinded clinical
      evaluation, blinded comparison of "before" and "after" photographs, and patients'
      own reports of satisfaction levels. RESULTS: Good to excellent results were
      obtained in most patients, except for a few suffering minor skin atrophy where
      very large vessels were treated. CONCLUSIONS: The copper bromide laser was an
      effective tool in the treatment of certain cutaneous vascular lesions.

PMID- 8646472
TI  - Dermabrasion is an effective treatment for acquired bilateral nevus of Ota-like
      macules.
AB  - BACKGROUND: Dermal pigmented lesion, or acquired bilateral nevus of Ota-like
      macules, is a common entity in Asian skin. There are no established data
      supporting the safety, effectiveness, and cosmesis of its treatment. The lesions
      do not respond to bleaching or peeling agents. OBJECTIVE: To search for a means
      of treatment that is cost effective, safe, and yields a good cosmetic result. If
      possible, these requirement should be accomplished within one session. METHODS:
      Three hundred and twenty patients who presented themselves with acquired
      bilateral nevus of Ota-like macules were included in the study. Area dermabrasion
      using a hand engine with a coarse diamond fraise was performed in every case.
      RESULTS: Three hundred and twenty patients (97%) achieved 100% clearance of the
      pigment. In the remaining 10 patients (3%) there was 5% residual pigment. The
      wound healed with excellent cosmesis, and without changing skin texture.
      CONCLUSION: Dermabrasion is an excellent modality for the treatment of acquired
      nevus of Ota-like macules.

PMID- 8646473
TI  - Mechanical properties of skin and liposuction.
AB  - BACKGROUND: Liposuction removes fat, setting the skin under tension, and could
      therefore alter the overall viscoelastic properties of the teguments. OBJECTIVE:
      To measure in vivo the mechanical properties of skin at the site of liposuction
      and to compare the viscoelastic values with those of the inner aspect of the
      forearms. METHODS: The Cutometer SEM 474 equipped with a 8-mm probe was used.
      RESULTS: Data show that cutaneous laxity, which is characteristic for an aging
      aspect, is not higher at the liposuction sites than on the reference area.
      CONCLUSION: Liposuction does not increase the clinical aspects of skin aging.

PMID- 8646475
TI  - Dermabrasion in xeroderma pigmentosum.
AB  - BACKGROUND: Dermabrasion is one choice of treatment for patients with severe
      actinic damage. OBJECTIVE: To report the youngest xeroderma pigmentosum patient
      ot have received the benefits of this procedure. METHODS: The dermabrasion was
      performed under general anesthesia using an acrotorque hand engine. RESULTS: New
      tumor formation was reduced for several months after the treatment. CONCLUSION:
      Dermabrasion can be considered as another therapeutic choice for young xeroderma
      pigmentosum patients with severe actinic damage.

PMID- 8646474
TI  - Prevention of earlobe keloid recurrence with postoperative corticosteroid
      injections versus radiation therapy: a randomized, prospective study and review
      of the literature.
AB  - BACKGROUND: Simple excision of earlobe keloids can result in recurrence rates
      approaching 80%. Many modalities have been suggested to reduce the risk of
      recurrence postoperatively, including intralesional steroids and radiotherapy.
      OBJECTIVE: In order to determine the most reliable method to prevent keloid
      recurrence, we have conducted the first randomized, prospective trial comparing
      corticosteroid injections versus radiation therapy. RESULTS: Thirty-one keloids
      were treated and followed for a minimum of 12.0 months. Two of 16 keloids (12.5%)
      recurred after surgery and radiation therapy, while 4 of 12 (33%) recurred after
      surgery and steroid injections. No alteration of skin pigmentation, wound
      dehiscence, chronic dermatitis, or neoplastic changes was observed in any patient
      in either group. Although a statistically significant difference was not
      observed, radiotherapy appeared to be more effective than steroid injections in
      preventing keloid recurrence. CONCLUSIONS: Radiotherapy is a simpler treatment
      modality with better patient compliance, and patients were much more likely to
      complete treatment than with corticosteroid injections. We believe that
      radiotherapy can play an important role in the prevention of earlobe keloid
      recurrences, and that with current techniques, complications can be minimized.
      Further randomized study with additional patients is needed to compare the
      effectiveness of corticosteroid injections and radiotherapy in preventing keloid
      recurrence.

PMID- 8646476
TI  - Research versus regulation: striking a balance.

PMID- 8646477
TI  - The biology and application of human bone marrow stromal cell precursors.
AB  - The importance of the stromal tissue of the bone marrow in regulating hemopoiesis
      is well documented. However, several features of marrow stromal cell biology
      remain poorly understood, in particular, the ontogeny and phylogeny of the
      various stromal elements that comprise the microenvironment of the bone marrow.
      In this article we review recent data concerning the immunophenotype and
      functional characteristics of precursor cells for marrow stromal tissue. The
      study of these stromal precursor cells (SPC) represents an exciting new field of
      research that will almost certainly expand in the future as we gain a greater
      understanding of the cellular and molecular events, environmental cues, and
      growth factors that physiologically regulate the commitment and subsequent
      development of SPC. Although the field of marrow SPC biology is in its infancy,
      we predict that future studies will result in several novel clinical applications
      for SPC. We, therefore, conclude this article by speculating on a number of these
      potential applications and, thus, view SPC and their progeny as likely vehicles
      for several novel and important cellular therapies, including gene therapy.

PMID- 8646478
TI  - Culture of purified stem cells from fetal liver results in loss of in vivo
      repopulating potential.
AB  - The development of in vitro conditions that promote a numerical expansion of
      hematopoietic stem cells (HSCs) with long-term reconstituting ability has been a
      long-standing goal in experimental hematology. In previous studies, we showed
      that input numbers of such cells, i.e., competitive repopulating units (CRU),
      could be maintained for 2 weeks when purified Sca-1 + Lin-WGA + adult bone marrow
      (BM) cells were cultured in serum-free and stromal cell-free cultures containing
      Steel factor (SF), interleukin 6 (IL-6), and erythropoietin (Epo). In separate
      studies, we showed that limiting numbers of purified fetal liver (FL) cells that
      are highly enriched for CRU display a higher proliferative and self-renewal
      potential in vivo compared with similar cells purified from adult BM. These
      findings prompted us to explore the possibility of achieving a numerical
      expansion of purified FL cells in culture. Although we observed an extensive
      increase in the number of nucleated FL cells in all culture conditions tested,
      none of the cultures, including cultures in serum-containing medium and
      cocultures on a preestablished feeder layer of BM stromal cells of S17 cells,
      sustained the expected expansion or even supported the maintenance of input
      numbers of FL CRU. Single cell cultures showed that the production of nucleated
      cells by purified Sca-1 ++ Lin.-AA4.1 + FL cells stayed behind that of purified
      Sca-1 + Lin-WGA + adult BM cells. Taken together, our results show that a variety
      of culture conditions tested, including conditions that support maintenance and
      limited expansion of adult BM CRU do not support the production of repopulating
      stem cells from FL. Because such expansion can be observed in vivo, this system
      appears useful to search for novel culture conditions and-perhaps yet
      unidentified-cytokines or other microenvironment-related factors that may be
      required for FL CRU to prevent loss of repopulation potential in vitro and allow
      these cells to exhibit their expected self-renewal potential.

PMID- 8646479
TI  - Dysregulation of cytokines during graft-versus-host disease.
AB  - Graft-versus-host disease (GVHD) remains a major complication following
      allogeneic stem cell transplantation. It is mediated by alloreactive donor T
      cells recognizing histocompatibility antigens of the host, and ex vivo depletion
      of these cells from the graft has been used as prophylaxis. This, however,
      carries increased risk of graft rejection, disease relapse, and impaired immune
      reconstitution. It now appears that GVHD may be primarily mediated by cytokines.
      A three-step hypothesis for the involvement of cytokines in the pathophysiology
      of acute and chronic GVHD is presented, with emphasis on the role of Th1 and Th2
      T cell subsets.

PMID- 8646480
TI  - A combination of CD34 selection and complement-mediated immunopurging (anti-CD15
      monoclonal antibody) eliminates tumor cells while sparing normal progenitor
      cells.
AB  - Autologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML) in
      first complete remission (CR) results in a prolonged disease-free survival (DFS)
      of 34%-57%. Relapse of the underlying disease is the major cause for failure of
      ABMT. Relapse can result fom tumor cells either surviving in the patient or
      reinfused in the autograft. Genetic marking of autografted cells has demonstrated
      that transplanted cells contribute to relapse. This finding supports the use of
      purged autografts. Several purging techniques have been used. Immunologic purging
      using the monoclonal antibody (mAb) PM-81 (anti-CD15) has been used by our center
      with a long-term DFS in 50% of AML patients. PM-81 reacts with 90% of AML
      patients, and we have used it for over 10 years. We have investigated a two-stage
      purging technique involving initial selection for CD34+ cells followed by mAb
      purging in bone marrow (BM) and peripheral blood stem cell (PBSC) harvests. This
      method achieved up to a 7 log diminution in leukemic cells and 1-4 log reduction
      in CD15+ cells, without a significant loss of hematopoietic progenitor cells.
      This double-purging technique has the advantages of cytoreduction, elimination of
      CD34- leukemic cells, and possible improvement in the clinical efficacy of
      purging by concentrating for CD34+ cells. Cytoreduction by CD34 enrichment
      followed by purging may facilitate the use of PBSC transplants in AML.

PMID- 8646481
TI  - Lymphokine-activated killer cells can discriminate CD34+ leukemia cells from
      normal hematopoietic progenitor cells.
AB  - The ability of lymphokine-activated killer (LAK) cells to discriminate between
      CD34+ leukemia cells and hematopoietic progenitor cells was investigated. As
      effector cells, CD4(-)-LAK generated from a CD4- subset of allogeneic peripheral
      blood lymphocytes were used. The target cell samples were obtained from
      peripheral blood stem cell (PBSC) collections. Detection of residual tumor cells
      was performed using a polymerase chain reaction (PCR) technique for chimeric
      bcr/abl messenger RNA. When PBSC were obtained from patients with seminoma and
      lung cancer, treated with the CD4(-)-LAK for 12 h and the CD34+ cells were
      isolated, colony formation (CFU-GM) by these cells was preserved. When PBSC were
      obtained from a patient with PCR-positive acute lymphocytic leukemia and treated
      with the CD4(-)-LAK for 3 h, reexamination showed conversion to PCR negativity.
      Furthermore, when the CD34+ cells isolated from the negative converted PBSC were
      cultured, they still exhibited colony formation. These results suggest that the
      CD4(-)-LAK can kill the CD34+ leukemia cells, discriminating from the normal
      hematopoietic progenitors.

PMID- 8646482
TI  - A comparison of immunohistochemistry, two-color immunofluorescence, and flow
      cytometry with cell sorting for the detection of micrometastatic breast cancer in
      the bone marrow.
AB  - A significant percentage of women with primary breast cancer have micrometastatic
      disease in the bone marrow. Bone marrow involvement may be an adverse prognostic
      factor, and more aggressive therapy may be indicated for these patients. There
      are a number of different techniques and antibodies used to detect tumor cells in
      the bone marrow. We used the same panels of four antibreast cancer antibodies and
      compared three immunodetection techniques: two-color immunofluorescence,
      immunohistochemical staining, and fluorescence-activated cell sorting with
      cytologic examination of the sorted cells. The two-color immunofluorescence
      technique was superior and consistently detected one tumor cell contaminating one
      million normal bone marrow cells and had no reactivity with normal bone marrow.

PMID- 8646483
TI  - G-CSF-induced mobilization of peripheral blood stem cells from healthy adults for
      allogeneic transplantation.
AB  - We investigated a dose-escalation effect of G-CSF (5, 10, and 15 micrograms/kg)
      on mobilization of committed and primitive hemopoietic progenitor cells,
      including CFU-GM, BFU-E, and long-term culture-initiating cells (LTC-IC) in
      addition to CD34+ cells and yields of progenitor cells in PBSC harvests obtained
      by leukapheresis of healthy adult donors. Results indicate that the mobilization
      of these progenitor cells is both dose and time dependent. Despite the very small
      number of healthy donors studied, it is estimated from our data that a sufficient
      number of CD34+ cells for allogeneic PBSC transplant (PBSCT) could be collected
      using a 5 day administration of 10 micrograms/kg of G-CSF to normal adult donors.
      Adverse effects include general fatigue and bone pain in most of the donors and
      fever and headache in some. These symptoms were well tolerated in most instances.
      Laboratory test abnormalities, including transient thrombocytopenia, increased
      platelet aggregation, and increased serum levels of some liver enzymes, were
      induced by G-CSF administration, but all were reversible within a short time.
      These observations suggest that hemopoietic stem cells for allogeneic PBSCT can
      be mobilized by short-term administration of a relatively high-dose G-CSF.

PMID- 8646484
TI  - High cellular concentration of peripheral blood progenitor cells during
      cryopreservation adversely affects CFU-GM but not hematopoietic recovery.
AB  - The effects of bone marrow (BM) and peripheral blood progenitor (PBPC)
      concentration during cryopreservation on subsequent hematopoietic engraftment
      following high-dose chemotherapy were studied in 24 patients. Seventeen BM
      harvests and 71 PBPC collections were performed between July 1991 and June 1994.
      The PBPC were frozen at significantly higher cellular concentrations than the BM
      (medians of 243 x 10(6)/ml versus 73 x 10(6)/ml respectively, p = 0.0003). The
      recovery of committed progenitor cell colonies (CFU-GM) was significantly lower
      from PBPC frozen at concentrations above the median, compared with 116% from
      those frozen at concentrations below the median (p = 0.0467). This phenomenon was
      not seen in BM, which was generally frozen at a threefold lower concentrations.
      Despite the lower recovery of CFU-GM when PBPC were frozen at a higher
      concentration, the patients receiving these grafts achieved good hematopoietic
      recovery. The higher number of PBPC probably compensated for the loss, and the
      patients still received a substantial number of clonogenic hematopoietic
      precursors.

PMID- 8646485
TI  - Early drop in protein C and antithrombin III is a predictor for the development
      of venoocclusive disease in patients undergoing hematopoietic stem cell
      transplantation.
AB  - Venoocclusive disease (VOD) of the liver remains one of the major obstacles for
      patients undergoing high-dose chemotherapy and hematopoietic stem cell
      transplantation (HSCT). Many factors have been associated with the development of
      VOD, including a hypercoagulable state secondary to a drop in protein C and
      antithrombin III (AT III). We conducted a prospective nonrandomized trial to try
      to determine whether the development of clinical VOD was associated with a drop
      in protein C, protein S, and AT III. A total of 42 patients undergoing high-dose
      chemotherapy and HSCT were enrolled in this study. Eleven patients underwent
      allogeneic bone marrow transplantation (BMT) following high-dose cyclophosphamide
      and fractionated total body irradiation (TBI). Thirty-one patients received
      autologous stem cell rescue following different preparative regimens.
      Measurements of protein C, protein S, and AT III levels were obtained prior to
      conditioning therapy and weekly thereafter for 2-3 weeks. A significant
      difference was noted in the mean levels of protein C on day 7 between those who
      developed VOD and those who did not (57.5 versus 72.1, p = 0.009). Similarly,
      there was a significant difference in the mean levels of AT III on days 7 and 14
      between the two groups (day 7, 95.5 versus 80.6, p = 0.002; day 14, 99.6 versus
      85.2, p = 0.01). The drop in protein S levels on days 7 and 14 was not
      statistically significant between the two groups. In conclusion, the degree of
      drop in protein C and AT III levels on day 7 was predictive for the development
      and severity of VOD.

PMID- 8646486
TI  - An Equiratio Mixture Model for non-additive components: a case study for
      aspartame/acesulfame-K mixtures.
AB  - The Equiratio Mixture Model predicts the psychophysical function for an equiratio
      mixture type on the basis of the psychophysical functions for the unmixed
      components. The model reliably estimates the sweetness of mixtures of sugars and
      sugar-alcohols, but is unable to predict intensity for aspartame/sucrose
      mixtures. In this paper, the sweetness of aspartame/acesulfame-K mixtures in
      aqueous and acidic solutions is investigated. These two intensive sweeteners
      probably do not comply with the model's original assumption of sensory dependency
      among components. However, they reveal how the Equiratio Mixture Model could be
      modified to describe and predict mixture functions for non-additive substances.
      To predict equiratio functions for all similar tasting substances, a new
      Equiratio Mixture Model should yield accurate predictions for components
      eliciting similar intensities at widely differing concentration levels, and for
      substances exhibiting hypo- or hyperadditivity. In addition, it should be able to
      correct violations of Stevens's power law. These three problems are resolved in a
      model that uses equi-intense units as the measure of physical concentration. An
      interaction index in the formula for the constant accounts for the degree of
      interaction between mixture components. Deviations from the power law are
      corrected by a nonlinear response output transformation, assuming a two-stage
      model of psychophysical judgment.

PMID- 8646487
TI  - Lotus lectin labels subpopulation of olfactory receptor cells.
AB  - Experiments were performed to test the hypothesis that subsets of olfactory
      receptor cells could be recognized based on their lectin binding and that mapping
      of their projections onto the olfactory bulb would reveal details of anatomic
      organization of the olfactory nerve projection to the olfactory bulb. The results
      from one lectin, Lotus, were examined in detail. Olfactory receptor cells in the
      lateral part of the main epithelium were labeled, as well as scattered cells in
      the remainder of the epithelium. Glomeruli labeled by Lotus were concentrated
      primarily in the region of the olfactory bulb that receives its input from the
      lateral epithelium, although scattered glomeruli could be identified in other
      regions. Within the terminal field of these axons there was a mosaic pattern,
      with some glomeruli densely labeled, some lightly labeled and others unlabeled.
      These findings support the notion that there are biochemically distinct
      populations of olfactory receptor cells having localized distributions in the
      epithelium, with axons that coalesce to terminate in specific glomeruli, rather
      than diffusely over their projection field.

PMID- 8646488
TI  - A model for pheromone discrimination in the insect antennal lobe: investigation
      of the role of neuronal response pattern complexity.
AB  - Based on anatomical and physiological data pertaining to several moth species and
      the cockroach, we propose a neural model for pheromone discrimination in the
      insect antennal lobe. The model exploits the variety of neuronal response
      patterns observed in the macroglomerulus, and predicts how these complex patterns
      of excitation and inhibition can participate in the discrimination of the species
      specific pheromone blend. The model also allows us to investigate the
      relationship between the distribution of observed response patterns and the
      neural organization from which these patterns emerge.

PMID- 8646489
TI  - Recalling taste intensities in sweetened and salted liquids.
AB  - The effect of training on recalling taste intensities over 6 weeks was studied
      using an ad libitum mixing procedure. Subjects tasted sweet and salty standards
      labeled as "weak' and "strong' (3 and 8% sucrose in redcurrant juice; 0.4 and
      1.2% NaCl in beef broth). They subsequently mixed unsweetened and sweetened
      juice, and unsalted and salted broth, to produce taste intensities that
      corresponded to the standards. A minimum training (MT) group (n = 13) produced
      comparison stimuli by tasting and directly comparing with standards in one
      session only; an extensive training (ET) group (n = 13) did this in six sessions
      before producing comparison stimuli based on memory only at 1 h, 1 day, 1 week
      and 6 weeks. An upward bias (chemically determined concentrations of comparison
      stimuli exceeding those of standards) occurred at 1 day or 1 week in MT subjects
      for 'weak' and 'strong' sweetness, and for 'strong' saltiness, and sustained
      thereafter. The upward tendency was also observed in ET subjects but was
      significant only for 'strong' sweetness. It is important to recognize memory
      effects such as the one described, as they affect food perceptions and can be a
      major source of bias in sensory food research.

PMID- 8646490
TI  - Switch and bait: probing the discriminative basis of odor identification via
      recognition memory.
AB  - When people misidentify everyday odors, as they often do, their errors may
      conceivably lie in faulty perceptions or in faulty access to the names.
      Discussions of the matter usually focus on the latter, as if people had no
      problems with perceptual accuracy. (The problem of faulty access may get
      attention because its high subjective impact makes it particularly memorable,
      when it does occur.) However, studies have demonstrated breakdowns in ability to
      discriminate quality, from which it follows that people will misidentify items
      through perceptual confusions. Furthermore, misidentifications often contain
      considerable information about the identities of items, as if people simply did
      not perceive the items accurately, but perhaps fuzzily or with some perceptual
      bias. Recognition memory, with a 2-day interval between inspection and test,
      provided a vehicle to address two questions on this topic: (i) Would people
      notice that we had switched items and had presented for recognition items that
      matched their misidentifications rather than the original items inspected? (ii)
      Would people not only fall for the false bait, but actually identify the switched
      items correctly, and thereby imply that they were 'tuned' to perceive those
      odors? People commonly failed to notice the switches, i.e. took the bait and
      commonly identified the switched items with veridical names. Although subject to
      further study, the outcome suggests that when people give such names as garlic
      for vinegar, orange for lime, soy sauce for molasses and many others, the errors
      often lie largely at a perceptual stage of processing, i.e. at input rather than
      output.

PMID- 8646491
TI  - Taste responses to binary mixtures of amino acids in the sea catfish, Arius
      felis.
AB  - In vivo electrophysiological recordings in the sea catfish, Arius felis, showed
      that the magnitude of the integrated facial taste responses to binary mixtures of
      amino acids was predictable with knowledge obtained from previous cross
      adaptation studies of the relative independence of the respective binding sites
      of the component stimuli. Each component from which equal aliquots were drawn to
      form the mixtures was adjusted in concentration to provide for approximately
      equal response magnitudes. The magnitude of the taste responses to binary
      mixtures whose component amino acids showed minimal cross-adaptation was
      significantly greater than that to binary mixtures whose components exhibited
      considerable cross-reactivity. There was no evidence for mixture suppression. The
      relative magnitude of the taste responses in the sea catfish to stimulus mixtures
      is similar to that previously reported for olfactory receptor responses in the
      freshwater channel catfish and chorda tympani taste responses in the hamster.

PMID- 8646492
TI  - Effects of calmodulin antisense oligonucleotides on chemoresponse in Paramecium.
AB  - The calcium/calmodulin-regulated Ca-ATPase of the plasma membrane is implicated
      in Paramecium chemosensory transduction. Calmodulin antisense oligonucleotides
      electroporated into Paramecium disrupt chemosensory responses to sodium acetate
      but not to ammonium chloride.

PMID- 8646493
TI  - Analysis of concentration-response relationship for enhanced sugar responses of
      the chorda tympani nerve in the diabetic db/db mouse.
AB  - Chorda tympani responses to sugars were greater in diabetic (db/db) than in non
      diabetic control mice. A kinetic analysis suggested that the greater sugar
      responses in db/db mice were unlikely due to the increased number of sugar
      receptors.

PMID- 8646494
TI  - A quantitative study of the enhancing effect of nickel ions on the taste response
      to sodium ions of single fibers of the frog glossopharyngeal nerve: competitive
      inhibition by calcium ions of the nickel-enhanced response to sodium ions.
AB  - Single water fibers of the frog glossopharyngeal nerve respond to relatively high
      concentrations of NaCl ( > 80 mM). NiCl2 at 1 mM enhanced the Na+ response and
      reduced the threshold concentration for NaCl to 20 mM. CaCl2 at 0.5-1 mM induced
      an inhibition of the Ni2+ -enhanced response to Na+ ions. A quantitative
      explanations for these results is provided by the hypothesis that Ni2+ ions
      secondarily affect a sodium receptor or channel (designated XNa*) that is
      responsible for the Na+ response and that Ca2+ ions inhibit the Ni2+ -enhanced
      response to Na+ ions by competing with Na+ ions for XNa*. Double-reciprocal plots
      of the experimental data indicate that the affinity of XNa* for both Na+ ions
      (agonist) and Ca2+ ions (competitive antagonist) in the presence of 1 mM NiCl2
      was five times higher than the previously reported values obtained in the absence
      of NiCl2 (Kitada, 1991). Ni2+ ions at 1 mM enhanced the maximal response to Na+
      ions by 190%. It appears that a sodium receptor (or channel) interacts with a
      Ni2+ -binding element that is affected by Ni2+ ions and, thus, Ni2+ ions can
      induce both an increase in the affinity of the sodium receptor for the respective
      cations and an enhancement of the Na+ response.

PMID- 8646495
TI  - Loss of olfactory function leads to a decrease of trigeminal sensitivity.
AB  - Healthy controls were compared to patients with decreased olfactory sensitivity
      (n = 32) to investigate interactions between the olfactory and trigeminal
      systems. Amplitudes of chemo-somatosensory event-related potentials in response
      to suprathreshold trigeminal stimuli (CO2) were found to be smaller in patients
      (P < 0.05) indicating a decrease of trigeminally mediated sensations.

PMID- 8646496
TI  - Cervical mediastinoscopy.
AB  - The continuity of cervicomediastinal fascial planes provides the anatomic basis
      for cervical mediastinoscopy and its derivatives. There are two such planes, both
      accessible through a single small neck incision: the retrovascular paratracheal
      plane (for standard cervical mediastinoscopy) and the prevascular retrosternal
      plane (the zone of extended mediastinal exploration). This article describes the
      evolution, technique, indications, applications, and complications of cervical
      mediastinoscopy in the diagnosis and therapy of thoracic diseases.

PMID- 8646497
TI  - Transcervical thymectomy.
AB  - Transcervical thymectomy has been used in the management of myasthenia gravis for
      over 20 years. Contraindications to this operation include advanced age, poorly
      controlled neurologic symptoms, and evidence for a thymoma. The procedure is
      associated with negligible morbidity and requires only a brief hospitalization.
      Remission rates are comparable with those reported for more extensive thymectomy
      operations.

PMID- 8646499
TI  - Diagnosis and management of chylothorax.
AB  - Chylothorax is the presence of lymphatic fluid in the pleural space resulting
      from a leak of the thoracic duct or one of its major divisions. This condition is
      being recognized more frequently after both cardiac and general thoracic surgical
      procedures. Increased understanding of the physiology, pathogenesis, diagnosis,
      and management of chylothorax has significantly decreased the initial mortality
      in the majority of medical centers.

PMID- 8646498
TI  - Open approaches to posterior mediastinal tumors and the spine.
AB  - Open operations continue to be the appropriate approach in the diagnosis and
      treatment of many posterior mediastinal lesions. Transthoracic approach to the
      spine is required for appropriate access to allow complex reconstructive
      procedures to be done. The surgeon must be aware of the anatomic details of the
      region to avoid disabling neurologic injuries and allow precise and appropriate
      surgical management. Thoracoscopic approaches are now being used in some
      situations. The role of open and thoracoscopic techniques in the treatment of
      mediastinal and spinal problems will certainly continue to evolve as experience
      with newer techniques increases.

PMID- 8646501
TI  - Extended cervical mediastinoscopy.
AB  - The technique of extended cervical mediastinoscopy is described in detail as well
      as its indications for use. The author has found extended cervical
      mediastinoscopy extremely valuable in staging lung carcinoma with regard to level
      V and VI lymph node involvement if a standard cervical mediastinoscopy fails to
      demonstrate metastatic disease and a CT scan suggests subaortic lymph node
      involvement. This technique has been found to be safe and accurate and only adds
      minimal operating time to a cervical mediastinoscopy without the need for a
      second incision.

PMID- 8646500
TI  - Transverse sternothoracotomy.
AB  - Transverse sternothoracotomy (the clamshell incision) has been resurrected from
      the early days of cardiac surgery and is now used for double lung
      transplantation, bilateral pulmonary tumors, and selected mediastinal tumors.
      Bulky mediastinal tumors that project into the pleural space are exposed well
      with this incision.

PMID- 8646502
TI  - Parasternal mediastinotomy (Chamberlain procedure).
AB  - The indications for and technical considerations related to the performance of a
      parasternal mediastinotomy (Chamberlain procedure) are described. The results,
      including diagnostic yield, morbidity, and mortality of the procedure, are
      reviewed. Its current role in the thoracic surgeons' armamentarium is discussed.

PMID- 8646503
TI  - Thoracoscopic resection of mediastinal tumors and the thymus.
AB  - Videothoracoscopic techniques have proven their usefulness in dealing with
      pathology in the anterior mediastinum and should be considered in many cases as
      the procedure of choice. The surgeon's judgment, as always, is key in deciding
      which procedure is best suited for dealing with a particular lesion in any given
      patient. Thoracic surgeons need to be facile with these techniques in order to be
      able to provide the best approach for each patient. We need to be vigilant in
      observing and reporting results with these still relatively new procedures to
      ensure that outcomes are equivalent to the standard open procedures. The cost
      effectiveness of these minimally invasive procedures compared with the analogous
      open procedure still remains to be determined. Despite a shortened hospital stay
      for many of these procedures the equipment is more expensive and time in the
      operating room may be longer. It is safe to say, however, that many of these
      minimally invasive procedures are here to stay even if they fail to show a
      reduction in costs.

PMID- 8646504
TI  - Thoracoscopic management of posterior mediastinal tumors.
AB  - Thoracoscopy provides a minimally invasive technique for the diagnosis and
      management of many posterior mediastinal masses. Benign neurogenic tumors,
      esophageal tumors, and bronchogenic cysts all can be approached using video
      assisted thoracic surgical (VATS) techniques. Malignant lesions are still best
      approached via open thoracotomy. VATS techniques allow for less pain and
      dysfunction and can result in shortened hospital stays.

PMID- 8646505
TI  - Thoracoscopic sympathectomy.
AB  - Thoracoscopic sympathectomy has become the most widely used approach to
      cervicothoracic sympathectomy. Appropriate selection of cases and a knowledge of
      the regional anatomy are essential in achieving good clinical results. The
      physiology and anatomy of the upper thoracic sympathectomy system and the
      indications, contraindications, and complications of the operation are described.
      The technique of the operation as done at the University of Virginia is then
      presented in a step-by-step manner.

PMID- 8646506
TI  - The combined cervical and partial sternotomy approach for thymectomy.
AB  - Removal of a normal appearing thymus gland may be necessary, particularly in
      patients with myasthenia gravis. Complete removal is a basic tenet of this type
      of operation. A combined cervical and upper sternotomy incision is described.
      This is appropriate for thymectomy in such patients because of the minimal
      morbidity and excellent exposure for the thoracic portion of the thymus gland.

PMID- 8646507
TI  - Extended transsternal thymectomy.
AB  - Extended transsternal thymectomy allows for the safe excision of the gross thymus
      as well as perithymic and anterior mediastinal fat and lymphatic tissue that may
      harbor foci of aberrant thymus. Additionally, it permits direct inspection of
      each pulmonary hilum for suspicious thymic remnants and even small thymomas not
      visualized on the CT scan. It achieves the objective of a safe, well-tolerated
      operation that provides the best chance for remission or improvement in the
      patient with myasthenia gravis.

PMID- 8646508
TI  - Practice guidelines for the early referral of patients to cancer specialists.

PMID- 8646509
TI  - Favorable clinical responses in subsets of patients from a randomized, multi
      institutional melanoma vaccine trial.
AB  - BACKGROUND: A phase III, randomized, double-blind, multi-institutional trial was
      performed evaluating active specific immunotherapy using vaccinia melanoma
      oncolysate (VMO) in the surgical adjuvant setting in patients with stage II
      melanoma (UICC staging). The first interim analysis showed no significant
      difference in disease-free and overall survival. The data were further analyzed
      to identify subsets of patients with improved outcome when treated with VMO.
      METHODS: Patients received either VMO or placebo of live vaccinia vaccine virus
      (V), once a week for 13 weeks and then once every 2 weeks for an additional 39
      weeks or until recurrence. Having stratified patients according to sex, age,
      number of positive nodes, tumor thickness, and clinical stage, data were analyzed
      for disease-free survival and overall survival. RESULTS: Male patients showed a
      17% difference in overall survival at 4 years when treated with VMO (p = 0.19). A
      subset of male patients < 57 years of age with one to five positive nodes showed
      a 30% difference at 4 years with VMO (p = 0.06). Patients with clinical stage I
      but pathological stage II disease (both male and female), who had undergone
      prophylactic node dissection, showed a 23% difference in survival at 3 years with
      VMO (p = 0.11). CONCLUSIONS: This subset analysis shows encouraging survival
      benefit in certain subsets of patients and an increasing trend in overall
      survival. Further follow-up of this phase III trial from a second interim
      analysis will be forthcoming.

PMID- 8646510
TI  - Cranial irradiation after surgical excision of brain metastases in melanoma
      patients.
AB  - BACKGROUND: Brain metastases account for 20-54% of reported deaths from melanoma.
      Duration and quality of survival depend on the extent of metastatic disease and
      response to treatment. Treatment goals are palliation of symptoms and
      prolongation of life. No studies have directly compared surgery alone and surgery
      with adjunctive cranial irradiation in patients with solitary brain metastases.
      METHODS: We evaluated postoperative adjunctive cranial irradiation in 34 patients
      with solitary brain metastases. RESULTS: Overall survival was significantly
      improved in the 22 patients who received adjunctive cranial irradiation versus
      that in the 12 patients who had surgery alone. Twenty-eight patients subsequently
      relapsed. Nine of 10 patients with surgery alone had brain recurrence as a
      component of failure. Six of 10 patients not receiving irradiation had brain
      recurrences as a component of relapse at multiple sites whereas only 1 of 18
      patients receiving irradiation relapsed with the brain. CONCLUSIONS: Adjunctive
      cranial irradiation is justified for melanoma patients who undergo surgical
      therapy for solitary brain metastases. Survival in patients presenting with
      solitary brain metastases was improved by a reduction of relapse in the brain as
      a component of failure by combined surgery and irradiation.

PMID- 8646511
TI  - Clinical significance of colorectal cancer: metastases in lymph nodes < 5 mm in
      size.
AB  - BACKGROUND: The clinical significance of metastases in small lymph nodes is not
      known. Our objective was to evaluate possible relationships between the number
      and size of lymph node metastases and survival after potentially curative
      colorectal resection. METHODS: A retrospective chart review was performed in
      patients with Dukes'C (any T, N(1-3') M0) colorectal cancers from July 31, 1971
      to December 31, 1987. All specimens underwent the lymph node clearing technique.
      Statistical analysis was performed with the log rank test and the Cox
      proportional hazards model. RESULTS: In 77 patients there were 253 (8%) of 3,087
      cleared lymph nodes with metastases. One hundred seventy-five (69%) of these
      metastatic nodes were 5 mm or less in diameter. The distal margin of resection (p
      = 0.011) and number of positive lymph nodes (p = 0.036) were statistically
      significant factors influencing overall survival. There was no significant
      difference in overall survival (p = 0.73) or disease-free survival (p = 0.56)
      whether the involved lymph nodes were < or > 5 mm in size. CONCLUSION: Most
      metastatic lymph nodes were < 5 mm in diameter. Based on our results, the size of
      lymph node metastases do not affect disease-free or overall survival in
      colorectal carcinoma.

PMID- 8646512
TI  - Preoperative adjuvant radiation with chemotherapy for rectal cancer: its impact
      on stage of disease and the role of endorectal ultrasound.
AB  - BACKGROUND: Preoperative adjuvant radiation combined with chemotherapy is a
      recent development in the management of patients with rectal cancer invading
      perirectal tissue and regional lymph nodes. This study was performed to assess
      the impact of preoperative adjuvant therapy in patients judged by endorectal
      ultrasound to have extramural invasion of rectal cancer and/or regional lymph
      node involvement on tumor regression in bowel wall and lymph nodes. The
      predictive value of ultrasound in staging wall penetration and lymph node
      involvement after preoperative adjuvant therapy was also assessed. METHODS:
      Patients (n = 43) were selected by ultrasound to have preoperative irradiation
      (4,500-5,040 cGy over 5-6 weeks). In 30 patients this was combined with 5
      fluorouracil, 370 mg/m(2), for 5 days in the first and last weeks of irradiation.
      Pretreatment ultrasound was compared with pathologic findings in the resected
      specimen in all patients. Twenty-one were assessed by ultrasound after adjuvant
      therapy and findings compared with histology. RESULTS: Downstaging was seen in 23
      (53%) patients with wall invasion and in 23 (72%) of 32 patients with lymph node
      involvement. Overall, downstaging was achieved in 30 (70%). Positive predictive
      values of ultrasound after irradiation were 72% and 56% for wall penetration and
      lymph node status, respectively. Negative predictive values of ultrasound after
      irradiation were 100% and 82%, respectively. CONCLUSION: In the majority of
      patients with rectal cancer invading perirectal tissues or lymph nodes, lesions
      may be downstaged by preoperative adjuvant therapy. Endorectal ultrasound after
      adjuvant therapy for rectal cancer is of a lesser predictive value chiefly
      because of overstaging.

PMID- 8646513
TI  - Synchronous colon carcinomas: molecular-genetic evidence for multicentricity.
AB  - BACKGROUND: The synchronous presentation of multiple colonic adenocarcinomas is
      an unusual, but well-recognized event accounting for approximately 2-11% of these
      neoplasms. Synchronous tumors may have a different biology and prognosis than
      solitary tumors. Evidence based on measurement of DNA ploidy suggests that a
      significant percentage of synchronous tumors have a common clonal origin,
      probably resulting from translumenal metastasis. METHODS: Fifteen synchronous
      colorectal cancers (30 tumors) were examined for histologic differences as well
      as genetic mutations. p53 gene abnormalities were detected by polymerase chain
      reaction (PCR) followed by single-strand conformation polymorphism analysis. Ki
      ras mutations were detected by PCR followed by oligonucleotide-specific
      hybridization. RESULTS: p53 gene mutations were detected in 12 of 30 tumors. In
      only one case was the same p53 mutation present in both tumors from one patient.
      Similarly, Ki-ras mutations were observed in 9 of 30 tumors. Concordant Ki-ras
      mutations were observed in only one case, which was also concordant for p53
      mutation. CONCLUSION: Because p53 and Ki-ras mutations tend to occur fairly early
      in tumor development, it seems likely that cases discordant for p53 and Ki-ras
      mutations represent independently developing tumor foci. Taken together, these
      findings strongly suggest that the great majority of synchronous colonic
      adenocarcinomas arise as independent neoplasms and their worsened prognosis is
      not a result of unusually early metastatic spread.

PMID- 8646514
TI  - The effect of 1, 25-dihydroxyvitamin D3 on the growth of soft-tissue sarcoma
      cells as mediated by the vitamin D receptor.
AB  - BACKGROUND: Soft-tissue sarcomas, malignant neoplasms originating from
      mesenchymal tissue, are rare but highly aggressive tumors. Present modes of
      therapy are associated with high rates of recurrence. 1, 25-Dihydroxyvitamin D3,
      the active metabolite of vitamin D, serves as a potent antiproliferative agent in
      human cancer cells. METHODS: In this study, six soft-tissue sarcoma cell lines
      were analyzed for vitamin D receptor (VDR) expression, which was then correlated
      with the degree of growth inhibition in response to 1, 25-dihydroxyvitamin D3.
      These cell lines included rhabdomyosarcoma (HS729, A204), fibrosarcoma (HS913t),
      synovial sarcoma (SW982), liposarcoma (SW872), and leiomyosarcoma (SKLMS-1). The
      level of VDR messenger RNA (mRNA) expression was determined using a ribonuclease
      protection assay, and functional receptor content was determined by using a
      ligand-binding assay. Growth studies, including [3H]thymidine uptake and growth
      curves, were performed on two of the six cell lines that expressed the highest
      and lowest receptor levels. RESULTS: Ribonuclease protection and ligand-binding
      assays demonstrated variable levels of VDR, with HS729 showing high expression
      and A204 showing no expression. In HS729, [3H]thymidine uptake was significantly
      decreased at 10(-7) M (33%) and 10(-6) M (40%) 1, 25-dihydroxyvitamin D3. Growth
      curve studies showed significant growth inhibition of 55% at 10(-6) M. A204 cells
      showed no growth inhibition upon treatment with 1, 25-dihydroxyvitamin D3.
      CONCLUSION: This study demonstrates the existence of VDR in soft-tissue sarcoma
      cells and suggests a correlation between the level of VDR in cells and the degree
      of growth inhibition caused by 1, 25-dihydroxyvitamin D3 which may potentially
      serve as an alternative form of therapy for soft-tissue sarcomas.

PMID- 8646515
TI  - Resectability and survival in retroperitoneal sarcomas.
AB  - BACKGROUND: Retroperitoneal sarcomas historically have presented difficulties in
      their management due to a high rate of unresectability, which affects the
      survival of these patients. METHODS: We retrospectively reviewed the charts of 87
      consecutive patients with retroperitoneal sarcomas treated in the period 1977
      1994. RESULTS: The resectability rate was 100% for the primary tumors (n = 55)
      and 87% for the locally recurrent tumors (n = 32). The 5-year survival rate was
      63% (66% for the primary tumors and 57% for those with local recurrence). The 10
      year survival rate was 46% (57% for primary tumors and 26% for those referred
      with locally recurrent tumor). The overall local recurrence rate was 31% (25% for
      the primary tumors and 41% for those referred with local recurrence); it was 56%
      after local excision and 15% after wide resection (p = 0.0003). The 10-year
      disease-free survival of patients with local excision (n = 25) was 7%, and that
      of patients with wide resection (n = 54) 59% (p = 0.0001). CONCLUSIONS: The
      overall resectability rate of retroperitoneal sarcomas was 95%. Wide resection
      produced a significantly higher survival rate compared with that of local
      excision. The survival rate for the primary tumors, varying significantly with
      the histologic grade, approached the rate reported for primary soft-tissue
      sarcomas of the extremity.

PMID- 8646516
TI  - Infantile fibrosarcoma: complete excision is the appropriate treatment.
AB  - BACKGROUND: Infantile fibrosarcoma and its pathological variants are unusual
      childhood tumors. During the past 25 years, 18 children with these lesions were
      seen at our institution. METHODS: These patients' records were analyzed to
      determine clinical and pathological findings and outcome. RESULTS: The mean age
      at diagnosis was 7 months. There were 16 boys and 2 girls. The sites of tumor at
      presentation were: Extremity, head, trunk, and pelvis. Pathological findings
      were: fibrosarcoma, myofibroma, and fibromatosis. Histologic characteristics
      varied from benign hypocellular to more cellular pleomorphism. The initial
      surgical procedure was a complete excision in 16. Of those patients with complete
      removal, 6 recurred and all had secondary reexcision. In addition to excision, 3
      patients received adjunctive therapy; chemotherapy in all 3 and radiation in 2.
      Sixteen (89%) children survived, including 4 of 6 with recurrent tumor and 2 of 2
      with incomplete initial resection. Two children ages 6 and 9 months at diagnosis
      died of progressive recurrent tumor at 1 month and 6 years from initial
      diagnosis, despite operative therapy, chemotherapy, and radiation therapy. Both
      had paraspinal tumors that were removed completely. Pathological examination
      revealed spindle cell tumors infiltrating muscle. Neither clinical nor histologic
      findings distinguished surviving from nonsurviving patients. CONCLUSIONS:
      Fibrosarcoma occurring in infants has an excellent outcome despite histologic
      findings. Initial complete excision should be attempted in all children.
      Recurrence indicates a more aggressive variant and warrants more aggressive
      complete reexcision wherever possible. Adjunctive therapy probably has no
      benefit. The occasional death indicates the need for close follow-up.

PMID- 8646517
TI  - Aggressive therapy for locoregional recurrence after mastectomy in stage II and
      III breast cancer patients.
AB  - BACKGROUND: To determine if aggressive treatment of locoregional recurrence
      affects survival, we retrospectively analyzed the clinical outcome of 69 breast
      cancer patients who developed locoregional disease as their first episode of
      recurrence following mastectomy and adjuvant chemotherapy. METHODS: Patients were
      identified from among 1,707 stage II and III breast cancer patients who enrolled
      in five different doxorubicin-based adjuvant chemotherapy protocols at The
      University of Texas M. D. Anderson Cancer Center from 1975 to 1986. Sixty-nine
      evaluable patients who had a locoregional recurrence as the first site of relapse
      after mastectomy formed the study group. Multifactorial analysis of clinical and
      histopathological characteristics of both the primary tumor and the subsequent
      recurrence was performed using a logistic regression method. Survival analysis
      was performed using an actuarial life-table method calculated from the date of
      registration into the adjuvant therapy protocols. RESULTS: Median follow-up was
      6.6 years. Two factors significantly affected survival: recurrence of disease
      during or after adjuvant treatment of the primary and whether the patient was
      rendered disease free after recurrence. CONCLUSIONS: Stage II and III breast
      cancer patients who have locoregional recurrence after adjuvant chemotherapy and
      can be rendered disease free may have a better survival rate. Aggressive
      treatment of locoregional recurrence including complete surgical excision should
      be considered in this subgroup of patients.

PMID- 8646518
TI  - Clinicopathologic factors and patient perceptions associated with surgical breast
      conserving treatment.
AB  - BACKGROUND: Clinical studies have shown equivalent survival rates between breast
      conserving surgery (BCS) and mastectomy in early breast cancer; however, rates
      for BCS remain low. The purpose of this study was to determine (a) the prevalence
      of BCS in a regional medical center, (b) clinicopathologic factors associated
      with BCS, and (c) patient perceptions of the treatment decision-making process.
      METHODS: We retrospectively reviewed 251 consecutive breast cancer cases during
      January 1990-December 1991; 77 patients were ineligible for BCS because of
      unfavorable pathology. We then interviewed 118 of the 160 women available for
      interview. RESULTS: BCS was performed in 31 of the eligible patients (18%).
      Multivariate analysis revealed that tumor size < 10 mm (p = 0.03) was the only
      significant predictive variable for BCS. Patient interviews revealed that 93%
      said their surgeon was the primary source of information regarding treatment
      options. Among 69% of the women whose surgeons reportedly recommended a
      particular option, 89% recommended mastectomy with 93% compliance, and 11%
      recommended BCS with 89% compliance. The BCS group more often obtained a second
      opinion (p = 0.04) and 60% said they made the decision themselves compared with
      only 37% of the mastectomy group (p = 0.05). CONCLUSION: Limiting BCS to women
      whose tumor size is < 10 mm is too restrictive; this excludes a large number of
      women who are clinically eligible for BCS. The surgical decision-making process
      for early-stage breast cancer is very much surgeon-driven, with a high degree of
      patient compliance.

PMID- 8646519
TI  - In situ cytokine production by breast cancer tumor-infiltrating lymphocytes.
AB  - BACKGROUND: Human breast cancers progressively grow despite the presence of
      extensive lymphocytic infiltration and specific antitumor immune recognition,
      thereby calling into question the competency of breast tumor-infiltrating
      lymphocytes (TIL). The function of breast TILs in vivo and their possible role in
      the suppression of an antitumor immune response are largely unknown. METHODS: The
      cytokines produced in situ by lymphocytes in 89 breast carcinomas and 14 benign
      breast lesions were assessed using immunohistochemistry. RESULTS: The majority of
      tumor and benign breast samples contained T-cell infiltrates, which were
      disclosed using an anti-CD3 antibody stain. The percentage of tumor samples in
      which > or =3% of the lymphocytes were producing cytokines was as follows:
      interleukin (IL)-2 45%, IL-4 36%, tumor necrosis factor-alpha (TNF-alpha) 28%,
      transforming growth factor-beta 1 (TGF-beta 1) 20%, IL-10 11%, interferon-gamma
      (IFN-gamma) 4%, and granulocyte-macrophage colony-stimulating factor (GM-CSF) 3%.
      Production of IL-2, IL-4, and TGF-beta 1 by TILs in breast cancers exceeded that
      detected in benign breast lesions (p < 0.005). Significantly more tumor samples
      contained lymphocytes producing IL-2, IL-4, TGF-beta 1, and TNF-alpha than IFN
      gamma and GM-CSF (p < 0.002 for each comparison). One or more of the potentially
      immunoinhibitory cytokines-IL-4, IL-10, or TGF-beta 1-were produced by
      lymphocytes in 44% of the specimens. No significant associations were seen
      between lymphocyte production of a particular cytokine and disease-free survival
      (median follow-up 43 months). CONCLUSIONS: Immunohistochemical techniques can be
      used to detect cytokine secretion by TILs in preserved tissue. The relative lack
      of secretion of IFN-gamma and GM-CSF, rather than a deficiency of IL-2, may
      explain why the antitumor immune response to breast cancer is impaired.

PMID- 8646520
TI  - Stereotactic fine-needle aspiration biopsy for the evaluation of nonpalpable
      breast lesions: report of an experience based on 2,988 cases.
AB  - BACKGROUND: The increasing use of mammography has led to a significant increase
      in the detection of clinically occult lesions, the majority of which prove to be
      benign. SFNB has been suggested as a means of expediting a diagnosis for lesions
      that are malignant while limiting surgical biopsies for those that are benign.
      METHODS: Clinically occult mammographic lesions were assessed by SFNB in 2,988
      patients. Definitive histologic diagnoses were made on surgical specimens in all
      instances in which the cytologic diagnosis was malignant, suspicious, or
      atypical. Patients with benign cytology were either followed with interval
      mammograms or underwent surgical biopsy. RESULTS: Two hundred ninety-one of the
      295 lesions (99%) diagnosed as cancer via SFNB were confirmed by histopathology.
      Twenty-two of the 22 lesions (100%) that were diagnosed as suspicious were
      diagnosed on histopathology as malignant. Forty-three of the 70 lesions (61%)
      with cytologic atypia were diagnosed on histopathology to be malignant.
      CONCLUSIONS: SFNB is an accurate means of diagnosing carcinoma, but must be
      followed by surgical biopsy when the cytology shows atypia. For lesions diagnosed
      as benign by SFNB, close interval mammography is essential.

PMID- 8646521
TI  - Isolation of differentially expressed genes in carcinoma of the esophagus.
AB  - BACKGROUND: The genetic alterations that occur in the transformation of normal
      esophageal mucosa (NEM) to carcinoma of the esophagus (CAE) are not well
      understood. Differential display of mRNA is a recently described technique that
      uses reverse transcription and PCR to compare cDNA from paired normal and
      malignant tissue to determine whether there is either genetic loss (putative
      tumor suppressor gene) or overexpression (putative oncogene) in malignant cells.
      Our goal was to identify some of these genes from patients with CAE. METHODS:
      Specimens of NEM and corresponding CAE were obtained from patients at endoscopy
      or surgical resection and immediately snap frozen. Total RNA was isolated,
      reverse transcribed to cDNA, and PCR amplified with a predefined 10-mer
      oligonucleotide. The products were displayed on a polyacrylamide gel.
      Differential bands were isolated and sequenced and/or used as probes for Northern
      analysis. RESULTS: Application of the differential display method resulted in the
      isolation of 49 cDNA clones from three patients with CAE. Sequencing of the
      clones has revealed five unique sequences not previously reported and one that
      has been identified as histone H3.3. Northern analysis of histone H3.3 has
      revealed overexpression in four of six CAEs but not the paired NEM. In addition,
      whereas only 5 of 13 normal human cell lines of various origins overexpressed
      this gene, 11 of 12 human cancer cell lines (9 of 9 adenocarcinomas)
      overexpressed it. CONCLUSIONS: Differential display can be used to isolate
      potential oncogenes and tumor suppressor genes. We have identified five unique
      sequences and one known gene that may contribute to the development of CAE.

PMID- 8646522
TI  - Role of endogenous interferon gamma in murine tumor growth and tumor necrosis
      factor alpha antitumor efficacy.
AB  - BACKGROUND: The anticancer role of tumor necrosis factor-alpha (TNF-alpha) has
      been limited by toxicity. These experiments evaluate blocking endogenous
      interferon-gamma (IFN-gamma) activity to abrogate TNF-alpha toxicity. METHODS:
      C57B1/6 mice bearing MCA 105 tumor were treated with TNF-alpha and anti-IFN-gamma
      antibody (Ab) to evaluate the effect on the acute lethality of TNF-alpha and
      their efficacy as evaluated by tumor growth rate, tumor histology, and survival.
      RESULTS: Anti-IFN-gamma Ab decreased TNF-alpha lethality. Anti-IFN-gamma Ab alone
      increased tumor growth significantly more than did nonimmune IgG (p2 < 0.0001).
      Tumor-bearing mice that received nonimmune IgG and TNF-alpha had slower tumor
      growth (p2 < 0.02) and a trend toward improved survival (p = 0.07) compared with
      saline-treated controls. Anti-IFN-gamma Ab abrogated the antitumor effect of TNF
      alpha, prevented acute tumor necrosis histologically, and resulted in tumor
      growth rate and host survival similar to that of controls. The findings in mice
      that received anti-IFN-gamma Ab and high-dose TNF-alpha were comparable with
      those in mice that received a lower, equitoxic dose of TNF-alpha alone.
      CONCLUSIONS: Blocking endogenous IFN-gamma accelerates tumor growth in this model
      and partially abrogates the toxic and antitumor activity of exogenous TNF-alpha
      equally. This suggests that blocking endogenous IFN-gamma activity is not a
      useful strategy for limiting TNF-alpha treatment toxicity.

PMID- 8646523
TI  - Pregnancy influences breast cancer stage at diagnosis in women 30 years of age
      and younger.
AB  - BACKGROUND: To evaluate the purported decreased survival of pregnancy-associated
      (PA) breast cancer, a previously described homogeneous cohort of women of
      childbearing age with primary operable cancer was studied. The current analysis
      was designed to (a) identify those patients among the cohort known to have PA
      cancer and (b) compare clinical factors, pathologic characteristics, stage at
      diagnosis, and survival statistics for PA and non-PA cancer subgroups. METHODS:
      All patients < or =30 years of age who underwent definitive operation between
      1950 and 1989 at the Memorial Sloan-Kettering Cancer Center (MSKCC) for primary
      operable (stages 0-IIIA) breast adenocarcinoma were analyzed. RESULTS: Twenty-two
      of the 227 young women with primary operable breast cancer had PA cancer. Disease
      related survival was decreased (p = 0.004) in these 22 women compared with the
      remaining 205 patients with non-PA cancer. PA cancer patients were found to have
      larger tumors (p < 0.005), and a greater proportion had advanced staged (IIB or
      IIIA) cancers (p < 0.02). Among patients diagnosed with early invasive cancers
      (stages I or IIA), no difference (p = NS) in survival was observed comparing PA
      and non-PA subgroups (73% vs. 74% 10-year survival). Patients with stage IIIA
      cancer had shorter disease-free and overall survival when associated with
      pregnancy (0% vs. 35% 10-year survival). CONCLUSIONS: Women 30 years of age or
      younger with PA breast cancer have decreased survival compared with patients with
      non-PA cancer from the same cohort. Women with PA cancer have larger, more
      advanced cancers at the time of definitive surgery. Women with early staged PA
      cancers appear to have survival similar to that for women with early staged non
      PA cancer.

PMID- 8646524
TI  - Immediate breast reconstruction by prosthesis: a safe technique for extensive
      intraductal and microinvasive carcinomas.
AB  - BACKGROUND: Immediate breast reconstruction (IBR) by prosthesis is frequently
      proposed after mastectomy. However, due to the morbidity of this operation,
      especially the early implant removal rate, its indications remain controversial.
      METHODS: We have performed 141 IBR by prosthesis (saline or gel-filled implant,
      tissue expander) in a homogeneous population of patients with extensive
      intraductal or microinvasive carcinoma, diagnosed after an initial local
      excision. This prospective study was designed to assess the feasibility and
      morbidity of IBR for an "ideal" population, allowing wide cutaneous preservation,
      without preoperative or postoperative treatment. RESULTS: The early prosthesis
      removal rate (< 2 months) was 0.7%, with only 2.1% of early surgical revisions
      and 3% of lymphoceles. Cutaneous complications (5%) were significantly correlated
      with the type of incision. Cosmetic results at 1 year were good or very good in
      66% of cases, similar to the percentage observed after delayed reconstruction by
      prosthesis. CONCLUSIONS: In this selected population, IBR by prosthesis did not
      induce any additional morbidity compared with mastectomy without reconstruction.
      IBR by prosthesis can be systematically proposed in cases of extensive
      intraductal or microinvasive carcinoma.

PMID- 8646526
TI  - Sphincter-sparing surgery.

PMID- 8646527
TI  - How to really heal with crystals.

PMID- 8646525
TI  - Vaccine therapy for cancer.
AB  - BACKGROUND: Tumor-specific cytotoxic T-lymphocytes (CTLs) can be isolated from
      the solid tumors, draining lymph nodes, metastatic effusions, and peripheral
      blood of cancer patients. Despite this evidence for a cell-mediated immune
      response to cancer, attempts at active specific immunotherapy using cancer
      vaccines have met with little success in clinical trials. METHODS: We have
      reviewed the immunobiology of the cell-mediated immune response to cancer by
      focusing on what is known about the major histocompatibility complex (MHC)
      restricted interaction between tumor cells and CD8+ or CD4+ T-cells. In addition,
      we review the recent advances in the identification of tumor-associated antigens
      (TAAs) that are recognized by tumor-specific CTLs in melanoma and other cancers.
      In discussing these antigens, we highlight the recent identification of several
      MHC-restricted antigenic peptides that are recognized by CTLs from patients with
      melanoma and those with ovarian and breast cancer. We examine the implications
      that the discovery of these TAAs and peptides will have on the development of new
      anticancer vaccines. We review the most recent vaccine trials in melanoma and
      other cancers and focus on current concepts aimed at improving the therapeutic
      efficacy of future vaccines, including genetically engineered tumor cell
      vaccines. CONCLUSIONS: With the recent identification of several TAAs and
      antigenic peptide epitopes in melanoma and other cancers, immunotherapy
      researchers are now focusing on new strategies for the development of anticancer
      vaccines. As the repertoire of known TAAs increases and our understanding of the
      immunobiology of cell-mediated immunity to cancer improves, immunotherapists
      remain cautiously optimistic in their quest for effective cancer vaccines.

PMID- 8646528
TI  - The problem with pyrimidines.

PMID- 8646529
TI  - How molten is the molten globule?

PMID- 8646530
TI  - The means to bind the ends.

PMID- 8646531
TI  - tRNA and mRNA both in the same molecule.

PMID- 8646532
TI  - DNA ligase shows restraint.

PMID- 8646533
TI  - Probing the native strain iin alpha1-antitrypsin.

PMID- 8646534
TI  - Pre-formation of the semi-open conformation by the apo-calmodulin C-terminal
      domain and implications binding IQ-motifs.

PMID- 8646535
TI  - Using buried water molecules to explore the energy landscape of proteins.
AB  - Buried water molecules constitute a highly conserved, integral part of nearly all
      known protein structures. Such water molecules exchange with external solvent as
      a result of protein conformational fluctuations. We report here the results of
      water (17)O and (2)H magnetic relaxation dispersion measurements on wild-type and
      mutant bovine pancreatic trypsin inhibitor in aqueous solution at 4-80 degrees C.
      These data lead to the first determination of the exchange rate of a water
      molecule buried in a protein. The strong temperature dependence of this rate is
      ascribed to large-scale conformational fluctuations in an energy landscape with a
      statistical ruggedness of approximately 10 kJ mol(-1).

PMID- 8646536
TI  - An engineered allosteric switch in leucine-zipper oligomerization.
AB  - Controversy remains about the role of core side-chain packing in specifying
      protein structure. To investigate the influence of core packing on the oligomeric
      structure of a coiled coil, we engineered a GCN4 leucine zipper mutant that
      switches from two to three strands upon binding the hydrophobic ligands
      cyclohexane and benzene. In solution these ligands increased the apparent thermal
      stability and the oligomerization order of the mutant leucine zipper. The crystal
      structure of the peptide-benzene complex shows a single benzene molecule bound at
      the engineered site in the core of the trimer. These results indicate that coiled
      coils are well-suited to function as molecular switches and emphasize that core
      packing is an important determinant of oligomerization specificity.

PMID- 8646537
TI  - Access of ligands to cavities within the core of a protein is rapid.
AB  - We have investigated the magnitude and timescale of fluctuations within the core
      of a protein using the exchange kinetics of indole and benzene binding to
      engineered hydrophobic cavities in T4 lysozyme. The crystal structures of variant
      benzene complexes suggest that relatively large scale fluctuations (1-2 angstrom)
      of backbone atoms are required for entry of these ligands into the core.
      Nonetheless, these ligands enter the cavities rapidly, with bimolecular rate
      constants of approximately 10(6)-10(7) M(-1) s(-1) and a low activation barrier,
      2-5 kcal mol(-1). These results suggest that protein cores undergo substantial
      fluctuations on the millisecond to microsecond timescale and that entry of small
      molecules into protein interiors is not strongly limited by steric occlusion.

PMID- 8646538
TI  - Hydrogen bonding and equilibrium isotope enrichment in histidine-containing
      proteins.
AB  - We have measured deuterium/hydrogen fractionation in three histidine-containing
      proteins, ecHPr, ecHPr mutant S31A, and bsHPr, and in random coil peptides using
      NMR and mass spectrometry. The amide protons of unstructured peptides exhibit
      equilibrium enrichment for deuterium, in agreement with previous studies.
      Enrichment for both protium and deuterium was observed in both HPrs, with
      fractionation factors ranging from 0.63 to 1.41. Enrichment for protium was seen
      in alpha-helical secondary structure. 'Strong' HBs previously identified by
      mutagenesis and thermodynamic measurements are significantly enriched for
      protium. Sites of protium enrichment are conserved in a structural context across
      species lines, though ecHPr and bsHPr share only 30% sequence identity,
      suggesting that strong HBs are conserved and may play an important role in
      stabilizing the folded state.

PMID- 8646539
TI  - Crystal structure of the Escherichia coli dUTPase in complex with a substrate
      analogue (dUDP).
AB  - We have determined the structure of the homotrimeric dUTPase from Escherichia
      coli, completed with an inhibitor and substrate analogue, dUDP. Three molecules
      of dUDP are found symmetrically bound per trimer, each in a shallow cleft between
      adjacent subunits, interacting with evolutionary conserved residues. The
      interactions of the uracil ring and the deoxypentose with the protein are
      consistent with the high specificity of the enzyme with respect to these groups.
      The positions of the two phosphate groups and adjacent water molecules are
      discussed in relation to the mechanism and kinetics of catalysis. The role that
      dUTPase plays in DNA metabolism makes the enzyme a potential target for
      chemotherapeutic drugs: the results presented here will aid in the design and
      development of inhibitory compounds.

PMID- 8646540
TI  - The structure of Desulfovibrio vulgaris rubrerythrin reveals a unique combination
      of rubredoxin-like FeS4 and ferritin-like diiron domains.
AB  - We have determined the structure of rubrerythrin, a non-haem iron protein from
      the anaerobic sulphate-reducing bacterium, Desulfovibrio vulgaris
      (Hildenborough), by X-ray crystallography. The structure reveals a tetramer of
      two-domain subunits. Each subunit contains a four-helix bundle surrounding a
      diiron-oxo site and a C-terminal rubredoxin-like FeS4 domain. The diiron-oxo site
      contains a larger number of carboxylate ligands and a higher degree of solvent
      exposure than do those in other diiron-oxo proteins. The four-helix bundle of
      rubrerythrin closely resembles those of the ferritin and bacterioferritin
      subunits, suggesting a relationship among these proteins-consistent with the
      recently demonstrated ferroxidase activity of rubrerythrin.

PMID- 8646541
TI  - Two structural configurations of the skeletal muscle calcium release channel.
AB  - Here we present the determination of the three-dimensional structure of the
      skeletal muscle Ca2+-release channel in an open state using electron
      cryomicroscopy and angular reconstitution. In contrast to our reconstruction of
      the channel in its closed state, the density map of the channel driven towards
      its open state, by the presence of Ca2+ and ryanodine, features a central opening
      in the transmembrane region-the likely passageway for Ca2+ ions from the
      sarcoplasmic reticulum to the cytosol. The opening of the channel is associated
      with a 4 degree rotation of its transmembrane region with respect to its
      cytoplasmic region, and with significant mass translocations within the entire
      cytoplasmic region of the channel tetramer.

PMID- 8646542
TI  - Three-dimensional structure of bovine cytochrome bc1 complex by electron
      cryomicroscopy and helical image reconstruction.
AB  - Cytochrome bc1 complex from bovine heart has been reconstituted into tubular
      crystals. The three-dimensional structure of the complex in lipid bilayer has
      been obtained at an effective resolution of 16 angstrom by electron
      cryomicroscopy and helical image reconstruction. The complex is in a dimeric
      form, in which the monomers are associated closely in extramembrane domains on
      both sides of the membrane. The large inner domain is distinctively hollow and
      the small outer domain consists of a flat mass and two bulbous extrusions. These
      domains are connected by two narrow transmembrane columns. Locations of the
      subunits and the redox centres in the model are proposed.

PMID- 8646543
TI  - Cancer therapy--the 21st century.
AB  - This century has seen a dramatic increase in the modalities available to prevent,
      control, or cure cancer. Dr. Rosenthal, Professor of Medicine at Harvard Medical
      School, reflects on the progress in cancer management made in the 20th century
      and predicts a continuing rapid evolution for the 21st century.

PMID- 8646544
TI  - Systemic treatment of cancer.
AB  - For the past 50 years, the search has continued for systematically administered
      agents that can produce profound and lasting effects on human cancers. This has
      led to the use of many cytoxically and hormonally active agents and, more
      recently, to the use of biologic agents. The author presents the 10th in a series
      of periodic updates in this journal on the current status of systematic treatment
      of cancer.

PMID- 8646545
TI  - The use of bone marrow and peripheral blood stem cell transplantation in the
      treatment of cancer.
AB  - Since its first successful application 25 years ago, the clinical use of bone
      marrow and peripheral blood stem cell transplantation has increased dramatically.
      Transplantation allows for the administration of high doses of systematic
      chemotherapy and radiotherapy and confers an antitumor effect separate from the
      effects of chemotherapy. However,complications including toxicity of treatment,
      graft failure, and graft-versus-host disease exist. This article reviews the
      history and current use of bone marrow and peripheral blood stem cell
      transplantation and outlines new approaches for clinical application.

PMID- 8646547
TI  - Clinical highlights from the National Cancer Data Base: 1996.
AB  - The National Cancer Data Base, a joint project of the American Cancer Society and
      the American College of Surgeons Commission on Cancer, provides a mechanism for
      periodic assessment of hospital-based cancer patient care. From its annual
      summary, health care professionals can evaluate trends in patient care to make
      more efficient treatment decisions. This article provides a first look at
      highlights from the 1996 annual summary.

PMID- 8646546
TI  - Hematopoietic growth factors.
AB  - Over the past ten years, the availability of pharmacologic quantities of
      hematopoietic growth factors has opened many avenues of study in basic science
      and clinical investigation. Numerous studies performed to date have demonstrated
      significant benefits from the use of these cytokines. The side effect profiles,
      particularly for "later acting" growth factors, indicate that they are generally
      well tolerated by most patients. The table summarizes the potential indications
      for hematopoietic growth factor use as discussed in this article, as justified by
      current evidence of benefit, harm, and cost effectiveness resulting from their
      use in various clinical settings. It has been clearly demonstrated in standard
      dose chemotherapy regimens that these agents shorten the duration of
      myelosuppression, reduce the incidence of significant infection, can shorten
      hospital stay, and reduce antibiotic use for most patients, although the
      cost/benefit ratio for growth factors such as G-CSF makes this a cost-effective
      approach only for regimens with a high (40 percent or more) incidence of febrile
      neutropenia. Limited indirect evidence supports the use of growth factors in
      patients with a prior episode of fever and neutropenia. The suppressive approach
      to growth factor use could potentially benefit patients with documented infection
      or clinical deterioration, but it has not otherwise been shown to be a
      particularly effective or cost-effective approach. Administration of
      hematopoietic growth factors has been instrumental in facilitating both
      autologous and allogeneic peripheral progenitor cell mobilization and techniques
      such as ex vivo expansion. There is an increasing body of data supporting the use
      of high-dose chemotherapy regimens with progenitor cell rescue for a number of
      malignancies and limited data supporting the benefits of maintaining dose
      intensity for certain malignancies in standard-dose settings. Although of
      continuing concern, clinically significant evidence of disease stimulation and
      recurrence has not been unequivocally demonstrated in studies to date. A
      comprehensive set of evidence-based guidelines has recently been published by the
      American Society of Clinical Oncology. As often is the case, current studies have
      perhaps generated more questions than answers. Future investigation will
      undoubtedly focus on use of hematopoietic growth factors in conjunction with
      other techniques, such as outpatient-based treatment of febrile neutropenia, CD34
      positive stem cell selection in autologous transplantation, selective
      manipulation of T-cell subsets (to decrease the incidence of severe graft-versus
      host disease) in allogeneic transplantation, and high-dose therapy with stem cell
      transplantation.

PMID- 8646548
TI  - Prospects for treating autoimmune and inflammatory diseases by gene therapy.

PMID- 8646549
TI  - Gene delivery systems for use in gene therapy: an overview of quality assurance
      and safety issues.
AB  - The development of safe and effective agents for gene therapy is founded on three
      main principles; careful choice and design of vectors, assessment of vector
      safety under GLP and production of the vector stocks under GMP. The first ensures
      the safe and appropriate contained delivery and expression of the required gene
      to the recipient of the therapy. GLP provides fully documented studies of
      potency, efficacy and safety of the product while the production of clinical
      grade agents under GMP is essential.

PMID- 8646550
TI  - Characterization of plasmid DNA transfer into mouse skeletal muscle: evaluation
      of uptake mechanism, expression and secretion of gene products into blood.
AB  - The expression of naked plasmid DNA coding for firefly luciferase (pRSVluc) or a
      secreted protein, human-alpha-1-antitrypsin (pRcCMVhAAT) in mouse skeletal muscle
      was characterized following administration by an improved intramuscular injection
      technique. Injection guided by intense illumination along the longitudinal axis
      of the mouse quadriceps muscle and parallel to the myofibers yielded 200-fold
      higher levels of luciferase expression than perpendicular injection. Luciferase
      expression was inhibited by an excess of non-coding DNA or dextran sulfate
      suggesting that muscle DNA uptake mechanism(s) can be saturated. Injected plasmid
      DNA was rapidly eliminated from the muscle as evidenced by tissue distribution
      studies of radiolabeled hAAT plasmid and Southern analysis. However, PCR analysis
      demonstrated that hAAT cDNA persisted in the muscle for at least 1 month after
      injection. Immunohistochemistry techniques indicated that the hAAT gene was
      expressed by the muscle fibers. ELISA analysis of serum samples collected from
      intramuscularly injected mice demonstrated that secreted hAAT protein
      concentration peaked in serum by day 7, started to decline by day 14 and was
      barely detectable 21 days post-injection. RT-PCR analysis demonstrated that hAAT
      transcript persisted at the site of injection for at least 1 month indicating
      that the decline of serum hAAT concentration 21 days post-injection was not due
      to the absence of hAAT transcript. However, the decline of hAAT protein
      concentration in the serum was inversely correlated with accumulation of murine
      anti-hAAT antibodies in circulation.

PMID- 8646551
TI  - LacZ gene transfer into tumor cells abrogates tumorigenicity and protects mice
      against the development of further tumors.
AB  - Numerous studies have shown that the expression of immuno-stimulatory genes in
      tumor cells can result in the development of antitumoral immunity resulting in
      the rejection of the tumor cells. We show here that the simple integration and
      expression of the lacZ gene in the highly tumorigenic murine mastocytoma cell
      line P815 strongly reduces the cell's tumorigenicity. All the animals having
      rejected P815-lacZ challenges develop a long-lasting immunity against unmodified
      P815 cells with all of the animals rejecting further challenges with tumorigenic
      doses of P815 cells. However, this protective immunity conferred by P815-lacZ,
      directed against both the nuclearly expressed lacZ and surface tumor antigens, is
      not sufficient to act as curative immunity. In this immunogenic tumor model the
      expression of the lacZ antigen is more efficient than the irradiation of the
      cells to induce a strong immune response and an antitumoral state of vaccination
      in syngeneic animals.

PMID- 8646553
TI  - Adeno-associated virus 2-mediated transduction and erythroid cell-specific
      expression of a human beta-globin gene.
AB  - Recombinant adeno-associated virus 2 (AAV) virions were constructed that
      contained the genomic copy of a normal human beta-globin gene marked with a 4-bp
      Clal linker, and the herpesvirus thymidine kinase (TK) promoter-driven bacterial
      gene for resistance to neomycin (v beta m-globin), as well as those containing
      the DNase l-hypersensitive site 2 (HS-2) from the locus control region (LCR) of
      the human beta-globin gene cluster (vHS2-beta m-globin). These recombinant
      virions were used to infect a human erythroleukemia cell line which normally does
      not express the beta-globin gene (K562), or a human nasopharyngeal carcinoma cell
      line (KB). Cell populations resistant to G418, a neomycin analogue, were obtained
      following infections with the recombinant virions, indicating high-efficiency
      transduction of the chimeric gene as well as functional activity of the
      transduced neo gene in both cell types. Southern blot analysis using a human beta
      globin DNA probe substantiated stable integration of the exogenous beta-globin
      allele in these cells. There was no expression of the transduced beta-globin gene
      in K562 or KB cells infected with the v beta m-globin virus. High-level
      expression of the transduced beta-globin gene occurred only in the vHS2-beta m
      globin virus-infected K562 cells, but not in KB cells, as determined by Northern
      blot as well as RNase protection analyses. Expression of the human beta-globin
      protein could also be detected in approximately 10-20% of the vHS2-beta m-globin
      virus-infected K562 cells. These studies suggest that the AAV-based vector system
      may prove useful for high-efficiency globin gene transfer in human hematopoietic
      cells.

PMID- 8646552
TI  - Lack of persistence of E1- recombinant adenoviral vectors containing a
      temperature-sensitive E2A mutation in immunocompetent mice and hemophilia B dogs.
AB  - Two recombinant adenoviruses expressing either human alpha 1-antitrypsin (hAAT)
      or canine factor IX (cFIX) were modified so that they also contained a
      temperature-sensitive mutation (ts125) in the DNA binding protein encoded within
      the viral E2A region. The effects of the inclusion of the ts125 mutation on
      transgene expression in vivo were evaluated in Balb/c mice and hemophilia B dogs
      by comparison with adenoviral vectors containing the same transgene but lacking
      the ts125 mutation. No significant differences in the duration of transgene
      expression were observed in either animal model. Insufficiency of the ts125
      mutation in the prolongation of transgene expression in these two animal models
      suggests that further modification of the vector backbone may be required to
      achieve long-term gene expression in a wide variety of applications.
      Additionally, humoral immune response to transgene products has been demonstrated
      in immunocompetent animal models, which will also need to be surmounted for long
      term efficacy in disease treatment by gene therapy.

PMID- 8646554
TI  - Loss of ganciclovir sensitivity by exclusion of thymidine kinase gene from
      transplanted proinsulin-producing fibroblasts as a gene therapy model for
      diabetes.
AB  - To establish a practical method of somatic gene therapy, we aimed to develop a
      regulatory system at the cellular level using a suicide vector. We introduced the
      herpes simplex virus type 1 thymidine kinase (HSV-tk) gene into the human
      proinsulin-producing Ltk-cells and examined whether ganciclovir (GCV)
      administration could control proinsulin production in vivo. The cells transfected
      with the HSV-tk gene showed more than 100-fold increase in sensitivity to GCV
      compared with the parent cells. Analysis of blood glucose in diabetic nude mice
      with transplanted cells showed that proinsulin production by these cells was
      strongly suppressed by GCV treatment in vivo as reflected by the reversal to
      hyperglycemia. However, in the in vivo experiment, the plasmid containing the HSV
      tk gene was spontaneously lost from the transplanted cells in one of six cases
      resulting in the resistance to GCV as reflected by the persistent hypoglycemia
      and increased tumor size. This system of HSV-tk and administration of GCV may be
      applicable to gene therapy as a suicide vector, but the system of stable
      expression of the HSV-tk gene must be established.

PMID- 8646555
TI  - Inhibition of HIV-1 replication and reactivation from latency by tat
      transdominant negative mutants in the cysteine rich region.
AB  - Tat mutants (tat22, tat37 and tat22/37) were constructed in the transactivation
      domain, where cysteines at positions 22 or/and 37 were substituted with glycine
      and serine, respectively. These mutants were expressed either in a BK virus
      episomal vector or in the retroviral vector LXSN. Constitutive production of
      tat22 by Jurkat T cells in the context of both vectors blocked HIV-1 replication
      during lytic infection. Conversely, the tat37 mutant did not show any inhibitory
      activity and tat22/37 displayed a mild effect on HIV-1 infection only when
      expressed by the recombinant retrovirus. However, constitutive production of
      tat22/37 by the BK virus vector in Jurkat T cells chronically infected by HIV-1
      was effective in blocking reactivation of viral replication induced by tumor
      necrosis factor-alpha or human herpesvirus-6. These results suggest that mutants
      in the transactivation domain of tat may be considered in designing alternative
      strategies to control HIV-1 replication and reactivation from latency during
      different phases of infection.

PMID- 8646556
TI  - An AAV promoter-driven neuropeptide Y gene delivery system using Sendai virosomes
      for neurons and rat brain.
AB  - An adeno-associated virus (AAV)-derived construct (pJDT95npy) containing rat
      neuropeptide Y (NPY) cDNA inserted downstream of endogenous AAV promoters was
      used to investigate AAV-driven NPY expression in postmitotic neurons in vitro and
      in the brain. NPY mRNA was expressed in NT2/N and rat brain primary neuronal
      cultures after transfection. There was a corresponding increase in the number of
      neurons staining for NPY-like immunoreactivity and an increase in NPY release
      during depolarization in the primary cultures. Injections of Sendai-virosome
      encapsulated pJDT95npy into neocortex increased NPY-like immunoreactivity in
      neurons but not glia indicating that the latter cell type did not have the
      translational, post-translational or storage capacity to accumulate the peptide.
      Injections into the rat hypothalamic para-ventricular nucleus increased body
      weight and food intake for 21 days, though NPY-like immunoreactivity remained
      elevated for at least 50 days. These studies demonstrate that AAV-derived
      constructs may be useful for delivering genes into post-mitotic neurons, and that
      Sendai virosomes are effective for delivering these constructs in vivo.

PMID- 8646557
TI  - Efficient transduction of human neurons with an adeno-associated virus vector.
AB  - An adeno-associated virus vector containing a lacZ gene driven by a CMV immediate
      early promoter (AAV beta-gal) was evaluated with respect to its transduction
      efficiency and integration ability in nondividing human NT neurons. A dose
      dependent pattern in transduction efficiency of the AAV beta-gal was demonstrated
      immunocytochemically, with up to 100% of the neurons expressing the gene product.
      No neurotoxic effects of the vector were detected. Quantitative PCR analyses of
      high molecular weight cellular DNA from the transduced neurons indicated that the
      copy number of the AAV beta-gal genome increased gradually in a time dependent
      manner, suggesting a slow but progressive rate of vector integration over a
      period of approximately 1 week following transduction. Equal or greater
      transduction efficiency of the AAV beta-gal into NT neurons than into a standard
      target cell line indicated that the NT neurons were readily susceptible to AAV
      mediated gene transfer. This study demonstrates that AAV-based vectors can
      efficiently transduce and stably express a foreign gene in post-mitotic human
      neurons.

PMID- 8646558
TI  - Gene gun delivery of mRNA in situ results in efficient transgene expression and
      genetic immunization.
AB  - The use of mRNA to transfer genetic information into mammalian somatic cells in
      vivo or ex vivo may be advantageous in a number of gene therapy protocols.
      Success in utilizing in vivo RNA delivery for transgene expression has been
      extremely limited, partially due to RNA instability and to the lack of an
      efficient intracellular delivery mechanism applicable to a wide variety of tissue
      or organ systems. We report here that a particle-mediated gene delivery
      technology can be used to effectively deliver RNA molecules into a number of
      mammalian somatic tissue types. Expression from RNA transcripts of three reporter
      genes, firefly luciferase, human growth hormone and human alpha-1 antitrypsin,
      was detected in monolayer and suspension cell cultures bombarded in vitro, and in
      in vivo bombarded rat liver tissues, and mouse liver and epidermal tissues. Gene
      gun treatment of mouse epidermis in vivo with human alpha-1 antitrypsin messenger
      RNA elicited a strong, consistent antibody response which showed an increased
      titer with subsequent boosts. Results from this study point to future
      opportunities of applying RNA delivery techniques for transgenic studies, genetic
      vaccination, and gene therapy.

PMID- 8646559
TI  - Atomic force microscopic analysis of the influence of the molecular weight of
      poly(L)lysine on the size of polyelectrolyte complexes formed with DNA.
AB  - We are developing self-assembling micellar vehicles based on multifunctional
      block copolymers as well-defined synthetic vehicles suitable for safe in vivo
      delivery of DNA. As a first stage, DNA expression vectors (6 kb) were condensed
      with poly(L)lysine of different molecular weights (3970-224 500) to form
      polyelectrolyte complexes and analysed by atomic force microscopy (AFM). Discrete
      complexes were formed in every case, although the highest molecular weight
      poly(L)lysine preparation (224 500) produced large complexes with significant
      polydispersity (diameters ranging from 120-300 nm), while the smallest
      poly(L)lysine (3970) produced more homogeneous complexes with diameters ranging
      from 20-30 nm. Poly (L)lysine preparations of molecular weight 53 700 and 23 800
      produced complexes of intermediate size and poly-dispersity. The mean volumes of
      the complexes formed using poly(L)lysine 224 500 and 3970 were 606 000 nm3 and
      3700 nm3, respectively. Polyelectrolyte complexes formed using low molecular
      weight poly(L)lysine also showed significantly decreased cytotoxicity. Given
      restrictions of access to many cellular targets and the need for good
      biocompatibility, synthetic vectors based on DNA condensed with low molecular
      weight polycations may be more appropriately developed for general use.

PMID- 8646560
TI  - Cytokines in the central nervous system: regulatory roles in neuronal function,
      cell death and repair.
AB  - Recent evidence suggests that neurons and glia can synthesize and secrete
      cytokines, which play critical roles in maintaining homeostasis in the central
      nervous system (CNS) by mediating the interaction between cells via autocrine or
      paracrine mechanisms. Circulating cytokines and soluble receptors also regulate
      neuronal function via endocrine mechanisms. Disturbance of the cytokine-mediated
      interaction between cells may lead to neuronal dysfunction and/or cell death and
      contribute to the pathogenesis of the CNS diseases (e.g., ischemia, Alzheimer's
      disease and HIV encephalopathy). Defining the molecular pathways of cytokine
      dysregulation and neurotoxicity may help to elucidate potential therapeutic
      interventions for many devastating CNS diseases.

PMID- 8646561
TI  - The role of arginine vasopressin in interleukin-1 beta-induced
      adrenocorticotropin secretion in the rat.
AB  - In this study we examined whether arginine vasopressin (AVP) in the brain is
      involved in the adrenocorticotropin (ACTH) secretion induced by interleukin (IL)
      1 beta in the rat. Human recombinant IL-1 beta (50 ng) was given
      intracerebroventricularly to freely moving male rats with or without a prior (15
      min before) administration of anticorticotropin releasing hormone (CRH) or AVP
      antibody via the same route. The ACTH response to IL-1 beta was significantly
      reduced by both anti-CRH and anti-AVP antisera compared to the levels after
      normal rabbit serum. These results suggest that not only CRH but also AVP may
      mediate the IL-1 beta stimulation of ACTH secretion in the rat.

PMID- 8646562
TI  - In vivo evidence that arginine vasopressin is involved in the adrenocorticotropin
      response induced by interleukin-6 but not by tumor necrosis factor-alpha in the
      rat.
AB  - We examined whether arginine vasopressin (AVP) is involved in the
      adrenocorticotropin (ACTH) response induced by interleukin (IL)-6 or tumor
      necrosis factor (TNF)-alpha in the rat. To accomplish this, we employed
      immunoneutralization of brain AVP by injecting anti-AVP antiserum
      intracerebroventricularly (i.c.v., 3rd ventricle). For comparison, we also tested
      the effect of immunoneutralization of corticotropin-releasing hormone (CRH) in
      the brain. Anti-CRH antibody, anti-AVP antibody, or normal rabbit serum (control)
      was given i.c.v. 15 min before an i.c.v. administration of human recombinant IL-6
      (100 ng) or TNF-alpha (100 ng). Both IL-6 and TNF-alpha significantly elevated
      plasma ACTH levels. The IL-6-induced ACTH response was significantly suppressed
      by both anti-CRH and anti-AVP antibodies. On the other hand, the TNF-alpha
      induced ACTH response was not significantly affected by anti-AVP antibody,
      although anti-CRH antibody could suppress the response. These results suggest
      that the IL-6-induced ACTH response may be mediated by both CRH and AVP, whereas
      the ACTH response to TNF-alpha is only via CRH.

PMID- 8646563
TI  - Localization of interleukin-1 beta converting enzyme mRNA in rat brain
      vasculature: evidence that the genes encoding the interleukin-1 system are
      constitutively expressed in brain blood vessels. Pathophysiological implications.
AB  - Interleukin (IL)-1 beta-converting enzyme (ICE) cleaves the biologically inactive
      precursor form of IL-1 beta into mature, bioactive IL-1 beta. Because of the
      potent effects of IL-1 in blood vessels, we conducted an in situ hybridization
      study to determine whether ICE mRNA is constitutively expressed in adult rat
      brain vasculature. Using in situ hybridization histochemistry, we were able to
      demonstrate that mRNA in blood vessels scattered throughout the brain. In a
      second set experiments, we found that the genes encoding not only ICE, but also
      IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1ra), and the IL-1 type I
      receptor are expressed in brain vasculature. To our knowledge this is the first
      report documenting the expression of the genes encoding all of the functional
      elements of the IL-1 system in the same tissue. Our findings have three
      pathophysiological implications. First, they indicate a possible site where
      peripheral IL-1 may act in the brain. The vascular IL-1 system stimulates the
      production of nitric oxide and prostanoids, which could act as mediators of the
      effects of peripheral IL-1 in the central nervous system. Additionally, vascular
      IL-1 is known to activate adhesion molecules; our data that the genes encoding
      the IL-1 system are expressed in brain vasculature further support the concept
      that IL-1 is implicated in the pathophysiology of atherosclerosis and stroke.
      Finally, in the context of previous studies documenting that IL-1ra inhibits the
      effects of IL-1 on endothelial cells, our findings of endogenous IL-1ra mRNA in
      brain vasculature indicate that IL-1ra might be an endogenous vascular protective
      agent.

PMID- 8646564
TI  - Interleukin-10 inhibits lipopolysaccharide-induced tumor necrosis factor and
      interleukin-1 beta production in the brain without affecting the activation of
      the hypothalamus-pituitary-adrenal axis.
AB  - Interleukin (IL) 10 inhibits endotoxin (lipopolysaccharide; LPS) induced tumor
      necrosis factor (TNF) production in vivo and in vitro. In turn, IL-10 is induced
      by LPS and acts as a negative feedback to limit TNF production. We investigated
      the effects of IL-10 on brain TNF and IL-1 beta production induced by a central
      LPS administration in mice. Because central LPS also induces peripheral TNF, we
      also measured the serum TNF levels. A single intracerebroventricular injection of
      murine recombinant IL-10 (75 ng/mouse) simultaneously with LPS (2.5
      micrograms/mouse) almost completely inhibited brain TNF production. The brain IL
      1 beta production was also inhibited, as was the serum concentration of the acute
      phase protein serum amyloid A. On the other hand, intracerebroventricular
      administration of an anti-IL-10 monoclonal antibody (JES5-2A5; 60
      micrograms/mouse) potentiated brain TNF and IL-1 beta production. Identical
      results were obtained when the serum TNF levels were measured. IL-10 did not
      affect the LPS-induced increase of serum corticosterone, the main endogenous
      inhibitor of TNF production, or the induction of IL-6. These results indicate
      that LPS-induced IL-10 can act as an important endogenous inhibitor of brain TNF
      production and suggest an anti-inflammatory role for IL-10 in the central nervous
      system.

PMID- 8646565
TI  - Immune and endocrine aspects of social and territorial behavior in male rabbits.
AB  - Although there have been some studies of the relation between behavior and
      mitogen-induced lymphocyte proliferation and immunoglobulin synthesis, few data
      are available about the effect of behavior on specific lymphokine production. In
      this study, we describe the effect of social and territorial behaviors on
      interferon-gamma (IFN-gamma) production by concanavalin A-stimulated peripheral
      blood mononuclear cells (PBMCs) in pairs of socially naive male rabbits living in
      a seminatural open-air environment. We also assayed PBMC glucocorticoid receptors
      (GcRs) and plasma corticosterone (C). Three groups of behaviors were identified:
      agonistic (Mount and Follow), affiliative (Groom) and territorial (Mark and Dig).
      Mount was correlated with Follow, while Mark was correlated with Dig. Groom was
      correlated with all the other behaviors. Groom, Mark, Mount and Follow were all
      positively correlated with PBMC GcRs. Groom and PBMC GcRs were each negatively
      correlated with plasma C. The two rabbits in each pair could be distinguished in
      terms of territorial behavior, since one animal always had a higher score. The
      animals with the higher level of territorial behavior within the pairs exhibited
      a significant increase in IFN-gamma production at the end of the experimental
      period. They also showed a positive correlation between the percentage variations
      of IFN-gamma production and PBMC GcRs. It is suggested that social factors,
      especially territorial behavior, affect adrenocortical activity and IFN-gamma
      production.

PMID- 8646566
TI  - Permeability of the blood-brain barrier to soluble cytokine receptors.
AB  - Soluble receptors for cytokines can be important regulators of cytokine function.
      By binding to their cytokine ligands, they act as antagonists and carrier
      proteins. We investigated whether the blood-to-brain saturable transport of human
      tumor necrosis factor-alpha (TNF) and human interleukin-1 alpha (IL-1)
      radioactively labeled with 125I could be blocked by preincubation with their
      soluble receptors. At ratios of 100:1 and 1,000:1 of receptor to cytokine, the
      soluble p75 human receptor to TNF (rhuTNFR:Fc) totally blocked the entry of human
      or murine TNF into the brain. However, the soluble murine receptor to IL-1 (muIL
      1R) only partially blocked IL-1 entry. Radioactively labeled rhuTNFR:Fc and muIL
      1R were not transported across the blood-brain barrier (BBB) and were no more
      able to penetrate the BBB than the vascular marker serum albumin. This indicates
      that the transporter at the BBB for IL-1, but not the one for TNF, can strip the
      cytokine from its soluble receptor. These findings might be useful in determining
      which, if any, of the actions exerted on the brain by blood-borne cytokines are
      due to penetration of the BBB.

PMID- 8646567
TI  - Effects of luteinizing-hormone-releasing hormone, alpha-melanocyte-stimulating
      hormone, naloxone, dexamethasone and indomethacin on interleukin-2-induced
      corticotropin-releasing factor release.
AB  - Our previous studies have shown that the microinjection of interleukin (IL)-2
      into the third ventricle of conscious rats evokes the release of
      adrenocorticotropin hormone (ACTH) and that its incubation with hemipituitaries
      in vitro was also effective in releasing ACTH. In the present experiments, we
      evaluated the effect of IL-2 on the release of corticotropin-releasing factor
      (CRF) from medial basal hypothalami (MBHs) incubated in vitro and studied the
      effect of other agents, whose release is altered in stress, on CRF release. IL-2
      significantly stimulated CRF release at concentrations of 10(-13) and 10(-14) M,
      whereas increasing the concentration to 10(-12) to 10(-10) M did not produce
      significant release of CRF. A high concentration of potassium (55 mM) in the
      medium also significantly stimulated CRF release and this stimulation was not
      modified by IL-2. Since high-potassium-induced release of CRF is probably due to
      opening of voltage-dependent calcium channels, it is likely that IL-2 is
      releasing CRF by this mechanism. Since the release of luteinizing-hormone
      releasing hormone (LHRH) is modified by stress, we evaluated the action of LHRH
      on CRF release and the release induced by IL-2. Although LHRH failed to alter
      basal CRF release, except for a slight decrease at 10(-7) M, it completely
      blocked IL-2-induced CRF release at this concentration. To examine a possible
      role for opioid peptides in CRF release, the opiate receptor blocker, naloxone
      (NAL), was tested. At concentrations of 5 x 10(-6) and 10(-5) M, it produced a
      marked increase in CRF release; however, the simultaneous exposure of MBHs to
      each of these concentrations of NAL plus IL-2 caused a dose-dependent decrease in
      IL-2-induced CRF release, suggesting that beta-endorphin or other opioid peptides
      may play a role in IL-2-induced CRF release. As has been previously shown for IL
      1 and IL-6, IL-2-induced CRF release was blocked by alpha-melanocyte-stimulating
      hormone (alpha-MSH), which at high concentrations also reduced basal CRF release.
      As in the case of IL-1 and IL-2, dexamethasone (DEX), the highly active synthetic
      glucocorticoid, although not altering basal CRF release, completely blocked the
      response to IL-2. The inhibitor of cyclooxygenase, indomethacin (IND), also
      blocked IL-2-induced CRF release just as it has previously been shown to block IL
      1- and IL-6-induced CRF release. The results are consistent with the hypothesis
      that IL-2 acts on its recently discovered receptors to induce an increase in
      intracellular calcium. In other experiments, we have shown that this activates
      nitric oxide (NO) synthase leading to production of NO by a NOergic neuron. NO
      diffuses to the CRF neuron and activates cyclo-oxygenase leading to generation of
      prostaglandin E2, which activates adenylate cyclase and increases cyclic AMP
      release, which then causes extrusion of CRF secretory granules. DEX presumably
      acts on its receptors on the CRF neuron to inhibit the increase in intracellular
      calcium and thereby blocks activation of phospholipase A2 necessary for
      activation of the arachidonic acid cascade. alpha-MSH and LHRH may similarly act
      on their receptors on these cells to, in some manner, block the pathway. On the
      other hand, beta-endorphin and/or other opioid peptides inhibit the pathway.
      Further experiments will be necessary to elucidate the exact points in the
      pathway at which these compounds are effective.

PMID- 8646569
TI  - Acta Ophthalmologica Award 1995.

PMID- 8646568
TI  - Effects of citrus fragrance on immune function and depressive states.
AB  - In our previous experiments on animals evidence was found that citrus fragrance
      can restore the stress-induced immunosuppression, suggesting that citrus
      fragrance may have an effect on restoring the homeostatic balance. Since a
      dysregulation of the neuroendocrine and immune function is thought to be
      associated with psychosomatic or psychiatric disorders an attempt was made to
      restore their mental health by stimulation of one of the sensory systems.
      Fragrance (citrus was our choice) which comforts through stimulation of the
      olfactory system was applied to depressive patients. It was given to 12
      depressive subjects and the results indicated that the doses of antidepressants
      necessary for the treatment of depression could be markedly reduced. The
      treatment with citrus fragrance normalized neuroendocrine hormone levels and
      immune function and was rather more effective than antidepressants.

PMID- 8646570
TI  - Perspectives for optimizing future research in diabetic retinopathy.

PMID- 8646571
TI  - Visual impairment in type 2 diabetic patients. A multicentre study in France.
      CODIAB-INSERM-ZENECA Pharma Study Group.
AB  - The prevalence and causes of visual impairment have been estimated in a sample of
      423 Type 2 diabetic outpatients, aged 35 to 74 years, recruited in 8 centres from
      all parts of France. The presence of retinopathy was assessed by fluorescein
      angiography with centralized interpretation. The presence of cataract and
      glaucoma was also recorded. Prevalence of blindness was 1.2%. Moderate visual
      impairment affected 7% of the patients. The major cause of blindness was
      cataract, explaining 38% of the cases of blindness. Retinopathy was associated to
      blindness in 2 cases out of 26. More than half of the patients with proliferative
      retinopathy and the third of those who had macular edema had been treated by
      photocoagulation. According to the present patient material, retinopathy is a
      minor cause of visual impairment in Type 2 diabetic patients, cataract remaining
      the major cause. This reflects the introduction of photocoagulation into
      ophthalmologic practice.

PMID- 8646572
TI  - Movement hyperacuity threshold deficit in juvenile onset diabetes mellitus.
AB  - Oscillatory movement displacement thresholds from a group of 18 normal children
      (mean age of 9.2 +/- 3.6 years) were compared with those obtained from a group of
      26 age-matched children (mean age of 9.9 +/- 2.9 years) having insulin-dependent
      diabetes mellitus. Disease durations ranged from 6 months to 12 years, although
      no ophthalmoscopic evidence of retinopathy was found in any subject. Up to about
      8 years of age there is no significant difference in the performance of diabetics
      and controls (t = 1.00, p = n.s.), oscillatory movement displacement thresholds
      correlating with age in both groups (r= -0.59, p < 0.02). Over about 8 years of
      age oscillatory movement displacement thresholds no longer improve and the two
      groups perform significantly differently, thresholds being degraded in the
      insulin-dependent diabetes mellitus group compared to normals (t = 5.25, p
      <<0.0001). It is suggested that the measurement of oscillatory movement
      displacement thresholds in children with insulin-dependent diabetes mellitus can
      reveal its effects in the absence of retinopathy.

PMID- 8646573
TI  - Dye laser treatment in proliferative diabetic retinopathy and maculopathy.
AB  - The aim of this study was to compare the efficacy of various dye laser
      wavelengths in different forms of retinopathies. The study material consisted of
      292 eyes of 210 diabetic retinopathy patients treated with dye laser
      photocoagulation between 1990 and 1992. All the patients were followed for at
      least 6 months after photocoagulation. Non-proliferative changes (maculopathy
      and/or preproliferative retinopathy) were present in 135 (46.3%) and
      proliferative retinopathy in 157 (53.7%) of the eyes undergoing photocoagulation.
      Of the 157 eyes with proliferative retinopathy, 60 (20.5%) had disc
      neovascularization, 71 (24.3%) had retinal neovascularization and 26 (8.9%) had
      retinitis proliferans. Yellow dye laser (580 nm) was applied in 92 (31.5%) eyes,
      red dye laser (630 nm) in 120 (41.1%) eyes and both yellow and red dye lasers in
      80 (27.4%) eyes. There was no significant difference between the different
      wavelength groups with regard to visual acuity changes before and after treatment
      (p < 0.01). Overall, the visual acuity was maintained in 56.2% and improved in
      25.0% of the eyes. After panretinal photocoagulation, disc neovascularization
      regressed partially or completely in 47 (78.3%) of the eyes. There was no
      significant difference among the various laser wavelengths with regard to
      treatment efficacy judged by the disappearance or regression of disc
      neovascularization (p < 0.01). All retinal neovascularizations regressed
      completely with laser treatment, but in 7 eyes (9.9%) new retinal
      neovascularizations in previously untreated areas developed. Dye laser has not
      resulted in any complications. It requires lower power settings compared to argon
      laser and thus facilitates photocoagulation. Another advantage of dye laser is
      the ability to use yellow and red wavelengths sequentially.

PMID- 8646574
TI  - The influence of age on the flash visual evoked potentials.
AB  - The effect of age on flash visual evoked potentials was investigate in 148 normal
      subjects aged 6 yo 84 years. The occurrence of the P1 wave progressively
      increased with age, while the P2 wave was recordable in all the subjects. There
      were significant effects of age on the P2 latency (p < or = 0.01). The latency of
      the N1 and N2 waves significantly changed with age. In particular, the N2 wave
      that occurred in the absence of the P1 wave had a latency similar to that of the
      N1 wave was present. We suggest that the cases apparently without the P1 wave
      could be explained with a merging of this was with the P2 wave in a major single
      deflection.

PMID- 8646575
TI  - Receptor and neural visual readaptation after exposure to colored flash.
AB  - The time needed to recover optokinetic nystagmus or electroretinography complexes
      after a glare inducing flash was measured to study the receptor and neural visual
      readaptation. Electroretinographs and optokinetic nystagmus were evoked with low
      intensity stimuli. The light from a flash tube was filtered with an interference
      filter (Tmax = 536 or 622 nm) and evenly distributed into a Goldmann hemisphere
      observed by the subject. The Recovery of the amplitude of the a-wave of the
      electroretinography is quicker than the recovery of optokinetic nystagmus after a
      low intensity glare inducing flash. The recovery time was shorter for a red than
      for a green flash of equivalent dose for both recovery modalities. The time
      difference between electroretinography a-wave and optokinetic nystagmus recovery
      was the same and independent of glare inducing flash wavelength. The recovery of
      the amplitude of the a-wave of the electroretinography was quicker than the
      recovery of optokinetic nystagmus after a low intensity glare inducing flash.
      This time difference between the recovery modalities may in part be due to the
      difference between the physiological stimuli used, but it is believed that most
      of the time difference is because the recovery of optokinetic nystagmus monitors
      more of the afferent visual pathway with complex post receptor neural mechanisms
      than the recovery of the a-wave.

PMID- 8646576
TI  - Dynamics of accommodative vergence movements controlled by the dominant and non
      dominant eye.
AB  - Accommodative vergence responses to accommodative stimuli presented at three
      different amplitudes in a stepwise and a sinusoidal mode to either the dominant
      or the non-dominant eye were studied. The motor control loop was opened by one
      eye viewing the target and the other eye covered. Each eye was stimulated
      monocularly and eye movements were recorded with an infra-red reflection system.
      Latency and time constant of the accommodative vergence response to step
      stimulation or the phase of the vergence response to sine wave stimulation, did
      not vary systematically with stimulus amplitude or eye stimulated. However, the
      gain of the accommodative vergence movements was highest in the non-dominant eye
      at a particular stimulus amplitude. This suggested that accommodative vergence
      angles can vary depending on which eye is leading and driving the accommodative
      vergence system in a specific fixation situation.

PMID- 8646577
TI  - An in vitro study of fusidic acid susceptibility amongst isolates from
      conjunctival swabs.
AB  - The aim of this study was to examine the in vitro activity of fusidic acid
      against bacterial isolates from conjunctival swabs. Conjunctival swabs from 213
      patients with conjunctivitis were examined. One or more pathogens were grown from
      73 patients. Forty per cent of isolates were resistant to fusidic acid on disc
      sensitivity testing. Reduced sensitivity was detected by minimum inhibitory
      concentration testing in many isolates of H. influenzae and an isolate of S.
      pneumoniae. In addition, the in vitro activity of fusidic acid was determined
      against upper respiratory tract isolates of H. influenzae, S. pneumoniae and M.
      catarrhalis; this showed that many isolates had a reduced sensitivity to fusidic
      acid. Topical fusidic acid may not be optimal empiric therapy of bacterial
      conjunctivitis.

PMID- 8646578
TI  - Selenium concentrations in serum, lens and aqueous humour of patients with senile
      cataract.
AB  - Selenium (Sc) is a trace element which incorporates into the selenoenzyme
      glutathion peroxidase. Cataractogenesis may be caused either by the excess or
      deficiency of this trace element. More recently, its potential of becoming a
      possible environmental pollutant has been emphasized. In an attempt to reveal the
      relationship of this element with cataractogenesis, we detected its level in 48
      serum, 36 lens and 9 aqueous humour samples of 48 patients with senile cataract,
      comparing the results with appropriate controls. Selenium levels (mean +/- SD) of
      cataractous patients were found to be 0.28 +/- 0.04 microgram/ml (CI: 0.27 to
      0.29 microgram/ml) in sera (controls: 0.32 +/- 0.04 microgram/ml; CI: 0.30 to
      0.34 microgram/ml, p < 0.0001), 5.43 +/- 3.07 microgram/g dry weight (CI: 4.43 to
      6.43 microgram/g dry weight) in lens (controls: 4.43 +/-2.53 microgram/g dry
      weight; CI: 2.78 to 6.08 microgram/g dry weight; p=0.374) and 0.19 +/- 0.06
      microgram/ml (CI:0.15 to 0.23 microgram/ml) in aqueous humour samples (controls:
      0.31 +/-0.12 microgram/ml; CI: 0.24 to 0.38 microgram/ml, p = 0.02). When patient
      subgroups were analyzed, serum Se levels were found to be 0.28 +/- 0.05
      microgram/ml (CI: 0.26 to 0.30 microgram/ml in the nuclear cataract and 0.28 +/-
      0.02 microgram/ml (CI: 0.27 to 0.30 microgram/ml) in the cortical cataract. Lens
      Se levels, on the other hand, were detected as 5.91 +/- 3.56 microgram/g dry
      weight (CI:4.49 to 7.33 microgram/g dry weight) in the nuclear cataract and 4.47
      +/- 1.40 microgram/g dry weight (CI: 3.68 to 5.26 microgram/g dry weight) in the
      cortical cataract. It is anticipated that decreased Se in aqueous humour and sera
      of patients with senile cataract may reflect defective antioxidative defense
      systems which may lead to the formation of cataract.

PMID- 8646579
TI  - Combined use of argon laser photocoagulation and cryotherapy in the treatment of
      retinopathy of prematurity.
AB  - The purpose of the paper is to describe results of combined use of argon laser
      photocoagulation and cryotherapy in the treatment of stage 3+ retinopathy of
      prematurity in a non-controlled clinical series of 6 premature children with a
      birth weight of 545-1610 g (mean 914 g) and a gestational age of 24-31 weeks.
      Both treatment modalities were performed in the same session, and in 5 cases both
      eyes were treated. Inactivation of the proliferative process was obtained with
      one treatment session in 3 cases, with two treatment sessions in 3 cases. No
      serious late sequelae of retinopathy of prematurity developed in any of the eyes,
      one eye has an ectopic macula and esotropia, and one child has high myopia (-8.0
      D) and exotropia. Laser treatment is less irritating and the scars are less
      pronounced compared with cryocoagulation, but in some cases treatment of the most
      anterior retina with laser is difficult. Combination of the two treatment
      modalities may in these cases give the best result.

PMID- 8646580
TI  - A simple and effective video keratometric system.
AB  - We tested a personal computer-based video keratometric system used to analyze
      projected placido disk rings. The system consists of a Maloney surgical
      keratometer that projects the rings and a video camera attached to an operating
      microscope. Images of the rings were transmitted to a video image processing
      board and analyzed on a personal computer using an analysis program we developed.
      System precision was evaluated in 18 eyes. The values were compared with those
      obtained using a commercial photokeratometer (control). In all eyes, the
      principal meridian values differed from the controls by < 0.04 mm. In 15 eyes
      (83%), the measurements were within 0.03 mm of the controls. The corneal
      astigmatism values and cylindrical axes were within 0.12 diopters in 17 eyes
      (94%) and within 5 degrees in all cases, respectively. Our system, which can
      analyze placido disc rings projected from other systems, is sufficiently precise
      to measure the corneal radius of curvature and astigmatism.

PMID- 8646581
TI  - Prognostic indicators following enucleation for posterior uveal melanoma. A
      multivariate analysis of long-term survival with minimized loss to follow-up.
AB  - Most previous reports on survival following enucleation for uveal malignant
      melanoma do not contain cumulative survival rates, do not use a multivariate
      approach and are liable to a considerable loss to follow-up. In this study, the
      long-term survival and tumour-related mortality were studied in 340 patients.
      Archival specimens containing posterior uveal melanomas were initially examined
      and sectioned by one pathologist. There was no loss to follow-up 6 to 22 years
      after enucleation. At the end of study, 233 (68.5%) individuals were dead; 137
      (40.3%) of melanoma-related causes and 96 (28.2%) of other causes. Melanoma
      related deaths appeared from 24 to 6848 days (18 years 8 months) after
      enucleation. The cumulative 5-year survival proportion based on melanoma-related
      deaths was 70% and the corresponding 10-year proportion was 56%. Multivariate Cox
      regression indicated that the largest tumour dimension, cell type, and tumour
      location all had independent prognostic value, the associated hazard ratios
      ranged from 1.2 to 1.4, suggesting a moderate increase of the relative risk. Pair
      wise comparisons of the parameters indicated that large tumours were more common
      in the anterior choroid or ciliary body than in the posterior choroid. Similarly,
      large tumours were more often necrotic, composed of epitheloid cells, or featured
      extrascleral extension. Tumours with significant scleral invasion or extrascleral
      extension were more common in elderly patients.

PMID- 8646582
TI  - Epidemiology of endogenous uveitis in south-western Finland.
AB  - We studied the case records of 1122 patients with endogenous uveitis including
      418 new cases treated at the University Eye Clinic in Turku during the years 1980
      1982 and 1988. The mean annual incidence and prevalence rates of anterior uveitis
      were, respectively, 21.3 and 68.7 per 100,000, of posterior uveitis 0.8 and 4.6
      per 100,000, of panuveitis 0.2 and 0.8 per 100 000, and of all uveitis cases 22.6
      and 75.4 per 100,000 population. The incidence of uveitis was higher in the age
      group 20-69 years than in the age groups 0-19 years (p < 0.001) and 70 years or
      over (p = 0.049). The incidence rates were not different between sexes in any age
      group (p = 0.2). The incidence of uveitis was higher in lower socio-economic
      groups than in higher socio-economic groups (p < 0.001). There were no
      significant differences in the incidence of uveitis between sexes in different
      socio-economic groups (p = 0.1).

PMID- 8646583
TI  - Results of out-patient cataract surgery in patients who live far from the
      surgeon.
AB  - We have performed this prospective study to address the question of whether there
      is an association between the outcome following cataract surgery and the distance
      from the patient's home to the place of surgery. Three hundred and forty
      consecutive out-patient extracapsular cataract extractions were evaluated.
      According to the distance, the cases were grouped into two categories, 183 cases
      in the nearest group (Group 1) and 157 cases in the farthest group (Group 2). A
      best corrected visual acuity of 0.5 or better was achieved in 90% of patients, 6
      between the groups. No significant differences in rates for operative and
      postoperative complications were identified. This study does not show that the
      distance from the patient's home to the surgical site has had any adverse effect
      of surgical outcome or in rates of complications.

PMID- 8646584
TI  - Sports-related eye injuries.
AB  - At the University Eye Hospital of Lund 272 patients were treated following blunt
      trauma during a two and half year period. The number of cases related to sports
      activity were extracted. The major sports responsible for the injuries and the
      type of injuries were identified and also an investigation into the sex and age
      distribution was made. Forty percent of the total number of cases were sports
      related. Floor ball was responsible for 46% of these cases.

PMID- 8646585
TI  - Ocular side effects associated with 13-cis-retinoic acid therapy for acne
      vulgaris: clinical features, alterations of tearfilm and conjunctival flora.
AB  - Isotretinoin (13-cis-retinoic acid) is commonly used for the treatment of acne
      vulgaris. We included 55 patients in this prospective study, and inspected them
      before, while and after therapy with isotretinoin regarding ocular side effects.
      Careful slit-lamp inspection, measurement of break-up-time and Schirmer-test and
      microbiological investigations of the conjunctival flora were performed. While
      staphylococcus aureus was cultured from the conjunctival sac before application
      of isotretinoin in 7.3%, this percentage increased to 61.8% during therapy. A
      pathological decrease of break-up-time was realized in 69.1% of the cases, the
      development of blepharitis in 40%. But in spite of the alteration of conjunctival
      flora, bacterial conjunctivitis developed in just 7.3% of the cases. However,
      only 34.5% of the patients showed symptoms of a conjunctivitis sicca, in spite of
      the impressive diminution of break-up-time in so many cases. All ocular side
      effects of isotretinoin were treatable and disappeared completely within 1 month
      after stopping therapy.

PMID- 8646586
TI  - Two outbreaks of adenovirus type 8 keratoconjunctivitis with different outcome.
AB  - In 1993, a case of adenovirus type 8 keratoconjunctivitis acquired in Central
      Europe was the starting point of an outbreak in Malmo, Sweden. Of the 33
      diagnoses cases, 23 were infected nosocomially. In 29 the diagnosis was verified
      by virus culture. The outbreak was recognised 15 days after the appearance of the
      first secondary case. Nosocomial transmission was stopped by protective measures
      which didn't include separation of the infected patients from others.
      Epidemiologic investigation disclosed unrecognised infections as the main source
      of virus transmission; contaminated hands and a dropper bottle appeared to be
      major vectors. A new case of adenovirus type 8 infection, again introduced from
      Central Europe, turned up in September 1994. There was only one secondary case.

PMID- 8646587
TI  - Tissue plasminogen activator (tPA) to facilitate removal of post-traumatic
      submacular haemorrhage.
AB  - A case report is presented of a 20-year-old man, who had posttraumatic choroidal
      rupture and thick submacular haemorrhage. The haemorrhage was successfully
      removed with vitrectomy and intraoperative fibrinolysis with subretinal tissue
      plasminogen activator. Six months postoperatively the visual acuity was 0.7
      (6/9).

PMID- 8646588
TI  - The HNK-1 carbohydrate epitope in the anterior segment of the eye. The inner
      connective tissue layer of the human ciliary body as a distinct element.

PMID- 8646589
TI  - Biomechanical studies of the human cornea. Development and application of a
      method for experimental studies of the extensibility of the intact human cornea.

PMID- 8646590
TI  - Excimer laser photo refractive keratectomies--yes or no!

PMID- 8646591
TI  - [Proceedings of 24th annual meeting of the Japanese Society of
      Neuropsychopharmacology].

PMID- 8646592
TI  - Cystic degeneration and carcinogenesis of the kidney.

PMID- 8646593
TI  - Early disease progression after intravesical bacillus Calmette-Guerin (BCG)
      therapy for superficial bladder cancer.
AB  - BACKGROUND: Disease progression after Bacillus Calmette-Guerin (BCG) instillation
      therapy for bladder cancer is not rare. The purpose of this study was to evaluate
      the outcome of patients treated with BCG for superficial bladder cancer, focusing
      on the patients who developed invasive disease during follow-up. The possible
      mechanism and risk factors for early progression after BCG therapy are discussed.
      METHODS: A total of 25 patients with superficial bladder cancer (pTa, pT1 and/or
      pTis) were treated with intravesical BCG instillation (80 mg in 80 ml saline)
      once a week for eight weeks. Four of the 25 patients received maintenance therapy
      with BCG (once a month for 3 to 10 months). Patients were followed every three
      months and underwent cystoscopy, biopsy, and urinary cytology at these intervals.
      Disease progression was defined as invasion to muscle or prostate, or development
      of metastatic disease. Clinicopathological features of the patients, especially
      those with progression, were analyzed. RESULTS: Progression was observed in six
      of the 25 patients, (including four of 19 patients with carcinoma in situ and two
      of five patients treated prophylactically with BCG). The average time to
      progression was 8.7 months. Four patients died of cancer despite intensive
      treatment. Two patients are alive: one without evidence of disease after
      cystectomy and the other with metastatic disease. CONCLUSIONS: Proper patient
      selection, careful follow-up, and immediate aggressive therapy in case of
      progression were considered to be important factors to obtain satisfactory
      results with BCG therapy for bladder cancer.

PMID- 8646594
TI  - Microlith formation in vitro by Madin Darby canine kidney (MDCK) cells.
AB  - BACKGROUND: The mechanism of renal stone genesis as well as the location of stone
      crystal formation in the kidney remains unclear. Possible sites of stone
      generation are either in the tubular lumen or tubular cell. METHODS: We cultured
      Madin Darby canine kidney (MDCK), LLC-PK1 and Magen Krebs Niigata-28 (MKN-28)
      cells in DMEM + 10% FBS medium in a well without passage for 30 days. RESULTS:
      MDCK cells produced microliths at the basolateral side but not on the lumen side
      of these cells. The other two cell lines did not form microliths. CONCLUSION: Our
      data show that microlith formation is a characteristic of MDCK cells and that
      biological mineralization of MDCK cells may serve as a human urolithiasis model
      in vitro. The findings support a significant role of the renal distal convoluted
      tubule and collecting ducts in the in vitro generation of urinary stones.

PMID- 8646595
TI  - Carbonate in struvite stone detected in Raman spectra compared with infrared
      spectra and X-ray diffraction.
AB  - BACKGROUND: In regard to identify the compositions of urinary stones, the
      infrared spectra is a contemporary routine method. However, it is difficult to
      detect the absorption of carbonate in struvite stone by infrared spectra, because
      NH4 absorption of magnesium ammonium phosphate overlaps CO3 absorption of
      carbonate at 1420-1435 cm-1. With the purpose of demonstrating the existence of
      carbonate in struvite stones, the analysis of these stones by means of Raman
      spectra has been tried. METHODS: Forty urinary stones, the chemical compositions
      of which were previously determined by infrared spectroscopy, were submitted to
      Raman spectrum analysis, and subsequently to analysis by x-ray diffraction.
      RESULTS: Thirty of 40 urinary stones were found to be composed of struvite and of
      mixed struvite-calcium oxalate by infrared analysis. Twelve of these stones were
      shown to have Raman spectra of magnesium ammonium phosphate, and the other stones
      to have spectra of apatite. By x-ray diffraction magnesium ammonium phosphate
      crystals were detected in 25 of these struvite stones and hydroxyl-apatite in
      another 3, and 2 cases were undeterminable. For other components, such as calcium
      oxalate, uric acid and cystine, the analytical results of infrared spectra
      coincided with those of Raman spectra and x-ray diffraction. Carbonate was
      detected in only a part of one struvite stone by Raman spectra. CONCLUSIONS:
      Above-mentioned results may indicate that carbonate is only a minor component of
      urinary stones. Therefore, most of 1420-1435 cm-1 bands on the infrared spectra
      of struvite stones do not indicate CO3 absorption of carbonate, but NH(4)
      absorption of magnesium ammonium phosphate.

PMID- 8646596
TI  - Reduction of oxalate content of foods by the oxalate degrading bacterium,
      Eubacterium lentum WYH-1.
AB  - BACKGROUND: Urinary oxalate may contribute far more than urinary calcium to the
      pathogenesis of urinary calculi. Urinary oxalate may be reduced by restricting
      the intake of foods high in oxalate. The oxalate content foods might be reduced
      by oxalate-degrading bacteria. The purpose of this experiment was to reduce the
      oxalate content of foods with an oxalate-degrading bacterium which was isolated
      from the feces of Japanese male. METHODS: An artificial intestinal juice was
      prepared by modifying Rogosa medium. An infusion of black tea was prepared from a
      commercial tea bag. The oxalate-degrading bacteria used were Eubacterium lentum
      WYH-1 which were have isolated. To 5 ml of the above oxalate-containing
      artificial intestinal juice and infusion of black tea, 0.5 ml of the bacterial
      culture was added and incubated anaerobically at 37 degrees C. Oxalic acid in the
      supernatant of the culture medium was assayed by high-performance liquid
      chromatography. RESULTS: In 24 hours, 1 x 10(6) cells/ml of Eubacterium lentum
      WYH-1 decomposed 100% of 1 mg/ml oxalate in the artificial intestinal juice. The
      oxalate in the black tea infusion (1 mg/mL) was also decomposed completely within
      48 hours by 1 x 10(7) cells/mL of bacteria. CONCLUSION: Eubacterium lentum WYH-1
      was able to efficiently decompose the oxalate in foods.

PMID- 8646597
TI  - Transurethral balloon laser thermotherapy: effects of a directionally shielded
      balloon in canine prostates.
AB  - BACKGROUND: Transurethral balloon laser thermotherapy (TUBAL-T) improves
      objective, but not subjective, symptoms of benign prostatic hyperplasia (BPH). We
      studied whether or not an Nd:YAG laser beam with a shielded balloon could
      successfully irradiate the prostate during TUBAL-T in selective manner, to
      improve the subjective symptoms. METHODS: TUBAL-T was performed on canine
      prostates using the balloon with a laser probe, which was shielded anteriorly at
      90 degrees (from the center of the balloon) and posteriorly at 90 degrees.
      RESULTS: At 20 watts laser power, the relative power density in the bilateral non
      shielded areas was 17.4 and 17.8, and in the shielded area it was 1.0.
      Observation by thermography revealed that the temperature after laser radiation
      in a non-shielded area of a fish cake phantom was higher than in a shielded area.
      Following transurethral thermotherapy using a shielded balloon in dogs, a cavity
      was formed bilaterally around the urethra, and the tissues at the anteroposterior
      sides and the urethra were preserved. CONCLUSIONS: TUBAL-T, which has been
      performed in clinical cases of benign prostatic hyperplasia, might be useful in
      selective irradiation of adenoma if a shielded balloon is used.

PMID- 8646598
TI  - Insulin-like growth factor (IGF) system components in human prostatic cancer cell
      lines: LNCaP, DU145, and PC-3 cells.
AB  - BACKGROUND: Evidence has been accumulating that in many tumors, insulin-like
      growth factors (IGFs) promote cancer cell growth in an autocrine/paracrine manner
      via the IGF-I receptor. In an effort to understand the role of IGFs in prostate
      cancer cell growth, we characterized the IGF system components produced by human
      prostatic cancer cell-lines, LNCaP, DU145, and PC-3, grown in serum-free medium.
      METHODS: IGFs, their receptors, and IGF binding proteins (IGFBPs) produced by the
      three human prostate cell lines were characterized by reverse transcriptase
      polymerase chain reaction (RT-PCR), radioimmunoassay (RIA), Western ligand blot,
      Western immunoblot, and Northern blot analyses. RESULTS: mRNA for IGF-II and
      receptors for IGF-I and IGF-II were detected in all three cell-lines by RT-PCR.
      In contrast to the published study, only LNCaP cells expressed a trace amount of
      IGF-I mRNA. RIA on conditioned media collected from these cells revealed that all
      three cell-lines produced measurable IGF-II but not IGF-I. Western Ligand blot,
      Western immunoblot, and Northern blot analyses revealed that LNCaP, DU145, and PC
      3 cells expressed IGFBP-2, IGFBP-2/-3/-4/-6, and IGFBP-2/-3/-4/-5/-6,
      respectively. IGF-II stimulated [3H]thymidine incorporation into DNA in DU145 and
      PC-3 cells significantly although the effect was small. DNA synthesis in PC-3
      cells but not in LNCaP and DU145 cells was significantly inhibited by the IGF-I
      receptor-specific monoclonal antibody. CONCLUSION: Theses results suggest
      potentially important roles of IGFs and IGFBPs in prostate cancer cell growth,
      and that in particular, IGF-II may play a critical role in prostate cancer cell
      growth.

PMID- 8646599
TI  - Mechanisms of veno-occlusion within and outside the canine corpus cavernosum
      penis using a pressure-flow technique and cavernoso-venography.
AB  - BACKGROUND: Physiological erection of the penis requires multiple mechanisms
      causing an increase in the arterial blood influx into, and decrease in the venous
      drainage out of the cavernous space. METHODS: We investigated the extent and
      location of the venous occlusion that occurs with penile erection within
      (intrinsic mechanism) and outside (extrinsic mechanism) the corpus cavernosum
      penis, using 15 adult male mongrel dogs. Under controlled flows produced by a
      combination of aortic ligation and constant infusion of saline into the corpus
      cavernosum penis, or into the deep dorsal vein, pressures within the cavernous
      space or deep dorsal vein were measured before and after electrical stimulation
      of the pelvic splanchnic (pelvic nerve), the hypogastric, and pudendal nerve. An
      increase in pressure following nerve stimulations represented an increase in
      outflow resistance due to occlusion of the venous system. Pre-and post
      stimulation radiologic evaluations were performed to determine the site(s) of
      venous occlusion. RESULTS: Unilateral stimulation of the pelvic nerve caused
      leftward shift of the corporeal pressure-flow curve. Bilateral stimulation of the
      pudendal nerve caused a marked rise in deep dorsal vein pressure. CONCLUSIONS:
      Both intrinsic and extrinsic venous occlusion mechanisms exist and that the
      former is activated primarily by unilateral stimulation of the pelvic nerve and
      the latter by bilateral stimulation of the pudendal nerve. The occlusion site for
      the extrinsic mechanism was localized to where the dorsal vein penetrates the
      muscles at the base of the pelvis, whereas the precise site for the intrinsic
      mechanism could not be determined.

PMID- 8646600
TI  - Parturition in six renal allograft recipients.
AB  - Between 1983 and 1994, we studied renal function and neonatal conditions for
      eight pregnancies and births to six women who had received renal transplants in
      order to assess the effect of an allograft on pregnancy and its outcome. The
      gestation period was 34 to 39 weeks (mean 36 weeks and 4 days), and four
      pregnancies ended before term. All eight babies were delivered by cesarean
      section. Intrauterine growth retardation (IUGR) was found in both babies of one
      woman who had been treated with conventional (without cyclosporin)
      immunosuppression. The serum creatinine level did not change during gestation in
      any of the women but was elevated after delivery in four. Four mothers suffered
      from proteinuria (25-364 mg/dl) during gestation, but the proteinuria disappeared
      after delivery in all but one case. The one exception, persistent proteinuria of
      100-200 mg/dl, was assumed to result from the recurrence of the original renal
      disease (lgA nephropathy). The reduction of creatinine clearance and
      hydronephrosis of one graft noted during gestation were later reversed. None of
      the eight babies (four females and four males) was congenitally malformed, and
      their Apar scores were 6 to 9 (median 8). They are now 3 months to 11 years old,
      and seven of them are healthy and show good growth. One of the two IUGR babies
      has not grown well; her weight and height are more than 1 SD below the mean for
      her age, and she is mentally retarded and suffers from muscle weakness. Compared
      with dialysis patients, female renal allograft recipient have a better quality of
      life because they can safely deliver a child if they observe the criteria for
      pregnancy established for renal allogaft recipients.

PMID- 8646601
TI  - Extracorporeal shock wave lithotripsy in von Willebrand's disease.
AB  - A renal calculus in a patient with von Willebrand's disease was successfully
      fragmented by extracorporeal shock wave lithotripsy (ESWL) with the
      administration of Haemate P. No serious bleeding was observed after ESWL. With
      supplementation of the missing von Willebrand's factor, ESWL may be applied to
      patients with this bleeding diathesis.

PMID- 8646602
TI  - Adrenal myelolipoma associated with hereditary spherocytosis.
AB  - Myelolipomas are benign tumors composed of mature fat and bone marrow elements.
      We report a case of adrenal myelolipoma associated with hereditary spherocytosis
      which was treated with splenectomy seventeen years ago. The hematopoietic
      stimulus of the hereditary spherocytosis might have been associated with the
      development of adrenal myelolipoma in the present case.

PMID- 8646603
TI  - Primary adenocarcinoma in an ileal conduit.
AB  - Reports of primary small intestine malignancies are rare. Even more uncommon is
      primary carcinoma in an ileal conduit. Here, we report a case of primary
      adenocarcinoma in an ileal conduit that developed 14 years after radical
      cystectomy and diversion to an ileal conduit for transitional cell carcinoma of
      the bladder. To our knowledge, only one case of primary adenocarcinoma developing
      in an ileal conduit after a radical surgery for bladder cancer has been reported
      previously.

PMID- 8646604
TI  - Acute renal failure in a patient with chronic glomerulonephritis after the
      administration of luteinizing hormone-releasing hormone analogue given for rectal
      obstruction due to prostate cancer.
AB  - We report a case in which rectal obstruction due to prostate cancer was
      exacerbated due to an ileus after the administration of luteinizing hormone
      releasing hormone analogue. The obstruction to led to copious vomiting,
      dehydration and renal failure which necessitated hemodialysis. Improvement of the
      patient was noted four weeks after the start of hormonal treatment with a
      decrease in rectal obstruction concomitant with decreases in testosterone and
      prostate specific antigen levels.

PMID- 8646605
TI  - Testicular cancer in father and son.
AB  - The occurrence of testicular tumors in closely related family members is rare. We
      report a case of testicular cancers in a father and son. The father had pure
      seminoma, and his son developed a mixed nonseminomatous germ cell tumor. The
      peripheral blood lymphocytes in both patients were tested for 52 HLA
      specificities, and the patients were found to have six in common. The son was
      homozygous for HLA A24. The association between certain HLA antigens, other
      genetic factors, and testicular cancer requires further study to improve the care
      and counseling of patients and their families.

PMID- 8646606
TI  - Intravesical ureterocele presenting bladder outlet obstruction in an adult male.
AB  - Large ureteroceles in adult males causing bladder outlet obstruction are rare. We
      report a case of a large intravesical orthotopic ureterocele in an adult male
      presenting as acute urinary retention. Incisional transurethral endoscopy was
      successful with decompression of ureteral end obstruction, enabling smooth
      urination immediately and no occurrence of vesicoureteral reflux.

PMID- 8646607
TI  - A case of angiomyolipoma diagnosed by thin slice non-enhanced CT and needle
      biopsy.
AB  - We report a case of a 52-year-old female with two intrarenal tumors in the left
      kidney and a contralateral non-functioning kidney. Two renal cell carcinomas were
      suspected on 10mm and 5mm thick slices of computed tomography (CT), while
      angiography could not exclude a diagnosis of angiomyolipoma. Thin section (2 mm
      thick) non-enhanced CT detected negative attenuation values (indicative of fat)
      within both tumors, but these values were higher than the value for normal fat
      tissue. Negative attenuation values within the tumor using non-enhanced thin
      sections are thought to be essential for a CT diagnosis of angiomyoplipoma,
      especially when angiomyolipoma is difficult to distinguish from renal cell
      carcinoma. We performed an ultrasonography-guided needle biopsy of the tumor and
      pathological examination confirmed the diagnosis of angiomyolipoma, consisting of
      rich angiomyomatous element and small amount of mature adipose tissue.

PMID- 8646608
TI  - [Expectancy effect in recognition of persons, or: on the tendency to corroborate
      perceptual hypotheses].
AB  - Two policemen who had been following and observing two young men for several
      hours appeared as witnesses in a criminal court case. They claimed that they had
      observed the young men from a distance of 375 meters putting concrete slabs onto
      a railway track. In order to determine whether person identification is possible
      at a distance of 375 meters, a field experiment was carried out. The results show
      that person identification at a distance of 375 meters is almost impossible. Any
      spontaneous identification with the naked eye is based on expectations. When
      using a pair of binoculars, identification is possible, but the rate of false
      alarms is higher than 60 percent. The results are discussed with reference to
      theories of perceptual and social psychology.

PMID- 8646609
TI  - [Experimental analysis of processing stressful information: differential and age
      related psychological aspects].
AB  - In two experimental studies with older subjects, the differential accessibility
      of palliative interpretations of negative situations was investigated using a
      scenario paradigm. Short episodes (formulated in a self-referent manner) were
      presented on a CRT-screen. Each story contained a palliative and distressing
      interpretation of a negative life situation. In a recognition test, the reaction
      time and the error variable were used as an index of accessibility of those
      aspects. In a pilot study (N = 62; age of subjects 49-79 years), it was found
      that the dispositional tendency to reinterpret negative life situations flexibly
      correlates positively with the accessibility of palliative information. Using a
      priming approach in the main study, it was shown that this result is based on a
      differential moderated association of the negative life-event and the type of
      information (i.e., palliative or distressing) (N = 120; age of subjects: 56-80
      years). Especially with respect to scenarios which are centered on age-related
      declines, results were more pronounced with increasing age. The results are
      discussed in terms of a theory which contrasts active-instrumental efforts of
      coping with accommodative mechanisms of adjustment and reinterpretation.

PMID- 8646610
TI  - [Recall errors in locating cities on a map].
AB  - Three experiments investigated whether hindsight bias--a systematic distortion of
      the recollections of numerical estimates--is also observed with visuo-spatial
      material. Subjects estimated the location of 20 German cities on an empty map,
      received feedback about the true locations, and were then requested to recall
      their earlier estimates. Additionally, we tested each subject's intelligence,
      field dependency, and visuo-spatial abilities. In experiment 1, in which
      experimental and control items (i.e. those with and without feedback) were given
      to the same subjects, hindsight bias was observed, but only in one out of three
      dependent measures. The same pattern of results emerged in experiment 2, despite
      the use of a different mode of data collection. Experiment 3, in which
      experimental and control items were given to different subjects, found a strong
      hindsight bias in all three dependent measures. The personality features showed
      no correlation with the amount of individual hindsight bias. All three
      experiments provided evidence that hindsight bias occurs with visuo-spatial
      material.

PMID- 8646611
TI  - [Cognitive load and listener orientation in monologue instruction].
AB  - It was experimentally tested whether high mental workload adversely affects the
      listener-adaptation of speakers giving an instruction. Forty-five subjects were
      randomly assigned to one of three groups with either low or high mental workloads
      and gave instructions on the assembly of a small machine model. Speakers in the
      low workload condition had the model available while instructing, whereas
      speakers in the high workload condition had to recall the assembly without
      external aids. In a third group, speakers were given a secondary task while
      instructing. Only in the low load condition were instructions apparently adapted
      to the listener. High load and dual task conditions, on the other hand, yielded
      messages that were equivalent as to their contents, regardless of the different
      communicative tasks. Additional assessment of speech characteristics demonstrated
      the experimental manipulation of mental workload to be effective. Results suggest
      that decreased listener-adaptation reflects a dissociation of the communicative
      demands of listener-adapted speech and the cognitive resources to meet these
      demands.

PMID- 8646612
TI  - Regulation of metallothionein in teleosts: induction of MTmRNA and protein by
      cadmium in hepatic and extrahepatic tissues of a marine flatfish, the turbot
      (Scophthalmus maximus).
AB  - Synthesis of the heavy metal-binding protein metallothionein (MT) was determined
      in the major organs of accumulation of Cd (liver, kidney and gills) of a marine
      flatfish, the turbot, after intraperitoneal (i.p.) administration of varying
      doses of Cd. Synthesis of MTmRNA and MT were linearly related to dose only at low
      Cd dosages (up to ca. 100 micrograms Cd/kg). Induction of MTmRNA was rapid,
      peaking 1-2 days after Cd administration in gills and kidneys, at 4 days in
      liver. In all three tissues, at low doses of Cd, MTmRNA levels declined with an
      apparent half life of 5-7 days and for a given dose of Cd, similar MTmRNA
      concentrations were attained. Induction of MT levels temporally followed that of
      MTmRNA. Steady state levels of MT were attained more quickly at a low dose of Cd.
      At acute Cd doses of > 200 micrograms Cd/kg, MT gene transcription and protein
      translation appeared to be progressively reduced, inferring that the rate of MT
      synthesis was limiting due to cytotoxicity of the high acute Cd dosage. In
      contrast to MTmRNA levels which were induced to similar levels in the three
      tissues, MT levels decreased in the order liver > kidneys > gills implying
      differences in translational processes.

PMID- 8646613
TI  - Metallothionein research in terrestrial invertebrates: synopsis and perspectives.
AB  - While most of metallothionein research during the past years has been carried out
      on mammals or vertebrates, only relatively few studies have been directed towards
      invertebrates. Even fewer investigations have focussed on terrestrial
      invertebrates. The best studied metallothioneins and/or metallothionein genes
      among terrestrial invertebrates are those from an insect species (Drosophila
      melanogaster), a nematode (Caenorhabditis elegans) and some terrestrial
      gastropods (Helix pomatia, Arianta arbustorum). From these few examples it
      already appears that terrestrial invertebrate metallothioneins provide intriguing
      models to better understand the multiplicity of functions of these proteins and
      their evolution within the animal kingdom. Like in mammals, metallothioneins in
      terrestrial invertebrates seem to perform different functions simultaneously.
      This is exemplified by terrestrial gastropods, which are able to accumulate
      different metals in different tissues, in which metal-specific metallothionein
      isoforms or conformation forms are expressed, allowing these organisms to
      detoxify more efficiently nonessential trace elements such as cadmium, and at the
      same time to maintain the homeostasis of essential trace elements such as copper.
      A major proportion of metallothionein research in terrestrial invertebrates
      addresses the ecophysiological and ecotoxicological significance of these
      proteins with regard to the increasing risk due to chemical pollution. One
      promising aspect in this concern is the potential utilization of metallothioneins
      as biomarkers for risk assessment in terrestrial environments.

PMID- 8646614
TI  - Role of metallothioneins in metal regulation by the guillemot Uria aalge.
AB  - Guillemots, like other seabird species living in the North Sea, appear to be
      heavily contaminated by copper. Metallothioneins are present in both liver and
      kidney but, at least in the specimens stranded along the Belgian coast, fail to
      maintain constant the copper, zinc and cadmium load of the high molecular weight
      soluble proteins of both organs, stressing the potential toxic role of these
      metals, mainly copper.

PMID- 8646615
TI  - Production of reactive oxygen species by hemocytes from the marine mussel,
      Mytilus edulis: lysosomal localization and effect of xenobiotics.
AB  - Hemolymph of M. Edulis is rich in phagocytic hemocytes. Hemocytes contain
      numerous lysosomes which, in turn, contain various hydrolytic enzymes. Phagocytic
      activity of M. edulis hemocytes is thought to be associated with NAD(P)H-oxidase
      activity of the plasma membrane. The laser dye, dihydrorhodamine 123 (DHR), was
      used for cytochemical and biochemical detection of the generation of reactive
      oxygen species (ROS) by isolated M. edulis hemocytes. Hemocytes readily take up
      DHR from the suspension medium and selectively concentrate it in the lysosomes,
      wherein DHR is oxidized to fluorescent rhodamine 123. Concomitant uptake of DHR
      with superoxide dismutase or the spin-trap, tert-phenylbutyl nitrone, but not
      catalase markedly reduced fluorescence in the lysosomes implicating superoxide
      anion (O2-) but not hydrogen peroxide (H2O2) in DHR oxidation. Uptake of the
      anthraquinone, purpurin, and FeEDTA with DHR greatly amplified fluorescence
      within the lysosomes. These data are consistent with uptake of xenobiotics by
      hemocytes and their concentration in lysosomes wherein, ROS are generated in
      response to their accumulation. The rate of DHR oxidation by hemocytes was not
      stimulated by zymosan, a known stimulator of the oxidative burst. In vitro
      studies using the xanthine oxidase/hypoxanthine reaction to generate O2- and
      selective inhibitors of ROS production indicated that DHR is oxidized by O2- and
      H2O2 but not by .OH and that iron can participate in the reaction. Incubating
      isolated hemocytes promoted low-level, SOD-sensitive, FeEDTA-stimulated
      production of ethylene from alpha-keto-gamma-methiolbutyric acid, indicating the
      in situ formation of .OH via production of O2-. The above suggest that enhanced
      production of ROS in M. edulis hemocytes by xenobiotic accumulation within the
      lysosomal compartment should be considered in the toxic sequelae of exposure of
      marine molluscs to chemical pollutants.

PMID- 8646616
TI  - Effect of tumor-promoting and anti-promoting chemicals on the viability and
      junctional coupling of human HeLa cells transfected with DNAs coding for various
      murine connexin proteins.
AB  - Gap-junctional intercellular communication is thought to be essential for
      maintaining cellular homeostasis and growth control. Its perturbation entails
      toxicological implications and it has been correlated with the in vivo tumor
      promoting potential of chemicals. Little is known about the mechanism(s)
      responsible for the tumor promoters interference with the cellular coupling.
      Moreover, nongenotoxic carcinogens, as well as connexins (gap-junctional protein
      subunits), are known to be organ-/tissue-specific; this implies that the effect
      of different agents should be evaluated on their specific target, that is,
      connexin. To investigate the role of different connexins in regulating gap
      junctional gating and to compare the properties of homotypic junctional channels,
      we evaluated the effects of tissue-specific tumor promoters and anti-promoters on
      the viability and intercellular coupling (dye-transfer) of HeLa cells stably
      transfected with cDNAs coding for connexin(cx)43, cx40, cx26 and cx32. The
      results demonstrate that the transfectants possess individual junctional
      permeabilities, differentially affected by the chemicals, they also show
      different sensitivities to the cytotoxic effect of the compounds. These findings
      confirm that connexin diversity may be responsible for the different gating
      properties of gap-junctional channels, being also suggestive for their separate
      functions and independent regulatory mechanisms.

PMID- 8646617
TI  - [Prognostic criteria of breast cancer metastasis to the lungs].

PMID- 8646619
TI  - [Changes in blood supply of the pancreas in patients with gastric cancer after
      surgery].

PMID- 8646618
TI  - [Features of angioarchitectonics of gastric tumors in the etiology of
      hemorrhage].

PMID- 8646620
TI  - [Method of selective catheterization of the gastric artery for regional
      chemotherapy].

PMID- 8646621
TI  - [Thyroid status in patients with stomach cancer].

PMID- 8646622
TI  - [Experience and perspectives in the use of liposomal form of antineoplastic drugs
      in clinical oncology].

PMID- 8646624
TI  - [Treatment of patients with neurogenic neoformations of the small pelvis].

PMID- 8646623
TI  - [New methods in the treatment of malignant melanoma of the skin].

PMID- 8646625
TI  - [Characteristics of the morphological structure of malignant tumors of the
      adrenal medulla].

PMID- 8646626
TI  - [Effects of surgery on the thyroid status of patients with gastric and rectal
      cancer].

PMID- 8646627
TI  - [Significant contribution of surgical services to the victory in the Great
      Patriotic War].

PMID- 8646628
TI  - [Clinical signs, diagnosis and treatment of gastric pseudolymphoma].

PMID- 8646630
TI  - [Tumors and tumor-like diseases of the bones in children].

PMID- 8646629
TI  - [Current aspects of the treatment of osteogenic sarcoma].

PMID- 8646631
TI  - [Surgical treatment of patients with cicatricial stricture of bile ducts].

PMID- 8646632
TI  - [Adjuvant chemotherapy of gastric cancer].

PMID- 8646633
TI  - [Adjuvant therapy of breast cancer without regional metastases].

PMID- 8646634
TI  - [Functional gastric stasis: specific complications after Roux operation].

PMID- 8646635
TI  - [Methods of prevention of complications and improving results of relaparotomy in
      the experience of aviation medicine].

PMID- 8646636
TI  - [Formation of clinical-statistical groups of oncologic patients].

PMID- 8646637
TI  - [Method of treatment in cardiospasm and esophageal stenosis].

PMID- 8646638
TI  - [Ivan Teodosovich Shevchenko (the 90th anniversary of his birthday)].

PMID- 8646639
TI  - [Aleksandr Lazarevich Pkhakadze (a centennial of his birthday)].

PMID- 8646640
TI  - [Ways of improving radical mastectomy].

PMID- 8646641
TI  - [Classification of breast diseases].

PMID- 8646642
TI  - Support for gun-control legislation.

PMID- 8646643
TI  - Can government afford universal health care coverage?

PMID- 8646644
TI  - Improving prescribing practices in nursing homes.

PMID- 8646645
TI  - A friend looks at euthanasia and suicide of BC couple.

PMID- 8646646
TI  - Statistical significance.

PMID- 8646647
TI  - Security and accuracy of medical information on the Internet.

PMID- 8646648
TI  - Zinc to prevent lead poisoning.

PMID- 8646649
TI  - Proposals for primary care remuneration: consultation or window-dressing?

PMID- 8646650
TI  - Army medical corps served during the Riel rebellion.

PMID- 8646652
TI  - Physician prescribing practices: What do we know? Where do we go? How do we get
      there?
AB  - Although drug prescribing is one of the most important components of medical
      care, little is known about how prescribing practices are determined and how they
      can be influenced. Enhancing the quality and effectiveness of drug prescribing
      requires research and better dissemination of information to physicians and other
      decision-makers. This requires a collaborative effort and a coordinated action
      plan. Participants at the Physician Prescribing Practices Workshop, held in
      Ottawa in October 1995, addressed issues and made recommendations in three areas:
      current knowledge and issues for research in the field of prescribing practices,
      and the capacity of Canadian databases to study these issues, strategies for
      disseminating and implementing knowledge and research findings to enhance the
      quality of prescribing; and the formation of a network to foster collaboration
      among stakeholders.

PMID- 8646653
TI  - Residents' experiences of abuse, discrimination and sexual harassment during
      residency training. McMaster University Residency Training Programs.
AB  - OBJECTIVE: To assess the prevalence of psychological abuse, physical assault, and
      discrimination on the basis of gender and sexual orientation, and to examine the
      prevalence and impact of sexual harassment in residency training programs.
      DESIGN: Self-administered questionnaire. SETTING: McMaster University, Hamilton,
      Ont. PARTICIPANTS: Residents in seven residency training programs during the
      academic year from July 1993 to June 1994. Of 225 residents 186 (82.7%) returned
      a completed questionnaire, and 50% of the respondents were women. OUTCOME
      MEASURES: Prevalence of psychological abuse, physical assault and discrimination
      on the basis of gender and sexual orientation experienced by residents during
      medical training, prevalence and residents' perceived frequency of sexual
      harassment. RESULTS: Psychological abuse was reported by 50% of the residents.
      Some of the respondents reported physical assault, mostly by patients and their
      family members (14.7% reported assaults by male patients and family members, 9.8%
      reported assaults by female patients and family members), 5.4% of the female
      respondents reported assault by male supervising physicians. Discrimination on
      the basis of gender was reported to be common and was experienced significantly
      more often by female residents than by male residents (p < 0.01). Ten
      respondents, all female, reported having experienced discrimination on the basis
      of their sexual orientation. Most of the respondents experienced sexual
      harassment, especially in the form of sexist jokes, flirtation and unwanted
      compliments on their dress or figure. On average, 40% of the respondents,
      especially women (p < 0.01), reported experiencing offensive body language and
      receiving sexist teaching material and unwanted compliments on their dress.
      Significantly more female respondents than male respondents stated that they had
      reported events of sexual harassment to someone (p < 0.001). The most frequent
      emotional reactions to sexual harassment were embarassment (reported by 24.0%),
      anger (by 23.4%) and frustration (20.8%). CONCLUSION: Psychological abuse,
      discrimination on the basis of gender and sexual harassment are commonly
      experienced by residents in training programs. A direct, progressive,
      multidisciplinary approach is needed to label and address these problems.

PMID- 8646655
TI  - Factors associated with immediate abortion complications.
AB  - OBJECTIVE: To identify factors associated with increased risk of immediate
      complications from induced abortion. DESIGN: Retrospective analysis of a
      provincial database. SETTING: All Ontario general hospitals in which abortions
      are performed and all free-standing abortion clinics in Ontario. POPULATION:
      Women in Ontario aged 15 to 44 years who underwent an induced abortion in the
      province (without concurrent sterilization) between Jan. 1, 1992, and Dec. 31,
      1993. OUTCOME MEASURES: Recording of complications at the time of the procedure,
      gestational age, type of procedure, place of abortion (hospital or clinic), and
      patient's age, parity and history of previous abortion (spontaneous or induced).
      RESULTS: During the study period 83 469 abortions were performed that met our
      inclusion criteria. Immediate complications were reported in 571 cases (0.7%).
      Multivariate logistic regression analysis revealed that, after other variables
      were controlled for, the patient's age, parity and history of previous abortions
      (spontaneous or induced) were not significant risk factors for immediate
      complications; however, gestational age, method of abortion and place of abortion
      were significant risk factors (p < 0.001). The odds ratio (OR) for having a
      complication from abortion was 1.3 (95% confidence interval [CI] 1.02 to 1.63)
      between 9 and 12 weeks, compared with having one after abortion at 9 weeks or
      earlier, and increased to 3.3 (95% CI 2.23 to 5.00) after abortion between 17 and
      20 weeks. Compared with surgical dilatation and curettage (D&C), instillation of
      saline and instillation of prostaglandins were more likely to be associated with
      immediate complications (OR 24.0, 95% CI 13.22 to 43.70, and OR 11.7, 95% CI 6.43
      to 21.18, respectively), whereas both suction D&C and insertion of a laminaria
      tent were less likely to be associated with immediate complications (OR 0.4, 95%
      CI 0.26 to 0.67, and OR 0.3, 95% CI 0.19 to 0.52, respectively). Compared with
      women who had an abortion in a free-standing clinic, the risk for immediate
      complications was greater among those who had an abortion in a hospital,
      especially a teaching hospital (OR 1.9, 95% CI 1.38 to 2.58), a nonteaching
      hospital with 200 to 399 acute care beds (OR 3.1, 95% CI 2.27 to 4.21) and a
      nonteaching hospital with fewer than 200 acute care beds (OR 5.9, 95% CI 4.04 to
      8.64). CONCLUSION: The risk of immediate complications from induced abortion is
      very low. Unlike in previous studies, the woman's age, parity and history of
      previous spontaneous or induced abortions were not found to be risk factors.
      However, advancing gestational age and procedures involving instillation of
      saline or prostaglandins were predictive factors of immediate complications.

PMID- 8646654
TI  - Canadian atrial fibrillation anticoagulation study: were the patients
      subsequently treated with warfarin? Canadian Atrial Fibrillation Anticoagulation
      Study Group.
AB  - OBJECTIVE: To determine the effect of the results of clinical trials on the
      behaviour of patients and physicians, the authors ascertained the proportion of
      patients participating in the Canadian Atrial Fibrillation Anticoagulation (CAFA)
      study who started or continued warfarin therapy at the end of the study and
      identified factors affecting the decision to use or not use warfarin. The CAFA
      study was a double-blind, randomized, placebo-controlled, multicentre study to
      evaluate the efficacy of warfarin in preventing stroke among patients with
      nonrheumatic atrial fibrillation. Recruitment and follow-up were stopped early
      because two other similar studies had shown a decrease in the rate of stroke
      among patients treated with warfarin. DESIGN: Mail survey 21 months after the end
      of the study. PARTICIPANTS: The personal physicians of 336 patients who had
      participated in the CAFA study. OUTCOME MEASURES: Type of antithrombotic therapy
      the patients had received since the CAFA study ended for patients who were not
      receiving warfarin, the reasons they were not. RESULTS: Questionnaires concerning
      254 (76%) of the patients who had participated in the study were returned. Since
      the end of the CAFA study, 153 (60%) of these patients had been treated
      continually with warfarin, 14 (6%) had been treated with warfarin but had
      subsequently stopped taking it, 59 (23%) had taken acetylsalicylic acid (ASA)
      continually, 5 (2%) had been taking ASA but had subsequently stopped taking it,
      and 23 (9%) had not taken either drug. The responding physicians stated that 58
      (67%) of the patients who were not treated with warfarin did not wish to take the
      drug. The patients who had received warfarin during the CAFA trial were more
      likely to be treated with warfarin after the trial (75%) than were those who had
      received a placebo (56%) (p = 0.001). The probability of the patients' being
      treated with warfarin also depended on which study centre they had been treated
      in (p = 0.001). CONCLUSIONS: Of the patients in the CAFA study for whom
      questionnaires were received, only 167 (66%) had been treated with warfarin after
      the end of the study. The patients were more likely to have been treated with
      warfarin after the study if they had received warfarin during the study. The
      positive results of clinical trials, on their own, are not enough to fully change
      the behaviour of patients and physicians.

PMID- 8646656
TI  - Hepatitis after the use of germander, a herbal remedy.
AB  - The authors report two cases of hepatic injury associated with the ingestion of
      germander, a herbal medicine used to facilitate weight loss. In both patients,
      hepatitis characterized by asthenia, jaundice and a marked increase in serum
      amino-transferase levels occurred after 5 to 6 months of germander use. The
      jaundice disappeared within 8 weeks after germander use was stopped, and the
      overall outcome was favourable. The subsequent resumption of germander therapy by
      one patient was soon followed by the recurrence of hepatitis. Similar reports
      from France have led to the banning of germander in that country. Like several
      other herbal remedies, germander may be hepatotoxic, and many herbal medicines
      may not be as safe as the public generally assumes.

PMID- 8646651
TI  - Periodic health examination, 1996 update: 2. Screening for chlamydial infections.
      Canadian Task Force on the Periodic Health Examination.
AB  - OBJECTIVE: To update the 1984 recommendations of the Canadian Task Force on the
      Periodic Health Examination on the routine screening of asymptomatic patients for
      infection with Chlamydia trachomatis. OPTIONS: Screening, with the use of culture
      or nonculture tests, of the general population, of certain high-risk groups or of
      all pregnant women; or no routine screening. OUTCOMES: Rates of asymptomatic and
      symptomatic chlamydial infection, perinatal complications, longterm complications
      of infection (i.e., pelvic inflammatory disease, infertility and ectopic
      pregnancy), coinfection with other sexually transmitted diseases, disease spread,
      hospital care, complications of therapy and costs of infection and of screening.
      EVIDENCE: Search of MEDLINE for articles published between Jan. 1, 1983, and Dec.
      31, 1995, with the use of the major MeSH heading "chlamydial infections,"
      references from recent review articles and recommendation by other organizations.
      VALUES: The evidence-based methods of the Canadian Task Force on the Periodic
      Health Examination were used. Advice from reviewers and experts and
      recommendations of other organizations were taken into consideration. Prevention
      of symptomatic disease and decreased overall costs were given high values.
      BENEFITS, HARMS AND COSTS: The greatest potential benefits of screening
      asymptomatic patients for chlamydial infections are the prevention of
      complications, especially infertility and perinatal complications, and the
      prevention of disease spread. There is no evidence that screening of the general
      population for chlamydial infections leads to a reduction in complications, and
      screening may increase costs. However, there is evidence that annual screening of
      selected high-risk groups and of pregnant women during the first trimester is
      beneficial in preventing symptoms and reducing the overall cost resulting from
      infection. RECOMMENDATIONS: There is fair evidence to support screening and
      treatment of pregnant women during the first trimester (grade B recommendation)
      as well as annual screening and treatment of high-risk groups (sexually active
      women less than 25 years of age, men or women with new or multiple sexual
      partners during the preceding year, women who use nonbarrier contraceptive
      methods and women who have symptoms of chlamydial infection: cervical friability,
      mucopurulent cervical discharge or intermenstrual bleeding; grade B
      recommendation). There is fair evidence to exclude routine screening of the
      general population (grade D recommendation). VALIDATION: These recommendations
      are similar to those of the US Preventive Services Task Force and the US Centers
      for Disease Control and Prevention, Atlanta. SPONSOR: These guidelines were
      developed and endorsed by the Canadian Task Force on the Periodic Health
      Examination, which is funded by Health Canada and the National Health Canada and
      the National Health Research and Development Program. The principal author
      (H.D.D.) was supported in part by the Ontario Ministry of Health and the Canadian
      Infectious Diseases Society Lilly Fellowship.

PMID- 8646657
TI  - Reporting on surveys: information for authors and peer reviewers.

PMID- 8646658
TI  - Abuse of residents: it's time to take action.
AB  - The scientific study of the sexual dynamics that come into play during residency
      training seems to both fascinate and repel trainees and their supervisors. One of
      the more provocative and shameful dimensions of this area of inquiry, the abuse
      of residents, causes a good deal of distress. How do we respond to findings of
      significant psychological abuse, discrimination on the basis of sex or sexual
      orientation and sexual harassment in medical settings? How can we ignore over a
      decade of research? How can we not heed the experience of so many young
      physicians? Given the uncertain times in Canadian medicine and the insecurity in
      our professional and personal lives, we must work together to improve the culture
      of our teaching institutions and implement measures nationally and locally to
      close this dark chapter.

PMID- 8646659
TI  - Uroscopy.

PMID- 8646661
TI  - Will operate for food.
AB  - After spending 15 years in university, Dr. Robert Patterson recently received the
      right to write FRCSC after his name, and then began to look for gainful
      employment as a general surgeon. It was a long and frustrating search. He
      recounts how he finally found work in northern Alberta, and wonders if next
      year's residents will encounter the same shortage of opportunities that he
      discovered.

PMID- 8646660
TI  - "I think we have a problem in Victoria": MDs respond quickly to toxoplasmosis
      outbreak in BC.
AB  - More than 110 people, including 12 newborns, were infected with Toxoplasma gondii
      in Victoria last year. A team of doctors, researchers and public-health officials
      determined that the source of the world's largest recorded outbreak of the
      infection was the water supply. Anne Mullens looks at how the BC medical and
      scientific communities responded to a unique challenge.

PMID- 8646662
TI  - McGill makes Canada's first attempt to put medical curriculum in computerized
      format.
AB  - A member of McGill University's Faculty of Medicine wants Canadian medical
      schools to collaborate to create a central repository for the best teaching
      materials. Dr. David Fleiszer fears that many individual efforts are being
      undertaken without an overall plan being in place. For its part, McGill is
      putting its medical-school curriculum on line over the next 2 years, and is
      collaborating with industrial partners to develop clinical simulations.

PMID- 8646663
TI  - Canadian firm's software helps physicians diagnose fetal abnormalities.
AB  - An Ottawa company has developed CD-ROM software that helps physicians diagnose
      fetal abnormalities. Suspicious prenatal ultrasound images can be compared,
      within seconds, with a collection of moving and still ultrasound images, along
      with text descriptions of 400 anomalies contained in a program called Platypus.

PMID- 8646664
TI  - Conflict of interest, physicians and physiotherapy.
AB  - Since Ontario introduced auto-insurance legislation that guaranteed extensive
      physiotherapy treatment for people who have been in car accidents, the cost of
      outpatient claims to insurance companies has skyrocketed. However, there has not
      been a measurable improvement in patient outcomes. At the same time, the average
      in-hospital stay for patients receiving hip and joint replacements has decreased
      greatly. Dr. Murray Waldman thinks these divergent trends in rehabilitation can
      be attributed to physician self-interest.

PMID- 8646665
TI  - US not the only country luring Canadian MDs.

PMID- 8646666
TI  - Issue of fraud raised as MD self-referral comes under spotlight in Ontario.
AB  - Physician self-referral, fraud and conflict of interest are causing increasing
      concern in Ontario, where 100 physicians are now being investigated for such
      activities. These and related offences recently have been pushed to the top of
      the agenda of the provincial college, which recently asked physicians to vote on
      what kind of self-referral regulations they prefer.

PMID- 8646668
TI  - Concerns about increasing use of ambulatory care raised at QMA annual meeting.
AB  - Quebec Health Minister Dr. Jean Rochon is pushing for a regionalized health care
      system that favours ambulatory care, day surgery and home care over hospital
      admissions and acute care in hospital. The Quebec Medical Association is
      concerned these changes will lower the quality of care in the province.

PMID- 8646667
TI  - Sale of prescribing data by pharmacists causes growing concern among physicians.

PMID- 8646669
TI  - Would you recommend a medical career to your children?
AB  - Physicians are frustrated by cutbacks, threats to their practices, income
      restrictions and government interference. However, in spite of complaints from
      practising physicians medicine remains an attractive career option for Canada's
      best and brightest, with four to five candidates for every first-year position in
      medical school.

PMID- 8646670
TI  - Physician-patient privilege: the legal assault continues.
AB  - The confidentiality of patient records, particularly in cases where sexual
      assault is alleged, has been called into question by two recent Supreme Court
      decisions. Toronto lawyer Marilou McPhedran discusses the recent Beharriell and
      O'Connor decisions and how they affect physicians.

PMID- 8646671
TI  - Diagnosis of cancer-associated vascular disorders.
AB  - BACKGROUND: Unexplained thromboembolism may be an early indicator of the presence
      of a malignant tumor before signs and symptoms of the tumor itself become
      obvious. METHODS: A survey of the MEDLINE data-base was conducted concerning
      cancer-associated vascular disorders and their role in the diagnosis of hidden
      cancer. The spectrum of vascular disorders heralding occult cancer and the
      associated laboratory abnormalities were scrutinized. RESULTS: Deep venous
      thrombosis was associated with a significantly higher frequency of malignancy
      during the first 6 months after diagnosis. Malignancies were found using simple
      clinical and diagnostic methods; additional screening was not cost-efficient.
      Other signs associated with deep venous thrombosis that increased the probability
      of an occult cancer were age older than 50 years, multiple sites of venous
      thrombosis, associated venous and arterial thromboembolism, thromboembolism
      resistant to warfarin therapy, and paraneoplastic syndrome. Among vascular
      syndromes, only cutaneous leukocytoclastic vasculitis presenting after the age of
      50 years was consistently associated with cancer. Preliminary data with an
      antigen specific to tumor tissue, the cancer procoagulant, suggested its possible
      role as a tumor marker. The sensitivity for all samples analyzed from cancer
      patients was 80% and the specificity was 83%. CONCLUSIONS: Data from the
      literature enabled us to outline clinical clues that might distinguish patients
      with cancer-associated vasculopathies from those unaffected by malignancies.
      Preliminary data with an antigen specific to tumor tissue, the cancer
      procoagulant, suggested its possible role in detecting early stage cancer.
      However, large-scale prospective studies are not currently available to evaluate
      the role of these clues and laboratory assays in the diagnosis of early stage
      cancer.

PMID- 8646672
TI  - Prognostic significance of T antigen expression in patients with gastric
      carcinoma.
AB  - BACKGROUND: Thomsen-Freidenreich (T) antigen, the immediate precursor antigen of
      the human blood MN system, has been detected in malignant cells, but not in most
      normal cells in which it is cryptic but can be unmasked by desialylation. In this
      study, we determined the prognostic significance of T antigen in specimens with
      gastric carcinoma. METHODS: Expression of T antigen was studied
      immunohistochemically in 157 gastric carcinoma tissue specimens obtained at
      surgery from the First Department of Surgery, Osaka City University Medical
      School between 1983 and 1987. RESULTS: T antigen expression was detected in 72 of
      the tumors (45.9%). The staining pattern was inclined to change from a luminal
      surface type to a cytoplasmic type in accordance with decreasing degree of cell
      differentiation. The rate of expression of T antigen significantly increased (P <
      0.05) with serosal invasion, and was significantly higher (P < 0.01) in patients
      with hepatic or lymph node metastasis or peritoneal dissemination than in those
      without such metastasis or dissemination. Furthermore, among patients with Stage
      III or IV disease, those with T antigen-positive tumors had a significantly
      poorer prognosis than those with T antigen-negative tumors. CONCLUSIONS: Our
      findings suggest that relationships exist between expression of T antigen and
      depth of invasion, hepatic metastasis, lymph node metastasis, or peritoneal
      dissemination, and that T antigen may be a good indicator of the prognosis of
      patients with gastric carcinoma.

PMID- 8646673
TI  - Age-related characteristics of gastric carcinoma in young and elderly patients.
AB  - BACKGROUND: The clinicopathologic features of young and elderly patients with
      gastric carcinoma have been analyzed. METHODS: We analyzed the data from 174
      patients with gastric carcinoma age 40 years and younger and from 356 patients
      with gastric carcinoma age 70 years and older who were surgically treated at the
      Department of Surgery II, Kyushu University, Japan. RESULTS: The rate of multiple
      gastric carcinomas was 2.9% (5/174) for the young patients and 13.2% (47/356) for
      the elderly. In subjects older than 70 years, male patients predominated, tumors
      were smaller, differentiated lesions more common, vascular involvement more
      frequent, tumors were less infiltrative, and the rate of liver metastasis was
      higher. For patients younger than age 40 years, undifferentiated type with
      infiltrative growth was frequent and the rate of liver metastasis was higher.
      There were no differences in the positive rate of p53 overexpression and the
      proliferating activity of the cancer cells determined by PCNA LI, between the
      young and elderly patients. The survival rate after curative resection was lower
      for the elderly compared with that for the young patients; hematogenous
      recurrence was higher in the former. CONCLUSIONS: The clinicopathological
      features of gastric carcinoma differed between the young and elderly patients,
      and these differences should be considered when age-oriented treatment is being
      designed.

PMID- 8646674
TI  - Clinical significance of simultaneous determinations of alpha-fetoprotein and des
      gamma-carboxy prothrombin in monitoring recurrence in patients with
      hepatocellular carcinoma.
AB  - BACKGROUND: Measurements of serum alpha-fetoprotein (AFP) concentration and
      plasma concentration of des-gamma-carboxy prothrombin (DCP) have been widely used
      for the early diagnosis of hepatocellular carcinoma (HCC). The two markers
      generally run parallel to each other. However, in our study, they sometimes
      fluctuated independently in response to tumor regression or recurrence. METHODS:
      A longitudinal series of concentrations of serum AFP and plasma DCP were
      determined simultaneously for 245 patients with HCC from the time of diagnosis to
      tumor recurrence after treatment. RESULTS: Positive reactions for AFP were noted
      in 168 patients (69%) and for DCP in 126 patients (51%). One hundred and ten of
      245 patients with HCC (45%) were positive for both AFP and DCP. In 35 patients
      (14%), these 2 tumor markers fluctuated independently in response to tumor
      regression and recurrence. These patients were categorized into four groups as
      follows: Group 1 had elevated AFP only at diagnosis; it then decreased after
      treatment, but DCP was elevated at the time of tumor recurrence without AFP
      elevation (3 patients); Group 2 had elevated DCP at diagnosis and elevated AFP at
      tumor recurrence (4 patients); Group 3 had elevated AFP and DCP at diagnosis, but
      only AFP (8 patients) or DCP (7 patients) was elevated at tumor recurrence; Group
      4 had only elevated AFP (2 patients) or DCP (11 patients) at diagnosis, but both
      AFP and DCP were elevated at tumor recurrence. CONCLUSIONS: The results of this
      study indicate that simultaneous determinations of AFP and DCP are useful for
      monitoring recurrence in patients with HCC after treatment, and that the decrease
      to normal levels of a single marker does not always indicate the absence of tumor
      recurrence.

PMID- 8646675
TI  - Hepatitis C and B virus infections in hepatocellular carcinoma. Analysis of
      direct detection of viral genome in paraffin embedded tissues.
AB  - BACKGROUND: Although there have been many seroepidemiologic studies on hepatitis
      C virus (HCV) infection and hepatocellular carcinoma (HCC) occurrence, the actual
      role of HCV in hepatocarcinogenesis is unknown. METHODS: We have previously
      reported on a highly sensitive method of detecting and identifying sequences of
      RNA genome in formalin fixed, paraffin embedded (FFPE) tissue by polymerase chain
      reaction (PCR) assay. Using this method, we carried out a retrospective study to
      determine the prevalence of HCV and hepatitis B virus (HBV) genomes in FFPE
      specimens from 102 Japanese patients with HCC. RESULTS: HCV-RNA was detected by
      nested PCR reverse transcription (RT) in 64 of the 102 patients (62.7%), and
      78.1% (50/64) of those HCV-RNA-positive patients had HCV genotype II. HCV-RNA was
      present in 54 of 70 (77.1%) anti-HCV-positive patients, and also in 5 of 20 (25%)
      anti-HCV-negative patients. HBV-DNA was detected by nested PCR in FFPE liver
      specimens from 21 of 102 (20.6%) patients. HBV-DNA positivity was consistent with
      seropositivity for serum HBV markers in 17 of these 21 patients (80.9%). HBV-DNA
      was present in FFPE samples from 2 patients who were seronegative for HBV
      markers, and in 1 patient who was seropositive for anti-HBs. Double infection of
      these two viruses was found in 6 patients (5.9%). Three patients (2.9%) were
      negative for both hepatic viral genomes and serum viral markers. CONCLUSIONS: The
      precise prevalence of HCV and/or HBV infection among HCC patients can be
      determined by studying routinely-processed FFPE HCC samples preserved for up to
      11 years using the technique of nested PCR. HCV-RNA was detected in the majority
      of our HCC cases; type II was the most common genotype of HCV encountered. The
      incidence of HCV-associated HCC was three times greater than that of HBV. Thus,
      the hepatitis virus infection most frequently associated, and probably
      ectologically implicated, with HCC in Japanese people is HCV infection.

PMID- 8646676
TI  - Local recurrence of hepatocellular carcinoma after percutaneous ethanol
      injection.
AB  - BACKGROUND: Percutaneous ethanol injection (PEI) therapy is now widely used for
      small hepatocellular carcinomas (HCC). However, only limited information is
      available regarding local tumor recurrence after PEI treatment. METHODS: We
      investigated the relationship of pretreatment clinicopathologic variables (tumor
      size, tumor cell differentiation and tumor staining) to local recurrence in 170
      PEI-treated HCC nodules (measuring 5-39 mm in greatest dimension) in 84 patients.
      RESULTS: Local recurrence was observed in 17 of 170 PEI-treated nodules. Among
      these, 13 local recurrences were observed as the first event of progression after
      PEI. Local recurrence rates at 1, 2, and 4 years were 6.6%, 14.2%, and 14.2%,
      respectively, and all recurrences were observed within 2 years after PEI. Of the
      3 variables investigated, large tumor size (31 mm or larger in greatest
      dimension) was significantly associated with a higher local recurrence rate.
      CONCLUSIONS: This study demonstrated that tumor size influences the local
      efficacy of PEI for small HCC. Therefore, we recommend that a reasonable
      indication for PEI therapy is HCC lesions measuring less than 30 mm in greatest
      dimension.

PMID- 8646677
TI  - Mechanisms of resistance of human small cell lung cancer lines selected in VP-16
      and cisplatin.
AB  - BACKGROUND: The combination of VP-16 and cisplatin is one of the most active
      regimens available for the treatment of small cell lung cancer (SCLC), however,
      most tumors eventually become resistant to these drugs. METHODS: To investigate
      the problem of resistance to VP-16 and cisplatin in patients with SCLC, we
      established two resistant sublines from the drug sensitive human SCLC line, NCI
      H209, by in vitro selection in VP-16 and cisplatin. RESULTS: The VP-16-selected
      cell line, H209/VP, was more than 100-fold resistant to VP-16, and displayed
      cross-resistance to VM-26 and other topoisomerase II interactive drugs, but not
      to vinca alkaloids. There was no difference in accumulation of VP-16 in H209/VP
      compared with its parent cell line. The level of topoisomerase II-alpha was
      reduced to 8% of that in the parent cell line, and there was an altered form of
      this enzyme with a molecular weight of 160 kilodaltons (kDa), in addition to the
      normal 170 kDa protein. The cisplatin-selected cell line, H209/CP, was 11.5-fold
      resistant to cisplatin, with only a low level of cross-resistance to other
      platinum compounds including carboplatin, tetraplatin, iproplatin, and
      lobaplatin. This line was highly cross-resistant to vinca alkaloids, but not to
      anthracyclines or epipodophyllotoxins. The H209/CP cell line was not resistant to
      cadium chloride, suggesting that alterations in metallothionein are unlikely to
      be a cause of resistance. Although glutathione (GSH) levels were increased nearly
      2-fold in H209/CP, there was no difference in levels of the GSH-related enzymes
      glutathione-S-transferase, glutathione peroxidase, and glutathione reductase,
      compared with the parent line. The H209/CP line had a 1.4-fold elevation of
      topoisomerase II-alpha. The accumulation of cisplatin was reduced in this cell
      line, and there were fewer DNA-interstrand cross links formed in the presence of
      cisplatin in H209/CP, compared with the parent line. Neither H209/VP nor H209/CP
      expressed MDR1, the gene for P-glycoprotein. The MRP gene was expressed at a
      slightly higher level in the H209/VP cell line, but there was no significant
      increase in expression of this gene in the H209/CP cell line. CONCLUSIONS: The
      resistance of the H209/VP cell line is associated with an alteration of
      topoisomerase II-alpha, whereas the resistance in the H209/CP line is associated
      with reduced drug accumulation.

PMID- 8646679
TI  - S-phase fraction of 155 soft tissue sarcomas: correlation with clinical outcome.
AB  - BACKGROUND: Traditionally, grade is considered the most important prognostic
      factor for soft tissue sarcomas (STS). However, because of the alleged
      difficulties in reproducibility of grading, new, objectively determined
      prognostic factors would be of value. The aim of our study was to establish if S
      phase fraction (SPF) measured with flow cytometry was of prognostic significance
      for STS. METHODS: In this study, we included all 193 adult STS patients with
      superficial trunk or limb tumors who were treated by the Helsinki University
      Central Hospital (HUCH) STS group between January 1987 and May 1993. One hundred
      and seventy-two formalin fixed paraffin embedded tumor samples were available.
      SPF measurement was successful in 155 cases. RESULTS: Eighty-six cases were
      diploid. Ploidy was found to have no effect on overall survival. The median SPF
      was 6.8% (diploid tumors, 4% and nondiploid tumors, 12.9%). A high SPF predicted
      a shorter survival in patients with diploid tumors (P=0.003). The prognostic
      value was even stronger when we studied disease specific survival and excluded
      from analysis samples that contained less than 50% tumor cells (P=0.011).
      However, no prognostic value could be detected in nondiploid tumors or in the
      material as a whole. CONCLUSIONS: Our results suggest that high SPF is an adverse
      prognostic factor for survival of patients with diploid STS. However, further
      studies are needed to confirm these results.

PMID- 8646678
TI  - Resection margins of 2 versus 5 cm for cutaneous malignant melanoma with a tumor
      thickness of 0.8 to 2.0 mm: randomized study by the Swedish Melanoma Study Group.
AB  - BACKGROUND: The traditional surgical treatment for primary malignant melanoma has
      often been a wide excision with a margin of about 5 cm. Since the risk of local
      recurrences is dependent on tumor thickness, thin tumors (<1 mm) have routinely
      been excised with a narrow margin. For thick tumors, the optimal resection margin
      is controversial, and can be determined only by prospective, randomized trials.
      METHODS: The Swedish Melanoma Study Group performed a prospective, randomized
      multicenter study to evaluate an excision margin of 2 versus 5 cm for patients
      with cutaneous malignant melanoma with tumor thickness > 0.8 and < or = 2.0 mm.
      The trial includes 769 patients. Patients with melanomas of the skin of the head,
      neck, hands, feet, or vulva were not included in the trial. In the event of an
      excision biopsy for diagnosis, radical surgery was completed within 6 weeks. The
      median follow-up time was 5.8 years for estimation of survival and 4.0 years for
      diagnosis of recurrent disease. RESULTS: No significant differences have been
      observed between the treatment groups regarding local or regional recurrences or
      survival. CONCLUSIONS: We recommend an excision with a margin of 2 cm for
      cutaneous malignant melanoma with a tumor thickness > 0.8 and < or = 2.0 mm.

PMID- 8646680
TI  - Prognostic factors for patients with localized primary malignant fibrous
      histiocytoma: a multicenter study of 216 patients with multivariate analysis.
AB  - BACKGROUND: The purpose of this study was to determine the independent prognostic
      variables in a well documented subset of 216 patients with localized primary
      malignant fibrous histiocytomas (MFH). METHODS: Between the years 1980 and 1989,
      216 patients with localized, primary (International Union Against Cancer
      [UICC]/American Joint Committee on Cancer [AJCC] Stage I-IVA) MFH were evaluated
      and treated in 10 participating centers of the sarcoma group of the French
      Federation of Cancer Centers (FNCLCC). Clinicopathologic factors were collected
      retrospectively and entered into a cooperative database. Tissue slides of all
      cases were jointly reviewed microscopically by the pathology subcommittee.
      Surgical treatment was performed on all but 6 (3%) patients. One hundred ninety
      five patients (90%) were free of gross disease, with complete local control at
      the end of the initial treatment. The adjuvant treatment was radiotherapy in 78
      patients (36%), chemotherapy in 19 patients (9%), and both in 61 patients (28%).
      RESULTS: The median follow-up was 3.5 years (range, 45 days to 12 years). Five
      year actuarial rates of disease specific (DSS), metastasis free (MFS), and local
      recurrence free (LRFS) survival were 70%, 63.3%, and 62.7%, respectively.
      Multivariate analyses showed that the adverse prognostic factors independently
      associated with decreased disease specific survival were UICC/AJC Stage III + IVA
      (P < 0.00001; relative risk [RR], 3.27; 95% confidence interval [CI], 1.6-6.58),
      residual macroscopic disease following primary local therapy (P = 0.00024; RR,
      3.99, CI, 2.04-7.82), deep tumor location (P = 0.0045; RR, 3.37; CI, 1.21-9.38),
      non-myxoid histology (P = 0.0056; RR, 9.28; CI, 1.03-83.41), and age older than
      50 years (P = 0.037; RR, 2.19; CI, 1.04-4.61). Two factors were significantly
      related to MFS in the patients with the poorest prognosis: histopathologic Grade
      3 (P < 0.0001, RR, 3.46; CI, 2.02-5.91) and tumor size greater than 8 cm in
      largest dimension (P = 0.0012; RR, 2.78; CI, 1.36-3.66). With regard to LRFS,
      patients who did not undergo radiotherapy had reduced local control (P = 0.0043;
      RR, 2.36; CI, 1.46-3.83). CONCLUSIONS: Resection of all macroscopic disease was
      independently associated with improved disease specific survival and adjuvant
      radiotherapy significantly decreased the local relapse risk. Histopathologic
      grade was the most important prognostic factor for DSS and MFS.

PMID- 8646681
TI  - Extensive apoptosis in ductal carcinoma in situ of the breast.
AB  - BACKGROUND: More than 50% of breast ductal carcinomas in situ (DCIS) contain
      significant histologic necrosis, an important prognostic factor for determining
      recurrence and progression to invasive breast cancer. We have examined whether
      the mechanism of this spontaneous cell death might be apoptosis, a genetically
      encoded suicide pathway that may be triggered by various events including
      dysregulated cell proliferation. METHODS: Twenty-five untreated DCIS cases
      accessioned at our institution were examined for subtype, grade, and presence of
      apoptosis using two criteria: (1) cellular morphology (shrinkage, nuclear
      condensation, fragmentation, apoptotic bodies, and lack of inflammatory
      component); and (2) terminal transferase (TUNEL) staining of DNA fragmentation, a
      characteristic though less specific feature of apoptosis. Immunohistochemical
      staining was also carried out to assess whether wild-type p53, a regulator of
      apoptosis, was associated with this cell death. RESULTS: In all 19 cases with
      intraductal necrosis, cellular morphology was consistent with apoptotic death,
      despite its presence within sheets of "geographic necrosis." Additionally, the
      identical regions were all strongly TUNEL-positive. No evidence of TUNEL staining
      was seen in 5 Grade I DCIS cases without intraductal necrosis.
      Immunohistochemical staining suggested that this apoptosis was independent of p53
      mutational status. CONCLUSIONS: Extensive intraductal necrosis in DCIS is likely
      to represent apoptosis. However, it is unlikely that this apoptosis is regulated
      by p53. The apparently abundant apoptosis identified here, particularly in high
      grade DCIS, may be important in explaining why spontaneous cell death in DCIS is
      associated with a worse prognosis.

PMID- 8646682
TI  - Molecular genetic evidence of the occurrence of breast cancer as an integral
      tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome.
AB  - BACKGROUND: The hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome is
      an autosomal dominant genetic disorder caused by the inheritance of a mutation in
      one of a family of genes encoding DNA mismatch repair (MMR) proteins. HNPCC
      manifests as genetic instability in linked tumors. Clinically, the syndrome is
      characterized by early onset malignancies, primarily of the colon and
      endometrium, with an increased incidence of tumors at other gastrointestinal
      sites, upper urologic tract, ovary, and pancreas as well. However, the inclusion
      of breast cancer as an integral tumor of this syndrome is controversial. METHODS:
      Mutation screening of MMR genes was carried out by single strand conformation
      polymorphism (SSCP) and sequencing analyses of genomic DNA prepared from normal
      lymphocytes. Expression analysis was performed by SSCP. Sequence analyses of cDNA
      was prepared from breast tumor tissue and normal lymphocytes. Genetic instability
      was assessed by comparing the electrophoretic mobility of polymerase chain
      reaction (PCR) products using multiple microsatellite markers. RESULTS: A 4-bp
      frameshift mutation in the hMLH1 gene was found to segregate with disease in the
      germlines of the affected members of a large kindred HNPCC. Expression of only
      the mutant allele was observed in the breast cancer tissue of one family member,
      however both alleles were observed in her normal tissue. This breast cancer
      exhibited widespread microsatellite instability, as did breast cancers obtained
      from several other HNPCC kindreds. CONCLUSIONS: These data indicate that breast
      cancer may result from the inheritance of a mutant MMR gene, and that breast
      cancer may occur as an integral tumor in the HNPCC syndrome.

PMID- 8646683
TI  - Invasive breast carcinoma: analysis of dynamic magnetic resonance imaging
      enhancement features and cell proliferative activity determined by DNA S-phase
      percentage.
AB  - BACKGROUND: There is little information regarding associations between magnetic
      resonance imaging (MRI) enhancement and biologic parameters of breast carcinoma.
      A prospective study was undertaken to correlate MRI dynamic contrast enhancement
      features with cell proliferative activity, as determined by DNA S-phase
      percentage. METHODS: Seventeen patients with invasive breast cancer underwent MRI
      at 1.5 tesla using a dynamic gadolinium-enhanced spoiled gradient recall echo
      technique. DNA analysis of samples of the excised lesions was then performed
      using flow cytometry. RESULTS: Invasive carcinomas with high DNA S-phase
      percentages (> or = 6.9%, the median value in this study), a measure of increased
      cell proliferation, were associated with a peripheral MRI enhancement pattern in
      4 of 6 (67%) lesions compared with 0 of 11 carcinomas with lower DNA S-phase
      percentages (< or = 6.9%) (P = 0.006). There was no significant association
      between a high DNA S-phase percentage and greater MRI enhancement amplitude,
      rate, or washout. There was no significant association between aneuploid DNA
      content and any MRI enhancement feature. CONCLUSIONS: Increased cell
      proliferation in invasive breast carcinoma, as determined by high DNA S-phase
      percentage, is significantly associated with a peripheral MRI enhancement pattern
      but unrelated to greater MRI enhancement amplitude, rate, or washout.

PMID- 8646684
TI  - Radiotherapy as a cisplatin-sensitizer in a resistant ovarian carcinoma cell
      line.
AB  - BACKGROUND: Stage III ovarian carcinoma has shown resistance to adjuvant
      chemotherapy following surgical cytoreduction. With recurrence of ovarian
      carcinoma, cell lines may develop resistance to previously used chemotherapy.
      This contributes to the fact that survival rates for patients with ovarian
      carcinoma have not been dramatically improved in decades. The objective of this
      study is to evaluate radiotherapy as a cisplatin-sensitizer in a cisplatin
      resistant ovarian carcinoma cell line. METHODS: In vitro OVCAR-3 human ovarian
      carcinoma cells were irradiated with external beam radiation (XRT) at doses of
      500, 1,500, and 4,500 centigray (cGy) in a single fractionation. Twelve hours
      after XRT, cells were treated with a dose of cisplatin for 2 hours (0, 1, 3, 9,
      and 90 micrograms/mL). Cell attachment was determined by cell counts using a
      hemocytometer under phase-contrast microscopy. Analysis of variance followed by
      the Student Newman Keuls Test were used for statistical analysis. RESULTS: Dose
      response curves demonstrate the results of this study as follows: (1) XRT has a
      significant direct effect on cell attachment of OVCAR-3 cells in a dose-response
      relationship. (2) cisplatin has no effect on cell attachment in the absence of
      XRT. (3) When cells are exposed to XRT, cisplatin demonstrates a dose-response
      effect on cell attachment with a dose of XRT as low as 500 Gy. CONCLUSIONS: This
      in vitro study suggests that XRT sensitizes cisplatin-resistant OVCAR-3 to
      cisplatin. This occurred with doses of radiation low enough to suggest a
      potential clinical role in treating resistant ovarian carcinoma.

PMID- 8646685
TI  - Cost-effective models for flutamide for prostate carcinoma patients: are they
      helpful to policy makers?
AB  - BACKGROUND: More than 50,000 male patients received hormonal therapy for
      metastatic prostate carcinoma in 1995. Nonsteroidal antiandrogens, such as
      flutamide, when used in conjunction with castration, are effective in prolonging
      the time to progression of disease and survival. Only one-third of newly
      diagnosed patients with metastatic prostate carcinoma receive flutamide.
      Physicians may be reluctant to prescribe flutamide because of quality of life,
      toxicity, and cost considerations. METHODS: Physician focus groups evaluated
      quality of life factors for metastatic prostate cancer. RESULTS: Using quality of
      life estimates with the National Cancer Institute's (NCI) 0036 clinical trial
      results, our revised model of flutamide use predicted that, for minimal disease,
      survival increased by 4.33 quality adjusted months (QAMs) at an incremental cost
      of $25,000 per quality adjusted life year (QALY) saved and for severe disease,
      survival increased by 4.11 QAM at a cost of $18,000 per QALY saved. However, if
      quality of life estimates are used in conjunction with the Prostate Cancer
      Trialists' Collaborative Group (PCTCG) meta-analysis estimates, survival
      increased by 2.1 QAM at an incremental cost of $41,000 per QALY saved for persons
      with severe disease and increased by 2.6 QAM at an incremental cost of $53,700
      per QALY saved for persons with minimal disease. CONCLUSIONS: Using NCI 0036
      trial data, flutamide has an incremental cost-effectiveness more favorable than
      most therapies, while estimates based on the PCTCG found a less favorable outcome
      for the drug. Concerns about out-of-pocket expenditures and efficacy limit
      flutamide utilization; quality of life considerations are less cogent.

PMID- 8646686
TI  - In vitro modulation of tumor progression-associated properties of hormone
      refractory prostate carcinoma cell lines by cytokines.
AB  - BACKGROUND: Cytokines exert cytostatic and immunomodulatory effects on carcinoma
      cells. Growth inhibition of human prostate carcinoma by cytokines has been
      demonstrated both in vitro and in vivo, whereas the cellular and molecular
      changes in prostate carcinoma properties after cytokine treatment have never been
      characterized. We have thus investigated whether the intrinsic properties of
      prostate carcinoma cells that are associated with tumor development and
      progression can be altered by direct cytokine treatment. METHODS: LNCaP, DU-145,
      and PC-3 cell lines were treated with tumor necrosis factor-alpha (TNF-alpha)
      (200 U/mL), interferon-gamma (IFN-gamma) (500 U/mL), human leukocyte interferon
      (IFN-alpha) (500 U/mL), and interleukin-2 (IL-2) (400 U/mL). The expression of
      (prostate-specific antigen [PSA] and prostate-specific membrane [PSM]), androgen
      receptor (AR), growth factors, oncogenes, collagenase, cell adhesion molecules,
      HLA antigens, cell adhesion to human bone marrow stroma, and cell growth were
      determined by quantitative polymerase chain reaction (PCR) analysis, fluorescence
      activated cell sorter (FACS) analysis, and cell attachment and proliferation
      assays, and were compared with non-treated cells. RESULTS: PCR analysis indicated
      that only LNCaP cells expressed PSA, PSM, and AR mRNA. Cytokine treatment did not
      alter PSM mRNA expression, whereas a 15-fold decrease in PSA and a 5-fold
      reduction in AR mRNA expression was detected in TNF-alpha-treated cells. The down
      regulation of PSA production was also demonstrated at the protein level in a dose
      dependent fashion. A fivefold decrease in PSA mRNA was also detected in IL-2
      treated LNCaP cells but without a reduction in AR. Down regulated epidermal
      growth factor receptor (EGF-R) and basic fibroblast growth factor (b-FGF) mRNA
      expressions were detected in TNF-alpha- and IFN-alpha-treated DU-145 and PC-3
      cells, whereas, only reduced EGF-R expression was observed in LNCaP cells. IFN
      gamma and IL-2 treatment down regulated the expression of collagenase Type IV
      mRNA in DU-145 and PC-3 cells, whereas tumor transforming growth factor-beta (TGF
      beta) and IL-6 mRNA expressions did not exhibit any essential changes after
      cytokine treatment. A reduction in c-myc mRNA expression was observed in TNF
      alpha- and IFN-alpha-treated cells, whereas no change in HER-2 expression was
      noted in any cytokine treated cells. Up regulated P-cadherin, but not E-cadherin,
      mRNA expression was detected in TNF-alpha- and IFN-gamma-treated PC-3 cells. FACS
      analysis revealed that all but IL-2-treated cells had enhanced HLA Class I
      expression, with the maximum effect seen in TNF-alpha-treated LNCaP cells
      (threefold increase). Up regulated HLA Class II expression was seen only in IFN
      gamma-treated cells. All cytokine-treated DU-145 and PC-3 cells expressed reduced
      levels of alpha3, but not beta1, integrin. Up regulated of ICAM-1 expression was
      seen in all cytokine treated DU-145 and PC-3 cells, whereas no change in CD44
      occurred. Cytokine treatment reduced the binding affinity of LNCaP and DU-145,
      but not of PC-3 cells, to human bone marrow stromal cells, and all cytokines but
      IL-2 showed a mild to moderate growth inhibition to prostate cancer cells, with a
      marked inhibition only observed in TNF-alpha-treated LNCaP cells. CONCLUSIONS:
      Cytokine treatment can effectively alter several prostate carcinoma properties
      that are closely associated with tumor invasion and a metastatic phenotype,
      suggesting that immunotherapy via the local delivery of cytokines may have a
      potentially therapeutic role in the treatment of hormone-refractory prostate
      cancer through both direct and indirect antitumor mechanisms.

PMID- 8646687
TI  - The management of spermatic cord sarcoma.
AB  - BACKGROUND: Between April 1963 and July 1991, 18 patients were treated for
      spermatic cord sarcoma. The histologic subtype distribution was: 7
      leiomyosarcoma, 7 liposarcoma, 2 malignant fibrous histiocytoma, and 1
      mesothelioma. METHODS: All patients underwent surgical resection: 16 radical
      orchiectomy and local excision. Nine were treated with orchiectomy alone, and 9
      received adjuvant radiation. The radiation fields encompassed the ipsilateral
      iliac and inguinal lymph nodes, vas deferens, and hemiscrotum in 7 patients, and
      iliac and inguinal lymph nodes in 2 patients. RESULTS: The actuarial 5 and 8-year
      disease free survivals for the 18 patients were 77% and 58%, with an overall
      survival of 78% and 70%, respectively. The 5 and 8-year locoregional control
      rates were 82% and 61%. Five of 9 patients treated with surgery alone developed
      locoregional recurrence while none of the nine who had adjuvant radiation
      relapsed. The median follow-up for the irradiated group, however, was shorter
      (123 vs 63 months) and staging studies more complete. These potential biases are
      discussed. CONCLUSION: In this series, relapse was common after orchiectomy
      alone. Adjuvant radiation therapy may reduce the incidence of locoregional
      failure.

PMID- 8646688
TI  - Expression of tissue factor correlates with grade of malignancy in human glioma.
AB  - BACKGROUND: Tissue factor (TF), a cell surface receptor of factor VII/VIIa, was
      initially recognized as an initiator of the extrinsic coagulation pathway. TF has
      recently been found to be expressed highly in certain types of malignant tumors.
      In addition, TF belongs to the interferon receptor family and is one of the
      immediate early genes, suggesting that TF may participate in the regulation of
      cell growth. However, the correlation between the expression of TF and cell
      growth is still unclear. METHODS: Expression of TF in 6 glioma cell lines and 44
      glioma surgical specimens was studied by Northern blot analysis, Western blot
      analysis, immunohistochemistry, and in situ hybridization. RESULTS: Northern blot
      analysis showed that glioma cells expressed minor novel transcripts of 3.3 kb and
      1.6 kb, in addition to the transcripts of 2.2 kb and 3.1 kb that were previously
      reported. Western blot analysis revealed that the level of TF protein did not
      correlate with that of TF transcripts. Although immunohistochemical analysis of
      surgical specimens showed that all gliomas were positive for TF, it was
      interesting that 1 of 10 benign gliomas (10%) was positive for TF (malignancy
      Grade I-II), 13 of 14 anaplastic astrocytomas (86%) (malignancy grade III) and 19
      of 20 glioblastomas (95%) (malignancy grade IV) were moderately or strongly
      positive for TF. In situ hybridization showed the expression of TF mRNA in glioma
      cells. CONCLUSIONS: TF is expressed in glioma and the level of expression
      correlates with the histologic grade of malignancy.

PMID- 8646689
TI  - Mesenchymal chondrosarcoma: a clinicopathologic and flow cytometric study of 13
      cases presenting in the central nervous system.
AB  - BACKGROUND: Mesenchymal chondrosarcomas arising in the central nervous system are
      extremely rare. Morphologic features have not been found to correlate reliably
      with prognosis. METHODS: Eight intracranial and five intraspinal mesenchymal
      chondrosarcomas were reviewed with regard to location, treatment, and long term
      follow-up data. The histopathologic and immunohistochemical results, including Ki
      67 nuclear staining frequency, were critically reviewed, and deoxyribonucleic
      acid content was analyzed by flow cytometry. RESULTS: Microscopically, all 13
      cases were remarkably similar. Immunoreactivity in the small cell component
      included vimentin in 100% and cytokeratin and glial fibrillary acidic protein in
      25% of cases. S-100 immunoreactivity was noted in the cartilaginous component of
      100% of cases, and in rare cells in the small cell component along the interface.
      Flow cytometry of the eight tumors studied revealed a diploid pattern in six,
      aneuploidy in two, and a wide range of S-phase fractions (0-36.5%). CONCLUSIONS:
      Review of the literature and the findings of the current series indicates that
      mesenchymal chondrosarcomas presenting in the brain and spinal cord pursue a
      progressive course that correlates most reliably with extent of surgical
      resection. This limited retrospective study also suggests that survival may be
      shorter for those patients with a high S-phase fraction and a high Ki-67 staining
      frequency.

PMID- 8646690
TI  - P-glycoprotein expression in canine lymphoma: a relevant, intermediate model of
      multidrug resistance.
AB  - BACKGROUND: Despite extensive investigation, the role of MDR of human cancer
      remains unclear. Canine lymphoma is a spontaneously arising correlate of human
      non-Hodgkin's lymphoma that may complement other in vivo models for investigation
      of issues related to MDR. METHODS: Immunoreactivity of primary antibodies to the
      human MDR1 gene product, p-glycoprotein 170 (Pgp), were determined in both a
      retrospective (n=76) and prospective (n=15) survey of canine lymphoma. Known
      prognostic factors and response to chemotherapy were correlated with categorical
      designations of Pgp expression. RESULTS: When combined, 61 of 91 samples (67%)
      were negative for Pgp, 16 of 91 (17.5%) had strong Pgp immunoreactivity in >50%
      of the malignant population and 14 of 91 (15.5%) had Pgp reactivity in 10-50% of
      cells. Pgp expression was greater after relapse compared with pretreatment
      samples [C494 83% vs. 25%; P=0.012 and C219 73% vs. 27%; P=0.04]. Pretreatment
      Pgp expression was an independent negative predictor of overall survival
      (median=225d vs. 367d; P=0.02). CONCLUSIONS: Pgp expression in spontaneous canine
      lymphoma is similar to that reported in human non-Hodgkin's lymphoma. Use of this
      model may expedite investigation of novel strategies for MDR prevention or
      modulation.

PMID- 8646692
TI  - Recursive partitioning analysis of 2105 patients treated in Radiation Therapy
      Oncology Group studies of head and neck cancer.
AB  - BACKGROUND: The Radiation Therapy Oncology Group conducts large-scale
      prospective, randomized trials to test new concepts in cancer patient care and
      provide information about pretreatment and treatment factors that may influence
      outcome. METHODS: Recursive partitioning analysis (RPA) was used to examine the
      data derived from 2105 patients. RPA grouped patients according to the influence
      of tumor, of host, and of treatment variables on outcome. RESULTS: For survival,
      the most important factor was T classification. For lesions less than T3, the
      primary tumor was the next most important factor, whereas for T3 and T4 lesions
      the Karnofsky score was the next most predictive factor. Six distinct groups were
      formed by RPA, with median survivals ranging from 6.8 to 151.8 months. For local
      regional control, the N classification was the most important factor. For
      patients with no adenopathy, T classification was the next most important factor,
      whereas for patients with adenopathy, the number of treatment fractions was the
      next most important factor. Such analysis created 5 distinct groups. In the most
      favorable, the median time to local-regional relapse has not yet been reached. In
      the least favorable group, fewer than 50% of the patients experienced complete
      response at any time following treatment. CONCLUSIONS: RPA clarifies the relative
      importance and potential interactions of pretreatment and treatment variables and
      should permit more accurate stratification of patients in future trials.

PMID- 8646691
TI  - Non-Hodgkin's lymphoma in an Asian population: 1968-1992 time trends and ethnic
      differences in Singapore.
AB  - BACKGROUND: Non-Hodgkin's lymphoma has increased in incidence in many countries,
      particularly in the West. Advances in diagnostic methods and the understanding of
      the disease over time pose a challenge to the interpretation of these trends. The
      aim of this study was to determine if the disease has increased in Singapore, a
      newly industrialized Asian country, and to examine the possible factors that may
      account for any observed changes. METHODS: Data from the population-based
      Singapore Cancer Registry for the period 1968 to 1992 were reviewed to determine
      time trends based on sex and ethnic group. The Poisson regression model was
      fitted to the cross-tabulated data to obtain the adjusted incidence density
      ratios. RESULTS: A total of 1988 cases of non-Hodgkin's lymphoma were included in
      the analysis. There was an overall increase in incidence among both Chinese and
      Malaysians. However, the rate of increase was greater in females (age
      standardized rate from 1.8 per 100,000 in 1968-1972 to 4.5 per 100,000 in 1988
      1992) than in males (3.2 per 100,000 to 5.9 per 100,000 in the same time
      periods). Between ethnic groups, Malay females were at higher overall risk
      compared with their Chinese counterparts (incidence density ratio 1.32; 95%
      confidence interval, 1.08-1.61). Although a substantial proportion of patients
      diagnosed with Hodgkin's disease between 1968 and 1972 were reclassified on
      review, using present criteria, as having non-Hodgkin's lymphoma, it is unlikely
      that this, and other recent changes in histologic interpretation, could have
      accounted for an increase of this magnitude. CONCLUSIONS: Non-Hodgkin's lymphoma
      has increased in incidence among the Chinese and Malay populations in Singapore.
      The pattern of increase differs from that of the common cancer sites, and
      suggests the need to look for environmental and genetic factors that have not yet
      been elucidated.

PMID- 8646693
TI  - Extent of skin involvement as a prognostic indicator of disease free and overall
      survival of patients with T3 cutaneous T-cell lymphoma treated with total skin
      electron beam radiation therapy.
AB  - BACKGROUND: The goal of this study was to define the prognostic significance of
      the extent of skin involvement (ESI) with respect to disease free survival (DFS)
      and overall survival (OS) of patients with T3 cutaneous T-cell lymphoma (CTCL)
      after total skin electron beam therapy (TSEBT). METHODS: Between 1974 and 1993,
      TSEBT (36 Gray [Gy], 1 Gy/day for 9 weeks, 6 MeV electrons) was administered to a
      total of 213 patients. Forty-six of the 213 patients were classified as having T3
      CTCL based on the presence of tumor nodules on the skin at diagnosis. Patient
      records were evaluated retrospectively, and the percentage of total skin surface
      involved was calculated. Patients were analyzed with respect to response to
      therapy, disease free and overall survival. The median follow-up was 37.5 months
      (range, 1.6-93 months). RESULTS: Thirty-six of 46 patients achieved complete
      clinical response (CCR) by the completion of TSEBT. DFS was 12% at 36 months with
      approximately 28% OS. When stratified by extent of skin involvement, 100% of
      patients with 9% or less ESI were disease free at 18 months compared with
      patients with 10% or greater ESI, all of whom had relapsed by 18 months (78%
      achieved CCR). Fifty percent of those with 9% or less ESI remained disease free
      at 36 months; median DFS and OS were not reached at 63 and 65 months,
      respectively. The median DFS and OS for the 10% or greater ESI group were 4 and
      24 months, respectively. These differences were statistically significant (P < or
      = 0.005). Toxicity of therapy was minimal. CONCLUSIONS: The extent of skin
      involvement of patients with T3 CTCL is a prognostic indicator of disease free
      and overall survival for those who have been treated definitively with TSEBT.

PMID- 8646694
TI  - Five-year experience with combined operative and radiotherapeutic treatment of
      recurrent gynecologic tumors infiltrating the pelvic wall.
AB  - BACKGROUND: Whereas 25 to 50% of selected patients with gynecologic tumors who
      relapse centrally in an irradiated pelvis can be salvaged by exenteration,
      postirradiation recurrence infiltrating the pelvic side wall generally has been
      fatal. We have designed the combined operative and radiotherapeutic treatment
      (CORT) procedure for the treatment of postirradiation recurrence infiltrating the
      pelvic wall and developed several new techniques for its realization. The aim of
      the surgery is as follows: (1) total resection of the tumor with only a
      microscopic margin (R1) at the pelvic wall, preserving the bony pelvis and the
      neurovascular support of the leg; (2) modulation of the therapeutic index for a
      second high-dose irradiation of the pelvic wall by transferring autologous tissue
      from the abdomen or the thigh, and (3) reconstruction of pelvic organ functions
      lost due to tumor resection. The tumor bed is irradiated postoperatively with
      brachytherapy through transcutaneous guide tubes implanted at the pelvic wall.
      METHODS: Between April 1989 and December 1994, we treated 48 patients with
      postirradiation recurrent or persistent gynecologic malignancies infiltrating the
      pelvic wall with CORT and followed them prospectively with the following
      endpoints: tumor control, survival, complications, and quality of life. RESULTS:
      At a median follow-up of 33 months (range, 3-71 months), the 5-year survival
      probability calculated with the Kaplan-Meier method was 44%. The overall local
      control rate was 68%, and 85% in the last 25 patients in the series. The censored
      severe complication rate at 5 years was 33%. No patient died as a consequence of
      the treatment. Quality of life was self-assessed with a validated questionnaire
      by 15 patients without evidence of disease, and was rated with a total of 74% of
      the maximum score points. Age of the patient, state of resection at the pelvic
      wall (R1 vs. R2), and recurrent tumor size independently influenced tumor
      progression after CORT in this series. CONCLUSIONS: CORT appears to be a
      feasible, innovative treatment with long term survival potential and acceptable
      quality of life for selected patients with postirradiation gynecologic tumor
      recurrence infiltrating the pelvic wall. R1 resection of the tumor at the pelvic
      wall is mandatory; however, the reconstruction options within the pelvis are
      limited.

PMID- 8646695
TI  - Radiation alone for carcinoma of the vagina: variation in response related to the
      location of the primary tumor.
AB  - BACKGROUND: A retrospective study of 40 patients with histologically confirmed
      carcinoma of the vagina is reported. The patients were treated by radiation alone
      (a combination of external beam therapy and implants) between October 1969 and
      September 1991 at the Medical College of Virginia Hospital in Richmond. METHODS:
      Thirty-three patients (82%) had squamous cell carcinoma, 2 patients (7%) had
      adenocarcinoma, and 2 patients (5%) had poorly differentiated cancers (1 melanoma
      and 1 leiomyosarcoma). The patients were staged according to the International
      Federation of Gynecology and Obstetrics (FIGO) staging system; there were 13
      patients (33%) in Stage 1, 21 (52%) in Stage II, 4 (10%) in Stage III, and 2 (5%)
      in Stage IV. Thirty-six patients (90%) were treated with external beam therapy
      and some combination of implant: cylinder, ovoid, or interstitial implants with
      iodine-125 or iridium-192 (afterloading). Only 4 patients (10%) received
      treatment by implant only. RESULTS: Based on their response, two groups of
      patients were identified. Group I had 23 patients with tumors predominantly
      located in the proximal half of the vagina; there were 8 patients in Stage I, 11
      in Stage II, 3 in Stage III, and 1 in Stage IV. Of these, three patients failed:
      one each in Stages III and IV and one Stage II patient was salvaged by surgery.
      Three patients died due to unrelated causes but with local control. The 5-year
      actuarial survival in this group was 81%. Group II had 17 patients with tumors
      located in the mid to distal half of the vagina; there were 5 patients in Stage
      I, 10 in Stage II, and 2 in Stage IV. Ten patients failed. Eight patients in
      Stage II had persistent disease, were lost to follow-up, and are presumed dead.
      Two patients with Stage IV disease also had inadequate local control. The overall
      actuarial survival in the distal group was 41%, which was significantly worse
      than the proximal group (81%), at a P value of 0.05. CONCLUSIONS: This study
      discusses the curability of carcinoma of the vagina based on its anatomic
      location when predominantly similar treatment techniques and radiation doses were
      applied to either the proximal or the distal part of the vagina, those with
      cancer in the proximal half had better survival (81%) than those whose cancer was
      in the distal half (41%).

PMID- 8646696
TI  - In vitro concurrent paclitaxel and radiation of four vulvar squamous cell
      carcinoma cell lines.
AB  - BACKGROUND: The antitubule agent paclitaxel causes a cell cycle blockage in the
      most radiosensitive part of the cell cycle, the G2/M phase. The possible
      radiosensitizing effect of paclitaxel was tested in four vulvar (UM-SCV-1A, UM
      SCV-1B, UM-SCV-2, and UM-SCV-4) squamous cell carcinoma (SCC) cell lines.
      METHODS: A 96-well plate clonogenic assay was performed with paclitaxel and
      radiation, both separately and concomitantly. Survival data were fitted to the
      linear quadratic model. The area under the curve, equivalent to the mean
      inactivation dose (D), was obtained by numerical integration. The effect of
      paclitaxel on radiosensitivity was measured as the AUC ratio (paclitaxel plus
      radiation: radiation alone). This ratio was compared with the surviving fraction
      (SFP) after paclitaxel alone. RESULTS: Paclitaxel concentrations of 0.4 to 2.0
      nanomolar (nM) caused 1 to 70% inhibition of clonogenic survival. The AUC values
      of the cell lines were 1.9 to 2.9 gray. A full additive effect was observed when
      paclitaxel and radiation were administered concurrently; however, a supra
      additive effect never occurred. The type of paclitaxel radiation interaction was
      not affected by the concentration of the drug nor did the type of interaction
      vary between cell lines studied. CONCLUSIONS: Paclitaxel and radiation used
      concomitantly produced a clear additive effect at all concentrations and in all
      vulvar carcinoma cell lines tested. Although no supra-additive effect was
      observed, the additive effect already in nM concentrations could be beneficial in
      clinical use and, therefore, requires further investigation.

PMID- 8646697
TI  - The National Cancer Data Base report on lung cancer.
AB  - BACKGROUND: Previous Commission on Cancer data from the National Cancer Data Base
      (NCDB) have examined time trends in stage of disease, treatment patterns, and
      survival for selected cancers. The most current (1992) data for lung cancer are
      described here. METHODS: Four Calls for Data have yielded a total of 560,455 lung
      cancer cases diagnosed in 1986-1987 and 599,597 cancer cases diagnosed in 1992,
      from hospital cancer registries across the United States. RESULTS: A total of
      91,115 lung cancer cases diagnosed in 1986-1987 and 92,182 diagnosed in 1992 were
      reported from cancer registries across the United States. Lung cancer occurs
      mainly in patients between the ages of 50 and 80 years. There was an increasing
      relative frequency of adenocarcinoma, and of lung cancer in women, and a
      noteworthy poor prognosis among African Americans. Lung cancer patients were
      reported from all types and sizes of hospitals in America, from smaller community
      hospitals to major teaching centers. Treatment by surgical resection occurred
      more frequently in the major cancer centers. The overall prognosis for lung
      cancer remains extremely poor. CONCLUSIONS: For a selective category of patients
      (Stage I), cancer-directed surgery offers reasonable cure rates, but these data
      underline the need for earlier diagnosis and improved treatment modalities in the
      overall management of lung cancer patients.

PMID- 8646698
TI  - A phase III evaluation of a somatostatin analogue (octreotide) in the treatment
      of patients with asymptomatic advanced colon carcinoma.

PMID- 8646699
TI  - Olfactory neuroblastoma: an immunohistochemical, ultrastructural, and flow
      cytometric study.

PMID- 8646700
TI  - Prospective study of combination chemotherapy with cyclophosphamide, doxorubicin,
      and cisplatin for unresectable or metastatic malignant pleural mesothelioma.

PMID- 8646701
TI  - Recombinant human erythropoietin for the correction of cancer associated anemia
      with and without concomitant cytotoxic chemotherapy.

PMID- 8646702
TI  - Diamond-Blackfan anemia and malignancy: a case report and a review of the
      literature.

PMID- 8646703
TI  - Looking forward in diagnostic pathology: the molecular superhighway.

PMID- 8646705
TI  - Patterns of breast cancer care in the elderly.
AB  - BACKGROUND: The elderly represent a large proportion of the women with breast
      cancer. However, there is a lack of information regarding breast cancer care in
      the elderly. METHODS: A patient care evaluation survey for breast carcinoma was
      conducted by the Commission on Cancer of the American College of Surgeons for
      1983 and 1990. Data were obtained from hospital tumor registries from all 50
      states, Puerto Rico, and Canada. Information regarding presentation, diagnostics,
      staging, treatment, recurrence, and survival were analyzed. Comparisons were made
      between women 75 years and older and those younger than 75 years. RESULTS:
      Included were 17,029 diagnosed with breast carcinoma during 1983 and 24,004
      diagnosed during 1990. In 1983 and 1990, 20.4% and 23.4% of women, respectively,
      were 75 years or older. Fewer cancers were detected mammographically and needle
      localized biopsies were performed less often in the elderly. There was no
      difference in tumor location or histology. Stage at diagnosis appeared more
      advanced in the elderly. Most women regardless of age, underwent modified radical
      mastectomy. Of the elderly who did undergo breast conserving surgery in 1983 and
      1990, 72% and 39%, respectively, did not receive radiation therapy. No difference
      was found in the local recurrence rates between the elderly and younger groups.
      In the elderly, 20% of deaths occurred from causes other than breast cancer.
      Overall disease specific survival was worse in the elderly but, when analyzed by
      stage, was significantly different for only certain stages. CONCLUSIONS: There
      are several differences in the detection, diagnostic methods, stage at diagnosis,
      treatment approaches, and outcome of breast cancer in elderly women compared with
      younger women.

PMID- 8646704
TI  - Polymerase chain reaction in the detection of micrometastases and circulating
      tumor cells.
AB  - BACKGROUND: The sensitive detection of circulating tumor cells and
      micrometastases may have important therapeutic and prognostic implications.
      METHODS: The molecular detection of occult tumor cells can be accomplished by
      amplifying tumor specific abnormalities present in the DNA or mRNA of malignant
      cells with the polymerase chain reaction (PCR). This approach has been used
      mainly for hemato-lymphoid malignancies. The other main PCR strategy for the
      detection of minimal residual disease (MRD) involves amplification of tissue
      specific mRNA. This method was applied for the detection of occult disease in
      solid tumors. RESULTS: PCR was shown to be superior to conventional techniques in
      detecting circulating tumor cells and micrometastases allowing the identification
      of 1 tumor cell diluted with 10(6)-10(7) normal cells. The central question of
      whether PCR positivity reliably predicts relapse remains unanswered for many
      tumor types. Serial analysis of a large number of samples is needed and currently
      undertaken in many institutions. CONCLUSIONS: PCR is a highly sensitive method
      for the detection of circulating tumor cells and micrometastases in solid and
      hematopoietic malignancies. If PCR positivity is found to be a reliable tool,
      this will likely have a major impact on the treatment of many cancers. Patients
      could be selected for systemic therapy at an earlier stage when the metastatic
      tumor burden is low. PCR may improve the preoperative staging of patients with
      epithelial malignancies and therefore help avoid unnecessary radical procedures.
      Furthermore, this test may be useful in monitoring the effectiveness of adjuvant
      therapy, the intensity and duration of which is tailored to the individual
      patient. The impact of this PCR based approach on clinical oncology is likely to
      be profound.

PMID- 8646706
TI  - Consequences of neural network technology for cervical screening: increase in
      diagnostic consistency and positive scores.
AB  - BACKGROUND: Screening programs for the early detection of cervical carcinoma are
      criticized because of the problem of false-negative diagnoses. A successful
      approach for solving this problem is applying neural network technology (PAP-NET)
      to assist the cytotechnologist (CT) in finding the (few) abnormal cells in the
      smear. METHODS: In 3 consecutive years (1992, 1993, and 1994), 25,767 smears were
      screened conventionally and 65,527 with the aid of PAPNET by 7 CTs. For each CT,
      the scores for atypias of undetermined significance, squamous or glandular
      (ASCUC/AGUS according to the Bethesda classification system), indicated by
      Positive 1, for low grade precursor lesions, by Positive II, for high grade
      lesions and invasive carcinoma, by Positive III, were calculated for both
      screening methods. The histologic scores were also calculated. RESULTS: The mean
      positive scores of the seven CTs were higher for PAPNET than for conventional
      screening, and the coefficients of variability were lower. For Positive III
      smears, the consistency in screening was significantly higher for PAPNET than for
      conventional screening. The higher histologically positive scores for carcinoma
      in situ and invasive carcinoma indicated an increased screening sensitivity.
      CONCLUSIONS: As demonstrated by the improvement in the performances of all CTs
      involved, screening efficacy was enhanced by the use of neural network
      technology.

PMID- 8646707
TI  - CA 125: a valid marker in ovarian carcinoma patients treated with paclitaxel?
AB  - BACKGROUND: Changes in serum CA 125 from baseline do not reflect response to
      paclitaxel in relapsed ovarian carcinoma patients. Our study aimed to determine
      whether CA 125 changes relate to tumor response and overall survival during
      paclitaxel salvage treatment. METHODS: Response data and CA 125 values of 77
      platinum pretreated ovarian carcinoma patients were included in the study.
      Patients received 496 courses of paclitaxel in total (median 6; range: 2-18
      courses). RESULTS: Response group numbers on the basis of World Health
      Organization (WHO) criteria were: 7 partial response, 22 stable disease, and 48
      progressive disease. CA 125 values at the moment of clinical response allocation,
      the median survival duration, and the 3-year survival rate did not differ among
      WHO defined response groups. For both the stable disease group and the
      responders, the slopes of the exponential CA 125 regression curves during
      paclitaxel treatment were negative. Response groups, as defined by CA 125
      changes, i.e., halving or doubling of baseline values, after 4 courses were
      concordant with WHO defined response groups in only 27%, but predicted survival
      far better. CONCLUSIONS: This study confirms that CA 125 changes in patients
      receiving paclitaxel treatment do not correlate with response allocations
      according to WHO criteria. In particular, patients with clinically and
      radiologically defined progression will often not show an increase in CA 125
      concentrations from baseline. Those patients who do show doubling of CA 125
      values, however, have a very poor prognosis. The CA 125 ratio, as determined
      after 4 courses of paclitaxel treatment, may be a better indicator of response
      than WHO defined response status.

PMID- 8646708
TI  - Renal medullary carcinoma: clinical and therapeutic aspects of a newly described
      tumor.
AB  - BACKGROUND: Renal medullary carcinoma is a newly described, aggressive kidney
      tumor. All patients with the disease have been African-American with sickle cell
      (SC) trait or hemoglobin SC disease. METHODS: Patient information was obtained
      from individual patient records and from the Department of Defense national data
      bank, The Defense Enrollment and Eligibility Reporting System. Data were obtained
      from either personal review of the patient's records or from discussion with the
      patient's physician. Cytogenetic studies were performed on one patient. RESULTS:
      Six patients are presented. All had SC trait. Median age was 24.5 years and 1
      patient was female. Time from diagnosis to death averaged 3 months (range 1-7
      mos). No objective responses were reported to a wide variety of chemo and
      immunotherapies: cyclophosphamide, doxorubicin, cisplatin; methotrexate,
      vinblastine, doxorubicin, and cisplatin; single agent interferon; single agent
      paclitaxel; or single agent vinblastine. Investigational regimens included
      topotecan, doxorubicin, and filgrastim; alpha-interferon, interleukin-2, and 5
      fluorouracil; and single agent paclitaxel. Cytogenetic studies revealed numerous
      structural, as well as numerical anomalies. Of the cells successfully karyotyped
      (n=4), 2 contained abnormalities of chromosome 3 and all contained monosomy 11.
      CONCLUSIONS: Renal medullary carcinoma is an aggressive, chemoresistant tumor.
      Time from discovery of tumor to patient death is very short and has been altered
      by a wide variety of chemotherapies and immunotherapies. An unidentified genetic
      component is likely present.

PMID- 8646709
TI  - MIB-1 staining index and peritumoral brain edema of meningiomas.
AB  - BACKGROUND: Growth rates and tumor aggressiveness of meningiomas are thought to
      be closely related to brain edema development. However, histopathologic data
      alone are not consistently accurate predictors of the behavior and clinical
      course of a meningioma. METHODS: The authors examined 57 histologically proven
      intracranial meningiomas to identify factors, including growth fractions
      determined by MIB-1 immunostaining, that may influence the development of
      meningioma-associated peritumoral brain edema. There were 54 benign, 2 atypical,
      and 1 anaplastic meningiomas. The MIB-1 staining index (SI) percentage was
      defined as the number of MIB-1 positive cells divided by the total number of
      tumor cells in a 1.037-square millimeter area on the slide. The extent of
      peritumoral brain edema was determined using preoperative magnetic resonance
      imaging. The extent of edema was classified as Grade 0,1, or 2 (GR0, GR1, or
      GR2), in order of increasing severity. RESULTS: The MIB-1 SIs of the 57 cases
      ranged from 0.06-6.8% (median, 0.80%). There were 26 GR0, 20 GR1, and 11 GR2
      edema cases. The MIB-1 SI rose in order of increasing edema severity. There was a
      statistically significant correlation between the MIB-1 SI and the extent of
      brain edema (P<0.0001), and also between the tumor size and the extent of brain
      edema (P=0.001). Meningothelial and atypical/anaplastic meningiomas were
      associated with peritumoral brain edema more often than any other subtype
      (P<0.005). CONCLUSIONS: Growth fractions, as determined by MIB-1 immunostaining,
      rise with increasing severity of peritumoral brain edema, indicating a close
      relationship between tumor aggressiveness and edema development.

PMID- 8646710
TI  - A double-blind comparison of the efficacy of two dose regimens of oral
      granisetron in preventing acute emesis in patients receiving moderately
      emetogenic chemotherapy.
AB  - BACKGROUND: The purpose of this study was to define an optimal administration
      schedule of granisetron for patients receiving moderately emetogenic chemotherapy
      by comparing the antiemetic efficacy and safety of 2 mg of the drug administrated
      orally. METHODS: In this double-blind, randomized, parallel study, 2-dose
      regimens of oral granisetron were evaluated in 697 adult cancer patients.
      Patients were stratified by gender and randomized to receive 2 mg oral
      granisetron, either as a divided dose given 1 hour prior to chemotherapy and 12
      hours after the start of chemotherapy, or as a single dose 1 hour prior to
      chemotherapy at Cycle 1. The primary efficacy endpoints assessed were the
      percentage of patients with complete response (no nausea, no emesis, and no
      additional antiemetic medication during the 24-hour post-chemotherapy interval)
      and the incidence of emesis and nausea. Following completion of Cycle 1, patients
      were given the opportunity to receive open-label granisetron (2 mg once daily) on
      the first day of each remaining cycle of chemotherapy. RESULTS: No statistically
      significant differences in any of the endpoints were observed between the two
      treatment groups. Approximately 50% of patients in both treatment groups achieved
      complete response. The proportion of patients with no episodes of emesis occurred
      with similar frequency in the two treatment groups. Approximately 52% of patients
      in either treatment group were free of nausea during the postchemotherapy period.
      There was no difference between treatment groups regarding the use of antiemetic
      rescue medication. Finally, the incidence of adverse experiences was similar for
      both treatment groups. CONCLUSIONS: Both dose regimens of oral granisetron were
      similarly effective in controlling nausea and vomiting in the 24-hour interval
      following chemotherapy. Granisetron was well tolerated with few adverse events
      attributable to the study drug.

PMID- 8646711
TI  - Skin ulceration potential of paclitaxel in a mouse skin model in vivo.
AB  - BACKGROUND: THe antimitotic agent paclitaxel is highly active in the therapy of
      several tumor types, including ovarian and breast cancer. The commercial
      formulation (Taxol) is supplied in a vehicle containing alcohol and the
      surfactant Cremophor EL (polyethoxylated castor oil). Whereas Phase I studies did
      not describe extravasation necrosis, more recent case reports have suggested that
      paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The
      efficacy of various antidotal maneuvers, if any, was not known. METHODS:
      Dehaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3
      mg, 0.6 mg, or 1.2 mg, or Cremophor EL, 0.1 mL, into the dorsal skin. The sites
      were observed thrice weekly for evidence of ulceration. Perpendicular widths of
      skin ulcers were measured by caliper and multiplied to yield a lesion area in
      cm2. The lesion area multiplied by time in days was integrated by computer to
      yield cumulative ulceration areas in (cm2 x days). Potential pharmacologic
      adjuvants were injected ID after paclitaxel. These included saline (0.05 mL),
      albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical
      adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 degrees
      C or heating to 43-44 degrees C for 30 minutes after ID paclitaxel. RESULTS: Dose
      dependent skin ulcers that lasted 12-17 days were created with the 3 ID
      paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were
      selected for antidote studies. Hyaluronidase and saline were effective ID
      antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the
      higher paclitaxel dose of 1.2 mg (P<0.05 by analysis of variance). None of the
      topical adjuvants or other ID adjuvants significantly reduced paclitaxel-induced
      skin ulcers in the mice. CONCLUSIONS: Paclitaxel has experimental vesicant
      potential in the ID mouse skin model. Clinical extravasations of paclitaxel may
      be treated by subcutaneous injections of hyaluronidase diluted in saline.

PMID- 8646712
TI  - Clinical evaluation of tumor targeting with the anticarcinoembryonic antigen
      murine monoclonal antibody fragment, MN-14 F(ab)2.
AB  - BACKGROUND: The initial clinical experience with the second-generation, high
      affinity, MN-14 immunoglobulin (IgG) anticarcinoembryonic antigen (CEA)
      monoclonal antibody (MoAb) in patients with CEA-producing tumors was reported
      previously. A bivalent fragment of this MoAb, MN-14 F(ab)2, was prepared, and its
      pharmacokinetics, targeting properties, dosimetry, and immunogenicity were
      investigated. METHODS: MN-14 F(ab)2(0.6-29 mg) was labeled with 131I(7.7-269
      millicuries and injected into 28 patients with CEA-producing cancers. External
      scintigraphy was used to evaluate tumor targeting. Quantitative external
      scintigraphy methods were used to determine the organ and tumor radiation doses.
      RESULTS: The overall sensitivity of tumor targeting on a lesion basis was 86%,
      similar to that reported previously for MN-14 whole IgG. The biologic T1/2's for
      the fragment in the blood and total body (in hours) were 16.8 +/- 4.1 and 59.4 +/
      9.4, respectively, compared with 27.3 +/- 15.7 and 69.6 +/- 32.2 reported for MN
      14 IgG. Depending on the protein dose given, high plasma CEA levels (>100ng/ML)
      resulted in a significant alteration of MoAb pharmacokinetics and organ
      dosimetry. Individual tumors received an average dose of 10.7 +/- 7.3 centigray
      [cGy]/mCi, and the tumor-to-total body, red marrow, lung, liver, and kidney dose
      ratios were 16.8 +/- 11.1, 5.6 +/- 3.6, 5.1 +/- 3.9, 6.0 +/- 3.8, and 3.1 +/-
      2.0, respectively (mean + standard deviation [SD]). Only 9 of 18 patients (50%)
      injected with >4 mg (range: 4-52.1 mg) of MN-14 F(ab)2 developed significant
      levels of human antimouse antibodies, suggesting that the F(ab)2 may be less
      immunogenic than the intact IgG. CONCLUSIONS: MN-14 F(ab)2 exhibits a similar
      targeting sensitivity and tumor dose as reported previously for the IgG form. The
      lower red marrow doses combined with lower immunogenicity expected for this
      agent, may make it a suitable alternative for future imaging and therapeutic
      applications.

PMID- 8646713
TI  - Birth defects in offspring of adult survivors of childhood acute lymphoblastic
      leukemia. A Childrens Cancer Group/National Institutes of Health Report.
AB  - BACKGROUND: It is not known if therapy for acute lymphoblastic leukemia (ALL)
      during childhood increases the risk of birth defects in the offspring of adult
      survivors. The Childrens Cancer Group (CCG), in collaboration with the National
      Institutes of Health (NIH), conducted a retrospective cohort study of adults
      successfully treated for childhood ALL to determine if their offspring had an
      increased incidence of birth defects compared with the offspring of their sibling
      controls. METHODS: Study subjects were patients who had been enrolled on CCG ALL
      protocols, who were treated for ALL prior to age 20, who survived at least 2
      years, and who were at least age 18. Survivors (N=593) and sibling controls
      (N=409) were interviewed by telephone. RESULTS: The mean age of survivors was
      22.6 years; the mean age of controls was 25.2 years. Among survivors, 93 (15.7%)
      had given birth to or fathered a total of 140 live-born offspring, (mean age, 3.4
      years), and 122 (29.8%) sibling controls had given birth to or fathered a total
      of 228 live-born offspring (mean age, 5.9 years). There was no difference in the
      rate of birth defects between offspring of survivors and offspring of controls
      (3.6% [5 of 140] vs. 3.5% [8 of 228]; relative risk, 1.02; 95% confidence
      interval, 0.34, 3.05). No specific ALL therapy was associated with an increased
      rate of birth defects. Only female survivors reported offspring with birth
      defects (P=0.0735). CONCLUSIONS: Adult survivors of childhood ALL in our study
      were not at greater risk for having offspring with birth defects compared with
      sibling controls. Although this is the largest group of ALL survivors studied to
      date, the number of offspring is still not large enough to detect small but
      significant differences in rare events such as birth defects. Studies following
      this cohort into later adulthood and studies of additional ALL survivors are
      necessary to adequately quantify the risks.

PMID- 8646714
TI  - p53, Rb, and cyclin D1 expression in human oral verrucous carcinomas.
AB  - BACKGROUND: The verrucous carcinoma (VC), a tumor with low grade malignancy,
      appears to be associated with tobacco and human papillomavirus. The pathobiology
      of these tumors has not been extensively studied, and molecular genetic
      alterations have not been reported. In this study we investigated by
      immunohistochemistry the expression of p53, Rb, and cyclin D1 in a series of well
      defined oral VC. Changes in the expression of these genes have been commonly
      reported in a variety of human tumors. METHODS: We studied 29 cases of VC, fixed
      in formalin and embedded in paraffin. Immunohistochemistry was carried out using
      the avidin-biotin immunoperoxidase technique. Polyclonal antibody CM-1 was used
      for p53, a rabbit polyclonal human RB antibody, Rb-WL-1 antibody for Rb and a
      rabbit polyclonal human cyclin D antibody for cyclin D1. RESULTS: Positive p53
      expression (protein accumulation) was detected in 15 of the 29 VC analyzed. In
      some cases, p53-positive areas were small foci but in most of the cases extensive
      positive areas were observed. None of the cases studied showed alterations of Rb
      protein. The expression of cyclin D1 was determined in 18 cases of VC. Positive
      nuclear immunostaining was seen in 11 cases. CONCLUSIONS: p53 protein
      accumulation is frequently observed in these tumors suggesting possible mutations
      of this gene in VC. Overexpression of cyclin D1 but no alterations of Rb staining
      were also observed in this low grade tumor suggesting that Rb may be functionally
      inactivated by overexpression of cyclin D1 or HPV infection.

PMID- 8646715
TI  - Sialosyl Tn antigen expression is associated with the prognosis of patients with
      advanced gastric cancer.

PMID- 8646716
TI  - Transferrin receptor expression in nonsmall cell lung cancer: histopathologic and
      clinical correlates.

PMID- 8646717
TI  - Overexpression or mutation of the p53 tumor suppressor gene does not occur in
      malignant ovarian germ cell tumors.

PMID- 8646718
TI  - Survival after radical retropubic prostatectomy of men with clinically localized
      high grade carcinoma of the prostate.

PMID- 8646719
TI  - Radiation therapy for glottic cancer using 6-MV photons.

PMID- 8646720
TI  - Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal
      and cancer cells of different types and origins.

PMID- 8646721
TI  - Expression of Epstein-Barr virus-encoded RNAs as a marker for metastatic
      undifferentiated nasopharyngeal carcinoma.
AB  - BACKGROUND: Epstein-Barr virus (EBV) is associated with undifferentiated
      nasopharyngeal carcinoma (NPC). EBV-encoded nonpolyadenlyated RNAs (EBERs) are
      often used as a marker to detect EBV-infected NPC cells. This study was conducted
      to document the expression and determine the significance of EBERs in NPC cells
      at various metastatic sites. METHODS: An in situ hybridization (ISH) technique
      was used to identify the presence of EBERs in paraffin embedded tissues of
      primary and metastatic sites obtained from 21 patients with NPC. Nineteen of
      these patients had undifferentiated lesions, and 2 had squamous cell carcinoma.
      One hundred and fifty specimens of normal tissues and tissues from patients with
      a variety of benign and malignant diseases other than NPC served as controls. In
      the NPC specimens, the expression of latent membrane protein (LMP) and a lytic
      protein, BZLF-1, were also examined by immunohistochemistry. RESULTS: Tissues
      from all patients with undifferentiated NPC and one patient with squamous cell
      carcinoma contained EBERs in the malignant cells; the other case of squamous cell
      carcinoma was negative. In metastatic NPCs, LMP was expressed in 18% (4 of 22) of
      tissues whereas BZLF-1 was not expressed in any tissues. EBERs were not detected
      in the 43 patients with normal tissues and benign lesions. In malignant diseases
      other than NPC, EBERs were detected in only 2 of 12 cases of non-Hodgkin's
      lymphoma, 1 of 2 cases of Hodgkin's lymphoma, and 1 of 6 cases of gastric cancer.
      CONCLUSIONS: By virtue of the direct correlation between latent EBV infection and
      NPC, the authors conclude that EBERs can be used as a sensitive marker to
      identify NPC cells at various metastatic sites by techniques of in situ
      hybridization, and that demonstration of EBERs in lesions of undifferentiated
      histology may be useful as a diagnostic adjunct for NPC presenting as metastatic
      cancer of unknown origin.

PMID- 8646722
TI  - Phase II clinical trial with 5-fluorouracil, recombinant interferon-alpha-2b, and
      cisplatin for patients with metastatic or regionally advanced carcinoma of the
      esophagus.
AB  - BACKGROUND: Recombinant interferon-alpha (IFN) augments the cytotoxicity of both
      5-fluorouracil (5-FU) and cisplatin in vitro. A phase II study of 5-FU and IFN
      resulted in response rates of 25-27% in patients with metastatic esophageal
      carcinoma. METHODS: A Phase II trial was initiated to determine the clinical
      utility of a three-drug combination (FIP) in patients with regionally advanced or
      metastatic esophageal carcinoma. Eligibility included biopsy-proven Stage III or
      IV squamous cell carcinoma or adenocarcinoma of the esophagus with no prior
      chemotherapy, adequate performance status, nutritional status, bone marrow,
      hepatic and renal function, and signed informed consent. Patients were treated in
      the exact sequence of IFN==>cisplatin==>5-FU. Patients received 5-FU, 750
      mg/m2/day for 5 days followed by weekly bolus therapy at the same dose;
      cisplatin, 100 mg/m2 on Day 1, followed by weekly therapy, 25 mg/m2 over the
      course of 1 hour; and IFN, 10 MU subcutaneously 3 times/week beginning on Day 1.
      All patients received sargramostim (granulocyte-macrophage colony-stimulating
      factor, Escherichia coli-derived), 5 micrograms/kg subcutaneously 5 times/week.
      No patients received radiotherapy. RESULTS: Twenty-four patients were enrolled;
      23 were eligible, and 1 was excluded on pathology review (patient was found to
      have a leiomyoblastoma). The demographics of the population were: median age, 63
      years (range, 43-73 years); 18 male patients; squamous cell carcinoma:
      adenocarcinoma ratio, 22:1, and Stage III:IV ratio, 10:13. Grade 3-4 National
      Cancer Institute Common Toxicity Criteria toxicities included: leukopenia (13),
      thrombocytopenia (14), and infection (9). Grade 3 diarrhea, mucositis, and
      vomiting occurred in 6 patients, 4 patients, and 1 patient, respectively. There
      were two instances of sudden death, likely related to tumor progression. Major
      responses occurred in 15 of 23 patients (65%; 95% confidence interval, 43%, 85%)
      (1 complete response, 14 partial responses). The median survival was 8.6 months;
      with a median follow-up of 26 months, estimated 30-month survival was 31%.
      CONCLUSIONS: This regimen, although moderately toxic, has substantial activity in
      metastatic and regionally advanced squamous cell carcinoma of the esophagus.
      Further investigations should be conducted to determine the role of IFN in the
      treatment of esophageal carcinoma.

PMID- 8646723
TI  - A dose-finding study of lanreotide (a somatostatin analog) in patients with
      colorectal carcinoma.
AB  - BACKGROUND: Laboratory data suggest that insulin-like growth factor-1 (IGF-1) may
      stimulate the growth of different human tumors. At least in acromegalic patients,
      somatostatin (SMS) analogs, such as lanreotide, suppress the serum levels of
      growth hormone (GH) and IGF-1. METHODS: To evaluate the tolerability and biologic
      activity of different doses of lanreotide in patients with advanced colorectal
      carcinoma, consecutive groups of 3 patients each were subcutaneous treated with
      lanreotide at doses of 1, 2, 3, 4, 5, or 6 mg three times a day for 2 months. In
      the event of Grade 3 side effects, 3 additional patients were treated with the
      same dose before the next dose escalation. Serum samples were obtained on Days 0,
      15, 30, and 60 for serum GH, IGF-1, and lanreotide assessment. RESULTS: Twenty
      four patients were enrolled and all were evaluable. Except for the 3 and 6 mg
      doses, for which the observation of a Grade 3 side effect required that an
      additional three patients be treated, it was sufficient to treat 3 patients at
      each dose. The overall incidence of side effects was as follows: changes in bowel
      habits, 83%; abdominal cramps, 79%; diarrhea, 17%; vomiting, 17%; nausea, 21%;
      steatorrhea, 78%; hyperglycemia, 35%; laboratory hypothyroidism, 39%; gallstones,
      13%; and weight loss, 17%. No evidence of an increase in the incidence,
      intensity, or duration of side effects was observed with dose escalation. Serum
      IGF-1 levels were as follows: Day 15: 63%, 60%, and 67% of the baseline values
      for the low (1-2 mg), intermediate (3-4 mg), and high (5-6 mg) dose groups,
      respectively; Day 30: 63%, 59%, and 51%, respectively; and Day 60: 73%, 69%, and
      47%, respectively. Serum lanreotide levels declined during treatment in all of
      the dose groups (90 ng/mL on Day 15, and 35 ng/mL on Day 60 for the 5-6 mg group;
      10 ng/mL on Day 15, and 1.5 ng/mL on Day 60 for the 1-2 mg group). No antitumor
      activity or tumor marker reduction was observed. CONCLUSIONS: No increase in
      toxicity was observed when subcutaneous lanreotide doses were escalated to 6 mg
      three times a day for 2 months. The highest doses seemed to maintain reduced
      serum IGF-1 levels; with the lowest doses, a "rebound" in serum IGF-1 levels was
      observed during treatment. Nevertheless, intermittent subcutaneous injections do
      not ensure constant serum drug concentrations over time.

PMID- 8646724
TI  - The revised European-American classification of lymphoid neoplasms: a belated
      commentary.

PMID- 8646725
TI  - Sulfatides as a predictive factor of lymph node metastasis in patients with
      colorectal adenocarcinoma.
AB  - BACKGROUND: Sulfatide is one of the acidic glycolipids that are components of the
      cellular membrane. It has been reported that sulfatide plays some important roles
      in cell functions, such as cell adhesion. The aim of this study was to
      investigate the relationship between sulfatide and the malignant potential of
      colorectal carcinoma. METHODS: Glycolipids were extracted from 22 primary
      colorectal cancer tumors and 6 adjacent normal mucosa using the Folch method.
      Qualitative analysis of the sulfatide contents was performed using thin-layer
      chromatography (TLC) and TLC immunostaining. Quantitative analysis was performed
      by densitometric scanning. RESULTS: Two bands of sulfatide were observed by TLC
      immunostaining and were designated as cerebroside sulfated ester (CSE)-A and CSE
      B. Levels of CSE-A were found to be significantly decreased whereas those of CSE
      B were significantly increased in cancerous tissue when compared with normal
      tissue (P<0.05). The CSE ratios (CSE-B/[CSE-A + CSE-B]) in the 15 tumors showing
      lymph node metastasisi were higher than in the 7 tumors without lymph node
      metastasis (P<0.05). The CSE ratios in 9 Dukes Stage C tumors and 6 Dukes Stage D
      tumors were higher than those in 7 Dukes Stage A tumors (P<0.02, and P<0.05,
      respectively). CONCLUSIONS: These data support the conclusion that changes in
      sulfatide composition may play an important role in lymph node metastasis of
      colorectal adenocarcinoma.

PMID- 8646726
TI  - A new approach to fecal occult blood testing based on the detection of
      haptoglobin.
AB  - BACKGROUND: Colorectal carcinoma is a common disease, occurring in 1 in 20 adults
      in Western society, and there is a compelling need for an effective early
      diagnostic test. Several serum tests, including carcinoembryonic antigen have
      been used, but none are sufficiently sensitive for the early diagnosis of the
      disease. METHODS: In a novel approach using fecal extracts from patients with
      colorectal cancer as the antigen for immunization, several MoAbs were produced.
      One (FE14.1) was found to react with the feces from patients with colon cancer,
      but not with those from normal subjects. A sandwich enzyme-linked immunoadsorbent
      assay was developed, and its ability to diagnose colorectal carcinoma evaluated.
      RESULTS: Of the patients with colorectal carcinoma, 91.5% (43/46) were positive
      compared with 1.9% of normal individuals (4/211). Analysis of the N-terminal
      amino acid sequence of a subunit of the molecule detected by FE14.1 shows it to
      be the beta chain of haptoglobin. CONCLUSIONS: The assay developed in this study
      has several advantages compared with current fecal occult blood tests, including
      no requirement for dietary restriction and the ability to distinguish between
      upper and lower gastrointestinal bleeding, while retaining the sensitivity and
      specificity of the current tests. Furthermore, the sensitivity of the tests
      increases to 100% if the FE14.1 and HemeSelect are combined. In addition, the
      study shows the potential to produce anticancer agents by immunizing with fecal
      material.

PMID- 8646727
TI  - Tumor markers in patients with pancreatic carcinoma.
AB  - BACKGROUND: Tumor markers are putative prognostic indicators for patients with
      carcinoma, but have not heretofore been evaluated in patients with Stage II and
      III pancreatic carcinoma. METHODS: Patients with Stage II (n=9) and Stage III
      (n=25) unresectable regional adenocarcinoma of the pancreas were treated with
      combined modality therapy. Treatment consisted of split course radiotherapy and
      simultaneous combination chemotherapy with fluorouracil infusion, streptozotocin,
      and cisplatin. Prior to treatment, patients free of both infection and jaundice
      provided blood for CA 19-9, carcinoembryonic antigen (CEA) and CA 125 assays.
      RESULTS: The overall median survival of Stage II patients was 21.1 months. Due to
      the small number of Stage II patients with markedly abnormal assays, it was not
      possible to test for a statistically significant association between pretreatment
      tumor assays and survival. Among patients with Stage III pancreatic carcinoma, a
      CA 19-9 assay of 2000 u/ML or less identified a group of 16 patients with a
      median survival of 12.8 months. In contrast, 8 Stage III patients with a CA 19-9
      assay of greater than 2000 u/mL had a median survival of 8 months and only 1
      patient survived for 1 year (P=0.020, log rank test; P=0.010, Wilcoxon test).
      Among Stage III patients, a comparison of those with a normal assay versus any
      degree of abnormal assay failed to provide prognostic information. Analyses based
      on a combination of CA 19-9 and CA 125 assays provided additional powerful
      prognostic information: (P=0.002, log rank test; P=0.005, Wilcoxon test). CEA
      assays failed to provide information alone or in combination with the CA 19-9
      assay. After adjusting for the CA 19-9 assay in multivariate analyses, neither
      performance status nor tumor size were significant prognostic variables for
      patients with Stage III cancers. CONCLUSIONS: Pretreatment CA 19-9 assays provide
      powerful independent and objective prognostic information.

PMID- 8646728
TI  - Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment
      of inoperable nonsmall cell lung carcinoma: a multicenter randomized clinical
      trial.
AB  - BACKGROUND: Lonidamine (LND) is an indazol-carboxylic acid derivative that
      selectively inhibits the energy metabolism of neoplastic cells, and increases the
      permeability of cell membranes. In vitro studies have demonstrated that LND can
      potentiate the oncolytic activity of cytotoxic drugs and is able to reverse the
      acquired multidrug resistance of neoplastic cells. Some clinical trials have
      suggested a synergism of LND with alkylating agents, cisplatin, and
      anthracyclines in various solid tumors. METHODS: From June 1990 to June 1993, 158
      previously untreated patients with Stage IIIB and IV nonsmall cell lung cancer
      (NSCLC) were enrolled into a multicentric randomized trial to evaluate the
      addition of LND to a cisplatin-epirubicin-vindesine regimen. Eighty patients in
      the control arm (A) received cisplatin, 60 mg/m2 intravenously (i.v.);
      epirubicin, 60 mg/m2 i.v.; and vindesine, 3 mg/m2 i.v. (PEV), on Day 1 every 4
      weeks, whereas 78 patients in the experimental arm (B) received the same regimen
      with the addition of LND from 75 mg orally three times on Day 1 to 150 mg orally
      three times on Day 7+ until tumor progression occurred. RESULTS: The experimental
      treatment achieved a significantly higher proportion of major responses in
      comparison with the control regimen (43% vs. 24%; P=0.02). The addition of LND
      apparently potentiated the activity of this cytotoxic treatment, particularly in
      patients with metastatic disease (overall response rate, 39% vs. 17%). The median
      time to progression (5 vs. 8 months; P=0.0007) and the median survival time (7.6
      vs. 11 months; P=0.0013) were also statistically improved in Arm B. The acute
      toxicity of the 2 treatments was low: only 6% of patients in Arm A and 4% of
      patients in Arm B had to withdraw from treatment due to Grade 4 World Health
      Organization toxicity. The main additional side effects related to the
      administration of LND were epigastralgia, myalgia, asthenia, and orchialgia.
      However, these symptoms were mild and controlled by the concomitant
      administration of low doses of steroids. CONCLUSIONS: The mild acute toxicity of
      the PEV regimen and the acceptable and nonoverlapping additional side effects of
      LND render our experimental therapy worthy of consideration for the management of
      NSCLC patients with poor performance status or low tolerance to more aggressive
      therapeutic approaches.

PMID- 8646729
TI  - Treatment of femoral Ewing's sarcoma.
AB  - BACKGROUND: The treatment of Ewing's sarcoma consists of chemotherapy for
      systemic and local disease. However, the role of radiation therapy, and/or
      surgical resection for definitive local treatment has yet to be determined.
      METHODS: A retrospective review of 32 patients (24 males and 8 females) treated
      for femoral Ewing's sarcoma between 1970 and 1985 was performed. Patients were
      divided into 3 treatment groups: chemotherapy and radiotherapy (CR) (10);
      chemotherapy and surgery (CS) (9); and chemotherapy, surgery, and radiotherapy
      (CSR) (13). Patients in the CR group received a mean of 5320 centigray (cGy) of
      radiation and patients in the CSR group received a mean of 3590 cGy. Multiagent
      cyclophosphamide/doxorubicin based chemotherapy was used in all cases. Surgery
      consisted of wide resection or amputation. RESULTS: Patients in the CR group had
      a higher risk of local recurrence than patients in the CS and CSR groups (P=0.02,
      log rank). The combination of local recurrences and treatment complications
      necessitated surgery for 7 of 10 CR patients, whereas 1 of 9 and 4 of 13 in the
      CS and CSR groups required additional surgery. The median survival for the entire
      group was 39 months. Minimum follow-up for surviving patients was 45 months. Five
      year survival consisted of 1 of 10 patients in the CR group, 2 of 9 in the CS
      group, and 7 of 13 in the CSR group. There were no statistically significant
      differences among the three survival curves. Tumor location within the femur was
      a significant prognostic variable. Distal femoral location had a survival
      advantage compared with proximal and mid-femur locations (P = 0.049, log rank).
      CONCLUSIONS: Femoral Ewing's sarcoma remains a disease with a poor prognosis.
      Radiation alone for local treatment results in a high rate of local recurrence
      and complications. Our current local treatment strategy for femoral Ewing's
      sarcoma includes surgery in all and adjuvant radiotherapy in many of the
      patients.

PMID- 8646730
TI  - Aggressive angiomyxoma: a clinicopathologic study of 29 female patients.
AB  - BACKGROUND: Aggressive angiomyxoma is an uncommon mesenchymal tumor that
      preferentially involves the pelvic and perineal regions of females. Since its
      initial description in 1983, approximately 65 cases have been reported in the
      English literature. METHODS: The clinical and pathologic features of 29 cases of
      aggressive angiomyxoma were evaluated in a review of archival material from the
      Armed Forces Institute of Pathology (1960-1992). Histochemical stains for
      mucosubstances and immunohistochemistry (avidin-biotin complex method) were
      utilized to characterize the neoplasms further. RESULTS: All patients were
      females, between 16 and 70 years (median; 34 years). The soft tissues of the
      pelvis, perineum, vulva, buttock, retroperitoneum, and inguinal regions were
      involved. The majority of the tumors were > or = 10 centimeters in greatest
      dimension. Follow-up ranging from 8 to 198 months (mean, 93 months; median, 95
      months) was available for 22 patients. Eight patients developed recurrent tumor,
      from 10 months to 7 years after the initial resection. No patient developed
      metastases and there were no tumor related deaths. Histologically, the neoplasms
      were sparsely to moderately cellular and predominantly composed of bland,
      relatively nondescript. stellate and spindled cells embedded in a loosely
      collagenized matrix with scattered vessels of varied caliber. A few cases
      contained some tumor cells with more abundant eosinophilic cytoplasm that raised
      the possibility of focal smooth muscle differentiation. The tumor matrix was no
      more than weakly reactive for mucosubstances; thus, while glycosaminoglycans are
      present to a limited extent, edema fluid appears to be a major component of the
      noncollagenous stroma. The neoplastic cells were at least focally immunoreactive
      for desmin (22/22), smooth muscle actin (19/20), muscle specific actin (16/19),
      vimentin (17/17), CD34/QBEND-10 (8/16), and estrogen (13/14) and progesterone
      (9/10) receptor. All of the examined tumors were negative for S100 protein
      (20/20). Ki67 (MIB1) immunoreactivity was present in <1% of the tumor nuclei in
      all 16 cases tested. CONCLUSIONS: Aggressive angiomyxoma is a distinctive,
      locally aggressive, mesenchymal tumor that appears to be relatively site specific
      and has a peak incidence in females in the fourth decade of life. There is a
      strong propensity for local recurrence but metastatic disease has not been
      reported. Since the first evidence of recurrence may be many years after the
      initial resection, long term follow-up is required. The neoplastic cells of
      aggressive angiomyxoma exhibit fibroblastic and myofibroblastic features and
      appear to be hormonally influenced. The possibility that the progenitor cell has
      a capacity for smooth muscle differentiation is raised.

PMID- 8646731
TI  - Evaluation of neoadjuvant chemotherapeutic response of locally advanced breast
      cancer by magnetic resonance imaging.
AB  - BACKGROUND: The implementation of new treatment protocols for locally advanced
      breast cancer is currently limited by inaccurate evaluation of response to
      neoadjuvant chemotherapy. A recently developed dedicated breast magnetic
      resonance imaging (MRI) method (RODEO MRI) was evaluated as a tool for
      determining tumor response and extent of residual disease after neoadjuvant
      chemotherapy. METHODS: Thirty-nine patients with Stage II, III, or IV breast
      carcinoma were prospectively evaluated prior to and following neoadjuvant
      chemotherapy by MRI, physical examination, and mammography. Assessment of
      response determined by the three methods was compared. In addition, detailed
      pathologic correlation of residual disease was determined by serial sectioning of
      31 mastectomy specimens from 30 patients. Nine patients had breast conservation,
      and were included in the response evaluation only. Estimates of tumor response
      were made by both surgical and medical oncologists. Independent interpretations
      of MRI studies without knowledge of clinical response were made by three
      radiologists. RESULTS: The surgical oncologists assessed complete response (CR),
      partial response (PR), and no response (NR) in 11, 22, and 7 cases, respectively.
      The medical oncologists assessed CR, PR, and NR in 12, 21, and 7 cases,
      respectively. The surgical and medical oncologists' clinical assessment of
      response agreed with the results of MRI in 52% and 55% of cases, respectively,
      and with each other in 30 of 40 cases (75%). Mammography correlated with MRI
      response in only 52% of cases. However, MRI accurately predicted the pathologic
      determination of residual disease in 30 of 31 cases (97%). There was no
      disagreement in the assessments of residual disease or response among the three
      radiologists. CONCLUSIONS: RODEO breast MRI accurately estimates residual disease
      after induction chemotherapy. It assesses response to neoadjuvant chemotherapy
      better than traditional methods of physical examination or mammography. The
      information obtained from this MRI technique may be used as an objective tool
      during clinical trials, and to select patients better for breast conservation
      after neoadjuvant chemotherapy for locally advanced disease.

PMID- 8646732
TI  - Incidence of homogeneously staining regions in non-Hodgkin lymphomas.
AB  - We report a series of 86 non-Hodgkin's lymphomas (NHL) studied cytogenetically in
      which two cases with a homogeneously staining region (HSR) located on chromosome
      19 and on chromosome 1, respectively, were observed. The low incidence detected
      (2.3%) suggests that HSR are rare events in NHL. An oncogenetic amplification
      study was performed with probes for genes that are currently known to undergo
      amplification and with probes for two genes located on chromosome 19q (AKT2 and
      BCL-3). We detected no amplification except for AKT2 putative oncogene in the
      lymphoma in which the HSR was located on chromosome 19. Because amplification of
      AKT2 putative oncogene has been detected in ovarian carcinomas bearing HSR and in
      this case NHL, we believe that this gene may be implicated in the pathogenesis of
      other neoplasias in cooperation with other genes. Further investigation is needed
      to confirm the low incidence of HSR in NHL and the origin of the amplified
      material.

PMID- 8646733
TI  - Translocation (3;3) in a patient with thrombocytopenia and erythroid dysplasia.
AB  - We describe a case with a translocation between the two chromosomes 3 with
      breakpoints q21 and q26, associated with a unique constellation of hematologic
      abnormalities. Megakaryocytic dysplasia and peripheral thrombocytosis are the
      most common abnormalities associated with this chromosome abnormality. Our
      patient had acute myeloid leukemia (AML), thrombocytopenia, dyserythropoiesis,
      and an increased myeloid/erythroid ration but no mekakaryocytic dysplasia.
      Although multilineage involvement has been reported, erythrocyte dysplasia
      associated with thrombocytopenia and without megakaryocyte dysplasia appears to
      be extremely rare. Our case supports the speculation that #3 abnormalities with
      breakpoints q21 and q26 affect a pluripotent stem cell and suggests that
      megakaryocytic involvement may not be pathognomonic in hematologic abnormalities
      with t(3;3)(q21;26).

PMID- 8646734
TI  - Cytogenetic characterization of the human prostate cancer cell line P69SV40T and
      its novel tumorigenic sublines M2182 and M15.
AB  - Cytogenetic studies of a SV40T antigen immortalized human prostate epithelial
      cell line (P69SV40T) and its increasingly tumorigenic tumor sublines, designated
      M2182 and M15, were done with GTG-banding and multicolor fluorescence in situ
      hybridization (FISH). The parental line and each of the two sublines were near
      diploid and contained several consistent abnormalities. Two structural chromosome
      anomalies were noted in all three lines; a der(7)t(5;20;7) and a der(5)t(5;9).
      Abnormalities that were acquired and retained in the tumor sublines after in vivo
      and/or in vitro selection included a der(1)t(1;8), der(3)t(3;14), der(20)t(7;20),
      and der(X)t(X;11). Findings unique to subline M2182 were a der(11)t(5;11) and 
      14. Those unique to M15 were a der(16)t(16;19) and -Y. Chromosome imbalances
      resulting from numerical and/or structural abnormalities in the tumor sublines
      involved several chromosome regions that have previously been implicated in human
      prostate cancer, such as loss of Xp, Y, 3p (M2182 and M15), 16q (M15), and gains
      for 5q (M2182) and 8q (M2182 and M15). Collectively, the characterization of
      these lines should assist with the localization of chromosome regions, and
      possibly genes, that are important in the development and progression of human
      prostate cancer.

PMID- 8646735
TI  - Sex chromosome abnormalities in lung cancer patients.
AB  - Chromosomal analyses of lymphocytes from lung cancer patients and normal subjects
      revealed that the X and the Y chromosomes have both structural and numerical
      abnormalities in higher frequency in patients compared to the controls. These
      abnormalities included chromatid/isochromatid breaks, translocations, ring
      formation, and selective nondisjunctions, resulting in multisomies of either the
      X or Y chromosomes. Possible significance of these genetic abnormalities are
      discussed in relation to lung cancer patients.

PMID- 8646736
TI  - A mucoepidermoid carcinoma of minor salivary gland with t(11;19)(q21;p13.1) as
      the only karyotypic abnormality.
AB  - We present the cytogenetic analysis of a mucoepidermoid carcinoma of the minor
      salivary gland with t(11,19)(q21;p13.1) as the sole karyotypic abnormality. Our
      findings, along with those of previous reports, indicate that this translocation
      is an early and most likely a primary event in the development of a least a
      subset of these neoplasms.

PMID- 8646737
TI  - Infant cardiac fibroma with clonal t(1;9)(q32;q22) and review of benign fibrous
      tissue cytogenetics.
AB  - Cardiac fibromas are rare lesions which occur more frequently in infants and
      children than in the adult population. These tumors are nonmalignant
      proliferations of connective tissue most often found in the left ventricular
      myocardium or septal myocardium. No cytogenetic studies of cardiac fibromas have
      been reported. We report a case of an infant with a subepicardial tumor in whom
      the cytogenetic analysis showed a clonal reciprocal translocation,
      46,XY,t(1;9)(q32;q22),inv(9)(p11q12)c. We review the literature regarding cardiac
      fibromas and briefly discuss the cytogenetics of benign fibrous neoplasias.

PMID- 8646738
TI  - Cytogenetic findings in a patient presenting simultaneously with chronic
      lymphocytic leukemia and acute myeloid leukemia.
AB  - A case of simultaneous presentation of B-chronic lymphocytic leukemia (CLL) and
      acute myeloid leukemia (AML) is described. CLL was documented by bone marrow and
      peripheral blood lymphocytosis with a typical B-CLL immunophenotype. The
      diagnosis of AML was supported by the presence of bone marrow and circulating
      blast cells positive for myeloperoxidase and myeloid-associated markers. Although
      the immunophenotyping and morphocytochemical studies indicated two different cell
      populations (mature B-CLL lymphocytes and myeloblasts), chromosome aberrations
      commonly associated with CLL and AML were found simultaneously in the same
      metaphases obtained from unstimulated 24-hour cultures of peripheral blood cells.

PMID- 8646739
TI  - t(1;5)(q23;q33) in a patient with high-risk B-lineage acute lymphoblastic
      leukemia.
AB  - The t(1;5)(q23;q33) is a rare genetic anomaly that was reported previously in two
      infants with a myeloproliferative disorder and eosinophilia and in one adult
      patient with acute nonlymphocytic leukemia (ANLL). A 13-year-old boy with high
      risk early pre-B acute lymphoblastic leukemia (ALL) who presented to our
      institution carried the t(1;5)(q23;q33). He had an initial blast count of 230 X
      10(9)/L and responded poorly to prednisone. Complete remission (CR) was achieved,
      and he had a bone marrow (BM) relapse 3 months after despite intensive
      consolidation therapy. He underwent allogeneic BM transplantation (BMT) from a
      human leukocyte antigen (HLA)-identical siblings in early relapse with total body
      irradiation (TBI) and cyclophosphamide conditioning. He had a short second CR
      with a central nervous system (CNS) relapse on day + 106 after BMT. Two of the
      previously reported patients also did not respond to chemotherapy. The
      t(1;5)(q23;q33) appears to be a rare lineage nonspecific anomaly related to
      hematologic malignancies that are resistant to current therapy.

PMID- 8646741
TI  - Acute myelogenous leukemia with dup(1)(p22p36),dup(1)(p22p36): a novel case?
AB  - A case of acute myelogenous leukemia (AML) French-American-British (FAB)-type M5b
      is described, secondary to myelodysplastic syndrome (MDS), in which a primary
      clone containing a dup(1)(p22p36) and a subclone containing dup(1)(p22p36), were
      identified. This is believed to be a novel mutation in AML.

PMID- 8646740
TI  - Chromosome breakpoint at 17q11.2 and insertion of DNA from three different
      chromosomes in a glioblastoma with exceptional glial fibrillary acidic protein
      expression.
AB  - A glioblastoma that retained glial fibrillary acidic protein (GFAP) in culture
      has a break in the long arm of chromosome 17 at band 17q11.2. DNA inserted at
      this breakpoint came from chromosome bands 3p21, 3q23, 16q11.2, and 22q11.2.
      These chromosome fragments were inserted in band 17q11.2 proximal to the
      neurofibromatosis-1 (NF-1) gene and neu (HER2; erbB2) oncogene loci. The
      glioblastoma also contained a reciprocal translocation between 16p12 and 20p12.
      These structural abnormalities, previously undescribed in gliomas, were
      demonstrated by high-resolution chromosome banding, microdissection, and
      fluorescence in situ hybridization (FISH). Numerical changes typical of
      glioblastoma were present: gain of chromosome 7 and losses of chromosomes 10, 13,
      and 22. The complex chromosome origin of DNA inserted in this glioma chromosome
      is described. The association of two infrequent events in this single
      glioblastoma line, this complex insertion and retention of GFAP expression, is
      not likely to be a chance occurrence. It raises the possibility of an association
      between the two events.

PMID- 8646742
TI  - t(1;19)(q23;p13) in a case of acute monocytic leukemia.
AB  - Translocation (1;19)(q23;p13) is considered a specific chromosome aberration in
      acute lymphoblastic leukemia (ALL). We report a case of M5 acute nonlymphocytic
      leukemia (ANLL) with t(1;19). In all mitoses studied from peripheral blood (PB)
      cells, the pathological karyotype 51,XX,t(1;19)(q23;p13),+8,
      +der(19)t(1;19)(q23;p13), +3mar was detected. No rearrangement of the E2A gene
      was detected. We believe this case shows that cytogenetically indistinguishable
      aberrations may be accompanied by quite different molecular events.

PMID- 8646744
TI  - Aspects of the neoplasms observed in patients with constitutional autosomal
      trisomy.
AB  - A review of the literature reveals numerous clinical case reports, systematic
      histologic analyses, epidemiologic studies, and large series of tumors showing
      that subjects with trisomy 8, 9, 13, 18, and 21 have an excess of hematologic and
      various solid tumors compared to the general population. These tumors more
      frequently affect particular organs for a given type of trisomy. A large
      proportion of tumors are observed during fetal and neonatal life, are
      incompletely developed, and subsequently regress. In older children or even
      adults, tumors are less frequent, are often found on the same organs as earlier
      in life, are more aggressive, and do not involute. The mechanism responsible for
      the development of these neoplasms could be similar to that which generates the
      malformations in these children and may result from cooperation of the
      chromosomal abnormality with physiologic growth phenomena, which are particularly
      active early in life. Trisomic subjects must be carefully followed in order to
      detect tumors as early as possible and to allow treatment under optimal
      conditions.

PMID- 8646743
TI  - Amplification of 19q13.1-q13.2 sequences in ovarian cancer. G-band, FISH, and
      molecular studies.
AB  - In this study of ovarian carcinoma, we extended previous findings by performing
      FISH using chromosome 19 paint and microFISH probes and patient samples with and
      without abnormalities of chromosome 19 identified by G-banding. Karyotype
      interpretations of der(19) were confirmed, while additional 19 translocations
      were also detected by FISH with 19WCP in some cases. Similar FISH studies of
      ovarian carcinoma cell lines found chromosome 19 abnormalities even after
      extensive in vitro culture. MicroFISH probes were generated by chromosome
      microdissection from two cases with hsr(19) and mapped to 19q13.2 and 19q13.1-.2,
      respectively. FISH with these microFISH probes alone or in combination with a
      19WCP probe to four patient samples and seven cell lines showed that 65% of
      chromosome 19 structural abnormalities contained 19q13.1-q13.2 sequences,
      sometimes as large hsrs. Ovarian cancer cell lines showed amplification and
      overexpression of the AKT2 putative oncogene, but not the ERCC-2 DNA repair gene
      in this chromosomal region. In addition to AKT2, amplification and overexpression
      of other yet-unidentified genes in the 19q13.1-q13.2 region may contribute to
      ovarian carcinoma pathogenesis or progression.

PMID- 8646745
TI  - Endoreduplication and telomeric association in a choroid plexus carcinoma.
AB  - Cytogenetic studies showed a hyperhaploid stemline,
      (32,XY,+1,+7,+9,+12,+13,+14,+19,+20) in a patient with choroid plexus carcinoma.
      Endoreduplication and doubling of the stemline to 200-400 chromosomes per cell
      and variation in numerical changes were also noted. Telomeric association was
      present in most cells. The 12p and 20q were by far the most frequently involved
      chromosome arms. Telomeric association is believed to have triggered further
      structural changes in this case since the 12p and 20q were always involved in the
      few structural abnormalities identified. A review of the literature suggests that
      hyperhaploidy may characterize choroid plexus carcinoma and hyperdiploidy choroid
      plexus papilloma.

PMID- 8646746
TI  - t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors?
AB  - We report an apparently balanced t(4;19)(q35;q13.1) as the sole cytogenetic
      change in a highly malignant extraskeletal sarcoma in a 12-year-old-boy. Tumor
      cells were negative for all immunocytochemical markers except vimentin and neuron
      specific enolase. Electron microscopy indicated chondroblastic differentiation.
      The tumor was categorized as a malignant sarcoma with differentiation toward
      extraskeletal mesenchymal chondrosarcoma. Reports of a similar translocation in
      an embryonal rhabdomyosarcoma (RMS) and in a dedifferentiated sarcoma with both
      rhabdomyosarcomatous and osteosarcomatous elements suggest that this
      translocation can arise in a primitive mesenchymal stem cell that can
      differentiate along at least these three pathways.

PMID- 8646747
TI  - New variant Ph translocation in chronic myeloid leukemia: t(Y;22)(p11;q11).
AB  - A 4-year-old boy with chronic myeloid leukemia (CML) was shown to have a variant
      Ph t(Y;22)(p11;q11). To our knowledge, this is the first report of a variant Ph
      translocation involving Y. Molecular analysis showed that the breakpoint on
      chromosome 22 is in the breakpoint cluster region (bcr), typical of CML with the
      classic t(9;22), suggesting that it might be a complex Ph translocation with the
      involvement of 9q34.

PMID- 8646748
TI  - del(1)(q12) in adenocarcinomas of the prostate.
AB  - A structural change of chromosome 1 in q12 may be a new, possibly consistent,
      chromosome change in adenocarcinoma of the prostate.

PMID- 8646749
TI  - Deletion of chromosome 20q associated with hypereosinophilic syndrome. A report
      of two cases.
AB  - Deletion of the long arm of chromosome 20--del(20q)--is commonly associated with
      myeloid malignancies, in particular with myeloproliferative disorders (MPD),
      myelodysplastic syndrome (MDS), and acute myelogenous leukemia (AML). Its
      association with the hypereosinophilic syndrome (HES) had never been reported. In
      the present study we describe two patients with long-standing hypereosinophilia
      and features of atypical MPD or MDS carrying a del(20q) as a constant and
      isolated chromosomal abnormality. One patient, with an aggressive clinical
      course, died within 2 years, despite several lines of treatment. The other
      patient had a more indolent course consistent with that of an atypical MDS with
      eosinophilia.

PMID- 8646750
TI  - A new cytogenetic subgroup in tenosynovial giant cell tumors (nodular
      tenosynovitis) is characterized by involvement of 16q24.
AB  - Cytogenetic investigations have already shown the nonrandom involvement of region
      1p11-p13 in the localized and diffuse forms of tenosynovial giant cell tumors. We
      describe a new case of modular tenosynovitis with rearrangement of 16q24. Our
      findings and the data from the literature strongly indicated band 16q24 as an
      important new breakpoint for the localized as well as diffuse forms of
      tenosynovial giant cell tumors.

PMID- 8646751
TI  - Aberrant mammary tissue and nephrourinary malignancy.
AB  - Polythelia (supernumerary nipple) provides a clue to congenital and hereditary
      malformations of the kidney and the urinary collecting system. It is also
      regarded as a cutaneous paraneoplastic marker because of the significant
      association with urogenital malignancies. A 38-year-old man with sporadic left
      supernumerary nipple without evidence of ear, facies, or gonadal defects or
      lateral displacement of the nipples was routinely examined for the presence of
      renal anomalies. Investigation revealed left polycystic kidney disease with
      adenocarcinoma in the upper pole. The nephrocutaneous defects and renal
      malignancy showed a peculiar ipsilaterality. The overlap between polythelia,
      polycystic kidney disease with adenocarcinoma in the upper pole. The
      nephrocutaneous defects and renal malignancy showed a peculiar ipsilaterality.
      The overlap between polythelia, polycystic kidney, and renal adenocarcinoma may
      provide a further clue to the embryonal origin of this cancer.

PMID- 8646752
TI  - No rearrangement of the CHOP and TLS/FUS genes in two cases of phyllodes tumor of
      the breast.

PMID- 8646753
TI  - Trisomy 13 in the myelodysplastic syndromes and acute leukemia.

PMID- 8646754
TI  - Laminar segregation of odorant receptor expression in the olfactory epithelium.
AB  - The laminar segregation of sensory neurons expressing a distinct receptor type
      was determined in tissue sections through the olfactory epithelium by in situ
      hybridization employing receptor-specific probes. Reactive cells were restricted
      to the mid-zone of the epithelium, the location of mature neurons. Detailed
      analyses revealed that neurons expressing a distinct receptor type were
      distributed in a characteristic manner throughout the layers of the neuronal
      zone, i.e. they were preferentially located in a particular laminar zone of the
      epithelium. Cells expressing different receptor types displayed different
      distribution patterns. In addition, sets of several reactive neurons within the
      same laminar zone were found to be arranged in an orderly fashion and were
      positioned at well-defined intervals. These results indicate that the
      localization of sensory neurons expressing a distinct receptor type is under
      stringent control leading to characteristic expression patterns.

PMID- 8646755
TI  - Subcellular distribution of glucose transporter (GLUT-1) during development of
      the blood-brain barrier in rats.
AB  - Electron microscopy was used to quantify the subcellular distribution of the GLUT
      1 isoform of the glucose transporter in developing microvessels of the brain of
      embryonic rats from E (embryonic stage) 13 to E19 and in adult rats. Gold
      conjugated secondary antibodies were used to localize, on ultrathin sections of
      brain, a rabbit polyclonal antiserum (anti-GLUT-1) raised against a synthetic
      peptide encoding 13 amino acids of the C-terminus of the human glucose
      transporter. Staining was weak at E13 but increased in density during development
      into adulthood. The increase represented an increase in the absolute amount of
      transporter per vessel profile, with a concomitant decrease in vessel size with
      the narrowing of the wall. At early stages, the percentages of total particles
      per profile of lumenal membrane, ablumenal membrane, and cytoplasm were
      approximately equivalent. The ratio of lumenal to ablumenal particle density then
      shifted from below 1 at E13 to above 2 at E19 and to 4 in the adult. In contrast,
      vessels of the choroid plexus were devoid of labeling, but the choroid plexus
      epithelium stained as early as E15. In the brain, no astrocytes, neurons, or
      pericytes were stained at any stage examined. Developmental upregulation of the
      GLUT-1 glucose transporter therefore seems to occur at the blood-brain barrier,
      and the modulation of the subcellular distribution of the transporter can be
      correlated with other observed changes in the microvessels as they develop the
      blood-brain barrier phenotype.

PMID- 8646756
TI  - Calretinin immunoreactivity of motor neurons in the guinea-pig distal colon and
      taenia coli.
AB  - Calretinin is a calcium-binding protein which occurs in neurons and endocrine
      cells, including neurons throughout the gastrointestinal tract. Calretinin
      immunoreactive (IR) neurons innervate the circular muscle in the guinea-pig
      distal colon and have descending as well as ascending projections. This suggests
      that calretinin-IR is in motor neurons, but whether it might be in excitatory or
      inhibitory motor neurons or both was previously undetermined. The presence of
      calretinin-IR in neurons innervating the taenia coli has not been previously
      reported. Numerous fibres in the circular muscle of the distal colon and in the
      taenia coli displayed immunoreactivity for calretinin. Tachykinin (TK),
      vasoactive intestinal peptide (VIP), calretinin, and gamma-aminobutyric acid
      (GABA) immunoreactivity was also in fibres innervating these targets. The
      abundances of these fibres was estimated to be TK > VIP > calretinin > GABA.
      Double label immunohistochemistry revealed the presence in both tissues of
      populations of calretinin-IR fibres which were also TK-IR, and fibres with
      calretinin and GABA-IR in the colon, but calretinin-IR fibres were never VIP-IR.
      TK- and VIP-IR were in separate populations of nerve fibres as were GABA- and TK
      IR. It is concluded that calretinin-IR does not provide a definitive labelling of
      a physiologically known subgroup of motor neurons, either in the distal colon or
      in the taenia coli, but that calretinin is most likely to be in excitatory motor
      neurons.

PMID- 8646757
TI  - Regulation of differentiation and keratin 10 expression by all-trans retinoic
      acid during the estrous cycle in the rat vaginal epithelium.
AB  - In rodents, the vaginal epithelium shows cyclic changes with an alternating
      pattern of keratinization under estrogen control and mucification under
      progesterone control. Retinoids are powerful regulators of cell differentiation,
      an excess of retinoids suppressing the keratinizing differentiation of
      keratinocytes. Here, we have examined the vaginal epithelium during the estrous
      cycle and compare the effects of retinoids on both types of hormonally induced
      differentiation, i.e. keratinization and mucification. All-trans retinoic acid
      was administered either by daily injections during the estrous cycle or by a
      single injection before the estrogen rise; these two protocols gave similar
      results. Retinoic acid suppressed estrogen-induced vaginal keratinization and
      cytokeratin K10 expression (a biochemical marker of terminal differentiation).
      Progesterone-induced mucification was not impaired; however, retinoic acid
      impeded mucous cell desquamation, suggesting an effect of retinoic acid on cell
      adhesiveness. Retinoic acid induced the appearance of apoptotic-like cells, as
      revealed by immunocytochemical staining of DNA fragmentation.

PMID- 8646759
TI  - Initial increase and subsequent loss of vasoactive intestinal polypeptide
      immunoreactivity in acetylcholinesterase-positive neurons of mouse islets
      transplanted to the kidney.
AB  - Collagenase-isolated pancreatic islets from C57BL/6J mice were cultured overnight
      and transplanted under the kidney capsule of non-diabetic syngeneic hosts.
      Cryostat sections of grafts and fresh islets were stained for
      acetylcholinesterase (AChE) and vasoactive intestinal polypeptide-like
      immunoreactivity (VIP-LI). Immediately after isolation, as well as 2-5 days after
      transplantation, VIP-LI- and AChE-positive nerve cell bodies were clearly seen in
      the periphery of the islets. Grafts 3-5 days old exhibited a transient and marked
      increase in VIP-LI nerve cell bodies and fibres. Seven days after transplantation
      VIP-LI nerve structures began to decrease in number and after 26-52 weeks they
      were no longer detectable. In contrast, AChE-positive nerve cell bodies and
      fibers, which showed a relatively constant pattern of distribution, were observed
      throughout the entire observation period. Restaining experiments demonstrated the
      coexistence of VIP-LI and AChE activity in the neurons. It is concluded that the
      grafts were extensively equipped with an intrinsic VIP-ergic and AChE-positive
      innervation. The initial, transient enhancement of VIP-LI expression probably
      reflects an adaptation of the neuro-insular complex to the preganglionic
      denervation, or to the ectopic environment, or both.

PMID- 8646758
TI  - The autoantigen La/SS-B: analysis of the expression of alternatively spliced La
      mRNA isoforms.
AB  - The gene for the nuclear autoantigen La/SS-B encodes two La mRNA isoforms. In
      order to study the function and expression of both La mRNA forms, an in situ
      hybridization procedure was developed allowing the selective identification of
      either exon 1 or exon 1'. For this purpose, digoxigenin-labeled exon-specific
      sense and anti-sense probes were prepared by in vitro transcription from plasmids
      that contained the respective exon sequence. Detection of the probes was carried
      out by using rhodamine-conjugated anti-digoxigenin antibody and confocal laser
      scanning microscopy. Both La mRNAs were found in the cytoplasm of endothelial
      cells but not in smooth muscle cells. In addition to the in situ technique, an
      assay system was established allowing the expression ratio of the two mRNA forms
      to be determined. The estimation was based on the amplification of exon 1 and 1'
      La cDNAs in parallel by using a three primer polymerase chain reaction. The ratio
      of the exon 1 to exon 1' La mRNA forms was determined to be about 5:1 in liver
      tissue and endothelial cells. The data support the conclusion that both La mRNA
      forms represent finally processed cytoplasmic mRNAs that are up- or downregulated
      in parallel.

PMID- 8646760
TI  - A comparative immunocytochemical study using an antiserum against a synthetic
      analogue of the corpora cardiaca peptide Pea-CAH-I (MI, neurohormone D) of
      Periplaneta americana.
AB  - An antiserum against the octapeptide Pea-CAH-I, a member of the adipokinetic
      hormone/red pigment-concentrating hormone family, has been produced for
      immunocytochemical staining in insects and various other invertebrate species.
      The anti-Pea-CAH-I serum stains the glandular corpora cardiaca cells of those
      insect species that synthesize identical or structurally similar peptides. In the
      corpora cardiaca of species producing peptides with a different C-terminus, these
      cells remain unstained. Pea-CAH-I-like immunoreactivity has also been found in
      neurons of the central nervous system of all invertebrate orders studied. The
      antiserum recognizes the C-terminal sequence Pro-Asn-Trp-NH2 of the Pea-CAH-I
      molecule as established by enzyme immunoassay. The widespread Pea-CAH-I-like
      immunoreactivity in all nervous systems of the studied animals probably does not
      reflect the presence of Pea-CAH-I but the occurrence of peptides carrying similar
      epitopes.

PMID- 8646761
TI  - Expression of adhesion molecules is specific and time-dependent in cytokine
      stimulated endothelial cells in culture.
AB  - The time course of expression of the adhesion molecules E-selectin, VCAM-1, ICAM
      1 and PECAM-1 was studied in interleukin-1 beta-stimulated human umbilical vein
      cells (HUVEC) and the subcellular sites of synthesis were determined by means of
      fluorescence immunohistochemistry. The maximal number of cells labelled for E
      selectin was observed at 2-4 h, for VCAM-1 at 4-8 h and ICAM-1 at 6-72 h. At 8 h,
      E-selectin and VCAM-1 started to disappear, but ICAM-1-positive cells persisted.
      PECAM-1 was constitutively expressed. De novo synthesis for E-selectin started at
      1 h and for both, VCAM-1 and ICAM-1 at 1.5-2 h. Maximal synthetic activity was
      observed at 2.5-4 h for E-selectin and at 4-6 h for VCAM-1 and ICAM-1;
      thereafter, synthesis slowly decreased. Transport granules occurred at 1.5 h for
      E-selectin and 4 h for VCAM-1; they were absent for ICAM-1. Diffuse cellular and
      membrane labelling indicative of the functional activity of the adhesion
      molecules began at 2-4 h for E-selectin, and 4 h for VCAM, but was constitutively
      present for ICAM-1. In conclusion, each adhesion molecule shows a specific time
      dependent course of appearance and disappearance in interleukin-1 beta-stimulated
      HUVECs in accordance with their physiological role in vivo. These morphological
      results confirm data obtained by flow cytometry and Western blotting, but they
      provide new information about the behaviour of individual cells with regard to
      the sites of synthesis and cellular localization of the adhesion molecules.

PMID- 8646762
TI  - The distribution and partial characterization of FMRFamide-related peptides in
      the salivary glands of the locust, Locusta migratoria.
AB  - The distribution and partial characterization of FMRFamide-related peptides in
      the salivary glands of the locust, Locusta migratoria, were investigated by means
      of immunohistochemistry, radioimmunoassay and reversed-phase high performance
      liquid chromatography. Whole-mount preparations of glands stained positively
      against anti-FMRFamide antisera, and contained the equivalent of 837 +/- 80 fmol
      FMRFamide/gland pair, as determined by radioimmunoassay. FMRFamide-like
      immunoreactivity occurred in the processes of the transverse nerves of both the
      prothoracic and mesothoracic ganglia, but was not found in the salivary
      motoneurons 1 or 2 of the suboesophageal ganglion, both of which directly
      innervate the salivary glands via the salivary nerve 7b; nor was it found within
      the salivary nerve 7b itself, leading to the salivary glands. It was, however,
      found as a superficial nerve plexus on the surface of nerve 7 at the
      suboesophageal ganglion, but did not appear to extend to the salivary glands. The
      origin of this staining is unclear. High performance liquid chromatography of
      salivary gland tissue extracts, monitored by radioimmunoassay, revealed 4 peaks
      of immunoreactive material, 2 of which co-migrated with AFIRFamide and
      GQERNFLRFamide, previously isolated from the locust ventral nerve cord. These 2
      synthetic peptides did not elevate basal levels of the second messengers cyclic
      AMP or cyclic GMP in the salivary glands.

PMID- 8646763
TI  - Tympanal hearing in tachinid flies (Diptera, Tachinidae, Ormiini): the
      comparative morphology of an innovation.
AB  - Tympanal hearing organs have been reported only recently for Diptera. All the
      cases documented so far relate to parasitoid tachinid flies of the ormiine tribe.
      In the ormiine flies, the presence of tympanal hearing is functionally linked to
      their reproductive behavior. Indeed, female ormiine flies detect and localize
      their host, typically singing orthopterans, by hearing their calling songs. The
      three ormiine fly species investigated here at the comparative level share the
      key morphological features associated with tympanal hearing. The extent of these
      structural modifications becomes evident in the light of comparison with the
      closely related atympanate tachinid Myiopharus doryphorae. We document a series
      of eight characters that constitute specialized modifications of the ventral
      prothorax: (1) an inflation of the probasisternum, providing a rigid frame to
      span the large tympanal membranes; (2) an increased surface area of the
      prosternal membranes that constitute very thin, corrugated tympanal membranes;
      (3) a forked, broad presternum with tympanal pits to which the sensory organs
      directly attach; (4) several modifications of the tracheal system comprising the
      enlargement of the prosternal air sac, a supplementary tracheal tube to the
      prosternal air sac accompanied by a subpartioning of the spiracular atrium, and
      larger mesothoracic spiracles; (5) the presence of two scolopophorous chordotonal
      organs in the unpartitioned prosternal air sac; (6) stiff cuticular apodemes
      linking the chordotonal organs to the presternum; (7) reduction in size of the
      cervical sclerites; and (8) several structural modifications of the prosternal
      apophyses, creating new attachment sites for neck muscles. This comparative
      approach brings out differences and similarities of the homologous cuticular
      structures found on the ventral prothorax of both tympanate and atympanate
      tachinids. It is proposed that, given the degree of similarity between the
      ormiine hearing organs, the ormiine tribe is monophyletic, whereby all members of
      this tribe evolved from a common ancestor, an acoustic parasitoid of a singing
      orthopteran insect.

PMID- 8646764
TI  - Elastogenesis is linked to epithelial-stromal interactions in postnatal hamster
      bronchioles.
AB  - In a previous study, direct epithelial-stromal cell contacts via foot processes
      perforating the basement membrane were investigated in bronchioles of postnatal
      hamster lungs. In the present study, analogous postnatal epithelial foot
      processes have been found on stromal cells exhibiting active elastogenesis as
      determined by morphological criteria. In addition, elastin is prominently present
      close to the epithelium, but less so in the deeper layers, in the bronchioles of
      the 14-day-old hamster. The elastin often has an asymmetrical distribution around
      the subepithelial fibroblast with preference for secretion toward the epithelium.
      Thus, elastogenesis can now be linked to epithelial-stromal interactions at the
      temporal, functional, and morphological levels.

PMID- 8646765
TI  - Immunoreactivity of sensory hair bundles of the guinea-pig cochlea to antibodies
      against elastin and keratan sulphate.
AB  - The stereociliary bundles of hair cells contain cross-linking extracellular
      filaments which have been suggested to play a role in mechanoelectrical
      transduction. To investigate the composition of these filaments, antibodies to
      the extracellular matrix molecules elastin and keratan sulphate have been used
      for light- and electron-microscopic immunocytochemistry of the guinea-pig organ
      of Corti. With the antibody to elastin, no immunoreactivity was found in hair
      bundles. This implies either that the epitope recognised by this antibody is not
      present in the links or that it is obscured. The antibody to keratan sulphate
      labelled the stereociliary bundles of both inner and outer hair cells but not
      supporting cells. The tips of the tallest stereocilia, especially on outer hair
      cells, the tips of the shorter stereocilia where the tip links attach to the
      stereociliary membrane, and the attachments of the lateral links, were labelled.
      This suggests that the links contain keratan sulphate proteoglycans, molecules
      which in other tissues are known to maintain structural integrity and fibrillar
      spacing, and to influence the microenvironment of the cell surface.

PMID- 8646766
TI  - An immuno-electron-microscopic study of human thymic B cells.
AB  - Thymic B cells are a constituent of normal human thymic medulla. They are
      supposed to play a role in T cell maturation. Thymic B cells have been
      characterized morphologically and immunohistochemically at the light-microscopic
      level. Their ultrastructural appearance in vivo has not been demonstrated. Six
      normal infantile thymi were immunolabelled with the pan-B cell marker CD20 using
      a pre-embedding technique and viewed at the electron-microscopic level. Cells
      expressing CD20 had long cytoplasmic processes. They were all "asteroid" in shape
      and in close contact with thymocytes. Also, their long cytoplasmic processes
      intermingled with cytoplasmic processes of cells that were presumed to be
      interdigitating reticulum cells (IDC) based on morphological criteria. Thymic B
      cells may act in concert with IDC during T cell maturation.

PMID- 8646767
TI  - Distribution of specific substance P binding sites in the heart and adjacent
      great vessels of the Wistar white rat.
AB  - Magnesium(Mg)-deficiency, whether dietary or an effect of a clinical condition
      such as diabetes, results in a variety of cardiovascular pathologies. Substance P
      (SP) has been implicated in the induction of cardiac focal inflammatory lesions
      that occur during Mg-deficiency. Blockade of SP receptors results in a
      significant reduction in the incidence of lesion formation. In an effort to
      identify potential endogenous cell populations of the heart, which may play a
      role in SP-dependent lesion formation, film- and light-microscopic
      autoradiography were used to map the distribution of specific SP binding sites in
      frozen sections of the normal rat heart and adjacent great vessels. Binding was
      assessed with 0.1 nM I-125 Bolton-Hunter labelled SP in the absence (total
      binding) or presence (non-specific binding) of excess unlabelled SP, prolactin,
      or L-703,606, a non-peptide antagonist of SP receptors. Film autoradiograms
      revealed prominent small foci of intense autoradiographic reactions dispersed
      intermittently around the periphery of the great vessels and coronary arteries,
      among the interstitial connective tissue of the heart, and along the cusps of the
      cardiac valves. Excess unlabelled SP caused a significant reduction (97.7%
      displacement; P < 0.001) in the focal autoradiographic reactions. L-703,606
      caused a similar reduction in SP binding (97.3% displacement; P < 0.001), while
      prolactin had no statistically significant effect on the binding of radiolabelled
      SP. Light-microscopic autoradiograms revealed that the SP binding sites occurred
      within clusters of connective tissue cells or in rarely observed parasympathetic
      ganglia. No evidence was found to suggest the presence of SP receptors on
      endothelial cells, cardiac muscle fibers, or smooth muscle fibers. The connective
      tissue cells which bound SP within the heart will likely include types that are
      susceptible to SP activation and thus may play a role in initiation of the focal
      inflammation characteristic of Mg-deficiency.

PMID- 8646768
TI  - Intracellular collagen-like material in mouse embryonic mesenchymal cells
      incubated with TNF-alpha and IL-1 beta in organoid culture.
AB  - Blastemal cells of embryonic mouse limb buds (day 12) were cultivated in organoid
      cultures in the presence of the human recombinant cytokines interleukin-1 beta
      (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha). The effects of both
      cytokines (applied alone or together) on mesenchymal cells were demonstrated by
      electron microscopy. Cultures treated with TNF-alpha (alone or in combination
      with IL-1 beta) showed several mesenchymal cells with numerous irregularly shaped
      membrane-bordered cavities containing thick bundled tannic-acid-positive
      fibrillar structures that resembled loosened collagen fibrils, whereas cells
      exposed to IL-1 beta alone did not exhibit such changes. These findings are
      discussed in the light of two hypotheses: the phagocytosis of extracellular
      collagen fibrils, and fibrillogenesis resulting from incongruity of synthesis and
      secretion rates of procollagen; our results favour the former.

PMID- 8646769
TI  - TRP: its role in phototransduction and store-operated Ca2+ entry.

PMID- 8646770
TI  - PH domains: diverse sequences with a common fold recruit signaling molecules to
      the cell surface.

PMID- 8646771
TI  - Recombination by replication.

PMID- 8646772
TI  - The molecules of mammalian fertilization.

PMID- 8646773
TI  - Drosophila photoreceptor axon guidance and targeting requires the dreadlocks
      SH2/SH3 adapter protein.
AB  - SUMMARY: Mutations in the Drosophila gene dreadlocks (dock) disrupt photoreceptor
      cell (R cell) axon guidance and targeting. Genetic mosaic analysis and cell-type
      specific expression of dock transgenes demonstrate dock is required in R cells
      for proper innervation. Dock protein contains one SH2 and three SH3 domains,
      implicating it in tyrosine kinase signaling, and is highly related to the human
      proto-oncogene Nck. Dock expression is detected in R cell growth cones in the
      target region. We propose Dock transmits signals in the growth cone in response
      to guidance and targeting cues. These findings provide an important step for
      dissection of signaling pathways regulating growth cone motility.

PMID- 8646774
TI  - The Drosophila light-activated conductance is composed of the two channels TRP
      and TRPL.
AB  - SUMMARY: Drosophila phototransduction is a G protein-coupled, calcium-regulated
      signaling cascade that serves as a model system for the dissection of
      phospholipase C (PLC) signaling in vivo. The Drosophila light-activated
      conductance is constituted in part by the transient receptor potential (trp) ion
      channel, yet trp mutants still display a robust response demonstrating the
      presence of additional channels. The transient receptor potential-like (trpl)
      gene encodes a protein displaying 40% amino acid identity with TRP. Mammalian
      homologs of TRP and TRPL recently have been isolated and postulated to encode
      components of the elusive I(crac) conductance. We now show that TRP and TRPL
      localize to the membrane of the transducing organelle, together with rhodopsin
      and PLC, consistent with a role in PLC signaling during phototransduction. To
      determine the function of TRPL in vivo, we isolated trpl mutants and
      characterized them physiologically and genetically. We demonstrate that the light
      activated conductance is composed of TRP and TRPL ion channels and that each can
      be activated on its own. We also use genetic and electrophysiological tools to
      study the contribution of each channel type to the light response and show that
      TRP and TRPL can serve partially overlapping functions.

PMID- 8646775
TI  - trp, a novel mammalian gene family essential for agonist-activated capacitative
      Ca2+ entry.
AB  - SUMMARY: Capacitative calcium entry (CCE) describes CA2+ influx into cells that
      replenishes CA2+ stores emptied through the action of IP3 and other agents. It is
      an essential component of cellular responses to many hormones and growth factors.
      The molecular basis of this form of Ca2+ entry is complex and may involve more
      than one type of channel. Studies on visual signal transduction in Drosophila led
      to the hypothesis that a protein encoded in trp may be a component of CCE
      channels. We reported the existence of six trp-related genes in the mouse genome.
      Expression in L cells of small portions of these genes in antisense orientation
      suppressed CCE. Expression in COS cells of two full-length cDNAs encoding human
      trp homologs, Htrp1 and Htrp3, increased CCE. This identifies mammalian gene
      products that participate in CCE. We propose that trp homologs are subunits of
      CCE channels, not unlike those of classical voltage-gated ion channels.

PMID- 8646776
TI  - Calcium spiking in plant root hairs responding to Rhizobium nodulation signals.
AB  - SUMMARY: Rhizobium lipochitooligosaccharide signal molecules stimulate multiple
      responses in legume host plants, including changes in host gene expression, cell
      growth, and mitoses leading to root nodule development. The basis for signal
      transduction in the plant is not known. We examined cytoplasmic free calcium in
      host root hairs using calcium-sensitive reporter dyes. Image analysis of injected
      dyes revealed localized periodic spikes in cytoplasmic calcium levels that ensued
      after a characteristic lag following signal application. Structural features of
      the signal molecules required to cause nodulation responses in alfalfa are also
      essential for stimulating calcium spiking. A nonnodulating alfalfa mutant is
      defective in calcium spiking, consistent with the possibility that this mutant is
      blocked in an early stage of nodulation signal perception.

PMID- 8646777
TI  - Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells
      by interaction with integrin alpha v beta 3.
AB  - SUMMARY: Cellular invasion depends on cooperation between adhesive and
      proteolytic mechanisms. Evidence is provided that the matrix metalloproteinase
      MMP-2 can be localized in a proteolytically active form on the surface of
      invasive cells, based on its ability to bind directly integrin alpha v beta 3.
      MMP-2 and alpha v beta 3 were specifically colocalized on angiogenic blood
      vessels and melanoma cells in vivo. Expression of alpha v beta 3 on cultured
      melanoma cells enabled their binding to MMP-2 in a proteolytically active form,
      facilitating cell-mediated collagen degradation. In vitro, these proteins formed
      an SDS-stable complex that depended on the noncatalytic C-terminus of MMP-2,
      since a truncation mutant lost the ability to bind alpha v beta 3. These findings
      define a single cell-surface receptor that regulates both matrix degradation and
      motility, thereby facilitating directed cellular invasion.

PMID- 8646778
TI  - Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the
      insulin receptor.
AB  - SUMMARY: Crystal structures of the insulin receptor substrate-1 (IRS-1)
      phosphotyrosine-binding (PTB) domain, alone and complexed with the juxtamembrane
      region of the insulin receptor, show how this domain recognizes phosphorylated
      "NPXY" sequence motifs. The domain is a 7-stranded beta sandwich capped by a C
      terminal helix. The insulin receptor phosphopeptide fills an L-shaped cleft on
      the domain. The N-terminal residues of the bound peptide form an additional
      strand in the beta sandwich, stabilized by contacts with the C-terminal helix.
      These interactions explain why IRS-1 binds to the insulin receptor but not to
      NPXpY motifs in growth factor receptors. The PTB domains of IRS-1 and Shc share a
      common fold with pleckstrin homology domains. Overall, ligand binding by IRS-1
      and Shc PTB domains is similar, but residues critical for phosphotyrosine
      recognition are not conserved.

PMID- 8646779
TI  - Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia,
      retinal dysplasia, and pituitary tumors.
AB  - SUMMARY: Mice lacking p27(Kip1) have been created by gene targeting in embryonic
      stem cells. These mice are larger than the control animals, with thymus,
      pituitary, and adrenal glands and gonadal organs exhibiting striking enlargement.
      CDK2 activity is elevated about 10-fold in p27(-/-) thymocytes. Development of
      ovarian follicles seems to be impaired, resulting in female sterility. Similar to
      mice with the Rb mutation, the p27(-/-) mice often develop pituitary tumors
      spontaneously. The retinas of the mutant mice show a disturbed organization of
      the normal cellular layer pattern. These findings indicate that p27(Kip1) acts to
      regulate the growth of a variety of cells. Unexpectedly, the cell cycle arrest
      mediated by TGFbeta, rapamycin, or contact inhibition remained intact in p27(-/-)
      cells, suggesting that p27(Kip1) is not required in these pathways.

PMID- 8646780
TI  - Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of
      p27(Kip1).
AB  - SUMMARY: Disruption of the cyclin-dependent kinase-inhibitory domain of p27
      enhances growth of mice. Growth is attributed to an increase in cell number, due
      to increased cell proliferation, most obviously in tissues that ordinarily
      express p27 at the highest levels. Disruption of p27 function leads to nodular
      hyperplasia in the intermediate lobe of the pituitary. However, increased growth
      occurs without an increase in the amounts of either growth hormone or IGF-I. In
      addition, female mice were infertile. Luteal cell differentiation is impaired,
      and a disordered estrus cycle is detected. These results reflect a disturbance of
      the hypothalamic-pituitary-ovarian axis. The phenotypes of these mice suggest
      that loss of p27 causes an alteration in cell proliferation that can lead to
      specific endocrine dysfunction.

PMID- 8646781
TI  - A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis,
      and female sterility in p27(Kip1)-deficient mice.
AB  - SUMMARY: Targeted disruption of the murine p27(Kip1) gene caused a gene dose
      dependent increase in animal size without other gross morphologic abnormalities.
      All tissues were enlarged and contained more cells, although endocrine
      abnormalities were not evident. Thymic hyperplasia was associated with increased
      T lymphocyte proliferation, and T cells showed enhanced IL-2 responsiveness in
      vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in
      enhanced proliferation in response to mitogens. In the spleen, the absence of p27
      selectively enhanced proliferation of hematopoietic progenitor cells. p27
      deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the
      pituitary pars intermedia, suggesting that p27 and Rb function in the same
      regulatory pathway. The absence of p27 also caused an ovulatory defect and female
      sterility. Maturation of secondary ovarian follicles into corpora lutea, which
      express high levels of p27, was markedly impaired.

PMID- 8646782
TI  - Perturbation of nuclear architecture by long-distance chromosome interactions.
AB  - SUMMARY: Position-effect variegation (PEV) describes the stochastic
      transcriptional silencing of a gene positioned adjacent to heterochromatin. Using
      FISH, we have tested whether variegated expression of the eye-color gene brown in
      Drosophila is influenced by its nuclear localization. In embryonic nuclei, a
      heterochromatic insertion at the brown locus is always spatially isolated from
      other heterochromatin. However, during larval development this insertion
      physically associates with other heterochromatic regions on the same chromosome
      in a stochastic manner. These observations indicate that the brown gene is
      silenced by specific contact with centromeric heterochromatin. Moreover, they
      provide direct evidence for long-range chromosome interactions and their impact
      on three-dimensional nuclear architecture, while providing a cohesive explanation
      for the phenomenon of PEV.

PMID- 8646783
TI  - Anatomy of a flexer-DNA complex inside a higher-order transposition intermediate.
AB  - SUMMARY: Escherichia coli HU, a nonsequence-specific histone- and HMG-like DNA
      binding protein, was chemically converted into a series of HU-nucleases with an
      iron-EDTA-based cleavage moiety positioned at 16 rationally selected sites.
      Specific DNA cleavage patterns from each of these HU-nucleases allowed us to
      determine the precise localization, stoichiometry, and orientation of HU binding
      in the Mu transpososome, a multiprotein structure that mediates the chemical
      reactions in DNA transposition. Correlation of the DNA cleavage data with the
      position of the cleavage moiety in the HU three-dimensional structure indicates
      the presence of a dramatic DNA bend, for which the bend center, direction, and
      magnitude were assessed. The data, which directly localize selected HU amino
      acids with respect to DNA in the transpososome, were used as constraints for
      computer-based molecular modeling to derive the first snapshot of an HU-DNA
      interaction.

PMID- 8646784
TI  - Two-dimensional crystallography of TFIIB- and IIE-RNA polymerase II complexes:
      implications for start site selection and initiation complex formation.
AB  - SUMMARY: Transcription factors IIB (TFIIB) and IIE (TFIIE) bound to RNA
      polymerase II have been revealed by electron crystallography in projection at
      15.7 A resolution. The results lead to simple hypotheses for the roles of these
      factors in the initiation of transcription. TFIIB is suggested to define the
      distance from TATA box to transcription start site by bringing TATA DNA in
      contact with polymerase at that distance from the active center of the enzyme.
      TFIIE is suggested to participate in a key conformational switch occurring at the
      active center upon polymerase-DNA interaction.

PMID- 8646785
TI  - An ESR and spectrophotometric study of the denitration of nitroheterocyclic drugs
      by liver homogenates and their metabolic consumption by liver microsomes from
      cytochrome P-450-induced mice.
AB  - This work extends a previous study on the mechanism of hepatic denitration of two
      nitroheterocyclic drugs (NHCD), quinifuryl and nitracrine, in which the release
      of nitric oxide (NO) from these compounds can be accompanied by the formation of
      a NO-heme iron complex. Pretreating mice with three inducers of cytochrome P-450
      (phenobarbital, clophen A50 and butylated hydroxytoluene (BHT)) increased the
      yield of the nitrosyl complex which correlated with a rise in the cytochrome P
      450 content of mouse liver microsomes. In contrast, treating the animals with
      beta-naphthoflavone decreased the complex yield while still increasing P-450
      content. Treating the animals with any of the above inducers significantly
      increased the rate of NHCD metabolism in mouse liver microsomes. Based on these
      results, a possible mechanism for hepatic NHCD denitration is discussed.

PMID- 8646786
TI  - A proton nuclear magnetic resonance investigation of the conformation of
      daunomycin.
AB  - The 500 MHz proton NMR spectra of 4.95 mM daunomycin in D2O have been
      investigated in the temperature range 277-350 K. Down field shifts of
      approximately 0.15 to 0.20 ppm in 1H, 2H and 3H protons with increasing
      temperature indicate that daunomycin exists in aggregated form at 277 K which is
      stabilized by stacking of aromatic rings. The 7H, 10axH and 10eqH protons show a
      change in chemical shift of 0.12 to 0.16 ppm, while other ring A/sugar protons
      shift by 0.0 to 0.08 ppm due to self association. The drug exists in monomer
      state at about 350 K. The conformational features have been ascertained from
      NOESY spectra at 297 K. The 7H proton is found to be strongly coupled to 8axH (J
      = 5 Hz) as compared to 8eqH (J = 2 Hz), while the 4'H-5'H connectivity is not
      observed in the COSY spectra. Besides the NOESY cross peaks between the spin-spin
      coupled protons, several intramolecular NOEs are seen. The 8axH and 8eqH are
      equally distant from 5'H proton. The distances of 3'H and 4'H daunosamine sugar
      protons from the ring A protons--7H, 8eqH, 9COCH3--are in the range 2.9-3.1 A,
      giving moderate cross peaks in NOESY spectra. The observed results imply the
      existence of predominantly 9H8 half chair conformation of ring A in aqueous
      solution, which is marginally different from that obtained by X-ray crystal
      analysis.

PMID- 8646787
TI  - Effects of latrunculin A on immunological phagocytosis and macrophage spreading
      associated changes in the F-actin/G-actin content of the cells.
AB  - Latrunculin A, a toxin from a Red Sea sponge, was shown to be a very potent
      inhibitor of immunological phagocytosis by normal and activated macrophages
      (obtained from mice injected i.p. with LPS), as well as by polymorphonuclear
      leukocytes. This toxin blocks the interiorization of the immune complexes but
      does not interfere with their binding to the phagocyte (recognition phase);
      activated macrophages were more susceptible to this inhibition than normal
      macrophages and polymorphonuclear leukocytes. The effect of the toxin on cellular
      spreading of macrophages was also studied using two kinds of substrate: glass,
      and glass covered with IgG immune complexes. Latrunculin A was able to impair the
      spreading of normal macrophages on glass covered with immune complexes, and could
      also completely reverse the spreading after it had occurred. Contrarily, in
      activated macrophages, this toxin could neither impede the spreading nor reverse
      it, a difference that might be a distinctive property of the activated state. We
      have also found that latrunculin A can reduce the percentage of F-actin in both
      normal and activated macrophages, the activated cells being more susceptible to
      this effect. Since latrunculin A is a blocking agent of actin polymerization in
      vitro, these results indicate that actin polymerization and assembly must be an
      essential component of the primary, active event of the engulfment phase of
      phagocytosis.

PMID- 8646788
TI  - Effects of ethanol metabolism on PKC activity in isolated rat hepatocytes.
AB  - Isolated rat hepatocytes were exposed to increasing concentrations of ethanol.
      During exposure of cells to ethanol a moderate but significant modification in
      the level of hepatic PKC c-isoforms has been observed. The ethanol-induced effect
      on liver protein kinase C was reversed by 4-methylpyrazole, an inhibitor of
      alcohol dehydrogenase, indicating that the conversion of ethanol to acetaldehyde
      may be involved in the enzyme inactivation. The involvement of the alcohol
      metabolite in PKC modifications was confirmed by the exposure of hepatocytes or
      partially purified liver enzyme to acetaldehyde concentrations of pathological
      interest.

PMID- 8646789
TI  - Comparison of DNA sequence selectivity of anthracycline antibiotics and their 3'
      hydroxylated analogs.
AB  - The sequence selectivity of three anthracyclines and their 3' hydroxylated
      analogs (in which an OH replaces NH3+ in the daunosamine at neutral pH) was
      examined in DNase I footprinting experiments on a 158-bp DNA fragment. We found
      that chemical modification of the daunosamine at C3' has more drastic
      consequences for sequence selectivity than chemical modification at C4 and C14 of
      the aglycone moiety. All anthracyclines and hydroxylated derivatives selectively
      recognize the triplet PyAPy. The importance of NH3+ in stabilizing the
      interaction was evidenced. First of all, comparable protection patterns require 5
      times more hydroxyanthracycline than regular anthracycline. Furthermore, it is
      only after the replacement of NH3+ by OH that an additional protection site - CGC
      -appears. GGC is the site of best selectivity of the hydroxyanthracyclines.
      Anthracyclines can be considered both intercalators (aglycone moiety) and minor
      groove binders (sugar moiety). Since intercalating drugs show a slight preference
      for GC base pairs, we suggest hydroxylated anthracyclines to have a sequence
      specificity closer that of pure intercalators. Chemical modifications at C4 and
      C14 only modify the hydrogen bonding stabilization of the DNA-aglycone moiety
      complex: the more the anthracycline or its analog is lipophilic, the less it will
      interact with the sugar-phosphate chain.

PMID- 8646790
TI  - Signal transduction mechanism in response to aflatoxin B1 exposure: protein
      kinase C activity.
AB  - A single dose of the carcinogen aflatoxin B1 (7 mg/kg body weight) to male Wistar
      rats significantly enhanced the hepatic activity of protein kinase C in the
      particulate and nuclear fractions. The particulate fraction showed stimulation at
      4 and 7 h, while the nuclear activity was increased at 17 h following
      administration of aflatoxin B1. The enzyme activity in cytosol revealed a
      significant decline corresponding to stimulation in particulate fraction. The
      carcinogen-activated protein kinase C stimulated autophosphorylation, and was
      found to accelerate in vitro phosphorylation of two model DNA synthesizing
      enzymes--the Klenow fragment of replicative DNA polymerase of E. Coli and a DNA
      primase-polymerase complex of yeast mitochondrial origin. Prior phosphorylation
      of these enzymes led to significant enhancement of their activities. The results
      imply that activation of protein kinase C and consequently the activation of DNA
      synthesizing enzymes may play an important role in the initiation of
      carcinogenesis.

PMID- 8646791
TI  - Comparative MO-QSAR studies in various species including man.
AB  - In the present study it is demonstrated that MO-QSARs (quantitative structure
      activity relationships based on calculated molecular orbital substrate
      characteristics) of cytochrome P450-catalysed biotransformation of benzene
      derivatives obtained in previous studies for Wistar rats, can be extrapolated to
      other species, including man. First, it was demonstrated that the
      regioselectivity of the in vivo aromatic hydroxylation of two fluorobenzene
      derivatives can be quantitatively predicted, on the basis of the calculated
      density distribution of the reactive pi-electrons in the aromatic ring of the
      fluorobenzene derivative, for all experimental animal species tested. Second, it
      was investigated whether the preferential site for in vitro aromatic
      hydroxylation of 3-fluoroaniline could be predicted on the basis of the same
      calculated parameter. This was done because extrapolation to human systems
      requires in vitro instead of in vivo experiments. The results obtained indicated
      that the variation in the regioselectivity of the aromatic hydroxylation of 3
      fluoroaniline by liver microsomes from different species, including man, was only
      a few percent, and was mainly directed by calculated chemical reactivity
      characteristics of the 3-fluoraniline substrate. Finally, possibilities for the
      extrapolation from rat to other species, of the MO-QSAR for the rate of in vitro
      C4 hydroxylation of a series of aniline derivatives converted in an iodosobenzene
      supported microsomal cytochrome P450 system, were investigated. Experiments with
      liver microsomes from rats, mice, rabbit and man resulted in clear MO-QSARs with
      correlation coefficients for the relationship between the 1n k(cat) and the
      E(HOMO) of the aniline substrates that were > or = to 0.97 in all cases. Thus,
      the results of the present study clearly demonstrate that MO-QSARs previously
      described for Wistar rats can be extrapolated to mice, rabbit, guinea pig and
      even to man. Regioselectivities obtained and QSAR lines for the rate of
      conversion plotted against calculated E(HOMO) values of the aniline derivatives
      are similar for the various species investigated. Altogether, these results
      strongly support the conclusion that the conversion of the relatively small
      benzene derivatives in the relatively large and aspecific active sites of the
      mammalian cytochromes P450, even when derived from various species, are mainly
      dependent on chemical reactivity parameters of the substrates. Therefore, the
      results of the present study support the hypothesis that MO-based QSARs obtained
      in rat for the cytochrome P450 catalysed aromatic hydroxylation of benzene
      derivatives can provide a basis for prediction of biotransformation pathways in
      different species, including man.

PMID- 8646792
TI  - Identification of dioxin-responsive elements (DREs) in the 5' regions of putative
      dioxin-inducible genes.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an exogenous ligand for the
      cytosolic aryl hydrocarbon receptor (AhR), a ligand-inducible transcription
      factor whose exact physiological role remains elusive. TCDD has been shown to
      modulate the expression of a large array of genes, albeit often indirectly, by
      demonstration of protein or mRNA upregulation. Here, by computer analysis of
      available promoter sequences, we identify dioxin-responsive elements in the
      promoter regions of many putative AhR regulated and therefore dioxin-inducible
      genes.

PMID- 8646793
TI  - ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose
      topoisomerase II poisons to CNS tumors.
AB  - The catalytic cycle of topoisomerase II is the target of some of the most
      successful antitumor agents used today, e.g. etoposide (VP-16), in the treatment
      of testicular cancer and small-cell lung cancer. The cell kill mediated by
      topoisomerase II poisons can be antagonized by distinct drug types. Thus, we have
      demonstrated etoposide antagonism with the type-II anthracycline aclarubicin, the
      antimalarial drug chloroquine, and the cardioprotective agent ICRF-187. In other
      setups, combinations of agonist and antagonists have led to high-dose regimens
      for counteracting drug resistance. Thus, the exploitation of folinic acid rescue
      for methotrexate toxicity and the use of mesna to protect against
      cyclophosphamide toxicity have enabled the use of high-dose methotrexate and
      cyclophosphamide protocols. Using a similar approach, we have studied possible
      ways to apply antagonists to topoisomerase II poisons. NDF1-hybrid female mice
      were treated with the various drugs and drug combinations. Lethality (LD10 and
      LD50 values) was computed by use of the maximum-likelihood method, and the
      antitumor effect of the drugs was compared in mice inoculated i.p. with either
      L1210 cells or Ehrlich ascites tumor cells. In addition, the compounds were
      tested on L1210 cells inoculated intracranially. The toxicity of the various
      drugs was evaluated by weight and leukocyte counts. ICRF-187 rescues healthy mice
      from lethal doses of topoisomerase II poisons. In mice the ICRF-187 LD10 was 500
      mg/kg. Within a wide non-toxic dose range (50-250 mg/kg) of ICRF-187 we found
      protection against m-AMSA and etoposide lethality. Thus, the LD10 of etoposide
      increased from 34 mg/kg for the single agent to 122 mg/kg for its combination
      with ICRF-187, corresponding to a 3.6-fold etoposide dose escalation. In
      contrast, ICRF-187 did not protect against lethal doses of the non-topoisomerase
      II-directed drug paclitaxel. We further investigated the anti-tumor effect of
      equitoxic schedules in mice inoculated i.p. with L1210 or Ehrlich ascites tumor
      cells. The L1210-bearing mice appeared to obtain a larger increase in life span
      from the etoposide and ICRF-187 combination as compared with etoposide alone,
      whereas this was not the case in mice inoculated with Ehrlich ascites tumor
      cells. As the hydrophilic ICRF-187 is not expected to cross the blood-brain
      barrier, in contrast to the lipophilic etoposide, we investigated the effect of
      the drug combination in mice inoculated intracranially with L1210 cells. We
      obtained a significant increase in life span in mice treated with ICRF-187 +
      etoposide as compared with mice treated with an equitoxic dose of etoposide
      alone. Thus, there appear to be potential routes by which one can benefit from
      this antagonism. ICRF-187 is a powerful nontoxic protector against the lethality
      of the topoisomerase II-directed drugs etoposide and m-AMSA in vivo. A brain
      tumor model demonstrates the superiority of high-dose etoposide treatment with
      ICRF-187 protection as compared with etoposide treatment alone. This implies that
      tumors in the brain can be reached by cytotoxic drug doses and that normal
      tissues can be protected due to differences in drug transport across the blood
      brain barrier. ICRF-187 is therefore a promising lead compound for the
      development of schedules using high-dose topoisomerase II poisons in the
      treatment of brain tumors and metastases.

PMID- 8646795
TI  - Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK
      611. A study by the AIO groups PHASE-I and APOH.
AB  - NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group
      replaces a hydroxyl group at the sugar moiety of etoposide. This results in
      profound physico-chemical differences: NK 611 is much less hydrophobic than
      etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of
      bioavailability and of the potency of its anticancer activity. A clinical phase I
      study was performed in cancer patients within the framework of the AIO.
      Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611
      was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated
      dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were
      collected from 25 patients and analyzed using a validated high-performance liquid
      chromatography (HPLC) assay procedure. The concentration versus time curve of
      total NK 611 in plasma samples was best described by a three-compartment model.
      The overall median pharmacokinetic values were as follows (ranges are given in
      parentheses): mean residence time (MRT) 16.5 (5.4-42.3)h, terminal half-life 14.0
      (8.2-30.5)h, volume of distribution at steady state (V(ss)) 11.4 (7.9-18.1) l/m2
      and plasma clearance (Cl(p)) 15.1 (3.6-36.4) ml min-1 m-2. The total systemic
      drug exposure, represented by the area under the curve (AUC), varied between 53.4
      and 532.0 micrograms ml-1 h. The mean AUC (+/- SD) increased with the dose from
      78.7 +/- 3.7 micrograms ml-1 h at 60 mg/m2 up to 202.8 +/- 157.2 micrograms ml-1
      h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48
      h after the end of the infusion varied between 3.0% and 25.8% of the total dose
      delivered. Analysis of ultrafiltrate samples showed a protein binding of approx..
      99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC)
      correlated with the dose, AUC, and AUC(free). The best relationship between the
      percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a
      nonlinear Hill-type form. The laboratory parameter for kidney or liver function
      did not correlate with the AUC. The variation of pharmacokinetic parameters
      within each dose level was profound. The reason for this pharmacological behavior
      remains unclear and should be investigated in further studies.

PMID- 8646794
TI  - Differential single- versus double-strand DNA breakage produced by doxorubicin
      and its morpholinyl analogues.
AB  - The morpholinyl analogues of doxorubicin (DOX) have previously been reported to
      be non-cross-resistant in multidrug resistant (MDR) cells due to a lower affinity
      for P-glycoprotein relative to the parent compound. In order to further
      investigate the mechanisms of action of these morpholinyl anthracyclines, we
      examined their ability to cause DNA single- and double-strand breaks (SSB, DSB)
      and their interactions with topoisomerases. Alkaline elution curves were
      determined after 2-h drug treatment at 0.5, 2 and 5 microM, while neutral elution
      was conducted at 5, 10 and 25 microM in a human ovarian cell line, ES-2. A pulse
      field gel electrophoresis assay was used to confirm the neutral elution data
      under the same conditions. Further, K-SDS precipitation and topoisomerase drug
      inhibition assays were used to determine the effects of DOX and the morpholinyl
      analogues on topoisomerase (Topo) I and II. Under deproteinated elution
      conditions (pH 12.1), DOX, morpholinyl DOX (MRA), methoxy-morpholinyl DOX (MMDX)
      and morpholinyl oxaunomycin (MX2) were equipotent at causing SSB in the human
      ovarian carcinoma cell line, ES-2. However, neutral elution (pH 9.6) under
      deproteinated conditions revealed marked differences in the degree of DNA DSB.
      After 2-h drug exposures at 10 microM, DSBs were 3300 rad equivalents for MX2,
      1500 for DOX and 400 for both MRA and MMDX in the ES-2 cell line. Pulse-field
      data substantiated these differences in DSBs, with breaks easily detected after
      MX2 and DOX treatment, but not with MRA and MMDX. DOX and MX2 thus cause DNA
      strand breaks selectively through interaction with Topo II, but not Topo I. In
      contrast, MRA and MMDX cause DNA breaks through interactions with both
      topoisomerases with a predominant inhibition of Topo I.

PMID- 8646796
TI  - Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by
      radioimmunoassay.
AB  - Dolastatins 10 and 15 are small peptides isolated from the marine sea hare
      Dolabella auricularia that have been shown to interact with tubulin. Their growth
      inhibitory properties were compared using panels of human ovarian and colon
      carcinoma cell lines. Both agents were very potent inhibitors of cell growth,
      with dolastatin 10 being an average of 9.1-fold more potent than dolastatin 15
      [mean 50% inhibitory concentrations (IC50 values) 2.3 x 10(-10) and 2.1 x 10(-9)
      M, respectively; P < 0.05] and more potent than paclitaxel or vinblastine. While
      neither dolastatin exhibited marked cross-resistance in cisplatin- or etoposide
      resistant cell lines, contrasting effects were observed using an acquired
      doxorubicin-resistant (CH1doxR, 100-fold resistant, P-glycoprotein
      overexpressing) cell line. Resistance was significantly higher to dolastatin 15
      (12.7-fold) than to dolastatin 10 (only 3.2-fold; P < 0.05) and was reversible in
      both cases by verapamil. In vivo, using a s.c. advanced-stage human ovarian
      carcinoma xenograft and equitoxic doses, greater activity was observed with
      dolastatin 10 (6.1-day growth delay) versus 0.4 days for dolastatin 15. A
      radioimmunoassay for dolastatin 10 (limit of detection in mouse plasma 5 ng/ml)
      was developed. The rabbit antiserum aslo cross-reacted by 65% with dolastatin 15.
      Comparative mouse pharmacokinetics following i.v. administration of 1 mg/kg
      showed that both compounds are rapidly eliminated, but with a shorter second
      phase half-life (t1/2 beta) being observed for dolastatin 15 (being detectable
      for only up to 4 h post-administration), the t1/2 beta being 3 times longer for
      dolastatin 10. In addition, areas under the plasma concentration-time curve (AUC
      values) were 1.6-fold higher for dolastatin 10 (333 versus 208 ng ml-1 h). Plasma
      binding of dolastatin 10 exceeded 90%. The highly sensitive RIA will be useful
      for pharmacokinetic studies in conjunction with the planned phase I clinical
      trials of these novel, extremely potent, tubulin-binding agents, of which
      dolastatin 10 appears to possess the more promising preclinical features.

PMID- 8646797
TI  - Exogenous hepatocyte growth factor markedly stimulates liver regeneration
      following portal branch ligation in dogs.
AB  - Portal branch ligation (PBL) or embolization prior to extensive hepatectomy has
      been employed to increase the functional reserve of the remaining liver. This
      study investigated the effects of human recombinant hepatocyte growth factor (rh
      HGF) on liver regeneration following PBL in dogs. Beagle dogs were subjected to
      PBL and were divided into two groups, a control group (n = 11) without rh-HGF and
      a treated group (n = 12) receiving postoperative rh-HGF at 250 ng/kg via the
      portal vein. Dogs were killed 72 h or 14 days following PBL. We studied the
      changes in serum HGF level, DNA synthesis of the liver, hepatocyte size, liver
      weight, and liver function tests. In the HGF group, the ratio of whole liver
      weight to body weight increased significantly, and both ligated and nonligated
      lobes showed marked increases in weight. The nonligated lobes in the HGF group
      showed significant increases in both DNA synthesis and hepatocyte size. Moreover,
      ligated lobes in the HGF group showed an increase in DNA synthesis without
      hypertrophy compared with the control group. Administration of rh-HGF did not
      significantly affect liver function tests. Ligation of the portal branch
      supplying the portion of liver to be resected, coupled with the administration of
      rh-HGF, is a useful strategy to increase hepatic reserve in advance of major
      hepatectomy.

PMID- 8646798
TI  - Antitumor mechanism of action of a cyclopropyl antiestrogen (compound 7b) on
      human breast cancer cells in culture.
AB  - Cyclopropyl compound 7b [(Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy] phenyl]
      2-(4-methoxyphenyl)-3-cyclopropane] has been shown to be a pure antiestrogen in
      mouse uterine tissue. Antitumor activity was examined by evaluating the influence
      of 7b on the proliferation, estrogen receptor (ER) affinity and cell-surface
      morphology of ER-positive and ER-negative human breast cancer cells in culture.
      The antiproliferative potency of 7b was found to be equal to tamoxifen in ER
      positive MCF-7 human breast cancer cells. Further, the antiproliferative
      activities of 7b and tamoxifen were reversed by coadministration of estradiol.
      Accordingly, the antiproliferative activity of compound 7b appears to be estrogen
      mediated since it did not influence the growth of either ER-negative MDA-MB-231
      human breast cells or A-549 human lung cancer cells in culture. An ER-dependent
      mechanism of action is also supported by the specific binding affinity of 7b for
      ER in MCF-7 cells. Further, a study of cell surface morphology using scanning
      electron microscopy (SEM) revealed that 7b reduced the density and distribution
      of microvilli (MV) on MCF-7 cells, which was reversed by coadministration of
      estradiol. Compound 7b did not alter the cell surface morphology of ER-negative
      MDA-MB-231 cells. In conclusion, 7b inhibited the growth of ER-positive MCF-7
      cells in an estradiol-reversible manner, and had no effect on either ER-negative
      MDA-MB-231 cells or A-549 lung cancer cells. The results of this study confirm an
      antiestrogenic mechanism of action for 7b as previously observed in vivo and
      suggest that 7b would be effective in the treatment of estrogen-dependent breast
      cancer or as a prophylactic treatment for women with a high risk of breast cancer
      development.

PMID- 8646799
TI  - Nucleotide excision repair in the human ovarian carcinoma cell line (2008) and
      its cisplatin-resistant variant (C13*).
AB  - Repair of cisplatin-damaged DNA was investigated in a human ovarian carcinoma
      cell line (2008) and its cisplatin-resistant variant (C13*) using a host-cell
      reactivation (HCR) assay. The HCR of cisplatin-damaged adenovirus (Ad) was not
      significantly different in C13* cells compared to 2008 cells. The cisplatin
      concentrations required to reduce the amount of viral DNA replicated to 50% were
      0.12 +/- 0.02 microM and 0.10 +/- 0.01 microM after 48 h of repair in 2008 and
      C13* cells respectively. Similarly, the cisplatin concentration required to
      reduce the expression of a reporter gene inserted in the viral DNA was not
      significantly altered in C13* cells compared to the parental line (IC50 values
      were 0.28 +/- 0.04 microM in 2008 cells and 0.17 +/- 0.06 microM in C13* cells
      after 48 h of repair). Pretreatment of the cells with cisplatin, immediately
      prior to Ad infection, did not significantly alter the HCR of cisplatin-damaged
      Ad in either cell type. In addition, a cisplatin-sensitive variant derived from
      the C13* cells, namely the RH4 cells, did not differ significantly from either
      the 2008 or C13* cells in their ability to reactivate cisplatin-damaged Ad.
      Furthermore, a component of the nucleotide excision repair (NER) pathway, DNA
      polymerase alpha, was investigated using the competitive inhibitor aphidicolin.
      The combination of cisplatin and aphidicolin resulted in similar synergistic
      growth inhibition in both the 2008 and C13* cells providing additional support to
      the HCR results which suggest that enhanced NER is not responsible for the
      cisplatin resistance in C13* cells.

PMID- 8646800
TI  - Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five
      schedule in phase II clinical trials using a limited-sampling procedure.
AB  - Topotecan is a novel semisynthetic derivative of the anticancer agent
      camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone
      structure of topotecan, which is in equilibrium with the inactive ring-opened
      hydroxy acid, is essential for this activity. We performed a pharmacokinetics
      study as part of phase II clinical trials in patients with various types of solid
      tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5
      consecutive days, with courses being repeated every 3 weeks. Previously validated
      limited-sampling models, using concentration measurements in samples obtained 2 h
      after infusion, were used to calculate the area under the plasma concentration
      time curves (AUCs) for both chemical forms. Samples were obtained from a total of
      36 patients over 136 treatment days. The mean AUC of the closed-ring form
      (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of
      the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day
      (interpatient variability 34-61%). In each patient the AUC values achieved on the
      1st day of administration were similar to and, thus, predictive for those
      achieved during the following days, with a day-to-day variation of 7.39% being
      recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no
      drug accumulation during the 5 consecutive treatment days of each cycle. However,
      despite the large interpatient pharmacokinetic variability, the importance of
      regular drug monitoring on this schedule can be questioned, as the
      pharmacodynamic variability was relatively small.

PMID- 8646801
TI  - The effect of 9-beta-D-arabinofuranosyl-2-fluoroadenine and 1-beta-D
      arabinofuranosylcytosine on the cell cycle phase distribution, topoisomerase II
      level, mitoxantrone cytotoxicity, and DNA strand break production in K562 human
      leukemia cells.
AB  - Antimetabolites and topoisomerase (topo) II-reactive drugs are frequently
      combined in the therapy of acute leukemia. The two types of agents are thought to
      be synergistic in their actions against malignant blasts but the mechanism for
      this synergism is incompletely described. This study sought to determine whether
      the combination of two rather than one anti-metabolite with the topo II-reactive
      intercalator mitoxantrone would be greater than the effect of the single
      antimetabolite ara-C on mitoxantrone's cytotoxic actions. We also aimed to
      determine a mechanism for synergism should it occur. The model system used was
      K562 human leukemia cells. The second anti-metabolite selected was F-ara-A, the
      active form of fludarabine. The resultant combination (F-ara-A, ara-C, and a topo
      II reactive drug) is one currently being tested against acute myelogenous
      leukemia in clinical trials. F-ara-A itself had little effect on the cytotoxicity
      or the topo II-mediated DNA cleaving actions of mitoxantrone, while ara-C
      potentiated these actions as it does those of other topo II-reactive drugs.
      Surprisingly F-ara-A enhanced the actions of ara-C on mitoxantrone-associated
      cytotoxicity by at least an order of magnitude. The effect of the addition of F
      ara-A to ara-C on mitoxantrone-induced DNA cleavage was considerably smaller, but
      present. Antimetabolite treatment did not increase the amount of topo II within
      cells measured directly by immunoblotting or indirectly by quantifying the
      maximum number of topo II-DNA complexes stabilized by mitoxantrone. Rather, the
      anti-metabolites altered the distribution of the cells in the cell cycle.
      Antimetabolite treatment caused a large increase in S-phase cells, a phase in
      which cells are more sensitive to topo II-reactive drugs than the associated topo
      II-mediated DNA cleavage would predict. Therefore, it is likely that this shift
      in the distribution of the cells within the cell cycle accounts for both the
      enhanced cytotoxicity of mitoxantrone in antimetabolite pretreated cells and the
      discrepancy between the magnitude of antimetabolite action on topo II-mediated
      DNA cleavage.

PMID- 8646802
TI  - Differentiation of HL-60 cells distinguishes between cytostatic and cytotoxic
      effects of the alkylphospholipid ET-18-OCH3.
AB  - The synthetic dialkylphospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3
      phosphocholine (ET-18-OCH3) inhibits growth of the acute myelogenous leukemia
      cell line HL-60. Incubation of HL-60 cells with demethyl-sulfoxide causes the
      cells to differentiate to a granulocyte-like phenotype and become quiescent.
      Incubation of the DMSO-treated cells with ET-18-OCH3 results in a reduction in
      cell numbers due to cytotoxicity. In contrast, treatment of undifferentiated HL
      60 cells with lower concentrations of ET-18-OCH3 leads to growth inhibition.
      These data indicate that the model of differentiated HL-60 cells currently used
      for the study of resistance to growth inhibition is inappropriate. HL-60 cells
      can be used to measure growth inhibition and at higher doses cytotoxicity.
      However, the differentiated, nonproliferative, cells can only be used to measure
      direct cytotoxicity. Therefore, the results of studies directly comparing the
      effects of ET-18-OCH3 in proliferative HL-60 cells and quiescent DMSO-treated HL
      60 cells should be reevaluated. An evaluation of the effects of low
      concentrations of ET-18-OCH3 (0.5-1.5 microM) in proliferative HL-60 cells
      indicated that ET-18-OCH3 was an effective cytostatic agent at nontoxic
      concentrations. In summary, studies on the mechanism of action of ET-18-OCH3, or
      related ether lipids, should carefully investigate differences in the effects at
      cytostatic versus cytotoxic concentrations.

PMID- 8646803
TI  - The formation and persistence of carboplatin-DNA adducts in rats.
AB  - The formation and persistence of platinum-DNA adducts were studied with
      immuno(cyto)chemical methods in male and female Sprague-Dawley rats treated with
      a single i.p. dose of carboplatin. Linear dose-effect curves were observed for
      kidney and liver with an immunocytochemical assay using NKI-A59 antiserum that
      recognizes intrastrand cross-links. With this method, no staining of the nuclei
      due to platinum-DNA damage could be observed in the spleen, testis, uterus, or
      ovary after administration of up to 80 mg/kg carboplatin. A homogeneous staining
      of the nuclei in the liver was observed. The nuclear staining in the kidney was
      somewhat more intense but less homogeneous, with small groups of intensely
      stained nuclei occasionally being seen in the outer cortex. An approximately 15
      to 20-times lower dose of cisplatin than of carboplatin was needed to reach equal
      staining levels in the liver and kidney. Plateau staining levels in both tissues
      were reached at between approximately 8 and 48 h after administration of the
      carboplatin. This was followed by a significant reduction in the kidney samples,
      whereas the staining levels in the liver section seemed to be more persistent. No
      major difference was observed between male and female rats in the formation and
      removal of DNA damage in these tissues. The levels of the various DNA adducts
      were measured with a competitive ELISA in liver, kidney, spleen, testis, and
      combined ovary/uterus samples collected at 8 and 48 h after carboplatin
      administration. At both 8 and 48 h, the highest platination levels were observed
      in the kidney, followed--in decreasing order--by the liver, combined uterus and
      ovary samples, spleen, and testis. At 8 h after administration of carboplatin,
      the relative occurrence of the bifunctional adducts Pt-GG (34%), Pt-AG (27%), and
      G-Pt-G (32%), was similar in all tissues. The same held for the monoadducts that
      amounted to about 7% of the total DNA platination. These data indicate that in
      the first few hours after carboplatin treatment, no preference for the formation
      of Pt-GG adducts was observed, which confirms our earlier observations obtained
      with cultured cells. When the total DNA-platination levels (calculated from the
      sum of the adducts) seen at 8 and 48 h after treatment were compared, a
      substantial decrease in DNA platination was observed in the kidney (37%), liver
      (30%) and ovary/uterus (39%), whereas the repair levels in the testis (9%) and,
      probably, the spleen (18%) were substantially lower. In all tissues studied, only
      the relative occurrence of the Pt-GG adducts increased between 8 and 48 h, and as
      a result, at 48 h, after carboplatin administration the Pt-GG adduct was the
      major adduct persisting in the DNA samples.

PMID- 8646804
TI  - Functional aspects of membrane folate receptors in human breast cancer cells with
      transport-related resistance to methotrexate.
AB  - Two methotrexate (MTX)-resistant human breast-cancer cell lines with impaired
      transport via the reduced folate carrier (RFC), one established in vitro (MTX(R)
      ZR-75-1) and another inherently resistant (MDA-231), were adapted to grow in
      medium containing 2 nM folic acid. This induced the expression of previously
      undetectable membrane folate receptors (MFR) to levels of 8.2 and 2.3 pmol/10(7)
      cells, respectively. Polymerase chain reaction (PCR) quantitation revealed that
      MFR messenger-RNA levels of the isoform first described in human nasopharyngeal
      carcinoma KB cells (MFR-alpha) were increased in low-folate-adapted MTX(R)-ZR-75
      1 cells, whereas placental transcripts (MFR-beta) coincided with MFR-alpha
      expression in low-folate (LF)-adapted MDA-231 cells. These cell lines were used
      to study the role of MFR in the uptake and growth-inhibitory effects of five
      different antifolates with varying affinities for MFR: N10-propargyl-5, 8
      dideazafolic acid (CB3717) > 5,10-dideazatetra-hydrofolic acid (DDATHF) > N-5-[N
      (3,4-dihydro-2-methyl-4-oxoquinazolin-6-methyl) -N-methyl-amino]-2-theonyl}
      glutamic acid (ZD1694) >> MTX > edatrexate (EDX). Expression of MFR only slightly
      decreased the resistant phenotype for MTX, EDX, and ZD1694, suggesting that these
      drugs are not transported intracellularly to cytotoxic concentrations at these
      levels of MFR expression. On the other hand, both cell lines became from at least
      180- to 400-fold more sensitive to growth inhibition by CB3717 and DDATHF, which
      may be correlated with their high affinity for MFR. These sensitivity/resistance
      profiles were largely similar following cell culture in medium containing 1 nM L
      leucovorin, a folate with an affinity for MFR 10-fold lower than that of folic
      acid, the one exception being the increased sensitivity for ZD1694 seen in the LF
      adapted cells with the highest level of MFR expression (MTX(R)-ZR-75-1). These
      results illustrate that the efficacy of MFR in mediating antifolate transport and
      cytotoxicity depends on their affinity for the folate antagonist, their degree of
      expression, and the levels of competing folates.

PMID- 8646805
TI  - A phase II study of CI-973 [SP-4-3(R)]-1,1-cyclobutane-dicarboxylato (2-)] (2
      methyl-1,4-butanediamine-N, N') platinum in patients with refractory advanced
      breast cancer.
AB  - CI-973 is a water-soluble platinum diamine complex whose antitumor activity is
      greater than that of cisplatin in some murine tumors. It has shown activity
      against cisplatin-resistant tumors. This phase II trial had the objectives of
      determining the therapeutic efficacy of CI-973 in patients with metastatic breast
      cancer who had been treated with one prior chemotherapy regimen, and of further
      defining the toxicity of the agent and the reversibility of its toxicity. CI-973
      was administered as an intravenous infusion over 30 min with no prehydration or
      antiemetic programs. Treatment cycles were repeated at 21-day intervals. Patients
      with histologically confirmed metastatic breast cancer, measurable disease, and
      good performance status who had received only one prior chemotherapy regimen for
      metastatic disease were eligible for treatment. Adequate hematologic, renal, and
      hepatic function were required. A total of 26 patients received a median of two
      courses of CI-973 (range, 1-18 courses). Hematologic toxicity was severe: nearly
      all patients experienced granulocytopenia with granulocyte counts of 0 at all
      dose levels. Nevertheless, neutropenic fever and documented systemic infection
      were uncommon, and there were no hospitalizations for neutropenic fever or
      infection. Visceral disease dominated in this patient group. Of the 26 patients,
      14 had visceral disease, 6 had bone or bone marrow disease, and 6 had skin, soft
      tissue, or lymph-node disease. Of the 26 patients treated, 25 were evaluable for
      response. There were two partial remissions, one in liver and one in bone, and
      three minor responses, for a response rate of 8%. Nonhematologic toxic effects
      were mild and consisted of nausea and vomiting, fatigue, minimum peripheral
      paresthesia, and hypomagnesemia. Further study of CI-973 at the dose and schedule
      used in this study is not warranted. Because this agent had no significant
      extramedullary toxicity, intensification of the dose of CI-973 with concomitant
      administration of colony-stimulating factors has the potential to improve
      response in this patient population.

PMID- 8646808
TI  - Human serum hyaluronidase: characterization of a clinical assay.
AB  - Hyaluronidase, a lysosomal endoglycosidase mediating hyaluronan (hyaluronic acid)
      turn-over, is thought to be important in many normal developmental and certain
      pathologic processes. Previous assays of serum hyaluronidase are limited with
      respect to their applicability for routine clinical chemistry or clinical
      biochemical genetics applications. We describe a new assay of human serum or
      plasma hyaluronidase activity based on the determination of released N
      acetylglucosamine reducing termini that allows the analysis of the enzyme with
      small, easily obtained sample volumes. Using 10 microliters of serum or plasma,
      sodium formate buffer and human umbilical cord hyaluronan as substrate, we found
      a pH optimum of 3.9 and a K(m) and Vmax of 114 mg/l and 5102 mU/l, respectively.
      In addition, the assay has excellent linearity, precision and reproducibility.

PMID- 8646806
TI  - Biochemical modulation of fluorouracil: comparison of methotrexate, folinic acid,
      and fluorouracil versus folinic acid and fluorouracil in advanced colorectal
      cancer: a randomized trial.
AB  - Recent advances in biochemical pharmacology have revealed the basis for the
      biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic
      acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in
      enhanced cell kill in vitro and in vivo. In addition, administration of FA prior
      to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary
      complex of thymidine synthase. In the present randomized study, two groups of
      patients with advanced colorectal cancer were treated as follows: 43 patients
      (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA
      + MTX. The dosage was as follows: group A received FA i.v. at 300 mg/m2 per day,
      prior to i.v. 5-FU at 500 mg/m2 per day on days 1-4; group B was given MTX i.v.
      at 130 mg/m2 per day on day 0, followed 24 h later by FA at 15 mg q6h x 6, and 5
      FU + FA was started on day 1 and given at the same doses and schedule described
      for group A. Objective responses were achieved by 8/43 pts in group A (1 complete
      response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15
      partial responses), all occurring in the liver. There was no significant
      difference in the median time to progression (group A 6.1 months, group B 6.8
      months) or the median survival (group A 9.2 months, group B 10.3 months).
      Toxicity was significantly greater in group B [grade 2-3 mucositis 20% versus
      only 2% in group A (P < 0.0001); grade 3 diarrhea in group B 15% versus 3% in
      group A (P < 0.001)]. According to our results, double biological modulation of 5
      FU with MTX + FA led to an enhanced response rate with increased toxicity as
      compared with the 5-FU + FA regimen given at less than its maximally tolerated
      dose.

PMID- 8646807
TI  - A combination of ifosfamide and mitoxantrone as salvage therapy in patients with
      advanced ovarian cancer.
AB  - Ifosfamide (IFX) and mitoxantrone (MXN) have been found to be effective against
      advanced epithelial ovarian cancer. The combination of these two agents has not
      yet been tested in this setting but seems to be rational, given the different
      action mechanisms of these drugs and their not completely overlapping side
      effects. Between June 1987 and November 1991, 37 patients with advanced ovarian
      carcinoma recurrent or refractory to primary cisplatin-based chemotherapy entered
      the study. Therapy consisted of MXN, given i.v. at 10 mg/m2 on day 1 and IFX
      given i.v. at 2,000 mg/m2 per day on days 1-3 with mesna. The cycles were
      repeated every 3 weeks. Four patients achieved a complete remission and three
      achieved a partial remission, for response rates of 18.9% [95% confidence
      interval (CI) 6.3-31.5%] in the whole sample and 38.8% (95% CI 16.3-61.3%) in the
      subset of 18 patients responding to first-line cisplatin. No response was
      obtained in the remaining patients, whose disease was refractory to primary
      platinum-based chemotherapy. Clinically significant toxicity (WHO grades 3-4)
      included leukopenia in 46% of the patients and anemia in 32.5%. The non
      hematologic toxicity was mild, except for reversible alopecia (57%) and nausea
      and vomiting (48.5%). This regimen seems attractive for patients who have either
      failed or not received platinum retreatment, especially when limiting
      neurotoxicity occurs. Further studies are warranted to establish the relative
      impact of both of these agents.

PMID- 8646809
TI  - Determination of phosphoribosylpyrophosphate synthetase activity in human cells
      by a non-isotopic, one step method.

PMID- 8646810
TI  - Problems and perspectives of clinical biochemistry training, and the example of
      Italy.
AB  - Even though Laboratory Medicine is a firmly established science, the taxonomy of
      its various branches differs not only between countries but also within the same
      country, largely because of conflicting interests and views. Two criteria can be
      used to define Laboratory Medicine: (1) it encompasses the life sciences such as
      biochemistry, immunology, molecular biology and other scientific disciplines as
      applied to clinical practice, and (2) it involves solving clinical problems and
      making related decisions applied to preventive, diagnostic or therapeutic aspects
      of medicine. Thus, Laboratory Medicine is an integrated science that is
      clinically oriented, but it depends upon the basic sciences for its operational
      and intellectual aspects. The education and training of Clinical Biochemistry
      professionals can be either multidisciplinary, which is the traditional approach,
      or interdisciplinary whereby the "student' undergoes a "structured' complementary
      training. Again, there is much debate as to the pitfalls and benefits of each
      approach. We suggest the interdisciplinary educational approach can better
      incorporate the rapid turnover of knowledge and the continuous changes in the
      various lines of activity that are characteristic of Laboratory Medicine, thereby
      providing a unifying mechanism by which Laboratory Medicine can enter
      unequivocally into the scenario of Medical Sciences. In this article, the
      situation in Italy is taken as an example of the different opinions and
      philosophies that should be accommodated to reach a training system acceptable to
      both sides of the debate.

PMID- 8646812
TI  - Helicobacter pylori infection and serum IgG avidity.

PMID- 8646811
TI  - Concentration of mRNA for von Willebrand factor in platelets of type I von
      Willebrand disease.

PMID- 8646813
TI  - Cardiac troponin I in the diagnosis of myocardial injury and infarction.
AB  - We used a cardiospecific enzymoimmunometric assay to measure cardiac troponin I
      (cTnI) in samples serially drawn from 78 patients with acute myocardial
      infarction (AMI), 7 patients with unstable angina (Braunwald class III), 22 multi
      traumatized patients, and in 30 athletes after eccentric exercise, as well as in
      101 non-traumatic chest pain patients on admission to the emergency department.
      cTnI assay crossreactivity with crude human skeletal muscle homogenates was <
      0.1%. cTnI could not be detected in athletes or multi-traumatized patients except
      for 2 trauma patients with myocardial damage. Increased cTnI concentrations were
      found in 6 of 7 patients with unstable angina at rest and in all AMI patients.
      After AMI, cTnI increased about 3.5 h (median) after the onset of chest pain,
      reached peak values parallel to CKMB, and stayed increased for at least 4 days.
      Cardiac troponin T (cTnT) increased and mostly peaked parallel to cTnI. cTnT
      sensitivity on the 7th day after AMI was significantly higher than that of cTnI.
      In contrast to cTnI, cTnT mostly showed a second, usually smaller, peak about day
      4 after AMI. During the first 4 h after the onset of chest pain and before
      thrombolytic therapy the sensitivities of myoglobin (0.43) and CKMB mass (0.56)
      were significantly higher than those of both troponins (cTnI, 0.29; cTnT, 0.25).
      Areas under receiver operator characteristic curves indicated only moderate
      diagnostic accuracies of bio-chemical markers for early AMI diagnosis in non
      traumatic chest pain patients that cTnI is a highly sensitive and specific marker
      for myocardial damage which is suitable for early and late diagnosis.

PMID- 8646814
TI  - Immunochemiluminometric assay with two monoclonal antibodies against the N
      terminal sequence of human parathyroid hormone.
AB  - We have developed an immunochemiluminometric assay (ICMA) with two monoclonal
      antibodies for the N-terminal sequence of human parathyroid hormone (hPTH). One
      monoclonal antibody (A1-70) was physically adsorbed onto polystyrene beads, the
      other (B1-70) was labelled with acridinium ester and synthetic hPTH (1-38) was
      used as standard. This assay has cross-reactions with synthetic hPTH (1-34) and
      hPTH (1-84) but no cross-reactions with hPTH (4-16), (28-48), (39-84), (44-68),
      (53-84) and hPTH-rP (1-86). The assay detection limit is 0.4 pmol/l. The normal
      range is 1.3-12 pmol/l based on 72 normal volunteers. About 91% of study patients
      (n = 58) with surgically proven primary hyperparathyroidism (1 degree HPT) had
      PTH values above normal and one of them showed a low normal intact PTH value but
      elevated PTH values with use of this assay. After immunoabsorption of plasma
      samples from patients with secondary hyperparathyroidism (2 degrees HPT) on
      hemodialysis with polystyrene beads containing antibodies against hPTH (39-84),
      some patients still showed significant amounts of PTH in this new ICMA but not
      intact PTH. The data reveal that significant amounts of amino-terminal
      immunoreactive PTH fragments rarely exist in 1 degree HPT but are present in some
      patients with 2 degrees HPT. The major advantage of this assay is to measure both
      amino-terminal PTH fragments and intact PTH with no interference from carboxy
      terminal PTH fragments because two anti-N-terminal hormone sequence monoclonal
      antibodies are used.

PMID- 8646815
TI  - A simple method for screening for Farber disease on cultured skin fibroblasts.
AB  - Farber disease is an inborn lysosomal storage disorder characterized by
      accumulation of ceramide in the patient's tissues due to the deficient activity
      of acid ceramidase. Currently, confirmation of the diagnosis is performed in an
      extremely limited number of laboratories. We therefore developed a procedure
      which does not require any particular sphingolipid substrate and is based on the
      quantitation of ceramide levels in cultured skin fibroblasts. In the method we
      devised, the ceramide present in cellular lipid extracts subjected to mild
      alkaline hydrolysis was quantified using the commercially available
      diacylglycerol kinase kit. We show that both primary cultures of skin fibroblasts
      and SV40-transformed fibroblasts derived from a series of patients with Farber
      disease exhibit ceramide excess as compared to their normal counterparts (2345-17
      153 pmol/mg cell protein in Farber cells vs. 432-1298 pmol/mg cell protein in
      controls). Use of this simple method should greatly facilitate the biochemical
      diagnosis of Farber disease.

PMID- 8646816
TI  - Stabilization of plasmin by lysine derivatives.
AB  - Plasmin is a serine protease with trypsin-like specificity and is activated from
      plasminogen by several plasminogen activators. Since plasmin has lysine binding
      site in its heavy chain, lysine derivatives react with plasmin and then modify
      its activity. The effects of lysine derivatives such as epsilon-aminocaproic acid
      (EACA) and tranexamic acid on bovine plasmin activity were investigated. In the
      absence of lysine derivatives, the bovine plasmin activity which was evaluated as
      the amidolytic activity was reduced in a time- or temperature-dependent manner.
      However, the bovine plasmin activity became stable upon adding EACA or tranexamic
      acid. When plasmin was incubated at 4 degrees C for 1, 3 or 5 days without lysine
      derivatives, the plasmin activity decreased to 43.9%, 19.9% and 11.9% of the
      initial activity, respectively. On the other hand, when plasmin was incubated at
      37 degrees C for 1, 3 or 5 days with tranexamic acid, its activity remained at
      110%, 95.6% and 85.9%, respectively. After bovine plasmin had been incubated for
      5 days at 4 degrees C in the absence of tranexamic acid, the plasmin activity
      declined to less than 20%. However, when bovine plasmin had been incubated for 5
      days at 37 degrees C in the presence of tranexamic acid, the residual plasmin
      activity was more than 80%. A similar effect of EACA on bovine plasmin was
      observed, but it was weaker than that of tranexamic acid. Reversed-phase HPLC
      followed by SDS-PAGE demonstrated that bovine plasmin was degraded into several
      fragments. Amino acid sequencing of these fragments revealed that the Lys77-Arg78
      or Arg78-Ile79, Arg342-Met343 and Arg557-Ile558 peptide bonds in the bovine
      plasmin molecule were cleft, respectively. Only the fragment consisting of the
      amino acid region from Met343 to the C-terminal amino acid, Asn786, exhibited
      amidolytic activity. In proportion to inactivation of the bovine plasmin, this
      fragment disappeared. The above findings suggest that lysine derivatives react
      with bovine plasmin and then stabilize the activity of plasmin by preventing the
      degradation of active fragment (Met343-Asn786).

PMID- 8646817
TI  - Age-related changes in amounts and concentrations of collagen and elastin in
      normotensive human thoracic aorta.
AB  - Twenty thoracic aortas were obtained post-mortem from subjects between the ages
      of 14 and 90 years who had previously been recorded as normotensive. Full wall
      thickness samples of 1 cm diameter were taken at six sites between heart valve
      and diaphragm. Lipid-free dry weight (mg per sample) and amounts (mg per sample)
      and concentrations (mg/mg dry weight) of collagen and elastin were determined.
      Lipid-free dry weight and amount of collagen showed highly significant decreases
      with age (P < 0.0001), with the amount of elastin less so (P = 0.003),
      representing losses of 92%, 80% and 62%, respectively, between the ages of 14 and
      90 years. In contrast, the concentrations of both collagen and elastin increased
      significantly with age (P < or = 0.0002) by 72% and 140%, respectively, over the
      age range studied. However, in both cases, the increase occurred substantially
      after the age of 45. Therefore, besides demonstrating loss of collagen and
      elastin from the aortic wall with age, these results suggest strongly that there
      is a parallel loss of other aortic components at a rate which outstrips that of
      either collagen or elastin in later life.

PMID- 8646818
TI  - A fast and simple screening method for detection of 2,8-dihydroxyadenine
      urolithiasis by capillary zone electrophoresis.
AB  - 2,8-Dihydroxyadenine urolithiasis is an inherited disorder caused by adenine
      phosphoribosyltransferase deficiency. A fast, simple, sensitive and selective
      capillary zone electrophoretic method for diagnosis of 2,8-dihydroxyadenine
      urolithiasis in adenine phosphoribosyltransferase deficiency is described. The
      method is based on direct measurement of 2,8-dihydroxyadenine in untreated urine
      in phosphate buffer at pH 3.0 within 8 min. Under the given separation conditions
      2,8-dihydroxyadenine is very well separated from other purine and pyrimidine
      substances and presents characteristic UV spectra which enable identification in
      case of doubt. The urine samples containing pathological 2,8-dihydroxyadenine
      could be successfully analysed in levels approaching those relevant for
      bioanalytical applications. The reliability of the method presented for screening
      of patients with adenine phosphoribosyltransferase deficiency is demonstrated on
      a urine sample of a patient with the defect who was already treated with
      allopurinol at the time of obtaining the sample. No interfering substances were
      found in 50 urine samples from healthy infants under the analytical condition
      described.

PMID- 8646819
TI  - Perilymph detection by beta 2-transferrin immunoblotting assay. Application to
      the diagnosis of perilymphatic fistulae.
AB  - beta 2-Transferrin, the asialotransferrin, is found in cerebrospinal fluid (CSF)
      and inner ear perilymph, but is absent from serum and other body fluids or
      secretions except the aqueous humor. The detection of this asialo-fraction of the
      transferrin in ear fluid microsamples with an immunoblotting technique is of
      great interest when a perilymphatic fistula (PLF) is suspected. beta 2
      Transferrin was detected on microsamples collected by syringe or on micro
      collagen sponges from 30 patients undergoing ear surgery. The problem is
      reviewed, the technique and sample preparation are explained and the results
      discussed. beta 2-Transferrin detection in the ear fluid allows the
      identification of perilymph, except in the CSF oto- or rhinorrheal context, and
      is proposed as a promising test to confirm perilymphatic fistula.

PMID- 8646820
TI  - Oral first-pass elimination of midazolam involves both gastrointestinal and
      hepatic CYP3A-mediated metabolism.
AB  - OBJECTIVE: To determine in humans the relative roles of intestinal and hepatic
      metabolism in the oral first-pass elimination of a CYP3A substrate using
      midazolam as a model compound. METHODS: Midazolam was administered intravenously
      (1 mg) or orally (2 mg) to 20 healthy young subjects (10 men and 10 women) in a
      random fashion, and the disposition of the drug and its 1'-hydroxy metabolite
      were determined. In separate in vitro studies, the CYP3A-mediated formation of 1'
      hydroxymidazolam by human hepatic and intestinal microsomes was investigated.
      RESULTS: No gender-related differences were noted in either the systemic (370 +/-
      114 ml/min [mean +/- SD]) or oral (1413 +/- 807 ml/min) clearance values of
      midazolam. Despite complete oral absorption, measured oral bioavailability was on
      average about 50% less than that predicted on the assumption that only the liver
      contributed to first-pass metabolism. Pharmacokinetic estimation of the
      intestinal component indicated an extraction ratio (0.43 +/- 0.24) that was
      similar to that of the liver (0.44 +/- 0.14). 1'-Hydroxymidazolam was extensively
      but variably formed in vitro by both hepatic and intestinal microsomes and,
      although the intrinsic clearance (V(max)/Km) was higher in the liver preparations
      (540 +/- 747 versus 135 +/- 92 microliters/min/mg protein), this difference was
      not statistically significant. CONCLUSIONS: These results show that the small
      intestine can be a major site for presystemic, CYP3A-mediated metabolism after
      oral administration. Moreover, it appears that this represents a true first-pass
      effect. In addition, intestinal and hepatic metabolism may be important factors
      in interindividual variability in disposition after oral administration of
      midazolam and similar CYP3A substrates. Finally, intestinal localization of CYP3A
      may be significant in metabolism-based drug-drug interactions.

PMID- 8646821
TI  - Disposition and first-pass metabolism of ethanol in humans: is it gastric or
      hepatic and does it depend on gender?
AB  - OBJECTIVE: To assess the extent and site of the first-pass metabolism of ethanol
      and to examine whether first-pass metabolism and disposition of ethanol are
      dependent on gender. METHODS: After a standardized lunch, healthy subjects (six
      women and six men) received on two separate occasions a 60-minute intravenous
      infusion of ethanol (0.3 gm/kg) and concomitantly an equimolar dose of d3
      ethanol/kg either orally (over 20 minutes) or intraduodenally (infused over 30
      minutes). Blood levels, urinary excretion of d0- and d3-ethanol, and sedative
      effects were monitored for 6 hours. Disposition and first-pass metabolism of
      ethanol were evaluated by applying an open two-compartment model with Michaelis
      Menten elimination. RESULTS: Comparison of the corresponding intravenous/oral
      versus intravenous/intraduodenal data of each individual revealed that total
      first-pass metabolism (gastric plus hepatic) was not pronounced in either males
      (9.1% +/- 4.0%; mean +/- SD) or females (8.4% +/- 3.1%) and that this first-pass
      metabolism was partly of gastric origin. Dose-corrected values for area under
      blood concentration-time curve were on average 28% higher (p < 0.0001) in the
      women than in the men. Mean total blood ethanol disappearance rate was higher (p
      < 0.001) in women (3.92 +/- 0.40 mmol/L . hr) than in men (3.19 +/- 0.48 mmol/L .
      hr). Renal clearance was gender-independent and negligible. A linear relationship
      (p < 0.001) could be found between the blood levels of ethanol and sedation
      index. Because the slope was steeper in women (1.04) than in men (0.42) a higher
      central nervous system sensitivity to the sedative effects of ethanol in women
      can be assumed. CONCLUSIONS: Under realistic life conditions (social drinking of
      moderate doses of ethanol after a light lunch) only a minor, gender-independent
      first-pass metabolism is observed that is partly of gastric origin.

PMID- 8646822
TI  - A kinetic and dynamic study of oral alprazolam with and without erythromycin in
      humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism.
AB  - OBJECTIVE: To assess the possible involvement of CYP3A4 in the metabolism of
      alprazolam in vivo. METHOD: Twelve healthy male volunteers were randomly
      allocated to one of the two different treatment sequences, placebo-erythromycin
      or erythromycin-placebo, with an at least 6-week washout period between the two
      trial phases. Each volunteer received 400 mg erythromycin or matched placebo
      given orally three times a day for 10 days and an oral dose (0.8 mg) of
      alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was
      measured up to 48 hours after the administration, and psychomotor function was
      assessed at each time of blood samplings with use of the Digit Symbol
      Substitution Test, visual analog scale, and Udvalg for kliniske undersogelser
      side effect rating scale. RESULTS: Erythromycin significantly (p < 0.001)
      increased the area under the plasma concentration-time curves (200 +/- 43 versus
      322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng .
      hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/-
      0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life
      (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor
      function variables did not differ significantly between the erythromycin and
      placebo trial phases. CONCLUSION: This study suggests that erythromycin, an
      inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo
      evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic
      change of alprazolam by erythromycin does not result in the pharmacodynamic
      change of this triazolobenzodiazepine, at least after single dosing.

PMID- 8646823
TI  - Pharmacokinetics of abecarnil in patients with renal insufficiency.
AB  - OBJECTIVE: To characterize the pharmacokinetics of a single 5 mg oral dose of
      abecarnil in subjects with varying degrees of renal impairment. METHODS: Twenty
      six subjects were enrolled in this open-label parallel-group study. Ten subjects
      had normal renal function (NRF; creatinine clearance [CLCR] > or = 85 ml/min/1.73
      m2), six subjects had mild to moderate renal insufficiency (MMRI; CLCR between 25
      and 73 ml/min/1.73 m2), and 10 subjects had severe renal insufficiency (SRI; CLCR
      < or = 10 ml/min/1.73 m2). Abecarnil plasma concentrations were determined by
      means of HPLC, and plasma protein binding was determined by use of
      ultracentrifugation. Pharmacokinetic parameters were obtained with use of model
      independent and model-dependent methods. RESULTS: In subjects with SRI, area
      under the concentration-time curve and maximum plasma concentration were reduced
      by 36% and 31%, respectively, compared with demographically matched subjects with
      NRF. The apparent total body clearance in the NRF, MMRI, and SRI groups was 13.0
      +/- 6.89, 12.9 +/- 3.64, and 25.0 +/- 13 ml/min/kg, and the apparent volume of
      distribution was 14.0 +/- 3.78, 12.8 +/- 2.4, and 19.4 +/- 5.76 L/kg,
      respectively (mean +/- SD). The patients with SRI had a significantly lower
      protein bound fraction than subjects with NRF (0.850 +/- 0.077 versus 0.948 +/-
      0.023). Despite an increase in the free fraction of abecarnil (f(u)), there was
      no significant change in the apparent unbound total body clearance and unbound
      volume of distribution between the SRI and NRF groups. The anticipated full
      effect of the increase in f(u) among the patients with SRI was not realized and
      suggests that the f(u) in tissue may be increased in patients with SRI.
      CONCLUSION: Dose adjustment will need to be made on the basis of titration to the
      desired clinical response and tolerability in patients with SRI just as in
      subjects with NRF.

PMID- 8646824
TI  - Hepatic drug clearance in patients with mild cystic fibrosis.
AB  - The plasma disposition of three model substrates (lorazepam, indocyanine green,
      and antipyrine) and the formation clearance of antipyrine metabolites (3
      hydroxymethylantipyrine, norantipyrine, and 4-hydroxyantipyrine) were evaluated
      in 15 subjects with mild cystic fibrosis and in 15 healthy control subjects.
      Plasma clearance was significantly greater in patients with cystic fibrosis for
      both lorazepam (1.7 +/- 0.4 versus 1.2 +/- 0.5 ml/min/kg) and indocyanine green
      (14.2 +/- 6.1 versus 9.1 +/- 3.0 ml/min/kg). In contrast, the clearance of
      antipyrine was not significantly different (1.0 +/- 0.7 versus 0.8 +/- 0.3
      ml/min/kg), but the formation clearance for 3-hydroxymethylantipyrine was
      significantly greater in patients with cystic fibrosis. Lorazepam and antipyrine
      apparent steady-state volume of distribution were not different between groups.
      These results suggest that clearance of drugs that undergo conjugation (e.g.,
      lorazepam) or biliary excretion (e.g., indocyanine green) is increased in
      patients with mild cystic fibrosis. In contrast, the increased formation
      clearance of only one antipyrine metabolite suggests that alterations in
      clearance of drugs metabolized by cytochrome P450 enzymes are substrate specific
      and isoform specific in patients with cystic fibrosis.

PMID- 8646825
TI  - Direct demonstration of small intestinal secretion and site-dependent absorption
      of the beta-blocker talinolol in humans.
AB  - OBJECTIVE: To examine the relevance of site-dependent small intestinal absorption
      for incomplete intestinal absorption of the poorly metabolized beta 1-adrenergic
      receptor antagonist talinolol. METHODS: The intestinal steady-state perfusion
      technique (triple lumen tubing system with a 30 cm test segment) for intraluminal
      measurements was combined with simultaneous determination of talinolol serum
      concentrations. Dissolved talinolol was perfused over 160 minutes into different
      parts of the small intestine. The middle of the test segment was located between
      25 and 235 cm beyond the teeth. Each of the six healthy subjects was studied
      twice with a proximal and a more distal site of perfusion to allow for
      comparisons within an individual subject. RESULTS: The area under the curve for
      serum concentrations from 0 to 480 minutes [AUC(0-480 min)] and the maximum serum
      concentration after distal perfusions corresponded to only 15% to 73% and 7% to
      90% of the proximal values, respectively. AUC decreased with increasing distance
      from the teeth. The mean amount of talinolol absorbed from the test segment per
      unit time (intestinal transport rate) corresponds to only one-tenth of the amount
      of drug offered to the test segment (perfusion rate). There was a direct
      correlation between the perfusion rate of talinolol and its transport rate for
      both regions and in all subjects investigated. However, to achieve the same
      transport rate in the distal region a higher perfusion rate is required, compared
      to the proximal small intestine. At perfusion rates lower than 600
      micrograms/min, net secretion of talinolol into the intestinal lumen occurred
      against a steep concentration gradient blood: lumen of about 1:4200. CONCLUSION:
      Talinolol oral bioavailability of 55% is due to a low absorption rate and a
      decrease of absorption capabilities along the small intestine. Net absorption of
      talinolol is reduced by the involvement of active intestinal secretion.

PMID- 8646827
TI  - Direct angiotensin converting enzyme inhibitor-mediated venodilation.
AB  - BACKGROUND: The vasodilator effects of angiotensin converting enzyme inhibitors
      have been ascribed to systemic inhibition of the angiotensin II generation.
      However, local mechanisms of vasodilation also have been suggested. We tested
      whether the angiotensin converting enzyme inhibitor enalaprilat mediated local
      vasodilation in human dorsal hand veins. METHODS: We infused enalaprilat and
      assessed changes in dorsal hand vein compliance using the linear variable
      differential transducer technique. Enalaprilat-mediated effects were assessed in
      small and large veins and in the presence and absence of one of two
      vasoconstrictors: exogenous norepinephrine or physiologic vasoconstriction by
      cooling. RESULTS: We infused locally in small dorsal hand veins at skin
      temperatures of less than 29.0 degrees C (baseline distention < 0.35 mm) in the
      absence of exogenous vasoconstrictors, enalaprilat mediated dose-dependent
      vasodilation (median effective dose [ED50], 12 ng/min to a maximal effect of 162%
      +/- 15% of baseline, p < 0.01). Maximal enalaprilat-mediated vasodilation was
      comparable to dilation mediated by insulin (175% +/-17% of baseline; p = 0.21)
      and less than dilation mediated by nitroglycerin (221% +/- 20% of baseline; p =
      0.011). At skin temperatures > 31 degrees C, enalaprilat mediated dose-dependent
      vasodilation in small vessels only when vessels were preconstricted with
      norepinephrine (ED50 = 5.1 ng/min, maximal enalaprilat-mediated effect of 164% +/
      21% of baseline; p < 0.05). CONCLUSIONS: These data suggest enalaprilat mediates
      local vasodilation in dorsal hand veins, with an ED50 comparable to plasma
      enalaprilat concentrations achieved with oral enalapril therapy. This effect is
      dependent on vessel size and on the presence of preconstruction. Local
      vasodilator effects may be important in the clinical hemodynamic effects of
      angiotensin converting enzyme inhibitors.

PMID- 8646826
TI  - Pharmacokinetics of lamivudine administered alone and with trimethoprim
      sulfamethoxazole.
AB  - OBJECTIVE: To determine the effect of multiple dosing of combined
      sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of
      lamivudine. METHODS: Fourteen subjects with human immunodeficiency virus who had
      CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine,
      separated by 7 to 14 days, in a randomized two-day crossover study. Treatment
      consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg)
      daily on days 1 through 4 followed by lamivudine plus trimethoprim
      sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to
      determine lamivudine, trimethoprim, sulfamethoxazole, and N-4
      acetylsulfamethoxazole concentrations. RESULTS: Coadministration of a single dose
      of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days
      altered the pharmacokinetics of lamivudine. A 43% increase in area under the
      concentration-time curve (AUC infinity) and a 35% decrease in renal clearance
      (CLR) were observed when lamivudine was coadministered with trimethoprim
      sulfamethoxazole compared with lamivudine alone. The geometric least-squares
      trimethoprim-sulfamethoxazole were as follows: AUC infinity, 10,124 (9,432
      10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CLR, 16.6 (14.1
      19.4) and 10.8 (9.5-12.6) L/hr, respectively. Coadministration did not
      significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole.
      CONCLUSIONS: Coadministration of lamivudine with trimethoprim-sulfamethoxazole
      resulted in an increased AUC infinity and a decreased CLR of lamivudine. However,
      given the favorable safety profile of lamivudine, it is unlikely that this
      interaction will result in a significant increase in concentration-related
      toxicity at the doses studied.

PMID- 8646828
TI  - Impaired beta 2-adrenergic agonist-induced venodilation in Indians of Asian
      origin.
AB  - OBJECTIVES: Vascular responsiveness to infusions of vasoactive substances varies
      between ethnic groups. Indians of Asian origin are a rapidly growing ethnic group
      in the United States but have not been extensively studied. We sought to
      determine whether there was any difference in venous responsiveness to a local
      infusion of vasoactive substances between Indians of Asian origin and white
      subjects. METHODS: We used the dorsal hand vein compliance technique to construct
      full dose-response curves to the beta 2-agonist isoproterenol (2 to 270 ng/min)
      in hand veins preconstricted with phenylephrine in 11 young white subjects and in
      11 young Asian Indian subjects. In addition, six subjects in each group were
      randomly selected to have full dose-response curves to nitroglycerin (0.006 to
      1485 ng/min) generated. RESULTS: The maximal response (E(max)) to isoproterenol
      was smaller in Asian Indians (33.9% +/- 41.1% in Asian Indians versus 107.0% +/-
      60.1% in white subjects; p < 0.01). There was no difference in the log of the
      dose that produced half-maximal venodilation [log(ED50)] between the two groups
      (1.10 +/- 0.57 in Asian Indians versus 1.15 +/- 0.50 in white subjects). However,
      nitroglycerin infusion produced similar responses for both the E(max) and the
      log(ED50) between the two groups. CONCLUSION: These results indicate that
      differences may exist in beta-adrenergic responsiveness among white subjects and
      Indians of Asian origin. Therapy for diseases that use beta-adrenergic responses,
      such as hypertension, must take into account these differential vascular
      responses because they may affect their efficacy in Asian Indians.

PMID- 8646829
TI  - Introducing medical students to medication noncompliance.
AB  - Medical students were introduced to issues relating to medication noncompliance
      in a simulated clinical setting. Compliance with either a twice-a-day or a three
      times-a-day regimen was monitored with use of electronic monitoring devices for a
      2-week interval. Compliance with the twice-a-day regimen was higher than
      compliance with the three-times-a-day regimen, although the difference was not
      significantly different. Overall, 71% of the prescribed doses were taken by the
      medical student participants; however, only 46.5% of the doses were taken at the
      prescribed dosing frequency and 28.5% were taken at the prescribed intervals. The
      majority of students linked dose taking with routine daily activities and
      reported that their hectic lifestyles adversely influenced compliance. Similar
      factors might be expected to influence compliance in patient populations. The
      goal of this exercise was to demonstrate to future physicians the difficulties
      that patients have with compliance to prescribed medications.

PMID- 8646830
TI  - Assessment of individual CYP2D6 activity in extensive metabolizers with renal
      failure: comparison of sparteine and dextromethorphan.
AB  - OBJECTIVES: To examine whether the variability of CYP2D6 activity in patients
      with chronic renal failure can be assessed, particularly among subjects with the
      extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6
      activity derived from oral administration of dextromethorphan and sparteine.
      METHODS: A single 100 mg oral dose of sparteine and a single 40 mg oral dose of
      dextromethorphan were administered on two occasions to 12 patients with chronic
      renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and
      sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio,
      and urinary recovery of dextrorphan were calculated. Patients and healthy control
      subjects were not selected on the basis of their CYP2D6 phenotypes. RESULTS:
      Chronic renal failure was associated with a decrease in sparteine partial
      metabolic clearance to dehydrosparteine (median of 322 ml/min and range of 62 to
      670 ml/min in patients with renal failure versus median of 635 ml/min and range
      of 77 to 1276 ml/min in normal subjects; p < 0.02). Sparteine apparent oral
      clearance (p < 0.03) and renal clearance (p < 0.001) decreased in patients with
      renal failure. However, sparteine metabolic ratio was not significantly altered
      in patients with renal failure and showed that all patients were extensive
      metabolizers of sparteine. Although fractional urinary excretion of dextrorphan
      decreased in patients with renal failure (median, 24.4%; range, 9.7% to 55.9%)
      compared with control (median, 47.5%; range, 24.1% to 72.1%) (p = 0.02), it also
      showed that all subjects were extensive metabolizers of dextromethorphan. The
      amount of dextromethorphan excreted in urine correlated with creatinine clearance
      independently from CYP2D6 activity measured as sparteine partial metabolic
      clearance. However, it did not correlate with sparteine metabolic ratio or with
      fractional urinary excretion of dehydrosparteine. CONCLUSION: Assessment of
      CYP2D6 activity by use of dextromethorphan and sparteine is possible in extensive
      metabolizer patients with chronic renal failure. However, in these subjects,
      dextromethorphan and sparteine do not reflect CYP2D6 activity in the same way.

PMID- 8646831
TI  - Nicotine deposition and body distribution from a nicotine inhaler and a cigarette
      studied with positron emission tomography.

PMID- 8646832
TI  - Nuclear pattern recognition by two-parameter texture analysis.
AB  - The present paper describes a simple procedure for the analysis of chromatin
      texture. High-resolution digitized images of nuclei are first standardized to
      render gray values invariant to staining and illumination conditions.
      Subsequently, the nucleus is subdivided by a square grid into 0.4 x 0.4 microns2
      quadrats and standard deviations of gray values within each quadrat are
      estimated. Finally, the overall mean and standard deviation of quadrat standard
      deviations are calculated. These values may be considered as pure descriptors of
      the nuclear texture, as they represent the distribution of chromatin changes,
      disregarding any absolute densitometric and morphometric feature. Using the above
      descriptors it is possible to recognize at least seven chromatin patterns in a
      mixed population of developing and degenerating neurons. Results are visually
      verified by mapping the original pictures at the corresponding bivariate plot
      points. Comparison with the Markovian texture analysis is discussed.

PMID- 8646833
TI  - Clinical evaluation of the DIABETES expert system for decision support by
      multiple regimen insulin dose adjustment.
AB  - A performance evaluation of the DIABETES rule-based expert system prototype for
      clinical decision making is presented. The system facilitates multiple insulin
      regimen and dose adjustment of insulin dependent Type I or II diabetic patients.
      The study was performed on 600 subjects from two diabetological centres and three
      diabetological offices of Greek hospitals. The responses of the attendant medical
      doctors were compared with those of the DIABETES system, with the aid of a
      specifically devised valuation range (0-5 degrees, 0 indicating full agreement
      and 5 full disagreement). The capabilities and the weakness of the system in
      terms of its practicality for decision support in assisting therapy of diabetes
      mellitus by blood glucose monitoring and subsequent insulin dose adjustment are
      discussed. The potential benefits of decision support systems for diabetic
      patient management are seen to be the cost saving they provide in terms of man
      hours of verbal instruction by medical experts, the support in terms of objective
      and consistent decision making, as well as the recording of medical knowledge in
      the ill-defined field of insulin administration, thus aiding the education and
      training of medical personnel.

PMID- 8646834
TI  - Hinge estimators of location: robust to asymmetry.
AB  - Robust estimators have been developed and tested for symmetric distributions via
      simulation studies. The primary objective of these robust estimators was to show
      that these estimators had a higher efficiency than the sample mean over these
      symmetric distributions. Little attention has been given to how these estimators
      perform on data that are from asymmetric distributions or from distributions that
      have inherent anomalies-so called 'messy data'. This study is intended to
      supplement previous studies by examining the behavior of several robust
      estimators over asymmetric distributions. The objective is to demonstrate several
      adaptive 'asymmetric' robust estimators which utilize sample selector statistics
      to identify the underlying distribution and to demonstrate the efficiency of
      these adaptive estimators. From a methodology point rather than a theoretical
      basis, reasonable alternatives should be available. In the asymmetric data
      distributions faced on a daily basis, estimators that adapt themselves to the
      data may be formulated and used. We recommend the use of the following algorithm
      in examining data sets: (a) compute the ancillary statistics-skewness and tail
      length to classify the data distribution; (b) analyze each data set using at
      least one alternative estimator to the usual XM; (c) if the results are similar,
      report the XM analysis; (d) if the results are dissimilar, report the alternative
      analysis and the reasons for using the alternative analysis (i.e. t-tests based
      on a T alpha, HQ1, HQ2, or SK5).

PMID- 8646835
TI  - Computation of first passage time moments for stochastic diffusion processes
      modelling nerve membrane depolarization.
AB  - For further understanding of neural coding, stochastic variability of interspike
      intervals has been investigated by both experimental and theoretical
      neuroscientists. In stochastic neuronal models, the interspike interval
      corresponds to the time period during which the process imitating the membrane
      potential reaches a threshold for the first time from a reset depolarization. For
      neurons belonging to complex networks in the brain, stochastic diffusion
      processes are often used to approximate the time course of the membrane
      potential. The interspike interval is then viewed as the first passage time for
      the employed diffusion process. Due to a lack of analytical solution for the
      related first passage time problem for most diffusion neuronal models, a
      numerical integration method, which serves to compute first passage time moments
      on the basis of the Siegert recursive formula, is presented in this paper. For
      their neurobiological plausibility, the method here is associated with diffusion
      processes whose state spaces are restricted to finite intervals, but it can also
      be applied to other diffusion processes and in other (non-neuronal) contexts. The
      capability of the method is demonstrated in numerical examples and the relation
      between the integration step, accuracy of calculation and amount of computing
      time required is discussed.

PMID- 8646836
TI  - Application of autoregressive and Fast Fourier Transform spectral analysis to
      tricuspid and mitral valve stenosis.
AB  - Tricuspid and mitral valve flow area was determined from an apical four-chamber
      view. Doppler signals were recorded from normal subjects and patients with
      tricuspid and mitral valve stenosis by using a pulsed Doppler unit. The location
      of sample volume was chosen at the ventricular side of the valve orifice and
      within the right ventricular tract. This was done with the aid of an integrated
      cardiac imaging facility. The analog signal at the output of the Doppler unit was
      sampled and digitized using an analog/digital interface board and transferred to
      a personal computer. The data were then analyzed using the Fast Fourier Transform
      (FTT) and autoregressive (AR) modeling methods of spectral analysis and all the
      sonograms were obtained. Statistical comparison between the FFT and AR methods
      was made. The results show that the AR method offers a superior performance over
      the FFT method as regards the assessment of tricuspid and mitral valve stenosis.

PMID- 8646837
TI  - A telemedicine system for remote cooperative medical imaging diagnosis.
AB  - Telemedicine is changing the classical form of health care delivery, by providing
      efficient solutions to an increasing number of new situations: here we consider
      those which require some type of computer-supported cooperative work (CSCW)
      between health care professionals located in different clinical sites. This paper
      presents the design and development of a telemedicine system for remote computer
      supported cooperative medical imaging diagnosis. The main and novel component of
      our system is a new CSCW distributed architecture, comprised by a collaborative
      toolkit to add audioconferencing, telepointing, window sharing, user's
      coordination and application synchronization facilities, either to existing or
      new medical imaging diagnosis applications. In comparison with existing CSCW
      products, mainly based on centralized architectures, our distributed toolkit is
      specially designed for telemedicine applications: to allow different levels of
      sharing between participants, to improve user feedback in highly interactive user
      interfaces, and to optimize the required communication bandwidth in order to
      implement a telemedicine CSCW application on almost any telecommunication
      network. This telemedicine CSCW system has been applied to build a cooperative
      medical imaging diagnosis application, in which two doctors, located in different
      hospitals, need to achieve a cooperative diagnosis on haemodynamic studies using
      cardiac angiography images. The design of the graphical user interface for this
      kind of telemedicine CSCW systems, a critical component which conforms any
      telemedicine application, is also addressed with a new methodological approach,
      to assure the system usability and final user acceptance. The telemedicine
      cardiac angiography pilot has been implemented, tested and evaluated within the
      Research Project 'FEST-Framework for European Services in Telemedicine' funded by
      EU AIM Programme.

PMID- 8646838
TI  - Computer analysis and plotting of physiologic signals in cardiac muscle research.
AB  - A program (Caphys) for IMB-compatible microcomputers is described which
      facilitates off-line analysis of muscle physiologic signals. Caphys was written
      as an analysis tool for data acquired through AxoTape program (Axon Instruments).
      Parameters for time course and amplitude of isometric contractions and
      intracellularly recorded action potentials are calculated by the program. The
      features of Caphys include low-pass filtering and derivation of the measured
      signals. The programs allows also screen display and printer output of the
      analyzed physiological tracings. Caphys is a suitable extension for the
      commercially available acquisition software, making the analysis and plotting of
      primary physiologic data faster and more efficient.

PMID- 8646839
TI  - Implementation of linear and quadratic discriminant analysis incorporating costs
      of misclassification.
AB  - Discriminant analysis plays an important role in biological and medical research.
      In practice, standard linear and quadratic methods are often applied which assume
      equal costs of misclassification. However, there can be situations where
      misclassifications between certain groups may be more serious than between other
      groups. Such considerations can be taken into account by using classification
      methods which incorporate misclassification costs. The widely applied statistical
      packages BMDP, SAS, and SPSS do not offer the possibility of using unequal
      misclassification costs for discriminant analysis with more than two groups. In
      this paper a menu-driven, user-friendly PC program written in Borland Pascal is
      introduced which performs linear and quadratic discriminant analysis for g > or =
      2 groups allowing for the incorporation of misclassification costs.

PMID- 8646840
TI  - A program for the user-independent computation of the correlation dimension and
      the largest Lyapunov exponent of heart rate dynamics from small data sets.
AB  - We propose a specially optimized computer program for the user-independent
      calculation of the correlation dimension D and the largest Lyapunov exponent L of
      heart rate dynamics on the basis of only 1024 electrocardiographically recorded
      RR intervals (heartbeat intervals). The validity of our program was established
      by analyzing a set of artificial standard signals. Our norm values of the
      correlation dimension (D = 5.37 +/- 0.62) and the largest Lyapunov exponent (L =
      0.561 +/- 0.037 bits/beat) of RR dynamics, obtained from 79 healthy adults aged
      26.3 +/- 4.8 years, were independent of gender and age; D and L correlated
      slightly with each other (Pearson correlation coefficient r = 0.26). Short-term
      reliability, tested for 25 of our subjects by two successive recordings, was
      fair: the intraclass correlation coefficients (ICCs) were 0.45 and 0.41 for D and
      L of RR dynamics, respectively. However, long-term reliability, tested for eight
      of our subjects by ten weekly recordings, was acceptable for L (ICC = 0.40) but
      not for D (ICC = 0.01). These results permit group comparisons on the basis of
      single measurements of L of RR dynamics. A reliable differentiation between young
      healthy individuals requires four measurements of L.

PMID- 8646841
TI  - Automated laboratory protocols.
AB  - A protocol is a program which controls, monitors and modifies the requests for
      laboratory services during the diagnostic work-up and/or monitoring of a patient.
      A protocol language and an OS/2 based system for the compilation, interpretation
      and execution of laboratory protocols written in this language is presented. The
      system is easily interfaced with any patient data base that supports the
      structured query language (SQL). A compiled protocol may be assigned to a patient
      and executed as specified in the protocol itself (regularly and/or when certain
      events such as test requests or arrival of results, occur). In the laboratory
      protocol language a patient's data are viewed as a set of test procedure groups
      each comprising data (request time, result, etc.) describing the status of one or
      more simultaneously made laboratory test requests. A pattern specification is a
      statement saying that a sequence of test procedure groups of specified types and
      ages is present in the data. Pattern specifications are linked to Boolean
      variables. If a pattern matching a pattern specification is found in the
      patient's database the corresponding Boolean variable is set equal to TRUE. The
      Boolean variables are utilized in the decision logic of the protocol.

PMID- 8646842
TI  - Automatic image analysis of antibody assays to measles virus.
AB  - A system for the automatic analysis of 24-well plates used in antibody assays to
      measles virus has been designed and developed based on digitising the information
      on the plate through a CCD camera, displaying the image and then analysing it
      using image processing methods. The system is being used in the analysis of sera
      from individuals vaccinated against measles and has been compared with the
      previous method where the plates were assessed by eye. The results from both
      methods are very similar although the manual method consisted of counting numbers
      of plaques (clear areas in the cells of the plate) and the automatic method
      measured plaque area. The automatic method is much faster than the original
      method and prevents operator fatigue. It does not deal, at present, with
      anomalies such as partially filled wells but could be developed to do so by
      incorporating intelligence into the system.

PMID- 8646843
TI  - VISAUDIO: a Windows software application for Bekesy audiogram analysis and
      hearing research.
AB  - A Windows software system has been designed to facilitate hearing research
      programs and decision aid for epidemiological surveys in a military context.
      VISAUDIO provides graphical displays of audiograms with the results of various
      processing (smoothing, pathological patterns detection and classification),
      audiograms with pathological patterns like scotoms and recruitments are described
      (number, impaired frequencies, severity of loss for scotoms). Classical French
      ORL indexes are calculated (Index 42 which is the French legal index in
      occupational medicine, PAM or Lafon's index, IPA from the French norm NF S31-013
      and IRB, a new occupational medicine index). An audiometric pattern
      classification is done for each audiogram using discriminant factorial analysis.
      The program allows audiogram comparisons on the same screen. The processing and
      analysis results can also be copied to any Windows software package via a PC
      clipboard. This prototype software is to be tested in a quasi real-time
      audiological information system comprising audiogram acquisition, processing,
      analysis and storage in a database. VISAUDIO software functions are illustrated
      with examples of screen displays.

PMID- 8646845
TI  - Mammalian aminoacyl-tRNA synthetases.

PMID- 8646844
TI  - Regulatory features of multicatalytic and 26S proteases.
AB  - It should be clear from the foregoing accounts that our understanding of MCP and
      26S regulation is still rudimentary. Moreover, we have only recently identified
      about a dozen natural substrates of these two proteases. Those outside the field
      may view the situation with some dismay. Those who study the MCP and 26S enzymes
      are provided with rich opportunities to address fundamental questions of protein
      catabolism and metabolic regulation.

PMID- 8646846
TI  - Regulation of interaction between signaling protein CheY and flagellar motor
      during bacterial chemotaxis.

PMID- 8646847
TI  - Chemical biology of nitric oxide: regulation and protective and toxic mechanisms.

PMID- 8646848
TI  - Nutritional and hormonal regulation of glutathione homeostasis.

PMID- 8646849
TI  - Protein folding and association: in vitro studies for self-organization and
      targeting in the cell.

PMID- 8646850
TI  - Calponin.

PMID- 8646851
TI  - Type III cyclic nucleotide phosphodiesterases and insulin action.

PMID- 8646852
TI  - Pseudoatrophic macules: a variant of neurofibroma.
AB  - A 19-year-old man with neurofibromatosis type 1 showed a cutaneous plaque on the
      right scapular area with grayish coloration and atrophic appearance.
      Histopathologic examination demonstrated features of neurofibroma. Dermatologists
      should be aware of this uncommon clinical variant of neurofibroma in order to
      diagnose neurofibromatosis.

PMID- 8646854
TI  - Sweet's syndrome associated with granulocyte colony-stimulating factor.
AB  - Sweet's syndrome has been reported to occur in patients with malignant and
      inflammatory diseases. It may occur as an adverse reaction to the use of drugs,
      particularly the recombinant human granulocyte colony-stimulating factor
      (Filgrastim).

PMID- 8646853
TI  - Kaposi's sarcoma with an intense parasitization by Leishmania.
AB  - Visceral leishmaniasis has been reported as a complication in patients infected
      with human immunodeficiency virus (HIV) who live in areas where leishmaniasis is
      endemic or in patients who have traveled to these areas. Kaposi's sarcoma has
      been found frequently in patients with acquired immunodeficiency syndrome (AIDS).
      We report a HIV-infected patient having visceral leishmaniasis associated with
      Kaposi's sarcoma in which a biopsy specimen obtained from a pigmented cutaneous
      lesion revealed the coexistence of a Kaposi's sarcoma pattern with Leishmania
      parasitic colonization.

PMID- 8646855
TI  - Loose anagen hair syndrome mimicking the uncombable hair syndrome.
AB  - A 7-year-old female presented with messy, difficult to manage scalp hair and
      mild, diffuse alopecia. Hair pull specimens, diagnostic for loose anagen hair
      syndrome, also showed hair shaft abnormalities described in the uncombable hair
      syndrome. We suggest that dysmorphic hair shafts observed on our patient account
      for her clinically unmanageable hair. Pertinent clinical, pathologic, and
      diagnostic features of both syndromes are reviewed.

PMID- 8646856
TI  - A simple method to predict whether topical agents will interfere with
      phototherapy.
AB  - The objective of this study was to assess the potential interference of topical
      agents commonly used in psoriasis with concurrent phototherapy. Twenty-one
      commercially available topical agents were tested. To create solutions from the
      creams, lotions, and ointments, extractions were made using three different
      solvents (95 percent ethanol, hexanes, and 1,4-dioxane) and their absorbance from
      260 to 400 nm was measured. The absorbance value of the solutions at 310 nm was
      used to rank the various agents in terms of potential interference with
      ultraviolet B (UVB) phototherapy. The absorbance at 360 nm was used to rank the
      agents for potential interference with psoralen/ultraviolet A (PUVA) therapy.
      Salicylic acid-containing preparations had substantial absorption in the UVB (280
      to 320 nm) range. The tar-based products had impressive absorbance in both the
      UVA (320 to 400 nm) and UVB ranges. Calcipotriene (Dovonex) showed a maximal
      absorbance in the ultraviolet C (UVC; 200 to 280 nm) and UVB range. Tretinoin
      (Retin-A) had substantial absorbance in the UVA range. Anthralin (Drithocreme)
      revealed maximal absorbance within the UVC and UVB ranges. Topical steroid
      preparations and ammonium lactate (Lac-Hydrin) had low absorbance in both UVB and
      UVA ranges. In conclusion, salicylic acid-containing preparations, tar-based
      products, calcipotriene, anthralin, and most tretinoin preparations should be
      removed before and/or applied after phototherapy.

PMID- 8646857
TI  - Esoteric contact dermatitis. part I: The paraben paradox.

PMID- 8646858
TI  - Onychomycosis.

PMID- 8646859
TI  - Chronic mucocutaneous candidiasis with widespread dermatophyte infection: the
      trailing scale sign.
AB  - The hallmark of cutaneous dermatophyte infection is scaling over an erythematous
      border. Widespread or recalcitrant dermatophyte infections may occur when there
      is underlying immunosuppression. A trailing fringe of scale has been noted in
      these infections. A patient with chronic mucocutaneous candidiasis and widespread
      dermatophyte infection demonstrating trailing scale is presented.

PMID- 8646860
TI  - Solar urticaria: a case report.
AB  - Solar urticaria is a rare disorder characterized by erythema, pruritus, and
      urticaria occurring minutes after exposure to a light source. It is one of
      several photosensitive conditions, such as phototoxic reaction, photoallergic
      reaction, systemic lupus erythematosus, and porphyria, that can cause
      photosensitivity. Herein we report a case of solar urticaria and review the
      rational approaches to its diagnosis and treatment.

PMID- 8646861
TI  - A neutrophilic drug reaction to Clomid.
AB  - A 33-year-old woman treated for infertility with multiple courses of clomiphene
      citrate (Clomid) presented with the complaint of a rash with every course of the
      medication. Examination revealed petechiae and palpable purpura on her lower
      extremities which, histologically, were found to be consistent with a
      neutrophilic drug reaction. The clinical course of this unusual presentation, as
      well as a brief review of the neutrophilic dermatoses, are provided.

PMID- 8646863
TI  - Fluticasone propionate: safety profile.
AB  - Fluticasone propionate is a potent fluorinated corticosteroid used for the
      topical therapy of dermatoses and as inhalation therapy for bronchial asthma and
      allergic rhinitis. This agent has a good safety profile with a low propensity for
      systemic side effects, such as suppression of the hypothalamic-pituitary-adrenal
      (HPA) axis, and a low incidence of local side effects such as pruritus, burning,
      or skin atrophy. The pharmacologic properties of fluticasone propionate-including
      high lipophilicity, high selectivity and affinity for the glucocorticoid
      receptor, low systemic absorption, and rapid metabolism and clearance-combine to
      give fluticasone propionate a high therapeutic index.

PMID- 8646862
TI  - Localized facial telangiectasias following frostbite injury.
AB  - Two patients presented with localized facial telangiectasias a consequence of
      superficial frostbite injury. Trauma from frostbite resulted in the permanent
      formation of these telangiectasias. We review the morphology of the different
      degrees of frostbite and discuss the involvement of angiogenesis as a response to
      tissue insult.

PMID- 8646864
TI  - Comparison of cosmetic and physicochemical properties of six topical
      corticosteroid creams.
AB  - The cosmetic and physicochemical properties of six topical corticosteroid creams
      were evaluated and compared. The following creams were provided in blinded tubes:
      Elocon, Westcort, Lidex, Kenalog, Valisone, and Cutivate. The following
      properties were evaluated in vitro: stiffness (hardness), grittiness, color,
      odor, homogeneity (phase separation), pH, weight loss, and tackiness
      (stickiness). Samples of the creams were evaluated by light microscopy and
      scanning electron microscopy to identify particle and droplet distribution,
      particulate contamination, and microscopic homogeneity of the products. Cutivate
      ranked number 1 in each category and received the best overall score for each of
      the cosmetic and physicochemical properties evaluated. The cosmetic and
      physicochemical properties of Elocon, Westcort, Lidex, and Kenalog were found to
      be similar to one another with regard to overall score but inferior to Cutivate.
      Valisone was also good with regard to overall score but was ranked less
      acceptable due to a strong odor.

PMID- 8646865
TI  - A comparison of twice-daily and once-daily administration of fluticasone
      propionate cream, 0.05%, in the treatment of eczema.
AB  - This multicenter, double-blind, randomized, parallel, four-week, vehicle
      controlled study compared the efficacy and safety of once- and twice-daily
      application of fluticasone propionate cream, 0.05%, over a twenty-eight-day
      treatment period in 238 patients with moderate-to-severe eczema. Clinical
      evaluations, which included the physician's gross assessment, the severity of
      signs and symptoms, and the patient's subjective evaluation, were conducted at
      baseline and at weekly intervals following initiation of treatment. Both
      fluticasone QD and BID were found to be superior to vehicle at each evaluation.
      Application of fluticasone BID was found to be superior to once-daily application
      at day 22 based on the physician's gross assessment, and at days 15 and 22 based
      on the patient's subjective assessment. There were, however, no statistically
      significant differences between QD and BID application at day 8 and at the end of
      the twenty-eight-day treatment period. The results of this study suggest that QD
      application may be recommended for the treatment of moderate-to-severe eczema in
      most patients. As always, treatment effectiveness should be monitored
      periodically and BID application may be necessary to maximize therapeutic
      benefits in some patients.

PMID- 8646866
TI  - Comparison of fluticasone propionate ointment, 0.005%, and betamethasone-17,21
      dipropionate ointment, 0.05%, in the treatment of psoriasis.
AB  - The efficacy, safety, and tolerability of the mid-potency corticosteroid,
      fluticasone propionate ointment, 0.005%, were compared with those of a high
      potency corticosteroid, betamethasone-17,21-dipropionate ointment, 0.05%, in a
      twelve-week randomized, double-blind, parallel-group, multicenter study of
      seventy-four patients with moderate-to-severe psoriasis. Efficacy was evaluated
      for four weeks; safety was evaluated over a twelve-week period. Fluticasone
      ointment, 0.005%, was not significantly different from betamethasone ointment,
      0.05%, at day 15 (P = 0.147), at the end of treatment analysis (P = 0.245), or at
      day 29 (P = 0.154). Neither medication resulted in any abnormal laboratory values
      over the twelve-week study period, including plasma cortisol levels. Both
      medications were well tolerated.

PMID- 8646868
TI  - A comparison of fluticasone propionate ointment, 0.005%, and hydrocortisone-17
      butyrate ointment, 0.1%, in the treatment of psoriasis.
AB  - The efficacy and safety of twice-daily topical application of fluticasone
      propionate ointment, 0.005%, and hydrocortisone-17-butyrate ointment, 0.1%, were
      compared in 113 adult patients with moderate-to-severe psoriasis in a
      multicenter, double-blind, randomized, parallel study. The majority of patients
      had psoriatic involvement of long duration over a large body surface area (mean,
      17%). The following efficacy assessments were made at weekly intervals for up to
      four weeks following initiation of treatment: physician's gross assessment of
      clinical response of the target lesion; severity of psoriatic signs and symptoms;
      and patients' assessment of treatment effects. Safety was assessed by monitoring
      and reporting any adverse events that occurred during the study. Fluticasone
      propionate ointment, 0.005%, was found to be therapeutically superior to
      hydrocortisone-17-butyrate ointment, 0.1%, as well as safe and well tolerated.
      Its onset of action was rapid and no systemic adverse effects occurred. Overall
      patients experienced progressive improvement with fluticasone propionate
      ointment, 0.005%.

PMID- 8646867
TI  - A comparison of the safety, tolerability, and efficacy of fluticasone propionate
      ointment, 0.005%, and betamethasone-17,21-dipropionate ointment, 0.05%, in the
      treatment of eczema.
AB  - A randomized, double-blind, parallel group study involving thirteen centers
      compared the safety, tolerability, and efficacy of twice-daily applications of
      fluticasone propionate ointment, 0.005%, and betamethasone-17, 21-dipropionate
      ointment, 0.05%, in ninety-two patients with moderate-to-severe eczema. Safety
      assessments included routine clinical laboratory evaluations, morning plasma
      cortisol levels, and reporting of adverse events. Efficacy assessments included
      (1) physician's gross assessment of clinical response of the target lesion, (2)
      severity of signs and symptoms of eczema, and (3) patients' assessment of
      treatment effects. Both treatments were well tolerated and showed minimal
      suppression of the hypothalamic-pituitary-adrenal axis as evidenced by morning
      plasma cortisol concentration determinations. Statistically significant
      improvement in the severity of each sign/symptom was found as early as two weeks
      following treatment initiation in both groups. The two treatments were found to
      be similar following two and four weeks of therapy with regard to almost all
      efficacy variables.

PMID- 8646869
TI  - Topical corticosteroids in clinical practice: focus on fluticasone propionate.
AB  - Topical corticosteroids are the most widely used agents for the treatment of
      inflammatory skin disease, particularly atopic dermatitis and psoriasis. In
      selecting the most appropriate steroid preparation to use-among the vast array
      currently available-the clinician must consider the severity and localization of
      the disease, the risk of drug-induced adverse reactions, the age of the patient,
      and the potency of the various agents. Due to differences in bioavailability, the
      vehicle and application technique of corticosteroids must also be evaluated.
      Numerous clinical trials have demonstrated that fluticasone propionate-a
      fluorinated corticosteroid-is effective, safe, well tolerated, and offers the
      advantage of a low potential for systemic and local side effects.

PMID- 8646870
TI  - Comparison of safety and efficacy of fluticasone propionate cream, 0.05%, and
      betamethasone valerate cream, 0.1%, in the treatment of moderate-to-severe
      psoriasis.
AB  - Investigators conducted two double-blind, randomized, parallel-group trials to
      compare the efficacy of fluticasone propionate cream, 0.05%, and betamethasone
      valerate cream, 0.1%, in the treatment of moderate-to-severe psoriasis. Up to 100
      gm/week of the study medication was applied topically to affected areas of the
      body twice daily for up to four consecutive weeks. Efficacy and safety were
      evaluated after seven, fourteen, twenty-one, and twenty-eight days of treatment.
      The data from the participating sites show that fluticasone propionate cream,
      0.05%, was as efficacious as betamethasone valerate cream. Investigators found no
      statistically significant differences between the two products by any of the
      three variables used to gauge efficacy (P > 0.05). Drug-related adverse events
      were few and mild. These findings support the conclusion that fluticasone
      propionate cream, 0.05%, is effective and well tolerated when used to treat
      moderate-to-severe psoriasis and is comparable to a widely used midpotency
      topical steroid.

PMID- 8646871
TI  - Comparison of fluticasone propionate cream, 0.05%, and hydrocortisone-17-butyrate
      cream, 0.1%, in the treatment of eczema.
AB  - This is a randomized, double-blind, parallel-group, multicenter study involving
      120 patients comparing the safety and tolerability of two midpotency topical
      preparations, fluticasone propionate cream, 0.05%, and hydrocortisone-17-butyrate
      cream, 0.1%, in the treatment of moderate-to-severe eczema. Safety of the study
      medications was determined over a twelve-week period using laboratory tests for
      selected fasting blood chemical levels, hematologic analysis, urinalysis, and
      morning plasma cortisol levels, and by analyzing both the nature and frequency of
      reported adverse events. Efficacy was evaluated during the first four weeks of
      the study. None of the fluticasone-treated patients experienced any severe drug
      related adverse events, but one hydrocortisone-17-butyrate-treated patient's
      eczema was severely exacerbated by drug therapy. Plasma cortisol monitoring
      revealed minimal hypothalamic-pituitary-adrenal axis suppression. Overall, the
      nature of drug-related adverse events in patients as young as 12 years old
      treated with fluticasone propionate cream, 0.05%, indicates this topical
      application was safe and well tolerated throughout the twelve-week study.
      Fluticasone cream was also found to be similar in efficacy to hydrocortisone-17
      butyrate cream.

PMID- 8646872
TI  - Efficacy and safety of fluticasone propionate 0.005% ointment in the treatment of
      psoriasis.
AB  - Two multicenter, double-blind, randomized, vehicle-controlled parallel-group
      trials involving 388 patients were conducted to compare the efficacy and safety
      of fluticasone propionate 0.005% ointment to those of its vehicle in the
      treatment of moderate-to-severe psoriasis. The study medication (up to 100
      gm/week) was applied topically to the affected target areas of the body twice
      daily for up to four consecutive weeks. Efficacy and safety were evaluated after
      one, two, three, and four weeks of treatment. In both studies, fluticasone
      ointment was clearly shown to be superior to vehicle throughout the four weeks of
      treatment. At the end of the treatment period, the superiority of fluticasone
      ointment was statistically significant for all efficacy measures. At the end of
      study 1, the skin of ten of eighty-eight patients (11%) who received fluticasone
      were rated as cleared by the investigators and fifty (57%) were rated as
      excellent or good. Of those who received vehicle, the skin of one of ninety (1%)
      was rated cleared and twenty-five (28%) were rated excellent or good. In study 2,
      the skin of three of 105 (3%) patients who received fluticasone were rated as
      cleared and sixty-nine (66%) were rated as excellent or good at the end of the
      study. Of those who were treated with vehicle, no patient's skin was rated
      cleared and thirty of 100 (30%) were rated excellent or good. Adverse events were
      few and mild. The most common drug-related adverse events were burning and
      pruritus at the site of application, which occurred in 6% of both the fluticasone
      treated patients and those who received vehicle. These findings support the
      conclusion that fluticasone, 0.005%, ointment is clinically superior to its
      vehicle in the treatment of psoriasis.

PMID- 8646874
TI  - Report of the Third International Workshop on Human Chromosome 12 Mapping 1995.

PMID- 8646873
TI  - Efficacy and safety of fluticasone propionate ointment, 0.005%, in the treatment
      of eczema.
AB  - The clinical efficacy and safety of fluticasone propionate ointment, 0.005%, were
      compared with those of its vehicle in the treatment of moderate-to-severe eczema
      of long duration in two multicenter, double-blind, vehicle-controlled, randomized
      studies. One of the two study medications (up to 100 gm/week) was applied
      topically to the affected areas of the body twice daily for up to four
      consecutive weeks. Drug efficacy was measured in terms of three variables: the
      physician's gross assessment of clinical response of the target lesion, severity
      scores of individual signs and symptoms, and the patient's subjective assessment
      of treatment effects. Efficacy and safety were evaluated after seven, fourteen,
      twenty-one, and twenty-eight days of treatment. The total number of patients in
      the two studies was 372 (203 in study 1 and 169 in study 2). Fluticasone
      propionate ointment, 0.005%, was more effective than vehicle at all postbaseline
      visits in both studies (study 1 P < or = 0.015, study 2 P < or = 0.018). In study
      1, approximately 80% of the patients on fluticasone were rated as cleared,
      excellent, or good by the investigators at treatment endpoint, compared with 38%
      of those receiving vehicle. In study 2, the sum of 80% of the fluticasone-treated
      patients was rated as cleared, excellent, or good by the investigators at the end
      of the study, compared with 34% of those receiving vehicle. The beneficial effect
      of fluticasone ointment, 0.005%, was early and sustained and was particularly
      noticeable for pruritus, erythema, and skin thickening. In study 1, no drug
      related adverse events were reported in the fluticasone group. Four patients
      (4.3%) in the vehicle group experienced a total of four drug-related adverse
      events. The most common was burning/stinging, reported by two patients. In study
      2, two patients (2.4%) in the fluticasone-treated group and three (4.1%) in the
      vehicle group reported a total of five drug-related adverse events, the most
      common event being pruritus (fluticasone group one patient, vehicle group two
      patients). These findings show that fluticasone propionate ointment, 0.005%,
      applied twice daily, is therapeutically superior to the vehicle and is well
      tolerated.

PMID- 8646875
TI  - Chromosomal mapping of the genes for the human CDK2/cyclin A-associated proteins
      p19 (SKP1A and SKP1B) and p45 (SKP2).
AB  - Many gene products associated with the cyclin-dependant kinases (CDKs) have been
      shown to regulate the active kinase complex during the transition points of the
      cell cycle. Some of these proteins have been implicated in human neoplasia,
      acting as either oncoproteins or tumour suppressors. The CDK2/cyclin A kinase
      complex can complex with several proteins, including p21, and PCNA or p45, p19,
      and p9. It was previously shown that at least two of these proteins, p19 and p45,
      are abnormally regulated in transformed cell lines. We describe here the mapping
      by fluorescence in situ hybridization of the gene for the CDK2/cyclin A
      associated protein p45 (SKP2) to 5p13 and the p19-related genes p19A (SKP1A) and
      p19B (SKP1B) to 7q11.2 and 12p12, respectively. All three of these loci are
      associated with karyotypic alterations, known amplifications, or suspected tumor
      suppressor genes.

PMID- 8646876
TI  - Spatial distribution of sex chromosomes and ribosomal genes: a study on human
      lymphocytes and testicular cells.
AB  - The location of the sex chromosomes in relation to the rRNA genes in the nuclei
      of human lymphocytes and testicular cells was examined. Sex chromosomes were
      found to be located closer to ribosomal genes than would be expected assuming a
      random arrangement of these chromosomes with respect to rRNA genes. This
      proximity could be observed irrespective of the transcriptional activity of
      ribosomal genes indicating that the chromosomal material and not transcriptional
      activity is responsible for the intranuclear order of these chromosomes.

PMID- 8646877
TI  - Fine mapping of human HOX gene clusters.
AB  - The chromosome localization of human HOX gene clusters has been reinvestigated by
      fluorescence in situ hybridization (FISH). Three loci were precisely localized in
      7p15.3 (HOXA@), 17q21.3 (HOXB@) and 12q13.3 (HOXC@). The localization of HOXD@
      was confirmed to 2q31.

PMID- 8646878
TI  - Chromosomal evolution in duiker antelope (Cephalophinae: Bovidae): karyotype
      comparisons, fluorescence in situ hybridization, and rampant X chromosome
      variation.
AB  - Fluorescence in situ hybridization (FISH) and conventional banding techniques
      were used to identify patterns of similarity among the genomes of six species of
      antelope, subfamily Cephalophinae. The G-banded euchromatic portions of the
      autosomes were invariable in all species; however, significant modifications of
      the X chromosomes were detected. Two of the taxa, Cephalophus maxwellii and C.
      monticola, were characterized by acrocentric X's, while X chromosome morphology
      varied from submetacentric to metacentric in the remaining species (C. dorsalis,
      C. natalensis, Sylvicapra grimmia, and C. silvicultor). The short arm of the X
      was heterochromatic in each species. Total genomic DNAs from these antelope were
      used as hybridization probes against Cephalophus metaphase chromosomes and
      resulted in robust fluorescence in the pericentromeric region of each autosome
      and in the heterochromatic short arm of the X chromosome, indicating
      complimentarity of DNA sequences in these regions. Conversely, chromosome
      painting involving genomic DNAs derived from the subfamilies Alcelaphinae
      (Pygargus dorcas) and Neotraginae (Oreotragus oreotragus) showed a marked absence
      of hybridization at these sites. Additionally, X chromosome comparisons between
      the Cephalophinae and Bovinae (represented by Bos taurus) revealed two
      euchromatic pericentric inversions which had occurred since their common
      ancestry. There is good G-band homoeology between the inverted cattle chromosome
      region Xq12 --> q34 and most of the proximal portion of Xq in duikers, as well as
      between the distal third of the duiker Xq and the cattle Xp. The latter
      rearrangement was further confirmed by in situ hybridization using a probe
      containing an insert spanning bands p12 to p14 of the cattle X chromosome.

PMID- 8646879
TI  - A stable marker chromosome with a cryptic centromere: evidence for centromeric
      sequences associated with an inverted duplication.
AB  - Centromere activation, an important mechanism in karyotype evolution, is
      occasionally observed in some human chromosome rearrangements. We report a
      possible occurrence of centromere activation in a marker chromosome containing an
      atypical centromere associated with an inverted duplication of the region 14q32 -
      > qter. The marker chromosome's reduced centromere lacks both the alpha and beta
      satellite sequences usually found at normal centromeres. In an attempt to
      identify the centromeric sequences, the marker chromosome was flow-sorted and
      amplified by a degenerate oligonucleotide primer polymerase chain reaction.
      Reverse chromosome painting experiments showed that the marker chromosome
      contains sequences that are unique to the distal region of chromosome 14, as well
      as a low copy number of (centromeric) sequences that are also highly represented
      in the centromeres of chromosomes 18 and 19. These data suggest the activation of
      a novel centromere in the 14q32 --> qter region, very likely consequent to the
      duplication of the region itself.

PMID- 8646880
TI  - Isolation and mapping of a human gene (RPD3L1) that is homologous to RPD3, a
      transcription factor in Saccharomyces cerevisiae.
AB  - We have isolated a novel human gene RPD3L1, that is highly homologous to a
      transcription factor in Saccharomyces cerevisiae, RPD3 (reduced potassium
      dependency 3), from a human fetal lung cDNA library. The cDNA clone, hRPD3,
      consists of 2,100 nucleotides that contain an open reading frame of 1446
      nucleotides encoding 482 amino acids. It shares 62% identity in nucleotide
      sequence and 52% identity in amino acid sequence to RPD3. This gene is expressed
      at various levels in all tissues examined. Furthermore, we were able to map it to
      chromosome band 1p34.1 by FISH.

PMID- 8646881
TI  - Isolation and characterization of a human cDNA clone (GCN5L1) homologous to GCN5,
      a yeast transcription activator.
AB  - We have isolated a novel human cDNA with a predicted amino acid sequence
      homologous to GCN5, a protein considered to be a regulator of transcriptional
      activation in yeast. This cDNA, termed GCN5L1 (GCN5-like 1), consists of 545
      nucleotides including an open reading frame of 378 bp that encodes a 126-amino
      acid peptide having 23.5% identity to yeast GCN5. Northern-blot analysis revealed
      transcription of this gene in all human tissues examined. We isolated a genomic
      clone corresponding to this cDNA from a human cosmid library and mapped it to
      chromosome 12q13 --> q14 by fluorescent in situ hybridization (FISH).

PMID- 8646882
TI  - Isolation and mapping of a human gene (RABL) encoding a small GTP-binding protein
      homologous to the Ras-related RAB gene.
AB  - Many subgroups of the RAB gene, a member of the RAS superfamily have been
      identified. Here we report the isolation and analysis of a cDNA encoding a
      putative small GTP-binding protein, designated RABL, from a human fetal lung cDNA
      library. RABL encodes 216 amino acids that are 86% identical to members of the
      RAB5 subfamily and it shows 94% homology in nucleotide sequence with RAB5C of
      dog. This gene was expressed ubiquitously in all human tissues examined. By
      fluorescence in situ hybridization we mapped RABL to chromosome band 17q21.2.

PMID- 8646883
TI  - An extended nomenclature of the canine karyotype.
AB  - In contrast to many other animals, knowledge about the canine karyotype is quite
      sparse. This is due in part to the rather difficult canine karyotypic pattern.
      Except for the X and the Y chromosome, there are only acrocentric chromosomes,
      which appear to be quite small and difficult to identify unambiguously. In
      previous reports, schematic representations of the canine karyotype have been
      described. However, a nomenclature comparable to that of the human karyotype or
      the karyotypes of sheep, cattle, or goats does not yet exist for the dog. Based
      on high-resolution banding of metaphase chromosomes from canine fibroblasts, we
      propose an ideogram of the canine karyotype with 460 numbered bands and
      characteristic landmarks. In addition, the centromere positions of the canine
      chromosomes are determined by a combined GTG-banding/FISH approach, and the R-
      and G-banding patterns are compared.

PMID- 8646885
TI  - Chromosomal localization of the major and 5S rRNA genes in the European eel
      (Anguilla anguilla).
AB  - The major (18S, 5.8S, and 28S) and 5S rRNA genes have been mapped by double
      fluorescent in situ hybridization to European eel metaphase chromosomes. The
      major rRNA genes were localized to a submetacentric pair of chromosomes that
      showed a consistent size polymorphism among the individuals studied. The 5S rRNA
      genes were clustered in a single locus that mapped to the centromeric region of
      an acrocentric pair. In contrast to the major rRNA genes, no detectable
      polymorphism, in either size or intensity of the fluorescent signal, was
      observed. The chromosomal organization of both families of rRNA genes are
      discussed in terms of genomic organization and chromosomal evolution.

PMID- 8646884
TI  - Assignment of the human gene for receptor-type protein tyrosine phosphatase IA-2
      (PTPRN) to chromosome region 2q35 --> q36.1 and identification of an intragenic
      genetic marker.
AB  - Using a mouse protein tyrosine phosphatase cDNA fragment as a probe, cosmid
      clones containing segments of the human IA-2 PTPase gene (PTPRN) were isolated.
      The gene was assigned to chromosome region 2q35 --> q36.1 by fluorescence in situ
      hybridization. In an intronic region of the IA-2 gene a polymorphic
      microsatellite sequence was found, which will be useful as a genetic marker for
      the 2q35 --> q36 region.

PMID- 8646886
TI  - Cloning, expression, and mapping of TCTEL1, a putative human homologue of murine
      Tcte1, to 6q.
AB  - From a human fetal-brain cDNA library we isolated a putative human homologue of
      the murine Tcte1 gene. The cDNA, designated TCTEL1, contained an open reading
      frame of 339 nucleotides encoding 113 amino acids. The predicted peptides of
      TCTEL1 showed 94% and 55% identity (100% and 94% similarity) with those of murine
      Tcte1 and human RP3. Northern-blot analysis revealed a 0.9-kb transcript in all
      tissues examined. This gene was mapped by FISH to chromosome bands 6q25.2 -->
      q25.3, the syntenic region of the murine t-complex locus of chromosome 17.

PMID- 8646887
TI  - Report of the International Meeting on Chromosome 12 Genes in Cancer.

PMID- 8646889
TI  - The 21q22.1 STS marker, VN02 (EST00541 cDNA), is part of the 3' sequence of the
      human Na+/myo-inositol cotransporter (SLC5A3) gene.
AB  - The human osmoregulatory Na+/myo-inositol cotransporter gene (SLC5A3) was
      recently cloned and localized to the region of 21q22. Fine mapping of this gene
      was accomplished by identifying YAC clones that contain SLC5A3 and utilizing
      known STS markers for 21q22.1 and 21q22.2 sub-bands that map to the positive YAC
      clones. Two bacteriophage P1 clones containing the SLC5A3 gene gave a positive
      PCR product when screened with the 21q22.1 marker VN02, an expressed sequence tag
      (EST00541). Through DNA sequence analysis, it was determined that this STS marker
      if part of the 3' untranslated region of the SLC5A3 gene.

PMID- 8646888
TI  - Report of the Second International Workshop on Y Chromosome Mapping 1995.

PMID- 8646890
TI  - Assignment of the gene for rat thromboxane receptor (Tbxa2r) to chromosome 7q11
      by fluorescence in situ hybridization.
AB  - Thromboxane plays physiological and pathophysiological roles in many tissues.
      Recently, we cloned a cDNA for rat kidney thromboxane receptor (Tbxa2r) and
      showed that Tbxa2r is expressed in the renal glomerulus, vasculature, and
      transitional cell epithelium of renal pelvis. Here, we map the gene for this
      receptor (Tbxa2r) to rat chromosome 7q11 by fluorescence in situ hybridization.

PMID- 8646891
TI  - Fine mapping of the autosomal recessive retinitis pigmentosa locus (RP12) on
      chromosome 1q; exclusion of the phosducin gene (PDC).
AB  - In a previous study on a large pedigree from a genetically isolated population in
      the Netherlands, we localized a gene for autosomal recessive retinitis pigmentosa
      with paraarteriolar preservation of the retinal pigment epithelium (PPRPE) on the
      long arm of chromosome 1. In this study, we present an integrated genetic map of
      the target region. The resulting genetic order of the markers was used to
      construct haplotypes and to screen for key-recombinants in the pedigree. The
      obligate RP12 region was reduced from 16 cM to 5 cM between the markers D1S533
      and CACNL1A3. The CACNL1A3 and phosducin (PDC) genes were placed outside the
      candidate gene region, thereby excluding the involvement of these genes in
      retinitis pigmentosa with PPRPE. Our data result in the following order of the
      markers and genes in the region 1q31 --> q32.1: cen-D1S158-(D1S238-D1S422)/PDC-
      D1S533-RP12/(F13B-D1S413)-CACNL1A3-DIS4 77-D1S306-D1S53-tel.

PMID- 8646892
TI  - Copy numbers of a clustered long-range repeat determine C-band staining.
AB  - A cluster of long-range repeats (LRRs) with a repeat size of roughly 100 kb is
      part of band D of chromosome 1 of the house mouse, Mus musculus. The cluster is
      cytogenetically polymorphic: it is either C-band negative or C-band positive. Our
      results show that the differential staining behavior depends on the LRR copy
      number and not on differences in DNA composition. There is a threshold between
      105 and 175 LRR copies per haploid genome; clusters with lower copy numbers stain
      C-band negative, whereas those with higher copy numbers are C-band positive.
      Above this threshold, the size of the C-band is linearly correlated with the LRR
      copy number. The results imply that sequences capable of forming heterochromatin
      may be dispersed throughout the genome but are not recognized as such by
      cytogenetic techniques, unless they reach the threshold amount and concentration.

PMID- 8646893
TI  - Molecular anatomy of human chromosome 9: comparative mapping of the
      immunoglobulin processed pseudogene C epsilon 3 (IGHEP2) in primates.
AB  - Karyotypic homology in relation to human chromosome 9 (HSA 9) was studied through
      comparative mapping of the immunoglobulin-processed pseudogene C epsilon 3
      (IGHEP2) in primates. IGHEP2, which has been mapped to 9p24.2 --> p24.1 in the
      human genome, was assigned to PTR 11q34 (common chimpanzee), PPA 11q34 (pygmy
      chimpanzee), PPY 13q16 (orangutan), HLA 8qter (white-handed gibbon), HAG 8qter
      (agile gibbon), and MFU 14q22 (Japanese macaque) by fluorescence in situ
      hybridization. To verify the breakpoints of presumed pericentric inversions on
      the ancestral great ape chromosomes, three DNA markers on HSA 9, cCI9-37 (9q22.1 
      -> q22.2), cCI9-135 (9q22.32 --> q22.33), and cCI9-208 (9p13.3 --> p13.2), were
      also assigned to PTR/PPA 11p11 (cCI9-37 and 135), PTR/PPA 11q22 (cCI9-208), PPY
      13q22 (cCI9-37 and 135), and PPY 13q12 (cCI9-208). These data more clearly define
      the position of the breakpoints of pericentric inversions that occurred in the
      human-chimp ancestral and chimpanzee ancestral chromosomes and support the
      hypothesis of HSA 9 genesis previously derived from banding analyses of HSA 9 and
      its homologs.

PMID- 8646894
TI  - The human gene encoding the heavy chain of the major histocompatibility complex
      class I-like Fc receptor (FCGRT) maps to 19q13.3.
AB  - FcRn is an Fc receptor that structurally resembles the major histocompatibility
      complex class I molecule. In this study, we isolated the human gene encoding the
      heavy chain of FcRn (FCGRT) and mapped it by fluorescence in situ hybridization
      to chromosome band 19q13.3. Thus, like its mouse counterpart, the human FCGRT
      gene is located outside the major histocompatibility complex.

PMID- 8646896
TI  - Video and computer games in the '90s: children's time commitment and game
      preference.

PMID- 8646895
TI  - Assignment of the human tryptophanyl-tRNA synthetase gene (WARS) to chromosome
      14q32.2 --> q32.32.
AB  - Tryptophanyl-tRNA synthetase catalyzes the aminoacylation of tRNAtrp with
      tryptophan, an essential function in the cell's protein synthesis machinery. It
      has been shown that tryptophanyl-tRNA synthetase is induced by interferon, and
      this has led to hypotheses about other possible functions of tryptophanyl-tRNA
      synthetase. We have mapped a cDNA probe of the tryptophanyl-tRNA synthetase gene
      (WARS) by a combination of somatic cell hybrid analysis, fluorescence in situ
      hybridization (FISH), and linkage analysis. Both FISH and linkage analysis
      independently supported a more distal position of WARS than had been previously
      reported. FISH mapping indicated a most likely location at 14q32.31. Linkage
      analysis was based on the 40 reference families from the CEPH collaboration and
      resulted in a 13-point map, placing WARS, with odds of more than 1,000:1, within
      an area of approximately 10 cM and, with odds of 198:1, in an approximately 6 cM
      interval between pCMM101 and D14S27. The study provides additional integration of
      the physical and genetic maps of the distal part of 14q, as well as genetic tools
      enabling a more complete understanding of the function of tryptophanyl-tRNA
      synthetase, especially with regard to the cryptic inducibility of interferon.

PMID- 8646897
TI  - [A case of inveterate metacarpo-phalangeal dislocation of the thumb treated
      surgically by the Kessler method].
AB  - A case of inveterate dorsal dislocation of the MCP joint of the thumb treated by
      open reduction and tendon reinforcement of the volar capsule. The paper reports
      rare cases of inveterate, complete dorsal dislocation of the thumb MCP joint.
      After open reduction there was a full passive flexion but dorsal dislocation
      recurred. The tendency to return of dislocation was abolish by tendon
      reinforcement of the capsule of the joint described by Kessler. Follow up studies
      revealed no significant instability, the range of motion was between 20 degrees
      and 55 degrees of flexion.

PMID- 8646898
TI  - [Use of a fascia-cutaneous island flap based on the posterior interosseus artery
      of the forearm--a case report].
AB  - The use of fascia-cutaneous island flap based posterior interosseous of the
      forearm to cover cutaneous defect of the thumb after resection of the scar is
      presented. Loss of the posterior interosseous artery does not influence adversely
      circulation of the hand. Preparation of is technically demanding; unsightly scar
      on the dorsal forearm restricts its use in women. The flap is being used in
      secondary repairs.

PMID- 8646899
TI  - [Present views on nonoperative treatment for idiopathic scoliosis].
AB  - The authors have presented valid modern procedure principles in nonoperative
      treatment of idiopathic scoliosis. It was referred to classification based on
      infantile, juvenile and adolescent scoliosis, discussing in each of them
      indications and treatment modes. Beside own experiences were cited many important
      observations of other authors and it was pointed out, that success of
      nonoperative treatment is variable and is being based on individual experience of
      many orthopaedic surgeons, and requires critical analysis of their procedure.
      Long follow up period of children with scoliosis, bracing and precise X-rays
      evaluation requires not only surgeons patience but also that of treated children
      and their parents. Arduous and apparently ineffectively treatment enable in many
      cases avoidance of serious spine surgery.

PMID- 8646900
TI  - [vertebral and spinal cord tumors associated with scoliosis and kyphosis].
AB  - Eighteen cases of vertebral and spinal cord tumors associated with spine
      deformity are included in this study. Thoracic spine was involved most
      frequently. Neurological deficits were found in 14 patients. Surgical management
      was carried out in 14 cases. In 4 patients with complete transversal spine lesion
      percutaneous needle biopsy was done to establish the diagnosis. Surgery was
      supplemented by radiotherapy or radiotherapy and chemotherapy in 10 cases.
      Neurological improvement was found in 15 cases.

PMID- 8646901
TI  - [Orthopedic problems in children after surgical treatment for lipoma of the conus
      medullaris].
AB  - Deformities locomotor system in 24 children who have been operated on because of
      lipoma of conus medullaris are presented. At follow-up examination 6 patients
      were deformity free. The remaining group had feet deformities either present at
      birth or developed on average in 19th month of life. They mostly progressed and
      tended to recur after surgical correction. Trophic skin ulcer or chronic
      osteomyelitis of the foot was present in 30% of children; in 17% of cases they
      induced amputation. In 60% of cases scoliosis was found with mean angle of 10.2
      degrees.

PMID- 8646902
TI  - [A case of spinal hemangioma uncommonly located within spinous processes and
      laminae of Th12].
AB  - Uncommonly located hemangioma within processus of spines and laminae of Th12 in
      25 years old female is presented. Neurological deficits resulted from meningeal
      compression. After surgical resection en bloc and subsequent radiotherapy
      neurological symptoms resolved.

PMID- 8646903
TI  - [The importance of medical history taking in diagnosis of shoulder arthropathy].
AB  - The data collected at taking medical history were analyzed on the basis of
      clinical, radiographic and sonographic differential diagnosis in shoulder
      pathology. Material included 236 patients. Hedtmann and Fett classification has
      used. Age of the patient, duration of the condition and its relation to the
      trauma in a broad meaning are of paramount importance. The authors recommend
      sonographic examination in all cases of shoulder contusion with no bony
      abnormalities on radiographs and in all cases of anterior shoulder dislocation in
      order to assess rotator cuff condition.

PMID- 8646904
TI  - [Long-term clinical assessment of the hip joint after conservative treatment for
      development dislocation complicated by avascular necrosis].
AB  - Clinical assessment of 61 hips in 36 adult patients treated in the past
      nonoperatively due to developmental dislocation of hip and affected with
      avascular necrosis of the proximal femur has been used as a base to present the
      fate of these joints. An attempt to relate the of avascular necrosis and clinical
      symptoms at the termination of growth has been made; clinical and radiographic
      examinations were compared with each other. At the final evaluation 30 excellent
      results were found, 20 good, 8 fair, and 3 cases were rated as poor. Clinical
      symptoms (pain, limp, extremity shortening, Trendelenburg and Duchenne signs)
      were present chiefly in cases of the most severe avascular necrosis of the
      femoral head and neck; in majority of patients clinical symptoms were present.
      Clinical outcome was usually more satisfactory than radiological one. Severity of
      avascular necrosis and deformity that followed clearly determined final clinical
      outcome.

PMID- 8646906
TI  - [A contribution to treatment of avulsion fracture of the ischial tuberosity].
AB  - Background of the injury and of treatment in two 15 years old girls with avulsion
      fracture of the ischial tuberosity are presented. The first case with little
      displacement good result has been achieved after conservative treatment; the
      second one required surgery 1.5 year due to great displacement, non-union and
      persistent pain; ischial tuberosity has been removed successfully.

PMID- 8646905
TI  - [Anatomy and development of the hip joint during growth. II. Anatomy and
      development of the proximal femur].
AB  - Anatomy and development of proximal femur during growth is discussed on the basis
      of vast literature. The issue of proximal femur growth zones and factors
      determining normal growth, that is static and kinetic forces within loaded joint
      and kinetic forces within loaded joint and muscle function are presented.

PMID- 8646907
TI  - [Fascial and fasciocutaneous flaps for treatment of posterior and distal area of
      the lower leg and heel area].

PMID- 8646908
TI  - [Surgical treatment for hallux valgus by metatarsal I osteotomy and soft tissue
      reconstruction in the area of the forefoot].
AB  - A series of 39 surgeries for hallux valgus has been analyzed. All cases had
      deformity exceeding 40 degrees (mean 61 degrees). Metatarsal I osteotomy has been
      supplemented with soft tissue reconstruction. McBride reconstruction and second
      toe extensors transfer were done in 32 cases; the best results were achieved in
      this group of patients.

PMID- 8646909
TI  - [Surgical treatment for cleft foot].
AB  - The methods and results of treatment of 13 cleft foot in 8 patients are
      presented. An approximating dexon-polyester suture has been used in Blauth I
      deformity. Joplin procedure (resection of the intermediate cuneiform) has been
      done in grade III deformities. If hallux valgus coexisted an arthrodesis of
      interphalangeal joint has been performed. Family history of hand and foot
      deformity in one case might prove genetic theory of autosomal dominant
      inheritance. At follow-up examination mean 11 years after surgery satisfactory
      cosmetics, efficient gait and standard shoes fitting were found.

PMID- 8646910
TI  - [Reduced loading of one lower limb as a cause of local osteopenia].
AB  - An impact of diminished mechanical loading of lower extremity on bone
      densitometry has been quantitatively assessed with ultrasound. Seventy-three
      females with lower limb fracture history, coxarthrosis or scoliosis were
      evaluated. Both heels were submitted to measurements with Achilles densitometer
      (Lunar, USA). The following parameters were analyzed: Speed of Sound, Broadband
      Ultrasound Attenuation and Stiffness Index. Decreased values of all parameters
      were found in unloaded extremities. Speed of Sound was reduced most and in the
      group with fracture history. To avoid local bone loss short immobilization, early
      rehabilitation and pharmacotherapy is suggested.

PMID- 8646912
TI  - ["Second opinion"--attempt at establishing a definition].

PMID- 8646911
TI  - [Long-term results of treatment for chondrosarcoma].
AB  - A series of 24 patients treated for chondrosarcoma between 1974 and 1991 is
      presented and compared with findings on patients treated from 1947 to 1973.
      Eleven patients were treated surgically alone, 7 were submitted to combined
      therapy (surgery and chemotherapy), in 6 cases palliative treatment was used. The
      survival after surgery ranged from 6 months to 23 years. Eleven patients died
      within 1 year after operation. Four patients lived longer than 5 years. Early
      diagnosis and treatment were prerequisites for good result. Radical resection of
      the tumor combined with chemotherapy resulted in extending patient's life;
      amputation had no such effect.

PMID- 8646913
TI  - [German clinical journals and the impact factor].

PMID- 8646914
TI  - [General aspects of organ donation].
AB  - The general and surgical aspects of organ donation are of great relevance for
      every surgeon in every hospital, as potential organ donor situations occur in
      every intensive care unit. Typical organ donors are patients suffering from
      intracerebral bleeding. There is no upper age limit. The implementation of a
      potential organ donor program is the indirect responsibility and task of every
      hospital in order to serve the patients waiting in the geographical region of the
      hospital; organs retrieved in another region should be available for patients in
      that other region. The general aspects of organ donation concern, for example,
      the question of the legal aspects of brain death and adequate surgical procedures
      concerning the dignity of the donor. The surgical aspects include a highly
      standardized technique using only aortal flush at an early stage of the operation
      without major manipulation of the organs prior to perfusion. The liver and
      pancreas are removed en bloc and consecutively the kidneys, one by one. This no
      touch technique is rapid and safe, especially for atypical hepatic arteries, as
      all the tissue between the superior mesenteric artery, celiac trunk and minor
      curvature of the stomach is preserved with liver, irrespective of arterial
      anomalies.

PMID- 8646915
TI  - [Perspectives of immunosuppressive therapy].
AB  - The goal of immunosuppressive therapy in organ transplantation is the achievement
      of transplant-specific immune tolerance. Elucidation of the molecular basis of
      the functions of human lymphocytes is a step towards the development of novel,
      more specific and less harmful measures for clinical immune intervention.

PMID- 8646916
TI  - [The role of reperfusion damage].
AB  - Following reperfusion of preserved organ grafts, various pathomechanisms are
      activated that may impair graft function and viability beyond ischemic damage.
      This so-called reperfusion injury includes generation of oxygen radicals,
      recruitment and activation of circulating inflammatory cells, and liberation of
      numerous mediators acting both locally and systemically. Alterations in
      microvascular perfusion are of central importance where further graft damage is
      concerned. The present review covers the current knowledge about the underlying
      mechanisms, the organ-specific application in the clinical setting, and the
      possible immunological consequences of reperfusion injury.

PMID- 8646917
TI  - [Xenotransplantation].
AB  - This paper describes the rationale behind the need for xenotransplantation and
      the physiological and immunological barriers associated with xenografting from
      pig to man. The scientific strategies developed for overcoming the immunological
      barriers associated with hyperacute rejection are described in detail as is the
      technology for producing transgenic pigs. Data on perfusion studies of transgenic
      pig hearts with human blood demonstrates the validity of this scientific
      approach.

PMID- 8646918
TI  - [Effect of liver transplantation on general techniques of liver resection].
AB  - The techniques of liver surgery and liver transplantation have benefited from one
      another. This is demonstrated by the sophisticated methods in modern transplant
      surgery, such as size reduction, splitting and resection during organ harvesting
      in living donors. However, techniques of transplantation have also influenced
      resection procedures by the use of one procedure or another (depending on the
      stage), as clearly shown by the evaluation of indications (assessment of liver
      function) in some diseases (Caroli syndrome, Klatskin tumor etc.). The exposure
      of the abdomen, the exploration of the liver, the knowledge about the tolerance
      of the liver to ischemia and the techniques of ex situ resection demonstrate the
      close ties between liver transplantation and liver resection. Standards of the
      procedure of liver transplantation and resection are explained. Details of
      techniques, parallels and influences are discussed.

PMID- 8646919
TI  - [Liver transplantation as school for visceral surgery--experiences for
      perioperative management].
AB  - Liver transplantation is one of the most extensive operations in visceral
      surgery. Preexisting cardiopulmonary abnormalities, disturbances of glucose,
      hormone, and electrolyte metabolism and cirrhosis-associated diseases, including
      hypersplenism with thrombopenia and severe coagulopathy, require advanced
      surgical skills. Optimal perioperative intensive care management is necessary
      because of the patient's immunosuppressed condition. In principle, patient
      management after liver transplantation is similar to that performed after major
      visceral surgery. However, special attention should be paid to initial liver
      perfusion and function. Like for sepsis in visceral surgery, in liver
      transplantation monitoring of cytokines and other mediators is important. New
      approaches for bioartificial liver support in patients with acute liver failure
      have primarily been developed as a bridging system to liver transplantation, but
      they may also be of value for patients with septic liver failure or liver failure
      after major liver resections.

PMID- 8646920
TI  - [Laparoscopic 2-level fusion of the lumbar spine with Bagby and Kuslich
      implants].
AB  - In a 50-year-old female patient, presenting with permanent low lumbar back pain
      and intermittent neurological alterations due to degenerative disc disease L4-5
      and L5-/S1 we demonstrate that two-level anterior interbody fusion can be
      performed via laparoscopic transabdominal instrumentation using BAK interbody
      implants. Intervertebral disc space L5-/S1 was stabilized approaching the spine
      caudally of the aortic bifurcation, while disc space L4-L5 required an approach
      from the left lateral aspect, mobilizing the aorta and vena cava to the right.
      The postoperative course was without complications and allowed discharge from the
      hospital on day 8. X-ray control 4 months later demonstrated restoration of
      adequate disc space at L4-L5 and L5-/S1 and appropriate positioning of the
      implants.

PMID- 8646921
TI  - [Early squamous epithelial carcinoma of the esophagus--multicentricity,
      metastatic pattern and prognosis].
AB  - The results of surgical treatment of 65 patients with pT1 squamous cell carcinoma
      of the esophagus and the histologic workup of the specimens were analyzed. The
      treatment of choice was transthoracic enbloc esophagectomy (n = 45); in 16
      patients with very distal carcinoma and restrained lung function transhiatal
      esophagectomy was performed. Two patients with concomitant early gastric
      carcinoma or lymphoma had total esophagogastrectomy, and in 2 other patients
      cervical esophagectomy was performed. The postoperative 30-day mortality was
      6.1%. 74% of the cases had an infiltration of the submucosa, whereas in 26% the
      carcinoma was limited to the mucosa. No patients with mucosal carcinoma had lymph
      node metastases, whereas 23% of the patients with submucosal infiltration showed
      lymph node involvement. Tumors of other organs, especially stomach and
      hypopharynx, were found in 15.4% of the patients. The 5-year survival rate of the
      total group of 65 patients was 61.3%. As 3 patients with mucosal carcinoma died
      during long-term follow-up due to recurrence or second cancer, no significant
      prognostic difference was found between patients with mucosal or submucosal
      infiltration. The survival curves of patients with pN0 and those with pN1 tumors
      were not significantly different.

PMID- 8646922
TI  - [Adjuvant regional chemotherapy in resected advanced pancreas carcinoma].
AB  - Systemic chemotherapy in patients who underwent resection of pancreatic carcinoma
      has not been significantly improved median survival times. We investigated
      whether regional chemotherapy administered via celiac trunc infusion increases
      survival rates in patients with locally advanced pancreatic carcinoma after
      resection of the primary. From 12/1992 to 2/1995 we treated 18 patients with
      regional chemotherapy consisting of mitoxantrone (d1), 5-FU + folinic acid (d2-4)
      and CDDP (d5) on five consecutive days. This cycle was repeated up to 6 times.
      Besides non-symptomatic GI-ulcerations (3/18) no severe side effects were
      observed. The median survival is actually 17.8 months (regression analysis).
      Compared to a historical control of our department survival times are
      significantly prolonged (17.8 vs. 9.3 months, p < 0,0003). In conclusion we state
      that adjuvant regional chemotherapy in patients with advanced pancreatic cancer
      is well tolerated and prolongs survival significantly.

PMID- 8646923
TI  - [Is liver resection in metastases of exocrine pancreatic carcinoma justified?].
AB  - From 1971 to 1995 we have performed 23 liver resections in 22 patients because of
      hepatic metastases of pancreatic (n = 20) or ampullary (n = 2) carcinomas. In 16
      patients the hepatic secondaries were removed synchronously with the pancreatic
      primary tumour. In 7 cases liver resection was performed for metachronous
      metastases. Only one patient died after simultaneous resection of liver and
      pancreas (operative lethality 4,3%). Curative R0-resection was accomplished in
      69% of patients with synchronous and 100% with metachronous liver metastases. The
      median survival time was 8,3 months after synchronous and 5,8 months after
      metachronous hepatic resection. The one-year survival amounted to 41 and 40%
      resp. Though distant metastases are a definite sign of a progressed tumour stage,
      the prognosis of patients with hepatic metastases should not be considered
      hopeless. In view of a comparatively small operative risk there is a chance for
      individual patients to gain valuable survival time.

PMID- 8646924
TI  - [Tumor of the gastrointestinal autonomic nervous system (GAN-tumor or plexus
      sarcoma)].
AB  - GAN-tumors or plexosarcomas, first described by Herrera et al. in 1984, are
      uncommon neurogenic stromal spindle cell tumors of the intestinal tract mainly
      located in the stomach and the small intestine. The distinctive
      immunohistochemical pattern is the positive staining for vimentin and neuron
      specific-enolase. Ultrastructural features are neuron-like cells with
      interdigitating cytoplasmic processes, dense-core neurosecretory granules, the
      lack of basement membranes and the presence of interstitial skeinoid fibers.
      Pain, chronic and acute bleeding are the most frequent but not specific symptoms
      and the diagnostic delay is reflected by a large average diameter of these
      tumors. For even smaller tumors and those with a low mitotic rate may
      metastasize, GAN-tumors must be considered malignant and need a radical surgical
      resection.

PMID- 8646926
TI  - [Ultrasound scalpel--initial experiences with use in laparoscopic surgery].
AB  - Worldwide the use of monopolar electrocautery is preferred in laparoscopic
      surgery. Beside the risk of thermal injury the technique involves some
      inconveniences for the surgeon. The ultrasonic scalpel offers theoretical
      advantages, which were clinically studied in a series of 443 operations. The
      absence of smoke, the reduced need for cleaning of the optic and the lack of
      complications due to the device lead us to believe that the ultrasonic scalpel is
      superior to electrocautery especially for beginners in laparoscopic surgery. The
      costs of the system--DM 150 per patient in our prospective series--are tolerable.

PMID- 8646925
TI  - [Ischemic colitis after vascular surgery reconstruction of an abdominal aortic
      aneurysm].
AB  - Between 1978 and 1994, a total of 678 patients were operated on for infrarenal
      (abdominal) aortic aneurysm at the Department of Surgery of Lubeck Medical
      University. Rupture had occurred in 165 patients, 351 were treated electively,
      and 162 presented with severe symptoms but no rupture. Only CT, angiography and
      intraoperative judgement were used for diagnosis. Reconstruction of the inferior
      mesenteric artery (IMA) was performed only in exceptional cases. Severe ischemic
      colitis occurred in 1.03% (in no case following elective surgery, in 0.66% of
      patients presenting with symptoms, and in 3.6% of patients in whom rupture had
      occurred prior to the operation). Three patients presented with mild ischemia,
      two with grade B ischemic colitis and three with transmural infarction. One
      patient had to be operated on for ischemic colitis despite open reconstruction of
      the IMA. We conclude from our data that there is no need to reconstruct the IMA
      as a routine procedure; this topic has been a controversial issue in the
      literature. We do reimplant a patent IMA when there is only oozing from the IMA
      and/or a borderline perfusion of the sigma following the operation, with at least
      one open internal iliac artery. When rupture had occurred, reconstruction should
      be performed if there is the slightest suspicion because of the increased risk,
      but only if the patient's cardiopulmonary condition allows this to be done.
      Analysis of our patients with ischemic colitis demonstrates the importance of
      maintaining stable circulatory conditions to prevent intestinal ischemia. Further
      diagnostic procedures (Doppler ultrasound, measuring of oxygen saturation or pH)
      may identify more patients at risk, but at the moment we do not consider these to
      be routine procedures.

PMID- 8646927
TI  - [Preperitoneal prosthesis implantation in surgical management of recurrent
      inguinal hernia. Retrospective evaluation of our results 1989-1994].
AB  - Recurrent inguinal hernia represents a great problem in surgery given the
      frequency of this operation, with a recurrence rate of 0.5-8%. Re-recurrence
      after repair without implantation of a prosthesis occurs in 1-23% of cases. We
      analyzed our results of patients with recurrent inguinal hernia, operated
      according to the method of Stoppa. Between 1989 and July 1994 there were 58
      operations upon 55 patients with an average age of 65 years, 79% of whom had
      unilateral and 21% bilateral hernias. 89% of all patients underwent surgery
      because of a recurrent inguinal hernia. A Marlex mesh was used in 79% of the
      case. All patients were followed up (mean 35 months, minimum 12 months). Early
      complications consisted in one hematoma (1.7%), which had to be drained, as well
      as one early recurrence (1.7%). No infections were observed. The overall
      recurrence rate was 12%. However, 60% of all recurrences occurred in the few
      first years after introduction of this technique at our clinic; with growing
      number of operations and experience with Stoppa's technique, we obtained a
      recurrence rate of 6-7% per year. In our opinion, supported by the results of
      other studies, Stoppa's technique is a successful method in the treatment of
      recurrent inguinal hernia.

PMID- 8646929
TI  - [Elastic intramedullary nailing--a concept for treatment of unstable forearm
      fractures in childhood].
AB  - The standard treatment for forearm fractures in children is usually conservative.
      Unstable fractures of the proximal parts of the forearm often show poor results
      after nonoperative management, so that these fractures require surgical
      intervention. We report about 20 children ranging in age from 6 to 14 years who
      were treated by elastic intramedullary nailing. Ten patients were treated by
      intramedullary pinning immediately after their accident; 10 required
      intramedullary nailing after failure of the conservative treatment and
      redislocations of their fractures. At the time of follow-up 6 months later,
      functional results were "excellent" in 16 children, "good" in 3 children and
      "fair" in one child. There were no serious complications apart from the
      occurrence of one delayed union. According to these results intramedullary
      nailing can be recommended for the treatment of unstable fractures of the
      proximal and middle parts of the forearm in children.

PMID- 8646928
TI  - [Prevalence of Helicobacter pylori infection in stomach carcinoma].
AB  - This report outlines the results of the first prospective case-controlled study
      performed within a defined geographic area of southern Germany showing a
      significant association between Helicobacter pylori infection and gastric
      carcinoma (odds ratio = 2.18, 95% confidence interval 1.04-4.56). Furthermore, it
      can be clearly demonstrated that no association exists between carcinoma of the
      gastric cardia and H. pylori infection. There is no difference in prevalence of
      H. pylori infection between intestinal and diffuse-type carcinoma (Lauren
      classification). H. pylori status determination and strain typing may be useful
      in identifying patient groups at risk for developing gastric carcinoma.

PMID- 8646930
TI  - [Surgical treatment of ankle joint fractures with biodegradable screws and plates
      of poly-l-lactide].
AB  - In a first clinical protocol 19 ankle fractures have been fixed by plates and
      screws made of biodegradable polylactic acid. Fracture confirmation was achieved
      within 6 weeks. 52% of our patients demonstrated an aseptic soft tissue problem
      caused by delayed clearance of the degrading polylactide particles. In a 2nd
      protocol with 7 patients volume reduced plates and screws with flat heads were
      applied. None of these patients had any soft tissue reaction. These results
      emphasize that the application of plates and screws of polylactic acid is
      acceptable for fixation of ankle fractures. Soft tissue inflammatory reactions
      can be avoided by using volume reduced implants.

PMID- 8646931
TI  - [Transinguinal preperitoneal mesh-plasty in inguinal hernia using local
      anesthesia].
AB  - Between January 1994 and December 1995 inguinal and femoral hernias were repaired
      in 689 adults. In 58 patients (4 primary hernias, 54 recurrent hernias, 1st-7th
      recurrence) a mesh prosthesis (Marlex) was implanted in the preperitoneal space
      using an open inguinal approach (TIPP). After intraoperative classification of
      the hernia, the indications for TIPP were L/M/Mc and F III type hernias and a
      weak or destroyed transverse fascia. The operative technique of TIPP is described
      in detail. Half of the procedures were done with the patient under local
      anesthesia. There were no intraoperative complications. Besides an increased
      number of seromas the postoperative course following TIPP was comparable with
      that after Shouldice procedures performed in the same period. During a follow-up
      period of 3-24 months to date, no recurrence has been observed. If intraoperative
      hernia classification is performed, TIPP is an appropriate technique for
      recurrence-prone inguinal and femoral hernias.

PMID- 8646932
TI  - [Video thoracoscopic lobectomy. Surgical technique and results].
AB  - For a variety of indications, thoracoscopic surgery has become established as a
      safe and effective alternative to open thoracotomy. Improvements in video
      technology and the development of instruments for thoracoscopic surgery now make
      it possible to perform lobectomies. In this paper the surgical technique of
      thoracoscopic lobectomy is described, and surgical and functional results are
      analysed. Since January 1993, in 38 of 47 patients who underwent endoscopic
      surgery, thoracoscopic lobectomy was possible. In 9 cases (19.1%) a change to
      open surgery was indicated for technical and oncological reasons. There were 24
      males and 14 females between the ages of 7 and 82 years (average age of 58.5
      years). The indications were benign pulmonary disease in 10 cases and non-small
      cell lung cancer (stage I) in 28 cases. Four trocars were inserted; the pulmonary
      arteries and veins, the bronchi and the interlobar fissures were closed and
      divided with endoscopic staplers. There were neither intraoperative complications
      nor postoperative deaths. The rate of postoperative complications was very low.
      Patients benefited from the short hospital stay, limited postoperative pain,
      excellent early pulmonary function and fast recovery time. We conclude that for
      selected indications thoracoscopic lobectomies are safe and effective, but
      further studies are necessary to determine the true merits of the procedure.

PMID- 8646933
TI  - [Methodology in puncture tracheostomy. Technique, indications and
      contraindications].
AB  - Percutaneous dilatational tracheostomy is a relatively new minimally invasive
      method for bedside tracheostomy of immobilized adult patients. This procedure is
      based on the Seldinger technique: after percutaneous puncture of the trachea
      beneath the cricoid a guidewire is placed into the trachea. Afterwards the wound
      channel around the wire is dilated until a tracheal cannula can be put in place.
      The surgeon requires not only precise knowledge of cervical anatomy and manual
      skills to perform this technique but should also be aware of contraindications
      and how to proceed if there are technical problems. Based on our personal
      experience of more than 300 percutaneous dilatational tracheostomies, appropriate
      recommendations are given.

PMID- 8646934
TI  - [Functional relevance of the type I arteria proatlantica in carotid
      disobliteration].
AB  - Primitive embryonic anastomotic vessels between the carotid and vertebrobasilar
      arterial systems occasionally persist into adult live. Coincidence with
      cerebrovascular disease may be of functional relevance. We report a case of
      segmental internal carotid occlusion and aplasia of both vertebral arteries in
      combination with persistence of proatlantal artery type I. Recurrent cerebral
      ischemia required revascularization of the segmental occluded internal carotid
      artery. Disobliteration was successfully performed with an uneventful
      postoperative course. The patient recovered well from his neurological deficits.
      Clinically, the combination of persistent proatlantal artery with occlusive
      disease of the carotid arteries may lead to atypical neurological deficits. In
      cerebrovascular surgery, a persisting proatlantal artery, as a main supply vessel
      of the vertebrobasilar system, is of great importance if the carotid artery is
      clamped.

PMID- 8646935
TI  - [Sporadic unilateral adrenal medullary hyperplasia--a rare cause of
      hypertension].
AB  - Sporadic adrenomedullary hyperplasia (AMH) is characterized by a clinical history
      of hypertension, increased plasma and/or urinary catecholamine levels and
      histomorphometric evidence of increased adrenal medullary mass in the absence of
      MEN 2 syndrome. The case of a 42-year-old female patient is reported who
      presented with typical clinical and laboratory findings of episodic hypertension
      and elevated plasma and urinary catecholamines. Sonography and computed
      tomography revealed no abnormality, but 131I-metaiodobenzylguanidine (131I-MIBG)
      scintigraphy showed increased uptake in the right adrenal. Transabdominal
      unilateral adrenalectomy was performed. The right adrenal gland was
      macroscopically inconspicuous. Upon histomorphometry, however, an increased
      adrenal medullary cell mass was shown, thus confirming AMH. Two years following
      surgery the patient is asymptomatic and normotensive.

PMID- 8646937
TI  - [The ultrasound scalpel in laparoscopic surgery].
AB  - The ultrasonically activated scalpel works by means of the longitudinally
      vibrating sharp blade. The most important advantages- compared with
      electrosurgery-are the lack of current flow through the patient and limited local
      heat generation. It can be used as an instrument for coagulation, dissection and
      preparation. There is no generation of smoke. It is easy to use. Disadvantages
      are the slow speed of cutting and the high costs. In the future it could be an
      alternative to preparation on with dissector, scissors, and electrosurgery.

PMID- 8646936
TI  - [Intraoperative monitoring of the recurrent laryngeal nerve. A new method].
AB  - Injury of the recurrent laryngeal nerve (RLN) is one of the most frequent
      complications in thyroid surgery. It leads to a significant morbidity of up to
      20%, depending on the type of surgery being performed. We present a new device
      for intraoperative monitoring of the RLN. The new monitoring system was evaluated
      in piglets. The system is reliable and easy to use. For the first time even
      imminent injury to the RLN can undoubtedly be demonstrated by signal changes. It
      will soon be available for use in humans.

PMID- 8646938
TI  - [The fully implantable minimally invasive hepatic artery catheter for
      locoregional chemotherapy of nonresectable liver metastases in defective
      conventional implanted therapy catheters].
AB  - Dysfunction of arterial access devices used in association with intra-arterial
      chemotherapy for the treatment of unresectable liver metastases usually requires
      stopping the therapy or relaporotomy and reimplantation of a new arterial
      catheter. In this article our initial experience of a new technique, the so
      called MIAH catheter (minimally invasive hepatic artery catheter) in 36 patients
      (age 37-78 years) are reported. The MIAH catheter was percutaneously inserted
      into the subclavian artery under sonographic guidance and advanced via the
      descending aorta selectively into the hepatic artery. Finally it was connected to
      a totally implantable pump. There were no deaths related to the operation.
      Operative or early complications occurred in 5 cases (13.8%); late complications
      were seen in 13 patients (36.1%). Nevertheless continuation of intra arterial
      chemotherapy was possible in all cases. In cases of dysfunction of conventional
      arterial access devices the MIAH catheter makes it possible to continue intra
      arterial chemotherapy without requiring laporotomy.

PMID- 8646939
TI  - [Regional lymphatic tumor cell dissemination in resectable non-small-cell
      bronchial carcinoma].

PMID- 8646940
TI  - [Standardized laparoscopic hernia-plasty vs. Shouldice repair].

PMID- 8646941
TI  - [Bile duct lesion in laparoscopic cholecystectomy].

PMID- 8646942
TI  - Colostomy closure. Ochsner Clinic experience.
AB  - PURPOSE: We retrospectively reviewed the records from our past five years of
      experience with colostomy closure at a large multispecialty hospital to determine
      postoperative morbidity. RESULTS: From March 1988 to April 1993, 46 patients
      underwent colostomy closure. Patients ranged in age from 24 to 87 (mean, 41.8)
      years, and 25 (54 percent) were women. Stomas had been created during emergency
      operations in 40 patients (87 percent); most operations (54 percent) were for
      complications of acute diverticulitis. Of the 46 procedures, 40 (87 percent) were
      end colostomies, and 6 were loop colostomies. Stomas were closed at a range of 11
      to 1,357 days after creation (mean, 207 days; median, 116 days). Twenty-six
      patients (57 percent) underwent colostomy closure alone, and the remainder
      underwent additional procedures ranging from appendectomy to hepatic lobectomy.
      Duration of operations ranged from 1 to 9.5 (mean, 4.2) hours, and estimated
      blood loss averaged 400 ml. Overall hospital stay for closure was 6 to 62 (mean,
      11.5) days. Inpatient complications occurred in 15 percent of patients, including
      congestive heart failure (2 percent), cerebrovascular accident (4 percent),
      pneumonia (2 percent), enterocutaneous fistula (2 percent), and pulmonary embolus
      with death (2 percent). The most common long-term complication was midline wound
      hernia, which occurred in 10 percent of surviving patients. Overall,
      complications occurred in 24 percent. CONCLUSIONS: Colostomy closure is a major
      operation; however, with good surgical judgement and technique, associated
      morbidity and mortality can be minimized.

PMID- 8646943
TI  - Sexual function following restorative proctocolectomy in women.
AB  - PURPOSE: This study was undertaken to identify the incidence and type of sexual
      dysfunction experienced by women after undergoing restorative proctocolectomy.
      METHODS: A questionnaire was sent to 262 females who underwent restorative
      proctocolectomy by a single surgeon from 1984 to 1993. The response rate was 35
      percent (92/262). Additional information was gained from our pelvic pouch data
      base. Mean follow-up was 43 (6-130) months. RESULTS: Following surgery, a
      significant increase was found in vaginal dryness, dyspareunia, pain interfering
      with sexual pleasure, and limiting of sexual activity because of concerns of
      stool leakage. There was no significant change in sexual desire, arousal,
      sensitivity, frequency of intercourse, or satisfaction with sexual relationship.
      CONCLUSION: Potential sexual dysfunction following restorative proctocolectomy in
      women merits discussion in preoperative counseling with the patient.

PMID- 8646944
TI  - Should HIV status alter indications for hemorrhoidectomy?
AB  - PURPOSE: There is a widespread belief that performing hemorrhoidectomy on a
      patient infected with human immunodeficiency virus (HIV) is an invitation for
      disaster. Aim of this study was to compare morbidity of hemorrhoidectomy in HIV
      positive (HIV+) with HIV-negative (HIV-) patients. METHODS: Charts of 27 HIV+ and
      30 HIV- male patients less than age 50 years who underwent hemorrhoidectomy were
      reviewed. RESULTS: Mean age of the 57 study group patients was 38 years. Open
      hemorrhoidectomy was performed in 26 patients (46 percent), and a closed
      technique was used in 31 patients (54 percent). HIV+ and HIV- patient groups were
      well matched to all preoperative and intraoperative variables. Mean T-cell helper
      count in the HIV+ patient group was 301 (range, 9-1,040) cells/microliter. There
      were no deaths, and complications were seen in 15 patients (26 percent). There
      was no difference in overall complication rates between HIV+ and HIV- patient
      groups. Urinary retention was seen in ten patients (18 percent), three of whom
      were HIV+ (11 percent) vs. seven of whom were HIV- (23 percent) (P = not
      significant). Although no patient required reoperation for bleeding,
      postoperative hemorrhage was seen in three patients (1 HIV+, 2 HIV-). None of the
      patients developed fecal incontinence. Mean time to complete wound healing was
      6.8 (range, 4-12) weeks for HIV+ patients vs. 6.6 (range, 4-14) weeks for HIV-
      patients (P = not significant). CONCLUSIONS: These data suggest that HIV status
      of a patient should not alter indications for surgical management of hemorrhoidal
      disease.

PMID- 8646945
TI  - Clostridium difficile colitis in the critically ill.
AB  - Morbidity and treatment of Clostridium difficile colitis (CDC) continue to be
      controversial. Some claim minimum morbidity, which may be a function of
      differences in patient population and/or bacterial virulence. METHODS: To
      evaluate the effect of CDC in the critically ill, we retrospectively reviewed the
      records of 59 intensive care unit patients with CDC who were diagnosed by fecal
      toxin assays or clinical evidence of pseudomembranous colitis from January 1991
      to October 1994. Symptoms, signs, antibiotic regimens, diagnostic tests, Acute
      Physiology and Chronic Health Evaluation II (APACHE II) scores, morbidity, and
      mortality were analyzed, and results of surgical treatment were compared with the
      literature. RESULTS: Mean age was 66.4 (17-95) years, with a male to female ratio
      of 1.8:1. First treatment was metronidazole by mouth in 15 patients (25.4
      percent), vancomycin by mouth in 30 patients (50.8 percent), sequential by mouth
      vancomycin/metronidazole in 3 patients (5.1 percent), and intravenous
      metronidazole in 5 patients (8.5 percent). Six patients had no medical therapy
      before surgery or discharge. Ten patients (17 percent) had recurrence and 12
      (20.3 percent) required surgery for progressive toxicity or peritonitis. Of three
      patients who were initially treated by diverting stomas, one died and two
      required total colectomy (TAC). Two underwent partial resection (1 that was
      nearly a total colectomy), and seven others had a TAC. Surgical patients had
      worse mean APACHE II scores at diagnosis (24.4 vs. 19.9; P < 0.001). Thirty-day
      mortality in surgical patients was 41.7 vs. 14.7 percent in medical patients (P <
      0.5). CONCLUSION: Twenty percent of critically ill patients with CDC required
      operation. TAC and diversion appeared to be more effective surgical treatments
      than diversion alone.

PMID- 8646946
TI  - Effect of octreotide on anal pressure and rectal compliance.
AB  - PURPOSE: The somatostatin analog, octreotide, has previously been found to
      influence rectal sensation and may also influence anal resting pressure. METHODS:
      We studied the effect of octreotide on anal resting pressure and rectal
      compliance in eight healthy patients. Octreotide was administered intravenously
      as a bolus injection in doses of 100 and 10 micrograms or as infusion of 250
      micrograms/hour on separate days and compared with placebo. RESULTS: Within one
      minute after a bolus injection of 100 micrograms of octreotide, anal resting
      pressure increased from 56 +/- 12 to 96 +/- 16 cm H2O (P < 0.005). Octrotide had
      no effect on rectal sensitivity or compliance measurements. Octreotide
      counteracted rectoanal reflex by increasing anal pressure almost to the level
      found with an empty rectum. CONCLUSION: Somatostatin thus seems to contribute to
      the regulation of rectoanal reflex.

PMID- 8646947
TI  - Effect of selenium on 1,2-dimethylhydrazine-induced intestinal cancer in rats.
AB  - PURPOSE: This study was designed to determine the cancer prevention and
      therapeutic effects of selenium on rats treated with 1,2-dimethylhydrazine (DMH).
      METHODS: One hundred sixty Spraque-Dawley male rats were divided into seven
      groups and received 20 mg/kg/week DMH, subcutaneously for 20 weeks. Two different
      dosages of selenium (8 and 4 ppm) were administered to the rats through drinking
      water during DMH treatment (B and C groups) or one month before and during DMH
      treatment (D and E groups). The rats of Groups A (control group), B, C, D, and E
      were killed immediately after the last DMH injection. The incidence of intestinal
      cancer in each group was compared. Eight ppm selenium was also administered to
      rats after DMH treatment (Group F), and survival times were observed and compared
      with Group G (treated with DMH only). RESULTS: Rats of Groups B and D received 8
      ppm selenium and had a significantly decreased incidence of intestinal cancer
      (from 65.8 percent (Group A) to 33.3 percent (Group B) and 27.8 percent (Group
      D); P = 0.0225 and 0.0038). Rats receiving 4 ppm selenium had a relatively
      decreased incidence of intestinal cancer (from 65.8 percent (Group A) to 44.4
      percent (Group C) and 47.1 percent (Group E) but P > 0.05). Survival time of
      Groups F and G showed no difference. CONCLUSIONS: Eight ppm selenium provided via
      drinking water has a significant intestinal cancer prevention effect in the
      presence of a high dose of DMH (20 mg/kg x 20 weeks), and the cancer therapeutic
      effect of selenium is doubtful in this animal model.

PMID- 8646948
TI  - Increased leukocyte adhesiveness/aggregation in patients with inflammatory bowel
      disease during remission. Further evidence for subclinical inflammation.
AB  - PURPOSE: We have used a novel leukocyte adhesiveness/aggregation test (LAAT) to
      show that many patients with inflammatory bowel disease (IBD) in clinical
      remission have a subclinical low grade inflammation. METHODS: Included in the
      study are 500 controls, 96 patients with IBD in remission, and 106 patients in
      relapse. RESULTS: The percent of aggregated white blood cells detected in the
      peripheral blood was 5.9 +/- 3.9, 9.1 +/- 5.9, and 18.8 +/- 9.4, respectively.
      The difference between each group and any other was significant at P < 0.0001.
      Similar results were obtained when other acute phase reactants like the
      erythrocyte sedimentation rate, white blood cell count, differential count, and C
      reactive protein level were examined. However, in a linear regression analysis,
      LAAT was the only significant (P < 0.0006) variable that could classify correctly
      each subject to the appropriate category of control and IBD in remission or
      relapse. CONCLUSIONS: Identification of patients with IBD in clinical remission
      who have ongoing inflammation may be of clinical-therapeutic relevance. The LAAT
      is a simple, rapid, and convenient test. The present study indicates that it is
      also very sensitive.

PMID- 8646949
TI  - Three-dimensional endorectal ultrasonography for staging of obstructing rectal
      cancer.
AB  - PURPOSE: Preoperative staging of advanced carcinoma of the rectum by conventional
      endorectal ultrasonography is often impossible because of the presence of
      obstruction, which does not allow passage of the endoprobe. In a prospective
      study, we investigated the value of three-dimensional endorectal ultrasonography
      for staging of obstructing rectal cancer. This technique permits examination of
      obstructing rectal tumors because scan planes can be chosen deliberately within a
      scanned volume. METHODS: Overall obstructing tumors not accessible for
      conventional endoprobes were found in 26 of 94 patients who were subjected to
      endorectal ultrasonography for staging of rectal cancer. Three-dimensional volume
      scanning was performed using a three-dimensional frontfire transducer or a three
      dimensional bifocal multiplane transducer (7.5/10 MHz). Data of the three
      dimensional scans were stored on a hard disk for subsequent evaluation with a
      combison 530 processor. RESULTS: Three-dimensional transrectal endosonography
      enabled visualization of local tumor spread in all 26 patients. In 18 patients,
      obstruction was caused by advanced primary rectal carcinoma. Endosonography
      accurately determined the tumor infiltration depth in three T2 tumors, eight T3
      tumors, and three T4 tumors. Overall accuracy for assessment of infiltration
      depth was 78 percent. Accuracy for assessment of perirectal lymph node
      involvement was 75 percent. In eight patients, the obstruction was attributable
      to extramural regrowth of rectal cancer after surgery. Diameter of the lesions
      ranged between 3 and 6 cm. Although all lesions were clearly depicted by three
      dimensional endosonography, only five lesions (62 percent) were detected by
      computed tomography. CONCLUSIONS: Three-dimensional endorectal ultrasonography
      provides previously unattainable scan planes and enables accurate staging of
      obstructing rectal tumors. This technique may improve therapy planning in
      advanced rectal cancer by selecting patients who require preoperative adjuvant
      therapy.

PMID- 8646950
TI  - Carcinoid tumor of the rectum. DNA ploidy is not a prognostic factor.
AB  - PURPOSE: This study was designed to evaluate the clinical characteristics,
      surgical treatment, and outcome of carcinoid tumors of the rectum and to assess
      flow cytometry deoxyribonucleic acid (DNA) analysis as a potential prognostic
      factor for management of these tumors. METHODS: Medical records, tumor registry
      database, and pathology slides were retrospectively reviewed. Flow cytometry DNA
      analysis was performed on archived specimens. RESULTS: One hundred nine patients
      with rectal carcinoid tumors underwent surgery between 1962 and 1987. Follow-up
      was available in 86 patients for a mean period of 12 years. Of 100 patients with
      tumors less than 2 cm, only one with a 1.5 cm ulcerated tumor developed liver
      metastases. Of nine patients with a tumor more than or equal to 2 cm, three with
      known liver metastases underwent rectal biopsy only, and three had rectal biopsy
      and laparotomy with biopsy of liver metastases. Three patients underwent radical
      resection. Following abdominoperineal resection, one patient died with local
      recurrence after 5 years, and one developed hepatic recurrence after 5.5 years
      and died at 9 years. One patient with coloanal anastomosis developed local and
      hepatic metastases seven years after surgery and died at ten years. No patients
      developed carcinoid syndrome. DNA ploidy did not correlate with metastases at
      presentation or recurrence of carcinoid tumor. CONCLUSION: Radical resection of
      rectal carcinoids with ulceration or size greater than or equal to 2 cm is
      associated with a poor prognosis; however, survival may be long term, even in the
      presence of metastatic disease. DNA ploidy does not appear to be a useful
      prognostic factor for rectal carcinoid tumors.

PMID- 8646952
TI  - Comparison of individual surgeon's performance. Risk-adjusted analysis with
      POSSUM scoring system.
AB  - Comparison of outcome after colorectal resection among different surgeons is
      difficult. Crude rates of morbidity and mortality can be misleading because such
      rates make no allowance for differences in case mix and fitness of patients. AIM:
      The aim of this study was to compare outcome among five surgeons by means of the
      simple, well-validated scoring system POSSUM for risk-adjusted analysis. METHODS:
      A total of 438 patients were studied prospectively. Each patient underwent
      colorectal resection by one of the five surgeons. Demographic details, operative
      procedure, and postoperative course were recorded, and physiologic and operative
      severity scores were determined. Risk of morbidity and mortality was calculated
      for each patient. RESULTS: Incidence of morbidity varied sharply among the five
      surgeons, from 13.6 to 30.6 percent, and the 30-day mortality varied from 4.5 to
      6.9 percent. However, application of POSSUM to allow risk-adjusted analysis of
      the data demonstrated that the incidence of morbidity and mortality predicted by
      POSSUM based on patients physiologic and operative risks factors was very similar
      to the observed outcome for each surgeon. CONCLUSION: Direct comparison of
      individual surgeon's performance based on crude rates of morbidity and mortality
      can be misleading. Risk-adjusted analysis allows more meaningful comparison.

PMID- 8646951
TI  - Establishment of a hereditary nonpolyposis colorectal cancer registry.
AB  - INTRODUCTION: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal
      dominant condition characterized by early age of onset colorectal cancer, right
      sided predominance, excess of synchronous and metachronous colonic neoplasms, and
      extracolonic cancers. The purpose of this study is to report clinical
      characteristics of HNPCC families in our registry. METHODS: This is a
      retrospective review of medical records of patients with a significant history of
      colorectal cancer and interviews with their families. RESULTS: Three hundred one
      people with cancer in 40 HNPCC families were identified. In 284 of 301 (94
      percent) people, 363 cancers were identified. Colorectal cancer only was
      identified in 182 people (64 percent) and, in conjunction with extracolonic
      tumors, in another 31 people (11 percent). Extracolonic cancer alone was noted in
      71 people (25 percent). Median age at diagnosis of colorectal cancer was 48
      (range, 17-92) years. In patients with documented pathology, right-sided tumors
      predominated (55 percent), synchronous and metachronous tumors were noted in 53
      percent, and synchronous of metachronous adenomas were documented in 51 percent
      of people. Generational anticipation was also noted. CONCLUSION: This study
      demonstrates and confirms characteristics that have been described in HNPCC.
      Namely, early age of onset of colorectal cancer, right-sided predominance,
      multiple synchronous and metachronous neoplasms, increased extracolonic cancers,
      and generational anticipation.

PMID- 8646953
TI  - Tissue prostaglandin levels in familial adenomatous polyposis patients treated
      with sulindac.
AB  - BACKGROUND: Recent work has demonstrated a correlation between frequency of
      aspirin ingestion and colorectal cancer prevention. Sulindac, another
      nonsteroidal anti-inflammatory drug (NSAID), has been shown to cause polyp
      regression and a fall in cell proliferation in patients with familial adenomatous
      polyposis, who are destined to develop colorectal cancer unless the colon is
      removed. However, the mode of action of NSAIDs in colorectal carcinogenesis
      prevention remains to be determined, although a prostaglandin-mediated mechanism
      seems likely. METHODS: Rectal or duodenal biopsies from 20 patients with familial
      adenomatous polyposis, who had been randomized to sulindac or placebo, were
      analyzed for prostaglandin (PG) E2 and F2 alpha levels before and after
      treatment. RESULTS: A significant fall in prostaglandin E2 and F2 alpha levels
      was seen in patients who were on sulindac; this correlated with a visual
      improvement in number and size of polyps in the same patients (P = 0.0096; PGE2,
      P = 0.036; PGF2 alpha, Spearman's rank correlation). CONCLUSIONS: Nonsteroidal
      anti-inflammatory drugs may prevent colorectal cancer by their inhibition of
      prostaglandin synthesis. Prostaglandins may be implicated in carcinogenesis
      through an increase in cell proliferation, through immunosuppression, by
      increasing neovascularization, or via a mutagenic effect.

PMID- 8646954
TI  - Influence of colostomy on in vivo and in vitro permeability of the rat colon.
AB  - PURPOSE: Barrier properties of an isolated colon loop and the remnant colon in
      continuity with the gastrointestinal tract after colostomy were studied in the
      rat. METHODS: The in vivo absorption after colonic loop administration of the
      marker fluorescein sodium was measured as the urinary recovery. The in vitro
      permeability was measured in Ussing diffusion chambers as the transmucosal
      passage of [14C]mannitol and of human serum albumin in the isolated and the
      nonexcluded colonic segments and was compared with the corresponding colonic
      regions from sham-operated rats at 1 to 14 days after operation. RESULTS: Body
      weight gain of the rats decreased and diarrhea appeared from day 2 after
      colostomy. Histologic examination showed mucosal atrophy with decreased villus
      height in the isolated colonic loop and an increased villus height in the
      nonexcluded colon segment. Absorption of fluorescein sodium in the isolated loop
      was increased at 8 and 14 days. Moreover, permeability in the isolated loop was
      increased for both mannitol and human serum albumin from four days after
      colostomy compared with the corresponding colonic segments after the sham
      operation, whereas a decrease in the passage of mannitol was noted in the
      nonexcluded colon. CONCLUSIONS: Experimentally performed colostomy diversion in
      the rat induced alterations of the barrier function in both the isolated colonic
      loop and the nonexcluded colon in continuity with the fecal stream.

PMID- 8646955
TI  - Long-term results of anterior levatorplasty for fecal incontinence. A
      retrospective study.
AB  - PURPOSE: To review the long-term results of anterior levatorplasty for fecal
      incontinence. METHODS: Fifty-four women with obstetric trauma and 31 with
      idiopathic incontinence responded to a questionnaire 1.5 to 18.5 (median, 8.5)
      years after anterior levatorplasty. Results were classified as excellent, good,
      fair, or poor. RESULTS: An excellent or good result was reported in 40 of 54 (74
      percent) patients with an obstetric injury and in 14 of 31 (45 percent) patients
      in the idiopathic group (P < 0.01). The presence of a cloaca (P < 0.05) and a
      young age (P < 0.05) were associated with a favorable outcome in the obstetric
      and idiopathic group, respectively. Length of follow-up and preoperative severity
      of incontinence were not significantly related to outcome. CONCLUSIONS: This
      study suggests that every second patient undergoing anterior levatorplasty for
      fecal incontinence has a successful result that is sustained in the long term.
      Obstetric trauma, presence of a cloaca, and young age are associated with a
      successful outcome.

PMID- 8646956
TI  - Endoscopic and surgical complications of work-up in screening for colorectal
      cancer.
AB  - BACKGROUND AND PURPOSE: In an ongoing randomized screening study of 68,306
      patients for early detection of colorectal neoplasm, those with positive
      Hemoccult II tests (Smith Kline Diagnostic, Sunnyvale, CA) were examined with a
      flexible sigmoidoscope (FS; 60 cm) and double-contrast barium enema (DCE). The
      aim of this study was to determine the rate of complications to the work-up.
      METHODS: A total of 2,108 FS, 1,987 DCE, 190 colonoscopies, and 104 laparotomies
      were performed because of a positive Hemoccult. RESULTS: One patient's large
      bowel was perforated during diagnostic endoscopy. Four perforations of the large
      bowel occurred during endoscopic polypectomy (0.8 percent of 513 adenomas
      removed), and one case of bleeding occurred 12 days after polypectomy. No
      complications occurred in connection with the 1,987 DCE. Five of 104
      laparotomized patients underwent relaparotomy, 3 after removal of a colorectal
      carcinoma, and 2 of 4 patients with diverticular disease. All five patients
      healed but required a longer stay at the hospital. CONCLUSIONS: Complications
      occurred in 0.3 percent of the endoscopies, and 5 percent of patients had to
      undergo laparotomy again. No mortality occurred. If mortality attributable to
      colorectal cancer will decrease because of screening, we find the complication
      rate is acceptable.

PMID- 8646957
TI  - A constipation scoring system to simplify evaluation and management of
      constipated patients.
AB  - PURPOSE: Constipation is a common complaint; however, clinical presentation
      varies with each individual. The aim of this study was to assess a standard
      scoring system for evaluation of constipated patients. MATERIALS AND METHODS: All
      consecutive patients with idiopathic constipation who were referred for anorectal
      physiologic testing were assessed. A subjective constipation score was calculated
      based on a detailed questionnaire that included over 100 constipation-related
      symptoms. Based on the questionnaire, scores ranged from 0 to 30, with 0
      indicating normal and 30 indicating severe constipation. The constipation score
      was then compared with the objective findings of the physiology tests, which
      include colonic transit time (CTT), anal manometry (AM), cinedefecography (CD),
      and electromyography (EMG). Colonic inertia was defined as diffuse marker delay
      on CTT without evidence of paradoxical contraction on AM, CD, or EMG. Pelvic
      outlet obstruction was defined as paradoxical puborectalis contraction, rectal
      prolapse or rectoanal intussusception, rectocele, or sigmoidocele. RESULTS: A
      total of 232 patients (185 females and 47 males) of a mean age of 64.9 (range, 14
      92) years were evaluated. All patients had a score of more than 15; on evaluation
      of the significance of different symptoms in the constipation score with the
      Pearson's linear correlation test, 8 of 18 factors were identified as significant
      (P < 0.05). These factors included frequency of bowel movements, painful
      evacuation, incomplete evacuation, abdominal pain, length of time per attempt,
      assistance for evacuation, unsuccessful attempts for evacuation per 24 hours, and
      duration of constipation. All 232 patients had objective obstruction attributable
      to one or more of the following causes: paradoxical puborectalis contraction
      (81), significant rectocele or sigmoidocele (48), rectoanal intussusception (64),
      and rectal prolapse (9). CONCLUSION: The proposed constipation scoring system
      correlated well with objective physiologic findings in constipated patients to
      allow uniformity in assessment of the severity of constipation.

PMID- 8646958
TI  - Unilateral pudendal neuropathy. Impact on outcome of anal sphincter repair.
AB  - PURPOSE: Our purpose was to study the effect of unilateral pudendal neuropathy on
      the results of anal sphincter repair. METHOD: Fifteen female patients who
      underwent external sphincter repair for fecal incontinence were studied. In all
      instances, incontinence was the result of obstetric delivery injury. Anal
      manometry and neurophysiologic investigations to document sphincter defects and
      pudendal neuropathy were performed in all patients. Sphincter repair was
      performed using an overlapping suture technique. RESULTS: All patients had
      anterior sphincter defects. Seven patients (47 percent) had pudendal neuropathy:
      six (85 percent) had unilateral neuropathy, and one (15 percent) had bilateral
      neuropathy. Six patients (40 percent) had excellent results; three (20 percent)
      had good results; four (27 percent) were improved; two (13 percent) experienced
      no improvement after sphincter repair. All patients with excellent results had
      normal pudendal nerve terminal motor latency on both sides. Of the three patients
      with good results, one patient had unilateral pudendal neuropathy. The patients
      in the remaining two groups (improved and failed) had unilateral (six patients)
      or bilateral (one patient) pudendal neuropathy. CONCLUSION: We conclude that both
      pudendal nerves must be intact to achieve normal continence after sphincter
      repair. Patients with unilateral pudendal neuropathy are more likely to have poor
      than to have good postoperative function.

PMID- 8646959
TI  - Microchip implants on the anterior sacral roots in patients with spinal trauma:
      does it improve bowel function?
AB  - PURPOSE: This study evaluated the effect of anterior sacral roots stimulator
      implants on bowel function of patients with spinal cord trauma. METHOD: Eight
      patients with spinal cord injury and constipation had anterior sacral roots
      stimulator implants inserted for concomitant bladder dysfunction. Questionnaires
      on bowel function and anorectal manometry tests were given before and after
      insertion of the implants. RESULTS: Six patients achieved improvement in bowel
      function. Four of these patients could defecate spontaneously following
      stimulation. Two patients had no improvement in bowel function. Anorectal
      manometry studies showed a negative rectoanal pressure difference at the time of
      stimulation. All patients were unable to defecate during stimulation. Positive
      rectoanal pressure difference was recorded in the six patients who had improved
      bowel function. This may be attributable to the slower relaxation of the smooth
      rectal muscle compared with the easily fatigable striated external anal
      sphincter. CONCLUSION: Anterior sacral roots stimulator implants can improve
      bowel function in patients with spinal cord trauma.

PMID- 8646960
TI  - Adults born with high anorectal atresia--how do they manage?
AB  - PURPOSE: We are interested in the way patients, who underwent surgery for high
      anorectal atresia, control their defecation. Considering that some patients,
      despite newer operative techniques, always will suffer from minor or major
      soiling we attempted to find some guidelines for postoperative support for future
      patients. METHOD: Fifty-eight patients (median age, 26 (range, 18.1-56.9) years)
      were personally interviewed. RESULTS: Regulating defecation is done in five
      different modes: 16 patients have stools after urge, 15 control their stools
      mainly by going to the toilet at regular times, 18 perform bowel-irrigations or
      use enemas, 2 have loss of feces continuously, and 7 patients have an ileostomy
      or colostomy. More than one-half of patients influence their defecation by diet.
      Of the patients with anal defecation, 6 never soil, 39 sometimes soil small
      amounts, and 6 often soil seriously. Eighteen patients occasionally suffer from
      constipation. There is no mode of defecation regulation outstanding in preventing
      soiling or constipation. However, patients who do not regulate defecation somehow
      suffer from serious soiling. Most patients are content with their level of
      cleanliness. CONCLUSION: Irrespective of the mode of defecation regulation, many
      patients soil sometimes small amounts and a few often soil seriously. In view of
      the fact that most patients had to find the current control of defecation
      regulation by themselves rather late and lacked professional support, it is
      questionable whether the chosen mode of defecation regulation is the most optimal
      mode for each patient. We assume that a stepwise protocol under professional
      support, starting by the most natural mode of defecation, will improve defecation
      regulation in a more efficient way (earlier and better).

PMID- 8646961
TI  - Use of a suture holder facilitates transanal anastomosis.
AB  - We report here that use of a suture holder facilitates transanal anastomosis in
      cases of total proctocolectomy or low rectal anastomosis. Feasible control of
      multiple interrupted suturing and unhampered visibility of the entire process are
      made possible with this approach.

PMID- 8646962
TI  - Angiodysplasia as the cause of massive lower gastrointestinal hemorrhage in a
      young adult. Report of a case.
AB  - PURPOSE: This study was undertaken to clarify the importance of bleeding vascular
      ectasia of the colon as the etiology of massive lower gastrointestinal hemorrhage
      in patients 40 years of age or younger. METHODS: An otherwise healthy 21-year-old
      male was admitted to a tertiary medical center with massive lower
      gastrointestinal hemorrhage. Technetium-labeled red blood cell scan, selective
      visceral angiography, and colonoscopy identified the source of bleeding as
      vascular abnormality of the descending colon. Segmental colonic resection was
      performed. RESULTS: Histologic review of the specimen demonstrated a vascular
      ectasia. The patient recovered uneventfully and has had no further stigmata of
      hemorrhage. A review of the literature was undertaken to make clear the
      significance of vascular ectasia as the source for massive colonic hemorrhage in
      the young adult. CONCLUSION: This is the first report that documents
      histologically a vascular ectasia as the source of massive lower gastrointestinal
      hemorrhage in an otherwise healthy patient less than 40 years of age. Vascular
      ectasia is an uncommon cause of lower gastrointestinal hemorrhage in the young
      adult.

PMID- 8646964
TI  - Granular cell tumor of the colon.

PMID- 8646963
TI  - Colonic ulceration associated with nonsteroidal anti-inflammatory drugs. Report
      of three cases.
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a variety of
      gastrointestinal side effects. Effects on the large intestine have been reported
      with increasing frequency. Recognition of NSAID-induced colonic lesions has been
      confounded by variable clinical presentations, variable pathologic findings, and
      unfamiliarity of this entity among clinicians. We have recently seen three cases
      of NSAID-induced cecal ulcerations in patients undergoing right colectomy. A
      correct preoperative diagnosis was not made in our patients, one of whom
      presented with an acute abdomen and two in whom there was an inability to rule
      out carcinoma. The gross, radiographic, and histologic findings in each case
      consisted of a characteristic transverse ulceration with thin diaphragm-like
      scarring. NSAID-induced cecal ulcers can have a variety of presentations to the
      general surgeon, are likely to be misdiagnosed preoperatively, but may be
      recognized based on characteristic gross features evident by radiography and
      colonoscopy, along with a careful history. Review of recent literature suggests
      that laparotomy can be avoided when diagnosis is considered, but operation is
      indicated for complications, such as hemorrhage, obstruction, or perforation, and
      when carcinoma cannot be adequately excluded.

PMID- 8646965
TI  - Patient selection is integral to the success of the electrically stimulated
      gracilis neosphincter.

PMID- 8646966
TI  - The primary glomerulopathies.
AB  - Disorders of glomerular structure and function are encountered frequently in
      clinical medicine. Many arise as part of a well-defined multisystem or multi
      organ disease process, while in others the clinical and laboratory manifestations
      are consequent to the sole or predominant involvement of glomeruli. The latter
      are known as the primary glomerulopathies. These disorders can evoke a variety of
      clinical syndromes, including acute glomerulonephritis, rapidly progressive
      glomerulo-nephritis, nephrotic syndrome, "symptomless" hematuria and/or
      proteinuria, and chronic glomerulonephritis. The identification of underlying
      morphology, through the application of renal biopsy techniques, can provide
      useful information for both prognosis and treatment. Pathogenic mechanisms
      involved in the primary glomerulopathies are varied, but immunologic
      perturbations underlie many disease entities. This article describes the clinical
      features, pathology, natural history, and treatment of the main categories of
      primary glomerulonephritis, with emphasis on recent developments and practical
      aspects of diagnosis and management.

PMID- 8646967
TI  - [Newly discovered functions of hemoglobin].

PMID- 8646968
TI  - [Quality control of long term treatment of diabetes in Europe].

PMID- 8646969
TI  - [Significance of gamma delta T cells in the pathogenesis and diagnosis of
      Behcet's disease].

PMID- 8646970
TI  - [Transgenic swine as organ donors in heart transplantation?].

PMID- 8646972
TI  - [Pancreatic carcinoma: a new suppressor gene has been found].

PMID- 8646971
TI  - [Viruses and oxidative stress].

PMID- 8646973
TI  - [Vitamin E treatment of patients with coronary disease (Cambridge Heart
      Antioxidant Study--CHAOS)].

PMID- 8646974
TI  - [Catheter treatment of hypertrophic obstructive cardiomyopathy].
AB  - BASIC PROBLEMS AND OBJECTIVE: In addition to medication with negative inotropic
      drugs, surgical myectomy and DDD pacemaker implantation are standard procedures
      in the treatment of hypertrophic obstructive cardiomyopathy (HOCM). In a
      preliminary series the results obtained with a recently described method,
      consisting of transcatheter myocardial reduction, are evaluated. PATIENTS AND
      METHODS: Six patients (two women, four men; mean age 52.7 [44-68] years), who
      remained in moderate heart failure despite medical treatment, underwent the
      procedure. After atrial transseptal puncture (via a catheter introduced
      percutaneously into the femoral vein) the left ventricular outflow tract (LVOT)
      gradient was measured at rest and after 5-minute balloon occlusion of the first
      septal branch of the left coronary artery. After demonstration of significant
      reduction of the gradient by the occlusion, one (n = 3) or two (n = 3) septal
      branches were occluded by the injection of 2-5 ml of 96% alcohol. RESULTS: The
      LVOT gradient was reduced from 57.8 +/- 22.4 (38-97) mm Hg to 11.3 +/- 8.6 (0-21)
      mm Hg and postextrasystolic from 131.0 +/- 40.7 (78-198) mm Hg to 44.0 +/- 35.6
      (19-69) mm Hg. All patients had angina for 24 hours after the procedure. Maximal
      rise in creatine kinase activity was 982 +/- 589 (392-1729) U/l after 8.0 +/- 3.9
      (4-15) hours. In three patients transitory complete atrioventricular block
      developed 10 min to 5 days later, requiring temporary pacemaker implantation. The
      further course was without complication in all patients and they were discharged
      after 7.5 +/- 1.8 (6-11) days. CONCLUSION: The described catheter method provides
      a nonsurgical means of reducing the amount of septal myocardium with subsequent
      reduction of the LVOT gradient in HOCM. Long-term observation in a larger group
      of patients and comparison with conventional forms of treatment are required to
      determined the method's ultimate place in the treatment of HOCM.

PMID- 8646975
TI  - [Intestinal cryptosporidiosis in HIV infection: clinical features, course and
      therapy].
AB  - OBJECTIVE: To determine retrospectively the clinical features and course of HIV
      associated intestinal Cryptosporidium infection and its response to paromomycin.
      PATIENTS AND METHODS: Case notes of all patients treated for cryptosporidiosis
      over a two-year period at an HIV out-patient clinic were analysed (26 men, four
      women; median CD4-lymphocyte count: 20/microliter). Median follow-up time was 6(1
      22) months. RESULTS: 15 patients had persistent diarrhoea, two remained
      asymptomatic, seven had a remission and in five the disease took a fulminant
      course with severe diarrhoea ending in death within 4 months. 15 of the patients
      died during the period of observation, eight of them of cryptosporidiosis
      associated cachexia. Mean survival time was about one year. Eight patients had
      multiple intestinal infections at the time the diagnosis was made and seven
      developed them later, which correlated with the poorer survival chances. Four
      patients had proven and 13 probably cryptosporidiosis-associated involvement of
      the biliary tract, but this did not affect the survival chances. 21 of 28
      patients with diarrhoea were treated with paromomycin. In 13 of them there was
      for a time complete or partial response to treatment, but no response in eight.
      Those who responded well or partially to paromomycin had a significantly better
      survival chance than those without response. There was no correlation between the
      severity of immunosuppression and the severity of the cryptosporidiosis
      associated diarrhoea, the response to paromomycin and the worse survival chance
      in the presence of multiple intestinal infections. CONCLUSIONS: The reasons for
      the different courses taken by HIV-associated cryptosporidiosis and the different
      therapeutic responses remain unclear. There is no known causal treatment, but 60%
      of patients improved temporarily on paromomycin.

PMID- 8646976
TI  - [Retroperitoneal, mediastinal and subcutaneous emphysema with pneumothorax after
      colonoscopy].
AB  - HISTORY: Severe ulcerative colitis had been diagnosed in a 25-year-old man six
      years ago. That same year he underwent laparoscopy for mechanical ileus. Since
      then he has been on a maintenance dose of sulphasalazine without any further
      symptoms. Because of a known pseudopolyposis coli, repeat coloscopy was
      performed. EXAMINATIONS AND FINDINGS: The endoscope was smoothly introduced and
      the examination was without pain. No premedication had been given. A biopsy was
      obtained during withdrawal of the endoscope. Suddenly the patient noticed marked
      scrotal swelling. The examination was terminated abruptly. No lesions of the wall
      of the distal colon were seen when the endoscope was pulled out immediately.
      Quickly, cutaneous emphysema developed over the right side of the abdomen and
      thorax up to the neck. The patient could no more properly hear his own voice.
      Radiology demonstrated bilateral pneumoretroperitoneum, mediastinal emphysema and
      pneumothorax. TREATMENT AND COURSE: The patient was put on parenteral nutrition
      for 4 days and prophylactically received amoxycillin, calvulanic acid and
      metronidazole. The air was gradually absorbed and the patient discharged symptom
      free after 7 days. CONCLUSION: In contrast to intraperitoneal perforation, which
      usually causes acute symptoms of peritonitis and requires urgent surgical
      treatment, the course of the much rarer retroperitoneal perforation is more
      benign with few symptoms and can be managed conservatively.

PMID- 8646977
TI  - [Therapy of hepatic encephalopathy].

PMID- 8646978
TI  - [Anti-endothelial cell antibodies].

PMID- 8646979
TI  - [Prostate-specific antigen].

PMID- 8646980
TI  - [Therapy of chronic pancreatitis].

PMID- 8646981
TI  - [AIDS studies with didanosine and stavudine].

PMID- 8646982
TI  - [The 13C-acetate breath test for the noninvasive assessment of the gastric
      emptying of a liquid/solid test meal in diabetics].
AB  - OBJECTIVE: To test in a prospective study whether the non-invasive 13C-acetate
      test is suitable for measuring gastric emptying time with a liquid/solid test
      meal. (99m)technetium scintigraphy served as the reference method. PATIENTS AND
      METHODS: 18 consecutive type 2 diabetics with symptoms of gastroparesis (nine
      men, nine women; mean age 64 [45-76] years) were, after a nocturnal fasting
      period, given a liquid/solid test meal (370 kcal; 100 ml coffee; doubly marked
      with 75 mg 13C-acetate and 0.5 mCi 99mTc-colloid). At ten-minute intervals breath
      samples were taken over two hours and examined by mass spectometry for the
      13CO2/12CO2 ratio. In parallel scintigraphy was performed for one hour at one
      minute intervals. Gastric emptying half-life (t1/2) was calculated and the
      correlation between the two methods determined. In addition, the 13C-acetate
      breath test was performed on 20 healthy subjects to assess reproducibility (ten
      men, ten women; mean age 44.4 [23-77] years). RESULTS: Median t1/2 with the
      scintigraphy was 93.5 min, with the breath test 55 min, i.e. a significant
      correlation (r = 0.8; P < 0.001). Four of five patients with delayed gastric
      emptying by scintigraphy also showed delay (compared with the control group) in
      the breath test (median t1/2: 41 min; 95th percentile: 86 min). CONCLUSION: The
      13C-acetate test correlated significantly with the results by scintigraphy. It
      can therefore be recommended as a non-invasive test for assessing gastric
      emptying time after a liquid/solid test meal in type 2 diabetics.

PMID- 8646983
TI  - [Atresia of the aortic arch. A rare cause of asymmetrical arterial hypertension
      in adulthood].
AB  - HISTORY AND CLINICAL FINDINGS: A 58-year-old man, previously resident in Russia,
      was known since the age of 18 years to have arterial hypertension of unknown
      cause in only the right arm. A single syncope was the only previous symptom. On
      examination the pressure was 230/110 mmHg in the right arm, 150/100 mmHg in the
      left one. The pulse in the right arm and neck was strong and heaving, that in the
      left arm and the legs much more weakly palpable. INVESTIGATIONS:
      Electrocardiogram and echocardiogram showed left ventricular hypertrophy. The
      chest radiogram demonstrated rib notching. Digital subtraction angiography
      revealed aortic arch atresia just distal to the common carotid artery. No other
      cardiovascular abnormalities were found. TREATMENT: The patient declined
      operative treatment. Cautious antihypertensive drug treatment with Atenolol (25
      mg daily) reduced the pressure in the right arm to 180/90 mmHg. CONCLUSION: This
      rare malformation of aortic arch atresia should be considered in the differential
      diagnosis of asymmetrical arterial hypertension in an adult.

PMID- 8646985
TI  - [The drug therapy of hypercholesterolemia].

PMID- 8646984
TI  - [Chronic recurrent subileus due to Strongyloides stercoralis infection under
      immunosuppressive therapy].
AB  - HISTORY AND CLINICAL FINDINGS: A 33-year-old woman from Laos was admitted due to
      recurrent vomiting and weight loss. Since one year, she was receiving
      immunosuppressive therapy (azathioprine 50 mg/d and methylprednisolone 18 mg/d)
      for a mixed connective tissue disease. Because of a drug induced Stevens-Johnson
      Syndrome one month earlier high doses of methylprednisolone (100 mg/d
      intravenously) had been administered. The patient's general condition was
      reduced. Examination elicited a mild pain in the middle abdomen on palpation but
      no resistance or tumour. The differential diagnosis included obstructive and (or)
      inflammatory disease of the gastrointestinal tract. INVESTIGATIONS: Elevated IgE
      levels (1111 IU/ml; normal up to 100 IU/ml) and eosinophilia (8%) lead to the
      suspicion of a helminthiasis. Oesophagogastroduodenoscopy showed a significant
      duodenal stenosis. Duodenal biopsy revealed a severe infestation with
      Strongyloides stercoralis. Stool examinations were negative though. TREATMENT AND
      COURSE: With administration of thiabendazole (2 g/d) a rapid recovery was noted.
      A second oesophagogastroduodenoscopy one week after the onset of therapy revealed
      no further stenosis. Since there was no activity of the mixed connective tissue
      disease the methylprednisolone dosage was reduced and the administration of
      azathioprine was ceased. 3 weeks after beginning of treatment the patient was
      discharged in improved condition. CONCLUSION: In immunocompromised patients
      suffering from gastrointestinal complaints who have been in endemic areas an
      infection with Strongyloides stercoralis should be excluded. Without treatment,
      this helminthiasis may be fatal.

PMID- 8646986
TI  - [Cytokines in chronic inflammatory intestinal diseases].

PMID- 8646987
TI  - [The therapy of liver cysts].

PMID- 8646988
TI  - ["Mild" hypertension].

PMID- 8646989
TI  - [The treatment of carcinoid of the small intestine with octreotide and alpha
      interferon. A call for participation in a randomized study].

PMID- 8646990
TI  - [The HIV-1 RNA serum level and the risk of perinatal HIV-1 transmission].

PMID- 8646991
TI  - [The prevalence of sleep-related breathing disorders in patients with implanted
      cardioverter-defibrillators. The effect on the incidence and circadian
      distribution of malignant ventricular tachyarrhythmias].
AB  - OBJECTIVE: To determine the prevalence of sleep-related breathing disorders
      (SRBD) on patients who, because of malignant ventricular tachyarrhythmias
      associated with cardiac disease, have an implanted cardioverter-defibrillator
      (ICD). It was also investigated whether the frequency and circadian distribution
      of spontaneous ventricular tachycardia and (or) fibrillation (VTF) can be
      influenced by SRBD. PATIENTS AND METHODS: 29 consecutive ICD patients (28 men,
      one woman; mean age 64 +/- 8 years) were investigated by multifunction
      recordings. 22 patients had coronary heart disease, and seven dilated
      cardiomyopathy. For each patient the number of VIF episodes per month were
      recorded, as well as the percentage distribution of the episodes during the day
      per hour and after grouping into four time periods. RESULTS: SRBDs were recorded
      in 13 of the 29 patients (45%) (apnoea-hypopnea index [AHI] > 10). The other 16
      patients had normal findings (AHI < or = 10). Mean frequency of the registered
      VTF attacks was similar in both groups (0.41/month with AHI < or = 10 vs
      0.44/month with AHI > 10; difference not statistically significant). Averaged
      percentage distribution pattern showed a maximum frequency in both groups between
      6 o'clock and 12 o'clock a.m. There was no significant increase of VTF during the
      night (10 o'clock p.m.-6 o'clock a.m.) in the group with SRBD (19% with AHI > 10
      vs 18.2% with ATF < or = 10; difference not significant). CONCLUSION: There was a
      high prevalence of SRBD in the patients with ICD and underlying cardiac disease.
      No influence of SRBD on frequency and circadian distribution of VTF was
      demonstrated in patients with ICD during long-term observation.

PMID- 8646992
TI  - [The prevention of the recurrence of endemic goiter. The efficacy of a once-a
      week dose of 1.53 mg iodide].
AB  - OBJECTIVE: To investigate the efficacy of 1.53 mg iodide administered once weekly
      in the prophylaxis of goitre recurrence in patients with endemic euthyroid goitre
      after initial treatment to reduce the goitre size. PATIENTS AND METHODS: 46
      consecutive patients who had undergone initial L-thyroxine, iodide or combined
      treatment were included in the prospective study. Thyroid volume was measured
      sonographically at the beginning as well as 6 and 18 months later. An increase in
      thyroid volume of more than 15% was taken as recurrence. RESULTS: The study was
      concluded in 41 patients. During the prophylaxis mean thyroid volume increased
      from initially 21.7 +/- 9.9 ml to 22 +/- 10.9 ml after 6 months and to 24.5 +/-
      12.1 ml after 18 months (P < 0.01). While thyroid volume remained unchanged in at
      least two thirds of patients, a recurrence occurred in 32% (n = 13; from
      initially 22.7 +/- 9.7 ml, to 26.3 +/- 11.3 ml at 6 months and to 29.7 +/- 12.3
      ml at 18 months). In all patients with a recurrence a doubling of the iodide
      dosage to twice weekly 1.53 mg for 6 months reduced thyroid volume again (mean of
      25.7 +/- 10.0 ml; P < 0.01). CONCLUSIONS: In at least two third of patients a
      once-weekly dose of 1.53 mg iodide is a reliable means of preventing a recurrence
      of endemic euthyroid goitre, but in the remainder the same dose must be increased
      to twice weekly.

PMID- 8646993
TI  - [Neuropsychiatric symptoms in vitamin B12 deficiency and microcarcinoidosis. The
      complications of chronic atrophic gastritis].
AB  - HISTORY AND FINDINGS: A 69-year-old woman reported marked restriction of
      voluntary movements of the hands in the preceding 6 months. She had also
      experienced loss of motivation, memory and concentration. Her skin was pale
      yellow, and scratches on her skin indicated marked pruritus. INVESTIGATIONS:
      Neurological examination revealed decreased vibratory sense in both legs.
      Haemoglobin concentration was 8.3 g/dl, mean corpuscular volume 114 fl, vitamin
      B12 level < 100 ng/l, folic acid level normal. Antibody titre against parietal
      cells was increased, vitamin B12 resorption diminished. Gastroscopy revealed
      small raised lesions, made up of hyperplastic cells which stained with
      chromogranin, indicating a diagnosis of microcarcinoid of the gastric mucosa.
      TREATMENT AND COURSE: On administration of cobalamine (1,000 micrograms i.m.
      daily for 2 weeks, twice weekly for 6 weeks, then once per week for the last 7
      months) the blood picture returned to normal, but the microcarcinoids, the
      psychological symptoms and the apraxia of the hands were unchanged.

PMID- 8646994
TI  - [The diagnosis of carotid stenosis].

PMID- 8646995
TI  - [Simvastatin].

PMID- 8646997
TI  - [Aluminum in deodorants].

PMID- 8646996
TI  - [The psychosomatics and psychotherapy of the cardiac anxiety syndrome].

PMID- 8646998
TI  - [Crusted scabies, an important dermatological differential diagnosis in AIDS].

PMID- 8646999
TI  - [The question of further rabies control in Germany].
AB  - By means of a mathematical model the question is considered whether and how
      rabies can be controlled in Germany by oral vaccination of foxes. The model shows
      that from the success obtained so far one should not yet assume to have rabies
      under control. Because immunization of foxes causes an increase in the fox
      population size, the number of available vaccine baits per fox decreases. Model
      calculations indicate, at least in some areas of Germany, it may be necessary to
      increase vaccine baits per area i order to reach and maintain a rabies free
      stage.

PMID- 8647000
TI  - [Animal welfare for animals kept for animal-supported therapy in homes and
      hospitals].
AB  - Three forms of animal husbandry for pet facilitated therapy from the society
      "Leben mit Tieren" e. V. Berlin, since 1988, are compared with actual animal
      welfare laws, criticism is pointed out, improvements are proposed.

PMID- 8647001
TI  - [Are nasal swabs for swine appropriate for the diagnosis of bacterial pneumonia
      agents?].
AB  - Nasal swabs and lungs of 150 pigs with pneumonia were tested by culture at post
      mortem examination. The isolated agents were Pasteurella multocida (P.m.), P.
      haemolytica, Bordetella bronchiseptica, Actinobacillus pleuropneumoniae,
      Staphylococcus aureus, Streptococcus spp. and Escherichia coli. P.m. was most
      frequently found, and this agent only showed a significant correlation between
      lungs and nasal swabs. In 80.6% of pigs with P.m. in the lung the agent was
      detected in the nose, too. Drug resistance patterns of P.m. isolates from lungs
      and noses of the single animals were identical or similar, also in case of
      different capsular types. The examination of porcine nasal swabs for bacteria
      capable of causing pneumonia should be limited to P. multocida. Demonstration of
      agents in lung material is generally more certain.

PMID- 8647002
TI  - [Thyroid hormones in cesarean-delivered suckling calves after birth and in the
      first days of life--maternofetal relations and early postnatal adaptation
      reactions].
AB  - Caesarean section delivered suckler calves and their dams from the mother cow
      herd were used for this investigation. Jugular venous blood samples taken
      immediately after delivery from the cow and the calf and in the calf at 24 hours
      and at 48 hours of postnatal age as well were analyzed for T4, FT4, T3 and FT3 by
      luminescence enzyme immunoassay. Strong correlation between the thyroid hormone
      values of the cow and those of the calf could be found. Higher thyroid hormone
      values were measured in calves increasing further at 24 hours of age and then
      decreasing a little at 48 hours of age with higher values in female than in male
      calves. A strong correlation existed between T3 and heart rate of the calves.

PMID- 8647003
TI  - [Automatic cell counting in cat blood].
AB  - The usability of the haematology analyzers ?F-800? and ?System 9000+? was
      investigated in cats using 40 blood samples. Reference measurements were done
      with a haemocytometer or the microhaematocrit method. Reliable leukocyte counts
      were measured with the analyzer F-800 in cases only, when the histogram rendered
      possible a clear demarcation of the leukocyte curve (r=0.97, n=25). With the
      analyzer System 9000+ a changed basic adjustment of the inferior discriminator
      (49 fl) vouched for a close correlation with the values measured visually
      (r=0.94). The volume distribution curves of the erythrocytes and thrombocytes
      which were partly overlapping allowed an approximate counting of the thrombocytes
      with both analyzers only of one half of the samples. The inaccuracy resulting
      from the inexact separation had only a relatively unimportant effect on the
      automatically measured erythrocyte count due to the numerical relation of erythro
      and thrombocytes. Here at a close correlation to the haemocytometer method
      (r=0.95) was found as well as slightly higher values with the automatic counting.
      The haematocrit measured with the analyzer F-800 and to a smaller extent by the
      use of the System 9000+ lay distinctly higher in relation to the values measured
      by microhaematocrit, when the analyzers were calibrated with human standards.
      Besides a species specific calibration of the haematocrit and a particular basic
      adjustment for leukocyte counting with the analyzer System 9000+, the use of the
      investigated haematology analyzers on feline blood requires an individual
      estimation of the histograms and removing of the discriminators as well as
      frequently a repetition of the leukocyte- and thrombocyte counting with a
      haemocytometer.

PMID- 8647004
TI  - [Drug residues in untreated swine].
AB  - The concentration of sulfadimidine was measured in the urine of pigs which were
      housed (over five days) in boxes where other pigs have been treated orally with
      sulfadimidine before. Sulfadimidine was measured in the urine of the unmedicated
      pigs in a concentration of up to 4 micrograms/ml. Considering these urine
      concentrations, violative sulfadimidine tissue residues would be expectable in
      the carcass after slaughter. The practice of fixing withdrawal times must be
      considered again to ensure that drug residues in tissues are below the MRL before
      slaughter also in unmedicated animals.

PMID- 8647005
TI  - [Results of multi-gas analysis in the raising of fattening swine in composted
      stalls or on slatted floors].
AB  - Using continuous multigasmonitoring on the basis of photoacoustic
      spectralanalysis a mean concentration of ammonia of 8.1 ppm, nitrous oxide of 2.1
      ppm and carbon dioxide of 0.12 Vol.-% was measured in a deep litter system for
      fattening pigs with additives. In slatted floor system with liquid manure storage
      the average concentration of ammonia (11.9 ppm) was significantly higher at the
      same period, whereas the concentration of nitrous oxide was appr. 0.2 ppm.
      Concentration of carbon dioxide in liquid manure system was lower (0.10 Vol.-%)
      than in deep litter system.

PMID- 8647006
TI  - Serum concentrations and tissue residues of spectinomycin in chickens.
AB  - Following a single intramuscular injection of 40 mg spectinomycin/kg.b.wt. in
      normal chickens, a maximum serum concentration was recorded at one hour, with
      half-lives of absorption [t0.5(ab)] and elimination [t0.5(beta)] valued with 0.21
      h and 3.27 h respectively. Following a single intravenous injection of 40 mg
      spectinomycin/kg b. wt. in normal chickens, the drug obeyed a three compartments
      open model. The mean systemic bioavailability following intramuscular injection
      was 3.72 %. The highest serum concentration of spectinomycin was achieved after
      one hour post each intramuscular dose during multiple dosage regimen. Serum and
      tissue concentrations of spectinomycin in slaughtered normal chickens following
      repeated intramuscular administration, three times daily for five consecutive
      days were investigated. In the present study, spectinomycin was bound in vitro
      with normal chicken serum protein at a level equal to 5.4 %.

PMID- 8647007
TI  - [The effect of a low molecular weight synthetic humic substance on selected
      reproductive parameters of male rats].
AB  - Influences of the low molecular humic substance HS 1500 on parameters of organs
      (testis weight, epididymis weight), FSH-, and LH-levels in plasma as well as on
      the spermatogenesis of male rats were studied. After a daily oral application of
      1000 mg/kg b.w. and 2000 mg/kg b.w., respectively over a period of 60 days (40th
      to 100th day of life) only 2 animals of the high dose group were observed with
      bilateral testicular atrophy. Despite of the two animals with testicular atrophy
      no significant differences between treated and control rats were observed with
      respect to testis morphology and spermatogenesis. There is no evidence whether
      the differences between the hormone levels and the testicular atrophy revealed is
      regarded to a HS 1500-effect or not. But otherwise a direct influence of HS 1500
      can be ruled out with high certainty. Possibly because of the thin covering layer
      on the gastrointestinal mucous membrane formed by HS 1500, the absorption of
      nutritive substances is inhibited. Therefore the growth of sensitive organs like
      testis and epididymis, in the development period, can be decreased. Nevertheless,
      even after long time application the spermatogenesis is not influenced.

PMID- 8647008
TI  - [Pharmacokinetics and tolerance of an orally administered combination preparation
      containing phenylbutazone and prednisolone in the dog].
AB  - Tolerance and pharmacokinetics of a combination of phenylbutazone and
      prednisolone (tablets) were studied in Beagle dogs. For two weeks, the drug was
      administered orally (3.33 mg/kg phenylbutazone combined with 0.1 mg/kg
      prednisolone and 6.66 mg/kg phenylbutazone combined with 0.3 mg/kg prednisolone
      twice daily). The dosage was reduced to 50 per cent after one week. No signs of
      intolerance were found. After treatment with 3.33 mg/kg phenylbutazone, a plasma
      concentration of 10 micrograms/ml was reached within 1 to 2 hours. No
      prednisolone concentration above 2 ng/kg was measured. Additionally, a
      synergistic antiinflammatory effect of the two ingredients was obvious (hind paw
      dextran edema in rats). In addition to results of ENGELKE et al. (1995) who
      studied the clinical efficacy of the combination, the presented data demonstrate
      a good tolerance.

PMID- 8647009
TI  - [pH, sodium, potassium, magnesium, calcium, phosphate and chloride in the rumen
      and abomasal contents of cows with abomasal displacement].
AB  - Ruminal and abomasal contents were collected from cows with left abomasal
      displacement (L), right abomasal displacement (R-), or abomasal volvulus (R+),
      before the abomasum was corrected, as well as one and three days later, pH and
      concentrations of sodium (Na), potassium (K), magnesium (Mg), calcium (Ca),
      phosphate (P), and chloride (Cl) were determined. Results were compared with
      those from healthy control cattle fed a balanced diet. Ruminal concentrations of
      Na and Ca were reduced in cattle with abomasal displacement, whereas those of K,
      P and Cl were increased, and those of Mg and pH remained nearly unchanged.
      Concentrations of K and P before abomasal correction were lower in cattle with L
      than in those with R+, and declined after the correction. Concentrations of Cl
      decreased continuously after the abomasum was corrected in cattle with L, whereas
      they increased after replacement in cattle with R and declined later. These
      findings imply that cattle with abomasal displacement took up less feed before
      surgical correction and that ruminal contents backed up in the rumen, whereby the
      backup was less with L than with R+, and that the backed-up contents passed on
      after the abomasum was corrected. The results also indicate that a reflux of
      abomasal contents into the rumen took place in cattle with all forms of abomasal
      displacement, whereby with R+ increased amounts of abomasal contents passed into
      the rumen following correction and were then later passed out. Compared to
      controls, abomasal concentrations of Cl were increased in cattle with
      displacement and the concentrations of K, Mg, Ca, and P were reduced. Before
      abomasal correction, pH was decreased in cattle with L and unchanged in those
      with R- and R+. The concentrations of Na and K before correction in L were lower
      than those with R+, whereas the concentrations of K, Mg, Ca, and P were higher.
      After abomasal correction, the concentrations of Na declined, and those of K, Mg,
      Ca, and P increased. On the third day after abomasal correction, pH and the
      concentrations of K, Mg, Ca, and P were lower and the concentrations of Cl higher
      than in controls. These findings indicate that before abomasal correction in
      cattle with abomasal displacement secretion from the abomasal glands was
      increased, abomasal contents backed up in the abomasum, whereby the
      secretion/backup was less with L than with R+, and that the backed-up contents
      are passed on after the abomasum is corrected. The findings also suggest that the
      increased rate of secretion from the abomasal glands or abomasal motility
      disorders continues on to the third day after abomasal correction.

PMID- 8647010
TI  - [The effect of timing of labor induction on the occurrence of congenital
      myofibrillar hypoplasia--short clinical report].
AB  - In an intensive pig production unit with routinely performed prostaglandin partus
      induction four groups of sows were formed shortly before parturition. The animals
      received 3 mg alfaprostol as a single intramuscular injection each. The sows of
      group 1 on the 112th, those of group 2 on the 113th and the animals of group 3 on
      the 114th day of pregnancy. Group 4 sows were not treated and formed the control
      group. We evaluated the number of live born piglets and the number of piglets
      born with congenital myofibrillar hypoplasia. The results showed no significant
      difference regarding live born piglets. As regards congenital myofibrillar
      hypoplasia the sows with early partus induction (group 1) showed significant
      higher incidence when compared to the other groups. It is likely that in cases of
      partus induction before the 113th day of pregnancy the fetus is still
      insufficiently protected by natural maturation, adaptation and tolerance ability
      against such congenital condition as CMH. Therefore it is the opinion of the
      authors that partus induction before the 113th day of pregnancy should not be
      performed.

PMID- 8647011
TI  - [Dangerous dogs as a problem of regulatory law--the GefHuVO NW].
AB  - The GefHuVO NW Council Regulation, introduced in September 1994 ("Official
      Ordinance with regard to the Breeding, Teaching, Special Training and Keeping of
      Dangerous Dogs") deals with the dangers for humankind and animals caused by
      dangerous dogs. Although the public is regularly disturbed by reports on injuries
      by certain thoroughbreds (so-called pit-bull terriers), the Regulation leaves out
      a conclusive catalogue of dog breeds to be classified as dangerous, and rather
      attempts to circumscribe the danger in abstract terms. Cooperation with the local
      veterinary surgeons is to provide the information necessary to prepare for the
      Council intervention. The Regulation lays down a canon with varying and
      increasing power of legal possibilities of intervention which extend from decrees
      regarding muzzles to a certificate of expertise, to a ban on keeping animals. In
      the author's estimation, this new Regulation proves to be legally superfluous and
      partly--insofar as it creates hitherto unknown possibilities of intervention--as
      impracticable, as it confronts the Council such as veterinary surgeons in
      administrative practice with difficult problems of assessment.

PMID- 8647012
TI  - [Hemophilia B in a mixed breed male dog: treatment of a hemorrhagic crisis with
      fresh frozen plasma].
AB  - A 6 months old male crossbred dog became conspicuous because of a considerable
      haematoma in the region of the left thigh without recognizable exterior trauma.
      The results of the screening tests of the haemostatic system (distinctly
      prolonged activated partial thromboplastin time [aPTT], normal thromboplastin
      time and platelet count as well as a shortening of thrombin time) yielded a
      tentative diagnosis of haemophilia. Haemophilia B could be diagnosed on the basis
      of a distinctly and isolated reduced factor IX activity (8%, reference range: 70
      140%). Two infusions with 20 ml/kg BW fresh frozen plasma each caused a clear
      clinical recovery of the patient. In addition, the efficacy of plasma infusion
      was documented in vitro by a temporary increase of factor IX activity as well as
      repeated measurements with the resonance thrombograph and of the aPTT.

PMID- 8647014
TI  - Proximal and segmental motor nerve conduction in the sciatic nerve produced by
      percutaneous high voltage electrical stimulation.
AB  - Percutaneous high voltage electrical stimulation was applied to the proximal
      sciatic nerve at the hip in 18 normal subjects to evaluate motor conduction in
      the proximal sciatic nerve, and short-segment stimulation of the sciatic and
      posterior tibial nerves was given in 6 normal subjects. Compound muscle action
      potentials (CMAPs) were recorded from the abductor hallucis (AH) and extensor
      digitorum brevis (EDB) muscles. Supramaximal stimulation was easily obtained at
      the proximal sciatic nerve and all the sites in the short-segment stimulation.
      The motor nerve conduction velocity of the sciatic nerve between the hip and the
      popliteal fossa was 49.2 +/- 4.24 m/sec in the tibial division and 54.1 +/- 6.48
      m/sec in the peroneal division. The respective peak-to-peak amplitude and
      negative-peak areas of the CMAPs at the hip were reduced to 86.8 +/- 5.65% and
      97.3 +/- 5.36% for the tibial division, and 93.4 +/- 7.06% and 96.8 +/- 5.09% for
      the peroneal division as compared to the values for the popliteal fossa. The
      negative-peak duration of the CMAPs at the hip point were increased to 109.2 +/-
      7.2% for the tibial nerve and 107.1 +/- 5.68% for the peroneal nerve as compared
      with the duration at the popliteal fossa. This method is non-invasive and useful
      for evaluating motor nerve conduction in the lower limb.

PMID- 8647013
TI  - [The effect of a low molecular weight synthetic humic substance on pre- and
      postnatal development in rats].
AB  - The influence of a low molecular synthetic humic substance (HS 1500) on pre- and
      postnatal development of rats was investigated. After oral application of 1000
      mg/kg and 2000 mg/kg b. w. HS 1500 during the period of organogenesis (6th to
      15th day p. c.) and from 16th day p. c. up to weaning neither adverse effects in
      the mothers nor in the fetuses were reported. The occurrence of a single
      malformation (gastroschisis) after application of 1000 mg/kg b. w. from day 6 to
      15 of pregnancy, few ossifications of phalanges and differences in swimming
      behaviour are not regarded as the effect of the substance. In conclusion, the
      oral use of HS 1500 in the treatment of gastrointestinal diseases in animals
      during pregnancy is regarded to be riskless.

PMID- 8647015
TI  - Guillain-Barre syndrome or "new" Chinese paralytic syndrome in northern China?
AB  - A serial study of clinical and magnetic stimulation motor evoked potentials (MEP)
      was accomplished in 44 patients with the acute flaccid paralytic syndrome which
      occurred in Northern China in 1991. Control data were provided by 70 healthy
      subjects from the same area. The cases came from the same area where a so-called
      new "Chinese paralytic syndrome" had been reported. We found the clinical
      features of these 44 patients to be similar to those of classical Guillain-Barre.
      Prolongation of MEP latency at 2 sites or on 2 occasions was found in 36 patients
      of whom 26 showed obvious clinical and electrophysiological recovery within 4-8
      weeks. Three cases showed reduced MEP amplitude with normal latency, but in 2 of
      them the amplitude recovered in 2-8 weeks. Only 2 cases had no response at all
      time. We think 41 patients (93.7%) had predominant nerve demyelination. The 3
      other patients (6.8%) showed axonal degeneration which is within the range found
      in previous reports of classical Guillain-Barre. We conclude that the acute
      paralytic syndrome seen in the summer of 1991 in Northern China represents a
      classical Guillain-Barre syndrome with demyelination of motor and sensory fibers.
      There is no reason to consider any special nomenclature such as "Chinese
      paralytic syndrome" or "acute motor axonal neuropathy."

PMID- 8647016
TI  - Impairment of posturo-kinetic co-ordination during initiation of forward oriented
      stepping movements in parkinsonian patients.
AB  - In order to differentiate between a specific impairment affecting gait initiation
      and a non-specific deficit in the postural adjustment which occurs prior to any
      forward oriented stepping movement, 3 forward oriented movements (FOMs),
      performed by a group of parkinsonian patients and a group of healthy age-matched
      subjects, were compared in the present study. These FOMs all consisted of
      initiating 1 step, but differed in their respective planning characteristics. The
      first consisted of initiating normal walking. The second consisted of initiating
      a single step, while the third was a visually guided task, consisting of placing
      the foot just behind a mark on the ground. In all 3 FOMs, the postural phase,
      i.e., the time elapsing between the initial shift of the center of pressure (CP)
      and the onset of the first step, was significantly longer in the patients than in
      the healthy subjects, whereas the duration of the subsequent movement phase,
      i.e., that of the first step, was within the same range in both groups. The
      horizontal reaction forces that led to a forward center of gravity (CG)
      acceleration during the postural phase were markedly reduced in the patients in
      all 3 FOMs, and the maximal velocity of the iliac crest marker, which corresponds
      approximately to that of the CG, decreased significantly in the patients. In
      addition, the length of the first step was significantly shorter in the patients
      than in the healthy subjects, in all 3 FOMs. The EMG pattern differed
      significantly between the patients and the healthy subjects; the amplitudes of
      the early tibialis anterior (TA) and vastus lateralis (VL) activations often
      decreased and were unilateral rather than bilateral. In addition, the
      gastrocnemius medialis (GM) burst associated with foot lift-off at the end of the
      postural phase was either absent or greatly reduced, thus suggesting that the co
      ordination between the preparatory postural adjustment of the whole body and the
      actual stepping movement was impaired. The present results suggested that the
      lengthening of the postural phase is a common deficit in all FOM tasks in
      parkinsonian patients and is due to the impaired production of the requisite
      propulsive forces providing the forward acceleration of the CG. Consequently, a
      shortening of the first step length occurs. However, the step length is reduced
      less in the FOM tasks which provide some information about the goal of the first
      step (single step, visually guided step) than in a normal walking task, during
      which such information is missing. This suggests that although the stepping
      movement can be improved with the aid of any sensory cue about the end of the
      step in patients with Parkinson's disease, the postural phase will always be
      prolonged whichever FOM task they perform.

PMID- 8647017
TI  - A new method of quantifying human muscle sympathetic nerve activity for frequency
      domain analysis.
AB  - We present a new method for quantitative analysis of muscle sympathetic nerve
      activity (MSNA), expressed as muscle sympathetic burst area (MSBA). This
      technique is likely to be useful for inter-individual comparisons and for
      frequency domain analysis of MSNA. After standardization of MSNA so that the
      burst of highest amplitude in the integrated MSNA trace was 1000 units, MSNA was
      assessed by measuring the area of each burst in the integrated MSNA trace, with
      baroreflex latency of about 1.3 sec while triggered by consecutive R-waves of the
      ECG. We examined the relationship between MSBA and burst rate (burst number/min)
      or plasma norepinephrine levels at rest in 50 healthy subjects, aged 23-82 years.
      MSBA showed positive correlations with burst rate (r = 0.91, n = 50) and plasma
      levels of norepinephrine (r = 0.64, n = 22). During head-up tilting in 6
      subjects, MSBA showed linear correlations with sine values of tilt angles and
      with plasma norepinephrine levels. These results suggest that MSBA is a useful
      index of MSNA for evaluating both intra-individual and inter-individual
      variations of MSNA.

PMID- 8647018
TI  - Evaluation of the diagnostic performance of the expert EMG assistant MUNIN.
AB  - The diagnostic performance of the medical expert system MUNIN for diagnosis of
      neuromuscular disorders was evaluated on a set of 30 test cases. The cases were
      provided by 7 experienced electromyographers who were subsequently invited to
      participate in the evaluation. To reasonably cover the range of disorders, the
      electromyographers were asked to provide cases from patients with different types
      of muscular dystrophy, with neuromuscular transmission disorders, with motor
      neurone disease, and with different types of polyneuropathies. In addition,
      patients with a range of local neuropathies were provided. Out of the 30 cases,
      11 cases were evaluated by an "almost peer review" method and the remaining 19
      cases were evaluated by a "silver standard" method. The number of cases evaluated
      by "almost peer review" was limited to 11 due to time constraints on the
      evaluation procedure. During the "almost peer review," each electromyographer was
      asked to diagnose patients, using a vocabulary that closely resembled MUNIN's
      vocabulary. Subsequently, we attempted to provide a consensus diagnosis for the
      patients based on discussion among the participating electromyographers. The
      electromyographers were also asked to assess how well MUNIN had performed in each
      case. The remaining 19 cases were evaluated by a "silver standard" procedure,
      where MUNIN's diagnosis was compared to the diagnosis of the expert who provided
      the case. The results indicated that MUNIN performed well, and the
      electromyographers considered "that MUNIN performed at the same level as an
      experienced neurophysiologist." In particular, it was noted that MUNIN handled
      cases with conflicting findings well, and that it was able to diagnose patients
      with multiple diseases.

PMID- 8647019
TI  - "Slinky" coils for neuromagnetic stimulation.
AB  - Future advances in neuromagnetic stimulation depend significantly on the design
      of coils with improved focality. Although in the absence of internal current
      sources, no true focusing of magnetically induced currents is possible,
      improvements in the focality of current concentrations passing through an area of
      biologic tissue are achievable through variations of the shape, orientation and
      size of neuromagnetic stimulating coils. The "butterfly" and the "4-leaf" coils
      are two examples of planar designs which achieve improved focality through
      centralization of the maximum coil current and peripheral distribution of the
      return currents. We introduce the "slinky" coil design as a 3-dimensional
      generalization of the principle of peripheral distribution of return currents and
      demonstrate its advantages over planar designs.

PMID- 8647021
TI  - Transverse-field activation mechanism in magnetic stimulation of peripheral
      nerves.
AB  - The activating function of peripheral nerves in magnetic stimulation is thought
      to be the gradient of the induced electric field component parallel to the nerve.
      This implies that there are several orientations of the coil that should not
      excite nerves. We show that these orientations, however, often yield high
      amplitude and even supramaximal muscle response, indicating that the model of the
      activating function has to be modified. We propose that the electric field
      component perpendicular to the nerve is responsible for these unexpected muscle
      responses. Our conclusion is based on practical experiments with different coils
      and on computer simulations of the induced electric field and its gradient.

PMID- 8647020
TI  - A new method using neuromagnetic stimulation to measure conduction time within
      the cauda equina.
AB  - Using principles derived from electric field measurements and studies of phrenic
      nerve in vitro, neuromagnetic stimuli in humans were predicted to excite
      selective low threshold sites in proximal and distal cauda equina. Physical
      models, in which induced electric fields were recorded in a segment of human
      lumbosacral spine immersed in a saline filled tank, supported this prediction.
      Conclusions from the model were tested and confirmed in normal human subjects.
      Ipsilateral motor evoked potentials were elicited in lower limb muscles and
      striated sphincters by magnetic coil (MC) stimulation of both proximal and distal
      cauda equina. Over proximal cauda equina a vertically oriented MC junction and
      cranially directed induced current elicited a newly identified compound muscle
      action potential (CMAP). The F response latency and lack of attenuation when the
      target muscle was vibrated suggest that the proximal response is a directly
      elicited M response arising near or at the rootlet exit zone of the conus
      medullaris. Over distal cauda equina, lumbar roots were optimally excited by a
      horizontally oriented MC junction, and sacral roots by an approximately
      vertically oriented MC junction, eliciting CMAPs with similar appearance but
      shorter latency consistent with the known intrathecal lengths of the lower lumbar
      and sacral nerve roots. The induced current was usually most effective when
      directed towards the spinal fluid filled thecal sac. Normal subjects showed
      stable CMAP onset latencies elicited at proximal and distal cauda equina despite
      wide variation in amplitude. Thus, cauda equina conduction time can be directly
      calculated. This new method may improve the detection and classification of
      peripheral neuropathies affecting lower limbs and striated sphincters.

PMID- 8647022
TI  - Activation and suppression of the sternocleidomastoid muscle induced by
      transcranial magnetic stimulation.
AB  - Responses in the stemocleidomastoid muscle (SCM) induced by transcranial magnetic
      stimulation (TMS) were investigated in 10 healthy subjects. Stimuli were given
      with the Dantec MagLiteTM magnetic stimulator using a 12.5 cm circular coil with
      counter-clockwise current direction. Monopolar needle electrodes with isolated
      shafts were used for simultaneous bilateral electromyographic (EMG) recordings of
      the SCM. TMS given on either side invariably induced an ipsilateral motor evoked
      potential of the SCM (SCM-MEP), whereas a contralateral SCM-MEP was just seen in
      25% of the performed stimulation series also when maximal intensity was used. The
      SCM-MEPs recorded ipsilaterally to the side of stimulation had significantly
      higher maximal amplitudes (P < 0.05) compared to the SCM-MEPs recorded
      contralaterally (mean +/- S.D.: 1.0 +/- 0.5 and 0.2 +/- 0.1 mV, respectively).
      These results support the concept of a predominantly ipsilateral control of SCM
      activation. The contralateral SCM-MEPs tended to have a shorter latency than the
      ipsilateral SCM-MEPs. The thresholds of the ipsilateral SCM-MEPs were
      significantly higher (P < 0.01) on the left side than on the right side (mean +/-
      S.D.: 78 +/- 18 and 60 +/- 16 A/microseconds, respectively), which could be due
      to the consistent use of counter-clockwise coil current direction. TMS given on
      either side induced suppression of voluntary SCM activity in all investigated
      subjects. Responses induced by TMS given ipsilaterally and contralaterally to the
      voluntary activated muscle did not differ significantly (P > or = 0.05) regarding
      threshold or latency of the suppression.

PMID- 8647023
TI  - Evaluation of Hjorth parameters in forearm surface EMG analysis during an
      occupational repetitive task.
AB  - The Hjorth parameters are normalized slope descriptors (NSDs) usually used in
      sleep EEG processing for data reducing and/or automatic sleep stage scoring. In
      the present study NSDs of forearm surface EMG recorded from 9 subjects performing
      occupational repetitive movements are compared to conventional FFT spectral
      analysis. The correlation coefficients between the NSD labelled mobility and the
      FFT mean frequency range from 0.81 to 0.93. Results show that these time domain
      properties can also describe the spectral content of surface EMG during
      repetitive movements. Moreover, the NSD method offers a low cost calculation time
      since it is based on the sole concept of variance.

PMID- 8647024
TI  - Generator sites for spontaneous activity in neuromyotonia. An EMG study.
AB  - A 16-year-old female patient with symptoms and signs compatible with
      neuromyotonia was studied with various neurophysiological tests and with muscle
      biopsy. Nerve conduction studies revealed signs of axonal motor neuropathy. EMG
      showed denervation in distal muscles, and moderate neurogenic changes in other
      muscles. Abundant spontaneous motor unit activity was recorded in all muscles.
      This activity did not disappear upon proximal nerve blockade with local
      anaesthetics. Based on the shape of spontaneous discharges and their behaviour on
      nerve stimulation and during voluntary effort, the site of generation was
      suggested. This varied for different discharges, from proximally in the nerve, to
      various sites along the intramuscular nerve tree. In some axons there were signs
      of conduction block proximal to the generation site for the spontaneous
      discharges. Different axons showed various degrees of abnormality; local
      hyperexcitability triggering new impulses only after the passage of a preceding
      impulse, increased hyperexcitability generating spontaneous activity, total
      impulse blocking, and finally axonal degeneration. Treatment with dihydantoin
      reduced the spontaneous activity with concomitant clinical improvement.

PMID- 8647025
TI  - Stretch reflexes of the proximal arm in a patient with mirror movements: absence
      of bilateral long-latency components.
AB  - The stretch reflex responses evoked by unilateral limb displacement in distal
      (first dorsal interosseus (FDI)) and in proximal (biceps brachii (Bb)) arm
      muscles were studied during matched bilateral contractions in a patient with
      congenital mirror movements. In this patient unilateral transcortical magnetic
      stimulation (TMS) elicited not only the normal contralateral EMG response but
      also a clear ipsilateral component in the EMG of both proximal and distal arm
      muscles. As expected from previous studies, the ipsilateral FDI muscle responded
      to stretch of the index finger with short- (M1) and long-latency (M2) reflex
      components. In addition, the FDI contralateral to displacement exhibited an
      abnormal mirrored response corresponding to the M2 interval. In contrast, whereas
      the ipsilateral Bb responded to imposed elbow extension with a marked M1/M2
      reflex response, no mirroring of either reflex component was apparent in the
      contralateral Bb EMG. If the mirroring of the M2 in the FDI is accepted as
      evidence for the transcortical nature of the M2 reflex response, then it follows
      that the absence of such mirroring in the Bb indicates that a transcortical
      mechanism cannot play a major role in the generation of long-latency stretch
      reflex responses in proximal arm muscles.

PMID- 8647026
TI  - Impaired "natural reciprocal inhibition" in patients with spasticity due to
      incomplete spinal cord injury.
AB  - Experiments were performed to compare the ability of normal subjects and patients
      with spinal spasticity to suppress antagonist H reflexes during isometric ankle
      contractions. Soleus H reflex suppression was examined during tonic pretibial
      muscle contractions in which the torque levels were constant and during dynamic
      pretibial muscle contractions in which the torque followed a predetermined ramp.
      As well, subjects were instructed to alternately contract ankle plantarflexors
      and dorsiflexors at various frequencies to examine patterns of EMG activity
      during rhythmically alternating isometric contractions in antagonist muscles.
      Patients with incomplete spinal cord injury demonstrated reduced ability to
      suppress soleus H reflexes during pretibial muscle contraction. At slow speeds of
      alternating contraction, spinal cord injured patients retained the ability to
      perform alternating isometric pretibial/soleus muscle contractions. The patients
      demonstrated abnormal coactivation in soleus muscle during faster alternating
      isometric ankle muscle contractions. Furthermore, the patients who demonstrated
      the greatest impairment in natural reciprocal inhibition, also displayed the
      largest amount of coactivation. In general, the results would suggest that
      impairment of natural reciprocal inhibition is correlated with an increase in the
      amount of antagonist muscle coactivation seen during alternating isometric muscle
      contractions.

PMID- 8647027
TI  - Modulation of human rhythmical jaw motor function by perioral argon laser
      stimuli.
AB  - The influence of peripheral afferent activity on human jaw motor function was
      examined in this study. Painful argon laser stimuli were applied to the upper lip
      in 10 subjects during rhythmical jaw movements and the effects on the jaw-closer
      electromyogram (EMG) and jaw movements were studied. The duration of the open
      close cycle (1 sec) and the voluntary level of the jaw-closer EMG burst were
      standardized by auditory and visual feedback, respectively. Laser stimuli (0.2
      sec) were delivered at predetermined percentages of the open-close cycle. Laser
      stimulation consistently had an excitatory effect on the jaw-closer EMG burst.
      The root-mean-square (RMS) value of the stimulus-related EMG burst was
      significantly larger than the preceding and the following EMG bursts. The
      excitatory effects on the jaw-closer EMG burst were modulated with respect to
      where in the open-close cycle the laser stimulus was applied, the voluntary force
      of the jaw-closer burst, and the laser stimulus intensity. Thus, the largest
      excitatory effects were seen during the start of jaw closure, with the most
      forceful voluntary contractions, and with the most painful laser stimuli. The
      stimulus-related changes in the jaw-closer EMG bursts were always associated with
      a significant shortening (30-90 msec) of the duration of the open-close cycle.
      The present results suggest that argon laser-induced activity in sensory
      afferents may generally have an excitatory effect on rhythmical jaw-closer motor
      performance.

PMID- 8647028
TI  - Electrophysiological findings in peripheral fibres of subjects with and without
      post-herpetic neuralgia.
AB  - The peripheral nervous system was studied using classical electrophysiological
      methods in 23 subjects with post-herpetic neuralgia (PHN), and compared with the
      same parameters in 64 herpes zoster (HZ) patients without PHN. The findings
      indicated sensory axonopathy, the severity of which varied in different patients.
      Ten percent of all cases showed segmental paresis corresponding to dermatomes
      affected by HZ. In another 17% of patients axonal motor damage was only
      detectable by EMG as denervation. No statistically significant difference was
      found between the two groups in the mean percentage differences of the
      electrophysiological data for peripheral sensory fibres with respect to mean
      control values, or between sides affected by HZ and healthy sides. Hence HZ is
      associated with sensory axonopathy, the severity of which is similar, on the
      whole, in the groups with and without PHN and stable in time. This suggests that
      damage to peripheral large-diameter sensory fibres is not the cause of PHN.

PMID- 8647029
TI  - Conduction velocity in the forearm segment of the median nerve in patients with
      impaired conduction through the carpal tunnel.
AB  - Conduction velocity, in the forearm segment of the median nerve, has been
      investigated in a group of patients with carpal tunnel syndrome. Motor conduction
      velocity was reduced below 50 m/s in 18% of the sample. Although a correlation
      between severity of compression and forearm motor conduction velocity was
      demonstrated, it was weak (r = 0.51) and slow forearm velocities occurred in some
      patients who had only a minor abnormality at the carpal tunnel itself. In
      patients with uncomplicated carpal tunnel syndrome, slow motor conduction in the
      forearm segment of the median nerve was accompanied by only a small reduction
      (approx. 5 m/s) in mixed nerve conduction velocity. By contrast, in patients
      whose abnormality at the carpal tunnel was accompanied by evidence of a more
      widespread sensorimotor neuropathy, mixed nerve conduction velocity was reduced
      in parallel with the change in motor conduction velocity.

PMID- 8647030
TI  - The axonal carpal tunnel syndrome.
AB  - Five patients with typical unilateral carpal tunnel syndrome features were
      studied. Each patient had a normal electrodiagnostic evaluation, including needle
      examination (C5 to C8T1), distal motor latency, palm to wrist orthodromic sensory
      conduction velocity, and special tests: median-ulnar latency difference of the
      4th digit, palmar centimetric technique. Only a new test, the orthodromic sensory
      ultra distal test of all the digits, revealed a significant axonal loss (60-90%)
      in at least two median digits allowing the diagnosis of median nerve impairment.
      These findings led us to propose the term, axonal carpal tunnel syndrome for this
      early stage of the disorder.

PMID- 8647031
TI  - High frequency discharge of a fraction (f) of motor unit action potential.
AB  - Two repetitive discharges, firing at 105 and 180 Hz, were evoked in muscles with
      chronic denervation. They were delayed following a motor unit action potential
      (M), and their maximum duration was 800 and 50 ms, respectively. The potential of
      both high frequency discharges was of low amplitude and short duration. It was
      considered to be a fraction (f) of the motor unit potential, and to depend on
      muscle fibres re-innervated by an axonal branch. The repetitive mechanism was
      tested by double stimulation. It seemed to be an ephaptic re-excitation of the
      axonal branch by a sprout rather than an ectopic trigger locus on the latter. The
      antidromic waves, associated with the repetitive discharges on the axonal branch,
      failed to be transmitted to the main axon. This failure, assimilated to a
      conduction block, was complete in the first case as M was not repetitive. It was
      intermittent in the second case as M was firing intermittently. Repetitive
      activity associated with 'terminal multifocal block' could be relevant to the
      fractional activation observed by others in some disease states.

PMID- 8647032
TI  - EMG spike trains of succinylcholine-induced fasciculations in myalgic patients.
AB  - Single spike activity from the surface electromyogram (EMG) of fasciculations
      induced by succinylcholine (Sch) were studied from limb muscles (biceps, triceps,
      anterior tibialis and gastrocnemius) in 100 female patients. About 2/3 of them (n
      = 72) also received nondepolarizing neuromuscular pretreatment (atracurium or
      vecuronium). We observed from 20% of EMG records in the myalgic (but not in the
      nonmyalgic) patients, sustained spike trains (mean duration 1.47 s) that
      resembled motor units firing at physiologically high rates (mean 21.7 spikes/s).
      The finding reflects Sch's distal actions at the muscle spindle. The implications
      for myalgia and the possible involvement of micro damage at the extrafusal
      muscles are discussed.

PMID- 8647033
TI  - Muscle modifications in Parkinson's disease: myoelectric manifestations.
AB  - The muscle changes occurring in Parkinson's disease (PD) may come about as a
      consequence of the modified pattern of motor unit activation and rigidity, which
      are characteristic of the disease. A tendency towards hypertrophy of type I
      fibers and, in some instances, atrophy of type II fibers has been observed.
      Fourteen patients affected by PD and 10 age-matched controls were studied in
      order to investigate these muscle changes. We indirectly evaluated muscle
      modifications by measuring muscle fiber conduction velocity (CV) and median
      frequency (MDF) of the power spectrum using automatic analysis of surface EMG.
      The tibialis anterior muscle was selected for the study of contractions
      electrically induced by 35 Hz pulse trains lasting 30 s; the myoelectric signal
      was detected using the 4-bar electrode technique described by Broman et al.
      (Broman, H., Bilotto, G. and De Luca, C.J. Myoelectric signal conduction velocity
      and spectral parameters: influence of force and time. J. Appl. Physiol., 1985,
      58: 1428-1437). Muscle biopsy specimens were obtained in 4 PD patients by
      surgical excision at the site where the EMG recording electrode had been placed.
      The main difference observed between PD subjects and controls was the rate of
      change of MDF and CV during the course of stimulated contraction; patients with
      PD sustained a smaller fatigue related decrease in both parameters compared to
      controls. According to our histological data, this result can be explained by a
      type I fiber percentage which accounts for 79% of the myofiber population on
      average. As expected, the CV basal values correlated directly with type I fiber
      diameter. These data suggest that non-invasive surface EMG techniques are useful
      in assessing the modifications of muscle characteristics that are observed in PD
      patients and for analyzing some aspects of the peripheral fatigue in this
      disease.

PMID- 8647034
TI  - Classical conditioning of the human flexion reflex.
AB  - The eyeblink conditioning paradigm is a well established model for studying
      learning processes in humans and animals. In this study a flexion reflex
      conditioning paradigm was established using the standard delay paradigm. The
      flexion reflex was elicited in 10 young, healthy subjects by a train of
      electrical pulses (100 ms, 100 Hz, 0.65 ms) applied to the medial plantar nerve
      (unconditioned stimulus, US). A tone (1000 Hz, 550 ms) was presented via
      headphones as the conditioning stimulus and which coterminated with the US.
      Responses were recorded from the anterior tibial muscles. Subjects were
      conditioned within one session of 120 trials of paired stimuli. This was
      established statistically via the continuous change in characteristic parameters
      of the responses throughout the experiment. Although the process of limb muscle
      conditioning takes longer than eyeblink conditioning, this type of flexion-reflex
      conditioning may possibly serve as a further model for the study of plastic
      changes within the nervous system. Moreover, the considerable versatility of limb
      movements offers the advantage of greater possibilities for testing the
      conditioning result.

PMID- 8647035
TI  - Actigraphic evaluation of handedness.
AB  - The utility of an objective evaluation of motor activity, actigraphy, was
      examined in the evaluation of handedness. Hand preference was assessed in a
      homogeneous group of 190 young volunteers using the Edinburgh Inventory (EI). The
      EI distribution obtained in the population studied was comparable with
      distributions cited in the literature. Simultaneous actigraphic recordings from
      both wrists were made in 58 of these subjects for 20 h, starting at 1000 h, using
      an epoch length of 4 s. Care was taken to include comparable numbers of right-
      and left-handers (based on EI score) in this subgroup. Two actigraphic parameters
      were defined. One of these, the Activity Index (AI[x]), is a measure of the
      difference in total motor activity between right and left wrist. The other,
      Movement Index (MIy[x]) is a measure of the difference in movement pattern. AI[x]
      showed a moderate but significant correlation with EI (r = 0.36, P < 0.005). The
      correlation between MIy[x] and EI was high (r = 0.65, P < 0.0001). Rebinning of
      the data into 60 s epochs decreased the degree of linear correlation between
      MIy[x] and EI. We conclude, in contrast to a previous study, that actigraphy can
      be used to discriminate between dominant and non-dominant hands; that the
      difference in movement pattern between right and left hand is larger than the
      difference in total motor activity; and that epoch lengths shorter than the
      conventional 60 s are more sensitive for this kind of discrimination.

PMID- 8647037
TI  - Hand motor cortex activation in a patient with congenital mirror movements: a
      study of the silent period following focal transcranial magnetic stimulation.
AB  - Motor evoked potentials (MEPs) to focal transcranial magnetic stimulation (TMS)
      have demonstrated that abnormal ipsilateral corticospinal projections are active
      in patients with congenital mirror movements. In addition, movement-related
      potentials and PET suggest that an abnormal pattern of motor cortex activation
      could be associated with an anomaly of the corticospinal tracts. In the present
      study the silent period (SP) following focal TMS was investigated in a woman with
      familial congenital mirror movements. Recordings were made from both abductor
      pollicis brevis (APB) muscles. When focal TMS was delivered during an intended
      contralateral APB muscle contraction, MEP and SP were bilaterally recorded and SP
      was significantly shorter than the contralateral SP observed in normal controls.
      An abnormal bilateral activation of the hand motor cortex can explain our
      findings. The non-stimulated motor cortex causes an early partial recovery of the
      background EMG activity when the stimulated motor cortex is still inhibited
      (beginning as soon as the transcallosal and the short-lasting segmental
      inhibition are both complete).

PMID- 8647036
TI  - Magnetic transcranial stimulation in acute stroke: early excitation threshold and
      functional prognosis.
AB  - Magnetic transcranial stimulation was used in 90 subjects (60 acute ischaemic
      sylvian strokes and 30 healthy controls) in order to evaluate the clinical value
      of the excitation threshold (ET) in the estimation of functional prognosis. ET
      mean values recorded 7, 30 and 90 days after stroke (at D7, D30 and D90) in two
      distal muscles of the upper limbs of the patients were compared with results
      obtained in 30 healthy control subjects. The data from the patients who
      ultimately achieved a satisfactory functional recovery at D90 were compared with
      those from patients who had not recovered in that time. Our results suggest that
      ET evolution differs according to functional outcome: (1) ET mean values were
      increased in the stroke patients at D7, but ET was constantly lower at D30 and
      D90 in patients who recovered than in those who did not. (2) ET temporal
      evolution showed a gradual decrease of the mean values from D7 to D90 in both
      stroke groups. This ET decrease was more marked in the patients who recovered
      from D30 to D90, but with only minor change after D30. (3) The localisation of
      the lesion had no significant effect on ET mean values at D7, D30 or D90. We
      conclude that the predictive value of ET estimation might be utilised at D30 in
      patients with ischaemic sylvian strokes.

PMID- 8647038
TI  - Clinical utility of magnetic corticospinal tract stimulation at the foramen
      magnum level.
AB  - We applied magnetic stimulation of the corticospinal tract at the foramen magnum
      level to 19 patients with various neurological disorders. Results were consistent
      with our previous speculation that activation occurs at the foramen magnum level.
      This method was clinically useful for the following conditions. (1) Detection of
      subclinical lesion: one patient who had transient ischemic attack that caused no
      clinical symptoms at examination was shown to have dysfunction of the
      corticospinal tract. (2) Multiple lesions: our method disclosed at least one
      lesion above and below the foramen magnum in two patients with multiple
      sclerosis. (3) Unmasking of dysfunction of the corticospinal tract masked by
      peripheral neuropathy: magnetic stimulation showed conduction delay in the
      corticospinal tract in two patients in whom no pyramidal signs were evident
      because of muscular atrophy due to neuropathy. One patient had multiple sclerosis
      and chronic inflammatory demyelinating polyradiculoneuropathy, the other had
      degenerative ataxia and neuropathy. (4) Association of disorders: conduction
      delay rostral to the foramen magnum, which should not occur in patients with only
      cervical myelopathy, was shown in a patient with cervical myeloradiculopathy and
      amyotrophic lateral sclerosis. We conclude that this magnetic stimulation method
      which is less painful than electrical stimulation has extensive clinical
      usefulness.

PMID- 8647039
TI  - Spatial differences in the sites of direct and indirect activation of
      corticospinal neurones by magnetic stimulation.
AB  - Transcranial magnetic stimulation (TMS) over the human motor cortex evokes
      multiple descending volleys possibly through activation of different elements
      within the brain. We have investigated whether such elements can be distinguished
      spatially. Using a figure of eight coil, TMS was delivered over multiple scalp
      sites during a low level voluntary contraction of the left first dorsal
      interosseous muscle. At near-threshold intensity, early or late surface
      electromyograph (EMG) components (relative to anodal response latency) could be
      preferentially evoked with the coil aligned in a medio-lateral (ML), antero
      posterior (AP), or postero-anterior (PA) orientation. The optimal location of the
      earliest component with ML coil orientation was 8 mm medial and 5 mm anterior
      compared to a later component with AP orientation. The optimal location for the
      same latency EMG component mapped using two different coil orientations (AP and
      ML) was not significantly different. The optimal location of two different late
      components, one obtained with AP and the other with PA coil orientations, was
      similar. It is argued that the earliest TMS-evoked component results from direct
      activation of corticospinal cell axons while later components result from
      activation of these cells trans-synaptically (indirectly), and that consequently
      there is a substantial spatial separation between these activation sites.

PMID- 8647040
TI  - Cortical potentials with antisaccades.
AB  - The term antisaccade refers to saccades that are performed towards the side
      opposite to that of target appearance. The performance of antisaccades is
      considered to be determined by intact frontal inhibitory areas as patients with
      frontal, and especially prefrontal, lesions show a striking impairment in
      suppressing an unwanted protarget saccade. We recorded cortical slow potentials
      from subjects performing saccades and antisaccades in a task, antitask and no
      move conditions in order to investigate possible topographic differences between
      these two types of eye movement. Our main findings concern both movement related
      as well as sensory related potentials. With regard to the saccadic potentials,
      performance of an antisaccade is preceded by a much more pronounced activity
      during the last 100 ms prior to the eye movement onset over central-anterior
      leads with a slight ipsilateral lateralization. As for the sensory potentials,
      the target related with antisaccade performance is followed by smaller, but
      nonstatistically significant, exogenous responses while at 300-350 ms after
      target appearance, the activity associated with the antisaccade's target is
      clearly larger over central midline leads. Although we could not precisely relate
      the electrical activity obtained with well circumscribed cortical function, the
      results support the view that the anterior and slightly ipsilateral cortical
      activation which precedes the performance of an antisaccade could reflect the
      frontal mechanisms of suppression of the unwanted saccade.

PMID- 8647041
TI  - Alerting effects on choice reaction time and the photic eyeblink reflex.
AB  - To test the possibility that a common mechanism might be responsible for alerting
      effects on voluntary and reflexive reactions, choice reaction times (RT) to
      intense flashes of light were compared with eyeblink reflexes simultaneously
      evoked by those stimuli. An acoustic accessory stimulus, irrelevant to the RT
      task, facilitated both voluntary and reflexive reactions. A time uncertainty
      manipulation also generated facilitation of both responses under conditions in
      which phasic arousal was presumably greatest. However, there were several
      dissociations between alerting effects on voluntary and reflexive reactions and
      between effects on the early and late subcomponents of the photic orbicularis
      oculi reflex. In conjunction with other research in humans and animals, these
      data support the assumption that alerting involves the activation of multiple
      neuromodulatory (e.g. monoamine) systems, each of which is characterized by a
      distinct behavioral, neuropharmacological, and electrophysiological profile.

PMID- 8647042
TI  - Electrophysiological evidence suggesting that sensory stimuli of unknown origin
      induce spontaneous K-complexes.
AB  - The present study was performed to determine whether or not spontaneous K
      complexes are induced by sensory stimuli. In the first part of the present study,
      sound stimuli were prescribed during sleep in 7 healthy, young, adult subjects.
      EEG segments in stage 2 sleep were averaged separately according to the presence
      or absence of an evoked K-complex appearing after each stimulus. The sound
      stimulus induced N100 and P200 components in averaged EEGs regardless of K
      complex appearance. The appearance of N100 and P200 components was considered to
      be an indicator of the presence of sensory stimuli. In the second part of the
      present study, EEG segments in stage 2 sleep containing an evoked K-complex or
      spontaneous K-complex were separately averaged with respect to the peak of N300,
      one of the main components constituting the K-complex. Small negative and
      positive components were found just before the main components of spontaneous K
      complexes in averaged EEGs. These two components were judged to correspond to
      N100 and P200 components induced by the sound stimulus, as they appeared just
      before the main components of the spontaneous K-complex with almost the same lag
      time between the two components, or between each of the two components and the
      main components of K-complex, as in the case of N100 and P200 appearing just
      before the evoked K-complex. The present findings suggest that the spontaneous K
      complex is not a spontaneous phenomenon, but that it is induced by sensory
      stimuli, probably of extracerebral origin.

PMID- 8647043
TI  - Discrimination of sleep stages: a comparison between spectral and nonlinear EEG
      measures.
AB  - During recent years, methods from nonlinear dynamics were introduced into the
      analysis of EEG signals. Although from a theoretical point of view nonlinear
      measures quantify properties being independent from conventional spectral
      measures, it is a crucial question whether in practice nonlinear EEG measures
      yield additional information, which is not redundant to the information gained by
      spectral analysis. Therefore, we compared the ability of several spectral and
      nonlinear measures to discriminate different sleep stages. We evaluated spectral
      measures (relative delta power, spectral edge, spectral entropy and first
      spectral moment), and nonlinear measures (correlation dimension D2, largest
      Lyapunov exponent LI, and approximated Kolmogorof entropy K2), and additionally
      the stochastic time domain based measure entropy of amplitudes. For 12 healthy
      subjects these measures were calculated from sleep EEG segments of 2:44 min
      duration, each segment unambiguously corresponding to one of the sleep stages I,
      II, SWS and REM. Results were statistically evaluated by multivariate and
      univariate analyses of variance and by discriminant analyses. Generally,
      nonlinear measures (D2 and L1) performed better in discriminating sleep stages I
      and II, whereas spectral measures showed advantages in discriminating stage II
      and SWS. Combinations of spectral and nonlinear measures yielded a better overall
      discrimination of sleep stages than spectral measures alone. The best overall
      discrimination was reached even without inclusion of any of the spectral
      measures. It can be concluded that nonlinear measures yield additional
      information, which improves the ability to discriminate sleep stages and which
      may in general improve the ability to distinguish different psychophysiological
      states. This confirms the importance and practical reliability of the application
      of nonlinear methods to EEG analysis.

PMID- 8647044
TI  - Occurrence of "microsleeps' during daytime sleep onset in normal subjects.
AB  - The main aim of this study was to explore whether the multiple sleep latency test
      (MSLT) could be made more sensitive to low daytime sleepiness in normal, healthy
      subjects by adopting a shorter period of sleep (microsleep) as a sleep onset
      criterion. Subjects underwent MSLTs under two conditions: after normal (baseline)
      nighttime sleep, and after nighttime sleep extension (creating a "floor effect'
      of minimal daytime sleepiness). MSLT sleep onset thresholds of 5 s (microsleeps),
      30 s (the norm) and 90 s of sustained sleep gave 3 separate sleep latency scores
      for 240 MSLT trials derived from 10 subjects. With low daytime sleepiness,
      whether this be in the morning after baseline sleep or throughout the day after
      sleep extension, the 5 s sleep onset criterion was a more sensitive measure of
      sleepiness than the established 30 s criterion. This was the case both for sleep
      onset latency and for the frequency of sleep onsets. Spectral analyses of the EEG
      indicated that successive microsleep episodes generally became more substantial,
      and, depending on the level of sleepiness, culminated in more overt signs of
      sleep. There was little difference between the 30 s and 90 s criteria for sleep
      onset latency scores, although there was a small but significant difference
      between them in the frequency of sleep onsets. As daytime sleepiness increased,
      particularly in the afternoon and under baseline, the 5 s criterion reached a
      ceiling, with the 30 s criterion becoming more sensitive.

PMID- 8647045
TI  - Comparison of coronal sphenoidal versus standard anteroposterior temporal montage
      in the EEG recording of temporal lobe seizures.
AB  - Chronic sphenoidal electrodes were developed to facilitate the recording and
      localization of temporal lobe seizures during long term monitoring. Many reports
      demonstrate their utility in displaying temporal interictal epileptiform
      activity, but there have been few direct comparisons of sphenoidal electrodes and
      surface temporal recordings actually. We compared simultaneous portions of 74 EEG
      recordings of temporal lobe seizures (from 42 patients), with one portion
      including sphenoidal electrodes in a coronal montage and one with a standard
      anterior posterior temporal montage. Separated tracings were reviewed by readers
      blinded to the other portion of the tracing. The coronal sphenoidal montage
      allowed recognition of temporal lobe seizures inapparent with standard surface
      temporal electrodes in 19% of seizures and led to an earlier identification
      (usually by > or = 5 s) of the onset in 70% of seizures. Indwelling, flexible
      sphenoidal electrodes assist in ambulatory recording of temporal lobe seizures,
      both in demonstrating the presence of seizures and in determining the
      localization and time of seizure onset.

PMID- 8647046
TI  - Estimation of interpolation errors in scalp topographic mapping.
AB  - Topographic maps are commonly constructed from electrical scalp recordings (such
      as EEGs and ERPs) using several different interpolation methods. It is important
      to determine the accuracy of such maps. Previous assessments of interpolation
      methods have been based on global error measures and the visual appearance of the
      topographic maps. However, the relationship of interpolation error to local
      contributing factors requires a more detailed analysis. In this paper, we use
      simulations to explore and quantify the relationship of error to global and local
      factors for different interpolation methods. We find that among the best
      interpolation methods, adequate electrode density is more important than the
      method used. For shallow sources, we show that local interpolation error is most
      correlated with potential gradient, and has a lesser correlation with distance to
      nearest electrode. The greatest correlation, however, is with the product of
      gradient and distance. Thus, interpolation error can be controlled locally by
      making the interelectrode distance inversely proportional to the expected
      potential gradient. With shallow sources, areas far from any electrode and having
      high apparent gradient are likely to have high interpolation error. Moreover, all
      areas far from any electrode may contain high interpolation errors, and should be
      interpreted with caution.

PMID- 8647047
TI  - Neuroimaging in pediatric epilepsy.
AB  - Neuroimaging techniques have advanced the diagnosis, management, and
      understanding of the pathophysiology underlying the epilepsies. High-resolution
      ultrasound is an important and useful technique in the investigation of
      prematures and neonates with seizures. Computed tomography (CT) scans have a
      diminishing role in the investigation of patients with epilepsy, but in the
      absence of magnetic resonance imaging (MRI), CT may detect gross structural
      pathology. MRI is the technique of choice for investigation of patients with
      seizure disorders. MRI provides excellent anatomic information and tissue
      contrast, resulting in high sensitivity. MRI studies should be customized to
      answer the appropriate clinical question. Functional imaging techniques including
      single photon emission computed tomography (SPECT), positron emission tomography
      (PET), magnetic resonance spectroscopy, and functional MRI are becoming
      increasingly important in the investigation and management of patients with
      seizures. These techniques permit noninvasive assessment of the epileptic
      substrate, functional status, ictal activity, blood flow changes, metabolism, and
      neuroreceptors. Application of these new techniques promises to advance our
      understanding and treatment of seizures in children.

PMID- 8647048
TI  - Developmental aspects of epileptogenesis.
AB  - Several factors may contribute to the propensity for the developing brain to have
      seizures and develop epilepsy. Hypersynchrony of neuronal circuits contributes to
      the seizure potential and several neurobiological features of the immature brain
      may support synchronized neuronal firing. The immature cerebral cortex and
      hippocampus have an increased density of synapses compared to adults and also a
      higher density of gap junctions and of excitatory amino acid receptors. Enhanced
      regenerative responses to injury in the developing brain may also contribute to
      the formation of abnormal hippocampal connections that support epilepsy.
      Molecular mechanisms that contribute to enhanced synaptic plasticity in the
      child's brain can also contribute to epileptogenesis in certain circumstances.
      The phenomenon of kindling, where repeated electrical stimulation of neuronal
      circuits leads to the development of epileptic seizures, is easily elicited in
      young animals. Long-term potentiation (LTP), where repeated synaptic stimulation
      leads to a reduced threshold for activation of that pathway and enhanced
      postsynaptic potentials, is much more robust in the immature cerebral cortex and
      may contribute to kindling and epileptogenesis. Age related enhancement of N
      methyl-D-aspartate-type glutamate receptors, which are important for the activity
      dependent plasticity in the developing brain, appears to participate in LTP. This
      information suggests that normal developmental features of synaptic development
      make the immature brain more excitable than the adult brain and may contribute to
      epileptogenesis.

PMID- 8647049
TI  - Surgery for catastrophic localization-related epilepsy in infants.
AB  - Cortical resection or hemispherectomy has been reported to result in cessation or
      dramatic reduction of seizures for small numbers of highly selected infants with
      severe, intractable epilepsy and developmental delay. However, identification of
      potential surgical candidates during infancy can be especially challenging
      because seizure semiology and EEG may sometimes give limited localizing
      information, e.g., in patients with infantile spasms and hypsarrythmia due to
      focal cortical dysplasia or a tumor. In infants as well as older patients, the
      location of a potentially resectable epileptogenic lesion must be defined by
      convergence of results from video EEG, anatomic and functional neuroimaging, and
      clinical examination. Reported outcomes after surgery in small series include 78%
      of 23 infants seizure-free or with at least 90% seizure reduction (1993
      University of California at Los Angeles series), and 75% of 12 infants seizure
      free or with rare seizures (1995 Cleveland Clinic series). A tendency of "catch
      up" developmental progress after surgery was observed in both series. A few
      reports of smaller groups of infants noted similar results. Prospective studies
      are in progress to better define the potential risks and benefits of early
      surgical intervention for infants and catastrophic localization-related epilepsy.

PMID- 8647050
TI  - Pediatric epilepsy syndromes: an update and critical review.
AB  - Epilepsy syndromes occupy an important position in the current nosology of the
      epilepsies, describing and classifying seizure disorders with shared clinical and
      EEG features. Increasingly, this schema is being refined as new information
      becomes available and our understanding of etiology and presentation of each
      syndrome widens. Advances in neuroimaging and neurogenetics have been
      particularly important and are likely to fundamentally change our concepts of
      syndrome classification. At present, the International League Against Epilepsy
      classification of epilepsy syndromes according to presumed localization (partial,
      generalized, undetermined) and etiology (idiopathic, cryptogenic, symptomatic).
      In clinical practice, it is often useful to conceptualize epilepsy syndromes
      according to their usual age at presentation, which greatly facilitates syndrome
      identification in new patients and recognizes the age-related expression of many
      childhood epilepsies. Definitional problems exist for many pediatric epilepsy
      syndromes, particularly the epileptic encephalopathies of early infancy, the
      benign epilepsies of infancy and childhood, the myoclonic epilepsies of infancy
      and early childhood, and the idiopathic generalized epilepsies of childhood and
      adolescence. It is likely that further input from the fields of molecular
      genetics and neuroimaging will enable the classification of epilepsies to become
      more etiologically oriented and disease specific.

PMID- 8647051
TI  - Avoiding the pitfalls of EEG interpretation in childhood epilepsy.
AB  - The accurate interpretation of the electroencephalogram (EEG) of infants and
      children being evaluated for suspected epilepsy is based on the appreciation of
      normal and expected age-dependent characteristics, an awareness of the
      significance of both epileptiform and non-epileptiform activity, and the
      correlation of epileptiform abnormalities with clinical findings. Avoiding the
      pitfalls of pediatric EEG interpretation include the recognition of such normal
      EEG features in wakefulness as posterior slow waves of youth, mu rhythm, and
      lambda waves. In addition, the understanding of age-dependent characteristics of
      EEG state-changes is essential, such as: monorhythmic and paroxysmal hypnagogic
      hypersynchrony, special features of vertex transients and sleep spindles,
      positive occipital sharp transients, initial arousal responses and post-arousal
      hypersynchrony. The EEG response to activation procedures such as
      hyperventilation and photic stimulation may also be a source of confusion.
      Patterns of uncertain diagnostic significance also may be present in children,
      including 14- and 6-Hz bursts and rhythmic temporal theta bursts of drowsiness
      (the so-called psychomotor variant). Some nonepileptiform EEG abnormalities may
      also be misinterpreted as epileptiform. The determination of the clinical
      significance of spike foci and generalized abortive spike-and-wave may pose more
      of a problem as a potential pitfall than the identification by visual analysis of
      these interictal discharges. Another problem posed to the electroencephalographer
      is the determination of the EEG response to antiepileptic drug therapy including
      effect on spike foci, generalized spike-and-wave and electrical seizure activity,
      and effect on background activity. The recognition of the differences between the
      EEG of children and adults will provide the basis for more accurate
      interpretation and assist the electroencephalographer in avoiding the
      identification of normal, age-dependent features as epileptiform.

PMID- 8647052
TI  - The contribution of EEG to the understanding of neonatal seizures.
AB  - The neonatal EEG is a thread that has linked past and present studies of neonatal
      seizures that have emerged over the last several decades. Instead of experiencing
      a waning of value or interest, the neonatal EEG has grown in significance for
      characterization and quantification of seizures in the neonate. At present, it
      serves as the ideal theoretical end point of antiepileptic drug (AED) therapy and
      provides invaluable prognostic information in the analysis of its interictal EEG
      background. The needs of the near future are to learn the real behavior of the
      electrographic neonatal seizure (ENS) burden as it erupts on the scene of an
      acute encephalopathy. The response of the neonatal seizure burden to AED
      treatment requires careful quantitative description and reliable, automated ENS
      detection by cerebral function monitors, which are on the technologic horizon.

PMID- 8647053
TI  - Antiepileptic drug therapy: when is epilepsy truly intractable?
AB  - We define intractable in the first 5 years of epilepsy treatment as an average of
      at least one seizure every 2 months. For the longer term, we define intractable
      as at least one seizure per year. Population studies from Chicago, IL, U.S.A.,
      Finland, and Nova Scotia, Canada indicate that with long follow-up, many children
      with intractable epilepsy eventually have remission of their seizure disorder.
      Epilepsy is no longer intractable when the seizures stop completely. How often
      does a new antiepileptic drug (AED) render a child seizure-free when one or more
      AEDs have failed? Literature on adults with epilepsy suggests that few with
      chronic epilepsy who have not achieved seizure control with several AEDs will
      achieve complete seizure control with additional AEDs. The Nova Scotia study
      suggests that if a child's seizure fails to be controlled with a first AED, there
      is an increased risk of intractable epilepsy. Nonetheless, the chance of
      eventual, complete remission of epilepsy (seizure-free without AED treatment) is
      approximately 40%. We conclude that intractability should not be considered until
      there has been failure of at least three first-line AEDs. Intractable epilepsy is
      rare. Careful definition of the characteristics of children with intractable
      epilepsy who do respond completely to new AEDs will likely provide the only
      rational approach to treatment of children with three drug failures.
      Collaboration by multiple epilepsy centers will be required to gain this
      information.

PMID- 8647054
TI  - Utilization of new antiepileptic drugs in children.
AB  - Studies of the newer antiepileptic drugs suggest that they are exciting additions
      with improved efficacy and a perhaps decreased toxicity in certain types of
      refractory childhood epilepsy. In some very rare syndromes only anecdotal reports
      exist and further study is needed. Issues of tolerability, long-term safety in
      very young children, and effects on learning, behavior and other cognitive
      functions must be balanced with the possibility of improved efficacy. Additional
      well-controlled studies taking into account both seizure types and epilepsy
      syndromes are very much needed in neonates, infants, school aged children and
      adolescents.

PMID- 8647055
TI  - Status epilepticus and acute repetitive seizures in children, adolescents, and
      young adults: etiology, outcome, and treatment.
AB  - Status epilepticus (SE) is one of the most common neurologic emergencies in
      children, adolescents, and young adults. SE may be due to acute neurologic
      conditions such as meningitis, encephalitis, or stroke, complicated febrile
      seizures, intractable epilepsy, degenerative diseases, intoxication, or may be
      the first manifestation of epilepsy. Initial treatment of convulsive SE is
      usually with an intravenous benzodiazepine (BZD) [lorazepam (LZP) or diazepam
      (DZP)], phenobarbital (PB), or phenytoin (PHT). LZP is less likely to cause
      respiratory depression than DZP and is therefore preferred. Sequelae and risk for
      recurrence of SE are primarily related to the underlying cause. Refractory SE
      (RSE) is most often symptomatic of an acute neurologic condition or
      neurodegenerative disease. Treatment for RSE is difficult, usually requiring
      intensive support of vital functions. Reported treatments for RSE include very
      high dose PB, continuous infusions of pentobarbital or BZDs (DZP, midazolam),
      lidocaine, inhalation anesthesia, and propofol. Outcome is related to underlying
      cause. Nonconvulsive SE may present as confusion or may mimic psychiatric
      illness. Response to BZDs is usually rapid but may not be sustained. Rapid
      initiation of oral or rectal valproate may be useful. Epilepsia partialis
      continua (EPC) is almost always due to an acute or chronic destructive lesion.
      Surgical treatment may be the only effective modality in some children with EPC.
      Acute treatment of breakthrough seizures and clusters of seizures at home with
      rectal BZDs (usually DZP, 0.2-0.5 mg/kg) may prevent progression to SE in some
      children and adolescents and reduce the need for visits to emergency facilities.

PMID- 8647057
TI  - The cow milk allergy complex: overlapping disease profiles in infancy.
AB  - Community based studies suggest reported reactions to cow's milk are very common
      in the first 12 months of life but many of them may not be reproduced on
      challenge. Recent laboratory based studies have identified three groups of
      infants with cow milk allergy (CMA) who demonstrate different symptom and
      laboratory profiles. The first, an IgE-sensitized group, shows features of
      immediate cutaneous eruptions and anaphylaxis. The second, a non-IgE sensitized
      group, develops gastrointestinal symptoms within hours of ingesting moderate
      amounts of cow milk, whereas the third group of patients shows symptoms of
      gastrointestinal disturbance with or without bronchitic and/or eczematous
      symptoms after ingesting cow milk over several hours or days. The late reacting
      non-IgE sensitized CMA patients demonstrate elevated T-cell reactivity in vitro
      to milk proteins. Hospital based studies, which are likely to reflect the more
      severe end of the spectrum of CMA, suggest adverse clinical reactions which
      persist longer may be associated with intolerance to a wide range of foods.
      Children with persistent CMA frequently develop eczema, asthma and rhinitis.
      Because of these complexities children with CMA should remain under the long term
      care of a medical practitioner familiar with the management of these problems.
      Medical practitioners responsible for the care of children with suspected CMA
      must be prepared to conduct cow milk challenges in a safe environment with
      facilities for resuscitation available. The notion that infants with suspected
      CMA should be referred to nutritionists and health workers for implementation of
      empirically devised low allergen diet programs without the diagnosis of CMA,
      being firmly established should be rejected. Where the diagnosis of CMA has not
      been made with certainty, parents may resort to unreasonable dietary
      restrictions.

PMID- 8647056
TI  - Alternative epilepsy therapies: the ketogenic diet, immunoglobulins, and
      steroids.
AB  - Despite the continued development and release of new antiepileptic drugs (AEDs),
      many children have seizures that do not respond to conventional therapy or have
      related side effects that preclude continued use. While some of these children
      are surgical candidates, the majority do not qualify for surgical resection. In
      these children alternative therapies are often considered by desperate physicians
      and parents. Three of the less conventional therapies which are currently used
      for intractable epilepsy are: the ketogenic diet, immunoglobulins, and steroids.
      None of these therapies has been adequately studied and it remains unclear which
      patients may benefit or be harmed by these therapies. Despite the lack of
      scientific vigor in evaluating these therapies, the television and print media
      has proclaimed these therapies as miraculous, yet grossly under-utilized by an
      ignorant medical community. The ketogenic diet has been demonstrated to reduce
      seizure frequency in some patients, but has an unclear mechanism of action, while
      immunoglobulins have both unknown efficacy and an unknown mechanism of action.
      While steroids are accepted as an effective therapy for infantile spasms, their
      role in the treatment of the Landau-Kleffner syndrome is far less clear. Although
      the ketogenic diet, immunoglobulins, and steroids may have a role in the
      treatment of severe childhood epilepsy, all three therapies need to be critically
      evaluated in regard to efficacy, mechanism of action, and safety.

PMID- 8647058
TI  - Hydrolysed protein formulas: thoughts from the Isle of Wight meeting.
AB  - The meeting held on the Isle of Wight on 3 March 1995 was organised to discuss
      some of the recent evidence concerning the use of hydrolysed milk formulas not
      only in the treatment of cow's milk allergy but also in programmes designed to
      reduce or prevent other atopic disease. These products and their prophylactic use
      in particular have generated an amount of controversy firstly when they were
      introduced as a starting formula in the United States and secondly in Europe
      where paediatric, allergy and nutrition groups have issued various statements on
      their use (ESPGAN, 1993; Bjorksten, 1994; ESPACI, 1993; Bindels & Boerma, 1994).
      The Isle of Wight meeting did not attempt to produce a concensus statement. Nor
      is this paper an attempt to summarise or bring together the views expressed.
      Rather it reflects the views of the authors tempered by experience and the
      evidence presented at the meeting. Seven questions are explored.

PMID- 8647059
TI  - The natural history of cow's milk protein allergy/intolerance.
AB  - In prospective studies th incidence of cow's milk protein allergy and intolerance
      (CMPA/CMPI) in infancy in western industrialized countries has been estimated to
      be about 2-3% based on strict diagnostic criteria. A significant association
      between early neonatal exposure to cow's milk formula feeding and subsequent
      development of CMPA/CMPI has been documented. The small amounts of 'foreign'
      protein in human milk may rather induce tolerance than allergic sensitization.
      The findings of specific IgE to individual cow's milk proteins in cord blood of
      the majority of infants who later develop CMPA/CMPI suggests a prenatal
      sensitization may play a role in the pathogenesis of CMPA/CMPI. Perhaps a weak
      intrauterine education of low IgE-response may need to 'boosted' neonatally in
      order to cause clinical disease. The prognosis of CMPA/CMPI is good with a
      recovery of about 45-56% at one year, 60-77% at two years and 71-87% at three
      years. Associated adverse reactions to other foods, especially egg, soy, peanut
      and citrus develop in about 41-54%. Allergy to potential environmental inhalant
      allergens has been reported in up to 28% by three years and up to 80% before the
      age of puberty. Especially, infants with an early increased IgE response to cow's
      milk protein have an increased risk of persisting CMPA, development of persistent
      adverse reactions to other foods and development of allergy against environmental
      inhalant allergens. Cow's milk protein/intolerance (CMPA/CMPI), meaning
      reproducible adverse reactions to cow's milk protein(s) may be due to the
      interaction between one or more milk proteins and one or more immune mechanisms,
      possible any of the four basic types of hypersensitivity reactions.
      Immunologically mediated reactions are defined as CMPA. Mostly, CMPA is caused by
      IgE-mediated (type I) reactions, but evidence for type III (immune complex)
      reactions and type IV (cell mediated reactions) have been demonstrated as
      reviewed by Host (1994) and Ortolani & Vighi (1995). Non immunologically
      reactions against cow's milk protein(s) are defined as CMPI. However, it should
      be stressed that many studies on 'cow's milk allergy' have not investigated the
      immunological basis of the clinical reactions. In most instances of cow's milk
      protein hypersensitivity only diagnostic investigations such as skin prick test
      and RAST indicative of IgE-mediated reactions are performed. In fact, CMPA cannot
      be ruled out unless extensive diagnostic tests for type II-III-IV reactions have
      proved negative. Thus, the classification of adverse reactions to cow's milk
      proteins depends on the extent and the quality of performed diagnostic tests for
      immune mediated reactions. At present, no single laboratory test is diagnostic of
      CMPA/CMPI, and differentiation between CMPA and CMPI cannot be based solely on
      clinical symptoms. Therefore the diagnosis has to be based on strict well-defined
      elimination and milk challenge procedure (Hill & Hosking, 1991), (Host, 1994).
      Preferably, double-blind placebo-controlled challenges (DBPCFC) should be carried
      out in children older than 1-2 years of age. In infants open controlled
      challenges have been shown to be reliable when performed under professional
      observation in a hospital setting (Host & Halken, 1990).

PMID- 8647060
TI  - Cow's milk allergy: therapeutic options and immunological aspects.
AB  - Adverse reaction to cow's milk and infant formulas are common during infancy.
      Cow's milk has more than 20 constituents proteins and in principle many are
      capable of giving rise to an IgE mediated response. The prevalence of cow's milk
      allergy is between 0.5-10% of the paediatric population (Frier & Kletter, 1970,
      Gerrard et al., 1973 Foucard, 1985). The clinical diagnosis of cow's milk allergy
      is difficult because of the great diversity and varying severity of symptoms and
      is often based on criteria which is then confirmed by challenge with cow's milk
      (Bock et al., 1988, Wershil & Walker, 1988). There is no doubt that various
      immunological mechanisms are involved in cow's milk allergy and in recent years a
      number of researchers have investigated the role of humoral and cell-mediated
      immunity in the pathogenesis of cow's milk allergy.

PMID- 8647061
TI  - Nutritional evaluation of protein hydrolysate formulas.
AB  - Growth parameters, biochemical indice of protein metabolism and plasma Amino acid
      (AA) concentrations were investigated during the first month of life in term
      infants (n = 61) fed various protein hydrolysate formulas (whey (WHF, n = 3), soy
      collagen (SCHF, n = 1) and whey-casein hydrolysate formulas (WCHF, n = 1)). In
      addition, metabolic balance studies were performed in 10 infants fed WHF and in 5
      fed WCHF. Comparatively to breast fed infants, growth reduction and decrease in
      plasma protein concentrations were observed with the use of one of the WHF and in
      a lesser extent with the SCHF and the WCHF. Plasma amino acid pattern reflected
      the AA content of the formulas. Whey hydrolysate formulas induced mainly an
      increase in threonine and a decrease in tyrosine concentrations. Soy-collagen
      hydrolysate formula led to an increase of non-essential amino acids, such as
      glycine and hydroxyproline and a decrease in plasma lysine and cystine. Whey
      casein hydrolysate formula induced a plasma amino acid pattern close to the
      profile observed in breast fed infant. Metabolic balance studies showed a
      relative reduction in nitrogen absorption and utilisation in the infants fed the
      WHF and the WCHF. In addition a drastic reduction in fat, calcium and phosphorus
      absorption was also observed with the use of the WCHF. In preterm infants (n =
      19) fed whey predominant hydrolysed preterm formulas (n = 3), metabolic balance
      studies an plasma AA concentration were evaluated at the end of the first month
      of life at 34 weeks of gestation age. Comparatively to similar preterm infants
      fed conventional preterm formulas, a relative reduction in nitrogen absorption
      (83% vs 90%) and retention (64 vs 70%) as well as in phosphorus absorption (78 vs
      89%) was observed. Calcium retention was similar (48 vs 45 mg/kg/d) but calcium
      intake was significantly higher in infants fed hydrolysate formulas 120 vs 91
      mg/kg/d. Plasma amino acid concentrations were related to amino acid composition
      of the formulas. Compared with the standard preterm formulas, all three protein
      hydrolysate formulas led to a significant increase in plasma threonine and a
      decrease in tyrosine and phenylalanine concentrations. In addition, there was a
      reduction in plasma histidine, valine, leucine, cystine, methionine and/or
      tryptophane with some of the hydrolysate formulas used. In conclusion, these
      studies provide evidence that protein hydrolysed formulas are not equivalent to
      whole protein formulas in terms of nutritional efficiency for preterm and term
      infants. Therefore further extensive nutritional studies on growth, biochemical
      indices of protein metabolism and metabolic balance, including minerals and trace
      elements, appear to be necessary before maintaining and promoting the use of such
      formulas for teh potential benefits on atopic disease in preterm and in full-term
      newborn infants.

PMID- 8647062
TI  - Symptomatology and growth in infants with cow's milk protein intolerance using
      two different whey-protein hydrolysate based formulas in a Primary Health Care
      setting.
AB  - Both growth and the course of allergic symptoms were evaluated in 79 infants with
      cow's milk protein intolerance, aged three months or younger, diagnosed by
      standard elimination/provocation and treated with a whey-hydrolysate based infant
      formula: Nutrilon Pept or Pepti Junior. The efficacy of both products, in terms
      of symptomatology and growth, was compared with each other. The products differ
      in fat source (Pepti Junior 50% of its fat as MCT, Nutrilon Pepti normal LCT fat
      blend) and the presence of lactose (Pepti Junior: lactose free; Nutrilon Pepti:
      40% of its carbohydrate as lactose). The study was part of a large project that
      aimed at standardising the approach towards cow's milk protein intolerance in
      Baby Health Clinics. Nearly 50 Baby Health Clinics participated in this project.
      In this study, growth and symptomatology (skin, respiratory tract,
      gastrointestinal tract) were monitored during an intervention period of at least
      10 weeks. Infants in both feeding groups showed normal growth, and in at least
      80% of the infants an improvement of the overall symptomatology could be seen
      during the intervention period. Most profound were the decreases in prevalence
      and severity of eczema and infantile colic. No differences in efficacy were found
      in this study between the two infant formulas. It was concluded that the
      exclusive use of either whey hydrolysate based infant formula resulted in an
      improvement of allergic symptoms and in normal growth in infants diagnosed by
      elimination/provocation for cow's milk protein intolerance in a Primary Health
      Care setting.

PMID- 8647063
TI  - The treatment of cow's milk allergy.
AB  - Current approach to the treatment of food allergy is directed towards elimination
      diets. The treatment of choice of cow's milk allergy is complete avoidance of
      cow's milk antigens. In infants it is necessary to use substitute formulas. The
      completeness of the elimination diet is questionable since immunoreactive
      components of cow's milk protein can be detected in substitute formulas and even
      breast milk. In most cases, extensively hydrolyzed cow's milk-derived formulas
      can be safely introduced, and these are efficient and clinically and
      metabolically well tolerated. The approach to control allergic inflammation by
      antigen elimination, however, is not satisfactory, particularly in patients with
      multiple food allergies. New approaches are urgently needed for teh treatment of
      cow's milk allergy. These may include antigen elimination supplemented with
      synthetic amino acid-derived formulas, immunotherapy to counteract the
      immunologic dysfunction and stabilization of the gut mucosal barrier to
      strengthen endogenous defence mechanisms.

PMID- 8647064
TI  - Which formula in cow's milk protein intolerance? The dietitian's dilemma.
AB  - During the last century a wide range of protein sources have been used to replace
      cow's milk to provide an alternative milk in the treatment of cow's milk protein
      intolerance. These include soya (Businco et al., 1992), ass's milk (Iacono et
      al., 1992), soya/beef hydrolysate (Dean et al., 1993), almonds (Moll, 1923),
      poppy seeds (Findelstein 1930), cereals (Wolpe & Silverstone, 1942), whey
      hydrolysate (Walker-Smith, Digeon & Phillips, 1989) casein hydrolysate (Walker
      Smith et al., 1989) and taro (Feingold, 1942). Important factors influencing the
      choice of milk substitute include nutritional composition, evidence of successful
      use with particular reference to satisfactory growth and nutritional status,
      palatablility, ease of preparation, cost, availability and allergenicity.

PMID- 8647065
TI  - Product development horizons--a view from industry.
AB  - Against the background of what appears to be an increasing incidence of many
      allergic disorders, the production of safe, effective 'hypoallergenic' diets on a
      commercial scale has become of increasing importance. Combining knowledge of
      protein biochemistry and immunology with clinical science has provided not only a
      greater understanding of what is required for effective treatment of allergic
      disorders, but is also facilitating a unique insight into the use of dietary
      management in allergy prevention. Infants who have become sensitised to intact
      proteins either in utero or during early feeding usually require a diet with
      significantly reduced allergenicity for a period of time. One of the most
      effective methods of allergen avoidance has traditionally been achieved by
      subjecting dairy proteins to extensive hydrolysis until virtually no antigenic
      epitopes remain recognisable to the infant's immune system (Sampson, Bernhisel
      Broadbent, Yang et al., 1991). This 'hypoallergenic' protein base can then be
      used together with other non-sensitizing ingredients, to create a formula feed
      which will meet the essential nutritional requirements of infants during the
      specified period for recovery--usually the first 12 months of life or beyond.

PMID- 8647066
TI  - Allergy prevention--an attainable objective?
AB  - Few authorities doubt that here has been a significant rise in IgE mediated
      diseases in almost all populations in which they have been studied. There is less
      agreement why this should have occurred and a number of genetic and environmental
      influences almost certainly play a part. Although the present discussions are
      concentrating on dietary factors these cannot be expected to play more than a
      partial role in the pathogenesis and expression allergy. The approach to the
      prevention of allergy, generally implying IgE mediated disease, has been
      described as primary, secondary or tertiary. Primary prevention means prevention
      of sensitisation, secondary prevention means prevention of manifestation of
      disease in an already sensitised individual, and tertiary means attempting to
      reduce or abolish expression of allergy in an individual already showing
      symptoms. Such as classification is convenient although the borders become
      blurred. It had until recently been assumed that sensitisation rarely if ever
      took place before birth. Recent studies from Melbourne (Tang et al., 1994),
      Southampton (Warner JA et al., 1994) and Japan (Kondo et al., 1992) suggest this
      may no be so. Their studies have given evidence of intrauterine programming.
      Warner showed a raised peripheral blood mononuclear proliferative response in
      infants born to atopic families in those who developed atopic eczema with
      positive skin prick test to foods. The Melbourne group has recently shown a
      reduced IFN-chi in cord blood mononuclear cells from infants of atopic families.
      Thus previous attempts at primary prevention may indeed be secondary prevention
      as immune responses are already developed at birth. Additionally it may be
      necessary to move attempts at intervention back into early pregnancy or even pre
      conception. This would compound the problems of an already difficult area of
      preventive medicine.

PMID- 8647067
TI  - The effect of hypo-allergenic formulas in infants at risk of allergic disease.
AB  - Development of atopic disease seems to depend on both genetic factors and
      exposure to several environmental factors. At present ther is evidence that the
      mode of early infant feeding influences the development of food allergy, whereas
      daily exposure to inhalant allergens and daily exposure to tobacco smoke is found
      to be associated with an increased risk of recurrent wheezing/asthma and inhalant
      allergy. In infants with atopic predisposition (first-degree relatives),
      exclusively breastfeeding > or = four months is found associated with a
      significant reduction of the cumulative prevalence of cow's milk
      allergy/intolerance (CMA/CMI) during the first 1-2 years of age. When breastmilk
      is insufficient or lacking a substitute formula is needed. Several recent
      prospective studies show a preventative effect of extensively hydrolysed formula
      (eHF) in combination with avoidance of cow's milk proteins and solid foods during
      > or = 4 months in high-risk infants on the cumulative prevalence of food allergy
      and atopic dermatitis during the first 2-4 years of life. Partially hydrolysed
      formulas (pHF) may be effective in allergy prevention, but due to drawbacks of
      study design and lack of documentation pHF cannot be recommended at present. The
      results of studies comparing the preventive effect of eHF and pHF are awaited.
      The protective effect on the development of cow's milk allergy is a real
      prevention and not only a postponement of the onset of symptoms. No studies have
      demonstrated a preventive effect of dietary measures as regards asthma/inhalant
      allergy, at present until the age of four years. As no studies concerning the
      preventive effect of avoidance of milk and other foods after the age of 4-6
      months of life have been performed, recommendation of preventive elimination
      diets beyond this age is empirically based. In order to reduce the costs, to
      minimize the risk of stigmatisation and the risk of malnutrition it is important
      to avoid unnecessary restrictive and prolonged diets. A diet period of 4-6 months
      seems sufficient in most infants. At present eHF are recommended for avoidance of
      cow's milk. Some high risk infants may benefit from maternal diet during
      lactation, but there is no documented beneficial effect of maternal diet during
      pregnancy.

PMID- 8647068
TI  - The use of hydrolysates in allergy prevention programmes.
AB  - The beneficial effect of a prevention programme regarding the frequency and
      severity of manifestations suggestive of atopic disease is difficult to prove
      since the genesis of atopy is multifactorial, including genetic and environmental
      factors. Twin studies indicate that genetic and environmental factors may each
      account for about 50% of the phenotype expression of allergic disease (Schultz
      Larsen, Holm & Henningsen, 1986). Family studies suggest a heterogenic
      inheritance (Lee, Geha & Leung, 1988). In order to increase the scientific
      persuasive impact, as many as possible of these influencing factors should be
      controlled. However, the more all these factors are controlled, the less
      persuasive the results will be in daily practice, when dealing with a
      'population' instead of a highly motivated selected study cohort. Results of most
      of the 'atopy prevention trials' starting at birth suggest that prevention is
      antigen-specific: elimination of cow's milk protein from feeding of high-risk
      infants, selected because of a family history of atopy, results in a life-long
      decreased incidence of cow's milk protein allergy. We present here five-year
      follow-up data of a prevention program using a partial hydrolysate. It is unclear
      if the introduction of 'tolerance' to cow's milk proteins early in life is
      relevant or not, since the natural history of allergy to cow's milk protein is
      transient in a majority of infants. It is also unclear if a high-degree
      hydrolysate would result in a more efficient prevention than a partial-degree
      hydrolysate, or that a partial-degree hydrolysate would result in a better
      development of tolerance than a high-degree hydrolysate.

PMID- 8647069
TI  - 'Prevention programmes'--a dietetic minefield.
AB  - Food allergy and intolerance (FAI) is undoubtedly a controversial subject
      surrounded by a great deal of publicity. One of the most confusing issues arises
      when considering the value of allergy prevention programmes. Although prevention
      strategies have now been extensively studied the results are still inconclusive.
      In childhood, atopic disorders eg asthma, eczema, dermatitis, urticaria, rhinitis
      and gastrointestinal related symptoms are relatively common with estimates of
      their prevalence ranging from two to 20 per cent (Mallet & Henocq, 1992). In
      addition, the proportion of young children with allergies seems to be increasing,
      although the extent to which food allergens contribute remains unclear (Hide,
      1991; Croner, 1992; DoH, 1994). In many of these cases, prevention of unpleasant,
      socially and psychologically disruptive and sometimes life threatening symptoms
      can be achieved by dietary modification. If atopic and gastrointestinal symptoms
      can be prevented growth failure may not be a problem, children may miss less
      schooling, and if long term prevention is achieved there may be a substantial
      reduction in the cost of medical care these children would otherwise require.
      Before prevention programmes are introduced, however, careful thought should be
      given to the implications of dietary treatment. The programmes are difficult to
      administrate in terms of both resources and expense. Specifically, from a
      nutritional point of view, the diets employed are often socially disruptive which
      inevitably leads to problems with compliance. Nutritional adequacy may also be
      difficult to achieve unless there is close supervision by a dietitian who is
      experienced in the management of the complex dietary manipulations involved.
      Unfortunately the dietetic resources essential for the safety of the programmes
      may be lacking in many hospitals. Preventive practice may be aimed at either the
      general population or at specially identified group who are considered to be at a
      greater risk of developing atopic disorders. Dietary intervention studies looking
      at prevention in this 'at risk' group have considered maternal dietary
      modification during pregnancy and lactation, the use of soya and hydrolysed
      protein feeds and the weaning diet. The nutritional consequences of these methods
      of dietary manipulation will be discussed in more detail.

PMID- 8647070
TI  - The regulation of enzymes involved in chlorophyll biosynthesis.
AB  - All living organisms contain tetrapyrroles. In plants, chlorophyll (chlorophyll a
      plus chlorophyll b) is the most abundant and probably most important
      tetrapyrrole. It is involved in light absorption and energy transduction during
      photosynthesis. Chlorophyll is synthesized from the intact carbon skeleton of
      glutamate via the C5 pathway. This pathway takes place in the chloroplast. It is
      the aim of this review to summarize the current knowledge on the biochemistry and
      molecular biology of the C5-pathway enzymes, their regulated expression in
      response to light, and the impact of chlorophyll biosynthesis on chloroplast
      development. Particular emphasis will be placed on the key regulatory steps of
      chlorophyll biosynthesis in higher plants, such as 5-aminolevulinic acid
      formation, the production of Mg(2+)-protoporphyrin IX, and light-dependent
      protochlorophyllide reduction.

PMID- 8647071
TI  - Quantitative analysis of the targeting of mannose-terminal glucocerebrosidase.
      Predominant uptake by liver endothelial cells.
AB  - Gaucher's disease is an inherited lysosomal storage disorder that is caused by a
      deficiency of glucocerebrosidase. The resulting accumulation of the substrate
      glucosylceramide in macrophages of liver, spleen, and bone marrow causes severe
      clinical symptoms. Gaucher's disease is treated by intravenous administration of
      a modified glucocerebrosidase (Alglucerase), which has exposed mannose residues
      to promote uptake by target macrophages. To evaluate the effectiveness of the
      targeting of Alglucerase, we studied the fate of the enzyme in the rat.
      Intravenously injected Alglucerase was rapidly cleared from the circulation (half
      life 2.0 +/- 0.5 min). The liver was the main site of uptake, with 65.6 +/- 1.2%
      of the dose present at 10 min after injection. Smaller amounts ( < 3% of the
      dose) were taken up by spleen and bone marrow. Previous injection with mannan
      substantially increased the plasma half-life of the enzyme (14.8 +/- 3.2 min
      versus 1.7 +/- 0.3 min in solvent-preinjected controls) and uptake of the enzyme
      by liver, spleen and bone marrow was reduced by > 90%. These findings indicate
      that the enzyme is taken up by these organs via mannose-specific receptors.
      Subcellular fractionation of the liver indicated that the enzyme is internalized
      and transported to the lysosomes. By isolating various liver cell types after
      injection of the Alglucerase, it was found that endothelial cells are the main
      site of uptake of the enzyme: 60.8 +/- 3.4% of the total liver uptake.
      Parenchymal and Kupffer cells were responsible for 31.0 +/- 3.1% and 8.2 +/- 0.7%
      of the hepatic uptake, respectively. We conclude that Alglucerase is rapidly
      cleared from the circulation by mannose-specific receptors in liver, spleen, and
      bone marrow. However, less than 10% of the enzyme taken up by the liver is
      accounted for by Kupffer cells, the hepatic target cells for therapeutic
      intervention. It is suggested that alterations of the formulation of the
      therapeutic enzyme may lead to a higher uptake by Kupffer cells and other
      macrophages, and thus to a more (cost)effective therapy of Gaucher's disease.

PMID- 8647072
TI  - Muconolactone isomerase of the 3-oxoadipate pathway catalyzes dechlorination of 5
      chloro-substituted muconolactones.
AB  - An enzyme of Alcaligenes eutrophus JMP 134 which catalyzes dechlorination of (4R,
      5R)- and (4R,5S)-5-chloro-3-methyl- and (4R, 5S)-5-chloromuconolactone of
      principally 3-methyl-trans-, 3-methyl-cis-dienelactone and cis-dienelactone,
      respectively, was purified to homogeneity. The enzyme was identified as
      muconolactone isomerase on the basis of its high activity with muconolactone and
      on its high degree of sequence similarity with previously described muconolactone
      isomerases. Molecular mass determinations of the highly hydrophobic and heat
      resistant enzyme indicated a decameric structure involving a single 10.100-kDa
      subunit similar to that of muconolactone isomerase of Pseudomonas putida. Kinetic
      analysis showed cooperative effects between the subunits during conversion of
      (4R, 5S)-5-chloro-3 -methylmuconolactone. (4R, 5S)-5-chloromuconolactone was the
      preferred substrate, over the natural substrate (4S)-muconolactone. The (4S, 5S)
      structure was found to be an inhibitor of (4R, 5R)-5-chloro-3-methylmuconolactone
      transformation. Methylsubstitution of the substrate results in a higher affinity
      for the enzyme, but a drastically lower velocity, resulting in a lower
      specificity constant.

PMID- 8647073
TI  - Metabolism of 5-chlorosubstituted muconolactones.
AB  - The stereochemistry of the four stereoforms of 5-chloro-3-methylmuconolactones
      could be deduced from NMR and stability data, and from the comparison with
      authentic (4R, 5S)-5-chloromuconolactone. Muconolactone isomerase of Alcaligenes
      eutrophus JMP 134 was shown to catalyze syn-elimination of hydrogen chloride from
      (4R, 5R)-5-chloro-3-methylmuconolactone, (4R, 5S)-5-chloro-3 -methylmuconolactone
      and (4R, 5S)-5-chloromuconolactone to form 3-methyl-trans-dienelactone, 3-methyl
      cis-dienelactone and a 3:1 mixture of cis- and trans-dienelactone, respectively.
      3-Methyl-trans-dienelactone was a substrate of pJP4-encoded dienelactone
      hydrolase of A. eutrophus JMP 134, whereas 3-methyl-cis-dienelactone
      transformation was negligible indicating a restricted substrate specificity of
      this enzyme. Both substrates were transformed into 3-methylmaleylacetate which in
      turn was a substrate for maleylacetate reductase. This compound was shown to
      possess a cyclic structure (4-hydroxy-3-methyl-muconolactone) under acidic
      conditions.

PMID- 8647074
TI  - cDNA cloning, expression, and chromosomal localization of Caenorhabditis elegans
      DNA topoisomerase I.
AB  - By screening Caenorhabditis elegans cDNA libraries, overlapping cDNA clones
      encoding DNA topoisomerase I were obtained. An open reading frame of 751 amino
      acids was found in 3.2-kb cDNA sequence. The open reading frame has 54% and 50%
      identities to the amino acid sequences of human and Drosophila melanogaster DNA
      topoisomerases I, respectively. Northern blot analysis showed the presence of an
      mRNA of 3.4 kb which suggests that the cDNA sequences is close to full length.
      The 72-kDa C-terminal polypeptide expressed in Escherichia coli cells showed
      catalytic DNA topoisomerase I activity. The DNA topoisomerase I gene was mapped
      to position 18 of chromosome I by screening polytene YAC plasmid DNAs.

PMID- 8647075
TI  - Pyruvate decarboxylase from Pisum sativum. Properties, nucleotide and amino acid
      sequences.
AB  - To study the molecular structure and function of pyruvate decarboxylase (PDC)
      from plants the protein was isolated from pea seeds and partially characterised.
      The active enzyme which occurs in the form of higher oligomers consists of two
      different subunits appearing in SDS/PAGE and mass spectroscopy experiments. For
      further experiments, like X-ray crystallography, it was necessary to elucidate
      the protein sequence. Partial cDNA clones encoding pyruvate decarboxylase from
      seeds of Pisum sativum cv. Miko have been obtained by means of polymerase chain
      reaction techniques. The first sequences were found using degenerate
      oligonucleotide primers designated according to conserved amino acid sequences of
      known pyruvate decarboxylases. The missing parts of one cDNA were amplified
      applying the 3'- and 5'-rapid amplification of cDNA ends systems. The amino acid
      sequence deduced from the entire cDNA sequence displays strong similarity to
      pyruvate decarboxylases from other organisms, especially from plants. A molecular
      mass of 64 kDa was calculated for this protein correlating with estimations for
      the smaller subunit of the oligomeric enzyme. The PCR experiments led to at least
      three different clones representing the middle part of the PDC cDNA indicating
      the existence of three isozymes. Two of these isoforms could be confirmed on the
      protein level by sequencing tryptic peptides. Only anaerobically treated roots
      showed a positive signal for PDC mRNA in Northern analysis although the cDNA from
      imbibed seeds was successfully used for PCR.

PMID- 8647076
TI  - Sequence-specific resonance assignments of the 1H-NMR spectra and structural
      characterization in solution of the HIV-1 transframe protein p6.
AB  - The frameshift protein p6* encoded directly upstream of the protease in the human
      immunodeficiency virus type 1 (HIV-1) pol reading frame is thought to be a
      natural inhibitor of protease activation and to play a role in the polyprotein
      processing of Gag and Gag-Pol precursors. To allow structural characterization of
      the p6* transframe protein, the p6* coding region was cloned into the vector pGEX
      KG and expressed in Escherichia coli as a fusion protein with glutathione S
      transferase (GST) under the control of the tac promoter. Thrombin cleavage of the
      construct resulted in a 70-amino-acid polypeptide which is extended by two
      additional residues at the N-terminus compared to the natural p6* sequence. The
      native purification procedure including an affinity and a size-exclusion
      chromatography step yielded sufficient amounts of highly pure protein suitable
      for NMR spectroscopy. Fluorescence, circular dichroism and 1H-NMR spectroscopy
      were applied to characterize the structure of protein. Two-dimensional NMR
      spectra provided essentially complete sequence-specific resonance assignments at
      pH 5.9. Although there is evidence for a helix-forming tendency in the N-terminus
      of the protein, the experiments indicate that p6* has no overall stable secondary
      or tertiary structure with the single tryptophan exposed in aqueous solution.
      However, the results reported herein open the way to characterize further the
      interaction of p6* with the HIV-1 protease in structural and functional in vitro
      studies.

PMID- 8647077
TI  - The structure of the Aeromonas proteolytica aminopeptidase complexed with a
      hydroxamate inhibitor. Involvement in catalysis of Glu151 and two zinc ions of
      the co-catalytic unit.
AB  - The structure of the complex of Aeromonas proteolytica aminopeptidase, a two-zinc
      exopeptidase, with the inhibitor p-iodo-D-phenylalanine hydroxamate has been
      determined by X-ray crystallography. Refinement of the structure, which includes
      220 water molecules, using data at 0.80-0.23-nm resolution resulted in a
      crystallographic residual R value of 16%. The hydroxamate group adopts a planar
      conformation whereby the two oxygen atoms interact with the zinc ions. The N
      hydroxyl group of the inhibitor is located between the two zinc ions, a position
      which is close to that occupied by a water molecule in the native structure. The
      carbonyl oxygen of the inhibitor binds to Zn1, which becomes pentacoordinated
      while Zn2 remains tetracoordinated, in contrast to the native protein where both
      zinc ions were shown to be tetracoordinated and structurally equivalent.
      Interactions of the carboxylate oxygens of Glu151 with the hydroxamate group play
      an important role in the stabilization of the complex.

PMID- 8647078
TI  - Identification of residues of Rhodobacter capsulatus ferredoxin I important for
      its interaction with nitrogenase.
AB  - In Rhodobacter capsulatus, ferredoxin I (FdI) serves as natural electron donor to
      nitrogenase. In order to probe amino acid residues possibly involved in the
      interaction with dinitrogenase reductase, FdI was subjected to site-specific
      mutagenesis. A three-dimensional structure of FdI was designed by computer
      modelling and used for selecting target residues. Mutant ferredoxins bearing
      substitutions of surface residues, as well as a variant having a Met2 --> Tyr
      replacement in the vicinity of one cluster, have been constructed. All FdI
      variants were expressed to similar levels both in Escherichia coli and in a FdI
      deleted mutant of the natural host. Once purified, the mutant ferredoxins
      exhibited molecular and spectroscopic properties almost identical to wild-type
      FdI. Determination of the reduction potential of FdI by cyclic voltammetry gave
      an E'o of -510 mV (pH 7.6) for both clusters, which is one of the lowest values
      reported for a 2[4Fe-4S] ferredoxin. Only the [Tyr2]FdI variant showed a
      significant difference in redox potential (delta E'o = -15 mV). Based on in vitro
      assays, a [Glu27, Glu28]FdI double mutant exhibited a twofold decrease in the
      electron transfer rate to dinitrogenase reductase while the affinity of this
      mutant for the enzyme was barely affected. On the other hand, an Asp36 --> His
      substitution resulted in a sevenfold increase of the apparent Km for
      dinitrogenase reductase. Unlike FdI and the other mutant ferredoxins, the
      [His36]FdI variant also failed to form a cross-linked complex with dinitrogenase
      reductase upon incubation with a carbodiimide. It is concluded that Asp36 in FdI
      probably participates in the interaction between the two protein partners.
      Nevertheless, all the FdI mutants proved competent in restoring a wild-type
      phenotype when expressed in a FdI-deleted mutant background, indicating that none
      of the studied residues was absolutely critical for electron transfer to
      nitrogenase.

PMID- 8647079
TI  - One molecule of molybdopterin guanine dinucleotide is associated with each
      subunit of the heterodimeric Mo-Fe-S protein transhydroxylase of Pelobacter
      acidigallici as determined by SDS/PAGE and mass spectrometry.
AB  - The molybdenum-containing iron-sulfur protein 1,2,3,5-tetrahydroxybenzene: 1,2,3
      trihydroxybenzene hydroxyltransferase (transhydroxylase) of Pelobacter
      acidigallici was investigated by various techniques including mass spectrometry
      and electron paramagnetic resonance. Mass spectrometry confirmed that the 133-kDa
      protein is a heterodimer consisting of an alpha subunit (100.4 kDa) and a beta
      subunit (31.3 kDa). The presence of a molybdenum cofactor was documented by
      fluorimetric analysis of the oxidized form A of molybdopterin. The enzyme
      contained 1.55 +/- 0.14 mol pterin and 0.92 +/- 0.25 mol molybdenum/mol enzyme
      (133 kDa). Alkylation of the molybdenum cofactor with iodoacetamide formed
      di(carboxamidomethyl)-molybdopterin. Upon acid hydrolysis, 1.4 mol 5'GMP/mol
      enzyme (133 kDa) was released indicating that molybdenum is bound by a
      molybdopterin guanine dinucleotide. The alpha and beta subunits were separated by
      preparative gel electrophoresis. Both subunit fractions were free of molybdenum
      but contained equal amounts of a fluorescent form of the molybdenum cofactors.
      Mass spectrometry at various pH values revealed that an acid-labile cofactor was
      released from the large subunit and also from the small subunit. At X-band, 5-25
      K, transhydroxylase (as isolated) showed minor EPR resonances with apparent g
      values around 4.3, 2.03 and, depending on the preparation, a further signal at g
      of approximately 1.98. This signal was still detectable above 70 K and was
      attributed to a Mo(V) center. Upon addition of dithionite, a complex set of
      intense resonances appeared in the region g 2.08-1.88. From their temperature
      dependence, three distinct sites could be identified: the Fe-S center I with
      gx,y,z at approximately 1.875, 1.942 and 2.087 (gav 1.968, detectable < 20 K);
      the Fe-S center II with gx,y,z at approximately 1.872, 1.955 and 2.051 (gav
      1.959, detectable > 20 K); and the Mo(V) center consisting of a multiple signal
      around g 1.98 (detectable > 70 K).

PMID- 8647080
TI  - Cloning and characterisation of angiotensin-converting enzyme from the dipteran
      species, Haematobia irritans exigua, and its expression in the maturing male
      reproductive system.
AB  - The angiotensin-converting enzymes (ACE) are involved in the regulation of the
      specific maturation or degradation of a number of mammalian bioactive peptides. A
      carboxydipeptidase similar to mammalian ACE has now been identified in the adult
      stage of the haematophagous fly, Haematobia irritans exigua (buffalo fly), a
      close relative of the horn fly of North America. The enzyme was purified by
      lectin-affinity chromatography and ion-exchange chromatography and migrated as a
      doublet of 70 kDa upon reducing SDS/PAGE. Unlike mammalian ACE, the fly
      carboxydipeptidase (HieACE) is not membrane bound. The amino acid sequence of an
      internal peptide from HieACE and a conserved amino acid region present in all
      mammalian ACE were used to design degenerate oligonucleotide primers suitable for
      PCR. A DNA fragment amplified from adult buffalo fly cDNA was used to identify a
      cDNA clone that encoded the enzyme. The cDNA sequence encodes a
      carboxydipeptidase with 41-42% amino acid identity to the mammalian testicular
      ACE. The active-site regions of mammalian ACE are conserved in the deduced amino
      acid sequence of HieACE. Enzymatically, HieACE is very similar to its mammalian
      counterparts, with comparable Km and V(max) values for the synthetic substrate,
      benzoylglycylglycylglycine, and similar patterns of inhibition by EDTA, ACE
      inhibitor peptide and captopril. HieACE also specifically activates angiotensin I
      to angiotensin II and degrades other mammalian ACE substrates such as bradykinin,
      substance P and cholecystokinin-8. In the adult fly, HieACE is expressed in the
      compound ganglion and in the posterior region of the midgut. Similar to the
      mammalian system, expression of this enzyme is induced in the maturing male
      reproductive system, which suggests conservation of ACE function in these
      species.

PMID- 8647082
TI  - Amino acid sequence of chicken Cu, Zn-containing superoxide dismutase and
      identification of glutathionyl adducts at exposed cysteine residues.
AB  - The copper, zinc-containing superoxide dismutase electromorphs from chicken
      erythrocytes have been isolated, their complete amino acid sequence determined
      and the identity of the protein moieties established. All electromorphs are
      constituted by a polypeptide chain made of 153 amino acid residues, corresponding
      to a molecular mass of 15,598 Da. Accurate molecular mass determination by
      electrospray mass spectrometry of the separated electromorphs unequivocally
      proved that, in the chicken superoxide dismutase, either one or two cysteine
      residues/subunit are involved in a mixed disulfide with glutathione. The same
      post-translational modification has been proven to occur in human superoxide
      dismutase. A different rate of S-thiolation by endogenous glutathione was also
      demonstrated to be responsible for charge heterogeneity in cells. Effect of this
      modification on the catalytic and molecular properties of superoxide dismutases,
      and possible mechanisms for the S-thiolation process, were also investigated and
      discussed.

PMID- 8647081
TI  - Purification and catalytic properties of two manganese peroxidase isoenzymes from
      Pleurotus eryngii.
AB  - The ligninolytic basidiomycetes Pleurotus eryngii, Pleurotus ostreatus, Pleurotus
      pulmonarius and Pleurotus sajor-caju did not exhibit detectable levels of
      manganese peroxidase (MP) when grown in liquid media with ammonium tartrate as N
      source. However, after examination of cells grown on different organic N-based
      media, high MP activity was obtained in peptone medium, up to nearly 3 U/ml in
      cultures of P. eryngii. Moreover, Mn2+ supplementation was not used to produce
      MP, since all Mn2+ concentrations assayed (1-4000 microM) inhibited production of
      this enzyme in liquid medium. Two MP isoenzymes were purified to homogeneity from
      shaken or stationary cultures of P. eryngii grown in peptone medium. The
      purification process (which included chromatography on Biorad Q-cartridge,
      Sephacryl S-200 and Mono-Q) attained 56% activity yield with a purification
      factor of 25. The isoenzymes differed in pI (3.75 and 3.65), N-terminal sequence
      and some catalytic properties. They were in some aspects (e.g, molecular mass of
      43 kDa) similar to Phanerochaete chrysosporium MP but exhibited some distinct
      characteristics, including Mn(2+)-independent peroxidase activities against 2,6
      dimethoxyphenol and veratryl alcohol, and higher resistance to H2O2. Recent
      studies have shown that MP are ubiquitous enzymes in ligninolytic fungi, but the
      results obtained suggest that differences in catalytic properties probably exist
      between different Mn(2+)-oxidizing peroxidases produced by these fungi.

PMID- 8647083
TI  - Characterization of the core promoter of the Na+/K(+)-ATPase alpha 1 subunit
      gene. Elements required for transcription by RNA polymerase II and RNA polymerase
      III in vitro.
AB  - We have analyzed the core promoter element of the Na+/K(+)-ATPase alpha 1 subunit
      gene by means of an in vitro transcription system composed of a HeLa nuclear
      extract. 5'-deletion and 3'-deletion analyses revealed that this gene is
      specifically transcribed by RNA polymerase II in a manner that is dependent on
      the upstream regulatory region of the gene (-102 to -61), and that the 3'
      boundary of the minimal promoter element does not extend beyond +5. Analysis of
      linker-substitution mutations and point mutations revealed that the TATA-like
      sequence (-33 to -26) is required for upstream-sequence-dependent transcription
      whereas linker-substitution mutations and point mutations near +1 did not abolish
      transcription. The gene was found to be transcribed by RNA polymerase III when
      phosphocellulose column fractions were assayed. Deletion analysis mapped the
      minimal RNA-polymerase-III--specific promoter element from -49 to +17. The
      phosphocellulose 0.3-M-KCl fraction is absolutely required for transcription by
      RNA polymerase III, while the 0.85-M-KCl fraction represses aberrant
      transcription from incorrect initiation sites. Analysis of linker-substitution
      mutations indicated that the TATA-like sequence is required for RNA-polymerase
      III--specific transcription. Although point mutations in the 5' half of the TATA
      like sequence did not affect transcription, those in the 3' half shifted the
      transcription initiation site 3 bp upstream. The results suggest the the Na+/K(+)
      ATPase alpha 1 subunit gene promoter contains a TATA-like sequence which can
      direct transcription by RNA polymerase III in vitro. The mechanism of alternative
      regulation of RNA polymerase II and RNA polymerase III is discussed.

PMID- 8647084
TI  - Mutation of the conserved Cys165 outside of the CuA domain destabilizes nitrous
      oxide reductase but maintains its catalytic activity. Evidence for disulfide
      bridges and a putative protein disulfide isomerase gene.
AB  - The single conserved Cys165 outside of the CuA domain of nitrous oxide reductase
      (N2OR) from Pseudomonas stutzeri was mutated to glycine to test its presumed
      function in metal coordination of the catalytic site, CuZ. The point mutation
      reduced the cellular level of N2OR 5--10-fold compared to the level of the
      control strain. In the mutant, the activity and the Cu content of the enzyme, as
      well as the transcript level of the N2OR structural gene, nosZ, remained
      unaffected. The mutant enzyme was processed and exported into the periplasm like
      the wild-type enzyme. Chemical analysis for sulfhydryl groups gave about nine -SH
      groups/monomer of the apoenzyme prepared from the wild-type enzyme, in accordance
      with the nine cysteine residues of the derived amino acid sequence. Eight -SH
      groups were found to form disulfide bridges in the holoenzyme dimer. We propose
      that in the native state of the enzyme Cys165 does not bind to CuZ, but may be
      part of a disulfide bridge essential for the stability of N2OR. Immediately
      downstream of the genes nosDFY, encoding the components for Cu incorporation into
      the reductase, we have identified the open reading frame, ORFL, whose derived
      product has the signature of a protein disulfide isomerase.

PMID- 8647085
TI  - The metabolism of sphingo(glyco)lipids is correlated with the differentiation
      dependent autophagic pathway in HT-29 cells.
AB  - Recently it was demonstrated that the metabolism of both glycoproteins and
      sphingo(glyco)lipids is dependent upon the state of enterocytic differentiation
      of HT-29 cells. Furthermore, it was shown that undifferentiated HT-29 cells
      display an important autophagic sequestration, controlled by a heterotrimeric Gi3
      protein. In order to correlate the metabolism of sphingo(glyco)lipids with the
      extent of autophagic sequestration, we have incubated undifferentiated and
      differentiated HT-29 cells with tritium-labelled GM1 ganglioside and sphingosine
      in the absence and presence of pertussis toxin (an inhibitor of autophagic
      sequestration) or asparagine (an inhibitor of autophagic vacuole maturation). In
      addition, undifferentiated HT-29 cells transfected with a cDNA encoding the G
      alpha i3 protein (cells expressing an amplified autophagic pathway) were labelled
      with both GM1 and sphingosine. The results show that the catabolism of
      sphingo(glyco)lipids is dramatically enhanced in parallel with the increase of
      the autophagic pathway while at the same time their biosynthesis is reduced. The
      inhibition of autophagy in both undifferentiated cells and alpha i3
      overexpressing cells restores sphingo(glyco)lipid metabolism, as normally
      expressed in differentiated cells, as well as in other mammalian cell types. We
      conclude that autophagy plays an important role in governing the metabolic fate
      of sphingo(glyco)lipids in HT-29 cells. Since autophagy regulates the N-linked
      glycoprotein metabolism in this cell line, our results corroborate the idea that
      glycolipid and glycoprotein metabolisms are controlled by similar mechanisms.

PMID- 8647086
TI  - Cyclin-dependent kinase-2 (Cdk2) forms an inactive complex with cyclin D1 since
      Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H.
AB  - Cyclin-dependent kinases (Cdks) form complexes with cyclins, and as a consequence
      they generally express kinase activities. One of these Cdks, Cdk2, is known to
      bind with cyclins A and E, and plays an important role in the progression of the
      cell cycle via phosphorylation of target proteins such as the product of the
      retinoblastoma tumor-suppressor gene (pRB). It has been suggested that Cdk2 bound
      with cyclin D1 and Cdk2-cyclin-D1 complex show neither H1 histone nor pRB kinase
      activity. However, it is not clear whether Cdk2-cyclin-D1 has unknown targets and
      why Cdk2 is not activated by binding with cyclin D1. We investigated these
      questions using Cdk, cyclin and Cdk-cyclin complexes produced in a baculovirus
      expression system. Cdk2 formed a complex with cyclin D1 in this system. After
      extensive purification, Cdk2 was still bound to cyclin D1. The Cdk2-cyclin-D1
      complex did not phosphorylate any tested substrates, such as H1 histone, pRB,
      SV40 large T antigen, p53, E2F-1 or a preparation of nuclear proteins from HeLa
      cells; in contrast, Cdk2-cyclin-E and Cdk2-cyclin-A phosphorylated these
      proteins. Moreover, the Cdk2-cyclin-D1 complex was not activated by incubation
      with Cdk4 or cyclin E. Thus, Cdk2 and cyclin D1 formed a stable complex that was
      not activated. In order to determine why Cdk2-cyclin-D1 lacks kinase activity, we
      investigated the phosphorylation of Cdk2. Under-shifted Cdk2, the active form of
      Cdk2, was not detected in the Cdk2-cyclin-D1 complex in the baculovirus system.
      In human WI-38 cells, cyclin D1 began to form a complex with Cdk2 as well as with
      Cdk4 from the mid-G1 phase of the cell cycle. The Cdk2 bound to cyclin D1 in
      human cells was also the inactive form that was slowly migrated. Moreover, we
      found that Cdk2 bound to cyclin D1 was not phosphorylated by Cdk7-cyclin-H, while
      Cdk2 bound to cyclin E, as well as free Cdk2, was was phosphorylated by Cdk7
      cyclin-H. Additionally, Cdk2 phosphorylated by Cdk7-cyclin-H did not bind to
      cyclin D1. These results strongly suggest that Cdk2 forms a stable complex with
      cyclin D1 but is not activated because the Cdk2 molecule in the complex is not
      phosphorylated by Cdk7-cyclin-H and the phosphorylated Cdk2, an active form, does
      not bind to cyclin D1.

PMID- 8647087
TI  - Chemical structure of lipid A isolated from Comamonas testosteroni
      lipopolysaccharide.
AB  - The chemical structure of lipid A of lipopolysaccharide isolated from Comamonas
      testosteroni was determined by quantitative analysis, methylation analysis, mass
      spectrometry and NMR spectroscopy. The lipid A backbone was found to consist of 6
      O-(2-deoxy-2-amino-beta-D-glucopyranosyl)-2-deoxy-2-amino-alpha-D-g luc ose which
      was phosphorylated in positions 1 and 4'. Hydroxyl groups at positions 4 and 6'
      were unsubstituted, and position 6' of the non-reducing terminal residue was
      identified as the attachment site of the polysaccharide part. Liquid secondary
      ion/mass spectrometry revealed a pseudomolecular ion at m/z 1572 [M-H]- as a
      major diphosphoryl lipid component carrying six acyl groups. Fatty acid
      distribution analysis and electrospray ionization/mass spectrometry of the lipid
      A showed that positions 2,2',3, and 3' of the sugar backbone were N-acylated or O
      acylated by (R)-3-hydroxydecanoic acid, and that the hydroxyl groups of the amide
      linked residues attached to positions 2 and 2' were further O-acylated by
      tetradecanoic and dodecanoic acids, respectively.

PMID- 8647088
TI  - Stereochemical requirements of chitin synthase for ligand binding at the
      allosteric site for N-acetylglucosamine.
AB  - The substrate kinetics of chitin synthase (CS) were non-Michaelian, irrespective
      of the type of enzyme preparation studied (105-S chitosomal CS, and 16-S ex
      walls), even in the presence of saturating GlcNAc. An unexplained idiosyncrasy of
      this enzyme, which is likely to be responsible for this phenomenon, is evident
      from the striking non-linearity of product deposition with time at low substrate
      or low enzyme concentrations, particularly in the absence of GlcNac. The
      possibility can be excluded that this non-linearity is due to the formation of
      soluble by-products or intermediates in the form of chito-oligomers, as shown by
      HPLC/pulsed amperometric detection analysis. Additional evidence was sought for
      the tenet that CS is homotropically-heterotropically regulated, at least under
      steady-state reaction conditions. Substrate kinetic curves established from rate
      data for the linear reaction phase only were used for modelling. These could be
      reasonably well parameterised on the basis of the Monod mathematical model for co
      operative ligand binding. Within a series of test compounds used to assess the
      stereochemical conditions of the allosteric site of CS for effector binding, N
      acetylglucosaminono-1,5-lactone oxime excelled. Requirements for effector binding
      are as follows: (a) an aminoglucopyranose skeleton with the amino function
      acetylated, and (b) a single-bonded oxo-function present at C(1), which is
      preferentially a hydrogen bond donor, that may be equatorially spaced off, but
      must not be alpha-anomeric. The implications of these findings for chitin
      synthesis in vivo are discussed in terms of a mechanistically based fitness of CS
      to operate efficiently under vastly different combinations of substrate could be
      coordinately linked to the catabolism of chitin.

PMID- 8647089
TI  - Colocalization of the dihydropyridine receptor, the plasma-membrane calcium
      ATPase isoform 1 and the sodium/calcium exchanger to the junctional-membrane
      domain of transverse tubules of rabbit skeletal muscle.
AB  - The subcellular distribution of the calmodulin-stimulated plasma-membrane Ca(2+)
      ATPase (PMCA) has been studied in rat and rabbit skeletal muscle cells by
      indirect (calmodulin gel overlays) and direct (Western blotting with specific
      antibodies) methods. It has also been studied in situ in immunocytochemistry
      experiments. The distribution of PMCA has been compared with that of the NA+/Ca2+
      exchanger and of the dihydropyridine receptor, which has been studied by Western
      blotting with specific antibodies. Both PMCA and the Na+/Ca2+ exchanger had a
      dual localization, i.e., they were found in the plasma membrane and in the
      transverse-tubule fractions of the two main types of skeletal muscles studied.
      The pump and the exchanger were not diffusely distributed in the transverse
      tubule-membrane system, but specifically confined to the membrane domain where
      the dihydropyridine receptor was also localized, i.e., the junctional membrane.
      Experiments with isoform-specific antibodies have shown that the pump isoform
      expressed in skeletal muscle is PMCA 1.

PMID- 8647090
TI  - Decreased rates of replicon initiation in mammalian cells.
AB  - We have designed an assay to measure the rate of initiation of DNA synthesis in
      Friend erythroleukemia cells and have shown that this parameter is reduced by
      gamma-radiation and treatment with 4'-demethyl-epipodophyllotoxin-9-(4,6-O
      ethylene-beta-D-glucopyranoside) (VP-16). It is concluded, that double-strand
      breaks in DNA are the immediate cause for this effect. The decrease in the rate
      of replicon initiation is affected differently by different agents such as cis
      diamminedichloroplatinum(II), cycloheximide, staurosporine, and 3-aminobenzamide.
      The analysis of these results indicates that the observed partial decrease of the
      rate of DNA initiation is most probably transmitted from the site of damage to
      the initiation site by one or more phosphorylation/dephosphorylation steps. It
      does not require de novo synthesis of protein factors, but is probably dependent
      on poly(ADP-ribosyl)ation of chromatin at the site of DNA breaks.

PMID- 8647091
TI  - Characterization of the functional gene encoding mouse class III alcohol
      dehydrogenase (glutathione-dependent formaldehyde dehydrogenase) and an
      unexpressed processed pseudogene with an intact open reading frame.
AB  - Multiple forms of vertebrate alcohol dehydrogenase (ADH) have been identified,
      but only one form, class III ADH, has been conserved in all organisms studied.
      Class III ADH functions in vitro as a glutathione-dependent formaldehyde
      dehydrogenase, which suggests that this was the original function that drove the
      evolution of ADH. Genetic analysis of class III ADH in yeast supports this view,
      but such studies are lacking in higher eukaryotes. The mouse ADH family has been
      previously analyzed and it contains three forms of ADH including the class III
      enzyme. We have initiated a molecular genetic analysis of the mouse class III ADH
      gene (Adh-2) by screening a genomic library with a full-length cDNA. Two
      overlapping clones contained the complete Adh-2 gene composed of nine exons in a
      12-kb region, with the placement of introns matching that observed in other
      mammalian ADH genes. In this screening, we also isolated a clone (psi Adh-2) that
      lacks introns and which resembles a processed pseudogene. psi Adh-2 contained 25
      point mutations relative to the previously analyzed Adh-2 cDNA, but still
      retained an intact open reading frame. Northern blot analysis using gene-specific
      probes provided evidence that psi Adh-2 does not produce a mRNA in either liver
      or kidney, whereas Adh-2 does. The functionality of the two genes was also
      compared by fusion of their 5'-flanking regions to a lacZ reporter gene. Reporter
      gene expression following transfection into mouse F9 embryonal carcinoma cells
      indicated that only Adh-2 possesses promoter activity.

PMID- 8647092
TI  - Characterization and molecular cloning of Sambucus nigra agglutinin V (nigrin b),
      a GalNAc-specific type-2 ribosome-inactivating protein from the bark of
      elderberry (Sambucus nigra).
AB  - The molecular structure of the Sambucus nigra agglutinin V (SNAV), which has been
      described previously as a type-2 ribosome-inactivating protein called nigrin b,
      has been studied in detail by analysis of the purified protein combined with cDNA
      cloning and molecular modelling. Native SNAV is a dimer of two [A-s-s-B] pairs.
      Hapten inhibition assays indicated that GalNAc is a 20-fold more potent inhibitor
      of SNAV than Gal. A cDNA clone encoding SNAV was isolated from a cDNA library
      constructed with mRNA from the bark. Sequence analysis of this cDNA revealed a
      striking similarity to the recently cloned NeuAc alpha-2,6-gal/GalNAc-specific S.
      nigra bark agglutinin I (SNAI) and to the previously sequenced type-2 ribosome
      inactivating proteins from Ricinus communis and Abrus precatorius. In addition,
      molecular modelling of SNAV further suggested that its structure closely
      resembles that of ricin. The N-terminal sequence of the B chain of SNAV also
      shows a marked similarity with the polypeptide of the previously described GalNAc
      specific s. nigra bark agglutinin II (SNAII), which unlike SNAV and SNAI has no
      ribosome-inactivating activity. It appears, therefore, that elderberry bark
      contains at least two different type-2 ribosome-inactivating proteins and a
      lectin built up of subunits which are closely related to the B chain of SNAV.

PMID- 8647093
TI  - Biotin-labelled and photoactivatable aldosterone and progesterone derivatives as
      ligands for affinity chromatography, fluorescence immunoassays and photoaffinity
      labelling.
AB  - New derivatives of progesterone and aldosterone were synthesized and functionally
      tested with commercially available antibodies. The covalent labelling of
      antibodies specific for aldosterone and progesterone was detected by SDS/PAGE
      analysis and subsequent autoradiography after using 3-(O-carboxymethyl)-oximino
      (3-[125I]iodo-4-azidosalicylamidobu tylamine) derivatives of aldosterone and
      progesterone, respectively, as photoactivatable radioligands. Labelling was not
      observed in the presence of an excess of the unlabelled steroid. Aldosterone was
      labelled with biotin and used as a tracer in a time-resolved fluorescence
      immunoassay. The nonradioactive tracer is highly selective for its antibody
      binding site, with almost no detectable cross-reactivity for other steroids.
      Biotin-labelled progesterone was immobilized by avidin-agarose and used for
      affinity chromatography. This yielded a more than 20-fold enrichment of an anti
      progesterone polyclonal antibody. These results demonstrate that derivatives of
      steroids are particularly useful for the development of nonradioactive assays for
      the determination of natural steroids and may be also useful for the detection of
      specific binding sites in biological material such as plasma membranes.

PMID- 8647094
TI  - Oxygenic photosynthesis. Electron transfer in photosystem I and photosystem II.
AB  - Photosystems I and II drive oxygenic photosynthesis. This requires biochemical
      systems with remarkable properties, allowing these membrane-bound pigment-protein
      complexes to oxidise water and produce NAD(P)H. The protein environment provides
      a scaffold in the membrane on which cofactors are placed at optimum distance and
      orientation, ensuring a rapid, efficient trapping and conversion of light energy.
      The polypeptide core also tunes the redox potentials of cofactors and provides
      for unidirectional progress of various reaction steps. The electron transfer
      pathways use a variety of inorganic and organic cofactors, including amino acids.
      This review sets out some of the current ideas and data on the cofactors and
      polypeptides of photosystems I and II.

PMID- 8647095
TI  - Differential binding of cAMP-responsive-element (CRE)-binding protein-1 and
      activating transcription factor-2 to a CRE-like element in the human tissue-type
      plasminogen activator (t-PA) gene promoter correlates with opposite regulation of
      t-PA by phorbol ester in HT-1080 and HeLa cells.
AB  - The human tissue-type plasminogen activator gene (t-PA) is induced by the phorbol
      ester, phorbol 12-myristate 13-acetate (PMA), in HeLa cells. Previous studies in
      transfected HeLa cells identified two cis-acting regulatory elements within the t
      PA gene promoter responsible for both constitutive and PMA-inducible expression.
      One element differs from the consensus cAMP response element (CRE) by a single
      nucleotide substitution (referred to in this report as t-PACRE) and another which
      bears similarity to the AP-2 recognition sequence. In HT-1080 fibrosarcoma cells,
      t-PA mRNA levels are expressed at higher constitutive levels and are suppressed
      by PMA. Nuclear run-on transcription experiments indicate that PMA-mediated
      suppression of t-PA in these cells is associated with a decrease in t-PA gene
      template activity. We designed experiments to determine whether nuclear t-PACRE
      or AP-2-like binding proteins were differentially expressed in HeLa and HT-1080
      cells and, accordingly, if these could be correlated with the opposite effect of
      PMA on t-PA expression. Band shift analyses indicated that the migration profiles
      of HeLa and HT-1080 nuclear proteins interacting with the AP-2-like site were
      indistinguishable; however, those produced with the t-PACRE binding site were
      qualitatively and quantitatively distinct. The distribution of t-PACRE binding
      proteins in these cells was investigated in a supershift assay using specific
      antibodies against members of the fos/jun and CRE-binding protein
      (CREB)/activating transcription factor (ATF) families. In HT-1080 cells, CREB-1
      was the most prominent t-PACRE-binding activity detected and was greatly
      increased in cells treated with PMA. In contrast, CREB-1 activity was absent in
      HeLa cells, but antibodies specific for ATF-2 produced a marked supershifted
      complex which was unaffected by PMA treatment. Since CREB-1 can repress
      transcription of other target genes (including c-jun) via association with
      identical cis-acting CRE-like sequences, we suggest that the mechanism for the
      transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1
      binding to the t-PACRE while ATF-2, by associating with the same site, plays a
      role in PMA-mediated induction of t-PA in HeLa cells.

PMID- 8647096
TI  - Impairment of DNA replication within one cell cycle after seeding of cells in the
      presence of a polyamine-biosynthesis inhibitor.
AB  - Chinese hamster ovary (CHO) cells in the plateau phase were seeded in the absence
      or presence of 5 mM 2-difluoromethylornithine (F2MeOrn), an enzyme-activated
      irreversible inhibitor of ornithine decarboxylase. The thymidine analogue
      bromodeoxyuridine (BrdUrd, 5 microM) was added to the culture medium 30 min
      before sampling of the cells, which occurred 1-17 h after seeding. Using flow
      cytometry, coupled with an indirect immunofluorescence technique, which utilized
      monoclonal BrdUrd and secondary fluorescein-isothiocyanate-conjugated antibodies,
      and the DNA stain propidium iodide, cellular BrdUrd and DNA contents were
      quantified. To determine if there was a perturbation in the progression of cells
      through the S phase, the distribution of BrdUrd-labelled cells in the S phase was
      evaluated in two ways: (a) by calculating the mean DNA content of BrdUrd-labelled
      cells in relation to the mean DNA contents of G1 and G2 cells (relative
      movementzero) and (b) by studying DNA histograms of BrdUrd-labelled cells. By
      using both evaluation methods, we show that DNA replication was impaired during
      the first cell cycle that was initiated after seeding CHO cells in the presence
      of F2MeOrn. The cells appeared to enter the S phase normally but were then
      delayed in their progression through this phase. The impairment of F2MeOrn
      treatment on DNA replication was apparent at 9 h after seeding, a time point at
      which the putrescine pool was depleted, the spermidine pool was approximately
      halved, and the spermine pool was unaffected, when compared to corresponding
      pools of control cells. When cells were seeded in the presence of F2MeOrn and
      putrescine, the effect on DNA replication was prevented. The rates of
      incorporation of [3H]uridine and [3H]leucine into RNA and protein, respectively,
      were the same in control and in F2MeOrn-treated cells for at least up to 11 h
      after seeding.

PMID- 8647097
TI  - Construction and functional characterization of recombinant fusion proteins of
      human lipoprotein lipase and apolipoprotein CII.
AB  - The hydrolysis of triacylglycerols of chylomicrons and very low density
      lipoproteins by lipoprotein lipase (LPL) requires the presence of apolipoprotein
      (apo) CII as a cofactor. To obtain further information on the interaction of apo
      CII and LPL, we generated two fusion proteins consisting of the complete LPL
      molecule and the mature form of apo CII. The cDNAs of both proteins were either
      connected directly or by a segment encoding a 16-amino-acid linker peptide. The
      fused cDNAs were stably expressed in human embryonic kidney (HEK) 293 cells and
      the enzymic properties of the recombinant proteins were examined. The fusion
      proteins hydrolysed both emulsified long-chain (lipase) triacyglycerol substrate
      and a water-soluble short-chain (esterase) fatty acid ester substrate (p
      nitrophenylbutyrate), regardless of whether or not they contained the linker
      peptide. In the absence of exogenous apo CII, the fusion proteins had up to 3.5
      times higher basal activity than wild-type LPL. Similar to wild-type LPL, the
      fusion proteins were inhibited by 1 M NaCl, however less than wild-type LPL. A
      polyclonal antibody specific for apo CII impaired their ability to hydrolyse
      triacylglycerol emulsions. A similar effect was seen when the tetrapeptide KGEE
      was used as inhibitor, which corresponds to the carboxy-terminal four amino acids
      of apo CII.

PMID- 8647098
TI  - Acetyl xylan esterase from Trichoderma reesei contains an active-site serine
      residue and a cellulose-binding domain.
AB  - The axe1 gene encoding acetyl xylan esterase was isolated from an expression
      library of the filamentous fungus Trichoderma reesei using antibodies raised
      against the purified enzyme. Apparently axe1 codes for the two forms, pI 7 and pI
      6.8, of acetyl xylan esterase previously characterized. The axe1 encodes 302
      amino acids including a signal sequence and a putative propeptide. The catalytic
      domain has no amino acid similarity with the reported acetyl xylan esterases but
      has a clear similarity, especially in the active site, with fungal cutinases
      which are serine esterases. Similarly to serine esterases, the axe1 product was
      inactivated with phenylmethylsulfonyl fluoride. At its C-terminus it carries a
      cellulose binding domain of fungal type, which is separated from the catalytic
      domain by a region rich in serine, glycine, threonine and proline. The binding
      domain can be separated from the catalytic domain by limited proteolysis without
      affecting the activity of the enzyme towards acetylated xylan, but abolishing its
      capability to bind cellulose.

PMID- 8647099
TI  - Assignment of 13C resonances and analysis of relaxation properties and internal
      dynamics of pike parvalbumin by 13C-NMR at natural abundance.
AB  - Pike parvalbumin is an 11.5-kDa globular protein which binds Ca2+ through EF-hand
      structural motifs. Nearly complete assignment of the protonated 13C resonances
      has been achieved by means of heteronuclear two-dimensional experiments. The
      study shows that 13Ca chemical shifts can be very sensitive to localised
      conformational aspects. To characterise internal dynamics of pike parvalbumin,
      longitudinal-relaxation and transverse-relaxation rates and 1H-13C NOEs were
      measured for alpha-carbons at natural abundance by means of two-dimensional NMR
      spectroscopy. Relaxation data were obtained at a spectrometer frequency of 600
      MHz for 69 residues with an even spread along the parvalbumin polypeptide chain.
      A double approach that included Lipari-Szabo analysis and direct mapping of
      spectral densities was used to interpret relaxation data in terms of internal
      dynamics. The former analysis provides valuable information about the overall
      rotational correlation time and S2 order parameters, while the mapping approach
      characterises the relative contributions of different motional frequencies. The
      results suggest that Ca(2+)-loaded pike parvalbumin has a rigid structure, even
      in the functional regions, i.e., the Ca(2+)-binding loops. The patterns of
      density-function values are more sensitive to the secondary structure than those
      of S2. Moreover, depending on the sampling frequency, these patterns reveal
      different aspects of structure-specific motions.

PMID- 8647100
TI  - Synthesis and solution structure of the antimicrobial peptide protegrin-1.
AB  - Protegrins are members of a family of five Cys-rich, cationic antimicrobial
      peptides recently isolated from porcine cells. We have synthesised an 18-amino
      acid peptide that corresponds to protegrin-1. After Cys oxidation, the peptide
      has bactericidal activity against gram-positive and gram-negative bacteria,
      similar to that described for the natural peptide. The solution structure of
      protegrin-1 was investigated by means of 1H-NMR spectroscopy in water and in
      (CD3)2SO, with distance-geometry and simulated-annealing calculations. The C6-C15
      and C8-C13 disulfide pattern was determined on the basis of NMR-derived
      constraints. These two parallel disulfide bridges stabilised a beta-sheet
      structure which comprised two antiparallel strands (residues 5-9 and 12-16)
      linked by a distorted beta-turn (residues 9-12). The N-terminus and C-terminus
      were essentially disordered. The distribution of hydrophobic and hydrophilic
      residues at the peptide surface was found to be a structural feature shared with
      tachyplesin-1, a related peptide which displays cytolytic activity, and, to a
      lesser extent, with mammalian defensins. These findings led us to assume that the
      distribution pattern could be required for the cytolytic activity of these
      peptides.

PMID- 8647101
TI  - Cloning of the maoA gene that encodes aromatic amine oxidase of Escherichia coli
      W3350 and characterization of the overexpressed enzyme.
AB  - The mao operon of Escherichia coli W3350, which comprises the genes maoC and
      maoA, was cloned and appeared to be similar to that of Klebsiella aerogenes
      [Sugino, H., Sasaki, M., Azakami, H., Yamashita, M. & Murooka, Y. (1992) J.
      Bacteriol. 174, 2485-2492]. The gene that encodes aromatic amine oxidase (maoA)
      was isolated, sequenced, and expressed in E. coli TG2. The purified enzyme
      exhibited properties characteristic of a copper/topaquinone(TPQ)-containing amine
      oxidase with respect to the optical absorption and EPR spectra, the size of the
      subunits, and the optical absorption spectra obtained upon derivatization with
      hydrazines. However, high-resolution anion-exchange chromatography revealed that
      the preparation was heterogeneous. The enzyme preparation appeared to consist of
      at least four enzyme species with different specific activities, A474nm/A340nm
      ratios and TPQ/subunit ratios. Since the overall properties of the overexpressed
      enzyme and the authentic enzyme were similar and the separated enzyme species had
      identical N-terminal amino acid sequences, the heterogeneity does not seem to be
      caused by improper expression of the gene in the recombinant strain but by
      factors that interfere with the processing of the specific tyrosine in the
      precursor enzyme to functional TPQ. Although other causes cannot be excluded, the
      spectral data and TPQ/subunit ratios reported in the literature for other amine
      oxidases suggest that suboptimal synthesis of functional TPQ also occurs in other
      organisms.

PMID- 8647102
TI  - Flavin motion in p-hydroxybenzoate hydroxylase. Substrate and effector
      specificity of the Tyr22-->Ala mutant.
AB  - The side chain of Tyr222 in p-hydroxybenzoate hydroxylase interacts with the
      carboxy moiety of the substrate. Studies on the Tyr222-->Phe mutant, [F222]p
      hydroxybenzoate hydroxylase, have shown that disruption of this interaction
      hampers the hydroxylation of 4-hydroxybenzoate. Tyr222 is possibly involved in
      flavin motion, which may facilitate the exchange of substrate and product during
      catalysis. To elucidate the function of Tyr222 in more detail, in the present
      study the substrate and effector specificity of the Tyr222-->Ala mutant, [A222]p
      hydroxybenzoate hydroxylase, was investigated. Replacement of Tyr222 by Ala
      impairs the binding of the physiological substrate 4-hydroxybenzoate and the
      substrate analog 4-aminobenzoate. With these compounds, [A222]p-hydroxybenzoate
      hydroxylase mainly acts as a NADPH oxidase. [A222]p-hydroxybenzoate hydroxylase
      tightly interacts with 2,4-dihydroxybenzoate and 2-hydroxy-4-aminobenzoate.
      Crystallographic data [Schreuder, H.A., Mattevi, A., Oblomova, G., Kalk, K.H.,
      Hol, W.G.J., van der Bolt, F.J.T. & van Berkel, W.J.H. (1994) Biochemistry 33,
      10161-10170] suggest that this is due to motion of the flavin ring out of the
      active site, allowing hydrogen-bond interaction between the 2-hydroxy group of
      the substrate analogs and N3 of the flavin. [A222]p-Hydroxybenzoate hydroxylase
      produces about 0.6 mol 2,3,4-trihydroxybenzoate from 2,4-dihydroxybenzoate/mol
      NADPH oxidized. This indicates that reduction of the Tyr222-->Ala mutant shifts
      the equilibrium of flavin conformers towards the productive "in' position.
      [A222]p-Hydroxybenzoate hydroxylase converts 2-fluoro-4-hydroxybenzoate to 2
      fluoro-3,4-dihydroxybenzoate. The regioselectivity of hydroxylation suggests that
      [A222]p-hydroxybenzoate hydroxylase binds the fluorinated substrate in the same
      orientation as wild-type. Spectral studies suggest that wild-type and [A222]p
      hydroxybenzoate hydroxylase bind 2-fluoro-4-hydroxybenzoate in the phenolate form
      with the flavin ring preferring the "out' conformation. Despite activation of the
      fluorinated substrate and in contrast to the wild-type enzyme, [A222]p
      hydroxybenzoate hydroxylase largely produces hydrogen peroxide. The effector
      specificity of p-hydroxybenzoate hydroxylase is not changed by the Tyr222-->Ala
      replacement. This supports the idea that the effector specificity is mainly
      dictated by the protein-substrate interactions at the re-side of the flavin ring.

PMID- 8647104
TI  - Non-structural protein 3 of hepatitis C virus inhibits phosphorylation mediated
      by cAMP-dependent protein kinase.
AB  - Inspection of the amino acid sequence of the non-structural region of the
      hepatitis C virus (HCV) gene product reveals a sequence of 14 amino acids,
      Arg1487-Arg-Gly-Arg-Thr-Gly-Arg-Gly-Arg-Arg-Gly-Ile-Tyr-Arg1500 , located in the
      non-structural protein, NS3. This sequence is highly similar to the inhibitory
      site of the heat-stable inhibitor of cAMP-dependent protein kinase (PKA) and to
      the autophosphorylation site in the hinge region of the PKA type II regulatory
      domain. A synthetic peptide that corresponds to the HCV sequence above and a set
      of shorter analogues act as competitive inhibitors of PKA. A 43.5-kDa fragment of
      NS3 that consists of residues 1189-1525 of the HCV polyprotein inhibits PKA in a
      similar range to the investigated synthetic peptides. In contrast to the short
      peptides, which show competitive inhibition, HCV-polyprotein-(1189-1525)
      influences PKA in a mixed-inhibition-type manner. A possible mechanism explaining
      these differences is the formation of complexes that consist of the protein
      substrate, the enzyme and the HCV-polyprotein-(1189-1525). Binding studies with
      PKA and the non-hydrolysable ATP analogue [14C]fluorosulfonylbenzoyladenosine and
      [3H]cAMP do not reveal any influence of the short HCV-derived peptides or HCV
      polyprotein-(1189-1525) upon the affinity of PKA for these nucleotides. The
      complex interactions of the NS3 fragments could influence one of the most
      important signal pathways of the cell and, therefore, could possibly provide new
      pathological mechanisms for HCV infections of liver.

PMID- 8647103
TI  - The synthesis of mRNA in isolated mitochondria can be maintained for several
      hours and is inhibited by high levels of ATP.
AB  - The dependence for the maintenance of the synthesis and maturation of
      mitochondrial RNA on the supply of nucleo-cytoplasmic factors has been
      investigated by a novel in organello RNA synthesis system. We found that
      mitochondrial DNA transcription can be maintained for several hours in isolated
      mitochondria. Analysis of the individual mitochondrial RNA species revealed that:
      the processing of the rRNA precursors and the stability of the mature rRNAs, but
      not the transcription itself, is severely impaired after short periods of
      incubation, indicating that these processes are strongly dependent on the
      mitochondrial interaction with the nucleo-cytoplasmic compartment; the events
      that lead to the synthesis, processing and turnover of the mitochondrial mRNAs do
      not require the continuous supply of nucleo-cytoplasmic factors, that are
      accumulated in excess by mitochondria. Furthermore, we present evidence
      indicating an inhibition of high ATP levels on the mitochondrial RNA polymerase
      activity, both in organello and in vitro. Consequently, it is proposed that
      mitochondrial mRNA synthesis can be regulated in response to changes in
      intramitochondrial ATP levels. This regulation of mitochondrial mRNA synthesis
      together with their very rapid turnover described here and elsewhere [Gelfand, R.
      & Attardi, G. (1981) Mol. Cell Biol. 1, 497-511], could represent a mechanism
      that would allow each individual mitochondrion to adjust its optimal levels of
      mRNA, and hence its translation capacity, in response to local energetic demands.

PMID- 8647105
TI  - Conformational transitions within the calmodulin-binding site of Bordetella
      pertussis adenylate cyclase studied by time-resolved fluorescence of Trp242 and
      circular dichroism.
AB  - The sequence situated around Trp242 in Bordetella pertussis adenylate cyclase, a
      bifunctional protein of 1706 amino acid residues, forms the core of the
      calmodulin-binding site. Peptides varying in size and in affinity for calmodulin,
      and preserving the same sequence around Trp242 were analyzed by time-resolved
      fluorescence spectroscopy. Their dynamic properties were compared to those of the
      catalytic domain of B. pertussis adenylate cyclase corresponding to the first 400
      amino acid residues of the protein and in which the Trp69 residue was replaced by
      Phe. The heterogeneity of the fluorescence intensity decays of Trp242 is likely
      due to the existence of conformers in equilibrium as is suggested by the effect
      of trifluoroethanol both on the secondary structure content and the lifetime
      distributions. Binding to calmodulin leads to striking effects on the lifetime
      distribution profiles by selecting a major excited state population and therefore
      one major conformer. Trp242 still presents some degree of rotational freedom in
      the complexes. The reduction of rotational freedom is more important for the
      shorter peptides than for the longest one. A similar selection of one major
      conformer with the same lifetime was also observed for the Trp242 in the mutant
      protein when bound to calmodulin, as in the complexes with the peptides. We
      conclude that the site of interaction of B. pertussis adenylate cyclase with
      calmodulin has similar conformational flexibility as that evidenced in the
      isolated peptides. This property of the molecule allows a better adjustment of
      the enzyme upon interaction with calmodulin.

PMID- 8647106
TI  - Similarities in the architecture of the active sites of Ni-hydrogenases and Fe
      hydrogenases detected by means of infrared spectroscopy.
AB  - Three groups that absorb in the 2100-1800-cm-1 infrared spectral region have
      recently been detected in Ni-hydrogenase from Chromatium vinosum [Bagley, K.A.,
      Duin, E.C., Roseboom, W., Albracht, S. P.J. & Woodruff, W.H. (1995) Biochemistry
      34, 5527-5535]. To assess the significance and generality of this observation, we
      have carried out an infrared-spectroscopic study of eight hydrogenases of three
      different types (nickel, iron and metal-free) and of 11 other iron-sulfur and/or
      nickel proteins. Infrared bands in the 2100-1800-cm-1 spectral region were found
      in spectra of all Ni-hydrogenases and Fe-hydrogenases and were absent from
      spectra of any of the other proteins, including a metal-free hydrogenase. The
      positions of these bands are dependent on the redox state of the hydrogenase. The
      three groups in Ni-hydrogenases that are detected by infrared spectroscopy are
      assigned to the three unidentified small non-protein ligands that coordinate iron
      in the dinuclear Ni/Fe active site as observed in the X-ray structure of the
      enzyme from Desulfovibrio gigas [Volbeda, A., Charon, M.-H., Piras, C.,
      Hatchikian, E.C., Frey, M. & Fontecilla-Camps, J.C. (1995) Nature 373, 580-587].
      It is concluded that these groups occur exclusively in metal-containing H2
      activating enzymes. It is proposed that the active sites of Ni-hydrogenases and
      of Fe-hydrogenases have a similar architecture, that is required for the
      activation of molecular hydrogen.

PMID- 8647107
TI  - Structural studies of the O-specific polysaccharide of Hafnia alvei strain 1209
      lipopolysaccharide.
AB  - The structure of the O-specific side chains of the Hafnia alvei strain 1209
      lipopolysaccharide has been investigated. Methylation analysis and 1H-NMR and 13C
      NMR spectroscopy were the principal methods used. It is concluded that the
      polysaccharide is composed of pentasaccharide repeating units that have the
      following structure: -->3)-beta-D-Galp-(1-->4)-alpha-D-Glcp-(1-->4)-beta-D-GlepA
      (1--> 3)-beta-D-GalpNAc-(1 --> 4 increases 1 alpha-L-Rhap The relative intensity
      of the signals from the terminal repeating unit in the 1H-NMR spectrum, the
      amount of 2,3,6-tri-O-methylgalactose in the methylation analysis, and the matrix
      assisted laser-desorption ionisation time-of-flight (MALDI-TOF) mass spectrum of
      the O-polysaccharide indicated that the structure is also the biological
      repeating unit and that the O-chains mainly consisted of 8-11 repeating units
      and, on average, ten repeating units.

PMID- 8647108
TI  - Induction of CYP1A1 gene by benzimidazole derivatives during Caco-2 cell
      differentiation. Evidence for an aryl-hydrocarbon receptor-mediated mechanism.
AB  - The Caco-2 cell line, derived from a human colon adenocarcinoma, is unique in its
      property of spontaneously differentiating into a mature enterocyte cell type
      during its growth in culture. In this work, we compared the response of the
      CYP1A1 gene with the benzimidazole derivatives omeprazole and lansoprazole, and
      with the classical inducer beta-naphthoflavone in the Caco-2 cells at various
      culture stages. In addition, we characterized the Caco-2 aryl-hydrocarbon
      receptor. The protein-synthesis inhibitor cycloheximide led to a derepression of
      the CYP1A1 gene transcription, and to a superinduction when combined with either
      beta-naphthoflavone or benzimidazoles. Taking advantage of the spontaneous
      differentiation of Caco-2 cells in long-term cultures, we observed a difference
      in behavior between the classical inducer beta-naphthoflavone and the atypical
      inducer omeprazole. In the poorly differentiated cells, both compounds elicited
      comparable dose/response and rate of induction of CYP1A1 gene expression. In the
      fully differentiated cells, in contrast, the induction by omeprazole was only
      transient, whereas the response to beta-naphthoflavone was long lasting. The Caco
      2 aryl-hydrocarbon receptor exhibited binding characteristics similar to those
      determined for human liver and other tissues. The induction of CYP1A1
      transcription by benzimidazole derivatives in Caco-2 cells occurred with no
      direct binding of benzimidazole derivatives to the aryl-hydrocarbon receptor, as
      in human hepatocytes. However, transient transfection experiments clearly showed
      that the xenobiotic-responsive element enhancer, with which the activated aryl
      hydrocarbon receptor interacts, could drive the induction of a heterologous
      promoter in the presence of benzimidazoles. Finally the presence of the activated
      aryl-hydrocarbon receptor in the nuclei of the Caco-2 cells exposed to these
      molecules was clearly demonstrated by gel-retardation experiments. These results
      question about the mechanism of ligand-independent activation of the aryl
      hydrocarbon receptor and intracellular signaling, initiated by benzimidazole
      derivatives.

PMID- 8647110
TI  - Efficient transfer of regulated genes in adipocytes and hepatoma cells by the
      combination of liposomes and replication-deficient adenovirus.
AB  - Efficient transfer of genes maintaining a correct hormonal control in transfected
      cells is the prerequisite for gene regulation studies and for gene therapy.
      Differentiated cells, like adipocytes or hepatocytes, are difficult to transfect.
      In an attempt to improve gene transfer, we first transiently transfected cultured
      3T3-F442A adipocytes with a construct containing the simian virus 40 (SV40)
      promoter fused to the chloramphenicol acetyltransferase (CAT) gene (pSV2-CAT),
      using various cationic liposomes. Among these, only lipofectAMINE was five times
      more efficient than the standard calcium phosphate procedure. To further augment
      efficiency, we transfected 3T3-F442A adipocytes and FAO hepatoma cells with the
      lipofectAMINE/pSV2-CAT complex in the presence of replication-deficient
      recombinant type-5 adenovirus at 200 pfu/cell. CAT activity of transiently
      transfected cells was increased about 50-fold when compared to the calcium
      phosphate procedure. To determine whether this methodology would be useful for
      obtaining stable transfectants and would not interfere with correct gene
      regulation, we used a construct containing -2100 to +69 bp of the
      phosphoenolpyruvate carboxykinase gene fused to the CAT gene (pPL1-CAT). This
      construct was shown previously to be cAMP-responsive after calcium-phosphate
      mediated transfection of adipocytes and hepatoma cells. 3T3-F442A or FAO cells in
      which pPL1-CAT was either transiently or stably transferred by lipofectAMINE and
      adenovirus responded to isoproterenol or cAMP, respectively, with a 2-3-fold
      increase in CAT activity. Therefore the association of liposomes and adenovirus
      is an efficient method for transient or stable transfer of regulated genes in
      adipocytes and hepatoma cells.

PMID- 8647109
TI  - Inconstant association between 27-kDa heat-shock protein (Hsp27) content and
      doxorubicin resistance in human colon cancer cells. The doxorubicin-protecting
      effect of Hsp27.
AB  - To investigate the role of the small 27-kDa heat-shock protein (Hsp27) in the
      intrinsic resistance of colon cancer cells to doxorubicin, we modified Hsp27
      expression either genetically by transfection or pharmacologically by cisplatin
      treatment. HT-29 cells were transfected with a full-length Hsp27 construct in the
      sense or antisense orientation. We found a good correlation between cell survival
      after doxorubicin treatment and Hsp27 content. A similar correlation was found
      for the thermoresistance of the Hsp27-transfected cells. In contrast, the
      sensitivity of the different transfected cells to 5-fluorouracil was not
      modified. cis-Platinum(II)diammine dichloride (cisplatin) treatment of HT-29 or
      Caco2 cells dramatically increased their Hsp27 mRNA and protein content.
      Accordingly, the cells became thermoresistant. Contrary to what has been
      previously assumed, however, cell resistance to doxorubicin was reduced. Our data
      suggest that the decreased resistance of the cells to doxorubicin may be due to a
      concomitant increase of topoisomerase II expression, the main target of
      anthracyclines. In conclusion, although Hsp27 seems to participate in the natural
      resistance of colon cancer cells to anthracyclines, its increase after cisplatin
      treatment is not associated with a decreased cytotoxicity to doxorubicin.

PMID- 8647111
TI  - Molecular cloning of endothelial, inducible nitric oxide synthase gene from rat
      aortic endothelial cell.
AB  - We have isolated and sequenced clones of an inducible nitric oxide synthase
      (iNOS) from cDNA library of interleukin-1 beta-treated rat aortic endothelial
      cells (EC) completely free from other cell types. The cloned cDNA contains an ORF
      consisting of 3441 bp, which encodes 1147 amino acid residues. The deduced amino
      acid sequence contains putative binding sites for NADPH, FMN, FAD, calmodulin and
      heme. By comparison with amino acid sequences of other isoforms, rat EC iNOS is
      very similar (92% similarity) to mouse macrophage iNOS. There are four AUUUA
      motifs, potentially responsible for the instability of the mRNA, in 3'non-coding
      region of rat EC iNOS cDNA. Transient transfection of cultured rat vascular
      smooth-muscle cells with a full-length rat EC iNOS cDNA/SR alpha 296 construct by
      electroporation resulted in massive NO production in proportion to the doses of
      cDNA used. Northern blot analysis using rat EC iNOS cDNA as a probe revealed that
      cycloheximide treatment led to a marked accumulation of iNOS mRNA in the presence
      and absence of interleukin-1 beta. No appreciable decay in the cycloheximide
      induced iNOS mRNA accumulation was observed, suggesting that blockade of de novo
      protein synthesis stabilizes mRNA. These results demonstrate that rat EC iNOS is
      identical (or very similar) to macrophage iNOS, and suggest that the EC iNOS gene
      is also regulated at the post-transcriptional level.

PMID- 8647112
TI  - Alcaligenes eutrophus possesses a second pyruvate dehydrogenase (E1).
AB  - Two gene loci, which hybridized with pdhA, the structural gene of the E1
      component of the Alcaligenes eutrophus pyruvate dehydrogenase complex [Hein, S. &
      Steinbuchel, A. (1994) J. Bacteriol. 176, 4394-4408], were identified on two
      nonrelated A. eutrophus chromosomal BamHI fragments by using a pdhA-specific DNA
      probe. These data indicated that A. eutrophus possesses, beside PdhA, two
      additional distinct pyruvate dehydrogenases (E1). A 6.8-kbp genomic BamHI
      fragment of A. eutrophus was cloned, and sequence analysis of a 3.896-kbp region
      revealed the structural gene pdhE (2.694 kbp) for a second pyruvate dehydrogenase
      (E1), which was not clustered with structural genes for other components of 2-oxo
      acid dehydrogenase complexes. The A. eutrophus pdhE gene product (898 amino acid
      residues) exhibited significant similarities to the E1 components of the pyruvate
      dehydrogenase complexes of A. eutrophus, Neisseria meningitidis, Escherichia coli
      and Azotobacter vinelandii, which are also composed of only one type of subunit.
      Heterologous expression of pdhE in the aceEF deletion mutant E. coli YYC202 was
      demonstrated by spectrometric detection of enzyme activities and by phenotypic
      complementation to acetate prototrophy. These complementation studies indicated
      that the E1 component of the A. eutrophus pyruvate dehydrogenase complex can be
      replaced by a functionally active pdhE gene product.

PMID- 8647113
TI  - The guanine-nucleotide-exchange complex (EF-1 beta gamma delta) of elongation
      factor-1 contains two similar leucine-zipper proteins EF-1 delta, p34 encoded by
      EF-1 delta 1 and p36 encoded by EF-1 delta 2.
AB  - We have cloned and sequenced a Xenopus cDNA referred to as EF-1 delta 2. The cDNA
      is homologous to EF-1 delta 1 encoding for EF-1 delta a protein of the guanine
      nucleotide exchange complex of elongation factor-1 (EF-1). The protein sequence
      deduced from the cDNA, contains the two characteristic features of EF-1 delta
      protein, the leucine-zipper domain and the guanine-nucleotide exchange domain. In
      vitro and in vivo translation leads to the production of a 36-kDa protein from EF
      1 delta and a 34-kDa protein from EF-1 delta 1. The clone EF-1 delta 2 therefore
      encodes for authentic p36 protein of EF-1 beta gamma delta complex, while EF-1
      delta 1 encodes for a newly characterised p34 protein of the leucine zipper
      family. Both EF-1 delta proteins are simultaneously present in oocytes extracts,
      at a molecular ratio around 1:10 for p34 versus p36 proteins. Both are associated
      in a macromolecular structure that is greater than 750 kDa upon gel filtration.
      The two proteins are targets for Cdc2 kinase in meiotic maturation.

PMID- 8647114
TI  - Characterization of DNA ligase from the fungus Coprinus cinereus.
AB  - DNA ligase was highly purified from the fungus Coprinus cinereus at the miotic
      recombination stage, pachytene. The pachytene DNA ligase showed three
      polypeptides with molecular masses of 88, 84 and 80 kDa, as estimated by the
      [32P]AMP-labeling assay. These three polypeptides were susceptible to reaction
      with an mAb against a 16-amino-acid sequence in human DNA ligase I, which is
      conserved in C-terminal regions of mammalian, vaccinia virus and yeast DNA
      ligases. Since rapidly purified preparations from fresh pachytene cells exhibited
      a single polypeptide of DNA ligase with a molecular mass of 88 kDa, the smaller
      polypeptides seemed to be limited-degradation products of the 88-kDa polypeptide
      during the isolation and purification procedures. K(m) values for ATP and (dT)20
      hybridized with (dA)n were 1.5 microM and 90 nM, respectively. This enzyme was
      capable of joining (dT)20.(rA)n and (rA)12-18 (dT)n as well as (dT)20.(dA)n and
      able to ligate blunt-ended DNA in the presence of poly(ethylene glycol) 6000. DNA
      ligases were also partially purified from zygotene cells at the meiotic pairing
      stage and mitotic mycelium cells. In their molecular mass, immuno-reactivity,
      K(m) value and substrate specificity, they were indistinguishable from pachytene
      DNA ligase. These results suggest that the fungus C. cinereus at the pachytene
      stage contains DNA ligase with a molecular mass of 88 kDa as a main or a single
      species, which is quite similar to DNA ligases from the zygotene and mycelium
      cells in molecular and catalytic properties.

PMID- 8647115
TI  - Purification and cDNA cloning of the alcohol dehydrogenase of the flesh fly
      Sarcophaga peregrina. A structural relationship between alcohol dehydrogenase and
      a 25-kDa protein.
AB  - We purified to homogeneity two proteins with molecular masses of 25 kDa from the
      fat body of the Sarcophaga larva. One was alcohol dehydrogenase (ADH) and the
      other was a 25-kDa protein of which the genomic DNA had been cloned. We isolated
      the cDNA for ADH and determined its amino acid sequence. Amino acid sequence
      identity between ADH and the 25-kDa protein was 40%, indicating that they are
      structurally related proteins. The amount of ADH in Sarcophaga was almost
      constant through the larval stage to the adult stage, but the 25-kDa protein was
      detected only within a restricted period between the final larval instar and the
      early pupal stage.

PMID- 8647117
TI  - Selection in vitro of trans-acting genomic human hepatitis delta virus (HDV)
      ribozymes.
AB  - In an effort to identify the functional structure as well as new active variants
      of the trans-acting genomic ribozyme of human hepatitis delta virus (HDV), we
      applied an in vitro selection procedure. A total of 14 rounds of selection and
      amplification was repeated and various mutant ribozymes in G10 and G14 pools
      analyzed. Active ribozymes which were isolated in the present study (from G10 and
      G14) all possessed conserved bases (that were identified earlier) in the cis
      acting molecule. A dominant clone G10-68 variant was accumulated in generation
      14. Interestingly, when base substitutions were analyzed in G10-68 variant, we
      found that this variant appears to be close to antigenome-like HDV ribozyme
      molecule. Further investigations of G10-68 confirmed that each mutated base was
      the most appropriate nucleotide at every position of the HDV ribozyme.

PMID- 8647116
TI  - Signaling pathway associated with stimulation of CB2 peripheral cannabinoid
      receptor. Involvement of both mitogen-activated protein kinase and induction of
      Krox-24 expression.
AB  - Cannabinoids, known for their psychoactive effects, also possess immunomodulatory
      properties. The recent isolation and cloning of the G-protein-coupled peripheral
      cannabinoid receptor (CB2), mainly expressed in immune tissues, have provided
      molecular tools to determine how cannabinoid compounds may mediate
      immunomodulation. We here investigated the CB2 signaling properties using stably
      transfected Chinese hamster ovary cells expressing human CB2. First, we showed
      that stimulation by a cannabinoid agonist activated mitogen-activated protein
      (MAP) kinase in time- and dose-dependent manners. The rank order of potency for
      MAP kinase activation of cannabinoid agonists correlated well with their binding
      capacities. Second, we demonstrated that, following MAP kinase activation,
      cannabinoids induced the expression of the growth-related gene Krox-24, also
      known as NGFI-A, zif/268, and egr-1. Pertussis toxin completely prevented both
      MAP kinase activation and Krox-24 induction, even more these responses appeared
      to be dependent of specific protein kinase C isoforms and independent of
      inhibition of adenylyl cyclase. A similar coupling of CB2 to a mitogenic pathway
      and to the regulation of Krox-24 expression was also observed in human
      promyelocytic cells HL60. Taken together, these findings provide evidence for a
      functional role of the CB2 receptor in gene induction mediated by the MAP kinase
      network.

PMID- 8647118
TI  - Heterologous expression and site-directed mutagenesis studies on the activation
      mechanism and the roles of the basic residues in the prosegment of
      aspergillopepsinogen I.
AB  - To study the structure/function relationship of the prosegment of aspartic
      proteinase, a putative proform of aspergillopepsin I (or proteinase B) from
      Aspergillus niger var. macrosporus was expressed by Escherichia coli, refolded in
      vitro, and purified. The conversion of the purified proenzyme
      (aspergillopepsinogen I, proproteinase B) into the active mature form occurred at
      pH < or = 4.5 and was completely inhibited by pepstatin A, a specific inhibitor
      for aspartic proteinase, suggesting autoprocessing. The N-terminus of this mature
      form was Glu67 (numbering in preproform), which was different from the N-terminal
      Ser70 of native proteinase B although there was no significant difference in
      enzymatic activity. During the conversion, two intermediates were observed on
      SDS/PAGE, indicating a stepwise mechanism. The Lys56-Phe57 sequence seems to be a
      counterpart of the Lys-Tyr pair highly conserved in the prosequences of aspartic
      proteinases. When the mutant proenzyme (K56N), in which Lys56 was replaced with
      Asn by site-directed mutagenesis, was allowed to refold under various conditions,
      no significant potential activity could be obtained. Proproteinase B was also
      expressed by Bacillus brevis HPD31. This system required no in vitro refolding to
      obtain potentially active proenzyme, which was secreted into the culture medium
      (30-120 mg/l) and had the same properties with that obtained by the E. coli
      system. The K56N mutant prepared by this system also had no potential activity,
      and was rapidly digested by incubation with native proteinase B, suggesting that
      the mutant did not fold correctly. On the other hand, the K56R mutant (Lys56-Arg)
      was potentially active. These results indicated that Lys56 is essential for the
      folding through electrostatic interaction with the catalytic Asp residues in the
      active site although it may be replaced with Arg. In the presence of a low
      concentration of pepstatin A, an incompletely processed form with N-terminal
      Ser53 was obtained. Further, the R52Q (Arg52-->Glin) mutant showed no processing
      but was converted to the active mature form by incubation with the native enzyme.
      Therefore, the cleavage between Arg52 and Ser53 is considered to be the initial
      and essential step of the autoactivation. The R26Q, K27Q, R36Q, K40Q, R42Q, and
      K66Q mutants were also potentially active. The K66Q mutant was processed to a
      form with N-terminal Ala55.

PMID- 8647119
TI  - An NMR-derived model for the solution structure of oxidized Thermotoga maritima
      1[Fe4-S4] ferredoxin.
AB  - The solution structure of the 60-residue 1[Fe4-S4] ferredoxin from the
      hyperthermophilic bacterium Thermotoga maritima was determined based on 683
      distance and 35 dihedral angle restraints that were obtained from NMR data. In
      addition, data known from crystallographic studies of ferredoxins was used for
      modeling of the iron-sulfur cluster and its environment. The protein shows a
      globular fold very similar to the fold of the related 1[Fe4-S4] ferredoxins from
      Desulfovibrio gigas and Desulfovibrio africanus, and elements of regular
      secondary structure similar to those in other ferredoxins were found in the T.
      maritima protein. In particular, the T. maritima protein displayed a beta-sheet
      structure made up of strands located at the very NH(2) and COOH termini of the
      protein, and an internal alpha-helix. The internal beta-sheet observed in the D.
      gigas and D. africanus ferredoxins could not be confirmed in T. maritima
      ferredoxin and is thus suggested to be only weakly present or even absent in this
      protein. This result suggests that thermostability in ferredoxins is not
      necessarily correlated with the content of stable elements of regular secondary
      structure.

PMID- 8647120
TI  - Involvement of Src-homology-2-domain-containing protein-tyrosine phosphatase 2 in
      T cell activation.
AB  - Activation of resting T lymphocytes by ligands to the complex of T cell antigen
      receptor (TCR) and CD3 is initiated by a series of critical tyrosine
      phosphorylation and dephosphorylation events. Protein-tyrosine kinases of the
      Syk, Src and Csk families and the CD45 protein-tyrosine phosphatase (PTPase) are
      known to be involved in these early biochemical reactions. We have found that one
      of the two T-cell-expressed SH2-domain-containing PTPases, SHPTP2, is rapidly
      phosphorylated on tyrosine upon addition of anti-CD3 mAbs. This response was
      absent in cells lacking the Src family kinase Lck. Concomitantly with tyrosine
      phosphorylation, SHPTP2 co-immunoprecipitated with two unphosphorylated cellular
      proteins; phosphatidylinositol 3-kinase p85 and Grb2. Binding of SHPTP2 to Grb2
      occurred through the SH2 domain of Grb2, while the association between SHPTP2 and
      p85 seemed to be mediated through Grb2 as an intermediate. In addition, many
      other molecules associate with Grb2 and may thereby become juxtaposed to SHPTP2.
      Our results indicate that SHPTP2 participates actively at an early stage in TCR
      signaling and that its phosphorylation on tyrosine may direct a Grb2-dependent
      association with selected substrates.

PMID- 8647121
TI  - Systematic mutational analysis of the receptor-binding region of the human
      urokinase-type plasminogen activator.
AB  - The amino-terminal fragment of human uPA (ATF; amino acids 1-135), which contains
      the binding site for the uPA receptor (uPAR, CD87) was expressed in the yeast
      Saccharomyces cerevisiae. Recombinant yeast ATF, modified and extended by an
      amino-terminal in-frame insertion of a His6 tract, was purified from total
      protein extracts by nickel chelate affinity chromatography and shown to be
      functionally active since it efficiently competes with uPA for binding to cell
      surface-associated uPAR. The ATF expression plasmid served as a template for the
      construction of a series of site-directed mutants in order to define those amino
      acids that are important for binding to uPAR. All mutant ATF proteins but one
      (deletion of Ser26) were expressed in a stable form (about 20-30 ng/mg total
      protein) and the binding capacity of each mutant was tested by a uPA-ligand
      binding assay employing recombinant uPAR immobilized to a microtiter plate. Each
      of the 11 amino acids of loop B of the binding region of uPA (amino acids 20-30)
      were individually substituted with alanine. Lys23, Tyr24, Phe25, IIe28, and Trp30
      were important determinants for uPAR binding. A systematic alanine scan was also
      performed with chemically synthesized linear peptides spanning amino acids 14-32
      of ATF. Comparable results to those with the yeast ATF mutants were obtained. In
      a different set of experiments, those amino acids of the uPAR-binding region of
      uPA that are only conserved between man and baboon but not in other species were
      altered: whereas substitution of Thr18 by alanine or Asn32 by serine had hardly
      any effect, replacement of Asn22 by tyrosine and Trp30 by arginine (both
      positions are strictly conserved in other mammals) led to ATF variants incapable
      of interacting with human uPAR. Deletion of either Val20, Ser21, Lys23, His29 or
      Val20 plus Ser21, respectively, also generated non-reactive ATF mutants. Finally,
      Lys23 in ATF was substituted with certain amino acids: whereas the replacement of
      Lys23 by alanine, histidine or glutamine generated ATF variants with moderate
      uPAR-binding activity, the introduction of a negatively charged amino acid
      (exchange of Lys23 by glutamic acid) completely abolished uPAR-binding activity.
      The results presented for the ATF mutants and uPA-derived peptides may provide
      clues necessary to establish the nature of the physical interaction of uPA with
      its receptor and may help to develop uPA-derived peptide analogues as potential
      therapeutic agents to block tumor cell-associated uPA/uPAR interaction.

PMID- 8647122
TI  - Different exon-intron organizations of the genes for two astacin-like proteases,
      high choriolytic enzyme (choriolysin H) and low choriolytic enzyme (choriolysin
      L), the constituents of the fish hatching enzyme.
AB  - The hatching enzyme of the teleost, Oryzias latipes, is composed of two
      proteases, high choriolytic enzyme (choriolysin H, HCE) and low choriolytic
      enzyme (choriolysin L, LCE), which are similar in some enzymological
      characteristics and protein structure (55% identity in amino acid sequence) and
      belong to the astacin family. Two isoforms of HCE are detected. In the present
      study, the genes for HCE and LCE were isolated from the genomic library
      constructed from DNA of the inbred drR strain fish. In contrast to the close
      similarity of the enzymes, there was a marked difference in their gene
      organization. The LCE gene was a single copy gene and composed of eight exons
      interrupted by seven introns. The HCE genes were multicopy genes and lacked
      introns. In the haploid genome of the drR strain fish, there are eight HCE genes,
      seven of which were cloned. Each HCE gene was identified as that for either of
      the two isoforms of HCE. 5' flanking regions of the LCE gene and the HCE genes
      had consensus TATA box sequences, but not CAT box nor GC box sequences. The big
      difference in the exon-intron organization between the HCE genes and the LCE gene
      is discussed from an evolutionary viewpoint.

PMID- 8647123
TI  - Cloning and functional characterization of the amphibian mesotocin receptor, a
      member of the oxytocin/vasopressin receptor superfamily.
AB  - Mesotocin is the oxytocin-like hormone found in most terrestrial vertebrates from
      lungfishes to marsupials, which includes all non-mammalian tetrapods (amphibians,
      reptiles, and birds). It has the largest distribution in vertebrates after
      vasotocin found in all non-mammalian vertebrates and isotocin identified in bony
      fishes. In this study, we report the cloning and functional characterization of
      the cDNA for the mesotocin receptor (MTR) from the urinary bladder of the toad
      Bufo marinus. The cloned cDNA encodes a polypeptide of 389 amino acids that shows
      the greatest similarity to the teleost fish isotocin receptor and to mammalian
      oxytocin receptors with mutations in extracellular loops which are involved in
      ligand binding. When expressed in COSM6 cells, MTR exhibits the following
      relative order of ligand affinity: mesotocin > vasotocin = oxytocin > vasopressin
      > hydrin 1, isotocin, hydrin 2. Injection of MTR cRNA into Xenopus laevis oocytes
      induces membrane chloride currents in response to mesotocin, which indicates the
      coupling of the mesotocin receptor to the inositol phosphate/calcium pathway.
      This response is inhibited by an oxytocin antagonist, but not by a vasopressin
      antagonist specific for V2 vasopressin receptors. MTR mRNA is not only found in
      toad urinary bladder, but also in kidney, muscle, and brain tissue of the toad as
      revealed by northern blot analysis and reverse-transcriptase PCR. The results
      suggest a variety of function for mesotocin and its receptor including, in
      particular, an involvement in the regulation of water and salt transport.

PMID- 8647124
TI  - Photoaffinity labeling of the human brain cholecystokinin receptor overexpressed
      in insect cells. Solubilization, deglycosylation and purification.
AB  - The human cholecystokinin B (CCKB) receptor was expressed in Sf9 cells by
      infection with recombinant baculovirus. For immunodetection a c-myc epitope tag
      (EQKLISEEDL) was fused at the amino-terminus of the CCKB receptor. In a second
      construct an additional hexa-histidine tag was introduced at the C-terminus of
      the CCKB receptor to enable employment of metal affinity chromatography. The two
      receptor constructs were expressed at densities of 6.0 +/- 1.1 pmol/mg protein
      and 7.2 +/- 1.1 pmol/mg protein, respectively which are 100-200-fold higher
      compared with the receptor amounts found in natural sources. Saturation of the
      binding sites with [3H]propionyl-CCK8 revealed Kd values of 4.5 +/- 0.5 nM and
      7.8 +/- 0.6 nM for the CCKB receptor without or with histidine tag. In SDS/PAGE
      and subsequent immunodetection the histidine-tagged CCKB receptor migrated as a
      55-kDa band, whereas the CCKB receptor without C-terminal modification revealed
      apparent molecular masses of 45 kDa and 49 kDa. The differences in the mass
      values observed for the two constructs suggest that the histidine tag could
      protect the CCKB receptor against proteolytical degradation from its C-terminus.
      Furthermore two new photoreactive derivatives of cholecystokinin octapeptide
      residues 26-33 (CCK8) with high labeling efficiency and specificity for the
      cholecystokinin receptor subtype B were developed: [3H]BzBz-des-Met28-[p-NH2Bz29]
      CCK8 and [3H]BzBz-biotinyl-des-Met28-[p-NH2Bz29]-CCK8. Both contain the p-benzoyl
      benzoyl (BzBz) residue at the N-terminus for photoactivation and a p-aminobenzoyl
      (p-NH2BZ) residue instead of Met28-Gly29 in cholecystokinin. Enzymatic
      deglycosylation of the CCKB receptor with N-glycosidase F after photoaffinity
      labeling demonstrated that the CCKB receptor with three potential glycosylation
      sites was slightly glycosylated, amounting to a molecular mass of about 4 kDa.
      Using the biotinylated cholecystokinin derivative the photoaffinity-labeled CCKB
      receptor could be purified 1260-fold by a two-step procedure including affinity
      chromatography on a streptavidin/avidin agarose matrix. For purification of the
      native receptor, an improved solubilization protocol for the CCKB receptor using
      dodecyl beta-D-maltopyranoside was developed. The solubilized CCKB receptors with
      C-terminal histidine tag retained their ligand binding characteristics after
      chromatography on a nickel affinity matrix.

PMID- 8647125
TI  - The anticoagulant effect of the human secretory phospholipase A2 on blood plasma
      and on a cell-free system is due to a phospholipid-independent mechanism of
      action involving the inhibition of factor Va.
AB  - Blood platelets play a central role in haemostasis by leading to plug formation
      and by increasing the efficiency of blood coagulation. We have previously shown
      that blood platelets contain a group II secretory phospholipase A2 (sPLA2 grII)
      which is released into the extracellular medium upon activation but is unable to
      stimulate blood platelets. We presently reported an investigation of the putative
      involvement of the human sPLA2 grII (hsPLA2 grII) in the coagulation process,
      both in the absence and in the presence of activated platelets. We show that this
      enzyme prolongs the recalcification time of blood plasma even in the presence of
      activated platelets. The positive action of blood platelets on coagulation is
      correlated, at least in part, with the appearance at the cellular surface of
      procoagulant phospholipids which constitute a potential target for hsPLA2 grII.
      We therefore investigated the involvement of its enzymatic activity in the
      anticoagulant effect of this enzyme. We observed that the replacement of CaCl2 by
      SrCl2 to initiate the coagulation cascade did not suppress, but rather increased,
      the inhibitory action of hsPLA2 grII. Moreover, hsPLA2 grII hydrolyzed only a
      minor proportion of platelet phospholipids, and it did not affect plasma
      phospholipids. Taken together, these observations strongly suggest that the major
      action of hsPLA2 grII on blood coagulation does not involve the hydrolysis of
      phospholipids, in contrast with the strong anticoagulant effect of the group II
      venom phospholipase A2 from Crotalus durrissus terrificus. We next studied which
      step of the coagulation cascade was affected by hsPLA2 grII. Using purified
      coagulation factors, we demonstrated that hsPLA2 grII strongly inhibited the
      prothrombinase activity. This inhibitory effect was independent of the presence
      of phospholipids but required factor Va, leading to the hypothesis that hsPLA2
      grII inhibited this factor. Further, the anticoagulant effect of hsPLA2 grII was
      observed on normal and factor-X-deficient plasma, but not on factor-V-deficient
      plasma. In conclusion, the anticoagulant action of hsPLA2 grII is based on a
      nonenzymatic mechanism of action involving the inhibition of factor Va.

PMID- 8647126
TI  - A Klebsiella pneumoniae strain that shares a type-specific antigen with Shigella
      flexneri serotype 6. Characterization of the strain and strain and structural
      studies of the O-antigenic polysaccharide.
AB  - A strain of Klebsiella pneumoniae was found as the only isolate with pathogenic
      potential from the stool of a two-year old patient with diarrhoea. A strong
      serological cross-reactivity with Shigella flexneri serotype 6 was demonstrated.
      The cross-reacting antigens were shown to reside in the cell wall lipopoly
      saccharide. Studies of the pathogenic potential of the Klebsiella strain showed
      low level of invasion of HEp-2 cells. However, tests for adherence to HEp-2 cells
      as well as tests for toxin production were negative. The strain had several small
      plasmids and was multidrug resistant. These data do not form a sufficient basis
      for estimating the pathogenic potential of the organism. No K antigen was
      detected. The structure of the O-antigenic polysaccharide from the K. pneumoniae
      strain was investigated using methylation analysis, NMR spectroscopy, and Smith
      degradation as the principal methods. The O-antigenic polysaccharide has the
      following pentasaccharide repeating unit: -->3)- alpha -L-Rhap-(1-->3)- alpha -L
      Rhap-(1-->2)- alpha-L-Rhap- (1-->2)- alpha-L-Rhap-(1-->2)- alpha-L-Rhap-(1-->.
      This structure is not identical to any of the previously described O-antigens of
      K. pneumoniae. The strong serological cross-reactivity with the Shigella flexneri
      serotype 6 O-antigen can most likely be attributed to the structural element
      alpha-L-Rhap-(1-->2)- alpha -L-Rhap present in the O-polysaccharide repeating
      unit of this serotype. Antiserum raised against the K. pneumoniae strain also
      agglutinated S. dysenteriae serotype 1 and strains of all different serotypes of
      S. flexneri. The Shigella strains contain the structural element alpha-L-Rhap-(1-
      >3)- alpha-L-Rhap in their O-antigen polysaccharides which may be responsible for
      the observed cross-reactivity.

PMID- 8647127
TI  - Identification, cDNA sequence and deduced amino acid sequence of the
      mitochondrial Rieske iron-sulfur protein from the green alga Chlamydomonas
      reinhardtii. Implications for protein targeting and subunit interaction.
AB  - Specific oligonucleotide probes were used to isolate a cDNA clone for the
      mitochondrial Rieske iron-sulfur protein of the green alga Chlamydomonas
      reinhardtii. The protein is synthesized as a longer precursor with a cleavable N
      terminal presequence of 54 amino acids but without a C-terminal extension.
      Comparison of the predicted secondary structure of this N-terminal sequence with
      that of the targeting signal of the chloroplast Rieske protein from C.
      reinhardtii [de Vitry (1994) J. Biol. Chem. 269, 7603-7609] indicates that,
      although they both have the potential to form amphiphilic alpha helices, the mito
      chondrial presequence may form a more hydrophobic helix that could penetrate
      deeper into the membrane. The N-terminal part of the mature mitochondrial Rieske
      protein is characterized by a long, strongly hydrophilic N-terminal domain and by
      a positive charge in the middle of the hydrophobic stretch that is presumed to
      interact with the bc1 complex. Thus, the protein from C. reinhardtii differs from
      the Rieske proteins from mammals or fungi.

PMID- 8647128
TI  - Analysis of the specificity of the AMP-activated protein kinase by site-directed
      mutagenesis of bacterially expressed 3-hydroxy 3-methylglutaryl-CoA reductase,
      using a single primer variant of the unique-site-elimination method.
AB  - The specificity of protein kinases is usually examined using synthetic peptide
      substrates, either designed variants, or, more recently random peptide libraries.
      However not all protein kinases utilize synthetic peptides efficiently as
      substrates. Even among those that do, these approaches neglect effects caused by
      three-dimensional protein conformation, or the existence of determinants remote
      from the phosphorylation site. To follow up our previous peptide studies on the
      specificity of the AMP-activated protein kinase (AMPK) [Dale, S., Wilson, W. A.,
      Edelman, A.M., & Hardie, D. G. (1995) FEBS Lett. 361, 191-195], we have expressed
      the C-terminal, catalytic domain of Chinese hamster hydroxymethylglutaryl-CoA
      reductase in Escherichia coli. The domain was expressed with an N-terminal His6
      tag which allowed rapid purification on Nj(2+)-agarose. The purified protein
      retained full enzymic activity, and as with the native enzyme, was totally
      inactivated by phosphorylation by AMPK at a single site corresponding to Ser871.
      Using a novel modification of the unique-site elimination method (which allowed
      direct mutagenesis of the double-stranded expression vector using a single
      oligonucleotide primer) we expressed 18 mutations involving residues around
      Ser871. The results broadly confirmed the recognition motif previously proposed
      on the basis of peptide studies. Three of the mutants were better substrates for
      AMPK than the wild type, and one of these (K872A) had hydroxymethylglutaryl-CoA
      reductase kinetic parameters virtually indistinguishable from the wild type. This
      suggests that hydroxymethylglutaryl-CoA reductase may have been selected to be a
      sub-optimal substrate for AMPK.

PMID- 8647129
TI  - The oligomeric state of 46-kDa mannose 6-phosphate receptor does not change upon
      intracellular recycling and binding of ligands.
AB  - 46-kDa mannose-6-phosphate receptor forms homooligomers in cell membranes and in
      detergent solution. The quaternary structure of detergent-solubilized 46-kDa
      mannose 6-phosphate receptor is regulated by the presence of ligands, pH and
      receptor concentration [Waheed, A. & von Figura, K. (1990) Eur. J. Biochem. 193,
      47-54). To find out whether the intracellular recycling of 46-kDa mannose 6
      phosphate receptor is accompanied by changes in its quaternary structure, we have
      performed chemical cross-linking in membranes of intact cells. In all conditions
      tested, the dimer was the predominating form (more than 67% of total 46-kDa
      mannose 6-phosphate receptor). The amount of trimeric and tetrameric forms varied
      among cell lines and contributed up to 20% of total endogenous 46-kDa mannose 6
      phosphate receptor in human and mouse fibroblasts. Within a given cell line, the
      ratio of the oligomers was not significantly changed upon elevating endosomal pH
      by bafilomycin A1, upon changes in receptor occupancy (treatment of cells with
      tunicamycin or use of mouse fibroblasts deficient in 300-kDa mannose 6-phosphate
      receptor), nor upon depletion of adaptors from clathrin-coated vesicles of the
      trans Golgi network by brefeldin A. At the cell surface, where 46-kDa mannose 6
      phosphate receptor does not bind ligands, the percentage of dimer was similar to
      that observed intracellularly. Thus, the oligomeric state of 46-kDa mannose 6
      phosphate receptor apparently does not change during recycling as well as binding
      and dissociation of ligands. In view of the abundance of the dimer of 46-kDa
      mannose 6-phosphate receptor in situ, our data suggest that it represents the
      main physiologically active form of the receptor, and therefore present indirect
      evidence that binding of ligands to 46-kDa mannose 6-phosphate receptor is
      probably regulated by conformational changes of receptor or ligand rather than by
      changes in the quaternary structure.

PMID- 8647130
TI  - Sphingomyelin-derived lipids differentially regulate the extracellular signal
      regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in
      airway smooth muscle.
AB  - In ASM cells platelet-derived growth factor stimulates rapid transient
      sphingosine phosphate formation, the activation of extracellular signal-regulated
      kinase 2 (ERK-2), the phosphorylation of p70(56K), and a ninefold increase in DNA
      synthesis. In contrast, this growth factor fails to activate c-Jun N-terminal
      kinase (JNK). Based upon these findings, we have tested whether the sphingomyelin
      derived sphingolipids play a role in growth factor signalling by assessing their
      effect on ERK-2, JNK, and p70(56K). We demonstrate that sphingosine phosphate
      induces the activation of ERK-2, is ineffective against JNK, and fails to induce
      the phosphorylation of p70(56K). The latter may explain why it is a poor mitogen
      when added directly to ASM cells. In contrast, sphingosine and cell-permeable
      ceramides elicit the prominent tyrosyl phosphorylation and activation of JNK, are
      poor stimulators of ERK-2, and do not induce the phosphorylation of p70(56K).
      Therefore, the specificity of signalling through either ERK-2 or JNK cascades may
      be determined by the rapid agonist-dependent interconversion of these
      sphingomyelin-derived lipids. This may also provide a dynamic mechanism that
      enables growth factors and cytokines to elicit pleiotropic cell responses, such
      as proliferation and cell survival. For instance, both ceramide and sphingosine
      will elicit growth arrest via activation of JNK, whereas sphingosine phosphate
      will potentiate growth-factor-stimulated DNA synthesis, a consequence of the
      activation of ERK-2, Furthermore, under certain conditions, sphingosine and
      ceramide stimulate cAMP formation, a negative modulator of cell growth, whereas
      sphingosine phosphate depresses cAMP, thereby enhancing its own growth-promoting
      properties. From these studies, it is evident that sphingosine phosphate displays
      a signalling profile that is consistent with it mediating part of the action of
      platelet-derived growth factor.

PMID- 8647131
TI  - Expression in Escherichia coli of Sin a 1, the major allergen from mustard.
AB  - Sin a 1, the major yellow mustard allergen, is a seed storage protein that
      belongs to the 2S albumin family. It is composed of two disulfide-bonded
      polypeptide chains. The cloning of this allergen has been carried out by means of
      the polymerase chain reaction using non-degenerate oligonucleotides encoding the
      N-terminal and C-terminal regions of the mature protein as primers. Five genomic
      nucleotide sequences have been analyzed, encoding both mature polypeptide chains
      linked by the internal processed fragment. The sequence data show the existence
      of microheterogeneities at ten positions, demonstrating the polymorphism
      exhibited by the natural protein. One of the genomic clones was expressed in
      Escherichia coli by fusion to glutathione S-transferase from Schistosoma
      japonicum. The resulting chimeric protein was purified by affinity chromatography
      on a glutathione-Sepharose 4B matrix, and digested with thrombin to release the
      recombinant allergen. The recombinant Sin a 1 is recognized by rabbit polyclonal
      and mouse monoclonal antisera raised against natural Sin a 1, as well as by the
      IgE of mustard-sensitive human sera. In addition, recombinant Sin a 1 possesses a
      high resistance to trypsin digestion, like the native mustard allergen.

PMID- 8647133
TI  - Solution 1H-NMR structure of the heme cavity in the low-affinity state for the
      allosteric monomeric cyano-met hemoglobins from Chironomus thummi thummi.
      Comparison to the crystal structure.
AB  - Solution 1H-NMR studies of the heme cavity were performed for the cyanomet
      complexes of monomeric hemoglobins III and IV from the insect Chironomus thummi
      thummi, each of which exhibit marked Bohr effects. The low pH 5, paramagnetic (S
      = 1/2) derivatives were selected for study because the large dipolar shifts
      provide improved resolution over diamagnetic forms and allow distinction between
      the two isomeric heme orientations [Peyton, D. H., La Mar, G. N. & Gersonde, K.
      (1988) Biochim. Biophys. Acta 954, 82-94]. The crystal structure for the low-pH
      form of the hemoglobin III derivative, moreover, has been reported and showed
      that the functionally implicated distal His58 side chain adopts alternative
      orientation, either in or out of the pocket [Steigemann, W. & Weber, E. (1979) J.
      Mol. Biol. 127, 309-338]. All heme pocket residues for the low-pH forms of the
      two hemoglobins were located, at least in part, and positioned in the heme cavity
      on the basis of nuclear Overhauser effects to the heme and each other, dipolar
      shifts, and paramagnetic-induced relaxation. The resulting structure yielded the
      orientation of the major axis of the paramagnetic susceptibility tensor. The heme
      pocket structure of the cyanomet hemoglobins III and IV were found to be
      indistinguishable, with both exhibiting a distal His58 oriented solely into the
      heme cavity and in contact with the ligand, and with two residues, Phe100 and
      Phe38, exhibiting small but significant displacements in solution relative to
      hemoglobin III in the crystal.

PMID- 8647132
TI  - Alternative mRNA splicing of the novel GTPase Rab28 generates isoforms with
      different C-termini.
AB  - A novel ras-related gene (rab28) was identified by a PCR-based cloning approach
      and subsequent screening of rat fat cell and brain cDNA libraries. The deduced
      amino acid sequence of the cDNA is distantly related with members of the Rab
      family (31-33% sequence identity, mainly restricted to the six GTP-binding
      motifs). Cloning of the human homologue of Rab28 by a PCR-based approach revealed
      the existence of two isoforms (hRab28S, hRab28L) which differ only by a 95-bp
      insertion within the coding region. This insertion generates an alternative
      sequence of the 30 C-terminal amino acids of the protein. Both C-termini of the
      human homologues comprise farnesylation motifs, but differ strikingly in a
      stretch of 13 amino acids. By PCR, mRNA of hRab28S was detected in most tissues
      investigated (cortex, liver, kidney, skeletal muscle, adipose tissue, testis and
      urothelium), whereas hRab28L was predominant in testis. Recombinant Rab28
      proteins showed specific binding of radiolabeled guanosine 5'-O-[gamma
      thio]triphosphate and rapidly hydrolysed [alpha-32P]GTP; there was no difference
      in the GTP binding characteristics of the two isoforms hRab28S and hRab28L. It is
      suggested that the isoforms are derived from the same gene by alternative mRNA
      splicing, and that their functions differ in a parameter unrelated to its basic
      role as a GTPase.

PMID- 8647134
TI  - Human and plant proliferating-cell nuclear antigen have a highly conserved
      binding site for the p53-inducible gene product p21WAF1.
AB  - The mechanism(s) whereby higher plants respond to environmental agents that
      damage their DNA, which leads to the arrest of cell division, is poorly
      understood. In mammalian cells, the tumour-suppressor protein p53 plays a central
      role in a DNA-damage-induced cell-cycle-checkpoint pathway by induction of
      transcription of a set of gene products that have a direct role in a DNA-damage
      induced cell-cycle growth arrest. One such protein, p21WAF1, has been shown to be
      essential for radiation-induced growth arrest. There appear to be at least two
      cellular targets of p21WAF1 during checkpoint control, the G1-cyclin-dependent
      kinases (CDK) and proliferating-cell nuclear antigen (PCNA). The aim of the
      research reported here was to determine whether the interactions between the
      human growth inhibitor p21WAF1 and PCNA from plants and humans are conserved. If
      so, this would suggest that modulation of PCNA activity may play an important
      role in plant responses to DNA damage and would imply that functional
      homologue(s) of p21WAF1 exist in plants. We show that the p21WAF1-interaction
      domain of PCNA is conserved between humans and plants. A peptide that contains
      the site of human p21WAF1 that binds human PCNA has been used to precipitate PCNA
      from crude pea (Pisum savitum) extracts. We used the p21WAF1 peptide as an
      affinity matrix and showed that pea PCNA bound in a specific high-affinity
      manner. This finding was used to develop a purification protocol that allowed
      PCNA from plant tissue to be purified to homogeneity. Pure pea PCNA forms a
      stable complex with full-length human p21WAF1 and the specific amino acids of
      p21WAF1 required for the interaction have been identified. The critical residues
      were identical to those required for binding to human PCNA, which indicates that
      the interaction of human p21WAF1 with PCNA is highly conserved at each amino acid
      position between pea and human.

PMID- 8647135
TI  - Thermal unfolding and proteolytic susceptibility of ribonuclease A.
AB  - With the aim to localize the structural region that becomes first accessible to
      proteolytic attack during thermal unfolding, the proteolysis of ribonuclease A
      was studied in the temperature range of 20-65 degrees C. Subtilisin, proteinase
      K, and elastase proved to be not appropriate as indicators of thermal unfolding,
      because even the native protein molecule was cleaved by these proteases. In
      contrast, chymotrypsin, trypsin, and thermolysin attacked ribonuclease A only
      after its thermal treatment. For thermolysin and trypsin, the first primary
      cleavage sites of ribonuclease A could be identified by blotting of the
      electrophoretic bands, partial N-terminal sequencing of the fragments and
      assignment according to their molecular masses. The results were confirmed by the
      separation of the proteolytic fragments by HPLC and subsequent matrix-assisted
      laser desorption ionization mass spectrometry. The first cleavage sites were
      determined to be Lys31-Ser32 and Arg33-Asn34 for trypsin and Asn34-Leu35 and
      Thr45-Phe46 for thermolysin. Hence the structural region from Lys31 to Leu35,
      together with the adjacent beta-structure containing Thr45-Phe46, is suggested to
      represent a labile region of the ribonuclease A molecule, which becomes exposed
      at thermal denaturation.

PMID- 8647136
TI  - Cys5 and Cys214 of NAD(P)H:flavin oxidoreductase from Escherichia coli are
      located in the active site.
AB  - The NAD(P)H:flavin oxidoreductase (NADPH:riboflavin oxidoreductase) from
      Escherichia coli, Fre, is a monomer of 26.1 kDa, which catalyzes the reduction of
      free flavins by NADPH or NADH. A sequential ordered mechanism, with NADPH binding
      first, operates. Fre is the prototype of a class of flavin reductases able to
      transfer electrons with no prosthetic group. It has been previously reported that
      several members of this family, including Fre, were inactivated by thiol reagents
      such as N-ethylmaleimide (MalNEt). Amino acid sequence similarities among these
      enzymes reveal that one of the three cysteines residues of Fre is highly
      conserved. Altogether this suggested a crucial role of cysteine residues for
      catalysis. The three cysteine residues were mutated to serine residues. Single
      mutant and double-mutant enzymes were as active as the wild-type and Km values
      for both substrates remained the same. Cysteine residues are thus not important
      for activity. Nevertheless, we showed that cysteines 5 and 214, but not cysteine
      149, were responsible for MalNEt inactivation. In addition, it has been found
      that riboflavin, but not NADPH, can protect Fre from MalNEt inactivation. This
      strongly suggested that Cys5 and Cys214 are located at the flavin-binding site of
      Fre and that flavin can bind to the enzyme in the absence of NADPH.

PMID- 8647137
TI  - Kinetics and energetics of trehalose transport in Saccharomyces cerevisiae.
AB  - Cells of Saccharomyces cerevisiae are able to transport trehalose against a
      concentration gradient, without efflux or counterflow of the labeled substrate.
      Uptake was inhibited by uncouplers, acetic acid, and organic mercury compounds.
      The addition of trehalose resulted in alkalinization of the medium. The ratio of
      H+ depletion to trehalose uptake by yeast cells was approximately 1:1, which
      indicates the existence of a trehalose-H+ symporter in these cells. The optimum
      pH for this active H+-trehalose symport was 5.0, and both the Km and the Vmax
      were negatively affected by increasing or decreasing the extracellular pH from
      its optimum value. Kinetic studies showed the existence of at least two different
      trehalose transport activities in yeast cells: a high-affinity H+-trehalose
      symporter (Km = 4 mM), and a low-affinity transport activity (Km > 100 mM) that
      could be a facilitated diffusion process. The high-affinity H+-trehalose
      symporter was repressed by glucose, whereas the low-affinity uptake was
      constitutively expressed in S. cerevisiae.

PMID- 8647138
TI  - Apoptosis: molecular regulation of cell death.

PMID- 8647139
TI  - Selective alpha 1-adrenoceptor antagonists in benign prostatic hyperplasia:
      rationale and clinical experience.
AB  - Symptomatic benign prostatic hyperplasia (BPH) is a common condition in older men
      and has a significant impact on their daily lives. Transurethral resection of the
      prostate is currently the most effective remedy for BPH but is not suitable for
      all patients. There is now clear evidence for the efficacy of alpha-adrenoceptor
      antagonists, particularly selective alpha 1-adrenoceptor antagonists, in the
      treatment of BPH. Inhibition of alpha-adrenoceptors significantly increases
      urinary flow and improves symptoms in BPH. alpha 1-Adrenoceptor antagonists have
      a place in the management of BPH patients with mild to moderate disease, who are
      bothered by their symptoms, or for those awaiting or wishing to delay surgery.
      Treatment with selective alpha 1-adrenoceptor antagonists is generally better
      tolerated than nonselective-alpha-blockers. alpha 1-Selective adrenoceptor
      antagonists with a long half-life such as terazosin, doxazosin and tamsulosin, as
      a modified release formulation, permit once-daily dosing. Tamsulosin is the first
      subtype-specific (cloned alpha 1c/functional alpha 1A) adrenoceptor antagonist in
      clinical practice. Initial reports suggest that it gives no clinically relevant
      lowering of blood pressure and that its (vasodilatory) side effect profile is
      minimal. The scientific rationale behind the therapeutic use of alpha-adrenergic
      blockade as treatment for BPH and the trials data relating to the various agents
      which are available for clinical use are reviewed in the context of the
      contemporary literature.

PMID- 8647140
TI  - Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist.
      Analysis of a multinational, multicentre, open-label study assessing the long
      term efficacy and safety in patients with benign prostatic obstruction
      (symptomatic BPH). European Tamsulosin Study Group.
AB  - OBJECTIVE: This open-label extension study evaluated the efficacy and safety of
      tamsulosin (0.4 mg as a modified release formulation) once daily in patients with
      benign prostatic enlargement, lower urinary tract symptoms and benign prostatic
      obstruction (symptomatic BPH) for up to 60 weeks. METHODS: Patients were enrolled
      from two European, 12-week, placebo-controlled trials. This 60-week interim
      analysis includes the patients (n = 244) randomized to tamsulosin in the two
      placebo-controlled trials. RESULTS: The significant improvements in the primary
      efficacy parameters, maximum urinary flow rate (Qmax) and total Boyarsky symptom
      score, that were observed during the placebo-controlled trials, were sustained
      throughout the long-term extension study. Mean Qmax improved from baseline
      (before initiation of tamsulosin) to endpoint by 13.7% (p < 0.001) and remained
      between 11.5 and 12 ml/s during the entire follow-up period. Total Boyarsky
      symptom score improved by 36.2% from baseline to endpoint (p < 0.001). Similarly,
      the percentage of treatment responders, defined as an increase in Qmax of > or =
      30% or a decrease in total symptom score of > or = 25%, remained constant
      throughout the 60-week period. At endpoint, 69% of patients demonstrated this
      clinically significant total Boyarsky symptom score response. During the 60-week
      study period, 51 patients (21%) experienced an adverse event considered to be
      possibly or probably related to study medication, the most common of which were
      dizziness and abnormal ejaculation, both occurring in 5% of patients. There were
      no clinically significant changes in blood pressure or pulse rate during the
      study. CONCLUSION: Long-term tamsulosin therapy is safe, well tolerated and
      improvements in urinary flow and symptoms are maintained for at least 60 weeks of
      treatment.

PMID- 8647141
TI  - Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta
      analysis of two randomized, placebo-controlled, multicentre studies in patients
      with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study
      Group.
AB  - OBJECTIVE: This meta-analysis of two European studies evaluated the efficacy and
      safety of modified-release tamsulosin 0.4 mg once daily compared with placebo in
      patients with benign prostatic enlargement, lower urinary tract symptoms and
      prostatic obstruction (symptomatic BPH). METHODS: Patients entered a 2-week
      placebo run-in period, followed by randomization to treatment with tamsulosin
      (382 patients) or placebo (193 patients) once daily for 12 weeks. RESULTS:
      Maximum urinary flow rate improved to a greater extent in the tamsulosin group
      (1.6 ml/s, 16%) than the placebo group (0.6 ml/s, 6%) (p = 0.002). Total Boyarsky
      symptom score also improved to a greater extent in the tamsulosin group (3.3
      points, 35.1% reduction) than the placebo group (2.4 points, 25.5% reduction) (p
      = 0.002). Significantly more tamsulosin patients (66%) than placebo patients
      (49%) had a > or = 25% decrease in total symptom score at endpoint (p < 0.001).
      Twelve weeks of treatment with tamsulosin also produced significant improvements
      in average urinary flow rate (p = 0.005) and voiding or "obstructive" (p = 0.008)
      and storage or "irritative' (p = 0.017) symptom scores. The incidence of drug
      related adverse events was comparable for the tamsulosin and placebo groups (13
      and 12% respectively, p = 0.802). The same applies to the incidence of adverse
      events commonly attributed to alpha 1-adrenoceptor antagonists, such as
      dizziness, headache, postural hypotension, syncope, asthenia, somnolence and
      rhinitis. There were no clinically significant changes in blood pressure or pulse
      rate in tamsulosin patients compared with placebo patients both in hypertensive
      and normotensive BPH patients. CONCLUSION: Tamsulosin 0.4 mg once daily is safe,
      well-tolerated and improves both the symptoms and urinary flow rate in patients
      with benign prostatic obstruction (symptomatic BPH).

PMID- 8647142
TI  - Radical prostatectomy: prospective assessment of mortality and morbidity.
AB  - OBJECTIVE: To prospectively analyse the morbidity of radical prostatectomy.
      METHODS: Morbidity data from 188 consecutive radical prostatectomy patients were
      collected prospectively. Mortality, intraoperative, early postoperative and late
      postoperative complications were analysed. RESULTS: 1.5% mortality. 3.7% suffered
      an intraoperative complication. Early postoperative problems were common (43%).
      Of those with greater than 1 year follow-up, 5.9% remained with some
      incontinence, and a further 11 patients had artificial sphincters implanted; 32%
      had narrowing of the anastomosis, requiring at least 1 dilation; 43% of patients
      retained their potency. CONCLUSIONS: It is concluded that radical prostatectomy
      can be performed with minimal mortality and acceptable morbidity.

PMID- 8647143
TI  - Treatment of prostate cancer with transrectal focused ultrasound: early clinical
      experience.
AB  - OBJECTIVES: To evaluate the efficacy of transrectal focused ultrasound on
      localized prostatic cancer. METHODS: Fourteen patients (mean age 72.5 years) with
      clinical stage T1 (3) and T2 (11) prostatic cancers, who were not suitable
      candidates for surgery were treated. The mean PSA pretreatment level was 12 +/-
      10 ng/ml (Hybritech). The device used (Ablatherm, Technomed M.S.) combines a 2.25
      MHz therapy transducer and a 7.5-MHz transrectal biplane ultrasound scanner probe
      (linked to a software enabling the operator to determine precisely the zone of
      the prostate to be treated. The prostate was treated in one (3 patients), two (7
      patients) or three sessions (4 patients) under spinal (25 sessions) or general
      anesthesia (4 sessions). RESULTS: Complications occurred in 9 of the 14 patients
      (64%): early complications occurred in 6 (rectal burns 3, urinary retention 2,
      transient incontinence 1) and late complications in 5 (incontinence 2, bladder
      neck stenosis 3). The median PSA NADIR value (1.79 +/- 2.35 ng/ml) was achieved
      at 6 months and the final PSA value was 2.94 +/- 3.27 ng/ml (mean follow-up 380
      days). Control biopsies demonstrated coagulative necrotic lesions of the treated
      prostate zones with secondary development into fibrosis. No residual cancer was
      observed in 7 patients after several random sextant biopsies. Residual cancer was
      found in 7 patients: 4 required complementary treatment (orchidectomy 2, external
      beam radiation therapy 2). Adjuvant therapy was deferred in 3 patients with
      stable PSA values under 2 ng/ml. CONCLUSIONS: A satisfactory local control with
      negative control biopsies was achieved in 50% of the cases in this pilot study.
      However, this therapy is an investigational procedure: long-term follow-up will
      be necessary to confirm these early results.

PMID- 8647144
TI  - Longitudinal evaluation of prostate-specific antigen levels in a case-control
      study.
AB  - BACKGROUND: Over the last period--late 1970 to early 1990--the incidence of
      prostate carcinoma has nearly doubled, even though many more patients die with
      prostate cancer rather than of it. This finding, together with the slow growth of
      this tumor and the absence of a controlled trial, makes early diagnosis for this
      pathology quite questionable. On the other hand, it is well known that prostatic
      carcinoma is curable as long as it is intracapsular and that there is an ever
      increasing encouragement for early detection in all diseases. Since prostatic
      pathology increases its incidence as age advances, the first step in early
      diagnosis is to be able to discriminate between healthy, benign prostatic
      hyperplasia and cancer cases with a well-accepted and easily understandable
      method. The problem is to find the best method to do it. METHODS: We measured
      serum prostate-specific antigen (PSA) levels in 435 men participating in an
      epidemiological study, at first in 1987 and again in 1992. Men with PSA levels
      above 4 ng/ml (in 1992) were invited to undergo other diagnostic tests (digital
      rectal examination, transrectal ultrasonography, biopsy) in sequence on the basis
      of the results of the previous tests. The pathological findings from biopsies
      were the reference test to determine the presence or absence of prostate cancer
      (2.5% of the population). RESULTS: We divided PSA concentrations into three
      categories, according to the most used cutoffs ( < 4, 4-10, > 10 ng/ml); in the
      meantime, we took into account the change rate in PSA concentration in time,
      defined as delta PSA. By the comparison between PSA categories and delta PSA, we
      found out that the first one does not discriminate between benign and malignant
      pathologies, while the use of delta PSA strongly discriminates them (p < 0.001).
      CONCLUSION: On the basis of our results, we think that delta PSA might be the
      best parameter to indicate the presence of prostate cancer cases in an
      asymptomatic population.

PMID- 8647145
TI  - The impact of prostate-specific antigen density in predicting prostate cancer
      when serum prostate-specific antigen levels are less than 10 ng/ml.
AB  - OBJECTIVE: To evaluate the impact of prostate-specific antigen density (PSAD)
      when serum levels of prostate-specific antigen (PSA) are less than 10 ng/ml.
      METHODS: We retrospectively analyzed 134 patients who underwent transrectal
      ultrasound (TRUS)-guided prostate biopsies according to Cooner's algorithm.
      RESULTS: Histopathological examination revealed prostate cancer (PCa) in 22 (16%)
      and benign prostatic hypertrophy (BPH) in 112 (84%) patients. Five patients (23%)
      with PCa had PSAD < 0.15 of whom 3 had PSA < 4 ng/ml and 2 had PSA between 4 and
      10 ng/ml. In the BPH group, 60 patients (54%) had PSAD below 0.15 whereas 52
      patients (46%) had PSAD over 0.15. With 0.15 as the cutoff level of PSAD, the
      sensitivity and specificity of PSAD was found as 77 and 54%, respectively. In
      this patient population, PSA with the cutoff level of 4 ng/ml has sensitivity and
      specificity levels of 77 and 33%, respectively. According to these results, a
      statistically significant difference was found between PSA and PSAD only in terms
      of diagnostic specificity (chi-square, p < 0.05). There were 29 patients with
      negative digital rectal examination (DRE) and TRUS and PSA 4-10 ng/ml who
      underwent biopsy because of PSAD > 0.15. No cancer was detected in this group of
      patients, suggesting that biopsy in this subgroup may be unnecessary. CONCLUSION:
      Although PSAD seemed to increase the specificity without any decrease in
      sensitivity in the diagnosis of prostate cancer, it did not bring any practical
      advantage in our selected population since all PCa cases had abnormal DRE and/or
      TRUS findings.

PMID- 8647146
TI  - Prognostic factors for survival in patients with transitional cell carcinoma of
      the bladder: evaluation by histopathologic grade, pathologic stage and flow
      cytometric analysis.
AB  - OBJECTIVE AND METHODS: Univariate and multivariate statistical analyses of
      prognostic factors were performed on 93 patients with transitional cell carcinoma
      of the bladder who had undergone cystectomies between 1978 and 1988. All patients
      underwent DNA flow cytometry by way of paraffin-embedded specimens. In univariate
      analysis, ploidy status, proliferation index, T stage, lymph node status and
      histopathologic grade were significant prognostic factors. However, in
      multivariate analysis, only ploidy status (p = 0.0000) and T stage (p = 0.0254)
      were significant as prognostic factors. With these two variables, we stratified
      the patients into three distinct groups with varying degrees of prognosis.
      RESULTS: The mean survival time was 91.3 months for group 1 (diploid T3a or
      less), 71.3 months for group 2 (diploid T3b, T4/aneuploid T3a or less) and 25.7
      months for group 3 (aneuploid T3b, T4). Group 1 patients had a significantly
      longer survival rate than did the group 2 patients. The difference in survival
      between groups 2 and 3 was also statistically significant. CONCLUSION: This study
      shows that DNA ploidy together with T stage may be a useful prognostic factor
      when identifying risk groups and planning management of patients with
      transitional cell carcinoma of the bladder.

PMID- 8647147
TI  - Marker tumour responses to the sequential combination of intravesical therapy
      with mitomycin-C and BCG-RIVM in multiple superficial bladder tumours. Report
      from the European Organisation for Research and Treatment on Cancer-Genitourinary
      Group (EORTC 30897).
AB  - OBJECTIVES: To study the ablative activity of intravesical mitomycin C followed
      by intravesical bacillus Calmette-Guerin (BCG) on a papillary marker tumour and
      to determine the incidence of side effects. METHODS: Thirty-five patients with
      multiple pTa or pT1 bladder tumours were treated with 4 instillations of
      mitomycin C at weekly intervals followed by 6 instillations at weekly intervals
      of BCG-RIVM. All visible tumours were resected before starting intravesical
      instillations except one marker tumour. Response was determined 2 weeks after the
      last instillation. RESULTS: The incidence of adverse effects was similar to
      previously reported toxicity of either mitomycin C or BCG alone. Complete
      response, histologically proven, was observed in 16 of 35 patients and in 3
      patients without histological confirmation. One patient showed progression.
      CONCLUSION: The sequential combination of mitomycin C and BCG is an efficacious
      treatment. The measurement of response to a marker tumour is a safe and efficient
      method to test new drugs or combinations of drugs.

PMID- 8647148
TI  - Lower urinary tract reconstruction following cystectomy: experience and results
      in 96 patients using the orthotopic ileal bladder substitution of Studer et al.
AB  - Between 1989 and 1993 96 patients (89 males and 7 females) affected with invasive
      neoplasms of the bladder underwent surgery consisting of the creation of an
      orthotopic ileal neobladder according to Studer et al., after radical cystectomy.
      Patient selection and details of the surgical procedure are described. An
      accurate follow-up of 3-60 months (mean: 28 months) is presented. There have been
      6 perioperative deaths (6.2%) and 11 early complications, all directly related to
      the neobladder and requiring reoperation in 6 cases (6.2%). Late complications
      required rehospitalization in 23 cases (23.9%) and a second reoperation was
      necessary in 10 (10.4%). The urodynamic tests show that the neobladder assumes an
      average capacity at about 330 cm3 after 1 year. Pressure at maximum capacity
      decreases in time and ranges from 10 to 20 cm H2O at 2 years. After 1 year, the
      complete urinary continence rate by day is 97% and the stress incontinence rate
      is 22%. Night-time continence, instead, increases to 74% after 1 year and to 83%
      after 2 years. In female patients, the functional results were satisfactory
      thanks to careful patient selection and to the surgical procedure adopted. Twenty
      four patients had disease progression; 17 of these patients with locally advanced
      neoplasms died. The authors believe that the orthotopic ileal continent reservoir
      can be a satisfactory solution after cystectomy for bladder cancer, offering the
      patients a better quality of life compared to other urinary diversions both in
      male and female patients.

PMID- 8647149
TI  - The sigmoidorectal pouch (Mainz pouch II).
AB  - A sigmoidorectal pouch was constructed in 20 patients (18 with invasive bladder
      cancer, 2 with complete urethral destruction with multiple vesicovaginal
      fistulas). The rectal-dynamic studies showed that by detubularization and
      reconfiguration of the sigmoid colon and rectum, we obtained a low-pressure
      reservoir, with the high-pressure contractions eliminated. Preoperatively, the
      basal rectum pressure was 21.4 cm H2O; rectum contractions reached a mean of 27.6
      cm H2O (maximum 48 cm H2). Postoperatively (9-36 months) the mean basal pressure
      of the pouch was 19.3 cm H2O (p > 0.05; t test comparison with the preoperative
      value), with a mean contraction value of 19.1 cm H2O (p < 0.05). All the patients
      experienced continence day and night with a pouch emptying frequency of four
      times during the day and once at night, after 9 months. By fixing the pouch to
      the promontory or psoas muscle, without compromising the blood supply to the
      pouch, the risk of ureteral kinking and upper urinary tract dilatation were
      considerably decreased. The price to be paid for almost perfect continence was
      hyperchloremic acidosis in most patients.

PMID- 8647150
TI  - Upper urinary tract involvement after cystectomy and ileal conduit diversion for
      primary bladder carcinoma.
AB  - OBJECTIVES: To design a proper follow-up for cystectomy and ileal conduit urinary
      diversion for primary bladder transitional carcinoma, we compared the
      radiographic characteristics of recurrent malignant upper tract lesions with
      those of benign ureteroileal anastomosis strictures. METHODS: Over a 20-year
      period, we followed 61 patients who underwent cystectomy and ileal conduit
      diversion at our hospitals for a minimum period of 3 years. Excretory urography
      was performed routinely at 1, 3, 6 and 12 months after cystectomy and once yearly
      thereafter. RESULTS: Five patients (8.2%) developed malignant ureteral
      obstruction (4 had metachronous upper tract tumors, and 1 patient had
      retroperitoneal lymph node metastasis which compressed the ureter). Eleven
      patients (18.0%) developed benign ureteroileal anastomotic stricture. The
      interval between cystectomy and initial detection of the malignant and benign
      upper tract lesion ranged between 34 and 118 months (mean 69 months) and between
      1 and 20 months (mean 5.1 months), respectively. In all patients with malignant
      upper tract obstruction, a complete loss of renal function occurred within 10
      months after the detection. Conversely, a progressive renal dysfunction was
      observed in patients with benign ureteroileal anastomotic stricture. All patients
      were asymptomatic before the detection of lesions on excretory pyelography.
      CONCLUSIONS: Our results suggest that cancer recurrence can occur even 10 years
      after cystectomy, typically progressing very rapidly within 1 year. A benign
      ureteroileal anastomotic stricture, on the other hand, tends to occur within 2
      years but advances slowly. Consequently, a proper follow-up necessitates annual
      excretory urography and/or renal ultrasonography in all patients with ileal
      conduit urinary diversion after cystectomy.

PMID- 8647151
TI  - Primary metastatic carcinoma of the prostate in younger men: a plea to think over
      usual therapeutic strategies.
AB  - METHOD: The time from first diagnosis of primary multiple metastatic prostate
      carcinoma until progression and until death in patients less than 60 years old
      under two different therapeutic regimens was evaluated. RESULTS: In the group
      with pure androgen deprivation (n = 21), the mean time until progression was 11.3
      (6-55) months, the mean survival time being 21.4 (11-75) months. In the group
      with androgen deprivation plus cytostatic therapy (n = 10), progression was noted
      after 26.7 (15-77) months with a medium survival time of 26.2 (16-82) months.
      CONCLUSION: The data argue in favor of changing the usual treatment strategy to
      combination therapy in "young' patients with primary metastatic prostatic cancer.

PMID- 8647152
TI  - Intraurethral prostaglandin improves quality of vacuum erection therapy.
AB  - OBJECTIVE: The aim of this study was to investigate whether intraurethral
      prostaglandin E1 (PGE1) improves vacuum-induced penile rigidity. METHODS:
      Nineteen patients with a mean age of 55 years (range 30-66 years) complaining of
      erectile dysfunction for 24 months (range 3-156 months) were investigated. The
      penile diameter was measured and a mark was made 50 mm proximal of the coronary
      sulcus on the flaccid penis. Twenty micrograms of liquid PGE1 (pH 4.5; 308
      mosm/l) were instilled intraurethrally; thereafter the meatus was occluded for 10
      min. Penile diameter and increase in length of the initially 50-mm line were
      measured with both pure vacuum-induced erection as well as combined with PGE1.
      RESULTS: The vacuum erection device alone lengthened the distance by 26 mm (range
      18-64 mm) and the diameter by 4 mm (range 2-10 mm). Combined with PGE1, 36 mm
      (range 27-70 mm; p = 0.016) and 7 mm (range 2-11 mm; p = 0.04) were found,
      respectively. CONCLUSION: We conclude that PGE1 significantly increases vacuum
      induced tumescence. Optimized pharmacological preparations for intraurethral
      application are a new way to further improve vacuum-assisted erection.

PMID- 8647153
TI  - Use of autologous buccal mucosal graft for urethral surgery in males.
AB  - OBJECTIVE: Description of our results with autologous buccal mucosa as a
      substitute for urethral epithelium in 8 patients with severe urethral strictures.
      METHODS: Patients were selected according to the intrinsic complexity or due to
      recurrence following previous surgery. Buccal mucosa was harvested from the lower
      lip, and no suture was used to close the wound. A full thickness mucosal graft
      measuring up to 8 cm was excised. RESULTS: The clinical results are satisfactory
      in 7 cases. No urethral fistulas were observed. CONCLUSION: Buccal mucosa offers
      an excellent option for repair of complicated urethral strictures.

PMID- 8647154
TI  - Urological abnormalities in 1,328 patients with nocturnal enuresis.
AB  - OBJECTIVES: Evaluation of the incidence of urological abnormalities as revealed
      by urological examinations of a large number of patients with enuresis. METHODS:
      Patients with the chief complaint of nocturnal enuresis were examined
      urologically. RESULTS: The incidence of urological abnormalities was 1.8% of 940
      patients on intravenous pyelography (IVP), 7.1% of 695 patients on voiding
      cystourethrography (VCG) and 11.5% of 487 patients on cystometry (CM). No
      abnormal findings were observed in 58 patients on renal ultrasonography (US).
      92.1% of reflux cases detected by VCG were low grade and only 8.9% of patients
      with reflux had pyuria. 20.2% of 446 patients who were submitted to all these
      examinations had some urological abnormality. Only pollakisuria was statistically
      more frequent in patients with urological abnormalities than in patients without
      them. CONCLUSION: These data suggest that the incidence of urological
      abnormalities was rather low when compared with the past literature. In
      particular, IVP was though to be unnecessary.

PMID- 8647155
TI  - Trans-scrotal approach for surgical correction of cryptorchidism and congenital
      anomalies of the processus vaginalis.
AB  - OBJECTIVES: Surgery of the inguinal canal is the most common practice in
      pediatric urology. Recently, the trans-scrotal approach has been described for
      orchidopexy of palpable undescended tests. The aim of this paper is to report our
      experience with this technique, emphasizing both the advantages and the
      disadvantages with respect to the usual approach. METHODS: Over a period of 2
      years, we used the trans-scrotal approach in 85 children with cryptorchidism,
      hydrocele and inguinal hernia. The scrotal incision was combined vertical and
      horizontal. RESULTS: All children with hernia and hydrocele were cured without
      complications. Among the cryptorchids, 3 children required an additional groin
      incision to complete the procedure, 3 experienced postoperative hematoma, 2 had
      mild testicular hypotrophy, and 1 recurrent cryptorchidism at follow-up.
      CONCLUSION: Most palpable undescended testes can be successfully treated by this
      operation. However, the dissection of the processus vaginalis from the cord below
      the external ring is time-consuming, requires more skill, and exposes to more
      complications. Conversely, the results are excellent in hydroceles.

PMID- 8647156
TI  - Physiological aging and penile erectile function: a study in the rat.
AB  - Erectile function of adult (8-month-old) and aged (27-month-old) rats was
      investigated by in vivo and in vitro assays. Reflexogenic tonic erections were
      evoked in vivo by electrostimulation of the dorsal nerve of the penis. Aged rats
      developed tendentially low intracavernosal pressures, and the kinetics of
      erection and detumescence were significantly lower than in adult animals. The
      erectile tissue isolated from aged rats exhibited poor response to papaverine.
      When precontracted with norepinephrine, aged tissues required a 3-fold increase
      of papaverine concentration to full relaxation. Functional measurements were
      coupled with morphological analysis of elastic fibres of the tunica albuginea.
      Light microscopy showed degenerative signs of elastic fibres of aged rat
      specimens. Taken together, the present findings show that physiological aging is
      associated with penile tissue stiffness and abnormal corporal compliance.

PMID- 8647157
TI  - The additional predictive value contributed by quantitative chromatin pattern
      description as compared to DNA ploidy level measurement in 257 superficial
      bladder transitional cell carcinomas.
AB  - The results of quantitative chromatin pattern description were compared with the
      determination of the DNA ploidy level, and the histological grading and clinical
      staging of superficial transitional cell carcinomas (sTCCs) of the bladder. We
      investigated whether this quantitative description adds useful information to the
      one obtained by the other methods used for predicting the biological behavior of
      sTCCs. The quantitative chromatin pattern description was carried out by means of
      the digital cell image analysis of Feulgen-stained nuclei in a series of 257
      sTCCs. The results show that according to the clinical sequence "remission (134
      patients) --> stable recurrence (101 patients) --> progression (13 patients) -->
      death (9 patients)', quantitative chromatin pattern description shows that
      certain areas of the nucleus undergo a continual process of condensation and that
      the distribution and spread of the chromatin becomes more and more heterogeneous.
      This is accompanied by a more frequent appearance of pale areas in the nucleus
      and an increase in nuclear size. Of the 257 sTCC patients, 148 had pTa/PpT1 grade
      I or III tumors. Of these 148, histological grading and clinical staging made it
      possible to correctly predict the biological behavior of the tumors of 120/148
      (81%). DNA ploidy level determination increased this correct prediction from 81
      to 84%. When the information contributed by quantitative chromatin pattern
      description was added to that contributed by the combination of histological
      grading, clinical staging and DNA ploidy level determination, the prediction
      level was 93%.

PMID- 8647158
TI  - Natural killer cell activation after interferon administration in patients with
      metastatic renal cell carcinoma: an ultrastructural and immunohistochemical
      study.
AB  - OBJECTIVE: We studied the intralesional number of natural killer (NK) cells and
      the ultrastructural evidence of their activation in patients with metastatic
      renal cell carcinoma, after preoperative interferon (IFN) administration.
      METHODS: Tumor sections from 10 patients with metastatic renal cell carcinoma who
      received preoperative IFN (5 MU x 3 days) and from 10 patients with renal cell
      carcinoma were obtained. The number of NK cells was estimated
      immunohistochemically in paraffin sections with the CD57 monoclonal antibody and
      their activation was evaluated ultrastructurally by routine electron microscopy
      processing. RESULTS: The number of NK cells was increased in the tumors of the
      IFN-administered patients (5.3 cells vs. 1.6 in the controls, p = 0.03) while
      their ultrastructural features revealed activation and enhanced cytolytic
      activity, through facilitation of granule content release. CONCLUSIONS: IFN
      promotes the aggregation and activation of NK cells within the renal cell tumor,
      further strengthening the concept of its immunomodulatory activity.

PMID- 8647159
TI  - A V beta 4-specific superantigen encoded by a new exogenous mouse mammary tumor
      virus.
AB  - The superantigen (SAg) expressed by mouse mammary tumor virus (MMTV) has been
      shown to play an essential role in the course of the viral life cycle. In the
      present study, we describe a V beta 4-specific SAg encoded by a new exogenous
      MMTV carried by the SIM mouse strain. This is the first report of a viral or
      bacterial SAg reacting with mouse V beta 4+ T cells. Injection of MMTV(SIM) into
      adult BALB/c mice leads to a rapid and strong stimulation of V beta 4+ CD4+ T
      cells, followed by a slow deletion of these cells. Neonatal exposure to the virus
      also leads to a progressive deletion of V beta 4+ T cells. In contrast to other
      strong MMTV SAg, this new SAg requires the presence of major histocompatibility
      complex class II I-E molecules to be presented efficiently to T cells. Sequence
      analysis revealed a new predicted amino acid sequence in the C-terminal
      polymorphic region of this SAg. Furthermore, sequence comparisons to the most
      closely related SAg with different V beta specificities hint at the specific
      residues involved in the interaction with the T cell receptor.

PMID- 8647160
TI  - Identification of a novel subpopulation of germinal center B cells characterized
      by expression of IgD and CD70.
AB  - CD27, which belongs to the tumor necrosis factor receptor family, is expressed on
      germinal center (GC) but not on naive B cells, suggesting an important function
      of this molecule in the regulation of the GC reaction. We described here the
      expression of CD70, which is the ligand for CD27. We observed that in most
      tonsils, CD70 is only expressed on part of the IgD-, CD38- B cell population,
      which have been described as memory B cells. However, in 10% of the tonsils
      tested, CD70+ IgD+ GC were found. The CD70+ GC B cells were small cells that also
      expressed CD44 and CD39, but were CD10- and CD38-, suggesting that they represent
      very recent immigrants that are in the process of forming a GC. The concordant
      expression of CD27 and its ligand CD70 on this primordial subset of GC B cells
      suggests an important role for CD27/CD70 interaction at this stage of GC
      formation.

PMID- 8647161
TI  - CD3-induced apoptosis of CD4+CD8+ thymocytes in the absence of clonotypic T cell
      antigen receptor.
AB  - Clonal selection of T cells mediated through the T cell antigen receptor (TCR)
      mostly occurs at the CD4+CD8+ double positive thymocyte stage. Immature CD4+CD8+
      thymocytes expressing self-reactive TCR are induced to die upon clonotypic
      engagement of TCR by self antigens. CD3 engagement by antibody of the surface TCR
      CD3 complex is known to induce apoptosis of CD4+CD8+ thymocytes, a process that
      is generally thought to represent antigen-induced negative selection in the
      thymus. The present study shows that the CD3-induced apoptosis of CD4+CD8+
      thymocytes can occur even in TCR alpha- mutant mice which do not express the TCR
      alpha beta/CD3 antigen receptor. Anti-CD3 antibody induces death of CD4+CD8+
      thymocytes in TCR alpha- mice either in cell cultures or upon administration in
      vivo. Interestingly, most surface CD3 chains expressed on CD4+CD8+ thymocytes
      from TCR alpha- mice are not associated with clonotypic TCR chains, including TCR
      beta. Thus, apoptosis of CD4+CD8+ thymocytes appear to be induced through the CD3
      complex even in the absence of clonotypic antigen receptor chains. These results
      shed light on previously unknown functions of the clonotype-independent CD3
      complex expressed on CD4+CD8+ thymocytes, and suggest its function as an
      apoptotic receptor inducing elimination of developing thymocytes.

PMID- 8647162
TI  - Inhibition of tumor necrosis factor activity minimizes target organ damage in
      experimental autoimmune uveoretinitis despite quantitatively normal activated T
      cell traffic to the retina.
AB  - Recent studies demonstrated that administration of a p55-tumor necrosis factor
      (TNF) receptor IgG-fusion protein (TNFR-IgG) prevented the clinical onset of
      experimental autoimmune encephalomyelitis but did not alter the number or tissue
      distribution of autoantigen-specific CD4+ effector T cells which trafficked into
      the central nervous system. To determine whether specific target tissues of
      autoimmune damage remain intact after TNFR-IgG treatment despite the presence of
      inflammatory cells within the tissues, we examined rats with experimental
      autoimmune uveoretinitis (EAU), as in this model, the main target of autoreactive
      CD4+ T cells, the retinal rod outer segments (ROS), can be examined readily by
      light microscopy. As judged by direct ophthalmoscopy, the onset of inflammation
      in the anterior chamber of the eye in EAU following administration of TNFR-IgG
      was delayed by 6 days compared to untreated controls, but the magnitude of the
      response was only slightly less than controls. Histological examination of the
      retinae and direct assessment of retinal inflammation revealed a disproportionate
      sparing of ROS in the TNFR-IgG-treated animals despite a level of retinal
      inflammation not substantially less than controls in which ROS damage was marked.
      Analysis of retinal leukocytes by immunofluorescence microscopy and flow
      cytometry indicated that approximately equal numbers of CD4+ alpha beta TCR+
      lymphocytes were present in treated and control retinae, more than 30% of CD4+
      cells in both experimental groups expressed the CD25 or MRC OX40 activation
      markers and most cells, which would include the CD4+ T lymphocytes, were
      activated as evidenced by MHC class II expression. Fewer activated macrophages
      and granulocytes were present in the treated retinae, possibly reflecting the
      lower level of tissue damage and subsequent accumulation of these inflammatory
      cells. The results demonstrate directly that a tissue specifically targeted for
      autoimmune destruction can be protected despite the influx of fully activated
      CD4+ T cells.

PMID- 8647163
TI  - Ribozyme modulation of lipopolysaccharide-induced tumor necrosis factor-alpha
      production by peritoneal cells in vitro and in vivo.
AB  - We have utilized synthetic ribozymes to modulate the lipopolysaccharide (LPS)
      induced production of tumor necrosis factor-alpha (TNF-alpha) by peritoneal
      cells. Two hammerhead ribozymes (mRz1 and mRz2) were prepared by transcription in
      vitro and their activities in vitro and in vivo were investigated. Both ribozymes
      cleaved their RNA target with an apparent turnover number (kcat) of 2 min(-1),
      and inhibited TNF-alpha gene expression in vitro by 50% and 70%, respectively.
      When mRz1 and mRz2, entrapped in liposomes, were delivered into mice by
      intraperitoneal injection, they inhibited LPS-induced TNF-alpha gene expression
      in vivo with mRz2 being the most effective. This enhanced activity could result
      from the facilitation of catalysis by cellular endogenous proteins, since they
      specifically bind to mRz2 as compared to mRz1. Furthermore, a significant mRz2
      activity can be recovered from peritoneal cells 2 days post-administration in
      vivo. The anti-TNF-alpha ribozyme treatment in vivo resulted in a more
      significant reduction of LPS-induced IFN-gamma protein secretion compared to IL
      10. In contrast to this pleiotropic effect, the anti-TNF-alpha ribozyme treatment
      did not affect the heterogenous expression of Fas ligand by peritoneal cells,
      indicating the specificity of the treatment. Taken together, the present data
      indicate that the biological effects of TNF-alpha can be modulated by ribozymes.
      In addition, the data suggest that ribozymes can be administered in a drug-like
      manner, and therefore indicate their potential in clinical applications.

PMID- 8647164
TI  - Use of monoclonal antibodies to study interleukin-1 beta-converting enzyme
      expression: only precursor forms are detected in interleukin-1 beta-secreting
      cells.
AB  - We have generated a series of monoclonal antibodies (mAb) using recombinant
      interleukin (IL)-1 beta-converting enzyme (ICE) p20 and p10 subunits as
      immunogens. The mAb have been selected for further study based on their
      reactivity with ICE in transfected COS cells and their lack of cross-reactivity
      with TX, the closest ICE homolog known to date. Two anti-p20 and one anti-p10 mAb
      have been used to study ICE expression by Western blotting and immunodetection.
      In ICE-transfected COS cells, the mAb recognize the p45 ICE precursor and the
      maturation products (p20 or p10 subunits) for which they are specific. In
      monocytes and cell lines expressing ICE, only precursor forms are detected and
      intracellular immunostaining followed by confocal microscopy shows that they are
      located in the cytoplasm. Quantification experiments show that THP1 cells express
      approximately 67,000 molecules of ICE precursor per cell, with an estimated
      precursor to mature ratio of at least 100. In these cells as well as in
      monocytes, lipopolysaccharide stimulation did not change the pattern of ICE
      expression, although efficient secretion of mature IL-1 beta was measured.
      However, upon cell disruption, precursor maturation was observed. Our results,
      therefore, show that ICE is present in cells as a large pool of intracytoplasmic
      precursor, and that very limited amounts of mature ICE protein are present, but
      nevertheless sufficient to allow efficient IL-1 beta cleavage. Altogether, these
      observations suggest that post-translational maturation of the precursor protein
      could represent a specific step in the regulation of ICE enzymatic activity.

PMID- 8647165
TI  - Peptides derived from IgE heavy chain constant region induce profound IgE isotype
      specific tolerance.
AB  - (BALB/c x SJL)F1 mice, perinatally injected with peptide-N-glyconase F-treated,
      deglycosylated IgE heavy chain or recombinant IgE heavy chain (CH epsilon 2-CH
      epsilon 4), were profoundly inhibited in antigen-specific IgE production. There
      exist minimally two tolerogenic IgE peptides, residing in the CH epsilon 2 and CH
      epsilon 4 domains. Peptide I, generated by V8 protease, comprises 39 amino acids
      within CH epsilon 2, beginning at amino acid 103. Peptide E begins at amino acid
      312 of the CH epsilon 4 domain and extends through the CH epsilon 4 domain. The
      total lack of antigen-specific IgE responses in IgE peptide-treated mice was not
      due to overproduction of interferon-gamma, nor lack of interleukin (IL)-4, as
      predicted by the Th2/IL-4 paradigm for IgE production. IgE-tolerant mice
      exhibited comparable levels of circulating anti-IgE antibodies to those of PBS
      treated control mice. IgG obtained from sera of both sources failed to inhibit
      IgE responses in vitro. Moreover, IgE responses of spleen cells from IgE peptides
      treated mice were restored by CD4+ T cells from PBS-treated control mice. We
      hypothesize that regulation of antigen-specific IgE responses is mediated by CD4+
      T cells which normally recognize IgE peptides on IgE precursor B cells, and can
      be rendered tolerant by perinatal IgE peptide treatment.

PMID- 8647166
TI  - Mycoplasma fermentans-derived lipid inhibits class II major histocompatibility
      complex expression without mediation by interleukin-6, interleukin-10, tumor
      necrosis factor, transforming growth factor-beta, type I interferon,
      prostaglandins or nitric oxide.
AB  - Mycoplasma cause several diseases in man and animals. Some strains can
      chronically infect humans, leading to fever or inflammatory syndromes such as
      arthritis, particularly in immunosuppressed patients. A set of pathogenicity
      factors shared by many mollicutes may be membrane components that activate
      macrophages to secrete cytokines and other inflammatory mediators. Mycoplasma
      derived high molecular weight material (MDHM) is a macrophage-activating
      amphiphilic lipid which was purified from Mycoplasma fermentans. We studied the
      influence of MDHM on the expression of major histocompatibility complex (MHC)
      class II molecules by mouse resident peritoneal macrophages with an ELISA. Highly
      purified MDHM at 4 ng/ml and 0.8 microgram/ml crude heat-killed M. fermentans
      (concentrations chosen to give maximal responses) suppressed interferon (IFN)
      gamma-dependent class II MHC induction when added simultaneously with IFN-gamma.
      MDHM was not toxic and did not result in loss of adherent cells. Kinetic data
      showed that MDHM first up-regulated, then down-regulated the expression of
      preformed class II MHC molecules, while expression of Mac-1 and F4/80 antigens
      remained constant. MDHM-dependent suppression of class II MHC molecule expression
      resulted in impaired antigen presentation to the helper T cell line D10.G4.1. We
      further attempted to identify hypothetical products of MDHM-stimulated
      macrophages as secondary mediators of class II MHC suppression such as were
      described for lipopolysaccharide (LPS)-stimulated macrophages. Type I IFN,
      prostaglandins and nitric oxide, all reported to cause down-regulation of class
      II MHC, could be excluded in this context. Of the cytokines tumor necrosis
      factor, interleukin (IL)-6, IL-10 and transforming growth factor-beta, only IL-10
      inhibited class II MHC expression, although less effectively than MDHM. The
      involvement of IL-10 was ruled out, as no evidence for its MDHM-dependent
      formation could be found. Our data suggest that MDHM interferes with class II MHC
      expression by up-regulating its turnover, and at the same time, inhibits the
      formation of new class II MHC molecules.

PMID- 8647167
TI  - Analysis of hypermutation in immunoglobulin heavy chain passenger transgenes.
AB  - Somatic hypermutation of immunoglobulin (Ig) genes plays a critical role in the
      maturation of the human antibody response. The molecular basis of this important
      process is, however, unknown. To identify cis-acting sequences that initiate and
      target hypermutation, we have made three minitransgenes containing different
      portions of an Ig heavy chain (IgH) locus. Each transgene is a passenger, bearing
      a nonsense mutation preventing its translation; thus, transgene mutations reflect
      the endogenous mutational process and are not subject to affinity selection. To
      study transgenes after their circulation through the compartment associated with
      hypermutation in vivo, we rescued B cells as hybridomas after hyperimmunizing
      mice with the hapten 4-hydroxy-3-nitrophenyl acetyl (NP). Hybridoma transgene and
      endogenous variable regions were amplified by polymerase chain reaction,
      subcloned, and sequenced. Endogenous anti-NP VDJ regions show the expected, at
      times extensive degree of base substitution. In mice bearing the smallest
      construct, which includes 2.4 kb of 5' IgH sequences, a rearranged VDJ region,
      the 5' matrix attachment region, and the intron enhancer, one of four evaluable
      hybridomas demonstrates two base substitutions in the V segment of one transgene
      copy. The two larger constructs include additional 3' IgH sequences (an alpha
      constant region and the 3' enhancer) and either the original VDJ segment or a
      substituted T cell receptor beta segment. Ten hybridomas derived from mice
      bearing these larger constructs demonstrate no evidence of targeted mutation,
      despite demonstrable transgene transcription in all hybridomas. In our system,
      mutation of a rearranged VDJ segment and surrounding promoter/enhancer regions is
      not increased by the juxtaposition of a constant region segment and the IgH 3'
      enhancer.

PMID- 8647168
TI  - The protein interactions of the immunoglobulin receptor family tyrosine-based
      activation motifs present in the T cell receptor zeta subunits and the CD3 gamma,
      delta and epsilon chains.
AB  - Immunoglobulin family tyrosine-based activation motifs (ITAM), which define the
      conserved signaling sequence EX2YX2L/IX7YX2L/I, couple the T cell antigen
      receptor (TCR) to cellular proteins including protein tyrosine kinases (PTK) and
      adapter molecules. The TCR is a multichain complex with four invariant chains CD3
      gamma, delta and epsilon that each contain a single ITAM and the TCR zeta chain
      that contains three ITAM. The present study explores the protein interactions of
      the doubly phosphorylated CD3 gamma, delta, epsilon ITAM to determine whether
      they have common or unique biochemical properties. The data show that the doubly
      phosphorylated ITAM all bind the PTK ZAP-70, but the ITAM also variably bind the
      PTK p59fyn and the adapters Shc, Grb-2 and the p85 regulatory subunit of
      phosphoinositol 3' kinase. The CD3 and zeta ITAM display a hierarchy of ZAP-70
      binding: zeta 1 = gamma = delta > zeta 3 > zeta 2 = epsilon. Shc, Grb-2 and p85
      could bind the zeta ITAM and the CD3 gamma and delta ITAM, but not the CD3
      epsilon ITAM. There were also subtle differences in the hierarchy of reactivity
      of these adapters for the CD3 gamma, delta and zeta ITAM that show that the zeta,
      CD3 gamma, delta and epsilon ITAM have different binding properties. The present
      study thus shows that the different ITAM of the TCR/CD3 complex can interact with
      different cytosolic effectors, indicating that differential ITAM phosphorylation
      during T cell activation could be a mechanism to generate signaling diversity by
      the TCR complex.

PMID- 8647169
TI  - Soluble CD40 ligand induces expression of CD25 and CD23 in resting human
      tonsillar B lymphocytes.
AB  - In this report, we describe the dose-dependent increase in both CD25 and CD23
      levels on resting human B cells in response to CD40 ligation, as mediated by
      soluble CD40 ligand (sCD40L) or anti-CD40 antibody. In combination with
      interleukin (IL)-4, sCD40L had limited additive effects on CD25 expression, but
      significantly enhanced CD23 expression on tonsillar B cells. Interferon-gamma
      (IFN-gamma) exerted no inhibitory effect upon increases in CD25 or CD23 driven by
      CD40 ligation with sCD40L or anti-CD40 antibody. These data suggest that the
      induction of CD25 and CD23 genes by IL-4 is mediated, at least in part, by an IFN
      gamma-sensitive component, whereas gene activation driven via CD40 ligation
      involves signaling pathways which are not sensitive to IFN-gamma.

PMID- 8647170
TI  - Human CD4 and human major histocompatibility complex class II (DQ6) transgenic
      mice: supersensitivity to superantigen-induced septic shock.
AB  - Rodents are significantly less sensitive to enterotoxin-induced shock, and are
      thus not valid human disease models. Here, we describe a mouse strain carrying
      the human CD4 and human major histocompatibility complex (MHC) class II (DQ6)
      transgenes in an endogenous CD4- and CD8-deficient background. T lymphocytes from
      these animals react to minute amounts (10-100 times less than control mice) of
      staphylococcal enterotoxin B (SEB) in vitro, similar to concentrations to which
      human cells react. In vivo, these double-transgenic, double-knockout mice succumb
      to normally sublethal amounts of SEB. This sensitivity is not due to a biased T
      cell receptor V beta repertoire, increased T cell reactivity, or increased
      sensitivity to macrophage-derived cytokines. Rather, tumor necrosis factor (TNF)
      alpha production by T cells and serum levels of TNF-alpha correlate precisely
      with the clinical syndrome, showing a biphasic T cell-dependent response. These
      data show that both human CD4 and MHC class II molecules can render mice
      supersensitive to superantigen-induced septic shock syndrome. This animal model
      mimics the progression of septic shock in man by transforming normally resistant
      mice into hypersensitive SEB responders, a trait that is characteristic of
      humans. Mice that have been humanized by exchanging autochthonous superantigen
      ligands by their human equivalents may be useful to decipher superantigen
      responses in vivo and to assess the pathogenesis of superantigen-associated
      diseases.

PMID- 8647171
TI  - Development in vitro of human CD4+ thymocytes into functionally mature Th2 cells.
      Exogenous interleukin-12 is required for priming thymocytes to produce both Th1
      cytokines and interleukin-10.
AB  - Fresh postnatal thymocyte cell suspensions were directly cloned under limiting
      dilution conditions with either phytohemagglutinin or toxic shock syndrome toxin
      1 (TSST-1), a bacterial superantigen. Cultures contained allogenic irradiated
      feeder cells and interleukin (IL)-2, in the absence or presence of exogenous IL
      4, interferon (IFN)-gamma or IL-12. The resulting CD4+ T cell clones generated
      under these different experimental conditions were then analyzed for their
      ability to produce IL-2, IL-4, IL-5, IL-10, IFN-gamma and tumor necrosis factor
      (TNF)-beta in response to stimulation with phorbol 12-myristate 13-acetate (PMA)
      + anti-CD3 monoclonal antibody or PMA + ionomycin. Different from T cell clones
      generated from peripheral blood, virtually all CD4+ T cell clones generated from
      human thymocytes produced high concentrations of IL-2, IL-4 and IL-5, but no IFN
      gamma, TNF-beta or IL-10. Moreover, after activation, these clones expressed on
      their surface membrane both CD30 and CD40 ligand, but not the product of
      lymphocyte activation gene (LAG)-3, and provided strong helper activity for IgE
      synthesis by allogeneic B cells. The Th2 cytokine pattern could not be modified
      by the addition of IFN-gamma. However, upon addition of exogenous IL-12, the
      resulting CD4+ thymocyte clones produced TNF-beta, IFN-gamma, and IL-10 in
      addition to IL-4 and IL-5. These results suggest that CD4+ human thymocytes have
      the potential to develop into cells producing the Th2 cytokines IL-4 and IL-5,
      whereas the ability to produce both Th1 cytokines and IL-10 is acquired only
      after priming with IL-12.

PMID- 8647172
TI  - An in vivo model of allergic inflammation: pulmonary human cell infiltrate in
      allergen-challenged allergic Hu-SCID mice.
AB  - CB.17 severe combined immunodeficient (SCID) mice were used to establish a model
      of allergic pulmonary inflammation. SCID mice were intraperitoneally
      reconstituted with 10(7) peripheral blood mononuclear cells (PBMC) from patients
      sensitive to Dermatophagoides pteronyssinus (Dpt) and 2 weeks later were exposed
      to Dpt aerosols. After Dpt nebulization, SCID mice engrafted with PBMC from Dpt
      sensitive patients developed a specific human IgE response as well as an intense
      pulmonary infiltrate of human cells. In contrast, SCID mice reconstituted with
      PBMC from patients allergic to grass pollen or from non-allergic donors failed to
      produce IgE or to exhibit a similar inflammatory response. The level of the IgE
      production was dependent on the IgE level of the allergic donor. In the lungs of
      the same allergic SCID mice, 2 months after Dpt inhalation, the cell infiltrate
      contained CD45+, CD45RO+, CD20+ and HLA-DR+ human cells. They were located in
      perivascular and peribronchial areas and disseminated in the mouse lung
      parenchyma. Moreover, mRNA IL-5+ cells and eosinophils were found in
      peribronchial infiltrates. The observations indicate that humanized allergic SCID
      mice may develop, after nebulization with the relevant allergen, immune reactions
      similar to those observed in man and suggest that SCID mice may represent a
      useful model to analyze the regulatory mechanisms of IgE-associated allergic
      diseases.

PMID- 8647173
TI  - T cell tolerance and activation to a transgene-encoded tumor antigen.
AB  - Much has been learned in recent years concerning the nature of tumor antigens
      recognized by T cells. To apply this knowledge clinically, the nature of the host
      response to individual and multiple tumor antigens has to be characterized. This
      will help to define the efficacy of immune surveillance and the immune status of
      the host following exposure to tumor antigens expressed on pre-neoplastic tissue.
      To approach these questions, we have developed a transgenic mouse which expresses
      the tumor-specific antigen P91A. The single amino acid substitution in P91A
      results in the expression of a new MHC class I (H-2Ld)-binding peptide. In
      transgenic tissue, the H-2Ld/P91A complex is expressed in isolation from other
      tumor-associated antigens, allowing definition of the immune response to a single
      defined tumor antigen, a situation closely analogous to events during
      tumorigenesis. We show that CD8+ T cell immune surveillance of P91A is
      ineffective without the introduction of a helper determinant operating through
      stimulation of CD4+ T cells. Recognition of the isolated P91A tumor antigen on
      normal tissue by CD8+ T cells is a tolerogenic process. Induction of T cell
      tolerance suggests tumor antigen-T cell interactions occurring during
      tumorigenesis may elicit T cell tolerance and hence confound some
      immunotherapeutic approaches.

PMID- 8647174
TI  - Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti
      C5a monoclonal antibodies.
AB  - The complement activation fragment C5a was recently shown to induce interleukin
      (IL)-6 synthesis by peripheral blood mononuclear cells. To understand better the
      role of C5a in cytokine regulation in vivo, we investigated the effects of
      complement depletion by cobra venom factor (CVF) or of anti-C5a monoclonal
      antibodies (mAb) on IL-6 generation in an animal model of septic shock.
      Complement-depleted pigs which were subsequently challenged with Escherichia coli
      generated significantly (p < 0.05) less IL-6 during the 6-h observation period
      than complement-sufficient controls. To address specifically the role of C5a in
      IL-6 regulation, we produced a C5a(57-74) peptide-specific mAb (T13/9) which
      neutralizes the bioactivity of porcine C5a. The mAb T13/9 does not cross-react
      with the precursor protein C5. The pretreatment of pigs with anti-C5a mAb T13/9
      prior to the induction of sepsis resulted in a decrease of over 75% in serum IL-6
      bioactivity compared to control animals (p < 0.0001). These results indicate a
      role for C5a in the modulation of IL-6 synthesis in Gram-negative bacteremia.

PMID- 8647176
TI  - Lack of detectable defect in DNA double-strand break repair and DNA-dependent
      protein kinase activity in radiosensitive human severe combined immunodeficiency
      fibroblasts.
AB  - The initial step of the V(D)J recombination occurs through the generation of a
      DNA double-strand break (dsb). Defects in the DNA-dependent protein kinase
      complex (DNA-PK) result in an inability to perform either V(D)J recombination or
      any dsb repair effectively. The human autosomal T-B-severe combined
      immunodeficiency (SCID) condition is characterized by an absence of both B and T
      lymphocytes and is accompanied in some patients by an increase in gamma-ray
      sensitivity (T-B-RS SCID) comparable to that found in mouse SCID cells. We show
      here that cells from six patients with T-B-RS SCID had normal DNA-dsb repair
      kinetics. Furthermore, DNA-PK activity was present in extracts from these human T
      B-RS SCID fibroblasts. We therefore conclude that some human T-B-RS SCID
      disorders are not caused by a defect in an essential DNA-PK component.

PMID- 8647175
TI  - Characterization of an epitope of the human cytomegalovirus protein IE1
      recognized by a CD4+ T cell clone.
AB  - CD4+ T cells specific for human cytomegalovirus (HCMV) IE1 protein are potential
      effectors of the control of HCMV infection through cytokine production. Better
      knowledge of major histocompatibility complex (MHC)-peptide-T cell receptor (TcR)
      interactions in the CD4+ T cell response should result in a better design of
      immunizing peptides and is a prerequisite for the development of vaccines or anti
      cytomegalovirus therapy. In this study, the recombinant protein comprising
      residues 86-491 encoded by exon 4 of IE1 (GST-e4) was cleaved by enzymatic
      digestion and analyzed by high pressure liquid chromatography-mass spectroscopy
      (HPLC-MS). We identified the 14-residue epitope 162-DKREMWMACIKELH-175 recognized
      by an HLA-DR8-restricted clone, BeA3. Synthetic elongated, truncated and di-Ala
      substituted peptides of the 18-mer IE1 158-IVPEDKREMWMACIKELH-175 sequence were
      used to analyze the amino acid motifs involved in binding to HLA-DR8 and
      recognition by the BeA3 clone. Substitutions which abolished (MW --> AA), or
      decreased (RE --> AA and MA --> AA) T cell clone proliferation, cytokine
      production and cytotoxicity were identified. Loss of T cell function induced by
      the MW --> AA substitution was associated with poor HLA-DR8 binding. Decreased T
      cell function (RE --> AA and MA --> AA) was associated with good HLA-DR8 binding,
      which suggested that these motifs were involved in TcR binding. Other
      substitutions induced potentiation of the T cell clone response: the IV --> AA
      substitution induced stronger proliferation, but equivalent cytokine production,
      when compared with the reference peptide IE1 (158-175). CI --> AA substitution
      induced strong potentiation of HLA-DR8 binding, proliferation and interferon
      gamma and interleukin-4 production, possibly due to the removal of negative
      effects of Cys, Ile, or both side chains. Cytotoxicity was not improved by any
      substitution. Our results show modulation of the CD4+ T cell response according
      to the peptide residues involved in the HLA-DR8-peptide-TcR interaction.

PMID- 8647177
TI  - A novel "chimeric" antibody class in cartilaginous fish: IgM may not be the
      primordial immunoglobulin.
AB  - Using a degenerate oligonucleotide primer specific for immunoglobulin (Ig)
      constant type 1 (C-1 set) domain genes, products were amplified by the reverse
      transcriptase-polymerase chain reaction from nurse shark spleen cDNA. The deduced
      protein sequence of one of these clones reveals a novel Ig class in cartilaginous
      fish. A complete mRNA could encode a mature protein bearing an amino-terminal
      variable (V) domain, followed by six C-1 set domains, and ending in a carboxy
      terminal tail typical of secreted IgM, IgA, and the new antigen receptor (NAR).
      The two amino-terminal C domains are orthologous to IgX (or IgR), an Ig heavy (H)
      chain class in the skate, and the last four domains are homologous to the carboxy
      terminal four domains of NAR. We designate this "chimeric" Ig class IgNARC for Ig
      new antigen receptor from cartilaginous fish. Like NAR, but unlike shark IgM,
      IgNARC is encoded by very few V and C genes which apparently are not closely
      linked. The number of bands that hybridize with exon-specific probes varies with
      genomic DNA from individual sharks, suggestive of different numbers of IgNARC
      genes in different animals. A protein of approximately 95 kDa, which is likely to
      be the IgNARC H chain, is immunoprecipitated with both light chain-specific
      monoclonal antibodies and with antisera generated to a peptide comprising the
      IgNARC carboxy-terminal tail. We conclude that the arsenal of secreted antigen
      receptors in cartilaginous fish is greater than previously believed. In addition,
      our data cast doubt on the dogma that IgM is the primordial Ig isotype.

PMID- 8647178
TI  - Dissociation between cytokine mRNA expression and protein production in
      shigellosis.
AB  - In our study, infection with Shigella dysenteriae type 1 (n = 16) or Shigella
      flexneri in adults (n = 5) was associated with a gradual accumulation of mRNA for
      interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, IL-6, transforming
      growth factor-beta, IL-10, IL-4, TNF-beta, interferon (IFN)-gamma and perforin in
      the rectal biopsy samples during the convalescent stage of the disease
      demonstrated by in situ hybridization. In contrast, immunohistochemical staining
      in rectal tissues of cytokine protein-producing cells at the single-cell level
      exhibited a steady-state expression during 2-36 days after the onset of the
      disease. The frequency of cytokine mRNA-expressing cells varied in the range of 3
      100-fold higher than that of the corresponding protein-synthesizing cells. The
      accumulation of cytokine mRNA in vivo during shigellosis represented a long
      lasting phenomenon throughout the disease course, and may be linked to its
      immunopathogenesis. The results also indicate that assessment of both protein and
      mRNA in vivo may provide complementary information. Stimulation in vitro of
      peripheral blood mononuclear cells from normal healthy donors with Shigella
      derived lipopolysaccharide or shiga toxin was carried out to elucidate the role
      of Shigella antigens in the regulation of translation of cytokine-specific mRNA.
      The incidence of cytokine (IFN-gamma, IL-6 and TNF-alpha) mRNA- and cytokine
      protein-expressing cells was very similar and congruent after both these Shigella
      derived stimuli. We could, thus, not find evidence for shiga toxin-induced down
      regulation of cytokine mRNA translation as the explanation for the observed
      discrepancy between cytokine mRNA and protein levels in the tissue biopsies.

PMID- 8647179
TI  - The macrophage cell surface glycoprotein F4/80 is a highly glycosylated
      proteoglycan.
AB  - Molecules whose expression is limited to particular leukocyte populations are of
      interest since they may perform unique functions for these cells. We therefore
      examined the biochemical nature of the F4/80 molecule, which is expressed solely
      on macrophage and dendritic cell subpopulations. Our study clearly indicates that
      post-translational modifications, which can influence both a protein's structural
      and functional features, constitute a major component of the 160-kDa cell-surface
      F4/80 molecule. The F4/80 molecule is synthesized as a single polypeptide chain
      which acquires numerous intramolecular disulfide bonds and requires an extended
      time period (T1/2 = 60 min) for transport to an endoglycosidase H-resistant form.
      The F4/80 molecule contains extensive N-linked glycosylation which contributes
      approximately 40 kDa to the mature molecule. The N-linked carbohydrates are of
      the branched, complex type, containing repeating N-acetylglycosamine or N
      acetyllactosamine units which mediate the reactivity of the F4/80 molecule with
      Datura stramonium lectin. O-linked glycosylation is also present and contributes
      approximately 10 kDa to the F4/80 molecule. Furthermore, the sialic acid
      modifications of the F4/80 molecule are primarily through alpha 2-6 linkages to
      galactose. Finally, we demonstrate that the F4/80 molecule is a proteoglycan
      modified by chondroitin sulfate glycosaminoglycans. In addition to clarifying the
      nature of the F4/80 molecule biochemically, these post-translational
      modifications have specific implications for molecular recognition processes. We
      conclude that the modifications of the F4/80 molecule may mediate cell-cell
      recognition, cell adhesion, or ligand binding independently of the F4/80 molecule
      protein core.

PMID- 8647181
TI  - Polyclonal expansion of adoptively transferred CD4+ alpha beta T cells in the
      colonic lamina propria of scid mice with colitis.
AB  - The adoptive transfer of low numbers of peripheral, non-fractionated CD4+ alpha
      beta T cells into histocompatible, severely immunodeficient (scid) hosts induces
      a colitis. This disease developed in C.B-17 scid/scid hosts after the injection
      of 10(5) CD4+ T cells purified from different peripheral lymphoid organs of
      immunocompetent C.B.-17 +/+ or BALB/cdm2 donor mice. Irrespective of their tissue
      origin, transferred CD4+ T cells selectively repopulated the scid host with gut
      seeking CD4+ T cells. A chronic inflammatory bowel disease (IBD) developed as
      polyclonal populations of mucosa-seeking memory/effector CD4+ T cells accumulated
      in the gut lamina propria and epithelial layer of the adoptive host. The
      manifestation of colitis in the scid host correlated with the in situ polyclonal
      activation and expansion of adoptively transferred CD4+ T cells in the colonic
      lamina propria. Attempts were unsuccessful to select in vivo an oligoclonal CD4+
      T cell population with an enhanced IBD-inducing potential by repeatedly
      reinjecting 10(5) donor-type CD4+ T cells from the colonic lamina propria of
      transplanted scid mice with an early and severe IBD into new scid hosts. The data
      indicate that the preferential repopulation of gut-associated lymphoid tissues
      with immunocompetent CD4+ T cells, and their polyclonal activation and in situ
      expansion in the lamina propria of the histocompatible, immunodeficient host are
      critical events in the pathogenesis of an IBD in this model.

PMID- 8647180
TI  - Human basophils release interleukin-4 after stimulation with Schistosoma mansoni
      egg antigen.
AB  - The elevated interleukin (IL)-4 and IgE production in Schistosoma mansoni
      infection seems to be induced essentially by the egg stage of the parasite. The
      underlying mechanism, however, is not known. Since basophils from human
      peripheral blood can produce IL-4, we asked, whether soluble S. mansoni egg
      antigens (SEA) would trigger basophils to release IL-4. Basophils from healthy
      human donors (n = 32) without prior history of schistosomiasis were incubated
      with SEA in the presence of IL-3. In all donors, IL-4 was produced at different
      concentrations. The IL-4 production was dependent on the dose of SEA, was
      correlated with the purity of the basophil preparation, and the IL-4
      concentration in the culture supernatant was maximal 5 h after stimulation with
      SEA. In addition to its IL-4-stimulatory effect, SEA triggered basophils to
      degranulate, thereby releasing histamine and sulfidoleukotrienes. Stripping of
      receptor-bound IgE from basophils inhibited both SEA- and anti-IgE-induced, but
      not ionomycin-induced IL-4 production. Moreover, resensitization of stripped
      basophils with stripping supernatants or human serum restored SEA-induced IL-4
      production. This suggests that IgE is involved in the mechanism of IL-4 induction
      by SEA. Since IL-4 is induced in basophils from nonexposed donors, basophils may
      play a role as an early source of IL-4 in S. mansoni infection.

PMID- 8647182
TI  - Fas-mediated apoptosis is modulated by intracellular glutathione in human T
      cells.
AB  - Fas antigen is a member of the tumor necrosis factor receptor family that
      transduces a lethal signal to the Fas-sensitive cells. We previously established
      the Fas-resistant variant cell lines LAC2D1R and JKT2D1R from the parental Fas
      sensitive cell lines, SUPT13 and Jurkat, respectively. Recently, we isolated the
      Fas-resistant variant CEM2D1R from CCRF-CEM. All of the variants were Fas+ but
      resistant to Fas-mediated apoptosis. Further biochemical analysis revealed that
      the intracellular glutathione (GSH) content of the Fas-resistant variants was
      higher than in the original cells. When the Fas-resistant variants were incubated
      with buthionine sulfoximine (BSO) or in GSH-free/cysteine-free medium to deplete
      GSH, Fas resistance was reversed. Incubation of the cells with cycloheximide also
      decreased intracellular GSH and reversed the Fas resistance. Furthermore,
      incubation of activated peripheral blood lymphocytes with BSO enhanced Fas
      mediated apoptosis. When the Fas-sensitive cells were incubated with N
      acetylcysteine (NAC), intracellular GSH was increased and Fas-mediated apoptosis
      was blocked. In contrast, Fas-resistant variants, as well as Fas-sensitive cells
      pre-treated with NAC remained susceptible to allogeneic lymphokine-activated
      killer cells, most likely due to perforin-dependent killing. The results suggest
      that Fas-mediated apoptosis, but not perforin-dependent killing, is modulated by
      intracellular GSH in human T lymphocytes.

PMID- 8647183
TI  - The role of oxygen in thymocyte apoptosis.
AB  - Signals generated by T cell receptor (TCR) cross-linking (or phorbol 12-myristate
      13-acetate + Ca2+ ionophore), glucocorticoids or ionizing radiation all stimulate
      apoptotic cell death in thymocytes by signals that are initially distinct from
      each other. However, when these stimuli were administered to thymocyte cultures
      that were maintained under an atmosphere containing less than 20 ppm oxygen as
      opposed to one that contained 18.5% molecular oxygen, cell death was inhibited or
      abrogated, suggesting that the induction of death by all three different stimuli
      depend on the presence of molecular oxygen. Studies of the effects of the
      cysteine analog N-acetyl cysteine (NAC) with normal thymocytes demonstrated that
      this antioxidant inhibited the induction of death by each of the different
      stimuli in a manner the paralleled anaerobiosis. Furthermore, studies with
      thymocytes demonstrated that the induction of nur77, a gene shown to be involved
      in thymocyte apoptosis signaled through the TCR or its surrogates, is not
      inhibited by NAC or dependent upon molecular oxygen. The possible implications
      for negative selection of NAC-mediated inhibition of TCR-signaled thymocyte cell
      death was examined in thymic organ culture. Treatment of these cultures with NAC
      provided significant protection against staphylococcal enterotoxin B-mediated
      deletion of V beta 8-expressing thymocytes.

PMID- 8647184
TI  - Recognition of out-of-frame major histocompatibility complex class I-restricted
      epitopes in vivo.
AB  - In the course of constructing a recombinant vaccinia virus encoding the influenza
      A nucleoprotein (NP) gene preceded by the hemagglutinin leader sequence, we
      isolated a single base-pair deletion mutant which gave rise to L+NP(1-159) in
      which only the first 159 amino acids were in frame. Despite this, when we
      infected target cells, we found that the point mutant was able to sensitize them
      for lysis not only by cytotoxic T cells recognizing residues 50-58 (the in-frame
      portion), but also by CTL to epitopes which are downstream of the mutation (366
      374 and 378-386). Furthermore, normal C57BL/6 mice can be primed with the
      frameshift NP to recognize the immunodominant Db-restricted epitope 366-374
      (which is out of frame). Experiments in which the mutant gene product was
      processed in the endoplasmic reticulum of target cells suggested that the
      apparent suppression occurred during polypeptide extension.

PMID- 8647185
TI  - T cell major histocompatibility complex class II molecules down-regulate CD4+ T
      cell clone responses following LAG-3 binding.
AB  - T cell response to its antigen requires recognition by the T cell receptor
      together with a co-receptor molecule, either CD4 or CD8. Additional molecules
      have been identified that are capable of delivering the co-stimulatory signals
      provided by APC. Following T cell priming, a number of T cell activation antigens
      are expressed that may play a role in the inactivation phase of the T cell
      response. The lymphocyte activation gene (LAG)-3 protein and its counter
      receptors, the major histocompatibility complex (MHC) class II molecules, are
      such activation antigens whose interaction may result in the down-regulation of
      the ongoing immune response. To investigate the role of LAG-3/class II molecule
      interaction, we produced a soluble form of LAG-3 by fusing the extracellular Ig
      domains of this membrane protein to the constant region of human IgG1 (LAG-3Ig).
      Here, we show a direct and specific binding of LAG-3Ig to class II molecules on
      the cell surface. In addition, we show that LAG-3/class II molecule interaction
      leads to the down-regulation of CD4+ Ag-specific T cell clone proliferation and
      cytokine secretion. This inhibitory effect is observed at the level of the
      effector cells and not the APC and is also found with anti-CD3 mAb, PHA + PMA or
      low-dose IL-2 driven stimulation in the absence of APC. These functional studies
      indicate that T cell MHC class II molecules down-regulate T cell proliferation
      following LAG-3 binding and suggest a role for LAG-3 in the control of the CD4+ T
      cell response.

PMID- 8647186
TI  - Induction of T cell unresponsiveness by anti-CD3 antibodies occurs independently
      of co-stimulatory functions.
AB  - Antibodies to the T cell receptor (TcR)-associated CD3 molecules represent potent
      immunosuppressive agents in vivo in both human and animals models, in spite of
      their well-characterized mitogenic properties. We demonstrate in this report that
      antibodies to the B7.2 molecule inhibit IL-2 production in vivo caused by anti
      CD3 administration, suggesting that anti-CD3 monoclonal antibodies (mAb)
      stimulate naive T cells in vivo in a co-stimulation-dependent fashion. To
      characterize better the mechanisms by which antibodies to CD3 induce antigen
      unresponsiveness in naive T cells, we developed a model of activation-induced T
      cell unresponsiveness in vitro. Our data indicate that following interaction with
      mitogenic anti-CD3 mAb in vitro, naive purified CD4+ T cells become refractory to
      a further stimulus. This unresponsive state develops independently of co
      stimulatory functions, as neither B7-expressing antigen-presenting cells nor anti
      CD28 mAb are able to prevent anergy induction in this model. We therefore
      conclude that induction of unresponsiveness in naive T cells by anti-CD3 mAb is
      not a consequence of co-stimulus-deficient stimulation, but may develop following
      a productive response both in vivo and in vitro. Unresponsive T cells display a
      defective calcium mobilization upon TcR triggering, suggesting that anergy is
      maintained in these cells through receptor desensitization. The potential role of
      co-stimulation-independent TcR desensitization in the down-regulation of immune
      responses in vivo is briefly discussed.

PMID- 8647187
TI  - Dissection of lymphocyte function-associated antigen 1-dependent adhesion and
      signal transduction in human natural killer cells shown by the use of cholera or
      pertussis toxin.
AB  - The effect of the guanosine triphosphate-binding protein (G-protein) inhibitors
      cholera toxin (Ctx) and pertussis toxin (Ptx) has been analyzed on lymphocyte
      function-associated antigen 1 (LFA-1)-dependent adhesion and signal transduction
      in human natural killer (NK) cells. Ctx, but not Ptx, inhibited the LFA-1
      dependent adhesion of NK cells to tumor target cells which constitutively express
      the intercellular cell adhesion molecule-1 (ICAM-1) and to NIH/3T3 mouse
      fibroblasts stably transfected with human ICAM-1. This effect was detectable only
      by the use of the entire Ctx but not of the Ctx B subunit. In addition, Ctx could
      inhibit both NK cell binding and spreading to purified ICAM-1 protein. NK cell
      treatment with Ctx modified neither the surface expression of LFA-1 nor its Mg2+
      binding site. These findings, together with the absence of any detectable effect
      of Ctx on the constitutive phosphorylation of LFA-1 alpha, suggests that this
      toxin modifies the avidity of LFA-1 for ICAM-1 by acting on LFA-1-cytoskeletal
      protein association. Unlike Ctx, Ptx did not affect NK cell adhesion. The effects
      of Ctx and Ptx are unlikely to depend on intracellular levels of cyclic adenosine
      3',5'-monophosphate (cAMP), since a strong increase of cAMP was induced by both
      toxins. Moreover, this was confirmed by the observation that the LFA-1-dependent
      adhesion was not inhibited by the adenylate cyclase activator forskolin (FSK),
      the phosphodiesterase inhibitor isobutyl-1-methylxanthine (IBMX), or both, which
      increase intracellular cAMP levels. Unlike the differential effect on cell
      adhesion, both the intracellular calcium [Ca2+]i increase and phosphoinositide
      breakdown mediated via LFA-1 were consistently inhibited in a dose-dependent
      manner by both Ctx and Ptx. Also in this case, the inhibitory effect did not
      depend on an increase of intracellular cAMP as indicated by NK cell treatment
      with FSK, IBMX, or both. Further evidence of the involvement of G-proteins in LFA
      1-mediated signal transduction was the inhibitory effect of the GDP analog
      guanosine-5'-O-2-thiodiphosphate (GDP beta S) on LFA-1-mediated calcium
      mobilization. Taken together, our data provide evidence that the LFA-1-mediated
      NK cell adhesion and signal transduction are partially independent phenomena
      which may be regulated by different G-proteins.

PMID- 8647188
TI  - A promiscuous T cell hybridoma restricted to various I-A molecules.
AB  - In a previous study, we identified T cell receptor and major histocompatibility
      complex (MHC) contact sites on the pigeon cytochrome c p43-58 peptide. Positions
      46 and 54 of p43-58 were shown to be the MHC-binding sites. Specific amino acids
      were identified on the MHC-binding sites which bound to the relevant I-A
      molecule. In the present study, using NOD (I-Ag7) mice, we established a T cell
      hybridoma specific for a p43-58 analog 46R50E54A with arginine (R) and alanine
      (A) at positions 46 and 54, respectively. Interestingly, NOE 33-1-2 recognized
      46R50E54A in the presence of not only I-Ag7, but also I-Ad, s, u and v. In
      contrast to previous reports that promiscuous T cells were able to recognize
      peptide antigens with various HLA-DR or I-E molecules consist of monomorphic
      alpha and polymorphic beta chains, the promiscuous T cell clone NOE33-1-2
      recognized peptides with various I-A molecules lacking the monomorphic chain.

PMID- 8647189
TI  - The myelin basic protein-specific T cell repertoire in (transgenic) Lewis
      rat/SCID mouse chimeras: preferential V beta 8.2 T cell receptor usage depends on
      an intact Lewis thymic microenvironment.
AB  - In the Lewis rat, myelin basic protein (MBP)-specific, encephalitogenic T cells
      preferentially recognize sequence 68-88, and use the V beta 8.2 gene to encode
      their T cell receptors. To analyze the structural prerequisites for the
      development of the MBP-specific T cell repertoire, we reconstituted severe
      combined immunodeficient (SCID) mice with fetal (embryonic day 15-16) Lewis rat
      lymphoid tissue, and then isolated MBP-specific T cell lines from the adult
      chimeras after immunization. Two types of chimera were constructed: SCID mice
      reconstituted with rat fetal liver cells only, allowing T cell maturation within
      a chimeric SCID thymus consisting of mouse thymic epithelium and rat
      interdigitating dendritic cells, and SCID mice reconstituted with rat fetal liver
      cells and rat fetal thymus grafts, allowing T cell maturation within the chimeric
      SCID and the intact Lewis rat thymic microenvironment. Without exception, the T
      cell lines isolated from MBP-immunized SCID chimeras were restricted by MHC class
      II of the Lewis rat (RT1.B1), and none by I-Ad of the SCID mouse. Most of the T
      cell lines recognized the immunodominant MBP epitope 68-88. In striking contrast
      to intact Lewis rats, in SCID mice reconstituted by rat fetal liver only, MBP
      specific T cell clones used a seemingly random repertoire of V beta genes without
      a bias for V beta 8.2. In chimeras containing fetal Lewis liver plus fetal thymus
      grafted under the kidney capsule, however, dominant utilization of V beta 8.2 was
      restored. The migration of liver-derived stem cells through rat thymus grafts was
      documented by combining fetal tissues from wild-type and transgenic Lewis rats.
      The results confirm that the recognition of the immunodominant epitope 68-88 by
      MBP-specific encephalitogenic T cells is a genetically determined feature of the
      Lewis rat T cell repertoire. They further suggest that the formation of the
      repertoire requires T cell differentiation in a syngeneic thymic
      microenvironment.

PMID- 8647190
TI  - JNK, but not MAPK, activation is associated with Fas-mediated apoptosis in human
      T cells.
AB  - Fas is a cell surface molecule that is expressed on a wide array of cell types
      and triggers apoptosis. While in most situations Fas ligation activates
      programmed cell death, on resting T lymphocytes it can co-stimulate proliferation
      with the T cell receptor (TCR)/CD3 complex. This incongruity suggests that Fas
      may elicit signaling events that overlap with those used by proliferation cues.
      We observe that in the human T cell line Jurkat and in human peripheral blood
      lymphocytes, Fas stimulation does not signal by the Ras/Raf-1/mitogen-activated
      protein kinase (MAPK) pathway or by increased intracellular calcium. Rather, Fas
      ligation strongly activates Jun kinase (JNK). This activity, as well as Fas
      induced apoptosis, is blocked by increased levels of cAMP. The balance between
      proliferation and apoptosis by Fas triggering of T lymphocytes may therefore
      reflect a signaling ratio between TCR activation of the Ras/Raf-1/MAPK pathway
      versus JNK activation by Fas.

PMID- 8647191
TI  - IL-12 inhibits endotoxin-induced inflammation in the eye.
AB  - Interleukin-12 (IL-12) is a heterodimeric cytokine that induces interferon (IFN)
      gamma production and an increased generation of Th1 cells. Both IL-12 and IL-12
      antagonists are being studied for the treatment of allergic reactions, autoimmune
      disease and malignancy. The goal of the present experiments was to examine the
      importance of IL-12 in endotoxin-induced ocular inflammation. The number of
      inflammatory cells infiltrating eyes with endotoxin-induced uveitis (EIU) was
      significantly increased in animals treated with intraperitoneal anti-IL-12
      antibody when compared to control animals, but there was no difference in
      infiltrating inflammatory cells in the eyes of animals treated with IL-12 when
      compared to controls. In contrast, intraocular injection of IL-12 significantly
      inhibited the development of endotoxin-induced intraocular inflammation. The
      infiltrating inflammatory cells were reduced in the eyes of animals receiving
      intraocular IL-12 when compared to controls. Cytokine analysis of the aqueous
      humor obtained from eyes with EIU showed increased levels of IFN-gamma and
      decreased levels of IL-6 in eyes receiving intraocular IL-12. These data show
      that IL-12 has an inhibitory effect on endotoxin-induced inflammation in the eye
      and suggest that IL-12 can have an immunoregulatory function in some forms of
      inflammatory disease.

PMID- 8647192
TI  - Divergent effects of Fc gamma RIIIA ligands on the functional activities of human
      natural killer cells in vitro.
AB  - The Fc gamma receptor (R)IIIA (CD 16) plays an important role in regulating the
      cytotoxic and non-cytotoxic functions of human natural killer (NK) cells. Some
      anti-CD 16 monoclonal antibodies (mAb) have been shown to stimulate NK activity,
      while human monomeric (m) IgG induces dose-dependent inhibition of NK activity.
      To explore further these interactions mediated via Fc gamma RIIIA, purified NK
      cells were cultured for 2-3 days in the presence of mIgG, 3G8 mAb, interleukin-2
      (IL-2) or a combination of mIgG or 3G8 with IL-2. Binding of mIgG or 3G8 to Fc
      gamma RIIIA induced divergent effects of functions of cultured NK cells: 3G8 mAb
      + IL-2 induced dose-dependent inhibition of proliferation attributable to
      apoptosis; in contrast, mIgG + IL-2 significantly increased NK cell
      proliferation. Incubation of NK cells in the presence of mIgG up-regulated
      expression of surface activation markers (CD69, IL-2R alpha, ICAM-1),
      cytotoxicity, cytokine production (IL-1 beta, IFN-gamma and TNF-alpha) and
      release of soluble IL-2R. Thus, mIgG binding to Fc gamma RIIIA induced
      stimulatory signals in human NK cells, leading to up-regulation of IL-2R alpha
      expression, cell proliferation and cytokine release.

PMID- 8647194
TI  - Death of germinal center B cells without DNA fragmentation.
AB  - During the selection of B cells within germinal centers (GC) on the basis of
      their affinity for T-dependent antigen, B cells not positively selected are
      eliminated within GC. This process of B cell death has been considered to be
      apoptosis. In a recent study, we have reported that, although a substantial
      number of thymocytes were considered to be dead because of their extremely small
      cell size and heavy chromatin condensation even though they were not yet
      phagocytosed (pyknosis), they were devoid of DNA fragmentation, the most
      characteristic feature for apoptosis. In this study, we examined in vivo the
      mechanism of B cell death within GC by using the terminal deoxynucleotidyl
      transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) method to detect
      DNA double-strand breaks. TUNEL+ B cells were scattered throughout the upper dark
      and the light zones of GC. Double staining of the sections by the TUNEL method
      and acid phosphatase (AcP) activities showed that all the TUNEL+ B cells were
      phagocytosed by macrophages. Light microscopic and ultrastructural studies
      revealed the presence of small unphagocytosed B cells within the light zone.
      These cells are undoubtedly dead because they were much smaller than surrounding
      lymphoid cells and have a heavy chromatin condensation. Furthermore,
      ultrastructural detection of DNA fragmentation confirmed that these small
      unphagocytosed B cells were TUNEL-, implying that DNA fragmentation is not
      primarily involved in the cell death process of these small dead B cells. These
      results indicate that most B cells, not positively selected and thus destined to
      be eliminated, die within GC without DNA fragmentation, and are subsequently
      phagocytosed by macrophages and become TUNEL+. Typical apoptosis, characterized
      by DNA fragmentation in situ, is not the predominant type of cell death that
      occurs during the selection of B cells in GC.

PMID- 8647193
TI  - Human dendritic cells activate T lymphocytes via a CD40: CD40 ligand-dependent
      pathway.
AB  - The CD40:CD40 ligand (CD40L) interaction provides T lymphocyte-mediated help for
      B lymphocyte and monocyte function but has also been shown to serve as a co
      stimulus for T lymphocyte activation. In this report, we studied the regulation
      of CD40 expression and its functional relevance for the human dendritic cell (DC)
      stimulation of T lymphocytes. Only a small subpopulation of directly isolated
      blood DC expressed CD40. However, CD40 was rapidly up-regulated by culture, and
      its expression was further enhanced by interleukin (IL)-1 alpha, IL-1 beta, IL-3,
      tumor necrosis factor-alpha and granulocyte/macrophage-colony-stimulating factor.
      Expression of CD40L on DC was not detected. The proliferation of T lymphocytes in
      an allogeneic mixed leukocyte reaction, stimulated by blood DC or epidermal
      Langerhans cells, was significantly reduced in the presence of the CD40
      immunoglobulin (CD40Ig) fusion protein or CD40L monoclonal antibodies. Cross
      linking of CD40 on directly isolated DC with mouse CD40L trimer (mCD40LT)
      markedly augmented CD80 and CD86 up-regulation. Nevertheless, the same cross
      linking mCD40LT inhibited DC stimulated T lymphocyte proliferation. When CD40Ig
      was added simultaneously with CTLA-4Ig, only minimal and variable additional
      inhibition of DC-stimulated allogeneic T lymphocyte proliferation and IL-2
      secretion was observed, compared to each fusion protein alone. These results
      suggest that both CD80/CD86-dependent and -independent components of DC-T
      lymphocyte CD40:CD40L co-stimulation exist and further emphasize that the
      majority of blood DC have to differentiate or be activated to express co
      stimulatory molecules.

PMID- 8647195
TI  - Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody
      subclass.
AB  - Interleukin-12 (IL-12) is a key immunoregulatory cytokine which promotes cell
      mediated immunity. Its influence on the humoral immune response is less clearly
      defined. In this study, the effect of systemic IL-12 treatment on the T cell
      dependent humoral immune response in the rat was examined using an experimental
      system in which PVG-RT1u congenic rats were immunized with class I Aa alloantigen
      in the form of a blood transfusion from the recombinant PVG.R8 rat strain.
      Administration of IL-12 following allo-immunization augmented the humoral immune
      response as determined by increased levels of cytotoxic anticlass I major
      histocompatibility complex antibodies. However, the effect of IL-12 on individual
      IgG isotypes was highly selective. Levels of allospecific antibodies of the IgG2b
      and IgG2c subclasses were markedly increased, whereas IgG1 alloantibody levels
      were profoundly reduced. The observed alterations in alloantibody response were
      dependent, in large part, on the stimulatory effect of IL-12 on interferon (IFN)
      gamma production by T lymphocytes and natural killer cells, since they were
      abrogated by co-administration of neutralizing anti-IFN-gamma monoclonal antibody
      following alloantigen immunization.

PMID- 8647196
TI  - Structure and chromosomal location of the mouse interleukin-12 p35 and p40
      subunit genes.
AB  - Interleukin-12 (IL-12) is a heterodimeric cytokine composed of p35 and p40
      subunits and is required for induction of T helper 1 (Th1) responses. Knowledge
      of how the IL-12 gene is regulated will permit an understanding of susceptibility
      and resistance to pathogenic microbes and to autoiummune diseases. In this
      report, we provide the gene structures, nucleotide sequences and chromosomal
      assignment for the p35 and p40 subunits of mouse IL-12. The p35 and p40 subunit
      genes are distributed over 8 kb and 14 kb, and map to chromosomes 3 and 11,
      respectively. The p35 subunit gene consists of eight exons, including a 5'
      noncoding exon that was defined by sequence comparison of genomic DNA with the
      5'ends of novel cDNA molecules. Transcription of p35 mRNA can start from the
      first exon but can also initiate further downstream. Potential transcription
      regulatory elements, AP1, AP2, AP3, NF-kB and GATA recognition sequences, are
      located within 523 bp upstream of the p35 gene; however, no TATA box was
      identified. The p40 subunit gene consists of eight exons. A TATA box is located
      30 bp upstream from the transcription start site, and AP1, AP3, GATA, and Pu.1
      recognition sequences are located within 690 bp upstream of the p40 gene. An
      AGTTTCTACTTT sequence, which acts as an interferon-gamma response element in the
      promoter of the major histocompatibility complex class I gene, was also found
      upstream of the p40 gene.

PMID- 8647197
TI  - CD4-dependent and -independent association of protein tyrosine kinases to the T
      cell receptor/CD3 complex of CD4+ mouse T lymphocytes.
AB  - Tyrosine phosphorylation of different substrates is the earliest intracellular
      signal detected after T cell receptor (TcR) ligation. Several tyrosine kinases
      have been detected associated to the CD3-TcR complex in stimulated or
      unstimulated cells, including p56lck, p59fyn and ZAP-70. We have observed, in one
      mouse T helper CD4 T cell line, that most TcR- or CD3-associated tyrosine kinase
      activity comes from CD4:p56lck (Diez-Orejas, R., Ballester, S., Feito, M. J.,
      Ronda, M., Ojeda, G., Criado, G., Portoles, P. and Rojo, J. M., EMBO J. 1994. 13:
      90). To analyze whether this is a major way of tyrosine kinase association to the
      TcR in normal CD4+ T cells, we examined the nature and mode of association of
      tyrosine kinases to the TcR complex in normal spleen CD4+ T lymphocytes. Our
      results show that, in normal CD4+ T lymphocytes, as in CD4+ T cell lines, there
      is a stable and readily detectable association between CD4:p56lck and the TcR/CD3
      complex, as determined by in vitro kinase activity in immunoprecipitates from
      cell lysates. However, TcR/CD3 complexes from nature CD4+ lymphocytes have
      detectable amounts of p56lck associated in a CD4-independent manner, as shown by
      immunodepletion of the lysates with anti-CD4 antibodies. In addition, TcR/CD3
      also bind p59fyn regardless of the presence of CD4. Conversely, we have observed
      that CD4 co-precipitates small quantities of p56fyn in a TcR/CD3-independent
      manner. Overall, our data suggest the existence of different possible molecular
      complexes between TcR/CD3, CD4 and their attending kinases, as well as some
      quantitative and qualitative differences between CD4+ T cells and CD4+ T cell
      lines in kinase association to the TcR/CD3 complex.

PMID- 8647198
TI  - Interleukin-15 up-regulates interleukin-2 receptor alpha chain but down-regulates
      its own high-affinity binding sites on human T and B cells.
AB  - The cytokines interleukin (IL)-2 and IL-15 share many biological activities as a
      consequence of their utilization of the beta and gamma chains of the IL-2
      receptor. However, each cytokine binds to a specific receptor alpha chain; IL-2
      with low affinity and IL-15 with high affinity. Here, we demonstrate that IL-15,
      like IL-2, up-regulates expression of IL-2R alpha on human T and B cells, but
      rapidly down-regulates IL-15 high-affinity binding sites, which represent IL-15R
      alpha. This leads to a decreased responsiveness to IL-15 as measured by induction
      of Jak3 tyrosine phosphorylation. These results suggest a mechanism by which IL
      15, a product of activated macrophages, may cooperate with IL-2 at the initiation
      of an immune response and enhance subsequent IL-2 responsiveness during T cell
      expansion.

PMID- 8647199
TI  - Demonstration of local clonality of mucosal T cells in human colon using DNA
      obtained by microdissection of immunohistochemically stained tissue sections.
AB  - Intraepithelial lymphocytes have been shown to be oligoclonal and to be
      disseminated widely along the human intestine. However, studies using monoclonal
      antibodies have suggested that superimposed on the widespread clones, there is
      local variability in the mucosal T cell population. We have investigated the
      possibility that local dominant clones of T cells are present in the colonic
      mucosa by polymerase chain reaction (PCR) amplification of T cell receptor beta
      chain junctional regions using DNA extracted from microdissected fragments of
      tissue sections. Colon from two right hemicolectomy specimens was sampled at 7-cm
      intervals. Adjacent areas of mucosa were microdissected from sections from each
      colon sample. When the PCR products were separated according to size on
      polyacrylamide gels, bands of identical size were often observed when DNA
      extracted from adjacent fragments of mucosa had been used. Different bands were
      present when the different samples of colon had been studied. Sequencing of the
      PCR products confirmed that clonally related T cells were present in adjacent
      areas of mucosa, whereas different clones dominated at distant sites. DNA
      extracted from cells microdissected from the T cell zone of Peyer's patch was
      treated identically. The sequences obtained from the Peyer's patch, as expected,
      were diverse. However, one of the sequences identified was identical to that of
      one of the clones in the colon, implying that this clone was either trafficking
      through the Peyer's patch or possibly originated from the Peyer's patch. In this
      study, we also identified the Peyer's patches as a site of proliferation of CD4+
      T cells. No T cell division was observed in the lamina propria. The molecular and
      immunohistochemical observations together support the hypothesis that the Peyer's
      patches are a source of mucosal T cells.

PMID- 8647200
TI  - Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase
      in signal transduction via the human B lymphocyte antigen CD22.
AB  - CD22 is a B lymphocyte-specific membrane protein that functions as an adhesion
      molecule via its interactions with a subset of alpha 2-6-linked sialic acid
      containing glycoproteins. Engagement of CD22 with a monoclonal antibody (HB22.23)
      that blocks the binding of CD22 to its ligands results in rapid CD22 tyrosine
      phosphorylation and in increased association of CD22 with p53/56lyn kinase, p85
      phosphatidyl inositol-3 kinase, and p72syk kinase. Synthetic peptides that span
      various regions of the intracellular portion of CD22 were used to map potential
      kinase binding sites. All three kinases associated with a tyrosine-phosphorylated
      peptide that spans tyrosine amino acid residues 822 and 842, implicating this as
      an important region in mediating CD22 signal transduction. In addition, purified
      p56lyn directly bound to the same peptide. Engagement of CD22 with HB22.23 was
      sufficient to stimulate normal B cell proliferation. This study further
      substantiates the importance of CD22 as a B lymphocyte signaling molecule and
      begins to unravel the mechanisms by which CD22 cross-linking can alter B cell
      function.

PMID- 8647202
TI  - Kinetics and functional implications of Th1 and Th2 cytokine production following
      activation of peripheral blood mononuclear cells in primary culture.
AB  - The importance of cytokine production in some disease processes is now widely
      recognized. To investigate temporal relationships between cytokines, we
      stimulated peripheral blood mononuclear cells (PBMC) in vitro using the T cell
      mitogen phytohemagglutinin (PHA) and various antigens chosen to induce
      predominantly Th1 (streptokinase: streptodornase or purified protein derivative)
      or Th2 (Dermatophagoides pteronyssinus, bee or wasp venom: allergens in sensitive
      subjects) responses. Cytokine production was measured by sensitive bioassays or
      enzyme-linked immunosorbent assays. Of the 30 subjects studied, 10 were normal
      and 20 individuals were allergic to either D. pteronyssinus (n = 10) or bee venom
      (n = 10) (examined before specific allergen immunotherapy). We examined the
      temporal profiles of a panel of cytokines produced in primary culture. In PHA
      driven cultures, cytokines were found to be sequentially produced in the order
      interleukin (IL)-2, IL-4, IL-5, IL-3, interferon (IFN)-gamma, IL-10, IL-6, IL-12
      and tumor necrosis factor (TNF)-alpha. The response to allergen in allergic
      patients was predominantly Th2 in nature, with the production of IL-4, IL-5, IL-6
      and IL-10, but little or no IFN-gamma. IL-2, IL-3, TNF-alpha and IL-12 were also
      produced in low amounts. The response of both atopic and normal subjects to
      recall bacterial antigens was predominantly Th1, with high levels of IFN-gamma,
      IL-2 and TNF-alpha. The relevance of the order, amount and speed of production,
      characteristic kinetics (production, consumption, homeostatic regulation) and the
      cell source of the cytokines are discussed.

PMID- 8647201
TI  - Selective inhibition of interleukin-1 beta gene expression in activated RAW 264.7
      macrophages by interferon-gamma.
AB  - The ability of interleukin-1 (IL-1) to activate epidermal cell populations
      supports its role as a key cytokine in the pathogenesis of a number of
      inflammatory skin diseases. In the present study, we have examined the effect of
      interferon (IFN)-gamma on the expression of the IL-1 beta gene in mouse RAW 264.7
      macrophages activated by lipopolysaccharide (LPS) plus tumor necrosis factor
      (TNF)-alpha. Incubation of macrophages with both LPS and TNF-alpha resulted in
      the expression of both IL-1 beta and inducible nitric oxide synthase (iNOS) mRNA
      transcripts and increased the release of IL-1 beta protein and nitrite production
      in culture supernatants. Addition of IFN-gamma up-regulated the expression of the
      iNOS gene in cells activated by LPS + TNF-alpha, but significantly suppressed the
      induction of IL-1 beta gene expression in a dose-dependent manner. The
      suppression required neither de novo protein synthesis nor involved
      destabilization of the mRNA transcripts. Together, these findings suggest that
      IFN-gamma can be an important regulatory cytokine in a chronic inflammatory site
      and may explain its purported anti-inflammatory effects in certain dermatological
      diseases.

PMID- 8647204
TI  - Differential modulation of B7-1 and B7-2 isoform expression on human monocytes by
      cytokines which influence the development of T helper cell phenotype.
AB  - The co-stimulatory molecules B7-1/B7-2 expressed on the surface of antigen
      presenting cells have been suggested to influence the development of T helper 1
      (Th1)-versus Th2-immune responses. These studies were conducted to elucidate the
      effect of immunoregulatory cytokines which influence the development of Th1/Th2
      immune responses on the expression of the B7 isoforms B7-1 and B7-2 on resting
      and activated human monocytes and B cells. Interleukin (IL)-4 and IL-10, which
      induce the development of Th2 immune responses, down-regulated B7-2 and
      moderately up-regulated B7-1 expression on resting CD14+ monocytes in peripheral
      blood mononuclear cells. Interferon-gamma (IFN-gamma), which induces the
      development of Th1 immune responses, enhanced the expression of both B7-1 and B7
      2 isoforms. Tumor necrosis factor (TNF)-alpha, which elicits both Th1- and Th2
      characteristics depending on experimental conditions, down-regulated B7-2 but did
      not alter B7-1 expression. The effect of TNF-alpha and B7-2 expression is not
      mediated through endogenously produced IL-10, as addition of anti-IL-10
      antibodies did not restore B7-2 expression. None of the other cytokines tested,
      including IL-1 alpha, IL-1 beta, IL-2, IL-5, IL-6, IL-12, granulocyte/macrophage
      colony-stimulating factor (GM-CSF), and transforming growth factor (TGF)-alpha,
      modulated the expression of B7 isoforms on resting monocytes. Lipoolysaccharide
      stimulation of monocytes down-regulated B7-2 and up-regulated B7-1 expression in
      a manner similar to IL-10. The expression of B7-1 and B7-2 on purified B cells
      were not altered by any of the cytokines tested, including IL-1 alpha, IL-1 beta,
      IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IFN-gamma, TNF-alpha, TGF-alpha and GM-CSF.
      Taken together, our results suggest that the cytokines which induce Th1/Th2
      immune responses exert differential effects on B7 isoform expression on resting
      monocytes but have no effect on resting or activated B cells.

PMID- 8647203
TI  - Expression of human NKRP1A by CD34+ immature thymocytes: NKRP1A-mediated
      regulation of proliferation and cytolytic activity.
AB  - In this study, we show that NKRP1A is expressed and functions on a subset of
      immature human thymocytes. We took advantage of the monoclonal antibody (mAb)
      191B8 that was obtained by immunizing mice with cultured human thymocytes
      characterized by an immature surface phenotype [CD2- CD3- CD4- CD8- stem cell
      factor receptor (SCFR)+] and expressing cytoplasmic CD3 epsilon chain. The 191B8
      antibody homogeneously reacted with the immunizing population but not with most
      unfractionated thymocytes. It stained a minor population of resting immature
      thymocytes co-expressing CD34, SCFR, or both. Following culture of the CD34+ or
      CD34- fractions of CD2- CD3- CD4- CD8- purified immature thymocytes with
      recombinant interleukin-2 (rIL-2), the 191B8-defined antigen was expressed on
      virtually all cells even when 191B8+ cells were removed from the starting
      population. On the other hand, no 191B8+ cells were detected in fresh or cultured
      thymocytes expressing a more mature phenotype. Biochemical analysis of 191B8 mAb
      reactive molecules revealed, under non-reducing conditions, two bands displaying
      apparent molecular masses of 80 and 44 kDa and a single band of 44 kDa under
      reducing conditions. Digestion with proteases indicated that the 80-kDa form
      represented a homodimeric form of two 44-kDa molecules, while deglycosylation
      with N-glycanase suggested the existence of four N-glycosylation sites.
      Transfection of COS7 or NIH3T3 cells with hNKRP1A cDNA showed that the 191B8 mAb
      recognized NKRP1A as shown by both immunofluorescence analysis and
      immunoprecipitation experiments. Functional studies showed that the 191B8/NKRP1A
      molecule mediated strong inhibition of the cytolytic activity of cultured CD2-
      CD3- immature thymocytes against a panel of tumor target cells. More importantly,
      191B8 mAb induced proliferation of CD2- CD3- fresh thymocytes which was not
      increased by rIL-2. Thus, we propose that NKRP1A molecules, which are expressed
      in highly immature thymocytes, may play a regulatory role in their growth and
      function.

PMID- 8647205
TI  - CD28-dependent killing by human YT cells requires phosphatidylinositol 3-kinase
      activation.
AB  - CD28/B7 interactions have been demonstrated to provide a co-stimulatory signal
      for the generation of CD8+ cytotoxic T lymphocytes in the absence of CD4+ T
      helper cells. The CD28 signals required for induction of cytotoxicity have yet to
      be described. To investigate further the biochemical signaling pathways
      associated with CD28-dependent cytotoxicity, we have studied the human thymic
      leukemia cell line, YT. YT cells kill B7+ targets in a non-major
      histocompatibility complex (MHC)-restricted, CD28-dependent manner. CD28 ligation
      on the surface of YT cells caused a rapid increase in the tyrosine
      phosphorylation of four major cellular substrates with masses estimated to be
      110, 95, 85, and 44 kDa. The 110 and 85 kDa substrates were identified as the
      catalytic and regulatory subunits, respectively, of phosphatidylinositol 3-kinase
      (PI3-K). Engagement of CD28 caused the rapid receptor association and activation
      of PI3-K but did not activate phospholipase C gamma. CD28-induced tyrosine
      phosphorylation and PI3-K activation was independent of p56lck protein tyrosine
      kinase (PTK) activity (previously reported to be associated with CD28) and was
      insensitive to inhibition by the PTK inhibitor herbimycin A. Two structurally and
      mechanistically dissimilar inhibitors of PI3-K, wortmannin and 2-(4-morpholinyl)
      8-phenyl-4H-1-benzopyran-4-one (LY294002) also failed to block CD28-dependent
      tyrosine phosphorylation events or the association of PI3-K with the CD28
      receptor. However, both drugs inhibited CD28-dependent cytotoxicity and CD28
      receptor associated PI3-K activity with IC50 values similar to the reported IC50
      values for PI3-K inhibition. Although herbimycin A did not significantly block
      the observed CD28-dependent tyrosine phosphorylation or PI3-K activation,
      herbimycin did block CD28-dependent cytotoxicity in a dose-dependent manner.
      These data support a role for PI3-K activation in the CD28-dependent initiation
      of cytotoxic effector function and suggest that a herbimycin sensitive step(s) is
      either CD28-independent, resides within a PI3-K-independent CD28 signaling
      pathway, or is downstream of CD28-dependent PI3-K activation.

PMID- 8647206
TI  - HLA-associated inverse correlation between T cell and antibody responsiveness to
      islet autoantigen in recent-onset insulin-dependent diabetes mellitus.
AB  - Insulin-dependent diabetes mellitus (IDDM) is a T cell-dependent immune-mediated
      disease. Recently, a novel islet cell antigen (ICA69) recognized by
      autoantibodies was described. We tested T cell responsiveness to ICA69 in
      peripheral blood of patients with recent onset IDDM (n = 46), patients with long
      standing IDDM (n = 44), non-diabetic age-matched, islet cell autoantibody- and
      glutamic acid decarboxylase (GAD)65 antibody-negative first-degree relatives of
      IDDM patients (n = 15) and rheumatoid arthritis patients (n = 22). T cell
      responsiveness was significantly higher in recent onset IDDM patients, compared
      to IDDM patients post-disease onset, non-diabetic first degree relatives and
      rheumatoid arthritis patients (p < 0.001). In responding IDDM patients a
      significant inverse correlation between T cell and autoantibody responsiveness to
      ICA69 was observed (p < 0.0005). Immunogenetic evaluation revealed an association
      of HLA-DR3 with T cell responsiveness to ICA69 (p < 0.02) and absence of ICA69
      reactive autoantibodies (p < 0.04). The increased T cell reactivity to ICA69 in
      the absence of antibody reactivity at onset of IDMM is associated with an HLA
      class II immune response gene, and therefore suggestive of a genetically
      controlled selective activation of T helper subsets to a specific autoantigen in
      humans.

PMID- 8647207
TI  - Cyclic AMP-dependent protein kinase (cAK) in human B cells: co-localization of
      type I cAK (RI alpha 2 C2) with the antigen receptor during anti-immunoglobulin
      induced B cell activation.
AB  - Cyclic AMP (cAMP) inhibits antigen-stimulated B cell proliferation through
      activation of cAMP-dependent protein kinases (cAK). We have examined the
      molecular composition and cellular localization of cAK in human B cells. We find
      that human B cells contain substantial amounts of mRNA for RI alpha, RII alpha, C
      alpha and C beta, barely detectable levels of RI beta mRNA, and no detectable RII
      beta or C gamma mRNA. At the protein level, using Western blotting and subunit
      specific antibodies against the different R subunits, we find RI alpha and RII
      alpha, but no RI beta or RII beta. The presence of catalytic subunits was
      demonstrated using a nonselective anti-C antiserum. By photoaffinity labeling of
      R subunits with 8-azido-[32P]cAMP, followed by immunoprecipitation with subunit
      specific antibodies, we were also able to demonstrate low levels of RI beta.
      Immunofluorescence staining of RI alpha and RII alpha demonstrates a rather
      homogeneous intracellular (but extranuclear) distribution of RI alpha, whereas
      the RII alpha subunits of cAK are localized to distinct perinuclear structures,
      previously identified as centrosomes in other cell types. Upon anti-Ig-mediated
      capping of B cells, RI alpha subunits redistribute to the cap, co-localizing with
      the antigen-receptors, whereas the intracellular localization of RII alpha
      subunits remains unchanged.

PMID- 8647208
TI  - Immune complex-induced interleukin-6, interleukin-10 and prostaglandin secretion
      by human monocytes: a network of pro- and anti-inflammatory cytokines dependent
      on the antigen:antibody ratio.
AB  - We have used two experimental models of immune complexes to study the secretion
      of interleukin (IL)-10, IL-6 and their connection with the immune complex-induced
      synthesis of prostaglandin (PG) E2 by human monocytes in vitro. Immune complexes
      formed of tetanus toxoid and polyclonal anti-tetanus toxoid antiserum as well as
      heat-aggregated human serum immunoglobulins induced the release of IL-6 and IL-10
      in a dose- and antigen: antibody ratio-dependent manner. Antigen-antibody
      complexes formed near equivalence were most effective in induction of a cytokine
      response. PGE2 could augment the immune complex-induced IL-6 and IL-10 secretion,
      but alone, did not induce cytokine secretion. IL-10 was capable of down
      regulating the release of IL-6 and PGE2. Additionally, we demonstrated that
      endogenously synthesized IL-10 limited the immune complex-induced secretion of
      proinflammatory cytokines tumor necrosis factor-alpha and IL-1 beta. All three
      regulatory factors examined here share anti-inflammatory properties and are
      closely associated with the T helper type 2 (Th2) immune response. We conclude
      that immune complexes, besides their well-known ability no cause acute and
      chronic inflammation, can mediate immunosuppressive effects and influence the
      balance of Th1/Th2 responses.

PMID- 8647209
TI  - Interleukin-15 induces adhesion receptor redistribution in T lymphocytes.
AB  - Chemotactic factors such as cytokines and chemokines direct the migration of
      leukocytes into inflammatory sites. Chemokines play a role regulating both the
      expression and adhesive properties of leukocyte integrins. We have recently
      described an additional function of chemokines in the induction of cell
      polarization and adhesion receptor redistribution during the initial step of
      leukocyte locomotion. We herein report that interleukin (IL)-15, a newly
      described cytokine with chemotactic properties, is able to induce uropod
      formation on T lymphoblasts to which intercellular adhesion molecule (ICAM)-3, a
      leukocyte-restricted counter-receptor for the lymphocyte function-associated
      antigen (LFA)-1 integrin, is redistributed. Other adhesion molecules, such as
      ICAM-1, ICAM-2, CD43 and CD44, also redistributed to the uropod, although in a
      lower proportion of the cells. The induction of uropod formation by IL-15 was
      observed on T lymphoblasts adhering to the integrin ligands fibronectin, vascular
      cell adhesion molecule (VCAM)-1 and ICAM-1, but not to bovine serum albumin or
      poly-L-lysine. The effect of IL-15 was dose dependent and specifically inhibited
      by a monoclonal antibody (mAb) against this cytokine. Blocking experiments with
      anti-IL-2 receptor beta chain mAb showed an inhibitory effect on IL-15-mediated
      redistribution of ICAM-3, whereas no effect was observed in the presence of anti
      IL-2 receptor alpha chain mAb. The uropod induced by IL-15 is enriched in many
      different adhesion receptors and, being well exposed to the external milieu, is
      likely to modulate the adhesive properties of lymphocytes.

PMID- 8647210
TI  - Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal
      transducing zeta molecules and inhibits tumor-specific T cell-and natural killer
      cell-mediated cytotoxicity.
AB  - Although alterations in CD3-associated signal-transducing molecules in tumor
      infiltrating T cells of patients with advanced cancer have been previously
      described, the mechanism behind these changes is not known. We demonstrate that
      macrophages isolated from metastatic lymph nodes of patients with malignant
      melanoma down-regulate levels of CD3 zeta in autologous peripheral blood T cells.
      Lipopolysaccharide (LPS)- or phorbol 12-myristate 13-acetate (PMA)-stimulated
      monocytes derived from peripheral blood of healthy donors also induced decreased
      expression of CD3 and CD16-associated zeta chains similar to that observed in T
      cells and natural killer (NK) cells of patients with advanced cancer. Co-culture
      with activated monocytes impaired Ca2+ mobilization in peripheral blood derived-T
      cells when stimulated with monoclonal antibodies to CD3 and also strongly
      inhibited melanoma-specific cytotoxic T lymphocyte (CTL) activity and NK
      activity. The presence of catalase, a scavenger of H2O2, during co-culture almost
      totally abrogated the inhibitory effect of activated monocytes on melanoma
      specific CTL lines and on NK cells. Pre-treatment of CTL or NK cells with
      nontoxic concentrations (1 x 10(-5) M) of H2O2 also severely reduced their
      cytotoxic activity which could be prevented by catalase. The decrease in CD3 zeta
      and in CD16 zeta expression, induced by macrophages isolated from metastatic
      lymph nodes or by LPS-stimulated monocytes, was also prevented by catalase when
      maintained throughout the co-culture period. The possibility that
      monocyte/macrophage-derived reactive oxygen metabolites contribute directly to
      alterations in signal transducing molecules of T cells and NK cells and to the
      mechanism of immunosuppression in individuals with cancer should be considered.

PMID- 8647211
TI  - Determination of the allele-specific antigen-binding site on I-Ak and I-Ab
      molecules.
AB  - Residues 46 and 54 on a pigeon cytochrome c 43-58 analog, 50E, function as major
      histocompatibility complex class II contact sites. A peptide, 46F50E54A, with
      phenylalanine (F) at position 46 and alanine (A) at 54 on 50E bound to Ab and a
      peptide, 46D50E54A, with aspartic acid (D) at 46 and alanine at 54, bound to Ak.
      To determine the allele-specific peptide contact sites on I-A molecules
      corresponding to the I-A contact sites of the peptides, we analyzed responses of
      Ak- and/or Ab-restricted T cell hybridomas to 46F50E54A or 46D50E54A using L cell
      transfectants expressing recombinant I-A molecules between Ak and Ab or point
      mutants of Ak as antigen presenting cells. It was shown that the N-terminal half
      of the alpha helix of the A alpha chain determined the allele-specific T cell
      responses. Furthermore, with arginine (k type amino acid) or alanine (b type
      amino acid) at position 56 of the Ak alpha chain, these T cell hybridomas were
      stimulated predominantly by 46D50E54A (Ak binding peptide) or 46F50E54A (Ab
      binding peptide), respectively. Thus, the amino acid at position 56 of the A
      alpha chain determines allele-specific antigen presentation. This postulate was
      confirmed by direct binding analysis of 50E analogs of various I-A molecules. A
      single amino acid change (arginine to alanine) at position 56 of the Ak alpha
      chain altered the peptide binding specificity (46D50E54A to 46F50E54A).

PMID- 8647212
TI  - Dispensability of Jak1 tyrosine kinase for interleukin-2-induced cell growth
      signaling in a human T cell line.
AB  - The tyrosine kinases Jak1 and Jak3 are known to be associated with the beta and
      gamma chains of interleukin-2 receptor (IL-2R). They are activated by stimulation
      with IL-2, IL-4, IL-7, IL-9, or IL-15, receptors of which share the gamma chain
      of the IL-2R. We have obtained direct evidence of Jak1 association with the alpha
      chains of receptors for IL-4, IL-7 and IL-9 and with the beta chain of IL-2R,
      which is also common to the IL-15R. Furthermore, we have prepared mutant IL-2R
      beta chains with a mutation in the box 1 region, which is conserved among the IL
      2R beta chain and the alpha chains of the other cytokine receptors sharing the IL
      2R gamma chain. Using MOLT-4 transfectants with the mutant beta chains, we found
      that two conserved proline residues within the box 1 region are essentially
      involved in association with Jak1. The MOLT-4 transfectants with the mutant beta
      chains lacking Jak1 association showed IL-2 responsiveness, in terms of
      activation of Jak3 and Stat5 and induction of cell growth, indicating that Jak1
      is dispensable for IL-2-mediated cell growth signaling and that Jak1 activation
      is not required for activation of Jak3 and Stat5 in the MOLT-4 transfectants.

PMID- 8647213
TI  - Characterization of CD4-CD8- T cell receptor alpha beta + T cells appearing in
      the subarachnoid space of rats with autoimmune encephalomyelitis.
AB  - Inflammation of the central nervous system (CNS) in experimental autoimmune
      encephalomyelitis (EAE) starts in the subarachnoid space (SAS) and spreads later
      to the adjacent CNS parenchyma. To characterize the nature of lesion-forming T
      cells in situ in more detail, T cells were isolated from the SAS and their
      surface phenotype and the nucleotide sequence of the junctional region of the T
      cell receptor (TCR) was determined and compared with those of the lymph node (LN)
      and spinal cord (SC) T cells. Characteristically, more than 70% of SAS TCR alpha
      beta + T cells isolated at the early stage of EAE lacked both CD4 and CD8
      molecules, whereas those from LN and SC were either CD4+ or CD8+. Analysis of
      nucleotide sequences of the junctional region of TCR revealed that T cells
      bearing a sequence identical to that for encephalitogenic T cell clones were
      found in both SAS and SC. Furthermore, purified CD4-CD8- T cells expressed CD4
      molecules after culture. At the same time, these T cells acquired reactivity to
      myelin basic protein and induced passive EAE in naive animals after adoptive
      transfer. Our results suggest that CD4-CD8- T cells in the SAS are precursors of
      lesion-forming T cells in the SC and that phenotype switching takes place during
      the process of T cell infiltration into the CNS parenchyma. The double-negative
      nature of these T cells may explain an escape of encephalitogenic T cells from
      negative selection in T cell differentiation.

PMID- 8647214
TI  - Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective
      antitumor immunity and therapy of established tumors.
AB  - Interleukin-12 (IL-12) promotes specific and long-lasting anti-tumor immunity
      mediated by T cells in a variety of murine tumor models. IL-12 also synergizes
      with B7.1 (CD80) co-stimulation to induce proliferation and cytokine production
      by both human and murine T cells in vitro. We evaluated the combined anti-tumor
      efficacy of IL-12 and B7.1 gene delivery in two apparently poorly immunogenic
      tumor models (TS/A and MCA207). In both of these models, expression of B7.1 and
      production of IL-12 in the inoculum led to improved anti-tumor immunity, with up
      to 80% long-term tumor-free animals (vs 0-20% of mice remaining tumor free when
      inoculated with either B7.1- or IL-12-transfected tumors alone). Tumor-free mice
      were capable of rejecting a subsequent rechallenge with the wild-type tumor in
      66% of the cases. Cooperativity was dependent upon the level of IL-12 secreted by
      engineered cells. IL-12 delivery required B7 expression of therapeutic effects to
      be observed in these models. Vaccines provided at a site distal to a control, non
      transfected tumor slowed (TS/A) or abrogated (MCA207) the progression of wild
      type tumors. The synergistic anti-tumor effects associated with combined
      application of B7.1- and IL-12-transfected tumors were partially negated by
      systemic administration of the CD28-B7.1/B7.2 antagonist CTLA4-Ig or by
      inoculation with neutralizing antibodies directed against murine interferon-gamma
      or tumor necrosis factor-alpha, two cytokines elicited in response to IL-12
      stimulation. These data support the potential clinical utility of combined gene
      therapy using IL-12- and B7.1-engineered autologous cells (tumor or fibroblasts)
      as a vaccine to elicit specific anti-tumor immunity.

PMID- 8647215
TI  - T cell recognition of Tn-glycosylated peptide antigens.
AB  - The mouse hemoglobin-derived decapeptide Hb (67-76), VITAFNEGLK, which binds well
      to Ek and is non-immunogenic in CBA/J mice, was O-glycosylated with the tumor
      associated carbohydrate Tn (alpha-D-N-acetylgalactosamine, or alpha-D-GalNAc).
      Each of the ten positions in the peptide was substituted with serine or threonine
      having the Tn antigen attached. The complete set of Tn-glycosylated peptides were
      then studied for binding to Ek and for immunogenicity in CBA/J mice. All of those
      glycopeptides which had the Tn attached to serine or threonine at a position in
      the peptide where, according to the crystal structure determinations, the amino
      acid side chain was oriented downwards into the binding site of the major
      histocompatibility complex (MHC) molecule, completely lost their capacity for
      binding to Ek. This was the case for the glycopeptides with Tn attached at
      position 68 and 76, which are the major anchor residues and for those with Tn
      attached at position 71 and 73, which function as secondary anchor residues.
      Those glycopeptides which had Tn attached to serine or threonine at positions
      where the side chain pointed away from the binding site maintained their capacity
      for binding to Ek, except for those with Tn attached at position 70 and 74.
      Furthermore, some of the MHC-binding glycopeptides were immunogenic. In
      particular, this was the case for the glycopeptide with Tn attached to the
      central position 72 in the decapeptide. From previous studies, this is known to
      be the dominant T cell receptor contact residue of Hb (67-76). The results
      suggest that T cells may be capable of recognizing epitopes which are partially
      defined by a small glycan group.

PMID- 8647216
TI  - Affinity maturation and hypermutation in a simulation of the humoral immune
      response.
AB  - By experimenting with a cellular automaton model of the immune system, we have
      reproduced affinity maturation of the antibody response, a somatic adaptation to
      a changing environment. The simulation allowed the isolation of a number of
      variables, e.g. the fraction of repertoire available, the magnitude of the change
      in affinity with mutation, the mutation frequency and its focus on the
      complementarity-determining regions (CDR) of the antibody. Multiple series of
      immunizations were run in machina where the contribution of each variable was
      evaluated against the maturation observed. We found that hypermutation is not
      necessary for affinity maturation if the repertoire of B cell specificities is
      sufficiently complete, but is essential when the B cell diversity is limited
      (which happens to be the case in vivo), as it fills the holes in the repertoire
      and allows selection by antigen. Maturation also depends on the magnitude of the
      change in affinity with mutation, and we supply some necessary limits on this
      parameter. For mutations confined to the CDR, the most efficient maturation
      occurs at mutation rates of 0.2 per paratope and per cell division. When
      mutations also affect the framework regions, the peak of the most effective CDR
      mutation rate moves progressively to lower values. A most sensitive parameter is
      the speed of maturation, which reflects the rate of expansion of mutated clones.
      Comparing it with biological observations can help to discriminate between
      alternative hypotheses on the phenomena of hypermutation and affinity.

PMID- 8647217
TI  - Human and rodent interferon-gamma as a growth factor for Trypanosoma brucei.
AB  - An example for the bidirectional exchange of activating signals between a
      pathogen and immunocompetent cells in the host is presented. Trypanosoma brucei,
      which include subspecies that cause African sleeping sickness, secrete a molecule
      that triggers lymphocytes to produce interferon (IFN)-gamma. We now report that
      proliferation of T. brucei is stimulated in axenic cultures by IFN-gamma. The
      growth-enhancing effect on the pathogen is inhibited by anti-IFN-gamma receptor
      (R) antibodies and does not occur after exposure to other cytokines, i.e. IFN
      alpha, IFN-beta and tumor necrosis factor (TNF)-alpha. While rodent-pathogenic T.
      brucei strains are stimulated by rat IFN-gamma, human pathogenic strains are more
      potently stimulated by human IFN-gamma. Rat and human IFN-gamma can partially
      block each others effects. Mice with disrupted IFN-gamma genes have reduced
      parasitemia and prolonged survival, while the outcome is reversed in mice that
      lack the IFN-gamma R gene.

PMID- 8647218
TI  - Elevated proliferation and interleukin-4 release from CD4+ cells after
      chemotherapy in human Schistosoma haematobium infection.
AB  - Cellular immune responses to schistosomal antigens were examined in 110
      Schistosoma haematobium-infected individuals before and 5 weeks after treatment
      with praziquantel. Chemotherapy resulted in significant decrease in worm load as
      measured by egg output and circulating antigens. The proliferative responses to
      adult worm antigen (AWA) increased significantly after treatment (p < 0.001)
      whereas purified protein derivative of tuberculin or phytohemagglutinin
      responsiveness was unaffected. Interleukin (IL)-4 production in response to both
      AWA and soluble egg antigen (SEA) increased markedly after treatment (p < 0.001),
      but IL-5 remained unchanged. None of the studied subjects released any measurable
      IL-2 and only 21% produced interferon (IFN)-gamma in response to parasite
      antigens. The deficiency in either IFN-gamma or IL-2 release was not restored by
      chemotherapy. Thus chronic infection with S. haematobium is associated with the
      reversible down-regulation of T cell proliferative responses and IL-4 release.
      Results from cell depletion experiments indicated that CD4+ T cells were the
      target of this down-modulation.

PMID- 8647219
TI  - Human epidermal keratinocytes are induced to secrete interleukin-6 and co
      stimulate T lymphocyte proliferation by a CD40-dependent mechanism.
AB  - Although the expression and function of CD40 on B lymphocytes has been well
      studied, the significance of CD40 on non-lymphoid cells such as keratinocytes
      (KC) is not as well characterized. We demonstrate in this report that CD40 is
      expressed by virtually all human KC, and that it functions as an important
      signaling molecule. Flow cytometry of undifferentiated and terminally
      differentiated KC indicated that both cell types expressed CD40, as determined by
      binding to monoclonal antibodies and a recombinant CD40 ligand fusion protein;
      interferon-gamma (IFN-gamma) treatment of KC increased CD40 expression. Cultured
      KC also expressed 1.5-kb CD40 transcripts. Activation of KC cell surface CD40
      using the monoclonal antibody G28.5 resulted in the rapid generation of a 50-kDa
      tyrosine phosphorylated polypeptide, as well as a dose-dependent increase in the
      secretion of interleukin-6, a cytokine that has been linked to KC proliferation.
      KC also co-stimulated a significant T lymphocyte proliferative response to the
      mitogen phytohemagglutinin that was CD40 dependent. These data indicate that KC
      constitutively express a low level of functional CD40 and regulate their
      expression in response to IFN-gamma. These data support the concept that KC, via
      their expression of CD40, have the capacity to amplify inflammation in the skin
      by interacting with CD40 ligand-bearing T cells.

PMID- 8647220
TI  - Detection of primary direct and indirect human anti-porcine T cell responses
      using a porcine dendritic cell population.
AB  - The pathways of human anti-pig T cell xenorecognition have been investigated.
      Freshly isolated porcine alveolar lavage (AL) cells induced primary proliferative
      responses by human peripheral and cord blood mononuclear cells which were
      inhibited by anti-HLA-DR antibody (indirect xenorecognition). Following over
      night culture, the AL cells acquired the capacity to stimulate proliferation by
      purified human T cells which was inhibited by anti-SLA-DR antibody (direct
      xenorecognition). The marked increase in immunogenicity in the porcine AL cells
      was accompanied by a phenotypic change consistent with dendritic cell maturation.
      Limiting dilution assays indicate that the total anti-pig T cell response, in
      particular that mediated by indirect xenorecognition, is stronger than comparable
      alloresponses.

PMID- 8647221
TI  - Contribution of interleukin-3 to antigen-induced Th2 cytokine production.
AB  - Short-term stimulation of mouse spleen cells in vitro with interleukin (IL)-3
      induces the secretion of the Th2 cytokines IL-4 and IL-6. Non-B/non-T cells were
      the target of this IL-3 effect. However, during long-term antigen-dependent
      culture, T cells are the major source of IL-4 and IL-6. The addition of IL-3 to
      such cultures also led to a significant increase in IL-4 and IL-6 production.
      This Th2 cytokine secretion was amplified by the addition of irradiated non-B/non
      T cells at the initiation of culture, and was inhibited by anti-IL-4 antibodies.
      These findings suggest that IL-3 induces the rapid release of IL-4 and IL-6 by
      non-B/non-T cells, thereby creating an immune milieu conducive to the development
      of antigen-specific IL-4 and IL-6-secreting Th2 cells.

PMID- 8647222
TI  - Triggering of CD23b antigen by anti-CD23 monoclonal antibodies induces
      interleukin-10 production by human macrophages.
AB  - The aim of this study was to evaluate the capacity of human macrophages to
      produce interleukin (IL)-10 upon stimulation of membrane CD23. An anti-CD23
      monoclonal antibody (mAb) was found to elicit the expression of the specific mRNA
      for IL-10 in CD23-bearing macrophages, and to induce a time-dependent production
      of this cytokine with a maximal effect reached after 12 h. Inasmuch as we
      previously reported that CD23 ligation evoked the generation of nitric oxide and
      of cAMP, the effect of the Rp diastereoisomer of adenosine 3', 5'-cyclic
      phosphorothioate (Rp-cAMP, an inhibitor of the cAMP pathway) and of NG-monomethyl
      L-arginine (L-NMMA, an inhibitor of the nitric oxide pathway) were evaluated on
      CD23-induced IL-10 production. In the presence of Rp-cAMP, the CD23-induced
      production of IL-10 and of the pro-inflammatory cytokine tumor necrosis factor
      alpha (TNF-alpha) was totally abrogated, whereas, in the presence of L-NMMA, IL
      10 production was enhanced and TNF-alpha production was suppressed. In addition,
      neutralization of IL-10 with an anti-IL-10 mAb increased both the magnitude and
      duration of CD23-driven TNF-alpha production. Such an inducing effect was
      observed with different anti-CD23 mAb (clone 135, MHM6 and 25), indicating that
      the triggering of the CD23 molecule at the surface of human macrophages induced
      the generation of IL-10 through a cAMP-dependent mechanism. Concomitantly this
      generation of IL-10 was down-regulated by nitric oxide, which was also produced
      after triggering of the CD23 antigen. Taken together these data indicated that
      human macrophages produced IL-10 after triggering of the CD23 molecule and that
      this production could regulate the inflammatory state of these cells.

PMID- 8647223
TI  - Evidence of a T helper type 2 activation in human schistosomiasis.
AB  - The lymphocyte proliferative response and cytokine production to S. mansoni
      antigen in vitro were evaluated in 22 schistosomiasis patients living in an area
      endemic for this disease. The majority of patients (86%) showed no lymphocyte
      proliferative response and none of them showed interferon-gamma (IFN-gamma)
      production, following in vitro stimulation with soluble adult worm antigen
      preparation (SWAP). In contrast, interleukin (IL)-5 (2038 +/- 1757 pg/ml) and IL
      10 (867 +/- 762 pg/ml) were detected in peripheral blood mononuclear cell (PBMC)
      cultures stimulated with SWAP. Moreover, mRNA for IL-4 was detected in SWAP
      stimulated PBMC from 4 of 6 patients evaluated. Restoration of
      lymphoproliferative response was achieved in 4 of 6 patients by adding anti-IL-10
      monoclonal antibody (mAb) to PBMC cultures [mean stimulation index (SI) in the
      presence of antigen = 2.7 +/- 2.9; SI in the presence of antigen plus anti-IL-10,
      21 +/- 16]. Restoration of IFN-gamma production by addition of anti-IL-10 mAb was
      achieved in 4 of 12 patients evaluated (248, 350, 687 and 710 pg/ml). Moreover,
      the addition of IL-10 to PBMC cultures of 3 schistosomiasis patients and 2 cured
      subjects who had high lymphoproliferative responses to SWAP resulted in the
      suppression of these responses by 90%, and completely suppressed IFN-gamma
      production in one of the subjects, whose PBMC produced IFN-gamma after
      stimulation with SWAP. The presence of IL-4 mRNA, high levels of IL-5, and the
      absence of IFN-gamma in PBMC culture supernatants from infected patients,
      supports the conclusion that patients living in an endemic area of
      schistosomiasis express a predominant T helper type 2 response. The high levels
      of IL-10 and the ability of neutralizing anti-IL-10 mAb to restore T cell
      responses indicate that this cytokine plays an important role in the modulation
      of T cell responses in schistosomiasis.

PMID- 8647224
TI  - On the interaction between agalactosyl IgG and Fc gamma receptors.
AB  - One of the serum abnormalities observed in autoimmune diseases such as rheumatoid
      arthritis (RA) and systemic lupus erythematosus (SLE) is the occurrence of IgG
      that lacks the terminal galactose on asparagine-linked biantennary complex type
      oligosaccharides [Gal(0)-IgG] located in the CH2 domain. Additionally, IgG
      without glycosylation is known to be defective in several effector functions due
      to a reduced ability to bind to its specific receptors (Fc gamma R). It has thus
      been speculated that, by analogy with unglycosylated IgG, Gal(0)-IgG may also be
      functionally impaired or exert altered effector mechanisms. If this were true,
      Gal(0)-IgG could contribute to the phenotype of above-mentioned autoimmune
      diseases, like impaired immune complex clearance and defective down-regulation of
      activated B cells. Here, we show by three different methods that the interaction
      of Gal(0)-IgG and normally glycosylated IgG with the low-affinity Fc gamma RII
      (CD32) is indistinguishable with respect both to binding and receptor-mediated
      signalling. These data argue against a prominent role for Fc gamma R-dependent
      Gal(0)-IgG interactions in the etiology or pathogenesis of autoimmune diseases.

PMID- 8647225
TI  - Granulocyte colony-stimulating factor administration and monocyte phenotype.

PMID- 8647226
TI  - Recombinant human bone morphogenetic protein-2 induces a hematopoietic
      microenvironment in the rat that supports the growth of stem cells.
AB  - In the mammalian bone marrow, stromal components support the growth and
      differentiation of blood cells. To study this complex system, we used a rat model
      in which ectopic hematopoietic tissue was induced to form after subcutaneous
      implantation of recombinant human bone morphogenetic protein (rhBMP-2). We showed
      that this organoid contained clonogenic precursors of both erythroid and myeloid
      lineages and progenitors competent to regenerate splenic lymphopoiesis.
      Furthermore, stem cells derived from ectopic foci conferred both short-term (30
      day) and long-term (>6-month) protection in vivo against radiation-induced marrow
      aplasia. Lead shielding of the ectopic marrow in situ also permitted endogenous
      recovery of hematopoiesis after sublethal irradiation. Extending previous
      observations that most fibroblastoid cells of the marrow stain with the anti-ST3
      antibody (but minimally with anti-ST4), whereas those growing from
      nonhematopoietic tissues react with anti-ST4, we found that analogous cells of
      the ectopic foci stained predominantly with anti-ST3. The ability to induce
      formation of a hematopoietic microenvironment from mesenchymal precursors may
      make possible the development of new strategies for the treatment of primary
      disorders of stem cells and irreversible stromal injury.

PMID- 8647227
TI  - Thymosin beta4, inhibitor for normal hematopoietic progenitor cells.
AB  - Thymosin beta4 (Tbeta4), isolated from the calf thymus fraction 5, has a
      ubiquitous localization and plays a pleiotropic role in both the immune and
      nonimmune systems. Because it contains at its N-terminal end the sequence of a
      known inhibitor of hematopoiesis, the acetylated tetrapeptide Ac-N-Ser-Asp-Lys
      Pro (AcSDKP, Goralatide), we have assayed Tbeta4 on human hematopoietic cells. We
      demonstrate that it inhibits normal bone marrow progenitor cell growth; indeed,
      it decreased the growth of both granulo-macrophagic and erythroid progenitors and
      reduces their percentage in S phase. Furthermore, we show that Tbeta4 reduces
      both the clonogenicity and the cell proliferation of purified CD34+ cells induced
      by a combination of seven growth factors. Although Tbeta4's inhibitory effect is
      very similar to that of AcSDKP, we demonstrate, using neutralizing antibodies and
      a truncated form of Tbeta4 devoid of the AcSDKP sequence, that the inhibitory
      effect of Tbeta4 is not mediated by the sequence AcSDKP. These data indicate that
      Tbeta4 is a novel inhibitor for human normal hematopoietic progenitors.

PMID- 8647228
TI  - Interleukin-4 (IL-4) in combination with IL-11 or IL-6 reverses the inhibitory
      effect of IL-3 on early B lymphocyte development.
AB  - We have previously described a two-step methylcellulose culture system in which
      individual primitive progenitors from 5-fluorouracil (5-FU)-treated mice were
      shown to have both myeloid and B lymphoid differentiation capacity. Highly
      enriched Lin-Sca+FU2d BM cells were cultured in methylcellulose in the presence
      of Steel factor (SF), interleukin-7 (IL-7), and pokeweed mitogen stimulated
      spleen cell conditioned medium (PWM-SCM). Primary mixed myeloid colonies were
      replated after 8-11 days into secondary cultures containing SF and IL-7, which
      supported the generation of B220+sIgM- pre-B cell colonies. A number of growth
      factors, including IL-6, IL-11, granulocyte colony-stimulating factor (G-CSF),
      and IL-12 were shown to be capable of substituting for PWM-SCM to support the B
      lymphoid potential of primary colonies. B lymphoid potential was not supported,
      however, in SF + IL-3 or in SF + IL-3 plus any single growth factor (IL-1 to -12,
      granulocyte-macrophage colony-stimulating factor [GM-CSF], G-CSF, erythropoietin
      [Epo], leukemia inhibitory factor [LIF], tumor necrosis factor-alpha [TNF-alpha],
      transforming growth factor-beta [TGF-beta], gamma interferon [IFN-gamma], or
      insulin-like growth factor-1 [IGF-1]), but was supported in SF + IL-3 + 5% PWM
      SCM. Experiments were designed to identify the factor or factors in PWM-SCM that
      reverse the inhibitory effects of IL-3 on B lymphoid potential. By substituting
      various cytokine combinations for PWM-SCM, we determined that combinations of IL
      4 + IL-6 or IL-4 + IL-11, but not IL-4 alone, can substitute for PWM-SCM to
      reverse the inhibitory effect of IL-3 on B lymphoid potential. Neutralizing
      antibodies to IL-4 completely eliminated the activity in PWM-SCM, but antibodies
      to IL-6 only partially inhibited the activity. IL-11 was not detected in PWM-SCM,
      and the activity co-purified with IL-4, but not with IL-6. Thus, IL-4 plus IL-6,
      IL-11, or one or more unidentified growth factors in PWM-SCM can reverse the
      inhibitory effects of IL-3 on early B lymphocyte development in culture.

PMID- 8647229
TI  - Angiotensin I-converting enzyme (ACE) polymorphism and ABO blood groups as
      factors codetermining plasma ACE activity.
AB  - The activity of serum angiotensin I-converting enzyme (ACE) was measured in 197
      unrelated healthy Caucasian subjects. Plasma ACE activity was correlated with
      sex, ABO blood groups, and ACE insertion/deletion (I/D) polymorphism. Marked
      differences in plasma ACE activity levels were observed both among the blood
      groups and among ACE phenotypes. The corresponding ACE activities were as
      follows: blood group A, 19.45+/-0.96 (mean+/-SE); O, 20.74+/-1.58; B, 26.17+/
      1.40; AB, 24.77+/-1.93 (U/mL: F=4.173; p=0.006983). With ACE genotypes: II,
      16.96+/-1.33; ID, 24.25+/-1.05; DD, 27.14+/-1.20 (U/mL; F=6.359; p=0.002165). No
      difference was observed between men and women. The I/D polymorphism and the ABO
      system turned out to be two independent (additive) factors influencing plasma ACE
      activity. Together, they are responsible for 9.56% of the phenotypic variability
      of ACE. We discuss the role of the ABO system in the known effects of
      glycosylation of proteins.

PMID- 8647230
TI  - Identification of CD34+ subsets after glycoprotease selection: engraftment of
      CD34+Thy-1+Lin- stem cells in fetal sheep.
AB  - Epitopes on the CD34 molecule detected by some CD34 antibodies can be cleaved by
      a unique glycoprotease from Pasteurella haemolytica, which cleaves only
      glycoproteins rich in O-linked glycans. A method to isolate CD34+ cells from
      adult bone marrow was developed subsequently, in which CD34+ cells were isolated
      in high purity and yield following immunomagnetic bead selection and detachment
      with the glycoprotease. Using a variety of other cell-surface markers shown here
      to be insensitive to glycoprotease, committed progenitors of T lymphoid, B
      lymphoid, monomyeloid, megakaryoblastic, or erythroid lineages could be
      identified. Significantly, candidate hematopoietic stem cells (HSC) that are
      contained within a CD34+Lin- (CD2-, CD14-, CD15-, CD16-, CD19-) (or CD34+CD38-)
      subset expressing the Thy-1 antigen (CDw90), c-kit receptor (CD117), and CDw109
      but lacking expression of CD71 and HLA-DR antigens also were detected.
      Functionally distinct subsets of glycoprotease-selected CD34+ cells were
      identified and subfractionated using flow cytometry and fluorescence-activated
      cell sorting (FACS). These subsets included candidate HSCs expressing the
      CD34+Thy-1+Lin- phenotype, which were sorted from a CD34+ fraction of a mobilized
      peripheral blood (MPB) sample. In a fetal sheep model, when CD34+Thy-1+Lin- cells
      were injected intraperitoneally, they were capable of homing to the marrow, where
      they generated long-term multilineage hematopoiesis and maintained human CD34+
      cells, indicating that candidate HSC subsets of CD34+ cells selected with this
      highly specific enzyme were capable of engraftment in vivo. The ability to
      identify and purify virtually any phenotypically defined subset of glycoprotease
      selected CD34+ stem/progenitor cells should facilitate the study of hematopoiesis
      in vitro and in animal models in vivo as well as the development of novel genetic
      techniques for the correction of specific blood cell disorders in humans.

PMID- 8647231
TI  - Assessment of potential doubling time (Tpot), argyrophilic nucleolar organizer
      regions (AgNOR), and proliferating cell nuclear antigen (PCNA) as predictors of
      therapy response in canine non-Hodgkin's lymphoma.
AB  - The predictive potential of several proliferation indices for therapeutic outcome
      was investigated in 55 dogs with spontaneously occurring non-Hodgkin's lymphoma
      (NHL). Indices included potential doubling time (Tpot), argyrophilic nucleolar
      organizer region (AgNOR) frequency, and proliferating cell nuclear antigen
      labeling index (PCNA-LI). All tumors were of intermediate- or high-grade
      histology as assessed by the Working Formulation, and all dogs presented with
      disease of advanced clinical stage. All tumors were treated with an identical
      chemotherapeutic protocol. Tpot determination by a bromodeoxyuridine (BrdU)
      delayed-biopsy technique was readily applied in the dog. AgNOR frequency and PCNA
      LI were easily obtained from archival, formalin-fixed, paraffin-embedded canine
      tissues. When accounting for all other prognostic variables by employing
      multivariate analysis, Tpot (p=0.017), and AgNOR frequency (p=0.021), but not
      PCNA-LI, were predictive of first remission duration. AgNOR frequency (p=0.033)
      was also predictive of survival time, and the predictive potential of Tpot
      approached significance (p=0.076). We conclude that Tpot and AgNOR frequency can
      be used as predictors of outcome in dogs with NHL, and spontaneous NHL in the dog
      may have significant potential as a model for further characterization of the
      association between tumor cell kinetics and chemoresponsiveness.

PMID- 8647232
TI  - Effect of cytokine treatment (granulocyte colony-stimulating factor and stem cell
      factor) on hematopoiesis and the circulating pool of hematopoietic stem cells in
      mice.
AB  - The mobilization of hematopoietic stem cells (HSCs) into the peripheral blood of
      mice was induced by recombinant human granulocyte colony-stimulating factor (rhG
      CSF) (250 microgram/kg/d) alone or combined with recombinant rat stem cell factor
      (rrSCF) (34 microgram/kg/d), injected subcutaneously (s.c.) once a day for 10 and
      17 days. After administering G-CSF plus SCF or G-CSF alone for 10 days, the level
      of day-11 spleen colony-forming units (CFU-S-11) in the peripheral blood
      increased 169- and 93-fold, respectively. The effect was lower--30- and 17-fold-
      after 17 days of treatment. A 1.5- to three-fold decrease in CFU-S-11 content in
      the bone marrow of treated mice was observed. In normal mice, the content of long
      term culture initiating cells (LTC-IC) in blood was below the threshold level.
      Cytokine treatment mobilized LTC-IC in the circulation. Following a 10- and 17
      day course of G-CSF plus SCF, the proliferation of CFU-S-11 in the peripheral
      blood but not in the bone marrow increased from <10% in the controls to 44 and
      72%, respectively, as measured by hydroxyurea (HU) suicide. Spleen-repopulating
      ability (SRA) of CFU-S (daughter CFU-S-8 content in an 11-day-old spleen colony)
      increased two-fold in the peripheral blood after a 10-day course and seven-fold
      after a 17-day course of combined cytokines. One month after the final cytokine
      injection, all hematopoietic indexes (including the number of different
      precursors, their proliferative rate, and their SRA) were near normal. The
      results suggest that the age structure of the mobilized progenitor population
      depends on both the cytokines used and the duration of the treatment: more
      immature CFU-S with higher proliferative activity and an increased SRA were
      mobilized preferentially after a 17-day course of combined cytokines.

PMID- 8647233
TI  - A phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing
      peripheral blood hematopoietic progenitor cells.
AB  - Fourteen patients with stage II-IV breast cancer were enrolled in a phase II
      study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral
      blood progenitor cells (PBPC). All 14 women tolerated PIXY321 well, with the
      predominant toxicities being erythema at the injection site, fever, and
      arthralgias. A median of two aphereses yielded a mean of 1.3 x 10(8) mononuclear
      cells/kg, 8.9 x 10(4) colony-forming units-granulocyte/macrophage (CFU-GM)/kg,
      and 4.5 x 10(6) CD34+ cells/kg. All 14 patients underwent high-dose chemotherapy
      with PBPC support, the median day to ANC >500 cells/microliter was 10.6, and the
      median day to platelets >20,000 cells/microliter was 13. The day of 90th
      percentile platelet recovery was 15. When compared to PBPCs mobilized by
      cyclophosphamide followed by GM-CSF, the use of PIXY321 may confer an advantage
      of enhanced platelet recovery.

PMID- 8647235
TI  - Recombinant human interleukin-3 (rhIL-3) enhances the mobilization of peripheral
      blood progenitor cells by recombinant human granulocyte colony-stimulating factor
      (rhG-CSF) in normal volunteers.
AB  - To identify a precisely timed and safe protocol for progenitor cell mobilization,
      we studied the effects of rhIL-3 and rhG-CSF administration to normal volunteers.
      rhG-CSF 5 micrograms/kg/d was administered subcutaneously (s.c.) for 7
      consecutive days either alone or preceded by rhIL-3 5 micrograms/kg/d s.c. for 4
      consecutive days in sequential or partially overlapping schedules. The combined
      cytokines were well-tolerated--adverse effects were similar to those of the
      individual agents. Total white blood cell (WBC) and neutrophil counts rose
      briskly in response to rhG-CSF, and peak mean values were similar between
      treatment cohorts. Mean platelet counts were modestly elevated during rhG-CSF
      treatment only in the cohorts receiving rhIL-3 and rhG-CSF. Mean circulating
      CD34+ cells peaked on day 5 in the rhG-CSF group (38.9+/-14.3/microliter), day 6
      in the sequential rhIL-3/rhG-CSF group (56.4+/-12.4/microliter), and day 6 in the
      partial overlap group (46.1+/-10.9/microliter). On day 3, mean CD34+ cell counts
      of the subjects who received sequential treatment were markedly higher than
      observed in the other groups (p<0.05) and were estimated to have been sufficient
      for collection of adequate grafts by single 10-L leukapheresis procedures in 60%
      of subjects. Circulating clonogenic cells (CFU-GM and/or BFU-E) were
      substantially higher in the sequential group than the rhG-CSF group on days 3-6
      but were only minimally elevated above baseline in the partial overlap group. The
      numbers of circulating CD34+/Lin-/Thy-1+ cells (putative stem cells) were
      increased substantially, especially in the sequential group. On the basis of this
      pilot trial, we conclude that priming with rhIL-3 is a safe and well-tolerated
      method for enhancing the mobilization of human blood progenitors and stem cells
      by rhG-CSF.

PMID- 8647234
TI  - In vivo analysis of the 'bystander effect': a cytokine cascade.
AB  - The "bystander effect" refers to the death of unmodified tumor cells when in
      contact with ganciclovir (GCV)-exposed, herpes simplex virus-thymidine kinase
      (HSV-TK)-modified tumor cells. Although the exact mechanism or mechanisms
      involved in mediating the bystander effect in vivo are unknown, our findings
      suggest that an intact host immune system is required for the phenomenon to
      occur. The present study was designed to establish the effect of HSV-TK-modified
      tumor cells and GCV on the tumor and its microenvironment in vivo. In sublethally
      irradiated and immunodeficient Balb/c mice, the bystander effect was observed to
      be diminished or abrogated. Histopathologic examination of the tumor mass from
      immunocompetent mice demonstrated centralized hemorrhagic tumor necrosis (38%)
      after inoculation of the HSV-TK-modified tumor cells and GCV in tumor-bearing
      mice compared with the control mice (5%), indicating that cytokines such as tumor
      necrosis factor-alpha (TNF-alpha) were being released locally. This hypothesis
      was underscored using reverse transcriptase polymerase chain reaction (RT-PCR),
      by the demonstration of cytokine mRNA expression in mice treated with HSV-TK
      expressing tumors and GCV. Semiquantitative PCR analysis for TNF-alpha using PCR
      MIMIC on tumor samples from mice treated on days 1 and 4 showed a two-fold
      increase in the level on mRNA expression. Also, immunohistochemical staining for
      TNF-alpha showed that mononuclear inflammatory cells infiltrating the tumor were
      its source. Finally, characterization of tumor-infiltrating lymphocytes (TIL) in
      experimental animals demonstrated a two- to three-fold increase in the number of
      macrophages and T cells compared with control animals. These results demonstrate
      that, in vivo, the bystander effect is mediated in part by an antitumor response
      through the release of cytokines. Further, the cytokine milieu and tumor
      microenvironment can be modulated following injection of HSV-TK cells and GCV to
      enhance the host immune response, which is of potential use in clinical trials.

PMID- 8647236
TI  - Leukopenia and altered hematopoietic activity in mice exposed to the abused
      inhalant, isobutyl nitrite.
AB  - Isobutyl nitrite is representative of a group of inhalants abused primarily by
      male homosexuals; abuse of this drug may be a risk factor for AIDS or Kaposi's
      sarcoma. Using a 14-day exposure regimen, we previously reported that inhaled
      isobutyl nitrite was immunotoxic to mice, severely compromising T-dependent
      antibody responses and cytotoxic T cell and macrophage tumoricidal activity. In
      addition, exposure to the inhalant dramatically reduced spleen cellularity. A
      single 45-minute inhalation exposure produced anemia in mice. In the present
      study, we examined the effects of subchronic exposure to the drug on peripheral
      blood cellularity and hematopoietic activity. Mice were exposed to 900 ppm
      isobutyl nitrite in an inhalation chamber for 45 minutes/day for 14 days. One day
      after the final exposure, the number of peripheral blood leukocytes was reduced
      by 32%; however, the number of erythrocytes was increased by 7%. This was
      accompanied by an apparent shift from myelopoiesis to erythropoiesis. The numbers
      of bone marrow and spleen burst-forming units-erythroid (BFU-E) were increased
      about two-fold, while the numbers of colony-forming units-granulocyte/macrophage
      (CFU-GM) were decreased by about half. Bone marrow stromal cells also had
      reductions in the production of myeloid colony-stimulating activity after
      subchronic exposure to the inhalant. In addition, the numbers of hematopoietic
      stem cells, colony-forming units-spleen (CFU-S), were reduced in both bone marrow
      and spleen. Peripheral blood erythrocyte and leukocyte counts returned to normal
      levels by 7 days after the final exposure, as did the number of BFU-E. The number
      of CFU-GM remained depressed, however, even after 7 days of recovery. These data
      suggest that repeated exposures nonspecifically depleted cells and that
      erythropoiesis was stimulated, apparently at the expense of myelopoiesis.

PMID- 8647238
TI  - Primary structure of desulfoferrodoxin from Desulfovibrio desulfuricans ATCC
      27774, a new class of non-heme iron proteins.
AB  - The primary structure of desulfoferrodoxin from Desulfovibrio desulfuricans ATCC
      27774, a redox protein with two mononuclear iron sites, was determined by
      automatic Edman degradation and mass spectrometry of the composing peptides. It
      contains 125 amino acid residues of which five are cysteines. The first four, Cys
      9, Cys-12, Cys-28 and Cys-29, are responsible for the binding of Center I which
      has a distorted tetrahedral sulfur coordination similar to that found in
      desulforedoxin from D. gigas. The remaining Cys-115 is proposed to be involved in
      the coordination of Center II, which is probably octahedrally coordinated with
      predominantly nitrogen/oxygen containing ligands as previously suggested by
      Mossbauer and Raman spectroscopy.

PMID- 8647237
TI  - Differential regulation of Raf isozymes by growth versus differentiation inducing
      factors in PC12 pheochromocytoma cells.
AB  - PC12 pheochromocytoma cells possess four known MEK activators: A-, B-, c-Raf-1
      and MEKK. In order to examine whether differentiation factors or growth factors
      have a Raf isozyme preference for activation of the mitogenic cytoplasmic Raf-MEK
      MAPK protein kinase cascade, the activation kinetics of these enzymes in response
      to epidermal growth factor (EGF) and nerve growth factor (NGF) were compared. An
      initial activation of all three Raf kinases was noticed, but only A- and B-Raf
      showed sustained activation by NGF, which was not seen after EGF treatment.
      Furthermore, expression of oncogenic versions of all three Raf kinases as well,
      as a potentially Raf-independent MEK activator, v-Mos, leads to activation of
      MAPK and to differentiation of PC12 cells. These data suggest a differential
      regulation of Raf kinases and that probably no alternative Raf substrates are
      involved in differentiation processes of PC12 cells.

PMID- 8647239
TI  - Specific transformation abolishes cyclin D1 fluctuation throughout the cell
      cycle.
AB  - We analysed cyclin D1 mRNA and protein expression in several different cell types
      after separating these cells according to their different cell cycle phases by
      centrifugal elutriation. In normal human and rat fibroblasts cyclin D1 expression
      is high in early to mid G1 and decreases about 6-7 fold before onset of
      replication. It has been demonstrated that specific transforming events, such as
      loss of functional retinoblastoma protein, overexpression of c-myc, and
      transfection with the human papillomavirus oncoproteins E6 and E7 cause
      transcriptional downregulation of cyclin D1 expression in logarithmically growing
      cells. We found that such transformed cells exhibit loss of the cell cycle
      dependent cyclin D1 fluctuation accompanied with reduced upregulation of cyclin
      D1 in G1 phase. The data presented here provide the experimental support for a
      recently suggested model involving the function of the retinoblastoma protein in
      cyclin D1 cell cycle regulation.

PMID- 8647240
TI  - Stimulation of mitogen activated protein kinase by LDL and oxLDL in human U-937
      macrophage-like cells.
AB  - Mitogen activated protein kinase in extracts of U-937 macrophage-like cells was
      stimulated by LDL and oxLDL. A maximum value (161% of the basal
      phosphotransferase activity) was obtained after 6 min exposure to oxidized LDL
      (27 microgram/ml) using APRTPGGRR peptide substrate. The activatory effect was
      more pronounced (LDL 181%, oxLDL 201%) when MAPK of stimulated cells was
      immunoprecipitated with anti-p42MAPK antibodies and phosphotransferase activity
      was assayed in immune complexes. Stimulation produced by oxLDL was inhibited by
      poly I, fucoidan, dextran sulfate and by the MAPKK inhibitor PD 098059 but not by
      PMA-mediated depletion of PKC or by pre-treatment with chloroquine or with
      pertussis toxin. These results suggest a direct mitogenic effect of LDL which, in
      the case of oxLDL, is dependent on scavenger receptor ligation but not on G
      protein mediated or PKC-dependent signal transduction.

PMID- 8647241
TI  - Modified 2S albumins with improved tryptophan content are correctly expressed in
      transgenic tobacco plants.
AB  - Brazil nut 2S albumins lack the essential amino acid tryptophan. In order to
      improve the protein's nutritional value and create a basis for structural
      investigations, three separate modified Brazil nut 2S albumin genes were
      constructed. The first mutant contains five consecutive tryptophan codons, while
      the other two modified genes encode proteins carrying single tryptophan residues
      at sites that will allow confirmation of the predicted protein structure through
      fluorescence quenching techniques. The modified genes, under the regulation of
      the CaMV 35S promoter, were introduced into Nicotiana tabacum. All three modified
      genes were correctly transcribed and the 2S albumin accumulated in the seeds of
      transgenic plants.

PMID- 8647242
TI  - SNAP-25 is differentially expressed by noradrenergic and adrenergic chromaffin
      cells.
AB  - This study examines chromaffin cell expression of the synaptosomal-associated
      protein SNAP-25 in the adrenal medulla by immunoblotting, immunocytochemistry and
      PCR. Both mRNAs coding for the SNAP-25 isoforms a and b were detected and SNAP-25
      was found to be present in all chromaffin cells in adult rat adrenal gland
      sections. It was essentially restricted to a zone close to the cytoplasmic face
      of the plasma membrane in the majority of cells, but located extensively
      throughout the cytoplasm in a chromaffin cell sub-population, identified by
      double immunofluorescence labelling to have a noradrenergic phenotype. This
      differential SNAP-25 expression may reflect different stages in the phenotypic
      development of the sympathoadrenal lineage and be related to an additional
      functional role in noradrenergic chromaffin cells not associated with secretion.

PMID- 8647243
TI  - Stable monomeric form of an originally dimeric serine proteinase inhibitor,
      ecotin, was constructed via site directed mutagenesis.
AB  - Ecotin, a homodimer protein of E. coli, is a unique member of canonical serine
      proteinase inhibitors, since it is a potent agent against a variety of serine
      proteinases having different substrate specificity. Monomers of ecotin are held
      together mostly by their long C-terminal strands that are arranged as a two
      stranded antiparallel beta-sheet in the functional dimer. One ecotin dimer can
      chelate two proteinase molecules, each of them bound to both subunits of ecotin
      at two different sites, namely the specific primary and the non-specific
      secondary binding sites. In this study the genes of wild type ecotin and its
      Met84Arg P1 site mutant were truncated resulting in new forms of ecotin that lack
      10 amino acid residues at their C-terminus. These mutants do not dimerize
      spontaneously, though in combination with trypsin they assemble into the familiar
      heterotetramer. Our data suggest that this heterotetramer exists even in
      extremely diluted solutions, and the interaction, which is responsible for the
      dimerization of ecotin, contributes to the stability of the heterotetrameric
      complex.

PMID- 8647244
TI  - Sucrose protects cell wall invertase but not vacuolar invertase against
      proteinaceous inhibitors.
AB  - Vacuolar (VI) and cell wall invertases (CWI) of higher plants can be inactivated
      in vitro and, possibly, in vivo by proteinaceous inhibitors. The respective
      mechanisms have not yet been compared. Therefore, partially purified CWI from
      transformed tobacco cells and VI from tomato fruit were preincubated with
      invertase-inhibitor fractions isolated from the same tissues. Both inhibitors
      were able to inhibit both invertases. However, VI was fully inhibited within less
      than 1 min by both inhibitors, whereas inactivation of CWI was much slower.
      Furthermore, CWI, but not VI, was strongly protected against inhibition by
      sucrose. A polyclonal antiserum directed against the tobacco inhibitor (I(NT))
      cross-reacted with a 19 kDa polypeptide in the partially purified tomato
      inhibitor (I(LE)) fraction. The results indicate that I(NT) and I(LE)have similar
      structural properties, whereas the mechanism of inactivation is clearly different
      for CWI and VI.

PMID- 8647245
TI  - Noradrenaline inhibition of Ca2+ channels and secretion in single patch-clamped
      insulinoma cells.
AB  - Noradrenaline effects on voltage-operated calcium channels and exocytosis were
      studied, for the first time, in single patch-clamped RINm5F insulin-secreting
      cells. Noradrenaline, despite small and variable inhibition of calcium currents,
      strongly inhibited the increase in membrane capacitance (a measure of exocytosis)
      stimulated by both step depolarizations and the calcium ionophore, ionomycin.
      Noradrenaline similarly inhibited KCl- and ionomycin-induced [3H]serotonin
      release from RINm5F cell populations. Noradrenaline effects were mediated by PTX
      sensitive G proteins. Noradrenaline inhibitory effects on secretion are,
      therefore, mainly exerted downstream from Ca2+ influx.

PMID- 8647246
TI  - Identification of three amino acid residues in the B-chain of platelet-derived
      growth factor with different importance for binding to PDGF alpha- and beta
      receptors.
AB  - The B-chain homodimer isoform of platelet-derived growth factor (PDGF) binds with
      high affinity both to alpha- and to beta-receptors. In order to localize amino
      acid residues in PDGF-BB of differential importance for the binding to the two
      receptors, PDGF-BB mutants were analyzed in which single amino acid residues were
      changed to alanine residues. We found that Phe-118 in loop 1 of the PDGF B-chain
      is crucial for binding to both receptors, and that the surrounding amino acids,
      Asn-117 and Leu-119, appear to be important primarily for binding to the beta
      receptor. In contrast, Lys-161 in loop 3 was found to be more important for
      binding to alpha-receptors than beta-receptors. Previous studies have shown that
      the receptor binding epitope of PDGF-BB is composed mainly of loops 1 and 3; the
      findings of the present study show that the alpha- and beta-receptors interact
      with different amino acid residues in these regions.

PMID- 8647247
TI  - Human guanylate kinase (GUK1): cDNA sequence, expression and chromosomal
      localisation.
AB  - Guanylate kinase (GK) catalyses the conversion of GMP to GTP as part of the cGMP
      cycle. In mammalian phototransduction, this cycle is essential for the
      regeneration of cGMP following its hydrolysis by phosphodiesterase. Mutations in
      different parts of this signalling cascade lead to retinal degeneration in
      humans. Protein studies have localized a locus for GK to a region of human
      chromosome 1 that also contains an autosomal recessive form of retinitis
      pigmentosa (RP12) and Usher's type 11a (USH2A). We report the sequence of this
      human GK (GUK1) and a further refinement of its localization to 1q32-41, placing
      it in the same interval as USH2A.

PMID- 8647248
TI  - First report of the inhibition of arbuscular mycorrhizal infection of Pisum
      sativum by specific and irreversible inhibition of polyamine biosynthesis or by
      gibberellic acid treatment.
AB  - DFMO (alpha-DL-difluoromethylornithine), a specific irreversible inhibitor of
      ornithine decarboxylase (ODC), a polyamine biosynthetic pathway enzyme, strongly
      inhibits root growth and arbuscular mycorrhizal infection of Pisum sativum (P56
      myc+, isogenic mutant of cv. Frisson). This inhibition is reversed when exogenous
      polyamine (putrescine) is included in the DFMO treatment, showing that the effect
      of DFMO on arbuscular mycorrhizal infection is indeed due to putrescine
      limitation and suggesting that ODC may have a role in root growth and mycorrhizal
      infection. However, treatment with gibberellic acid (GA3) which increased root
      titers of polyamines strongly inhibited arbuscular mycorrhizal development. The
      possible role of polyamines in the regulation of the development of arbuscular
      mycorrhizal infection is discussed.

PMID- 8647249
TI  - Gene duplication and the evolution of photosynthetic reaction center proteins.
AB  - We investigate the evolutionary relationships between photosynthetic reaction
      center proteins (D1, D2, L and M) and demonstrate that the pattern of nucleotide
      substitution in these is more complicated than has been assumed in previous
      phylogenetic analyses. We show that there are serious violations of
      methodological assumptions in previous published studies. We conclude that there
      is equal support for hypotheses indicating (i) a single gene duplication of an
      ancestral reaction center protein followed by diversification and (ii) two
      independent gene duplications giving rise to proteins in oxygenic and anoxygenic
      systems.

PMID- 8647250
TI  - CMP-N-acetylneuraminic acid hydroxylase: the first cytosolic Rieske iron-sulphur
      protein to be described in Eukarya.
AB  - Electron paramagnetic resonance (EPR) spectroscopy and analysis of the primary
      structure of the CMP-N-acetylneuraminic acid hydroxylase revealed that this
      enzyme is the first iron-sulphur protein of the Rieske type to be found in the
      cytosol of Eukarya. The dithionite-reduced hydroxylase exhibited an EPR signal
      known to be characteristic for a Rieske iron-sulphur centre (2Fe-2S), the g
      values being 1.78, 1.91 and 2.01, respectively. An analysis of the primary
      structure of the hydroxylase led to the identification of an amino acid sequence,
      known to be characteristic for Rieske proteins. Furthermore, possible binding
      sites for cytochrome b5, the substrate CMP-Neu5Ac and a mononuclear iron centre
      were also identified.

PMID- 8647251
TI  - Inhibition of neutrophil elastase by the alpha1-proteinase inhibitor
      immunoglobulin A complex.
AB  - Neutrophil elastase is thought to be involved in cartilage destruction occurring
      in rheumatoid arthritis despite the local presence of alpha1-proteinase
      inhibitor. Part of synovial fluid alpha1-proteinase inhibitor forms a mixed
      disulfide with immunoglobulin A, which has been postulated to lack inhibitory
      activity. We show here that the immunoglobulin-inhibitor complex tightly inhibits
      neutrophil elastase and cathepsin G, bovine pancreatic trypsin and chymotrypsin,
      and porcine pancreatic elastase. Although the rate constant of inhibition of
      neutrophil elastase by immunoglobulin A-bound alpha1-proteinase inhibitor (k(ass)
      = 9.2 X 10(5) M(-1) x s(-1)) is about 10-fold lower than that measured with the
      free inhibitor, it is high enough to enable efficient inhibition of elastase in
      vivo.

PMID- 8647252
TI  - Circadian rhythm in the Ca(2+)-inhibitable adenylyl activity of the rat striatum.
AB  - In the present study, we demonstrate that the Ca(2+)-inhibitable adenylyl cyclase
      (AC) activity in the striatum exhibits a daily oscillation with a peak occurring
      around 10:00 h. A circadian fluctuation of the AC activity evoked by an A2a
      adenosine-selective agonist was also observed. Intrastriatal injection of an A2a
      selective adenosine agonist or antagonist during the interval in which the Ca(2+)
      inhibitable AC activity was at its peak resulted in a more significant alteration
      of locomotor activity than those observed at a later interval. The marked
      circadian variation in the Ca(2+)-inhibitable AC activity in the striatum appears
      to cause a circadian fluctuation in the action of at least one neuromodulator.

PMID- 8647253
TI  - Shortcut of the photosynthetic electron transfer in a mutant lacking the reaction
      center-bound cytochrome subunit by gene disruption in a purple bacterium,
      Rubrivivax gelatinosus.
AB  - A mutant lacking the reaction center-bound cytochrome subunit was constructed in
      a purple photosynthetic bacterium, Rubrivivax gelatinosus IL144, by inactivation
      of the cytochrome gene. Photosynthetic growth of the C244 mutant strain occurred
      at approximately half the rate of the wild-type strain. Although mutagenesis
      resulted in a greatly reduced amount of membrane-bound cytochromes c,
      illumination induced cyclic electron transfer and the generation of membrane
      potential in the mutant as observed in the wild-type strain. These findings are
      consistent with previous observations that the cytochrome subunit is absent in
      the reaction center complex in some species of purple bacteria and that the
      biochemical removal of the subunit did not significantly affect the in vitro
      electron transfer from the soluble cytochrome c to the photosynthetic reaction
      center. These results suggest that the cytochrome subunit in purple bacteria is
      not essential for photosynthetic electron transfer and growth, even in those
      species generally containing the subunit.

PMID- 8647254
TI  - Ancient divergence of long and short isoforms of adenylate kinase: molecular
      evolution of the nucleoside monophosphate kinase family.
AB  - Adenylate kinases (AK) from vertebrates are separated into three isoforms, AK1,
      AK2 and AK3, based on structure, subcellular localization and substrate
      specificity. AK1 is the short type with the amino acid sequence being 27 residues
      shorter than sequences of the long types, AK2 and AK3. A phylogenetic tree
      prepared for the AK isozymes and other members of the nucleoside monophosphate
      (NMP) kinase family shows that the divergence of long and short types occurred
      first and then differentiation in subcellular localization or substrate
      specificity took place. The first step involved a drastic change in the three
      dimensional structure of the LID domain. The second step was caused mainly by
      smaller changes in amino acid sequences.

PMID- 8647255
TI  - Characterization of the interaction between RhoA and the amino-terminal region of
      PKN.
AB  - The yeast two-hybrid system and in vitro binding assay were carried out to
      characterize the interaction between PKN and a small GTP-binding protein, RhoA.
      It was revealed that the region corresponding to the amino acid residues 33-111
      in the amino-terminal region of PKN was sufficient to confer the ability to
      associate with RhoA. Each synthetic peptide fragment corresponding to the amino
      acid residues 74-93 and 94-113 of PKN inhibited the interaction between PKN and
      RhoA in the in vitro binding assay, suggesting that this region is important in
      the association with RhoA. The endogenous and the GAP-stimulated GTPase activity
      of RhoA was inhibited by the interaction with PKN, suggesting the presence of a
      regulatory mechanism that sustains the GTP-bound active form of RhoA.

PMID- 8647256
TI  - Identification and immunohistochemical localization of macrophage migration
      inhibitory factor in human cornea.
AB  - We identified macrophage migration inhibitory factor (MIF) mRNA expression in
      human cornea, and demonstrated its immunohistological localization. Reverse
      transcription-polymerase chain reaction analysis revealed that MIF mRNA was
      expressed in both the corneal epithelial and endothelial cells.
      Immunohistochemical study using the polyclonal antibody prepared from immunizing
      a rabbit with human recombinant MIF showed that MIF was present in the basal
      cells of corneal epithelium and endothelial cells. The fact that MIF exists in
      those cells of the cornea indicates that MIF may play an important role in
      corneal cell immunity and cellular differentiation.

PMID- 8647257
TI  - An SH3 domain-mediated interaction between the phagocyte NADPH oxidase factors
      p40phox and p47phox.
AB  - The phagocyte NADPH oxidase is activated during phagocytosis to produce
      superoxide, following assembly of a membrane-integrated cytochrome b558 with
      cytosolic proteins, p47phox, p67phox and p40phox, each containing Src homology 3
      (SH3) domains. While both p47phox and p67phox are indispensable for the oxidase
      activity, role of p40phox remains obscure. Here we study interaction between
      p40phox and p47phox by two independent methods, a two-hybrid system in the yeast
      and an in vitro binding assay using purified proteins. The present results show
      that the interaction is mediated via binding of the SH3 domain of p40phox to a C
      terminal proline-rich region of p47phox. This proline-rich region is also the
      target for binding of p67phox, and the SH3 domain of p40phox can inhibit the
      binding of the C-terminal one of p67phox to p47phox.

PMID- 8647258
TI  - Glucose catabolism in cancer cells: regulation of the Type II hexokinase promoter
      by glucose and cyclic AMP.
AB  - The increased glucose consumption of many tumor cells depends to a large extent
      on the overexpression of hexokinase Type II. In a previous study we isolated and
      sequenced the hepatoma Type II hexokinase promoter and showed that it is
      activated by glucose in the highly glycolytic AS-30D hepatoma cell line under
      study, but not activated in control hepatocytes [Mathupala, S.P., Rempel, A. and
      Pedersen, P.L. (1995) J. Biol. Chem. 270, 16918-16925]. Here we report that the
      promoter of the hexokinase Type II gene is maximally activated by glucose at
      concentrations above 5 mM. Moreover, the data strongly suggest that glucose can
      act alone without requirement for metabolism. Also, glucose-mediated promoter
      activation is markedly potentiated by cAMP. This response may serve as a strategy
      for cancer cells to maintain the hexokinase transcription rate high to ensure an
      efficient glucose utilization even under conditions where carbohydrates are
      limiting.

PMID- 8647259
TI  - Cell surface binding and activation of gelatinase A induced by expression of
      membrane-type-1-matrix metalloproteinase (MT1-MMP).
AB  - Gelatinase A is secreted as a proenzyme (progelatinase A) which is activated and
      bound on the surface of tumor and normal cells. We have reported that the
      expression of a membrane-type-1-matrix metalloproteinase (MT1-MMP) induces
      activation of progelatinase A. Here we demonstrate that the expression of MT1-MMP
      in COS-1 cells induces cell-surface binding of progelatinase A which is
      consequently processed to an intermediate form. Processing from the intermediate
      to the fully active form is dependent on the gelatinase A concentration. These
      results suggest that the cell-surface binding concentrates the gelatinase A
      intermediate form locally to allow autoproteolytic processing to the fully active
      form.

PMID- 8647261
TI  - Commentary on: 'Thermostability of beta-xylosidase from Aspergillus sydowii MG49'
      by M. Ghosh and G. Nanda, FEBS Letters 330, 275-278 (1993)

PMID- 8647260
TI  - Site-directed mutagenesis but not gamma-carboxylation of Glu-35 in factor VIIa
      affects the association with tissue factor.
AB  - Factor VIIa is a vitamin K-dependent enzyme whose gamma-carboxyglutamic acid
      (Gla)-containing domain is important for calcium ion-dependent binding to the
      cofactor tissue factor and membrane surfaces. This domain contains 10 Gla
      residues, the individual roles and importance of which are not known. Comparisons
      with the homologous protein C, factor IX and prothrombin may provide functional
      information on the first nine Gla residues, whereas no data can be extrapolated
      to Gla-35 in factor VIIa. Therefore, the effects of posttranslational gamma
      carboxylation and site-directed mutagenesis of Glu-35 were investigated.
      Mutations to Asp, Gln or Val all lead to a lower affinity for tissue factor by
      decreasing the rate of association, in the case of the Val mutant by a factor of
      200, as measured by surface plasmon resonance. In contrast, Glu or Gla side
      chains at position 35 appear to fulfil the functional roles equally well.

PMID- 8647262
TI  - RNGB: a Dictyostelium RING finger protein that is specifically located in
      maturing spore cells.
AB  - The RING finger is a form of zinc finger motif found in proteins of widely
      varying biological function. The Dictyostelium RNGB protein contains a RING
      finger and also a K-box, a sequence motif found in several plant homeotic
      proteins. The rngB mRNA is present at low concentration in growing cells and
      gradually increases in abundance throughout development. However, the RNGB
      protein is not detected until culmination and we present evidence that suggests
      it is translationally regulated. The protein is specifically localised in
      maturing spore cells and is cytoplasmic, suggesting that the RING finger does not
      function as a DNA binding domain.

PMID- 8647263
TI  - Phosphorylation of the N-terminal domain of Xenopus TATA-box binding protein by
      DNA-dependent protein kinase depends on the C-terminal core domain.
AB  - DNA-dependent protein kinase (DNA-PK) has been shown to phosphorylate several
      transcription factors in vitro, suggesting that this nuclear enzyme - in addition
      to its role in DNA repair and recombination - may be involved in transcriptional
      regulation. In the typical mechanism the DNA-bound kinase phosphorylates a
      substrate that is bound to the same DNA molecule. Here I report that the Xenopus
      TATA-box binding protein (xTBP) is hyperphosphorylated by DNA-PK in vitro. The
      phosphorylation is in the N-terminal domain of the protein but depends fully on
      the presence of the C-terminal core domain.

PMID- 8647264
TI  - Ligation of CD40 rescues Ramos-Burkitt lymphoma B cells from calcium ionophore-
      and antigen receptor-triggered apoptosis by inhibiting activation of the cysteine
      protease CPP32/Yama and cleavage of its substrate PARP.
AB  - The new and growing family of interleukin-1beta-converting enzyme (ICE) cysteine
      proteases are now recognised to be major effectors of cellular death by
      apoptosis. Like other members of this family, the CPP32/Yama proform is activated
      by processing to its active heterodimeric enzyme or apopain when it likely
      contributes to the process of apoptosis by cleaving poly(ADP-ribose) polymerase
      (PARP) and thereby inhibiting much of its DNA repair activity. Apoptosis plays a
      fundamental role in the regulation of the immune system where it is involved in
      the selection of both T and B lymphocytes bearing antigen receptor (AgR) for non
      self. Cells of the Ramos Epstein-Barr virus (EBV)-genome-negative Burkitt
      lymphoma (BL) B cell line (Ramos-BL) can be triggered into growth arrest and
      apoptosis by treating with the calcium ionophore ionomycin or by crosslinking
      their surface AgR with antibodies directed against immunoglobulin (Ig)M (anti
      IgM). Ionomycin- and AgR-triggered growth arrest and apoptosis are arrested by
      signals transduced through the surface CD40 of Ramos-BL B cells. Both ionomycin
      and anti-IgM trigger activation of CPP32 and cleavage of PARP prior to the onset
      of apoptosis; this process is abrogated by treatment with anti-CD40 and is
      independent of Bcl-2 expression. A tripeptide inhibitor of ICE family cysteine
      proteases, Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) inhibits ionomycin- and
      AgR-triggered CPP32 activation, PARP cleavage and apoptosis, but not growth
      arrest, in Ramos-BL B cells. Thus, in this report we demonstrate that in a
      physiological system, activation of endogenous members of the ICE family,
      including CPP32, and cleavage of the death substrate PARP act as major effectors
      of apoptotic death.

PMID- 8647265
TI  - Intracellular free Ca2+ dynamic changes to histamine are reduced in cystic
      fibrosis human tracheal gland cells.
AB  - This study documents a difference between cystic fibrosis human (CF-HTG) and
      normal human (HTG) tracheal gland cells: the ability of histamine to induce an
      increase of intracellular free calcium concentration [Ca2+]i was abnormally
      reduced in CF-HTG cells. The magnitude of the [Ca2+]i peak rise in response to
      histamine is smaller in CF-HTG cells than in HTG cells, and the percentage of CF
      HTG cells that increase [Ca2+]i is decreased compared with HTG cells. In contrast
      to histamine, the human neutrophil elastase (HNE) stimulation of both CF-HTG and
      HTG cells generated [Ca2+]i asynchronous oscillations and the magnitude of the
      peak [Ca2+]i response as well as the percentage of responding cells were similar
      for both groups. By videomicroscopy observations, the secretory response
      (exocytosis of secretion granules) of CF-HTG cells occurred with HNE, but not
      with histamine, thus suggesting that [Ca2+]i asynchronous oscillations may be
      linked to the exocytosis process in human tracheal gland cells.

PMID- 8647266
TI  - Molecular structure and genetic mapping of the mouse gastrin gene.
AB  - The mouse gastrin gene has three exons totalling 460 bp and a deduced
      preprogastrin of 101 amino acids. The sequence of murine gastrin-34 is 94%
      identical to rat gastrin-34 and 76% identical to human gastrin-34. At Arg79,
      mouse progastrin has a unique cleavage site that might allow species-specific
      synthesis of gastrin-13. Northern analysis and RT-PCR demonstrated that gastrin
      gene transcripts are abundant in mouse stomach and duodenum and present at low
      levels in brain, ovary and pancreas, similar to the pattern described for other
      mammals. The gastrin gene was mapped to the distal region of mouse chromosome 11.

PMID- 8647267
TI  - Substrate residues N-terminal to the cleavage site of botulinum type B neurotoxin
      play a role in determining the specificity of its endopeptidase activity.
AB  - Clostridium botulinum type B neurotoxin is a highly specific zinc-endopeptidase
      which cleaves vesicle-associated membrane protein (VAMP/synaptobrevin), a
      critical component of the vesicle docking/fusion mechanism. In this study,
      substrate residues flanking the N-terminal side of the cleavage site are shown to
      play a key role in enzyme substrate recognition. Two aspartate residues in this
      region are identified as critical determinants of the neurotoxin's specificity.
      These findings are discussed in relation to the mechanism by which botulinum type
      B neurotoxin cleaves its substrate.

PMID- 8647268
TI  - Botulinum neurotoxin light chains inhibit both Ca(2+)-induced and GTP analogue
      induced catecholamine release from permeabilised adrenal chromaffin cells.
AB  - Using digitonin-permeabilised bovine adrenal chromaffin cells, the effects of
      botulinum neurotoxin light chains on exocytosis triggered by Ca2+ or by GppNHp
      were examined. Botulinum neurotoxin D light chain, prepared as a His(6)-tagged
      recombinant protein, cleaved VAMP and substantially inhibited catecholamine
      release due to Ca2+ and GppNHp. Botulinum neurotoxin C1 and E light chains
      produced partial inhibition of both Ca(2+)- and GppNHp-induced catecholamine
      release. These results suggest that Ca(2+)-dependent exocytosis and Ca(2+)
      independent exocytosis triggered by a non-hydrolysable GTP analogue occurs via a
      SNARE-dependent mechanism in chromaffin cells.

PMID- 8647269
TI  - Flow cytometry analysis of alpha1-adrenoceptor subtypes.
AB  - To characterize the alpha1-adrenoceptor subtypes, we developed a flow cytometry
      method using the fluorescent ligand BODIPY-FL prazosin and the anti-peptide
      antibody against the alpha1b-adrenoceptor amino terminus (designated 1B-N1-C) as
      probes. Three alpha1-adrenoceptors (alpha1a, alpha1b and alpha1d) expressed in
      CHO cells were detected by BODIPY-FL prazosin; however, only alpha1b-adrenoceptor
      subtype was detected by the anti-peptide antibody 1B-N1-C. Furthermore, the flow
      cytometry analysis with 1B-N1-C specifically identified alpha1b-adrenoceptor in
      native cells of hamster DDT1-MF2 cells, rat hepatocytes and cardiomyocytes.

PMID- 8647270
TI  - Keratin 9 point mutation in the pedigree of epidermolytic hereditary palmoplantar
      keratoderma perturbs keratin intermediate filament network formation.
AB  - Keratins form an intracellular keratin filament network in keratinocytes. Point
      mutations in the epidermal keratins could lead to the disruption of keratin
      filament formation, developing skin diseases such as epidermolytic hereditary
      palmoplantar keratoderma (EHPPK). We found a G to A transition in keratin 9 (K9)
      cDNA, resulting in the substitution of glutamine for arginine at 162, in all
      patients of a pedigree of EHPPK. Transfection into MDCK cells and DJM-1 cells
      revealed that the plasmid CMX vector containing normal keratin 9 cDNA showed
      normal keratin network formation, whereas the vector with a G to A point mutated
      keratin 9 cDNA showed disrupted keratin filaments with droplet formation in the
      cells. These results indicate that the point mutation seen in our patients had a
      dominant-negative effect on keratin network formation.

PMID- 8647271
TI  - Molecular characterization of a new urea transporter in the human kidney.
AB  - A cDNA clone (HUT2) sharing 61.1% and 89.9% sequence identity with the human
      erythroid (HUT11) and the rabbit (UT2) urea transporters, respectively, was
      isolated by homology cloning from a human kidney library. HUT2 transcripts were
      restricted to the kidney and the HUT2 polypeptide was not immunoprecipitated with
      blood group Kidd-related antibodies (anti-Jk3) in coupled transcription
      translation assays. Functional expression studies in Xenopus oocytes demonstrated
      that HUT2-mediated urea transport was not inhibited by p-chloromercuribenzene
      sulfonate (pCMBS) which, however, inhibited the urea flux mediated by HUT11.
      These findings demonstrate that at least two distinct urea transporters are
      present in human tissues. By in situ hybridization, the gene encoding HUT2 has
      been assigned to chromosome 18q12.1-q21-1, as found previously for the Kidd/urea
      transporter HUT11, suggesting that both genes evolved from duplication of a
      common ancestor.

PMID- 8647272
TI  - The vacuolar ATPase proton pump is required for the cytotoxicity of Bacillus
      anthracis lethal toxin.
AB  - The nature of the cytopathic effect exerted by the lethal factor toxin (LF) of
      Bacillus anthracis on sensitive cells is unknown. The toxin requires the passage
      through acidic vesicles in order to exert its effect within the cytosol. Here, we
      show that bafilomycins and concanamycin A, selective inhibitors of the vacuolar
      ATPase proton pump, are the most powerful known inhibitors of LF macrophage
      toxicity. These inhibitors are fully active long after LF addition to
      macrophages, suggesting that LF enters the cytosol after having reached a late
      endosomal compartment.

PMID- 8647273
TI  - Prostaglandin E receptor EP3gamma isoform, with mostly full constitutive Gi
      activity and agonist-dependent Gs activity.
AB  - We recently demonstrated that two exclusively Gi-coupled isoforms of the mouse
      EP3 receptor, EP3alpha and beta, with different carboxyl-terminal tails, differed
      in agonist-independent constitutive Gi activity, and the carboxyl-terminal tail
      truncated receptor showed full constitutive activity (Hasegawa, H., Negishi, M.,
      and Ichikawa, A. (1996) J. Biol. Chem. 271, 1857-1860). Here we further examined
      Gi and Gs activities of the third isoform, EP3gamma, coupled to both Gi and Gs.
      The My receptor showed mostly full constitutive Gi activity and agonist-dependent
      Gs activity. The truncated receptor also showed agonist-dependent Gs activity,
      but the level was lower than that of the EP3gamma receptor. Thus, the carboxyl
      terminal tail would differentially regulate Gi and Gs activities of the EP3
      receptor.

PMID- 8647275
TI  - Fractionation of carbon (13C/12C) isotopes in glycine decarboxylase reaction.
AB  - Fractionation of carbon isotopes (13C/12C) by glycine decarboxylase (GDC) was
      investigated in mitochondrial preparations isolated from photosynthetic tissues
      of different plants (Pisum, Medicago, Triticum, Hordeum, Spinacia, Brassica,
      Wolffia). 20 mM glycine was supplied to mitochondria, and the CO2 formed was
      absorbed and analyzed for isotopic content. CO2 evolved by mitochondria of Pisum
      was enriched up to 8% in 12C compared to the carboxylic atom of glycine. CO2
      evolved by mitochondria of the other plants investigated was enriched by 5-16% in
      13C. Carbon isotope effects were sensitive to reaction conditions (pH and the
      presence of GDC cofactors). Theoretical treatment of the reaction mechanism
      enabled us to conclude that the value and even the sign of the carbon isotope
      effect in glycine decarboxylation depend on the contribution of the enzyme
      substrate binding step and of the decarboxylation step itself to the overall
      reaction rate. Therefore, the fractionation of carbon isotopes in GDC reaction
      was revealed which provides essential isotopic effects in plants in addition to
      the well-known effect of carbon isotope fractionation by the central
      photosynthetic enzyme, ribulose-1,5-biphosphate carboxylase.

PMID- 8647274
TI  - Fibrillin: evidence that chondroitin sulphate proteoglycans are components of
      microfibrils and associate with newly synthesised monomers.
AB  - We have investigated the potential association of proteoglycans with intact
      fibrillin-containing microfibrils from foetal bovine elastic tissues and with
      newly synthesised fibrillin in human and bovine cell cultures. Microfibril
      integrity was disrupted by chondroitinase ABC lyase and chondroitinase AC lyase,
      but not by keratanase or hyaluronidase. Following chondroitinase treatment, beads
      were disrupted but the underlying fibrillar scaffold appeared intact. Cuprolinic
      blue was prominently associated with beaded domains at a critical electrolyte
      concentration. Electron-dense rods were often associated with cuprolinic blue
      treated microfibrils isolated from fixed tissues. Positive staining revealed
      charged foci at the beads. Newly synthesised fibrillin could be labelled with 35S
      TransLabel, [3H]glucosamine or 35SO4 but its electrophoretic mobility was not
      influenced by treatment with chondroitinase ABC or AC lyase. A diffuse 35SO4
      labelled chondroitinase-sensitive component with a resistant band (Mr 35000) co
      immunoprecipitated with fibrillin. These experiments indicate that chondroitin
      sulphate proteoglycans associate with fibrillin and contribute to microfibril
      assembly. This association has major implications for microfibril function in
      health and disease.

PMID- 8647276
TI  - RpoS-dependent regulation of genes expressed at late stationary phase in
      Escherichia coli.
AB  - We have identified 6 Escherichia coli genomic genes, including 4 new genes,
      responsive to the stationary phase. One of them was regulated positively by RpoS
      at the stationary phase, and the remaining 5 negatively at a late stationary
      phase, all of them responding to multiple environmental stresses. Nucleotide
      sequences as well as such multiple responses revealed that those genes may have
      more than one overlapping-promoter recognized by different sigma-factors which
      regulate gene expressions during their cell growth.

PMID- 8647277
TI  - Possible nystatin-protein interaction in yeast plasma membrane vesicles in the
      presence of ergosterol. A Forster energy transfer study.
AB  - The Forster energy transfer from tryptophan residues of membrane proteins to
      nystatin was measured in reconstituted yeast plasma membrane vesicles free of, or
      doped with, ergosterol. We wanted to elucidate whether the functional change of
      membrane transport proteins from H+ symporters to facilitators, observed in
      ergosterol-containing plasma membrane vesicles on addition of nystatin [Opekarova
      and Tanner (1994) FEBS Lett. 350, 46-50], is reflected in altered protein
      nystatin relations within the membrane. Both frequency-domain and time-domain
      time-resolved fluorescence spectroscopy showed that in the presence of ergosterol
      nystatin is located much closer to membrane proteins than in its absence.

PMID- 8647278
TI  - Protein kinase C and F-actin are essential for stimulation of neuronal FAK
      tyrosine phosphorylation by G-proteins and amyloid beta protein.
AB  - Focal adhesion kinase (FAK) is a protein tyrosine kinase implicated in signal
      transduction pathways for integrins, neuropeptides, and lysophosphatidic acid.
      FAK, first discovered in non-neuronal cells, recently has been reported to occur
      in neurons, where its tyrosine phosphorylation is upregulated by fibronectin and
      by the Alzheimer's Abeta peptide. The current work has elucidated molecular
      events leading to tyrosine phosphorylation of FAK in the rat B103 CNS nerve cell
      line. Activation of receptor-coupled G-proteins by Mas-7 was found to evoke rapid
      upregulation of FAK tyrosine phosphorylation (Tyr(P)). Upregulation by Mas-7 was
      blocked by GF109203X, a potent inhibitor of protein kinase C (PKC). Phorbol ester
      also upregulated FAK-YP, verifying a role for PKC in the transduction cascade.
      Upregulation of FAK-YP by activation of G-proteins and PKC was dependent upon
      intact F-actin, as cytochalasin D abolished stimulation by Mas-7 and by phorbol
      ester. The relatively slow increase in FAK-YP evoked by chronic exposure to Abeta
      also was abolished by GF109203X and by cytochalasin D. The results show that
      tyrosine phosphorylation of FAK in neurons is regulated positively by PKC,
      functioning down-stream from G-proteins through an F-actin-dependent mechanism.
      The Alzheimer's Abeta peptide is capable of activating elements of this same
      signal transduction pathway, via membrane events that remain to be determined.

PMID- 8647279
TI  - Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1
      (EAAT-1): gene structure and localization to chromosome 5p11-p12.
AB  - The gene of the human L-glutamate transporter hGLAST-1 (EAAT-1) has been isolated
      and characterized. The 1626 bp cDNA open reading frame (542 aa) is distributed
      over ten exons and at least 85 kb on chromosome 5p11-p12. The gene is unrelated
      to any other previously described neurotransmitter transporter gene family, but
      its exon/intron structure corresponds largely to that of the Na(+)-dependent
      neutral amino acid transporter ASCT-1. GLAST-1, ASCT-1 and the glutamate
      transporters GLT-1 and EAAC-1 have strongly similar amino acid sequences. The L
      glutamate transporter gene structures might help to understand the correlation of
      L-glutamate reuptake in neurodegenerative disorders.

PMID- 8647280
TI  - The design of an alternative, covalently flavinylated 6-hydroxy-D-nicotine
      oxidase by replacing the FAD-binding histidine by cysteine and reconstitution of
      the holoenzyme with 8-(methylsulfonyl)FAD.
AB  - The cofactor of several flavoenzymes is autocatalytically bound to the
      polypeptide via a histidyl(N3)-(8alpha)-FAD linkage which makes the generation of
      apoenzyme difficult. We introduced an alternative covalent protein-FAD bond at
      the active site of 6-hydroxy-D-nicotine oxidase (6HDNO) by replacing the FAD
      binding histidine with cysteine. The resulting mutant enzyme was expressed with
      noncovalently attached cofactor. Incubation with 8-(methylsulfonyl)FAD, and less
      efficiently with 8-chloro-FAD, resulted in the spontaneous replacement of the
      noncovalently bound FAD by the flavin derivative and the formation of an 8-(N
      acetylcysteinyl)FAD linkage. The flavinylated 6HDNO.cys exhibited close to wild
      type activity levels. This strategy may be generally applicable to the attachment
      of artificially designed flavin derivatives to the active site of covalently
      flavinylated enzymes.

PMID- 8647281
TI  - Very low density lipoprotein receptor binds apolipoprotein E2/2 as well as
      apolipoprotein E3/3.
AB  - The VLDL receptor, a newly identified lipoprotein receptor, recognizes apoE
      containing lipoproteins. The human VLDL receptor was overexpressed in 1d1A-7, a
      mutant Chinese hamster ovary cells lacking LDL receptors. Each VLDL obtained from
      a normolipidemic subject with two epsilon3 or epsilon2 alleles similarly competed
      for the binding of radiolabeled rabbit beta-VLDL to the VLDL receptors. The anti
      apoE monoclonal antibody 1D7, which inhibited binding of apoE3 to the LDL
      receptors, failed to compete for the binding of VLDL (apoE3 or apoE2) to the VLDL
      receptors. Results indicate that the binding site of apoE on the VLDL receptor
      may differ from its binding site on the LDL receptor.

PMID- 8647282
TI  - Limulus kexin: a new type of Kex2-like endoprotease specifically expressed in
      hemocytes of the horseshoe crab.
AB  - A Kex2-like protease was identified in hemocytes of the horseshoe crab
      (Tachypleus tridentatus), named limulus kexin, and a full-length cDNA was
      obtained from a hemocyte cDNA library. The deduced amino acid sequence contains
      752 residues, composed of five domains with a signal sequence, a propeptide, a
      catalytic domain, a Ser/Thr-rich domain, and a transmembrane domain. The domain
      organization is very similar to that of the yeast Kex2 except that limulus kexin
      does not have a cytoplasmic tail. The catalytic domain exhibits striking sequence
      identities with those of furins, especially Drosophila furin1 (79%). Northern
      blotting showed specific expression of limulus kexin in hemocytes, suggesting the
      involvement in proteolytic processing of the granule components of hemocytes.

PMID- 8647283
TI  - VDAC/porin is present in sarcoplasmic reticulum from skeletal muscle.
AB  - In this study we demonstrate the existence of a protein with properties of the
      voltage-dependent anion channel (VDAC) in the sarcoplasmic reticulum (SR) using
      multiple approaches as summarized in the following: (a) 35 and 30 kDa proteins in
      different SR preparations, purified from other membranal systems by Ca2+/oxalate
      loading and sedimentation through 55% sucrose, cross-react with four different
      VDAC monoclonal antibodies. (b) Amino acid sequences of three peptides derived
      from the SR 35 kDa protein are identical to the sequences present in VDAC1
      isoform. (c) Similar to the mitochondrial VDAC, the SR protein is specifically
      labeled by [14C]DCCD. (d) Using a new method, a 35 kDa protein has been purified
      from SR and mitochondria with a higher yield for the SR. (e) Upon reconstitution
      into a planar lipid bilayer, the purified SR protein shows voltage-dependent
      channel activity with properties similar to those of the purified mitochondrial
      VDAC or VDAC1/porin 31HL from human B lymphocytes, and its channel activity is
      completely inhibited by the anion transport inhibitor DIDS and about 80% by DCCD.
      We also demonstrate the translocation of ATP into the SR lumen and the
      phosphorylation of the luminal protein sarcalumenin by this ATP. Both ATP
      translocation and sarcalumenin phosphorylation are inhibited by DIDS, but not by
      atractyloside, a blocker of the ATP/ADP exchanger. These results indicate the
      existence of VDAC, thought to be located exclusively in mitochondria, in the SR
      of skeletal muscle, and its possible involvement in ATP transport. Together with
      recent studies on VDAC multicompartment location and its dynamic association with
      enzymes and channels, our findings suggest that VDAC deserves attention and
      consideration as a protein contributing to various cellular functions.

PMID- 8647284
TI  - Kir2.2v: a possible negative regulator of the inwardly rectifying K+ channel
      Kir2.2.
AB  - We have cloned the human genes encoding the inwardly rectifying K+ (Kir) channel
      subunits, Kir2.2 (hKir2.2) and its variant, termed hKir2.2v. When expressed in
      Xenopus oocytes, hKir2.2 produced strong inwardly rectifying K+ currents, whereas
      the expression of hKir2.2v did not elicit significant currents. Coexpression of
      hKir2.2v with hKir2.2 showed an hKir2.2v inhibition of hKir2.2 K+ currents,
      indicating that it acts as a negative regulator of hKir2.2 channel activity.
      Mutational analysis of hKir2.2v and studies of chimeras between hKir2.2 and
      hKir2.2v suggest that the intracellular C-terminal region of hKir2.2v
      participates in the negative regulation of the hKir2.2v channel activity.

PMID- 8647285
TI  - The cloning, expression and crystallisation of a thermostable arginase.
AB  - The gene for the thermostable arginase from the thermophilic bacterium 'Bacillus
      caldovelox' has been cloned and sequenced. Expression of recombinant arginase at
      high levels has been achieved in E. coli using an inducible T7 RNA polymerase
      based system. A facile purification procedure incorporating a heat-treatment step
      yielded 0.2 g of recombinant arginase per litre of induced culture. The kinetic
      properties of the purified recombinant protein are essentially identical to the
      native enzyme. The recombinant protein has been crystallised and one crystal form
      is isomorphous to crystals of the native protein.

PMID- 8647287
TI  - Differential display PCR reveals increased expression of 2',3'-cyclic nucleotide
      3'-phosphodiesterase by lithium.
AB  - Differential display PCR was used to study the effects of lithium on gene
      expression. Four candidate genes were isolated and verified by Northern
      hybridization after 1 week treatment of C6 glioma cells with therapeutically
      relevant concentrations of LiCl (1 mM). Sequencing analysis revealed three
      previously unidentified cDNA fragments in addition to a sequence with 99%
      homology with the cDNA for 2',3'-cyclic nucleotide 3'-phosphodiesterase type II
      (CNPaseII). Since CNPaseII is important in myelinogenesis and possibly neuronal
      growth and repair, the present findings suggest that lithium treatment may
      regulate these processes.

PMID- 8647286
TI  - Cloning of a melatonin-related receptor from human pituitary.
AB  - We have cloned an orphan G protein-coupled receptor from a human pituitary cDNA
      library using a probe generated by PCR. The cDNA, designated H9, encodes a
      protein of 613 amino acids that is 45% identical at the amino acid level to the
      recently cloned human Mel(1a) and Mel(1b) melatonin receptors. Structural
      analyses of the encoded protein and its gene, along with phylogenetic analysis,
      further show that H9 is closely related to the G protein-coupled melatonin
      receptor family. Unusual features of the protein encoded by H9 include a lack of
      N-linked glycosylation sites and a carboxyl tail >300 amino acids long. H9
      transiently expressed in COS-1 cells did not bind [125I]melatonin or
      [3H]melatonin. H9 mRNA is expressed in hypothalamus and pituitary, suggesting
      that the encoded receptor and its natural ligand are involved in neuroendocrine
      function.

PMID- 8647288
TI  - Tyrosine phosphorylation of ACK in response to temperature shift-down,
      hyperosmotic shock, and epidermal growth factor stimulation.
AB  - The mammalian Cdc42 protein regulates various kinds of cellular responses,
      including formation of filopodia, polarization of T cells, and cell cycle
      progression. A non-receptor tyrosine kinase ACK, which specifically binds to the
      GTP-bound form of Cdc42, was isolated as a putative target of Cdc42. Here we show
      the induction of tyrosine phosphorylation of ACK in response to temperature shift
      down to 25 degrees C, and hypertonic shock, as well as stimulation with epidermal
      growth factor (EGF) in human embryonic kidney (HEK) 293 cells. The increased
      tyrosine phosphorylation level upon temperature shift-down was sustained for at
      least 60 min, whereas reversion of the temperature to 37 degrees C caused rapid
      tyrosine dephosphorylation to the initial level. The responses to EGF and the
      high osmolarity were transient. Furthermore, we observed association of ACK with
      an adaptor protein Grb2, which may suggest the involvement of Grb2 in EGF
      receptor-mediated tyrosine phosphorylation of ACK.

PMID- 8647289
TI  - Deletion of the ATH1 gene in Saccharomyces cerevisiae prevents growth on
      trehalose.
AB  - The biological function of the yeast trehalases (EC 3.2.1.28) consists of down
      regulation of the concentration of trehalose via glucose formation by trehalose
      hydrolysis. While it is generally accepted that the cytosolic neutral trehalase
      (encoded by the NTH1 gene) is responsible for trehalose hydrolysis in intact
      cells, very little is known about a role of the vacuolar acid trehalase and the
      product of the recently described neutral trehalase gene YBRO106 (NTH2). We have
      analyzed the role of the acid trehalase in trehalose hydrolysis using the ATH1
      deletion mutant (delta ath1) of Saccharomyces cerevisiae [M. Destruelle et al.
      (1995) Yeast 11, 1015-10251 deficient in acid trehalase activity under various
      nutritional conditions. In contrast to wild-type and a mutant deficient in the
      neutral trehalase (delta nth1), the delta ath1 mutant does not grow on trehalose
      as a carbon source. Experiments with diploid strains heterozygous for delta ath1
      show a gene dosage effect for the ATH1 gene for growth on trehalose. The need for
      acid trehalase for growth on trehalose is supported by the finding that acid
      trehalase activity is induced during exponential growth of cells on trehalose
      while no such induction is measurable during growth on glucose. Our results show
      that the vacuolar acid trehalase Ath1p is necessary for the phenotype of growth
      on trehalose, i.e. trehalose utilization, in contrast to cytosolic neutral
      trehalase Nth1p which is necessary for intracellular degradation of trehalose.
      For explanation of the need for vacuolar acid trehalase and not cytosolic neutral
      trehalase for growth on trehalose, the participation of endocytosis for uptake of
      trehalose from medium to the vacuoles is discussed.

PMID- 8647290
TI  - Granulocyte colony-stimulating factor induces the binding of STAT1 and STAT3 to
      the IFNgamma response region within the promoter of the Fc(gamma)RI/CD64 gene in
      human neutrophils.
AB  - Granulocyte colony-stimulating factor (G-CSF) has been recently shown to induce
      the high-affinity Fc receptor for IgG (Fc(gammaRI)/CD64) in human
      polymorphonuclear neutrophils (PMN). To elucidate the molecular mechanisms
      whereby G-CSF exerts this effect, we examined whether the cytokine induces the
      binding of transcription factors to the IFNgamma response region (GRR), a well
      characterized regulatory element in the Fc(gammaRI) promoter that is responsible
      for the transcriptional induction of this gene. Using electrophoretic mobility
      shift assays, we show that in human PMN, G-CSF activates a GRR-binding complex
      which contains members of the signal transducer and activator of transcription
      (STAT) family of proteins, namely STAT1 and STAT3. In keeping with this result,
      treatment of neutrophils with G-CSF led to tyrosine phosphorylation of STAT3, as
      determined by immunoprecipitation followed by immunoblotting with
      antiphosphotyrosine antibodies. This is the first demonstration that in human
      neutrophils, the induction by G-CSF of Fc(gammaRI) gene expression may be
      mediated by the binding of STAT1 and STAT3 to the GRR sequence.

PMID- 8647291
TI  - Insertion of poly(ethylene glycol) derivatized phospholipid into pre-formed
      liposomes results in prolonged in vivo circulation time.
AB  - Transfer of MPEG(1900)-DSPE from micellar phase to pre-formed liposomes imparts
      long in vivo circulation half-life to an otherwise rapidly cleared lipid
      composition. MPEG(1900)-DSPE transfers efficiently and quickly in a time and
      temperature dependent manner. There is negligible content leakage and a strong
      correlation between assayed mol% MPEG(1900)-DSPE, liposome diameter increase, and
      pharmacokinetic parameters such as distribution phase half-life. Since a
      biological attribute (liposome clearance rate) can be modified by the insertion
      process, it suggests a simple and economical way to impart site-specific
      targeting to a variety of liposome delivery systems. This method is also a
      convenient way to measure the 'brush' thickness of such conjugates directly.

PMID- 8647292
TI  - Structures of new acidic O-specific polysaccharides of the bacterium Proteus
      mirabilis serogroups O26 and O30.
AB  - The polysaccharide chains of the lipopolysaccharides of the Proteus mirabilis
      serogroups O26 and O30 were studied using sugar and methylation analysis and 1H
      and 13C NMR spectroscopy, including two-dimensional correlation spectroscopy and
      rotating-frame NOE spectroscopy. The polysaccharides were found to be acidic due
      to the presence of D-galacturonic acid and its amide with L-lysine in serogroup
      O26 or D-glucuronic acid in serogroup O30, and the structures of their
      tetrasaccharide repeating units were established. The O26-specific polysaccharide
      is structurally and serologically related to the O-specific polysaccharide of P.
      mirabilis O28, which includes amides of D-GalA with L-lysine and L-serine
      [Radziejewska-Lebrecht, J. et al. (1995) Eur. J. Biochem. 230, 705-712].

PMID- 8647293
TI  - Direct involvement of hydrogen peroxide in bacterial alpha-hydroxylation of fatty
      acid.
AB  - We have reported that fatty-acid alpha-hydroxylase partially purified from
      Sphingomonas paucimobilis required NADH and molecular oxygen. In this study, we
      found that the reaction was greatly inhibited by catalase. Glutathione and
      glutathione peroxidase also inhibited alpha-hydroxylation, but superoxide
      dismutase and mannitol did not. Replacement of NADH and molecular oxygen by
      hydrogen peroxide increased the alpha-hydroxylation activity. In the presence of
      hydrogen peroxide, molecular oxygen was not required for the activity. These
      findings suggest that hydrogen peroxide was essential for bacterial alpha
      hydroxylase.

PMID- 8647294
TI  - ADP delivery from adenylate kinase in the mitochondrial intermembrane space to
      oxidative phosphorylation increases in the presence of macromolecules.
AB  - Macromolecules were added to isolated rat liver mitochondria to mimic cytosolic
      macromolecules and tested for their effects on the ADP delivery from adenylate
      kinase in the intermembrane space to oxidative phosphorylation. In the presence
      of 10% (w/v) dextran M20 or bovine serum albumin, approximately 60% of the
      maximal ADP flux from adenylate kinase to oxidative phosphorylation was not
      accessible to an extramitochondrial ADP scavenger. In the absence of
      macromolecules this was 34%. ADP determinations from incubations with
      macromolecules demonstrated the existence of flux-dependent ADP concentration
      gradients across the outer membrane which can be as high as 12 microM.

PMID- 8647295
TI  - 5S rRNA binding ribosomal proteins from Thermus thermophilus: identification and
      some structural properties.
AB  - An unusual acidic ribosomal protein from Thermus thermophilus, TL5, that binds to
      5S rRNA specifically and strongly, has been investigated. The N-terminal sequence
      of TL5 does not reveal any homology with known ribosomal proteins. Two large
      tryptic fragments of TL5 have been isolated and characterized. 5S rRNA protected
      TL5 and its unstable N-terminal fragment against trypsin action. The 5S rRNA
      binding ability of TL5 is probably inherent in its N-terminal part. The other 5S
      rRNA binding ribosomal protein from T. thermophilus, TL4, has been identified as
      a homolog of the ribosomal protein L5 from Escherichia coli.

PMID- 8647296
TI  - Molecular cloning of a levocabastine-sensitive neurotensin binding site.
AB  - A search for sequences homologous to the neurotensin receptor cDNA in a rat
      hypothalamic library has identified a novel neurotensin receptor (NTR-2). The
      1539 bp cDNA encodes a 416 amino acid protein and shows highest homology to the
      previously cloned neurotensin receptor (NTR-1) (64% homology and 43% identity).
      Binding and pharmacological studies demonstrate that NTR-2 expressed in COS cells
      recognizes neurotensin (NT) with high affinity as well as several other agonists
      and antagonists. However, a fundamental difference was found; unlike NTR-1, NTR-2
      recognizes, with high affinity, levocabastine, a histamine H1 receptor antagonist
      previously shown to compete with NT for low-affinity binding sites in brain.

PMID- 8647297
TI  - A 6 kDa protein homologous to the N-terminus of the HMG1 protein promoting
      stimulation of murine erythroleukemia cell differentiation.
AB  - Murine erythroleukemia (MEL) cells, in addition to an mRNA coding for a 30 kDa
      high mobility group (HMG)-1 protein, contain an mRNA coding for a 6 kDa HMG1
      protein having the following structural properties: (1) its primary structure has
      90% homology with the N-terminal sequence of the 30 kDa HMG1 protein; (2) it
      contains a consensus region of the HMG1 protein family; (3) it is deprived of the
      cluster of acidic amino acids that characterizes the C-terminal region of the 30
      kDa HMG1 protein. This novel small Mr HMG1 protein has been expressed in
      prokaryotic cells and tested to establish similarities and differences in
      activity compared to the homologous higher Mr HMG1 protein. It has been found
      that the low Mr HMG1 form is not released from MEL cells following induction to
      erythroid differentiation, but is still effective, although with much less
      efficiency, when added to the external medium, in promoting acceleration in the
      rate of MEL cell differentiation as well as in activation of alpha-protein kinase
      C. Altogether these results provide evidence for the presence in MEL cells of a
      multigene family that encodes at least two different HMG1-type sequences most
      presumably involved, at distinct cellular sites, in different functions although
      commonly related to the promotion of cell differentiation. Additional information
      can be considered concerning the relationship between the characteristic N
      terminal sequence of HMG1 protein and the extracellular activity on MEL cell
      differentiation.

PMID- 8647298
TI  - Dependence on Mg2+ ions of the activities of dimeric hammerhead minizymes.
AB  - A minizyme is a hammerhead ribozyme with short oligonucleotide linkers instead of
      stem/loop II. In a previous study we demonstrated that a minizyme with high-level
      activity forms a dimeric structure with a common stem II [Amontov and Taira
      (1996) J. Am. Chem. Soc. 118, 1624-1628]. We now demonstrate that the stability
      of the dimeric structure is influenced by Mg2+ ions. We found that the dependence
      on Mg2+ ions of the activity of homodimeric minizyme (a dimer with two identical
      binding sites) has composite biphasic characteristics. When the concentration of
      Mg2+ ions reached a specific critical level, the dependence on the concentration
      of Mg2+ ions lost its tendency to reach a plateau. In the case of the
      heterodimeric minizyme (a dimer with two different binding sites), we
      investigated the kinetic behavior of two different forms of the dimer, namely,
      free dimer and the complex of the dimer with an uncleavable substrate. The
      kinetic behavior of the free heterodimer was very similar to that of the
      homodimeric minizyme. In contrast, in the presence of the uncleavable substrate
      at a concentration as high as that of the minizyme, the curve for the dependence
      on Mg2+ ions showed normal saturation kinetics. While, at low concentrations of
      Mg2+ ions, the activity of the heterodimers was much higher when the dimeric
      structure was stabilized by the presence of the uncleavable substrate, at high
      concentrations of Mg2+ ions, this difference in activity became less and less
      significant. Thus, high concentrations of Mg2+ ions were able to stabilize the
      dimeric minizymes in the absence of the uncleavable substrate.

PMID- 8647299
TI  - Comparison of official methods for 'readily oxidizable substances' in propionic
      acid as a food additive.
AB  - The official methods for 'readily oxidizable substances (ROS)' in propionic acid
      as a food additive were compared. The methods examined were those adopted in the
      Compendium of Food Additive Specifications (CFAS) by the Joint FAO-WHO Expert
      Committee on Food Additives, FAO, The Japanese Standards for Food Additives
      (JSFA) by the Ministry of Health and Welfare, Japan, and the Food Chemicals Codex
      (FCC) by the National Research Council, USA. The methods given in CFAS and JSFA
      are the same (potassium permanganate consumption). However, by this method,
      manganese (VII) in potassium permanganate was readily reduced to colourless
      manganese(II) with some substances contained in the propionic acid before
      reacting with aldehydes, which are generally considered as 'readily oxidizable
      substances', to form brown manganese (IV) oxide. The FCC method (bromine
      consumption) for 'ROS' could be recommended because it was able to obtain
      quantitative results of 'ROS', including aldehydes.

PMID- 8647300
TI  - Determination of hydrolysed fumonisin B1 (HFB1) in corn by competitive direct
      enzyme-linked immunosorbent assay.
AB  - Fumonisin B1, a mycotoxin produced by certain Fusarium moulds, consists of two
      tricarballyic acid groups esterified to a 20-carbon backbone. Under alkaline
      conditions, or through metabolism, the aminopentol backbone, also known as
      hydrolysed Fumonisin B1 (HFB1) can be formed and is itself cytotoxic. Although
      the occurrence of HFB1 in corn-based foods is suspected, because of the
      ubiquitous nature of FB1 in corn, analytical methods for its detection are
      difficult. In the present report we describe a monoclonal antibody-based
      competitive direct enzyme-linked immunosorbent assay (CD-ELISA) for the rapid
      analysis of HFB1 in corn. The concentration required to inhibit enzyme conjugate
      binding by 50% (IC50) was 36 ng/ml. The limit of detection of HFB, by the CD
      ELISA was 2ng/ml, when HFB1 was added in bovine serum albumin-phosphate buffered
      saline. The antibody also cross-reacted with the hydrolysis products of FB2, FB3,
      and FB4, having IC50 values of 331, 174, and 1700 ng/ml respectively. The
      antibody did not react with the intact fumonisins, sphingosine, sphinganine, or
      tricarballylic acid. Samples of corn spiked with HFB1 over the range of 5-1000
      ng/g indicated the CD-ELISA has a limit of detection of 5 ng/g and an IC50 of 41
      ng/g in the matrix. The CD-ELISA provides a sensitive and rapid tool for the
      analysis of corn-based foods for HFB1.

PMID- 8647302
TI  - A UK retail survey of aflatoxins in herbs and spices and their fate during
      cooking.
AB  - A survey of aflatoxins in herbs and spices has been carried out and cooking
      experiments conducted to assess the stability of aflatoxin in spice sauces. Of
      157 retail samples which included curry powders, pepper, cayenne pepper, chilli,
      paprika, ginger, cinnamon and coriander, nearly 95% of samples contained below 10
      micrograms/kg total aflatoxins and only nine samples had higher levels. The
      highest concentration in a retail sample was 48 micrograms/kg in a chilli powder.
      In addition to retail sampling, 14 consignments of whole chilli and chilli powder
      were sampled at the port of entry. Only two samples, both chilli powder, were
      above 10 micrograms/kg; containing 35 and 51 micrograms/kg total aflatoxins.
      Cooking experiments showed that aflatoxin levels in spiced sauces are not reduced
      by domestic cooking with either microwave or conventional gas oven heating.

PMID- 8647301
TI  - A survey of the natural occurrence of aflatoxins and zearalenone in Argentine
      field maize: 1983-1994.
AB  - A survey was carried out from 1983 to 1994 to determine the natural occurrence of
      aflatoxins and zearalenone in maize samples from Buenos Aires and Santa Fe
      provinces, Argentina. Among 2271 samples analysed, 1214 (53.5%) were contaminated
      with mycotoxins. Aflatoxin B1 was identified in 445 samples (19.6%), aflatoxin B2
      was identified in 92 samples (4.1%) and zearalenone was identified in 676 samples
      (29.8%). Aflatoxin G1 was detected in only one sample and none of the samples
      contained detectable amounts of aflatoxin G2. Aflatoxin contamination was not
      detected in the 1988, 1993 and 1994 harvests and, in the other years, with the
      exception of 1989, the contamination levels were low. Zearalenone was found in
      every year.

PMID- 8647303
TI  - Evaluation of a multiple bioassay technique for determination of antibiotic
      residues in meat with standard solutions of antimicrobials.
AB  - A multiple bioassay technique (FSIS-USDA) has been evaluated with standard
      solutions of 38 antibiotics and sulphonamides. Activity patterns at five levels
      were obtained when antibiotic solutions were assayed on seven plates prepared
      with different media and microorganisms. A different activity pattern was
      obtained for the main antibiotic groups: tetracyclines, beta-lactam antibiotics,
      macrolides and aminoglycosides. Sulphonamides were not detected at levels at
      under 100 micrograms/ml. This technique, as a post-screening test for antibiotic
      residues, can be used after a screening test to identify antibiotic groups to
      which more specific techniques can be applied for full identification and
      quantification.

PMID- 8647304
TI  - Influence of organic acids on aluminium absorption and storage in rat tissues.
AB  - Six groups of 16 rats each were fed a standard diet for 8 weeks. Aluminium (Al)
      complexed with organic anions (citrate, lactate, malate, or tartrate) was added
      to the diet of four of the groups and aluminium hydroxide to the diet of one
      group (control 'Al +'). Aluminium concentrations in the diets were 1500-2000
      mg/kg. The sixth group (control 'Al -') served as control. Plasma, bone (femur),
      kidneys, cerebral cortex and cerebellum levels of aluminium were determined at 4
      and 8 weeks. All the complexing agents increased tissue accumulations, compared
      with values in the two control groups, especially citrate in bone and kidneys and
      lactate in cerebral cortex. There were no significant differences (P < 0.05) in
      aluminium levels in the tissues considered between the 'Al +' and 'Al -' control
      groups. Our results show the ability of dietary organic acids to increase
      aluminium absorption and tissue accumulation and indicate that concurrent intake
      of aluminium and dietary organic acids is not appropriate.

PMID- 8647305
TI  - Food surveillance in the Basque Country (Spain). II. Estimation of the dietary
      intake of organochlorine pesticides, heavy metals, arsenic, aflatoxin M1, iron
      and zinc through the Total Diet Study, 1990/91.
AB  - Total diet samples purchased at monthly intervals between March 1990 and December
      1991 were analysed for different contaminants and nutrients. Each total diet
      sample included 91 food items which were combined after preparation and/or
      cooking into 16 groups of similar foods. The 'market basket' was based on a food
      survey which referred to the adult population (25-60 years) carried out in the
      Basque Country between 1988 and 1990. The dietary intakes (micrograms/day) of
      lead (43), cadmium (11), mercury (18), arsenic (291), hexachlorobenzene (HCB)
      (0.2), alpha-hexachlorocyclohexane (alpha-HCH) ( < 0.1), beta
      hexachlorocyclohexane (beta-HCH) (0.1), gamma-hexachlorocyclohexane (gamma-HCH)
      (2.9), dichlorodiphenyltrichloroethane (DDT) (0.3),
      dichlorodiphenyldichloroethene (DDE) (0.9), dichlorodiphenyldichloroethane
      (DDD)(0.2), dieldrin (0.5), heptachlor epoxide ( < 0.1), alpha-endosulphan (0.1)
      and beta-endosulphan (0.1) were all well below the respective Acceptable Daily
      Intakes or Provisional Tolerable Weekly Intakes. However, arsenic intake was much
      higher than that estimated in other countries and gamma-HCH was detected in
      anomalously high levels in the bread group. Dietary intakes of delta
      hexachlorocyclohexane (delta-HCH), aldrin, endrin, heptachlor and methoxychlor
      were not calculated because no residues were detected in any of the samples.
      Aflatoxin M1 intake was not estimated owing to the low levels detected. Finally,
      zinc intakes (11.6 mg/day) were below the recommended dietary allowances for
      Spain and the same was true for iron (11.3 mg/day), but only for females.

PMID- 8647306
TI  - Effect of organic synthetic food colours on mitochondrial respiration.
AB  - Eleven organic synthetic dyes, currently or formerly used as food colours in
      Brazil, were tested to determine their effect on mitochondrial respiration in
      mitochondria isolated from rat liver and kidney. The compounds tested were:
      Erythrosine, Ponceau 4R, Allura Red, Sunset yellow, Tartrazine, Amaranth,
      Brilliant Blue, Blue, Fast Red E, Orange GGN and Scarlet GN. All food colours
      tested inhibited mitochondrial respiration (State III respiration, uncoupled)
      supported either by alpha-ketoglutarate or succinate. This inhibition varied
      largely, e.g. from 100% to 16% for Erythrosine and Tartrazine respectively, at a
      concentration of 0.1 mg food colour per mitochondrial protein. Both rat liver and
      kidney mitochondria showed similar patterns of inhibition among the food colours
      tested. This effect was dose related and the concentration to give 50% inhibition
      was determined for some of the dyes. The xanthene dye Erythrosine, which showed
      the strongest effect, was selected for further investigation on mitochondria in
      vivo.

PMID- 8647307
TI  - Identification and reduction of sources of dietary lead in the United States.
AB  - Lead, an environmental contaminant, originates from a variety of sources. For
      over two decades, the US Food and Drug Administration (FDA) has made a number of
      efforts to reduce dietary lead exposure of the general population, and especially
      of vulnerable subpopulations such as infants and children and, indirectly, the
      foetus. Through cooperation with infant food manufacturers, reductions of about
      80-90% in the lead content of infant foods were achieved, primarily through
      eliminating the use of cans for infant food products and following good
      manufacturing practices. Another major reduction in dietary lead was realized by
      discontinuing the use of lead solder in domestically produced food cans. FDA has
      also taken steps to minimize or further reduce sources of lead in the diet from
      lead glazes on ceramicware, leaded crystalware, dietary supplements bottle water,
      and lead capsules on wine bottles. These actions have resulted in a considerable
      decrease in the exposure of the United States population to dietary lead.

PMID- 8647308
TI  - Risk analysis of dietary lead exposure.
AB  - Distribution of intake and lead levels in dietary and non-dietary sources and of
      lead absorption were used in a Monte-Carlo simulation to predict blood lead
      levels in populations of concern. Blood lead levels were determined with and
      without particular dietary sources, and added risk was estimated for each source.
      These calculations permit comparisons of relative risk used to evaluate and limit
      dietary exposure to lead. Added risk of exposure to lead in wine, calcium
      supplements and ceramic-ware, and drinking water were calculated for adult men,
      pregnant women, and children, respectively.

PMID- 8647309
TI  - A survey of nitrate contents in Indonesian milk by enzymic analysis.
AB  - In this paper, a rapid and simple enzymic method is described for the
      determination of nitrate in 32 fresh and five dry Indonesian milk samples,
      deproteinized by Carrez reagents. Interference from albumin, casein, lactose and
      chloride ions was controlled. The calibration graph was linear over the range l
      12.5 micrograms/ml NO3-; r = 0.9998. The limits of detection and quantification
      were found to be 0.45 micrograms/ml NO3- and 1 microgram/ml NO3- respectively.
      Standard nitrate solutions (10 micrograms/ml NO3-) were used to evaluate the
      precision. The results showed an average of 10.1 micrograms/ml, a standard
      deviation of 0.3 and a relative standard deviation of 3.4%. Adequate agreement
      was found between results obtained by the enzymic method and those of the French
      official reduction/photometric reference method (AFNor). Good recoveries (100% +/
      5%) were found for nitrate added to milk. The nitrate levels were in the range 1
      2.6 mg/kg NO3- for fresh milk and 1.1-18 mg/kg NO3- for dry milk. All the results
      are in good agreement with those previously published for UK and American milk.

PMID- 8647310
TI  - The effect of cooking on ochratoxin A content of beans, variety 'Carioca'.
AB  - The effect of cooking on the reduction of ochratoxin A (OA) content in beans
      (Phaseolous vulgaris L.), variety 'Carioca', was evaluated. Beans were placed in
      glass desiccators at 25 degrees C in equilibrium with 90% relative humidity and
      inoculated with spore suspensions of Aspergillus alutaceus Berk. & Curt.
      (formerly A. ochraceus Wilh.) NRRL 3174, an ochratoxigenic strain. After 10 days,
      samples were taken, analysed for their OA content, and then cooked under
      pressure, with and without previous soaking. It was observed that cooking caused
      a substantial reduction in the levels of OA (up to 84%). This effect was even
      more pronounced when the bean grains were soaked in the water for 12 h before
      cooking under pressure, at 115 degrees C, for 45 min.

PMID- 8647311
TI  - Ochratoxin A in Danish cereals 1986-1992 and daily intake by the Danish
      population.
AB  - Ochratoxin A is a common contaminant in Danish cereals, and surveillance of
      ochratoxin A in cereals has been a part of the Danish monitoring system since
      1986. Occurrence of ochratoxin A is highly related to the climatic conditions
      during harvest. Rye is the crop which is most often contaminated and contains the
      highest levels of ochratoxin A. The result of the survey period from 1986 to 1992
      (total of 1431 samples) together with food consumption data is the basis of
      intake calculations. Especially in years with wet weather during harvest, the
      daily intake of ochratoxin A for some individuals in the Danish population could
      reach levels which exceed the tolerable daily intake (TDI) for ochratoxin A of 5
      ng/kg bw suggested by The Nordic Working Group on Food Toxicology and Risk
      Evaluation. A maximum limit of 5 micrograms ochratoxin A per kg cereal would keep
      the daily intake below 5 ng/kg bw.

PMID- 8647312
TI  - Unresponsiveness of human epidermal melanocytes to melanocyte-stimulating hormone
      and its association with red hair.
AB  - There is increasing evidence that pro-opiomelanocortin-derived peptides have a
      role in controlling human skin pigmentation. In vitro, human epidermal
      melanocytes respond to melanocyte-stimulating hormone (MSH) with increases in
      melanogenesis and cell dendricity. However, in the present study, not all
      melanocyte cultures exhibited these changes and 24% were totally unresponsive to
      MSH. This unresponsiveness was limited to melanocytes from white Europeans but
      was particularly prevalent in cultures from individuals with red hair. Cyclic
      AMP, the second messenger of the melanocyte-associated MSH (MC-1) receptor,
      induced melanocyte dendricity, even in those cultures which were morphologically
      unresponsive to MSH. The cyclic nucleotide also increased melanogenesis in the
      cultures that responded melanogenically to MSH but its effect was reduced in
      those cultures that were unresponsive to MSH. Thus, while the morphological data
      support the hypothesis that unresponsiveness is mediated at the MSH receptor,
      intracellular events may also be important in determining melanogenic
      unresponsiveness to MSH.

PMID- 8647313
TI  - Molecular modeling and in vitro investigations of the human androgen receptor DNA
      binding domain: application for the study of two mutations.
AB  - In two families with complete androgen insensitivity, we have identified
      naturally occurring point mutations in the human androgen receptor gene that
      encode amino acid substitutions within the DNA-binding domain. The two amino acid
      substitutions, a valine to phenylalanine and a leucine to proline, occur at
      positions 581 and 616, respectively, of the androgen receptor. The mutations were
      recreated by site-directed mutagenesis. Expression of the mutants androgen
      receptors in COS 7 and CV 1 cells revealed a normal size 110-kDa receptor protein
      on Western blots, normal androgen binding capacities and affinities, but absence
      of binding to target DNA on electrophoretic mobility shift assays. In
      cotransfection assays, the mutant ARs failed to activate transcription of an
      androgen-responsive reporter gene. To study the possible structural impact of
      these mutations, three-dimensional models of the normal androgen receptor and of
      each mutant were built by homology with the glucocorticoid receptor. Analysis of
      the models predicts that mutation Val581Phe would affect interaction between the
      protein and DNA, whereas the Leu616Pro mutation would more likely be involved in
      destabilizing the protein structure or protein dimerization. Taken together, the
      experimental investigations and the molecular modeling studies of the mutant
      androgen receptors observed in families with complete androgen insensitivity
      syndrome, highlight the role of Val-581 and Leu-616 in receptor structure and
      function.

PMID- 8647314
TI  - Regulation of NGF, BDNF and LNGFR gene expression in ROS 17/2.8 cells.
AB  - The secosteroid hormone 1.25-dihydroxyvitamin D3 (1,25(OH)2D3) has been recently
      shown to enhance the synthesis of NGF to mouse L929 fibroblasts. In view of the
      critical role of 1,25(OH)2D3 on bone metabolism, it has been investigated if ROS
      17/2.8 osteoblastic cells were able to express the nerve growth factor (NGF) gene
      and if this process was responsive to 1,25(OH)2D3. Results indicate that these
      cells respond in a dose-dependent manner to the presence of 1,25(OH)2D3 by an
      increase in NGF mRNA levels. However, the phorbol ester PMA, previously reported
      to augment the synthesis of NGF via the recruitment of AP-1 complexes, depressed
      the expression of the NGF gene in ROS cells. In contrast, the mRNA levels of an
      NGF-related trophic factor, brain-derived neurotrophic factor (BDNF), was
      increased by PMA but not following 1,25(OH)2D3 treatment. Binding of 125I-NGF to
      ROS cells displayed the properties of a low affinity NGF receptor (dissociation
      constant Kd approximately 10(-9) M). In agreement with this result, the mRNA
      encoding the low affinity NGF receptor (LNGFR) was detected in ROS 17/2.8 cells,
      unlike trkA transcripts which encode the high affinity receptor. These data
      suggest that neurotrophins and their low affinity receptor could play an
      unsuspected role in bone tissue.

PMID- 8647315
TI  - Expression of multiple forms of 3 beta-hydroxysteroid dehydrogenase in the mouse
      liver during fetal and postnatal development.
AB  - The enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) is essential for the
      biosynthesis of all steroid hormones. To date this laboratory has isolated and
      characterized five distinct 3 beta HSD cDNAs in the mouse (3 beta HSD I-V). The
      different isoforms fall into two functionally distinct groups. 3 beta HSD I and
      III function as dehydrogenase/isomerases and 3 beta HSD IV and V function as 3
      ketosteroid reductases. Previously it was shown that the liver of the adult mouse
      expresses 3 beta HSD II, III and V, with 3 beta HSD III being the major isoform.
      This study examines the expression of the different forms of 3 beta HSD mRNAs and
      proteins in the livers of male and female mice during fetal and postnatal
      development. 3 beta HSD I, which in the adult mouse is expressed only in the
      gonads and adrenal glands, is the major isoform expressed in both male and female
      livers during fetal development until the first postnatal (pn) day after which
      time 3 beta HSD III becomes the major isoform. Expression of 3 beta HSD I mRNA
      and protein completely ceases after day 20 pn. The expression of 3 beta HSD V is
      first detected at day 40 pn and is observed only in the male. Very low expression
      of 3 beta HSD II mRNA is detected throughout development. Previous
      characterization of enzymatic activity of the expressed proteins showed that 3
      beta HSD I exhibits lower Km values for the delta 5-3 beta-hydroxysteroids than 3
      beta HSD III, indicating that 3 beta HSD I functions as a more efficient 3 beta
      hydroxysteroid dehydrogenase/isomerase than 3 beta HSD III. The results of this
      study suggest that the liver may play an important role in the biosynthesis of
      steroid hormones during murine fetal development.

PMID- 8647316
TI  - Human thyroid epithelial cells cultured in monolayers. I. Decreased thyroglobulin
      and cAMP response to TSH in 12-week-old secondary and tertiary cultures.
AB  - An in vitro system of secondary and tertiary cultures of human thyroid epithelial
      cells (TFECs) in monolayer is described. The function of the cells was evaluated
      by the second messenger cAMP and the end product thyroglobulin (Tg). The Tg
      production from the cells was measured in the supernatant by a newly developed
      enzyme-linked immunosorbent assay. The TFECs in secondary monolayer cultures had
      preserved the ability to produce Tg and cAMP despite lack of polarization.
      Furthermore, a preserved ability of TSH-stimulated production of Tg and cAMP in
      12-week-old secondary and tertiary cultures was found. However, the Tg and cAMP
      levels decreased gradually with the age of the cultures. In the secondary culture
      the TSH-stimulated Tg production decreased from 253 ng/micrograms DNA (205-263)
      after 3 weeks to 18 ng/micrograms DNA (6-81), P < 0.001, n = 6 after 12 weeks and
      TSH-stimulated cAMP production from 660 pmol/micrograms DNA (500-840) to 60 (40
      200), P < 0.001, n = 6. The decreased responsiveness of long-term cultures
      results in preference of short-term secondary cultures, which provide a more
      suitable experimental model for in vitro investigation of human thyroid cell
      functions.

PMID- 8647317
TI  - Human thyroid epithelial cells cultured in monolayers. II. Influence of serum on
      thyroglobulin and cAMP production.
AB  - An in vitro system of secondary cultures of human thyroid follicular epithelial
      cells in monolayer is described. The 72-h influence of serum and six supplements
      (thyrotropin, insulin, somatostatin, transferrin, hydrocortisone, glycyl-histidyl
      lysine acetate) on growth and function in presence of 3-isobutyl-L-methyl
      xanthine (IBMX) was investigated. The function of the cells was evaluated by
      production of the second messenger adenylate cyclase (cAMP) and the end product
      thyroglobulin (Tg). Growth was measured as the 3H-thymidine uptake of the cells.
      Three days of TSH-depletion preceeded the experiments. In presence of IBMX TSH
      stimulated cAMP production, while stimulation of Tg was only present in some
      cultures. In absence of IBMX TSH always stimulated the Tg production. The
      stimulation was independent of the presence of the other five investigated
      nutritional factors in physiological concentrations. TSH in concentrations from
      0.1-10 U/1 stimulated the 72ih 3H-thymidine uptake of the cells. The TSH
      stimulated production of Tg and cAMP decreased significantly with increasing
      concentrations of fetal calf serum (0-10%), (tau = 0.49, P < 0.001, n = 6-29 and
      tau = 0.75, P < 0.001, n = 6-29, respectively). Thus, serum as a complex,
      variable and not fully characterized mixture of hormones and growth factors was
      crucial to the attachment of the cells to the substrate, but inhibited
      differentiated functions of the human thyroid cells.

PMID- 8647318
TI  - Growth hormone (GH) status regulates GH receptor and GH binding protein mRNA in a
      tissue- and transcript-specific manner but has no effect on insulin-like growth
      factor-I receptor mRNA in the rat.
AB  - The effect of growth hormone-deficiency (GHD) and treatment with recombinant
      bovine GH (bGH) or human IGF-I (hIGF-I) for 10 days on the expression of GH
      receptor (GHR), GH binding protein (GHBP) and of insulin-like growth factor-I
      receptor (IGF-IR) mRNA was examined using dw/dw and normal Lewis rats. Hepatic
      GHR and GHBP mRNA expression was significantly lower in dw/dw rats in comparison
      to Lewis rats (P < 0.01) while specific 125I-bGH binding to hepatic microsomal
      membranes was significantly higher (P < 0.01), suggesting a reduction in hepatic
      GHR turnover with GHD. Treatment with bGH reduced hepatic specific 125I-bGH
      binding in dw/dw rats, but had no effect in Lewis rats. Treatment with hIGF-I
      increased hepatic specific 125I-bGH binding in Lewis rats. Hepatic GHR and GHBP
      mRNA expression was not changed by bGH or hIGF-I treatment, suggesting that
      differences in hepatic specific 125I-bGH binding may be due to
      posttranscriptional mechanisms. GHBP mRNA expression was higher in kidney, heart,
      and muscle of dw/dw rats in comparison to Lewis rats (P < 0.01), while GHR mRNA
      abundance was not changed. Treatment of dw/dw rats with hIGF-I or bGH resulted in
      a coordinate reduction of GHR and GHBP mRNAs in kidney (P < 0.01). IGF-IR mRNA
      was not detected in liver and despite reduced plasma IGF-I levels and IGF-I mRNA
      expression IGF-IR mRNA abundance was not changed in nonhepatic tissues by GHD.
      Our data suggest that changes in plasma IGF-I levels and local IGF-I mRNA do not
      influence IGF-IR mRNA expression, while GHR and GHBP mRNA expression in different
      rat tissues are regulated independently. The increased nonhepatic GHBP mRNA
      expression with GHD suggests that nonhepatic GHBP may have an important
      physiological function distinct from that of GHBP in liver or in plasma.

PMID- 8647319
TI  - Differential effects of oxytocin on steroid production by bovine granulosa cells.
AB  - Oxytocin (OT) and its mRNA are expressed at very low levels in granulosa cells
      from bovine preovulatory follicles isolated before the LH/FSH surge and increase
      dramatically between the surge and ovulation. We have shown previously that OT
      stimulates progesterone secretion by granulosa cells obtained before, but not
      after the gonadotropin surge, suggesting that OT may be involved in the
      follicular/luteal phase shift in steroidogenesis from estradiol/androgen to
      progesterone. One objective of this study was to determine if OT affects
      estradiol as well as progesterone production by utilizing culture conditions that
      maintain estradiol secretion in vitro. A second objective was to determine if OT
      regulates steroidogenesis by effects on the levels of mRNA for the steroidogenic
      enzymes involved in progesterone synthesis, cytochrome P450 side-chain cleavage
      (P450scc) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), or in estradiol
      production, cytochrome P450 aromatase (P450arom). Granulosa cells were isolated
      from bovine preovulatory follicles and cultured for 3 days with or without OT in
      medium supplemented with either insulin (1 microgram/ml) + 1% fetal calf serum
      (FCS), which maintains basal estradiol secretion, or low doses of FSH (1 and 2
      ng/ml) + 1% FCS, a culture condition that maximizes effects of FSH on estradiol
      secretion. After the first day of culture, OT stimulated progesterone (P < 0.01)
      and inhibited estradiol production (P < 0.01) in both control and FSH-treated
      cultures. In contrast, OT had only a small stimulatory effect on the levels of
      mRNA for P450scc and 3 beta-HSD and no effect on mRNA for P450arom. These
      findings suggest that: (1) OT plays an autocrine role in regulating the
      follicular luteal phase shift in steroidogenesis by both increasing progesterone
      and inhibiting estradiol production and (2) the differential effects of OT on
      steroid production are not mediated primarily by effects on levels of mRNA for
      steroidogenic enzymes.

PMID- 8647320
TI  - Calcium-dependent action of hypertrehalosemic hormone on activation of glycogen
      phosphorylase in cockroach fat body.
AB  - Signaling mechanisms for Blaberus discoidalis hypertrehalosemic hormone (Bld
      HrTH)-dependent glycogen phosphorylase activation were investigated in vitro
      using fat body of the tropical cockroach, B. discoidalis. Brief treatment of fat
      bodies with Bld-HrTH in the absence of extracellular Ca2+ showed a significant
      activation of phosphorylase. Although extracellular Ca2+ was required for a full
      activation of phosphorylase by Bld-HrTH, stimulation in the absence of
      extracellular Ca2+ suggested that intracellular Ca2+ was also involved in Bld
      HrTH signal transduction. Thapsigargin and thimerosal mobilize Ca2+ from
      intracellular stores by different mechanisms, and both chemicals stimulated
      phosphorylase activities as effectively as a maximum dose of Bld-HrTH. Bld-HrTH
      likely induces intracellular Ca2+ release followed by extracellular Ca2+ entry
      across the plasma membrane. Inositol-1,4,5-trisphosphate (InsP3) levels were
      greatly increased by Bld HrTH in a time- and dose-dependent manner, suggesting
      that InsP3 might be a Ca(2+)-mobilizing intracellular second messenger for Bld
      HrTH.

PMID- 8647321
TI  - Determination of transcription start sites in the human estrogen receptor gene
      and identification of a novel, tissue-specific, estrogen receptor-mRNA isoform.
AB  - The human estrogen receptor (ER) gene has previously been shown to be transcribed
      from two different promoters which are expressed in a cell- and tissue-specific
      manner. Whereas the transcriptional start sites of the proximal promoter are
      known, the transcriptional initiation site(s) of the distal promoter has not been
      identified. In this study, a PCR-based technique was used to isolate the 5' ends
      of ER cDNAs from different human cell lines and tissues. Using this technique the
      positions of the transcription initiation sites in the distal promoter were
      determined. In addition a novel 5' untranslated exon was isolated from human
      liver. These results demonstrate that the human ER gene contains a third,
      previously not described promoter which appears to be predominantly expressed in
      liver.

PMID- 8647322
TI  - Crosstalk between the thyroid hormone and peroxisome proliferator-activated
      receptors in regulating peroxisome proliferator-responsive genes.
AB  - Peroxisome proliferators and thyroid hormones have overlapping metabolic effects
      and regulate a similar subset of genes involved in maintaining lipid homeostasis.
      Transcriptional activation by peroxisome proliferators is mediated by peroxisome
      proliferator-activated receptors (PPARs) that bind to specific peroxisome
      proliferator-response elements (PPREs) through heterodimerization with retinoid X
      receptors (RXRs). We examined the effect of thyroid hormone receptor alpha (TR
      alpha) on DNA binding in vitro and transcriptional activation in vivo by rat
      PPAR. Gel mobility shift assays using in vitro translated receptors demonstrated
      that TR alpha was capable of binding on its own and cooperatively with RXR alpha
      to the rat acyl-CoA oxidase PPRE and of inhibiting the binding of rat PPAR/RXR
      alpha heterodimers to this element. This inhibition was the result of competition
      between TR alpha and PPAR for limiting amounts of the heterodimerization partner
      RXR alpha and for binding to the PPRE. Interestingly, cotransfection of a TR
      alpha expression plasmid into mammalian cells resulted in potentiation of the
      peroxisome proliferator- and PPAR/RXR alpha-dependent transcriptional induction
      of a reporter gene containing the acyl-CoA oxidase PPRE. TR alpha therefore
      appears to cooperate with RXR and PPAR to positively modulate peroxisome
      proliferator-dependent transactivation in vivo. Our findings suggest that there
      is crosstalk between the thyroid hormone and peroxisome proliferator signaling
      pathways in the regulation of peroxisome proliferator-responsive genes.

PMID- 8647323
TI  - Promotion of animal growth with a monoclonal antibody specific to growth hormone
      receptor.
AB  - A monoclonal antibody (mAb), designated 2C3, was raised against the growth
      hormone receptor (GHR) of rats. In a radioimmunoassay, 2C3 was found to compete
      with iodinated porcine GH (pGH) tracer for the binding to GHR, suggesting that
      GHR binding sites for pGH and 2C3 were identical or closely adjacent. The
      competition curve generated by 2C3 was identical to that generated by cold pGH,
      suggesting that the binding affinities of 2C3 and pGH to GHR were very similar.
      Administration of hypophysectomized rats with 2C3 resulted in the growth of these
      GH-deficient animals for a long period of time, mimicking the somatogenic effect
      of GH. However, this effect was abolished when 2C3 was injected into animals in
      the presence of exogenous GHR. A control mAb recognizing a GHR epitope distal
      from its binding site for GH failed to produce the growth in rats. Taken
      together, findings from the present study indicate that 2C3 is fully capable of
      engaging with GHR and subsequently triggering the growth response in rats. This
      mAb may also prove useful as a biologically active agonist for better
      understanding the initiation of the physiological process of GHR.

PMID- 8647324
TI  - TGF-beta: receptors and cell cycle arrest.
AB  - Transforming growth factor-beta (TGF-beta) is the prototypic member of a
      superfamily of proteins important in normal growth and development. The recent
      molecular cloning and characterization of TGF-beta receptors represents a major
      advance in our understanding of the mechanism of action of this cytokine. These
      studies have revealed that TGF-beta elicits its diverse biological responses
      following the formation of a heteromeric complex involving two distantly related
      transmembrane serine/threonine kinases, both of which are required for
      signalling. Furthermore, there has been very rapid progress in the identification
      of key components that regulate the cell cycle, including the cyclin-dependent
      kinases (CDKs) and their partners, the cyclins. Perhaps the most significant
      development has been the isolation of a family of proteins that bind to and
      inactivate CDKs. The ability of TGF-beta to regulate the action of these CDK
      inhibitors results in growth arrest of mammalian cells in G1.

PMID- 8647326
TI  - A call for advocacy.

PMID- 8647325
TI  - Methods for studying synthesis, turnover, and phosphorylation of catalytic
      subunit of cAMP-dependent protein kinase in mammalian cells.
AB  - Because of the low abundance of the two major isoforms (C alpha and C beta) of
      catalytic (C) subunit of cAMP-dependent protein kinase, it has been difficult to
      monitor their expression and virtually impossible to quantify their synthesis,
      phosphorylation, and turnover in intact mammalian cells. We now describe
      sensitive and quantitative immunochemical methods using a goat antibody raised
      against the recombinant C alpha isoform of murine C subunit that enable studies
      of the expression and metabolism of C subunit in cultured cells. The antibody
      reacts well with C alpha and C beta isoforms of murine C subunit and with C
      subunits from rat, hamster, and human cell lines, so it should have widespread
      utility. Immunoreactivity with bovine heart C subunit was substantially weaker.
      For quantitation of C subunit radioactivity in extracts of cells labeled
      metabolically with [35S]methionine, we developed a two-cycle immunoadsorption
      protocol that reduces nonspecific adsorption to negligible levels. A tritium
      labeled, truncated C subunit marker protein is added to extracts as an internal
      marker to monitor C subunit recoveries in different samples. For analysis of
      expression of C subunit isoforms in different cells or tissues, we describe a
      nonradioactive Western immunoblot procedure that can quantitate C subunit in
      amounts as low as 12 pg. Using extraction conditions that either stabilize or
      destabilize the phosphate on Thr-197, we show how the relative expression and
      phosphorylation of C alpha and C beta isoforms can be estimated from SDS-gel
      patterns resulting from either immunoblot or immunoadsorption procedures.

PMID- 8647327
TI  - Hemispheric function in developmental language disorders and high-level autism.
AB  - Two groups of children with contrasting types of developmental language disorder
      (phonologic-syntactic and semantic-pragmatic) were compared with a group of
      children with high-level autism and with a control group of normal children on a
      broad battery of neuropsychological tests, known to be sensitive to left-right
      hemisphere damage. Significant differences found between the groups suggest
      contrasting forms of hemispheric dysfunction.

PMID- 8647328
TI  - Social cognition in developmental language disorders and high-level autism.
AB  - Two groups of children with contrasting types of developmental language disorder
      (phonologic-syntactic and semantic-pragmatic) were compared with a group of
      children with high-level autism and with a control group of normal children on
      tests of social cognition (theory of mind; social comprehension; and detection of
      eye direction). The similarly poor performances of the semantic-pragmatic group
      and the autistic group suggest that semantic-pragmatic language disorder lies on
      the autistic spectrum.

PMID- 8647329
TI  - Assessment of visuoperceptual disturbance in children with spastic diplegia using
      measurements of the lateral ventricles on cerebral MRI.
AB  - The authors estimated perceptual disturbance in children with spastic diplegia
      from the difference between the visual and performance IQ scores (VIQ-PIQ) on the
      Wechsler Intelligence Scale for Children-Revised (WISC-R), having found a strong
      negative correlation between this score and the PQ obtained on the Frostig
      Developmental Test of Visual Perception (DTVP). The ratio of the areas of the
      posterior horns to the anterior horns (P/A) correlated negatively with
      visuoperceptual disturbance. This ratio can therefore be used to assess
      perceptual disturbance at an early age in children with spastic diplegia.

PMID- 8647330
TI  - Co-ordination of tongue movements and peri-oral muscle activities during
      nutritive sucking.
AB  - A feeding bottle equipped with micro-video-camera and pressure sensor was devised
      to show the inside of the mouth and record sucking pressure. Activities of the
      temporal (TM), masseter muscle (MM), orbicular muscle of the mouth (OM) and
      suprahyoid muscles (SM) of 25 healthy infants were examined. Tongue and jaw
      movements, EMGs and sucking waves were scanned simultaneously. The tongue
      movements included elevation of the medial part of the tongue in a backward
      moving peristaltic wave; significant correlations were found between jaw motion,
      tongue movement and sucking pressure. The TM, MM and OM were most active when the
      sucking pressure became positive and the jaw was closing, the SM showing highest
      activity in the negative-pressure phase. These findings show that each suckling
      cycle is biphasic, with sucking pressure, peri-oral muscle activities and jaw
      motion all closely correlated.

PMID- 8647331
TI  - Hypoxaemia and cardiorespiratory changes during epileptic seizures in young
      children.
AB  - In order to measure epileptic seizure(ES)-induced hypoxaemia and explore its
      relation to other physiological changes, 53 seizures were documented in 10
      children (aged 1 week to 5 years) during continuous recordings of breathing, ECG,
      oxygenation and EEG. Hypoxaemia was demonstrated in 42 ESs with an arterial
      oxygen saturation (SaO2) below baseline for a median duration of 100s and < or =
      60% for 17s, despite resuscitation. There were pauses in breathing movements in
      45 seizures, but only 35 of these were hypoxaemic; pauses of comparable severity
      occurred in the 10 seizures without hypoxaemia. In seven seizures there was
      hypoxaemia without pauses in breathing movements, although continued nasal
      airflow was not demonstrable. Sinus tachycardia occurred in 35 seizures and T
      wave changes in 20, but no sinister arrhythmias were observed.

PMID- 8647332
TI  - Evaluation of two-point discrimination in children: reliability, effects of
      passive displacement and voluntary movements.
AB  - Two-point discrimination (2-PD) thresholds were studied at three sites (tip of
      index finger, thenar eminence, external malleolus) and under various testing
      conditions (dynamic vs static, with and without displacement of instrument on
      skin; and active vs passive, with and without voluntary movement of subject) in
      47 healthy children between 6 and 13 years of age. Reliability was fair to
      moderate, with slightly better perception (learning effect) during the second
      testing session. The threshold values of these children were similar to those of
      adults. For the passive conditions, the threshold values were lower for dynamic
      than for static tests at all sites. For the active condition at the index finger,
      there were no differences between dynamic and static values and there was no
      active/passive main effect. It is concluded that: (1) the hand is more sensitive
      than the ankle, with the finger being the most sensitive area, (2) the 2-PD test
      procedure used was most reliable at the index finger and least reliable at the
      external malleolus and (3) displacement of the instrument on the skin can improve
      2-PD threshold values in children but the discrimination thresholds are not
      changed by active movement of the subject.

PMID- 8647333
TI  - Sleep problems in children with Sanfilippo syndrome.
AB  - Sanfilippo syndrome is a rare degenerative disorder which has severe intellectual
      and behavioural sequelae, commonly including sleep problems. A parental
      questionnaire was used to gather information on the sleep patterns of 80 children
      with Sanfilippo syndrome (mean age 10 years 2 months). The majority were found to
      have sleep problems (78%). Many also exhibited other distressing and unusual
      night time behaviours (staying up all night, chewing the bedclothes or crying out
      suddenly), and a few laughed or sang. Such problems may have been more severe in
      those with Sanfilippo syndrome type B. In four of the families offered
      individually tailored behaviour-management advice there was immediate
      improvement, which was maintained at followup in two cases. These results
      demonstrate the usefulness of even such a minimal intervention, even in a very
      difficult population such as this.

PMID- 8647335
TI  - Spinal arteriovenous malformation presenting as meningitis.
AB  - An 8-month-old boy presented with a two-day history of lethargy. Meningitis was
      suspected, and cerebrospinal fluid examination demonstrated pleocytosis and
      elevated protein. After initial improvement with antibiotic and steroid therapy,
      progressive lower extremity weakness developed, and a midthoracic spinal cord
      arteriovenous malformation (AVM) was diagnosed. These lesions present rarely in
      infancy; the classification and pathophysiology of spinal cord AVMs are reviewed.

PMID- 8647334
TI  - Autism and multiple pituitary deficiency.
AB  - We describe a 9-year-old boy who presented with abnormal development in language
      and social interaction. He also showed evidence of stereotyped behaviour, thus
      fulfilling all the criteria for an ICD-10 diagnosis of autism. This was
      associated with multiple pituitary deficiency. No case of autism associated with
      hypopituitarism has hitherto been reported. The authors discuss the evidence for
      linking the two conditions as opposed to accepting them as coincidental. In some
      studies of autism, anatomical and imaging studies have provided evidence of
      pathology in the limbic lobe. This lobe plays an essential role in the
      modification and expression of emotional reactions. Together with other areas,
      the limbic system sends outputs from the hypothalamus and from there to the
      pituitary. Our case illustrates a possible link between emotional expression and
      hypopituitarism.

PMID- 8647336
TI  - Dopa-responsive dystonia: a widening spectrum.

PMID- 8647337
TI  - Introduction: blood safety in the age of AIDS.

PMID- 8647338
TI  - Blood safety in the age of AIDS.
AB  - This series of essays was developed as part of FASEB's efforts to educate the
      general public and the legislators whom it elects about the benefits of
      fundamental biomedical research--particularly how investment in such research
      leads to scientific progress, improved health, and economic well-being. "Blood
      safety in the age of AIDS" examines the effects of the AIDS epidemic on the
      safety of the blood supply. Just as a pebble tossed in a lake sends out ripples
      that last long after the pebble sinks, the discovery more than a decade ago that
      the AIDS virus was in the blood supply is still having repercussions on research
      and transfusion practices. New screening tests for blood and new ways of using
      one's own blood during surgery are among the steps that have made blood
      transfusions much safer. Meanwhile, researchers continue tracking down new
      threats and devising ways to circumvent them.

PMID- 8647339
TI  - Carotenoids 3: in vivo function of carotenoids in higher plants.
AB  - The function of the long-chain, highly unsaturated carotenoids of higher plants
      in photoprotection is becoming increasingly well understood, while at the same
      time their function in other processes, such as light collection, needs to be
      reexamined. Recent progress in this area has been fueled by more accurate
      determinations of the photophysical properties of these molecules, as well as
      extensive characterization of the physiology and ecology of a particular group of
      carotenoids, those of the xanthophyll cycle, that play a key role in the
      photoprotection of photosynthesis under environmental stress. The deepoxidized
      xanthophylls zeaxanthin and antheraxanthin, together with a low pH within the
      photosynthetic membrane, facilitate the harmless dissipation of excess excitation
      energy directly within the light-collecting chlorophyll antennae. Evidence for
      this function as well as current contrasting hypotheses concerning its molecular
      mechanism are reviewed. In addition, the acclimation of the xanthophyll cycle
      content and composition of leaves to contrasting environments with different
      demands for photoprotection is summarized.

PMID- 8647340
TI  - Liver regeneration 4: transcriptional control of liver regeneration.
AB  - Determining what factors are responsible for initiating regeneration following
      partial hepatectomy or toxic damage, and how the liver maintains differentiated
      functions while the hepatocytes are undergoing cellular proliferation are central
      issues in understanding the molecular bases of liver regeneration. Examination of
      the transcriptional milieu in the regenerating liver provides clues to the
      answers to these questions. Growth factor-generated intracellular signals that
      trigger liver regeneration result in activation via posttranslational
      modifications of latent, normally inactive transcription factors that preexist in
      the liver. Two transcription factors that are activated by this mechanism include
      posthepatectomy factor/nuclear factor-kappa B) and Stat3. Because cytokines such
      as tumor necrosis factor-alpha (TNF-alpha), interleukin-l (IL-1), and IL-6 can
      induce these factors in the liver, the finding of activated Stat3 and PHF/NF
      kappa B suggests that these cytokines may play a role in some aspects of growth
      regulation during liver regeneration. Rapidly induced transcription factors,
      Stat3, PHF/NF-kappa B, and others are responsible for activation of the primary
      growth response or immediate-early genes, which play a role in regulating later
      phases of cell growth in regenerating liver and other mitogen-activated cells.
      Immediate-early genes encode many members of diverse transcription factor
      families including the Jun-Fos-LRF-1, nuclear receptor, and myc families to name
      a few. In this way a transcriptional cascade is established during the G1 phase
      of liver regeneration. Coexisting with these induced factors are liver-specific
      transcription factors such as the CAAT enhancer binding proteins and hepatocyte
      nuclear factors, which may interact with growth-induced factors to help the liver
      maintain metabolic homeostasis during regeneration. As a result the liver is able
      to accomplish the goals of reestablishing its mass while it maintains its
      functional capacity during regeneration.

PMID- 8647342
TI  - Masking of mRNA by Y-box proteins.
AB  - The Y-box proteins are defined by their ability to bind to Y-box promoter
      elements and to help regulate transcription of a wide variety of genes. However,
      Y-box proteins are also identified as abundant proteins in the cytoplasm of germ
      cells, where they are found bound to stored mRNA molecules. Binding of Y-box
      proteins to mRNA sequences, both in vitro and in vivo, has been shown to effect
      their translational repression ("masking"). Here we discuss the ability of Y box
      proteins to recognize different nucleic acid structures and to become involved in
      regulation of both transcription and translation.

PMID- 8647341
TI  - Cytochrome P450 2: peroxidative reactions of diversozymes.
AB  - Cytochrome P450, the most versatile biological catalyst known, was originally
      named as a pigment having a carbon monoxide difference spectrum at about 450 nm
      and no known function. Recent progress in many laboratories has revealed that the
      P450 superfamily has immense diversity in its functions, with hundreds of
      isoforms in many species catalyzing many types of chemical reactions. We believe
      it is safe to predict that each mammalian species may be found to have up to a
      hundred P450 isoforms that respond in toto to a thousand or more inducers and
      that, along with P450s from other sources, metabolize a million or more potential
      substrates. Accordingly, the name DIVERSOZYMES is proposed for this remarkable
      family of hemoproteins. This paper reviews the peroxidative reactions of
      Diversozymes, including peroxides as oxygen donors in hydroxylation reactions, as
      substrates for reductive beta-scission, and as peroxyhemiacetal intermediates in
      the cleavage of aldehydes to formate and alkenes. Lipid hydroperoxides undergo
      reductive beta-cleavage to give hydrocarbons and aldehydic acids. One of these
      products, trans-4-hydroxynonenal, inactivates P450, particularly alcohol
      inducible 2E1, in what may be a negative regulatory process. Although a P450 iron
      oxene species is believed to be the oxygen donor in most hydroxylation reactions,
      an iron-peroxy species is apparently involved in the deformylation of many
      aldehydes with desaturation of the remaining structure, as in aromatization
      reactions.

PMID- 8647343
TI  - Nicotinamide nucleotide transhydrogenase: a model for utilization of substrate
      binding energy for proton translocation.
AB  - The energy-transducing nicotinamide nucleotide transhydrogenases of mammalian
      mitochondria and bacteria are structurally related membrane-bound enzymes that
      catalyze the direct transfer of a hydride ion between NAD(H) and NADP(H) in a
      reaction that is coupled to transmembrane proton translocation. The protonmotive
      force alters the affinity of the transhydrogenase for substrates, accelerates the
      rate of hydride ion transfer from NADH to NADP, and shifts the equilibrium of
      this reaction toward NADPH formation. Transhydrogenation in the reverse direction
      from NADPH to NAD is accompanied by outward proton translocation and formation of
      a protonmotive force. In reverse transhydrogenation, the enzyme utilizes
      substrate binding energy for proton pumping. Therefore, with regard to the
      mechanism of energy transduction, the transhydrogenase works according to the
      same principles as the ATP synthase complex of mitochondria and bacteria, the
      proton and cation ATPases, and possibly certain redox-linked proton pumps.
      However, the relatively simple structure of the transhydrogenase recommends it as
      a model for study of the utilization of binding energy for vectorial
      translocation of protons and other cations.

PMID- 8647344
TI  - Regulation of gene expression by alternative promoters.
AB  - Promoters have been defined as modulatory DNA structures containing a complex
      array of cis-acting regulatory elements required for accurate and efficient
      initiation of transcription and for controlling expression of a gene. It is
      becoming increasingly evident that they also constitute prime target elements
      through which diversity and flexibility in the complex patterns of gene
      expression in multicellular organisms are created. The use of multiple promoters
      and transcription start sites is apparently a frequently used mechanism, whereas
      at the same time there is considerable variation and complexity in the patterns
      of alternative promoter usage. This review discusses the use of alternative
      promoters as a versatile mechanism to create diversity and flexibility in the
      regulation of gene expression. Alternative promoter usage can influence gene
      expression in very diverse ways. The level of transcription initiation can vary
      between alternative promoters, the turnover or translation efficiency of mRNA
      isoforms with different leader exons can differ, alternative promoters can have
      different tissue specificity and react differently to some signals, and finally,
      alternative promoter usage can lead to the generation of protein isoforms
      differing at the amino terminus.

PMID- 8647345
TI  - The Leloir pathway: a mechanistic imperative for three enzymes to change the
      stereochemical configuration of a single carbon in galactose.
AB  - The biological interconversion of galactose and glucose takes place only by way
      of the Leloir pathway and requires the three enzymes galactokinase, galactose-1-P
      uridylyltransferase, and UDP-galactose 4-epimerase. The only biological
      importance of these enzymes appears to be to provide for the interconversion of
      galactosyl and glucosyl groups. Galactose mutarotase also participates by
      producing the galactokinase substrate alpha-D-galactose from its beta-anomer. The
      galacto/gluco configurational change takes place at the level of the nucleotide
      sugar by an oxidation/reduction mechanism in the active site of the epimerase
      NAD+ complex. The nucleotide portion of UDP-galactose and UDP-glucose
      participates in the epimerization process in two ways: 1) by serving as a binding
      anchor that allows epimerization to take place at glycosyl-C-4 through weak
      binding of the sugar, and 2) by inducing a conformational change in the epimerase
      that destabilizes NAD+ and increases its reactivity toward substrates. Reversible
      hydride transfer is thereby facilitated between NAD+ and carbon-4 of the weakly
      bound sugars. The structure of the enzyme reveals many details of the binding of
      NAD+ and inhibitors at the active site. The essential roles of the kinase and
      transferase are to attach the UDP group to galactose, allowing for its
      participation in catalysis by the epimerase. The transferase is a Zn/Fe
      metalloprotein, in which the metal ions stabilize the structure rather than
      participating in catalysis. The structure is interesting in that it consists of
      single beta-sheet with 13 antiparallel strands and 1 parallel strand connected by
      6 helices. The mechanism of UMP attachment at the active site of the transferase
      is a double displacement, with the participation of a covalent UMP-His 166-enzyme
      intermediate in the Escherichia coli enzyme. The evolution of this mechanism
      appears to have been guided by the principle of economy in the evolution of
      binding sites.

PMID- 8647346
TI  - S-Adenosylmethionine and methylation.
AB  - S-Adenosylmethionine (AdoMet or SAM) plays a pivotal role as a methyl donor in a
      myriad of biological and biochemical events. Although it has been claimed that
      AdoMet itself has therapeutic benefits, it remains to be established whether it
      can be taken up intact by cells. S-Adenosylhomocysteine (AdoHcy), formed after
      donation of the methyl group of AdoMet to a methyl acceptor, is then hydrolyzed
      to adenosine and homocysteine by AdoHcy hydrolase. This enzyme has long been a
      target for inhibition as its blockade can affect methylation of phospholipids,
      proteins, DNA, RNA, and other small molecules. Protein carboxymethylation may be
      involved in repair functions of aging proteins, and heat shock proteins are
      methylated in response to stress. Bacterial chemotaxis involves
      carboxymethylation and demethylation in receptor-transducer proteins, although a
      similar role in mammalian cells is unclear. The precise role of phospholipid
      methylation remains open. DNA methylation is related to mammalian gene
      activities, somatic inheritance, and cellular differentiation. Activation of some
      genes has been ascribed to the demethylation of critical mCpG loci, and silencing
      of some genes may be related to the methylation of specific CpG loci. Viral DNA
      genomes exist in cells as extrachromosomal units and are generally not
      methylated, although once integrated into host chromosomes, different patterns of
      methylation are correlated with altered paradigms of transcriptional activity.
      Some viral latency may be related to DNA methylation. Cellular factors have been
      found to interact with methylated DNA sequences. Methylation of mammalian
      ribosomal RNAs occurs soon after the synthesis of its 47S precursor RNA in the
      nucleolus before cleavage to smaller fragments. Inhibition of the methylation of
      rRNA affects its processing to mature 18S and 28S rRNAs. The methylation of 5'
      terminal cap plays an important role in mRNA export from the nucleus, efficient
      translation, and protection of the integrity of mRNAs. Another important function
      of AdoMet is that it serves as the sole donor of an aminopropyl group that is
      conjugated with putrescine to form, first, the polyamine spermidine, and then
      spermine.

PMID- 8647347
TI  - Differentiation-dependent expression of CA V and the role of carbonic anhydrase
      isozymes in pyruvate carboxylation in adipocytes.
AB  - The incorporation of radioactivity from 14C-labeled compounds into metabolic
      intermediates and total lipids was examined in 3T3 adipocytes. The heterocyclic
      sulfonamide carbonic anhydrase inhibitor (SCAI) 6-ethoxyzolamide (ETZ) caused a
      decrease (42+/-7% of control, IC50 = 2.2+/-1.1 x 10(-7) M) in the incorporation
      of [14C] bicarbonate into several Krebs cycle intermediates in 3T3-F442A
      adipocytes. This decrease in pyruvate carboxylase-mediated [14C] carbon fixation
      was associated with a reduction in fluorometrically determined [citrate] and
      [malate]. The ability of ETZ to decrease both the incorporation of radioactivity
      into and the concentrations of Krebs cycle intermediates was not of sufficient
      magnitude to lower [ATP], but was associated with a decrease in de novo
      lipogenesis from [14C]glucose. De novo lipogenesis was also inhibited to a
      similar extent by trifluormethanesulfonamide, an aliphatic SCAI, which suggests
      that the effects are mediated by carbonic anhydrase. ETZ did not inhibit de novo
      lipogenesis from [14C]glutamine (12.38+/-1.068 nmol/mg protein, ETZ; 12.5+/-0.846
      nmol/mg protein, DMSO). This suggests that ETZ inhibition of lipogenesis involves
      an inhibitory effect on pyruvate carboxylase as opposed to acetyl CoA
      carboxylase, because the incorporation of glutamine into lipids does not involve
      pyruvate carboxylase. Decreased de novo lipogenesis was also observed by
      incubating cultures in media that contained 1 mM bicarbonate (atmosphere:100%
      humidified air) rather than 25 mM bicarbonate (atmosphere: 95% humidified air/5%
      CO2). This suggests that exogenous CO2/bicarbonate may be required to sustain
      maximal rates of de novo lipogenesis. Because these results implied that CA V,
      the mitochondrial isoform of carbonic anhydrase, might be present in adipocytes,
      CA V levels were measured by immunoblotting. Mitochondrial preparations of
      adipocytes and liver were found to contain similar concentrations of CA V. Unlike
      adipocyte CA III, CA V concentrations were not significantly different in lean
      and obese Zucker rats. However, CA V levels were ninefold higher in
      differentiated 3T3-F442A adipocytes compared to undifferentiated adipoblasts. Our
      data indicate that CA V is relatively abundant in adipocyte mitochondria and
      exhibits differentiation-dependent expression like pyruvate carboxylase and the
      cytosolic isozymes CA II and CA III. The possible roles of CA II and CA V in
      pyruvate carboxylation are discussed.

PMID- 8647348
TI  - Effects of calcium on the migration and recruitment of macrophages and macrophage
      derived foam cells.
AB  - Calcium is thought to play an important role in the genesis of atherosclerotic
      lesions, but the precise mechanisms involved are unclear. In the present
      investigation, we have used in vitro systems to investigate the effects of
      calcium on one key aspect of lesion development: the migration of macrophages and
      macrophage/foam cells. Using agarose plate migration assays, the migratory
      characteristics of macrophages exposed to 1) no lipoprotein, 2) low density
      lipoprotein (LDL), 3) acetylated low density lipoprotein (acLDL), and ) oxidized
      low density lipoprotein were examined. The most marked stimulatory effect on
      macrophage mobility was observed when freshly isolated cells were exposed to
      acLDL during the migration assay. High levels of exogenous calcium were found to
      suppress the stimulatory effect of acLDL on migration. As the responses of
      macrophages exposed to a uniform concentration of agents in the surrounding
      medium may differ from chemotactic responses to a concentration gradient, the
      migration of macrophages, with and without preexposure to acLDL or LDL, was
      studied using microchemotaxis Boyden chambers. Under these conditions, calcium
      acted as a highly potent chemoattractant, especially to cells that had been
      preincubated with acLDL. These results suggest how elevated external calcium
      concentration leads initially to macrophage recruitment, and subsequently to foam
      cell aggregation and lipid core formation, in association with calcification, in
      the developing atherosclerotic plaque.

PMID- 8647349
TI  - Mechanical load induces sarcoplasmic wounding and FGF release in differentiated
      human skeletal muscle cultures.
AB  - The transduction mechanism (or mechanisms) responsible for converting a
      mechanical load into a skeletal muscle growth response are unclear. In this study
      we have used a mechanically active tissue culture model of differentiated human
      skeletal muscle cells to investigate the relationship between mechanical load,
      sarcolemma wounding, fibroblast growth factor release, and skeletal muscle cell
      growth. Using the Flexcell Strain Unit we demonstrate that as mechanical load
      increases, so too does the amount of sarcolemma wounding. A similar relationship
      was also observed between the level of mechanical load inflicted on the cells and
      the amount of bFGF (FGF2) released into the surrounding medium. In addition, we
      demonstrate that the muscle cell growth response induced by chronic mechanical
      loading in culture can be inhibited by the presence of an antibody capable of
      neutralizing the biological activity of FGF. This study provides direct evidence
      that mechanically induced, sarcolemma wound-mediated FGF release is an important
      autocrine mechanism for transducing the stimulus of mechanical load into a
      skeletal muscle growth response.

PMID- 8647351
TI  - Modulation of the immunologic response to acute stress in humans by beta-blockade
      or benzodiazepines.
AB  - Acute stress evokes immediate responses in the cardiovascular endocrine, and
      immune systems. In particular, the number and activity of natural killer (NK)
      lymphocytes increase after stress. Here, we investigate the possibility to
      pharmacologically interfere with these stress-induced immunologic changes. Twenty
      five healthy males were subjected to an acute stressor, a first-time tandem
      parachute jump. Subjects were randomly assigned to a beta-adrenoceptor antagonist
      (propranolol), a benzodiazepine (alprazolam), or placebo group. To analyze the
      role of the spleen in lymphocyte redistribution, splenectomized subjects
      performed a parachute jump. Propranolol, but no alprazolam, inhibited the heart
      rate increase during jumping. Increases in epinephrine and cortisol in the
      propranolol group were comparable to placebo, but were attenuated by alprazolam.
      The number and activity of NK cells significantly increased in the placebo group
      but not in the propranolol group immediately after stress. Alprazolam treatment
      did not alter the increase in NK cell numbers but did inhibit the increase in NK
      activity. In splenectomized subjects, NK cell numbers, but not NK activity,
      increased as in placebo subjects. We conclude that stress-induced changes in the
      immune system are controlled by beta-adrenergic mechanisms and only partly depend
      on the spleen; central interference with alprazolam differentially affects stress
      induced changes in the NK cell compartment.

PMID- 8647352
TI  - The story of penicillin: the view from Oxford in the early 1950s.

PMID- 8647350
TI  - Choline deficiency induces apoptosis in SV40-immortalized CWSV-1 rat hepatocytes
      in culture.
AB  - Immortalized CWSV-1 rat hepatocytes, in which p53 protein is inactivated by SV40
      large T antigen, had increased numbers of cells with strand breaks in genomic DNA
      (terminal dUTP end labeling) when grown in 0 Micron choline (67-73% of cells)
      than when grown in 70 Micron choline (2-3% of cells). Internucleosomal
      fragmentation of DNA (DNA ladders) was detected in cells grown with 5 Micron and
      0 Micron choline for 72h. Cells treated with 0 or 5 Micron choline for 72h
      detached from the substrate in high numbers (58% of choline deficient cells vs.
      1.4% of choline sufficient cells detached) exhibited a high incidence of
      apoptosis (apoptotic bodies were seen in 55-75% of cells; 67-73% had DNA strand
      breaks), and an absence of mitosis and proliferating cell nuclear antigen (PCNA)
      expression. Cells undergoing DNA fragmentation had functioning mitochondria. At
      24h, cells grown in 0 or 5 Micron choline synthesize DNA more rapidly than those
      grown in 70 Micron choline. By 72h, the cells grown in 0 or 5 Micron choline were
      forming DNA much more slowly than control cells (assessed by thymidine
      incorporation, PCNA expression, and mitotic index). Western blot analysis showed
      that p53 in the nucleus of cells was detected in direct association with SV40 T
      antigen, and was therefore likely to be inactive. We conclude that choline
      deficiency kills CWSV-1 hepatocytes in culture by inducing apoptosis via what may
      be a p53-independent process, and that this process begins in viable cells before
      they detach from the culture dish.

PMID- 8647354
TI  - Educating the biochemical scientist.

PMID- 8647353
TI  - No crystals --no grant.

PMID- 8647355
TI  - -Physiological nutritional quality of standard hospital diet-.

PMID- 8647356
TI  - -Exercise and sports as a therapeutic possibility in cancer after-care-.

PMID- 8647357
TI  - -Problems with autologous blood donation in gynecology and obstetrics-.

PMID- 8647358
TI  - -Paraplegia and fertility.

PMID- 8647359
TI  - -Case report of clinical and pathophysiological similarities of Moschkowitz
      disease and HELLP syndrome-.
AB  - This case report describes for the first time a manifestation of thrombotic
      thrombocytopenic purpura (TTP, Moschcowitz's disease) during pregnancy. The
      characteristic neurologic symptoms of TTP were missing, while the typical
      clinical signs of the HELLP syndrome could be observed. Furthermore the
      biochemical proof of TTP was obtained by tracing ultra-large clotting factor VIII
      (von Willebrand factor) multimers in the patient's plasma. Thus the assumption is
      supported that TTP and HELLP syndrome are diseases of one pathophysiological
      entity with different symptomatologies. Because of the frequent relapse of TTP,
      differentiation between TTP and HELLP syndrome is of great clinical importance,
      independent of future pregnancies.

PMID- 8647360
TI  - -Intravenous or oral etoposide therapy of platinum refractory ovarian cancer with
      early recurrence. Results of a prospective randomized study-.
AB  - 121 patients with advanced ovarian cancer resistant to or relapsing following
      platinum-based chemotherapy participated in this prospective randomised
      multicenter study. The second-line treatment was indicated according to the
      relapse-free interval. 36 assessable patients were resistant to platinum-based
      chemotherapy or relapsed within 12 months following primary surgery. This group
      of patients with early relapse was randomized to oral or parenteral etoposide. 82
      patients relapsed within an interval longer then 12 months following primary
      surgery; these patients with delayed relapse underwent a secondary tumour
      debulking surgery. The data of this group of patients with delayed relapse will
      be published as soon as the time of observation allows adequate results. In this
      paper the efficiency of etoposide in the patients with early relapse is analysed
      according to the application form of the drug (oral vs. parenteral). No
      statistically significant difference in response rate, toxicity, and median
      survival time was found between the oral (n = 18) and parenteral (n = 18)
      treatment. In both application groups the response rate was 22%, the median
      survival time 14 and 13 months respectively. Alopecia and leucopenia were the
      most frequent toxicities. As a result etoposide is efficient in unfavorable
      ovarian cancer patients with early relapse. Because of better compliance
      etoposide should be administered parenterally. In respect of response rate and
      median survival time, etoposide is comparable with paclitaxel.

PMID- 8647361
TI  - -Therapy of vulvar carcinoma in the early stages-.
AB  - In the past, and still in some centres, patients with clinical stage I and II
      squamous cell vulvar cancer were treated by radical vulvectomy and bilateral
      inguinal-femoral lymphadenectomy. Modern management of vulvar cancer during the
      last 20 years has developed towards more conservative procedures in the therapy
      of early stage disease. At the Royal Hospital for Women, Sydney, women with
      invasive tumours < 20 mm (T1), are treated by a radical local excision. The
      lesion should be unifocal and the rest of the vulva healthy. A surgical margin of
      at least 10 mm should be obtained. If no focus with greater than 1 mm of stromal
      invasion is present, lymph node dissection may be omitted. Lateral lesions with a
      depth of invasion > 1 mm may undergo unilateral inguinal-femoral lymphadenectomy.
      Midline lesions and those involving the labia minora require bilateral groin
      dissection. In selected cases radical local excision of the primary lesion may
      also be performed in T2 lesions > 20 mm but should always be combined with a
      bilateral inguino-femoral lymphadenectomy. Adjuvant pelvic and groin irradiation
      should be given if at least one large node has undergone a tumorous change of if
      there are multiple nodes containing micrometastases. Careful patient selection is
      necessary to successfully achieve high cure rates, acceptable cosmetic results
      and psychosexual wellbeing.

PMID- 8647362
TI  - -Chemosensitivity testing in gynecologic oncology. Experiences with an ATP
      bioluminescence assay-.
AB  - In the present study, our first experiences with the ATP Tumour Chemosensitivity
      Assay (ATP-TCA), a novel method for pretherapeutic drug testing, are reported.
      During one year, a total of 111 samples obtained from patients suffering from
      different gynaecological malignancies (ovary: 53, breast: 41, others: 17) were
      sent for chemosensitivity testing. The quality of 104 single cell suspensions was
      sufficient for further processing. Evaluability rates ranged from 71% (breast
      cancers and non-ovarian tumours) to 83% (ovarian cancers) with an average of 77%.
      Evaluability of recurrences was slightly better compared to primaries. A total of
      18 different antineoplastic agents and 67 drug combinations was used for in vitro
      testing with an average of 12.4 drugs/combinations tested per each sample (ovary:
      14.8, breast: 9.7, others: 10.2). In 70 of 111 cases, the ATP-TCA was followed by
      chemotherapy with 44 cases treated in respect of the assay results and 29 cases
      receiving an antineoplastic regime, which differed from the standard treatment
      protocol. Compared to untreated patients, recurrences were treated more
      frequently based on the ATP-TCA, with a majority receiving an alternative
      protocol as proposed by the assay. In ovarian carcinoma, chemosensitivity testing
      was of particular importance for the further therapy. 41 of 53 patients were
      treated by chemotherapy with 29 therapies basing on the results of the assay
      (alternative protocol: 17). The good correlation of the ATP-TCA and the
      individual clinical course of the patients was demonstrated by two case reports
      of recurrent ovarian carcinomas, one of them responding well to platinum-based
      combinations and the other presenting in vitro and in vivo platinum-resistance.
      In conclusion, our first experiences with the ATP-TCA were promising. Our
      results, however, warrant confirmation by studies with a sufficient number of
      cases and an extended observation period.

PMID- 8647363
TI  - -CA-125 antigen as a prognostic factor for survival in patients with epithelial
      ovarian carcinoma of FIGO stage I--preliminary results-.
AB  - The tumour marker CA 125 has proved useful in monitoring the course of disease
      and in indicating responsiveness to therapy in patients suffering from epithelial
      ovarian cancer. Due to its poor sensitivity, however, attempts to improve early
      detection by screening with this tumour marker have been unsuccessful to date.
      This study was performed to evaluate whether there was a relation between pre
      operative CA 125 levels and the survival of patients with epithelial ovarian
      cancer FIGO stage I. If such a relation exists, CA 125 may be an effective
      variable in singling out those subsets of patients with stage I disease for whom
      adjuvant chemotherapy would bring an additional therapeutic benefit. Our results
      suggest CA 125 may be a significant prognostic factor. With a 5-year survival of
      43%, marker-positive ovarian cancer carries a poor prognosis. Since the question
      as the whether follow-up treatment is required in this early, potentially curable
      stage of disease, is contingent upon numerous factors and since an individualised
      therapeutic regimen may lead to increased survival rates, the prognostic
      influence of CA 125 and its relationship to other prognostic factors should be
      evaluated by multivariate analysis.

PMID- 8647364
TI  - -Cytokine level in malignant ascites and peripheral blood of patients with
      advanced ovarian carcinoma-.
AB  - The concentrations of various cytokines were examined by ELISA in blood and in
      ascites from 14 patients with advanced ovarian cancer (stage IV). The control
      group consisted of 6 patients with benign gynaecological disorders. Compared with
      patients with benign gynaecological disorders, ascites and/or plasma of patients
      with ovarian cancer showed significantly higher levels of IL-6, IL-8, IL-10, TNF
      alpha, and sIL-2R. There were no increases of IL-1 alpha, IL-1 beta, IL-2, IFN
      gamma, and sCD14 levels. The possible pathogenetic significance of cytokines in
      ovarian cancer is discussed.

PMID- 8647365
TI  - -Is prevention of pre-eclampsia with low dosage aspirin possible? Critical
      assessment of available studies-.
AB  - The efficacy of low-dose aspirin treatment to prevent preeclampsia was assessed
      by reviewing studies of the available literature. 9 studies were performed
      examining nearly 13,000 pregnant women. Aspirin treatment compared with untreated
      control groups led to a significant reduction of preeclampsia in 5 small-scale
      studies. However, no prophylaxis could be achieved in 4 studies comprising more
      than 12,000 pregnant women. A assessment of low-dose aspirin treatment is
      difficult, since no dose-response study was performed to determine the optimal
      dose; the duration of treatment--beginning and end--was not defined and the drug
      risk for mother and child was not documented in accordance with GCP guidelines.
      The major problem of all studies, however, consisted in the recruitment of the
      patients since there are no easily performable and well-recognised screening
      tests available to estimate the risk of preeclampsia. In conclusion, at present
      no statement is possible if and under which conditions low-dose aspirin treatment
      will be able to prevent preeclampsia.

PMID- 8647366
TI  - -Obstetric prognosis after pre-eclampsia, eclampsia or HELLP syndrome-.
AB  - Preeclampsia, eclampsia and the HELLP syndrome are serious pregnancy
      complications associated with increased maternal and perinatal mortality and
      morbidity. The question of subsequent pregnancy outcome in these patients is of
      great importance for the patient and the obstetrician. The risk of recurrence of
      hypertensive complications during subsequent pregnancy is related to the time of
      the onset and the clinical signs of hypertension during the first pregnancy.
      Patients having hypertensive pregnancies should be examined for chronic
      hypertension, kidney disease and other internal diseases. The recurrence risk is
      for preeclampsia between 19.5% and 25.9% and for eclampsia between 21.9% and
      46.8%. Patients developing the disease early in pregnancy and with chronic
      hypertension are at higher risk. For the HELLP syndrome the risk of recurrence is
      between 3% and 5%. These patients should be considered to be at increased risk
      for obstetric complications in subsequent pregnancies and close perinatal care is
      indicated in subsequent pregnancies.

PMID- 8647367
TI  - -Interruption of umbilical blood flow in an acardiac twin by endoscopic laser
      coagulation-.
AB  - We report on the successful intrauterine surgical treatment of a twin pregnancy
      with an acardiac fetus. At 18 weeks of gestation the patient presented with
      polyhydramnios and a hydropic acardius acephalus and the donor twin showed signs
      of congestive heart failure. Colour Doppler ultrasound allowed localisation of
      the communicating vessels running on the placental surface towards the umbilicus
      of the acardiac twin. At 20 weeks we performed endoscopic laser coagulation of
      the umbilical vessels of the acardiac twin. A sheath (9.8 Charriere) with a 1.9
      mm diameter rigid fetoscope (field of vision 60 degrees) was introduced
      percutaneously under local anesthesia into the amniotic cavity of the "pump"
      twin. Under sonographic control the fetoscope was directed towards the
      communicating vessels on the placental surface. A Nd-YAG laser (0.4 mm diameter
      fiber) was used to coagulate two vessels, artery and vein, until interruption of
      the reversed arterial perfusion was accomplished. Tricuspid regurgitation of the
      normal twin disappeared throughout the following two weeks and no further
      complications occurred throughout pregnancy. At 39 weeks a healthy girl was
      delivered vaginally. No at the age of 3 months she is developing normally.
      Minimal invasive endoscopic laser coagulation of the umbilical vessels of the
      acardiac twin appears to be the optimal currently available treatment for the
      normal twin, for which otherwise a high mortality ( > 50%) and morbidity must be
      expected.

PMID- 8647368
TI  - Multidrug resistance in enteric and other gram-negative bacteria.
AB  - In Gram-negative bacteria, multidrug resistance is a term that is used to
      describe mechanisms of resistance by chromosomal genes that are activated by
      induction or mutation caused by the stress of exposure to antibiotics in natural
      and clinical environments. Unlike plasmid-borne resistance genes, there is no
      alteration or degradation of drugs or need for genetic transfer. Exposure to a
      single drug leads to cross-resistance to many other structurally and functionally
      unrelated drugs. The only mechanism identified for multidrug resistance in
      bacteria is drug efflux by membrane transporters, even though many of these
      transporters remain to be identified. The enteric bacteria exhibit mostly complex
      multidrug resistance systems which are often regulated by operons or regulons.
      The purpose of this review is to survey molecular mechanisms of multidrug
      resistance in enteric and other Gram-negative bacteria, and to speculate on the
      origins and natural physiological functions of the genes involved.

PMID- 8647369
TI  - Response of Mycobacterium smegmatis to acid stress.
AB  - Evidence was sought for the existence of an inducible acid tolerance response in
      Mycobacterium smegmatis. Exposure of M. smegmatis to a sub-lethal, adaptive
      acidic pH was found to confer a significant level of protection against
      subsequent exposure to a lethal pH, compared to unadapted cells. Adaptation was
      dependent on de novo protein synthesis.

PMID- 8647370
TI  - Modular structure of the Rhizobium meliloti DctB protein.
AB  - To investigate the modular structure of the Rhizobium meliloti dicarboxylic acid
      sensor protein, DctB, three truncated DctB proteins (DctB4, DctB5 and DctB4G)
      were constructed, overproduced in Escherichia coli and purified. The DctB4G
      protein was composed of 446 amino acids of the DctB C-terminus and displayed
      strong autophosphorylation activity in vitro. This activity was sustained when a
      further 120 amino acids at the N-terminus of the polypeptide were deleted
      (DctB5). This protein which has an intact transmitter domain exhibits specific
      but inefficient phospho-transfer capabilities. Removal of 58 amino acids from the
      DctB4G C-terminus which included blocks F and G2 of the transmitter domain,
      rendered the resultant protein (DctB4) incompetent in autophosphorylation.
      Phosphorylation activity was restored to DctB4 through intramolecular
      complementation with DctB. Therefore, it would appear that the R. meliloti DctB
      protein is active as a dimer (or higher order oligomer). Furthermore, the
      intramolecular complementation experiments indicate that the amino acids 171-291,
      a predicted periplasmic stretch, play an important role in the dimerization
      process.

PMID- 8647371
TI  - A modular xylanase from mesophilic Cellulomonas fimi contains the same cellulose
      binding and thermostabilizing domains as xylanases from thermophilic bacteria.
AB  - The xynC gene from mesophilic Cellulomonas fimi encodes a large 125 kDa modular
      xylanase (XYLC), consisting of six distinct functional domains. In addition to a
      single Family 10 catalytic domain, XYLC contains a domain homologous with the
      nodulation protein, NodB, from nitrogen-fixing bacteria and thermostabilizing and
      cellulose-binding domains found previously only in xylanases from thermophilic
      bacteria.

PMID- 8647372
TI  - The location and deletion of the genes which code for SSI-like protease
      inhibitors in Streptomyces species.
AB  - The genes coding for the protease inhibitors, SSI and API-2c', have been analyzed
      by comparing DNA macrorestriction patterns of Streptomyces albogriseolus S-3253
      and S. griseoincarnatus KTo-250 with those of inhibitor-deficient mutants. The
      mutants were found to suffer from chromosomal deletions rather than plasmid loss
      which resulted in the loss of the relevant genes. Hybridization experiments
      indicated that the ssi homologs in S. lividans and S. coelicolor A3(2) are
      located near the end of the linear chromosome.

PMID- 8647373
TI  - Cloning, nucleotide sequence and expression of the gene encoding the cellulose
      binding protein 1 (CBP1) of Fibrobacter succinogenes S85.
AB  - The nucleotide sequence of the gene encoding the Fibrobacter succinogenes S85
      cellulose-binding protein 1 (CBP1) has been determined. The gene encodes a
      protein of 1054 amino acids with a molecular mass of 118614. The deduced amino
      acid sequence of CBP1 showed an extensive similarity to the cellulose-binding
      domain of an endoglucanase (EGCCD) from Clostridium cellulolyticum and contained
      the reiterated regions. The cloned gene was inserted into an expression vector,
      pRSETA, and was expressed in E. coli as a fused protein with the peptide
      consisting of six consecutive histidine residues. The fused protein was detected
      by immunoblotting using antiserum against CBP1, and exhibited the cellulose
      binding activities.

PMID- 8647374
TI  - New MspI polymorphism at +83 bp of the human apolipoprotein AI gene: association
      with increased circulating high density lipoprotein cholesterol levels.
AB  - We recently showed that loss of a MspI restriction site in the 5'-end (intron 1)
      of the apolipoprotein (apo) AI gene is due to a C to T transition (+83 bp) and/or
      a G to A transition (+84 bp). Since this region may be relevant to the regulation
      of apo AI gene expression and therefore to plasma high density lipoprotein
      cholesterol (HDL-C), we explored the association between this MspI polymorphic
      site and circulating HDL-C levels in 243 healthy Caucasians. There were 143 aged
      18-67 years (60 males and 83 females) and 100 aged 6-12 years (58 males and 42
      females). We also compared this association with a known MspI polymorphic site, a
      G to A transition at -75 bp of the apo AI gene. The rare allele (-) frequency for
      the polymorphism at +83 bp was 4.1% and 22.1% for the polymorphism at -75 bp.
      Subjects heterozygous for the loss of the MspI restriction site at +83 bp
      (genotype: M2+-, n = 20) had higher HDL-C levels than M2+2 subjects (mean +/- SD:
      1.73 +/- 0.31 vs. 1.41 +/- 0.39 mmol/l, P < 0.05 for adults; 1.71 +/- 0.33 vs.
      1.34 +/- 0.29 mmol/l, P < 0.01 for children). Adults with the G to A substitution
      at -75 bp also had higher HDL-C levels (1.56 +/- 0.36 mmol/l for AA, 1.53 +/-
      0.38 mmol/l for GA, and 1.36 +/- 0.38 mmol/l for GG, P < 0.05); this difference
      was not observed in the children. The MspI polymorphisms at both sites were in
      linkage disequilibrium. Their joint effect on the HDL-C levels was also
      significant and individuals with rare alleles (-) at both sites had the highest
      HDL-C levels. In an analysis of variance, the MspI polymorphism at +83 bp, and at
      -75 bp and gender independently accounted for 6.5%, 1.7%, and 5.9%, respectively,
      of the variance in circulating HDL-C levels when age was controlled as a
      covariate. We conclude that loss of the MspI site by the C to T (+83 bp) and/or
      the G to A (+84 bp) transitions is highly associated with increased HDL-C levels.
      The association appears to be more significant than that of the G to A transition
      at -75 bp.

PMID- 8647375
TI  - Penetrance of schizophrenia-related disorders in multiplex families after
      correction for ascertainment.
AB  - Penetrance of schizophrenia and related disorders was calculated in 27 multiplex
      pedigrees ascertained by a consistent set of screening and selection criteria.
      The rationale for the study was that single major locus linkage models are
      frequently used on a pragmatic basis to analyze data for schizophrenia which is
      most likely to have a polygenic mechanism. Penetrance estimates assuming
      Mendelian inheritance represent maximum values and thus can provide guidance for
      construction of appropriate linkage models. Four diagnostic models were
      considered: narrow (schizophrenia and chronic schizoaffective disorder),
      intermediate (including other non-affective psychoses), broad (including
      schizotypal and paranoid personality disorders), and broad + suspected (including
      suspected schizophrenia spectrum disorders). Penetrance was calculated in the
      youngest affected adult sibship, under both dominant and recessive inheritance
      assumptions, either without correction, or with a correction that excluded
      individuals necessary to meet pedigree selection criteria. Without correction,
      penetrance values ranged from 0.70 to 0.90 assuming dominant and 1.0 to > 1.0
      assuming recessive inheritance. After correction, the ranges were 0.30-0.51 for
      dominant and 0.47-0.59 for recessive models. The corrected values are likely to
      be overestimates given that the penetrance of any one locus in a multilocus model
      must be lower. It is suggested that lod score analyses of schizophrenia should
      attempt to derive information primarily from affected diagnoses, because
      information derived from unaffecteds under high penetrance models is likely to be
      spurious.

PMID- 8647376
TI  - Heterogeneity of familial risk in sarcoidosis.
AB  - Familial clustering of sarcoidosis and the higher prevalence and clinical
      severity of sarcoidosis in African Americans suggests etiologic heterogeneity. To
      test for heterogeneity in familial risk of sarcoidosis, we studied 3,395 siblings
      and parents of 558 index cases (361 African American, 197 Caucasian) diagnosed at
      Henry Ford Hospital between 1951 and 1994. Using the age- and sex-specific
      cumulative incidence of sarcoidosis in our sample, we found a statistically
      significant heterogeneity in familial risk of disease (P < .001). To determine if
      this was due to a greater risk of sarcoidosis in African Americans, we
      recalculated disease probabilities using age-, sex-, and race-specific disease
      cumulative incidence and found the same amount of heterogeneity in familial risk
      (P < .001). Index cases (n = 69) from high-risk families were more likely to be
      African American (odds ratio [OR] = 3.24; 95% confidence interval (CI) = 1.71
      6.14) and to have an offspring or second- degree relative affected (OR = 6.21;
      95% CI = 2.86-13.45). We conclude that the heterogeneity of familial sarcoidosis
      risk found in this study is supportive of multiple etiologies. Our results also
      show that a quantitative assessment of familial risk based on siblings and
      parents may be a useful screening tool for identifying families with additional
      affected members. Of the high-risk families, African Americans made up a greater
      than-expected percentage even after accounting for differences in disease
      prevalence. We suggest targeting African Americans for studies of sarcoidosis
      that focus on Mendelian hypotheses and genetic linkage.

PMID- 8647377
TI  - Segregation analysis of two lung function indices in a random sample of young
      families: the Humboldt Family Study.
AB  - The Humboldt Family Study was conducted in the town of Humboldt, Saskatchewan, in
      1993. Familial correlations and segregation analyses of lung function were
      carried out in 799 individuals in 214 nuclear families that included 214 fathers,
      214 mothers, and 371 children. Forced expiratory volume in 1 second (FEV1) and
      maximal mid-expiratory flow rate (MMFR) were first regressed on age, height,
      weight, and their quadratic and cubic terms as well as on smoking status in four
      groups separately (mothers, fathers, daughters, and sons), with terms significant
      at the 0.10 level being retained. Residual phenotypes were standardized within
      the four groups. Class D regressive models were used to perform familial
      correlations and segregation analyses. For both FEV1 and MMFR, father-mother
      correlations were not significantly different from zero, and mother-offspring,
      father-offspring, and sibling-sibling correlations showed no statistically
      significant difference from each other. Based on the "polygenic" models, the
      estimated intraclass correlation is 0.132 (+/- 0.035) for FEV1 and 0.171 (+/-
      0.039) for MMFR, and the narrow-sense heritability is 0.264 for FEV1 and 0.342
      for MMFR. Segregation analysis shows that the "mixed" model with both single
      locus and polygenic components had a better fit for FEV1 than single-locus or
      polygenic only models. However, the model which included a nontransmitted
      environmental factor [tau(AA) = tau(AB) = tau(BB) = qA] and polygenic loci had a
      better fit than the Mendelian model [tau(AA) = 1, tau(AB) = 1/2, tau(BB) = 0]
      [Akaike's information criterion (AIC) = 2219.47 vs. AIC = 2222.14]. For MMFR, the
      Mendelian "mixed" model gave a nonsignificant improvement in loge likelihood
      compared to the simple polygenic model. Comparison of the single-locus model and
      Mendelian "mixed" model shows no difference in fitting the data. This study
      suggests that FEV1 and MMFR are controlled by many loci with no major effects
      and/or common environmental factors.

PMID- 8647378
TI  - Genetic analysis of sex and generation differences in plasma lipid, lipoprotein,
      and apolipoprotein levels in adolescent twins and their parents.
AB  - In a sample of Dutch families consisting of parents aged 35-65 years and their
      twin offspring aged 14-21 years, a significant difference between generations was
      observed in phenotypic variances and in genetic heritabilities for plasma levels
      of total cholesterol, triglycerides, high density lipoprotein (HDL) and low
      density lipoprotein (LDL) cholesterol, and apolipoproteins (apo) A1, A2, B, and
      E. For all traits parents were more variable than their offspring. This increase
      in phenotypic variance was best explained by a genetic model in which individual
      specific environmental variance increased with increasing age. Genetic variance
      was the same across generations for nearly all traits except triglycerides and
      apoE, for which a decrease in genetic variance was observed. This model led to
      large intergenerational differences in genetic heritabilities. Heritabilities for
      children were between 65 and 87%, while heritabilities for their parents were
      between 10 and 50%. No evidence was found for effects of a shared family
      environment.

PMID- 8647380
TI  - Univariate analysis of dichotomous or ordinal data from twin pairs: a simulation
      study comparing structural equation modeling and logistic regression.
AB  - The univariate analysis of categorical twin data can be performed using either
      structural equation modeling (SEM) or logistic regression. This paper presents a
      comparison between these two methods using a simulation study. Dichotomous and
      ordinal (three category) twin data are simulated under two different sample sizes
      (1,000 and 2,000 twin pairs) and according to different additive genetic and
      common environmental models of phenotypic variation. The two methods are found to
      be generally comparable in their ability to detect a "correct" model under the
      specifications of the simulation. Both methods lack power to detect the right
      model for dichotomous data when the additive genetic effect is low (between 10
      and 20%) or medium (between 30 and 40%); the ordinal data simulations produce
      similar results except for the additive genetic model with medium or high
      heritability. Neither method could adequately detect a correct model that
      included a modest common environmental effect (20%) even when the additive
      genetic effect was large and the sample size included 2,000 twin pairs. The SEM
      method was found to have better power than logistic regression when there is a
      medium (30%) or high (50%) additive genetic effect and a modest common
      environmental effect. Conversely, logistic regression performed better than SEM
      in correctly detecting additive genetic effects with simulated ordinal data (for
      both 1,000 and 2,000 pairs) that did not contain modest common environmental
      effects; in this case the SEM method incorrectly detected a common environmental
      effect that was not present.

PMID- 8647379
TI  - Familial clustering of obesity and breast cancer.
AB  - One of the most striking characteristics of breast cancer (BC) is a tendency to
      familial aggregation. In order to evaluate whether familial clustering of obesity
      could account, at least in part, for the familial aggregation of BC, we compared
      the adult body size of entire sets of first-degree relatives belonging to 60
      families with two or more cases of BC (case families) and 120 BC-free families
      (control families). Case families included an index case recently admitted for
      primary BC who had a confirmed first-degree family history for the disease.
      Control families included one population-based healthy index control with no
      family history and age-matched (2:1) to index cases. Index cases and controls,
      recruited from a pool of participants in a large case-control study, completed a
      questionnaire covering their own body size history as well as that of each of
      their first-degree relatives (598 case and 1,128 control relatives) using a
      validated system of body silhouette drawings. The odds ratio (OR) for
      premenopausal familial BC associated with having one parent markedly obese
      compared to none was 0.17 (95% confidence interval [CI] 0.04-0.65), while having
      both parents obese resulted in an OR of 0.25 (95% CI 0.04-1.56). Obesity among
      siblings was not related to premenopausal familial BC risk nor was familial
      obesity a significant predictor of familial BC after menopause. Index cases from
      both menopausal groups tended to be thinner than their unaffected relatives at
      age 40 years and thereafter. The inverse relationship between parental obesity
      and premenopausal BC risk is concordant with the protective effect of obesity on
      early-onset BC previously reported at the individual level.

PMID- 8647381
TI  - Pedigree analysis package vs. MIXD: fitting the mixed model on a large pedigree.
AB  - Results of a simulation study with two methods of analysis of data simulated
      under the mixed model on a 232-member pedigree are presented. The programs
      Pedigree Analysis Package (PAP), which approximate the likelihoods needed in a
      complex segregation analysis, and MIXD, which uses Monte Carlo Markov chain
      (MCMC), to estimate likelihoods were used. PAP obtained unbiased estimates of the
      major locus genotype means and the gene frequency, but biased estimates of the
      environmental variance component, and thus the heritability. A substantial
      fraction of the runs did not converge to an internal set of parameter estimates
      when analyzed with PAP. MIXD, which uses the Gibbs sampler to perform the MCMC
      sampling, produced unbiased estimates of all parameters with considerably more
      accuracy than obtained with PAP, and did not suffer from convergence of estimates
      to the boundary of the parameter space. The difference in behavior and accuracy
      of parameter estimates between PAP and MIXD was most apparent for models with
      either high or low residual additive genetic variance. Thus in situations where
      accuracy of the model is important, use of MCMC methods may be useful. In
      situations where less accuracy is needed, approximation methods may be adequate.
      Practical issues in using MCMC as implemented in MIXD to fit the mixed model are
      also discussed. Results of the simulations indicate that, unlike PAP, the
      starting configurations of most parameter estimates do not substantially
      influence the final parameter estimates in analysis with MIXD.

PMID- 8647382
TI  - The amber mutants of phage T4.

PMID- 8647384
TI  - Extragenic suppressors of nudC3, a mutation that blocks nuclear migration in
      Aspergillus nidulans.
AB  - Nuclear migration plays an important role in the growth and development of many
      organisms including the filamentous fungus Aspergillus nidulans. We have cloned
      three genes from A. nidulans, nudA, nudC, and nudF, in which mutations affect
      nuclear migration. The nudA gene encodes the heavy chain of cytoplasmic dynein.
      The nudC gene encodes a 22-kD protein. The nudF gene was identified as an extra
      copy suppressor of the temperature sensitive (ts-) nudC3 mutation. The nudC3
      mutation substantially decreases the intracellular concentration of the nudF
      protein at restrictive temperature. This is restored toward the normal level by
      an extra copy of nudF. To identify other genes whose products interact directly
      or indirectly with the NUDC protein, we have isolated a set of extragenic
      suppressors showed them to represent nine different genes, designated sncA-sncI
      (for suppressor of nudC). sncA-sncH were either dominant or semidominant in
      diploids homozygous for nudC3 and heterozygous for the snc mutations. All of the
      suppressors reversed the ts- phenotype of nudC3 by restoring the intracellular
      concentration of the NUDF protein.

PMID- 8647383
TI  - Genetic analysis of delta helD and delta uvrD mutations in combination with other
      genes in the RecF recombination pathway in Escherichia coli: suppression of a
      ruvB mutation by a uvrD deletion.
AB  - Helicase II (uvrD gene product) and helicase IV (helD gene product) have been
      shown previously to be involved in the RecF pathway of recombination. To better
      understand the role of these two proteins in homologous recombination in the RecF
      pathway [recBCsbcB(C) background, we investigated the interactions between helD,
      uvrD and the following RecF pathway genes: recF, recO, recN and ruvAB. We
      observed synergistic interactions between uvrD ant the recF, recN, recO and recG
      genes in both conjugational recombination and the repair of methylmethane
      sulfonate (MMS)-induced DNA damage. No synergistic interactions were detected
      between helD and the recF, recO and regN genes when conjugational recombination
      was analyzed. We did, however, detect synergistic interactions between helD and
      recF/recO in recombinational repair. Surprisingly, the uvrD deletion completely
      suppressed the phenotype of a ruvB mutation in a recBCsbcB(C) background. Both
      conjugational recombination efficiency and MMS-damaged DNA repair proficiency
      returned to wild-type levels in the deltauvrDruvB9 double mutant. Suppression of
      the effects of the ruvB mutation by a uvrD deletion was dependent on the recG and
      recN genes and not dependent on the recF/O/R genes. These data are discussed in
      the context of two "RecF" homologous recombination pathways operating in a
      recBCsbcB(C) strain background.

PMID- 8647386
TI  - Increased expression of Saccharomyces cerevisiae translation elongation factor 1
      alpha bypasses the lethality of a TEF5 null allele encoding elongation factor 1
      beta.
AB  - Translation elongation factor 1beta (EF-1beta) catalyzes the exchange of bound
      GDP for GTP on EF-1alpha. The lethality of a null allele of the TEF5 gene
      encoding EF-1beta in Saccharomyces cerevisiae was suppressed by extra copies of
      the TEF2 gene encoding EF-1alpha. The strains with tef5::TRP1 suppressed by extra
      copies of TEF were slow growing, cold sensitive, hypersensitive to inhibitors of
      translation elongation and showed increased phenotypic suppression of +1
      frameshift and UAG nonsense mutations. Nine dominant mutant alleles of TEF2 that
      cause increased suppression of frameshift mutations also suppressed the lethality
      of tef5::TRP1. Most of the strains in which tef5::TRP1 is suppressed by dominant
      mutant alleles of TEF2 grew more slowly and were more antibiotic sensitive than
      strains with tef5::TRP1 is suppressed by wild-type TEF2. Two alleles, TEF2-4 and
      TEF2-10, interact with tef5::TRP1 to produce strains that showed doubling times
      similar to tef5::TRP1 strains containing extra copies of wild-type TEF2. These
      strains were less cold sensitive, drug sensitive and correspondingly less
      efficient suppressor of +1 frameshift mutations. These phenotypes indicate that
      translation and cell growth are highly sensitive to changes in EF-1alpha and EF
      1beta activity.

PMID- 8647385
TI  - Isolation of mutants of Saccharomyces cerevisiae requiring DNA topoisomerase I.
AB  - Despite evidence that DNA topoisomerase I is required to relieve torsional stress
      during DNA replication and transcription, yeast strains with a top1 null mutation
      are viable and display no gross defects in DNA or RNA synthesis, possibly because
      other proteins provide overlapping functions. We isolated mutants whose
      inviablility or growth defect is relieved when TOP1 is expressed [trf mutants
      (topoisomerase one-requiring function)]. The TRF genes define at least four
      complementation groups. TRF3 is allelic to TOP2. TRF1 is allelic to HPR1,
      previously shown to be homologous to TOP1 over two short regions. TRF4 encodes a
      novel 584-amino acid protein with homology to the N-terminus of Saccharomyces
      cerevisiae topo I. Like top1 mutants, trf4 mutants have elevated rDNA
      recombination and fail to shut off RNA polymerase II transcription in stationary
      phase. trf4 null mutants are cs for viability, display reduced expression of GAL1
      and Cell Cycle Box UAS::LacZ fusions, and are inviable in combination with trfI
      null mutants, indicating that both proteins may share a common function with DNA
      topoisomerase I. The existence of multiple TRF complementation groups suggests
      that not all biological functions of topo I can be carried out by topo II.

PMID- 8647388
TI  - Genetic mapping and non-Mendelian segregation of mating type loci in the
      oomycete, Phytophthora infestans.
AB  - DNA markers linked to the determinants of mating type in the oomycete,
      Phytophthora infestans, were identified and used to address the genetic basis of
      heterothallism in the normally diploid fungus. Thirteen loci linked to the A1 and
      A2 mating types were initially identified by bulked segregant analysis using
      random amplified polymorphic DNA markers (RAPDs) and subsequently scored in three
      crosses polymorphisms (SSCP), cleaved amplified polymorphisms (CAPS), or allele
      specific polymerase chain reaction markers (AS-PCR). All DNA markers mapped to a
      single region, consistent with a single locus determining both mating types. Long
      range restriction mapping also demonstrated the linkage of the markers to one
      region and delimited the mating type locus to a 100-kb region. The interval
      containing the mating type locus displayed non-Mendelian segregation as only two
      of the four expected genotypes were detected in progeny. This is consistent with
      a system of balance lethal loci near the mating type locus. A model for mating
      type determination is presented in which the balanced lethals exclude form
      progeny those with potentially conflicting combinations of mating type alleles,
      such as those simultaneously expressing A1 and A2 functions.

PMID- 8647387
TI  - Mutations in the myp1 gene of Ustilago maydis attenuate mycelial growth and
      virulence.
AB  - Mating between haploid, budding cells of the dimorphic fungus Ustilago maydis
      results in the formation of a dikaryotic, filamentous cell type. Mating
      compatibility is governed by two mating-type loci called a and b; transformation
      of genes from these loci (e.g. a1 and b1) into a haploid strain of different
      mating type (e.g. a2 b2) allows filamentous growth and establishes a pathogenic
      cell type. Several mutants with a nonmycelial colony morphology were isolated
      after insertional mutagenesis of a filamentous, pathogenic haploid strain. The
      mutagenized region in one such mutant was recovered by plasmid rescue and
      employed to isolate a gene involved in conditioning the mycelial phenotype
      (myp1). An 1150 amino acid open reading frame is present at the myp1 locus; the
      predicted polypeptide is rich in serine residues and contains short regions with
      similarity to SH3 domain ligands. Construction of myp1 disruption and deletion
      mutants in haploid strains confirmed that this gene plays a role in mycelial
      growth and virulence.

PMID- 8647389
TI  - Spatial and temporal patterns of lin-12 expression during C. elegans
      hermaphrodite development.
AB  - The lin-12 gene encodes a receptor that mediates certain cell-cell interactions
      during Caenorhabditis elegans development. We have examined the expression of a
      lin-12::lacZ reporter gene in individual cells during the development of C.
      elegans hermaphrodites. lin-12::lacZ is expressed in a discrete spatial and
      temporal pattern during development and teh lin-12::lacZ reporter gene will
      provide a useful marker for other studies, particularly of somatic gonadal and
      vulval development. In general, the cells that express lin-12:: lacZ correspond
      to cells whose fates are known to be altered in lin-12 mutants implying that
      restriction of lin-12 expression may be an important regulatory mechanism; the
      exceptions to this statement may reveal the cellular defects that underlie
      aspects of the lin-12 phenotype that have not been previously explained. For
      decisions that are not naturally variable, lin-12::lacZ expression does not
      appear to change before or upon commitment to a cell fate implying that in these
      cases postranscriptional regulation of lin-12 activity may control cell fate
      specification.

PMID- 8647390
TI  - Isolation of dominant XO-feminizing mutations in Caenorhabditis elegans: new
      regulatory tra alleles and an X chromosome duplication with implications for
      primary sex determination.
AB  - A strain of Caenorhabditis elegans was constructed that permits selection of
      dominant or sex-linked mutations that transform XO animals (normally male) into
      fertile females, using a feminizing mutation, tra-2(e2046gf), which by itself
      does not sexually transform XO males. Twenty-three mutations were isolated after
      chemical mutagenesis and found to fall into both expected classes (four dominant
      tra-1 mutations and eight recessive xol-1 mutations) and novel classes. The novel
      mutations include 10 second-site mutations of tra-2, which are called eg
      mutations, for enhanced gain-of-function. The tra-2(gf, eg) alleles lead to
      complete dominant transformation of XO animals from fertile male into fertile
      female. Also isolated was a duplication of the left end of the X chromosome,
      eDp26, which has dominant XO lethal and feminizing properties, unlike all
      previously isolated duplications of the X chromosome. The properties of eDp26
      indicate that it carries copies of one or more numerator elements, which act as
      part of the primary sex-determination signal, the X:A ratio. The eDp26
      duplication is attached to the left tip of the X chromosome in inverted
      orientation and consequently can be used to generate unstable attached-X
      chromosomes.

PMID- 8647391
TI  - Localization of the nic-7, ac-29 and thi-10 genes within the mating-type locus of
      Chlamydomonas reinhardtii.
AB  - The tight linkage observed between the mating-type (mt) locus of Chlamydomonas
      reinhardtii and three auxotrophic mutations--nic-7 (nicotinamide-requiring), ac
      29 (acetate-requiring), and thi-10 (thiamine-requiring)--has led to the
      hypothesis that recombination is suppressed in the mt region. The physical
      location of these three genes has been established by transformation with sets of
      cloned DNA from the mt region. They lie to the left and right of the highly
      rearranged (R) domain of the mt locus, which has been proposed to be responsible
      for teh recombinational suppression in the region. The cloned nic-7+ and thi-10+
      genes will be useful as selectable markers for cotransformation markers for
      cotransformation experiments.

PMID- 8647392
TI  - Enhancers of glp-1, a gene required for cell-signaling in Caenorhabditis elegans,
      define a set of genes required for germline development.
AB  - The distal tip cell (DTC) regulates the proliferation or differentiation choice
      in the Caenorhabditis elegans germline by an inductive mechanism. Cell signaling
      requires a putative receptor in the germline, encoded b y the glp-1 gene, and a
      putative signal from the DTC, encoded by the lag-2 gene. Both glp-1 and lag-2
      belong to multigene gene families whose members are essential for cell signaling
      during development of various tissues in insects and vertebrates as well as C.
      elegans. Relatively little is known about how these pathways regulate cell fate
      choice. To identify additional genes involved in the glp-1 signaling pathway, we
      carried out screens for genetic enhancers of glp-1. We recovered mutations in
      five new genes, named ego (enhancer of glp-1), and two previously identified
      genes, lag-1 and glp-4, that strongly enhance a weak glp-1 loss-of-function
      phenotype in the germline. Ego mutations cause multiple phenotypes consistent
      with the idea that gene activity is required for more than one aspect of germline
      and, in some cases, somatic development. Based on genetic experiments, glp-1
      appears to act upstream of ego-1 and ego-3. We discuss the possible functional
      relationships among these genes in light of their phenotypes and interactions
      with glp-1.

PMID- 8647393
TI  - Evidence for an inducible repair-recombination system in the female germ line of
      Drosophila melanogaster. I. Induction by inhibitors of nucleotide synthesis and
      by gamma rays.
AB  - In the I-R system of hybrid dysgenesis in Drosophila melanogaster, the
      transposition frequency of I factor, a LINE element-like retrotransposon, is
      regulated by the reactivity level of the R mother. This reactivity is a cellular
      state maternally inherited but chromosomally determined, which has been shown to
      undergo heritable, cumulative and reversible changes with aging and some
      environmental conditions. We propose the hypothesis that this reactivity level is
      one manifestation of an inducible repair-recombination system whose biological
      role might be analogous to the SOS response in bacteria. In this paper, we show
      that inhibitors of DNA synthesis and gamma rays enhance the reactivity level in a
      very similar way. This enhancement is heritable, cumulative and reversible.

PMID- 8647394
TI  - Evidence for an inducible repair-recombination system in the female germ line of
      Drosophila melanogaster. II. Differential sensitivity to gamma rays.
AB  - In a previous paper, we reported that the reactivity level, which regulates the
      frequency of transposition of I factor, a LINE element-like retrotransposon, is
      enhanced by the same agents that induce the SOS response in Escherichia coli. In
      this report, we describe experimental evidence that, for identical genotypes, the
      reactivity levels correlate with the sensitivity of oogenesis to gamma rays,
      measured by the number of eggs laid and by frequency of dominant lethals. This
      strongly supports the hypothesis that the reactivity level is one manifestation
      of an inducible DNA repair system taking place in the female germ line of
      Drosophila melanogaster. The implications of this finding for the understanding
      of the regulation of I factor are discussed and some other possible biological
      roles of this system are outlined.

PMID- 8647395
TI  - A role for the KP leucine zipper in regulating P element transposition in
      Drosophila melanogaster.
AB  - The KP element can repress P element mobility in Drosophila melanogaster. Three
      mutant KP elements were made that had either two amino acid substitutions or a
      single amino acid deletion in the putative leucine zipper domain found in the KP
      polypeptide. Each KP element was expressed from the actin 5C proximal promoter.
      The wild-type control construct strongly repressed P element mobility, measured
      by the GD sterility and sn(w) mutability assays, in a position-independent
      manner. The single amino acid deletion mutant failed to repress P mobility by the
      double amino acid substitution mutants was position dependent. The results show
      that the leucine zipper of the KP polypeptide is important for P element
      regulation. This supports the multimer-poisoning model of P element repression,
      because leucine zipper motifs are involved in protein-protein interactions.

PMID- 8647397
TI  - Molecular analysis of scabrous mutant alleles from Drosophila melanogaster
      indicates a secreted protein with two functional domains.
AB  - Mutations at the scabrous locus (sca) affect cell-cell signaling during neural
      development. Twenty-one mutant alleles of scabrous have been analyzed. Many
      synthesize no sca protein. In others, a defective protein is arrested
      intracellularly. Two mutants in which protein is not arrested must affect sca
      protein function outside the cell. Both affect the fibrinogen related domain
      (FReD), a 200-amino acid segment conserved in fibrinogen, tenascins, and other
      proteins. In fibrinogen, this region is involved in protein interactions and is
      altered in human mutations affecting blood clotting. In sca(UM2), an invariant
      Asp residue is replaced by Asn. In sca(MSKF) allele has dominant negative
      properties, indicating that the truncated amino-terminal portion interferes with
      the function of so me other gene product. These mutations show that the conserved
      FReD is essential for wild-type sca function, but suggest that the amino-terminal
      domain also interacts with other proteins, but other neural mutations were
      without effect. Models for the role of a two-domain protein in neural development
      are discussed.

PMID- 8647396
TI  - Genetic interactions between the Drosophila Abelson (Abl) tyrosine kinase and
      failed axon connections (fax), a novel protein in axon bundles.
AB  - Mutations in the failed axon connections (fax) gene have been identified as
      dominant genetic enhancers of the Abl mutant phenotype. These mutations in fax
      all result in defective or absent protein product. In a genetic background with
      wild-type Abl function, the fax loss-of-function alleles are homozygous viable,
      demonstrating that fax is not an essential gene unless the animal is also mutant
      for Abl. The fax gene encodes a novel 47-kD protein expressed in a developmental
      pattern similar to that of Abl in the embryonic mesoderm and axons of the central
      nervous system. The conditional, extragenic noncomplementation between fax and
      another Abl modifier gene, disabled, reveal that the two proteins are likely to
      function together in a process downstream or parallel to the Abl protein tyrosine
      kinase.

PMID- 8647400
TI  - Heritability of nestling growth in cross-fostered European Starlings Sturnus
      vulgaris.
AB  - In altricial birds, growth rates and nestling morphology vary between broods. For
      natural selection to produce evolutionary change in these variables, ther must
      exist heritable variation. Since nestling traits are not any longer presents in
      parents, traditional offspring-parent regressions cannot estimate heritabilities
      of these. In this study, a partial cross-fostering experiment was performed,
      where nestlings of the European Starling (Sturnus vulgaris) were reciprocally
      exchanged between nests. The experiment demonstrated a significant heritability
      of nestling tarsus length and body mass, but not of the growth trajectories
      followed by individual nestlings. the heritability estimate for tarsus length
      obtained in the cross-fostering experiment using full-sib analysis was lower than
      those obtained by offspring-parent regressions. This is likely due to a genotype
      by-environment effect on tarsus length, with nestlings destined to become large
      but in poor condition having a low probability of appearing as parents. The main
      reason for the low heritability of growth was probably the large within-brood
      variation in growth pattern due to the initial size hierarchy of nestlings.
      Nestlings demonstrated targeted growth, where small-sized nestlings that
      initially grew slower than their siblings, managed to catch up.

PMID- 8647398
TI  - The Drosophila meiotic recombination gene mei-9 encodes a homologue of the yeast
      excision repair protein Rad1.
AB  - Meiotic recombination and DNA repair are mediated by overlapping sets of genes.
      In the yeast Saccharomyces cerevisiae, many genes required to repair DNA double
      strand breaks are also required for meiotic recombination. In contrast, mutations
      in genes required for nucleotide excision repair (NER) have no detectable effects
      on meiotic recombination in S. cerevisiae. The Drosophila melanogaster mei-9 gene
      is unique among known recombination genes in that it is required for both meiotic
      recombination and NER. We have analyzed the mei-9 gene at the molecular level and
      found that it encodes a homologue of the S. cerevisiae excision repair protein
      Rad1, the probable homologue of mammalian XPF/ERCC4. Hence, the predominant
      process of meiotic recombination in Drosophila proceeds through a pathway that is
      at least partially distinct from that of S. cerevisiae, in that it requires an
      NER protein. The biochemical properties of the Rad1 protein allow us to explain
      the observation that mei-9 mutants suppress reciprocal exchange without
      suppressing the frequency of gene conversion.

PMID- 8647401
TI  - Nondisjunction rates and abnormal embryonic development in a mouse cross between
      heterozygotes carrying a (7, 18) robertsonian translocation chromosome.
AB  - Mice bearing Robertsonian translocation chromosomes frequently produce aneuploid
      gametes. They are therefore excellent tools for studying nondisjunction in
      mammals. Genotypic analysis of embryos from a mouse cross between two different
      strains of mice carrying a (7,18) Robertsonian chromosome enabled us to measure
      the rate of nondisjunction for chromosomes 7 and 18. Embryos (429) were harvested
      from 76 litters of mice and the parental origin of each chromosome 7 and 18
      determined. Genotyping these embryos has allowed us to conclude the following:
      (1) there were 96 embryos in which at least one nondisjunction event had taken
      place; (2) the rate of maternal nondisjunction was greater than paternal
      nondisjunction for teh chromosomes sampled in these mice; (3) a bias against
      chromosome 7 and 18 nullisomic gametes was observed, reflected in a smaller than
      expected number of uniparental disomic embryos; (4) nondisjunction events did not
      seem to occur at random throughout the 76 mouse litters, but were clustered into
      fewer than would be expected cy chance; and (5) a deficiency of paternal
      chromosome 18 uniparental disomic embryos was observed along with a higher than
      normal rate of developmental retardation at 8.5 days post coitum, raising the
      possibility that this chromosome has at least one imprinted gene.

PMID- 8647399
TI  - The genetic and molecular organization of the Dopa decarboxylase gene cluster of
      Drosophila melanogaster.
AB  - We report the complete molecular organization of the Dopa decarboxylase gene
      cluster. Mutagenesis screens recovered 77 new Df(2L)TW130 recessive lethal
      mutations. These new alleles combined with 263 previously isolated mutations in
      the cluster to define 18 essential genes. In addition, seven new deficiencies
      were isolated and characterized. Deficiency mapping, restriction fragment length
      polymorphism (RFLP) analysis and P-element-mediated germline transformation
      experiments determined the gene order for all 18 loci. Genomic and cDNA
      restriction endonuclease mapping, Northern blot analysis and DNA sequencing
      provided information on exact gene location, mRNA size and transcriptional
      direction for most of these loci. In addition, this analysis identified two
      transcription units that had not previously been identified by extensive
      mutagenesis screening. Most of the loci are contained within two dense
      subclusters. We discuss the effectiveness of mutagens and strategies used in our
      screens, the variable mutability of loci within the genome of Drosophila
      melanogaster, the cytological and molecular organization of the Ddc gene cluster,
      the validity of the one band-one gene hypothesis and a possible purpose for the
      clustering of genes in the Ddc region.

PMID- 8647402
TI  - Genomic localization of tomato genes that control a hypersensitive reaction to
      Xanthomonas campestris pv. vesicatoria (Doidge) dye.
AB  - Xanthomonas campestris pv. vesicatoria causes bacterial spot, one of the most
      serious diseases of tomatoes. The lycopersicon esculentum accession 'Hawaii 7998'
      is the only reliable source of resistance to race 1 strains of the pathogen. This
      resistance is associated with a hypersensitive reaction controlled by multiple
      nondominant genes. The inoculated area becomes fully necrotic 24 hr after
      inoculation in 'Hawaii 7998,' whereas full necrosis is observed 5 and 4 days
      after inoculation in the susceptible species L. pennellii (LA 716) and their F1,
      respectively. An interspecific backcross population, using 'Hawaii 7998' as the
      recurrent parent, was analyzed to determine the linkage relationships between the
      resistance genes and 135 molecular marker loci. The range of responses of the BC1
      population included those of the parents. Linkage to a hypersensitive response
      factor was assessed by comparing the rates of necrosis development between
      homozygous and heterozygous plants at 8 hr-intervals. Three factors that affect
      the hypersensitive response of 'Hawaii 7998' were detected. One factor is on the
      short arm of chromosome I, another on the long arm of chromosome I, and a third
      on the long arm of chromosome 5. These factors appeared to act independently and
      to have additive effects.

PMID- 8647403
TI  - Two-dimensional spreads of synaptonemal complexes from solanaceous plants. VI.
      High-resolution recombination nodule map for tomato (Lycopersicon esculentum).
AB  - We have produced a high-resolution physical recombination map for tomato
      chromosomes by determining the frequency and distribution of recombination
      nodules (RNs) on tomato synaptonemal complexes (SCs). We present evidence that
      there is a 1:1 relationship between RNs and chiasmata. Every SC has at least one
      RN. There are no RNs at the ends of SCs, in kinetochores, or in the
      heterochromatic short arm of SC 2 that carries the nucleolus organizer. RNs are
      more common per unit length of SC in euchromatin compared with SC in
      heterochromatin . The average number of RNs per SC and the average number of RNs
      per SC arm are directly correlated with the length of SC in euchromatin. When SCs
      have only one RN, that RN occurs on the long arm more frequently than predicted
      based on SC arm length. Patterns of multiple Rns on SCs indicate RN (crossover)
      interference. Rns probably can occur anywhere on SCs in euchromatin, but RNs are
      not distributed randomly along SCs in euchromatin or in heterochromatin. The
      lengths of tomato's physical recombination (RN) map, classical genetic linkage
      map, and molecular linkage map all differ from each other for a variety of
      reasons.

PMID- 8647405
TI  - Molecular mapping of wheat: major genes and rearrangements in homoeologous groups
      4, 5, and 7.
AB  - A molecular-marker linkage map of hexaploid wheat (Triticum aestivum L. em.
      Thell) provides a framework for integration with teh classical genetic map and a
      record of the chromosomal rearrangements involved in the evolution of this crop
      species. We have constructed restriction fragment length polymorphism (RFLP) maps
      of the A-, B-, and D-genome chromosomes of homoeologous groups 4, 5, and 7 of
      wheat using 114 F7 lines from a synthetic X cultivated wheat cross and clones
      from 10 DNA libraries. Chromosomal breakpoints for known ancestral reciprocal
      translocations involving these chromosomes and for a known pericentric inversion
      on chromosome 4A were localized by linkage and aneuploid analysis. Known genes
      mapped include the major vernalization genes Vrn1 and Vrn3 on chromosome arms 5AL
      and 5DL, the red-coleoptile gene Rc1 on 7AS, and presumptively the leaf-rust
      (Puccinia recondita f.sp. tritici) resistance gene Lr34 on 7DS and the kernel
      hardness gene Ha on 5DS. RFLP markers previously obtained for powdery-mildew
      (Blumeria graminis f.sp. tritici) resistance genes Pm2 and Pm1 were localized on
      chromosome arms 5DS and 7AL.

PMID- 8647404
TI  - Allelic interactions heritably alter the activity of a metastable maize pl
      allele.
AB  - The maize pl locus encodes a transcriptional activator of anthocyanin
      biosynthetic genes. The Pl-Rhoades (Pl-Rh) allele confers robust purple
      anthocyanin pigment in several tissues. Spontaneous derivatives of Pl-Rh, termed
      Pl'-mahogany (Pl'-mah), arise that confer reduced pigment and are meiotically
      heritable. These derivatives influence other Pl-Rh alleles such that only Pl'-mah
      alleles are transmitted form a Pl-Rh/Pl'mah heterozygote. Genetic crosses
      establish that chromosomal segregation distortion does not explain this exclusive
      transmission and suggest that Pl-Rh invariably changes to Pl'-mah when exposed to
      Pl'-mah. Such behavior is a hallmark of paramutation. Cosegregation experiments
      demonstrate that this paramutagenic activity is genetically linked to the pl
      locus. By visually quantifying pl action through successive crosses, we find that
      phenotypic expression is inversely related to paramutation at two other maize
      loci, b and r. Previous analysis of b and r paramutation revealed extensive
      differences and led to suggestions of distinct molecular mechanisms.
      Consideration of the common features of all three systems reinvigorates the
      interpretation that the mechanistic processes of these three allelic interactions
      are similar.

PMID- 8647406
TI  - The Fundamental Theorem of Natural Selection in Ewens' sense (case of fertility
      selection).
AB  - We show that the Fundamental Theorem of Natural Selection in Ewens' sense is
      valid in the case of fertility selection: the additive genetic variance in
      fertility divided by the mean fertility is exactly equal to the partial change in
      the mean fertility from the current generation to the next. This partial change
      is the increase in the mean additive value caused by frequency changes from on
      generation to the next. This partial change is the increase in the mean additive
      value caused by frequency changes from one generation to the next but keeping
      unchanged the additive values. The only hypothesis on mating is that it does not
      affect the allelic frequencies in the sense that these are the same before and
      after mating in the parental generation, which occurs for a wide range of mating
      patterns going from random mating to several regular systems of inbreeding and
      cases of assortative mating. The fertility of couples is determined by the genes
      at an arbitrary number of loci, and the additive (average) allelic allelic
      effects are defined by a linear system of equations, which is used to extend
      Ewens' optimality principle to the case of fertility selection.

PMID- 8647407
TI  - Mitochondrial portraits of human populations using median networks.
AB  - Analysis of variation in the hypervariable region of mitochondrial DNA (mtDNA)
      has emerged as an important tool for studying human evolution and migration.
      However, attempts to reconstruct optimal intraspecific mtDNA phylogenies
      frequently fail because parallel mutation events partly obscure the true
      evolutionary pathways. This makes it inadvisable to present a single phylogenetic
      tree at the expense of neglecting equally acceptable ones. As an alternative, we
      propose a novel network approach for portraying mtDNA relationships. For small
      sample sizes (< approximately 50), an unmodified median network contains all most
      parsimonious trees, displays graphically the full information content of the
      sequence data, and can easily be generated by hand. For larger sample sizes, we
      reduce the complexity of the network by identifying parallelisms. This reduction
      procedure is guided by a compatibility argument and an additional source of
      phylogenetic information: the frequencies of the mitochondrial haplotypes. As a
      spin-off, our approach can also assist in identifying sequencing errors, which
      manifest themselves in implausible network substructures. We illustrate the
      advantages of our approach with several examples from existing data sets.

PMID- 8647408
TI  - Methodology and accuracy of estimation of quantitative trait loci parameters in a
      half-sib design using maximum likelihood.
AB  - Maximum likelihood methods were developed for estimation of the six parameters
      relating to a marker-linked quantitative trait locus (QTL) segregating in a half
      sib design, namely the QTL additive effect, the QTL dominance effect, the
      population mean, recombination between the marker and the QTL, the population
      frequency of the QTL alleles, and the within-family residual variance. The method
      was tested on simulated stochastic data with various family structures under two
      genetic models. A method for predicting the expected value of the likelihood was
      also derived and used to predict the lower bound sampling errors of the parameter
      estimates and the correlations between them. It was found that standard errors
      and confidence intervals were smallest for the population mean and variance,
      intermediate for QTL effects and allele frequency, and highest for recombination
      rate. Correlations among standard errors of the parameter estimates were
      generally low except for a strong negative correlation (r = -0.9) between the
      QTL's dominance effect and the population mean, and medium positive and negative
      correlations between the QTL's additive effect and, respectively, recombination
      rate (r = 0.5) and residual variance (r = -0.6). The implications for
      experimental design and method of analysis on power and accuracy of marker-QTL
      linkage experiments were discussed.

PMID- 8647411
TI  - [Analysis of trinucleotide repeat expansion as a new mechanism of mutation in
      Huntington's chorea: theoretical and applied aspects].
AB  - The Huntington's chorea mutation consists of expansion of trinucleotide CAG
      repeats in the recently discovered gene IT-15. In this work, for the first time
      in a population of Russian patients, correlations between the number of copies of
      CAG repeats and various clinical characteristics of the disease are investigated.
      It is established that the degree of triplet expansion determines the age of
      onset of the disease and the rate of progression of the neurological and mental
      symptoms of Huntington's chorea, and it is also shown that the genetic
      instability of the mutant allele is considerably higher upon transmission of the
      disease gene along the paternal line. We obtained direct confirmation of the
      possibility of genetic instability of a normal allele inherited paternally. In
      this work, the first successful direct (including preclinical) DNA diagnosis in
      Russia of Huntington's chorea was obtained.

PMID- 8647409
TI  - Estimating substitution rates in ribosomal RNA genes.
AB  - A model is introduced describing nucleotide substitution in ribosomal RNA (rRNA)
      genes. In this model, substitution in the stem and loop regions of rRNA is
      modeled with 16- and four-state continuous time Markov chains, respectively. The
      mean substitution rates at nucleotide sites are assumed to follow gamma
      distributions that are different for the two types of regions. The simplest
      formulation of the model allows for explicit expressions for transition
      probabilities of the Markov processes to be found. These expressions were used to
      analyze several 16S-like rRNA genes from higher eukaryotes with the maximum
      likelihood method. Although the observed proportion of invariable sites was only
      slightly higher in the stem regions, the estimated average substitution rates in
      the stem regions were almost two times as high as in the loop regions. Therefore,
      the degree of site heterogeneity of substitution rates in the stem regions seems
      to be higher than in the loop regions of animal 16S-like rRNAs due to presence of
      a few rapidly evolving sites. The model appears to be helpful in understanding
      the regularities of nucleotide substitution in rRNAs and probably minimizing
      errors in recovering phylogeny for distantly related taxa from these genes.

PMID- 8647410
TI  - The molecular evolution of the small heat-shock proteins in plants.
AB  - The small heat-shock proteins have undergone a tremendous diversification in
      plants; whereas only a single small heat-shock protein is found in fungi and many
      animals, over 20 different small heat-shock proteins are found in higher plants.
      The small heat-shock proteins in plants have diversified in both sequence and
      cellular localization and are encoded by at least five gene families. In the
      study, 44 small heat-shock protein DNA and amino acid sequences were examined,
      using both phylogenetic analysis and analysis of nucleotide substitution patterns
      to elucidate the evolutionary history of the small heat-shock proteins. The
      phylogenetic relationships of the small heat-shock proteins, estimated using
      parsimony and distance methods, reveal the gene duplication, sequence divergence
      and gene conversion have all played a role in the evolution of the small heat
      shock proteins. Analysis of nonsynonymous substitutions and conservative and
      radical replacement substitutions )in relation to hydrophobicity) indicates that
      the small heat-shock protein gene families are evolving at different rates. This
      suggests that the small heat-shock proteins may have diversified in function as
      well as in sequence and cellular localization.

PMID- 8647412
TI  - [Genetic-demographic characteristics of highland Mari].
AB  - Genetic and demographic characteristics of the population of the Gornomariiskii
      raion, Marii El Republic, were estimated. The length of generation was 28.16 +/-
      0.45 years, the average sibship size was 2.17, Crow index was 0.687, and its
      components were the following: Im = 0.114 and I(f) = 0.515. the position of the
      population of highland Mari among other populations studied in the space of
      genetic and demographic characteristics is discussed.

PMID- 8647413
TI  - [Hereditary chromosome instability in the common vole (Microtus arvalis) from the
      region of the Kyshtym nuclear accident--fact or hypothesis?].
AB  - In bone marrow cells of common voles living within the Eastern Urals radioactive
      track (EURT) and adjacent area, the frequency of chromosomal aberrations was
      higher than in cells of control animals. In several animals, the proportion of
      aberrant cells was significantly higher; cells with multiple chromosomal lesions
      prevailed among the aberrant cells. Frequency of chromosomal aberrations did not
      depend on the absorbed dose of beta-radiation. Taking into account the radiation
      background in trapping sites, the level of cytogenetic damage in the animals
      studies should be considered unexpectedly high. Outside the EURT, two voles with
      mutant karyotypes were caught. It was hypothesized that carriers of hereditary
      chromosome instability appeared in the population studies as a result of exposure
      to ionizing radiation.

PMID- 8647414
TI  - [Estimation of allele frequencies using pedigree samples].
AB  - Maximum likelihood (ML) estimations of gene frequency, deduced from data on small
      pedigree samples, are considered. It is demonstrated that a range ("gap") of
      possible values of gene frequency exists, within which no ML frequency estimation
      falls. The dependence of the size of this range on sample size is studied in
      samples consisting of nuclear pedigrees and pedigrees of a more complex
      structure. The practical importance of the effect revealed is discussed.

PMID- 8647415
TI  - [Homology and evolution of gene order: a simple method for testing a hypothesis
      on the nature of this evolution].
AB  - A method of testing various hypotheses concerning the mechanisms of evolution of
      gene order is suggested. Estimating the possibility of constructing an
      evolutionary tree that reflects the observed similarity between gene orders
      studied is proposed, provided that the distances between gene orders correspond
      to estimations obtained on the basis of the hypothesis tested. The required IBM
      PC software was developed. It was found that gene orders of the mouse, rabbit,
      cow, cat, lemur, capuchin monkey, rhesus monkey, gorilla, chimpanzee, and man
      could be readily interpreted in terms of the simplest ("map") model of
      transformation of these orders.

PMID- 8647416
TI  - [Computer programs SAN and EPID: family analysis and epidemiology of
      multifactorial diseases].
AB  - SAN software, a database management system, is elaborated. It is subject-oriented
      to family analysis in the genetics of multifactorial traits (diseases). The
      software allows creating and maintaining a family-oriented database and using the
      inputted information to calculate relative risk of disease, heritability, and
      correlations between several diseases or forms, with both actual frequency of the
      trait (prevalence) and probability of new cases (incidence). If appropriate data
      on sibships or nuclear families are available, one can calculate an empirical
      estimation of the risk of repeated cases of the disease in a family in relation
      to family anamnesis in different methods of sampling, sex-related morbidity, and
      varying age of onset. The database may also be used independently as a card
      index. The software allows one to represent pedigrees graphically, highlighting
      the desired set of traits. As application program, EPID, was developed, aimed at
      calculation and graphical presentation of age-related estimations of prevalence
      and incidence, as well as of the population risk of an individual to develop a
      disease within a time interval from birth to a certain age (accumulated
      morbidity).

PMID- 8647417
TI  - [The problem of systemic mutation].
AB  - The problems of the rearrangement of genome architecture during speciation are
      considered. The history of the problem of the role of systemic mutations in
      evolution is analyzed. The author's own phenomenological data on the spatial
      rearrangement of the chromosomal apparatus of germline tissue (that is regarded
      as systemic mutations) during the phylogeny of a number of dipterous insects are
      systematized. A concept on the essence of systemic mutations and their crucial
      role in saltatory transformation of genomes in the course of species evolution is
      advanced.

PMID- 8647418
TI  - [Presence of the binding site for the ribosomal protein L10 in the untranslated
      leader sequence upstream from the rplJ gene in Thermotoga maritima is evidence
      for autogenous control of the expression of this gene].
AB  - Comparative analysis of the structural organization of an untranslated sequence
      upstream from the rplJ gene in Thermotoga maritima revealed a potential binding
      site for the L10 ribosomal protein. The structure of the site detected is highly
      homologous to that of the 23S rRNA L10 target sequence. Structural organization
      of the potential mRNA L10 target site detected in T. Maritima is similar to that
      of mRNA targets of seven species of Enterobacteria and Synechocystis PCC 6803.
      Additional elements of structural homology between the mRNA and rRNA L10 targets
      in T. maritima are also shown. Location of the target site within the rplJ mRNA
      leader and ability of this region to form alternative conformations show that
      expression of the rplJ gene is autogenously controlled by the L10 ribosomal
      protein.

PMID- 8647419
TI  - [Introduction of mutator phage D3112 of Pseudomonas aeruginosa into Alcaligenes
      eutrophus var. metallotollerans (Strain CH34)].
AB  - It is demonstrated that the intact genome of a D3112 tranposable phage (TP) of
      Pseudomonas aeruginosa, integrated into a recombinant plasmid RP4 :: D3112, can
      be transferred by means of conjugation from P. putida PpG1 (RP4npt :: D3112)
      donor cells into Alcaligenes eutrophus var. metallotollerans cells. P. aeruginosa
      strains are unacceptable as donors because they have a bactericidal effect on A.
      eutrophus. RP4npt :: D3112 plasmid is stably inherited by A. eutrophus with D3112
      being expressed and successfully reproduced. However, TP loses the induction
      ability after UV irradiation or mitomycin C treatment. It is suggested that D3112
      TP and its miniderivatives could be used in manipulations with A. eutrophus var.
      metallotolerans.

PMID- 8647420
TI  - [Analysis of copies of the suffix-retroposon of Drosophila, produced using PCR on
      genomic DNA].
AB  - Nineteen DNA clones, containing copies of the suffix element retroposon of the
      Drosophila genome and produced by a polymerase chain reaction (PCR), were
      sequenced. Insertions of the copies in both orientations into microsatellite
      sequences (CAACA)n/(TGTTG)n and (TTTGT)n/(CACAAA)n were revealed. It was found
      that, if the microsatellite sequence has both a decanucleotide GCGGCCCGGG (GC
      box) and a colinear alternating sequence (A)5(T)4(A)3(T)2(A)1(t)n (AT-box), the
      insertion of the suffix occurs in only one orientation. It is suggested, that in
      such apparently heterochromatic sequences, suffix element copies and probably
      some other retroposons can be inserted a particular orientation by means of site
      specific recombination. An approach to analysis of the molecular organization of
      such sequences is proposed.

PMID- 8647421
TI  - [Physical mapping of Escherichia coli genome rearrangements using pulsed-field
      gel electrophoresis and the PCR method].
AB  - Physical mapping of Tn10-induced chromosomal rearrangements in Escherichia coli
      was carried out by means of pulse-field electrophoresis, Southern hybridization,
      and PCR analysis. Mutants with chromosomal rearrangements were obtained by a
      method of selection of strains with constitutive udp-gene expression elaborated
      earlier. Screenings were performed in two E. coli strains that had a udp gene
      orientation diametrical to oriC and carried in metE :: Tn10- insertion and
      mutation in the dam gene encoding DNA-methylase. Selection of mutants with
      constitutive uridine phosphorylase synthesis was aimed at placing the udp-gene
      under the control of a novel, strong promoter via genome rearrangements. Physical
      mapping indicated that chromosomal rearrangements, in all cases studied, involved
      regions of operons encoding ribosomal RNA synthesis and placed the udp gene under
      the control of an rrn promoter. The majority of rearrangements are inversions of
      the chromosomal segment between the IS10-element, located in the metE gene, and
      various sites in different rrn operons. It is shown that the involvement of a
      particular operon in inversion depends on the direction of rrn operon and udp
      gene transcription. The rearrangement frequency increases 8-10 times in the
      presence of dam mutation.

PMID- 8647422
TI  - [Evolution modes of eukaryote retrotransposons].
AB  - A number of general problems of molecular macroevolution of retroposons were
      examined, including the question of the ratio of the contributions of genomic
      replication and retrotransposition to mutational variability of retrotransposons,
      as well as that of the influence of stress-induced transpositional variability on
      the rate of evolution and the phylogenetic trees of retrotransposons. It is
      thought that the substitution fixation rate in genes of retrotransposons is
      determined by the transposition rate and the probability of mutation upon
      replication of copies of retransposons in the genome and upon retrotransposition,
      as well as by selection stabilizing the function of proteins of the
      retroreplicative mechanism. By means of molecular-evolutionary parameters,
      estimated for Drosophila retrotransposons and animal retroviruses, it was shown
      that spontaneous retrotransposition makes the dominant contribution to the
      frequency of mutation, and the expected fixation rate of nucleotide substations
      is on the order of 2 x 10(-8) per position per year. This version of evolution of
      retrotransposons agrees with the results of phylogenetic analysis of trees of
      macroevolution. Another version, associated with stress-induced transpositions,
      gives a very high rate of evolution, on the order 3 x 10(-6) fixations of
      nucleotide substitutions per position per year. This version seems improbable, as
      it leads to a significant hidden genetic load.

PMID- 8647423
TI  - [Unequal crossing over in Escherichia coli: genetic and physical mapping of
      duplications isolated in conjugational matings].
AB  - We previously demonstrated that stable heterozygous duplications deoA deoB ::
      Tn5/deoC deoD can be isolated among Deo+ recombinants obtained in conjugational
      matings between Escherichia coli strains HfrH deoA deoB :: Tn5 and HfrH deoC
      deoD. In this work, 30 duplications were tested by transduction for the inclusion
      of a set of genetic markers adjoining the deo operon (99.5 min) at the genetic
      map of E. coli: cycA :: Tn10 (96 min), zji :: Tn10 (98.2 min), thr :: Tn9 (100/0
      min), car :: Tn10 (1 min), leu :: Tn9 (2 min), and proAB :: Tn10 (6 min). The
      results obtained indicate that only three out of 30 duplications could have
      originated from unequal crossing over between the rrn operons. In eight strains,
      duplications were chosen for physical mapping by the use of Not I restriction,
      pulsed-field electrophoresis, and Southern blot hybridization with DNA of the deo
      operon. In all these strains, the presence of duplications (once a triplication)
      was confirmed by corresponding changes in the set of Not I digests, although some
      strains had additional genetic rearrangements. The order of operon copies in a
      tandem was determined, and the length of a duplicated chromosomal segment was
      calculated as equal to 25, 46, 80, 150.5, and 175 kb in duplication D49, D4, D5,
      D9, and D18, respectively. Thus, the use of the conjugational Hfr x Hfr system
      allows the generation of unique rearrangements of the E. coli genetic material.

PMID- 8647424
TI  - [Homologue pairing: initiation sites and effects on crossing over and chromosome
      disjunction in Drosophila melanogaster].
AB  - The role of homologue pairing and chromocentral association of chromosomes in
      recombination and segregation during cell division is discussed. Peculiarities of
      mitotic and meiotic chromosome pairing in Drosophila males and females are
      considered. On the basis of our own and published data, the presence and
      localization of sites of homologue pairing initiation in euchromatin are
      substantiated. The effects of transfer of initiation sites along a chromosome
      (exemplified by inversions) on chromosome pairing (asynapsis), crossing over
      (intrachromosomal, interchromosomal, and centromeric effects), and segregation
      are discussed. To record the effects of pairing sites on crossing over, a method
      of comparing crossing-over frequencies in an inverted region with those in a
      region of the same size and position with regard to the centromere on cytological
      maps was proposed. Chromosomes orient toward opposite division poles during
      paracentromeric heterochromatin pairing. This occurs after successful euchromatin
      pairing, during which the chromocentral circular structure is reorganized. If
      heterochromatin pairing is disrupted because of structural or locus mutations,
      nonexchange bivalents segregate randomly. In this case, chromosome coordination
      may occur due to proximal chiasmata or chromocentral associations between
      homologues.

PMID- 8647425
TI  - [Genetic analysis of differences in alkaline phosphatase activity in two
      Drosophila virilis strains differing in heat stress response].
AB  - Genetic control of changes in alkaline phosphatase activity was studied in adult
      individuals from two strains of Drosophila virilis under normal conditions and at
      a high temperature (38 degrees C). Flies from strain 101 responded to the heat
      shock with a reduction in enzyme activity, whereas flies from strain 147 lacked
      this response. Strains 101 and 147 were shown to differ in alkaline phosphatase
      activity at a normal temperature. Genetic analysis of these differences was
      performed. They were shown to be controlled monogenically (or by a battery of
      tightly linked genes). The gene determining alkaline phosphatase activity was
      localized on an autosome.

PMID- 8647427
TI  - [Comparative cytogenetics of three species of South American field hamsters of
      the genus Akodon (Rodentia, Cricetidae)].
AB  - A karyological analysis of three species of South American field mice of the
      genus Akodon from four different localities of the Department of Tarija, Bolivian
      Republic, was performed. In Akodon simulator, 2n = 40 - 42, NFa = 42. The
      variation of the diploid number is caused by a polymorphism of the Robertsonian
      type involving six pairs of acrocentric chromosomes. Five variants of karyotypes
      were revealed. The chromosome set of A. sp. has 2n = 36, NFa = 40; in A. toba, 2n
      = 42 - 43, NFa = 44 - 46. The variation of the diploid number and the number of
      autosomal arms is caused by the polymorphism of the first autosomal pair. A
      comparative karyological analysis of A. simulator, A. sp., and A. toba revealed a
      high level of similarity of all karyotypic elements. Fifteen autosomal pairs of
      these three species have identical G-banding patterns; the others are involved in
      formation of larger chromosomes, representing one possible combination of the
      same chromosomal material. The set of rearrangements is limited only to tandem
      chromosome fusions.

PMID- 8647426
TI  - [Variability of cytogenetic characteristics of the spotted ground squirrel Guld.
      1770].
AB  - Females with abnormal karyotype have been found during studies of genetic
      variability in the Spermophilus suslicus application of the methods of
      differential staining has shown that the chromosome aberration are due to
      deletions of heterochromatin arms. Possible causes of chromosome in the S.
      suslicus are discussed.

PMID- 8647428
TI  - [A genetic and demographic study of Dagestan highland populations and migrants to
      the lowlands. The relationship between levels of consanguinity, homozygosity and
      physiologic sensitivity].
AB  - This is a continuation of a series of papers devoted to studying the genetic
      mechanisms of adaptation in migrants from isolated highland populations of
      Dagestan to new ecological conditions (lowlands). This paper describes the main
      results of studying the relationship between levels of inbreeding, homozygosity,
      and physiological sensitivity. Earlier, we found that decreased resistance to
      changing environmental factors in migrants to lowlands from the Dagestan
      highlands was connected with their high level of homozygosity. The data obtained
      allow us to assume that missing links in this chain of events include, in
      addition to parameters of inbreeding level, parameters of neurophysiological
      sensitivity, including absolute and differential sensitivity of various analyzers
      sensory systems, which are from 65 to 75% genetically determined. Migrants from
      highland auls (villages) to lowlands exhibited a decreased rate of sensomotor
      reactions in response to light and sound of various intensities, as well as
      decreased differential color sensitivity in the long-, medium-, and short-wave
      ranges of the spectrum, compared to highlanders. The results suggest the
      selective mortality of migrants from highlands to lowlands during adaptation to
      new conditions. Those migrants who dies were characterized by specific gene
      complexes that determined the characteristic features of expression of a number
      of interrelated polymorphic and quantitative traits. Thus, the high levels of
      homozygosity and inbreeding were accompanied by a greater neurophysiological
      sensitivity and lower indices of body weight and height.

PMID- 8647429
TI  - Silencing of genes at nontelomeric sites in yeast is controlled by sequestration
      of silencing factors at telomeres by Rap 1 protein.
AB  - Rap1p binds to silencer elements and telomeric repeats in yeast, where it appears
      to initiate silencing by recruiting Sir3p and Sir4p to the chromosome through
      interactions with its carboxy-terminal domain. Sir3p and Sir4p interact in vitro
      with histones H3 and H4 and are likely to be structural components of silent
      chromatin. We show that targeting of these Sir proteins to the chromosome is
      sufficient to initiate stable silencing either at a silent mating-type locus
      lacking a functional silencer element or at a telomere in a strain in which the
      Rap1p carboxy-terminal silencing domain has been deleted. Silencing by Sir
      protein targeting can also be initiated at a telomere-proximal site (ADH4), but
      is much weaker at an internal chromosomal locus (LYS2). Strikingly, deletion of
      the Rap1p silencing domain, which abolishes telomeric silencing, improves
      targeted silencing at LYS2 by both Sir3p and Sir4p, while weakening the silencing
      activity of these proteins at or near a telomere. This effect may result from the
      release of Sir proteins from the telomeres, thus increasing their effective
      concentration at other chromosomal sites. We suggest that telomeres and Rap1p
      serve a regulatory role in sequestering Sir proteins at telomeres, controlling
      silencing at other loci in trans and preventing indiscriminate gene silencing
      throughout the genome.

PMID- 8647430
TI  - A novel mechanism for telomere size control in Saccharomyces cerevisiae.
AB  - One of the central requirements for eukaryotic chromosome stability is the
      maintenance of the simple sequence tracts at telomeres. In this study, we use
      genetic and physical assays to reveal the nature of a novel mechanism by which
      telomere length is controlled. This mechanism, telomeric rapid deletion (TRD), is
      capable of reducing elongated telomeres to wild-type tract length in an
      apparently single-division process. The deletion of telomeres to wild-type
      lengths is stimulated by the hpr1 mutation, suggesting that TRD in these cells is
      the consequence of an intrachromatid pathway. Paradoxically, TRD is also
      dependent on the lengths of the majority of nonhomologous telomeres in the cell.
      Defects in the chromatin-organizing protein Sir3p increase the rate of hpr1
      induced rapid deletion and specifically change the spectrum of rapid deletion
      events. We propose a model in which interactions among telosomes of nonhomologous
      chromosomes form higher order complexes that restrict the access of the
      intrachromatid recombination machinery to telomeres. This mechanism of size
      control is distinct from that mediated through telomerase and is likely to
      maintain telomere length within a narrow distribution.

PMID- 8647431
TI  - A search for proteins that interact genetically with histone H3 and H4 amino
      termini uncovers novel regulators of the Swe1 kinase in Saccharomyces cerevisiae.
AB  - In a genetic screen for second-site mutations that are lethal in combination with
      a deletion of the amino terminus of histone H3, we have uncovered three new gene
      products that regulate the Saccharomyces cerevisiae Swe1 kinase. The Swe1 protein
      kinase phosphorylates tyrosine residue 19 of Cdc28 and inhibits its activity. One
      histone synthetic-lethal gene, HSL1, encodes a putative protein kinase that has
      high sequence and functional homology to fission yeast cdr1/nim1, an inhibitory
      kinase of wee1. Another gene, HSL7, is a novel negative regulator of Swe1
      function. Sequences similar to Hsl7 exist in Caenorhabditis elegans and humans.
      In addition, we have isolated a dosage-dependent suppressor, OSS1, of hsl1 and
      hsl7. OSS1 is important for the transcriptional repression of SWE1 and CLN2 in
      G2. Mutations in HSL1 and HSL7 therefore cause hyperactivity of the Swe1 kinase,
      which in turn decreases mitotic Cdc28 kinase activity. Moreover, HSL5 is
      identical to CDC28, further suggesting that it is the decreased Cdc28 kinase
      activity in these hsl mutants that causes lethality in the histone mutant
      background. Because neither HSL1 nor HSL7 is essential in yeast, and histone
      transcription is unaffected by the hsl5/cdc28 mutation, it is unlikely that
      synthetic lethality results from reduced transcription of HSL1 and HSL7 caused by
      histone mutations, or from reduced histone transcription when Cdc28 kinase
      activity is compromised. We suggest that these cell cycle regulators function in
      a pathway upstream of both histones H3 and H4, thereby modulating histone
      function in the cell cycle.

PMID- 8647432
TI  - Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel p130Cas
      related protein, Sin.
AB  - To understand how protein-protein interactions mediated by the Src-SH3 domain
      affect c-Src signaling, we screened for proteins that interact with the Src-SH3.
      We found a novel protein, Sin (Src interacting or signal integrating protein),
      that binds to Src-SH3 with high affinity, contains numerous tyrosine residues in
      configurations suggestive of SH2-binding sites, and is related to the v-Src
      substrate p130Cas. In cotransfection assays, a small fragment of Sin retaining
      the Src-SH3-binding site and one tyrosine-containing motif induced c-Src
      activation as measured by a transcriptional reporter. Phosphorylation of the
      peptide on tyrosine by c-Src, as a consequence of Src-SH3 binding, was necessary
      for its stable interaction with c-Src in vivo and for transcriptional activation.
      Phosphorylation of multiple tyrosine-containing motifs found on Sin correlated
      with c-Crk and cellular phosphoprotein binding to Sin as well as increased c-Src
      activity. These data suggest that (1) SH2 and SH3 ligand sites on Sin
      cooperatively activate the signaling potential of c-Src, (2) Sin acts as both an
      activator and a substrate for c-Src, and (3) phosphorylated Sin may serve as a
      signaling effector molecule for Src by binding to multiple cellular proteins.

PMID- 8647433
TI  - The splicing factor U2AF35 mediates critical protein-protein interactions in
      constitutive and enhancer-dependent splicing.
AB  - The splicing factor U2AF (U2 snRNP auxiliary factor) is a heterodimer with
      subunits of 65 and 35 kD (U2AF65 and U2AF35). U2AF65 binds specifically to 3'
      splice sites, but previous studies failed to demonstrate a function for U2AF35.
      Here, we report that U2AF35 is required for constitutive splicing and also
      functions as a mediator of enhancer-dependent splicing. Nuclear extracts
      deficient in U2AF35 were inactive; however, both constitutive and enhancer
      dependent splicing could be restored by the addition of purified recombinant
      U2AF35. In vitro protein-RNA interaction studies with pre-mRNAs containing either
      a constitutive or regulated splicing enhancer revealed that U2AF35 directly
      mediates interactions between U2AF65 and proteins bound to the enhancers. Thus,
      U2AF35 functions as a bridge between U2AF65 and the enhancer complex to recruit
      U2AF65 to the adjacent intron.

PMID- 8647434
TI  - TAF-like function of SV40 large T antigen.
AB  - The simian virus 40 (SV40) early gene product large T antigen promiscuously
      activates simple promoters containing a TATA box or initiator element and at
      least one upstream transcription factor-binding site. Previous studies have
      suggested that promoter activation requires that large T antigen interacts with
      both the basal transcription complex and the upstream-bound factor. This
      mechanism of activation is similar to that proposed for TBP-associated factors
      (TAFs). We report genetic and biochemical evidence suggesting that large T
      antigen performs a TAF-like function. In the ts13 cell line, large T antigen can
      rescue the temperature-sensitive (ts) defect in TAF(II)250. In contrast, neither
      E1a, small t antigen, nor mutants of large T antigen defective in transcriptional
      activation were able to rescue the ts defect. These data suggest that
      transcriptional activation by large T antigen is attributable, at least in part,
      to an ability to augment or replace a function of TAF(II)250. In addition, we
      show that large T antigen interacts in vitro with the Drosophila TAFs (dTAFs)
      dTAF(II)150, dTAF(II)110, and dTAF(II)40, as well as TBP. The relevance of these
      in vitro results was established in coimmunoprecipitation experiments using
      extracts of SV40-infected alpha3 cells that express an epitope-tagged TBP. Large
      T antigen was coimmunoprecipitated by antibodies to epitope-tagged TBP,
      endogenous TBP, hTAF(II)100, hTAF(II)130, and hTAF(II)250, under conditions where
      holo-TFIID would be precipitated. In addition, large T antigen copurified and
      coimmunoprecipitated with phosphocellulose-purified TFIID from SV40-infected
      alpha3 cells. Large T antigen also coprecipitated with anti-TBP antibody from
      extracts of ts13 cells expressing wild-type large T antigen under conditions
      where the ts defect in TAF(II)250 was rescued. In contrast, a transactivation
      mutant of large T antigen, which was unable to rescue the ts defect, failed to
      coprecipitate. We conclude from these data that transcriptional activation of
      many promoters by large T antigen results from its performing a TAF-like function
      in a complex with TFIID.

PMID- 8647435
TI  - Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions
      in tooth and hair development.
AB  - Targeted inactivation of the murine gene encoding the transcription factor LEF-1
      abrogates the formation of organs that depend on epithelial-mesenchymal tissue
      interactions. In this study we have recombined epithelial and mesenchymal tissues
      from normal and LEF-1-deficient embryos at different stages of development to
      define the LEF-1-dependent steps in tooth and whisker organogenesis. At the
      initiation of organ development, formation of the epithelial primordium of the
      whisker but not tooth is dependent on mesenchymal Lef1 gene expression.
      Subsequent formation of a whisker and tooth mesenchymal papilla and completion of
      organogenesis require transient expression of Lef1 in the epithelium. These
      experiments indicate that the effect of Lef1 expression is transmitted from one
      tissue to the other. In addition, the finding that the expression of Lef1 can be
      activated by bone morphogenetic protein 4 (BMP-4) suggests a regulatory role of
      this transcription factor in BMP-mediated inductive tissue interactions.

PMID- 8647436
TI  - Lineage-specific regulators couple cell lineage asymmetry to the transcription of
      the Caenorhabditis elegans POU gene unc-86 during neurogenesis.
AB  - The POU homeo box gene unc-86 specifies neuroblast and neural identities in the
      developing Caenorhabditis elegans nervous system. After an asymmetric neuroblast
      division, unc-86 is expressed in one of two daughter cells in 27 lineage classes
      that are not obviously related by function or position. We show here that unc-86
      transcriptional regulatory regions detect cell lineage asymmetry to activate unc
      86 expression in one of two neuroblast daughter cells. Distinct regulatory
      regions activate unc-86 expression in particular sets of sublineages. Therefore
      the unc-86 regulatory region integrates distinct cell lineage asymmetry cues to
      activate unc-86 expression in the many classes of neuroblast cell lineages. In
      agreement with such lineage-specific regulation of unc-86 asymmetric activation,
      mutations in lin-11 (LIM homeo box), ham-1, and lin-17 affect the asymmetry of
      unc-86 expression in particular cell lineages, and mutations in lin-32
      (achaete/scute family), vab-3 (Pax-6 homolog) and egl-5 (Abd-B homolog) affect
      the establishment of unc-86 expression in other cell lineages. Homologs of unc-86
      and many of these unc-86 regulators have been implicated in control of
      neurogenesis in vertebrates and invertebrates. These data suggest that unc-86
      acts in a phylogenetically conserved pathway that couples neuroblast cell lineage
      asymmetry to the generation of diverse neural types.

PMID- 8647437
TI  - The transcriptional factor CF2 is a mediator of EGF-R-activated dorsoventral
      patterning in Drosophila oogenesis.
AB  - Establishment of dorsoventral polarity during Drosophila oogenesis requires
      localized intercellular communication between the follicular cells and the
      oocyte. This is initiated by the transmission of a "dorsal signal" from the
      oocyte to the anterior dorsal follicle cells by the EGF receptor (EGF-R) pathway
      and is followed by transmission of a second signal from the ventral follicle
      cells back to the embryo. We show that the zinc finger transcription factor CF2
      participates in these processes. CF2 is suppressed by EGF-R signaling in the
      anterior dorsal follicle cells. Altered expression patterns of CF2 result in
      specific dorsoventral patterning defects in egg chambers and in embryos, as
      demonstrated phenotypically and with molecular markers. CF2 appears to act as a
      repressor of dorsal follicle cell fates and specifically as a repressor of the
      rhomboid gene transcription.

PMID- 8647438
TI  - Ectopic E2F expression induces S phase and apoptosis in Drosophila imaginal
      discs.
AB  - Previous experiments suggest that a key event in the commitment of cultured
      mammalian cells to entering S phase is a rise in activity of the transcription
      factor E2F. In this report, we study the role of Drosophila E2F in imaginal disc
      cells in vivo, by examining the distribution of the endogenous protein and
      studying the consequences of ectopic E2F expression. First, we find that
      endogenous E217 falls from high to very low levels as cells initiate DNA
      synthesis during a developmentally regulated G1-S-transition in the eye disc.
      Second, we find that ectopic E2F expression drives many otherwise quiescent cells
      to enter S phase. Subsequently, cells throughout the discs express reaper (a
      regulator of apoptosis) and then die. Third, we find that ectopic E2F expression
      during S phase in normally cycling cells blocks their re-entry into S phase in
      the following cell cycle. Although we do not know the fate of these cells, we
      suspect that ultimately they are killed by ectopic E2F. Taken together, our
      results show that an elevation in the level of E2F is sufficient to induce
      imaginal disc cells to enter S phase. Furthermore, they suggest that the
      downregulation of E2F upon entry into S phase may be essential to prevent the
      induction of apoptosis.

PMID- 8647439
TI  - Identification of functional and structural amino-acid residues by parsimonious
      mutagenesis.
AB  - For in vitro evolution of protein function, we previously proposed using
      parsimonious mutagenesis (PM), a technique where mutagenic oligodeoxynucleotides
      (oligo) are designed to minimize coding sequence redundancy and limit the number
      of amino acid (aa) residues which do not retain parental structural features. For
      this work, PM was used to increase the affinity of C6.5, a human single-chain Fv
      (scFv) that binds the glycoprotein tumor antigen, c-erbB-2. A phage antibody
      library was created where 19 aa located in three of the heavy (H) and light (L)
      chain antigen-binding loops (L1, L3 and H2) were simultaneously mutated. After
      four rounds of selection, 50% of scFv had a lower dissociation rate constant
      (koff) than the parental scFv. The Kd of these scFv ranged from twofold (Kd=7.0 x
      10(-9) M) to sixfold (Kd=2.4 x 10(-9) M) lower than the parental scFv (Kd=1.6 x
      10(-8) M). In higher affinity scFv, substitutions occurred at 10/19 of the
      positions, with 21/28 substitutions occurring at only four positions, two in H2,
      and one each in L1 and L3. Only the wild type (wt) aa was observed at 9/19 aa.
      Based on a model of C6.5, seven of the nine conserved aa have a structural role
      in the variable domain, either in maintaining the main chain conformation of the
      loop, or in packing on the H-chain variable domain. Two of the conserved aa are
      solvent exposed, suggesting they may play a critical role in recognition. Thus,
      PM identified three types of aa: structural aa, functional aa which modulate
      affinity, and functional aa, which are critical for recognition. Since the
      sequence space was not completely sampled, higher affinity scFv could be produced
      by subjecting functional aa which modulate affinity to a higher rate of mutation.
      Furthermore, PM could prove useful for modifying function in other proteins that
      belong to structurally related families.

PMID- 8647440
TI  - Characterization of a complex satellite DNA in the mollusc Donax trunculus:
      analysis of sequence variations and divergence.
AB  - A highly repetitive sequence in the genomic DNA of the bivalve mollusc Donax
      trunculus (Dt) has been identified upon restriction with EcoRV. During the time
      course of DNA digestion, genomic fragments resolved electrophoretically into a
      ladder-like banding pattern revealing a tandem arrangement of the repeated
      elements, thus representing satellite DNA sequences. Cloning and sequence
      analysis unraveled the presence of two groups of monomer units which can be
      considered distinctive satellite subfamilies. Each subclass is distinguishable by
      the presence of 17 evenly spread diagnostic nucleotides (nt). The respective
      consensus sequences are 155 bp in length and differ by 11%, while relevant
      internal substructures were not observed. The two satellite subfamilies
      constitute 0.23 and 0.09% of the Dt genome, corresponding to 20 000 and 7600
      copies per haploid complement, respectively. Sequence mutations often appear to
      be shared between two or more monomer variants, indicating a high degree of
      homogenization as opposed to that of random mutational events. Shared mutations
      among variants appear either as single changes or in long stretches. This pattern
      may arise from gene conversion mechanisms acting at different levels, such as the
      spread of nt sequences of a similar length to the monomer repeat itself, and the
      diffusion of short tracts a few bp long. Subfamilies might have evolved from the
      occasional amplification and spreading of a monomer variant effected by gene
      conversion events.

PMID- 8647441
TI  - Cloning, sequencing and expression of the bovine CD3 epsilon and TCR-zeta chains,
      two invariant components of the T-cell receptor complex.
AB  - CD3 epsilon and the zeta-chain of the bovine T-cell receptor (TCR) are two
      invariant molecules with an important role in signal transduction via the TCR/CD3
      complex. The nucleotide sequence of a bovine CD3 epsilon cDNA clone containing
      the complete coding sequence was determined and the deduced amino acid (aa)
      sequence compared to that of other species. The cytoplasmic domains of the
      different CD3 epsilon clearly show a higher degree of conservation than the
      extracellular domains. Bovine CD3 epsilon produced in Escherichia coli using
      different bacterial expression vectors was recognised by antibodies (Ab) directed
      against the intracytoplasmic domain of human CD3 epsilon. A partial bovine TCR
      zeta-chain cDNA was generated by the polymerase chain reaction (PCR) using
      primers that were based on sequences that are conserved between different
      species; 3' and 5' RACE-PCR were carried out to obtain the complete TCR zeta
      chain cDNA sequence. A comparison of the predicted TCR zeta-chain aa sequence
      reveals that the GDP/GTP-binding motif, which is conserved in other species,
      shows marked differences in the bovine and ovine TCR zeta-chains. In contrast to
      CD3 epsilon, the short extracellular domain of the TCR zeta-chain is 100%
      conserved between the different species and the transmembrane domain also shows a
      high degree of identity. Ab were raised against the TCR zeta-chain, produced as a
      glutathione S-transferase fusion protein in E. coli, and were used in Western
      blot analysis to further characterise TCR zeta-chain expression in T-cells. The
      regents provide valuable tools for the study of signal transduction pathways in
      normal and transformed bovine T-cells.

PMID- 8647443
TI  - The human S3a ribosomal protein: sequence, location and cell-free transcription
      of the functional gene.
AB  - The intron-containing gene encoding human ribosomal protein S3a (hRPS3a) was
      isolated by utilizing a PCR-based strategy to detect a gene-specific intron which
      was subsequently used as a probe for cloning of the entire gene. The hRPS3a gene
      is composed of six exons and five introns spanning 5013 bp. As described for
      other hRP-encoding genes, the promoter lacks a canonical TATA sequence and a
      defined CAAT box. Primer extension experiments, as well as cell-free
      transcription, revealed that a cytosine functions as the major transcription
      start point in a polypyrimidine region, but a guanosine at position -1 was also
      able to initiate transcription. Hybridization analysis of chromosomal DNA from a
      panel of human-rodent somatic cell hybrids revealed that hRPS3a is encoded by a
      single locus in the human genome, present on chromosome 4.

PMID- 8647442
TI  - Chromatin nucleoprotein complexes containing tightly bound c-abl, p53 and bcl-2
      gene sequences: correlation with progression of chronic myelogenous leukemia.
AB  - We previously developed a technique to isolate subchromatin nucleoprotein
      complexes (NPC) that contain tightly bound genes and enzymatic activities. NPC
      fractions (NPCF) were prepared by directly treating isolated nuclei with MspI to
      generate six NPCF (S1, M1, S2, M2, 0.1K and R). The NPCF have been used to
      predict the potential efficacy of interferon-alpha (IFN-alpha) treatment in
      patients with chronic myelogenous leukemia (CML) [Nicolson et al., Gene 159
      (1995) 105-111]. Here the NPCF were probed for the presence of tightly bound c
      abl, p53 and bcl-2 genes. We found that the NPCF isolated from the nuclei of
      leukocytes of normal individuals rarely contained detectable quantities of
      tightly-bound c-abl, p53 or blc-2 genes or gene sequences, whereas in CML nuclei
      these genes were often found in tight association with multiple NPCF. Examination
      of NPCF isolated from the leukocyte nuclei from patients with highly progressive
      CML for the presence of the three genes revealed that more NPCF contained the
      three tightly-bound genes than leukocyte NPCF from patients with stable or less
      progressed CML. These data suggest that as CML progresses to more malignant
      states, oncogenes, suppressor genes and apoptosis-associated genes become tightly
      associated with NPCF.

PMID- 8647444
TI  - A new set of versatile vectors for the heterologous expression of foreign genes
      using the baculovirus system.
AB  - A new set of versatile advanced baculovirus (BV) vectors for the production of
      fused proteins in insect cells, under the control of the strong polyhedrin
      promoter of the Autographa california nuclear polyhedrosis virus (AcMNPV), has
      been constructed. The vectors contain peptide tags which allow immunological
      detection, as well as purification of recombinant protein produced via the BV
      expression system.

PMID- 8647445
TI  - Characteristic sequences in the promoter region of the chicken tyrosinase
      encoding gene.
AB  - We have isolated and sequenced a genomic DNA sequence encoding chicken tyrosinase
      (TYR) that includes 2125 nt of 5' flanking sequence, the first exon and a part of
      the first intron. The 5' flanking sequence was able to drive transcription of a
      reporter gene in immortalised quail neural crest cells. The sequence, which is
      the most extensive to be reported for a lower vertebrate TYR gene to date, was
      further analyzed using primer extension and computer-aided homology searches.
      Transcription initiation appears to occur at heterogeneous start points and in
      the absence of a TATA box, but may be mediated via a potential initiator (Inr)
      element and Sp1-binding motif. We have identified two evolutionarily conserved
      regions within the 5' flanking sequence that may be functionally significant, as
      they contain regulatory elements previously reported to play a role in melanocyte
      specific expression of TYR in mammals. This study contributes towards an
      understanding of the requirements for melanocyte-specific TYR expression in lower
      vertebrates.

PMID- 8647446
TI  - Cell-cycle-dependent expression of the STK-1 gene encoding a novel murine
      putative protein kinase.
AB  - We have cloned a novel putative serine/threonine kinase-encoding gene, designed
      STK-1, from murine embryonic stem (ES) cell and testis cDNA libraries. The kinase
      most closely related to STK-1 is Xenopus laevis XLP46 protein kinase which shows
      71% amino-acid identity to STK-1 between their kinase domains. Nevertheless, STK
      1 is conserved throughout phylogeny with hybridizing sequences being detected in
      DNA from mammals, amphibians, insects and yeast. STK-1 mRNA is detected in
      testis, intestine and spleen, tissues that contain a large number of
      proliferating cells, but not in other tissues. All cell lines tested expressed
      STK-1 mRNA with levels being dependent upon proliferation rates. In NIH 3T3
      cells, STK-1 is expressed in a cell-cycle-dependent fashion. These findings
      suggest a role for STK-1 in cell growth.

PMID- 8647447
TI  - A novel putative helicase produced in early murine lymphocytes.
AB  - DNA helicases (Hel) play a role in a number of processes involving DNA strand
      separation, including replication, repair, recombination and transcription.
      Rearrangement of receptor genes, which occurs in immature lymphocytes, could also
      be mediated by Hel. We report here the cloning from murine fetal thymus tissue of
      a novel putative Hel containing seven conserved Hel domains and belonging to the
      DEGH subclass of DNA Hel. We term the encoding gene lsh (lymphoid-specific Hel),
      since the gene is expressed in early thymocytes, but not in heart, liver, lung,
      muscle, brain or kidney, as judged by Northern analysis. Spleen cells expressed
      lsh following activation. T- and B-cell lines, at both the immature and mature
      stage, expressed lsh. To examine the earliest stages of lymphopoiesis, mouse
      embryonic tissues were examined; lsh was not detected in the yolk sac of day 12
      of gestation, but was expressed in fetal liver and at high levels in fetal thymus
      at day 15 of gestation.

PMID- 8647448
TI  - Structure of the growth hormone-encoding gene and its promoter in mice.
AB  - The isolation and nucleotide sequence determination of the 5' flanking region of
      the mouse growth hormone (mGH)-encoding gene (mGH) is described. The mGH gene
      consists of five exons and four introns, as is observed in other mammalian
      species. The second intron in mGH is much smaller than its rat counterpart, thus
      being similar in size to human, bovine and porcine GH. The transcription start
      point was determined to be a C residue 62 bp upstream from the start codon, ATG.
      Analysis of 1767 bp of the 5' flanking region, with respect to putative
      regulatory elements, revealed a TATA box, two binding sites for growth hormone
      factor (GHF1), a GC box (SP1), a thyroid-response element (TRE) and a silencer
      (SiL) sequence motif. As expected, the mGH promoter shows a higher degree of
      homology with rat, as compared to the other mammalian species like pig, cattle
      and human, where an overall homology exists only at the proximal promoter region.

PMID- 8647449
TI  - The murine homolog of TB2/DP1, a gene of the familial adenomatous polyposis (FAP)
      locus.
AB  - The cDNA of the murine counterpart of the human TB2/DP1 (deleted in polyposis)
      gene, one of the six genes deleted in severe cases of familial adenomatous
      polyposis (FAP) disease, was isolated and analyzed. The murine transcript is 734
      bp long and thereby considerably shorter than the 3100-bp human counterpart. This
      is due to a completely different 3' untranslated region in mouse which starts
      immediately after the translational stop codon, thereby deleting a RFLP
      (restriction-fragment length polymorphism) marker for this disease. The amino
      acid sequence, however, is 92% conserved between mouse and man. Triggering of
      murine mast cells by IgE plus antigen results in a decrease of TB2/DP1 mRNA up to
      60% after 2 h implying a possible role of this gene in regulation of the allergic
      effector cell. Reverse transcription-polymerase chain reaction (RT-PCR) analysis
      shows an ubiquitous expression pattern in a number of mouse cell lines and
      tissues.

PMID- 8647450
TI  - Cloning of a rat cDNA encoding retinol dehydrogenase isozyme type III.
AB  - The primary and rate-limiting step in retinoic acid (RA) biosynthesis requires
      the conversion of retinol into retinal. Previously, two genes encoding retinol
      dehydrogenases (RoDH), which recognize holo-cellular retinol-binding protein as
      substrate, had been cloned, expressed and identified as members of the short
      chain dehydrogenase/reductase (SDR) gene family. This work reports the cloning of
      a cDNA encoding a third RoDH isozyme, RoDH(III). The deduced amino-acid sequence
      of RoDH(III) indicates 97.8% identity with RoDH(I) and 82.3% identity with
      RoDH(II). RNase protection assays revealed RoDH(III) mRNA expression only in rat
      liver, in contrast to RoDH(I) and RoDH(II), which had their mRNA expressed in rat
      liver, kidney, lung, testis and brain. These data extend the insight that a
      subfamily of SDR isozymes, tissue-distinctively expressed, catalyzes the first
      step in RA biogenesis.

PMID- 8647451
TI  - HEP-COP, a novel human gene whose product is highly homologous to the alpha
      subunit of the yeast coatomer protein complex.
AB  - A 4333-bp novel human cDNA sequence designated HEP-COP was isolated from the
      Hep3B hepatocellular carcinoma cell line by the RACE technique. Within HEP-COP
      was identified an ORF of 3672 bp encoding a deduced 1224-amino-acid (aa) sequence
      which exhibited striking homology with the 1201-aa sequence of RET1P, the alpha
      subunit of the coatomer complex (alpha-COP) in Saccharomyces cerevisiae which
      participates in membrane transport between the endoplasmic reticulum and Golgi
      apparatus. The aa homology was highest in their N-terminal regions which each
      contained six WD-40 repeat motifs [Van der Voorn and Ploegh, FEBS Lett. 307
      (1992) 131-134], and both proteins were predicted to be hydrophilic with similar
      estimated molecular masses of 138 324 and 135 599 Da, respectively. Northern blot
      hybridization demonstrated that HEP-COP was expressed in a wide range of human
      adult and fetal tissues. RT-PCR analysis revealed no differential expression of
      HEP-COP in 14 human cancer cell lines, as compared with normal control cells.
      Considering the close similarities between HEP-COP and yeast alpha-COP, and the
      ubiquitous expression of HEP-COP implying an essential cellular role, it is
      likely that HEP-COP is the human homologue of alpha-COP.

PMID- 8647452
TI  - Identification of a human RAD52 pseudogene located on chromosome 2.
AB  - A human testis cDNA library was screened with a hybridization probe encoding the
      mouse RAD52 gene. Two classes of clones were identified, one derived from the
      human RAD52 homolog (hRAD52), the other derived from a pseudogene. In addition to
      many point mutations, several of which encode stop codons, the pseudogene
      contains a number of frame shifts and a 103-bp deletion. We further determined
      that the pseudogene is processed and is located on human chromosome 2, in
      contrast to hRAD52 which is found on chromosome 12. Reverse transcription-PCR
      analysis of cultured human diploid fibroblasts, as well as fibrosarcoma cells,
      revealed that while hRAD52 is expressed at low, but detectable levels in these
      cells, the pseudogene is not.

PMID- 8647453
TI  - Alternative splicing gives rise to two novel long isoforms of Zn-alpha 2
      glycoprotein, a member of the immunoglobulin superfamily.
AB  - We have isolated, from a rat liver cDNA library, two cDNAs encoding novel long
      isoforms of Zn-alpha2-glycoprotein (Zn-alpha2-gp), a member of the immunoglobulin
      superfamily with a high degree of sequence similarity to class-I major
      histocompatibility complex (MHC) antigens. Nucleotide (nt) sequence analysis of
      these two novel cDNAs has revealed that they contain insertions of 138 and 123 nt
      between the second and third exons of Zn-alpha2-gp, resulting in in-frame
      insertions of 46 and 41 amino acids (aa), respectively. Analysis of the mechanism
      of generation of both isoforms, named Zn-alpha2-gpA and Zn-alpha2-gpB, has shown
      that they result from a series of alternative splicing events, including
      alternative use of two additional exons, and of two different 3'-splice sites
      present in the first of these novel exons. The occurrence of these alternative
      splicing events in Zn-alpha2-gp could contribute to increasing the diversity of
      this nonpolymorphic and soluble class-I MHC antigen.

PMID- 8647454
TI  - Cloning and characterization of cDNAs coding for heavy and light chains of a
      monoclonal antibody (MabB23) specific for human plasma apolipoprotein B-100.
AB  - We have determined the nucleotide sequences encoding the heavy and light chains
      of the Fab fragment of murine monoclonal antibody MabB23(gamma2b,lambda), which
      is specific for human plasma apolipoprotein B-100 of low-density lipoproteins.
      The sequence analyses revealed that the variable regions of the heavy and light
      chains are members of mouse heavy-chain subgroup I(B) and lambda light-chain,
      respectively. A few unusual amino acids in the framework and constant regions of
      the heavy-chain were also noticed.

PMID- 8647455
TI  - Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and
      amphetamine-regulated transcript.
AB  - PCR differential display screening has recently identified a rat mRNA termed CART
      (cocaine- and amphetamine-regulated transcript) which is transcriptionally
      regulated in the striatum following acute administration of psychomotor
      stimulants. The endogenous CART transcript is expressed in diverse rat brain
      structures, as well as endocrine tissues. The deduced CART protein contains a
      hydrophobic signal sequence, suggesting that it may be targeted for secretion.
      Thus, the CART protein may represent a novel neuroendocrine signaling molecule.
      The study described here represents a complete analysis of the human CART cDNA
      and gene. The complete nucleotide (nt) sequence of the approx. 900-nt human CART
      transcript is contained within three distinct exons, with the entire human CART
      gene localized to a segment of genomic DNA approx. 2 kb in length. The human CART
      cDNA sequence is 80% identical to the corresponding rat cDNA, with 92% homology
      observed within the deduced protein-coding region. Third-nt changes account for
      most of the latter differences, with CART exhibiting 95% identity between these
      two species at the amino-acid sequence level. PCR/Southern blot analysis of DNA
      isolated from human/rodent somatic cell hybrid panels localizes the CART gene to
      human chromosome 5. Lastly, Northern blot analysis reveals that the gross pattern
      of distribution of CART mRNA in human brain is similar to that previously
      observed in rat. These overall similarities suggest that CART plays a conserved
      role within the mammalian neuroendocrine system.

PMID- 8647456
TI  - Olfactory receptor-encoding genes and pseudogenes are expressed in humans.
AB  - A putative olfactory receptor-encoding gene was cloned from human genomic DNA and
      shown to be expressed by isolation of a full-length cDNA from olfactory tissue. A
      second cDNA clone was found to encode an olfactory receptor pseudogene. The
      expression of a pseudogene from the olfactory gene repertoire, in neurons which
      express only a single receptor type, implies that many neurons will be non
      functional.

PMID- 8647457
TI  - Synthesis of a modified gene encoding human ornithine transcarbamylase for
      expression in mammalian mitochondrial and universal translation systems: a novel
      approach towards correction of a genetic defect.
AB  - The mitochondrial (MT) genome is a potential means of gene delivery to human
      cells for therapeutic expression. As a first step towards this, we have
      synthesized a gene coding for mature human ornithine transcarbamylase (OTC) by
      recursive PCR using 18 oligodeoxyribonucleotides, each 70-80 nucleotides in
      length, using codons which should allow translation in accordance with both
      mammalian mt and universal codon usage. Flanking mt DNA sequences were
      incorporated which are designed to facilitate site-specific cloning into the mt
      genome. Expression of this human gene in Escherichia coli leads to an
      immunoreactive OTC product of the correct size and N-terminal amino-acid
      sequence, but which forms inclusion bodies and lacks enzymatic activity.

PMID- 8647459
TI  - Isolation and characterization of a cDNA encoding a novel human transcription
      factor TFIID subunit containing similarities with histones H2B and H3.
AB  - Using the yeast two-hybrid system, we isolated a human cDNA that encodes a
      protein (hp22) interacting with TATA box-binding factor TFIID subunit p80
      containing similarity with histone H4. Sequence analysis showed that the open
      reading frame (ORF) specifies a 161-amino-acid (aa) polypeptide homologous to
      Drosophila melanogaster TFIID subunit p22 (dp22). Comparison of the aa sequence
      of human TFIID subunit p22 (hp22) with that of dp22 revealed that p22 is composed
      of two distinct regions; the less conserved N-terminal (20% identity) and the
      highly conserved C-terminal (65% identity) regions. Additionally, the C-terminal
      region was found to contain similarities with histones H2B and H3. Northern blot
      analysis showed mRNA corresponding to hp22 to be expressed in all tissues
      examined.

PMID- 8647458
TI  - The gene encoding human ribosomal protein S24 and tissue-specific expression of
      differentially spliced mRNAs.
AB  - Starting with a cloned cDNA encoding human ribosomal protein S24 [Brown et al.,
      Gene 91 (1990) 293-296], we PCR-amplified two introns from the human RPS24 locus.
      These then were used as unique nucleic-acid probes to isolate a 12-kb RPS24 gene
      fragment from a library of human genomic DNA. The nucleotide sequence of human
      RPS24 (4942 bp), its exon-intron organization and mRNA transcription start point
      were determined using standard procedures. RT-PCR analyses of S24 mRNAs from
      multiple human tissues and cell lines revealed two mRNA isoforms which differ
      from each other, as well as murine S24 mRNAs due to alternative exon splices near
      the 3' end of the gene.

PMID- 8647460
TI  - Processing and expression of rat and human clotting factor-X-encoding cDNAs.
AB  - The cDNA encoding clotting factor X, which participates in the middle stage of
      the blood coagulation cascade was cloned from a rat liver cDNA library.
      Sequencing of the rat factor-X-encoding cDNA revealed that this vitamin-K
      dependent protein has a dibasic Arg-Arg sequence at the propeptide cleavage site,
      as occurs in other vitamin-K-dependent proteins. Although the human and rat
      deduced amino acid sequences are remarkably similar (76% identical), they do
      significantly differ in that human factor-X contains a unique Thr-Arg sequence at
      the propeptide cleavage site [Fung et al., Proc. Natl. Acad. Sci. USA 82 (1985)
      3591-3595], where a dibasic sequence would normally be expected. This specific
      site is the recognition motif for the endoprotease, furin, which is located in
      the Golgi apparatus. Both rat and human cDNAs expressed in Cos-1 cells resulted
      in secretion of a mixture of single- and two-chain forms of factor X. The two
      chain forms were devoid of the propeptide and were produced at similar rates by
      the transfected cells. The efficient processing of human factor X, when compared
      to rat factor X, may indicate that an additional protease(s), which recognizes
      the Thr-Arg motif, may be involved in proteolytic processing of the human enzyme.

PMID- 8647461
TI  - Production, purification and characterization of non-myristylated human T-cell
      protein tyrosine kinase in a baculovirus expression system.
AB  - A non-myristylated form (LCK M) of the human T-lymphocyte-specific protein
      tyrosine kinase (LCK) was produced at high levels in a baculovirus expression
      system (BVES) using two strategies. First, LCK M was produced by direct
      expression of a Gly2 --> Ala mutant of LCK. Second, LCK was produced as a
      glutathione S-transferase (GST) fusion, and LCK M was derived from the fusion
      protein by cleavage with thrombin. Both recombinant proteins (re-proteins) were
      produced at 5% of the total protein of infected Spodoptera frugiperda (Sf9) cells
      and were purified to >95% homogeneity. The enzymatic properties of the re
      proteins and their inhibition by protein kinase inhibitors were comparable to the
      native enzyme (LCK N) derived from Jurkat cells and wild-type LCK derived from
      the BVES. The high production levels will facilitate the recovery of large
      quantities of re-protein for use in biochemical and biophysical studies.

PMID- 8647462
TI  - pLEF, a novel vector for expression of glutathione S-transferase fusion proteins
      in mammalian cells.
AB  - An expression vector, pLEF, has been used to produce the intracellular domain
      (IC) of the human CD95 (Fas/APO-1) apoptosis receptor as a glutathione S
      transferase (GST) fusion protein in murine L929 fibroblasts. GST::CD95IC was
      affinity-purified in a single step using glutathione-Sepharose. Purification of
      GST::CD95IC from 32P-labelled L929 cells and cleavage with thrombin revealed that
      CD95IC was phosphorylated in vivo when produced as a GST fusion protein.
      Therefore, pLEF may facilitate the mapping of in vivo-modified sites of
      eukaryotic proteins.

PMID- 8647463
TI  - Pk92B: a Drosophila melanogaster protein kinase that belongs to the MEKK family.
AB  - A Drosophila melanogaster cDNA, encoding a protein with sequence similarity to
      the MEKK family of Ser/Thr kinases, was isolated from an eye-antennal imaginal
      disc cDNA library using a PCR-based approach. The deduced protein, Pk92B, has a
      kinase domain that is 40-48% identical to MEKK family members. The Pk92B gene was
      mapped to 92B8-10 on the third chromosome by in situ hybridization to polytene
      chromosomes.

PMID- 8647464
TI  - Isolation of Xenopus laevis TFIID subunit p22 reveals two distinct structural
      regions.
AB  - A cDNA clone encoding a Xenopus laevis (Xl) homologue of the TATA box-binding
      factor TFIID subunit p22, which shows similarities to histones H2B and H3, was
      isolated and sequenced. The deduced 164-amino-acid (aa) sequence was compared to
      those of homologues cloned from human and Drosophila melanogaster (Dm). Analysis
      showed that the TFIID subunit p22 consists of an approx. 60-aa less-conserved N
      terminus and approx. 100-aa highly-conserved C terminus.

PMID- 8647465
TI  - Functional expression and characterization of the mouse epitope tag-protein
      kinase C isoforms, alpha, beta I, beta II, gamma, delta and epsilon.
AB  - To simplify the detection of the exogenously produced protein kinase C (PKC)
      isoforms, we constructed the T7-Tag PKC alpha, betaI, betaII, gamma, delta and
      epsilon expression plasmids. T7-Tag sequences (AlaSerMetThrGlyGlyGlnGlnMetGlyArg)
      were inserted at the 5'-end of the translational initiation site. Transient
      transfection of T7-Tag PKC expression plasmids into CV-1 cells increased the
      levels of PKC protein, and PKC activity. T7-Tag-PKC epsilon, like native PKC
      epsilon, transactivated the transcription of a NF-kappa B reporter construct.
      These results indicate that the plasmids encoding T7-Tag PKC are functional and
      may be useful to define the role PKC isoforms play in cell proliferation,
      differentiation and tumor promotion.

PMID- 8647466
TI  - Cloning of a cDNA encoding a mouse transcriptional repressor displaying striking
      sequence conservation across vertebrates.
AB  - The nucleotide sequence encoding an approx. 120-kDa transcriptional repressor
      (MEB1) was determined from a cDNA which was cloned from a mouse brain library. An
      alignment of the deduced amino-acid sequences of the putative functional domains
      of MEB1 with those from the human, hamster and chicken homologues reveals a
      dramatic degree of conservation.

PMID- 8647467
TI  - Characterization of the gene encoding murine heparin-binding epidermal growth
      factor-like growth factor.
AB  - The mouse gene (mHB-EGF) encoding heparin-binding epidermal growth factor-like
      growth factor was isolated from a mouse 129SVJ genomic library. DNA sequence
      analysis confirmed that the clone contained six exons (I-VI) and five introns (A
      E), and spanned approx. 14 kb of DNA. PCR analysis showed that introns A-E of mHB
      EGF are 203 bp, 2.5 kb, 5.5 kb, 825 bp and 272 bp in length, respectively. These
      results establish that mHB-EGF is similar in organization to human HB-EGF (hHB
      EGF). However, DNA sequence analysis of introns A-E of mHB-EGF failed to show
      significant overall homology with those of hHB-EGF.

PMID- 8647468
TI  - A mammalian homologue of SLY1, a yeast gene required for transport from
      endoplasmic reticulum to Golgi.
AB  - We characterized rat cDNAs that predict a protein, r-Sly1, which is similar to
      SLY1, a yeast protein that plays a critical role in endoplasmic reticulum to
      Golgi apparatus vesicle trafficking. The r-Sly1 gene is expressed in all tissues
      examined.

PMID- 8647469
TI  - Sequence of the gene encoding cat (Felis domesticus) serum albumin.
AB  - The complete nucleotide (nt) sequence of the gene encoding cat serum albumin has
      been determined. The nt and deduced amino-acid sequences were compared to those
      of other known mammalian serum albumins (SA).

PMID- 8647470
TI  - The bovine PP3 gene is homologous to the murine GlyCAM 1 gene.
AB  - Proteose peptone component 3 (PP3) is a protein synthesized in the bovine mammary
      gland. A genomic 4.5-kb clone has been sequenced comprising a 2.9-kb PP3
      transcriptional unit plus 1 kb of 5' and 0.6 kb of 3' flanking sequence. Bovine
      retroposons of the short interspersed nuclear element sequence class (SINES) and
      one microsatellite were localized in the PP3 gene. PP3 is homologous with the
      murine glycosylation-dependent cell-adhesion molecule 1 (GlyCAM 1) and this
      homology also extends to the exon/intron organization of the genes.

PMID- 8647471
TI  - Geriatrics photo quiz. Paget's disease: skeletal deformity with or without pain.

PMID- 8647472
TI  - Dark discoloration of the tongue.

PMID- 8647473
TI  - Anticoagulation: risks and benefits in atrial fibrillation.
AB  - Anticoagulation with warfarin has been shown to be effective in preventing
      ischemic stroke in patients with atrial fibrillation. However, physicians have
      been reluctant to prescribe this therapy for patients age 60 and older because of
      the associated risk of bleeding during antithrombotic therapy. Four clinical
      features independently increase the risk of stroke in individuals with atrial
      fibrillation: previous stroke or transient ischemic attack, diabetes, history of
      hypertension, and advancing age. In individual patients, bleeding complications
      can be reduced by eliminating loading doses, monitoring therapy frequently during
      the initiation phase, targeting lower INRs, recognizing the potential for drug
      interactions, and identifying clinical risk factors.

PMID- 8647474
TI  - A peaceful death: how to manage pain and provide quality care. A roundtable
      discussion: Part 2.
AB  - One of the most important components of a peaceful death is adequate control of
      pain and other distressing symptoms, such as dyspnea, agitation, and
      restlessness. Pain is an important symptom in 75 to 80% of noncancer patients in
      the last year of life. Opioid analgesics are often the mainstay of pain treatment
      for dying patients. A primary care physician also needs to know about anesthetic
      and neurosurgical approaches, the use of cognitive behavioral approaches, and the
      availability of specialized pain experts. A sizeable minority of physicians
      receive requests for an assisted death, which should be seen as a cry for help.
      The most useful function of advance directives is that they open an avenue for
      discussion between the doctor and the patient about a difficult subject.

PMID- 8647475
TI  - Cervical cancer: how often--and why--to screen older women.
AB  - Cervical cancer continues to be an important cause of avoidable cancer deaths in
      older women. Despite the benefits of screening in reducing morbidity and
      mortality, older patients are under-represented in screening programs. Most
      professional groups recommend an annual Pap smear for all women, with no upper
      age limit. In most cases, women can safely undergo triennial screening after
      several annual negative smears. Screening is well-accepted among older patients,
      as up to 92% will accept a Pap smear offered in a clinical setting. To insure
      that screening is cost-effective, use sensitive and specific testing methods and
      limit screening to appropriate candidates.

PMID- 8647476
TI  - Lumbar puncture: essential steps to a safe and valid procedure.

PMID- 8647477
TI  - We must have a surgeon general. The special health needs of the American public
      require an independent champion.

PMID- 8647478
TI  - [Concentration of magnesium in the amniotic fluid of a patient with diabetes].
AB  - Amniotic fluid magnesium concentration in normal and diabetic pregnancy was
      analyzed. The mean amniotic fluid concentration of this metal was 0.28 +/- 0,03
      mmol/l in diabetic group and 0,43 +/- 0,09 mmol/l in control group (p < 0,0001).
      The role of hypomagnesemia in the course of diabetic pregnancy was discussed.

PMID- 8647479
TI  - [Decreased activity of oxidoreductases in erythrocytes and blood platelets from
      venous and umbilical blood of women with pregnancy-induced hypertension].
AB  - Thirty two pregnancies with pregnancy-induced hypertension (PIH) and twenty seven
      control normal pregnancies were analysed with regard to maternal and fetal blood
      enzymatic antioxidants. In PIH maternal erythrocyte, platelet and serum blood and
      in umbilical cord blood levels of lipid peroxides were higher than in normal
      pregnancy. Also the activities of platelet and erythrocyte superoxide dismutase
      and glutathione peroxidase were lower in PIH women. The concentration of lipid
      peroxides was higher, and the activity of glutathione peroxidase were lower in
      umbilical cord elements of women with PIH, than corresponding values of women
      with normal pregnancy. We suggest that disturbances in antioxidant enzymatic
      system are involved in the pathogenesis of maternal PIH, and it may also have
      effects on the function of antioxidant status of the fetus.

PMID- 8647480
TI  - [An attempt at optimization of diagnosis for patients in puerperium treated due
      to eclampsia and systemic complications in the Department of Anesthesiology and
      Intensive Therapy in the Silesian Medical Academy in Katowice].
AB  - Conditions under which episodes of eclampsia occurred in puerperal, who were than
      admitted to the Intensive Care Units for treatment are presentation the paper.
      Multidirectional diagnostic procedures introduced in those 30 patients are
      discussed. In the analysed group of patients various types of organ complications
      were diagnosed. The paper underlines value and benefits of the interdisciplinary
      consultation in diagnostic procedure in cases of dramatic and rapidly occurring
      complications overlapping existing puerperal status.

PMID- 8647481
TI  - [Complex therapy of obstetric patients hospitalized for eclampsia and systemic
      complications in the Department of Anesthesiology and Intensive Therapy in the
      Silesian Medical Academy in Katowice].
AB  - The paper reviews the treatment introduced to control cerebral oedema in 30
      puerperal women with eclampsia, tonic-clonic seizures and symptoms of increased
      JcP. Methods of hypotensive treatment, introduced in 23 of 30 patients are
      presented. Other elements of the therapeutical management aimed at the
      maintenance of homeostasis, normothermia, normotension and normoglycaemia are
      also discussed in the paper. Patients required not only complex pharmacological
      therapy but also mechanical ventilation by means of respirator, often with use of
      special techniques.

PMID- 8647482
TI  - [Evaluation of the course of pregnancy and the newborn state in women with
      bronchial asthma].
AB  - The course of pregnancy and the condition of newborn babies were studied in 18
      women who suffer from severe bronchial asthma, intensified during the time of
      pregnancy, and 20 with a mild course of the same disease. The danger of
      intrauterine hypotrophia of the fetus was proved in women with the active
      bronchial asthma. Additional studies showed that the more serious the case was,
      the bigger decrease of the value of estrogen and placental lactogen was. Because
      of the possibility of sudden deterioration of a patient's condition, detailed
      assessment in necessary in all women with bronchial asthma.

PMID- 8647483
TI  - [Level of antifibrinogen antibodies in newborns and women during the postpartum
      period].
AB  - In newborns and women who have just delivered antifibrinogen antibodies level was
      measured by means of immunoenzymatic method (ELISA). It has been found
      significantly higher antibodies level in women than in newborns. All newborns had
      lower antibodies level than their mothers. It has been found significantly
      lowered antibodies level before 38 week of gestation. Especially high antibodies
      level was observed in women who gave birth after 42 week of gestation and in
      newborns born in the same time.

PMID- 8647484
TI  - [An attempt to choose the optimal antibiotic for early treatment of neonates with
      bacterial sepsis].
AB  - Aim of our study was making easier choice of right antibiotic to treatment
      newborns with sepsis after receiving results of bacteriological test. We analysed
      antibiograms that were results of first bacteriological test of blood samples
      taken from 59 neonates, who were admitted in first week of life to the Neonatal
      Pathology Clinic in Zabrze. On the ground of our analysis we propose applying
      netilmicin and cephalotin in every case of neonate with symptoms suggesting the
      sepsis. These two antibiotics have the best effects in treatment the sepsis.

PMID- 8647485
TI  - [Usefulness of a scoring system based on selected hematologic values in early
      diagnosis of neonatal bacterial infections].
AB  - The aim of our work is to estimate usefulness of morphological blood tests, as
      simple to make and easy to estimation, in screening diagnostics of neonatal
      infections. We chose the following indications for estimation, as possible to
      obtain in every hospital: total leucocyte count, total neutrophil count, total
      immature neutrophil count, total thrombocyte count, ratio of immature neutrophil
      count to total neutrophil count (I : T), ratio of immature neutrophil count to
      mature ones. We examined 143 newborns admitted to the Neonatal Pathology Clinic
      in Zabrze in first week of life, divided into three groups: with sepsis, with
      suspicion of sepsis, and without infection. We assume that deviation of (at
      least) three indicators or two (necessary with I : T) is incorrect result. We
      obtain sensitivity: 54.35% for sepsis, 50% for suspicion of sepsis, and 52,70%
      for both groups (together with infection), and specificity 98.55%. We consider
      that our haematological scoring system is helpful in early diagnostics of
      neonatal bacterial infections.

PMID- 8647486
TI  - [Endometrial microprobe biopsy using Novak's and Pipelle's probes].
AB  - It has been presented comparative studies of biopsies by means of two above
      mentioned probes in outpatients. It has been assessed the quality and quantity of
      obtained histopathological specimens and it has been compared relative pain
      perception during procedure among patients. Micro-curettage was performed twice
      in each woman. In the first group--the first curettage with Novak's probe and the
      second one the Pipelle's probe; in the second group--conversely. Aspirated
      endometrium was studied histopathologically. It has not been obtained specimen in
      5 cases using Pipelle's probe that means in 20.83%; using Novak's probe in 25.0%.
      Microcuretage with Pipelle's probe was described as painless by 37.5% patients.
      The procedure with Novak's probe was always more or less painful. It has been
      found that both types of ++micro-curettage have the same effectiveness allowing
      to obtain histopathological specimens. It has been noticed that Pipelle's probe
      ensured higher comfort that means it has been more painless. It is a disposable
      probe giving full sterility of performing procedure.

PMID- 8647487
TI  - -Psychosomatic aspects around the period of menopause-.

PMID- 8647489
TI  - [Invasive vulvar carcinoma in a sixteen year old patient].
AB  - A case of vulvar carcinoma diagnosed in 16 year old patient is described.
      Presented are steps in diagnosis and multi-stage conservative surgical treatment
      aimed at cure without unnecessary mutilation of the young woman.

PMID- 8647488
TI  - [Rare foreign body in the lumen of the small intestine].
AB  - The pathologic conditions caused by forgotten surgical gauze give rise to many
      different clinical pictures and are very hazardous for the patient. Such patient
      are seldom reported in the medical literature, mainly due to legal implications.
      That's why authors describe a case of surgical gauze forgotten after gynecologist
      procedure. The interval between the causative operation and the admission in our
      hospital was 7 months. The tentative diagnosis was jejunal tumor. Definitive
      diagnosis was made intraoperatively, we find surgical gauze 25 cm x 30 cm of
      diameter in jejunum with jejuno-jejunal fistula which protect patient against
      ileus.

PMID- 8647490
TI  - [Evaluation of selected parameters of lymphocyte activity in umbilical blood. I.
      Natural cytotoxicity].
AB  - Natural cytotoxic activity in the umbilical blood was estimated in 52 healthy
      newborns. Mononuclear cells were isolated from the umbilical blood using Boym's
      method. The mean natural cell cytotoxicity in the examined group was 7.05 +/- 0.9
      (SD).

PMID- 8647491
TI  - [Evaluation of selected parameters of lymphocyte activity in umbilical blood. II.
      Release of angiogenic cytokines].
AB  - Angiogenic abilities of mononuclear cells in the umbilical blood was estimated in
      31 healthy newborns. LIA test was performed on 6-8 weeks old mice, which
      underwent immunosuppression before intracutaneous injection of leucocytes and
      were narcotized after 72 hours. The mean number of newly formed vessels was 12.85
      +/- 0.2 (SD).

PMID- 8647492
TI  - [Evaluation of selected parameters of lymphocyte activity in umbilical cord
      blood. III. Expression of receptors for SRCB susceptible and insusceptible to
      theophylline].
AB  - Subpopulation of lymphocytes T in the umbilical blood was estimated in 30 healthy
      newborns. ARFC and CRFC fractions were isolated and analysed.

PMID- 8647493
TI  - [Increased cholesterol in red cell membranes in women with pregnancy induced
      hypertension].
AB  - The group of 24 women in the course of the first pregnancy complicated by
      hypertension was investigated. The higher amount of cholesterol in red cells
      membrane was found comparing to healthy pregnant and nonpregnant women.
      Cholesterol amount in red cells membranes is related to LDL cholesterolemia.

PMID- 8647494
TI  - [Antioxidant enzyme activities in fetal and neonatal lung: lowered activities of
      these enzymes in children with RDS].
AB  - Lung tissue was obtained within 24 h of death from 49 fetuses and neonates (31
      weeks gestation to 3 months post term). 24 neonates died from RDS, other neonates
      died from inherited heart abnormalities. All three antioxidant enzymes:
      superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px)
      activities increased with gestational age. After term, SOD increased further by
      51-60 weeks, while GSPH-Px exhibited a transient increase between 41-50 weeks.
      Activities of these enzymes in lung of neonates who died after RDS were
      significantly lower, and the peroxidation processes were significantly higher.
      These results suggest existence of oxidative stress, i.e. overproduction of
      oxygen free radicals in lung neonates who died after RDS.

PMID- 8647495
TI  - [Tobacco smoking--a risk factor for intrauterine growth retardation, preterm
      delivery and low birth weight].
AB  - The risk of intrauterine growth retardation (IUGR) and preterm delivery, in the
      group of 551 females from the area of Lodz, was related to the amount of
      cigarettes smoked per day. In subjects smoking more than 20 cigarettes, the risk
      of IUGR and preterm delivery was five times as high as in the nonsmoking females.
      The average weight of the newborns was found to be 510 g lower in the group of
      the most heavy smokers as compared with the nonsmoking subjects. The study has
      not provided any clear evidence for the pre-pregnancy smoking and the passive
      smoking as the risk factors for the pathologies under study.

PMID- 8647496
TI  - [Ultrasonographic evaluation of pelvis minor and lower extremity veins during
      pregnancy and puerperium].
AB  - Thrombophlebitis of iliac and lower extremity veins is still an actual diagnosis
      problem in obstetrics and gynaecology. Classical ultrasonography and color
      doppler usefulness were compared. High efficacy of both methods in early
      diagnosis was concluded. The color doppler method is more effective in
      postphlebitic syndrome recognition. Spread out of veins ultrasonography with
      compression test gives a possibility of early diagnosis of thrombophlebitis in
      the course of pregnancy and puerperium.

PMID- 8647497
TI  - [Ovarian endometrial cysts--management and treatment].
AB  - The authors estimated the effects of combined operative and hormonal therapy in
      23 women suffering from ovarian endometrial cysts. In the therapy the authors
      used Danazol. The authors concluded that removal of an ovarian endometrial cyst
      combined with 6-th month Danazol therapy prevents recurrence of endometriosis and
      in some women restores fertility.

PMID- 8647498
TI  - [The role of transvaginal ultrasonography in early diagnosis of ectopic ovarian
      pregnancy].
AB  - Ovarian pregnancy is very rare finding occurring with frequency 1:2500 to
      1:40,000 of pregnancies. The main method of early diagnosis is transvaginal
      ultrasonography. The image of ovary tumor is highly characteristic with double
      hyperechogenic ring surrounding small hypoechogenic field. The case of 28 old
      woman was described. Early diagnosis and ovariectomy were performed.

PMID- 8647499
TI  - [Alveolar rhabdomyosarcoma of the uterine cervix].
AB  - A rare case of cervical alveolar rhabdomyosarcoma in a 45-year old female is
      presented. The removal of the tumour was performed in two stage-procedure, due to
      its large dimensions: first the bulk of the tumour was removed per vaginam,
      proceeding afterwards to a radical hysterectomy. Metastases were detected in
      pelvic lymph nodes. The patient was given postoperative radiotherapy, but a
      dissemination of the tumour was found at the termination of the treatment and the
      patent died 3.5 months after surgery.

PMID- 8647500
TI  - [A case of Munchausen syndrome].
AB  - Presented patient was many times admitted to gynaecological wards and surgically
      treated with irreversible results. The complaints were mainly related to specific
      psychological disturbances.

PMID- 8647501
TI  - [Magnesium concentration in serum of pregnant women in selected pathologic states
      of pregnancy].
AB  - Examination of magnesium concentrations in the blood serum was carried out on a
      population of 246 patients 17-39 years old in pathologic/imminent abortion,
      imminent immature and premature labour and normal pregnancies as well as in first
      periods of parturition. In spite of considerable oscillations of magnesium
      concentrations in respective periods of normal and imminent pregnancies, the
      differences were statistically insignificant. A significant decrease of magnesium
      concentrations was found in the first period of parturition as compared with the
      imminent and normal pregnancies of the first and second trimester.

PMID- 8647502
TI  - [Infection with parvovirus B19 in pregnant women].
AB  - The viral infection caused by Parvovirus B19 which occurs at pregnant women may
      be reason of many different kinds of complications during pregnancy. Until this
      time it is not known the frequency of the Parvovirus infections at pregnant women
      in Poland. We have based our studies on a group of 78 pregnant women with
      symptoms of a abortion, a premature imminent labour, premature labor and
      intrauterine death of foetus. In 10 cases (12.8%) we have confirmed a presence of
      antibodies IgM class antiparvovirus B19 at patients serum. It seems that the
      Parvovirus infection is one of most often reasons of unsuccessful pregnant.

PMID- 8647503
TI  - [Biochemical changes in extracellular matrix components of the amniotic sac
      during its premature rupture].
AB  - In the fetal membranes that have ruptured 12 hours before onset of the labour the
      tissue collagen content was lower than in control accompanying by similar local
      collagenase and elastase activity. These results excluded the inflammatory
      process as the main cause of prelabour preterm rupture of membranes (PPROM). The
      analysis of the collagen fractions taken from the site of rupture and the
      location close to umbilical cord indicates that in PPROM there are changes in
      posttranslational collagen molecule modification.

PMID- 8647504
TI  - [Contents of zinc, copper and cadmium in mild of women living in Poznan].
AB  - A research concerning the contents of Zn, Cu, Cd was carried out in 33 samples of
      human milk. The woman were inhabitants of Poznan (urban industrial area). The
      following concentrations of the metals were found: Zn 8.20 +/- 2.76 mg/l
      (colostrum 9.67, transitional 7.48 mg/l), Cu 0.54 +/- 0.16 mg/l (colostrum 0.47,
      transitional 0.60 mg/l), Cd 0.62 +/- 0.28 micrograms/l. The obtained results were
      considered regarding the woman's age, the day of puerperium on which the samples
      was taken, the number of deliveries and smoking factor. A negative correlation
      between the concentration of Zn and the day of puerperium was stated (p < 0.05).
      The contents of Zn and Cu doesn't exceed the accepted quantities in dairy
      products for babies. The contents of Cd in milk was the source of 1/6 PTWI given
      by FAO/WHO for adults. However it can present the danger to their health. The
      results of research point out the necessity for undertaking preventive measures
      and continuing the research on a larger scale.

PMID- 8647505
TI  - [Ovarian teratomas: some clinical and statistical factors based on 456 patients
      operated on in the Institute of Gynecology and Obstetrics Academy of Medicine in
      Lodz].
AB  - In the years 1977-1994 456 cases of teratomas located in one ovary and 47 in two
      ovaries were diagnosed. 88,8% of patients were between 16 and 50 years old, with
      the peak of occurrence between 25 and 30 years. In 5% malignant teratomas were
      diagnosed.

PMID- 8647507
TI  - [Comparative study of observer agreement on location and size of ovarian tumor in
      transvaginal and transabdominal ultrasonic examinations with intraoperative
      evaluations from material of patients operated on in the Gynecology-Obstetrics
      Department of the Ministry of Internal Affairs Clinic in the years 1991-1994].
AB  - In a group of 154 women operated on because of ovarian tumors at the
      Gynecological-Obstetrics Department of the Ministry of Internal Affairs Clinic in
      Warsaw a comparison of the location and size of the tumor performed by means of
      transvaginal and transabdominal ultrasonography and the operational evaluation
      was carried out. In 76.9% of cases the agreement between the location in
      transabdominal and transvaginal ultrasonography and the operational evaluation
      was found. However, the comparison between transabdominal and transvaginal
      ultrasonography of the tumor size and operational evaluation was ascertained in
      79.1% of cases.

PMID- 8647506
TI  - [The significance of endocervical cells in cytologic smears on diagnosis of
      uterine cervix pathology].
AB  - The significance of the presence of endocervical cells (EC) on the cytologic
      prediction of cervical epithelial abnormalities has been studied. The material
      consisted of 124 smears with correct cytological diagnosis of CIN, 80 with false
      positive and 24 false-negative diagnosis. Influence of the presence of EC on the
      detection of CIN II, CIN III and Carcinoma have been stated.

PMID- 8647508
TI  - [Clinical analysis of women with cervical carcinoma treated in the years 1989
      1994].
AB  - Investigation covered 112 women treated for invasive cervical carcinoma. Standard
      clinical data were analysed: age, residence, number of pregnancies and
      deliveries. According to FIGO classification clinical development level and
      histological type of the carcinoma were assessed. Surgical treatment was applied
      in 53 cases with carcinoma I degree (47.3% of all women with invasive cervical
      carcinoma). The other patients with higher degrees of disease development
      underwent curie-therapy. No considerable differences between our own results and
      nationwide data were observed.

PMID- 8647509
TI  - [Postterm pregnancy--importance of this problem in modern obstetrics].
AB  - Postterm pregnancy remains constantly a difficult and controversial problem in
      modern obstetrics. The aim of this study is to discuss the definition of the
      postterm pregnancy, complications for both the foetus (macrosomia associated with
      birth trauma and shoulder dystocia, oligohydramnios, meconium aspiration,
      postmaturity syndrome) and mother (increase rate of caesarean births). We
      discussed also the antepartum surveillance and the management of the postterm
      gestation (time and way of delivery). The management of postterm pregnancy should
      be individualised and based on the above findings. Treatment includes active
      methods (induction of labour, elective caesarean section) or conservative way
      (strict foetal antenatal surveillance).

PMID- 8647510
TI  - [Hyperthyreosis during pregnancy. Case reports].

PMID- 8647511
TI  - [Spontaneous rupture of an endometriotic cyst in pregnancy near term].
AB  - The spontaneous rupture of endometriotic ovarian cyst in near term pregnancy is
      presented. The clinical symptoms of this case suggested the abruption of normally
      localised placenta. Because of acute abdominal symptoms urgent cesarean section
      was performed and healthy fetus was delivered. The proper diagnosis was settled
      after the posterior uterine wall was controlled. The cyst was removed and then
      the ovary was sewn. Histopathological examination of removed cyst confirmed the
      diagnosis.

PMID- 8647512
TI  - Depression of stimulated erythropoietin production in mice with enhanced
      erythropoiesis.
AB  - BACKGROUND: The reports of lower plasma erythropoietin (EPO) in anemic patients
      with active erythropoiesis (hyperplastic) than in comparably anemic subjects with
      erythroid hypoplasia have generally been interpreted as the result of EPO
      utilization by the target cells of the hormone. An alternative explanation could
      be that there is a feedback mechanism through which EPO formation by EPO
      producing cells is modulated by the erythroid activity of the erythropoietic
      organs. The present study was thus designed to investigate EPO production during
      acute hypoxemia in a mouse model in which the oxygen-carrying capacity of blood,
      the plasma EPO level, the blood viscosity and the plasma EPO half-life are within
      normal values in spite of an intense stimulation of erythropoiesis. MATERIALS AND
      METHODS: Adult female mice of the CF1 strain with either normal or increased
      rates of erythropoiesis were used in this study. Erythropoiesis was stimulated by
      two injections of 10 units of rhEPO given 24 h apart. All experimental
      determinations were performed 24 h after the second EPO injection. Erythropoiesis
      was measured by the percent of a tracer dose of 59Fe incorporated into the
      spleen. Hypobaric hypoxemia was induced by exposing mice to atmospheric air
      maintained at 50% atmospheric pressure for 6 h. Plasma EPO concentration was
      determined by RIA. Plasma disappearance of radiolabeled rhEPO was determined by
      i.v. injection of the hormone and sampling by cardiac puncture every hour for 6
      h. RESULTS: Administration of rhEPO to mice increased splenic 59Fe uptake
      significantly without affecting the hematocrit, the plasma EPO level or the
      plasma disappearance of radiolabeled EPO. Plasma EPO titer after 6 h of exposure
      to hypobaric air was about 70% lower in mice with EPO-induced stimulation of
      erythropoiesis than in mice with normal erythropoiesis. CONCLUSIONS: The results
      of this study suggest that there is an inverse relationship between the rate of
      stimulated EPO production and erythropoietic marrow activity. They also suggest
      that the variations in plasma EPO levels during periods of rapidly increasing
      erythropoiesis are the reflection of a decrease in the rate of production rather
      than an increase in the rate of utilization by a proliferating pool of erythroid
      cells.

PMID- 8647513
TI  - Quantitation of bcl-2 oncogene in cultured lymphoma/leukemia cell lines and in
      primary leukemia B-cells by a highly sensitive RT-PCR method.
AB  - BACKGROUND: The bcl-2 gene, isolated from the t(14;18) chromosomal translocation
      breakpoint, is able to prevent apoptotic death induced by various stimuli in
      different tissues. Therefore bcl-2 oncogene expression could be a key parameter
      for investigating the molecular mechanisms involved in the apoptosis of normal
      and neoplastic hematopoietic cells. METHODS: In order to evaluate bcl-2
      expression in both follicular B-lymphomas carrying or not carrying the 14;18
      translocation and in lymphatic leukemias, we optimized an internal standard-based
      method of reverse transcriptase-polymerase chain reaction (RT-PCR) for the rapid
      quantitation of bcl-2 mRNA cellular levels. A simple purification of the reverse
      transcription products resulted in very high PCR efficiency, so that radioactive
      labelling of the amplification products was avoided. RESULTS: bcl-2 mRNA levels
      proved to be higher in t(14;18) than in t(14;18) negative cell lines, and higher
      in primary leukemia pre-B cells than in early-B cells. Tested for sensitivity by
      identifying minimal residual t(14;18) B cells expressing the bcl-2/IgH gene, this
      RT-PCR method was able to detect bcl-2/IgH mRNA from just one t(14;18) positive
      cell out of ten million t(14;18) negative cells. CONCLUSIONS: The RT-PCR method
      we optimized appears to be suitable for clinical use in both leukemia/lymphoma
      characterization and in lymphomatous disease follow-up.

PMID- 8647514
TI  - Serum selenium concentrations in patients with newly diagnosed lymphoid
      malignancies.
AB  - BACKGROUND: Increased mortality from lymphoid malignancies following exposure to
      environmental selenium has recently been reported. Moreover, conflicting results
      have been found in investigations examining the relationship between serum
      concentrations of selenium and some clinical features of malignant
      lymphoproliferative diseases. METHODS: Serum concentrations of selenium were
      analyzed by atomic absorption spectrometry in fifty-nine patients with newly
      diagnosed chronic lymphoid malignancies and in forty control subjects. RESULTS:
      Selenium concentrations were significantly lower in patients than in control
      subjects. However, when only patients with localized disease were compared to
      controls, no significant difference in serum selenium concentrations was
      observed. Clinical stage was inversely associated with selenium levels. High
      grade non-Hodgkin's lymphoma was characterized by lower selenium levels than low
      grade and intermediate-grade disease. Selenium levels were positively associated
      with albumin and hemoglobin, and inversely correlated with serum concentrations
      of beta 2-microglobulin and with erythrocyte sedimentation rate. CONCLUSIONS: The
      findings of this study do not suggest that a high selenium intake represents a
      risk factor for malignant lymphoproliferative diseases, but limitations of the
      investigation hamper evaluation of the results. The possible utility of
      determining serum concentrations of selenium in the clinical evaluation of
      patients with lymphoid malignancies merits examination in larger studies.

PMID- 8647515
TI  - Efficacy of different prophylactic antifungal regimens in bone marrow
      transplantation.
AB  - BACKGROUND: Fungal infections still represent a major clinical problem in
      neutropenic patients; the recent availability of active imidazole derivatives,
      particularly fluconazole and itraconazole, has increased interest in prophylaxis.
      MATERIALS AND METHODS: Fifty-nine consecutive bone marrow transplant (BMT)
      recipients were randomized to receive either itraconazole 400 mg/day or
      fluconazole 300 mg/day as oral antimycotic prophylaxis during the pancytopenic
      phase; they were retrospectively compared with a historical control group of 30
      patients who had received fluconazole 50 mg/day. Every febrile episode was
      treated with the same empirical antibiotic combination; amphotericin-B was added
      after 4-5 days in the case of persistent fever. Proven or suspected mycotic
      infections and the empirical use of amphotericin-B were considered as failures of
      prophylaxis. RESULTS: There were no differences in the number of febrile episodes
      in the three groups. Five patient died of bacterial sepsis: two in the
      fluconazole 300, two in the itraconazole and one in the fluconazole 50 group. The
      addition of amphotericin-B was required in 12, 16 and 11 cases, respectively, in
      the three groups. There were four documented fungal infections in the
      intraconazole and one in both fluconazole groups; three suspected fungal
      infections were observed in the fluconazole 300 group and two in both the
      itraconazole and the fluconazole 50 group. None of the differences were
      statistically significant. CONCLUSIONS: The present results indicate that high
      dose fluconazole and itraconazole are equivalent; neither of them was superior to
      low-dose fluconazole, which is regarded as being devoid of prophylactic activity
      against systemic mycoses.

PMID- 8647516
TI  - Excessive tea consumption can inhibit the efficacy of oral iron treatment in iron
      deficiency anemia.
AB  - Intestinal absorption of non-heme food iron may be inhibited by tea, which, on
      the contrary, does not exert any appreciable effect on heme iron assimilation.
      Therefore, while an iron-deficiency anemia cannot develop in non-vegetarian
      subjects as a consequence of tea consumption only, it is possible that tea could
      inhibit the therapeutic effect of oral iron drugs, which are usually non-hemic
      ferrous salts, in iron-deficient subjects. This view is supported by the case we
      describe here, a young woman affected by hypermenorrhea and iron-deficiency
      anemia, who did not respond to oral iron treatment until she stopped her long
      established habit of consuming large quantities of tea. We also believe that oral
      iron drugs should never be taken together with a cup of tea; therefore we think
      it useful to advise our iron-deficient patients clearly not to combine tea with
      the oral consumption of non-hemic ferrous salts.

PMID- 8647517
TI  - Expansion of large granular lymphocyte subsets in Wiskott-Aldrich syndrome.
AB  - We describe a 9-year-old boy with Wiskott-Aldrich syndrome and IgM-rheumatoid
      factor-positive arthritis who presented expansion of two distinct subsets (one
      CD8dim and the other CD8-) of large granular lymphocytes. Natural killer activity
      against the K-562 cell line was absent. An increased percentage of CD5+ B cells
      was also observed. Since patients with Wiskott-Aldrich syndrome are at risk of
      developing autoimmune disorders - conditions in which increased CD5+ B cells have
      been observed - the high percentage of CD5+ B cells together with the presence of
      IgM-rheumatoid factor and anti-platelet antibodies may represent an early
      manifestation of an autoimmune process. The possible relationship between CD5+ B
      cells and large granular lymphocyte expansion is discussed.

PMID- 8647518
TI  - Translocation t(8;22) and monosomy 7 in a case of acute lymphoblastic leukemia
      expressing myeloid markers.
AB  - The simultaneous coexpression of lymphoid and myeloid markers has been observed
      in some cases of childhood acute lymphoblastic leukemias (ALL). In this paper, we
      describe a 6-year-old male patient with an ALL expressing myeloid antigens in
      whom a novel karyotypic association, t(8;22) and monosomy 7, and high Ag-NOR
      activity were found concomitantly with a very short survival.

PMID- 8647519
TI  - Cutaneous vasculitis in non Hodgkin's lymphoma.
AB  - Cutaneous vasculitis has been described in association with various hematological
      malignancies, but it seems to be very uncommon among non Hodgkin's lymphomas
      (NHL). For this reason no attention has been given to the peculiarity of this
      rare association. We identified 5 cases of cutaneous vasculitis among 315 NHL
      patients examined at our Institution from 1984 through 1990 and after the
      appearance of vasculitis, we observed some heterogeneity in either the degree of
      activity or in the clinical outcome of the NHL. The onset of cutaneous vasculitis
      appeared to mark two different clinical patterns: a vasculitis present from
      diagnosis characterized an indolent course of the neoplasia, while a late
      appearing vasculitis was followed by rapid lymphoma progression and short
      survival.

PMID- 8647520
TI  - Clonazepam prophylaxis and busulfan-related myoclonic epilepsy in autografted
      acute leukemia patients.
AB  - A prospective neurological and electroencephalographic (EEG) study was performed
      in sixteen leukemia patients receiving busulfan (BU) and cyclophosphamide before
      autologous bone marrow transplantation. All patients were given anticonvulsant
      prophylaxis with a combination of phenobarbital (PB) and clonazepam (CLZ).
      Neurological examination and EEG were performed prior to and soon after
      completion of BU treatment and were repeated two months later. No tonic-clonic
      and/or myoclonic convulsions were observed. In two patients, comparison of EEG
      recorded before and upon completion of BU administration revealed modification of
      features. EEG re-evaluated two months after BU showed normalization in one of the
      two patients. BU may trigger both generalized and myoclonic seizures together
      with EEG abnormalities; PB combined with CLZ may be useful prophylactic
      treatment.

PMID- 8647521
TI  - Identification and treatment of late onset Fanconi's anemia.
AB  - We diagnosed Fanconi's anemia (FA) in a 34-year-old lady, daughter of
      consanguineous parents, from a small Southern Italian town. The patient was
      pancytopenic when she was 31, and was found to be aplastic at the age of 34.
      Spontaneous chromosomal breakages were not evident in peripheral blood lymphocyte
      cultures but the diepoxybutane (DEB) test, carried out during the aplastic phase,
      was clearly positive. Danazol treatment significantly improved her hematological
      condition, yielding a Hb peak value of 13.4 g/dL. Four years later moderate
      pancytopenia has recurred. This case demonstrates that even adult pancytopenic
      patients may have FA and that a test detecting chromosomal hypersensitivity to
      cross-linking agents is the only key to a correct diagnosis, which in turn is
      essential to avoid improper treatment.

PMID- 8647522
TI  - The PIG-A gene somatic mutation responsible for paroxysmal nocturnal
      hemoglobinuria.
AB  - Paroxysmal nocturnal hemoglobinuria is the first example of a non neoplastic
      human disease caused by the somatic mutation of an X-linked gene. The PIG-A gene
      maps to Xp22.1 and is required for the transfer of N-acetyl glucosamine to
      phosphoinositol, an early step in the production of the GPI anchor. A deficiency
      of GPI-linked proteins on the cell surface is responsible for the PNH cell
      defect, which can be detected by flow cytometry not only on red cells, but also
      on myeloid cells and in some patients even on lymphoid cells. Its location on the
      X-chromosome explains how a single recessive mutation can cause the appearance of
      the abnormal clone. A number of patients may have more than one PNH clone,
      suggesting that the expansion of GPI-deficient clones occurs under the pressure
      of a selection mechanism.

PMID- 8647523
TI  - Immunotoxin therapy of hematological malignancies.

PMID- 8647524
TI  - Cell cycle regulation and human leukemias: the role of p16INK4 gene inactivation
      in the development of human acute lymphoblastic leukemia.
AB  - Recent advances in cancer biology have clearly demonstrated that the development
      of neoplasms as well as their progression are strictly linked to the alteration
      of molecular mechanisms controlling the cell division cycle. Among these
      mechanisms the functional inactivation of two important tumor suppressor genes,
      namely RB1 and p53, has been widely recognized as a pivotal step in human
      cancerogenesis. In addition to such well-known genes, a new tumor suppressor
      gene, mapping on chromosome 9p21, has recently been identified and cloned.
      Several findings suggest that its loss of function is involved in the initiation
      and/or progression of an enormous number of different malignancies. This gene,
      named p16INK4, codifies for a small protein capable of binding to, and thus of
      inhibiting, some specific cyclin-dependent threonine-serine kinases that
      represent key enzymatic activities essential for the G1-S transition in mammalian
      cells. This review will summarize some aspects of the cell cycle control
      mechanisms, with major emphasis devoted to the role played by this recently
      characterized inhibitor and to the possible linkage between its inactivation and
      cancer formation. In particular, we will discuss these aspects in the light of
      the role of p16INK4 gene inactivation in the development of human acute
      lymphoblastic leukemias. Indeed this gene seems to be the first, and so far the
      only tumor suppressor gene consistently altered in specific acute hematological
      malignancies. Finally, future trends in the investigation of cell cycle control
      and leukemogenesis will be analyzed.

PMID- 8647525
TI  - Computed tomography, magnetic resonance and gallium 67 scintigraphy for the
      imaging of residual lymphoma.

PMID- 8647526
TI  - Bone marrow necrosis in acute lymphoblastic leukemia.

PMID- 8647527
TI  - Low prevalence of hepatitis E virus in type II mixed cryoglobulinemia.

PMID- 8647528
TI  - [Lymphocyte subpopulations in spleen and blood after early wound debridement and
      acute/chronic treatment with hyperbaric oxygen].
AB  - Thermal burns as well as hyperbaric oxygen (HBO) may cause immuno-suppression.
      This is one of the reasons why there is some controversy in the literature
      regarding adjuvant HBO treatment for thermal burn patient, despite the fact that
      HBO is known to decrease edema formation and possibly inhibits the progression
      from second to third degree burns. In this study, lymphocyte subpopulations were
      labelled with monoclonal antibodies W3/25 for helper cells, and OX-8 for
      cytotoxic/suppressor cells, to determine changes following early burn wound
      excision and acute or chronic HBO treatment in a 10% full-thickness burn model in
      rats. Lymphocyte subpopulations were extracted from blood and spleen on day 1, 8,
      and 15 following burn and/or treatment. W3/25 cells did not show any significant
      changes in blood or spleen over time. Significantly lower OX-8 cell counts were
      found in the group with burn + excision + chronic HBO treatment on day 8 and 15.
      Acute or chronic HBO treatment alone did not produce evidence of immuno
      suppression.

PMID- 8647529
TI  - [Trigger thumb in the child].
AB  - The trigger thumb is a quite frequent finding in the adult woman over 50 years.
      In newly born and small children we do, however, also occasionally observe
      trigger thumbs. As even pediatric specialists are not necessarily familiar with
      this diagnosis, they tend to refer these small patients as emergencies for acute
      distortions or subluxations. We describe the clinical findings and therapy for
      trigger thumb in the child and our own results in comparison with the literature.
      Except in the small child under six months, who displays a spontaneous recovery
      in about 30% of the cases, early surgical release of the pulley is the treatment
      of choice.

PMID- 8647530
TI  - [Bilateral biceps replacement-plasty by transposition of the latissimus dorsi
      muscle in arthrogryposis multiplex congenita. A case report].
AB  - The case of a four-year old girl with arthrogryposis multiplex congenita is
      reported. Primary clinical examination revealed bilateral passive elbow flexion
      only 0-20-70 without active elbow flexion. A two-stage operative procedure was
      chosen for both sides. At first an elbow arthrolysis was performed with
      subsequent intensive physiotherapy. In a second session we performed a bipolar
      transposition of the latissimus dorsi as a myocutaneous flap. The patient was
      first operated on the left and afterwards on the right side. By this procedure,
      the patient achieved a significant improvement of both passive and active elbow
      flexion mobility. The range of active motion was 0-30-90 and 0-40-90 degrees.

PMID- 8647531
TI  - [Therapy of osteomyelitis in the metacarpal region with local pedicle m.
      interosseus dorsalis II and III-flap-plasty. Anatomic principles and case
      report].
AB  - Both experimental and clinical studies showed that muscle flap transposition is a
      reliable method for treating chronic infections of the bone. Advantages of muscle
      flaps are: treatment of infection with well perfused autogenous tissue obviating
      the use of implants, cure of infection usually within four weeks and
      consequently, short immobilisation time. Disadvantages of muscle flaps are loss
      of muscle function with possible donor-site morbidity. The first dorsal
      interosseous muscle and the abductor digiti minimi muscle have been used
      successfully for the treatment of osteomyelitis of the metacarpals. The second
      and third dorsal interosseous muscle are presented for the first time. After
      discussing anatomy, especially vascularisation of these muscles, the operative
      technique is shown and a case of osteomyelitis of the third metacarpal treated by
      this new transposition is reported.

PMID- 8647532
TI  - [Donor site defect after removal of free and pedicled forearm flaps: functional
      and cosmetic results].
AB  - The donor-site defect poses a special problem in free and pedicled forearm flaps.
      A multi-center-study of seven departments for Hand and Plastic Surgery in Germany
      and Switzerland studied the problem and showed the functional and cosmetic
      results. 342 questionnaires were checked. 267 patients came for a follow-up
      examination. 83.9% of them were satisfied with the result of the operation.
      Restrictions of movement in the wrist, forearm, and elbow appeared to be very
      rare. Half of the patients considered the donor-site defect to be ugly. Nearly
      the same number objected to preoperative information about the appearance of the
      donor-site defect. Based on the results of this study, we can still recommend the
      radial forearm flap for small and medium size soft-tissue defects, delicate
      technique of closure of the donor site defect provided.

PMID- 8647533
TI  - [Biomechanical changes in the hip, femur and knee joint after removal of a tensor
      fasciae latae flap].
AB  - The TFI-musculofasciocutaneous flap has become a standard procedure in recent
      years. Donor-site problems of this method, especially the biomechanical changes
      of the hip, the proximal femur and the knee joint are evaluated, employing
      biomechanical techniques. Harvesting of a TFL-flap leads to functional loss of
      the M. tensor fasciae latae and the iliotibial tract and band. This might lead to
      a weakening of active and passive stabilising structures of the hip and the knee
      joint. Loss of the iliotibial tract causes a loss of the lateral tension-band of
      the proximal femur and leads to a significant increase of shear forces on the
      proximal femoral shaft. The functionally important structures of the iliotibial
      tract for knee biomechanics are not influenced by harvesting of the TFL flap.
      Loss of the M. tensor fasciae latae leads to a mild reduction of hip flexion and
      internal rotation. The indication for a TFL-flap should consider the patient's
      activity to prevent overload damage of the proximal femoral shaft. In childhood,
      harvesting of the TFL flap is likely to influence the growing axial skeleton due
      to the loss of the iliotibial tract.

PMID- 8647534
TI  - [Circulatory support by an electrically stimulated muscle flap. Experimental
      experiences].
AB  - Functional electrical stimulation of the latissimus dorsi muscle flap for
      circulatory assistance extends the traditional concept of using this flap for
      reconstructive procedures into the field of cardiac surgery. It requires a
      transformed muscle which is able to contract for long periods of time without
      fatigue. Two main groups of experiments have been carried out in sheep. In six
      sheep the latissimus dorsi muscle (MLD) was transformed into a fatigue-resistant
      muscle by the means of multichannel stimulation of the supplying motor nerve.
      After that, stimulation of MLD at a frequency of 70 contractions per minute could
      be performed continuously without significant muscle fatigue. The loss of maximal
      force caused by the conditioning procedure was about one third of the initial
      force. In a second series of acute experiments the MLD was used for
      cardiomyoplasty. The muscle was divided into two parts which were wrapped around
      the heart in two different forms. The resting tension of the muscle was
      preserved. EKG-synchronous stimulation resulted in an increase in left
      ventricular pressure between 12 and 53%. The increase in arterial pressure was
      between 10,6 and 58%.

PMID- 8647535
TI  - [Functional long-term result after mandibular reconstruction with vascularized
      iliac bone graft. A case report].
AB  - In an eleven-year-old boy with a large sarcoma of the left mandible, a
      hemimandibulectomy with en bloc soft tissue resection was performed.
      Preoperatively a chemo-and radiotherapy was administered and after resection of
      the sarcoma stabilization of the remaining mandible was achieved by temporary
      reconstruction plate articulating in the temporomandibular fossa. Postoperative
      cytostatic therapy was then given and further development of the remaining
      mandible awaited. In the ensuing years no loco-regional or systemic
      manifestations of the sarcoma could be detected, therefore definitive
      reconstruction of the mandible was undertaken at the age of 16 years. A free
      osseo-musculo-cutaneous composite graft was taken from the left iliac crest and
      revascularisation established microsurgically. In a short time, primary healing
      and remodelling of the new hemimandible could be seen, hence osseointegrated
      dental implants were inserted in order to allow normal mastication. The process
      of remodelling of the reconstructed hemimandible was examined ten years later
      comparing X-ray findings during different periods of growth.

PMID- 8647536
TI  - [Indications and concepts for plastic surgery therapy in chronic varicose ulcer].
AB  - In the treatment of extensive leg ulcers, surgical therapy is superior to
      conservative methods in many respects. Radical resection of sclerotic tissue
      around the ulcer and its causing veins is essential, followed by defect cover
      with mesh-skin grafts. Surgery leads to prompt healing with a shortened
      hospitalization and therefore decreases costs; it leads to a prompt relief of
      pain and a low rate of recurrence. Especially in the aged patient the indication
      for operation must be well-considered and discussed interdisciplinarily. Even
      though operative technique seems to be simple, it should be reserved for the
      plastic surgeon experienced in the treatment of these lesions.

PMID- 8647537
TI  - [Uveal malignant melanoma in Israel (1970-1989)].
AB  - The treatment of uveal melanoma is controversial. In retrospective survival
      studies no therapeutic method was found to be superior. A few risk factors were
      found to influence survival, without relation to the method of treatment. The
      main ones were size of tumor, anterior location, and age of patient. In the
      present study all cases of uveal melanoma treated between 1970-1989 were reviewed
      retrospectively and 135 of the 182 cases were included in the study. There was no
      relationship between method of treatment (irradiation vs enucleation) and
      survival, nor did any clinical risk factor influence survival. Thus, whenever
      possible, conservative treatment should be used in order to save the eye. Further
      investigation on a larger group of patients is needed.

PMID- 8647538
TI  - [Relationship between spermatogenic maturation stages and male hormone levels].
AB  - The relationship between stages of the spermatogenic maturation process and male
      hormone levels was evaluated in 41 azoospermic, infertile men. Patients were
      categorized into groups according to the most mature spermatogenic cell type
      present in testicular aspirates: spermatocytes, spermatids or spermatozoa. High
      FSH and LH plasma levels were found in those with spermatocytes. Their hormone
      levels differed statistically (p < 0.005) from those in patients with maturation
      arrest at the spermatid stage, or those with spermatozoa in their testes. No
      statistically significant differences were found between the 3 groups with regard
      to plasma levels of testosterone, free testosterone and prolactin. However, there
      were positive correlations, higher for free testosterone than for testosterone,
      with stage of spermatogenic maturation.

PMID- 8647540
TI  - [Transseptal left heart catheterization: a new application of an old invasive
      technique].
AB  - In this evolving era of balloon mitral valvotomy (BMV), radiofrequency ablation
      (RF) of left-sided bypass tracts via catheter, and hemodynamic evaluation of
      aortic mechanical prostheses, there has been renewed interest in transseptal left
      heart catheterization (TSLHC). In the 3 years 1990-1994, 122 consecutive patients
      were referred for TSLHC to our institute (which lacks thoracic surgical
      facilities). 12 patients were excluded; 10 with a LA mass proven by
      transesophageal echocardiography (TEE), 1 with a vascularized thrombus in the
      circumflex coronary system and 1 with congenital interruption of the inferior
      vena cava with azygous continuity. In the remaining 110 cases TSLHC was performed
      for interventions in 90 cases (82%) of BMV, and for left-sided catheter
      radiofrequency (RF) ablation in 3 (3%). For diagnostic purposes it was performed
      in 17 (15%) cases for hemodynamic evaluation of mechanical aortic valve
      prostheses. Using the Brockenbrough needle, the adult Mullins sheath system (MSS)
      and single plane fluoroscopy, 100% technical success was achieved. Needle
      puncture was not needed in 30 (27%) due to direct crossing with the MSS through a
      stretched foramen ovale. In 2 we had to perform SVC dye injection for better
      interatrial septum localization. There were no complications when TSLHC was only
      used for diagnostic procedures. 1 patient had perforation of the LA due to right
      lower pulmonary vein laceration following septal dilatation. Following
      stabilization by immediate pericardiocentesis, the patient was transferred for
      open heart surgery. There were no great vessel perforations, systemic
      embolization or periprocedural deaths. TSLHC can be performed quite safely with
      single-plane fluoroscopy without an onsight surgical team, as with an experienced
      staff this procedure has very low morbidity and mortality.

PMID- 8647539
TI  - [Changes in semen after low inguinal spermatic vein ligation].
AB  - We examined semen characteristics of 128 patients prior to low-inguinal,
      spermatic vein ligation for varicocele and every 2 or 3 months over the course of
      a year. There was a higher sperm count 26 months after surgery, and after 68
      months improved motility and a higher proportion of sperm with normal morphology.
      10 months to 1 year after surgery there was improvement in all 3 parameters in
      106 patients (82.8%), in 17 (13.2%) no change, and in 5 (3.9%) deterioration.
      Changes in sperm parameters (SP) were compared with retrograde flow (RF) into the
      pampiniform plexus 10-12 months after operation. Of the 106 patients with
      improvement in SP, only 14 (13.7%) had RF; of the 17 with no improvement, 14
      (82.4%) had RF; and in all 5 in whom SP deteriorated there was bilateral RF. The
      study points to the necessity of continued follow-up of varicocele patients for
      at least a year after operation. Further management should be based on
      postoperative changes and the presence or absence of RF and improvement in SP.

PMID- 8647541
TI  - [Patient involvement in medical care].
AB  - Models of doctor-patient relationship may be broadly classified as
      "paternalistic"(doctor decides, patient complies) and "shared decisions" (doctor
      informs patient and considers patient's preferences). During recent decades there
      has been increasing emphasis on respect for the patient's autonomy. Physicians
      agree that clinical decisions require understanding of how patients view
      alternative treatment outcomes, and that when they can and wish to do so,
      patients should participate in the choice of management options. However,
      involving patients in medical decisions is difficult. Although population surveys
      have indicated an almost unanimous rejection of the paternalistic model, they
      have not yielded consistent results on the proportion of patients who want to
      participate in decision making, and of those who would prefer information and
      guidance, with a view to following the doctor's advice. A second difficulty
      relates to method: how should the various options be explained to those who want
      to participate in decision making? Framing, order of presentation of data and
      amount of data to be presented have all been shown to affect the way patients
      perceive aand respond to probabilistic information on treatment outcome.
      Therefore, there is considerable doubt regarding the applicability of the shared
      decision model in an unselected patient population. Further research will
      hopefully identify ways to elicit patient preferences and to communicate
      information about treatment outcomes, such as life expectancy, morbidity, burdens
      of taking medication and economic costs. For the present, there seems to be no
      substitute for the compassionate physician who treats patients with respect and
      who tries to understand their needs.

PMID- 8647542
TI  - [Short course for primary physicians care].
AB  - This department of family medicine has been challenged with helping a group of
      Russian immigrant physicians find places in primary care clinics, quickly and at
      minimal expense. A 3-month course was set up based on the Family Practice
      Residency Syllabus and the SFATAM approach, led by teachers and tutors from our
      department. 30 newly immigrated Russian physicians participated. The course
      included: lectures and exercises in treatment and communication with patients
      with a variety of common medical problems in the primary care setting;
      improvement of fluency in Hebrew relevant to the work setting; and information on
      the function of primary care and professional clinics. Before-and-after
      questionnaires evaluating optimal use of a 10- minute meeting with a client
      presenting with headache were administered. The data showed that the physicians
      had learned to use more psychosocial diagnostic question and more psychosocial
      interventions. There was a cleared trend toward greater awareness of the
      patient's environment, his family, social connections and work. There was no
      change in biomedical inquiry and interventions but a clear trend to a decrease in
      recommendations for tests and in referrals. The authors recommend the following
      didactic tools: adopting a biopsychosocial attitude, active participation of
      students in the learning situation, working in small groups, use of simulations
      and video clips, and acquiring basic communication experience.

PMID- 8647544
TI  - [Physician as patient].

PMID- 8647543
TI  - [Use of medication for hypertension and coronary heart disease by Russian
      immigrants].
AB  - 397 recent immigrants (olim) were under medical treatment at a primary care
      clinic during their first year (1990-1991) after immigration to Israel (aliya)
      from 14 republics of the Commonwealth of Independent States (CIS, formerly the
      Soviet Union). While in the CIS 3/4 had used medication for hypertension
      intermittently for only 2-4 weeks, whenever blood pressure was elevated. More
      than 3/4 took prophylactic drugs for coronary heart disease only when chest pain
      appeared and for only approximately 4 weeks, in contrast with continuous,
      prolonged treatment used in Israel and western countries. Immigrants brought with
      them stocks of drugs and continued to take them intermittently as they had in the
      CIS. This form of treatment is described in the official pharmacology book. Only
      after intervention of the family physician did the immigrants begin to take their
      drugs for hypertension and coronary heart disease continuously.

PMID- 8647545
TI  - [Bone marrow transplantation].

PMID- 8647546
TI  - [Hyperhomocysteinemia as a risk factor in atherosclerotic and thrombotic vascular
      processes].

PMID- 8647547
TI  - [Colchicine in familial Mediterranean fever: practical problems and their
      solutions].

PMID- 8647548
TI  - [Molecular biology of human papilloma virus infection of the female genital
      tract].

PMID- 8647550
TI  - [Depression and epilepsy].

PMID- 8647549
TI  - [The hantaviruses--clinical syndromes].

PMID- 8647551
TI  - [Ticlopidine in coronary artery diseases].

PMID- 8647552
TI  - [Ethylene oxide in hospitals--occupational medicine and hygienic aspects].

PMID- 8647553
TI  - [Mechanisms of injury by ballistic missiles].

PMID- 8647554
TI  - [Nutrition education in medical schools].

PMID- 8647555
TI  - Preprosthetic orthodontics.
AB  - Preprosthetic orthodontic measures are often an integral part of comprehensive
      oral rehabilitation. The individual aspects of treatment are aimed at optimizing
      dentofacial esthetics and at improving masticatory function, hygiene potential of
      prosthetic restorations and abutment quality. The therapeutic systematics of
      orthodontic/prosthetic cooperation, the limits and problems are outlined and
      documented with examples of treatment sequences. The conclusion drawn is that
      preprosthetic orthodontics will continue to gain significance in future esthetic
      functionally oriented dentistry and that its integration into multidisciplinary
      rehabilitation is often indispensable.

PMID- 8647556
TI  - A clinical report for distalizing maxillary molars by using super-elastic wires.
AB  - A class II/2 malocclusion with considerable amount of crowding was treated non
      extraction by distalization. The upper molars were moved posteriorly with the use
      of superelastic wires. The orthodontic therapy-mode is presented and the results
      are discussed. This treatment approach shows another use of superelastic wires.

PMID- 8647557
TI  - Report from the 8th German Symposium of the Interdisciplinary Study Group of
      Cleft Lip and Palate.

PMID- 8647558
TI  - Foundation of Initiativkreis Umfassende Kieferorthopadie (IUK). The Initiative
      Circle in Comprehensive Orthodontics.

PMID- 8647560
TI  - In-vitro study of the adhesive strengths of brackets on metals, ceramic and
      composite. Part 1: Bonding to precious metals and amalgam.
AB  - Adult patients often have fillings, artificial crowns and/or bridges that make
      fitting of conventional bands difficult or even impossible. In such cases bonding
      rather than banding would be preferable. The present paper presents the
      investigation of more than 25 resin/conditioner combinations with respect to
      their bond strength to different metals as well as to amalgam. For that purpose
      stainless steel lingual buttons were bonded with the various adhesives and their
      shear bond strengths and types of bond failure were determined after 24 hours.
      All specimens were air-abraded with 50 microns Al2O3 for 2 or 4 seconds by means
      of a Microetcher before bonding. For comparison, buttons were also bonded to
      bovine enamel after air-abrasion or conventional etching with 37% H3PO4. Results
      show that, on all metals investigated, several materials yield bond strengths
      which are similar to or higher than what is achieved with the conventional acid
      etch technique on enamel. Maximum adhesive strength is not always desirable,
      however, for bonding brackets. The type of bond failure and the risk of
      irreversible damage to the bonded material have also to be taken into
      consideration. Al2O3 abrasion may cause considerable damage to enamel within 4
      seconds. Since the bond strength on air-abraded enamel is about the same as on
      acid etched enamel, conventional etching with H3PO4 is preferable to the
      sandblasting of enamel.

PMID- 8647559
TI  - Three-dimensional interpretation of alveolar bone dehiscences. An anatomical
      radiological study--Part I.
AB  - In an anatomical-radiological in-vitro study dental radiographs were compared
      with axial, sagittal and coronal CT-scans, with respect to the identification and
      quantitative assessment of bone dehiscences and the buccal or lingual bone plates
      over the roots of the teeth. After removal of soft tissue and metallic
      restorations in 16 dentate jaw specimens, 60 lingual or buccal defects of
      different dimensions were artificially created over the roots. None of the
      defects could be identified on conventional dental radiographs. In contrast, 42
      of the 60 (70%) artificial defects were identified in the CT-scans.
      Identification and demarcation of the facial/lingual bone plate depends on the
      orientation of the CT-scanning, the visibility of the periodontal ligament space,
      the dimension of the defect, and the thickness and histological structure of the
      adjacent bone. A visible periodontal ligament space improves the measuring
      accuracy of buccal or lingual bone plates up to 0.2 mm.

PMID- 8647561
TI  - Assessment of the combined orthodontic-surgical treatment from the patients'
      point of view. A longitudinal study.
AB  - In a longitudinal study, 40 patients who underwent a combined orthodontic
      surgical treatment, were interviewed 4 weeks before operation and 1 week and/or
      half a year after surgery in order to evaluate patients' expectations and
      appraisal of the operation and their psycho-social situation. The comparisons
      between the patients' pre- and postoperative statements yielded the following
      picture: the patients showed a high degree of satisfaction with the result of the
      operation. They judged their postoperative facial appearance, with the help of a
      "semantic differential', to be significantly more attractive. Satisfaction also
      was expressed in a higher degree of psychological well-being and thus an increase
      in self-confidence and motivation. Postoperatively, the "Giessen test' showed
      also a distinctly positive change of the patients' mood and improved experiences
      with social interaction. Before the operation almost half of the patients feared
      sensitivity loss or disturbance. One out of 5 patients did in fact suffer from
      this problem--but not from pain--half a year after the operation. Some patients
      felt they had received insufficient prior information about the procedure and the
      risk of the operation. In spite of all burdens for the patients, the assessment
      of the result of the operation is (generally) positive, not only from the medical
      point of view.

PMID- 8647562
TI  - [Sudden cardiac death: diagnostic help from chaos research? Prof. Dr. med. Georg
      Schmidt, Munich, on preventive diagnostic criteria. Interview by Beatrice
      Wagner].

PMID- 8647563
TI  - [Rheumatism: a too long pathway to adequate therapy. Experiences of a physician
      as rheumatism patient].

PMID- 8647564
TI  - [Rheumatoid arthritis: general practice searches for effective healing methods.
      Interview by Elisabeth B. Moosmann].

PMID- 8647565
TI  - [Routine hip ultrasonography in inflammatory rheumatoid diseases. Results in 119
      consecutive patients of a rheumatism clinic].
AB  - METHOD: In 119 consecutive inpatients with rheumatic diseases--mainly rheumatoid
      arthritis, ankylosing spondylitis and psoriatic arthritis--both hips were
      routinely investigated by sonography. RESULTS: In 52 of the 119 patients definite
      or possible pathological findings (in 18 cases bilateral) were observed. The
      relative frequency of sonographic findings in 223 evaluable hips was 33% and was
      somewhat higher in patients with rheumatoid arthritis than in those with other
      diagnoses. Changes were found significantly more often when the patient had joint
      complaints, limitation of movement, pathological X-ray changes or serological
      signs of inflammation (elevated ESR, positive C-reactive protein). The relative
      frequencies were higher than were expected on the basis of data in the
      literature. Of the pathological sonographic findings, 22% occurred in clinically
      and radiologically asymptomatic patients. CONCLUSIONS: In view of the therapeutic
      consequences and the importance of early treatment, routine sonographic
      examination of the hip joint is recommended.

PMID- 8647566
TI  - [Therapeutic effectiveness of Crataegus].
AB  - Hawthorn (crataegus) has been used since antiquity for medicinal purposes. More
      recent research suggests it to be useful in congestive heart failure. Rigorous
      clinical trials show benefit concerning objective signs and subjective symptoms
      of congestive heart failure stage NYHA-II. No adverse drug reactions have been
      reported. It is therefore concluded that crataegus is an effective and safe
      therapeutic alternative for this indication.

PMID- 8647567
TI  - [Education of paramedics in resuscitation: after 6 months some procedures
      forgotten. Knowledge and capability of medical lay personnel after education in
      cardiovascular resuscitation].

PMID- 8647568
TI  - [Diagnosis and clinical course in gastroesophageal reflux].
AB  - METHODS: We have previously shown, that longterm pH-monitoring is of high
      clinical value for the diagnosis of gastro-oesophageal reflux disease. With this
      method, we were able to define a sample of 166 patients with proven reflux
      disease. All patients had typical reflux symptoms (heartburn and/or acid
      regurgitation) and pathologic pH-monitoring (diurnal reflux time > 8.2% and/or
      nocturnal reflux time > 3.0%). They were followed up by questionnaire and
      interview for a mean of 41 (range: 7-86) months after diagnosis of reflux
      disease. RESULTS: Ten patients died of causes unrelated to reflux. In 117 (75%)
      of the remaining 156 patients data on the further course of the disease could be
      obtained. Twelve patients underwent anti-reflux surgery. Forty-one (39%) of the
      remaining 105 patients stopped taking medication, 13 of whom had no longer any
      symptoms. Sixty-four (61%) patients continued to use medication (40 as needed, 24
      regularly). In comparison with baseline, symptoms were either unchanged or worse
      without medication in 71 patients, and better in 21. Patients with persisting
      symptoms during follow-up had significantly more nocturnal reflux initially (p <
      0.05). The parameters oesophageal erosions at initial endoscopy, duration of
      reflux, age, sex, and smoking habits had no predictive value for the course of
      the disease. In conclusion, reflux symptoms appear to clear up spontaneously only
      in a minority of patients. More than half of all patients continue to use
      medication either as needed or regularly, with quite good results. Severe
      nocturnal reflux is an unfavorable prognostic factor.

PMID- 8647569
TI  - [Dermatomycoses. 17: Topical therapy of skin and mucous membrane mycoses].

PMID- 8647570
TI  - [Medical consultation becomes a mathematical problem].

PMID- 8647571
TI  - [Ginkgo biloba in treatment of intermittent claudication. A systematic research
      based on controlled studies in the literature].
AB  - The aim of this systematic review was to evaluate the effectiveness of ginkgo
      biloba in the treatment of intermittent claudication. A Medline-search identified
      ten controlled trials on the subject. These were heterogeneous in all respects
      and, with only few exceptions, of poor methodological quality. All the studies
      implied that ginkgo biloba is an effective therapy for intermittent claudication.
      This hypothesis should be confirmed in further trials employing meticulous
      methodology. Furthermore it would also be important to determine whether oral
      ginkgo biloba can be usefully combined with walking exercise.

PMID- 8647572
TI  - [Motivation for smoking cessation by the general practitioner].

PMID- 8647573
TI  - [HMG-CoA reductase inhibitors for prevention and treatment of coronary heart
      disease. Effective reduction of cardiac events and mortality].

PMID- 8647574
TI  - [Reduction of cardiovascular events with pravastatin. A pooled analysis of
      clinical events within the scope of the Pravastatin Atherosclerosis Intervention
      Program].
AB  - BACKGROUND: It has been documented that the HMG coenzyme A reductase inhibitors,
      or statins, can decrease cardiovascular events and mortality in patients with
      clinical coronary disease and moderately to severely elevated lipid levels.
      Additional data are required to demonstrate a reduction of vascular events in
      coronary patients with less than severely elevated lipid levels and in subgroups
      of this population. METHODS AND RESULTS: Clinical data from four atherosclerosis
      regression trials that evaluated pravastatin were pooled for a predetermined
      analysis of the effect of that agent on the risk of coronary events. All trials
      were double-masked, placebo-controlled designs that used pravastatin as
      monotherapy for 2 to 3 years. The 1891 participants in the trials had evidence of
      atherosclerosis and mildly to moderately elevated lipid levels. For fatal or
      nonfatal myocardial infarction, there was a 62% reduction in events attributable
      to pravastatin (p = .001). This effect was evident in younger and older patients,
      men and women, and patients with and without histories of hypertension and prior
      infarction. There was a 46% reduction in all-cause mortality (p = 17), which,
      although not statistically significant, is consistent with the results of other
      statin trials. There also was a 62% reduction in the risk of fatal or nonfatal
      stroke (p = .054). CONCLUSIONS: These pooled results provide strong evidence that
      pravastatin reduces the risk of cardiovascular events in patients with
      atherosclerotic disease and mildly to moderately elevated lipid levels. The
      benefit for reducing myocardial infarction is evident in older and younger
      patients, men and women, and patients with and without histories of hypertension
      and prior infarction.

PMID- 8647575
TI  - -New aspects in antithrombotic therapy--platelet inhibitors-.
AB  - The aim of platelet inhibitory therapy in cardiology is to prevent undesired
      thrombus formation and, thus, to prevent complications of cardiovascular
      diseases. In Germany, 5 substances are approved for antiplatelet therapy.
      Acetylsalicylic acid, an inhibitor of platelet cyclooxygenase, has been shown to
      be effective at both high and low doses in the secondary prevention of myocardial
      infarction, coronary heart disease, and cerebrovascular disease. In addition,
      acetylsalicylic acid is effective in reducing the complications of unstable
      angina pectoris and coronary angioplasty, and in reducing the occlusion rate of
      aortocoronary bypass grafts. The addition of dipyridamole to acetylsalicylic acid
      has not been shown to result in any additional benefit in many clinical studies.
      Ticlopidine, an antagonist of ADP-induced platelet aggregation has been similarly
      effective as acetylsalicylic acid in the treatment of coronary heart disease. The
      principal side effect of the drug, the occurrence of neutropenia in about 1% of
      treated patients, makes regular blood cell counts mandatory during treatment. In
      the secondary prevention of cerebrovascular disease, the drug may be superior to
      acetylsalicylic acid. Trapidil is an anti-platelet substance which acts on
      platelets through various mechanisms including inhibition of the release of
      "platelet derived growth factor". In 3 smaller randomized studies, trapidil has
      been found to reduce the restenosis rate after coronary angioplasty. Abciximab,
      the Fab-fragment of an antibody against the platelet fibrinogen receptor
      glycoprotein 11b/IIIa has been shown to be effective in the prevention of acute
      and long-term complications of high-risk coronary angioplasty.

PMID- 8647577
TI  - [Anticoagulation in patients with atrial fibrillation].
AB  - Nonvalvular atrial fibrillation is a frequent finding in elderly patients; the
      risk of thromboembolic complications is comparable to that reported in patients
      with rheumatic atrial fibrillation. Recently, 6 multicenter clinical trials (5
      primary prevention, 1 secondary prevention trail) have been published which
      demonstrate equivocally that oral anticoagulation therapy significantly reduces
      the embolic risk in patients with nonvalvular atrial fibrillation by about 67% to
      87%. The target INR of anticoagulation with warfarin in 2 of these trials was 1.4
      to 2.8 ("low-dose" warfarin); interestingly, the magnitude of risk reduction was
      similar to these 2 studies with "low-dose" warfarin as it has been reported by
      the others using full-dose warfarin with an INR target between 2.0 and 4.5. Side
      effects of oral anticoagulation (severe bleeding complications) were low in these
      trials. Thus, the benefit-risk ratio in these 6 clinical trials encourage the use
      of oral anticoagulation in patients with nonvalvular atrial fibrillation. It will
      be a challenge to transfer these results to clinical practice, and to define in
      more detail the risk-benefit ratios for subgroups of patients with atrial
      fibrillation, e.g. patients > 75 years of age, or patients with "lone" or
      paroxysmal atrial fibrillation. It is well established that patients with chronic
      atrial fibrillation undergoing medical or DC-cardioversion are at risk for
      thromboembolic complications. In previous studies, this risk appears to be in the
      range of 2% without concomitant anticoagulation, but only 0.33% in those patients
      with concomitant anticoagulation. Thus, it is widely accepted that patients
      should be anticoagulated for at least 2 weeks prior and after planned
      cardioversion. Recently, an alternative concept has been proposed omitting
      anticoagulation before cardioversion; instead, transesophageal echocardiography
      is used to exclude intracardiac thrombi. Because it is known that mechanical
      function of the left atrium and appendage is still impaired after cardioversion,
      this concept of echocardiographic-guided cardioversion does not assign the
      necessity of anticoagulation at the day of cardioversion, and 2 weeks afterwards.
      The safety aspects of this concept of echocardiographic-guided cardioversion is
      under current investigation.

PMID- 8647576
TI  - -Anticoagulant drugs-.
AB  - In todays medicine, anticoagulant drugs like heparin and coumadin derivatives
      have become indispensable for the treatment of thrombo-embolic diseases. Heparin,
      consisting of long poly-sulfated polysaccharide chains of variable length and
      sequences is mostly derived from porcine mucosa. Its bioavailability by other
      than the parenteral way of administration is almost negligible. Therefore, with
      only few exceptions, it is almost exclusively applied in hospitalized patients
      (short-term therapy) or to bridge 2 phases of treatment with oral anticoagulant
      drugs. Today, besides the conventional high-molecular weight heparins, new
      fractionated heparins are gaining more and more attention. They offer the
      advantage of a more reliable resorption from the subcutaneous tissue and thus
      warrant reliable plasma levels. In many recent randomized trials of deep vein
      thrombosis and pulmonary embolism, those fractionated heparins have proven to
      successfully substitute for intravenously applied, aPTT-controlled unfractionated
      heparin. It remains however open, whether this also translates into the
      prevention of arterial thrombo-embolic diseases. Heparin may not pass through the
      placental barrier nor into the milk and is regarded non-teratogenic. Therefore,
      it may be regarded the ideal anticoagulant for pregnant women and lactating
      mothers. Those women, however, still carry the heparin-associated risk of
      bleeding and osteoporosis. In comparison: Coumadin derivatives interfere with the
      carboxylation of the clotting factors II, VII, IX, and X as well as proteins C
      and S. By inhibiting the synthesis of these proteins they shift the haemostatic
      balance to a lower level. In addition, they are almost completely bioavailable by
      the enteral pathway. They are, therefore, regarded the drugs of choice for long
      term anticoagulant therapy in patients at particular thromboembolic risk. For
      their therapeutic range, being extremely narrow, meticulous drug monitoring by
      repeated INR-measurements as well as a reliable compliance of the patient to drug
      intake and dietary restrictions are mandatory to exclude phases with over- or
      under-anticoagulation. Above all, coumadin therapy is characterized by numerous
      drug interactions. Thus, whenever the basal medication is changed, for whatever
      reason, more intense care must be laid to drug monitoring, and the intervals for
      INR determinations must transiently be shortened. Coumadin derivatives do pass
      through the placental barrier and in minor amounts also into the milk of breast
      feeding mothers. Furthermore, they are highly teratogenic. If taken during
      pregnancy, malformations of the central nervous system are reported to occur in
      some 10% to 30% of the infants. Thus during pregnancy and in the lactation
      period, coumadin therapy should be avoided. Bleeding episodes of different
      severity are the most frequent adverse effects of anticoagulant therapy, no
      matter whether heparin or coumadin is given. There is a direct relation between
      the intensity of anticoagulant therapy and the frequency of bleeds. Luckily, most
      bleeding episodes do not create major therapeutic problems. In case of severe
      bleeds, however, the anticoagulant therapy must immediately be suspended. In case
      of coumadin therapy the immediate administration of 4 packs of PPSB (prothrombin
      complex-concentrates) or FFP (fresh-frozen-plasma) with concomitant low doses of
      heparin is additionally advised. Allopecia diffusa, urticartia and allergic
      reactions are known side effects of anticoagulant therapy. Patients on long-term
      heparin may also suffer from severe osteoporosis. On the other hand, heparin
      treatment raises the hazzards of a HAT-Syndrome (heparin-associated
      thrombocytopenia) (estimated frequency 0.01% to 0.1% of treated patients), giving
      rise to severe and life-threatening thrombo-embolic side effects predominantly in
      the arterial tree. In these cases, heparin must be suspended despite those severe
      thrombo-embolic episodes.

PMID- 8647578
TI  - -New perspectives in therapy of unstable angina-.
AB  - Unstable angina is a critical phase of coronary heart disease with high risk of
      myocardial infarction and death. Recently, major advances have been made
      concerning therapeutic management and risk stratification. PATHOGENETIC
      MECHANISMS: Plaque rupture followed by local thrombus formation is the underlying
      mechanism for the majority of patients with unstable angina. The process that
      leads to plaque rupture is a complex sequence of events which includes local
      inflammatory activity. Rapid progression and vasospasm play a pathogenetic role
      only in a few patients. NEW THERAPEUTIC STRATEGIES: Pain relief is frequently
      successfully achieved by intravenous nitrates combined with betablockers.
      Calciumantagonists may be added, if angina persists. Prognostic improvement is
      achieved by platelet inhibitors, like acetylsalicylic acid or ticlopidine. In
      patients with persisting angina at rest platelet inhibitors should be combined
      with high-dose heparin. Thrombolytics have no advantage and should not be given
      without electrocardiographic evidence of myocardial infarction. The potential
      additional benefit of new glycoprotein IIb/IIIa receptor inhibitors or more
      potent anti-thrombins, like hirudin or hirulog, need to be further evaluated in
      larger trials. THERAPY CONTROL: The detection of minor myocardial cell injury by
      measurements of new cardiac markers like troponin T is associated with an
      unfavourable outcome. Troponin T may therefore serve as parameter for risk
      stratification in emergency rooms and control therapeutic regimens.

PMID- 8647579
TI  - -Differential antithrombotic therapy in patients with low and high PTCA risk-.
AB  - Acute coronary occlusion as well as restenosis still represent the major
      limitations of coronary interventions. Either event seems to be related to
      thrombus formation. The purpose of this overview is to summarize the current
      status of the usefulness of conventional and newer antithrombotic drugs regarding
      the prevention of acute occlusion and restenosis (excluding stents).
      ANTICOAGULATION: For ethical reasons, no placebo-controlled studies were
      conducted to prove the usefulness of heparin in preventing acute occlusions. The
      dosage mostly used is 10,000 U, although a relationship between dosage and
      complication rate has not been documented. A prolonged heparin infusion in
      patients with low risk and uncomplicated PTCA has no advantages. Restenosis is
      not influenced by prolonged infusion of heparin or administration of coumadin as
      well. Low molecular weight heparin is currently under investigation. Hirudin and
      hirulog have shown promising results with less acute occlusions; however, their
      therapeutic range must be considered. ANTIAGGREGATION: In controlled studies, ASA
      significantly reduced acute occlusions during PTCA when given in addition to
      heparin. Ticlopidin is as effective as ASA, but due to its side effects should
      only be administered when contraindications to ASA exist. ASA significantly
      reduced restenosis in only 1 of 4 studies with limited number of patients.
      Thromboxane inhibitors such as ridogrel or clopidogrel showed promising initial
      results. Trapidil significantly reduced restenosis in 2 studies; quantitative
      stenosis analysis, however, was not performed. Inhibition of platelets by
      glycoprotein (GP) IIb/IIIa receptor antagonists represents an innovative
      therapeutic concept: numerous controlled trials have documented a significant
      reduction in cardiac ischemic events and therefore indirectly in restenosis
      rates. The recombinant monoclonal antibody c7E3 Fab seems to be more effective
      than the synthetic integrelin. Unfortunately, efficacy appears to be in direct
      relationship to the risk of bleeding complications. The clinical role of oral GP
      IIb/IIIa inhibitors has yet to be established. For patients with high risk PTCA,
      the use of hirudin instead of heparin as well as the addition of GP IIb/IIIa
      inhibitors should be considered.

PMID- 8647580
TI  - -Anticoagulation after intracoronary stent implantation-.
AB  - The success of percutaneous transluminal coronary angioplasty (PTCA) is limited
      by vessel dissection with subsequent vessel occlusion in the acute phase and by
      restenosis chronically. The implantation of intracoronary stents allows to manage
      acute complications more efficiently and reduce restenosis rate. Anticoagulation
      and inhibition of platelet function play an important role in reducing the risk
      of stent thrombosis triggered by the thrombogenic surface of the stents available
      today. Among the risk factors for stent thrombosis are stent implantations in
      emergency situations, a low coronary blood flow secondary to more distal stenoses
      or to small vessel diameter, and several stents implanted in a single vessel
      region. In 2 large randomized studies (BENESTENT, STRESS), combination therapy
      using aspirin, dipyridamole, dextrane, and heparin continued by warfarin lead to
      a high incidence of bleedings and vascular complications at the site of arterial
      punction. Subsequent studies documented that dipyridamole and dextrane do not
      improve the outcome after stent implantation. Recently, the combination of
      aspirin and ticlopidine has been show to reduce the rate of stent thrombosis;
      with coronary stents implanted optimally anticoagulation may be handled without
      warfarin. Most stent thromboses occur even if anticoagulation is monitored and
      controlled accurately. The search for markers to predict stent thrombosis such as
      the prothrombin fragment F1+2 or the thrombin-antithrombin complex has not been
      successful so far. The direct antithrombin hirudin, platelet receptor blockers
      such as the antibody 7E3, and new stents with reduced thrombogenic surface offer
      new perspectives in anticoagulation with stent implantation.

PMID- 8647581
TI  - -Practical implementation of stress echocardiography--what should be monitored?-.

PMID- 8647582
TI  - 4th European Congress of Extracorporeal Life Support. Bergamo, Italy, May 10-12,
      1995. Proceedings.

PMID- 8647583
TI  - Neonatal ECMO: are indications changing?

PMID- 8647584
TI  - The influence of lung injury due to mechanical ventilation on the initiation of
      ECMO.
AB  - Before the entry criteria for extracorporeal membrane oxygenation (ECMO) are met,
      newborns may require aggressive mechanical ventilation which may result in lung
      injury. The question arises whether the presence of a pneumothorax in these
      infants plays a role in the prognosis. Of the 21 newborns transferred to our
      hospital for ECMO, 8 were treated with ECMO. 9 of the 21 newborns developed a
      pneumothorax with conventional ventilation and 6 of these 9 newborns subsequently
      required ECMO. Infants who developed a pneumothorax but did not meet ECMO
      criteria and remained in the oxygenation index (OI) range between 25 and 40 for
      more than 2 days had a poorer prognosis. If adequate oxygenation cannot be
      attained with acceptable mechanical ventilation and a more aggressive ventilation
      results in a pneumothorax, ECMO should be considered even if the oxygenation
      index is below 40.

PMID- 8647585
TI  - Prognosis and outcome of neonates treated either with veno-arterial (VA) or veno
      venous (VV) ECMO.
AB  - A comparison was done between neonates requiring veno-arterial (VA) ECMO (too
      small jugular vein, inability to insert a 12 Fr double lumen catheter or cardio
      circulatory instability) and neonates treated with veno-venous (VV) ECMO in the
      same period of time. From 1991-1995 ECMO was done in 48 neonates after failure of
      maximum conventional treatments, NO-inhalation and HFOV. 30/48 babies were
      treated with VV-ECMO, with a switch to VA-ECMO later on in 3 of them. In 18
      infants VA-ECMO was installed primarily. Differences between the VA- and VV-ECMO
      group were: the OI was higher in the VV-treated babies (62 +/- 20 vs. 48 +/- 13,
      p < 0.03), as were birth weight (3385 +/- 570 vs. 2963 +/- 653 g, p < 0.04),
      gestational age (39.7 +/- 1.6 vs. 37.9 +/- 2.7 weeks, p < 0.01) and MAP (18.7 +/-
      2.2 vs. 17.1 +/- 2.4 cm H2O, p < 0.05). Severe ICH's occurred more frequently in
      the VA-treated babies (29 vs. 7%, p < 0.05), the rate of other complications was
      equal. The mortality rates were 43% (VA) and 15% (VV), p < 0.05. About one third
      of neonatal ECMO candidates will be treated with VA-ECMO, even if the VV-ECMO
      technique is available. Need for VA-ECMO implies--due to a higher number of
      preterm babies and a greater severity of illness before ECMO--a higher incidence
      of ICH's and a higher mortality rate.

PMID- 8647587
TI  - Congenital diaphragmatic hernia.

PMID- 8647586
TI  - Extracorporeal membrane oxygenation with veno-venous bypass and apneic
      oxygenation for treatment of severe neonatal respiratory failure.
AB  - Seven newborn infants with life-threatening respiratory failure were treated with
      veno-venous (V-V) extracorporeal lung support and apneic oxygenation after
      maximal ventilatory and pharmacological treatment failed. Diagnosis were meconium
      aspiration syndrome in 3 cases, respiratory distress syndrome in 2, sepsis in 1,
      congenital diaphragmatic hernia in 1. Before ECMO 6 infants received tolazoline,
      4 surfactant, 3 high frequency ventilation, 1 prostaglandin E, 1 epoprostenol, 2
      nitric oxide. Newborns were highly hypoxemic at admission and all but one
      underwent rescue cannulation. V-V bypass was performed with a single lumen single
      cannula and tidal flow was generated by an alternating clamp using a non
      occlusive roller pump. The mean duration of bypass was 162.4 +/- 162.3 hours and
      infants were extubated 94.5 +/- 74.8 hours after decannulation. Five newborns
      survived and two died. Growth and neurologic development of the older children is
      normal. The extracorporeal lung support with V-V bypass associated with apneic
      oxygenation was effective in reversing severe neonatal respiratory failure
      unresponsive to maximal ventilatory and pharmacological support. An early
      referral, prior to meeting ECMO criteria, is important in order to avoid hypoxic
      complications preceding ECMO.

PMID- 8647588
TI  - Follow-up in neonatal extracorporeal membrane oxygenation (ECMO).
AB  - In 34 survivors of the first 43 ECMO patients from our institution before
      discharge to another hospital or home an EEG, BAER, Head Ultrasonography,
      cerebral CT scan, Dubowitz score and ophthalmological inspection were performed.
      At one year of age Mental Developmental Index of the Bayley scales, Motor
      Quotient as well as pulmonary and neurological status were assessed. In 29
      patients follow-up took place in our hospital. In 17 of them (59%) all tests
      before discharge were normal, 2 patients (7%) showed an abnormal BAER, an
      additional 5 patients (17%) had abnormal EEG and 2 patients (7%) had abnormal HUS
      in combination with abnormal cerebral CT scan. In 19 patients (33%) the Dubowitz
      score was abnormal at discharge. At one year of age neurological status was
      normal in 25 (86%) patients, respiratory status was normal in 22 (76%) and Mental
      Development Index was > 80 in 23 of the patients (79%). A significant correlation
      between Mental Development Index and Motor Quotient was found r = 0.50, p =
      0.0065. It is concluded that more than one abnormal neurophysiological test
      before discharge may identify patients with additional risks for adverse outcome
      and that the respiratory status influenced psychomotor development at one year of
      age.

PMID- 8647589
TI  - High-frequency oscillatory ventilation and nitric oxide: alternative or
      complementary to ECMO.
AB  - One hundred and seventy-seven term or near-term neonates were referred to an ECMO
      center for severe PPHN-associated diseases. In 2 time periods from 1987 to 1991
      and from 1992 to April 1995 alternative treatment modes were tried in an attempt
      to obviate ECMO. During the first time period patients underwent trial high
      frequency oscillatory ventilation before ECMO. In the second time period patients
      first received inhaled NO followed by HFOV in a non-responders. If this also
      failed HFOV was combined with INO. In both time periods about 40% of the patients
      were spared ECMO treatment by these alternative treatment modalities. INO only
      benefited 15% of the ECMO candidates who apparently had fared just as well on
      HFOV alone in the preceding time period. While patients who were improved by INO
      were spared HFOV with its potential severe complications, i.e. air leaks and
      cardiocirculatory instability, more extended long-term studies will have to show
      which of these 2 treatment modalities (INO or HFOV) should be given first
      priority in an attempt to avoid ECMO in neonates with severe respiratory failure.

PMID- 8647591
TI  - Extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure in
      children: the Leicester experience.

PMID- 8647590
TI  - Treatment of severe non-neonatal ARDS in children with surfactant and nitric
      oxide in a "pre-ECMO"-situation.
AB  - The use of exogenous surfactant and nitric oxide in neonates has reduced the
      number of infants requiring ECMO. The purpose of this study was to demonstrate
      whether these two therapeutic options might reduce the number of over 28 days old
      children with severe ARDS requiring ECMO, without reducing changes of survival
      and morbidity. Over a 30 month period all non-neonatal ARDS patients transferred
      to our institution for ECMO evaluation were treated based on a study-algorithm.
      If they did not fulfill "fast entry criteria" (paO2 < 40 for more than 3 hrs.) we
      first tried different ventilation, vasodilatation, and hemodynamic strategies for
      max. 4 hrs. (inv. I/E ratio, HFOV, epoprostenol, high doses norepinephrine. If
      the OI did not decrease by < 10, 30-280 mg natural surfactant or 1-20 ppm nitric
      oxide were treatment options depending on the degree of pulmonary hypertension
      measured by echocardiography and by mixed venous saturation measurements. It was
      possible to use NO and surfactant sequentially. The patients had different
      etiologies of ARDS as near drowning, pneumonia, immunosuppression, and sepsis. If
      their OI did not decrease by 10 in 8 hrs. ECMO was installed. Nineteen patients
      were evaluated, 6 improved with conventional therapy, their OI decreased without
      a relapse (mean OI at begin of the study: 38). Six patients improved with
      surfactant therapy alone (mean OI: 54), 4 patients improved after surfactant and
      sequential NO-treatment, 3 patients were initially treated with NO, 1
      sequentially with surfactant. One patient did not show any benefit from NO or
      surfactant and was put on ECMO. Three patients died (withdrawal of life support
      because of severe brain damage caused by the underlying disease). We could not
      observe any respiratory related failure. No patient had to be discharged on
      oxygen. A sophisticated treatment algorithm integrating different modern ARDS
      treatment options can reduce the number of patients requiring ECMO. We speculate
      however that these options can only be used effectively in centers involved in
      ARDS treatment quite frequently and that these centers have to provide ECMO as
      one of their therapeutic tools.

PMID- 8647592
TI  - Severity and outcome of ARDS: the present place of extracorporeal lung assist
      (ECLA).
AB  - Within the last decade extracorporeal lung assist has been recommended for the
      treatment of acute respiratory distress syndrome. However, this recommendation
      was challenged by several recent clinical studies and reviews. The goal of our
      analysis was therefore to investigate data on outcome and severity of gas
      exchange disturbance published from patients treated with ECLA. These data were
      compared to a historical control group consisting of ARDS patients treated
      conventionally. Computerized (MEDLINE 1967-95) literature search using the
      keywords ARDS, ECLA, ECMO, ECCO2R and HUMAN was performed. Only clinical studies
      published as full papers reporting data on both, patients mortality and
      oxygenation index (PaO2/FiO2) were included. Overall mean mortality reported was
      53 +/- 22% in 17 studies (419 patients), with no apparent trend towards a higher
      survival within the last decade with a mean PaO2/FIO2 (14 papers; 61 +/- 17
      mmHg). However, mean mortality rates of ARDS patients requiring ECLA was 52.3%
      and 44.9% if patients undergoing ECMO were excluded (3 papers). Therefore the
      mortality of these patients with severe lung injury was in the range of patients
      treated conventionally. Patient outcome observed in our analysis is in accordance
      with the mortality rates from the European ECLA centres published recently (49%
      in 1993). Therefore, we conclude that the mean mortality rate of patients
      suffering from severe ARDS treated with ECLA is in the 50% range and does not
      differ significantly from those of patients treated conventionally, despite
      significantly poorer pulmonary function.

PMID- 8647593
TI  - Treatment of ARDS with nitric oxide and ECMO.

PMID- 8647594
TI  - Extracorporeal life support (ECLS) for adult respiratory failure: the North
      American Experience.

PMID- 8647595
TI  - Veno-venous ELS with heparin bonded circuits.

PMID- 8647596
TI  - Changes in "inflammatory" mediators and total body water during extra-corporeal
      membrane oxygenation (ECMO). A preliminary study.
AB  - We studied six patients (5 paediatric, 1 neonate) treated with ECMO to quantify
      changes in inflammatory mediators (neutrophil elastase (NE), free radical
      activity (FR), interleukin 8 (IL8)) and total body water (TBW). Blood samples
      were taken before instigation of ECMO, 4, 12, 24 hours post-ECMO and daily for
      six days. FR activity was quantified using the oxidised IgG FI/UV ration. NE and
      IL8 levels were measured by ELISA. TBW was assessed by electrical bioimpedance.
      Statistical analysis was made using repeated measures analysis of variance and
      modified t-test where appropriate. Results are presented as mean +/- standard
      error of the mean. FR activity increased 4 hours after instigation of ECMO (IgG
      FI/UV 32.1 +/- 3.2 from 24.1 +/- 3.0 p = 0.005) and remained elevated. NE also
      increased by 4 hours (94.8 micrograms/L +/- 8.9 to 678 micrograms/L +/- 153.4, p
      = 0.005) but returned to pre-ECMO values by day 6. IL8 levels rose after ECMO
      (from 98 pg/ml +/- 39, to 24 pg/ml +/- 117.4) although no statistical difference
      was noted over time due to the large variation between subjects (p = 0.009). TBW
      (% pre-ECMO body weight) fell by 24 hours (from 118.6 +/- 12.6 to 96.5 +/- 8.2 p
      = 0.0004). This study demonstrated that ECMO stimulates an 'inflammatory'
      response to extracorporeal perfusion (increased FR, NE) but despite this, results
      in a reduction in total body water. The complex relationship between the
      inflammatory response to prolonged extracorporeal perfusion and its effect on
      tissue oedema merits further investigation.

PMID- 8647597
TI  - Control and treatment of hemostasis in cardiovascular surgery. The experience of
      La Pitie Hospital with patients on total artificial heart.
AB  - The hemostasis protocol applied at the Cardiovascular Surgery Dept. of La Pitie
      Hospital has greatly reduced thromboembolic accidents and excessive bleeding,
      with consequent benefits for patients as well as cost reduction. Protocol also
      has been adopted for patients implanted with a circulatory assist device or a
      TAH. This paper presents our criteria on supervision and treatment of coagulation
      with such patients, who reflect all the acquired pathology in clinical
      hemostasis. From 04/86 to 07/94, 82 patients underwent TAH as a bridge to
      transplantation. Mean age: 38. Overall duration of mechanical support: 1930 days
      (mean: 23), of which 137 and 603 for 2 patients. Average duration of CPB: 150
      min. Systematic approach to complex TAH-blood interaction and pre-operative
      multiple organ dysfunction used to control bleeding and/or thromboembolism after
      CPB. In addition to routine tests, specific regular testing was carried out at
      least once a day for platelet functions, for thrombin formation and its
      regulatory pathways, and for the fibrinolytic system. Patients were treated with
      small doses of Heparin, large doses of Dypyridamole, small doses of Aspirin,
      modulated doses of Aprotinin, Ticlopidine, Pentoxifylline, FFP, as well as
      Fibrinogen and AT III concentrates. Dosage was adapted to patient's clinical
      profile as well as to test interpretation criteria to provide personalized
      treatment. DIC, widely present in its different phases, was thus diagnosed and
      treated. All DIC bleeding was controlled, making it possible to detect other
      causes of post-operatory bleeding and use blood derivates rationally. There were
      no thromboembolic complications and no iatrogenic bleeding. TAH explanation shows
      no evidence of macroscopic clots in high risk sites, confirmed by microscopic
      analysis.

PMID- 8647598
TI  - Reduction of haemorrhagic complications during mechanically assisted circulation
      with the use of a multi-system anticoagulation protocol.
AB  - Two different anticoagulation protocols were used in 49 consecutive patients
      mechanically supported either for bridge to transplantation (11) or for recovery
      of myocardial function after cardiac surgery (35). In 46 patients a Biomedicus
      centrifugal pump was used and in 3 patients a Pierce-Donachy ventricles.
      Mechanical support was provided to the left ventricle in 14 patients, to the
      right ventricle in 6 and to both ventricles in 12 patients; an extra-corporeal
      membrane oxygenator (ECMO) support was used in 17 patients. Thirty-seven males
      and 12 females, aged 0.2 to 58 years, were supported for an average time of 6.3
      days (range 1-43). Anticoagulation was either based on a continuous infusion of
      heparin in the first 27 patients (group A) or on a multi-system therapy ("La
      Pitie" protocol) in the other 22 patients (group B). Overall survival rate was
      47%. Patients in group A had a 30% (8/27) survival rate, whereas in group B a 68%
      (15/22) survival rate was observed (p = 0.006). Transplantation and ventricular
      assist device (VAD) removal was successfully obtained in 59% (16/27) and 91%
      (20/22) of patients in group A and group B respectively (p = 0.05). Significant
      bleeding occurred in 21 patients (81%) in group A and in 2 (9%) of group B (p =
      0.001). In these patients bleeding averaged 230 +/- 231 ml/kg in group A versus
      55 +/- 18 ml/kg in group B (p = 0.001). Surgical revision was necessary for
      cardiac tamponade or persistent bleeding in 12 patients of group A (25
      procedures: mean 0.9/patient) and in 3 patients of group B (one each patient:
      mean 0.1/patient) (p = 0.01). Infection, thrombo-embolism and brain hemorrhage
      were also less frequent in group A than in group B. Our data suggest that the "La
      Pitie" protocol provides a better control of bleeding than the conventional
      heparin infusion in patients receiving assist device. this reduction in thrombo
      hemorrhagic complications might improve the results of mechanical circulatory
      support.

PMID- 8647600
TI  - The current status of intratracheal-pulmonary ventilation (ITPV).

PMID- 8647599
TI  - Clinical application of novel ventilation techniques.

PMID- 8647601
TI  - Perfluorochemical liquid ventilation: from the animal laboratory to the intensive
      care unit.
AB  - Perfluorochemical or perfluorocarbon liquids have an enormous gas-carrying
      capacity. During tidal liquid ventilation the respiratory medium of both
      functional residual capacity and tidal volume is replaced by neat perfluorocarbon
      liquid. Tidal liquid ventilation is characterized by convective and diffusive
      limitations, but offers the advantage of preserved functional residual capacity,
      high compliance and improved ventilation-perfusion matching. During partial
      liquid ventilation only the functional residual capacity is replaced by
      perfluorocarbon liquid. Both tidal and partial liquid ventilation improve gas
      exchange and lung mechanics in hyaline membrane disease, adult respiratory
      distress models and meconium aspiration. Compared to gas ventilation, there is
      less histologic evidence of barotrauma after liquid ventilation. Cardio-pulmonary
      interaction, inherent to the high density of liquid, and long term safety need
      further study. However, extrapolating from animal data, and taking into account
      promising human pilot studies, liquid ventilation has the desired properties to
      occupy an important place in the therapy of restrictive lung disease in man.

PMID- 8647602
TI  - Practical aspects of renal replacement therapy.

PMID- 8647603
TI  - Management of fluid imbalance.

PMID- 8647604
TI  - Treatment of acute renal failure in intensive care patients.

PMID- 8647605
TI  - Use of continuous renal replacement therapy for detoxification?

PMID- 8647606
TI  - Pharmacokinetics during continuous renal replacement therapy.

PMID- 8647607
TI  - Impact of continuous renal replacement therapies on metabolism.

PMID- 8647608
TI  - Acute renal failure in infants and children.

PMID- 8647609
TI  - Elimination of inflammatory mediators by hemofiltration.

PMID- 8647610
TI  - Plasmapheresis in the therapy of septic disease.

PMID- 8647611
TI  - Adequacy of dialysis in the acute renal failure of the critically ill: the case
      for continuous therapies.

PMID- 8647612
TI  - Special issue: Continuous renal replacement therapies in intensive care medicine.

PMID- 8647613
TI  - Pathophysiology of ARF in the ICU.

PMID- 8647614
TI  - Practical guide to diagnosis and differential diagnosis of ARF in the ICU.

PMID- 8647615
TI  - Prophylaxis and conservative management of acute renal failure in the ICU.

PMID- 8647616
TI  - Basic mechanisms and definitions for continuous renal replacement therapies.

PMID- 8647617
TI  - Cancer among patients on renal replacement therapy: a population-based survey in
      Lombardy, Italy.
AB  - Longer and better survival of End-Stage Renal Disease (ESRD) patients undergoing
      renal replacement therapy (RRT) is now associated with a higher prevalence of new
      elderly patients receiving renal replacement therapy (dialysis). In order to help
      clarify the association of cancer risk with RRT, the incidence of cancer in a
      population-based cohort of uraemic patients in the Region of Lombardy, northern
      Italy, was undertaken using data from the Lombardy Regional Dialysis and Renal
      Transplant Registry. A total of 479 cases of cancer of all sites was recorded in
      this population. There were statistically significantly elevated risks of primary
      liver cancer, kidney cancer, thyroid cancer, lymphoma and multiple myeloma. When
      the data were examined according to primary renal diseases, there did not appear
      to be any particular association between excess cancer risk and the underlying
      pathology. While some caution must be expressed in interpreting these data, due
      to the relatively small numbers of cases expected in many of the disease
      entities, the results indicate an excess of renal-cell and liver carcinomas and
      lymphomas in patients receiving RRT and highlight the necessity of careful follow
      up and awareness of these associations, together with the need for early
      detection of such tumours.

PMID- 8647618
TI  - Numerical aberration and point mutation of p53 gene in human gastric intestinal
      metaplasia and well-differentiated adenocarcinoma: analysis by fluorescence in
      situ hybridization (FISH) and PCR-SSCP.
AB  - This study examined p53 gene alterations in human gastric mucosa, intestinal
      metaplasia and well-differentiated (cohesive type) adenocarcinomas to clarify to
      the role of the p53 gene in gastric tumorigenesis by means of fluorescence in
      situ hybridization (FISH), polymerase-chain-reaction-single-strand-conformation
      polymorphism (PCR-SSCP) and immunohistochemistry. Gene alterations were compared
      with numerical changes of chromosome 17. Samples were obtained from 31 surgically
      resected stomachs affected with gastric cancer. There was no nuclear p53 protein
      in cells from normal gastric mucosa. Among 23 specimens of intestinal metaplasia,
      cells with p53 protein were variably detected in 5 incomplete metaplasias
      (colonic type). A histological study revealed a mildly dysplastic appearance. PCR
      SSCP identified p53-gene mutation in exons 5 and 8 in 2 of the 5 samples.
      Numerical aberrations of chromosome 17 and the p53 gene were undetectable both in
      normal mucosa and in intestinal metaplasia. Variable numbers of tumor cells
      contained p53 protein in 13 (54%) of 24 carcinomas, and PCR-SSCP revealed
      abnormal bands in 5 of them. Mutations were detected in exons 5, 7, 7, 7 and 8.
      FISH analysis demonstrated that 6 carcinomas emitted 3 or 4 signals for
      chromosome 17, and 7 gave one signal for the p53 gene in over 20% of the cells.
      Ten (77%) of 13 carcinomas examined by FISH appeared to show a p53-gene deletion.

PMID- 8647619
TI  - A monoclonal antibody KIS-1 recognizing a new membrane antigen on human squamous
      cell carcinoma.
AB  - A KIS-1 monoclonal antibody (MAb) (IgG1, kappa) recognizing a membrane antigen on
      human squamous-cell carcinomas (SCC) was developed to understand their
      antigenicity using an esophageal SCC as an immunogen. The KIS-1 MAb recognized a
      membrane antigen on a majority of esophageal, lung, and oral- cavity SCC by
      immunofluorescent and by immunohistochemical analyses. In contrast, it showed
      little reactivity to adenocarcinomas from different organs, and none to
      keratinocyte cell lines. This MAb showed reactivity to the cells in the basal
      layer of normal esophageal epithelium adjacent to the esophageal SCC, but none of
      the other normal tissues, including esophageal epithelium far from the SCC and
      that from patients with non-malignant disease. The KIS-1 MAb immunoprecipitated a
      46-kDa membrane protein of the esophageal SCC in non-reducing and in reducing
      conditions. It recognized the 46- and the 40-kDa proteins of the esophageal SCC
      by immunoblot analysis. These results suggest that the KIS-1 MAb recognizes a new
      membrane antigen preferentially expressed on SCC, and that this antigenicity is
      shared only by the cells in the basal layer of the esophageal epithelium adjacent
      to SCC. The KIS-1 MAb may be a new tool for understanding the antigenicity of
      SCC.

PMID- 8647620
TI  - Interleukin-10 production in malignant melanoma: preferential detection of IL-10
      secreting tumor cells in metastatic lesions.
AB  - IL-10 mRNA expression and protein production in established melanoma cell lines
      and freshly cultured primary and metastatic melanoma cells was examined. The in
      situ distribution of IL-10 in native melanoma tissue was also investigated by
      immunohistochemistry in primary tumors, metastases, benign melanocytic nevi and
      normal skin of healthy persons and melanoma patients. IL-10 mRNA, but not IL-10
      protein in the culture supernatant, was found in 1 of 4 cultured melanoma cells
      of primary tumors, while 3 of 6 melanoma-metastasis-derived cultures expressed
      both IL-10 mRNA and protein. No IL-10 was detected in skin biopsies of healthy
      volunteers or in the healthy skin of melanoma patients; nor was IL-10 found in
      congenital melanocytic nevi. In only 1 of the 11 examined primary malignant
      melanomas was IL-10 immunoreactivity detected within the cytoplasm of cells in
      the tumor. On the other hand, 4 of 9 metastases clearly displayed scattered IL
      1O+ cells. In all sections with IL-10-positive cells, the cells were positive for
      HMB-45. No co-expression of CD3 and IL-10 was observed. The data suggest that
      melanoma cells themselves are the main origin of IL-10 in tumor specimens in
      vivo. The preferential expression of IL-10 in metastatic lesions and in cultured
      cells from metastases might indicate an increased spreading potential of IL-10
      secreting melanoma-cell clones.

PMID- 8647621
TI  - Risk of cancer following splenectomy.
AB  - Only 2 small population-based studies have previously evaluated cancer risk in
      splenectomized patients. Our objective was thus to investigate cancer incidence
      following splenectomy for external trauma or for surgical treatment of non
      malignant conditions of adjacent organs. Using the unique personal identification
      number assigned to each Swedish resident, we linked centralized hospitalization
      records with nationwide total population and cancer incidence data. We excluded
      cancers diagnosed within the first 12 months after splenectomy and computed
      standardized incidence ratios for 1,295 patients (contributing 14,390 person
      years) splenectormized for external trauma and for 985 patients (contributing
      8,91 1 person-years) whose splenectomy accompanied surgical treatment of non
      malignant conditions of adjacent organs (mostly peptic ulcers), using age-, sex-
      and period-specific rates for cancer incidence derived from the entire Swedish
      population. Patients undergoing splenectomy for external trauma had no
      significant excess of total or site-specific cancers. Individuals splenectormized
      in conjunction with surgery for non-malignant conditions of adjacent organs had a
      non-significant 40% elevated risk of total cancer, with significant increases of
      lung and ovarian cancers. The excesses of lung and ovarian cancers may be due to
      chance, but we could not exclude the conditions for which the surgery was
      performed, other treatments or common predisposing factors (such as cigarette
      smoking, which has been linked with both peptic ulcer and lung cancer).

PMID- 8647622
TI  - Distinct sub-populations of carcinoma-associated MUC1 mucins as detected by the
      monoclonal antibody 9H8 and antibodies against the sialyl-Lewis a and sialyl
      Lewis x epitopes in the circulation of breast-cancer patients.
AB  - The cancer-associated epitope defined by the monoclonal antibody (MAb) 9H8 was
      shown to be closely related to the T antigen (Thomsen-Friedenreich antigen) by
      its sensitivity to 0-glycanase treatment of a mucin glycopeptide known to express
      this epitope. The reactivity with this glycopeptide increased upon neuraminiclase
      treatment, and among several MAbs tested for ability to block binding of the 9H8
      antibody, the one specific for the T antigen was the most efficient. Out of 41
      serum samples from breast-cancer patients, 11 showed elevated levels of the 9H8
      epitope, and several sera also showed elevated levels of the cancer-associated
      carbohydrate epitopes sialyl-Lewis a and sialyl-Lewis x. By the use of antibodies
      specific for the MUC1 apoprotein (Ma552 and HMFG-2) it could be shown that these
      epitopes were attached to the MUC1 apoprotein in at least 4 of the cases. By
      combining antibodies specific to 9H8, sialyl-Lewis a and sialyl-Lewis x in
      catcher and tracer positions in several types of immunofluorometric assays, it
      was shown that the 9H8 epitope was rarely co-expressed with sialyl-Lewis a or
      sialyl-Lewis x epitopes an the same molecule, though all were expressed on MUC1
      mucins. In fact, they can be considered as mutually exclusive epitopes,
      suggesting that these sera contained different populations of MUC1 mucins
      distinguishable by different sets of oligosaccharides. The existence of mutually
      exclusive carbohydrate epitopes on different MUC1 mucins in one and the same
      patient should be taken into account when designing immunoassays exploiting MUC1
      reactive antibodies.

PMID- 8647623
TI  - Autoantibodies against insulin and beta-islet cells in pancreatic adenocarcinoma:
      a possible explanation for diabetes mellitus.
AB  - To evaluate the prevalence of autoantibodies against the b-islet cells (ICA) and
      the molecule of insulin (IAA) in the serum of patients with pancreatic
      adenocarcinoma (PA), we examined the sera of 36 newly diagnosed pancreatic
      adenocarcinoma patients for the presence of these antibodies, using an enzyme
      linked immuno-assay method. These results were correlated with survival. Ten
      patients with insulin-dependent diabetes mellitus (IDDM) and 21 healthy
      volunteers were evaluated as age-matched controls. Twenty out of 36 (57%) PA
      patients were found to have detectable ICA autoantibodies and 17 (48%) PA
      patients had detectable IAA antibodies. Five out of 10 (50%) and 3 out of 10
      (30%) IDDM patients had ICA and IAA antibodies, respectively. None of the healthy
      volunteers was positive for either of the autoantibodies examined. The difference
      was statistically very significant and the presence of high serum titers of both
      autoantibodies was associated with a worse outcome for these patients than for
      those without such autoantibodies. Our data suggest that the high incidence of
      diabetes mellitus in patients with PA may be attributed to the presence of these
      autoantibodies. Further clinical studies are needed to establish the above
      autoantibodies as prognostic markers of pancreatic cancer.

PMID- 8647624
TI  - Cancer risk in fathers and brothers of testicular cancer patients in Denmark. A
      population-based study.
AB  - There are several reports of familial testicular cancer in the literature but few
      systematic attempts have been made to estimate the risk of testicular cancer in
      first-degree relatives of patients with this neoplasm, and the risk remains to be
      fully assessed in population-based studies. By means of data from the Danish
      Cancer Registry, we identified all testicular cancer patients (index cases) born
      and diagnosed during 1950-1993 in Denmark. Their fathers were identified from
      national registries, as were the brothers of a subcohort of these patients.
      Familial cancer occurrence was determined through linkage with the cancer
      registry and compared with the cancer incidence in the general male population in
      Denmark. The ratio of observed to expected cancers generated the measure used for
      the relative risk. Fathers of 2,113 index cases with testicular cancer
      experienced an almost 2-fold risk of developing testicular cancer themselves (RR
      = 1.96; 95% CI: 1.01-3.43). Overall, the fathers had a decreased relative cancer
      risk (RR = 0.84; 95% CI: 0.74-0.95) with a significantly decreased risk of
      cancers of the lung and digestive organs. Brothers of a subcohort of 702 index
      cases showed a markedly increased risk of testicular cancer (RR = 12.3; 95% CI:
      3.3-3 1.5). In conclusion, we documented a significantly increased familial risk
      of testicular cancer which was relatively more pronounced between brothers than
      between fathers and sons. These findings support the possible involvement of a
      genetic component in the aetiology of testicular cancer, but also leave room for
      a hypothesized influence of in-utero exposures, such as specific maternal hormone
      levels, that might be shared by brothers.

PMID- 8647625
TI  - Extracellular pH controls pre-mRNA alternative splicing of tenascin-C in normal,
      but not in malignantly transformed, cells.
AB  - In cultured normal human fibroblasts, 2 main tenascin-C (TN-C) isoforms are
      generated by alternative splicing of the single TN-C primary transcript, 8 type
      III repeats being included or omitted in the mRNA. In these cultured cells, small
      pH variations of the culture medium (from 7.2 to 6.8) strikingly modify the
      alternative splicing pattern of the TN-C primary transcript. We report that
      malignantly transformed cells do not respond to extracellular pH variations as
      normal cells do. Indeed, malignantly transformed cells kept in culture media at
      pH values from 6.6 to 7.6 show no variations in the splicing pattern of the TN-C
      primary transcript and accumulate almost exclusively the large TN-C mRNA. These
      observations may explain the preferential accumulation in vivo of the large TN-C
      isoform in the extracellular matrix of different types of neoplasia.

PMID- 8647626
TI  - Characterisation of the tumour-associated carbohydrate epitope recognised by
      monoclonal antibody 4D3.
AB  - The tumour-associated epitope recognised by monoclonal antibody (MAb) 4D3 is
      expressed on a high m.w. mucin glycoprotein preparation known as small intestinal
      mucin antigen (SIMA). This epitope is detected in tissue from a high proportion
      of patients with colorectal cancer, and elevated levels occur in serum from a
      significant number of such patients, highlighting the potential clinical utility
      of MAb 4D3. In the present study, insight into the composition and structure of
      the carbohydrate epitope recognised by MAb 4D3 was gained following
      characterisation of 2 glycopeptides that co-purified with SIMA. Sequence analysis
      of 1 of these glycopeptides revealed that it was identical to the glycoprotein
      alpha-1-anti-chymotrypsin. This glycoprotein was subsequently deglycosylated to
      yield 5 forms corresponding to alpha-1-anti-chymotrypsin substituted with 4, 3,
      2, 1 or no branched glycans. MAb 4D3 was reactive with each of the glycosylated
      forms, including the form carrying only 1 branched glycan, but did not react with
      fully deglycosylated alpha-1-anti-chymotrypsin. MAb 4D3 also reacted to different
      extents with ovine, bovine or porcine submaxillary mucins, each of which has a
      different amount of the O-linked sialylated disaccharide known as sialosyl Tn. Of
      these mucins, MAb 4D3 was most reactive with ovine submaxillary mucin, in which
      almost all of the carbohydrate chains are sialosyl Tn. Reactivity of MAb 4D3
      towards isolated glycans, sialosyl Tn and related structures led to the
      conclusion that the preferred MAb 4D3 epitope involves the sialylated N-acetyl
      galactosamine disaccharide as well as an additional monosaccharide present on a
      neighbouring carbohydrate chain. Although the preferred epitope recognised by MAb
      4D3 involves this sialylated disaccharide, the specificity of MAb 4D3 was
      different from that of other MAbs with a reported specificity for sialosyl Tn.

PMID- 8647627
TI  - Three-dimensional co-culture of human monocytes and macrophages with tumor cells:
      analysis of macrophage differentiation and activation.
AB  - Here we report on an experimental system for generating TAM in vitro by culturing
      human MO and MO-derived macrophages (MAC) within 3-dimensional multicellular
      tumor spheroids (MCS). MO as well as MO-derived MAC migrate into tumor spheroids
      and spread throughout the entire spheroid within 16 hr. In contrast, fibroblast
      spheroids were not infiltrated. The regular expression of MAC maturation
      associated antigens on infiltrating MO was suppressed within MCS of the
      undifferentiated bladder carcinoma line J82 with regard to carboxypeptidase M
      (CPM), MAX.3 antigen and CD105. However, MAC within spheroids of highly
      differentiated papillary RT4 cells failed only the single antigen CD51, whereas
      MAC expressed the complete maturation-associated phenotype within non-tumorigenic
      HCV29 spheroids. Interestingly, the suppressive effect of J82 carcinoma cells
      could only be observed in 3-dimensional but not in monolayer cultures. The J82
      MCS induced suppression of CPM and MAX.3 expression was only seen to be operative
      on infiltrating blood MO: MO first differentiated for 2 days and subsequently co
      cultured with J82-MCS showed normal expression of MAX.3 and CPM within the
      spheroid. Besides the modulation of MAC phenotype, the cytokine response of
      intraspheroidal MAC was analyzed: upon co-culture MO secreted high IL-1beta and
      IL-6 but low amounts of TNF-alpha as compared to MAC. This MO typical cytokine
      pattern remained constant for up to 8 days in culture, again indicating a
      disturbed MO to MAC maturation within tumor spheroids. In conclusion, a 3
      dimensional interaction with tumor cells in vitro results in significant changes
      in the phenotype and function of the spheroid-associated MO and MAC.

PMID- 8647628
TI  - Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine
      extended gastrin.
AB  - Glycine-extended gastrin (gastrin-Gly) stimulates proliferation of AR4-2J
      pancreatic tumor cell line through a specific receptor, different from the
      gastrin-cholecystokinin B receptor. Our purpose was to determine whether AR4-2J
      cells produced gastrin-Gly and then whether the peptide was involved in an
      autocrine loop. First, proliferation of AR4-2J cells in serum-free medium was
      inhibited by a gastrin anti-sense oligodeoxynucleotide phosphorothioate and by
      antibodies specific for gastrin-Gly. In contrast, antibodies specific for alpha
      amidated gastrin were without effect. By using RT-PCR, we have shown that AR4-2J
      cells expressed gastrin mRNA. The presence of gastrin-Gly, but not alpha-amidated
      gastrin, in serum-free media was detected by radioimmunoanalysis. Gel
      chromatography revealed that the predominant molecular forms secreted were
      glycine-extended gastrin-34 and gastrin- 17. Furthermore, epidermal growth factor
      (EGF), a stimulator of gastrin gene transcription, modulates gastrin-Gly
      secretion by AR4-2J. These data together suggest that gastrin-Gly is an autocrine
      growth factor for AR4-2J cells and that it participates with EGF in the
      regulation of AR4-2J-cell proliferation.

PMID- 8647629
TI  - Induction of cytotoxic T lymphocytes to murine mammary tumor cells with a Kd
      restricted immunogenic peptide.
AB  - A synthetic peptide E474 SFAVATTAL, derived from the sequence of mouse mammary
      tumor virus envelope protein, was previously shown to bind class I MHC Kd.
      Immunization of BALB/c mice with E474 in 50% incomplete Freund's adjuvant (IFA)
      followed by in vitro stimulation of immune cells with E474-coated antigen
      presenting cells resulted in peptide-specific cytotoxic T lymphocytes (CTL).
      Furthermore, anti-E474 CTL lysed mammary tumor cell lines D2F2 and D2A1, derived
      from a spontaneous tumor that arose in BALB/c pre-neoplastic hyperplastic
      alveolar nodule (HAN) D2 line. Expression of Kd by D2A1 and D2F2 cells was
      verified by flow cytometry, and lysis of D2 tumor cells was blocked by monoclonal
      antibody 31-34-S, which interacted with the peptide-binding region of Kd,
      supporting the recognition of E474 in Kd by anti-E474 CTL. Immunization of BALB/c
      mice with E474 before D2F2 tumor challenge resulted in reduced tumor growth.
      Therefore, E474 is naturally processed and presented by these tumor cells and can
      induce anti-tumor immunity.

PMID- 8647630
TI  - Evidence of involvement of CD44 in endothelial cell proliferation, migration and
      angiogenesis in vitro.
AB  - Angiogenesis is essential for tumor growth and metastasis. In the process of
      angiogenesis, the interaction between adhesive proteins of endothelial cells and
      extracellular matrix components plays an important role by mediating cell
      attachment, which is indispensable for their motility, and by transmitting the
      regulatory signals for cell locomotion and proliferation. In this study, we
      examined the hypothesis that CD44 expressed on the endothelial cell surface is
      involved in the angiogenesis process. The experiments using calf pulmonary artery
      endothelial cells (CPAE) and a human microvascular endothelial cell line (HMEC-1)
      show that a monoclonal antibody against CD44 (clone J 173) inhibits endothelial
      cell proliferation by about 30% and migration by 25-50%, and abolishes the
      stimulating effect of hyaluronan polysaccharides on endothelial cell migration
      and proliferation. This antibody also suppresses the capillary formation of CPAE
      in an in vitro model of angiogenesis using fibrin matrix. These results provide
      evidence of the involvement of endothelial-cell-associated CD44 in angiogenesis.

PMID- 8647631
TI  - Growth factor PDGF-B/v-sis confers a tumorigenic phenotype to human tumor cells
      bearing PDGF receptors but not to cells devoid of receptors: evidence for an
      autocrine, but not a paracrine, mechanism.
AB  - Numerous established human tumor lines co-express platelet-derived growth factor
      (PDGF) and cognate receptors, suggesting that an autocrine and/or paracrine
      growth mechanism may be a causal or contributing mechanism to their transformed
      phenotype. Indeed, it is known that a PDGF-autocrine system is functional in
      several established tumor lines, especially in human gliomas, and a model for a
      functional paracrine mechanism has been established in a human melanoma line.
      However, at least 168 human cell lines representing 26 different human tumor
      types have been reported to continuously express PDGF-A and/or -B chains, and 55
      of these also express PDGF receptors. For the majority of these cases, the
      significance of co-expression and the relative roles of autocrine and paracrine
      mechanisms in transformation remains unclear. Here, we show that human
      glioblastoma T98G cells co-express PDGF-B/c-sis and moderate levels of the
      cognate beta-type PDGF receptor (PR-beta) but are not tumorigenic in athymic
      mice. In contrast, human breast carcinoma MCF-7 cells do not express PR-beta and
      are tumorigenic. Clonal lines of each cell type with greatly increased secretion
      of p16w(T98Gsis and MCF-7sis cells) were characterized. T98Gsis cells are 85%
      tumorigenic and occasionally develop pulmonary metastases, showing that
      endogenous PR-beta can mediate complete transformation upon sufficient
      stimulation. In contrast, MCF-7sis cells exhibit some growth slowing in vitro and
      an exactly proportional decrease in tumor growth rate. We conclude that a PDGF
      autocrine, and not a paracrine, mechanism best accounts for the acquired
      tumorigenicity of T98Gsis cells, thereby emphasizing the potential significance
      of expression of even moderate levels of PR-beta by human tumor cells.

PMID- 8647632
TI  - Effects of hepatocyte growth factor (HGF) on human glioma cells in vitro: HGF
      acts as a motility factor in glioma cells.
AB  - Expression of c-Met, the receptor for hepatocyte growth factor (HGF), and the
      biological roles of HGF were examined in cultured human glioma cells. All of the
      5 glioma cell lines examined expressed c-Met protein as well as the c-met gene.
      Expression of the c-met gene was also confirmed in a glioblastoma tissue. Three
      cell lines (MGM-3, U251, KG-1-C) demonstrated chemotactic response to HGF in a
      dose-dependent manner. The response was not only chemotactic but also
      chemokinetic as judged by a checkerboard analysis. The amounts of c-Met mRNA and
      protein were abundant in the cell lines which showed a migratory response to HGF.
      Moreover, c-Met protein expression was highest in U251 with the highest migratory
      response to HGF. Among the cell lines, KG-1-C produced notable amounts of HGF
      protein as well as of c-Met, suggesting that HGF may act in an autocrine fashion
      in this case. HGF did not act as an apparent growth factor in the glioma cell
      lines examined. Furthermore, HGF stimulated the production of metalloproteinase,
      probably gelatinase A, in U251 cells.

PMID- 8647633
TI  - Efficient tumor eradication by adoptively transferred cytotoxic T-cell clones in
      allogeneic hosts.
AB  - Tumor-specific cytotoxic T cells (CTLs) can play an important role against cancer
      as illustrated by the observation that adoptive transfer of tumor-specific CTLs
      can mediate potent anti-tumor effects. Although such CTLs can be detected at the
      tumor site, relatively little is known about the mechanisms by which they enter
      the tumor. In this study, the role of major histocompatibility complex (MHC)
      class 1 molecules on vascular endothelium in the tumor in entry of, and tumor
      eradication by, tumor-specific CTL was investigated. Two H-2Db-restricted CTL
      clones recognizing peptide VNIRNCCYI on human adenovirus type 5 early region 1
      (Ad5E1)-induced tumors were used to test whether CTLs were able to cross the
      vascular endothelium lacking the restricting MHC molecule. One CTL clone
      recognizes peptide VNIRNCCYI in the context of both H-2Db and H-2Dbm14 molecules.
      The other CTL clone recognizes this peptide only in the context of H-2Db.
      Adoptive transfer of these CTLs leads to eradication of Ad5E 1-induced, H-2Db
      expressing tumors in B6(H-2Db+) and Bm14(H-2Db-) nude mice. Our data show that
      presentation of tumor-derived peptides by MHC molecules on endothelial cells of
      blood vessels in a tumor do not play a major role in eradication of tumors by
      adoptively transferred CTL in combination with interleukin-2. Moreover, our data
      show that successful adoptive CTL immunotherapy is possible across allogeneic
      barriers, without inducing severe side effects, provided the tumor expresses the
      MHC class 1-peptide complex recognized by the CTLs.

PMID- 8647634
TI  - Differential patterns of HOX gene expression are associated with specific
      integrin and ICAM profiles in clonal populations isolated from a single human
      melanoma metastasis.
AB  - Homeobox-containing genes comprise a gene family coding for transcription factors
      involved in normal development. Class I human homeobox (HOX) genes display a
      peculiar chromosomal organization, perhaps directly related to their function.
      Aberrant expression of homeobox genes has been associated with both morphological
      abnormalities and oncogenesis. We have reported that HOX gene expression is (i)
      specific for normal adult human organs (kidney, colon, lung) and (ii) altered in
      cancer specimens according to their histological type and stage of tumor
      progression. Here, we have investigated whether patterns of HOX gene expression
      are associated with tumor heterogeneity by analyzing the expression of the entire
      panel of 38 HOX genes in clones isolated from a single human metastatic melanoma
      call line (Me 665/2). The differential expression of a block of genes located at
      the 5' end of the HOX C locus allows melanoma clones to be classified into 2
      major groups. The 2 patterns of HOX gene expression are inversely associated with
      2 distinct surface phenotypes for integrins (VLA-2, VLA-5 and VLA-6) and the
      adhesion molecule ICAM-1. The genes of the HOX C locus are silent in the clones
      with high levels of integrins VLA-2, VLA-5 and VLA-6 and of the adhesion molecule
      ICAM-1 but actively expressed in the clones with low levels of ICAM-1 and lacking
      VLA-2, VLA-5 and VLA-6. Our results indicate that HOX gene expression reflects
      the intra-tumor heterogeneity of melanoma clones and suggest that the expression
      of surface molecules involved in cell-cell and cell-matrix interactions may be
      related to the patterns of HOX gene expression.

PMID- 8647635
TI  - Mutation in p53 and de-regulation of p53-related gene expression in three human
      cell lines immortalized with 4-nitroquinoline 1-oxide or 60Co gamma rays.
AB  - In vitro models of malignant transformation of human cells may provide
      considerable insight into the mechanisms of multi-step carcinogenesis. It is well
      established that normal human cells must be immortalized before they can be
      malignantly transformed; however, they are stringently destined for aging and are
      rarely immortalized. The mechanism of cellular aging and immortalization is still
      unknown. We detected expression of only mutated p53 mRNA by direct sequencing of
      the reverse-transcribed mRNA in 3 human cell lines immortalized either with 4
      nitroquinoline 1-oxide or with 60Co gamma rays. Consequently, only the mutated
      pS3 protein was expressed in each immortalized cell line. The expression of
      sdiI/p21 and mdm2, both of which are positively regulated by wild-type p53, was
      significantly down-regulated in the immortalized cell lines, resulting in over
      expression of cdk2 and cdk4. Introduction of the sdiI/p21 gene into these cells
      was followed by a remarkable decrease in their ability to synthesize DNA. These
      results indicate that the p53 cascade may play an important role in the
      immortalization of human cells.

PMID- 8647636
TI  - Integrin alpha3beta1 can promote adhesion and spreading of metastatic breast
      carcinoma cells on the lymph node stroma.
AB  - We have reported that metastatic human melanoma cells utilize the alpha (v)beta3
      integrin to adhere to lymph node vitronectin (VN). In the present study, the
      adhesion of human and rat breast carcinoma cells to lymph node tissue was
      analyzed. We have previously shown a correlation between the metastatic potential
      of breast carcinoma cells and an RGD-mediated adhesion to cryostat sections of
      peripheral lymph nodes; this adhesion could be blocked by an antibody to the
      integrin beta1 subunit. Here, we show that the metastatic breast carcinoma cells
      were significantly more adherent to fibronectin (FN) expressed by lymph node
      derived stromal cells than non-metastatic cells. Metastatic cells also spread
      more rapidly than non-metastatic cells on FN-coated substrates. Using a
      combination of immunofluorescence microscopy, immunoprecipitation and blocking
      assays with integrin-specific antibodies, we found (i) that expression of the
      alpha3beta1 integrin on metastatic mammary carcinoma cells was specifically
      increased in comparison to non-metastatic cells and (ii) that the alpha3beta1
      receptor was involved in the increased adhesion of metastatic cells to lymph node
      FN and in cell spreading on FN-coated substrates. Our data also suggest that the
      alpha5beta1 integrin, which is also expressed on the metastatic cells, did not
      contribute to this increase in adhesion. Our data implicate the alpha3beta1
      integrin in adhesion to lymph node stromal cell FN and suggest that metastatic
      cells of different tissue origins (e.g., melanoma and breast carcinoma) may
      utilize distinct integrin-ligand combinations to colonize the same target organ.

PMID- 8647637
TI  - Prevalence of LMP1 deletion variant of Epstein-Barr virus in nasopharyngeal
      carcinoma and gastric tumors in Hong Kong.

PMID- 8647638
TI  - Latent BK virus infection and Kaposi's sarcoma pathogenesis.
AB  - We have analyzed by PCR skin lesions from classic, endemic and AIDS-related
      Kaposi's sarcoma (KS), as well as from KS-derived cell lines, the presence of
      ubiquitous transforming viruses. BK virus (BKV), a transforming human papovavirus
      which has been associated with human tumors, was detected in 100% of KS skin
      lesions and 75% of KS cell lines. KS specimens contained a full-length, intact
      BKV early region, but minor rearrangements were observed in some tumors. BKV was
      also detected with a high prevalence (57-67%) in genital tissues and sperm, thus
      fulfilling the role of a sexually transmitted agent in KS. The closely related JC
      virus (JCV), which has never been associated with human malignancies, was present
      in 11-20% of KS specimens and was detected with a low prevalence (0-21%) in
      genital tissues and sperm. Simian virus 40 (SV40) was not detected in any KS
      lesions. Herpes simplex virus (HSV) DNA sequences were detected in 20-25% of KS
      lesions. Malignant human papillomavirus (HPV) types 16 and 18 and benign HPV
      types 6 and 11 were detected in KS specimens with a similar prevalence of 11-83%,
      suggesting that the presence of HPV-transforming sequences is not a specific
      trait of HPV interaction with KS tissue. Furthermore, JCV, SV40, HSV and HPV DNA
      sequences were not detected in KS cell lines, suggesting that these viruses are
      not associated to KS neoplastic cells in KS tissue. KS cell lines were also
      negative for DNA sequences of KS-HV, the novel herpesvirus detected in primary KS
      lesions. The constant association of BKV DNA with KS lesions and KS cell lines
      suggests that BKV-transforming functions may participate in the development of
      KS.

PMID- 8647639
TI  - International renal-cell-cancer study. VI. the role of medical and family
      history.
AB  - A number of medical conditions have been linked with renal-cell cancer, although
      the evidence is not consistent in every case. In a large international case
      control study of renal-cell cancer, we examined, among other hypotheses,
      associations with a personal history of certain medical conditions and a family
      history of cancer of the kidney or thyroid. Relative risks (RR), adjusted for the
      effects of age, gender, body-mass index, tobacco smoking and study centre, were
      significantly increased by a history of kidney stones or thyroid or kidney
      disease. The RR were not altered by additional adjustment for hypertension, or
      when diagnoses were restricted to those made at least 5 or 10 years before 1987
      (the usual "cut-off" date). The link with kidney injury is particularly likely to
      be affected by recall bias. Increased RR of borderline significance were found
      for kidney infection (RR, 1.2) and diabetes (RR, 1.4). Having one first-degree
      relative with kidney cancer was associated with a significantly increased risk of
      renal-cell cancer (RR, 1.6; 95% Cl, 1.1-2.4). Seven cases reported 2 first-degree
      relatives with kidney cancer. No controls had first-degree relatives with kidney
      cancer. None of our participants reported having von Hippel-Lindau disease. The
      data suggests that a few conditions of the kidney are strongly associated with
      renal-cell cancer and that heredity plays a role in a small proportion of cases.

PMID- 8647640
TI  - Mammographic screening after the age of 65 years: evidence for a reduction in
      breast cancer mortality.
AB  - We evaluated whether regular mammographic screening of women aged 65 years or
      older affected breast cancer mortality. In Nijmegen, a population-based screening
      program for breast cancer was started in 1975, with biennial mammography for
      women aged 35-64 years. Since 1977, elderly women have also been participating.
      For the present case-control study, women were selected who were over 64 years of
      age at the most recent invitation. Eighty-two of them had died from breast
      cancer. For these cases, 410 age-matched population controls were selected. The
      ratio of breast cancer mortality rates of the women who had participated
      regularly (ie., in the 2 most recent screening rounds prior to diagnosis) vs. the
      women who had not participated in the screening was 0.56 (95% CI = 0.28-1.13).
      The rate ratio was 0.45 in the women aged 65-74 years at the most recent
      invitation (95% CI = 0.20-1.02), whereas it was 1.05 in the women aged 75 years
      and older (95% CI = 0.27- 4.14). While the breast cancer survival rate of the non
      participant patients was fairly equal to that of patients from a control
      population, the underlying incidence rate of breast cancer was higher in the
      participants than in the non-participants. Therefore, we conclude that bias was
      present, but that it had decreased our effect estimate. The real reduction in
      breast cancer mortality due to regular screening will be even larger. Regular
      mammographic screening of women over age 65 (at least up to 75 years) can reduce
      breast cancer mortality by approximately 45%.

PMID- 8647641
TI  - Expression of CDK7/CAK in normal and tumor cells of diverse histogenesis, cell
      cycle position and differentiation.
AB  - The cyclin-dependent kinase 7 (CDK7) represents the 40-kDa catalytic subunit of
      the CDK-activating kinase, the enzyme responsible for activatory phosphorylation
      of multiple CDKs controlling G1, S and G2/M phases of the cell cycle. Here, we
      surveyed a wide range of normal and tumour cell types, in both cell culture and
      biopsy specimens, for abundance and subcellular localisation of the CDK7 protein.
      Immunoblotting and immunocytochemical analyses showed that CDK7 was (i)
      ubiquitously expressed in all cell types examined; (ii) exclusively nuclear;
      (iii) moderately elevated in tumour cells when compared with their normal cell
      counterparts; (iv) invariant throughout the cell cycle of normal lymphocytes,
      fibroblasts, breast epithelium and several cancer cell lines; and (v) clearly
      detectable even in quiescent cells, including highly differentiated cell types in
      situ. Our data are consistent with the emerging role for CDK7/CAK in multiple
      biological processes, possibly providing a link between cell-cycle control,
      transcriptional regulation and genomic integrity control.

PMID- 8647642
TI  - Infrequent expression of the MAGE gene family in uveal melanomas.
AB  - It has previously been reported that MAGE-1, -2, -3 and -4 genes are expressed in
      human cancers including cutaneous melanoma. MAGE-1 and MAGE-3 represent targets
      for specific immunotherapy because they encode peptide antigens which are
      recognised by cytotoxic T lymphocytes (CTL) when presented by HLA class I
      molecules, and pilot clinical trials with these peptides are currently in
      progress. It is likely that other members of the MAGE gene family may also encode
      antigens recognised by CTL. Uveal melanomas, like cutaneous melanomas, arise from
      melanocytes that are derived from the neural crest. To determine if uveal
      melanoma patients would be suitable for MAGE-peptide immunotherapy, the
      expression of MAGE-1, -2, -3 and -4 genes was assessed by reverse transcription
      followed by polymerase chain reaction (RT-PCR) amplification and ethidium bromide
      staining. Expression of MAGE genes was not detected in any of 27 primary tumours.
      Either MAGE-1 or MAGE-4 was expressed in only 2 of 26 metastatic samples, but
      expression of MAGE-2 or -3 was not detected. Our data suggest that, unlike
      cutaneous melanomas, uveal melanomas may not be suitable candidates for MAGE
      peptide immunotherapy.

PMID- 8647643
TI  - Prostate-specific antigen in breast cyst fluid: possible role of prostate
      specific antigen in hormone-dependent breast cancer.
AB  - Prostate-specific antigen (PSA) is a 33 kDa serine protease which is produced by
      many different tissues in the body and has been shown to be present in low
      concentrations in breast milk and in about 30% of breast cancers. The presence of
      PSA in breast cancers is associated with the presence of steroid-hormone
      receptors and may be a favourable prognostic indicator. In this study, PSA
      immunoreactivity was measured in breast cyst fluid obtained from women with
      palpable breast cysts which is the most common benign breast disease. PSA was
      found to be present in very low concentrations in breast cyst fluid. In an
      attempt to understand the possible role of PSA in the breast, the effect of PSA
      on growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 human
      breast cancer cell lines was studied. In addition, the effect of PSA on oestrone
      sulphatase activity and oestrogen 17-oxidoreductase activity in these cell lines
      was investigated. PSA, in low concentrations, was found to inhibit MCF-7 cell
      growth and to stimulate the conversion of oestradiol to the less potent oestrogen
      oestrone in this cell line. PSA had no effect on the MDA-MB-231 cell line. Our
      findings suggest that PSA may act as a negative growth regulator in hormone
      dependent breast cancers.

PMID- 8647644
TI  - Mechanisms of unusually high antioxidant activity of RSV-SR-transformed cells and
      of its suppression by activated p21ras.
AB  - We have previously demonstrated that hamster embryo fibroblasts (HEFs)
      transformed by Rous Sarcoma virus, Schmidt-Ruppin strain (RSV-SR) are highly
      resistant to damage by H202 (H2O2R), (in contrast to HEFs transformed
      spontaneously, or by bovine adenovirus and SV40), while N-ras transfection of RSV
      SR transformants leads to suppression of pp6Ov-scr and of H2O2R. In this study we
      have examined (1) mechanisms of antioxidant activity (AOA) of HEFs transformed by
      these agents and (2) the possible role of the v-src gene in unusually high AOA of
      RSV-SR transformants and of activated ras oncogenes in its suppression. All
      transformants exhibit increased catalase and glutathione peroxidase (GP)
      activities, while SOD, glutathione and glutathione reductase (GR) were reduced.
      As compared with other transformants, the significantly higher catalase and the
      low SOD activities were characteristic of RSV-SR-transformants, while an increase
      in GP was observed in all types of transformants. Correspondingly, RSV-SR
      transformants showed an extremely high H202-catabolizing activity (H2O2CA) and no
      lipid peroxidation chain reaction (LPCR). N-ras-induced suppression of pp60v-scr
      of RSV-SR-transformed HEFs coincided with the suppression of catalase, GP, H202
      and H202CA. However, suppression of catalase and GP was also observed in N-ras-
      and Ha-ras-transfected, spontaneously transformed HEFs. Thus, extremely high
      catalase activity and suppression of LPCR are apparently the main mechanisms of
      the unusually high H202R of RSV-SR transformants, while its suppression by
      activated ras oncogenes may also take place in some transformants, free of v-src
      activity.

PMID- 8647645
TI  - A strategy for screening anti-tumor drugs utilizing oncogenes encoded in
      retroviral vectors.
AB  - A novel strategy for isolating potential anti-tumor drugs is presented. It is
      predicated on the idea that future anti-tumor drugs will be specific inhibitors
      of the signal-transduction pathways responsible for cell proliferation. Briefly,
      retroviral vectors are used to introduce focus-forming oncogenes into a test
      population of target cells, which are grown to confluence and treated with signal
      transduction inhibitors. The inhibitors are screened for the ability to suppress
      the development of transformed foci without killing the confluent monolayer of
      non-transformed quiescent cells. For this work, a panel of inhibitors was first
      screened against the oncogene ras. The protein kinase C (PKC) inhibitor CGP 41251
      and the protein tyrosine kinase (PTK) inhibitor CGP 45047 suppressed ras-induced
      focus formation and left a viable monolayer of quiescent cells. Focus inhibition
      was reversible; conversely, drug addition to developing foci retarded further
      expansion. CGP 41251 generally blocked proliferation of ras or control cells,
      suggesting that oncogenes cannot substitute for PKC. PTK inhibitors erbstatin and
      CGP 520 and phosphatase inhibitor okadaic acid failed to inhibit focus formation
      at concentrations toxic to the monolayer. Lavendustin A and CGP 47778A showed
      neither focus inhibition nor toxicity. In the complementary screen, a single
      inhibitor (CGP 41251) was tested against several oncogenes, including src, raf
      and polyomavirus middle T antigen. Focus formation by all oncogenes was
      suppressed. The strategy has several advantages over current drug-screening
      assays, and it can be adapted to large-scale screening with many drugs and many
      oncogenes.

PMID- 8647646
TI  - MRP is frequently expressed in human lung-cancer cell lines, in non-small-cell
      lung cancer and in normal lungs.
AB  - The multidrug resistance-associated protein (MRP), a new membrane transporter
      related to non-Pgp multidrug resistance, is overexpressed in some drug-selected
      cancer-cell lines. The role of MRP in unselected cell lines and in human cancer
      is unknown. MRP gene expression, determined by RNase protection assay and
      chemosensitivity to doxorubicin, etoposide and cisplatin, determined by MTT
      assay, were assessed in 18 non-drug-selected lung-cancer cell lines (10 small
      cell lung cancer, 6 non-small-cell lung cancer, and 1 carcinoid). MRP gene
      expression was also investigated in normal lung tissue and primary non-small-cell
      lung cancer. All cell lines except one and all normal lung tissues and primary
      non-small-cell lung cancers expressed detectable levels of MRP. Expression was
      significantly lower in cell lines than in normal and neoplastic lung. MRP protein
      expression was also assessed by immunohistochemistry using the monoclonal
      antibody MRPr1; comparable levels of expression were observed between mRNA and
      protein in cell lines; however, in tumor samples intense staining was observed in
      tumor cells as well as in infiltrating normal cells in tumors, making the results
      less comparable to those obtained by RNase expression. MRP expression did not
      directly correlate with function in a calcein accumulation assay in 2 unselected
      cell lines. No gene amplification was observed by Southern-blot analysis, in the
      unselected cell lines or in tumor samples. In general, in cell lines, MRP gene
      expression was correlated with lower chemosensitivity to doxorubicin and
      etoposide, but not to cisplatin. However, MRP expression did not directly
      correlate with MRP function as assessed by a calcein accumulation assay in one of
      2 unselected cell lines examined. Our results suggest that MRP may be implicated
      in drug resistance in unselected lung-cancer cell lines and its role in normal
      lung and primary lung cancer warrants further investigation in patients
      undergoing chemotherapy.

PMID- 8647647
TI  - Site-directed mutagenesis of hamster complement C1S: characterization with an
      active form-specific antibody and possible involvement of C1S in tumorigenicity.
AB  - We have previously shown that non-transformed mouse A31 cells became tumorigenic
      when they were transfected with hamster C1s cDNA expression plasmid BCMGSNeoCS.
      In the present study, mutations were introduced into the cDNA at the activation
      cleavage site, Arg423(AGG) and the active center Ser617(AGC). These amino-acids
      were replaced by His423(CAC) and Thr617(ACC), respectively. The mutated cDNAs
      were inserted into BCMGSNeo and transfected to A31 and its polyoma-virus
      transformed SEA7 cells. C1s produced from these transfectants lost their enzyme
      activity. Transfectants of these mutated C1s cDNA did not form tumors in nude
      mice, To distinguish between active and inactive C1s in situ, we have developed
      novel antibodies, one directed to the NH2-terminal neoepitope of the L chain and
      the other specific for uncleaved inactive C1s. These antibodies were used to
      characterize C1s produced by transfectants, so as to determine whether or not it
      was cleaved at the right position.

PMID- 8647648
TI  - Expression of the ATDC (ataxia telangiectasia group D-complementing) gene in A431
      human squamous carcinoma cells.
AB  - The ATDC gene was originally identified by its ability to complement the
      radiosensitivity defect of an ataxia telangiectasia (AT) fibroblast cell line.
      Because hypersensitivity to ionizing radiation is an important feature of the AT
      phenotype, we reasoned that ATDC may function generally in the suppression of
      radiosensitivity. Previous work in our laboratory focused on radiosensitization
      mechanisms in human squamous carcinoma (SC) cells, especially A431 cells. To
      establish a basis for investigating the role of ATDC in radiation-responsive
      signaling pathways in human SC cells, we characterized ATDC message and protein
      expressions in A431 cells. ATDC message expression was also compared among human
      epidermoid cells (A431 cells, HaCaT spontaneously immortalized human
      keratinocytes and normal human epidermal keratinocytes) and a normal human
      fibroblast cell line (LM217). We made the following major observations: (i) the
      relative abundance of ATDC message is substantially higher in the epidermoid
      cells than in the fibroblast cell line, which has a message level comparable to
      those reported for other fibroblast lines; (ii) ATDC is constitutively
      phosphorylated on serine/threonine in A431 cells; (iii) in A431 cells, ATDC is a
      substrate for the serine/threonine protein kinase C (PKC) but not the epidermal
      growth factor (EGF) receptor tyrosine kinase; and (iv) EGF decreases ATDC message
      and protein expressions in A431 cells after a 24-hr exposure. The phosphorylation
      studies suggest that the ability of ATDC to modulate cellular radiosensitivity
      may be mediated in part through a PKC signaling pathway.

PMID- 8647649
TI  - Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision
      repair to different anti-cancer agents.
AB  - Nucleotide excision repair (NER) is one of the major DNA repair systems in
      mammalian cells, able to remove a broad spectrum of unrelated lesions. In this
      report the role of ERCC (excision repair cross-complementing) 1, ERCC2, ERCC3,
      ERCC4, and ERCC6 genes in removing the lesions caused by alkylating agents with
      different structures and mechanisms of action has been studied using UV-sensitive
      DNA repair-deficient mutant CHO cell lines. We confirmed that ERCC1 and ERCC4
      play a role in the repair of cis-diamminedichloroplatinum (DDP)- and Melphalan (L
      PAM)-induced DNA damage, while a marginal role of ERCC2 and ERCC3 in the cellular
      response to DDP and L-PAM treatment has been observed. Treatment with methylating
      agents (DM and MNNG) showed a lack of a preferential cytotoxicity between the
      parental and the different NER. deficient cell lines, emphasizing the importance
      of other repair systems such as 3-methyladenine glycosylase and O6 alkyl-guanine
      DNA-alkyl-transferase. ERCC1, ERCC2, ERCC3 and ERCC4, but not ERCC6 gene products
      seem to be involved in removing the lesions caused by Tallimustine and CC1065,
      minor groove alkylating agents that alkylate N3 adenine in a sequence-specific
      manner. ERCC6-deficient cells were as sensitive as the parental cell line to all
      the cytotoxic drugs tested, except DDP. These data emphasize the importance of
      the CHO mutant cell lines with specific defects in the DNA repair system for
      investigating the mechanism of action of different anti-cancer agents.

PMID- 8647650
TI  - Modulation of human endothelial cell procoagulant activity in tumour models in
      vitro.
AB  - Several tumour-derived factors have recently been identified which induce tissue
      factor (TF) expression in endothelial cells in vitro. However, there is only
      limited evidence that endothelial cells lining tumour blood vessels express
      elevated procoagulant activity (PCA) in vivo. We have investigated the effects of
      human breast and small cell lung cancer cell lines on the PCA of human micro- and
      macrovessel endothelial cell monolayers using a one-stage clotting assay, as well
      as detection of TF mRNA by RT-PCR. Only conditioned medium from the MDA-MB-231
      breast adenocarcinoma cell line produced a consistent although transient increase
      in endothelial cell surface PCA, which was maximal by 6-9 hr. TF mRNA was
      detectable in the endothelial cells after 1 hr incubation with MDA-MB-231
      conditioned medium and subsequently fell below detectable levels. Following 24 hr
      stimulation, nearly half the endothelial cell PCA was due to the presence of TF
      containing membrane vesicles shed by the MDA-MB-231 cells. Consistent with these
      findings, the MDA-MB-231 cell line expressed high levels of cell surface
      associated TF activity. Co-culture of MDA-MB-231 and endothelial cells for up to
      5 days increased (approx. 118-fold) PCA associated with endothelial cell
      monolayers, due mainly to sequestration of shed tumour cell vesicles. Our results
      suggest that induction of TF de novo is not a common feature in the supporting
      endothelium of these tumour types.

PMID- 8647651
TI  - The anti-cancer drug cisplatin induces H25 in Ehrlich ascites tumor cells by a
      mechanism different from transcriptional stimulation influencing predominantly
      H25 translation.
AB  - Treatment of Ehrlich ascites tumor (EAT) cells with the anti-cancer drug
      cisplatin induces an increase of the intracellular level of the small heat shock
      protein Hsp25 without stimulating the general stress response. The mechanism of
      this induction process was investigated at the levels of gene transcription,
      protein synthesis and stability. We show that an increased synthesis of Hsp25 is
      predominantly responsible for the increased intracellular level of this protein.
      In addition, there is a slightly increased metabolic stability of Hsp25 in
      cisplatin-treated EAT cells. In contrast to the mechanism of Hsp25 induction by
      heat shock and other chemical stresses, stimulated synthesis of Hsp25 after
      treatment with cisplatin is not the result of increased transcription of the
      hsp25 gene. Cisplatin treatment does not significantly influence the
      oligomerization of heat shock transcription factors 1 and 2, hsp25 promoter
      activity or hsp25 mRNA stability, as judged by cross-linking experiments,
      reporter gene assay and Northern blot analysis. Hence, cisplatin specifically
      induces Hsp25 synthesis at the level of mRNA translation without any changes in
      hsp25 gene transcription.

PMID- 8647652
TI  - Divergent effect of TGFbeta1 on growth and proteolytic modulation of human
      prostatic-cancer cell lines.
AB  - Plasminogen activators (PAs) play a key role in malignant transformation. PA
      secretion by tumoral cells is strongly correlated with their aggressive
      phenotype. Regulation of invasive potential by growth factors has been also
      demonstrated. This study was designed to investigate the effects of 5alpha
      dihydrotestosterone (DHT), epidermal growth factor (EGF), transforming growth
      factor beta1 (TGFbeta1), retinoic acid and basic fibroblastic growth factor
      (bFGF) on cell growth and PA expression and secretion in DU145 and PC3 cells, 2
      human prostatic-cancer cell lines. The proliferation of 2 cell lines was
      significantly increased only by EGF (about 30%), but decreased by TGFbeta1 (40%
      inhibition). However, EGF-treated cells showed significant enhancement (about
      400%) of u-PA secretion. A similar effect was observed when cells were cultured
      with DHT (200%) and with TGFbeta1 (300%). Nevertheless, u-PA mRNA level in EGF-,
      TGFbeta1 - or DHT-treated cells was amplified only between 110 and 180% of
      control, suggesting that growth factors differently controlled the steps of PA
      expression. Furthermore, our results clearly showed the divergent effect of
      TGFbeta1, i.e., an inhibition of prostatic-cell-line growth accompanied by an
      increase in proteolytic activity.

PMID- 8647653
TI  - Lack of expression of transforming growth factor-beta type II receptor associated
      with malignant progression in human salivary gland cell clones.
AB  - To understand the molecular mechanisms whereby normal human salivary gland cells
      become malignant and escape growth-inhibitory control by transforming growth
      factor (TGF)-betaI, we examined the effect of TGF-betaI on the proliferation and
      expression of TGF-beta receptors in cells and the expression of TGF-beta type II
      receptor (TbetaR-II) mRNA. An SV40-immortalized normal human salivary gland duct
      cell clone (NS-SV-DC) with no tumorigenic ability, originally obtained via s.c.
      implantation into nude mice, was partially resistant to the growth-inhibitory
      effect of TGF-betaI, while a neoplastic human salivary gland duct cell clone
      (HSGc) with tumorigenic, but not metastatic, potential in nude mice was more
      resistant to the growth-suppressive effect of TGF-betaI than NS-SV-DC. Metastatic
      cell clones derived from carcinogen-treated HSGc were completely refractory to
      the anti-proliferative effect of TGF-betaI. Affinity cross-linking revealed that
      NS-SV-DC possesses the types I, II (TbetaR-II) and III receptors. However, HSGc
      and metastatic cell clones lacked expression of detectable levels of the TbetaR
      II protein. Moreover, we evaluated TbetaR-II mRNA expression in these cell clones
      by Northern blot analysis and observed that, although NS-SV-DC expressed a large
      amount of TbetaR-II mRNA, a small amount of TbetaR-II mRNA was detectable in
      HSGc. In contrast, no significant bands were detected in metastatic cell clones.
      Our results, therefore, suggest that one of the possible mechanisms of escape
      from autocrine or paracrine growth inhibition by TGF-betaI during human salivary
      gland carcinogenesis involves reduced expression or lack of TbetaR-II.

PMID- 8647654
TI  - Comparative analysis of cell surface antigens expressed by cell lines derived
      from human germ cell tumours.
AB  - The pattern of cell surface antigen expression of a set of cell lines derived
      from human germ cell tumours and corresponding to various cell phenotypes found
      within these tumours was studied using immunofluorescence. Twenty-two different
      antibodies were used. Many of these antibodies have been noted to recognise
      epitopes that are either preferentially expressed by embryonal carcinoma (EC)
      cells, or by more differentiated cell types. Using scatter plots and rank
      correlations, 6 groups of antibodies were distinguished with respect to their
      staining patterns on the cell lines tested. Several antibodies showed a specific
      staining pattern in relation to the differentiation state of the cells. Two
      groups of antibodies included those recognising high m.w. glycoproteins
      (antibodies TRA-1-60, TRA-1-81, GCTM2, 3-177, K4 and K21) and the ganglioseries
      glycolipid antigens SSEA-3 and -4 (antibodies MC631 and MC813-70). These
      antibodies mostly stained EC cells but not other cell types, confirming
      previously published data. However, one of these groups, comprising antibodies K4
      and MC631, was more exclusively associated with the EC cell phenotype than was
      the other group. Antibodies recognising the liver isozyme of alkaline phosphatase
      (TRA-2-49 and TRA-2-54) also reacted strongly with most EC cell lines, although
      they reacted significantly with a number of other cell lines as well, whereas
      antibodies to the placental isozyme tended to react only weakly with EC cells.
      The antibodies recognising the ganglioseries glycolipids GD2 and GD3 (VIN2PB22
      and VINIS56) preferentially stained cells with neuroectodermal characteristics.
      Other antibodies showed a heterogeneous staining pattern for the cell lines with
      different phenotypes. The data obtained from the cell lines were, in general,
      similar to data obtained from immunohistochemical studies on tissue sections of
      primary germ cell tumours of the adult testis, including carcinoma in situ.

PMID- 8647655
TI  - Oxytocin and oxytocin-analogue F314 inhibit cell proliferation and tumor growth
      of rat and mouse mammary carcinomas.
AB  - The effects of oxytocin (OT) and the OT-analogue F314 were investigated an
      xenografts of mouse mammary and colon carcinomas (TS/A and C26 tumors) and of rat
      mammary carcinoma (D-R3230AC). In all cases, proliferation was previously
      assessed by cell counting in cultured cell lines, whereas tumor growth was
      checked by serial measures of tumor volume and by evaluation of tumor weight at
      the end of the experiment. Both cell proliferation and tumor growth were
      inhibited by OT and F314. These data support previous observations on the
      inhibitory effect of OT and F314 on the growth of MCF7, T47D and MDA-MB231 human
      breast cancer cell lines and open new prospects for testing the effect of this
      hypothalamic hormone and its analogues on the control of breast carcinoma growth.

PMID- 8647657
TI  - Congenital nevi.

PMID- 8647656
TI  - Photodynamic therapy of tumours with hexadecafluoro zinc phthalocynine formulated
      in PEG-coated poly(lactic acid) nanoparticles.
AB  - Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second-generation sensitizer for
      the photodynamic therapy (PDT) of cancer, was formulated in polyethylene-glycol
      coated poly(lactic acid) nanoparticles (PEG-coated PLA-NP) and tested in EMT-6
      tumour-bearing mice for its photodynamic activity. The tumour response was
      compared to that induced by the same dye formulated as a Cremophor EL (CRM)
      emulsion. Formulation in the biodegradable NP improved PDT response of the tumour
      while providing prolonged tumour sensitivity towards PDT.

PMID- 8647658
TI  - Orofacial granulomatosis.

PMID- 8647659
TI  - Tibetan medicine and dermatology in the fifteenth century.

PMID- 8647660
TI  - Morphologic observations on the dermal nerves in vitiligo: an ultrastructural
      study.
AB  - BACKGROUND: Vitiligo is a common idiopathic skin disorder. The etiology is
      unknown, although various hypotheses have been advanced. These include the
      neuronal hypothesis, where neuronal factors are thought to play a role in the
      pathogenesis of this disease. METHODS: Skin biopsies were taken from marginal and
      central parts of four vitiligo patients. Biopsies were also taken from
      nonvitiliginous skin of each patient and from four normal control subjects.
      Sections were examined under the electron-microscope. Nerve fibers in the
      superficial dermis were examined. RESULTS: Subtle ultrastructural changes,
      including regeneration and degeneration, were consistently found in dermal nerves
      of vitiligo lesions. The most consistent feature, seen in all four vitiligo
      patients studied (in both lesional and marginal areas), was an increased
      thickness of the basement membrane of Schwann cells. This change was found in
      approximately three-quarters of all dermal nerves in vitiligo biopsies, but in
      only about one-quarter of dermal nerves in normal control skin. About half the
      abnormal dermal nerves in vitiligo skin showed minor axonal damage, although
      indicators of regeneration (increased mitochondria and rough endoplasmic
      reticulum) predominated. The dermal nerves in vitiligo showed no difference in
      fiber diameter or fiber density in comparison with controls. CONCLUSIONS: In
      vitiligo both axonal degeneration and nerve regeneration may occur, with the
      latter possibly being a reactive change to earlier axonal damage. These findings
      support the hypothesis that there is a neuronal component to this disease.

PMID- 8647661
TI  - Circulating immune complexes in various forms of Behcet's disease.
AB  - BACKGROUND: The etiology of Behcet's disease (BD) is uncertain but there is
      strong evidence that the immune system is implicated in its pathogenesis.
      METHODS: We assessed circulating immune complexes (CIC) in peripheral blood of 34
      patients with BD, forming eight clinical groups, using a laser nephelometer to
      obtain more insight in the pathogenesis of different clinical forms of BD. Twenty
      healthy controls and eight patients with recurrent oral ulcerations were also
      included in the study. RESULTS: Levels of CIC were significantly higher in
      patients (1.83 +/- 0.93 microgram/mL) than in controls (0.84 +/- 0.51
      microgram/mL; P < 0.001). High titers were found in the groups of patients with
      erythema nodosum (3.14 +/- 0.44 microgram/mL), neurologic manifestations (2.9 +/-
      0.58 microgram/mL), and ocular manifestations (2.34 +/- 0.93 microgram/mL).
      Compared to patients with recurrent oral ulcerations (1.91 +/- 0.77
      microgram/mL), the mean value of CIC in patients with BD did not differ
      significantly, but the groups of patients having erythema nodosum, positive
      pathergy, and neurologic manifestations had significantly higher levels (P <
      0.05) and the group of patients at the mild end of the spectrum (group 8) had a
      significantly lower level (1.09 +/- 0.41 microgram/mL) (P < 0.05). Only the
      groups having erythema nodosum, positive pathergy, and neurologic manifestations
      had significantly higher levels of CIC when compared to other groups lacking
      these clinical features, whereas group 8 had a significantly lower level (P <
      0.05) when compared to all other groups. CONCLUSION: Our results show that CIC
      may be involved in the pathogenesis of BD, especially in those clinical forms of
      the disease with erythema nodosum, neurologic manifestations, and ocular
      manifestations. Patients at the mild end of the BD spectrum do not show
      significant changes in CIC levels compared to healthy control subjects. We can,
      therefore, suggest that in BD CIC may be implicated more in the pathogenesis of
      some features than of others.

PMID- 8647662
TI  - Cell infiltrate in progressive pigmented purpura (Schamberg's disease):
      immunophenotype, adhesion receptors, and intercellular relationships.
AB  - BACKGROUND: Progressive pigmented purpura (Schamberg's disease), a form of
      purpura pigmentosa chronica, is a lymphocytic capillaritis of unknown etiology
      and obscure pathogenesis. Our purpose was to assess the expression of cell
      membrane antigens (CD3, CD4, CD1a, CD36), of adhesion receptors (leukocyte
      function adhesion 1, LFA-1, endothelial leukocyte adhesion molecule 1, ELAM-1)
      intercellular adhesion molecule 1, ICAM-1), and the intercellular relationships
      in the early phase of the disease. METHODS: Quantitative immunohistochemistry and
      electron-microscopy were performed on specimens of five subjects, aged 45 to 63
      years. These studies were repeated in two patients after treatment with topical
      corticosteroid (betamethasone valerate cream 0.1%) and psoralen-ultraviolet A
      (PUVA). RESULTS: The infiltrate consisted mainly of CD4+ lymphocytes and CD1a+
      dendritic cells. Electron-microscopic investigation showed typical lymphocytes
      and two distinct types of dendritic cells. In the very early phase of the disease
      the adhesion receptors LFA-1 and ICAM-1 were expressed intensely by all
      infiltrating cells; the adhesion receptors ICAM-1 and ELAM-1 were expressed by
      endothelial cells. Close contact occurred between lymphocytes and dendritic
      cells. After PUVA (120 J per cm2) and topical steroid therapy the infiltrate
      disappeared completely. CONCLUSIONS: These data suggest that a cell-mediated
      immune mechanism may be important in progressive pigmented purpura and that the
      early endothelial expression of adhesion receptors may determine the pattern of
      organization of the pericapillary infiltrate.

PMID- 8647663
TI  - Keratoacanthoma in Japanese Hawaiians in Kauai, Hawaii.
AB  - BACKGROUND: This is the first incidence report of keratoacanthoma (KA) in a
      Japanese ethnic population. METHODS: The study was designed as a 5-year
      prospective incidence study using an island-wide survey of Japanese residents in
      Kauai, Hawaii, during the years 1983 through 1987. RESULTS: Eleven Japanese
      residents of Kauai, three men and eight women, had KA. The crude incidence is
      22.1 per 100,000 Japanese Kauaiian population. Two thirds of the lesions were on
      the extremities. No recurrence was noted, but a nonmelanoma skin cancer developed
      in some patients. CONCLUSIONS: The incidence of KA in a Japanese ethnic
      population is not low. Ultraviolet light exposure must, in part, contribute to
      the development of KA. This is supported by fact that the incidence of KA in
      Japanese residents in Kauai is much higher than in Japan and that most of the KAS
      appear on exposed skin.

PMID- 8647664
TI  - Revisit to Kaposi's varicelliform eruption: role of IL-4.
AB  - BACKGROUND: Kaposi's varicelliform eruption (KVE) is characterized by
      disseminated cutaneous eruptions usually caused by infection with herpes simplex
      virus (HSV). Kaposi's varicelliform eruption is commonly observed among patients
      with atopic dermatitis (AD). Why AD patients are prone to HSV infections is still
      an enigma. Recent findings suggest that an increased number of IL-4-secreting
      cells can be cloned from lesions of AD. Because IL-4 is a known Th1 cell
      inhibitor, theoretically, by inhibiting the Th1 cells, it could downregulate the
      immune response against HSV. In this study, we have evaluated the role of IL-4 on
      HSV replication. METHODS: Peripheral blood mononuclear cells (PBMC) from 10 HSV
      seronegative and five seropositive healthy individuals were stimulated with PHA,
      recall antigen (tetanus toxoid), and HSV antigen in combination with IL-4 and
      anti-IL-4. Supernatants were assessed for interferon (IFN) gamma, IL-4 by enzyme
      linked immunosorbent assay (ELISA), and for anti-HSV effect. Anti-HSV effect was
      assessed by measuring inhibition of the cytopathic effect (CPE) of HSV on a Vero
      cell line. RESULTS: Both seropositive and seronegative groups showed significant
      inhibition of IFN-gamma secretion with addition of IL-4 (P < .001, Wilcoxon rank
      sum test) and this effect could be neutralized by anti-IL-4. There was a direct
      relationship between the IFN-gamma concentration and the HSV cytopathic effect
      and an inverse relationship between IL-4 concentration and HSV CPE: CONCLUSIONS:
      This study provides evidence that IL-4 can enhance HSV infection. Therefore, it
      is conceivable that patients with conditions of increased activity of IL-4, as in
      AD, would be prone to extensive forms of HSV infection.

PMID- 8647665
TI  - Pigmented eccrine poroma: a simulant of nodular melanoma.

PMID- 8647667
TI  - Osteogenic sarcoma of the scalp.

PMID- 8647666
TI  - Eccrine carcinoma of the forearm.

PMID- 8647668
TI  - Spitz nevus arising on congenital compound nevus pigmentosus.

PMID- 8647669
TI  - Treatment-resistant pemphigus vegetans of the scalp.

PMID- 8647670
TI  - Follicular mucinosis plus mycosis fungoides and acanthosis nigricans plus
      alveolar bronchiolar carcinoma.

PMID- 8647671
TI  - Limited Wegener's granulomatosis treated with dapsone.

PMID- 8647672
TI  - Local interferon therapy for melanoma patients.
AB  - BACKGROUND: Melanoma, once considered a rare form of cancer, is increasing in
      incidence throughout the world. The prognosis of malignant melanoma is inversely
      related to the depth of tumor invasion. METHODS: Twenty-seven patients were
      treated with r.IFN alpha 2c. Four patients were treated with human natural
      leukocyte interferon (HNLI). Interferon was applied locally. Historical control
      groups were used for comparison in the statistical analysis. The data were
      evaluated taking into account the single risk factor Clark levels III and IV. In
      the control group there were 10 patients with Clark levels III and IV; in the
      group of r.IFN apha 2c-treated patients there were 20 patients. The data were
      analyzed by using the Kaplan-Meier and Cox methods. RESULTS: The percentage of
      survivals was higher in the interferon-treated groups with Clark levels III and
      IV, than in the control group, that is 60% compared to 25%, and 40% compared to
      33%, respectively. The results of the statistical analysis after 60 months of
      follow-up are significantly better in the interferon group (P = 0.0175).
      CONCLUSIONS: The control group was not selected at random. Therefore, on the
      basis of our results, one can say that the treatment of the melanoma patients,
      Clark levels III and IV, with the r.IFN alpha 2c is promising and that further
      investigation is justified.

PMID- 8647673
TI  - Dexamethasone-cyclophosphamide pulse therapy for pemphigus.
AB  - BACKGROUND: During the last 12 years, we have used a different approach,
      arbitrarily designed by us, for treating pemphigus patients that has given us
      very different and encouraging results. METHOD: The treatment schedule consists
      of giving 100 mg dexamethasone on 3 consecutive days and 500 mg cyclophosphamide
      on one day and repeating these pulses (DCPS) every 4 weeks. In between the DCPS,
      the patient receives only 50 mg cyclophosphamide orally daily and generally no
      corticosteroids. An essential component of the regimen is to administer a
      specified amount of the treatment for 1.5 years after achieving clinical
      remission. RESULTS: Of the 300 patients enrolled for this treatment, 61 patients
      could not complete the treatment, whereas 12 patients have died, some of them due
      to unrelated causes. Of the remaining 227 patients, 190 patients (84%) have
      already completed the treatment and are free of the disease even after complete
      withdrawal of all treatment, the duration of posttreatment follow-up being more
      than 5 years in 48 patients, 2 to 5 years in 75 patients, and less than 2 years
      in 67 patients. The maximum duration of posttreatment follow-up is 9 years. The
      remaining patients are also showing the same trend. Twenty-four patients are in
      remission but have not yet completed the treatment schedule, whereas 13 patients
      are still having evidence of clinically active disease, although it has already
      become much milder. The blood levels of intercellular antibody also decrease as
      the treatment progresses. The side effects commonly observed during treatment
      with corticosteroids are generally absent or insignificant. The relapses of the
      disease, seen so far in 59 patients, have been observed mostly in those patients
      who defaulted during the treatment, but a further course of the DCP regimen led
      again to complete recovery. CONCLUSIONS: If substantiated by further follow-up,
      this treatment schedule may prove curative in this potentially fatal disease.

PMID- 8647674
TI  - A medical odyssey to Dante's inferno.

PMID- 8647675
TI  - Influence of biopsy on the prognosis of cutaneous melanoma of the head and neck.
AB  - BACKGROUND: This study was performed to determine the effect of biopsy type on
      survival rates and on local, regional, and distant metastasis in patients with
      head and neck cutaneous melanoma. METHODS: A case series of 159 patients with
      melanoma of the head and neck referred to a tertiary-care center between 1983 and
      1991, with a median follow-up of 38 months, was reviewed. Information analyzed
      included patient's age, sex, type of treatment, mode of biopsy, presence of
      residual melanoma in reexcision, location of lesion, presence of ulceration,
      Clark's level, Breslow thickness, and histologic type of the melanoma. RESULTS:
      Excisional biopsy was performed in 79 patients, incisional biopsy in 48, and
      other procedures (shave, needle biopsy, cauterization, or cryotherapy) in 32.
      There were no significant pretreatment differences among the three groups in sex,
      thickness, histologic type, presence of nodal disease, or type of treatment.
      Pretreatment location of lesion was significantly different (p = .03) between the
      excisional and other biopsy types. Association between type of biopsy and
      survival rate was significant (p<.001):31.3% of patients in the incisional biopsy
      group died of disease, as did 25% of the other biopsy group, versus 8.9% of the
      excisional biopsy group; 31.3% of patients in the incisional biopsy group
      developed distant metastases, as did 28.1% of the other biopsy type, versus 10.1%
      of those in the excisional biopsy group (p = .01). There was no significant
      difference in local p = .37) or regional (p = 1.00) recurrence among the three
      biopsy groups. Multivariate analysis showed presence of tumor in the re-excision
      specimen, biopsy type, and nodal disease to be independent prognostic factors.
      CONCLUSIONS: Our study suggests that the type of biopsy of cutaneous melanoma of
      the head and neck may influence the clinical outcome.

PMID- 8647676
TI  - Prognostic factors in follicular carcinoma of the thyroid: a study of 198 cases.
AB  - BACKGROUND: Prognostic parameters for papillary carcinoma of the thyroid have
      been defined by several groups. However, no such study has been reported for
      follicular carcinoma. METHODS: We undertook a retrospective study of well
      differentiated carcinoma of the thyroid operated at the Tata Memorial Hospital
      during the period 1970-1985. In our series, follicular carcinoma formed 48% of
      the well-differentiated carcinomas of the thyroid. The variables age, sex, size,
      extrathyroidal spread, distant metastases, and lymph node metastases were
      evaluated. The survival was plotted according to the Kaplan-Meier method, and
      graphs compared by log-rank test. Univariate and multivariate analyses were
      performed. RESULTS: Based on our experience we stratified the cases into low-risk
      and high-risk groups. The low-risk group included: age below 40 years, tumor size
      less than 5 cm. and no extrathyroidal extension or metastases. This low risk
      group had 100% survival at 15 years, compared with 40% survival for the high-risk
      group (P <.001). Seventy-three percent (73%) of our cases were in the high-risk
      group. CONCLUSIONS: Based on our findings that the majority of our patients were
      in the high-risk group, we advocate a total or near-total thyroidectomy in
      treatment of follicular carcinoma of the thyroid. There is a need to arrive at a
      universally acceptable classification of risk groups in follicular carcinoma of
      the thyroid gland.

PMID- 8647677
TI  - Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a
      matched-pair analysis.
AB  - BACKGROUND: Cervical lymph node metastasis in differentiated thyroid carcinoma
      has mostly been found to have little relationship to prognosis. However, some
      studies report nodal involvement to be an adverse factor, while others have found
      it to be favorable. We have undertaken a matched-pair analysis of previously
      untreated patients, with and without ipsilateral neck metastasis, to examine the
      significance of nodal spread in patients with otherwise equivalent prognostic
      factors for differentiated thyroid cancer. METHOD: From a database of 931
      patients, treated from 1930 to 1980, we used a computer to match patients with
      confirmed lateral neck metastasis (N1) to those who were stage NO, and had the
      following identical prognostic factors: no distant metastasis, age (within 4
      years), and tumor size, histology, and intrathyroidal extent. When possible,
      matches were also made for gender, multifocality, and extent of thyroid surgery.
      Survival and treatment failures were analyzed, with and without stratification
      for age. RESULTS: We were able to select 100 N1 patients with corresponding NO
      patients, sharing the major prognostic risk factors as listed. Overall, there was
      no difference in survival, although N1 patients more often had recurrence.
      Mortality increased with age. Analysis at high-risk age (45 years and older)
      showed significantly more recurrences in N1 patients (p = .008). Twenty-year
      survival in N1 patients over the age of 45 was lower than that of NO patients. On
      the other hand, under the age of 45, N1 patients had better survival. These
      differences, however, did not reach statistical significance. CONCLUSION: Nodal
      involvement in older patients with thyroid cancer increases the risk of
      recurrence, although no significant difference in survival is observed in
      relation to age.

PMID- 8647678
TI  - Nodal failures in patients with NO N+ oral squamous cell carcinoma without
      capsular rupture.
AB  - BACKGROUND: The efficacy of postoperative irradiation of the neck after lymph
      node dissection in terms of prevention of cervical node recurrence (NR) has not
      been demonstrated in patients with NO squamous cell carcinoma of the oral cavity.
      METHODS: This multicenter retrospective analysis comprises 826 patients with
      squamous cell carcinoma of the oral cavity, all clinically NO. The primary tumor
      was treated by resection or brachytherapy. All patients underwent cervical
      dissection adapted to the site of the tumor. Fourty seven N+ patients with
      capsular rupture were excluded; 160 patients were N+ without capsular rupture (N+
      CR-), and 619 were N-. Postoperative cervical irradiation was performed in 67 of
      160 N+ CR- patients and in 49 of 619 N- patients. RESULTS: NR developed in 78
      patients, associated with local recurrence in 33 cases and isolated in 45 cases.
      Twenty-six of the 45 cases of isolated NR occurred in the 619 N- patients (4%),
      and 19 occurred in the 160 N+ CR- patients (12%, p = .001). The 26 NR observed in
      the N- patients occurred in nonirradiated patients. Among the 19 NR observed in
      the N+ CR- patients, the incidence of recurrence was not significantly different
      between irradiated patients (6 NR of 67.9%) and nonirradiated patients (13 NR of
      93, 14%). NR rates also did not differ according to the number of lymph nodes
      invaded nor according to the level of the positive nodes; 14 of 45 isolated NR
      occurred in a nondissected suprahyoid region. Of 779 patients, 255 (33%)
      subsequently developed a metachronous cancer; 153 upper respiratory and digestive
      tract tumors, 37 lung tumors, 33 esophageal tumors, and 32 other tumors. Isolated
      cervical failure was responsible for 40 deaths. CONCLUSION: The low NR rate in NO
      N+ CR- patients means that postoperative irradiation can be confined to N+ CR+
      patients and, as a precautionary measure, to patients with more than 3 N+ CR-.
      Keeping irradiation in reserve allows the treatment of metachronous cancers,
      which are particularly frequent in these patients, in whom the 5-year survival
      rate is 54% in N+ CR- and 69% in N-.

PMID- 8647679
TI  - Gag reflex and dysphagia.
AB  - BACKGROUND: The gag reflex is a protective response that prevents foreign objects
      or noxious material from entering the pharynx, larynx, or trachea; it is not
      elicited during a normal swallow. Although no data have been reported to support
      a relationship between the gag reflex and dysphagia, the gag reflex is
      nevertheless routinely assessed during the bedside dysphagia evaluation. The
      purpose of the present study was to investigate whether absence of a gag reflex
      is a predictor of dysphagia. METHOD: Fourteen consecutive adult subjects referred
      for a bedside dysphagia evaluation because they were considered to be at
      increased risk for aspiration, specifically due to absence of a gag reflex, were
      investigated. In addition, the gag reflex was assessed in 69 normal adult
      volunteers. RESULTS: Although all subjects were referred for bedside dysphagia
      evaluations specifically because they had no gag reflex, 86% (12/14) were
      nevertheless able to eat at least a puree diet. In addition, 86% (12/14) of
      subjects with no gag reflex had normal velar movement, reinforcing the
      physiologic differences between velar functioning during phonation and the gag
      reflex. The gag reflex, traditionally considered part of the bedside dysphagia
      evaluation, was absent in 13% (9/69) of nondysphagic subjects, raising further
      doubts regarding its clinical relevancy. CONCLUSION: The absence of a gag reflex
      does not appear to be a predictor of dysphagia.

PMID- 8647680
TI  - Histopathologic, stereologic, epidemiologic, and clinical parameters in the
      prognostic evaluation of squamous cell carcinoma of the oral cavity.
AB  - BACKGROUND: Prognostic indicators that could assist in a more precise selection
      of patients with oral cancer for differentiated therapy would be clinically
      valuable. METHODS: A consecutive series of 161 cases of intraoral squamous cell
      carcinoma (SCC) occurring during a 5-year period in a population of 1.4 million
      inhabitants, was evaluated by histopathologic (the modified classification of
      Jakobsson et al.), stereologic, clinical, and epidemiologic parameters and the
      serum markers hemoglobin and rhesus blood group. RESULTS: Univariate analysis
      established a significant prognostic value in terms of cause-specific survival
      for T stage (P < .0001), stage (P < .0001), maximum tumor diameter (P < .0001), N
      stage (N+/NO) (P < .0001), alcohol consumption (P = .03), stereologic estimates
      of nuclear volume (P = .04), and the histomorphologic parameters mode of invasion
      (P = .001), pattern (P = .01), vascular invasion (P = .02), depth (P = .006), and
      mean histologic score. Tobacco consumption was borderline significant (P = .055).
      A multivariate analysis using the Cox proportional hazard analysis showed that
      both clinical (stage, P < .0001; size, P = .0027), epidemiologic (tobacco
      consumption, P = .0054), morphohistopathologic (mode of invasion P < .0001), and
      stereologic (nuclear volume, P = .0010) parameters had an independent significant
      effect on survival. Inversely, the mean histologic score had no prognostic value.
      From the final regression model prognostic forecasts were calculated. Twelve
      patients (25%) with stage I disease had unfavorable histologic and stereologic
      parameters. The observed survival (+/- 1 standard error of the estimate) for
      these patients was 33% +/- 18%. The observed survival for stage I patients with
      more favorable histologic and stereologic characteristics (n = 36) was 76% +/-
      8%. CONCLUSION: The use of a combination of clinical, histologic, epidemiologic,
      and stereologic parameters will assist the design of treatment strategies for
      intraoral SCC.

PMID- 8647681
TI  - Mode of tumor invasion in oral squamous cell carcinoma: improved grading based on
      immunohistochemical examination of extracellular matrices.
AB  - BACKGROUND: To predict the nodal involvement of oral squamous cell carcinoma
      (OSCC) many investigators have studied the histologic features of primary tumors.
      However, conventional histologic grading still is not sufficient to provide an
      objective and practical evaluation. In this study we tried to modify one standard
      type of histologic grading, namely, mode of invasion (MI), on the basis of the
      extracellular matrix (ECM) staining pattern. METHODS: One hundred seventeen
      initial biopsies of primary OSCC were histologically examined, and the MI was
      graded. The expression of a series of ECMs-laminin, type IV collagen, heparin
      sulphate proteoglycan, fibronectin, tenascin, decorin, and vitronectin-was
      immunohistochemically examined. RESULTS: The ECM staining pattern showed a close
      association with the MI, and was classified into types I and II. The type I
      staining pattern was observed in the noninvasive cases (MI grades 1 and 2), while
      type II was in the highly invasive cases (MI grades 4c and 4d). Because the ECM
      staining pattern in the moderately invasive cases (MI grade 3) included both
      types I and II, these cases were subdivided and compared. As a result, the type
      II cases showed a significantly higher incidence of nodal involvement than did
      the type I cases. CONCLUSION: An examination of a series of the ECMs, in addition
      to the conventional histologic examination, is thus considered to provide more
      objective and practical data to evaluate the invasive and metastatic potential of
      OSCC.

PMID- 8647682
TI  - Radiosurgery for recurrent cranial base cancer arising from the head and neck.
AB  - BACKGROUND: Treatment options for head and neck cancers that recur at the cranial
      base are limited. METHODS: Twelve patients with head and neck cancers recurrent
      after resection and fractionated radiotherapy (n = 11) at the cranial base had
      stereotactic radiosurgery using the gamma unit. The median dose to the tumor
      margin was 16 Gy. Imaging follow-up varied from 3 to 17 months; the longest
      clinical follow-up was at 35 months. RESULTS: Three of 8 tumors studied by
      postradiosurgery imaging remained unchanged in size, 3 decreased, and 2 were no
      longer visible. There was no morbidity or worsening of symptoms after
      radiosurgery. Four patients died between 4 and 8 months and did not have
      postradiosurgery imaging performed. Mean survival after radiosurgery was 10.5
      months, with 7 patients (58%) still living. CONCLUSIONS: Radiosurgery proved safe
      and effective in providing local control for recurrent cranial base cancers
      arising from the extracranial head and neck. Radiosurgery should be considered
      for those patients who have failed prior fractionated radiation or surgical
      resection, those who have tumors in high-risk cranial locations, or those who are
      poor medical candidates. Although this study shows its potential adjuvant role,
      longer follow-up and increased clinical experience will be necessary to evaluate
      the overall role of radiosurgery in head and neck cancer.

PMID- 8647683
TI  - Radiotherapy for early vocal cord cancer: a dosimetric analysis of 60CO versus 6
      MV photons.
AB  - BACKGROUND: Currently, many patients with early vocal cord cancers are treated
      with 6 MV photons, but almost all the published radiotherapy data are based on
      patients treated with 60Co, 2-MV, or 4-MV X-rays. A theoretical risk of
      underdosage exists with higher energy beams due to lack of dose build-up. This
      dosimetric study compares 6-MV photons with 60Co. METHODS: A tissue-equivalent
      phantom was constructed of a stack of 0.5-cm-thick acrylic plates. With a male
      subject in treatment position as the model, the external surfaces of the phantom
      were machined to match the contour of the neck. To precisely represent the
      internal contour of the airway, computed tomography (CT) was performed on the
      subject in treatment position, with images at 0.5-cm intervals, and the airway
      shown on the CT was cut out of each corresponding acrylic plate.
      Thermoluminescent dosimetry (TLD) rods were inserted into the phantom. For each
      measurement, a calculated tumor dose of 10 Gy was delivered to the volume
      specified as the entire right true vocal cord in the phantom, with either 60Co or
      6-MV photons (15 measurements were made with each). In a second series of eight
      experiments with each modality, TLD minichips were used to measure the dose
      received by the immediate surface of the vocal cords with delivery of a
      calculated tumor dose of 0.5 Gy. RESULTS: The doses received at the vocal cords,
      as well as a point 6 mm beneath the anterior skin surface, did not differ
      significantly for the two energies compared. The dose delivered to the skin and a
      point 3 mm beneath the anterior skin surface was significantly lower with the use
      of 6-MV photons. CONCLUSION: Although there is no difference in the dose received
      by the vocal cords, underdosage of the anterior tissues may occur with the use of
      6-MV photons.

PMID- 8647685
TI  - Infratemporal fossa mass in a pediatric patient.

PMID- 8647684
TI  - Anatomic considerations in the surgical treatment of unilateral laryngeal
      paralysis.

PMID- 8647687
TI  - Hemangioma of the temporal muscle.
AB  - BACKGROUND: Hemangiomas are benign vascular tumors. Because less than 1% of all
      hemangiomas are intramuscular, only 8 cases of temporal muscle hemangioma have
      been described to date. This is a case study of a 13-year-old girl who was
      referred to our institution because of a soft swelling located in the left temple
      that has enlarged progressively since birth. METHODS: CT scan, angiography and
      MRI showed a tumor mass lying in the temporal muscle, with homogeneous contrast
      enhancement. No tumor blush or feeding arteries were detected. At surgical
      exploration, the tumor appeared to be well demarcated. It was totally excised,
      sparing the surrounding temporal muscle, which did not present any sign of
      infiltration. Histopathologic examination showed the lesion to be a cavernous
      hemangioma. RESULTS: The cosmetic result was excellent, and MRI after 1 month and
      2 years showed complete absence of the lesion and no evidence of recurrence.
      CONCLUSIONS: Although this type of tumor may be treated by various methods
      surgical excision yields the best results in the short and the long term. The
      surrounding tissue is spared as much as possible when no signs of infiltration
      are noted at operation, especially when involving small and functionally
      important muscles, as in our case.

PMID- 8647686
TI  - Descending necrotizing mediastinitis: a complication of dental implant surgery.
AB  - BACKGROUND: The placement of osseointegrated dental implants is considered a
      minimally invasive procedure with a low complication rate. Reported complications
      include local trauma to neurovascular structures, mandible fractures, sinusitis,
      and localized gingivitis. Major life-threatening complications are extremely
      rare. Severe infection has not been reported in a review of the English
      literature. METHOD: Case study. RESULTS: We present a case of life-threatening
      deep neck space infection resulting in descending necrotizing mediastinitis
      following osseointegrated dental implant placement. Treatment included
      intravenous antibiotics, aggressive neck debridement, and removal of the infected
      dental implants. CONCLUSION: Severe infection can result from the placement of
      dental implants. Principles of treatment include antibiotics, surgical drainage
      and debridement, and careful assessment and removal of the involved implants.

PMID- 8647688
TI  - Mergers, networking, and vertical integration: managed care and investor-owned
      hospitals.
AB  - This article links the forces of managed care and investor-owned firms as major
      factors driving the industry toward consolidation into vertically integrated,
      merged firms, often financed with investor capital. This relentless pressure to
      build regional systems of health services has transformed the industry from a
      charitable, community orientation to one of business, market shares, and profits.

PMID- 8647689
TI  - Breakeven under capitation: pure and simple?
AB  - This article addresses the issue of breakeven analysis as applied to managed care
      under capitation. The traditional two-dimensional breakeven analysis is expanded
      into three dimensions: cost, enrollment, and utilization. This issue is examined
      and then visualized through the use of three-dimensional graphics.

PMID- 8647690
TI  - Keys for successful implementation of total quality management in hospitals.
AB  - This article reports the findings of an analysis of the implementation of
      continuous quality improvement (CQI) or total quality management (TQM) programs
      in 10 hospitals. This analysis is the result of a 2-year study designed to
      identify and assess the ingredients that lead to the successful implementation of
      CQI programs in acute care hospitals.

PMID- 8647691
TI  - Observations regarding the Brown-Johnson debate.

PMID- 8647693
TI  - The problematic fit of diagnosis and strategy for medical group stakeholders-
      including IDS/Ns.
AB  - This article extends stakeholder management theory using data from 270 medical
      practice executives to identify key stakeholders and determine the "fit" between
      stakeholder diagnosis and stakeholder management strategy. Four optimal and 12
      suboptimal situations are identified.

PMID- 8647694
TI  - Implementing TQM in the health care sector.
AB  - This article examines the issue of implementing TQM/CQI programs in the health
      care industry by grouping the prescriptive literature into four research streams.
      Based on the literature, a strategic programming model for implementing TQM/CQI
      in the health care industry is suggested. Finally, issues relating to TQM in the
      health care sector, which need to be addressed within each research stream in the
      future, are provided.

PMID- 8647692
TI  - Integrated pathways for managing rural health services.
AB  - Rural providers must redefine their role in the changing health care system to
      include a more integrated approach to health care delivery. The rural provider
      must develop integrated pathways to coordinate all medical, behavior, and social
      services to ensure that appropriate services are available, locally or through
      linkages with other providers, for the population. The integrated pathway must
      manage care across the continuum of services and coordinate decisions occurring
      at the point of service.

PMID- 8647695
TI  - Owned vertical integration and health care: promise and performance.
AB  - This article examines the alleged benefits and actual outcomes of vertical
      integration in the health sector and compares them to those observed in other
      sectors of the economy. This article concludes that the organizational models on
      which these arrangements are based may be poorly adapted to the current
      environment in health care.

PMID- 8647696
TI  - Why TQM doesn't usually work.

PMID- 8647697
TI  - [Adhesion molecules in dermato-oncology].
AB  - Adhesion molecules are cell surface proteins responsible for cell-cell and cell
      matrix interactions. They represent a basis for physiologic and pathologic
      processes, especially for homing behavior, homeostasis of the immune response,
      inflammations and tumor metastasis. Recently, adhesions molecules such as CD44v6
      have been shown to be expressed on tumor cells of cutaneous lymphomas with
      systemic tumor spread and thus play an important role in metastasis.

PMID- 8647698
TI  - [Trans-acitretin is metabolized back to etretinate. Importance for oral retinoid
      therapy].
AB  - The oral retinoid etretinate (Tigason) has recently been replaced by trans
      acitretin (Neotigason) in the treatment of severe psoriasis, primarily because of
      its short half-life and the assumption that a shorter period of subsequent
      contraception would be required. After introduction of the new drug, however,
      circulating quantities of etretinate were detected in patients treated with trans
      acitretin. Thus far, re-esterification has been detected in at least 83 cases.
      The 2-month period of strict contraception initially recommended after oral
      intake of trans-acitretin has been extended to 2 years, as with etretinate. We
      review some aspects of trans-acitretin metabolism, with special emphasis on
      etretinate formation. Re-esterification of trans-acitretin into etretinate takes
      place under varying conditions in volunteers and patients, as well as in animal
      models. Ethanol is a co-factor for the enzymatic re-esterification of trans
      acitretin. It is unclear whether the introduction of trans-acitretin has been of
      any significant benefit to patients. Monitoring of plasma retinoid levels during
      and after retinoid therapy remains of decisive importance in managing difficult
      cases and or in approving decisions for pregnancy.

PMID- 8647699
TI  - [Comments on the suitability of swine skin as a biological model for human skin].
AB  - The use of porcine skin as a biomedical model for the human integument is
      discussed with reference to the literature. The epidermis and dermis can be used
      as a model as there are clear structural, functional and biochemical similarities
      with human skin layers. The actual utilization of porcine skin in dermatological
      research is reviewed. Practical difficulties are emphasized: in particular, the
      conditions required for use of porcine skin in experimental research, the most
      suitable breeds, and restrictions on biological interpretation of the results.

PMID- 8647700
TI  - [Treatment of pediatric hemangiomas with the flashlamp-pumped pulsed dye laser].
AB  - We treated 166 infants and children with 177 hemangiomas with the flashlamp
      pumped pulsed dye laser (FPDL, 585 nm, 450 microseconds, 5 mm phi). The
      hemangiomas were classified as initial, superficial, cutaneous-nodular, and
      compound (cutaneous-subcutaneous) lesions according to the clinical involvement.
      After one treatment (n = 124), good results ( > 75% clearance) were obtained in
      56% of initial and in 36% of the nodular lesions. With repeated treatment
      sessions (n = 82), good results were achieved in 63% of the initial, in 67% of
      the superficial and in 70% of the nodular angiomas. Complete resolution requiring
      one or more treatment sessions was reached in 44% of the initial, in 42% of the
      superficial and in 16% of the nodular lesions. In compound lesions, only the
      cutaneous part responds to treatment owing to the limited penetration depth of
      the laser light. In our opinion, early FPDL therapy of most initial and/or
      rapidly growing hemangiomas should be recommended especially since this therapy
      is fast, has few side effects and can even be used in newborns.

PMID- 8647702
TI  - [Detection of tyrosinase mRNA using reverse transcription/polymerase chain
      reaction with fine needle punctures of melanoma metastases].
AB  - Tyrosinase mRNA produced by melanoma cells can be detected by reverse
      transcriptase-polymerase chain reaction (rt-pcr) with fine-needle tissue
      punctures. Fine-needle punctures from six suspected skin and lymph node
      metastases in three patients with malignant melanoma were analysed via rt-pcr for
      tyrosinase mRNA. All the suspected metastases were surgically removed and
      histologically examined separately. In each case the rt-pcr results and the
      histological diagnosis corresponded. This less invasive and highly sensitive
      method could prove to be a useful alternative in the diagnosis of melanoma
      metastasis.

PMID- 8647701
TI  - [Efficacy and safety profile of fumaric acid esters in oral long-term therapy
      with severe treatment refractory psoriasis vulgaris. A study of 83 patients].
AB  - The therapeutic effect and the side of effects fumaric acid derivatives used in
      treatment of psoriasis vulgaris have been subjects of controversy for more than
      30 years. A total of 83 patients with severe psoriasis vulgaris were investigated
      in a single-centre, long-term open (12 months) clinical trial to evaluate the
      efficacy and safety profile of the fumaric acid ester preparations Fumaderm
      initial and Fumaderm. The antipsoriatic effect of the fumaric acid derivatives
      was clear, with a mean reduction of 76% in PASI. Adverse events in were noted in
      62% of the patients (mainly flushing and gastrointestinal complaints). These were
      dose-dependent and decreased in frequency in the course of the study. No severe
      adverse events occurred. We believe that of fumaric acid derivatives are
      indicated in cases of severe therapy-resistant psoriasis to and can be used even
      for long-term application.

PMID- 8647703
TI  - [Cancer prognosis, psychosocial stress and attitude of melanoma patients to
      supportive psychotherapy].
AB  - A total of 205 patients suffering from stage I and stage II melanoma were
      investigated with reference to psychological stress, social support and attitude
      to offers of psychotherapeutic support. Additional counselling by their
      dermatologist was considered helpful by 59% of the patients, and interviews with
      a psychotherapist, by 20%. Patients who where more anxious about a progression of
      the cancer and thought they had not been given sufficient information about their
      illness preferred to seek help from the dermatologist. Patients who appreciated
      additional counselling by a psychotherapist were usually those with a poorer
      prognosis for their melanoma and those on whom psychosocial distress weighed
      especially heavily and who had less social support.

PMID- 8647704
TI  - [Nail changes within the scope of reflex dystrophy].
AB  - We describe a 16-year-old boy with reflex sympathetic dystrophy after a fracture
      of the right hand. He had inflammation of the proximal nail folds and arrested
      nail growth of digits 3, 4 and 5 on the right hand. After 2 months lymphatic
      drainage treatment, the changes of the nails had disappeared.

PMID- 8647705
TI  - [Papillomatosis confluens et reticularis. Successful therapy with minocycline].
AB  - Confluent and reticulated papillomatosis (CRP) is a rare dermatosis of unknown
      aetiology. Recent electron microscopic studies suggest that CRP is a disorder of
      keratinisation. In our case we could not confirm the previously reported
      ultrastructural findings. CRP is generally resistant to therapy. We treated a 19
      year-old patient with typical CRP with oral minocycline. Within a few weeks the
      eruption resolved completely. A mild relapse 7 months later responded promptly to
      a repeated course of minocycline. Twelve months after discontinuation of therapy
      there is no evidence of recurrence. In CRP minocycline should be preferred to
      systemic retinoid therapy because of its minor side effects.

PMID- 8647706
TI  - [Scleredema diabeticorum. Report of 4 cases].
AB  - We report on four patients who developed thickened skin on the neck and back
      after a long history of insulin-dependent diabetes mellitus. Pathogenesis,
      histology and methods of treatment are discussed.

PMID- 8647707
TI  - [2 unusual cutaneous T-cell lymphomas with extracutaneous involvement].
AB  - In this paper we present two patients with T-cell lymphomas, who presented with
      unique skin lesions, but later developed extracutaneous involvement. The first
      patient showed marked edematous infiltration of the trunk and legs as well as
      grouped, umbilicated red-to-blue papules limited to the body folds. The second
      patient had lesions reminiscent of poikiloderma vascular atrophicans, with
      erythema, teleangiectasia, hypo- and hyperpigmentation, and bizarre scarring,
      followed by development of papules and nodules. The first patient also had marked
      leukocytosis and lymph node enlargement. Histology, immunohistology, and
      immunophenotyping revealed an unclassifiable CD8+, alpha, beta +, CD10+ cutaneous
      T cell lymphoma with leukemic involvement. Unclassifiable cutaneous T-cell
      lymphoma was also diagnosed in the second patient: it was associated with a
      monoclonal proliferation of T-cell receptor V gamma 9, delta + large granular T
      lymphocytes and finally developed into frank, acute pre-T lymphatic leukemia.

PMID- 8647708
TI  - [Modification of the effectiveness of contraceptives].

PMID- 8647709
TI  - [Meeting report on the "2nd Dermatologic Alps Seminar" Allergology, Occupational
      and Environmental Dermatology 25 to 28 May 1995 in Berchtesgaden].

PMID- 8647710
TI  - [Pruritus].

PMID- 8647711
TI  - The effects of contralateral noise on masked compound action potential in humans.
AB  - The effects of contralateral noise on the masked compound action potential (CAP)
      were examined in human subjects. Small but significant enhancements of masked CAP
      amplitude (anti-masking effects) were observed in some patients with facial
      palsy, as well as in some subjects with healthy ears when noise was added to the
      contralateral ear. There were no significant differences in fractional changes of
      CAP by the addition of contralateral noise between subjects with healthy ears and
      patients with facial palsy in which acoustic reflexes of middle ear muscles
      (MEMs) had disappeared or were impaired. It is suggested that the anti-masking
      effects seen in the present study were possibly caused via the olivocochlear (OC)
      efferent system.

PMID- 8647712
TI  - Elevation of intracellular calcium levels in spiral ganglion cells by
      trimethyltin.
AB  - The neurotoxicant, trimethyltin (TMT) produces cochlear impairment at far lower
      dose levels and far more rapidly than it does central nervous system effects. The
      initial effects of TMT in the cochlea, in vivo, are consistent with disruption of
      the inner hair cell type-1 spiral ganglion cell synapse although it is uncertain
      whether the effect is on presynaptic and/or postsynaptic units. This synapse is
      believed to be an excitatory glutamatergic one, providing the possibility that
      TMT could induce an excitotoxic process resulting in elevations in intracellular
      calcium ([Ca2+]i). The objective of this study was to determine whether TMT had
      direct toxic effects on the postsynaptic spiral ganglion cells studied in primary
      culture and to identify the role of extracellular calcium in such an effect. The
      marker of interest was the effect of this agent on [Ca2+]i levels as determined
      using quantitation of the fluorescent calcium dye, Fura-2. TMT did induce a
      marked and sustained elevation in [Ca2+]i level in the spiral ganglion cells that
      appeared to have a rapid initial phase and a slower saturating phase. Studies
      performed using calcium-free medium showed that elevation of [Ca2+]i in spiral
      ganglion cells by TMT was attenuated but not entirely blocked. Further, the L
      type calcium channel blocker, nifedipine, was able to inhibit the initial
      increase in [Ca2+]i, suggesting that at least this phase of the TMT effect was
      mediated by calcium channels, although nifedipine had no significant effect on
      the time to reach the maximal [Ca2+]i level. Parallel control experiments
      performed using application of exogenous glutamate and depolarizing K+
      concentrations also produced elevation in [Ca2+]i levels. The data indicate that
      TMT elevates [Ca2+]i in isolated spiral ganglion cells both by increasing
      extracellular uptake via Ca2+ channels and also by releasing Ca2+ from
      intracellular stores. Thus TMT ototoxicity appears to include a direct
      postsynaptic toxic event.

PMID- 8647713
TI  - Phase effects in forward masking of the compound action potential: a comparison
      of responses to stimulus and distortion frequencies.
AB  - When a complex stimulus is presented, new frequencies (distortion products, DPs)
      are generated within the cochlea. The most intense DPs are lower in frequency
      than the stimulus tones (primaries). It is not clear whether the relative phase
      of stimuli is encoded by neural channels tuned to the primaries or by channels
      tuned to the DPs. We estimated the response of auditory nerve fibres tuned to
      each of these channels as a function of the relative phase of harmonic stimuli.
      The compound action potential (CAP) evoked by probes at the primary or distortion
      frequencies was masked by harmonic 2-tone maskers and cochlear generated DPs. The
      degree of masking reflected the response to the masker of fibres tuned to the
      probe. Changes in relative phase of the primaries resulted in a large modulation
      of the response of fibres tuned to the DPs. Except for a primary frequency ratio
      of 1:2, the response of fibres tuned to the primaries was only shallowly
      modulated by changes in relative phase. However, the level of response to the DPs
      was much lower than the response to the stimulus tones.

PMID- 8647714
TI  - Cytoskeletal and calcium-binding proteins in the mammalian organ of Corti: cell
      type-specific proteins displaying longitudinal and radial gradients.
AB  - Whole mounts and tissue sections of the organ of Corti from two representative
      mammalian species, the Mongolian gerbil (Meriones unguiculatus) and the guinea
      pig (Cavea porcellus) were probed with antibodies to cytoskeletal and calcium
      binding proteins (actin, tubulin, including post-translational modifications,
      spectrin, fimbrin, calmodulin, parvalbumin, calbindin, S-100 and calretinin). All
      of the proteins tested were expressed in both species. New findings include the
      following. Actin is present in large accumulations in cell bodies of the Deiters
      cells under the outer hair cells (OHC), as well as in the filament networks
      previously described. These accumulations are more prominent in the apical turns.
      Tubulin is present in sensory cells in the tyrosinated (more dynamic) form, while
      tubulin in the supporting cells is post-translationally modified, indicating
      greater stability. Fimbrin, present in the stereocilia of both IHCs and OHCs, is
      similar to the isoform of fimbrin found in the epithelial cells of the intestine
      (fimbrin-I), which implies that actin bundling by fimbrin is reduced in the
      presence of increased calcium. Parvalbumin appears to be an IHC-specific calcium
      binding protein in the gerbil as well as in the guinea pig; labeling displays a
      longitudinal gradient, with hair cells at the apex staining intensely and hair
      cells at the base staining weakly. Calbindin displays a similar longitudinal
      gradient, with staining intense in the IHCs and OHCs at the apex and weak to
      absent in the base. In the middle turns of the guinea pig cochlea, OHCs in the
      first row near the pillar cells lose immunoreactivity to calbindin before those
      in the second and third rows. Calmodulin is found throughout the whole cochlea in
      the IHCs and OHCs in the stereocilia, cuticular plate, and cell body. Calretinin
      is present in IHCs and Deiters cells in both species, as well as the tectal cell
      (modified Hensen cell) in the gerbil. S-100 is a supporting cell-specific calcium
      binding protein which has not been localized in the sensory cells of these two
      species. The supporting cells containing S-100 include the inner border, inner
      phalangeal, pillar, Deiters, tectal (in gerbil) and Hensen cells, where labeling
      displays a longitudinal gradient decreasing in intensity towards the apex
      (opposite to what has been seen with labeling for other proteins in the cochlea).

PMID- 8647715
TI  - Post-translational modifications of tubulin suggest that dynamic microtubules are
      present in sensory cells and stable microtubules are present in supporting cells
      of the mammalian cochlea.
AB  - Post-translational modifications to tubulin in the sensory and supporting cells
      of the cochlea were studied using antibodies specific to the tyrosinated,
      detyrosinated, acetylated and polyglutamylated isoforms. In the sensory cells,
      microtubules which label intensely with antibodies to tyrosinated tubulin are
      found in networks within the cytoplasm. Microtubules which label with antibodies
      to detyrosinated tubulin and polyglutamylated tubulin, but not acetylated
      tubulin, form a small component of the microtubules found in the cytoplasm only
      in the region below the cuticular plate. Microtubules in the supporting cells
      (inner and outer pillar cells and Deiters cells) are arranged in bundles and
      contain little tyrosinated tubulin. They are composed instead of predominantly
      post-translationally modified isoforms which include detyrosinated, acetylated
      and polyglutamylated tubulin. The findings suggest that microtubules in the
      sensory cells form dynamic structures, since microtubules that undergo cyclic
      polymerization and depolymerization predominantly contain tubulin that has not
      yet had its carboxy-terminal tyrosine residue removed. The presence of
      microtubules in the supporting cells in which the tubulin has been polymerized
      into microtubules long enough to be post-translationally modified, provides
      evidence that these microtubules are stable, long-lived and could contribute to
      the structural support of the sensory organ of Corti.

PMID- 8647716
TI  - Migration of hyaline cells into the chick basilar papilla during severe noise
      damage.
AB  - Severe acoustic damage in the chick cochlea causes a destruction of both hair
      cells and supporting cells in a localized area on the basilar papilla. In this
      region, the sensory cells are replaced by a layer of flattened epithelial cells.
      We have employed scanning electron microscopy (SEM) and confocal laser scanning
      microscopy (CLSM) to examine the structure and cytoskeletal changes involved in
      this process. Immunocytochemical staining for actin indicates that the flattened
      cells are derived from the hyaline cells normally located along the inferior edge
      of the basilar papilla. In control cochleae the hyaline cells contain dense
      bundles of actin filaments that anchor into the basal surface of the cells. The
      hyaline cells appear to redistribute into the severely damaged region by
      extending the actin bundles at their basal surfaces. Moreover, the efferent
      nerves that normally form a network among the hyaline cells move into the
      severely damaged area along with the hyaline cells. In moderately damaged
      cochleae, where only hair cells are lost, the hyaline cells do not spread into
      the damaged region. The functional role of this hyaline cell migration is
      unknown, but it may be involved in maintenance or repair of the severely damaged
      cochlea.

PMID- 8647717
TI  - GABA alters the discharge pattern of chopper neurons in the rat ventral cochlear
      nucleus.
AB  - The effect of microiontophoretically applied gamma-aminobutyric acid (GABA) on
      chopper neurons in the ventral cochlear nucleus of the rat is described. The
      predominantly inhibitory effect of GABA resulted in a change of the regular
      discharge pattern. The interspike interval increased and the pattern became less
      regular as indicated by an increase of its coefficient of variation. These
      results suggest that the release of GABA may be responsible for the transient
      chopper behavior of some neurons which loose their regular discharge pattern
      within 20 ms after onset of the response to pure-tone stimulation.

PMID- 8647718
TI  - Suppression of stimulus frequency otoacoustic emissions by contralateral noise.
AB  - The effect of different bands of contralaterally presented noise at low and
      moderate intensities on stimulus frequency otoacoustic emissions (SFOAE) from
      human ears is examined. A SFOAE evoked by a continuous stimulus tone and
      suppressed by a second tone to produce an SFOAE residual was chosen as the probe
      to determine the effect of the efferent input. At low levels of contralateral
      noise, a band centred on the ipsilateral stimulus frequency was the most
      effective suppressor of the SFOAE residual. For higher levels of the
      contralateral stimulus, noise bands containing higher frequency components
      produced most reductions in the SFOAE residual. Small changes in the phase of the
      SFOAE residual during the contralateral noise were also recorded. Increases in
      the SFOAE residual onset latency were also found to be small, being around 1 ms.
      In some cases increases in the level of the SFOAE residual produced by low
      frequency suppressors were recorded during the contralateral noise presentation.
      The results are discussed in the context of current knowledge of the functioning
      of the auditory efferent innervation, and it is suggested that the method of
      evoking SFOAEs presents a viable method for determining the effect of efferent
      stimulation on cochlear mechanics which also allows possible artifact
      contamination to be readily identified.

PMID- 8647719
TI  - The cochlea of Tadarida brasiliensis: specialized functional organization in a
      generalized bat.
AB  - Tadarida brasiliensis mexicana employs a broad-band sonar system at frequencies
      between 80 and 20 kHz and is characterized by non-specialized hearing
      capabilities. The cochlear frequency map was determined with extracellular
      horseradish peroxidase tracing in relation to quantitative morphological data
      obtained with light, scanning and transmission electron microscopy. These data
      reveal distinct species characteristic specializations clearly separate from the
      patterns observed in other bats with either broad-band or narrow-band sonar
      systems. The basilar membrane (BM) is coiled to 2.5 turns and about 12 mm long.
      Its thickness and width only change within the extreme basal and apical ends. The
      frequency range from about 30 to 80 kHz is represented in the lower basal turn
      with a typically mammalian mapping coefficient of about 3 mm/octave. This region
      exhibits morphological features correlated with non-specialized processing of
      high frequencies. (1) The BM is radially segmented by thickenings of pars tecta
      and pars pectinata. (2) The 3 rows of outer hair cells (OHCs) have similar
      morphology. Between 35 and 86% distance from base, frequencies between 30 and 12
      kHz are represented with a slightly expanded mapping coefficient of about 6
      mm/octave. In analogy to previous work, this cochlea region is termed acoustic
      fovea. It includes the frequency range of maximum sensitivity and sharpest tuning
      (21-27 kHz) but also frequencies below the sonar signals. The fovea is
      characterized by several morphological specializations. (1) The BM features a
      continuous radial thickening mainly composed of hyaline substance. (2) There is
      an increased number of layers of tension fibroblasts in the spiral ligament. (3)
      There are morphological differences in the arrangements of stereocilia bundles
      among the 3 rows of OHCs. The transitions between non-specialized and specialized
      cochlear regions occur gradually within a distance of about 600 microns. The
      gradients in stereocilia length of both receptor cell types and the gradations in
      length of the OHC bodies match specialized aspects of the frequency map.

PMID- 8647720
TI  - Quantitative evaluation of myelinated nerve fibres and hair cells in cochleae of
      humans with age-related high-tone hearing loss.
AB  - In this study 9 human temporal bones from 8 individuals were fixed with Karnovsky
      solution by perilymphatic perfusion within 1-3 h after death and examined using
      the "block-surface method' (Spoendlin and Brun, 1974; Spoendlin and Schrott,
      1987) and the "micro-dissection method' (Johnsson and Hawkins, 1967). The
      audiogram of 7 individuals showed high-tone hearing loss, typical for sensory
      neural presbycusis. The inner (IHC) and outer hair cells (OHC) and the myelinated
      nerve fibers in the osseous spiral lamina were counted to correlate audiometric
      curves with hair-cell and nerve-fibre densities. The "block-surface' method
      allows accurate hair-cell and myelinated nerve-fibre enumeration with maximal
      preservation of cochlear structures. The most significant change in the cochlea
      was not the expected loss of hair cells but an evident loss of nerve fibres in
      the spiral lamina along the entire length of the cochlea. This loss of nerve
      fibres was found to be age-related. Reductions up to 30-40% in comparison to
      normal-hearing middle-aged persons were found in cochleae from persons older than
      60 years. In 2 cases only 13% of the fibres remained in some regions of the
      cochlea. The hair-cell counts showed a reduction of approximately 80% of the
      OHCs, mainly in the apical parts of the cochlea, and only little differences in
      the number of IHCs as compared with a group of normal-hearing middle-aged
      persons. We conclude that neither loss of hair cells nor primary degeneration of
      nerve fibres alone can fully explain the high-tone loss. Probably injuries of
      hair cells or neuronal elements at the cellular level can cause threshold
      elevation.

PMID- 8647722
TI  - Influence of hyperthermia on cochlear micromechanical properties in humans.
AB  - We investigated the effect of body temperature on transient evoked otoacoustic
      emissions (TEOAEs) in humans. Hyperthermic conditions were obtained in adults in
      a climatic chamber. During hyperthermia up to an average temperature of 38.4
      degrees C, significant falls were found in total amplitude and peak values of
      TEOAEs: by 1.3 dB SPL/degree C and 2.3 dB/degree C, respectively. This inhibition
      affected all spectrum components equally. These findings indicate that the outer
      hair cell micromechanical activity that is presumed to be measured by TEOAEs is
      not independent of variations in body temperature. The reduction found in
      hyperthermia suggests that temperature-dependent mechanisms are involved in the
      generation of TEOAEs.

PMID- 8647721
TI  - Voltage-dependent Ca2+ channels in the spiral ganglion cells of guinea pig
      cochlea.
AB  - Voltage-dependent Ca2+ channels in spiral ganglion cells (SGCs) isolated from
      guinea pig cochlea were investigated using the patch-clamp technique in a whole
      cell recording mode. The voltage-dependent Na+ and K+ currents were blocked by
      adding tetrodotoxin, 4-aminopyridine, and tetraethylammonium to the external
      solution and by using choline or Cs+ in the external and internal solutions
      instead of Na+ or K+, respectively. The depolarizing voltage steps evoked inward
      currents with slow current decay. The maximum amplitude of the inward current
      increased in a hyperbolic manner with increasing extracellular Ca2+
      concentration, indicating that the inward current was a voltage-dependent Ca2+
      current (ICa). In 5 mM Ca2+ external solution, the ICa activated from a membrane
      potential around -60 mV and reached full activation at about -10 mV. The ICa
      inactivated from about -60 mV and became fully inactivated at about O mV,
      consistent with the high-voltage-activated Ca2+ channel subtype. Ionic
      selectivities for Ca2+ channels in SGCs were as follows: Ca2+ > Ba2+ > Sr2+.
      Effects of both inorganic and organic Ca2+ antagonists also were examined. The
      inhibitory strength was as follows: La3+ > Cd2+ > Ni2+ > or = Co2+ for inorganic
      Ca2+ antagonists, and flunarizine > nicardipine > methoxyverapamil > diltiazem
      for organic ones.

PMID- 8647723
TI  - Quantity, bundle types, and distribution of hair cells in the sacculus of Xenopus
      laevis during development.
AB  - Proliferation of saccular hair cells of the amphibian, Xenopus laevis, was
      examined at various stages of development. Numbers of total hair cells and of
      hair cell bundle types were determined in larval (stages 47, 52 and 56), recently
      metamorphosed juvenile (1 g), and adult (60 g) animals with scanning electron
      microscopy (SEM). Hair cells were identified by ultrastructural analysis of the
      stereociliary bundle. Two general bundle types were present on the sensory
      epithelium: long stereociliary (LS) and short stereociliary (SS) bundles. Based
      on the kinocilium length, the SS bundle type was further divided into SS1
      (kinocilium > or = 8 microns) and SS2 (kinocilium < 8 microns). The sensory
      epithelium was composed of a central zone containing all LS and some SS bundles,
      and a peripheral zone containing only SS bundles. Our results show that in X.
      laevis, the number of LS and SS bundles, as well as the ratio of LS/SS bundles
      increased continuously during larval and post-metamorphic development, with an
      associated enlargement in the sensory epithelium area. These increases were more
      pronounced during larval life. The percentage of hair cells with SS1 bundles was
      greater in larval stages, while that of hair cells with SS2 bundles was
      comparatively higher in juvenile and adult specimens.

PMID- 8647724
TI  - Postnatal development of membrane specialisations of gerbil outer hair cells.
AB  - Using a combination of freeze-fracture and thin sections, this study examines the
      maturation of the membrane specialisations of the gerbil outer hair cells (OHC)
      between 2 and 16 days after birth (DAB). The apical membrane, the junctional
      region around the neck of the cell, and the lateral and basal membranes are
      described. The results suggest a sequential development of the different
      components of the lateral wall. Intramembrane protein particles (IMP), the
      putative OHC motor elements, were found to be present at low density at 2 DAB and
      increased in density from 2200 IMP/microns 2 at 2 DAB to 4131/ microns 2 at 8
      DAB. OHCs have been reported as showing electromotility from 8 DAB onward. IMPs
      continue to increase in density until mature values are attained at 16 DAB. Sub
      surface cisternae did not appear until 8 DAB, with a single layer being complete
      by 10 DAB. Pillar structures, proposed to be related to the cytoskeletal lattice,
      first appear at 10 DAB. The apical membrane of the immature hair cell is
      characterised by the presence of pits related to the endocytosis of vesicles, and
      tip-links between stereocilia, thought to be associated with sites of ion channel
      opening, are present at 2 DAB. The junctional region comprises two areas which
      mature at differing rates: an apical-most region which attains an adult-like
      appearance by 8 DAB and a basal-ward region which continues to increase in
      complexity until mature at 16 DAB. The functional significance of the results are
      discussed in relation to the possible roles of the junctional regions and the
      proposed sites of the OHC motor elements.

PMID- 8647725
TI  - Damage and recovery of hair cells in fish canal (but not superficial) neuromasts
      after gentamicin exposure.
AB  - Recent evidence demonstrating the presence of two types of sensory hair cell in
      the ear of a teleost fish (Astronotus ocellatus, the oscar) indicates that hair
      cell heterogeneity may exist not only in amniotic vertebrates but also in
      anamniotes. Here we report that a similar heterogeneity between hair cell types
      may also occur in the other mechanosensory organ of the oscar, the lateral line.
      We exposed oscars to the aminoglycoside (ototoxic) antibiotic gentamicin sulfate
      and found damaged sensory hair cells in one class of the lateral line receptors,
      the canal neuromasts, but not in the other class, the superficial neuromasts.
      This effect was not due to the canal environment. Moreover, new ciliary bundles
      on hair cells of the canal neuromasts were found after, and during, gentamicin
      exposure. The pattern of hair cell destruction and recovery in canal neuromasts
      is similar to that of type I-like hair cells found in the striolar region of the
      utricle and lagena of the oscar after gentamicin treatment. These results suggest
      that the hair cells in the canal and superficial neuromasts may be similar to
      type I-like and type II hair cells, respectively, in the fish ear.

PMID- 8647726
TI  - Expression of glycine receptor subunits in the cochlear nucleus and superior
      olivary complex using non-radioactive in-situ hybridization.
AB  - The distribution of glycine receptor (GlyR) subunit mRNAs was examined in the
      cochlear nucleus (CN) and superior olivary complex of 5-6-week-old and 8-10-week
      old rats using a non-radioactive in-situ hybridization method. In the younger
      rats, GlyR alpha 1-, alpha 2-, and alpha 3- and beta-subunits were observed in
      all major ventral cochlear nucleus (VCN) and superior olivary complex (SOC)
      neurons, while only alpha 1-, alpha 3- and beta-subunits were observed in dorsal
      cochlear nucleus (DCN) neurons. In 8-10-week-old rats, GlyR alpha 1-, alpha 3-
      and beta-subunits were observed in all major CN and SOC neurons, while mRNA for
      GlyR alpha 2-subunit was not observed. These results indicate that GlyR is being
      expressed all major CN and SOC neurons, with alpha 1-, alpha 3- and beta-subunit
      components of the mature receptor and the alpha 2-subunit, a component of the
      immature GlyR, which is not down-regulated until after 6 weeks of age in most CN
      and SOC neurons.

PMID- 8647727
TI  - Estimating the contribution of non-sensory factors to infant-adult differences in
      behavioral thresholds.
AB  - Estimates of behavioral thresholds of infants are elevated relative to those of
      adults. Explanations for the differences include auditory sensory factors and non
      sensory factors, but no direct estimates of the relative contributions of these
      two factors have been made. In this investigation, thresholds in quiet and in
      increasing levels of a masking noise for a 1 kHz tone, in infants 8 to 11 months
      old and in adults, were determined. The infant-adult differences in unmasked
      threshold was compared to the infant-adult difference in an estimate of the
      minimum masking level (MML) that was derived from the masking data. The intensity
      level of a masking noise at which masking begins is assumed to be independent of
      the non-sensory factors that impact on the threshold value itself. Therefore, it
      is reasoned that the infant-adult difference in MML reflects more closely
      differences in auditory sensory factors than does the infant-adult difference in
      unmasked threshold. In the region of 1 kHz, the infant-adult difference in
      behavioral threshold was 12 dB and the infant-adult difference in MML was 8 dB.
      Therefore, according to our assumptions, 8 dB of the infant-adult difference in
      unmasked threshold is accounted for by sensory factors and the remaining 4 dB
      must be attributable to non-sensory factors.

PMID- 8647729
TI  - Filtering of distortion-product otoacoustic emissions in the inner ear of birds
      and lizards.
AB  - When the output magnitude of more than one order of distortion-product
      otoacoustic emission (DPOAE) is measured, they reach their maximum at the same
      DPOAE frequency. This fact led several authors to the assumption that, subsequent
      to their generation in the cochlea, the DPOAE are band-pass filtered. It was
      suggested that the tectorial membrane is the structure responsible for this
      filtering. In this report, we show that the same kind of "DPOAE tuning' is shown
      by animals which have hearing organs with tectorial structures of very different
      morphology, or even with no tectorial membrane at all. We therefore conclude that
      it is unlikely that the filter is the tectorial membrane.

PMID- 8647728
TI  - Combined effects of adrenalectomy and noise exposure on compound action
      potentials, endocochlear potentials and endolymphatic potassium concentrations.
AB  - The effects of removal of endogenous corticosteroids via bilateral adrenalectomy
      in combination with noise exposure (30 min at 100 dB) were determined by
      recording compound action potential (CAP) and endocochlear potentials (EP), and
      by measuring potassium concentrations (K+e) within the endolymph. Thirty-eight
      Long-Evans rats were divided into groups according to experimental treatments:
      adrenalectomy (ADX) or non-ADX and noise exposure or non-noise exposure. CAP
      thresholds, EP and K+e values were subjected to repeated-measures analysis of
      variance with group and time as factors classifying the measurements. Noise
      exposure resulted in significant elevations of CAP thresholds in both the ADX and
      non-ADX animals, but had no effect on either EP or endolymphatic K+e. Recovery
      was noted during all post-exposure measurement periods and was significantly
      faster for ADX animals. EP and K+e did not change during or after noise exposure.
      ADX animals showed a non-significant reduction of EP and a statistically
      significant increase of K+e during all measurement periods as compared to non-ADX
      animals.

PMID- 8647730
TI  - Acoustic enhancement of electrically evoked otoacoustic emissions reflects
      basilar membrane tuning: a model.
AB  - A simple model for the acoustic enhancement of electrically evoked otoacoustic
      emissions (EEOEs) is presented in this paper. The model is based on the
      assumption that the enhancement is a result of the local interaction between the
      electrical current spreading in the scala media and the basilar membrane (BM)
      response to acoustic input. The analytical, steady-state response of the 1
      dimensional linear cable to sinusoidal current injection is derived and is used
      to predict the current spreading in the cochlea. Acoustic enhancement at an
      emission generator is modeled as a magnitude change that is a sigmoid function of
      the local BM motion. The model results are in good agreement with the
      experimental findings and support our interpretation that the acoustic
      enhancement of EEOEs reflects BM tuning.

PMID- 8647731
TI  - Nonlinear effects of noise on phase-locked cochlear-nerve responses to sinusoidal
      stimuli.
AB  - It is well known that, in a cochlear afferent axon with background spike
      activity, a sinusoidal stimulus (tone) of sufficiently low frequency will produce
      periodic modulation of the instantaneous spike rate, the alternating half cycles
      of which comprise excursions above and below the mean background spike rate. It
      also is known that if the amplitude of the stimulus is sufficiently small, the
      instantaneous spike rate follows very nearly a sinusoidal trajectory through
      these positive and negative excursions. For such cases, we define the AC
      responsiveness of a primary auditory afferent axon to be the amplitude of
      sinusoidal modulation of the instantaneous spike rate divided by the amplitude of
      the tone producing that modulation. In the experiments described in this paper,
      changes in AC responsiveness were followed during and after sudden changes in the
      background noise level. When the amplitude of the tone was sufficiently small
      relative to that of the noise, we found that the AC responsiveness can be
      strongly dependent on the time elapsed since the last change in noise level,
      while being nearly independent of the amplitude of the tone itself. Under those
      circumstances, after transitions between noise levels 20 dB apart, we observed
      changes in AC responsiveness that consistently followed time courses similar to
      those of the short-term mean (background) spike rate (approximating the adapting
      response to the noise alone), unfolding over several milliseconds or tens of
      milliseconds. At the time of the transition between noise levels, there was
      another change in AC responsiveness, which appeared to be instantaneous; as the
      noise level increased, the AC responsiveness immediately increased with it. This
      seemingly paradoxical effect and the similarity of the time courses of AC
      responsiveness and short-term mean spike rate both are consistent with a simple,
      descriptive model of spike generation involving the shifting of threshold along a
      bell curve.

PMID- 8647732
TI  - Functional responses from guinea pigs with cochlear implants. II. Changes in
      electrophysiological and psychophysical measures over time.
AB  - This study, the second of a two-part investigation, assessed changes over time in
      functional measures of the electrically stimulated auditory system following
      ototoxic deafening. Guinea pigs were trained to respond behaviorally to threshold
      level acoustic stimuli and then unilaterally deafened and implanted with a
      bipolar pair of electrodes within the cochlea and a single extracochlear
      electrode. Using pulsatile stimuli, thresholds for the electrically evoked
      auditory brainstem response (EABR) and psychophysical detection were repeatedly
      collected from the same animals over 3-month post-implantation periods.
      Thresholds were obtained as a function of stimulus phase duration primarily using
      bipolar intracochlear stimulation. As in earlier studies, the threshold measures
      exhibited both intra- and intersubject variability. Analysis of group data failed
      to show any statistically significant changes over time in either EABR or
      psychophysical threshold at any fixed pulse duration. However, significant
      changes over time were found in the slopes of the strength-duration functions for
      both measures. Slopes became shallower with time, suggesting a reduction in the
      efficiency of stimulus current integration, a trend presumed to occur with neural
      degeneration. This result suggests that strength-duration functions could be
      useful as a clinical diagnostic measure.

PMID- 8647733
TI  - Expression of plasma membrane Ca-ATPase in the adult and developing gerbil
      cochlea.
AB  - The distribution of the plasma membrane Ca-ATPase (PMCA) was mapped in the adult
      and developing gerbil cochlea by immunostaining with a monoclonal antibody
      against the human erythrocyte PMCA. In the mature cochlea, intense
      immunoreactivity was present at the surface of stereocilia of both inner (IHC)
      and outer (OHC) hair cells. The basolateral plasma membrane of IHCs but not OHCs
      stained strongly whereas that of strial marginal cells and the epithelial cell
      layer of Reissner's membrane showed only weak reactivity. Nerve terminals
      underlying IHCs were also selectively stained. At birth, strong to moderate
      reactivity for PMCA was present in the basolateral plasma membrane of IHCs and
      OHCs, strial marginal cells, and epithelial cells lining the scala media surface
      of Reissner's membrane and in the neurolemma of spiral ganglion cells.
      Immunostaining in the basolateral plasmalemma of OHCs, strial marginal cells, and
      epithelial cells lining Reissner's membrane remained strong to moderate up to 14
      days after birth when it diminished or disappeared entirely, suggesting a
      developmental role for PMCA activity in these sites. Expression of PMCA at the
      surface of IHC and OHC stereocilia was first observed at 10 days after birth and
      staining reached adult levels by 14 days after birth. The abundance of PMCA in
      the stereociliary plasma membrane of mature hair cells supports the suggested
      involvement of Ca2+ in regulating transduction and adaptation mechanisms.

PMID- 8647734
TI  - Effect of stress on cochlear glucocorticoid protein. II. Restraint.
AB  - The effect of restraint stress via immobilization on rat cochlear glucocorticoid
      receptor (GR) levels was determined using an enzyme-linked immunosorbent assay
      (ELISA). Results demonstrated that GR levels in cochlear tissues exhibited tissue
      specific and time-dependent responses to immobilization (6 hours daily). Similar
      responses of the GR were observed in rats restrained during two different times
      of the day. A significant quadratic trend (P = 0.019, R2 = 0.58) was observed in
      levels of GR in spiral ligament tissues of rats restrained from 10:00 to 16:00 h;
      levels of GR were elevated by day 2, and by day 21 GR levels had returned to near
      normal levels. GR levels in the spiral ligament tissues also were found to
      increase significantly after 2 days in response to repeated restraint stress
      administered from 06:00 to 12:00 h (P = 0.017, R2 = 0.34). Interestingly, a
      subtle, but statistically significant, decreasing trend in the organ of Corti's
      GR levels was detected when the daily restraint stress was applied from 06:00 to
      12:00 h for up to 7 days. No significant trends (P > 0.05) were observed in GR
      levels of stria vascularis tissues regardless of the time of day of the restraint
      protocol. Stress has been implicated as an etiological factor in Meniere's
      disease and other ear pathologies. The data presented here indicate that the
      effect of stress is specific to tissue region and that, as in tissues of other
      systems, the GR of cochlear tissues are responsive to stress.

PMID- 8647735
TI  - Nuclear transition of heat shock protein in guinea pig cochlea after
      hyperthermia.
AB  - The main reaction of heat shock protein (hsp) 70 family to heat shock is 2-fold,
      one is an increased synthesis in the cytoplasm and the other is a transition from
      the cytoplasm to the nucleus. Although the former has been already reported in
      the cochlea by several authors, there has been no description as to the latter.
      The present study was designed to determine whether this nuclear transition of
      hsp70 family is also present in the cochlea as in the other organs. Albino guinea
      pigs subjected to hyperthermia treatment (42 degrees C, 10 min) were killed at 0,
      6, 18 or 24 h after the cessation of hyperthermia treatment. Immunohistochemical
      studies in the cochlea of the untreated animals revealed anti-hsp70 family
      immunoreactivity mainly in the cytoplasm of the various cells in the cochlea,
      including the interdental cells, the spiral ganglion cells or the outer hair
      cells. However, immunoreactivity remarkably increased in the nucleus immediately
      after the cessation of hyperthermia treatment and this increased immunoreactivity
      disappeared at 6 h or later. It is concluded that the nuclear transition of hsp70
      family also takes place under hyperthermal stress in the cells of the cochlea as
      in other organs.

PMID- 8647736
TI  - Onset of ototoxicity in the cat is related to onset of auditory function.
AB  - Cats are altricial mammals; they are born deaf and undergo rapid maturation of
      the auditory periphery late in the first and throughout the 2nd week of life.
      Previous studies, using multiple aminoglycoside administration over several days
      or weeks, have indicated that there is a reduction in the degree of ototoxicity
      in young animals provided the drug is administered prior to the onset of auditory
      function. In order to provide a more precise relationship between the degree of
      ototoxicity and auditory development, we used a single administration of
      Kanamycin (KA) and the loop diuretic ethacrynic acid (EA), as the co
      administration of these drugs is known to produce a rapid and profound hearing
      loss in adult animals. Thirty kittens were administered with KA and EA at ages
      that varied from 2 to 16 days after birth (DAB) using a fixed dose per kilogram
      body weight sufficient to profoundly deafen adult animals. All animals made an
      uneventful recovery from the procedure. At 26 DAB, tone-pip-evoked auditory
      brainstem responses (ABR) were recorded from each animal in order to establish
      the extent of the hearing loss. The degree of hearing loss was compared with
      normal ABR audiograms recorded from 6 age-matched control animals. All animals
      treated with KA/EA at 9 DAB or older had a profound hearing loss similar to adult
      animals. Animals treated between 2 and 8 DAB exhibited severe high-frequency
      hearing losses. The extent of the loss was correlated with age (r = 0.63) and
      body weight (r = 0.72) such that hearing loss tended to spread towards lower
      frequencies as age and/or weight increased. All animals exhibited bilaterally
      symmetrical hearing losses which remained relatively stable over monitoring
      periods of up to 6 months following the drug treatment. These findings imply that
      the onset of ototoxicity is related, at least in part, to the onset of auditory
      function in the kitten. The rapid onset of deafness following this procedure
      makes it a useful technique in the study of both ototoxicity and cochlear
      development.

PMID- 8647737
TI  - Ontogeny of hearing in the marsupial, Monodelphis domestica, as revealed by
      brainstem auditory evoked potentials.
AB  - Auditory development was studied in the Brazilian short-tailed opossum,
      Monodelphis domestica, using the brainstem auditory evoked potential (BAEP).
      Consistent responses can first be recorded 29 days after birth. The hearing range
      at the onset of hearing is limited to 5-20 kHz with lowest thresholds of 60 dB
      SPL at 8-12 kHz. During ontogeny, the hearing range expands towards lower and
      higher frequencies and thresholds decrease until the adult audiogram is obtained
      by about day 40. Peak latencies and central conduction times are very long at the
      onset of hearing and decrease until about day 37. In Monodelphis, ontogenetic
      changes of auditory function are in good agreement with those described for
      eutherian mammals, suggesting that this small marsupial species can be used as a
      general model system for auditory development in mammals.

PMID- 8647738
TI  - A functional map of the pigeon basilar papilla: correlation of the properties of
      single auditory nerve fibres and their peripheral origin.
AB  - The purpose of the investigation was to correlate the functional properties of
      primary auditory fibres with the location of appertaining receptor cells in the
      avian basilar papilla. The functional properties of 425 single afferent fibres
      from the auditory nerve of adult pigeons were measured. The peripheral
      innervation site of 39 fibres was identified by intracellular labelling and
      correlated with the fibre's functional properties. Mean spontaneous firing rate
      (SR, 0.1-250/s) was distributed monomodally (mean: 91 +/- 47/s) but not normally.
      Characteristic frequencies (CFs) were in the range of 0.02-4 kHz. SR, threshold
      at CF (4-76 dB SPL) and sharpness of tuning (Q10 dB, 0.1-8.8) varied
      systematically with CF. For a given CF there was a strong correlation of
      threshold and Q10 dB and of threshold and SR. Labelled fibres innervated
      different hair cell types over 93% of the length and 97% of the width of the
      basilar papilla. The majority of fibres innervated hair cells located between 30
      and 70% distance from the apex and 0 and 30% distance from the neural edge of the
      papilla. CFs are mapped tonotopically from high at the base to low at the apex of
      the papilla, with a mean mapping constant of 0.63 +/- 0.05 mm/octave (in vivo).
      The highest CF at the base extrapolates to 5.98 +/- 1.17 kHz. The lowest CF
      mapped at the apex is 0.021 kHz. From the data, together with data from
      mechanical measurements (Gummer et al., 1987), a frequency-place function of the
      pigeon papilla was calculated. Transverse gradients of threshold at CF and of Q10
      dB were observed across the width of the papilla. Thresholds were lowest and
      sharpness of tuning was highest above the neural limbus at a distance of 23% from
      the neural edge of the papilla. Hair cells in this sensitive strip are the
      tallest and narrowest ones across the width of the papilla. They are packed most
      densely and receive the largest number of afferent fibres. Fibres innervating
      (mostly short) hair cells on the free basilar membrane were spontaneously active
      and responsive to sound. Their Q10 dB was less than average but their sensitivity
      and SR were comparable to the mean population values. It is concluded that
      functional properties change gradually not only along the length but also across
      the width of the pigeon basilar papilla. The results support the idea that sharp
      frequency tuning of avian primary auditory fibres involves tuning mechanisms
      supplementary to the tuning of the free part of the basilar membrane.

PMID- 8647739
TI  - Avian cochlear hair cell regeneration: stereological analyses of damage and
      recovery from a single high dose of gentamicin.
AB  - Hair cell regeneration after acoustic trauma has been conclusively documented in
      birds. Previous studies of aminoglycoside ototoxicity have typically used 5-10
      day courses of drug to damage the cochlea and trigger regeneration. This long
      term lesion prevented analysis of the early events of regeneration. We set out to
      determine how much damage would occur and how recovery would proceed after a
      single high-dose injection of the aminoglycoside gentamicin. White Leghorn chicks
      were given a single high dose of gentamicin (100 mg/kg). Three post-injection
      survival groups with age-matched controls were studied: short-term (3-5 days),
      intermediate-term (2 weeks) and long-term (5 weeks). After sacrifice, cochleae
      were dissected and processed for scanning electron microscopy. Using
      stereological techniques, a quantitative analysis of cochlear hair cell counts
      along the proximal 50% of the cochlea was performed from scanning electron
      micrographs on 4-7 chicks from each group. Variable degrees of damage were seen 3
      5 days after the drug injection. All hair cells were lost from the proximal 20%
      of the cochlea in all chicks. This complete hair cell loss could extend to 50% of
      the cochlea. Immature appearing hair cells could be first identified by their
      immature stereocilia at 3 days. Immature appearing hair cells were present in
      greatest number in regions which had been denuded of native hair cells and in
      regions where partial loss occurred. Interestingly, immature appearing hair cells
      also occasionally appeared in adjacent areas in which there was no apparent loss
      of native hair cells. Two-week survivors showed an elevation in hair cell number
      compared to controls in regions which had sustained damage and immediately
      adjacent regions. This elevation implies that an overproduction of hair cells
      might occur as part of the regeneration response. By 5 weeks after damage hair
      cell numbers approximated controls.

PMID- 8647740
TI  - Electromotile hearing: evidence from basilar membrane motion and otoacoustic
      emissions.
AB  - Electrical stimulation of the cochlea is known to cause auditory sensations in
      humans and other animals. It also has been shown to produce emissions of sound
      from the inner ear. In the current study we investigate the relationship between
      electrically induced motion of the basilar membrane (BM) and the production of
      otoacoustic emissions. We test the hypothesis that electrical current-induced
      movements of the outer hair cell (OHC electromotility) result in intracochlear
      acoustic pressure which causes traveling waves on the BM. Our results demonstrate
      that the dominant response of the guinea pig inner ear to electric stimulation,
      at the round window membrane (RW) or across the cochlear duct, is a mechanical
      response of the organ of Corti. We observed that electrical stimulation of the
      cochlea produced traveling wave activity on the BM, measured with a laser Doppler
      velocimeter. The BM motion was accompanied by sound emitted by the cochlea for
      frequencies up to at least 25 kHz. Furthermore, bipolar rectangular current
      stimulation produced steady, bipolar displacements of the BM (to 2 nm),
      indicating functional elongation or contraction of OHCs occurs depending on the
      polarity of the current pulse. All of the evoked responses were absent after drug
      treatments eliminated the OHCs. Our data indicate that OHCs undergo electrically
      evoked displacements capable of producing high-fidelity, high-frequency acoustic
      energy. The electrically evoked intra-cochlear energy results in conventional
      traveling waves within the cochlea, as well as emissions of sound from the
      cochlea. These data provide direct support for a mechanism of cochlear
      sensitivity and tuning involving high-frequency OHC electromotility. Moreover,
      the data also indicate that any intra- or extracochlear electric current which
      affects the electric polarization of OHCs could induce BM traveling waves and
      cause 'electromotile hearing'. This form of hearing would be one component under
      the more general definition of the electrophonic effect.

PMID- 8647741
TI  - Extracochlear electrically evoked otoacoustic emissions: a model for in vivo
      assessment of outer hair cell electromotility.
AB  - Cochlear outer hair cell (OHC) motion in response to changes in membrane
      potential (electromotility) has been extensively studied in vitro.
      Electromotility is thought to actively control the micromechanical properties of
      the sensory epithelium. In order to understand how OHC electromotility
      contributes to normal cochlear responses, its role must be assessed in vivo. We
      have developed a novel animal model for the study of electromotility in vivo.
      Alternating current is delivered by an electrode to the round window (RW) of
      gerbil cochlea and the electrically evoked otoacoustic emission (EEOE) is
      measured from the external ear canal. As much as 45 dB SPL sound could be
      generated by about 200 micro A RMS extracochlear current delivered to the RW.
      Except for the fine structure of EEOE transfer function curves, the magnitude of
      the EEOE has a bandpass appearance ranging from about 4 to 32 kHz and shows a
      positive linear relationship to the current intensity. The phase has a linear
      relationship with frequency and shows no significant change with current
      intensity. Local intracochlear perfusion of 4% paraformaldehyde caused EEOE to
      decrease by approximately 20 dB. These results indicate that the EEOE is probably
      generated by OHCs near the electrode location and propagates to the external ear
      canal. In addition, the force generated by OHCs in vivo is a linear function of
      the electrical stimulus. The major advantages of our model include: (1) non
      invasive procedure and normal cochlea; (2) wide dynamic range of the measurement;
      (3) simple and easy preparation. With these features this model has potential
      applications in basic hearing research and in the diagnosis and treatment of
      otological patients.

PMID- 8647742
TI  - Visualization of newt aragonitic otoconial matrices using transmission electron
      microscopy.
AB  - Otoconia are calcified protein matrices within the gravity-sensing organs of the
      vertebrate vestibular system. These protein matrices are thought to originate
      from the supporting or hair cells in the macula during development. Previous
      studies of mammalian calcitic, barrel-shaped otoconia revealed an organized
      protein matrix consisting of a thin peripheral layer, a well-defined organic core
      and a flocculent matrix inbetween. No studies have reported the microscopic
      organization of the aragonitic otoconial matrix, despite its protein
      characterization. Pote et al. (1993b) used densitometric methods and inferred
      that prismatic (aragonitic) otoconia have a peripheral protein distribution,
      compared to that described for the barrel-shaped, calcitic otoconia of birds,
      mammals, and the amphibian utricle. By using tannic acid as a negative stain, we
      observed three kinds of organic matrices in preparations of fixed, decalcified
      saccular otoconia from the adult newt: (1) fusiform shapes with a homogenous
      electron-dense matrix; (2) singular and multiple strands of matrix; and (3) more
      significantly, prismatic shapes outlined by a peripheral organic matrix. These
      prismatic shapes remain following removal of the gelatinous matrix, revealing an
      internal array of organic matter. We conclude that prismatic otoconia have a
      largely peripheral otoconial matrix, as inferred by densitometry.

PMID- 8647743
TI  - A reversible ischemia model in gerbil cochlea.
AB  - A completely reversible cochlear-ischemia animal model was developed, and an
      initial study of ischemia/reperfusion-induced cochlear function change is
      presented. The bulla of the anesthetized gerbil was opened through a ventral
      approach and the anterior inferior cerebellar artery and its branches were
      exposed. Cochlear blood flow (CBF) from the basal turn of the cochlea was
      monitored with a laser Doppler flowmeter. An electrically isolated microclamp was
      used to occlude the labyrinthine artery (LA). During LA clamping, the cubic
      distortion product (DP) was continuously recorded. The LA was repeatedly clamped
      for different durations in all animals, and CBF consistently showed full recovery
      after clamp release. No obvious change in vessel diameter or flow pattern was
      observed under a stereomicroscope. Mean blood pressure did not show significant
      change during clamping. Immediately upon LA clamping, CBF decreased rapidly
      nearly to zero. After clamp release, CBF demonstrated an immediate rapid
      increase, followed by a secondary gradual recovery to baseline. CBF recovery
      patterns were clamp duration-related. Within a few seconds of occlusion, DP
      decreased and reached a minimum of approximately 24% of the initial level in less
      that 30 s. Following reperfusion of the cochlea, DP gradually increased,
      decreased again, then slowly recovered. Time delay between CBF reperfusion and
      the first increase of DP was proportional to clamping duration, and the increased
      amplitudes demonstrated a negative relationship to clamp duration. We assume that
      the first decrease in DP during clamping was caused by ischemia in the cochlea;
      the second decrease, during the cochlear reperfusion, could be a form of
      reperfusion-induced change in cochlear function. This ischemia/reperfusion model
      in gerbil cochlea demonstrates excellent repeatability and reversibility. Since
      DP and other measurements can be used to dynamically monitor cochlear or hair
      cell functions, this model is useful in studies of auditory physiology and
      pathophysiology.

PMID- 8647744
TI  - Envelope-following response and modulation transfer function in the dolphin's
      auditory system.
AB  - Potentials following the envelopes of sinusoidally amplitude-modulated tones
      (envelope response, EFR) were recorded from the head surface in bottle-nosed
      dolphins. EFR appeared at modulation rates from 300 to 3400 Hz. EFR amplitude was
      higher at rates from 500 to 1400 Hz with peaks at 600 and 1000 Hz and troughs at
      700-850, 1200, and 2000 Hz; at rates above 1700 Hz it fell steeply. EFR
      dependence on modulation depth was linear except at the highest response
      amplitudes, which made it possible to obtain the modulation transfer function
      (MTF). EFR appears to be generated by several sources. One source had a latency
      of about 4 ms and followed modulation rates up to 1700 Hz, while another had a
      latency of 2 ms and followed modulation rates up to 3.4 kHz. The latencies of
      both sources coincided with those of waves of the auditory brainstem response
      (ABR). Comparison of MTF with the ABR spectrum had shown that several MTF peaks
      and troughs reflected the ABR spectrum. The latencies of the two sources were
      consistent with origins in the midbrain and auditory nerve, respectively.

PMID- 8647745
TI  - Cortical sources of middle latency responses of auditory evoked magnetic field.
AB  - In the recordings of middle latency responses of auditory evoked magnetic fields
      in 4 male subjects, we observed distinct components at 11, 19 and 33 ms after
      click stimulus. Equivalent current dipole sources of these components were
      located in the supratemporal auditory cortex, where the earliest component source
      was found at the most medial site.

PMID- 8647746
TI  - Regenerated nerve fibers in the noise-damaged chinchilla cochlea are not
      efferent.
AB  - Nerve-fiber regeneration in the chinchilla cochlea following a traumatic noise
      exposure was systematically described by Bohne and Harding (1992). However, their
      study did not determine the origin of the regenerated nerve fibers (RNFs). In the
      present study, 23 chinchillas were exposed for 12 h to a 0.5 kHz octave band of
      noise at 120 dB SPL. After a 3-month or 1-year recovery period, their right
      cochleas were incubated to demonstrate acetylcholinesterase (AChE) activity and
      then briefly counterstained with Neutral Red or OsO4. Their left cochleas were
      fixed with OsO4 and dissected using a combined organ of Corti (OC)/modiolus
      technique that preserved both structures for high-resolution microscopy. All
      cochleas were prepared as plastic-embedded flat preparations. Damage was located
      in the basal two-thirds of the cochlea and generally consisted of multiple
      lesions in the OC, often involving total degeneration of one or more OC segments
      (i.e., OC wipeouts). The OC wipeouts were separated from one another by areas
      which contained some identifiable cells of the OC (i.e., OC remnants). Most RNFs
      were found in OC wipeouts adjacent to OC remnants. In those animals (83%) with
      significant OC damage, 13 (100%) 3-month-recovery chinchillas had 1-96 RNFs while
      6 (86%) 1-year-recovery chinchillas had 7-62 RNFs. In the AChE-stained cochleas,
      none of the RNFs were AChE-positive, but normal AChE-positive fibers were found
      in the undamaged apical turn. A variable number of surviving spiral ganglion
      cells was present in those regions of Rosenthal's canal that had originally
      innervated the missing hair cells in the OC wipeouts and remnants. It is
      concluded that RNFs are not part of the efferent cochlear system and therefore,
      most likely belong to the afferent system.

PMID- 8647747
TI  - Middle latency responses to acoustical and electrical stimulation of the cochlea
      in cats.
AB  - The middle latency responses (MLR) to acoustical stimulation (A-MLR) as well as
      to electrical stimulation (E-MLR) of the inner ear were recorded in pentobarbital
      anaesthetised cats. Monopolar and bipolar MLR recordings were performed with
      electrodes located at different places on the primary auditory cortex (AI). The
      cochlea was electrically stimulated (ES) through a single round-window electrode
      or through a multichannel intracochlear implant. The slope of amplitude-intensity
      functions of the A-MLR was steeper when the stimulus frequency of the acoustical
      stimuli corresponded to the tonotopical recording place on the auditory cortex.
      Other response properties (waveshape, thresholds and latencies) were related to
      the recording site and stimulus frequency in only two-thirds of animals.
      Parameters of E-MLRs evoked by high-frequency ( > 4 kHz) and low-intensity ES in
      hearing cats, which produced an electrophonic effect, were similar to parameters
      of acoustically evoked MLRs. In deafened cats, the properties of responses to
      extracochlear ES were different from those recorded to acoustical stimulation and
      they were almost uniform in all cortical places. Variations in thresholds, in
      latencies and in the slope of the amplitude-intensity functions of the E-MLRs
      recorded in individual tonotopical cortical places were observed when the
      auditory nerve was stimulated with different configurations of electrodes through
      a multichannel intracochlear implant.

PMID- 8647748
TI  - Detection of mRNA encoding guanylate cyclase A/atrial natriuretic peptide
      receptor in the rat cochlea by competitive polymerase chain reaction and in situ
      hybridization.
AB  - Expression of mRNA encoding guanylate cyclase A (GC-A)/atrial natriuretic peptide
      (ANP) receptor in the rat cochlea was examined by polymerase chain reaction (PCR)
      and in situ hybridization (ISH). After reverse-transcription, PCR amplification,
      subcloning, and sequencing, we found that GC-A mRNA with sequence identical to
      that previously cloned from the rat brain (Chinkers et al., 1989) was expressed
      in the rat spiral ligament as well as in the spiral ganglion. However, GC-A mRNA
      was not detected in the stria vascularis. Competitive PCR using internal standard
      DNAs indicated that the expression of GC-A in the cochlea occurred at a level
      approximately 16 times less than that measured in kidney cortex. ISH
      histochemistry using a 35S-labeled antisense riboprobe showed the highest level
      of expression of GC-A mRNA to be in oligodendrocytes of the cochlear nerve root.
      The results suggest that ANP may play a role in the cochlear nerve function.

PMID- 8647749
TI  - Functional responses from guinea pigs with cochlear implants. I.
      Electrophysiological and psychophysical measures.
AB  - We examined electrophysiological and psychophysical measures of the electrically
      stimulated auditory system of guinea pigs implanted with chronic intracochlear
      electrodes. Guinea pigs were trained to detect low-level acoustic stimuli and
      then unilaterally deafened and implanted with one extracochlear and two
      intracochlear electrodes. Electrically evoked auditory brainstem responses
      (EABRs) and psychophysical detection thresholds were obtained from the same
      animals using pulsatile stimuli. Supplementary EABR data were obtained from
      additional, untrained, animals. Thresholds were obtained as a function of
      stimulus phase duration and monopolar and longitudinal-bipolar electrode
      configurations. The slopes of the EABR and psychophysical functions for bipolar
      stimulation, averaged across subjects within 1 month after implantation, were 
      5.25 and -6.18 dB per doubling of pulse duration, respectively. These slopes were
      obtained with pulse durations ranging from 20 to 400 microseconds/phase; slope
      was reduced at longer pulse durations. Strength-duration slope also varied as a
      function of electrode configuration: monopolar stimulation produced steeper
      functions than did bipolar stimulation. Differences between EABR and
      psychophysical strength-duration measures suggest the existence of central
      mechanisms of stimulus integration in addition to that occurring at the level of
      the auditory nerve. Differences observed with variation of stimulus parameters
      (e.g., monopolar vs. bipolar stimulation modes) suggest that the specific mode of
      intracochlear electrical stimulation can influence stimulus integration. Such
      observations may be useful in the design of prosthetic devices and furthering our
      understanding of electrical excitation of the auditory system.

PMID- 8647750
TI  - Concentration controlled and concentration defined clinical trials: do they offer
      any advantages for antimicrobial chemotherapy?

PMID- 8647751
TI  - Intracellular distribution of ampicillin in murine macrophages infected with
      Salmonella typhimurium and treated with (3H)ampicillin-loaded nanoparticles.
AB  - The intracellular distribution of (3H)ampicillin-loaded polyisohexylcyanoacrylate
      nanoparticles was studied in murine macrophages (peritoneal cells and the J774
      cell line) infected by Salmonella typhimurium C5, using ultrastructural
      autoradiography. Ampicillin penetration and retention into the cells obviously
      increased by means of nanoparticles. After short-term (2-4 h) treatment with the
      nanoparticle formulation, numerous intracellular bacteria were seen to be in the
      process of destruction. The tritium labelling was located in the cell cytoplasm
      and inside vacuoles in which bacteria undergoing degradation were often present.
      After long-term (12 h) treatment, numerous spherical bodies (d: 100 nm to 500 nm)
      and larger forms (2 microns) were seen in the vacuoles. Radioactivity was mainly
      found to be localized on the spherical bodies, indicating marked damaging action
      of the ampicillin on the bacterial walls. The targeting of ampicillin therefore
      allowed its penetration into the macrophages and vacuoles infected with S.
      typhimurium.

PMID- 8647752
TI  - In-vitro activity of levofloxacin against clinical isolates of Legionella spp,
      its pharmacokinetics in guinea pigs, and use in experimental Legionella
      pneumophila pneumonia.
AB  - The activities of levofloxacin and ofloxacin against 22 clinical legionella
      isolates was determined by microbroth dilution susceptibility testing. Growth
      inhibition of two Legionella pneumophila strains grown in guinea pig alveolar
      macrophages by levofloxacin, ofloxacin, or erythromycin was also determined. The
      drug concentrations required to inhibit 90% of strains tested was 0.032 mg/L for
      levofloxacin or ofloxacin, and was 0.016 mg/L for ciprofloxacin. BYE alpha broth
      significantly inhibited the activities of all three drugs tested, as judged by
      the susceptibility of control Escherichia coli strains. Levofloxacin (0.25 mg/L)
      reduced bacterial counts of two L. pneumophila strains grown in guinea pig
      alveolar macrophages by 1 log10, but regrowth occurred over a 3 day period;
      levofloxacin (1 mg/L) reduced bacterial counts by 2-3 log10 cfu/mL. Levofloxacin
      was significantly more active than erythromycin, and as active as ofloxacin or
      ciprofloxacin in this assay. Pharmacokinetic and therapy studies of levofloxacin
      and ofloxacin were performed in guinea pigs with L. pneumophila pneumonia. For
      the pharmacokinetic study, levofloxacin was given (10 mg/kg) by the
      intraperitoneal route to infected guinea pigs; mean peak plasma and lung
      concentrations were 3.4 mg/L and 1.4 micrograms/g, respectively, at 0.5 h and 2.6
      mg/L and 0.6 micrograms/g at 1 h. The terminal half-life phase of elimination
      from plasma and lung was c. 1 h. All 15 infected guinea pigs treated with
      levofloxacin (10 mg/kg/day given ip once daily) for 5 days survived for 9 days
      after antimicrobial therapy, as did all 14 guinea pigs treated with the same dose
      of ofloxacin. None of 13 animals treated with saline survived. Levofloxacin is
      effective against L. pneumophila in vitro and in a guinea pig model of
      legionnaire's disease. Levofloxacin should be evaluated as a treatment of human
      legionnaires' disease.

PMID- 8647753
TI  - Treatment of experimental endocarditis due to multidrug-resistant Enterococcus
      faecium with clinafloxacin and penicillin.
AB  - Clinafloxacin, a new quinolone antibiotic with enhanced activity against Gram
      positive bacteria, has demonstrated in-vitro activity against multidrug-resistant
      Enterococcus faecium, particularly when combined with penicillin. Rabbits with
      experimental endocarditis due to a multidrug-resistant strain of E. faecium were
      treated with clinafloxacin and/or penicillin. After three days of therapy,
      significant reduction of bacterial concentrations were found in vegetations,
      kidneys, and spleens of animals treated with clinafloxacin. The combination of
      clinafloxacin and penicillin was significantly better in reducing vegetation
      bacterial concentrations compared to the other groups (-4.4 log10 cfu/g compared
      with control). Serum levels of clinafloxacin consistently exceeded the MIC of the
      strain, and clinafloxacin-resistant isolates could not be detected. Clinafloxacin
      demonstrated promising activity in vivo against multidrug-resistant E. faecium,
      and further studies are warranted.

PMID- 8647755
TI  - Tentative interpretive criteria and quality control parameters for in-vitro
      susceptibility testing of Neisseria gonorrhoeae to two fluoroquinolones (PD
      131628 and grepafloxacin (OPC 17116)).
AB  - The susceptibility of Neisseria gonorrhoeae to PD 131628 and grepafloxacin (OPC
      17116) was evaluated by agar dilution and disc diffusion methods. A tentative
      susceptibility category for both fluoroquinolones included strains for which the
      MICs are < or = 0.06 mg/L and the zones of inhibition are > or = 38 mm for PD
      131628 and > or = 37 mm for grepafloxacin. Quality control studies with N.
      gonorrhoeae ATCC 49226 suggested that agar dilution MIC limits were 0.002-0.008
      mg/L and 0.004-0.03 mg/L for PD 131628 and grepafloxacin, respectively. The zone
      size limits were 50-58 mm for PD 131628 and 44-52 mm for grepafloxacin.

PMID- 8647754
TI  - Phenoxymethyl penicillin versus co-amoxiclav in the treatment of acute
      streptococcal pharyngitis, and the role of beta-lactamase activity in saliva.
AB  - One hundred and sixty-five consecutive patients ( > 2 years of age) with acute
      group A streptococcal (GAS) pharyngitis randomly received co-amoxyclav (79
      patients) or phenoxymethyl penicillin (86 patients). beta-Lactamase activity in
      saliva was determined for each patient. At follow up after seven days, tonsillar
      cultures from seven patients (9.6%) in the penicillin V group grew group A
      streptococcus; three of these patients had tonsillitis clinically. In the co
      amoxiclav group these figures were three (3.8%) and two respectively (P > 0.05).
      Within the 12 month follow up period, there were four clinical recurrences (6.1%)
      in the penicillin V group and seven (9.3%) in the co-amoxiclav group (P > 0.1).
      beta-Lactamase activity in the saliva was demonstrated in 29 patients (19.2%).
      Fourteen (74%) of 19 bacteriological failures or clinical recurrences had beta
      lactamase activity, versus 15 (12%) of 129 successfully treated patients (P <
      0.001). There is no evidence that oral co-amoxiclav is better than oral
      penicillin V for the first treatment of acute GAS pharyngitis, but
      bacteriological failure and clinical recurrence are strongly associated with the
      presence of beta-lactamase activity in commensal flora.

PMID- 8647756
TI  - Omeprazole inhibits growth of gram-positive and gram-negative bacteria including
      Helicobacter pylori in vitro.
AB  - The antibacterial effects of omeprazole (100, 200 and 300 mg/L) were assessed
      using bacterial growth curves. A dose-related permanent inhibition was seen with
      actively growing Gram-positive cocci. A reduced and only temporary effect was
      observed with Gram-negative bacilli. After 1 day the bacterial count of
      Helicobacter pylori in the presence of omeprazole 200 mg/L was reduced from 10(4)
      cfu/mL for the control to zero. No synergic or antagonistic interaction of
      omeprazole with amoxycillin or doxycycline was observed for Escherichia coli and
      Enterococcus faecalis.

PMID- 8647757
TI  - Comparative in-vitro activity of sparfloxacin and eight other antimicrobial
      agents against clinical isolates of non-tuberculous mycobacteria.
AB  - The in-vitro activity of sparfloxacin and eight other antimicrobial agents
      against 64 non-tuberculous mycobacteria (non-MAI) (40 rapidly growing and 24
      slowly growing) was compared with those of ciprofloxacin, ofloxacin, amikacin,
      tobramycin, cefoxitin, imipenem, clarithromycin and doxycycline. Sparfloxacin
      presented the same activity as ciprofloxacin, being highly active against rapidly
      growing mycobacteria and showing good in-vitro activity against slowly growing
      mycobacteria. Amikacin was very active against rapidly growing mycobacteria and
      clarithromycin presented good activity against all mycobacteria tested. These
      results suggest that sparfloxacin is a valid agent to be considered in the
      treatment of Mycobacterium spp. infections.

PMID- 8647758
TI  - In-vitro activity of cephalosporins alone and combined with sulbactam against
      various strains of Acinetobacter baumannii with different antibiotic resistance
      profiles.
AB  - The beta-lactamases of six strains of Acinetobacter baumannii were investigated
      using analytical isoelectric focusing, and the MIC values for 16 beta-lactam
      antibiotics determined against the strains. Three strains produced a chromosomal
      cephalosporinase (pI > 8.5), one strain a CARB-5 beta-lactamase (pI = 6.35), one
      strain a TEM-1 penicillinase (pI = 5.4) as well as a cephalosporinase (pI > 8.5),
      and one carbapenem-resistant strain a beta-lactamase with a pI > 8.5.
      Ceftazidime, cefepime, cefpirome, imipenem and meropenem were found to be the
      most effective beta-lactams against five strains. Sulbactam was active against
      four of the strains at 1-4 mg/L and showed enhanced killing effects with
      cefpirome.

PMID- 8647759
TI  - Penetration of cefuroxime into the cerebrospinal fluid of patients with traumatic
      brain injury.
AB  - Cefuroxime levels were measured in cerebrospinal fluid (CSF) and serum of four
      patients with traumatic brain injury following the implantation of
      intraventricular catheters. The levels ranged from 0.15 to 2.03 micrograms/mL in
      CSF and from 1.8 to 66.9 micrograms/mL in serum. No ventriculostomy related
      infections were detected.

PMID- 8647760
TI  - Colonization of resistant faecal aerobic gram-negative bacilli among geriatric
      patients in hospital and the community.
AB  - Among the elderly most infections are caused by organisms of faecal origin. The
      study of the resistance of such Gram-negative bacilli should therefore be a
      priority. In this study, we determine the occurrence of resistance to five
      antimicrobials commonly used in geriatric outpatient care, and compare it with
      long-term and short-term hospitalized geriatric patients treated and not treated
      with antimicrobials.

PMID- 8647761
TI  - An audit of the use of antifungal agents.
AB  - The three month prospective audit of systemic antifungal therapy was undertaken
      in a university hospital in the United Kingdom to determine the patterns of usage
      of systemic antifungal drugs. The case notes of all patients receiving systemic
      antifungal agents were reviewed daily and the appropriateness of therapy was
      determined according to standards in the authoritative literature. One hundred
      and fifteen courses of treatment with antifungal agents for 1481 days were
      administered to 74 patients. When a patient has received more than one course of
      antifungals, both the individual courses and the combination of courses, i.e. a
      regimen, were judged. Antifungal agents were given as an empirical therapy or as
      prophylaxis in 68% of the courses, with fluconazole and amphotericin B
      desoxycholate being the agents most frequently used. Therapy was considered
      unconventional in 26.9% of the courses and 40.5% of the regimens, mainly because
      either the indication or the duration of treatment did not conform to
      conventional practice. Improvement in prescribing practices and standards for
      ongoing audit can only be achieved if a consensus can be reached on how these
      agents can be used appropriately.

PMID- 8647762
TI  - A survey of antimicrobial susceptibility testing in the United Kingdom.

PMID- 8647763
TI  - The issue of the true postantibiotic effect.

PMID- 8647764
TI  - Problems encountered in the characterization of IRT beta-lactamase-producing
      clinical Escherichia coli isolates intermediate-resistant to cephalothin.

PMID- 8647765
TI  - In-vitro activity of chlorhexidine, hexetidine and bacitracin against perinatal
      pathogens.

PMID- 8647766
TI  - Paradoxical susceptibility to cephalothin and cefamandole of a Klebsiella
      pneumoniae isolate producing extended-spectrum beta-lactamase (TEM-3)

PMID- 8647767
TI  - In-vitro and intracellular antimycobacterial activity of trifluoperazine.

PMID- 8647768
TI  - Efficacy and safety of teicoplanin in infections caused by methicillin-resistant
      Staphylococcus aureus.

PMID- 8647769
TI  - Therapy of brain abscess with imipenem--a safe therapeutic choice?

PMID- 8647770
TI  - Treatment failure due to extended spectrum beta-lactamase.

PMID- 8647771
TI  - The 'hidden' carbapenemase of Aeromonas hydrophila.
AB  - It has been presumed that there are just two beta-lactamases in the motile
      Aeromonas species, a carbapenemase and a cephalosporinase, based on the premise
      that all beta-lactamases can be detected by hydrolysis of the chromogenic
      cephalosporin, nitrocefin. However, when it was recently found that a non-motile
      species of Aeromonas that causes furunculosis in salmon, contained three beta
      lactamases, one of which was a carbapenemase which could not be detected with
      nitrocefin, it was hypothesised that genetic exchange could occur between fish
      pathogens and human pathogens resulting in the transfer of the carbapenemase
      encoding gene. This could have a potentially serious impact on intensive therapy
      units where carbapenems are employed. The purpose of this study was to determine
      whether the human pathogen Aeromonas hydrophila demonstrated the same beta
      lactamase profile. After anion and cation exchange chromatography had been
      employed to separate the beta-lactamases of a clinical strain of A. hydrophila,
      three different beta-lactamases were found, one of which is a carbapenemase which
      does not hydrolyse nitrocefin. It is, therefore, probable that many strains of
      Aeromonas spp. contain a similar array of beta-lactamases which include a
      carbapenemase that cannot be detected with nitrocefin. Similar carbapenemases may
      well remain hidden in other species of bacteria unless appropriate techniques to
      detect the enzymes are employed.

PMID- 8647772
TI  - Susceptibility of Helicobacter pylori to simethicone and other non-antibiotic
      drugs.
AB  - The antifoaming agent simethicone (Lefax), the protease inhibitor gabexate
      mesilate (FOY), the antimycotic ketoconazole, and the hydroxyl scavangers
      dimethylsulphoxide (DMSO) and allopurinol were investigated for growth inhibition
      of Helicobacter pylori and representative strains of other bacterial species. H.
      pylori were selectively inhibited by 64-128 mg/L of simethicone, 64-128 mg/L
      gabexate mesilate, and 16-64 mg/L ketoconazole. Dimethylsulphoxide and
      allopurinol showed no antibacterial effect at concentrations used
      therapeutically. It is concluded that gabexate mesilate, ketoconazole and,
      particularly, simethicone are candidates for treatment of H. pylori infection.

PMID- 8647773
TI  - Multiple drug resistant tuberculosis: centralized mycobacterial reference using
      molecular techniques can help.

PMID- 8647774
TI  - Detection of the mec-A gene and phenotypic detection of resistance in
      Staphylococcus aureus isolates with borderline or low-level
      methicillinresistance.
AB  - Eighty-three isolates of Staphylococcus aureus for which MICs of methicillin of 4
      16 mg/L had previously been recorded were tested for the presence of the mecA
      gene with a DNA probe and a PCR assay. There was complete agreement between the
      results obtained by these methods; 39 isolates were mecA-positive and 44 were
      mecA-negative. Using the presence of mecA as the defining standard, several
      phenotypic methods for determining resistance to methicillin were evaluated and a
      high-inoculum, agar-incorporation breakpoint test was found to offer the best
      combination of high sensitivity and high specificity. However twenty-seven of the
      44 mecA-negative strains were methicillin-resistant according to agar dilution
      MICs (MIC > 4 mg/L on at least one of the four media used) but none had MICs
      exceeding 32 mg/L. One of the mecA-positive strains had a methicillin MIC of only
      8 mg/L and did not appear to be heteroresistant. The clinical significance of
      these two groups of 'atypical' isolates may need further investigation. This
      study highlights the problems of detecting reliably S. aureus with low level
      methicillin resistance by phenotype methods and the usefulness of direct
      detection of the mecA gene.

PMID- 8647775
TI  - Bleomycin resistance in Staphylococcus aureus clinical isolates.
AB  - Among clinical isolates of Staphylococcus aureus tested for resistance to the
      antibiotic bleomycin, 197 were found to be resistant; most of them were also
      resistant to tobramycin and contained plasmids. DNA dot-blot hybridization
      analysis of the bleomycin resistant isolates with an 171 bp probe derived from
      the plasmid pUB110 indicated that 43 strains (22%) carried pUB110-like bleomycin
      resistance DNA sequences. Analysis of bacterial cell lysates derived from the
      bleomycin resistant isolates indicated that many contained bleomycin-binding
      properties (BBP), that prevent DNA damage by the antibiotic. Of 13 strains that
      were analysed by DNA gel electrophoresis and Southern blot DNA hybridization, six
      were found to carry pUB110-like bleomycin resistance DNA sequences. These studies
      indicate that there may be more than one genetic determinant for bleomycin
      resistance in S. aureus whose DNA is protected.

PMID- 8647776
TI  - Drug chirality: a consideration of the significance of the stereochemistry of
      antimicrobial agents.
AB  - Approximately 25% of drugs are marketed as either racemates or mixtures of
      diastereoisomers. Such stereoisomers frequently differ in terms of their
      biological activity and pharmacokinetic profiles and the use of such mixtures may
      contribute to the adverse effects of the drug particularly if they are associated
      with the inactive or less active isomer. In recent years drug stereochemistry has
      become a significant issue for both the pharmaceutical industry and the
      regulatory authorities. The significance of stereoisomerism in antimicrobial
      agents is addressed in this review using examples drawn from the beta-lactams, as
      being representative of semisynthetic agents, and the quinolones, as examples of
      synthetic agents. Within these two groups of compounds it is clear that
      stereochemical considerations are of significance for an understanding of
      concentration effect relationships, selectivity in both action and inactivation
      and for an appreciation of the mode of action at a molecular level. In the case
      of some agents the use of a single isomer is precluded due to their facile
      epimerization, e.g. carbenicillin, in the case of others there are potential
      advantages with the use of single isomers, e.g. ofloxacin. However, in the case
      of latamoxef, a compound which undergoes in-vivo epimerization with a half-life
      similar to its apparent serum elimination half-life the situation is by-no-means
      clear cut. These agents emphasise the importance of considering each compound
      individually, i.e. on a case-by-case basis, before deciding to use a single
      isomer or stereoisomeric mixture.

PMID- 8647777
TI  - Activity of CP 99,219 (trovafloxacin) compared with ciprofloxacin, sparfloxacin,
      clinafloxacin, lomefloxacin and cefuroxime against ten penicillin-susceptible and
      penicillin-resistant pneumococci by time-kill methodology.
AB  - Activity of CP 99,219 (trovafloxacin), clinafloxacin, ciprofloxacin,
      sparfloxacin, lomefloxacin and cefuroxime against 4 penicillin-susceptible, 2
      penicillin-intermediate and 4 penicillin-resistant pneumococci was tested by MIC
      and time-kill methodology. Bacteriostatic values for all three groups did not
      differ significantly with all compounds tested except cefuroxime, and were lowest
      for trovafloxacin and clinafloxacin, followed by sparfloxacin, ciprofloxacin and
      lomefloxacin; cefuroxime yielded values which increased in line with those of
      penicillin G. The test compounds were bactericidal (i.e. they reduced original
      counts by > or = 3 log10 cfu/mL at one dilution above bacteriostatic levels) in
      most cases, though some strains showed slightly greater discrepancies between
      bacteriostatic and bactericidal levels of all compounds tested. Trovafloxacin,
      clinafloxacin and sparfloxacin yielded MIC and time-kill results which point to
      possible efficacy in treatment of penicillin-susceptible and -resistant
      pneumococcal infections.

PMID- 8647778
TI  - Increasing ciprofloxacin resistance in salmonellas in England and Wales 1991
      1994.
AB  - Ciprofloxacin is now widely used as the drug of choice for those severe
      salmonella infections where antibiotic therapy is indicated. Between 1991 and
      1994 ciprofloxacin resistance in salmonellas isolated from humans in England and
      Wales increased from 0.3% to 2.1%. Among the most prevalent serotypes the highest
      incidence was seen in Salmonella hadar where ciprofloxacin resistance has
      increased from 2.0% in 1991 to 39.6% in 1994. The incidence of ciprofloxacin
      resistance remains uncommon in other serotypes and in 1994 5.1% of Salmonella
      virchow and Salmonella newport were resistant compared with 1.4% of Salmonella
      typhimurium and 0.4% of Salmonella enteritidis. There has been a number of
      examples of development of resistance to quinolone drugs during treatment of
      human infections. Ciprofloxacin resistance also occurs in salmonellas isolated
      from food animals and human food. This increasing incidence of ciprofloxacin
      resistance reflects the more widespread use of fluoroquinolone drugs in both
      humans and food animals.

PMID- 8647779
TI  - In-vitro effects of cefodizime on leucocyte functions and colony formation from
      granulocyte-monocyte progenitors.
AB  - Infections in immunocompromised patients are often difficult to treat, even with
      currently available antimicrobial agents. An understanding of the effects of
      antibiotic therapy on the host's immune response is therefore important when
      deciding on the clinical management of such patients. Antimicrobial agents which
      lack immunodepressive effects and/or potentiate the immune response are the goal
      of current research into the treatment of infections in immunocompromised
      patients. The effects of cefodizime (1-250 micrograms/mL) in vitro on some
      functional activities of leucocytes and on colony formation by granulocyte
      monocyte progenitors were studied to investigate the effects of the antibiotic on
      the host's immune response. A marked enhancement in the lymphocyte transformation
      reaction was observed in cells exposed to cefodizime. This effect was dose
      dependent. Cefodizime had no significant effect on antibody-dependent cell
      cytotoxicity or on natural killer cell-mediated cytotoxicity. The chemotactic
      activity of neutrophils was not influenced by the presence of cefodizime (P >
      0.05). The phagocytic activity of neutrophils was significantly increased by
      cefodizime (P > 0.01). Cefodizime significantly stimulated, in a dose-dependent
      manner, colony formation by granulocyte-monocyte progenitors (P < 0.01). Results
      suggest that cefodizime has certain stimulatory effects on immunocompetent cells
      such as enhancing the transformation reaction of lymphocytes, neutrophil
      phagocytosis and colony formation by granulocyte-monocyte progenitors. Further
      studies are required to clarify the mechanisms responsible for these effects.

PMID- 8647780
TI  - [Contribution of Doppler sonography in inflammatory pathology of the large
      bowels].
AB  - At the end of the eighties, Doppler equipment added to conventional
      ultrasonography a new dynamic dimension. On the basis of radiological (US, CT,
      barium studies), clinical, biological, surgical and/or pathological correlations
      in 30 cases, the following considerations were emphasized. In case of intestinal
      obstruction, viability of the obstructed segment is compromised when Doppler
      parietal flow remains undetectable. In Crohn's disease or ulcerative colitis, as
      well as in acute appendicitis, presence of Doppler parietal flow throughout the
      affected thickened segment indicates an acute condition; similarly, abnormally
      high mean portal velocity (30-48 cm/sec; normal: 15 +/- 7 cm/sec), and abnormally
      low resistive index in the superior mesenteric artery (0.58-0.78; normal: 0.908 =
      0.026) are detected. In colonic diverticulitis, similar characteristics can be
      observed, but are subtle and usually predominant at the mesenteric side of the
      affected segment in moderate diverticulitis. These abnormal Doppler findings
      disappear with successful therapy.

PMID- 8647781
TI  - Magnetic resonance imaging of pelvic bone tumors.
AB  - The aim of our study was to determine the value of magnetic resonance (MR)
      imaging in the diagnostic workup of pelvic bone tumors. We retrospectively
      evaluated the MR findings in 60 pelvic bone tumors. Owing to its high contrast
      resolution and multiplanar imaging capabilities, MR offers a clear depiction of
      cortical, medullar or soft tissue involvement, intratumoral necrosis, and
      relationship to neurovascular structures, and may be considered as the modality
      of choice for the staging of pelvic bone tumors. Since grading of bone tumors
      reaches a high accuracy on conventional radiography (CR), the value of MR imaging
      is rather complementary. Although the role of MR imaging in tissue
      characterization is mostly limited to recognition of tumoral components, accurate
      tissue characterization if often possible (e.g. in low-grade chondrosarcoma,
      eosinophilic granuloma, aneurysmal bone cyst, giant cell tumor, and chordoma). MR
      imaging in osteochondromas, metastases, and fibrous dysplasia remains of limited
      value since most of these lesions are well recognized on CR and/or CT. CR remains
      the first choice examination in diagnosis and grading of bone tumors, but MR
      imaging has significantly improved staging and tissue characterization in bone
      tumor imaging. The aim of our study is to determine the value of magnetic
      resonance (MR) imaging in the diagnostic workup of pelvic bone tumors, i.e. in
      staging, in differentiating benign from malignant tumors (grading), and in
      further characterization of tumors or tumoral components.

PMID- 8647782
TI  - Diagnostic improvement in MRI of gynecological neoplasms.
AB  - The use of pelvic MRI is still limited because of motion artifacts due to
      respiration, blood flow and peristalsis and because of lack of contrast between
      bowel loops and adjacent organs. As in CT it has been suggested that the
      administration of an oral contrast agent might improve MR image quality. Both
      positive (T1) and negative (T2) agents have already been used in clinical trials.
      Lumirem (AMI-121) is a negative oral contrast agent consisting of a solution of
      superparamagnetic iron oxide particles with silicone coating. In a phase III
      clinical trial we have determined the safety and efficacy of Lumirem in the
      assessment of gynecological neoplasms. Twenty (20) patients underwent MRI at 1.5
      Tesla. T1w SE and T2w fast SE images were obtained before and after the ingestion
      of 600-900 ml Lumirem.

PMID- 8647783
TI  - Recurrent hepatic hydatid disease with secondary splenic infestation.
AB  - Hydatid disease caused by Echinococcus granulosus is a common problem throughout
      the world, but is rarely encountered in the Western Countries. The liver and
      lungs are the most frequently involved organs in hydatid disease. The cyst may
      become very large and rupture. Abdominal, pelvic and pleural dissemination due to
      spread of parasitic contents may follow. Splenic involvement in hydatid disease
      is uncommon, representing less than 2% of all human infestations by Echinococcus.
      We report a recurrent liver hydatidosis with secondary splenic infestation.

PMID- 8647784
TI  - Parinaud's syndrome in a patient with multifocal glioma.
AB  - We describe the clinical and neuroradiological findings in a 63-year-old man with
      Parinaud's syndrome. Magnetic resonance (MR) imaging showed a mass lesion within
      the quadrigeminal plate. Additional MR findings included a right frontoparietal
      subcortical lesion as well as periventricular white matter edema due to acute
      deterioration of hydrocephalus. On MR, the diagnosis of multifocal glioma was
      proposed. Neuropathological examination after resection of the supratentorial
      lesion revealed an oligodendroglioma, grade II.

PMID- 8647785
TI  - Symptomatic adrenal pseudocyst.
AB  - A case of symptomatic adrenal pseudocyst due to recurrent hemorrhage is
      presented. Because of the hemorrhages, the cyst-like lesion had unusual
      appearances at US, CT and MRI, resembling a malignant cystic tumor.

PMID- 8647786
TI  - [Late diagnosis of a traumatic pseudo-aneurysm of the subclavian artery].
AB  - The authors report a rare case of subclavian pseudoaneurysm diagnosed six months
      after a left clavicular fracture. The leading symptoms were pain and claudication
      in the left arm related to peripheral embolization. The essential diagnosis was
      made by selective arteriography followed by arterio-CT. Peripheral embolization
      or brachial nerve compression are the most common presentations of subclavian
      pseudoaneurysms. To avoid such late complications, the authors emphasize the
      importance of the initial vascular examination of the shoulder after blunt trauma
      with or without clavicular fracture. Surgery is imperative and the use of
      autologous vein graft is the method of choice.

PMID- 8647787
TI  - Unusual presentation of ovarian pathology on CT.
AB  - A prospective study including seventy-seven consecutive patients suspected of
      having ovarian tumoral or pseudotumoral pathology on CT was carried out. Fifty
      nine patients had surgery with histological diagnosis. When comparing the CT and
      histological findings in benign and malignant lesions we obtained an overall
      accuracy of 95% with only three misdiagnosed cases on CT. False positive
      diagnosis of malignancy was established in a case of abdominal actinomycotic
      infection, a case of chronic appendicitis, and in a ruptured ectopic pregnancy.
      These three cases are discussed in detail.

PMID- 8647788
TI  - Use of serotonin selective reuptake inhibitors in geriatric depression.
AB  - The treatment of depression can be problematic in the elderly patient. The advent
      of the serotonin selective reuptake inhibitors (SSRIs) represents a significant
      advance in the treatment of depression. Sufficient data from controlled studies
      now exist on the efficacy and safety of these agents in geriatric patients to
      recommend them as a primary treatment for major depressive disorder. SSRIs appear
      to have significant advantages over older drugs, especially tricyclic agents, in
      this age group. The lack of significant anticholinergic and antihistaminergic
      side effects results in better tolerability and better compliance. While SSRIs
      are not free of side effects, those that occur can usually be managed in the
      context of continued treatment of the depressive episode. This article reviews
      data from controlled studies of the treatment of geriatric depression for all
      four available SSRIs in the United States-fluoxetine, sertraline, paroxetine, and
      fluvoxamine (which is approved in the United States for treating only obsessive
      compulsive disorder). Differences among the SSRIs are examined, particularly with
      reference to clinically relevant differences in pharmacokinetics and hepatic
      isoenzyme inhibition. Principles of clinical management are discussed, including
      dose initiation and titration, side effect management, augmentation and
      combinations, and length of treatment. Finally, the use of SSRIs in special
      elderly populations is discussed.

PMID- 8647789
TI  - Efficacy and tolerability of antidepressant therapy in the old-old.
AB  - As the number of elderly increases worldwide, there will be a concurrent increase
      in the absolute number of people over 70 years of age who suffer from major
      depressive disorders. There is a paucity of research in this old-old population,
      although each of the following drugs has been studied in at least one clinical
      drug trial: amitriptyline, bupropion, dothiepin, fluoxetine, mianserin,
      nortriptyline, paroxetine, and sertraline. The results to date, though limited,
      suggest similar efficacy and greater tolerability of serotonin selective reuptake
      inhibitors compared with tricyclic antidepressants in the elderly.

PMID- 8647790
TI  - Cognitive-behavioral therapy and treatment for late-life depression.
AB  - Cognitive-behavioral therapy is a brief psychotherapy stemming from a model that
      emphasizes the importance of distorted thoughts and the lack of pleasurable
      activities in the development of affective disorders. The focus of the therapy
      can be on either eliminating distorted thought systems or increasing the number
      of pleasant events that occur on a daily basis, or both. The highly structured
      therapy presents various skills for patients to learn through class exercises and
      homework assignments. Older adults respond well to cognitive-behavioral therapy,
      reporting that they appreciate the structure and the opportunity to learn skills
      that can help when they are confronted with new stresses. Many also like the
      focus on here-and-now problems rather than the past. A few treatment
      modifications are necessary to accommodate community elders complaining of
      depression. Generally, information must be presented more slowly, taking
      advantage of multiple modes of presentation. To maintain an active learning
      process, elder patients should be asked frequently to summarize the material
      being presented. They should also be given handouts of complex materials and
      encouraged to maintain notebooks. Other modifications may be required for special
      populations of older patients.

PMID- 8647791
TI  - Antidepressants and cognitive impairment in the elderly.
AB  - Cognitive impairment is an important consideration in the treatment of depression
      in the elderly because such impairment increases with age, is a symptom of
      depression, and is a side effect of many antidepressant drugs. Older depressed
      patients are more likely to suffer acute cognitive impairment from medications
      including antidepressants, often superimposed on the cognitive impairment of
      depression. Even mild cognitive impairment can contribute to increased disability
      in the elderly. The occurrence of severe cognitive impairment (i.e., delirium)
      with tricyclic antidepressants is probably related to anticholinergic effects.
      Since the serotonin selective reuptake inhibitors (SSRIs) and some reversible
      inhibitors of monoamine oxidase (RIMAs) have little if any anticholinergic
      activity, these agents are expected to result in less cognitive impairment. This
      hypothesis is supported by a variety of comparative studies. The SSRIs and some
      RIMAs also have fewer additive effects with other psychoactive agents. Additional
      evidence suggests that some SSRIs and RIMAs may even improve cognitive functions
      through mechanisms separate from their antidepressant effects.

PMID- 8647793
TI  - OCD: where the serotonin selectivity story begins.
AB  - Since concomitant anxiety is frequent and prominent, obsessive-compulsive
      disorder (OCD) is classified as an anxiety disorder. However, effective
      antidepressant and anxiolytic agents that are nonserotonin-selective are
      generally ineffective in significantly reducing OCD symptoms, while the potent
      serotonin reuptake inhibitor, the tricyclic clomipramine, and several serotonin
      selective reuptake inhibitors (SSRIs) are efficacious. These results suggest that
      serotonergic transmission may be important in achieving significant antiobsessive
      efficacy. Although no significant differences in efficacy between SRIs and SSRIs
      have been demonstrated in the treatment of OCD, there are important differences
      in side effect profiles and pharmacokinetic factors. Further research in the
      treatment of OCD is required on comparative efficacy of SRIs, the choice of SRI
      agents following initial nonresponse, and effects resulting from the long-term
      use of SRIs.

PMID- 8647792
TI  - The diagnosis and treatment of late-life depression.
AB  - Depression in the elderly occurs commonly and is a major public health problem.
      Unfortunately, despite the availability of safe and effective treatments, late
      life depression is often underdiagnosed because the symptoms are unrecognized by
      the patient and the health care provider. Late-life depression is described in
      this review, with a focus on symptoms, prevalence, diagnosis, and available
      treatment modalities.

PMID- 8647794
TI  - Panic disorder and agoraphobia: hypothesis hothouse.
AB  - Panic disorder and agoraphobia have been postulated to occur when (1) fear is
      elicited by some automatic mechanism that requires catastrophic cognition, (2)
      there is a flaw in the physiology of fear, with special reference to the
      noradrenergic system, or (3) a putative suffocation alarm mechanism sends out
      false alarms. The presence of a suffocation alarm system has been supported by
      studies of children who lack this protective mechanism because they suffer from
      congenital central hypoventilation syndrome. Antidepressants with serotonin
      activity seem to control panic disorder by down-regulating the suffocation alarm
      system. Serotonin selective reuptake inhibitors (SSRIs) are among the most
      effective drugs for panic disorder, emphasizing the role of serotonin in
      respiratory regulation. Dyspnea and hyperventilation are the cardinal signs of a
      panic attack. Because carbon monoxide (CO) does not cause panic, it may sabotage
      the suffocation alarm system by acting as an inhibitory neurotransmitter within
      the carotid body.

PMID- 8647795
TI  - Social phobia: everyone's disorder?
AB  - Several findings suggest that serotonin dysfunction may play at least a partial
      role in the etiology of social phobia. The cortisol response to fenfluramine, a
      serotonin agonist, is enhanced in patients with social phobia. Serotonin may be a
      common denominator between the blushing commonly seen in social phobics and the
      cutaneous flushing occurring in patients with carcinoid syndrome, although this
      is unlikely. Drugs that have demonstrated effectiveness in social phobia include
      the serotonin selective reuptake inhibitors (SSRIs), clonazepam (a benzodiazepine
      that potentiates serotonin function and synthesis), monoamine oxidase inhibitors
      (MAOIs) (which block the oxidative deamination of serotonin), and beta
      adrenoceptor blockers (which control the synthesis of melatonin from serotonin).
      A variety of beta-blockers, some acting centrally and some peripherally, have
      been effective in the treatment of performance anxiety, a specific form of social
      phobia.

PMID- 8647796
TI  - Anxiety disorders: the role of serotonin.

PMID- 8647797
TI  - Behavior therapy: endogenous serotonin therapy?
AB  - In numerous controlled trials, behavior therapy involving exposure and ritual
      prevention, either alone or in combination with pharmacotherapy, has been found
      to be highly effective in treating obsessive-compulsive disorder (OCD) and panic
      disorder. Although some animal research suggests that serotonin level affects
      classical conditioning, there is little knowledge of the effect of conditioning
      or reconditioning on serotonin. Indirect support for such an effect comes from
      the neuroimaging research finding that behavior therapy, as well as
      pharmacotherapy with a serotonin reuptake inhibitor, normalizes glucose
      metabolism in successfully treated OCD patients. A novel, automated approach to
      making behavior therapy more widely available via telephone is discussed.

PMID- 8647798
TI  - Serotonin receptor specificity in anxiety disorders.
AB  - The demonstrated efficacy in anxiety disorders of drugs such as buspirone or
      fluoxetine has emphasized the importance of 5-hydroxytryptamine (5-HT or
      serotonin). Buspirone is a selective agonist at a subtype of serotonin receptor
      termed 5-HT1A, whereas fluoxetine is a selective inhibitor of the reuptake of 5
      HT. At least 14 types of mammalian serotonin receptors have been isolated and
      classified into seven major families, using pharmacologic, transductional, and
      structural criteria. The subtypes of serotonin receptors are localized in
      different regions of the brain. Selective compounds for particular subtypes of
      serotonin receptors may yield selective pharmacologic effects. Since the latency
      between the initiation of treatment with an SSRI and the appearance of clinical
      effects may be due to the desensitization of presynaptic autoreceptors, the
      development of drugs to decrease latency is an active area of investigation. This
      article provides a brief overview of the physiology and pharmacology of serotonin
      systems so that the relationship between serotonin compounds and anxiety can be
      better understood.

PMID- 8647799
TI  - Oligosaccharides containing beta 1,4-linked N-acetylgalactosamine, a paradigm for
      protein-specific glycosylation.

PMID- 8647800
TI  - Insulin stimulates the serine phosphorylation of the signal transducer and
      activator of transcription (STAT3) isoform.
AB  - Insulin stimulation of Chinese hamster ovary cells expressing the human insulin
      receptor and differentiated 3T3L1 adipocytes resulted in a time-dependent
      reduction in the SDS-polyacrylamide gel electrophoretic mobility of STAT3. The
      decreased STAT3 mobility initially occurred by 2 min and was quantitative by 5
      min. In addition, the change in STAT3 mobility was concentration-dependent and
      was detectable at 0.3 nm insulin with maximal effect between 1 and 3 nm. Although
      both these cell types also express the STAT1 alpha, STAT1 beta, STAT5, and STAT6
      isoforms, only STAT3 was observed to undergo an insulin-dependent reduction in
      mobility. Immuno-precipitation of STAT1 and STAT3 from 32P-labeled cells
      demonstrated that only STAT3 was phosphorylated in response to insulin whereas
      phosphoamino acid analysis indicated that this phosphorylation event occurred
      exclusively on serine residues. Furthermore, treatment of cell extracts with
      alkaline phosphatase reversed the insulin-stimulated decrease in STAT3 mobility.
      Together, these data demonstrate that insulin is a specific activator of STAT3
      serine phosphorylation without affecting the other STAT isoforms.

PMID- 8647801
TI  - A mammalian patched homolog is expressed in target tissues of sonic hedgehog and
      maps to a region associated with developmental abnormalities.
AB  - Drosophila patched is a segment polarity gene required for the correct patterning
      of larval segments and imaginal discs during fly development and has a close
      functional relationship with hedgehog. We have isolated a complete human PATCHED
      cDNA sequence, which encodes a putative protein of 1296 amino acids, and displays
      39% identity and 60% similarity to the Drosophila PATCHED protein. Hydropathy
      analysis suggests that human PATCHED is an integral membrane protein with a
      pattern of hydrophobic and hydrophilic stretches nearly identical to that of
      Drosophila patched. In the developing mouse embryo, patched is initially detected
      within the ventral neural tube and later in the somites and limb buds. Expression
      in the limb buds is restricted to the posterior ectoderm surrounding the zone of
      polarizing activity. The results show that patched is expressed in target tissues
      of sonic hedgehog, a murine homolog of Drosophila hedgehog suggesting that
      patched/hedgehog interactions have been conserved during evolution. Human PATCHED
      maps to human chromosome 9q22.3, the candidate region for the nevoid basal cell
      carcinoma syndrome. Patched expression is compatible with the congenital defects
      observed in the nevoid basal cell carcinoma syndrome.

PMID- 8647802
TI  - Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the
      Ras pathway.
AB  - A human cytoplasmic signaling protein has been cloned that possesses the same
      structural arrangement of SH3-SH2-SH3 domains as Grb2. This protein is designated
      Grap for Grb2-related adaptor protein. The single 2.3-kilobase (kb) grap
      transcript was expressed predominantly in thymus and spleen, while the
      ubiquitously expressed grb2 gene produced two mRNA species of 3.8 and 1.5 kb.
      Grap and Grb2 consist of 217 amino acids and share 59% amino acid sequence
      identity, with highest homology in the N-terminal SH3 domain. The GrapSH2 domain
      interacts with ligand-activated receptors for stem cell factor (c-kit) and
      erythropoietin (EpoR). Grap also forms a stable complex with the Bcr-Abl
      oncoprotein via its SH2 domain in K562 cells. Furthermore, Grap is associated
      with a Ras guanine nucleotide exchange factor mSos1, primarily through its N
      terminal SH3 domain. These results show that a family of Grb2-like proteins exist
      and couple signals from receptor and cytoplasmic tyrosine kinases to the Ras
      signaling pathway.

PMID- 8647803
TI  - Phosphatidylinositol 3-kinase is an early intermediate in the G beta gamma
      mediated mitogen-activated protein kinase signaling pathway.
AB  - The beta gamma-subunit of Gi mediates mitogen-activated protein (MAP) kinase
      activation through a signaling pathway involving Shc tyrosine phosphorylation,
      subsequent formation of a multiprotein complex including Shc, Grb2, and Sos, and
      sequential activation of Ras, Raf, and MEK. The mechanism by which G beta gamma
      mediates tyrosine phosphorylation of Shc, however, is unclear. This study
      assesses the role of phosphatidylinositol 3-kinase (PI-3K) in G beta gamma
      mediated MAP kinase activation. We show that Gi-coupled receptor- and G beta
      gamma-stimulated MAP kinase activation is attenuated by the PI-3K inhibitors
      wortmannin and LY294002 or by over expression of a dominant negative mutant of
      the p85 subunit of PI-3K. Wortmannin and LY294002 also inhibit Gi-coupled
      receptor-stimulated Ras activation. The PI-3K inhibitors do not affect MAP kinase
      activation stimulated by over-expression of Sos, a constitutively active mutant
      of Ras, or a constitutively active mutant of MEK. These results demonstrate that
      PI-3K activity is required in the G beta gamma-mediated MAP kinase signaling
      pathway at a point upstream of Sos and Ras activation.

PMID- 8647804
TI  - Evidence for a physical association between the Shc-PTB domain and the beta c
      chain of the granulocyte-macrophage colony-stimulating factor receptor.
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates the growth
      and function of several myeloid cell types at different stages of maturation. The
      effects of GM-CSF are mediated through a high affinity receptor that is composed
      of two chains: a unique, ligand-specific alpha chain and a beta common chain
      (beta c) that is also a component of the receptors for interleukin 3 (IL-3) and
      IL-5. Beta c plays an essential role in the transduction of extra cellular
      signals to the nucleus through its recruitment of secondary messengers. Several
      downstream signaling events induced by GM-CSF stimulation have been described,
      including activation of tyrosine kinases and tyrosine phosphorylation of cellular
      proteins (including beta c) and activation of the Ras/mitogen-activated protein
      kinase and the JAK/STAT pathways. A region within the beta c cytoplasmic tail
      (amino acids 517-763) has been reported to be necessary for tyrosine
      phosphorylation of the adapter protein, Shc, and for the subsequent GM-CSF
      induced activation of Ras. In this paper, we describe a physical association
      between the tyrosine phosphorylated GM-CSF receptor (GMR)-beta c chain and Shc in
      vivo. Using a series of cytoplasmic truncation mutants of beta c and various
      mutant Shc proteins, we demonstrate that the N-terminal phosphotyrosine-binding
      (PTB) domain of Shc binds to a short region of beta c (amino acids 549-656) that
      contains Tyr577. Addition of a specific phosphopeptide encoding amino acids
      surrounding this tyrosine inhibited the interaction between beta c and shc.
      Moreover, mutation of a key residue within the phosphotyrosine binding pocket of
      the Shc-PTB domain abrogated its association with beta c. These observations
      provide an explanation for the previously described requirement for Tyr577 of
      beta c for GM-CSF-induced tyrosine phosphorylation of Shc and have implications
      for Ras activation through the GM-CSF, IL-3, and IL-5 receptors.

PMID- 8647805
TI  - Enzyme-DNA interactions required for efficient nucleotide incorporation and
      discrimination in human DNA polymerase beta.
AB  - In the crystal structure of a substrate complex, the side chains of residues
      Asn279, Tyr271, and Arg283 of DNA polymerase beta are within hydrogen bonding
      distance to the bases of the incoming deoxynucleoside 5'-triphosphate (dNTP), the
      terminal primer nucleotide, and the templating nucleotide, respectively
      (Pelletier, H., Sawaya, M. R., Kumar, A., Wilson, S. H., and Kraut, J. (1994)
      Science 264, 1891-1903). We have altered these side chains through individual
      site-directed mutagenesis. Each mutant protein was expressed in Escherichia coli
      and was soluble. The mutant enzymes were purified and characterized to probe
      their role in nucleotide discrimination and catalysis. A reversion assay was
      developed on a short (5 nucleotide) gapped DNA substrate containing an opal codon
      to assess the effect of the amino acid substitutions on fidelity. Substitution of
      the tyrosine at position 271 with phenylalanine or histidine did not influence
      catalytic efficiency (kcat/Km) or fidelity. The hydrogen bonding potential
      between the side chain of Asn279 and the incoming nucleotide was removed by
      replacing this residue with alanine or leucine. Although catalytic efficiency was
      reduced as much as 17-fold for these mutants, fidelity was not. In contrast, both
      catalytic efficiency and fidelity decreased dramatically for all mutants of
      Arg283 (Ala > Leu > Lys). The fidelity and catalytic efficiency of the alanine
      mutant of Arg283 decreased 160- and 5000-fold, respectively, relative to wild
      type enzyme. Sequence analyses of the mutant DNA resulting from short gap-filling
      synthesis indicated that the types of base substitution errors produced by the
      wild-type and R283A mutant were similar and indicated misincorporations resulting
      in frequent T.dGTP and A.dGTP mispairing. With R283A, a dGMP was incorporated
      opposite a template thymidine as often as the correct nucleotide. The x-ray
      crystallographic structure of the alanine mutant of Arg283 verified the loss of
      the mutated side chain. Our results indicate that specific interactions between
      DNA polymerase beta and the template base, but not hydrogen bonding to the
      incoming dNTP or terminal primer nucleotide, are required for both high catalytic
      efficiency and nucleotide discrimination.

PMID- 8647806
TI  - DAB389 interleukin-2 receptor binding domain mutations. Cytotoxic probes for
      studies of ligand-receptor interactions.
AB  - Site-directed mutagenesis was used to generate point mutations in the diphtheria
      toxin-related fusion protein, DAB389 interleukin-2 (IL-2). Thr-439, in the IL-2
      receptor binding domain of the fusion toxin, was changed to a Pro residue. The
      resultant fusion toxin, DAB389 IL-2(T439P), was 300-fold less cytotoxic than wild
      type DAB389 IL-2, partially as the result of a 100-fold decrease in binding
      affinity for the high affinity form of the IL-2 receptor. However, DAB389 IL
      2(T439P) stimulated DNA synthesis to a greater extent than expected. Studies of
      intoxication kinetics indicated that the increased stimulation might result from
      an increased contact time between the mutated IL-2 receptor binding domain and
      the receptor, perhaps due to a decreased internalization rate. Another mutant,
      DAB389 IL-2(Q514D), in which a Gln residue at position 514 was changed to an Asp,
      was 2000-fold less cytotoxic than wild type DAB389 IL-2. This mutant had a 50
      fold decrease in binding affinity, did not stimulate DNA synthesis and also had a
      reduced rate of intoxication. Gln-514 appears to play a role in receptor binding
      and activation, whereas Thr-439 appears to be involved with receptor binding and
      signaling internalization of the fusion toxin-receptor complex.

PMID- 8647807
TI  - The Arabidopsis thaliana UBC7/13/14 genes encode a family of multiubiquitin chain
      forming E2 enzymes.
AB  - Covalent modification of proteins by attachment of multiubiquitin chains serves
      as an essential signal for selective protein degradation in eukaryotes. The
      specificity of ubiquitin-protein conjugation is controlled in part by a diverse
      group of ubiquitin-conjugating enzymes (E2s or UBCs). We have previously reported
      that the product of the wheat TaUBC7 gene recognizes ubiquitin as a substrate for
      ubiquitination in vitro, catalyzing the condensation of free ubiquitin into
      multiubiquitin chains linked via lysine 48 (van Nocker, S., and vierstra, R. D.
      (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 10297-10301). Based on this activity,
      this E2 may play a central role in the ubiquitin proteolytic pathway by
      assembling chains in vivo. Here, we describe the cloning and characterization of
      a three-member gene family from Arabidopsis thaliana (designated AtUBC7/13/14)
      encoding structural homologs of TaUBC7. Like TaUBC7, recombinant AtUBC7/13/14
      proteins formed multiubiquitin chains in vitro. AtUBC7/13/14 mRNAs were found in
      all tissues examined, and unlike related UBCs from yeast, the levels of mRNA were
      not elevated by heat stress or cadmium exposure. Transgenic Arabidopsis were
      engineered to express increased levels of active AtUBC7, for the first time
      altering the level of an E2 in a higher eukaryote. Plants expressing high levels
      of AtUBC7 exhibited no phenotypic abnormalities and were not noticeably enriched
      in multiubiquitinated conjugates. These findings indicate that the in vivo
      synthesis of multiubiquitin chains is not rate-limited by the abundance of AtUC7
      and/or involves other, yet undefined components.

PMID- 8647808
TI  - Induction of high affinity glutamate transport activity by amino acid deprivation
      in renal epithelial cells does not involve an increase in the amount of
      transporter protein.
AB  - In renal epithelial cells amino acid deprivation induces an increase in L-Asp
      transport with a doubling of the Vmax and no change in Km (4.5 micronM) in a
      cycloheximide-sensitive process. The induction of sodium-depending L-aspartate
      transport was inhibited by single amino acids that are metabolized to produce
      glutamate but not by those that do not produce glutamate. The transaminase
      inhibitor aminooxyacetate in glutamine-free medium caused a decrease in cell
      glutamate content and an induction of glutamate transport. In complete medium
      aminooxyacetate neither decreased cell glutamate nor increased transport
      activity. These results are consistent with a triggering of induction of
      transport by low intracellular glutamate concentrations. High affinity glutamate
      transport in these cells is mediated by the excitatory amino acid carrier 1
      (EAAC1) gene product. Western blotting using antibodies to the C-terminal region
      of EAAC1 showed that there is no increase in the amount of EAAC1 protein on
      prolonged incubation in amino acid-free medium. Conversely, the induction of high
      affinity glutamate transport by hyperosmotic shock was accompanied by an increase
      in EAAC1 protein. It is proposed that low glutamate levels lead to the induction
      of a putative protein that activates the EAAC1 transporter. A model illustrating
      such a mechanism is described.

PMID- 8647809
TI  - Gap junctional intercellular communication contributes to hormonal responsiveness
      in osteoblastic networks.
AB  - To evaluate whether intercellular coupling via connexin43 gap junction channels
      modulates hormonal responsiveness of cells in contact, we have created
      osteoblastic cell lines deficient in connexin43. Osteoblastic ROS 17/2.8 cells
      were transfected with a plasmid containing an antisense cDNA construct to rat
      connexin43. Control transfection did not alter cell-to-cell coupling nor
      connexin43 mRNA or protein expression relative to nontransfected ROS 17/2.8
      cells. In contrast, stable transfection with an antisense connexin43 cDNA
      resulted in two clones, RCx4 and RCx16, which displayed significant decreases in
      connexin43 mRNA and protein expression and were dramatically deficient in cell-to
      cell coupling. Phenotypically, all transfectants retained osteoblastic
      characteristics. However, cells rendered connexin43-deficient through antisense
      transfection displayed a dramatic attenuation in the cAMP response to parathyroid
      hormone. Alterations in hormonal responses were not due to changes in parathyroid
      hormone receptor number or binding kinetics nor to alterations in adenylyl
      cyclase activity. These results indicate that gap junctions may be required for
      mediating hormonal signals. Furthermore, these experiments support a regulatory
      role for connexin43-mediated intercellular communication in the modulation of
      hormonal responses within elaborately networked bone cells.

PMID- 8647810
TI  - Neutralization and transfer of lipopolysaccharide by phospholipid transfer
      protein.
AB  - Phospholipid transfer protein (PLTP) and lipopolysaccharide-binding protein (LPB)
      are lipid transfer proteins found in human plasma. PLTP shares 24% sequence
      similarity with LBP. PLTP mediates the transfer and exchange of phospholipids
      between lipoprotein particles, whereas LBP transfers bacterial lipopolysaccharide
      (LPS) either to lipoprotein particles or to CD14, a soluble and cell-surface
      receptor for LPS. We asked whether PLTP could interact with LPS and mediate the
      transfer of LPS to lipoproteins or to CD14. PLTP was able to bind and neutralize
      LPS: incubation of LPS with purified recombinant PLTP (rPLTP) resulted in the
      inhibition of the ability of LPS to stimulate adhesive responses of neutrophils,
      and addition of rPLTP to blood inhibited cytokine production in response to LPS.
      Transfer of LPS by rPLTP was examined using fluorescence dequenching experiments
      and native gel electrophoresis. The results suggested that rPLTP was able to
      mediate the exchange of LPS between micelles and the transfer of LPS to
      reconstituted HDL particles, but it did not transfer LPS to CD14. Consonant with
      these findings, rPLTP did not mediate CD14-dependent adhesive responses of
      neutrophils to LPS. These results suggest that while PLTP and LBP both bind and
      transfer LPS, PLTP is unable to transfer LPS to CD14 and thus does not mediate
      responses of cells to LPS.

PMID- 8647811
TI  - AUF1 binding affinity to A+U-rich elements correlates with rapid mRNA
      degradation.
AB  - Rapid degradation of many labile mRNAs is regulated in part by an A + U-rich
      element (ARE) in their 3'-untranslated regions. Extensive mutational analyses of
      various AREs have identified important components of the ARE, such as the nonamer
      motif UUAUUUAUU, two copies of which serve as a potent mRNA destabilizer. To
      investigate the roles of trans-acting factors in ARE-directed mRNA degradation,
      we previously purified and molecularly cloned the RNA-binding protein AUF1 and
      demonstrated that both cellular and recombinant AUF1 bind specifically to AREs as
      shown by UV cross-linking assays in vitro. In the present work, we have examined
      the in vitro RNA-binding properties of AUF1 using gel mobility shift assays with
      purified recombinant His6-AUF1 fusion protein. We find that ARE binding
      affinities of AUF1 correlate with the potency of an ARE to direct degradation of
      a heterologous mRNA. These results support a role for AUF1 in ARE-directed mRNA
      decay that is based upon its affinity for different AREs.

PMID- 8647812
TI  - A di-hydrophobic Leu-Val motif regulates the basolateral localization of CD44 in
      polarized Madin-Darby canine kidney epithelial cells.
AB  - Both in vivo and in vitro the distribution of the resident plasma membrane
      adhesion protein, CD44, is restricted to the basolateral domain of polarized
      epithelial cells, suggesting a role in interepithelial interactions. To determine
      how this localization might be regulated a range of CD44 cytoplasmic domain
      mutations were generated and a minimal 5 amino acid sequence, His330-Leu-Val-Asn
      Lys334, was identified which when deleted results in expression of CD44 on the
      apical microvillal membrane. Further mutagenesis throughout this regions
      pinpointed a critical di-hydrophobic motif, Leu331/Val332. The ability of wild
      type but not mutant CD44 cytoplasmic domains to redirect an apically targeted
      protein, placental alkaline phosphatase, to the basolateral plasma membrane
      demonstrates that this sequence can function as a dominant localization signal.
      This His330-Lys334 sequence is spatially separate from other CD44 regulatory
      elements and as discussed here, a comparison with known basolateral sorting
      sequences identified in other transmembrane proteins suggests that a distinct
      mechanism operates to retain resident plasma membrane proteins in their correct
      plasma membrane subdomains.

PMID- 8647813
TI  - Structural studies of human autoantibodies. Crystal structure of a thyroid
      peroxidase autoantibody Fab.
AB  - The three-dimensional structure of the Fab of TR1.9, a high-affinity IgG1, kappa
      human autoantibody to thyroid peroxidase, was determined crystallographically to
      a resolution of 2.0 A. The combining site was found to be relatively flat, like
      other antibodies to large proteins. Sequence differences from the most closely
      related germline genes mainly occur at positions occupied by residues with
      outward-pointing side chains. An increased deformability of the second and third
      complementarity-determining regions of the heavy chain may result from the
      replacement of two germline asparagines and the presence of several glycines, and
      may allow "induced fit" in the binding to antigen. Four exposed charged residues,
      resulting from the use of a particular D (diversity) and J (joining) segments in
      the assembly of the heavy chain, may contribute to the high affinity of antigen
      binding. The crystal structure of TR1.9 Fab is the first for a human IgG high
      affinity autoantibody.

PMID- 8647814
TI  - Characterization of the human cyclin-dependent kinase 2 gene. Promoter analysis
      and gene structure.
AB  - Cyclin-dependent kinase 2 is a serine/threonine protein kinase essential for
      progression of the mammalian cell cycle from G1 to S phase. CDK2 mRNA has been
      shown to be induced by serum in several cultured cell types. Therefore, we set
      out to identify elements that regulate the transcription of the human CDK2 gene
      and to characterize its structure. This paper describes the cloning of
      approximately 2.4-kilobase pair genomic DNA fragment from the upstream region of
      the human CDK2 gene. This fragment contains five transcription initiation sites
      within a 72-nucleotide stretch. A 200-base pair sub-fragment that confers 70% of
      maximal basal promoter activity was shown to contain two synergistically acting
      Sp1 sites. However, a much larger DNA fragment containing approximately 1.7
      kilobase pairs of upstream sequence is required for induction of promoter
      activity following serum stimulation. The intron exon boundaries of seven exons
      in this gene were also identified, and this information will be useful for
      analyzing genomic abnormalities associated with CDK2.

PMID- 8647815
TI  - Spermidine-preferential uptake system in Escherichia coli. Identification of
      amino acids involved in polyamine binding in PotD protein.
AB  - Spermidine-binding sites on PotD protein, substrate-binding protein in periplasm,
      in the spermidine-preferential uptake system in Escherichia coli were studied by
      measuring polyamine transport activities of right-side-out membrane vesicles with
      mutated PotD proteins prepared by site-directed mutagenesis of the potD gene and
      by measuring polyamine binding activities of these mutated PotD proteins.
      Polyamine transport activities of the mutated PotD proteins paralleled their
      polyamine binding activities. It was found that Trp-34, Thr-35, Glu-36, Tyr-37,
      Ser-83, Tyr-85, Asp-168, Glu-171, Trp-229, Trp-255, Asp-257, Tyr-293, and Gln-327
      of PotD protein were involved in the binding to spermidine. When spermidine
      uptake activities were measured in intact cells expressing the mutated PotD
      proteins, it was found that Glu-171, Trp-255, and Asp-257 were more strongly
      involved in the binding of spermidine to PotD protein than the other amino acids
      listed above. The dissociation constants of spermidine for the mutated PotD
      proteins at Glu-171, Trp-255, and Asp-257 increased greatly in comparison with
      those for the other mutated PotD proteins. Since these three amino acids clearly
      interact with the diaminopropane moiety of spermidine, the results are in
      accordance with the finding that PotD protein has a higher affinity for
      spermidine than for putrescine. Putrescine was found to bind at the position of
      the diaminobutane moiety of spermidine.

PMID- 8647816
TI  - AGN193109 is a highly effective antagonist of retinoid action in human
      ectocervical epithelial cells.
AB  - Retinoids are important physiological agents that regulate epithelial cell
      differentiation and proliferation. The importance of these agents in regulating
      growth, development, and differentiation has led to a search for new retinoid
      agonists and antagonists. In the present manuscript we show that AGN193109, a
      retinoid analog, is an efficient antagonist of retinoid action in human cervical
      epithelial cells. Treatment of ECE16-1 cells with natural or synthetic retinoids
      reduces cytokeratin K5, K6, K14, K16, and K17 levels, increases cytokeratin K7,
      K8, and K19 levels, increases retinoic acid receptor-beta (RAR beta) mRNA levels,
      suppresses proliferation, and alters cell morphology. Co-treatment with AGN193109
      prevents these responses. Half-maximal and maximal antagonism is observed at a
      molar ratio of AGN193109: retinoid agonist of 1:1 and 10:1, respectively. When
      administered alone AGN193109 has no agonist activity. Thus, AGN193109, which
      binds to RAR alpha, RAR beta, and RAR gamma with Kd values = 2,2, and 3 nm,
      respectively, but is unable to bind to the retinoid X receptors, is a highly
      active antagonist of retinoid action in ECE16-1 cells.

PMID- 8647817
TI  - Role of the "helix clamp" in HIV-1 reverse transcriptase catalytic cycling as
      revealed by alanine-scanning mutagenesis.
AB  - Residues 259-284 of HIV-1 reverse transcriptase exhibit sequence homology with
      other nucleic acid polymerases and have been termed the "helix clamp" (Hermann,
      T., Meier, T., Gotte, M., and Heumann, H. (1994) Nucleic Acids Res. 22, 4625
      4633), since crystallographic evidence indicates these residues are part of two
      alpha-helices (alpha H and alpha I) that interact with DNA. Alanine-scanning
      mutagenesis has previously demonstrated that several residues in alpha H make
      important interactions with nucleic acid and influence frameshift fidelity. To
      define the role of alpha I (residues 278-286) during catalytic cycling, we
      performed systematic site-directed mutagenesis from position 277 through position
      287 by changing each residue, one by one, to alanine. Each mutant protein was
      expressed and, except for L283A and T286A, was soluble. The soluble mutant
      enzymes were purified and characterized. In contrast to alanine mutants of alpha
      H, alanine substitution in alpha I did not have a significant effect on
      template.primer (T.P) binding as revealed by a lack of an effect on Km, T.P, Ki
      for 3'-azido-2',3'-dideoxythymidine 5'-triphosphate, koff, T.P and processivity.
      Consistent with these observations, the fidelity of the mutant enzymes was not
      influenced. However, alanine mutagenesis of alpha I lowered the apparent activity
      of every mutant relative to wild-type enzyme. Titration of two mutants exhibiting
      the lowest activity with T.P (L282A and R284A) demonstrated that these mutant
      enzymes could bind T.P stoichiometrically and tightly. In contrast, active site
      concentrations determined from "burst" experiments suggest that the lower
      activity is due to a smaller populations of enzyme bound productively to T.P. The
      putative electrostatic interactions between the basic side chains of the helix
      clamp and the DNA backbone are either very weak or kinetically silent. In
      contrast, interactions between several residues of alpha H and the DNA minor
      groove, 3-5 nucleotides from the 3'-primer terminus, are suggested to be critical
      for DNA binding and fidelity.

PMID- 8647818
TI  - Structural requirements for RNA editing in glutamate receptor pre-mRNAs by
      recombinant double-stranded RNA adenosine deaminase.
AB  - Pre-mRNAs for brain-expressed ionotropic glutamate receptor subunits undergo RNA
      editing by site-specific adenosine deamination, which alters codons for molecular
      determinants of channel function. This nuclear process requires double-stranded
      RNA structures formed by exonic and intronic sequences in the pre-mRNA and is
      likely to be catalyzed by an adenosine deaminase that recognizes these structures
      as a substrate. DRADA, a double-stranded RNA adenosine deaminase, is a candidate
      enzyme for L-glutamate-activated receptor channel (GluR) pre-mRNA editing. We
      show here that DRADA indeed edits GluR pre-mRNAs, but that it displays
      selectivity for certain editing sites. Recombinantly expressed DRADA, both in its
      full-length form and in an N-terminally truncated version, edited the Q/R site in
      GluR6 pre-mRNA and the R/G site but not the Q/R site of GluR-B pre-mRNA. This
      substrate selectivity correlated with the base pairing status and sequence
      environment of the editing-targeted adenosines. The Q/R site of GluR-B pre-mRNA
      was edited by an activity partially purified from HeLa cells and thus differently
      structured editing sites in GluR pre-mRNAs appear to be substrates for different
      enzymatic activities.

PMID- 8647819
TI  - Cloning of a cDNA encoded by a member of the Arabidopsis thaliana ATP sulfurylase
      multigene family. Expression studies in yeast and in relation to plant sulfur
      nutrition.
AB  - An Arabidopsis thaliana ATP sulfurylase cDNA (ASA1), encoding a putative
      chloroplastic isoform, has been cloned by functional complementation of a
      Saccharomyces cerevisiae (met3) ATP sulfurylase mutant which also has a poor
      sulfate transport capacity. Homologous complementation of the yeast mutant with
      the ATP sulfurylase gene restores both ATP sulfurylase function and sulfate
      transport. Heterologous complementation restores only ATP sulfurylase function as
      demonstrated by low [35S]sulfate influx measurements and selenate resistance. A
      structural relationship between ATP sulfurylase and sulfate membrane transporters
      in yeast is proposed. The sequence of ASA1 is homologous to deduced plant and
      animal ATP sulfurylase sequences. Analyses indicate a potential tyrosine
      phosphorylation site which is unique to higher eukaryote sequences. ASA1 is
      specified by a single copy gene that is part of a multigene family in A.
      thaliana. At least two ASA1 copies are found in Brassica napus plants. ASA1
      transcripts were found in all organs examined, with the highest transcript
      abundance and ATP sulfurylase activity in leaves or cotyledons. Absence of
      sulfate from culture media transiently increased B. napus transcript abundance,
      indicating that initially, the response to sulfate deprivation is
      transcriptionally regulated.

PMID- 8647820
TI  - Promotion of fibroblast adhesion by triple-helical peptide models of type I
      collagen-derived sequences.
AB  - The dissection of the activities mediated by type I collagen requires an approach
      by which the influence of triple-helical conformation can be evaluated. The alpha
      1 beta 1 and alpha 2 beta 1 integrin binding sites within type I collagen are
      dependent upon triple-helical conformation and contained within residues 14-822
      from alpha 1(I). Seven alpha 1(I)-derived triple-helical peptides (THPs) were
      synthesized based on charge clustering (alpha 1(I)256-270, alpha 1(I)385-396,
      alpha 1(I)406-417, alpha 1(I)415-423, alpha 1(I)448-456, alpha 1(I)496-507, and
      alpha 1(I)526-537). Three additional THPs were synthesized (alpha 1(I)85-96,
      alpha 1(I)433-441, and alpha 1(I)772-786) based on previously described or
      proposed activities (Kleinman, H. K., McGoodwin, E.B., Martin, G. R., Klebe, R.
      J., Fietzek, P. P., and Wooley, D. E. (1978) J. Biol. Chem. 253, 5642-5646;
      Staatz, W. D., Foik, K. F., Zutter, M. M., Adams, S. P., Rodriquez, B. A., and
      Santoro, S. A. (1991) J. Biol. Chem. 266, 7363-7367; San Antonio, J. D., Lander,
      A. D., Karnovsky, M. J., and Slayter, H. S. (1994) J. Cell Biol. 125, 1179-1188).
      Of the ten THPs, alpha 1(I)772-786 THP had the greatest activity, with half
      maximal normal dermal fibroblast adhesion occurring at a peptide concentration of
      1.6 microM. Triple-helicity was essential for activity of this sequence, as the
      non-triple-helical peptide analog (alpha 1(I)772-786 SSP) exhibited considerably
      lower levels of cell adhesion promotion even at peptide concentrations as high as
      100 microM. Within the sequence itself, residues 784-786 (Gly-Leu-Hyp) were
      important for cellular recognition, as the alpha 1(I)772-783 THP had greatly
      reduced cell adhesion activity compared with alpha 1(I)772-786 THP. Preliminary
      studies indicate that the beta 1 integrin subunit mediates fibroblast adhesion to
      alpha 1(I)772-786 THP. The identification of fibroblast integrin binding sites
      within type I collagen may have important implications for understanding collagen
      metabolism.

PMID- 8647821
TI  - Equilibrium binding studies of recombinant anti-single-stranded DNA Fab. Role of
      heavy chain complementarity-determining regions.
AB  - We previously isolated nucleic acid-binding antibody fragments (Fab) from
      bacteriophage display libraries representing the immunoglobulin repertoire of
      automimune mice to expedite the analysis of antibody-DNA recognition. In the
      present study, the binding properties of one such anti-DNA Fab, high affinity
      single-stranded (ss) DNA-binding Fab (DNA-1), were defined using equilibrium gel
      filtration and fluorescence titration. Results demonstrated that DNA-1 had a
      marked preference for oligo(dT) (100 nM dissociation constant) and required
      oligo(dT) >5 nucleotides in length. A detailed analysis of the involvement of the
      individual heavy chain (H) complementarity-determining regions (CDR) ensued using
      previously constructed HCDR transplantation mutants between DNA-1 and low
      affinity ssDNA-binding Fab (D5), a Fab that binds poorly to DNA (Calcutt, M. J.
      Komissarov, A. A., Marchbank, M. T., and Deutscher, S. L. (1996) Gene (Amst.)
      168, 9-14). Circular dichroism studies indicated that the wild type and mutant
      Fab studied were of similar overall secondary structure and may contain similar
      combining site shapes. The conversion of D5 to a high affinity oligo(dT)-binding
      Fab occurred only in the presence of DNA-1 HCDR3. Results with site-specific
      mutants in HCDR1 further suggested a role of residue 33 in interaction with
      nucleic acid. The results of these studies are compared with previously published
      data on DNA-antibody recognition.

PMID- 8647822
TI  - A direct role for sterol regulatory element binding protein in activation of 3
      hydroxy-3-methylglutaryl coenzyme A reductase gene.
AB  - In earlier studies the DNA site required for sterol regulation of 3-hydroxy-3
      methylglutaryl coenzyme A reductase was shown to be distinct from the classic
      sterol regulatory element (SRE-1) of the low density lipoprotein receptor gene
      (Osborne, T. F. (1991) J. Biol. Chem 266, 13947-13951). However, oxysterol
      resistant cells that continuously overproduce one of the sterol regulatory
      element binding proteins in the nucleus result in high unregulated expression of
      both genes (Yang, J., Brown, M. S., Ho, Y. K., and Goldstein, J. L. (1995) J.
      Biol. Chem. 270, 12152-12161) suggesting a direct role for the SREBPs in the
      activation of the reductase gene. In the present studies we demonstrate that
      SREBP-1 binds to two adjacent sites within the previously identified sterol
      regulatory element of the reductase gene even though there is only limited
      homology with the SRE-1 of the receptor. We also show that SREBP-1 specifically
      activates the reductase promoter in transient DNA transfection studies in HepG2
      cells and that mutations which eliminate sterol regulation and SREBP-1 binding
      also abolish transient activation by SREBP-1. Although specific, the magnitude of
      the activation observed is considerably lower than for the low density
      lipoprotein (LDL) receptor analyzed in parallel, suggesting there is an
      additional protein required for activation of the reductase promoter that is
      limiting in the transient assay. SREBP also binds to two additional sites in the
      reductase promoter which probably plan an auxiliary role in expression. When the
      DNA sequence within the sites are aligned with each other and with the LDL
      receptor SRE-1, a consensus half-site is revealed 5'-PyCAPy-3'. The LDL receptor
      element contains two half-sites oriented as a direct repeat spaced by one
      nucleotide. The SREBP proteins are special members of the basic-helix-loop-helix
      zipper (bHLHZip) family of DNA binding proteins since they bind the classic
      palindromic E-box site as well as the direct repeat SRE-1 element. The SREBP
      binding sites in both the reductase and those recently identified in other sterol
      regulated promoters appear to contain a half-site with considerable divergence in
      the flanking residues. Here we also show that a 22-amino acid domain located
      immediately adjacent to the basic domain of the bHLHZip region is required for
      SREBP to efficiently recognize divergent sites in the reductase and 3-hydroxy-3
      methylglutaryl-CoA synthase promoters but, interestingly, this domain is not
      required for efficient binding to the LDL direct repeat SRE-1 or to a palindromic
      high-affinity E-box element.

PMID- 8647823
TI  - Effect of mutations at serines 1280-1283 on the mitogenic and transforming
      activities of the insulin-like growth factor I receptor.
AB  - The insulin-like growth factor I receptor (IGF-IR) controls the extent of cell
      proliferation in a variety of cell types by at least 3 different ways: it is
      mitogenic, it causes transformation, and it protects cells from apoptosis.
      Previous reports indicated that certain domains in the C terminus of the IGF-IR
      transmitted a transforming signal that is additional to and separate from the
      mitogenic signal. We have now mutated the four serine residues at 1280-1283 of
      the IGF-IR, and transfected the mutant receptor into R- cells. Cells expressing
      the mutant receptor are fully responsive to IGF-I mediated mitogenesis, but are
      not transformed (no colony formation in soft agar). Several downstream signal
      transducers are not affected by the mutation, again suggesting a separate pathway
      for transformation. The mutant receptor can act as a dominant negative for
      growth, but cannot induce apoptosis in cells with endogenous wild-type receptors.

PMID- 8647824
TI  - The N-terminal region of E2F-1 is required for transcriptional activation of a
      new class of target promoter.
AB  - Because of its expression in numerous cells, the herpes simplex virus thymidine
      kinase promoter (HSV-TK) is one of the best characterized promoters. Using the
      HSV-TK promoter as a model system, we have defined a new mode of E2F-1
      transcriptional activation which utilizes the N-terminal region of E2F-1. We
      demonstrate that E2F-1 strongly activated HSV-TK, but in the absence of consensus
      E2F DNA elements. Nonetheless, E2F-1 could bind to GC-rich elements, which were
      conclusively identified in classic studies of HSV-TK as SP-1 sites. Second, the
      transcriptional activation of HSV-TK required the entire E2F-1 protein, including
      the N-terminal 89 amino acids. In contrast, the N-terminal 89 amino acids of E2F
      1 were dispensable for transcriptional activation through consensus E2F sites.
      Third, we demonstrated that S phase entry is not sufficient for activation of HSV
      TK by E2F-1, while the activation through consensus E2F sites is strictly linked
      to the cell cycle. Taken together, the activation of HSV-TK by E2F-1 proceeds by
      a different mechanism directed in part through the N-terminal region of E2F-1 and
      may be uncoupled from the known cell cycle regulatory role.

PMID- 8647825
TI  - Kinetic and thermodynamic analysis of the interaction between TRAP (trp RNA
      binding attenuation protein) of Bacillus subtilis and trp leader RNA.
AB  - In Bacillus subtilis, expression of the tryptophan biosynthetic genes is
      regulated in response to tryptophan by an RNA-binding protein called TRAP (trp
      RNA-binding attenuation protein). TRAP has been shown to contain 11 identical
      subunits arranged in a symmetrical ring. Kinetic and thermodynamic parameters of
      the interaction between tryptophan-activated TRAP and trp leader RNA were
      studied. Results from glycerol gradients and mobility shift gels indicate that
      two TRAP 11-mers bind to each trp leader RNA. A filter binding assay was used to
      determine an apparent binding constant of 8.0 +/- 1.3 x 10(9) m-1 (Kd = 0.12 +/-
      0.02 nM) for TRAP and an RNA containing residues +36 to +92 of the trp leader RNA
      in 1 mM L-tryptophan at 37 degrees C. The temperature dependence of Kapp was
      somewhat unexpected demonstrating that the delta H of the interaction is highly
      unfavorable at + 15.9 kcal mol-1. Therefore, the interaction is completely driven
      by a delta S of +97 cal mol-1 K-1. The interaction between tryptophan-activated
      TRAP and trp leader RNA displayed broad salt and pH activity profiles. Finally,
      the rate of RNA dissociation from the RNA-TRAP.tryptophan ternary complex was
      found to be very slow in high concentrations of tryptophan (> 40 microM) but
      increased in lower tryptophan concentrations. This suggests that dissociation of
      tryptophan from the ternary complex is the rate-limiting step in RNA
      dissociation.

PMID- 8647826
TI  - Superoxide dismutase activity is essential for stationary phase survival in
      Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in
      vivo.
AB  - Yeast lacking copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide
      dismutase (SOD), catalase T, or metallothionein were studied using long-term
      stationary phase (10-45 days) as a simple model system to study the roles of
      antioxidant enzymes in aging. In well aerated cultures, the lack of either SOD
      resulted in dramatic loss of viability over the first few weeks of culture, with
      the CuZnSOD mutant showing the more severe defect. The double SOD mutant died
      within a few days. The severity reversed in low aeration; the CuZnSOD mutant
      remained viable longer than the manganese SOD mutant. To test whether reactive
      oxygen species generated during respiration play an important role in the
      observed cellular death, growth in nonfermentable carbon sources was measured.
      All strains grew under low aeration, indicating respiratory competence. High
      aeration caused much reduced growth in single SOD mutants, and the double mutant
      failed to grow. However, removal of respiration via another mutation dramatically
      increased short term survival and reversed the known air-dependent methionine and
      lysine auxotrophies. Our results suggest strongly that mitochondrial respiration
      is a major source of reactive oxygen species in vivo, as has been shown in vitro,
      and that these species are produced even under low aeration.

PMID- 8647827
TI  - Metabolism of serotonin to N-acetylserotonin, melatonin, and 5-methoxytryptamine
      in hamster skin culture.
AB  - Biotransformation of [3H]serotonin by cultured hamster skin to 3H-metabolites
      corresponding to N-acetylserotonin (NAS), melatonin, and 5-methoxytryptamine (5
      MT) was demonstrated. This process was time-dependent, with the highest
      production of radioactive NAS and melatonin metabolites after 3 and 5 h of
      incubation followed by a decrease in the rate of metabolite release into the
      media. Conversely, the formation of radioactive metabolite corresponding to 5-MT
      increased gradually during skin culture, reaching the highest level after 24 h of
      incubation. The production of 3H-metabolites, corresponding to NAS, melatonin,
      and 5-MT, was stimulated by forskolin with a maximum effect of forskolin at 10
      microM concentration. The gas chromatographic/mass spectroscopy analysis of the
      fraction eluting at the retention time of NAS standard material showed that it
      contained NAS, further confirming production and release of NAS into the media by
      hamster skin. Therefore, we conclude that mammalian skin can acetylate serotonin
      to NAS and postulate that the NAS is further metabolized by the skin to form
      melatonin which is subsequently transformed to 5-MT.

PMID- 8647828
TI  - Threshold for inositol 1,4,5-trisphosphate action.
AB  - We developed a unidirectional 45Ca2+ efflux technique in which 60 cumulative
      doses of inositol 1,4,5-trisphosphate (InsP3), each lasting 6 s, were
      subsequently added to permeabilized A7r5 cells. This technique allowed an
      accurate determination of the threshold for InsP3 action, which was around 32 nM
      InsP3 under control conditions. The InsP3-induced Ca2+ release was characterized
      by an initial rapid phase, after which the normalized rate progressively
      decreased. The slowing of the release was associated with a shift of the
      threshold to higher InsP3 concentrations. Stimulatory concentrations of
      thimerosal (10 microM) shifted the threshold to 4.5 nM InsP3 and increased both
      the cooperativity and the maximal normalized rate of Ca2+ release. This low
      threshold was maintained when the thimerosal concentration was increased to
      inhibitory levels (100 microM) but then the effects on the cooperativity and on
      the normalized rate of Ca2+ release disappeared. Oxidized glutathione (5 mM) was
      much less effective in stimulating the release and did not have an effect on the
      threshold or on the cooperativity. ATP (5 mM) stimulated the release despite a
      shift in threshold toward higher InsP3 concentrations. Luminal Ca2+ did not
      affect the threshold for InsP3 action but stimulated the normalized release at
      each InsP3 concentration. The inhibitory effect of 10 microM free cytosolic Ca2+
      was associated with a shift in threshold to higher InsP3 concentrations and a
      decreased cooperativity of the release process. We conclude that this novel
      technique of accurately measuring the threshold for InsP3 action under various
      experimental conditions has allowed us to refine the analysis of the kinetic
      parameters involved in the regulation of the InsP3 receptor.

PMID- 8647829
TI  - Biosynthesis of lantibiotic nisin. Posttranslational modification of its
      prepeptide occurs at a multimeric membrane-associated lanthionine synthetase
      complex.
AB  - The lantibiotic nisin of Lactococcus lactis is matured from a ribosomally
      synthesized prepeptide by postranslational modification. Genetic and biochemical
      evidence suggests that genes nisB and nisC of the nisin gene cluster encode
      proteins necessary for prenisin modification. Inactivation of both genes resulted
      in complete loss of nisin production. The preparation of membrane vesicles
      revealed that NisB and NisC are attached to the cellular membrane, and co
      immunoprecipitation experiments showed that they are associated with each other.
      By using the yeast two-hybrid system, which is a highly sensitive method to
      unravel protein-protein interactions, we could show that the nisin prepeptide
      physically interacts with the NisC protein, suggesting that NisC contains a
      binding site for prenisin. This was also confirmed by co-immunoprecipitation of
      the NisC protein and the NisA prepeptide by antibodies directed against the
      leader sequence of the nisin prepeptide. The two-hybrid analysis also confirmed
      the interaction between NisB and NisC as well as the interaction between NisB and
      NisC as well as the interaction between NisC and the NisT ABC transporter. A
      minor interaction was also indicated between prenisin and the NisB protein.
      Furthermore, the two-hybrid investigations also revealed that at least two
      molecules of NisC and two molecules of NisT are part of the modification and
      transport complex. Our results suggest that lantibiotic maturation and secretion
      occur at a membrane-associated multimeric lanthionine synthetase complex
      consisting of proteins NisB, NisC, and the ABC transporter molecules NisT.

PMID- 8647830
TI  - Role of nucleotide exchange and hydrolysis in the function of profilin in action
      assembly.
AB  - Profilin, an essential G-actin-binding protein, has two opposite regulatory
      functions in actin filament assembly. It facilitates assembly at the barbed ends
      by lowering the critical concentration (Pantaloni, D., and Carlier, M.-F. (1993)
      Cell 75, 1007-1014); in contrast it contributes to the pool of unassembled actin
      when barbed ends are capped. We proposed that the first of these functions
      required an input of energy. How profilin uses the ATP hydrolysis that
      accompanies actin polymerization and whether the acceleration of nucleotide
      exchange on G-actin by profilin participates in its function in filament assembly
      are the issues addressed here. We show that 1) profilin increases the
      treadmilling rate of actin filaments in the presence of Mg2+ ions; 2) when
      filaments are assembled from CaATP-actin, which polymerizes in a quasireversible
      fashion, profilin does not promote assembly at the barbed ends and has only a G
      actin-sequestering function; 3) plant profilins do not accelerate nucleotide
      exchange on G-actin, yet they promote assembly at the barbed end. The enhancement
      of nucleotide exchange by profilin is therefore not involved in its promotion of
      actin assembly, and the productive growth of filaments from profilin-actin
      complex requires the coupling of ATP hydrolysis to profilin-actin assembly, a
      condition fulfilled by Mg-actin, and not by Ca-actin.

PMID- 8647831
TI  - Cooperative interaction between AhR.Arnt and Sp1 for the drug-inducible
      expression of CYP1A1 gene.
AB  - Expression of CYP1A1 gene is regulated in a substrate-inducible manner through at
      least two kinds of regulatory DNA elements in addition to the TATA sequence, XRE
      (xenobiotic responsive element), and BTE (basic transcription element), a GC box
      sequence. The trans-acting factor on the XRE is a heterodimer consisting of
      arylhydrocarbon receptor (AhR) and AhR nuclear translocator (Arnt), while Sp1
      acts as a regulatory factor on the BTE. We have investigated how these factors
      interact with one another to induce expression of the CYP1A1 gene. Both in vivo
      transfection assays using Drosophila Schneider line 2 (SL2) cells, which is
      devoid of endogenous Sp1, AhR, and Arnt, and in vitro transcription assays using
      baculovirus-expressed AhR, Arnt, and Sp1 proteins revealed that these factors
      enhanced synergistically expression of the reporter genes driven by a model
      CYP1A1 promoter, consisting of four repeated XRE sequences and a BTE sequence, in
      agreement with previous observation (Yanagida, A., Sogawa, K., Yasumoto, K., and
      Fujii-Kuriyama, Y. (1990) Mol. Cell. Biol. 10, 1470-1475). We have proved by
      coimmunoprecipitation assays and DNase I footprinting that both AhR and Arnt
      interact with the zinc finger domain of Sp1 via their basic HLH/PAS domains. When
      either the AhR.Arnt heterodimer of Sp1 was bound to its cognate DNA element, DNA
      binding of the second factor was facilitated. Survey of DNA sequences in the
      promoter region shows that the XRE and GC box elements are commonly found in the
      genes whose expressions are induced by polycyclic aromatic hydrocarbons,
      suggesting that the two regulatory DNA elements and their cognate trans-acting
      factors constitute a common mechanism for induction of a group of drug
      metabolizing enzymes.

PMID- 8647832
TI  - Binding of 2'(3')-O-(2,4-6-trinitrophenyl) ADP to soluble alpha beta protomers of
      Na, K-ATPase modified with fluorescein isothiocyanate. Evidence for two distinct
      nucleotide sites.
AB  - The overall reaction of well-defined solubilized protomers of Na,K-ATPase (one
      alpha plus one beta subunit) retains the dual ATP dependence observed with the
      membrane-bound enzyme, with distinctive ATP effects in the submicromolar and
      submillimolar ranges (Ward, D. G., and Cavieres, J. D. (1993) Proc. Natl. Acad.
      Sci. U. S. A. 90, 5332-5336). We have now found that the K+/-phosphatase activity
      of the alpha beta protomers is still inhibited by 2'(3')-O-(2,4,6
      trinitrophenyl)adenosine 5'-diphosphate (TNP-ADP). What is most significant is
      that the TNP-ADP effect can be observed clearly with protomeric enzyme whose high
      affinity ATP site has been blocked covalently with fluorescein isothiocyanate. We
      conclude that nucleotides can bind at two discrete sites in each protomeric unit
      of Na,K-ATPase.

PMID- 8647833
TI  - Membrane topology and glycosylation of the human multidrug resistance-associated
      protein.
AB  - The membrane topology of the human multidrug resistance-associated protein (MRP)
      was examined by flow cytometry phenotyping, immunoblotting, and limited
      proteolysis in drug-resistant human and baculovirus-infected insect cells,
      expressing either the glycosylated or the underglycosylated forms of this
      protein. Inhibition of N-linked glycosylation in human cells by tunicamycin did
      not inhibit the transport function or the antibody recognition of MRP, although
      its apparent molecular mass was reduced from 180 kDa to 150 kDa. Extracellular
      addition of trypsin or chymotrypsin had no effect either on the function or on
      the molecular mass of MRP, while in isolated membranes limited proteolysis
      produced three large membrane-bound fragments. These experiments and the
      alignment of the MRP sequence with the human cystic fibrosis transmembrane
      conductance regulator (CFTR) suggest that human MRP, similarly to CFTR, contains
      a tandem repeat of six transmembrane helices, each followed by a nucleotide
      binding domain, and that the C-terminal membrane-bound region is glycosylated.
      However, the N-terminal region of MRP contains an additional membrane-bound,
      glycosylated area with four or five transmembrane helices, which seems to be a
      characteristic feature of MRP-like ATP-binding cassette transporters.

PMID- 8647834
TI  - Osmotic stress protein 94 (Osp94). A new member of the Hsp110/SSE gene subfamily.
AB  - Preservation of cell viability and function in the hyperosmolar environment of
      the renal medulla is a complex process that requires selective gene expression.
      We have identified a new member of the heat shock protein (hsp) 70 superfamily
      that is up-regulated in renal inner medullary collecting duct cells (mIMCD3
      cells) during exposure to hyperosmotic NaCl stress. Known as osmotic stress
      protein 94, or Osp94, this 2935-base pair cDNA encodes an 838-amino acid protein
      that shows greatest homology to the recently discovered hsp110/SSE gene
      subfamily. Like the hsps, Osp94 has a putative amino-terminal ATP-binding domain
      and a putative carboxyl-terminal peptide-binding domain. The in vitro translated
      Osp94 product migrated as a 105-110-kDa protein on SDS-polyacrylamide gel
      electrophoresis. In mIMCD3 cells, Osp94 mRNA expression was greatly up-regulated
      by hyperosmotic NaCl or heat stress. In mouse kidney, Osp94 mRNA expression
      paralleled the known corticomedullary osmolality gradient showing highest
      expression in the inner medulla. Moreover, inner medullary Osp94 expression was
      increased during water restriction when osmolality is known to increase. Thus,
      Osp94 is a new member of the hsp110/SSE stress protein subfamily and likely acts
      as a molecular chaperone.

PMID- 8647835
TI  - Novel O-methylated terminal glucuronic acid characterizes the polar
      glycopeptidolipids of Mycobacterium habana strain TMC 5135.
AB  - Mycobacterium "habana" strain TMC 5135, which has been proposed as a vaccine
      against both leprosy and tuberculosis, is considered to be a strain of serotype I
      of the recognized species Mycobacterium simiae. We have now shown that each of
      these strains possesses characteristic polar glycopeptidolipids (GPL) which are
      sufficiently different to allow unequivocal strain identification. Thin layer
      chromatographic analysis demonstrated that M. habana synthesizes a family of
      apolar GPLs and three distinct polar GPLs (pGPL-I to -III) which exhibited
      migration patterns different from those of M. simiae serotype I (pGPL-Sim). Using
      a combination of chemical, mass spectrometric, and proton-NMR analyses, the GPLs
      from M. habana were determined to be based on the same generic structure as those
      from the M. avium complex, namely N-fatty acyl-D-Phe-(O-saccharide)-D-allo-Thr-D
      Ala-L-alaninyl-O-m onosaccharide. The de-O-acetylated apolar GPLs contain a 3-O
      Me-6-deoxy-Tal attached to the allo-Thr and either a 3-O-Me-Rha or a 3,4-di-O-Me
      Rha attached to the alaninol. In the pGPLs, oligosaccharides were found to be
      attached to the allo-Thr. The oligoglycosyl alditol reductively released from the
      least polar pGPL-I was fully characterized as L-Fucp alpha 1 in --7 with 3-(6-O
      Me)-D-Glcp beta 1 in --7 with 3-(4-O-Me)-L-Rhap alpha 1 in --7 with 3-L-Rhap
      alpha 1 in --7 with 2-(3-O-Me)-6-deoxy-Tal. In pGPl-II and -III, the terminal Fuc
      residue is further 3-O-methylated and 4-O-substituted with an additional 2,4-di-O
      Me-D-GlcA and 4-O-Me-D-GlcA, respectively. The corresponding oligosaccharide from
      pGPL-Sim was shown to be of identical molecular weight to pGPL-II but terminating
      with a 3,4-di-O-Me-GlcA. Enzyme-linked immunosorbent assay-based serological
      studies using anti-M. habana and anti-M. simiae sera against whole cells and
      purified pGPLs firmly established the polar GPLs as important antigens and
      indicated that the terminal epitopes L-Fuc-, 2,4-di-O-Me-D-GlcA, and 4-O-Me-D
      GlcA uniquely present in pGPL-I, -II, and -III, respectively, confer sufficient
      specificity for the identification of M. habana as a distinct serotype of M.
      simiae.

PMID- 8647836
TI  - Identification of an additional member of the cytochrome c oxidase subunit VIIa
      family of proteins.
AB  - We report the cloning, nucleotide sequence, evolutionary analysis, and
      intracellular localization of SIG81, a silica-induced cDNA from mouse
      macrophages. The cDNA encodes a 111-amino acid protein with extensive sequence
      identity with members of the mammalian cytochrome c oxidase subunit VIIa (COX7a)
      family. A human SIG81 sequence >80% identical with the mouse cDNA was deducted
      from homologous sequences in the human expressed tags data base. The deduced
      aminoterminal region shows features common to mitochondrial targeting sequences.
      A phylogenetic analysis of the carboxyl-terminal domain homologous to COX7a
      identifies SIG81 as a divergent member of the family with an ancient origin.
      Southern blot analysis showed that the mouse genome contains two to three copies
      of the SIG81 gene. Northern blot analysis revealed that the SIG81 transcript is
      approximately 1 kb and expressed in every tissue tested, with higher levels of
      expression observed in kidney and liver. Antibodies raised against a glutathione
      S-transferase SIG81 fusion protein detected a 13.5-kDa protein that co
      fractionates with mitochondrial localized enzymatic activity. Taken together, our
      data suggest that SIG81 is a novel member of the COX7a family that is
      constitutively expressed in mouse cells.

PMID- 8647837
TI  - Nitrogen metabolism in Lignifying Pinus taeda cell cultures.
AB  - The primary metabolic fate of phyenylalanine, following its deamination in
      plants, is conscription of its carbon skeleton for lignin, suberin, flavonoid,
      and related metabolite formation. Since this accounts for approximately 30-40% of
      all organic carbon, an effective means of recycling the liberated ammonium ion
      must be operative. In order to establish how this occurs, the uptake and
      metabolism of various 15N-labeled precursors (15N-Phe, 15NH4Cl, 15N-Gln, and 15N
      Glu) in lignifying Pinus taeda cell cultures was investigated, using a
      combination of high performance liquid chromatography, 15N NMR, and gas
      chromatograph-mass spectrometry analyses. It was found that the ammonium ion
      released during active phenylpropanoid metabolism was not made available for
      general amino acid/protein synthesis. Rather it was rapidly recycled back to
      regenerate phenylalanine, thereby providing an effective means of maintaining
      active phenylpropanoid metabolism with no additional nitrogen requirement. These
      results strongly suggest that, in lignifying cells, ammonium ion reassimilation
      is tightly compartmentalized.

PMID- 8647838
TI  - Potential induced redox reactions in mitochondrial and bacterial cytochrome b-c1
      complexes.
AB  - Purified cytochrome b-c1 complexes from beef heart mitochondria and Rhodobacter
      sphaeroides were reconstituted into potassium-loaded asolectin liposomes for
      studies of the energy-dependent electron transfer reactions within the complexes.
      Both complexes in a ubiquinone-sufficient state exhibit antimycin-sensitive
      reduction of cytochromes b (both low and high potential ones) upon induction of a
      diffusion potential by valinomycin in the presence of ascorbate. Addition of
      N,N,N',N'-tet-ramethyl-p-phenylenediamine (TMPD) to the ascorbate-reduced
      potassium-loaded asolectin proteoliposomes resulted in reduction of cytochrome
      b262. Upon addition of valinomycin, the induced diffusion potential caused a
      partial reoxidation of cytochrome b562 and partial reduction of cytochrome b566
      in beef heart cytochrome b-c1 complex in the presence of antimycin and/or
      myxothiazol. Surprisingly, when ubiquinone-depleted beef heart cytochrome b-c1
      complex liposomes were treated under the same conditions, no cytochrome b566
      reduction was observed but only the oxidation of cytochrome b562, and the
      oxidation was not oxygen-dependent. We explain this effect by b566, iron-sulfur
      protein short-circuiting under these conditions, assuming that both antimycin and
      myxothiazol markedly affect subunit b conformation. The electrochemical midpoint
      potential of heme b566 appears to be significantly higher than that of heme b562
      in the presence of myxothiazol, which cannot be accounted for only by the
      potential-driven electron transfer between these two hemes plus the shift in
      chemical midpoint potentials caused by myxothiazol. A model for energy coupling
      consistent with structural findings by Ohnishi et al. (Ohnishi, T., Schagger, H.,
      Meinhardt, S. W., LoBrutto, R., Link, T. A., and von Jagow, G. (1989) J. Biol.
      Chem. 264, 735-744) is presented. This model is a compromise between pure "redox
      loop" and pure "proton-pump" mechanisms. Reoxidation of high potential heme b is
      observed in an antimycin- or antimycin plus myxothiazol-inhibited, ascorbate plus
      TMPD-prereduced R. sphaerodies b-c1 complex, upon membrane potential development,
      suggesting that a similar electron transfer mechanism is also operating in the
      bacterial complex.

PMID- 8647839
TI  - The association of cardiac dystrophin with myofibrils/Z-disc regions in cardiac
      muscle suggests a novel role in the contractile apparatus.
AB  - Dystrophin serves a variety of roles at the cell membrane through its
      associations, and defects in the dystrophin gene can give rise to muscular
      dystrophy and genetic cardiomyopathy. We investigated localization of cardiac
      dystrophin to determine potential intracellular sites of association. Subcellular
      fractionation revealed that while the majority of dystrophin was associated with
      the sarcolemma, about 35% of the 427-kDa form of dystrophin was present in the
      myofibrils. The dystrophin homolog utrophin was detectable only in the
      sarcolemmal membrane and was absent from the myofibrils as were other sarcolemmal
      glycoproteins such as adhalin and the sodium-calcium exchanger. Extraction of
      myofibrils with KC1 and detergents could not solubilize dystrophin. Dystrophin
      could only be dissociated from the myofibrillar protein complex in 5 M urea
      followed by sucrose density gradient centrifugation where it co-fractionated with
      one of two distinctly sedimenting peaks of actin. Immunoelectron microscopy of
      intracellular regions of cardiac muscle revealed a selective labeling of Z-discs
      by hystrophin antibodies. In the genetically determined cardiomyopathic hamster,
      strain CHF 147, the time course of development of cardiac insufficiency
      correlated with an overall 75% loss of myofibrillar dystrophin. These findings
      collectively show that a significant pool of the 427-kDa form of cardiac
      dystrophin was specifically associated with the contractile apparatus at the Z
      discs, and its loss correlated with progression to cardiac insufficiency in
      genetic cardiomyopathy. The loss of distinct cellular pools of dystrophin may
      contribute to the tissue-specific pathophysiology in muscular dystrophy.

PMID- 8647840
TI  - Differential effect of precursor ribose binding protein of Escherichia coli and
      its signal peptide on the SecA penetration of lipid bilayer.
AB  - Digestion of vesicle-bound SecA by trypsin entrapped within the vesicles showed
      that refolding precursor ribose-binding protein (pRBP) of Escherichia coli
      retards the lipid bilayer penetration by SecA while the signal peptide enhances
      it. This discrepancy was found to be due to reduced SecA binding to the vesicles
      in the presence of the pRBP while the signal peptide induced a tight binding.
      Studies on the binding of 1-anilino-8-naphthalene sulfonate (ANS) to SecA
      indicated that SecA assumes more closed conformation upon interaction with pRBP
      and signal peptide induces more open structure of SecA. Kinetic studies of ANS
      binding to SecA upon dilution of unfolded pRBP with SecA solution showed an
      initial fast ANS binding, which was followed by a slow release of ANS. This
      suggests that first the signal peptide portion of the pRBP binds with the SecA
      making its structure more open and then the subsequent binding of the mature
      domain makes the SecA structure more compact. The pRBP enhanced the digestion of
      SecA added to the E. coli inverted vesicles, suggesting an inhibition of SecA
      penetration while the signal peptide had an opposite effect, agreeing with the
      results from the model systems above. When the pRBP and ATP were present
      together, however, the penetration of SecA increased dramatically underlining the
      importance of the SecY/E complex for the membrane insertion of SecA.

PMID- 8647841
TI  - Kinetics of association of myosin subfragment-1 to unlabeled and pyrenyl-labeled
      actin.
AB  - The kinetics of reaction of myosin subfragment-1 (S1) with F-actin have been
      monitored by the changes in light scattering and in pyrenyl-actin fluorescence at
      20 degrees C, pH 7.5, and physiological ionic strength. The association rate
      constant of S1 to F-actin decreases about 10-fold as the molar ratio of bound S1
      increases from 0 to 1. This decrease in k+ is most likely due to the steric
      hindrance of available binding sites by initially bound S1. The apparent rate
      constant for association of S1 to bare filaments is 9 microM-1 s-1, a value 1
      order of magnitude higher than the one previously estimated from experiments in
      which S1 was in excess over F-actin. The anticooperative binding kinetics of S1
      to F-actin are consistent with the negative cooperativity displayed in the
      equilibrium binding curves of S1 to pyrenyl-F-actin. Fluorescence titration
      curves of partially labeled pyrenyl-F-actin by S1 are sigmoidal, consistent with
      a 4-fold higher affinity of S1 for unlabeled than for labeled action. This
      conclusion is strengthened by kinetic data of S1 binding to partially labeled F
      actin, which exhibit a biphasic behavior due to the slower dissociation of S1
      from unlabeled than from labeled actin.

PMID- 8647842
TI  - Enhanced expression of the eosinophil-derived neurotoxin ribonuclease (RNS2) gene
      requires interaction between the promoter and intron.
AB  - The eosinophil-derived neurotoxin (EDN/RNS2) is a member of the mammalian
      ribonuclease gene family and is one of four proteins found in the large specific
      granules of human eosinophilic leukocytes. The gene encoding EDN consists of two
      exons, including a noncoding exon 1, separated by a single intron from the coding
      sequence in exon 2. We have identified a functional promoter of the EDN gene and
      shown that optimal expression depends on interaction between the promoter and one
      or more sequence elements found in the single intron. Cells of the clone 15
      eosinophilic variant of the human promyelocytic HL-60 cell line were transfected
      with constructs that included the promoter region of the EDN gene alone, promoter
      with exon 1, and promoter with both exon 1 and the intron positioned 5' to the
      chloramphenicol acetyltransferase (CAT) reporter gene (constructs referred to as
      PrCAT, PrExCAT, and PrExIn CAT, respectively). Although reporter gene activity
      from either PrCAT or PrExCAT was only 2-3 fold higher than baseline (CAT alone),
      inclusion of the single intron (PrExInCAT) resulted in a 28-fold increase in
      reporter gene activity in uninduced clone 15 cells, and an 80-fold in activity
      when clone 15 cells were induced to differentiate toward eosinophils with butyric
      acid. The intron-mediated enhancer activity was reproduced in other human
      hematopoietic cell lines (K562, Jurkat, U937, and HL-60), but was not found in
      human 293 kidney cells, suggesting that the function of the enhancer element(s)
      may be tissue-specific. A significant portion of the observed enhancer activity
      resides in the first 60 base pairs the the intron, which includes consensus
      binding sites for both AP-1, and NF-ATp transcription factors, and a 15-base pair
      segment that is identical to a sequence found in the promoter of the gene
      encoding the neutrophil granule protein, lactoferrin. The noncoding exon 1/single
      intron/coding exon 2 genomic structure is a common feature among the mammalian
      ribonucleases; this finding suggests the possibility of a conserved mechanism of
      regulation in this gene family.

PMID- 8647843
TI  - Insertion of the polytopic membrane protein MalF is dependent on the bacterial
      secretion machinery.
AB  - We examined the dependence of protein export and membrane protein insertion on
      SecE and SecA, two components of the secretion (Sec) apparatus of Escherichia
      coli. The magnitude of the secretion defect observed for signal sequence
      containing proteins in cells depleted of SecE is larger and more general than
      that in many temperature- or cold-sensitive Sec mutants. In addition, we show
      that the proper insertion of the polytopic MalF protein (synthesized without a
      signal sequence) into the cytoplasmic membrane is also SecE-dependent. In
      contrast to an earlier study (McGovern, K., and Beckwith, J. (1991) J. Biol.
      Chem. 266, 20870-20876), the membrane insertion of MalF also is inhibited by
      treatment of cells with sodium azide, a potent inhibitor of SecA. Therefore, our
      data strongly suggest that the cytoplasmic membrane insertion of MalF is
      dependent on the same cellular machinery as is involved in the export of signal
      sequence-containing proteins. We propose that the mechanism of export from the
      cytoplasm is related for both signal sequence-containing and cytoplasmic membrane
      proteins, but hydrophobic membrane proteins such as MalF may have a higher
      affinity for the Sec apparatus.

PMID- 8647844
TI  - Nucleotides increase the internal flexibility of filaments of dephosphorylated
      Acanthamoeba myosin II.
AB  - The actin-activated Mg(2+)-ATPase activity of Acanthamoeba myosin II
      minifilaments is dependent both on Mg2+ concentration and on the state of
      phosphorylation of three serine sites at the C-terminal end of the heavy chains.
      Previous electric birefringence experiments on minifilaments showed a large
      dependence of signal amplitude on the phosphorylation state and Mg2+
      concentration, consistent with large changes in filament flexibility. These
      observations suggested that minifilament stiffness was important for function. We
      now report that the binding of nucleotides to dephosphorylated minifilaments at
      Mg2+ concentrations needed for optimal activity increases the flexibility by
      about 10-fold, as inferred from the birefringence signal amplitude increase. An
      increase in flexibility with nucleotide binding is not observed for
      dephosphorylated minifilaments at lower Mg2+ concentrations or for phosphorylated
      minifilaments at any Mg2+ concentrations examined. The relaxation times for
      minifilament rotations that are sensitive to the conformation myosin heads are
      also observed to depend on phosphorylation, Mg2+ concentration, and nucleotide
      binding. These latter experiments indicate that the actin-activated Mg2+
      concentration, and nucleotide binding. These latter experiments indicate that the
      actin-activated Mg(2+)-ATPase activity of Acanthamoeba myosin II correlates with
      both changes in myosin head conformation and the ability of minifilaments to
      cycle between stiff and flexible conformations coupled to nucleotide binding and
      release.

PMID- 8647845
TI  - Application of genomic DNA affinity chromatography identifies multiple interferon
      alpha-regulated Stat2 complexes.
AB  - Interferon-alpha (IFN-alpha)-induced signal transduction is mediated by the
      phosphorylation-activation of the signal transducer and activator of
      transcription (STAT) proteins Stat1, Stat2, and Stat3. Previous studies have
      shown that these activated STATs dimerize to form four distinct STAT complexes
      which translocate to the nucleus and activates transcription by binding to
      specific promoter elements. The interferon-stimulated gene factor-3 (ISGF3)
      consists of Stat2 and Stat1 heterodimers in association with a DNA-binding
      protein, p48, that binds to the interferon stimulated response element. Homo-and
      heterodimers of Stat1 and Stat3 bind to the palindromic interferon response
      element (pIRE). In this report we demonstrate the utility of a biochemical
      procedure that we have developed, based on genomic DNA affinity chromatography,
      for the identification of IFN-alpha-induced STAT complexes. Using this approach,
      we identified ISGF3-independent Stat2-containing STAT complexes. Results from the
      analysis of Stat2 complexes in the electrophoretic mobility shift assay were
      consistent with genomic DNA affinity chromatography results and identified a
      Stat2:1 complex that binds with low affinity to the pIRE of the interferon
      regulatory factor-1 gene. Immunoprecipitation studies of Stat2 revealed an IFN
      alpha dependent co-precipitation of both Stat1 and Stat3. Taken together, our
      results suggest that IFN-alpha activates, in addition to ISGF3, other Stat2
      containing STAT complexes, one of which binds to an element related to the
      interferon regulatory factor-1 pIRE.

PMID- 8647847
TI  - Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and
      Egr-1 to the tissue factor promoter.
AB  - These studies examine the molecular basis for increased transcription of tissue
      factor (TF) in THP-1 cells stimulated with lipopolysaccharide (LPS). DNase I
      footprinting identified six sites of protein-DNA interaction between -383 and the
      cap site that varied between control and induced extracts. Four footprints show
      qualitative differences in nuclease sensitivity. Footprints I (-85 to -52) and V
      (-197 to -175) are induction-specific and localize to regions of the promoter
      that mediate serum, phorbol ester, partial LPS response (-111 to +14), and the
      major LPS-inducible element (-231 to -172). Electrophoretic mobility shift assays
      with the -231 to -172 probe demonstrate JunD and Fos binding in both control and
      induced nuclear extracts; however, binding of c-Jun is only detected following
      LPS stimulation. Antibody inhibition studies implicate binding of Ets-1 or Ets-2
      to the consensus site between -192 and -177, a region that contains an induction
      specific footprint. The proximal region (-85 to -52), containing the second
      inducible footprint, binds Egr-1 following induction. These data suggest that LPS
      stimulation of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the TF
      promoter and implicates these factors in the transcriptional activation of TF
      mRNA synthesis.

PMID- 8647846
TI  - p53 stimulates promoter activity of the sgk. serum/glucocorticoid-inducible
      serine/threonine protein kinase gene in rodent mammary epithelial cells.
AB  - sgk is a novel member of the serine/threonine protein kinase gene family that is
      transcriptionally regulated by serum and glucocorticoids in mammary epithelial
      cells. To functionally determine if the sgk promoter is regulated by the p53
      tumor suppressor protein in mammary cells, a series of sgk promoter fragments
      with 5'-deletions were linked to the bacterial chloramphenicol acetyltransferase
      gene (sgk-CAT) and transiently co-transfected into nontumorigenic NMuMG or
      transformed Con8Hd6 mammary epithelial cells with p53 expression plasmids. Wild
      type p53, but not mutant p53, strongly stimulated sgk promoter activity in both
      mammary epithelial cell lines. These effects were mediated by specific regions
      within the sgk promoter containing p53 DNA-binding sites. The sgk p53 sequence at
      1380 to-1345 (site IV) was sufficient to confer p53-dependent transactivation to
      a heterologous promoter, and p53 was capable of binding to this sequence in vitro
      as assessed by gel shift analysis. In the nontumorigenic NMuMG epithelial cell
      line, cotransfection of wild-type p53 strongly stimulated the activities of both
      the sgk promoter and the well characterized p53-responsive p21/Waf1 promoter,
      whereas in Rat-2 fibroblasts, wild-type p53 repressed the basal activities of
      both promoters, revealing that sgk and p21/Waf1 are similarly regulated in a cell
      type-specific manner. Taken together, these results demonstrate that sgk is a new
      transcriptional target of p53 in mammary epithelial cells and represent the first
      example of a hormone-regulated protein kinase gene with a functionally defined
      p53 promoter recognition element.

PMID- 8647848
TI  - Control of gamma-glutamyl transpeptidase expression by glucocorticoids in the rat
      pancreas. Correlation with granule formation.
AB  - Glucocorticoids are known to promote the formation of zymogen granules in acinar
      cells of the exocrine pancreas in vivo as well as in vitro. To gain insight into
      the mechanism of this regulation, we studied the effects of glucocorticoids on
      the synthesis of two components of the secretory granule membrane, the
      glycoprotein 2 (GP-2) and the gamma-glutamyl transpeptidase (GGT). It was
      demonstrated that following adrenalectomy, degranulation of pancreatic acinar
      cells is accompanied by a sharp decrease in GGT and GP-2 synthesis as measured by
      mRNA and protein accumulation. The decline of GGT synthesis was prevented by
      glucocorticoid replacement therapy, whereas GP-2 synthesis could be maintained
      with either glucocorticoid or estradiol treatment. These in vivo observations
      were corroborated and extended in an in vitro study using AR42J pancreatic cells.
      With this cell line, it was demonstrated that dexamethasone induces the formation
      of zymogen granules and the accumulation of a specific GGT transcript (mRNA III)
      by decreasing its degradation rate. At the same time, the GP-2 mRNA level was not
      modified by the hormonal treatment. These data demonstrate that glucocorticoids
      exert a positive control on the GGT expression in pancreatic cells at a post
      transcriptional level. GGT, an enzyme of the glutathione metabolism, could play a
      significant role in protein packaging in secretory cells.

PMID- 8647849
TI  - Functional co-localization of transfected Ca(2+)-stimulable adenylyl cyclases
      with capacitative Ca2+ entry sites.
AB  - Three adenylyl cyclases (ACI, ACIII, and ACVIII) have been described, which are
      putatively Ca(2+)-stimulable, based on in vitro assays. However, it is not clear
      that these enzymes can be regulated by physiological rises in [Ca2+]i when
      expressed in intact cells. Furthermore, it is not known whether transfected
      adenylyl cyclases might display the strict requirement for capacitative Ca2+
      entry that is shown by the Ca(2+)-inhibitable ACVI, which is indigenous to C6-2B
      glioma cells (Chiono, M., Mahey, R., Tate, G., and Cooper, D. M. F. (1995) J.
      Biol. Chem. 270, 1149-1155). In the present study, ACI, ACIII, and ACVIII were
      heterologously expressed in HEK 293 cells, and conditions were devised that
      distinguished capacitative Ca2+ entry from both internal release and nonspecific
      elevation in [Ca2+]i around the plasma membrane. Remarkably, not only were ACI
      and ACVIII largely insensitive to Ca2+ release from stores, but they were
      robustly stimulated only by capacitative Ca2+ entry and not al all by a
      substantial increase in [Ca2+]i at the plasma membrane elicited by ionophore.
      (ACIII, reflecting its feeble in vitro sensitivity to Ca2+, was unaffected by any
      [Ca2+]i rise.) These results suggest a quite unsuspected, essential association
      of Ca(2+)-sensitive adenylyl cyclases with capacitative Ca2+ entry sites, even
      when expressed heterologously.

PMID- 8647850
TI  - The mechanism of the acyl-carbon bond cleavage reaction catalyzed by recombinant
      sterol 14 alpha-demethylase of Candida albicans (other names are: lanosterol 14
      alpha-demethylase, P-45014DM, and CYP51).
AB  - The Candida albicans sterol 14 alpha-demethylase gene (P-45014DM, CYP51) was
      transferred to the yeast plasmid YEp51 placing it under the control of the GAL10
      promoter. The resulting construct (YEp51:CYP51) when transformed into the yeast
      strain GRF18 gave a clone producing 1.5 mu mol of P-450/liter of culture, the
      microsomal fraction of which contained up to 2.5 nmol of P-450/mg of protein. Two
      oxygenated precursors for the 14 alpha-demethylase, 3 beta-hydroxylanost-7-en-32
      al and 3 beta-hydroxylanost-7-en-32-ol, variously labeled with 2H and 18O at C-32
      were synthesized. In this study the conversion of [32-2H,32-16O]- and [32-2H,32
      18O]3 beta-hydroxylanost-7-en-32-al with the recombinant 14 alpha-demethylase was
      performed under 16O2 or 18O2 and the released formic acid analyzed by mass
      spectrometry. The results showed that in the acyl-carbon bond cleavage step (i.e.
      the deformylation process) the original carbonyl oxygen at C-32 of the precursor
      is retained in formic acid and the second oxygen of formate is derived from
      molecular oxygen; precisely the same scenario that has previously been observed
      for the acyl-carbon cleavage steps catalyzed by aromatase (P-450arom) and 17
      alpha-hydroxylase-17,20-lyase (P-45017 alpha,CYP17). In the light of these
      results the mechanism of the acyl-carbon bond cleavage step catalyzed by the 14
      alpha-demethylase is considered.

PMID- 8647851
TI  - Oxygen equilibrium properties of chromium (III)-iron (II) hybrid hemoglobins.
AB  - Cr(III)-Fe(II) hybrid hemoglobins, alpha 2(Cr) beta 2(Fe) and alpha 2(Fe) beta
      2(Cr), in which hemes in either the alpha- or beta-subunits were substituted with
      chromium(III) protoporphyrin IX (Cr(III)(PPIX), were prepared and characterized
      by oxygen equilibrium measurements. Because Cr(III)PPIX binds neither oxygen
      molecules nor carbon monoxide, the oxygen equilibrium properties of Fe(II)
      subunits within these hybrids can be analyzed by a two-step oxygen equilibrium
      scheme. The oxygen equilibrium constants for both hybrids at the second
      oxygenation step agree with those for human adult hemoglobin at the last
      oxygenation step (at pH 6.5-8.4 with an without inositol hexaphosphate at 25
      degrees C). The similarity between the effects of the Cr(III)PPIX and each
      subunits' oxygeme on the oxygen equilibrium properties of the counterpart Fe(II)
      subunits within hemoglobin indicate the utility of Cr(III)PPIX as a model for a
      permanently oxygenated heme within the hemoglobin molecule. We found that Cr(III)
      Fe(II) hybrid hemoglobins have several advantages over cyanomet valency hybrid
      hemoglobins, which have been frequently used as a model system for partially
      oxygenated hemoglobins. In contrast to cyanomet heme, Cr(III)PPIX within
      hemoglobin is not subject to reduction with dithionite or enzymatic reduction
      systems. Therefore, we could obtain more accurate and reasonable oxygen
      equilibrium curves of Cr(III)-Fe(II) hybrids in the presence of an enzymatic
      reduction system, and we could obtain single crystals of deoxy-alpha 2(Cr) beta
      2(Fe) when grown in low salt solution in the presence of polyethylene glycol 1000
      and 50 mM dithionite.

PMID- 8647852
TI  - Bacillus stearothermophilus qcr operon encoding rieske FeS protein, cytochrome
      b6, and a novel-type cytochrome c1 of quinol-cytochrome c reductase.
AB  - The gcr of Bacillus stearothermophilus K1041 encoding three subunits of the
      quinol-cytochrome c oxidoreductase (cytochrome reductase, b6c1 complex) was
      cloned and sequenced. The gene (qcrA) for a Rieske FeS protein of 19,144 Da with
      169 amino acid residues, and the gene (qcrC) for cytochrome c1 of 27,342 Da with
      250 amino acid residues were found at adjacent upstream and downstream sides of
      the previously reported qcrB (petB) for cytochrome b6 of subunit 25,425 Da with
      224 residues (Sone, N., Sawa, G., Sone, T., and Noguchi, S. (1995) J. Biol. Chem.
      270, 10612-10617). The three structural genes for thermophilic Bacillus
      cytochrome reductase form a transcriptional unit. In the deduced amino acid
      sequence for the FeS protein, the domain including four cysteines and two
      histidines binding the 2Fe-2S cluster was conserved. Its N-terminal part more
      closely resembled the cyanobacteria-plastid type than the proteobacteria
      mitochondria type when their sequences were compared. The amino acid sequence of
      cytochrome c1 was not similar to either type; the thermophilic Bacillus
      cytochrome c1 is composed of an N-terminal part corresponding to subunit IV with
      three membrane-spanning segments, and a C-terminal part of cytochrome c
      reminiscent of cytochrome c-551 of thermophilic Bacillus. The subunit IV in the
      enzyme of cyanobacteria and plastids is the counterpart of C-terminal part of
      cytochrome b of proteobacteria and mitochondria. These characteristics indicate
      that Bacillus cytochrome b6c1 complex is unique.

PMID- 8647853
TI  - HLA photoaffinity labeling reveals overlapping binding of homologous melanoma
      associated gene peptides by HLA-A1, HLA-A29, and HLA-B44.
AB  - Melanoma-associated genes (MAGEs) encode tumor-specific antigens that can be
      recognized by CD8+ cytotoxic T lymphocytes. To investigate the interaction of the
      HLA-A1-restricted MAGE-1 peptide 161-169 (EADPT-GHSY) with HLA class I molecules,
      photoreactive derivatives were prepared by single amino acid substitution with N
      beta-[iodo-4-azidosalicyloyl]-L-2,3-diaminopropionic acid. These derivatives were
      tested for their ability to bind to, and to photoaffinity-label, HLA-A1 on C1R.A1
      cells. Only the derivatives containing the photoreactive amino acid in position 1
      or 7 fulfilled both criteria. Testing the former derivative on 14 lymphoid cell
      lines expressing over 44 different HLA class I molecules indicated that it
      efficiently photoaffinity-labeled not only HLA-A1, but possibility also HLA-A29
      and HLA-B44. MAGE peptide binding by HLA-A29 and HLA-B44 was confirmed by
      photoaffinity labeling with photoreactive MAGE-3 peptide derivatives on C1R.A29
      and C1R.B44 cells, respectively. The different photoaffinity labeling systems
      were used to access the ability of the homologous peptides derived from MAGE-1, 
      2, -3, -4a, -4b, -6, and -12 to bind to HLA-A1, HLA-A29, and HLA-B44. All but the
      MAGE-2 and MAGE-12 nonapeptides efficiently inhibited photoaffinity labeling of
      HLA-A1, which is in agreement with the known HLA-A1 peptide-binding motif (acidic
      residue in P3 and C-terminal tyrosine). In contrast, photoaffinity labeling of
      HLA-A29 was efficiently inhibited by these as well as by the MAGE-3 and MAGE-6
      nonapeptides. Finally, the HLA-B44 photoaffinity labeling, unlike the HLA-A1 and
      HLA-A29 labeling, was inhibited more efficiently by the corresponding MAGE
      decapeptides, which is consistent with the reported HLA-B44 peptide-binding motif
      (glutamic acid in P2, and C-terminal tyrosine or phenylalanine). The overlapping
      binding of homologous MAGE peptides by HLA-A1, A29, and B44 is based on different
      binding principles and may have implications for immunotherapy of MAGE-positive
      tumors.

PMID- 8647854
TI  - Probing the alpha 1 beta 2 interface of human hemoglobin by mutagenesis. Role of
      the FG-C contact regions.
AB  - The allosteric transition of hemoglobin involves an extensive reorganization of
      the alpha 1 beta 2 interface, in which two contact regions have been identified.
      This paper concerns at the effect of two mutations located in the "switch" (alpha
      C3 Thr --> Trp) and the "flexible joint" (beta C3 Trp --> Thr). We have expressed
      and characterized one double and two single mutants: Hb alpha T38W/beta W37T, Hb
      beta W37T, and Hb alpha T38W, whose structure has been determined by
      crystallography. We present data on: (i) the interface structure in the contact
      regions, (ii) oxygen and CO binding kinetics and cooperativity, (iii)
      dissociation rates of deoxy tetramers and association rates of deoxy dimers, and
      (iv) the effect of NaI on deoxy tetramer dissociation rate constant. All the
      mutants are tetrameric and T-state in the deoxygenated derivative. Reassociation
      of deoxygenated dimers is not modified by interface mutations. DeoxyHb alpha
      T38W/beta W37T dissociate much faster. We propose a binding site for I- at the
      switch region. The single mutants binds O2 cooperatively; the double one is
      almost non-cooperative, a feature confirmed by CO binding. The functional data,
      analyzed with the two-state model, indicate that these mutations reduce the value
      of the allosteric constant LO.

PMID- 8647855
TI  - Modulation of the SH2 binding specificity and kinase activity of Src by tyrosine
      phosphorylation within its SH2 domain.
AB  - The Src family of kinases are held in an inactive state by interaction of their
      SH2 domain with a C-terminal phosphotyrosine. Dephosphorylation of this site can
      reactivate Src; however, recent evidence suggests that activation can also occur
      without dephosphorylation. In this study, platelet-derived growth factor receptor
      phosphorylation of Src on Tyr-213 specifically blocked binding of its SH2 domain
      to a phosphopeptide corresponding to the C-terminal regulatory sequence, while
      binding to other sequences, such as the platelet-derived growth factor receptor
      or a peptide from the epidermal growth factor receptor, was unaffected.
      Consequently, Src was activated over 50-fold. This is the first demonstration of
      regulation of a SH2 domain specificity by post-translational modification and is
      likely to be a general mechanism for regulation of all Src-like kinases.

PMID- 8647856
TI  - Regulation of avian osteoclastic H+ -ATPase and bone resorption by tamoxifen and
      calmodulin antagonists. Effects independent of steroid receptors.
AB  - We used highly purified avian osteoclasts and isolated membranes from osteoclasts
      to study effects of tamoxifen, 4-hydroxytamoxifen, calmodulin antagonists,
      estrogen, diethylstilbestrol, and the anti-estrogen ICI 182780 on cellular
      degradation of 3H-labeled bone in vitro and on membrane HCl transport. Bone
      resorption was reversibly inhibited by tamoxifen, 4-hydroxytamoxifen, and
      trifluoperazine with IC50 values of approximately 1 microM. Diethylstilbestrol
      and 17-beta-stradiol had no effects on bone resorption at receptor-saturating
      concentrations, while ICI 182780 inhibited bone resorption at concentrations
      greater than 1 microM. At these concentrations ICI 182780, like tamoxifen,
      inhibits calmodulin-stimulated cyclic nucleotide phosphodiesterase activity.
      Membrane HCl transport, assessed by ATP-dependent acridine orange uptake, was
      unaffected by 17-beta-estradiol and diethylstilbestrol at concentrations up to 10
      microM, while ICI greater than 1 microM. In contrast HCl transport was inhibited
      by tamoxifen, 4-hydroxytamoxifen, and the calmodulin antagonists, trifluoperazine
      and the calmidazolium, with IC50 values of 0.25-1.5 microM. These results
      suggested the presence of a membrane-associated non-steroid receptor for
      tamoxifen in osteoclasts. Tamoxifen binding studies demonstrated saturable
      binding in the osteoclast particulate fraction, but not in the nuclear or
      cytosolic fractions. Membranes enriched in ruffled border by differential
      centrifugation following nitrogen cavitation showed binding consistent with one
      site, Kd approximately microM. Our findings indicate that tamoxifen inhibits
      osteoclastic HCl transport by binding membrane-associated target(s), probably
      similar or related to calmodulin antagonist targets. Further, effects of
      estrogens or highly specific anti-estrogens on bone turnover do not support the
      hypothesis of a direct effect on osteoclasts by these compounds in this species.

PMID- 8647857
TI  - Identification of residues 99, 220, and 221 of human cytochrome P450 2C19 as key
      determinants of omeprazole activity.
AB  - Human P450 2C19 is selective for 4'-hydroxylation of S-mephenytoin and 5
      hydroxylation of omeprazole, while the structurally homologous P450 2C9 has low
      activity toward these substrates. To identify the critical amino acids that
      determine the specificity of human amino acids that determine the specificity of
      human P450 2C19, we constructed chimeras of p450 2C9 replacing various proposed
      substrate binding sites (SRS) with those of P450 2C19 and then replaced
      individual residues of P450 2C19 and then replaced individual residues of P450
      2C9 by site-directed mutagenesis. The 339 NH2-terminal amino acid residues (SRS-1
      SRS-4) and amino acids 160-383 (SRS-2-SRS-5) of P450 2C19 conferred omeprazole 5
      hydroxylase activity to P450 2C9. In contract, the COOH terminus of P450 2C19
      (residues 340-490 including SRS-5 and SRS-6), residues 228-339 (SRS-3 and SRS-4)
      and residues 292-383 (part of SRS-4 and SRS-5) conferred only modest increases in
      activity. A single mutation Ile99 --> His increased omeprazole 5-hydroxylase to
      approximately 51% of that of P450 2C19. A chimera spanning residues 160-227 of
      P450 2C19 also exhibited omeprazole 5-hydroxylase activity which was dramatically
      enhanced by the mutation Ile99 --> His. A combination of two mutations, Ile99 -->
      His and Ser200 --> Pro, converted P450 2C9 to an enzyme with a turnover number of
      omeprazole 5-hyrdroxylation, which resembled that of P450 /c19. Mutation of
      Pro221 --> Thr enhanced this activity. Residue 99 is within SRS-1, but amino
      acids 220 and 221 are in the F-G loop and outside any known SRS. Mutation of
      these three amino acids did not confer significant S-mephenytoin 4'-hydroxylase
      activity to P450 2C9, although chimeras containing SRS-1-SRS-4 and SRS-2-SRS-5 of
      P450 2C19 exhibited activity toward this substrate. Our results thus indicate
      that amino acids 99, 220, and 221 are key residues that determine the specificity
      of P450 2C19 for omeprazole.

PMID- 8647858
TI  - Cloning and characterization of GRB14, a novel member of the GRB7 gene family.
AB  - Screening of a human breast epithelial cell cDNA library with the tyrosine
      phosphorylated C terminus of the epidermal growth factor receptor identified a
      novel member of the GRB7 gene family, designated GRB14. In addition to a
      pleckstrin homology domain-containing central region homologous to the
      Caenorhabditis elegans protein F10E9.6/mig 10 and a C-terminal Src homology 2
      (SH2) domain, a conserved N-terminal motif, P(S/A)IPNPFPEL, can now be included
      as a hallmark of this family. GRB14 mRNA was expressed at high levels in the
      liver, kidney, pancreas, testis, ovary, heart, and skeletal muscle. Anti-Grb14
      antibodies recognized a protein of approximately 58 kDa in a restricted range of
      human cell lines. Among those of breast cancer origin, GRB14 expression strongly
      correlated with estrogen receptor positivity, and differential expression was
      also observed among human prostate cancer cell lines. A GST-Grb14 SH2 domain
      fusion protein exhibited strong binding to activated platelet-derived growth
      factor (PDGF) receptors (PDGFRs) in vitro, but association between Grb14 and beta
      PDGFRs could not be detected in vivo. In serum-starved cells, Grb14 was
      phosphorylated on serine residues, which increased with PDGF, but not EGF,
      treatment. Grb14 is therefore a target for a PDGF-regulated serine kinase, an
      interaction that does not require PDGFR-Grb14 association.

PMID- 8647859
TI  - Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human
      osteoclasts.
AB  - Random high throughput sequencing of a human osteoclast cDNA library was employed
      to identify novel osteoclast-expressed genes. Of the 5475 ESTs obtained,
      approximately 4% encoded cathepsin K, a novel cysteine protease homologous to
      cathepsins S and L; ESTs for other cathepsins were rare. In addition, ESTs for
      cathepsin K were absent or at low frequency in cDNA libraries from numerous other
      tissues and cells. In situ hybridization in osteoclastoma and osteophyte
      confirmed that cathepsin K mRNA was highly expressed selecively in osteoclasts;
      cathepsins S, L, and B were not detectable. Cathepsin K was not detected by in
      situ hybridization in a panel of other tissues. Western blot of human
      osteoclastoma or fetal rat humerus demonstrated bands of 38 and 27 kDa,
      consistent with sizes predicted for pro- and mature cathepsin K.
      Immunolocalization in osteoclastoma and osteophyte showed intense punctate
      staining of cathepsin K exclusively in osteoclasts, with a polar distribution
      that was more intense at the bone surface. The abundant expression of cathepsin K
      selectively in osteoclasts strongly suggests that it plays a specialized role in
      bone resorption. Furthermore, the data suggest that random sequencing of ESTs
      from cDNA libraries is a valuable approach for identifying novel cell-selective
      genes.

PMID- 8647860
TI  - Proteolytic activity of human osteoclast cathepsin K. Expression, purification,
      activation, and substrate identification.
AB  - Human cathepsin K is a recently identified protein with high primary sequence
      homology to members of the papain cysteine protease superfamily including
      cathepsins S, L, and B and is selectively expressed in osteoclasts (Drake, F.H.,
      Dodds, R., James I., Connor J., Debouck, C., Richardson, S., Lee, E., Rieman, D.,
      Barthlow, R., Hastings, G., and Gowen, M. (1996) J. Biol., Chem. 271, 12511
      12516). To characterize its catalytic properties, cathepsin K has been expressed
      in baculovirus-infected SF21 cells and the soluble recombinant protein isolated
      from growth media was purified. Purified protein includes an inhibitory pro
      leader sequence common to this family of protease. Conditions for enzyme
      activation upon removal of the pro-sequence have been identified. Fluorogenic
      peptides have been identified as substrates for mature cathepsin K. In addition,
      two protein components of bone matrix, collagen and osteonectin, have been shown
      to be substrates of the activated protease. Cathepsin K is inhibited by E-64 and
      leupeptin, but not for by pepstatin, EDTA, phenylmethylsulfonyl fluoride, or
      phenanthroline, consistent with its classification within the cysteine protease
      class. Leupeptin has been characterized as a slow binding inhibitor of cathepsin
      K (kobs/[I] = 273,000 m(-1).s(-1)). Cathepsin K may represent the elusive
      protease implicated in degradation of protein matrix during bone resorption and
      represents a novel molecular target in treatment of disease states associated
      with excessive bone loss such as osteoporosis.

PMID- 8647861
TI  - A large DNA-binding nuclear protein with RNA recognition motif and
      serine/arginine-rich domain.
AB  - cDNA species encoding a large DNA-binding protein (NP220) of 1978 amino acids was
      isolated from human cDNA libraries. Human NP220 binds to double-stranded DNA
      fragments by recognizing clusters of cytidines. Immunofluorescent microscopy with
      antiserum directed against NP220 revealed a punctate or "speckled" pattern and
      coiled body-like structures in the nucleoplasm of various human cell lines. These
      structures diffused in the cytoplasm during mitosis. Western blot analysis showed
      that NP220 is enriched in the lithium 3,5-diiodosalicylate-insoluble fraction of
      nuclei. The domain essential for DNA binding is localized in C-terminal half of
      NP220. Human NP220 shares three types of domains (MH1, MH2, and MH3) with the
      acidic nuclear protein, matrin 3 (Belgrader, P., Dey, R., and Berezney, R. (1991)
      J. Biol. Chem. 266, 9893-9899). MH1 is a 48-amino acid sequence near the N
      terminus of both human NP220 and rat matrin 3. MH2 is a 75-amino acid sequence
      homologous to the RNA recognition motifs of heterogeneous nuclear RNP I and L. It
      is repeated three times in NP220 and twice in matrin 3. MH3 is a 60-amino acid
      sequence at the C terminus of both NP220 and matrin 3. NP220 has an
      arginine/serine-rich domain commonly found in pre-mRNA splicing factors. Close to
      the domain essential for DNA binding, there are nine repeats of the sequence
      LVTVDEVIEEEDL. Thus, NP220 is a novel type of nucleoplasmic protein with multiple
      domains.

PMID- 8647862
TI  - Functional characterization of mouse syndecan-1 promoter.
AB  - The members of the syndecan family are temporally and spatially expressed heparan
      sulfate proteoglycans of various tissues, where they mediate extracellular
      influences on cell morphology and behavior. Functional characterization of the
      mouse syndecan-1 promoter was carried out in order to elucidate the mechanisms
      involved in the maintenance of the high transcription levels of syndecan-1 gene
      in various epithelia. For that 9.5 kilobase pairs of the upstream region of mouse
      syndecan-1 gene were cloned, sequenced, and used to prepare chimaeric constructs
      with a reporter gene followed by transient or stable transfections into NMuMG
      cells, cultured either in the presence or absence of serum, the 2.5-kilobase pair
      promoter region resulted in the constitutive transcription activity, whereas in
      3T3 cells the serum depletion decreased the promoter activity significantly.
      Deletion of the upstream sequences to -437 base pairs relative to the translation
      initiation site had little effect on this promoter activity. Further deletion to 
      365 base pairs removed three GT boxes and slightly increased the promoter
      activity, whereas the deletion of the next two GC boxes (to -326 base pair)
      reduced the promoter activity dramatically. All of the GC or GT box sequences
      bound the same set of Sp1-like nuclear protein in gel shift assays. Nuclear
      protein binding was also demonstrated around both of the most intense
      transcription initiation sites. Mutation of these regions separately resulted in
      total loss of transcription initiation from the deleted site and decreased the
      promoter activity in relation to the intensity of the abolished start site. This
      indicates that the transcription initiation of the syndecan-1 gene is directed
      through initiator-like elements directly overlapping the start sites, as shown
      for several TATA-less housekeeping and growth regulated genes. We assume that the
      constitutive high level gene expression in epithelial cells is achieved by the
      proximal promoter, which is controlled by members of Sp1 transcription factor
      family.

PMID- 8647863
TI  - ADP-ribosylation of the G protein Rho inhibits integrin regulation of tumor cell
      growth.
AB  - Using a gastric derived tumor line, we investigated the involvement of beta 1
      integrin and Rho in cell growth regulation in response to collagen. The addition
      of C3 exoenzyme from clostridium botulinum to specifically ribosylate and inhibit
      the function of the rho gene products inhibited cellular proliferation in a dose
      dependent fashion. C3 exoenzyme exhibited broad cytostatic activity toward a
      number of tumor lines and induced G0/G1 accumulation, cyclin A inhibition, and
      pronounced alterations in cell morphology. Integrin-mediated adhesion to collagen
      led to the expression of the cyclin A gene whose expression could be blocked
      using anti-beta 1 integrin monoclonal antibodies. Phospholipid levels were
      induced upon beta 1 integrin-mediated adhesion to collagen, and the phospholipid
      induction was inhibited by either antibodies to beta 1 integrin or pretreatment
      of cells with C3 exoenzyme. Significant reduction in phospholipid levels
      correlated with proliferation for a panel of tumor lines deprived of adhesion to
      substrate. These results implicate a novel role for integrins and Rho in the
      regulation of tumour growth in response to matrix.

PMID- 8647864
TI  - Stimulation of phosphorylation of Tyr394 by hydrogen peroxide reactivates
      biologically inactive, non-membrane-bound forms of Lck.
AB  - Lck, a lymphocyte-specific tyrosine protein kinase, is bound to cellular
      membranes as the result of myristoylation and palmitoylation of its amino
      terminus. Its activity is inhibited by phosphorylation of tyrosine 394. The Tyr
      505 --> Phe mutant of Lck (F505Lck) exhibits elevated biological activity and
      constitutive phosphorylation of Tyr-394 in vivo. Mutations at sites of fatty
      acylation that prevent F505Lck from associating with cellular membranes abolish
      the biological activity as a protein kinase in vivo and in vitro, and eliminate
      the phosphorylation of Tyr-394. Here, we show that exposure of cells expressing
      cytoplasmic or nuclear forms of F505Lck to H2O2, a general inhibitor of tyrosine
      protein phosphatases, restores the catalytic activity of these mutant proteins
      through stimulation of phosphorylation of Tyr-394. H2O2 treatment induced the
      phosphorylation of Tyr-394 therefore need not occur by autophosphorylation. Thus,
      there appear to be two mechanisms through which the phosphorylation of Lck at Tyr
      394 can occur. One is restricted to the plasma membrane and does not require the
      presence of oxidants. The other is operational in the nucleus as well as the
      cytosol and is responsive to oxidants.

PMID- 8647865
TI  - High molecular weight microtubule-associated proteins contain O-linked-N
      acetylglucosamine.
AB  - We have examined the post-translational modification of high molecular weight
      microtubule-associated proteins (MAPs) have shown that MAP1, MAP2, and MAP4 are
      glycosylated. The presence of carbohydrate residues on these proteins was
      indicated by labeling with biotin hydrazide following periodate oxidation, a
      specific and well established method for detecting saccharide moieties on
      proteins. Both MAP2 and MAP4 were also labeled in vitro by UDP-[3H]galactose in
      the presence of galactosyltransferase. Labeling by galactosyltransferase
      indicated that MAP2 and MAP4 contained terminal nonreducing GlcNAc residues, and
      they appeared to be O-linked to the proteins as shown by their sensitivity to
      beta-elimination. Chromatographic analysis showed that the GlcNAc residues were
      directly linked to the proteins as monosaccharides. Thus, we have added MAP2 and
      MAP4 to the list of intracellular O-GlcNAc-modified proteins, which includes
      other cytoskeletal proteins such as cytokeratins 8, 13, and 18 and neurofilament
      proteins NF-L and NF-M. We further characterized the O-GlcNAc modification of
      MAP2, and stoichiometric analysis indicated that nearly 10% of the MAP2 isolated
      from rat brain is modified by O-GlcNAc. However, this estimate is thought to
      reflect the minimal level of O-GlcNAc modification present on MAP2. We have also
      shown that both the O-GlcNAc and biotin hydrazide-reactive carbohydrate moieties
      are located on the projection domain of MAP2. Three O-GlcNAc-containing peaks
      were observed following fast protein liquid chromatography of a tryptic digest of
      MAP2, suggesting that multiple modification sites exist. The specific
      modification sites and functional significance of the O-GlcNAc glycosylation on
      the high Mr MAPs remain to be determined.

PMID- 8647866
TI  - Protein kinase C phosphorylates G12 alpha and inhibits its interaction with G
      beta gamma.
AB  - Of nine G protein alpha subunits examined, only alpha 12 and alpha z served as
      substrates for phosphorylation by various isoforms of protein kinase C in vitro.
      A close homolog of alpha 12, alpha 12 was not phosphorylated. Exposure of NIH 3T3
      cells that stably express alpha 12 to phorbol 12-myristate 13-acetate also
      resulted in phosphorylation of the protein. Phosphorylation in vitro occurred
      near the amino terminus (probably Ser38), and approximately 1 mol of phosphate
      was incorporated per mol of alpha 12. Although G protein heterotrimers containing
      either alpha 12 or a z were poor substrates for phosphorylation, the isolated
      alpha subunits were phosphorylated equally well in their GDP- or GTP gamma S
      bound forms. The guanine nucleotide binding properties of purified alpha 12 and
      alpha z were unaltered by phosphorylation, as was the capacity of alpha z to
      inhibit type V adenylyl cyclase. However, phosphorylation of either protein
      greatly reduced its affinity for G protein beta gamma subunits, consistent with
      the newly determined crystal structure of a G protein heterotrimer. We suggest
      that protein kinase C regulates alpha 12- and alpha z-mediated signaling pathways
      by preventing their association with beta gamma.

PMID- 8647867
TI  - Function of directly repeated half-sites as response elements for steroid hormone
      receptors.
AB  - The mouse mammary tumor virus promoter has been shown to be inducible by
      glucocorticoids and progesterone. Although steroid hormone receptors bind with
      high affinity to palindromic response elements, the hormone-responsive region of
      the mouse mammary tumor virus promoter contains a pair of directly repeated half
      sites that are important for hormone inducibility. Recent experiments have also
      indicated that direct repeats can function as estrogen response elements. Here,
      we have investigated DNA binding by steroid receptors to direct repeats and
      provide evidence using gel retardation assays, methylation interference, and gene
      transfer experiments that direct repeats of TGTTCT or RGGTCA motifs function as
      response elements for glucocorticoid (GR) or estrogen receptors (ER),
      respectively, by binding receptor homodimers. Specific GR- or ER-DNA complexes
      were observed on direct repeats with different spacings between half-sites,
      indicating that binding of steroid receptors to direct repeats is more flexible
      than binding to palindromic elements. This flexibility was further emphasized by
      the observation that the GR could also bind to everted repeats of TGTTCT motifs
      separated by 9 base pairs. The isolated DNA binding domains of the GR and ER
      bound cooperatively to palindromes, but no evidence was observed for cooperative
      binding to direct repeats. Under similar conditions the DNA binding domains of
      retinoid receptors retinoid X receptor and retinoic acid receptor bound to direct
      repeats cooperatively as heterodimers. Similarly, ER derivative HE15, which lacks
      a functional ligand binding domain, bound palindromic response elements but
      failed to bind direct repeats. These results indicate that the dimerization
      domain in the ligand binding domain is essential for binding of steroid receptors
      to direct repeats and that the dimerization domain in the D-box of the DNA
      binding is not functional under these conditions. Moreover, the results suggest
      that steroid receptor DNA binding domains may lack dimerization domains outside
      the D-box, which would function in binding to direct repeats, in contrast to
      receptors for retinoids and thyroid hormone. A comparison of the mechanisms of
      binding of steroid receptors and retinoid and thyroid hormone receptors to direct
      repeats is presented.

PMID- 8647868
TI  - Antisense inhibition of basic fibroblast growth factor induces apoptosis in
      vascular smooth muscle cells.
AB  - Basic fibroblast growth factor (bFGF), a potent mitogen for many cell types, is
      expressed by vascular smooth muscle cells and plays a prominent role in the
      proliferative response to vascular injury. Basic FGF has also been implicated as
      a survival factor for a variety of quiescent or terminally differentiated cells.
      Autocrine mechanisms could potentially mediate both proliferation and cell
      survival. To probe such autocrine pathways, endogenous bFGF production was
      inhibited in cultured rat vascular smooth muscle cells by the expression of
      antisense bFGF RNA. Inhibition of endogenous bFGF production induced apoptosis in
      these cells independent of proliferation, and apoptosis could be prevented by
      exogenous bFGF but not serum or epidermal growth factor. The induction of
      apoptosis was associated with an inappropriate entry into S phase. These data
      demonstrate that interruption of autocrine bFGF signaling results in apoptosis of
      vascular smooth muscle cells, and that the mechanism involves disruption of
      normal cell cycle regulation.

PMID- 8647869
TI  - The predominant protein-arginine methyltransferase from Saccharomyces cerevisiae.
AB  - We have identified the major enzymatic activity responsible for the S-adenosyl-L
      methionine-dependent methylation of arginine residues (EC 2.1.1.23) in proteins
      of the yeast Saccharomyces cerevisiae. The RMT1 (protein-arginine
      methyltransferase), formerly ODP1, gene product encodes a 348-residue polypeptide
      of 39.8 kDa that catalyzes both the NG-mono- and NG, NG-asymmetric dimethylation
      of arginine residues in a variety of endogenous yeast polypeptides. A yeast
      strain in which the chromosomal RMT1 gene was disrupted is viable, but the level
      of NG,NG-[3H]dimethylarginine residues detected in intact cells incubated with S
      adenosyl-L-[methyl-3H]methionine is reduced to less than 15% of the levels found
      in the parent strain, while the NG-[3H]monomethylarginine content is reduced to
      less than 30%. We show that soluble extract from parent cell, but not from mutant
      rmt1 cells, catalyzes the in vitro methylation of endogenous polypeptides of 55,
      41, 38, 34, and 30 kDa. The hypomethylated form of these five polypeptides, as
      well as that of several others, can be mono- and asymmetrically dimethylated by
      incubating the mutant rmt1 extract with a purified, bacterially produced,
      glutathione S-transferase-RMT1 fusion protein and S-adenosyl-L-[methyl
      3H]methionine. This glutathione S-transferase-RMT1 fusion protein is also able to
      methylate a number of mammalian polypeptides including histones, recombinant
      heterogeneous ribonucleoprotein A1, cytochrome c, and myoglobin, but cannot
      methylate myelin basic protein. RMT1 appears to be a yeast homolog of a recently
      characterized mammalian protein-arginine methyltransferase whose activity may be
      modulated by mitotic stimulation of cells.

PMID- 8647870
TI  - Expression of dominant negative mutant SHPTP2 attenuates phosphatidylinositol 3'
      kinase activity via modulation of phosphorylation of insulin receptor substrate
      1.
AB  - To clarify the role of protein-tyrosine phosphatase (PTPase) containing Src
      homology 2 regions (SHPTP2) in insulin signaling, either wild-type or mutant
      SHPTP2 (delta PTP; lacking full PTPase domain) was expressed in Rat 1 fibroblasts
      overexpressing human insulin receptors. In response to insulin, phosphorylation
      of insulin receptor substrate 1 (IRS-1), IRS-1-associated PTPase activities and
      phosphatidylinositol (PI) 3'-kinase activities were slightly enhanced in wild
      type cells when compared with those in the parent cells transfected with
      hygromycin-resistant gene alone. In contrast, introduction of delta PTP inhibited
      insulin-induced association of IRS-1 with endogenous SHPTP2 and impaired both
      insulin-stimulated phosphorylation of IRS-1 and activation of PI 3'-kinase.
      Furthermore, decreased content of p85 subunit of PI 3'-kinase was also found in
      mutant cells. Consistently, the insulin-stimulated mitogen-activated protein
      kinase activities and DNA synthesis were also enhanced in wild-type cells, but
      impaired in mutant cells. Thus, the interaction of SHPTP2 with IRS-1 may be
      associated with modulation of phosphorylation levels of IRS-1, resulting in the
      changes of PI 3'-kinase and mitogen-activated protein kinase activity.
      Furthermore, an impaired insulin signaling in mutant cells may be partly
      reflected in a decreased content of p85 protein of PI 3'-kinase.

PMID- 8647871
TI  - Alternative splicing of the human cholesteryl ester transfer protein gene in
      transgenic mice. Exon exclusion modulates gene expression in response to dietary
      or developmental change.
AB  - The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of
      cholesteryl ester from high density lipoprotein to other lipoproteins. The human
      DETP gene produces two forms of mRNA, with or without exon 9 (E9)-derived
      sequences. To study the function and regulation of alternative splicing the CETP
      gene, transgenic mice were prepared 1) with the metallothionein (mT) promoter
      driving an E9-deleted construct (mT.CETP(-E9) transgene), and 2) with the natural
      flanking regions (NFR) controlling expression of genomic sequences which permit
      alternative splicing of E9 (NFR.CETP(+/-E9) transgene). With zinc induction, the
      mT.CETP(-E9) transgene gave rise to abundant E9-deleted CETP mRNA in liver and
      small intestine, but only relatively small amounts of E9-deleted protein were
      found in plasma. The E9-deleted form of CETP was inactive in lipid transfer and
      produced no changes in plasma lipoprotein profile. The NFR.CETP(+/-E9) transgene
      gave rise to full-length (FL) and E9-deleted forms of CETP mRNA in liver and
      spleen. In response to hypercholesterolemia induced by diet and breeding into an
      apoE gene knock-out background, the FL CETP mRNA was induced more than the E9
      deleted mRNA, resulting in a 2-fold increase in ratio of FL/E9-deleted mRNA. The
      expression of CETP mRNA was found to be developmentally regulated. In NFR.CETP(+/
      E9) transgenic mice CETP mRNA levels were markedly increased in the liver and
      small intestine in the perinatal period and decreased in adult mice, whereas CETP
      mRNA in the spleen was low in perinatal mice and increased in adults. The
      developmental increase in CETP mRNA in the liver and spleen was preceded by an
      increased ratio of FL/E9-deleted forms. Thus, the E9-deleted mRNA appears to be
      poorly translated and/or secreted, and the cognate protein is inactive in lipid
      transfer and lipoprotein metabolism. CETP gene expression was found to be highly
      regulated in a tissue-specific fashion during development. Increased CETP gene
      expression during development or in response to hypercholesterolemia is
      associated with preferential accumulation of the full-length CETP mRNA.

PMID- 8647872
TI  - Suppression of doxorubicin cardiotoxicity by overexpression of catalase in the
      heart of transgenic mice.
AB  - Weak antioxidant capacity, particularly low catalase activity in the heart, may
      be a factor responsible for the high sensitivity of this organ to doxorubicin
      induced oxidative damage. To test this hypothesis, a heart-specific promoter was
      used to drive the expression of murine catalase cDNA in transgenic mice. Fifteen
      healthy transgenic mouse lines were produced. Cardiac catalase activity was
      constitutively overexpressed in both atrium and ventricule, ranging from 2- to
      630-fold higher than normal. This enzyme activity was not altered in liver,
      kidneys, lungs, and skeletal muscles. Other antioxidant components, including
      glutathione, glutathione peroxidase, glutathione reductase, metallothionein, and
      superoxide dismutase, were not altered in the catalase-overexpressing heart. Mice
      (7 weeks old) from several transgenic lines and from nontransgenic controls were
      treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg and
      sacrificed on the 4th day after treatment. As compared to normal controls,
      transgenic lines expressing catalase activity 60- or 100-fold higher than normal
      exhibited a significant resistance to doxorubicin-induced cardiac lipid
      peroxidation, elevation of serum creatine phosphokinase, and functional changes
      in the isolated atrium. Interestingly, 200-fold or greater elevation of catalase
      activity did not provide protection. The results provide direct evidence for the
      role of catalase in doxorubicin cardiotoxic responses.

PMID- 8647873
TI  - Characterization of p18, a component of the lamin B receptor complex and a new
      integral membrane protein of the avian erythrocyte nuclear envelope.
AB  - Employing avian erythrocytes, we have previously isolated a multimeric complex
      consisting of the lamin B receptor (LBR, or p58), the nuclear lamins, an LBR
      specific kinase, a 34-kDa protein, and an 18-kDa polypeptide termed p18. As the
      LBR kinase and the 34-kDa component have been recently characterized, we now
      proceed in the characterization of p18. We show here that p18 is an integral
      membrane protein specific to the erythrocyte nuclear envelope which binds to LBR
      and B-type lamins. NH2-terminal sequencing indicates that p18 is distinct from
      other nuclear envelope components, but has similarity to the mitochondrial
      isoquinoline-binding protein. In situ analysis by immunoelectron microscopy and
      examination of digitonin-permeabilized cells by indirect immunofluorescence show
      that p18, unlike LBR and other lamin-binding proteins, is equally distributed
      between the inner and outer nuclear membrane. Furthermore, cycloheximide
      inhibition experiments reveal that the fraction of p18 that resides in the outer
      nuclear membrane does not represent nascent chains en route to the inner nuclear
      membrane, but rather material in equilibrium with the p18 that partitions with
      the inner nuclear membrane. The paradigm of p18 suggests that transmembrane
      complexes formed by the nuclear lamins and LBR provide potential docking sites
      for integral membrane proteins of the nuclear envelope that equilibrate between
      the rough endoplasmic reticulum and the inner nuclear membrane.

PMID- 8647874
TI  - DNA binding exerted by a bacterial gene regulator with an extensive coiled-coil
      domain.
AB  - Although quite common in the eukaryotic cell, bacterial proteins with an
      extensive coiled-coil domain are still relatively rare. One of the few thus far
      documented examples, TlpA from Salmonella typhimurium, is characterized by a
      remarkably long (250 amino acids) alpha-helical coiled-coil domain. Herein, we
      demonstrate that TlpA is a novel sequence-specific DNA-binding protein. Several
      tlpA deletion mutants have been constructed, and their corresponding protein
      products were purified and tested for DNA binding. Two of the mutant proteins
      were shown to be deficient in DNA binding. Both mutants were analyzed by circular
      dichroism and electron microscopy, supporting the notion that mutant proteins wre
      shown to be deficient in DNA binding. Both mutants were analyzed by circular
      dichroism and electron microscopy, supporting the notion that mutant proteins
      were largely intact despite lacking the amino acid residues necessary for DNA
      binding. In vivo studies with transcriptional tlpA-lacZ fusions demonstrated that
      TlpA acts as a repressor. Using the repressor phenotype as a readout, the chain
      exchange previously described in vitro could also be confirmed in vivo. We
      believe the coiled-coil domain acts not only as a dimerization interface but
      could also serve a role as a flexible modulator of the protein-DNA interaction.

PMID- 8647875
TI  - Phosphorylation of human fascin inhibits its actin binding and bundling
      activities.
AB  - Human fascin is an actin-bundling protein that is thought to be involved in the
      assembly of actin filament bundles present in microspikes as well as in membrane
      ruffles and stress fibers. We have found that human fascin is phosphorylated in
      vivo upon treatment with 12-O-tetradecanoylphorbol-13-acetate, a tumor promoter.
      The in vivo phosphorylation is gradually increased from 0.13 to 0.30 mol/mol
      during 2 h of treatment, concomitant with disappearance of human fascin from
      stress fibers, membrane ruffles, and microspikes. Human fascin can also be
      phosphorylated in vitro as judged by phosphopeptide mapping. The extent of
      phosphorylation depends on pH: the stoichiometries are 0.05, 0.38, and 0.6 alone
      does not affect fascin-actin binding. With the incorporation of 0.25 mol of
      phosphate/mol of protein, the actin binding affinity is reduced from 6.7 x 10(6)
      to 1.5 x 10(6) m(-1). The actin bundling activity is also decreased. These
      results suggest that phosphorylation of fascin plays a role in actin
      reorganization after treatment with 12-O-tetradecanoylphorbol-13-acetate.

PMID- 8647876
TI  - Identification of cysteine 354 of beta-tubulin as part of the binding site for
      the A ring of colchicine.
AB  - The colchicine analog 3-chloroacetyl-3-demthylthio-colchicine (3CTC) is a
      competitive inhibitor of colchicine binding to tubulin, binds to tubulin at 37
      degrees C, but not at 0 degree C, and covalently reacts with beta-tubulin at 37
      degree C, but not at 0 degree C, in a reaction inhibited by colchicine site
      drugs. The approximate intramolecular distance between the oxygen at position C-3
      in 3CTC and the chlorine atom of the 3-chloroacetyl group is 3 A. using
      decylagarose chromatography, we purified beta-tubulin that had reacted with 3
      (chloromethyl-[14C] Carbonyl)-3- demethylthiocolchicine ([14C]3CTC). This beta
      tubulin that had reacted with 3-(chloromethyl-[14C]carbonyl)- 3
      demethythiocolchicine ([14C]3CTC). This beta-tubulin was digested with formic
      acid, cyanogen bromide, endoproteinase Glu-C, or endoproteinase Lys-C, and the
      radio-labeled peptide(s) were isolated. The sequences of these peptides indicated
      that as much as 90% of the covalent reaction between the [14C]3CTC and beta
      tubulin occurred at cysteine 354. This finding indicates that the C-3 oxygen atom
      of colchicinoids is within 3 A of the sulfur atom of the Cys-354 residue,
      suggests that the colchicine A ring lies between Cys-354 and Cys-239, based on
      the known 9 A distance between these residues, and may indicate that the
      tropolone C ring lies between the peptide region containing Cys-239 and the amino
      terminal beta-tubulin sequence, based on the labeling pattern observed following
      direct photoactivation of tubulin-bound colchicine.

PMID- 8647877
TI  - (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of
      ceramidase.
AB  - In this study, we have examined the cellular and biochemical activities of the
      ceramide analog (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D
      erythro-MAPP). Addition of 5 microM D-e-MAPP to HL-60 human promyelocytic
      leukemia cells resulted in a concentration- and time-dependent growth suppression
      accompanied by an arrest in the G0/G1 phase of the cell cycle; thus mimicking the
      action of exogenous ceramides. Its enantiomer L-e-MAPP was without effect. Two
      lines of evidence suggested that D-e-MAPP may not function as a direct analog of
      ceramide. First, D-e-MAPP possesses a stereochemical configuration opposite to
      that of D-erythro-ceramide. Second, D-e-MAPP failed to activate ceramide
      activated protein phosphatase in vitro. Therefore, we examined if D-e-MAPP
      functioned indirectly by modulating endogenous ceramide levels. The addition of D
      e-MAPP to cells, but not L-e-MAPP, caused a time- and concentration-dependent
      elevation in endogenous ceramide levels reaching greater than 3-fold over
      baseline following 24 h of treatment. Both D-e-MAPP and L-e-MAPP underwent
      similar uptake by HL-60 cells. D-e-MAPP was poorly metabolized, and remained
      intact in cells, whereas L-e-MAPP underwent a time- and concentration-dependent
      metabolism; primarily through N-deacylation. In vitro, L-e-MAPP was metabolized
      by alkaline ceremidase to an extent similar to that seen with C16-ceramide. D-e
      MAPP was not metabolized. Instead, D-e-MAPP inhibited alkaline ceramidase
      activity in vitro with an IC50 of 1-5 microM. D-e-MAPP did not modulate the
      activity of other ceramide metabolizing enzymes in vitro or in cells, and it was
      a poor inhibitor of acid ceramidase (IC50>500 microM). Finally, D-e-MAPP
      inhibited the metabolism of L-e-MAPP in cells. These studies demonstrate that D-e
      MAPP functions as an inhibitor of alkaline ceramidase in vitro and in cells
      resulting in elevation in endogenous levels of ceramide with the consequent
      biologic effects of growth suppression and cell cycle arrest. These studies point
      to an important role for ceramidases in the regulation of endogenous levels of
      ceramide.

PMID- 8647878
TI  - Homeostasis of cell-surface glycosphingolipid content in B16 melanoma cells.
      Evidence revealed by an endoglycoceramidase.
AB  - This paper describes the homeostasis of glycosphingolipid (GSL) on the cell
      surface as revealed for the first time by an application of endoglycoceramidase
      (EGCase) capable of hydrolyzing the linkage between the oligosaccharide and the
      ceramide of various GSLs. When cell-surface GSLs of B16 melanoma cells were
      hydrolyzed by the action of EGCase, the synthesis of GSLs was found to increase
      transiently, possibly due to activation of UDP-glucose:ceramide
      glucosyltransferase. As a result, the cell-surface GSL content was restored
      quickly to exactly the same level found without the EGCase treatment, if EGCase
      was removed from the cell culture. Treatment of erythrocytes with EGCase caused
      the suppression of de novo ceramide production, resulting in maintenance of the
      ceramide content of B16 cells at the same level even after EGCase treatment. The
      signal for homeostatic regulation could be the ceramide release found to mimic in
      part the action of EGCase; it suppressed de novo production of ceramide and was
      directly converted to GSL, NeuAc alpha 2,3GAl beta 1,4Glc beta 1,1 N
      acetylsphingosine (C2-ceramide GM3). Our finding demonstrates a novel form
      homeostatic regulation coupled to the GSL-synthesizing system in mammalian cells
      for maintaining the contents of both cell-surface GSLs and free ceramide. Since
      many opportunistic pathogens were found to produce EGCase extracellularly, this
      restoration mechanism could also be present as a defense mechanism against
      microbial EGCase.

PMID- 8647879
TI  - Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of
      the prion protein.
AB  - Prion diseases are thought to be caused by the conversion of the normal, or
      cellular, prion protein (PrPC)(PrPres). There are three familial forms of human
      prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker
      syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced
      age despite the congenital presence of the mutant prion protein (PrPM). The
      cellular mechanisms that result in the age-dependent conversion of PrPM into
      PrPres and the unique phenotypes associated with each PrPM are unknown. FFI and a
      familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in
      the PrP gene but have distinct phenotypes linked to codon 129, the site of a
      methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells
      transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N
      mutation results in instability of the mutant PrP which is partially corrected by
      N-glycosylation. Hence, only the glycosylated forms of PrPM reach the cell
      surface whereas the unglycosylated PrPM is also under-represented in the brain of
      FFI patients validating the cell model. These results offer new insight into the
      effect of the D178N mutation on the metabolism of the prion protein.

PMID- 8647880
TI  - Identification of tyrosine residues in the intracellular domain of the growth
      hormone receptor required for transcriptional signaling and Stat5 activation.
AB  - The binding of growth hormone (GH) to its receptor results in its dimerization
      followed by activation of Jak2 kinase and tyrosine phosphorylation of the GH
      receptor itself, as well as Jak2 and the transcription factors Stat1, -3, and -5.
      In order to study the role of GH receptor tyrosine phosphorylation in
      intracellular signaling, we constructed GH receptors in which combinations of
      tyrosines were mutated to phenylalanines. We identified three tyrosine residues
      at positions 534, 566, and 627 that were required for activation of GH-stimulated
      transcription of the serine protease inhibitor (Spi) 2.1 promoter. Any of these
      three tyrosines is able to independently mediate GH-induced transcription,
      indicating redundancy in this part of the GH receptor. Tyrosine phosphorylation
      was not required for GH stimulation of mitogen-activated protein (MAP) kinase
      activity or for GH-stimulated Ca2+ channel activation since these pathways were
      normal in cells expressing a GH receptor in which all eight intracellular
      tyrosines were mutated to phenylalanines. Activation of Stat5 by GH was, however,
      abolished in cells expressing the GH receptor lacking intracellular tyrosines.
      This study demonstrates that specific tyrosines in the GH receptor are required
      for transcriptional signaling possibly by their role in the activation of
      transcription factor Stat5.

PMID- 8647881
TI  - Assembly and secretion of fibrinogen. Involvement of amino-terminal domains in
      dimer formation.
AB  - Fibrinogen is a dimer with each half-molecule composed of three different chains
      (A alpha, B beta, gamma). Previous studies showed that amino-terminal disulfide
      bonds, as well as the disulfide rings that flank the "coiled-coil" region, are
      necessary for chain assembly and secretion (Zhang, J.Z., and Redman, C.M. (1994)
      J. Biol. Chem. 269, 652-658). We now determine whether other amino-terminal
      domains are involved in linking the half-molecules. Fibrinogen chains, with
      deletions at the amino terminus, were co-expressed in COS cells together with
      normal fibrinogen chains. Elimination of the first 8 amino acids of the B beta
      chain did not affect dimer assembly, but deletion of amino acid residues 9-72 had
      a small inhibitory effect on dimer formation. Deletion of the first 72 amino
      acids of the B beta chain further inhibited dimer formation and resulted in
      nearly equal amounts of half-molecule and dimeric fibrinogen being formed and
      secreted. Deletion of the first 80 residues, which includes the cysteine residues
      that form the amino-terminal disulfide ring, completely eliminated dimer
      formation, and only half-molecules were secreted. By contrast deletion of the
      fist 41 amino acid residues of the A alpha chain or the first 15 residues of the
      gamma chain, which correspond to B beta delta 1-72, did not affect chain assembly
      and secretion. However, co-expression of both A alpha delta 1-41 and gamma delta
      1-15 with normal B beta, inhibited dimer formation. Taken together, these results
      indicate that in addition to disulfide bonds, noncovalent interactions of other
      amino-terminal amino acid residues in the three fibrinogen chains also
      participate in dimer formation.

PMID- 8647882
TI  - JAK2 is essential for activation of c-fos and c-myc promoters and cell
      proliferation through the human granulocyte-macrophage colony-stimulating factor
      receptor in BA/F3 cells.
AB  - Interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF)
      is known to activate JAK2 in various cells, but the role of JAK2 in IL-3 or GM
      CSF receptor signal transduction is largely unknown. We have now examined the
      role of JAK2 in GM-CSF-induced signaling events in BA/F3 cells. In BA/F3 cells
      expressing hGMR, activation of JAK2 by hGM-CSF requires the box1 region of hGMR
      beta. Dominant negative JAK2 (delta JAK2), which lacked the kinase domain
      suppressed mIL-3 or hGM-CSF-induced c-fos promoter activation as well as c-myc
      promoter activation/cell proliferation, thereby suggesting that JAK2 is involved
      in the signaling of both pathways. Further analyses of the role of JAK2 in c-fos
      gene activation in BA/F3 cells expressing hGMR revealed that delta JAK2 inhibited
      hGM-CSF-induced phosphorylation of Shc and protein tyrosine phosphatase 1D.
      Within hGMR beta, the several tyrosine residues which exist are related to
      activation of Shc or protein tyrosine phosphate 1D, and are phosphorylated in
      response to hGM-CSF stimulation. In addition, we observed that delta JAK2
      inhibited hGM-CSF-induced phosphorylation of hGMR beta. Taken together, our
      results suggest that JAK2 activated by the box1 region of hGMR mediates hGM-CSF
      induced c-fos promoter activation through phosphorylation of hGMR.

PMID- 8647883
TI  - ER membrane protein complex required for nuclear fusion.
AB  - Diploid cells of the yeast Saccharomyces cerevisiae form after the mating of two
      haploid cells of the opposite mating type. After fusion of the two plasma
      membranes of the mating cells, a dinucleated cell forms initially in which the
      two haploid nuclei then rapidly fuse to form a single diploid nucleus. This
      latter event, called karyogamy, can be divided into two distinct steps: the
      microtubule-based movement that causes the two nuclei to become closely
      juxtaposed and the fusion of the nuclear membranes. For the membrane fusion step,
      one required component, the ER luminal protein Kar2p (BiP), has been identified.
      For topological reasons, however, it has been unclear how Kar2p could function in
      this role. Kar2p is localized to the luminal (i.e., noncytoplasmic) face of the
      ER membrane, yet nuclear fusion must initiate from the cytosolic side of the
      outer nuclear membrane or the ER membrane with which it is contiguous. There is
      both genetic and biochemical evidence that Kar2p interacts with Sec63p, an ER
      membrane protein containing both luminal and cytosolic domains that is involved
      in protein translocation across the membrane. We have isolated novel sec63 mutant
      alleles that display severe karyogamy defects. Disruption of the genes encoding
      other Sec63p-associated proteins (Sec71p and Sec72p) also results in karyogamy
      defects. A suppressor mutant (sos1-1) partially corrects the translocation defect
      but does not alleviate the karyogamy defect. sec61 and sec62 mutant alleles that
      cause similar or more severe protein translocation defects show no karyogamy
      defects. Taken together, these results suggest a direct role for Sec63p, Sec71p,
      and Sec72p in nuclear membrane fusion and argue against the alternative
      interpretation that the karyogamy defects result as an indirect consequence of
      the impaired membrane translocation of another component(s) required for the
      process. We propose that an ER/nuclear membrane protein complex composed of
      Sec63p, Sec71p, and Sec72p plays a central role in mediating nuclear membrane
      fusion and requires ER luminally associated Kar2p for its function.

PMID- 8647884
TI  - Activation of transcription factor NF-kappaB by the adenovirus E3/19K protein
      requires its ER retention.
AB  - We have recently shown that the accumulation of diverse viral and cellular
      membrane proteins in the ER activates the higher eukaryotic transcription factor
      NF-kappaB. This defined a novel ER-nuclear signal transduction pathway, which is
      distinct from the previously described unfolded protein response (UPR). The well
      characterized UPR pathway is activated by the presence of un- or malfolded
      proteins in the ER. In contrast, the ER stress signal which activates the NF
      kappaB pathway is not known. Here we used the adenovirus early region protein
      E3/19K as a model to investigate the nature of the NF-kappaB-activating signal
      emitted by the ER. E3/19K resides in the endoplasmic reticulum where it binds to
      MHC class I molecules, thereby preventing their transport to the cell surface. It
      is maintained in the ER by a retention signal sequence in its carboxy terminus,
      which causes the protein to be continuously retrieved to the ER from post-ER
      compartments. Mutation of this sequence allows E3/19K to reach the cell surface.
      We show here that expression of E3/19K potently activates a functional NF-kappaB
      transcription factor. The activated NF-kappaB complexes contained p50/p65 and
      p50/c-rel heterodimers. E3/19K interaction with MHC class I was not important for
      NF-kappaB activation since mutant proteins which no longer bind MHC molecules
      remained fully capable of inducing NF-kappaB. However, activation of both NF
      kappaB DNA binding and kappaB-dependent transactivation relied on E3/19K ER
      retention: mutants, which were expressed on the cell surface, could no longer
      activate the transcription factor. This identifies the NF-kappaB-activating
      signal as the accumulation of proteins in the ER membrane, a condition we have
      termed "ER overload." We show that ER overload-mediated NF-kappaB activation but
      not TNF-stimulated NF-kappaB induction can be inhibited by the intracellular Ca2+
      chelator TMB-8. Moreover, treatment of cells with two inhibitors of the ER
      resident Ca(2+) -dependent ATPase, thapsigargin and cyclopiazonic acid, which
      causes a rapid release of Ca2+ from the ER, strongly activated NF-kappaB. We
      therefore propose that ER overload activates NF-kappaB by causing Ca2+ release
      from the ER. Because NF-kappaB plays a key role in mounting an immune response,
      ER overload caused by viral proteins may constitute a simple antiviral response
      with broad specificity.

PMID- 8647885
TI  - The AP-1 adaptor complex binds to immature secretory granules from PC12 cells,
      and is regulated by ADP-ribosylation factor.
AB  - Immature secretory granules (ISGs) in endocrine and neuroendocrine cells have
      been shown by morphological techniques to be partially clathrin coated (Orci, L.,
      M. Ravazzola, M. Amherdt, D. Lonvard, A. Perrelet. 1985a. Proc. Natl. Acad. Sci.
      USA. 82:5385-5389; Tooze, J., and S. A. Tooze. 1986. J. Cell Biol. 103:839-850).
      The function, and composition, of this clathrin coat has remained an enigma. Here
      we demonstrate using three independent techniques that immature secretory
      granules isolated from the rat neuroendocrine cell line PC12 have clathrin coat
      components associated with their membrane. To study the nature of the coat
      association we have developed an assay whereby the binding of the AP-1 subunit
      gamma-adaptin to ISGs was reconstituted by addition of rat or bovine brain
      cytosol. The amount of gamma-adaptin bound to the ISGs was ATP independent and
      was increased fourfold by the addition of GTPgammaS. The level of exogenous gamma
      adaptin recruited to the ISG was similar to the level of gamma-adaptin present on
      the ISG after isolation. Addition of myristoylated ARF1 peptide stimulated
      binding. Reconstitution of the assay using AP-1 adaptor complex and recombinant
      ARF1 provided further evidence that ARF is involved in gamma-adaptin binding to
      ISGs; BFA inhibited this binding. Trypsin treatment and Trisstripping of the ISGs
      suggest that additional soluble and membrane-associated components are required
      for gamma-adaptin binding.

PMID- 8647886
TI  - Endocytosis of VAMP is facilitated by a synaptic vesicle targeting signal.
AB  - After synaptic vesicles fuse with the plasma membrane and release their contents,
      vesicle membrane proteins recycle by endocytosis and are targeted to newly formed
      synaptic vesicles. The membrane traffic of an epitope-tagged form of VAMP-2 (VAMP
      TAg) was observed in transfected cells to identify sequence requirements for
      recycling of a synaptic vesicle membrane protein. In the neuroendocrine PC12 cell
      line VAMP-TAg is found not only in synaptic vesicles, but also in endosomes and
      on the plasma membrane. Endocytosis of VAMP-TAg is a rapid and saturable process.
      At high expression levels VAMP-TAg accumulates at the cell surface. Rapid
      endocytosis of VAMP-TAg also occurs in transfected CHO cells and is therefore
      independent of other synaptic proteins. The majority of the measured endocytosis
      is not directly into synaptic vesicles since mutations in VAMP-TAg that enhance
      synaptic vesicle targeting did not affect endocytosis. Nonetheless, mutations
      that inhibited synaptic vesicle targeting, in particular replacement of
      methionine-46 by alanine, inhibited endocytosis by 85% in PC12 cells and by 35%
      in CHO cells. These results demonstrate that the synaptic vesicle targeting
      signal is also used for endocytosis and can be recognized in cells lacking
      synaptic vesicles.

PMID- 8647887
TI  - The PAL1 gene product is a peroxisomal ATP-binding cassette transporter in the
      yeast Saccharomyces cerevisiae.
AB  - The PAL1 gene was isolated using PCR and degenerate oligonucleotide primers
      corresponding to highly conserved amino acid sequence motifs diagnostic of the
      ATP-binding cassette domain of the superfamily of membrane-bound transport
      proteins typified by mammalian multidrug resistance transporter 1 and
      Saccharomyces cerevisiae Ste6. The deduced PAL1 gene product is similar in length
      to, has the same predicted topology as, and shares the highest degree of amino
      acid sequence identity with two human proteins, adrenoleukodystrophy protein and
      peroxisomal membrane protein (70 kD), which are both presumptive ATP-binding
      cassette transporters thought to be constituents of the peroxisomal membrane. As
      judged by hybridization of a PAL1 probe to isolated RNA and by expression of a
      PAL1-lacZ fusion, a PAL1 transcript was only detectable when cells were grown on
      oleic acid, a carbon source which requires the biogenesis of functional
      peroxisomes for its metabolism. A pal1delta mutant grew normally on either
      glucose- or glycerol-containing media; however, unlike PAL1+ cells (or the
      pal1delta mutant carrying the PAL1 gene on a plasmid), pal1delta cells were
      unable to grow on either a solid medium or a liquid medium containing oleic acid
      as the sole carbon source. Antibodies raised against a chimeric protein in which
      the COOH-terminal domain of Pal1 was fused to glutathione S-transferase
      specifically recognized a protein in extracts from wild-type cells only when
      grown on oleic acid; this species represents the PAL1 gene product because it was
      missing in pal1delta cells and more abundant in pal1delta cells expressing PAL1
      from a multicopy plasmid. The Pal1 polypeptide was highly enriched in the
      organellar pellet fraction prepared from wild-type cells by differential
      centrifugation and comigrated upon velocity sedimentation in a Nycodenz gradient
      with a known component of the peroxisomal matrix, e-oxoacyl-CoA thiolase. As
      judged by both subcellular fractionation and indirect immunofluorescence,
      localization of 3-oxoacyl-CoA thiolase to peroxisomes was unchanged whether Pal1
      was present, absent, or overexpressed. These findings demonstrate that Pal1 is a
      peroxisome-specific protein, that it is required for peroxisome function, but
      that it is not necessary for the biogenesis of peroxisomes or for the import of 3
      oxoacyl-CoA thiolase (and at least two other peroxisomal matrix proteins).

PMID- 8647888
TI  - The targeting of Lamp1 to lysosomes is dependent on the spacing of its
      cytoplasmic tail tyrosine sorting motif relative to the membrane.
AB  - Lamp1 is a type I transmembrane glycoprotein that is localized primarily in
      lysosomes and late endosomes. Newly synthesized molecules are mostly transported
      from the trans-Golgi network directly to endosomes and then to lysosomes. A minor
      pathway involves transport via the plasma membrane. The 11-amino acid cytoplasmic
      tail of lamp1 contains a tyrosine-based motif that has been previously shown to
      mediate sorting in the trans-Golgi network and rapid internalization at the
      plasma membrane. We studied whether this motif also mediates sorting in
      endosomes. We found that mutant forms of lamp1 in which all the amino acids of
      the cytoplasmic tail were modified except for the RKR membrane anchor and the
      YXXI sorting motif still localized to dense lysosomes, indicating that the YXXI
      motif is sufficient to confer proper intracellular targeting. However, when the
      spacing of the YXXI motif relative to the membrane was changed by deleting one
      amino acid or adding five amino acids, lysosomal targeting was almost completely
      abolished. Kinetic studies showed that these mutants were trapped in a recycling
      pathway, involving trafficking between the plasma membrane and early endocytic
      compartments. These findings indicate that the YXXI signal of lamp1 is recognized
      at several sorting sites, including the trans-Golgi network, the plasma membrane,
      and the early/sorting endosomes. Small changes in the spacing of this motif
      relative to the membrane dramatically impair sorting in the early/sorting
      endosomes but have only a modest effect on internalization at the plasma
      membrane. The spacing of sorting signals relative to the membrane may prove to be
      an important determinant in the functioning of these signals.

PMID- 8647889
TI  - Cysteine34 of the cytoplasmic tail of the cation-dependent mannose 6-phosphate
      receptor is reversibly palmitoylated and required for normal trafficking and
      lysosomal enzyme sorting.
AB  - We have examined whether the two cysteine residues (Cys30 and Cys34) in the
      cytoplasmic tail of the cation-dependent mannose 6-phosphate receptor are
      palmitoylated via thioesters and whether these residues influence the biologic
      function of the receptor. To do this, mouse L cells expressing wild-type and
      mutant receptors were analyzed by metabolic labeling with [3H]palmitate,
      immunoprecipitation, and SDS-PAGE. Both Cys30 and Cys34 were found to be sites of
      palmitoylation and together they accounted for the total palmitoylation of the
      receptor. The palmitate rapidly turned over with a half-life of approximately 2 h
      compared to a half-life of greater than 40 h for the protein. Mutation of Cys34
      to Ala resulted in the gradual accumulation of the receptor in dense lysosomes
      and the total loss of cathepsin D sorting function in the Golgi. A Cys30 to Ala
      mutation had no biologic consequences, showing the importance of Cys34. Mutation
      of amino acids 35-39 to alanines impaired palmitoylation of Cys30 and Cys34 and
      resulted in abnormal receptor trafficking to lysosomes and loss of cathepsin D
      sorting. These data suggest that palmitoylation of Cys30 and Cys34 leads to
      anchoring of this region of the cytoplasmic tail to the lipid bilayer. Anchoring
      via Cys34 is essential for the normal trafficking and lysosomal enzyme sorting
      function of the receptor.

PMID- 8647890
TI  - Different fates of phagocytosed particles after delivery into macrophage
      lysosomes.
AB  - Phagocytosis in macrophages is often studied using inert polymer microspheres. An
      implicit assumption in these studies is that such particles contain little or no
      specific information in their structure that affects their intracellular fate. We
      tested that assumption by examining macrophage phagosomes containing different
      kinds of particles and found that although all particles progressed directly to
      lysosomes, their subsequent fates varied. Within 15 min of phagocytosis, >90% of
      phagosomes containing opsonized sheep erythrocytes, poly-e-caprolactone
      microspheres, polystyrene microspheres (PS), or polyethylene glycol-conjugated PS
      merged with the lysosomal compartment. After that point, however, the
      characteristics of phagolysosomes changed in several ways that indicated
      differing degrees of continued interaction with the lysosomal compartment. Sheep
      erythrocyte phagolysosomes merged together and degraded their contents quickly,
      poly-e-caprolactone phagolysosomes showed intermediate levels of interaction, and
      PS phagolysosomes became isolated within the cytoplasm. PS were relatively
      inaccessible to an endocytic tracer, Texas red dextran, added after phagocytosis.
      Moreover, immunofluorescent staining for the lysosomal protease cathepsin L
      decreased in PS phagolysosomes to 23% by 4 h after phagocytosis, indicating
      degradation of the enzyme without replacement. Finally, PS surface labeled with
      fluorescein-labeled albumin showed a markedly reduced rate of protein degradation
      in phagolysosomes, when compared to rates measured for proteins in or on other
      particles. Thus, particle chemistry affected both the degree of postlysosomal
      interactions with other organelles and, consequently, the intracellular half-life
      of particle-associated proteins. Such properties may affect the ability of
      particles to deliver macromolecules into the major histocompatibility complex
      class I and II antigen presentation pathways.

PMID- 8647891
TI  - Potential sites of PI-3 kinase function in the endocytic pathway revealed by the
      PI-3 kinase inhibitor, wortmannin.
AB  - Previously we have shown that PDGF receptor mutants that do not bind PI-3 kinase
      internalize after ligand binding, but fail to downregulate and degrade. To define
      further the role of PI-3 kinase in trafficking processes in mammalian cells, we
      have investigated the effects of a potent inhibitor of PI-3 kinase activity,
      wortmannin. At nanomolar concentrations, wortmannin inhibited both the transfer
      of PDGF receptors from peripheral compartments to juxtanuclear vesicles, and
      their subsequent degradation. In contrast, the delivery of soluble phase markers
      to lysosomes, assessed by the accumulation of Lucifer yellow (LY) in perinuclear
      vesicles after 120 min of incubation, was not blocked by wortmannin. Furthermore,
      wortmannin did not affect the rate of transferrin uptake, and caused only a small
      decrease in its rate of recycling. Thus, the effects of wortmannin on PDGFr
      trafficking are much more pronounced than its effects on other endocytic events.
      Unexpectedly, wortmannin also caused a striking effect on the morphology of
      endosomal compartments, marked by tubulation and enlargement of endosomes
      containing transferrin or LY. This effect was somewhat similar to that produced
      by brefeldin A, and was also blocked by pre-treatment of cells with aluminum
      fluoride (AlF4-). These results suggest two sites in the endocytic pathway where
      PI-3 kinase activity may be required: (a) to sort PDGF receptors from peripheral
      compartments to the lysosomal degradative pathway; and (b) to regulate the
      structure of endosomes containing lysosomally directed and recycling molecules.
      This latter function could be mediated through the activation of AlFt4-)
      sensitive GTP-binding proteins downstream of PI-3 kinase.

PMID- 8647892
TI  - Calcium release in HSY cells conforms to a steady-state mechanism involving
      regulation of the inositol 1,4,5-trisphosphate receptor Ca2+ channel by luminal
      [Ca2+].
AB  - In many cell types, low concentrations of inositol 1,4,5-trisphosphate (IP3)
      release only a portion of the intracellular IP3-sensitive Ca2+ store, a
      phenomenon known as "quantal" Ca2+ release. It has been suggested that this
      effect is a result of reduced activity of the IP3-dependent Ca2+ channel with
      decreasing calcium concentration within the IP3-sensitive store ([Ca2+]s). To
      test this hypothesis, the properties of IP3-dependent Ca2+ release in single
      saponin-permeabilized HSY cells were studied by monitoring [Ca2+]s using the
      Ca(2+)-sensitive fluorescent dye mag-fura-2. In permeabilized cells, blockade of
      the sarco/ER Ca(2+)-ATPase pump in stores partially depleted by IP3 induced
      further Ca2+ release via an IP3-dependent route, indicating that Ca2+ entry via
      the sarco/ER Ca(2+)-ATPase pump had been balanced by Ca2+ loss via the IP3
      sensitive channel before pump inhibition. IP3-dependent Mn2+ entry, monitored via
      quenching of luminal mag-fura-2 fluorescence, was readily apparent in filled
      stores but undetectable in Ca(2+)-depleted stores, indicating markedly reduced
      IP3-sensitive channel activity in the latter. Also consistent with reduced
      responsiveness of Ca(2+)-depleted stores to IP3, the initial rate of refilling of
      these stores was unaffected by the presence of 0.3 microM IP3, a concentration
      that was clearly effective in eliciting Ca2+ release from filled stores. Analysis
      of the rate of Ca2+ release at various IP3 concentrations indicated a significant
      shift of the IP3 dose response toward higher [IP3] with decreasing [Ca2+]s. We
      conclude that IP3-dependent Ca2+ release in HSY cells is a steady-state process
      wherein Ca2+ efflux via the IP3 receptor Ca2+ channel is regulated by [Ca2+]s,
      apparently via changes in the sensitivity of the channel to IP3.

PMID- 8647893
TI  - Molecular characterization of the 50-kD subunit of dynactin reveals function for
      the complex in chromosome alignment and spindle organization during mitosis.
AB  - Dynactin is a multi-subunit complex which has been implicated in cytoplasmic
      dynein function, though its mechanism of action is unknown. In this study, we
      have characterized the 50-kD subunit of dynactin, and analyzed the effects of its
      overexpression on mitosis in living cells. Rat and human cDNA clones revealed p50
      to be novel and highly conserved, containing three predicted coiled-coil domains.
      Immunofluorescence staining of dynactin and cytoplasmic dynein components in
      cultured vertebrate cells showed that both complexes are recruited to
      kinetochores during prometaphase, and concentrate near spindle poles thereafter.
      Overexpression of p50 in COS-7 cells disrupted mitosis, causing cells to
      accumulate in a prometaphase-like state. Chromosomes were condensed but
      unaligned, and spindles, while still bipolar, were dramatically distorted.
      Sedimentation analysis revealed the dynactin complex to be dissociated in the
      transfected cultures. Furthermore, both dynactin and cytoplasmic dynein staining
      at prometaphase kinetochores was markedly diminished in cells expressing high
      levels of p50. These findings represent clear evidence for dynactin and
      cytoplasmic dynein codistribution within cells, and for the presence of dynactin
      at kinetochores. The data also provide direct in vivo evidence for a role for
      vertebrate dynactin in modulating cytoplasmic dynein binding to an organelle, and
      implicate both dynactin and dynein in chromosome alignment and spindle
      organization.

PMID- 8647894
TI  - Detection of protein kinase activity specifically activated at metaphase-anaphase
      transition.
AB  - We have previously reported that Ser13 and Ser34 on glial fibrillary acidic
      protein (GFAP) in the cleavage furrow of glioma cells are phosphorylated during
      late mitotic phase (Matsuoka, Y., K. Nishizawa, T. Yano, M. Shibata, S. Ando, T.
      Takahashi, and M. Inagaki. 1992, EMBO (Eur. Mol. Biol. Organ.) J. 11:2895-2902).
      This observation implies a possibility that there is a protein kinase
      specifically activated at metaphase-anaphase transition. To further analyze the
      cell cycle-dependent GFAP phosphorylation, we prepared monoclonal antibodies KT13
      and KT34 which recognize the phosphorylation of GFAP at Ser13 and Ser34,
      respectively. Immunocytochemical studies with KT13 and KT34 revealed that the
      GFAP phosphorylation in the cleavage furrow during late mitotic phase occurred
      not only in glioma cells but also in human SW-13 and mouse Ltk- cells in which
      GFAP was ectopically expressed, thus the phosphorylation can be monitored in a
      wide range of cell types. Furthermore, we detected kinase activity which
      phosphorylates GFAP at Ser13 and Ser34 in the lysates of late mitotic cells but
      not in those of interphase cells or early mitotic cells. These results suggest
      that there exists a protein kinase which is specifically activated at the
      transition of metaphase to anaphase not only in GFAP-expressing cells but also in
      cells without GFAP.

PMID- 8647895
TI  - Filensin and phakinin form a novel type of beaded intermediate filaments and
      coassemble de novo in cultured cells.
AB  - The fiber cells of the eye lens possess a unique cytoskeletal system known as the
      "beaded-chain filaments" (BFs). BFs consist of filensin and phakinin, two
      recently characterized intermediate filament (IF) proteins. To examine the
      organization and the assembly of these heteropolymeric IFs, we have performed a
      series of in vitro polymerization studies and transfection experiments. Filaments
      assembled from purified filensin and phakinin exhibit the characteristic 19-21-nm
      periodicity seen in many types of IFs upon low angle rotary shadowing. However,
      quantitative mass-per-length (MPL) measurements indicate that filensin/phakinin
      filaments comprise two distinct and dissociable components: a core filament and a
      peripheral filament moiety. Consistent with a nonuniform organization,
      visualization of unfixed and unstained specimens by scanning transmission
      electron microscopy (STEM) reveals the the existence of a central filament which
      is decorated by regularly spaced 12-15-nm-diam beads. Our data suggest that the
      filamentous core is composed of phakinin, which exhibits a tendency to self
      assemble into filament bundles, whereas the beads contain filensin/phakinin
      hetero-oligomers. Filensin and phakinin copolymerize and form filamentous
      structures when expressed transiently in cultured cells. Experiments in IF-free
      SW13 cells reveal that coassembly of the lens-specific proteins in vivo does not
      require a preexisting IF system. In epithelial MCF-7 cells de novo forming
      filaments appear to grow from distinct foci and organize as thick, fibrous
      laminae which line the plasma membrane and the nuclear envelope. However,
      filament assembly in CHO and SV40-transformed lens-epithelial cells (both of
      which are fibroblast-like) yields radial networks which codistribute with the
      endogenous vimentin IFs. These observations document that the filaments formed by
      lens-specific IF proteins are structurally distinct from ordinary cytoplasmic
      IFs. Furthermore, the results suggest that the spatial arrangement of
      filensin/phakinin filaments in vivo is subject to regulation by host-specific
      factors. These factors may involve cytoskeletal networks (e.g., vimentin IFs)
      and/or specific sites associated with the cellular membranes.

PMID- 8647896
TI  - Myogenin expression, cell cycle withdrawal, and phenotypic differentiation are
      temporally separable events that precede cell fusion upon myogenesis.
AB  - During terminal differentiation of skeletal myoblasts, cells fuse to form
      postmitotic multinucleated myotubes that cannot reinitiate DNA synthesis. Here we
      investigated the temporal relationships among these events during in vitro
      differentiation of C2C12 myoblasts. Cells expressing myogenin, a marker for the
      entry of myoblasts into the differentiation pathway, were detected first during
      myogenesis, followed by the appearance of mononucleated cells expressing both
      myogenin and the cell cycle inhibitor p21. Although expression of both proteins
      was sustained in mitogen-restimulated myocytes, 5-bromodeoxyuridine incorporation
      experiments in serum-starved cultures revealed that myogenin-positive cells
      remained capable of replicating DNA. In contrast, subsequent expression of p21 in
      differentiating myoblasts correlated with the establishment of the postmitotic
      state. Later during myogenesis, postmitotic (p21-positive) mononucleated
      myoblasts activated the expression of the muscle structural protein myosin heavy
      chain, and then fused to form multinucleated myotubes. Thus, despite the
      asynchrony in the commitment to differentiation, skeletal myogenesis is a highly
      ordered process of temporally separable events that begins with myogenin
      expression, followed by p21 induction and cell cycle arrest, then phenotypic
      differentiation, and finally, cell fusion.

PMID- 8647897
TI  - Selective stabilization of tau in axons and microtubule-associated protein 2C in
      cell bodies and dendrites contributes to polarized localization of cytoskeletal
      proteins in mature neurons.
AB  - In mature neurons, tau is abundant in axons, whereas microtubule-associated
      protein 2 (MAP2) and MAP2C are specifically localized in dendrites. Known
      mechanisms involved in the compartmentalization of these cytoskeletal proteins
      include the differential localization of mRNA (MAP2 mRNA in dendrites, MAP2C mRNA
      in cell body, and Tau mRNA in proximal axon revealed by in situ hybridization)
      (Garner, C.C., R.P. Tucker, and A. Matus. 1988. Nature (Lond.). 336:674-677;
      Litman, P., J. Barg, L. Rindzooski, and I. Ginzburg. 1993. Neuron. 10:627-638),
      suppressed transit of MAP2 into axons (revealed by cDNA transfection into
      neurons) (Kanai, Y., and N. Hirokawa. 1995. Neuron. 14:421-432), and differential
      turnover of MAP2 in axons vs dendrites (Okabe, S., and N. Hirokawa. 1989. Proc.
      Natl. Acad. Sci. USA. 86:4127-4131). To investigate whether differential turnover
      of MAPs contributes to localization of other major MAPs in general, we
      microinjected biotinylated tau, MAP2C, or MAP2 into mature spinal cord neurons in
      culture (approximately 3 wk) and then analyzed their fates by antibiotin
      immunocytochemistry. Initially, each was detected in axons and dendrites,
      although tau persisted only in axons, whereas MAP2C and MAP2 were restricted to
      cell bodies and dendrites. Injected MAP2C and MAP2 bound to dendritic
      microtubules more firmly than to microtubules in axons, while injected tau bound
      to axonal microtubules more firmly than to microtubules in dendrites. Thus,
      beyond contributions from mRNA localization and selective axonal transport,
      compartmentalization of each of the three major MAPs occurs through local
      differential turnover.

PMID- 8647898
TI  - Tenascin-C contains distinct adhesive, anti-adhesive, and neurite outgrowth
      promoting sites for neurons.
AB  - The glia-derived extracellular matrix glycoprotein tenascin-C (TN-C) is
      transiently expressed in the developing CNS and may mediate neuron-glia
      interactions. Perturbation experiments with specific monoclonal antibodies
      suggested that TN-C functions for neural cells are encoded by distinct sites of
      the glycoprotein (Faissner, A., A. Scholze, and B. Gotz. 1994. Tenascin
      glycoproteins in developing neural tissues--only decoration? Persp. Dev.
      Neurobiol. 2:53-66). To characterize these further, bacterially expressed
      recombinant domains were generated and used for functional studies. Several short
      term-binding sites for mouse CNS neurons could be assigned to the fibronectin
      type III (FNIII) domains. Of these, the alternatively spliced insert
      TNfnA1,2,4,B,D supported initial attachment for both embryonic day 18 (E18) rat
      and postnatal day 6 (P6) mouse neurons. Only TNfn1-3 supported binding and growth
      of P6 mouse cerebellar neurons after 24 h, whereas attachment to the other
      domains proved reversible and resulted in cell detachment or aggregation. In
      choice assays on patterned substrates, repulsive properties could be attributed
      to the EGF-type repeats TNegf, and to TNfnA1,2,4. Finally, neurite outgrowth
      promoting properties for E18 rat hippocampal neurons and P0 mouse DRG explants
      could be assigned to TNfnB,D, TNfnD,6, and TNfn6. The epitope of mAb J1/tn2 which
      abolishes the neurite outgrowth inducing effect of intact TN-C could be allocated
      to TNfnD. These observations suggest that TN-C harbors distinct cell-binding,
      repulsive, and neurite outgrowth promoting sites for neurons. Furthermore, the
      properties of isoform-specific TN-C domains suggest functional significance of
      the alternative splicing of TN-C glycoproteins.

PMID- 8647900
TI  - MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand
      domains.
AB  - Cellular disintegrins are a family of proteins that are related to snake venom
      integrin ligands and metalloproteases. We have cloned and sequenced the mouse and
      human homologue of a widely expressed cellular disintegrin, which we have termed
      MDC9 (for metalloprotease/disintegrin/cysteine-rich protein 9). The deduced mouse
      and human protein sequences are 82% identical. MDC9 contains several distinct
      protein domains: a signal sequence is followed by a prodomain and a domain with
      sequence similarity to snake venom metalloproteases, a disintegrin domain, a
      cysteine-rich region, an EGF repeat, a membrane anchor, and a cytoplasmic tail.
      The cytoplasmic tail of MDC9 has two proline-rich sequences which can bind the
      SH3 domain of Src, and may therefore function as SH3 ligand domains. Western blot
      analysis shows that MDC9 is an approximately 84-kD glycoprotein in all mouse
      tissues examined, and in NIH 3T3 fibroblast and C2C12 myoblast mouse cell lines.
      MDC9 can be both cell surface biotinylated and 125I-labeled in NIH 3T3 mouse
      fibroblasts, indicating that the protein is present on the plasma membrane.
      Expression of MDC9 in COS-7 cells yields an 84-kD protein, and immunofluorescence
      analysis of COS-7 cells expressing MDC9 shows a staining pattern that is
      consistent with a plasma membrane localization. The apparent molecular mass of 84
      kD suggests that MDC9 contains a membrane-anchored metalloprotease and
      disintegrin domain. We propose that MDC9 might function as a membrane-anchored
      integrin ligand or metalloprotease, or that MDC9 may combine both activities in
      one protein.

PMID- 8647899
TI  - Human multidrug resistance 3-P-glycoprotein expression in transgenic mice induces
      lens membrane alterations leading to cataract.
AB  - We have generated mice transgenic for a human multidrug resistance (MDR)3 mini
      gene driven by a hamster vimentin promoter. The MDR3 gene encodes a P
      Glycoprotein that resembles the mouse multidrug resistance 2 P-Glycoprotein shown
      to be involved in the translocation of the phospholipid phosphatidylcholine
      through the hepatocyte canalicular membrane (Smit et al., 1993. Cell. 75:451
      462). The vimentin promoter drives expression of the MDR3 transgene in
      mesenchymal tissues and in the eye lens. We show here that the presence of human
      multidrug resistance 3 P-Glycoprotein in the lens results in a severe lenticular
      pathology. Lens structural abnormalities initiate at a late embryonic stage and
      increase during postnatal lens development. Differentiation of the primary fibers
      is affected, and the terminal differentiation of the lens epithelium into
      secondary fibers is also perturbed. The ultrastructural alterations, particularly
      of the lens plasma membranes, resemble those identified in congenital mouse
      osmotic cataract.

PMID- 8647901
TI  - Anchorage mediated by integrin alpha6beta4 to laminin 5 (epiligrin) regulates
      tyrosine phosphorylation of a membrane-associated 80-kD protein.
AB  - Detachment of basal keratinocytes from basement membrane signals a
      differentiation cascade. Two integrin receptors alpha6beta4 and alpha3beta1
      mediate adhesion to laminin 5 (epiligrin), a major extracellular matrix protein
      in the basement membrane of epidermis. By establishing a low temperature adhesion
      system at 4 degrees C, we were able to examine the exclusive role of alpha6beta4
      in adhesion of human foreskin keratinocyte (HFK) and the colon carcinoma cell
      LS123. We identified a novel 80-kD membrane-associated protein (p80) that is
      tyrosine phosphorylated in response to dissociation of alpha6beta4 from laminin
      5. The specificity of p80 phosphorylation for laminin 5 and alpha6beta4 was
      illustrated by the lack of regulation of p80 phosphorylation on collagen,
      fibronectin, or poly-L-lysine surfaces. We showed that blocking of alpha3beta1
      function using inhibitory mAbs, low temperature, or cytochalasin D diminished
      tyrosine phosphorylation of focal adhesion kinase but not p80 phosphorylation.
      Therefore, under our assay conditions, p80 phosphorylation is regulated by
      alpha6beta4, while motility via alpha3beta1 causes phosphorylation of focal
      adhesion kinase. Consistent with a linkage between p80 dephosphorylation and
      alpha6beta4 anchorage to laminin 5, we found that phosphatase inhibitor sodium
      vanadate, which blocked the p80 dephosphorylation, prevented the alpha6beta4
      dependent cell anchorage to laminin 5 at 4degreesC. In contrast, adhesion at 37
      degrees C via alpha3beta1 was unaffected. Furthermore, by in vitro kinase assay,
      we identified a kinase activity for p80 phosphorylation in suspended HFKs but not
      in attached cells. The kinase activity, alpha6beta4, and its associated adhesion
      structure stable anchoring contacts were all cofractionated in the Triton
      insoluble cell fraction that lacks alpha3beta1. Thus, regulation of p80
      phosphorylation, through the activities of p80 kinase and phosphatase, correlates
      with alpha6beta4-SAC anchorage to laminin 5 at 4 degrees C in epithelial cells of
      the skin and intestine. Transmembrane signaling through p80 is an early tyrosine
      phosphorylation event responsive to and possibly required for anchorage to
      laminin 5 by HFK and LS123 epithelial cells.

PMID- 8647903
TI  - Prostaglandin mediated modulation of transforming growth factor-beta metabolism
      in primary mouse osteoblastic cells in vitro.
AB  - Prostaglandins and transforming growth factor-beta (TGF-beta) are both important
      local regulators of bone metabolism, but their actions on bone are complex.
      Prostaglandins mediate bone loss due to immobilization, but prostaglandin E2
      (PGE2) treatment stimulates bone formation in vivo. TGF-beta may have both
      anabolic and catabolic effects on bone in vitro. In this study, we tested the
      effects of PGE2 on TGF-beta release and on TGF-beta messenger RNA (mRNA) levels
      in neonatal mouse calvarial cell cultures. We also examined the relationship
      between endogenous prostaglandin production as a result of mechanical stress and
      the release of TGF-beta. Addition of PGE2 (10(-8)-10(-6)M) to the culture medium
      stimulated the release of TGF-beta peptide (active plus latent) after 24 and 48 h
      in a dose-related manner. This upregulation was paralleled by an increased
      expression of TGF-beta mRNA levels. Mechanical stimulation by 1 h treatment with
      pulsating fluid flow (producing a shear stress of 0.5 +/- 0.02 Pa at 5 Hz)
      resulted 1 h posttreatment in increased production of PGE2, prostaglandin l2
      (PGI2), and prostaglandin F2a. In addition, the release of TGF-beta activity but
      not TGF-beta peptide was decreased 24 h after PFF treatment. Addition of
      indomethacin, which blocks endogenous prostaglandin production, neutralized the
      effect of PFF treatment on TGF-beta activity, indicating that the effect of
      stress was mediated by endogenous prostaglandins. These results suggest that PGE2
      and other prostaglandins (probably PGI2 and/or PGF2a) have opposite effects on
      TGF-beta metabolism in bone cells, as PGE2 upregulates TGF-beta expression and
      synthesis while other prostaglandins downregulate TGF-beta activation.

PMID- 8647902
TI  - Stimulation of beta1 integrins on fibroblasts induces PDGF independent tyrosine
      phosphorylation of PDGF beta-receptors.
AB  - We report that integrin-mediated signaling induces a rapid and transient tyrosine
      phosphorylation of platelet-derived growth factor (PDGF) beta-receptors in human
      diploid foreskin AG 1518 fibroblasts. A transient tyrosine phosphorylation of
      PDGF beta-receptors was evident one and two hours after cells had been plated on
      collagen type I and fibronectin, as well as on immobilized anti-integrin subunit
      IgG, but not on poly-L-lysine. In contrast EGF or PDGF alpha-receptors were not
      phosphorylated on tyrosine residues under these conditions. Tyrosine
      phosphorylation of PDGF beta-receptors induced by plating on collagen type I was
      inhibited by cytochalasin D and herbimycin A, unaffected by cycloheximide and
      enhanced by orthovanadate. Furthermore, a transient phosphorylation of PDGF beta
      receptors occurred when AG 518 fibroblasts were cultured in three-dimensional
      collagen lattices or exposed to external strain exerted through centrifugation.
      The latter effect was evident already after two minutes. Clustering of cell
      surface beta1 integrins led to PDGF beta-receptor phosphorylation both in
      suspended and firmly attached AG 1518 fibroblasts. Plating of cells on collagen
      type I, fibronectin, and anti-beta1-integrin IgG resulted in the formation of
      PDGF beta-receptor aggregates as detected by immunofluorescence. Suramin or anti
      PDGF-BB IgG had no effect on the plating-induced tyrosine phosphorylation of PDGF
      beta-receptors. PDGF-B chain mRNA, or protein, were not detected in AG 1518
      fibroblasts. Our data suggest that a ligand-independent PDGF beta-receptor
      activation during cell adhesion and early phases of cell spreading is involved in
      integrin-mediated signaling in fibroblasts, and constitutes parts of a mechanism
      for cells to respond during the dynamic phases of externally applied tension as
      well as fibroblast-mediated tension during cell adhesion and collagen gel
      contraction.

PMID- 8647904
TI  - RNA polymerase II inhibitor, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole
      (DRB) causes erythroleukemic differentiation and transcriptional activation of
      erythroid genes.
AB  - Friend virus-transformed murine erythroleukemia (MEL) cells are a useful system
      for studying the regulation of erythroid growth and differentiation. As a
      manifestation of the leukemic process, these erythroblasts are blocked in their
      ability to terminally differentiate. However, this block is reversible as a
      variety of different agents are capable of inducing differentiation of these
      malignant erythroblasts. The mechanisms by which these agents cause
      differentiation remains unknown. We report here that 5,6-dichlorobenzimidazole
      (DRB), which inhibits RNA polymerase II by causing premature termination of
      transcription, induces differentiation of these cells, including the
      transcriptional activation of erythroid genes. The effects of DRB on nonerythroid
      gene expression and on cell growth are substantially different than that of the
      commonly used inducer, dimethyl sulfoxide (DMSO). The shared ability of DMSO,
      DRB, and other unrelated agents to induce erythroid gene expression in MEL cells
      while having differing effects on nonerythroid gene expression and on cell growth
      suggests that expression of the terminally differentiated phenotype represents a
      common pathway that can be triggered by different mechanisms.

PMID- 8647905
TI  - Association of BCL-2 with membrane hyperpolarization and radioresistance.
AB  - The resting membrane potential of parental, neomycin control, and Bcl-2
      transfected cells was measured, and the effect of membrane hyperpolarization or
      depolarization on radiosensitivity was studied. Bcl-2 transfected cells were
      significantly more radioresistant than control cells and were significantly
      hyperpolarized compared to parental and neomycin control transfected PW and HL60
      cells. Hyperpolarization of the parental and neomycin control transfected cells
      by valinomycin significantly increased the radioresistance of these cells to such
      an extent that there was no longer a significant difference in the survival of
      the valinomycin treated and irradiated control cells compared to similarly
      irradiated Bcl-2 transfected cells. In contrast, depolarization of the Bcl-2
      transfected PW and HL60 cells decreased the radioresistance of the Bcl-2
      transfectants to a level similar to that of the control cells. The data presented
      here suggest that overexpression of Bcl-2 affects membrane potential and that
      this hyperpolarization is associated with increased radioresistance of cells that
      overexpress Bcl-2. Furthermore, Bcl-2 transfected cells were also less
      susceptible to the specific Na+/K(+)-ATPase inhibitor ouabain, suggesting that
      Bcl-2 may act at the level of the Na+/K(+)-ATPase pump.

PMID- 8647906
TI  - Ability of trypsin in mimicking germ cell factors that affect Sertoli cell
      secretory function.
AB  - A biological factor that inhibits the in vitro secretion of testin by Sertoli
      cells was purified to apparent homogeneity from conditioned medium of germ cells
      isolated using trypsin. Partial N-terminal amino acid sequence analysis of the
      purified germ cell factor revealed a sequence of NH2-IVGGYTXAAN. Comparison of
      the sequence with the existing protein database revealed that it is homologous to
      trypsin. Immunoprecipitation experiments using either [35S]-labeled germ or
      Sertoli cell proteins and a monospecific anti-trypsin antibody failed to
      demonstrate the synthesis and secretion of trypsin by these testicular cells,
      suggesting the isolated factor is the residuary trypsin that was used for
      isolating germ cells from seminiferous tubules. Subsequent experiments revealed
      that trypsin per se can inhibit the secretion of Sertoli cell testin and
      clusterin dose-dependently, whose effect can be prohibited by soybean trypsin
      inhibitor (STI). In view of these findings, a nonenzymatic procedure was deemed
      necessary to prepare germ cell conditioned medium (GCCM) to assess whether an
      authentic biological factor(s) is indeed present. Four batches of conditioned
      medium of germ cells isolated by a mechanical procedure without the use of
      trypsin were fractionated by sequential Mono Q anion exchange and C8 reversed
      phase HPLC. When these fractions were monitored for testin modulatory activity
      using an in vitro bioassay with primary cultures of Sertoli cells, it was shown
      that GCCM prepared by this procedure indeed contained testin modulatory
      bioactivity. Since testin is a novel component of specialized junctions between
      Sertoli and germ cells, the identification of a germ cell factor(s) that affects
      its secretion by Sertoli cells suggests a dynamic biochemical relationship
      between these cell types in the seminiferous epithelium.

PMID- 8647907
TI  - Effect of neuromimetics upon the release of atrial natriuretic peptide granules:
      are multiple pathways involved in secretion?
AB  - The release of atrial natriuretic peptide (ANP) in response to the application of
      neurohumoral agonists (neuromimetics) is directly demonstrated and quantified at
      the cellular level, using an ultrastructural assay developed to quantify
      secretion. The assay uses an in situ tannic acid perfusion technique to arrest
      the exocytosis of atrial secretory granules in the anesthetized rat. The animal
      is perfused with the neuromimetic, and secretory granules, which retain the
      capacity to undergo exocytosis throughout the subsequent 30 min tannic acid
      perfusion, accumulate at the cell surface in a state of fusion with the plasma
      membrane. Quantification of arrested granules thus provides a measure of the rate
      of granule release and allows the responses to different agents to be assessed.
      The actions of three different agents were investigated: isoproterenol,
      phenylephrine, and acetylcholine. In previously published studies, investigations
      of the actions of these agents on ANP release has produced unclear and sometimes
      contradictory results. Using our ultrastructural assay, it was found that during
      the 30 min perfusion period neither isoprenaline nor phenylephrine caused a
      significant change in the rate of secretory granule release, whereas
      acetylcholine significantly decreased the rate of granule release. A new model of
      secretion is proposed to integrate these findings with previous results and help
      clarify the complex picture of atrial natriuretic peptide release.

PMID- 8647908
TI  - Comitogenic effects of vasoactive intestinal polypeptide on rat hepatocytes.
AB  - The primary mitogens such as epidermal growth factor and transforming growth
      factor-alpha are known to stimulate DNA synthesis in primary cultures of adult
      rat hepatocytes. Vasoactive intestinal polypeptide (VIP) was found to amplify DNA
      synthesis induced by the primary mitogens and thus acted as a comitogen. The
      comitogenic effect of VIP was specific for the culture medium, suggesting that
      minor components in the medium were required for hepatocytes to fully respond to
      VIP. Glutamic acid is probably one of these minor components, although other
      components present in the nutrient-rich medium were also necessary for the full
      comitogenic effect. Other comitogens such as insulin, vasopressin, and
      angiotensin II interacted additively with low concentrations of VIP. The
      comitogenic effect of VIP was also found in hepatocytes cultured from
      regenerating rat liver after a partial hepatectomy. In the regenerating
      hepatocyte cultures, VIP can act as a mitogen even in the absence of the primary
      mitogen EGF. VIP mRNA was found in several organs including brain, intestine, and
      liver, and its expression was slightly induced in liver 24 h after a partial
      hepatectomy. These results suggest that VIP can act as a hepatic comitogen and
      may play a role in liver cell proliferation.

PMID- 8647909
TI  - Protein patterns, osmolytes, and aldose reductase of L-929 cells exposed to
      hyperosmotic media.
AB  - L-929 cells acclimated to media made hyperosmotic (600 mosmol/kgH2O) by addition
      of NaCl, sorbitol, or mannitol show, on SDS-polyacrylamide gels, a markedly
      enhanced protein band at 40 kDa, most likely corresponding to the enzyme aldose
      reductase. The effect was not observed in cells acclimated to a medium rendered
      hyperosmotic by addition of proline. The major organic osmolyte accumulated is
      sorbitol in cells acclimated to high-sorbitol or high-NaCl medium, proline in
      cells acclimated to high-proline medium. Cells acclimated to any of these
      hyperosmotic media display unaltered Na+ levels and similarly increased K+ levels
      and decreased Cl-levels. These results are interpreted in terms of the mechanisms
      involved in aldose reductase induction and in regulation of the enzyme activity
      in long-term acclimation to hyperosmotic media.

PMID- 8647910
TI  - Transmembrane potential responses during HL-60 promyelocyte differentiation.
AB  - Myeloid cells, including granulocytes and monocyte/macrophages, are important in
      disease-associated inflammatory reactions. These cells come from a common
      progenitor, the promyelocyte. The human promyelocytic cell line, HL-60, can be
      induced to terminally differentiate into granulocytes or monocyte/ macrophages in
      a controlled fashion providing a model to study various aspects of myelomonocytic
      differentiation. The expression of several ion channels is controlled in HL-60
      cells in a differentiation specific pattern. The purpose of this study was to
      determine if lineage-specific ion channel expression during HL-60 differentiation
      resulted in differences in functional responses to external stimuli. This was
      investigated by examining transmembrane potential responses in HL-60
      promyelocytes, HL-60-derived polymorphonuclear cells (PMNs), and monocytes to
      various stimuli using the transmembrane potential sensitive dye, diSBAC2-(3).
      Exposure of HL-60 promyelocytes to ionomycin or ATP produced a membrane
      hyperpolarization. Studies using ion substitutions and ion channel blockers
      indicate that the hyperpolarization was mediated by KCa channels. During HL-60
      promyelocyte differentiation to PMNs, the membrane potential response to
      ionomycin and ATP shifted from a hyperpolarization to a depolarization over 7
      days. Conversely, HL-60-derived monocytes exhibited a membrane hyperpolarization
      in response to ionomycin and ATP. HL-60-derived monocytes also exhibit a Cl-
      conductance specifically induced by ATP. Lineage-specific expression of ion
      channels during HL-60 cell differentiation is important in determining the
      transmembrane potential response of these cells. This may be translated into
      functional responses of various myelomonocytic cells during disease-associated
      inflammatory reactions.

PMID- 8647911
TI  - G-protein coupling of muscarinic receptors in adult and neonatal rat
      submandibular cells.
AB  - The submandibular glands of neonatal and adult rats express muscarinic
      cholinergic receptors. Receptor occupancy initiates signaling through activation
      of phospholipase C, hydrolysis of inositol phospholipids, and calcium
      mobilization. The increased cytoplasmic [Ca2+] activates ion transport pathways,
      resulting in secretion of primary saliva. We have previously shown that
      muscarinic receptors are present in the gland of neonates and that they couple
      effectively to inositol trisphosphate production and Ca2+ mobilization but that
      the monovalent ion transport paths are poorly activated. To characterize age
      related differences in signal transduction further, we examined the coupling of
      muscarinic receptors to G-proteins by determining the effect of GTP on the IC50
      for competition by the muscarinic agonist carbachol with the radiolabeled
      antagonist, 3H-quinuclidinyl benzylate. Data were fit to one-site and two-site
      models, and in all cases the two-site model provided the better fit. Using the
      two-site model, a substantial GTP-induced shift from high affinity to low
      affinity binding was observed in membranes from adults, whereas more of the
      receptors were already in the low affinity form in the membranes from neonates,
      and little additional shift was induced by GTP. These results suggest differences
      in the G-protein coupling of muscarinic receptors in submandibular cells of adult
      and early postnatal rats that may be associated with differences in the content,
      affinity, or properties (i.e., posttranslational modifications) of G-proteins as
      the cells mature.

PMID- 8647912
TI  - Pasteurella multocida toxin stimulates mitogenesis and cytoskeleton
      reorganization in Swiss 3T3 fibroblasts.
AB  - Pasteurella multocida toxin (PMT) causes cytoplasmic retraction in epithelial
      cells, activates osteoclast neoformation, and is a potent mitogen for Swiss 3T3
      fibroblasts. In the present study designed to further investigate the effects of
      PMT on cell shape and proliferation, we report that the mitogenic effect of
      affinitypurified PMT on quiescent 3T3 cells was even superior at 5 ng/ml to that
      of fetal bovine serum or bombesin. This positive effect was inhibited by heat
      denaturation and methylamine treatment (this agent blocks internalization).
      Preincubation of PMT with gangliosides GM1, GM2, or GM3 counteracted its effect
      on DNA synthesis, suggesting that the toxin binds to GM-type ceramides on target
      cells. The distribution of F-actin was analyzed in control/treated cells using
      FITC-conjugated phalloidin. In comparison with FBS and bombesin, PMT triggered a
      more rapid and profound reorganization of cortical actin into prominent stress
      fibers after only 5-10 min. This event lead to the retraction of cells after only
      30 min and ultimately to the induction of mitotic figures. Interestingly,
      methylamine blocked the effects of PMT on stress fiber formation and cell
      retraction but not the ruffling response, suggesting that some early events may
      not require toxin internalization. In summary, these findings indicate that PMT
      concomitantly exerts a strong mitogenic activity and a rapid stimulation of
      cytoskeletal rearrangements, possibly after binding to membrane gangliosides and
      subsequent internalization. We propose that this toxin could be used in the
      future as a defined inducer of transduction signals involved in cellular
      proliferation and control of cell shape.

PMID- 8647913
TI  - Increased stringency of the 1,25-dihydroxyvitamin D3-induced G1 to S phase block
      in polyploid HL60 cells.
AB  - Treatment of mammalian cells with 1,25-dihydroxyvitamin D3 (1,25D3) produces a G1
      to S (G1/S) phase cell cycle block. In addition, it has been noted that a smaller
      proportion of cells accumulates in the G2/M compartment in 1,25D3-treated
      cultures. Since cyclins have a major influence on the regulation of cell cycle
      progression, we determined the expression of cyclins A and B as markers of the G2
      phase and of cyclin E as the marker of G1/S transition. No increase in the steady
      state levels of cyclin A or cyclin B mRNA was detected in the total cell
      population or in the cyclin B1 protein in the G2/M cell cycle compartment. In
      contrast, immunodetectable cyclin E protein was increased in cell cultures as a
      whole and specifically in the G2/M compartment cells. Determination of BrdU
      incorporation into DNA by flow cytometry showed marked inhibition of DNA
      replication in cells with DNA content higher than 4C, and autoradiography of 3H
      TdR-pulsed cells showed that polynucleated cells did not replicate DNA after 96 h
      of treatment with 1,25D3 or analogs. Taken together, these experiments show that
      at least a portion of the G2/M compartment in 1,25D3-arrested cultures of HL60
      cells represents G1 cells at a higher ploidy level, which are blocked from
      entering the high ploidy S phase.

PMID- 8647914
TI  - Methotrexate inhibits superoxide production and chemotaxis in neutrophils
      activated by granulocyte colony-stimulating factor.
AB  - Treatment of circulating human neutrophils with recombinant human granulocyte
      colony-stimulating factor (rhG-CSF) for 30 min augmented superoxide generation
      and chemotaxis induced by N-formylmethionyl-leucyl-phenylalanine (fMLP) in a dose
      dependent manner. When neutrophils were treated with 1 microM of methotrexate
      (MTX) for 60 min after incubation with rhG-CSF (10 ng/ml), the effects of rhG-CSF
      on superoxide generation and chemotaxis were inhibited by approximately 49 and
      29%, respectively. Although inhibitory effects of MTX were also seen in
      neutrophils not pretreated with rhG-CSF, the degree of inhibition was much less.
      The addition of either hypoxanthine or guanosine at a concentration of 100 microM
      to the culture medium significantly attenuated the effects of MTX. However, in
      neutrophils obtained from a patient with Lesch-Nyhan syndrome, which lacked
      hypoxanthine-guanine phosphoribosyl transferase activity neither hypoxanthine nor
      guanosine had any rescue effect. These results suggest that MTX inhibits
      superoxide generation and chemotaxis in rhG-CSF-activated neutrophils, at least
      in part, by disturbing purine nucleotide biosynthesis.

PMID- 8647915
TI  - Tissue origin and extracellular matrix control neutral proteinase activity in
      human fibroblast three-dimensional cultures.
AB  - Remodeling of the extracellular matrix by fibroblasts is an important step in the
      process of wound healing and tissue repair. We compared the behavior of
      fibroblasts from two different tissues, dermis and gingiva, in three-dimensional
      lattices made of two different extracellular matrix macromolecules, collagen and
      fibrin. Cells were grown in monolayer cultures from normal skin or gingiva and
      seeded in three-dimensional lattices made of either collagen of fibrin. Photonic
      and scanning electron microscopy did not reveal any morphological differences
      between the two types of fibroblasts in both sets of lattices. Both types of
      fibroblasts retracted collagen lattices similarly and caused only a slight
      degradation of the collagen substratum. By contrast, when seeded in fibrin
      lattices, gingival fibroblasts completely digested their substratum in less than
      8 days, whereas only a slight fibrin degradation was observed with dermal
      fibroblasts. The ability of gingival but not dermal fibroblasts to express high
      levels of tissue plasminogen activators (tPA) when cultured in fibrin lattices
      was assessed on an immunological basis. Also, deprivation of plasminogen
      contaminating fibrinogen preparations or use of tPA inhibitors markedly inhibited
      both fibrinolysis and retraction rates of fibrin lattices by gingival
      fibroblasts. Casein-zymography confirmed the intense proteolytic activity induced
      by fibrin in gingival fibroblasts. It was inhibited by aprotinin and phenyl
      methylsulfonyl fluoride (PMSF), two non-specific inhibitors of serine
      proteinases, and by epsilon-amino-caproic acid (epsilon ACA), an inhibitor of
      plasminogen activators. Monolayer cultures exhibited only trace amounts of
      caseinolytic activity. Our results demonstrate that the expression of proteinases
      by fibroblasts is dependent not only on their tissue origin but also on the
      surrounding extracellular matrix. The intense fibrinolytic activity of gingival
      fibroblasts in fibrin lattices may explain partially the high rate of healing
      clinically observed in gingiva.

PMID- 8647916
TI  - Tumor necrosis factor-alpha induces transcription of the colony-stimulating
      factor-1 gene in murine osteoblasts.
AB  - Tumor necrosis factor-alpha (TNF-alpha) stimulates bone resorption both in vitro
      and in vivo. The cellular mechanisms for this effect are not known but one
      pathway may be via release of osteoblast derived factors which stimulate
      osteoclast formation. Because colony-stimulating factor-1 (CSF-1) is essential
      for osteoclast progenitor proliferation, we examined the effect of TNF-alpha on
      osteoblast expression of CSF-1. TNF-alpha treatment of MC3T3-E1 or primary mouse
      osteoblasts stimulated the secretion of an activity that was mitogenic for a CSF
      1 responsive cell line and was completely neutralized by antiserum to CSF-1. By
      Northern analysis, TNF-alpha caused a dose and time (3 to 24 h) dependent
      increase in CSF-1 transcript expression in MC3T3-E1 cells. mRNA stability studies
      using actinomycin D revealed that TNF-alpha does not affect CSF-1 mRNA half-life
      in MC3T3-E1 cells, while nuclear-run off analysis demonstrated that TNF-alpha
      increases CSF-1 gene transcription. Cycloheximide treatment of MC3T3-E1 cells up
      regulated CSF-1 mRNA, and compared to either agent alone, cycloheximide and TNF
      alpha in combination resulted in augmentation of CSF-1 expression. A series of
      studies using both agonists and inhibitors indicated that TNF-alpha-induced CSF-1
      expression did not involve the arachidonic acid, PKC, or cAMP pathways. These
      results suggest that TNF-alpha induces CSF-1 expression in osteoblasts by a
      transcriptional mechanism which is largely independent of new protein synthesis
      and of the second messenger pathways examined.

PMID- 8647917
TI  - Thrombin induces proliferation of osteoblast-like cells through
      phosphatidylcholine hydrolysis.
AB  - We examined the effect of thrombin on phosphatidylcholine-hydrolyzing
      phospholipase D activity in osteoblast-like MC3T3-E1 cells. Thrombin stimulated
      the formation of choline dose dependently in the range between 0.01 and 1 U/ml,
      but not the phosphocholine formation. Diisopropylfluorophosphate (DFP)-
      inactivated thrombin had little effect on the choline formation. The combined
      effects of thrombin and 12-O-tetradecanoylphorbol-13-acetate, a protein kinase C
      activating phorbol ester, on the choline formation were additive. Staurosporine,
      an inhibitor of protein kinases, had little effect on the thrombin-induced
      formation of choline. Combined addition of thrombin and NaF, an activator of
      heterotrimeric GTP-binding protein, did not stimulate the formation of choline
      further. Pertussis toxin had little effect on the thrombin-induced formation of
      choline. Thrombin stimulated Ca2+ influx from extracellular space time and dose
      dependently. The depletion of extracellular Ca2+ by EGTA exclusively reduced the
      thrombin-induced choline formation. Thrombin had only a slight effect on
      phosphoinositide-hydrolyzing phospholipase C activity. Thrombin induced
      diacylglycerol formation and DNA synthesis, and increased the number of MC3T3-E1
      cells, but DFP-inactivated thrombin did not. Thrombin suppressed both basal and
      fetal calf serum-induced alkaline phosphatase activity in these cells.
      Propranolol, an inhibitor of phosphatidic acid phosphohydrolase, inhibited both
      the thrombin-induced diacylglycerol formation and DNA synthesis. These results
      suggest that thrombin stimulates phosphatidylcholine-hydrolyzing phospholipase D
      due to self-induced Ca2+ influx independently of protein kinase C activation in
      osteoblast-like cells and that its proliferative effect depends on phospholipase
      D activation.

PMID- 8647919
TI  - Supplemental L-arginine HCl augments bacterial phagocytosis in human
      polymorphonuclear leukocytes.
AB  - That L-arginine (L-Arg) augments the host response to acute bacterial sepsis
      suggests that this amino acid intervenes early in the immune response, perhaps
      via the nitric oxide synthetase (NOS) pathway. The effect of L-Arg
      supplementation on in vitro phagocytosis of fluorescein-labeled, heat-killed
      Staphylococcus aureus by peripheral blood neutrophils (PMNs) from 12 normal human
      volunteers was studied. Separated PMNs were incubated for 2 h with labeled
      bacteria, with and without supplemental L-Arg, D-arginine, glycine, and/or the
      NOS inhibitors L-canavanine, aminoguanidine, or L-NG-nitroarginine methyl ester.
      PMNs were fixed and extracellular fluorescence quenched with crystal violet. By
      flow cytometry and confocal microscopy, L-Arg supplementation was shown to result
      in a highly significant increase in PMN bacterial phagocytosis, the maximal
      effect being seen with L-Arg 380 microM and falling off with higher
      concentrations. This augmentation was completely abrogated by NOS inhibitors in
      molar excess, but inhibitors alone did not suppress phagocytosis below that of
      unsupplemented controls. Neither D-arginine nor glycine affected phagocytosis;
      the L-Arg effect was stereospecific and not related to utilization of L-Arg as an
      energy source. L-Arg supplementation significantly enhances bacterial
      phagocytosis in human neutrophils, perhaps by effects on cytoskeletal phenomena,
      and this appears to be mediated through NOS activity. Phagocytosis by nonspecific
      immune cells which intervene early in the response to sepsis is critically
      important, and beneficial effects of L-Arg on the clinical course of sepsis may
      be due at least in part to augmentation of phagocyte function.

PMID- 8647918
TI  - Neutrophil thrombospondin receptors are linked to GTP-binding proteins.
AB  - The extracellular matrix (ECM) protein thrombospondin (TSP) binds to specific
      receptors on polymorphonuclear leukocytes (PMNs) and stimulates motility. TSP can
      also enhance the response of PMNs to the formylated peptide, N-formyl-methionyl
      leucyl-phenylalanine (FMLP). Our initial evidence suggesting that PMN TSP
      receptors were linked to GTP-binding proteins (G-proteins) came from studies
      using pertussis toxin (PT) and cholera toxin (CT) to inhibit TSP-mediated
      motility. Both PT and CT inhibited TSP-mediated chemotaxis and substrate
      associated random migration. Inhibition was not indirectly caused by a rise in
      cAMP since neither dibutyryl cAMP (300 microM) nor 8-bromo-cAMP (300 microM)
      significantly affected TSP-mediated motility. In fact, TSP itself caused a
      significant rise in intracellular cAMP levels (from 7.2 +/- 0.3 to 14.2 +/- 0.1
      pmol/10(6) cells). Although we could not test the PT sensitivity of TSP priming
      for FMLP-mediated chemotaxis (as PT inhibits FMLP-mediated chemotaxis itself), we
      evaluated the effect of CT on this response. CT completely abolished TSP
      dependent priming of FMLP-mediated chemotaxis. Direct evidence for an interaction
      between TSP receptors and G-proteins was obtained by examining the effect of TSP
      on alpha-subunit ADP-ribosylation, GTPase activity, and GTP gamma S binding. We
      observed a decrease in the ability of FMLP to stimulate GTPase activity on
      membranes isolated from PMNs incubated with TSP. Furthermore, the PT-dependent
      ribosylation of Ci alpha 2,3 stimulated by FMLP was eliminated by TSP treatment.
      These data indicated that the two receptors share a pool of G-proteins. However,
      TSP did not block the CT-dependent ribosylation stimulated by FMLP, suggesting
      that TSP receptors may also interact with a different pool of Gi alpha 2,3. TSP
      itself significantly (P < 0.005) increased GTP hydrolysis in PMN membranes (to
      110.6 +/- 2.7% of control values). In addition, GTP gamma S binding to membranes
      increased significantly (P < 0.005) following exposure to 10 nM TSP (to 108 +/-
      1.4% of control values). Conversely, GTP treatment reduced the affinity of TSP
      for its receptor without altering total binding. These data demonstrate that TSP
      receptors are linked to G-proteins, a subpopulation of which also associates with
      FMLP receptors.

PMID- 8647920
TI  - Overexpression of the type-1 insulin-like growth factor receptor increases ligand
      dependent proliferation and differentiation in bovine skeletal myogenic cultures.
AB  - Previous studies demonstrated that overexpression of the type-1 insulin-like
      growth factor (IGF) receptor (IGF-1R) in skeletal myogenic cell lines increased
      proliferation and differentiation responses to IGF. However, it was unclear if
      such manipulations in primary, untransformed skeletal myogenic cells would result
      in modulation of these responses, which may be more stringently regulated in
      primary cells than in myogenic cell lines. In this study, low passage
      untransformed fetal bovine myogenic cultures were infected with a replication
      deficient retroviral expression vector (LISN) coding for the human IGF-1R or with
      a control retroviral vector (LNL6). Bovine myogenic cultures infected with the
      LISN vector (Bov-LISN) displayed ten times more IGF-1Rs than controls (Bov-LNL6).
      Bov-LISN myogenic cultures exhibited elevated rates of IGF-I-stimulated
      proliferation and increased rates of terminal differentiation which were reduced
      to control levels by the anti-human IGF-1R antibody alpha IR3. These findings
      indicate overexpression of the IGF-1R can enhance IGF sensitivity and thereby
      modify the proliferation and differentiation behavior of untransformed low
      passage myoblasts. Such manipulations may be useful to increase muscle mass in
      clinical or agricultural applications.

PMID- 8647921
TI  - Regulation of avian precardiac mesoderm development by insulin and insulin-like
      growth factors.
AB  - Endoderm within the heart forming regions of vertebrate embryos has pronounced
      effects on myocardial cell development. Previous studies have suggested that
      these effects are mediated by soluble growth factors, in particular fibroblast
      growth factor 2 (FGF-2) and activin-A. Since both insulin and insulin-like growth
      factors (IGFs) are present in developing avian embryos at the time of heart
      formation, we have investigated the potential role of these molecules in
      promoting development of premyocardial cells in quail. Culture of precardiac
      mesoderm explants from stage 5 quail embryos in medium containing insulin, IGF-I,
      or IGF-II increased proliferation of premyocardial cells, with maximal
      stimulation observed at approximately 25 nM for each ligand. A direct comparison
      of the proliferative response of precardiac mesoderm to endoderm, fetal calf
      serum, insulin, IGF-I, IGF-II, activin-A, and FGF-2 showed that FGF-2 and activin
      A increased proliferation of premyocardial cells approximately 2-fold, while
      insulin, IGF-I, and IGF-II stimulated proliferation approximately 3-fold. Insulin
      and IGF-I enhanced the rate of myocyte differentiation, similar to previously
      reported effects of endoderm. In contrast, exposure of precardiac mesoderm
      explants to transforming growth factor beta (TGF beta) reduced proliferation of
      premyocardial cells and moderated the proliferative effects of IGF-I. TGF beta
      did not block the differentiation of stage 5 premyocardial cells. Reverse
      transcription-polymerase chain reaction (RT-PCR) analyses showed that mRNAs
      encoding insulin, IGF-II, insulin receptor, and IGF-I receptor were present in
      both precardiac mesoderm and endoderm, as well as in the forming heart at stage
      8. Since premyocardial cells can survive and differentiate in a defined medium
      lacking these factors, precardiac mesoderm may produce IGF-II and insulin at
      levels that are sufficient to stimulate myocyte development. Taken together,
      these results suggest that insulin and/or IGF-II may promote cardiac development
      in vivo by both autocrine and paracrine mechanisms. Cardiogenesis may therefore
      be promoted by the combined action of several classes of growth factors.

PMID- 8647922
TI  - Effects of the carbohydrate-binding protein galectin-3 on the invasiveness of
      human breast carcinoma cells.
AB  - Galectin-3 is a Mr 30,000 protein with carbohydrate-binding specificity for type
      I and II ABH blood group epitopes and polylactosamine glycans expressed on cell
      surface and extracellular matrix glycoproteins such as laminin. Cell lines
      propagated from human normal mammary epithelia and from benign or infiltrating
      components of primary breast tumours express low levels of galectin-3 in the
      cytoplasm. However, galectin-3 when added exogenously in solution or when bound
      within a three-dimensional matrix markedly enhanced the migration of the primary
      tumour cell lines through a Matrigel barrier. Galectin-3 expression in the
      cytoplasm and intercellularly on surface membranes was greatly increased in cell
      lines propagated from malignant ascites and pleural effusions of late stage
      breast cancer. These cell lines were non-invasive in the Matrigel assay and
      exogenous galectin-3 had no enhancing effect on invasiveness. These results
      suggest that galectin-3 could play multiple roles in cell metastasis at an early
      invasive stage by acting in a paracrine manner to stimulate cell migration
      through an extracellular matrix, and in later stage cancers in synergy with other
      mediators of cell-cell aggregation. However, endogenous galectin-3 expression in
      human breast cancers is not correlated directly with their invasive potential in
      vitro.

PMID- 8647923
TI  - c-Myc expression is controlled by the mitogenic cAMP-cascade in thyrocytes.
AB  - In dog thyroid epithelial cells in primary culture, thyrotropin (TSH), acting
      through cAMP, induces proliferation and differentiation expression, whereas
      epidermal growth factor (EGF) and phorbol esters induce proliferation and
      dedifferentiation. In these cells, we have detailed the regulation by cAMP of the
      c-myc protooncogene mRNA and protein. The cAMP signaling pathway induces a
      biphasic increase of c-myc mRNA and protein. c-Myc protein accumulation follows
      the abundance and kinetics of its mRNA expression. Using in vitro elongation of
      nascent transcripts to measure transcription and actinomycin D (AcD) chase
      experiments to study mRNA stability, we have shown that in the first phase cAMP
      releases a transcriptional elongation block. No modification of transcriptional
      initiation was observed. After 30 min of treatment with TSH, c-myc mRNA was also
      stabilized. During the second phase, cAMP stabilization of the mRNA disappears
      and transcription is again shut off. Thus, in a tissue in which it stimulates
      proliferation and specific gene expression, cAMP regulates biphasically c-myc
      expression by mechanisms operating at the transcriptional and posttranscriptional
      levels.

PMID- 8647924
TI  - Hemopexin in the human retina: protection of the retina against heme-mediated
      toxicity.
AB  - The existence of the blood-retinal barrier means that proteins that protect the
      retina from damage by reactive oxygen species must either be made locally or
      specifically transported across the barrier cells; however, such transepithelial
      transport does not seem to occur. Among the circulatory proteins that protect
      against iron-catalyzed production of free radicals are apo-transferrin, which
      binds ferric iron and has previously been shown to be made by cells of the neural
      retina (Davis and Hunt, 1993, J. Cell Physiol., 156:280-285), and the
      extracellular antioxidant, apo-hemopexin, which binds free heme (iron
      protoporphyrin IX). Since hemorrhage and heme release can be important
      contributing factors in retinal disease, evidence of a hemopexin-based retinal
      protection system was sought. The human retina has been shown to contain apo
      hemopexin which is probably synthesized locally since its mRNA can be detected in
      retinal tissue dissected from human donor eyes. It is likely that the retina
      contains a mechanism for the degradation of hemopexin-bound heme since the blood
      retinal barrier also precludes the exit of heme-hemopexin from the retina.
      Retinal pigment epithelial cells have been found to bind and internalize heme
      hemopexin in a temperature-dependent, saturable, and specific manner, analogous
      to the receptor-mediated endocytic system of hepatoma cells. Moreover, the
      binding of heme-hemopexin to the cells stimulates the expression of heme
      oxygenase-1, metallothionein-1, and ferritin.

PMID- 8647925
TI  - Examination of the role for Ca2+ in regulation and phosphorylation of the Na+/H+
      antiporter NHE1 via mitogen and hypertonic stimulation.
AB  - It has been suggested that Ca2+ transients, acting through calmodulin-binding
      proteins, play a role in the activation of the Na+/H+ exchanger isoform NHE1
      (Owen and Villereal, 1982a, Biochem. Biophys. Res. Commun., 109:762-768; 1982b,
      Proc. Natl. Acad. Sci. U.S.A., 79:3537-3541, Ober and Pardee, 1987, J. Cell.
      Physiol., 132:311-317). This is supported by a recent report that NHE1 is a
      calmodulin-binding protein and that loss of the high-affinity calmodulin-binding
      site results in alterations in antiporter function (Bertrand, et al., 1994, J.
      Biol. Chem., 269:13703-13709). An additional mechanism by which NHE1 is activated
      by mitogens is thought to be phosphorylation (Sardet, et al., 1990, Science
      247:723-726). Although the calmodulin-binding region appears vital to antiporter
      activation, the role of phosphorylation is unclear. The studies presented here
      examine a role for Ca2+ in the activation and phosphorylation of NHE1 induced by
      serum and hypertonicity. It is apparent that the microsomal Ca2+ ATPase inhibitor
      thapsigargin activates antiporter function in human foreskin fibroblasts (HSWP)
      as determined by increased intracellular alkalinization examined by image
      analysis. This effect is Ca(2+)-dependent as the alkalinization is blocked when
      cells are preincubated with BAPTA, an intracellular Ca2+ chelator. Similarly, the
      effects of serum-induced intracellular alkalinization are inhibited by BAPTA. In
      contrast, activation of NHE1 by increased osmolarity was not inhibited by BAPTA.
      This suggests that serum, and not hypertonicity, increases intracellular pH via a
      Ca(2+)-dependent process. It was also observed that both thapsigargin and
      hypertonicity activate NHE1 by a phosphorylation-independent mechanism and that
      BAPTA did not block the serum-induced increase in phosphorylation of NHE1. These
      results indicate that Ca2+ plays the predominant role in the serum-induced
      activation of NHE1, while phosphorylation plays only a minor, if any, role in
      this process. However, Ca2+ does not appear to be involved in the osmotic
      regulation of NHE1.

PMID- 8647926
TI  - Heme-mediated reactive oxygen species toxicity to retinal pigment epithelial
      cells is reduced by hemopexin.
AB  - Catalysis of the formation of reactive oxygen species (RO2S) by low molecular
      weight complexes of iron has been implicated in several pathological conditions
      in the retina since photoreceptors and retinal pigment epithelial cells are
      likely to be especially sensitive to RO2S. Since protective proteins cannot cross
      the blood-retinal barrier, it is likely that the retina performs its own
      protective functions by synthesizing proteins that bind iron and nonprotein iron
      complexes, the major catalysts of RO2S generation. Investigations were carried
      out to determine whether pigment epithelial cells are themselves sensitive to
      iron-generated RO2S and whether apo-transferrin and apo-hemopexin, known to be
      made locally in the retina, can perform a protective function. In 51Cr release
      assays, the toxicity of exogenous RO2S including hydrogen peroxide or superoxide
      (generated by xanthine oxidase/hypoxanthine) to human retinal pigment epithelial
      cells was inhibited by the iron chelators, desferrioxamine and apo-transferrin.
      Free but not protein-bound ferric iron and heme exacerbated the toxic effect. The
      toxic effect of heme was abolished by the heme-scavenging, extracellular
      antioxidant, apo-hemopexin, and also by exogenous bovine serum albumin. In
      addition, heme toxicity was inhibited by a 3 h preincubation of cells with either
      heme, apo-hemopexin, or heme-hemopexin 24 h prior to the toxicity assay. It is
      concluded, first, that toxic effects of iron and heme can be prevented by apo
      transferrin or apo-hemopexin and, second, that exposure of RPE cells to free heme
      or hemopexin sets in motion a series of biochemical events resulting in
      protection against oxidative stress. It is probable that these include heme
      oxygenase induction.

PMID- 8647927
TI  - Induction of down-regulation of the kinase activities of Mek, p42Erk, p90RSK, and
      p63SAMK in chicken embryo fibroblast at the late stage of src-induced cellular
      transformation.
AB  - Two distinct stages in regulation of protein kinases are detectable upon cellular
      transformation of CEF induced by pp60v-src. Upon cellular transformation induced
      by ts v-src mutants, the kinase activities of Mek and p42Erk are rapidly induced
      at the early stage and significantly decreased at the late stage of cellular
      transformation. In contrast, a novel p63SAMK is partially activated at the early
      stage and is fully activated at the late stage of cellular transformation.
      However, p90RSK is activated through the entire course of cellular
      transformation. In this study, I detect a transient down-regulation of p90RSK
      activity that is inducible in cultures at the late stage of the src-induced
      cellular transformation by an increase of extracellular pH value from 7 to 8 and
      unidentified components in DMEM, but not in cultures which are at the early
      stage. Concomitant with down-regulation of p90RSK activity, the kinase activities
      of Mek, p42Erk, and p63SAMK are also down-regulated. Blockage of down-regulation
      of p90RSK activity by pretreatment of cells with different phosphatase inhibitors
      correlates with blockage of the down-regulation of either p42Erk or p63SAMK
      activity. Multiple pathways appear to involve in regulation of p90RSK activity.
      The discrepancy in regulation of protein kinase activity between the early and
      late stages of cellular transformation induced by pp60src may indicate a change
      in signaling cascades during the progress of cellular transformation. The
      induction of the down-regulation event in this study may provide a new approach
      to investigate the regulation not only of protein kinases but also phosphatases
      in transformed cells.

PMID- 8647928
TI  - Glycosaminoglycans enhance megakaryocytopoiesis by modifying the activities of
      hematopoietic growth regulators.
AB  - We have previously reported that heparin is capable of stimulating in vitro and
      in vivo megakaryocytopoiesis in mice and has a thrombopoietic effect when given
      in chronic immune thrombocytopenic purpura and that heparin and several other
      glycosaminoglycans (GAGs) promote the growth of human megakaryoblastic cell lines
      in the presence of serum. We show here that GAGs, including heparan sulfate (HS),
      chondroitin sulfate (CS), dermatan sulfate (DS), and hyaluronic acid (HA), also
      stimulate in vitro growth of murine megakaryocyte progenitors and augment the
      diameter of individual megakaryocytes in the presence of serum. However, in a
      serum-free agar system, the GAGs alone had no effect on megakaryocyte colony
      formation, suggesting that GAGs cooperate with some serum factor(s) to exert
      their activity. We also show that heparin significantly potentiates the
      megakaryocytopoietic activity of C-Mpl ligand and interleukin (IL)-6 but not IL3,
      GM-CSF, SCF, and Epo. In addition, the GAGs significantly neutralize the
      inhibitory action of platelet factor 4 (PF4) and transforming growth factor beta
      1 (TGF beta 1) on megakaryocyte colony growth. These results demonstrate a
      stimulating activity of GAGs on megakaryocytopoiesis by modifying the activity of
      several growth-regulating factors.

PMID- 8647929
TI  - Balancing cell life and death: bax, apoptosis, and breast cancer.

PMID- 8647930
TI  - Finally, a noncontroversial role for Apo A-I in HDL-mediated cholesterol flux to
      cells.

PMID- 8647931
TI  - The enigma of the Wiskott-Aldrich syndrome begins to unravel.

PMID- 8647933
TI  - Alterations in basal and glucose-stimulated voltage-dependent Ca2+ channel
      activities in pancreatic beta cells of non-insulin-dependent diabetes mellitus GK
      rats.
AB  - In genetically occurring non-insulin-dependent diabetes mellitus (NIDDM) model
      rats (GK rats), the activities of L- and T-type Ca2+ channels in pancreatic beta
      cells are found to be augmented, by measuring the Ba2+ currents via these
      channels using whole-cell patch-clamp technique, while the patterns of the
      current-voltage curves are indistinguishable. The hyper-responsiveness of insulin
      secretion to nonglucose depolarizing stimuli observed in NIDDM beta cells could
      be the result, therefore, of increased voltage-dependent Ca2+ channel activity.
      Perforated patch-clamp recordings reveal that the augmentation of L-type Ca2+
      channel activity by glucose is markedly less pronounced in GK beta cells than in
      control beta cells, while glucose-induced augmentation of T-type Ca2+ channel
      activity is observed neither in the control nor in the GK beta cells. This lack
      of glucose-induced augmentation of L-type Ca2+ channel activity in GK beta cells
      might be causatively related to the selective impairment of glucose-induced
      insulin secretion in NIDDM beta cells, in conjunction with an insufficient plasma
      membrane depolarization due to impaired closure of the ATP-sensitive K+ channels
      caused by the disturbed intracellular glucose metabolism in NIDDM beta cells.

PMID- 8647932
TI  - Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human
      apolipoprotein A-I transgenic mice.
AB  - The regulation of liver apolipoprotein (apo) A-I gene expression by fibrates was
      studied in human apo A-I transgenic mice containing a human genomic DNA fragment
      driving apo A-I expression in liver. Treatment with fenofibrate (0.5% wt/wt) for
      7 d increased plasma human apo A-I levels up to 750% and HDL-cholesterol levels
      up to 200% with a shift to larger particles. The increase in human apo A-I plasma
      levels was time and dose dependent and was already evident after 3 d at the
      highest dose (0.5% wt/wt) of fenofibrate. In contrast, plasma mouse apo A-I
      concentration was decreased after fenofibrate in nontransgenic mice. The increase
      in plasma human apo A-I levels after fenofibrate treatment was associated with a
      97% increase in hepatic human apo A-I mRNA, whereas mouse apo A-I mRNA levels
      decreased to 51%. In nontransgenic mice, a similar down-regulation of hepatic apo
      A-I mRNA levels was observed. Nuclear run-on experiments demonstrated that the
      increase in human apo A-I and the decrease in mouse apo A-I gene expression after
      fenofibrate occurred at the transcriptional level. Since part of the effects of
      fibrates are mediated through the nuclear receptor PPAR (peroxisome proliferator
      activated receptor), the expression of the acyl CoA oxidase (ACO) gene was
      measured as a control of PPAR activation. Both in transgenic and nontransgenic
      mice, fenofibrate induced ACO mRNA levels up to sixfold. When transgenic mice
      were treated with gemfibrozil (0.5% wt/wt) plasma human apo A-I and HDL
      cholesterol levels increased 32 and 73%, respectively, above control levels. The
      weaker effect of this compound on human apo A-I and HDL-cholesterol levels
      correlated with a less pronounced impact on ACO mRNA levels (a threefold
      increase) suggesting that the level of induction of human apo A-I gene is related
      to the PPAR activating potency of the fibrate used. Treatment of human primary
      hepatocytes with fenofibric acid (500 microM) provoked an 83 and 50% increase in
      apo A-I secretion and mRNA levels, respectively, supporting that a direct action
      of fibrates on liver human apo A-I production leads to the observed increase in
      plasma apo A4 and HDL-cholesterol.

PMID- 8647934
TI  - Reduced epidermal growth factor receptor expression in hypohidrotic ectodermal
      dysplasia and Tabby mice.
AB  - Patients with hypohidrotic ectodermal dysplasia (HED) and Tabby (Ta) mice lack
      sweat glands and there is compelling evidence that these phenotypes are caused by
      mutations in the same highly conserved but unidentified X-linked gene. Previous
      studies showed that exogenous epidermal growth factor (EGF) reversed the Ta
      phenotype but the EGF status in HED patients has not been studied at all. Studies
      reported herein investigated the hypothesis that the EGF signaling pathway is
      involved in HED/Ta. Fibroblasts from HED patients had a two- to eightfold
      decrease in binding capacity for (125)I-labeled EGF, a decreased expression of
      the immunoreactive 170-kD EGF receptor (EGFR) protein, and a corresponding
      reduction in EGFR mRNA. Reduced expression of the EGFR also was observed in Ta
      fibroblasts and liver membranes. Other aspects of the EGF signaling pathway,
      including EGF concentration in urine and plasma, were normal in both HED patients
      and Ta mice. We propose that a decreased expression of the EGFR plays a causal
      role in the HED/Ta phenotype.

PMID- 8647935
TI  - Immunosuppressant FK506 induces interleukin-6 production through the activation
      of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506
      nephropathy.
AB  - FK506 is a powerful immunosuppressive drug currently in use that inhibits the
      activation of several transcription factors (nuclear factor (NF)-AT and NF
      kappaB) critical for T cell activation. We show here that, contrary to the
      situation in T cells, FK506 activates transcription factor NF-kappaB in
      nonlymphoid cells such as fibroblasts and renal mesangial cells. We further show
      that FK506 induces NF-kappaB-regulated IL-6 production in vitro and in vivo, in
      particular in kidney. IL-6 has been shown previously to produce renal
      abnormalities in vivo, such as mesangioproliferative glomerulonephritis. Similar
      renal abnormalities were also observed in FK506-treated animals. These results
      thus suggest a causal relationship between FK506-induced NF-kappaB activation/IL
      6 production and some of FK506-induced renal abnormalities.

PMID- 8647936
TI  - Fibrin deposition in tissues from endotoxin-treated mice correlates with
      decreases in the expression of urokinase-type but not tissue-type plasminogen
      activator.
AB  - The primary hypothesis of this report is that the formation and subsequent
      removal of fibrin in specific tissues during pathologic processes reflects
      temporal changes in the local expression of key procoagulant and fibrinolytic
      genes. To begin to test this hypothesis, we have used quantitative PCR assays and
      in situ hybridization analysis to examine the effects of endotoxin on the
      expression of specific genes in murine tissues, and to relate these changes to
      fibrin deposition/dissolution using immunohistochemical approaches. Endotoxin
      caused large increases in plasminogen activator inhibitor-1 mRNA and modest
      increases in tissue factor mRNA in most tissues examined. However, fibrin was
      only detected in the kidneys and adrenals of endotoxin-treated mice, and it was
      transient. Unexpectedly, changes in urokinase-type plasminogen activator mRNA but
      not tissue-type plasminogen activator mRNA correlated with fibrin
      deposition/dissolution in these tissues. Pretreatment of mice with the
      fibrinolytic inhibitor epsilon-aminocaproic acid before endotoxin increased both
      the number of fibrin-positive tissues and the duration of fibrin deposition in
      the kidneys and adrenals. These results suggest that the absence of fibrin in
      some tissues reflects ongoing local fibrinolysis, and that increases in
      plasminogen activator inhibitory and tissue fac- tor gene expression and
      decreases in urokinase-type plasminogen activator expression are necessary for
      tissue-specific fibrin deposition. Changes in tissue-type plasminogen activator
      gene expression do not appear to be essential for fibrin deposition/dissolution
      in this murine model of sepsis.

PMID- 8647938
TI  - The alpha1beta1 integrin is expressed during neointima formation in rat arteries
      and mediates collagen matrix reorganization.
AB  - Remodeling of the extracellular matrix by activated mesenchymal cells
      (myofibroblasts) is a critical aspect of wound repair in all adult organs.
      Collagen-dependent gel contraction, a process requiring integrin function, is an
      established in vitro assay thought to mimic in vivo matrix remodeling. Numerous
      data have implicated the alpha2beta1 integrin in various cell types as the
      primary collagen receptor responsible for collagen gel contraction. However,
      evidence from the literature suggests that the major collagen binding integrin
      expressed on mesenchymally derived cells in situ is the alpha1beta1 integrin, not
      the alpha2beta1 integrin. In this report, we use a rat vascular injury model to
      illustrate that the alpha1beta1 integrin is the major collagen receptor expressed
      on vascular smooth muscle cells after injury. Using two smooth muscle cell lines,
      expressing either the alpha1beta1 integrin alone or both the alpha1beta1 and
      alpha2beta1 integrins, along with Chinese hamster ovary cells transfected with
      the alpha1 integrin, we demonstrate that alpha1beta1 supports not only collagen
      dependent adhesion and migration, but also gel contraction. These data suggest
      that in vivo the alpha1beta1 integrin is a critical collagen receptor on
      mesenchymally derived cells potentially involved in matrix remodeling after
      injury.

PMID- 8647937
TI  - Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary
      arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac
      transplantation.
AB  - We have related experimentally induced post-cardiac transplant coronary
      arteriopathy to increased elastolytic activity, IL-1beta, fibronectin-mediated
      inflammatory and smooth muscle cell (SMC) migration, and SMC proliferation. Since
      our in vitro studies show that a serine elastase releases SMC mitogens and
      facilitates IL-lbeta induction of fibronectin, we hypothesized that
      administration in vivo of the specific serine elastase inhibitor, elafin, would
      decrease the post-cardiac transplant coronary arteriopathy. Cholesterol-fed
      rabbits underwent a heterotopic cardiac transplant without immunosuppression and
      received elafin (1.79 mg/kg per d continuous infusion after a 9 mg bolus, n = 6)
      or vehicle (n = 6). 1 wk later, hearts were harvested for morphometric,
      immunohistochemical, and biochemical analyses. A > 70% decrease in the total
      number of coronary arteries with intimal thickening in elafin-treated compared to
      control donor hearts (P < 0.002) was associated with reduced vascular elastolytic
      activity judged by fewer breaks in the internal elastic lamina (P < 0.03), less
      accumulation of immunoreactive fibronectin (P < 0.02), and reduced cell
      proliferation quantified by proliferating cell nuclear antigen (P < 0.0001).
      Despite myocardial lymphocytic infiltration, wet weight of elafin-treated donor
      hearts was reduced by 50% compared to untreated controls (P < 0.002) and
      associated with relative preservation of myocyte integrity, instead of extensive
      myocardial necrosis (P < 0.004). This protective effect correlated with decreased
      myocardial elastolytic activity (P < 0.0001) and inflammatory cell proliferation
      (P < 0.0001) and with an elafin-inhibitable elastase in lymphocytes. Serine
      elastase activity thus appears an important therapeutic target for post-cardiac
      transplant coronary arteriopathy and myocardial necrosis induced by rejection.

PMID- 8647939
TI  - The kidney is a major site of alpha(2)-antiplasmin production.
AB  - The serpin alpha2-antiplasmin (alpha2-AP) is the major circulating inhibitor of
      plasmin; it plays a determining role in the regulation of intravascular
      fibrinolysis, In addition to blood plasma, plasmin formation occurs in various
      organs where it is thought to fulfill a spectrum of functions not restricted to
      clot lysis. Alpha2-AP is synthesized by hepatocytes, but other possible sites of
      production have not been investigated. To explore the potential extravascular
      contribution of alpha2-AP in the regulation of proteolysis, we have isolated the
      murine alpha2-AP cDNA and determined its mRNA distribution in adult tissues. In
      addition to liver, kidneys are major sites of alpha2-AP mRNA accumulation in the
      mouse. The transcript is present in epithelial cells lining the convoluted
      portion of proximal tubules, and its accumulation is under androgen control.
      Human kidneys also contain high levels of alpha2-AP mRNA. Moderate amounts Of
      alpha2-AP mRNA are detected in other murine tissues such as muscle, intestine,
      central nervous system, and placenta. Our observations indicate that alpha2-AP
      can be synthesized in a number of tissues, where it could function as a distal
      regulator of plasmin-mediated extracellular proteolysis.

PMID- 8647940
TI  - Cytokine-induced meningitis is dramatically attenuated in mice deficient in
      endothelial selectins.
AB  - Leukocyte accumulation in cerebrospinal fluid and disruption of the blood-brain
      barrier are central components of meningitis and are associated with a poor
      prognosis. Genetically engineered deficiencies or functional inhibition of
      endothelial leukocyte adhesion receptors P-, or P- plus E-selectins, lead to
      deficits in leukocyte rolling and extravasation. However, their impact on
      meningeal inflammation has not been tested previously. An acute cytokine-induced
      meningitis model associated with significant cerebrospinal fluid leukocyte
      accumulation (averaging 14,000 leukocytes/microl as early as 4 h) and blood-brain
      barrier permeability was developed in adult mice. This model was applied to mice
      deficient in P-selectin and mice doubly deficient in P- and E-selectins. Partial
      inhibition of cerebrospinal fluid leukocyte influx and permeability was noted in
      P-selectin-deficient mice. Mice doubly deficient in P- and E-selectins displayed
      a near complete inhibition of these parameters. Our results suggest that P- and E
      selectins cooperatively contribute to meningitis and that functional blocking of
      both endothelial selectins in conjunction with antibiotics may provide a
      therapeutic approach for treatment of bacterial meningitis.

PMID- 8647941
TI  - Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular
      reactivity and pulmonary hypertension in hypoxic rats.
AB  - Chronically elevated shear stress and inflammation are important in hypertensive
      lung vessel remodeling. We postulate that 5-lipoxygenase (5-LO) is a molecular
      determinant of these processes. Immunohistology localized the 5-LO to macrophages
      of normal and chronically hypoxic rat lungs and also to vascular endothelial
      cells in chronically hypoxic lungs only. In situ hybridization of normal and
      chronically hypoxic lungs demonstrated that 5-LO mRNA is expressed in
      macrophages. Rats hypoxic for 4 wk-developed pulmonary hypertension increased
      translocation of the lung 5-LO from the cytosol to the membrane fraction and
      increased levels of lung tissue 5-lipoxygenase-activating protein (FLAP). A FLAP
      ligand, 3-[l-(4-chlorobenzyl)-3-t-butyl-thio-t-isopropylindol-2-yl]-2,2-
      dimethylpropanoic acid (MK-886), inhibited the acute angiotensin II and hypoxia
      induced pulmonary vasoconstriction in vitro and the development of chronic
      hypoxic pulmonary hypertension in rats in vivo. Mice bred with the deletion of
      the 5-LO enzyme (5-LO knockout) developed less right heart hypertrophy than age
      matched 5-LO competent mice. Our results support the hypothesis that the 5-LO is
      involved in lung vascular tone regulation and in the development of chronic
      pulmonary hypertension in hypoxic rodent models.

PMID- 8647942
TI  - The cytoskeletal linking proteins, moesin and radixin, are upregulated by
      platelet-derived growth factor, but not basic fibroblast growth factor in
      experimental mesangial proliferative glomerulonephritis.
AB  - The expression of the two cytoskeletal linking proteins, moesin and radixin, was
      examined in experimental mesangial proliferative nephritis in rats (anti-Thy1
      model). Moesin and radixin mRNA and protein are constitutively expressed in all
      cell types of normal rat glomeruli, except podocytes. In the anti-Thy1 model the
      expression of moesin and radixin was increased in infiltrating macrophages and in
      activated, alpha-smooth muscle actin-positive mesangial cells and was
      concentrated in the cellular extensions of mesangial cells in areas of glomerular
      remodelling. Studies using neutralizing antibodies demonstrated that the increase
      in moesin and radixin expression by mesangial cells is mediated by PDGF, but not
      bFGF. The increase in these cytoskeletal proteins appears to be regulated
      primarily (radixin) or partially (moesin) posttranscriptionally. The data suggest
      that PDGF mediated upregulation of the cytoskeletal proteins, moesin and radixin,
      is important for cell migration and other changes that accompany the coordinated
      restoration of glomerular architecture after injury.

PMID- 8647944
TI  - P-glycoprotein in the blood-brain barrier of mice influences the brain
      penetration and pharmacological activity of many drugs.
AB  - The mouse mdr1a (also called mdr3) P-GP is abundant in the blood-brain barrier,
      and its absence in mdr1a (-/-) mice leads to highly increased levels of the drugs
      ivermectin, vinblastine, digoxin, and cyclosporin A in the brain. We show here
      that the drugs loperamide, domperidone, and ondansetron are transported
      substrates for the mouse mdr1a P-GP and its human homologue MDR1. Phenytoin is a
      relatively weaker substrate for each, and the drugs haloperidol, clozapine, and
      flunitrazepam are transported hardly or not at all. Tissue distribution studies
      demonstrated that the relative brain penetration of radiolabeled ondansetron and
      loperamide (and their metabolites) is increased four- and sevenfold,
      respectively, in mdr1a (-/-) mice. A pilot toxicity study with oral loperamide
      showed that this peripherally acting antidiarrheal agent gains potent opiatelike
      activity in the central nervous system of mdr1a (-/-) mice. mdr1a (-/-) mice also
      showed increased sensitivity to neurolepticlike side effects of oral domperidone.
      These results point to the possible role that the drug-transporting P-GP(s) may
      play in the clinical use of many drugs, especially those with potential targets
      in the central nervous system.

PMID- 8647943
TI  - Angiotensin II causes weight loss and decreases circulating insulin-like growth
      factor I in rats through a pressor-independent mechanism.
AB  - The renin-angiotensin system regulates normal cardiovascular homeostasis and is
      activated in certain forms of hypertension and in heart failure. Angiotensin II
      has multiple physiological effects and we have shown recently that its growth
      promoting effects on vascular smooth muscle require autocrine activation of the
      IGF I receptor. To study the effect of angiotensin II on circulating IGF I, we
      infused rats with 500 ng/kg/min angiotensin II for up to 14 d. Angiotensin II
      markedly reduced plasma IGF I levels (56 and 41% decrease at 1 and 2 wk,
      respectively) and IGF binding protein-3 levels, and increased IGF binding protein
      2 levels, a pattern suggestive of dietary restriction. Compared with sham,
      angiotensin II-infused hypertensive rats lost 18-26% of body weight by 1 wk, and
      pair-feeding experiments indicated that 74% of this loss was attributable to a
      reduction in food intake. The vasodilator hydralazine and the AT1 receptor
      antagonist losartan had comparable effects to reverse angiotensin II-induced
      hypertension, but only losartan blocked the changes in body weight and in
      circulating IGF I and its binding proteins produced by angiotensin II. Moreover,
      in Dahl rats that were hypertensive in response to a high-salt diet, none of
      these changes occurred. Thus, angiotensin II produces weight loss through a
      pressor-independent mechanism that includes a marked anorexigenic effect and an
      additional (likely metabolic) effect. These findings have profound implications
      for understanding the pathophysiology of conditions, such as congestive heart
      failure, in which the renin-angiotensin system is activated.

PMID- 8647945
TI  - Molecular cloning of a glibenclamide-sensitive, voltage-gated potassium channel
      expressed in rabbit kidney.
AB  - Shaker genes encode voltage-gated potassium channels (Kv). We have shown
      previously that genes from Shaker subfamilies Kv1.1, 1.2, 1.4 are expressed in
      rabbit kidney. Recent functional and molecular evidence indicate that the
      predominant potassium conductance of the kidney medullary cell line GRB-PAP1 is
      composed of Shaker-like potassium channels. We now report the molecular cloning
      and functional expression of a new Shaker-related voltage-gated potassium
      channel, rabKv1.3, that is expressed in rabbit brain and kidney medulla. The
      protein, predicted to be 513 amino acids long, is most closely related to the
      Kv1.3 family although it differs significantly from other members of that family
      at the amino terminus. In Xenopus oocytes, rabKv1.3 cRNA expresses a voltage
      activated K current with kinetic characteristics similar to other members of the
      Kv1.3 family. However, unlike previously described Shaker channels, it is
      sensitive to glibenclamide and its single channel conductance saturates. This is
      the first report of the functional expression of a voltage-gated K channel clone
      expressed in kidney. We conclude that rabKv1.3 is a novel member of the Shaker
      superfamily that may play an important role in renal potassium transport.

PMID- 8647946
TI  - Phosphorus restriction prevents parathyroid gland growth. High phosphorus
      directly stimulates PTH secretion in vitro.
AB  - Dietary phosphorus (P) restriction is known to ameliorate secondary
      hyperparathyroidism in renal failure patients. In early renal failure, this
      effect may be mediated by an increase in 1,25-(OH)2D3, whereas in advanced renal
      failure, P restriction can act independent of changes in 1,25-(OH)2D3 and serum
      ionized calcium (ICa). In this study, we examined the effects of dietary P on
      serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats.
      Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for
      2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in
      uremic rats fed the 0.2% P diet. In contrast, there were significant increases in
      serum PTH (130 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13
      vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/-
      0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 0.01) in the uremic rats fed the
      0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25
      (OH)2D3 were not altered over this range of dietary P, suggesting a direct effect
      of P on PTG function. We tested this possibility in organ cultures of rat PTGs.
      While PTH secretion was acutely (30 min) regulated by medium calcium, the effects
      of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation
      was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium
      (1,706 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 0.02); the medium ICa was
      1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but
      cycloheximide (10 microg/ml) abolished the effect of P on PTH secretion. Thus,
      the effect of P is posttranscriptional, affecting PTH at a translational or
      posttranslational step. Collectively, these in vivo and in vitro results
      demonstrate a direct action of P on PTG function that is independent of ICa and
      1,25-(OH)2D3.

PMID- 8647947
TI  - CD44-related chondroitin sulfate proteoglycan, a cell surface receptor implicated
      with tumor cell invasion, mediates endothelial cell migration on fibrinogen and
      invasion into a fibrin matrix.
AB  - Microvascular endothelial cell invasion into the fibrin provisional matrix is an
      integral component of angiogenesis during wound repair. Cell surface receptors
      which interact with extracellular matrix proteins participate in cell migration
      and invasion. Malignant cells use CD44-related chondroitin sulfate proteoglycan
      (CSPG) as a matrix receptor to mediate migration and invasion. In this study, we
      examine whether cell surface CSPG can mediate similar events in nonmalignant
      wound microvascular endothelial cells or whether use of CSPG for migration and
      invasion is a property largely restricted to malignant cells. After inhibiting
      CSPG synthesis with p-nitrophenyl beta-d xylopyranoside (beta-d xyloside), wound
      microvascular endothelial cells were capable of attaching and spreading on the
      surface of a fibrin gel; however, their ability to invade the fibrin matrix was
      virtually eliminated. To begin to examine the mechanism by which endothelial
      cells use CSPG to invade fibrin matrices, cell adhesion and migration on
      fibrinogen was examined. Endothelial cell adhesion and migration on fibrinogen
      were inhibited by both beta-d xyloside and after cleavage of chondroitin sulfate
      from the core protein by chondroitinase ABC. We have determined that wound
      microvascular endothelial cells express the majority of their proteoglycan as
      CSPG and that the CSPG core protein is immunologically related to CD44. PCR
      studies show that these cells express both the "standard" (CD44H) isoform and an
      isoform containing the variably spliced exon V3. In addition, anti-CD44 antibody
      blocks endothelial cell migration on fibrinogen. Affinity chromatography studies
      reveal that partially purified microvascular endothelial cell CSPG binds
      fibrinogen. These findings suggest that CD44-related CSPG, a molecule implicated
      in the invasive behavior of tumor cells, is capable of binding fibrinogen/fibrin,
      thereby mediating endothelial cell migration and invasion into the fibrin
      provisional matrix during wound repair.

PMID- 8647948
TI  - Regulation of PPAR gamma gene expression by nutrition and obesity in rodents.
AB  - The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR)
      gamma, is implicated in mediating expression of fat-specific genes and in
      activating the program of adipocyte differentiation. The potential for regulation
      of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR
      gamma cDNA and developed an RNase protection assay that permits simultaneous
      quantitation of mRNAs for both gamma l and gamma 2 isoforms encoded by the PPAR
      gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin,
      and 18S mRNAs were also employed. Both gamma l and gamma 2 mRNAs were abundantly
      expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower
      levels in liver, spleen, and heart; whereas, gamma l and gamma 2 mRNA were
      expressed at low levels in skeletal muscle. Adipose tissue levels of gamma l and
      gamma 2 were not altered in two murine models of obesity (gold thioglucose and
      ob/ob), but were modestly increased in mice with toxigene-induced brown fat
      ablation uncoupling protein diphtheria toxin A mice. Fasting (12-48 h) was
      associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma mRNA
      levels in adipose tissue. Western blot analysis demonstrated a marked effect of
      fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of
      fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin
      deficient (streptozotocin) diabetes suppressed adipose tissue gamma l and gamma 2
      expression by 75% in normal mice with partial restoration during insulin
      treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in
      normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria
      toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2
      expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most
      abundant in adipocytes in normal mice, but lower level expression is seen in
      skeletal muscle; (b) expression of adipose tissue gamma1 or gamma2 mRNAs is
      increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma
      2 expression is downregulated by fasting and insulin-deficient diabetes; and (d)
      exposure of mice to a high fat diet increases adipose tissue expression of PPAR
      gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in
      obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA
      levels over a fourfold range and provide an additional level of regulation for
      the control of adipocyte development and function.

PMID- 8647949
TI  - Nitric oxide-mediated cyclooxygenase activation. A key event in the antiplatelet
      effects of nitrovasodilators.
AB  - We have evaluated the contributions of nitric oxide (NO) and prostacyclin (PGI2)
      in the in vivo antiplatelet effects of clinically useful nitrovasodilators. In
      rats, intravenous infusion of three NO donors, glyceryl trinitrate, sodium
      nitroprusside, or 3'-morpholinosydnonimine, the stable metabolite of molsidomine,
      released 6-keto PGF1alpha (the stable metabolite of PGI2) and inhibited ex vivo
      human platelet aggregation to adenosine diphosphate by at least 80%. In in vitro
      studies, glyceryl trinitrate, sodium nitroprusside, and 3'-morpholinosydnonimine,
      at clinically attainable concentrations, increased cyclooxygenase activity in
      endothelial cells (EC), which resulted in a four- to sixfold release of 6-keto
      PGF1alpha. Pretreatment of the EC with hemoglobin which binds to and inactivates
      the biological actions of NO, but not by methylene blue (MelB), attenuated the NO
      mediated PGI2 from the EC by at least 70%. Release of 6-keto PGF1alpha by the NO
      donors increased the ability of these compounds to inhibit thrombin-induced human
      platelet aggregation by at least 10 times; this potentiation was inhibited by
      hemoglobin but not by MeB. MeB blocked the direct anti-platelet effect of the NO
      donors in the absence of EC. In summary, we have demonstrated that NO, directly
      as well as together with an NO-driven cyclooxygenase activation (and hence PGI2),
      release contributes to the marked anti-platelet effects observed after the in
      vivo administration of clinically used nitrovasodilators.

PMID- 8647950
TI  - A common amino acid polymorphism in insulin receptor substrate-1 causes impaired
      insulin signaling. Evidence from transfection studies.
AB  - Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the
      insulin and IGF-1 receptors. Recent studies have identified multiple sequence
      variants of IRS-1, especially in patients with non-insulin-dependent diabetes
      mellitus. In the present study, we have examined insulin-stimulated processes in
      32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin
      receptor, transfected with wild-type human-IRS-1 or the most common human variant
      of IRS-1 in which glycine 972 is replaced by arginine. As compared to wild-type
      IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32%
      decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease
      in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a
      25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P
      = 0.002). There was also a tendency for a decrease in Grb2 binding to IRS-1 and
      insulin-stimulated mitogen-activated protein kinase activity, however, these were
      not statistically significant. The changes occurred with no change in insulin
      receptor or IRS-1 tyrosine phosphorylation. These data indicate that the mutation
      in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the
      PI 3-kinase pathway, and may contribute to insulin resistance in normal and
      diabetic populations.

PMID- 8647951
TI  - Hormonal basis for the gender difference in epidermal barrier formation in the
      fetal rat. Acceleration by estrogen and delay by testosterone.
AB  - Previous studies have shown that ontogeny of the epidermal permeability barrier
      and lung occur in parallel in the fetal rat, and that pharmacologic agents, such
      as glucocorticoids and thyroid hormone, accelerate maturation at comparable
      developmental time points. Gender also influences lung maturation, i.e., males
      exhibit delayed development. Sex steroid hormones exert opposite effects on lung
      maturation, with estrogens accelerating and androgens inhibiting. In this study,
      we demonstrate that cutaneous barrier formation, measured as transepidermal water
      loss, is delayed in male fetal rats. Administration of estrogen to pregnant
      mothers accelerates fetal barrier development both morphologically and
      functionally. Competent barriers also form sooner in skin explants incubated in
      estrogen-supplemented media in vitro. In contrast, administration of
      dihydrotestosterone delays barrier formation both in vivo and in vitro. Finally,
      treatment of pregnant rats with the androgen antagonist flutamide eliminates the
      gender difference in barrier formation. These studies indicate that (a) estrogen
      accelerates and testosterone delays cutaneous barrier formation, (b) these
      hormones exert their effects directly on the skin, and (c) sex differences in
      rates of barrier development in vivo may be mediated by testosterone.

PMID- 8647952
TI  - Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA
      levels of cholesteryl ester transfer protein in syrian hamsters.
AB  - Endotoxin alters the metabolism of lipoproteins, including that of high density
      lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) facilitates exchange
      of HDL cholesterol for very low density lipoprotein (VLDL) triglyceride, leading
      to catabolism of HDL. We investigated the effects of endotoxin and cytokines on
      CETP in Syrian hamsters. Endotoxin induced a rapid and progressive decrease in
      serum CETP levels, by 48 h CETP had decreased to < 20% of control levels.
      Endotoxin also decreased CETP mRNA and protein levels in adipose tissue, heart,
      and muscle, the tissues with highest levels of CETP mRNA, providing a plausible
      mechanism for the endotoxin-induced decrease in circulating CETP. Dexamethasone
      did not mimic the effects of endotoxin on CETP, but the combination of tumor
      necrosis factor and interleukin-1 did, indicating that these cytokines may in
      part mediate the effects of endotoxin on CETP. The endotoxin-induced decrease in
      CETP may help maintain HDL cholesterol levels during infection and inflammation
      when increased triglyceride levels could drive the exchange of HDL cholesteryl
      ester for VLDL triglyceride. Maintaining circulating HDL may be important because
      HDL protects against the toxic effects of endotoxin and provides cholesterol for
      peripheral cells involved in the immune response and tissue repair.

PMID- 8647953
TI  - Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in
      airway smooth muscle.
AB  - To elucidate the role of specific proinflammatory cytokines in regulating airway
      responsiveness, we examined the effects and mechanisms of action of IL-1beta, TNF
      alpha, and IL-2 on the beta-adrenoceptor- and postreceptor-coupled transmembrane
      signaling mechanisms regulating relaxation in isolated rabbit tracheal smooth
      muscle (TSM) segments. During half-maximal isometric contraction of the tissues
      with acetylcholine, relaxation responses to isoproterenol, PGE2, and forskolin
      were separately compared in control (untreated) TSM and tissues incubated for 18
      h with IL-1beta (10 ng/ml), TNF-(alpha (100 ng/ml), or IL-2 (200 ng/ml). Relative
      to controls, IL-1beta- and TNF-alpha-treated TSM, but not IL-2-treated tissues,
      depicted significant attenuation of their maximal relaxation and sensitivity
      (i.e., -log dose producing 50% maximal relaxation) to isoproterenol (P < 0.001)
      and PGE2 (P < 0.05); whereas the relaxation responses to direct stimulation of
      adenylate cyclase with forskolin were similar in the control and cytokine-treated
      tissues. Further, the attenuated relaxation to isoproterenol and PGE2 was ablated
      in the IL-1beta-treated TSM that were pretreated with either the muscarinic M2
      receptor antagonist, methoctramine (10(-6) M), or pertussis toxin (100 ng/ml).
      Moreover, Western immunoblot analysis demonstrated that: (a) Gi protein
      expression was significantly enhanced in membrane fractions isolated from IL
      1beta-treated TSM; and (b) the latter was largely attributed to induced enhanced
      expression of the Gi alpha2 and Gi alpha3 subunits. Collectively, these
      observations provide new evidence demonstrating that IL-lbeta and TNF-alpha
      induce impaired receptor-coupled airway relaxation in naive TSM, and that the
      latter effect is associated with increased muscarinic M2-receptor/Gi protein
      coupled expression and function.

PMID- 8647954
TI  - Obesity/insulin resistance is associated with endothelial dysfunction.
      Implications for the syndrome of insulin resistance.
AB  - To test the hypothesis that obesity/insulin resistance impairs both endothelium
      dependent vasodilation and insulin-mediated augmentation of endothelium-dependent
      vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral
      artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP)
      during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive
      controls (C), in obese insulin-resistant subjects (OB), and in subjects with non
      insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were
      approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C
      (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by -
      50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable
      increments in LBF in all groups. Regression analysis revealed a significant
      inverse correlation between the maximal LBF change in response to MCh and body
      fat content. Thus, obesity/insulin resistance is associated with (a) blunted
      endothelium-dependent, but normal endothelium-independent vasodilation and (b)
      failure of euglycemic hyperinsulinemia to augment endothelium-dependent
      vasodilation. Therefore, obese/insulin-resistant subjects are characterized by
      endothelial dysfunction and endothelial resistance to insulin's effect on
      enhancement of endothelium-dependent vasodilation. This endothelial dysfunction
      could contribute to the increased risk of atherosclerosis in obese insulin
      resistant subjects.

PMID- 8647956
TI  - Distinctive immune response patterns of human and murine autoimmune sera to U1
      small nuclear ribonucleoprotein C protein.
AB  - The Ul small nuclear ribonucleoprotein (snRNP), a complex of nine proteins with
      Ul RNA, is a frequent target of autoantibodies in human and murine systemic lupus
      erythematosus (SLE). Anti-Sm antibodies recognizing the B'/B, D, E, F, and G
      proteins of Ul snRNPs are highly specific for SLE, and are nearly always
      accompanied by anti-nRNP antibodies recognizing the Ul snRNP-specific 70K, A,
      and/or C proteins. Previous studies suggest that human anti-nRNP antibodies
      recognize primarily the U1-70K and Ul-A proteins, whereas recognition of Ul-C is
      less frequent. We report here that autoantibodies to U1-C are more common in
      human autoimmune sera than believed previously. Using a novel immunoprecipitation
      technique to detect autoantibodies to native Ul-C, 75/78 human sera with anti
      nRNP/ Sm antibodies were anti-Ul-C (+). In striking contrast, only 1/65 anti
      nRNP/Sm (+) MRL mouse sera of various Igh allotypes was positive. Two of ten anti
      nRNP/Sm (+) sera from BALB/c mice with a lupus-like syndrome induced by pristane
      recognized Ul-C. Thus, lupus in MRL mice was characterized by a markedly lower
      frequency of anti-U1-C antibodies than seen in human SLE or pristane-induced
      lupus. The results may indicate different pathways of intermolecular
      intrastructural diversification of autoantibody responses to the components of Ul
      snRNPs in human and murine lupus, possibly mediated by alterations in antigen
      processing induced by the autoantibodies themselves.

PMID- 8647955
TI  - Metabolic effects of successful intraportal islet transplantation in insulin
      dependent diabetes mellitus.
AB  - The intraportal injection of human pancreatic islets has been indicated as a
      possible alternative to the pancreas transplant in insulin-dependent diabetic
      patients. Aim of the present work was to study the effect of intraportal
      injection of purified human islets on: (a) the basal hepatic glucose production;
      (b) the whole body glucose homeostasis and insulin action; and (c) the regulation
      of insulin secretion in insulin-dependent diabetes mellitus patients bearing a
      kidney transplant. 15 recipients of purified islets from cadaver donors
      (intraportal injection) were studied by means of the infusion of labeled glucose
      to quantify the hepatic glucose production. Islet transplanted patients were
      subdivided in two groups based on graft function and underwent: (a) a 120-min
      euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min
      glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven
      patients with chronic uveitis on the same immunosuppressive therapy as grafted
      patients, twelve healthy volunteers, and seven insulin-dependent diabetic
      patients with combined pancreas and kidney transplantation were also studied as
      control groups. Islet transplanted patients have: (a) a higher basal hepatic
      glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all
      other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min)
      with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5
      mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in
      patients with islet function) with respect to normals (P < 0.01 for both
      comparisons); (c) a blunted first phase insulin peak and a similar second phase
      secretion with respect to controls. In conclusion, in spite of the persistence of
      an abnormal pattern of insulin secretion, successful intraportal islet graft
      normalizes the basal HGP and improves total tissue glucose disposal in insulin
      dependent diabetes mellitus.

PMID- 8647957
TI  - Studies of the expression of the Wiskott-Aldrich syndrome protein.
AB  - The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by
      thrombocytopenia, eczema, disorders in cell-mediated and humoral immunity, and a
      proclivity to lymphoproliferative disease. The gene responsible encodes a 53-kD
      proline-rich protein of unknown function (WASP). We produced a FLAG-WASP fusion
      protein that was used to immunize mice and produce mAbs against WASP. Using
      monoclonal anti-WASP in Western immunoblots, we have determined that WASP is
      present in the cytoplasmic but not nuclear fraction of normal human peripheral
      blood mononuclear cells, in normal human platelets, in T lymphocytes, non-T
      lymphocytes, and monocytes. The protein is produced in the B cell immunoblastic
      cell line DS-1, in normal EBV-transformed B cell lines, and in HEL92.1.7, but is
      barely detectable in MOLT-4 and not detectable in K562. WASP was present in two
      of four EBV-transformed cell lines from WAS patients. Splenic tissue
      immunostaining was performed in two patients, and the results correlated with the
      results of the Western blots. Sequence analysis of WASP cDNA from two patients
      who produce WASP show mutations causing amino acid substitutions. These studies
      establish a foundation for further studies aimed at understanding the function of
      WASP.

PMID- 8647958
TI  - Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis
      factor-dependent release of arachidonic acid and prostaglandin E2 in human
      monocytes.
AB  - Cytomegalovirus (CMV) has been associated with immunosuppression. Previously CMV
      was reported to interfere with signal transduction pathways in T cells. In this
      report the mechanisms underlying CMV-mediated immunosuppression were examined.
      Supernatants of CMV (Strains C-87, AD-169)-infected primary human monocyte (MO)
      cultures inhibited mitogenic T cell proliferative responses by > 95%. The
      inhibitory activity was observed 24 h through day 7 postinfection. The infection
      of MO was associated with a sustained elevation of intracellular levels of cAMP
      and the release of arachidonic acid (AA) and its metabolite PGE2 (activator of
      adenylate cyclase) in culture supernatants. The AA release was incidentally
      associated with TNF-alpha production. Monoclonal antibodies to TNF-alpha and
      pentoxyphylline (inhibitor of TNF synthesis) inhibited both AA and PGE2 release.
      The release of AA required protein synthesis and occurred under conditions
      consistent with the expression of CMV immediate early genes. Treatment of MO
      cultures at time of infection with 100 microM indomethacin or 1 microg of TNF
      alpha mAb abolished the CMV-induced T cell inhibitory activity of the
      supernatants by 100%. These data suggest that TNF dependent release of AA and
      PGE2 contributes to CMV-induced immunosuppression.

PMID- 8647959
TI  - T cell receptor biases and clonal proliferations among lung transplant recipients
      with obliterative bronchiolitis.
AB  - Obliterative bronchiolitis (OB) is the most serious late complication of lung
      transplantation, but the pathogenesis of this disorder has not been elucidated.
      We sought evidence that OB is mediated by a cellular immunologic response by
      characterizing T cell antigen receptor beta-chain variable gene (TCRBV)
      repertoires in lung allograft recipients. Expression levels of 27 TCRBV among
      recipients were determined by multiprobe RNase protection assay after PCR
      amplification. In comparison to recipients with no evidence of rejection (n = 9),
      the PBL TCRBV repertoires of OB subjects (n = 16) exhibited more frequent
      expansions (16 vs. 9% of all measured TCRBV, P < 0.02), and the magnitudes of
      these abnormalities were greater (8.2 +/- 0.8 vs. 4.5 +/- 0.3 SD from mean normal
      values, P < 0.01). TCRBV sequencing showed these expansions were composed of
      clonal or oligoclonal populations. Thus, T cell responses in the recipients are
      marked by highly selective clonal expansions, presumably driven by indirect
      recognition of a limited number of immunodominant alloantigens. These processes
      are exaggerated among allograft recipients with OB, implying that cognate immune
      mechanisms are important in the pathogenesis of the disorder. Furthermore, the
      prominence of finite, distinct TCR phenotypes raise possibilities for development
      of novel diagnostic modalities and targeted immunotherapies for OB and other
      manifestations of chronic allograft rejection.

PMID- 8647960
TI  - Overexpression of the death-promoting gene bax-alpha which is downregulated in
      breast cancer restores sensitivity to different apoptotic stimuli and reduces
      tumor growth in SCID mice.
AB  - We have studied the expression of members of the bcl-2 family in human breast
      cancer. The expression pattern of these genes in breast cancer tissue samples was
      compared with the expression pattern in normal breast epithelium. No marked
      difference with regard to bcl-2 and bcl-xL expression was observed between normal
      breast epithelium and cancer tissue. In contrast, bax-alpha, a splice variant of
      bax, which promotes apoptosis, is expressed in high amounts in normal breast
      epithelium, whereas only weak or no expression could be detected in 39 out of 40
      cancer tissue samples examined so far. Of interest, downregulation of bax-alpha
      was found in different histological subtypes. Furthermore, we transfected bax
      alpha into breast cancer cell lines under the control of a tetracycline-dependent
      expression system. We were able to demonstrate for the first time that induction
      of bax expression in breast cancer cell lines restores sensitivity towards both
      serum starvation and APO-I/Fas-triggered apoptosis and significantly reduces
      tumor growth in SCID mice. Therefore, we propose that dysregulation of apoptosis
      might contribute to the pathogenesis of breast cancer at least in part due to an
      imbalance between members of the bcl-2 gene family.

PMID- 8647962
TI  - Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and
      expression of COX-2 and interleukin 6 in rat adjuvant arthritis.
AB  - Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators
      of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to
      inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2
      expression in normal and arthritic paws and by pharmacological inhibition of COX
      2 activity. The injection of adjuvant induced a marked edema of the hind footpads
      with coincident local production of PGE2. PG production was associated with
      upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the
      level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6
      mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum.
      Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly
      reversed paw edema and reduced the level of PGE2 in paw tissue to baseline.
      Interestingly, treatment with the COX-2 inhibitor also reduced the expression of
      COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also
      reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2
      resulted in a reduction of the inflammatory cell infiltrate and decreased
      inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125
      were indistinguishable from the effects observed for indomethacin. These results
      suggest that COX-2 plays a prominent role in the inflammation associated with
      adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6
      expression at inflammatory sites.

PMID- 8647961
TI  - Apolipoprotein A-I is required for cholesteryl ester accumulation in
      steroidogenic cells and for normal adrenal steroid production.
AB  - In addition to its ability to remove cholesterol from cells, HDL also delivers
      cholesterol to cells through a poorly defined process in which cholesteryl esters
      are selectively transferred from HDL particles into the cell without the uptake
      and degradation of the lipoprotein particle. The HDL-cholesteryl ester selective
      uptake pathway is known to occur in human, rabbit, and rodent hepatocytes where
      it may contribute to the clearance of plasma cholesteryl ester. The selective
      uptake pathway has been studied most extensively in steroidogenic cells of
      rodents in which it accounts for 90% or more of the cholesterol destined for
      steroid production or cholesteryl ester accumulation. In this study we have used
      apo A-I-, apo A-II-, and apo E-deficient mice created by gene targeting in
      embryonic stem cells to test the importance of the three major HDL proteins in
      determining cholesteryl ester accumulation in steroidogenic cells of the adrenal
      gland, ovary, and testis. apo E and apo A-II deficiencies were found to have only
      modest effects on cholesteryl ester accumulation. In contrast, apo A-I deficiency
      caused an almost complete failure to accumulate cholesteryl ester in
      steroidogenic cells. These results suggest that apo A-I is essential for the
      selective uptake of HDL-cholesteryl esters. The lack of apo A-I has a major
      impact on adrenal gland physiology causing diminished basal corticosteroid
      production, a blunted steroidogenic response to stress, and increased expression
      of compensatory pathways to provide cholesterol substrate for steroid production.

PMID- 8647963
TI  - Preservation of complement-induced lung injury in mice with deficiency of NADPH
      oxidase.
AB  - Mice with chronic granulomatous disease (X-CGD mice) generated by mutating the X
      linked gene for a subunit of NADPH oxidase have been analyzed for their ability
      to respond to intravenous injection of purified cobra venom factor (CVF). This
      agent in wild-type mice produces a neutrophil-dependent and catalase-sensitive
      form of lung injury. Lung injury was evaluated by measuring the accumulation of
      extravascular albumin. Quite unexpectedly, the lungs of X-CGD mice showed no
      difference in the increased accumulation of extravascular albumin after injection
      of CVF when compared to wild-type mice. In both X-CGD and wild-type mice, full
      development of injury required neutrophils. While catalase was highly protective
      in wild-type mice, its protective effects were completely lost in the X-CGD mice.
      Furthermore, a competitive antagonist of L-arginine, N(G)-methyl-L-arginine, was
      protective in X-CGD mice but not in wild-type mice. Allopurinol was protective in
      both types of mice. Both the basal and the CVF-inducible lung mRNA for inducible
      nitric oxide synthase and IL-1beta was similar in X-CGD and wild-type mice. These
      data indicate that oxygen radical production and lung injury in response to
      injection of CVF occurs through alternative pathways in mice with genetic
      deletion of NADPH oxidase.

PMID- 8647964
TI  - Are all 585 nm pulsed dye lasers equivalent? A prospective, comparative,
      photometric, and histologic study.
AB  - BACKGROUND: Flashlamp-pumped pulsed dye lasers (585 nm) are used to treat port
      wine stains and other cutaneous vascular lesions. Strikingly different tissue
      effects were seen after two apparently similar 585 nm pulsed dye lasers at
      equivalent fluences were used. OBJECTIVE: We compared the photometric and
      histologic effects of two apparently similar 585 nm flashlamp-pumped pulsed dye
      laser systems. METHODS: The burn pattern and beam profile analysis of two Candela
      SPTL-1 lasers and two Cynosure Photogenica V lasers were compared. Various
      fluences and spot sizes of the Cynosure laser were placed on normal skin and
      evaluated for histologic change. RESULTS: Variation between the stated area of
      the spot and the actual measured area of the spot was found in all lasers
      studied. The area of the 5 mm spot of the two Candela lasers studied was 35% and
      31% larger, respectively, than the stated area. The Cynosure lasers had areas
      that were 8% and 4% smaller than the stated area. Neither beam profile was
      uniform. The Candela laser maintained a gaussian-like distribution of energy,
      whereas the Cynosure laser beam profile resembled a top hat with a more even
      distribution of energy. Histologic studies confirmed the maintenance of vascular
      specificity without nonspecific thermal damage. CONCLUSION: When changing from
      one 585 nm pulsed dye laser to another and using supposedly equivalent fluences,
      one cannot guarantee that clinical results will be equivalent. In an effort to
      achieve consistent treatments when moving between lasers manufactured by
      different companies, it would be prudent to place a single spot of energy onto
      burn paper and measure the diameter of the spot.

PMID- 8647965
TI  - Cimetidine therapy for warts: a placebo-controlled, double-blind study.
AB  - BACKGROUND: Cimetidine, an H2-receptor antagonist, has been used successfully to
      treat patients with mucocutaneous candidiasis, common variable immunodeficiency,
      herpes simplex, and herpes zoster because of its immunomodulatory effects.
      Recently, some trials have suggested that cimetidine may also be useful for the
      treatment of warts. OBJECTIVE: The aim of the present study was to determine
      whether cimetidine is effective in the treatment of warts. METHODS: Seventy
      patients with multiple warts were included in a placebo-controlled, double-blind
      study. Patients were randomly allocated to treatment groups equally. The groups
      received cimetidine, 25 to 40 mg/kg daily, or placebo for 3 months. Patients were
      examined at monthly intervals. RESULTS: At the end of the therapy, 28 cimetidine
      treated and 26 placebo-treated patients were examined to determine the efficacy
      of treatment. Cure rates obtained were 32% (9 of 28) in the cimetidine-treated
      group and 30.7% (8 of 26) in the placebo-treated group. No significant difference
      was found between cimetidine and placebo in effectiveness (p = 0.85). CONCLUSION:
      Our results show that cimetidine is no more effective than placebo in the
      treatment of patients with common warts.

PMID- 8647966
TI  - Effects of psychologic intervention on psoriasis: a preliminary report.
AB  - BACKGROUND: Case reports have indicated that psychologic treatments may have a
      beneficial effect on psoriasis activity. OBJECTIVE: Our purpose was to further
      investigate the hypothesis that psychologic intervention has a beneficial effect
      on psoriasis activity in a blinded, controlled manner. METHODS: Fifty-one
      patients with psoriasis vulgaris were randomly assigned to a treatment or a
      control group. Patients in the treatment group participated in seven individual
      psychotherapy sessions in 12 weeks. Intervention techniques included stress
      management, guided imagery, and relaxation. The Psoriasis Area Severity Index
      (PASI), Total Sign Score (TSS), and Laser Doppler Skin Blood Flow (LDBF) of a
      selected reference plaque was measured in a blinded fashion at baseline (week 0),
      week 4, week 8, and after treatment (week 12). RESULTS: Slight, but significant,
      changes in TSS and LDBF were found in the treatment group but not in the control
      group. When analyses were performed for both groups separately, the treatment
      group displayed significant reductions for all three psoriasis activity measures,
      whereas no changes were seen in the control group. CONCLUSION: Our preliminary
      results suggest that psychologic intervention may have a moderate beneficial
      effect on psoriasis activity.

PMID- 8647967
TI  - Cyclosporine in severe childhood atopic dermatitis: a multicenter study.
AB  - BACKGROUND: Severe atopic dermatitis (AD) remains difficult to treat.
      Cyclosporine is effective in adults but has not previously been investigated in
      children with AD. OBJECTIVE: The aims were to investigate the efficacy, safety,
      and tolerability of cyclosporine in severe refractory childhood AD. METHODS:
      Subjects 2 to 16 years of age were treated for 6 weeks with cyclosporine, 5 mg/kg
      per day, in an open study. Disease activity was monitored every 2 weeks by means
      of sign scores, visual analogue scales for symptoms, and quality-of-life
      questionnaires. Adverse events were monitored. Efficacy and tolerability were
      assessed with five-point scales. RESULTS: Twenty-seven children were treated.
      Significant improvements were seen in all measures of disease activity. Twenty
      two showed marked improvement or total clearing. Quality of life improved for
      both the children and their families. Tolerability was considered good or very
      good in 25 subjects. CONCLUSION: Cyclosporine may offer an effective, safe, and
      well-tolerated short-term treatment option for children with severe AD.

PMID- 8647968
TI  - Combined modality therapy for cutaneous T-cell lymphoma.
AB  - BACKGROUND: Cutaneous T-cell lymphoma (CTCL) may respond to many therapies, but
      long-term disease-free survival is uncommon. Patients with advanced disease have
      a median survival of approximately 3 years. OBJECTIVE: Our purpose was to combine
      known effective agents sequentially to determine whether we could achieve
      remission in more patients or for longer duration. METHODS: Patients with mycosis
      fungoides (n = 23) or Sezary syndrome (n = 5) were treated with 4 months of
      recombinant interferon alfa together with isotretinoin, followed by total skin
      electron beam therapy alone (for stage I to II disease) or preceded by
      chemotherapy (for stage III to IV disease). Maintenance therapy consisted of
      interferon for 1 year and topical nitrogen mustard for 2 years. RESULTS: Twenty
      eight patients were treated. The overall response rate (complete and partial
      remissions) was 82%. Although the median duration of remission was 5 months in
      patients with stage III to IV disease, two patients remain in complete remission
      at 39 + and 46 + months. In patients with stage I to II disease the median
      duration of remission has not been reached at a median follow-up of 18 months.
      Five patients, all with stage III to IV disease, have died. Overall, the regimen
      was well tolerated with one treatment-related death from neutropenic sepsis.
      CONCLUSION: Combined modality therapy may be effective for the treatment of CTCL
      with similar response rates to other current therapies.

PMID- 8647969
TI  - Psychodermatology: an update.
AB  - It has been estimated that in at least one third of dermatology patients,
      effective management of the skin disorder involves consideration of associated
      emotional factors. This article provides an overview of psychodermatology with a
      focus on the more recent literature and an emphasis on the clinical aspects and
      psychologic therapies for (1) cutaneous associations of psychiatric disorders and
      (2) psychiatric associations of certain cutaneous disorders that are known to be
      influenced by psychosomatic factors. This article also provides an update on the
      use of psychotropic drugs (i.e., the antianxiety, antidepressant, and
      antipsychotic agents) for the treatment of mental disorders that occur in
      conjunction with cutaneous conditions. Some of their other pharmacologic
      properties, such as the antihistaminic and analgesic effects of some
      antidepressant agents are also reviewed.

PMID- 8647970
TI  - Treatment of pyoderma gangrenosum.
AB  - Critical to the proper management of pyoderma gangrenosum are correct diagnosis,
      identification and treatment of any underlying disorder, and the proper choice of
      topical and systemic therapy. Many agents are available for the treatment of
      pyoderma gangrenosum. We review the current therapeutic options, their efficacy
      and side effects, and we offer some guidelines for their proper selection.

PMID- 8647971
TI  - Surgical pearl: using the liposuction cannula/syringe apparatus for conservative
      evacuation of postoperative hematomas.

PMID- 8647972
TI  - Basic skin cancer triage for teaching melanoma detection.

PMID- 8647973
TI  - State of dermatology training: the residents' perspective.
AB  - Changes in health care delivery necessitate modification in dermatology training.
      While the residents at The University of Alabama at Birmingham were planning
      their 1995-1996 curriculum, several questions regarding the most appropriate
      allocation of time and resources arose. Interest in other residency curricula
      prompted the development of a national survey of dermatology residents. Our
      purpose was to provide comprehensive data regarding the didactic, clinical,
      surgical, and other aspects of today's U.S. dermatology residency training from
      the perspective of the residents. It is hoped these data will assist dermatology
      residency programs with evaluation of their current curricula. A comprehensive 31
      question multiplechoice survey was mailed to 631 residents in 70 U.S. dermatology
      residency programs. Results were tabulated and median values and percentages of
      responses were obtained. A Wilcoxon rank-sum test, a chi-square analysis, and
      logistic regression analysis were performed on survey items on the basis of
      residents' satisfaction with the training program. Two hundred forty-eight
      responses (39%) were returned with all years of training well represented. Median
      values and percentages obtained outlined the didactic, clinical, surgical, and
      other aspects of dermatology residency training. Seventeen percent of residents
      believed they were not being adequately trained. Satisfaction with training was
      noted with more didactic faculty involvement, consultations and research, and
      surgical procedures performed per month. Residents with enriched didactic,
      clinical, and surgical training experiences are more satisfied with their
      training programs.

PMID- 8647974
TI  - Multiple cutaneous B-cell pseudolymphomas after allergen injections.

PMID- 8647976
TI  - Interleukin-3-induced urticaria-like eruption.

PMID- 8647975
TI  - Leukokeratoderma estrovale digitorum inversa.

PMID- 8647977
TI  - Acquired ichthyosis associated with eosinophilic fasciitis.

PMID- 8647978
TI  - Metastatic periungual squamous cell carcinoma: detection of human papillomavirus
      type 35 RNA in the digital tumor and axillary lymph node metastases.

PMID- 8647979
TI  - Carcinoma erysipelatoides from the colon.

PMID- 8647980
TI  - Predictive value of seborrheic dermatitis and other common dermatoses for HIV
      infection in Bamako, Mali.

PMID- 8647981
TI  - Scutular favus-like tinea cruris et pedis in a patient with AIDS.

PMID- 8647982
TI  - Renal involvement in toxic epidermal necrolysis.

PMID- 8647983
TI  - Deep dermatophytosis caused by Trichophyton rubrum in a patient with AIDS.

PMID- 8647984
TI  - Necrolytic migratory erythema without glucagonoma in patients with liver disease.

PMID- 8647985
TI  - Metastatic carcinoma of the parotid gland resembling carcinoma of the breast.

PMID- 8647986
TI  - Elastoderma.

PMID- 8647987
TI  - The lunula.
AB  - The lunula is the visible portion of the distal nail matrix that extends beyond
      the proximal nailfold. It is white, half-moon-shaped, appears by week 14 of
      gestation, has unique histologic features. The lunula has a primary structural
      role in defining the free edge of the distal nail plate. Lunular anomalies
      include changes in form and structure and in color. Lunular dysmorphologic
      features can be characterized by macrolunula, microlunula or anolunula, and
      nonconvex lunula. Lunular dyschromias can be confluent or spotted or can be
      characterized by longitudinal colored bands that traverse the lunula. Alterations
      in the morphologic features or color (or both) of the lunula can be an indication
      of either a cutaneous or a systemic disorder.

PMID- 8647988
TI  - Interstitial granulomatous dermatitis with arthritis.
AB  - BACKGROUND: Interstitial granulomatous dermatitis with arthritis is an uncommon
      systemic disorder involving the cutaneous and musculoskeletal systems. The
      eruption may mimic other dermatoses including granuloma annulare, erythema
      chronicum migrans, and the inflammatory stage of morphea. Key histopathologic
      characteristics, along with clinical correlation, allow accurate diagnosis.
      OBJECTIVE: We describe the clinical, serologic, and histologic features in three
      patients with interstitial granulomatous dermatitis with arthritis. METHODS: Skin
      biopsy specimens were examined and correlated with the clinical and laboratory
      findings. RESULTS: Erythematous, annular, indurated plaques on the extremities
      were present in two women. An erythematous, papular eruption on the head and neck
      was present in a third patient. All patients had myalgia and migratory
      polyarthralgias of the extremities along with various serologic abnormalities.
      Histologic examination revealed a dense lymphohistiocytic interstitial infiltrate
      involving primarily the reticular dermis. Foci of necrobiotic collagen were
      present. Vasculitis was absent. CONCLUSION: Interstitial granulomatous dermatitis
      with arthritis is unique multisystem disease with variable cutaneous expression.
      Abnormal serologic findings indicate a possible connection to collagen vascular
      disease.

PMID- 8647989
TI  - Melanoma awareness and self-examination practices: results of a United States
      survey.
AB  - BACKGROUND: Skin cancers are common and there has been a dramatic increase in
      their incidence, particularly melanoma. However, little is known about awareness
      of melanoma and early detection practices in the general U.S. population.
      OBJECTIVE: In 1995, the American Academy of Dermatology increased their efforts
      to promote awareness of melanoma. This study was conducted to document current
      knowledge of melanoma and self-examination practices. METHODS: In February 1995,
      a telephone survey was conducted in a nationally representative sample of 1001
      persons at least 18 years of age (3% margin of error) that included questions on
      knowledge, attitudes, and practices regarding early detection of melanoma.
      RESULTS: Almost 42% of those surveyed were unaware of melanoma, and only 26% of
      those who were aware could identify its specific signs. Most recognized at least
      one common risk factor for melanoma (e.g., sun exposure, fair skin). However,
      many did not distinguish melanoma from other skin cancers in terms of risk
      factors, signs of early disease, and body site distribution. The lowest measures
      of melanoma knowledge and attitudes were found among those who are male,
      nonwhite, and parents, and those with the lowest level of education and income.
      More than half (54%) did not conduct a self-examination. This practice was most
      frequently reported by women, white persons, and the elderly, as well as those
      with a greater knowledge of melanoma. CONCLUSION: Our research documents
      deficiencies in knowledge and practices related to early detection of melanoma in
      the general U.S. population and supports the need for public education about
      melanoma.

PMID- 8647990
TI  - Evaluation of the American Academy of Dermatology's National Skin Cancer Early
      Detection and Screening Program.
AB  - BACKGROUND: Increasing incidence and mortality rates from cutaneous melanoma are
      a major public health concern. As part of a national effort to enhance early
      detection of melanoma/skin cancer, the American Academy of Dermatology (AAD) has
      sponsored an annual education and early detection program that couples provision
      of skin cancer information to the general public with almost 750,000 free skin
      cancer examinations (1985-1994). OBJECTIVE: To begin to evaluate the impact of
      this effort, we determined the final pathology diagnosis of persons attending the
      1992-1994 programs who had a suspected melanoma at the time of examination.
      METHODS: We directly contacted all such persons by telephone or mail and received
      pathology reports from those who had a subsequent biopsy. RESULTS: We contacted
      96% of the 4458 persons with such lesions among the 282,555 screenings in the
      1992-1994 programs. We obtained a final diagnosis for 72%, and the positive
      predictive value for melanoma was 17%. Three hundred seventy-one melanomas were
      found in 364 persons. More than 98% had localized disease. More than 90% of the
      confirmed melanomas with known histology were in situ or "thin" lesions (< or =
      1.50 mm thick). The median thickness of all melanomas was 0.30 mm. The 8.3% of
      AAD cases with advanced melanoma (metastatic disease, regional disease, or
      lesions > or = 1.51 mm) is a lower proportion than that reported by the 1990
      Surveillance, Epidemiology and End Result Registry. The rate of thickest lesions
      (> or = 4 mm) and late-stage melanomas among all participants was 2.83 per
      100,000 population. Of persons with a confirmed melanoma, 39% indicated (before
      their examination) that without the free program, they would not have considered
      having a physician examine their skin. CONCLUSION: The 1992-1994 free AAD
      programs disseminated broad skin cancer educational messages, enabled thousands
      to obtain a free expert skin cancer examination, and found mostly thin, localized
      stage 1 melanomas (usually associated with a high projected 5-year survival
      rate). Because biases impose possible limitations, future studies with long-term
      follow-up and formal control groups should determine the impact of early
      detection programs on melanoma mortality.

PMID- 8647991
TI  - Unilateral laterothoracic exanthem. A clinicopathologic study of forty-eight
      patients.
AB  - BACKGROUND: Four years ago, we began seeing young children with an unusual,
      predominantly unilateral, morbilliform and eczematous, self-limited cutaneous
      eruption. It appeared to correspond to unilateral laterothoracic exanthem (ULE)
      reported from France and to an eruption described as "a new papular erythema of
      childhood" in the United States. OBJECTIVE: We conducted a prospective study of
      ULE to define its clinical evolution, pathology, and therapy. In addition, we
      performed epidemiologic and microbiologic investigations in an attempt to
      determine the cause of ULE. METHOD: We studied 48 children with ULE. In some
      patients, blood, urine, stool, as well as skin biopsy specimens were analyzed.
      RESULTS: ULE is a morbilliform, eczematous eruption that often begins close to
      the axilla and spreads to become bilateral, although it usually retains a
      unilateral predominance. Patients' mean age at onset is 24.3 months, with a
      female predominance (2:1) and mean duration of 5 weeks, followed by spontaneous
      resolution that may or may not be improved with topical corticosteroids. It is
      characterized by a unique eccrine lymphocytic infiltration. Although signs of
      infection were reported by most patients, no one infectious agent was identified.
      No significant epidemiologic factor was found. CONCLUSION: ULE, in young
      children, is a self-limited morbilliform and scarlatiniform eruption that may
      represent a specific skin reaction to one or more infectious agents.

PMID- 8647992
TI  - Somatostatin receptor scintigraphy in cutaneous malignant lymphomas.
AB  - BACKGROUND: Lymphoid cells may express somatostatin receptors (SS-Rs) on their
      cell surface. Therefore radiolabeled somatostatin analogues may be used to
      visualize SS-R-positive lymphoid neoplasms in vivo. Exact staging is the basis
      for treatment decisions in cutaneous malignant lymphoma. We considered the
      possibility that SS-R scintigraphy might offer a clinically useful method of
      diagnostic imaging in patients with cutaneous malignant lymphoma. OBJECTIVE: We
      evaluated SS-R scintigraphy in comparison with conventional staging methods in
      the staging of cutaneous malignant lymphoma. METHODS: We conducted a prospective
      study in 14 consecutive patients with histologically proven cutaneous malignant
      lymphoma. SS-R scintigraphy was compared with physical, radiologic, and bone
      marrow examinations. Lymph node excisions were performed in patients with
      palpable lymph nodes. RESULTS: SS-R scintigraphy was positive in the lymph nodes
      in all four patients with malignant lymph node infiltration and negative in the
      three patients with dermatopathic lymphadenopathy. In two patients, previously
      unsuspected lymphoma localizations were visualized by SS-R scintigraphy. In only
      three patients all skin lesions were visualized by SS-R scintigraphy; these three
      patients had not been treated with topical corticosteroids. SS-R scintigraphy
      failed to detect an adrenal mass in one patient and bone marrow infiltration in
      two patients. CONCLUSION: SS-R scintigraphy may help distinguish dermatopathic
      lymphadenopathy from malignant lymph node infiltration in patients with cutaneous
      malignant lymphoma.

PMID- 8647993
TI  - Histology of hidradenitis suppurativa.
AB  - BACKGROUND: Hidradenitis suppurativa is traditionally classified as a disease of
      the apocrine gland. However, different histologic descriptions exist. OBJECTIVE:
      Our purpose was to describe prospectively the histopathologic characteristics of
      hidradenitis. METHODS: We systematically described and classified 60 consecutive
      biopsy specimens from patients with hidradenitis and compared them with 33
      specimens from clinically noninvolved regional controls. RESULTS: A heterogeneous
      histologic picture was found. Apocrine glands were involved in a minority of the
      60 specimens, 17 showed poral occlusion, 17 simple folliculitis without poral
      occlusion, 9 sinus tracts, 6 epithelial cyst, 5 abscess, 3 apocrinitis, 2 diffuse
      dermal inflammation, and 1 pyogenic granuloma and scarring. Secondary involvement
      of apocrine glands was found in 12% of all specimens, and secondary involvement
      of eccrine glands was found in 25%. Sinus tracts were found significantly more
      often in the presence of poral occlusion or epithelial cysts. Control specimens
      frequently revealed changes compatible with early stages of follicular
      involvement. Apocrine glands were observed significantly more often in the
      axillae than in the groin. CONCLUSION: The clinical picture of hidradenitis
      suppurativa covers a broad histologic spectrum. This may help explain the
      therapeutic problems posed by this disease. The disease appears to be
      predominantly follicular, and apocrine glands appear to be primarily involved in
      only a minority of axillary lesions.

PMID- 8647994
TI  - Regulatory effects of gamma-interferon on IL-6 and IL-8 secretion by cultured
      human keratinocytes and dermal fibroblasts.
AB  - Gamma-interferon (IFN-gamma) is produced by T cells and plays an important role
      in immunological and inflammatory processes. To determine the effects of IFN
      gamma on interleukin (IL)-6 and IL-8 secretion, normal human keratinocytes
      (NHKs), human squamous cell carcinoma cell line (HSC-1) cells, and human dermal
      fibroblasts (HDFs) were incubated with 100 U/ml of recombinant (r) IFN-gamma in
      the presence of various stimulants. HSC-1 cells and HDFs spontaneously secreted
      both IL-6 and IL-8 into the culture medium. NHKs secreted detectable levels of IL
      8, but not of IL-6, and IL-8 secretion increased over 20 fold by stimulation with
      10 nM of phorbol 12-myristate 13-acetate (PMA). rIFN-gamma inhibited IL-8
      secretion in both HSC-1 cells and PMA-stimulated NHKs. On the other hand, it
      enhanced IL-1 alpha- and TNF alpha-induced IL-8 secretion in NHKs. In HDFs, rIFN
      gamma inhibited IL-8 secretion, but enhanced secretion of IL-6, regardless of
      whether they were stimulated with IL-1 alpha or PMA. These results suggest that
      IFN-gamma has different regulatory effects on IL-6 and IL-8 secretion in NHKs and
      HDFs, depending on the stimulus.

PMID- 8647995
TI  - Induction of the 72-kD heat shock protein in human skin melanoma and squamous
      cell carcinoma cell lines.
AB  - Heat shock proteins (HSPs) or stress proteins comprise a characteristic group of
      proteins synthesized in cells exposed to heat or other environmental stimuli. Of
      the many HSPs, the 72-kD heat shock protein (HSP72) is the most stress-inducible
      one. In the present study, we examined the effects of heat, chemicals (azetidine
      and sodium arsenite), ultraviolet (UV) light, and gamma-ray irradiation on the
      induction of HSP72 in cultured human skin melanoma cell lines (P-39 and G-361), a
      human skin squamous cell carcinoma cell line (HSC-1), and an SV40-transformed
      human lung fibroblast cell line (WI38VA13) as a control. In these cell lines,
      heat treatment induced HSP72 more rapidly and intensely than did chemical
      exposure. Compared with the SCC cell line, the two melanoma cell lines produced
      less HSP72 with heat treatment. UVC irradiation (20 J/m2) induced HSP72 only in
      the WI38VA13 cells. After gamma-ray irradiation, no HSP72 induction was detected
      in any of the cell lines examined. These observations suggest that, in cultured
      cells, inducibility of HSP72 depends not only on the inducer but also on the
      origin of each cell line.

PMID- 8647996
TI  - Expression of Lewis Y (Le(y)) antigen in human anagen hair follicles.
AB  - Lewis Y (Le(y)) antigen, a difucosylated tetrasaccharide found on type 2 blood
      group oligosaccharides of glycolipids and glycoproteins, is thought to be a
      phenotypic marker predictive of cell differentiation. The distribution of this
      antigen in human anagen hair follicles was examined by immunohistochemical
      staining using a monoclonal antibody (AH-6) to Le(y). In the bulbar and
      suprabulbar portion of anagen hair follicles, Le(y) antigen was detected in the
      three layers of the inner root sheath. Subsequently, the positive staining became
      translocated to the innermost layer of the outer root sheath in the middle part
      of the hair follicles. In the upper portion of the hair follicles, Le(y) antigen
      was found in the outer cells of the outer root sheath. These findings suggested
      that the expression of Le(y) antigen in the anagen hair follicles was correlated
      with the processes of keratinization or terminal differentiation.

PMID- 8647997
TI  - Apoptosis identified by DNA fragmentation in epidermal neoplasms.
AB  - In the previous study, we demonstrated apoptotic cells in basal cell carcinomas
      by means of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end
      labeling (TUNEL). Positive staining cells were present at the peripheries and
      centers of the nests. The number of positive cells increased in cases showing
      deep infiltration. We also stained other epidermal neoplasms using this modified
      TUNEL method. In squamous cell carcinomas, many positive cells were observed in
      poorly differentiated types, but only a few cells were stained in well
      differentiated types. TUNEL positive cells were rare in Bowen's disease. No
      positive cells were seen in seborrheic keratosis or verruca vulgaris. Our studies
      showed that apoptotic cells were more common in rapid growth neoplasms than in
      slow growth neoplasms.

PMID- 8647998
TI  - Image analysis of nailfold capillaries in patients with undifferentiated
      connective tissue syndromes.
AB  - Several studies have reported patients that show nailfold capillary abnormality
      without fulfilling any of the criteria for rheumatic diseases. Our objective was
      to define how many patients with undifferentiated connective tissue syndrome
      (UCTS) have nailfold capillary abnormalities and to determine the correlation
      between capillary abnormality and clinical findings. We analyzed videograph
      images of nailfold capillaries in 75 patients with UCTS, comparing them with 22
      normal controls (NL) and 55 patients with systemic sclerosis (SS), using
      standardized canonical discriminant analysis. Sixty patients with UCTS showed the
      SS type pattern and 15, the NL type pattern. The SS type pattern in patients with
      UCTS significantly correlated with Raynaud's phenomenon, telangiectasia, and anti
      nuclear antibody. The UCTS patients with nailfold capillary abnormalities
      correlated with symptoms of SS have a possibility of progressing to SS. The
      follow up study of these patients will show whether progression to SS occurs.

PMID- 8647999
TI  - Prognosis and clinical relevance of recurrent oral ulceration in Behcet's
      disease.
AB  - There is no way of predicting whether a patient with recurrent oral ulcerations
      (ROU) will develop Behcet's disease (BD). In the absence of a valid laboratory
      test to exclude BD, such oral ulcerations result in a diagnostic problem when
      they occur as the sole and earliest manifestation of disease. We assessed the
      prognosis of ROU by performing prospective evaluations of 67 patients who had
      only a history of ROU and were registered at the Behcet's Disease Specialty
      Clinic at Severance Hospital of Yonsei University, Seoul, Korea. Thirty-five
      patients (52.2%) developed overt manifestations of BD at an average of 7.7 years
      after the onset of ROU. The frequency of recurrence was 9.8 times per year in
      progressive cases. From these results, it appears that highly recurrent ROU is a
      warning signal for BD. Careful examinations of patients, including their minor
      symptoms, additional laboratory tests, and regular follow-ups by physicians are
      required for proper diagnosis.

PMID- 8648000
TI  - The relationships of onset and exacerbation of pustulosis palmaris et plantaris
      to smoking and focal infections.
AB  - Clinical data, including focal infection and habitual cigarette smoking, were
      obtained from 203 male patients with pustulosis palmaris et plantaris (PPP) (age:
      43.3 +/- 13.4) and 266 female patients (age: 44.0 +/- 13.7) for the 20 years from
      1975 through 1994 to evaluate the relationship between the onset or severity of
      PPP and smoking. Seasonal incidences of onset were also studied. The incidence of
      onset of PPP symptoms was highest in June, when it is the most humid in Japan,
      and lowest in December. The most common infectious disease associated with PPP
      was tonsillitis. The percentages of heavy smoking (more than 20 cigarettes per
      day) were 74.7% and 32.9% for male and female patients, while those in the normal
      control population in Japan were 37.2% and 9.8% for males and females. These
      results suggest that heavy smoking, tonsillitis, and seasonal factors such as
      high humidity and high temperature may be related to the onset and exacerbation
      of PPP.

PMID- 8648001
TI  - In vitro and in vivo antibiotic susceptibility of Lyme disease Borrelia isolated
      from the ixodid tick in Japan.
AB  - Antimicrobial susceptibility of the Lyme disease Borrelia, strain HP1 vi,
      isolated from the tick ixodes persulcatus in Hokkaido, Japan, was determined in
      vitro and in vivo. A broth dilution technique was used to determine the minimum
      inhibitory concentrations (MICs) and minimum borreliacidal concentrations (MBCs)
      of five antimicrobial agents. Strain HP1 vi was most susceptible to minocycline
      (MBC, 0.2 micrograms/ml). The other antimicrobial agents tested, aspoxicillin,
      cefmetazole sodium, imipenem cilastatin sodium, and panipenem betamipron, had
      higher MBCs of 12.5 micrograms/ml, 25 micrograms/ml, > 25 micrograms/ml, and > 25
      micrograms/ml, respectively. In vivo antibiotic susceptibility study using a ddY
      mouse model demonstrated that minocycline and amoxicillin were effective;
      minocycline had a lower 50% effective dose (ED50) value (6.25 mg/kg) than
      amoxicillin (30 mg/kg).

PMID- 8648002
TI  - Sebaceous adenomas, squamous cell carcinoma and skin infections in a patient with
      carcinoma of the colon, rectum and bladder.
AB  - Sebaceous adenomas and squamous cell carcinoma developed in a male patient in
      addition to viral, mycotic and bacterial infections, several years after the
      removal of three malignant tumors from his lower gastrointestinal and urinary
      tract. Skin tests with trichophytin, candidin, and mixed bacteria were negative.
      Various aspects regarding cutaneous changes associated with colorectal and
      bladder carcinomas are discussed.

PMID- 8648003
TI  - Late onset systemic lupus erythematosus diagnosed in an elderly man with unusual
      skin eruptions and sudden death.
AB  - A rare case of late onset SLE in an elderly man presented with generalized
      toxicoderma-like eruptions. The rash first appeared at age 64 years and was
      characterized by dark or purplish erythematous eruptions disseminated over the
      body surface. Histological examination revealed marked liquefaction degeneration
      and leukocytoclastic vasculitis. Direct immunofluorescence study and serological
      examination results were suggestive of SLE; however, the patient had no episodes
      of photosensitivity, malar erythema, or arthralgia. He was diagnosed as having
      SLE 11 months after his first visit and died suddenly 16 months after onset.
      Elderly men with SLE can present with unusual clinical manifestations; careful
      examination of these patients is required to reach a correct diagnosis.

PMID- 8648004
TI  - A case of pretibial myxedema associated with Graves' disease: an
      immunohistochemical study of serum-derived hyaluronan-associated protein.
AB  - The myxomatous materials in cutis from a patient with pretibial myxedema (PTM)
      with Graves' disease were found to be mainly hyaluronic acid (HA), which had
      accumulated extensively in the upper dermis. Fibroblasts were increased in number
      in the mid to lower dermis. To clarify the mechanism of the deposition of HA in
      the dermis, we employed an antibody against serum-derived hyaluronan-associated
      protein (SHAP). This immunohistochemical study disclosed that the greater part of
      the fibroblasts in the mid to lower dermis stained positively, while the
      fibroblasts surrounded by fairly large amounts of HA in the upper dermis stained
      faintly or not at all. From these results, we suspect that the accumulation of HA
      progresses from the upper to the low dermis and that the interaction of
      fibroblasts and SHAP leads to development of the physiophathological cutaneous
      changes seen in our case.

PMID- 8648005
TI  - A case of sarcoidosis which relapsed twice after successive parturitions.
AB  - A 30-year-old Japanese woman relapsed into sarcoidosis after two successive
      parturitions. The cutaneous lesions consisted of scar sarcoidosis, papular type,
      nodular type, and subcutaneous nodules with histologically typical "naked
      tubercles". Hypergammaglobulinemia, elevation of both serum angiotensin
      converting enzyme and lysozyme levels, and bilateral hilar lymphadenopathy were
      found in the acute and subacute stages, and spontaneously returned to normal
      levels 16 months after the onset. Our case suggests that parturition may trigger
      the onset of sarcoidosis.

PMID- 8648006
TI  - Partial unilateral lentiginosis associated with segmental neurofibromatosis.
AB  - Partial unilateral lentiginosis associated with segmental neurofibromatosis is
      rate. Therefore, we describe here a patient with partial unilateral lentiginosis
      associated with ipsilateral segmental neurofibromatosis who developed multiple,
      rice-sized, brown macules on the right side of her face, trunk, and upper arm and
      several bean-sized, cafe-au-lait spots on the right upper arm and right upper
      back. To our knowledge, partial unilateral lentiginosis associated with
      ipsilateral segmental neurofibromatosis has not been reported in the English
      literature.

PMID- 8648007
TI  - A case of subacute necrotizing fasciitis.
AB  - We report a 48-year-old woman who developed necrotizing groin fasciitis with
      insidious onset. Before she visited us, she had been unsuccessfully treated with
      several kinds of antibiotics by other doctors for one month, because of a small
      ulcer covered by blackish necrotic tissue. She was referred to us because of high
      fever, an ulcer on the left labium majus, and a cellulitis-like lesion with
      severe pain on the lower abdomen. Methicillin-resistant Staphylococcus aureus
      (MRSA), Streptococcus intermedius, and Bacteroides uniformis were isolated from
      the wound. After aggressive debridement on the eighth day after admission of the
      whole indurated area and the fascia of the underlying muscle, healthy granulation
      tissue covered the defect, and the wound was finally closed with a skin graft
      Long-term administration of antibiotics along with insufficient and delayed
      surgical treatment were considered to have caused the full development of this
      disease.

PMID- 8648008
TI  - Giant porokeratosis.

PMID- 8648009
TI  - Increased intestinal permeability in bronchial asthma.
AB  - T lymphocytes are a major component of bronchial inflammatory processes in
      asthma. Because lymphocytes have the ability to migrate from one mucosal site to
      another, we initiated this prospective study to demonstrate mucosal abnormalities
      of the digestive barrier in asthma. To establish this we studied intestinal
      permeability in a group of 37 patients with asthma (21 allergic and 16
      nonallergic) by measuring chromium 51-labeled ethylenediaminetetraacetatic acid
      (CrEDTA) urinary recovery. The results were compared with those obtained in a
      group of 13 nonasthmatic patients with chronic obstructive pulmonary disease and
      26 healthy control subjects. Urinary recovery of CrEDTA was significantly higher
      in patients with asthma (2.5% +/- 1.95%) than in patients with chronic
      obstructive pulmonary disease (1.16% +/- 0.48%) and healthy control subjects
      (1.36% +/- 0.14%). There was no significant difference in intestinal permeability
      between patients with allergic asthma (2.94% +/- 2.4%) and those with nonallergic
      asthma (1.92% +/- 0.9%). Intestinal permeability was not correlated with the
      severity of asthma as measured by FEV1. Similarly, intestinal permeability did
      not significantly vary according to Aas score or steroid treatment. Serum IgE
      values and eosinophil blood count were not correlated with intestinal
      permeability. Intestinal permeability was evaluated sequentially in seven
      patients with asthma (4 allergic and 3 nonallergic) with a mean interval of 7.6
      months (range, 2 to 13 months) and did not significantly change. Our results
      support the hypothesis that a general defect of the whole mucosal system is
      present as a cause or a consequence of bronchial asthma.

PMID- 8648010
TI  - Urinary eosinophil protein X in children with atopic asthma: a useful marker of
      antiinflammatory treatment.
AB  - BACKGROUND: Bronchial asthma is associated with elevated serum levels of
      eosinophil products, such as eosinophil protein X (EPX), but the occurrence in
      urine of this substance in patients with asthma has not previously been studied.
      OBJECTIVE: This study was performed to clarify whether increased amounts of
      eosinophil granulocyte proteins in urine and serum reflect ongoing asthmatic
      inflammation and whether decreasing values reflect successful treatment. METHODS:
      Twelve children with a median age of 12.5 years who had mild or moderate atopic
      asthma were studied for 3 months. At the time of inclusion in the study,
      treatment with inhaled budesonide was initiated. Nine children of the same age
      without atopic disease served as control subjects. Levels of EPX, eosinophil
      cationic protein (ECP), and myeloperoxidase in serum and in urine (urinary EPX)
      were determined at inclusion and then after 3 months of treatment. Spirometry was
      performed on the same occasions. RESULTS: At the time of inclusion, urinary EPX
      and serum ECP were significantly higher in children with atopic asthma than in
      the control subjects (mean, 116.4 vs 43.0 micrograms/mmol creatinine [p = 0.004]
      and 37.0 vs 14.8 micrograms/L [p = 0.004]). In the asthma group urinary EPX, as
      well as serum ECP, decreased significantly after 3 months of treatment with
      budesonide (116.4 to 68.4 micrograms/mmol creatinine [p = 0.005] and 37.0 to 24.0
      micrograms/L [p = 0.04]). At the same time, peak expiratory flow values increased
      significantly in the children with asthma (76.0% to 87.8% of predicted value [p =
      0.005]) but not in the control subjects (87.0% to 90.1%). In the asthma group the
      levels of myeloperoxidase were similar to those in the control group, both at
      inclusion and after 3 months. CONCLUSION: Increased urinary EPX and serum ECP
      levels seem to reflect active atopic asthma, whereas decreased levels after
      antiinflammatory treatment probably reflect normalization of airway inflammation,
      and indirectly, improved lung function.

PMID- 8648011
TI  - The prevalence of anti-latex IgE antibodies in 1000 volunteer blood donors.
AB  - BACKGROUND: Latex allergy has been recognized as a medical problem with
      increasing frequency since the mid 1980s. Although certain groups of individuals,
      such as health care workers, have been recognized as having increased risk for
      latex allergy, little is known about the prevalence of latex allergy in the
      general population. METHODS: To estimate the prevalence of latex allergy among
      healthy adults, we measured anti-latex IgE antibodies in residual serum samples
      from 1000 volunteer Red Cross blood donors. The 1000 samples were from a sample
      of blood units collected from workplace mobile sites throughout Southeastern
      Michigan. Samples collected from mobile sites operating at health care
      institutions were excluded to minimize sampling of health care workers. Anti
      latex IgE antibodies were measured by using the AlaSTAT assay (Diagnostic
      Products Corp., Los Angeles, Calif.) according to the manufacturer's directions.
      Samples with anti-latex IgE concentrations of 0.35 IU/ml or greater were
      classified as positive and samples with IgE concentrations of 1.50 IU/ml or
      greater were classified as strongly positive. All positive samples were assayed a
      second time to confirm the result. All positive samples were also measured with
      the CAP assay (Pharmacia Diagnostics, Dublin, Ohio). RESULTS: The samples tested
      were from donors with a mean age of 37.8 years, and 47% were women. Sixty-four
      (6.4%, 95% confidence interval = 4.9-8.1%) of the samples were confirmed as
      repeatedly positive for anti-latex IgE, and 23 of the 64 positive samples were
      strongly positive (2.3% of the 1000). Sixty-one percent of the samples positive
      as determined by the AlaSTAT assay were also positive as determined by the CAP
      assay. Samples from male donors were more likely to be positive than those from
      female donors (8.7% vs 4.1%, p = 0.003). Prevalence of positive samples was not
      related to age or race. CONCLUSIONS: We conclude that the prevalence of
      detectable anti-latex IgE antibodies, in a large and relatively unselected adult
      population, is higher than previous estimates have suggested. Although the
      clinical significance of these observations needs further evaluation, the data
      suggest that latex allergy is not confined to individuals in previously
      recognized high-risk groups.

PMID- 8648012
TI  - An assessment of the role of intradermal skin testing in the diagnosis of
      clinically relevant allergy to timothy grass.
AB  - BACKGROUND: Immediate skin testing is generally the preferred method for
      establishing the presence of allergy in clinical practice. There is no agreement,
      however, as to whether intradermal testing should be routinely performed if skin
      prick test results are negative. PURPOSE: The study was done to address the value
      of intradermal skin testing in the diagnosis of clinically significant
      sensitivity to grass pollen in patients exhibiting negative skin prick test
      responses to timothy extract. METHODS: Four groups were studied. Group I had a
      history of seasonal allergic rhinitis, negative skin prick test responses to
      timothy and Bermuda grass, but positive intradermal skin test responses to
      timothy grass. Group II had a history of seasonal allergic rhinitis and positive
      skin prick test responses to timothy grass. Group III had a history of seasonal
      allergic rhinitis but had negative responses to both prick and intradermal
      testing with timothy and Bermuda grass. Group IV had no history of rhinitis, had
      negative responses to skin testing with a panel of locally important allergens,
      as well as Bermuda and timothy grass, and had a serum IgE value of less than 20
      IU/ml. Clinical sensitivity to grass was assessed by two methods: (1) nasal
      challenge with threefold increasing amounts of timothy pollen performed out of
      the pollen season and (2) correlation of subjects' daily symptom and medication
      scores with daily grass pollen counts during the grass pollen season. RESULTS: On
      the basis of nasal challenge with timothy grass, pollen allergic reactions were
      present in 11% of group I, 68% of group II, 11% of group III, and 0% of group IV.
      As determined by correlation of symptoms during the grass pollen season with
      grass pollen counts, 22% of group I, 64% of group II, 21% of group III, and 0% of
      group IV were considered allergic. If both criteria were required for a diagnosis
      of clinical allergy to grass, the percent positive was 0 for group I, 46 for
      group II, 0 for group III, and 0 for group IV. CONCLUSION: Under the conditions
      of this study the presence of a positive intradermal skin test response to
      timothy grass (1000 AU/ml) in the presence of a negative skin prick test response
      to timothy grass (100,000 AU/ml) did not indicate the presence of clinically
      significant sensitivity to timothy grass, and by inference, to other cross
      reacting grasses.

PMID- 8648013
TI  - The relationship between latex skin prick test responses and clinical allergic
      responses.
AB  - BACKGROUND: Allergic responses to latex have been reported more frequently in the
      past 5 years. Although commercial skin prick test solutions are available and can
      be used in the diagnosis of latex allergy in some countries, the characteristics
      of patients sensitized to latex relative to their skin test responses have not
      been reported. OBJECTIVE: The purpose of this study is to relate the clinical
      characteristics of patients with latex sensitivity to the size of their latex
      skin prick test response. METHODS: A retrospective review of patients who were
      attending a hospital-based allergy and asthma clinic and who had positive skin
      test responses to a commercial latex skin test solution was undertaken. RESULTS:
      Of 47 patients who had skin test responses to latex, 36 had a mean wheal diameter
      at least 3 mm greater than the negative control (diluent). Sixty-eight percent
      were health care workers. There was a positive association between the size of
      skin test response and severity of latex-induced symptoms (p < 0.001). A history
      of banana sensitivity was also associated with larger skin test responses (p <
      0.05). CONCLUSION: The size of the skin prick test response to latex solution
      that is commercially available in Canada reflects the severity of latex-induced
      clinical allergic responses.

PMID- 8648014
TI  - Antihistamine premedication in specific cluster immunotherapy: a double-blind,
      placebo-controlled study.
AB  - BACKGROUND: Specific immunotherapy treatment in allergic diseases involves a risk
      of systemic side effects. A double-blind, placebo-controlled study was performed
      in 45 patients allergic to pollen to determine whether pretreatment with
      loratadine could reduce the number and severity of systemic reactions during the
      dose-increase phase of cluster immunotherapy. METHODS: The patients received
      cluster immunotherapy with a standardized birch (Betula verrucosa) or grass
      (Phleum pratense) pollen extract adsorbed to aluminum hydroxide. The
      immunotherapy schedule involved seven visits and 14 injections to reach a
      maintenance dose of 100,000 standardized quality units. Loratadine, 10 mg, or
      placebo tablets were administered 2 hours before the first injection at each
      visit. RESULTS: A total of 720 injections were given (309 injections in 21
      patients receiving loratadine and 411 injections in 24 patients receiving
      placebo). The median numbers of injections to reach maintenance dose were 15
      (range, 14 to 18) in the loratadine group and 16 (range, 14 to 23) in the placebo
      group (p = 0.037). The numbers of patients with systemic reactions were seven
      (33%) and 19 (79%) in the loratadine and placebo groups, respectively (p =
      0.002). Twenty-five reductions caused by systemic reactions were observed in the
      placebo group in contrast to nine in the loratadine group (p = 0.047). No life
      threatening systemic reactions were observed in either group. Systemic reactions
      were, however, more severe in the placebo group, mainly because of a
      significantly higher incidence of urticaria (10 vs 1, p = 0.022). CONCLUSION:
      Pretreatment with loratadine seems to reduce both the number and severity of
      systemic reactions in specific cluster immunotherapy.

PMID- 8648015
TI  - The control of house dust mites in rugs through wet cleaning.
AB  - Nine rugs from the bedrooms of seven private homes were cut into strips. Half of
      the strips were wet-cleaned according to a commercial procedure, and the others
      were kept as controls. Subsequently the cleaned and noncleaned strips were
      stitched together again and returned to their respective bedrooms. After 0, 1,
      and 3 months, parts of the strips were taken to the laboratory for tests. The
      tests were designed to measure the suitability of the rugs as a habitat for house
      dust mites. To do this, a number of house dust mites were introduced into
      fragments of the rugs, and the number of survivors and offspring after 4 weeks
      was determined. Immediately after cleaning, the habitat was markedly less
      suitable than before. After 1 month, the habitat suitability was partly but not
      totally recovered. After 3 months, no effect of cleaning could be discerned.

PMID- 8648016
TI  - An evaluation of the efficacy and safety of azelastine in patients with chronic
      asthma. Azelastine-Asthma Study Group.
AB  - BACKGROUND: Azelastine, an oral nonsteroidal, antiinflammatory drug with a good
      safety profile, has demonstrated relief of symptoms in patients with asthma.
      OBJECTIVE: The study was designed to evaluate the efficacy and safety of
      azelastine, a novel antiallergy compound, in patients with asthma who required
      maintenance therapy. METHODS: During this 16-week, double-blind, randomized,
      parallel-group study, patients received orally administered azelastine (4 mg
      twice daily), albuterol sulfate (4 mg twice daily), or placebo. RESULTS: Overall,
      patients in the azelastine group used 2.5 times less backup medication (p =
      0.024) for relief of their asthma symptoms than patients in the placebo group.
      Reductions in asthma symptoms in the azelastine group were also noted throughout
      the double-blind treatment period. Moreover, the azelastine group had
      statistically significant improvements in FEV1 after the first dose of
      medication. The only notable adverse experiences in the azelastine group were
      alterations in taste perception and a small mean increase in body weight.
      CONCLUSION: Oral administration of azelastine to patients with asthma resulted in
      overall improvement in airway function while reducing the requirement for
      adjunctive antiasthma medications.

PMID- 8648017
TI  - Effects of luminal antigen on intestinal albumin and hyaluronan permeability and
      ion transport in atopic patients.
AB  - BACKGROUND: Increased luminal transport of proteins and fluid is part of the
      inflammatory reaction in inflammatory disease of the bowel and of the airways in
      allergic diseases and asthma. The objective of this study was to determine
      intestinal appearance rates of albumin and hyaluronan in vivo in atopic patients
      allergic to birch, as well as changes in net jejunal transport of monovalent ions
      and water induced by the antigen. METHODS: Secretion studies were performed with
      the use of a segmental jejunal perfusion system with a small two-balloon, six
      channel tube. The intestinal mucosa was challenged with birch allergen in
      patients allergic to birch and in matched control subjects (n = 12 in both
      groups). RESULTS: In patients, but not in control subjects, the luminal antigen
      induced a net increase in albumin of 2689 +/- 567 micrograms/cm/hr and in
      hyaluronan of 2609 +/- 737 ng/cm/hr (p < 0.01 vs control subjects in both cases).
      Furthermore, basal net absorption of Cl- ions, Na+ ions, and water was converted
      to a net secretion after antigen challenge. CONCLUSION: Exposure to antigen
      normally acting on the respiratory tract induced increased permeability of the
      gastrointestinal mucosa. This would suggest less organ specificity and more
      general allergic recognition shared by several immunocompetent tissues in the
      body, probably mediated by circulating IgE antibodies.

PMID- 8648018
TI  - Model for outcomes assessment of antihistamine use for seasonal allergic
      rhinitis.
AB  - BACKGROUND: Drug selection for optimal treatment of common medical conditions may
      be difficult and involve many diverse factors. OBJECTIVE: The efficacy, safety,
      quality of life, and cost of treatment of seasonal allergic rhinitis with
      cetirizine, chlorpheniramine, or terfenadine were compared in a prospective, two
      phase, randomized, single-blind clinical trial conducted in a managed care
      setting. METHODS: In phase I, which lasted 2 weeks, patients were randomized to
      receive one of the study drugs. In phase II, which lasted 4 weeks, the initial
      treatment was continued unless patients were dissatisfied, in which case they
      could be randomly assigned to receive another study drug. In both phases
      pseudoephedrine could be taken as needed. Patients kept daily diaries of symptoms
      and costs, and study drugs were evaluated at the end of each phase for efficacy,
      safety, and effect on quality of life by means of a validated questionnaire. A
      multiattribute outcomes assessment model for formulary decision making was used
      to rank the antihistamines. RESULTS: Physicians' and patients' assessments in
      phases I and II indicated that cetirizine and chlorpheniramine were significantly
      more effective than terfenadine (p < 0.05). Incidence of sedation in phase I and
      phase II was 40.5% and 16.7% for chlorpheniramine, 11.6% and 9.8% for cetirizine,
      and 6.7% and 5.1% for terfenadine, respectively. At the end of phase I, 28.9% of
      the patients treated with chlorpheniramine, 50% of the patients treated with
      terfenadine, and 69.4% of the patients treated with cetirizine were satisfied
      with their therapy and chose not to switch their medication. Quality of life
      scores improved most after treatment with cetirizine and least after treatment
      with terfenadine. CONCLUSION: The result of this trial indicate that
      antihistamine selection is best made with the use of a multiattribute evaluation
      that includes quality of life. In this study cetirizine was favored by patients
      and physicians most often, followed by chlorpheniramine and then terfenadine.

PMID- 8648020
TI  - Public perception of food allergy.
AB  - BACKGROUND: Although studies that use the double-blind placebo-controlled food
      challenge suggest that the prevalence of food allergy is about 2%, public belief
      in food allergy appears to be considerably higher. OBJECTIVE: The study was
      undertaken to determine the magnitude and features of the American public's
      belief in food allergy by surveying a large, demographically balanced population.
      METHODS: A simple question about food allergy was incorporated into a broad, self
      reported, mailed consumer questionnaire. Five thousand demographically
      representative American households were surveyed by means of quota sample in
      1989, 1992, and 1993. RESULTS: The response rates were 79%, 75%, and 74%,
      respectively. Of responding households, 16.2%, 16.6%, and 13.9%, respectively,
      reported an average of 1.17 household members with food allergy. Individuals
      reported to be allergic to foods were more likely to be female, particularly
      adult women. Male individuals with reported food allergy tended to be young,
      whereas no such skew was noted among female subjects. Geographic differences were
      observed in reported food allergy, with the highest rate in the Pacific region.
      Milk and chocolate were the individual foods most frequently implicated in food
      allergy. Trends were consistent over the period studied. CONCLUSIONS: Perceived
      food allergy is widespread and persistent. The characteristics and demographic
      patterns of this belief are not reflective of known food allergy epidemiology
      derived from studies in which the double-blind placebo-controlled food challenge
      is used.

PMID- 8648019
TI  - Theophylline: potential antiinflammatory effects in nocturnal asthma.
AB  - BACKGROUND: Recent information suggests that one of the therapeutic properties of
      theophylline is an antiinflammatory effect. OBJECTIVE: We evaluated this
      potential effect of theophylline in eight patients with nocturnal asthma.
      METHODS: The study design was a randomized, double-blind, placebo-controlled
      crossover of 2-week treatment periods, separated by a 1-week washout period.
      Spirometry and bronchoscopy were performed. RESULTS: Theophylline, compared with
      placebo, significantly improved the overnight decrement in lung function. The
      higher the nocturnal theophylline level, the greater the improvement in lung
      function. Theophylline also significantly decreased the percentage of neutrophils
      in the 4:00 AM bronchoalveolar lavage fluid and stimulated leukotriene B4 levels
      from macrophages obtained at 4:00 AM. The greater change in neutrophils
      correlated with increasing serum theophylline concentration. Also, the change in
      leukotriene B4 production was significantly correlated with the theophylline
      induced decrement in lavage granulocytes (neutrophils and eosinophils).
      CONCLUSION: This study suggests that one action of theophylline is to alter
      inflammatory cell number and function in nocturnal asthma and that it may do this
      through an leukotriene B4-mediated mechanism.

PMID- 8648021
TI  - Evidence that enhanced nasal reactivity to bradykinin in patients with
      symptomatic allergy is mediated by neural reflexes.
AB  - OBJECTIVE: The aim of this study was to determine whether allergic inflammation
      induces nasal hyperreactivity to bradykinin by enhancing neuronal responsiveness.
      METHODS: We compared the response to localized, unilateral nasal challenge with
      bradykinin in patients with perennial allergic rhinitis and nonallergic subjects,
      and in patients with seasonal allergic rhinitis challenged in and out of season.
      Weights of secretions from each nostril were recorded, and levels of albumin and
      lactoferrin in secretions recovered from each nostril were assayed. Contralateral
      administration of atropine (0.32 mg) was used to evaluate the role of cholinergic
      reflexes in nasal hyperresponsiveness to bradykinin. RESULTS: In patients with
      symptomatic allergy, bradykinin induced greater symptom scores than in
      asymptomatic atopic or nonallergic control subjects. Moreover, bradykinin caused
      sneezing in a majority of patients with symptomatic allergy but in none of the
      asymptomatic atopic or nonallergic control subjects. Only patients with
      symptomatic allergy showed dose-dependent bilateral increases in secretion
      weights and levels of the serous glandular marker, lactoferrin. In contrast,
      bradykinin induced similar increases in ipsilateral, but not contralateral,
      levels of albumin in all patient populations. Atropine inhibited contralateral
      secretion and lactoferrin production (p < 0.05) in patients with symptomatic
      allergy. CONCLUSION: The induction of sneezing and of atropine-inhibitable
      contralateral glandular secretion demonstrates that allergic inflammation causes
      nasal hyperreactivity to bradykinin, at least in part, by enhancing neuronal
      responsiveness.

PMID- 8648022
TI  - Cross-reactivity between the major allergen from olive pollen and unrelated
      glycoproteins: evidence of an epitope in the glycan moiety of the allergen.
AB  - Ole e 1, the major allergen from olive pollen, is a glycoprotein containing a
      single Asn-linked glycan moiety. Rabbit antiserum against this protein has been
      obtained; and its immunologic cross-reactivities in Western blotting with
      ascorbate oxidase, horseradish peroxidase, bromelain, ovalbumin, and honeybee
      venom phospholipase A2 have been studied. Ascorbate oxidase, peroxidase, and
      bromelain are recognized by the Ole e 1 antiserum. When these three proteins are
      deglycosylated by periodate treatment, such an immunologic reaction does not
      occur. The relative affinities of these proteins have been analyzed by direct and
      inhibition ELISA experiments. A commercially available antibody against
      horseradish peroxidase has also been considered in these studies. This antibody
      reacts with Ole e 1 but not with the periodate-deglycosylated allergen.
      Horseradish peroxidase, bromelain, and ascorbate oxidase are recognized by the
      IgE of sera from patients who are hypersensitive to olive tree pollen. This
      binding is also abolished by periodate treatment. The results are interpreted in
      terms of the presence of an epitope in the carbohydrate moiety of Ole e 1, which
      would contain a xylose involved in recognition by both IgE and IgG antibodies.

PMID- 8648023
TI  - Eosinophil recruitment is associated with IL-5, but not with RANTES, twenty-four
      hours after allergen challenge.
AB  - Several lines of evidence suggest that the chemokine RANTES may play a role in
      eosinophilia observed during allergic inflammation. To test this hypothesis, six
      patients with allergic asthma were studied. After performing bronchoalveolar
      lavage in a lung segment (baseline), segmental bronchoprovocation was performed
      with saline solution in another segment and with ragweed in a third segment.
      Bronchoalveolar lavage was performed 24 hours later in the saline-challenged
      (sham) and ragweed-challenged lung segments. The bronchoalveolar lavage fluids
      from the baseline, sham, and ragweed segments were analyzed for cell counts and
      for the levels of IL-5, RANTES, and eosinophil-derived neurotoxin. IL-5 levels
      were elevated in the ragweed (984 +/- 588 pg/ml) compared with sham segments (2.8
      +/- 0.2 pg/ml, p = 0.02). Likewise, RANTES levels were elevated in the ragweed
      (12.93 +/- 3.4 pg/ml) compared with the sham segments (3.05 +/- 1.19 pg/ml, p =
      0.006). The IL-5 levels correlated with both eosinophil numbers (r = 0.90, p <
      0.02) and eosinophil-derived neurotoxin levels (r = 0.89, p < 0.02). In contrast,
      RANTES levels did not correlate with either eosinophil numbers or eosinophil
      derived neurotoxin levels. These results indicate that although both IL-5 and
      RANTES are elevated 24 hours after allergen challenge, only IL-5 correlates with
      eosinophil recruitment and degranulation.

PMID- 8648024
TI  - Nonreleasing basophils convert to releasing basophils by culturing with IL-3.
AB  - The extent of basophil histamine release initiated by IgE cross-linking stimuli
      has been known to vary greatly among donors. Studies on anti-IgE nonreleasing
      basophils are useful in understanding the IgE-specific control mechanism of
      mediator release. We attempted to determine (1) whether a mutation of Fc epsilon
      RI is present in nonreleasing basophils and (2) whether treatment with IL-3
      converts anti-IgE nonreleasing basophils to releasing basophils. Basophils were
      purified from normal human blood and donors were divided into releasers (maximal
      histamine release > 5%) and nonreleasers (< 5%). The mutation of Fc epsilon RI
      alpha, beta, and gamma was evaluated by reverse transcriptase-polymerase chain
      reaction, and the DNA sequence was determined from amplified polymerase chain
      reaction products. Although antibodies against Fc epsilon RI failed to cause
      histamine release in anti-IgE nonreleasing basophils, no primary structural
      change of Fc epsilon RI was observed in nonreleaser basophils. After culturing
      with IL-3 for 7 days, nonreleasing basophils released histamine in response to
      anti-IgE, and dose-response curves of anti-IgE were equal in both releasers and
      nonreleasers. The conversion of nonreleasing basophils to releasing basophils was
      evident after 3 days of culture with IL-3. These findings indicate that
      nonreleasing basophils have recoverable defect(s) in the signal transduction
      pathway after IgE cross-linking.

PMID- 8648025
TI  - Interleukin-10 regulation in normal subjects and patients with asthma.
AB  - Interleukin-10 or cytokine synthesis inhibitory factor has important
      antiinflammatory activities in immune diseases. We speculated that diminished IL
      10 production in asthma would permit the unopposed synthesis of proinflammatory
      cytokines, contributing to the development and severity of asthma. Our data
      demonstrate constitutive secretion of IL-10 into bronchoalveolar lavage (BAL)
      fluid of normal, nonasthmatic subjects (130 +/- 61 pg/ml; n = 8). Asthmatic
      patients' BAL fluid was characterized by diminished concentrations of IL-10 (9 +/
      18 pg/ml; n = 8; p < 0.01 compared with that of normal subjects). By using the
      RNA-based polymerase chain reaction, we demonstrated that diminished IL-10
      occurred as a result of inhibition of transcription. IL-10 transcription, but not
      protein, was observed at the time of the late asthmatic response. We speculate
      that the subsequent appearance of IL-10 protein could contribute to the
      resolution of the late asthmatic response. Similar to what was observed in the
      BAL fluid, peripheral blood mononuclear cells of patients with asthma
      demonstrated decreased spontaneous (0.01 +/- 0.01 ng/ml-asthmatic and 0.09 +/-
      0.04 ng/ml-normal; p < 0.05) and stimulated (0.60 +/- 0.22 ng/ml-asthmatic and
      1.69 +/- 0.49 ng/ml-normal; p < 0.05) IL-10 production compared with normal
      subjects. In support of the hypothesis that IL-10 mitigates the development of
      inflammation, we demonstrated that the addition of a neutralizing anti-IL-10
      antibody to resting peripheral blood mononuclear cell cultures of normal subjects
      stimulated the spontaneous production of interferon-gamma (10.4 +/- 4.3 to 152.4
      +/- 23.6 ng/ml; p < 0.01). Finally, we reasoned that corticosteroids might exert
      at least part of their antiinflammatory activity through the induction of IL-10
      secretion. However, methylprednisolone inhibited the lipopolysaccharide
      stimulated production of IL-10 (2.34 +/- 0.49 ng/ml IL-10 with lipopolysaccharide
      alone to 1.11 +/- 0.38 ng/ml in the additional presence of 10(-6) mol/L
      methylprednisolone; p < 0.05).

PMID- 8648026
TI  - Complementary DNA cloning of the predominant allergen of bovine dander: a new
      member in the lipocalin family.
AB  - BACKGROUND: A number of allergenic proteins in animal danders have been
      characterized at the molecular level, but little is known of their biologic
      functions. We have found that the prevalence of IgE antibodies among patients
      with cattle-associated asthma is highest against a dander protein referred to as
      BDA20. OBJECTIVE: The study was performed to characterize the molecular structure
      of BDA20,* the predominant allergen in bovine dander. METHODS: Clones encoding
      allergens were identified and isolated from a complementary DNA library by
      immunoblotting and DNA hybridization and sequenced. Recombinant proteins were
      produced in Escherichia coli. Immunoreactivity of the recombinant proteins and
      amino acid sequences of peptides obtained from native BDA20 after Lys-C cleavage
      were used to identify clones coding for BDA20. RESULTS: In this article we report
      the cDNA and amino acid sequences of BDA20. Homology comparisons showed that
      BDA20 belongs to the family of lipocalins. CONCLUSIONS: The results link a dander
      allergen to a group of functionally important proteins. Lipocalins are present in
      various body fluids and secretions of several animal species in which they
      function as carriers of small hydrophobic molecules, such as retinoids and
      pheromones. If allergenicity proves to be a property shared by lipocalins, our
      results will have considerable implications for allergen research.

PMID- 8648027
TI  - Allergy to the heat-labile proteins alpha-lactalbumin and beta-lactoglobulin in
      mare's milk.
AB  - BACKGROUND: Allergy to mare's milk is rare. Recently, however, mare's milk has
      been recommended for treatment of various ailments by practitioners of
      "alternative medicine," and it is available in health food stores. OBJECTIVE: We
      report a case of allergic reaction to mare's milk in a 51-year-old woman who was
      able to tolerate cow's milk. METHODS: The protein composition of mare's milk was
      determined by methods based on measurement of nitrogen content. The patient
      underwent prick and intracutaneous tests with commercially available bovine milk
      proteins and several mare's milk preparations, including mare's milk granulate
      and boiled mare's milk. RAST and immunoblotting were also performed. RESULTS:
      Results of skin testing and RAST with cow's milk were negative but demonstrated
      an IgE-mediated allergy to mare's milk. Immunoblotting revealed two allergen
      bands with molecular weights of 16 and 18 kd, most likely representing the whey
      proteins alpha-lactalbumin and beta-lactoglobulin. The bands disappeared after
      the mare's milk was boiled, indicating that the proteins are heat-labile.
      CONCLUSION: The results of this study demonstrate the existence of an IgE
      mediated mare's milk allergy caused by low molecular weight heat-labile proteins,
      most likely alpha-lactalbumin and beta-lactoglobulin, which do not cross-react
      with the corresponding whey proteins in cow's milk.

PMID- 8648028
TI  - Late respiratory response and associated eosinophilic inflammation induced by
      repeated exposure to toluene diisocyanate in guinea pigs.
AB  - OBJECTIVE: The study was designed to establish an animal model of toluene
      diisocyanate (TDI)-induced late respiratory response and to investigate airway
      inflammatory cell dynamics in this model. METHODS: Guinea pigs were exposed to 2,
      4-TDI dissolved in ethyl acetate by nasal application according to three
      schedules. Schedule 1 consisted of sensitization and multiple challenge (n = 58):
      10% TDI was applied once daily for 7 days (sensitization) followed by challenges
      with 5% TDI once weekly for 4 weeks. Schedule 2 consisted of sensitization only
      (n = 5): 10% TDI was applied once daily for 7 days. Schedule 3 consisted of
      single challenge only (n = 12): 5% TDI was applied only once. As controls, ethyl
      acetate was applied according to the three schedules described above. Each animal
      was premedicated with metyrapone before each challenge. Bronchoalveolar lavage
      and histologic examination were performed at various times after the last
      challenge. RESULTS: Schedule 1 induced immediate and late respiratory responses
      at a prevalence of 63% and 56%, respectively. Schedules 2 and 3 induced an
      immediate response in some animals but no late response. Neither immediate nor
      late response was observed in control animals. All of the subgroups of schedule 1
      that developed late responses (examined at 2, 3, 6, 24 and 168 hours) showed a
      significant increase of eosinophils in bronchoalveolar lavage fluid and tissue
      compared with the corresponding control of each (examined at the same time
      points). Two of the subgroups with late responses (examined at 3 and 6 hours)
      were compared with their corresponding subgroups, which were given the same
      treatment, failed to develop late response, and were examined at the same time
      points; they again proved to have a significant increase of eosinophils in both
      samples. Subgroups of schedule 1 without late response (30 minutes, 3 and 6
      hours), schedule 2 (6 hours), or schedule 3 (2 and 6 hours) did not show
      significant changes in lavage or tissue cell composition, except for the schedule
      1 subgroup examined at 6 hours, which showed a significant increase of
      eosinophils only in the tissue compared with its control. CONCLUSIONS:
      Sensitization and multiple challenge with TDI induced immediate and/or late
      respiratory responses at a high prevalence in guinea pigs. Eosinophilic but not
      neutrophilic inflammation was involved in the late response.

PMID- 8648029
TI  - Interleukin-5 messenger RNA expression in peripheral blood CD4+ cells in asthma.
AB  - BACKGROUND: IL-5 has been implicated in the pathogenesis of asthma through its
      regulatory role on eosinophil survival, proliferation, and effector function.
      OBJECTIVE: The study was designed to investigate the relationships between IL-5
      messenger RNA expression in circulating CD4+ cells and serum concentrations of
      eosinophil cationic protein (ECP), a marker of eosinophil activation, and disease
      activity in asthma. METHODS: IL-5 gene expression was assessed semiquantitatively
      in ex vivo stimulated CD4+ cells by reverse transcription-polymerase chain
      reaction and serum ECP concentration measured from venous blood samples collected
      from patients with acute severe asthma before the commencement of systemic
      steroid therapy (day 1) and on day 7 and from patients with stable asthma and
      healthy volunteers. RESULTS: IL-5 gene expression was significantly higher in
      patients with acute asthma before steroid treatment than in those with stable
      disease and healthy subjects (p < 0.0001). Similar results were obtained with
      serum ECP levels: levels in patients with acute asthma were highest (20.30 +/-
      5.31 micrograms/L), followed by levels in patients with stable asthma (2.76 +/-
      0.65 micrograms/L) and levels in normal control subjects (1.37 +/- 0.06
      micrograms/L; p < 0.01 for all comparisons). Significant falls in both IL-5
      expression and serum ECP level were seen on day 7 (p < 0.001) and coincided with
      a significant improvement in peak expiratory flow (p < 0.0001). Significant
      correlations were observed between IL-5 expression and ECP level (rho = 0.39, p <
      0.01), IL-5 expression and peak expiratory flow (rho = -0.55, p < 0.0002), and
      peak expiratory flow and ECP level (rho = -0.32, p < 0.04). CONCLUSION: Our data
      therefore support an important regulatory role of IL-5 on eosinophil function in
      human asthma in vivo.

PMID- 8648031
TI  - Establishment and characterization of alpha s1-casein-specific T-cell lines from
      patients allergic to cow's milk: unexpected higher frequency of CD8+ T-cell
      lines.
AB  - To study cow's milk allergy at the cellular level, we assessed the reactivity of
      peripheral blood mononuclear cells from patients allergic to cow's milk to alpha
      s1-casein, which is one of the major allergens in cow's milk. Proliferation of
      the cells to alpha s1-casein activation showed a rather weak response. Therefore
      to understand T-cell reactivity to alpha s1-casein in more detail, we prepared
      alpha s1-casein-specific T-cell lines from patients allergic to cow's milk and
      established 26 T-cell lines. These T-cell lines could be classified into three
      groups by analyzing their surface marker expression: those containing
      predominantly CD4+ CD8- T cells, those containing both CD4+CD8- and CD4-CD8+ T
      cells, and those containing predominantly CD4- CD8+ T cells. The CD8+ T cells
      were obtained at an unexpectedly higher frequency from the patients. These T-cell
      lines produced interferon-gamma and IL-4. These results suggest that CD8+ T cells
      specific for alpha s1-casein and CD4+ T cells were primed by the stimulation with
      alpha s1-casein in patients allergic to milk and that both T cells may play a key
      role in the onset, progression of, or recovery from cow's milk allergy.

PMID- 8648030
TI  - Alterations in arachidonic acid metabolism in mouse mast cells induced to undergo
      maturation in vitro in response to stem cell factor.
AB  - We studied arachidonic acid (AA) metabolism during the maturation of bone marrow
      derived cultured mast cells (BMCMCs) into mast cells with phenotypic
      characteristics, which were more similar to those of connective tissue-type mast
      cells. BMCMCs were maintained in medium containing 100 ng/ml recombinant rat stem
      cell factor (SCF) for 1 to 6 weeks. After 3 to 4 weeks in SCF, BMCMCs acquired
      many phenotypic characteristics of maturation, including enlarged size, numerous
      electron-dense cytoplasmic granules, and a 50-fold elevation in histamine
      content. Maintenance in SCF for 6 weeks did not significantly alter the amounts
      or species of eicosanoids that were produced by BMCMCs stimulated with calcium
      ionophore A23187. However, SCF-treated mast cells released 2.6 +/- 0.13 times
      more free AA and accumulated 6.4 +/- 1.0 times higher levels of intracellular
      free AA than did immature BMCMCs not exposed to SCF. There was no increase in the
      mobilization of other fatty acids (e.g., linoleic or oleic acid), indicating
      specificity for AA. Moreover, there were no differences between the 5
      lipoxygenase activities of SCF-treated or untreated cells, as assayed in cell
      homogenates prepared by nitrogen cavitation. Although the total AA content in SCF
      treated cells was significantly elevated, the distribution of AA in phospholipid
      and neutral lipid classes was not altered by SCF treatment. Total phospholipase
      (PL)A2 activity increased 85% +/- 11.5% in SCF-treated cells. In homogenates of
      immature BMCMCs, 51.0% +/- 13.7% of the PLA2 activity was inhibited by 0.5 mmol/L
      dithiothreitol, whereas the same concentration of dithiothreitol caused only a
      2.2% +/- 10.7% reduction in the PLA2 activity in homogenates of SCF-treated
      BMCMCs (p < or = 0.05, n = 4). These findings suggest that SCF treatment induces
      a dithiothreitol-resistant PLA2 and that this PLA2 may contribute to the
      mobilization of AA that is not further metabolized to eicosanoids.

PMID- 8648032
TI  - Serum levels of eosinophil cationic protein in allergic diseases and natural
      allergen exposure.
AB  - BACKGROUND: Eosinophil cationic protein (ECP) is a cytotoxic performed mediator
      stored in eosinophil granules and released under various in vitro and in vivo
      conditions. OBJECTIVE: This study was carried out to evaluate the clinical value
      of ECP as a marker of allergic inflammation. METHODS: ECP was measured by a
      competitive radioimmunoassay in serum samples from 265 patients and 45 matched
      control subjects and related to the type of allergic disease (asthma, rhinitis,
      conjunctivitis) and to the type of allergic sensitization. RESULTS: All the
      patient groups studied showed significantly higher levels of serum ECP than
      control groups (p < 0.001). The type of sensitization was shown to be the only
      variable influencing ECP serum levels. In fact, subjects sensitized to perennial
      allergens had significantly higher ECP values than subjects with seasonal allergy
      (p < 0.001), whereas in patients with seasonal allergy ECP levels were
      significantly increased only during the pollen season. Differences in ECP values
      between various allergic diseases or age groups were only due to a nonhomogeneous
      distribution of the type of sensitization or to time of sera collection.
      CONCLUSIONS: Results obtained indicate that persistent natural exposure to a
      sensitizing allergen is responsible for a measurable increase in serum ECP levels
      in patients with allergy.

PMID- 8648033
TI  - Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T
      lymphocytes and eosinophils in the nasal mucosa and increases the number of cells
      expressing messenger RNA for interferon-gamma.
AB  - BACKGROUND: Grass pollen injection immunotherapy is effective in patients with
      summer hay fever, although efficacy must be balanced against possible side
      effects. The mechanism of immunotherapy is unknown but may be related to its
      ability to inhibit allergen-induced late responses, which are known to be
      characterized by infiltration of T lymphocytes, eosinophils, and cells with
      messenger RNA for so-called TH2-type cytokines (IL-4 and IL-5). OBJECTIVE: This
      study was designed to observe the effect of grass pollen immunotherapy on late
      nasal responses and associated cellular infiltration and cytokine mRNA
      expression. METHODS: We performed local nasal provocation with grass pollen (and
      a control challenge) in 28 patients after a 12-month double-blind, placebo
      controlled trial of immunotherapy. Nasal biopsy specimens were obtained at 24
      hours and processed for immunohistology and in situ hybridization studies.
      RESULTS: Grass pollen immunotherapy inhibited allergen-induced immediate (0 to 60
      minutes) increases in sneezing (p < 0.02) and nasal blocking (p < 0.01) and late
      (0 to 24 hours) nasal symptoms (p < 0.05). Immunotherapy also inhibited the
      associated infiltration of the nasal mucosa by CD4+ T lymphocytes and total
      (major basic protein-containing) and "activated" (cationic protein-secreting)
      eosinophils (all p = 0.03). There was a significant (p = 0.04) increase in cells
      expressing mRNA for interferon-gamma at 24 hours after allergen challenge, which
      correlated inversely with patients' seasonal symptoms (r = -0.65, p < 0.05) and
      medication requirements (r = -0.75, p < 0.02) during the pollen season.
      CONCLUSION: The results suggest that successful grass pollen immunotherapy for
      summer hay fever may act by inhibiting allergen-induced T lymphocyte and
      eosinophil recruitment and eosinophil activation in the target organ, possibly
      through a mechanism involving protective local increases in TH1-type cells.

PMID- 8648034
TI  - Detection of IL-5 and IL-1 receptor antagonist in bronchoalveolar lavage fluid in
      acute eosinophilic pneumonia.
AB  - BACKGROUND: Acute eosinophilic pneumonia is an idiopathic cause of respiratory
      failure, characterized by very high numbers of alveolar eosinophils without
      significant blood eosinophilia. OBJECTIVE: The purpose of this study was to
      determine which cytokines are associated with acute eosinophilic pneumonia.
      METHODS: Soluble IL-1 type II receptor and the cytokines IL-1 beta, IL-1ra, IL-3,
      IL-5, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor
      alpha were measured in serum and in bronchoalveolar lavage fluid from two
      patients with acute eosinophilic pneumonia during both acute and convalescent
      phases. RESULTS: Compared with patients with adult respiratory distress syndrome,
      the patients with acute eosinophilic pneumonia had high bronchoalveolar lavage
      fluid levels of IL-5, IL-1ra, and soluble type II IL-1 receptor but not IL-1
      beta, tumor necrosis factor-alpha, IL-3, or granulocyte-macrophage colony
      stimulating factor. Bronchoalveolar lavage fluid levels of IL-5 and IL-1ra fell
      after resolution of symptoms. In the serum of patients with acute eosinophilic
      pneumonia, IL-5 was not detectable, and IL-1ra was initially high but fell after
      corticosteroid treatment. CONCLUSION: Acute eosinophilic pneumonia is
      characterized by locally high levels of IL-5, IL-1ra, and soluble type II IL-1
      receptor in the alveolar space.

PMID- 8648035
TI  - Immunomorphologic studies of mast cell heterogeneity, location, and distribution
      in the rat conjunctiva.
AB  - Mast cells are crucial components of immediate and some delayed-type
      hypersensitivity reactions. They play a pivotal role in allergic conjunctivitis
      and other immunoinflammatory disorders of the ocular surface, yet little is known
      of their distribution and heterogeneity in the conjunctiva of potential animal
      models, such as the rat. In this study, mast cell types were investigated in
      histologic sections and corneal-conjunctival-lid whole mounts by using toluidine
      blue, alcian blue-safranin, and immunohistochemical staining methods (anti-rat
      mast cell proteinase [RMCP] antibodies). Quantitative analyses were performed on
      corneal-conjunctival-lid whole mounts by using the optical dissector procedure to
      obtain the density of mast cells per unit volume in different regions of the
      conjunctiva. Single and double immunohistochemical analyses revealed that the
      mast cells in the conjunctiva of the limbus, fornices, and lid margin were
      strongly RMCP I+, suggesting that they were of the connective tissue phenotype.
      Mast cells containing the mucosal mast cell proteinase RMCP II were not present
      in the normal conjunctiva. Histochemical analysis revealed that the maturity of
      the connective tissue mast cells, as assessed by the presence or absence of
      safranin (heparin)-positive granules in their cytoplasm varied in different
      regions. In the lid margin 60% to 78% of the mast cells were solely alcian blue
      positive, whereas in the fornices 68% to 78% were safranin-positive. In the
      limbus the predominant type of mast cell was either safranin-positive or
      contained mixed granules. Mast cell densities were greatest close to the lid
      margin (10,000 to 12,000 cells/mm3), followed by the limbus (3400 to 4800
      cells/mm3) and were rare in the remainder of the conjunctiva (500 to 1000
      cells/mm3), with the exception of the region around the nictitating membrane.
      This study of rat conjunctival mast cells provides essential baseline data for
      future studies of the role of mast cells in models of allergic conjunctivitis.

PMID- 8648036
TI  - Delayed expansion of V delta 2+ and V delta 1+ gamma delta T cells after acute
      Plasmodium falciparum and Plasmodium vivax malaria.
AB  - T lymphocytes that express T-cell receptors encoded by the gamma and delta T-cell
      receptor genes (gamma delta T cells), and preferentially those expressing the V
      gamma 9 and V delta 2 gene segments, are activated by microbial and parasitic
      organisms in vitro and have been implicated in the pathogenesis of the fever and
      rigors during acute malaria. We have found, in a cohort of nine nonimmune
      patients who contracted malaria during travel to endemic areas (five with
      Plasmodium falciparum and four with P. vivax infections) that gamma delta T
      lymphocytes expanded to comprise 17.92% +/- 11% of the peripheral blood
      mononuclear cells (vs 3.08% +/- 2.4% gamma delta cells in normal control
      subjects). Although V delta 2+ cells predominated among the gamma delta subset,
      gamma delta lymphocytes expressing the V delta 1 gene segment also expanded
      significantly in some patients. Importantly, the gamma delta cells continued to
      expand for 2 months after the infection, and the mean level of gamma delta cells
      peaked during the second month after the acute clinical syndrome, when patients
      were free of symptoms. Thus although gamma delta T cells may contribute to the
      pathogenesis of the acute clinical syndrome, our findings suggest that gamma
      delta lymphocytes could also play a role in generating an immune response to
      plasmodia.

PMID- 8648037
TI  - Socioeconomic status and race as risk factors for cockroach allergen exposure and
      sensitization in children with asthma.
AB  - BACKGROUND: The domestic cockroach has been identified as an important source of
      indoor aeroallergens worldwide in both temperate and tropical climates. Because
      cockroach populations are highest in crowded urban areas, some have suggested
      that the increased asthma morbidity and mortality rates in inner cities could be
      related in part to cockroach allergen exposure. We have examined cockroach
      allergen exposure in the homes of children with asthma in both urban and suburban
      locations and have related the rates of exposure and sensitization to
      socioeconomic, racial, and demographic factors. OBJECTIVE: The study was designed
      to determine the independent contribution of race, socioeconomic status, and
      place of residence to the risk of cockroach allergen exposure and sensitization
      in children with asthma. METHODS: Eighty-seven children with moderate to severe
      allergic asthma, aged 5 to 17 years, participating in a prospective trial of
      immunotherapy, were evaluated. Extracted dust samples from three home locations
      were analyzed by using two-site monoclonal immunoassays for major cockroach
      allergens (Bla g 1 and Bla g 2). A puncture skin test with a mixed cockroach
      allergen extract was performed in 81 of the 87 subjects. RESULTS: In the 87 homes
      evaluated, 26% of the bedroom dust samples had detectable levels of cockroach
      allergen. In homes with detectable bedroom cockroach allergen levels, mean Bla g
      1 and Bla g 2 concentrations in urban and suburban homes were similar. Over 80%
      of children with bedroom Bla g 1 or Bla g 2 of 1 U/gm or greater demonstrated
      skin sensitivity to cockroach allergen. The rate of cockroach sensitization was
      directly related to the level of bedroom exposure. African-American race was the
      only factor that was independently associated with cockroach allergen exposure (p
      = 0.05). Lower socioeconomic status, age greater than 11 years, cockroach
      exposure, and African-American race were all independently associated with
      cockroach allergen sensitization on the basis of stepwise multiple linear
      regression analysis. CONCLUSIONS: African-American race and low socioeconomic
      status were both independent, significant risk factors for cockroach allergen
      sensitization in children with atopic asthma. Cockroach allergen is detectable
      throughout the house, including the critical bedroom environment.

PMID- 8648038
TI  - Regulation of disease susceptibility: decreased prevalence of IgE-mediated
      allergic disease in patients with multiple sclerosis.
AB  - The development of restricted cytokine profiles by subsets of CD4+ T cells is a
      pivotal point in the regulation of immune responses. T cells producing Th1
      cytokines (IL-2 and interferon-gamma) induce cell-mediated immunity, whereas T
      cells producing Th2 cytokines (IL-4, IL-5, and IL-10) play a prominent role in
      the induction of humoral immunity. We examined a group of patients with multiple
      sclerosis, a disease caused by excess production of Th1 cytokines in myelin
      reactive T cells, and control patients with noninflammatory neuroconvulsive
      disorders, for the presence of allergic disease, which is caused by excess
      production of Th2 cytokines in allergen-specific T cells. The patients with
      multiple sclerosis had significantly fewer allergic symptoms, a lower number of
      positive allergen-specific IgE test results, and lower composite allergy indexes
      than control subjects. These results demonstrate that the prevalence of IgE
      mediated allergic disease is decreased in a group of patients with multiple
      sclerosis and support the hypothesis that genetic factors that promote
      susceptibility to Th1-mediated inflammatory disease in human beings protect
      against the development of Th2-mediated disease.

PMID- 8648039
TI  - Occupational asthma induced by Chrysonilia sitophila in the logging industry.

PMID- 8648040
TI  - Anaphylaxis to omeprazole.

PMID- 8648041
TI  - Allergy to supplemental lactase enzyme.

PMID- 8648043
TI  - Recall urticaria: a case report.

PMID- 8648042
TI  - Occupational asthma caused by sarsaparilla root dust.

PMID- 8648044
TI  - Association between sensitization to natural rubber latex and papain.

PMID- 8648045
TI  - Safety and efficiency of an accelerated method for venom skin testing.

PMID- 8648046
TI  - Ciprofloxacin desensitization.

PMID- 8648047
TI  - Intravaginal desensitization and successful pregnancy in a woman with seminal
      fluid allergy.

PMID- 8648048
TI  - The diagnosis of liver diseases by laboratory tests. An alternative to biopsy.

PMID- 8648049
TI  - The Yale-Affiliated Gastroenterology Program: 1965-1995. A community-university
      model of collaboration.
AB  - The Yale-Affiliated Gastroenterology Program (YAGP) originated in 1965 from the
      informal arrangements of two gastroenterologists, one university based and the
      other in a community hospital. Conceived at a time when there was little central
      authority, either on a national or on a hospital/medical school level, its links
      were forged by the personal relationships of its directors. The process of growth
      remained informal and flexible enough for the directors to meet the special
      requirements of their own community and hospital. YAGP provided an important
      model for improving medical care and education in community hospitals since it
      addressed personnel needs, contributed to the education of physicians, and
      fostered clinical research in digestive diseases. YAGP evolved its own standards
      and its own accreditation mechanism, but faltered when the Accreditation
      Committee on Graduate Medical Education provided national rather than local
      criteria. Increased controls by hospitals and medical schools led to more formal
      ties and programs, and YAGP ceased to matter. Still, there may be lessons from
      what was in its time an innovation, on a local and state level rather than on a
      national level.

PMID- 8648050
TI  - Sociodemographic characteristics, life stressors, and peptic ulcer. A prospective
      study.
AB  - The role of psychosocial factors in peptic ulcer remains controversial. We have
      investigated the relationship between socioeconomic status, concrete stressors,
      and ulcers in a longitudinally followed, population-based cohort, taking
      confounding risk factors into account. A total of 6,928 adults completed the
      Alameda County Study's baseline questionnaire in 1965; 4,595 ulcer-free on
      enrollment responded again in 1973-1974. Reported cases of ?stomach or duodenal?
      ulcer during the year before each of the two surveys were examined with relation
      to 1965 characteristics: 288 subjects reported ulcers at baseline, and 104
      reported new ulcers on follow-up. Sociodemographic characteristics associated
      with incident ulcers (age-adjusted) were, in women, low education, a blue-collar
      household, overcrowding, unemployment, marital strain, and children's problems;
      in men, nonwhite race. Prevalent ulcers were associated in women with sociability
      and children's problems; in men, with blue-collar occupation, low education,
      financial difficulties, marital strain, children's problems, and a sense of
      failure. Adjustment for smoking, alcohol, chronic bronchitis, arthritis, liver
      disease, and skipping breakfast weakened but did not eliminate these
      associations; adjustment for socioeconomic status further attenuated the
      associations of specific problems. Low socioeconomic status and concrete life
      difficulties are associated with peptic ulcer in the general population cross
      sectionally and prospectively after adjustment for major physical risk factors,
      lending credence to a relationship between psychological stress and peptic ulcer.

PMID- 8648051
TI  - Chronic gastritis: its clinical and physiopathological meaning.
AB  - Chronic gastritis (CG) is the chronic inflammation of gastric mucosa associated
      with varying degrees of damage of superficial and glandular epithelia. The causes
      of CG are exogenous (mainly Helicobacter pylori) and endogenous. The process is
      concluded by atrophy of parenchyma. CG is associated with dyspepsia in
      approximately 50% of cases, but frequently with gastric and duodenal ulcer. The
      role of chronic atrophic gastritis (AG) is relevant in development of cancer or
      of other tumors like carcinoids and polyps. The specific secretive cells of the
      glandular parenchyma and of the superficial epithelium reveal a good correlation
      with secretory component behavior, but they are only partially influenced by H.
      pylori. It emerges that CG is an anatomic-functional condition. The
      cytofunctional profile in AG causes achlorhydria and therefore chronic luminal
      alkalosis. This condition favors intestinal metaplasia (IM) and important
      intraluminal troubles. Finally, nutritional deficiencies or H. pylori seem to
      interfere with the intragastric metabolism and therefore play a relevant role in
      the rise of IM.

PMID- 8648052
TI  - A multicenter, multiyear, case-controlled study of the risk of colonic polyps in
      patients with gastric polyps. Are gastric adenomas a new indication for
      surveillance colonoscopy?
AB  - A multicenter, multiyear, case-controlled colonoscopic study of 41 patients with
      gastric polyps undergoing colonoscopy analyzed whether patients with gastric
      polyps, particularly adenomas, run an increased risk of having colonic polyps.
      The primary controls were 109 patients undergoing colonoscopy matched for age and
      colonoscopy indications. A secondary control group was 69 of these 109 patients
      who, in addition to matching for age and colonoscopy indications with study
      patients, had no gastric polyps demonstrated by upper gastrointestinal
      examination. Patients with nonmalignant mucosal gastric polyps had a
      significantly greater incidence than primary controls of colonic polyps [odds
      ratio (OR) = 3.19, OR confidence interval = 1.46 - 6.99, p < 0.004, chi(2)],
      colonic neoplasms (OR = 3.58, OR confidence interval = 1.56 - 8.23, p < 0.006,
      chi(2)), and colonic cancer (OR = 4.5, OR confidence interval = 1.05 - 19.4, p <
      0.04, Fisher's exact test). Moreover, patients with gastric adenomas had a
      significantly greater incidence than did primary controls of colonic polyps (OR =
      7.6, OR confidence interval = 1.29 - 44.7, p < 0.02, Fisher's exact test). The
      association between gastric and colonic polyps did not arise as an artifact of
      the significantly higher frequency of females in the study group because this
      association remained after patient stratification by sex. The higher risk of
      colonic polyps in study patients did not arise as an artifact of unappreciated
      gastric polyps in the primary controls because study patients also had a
      significantly higher risk of colonic polyps than the secondary controls (OR =
      3.21, OR confidence interval = 1.35 - 7.63, p , 0.01, chi(2). Our retrospective
      case-controlled study suggests that gastric adenomas may be a new, significant
      risk factor for colonic polyps. A strong association would require that patients
      with gastric adenomas undergo surveillance colonoscopy to diagnose and remove
      colonic polyps. However, before we apply this finding to clinical practice, the
      apparent association should be confirmed by another, preferably prospective
      study.

PMID- 8648053
TI  - Clinicopathologic characteristics of Helicobacter pyloric seropositive gastric
      adenocarcinomas.
AB  - To compare and characterize retrospectively the clinicopathologic features of
      gastric cancers with and without previous Helicobacter pylori infection, we
      determined the preoperative seropositivity of H. pylori in 151 patients who had
      undergone gastric resection for primary gastric adenocarcinoma between 1988 and
      1993. The overall seroprevalence of H. pylori was 60.9%. H. pylori-positive
      gastric cancers were frequently associated (p<0.05) with macroscopic localized
      types (Borrmann I and II) in which negative cancer associated with infiltrative
      types (Borrmann III and IV) and cancer invasion of the duodenum. Multivariate
      analysis showed that H. pylori seropositivity was not an independent prognostic
      factor. Pathologic tumor-node-metastases (TNM) stage remained the only prognostic
      indicator. Our study suggests that H. pylori has a significant impact on the
      clinically relevant tumor biology of gastric cancer. Investigation along this
      line is warranted.

PMID- 8648054
TI  - Long-term survival after resection for advanced gastric carcinoma.
AB  - Although several prognostic indicators for gastric carcinoma have been reported,
      characteristics of long-term survivors with advanced gastric carcinoma have not
      yet been clarified. We compared clinicopathologic features of 54 patients who
      survived for >10 years after resection for advanced gastric carcinoma with those
      of 72 patients who died of recurrence. Long-term survivors were characterized by
      small tumor size (6.2 cm vs. 8.1 cm, p < 0.01), negative serosal invasion (50%
      vs. 32%, p < 0.05), few lymph node metastases (fewer than seven) (89% vs. 56%, p
      < 0.01), limited lymph node metastases (nO, nl) (89% vs. 40%, p < 0.01), and
      earlier stage (I or II) (50% vs. 16%, p < 0.01). These results indicate that
      small tumor size, negative serosal invasion, and fewer than seven positive nodes
      were the predictors of long-term survival after resection for advanced gastric
      carcinoma.

PMID- 8648055
TI  - Effect of some abdominal surgical operations on small bowel motility in humans:
      our experience.
AB  - Until recently, it was only possible to make inferences about small bowel
      motility from experimental animal models, but manometric techniques now allow
      prolonged recordings of small bowel motor activity in humans. We have studied the
      effect of abdominal surgery on motor behavior of the small intestine and here
      report our observations after various surgical procedures (total gastrectomy,
      Billroth I and II gastrectomy, ileoanal anastomosis). We discuss the data
      together with the experiences of others.

PMID- 8648057
TI  - Gastrointestinal blood loss due to cholesterol crystal embolization.
AB  - Gastrointestinal blood loss in elderly atherosclerotic patients may be due to
      cholesterol crystal embolization (CCE) leading to ischemic lesions in the
      gastrointestinal tract. The diagnosis of CCE is favored by accompanying clinical
      or biochemical signs, such as blue toes, renal insufficiency, and eosinophilia.
      Our report describes the clinical data of four patients with gastrointestinal
      blood loss due to CCE. In two the bleeding source was in the duodenum, and in the
      other two the source was in the distal colon. The diagnosis was made by
      histological examination of endoscopic biopsies in three and of a sigmoid
      resection specimen in one. Provoking factors were anticoagulant therapy in one,
      anticoagulant therapy and aortography in another, and aortography followed by
      aorta bifurcation prosthesis implantation in the third, whereas no provoking
      factor could be identified in the remaining patient. Accompanying signs included
      eosinophilia in one, a blue toe with renal insufficiency in one, and retinal
      cholesterol crystals in another patient. Our findings, in line with previous
      reports, highlight the importance of CCE in the differential diagnosis of
      gastrointestinal blood loss in elderly patients.

PMID- 8648056
TI  - Six patients whose perianal and ileocolic Crohn's disease improved in the Dead
      Sea environment.
AB  - Hyperbaric oxygen has been used in the management of perianal Crohn's disease on
      the assumption that tissue oxygenation is impaired. The Dead Sea region of Israel
      is the lowest point on earth (402 m below sea level), and therefore the oxygen
      pressure is increased. We hypothesized that this elevation in oxygen pressure
      over an extended time might be as effective as shorter periods of high-pressure
      oxygen in a hyperbaric chamber. So we investigated whether the Dead Sea
      environment might affect the activity and perianal complications of Crohn's
      disease. Six patients with Crohn's disease unresponsive to medical treatment
      spent periods of 1-3 weeks at the Dead Sea. Four patients had discharging
      perianal fistulas. All were given advice concerning diet, physical activity, and
      immersion in the Dead Sea. The Clamp-Softley modification of the Harvey-Bradshaw
      Crohn's disease activity index was used to assess disease activity initially and
      at weekly intervals during treatment. Drug therapy was tailored to patient
      symptoms. Mean disease activity index before treatment was 9.0 +/- 1.4 (mean +/-
      SEM) and after a week at the Dead Sea 3.5 +/- 1.4 (p = 0.006). After 2 weeks the
      index decreased to 2.0 +/- 0.4 (p = 0.037) in four patients. In one patient,
      complete healing of perianal fistulae occurred after 2 weeks, and in two others
      there was striking improvement. Two patients with active Crohn's disease and on
      high-dose corticosteroids were able to stop all medication during their stay.
      Decrease in activity index occurred rapidly, whereas the improvement in perianal
      disease was more gradual. The Dead Sea environment was highly effective in
      managing patients with severe Crohn's disease, including perianal complications
      in this small, uncontrolled series.

PMID- 8648058
TI  - Novel colorectal adenocarcinoma-associated 40- and 47-kDa protein antigens
      recognized by anti-60-kDa heat shock protein antibody.
AB  - Expression of 40- and 47-kDa proteins recognized by anti-60-kDa heat shock
      protein antibody was investigated in colorectal adenocarcinoma tissue. In all
      cases of colorectal adenocarcinoma tissue (n = 9), 40- and 47-kDa proteins were
      detected by immunoblot analysis. However, expression of these two proteins was
      extremely low or was not expressed in control tissue. There was no correlation
      between the quantity of these two bands and histologic type or the location of
      the tumors. Our results first demonstrate the accumulation of structurally
      altered 60-kDa heat shock protein-associated antigens in carcinoma tissue and
      suggest that these two proteins could be a possible candidate for tumor-specific
      60-kDa heat shock protein-related protein antigens.

PMID- 8648059
TI  - Torulopsis glabrata-infected pancreatic pseudocysts. Diagnosis and treatment.
AB  - Torulopsis glabrata, a fungus commensal with the human gastrointestinal tract, so
      far has not been recognized as a cause of pancreatic sepsis. We report the cases
      of two patients with pancreatic pseudocysts that became infected with T.
      glabrata. A 20-year-old woman 6 weeks postpartum had acute gallstone pancreatitis
      complicated by pseudocyst formation and pancreatic sepsis. Pseudocyst fluid
      obtained at cystogastrostomy showed a pure culture of T. glabrata. A 52-year-old
      man with multiple medical problems showed signs of an infected pseudocyst 9 days
      after he was hospitalized for alcoholic pancreatitis. Computed tomography (CT)
      guided aspiration of the the pseudocyst fluid confirmed T.glabrata as the
      infecting organism. Neither patient had a history of endoscopic or surgical
      manipulation. Prolonged therapy with broad-spectrum antibiotics and parenteral
      hyperalimentation were implicated as risk factors, and other possible pathogenic
      mechanisms were considered. Both patients were treated successfully with a
      combination of percutaneous or surgical drainage and amphotericin B, which
      appears to be the most active drug in vitro. The efficacy of other antifungal
      agents is discussed. In the context of pancreatitis and/or pseudocysts, empiric
      therapy with broad-spectrum antibiotics should be minimized because it
      predisposes patients to superinfection by opportunistic pathogens.

PMID- 8648060
TI  - Genotypes of hepatitis C virus in Taiwan and the progression of liver disease.
AB  - The existence of four genotypes of hepatitis C virus (HCV)--types 1a, 1b, 2a, and
      2b--has been suggested based on variations in nucleotide sequences of the core
      region. The aim of this study was to investigate the prevalence of HCV genotypes
      in chronic type C liver disease in Taiwan and correlate distinct genotypes to
      severity of liver disease. The genotypes of 175 patients with chronic type C
      liver disease were determined by a polymerase chain reaction with type-specific
      primers. The prevalence of each genotype in Taiwan was as follows: type 1a, n = 1
      (0.6%); 1b, n = 125 (71.4%); 2a, n = 21 (12%); 2b, n = 6 (3.4%); mixed types, n =
      18 (10.3%); and unclassified, n = 4 (2.3%). The demographic and clinical features
      were comparable between patients with different genotypes, except that the mean
      peak serum transaminase levels of patients with double viruses and type 1b HCV
      infections were significantly higher than were those of patients with type 2a
      virus. Moreover, type 1b HCV was more prevalent in patients with liver cirrhosis
      alone or with hepatocellular carcinoma. In conclusion, type 1b virus is the
      predominant genotype in chronic hepatitis C in Taiwan, and type 1b virus and
      mixed infection may trigger more severe liver disease.

PMID- 8648062
TI  - Recurrence of acute fatty liver of pregnancy.
AB  - We report this rare recurrence of biopsy-proven acute fatty liver of pregnancy.
      In two successive pregnancies, an emergency cesarean section was performed with
      delivery of healthy babies and rapid maternal recovery with complete
      normalization of liver function. This is the third such report.

PMID- 8648061
TI  - Spontaneous rupture of hepatocellular carcinoma. A review of 141 Taiwanese cases
      and comparison with nonrupture cases.
AB  - We reviewed the records and statistics of 560 patients hospitalized with
      hepatocellular carcinoma (HCC) over a 5-year period. One hundred and forty-one
      patients (26%) had spontaneous rupture of their HCCs. Different characteristics
      of the rupture (R) and nonrupture (NR) groups were compared; there were
      statistically significant differences (p < 0.05) in the size of the tumor (R,
      9.83 +/- 4.36 cm, and NR, 7.67 +/- 4.01 cm; p < 0.0001), and the minimal
      thickness of peritumor liver parenchyma (R, 0.03 +/- 0.20 cm, and NR, 0.30 +/-
      0.70 cm; p < 0.001), the presence of the ?hump sign? (R, 87.8%, and NR, 45.7%; p
      < 0.0001), and the minimal thickness of peritumor liver parenchyma (R, 0.03 +/-
      0.20 cm, and NR, 0.30 +/- 0.70 cm; p < 0.001). The percentage of left-lobe tumors
      was significantly higher in the rupture group than in the nonrupture group (p <
      0.05). In addition, the Child-Pugh's score and serum transaminase levels were
      higher, and the prothrombin times more prolonged, in the rupture group. Factors
      that were not statistically significant included sex, age, etiology of cirrhosis,
      platelet count, portal vein thrombosis, and the presence of a varix. Multivariate
      logistic regression analysis indicated that the tumor size, the presence of a
      hump sign, and the Pugh's score correlated the best with HCC rupture (p < 0.05).
      Ninety-four patients from the rupture group died during hospitalization. The
      mortality rate was 66.7%. We conclude that (a) spontaneous rupture of HCC is a
      likely sequel of progressive expansion of tumor that finally protrudes outside
      the liver surface and hemorrhages, (b) left-lobe tumor presents a higher risk of
      rupture, and (c) portal hypertension does not play a major role in the
      pathogenesis of tumor rupture.

PMID- 8648063
TI  - Hyperthyroxinemia and elevated lipids as paraneoplastic phenomena in
      hepatocellular carcinoma. A case report.
AB  - In the United States and Western Europe, primary hepato-cellular carcinoma is an
      uncommon malignancy. Even though many well-defined associations have been
      reported, paraneoplastic manifestations are rare in North American patients. We
      describe an adolescent with complaints of weight loss, weakness, and a sensation
      of ?fullness in the upper abdomen.? On initial laboratory workup a lactescent
      serum was found, with the following abnormalities; serum cholesterol level of 573
      mg/dl (normal 120-260), triglycerides of 1,761 mg/dl (normal 10-190), and serum
      thyroxine level of 21 microgram/dl (normal 5.5-12.3). Serum albumin, calcium, and
      thyroid-stimulating hormone levels were also minimally elevated. Liver biopsy
      confirmed hepatocellular carcinoma. This is a rare hepatoma, which in our case
      manifested with multiple paraneoplastic phenomena, including hyperthyroxinemia,
      hypercholesterolemia, hypertriglyceridemia, and hyperalbuminemia. We review the
      pertinent literature.

PMID- 8648064
TI  - Crohn's disease. Pilot study comparing MRI of the abdomen with clinical
      evaluation.
AB  - Fourteen patients underwent magnetic resonance imaging (MRI) examination (16
      studies) and clinical evaluation concurrently. MRI studies included gadolinium
      enhancement and TI-weighted fat-suppressed spin echo. Separate investigators
      determined the severity of disease on MR images and on clinical evaluation in a
      blinded fashion. MRI studies were evaluated for percentage of mural contrast
      enhancement, wall thickness, and length of diseased bowel. An MR product was
      generated using these parameters. Clinical evaluation used the Crohn's Disease
      Activity Index (CDAI) and modified Index of the International Organization for
      the Study of Inflammatory Bowel Disease (IOIBD). Linear correlation was found
      between the MR product and clinical indexes of disease activity. The correlation
      between MR product and the modified IOIBD index was statistically significant
      (R(2) = 0.633, p = 0.0012). The correlation of MR product and CDAI was less close
      (R(2) = 0.274, p = 0.0373). Among individual MR parameters, length of diseased
      bowel showed the greatest correlation with CDAI (R(2) = 0.537, p = 0.012).
      Percentage contrast enhancement and bowel wall thickness showed significant
      correlation to the modified IOIBD index (R(2) = 0.739, p = 0.021) but not to the
      CDAI (R(2) = 0.004, p = 0.825). The results of this study show that the product
      of mural contrast enhancement, wall thickness, and length of diseased bowel
      correlated with clinical indexes of disease activity in Crohn's disease. Our
      findings suggest that MRI may be useful in evaluating the severity of Crohn's
      disease and may provide information complementary to clinical evaluation.

PMID- 8648065
TI  - More evidence for the increasing prevalence of adenocarcinoma of the esophagus
      over an 18-year period.

PMID- 8648066
TI  - Failure of immunosuppressive therapy to prevent relapse of celiac sprue.

PMID- 8648067
TI  - Sigmoidorectal intussusception from a sigmoid lipoma.

PMID- 8648068
TI  - Possible association of acute pancreatitis with naproxen.

PMID- 8648069
TI  - Large cell lymphoma of the colon presenting as a second malignancy in a patient
      with hairy cell leukemia.

PMID- 8648070
TI  - Portal hypertension due to incomplete membranous obstruction of the portal vein.

PMID- 8648071
TI  - Spontaneous peritonitis caused by Streptococcus bovis: search for colonic
      neoplasia.

PMID- 8648072
TI  - The Internet: practical uses for your office.

PMID- 8648073
TI  - Indiana court enforces 'any willing provider'.

PMID- 8648074
TI  - Seven ways to avoid frivolous malpractice claims.

PMID- 8648075
TI  - Utilizing generation skipping techniques.

PMID- 8648076
TI  - Sleeping position and sudden infant death syndrome: a review of the literature
      and the implications for infants in the United States.

PMID- 8648077
TI  - IU dean lists funding as top challenge. Interview by Bob Carlson.

PMID- 8648078
TI  - Free telephone service offers HIV information.

PMID- 8648079
TI  - Use of nanogold- and fluorescent-labeled antibody Fv fragments in
      immunocytochemistry.
AB  - Recombinant antibody fragments are emerging as a versatile tool in both basic
      research and medical therapy. We describe the procedures for direct labeling of
      engineered antibody fragments (Fv) with fluorescein or nanogold and their use in
      fluorescence and immunoelectron microscopy, respectively. The Fv fragments were
      produced in Escherichia coli, purified by one-step Strep tag affinity
      chromatography, chemically labeled with the marker, and employed in microscopy to
      localize epitopes on the membrane protein bacteriorhodopsin in purple membranes
      of Halobacterium halobium and the cytochrome c oxidase of Paracoccus
      denitrificans. In both cases, methods involving directly labeled antibody
      fragments show results identical to those in which antibodies or Fv fragments are
      detected by a secondarily labeled conjugate. The multifunctional design of the
      recombinant Fv fragments, however, offers more all-around applications in
      immunocytochemistry. The directly labeled Fv fragments, half the size of an Fab
      fragment, are at the molecular level the smallest antibody fragments yet
      described for visualization of biomolecules in microscopy.

PMID- 8648080
TI  - Fundamental cellular heterogeneity of the exocrine pancreas.
AB  - Homogeneity in structure and function are broadly assumed to be characteristics
      of the acinar pancreatic digestive enzyme-secreting tissue. In recent years,
      physiological studies have shown that the pancreas stores the digestive enzymes
      in heterogeneously composed pools and releases them from these pools in a cyclic
      and secretagoguec fashion. The cellular basis for pancreatic heterogeneity is
      unknown; classical light and electron microscopic preparations appear
      homogeneous. We applied a panel of biotinylated lectins to pancreatic tissue
      sections; acinar cell glycoconjugates were localized in situ with peroxidase and
      fluorescent techniques and lectin-gold complexes. The lectin-binding properties
      of both fasting rabbit and rat pancreas revealed extensive and specific
      heterogeneity of the acinar cell population. Light and electron microscopy
      demonstrated highly heterogeneous labeling of the zymogen granule contents of
      specific acinar cells with the lectins Ulex europaeus agglutinin (UEA) and
      Erythrina cristagalli (ECA), which also showed preferential labeling of peri
      insular acini. Other lectins also demonstrated heterogeneous binding to specific
      cellular regions. The striking acinar cell heterogeneity confirms earlier
      predictions, and may eventually prove to be the cellular basis for the secretion
      of different enzyme mixtures from heterogeneous sources within the pancreas.

PMID- 8648081
TI  - Validation of the S-phase specificity of histone (H3) in situ hybridization in
      normal and malignant cells.
AB  - Several different methods of measuring proliferation indices have been developed,
      including measurements of cellular DNA content (flow cytometry), S-phase
      incorporation of thymidine analogues into DNA (e.g., tritiated thymidine and 5'
      bromodeoxyuridine), and immunostaining of cell cycle-restricted proteins (e.g.,
      Ki-67 antigen and PCNA). Theoretical and practical problems with each method have
      made it difficult to compare absolute proliferation rates among cells of
      different lineages and degrees of malignancy. More recently, in situ
      hybridization (ISH) for histone 3 (H3) mRNA has been introduced. We used a double
      labeling method for comparing H3 mRNA expression and S-phase incorporation of 5'
      bromodeoxyuridine (BrdU) to determine if H3 mRNA expression was tightly
      associated with S-phase in a variety of malignant and nontransformed cell types.
      In addition, labeling results were compared in methacarn- and formalin-fixed
      tissues to extend the potential usefulness of H3 ISH, using a postfixation
      technique for the alcohol-fixed specimens. As expected for a cumulative marker,
      variation was noted in the percentage of the BrdU-positive cells double labeled
      with H3 ISH (53-89%), depending on cell type and length of BrdU incubation. In
      contrast, the percentage of the H3 ISH-positive cell population double labeled
      for BrdU was independent of the cell type of BrdU incubation time (mean 78%).
      Similarly, a consistent percentage of H3 ISH-positive cell populations was double
      labeled for BrdU in normal tissues (mean 97%). These findings support a well
      conserved timing mechanism for H3 mRNA expression and DNA replication. We
      conclude that H3 ISH is an extremely accurate technique for assessment of S-phase
      cell proliferation indices.

PMID- 8648082
TI  - Differential distribution of Met and epidermal growth factor receptor in normal
      and carcinogen-treated rat liver.
AB  - Transforming growth factor-alpha (TGF-alpha) and hepatocyte growth factor (HGF)
      are strong hepatocyte mitogens and important regulators of liver regeneration.
      The TGF-alpha receptor EGFr appears primarily to mediate a proliferative signal,
      whereas mitogenic, motogenic, and morphogenic effects have been attributed to
      activation of the HGF receptor Met. We have studied the localization of Met and
      EGFr in normal and carcinogen-treated rat livers. Oval cells and preneoplastic
      lesions were induced by diethylnitrosamine initiation, followed by promotion with
      2-acetylaminofluorene combined with a partial hepatectomy. Different liver cell
      populations and their receptor expression were characterized by two-color
      immunofluorescence and confocal laser scanning microscopy. Hepatocytes were
      detected by keratin K8 staining, and oval cells and bile ducts were recognized by
      keratin K19 expression. Enzyme-altered preneoplastic lesions ere identified by
      expression of placental glutathione S-transferase (GST-pi). Staining for these
      cellular markers was combined with immunodetection of EGFr and Met. Normal liver
      exhibited strong staining for EGFr in hepatocytes, whereas blood vessels, bile
      ducts, and some sinusoidal cells were Met-positive. In carcinogen-treated livers,
      oval cells showed Met but not EGFr immunostaining. GST-pi-positive foci displayed
      EGFr immunostaining at a similar intensity as surrounding hepatocytes, whereas
      Met was not detected. Our data indicate that putative liver cells (oval cells)
      have a growth receptor phenotype similar to that of bile ducts, whereas
      preneoplastic live lesions appear hepatocyte-like. These results indicate that
      the preferential proliferation of preneoplastic liver lesions compared to
      surrounding hepatocytes is not associated with an altered EGFr or Met phenotype.

PMID- 8648083
TI  - Epitope enhancement for immunohistochemical demonstration of tartrate-resistant
      acid phosphatase.
AB  - We have developed a monoclonal antibody (9C5) for immunohistochemical
      localization of tartrate-resistant acid phosphatase (TRAcP). This antibody reacts
      with a denatured epitope of TRAcP and requires enhancement methods to promote
      antigenicity in paraffin-embedded tissues. We used this antibody to
      systematically examine proteolytic digestion and heat denaturation conditions for
      epitope enhancement in both paraffin sections and fixed smears. The goal was to
      increase the sensitivity of the immunohistochemical stain for TRAcP. Optimal
      conditions for proteolytic digestion were established. Denaturation in a
      conventional boiling water bath was compared to microwave irradiation in several
      commonly used solutions. Immunohistochemistry was compared directly to TRAcP
      cytochemistry in fixed smears from hairy cell leukemia specimens to gauge the
      level of sensitivity of our improved method. Attempts were made to "retrieve" the
      9C5 epitope from overfixed tissues and aged smears. Maximal immunoreactivity of
      TRAcP was achieved by microwave irradiation in a citrate or Tris buffer of pH 6.0
      8.0 without the need for a subsequent protease digestion step. With this method
      of epitope enhancement, immunohistochemistry with antibody 9C5 was as sensitive
      as direct cytochemical staining of TRAcP activity. However, once a tissue
      specimen had been overfixed or a smear stored for a year or more, the 9C5 epitope
      was no longer retrievable. The key element in epitope enhancement for 9C5
      immunohistochemistry is heat denaturation of the target epitope.
      Immunohistochemistry of TRAcP in paraffin sections would be a great asset to the
      study of specialized forms of the monocyte/macrophage lineage and to the process
      of macrophage activation. It would also provide another means for more precise
      evaluation of residual disease in bone marrow of patients treated for hairy cell
      leukemia.

PMID- 8648084
TI  - Carbonic anhydrase isoenzyme II is located in corticotrophs of the human
      pituitary gland.
AB  - We studied the location of carbonic anhydrase (CA) isoenzymes I, II, and VI in
      human pituitary gland using specific antisera in conjunction with immunoblotting,
      immunoperoxidase, and double immunofluorescence staining techniques. Stainings
      with anti-CA II serum showed intense cytoplasmic reaction in the anterior lobe of
      the pituitary gland. Double immunofluorescence staining was used to identify the
      cells that expressed CA II. Confocal laser scanning microscopy revealed that, of
      the anterior pituitary hormones studied, ACTH coincides mainly with CA II in
      these cells. Stainings with anti-CA I and VI sera were negative in the endocrine
      cells of the pituitary gland. Western blotting of the pituitary gland with anti
      CA II revealed a distinct 29-KD polypeptide band corresponding in molecular
      weight to CA II, suggesting that the antiserum does not detect any nonspecific
      protein. Anti-CA I serum similarly showed a major 29-KD band, possibly
      recognizing the enzyme, which is abundantly present in erythrocytes. The results
      indicate that CA II is expressed in corticotrophs of human pituitary gland, in
      which its physiological role may be linked to the regulation of optimal pH in the
      secretory vesicles for the cleavage of ACTH from its precursor.

PMID- 8648085
TI  - Prostaglandin F synthase is localized to contractile interstitial cells in bovine
      lung.
AB  - It was recently found that certain cells in the alveolar septum of the bovine
      lung are enriched in prostaglandin F (PGF) synthase. In this study we used
      immunohistochemical techniques at both light and electron microscopic levels to
      further characterize the PGF synthase-positive cells. By double
      immunofluorescence staining of bovine lung cryostat sections, the alveolar septal
      cells labeled by anti-PGF synthase antibody were also intensely labeled for
      cytoplasmic actin but not for alpha-smooth muscle actin. This labeling pattern
      suggests that the PGF synthase-positive cells in the septum are "contractile
      interstitial cells," which resemble conventional fibroblasts but
      characteristically contain prominent bundles of actin filaments. Immunogold
      electron microscopy of ultra-thin frozen sections of bovine lung showed that
      alveolar interstitial cells extending long cytoplasmic processes and closely
      associated with alveolar capillaries were intensely labeled for PGF synthase.
      Capillary endothelial cells, alveolar epithelial cells, and some fibroblastic
      cells were devoid of labeling. On the basis of these findings, we conclude that
      PGF synthase is specifically expressed in contractile interstitial cells within
      the alveolar septum. The protein may be a useful marker for contractile
      interstitial cells, whose physiological function and role in various pathological
      conditions have not been characterized in detail.

PMID- 8648086
TI  - A comparative study of histological conditions suitable for both
      immunofluorescence and in situ hybridization in the detection of Herpesvirus and
      its antigens in chicken tissues.
AB  - Our objective was to identify an optimal single set of conditions for use in both
      indirect immunofluorescence assays (IFA) and in situ hybridization (ISH) to
      detect viral proteins and nucleic acids in avian lymphoid and neural tissues.
      Various fixatives were evaluated for use with IFA to detect turkey Herpesvirus
      (HVT) glycoprotein B (gB) and ISH to identify HVT mRNA in chicken tissues. A
      precipitating fixative (acetone) was compared to crosslinking fixatives [buffered
      glutaraldehyde-picric acid (BGPA), 10% formalin, and 4% paraformaldehyde] for
      both IFA and ISH using spleen, thymus, bursa, sciatic plexus, and brachial plexus
      of 28-day-old chickens. Four percent paraformaldehyde was found to be the optimal
      fixative for preservation of all chicken tissues examined with both IFA and ISH.
      Glass slide preparation, incubation temperatures, and tissue processing were each
      individually evaluated for ISH and IFA. Silylated slides provided the best
      retention of tissue sections for both procedures. For IFA, 37 degrees C was the
      ideal incubation temperature tested, whereas the optimal incubation temperature
      tested for ISH was 47 degrees C. Of the blocking agents compared, Evans blue dye
      prevented background fluorescence to a greater extent than either calf serum or
      bovine serum albumin. These findings provide a technical basis for investigations
      into various aspects of the molecular pathology of avian diseases.

PMID- 8648087
TI  - Rhodamine B, a fluorescent probe for acidic organelles in denervated skeletal
      muscle.
AB  - We describe a very efficient method for fluorescent labeling of acidic structures
      in denervated skeletal muscle with rhodamine B. Rhodamine B at 50 ng/ml gave
      selective and distinct segmental labeling of denervated muscle fibers after 5-min
      incubation at room temperature. Labeling was also achieved at 4 degrees C. The
      labeling was disrupted by the ionophores monensin and nigericin, suggesting a
      labeling confined to acidic structures. Rhodamine B co-localized with the
      lysosomotropic dye Lyso Tracker Green and a marker for endocytosis (fluorescein
      isothiocyanate-labeled dextran). Rhodamine B, which is highly lipophilic, showed
      pH-dependent fluorescence emission in saturated aqueous N-octanol.
      Tetramethylrhodamine showed similar characteristics for labeling of denervated
      muscle fibers and pH-dependent fluorescence in N-octanol. The carboxyl group
      present in these two compounds appears important, because structurally related
      compounds that either lack this group or have it esterified failed to label
      denervated muscle fibers and showed no pH-dependent fluorescence in N-octanol.
      The results suggest that rhodamine B labels acidic organelles belonging to the
      endosomal/lyosomal system of denervated skeletal muscle fibers. Nevertheless, it
      failed to label such organelles in a number of mammalian cell types other than
      denervated skeletal muscle fibers.

PMID- 8648088
TI  - Detection of vitronectin in mineralized bone matrix.
AB  - Adhesive glycoproteins in the bone matrix are of critical importance for cell
      anchorage, proliferation, migration, differentiation, and regulation of bone
      metabolism. The localization of the adhesive glycoprotein vitronectin (Vn) in
      murine bone tissue was evaluated by immunohistochemical staining. Vitronectin was
      present throughout the mineralized bone matrix of cancellous and cortical bone,
      whereas cartilage was devoid of Vn staining. To exclude the possibility that the
      positive Vn staining resulted from plasma Vn in blood vessels within the bone
      sections, adjacent tissue sections were stained with antibodies to fibrinogen,
      and abundant plasma protein. Fibrinogen immunoreactivity was confined to blood
      vessels in the bone marrow and Haversian system, whereas the mineralized bone
      matrix was devoid of staining. The presence of Vn in murine bones was confirmed
      by sequential extraction, followed by fractionation of the resulting polypeptides
      by gel electrophoresis and immunoblotting analysis. Hydroxyapatite affinity
      chromatography raises the possibility that mineral interactions, at least in
      part, mediate the incorporation of Vn into the bone matrix. These results
      indicate that Vn is a specific component of bone tissue and raise the possibility
      that Vn is involved in regulation of bone metabolism.

PMID- 8648089
TI  - A simple, reliable, and sensitive method for nonradioactive in situ
      hybridization: use of microwave heating to improve hybridization efficiency and
      preserve tissue morphology.
AB  - The digestion of fixed tissue sections is a critical step in the optimization of
      any in situ hybridization protocol. We describe a novel application of microwave
      oven heating to optimize mRNA detection in paraformaldehyde-fixed tissues by in
      situ hybridization using digoxigenin-labeled probes. This technique replaces
      protease digestion of fixed tissue sections with 10 min of microwave
      pretreatment, followed by either conventional hybridization or hybridization
      involving microwave incubation. This new technique has several advantages over
      the standard protease treatment-based methods presently in use. (a) Microwave
      oven heating is a simple, rapid, and highly reproducible technique. (b) Microwave
      pretreatment significantly increased the hybridization signal and reduced the
      background compared to conventional protease digestion. Consequently, the
      hybridization time required to obtain optimal mRNA detection was reduced to 30
      min. (c) Ten minutes of microwave pretreatment produced an optimal hybridization
      signal in six different tissues using a variety of probes, demonstrating the
      general applicability of this technique. (d) Microwave heating of the probe
      during the hybridization step itself further reduced the hybridization time and
      substantially enhanced the hybridization signal obtained from proteinase K
      digested tissue. (e) Microwave pretreatment caused no discernible loss of fine
      cell structure and tissue morphology compared to untreated tissue sections. In
      conclusion, microwave oven heating can replace the complicated strategies and
      poor reproducibility of protease treatment of tissue sections, resulting in a
      simple, rapid, more reliable and sensitive method that has general applicability
      for in situ hybridization.

PMID- 8648090
TI  - Comparison of LR White and Unicryl as embedding media for light and electron
      immunomicroscopy of chromaffin cells.
AB  - LR White and Unicryl are members of the same family of acrylic embedding resins
      and are very suitable for "on grid" postembedding immunogold labeling. We studied
      the ultrastructure of LR White- and Unicryl-embedded cultured chromaffin cells
      and the immunolocalization of three chromaffin cell proteins, the enzymes
      dopamine-beta-hydroxylase (DbetaH) and tyrosine hydroxylase (TH), and the
      membrane fusion and Ca2+ channel protein synexin (annexin VII). We report here
      that Unicryl is preferable to LR White as an embedding medium for electron
      microscopy when osmium tetroxide fixation is omitted. The basis for this
      distinction is better ultrastructural preservation and improved immunodetection
      efficiency.

PMID- 8648091
TI  - Possible involvement of C5/C5a in the efferent and elicitation phases of contact
      sensitivity.
AB  - The elicitation of 24-h contact sensitivity (CS) in mice requires a serotonin
      dependent, 2-h response called CS initiation. We studied the role of complement
      (C) by comparing CS in DBA/1 (C5-normal) vs DBA/2 (C5-deficient) mice and found
      impaired 2-h, but not 24-h, CS. We showed previously that 2-h responses represent
      CS initiation and are required for elicitation of 24-h responses. Treatment of C5
      deficient mice with absent macroscopic responses (ear swelling) with a selective
      serotonin antagonist inhibited 24-h CS, suggesting that C5-deficient mice had
      submacroscopic (i.e., microscopic), serotonin-dependent CS initiation. When
      normal mouse serum was used as a source of C5 to reconstitute C5-deficient mice,
      significant 2-h responses were restored. Furthermore, heat treatment of normal
      mouse serum to inactivate C abrogated restoration of 2-h responses. Thus, C5 was
      suggested to be involved in CS initiation. Using a suboptimal immunizing dose of
      Ag revealed an impaired 24-h component of CS in DBA/2 mice, but not in DBA/1
      mice, and also in C5-deficient B10.D2/o mice compared with C5-normal B10.D2/n
      mice with a suboptimal eliciting dose of Ag. Again, reconstitution of B10.D2/o
      mice with normal mouse serum restored deficient 24-h CS responses. Thus, 2-h and
      classical 24-h CS probably depend in part on C5. These results imply that C5 may
      play a role in the elicitation of 24-h CS, probably via required preceding CS
      initiation.

PMID- 8648092
TI  - Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein
      tyrosine phosphatases.
AB  - NK cells express cell surface receptors for MHC class I proteins (KIR).
      Engagement of these receptors inhibits NK cell cytotoxic programs. KIR can be
      expressed on T cells, and their engagement also results in inhibition of effector
      functions initiated by the CD3/TCR complex. While human KIR genes belong to the
      Ig gene superfamily, mouse KIR belong to a family of dimeric lectins. Despite
      these distinct evolutionary origins, we show here that both HLA-Cw3-specific
      human p58.183 receptors and H-2D d/k-specific mouse Ly49A receptors recruit the
      same protein tyrosine phosphatases, PTP1C and PTP1D, upon phosphorylation of
      critical intracytoplasmic tyrosine residues. These results document a common
      pathway by which diverse KIR can down-regulate NK and T cell activation programs,
      and further define the sequence of the immunoreceptor tyrosine-based inhibitory
      motif (ITIM), initially described in FcgammaRIIB1, and expressed in both human
      and mouse KIR.

PMID- 8648093
TI  - Intrathymic signals in thymocytes are mediated by p38 mitogen-activated protein
      kinase.
AB  - Thymocytes develop into mature functional T cells in the inductive environment of
      the thymus where thymocyte-stromal cell interactions and cytokines provide
      survival and differentiation signals as cues for thymocyte maturation. Disruption
      of the thymic microenvironment results in attenuation of T cell maturation,
      suggesting that intrathymic signals are essential for differentiation and
      repertoire selection. We have previously shown that several inducible nuclear
      factors such as AP-1, NF-AT, and NF-kappaB are activated in response to
      intrathymic signals. Here we demonstrate that in thymocytes p38 mitogen-activated
      protein (MAP) kinase, a member of the MAP kinase family of proteins that include
      the extracellular-signal regulated kinases and Jun aminoterminal kinases, is
      highly activated in response to intrathymic signals in vivo. These studies
      suggest a role for p38 MAP kinase in T cell survival and differentiation.

PMID- 8648095
TI  - Phosphatidylinositol 3-kinase activation in normal human B lymphocytes.
AB  - A variety of signals, mediated via either the B cell Ag receptor (BCR), or non
      BCR molecules such as CD40 or cytokine receptors, have been shown to be crucial
      for the regulation of B cell survival, growth, and differentiation. Although it
      is clear that a variety of signaling pathways can be activated in B cells in a
      stimulus-dependent manner, it remains unknown whether differential activation of
      these signaling pathways is the underlying mechanism controlling B cell fate,
      i.e., growth vs differentiation. Initial studies reported here indicated that
      stimulation of highly purified peripheral blood B cells with the polyclonal B
      cell activators Staphylococcus aureus and CD40 ligand (CD40L) resulted in the
      rapid induction of phosphatidylinositol 3-kinase (PI 3-kinase) activity.
      Moreover, pretreatment of B cells with wortmannin, a specific inhibitor of PI 3
      kinase, resulted in a complete block in induction of PI 3-kinase activity. The
      effects of wortmannin, as well as a second PI 3-kinase inhibitor, LY294002, on
      the induction of both B cell growth and differentiation were therefore
      investigated. Although these PI 3-kinase inhibitors variably inhibited B cell DNA
      synthesis in a stimulus-dependent manner, both drugs effected a near-complete
      block of the ability of each of these stimuli to induce Ig production.
      Furthermore, separation of B cells into naive IgD+ and postswitch IgD- B cells
      failed to reveal differential sensitivity of these populations to wortmannin.
      These results suggest that activation of PI 3-kinase, or other wortmannin- and
      LY294002-sensitive targets, is a crucial event that occurs during the
      differentiation of normal human B lymphocytes. The differential sensitivity of B
      cell responses to inhibitors of PI 3-kinase supports the notion that distinct
      signal transduction pathways are involved in differentiation vs proliferation of
      normal human B lymphocytes.

PMID- 8648094
TI  - Structural requirements for CD28-mediated costimulation of IL-2 production in
      Jurkat T cells.
AB  - Although under certain conditions an association with phosphatidylinositol 3'
      kinase (PI3-K) appears to be critical for CD28 signaling, mutation of the PI3-K
      binding site (Tyr 170) does not alter the costimulatory ability of murine CD28
      (mCD28) in Jurkat T cells. To define the structural requirements for this PI3-K
      independent signaling, we expressed a series of mCD28 mutants in Jurkat. Mutation
      to Phe of all four cytoplasmic Tyr residues together (ALL F mutant) greatly
      reduced the ability of mCD28 to augment IL-2 production. Isolated re-constitution
      of Tyr 188, but not 170, 185, or 197, restored the ability of ALL F mCD28 to
      deliver a costimulus. Thus, a signal based upon Tyr 188 can deliver a costimulus
      for the enhancement of IL-2 production by Jurkat cells.

PMID- 8648096
TI  - Dexamethasone inhibits the early steps of antigen receptor signaling in activated
      T lymphocytes.
AB  - Glucocorticoids are very effective in inhibiting inflammatory and immune
      responses. In particular, the synthetic analogue dexamethasone has been shown to
      inhibit T cell proliferation and IL-2 production by interfering with the
      transcriptional activation of the IL-2 gene. The experiments described in this
      report were performed to determine whether dexamethasone treatment affects the
      early steps of TCR signal transduction in T cell hybrids. Incubation of murine T
      cell hybrids in the presence of dexamethasone prevents the intracellular calcium
      increase that normally follows TCR/CD3 aggregation. Accordingly, dexamethasone
      treatment decreases inositol phosphates production and phospholipase-Cgamma1
      tyrosine phosphorylation induced after TCR/CD3 stimulation. Dexamethasone has no
      effect on cell surface expression of TCR-associated structures nor does it
      inhibit calcium responses induced by a heterologous G protein-coupled muscarinic
      receptor, suggesting that this hormone analogue specifically inhibits the TCR
      signaling pathway at a postreceptor stage. We also show that inhibition of
      membrane proximal events by dexamethasone requires binding to the intracellular
      glucocorticoid receptor and de novo protein synthesis. When splenic T cells were
      assayed, only activated but not resting T cells were found to be sensitive to
      this new immunomodulatory effect of dexamethasone. These findings indicate that
      in addition to their previously described inhibitory effects on cytokine gene
      transcription, glucocorticoids block IL-2 production in activated T cells by
      interfering with an early step of the signal transduction cascade initiated by
      TCR/CD3 cross-linking.

PMID- 8648097
TI  - Immature stage B cells enter but do not progress beyond the early G1 phase of the
      cell cycle in response to antigen receptor signaling.
AB  - In contrast to mature B cells, immature stage B cells do not proliferate
      following Ag receptor cross-linking with anti-Ig Abs. To determine where in the
      cell cycle immature B cells arrest, we have examined the expression of specific
      G, cell cycle regulators. Following surface IgM (sIgM) cross-linking on mature B
      cells, we observed increased expression of the early G1 kinase, cyclin-dependent
      kinase 4 (cdk4), and one of its regulatory subunits, cyclin D2. Mature B cells
      also showed increased expression of components required for G1/S transition,
      including cyclin E and cdk2. Whereas immature stage B cells increased expression
      of cyclin D2 and cdk4 after anti-IgM stimulation, unlike mature stage B cells
      they failed to express cyclin E and cdk2. Expression of cyclin D2 and cdk4
      indicates that these cells can exit G0 and enter the initial G1 phase following
      sIgM ligation. Interestingly, IL-4, which by itself does not stimulate
      proliferation of immature B cells, induced expression of cyclin E and cdk2. These
      latter results suggest that IL-4 complements sIgM, signaling for proliferation by
      increasing the basal levels of late G1 cell cycle regulators. Consistent with
      this idea, IL-4 synergizes with anti-Ig Abs to promote cell cycle progression and
      proliferation of immature B cells. Finally, c-myc, a transcriptional regulator of
      some members of the cell cycle machinery, is not induced following sIgM cross
      linking of immature cells. This lack of inducible expression contrasts with that
      seen in mature stage B cells, and in immature stage cells stimulated to
      proliferate with LPS. These results suggest that c-myc may be a component of the
      signaling pathway that induces cyclin E and cdk2 expression.

PMID- 8648098
TI  - Bacterial DNA induces NK cells to produce IFN-gamma in vivo and increases the
      toxicity of lipopolysaccharides.
AB  - Microbial products released during bacterial infection induce cytokine-mediated
      inflammatory responses that can be protective, but excessive release of
      inflammatory cytokines may promote development of the sepsis syndrome. We
      examined the ability of bacterial DNA to induce in vivo cytokine release and to
      potentiate the toxicity of LPS. Intravenous treatment of mice with Escherichia
      coli (EC) DNA, but not calf thymus (CT) DNA, induced a rapid (within 4 h) dose
      dependent increase in serum IFN-gamma and splenic IFN-gamma-forming cells. Over
      90% of splenic IFN-gamma-producing cells were identified by surface phenotype as
      NK cells. Mice also mounted an IFN-gamma response following challenge with 20
      base oligonucleotide that contained an internal CG motif (but did not respond to
      a control oligonucleotide). Treatment of mice with EC DNA followed by a sublethal
      LPS challenge resulted in a 3-fold increase in the peak serum level of TNF-alpha
      and a 10-fold increase in the peak level of IL-6 compared with mice that received
      CT DNA followed by LPS. Mice treated with EC DNA followed by LPS showed 75%
      mortality, compared with no deaths in mice treated with CT DNA followed by LPS.
      EC DNA/LPS treatment of mice with disrupted IFN-gamma genes resulted in a 5%
      mortality while 59% of similarly treated +/+ mice died. Thus, bacterial DNA
      induces in vivo release of IFN-gamma which, in turn, is associated with an
      increase in LPS-induced TNF-alpha and IL-6 release, and with increased
      sensitivity to the toxic effects of LPS.

PMID- 8648099
TI  - CD28 is required for germinal center formation.
AB  - Previous studies have demonstrated that the T cell costimulatory molecule, CD28,
      is important in the development of humoral immunity. CD28-deficient mice exhibit
      defects in isotype switching and are more susceptible to pathogens that depend on
      an effective Ab response. To determine the basis of these defects, we have
      examined B cell responses of CD28-deficient mice at the microenvironmental level.
      Early in a normal T-dependent immune response, small numbers of B cells undergo
      activation in the T cell-rich zone of secondary lymphoid tissues and then migrate
      to B cell areas. These migrant B cells found developing germinal centers by
      proliferative expansion, during which individual cells acquire mutations in their
      rearranged Ig genes. B cell mutants retaining higher affinities for Ag undergo
      positive selection in germinal centers, resulting in the establishment of the
      memory B cell compartment. In the present study, we demonstrate that although
      potentially Ag-reactive cells within the lymphoid follicle accumulate following
      antigenic challenge, these cells fail to undergo proliferative expansion to form
      germinal centers and do not acquire somatic mutations in CD28-deficient animals.
      Thus, the CD28 activation pathway is required for Ab responses to T-dependent
      Ags. cell compartment. In the present study, we demonstrate that although
      potentially Ag-reactive cells within the lymphoid follicle accumulate following
      antigenic challenge, these cells fail to undergo proliferative expansion to form
      germinal centers and do not acquire somatic mutations in CD28-deficient animals.
      Thus, the CD28 activation pathway is required for Ab responses to T-dependent
      Ags.

PMID- 8648101
TI  - A role for calcium influx in setting the threshold for CD4+CD8+ thymocyte
      negative selection.
AB  - We have applied an in vitro system that mimics thymic negative selection to
      investigate signaling pathways that may be important for the removal of
      autoreactive cells from the thymus. We sought to more precisely determine the
      contribution of calcium-dependent pathways to CD4+CD8+ thymocyte deletion that is
      mediated by either an antigenic peptide or a peptide analogue. We show that the
      requirement for external calcium influx is dependent upon the strength of the
      deleting ligand. Furthermore, these results correlate well with a requirement,
      under certain circumstances, for signaling through the calcium/calmodulin
      dependent phosphatase calcineurin. The use of suboptimal stimuli may, therefore,
      be useful in revealing biochemical pathways important for CD4+CD8+ thymocyte
      negative selection.

PMID- 8648100
TI  - Late induction of CREB/ATF binding and a concomitant increase in cAMP levels in T
      and B lymphocytes stimulated via the antigen receptor.
AB  - Transcription factors of the cAMP-responsive element (CRE) binding
      protein/activating transcription factor (CREB/ATF) family were implicated in the
      expression of T cell-specific genes and in the expression of oncogenic
      retroviruses associated with leukemia in T and B lymphocytes. To study the
      regulation of CREB/ATF transcription factors during lymphocyte activation,
      studies were pursued in primary cultures of resting murine splenic T and B
      lymphocytes stimulated via the Ag receptor. Using consensus/CRE and proliferating
      cell nuclear Ag (PCNA)/CRE as probes in the DNA binding assay, we showed that a
      marked induction of CRE binding is associated with activation of splenic T
      lymphocytes with anti-CD3 Ab. CRE binding was markedly induced after 48 h; it
      gradually declined at 72 h, but remained elevated above control levels after 120
      h. Most significant, activation by anti-CD3 was associated with a marked
      induction of cAMP levels that preceded the onset of DNA synthesis and the
      induction of IL-2 secretion and reached a peak after 48 h (9.5- to 11-fold),
      concomitant with the peak in CRE binding. Rapamycin, a potent immunosuppressant,
      inhibited the induction of cAMP levels by anti-CD3 concomitant with inhibition of
      CRE binding activity and arrest of DNA synthesis. A marked induction in CRE
      binding after 48 h was also found in splenic B lymphocytes stimulated by LPS and
      anti-Ig and was correlated with a 3- to 4-fold increase in the intracellular
      levels of cAMP. Two inducible CRE complexes were found to bind to consensus/CRE
      and PCNA/CRE; the major complex contained primarily CREB homodimers and was
      constitutively expressed in resting lymphocytes. Conversely, stimulation of
      lymphocytes was associated with formation of a new, slow migrating CRE complex
      that demonstrated high inducibility in both consensus/CRE and PCNA/CRE. We show
      that this de novo inducible CRE complex contains CREB and ATF2, but not ATF1.
      Taken collectively, these results suggest that recruitment of CREB and ATF2 to
      the promoter of genes is tightly regulated during activation of T and B
      lymphocytes and implicate a cross-talk of cAMP and non-cAMP pathways in the
      regulation of transcriptional processes at late stages of activation in T and B
      lymphocytes stimulated via the Ag receptor.

PMID- 8648103
TI  - Thymic-independent T cell regeneration occurs via antigen-driven expansion of
      peripheral T cells resulting in a repertoire that is limited in diversity and
      prone to skewing.
AB  - Thymic regenerative capacity in humans decreases with age, suggesting that thymic
      independent pathways of T cell regeneration may predominate during adulthood.
      Using a murine bone marrow transplantation model, we present evidence that thymic
      independent T cell regeneration occurs primarily via expansion of peripheral T
      cells and is Ag driven since significant expansion of CD4+ or CD8+ transgenic
      (Tg+)/TCR-bearing cells occurs only in the presence of Ag specific for the TCR.
      Such expansion resulted in skewing of the regenerated repertoire with 40 to 65%
      of the regenerated CD4+ or CD8+ T cells expressing the Tg+/TCR in thymectomized
      hosts after bone marrow transplantation. In experiments in which nontransgenic
      population are used as T cell inocula, we noted decreased CD4 expansion when
      Class II MHC was blocked by mAb treatment in vivo, an CD8 expansion failed to
      occur in Class I MHC-deficient hosts providing evidence that T cell regeneration
      in thymic-deficient hosts largely occurs via TCR-MHC-mediated selection of
      peripheral T cell populations. This process results in a T cell repertoire
      comprised exclusively of T cells recently activated by the antigenic milieu of
      the host, with negligible numbers of residual "naive" cells bearing TCRs for Ags
      absent at the time of expansion. These findings have important implications for
      approached to enhance T cell regeneration in humans and provide evidence that
      vaccine strategies could skew the T cell repertoire toward a specific antigenic
      target if administered to thymic-deficient hosts during immune reconstitution.

PMID- 8648102
TI  - In vivo T cell response to viral superantigen. Selective migration rather than
      proliferation.
AB  - Superantigens induce T cell activation and proliferation in vitro, and some also
      induce cell activation in vivo. MMTV(SW) is an infectious mouse mammary tumor
      virus (MMTV) encoding a superantigen with the same Vbeta specificity as MIs-1a
      (Mtv-7), which induces a strong local response in vivo. injection of MMTV(SW)
      into mouse footpads leads to accumulation of superantigen-reactive T cells
      (Vbeta6+CD4+) and B cells in the draining lymph nodes (LN). We investigated the
      kinetics of this cell accumulation by measuring cell activation (blastogenesis,
      CD25 and CD69 expression), cell migration (using syngenic FITC-labeled CD4+ cells
      and L-selectin detection), and cell proliferation (using in vivo labeling with
      bromodeoxyuridine). Specific T cells selectively migrated to the draining LN.
      Accumulating Vbeta6+CD4+ T cells were large CD69+ cells, but remained CD25
      negative and showed down-regulated L-selectin expression. Their DNA synthesis
      rate, studied by pulse labeling and continuous administration of
      bromodeoxyuridine, was increased, but remained too low to explain the draining LN
      hyperplasia. These data show that the local T cell response to MMTV(SW) mainly
      consists of selective migration followed by local activation of reactive T cells,
      and that cell proliferation is only a minor component of the response. By
      contrast, the optimal dose of staphylococcal enterotoxin B that, nevertheless,
      leads to a lower reactive T cell accumulation in the draining LN induces a very
      high proliferation rate.

PMID- 8648104
TI  - Is there a role for nitric oxide in regulation of T cell secretion of IL-2?
AB  - Nitric oxide (NO) can have both effector (cytotoxic) and regulatory roles in
      immune function. In this study, we have re-examined the potential role of nitric
      oxide in mediating the macrophage-dependent suppression of IL-2 synthesis. In our
      model, TNP-specific CD4+ T cells are cocultured with Ag and either peritoneal or
      alveolar macrophages. Both populations of macrophages after in vitro stimulation
      with IFN-gamma can inhibit IL-2 release. In vitro stimulation also induces
      substantial levels of NO release by these macrophages, as well as high levels of
      prostaglandin E2 (PGE2). However, there was no correlation between NO levels and
      inhibitory activity. Furthermore, NG-monomethyl-L-arginine monoacetate, a
      specific inhibitor of NO release had no effect on IL-2 release, while
      indomethacin, which blocked prostaglandin synthesis, largely abrogated the
      suppressor activity of both macrophage populations. Although the addition of
      exogenous NO donors at high concentrations could inhibit IL-2 release by T cells,
      our data does not support the hypothesis that NO is a major macrophage mediator
      of suppression in this model.

PMID- 8648105
TI  - An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell
      death in vitro.
AB  - Fas/Apo-1 molecule, also designated as CD95, is a member of the TNF receptor
      family. Fas cross-linking by its natural ligand or by agonistic mAbs results in
      rapid induction of apoptosis in susceptible cells. in addition to the Fas full
      length mRNA, human activated PBMC and tumor cell lines express several mRNA Fas
      variants that derive from alternative splicing of the primary transcript. All
      five variants identified, two of which are newly described here, code for soluble
      proteins that, with the exception of FasTMDel, are truncated in the
      extracytoplasmic region and possess short C-terminal amino acid sequences
      corresponding to a different reading frame. We have identified Abs that recognize
      all splicing variants and established a sandwich ELISA by which the soluble Fas
      molecules could be detected in culture supernatants of transfected cell lines and
      in PBMC following T cell activation. Next, we have studied in detail the
      functional role of these variants by apoptosis inhibition studies. We found that
      all soluble proteins block the apoptosis induced by either an agonistic Ab or,
      more importantly, by the natural Fas ligand in Fas-positive sensitive cell lines.
      interestingly, this functional property can be assigned to the first 49 amino
      acids of the mature protein that is the only region shared by the five soluble
      Fas molecules.

PMID- 8648106
TI  - CD95 engagement releases calcium from intracellular stores of long term
      activated, apoptosis-prone gammadelta T cells.
AB  - Engagement of the CD95 (Apo-1, Fas) membrane receptor is known to induce
      apoptosis in a variety of sensitive cells, even in the absence of extracellular
      Ca2+. The signal transduction events implicated in this pathway are poorly
      understood. We have recently characterized normal human Vgamma9/Vdelta2+ T cell
      clones that maintain similar levels of CD95 membrane expression throughout the
      culture. Here we show that 3 wk of culture after in vitro restimulation are
      necessary for the cells both to die and to acquire the ability to mobilize
      intracellular Ca2+ upon CD95 ligation. Buffering of intracellular Ca2+ by
      accumulation of the chelator 1,2-bis(2-amino phenoxy)ethane-N,N,N1,N-tetraacetic
      acid protects from CD95-triggered apoptosis, suggesting that the two phenomena
      are causally related. As intracellular Ca2+ release by inhibition of endoplasmic
      reticulum ATPases induces apoptosis in both recently and long term activated
      gamma delta cells, the molecular regulation of activation-dependent apoptosis is
      likely to involve events upstream of CD95-dependent Ca2+ release. The CD95
      triggered increase in the intracellular Ca2+ concentration depends on depletion
      of the same intracellular Ca2+ stores mobilized by ligation of the TCR, and Ca2+
      release does not depend on inositol 1,4,5-trisphosphate generation.

PMID- 8648107
TI  - Enhancement of delayed-type hypersensitivity to sheep red blood cells in mice by
      granulocyte colony-stimulating factor administration at the elicitation phase.
AB  - We previously demonstrated that selective depletion of polymorphonuclear
      neutrophils by a mAb inhibits both the priming and effector phases of delayed
      type hypersensitivity (DTH) to SRBC. To better understand the role of
      polymorphonuclear neutrophils in DTH, we examined the effect of granulocyte CSF
      (G-CSF) on DTH to SRBC in mice. G-CSF administered at the elicitation phase
      enhanced a DTH response that was weak in control G-CSF-untreated mice. This
      treatment also augmented mononuclear leukocyte recruitment in DTH in these mice.
      However, G-CSF administration failed to augment priming of DTH to SRBC under any
      conditions examined.

PMID- 8648108
TI  - Murine NK cell allospecificity-1 is defined by inhibitory ligands.
AB  - Hemopoietic allografts of normal and neoplastic origin are subject to NK cell
      mediated resistance in mice. Susceptibility to this resistance is controlled by
      MHC-linked genes in a recessive manner. Several distinct specificities could be
      postulated to explain the strain-dependent pattern of resistance. These
      presumptive specificities for recognition are H-2 haplotype dependent, but the
      correspondence is not one-to-one. For example, resistance of H-2d or H-2b/d host
      to H-2 b graft operationally defines specificity-1, establishing its link with
      haplotype H-2b. To examine the molecular basis of specificity-1, spontaneous Dd
      loss mutant clones were isolated from H-2b/d and H-2d hemopoietic cell lines,
      i.e., 416B of (C57BL/6 x DBA/2)F1 (B6D2F1) origin and L1210 of DBA/2 origin, both
      of which lack specificity-1. The expression of specificity-1 in the mutant clones
      was examined in vivo and in vitro. The results indicate that Dd-loss clones of
      416B and L1210 lines express specificity-1. These data suggest that murine NK
      cell allospecificity-1 is defined primarily by the absence of the Dd molecule or
      other class I molecules sharing the protective motifs; no H-2b-associated genes
      play a relevant role. This conclusion is consistent with the missing self
      hypothesis of NK cell reactivity, and is in agreement with the observation that
      lysis of B6 targets by B6D2F1 NK cells is mediated mostly by cells that express
      Ly-49A and/or Ly-49G2.

PMID- 8648110
TI  - Analysis of the CDR3 region of the rearranged IgH chain genes in patients with
      severe combined immunodeficiency and severe lymphopenia.
AB  - Human B cell-negative severe combined immunodeficiency (B-SCID) is a primary
      immunodeficiency disease characterized by both T and B lymphocytopenia and
      agammaglobulinemia. Although lymphocytes of B-SCID patients express defective
      recombinase activity and rarely succeed in making Ag receptors, the molecular
      defect of the human B-SCID remains to be identified. To gain more insight into
      the human B-SCID defect and its effect on the Ab repertoire, we examined the Ig
      heavy (H) chain genes of the peripheral blood leaky B cells from three B-SCID
      patients. Although the number of B cells in their peripheral blood was very
      limited, we could obtain 41 productive VDJ recombinations from the 58 joints. The
      recombinations showed a grossly altered pattern characterized by short N
      nucleotides, short deleted nucleotides from 5' JH segments, immature JH and D
      segment utilization, absence of VDDJ recombination, and all but one JH segment
      equal to germline JH segments. Therefore, Ab repertoire of IgH chain gene in
      human B-SCID was limited because of restricted junctional and combinatorial
      diversity and few somatic mutations. Furthermore, unusually long P nucleotides
      were inserted in junctional sequences, which might indicate that resolution of
      hairpin is impaired in human B-SCID as in the murine SCID.

PMID- 8648109
TI  - The MHC class I genes of the rhesus monkey. Different evolutionary histories of
      MHC class I and II genes in primates.
AB  - Homologues of the human HLA-A and -B MHC class I loci have been found in great
      apes and Old World primates suggesting that these two loci have existed for at
      least 30 million years. The C locus, however, shows some sequence similarity to
      the B locus and has been found only in gorillas, chimpanzees, and humans. To
      determine the age of the MHC class I C locus and to examine the evolution of the
      A and B loci we have cloned, sequenced, and in vitro translated 16 MHC class I
      cDNAs from two unrelated rhesus monkeys (Macaca mulatta) using both cDNA library
      screening and PCR amplification. Analyses of these sequences suggest that the C
      locus is not present in the rhesus monkey, indicating that this locus may be of
      recent origin in gorillas, chimpanzees, and humans. The rhesus monkey's
      complement of MHC class I genes includes the products of at least one expressed A
      locus and at least two expressed B loci, indicating that a duplication of the B
      locus has taken place in the lineage leading to these Old World primates.
      Comparison of rhesus monkey MHC class I cDNAs to their primate counterparts
      reveals fundamental differences between MHC class I and class II evolution in
      primates. Although MHC class II allelic lineages are shared between humans and
      Old World primates, no such trans-species sharing of allelic lineages is seen at
      the MHC class I loci.

PMID- 8648111
TI  - Purification of a novel MHC class I element binding activity from thymus nuclear
      extracts reveals that thymic RBP-Jkappa/CBF1 binds to NF-kappaB-like elements.
AB  - We purified a DNA binding protein that recognizes a portion of the MHC class I
      regulatory element region 1/NF-kappaB binding site whose expression correlates
      with the expression of a MHC class I transgene in the thymus. The N-terminal
      amino acid sequence and the molecular size matched the RBP-Jkappa protein, also
      known as the EBV C-promoter binding factor, CBF1. Anti-peptide sera reactive with
      RBP-Jkappa/CBF1 also reacted with this protein in gel mobility shift assays.
      Although RBP-Jkappa/CBF1 is ubiquitously expressed, binding to the MHC class Ia
      NF-kappaB site was limited to the thymus. Comparison of the DNA binding
      specificities of RBP-Jkappa/CBF1 in thymic and splenic nuclear extracts revealed
      strong binding from both extracts to an IFN-beta kappaB site containing the RBP
      Jkappa/CBF1 consensus sequence (CGTGGGAA). In contrast, only the thymic nuclear
      extract showed strong DNA binding activity with probes containing the NF-kappaB
      recognition sequences present in the MHC class Ia, IL-2Ralpha, and granulocyte
      macrophage CSF promoters. Thus, RBP-Jkappa/CBF1 in thymic extracts demonstrates a
      clearly distinguishable DNA binding specificity that correlates with tissue
      specific expression of a class I transgene. This, coupled with the fact that our
      previous study showed enhanced expression of the transgene in CD4+CD8+
      thymocytes, suggests that RBP-Jkappa/CBF1 may play a role in the development of
      the immune system.

PMID- 8648112
TI  - Characterization of molecular interactions between intercellular adhesion
      molecule-1 and leukocyte function- associated antigen-1.
AB  - The ability of soluble ICAM-1 (sICAM-1) to inhibit ICAM-1/LFA-1 adhesion events
      has been reported previously by numerous investigators. sICAM-1 has been
      demonstrated to inhibit various in vitro assays at concentrations ranging from 2
      nM to greater than 40 microM. Given the hypothesis that circulating ICAM-1
      modulates immune functions, the ability of sICAM-1 to inhibit cellular functions
      may have significant ramifications. Considering the potential clinical importance
      of the interaction between ICAM-1 and its receptor, LFA-1, it is necessary to
      understand this receptor-ligand interaction at a molecular level. In this study,
      direct binding experiments were utilized to determine the affinity between
      biotinylated monomeric sICAM-1 and immobilized LFA-1 (approximately 130 nM).
      Competitive binding experiments with unlabeled sICAM-1 and a truncated form of
      sICAM-1 (D1D2) yielded similar affinities. The specificity of this interaction
      was characterized using mAbs directed against sICAM-1 or LFA-1. This assay system
      was extended to include multimeric species using nonblocking mAbs directed
      against domains D4 and D5 of sICAM-1. Dimerizing sICAM-1 with a mAb alphaD4 or
      alphaD5 increased the affinity for immobilized LFA-1 by two orders of magnitude
      (approximately 4 nM), an effect presumably due to avidity. These results indicate
      that while the monomeric sICAM-1/LFA-1 interaction may involve only a moderate
      binding affinity, multimeric ICAM-1 present on a cell surface may bind cell
      surface-immobilized LFA-1 with very high avidity. These sICAM-1/LFA-1 molecular
      assays should be useful in defining the efficacy of potential antagonists.

PMID- 8648113
TI  - Murine IL-12 is involved in Calmette-Guerin bacillus-induced sensitization and is
      by itself sufficient to sensitize mice to the lethal effects of human TNF1.
AB  - Human TNF, a specific agonist of murine (m)TNF-R55, is fairly harmless in healthy
      mice, but readily induces lethality in animals sensitized by a malignant tumor or
      a bacterial infection. We here report that IL-12 is both a necessary and
      sufficient mediator in Calmette-Guerin bacillus-induced sensitization to the
      lethal effects of hTNF. Evidence for this involvement is provided by the
      protection observed after anti-mIL-12 Ab treatment and by the fact that Calmette
      Guerin bacillus-induced sensitization can be mimicked by repetitive mIL-12
      administration. IL-12 exerts this effect by inducing IFN-gamma in NK cells. Tumor
      induced sensitization, however, does not seem to involve mIL-12.

PMID- 8648114
TI  - C-reactive protein binds to a novel ligand on Leishmania donovani and increases
      uptake into human macrophages.
AB  - C-reactive protein (CRP) is a major acute phase protein of man, with serum
      concentrations increasing dramatically following stimulation of hepatocytes by
      inflammatory cytokines. However, the role of CRP in inflammation and resistance
      to infection is still poorly understood. Here, the specificity of CRP binding to
      the surface of Leishmania donovani, an obligate intracellular parasite of
      mononuclear phagocytes, is described. CRP is shown to bind to promastigotes at
      the infectious metacyclic stage of development, at concentrations found in normal
      human serum. The presence of CRP on the surface of promastigotes substantially
      increases uptake into human monocyte-derived macrophages. Unusually, CRP does not
      bind via its characteristic ligand, phosphorylcholine. We show that CRP binds to
      the lipophosphoglycan (LPG) component of the promastigote cell surface, a
      molecule implicated in both uptake and survival of these parasites within the
      macrophage, and also to the major secreted protein of promastigotes, secreted
      acid phosphatase. Using mAb to LPG with known ligand specificities, we define a
      novel ligand for CRP as the repeating phosphorylated disaccharide units that form
      the backbone of LPG.

PMID- 8648115
TI  - In vivo induction of CTL responses by recombinant adenylate cyclase of Bordetella
      pertussis carrying viral CD8+ T cell epitopes.
AB  - Exogenous Ags enter the endosomal pathway and are presented to CD4+ T cells in
      association with class II molecules whereas endogenously synthesized Ags, such as
      viral proteins, are presented to CD8+ T cells in association with MHC class I
      molecules. Therefore, most CTL activation strategies use live vectors although an
      alternative possibility could be to deliver the epitope into the cytosol by
      targeting it to an invasive nonreplicative vector. The adenylate cyclase toxin of
      Bordetella pertussis is able to invade a large number of eukaryotic cells and to
      deliver its catalytic domain to the cytosol of the cells. In the present study,
      we have tested the in vivo immunogenicity of recombinant adenylate cyclase toxins
      expressing CTL epitopes either from the nucleoprotein of lymphocytic
      choriomeningitis virus or from the V3 region of HIV-1 gp120. BALB/c mice
      immunized with these toxins developed high specific CTL responses that were shown
      to be mediated by class I-restricted CD8+ CTL. The induction of CTL responses by
      recombinant toxins did not require CD4+ T cells and the cytotoxic activity
      persisted 2 mo after immunization. The activation of CTL responses by the
      recombinant adenylate cyclase toxin required the full-length invasive activity of
      the toxin but did not depend upon its catalytic adenylate cyclase activity as
      demonstrated with a genetically inactivated recombinant toxin expressing the
      lymphocytic choriomeningitis virus epitope. This genetically detoxified invasive
      toxin represents, therefore, an attractive new vector for CTL activation.

PMID- 8648116
TI  - NK cell infiltration into lung, liver, and subcutaneous B16 melanoma is mediated
      by VCAM-1/VLA-4 interaction.
AB  - The mechanisms that regulate the adhesion and migration of NK cells to and across
      endothelium have been studied under nonflow conditions; however, the involvement
      of these processes in vivo is poorly understood. The present studies investigated
      the potential vascular adhesion ligand interactions that determine the in vivo
      recruitment of NK cells to pulmonary and hepatic parenchyma, and s.c. tumor after
      treatment of mice with biologic response modifiers. Seventy-two hours after a
      single injection of the cytokine-inducing agent poly-L-lysine stabilized in
      carboxylmethyl cellulose (poly-ICLC), pulmonary NK cell lytic activity and N
      alpha-carbobenzoxy-L-lysine thiobenzyl ester (BLT)-esterase were augmented 29-
      and 14-fold, respectively, and the number of lung-associated NK cells was
      increased from 2.3 x 10(5) to 7.4 x 10(5). Similar fold increases in NK cell
      number and activity were observed in the liver and s.c. B16 melanoma after poly
      ICLC injection or in the lungs and liver of mice treated with IL-2. Concomitant
      treatment of mice with alpha-VCAM-1 or alpha-VLA-4 mAb, but not alpha-ICAM-1 or
      alpha-LFA-1, abrogated the poly-ICLC and IL-2-induced increase in organ
      associated NK activity and percentage of tumor-associated NK cells, resulted in a
      61 to 76% decrease in pulmonary and hepatic NK cell number, and was independent
      of T and/or B cells. The decrease in NK cell number in organ parenchyma and tumor
      lesions was correlated to an increase in the number of NK cells in peripheral
      blood, but not bone marrow. These results demonstrate that VCAM-1/VLA-4
      interaction is critically involved in the infiltration of newly recruited NK
      cells in to lung, liver, and progressively growing tumor after mobilization from
      the bone marrow.

PMID- 8648117
TI  - Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL
      10 modulates lymphocyte reactivity.
AB  - Humans chronically infected with schistosomiasis usually have impaired parasite
      Ag-specific lymphocyte proliferation and IFN-gamma production that may facilitate
      persistence of the parasite while producing little clinical disease. The
      mechanisms that contribute to the immunologic hyporesponsiveness in these
      patients remain undefined. IL-10 has been shown to exert an inhibitory effect on
      cell-mediated immunity. To determine whether endogenous IL-10 has a role in
      regulating parasite-specific anergy in schistosomiasis, neutralizing anti-IL-10
      added to PBMC from Schistosoma haematobium patients' enhanced adult worm (SWAP)-
      or egg Ag (SEA)-driven lymphocyte proliferation and/or IFN-gamma production by 2-
      to >100-fold in 32 of 38 subjects. In contrast, anti-IL-10 failed to
      significantly augment the mycobacterial Ag, purified protein derivative (PPD)
      driven lymphocyte proliferation, or IFN-gamma production in 9 or 10 of 14
      individuals, respectively. SWAP or SEA triggered IL-10 release from PBMC of both
      patients and healthy individuals; however, CD4+ cells were a significant source
      of IL-10 only in infected subjects. PPD relative to SWAP induced fivefold less IL
      10 release by CD4+ cells (p < 0.01). A possible mechanism whereby IL-10
      suppressed Ag-specific T cell responses was demonstrated by the ability of SWAP
      and not PPD to suppress B7 expression on PBMC. Anti-IL-10 completely inhibited
      the parasite Ag-induced down-regulation of B7 expression. These studies indicate
      that IL-10 contributes to parasite Ag-induced T cell hyporesponsiveness observed
      in patients with chronic schistosomiasis hematobia.

PMID- 8648118
TI  - Relation of oxidative stress and glutathione synthesis to CD95(Fas/APO-1)
      mediated apoptosis of adult T cell leukemia cells.
AB  - An IL-2 dependent adult T cell leukemia cell line (SO4) has been established that
      is sensitive to CD95-mediated apoptosis as well as a subline (R-SO4) that is
      resistant. Incubating SO4 cells with anti-CD95 IgM mAb caused concentration
      dependent cell death. On the contrary, R-SO4 cells did not die even at 1000 ng/ml
      of anti-CD95 IgM mAb. The levels of CD95 expression on R-SO4 cells were one-third
      of those on SO4 cells. However a blocking Ab, anti-CD95 IgG mAb, did not induce
      complete resistance of SO4 cells to anti-CD95 IgM mAb as R-SO4 cells. As CD95 and
      TNF receptor are similar, and TNF/TNF receptor binding induces oxygen radicals,
      the involvement of oxidant and antioxidant systems in CD95-mediated apoptosis has
      been examined. The addition of anti-CD95 IgM mAb resulted in formation of
      intracellular oxygen radical species in the SO4 cells as measured using 2',5',
      dichlorofluorescein as substrate. The oxygen radical production induced DNA
      damage as determined by formation of 8-hydroxydeoxyguanosine. No increase in the
      formation of oxygen radicals was observed in R-SO4 cells. Concentrations of the
      intracellular antioxidant, glutathione, and the key enzyme for its synthesis,
      gamma-glutamylcysteine synthetase, were 150% increased in R-SO4 cells in
      comparison with that of SO4 cells. Moreover, glutathione ester decreased the
      formation of 8-hydroxydeoxyguanosine. These results suggested that apoptosis
      mediated by CD95 in ATL cells is related to the production of oxygen radical
      species and cellular antioxidant systems, especially, glutathione synthesis.

PMID- 8648119
TI  - Helicobacter-specific cell-mediated immune responses display a predominant Th1
      phenotype and promote a delayed-type hypersensitivity response in the stomachs of
      mice.
AB  - Studies regarding the nature of cell-mediated immunity in Helicobacter pylori
      infection and its role in pathogenesis have yielded controversial results. To
      address this issue in a controlled manner, we have employed the well
      characterized Helicobacter felis-mouse model. Immunized/challenged and
      nonimmunized/infected mice were evaluated for cellular proliferation, gastric
      inflammation, and cytokine and Ab production at various times after infection. We
      observed two types of cell-mediated immune responses depending on the nature of
      the Ag preparation. The first response is a Helicobacter-independent response,
      present in all experimental groups, which is directed toward Ags such as urease
      and heat shock proteins. The second is a Helicobacter-dependent cellular response
      restricted to mice previously exposed to Helicobacter Ags either by immunization
      or infection. This response was not seen in noninfected controls. The
      Helicobacter-dependent cellular response had a Th1 phenotype, as either infected
      or immunized/challenged mice demonstrated local and systemic production of IFN
      gamma and undetectable levels of IL-4 or IL-5. Cellular proliferation correlated
      with the severity of gastric inflammation in both immunized/challenged
      (protected) and nonimmunized/infected mice. Finally, in vivo neutralization of
      IFN-gamma resulted in a significant reduction of gastric inflammation in H. felis
      infected, as well as immunized/challenged, mice. This treatment also revealed the
      presence of Th2 cells, restricted to immunized/challenged mice, as demonstrated
      by local and systemic production of IL-4 in these mice. These data demonstrate
      that Helicobacter infection and/or immunization stimulate a predominantly Th1
      type, Ag-specific response and promote a local delayed-type hypersensitivity
      response in the stomach that may be inhibited by depletion of IFN-gamma.

PMID- 8648120
TI  - Induction of Th1 cell-mediated protective immunity to Schistosoma mansoni by co
      administration of larval antigens and IL-12 as an adjuvant.
AB  - In this study, rIL-12, which is a powerful inducer of Th1 lymphocyte development,
      was administered to mice as an adjuvant in conjunction with a soluble lung-stage
      Ag preparation (SLAP) derived from lung-stage larvae of Schistosoma mansoni to
      potentiate Th1-mediated immune responses and induce resistance to reinfection.
      Immunization of mice with one or two doses of SLAP + IL-12 elicited a dominant
      population of Ag-specific Th1 lymphocytes in the draining lymph nodes, as judged
      by the secretion of abundant IFN-gamma but undetectable levels of IL-4, upon
      antigenic restimulation in vitro. In contrast, SLAP alone induced a mixed
      population of Th1 and Th2 cells with secretion of IFN-gamma, IL-4, and IL-10. The
      development of a biased Th1 cell population in mice immunized with SLAP + IL-12
      was reflected in enhanced levels of Ag-specific IgG2a but decreased levels of
      IgG1 and total IgE serum Abs. Ablation of NK1.1+ cells before the administration
      of a single dose of SLAP + IL-12 reduced Th cell proliferation and almost
      completely inhibited secretion of IFN-gamma by in vitro-cultured lymph node
      cells. This indicates that NK cells stimulated by IL-12 shortly after vaccination
      are critical to the subsequent development of Ag-specific Th1 cells. Finally, it
      is demonstrated that the delivery of two doses of SLAP + IL-12 to mice is
      sufficient to elicit moderate but highly significant levels of protective
      immunity against challenge infection.

PMID- 8648121
TI  - Characterization of early IL-12, IFN-alphabeta, and TNF effects on antiviral
      state and NK cell responses during murine cytomegalovirus infection.
AB  - Murine cytomegalovirus (MCMV) infection of mice induces early cytokines. Although
      certain of these can directly inhibit viral replication, they also can promote
      defense by activating NK cells. MCMV induces IFN-alphabeta-dependent NK cell
      cytotoxicity and IL-12-dependent NK cell IFN-gamma production. Studies were
      initiated to define cytokine-mediated NK and T cell-independent antiviral defense
      and specific cytokine-elicited NK cell responses during MCMV infections. IFN
      alphabeta, TNF, IL-12, and IFN-gamma were all shown to be induced 2 days after
      infection of immunocompetent mice. Infections of NK and T cell-deficient mice
      demonstrated that virus-induced IFN-alphabeta, TNF, and IL-12, but not IFN-gamma,
      were produced independently of these populations, and that IL-12 production
      occurred in the absence of detectable IFN-gamma. In vivo neutralization studies
      of IFN-alphabeta, TNF, and IL-12 showed that each of these factors had NK and T
      cell-independent antiviral functions, as well as specific effects on NK cell
      responses. Examination of NK cell cytotoxicity, blastogenesis, and IFN-gamma
      production demonstrated that: IL-12 was required for NK cell IFN-gamma production
      but not blastogenesis and cytotoxicity; IFN-alphabeta was necessary for NK cell
      blastogenesis and cytotoxicity but not IFN-gamma production; and TNF facilitated
      IFN-gamma production but inhibited NK cell cytotoxicity. This work defines the
      biologic consequences of early cytokine expression during viral infection.

PMID- 8648122
TI  - Resistance to murine AIDS in offspring of mice infected with LP-BM5. Role of CD8
      T cells.
AB  - The murine-acquired immunodeficiency syndrome (MAIDS) is caused by a mixture of
      murine leukemia viruses (LP-BM5 MuLV). The influence of perinatal contact with
      retroviruses or their Ags on the response to infection was tested by infecting
      with LP-BM5 (MuLV) the adult offspring of mice with MAIDS. These offspring were
      resistant to disease after virus challenge. Most of them were free of defective
      viral DNA, and even those with molecular evidence of infection had lymphoid cells
      with a lower infectious capacity to cause MAIDS in naive recipients. No
      ecotropic, xenotropic, or mink cell focus-forming (MCF) virus expression was
      found at the age of 5 wk, which is the time of LP-BM5 (MuLV) challenge. However,
      at 22 wk of age, one-half of the offspring from MAIDS mothers had ecotropic virus
      expressing cells in their spleens. At the time of suckling, offspring from
      infected mothers had enhanced percentages of B cells and CD4 and CD8 T cells in
      the spleen, possibly followed by a slight persistent splenomegaly. These results
      suggest that immune reactivity, rather than tolerance to the virus, is
      responsible for resistance to disease after challenge. The offspring of MAIDS
      mice could clear the virus after challenge. This clearance was mediated by CD8 T
      cells, as continuous CD8 T cell depletion initiated at the time of viral
      challenge abrogated the resistance of these mice to MAIDS.

PMID- 8648123
TI  - Mycobacterium avium- and Mycobacterium tuberculosis-containing vacuoles are
      dynamic, fusion-competent vesicles that are accessible to glycosphingolipids from
      the host cell plasmalemma.
AB  - The vacuoles inhabited by viable Mycobacterium avium and Mycobacterium
      tuberculosis show limited fusion with endosomal and lysosomal compartments. This
      ability to regulate the maturation of their phagosomal compartments and restrict
      their differentiation into hydrolytically active vacuoles appears to correlate
      with the survival of the bacilli. Data presented in this current study
      demonstrate that despite the apparent isolation of mycobacterial vacuoles from
      the lysosomal network, they are dynamic, fusion-competent vesicles. Exploiting
      the ability of cholera toxin B subunit to bind to GM1 ganglioside on the
      macrophage plasmalemma, we demonstrate that these glycosphingolipids have ready
      access to the mycobacterial vacuoles. Entry into mycobacterial vacuoles is rapid,
      within 5 min of addition to the cells, and does not proceed through a brefeldin A
      sensitive pathway. Furthermore, the gangliosides follow a route that differs from
      that taken by fluid-phase markers. TLC analysis gangliosides isolated from
      Mycobacterium-containing vacuoles, and IgG-bead phagosomes reveal similar
      profiles. These data indicate that rather than being fusion incompetent,
      mycobacterial vacuoles are actually highly dynamic, fusion-competent vesicles
      that behave like an extension of the recycling endosomal apparatus.

PMID- 8648124
TI  - Respiratory syncytial virus infection enhances neutrophil and eosinophil adhesion
      to cultured respiratory epithelial cells. Roles of CD18 and intercellular
      adhesion molecule-1.
AB  - Respiratory syncytial virus (RSV) infections in children precipitate acute
      episodes of respiratory obstruction that are associated with influx of
      inflammatory cells into the airway. Since RSV can induce the expression of
      adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by
      the respiratory epithelium, the hypothesis has been proposed that ICAM-1
      expression contributes to airway inflammation by supporting adhesion and
      retention of infiltrating inflammatory leukocytes. To test this hypothesis, A549
      cells (an immortalized human alveolar epithelial type II cell-like fine) were
      infected with RSV, and the ability of these infected monolayers to support
      adhesion by human neutrophils (NEUT) and eosinophils (EOS) was measured. RSV
      infection significantly increased ICAM-1 expression by A549 monolayers (p <
      0.001). Although NEUT adhesion to A549 monolayers was significantly enhanced
      following RSV infection (p < 0.001), infection alone resulted in little change in
      EOS adherence. However, if EOS were first activated with phorbol ester (PMA),
      adhesion to both control and RSV-infected A549 cells was enhanced, with greater
      levels of adhesion supported by RSV-infected cultures (p < 0.001). The
      requirement for EOS activation (but not for NEUT activation) before adhesion
      remained when NEU and EOS were prepared and compared from the same donor. Despite
      this difference, NEUT and EOS adhesion was reduced by blocking Abs to epithelial
      ICAM-1 or granulocyte CD18 adhesion proteins (p < 0.01). However, only NEUT
      adhesion was blocked by Ab to CD11a. Our results show that RSV infections of
      respiratory epithelial monolayers can promote inflammatory cell adherence which
      could, in turn, potentially contribute to the airway injury and obstruction that
      accompanies bronchiolitis.

PMID- 8648125
TI  - The effect of acute phase proteins on clearance of chromatin from the circulation
      of normal mice.
AB  - The clearance of nucleosome core particles and H1-stripped chromatin from the
      circulation of mice was examined. Radiolabeled chromatin preparations were
      injected into mice, and blood samples were obtained over 60 min. The animals were
      then killed, and the selected organs were collected and radioactivity was
      measured. The acute phase response (APR) was induced by i.p. injections of casein
      before some clearance studies. Serum amyloid P component, the major acute phase
      protein in mice, increased from 27 microg/ml to 339 microg/ml during the acute
      phase. The rate of chromatin clearance decreased during the acute phase in
      C57BL/10J mice. At 5 min, 18% +/- 3% of the originally measured radioactivity
      remained in control animals compared with 49% +/- 2% in acute phase animals (p <
      0.001). Co-injection of either serum amyloid P component or C-reactive protein,
      the major acute phase protein in humans, caused a decrease in the rate of
      chromatin clearance similar to that observed following the induction of the APR.
      APR induction also caused a higher percentage of the chromatin to localize in the
      liver compared with the spleen, with the ratio changing from 10.2 +/- 0.7 to 16.1
      +/- 1.9 (p < 0.004). In addition, the APR caused a decrease in the percentage of
      chromatin localized in the kidney. The lack of radioactivity associated with
      cells in the circulation indicates that complement is not a major factor in the
      clearance mechanism of chromatin. These findings suggest that the APR produces
      major changes in the rate and path of chromatin clearance. These changes may
      protect against deposition of chromatin in target organs of systemic lupus
      erythematosus.

PMID- 8648126
TI  - Both N- and C-terminal regions of the bioactive N-terminal fragment of the
      neutrophil granule bactericidal/permeability-increasing protein are required for
      stability and function.
AB  - An N-terminal fragment (residues 1-199) of the 456-residue human
      bactericidal/permeability-increasing protein (BPI), isolated after limited
      proteolysis, exhibits antibacterial and LPS-neutralizing activities equal to or
      greater than those of holo-BPI. To assess minimal structural requirements for
      bioactivity, mutant species of BPI were expressed in vivo by transient
      transfection and in vitro by cellfree transcription/translation. BPI1-456 and
      BPI1-193 demonstrated the expected antibacterial and LPS-binding activities.
      Deletion of the N-terminal 12 residues did not diminish BPI function. However,
      further truncation either from the C-terminus to residue 169 (BPI1-169) or from
      the N-terminus (BPIdelta15-56) yielded in vitro products with little or no LPS
      binding activity and in vivo products that could not be recovered from the
      culture medium or cellular acid extracts. The possible role of cysteine-175 (the
      three cysteines in human BPI are at residues 132, 135, and 175) in BPI
      stability/function was examined by substitution of Cys(175) with serine. Recovery
      of C175S BPI from extracellular medium was reduced 10-fold, and C175S BPI
      produced in vitro had little LPS-binding activity. Compared with wild-type holo
      BPI and BPI1-193, BPI1-169, BPIdelta15-56, and C175S BPI showed increased
      susceptibility to cleavage by elastase in the region 1-193 (but not in the region
      200-456), indicating conformational changes that may account for the loss of
      function. These findings suggest that the proteolytic N-terminal fragment of BPI
      corresponds closely to the minimum functional (antibacterial/anti-LPS) domain of
      BPI and that residues near both ends of this fragment are essential for
      structural stability and functional integrity.

PMID- 8648127
TI  - Lipopolysaccharide up-regulates platelet-derived growth factor (PDGF) alpha
      receptor expression in rat lung myofibroblasts and enhances response to all PDGF
      isoforms.
AB  - Differential expression of PDGF receptor alpha and beta subunits controls the
      response of mesenchymal cells to the three PDGF isoforms (AA, AB, and BB).
      Cultured rat lung myofibroblasts (RLMF) possess abundant PDGF receptor-beta (PDGF
      Rbeta) and little PDGF receptor-alpha (PDGF-Ralpha). Here we show that LPS up
      regulates expression of PDGF-Ralpha and increases the sensitivity of RLMF to all
      three PDGF isoforms. Treatment of RLMF for 4 to 48 h with LPS enhanced PDGF
      Ralpha surface expression and mRNA 5- to 10-fold but caused no change in
      expression of PDGF-Rbeta. Both RNA and protein synthesis were necessary for up
      regulation of PDGF-Ralpha, and the increase in PDGF-Ralpha mRNA was most likely
      regulated at the transcriptional level. PDGF-Ralpha up-regulation was not
      mediated by the IL-1R system and was independent of LPS-binding proteins in
      serum. Highly confluent cultures of RLMF responded more strongly to LPS than did
      subconfluent cultures. LPS treatment enhanced the mitogenic and chemotactic
      responses of RLMF to all PDGF isoforms at least threefold. We postulate that
      signal transduction by PDGF-receptor alphabeta heterodimers was important in the
      enhanced responses to PDGF-AB and -BB. We propose that regulation of PDGF-Ralpha
      is a critical event in the genesis of pulmonary fibroproliferative diseases.

PMID- 8648128
TI  - IL-4 and IFN-gamma synergistically increase total polymeric IgA receptor levels
      in human intestinal epithelial cells. Role of protein tyrosine kinases.
AB  - IL-4 and IFN-gamma increase release of secretory component (SC), the polymeric
      IgA (plgA)-binding segment of the plgA receptor (plgAR), by the human intestinal
      epithelial cell line HT29. Moreover, these two cytokines synergistically increase
      plgA binding and cell surface staining for the receptor. To understand better the
      mechanism by which these cytokines regulate plgAR, we did quantitative
      immunoblotting using Abs against secretory component. We found that synergy
      occurs at the level of total cellular plgAR. Additionally, time course studies
      indicated that maximal receptor levels required >24-h incubation, that reaching
      maximal levels required at least 18 h of cytokine treatment, and that receptor
      levels remained elevated as long as cytokines were present. Conversely, if
      cytokines were removed, then cellular plgAR levels decreased with an approximate
      t1/2 of 20 h. Finally, synergy required the simultaneous presence of both
      cytokines throughout the treatment period. Direct measurement of second
      messengers and inhibitor studies suggest that Ca2+, cAMP, protein kinase A, and
      protein kinase C do not play major roles in regulating cellular plgAR levels by
      either cytokine, and do not contribute to the mechanism of synergy. In contrast,
      protein tyrosine kinase inhibitors potently inhibited all cytokine-dependent
      increases in total cellular plgAR. These results suggest that IL-4 and IFN-gamma
      increase cellular plgAR levels in HT29 cells predominantly by activating protein
      tyrosine kinase-dependent signaling pathways.

PMID- 8648129
TI  - Expression of C-reactive protein by alveolar macrophages.
AB  - C-reactive protein (CRP) is well characterized as one of the serum acute phase
      proteins, the levels of which increase dramatically after infection. CRP has been
      shown to be involved in multiple immunoregulatory functions. For example, it
      activates the classical complement cascade, opsonizes bacteria for phagocytosis,
      and stimulates phagocytic cells. Although CRP is predominantly produced and
      secreted by hepatocytes, other cells including subsets of lymphocytes, Kupffer
      cells, and blood monocytes have been shown to synthesize this protein as well. We
      hypothesized that CRP may be produced in the lung, and therefore it could
      function directly in pulmonary host defense. Western blot analysis showed that
      CRP was present in the lung tissue, lung lavage, and alveolar macrophages. This
      result was further confirmed by immunohistochemical staining of lung sections
      that showed the localization of CRP in alveolar macrophages. The CRP mRNA was
      detected subsequently by reverse-transcriptase PCR (RT-PCR), and a single
      amplified product was obtained from alveolar macrophages as well as from whole
      lung tissue. Both were the same size as the amplified product obtained from liver
      mRNA. Furthermore, in situ hybridization with CRP riboprobe demonstrated specific
      staining of alveolar macrophages both in lung sections and isolated cells. In
      addition, in situ hybridization showed that CRP mRNA levels in isolated alveolar
      macrophages were up-regulated by in vitro LPS stimulation. In summary, these
      results indicate that CRP is produced by alveolar macrophages, and suggest that
      CRP may be involved in the pulmonary immune response.

PMID- 8648131
TI  - IL-13 released by and localized in human basophils.
AB  - We and others have shown that human basophils can synthesize and release IL-4.
      However, IL-13, a cytokine that closely resembles IL-4, has not hitherto been
      described as a basophil product. The production of IL-13 by basophils was
      demonstrated by immunocytochemistry. Approximately 70% of basophils stimulated
      with anti-FcepsilonRIalpha (antibody to the alpha subunit of IgE receptor type I)
      stained for IL-13. Under similar experimental conditions, mononuclear cells
      failed to stain for IL-13. The cytokine was localized to basophilic granules by
      electron microscopic examination of immunogold staining. The secretion of IL-13
      into the culture supernatant was assayed by ELISA. Kinetic studies showed
      detectable IL-13 release at 3 h, which steadily increased up to 24 h. This is
      significantly different from the kinetics of basophil histamine and IL-4 release.
      IL-13 production was also observed upon stimulation with anti-IgE, anti
      FcepsilonRIalpha, IL-3, and A23187 in a dose-dependent manner. PBMC, neutrophils,
      and eosinophils isolated from the same donors did not release IL-13 after anti
      IgE stimulation. The anti-IgE-induced basophil IL-13 synthesis could be enhanced
      by IL-3 preincubation (with and without IL-3 preincubation, anti-IgE-induced IL
      13 production was 227 +/- 99 and 42 +/- 13 pg/10(6) basophils, respectively).
      PBMC produced a significant amount of IL-1 3 upon stimulation with PHA, but a low
      level of IL-13 in response to A23187 and/or PMA. Eosinophils and neutrophils did
      not produce IL-13 when cultured with A23187, IL-5, and anti-FcepsilonRIalpha.
      This is the first demonstration of IL-1 3 production by basophils. Our data
      suggest that basophils, in addition to secreting mediators, can represent an
      important source of proallergic cytokines.

PMID- 8648130
TI  - Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and
      functional sites in the third complement component.
AB  - Previous studies have suggested that the residues 727-768 of human (Hu) C3
      contain the binding sites for CR1, factor H, and factor B. Here, we have (1)
      characterized further some of the C3 structural requirements for its binding to
      CR1, H, and B, (2) investigated the functions associated with these C3-ligand
      interactions, and (3) studied the relationship of MCP-binding sites in C3 with
      those for CR1, H, and B. Hu C3 molecules in which residues 727-768 were deleted
      (designated C3delta727-768) or substituted with the corresponding segment of
      cobra venom factor, Xenopus, or trout C3 (chimeric C3s) were expressed in the
      baculovirus system and analyzed for their reactivity with C3-binding proteins. In
      contrast to wild-type iC3 which, in the presence of CR1, is cleaved by factor I
      to iC3b-a and C3c-a and C3dg, all chimeric C3s were cleaved only to iC3b-a. In
      addition, the cleavage of deleted (C3delta727-768) iC3 to iC3b-a by factor I in
      the presence of CR1 was significantly reduced, whereas it remained unaltered in
      the presence of MCP. Cleavage of iC3 to iC3b-a by factor I and H was similar in
      all expressed C3s except C3delta727-768, whose cleavage was significantly
      reduced. All of the expressed molecules except C3delta727-768 were capable of
      forming the fluid-phase alternative pathway C3 convertase, and all reacted with
      properdin. These results suggest that during cleavage of iC3 by factor I and CR1,
      or H, CR1 and H bind to at least two sites on C3 and that the MCP binding site(s)
      on C3b are different from those for CR1. They also indicate that some or all of
      the C3 residues that are directly involved in, or contribute to, the structure of
      one of the CR1 and H binding sites are located within residues 727-768. These
      studies also demonstrate that, although this segment of C3 may be involved in C3
      factor B interaction, other residues in addition to 736EE (previously implicated
      in B binding) must also contribute significantly to this interaction.

PMID- 8648132
TI  - Mast cells expressing chymase but not tryptase can be derived by culturing human
      progenitors in conditioned medium obtained from a human mastocytosis cell strain
      with c-kit ligand.
AB  - Human mast cells (MC) were derived from umbilical cord blood and bone marrow
      progenitors cultured in the presence of a conditioned medium from a human
      mastocytosis cell strain and recombinant human kit ligand. MCs were studied using
      a sequential double immunoenzymatic analysis to determine the heterogeneity of
      expression of tryptase and chymase, two MC-specific proteases. The conditioned
      medium and kit ligand promoted the development of distinct MC subtypes from bone
      marrow and umbilical cord blood progenitors. kit ligand induced MC from umbilical
      cord blood predominantly of two immunophenotypes, MCT positive for tryptase but
      negative for chymase, and MCTC positive for tryptase and chymase. In contrast,
      the conditioned medium induced MC subtype MCTC and a third subtype, MCC, positive
      for chymase but negative for tryptase from both bone marrow and umbilical cord
      blood progenitors. In situ hybridization analyses confirmed the existence of a
      chymase-positive, tryptase-negative human MC in the culture. In umbilical cord
      blood cultures supplemented with both conditioned medium and kit ligand, the
      number of MCC cells was up-regulated from 2.7 to 34.0% of the total cells in the
      culture. In contrast, the number of MCT cells declined from 54.3 to 21.5% on day
      49 of culture. In bone marrow cultures supplemented with conditioned medium
      alone, the MCC subtype represented 100% of the MCs on day 10 of culture. This
      study clearly demonstrates that a third type of MC, MCC, expressing chymase
      without concomitant expression of tryptase can be induced in vitro from normal
      human progenitors. In addition, it shows that tryptase and chymase, two MC
      specific proteases, can be differentially expressed in in vitro derived human MCs
      by changing the cytokine combination of the culture.

PMID- 8648133
TI  - Morphine-induced conformational changes in human monocytes, granulocytes, and
      endothelial cells and in invertebrate immunocytes and microglia are mediated by
      nitric oxide.
AB  - We evaluated the contribution of nitric oxide (NO) to morphine-induced rounding
      of spontaneously activated (mobile) ameboid human monocytes, granulocytes, or
      arterial endothelial cells and invertebrate immunocytes and microglia. Morphine
      induced significant rounding and inactivation of ameboid cells within 20 min
      except for arterial endothelial cells, which became rounded 24 h after morphine
      exposure. The effects of morphine on cell conformation were blocked in the
      presence of N-nitro-L-arginine, a nitric oxide synthase inhibitor. Treatment of
      cells with the NO donor, sodium nitroprusside, induced cell rounding similar to
      that observed following morphine exposure, suggesting that NO release may mediate
      morphine-induced changes in cell conformation. The contribution of NO release to
      morphine-induced cell rounding was determined by direct evaluation of NO
      concentration in real-time using a NO-specific amperometric probe. Significant
      increases in NO concentration were observed 2 min after morphine stimulation,
      whereas morphine-induced NO release was markedly impaired by pretreatment with N
      nitro-L-arginine or the opiate alkaloid antagonist, naloxone. In contrast, opioid
      peptides failed to induce NO release, consistent with our previous observations
      that demonstrated the failure of opioid peptides to promote cell rounding. Taken
      together, these data suggest that morphine-induced NO release may be mediated by
      activation of the opiate alkaloid-selective, opioid peptide-insensitive micro3
      receptor, and that functional coupling of morphine to NO production has been
      conserved during evolution and may modulate cellular activation.

PMID- 8648134
TI  - Identification of surface molecules associated with physiologic activation of
      eosinophils. Application of whole-blood flow cytometry to eosinophils.
AB  - Activation is central to the eosinophil's functional role as an immune responder
      cell. To evaluate such activation in cells freshly isolated from peripheral
      blood, a method for whole-blood immunostaining and flow cytometry-based
      eosinophil selection was developed. Simultaneous comparison of purified
      eosinophils and whole-blood cells revealed significant differences in the levels
      of expression of various surface molecules, which suggested that the purification
      process activated the eosinophils. Subsequent analyses were conducted with the
      whole-blood assay. When eosinophils from helminth-infected persons (n = 18) were
      compared with those from normal individuals (n = 10), the early activation marker
      CD69 was found to be significantly increased (geometric mean (GM) = 4.3 vs. 1.0%,
      p = 0.04). The granulocyte activation marker CD66 was also up-regulated on
      eosinphils from helminth patients (GM = 53.3 vs. 31.0%, p = 0.044), as was the
      tetraspan family molecule CD81 (TAPA-1; GM = 79.4 vs. 48.2%, p = 0.02).
      Conversely, in vivo CD23 (FcepsilonRII) expression on eosinophils was decreased
      in the presence of parasitic infection (GM = 0.9 vs. 5.7%, p = 0.02). Expression
      of the eosinophil surface molecules CD69, CD81, and CD23 was significantly
      enhanced after cytokine stimulation in vitro with IL-3 or GM-CSF. In vivo,
      specific anthelmintic therapy resulted in decreased CD66 and CD25 expression (p <
      0.05 compared with pretreatment) to levels approaching those seen in uninfected
      normal individuals. These findings indicate the dynamic nature of eosinophil
      surface molecules and demonstrate an important role for whole-blood staining in
      developing an understanding of the nature of eosinophil activation and of their
      role in inflammatory reactions to helminth parasites.

PMID- 8648135
TI  - Constitutive production of IL-4 and IL-10 and stimulated production of IL-8 by
      normal peripheral blood eosinophils.
AB  - To study the capacity and regulation of cytokine production by normal peripheral
      blood eosinophils, we isolated eosinophils from healthy individuals and
      stimulated them with immobilized Ig or TNF-alpha, with or without exogenous IL-5.
      By reverse transcription-PCR, uncultured, freshly isolated eosinophils
      constitutively expressed mRNA for IL-4, IL-10, and TGF-beta1. Eosinophils
      stimulated by immobilized secretory IgA, immobilized IgA, immobilized IgG, or TNF
      alpha for 3 h expressed mRNA encoding IL-3, IL-4, IL-8, IL-10, granulocyte
      macrophage CSF, TNF-alpha, TGF-beta, and RANTES. The mRNA for IL-2, IL-5, or IFN
      gamma was not detected. IL-4 and IL-10 protein, but not IL-8, were measurable in
      lysates of fresh eosinophils or eosinophils cultured with medium alone for 24 h.
      Eosinophils incubated with immobilized Ig or TNF-alpha released IL-8 protein into
      the supernatants. In contrast, IL-4 and IL-10 proteins were not detectable.
      Soluble secretory IgA immune complexes also induced degranulation, as measured by
      eosinophil-derived neurotoxin, and IL-8 release, but not IL-4 or IL-10 release,
      from eosinophils. Release of IL-8 protein and storage of IL-4 and IL-10 proteins
      were enhanced by exogenous IL-5 and inhibited by a transcription inhibitor,
      actinomycin D. Degranulation of stored granule proteins was not affected by
      actinomycin D. Therefore, normal peripheral blood eosinophils can transcribe and
      synthesize several cytokines, including IL-4, IL-8, and IL-10; some are stored,
      and some are released. These cytokines may play important roles in modulating
      immune responses in diseases associated with eosinophils.

PMID- 8648136
TI  - Activation of a p38 mitogen-activated protein kinase in human neutrophils by
      lipopolysaccharide.
AB  - Stimulation of human neutrophils by LPS is central to the pathogenesis of sepsis
      and the adult respiratory distress syndrome. The intracellular signaling pathway
      that results in cellular responses following LPS stimulation in neutrophils is
      unknown. We report that exposure of neutrophils to LPS results in the
      phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase,
      occurring in a concentration-dependent manner, with maximum response at 20 to 25
      min. Partial purification of a p38 MAP kinase by ion exchange chromatography
      established it as distinct from the p42/p44 (extracellular signal-regulated
      kinases (ERK-1 and ERK-2) MAP kinases). Activation of the p38 MAP kinase by LPS
      in human neutrophils occurs via CD14, a proposed LPS receptor, and requires the
      presence of plasma containing the LPS-binding protein. This intracellular
      signaling pathway is independent of protein kinase C and does not involve Raf,
      MAP/ERK kinase kinase-1, MAP/ERK kinase-1, or MAP/ERK kinase-2 and does not
      result in the activation of the p42/p44 ERK MAP kinases or the c-jun N-terminal
      kinases.

PMID- 8648137
TI  - Functional contributions of the FcepsilonRIalpha and FepsilonRIgamma subunit
      domains in FcepsilonRI-mediated signaling in mast cells.
AB  - The functional contributions of the alpha and gamma subunit domains of the high
      affinity receptor for IgE (Fcepsilon-RI) were determined following chimeric
      receptor aggregation. Chimeric receptors of the extracellular (EC) and
      cytoplasmic tail (CT) domains of FcepsilonRI and the IL-2R p55 subunit (I) were
      constructed and stably expressed in RBL-2H3 cells. Signaling (inositol phosphate
      production, tyrosine phosphorylation, Ca2+ mobilization, and secretion of
      histamine and arachidonic acid metabolites) via alpha/gamma/gamma or
      I/gamma/gamma was similar to the native rat receptor, and both were shown to
      associate with endogenous FcepsilonRIbeta and FcepsilonRIgamma subunits.
      Therefore, the contributions of the EC domains could not be evaluated. The
      chimeras alpha/I/gamma and I/I/gamma were found to be single polypeptide chains,
      as they did not associate with beta and gamma. Signaling via alpha/I/gamma
      resulted in the appearance of biochemical events common to the native receptor.
      Cross-linking I/I/gamma elicited histamine release, [14C]arachidonic acid
      metabolites, tyrosine phosphorylation, Ca2+ mobilization, and only inositol
      trisphosphate production, which were not of a similar magnitude to the native
      FcepsilonRI. No biochemical events were elicited by cross-linking alpha/I/I or
      I/I/I. These results demonstrate that both the FcepsilonRIalpha EC domain and the
      FcepsilonRIgamma CT domain are essential for the FcepsilonRI signaling process,
      and that while FcepsilonRIIgamma CT plays a critical role in FepsilonRI
      signaling, the EC domain of FcepsilonRIalpha has a major contribution in
      signaling, as well as a role in modulating the magnitude of the biochemical
      events.

PMID- 8648138
TI  - The IL-1 and IL-1 receptor antagonist (IL-1Ra) response of human neutrophils to
      EBV stimulation. Preponderance of IL-Ra detection.
AB  - The present study investigated the effect of EBV on gene expression and protein
      synthesis of IL-1 and its natural IL-1R antagonist (IL-1Ra) in human peripheral
      blood neutrophils. EBV induced a rapid accumulation of IL-1 and IL-lRa mRNA in
      neutrophils that was associated with the later appearance of considerable amounts
      of IL-1alpha, IL-1beta, and IL-Ra proteins. Approximately 3200 and 610 times more
      IL-Ra than IL-1alpha a or IL-1beta, respectively, was secreted by neutrophils in
      response to EBV. The effect induced by EBV cannot reflect an overall metabolic
      activity of neutrophils, since EBV failed to induce granulocyte-macrophage OF
      synthesis. Heat-inactivated virus was unable to stimulate cytokine synthesis,
      whereas UV-irradiated virus retained the full IL-1- and IL-1Ra-inducing potential
      of the native particle. Furthermore, pretreatment of cells with cycloheximide or
      phosphonoacetic acid did not abrogate the effect of EBV, suggesting that EBV does
      not penetrate the cell, but that a virion's structural molecule is required to
      induce such an effect. In this respect, neutralization of the viral particles
      with the mAb 72A1, which is known to react with glycoprotein gp350 of the viral
      envelope, inhibits the production of IL-1 and IL-1Ra, suggesting that gp350 could
      be involved in this process. Thus, the elevated levels of IL-1Ra detected for EBV
      stimulated neutrophils might be part of a mechanism used by the virus to evade
      the immune system.

PMID- 8648139
TI  - Sublytic complement attack induces cell cycle in oligodendrocytes.
AB  - Sublytic complement attack on oligodendrocytes (OLG) by activation of terminal
      complement complexes (TCC) selectively enhances the decay of myelin protein
      mRNAs. We have investigated whether TCC also stimulate differentiated OLG to
      enter the cell cycle and whether the cell cycle induction is related to the
      oncogene expression. Complement activation and TCC assembly induced expression of
      c-jun, JunD, and c-fos mRNAs, increased AP-1 DNA-binding activity within 1 h, and
      increased [3H]thymidine uptake. The c-jun NH2-terminal kinase activity was
      increased to the maximum level 20 min after TCC assembly. The increase in
      thymidine uptake was inhibited by pretreatment of OLG with antisense c-jun
      oligonucleotides. Studies on cyclin-dependent kinase (cdk) activation revealed
      that complement increased cyclin-dependent cell cycle associated kinase-2
      activity in G1, while cdk2 and cdk4 showed low activity during G1 progression.
      However, the activity of cdk4 complexed with cyclin D2 showed a marked increase
      in G1/S transition. Our data provide evidence that sublytic TCC stimulate OLG to
      enter the cell cycle by induction of c-jun through activation of the c-jun NH2
      terminal kinase pathway. In addition, sublytic TCC assembly significantly reduced
      the number of OLG undergoing apoptotic cell death, which occurs spontaneously in
      defined medium. These changes together with enhanced degradation of myelin
      protein mRNA may represent a mechanism for differentiated primary OLG to respond
      to limited complement activation in inflammation.

PMID- 8648140
TI  - Down-regulation of secretion of human complement component C2 by the product of
      an alternatively spliced C2 messenger RNA.
AB  - We have previously described alternatively spliced transcripts of the human C2
      gene. Among those, C2delta(17), in which exon 17 has been spliced out, encodes a
      polypeptide that contains the C4b binding and the CIs cleavage sites of C2, but
      lacks the serine protease active center. To study the possible function of this
      variant, we constructed C2delta(17) cDNA by deletional mutagenesis and expressed
      it transiently in COS cells. Transfected COS cells secreted only trace amounts of
      the C2delta(17) polypeptide, which had no detectable hemolytic activity and could
      not be cleaved by CIs. Pulse-chase experiments using [35S]methionine demonstrated
      that the majority of the 88-kDa C2delta(17) remained intracellular. Control wild
      type (wt) C2 in the intracellular compartment consisted of two bands of 93 and 99
      kDa, the latter corresponding to mature secreted C2. Intracellular C2delta(17)
      and only the 93-kDa wt C2 were sensitive to endoglycosidase H, a marker for
      transport from the endoplasmic reticulum (ER) to the Golgi. Experiments using
      brefeldin A and double label immunofluorescence staining indicated that
      C2delta(17) exhibited a typical ER distribution pattern, while wt C2 accumulated
      in the ER-Golgi intermediate compartment. Secretion of C2 by COS cells
      cotransfected with wt C2 and C2delta(17) cDNA was significantly decreased
      compared with that by cells transfected with wt C2 alone. These combined results
      indicate that C2delta(17) is retained in the ER probably because it is
      incorrectly folded and that it could down-regulate the expression of the wt C2
      gene.

PMID- 8648141
TI  - Characterization of murine intercellular adhesion molecule-2.
AB  - Rat mAbs were raised against murine intercellular adhesion molecule-2 (ICAM-2).
      Immune precipitation and purification reveal that the murine ICAM-2 glycoprotein
      is 55 kDa and is similar in size to human ICAM-2. ICAM-2 is expressed on a
      variety of leukocyte cell lines, including T and B lymphoma, mastocytoma, and
      macrophage lines. ICAM-2 is well expressed on endothelioma cell lines, and in
      contrast to ICAM-1, expression is not increased by inflammatory cytokines. One of
      the mAb to ICAM-2 partially or completely inhibits binding of cells expressing
      LFA-1 to purified ICAM-2, and binding of cells expressing ICAM-2 to purified LFA
      1. The findings in the mouse are congruent with those in the human, suggesting
      functional conservation of ICAM-2 across species.

PMID- 8648142
TI  - Inhibition by CTLA4Ig of experimental allergic encephalomyelitis.
AB  - B7-1 and B7-2 are well characterized costimulatory ligands on Ag presentation
      cells for the CD28 and CTLA4 receptors on T cells. The fusion protein CTLA4Ig can
      block this interaction and prevent specific T cell activation. The development of
      fatal CD4+ T cell-mediated experimental allergic encephalomyelitis (EAE) in
      susceptible female Lewis rats was optimized by immunization with 20 mg of guinea
      pig spinal cord homogenate in CFA on day 0 with three doses of 1 microgram
      pertussis toxin given i.v. on days 0, 3, and 7. This immunization regimen
      uniformly resulted in the development of severe clinical neurologic signs of EAE
      with 100% mortality by day 17 postimmunization. Treatment with 0.5 mg/dose of
      rhCTLA4-Ig on days - 2, 0, 3, 6, 9, 12, 15 and 18 significantly decreased the
      incidence, delayed the onset, and reduced the severity of clinical EAE (p =
      0.0002 vs control by the Mann-Whitney U test) enough to completely prevent fatal
      EAE, whereas treatment with control human IgG had no effect. Histologically,
      perivascular neutrophilic infiltrates were also dramatically decreased in the
      spinal cords of animals treated with CTLA4 but not in those treated with control
      human IgG. The proliferative response to encephalitogenic Ags (guinea pig myelin
      basic protein and proteolipid protein) by lymph node cells from animals immunized
      with guinea pig spinal cord 10 days before was also significantly suppressed in
      vitro by CTLA4Ig (1 microg/ml). However, the protective effect of CTLA4Ig could
      be completely prevented by the daily i.p. administration, from day 0 to 10, of
      exogenous human rIL-2 (180,000 IU). These results indicate a critical requirement
      of the costimulatory B7/CD28 pathway early in the development of CD4+ T cell
      mediated EAE in the rat.

PMID- 8648143
TI  - Tolerance to rat liver allografts. III. Donor cell migration and tolerance
      associated cytokine production in peripheral lymphoid tissues.
AB  - The aim of this work was to investigate the mechanism of spontaneous rat liver
      allograft tolerance. Liver allografts from a LEW donor into DA recipient (LEW-
      >DA) or of PVG-->DA were spontaneously tolerated (TOL) across a complete MHC
      mismatch. In contrast, DA-->LEW or PVG-->LEW liver allografts were rejected in 10
      to 15 days (REJ). We examined whether donor cell migration to recipient lymphoid
      tissues might be associated with TOL. Many donor cells were observed in draining
      (celiac) lymph nodes (LN) and spleen, reaching a peak on day 1 and then
      decreasing rapidly thereafter. Irradiation of liver donors, which we have
      previously shown to delete tolerance, significantly reduced the number of donor
      leukocytes in recipient lymphoid tissues. While this suggested an association
      between donor cell migration and tolerance, the number, distribution, and type of
      donor cells in recipient lymphoid tissues of REJ was similar to those of TOL.
      Expression of cytokine mRNA in LN and spleen showed an early increase in the
      expression of IL-2 and IFN-gamma mRNA on day 1 and then a rapid decrease to
      constitutive levels. Spleen and LN levels of IL-6, IL-10, TNF-alpha, or TGF-beta
      mRNA showed much less up-regulation than IL-2 or IFN-gamma. Paradoxically, there
      was greater expression of IL-2 and IFN-gamma mRNA in TOL lymphoid tissues than in
      REJ, and this superinduction was partially prevented by donor irradiation.
      Superinduction of IL-2 and IFN-gamma was, therefore, more closely associated with
      TOL than was donor cell migration. This was confirmed by treatment of TOL
      recipients with a short course of methylprednisolone, which reduced survival of
      subsequent donor strain skin grafts. This finding has implications for treatment
      of human liver transplants and is evidence for a novel pathway of transplant
      tolerance.

PMID- 8648144
TI  - beta2-microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr
      mice.
AB  - MRL-lpr/lpr mice develop a distinctive immunologic disease characterized by
      accumulation of unusually large numbers of T cells in the peripheral lymphoid
      organs. Most of the accumulating T cells express an alpha beta-TCR but are
      peculiar in that they express neither CD4 nor CD8 co-ligands. Concurrent with
      lymphoaccumulation of such double negative (DN) T cells, MRL-lpr/lpr mice develop
      a lethal systemic lupus erythematosus-like autoimmune syndrome. This study
      focuses on the role of MHC class I molecules in this latter pathologic process.
      Highly backcrossed class I molecule-deficient MRL and MRL-lpr mice carrying a
      functionally defective allele of the gene beta 2-microglobulin (B2m) were
      produced. Class I deficient MRL-lpr/lpr mice demonstrated a substantial reduction
      in DN T cells, confirming other reports indicating that most DN T cells arise
      from progenitors positively selected on MHC class I molecules. Significantly,
      class I-deficient MRL-lpr/lpr mice also demonstrated a diminution of every
      autoimmune disease indicator analyzed including hypergammaglobulinemia;
      autoantibodies including anti-DNA, anti-Smith antigen, and rheumatoid factor; and
      glomerulonephritis. The results indicate that class I-dependent T cells are
      crucial not only for the development of DN T cells, but for multiple features of
      the MRL-lpr/lpr systemic lupus erythematosus syndrome. Moreover, the pattern of
      hypergammaglobulinemia suggests that the requirement for MHC class I proteins is
      restricted temporally to later stages of the disease.

PMID- 8648145
TI  - Exploitation of the Vbeta8.2 T cell receptor in protection against experimental
      autoimmune encephalomyelitis using a live vaccinia virus vector.
AB  - This study takes advantage of the predominant usage of Vbeta8.2 by the TCRs of
      encephalitogenic T cells specific for myelin basic protein. Vaccinia virus
      recombinants expressing Vbeta8.2 (VVbeta8.2) 8.2) and Vbeta3 (VVbeta 3) proteins
      were constructed, and their abilities to confer protection against experimental
      autoimmune encephalomyelitis (EAE) induction in H-2u mice were examined. Mice
      immunized with VVbeta8.2 developed very mild EAE by comparison with mice that
      were vaccinated with VVbeta3, which developed severe clinical symptoms. This
      reduction in EAE correlated with a diminished T cell proliferative response to
      myelin basic protein in the mice that received VVbeta8.2 compared with that in
      mice receiving VVbeta3.

PMID- 8648146
TI  - Pathogenic role of anti-endothelial cell antibodies in vasculitis. An idiotypic
      experimental model.
AB  - Idiotypic manipulation of naive mice has previously been used for induction of
      systemic autoimmune diseases (e.g., antiphospholipid syndrome, systemic lupus
      erythematosus, and Wegener's granulomatosis). The aim of this study focused on
      the utilization of this technique to induce the production of anti-endothelial
      cells Abs (AECA) and autoimmune vasculitis in a murine model. AECA were derived
      from a Wegener's granulomatosis patient's plasma. IgG was purified by absorption
      on a proteinase-3 affinity column resulting in the depletion of anti-neutrophil
      cytoplasmic Ab activity. The absorbed IgG fraction displayed a high titer of AECA
      as evidenced by a cyto-ELISA against unfixed human umbilical vein endothelial
      cells. BALB/c mice were actively immunized with the purified AECA. Three months
      after a boost injection with the human AECA, mice developed endogenous AECA (AB),
      but not Abs to proteinase-3, cardiolipin, or DNA. Histologic examination of lungs
      and kidneys revealed both lymphoid cell infiltration surrounding arterioles and
      venules; as well as deposition of Igs at the outer part of blood vessel walls.
      This experimental animal model of vasculitis, a product of our method of
      idiotypic manipulation, provides the first direct proof for the pathogenicity of
      AECA.

PMID- 8648147
TI  - Enhanced expression of IL-12 associated with Th1 cytokine profiles in active
      pulmonary sarcoidosis.
AB  - Sarcoidosis is a multisystem granulomatous disease of unknown etiology
      characterized by the expansion of activated oligoclonal CD4+ T cells and
      macrophages at sites of disease. To investigate the immunopathogenesis of
      sarcoidosis, we analyzed patterns of cytokine expression in bronchoalveolar
      lavage cells and fluid from patients with pulmonary sarcoidosis and idiopathic
      pulmonary fibrosis and from normal volunteers. We found dominant type 1 cytokine
      expression, with elevated mRNA and protein levels of IFN-gamma, but not IL-4, in
      sarcoid lung cells and fluid compared with those in normal samples. To define
      immunoregulatory mechanisms important to this type 1 response, we analyzed the
      expression of IL-12 and IL-10 in lung cells and fluid. Using semiquantitative
      PCR, we found significantly higher mRNA expression of the regulated IL-12 p40
      subunit, but not IL-10, in sarcoid compared with normal lung cells. Consistent
      with these observations, strikingly elevated levels of p40 protein were found in
      sarcoid compared with normal bronchoalveolar lavage fluid. Unstimulated and
      Staphylococcus aureus-stimulated sarcoid alveolar macrophages produced greater
      amounts of IL-12 than normal alveolar macrophages when cultured in vitro. We
      hypothesize that sarcoidosis is a Th1-mediated disease driven by chronic,
      dysregulated production of IL-12 at sites of disease.

PMID- 8648148
TI  - Restriction of the TCR repertoire inhibits the development of memory T cells and
      prevents autoimmunity in lpr mice.
AB  - The lpr mutation, a disruption of the fas gene, induces spontaneous autoimmunity
      characterized by high titers of autoantibodies, lymphadenopathy, autoreactive T
      cells, and early mortality. The mechanism of autoimmunity, however, remains
      unknown. The driving force for disease could result from the T cell recognition
      of autoantigen or, alternatively, an intrinsic T cell defect that promotes
      autoreactivity. We investigated the role of antigen-TCR interaction in the
      pathogenesis of lpr autoimmunity by transferring the DO-11.10 TCR beta-chain
      transgene (Vbeta8.2-Dbeta1.1-Jbeta1.1) to the MRL-lpr/lpr background producing
      the MRL-lprbeta strain. Our results show that the MRL-lpr beta transgenic strain
      has increased survival, lower titers of autoantibodies, and decreased
      lymphadenopathy compared with nontransgenic littermates. These beneficial effects
      were associated with decreased expansion of CD4+ T cells expressing memory
      phenotypes (CD44+, CD45RB-, and LECAM-) in the transgenic compared with
      nontransgenic strains. A role for impaired recognition of autoantigen by T cells
      expressing the TCR transgene was suggested by comparing the phenotypes of
      Vbeta8.2+ (transgene+) vs Vbeta8.2- (transgene-) CD4+ T cells within the
      transgenic mice. These experiments show that Vbeta8.2- T cells, which express
      endogenously rearranged TCR, are the major contributors to the expansion of
      memory T cells in the transgenic mice. In contrast, T cells with memory
      phenotypes expand similarly in both the Vbeta8.2+ and Vbeta8.2- subsets of
      nontransgenic mice. Based on these results, we hypothesize that TCR recognition
      of autoantigen is a major contributor to autoimmunity in lpr mice and that T
      cells expressing a memory phenotype are perpetrators of this process.

PMID- 8648149
TI  - Release of bactericidal/permeability-increasing protein in experimental
      endotoxemia and clinical sepsis. Role of tumor necrosis factor.
AB  - Bactericidal/permeability-increasing protein (BP]) is contained within the
      azurophilic granules of neutrophils and is able to neutralize endotoxin and kill
      Gram-negative bacteria. TNF has been implicated as a mediator of endotoxin
      induced neutrophil degranulation. To assess the role of TNF in the elevated BPI
      levels during sepsis, the following studies were performed. 1) In 31 consecutive
      patients with sepsis syndrome, plasma BPI levels were markedly elevated compared
      with those in healthy controls, but showed no correlation with simultaneously
      measured TNF concentrations. 2) In four healthy men, i.v. injection of
      recombinant human TNF (50 microg/m2) induced a rapid rise in plasma BPI levels.
      3) In eight normal subjects, i.v. administration of Escherichia coli endotoxin (4
      ng/kg) elicited subsequent increases in the plasma concentrations of TNF and BPI.
      4) Eight healthy chimpanzees were investigated after i.v. injection of endotoxin
      (4 ng/kg); four animals received endotoxin only, and four animals received an
      anti-TNF mAb simultaneously. Although anti-TNF completely prevented the endotoxin
      induced appearance of TNF activity, the rise in BPI levels remained unaltered.
      These results suggest that TNF is not critical for the release of BPI from
      neutrophils during experimental endotoxemia or clinical sepsis.

PMID- 8648150
TI  - Health care delivery--the roads not taken.

PMID- 8648151
TI  - Evaluation of serum lipid profile and cardiac enzyme changes in cerebrovascular
      accidents.
AB  - Serum lipid profile is, total cholesterol, high density lipoprotein (HDL), low
      density lipoprotein (LDL) and triglycerides and serum cardiac enzymes ie,
      creatinine phosphokinase (CPK), creatinine phosphokinase isoenzyme MB (CPK-MB),
      lactate dehydrogenase (LDH) and serum aspartate aminotransferase (AST/SGOT)
      levels were estimated in 50 cases of cerebrovascular accidents (CVA) consisting
      of 26 cases of cerebral haemorrhage and 24 cases of cerebral thrombosis. All
      analyses were made on day 1 and day 7. Serum cholesterol, LDL and triglycerides
      levels were significantly higher in CVA patients on day 1. Lipid level fell
      significantly on day 7 in respect to day 1. On comparing the lipid levels between
      cerebral haemorrhage and cerebral thrombosis, no significant difference was
      observed. Cardiac enzymes like CPK and CPK-MB were significantly raised whereas,
      AST/SGOT and LDH were marginally raised on day 1 in CVA patients. However, there
      was no change in cardiac enzyme levels between cerebral haemorrhage and cerebral
      thrombosis patients.

PMID- 8648152
TI  - Non-sporing anaerobes in certain surgical group of patients.
AB  - The magnitude of non-sparing anaerobic (NSA) infections has been defined in the
      postoperative wounds on colorectum in children (57.1%), general surgery (0%),
      abdominoperineal and uterocervical operations (11-45%) in gynaecologic and
      obstetrical cases and perforative peritonitis (25.8-32.3%). Children below the 6
      months age group bear less risk of acquiring NSA infection. Under certain
      situations, metronidazole combats NSA infections in a better way than other
      antibacterials. The bacteriology of NSA infections has been probed at the species
      level in the gynaecologic and obstetrical patients. The species of normal cervix
      (44.6%) are represented in wounds involving abdominal wall (11%), perineum
      (22.8%) and uterocervix (45.6%) to suggest endogenous infection. Out of the 22
      species of NSA isolated, Peptostreptococcus anaerobius, Acidaminococcus
      fermentans and Peptococcus prevotii are the commonest. Others were Peptococcus
      niger, Gaffkya anaerobia, Lactobacillus bulgaricus, Actinomyces bovis,
      Bacteroides oralis, Fusobacterium gonidiaformans and the different species of
      peptococcus, peptostreptococcus, eubacterium, propionibacterium and
      fusobacterium. The weight of evidence indicated a pathogenic role of
      Peptostreptococcus anaerobius and Ruminococcus flavefaciens, in view of their
      heavy growth. The umbrella of antibacterials reduced Gram-positive anaerobic
      cocci from 40% to 16%. The facultative anaerobes Staph aureus, Staph epidermidis,
      Kl pneumoniae and proteus appeared as the exogenous agents of nosocomial
      infections.

PMID- 8648153
TI  - Pattern of descent of foetal head in normal labour.
AB  - The phenomenon of foetal head descent and the effect of station of foetal head at
      admission on the course of labour were studied on the basis of a prospective
      partographic study in 100 cases of normal labour. Only 16.9% of nulliparous women
      had engaged foetal head at admission in labour. Engagement of foetal head
      occurred during the period of maximum slope of cervical dilatation in nulliparous
      women and at the onset of deceleration phase in multiparous women. Parturients
      with unengaged foetal head entered hospital much earlier in labour than those
      with engaged foetal based. Course of labour was uninfluenced by the degree of
      engagement of foetal head. However, multiparous women showed faster rate of
      foetal head descent than nulliparous women (p < 0.001) and women with lesser
      haemoglobin concentration demonstrated slower rate of descent of foetal head (p <
      0.01).

PMID- 8648154
TI  - Cytopathology of neuroblastoma, ganglioneuroblastoma and ganglioneuroma.
AB  - Four cases of neuroblastomas, two cases of ganglioneuroblastomas and one case of
      ganglioneuroma diagnosed by fine needle aspiration cytology (FNAC) are presented.
      Five tumors were in the retroperitoneum and two tumors occurred in the posterior
      mediastinum. Complete clinical history, physical examination, radiological
      investigation, laboratory parameters, cytological study of multiple slides aided
      with special stains and cell block preparation of aspirated material helped in
      diagnosis of these tumours. Cytohistopathological correlation was carried out
      from surgically resected specimens and from autopsy studies.

PMID- 8648155
TI  - Cystoscopy in cases of carcinoma of the cervix uteri: clinical experience with 85
      cases.
AB  - A retrospective study involving 85 cases of cystoscopy carried out between
      December, 1989 and July, 1992 in selected cases of carcinoma cervix was
      undertaken with the purpose of determining the place of cystoscopy in this
      condition. Cystoscopy was performed only when there was a clinical suspicion of
      the urinary bladder being involved. Of 67 cases in which cystoscopy was performed
      as part of staging of carcinoma cervix, one was in stage II, 48 in stage III and
      18 in stage IV (stages determined prior to cystoscopy). On cystoscopy of the
      stage III cases, 50% showed apparent involvement of bladder, 29.17% showed
      suspicious findings and 20.83% showed negative findings. Of the stage IV cases,
      61.11% showed apparent involvement of bladder, 33.33% showed suspicious findings
      and 5.56% showed negative findings. Of 13 cases in which biopsy was taken
      cystoscopically, 8 were histologically positive, 4 were histologically negative
      and one was histologically suspicious for malignancy of the urinary bladder. In
      the remaining 18 cases cystoscopy was performed during follow-up period.

PMID- 8648156
TI  - Rational drug use--evaluation of a training programme for interns.
AB  - A workshop covering various aspects of rational drug use was conducted for
      interns of Christian Medical College, Ludhiana. Evaluation of the workshop
      revealed that it was able to bring about an attitudinal change regarding rational
      drug use. The methodology and evaluation procedures have been described. It is
      suggested that similar attempts should be made at all medical colleges so that
      every graduate enters medical practice with a positive attitude towards rational
      drug use.

PMID- 8648157
TI  - Place of transvaginal sonography in the evaluation of reproductive endocrinology.
AB  - A high frequency vaginal probe with improved resolution offers a remarkable sharp
      clear image of pelvic organs. This is possible because of its closed proximity
      with target organ and non-intervention by gut or omentum. Study of ovarian
      follicular dynamics (folliculometry), identification of proliferative, secretory
      and decidual changes of endometrium (endometrial dating) in different phases of
      menstrual cycle and imaging of mucus secretion in the cervical canal (cervical
      mucus study) in the pre-ovulatory phase is possible by transvaginal probe. It is
      non-invasive, acceptable to patients, and thus can be repeated any number of
      times. A close serial monitoring offers immense wealth of information about the
      anatomical as well as reproductive endocrinal status of the patient. Ovulation
      can be predicted in advance. The case of dysovulation can be identified in first
      cycle of study; corrective therapy can be started in another two or three cycles,
      aiming at achieving perfect folliculogenesis. Once well tuned synchronised cycle
      is restored, the pregnancy outcome is remarkable. Thus transvaginal sonography
      offers one of the best reproductive endocrinology evaluation in the hand of a
      modern gynaecological sonologist and infertility specialist.

PMID- 8648158
TI  - Acute respiratory infections with special reference to pneumonia in underfives.

PMID- 8648159
TI  - Idiopathic thrombocytopenic purpura in Hodgkin's lymphoma.

PMID- 8648160
TI  - An unusual foreign body obstructing endotracheal tube connector.

PMID- 8648161
TI  - Hypokalaemic periodic paralysis associated with thyrotoxicosis.

PMID- 8648162
TI  - Massive oedema of the ovary.

PMID- 8648163
TI  - Teratoma of the placenta.

PMID- 8648164
TI  - Malignant mixed muellerian tumour of uterus.

PMID- 8648165
TI  - Characterization of an immortalized cell line from a patient with epidermolytic
      hyperkeratosis.
AB  - The most frequent mutation that causes the autosomal dominant skin disease
      epidermolytic hyperkeratosis (EHK) is an arginine to histidine substitution at
      position 10 in the 1A segment of the rod domain of keratin 10. As an initial step
      toward developing a strategy for treating EHK, a cell line, EH18-1, was
      established after keratinocytes derived from an EHK patient with this mutation
      were immortalized by a recombinant retrovirus encoding the E6 and E7 genes of
      human papillomavirus type 18. EH18-1 cells synthesize considerable amounts of
      keratin 10 mRNA and protein when maintained in either submerged cultures or in
      organotypic cultures. When grown in organotypic culture, EH18-1 cells form
      multiple layers and express keratin 10 and filaggrin predominantly in the upper
      layers. Thus, the EH18-1 cell line exhibits several morphological and biochemical
      markers of terminal epidermal differentiation. A semiquantitative reverse
      transcriptase polymerase chain reaction assay for keratin 10 mRNA was developed
      to distinguish between expression of the normal and the mutant alleles. The EH18
      1 keratinocyte cell line will be useful in developing protocols for gene therapy
      of EHK that may be monitored by reverse transcriptase polymerase chain reaction
      of either allele.

PMID- 8648166
TI  - Growth factor and growth factor receptor localization in the hair follicle bulge
      and associated tissue in human fetus.
AB  - The bulge region of the hair follicle has been thought to contain follicular stem
      cells. The bulge in the human follicle is a collection of undifferentiated cells
      that is prominent only in the fetal period. Antibodies that recognize epidermal
      growth factor (EGF), transforming growth factor-alpha (TGF-alpha), EGF receptor,
      platelet-derived growth factor (PDGF) A and B chains, PDGF alpha and beta
      receptors, and the low-affinity nerve growth factor receptor (p75) were used to
      study the bulge and associated mesenchymal cells in this fetal period. Weak EGF
      and TGF-alpha immunoreactivities were seen in the bulge. Confocal laser scanning
      microscopic images revealed intracytoplasmic and intranuclear punctate patterns
      of immunoreactivities in the bulge cells labeled by anti-EGF and anti-TGF-alpha
      antibodies. All the bulge cells stained strongly for EGF receptor. Cells within
      the bulge were labeled both with PDGF A chain and with PDGF B chain, although the
      immunoreactivities were weak in the outermost layer of cells. The follicular
      sheath was strongly immunoreactive with antibodies against both PDGF alpha and
      beta receptors. p75 was expressed in mesenchymal cells around the hair follicle
      and in the lower portion of the bulge. These differential labeling patterns
      suggested that EGF, TGF-alpha, and nerve growth factor may be involved in
      regulation of the growth and differentiation of bulge cells and that PDGFs may
      have related functions in the interaction arising between the bulge and
      associated tissue during follicle morphogenesis.

PMID- 8648167
TI  - Barrier disruption stimulates interleukin-1 alpha expression and release from a
      pre-formed pool in murine epidermis.
AB  - Previous studies have shown that barrier disruption increases epidermal mRNA
      levels of interleukin-1 alpha (IL-1 alpha). We used immunohistochemistry to
      examine IL-1 alpha expression in hairless mouse skin under basal conditions and
      following barrier abrogation. In untreated mice, IL-1 alpha was present in the
      dermis and nucleated epidermal layers in a diffuse, generalized pattern. In
      essential fatty acid deficient mice IL-1 alpha was present in all epidermal
      layers and the dermis, with prominent staining in the stratum corneum. After
      acute barrier disruption with tape-stripping, IL-1 alpha increased in the
      epidermis and dermis within 10 min, remained elevated at 2 and 4 h, and decreased
      to near basal levels by 24 h. Moreover, intense, perinuclear, basal cell staining
      appeared at 10 min, persisting until 4 h after barrier disruption. Since the
      increase in IL-1 alpha immunostaining after acute barrier abrogation precedes the
      increase in mRNA, we hypothesized that the IL-1 alpha might derive from a pre
      formed pool. Prolonged occlusion of normal skin, a treatment that specifically
      reduces epidermal mRNA levels of IL-1 alpha, decreased basal immunostaining for
      IL-1 alpha and blunted the increase in IL-1 alpha usually seen following barrier
      disruption. Moreover, tape-stripping of skin, maintained ex vivo at 4 degrees C,
      resulted in increased IL-1 alpha immunostaining within the upper nucleated
      epidermal layers, as well as release of mature IL-1 alpha into the medium, as
      measured by Western blotting and enzyme-linked immunosorbent assay. In addition,
      the stratum corneum attached to the tape contained IL-1 alpha. These studies show
      that acute barrier disruption induces both the immediate release and dispersion
      of IL-1 alpha from a pre-formed, epidermal pool, as well as increased IL-1 alpha
      synthesis; both mechanisms are consistent with a role for IL-1 alpha in the
      regulation of proinflammatory and homeostatic processes in the skin.

PMID- 8648168
TI  - Epidermal barrier ontogenesis: maturation in serum-free media and acceleration by
      glucocorticoids and thyroid hormone but not selected growth factors.
AB  - Because the cutaneous permeability barrier develops late in gestation,
      prematurity may result in increased morbidity and mortality due to barrier
      incompetence. The purpose of the present study was to develop an in vitro model
      of barrier ontogenesis in order to identify those factors critical for fetal
      barrier formation. Skin explants from gestational day 17 fetal rats (term is 22
      days) were incubated in hormone- and serum-free media. After 4 d in culture, a
      multi-layered stratum corneum (SC) developed that demonstrated a membrane pattern
      of fluorescence using the hydrophobic probe, nile red, and the deposition of
      mature lamellar unit structures throughout the SC interstices, ultrastructurally.
      Transepidermal water loss rates declined during explant culture such that after 4
      d a competent barrier was present. Similarly, lanthanum permeation studies showed
      tracer penetration into all cell layers in 2-d explants, whereas it did not
      penetrate above the stratum granulosum in 4-d explants. Thus, the chronology of
      epidermal development in the explants precisely mirrored that observed in utero.
      Treatment with either 10 nM dexamethasone or 10 nM triiodothyronine accelerated
      SC development and barrier formation by 2 d. These results indicate that (i) the
      late events of fetal epidermal development progress in vitro under serum- and
      growth factor-free conditions, culminating in the formation of a functional
      barrier, and (ii) both dexamethasone and triiodothyronine accelerate barrier
      development.

PMID- 8648169
TI  - Increased oligonucleotide permeability in keratinocytes of artificial skin
      correlates with differentiation and altered membrane function.
AB  - We tested the permeability of fluorescent oligonucleotides in cultured human
      epidermal keratinocyte monolayers and keratinocytes grown in a 3-dimensional skin
      model. Oligonucleotide permeability in living cells was determined by confocal
      microscopy after either simple addition to the culture medium or topical
      application via oligonucleotide-saturated filters placed atop the artificial
      skin. In cultured monolayers, few keratinocytes (9%) were found to acquire
      intracellular oligonucleotides that were primarily localized to the nucleus. In
      contrast, keratinocytes grown in an artificial, 3-dimensional skin matrix
      acquired extensive oligonucleotide permeability as differentiation progressed.
      About 95% of the granular cells showed nuclear accumulation of oligonucleotides.
      About 70% of the oligonucleotide-permeable granular cells were viable as verified
      by a mitochondria-specific, potential-sensitive dye, tetramethyl rhodamine ethyl
      ester. A marker used to study apoptotic cells with altered membrane potential,
      merocyanine 540, was found elevated in the cytoplasm of granular cells. In
      contrast, cultured keratinocyte monolayers or basal keratinocytes of skin showed
      a membrane staining pattern typical of undifferentiated cells. Few cells (<3%) of
      the basal layer had nuclear oligonucleotides, but none of the labeled cells were
      viable. These results suggest that the development of oligonucleotide and
      merocyanine 540 permeability in differentiated granular cells parallels the
      changes in membrane permeability found in other apoptotic systems.

PMID- 8648171
TI  - Constitutive nitric oxide synthase is present in normal human keratinocytes.
AB  - Normal human keratinocytes in culture exhibit a nitric oxide synthase (NOS)
      activity ranging from 50 to 150 pmol/min/mg of protein. The enzyme is cytosolic
      and requires the presence of calcium, nicotinamide adenine dinucleotide
      phosphate, reduced form (NADPH), and flavin adenine dinucleotide. Calmodulin
      antagonists (trifluoperazine and calmidazolium) inhibit the enzyme activity. We
      show that NG-nitro-L-arginine inhibits NOS more potently than NG-monomethyl-L
      arginine and that L-canavanine is a weak inhibitor. NOS was partially purified
      using a 2',5'-ADP Sepharose affinity column eluted with NADPH. A partially
      purified fraction was analyzed by sodium dodecyl sulfate-polyacrylamide gel
      electro-phoresis and Western blotting. A protein with an apparent molecular
      weight of 152 kDa cross-reacted with monoclonal antibodies raised against the
      neuronal constitutive isoform of NOS. The enzyme had a Vmax of 7.3 nmol/min/mg of
      protein and a Km for L-arginine of 22.3 microM. These results indicate that
      normal human keratinocytes contain a constitutive nitric oxide synthase related
      to NOS I.

PMID- 8648170
TI  - Human dermal fibroblasts produce nitric oxide and express both constitutive and
      inducible nitric oxide synthase isoforms.
AB  - Nitric oxide (NO) is produced by a variety of human and animal cells and is
      involved in a broad array of physiological and pathophysiological processes. It
      can cause vasodilation, serve as a neurotransmitter, and have anti-neoplastic,
      anti-microbial, and anti-proliferative effects. In this study, we have
      demonstrated that fibroblasts derived from human skin spontaneously produce NO
      and that this production can be enhanced by stimulating the cells with interferon
      gamma and lipopolysaccharide. The production of NO by human dermal fibroblasts
      can be blocked by NG-monomethyl-L-arginine (L-NMMA). The inhibitory effect of L
      NMMA on NO production was restored by addition of L-arginine but not D-arginine.
      By measuring the rate of conversion of [14C]L-arginine to [14C]L-citrulline, we
      show that unstimulated cells expressed only Ca2+-dependent NO synthase (NOS)
      activity (1.36 +/- 0.57 pmol/mg/min; n = 4) whereas stimulated cells expressed
      both Ca2+-dependent (2.60 +/- 0.54 pmol/mg/min; n = 4) and -independent (1.59 +/-
      0.14 pmol/mg/min; n = 4) NOS activities. With reverse transcription polymerase
      chain reaction (RT-PCR), the 422-bp RT-PCR product for human endothelial
      constitutive NOS and the 462-bp RT-PCR product for human hepatocyte inducible NOS
      were detected in proportion to the amount of mRNA-related RT-cDNA added to the
      reaction mixture. Further evidence by immunocytochemistry demonstrated that human
      dermal fibroblasts express both constitutive and inducible NOS proteins. These
      data collectively suggest that in addition to macrophages and other inflammatory
      cells, nitric oxide production by dermal fibroblasts could be important during
      the inflammatory stages of wound healing and possibly also in the later stages of
      proliferation and tissue remodeling after skin injury in humans.

PMID- 8648172
TI  - Chromosome 17 allelic loss and NF1-GRD mutations do not play a significant role
      as molecular mechanisms leading to melanoma tumorigenesis.
AB  - Allelic loss in human cutaneous melanoma has been detected on chromosomes 1p, 6q,
      9p, 10q, and 11q. Chromosome 17 contains important tumor suppressor genes such as
      p53, NM23, and neurofibromatosis type 1 (NF1), which have been implicated in
      melanoma tumorigenesis. The role of p53 has already been studied by a number of
      laboratories, showing contrasting results. In the present study, two restriction
      fragment length polymorphism (RFLP) probes for the NM23 and NF1 genes, together
      with five other RFLP and four variable number of tandem repeat chromosome 17
      probes, were investigated at the loss of heterozygosity (LOH) level in a Southern
      blot-based assay. The NF1 gene was also tested for LOH by a polymerase chain
      reaction (PCR)-based approach in two different experiments, using a dinucleotide
      repeat polymorphic probe at locus D17S250 (17q11.2-q12), and an Alu probe
      intragenic to the NF1 gene (17q11.2). A PCR single-strand conformation
      polymorphism assay was included in the study for mutation detection at the NF1
      GTPase-activating protein-related domain (GRD). A total of 68 melanocytic tumors
      were analyzed. LOH was detected in 9 of 87 informative cases (10%). LEW301
      (17p11.2-pcen) presented the highest LOH frequency (22%). NM23 showed LOH in 17%
      of the informative cases, while NF1 did not show either LOH in the Southern blot-
      and PCR-based experiments or mutations at the NF1-GRD. These results are in
      concordance with those of previous smaller studies, but when compared with higher
      LOH frequencies obtained from other chromosomes, these findings indicate that the
      LOH values found in our study can most likely be attributed to background effect.
      Thus, chromosome 17 LOH is likely to play and unimportant role as a genetic event
      in melanoma tumorigenesis. Nevertheless, NF1 merits further study, since
      homozygous deletions have been detected at this locus in melanoma cell lines.

PMID- 8648173
TI  - Increased nuclear volume in metastasizing "thick" melanomas.
AB  - Tumor invasion is the most reliable prognostic factor for primary stage I
      melanoma. "Thick" melanomas, with a Breslow thickness of more than 4 mm, tend to
      have a poor prognosis. Exceptions occur: some patients have no further recurrence
      of tumor. In an attempt to determine prognostic markers for "thick" clinical
      stage I melanomas, we investigated the volume-weighted mean nuclear volume of
      primary melanomas with tumor invasions > or = 4.0 mm in 32 patients. Seventeen of
      these patients developed melanoma metastases within a follow-up period of 60 mo;
      15 patients who did not developed metastases and were comparable with regard to
      clinical and histological criteria were selected as a comparison group. Volume
      weighted mean nuclear volume (Vv) is determined by a technique that permits an
      unbiased, efficient, shape- and orientation-independent, 3-dimensional estimation
      of nuclear size in tissues. This technique has been employed successfully in the
      prognostic assessment of stage I and II melanomas and was recently proven to be a
      sensitive marker for thin, high-risk melanomas. In our patients, Vv was
      determined by computer-assisted image analysis on Feulgen-stained sections by
      stereologic estimation of the Vv. The mean Vv (+/-SD) of primary melanomas with
      subsequent metastatic course was 794.99 +/- 209.18 micron3 (range: 409.48-1161.9
      micron3), whereas primary melanoma lesions without subsequent metastases
      exhibited a mean Vv 640.54 +/- 205.07 micron3 (range: 206.7-927.48 micron3). This
      difference was found to be statistically significant (p = 0.0439). "Thick"
      melanomas with subsequent metastases thus exhibited a significantly higher Vv
      than did melanomas that did not metastasize.

PMID- 8648175
TI  - Immunomorphological and ultrastructural characterization of Langerhans cells and
      a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin
      of atopic eczema.
AB  - We investigated epidermal cell suspensions prepared from lesional and nonlesional
      atopic eczema skin, other inflammatory skin conditions, and normal human skin for
      high-affinity IgE receptor (Fc epsilon RI) expression on dendritic CD1a cells by
      quantitative flow cytometric analysis. A single CD1a bright/CD1b neg/Fc epsilon
      RI dim/CD23 neg/CD32 dim/HLA-DR bright/CD36 neg population was found in normal
      skin. In contrast, lesional skin of atopic eczema and other inflammatory skin
      diseases harbored variable proportions of two distinct CD1a populations. Both
      populations exhibited typical ultrastructural features of Langerhans cells, but
      the second one lacked Birbeck granules and was unreactive to the Birbeck granule
      specific LAG antibody. Both populations differed phenotypically: classical
      Langerhans cells were CD1a bright/CD1b neg/Fc epsilon RI dim/CD23 neg/CD32
      dim/HLA-DR bright/CD36 dim, while the second population was CD1a dim/CD1b dim/Fc
      epsilon RI bright/CD23 dim/CD32 dim/HLA-DR bright/CD36 bright. The highest Fc
      epsilon RI expression was found on the second CD1a population in lesional atopic
      eczema skin. Furthermore, Fc epsilon RI expression on CD1a cells correlated
      significantly with the serum IgE level of the patients. Thus, a distinct
      population of CD1a inflammatory dendritic epidermal cells different from
      classical Langerhans cells appears in the epidermis of lesional skin and is
      subjected to specific signals leading to the upregulation of Fc epsilon RI in
      atopic eczema skin.

PMID- 8648174
TI  - Interleukin-1 beta and granulocyte-macrophage colony-stimulating factor mediate
      Langerhans cell maturation differently.
AB  - It has been reported that the in vivo maturation of Langerhans cells after hapten
      painting is mediated by IL-1 beta while Langerhans cell maturation after in vitro
      culture is mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF).
      To clarify the reason for this discrepancy, we examine the expression of Ia
      antigen and several co-stimulatory molecules on Langerhans cells that were
      activated by in vitro culture, by hapten painting, or by an intradermal injection
      of several cytokines. Both cultured Langerhans cells and those activated by
      hapten painting increased the expression of Ia antigen and all the co-stimulatory
      molecules (i.e., intercellular adhesion molecule-1 [ICAM-1], B7-1, B7-2, and
      CD40). In contrast, an intradermal injection of interleukin-1 beta (IL-1 beta) or
      tumor necrosis factor-alpha (TNF-alpha) increased the expression of Ia antigen,
      ICAM-1, B7-2, and CD40, but not that of B7-1. These data indicate that IL-1 beta
      or TNF-alpha is not sufficient to induce B7-1 expression on Langerhans cells in
      vivo. Subsequently we examined the effect of anti-cytokine antibodies (Abs) on
      the expression of those molecules on cultured Langerhans cells. While none of the
      Abs to IL-1 beta, TNF-alpha, or GM-CSF changed the upregulation of Ia antigen,
      ICAM-1, or CD40 on cultured Langerhans cells, anti-GM-CSF Ab suppressed that of
      B7-1 and B7-2. Taken together, our present results suggest that IL-1 beta is
      required for the upregulation of Ia, ICAM-1, B7-2, and CD40, while GM-CSF is
      required for the upregulation of B7-1 and B7-2, although it still remains unclear
      why the injected GM-CSF could not augment B7-1 expression on Langerhans cells in
      vivo and why anti-IL-1 beta Ab did not suppress the upregulation of Ia, ICAM-1,
      or CD40 on cultured Langerhans cells.

PMID- 8648176
TI  - The improved organ maintenance of the human sebaceous gland: modeling in vitro
      the effects of epidermal growth factor, androgens, estrogens, 13-cis retinoic
      acid, and phenol red.
AB  - We have previously reported that human sebaceous glands can be maintained for up
      to 14 d as whole organs with full retention of the physiological rate and pattern
      of new cell formation, but we have also reported that the newly formed cells did
      not differentiate normally, causing a progressive loss of lipogenesis in vitro.
      We now show that this abnormal sebocyte differentiation was attributable to the
      presence of epidermal growth factor (EGF) and phenol red in our maintenance
      medium. In their absence, human sebaceous glands apparently retain in vivo rates
      of cell division and lipogenesis over 7 d of maintenance in addition to a
      retention of in situ morphology. This is reversible on the re-addition of 10 ng
      EGF/ml and 10 mg phenol red/ml. The addition of 600 pM 17 beta-estradiol results
      in a significant fall in the rate of lipogenesis over 7 d of maintenance, without
      affecting the rate of cell division. This effect is apparently due to abnormal
      differentiation of newly formed sebocytes. Neither 1 nM testosterone nor 1 nM
      dihydrotestosterone (DHT) has any effect on rates of cell division of lipogenesis
      over 7 d. In the presence of phenol red, however, 1 nM testosterone or 1 nM DHT
      cause a significant reduction in the rate of lipogenesis over 7 d of maintenance.
      One micromolar 13-cis retinoic acid caused a significant reduction in the rate of
      lipogenesis over 7 d in both the presence and absence of phenol red. These
      findings show that we can model the physiological effects of steroids, EGF, and
      13-cis retinoic acid in vitro.

PMID- 8648177
TI  - Hairs from patients with maple syrup urine disease show a structural defect in
      the fiber cuticle.
AB  - Models for the surface of cuticle cells in hair fibers consist of a monolayer of
      fatty acids covalently bound to the underlying protein membrane by thioester
      linkages. The most prominent of these fatty acids is 18-methyleicosanoic acid
      (C21a), the synthesis of which requires the oxidative decarboxylation of
      isoleucine. Maple syrup urine disease (MSUD) is caused by an inherited deficiency
      in the enzyme branched chain 2-oxo acid dehydrogenase, which leads to the
      accumulation of branched chain alpha-keto-acids derived from the amino acids,
      leucine, isoleucine, and valine. Transmission electron microscopy studies of
      developing hair fibers show a structural defect in the fiber shaft in hair from
      patients with MSUD. This defect is confined to the cuticle of the fiber, where
      the cuticle membrane directly apposes the intercellular material. Thus, the
      defect indicates that C21a is located exclusively on the upper surface of fiber
      cuticle cells. Lipid analysis of MSUD hairs has demonstrated significant changes
      in the relative abundance of the covalently bound fatty acids and an almost
      complete absence of C21a, whereas there was little difference in the amino acid
      composition compared with normal hair. These results provide further evidence for
      the existence of the surface lipid monolayer and its crucial role in cellular
      adhesion.

PMID- 8648178
TI  - A novel subepidermal blistering disease with autoantibodies to a 200-kDa antigen
      of the basement membrane zone.
AB  - Several components of the basement membrane zone (BMZ) have been identified as
      antigenic targets in autoimmune bullous diseases. We report a novel disease with
      autoantibodies to a BMZ antigen that is different from the targets described so
      far. The patient suffering from this disorder showed tense bullae and severe
      mucous membrane involvement rapidly responding to oral tetracyclines and
      colchicine. Histopathologic findings resembled those of dermatitis herpetiformis.
      Direct immunofluorescence microscopy showed linear deposits of IgG and C3 at the
      BMZ. By indirect immunofluorescence studies on split human skin, using both 1 M
      NaCl and suction blistering for dermal-epidermal separation, IgG antibodies
      localized exclusively to the dermal side of the split. The antibodies were mainly
      of the IgG4 sub-class. By Western blot analysis of epidermal and dermal extracts,
      the patient's serum unequivocally reacted with a dermal antigen of 200 kDa. It
      did not recognize bullous pemphigoid antigens (the autoantigen of epidermolysis
      bullosa acquisita), purified preparations of laminin-1 and laminin-5, or the
      recently described 105-kDa BMZ antigen. By immunoblotting of concentrated
      conditioned SCC-25 medium, the patient's antibodies reacted with a band of 200
      kDa and several bands of lower molecular weight. No reactivity was seen with
      extracts of cultured human fibroblasts. By indirect immunogold electron
      microscopy, immunoreactants localized to the lower lamina lucida. After clearance
      of skin lesions, both indirect immunofluorescence and Western blot analysis
      became negative. This patient suffers from a novel autoimmune bullous disease
      with autoantibodies to a 200-kDa antigen of the BMZ.

PMID- 8648179
TI  - Identification and localization of insulin-like growth factor-binding protein
      (IGFBP) messenger RNAs in human hair follicle dermal papilla.
AB  - The role of the insulin-like growth factors (IGFs) in hair follicle biology has
      recently been recognized, although their actions, sites of production, and
      modulation by the insulin-like growth factor-binding proteins (IGFBPs) have not
      to date been defined. IGF-I is essential for normal hair growth and development,
      and may be important in regulation of the hair growth cycle. In many culture
      systems, IGF-I actions are modulated by the IGFBPs. Thus, if IGFBPs are produced
      in the human hair follicle, they may play a role in targeting IGF-I to its
      receptor or may modulate IGF-I action by interaction with matrix proteins. We
      have used in situ hybridization to localize messenger RNA for the six IGFBPs in
      anagen hair follicles. Anti-sense and sense RNA probes for the IGFBPs (IGFBP-1 to
      -6) were produced, and 5-micrometer sections of adult facial skin were probed.
      Messenger RNA for IGFBP-3, -4, and -5 were identified, with predominantly IGFBP-3
      and -5 mRNA found in the dermal papilla, and to a lesser extent IGFBP-4 mRNA.
      IGFBP-4 mRNA was also found at the dermal papilla/epithelial matrix border.
      Messenger RNAs for both IGFBP-4 and -5 were also demonstrated in the dermal
      sheath surrounding the hair follicle. Messenger RNAs for IGFBP-1, -2, and -6 were
      not identified. These studies demonstrate specific localization of IGFBP mRNAs in
      hair follicles, suggesting that they each play specific roles in the local
      modulation of IGF action during the hair growth cycle.

PMID- 8648180
TI  - Collagenase production is lower in post-burn hypertrophic scar fibroblasts than
      in normal fibroblasts and is reduced by insulin-like growth factor-1.
AB  - We recently demonstrated that the accumulation of extracellular matrix in post
      burn hypertrophic scarring (HSc) tissues is, in part, caused by an overexpression
      of mRNA for fibronectin, type I, and type III procollagen. Here, we report that
      five different fibroblast cell strains derived from HSc tissues are deficient in
      collagenase activity relative to paired fibroblasts from normal skin of the same
      patients. Quantitative analysis demonstrated significantly lower (52.5 +/- 16.8%
      vs 100 +/- 8.3%; n = 9; p < 0.05) collagenase activity in conditioned medium from
      HSc fibroblasts relative to that obtained from the control. The expression of
      collagenase mRNA was also significantly depressed (51 +/- 7% vs 100 +/- 11%; n =
      5; p < 0.05) in four of five strains of HSc fibroblasts examined. The level of
      mRNA for collagenase in both HSc and normal fibroblasts increased with serial
      passage, but at any given passage number, the expression of this transcript was
      lower in HSc fibroblasts. Insulin-like growth factor 1 (IGF-1), which is present
      at the site of HSc in high quantity, reduced collagenase mRNA but increased type
      I collagen mRNA expression in a time-dependent manner. The collagenase activity
      in conditioned medium derived from IGF-1-treated normal dermal fibroblasts was
      reduced (23.1 +/- 7.81% vs 100 +/- 6.6%; n = 7; p < 0.05). A significant
      reduction in collagenase mRNA and activity was also found in HSc fibroblasts
      following IGF-1 treatment. These findings suggest that IGF-1-induced suppression
      of collagenase mRNA and activity may be a mechanism by which IGF-1 promotes the
      development of post-burn HSc.

PMID- 8648181
TI  - Staurosporine induces a sequential program of mouse keratinocyte terminal
      differentiation through activation of PKC isozymes.
AB  - Staurosporine (stsp) induces assembly of cornified envelopes in mouse
      keratinocyte cultures. To clarify whether this effect is the consequence of a
      coordinated differentiation program similar to that observed in epidermis, we
      assessed the expression of multiple differentiation-specific markers in stsp
      treated keratinocytes. In medium containing 0.05 mM Ca2+, in which the basal cell
      phenotype is normally maintained, stsp induced dose-dependent increases in
      keratin 1, epidermal and keratinocyte transglutaminases, SPR-1, loricrin, and
      profilaggrin mRNA. Based on nuclear run-on analysis, stsp-mediated marker
      expression was found to be due at least in part to increased transcription. Since
      protein kinase C (PKC) activation is required for keratinocyte differentiation,
      we tested whether stsp influenced this signaling pathway. Stsp induced the
      translocation of multiple PKC isoforms from the cytosol to membrane and/or
      cytoskeletal fractions, inducing isozyme downregulation within 24 h. Moreover, AP
      1 DNA binding activity was elevated in stsp-treated keratinocytes, consistent
      with the notion that this agent influences keratinocyte-specific gene expression
      via the PKC pathway. Stsp-mediated marker expression was inhibited by the PKC
      inhibitor GF 109203X. In cells pre-treated with bryostatin 1 to selectively down
      modulate specific PKC isoforms, stsp-induced loricrin, filaggrin, and SPR-1
      expression was suppressed when PKC alpha, epsilon, and/or delta were
      downregulated, suggesting that these isozymes may be necessary for marker
      expression in response to this agent. Thus, in addition to its effects on
      cornified envelope assembly, stsp induces a coordinate program of differentiation
      specific keratinocyte gene expression that is mediated at least in part by the
      PKC signaling pathway.

PMID- 8648182
TI  - The opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor are
      present in human and mouse skin and tonically act to inhibit DNA synthesis in the
      epidermis.
AB  - Opioid peptides serve as tonically active negative growth factors in neural and
      non-neural cells, in addition to being neuromodulators. To investigate the
      involvement of opioids in homeostatic renewal of epithelial cells in the
      epidermis, mice were given systemic injections of the potent opioid antagonist,
      naltrexone (NTX) (20 mg/kg). Disruption of opioid-receptor interaction by NTX
      resulted in an elevation of 42 and 72% in DNA synthesis in skin from the dorsum
      and plantar surface of the hindfoot, respectively, within 2 h; response to NTX
      was dependent on the circadian rhythm in each region examined. Injection of the
      naturally occurring and potent opioid growth factor (OGF), [Met5]-enkephalin, at
      1 mg/kg depressed DNA synthesis in the dorsum and plantar surface by 42 and 19%,
      respectively, within 2 h; the effects of OGF complied with the pattern of
      circadian rhythm in each area of skin. The decreases in labeling index evoked by
      OGF were blocked by concomitant administration of the opioid antagonist, naloxone
      (10 mg/kg); naloxone alone at the dosage utilized had no influence on cell
      replicative processes. In tissue culture studies, OGF and NTX respectively
      depressed and elevated DNA synthesis. Both OGF and its receptor, zeta, were
      detected in all but the cornified layer of the epidermis in murine skin from the
      dorsum, plantar surface, pinnae, and tail. In addition, both peptide and receptor
      were observed in basal and suprabasal cells of the human epidermis. These results
      lead to the suggestion that an endogenous opioid peptide and its receptor are
      present and govern cellular renewal processes in the skin in a direct manner,
      regulating DNA synthesis in a tonically inhibitory, circadian rhythm-dependent
      fashion.

PMID- 8648183
TI  - Interkeratinocyte adherens junctions: immunocytochemical visualization of cell
      cell junctional structures, distinct from desmosomes, in human epidermis.
AB  - Vinculin and beta-catenin are intracellular attachment proteins linking
      transmembrane adhesion molecules (E-cadherin) to the actin microfilament
      cytoskeleton, thus participating in formation of cell-cell adherens junctions, or
      zonulae adherentes. This type of junction was only recently described in human
      epidermis due to the imprecise morphological criteria for its recognition. In
      this study, we investigated the relationship between the expression of the zonula
      adherens-associated proteins vinculin, beta-catenin, E-cadherin, and actin, on
      the one hand, and the presence of electron microscopically discernable structures
      in normal human epidermis on the other. Mouse jejunal epithelium with its orderly
      arrangement of various junctional structures served as a positive control. Simple
      and dual post-embedding immunogold labeling was performed on ultrathin sections
      of Lowicryl K4M and Lowicryl K11M embedded tissues. The overall distribution of
      the antigens in human epidermis was evaluated on frozen tissue sections using
      immunofluorescence and laser confocal scanning microscopy. Antibodies against
      proteins associated with desmosomes (i.e., keratins, desmoglein 1, and
      plakoglobin) were used as controls. Vinculin and beta-catenin were localized to
      junctional structures distinct from desmosomes, thus defining the presence of
      zonulae adherentes. Labeling of actin and E-cadherin was less clearly restricted
      to the junctions, but these two proteins were also co-expressed at zonulae
      adherentes and not at desmosomes. In human epidermis, zonula adherens-associated
      labeling was consistently detected near desmosomes, indicating the possibility of
      a functional relationship between the two types of junctions.

PMID- 8648184
TI  - Hyaluronic acid and dermatan sulfate are selectively stimulated by retinoic acid
      in irradiated and nonirradiated hairless mouse skin.
AB  - All-trans retinoic acid (RA) has been shown to enhance subepidermal repair in
      photoaged hairless mice. The current study assesses the effects of RA on the
      glycosaminoglycan (GAG) content in irradiated and nonirradiated mouse skin. Mice
      were exposed to ultraviolet B (UVB) for 10 wk, after which they were treated
      either with 0.05% RA or with an ethanolpolyethylene glycol 400 vehicle three
      times a week for 10 or 20 wk. When assessed at the end of 10 wk of UVB
      irradiation, the GAG content had doubled, without a change in the hyaluronic acid
      (HA) to dermatan sulfate (DS) ratio. When irradiation was discontinued, the GAG
      content decreased progressively until the end of the experimental period. This
      decline was totally inhibited by RA treatment and could be ascribed to a marked
      increase in hyaluronic acid (78%), whereas no significant change in DS was
      observed. In nonirradiated skin, however, topical RA increased GAG levels mainly
      by a pronounced increase in the content (50%) and the synthesis (40%) of DS. In
      untreated mice, the HA/DS ratio decreased significantly with age in both
      irradiated and nonirradiated mice. Interestingly, RA maintained this ratio only
      in animals exposed to UVB. In addition, there was a marked stimulation in the
      heparin content, up to approximately 20-fold, after irradiation, whereas the
      amount of heparin in both irradiated and nonirradiated skin increased about 2- to
      3-fold with RA treatment. In summary, the alterations induced in HA and DS
      contents in irradiated and nonirradiated skin indicate the specificity of the RA
      induced effects for the various GAGs.

PMID- 8648185
TI  - Stimulation versus inhibition of keratinocyte growth by 1,25-Dihydroxyvitamin D3:
      dependence on cell culture conditions.
AB  - 1,25-Dihydroxyvitamin D3 (1,25[OH]2D3) inhibits proliferation of keratinocytes in
      vitro and psoriatic epidermal cells in vivo and is considered to be a negative
      regulator of keratinocyte growth. It has been recently observed, however, that
      1,25(OH)2D3 and its active analogs stimulate epidermal proliferation after
      topical application in mice. In this study we show that 1,25(OH)2D3, depending on
      the culture conditions, can either stimulate or inhibit DNA synthesis in human
      keratinocytes. In cells cultured with 0.15 mM calcium in the absence or with low
      levels (0.1 ng/ml) of epidermal growth factor, exposure to 10(-11) - 10(-6) M
      1,25(OH)2D3 imposed cell cycle block in the late G1 phase. When keratinocytes
      were cultured in the presence of high extracellular calcium concentration (1.8
      mM), 1,25(OH)2D3 in concentrations of 10(-11) - 10(-9) M stimulated cell growth
      by increasing the proportion of cells entering S phase. 1,25(OH)2D3 also
      stimulated growth of keratinocytes cultured in low calcium concentrations when
      the cells were previously suspended for a short time in a semisolid medium.
      Growth stimulation was absent in the presence of the anti-E-cadherin antibody,
      which is known to inhibit calcium-dependent differentiation. These results
      suggest that keratinocytes committed to terminal differentiation by an elevation
      of calcium concentration or suspension in a semisolid medium respond to
      1,25(OH)2D3 with an increase in DNA synthesis. In contrast, proliferating
      undifferentiated keratinocytes may be the main target for the anti-proliferative
      activity of 1,25(OH)2D3.

PMID- 8648186
TI  - Retinoid induction of CRABP II mRNA in human dermal fibroblasts: use as a
      retinoid bioassay.
AB  - Cellular retinoic acid binding protein II (CRABP II) mRNA is selectively induced
      by all-trans retinoic acid in human skin and dermal fibroblasts. In order to
      determine whether this response can be used as a reliable measure of retinoid
      potency and activity, we treated human skin fibroblasts for 24 h with increasing
      concentrations of several natural and synthetic retinoids. CRABP II mRNA levels
      were measured by quantitative Northern blotting and compared, when possible, with
      those obtained after topical application of the same retinoids to human skin. All
      eight active retinoids tested induced a concentration-dependent CRABP II mRNA
      response in the fibroblast assay. In contrast, one known inactive retinoid (meta
      carboxy TTNPB), differing from the active form only in the position of the
      carboxyl substituent, failed to evoke a response. The fibroblast and human skin
      bioassays agreed with respect to relative potency and response amplitude for
      three of the three retinoids tested. Retinoic acid was approximately 10-fold more
      potent than retinal in both assays, suggesting that oxidation to retinoic acid
      underlies the activity of retinol in fibroblasts as well as in intact skin. In
      support of this hypothesis, treatment with liarozole, an inhibitor of P450
      mediated retinoic acid oxidative catabolism, significantly increased fibroblast
      CRABP II mRNA levels and potentiated the effects of retinol by 1.5-fold at
      concentrations at which it had no effect on its own. Taken together, these
      results identify the fibroblast CRABP II response as a reproducible measure of
      retinoid bioactivity with promise as a predictor of human skin responses and
      further suggest that metabolism is an important determinant of retinoid
      bioactivity in vivo.

PMID- 8648187
TI  - Squamous carcinoma cell lines fail to respond to 1,25-Dihydroxyvitamin D despite
      normal levels of the vitamin D receptor.
AB  - Squamous carcinoma cells (SCC) fail to differentiate under conditions that are
      favorable for the growth and differentiation of normal human keratinocytes. Human
      keratinocytes differentiate from a highly proliferative basal cell to a
      terminally differentiated cornified cell in culture in the presence of
      physiological levels of extracellular calcium. 1,25-Dihydroxyvitamin D
      (1,25[OH]2D3) potentiates this process. Previous studies have shown that the
      differentiation process in keratinocytes is associated with increased expression
      of the genes for involucrin and transglutaminase, the products of which
      participate in cornified envelope formation. The mRNA for involucrin and
      transglutaminase was not detected in the SCC lines studied (viz. SCC4, 12B2,
      12F2, A431, and HACAT) when they were grown in serum free medium. Addition of at
      least 2% fetal bovine serum for 48 h triggered the expression of these genes,
      which could then be maintained in the absence of serum. Serum was not required
      for induction of these genes in keratinocytes. In these cells, 1,25(OH)2D3
      stimulated the expression of involucrin and transglutaminase in a concentration
      dependent manner, while the SCC lines failed to respond to 1,25(OH)2D3 regardless
      of whether these cells had been pre-exposed to serum. An important factor that
      mediates 1,25(OH)2D3-stimulated gene expression is the vitamin D receptor, but
      vitamin D receptor mRNA levels in all the SCC lines examined were comparable to
      those in keratinocytes. Furthermore, the vitamin D receptor protein levels in SCC
      lines as assessed by ligand-binding analysis were comparable to those of
      keratinocytes. Thus, the mediators of 1,25(OH)2D3 action on gene expression other
      than the vitamin D receptor may be missing or defective in SCC lines, whereas the
      mediators of as yet undefined agents in serum may be better expressed in SCC
      lines than in keratinocytes. Our results indicate that, although SCC lines are
      capable of expressing the genes for the proteins involved in differentiation, the
      control of the expression of these genes by 1,25(OH)2D3 is abnormal in SCC
      despite the presence of a functional vitamin D receptor in concentrations
      equivalent to those in keratinocytes.

PMID- 8648188
TI  - Co-localized overexpression of GRO-alpha and IL-8 mRNA is restricted to the
      suprapapillary layers of psoriatic lesions.
AB  - Epidermal infiltration by polymorphonuclear cells is a prominent feature in
      psoriatic lesions. Expression of neutrophil-specific chemoattractants by lesional
      keratinocytes could play an important role in the regulation of this infiltration
      process. We therefore examined the mRNA expression of GRO-alpha, a well
      characterized peptide with neutrophil-specific activation profile in psoriatic
      lesions by in situ hybridization. Clusters of clearly detectable and in some
      cases highly abundant GRO-alpha hybridization signals could be demonstrated in
      the differentiated layers of psoriatic epidermis. The signals were clearly
      associated with keratinocytes, with no nearby neutrophils detectable by
      microscopic examination. When additional tissue sections of GRO-alpha-expressing
      lesions were examined with an interleukin-8/neutrophil-activating peptide-8 (IL
      8)-specific anti-sense probe, IL-8 expression was detectable and confined to
      areas also expressing GRO-alpha. Expression of both GRO-alpha and IL-8 is focally
      upregulated by an as yet unknown mechanism in lesional psoriatic keratinocytes,
      ultimately leading to neutrophil tissue infiltration. We suggest that the focal
      expression of GRO-alpha and IL-8 in the epidermal layers above the dermal
      papillae may be involved in the "squirting papilla" reaction described as a
      characteristic feature of psoriatic plaque-type lesions.

PMID- 8648189
TI  - Basement membrane proteoglycans are of epithelial origin in rodent skin.
AB  - Basement membrane proteoglycans in mammalian skin comprise at least one
      chondroitin sulfate proteoglycan and heparan sulfate proteoglycans, including
      perlecan. In this study, the origins of basement membrane chondroitin sulfate
      proteoglycan and perlecan were investigated both in vivo and in vitro. For in
      vivo experiments, pieces of newborn rat epidermis obtained by dispase treatment
      were grafted onto athymic nude mice. Three and six weeks after grafting,
      immunofluorescence analysis of the grafted skin was carried out, using monoclonal
      antibodies specific for rat basement membrane chondroitin sulfate proteoglycan
      and rat and mouse perlecan. While the isolated rat epidermis was shown to
      completely lack rat basement membrane chondroitin sulfate proteoglycan and rat
      basement membrane heparan sulfate proteoglycans, including perlecan,
      immunofluorescence staining of tissue sections from the grafted sites on mice
      demonstrated the presence of rat basement membrane chondroitin sulfate
      proteoglycan and rat perlecan on interfollicular and follicular basement
      membranes including that separating dermal papillae from adjacent hair follicle
      epithelium. In contrast, the basement membranes of all dermal capillaries were
      positive for mouse perlecan, but negative for rat basement membrane chondroitin
      sulfate proteoglycan and rat perlecan, including the basement membranes of
      papillary dermal capillaries beneath the rat epidermis. These data suggest that
      basement membrane proteoglycans of the dermal-epidermal junction and hair
      follicle epithelium are of epidermal (epithelial) origin in vivo. Stratified rat
      keratinocytes cultured on a collagen matrix at the air-liquid interface showed
      the synthesis of perlecan, laminin 1, and type IV collagen in basement membranes,
      but not clearly detectable basement membrane chondroitin sulfate proteoglycan.

PMID- 8648190
TI  - Interactions of immature human mast cells with extracellular matrix: expression
      of specific adhesion receptors and their role in cell binding to matrix proteins.
AB  - Interactions of cells with their extracellular matrix (ECM) are central to tissue
      specific migration, localization, and function of migratory cells. Since mast
      cells circulate as immature precursor cells and home to tissues in a
      characteristic distribution, with increases in various disease states, we used
      the immature human mast cell line HMC-1 as a model to investigate the poorly
      understood mast cell-ECM interactions in humans. Functional adhesion studies
      showed that HMC-1 cells spontaneously adhere to fibronectin and laminin (80% at 6
      and 12 microgram/ml, respectively) and to collagen type I and III (50% at 20
      microgram/ml), whereas binding to vitronectin and collagen type IV required cell
      activation by phorbol myristate acetate. HMC-1 cells did not adhere to hyaluronic
      acid. Moreover, both fibronectin and laminin supported pronounced cytoplasmatic
      spreading with formation of isolated lamellipodia, whereas these cells exhibited
      a round cell shape on collagen and vitronectin, as shown by scanning electron
      microscopy. On flow cytometric analysis, HMC-1 cells expressed several adhesion
      molecules including the integrins beta 1, alpha 2 through alpha 6, alpha v, and
      alpha v beta 5, as well as CD44. Adhesion to fibronectin and vitronectin was
      found to be divalent cation- and arginine-glycine-aspartic acid-dependent, and
      could be blocked by antibodies to beta 1 or alpha 5, and alpha v or alpha v beta
      5, respectively. In contrast, binding to laminin and collagen could not be
      blocked by monoclonal antibodies to any of the cell surface adhesion receptors
      expressed. Our results show that immature mast cells are able to modify their
      adhesive behavior in response to various ECM proteins and activating stimuli, and
      that this phenomenon is partly integrin mediated. These findings may be important
      for our understanding of the mechanisms leading to tissue-specific localization
      of mast cells.

PMID- 8648191
TI  - The region coding for the helix termination motif and the adjacent intron 6 of
      the human type I hair keratin gene hHa2 contains three natural, closely spaced
      polymorphic sites.
AB  - Mutations in distinct sites of epidermal keratins, in particular in the helix
      initiation and termination regions, cause human genodermatoses due to faulty
      intermediate filament formation. Extension of this observation to human
      hereditary hair and nail diseases includes population analyses of human hair
      keratin genes for natural sequence variations in the corresponding sites. Here we
      report on a large-scale genotyping of the short helix termination region (HTR) of
      the human type I cortical hair keratins hHa1, a3-I, and a3-II, and the cuticular
      hair keratin hHa2. We describe two polymorphic loci, P1 and P2, exclusively in
      the cuticular hHa2 gene, both creating dimorphic protein variants. P1 is due to a
      C to T mutation in a CpG element leading to a threonine to methionine
      substitution; P2 concerns a serine codon AGT that also occurs as an asparagine
      coding variant AAC. A third polymorphism, P3, is linked with a C to T point
      mutation located at the very beginning of intron 6. The three polymorphic sites
      are clustered in a 39-nucleotide sequence of the hHa2 gene. Both allelic
      frequency calculations in individuals of different races and pedigree studies
      indicate that the two-allelic hHa2 variants resulting from P1 and P2 occur
      ubiquitously in a ratio of about 1:1 (P1) and 2:1 (P2) respectively in our
      survey, and are clearly inherited as Mendelian traits. A genotype carrying both
      mutations simultaneously on one allele could not be detected in our sampling, and
      there was no association of a distinct allelic hHa2 variant with the known ethnic
      form variations of hairs. Sequence comparisons of the HTR of hHa2 with those of
      other type I hair keratins including the hHa2-ortholog from chimpanzee provide
      evidence that the P1- and P2-linked mutations must have occurred very early in
      human evolution and that the two P2-associated codon variants may be the result
      of two independent point mutations in an ancestral AGC serine codon. These data
      describe natural polymorphisms in the HTR of a member of the keratin multigene
      family.

PMID- 8648192
TI  - Cholesterol sulfate protects Candida albicans from inhibition by sphingosine in
      vitro.
AB  - Sphingosine is known to have potent biological activity, including pronounced
      anti-microbial action in vitro against Candida albicans and some bacteria.
      Several sphingosine bases are present in stratum corneum at concentrations
      several orders of magnitude above those in other tissues. Sphingosine forms an
      undissociated salt with organic sulfates, however, so that the free sphingosine
      in the epidermis may be inactivated by the cholesterol sulfate known to be
      present. To investigate this hypothesis, C. albicans was grown in cultures with
      graded concentrations of sphingosine added in ethanol. In 1% ethanol, 0.1-100
      microgram/ml sphingosine completely prevented growth of the organism for 12 h.
      All cultures eventually entered log-phase growth and reached limiting density at
      a rate inversely proportional to sphingosine concentration. When sphingosine was
      added, together with an equimolar amount of cholesterol sulfate, there was no
      delay in the onset of growth of the yeast and the rate of growth and final
      density were similar to control cultures. These results demonstrate that natural
      ratios of cholesterol sulfate neutralize the anti-microbial activity of
      sphingosine in vitro. In the epidermis, endogenous cholesterol sulfate is
      hydrolyzed by sterol sulfatase at the skin surface, where the released
      sphingosine may resist microbial colonization of the stratum corneum. This
      mechanism for liberating anti-microbial sphingosine base only at the skin surface
      may protect the viable epidermis against known cytotoxic effects of free
      sphingosine.

PMID- 8648193
TI  - Contact allergens and epidermal proinflammatory cytokines modulate Langerhans
      cell E-cadherin expression in situ.
AB  - After exposure to antigen, Langerhans cells (LC) migrate from the epidermis to
      lymph nodes, where they initiate primary immune responses in T cells. The
      adhesion molecule E-cadherin mediates adhesion of LC to keratinocytes in vitro
      and may be responsible for localization of LC in epidermis. To determine if
      levels of LC E-cadherin are modulated during LC emigration from epidermis, we
      utilized flow cytometry to evaluate E-cadherin expression on BALB/c LC exposed in
      situ to the contact allergen 2,4,6-trinitrochlorobenzene (TNCB). TNCB induced
      increased I-A/E antigen and decreased E-cadherin expression on a subpopulation of
      LC as early as 12 h, and as late as 48 h, after application. At 24 h,
      approximately 30% of LC in TNCB-treated skin expressed increased I-A/E antigens;
      of these activated LC, approximately 40% expressed decreased levels of E
      cadherin. E-cadherin levels on this latter subset were approximately 15% of those
      expressed by LC in normal skin, and were similar to levels on cultured LC and LC
      that migrated from skin explants. The effect was specific for allergens; no
      changes occurred in LC following treatment with several contact irritants or the
      tolerogen dinitrothiocyanobenzene. To determine if cytokines modulated LC E
      cadherin expression, we introduced various cytokines into BALB/c ear skin and
      assayed I-A/E antigen and E-cadherin levels. Of the cytokines tested, only
      interleukin-1 and tumor necrosis factor alpha reproduced the effects of TNCB. We
      propose that downmodulation of E-cadherin expression occurs as a consequence of
      local cytokine production during antigen-induced LC activation, facilitating LC
      emigration and the initiation of immune responses against antigens encountered in
      epidermis.

PMID- 8648194
TI  - Agouti alleles alter cysteine and glutathione concentrations in hair follicles
      and serum of mice (A y/a, A wJ/A wJ, and a/a).
AB  - Ectopic overexpression of the agouti protein in the lethal yellow (A y/a) mouse
      causes a yellow coat as well as the lethal yellow syndrome. Presence of thiols
      like glutathione (GSH) or cysteine (Cys) may regulate the conversion of
      dopaquinone to phaeomelanin in hair follicle melanocytes. GSH also plays
      important roles in cellular health and maintenance. Cys and GSH were measured
      using high-performance liquid chromatography in hair follicles and serum of A
      wJ/A wJ (agouti), A y/a (yellow), and a/a (black) mice over a 20-d hair growth
      regeneration period. Agouti alleles modulate thiol concentrations. A y/a hair
      follicles exhibited higher total thiol levels and an increased ratio of Cys to
      GSH. A wJ/A wJ mice showed intermediate levels, while a/a mice had lowest total
      thiol concentrations and a decreased ratio of Cys to GSH. Hair follicle cysteine
      concentrations showed yellow > agouti > black (p < 0.01). In all genotypes,
      unplucked skin and day 0 hair follicles showed GSH as the major thiol, but a
      shift to predominantly Cys on peak melanogenic days was seen. Presence of high
      concentrations of free cysteine support the hypothesis of phaeomelanin synthesis
      via cysteinyldopas. The A y/a mouse had the most dramatic follicular thiol
      changes as well as a depression in serum thiols. An altered thiol metabolism in
      these and other A y/a tissues might impair normal cell functioning to contribute
      to the lethal yellow syndrome.

PMID- 8648195
TI  - The insulin-like growth factor 1 receptor is expressed by epithelial cells with
      proliferative potential in human epidermis and skin appendages: correlation of
      increased expression with epidermal hyperplasia.
AB  - Ligand-mediated activation of the insulin-like growth factor 1 (IGF-1) receptor
      is critical for epidermal keratinocyte proliferation in vitro, and its expression
      in normal and psoriatic epidermis suggests that it might regulate keratinocyte
      proliferation in vivo. In this study, we used a monoclonal antibody (alpha-IR3)
      that binds to the alpha-chain of this receptor to study its expression (i) in
      other epithelial cell types in human skin and (ii) in growth-activated epidermis
      associated with various cutaneous pathologies. In normal skin, IGF-1 receptors
      were expressed by basal epidermal keratinocytes as well as by basal-like or
      undifferentiated germinative epithelial cells associated with the follicular
      outer root sheath, sebaceous glands, and the hair matrix. There was minimal IGF-1
      receptor expression in differentiating outer root sheath, hair shaft, and
      sebaceous epithelial cells. IGF-1 receptor expression in non-growth-activated
      epidermis of long-standing seborrheic keratoses was confined to the basal
      epidermal layer, as in normal epidermis. In contrast, hyperplastic epidermis
      undergoing "regenerative" differentiation (keratin 16+, Ki67+ suprabasal
      keratinocytes) from psoriasis, chronic skin wounds, and plaques of mycosis
      fungoides consistently showed increased expression of IGF-1 receptor. In these
      conditions, the region of expanded IGF-1 receptor expression delimited the
      epidermal zone of keratinocyte proliferation. In cultured keratinocytes, the
      subcellular localization of the IGF-1 receptor could be modulated from plasma
      membranes to the cell cytoplasm by ligand binding, suggesting that the in vivo
      cytoplasmic staining occasionally observed represents internalization of
      receptors following ligand stimulation. Our results suggest that cell surface IGF
      1 receptors are widely expressed by epithelial cells with proliferative
      potential, that receptor expression can be modulated with differing epidermal
      growth states, and that these receptors are largely downregulated in highly
      differentiated epithelial cells.

PMID- 8648196
TI  - Identification and characterization of novel dermal Thy-1 antigen-bearing
      dendritic cells in murine skin.
AB  - Using immunofluorescence on dermal sheets of mouse ear, we identified novel Thy
      1+ dermal dendritic cells in murine skin. These cells are resistant to topical
      corticosteroid treatment. The number of these dermal Thy-1+ dendritic cells is
      not altered with aging of the mice or with 3 d of culture. Dermal Thy-1+
      dendritic cells have melanosomes in their cytoplasm; hence, phagocytic activity
      is likely to be present. Double immunofluorescence revealed that most of these
      dermal Thy-1+ dendritic cells express CD45. Furthermore, conventional
      immunofluorescence and confocal laser scanning microscopic findings showed that
      most of these Thy-1+ dermal dendritic cells express gamma delta and V gamma 3 T
      cell receptors. The relationship between these dermal Thy-1+ dendritic cells and
      dendritic epidermal T cells is discussed.

PMID- 8648197
TI  - Loss of expression of a retrovirus-transduced gene in human keratinocytes.
AB  - Retroviral-mediated transfer of new genetic information into keratinocytes is a
      key step in epidermal gene therapy. An obstacle to the use of retroviruses for
      gene therapy is that although high levels of expression of the transduced gene
      can be maintained in tissue culture, expression is often lost when the cells are
      transplanted to an animal host. To examine some of the factors involved in this
      instability of expression, we transduced keratinocytes with a retrovirus encoding
      the gene for human factor IX and monitored secretion of the transduced gene. We
      observed continued secretion of factor IX through five passages in culture. When,
      however, sheets of these cells were grafted to athymic mice, factor IX expression
      was reduced or lost within 6 wk. We show that the reduction of factor IX
      expression in grafted keratinocytes did not result from a loss of grafted cells,
      nor was there a block to systemic delivery of a secreted endogenous product.

PMID- 8648199
TI  - Oxybenzone oxidation following solar irradiation of skin: photoprotection versus
      antioxidant inactivation.
AB  - We used noninvasive Fourier transform (FT) Raman spectroscopy to follow the fate
      of the broadly used ultraviolet UVA sun blocker, oxybenzone, after topical
      application to the skin. Our results showed that oxybenzone is rapidly photo
      oxidized, yielding oxybenzone semiquinone, a potent electrophile, which reacts
      with thiol groups on important anti-oxidant enzymes and substrates, such as
      thioredoxin reductase and reduced glutathione, respectively. Although oxybenzone
      is an excellent broad spectrum UVA filter, its rapid oxidation followed by the
      inactivation of important antioxidant systems indicates that this substance may
      be rather harmful to the homeostasis of the epidermis. Furthermore, these results
      demonstrate that FT-Raman spectroscopy is a useful method for studying the
      transport and metabolism of active ingredients in topical preparations.

PMID- 8648198
TI  - Clonality of basal cell carcinoma--molecular analysis of an interesting case.
AB  - Tumor cells represent a single clone of cells that have undergone a series of
      mutations in genomic DNA. This process, known as clonal evolution, is a
      distinguishing feature of cancer. The human androgen receptor gene (HUMARA;
      GenBank) contains a highly polymorphic cytosine-adenine-guanine trinucleotide
      repeat that can be used to determine clonality by depicting X chromosome
      inactivation patterns. Random X chromosome inactivation is consistent with
      polyclonality; nonrandom X chromosome inactivation indicates a clonal population
      of cells. Basal cell carcinoma (BCC) demonstrates an atypical growth pattern in
      that it grows slowly, rarely metastasizes, and is rarely lethal. Whether this
      tumor results from the accumulation of mutations in a single cell with subsequent
      clonal expansion or reflects a polyclonal response by a group of cells to a
      growth stimulus is unknown. To provide further insight into the molecular events
      characterizing BCCs, we determined the clonal origin of five modular BCCs from a
      female patient by analyzing X chromosome inactivation patterns at the HUMARA
      locus. All tumors demonstrated a nonrandom pattern of X chromosome inactivation,
      consistent with monoclonal proliferation. These findings provide strong genetic
      evidence that sporadic BCCs develop by clonal evolution and support the
      contention that a series of mutations in a single cell is responsible for the
      altered growth state seen in these transformed epithelial cells.

PMID- 8648200
TI  - Hantavirus pulmonary syndrome: the first 100 US cases.
AB  - In the spring of 1993, hantavirus pulmonary syndrome (HPS) "emerged" in the
      southwestern United States, where a multiagency investigation led to the rapid
      description of this new clinical entity and its etiology. Analysis of the first
      100 US cases identified showed that the disease was distributed in 21 states, had
      gone unrecognized since at least 1959, and had a distinct spring-early summer
      seasonality. Of the infected persons, 54% were male; 63% were Caucasian, 35% were
      Native American, and 2% were African American. The average age of case-patients
      was 34.9 years, and 8 were children or adolescents aged < or = 16 years. The
      overall case-fatality rate was 52%. There was a 91% concordance among serologic,
      immunohistochemical, and molecular results. HPS in the United States is caused by
      at least three newly described pathogenic hantaviruses, each of which has a
      distinct rodent host, and cases of HPS have been recently recognized in Canada
      and South America. National surveillance of this sporadic disease remains
      essential for further defining the epidemiology and clinical spectrum.

PMID- 8648201
TI  - Quantitation of cytomegalovirus DNA and characterization of viral gene expression
      in bronchoalveolar cells of infected patients with and without pneumonitis.
AB  - Cytomegalovirus (CMV) is often present in bronchoalveolar lavage (BAL) fluid of
      immunosuppressed patients without CMV pneumonitis. The amount of viral DNA within
      BAL cells of patients with definite CMV pneumonitis and of viral shedders was
      quantitated by polymerase chain reaction (PCR) and the extent of CMV gene
      expression within BAL cells was defined by reverse transcription - PCR. No viral
      DNA was detected in 6 viral shedders, and 12 had low copy numbers (mean, 72
      copies/10(5) BAL cells; median, 20) compared with numbers in pneumonitis patients
      (267,580 and 57,000, respectively). When CMV intranuclear inclusions were absent
      within BAL cells of patients with pneumonitis, copy numbers (mean, 9362; median,
      7110) were still significantly higher than among shedders. Expression of viral
      glycoprotein H mRNA was detected in BAL cells of all 11 pneumonitis patients
      tested but in 0 of 18 viral shedders. Thus, high-grade infection and viral
      replication within BAL cells are integral features of CMV pneumonitis but not
      viral shedding.

PMID- 8648202
TI  - Evaluation of live attenuated influenza vaccines in children 6-18 months of age:
      safety, immunogenicity, and efficacy. National Institute of Allergy and
      Infectious Diseases, Vaccine and Treatment Evaluation Program and the Wyeth
      Ayerst ca Influenza Vaccine Investigators Group.
AB  - Live attenuated, cold-adapted (ca) monovalent and bivalent influenza A vaccines
      were evaluated in seronegative infants (ages 6-18 months) in a double-blind
      placebo-controlled trial to assess safety and immunogenicity. A total of 182
      seronegative subjects received a single intranasal dose (10(6.2) TCID50) of ca
      A/Kawasaki/9/86 (H1N1) or ca A/Los Angeles/2/87 (H3N2), both as a bivalent
      vaccine, or placebo. Respiratory and systemic symptoms did not differ between
      groups after vaccination. Hemagglutination antibody seroconversions (> or = 1:8)
      to H3N2 exceeded 90%. In contrast, seroconversions to A/Kawasaki/9/86 (H1N1) were
      significantly less frequent in bivalent ca vaccine recipients (31%) than in
      monovalent ca H1N1 recipients (83%) (P < .002). During a subsequent H3N2
      epidemic, nasal washes were cultured for viruses from any subject with
      respiratory illness. H3N2 infections documented by virus isolation were reduced
      by 65% in ca H3N2 recipients compared with placebo or ca HIM recipients (P =
      .01).

PMID- 8648203
TI  - The effect of Edmonston-Zagreb and Schwarz measles vaccines on immune response in
      infants.
AB  - The effects of measles immunization on immune responses in infants and the roles
      of vaccine strain and age of immunization are not known. Eighty-eight children
      were immunized at 6 or 9 months of age with the Edmonston-Zagreb (EZ) or Schwarz
      (SW6, SW9) strain of measles vaccine. Children were studied before and 2 weeks
      and 3 months after immunization. Seroconversion was similar, but geometric mean
      neutralizing titers at 3 months differed by vaccine group: SW9, 1367 mIU/mL; SW6,
      982; and EZ, 303 (P = .003). Mitogen-induced lymphoproliferation was decreased at
      2 weeks in the SW9 group and at 3 months in all groups and was negatively
      correlated with measles antibody level at 3 months (r = -.387, P = .003). CD8 T
      cells, soluble CD8, neopterin, and beta2-microglobulin were increased at 2 weeks
      in the SW9 group, and soluble CD8 and beta2-microglobulin remained elevated at 3
      months. Therefore, measles immunization resulted in suppression of
      lymphoproliferation, which was most evident in infants with the highest antibody
      responses and most immune activation.

PMID- 8648204
TI  - Vaccination of pregnant macaques protects newborns against mucosal simian
      immunodeficiency virus infection.
AB  - Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a
      rapid, sensitive animal model of human pediatric AIDS. Newborn macaques were
      readily infected by uncloned SIVmac following oral-conjunctival exposure and had
      persistently high viremia and rapid development of AIDS. In contrast, when 3
      pregnant macaques were vaccinated against SIV, 2 of the newborns that had
      transplacentally acquired antiviral antibodies were protected against mucosal SIV
      infection at birth. These results suggest that intervention strategies such as
      active immunization of human immunodeficiency virus (HIV)-infected pregnant women
      and anti-HIV immunoglobulin administration may decrease the rate of perinatal HIV
      infection.

PMID- 8648205
TI  - A randomized, placebo-controlled study of the immunogenicity of human
      immunodeficiency virus (HIV) rgp160 vaccine in HIV-infected subjects with > or =
      400/mm3 CD4 T lymphocytes (AIDS Clinical Trials Group Protocol 137).
AB  - Immune responses provoked by human immunodeficiency virus (HIV) infection
      ultimately are insufficient to control the disease and do not include strong
      lymphocyte-proliferative responses to HIV antigens or antibodies to many viral
      epitopes. A randomized double-blind, placebo-controlled trial evaluated the
      immunogenicity of recombinant HIV envelope vaccine (rgp160) in HIV-infected
      subjects with > or = 400/mm3 CD4 T cells. Controls received hepatitis B vaccine.
      Of subjects receiving rgp160, 98% developed lymphocyte-proliferative responses to
      the immunogen, 33% to a different envelope protein, and 56% and 60% to p24 and
      p66, respectively. All doses of vaccine (20, 80, 320, 1280 microgram) induced new
      responses. New antibodies to epitopes on rgp160 developed only in recipients of
      higher doses of rgp160. CD4 T cell percentages declined less rapidly in
      recipients of rgp160 than in controls. Vaccination of HIV-infected subjects with
      rgp160 results in cellular and humoral immune responses to HIV that infection
      itself had not stimulated.

PMID- 8648206
TI  - IgG antibody to pneumococcal capsular polysaccharide in human immunodeficiency
      virus-infected subjects: persistence of antibody in responders, revaccination in
      nonresponders, and relationship of immunoglobulin allotype to response.
AB  - Human immunodeficiency virus (HIV)-infected persons are less likely than are
      noninfected persons to respond to vaccination with pneumococcal polysaccharides
      (PPS). Among those who respond, however, similar IgG levels may be achieved. HIV
      infected men immunized with pneumococcal vaccine were classified as high- or low
      level responders (IgG > or = 1 microgram/mL for > or = 3 of 5 PPS [high] or for <
      or = 1 PPS [low]). One and 2 years after immunization, geometric mean IgG levels
      and the percentages of subjects with IgG levels > or = 1 microgram/mL were
      similar for HIV-infected and for healthy high-level responders (controls) for all
      PPS except for serotype 8. Among HIV-infected low-level responders, revaccination
      with a double dose of pneumococcal vaccine did not stimulate IgG responses.
      Responsiveness of HIV-infected white patients was significantly associated with
      the Km(1)- negative allotype. These findings support current general recommended
      guidelines for administering pneumococcal vaccine to HIV-infected persons.
      Nonresponders will not benefit from revaccination.

PMID- 8648207
TI  - Virologic and immunologic benefits of initial combination therapy with zidovudine
      and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome
      Resistance Study Collaborative Group.
AB  - A randomized controlled study was done to determine whether initial combination
      therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay
      the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1
      infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine
      therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine
      plus didanosine. Combination therapy did not delay the emergence of zidovudine
      resistant virus isolates. However, combination therapy resulted in a significant
      increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a
      greater and more sustained decline in serum HIV-1 RNA. Although this trial was
      not designed as a clinical end-point study, patients assigned to zidovudine plus
      didanosine combination therapy experienced a significant delay in time to first
      AIDS-defining event or death compared with those assigned to zidovudine
      monotherapy.

PMID- 8648208
TI  - Human immunodeficiency virus-induced cell death in cytokine-treated macrophages
      can be prevented by compounds that inhibit late stages of viral replication.
AB  - The basis of the cytopathic effect induced by a laboratory strain and several
      clinical isolates of human immunodeficiency virus (HIV) in human macrophages
      cultured in the presence of macrophage colony-stimulating factor was studied.
      Infected macrophages die of necrosis, the consequence of the production of mature
      virions in infected cells. Cell death can be prevented by antiviral compounds
      that interfere with the assembly and budding of virions. Programmed cell death
      (apoptosis), a potential mechanism of HIV-mediated cell death in CD4 T
      lymphocytes, does not occur in infected macrophages as shown by electron
      microscopy, cytofluorometric and gel electrophoretic DNA analysis, and nuclear
      fluorescent staining by Hoechst and terminal dUTP-nick-end-labeling (TUNEL)
      assay. The data suggest that macrophage killing by HIV may occur in vivo. Thus,
      combination therapies that include compounds that inhibit the cytopathic effect
      of HIV in macrophages should be considered for AIDS patients.

PMID- 8648210
TI  - Prognostic value of viremia in patients with long-standing human immunodeficiency
      virus infection. Swiss HIV Cohort Study Group.
AB  - Human immunodeficiency virus (HIV) viremia was evaluated in 73 patients with long
      standing infection to investigate its relationship with clinical or biologic
      parameters and to assess its use as a predictor of clinical progression and
      death. After adjustment for other parameters, baseline HIV RNA level was
      significantly associated with baseline clinical stage and CD4 cell count. During
      follow-up (mean, 14.6 months), 16 patients died; 34 others had clinical
      progression of disease. In multivariate analysis, mortality was better predicted
      by baseline CD4 cell count (relative hazard [RH] for 100-cell decrease, 3.5; 95%
      confidence interval [CI], 1.5-8.2; P = .003) than by HIV RNA (P = .28) or
      clinical stage. HIV RNA level was the best predictor of clinical progression (RH
      for 1 log increase, 2.8; 95% CI, 1.6-4.9; P < .001). Monitoring of HIV RNA level
      may help to identify patients who might benefit from antiretroviral or
      prophylactic therapy.

PMID- 8648209
TI  - In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor:
      mutations, kinetics, and frequencies.
AB  - Resistance to saquinavir (Ro 31-8959), an inhibitor of human immunodeficiency
      virus type I proteinase, was studied in peripheral blood mononuclear cell-derived
      proviral DNA from patients undergoing prolonged treatment. A Leu90-->Met exchange
      was the predominant resistance mutation in vivo; Gly48-->Val or doubly mutant
      virus was rarely observed. After 8-12 months of treatment with saquinavir alone
      (600 mg, 3 times/day) or in combination with zidovudine (200 mg, 3 times/day),
      approximately 45% of all patients carried provirus with mutant proteinase; the
      incidence was lower (22%) in patients treated with a combination of saquinavir,
      zidovudine, and dideoxycytidine. There was a good relationship between genotypic
      analysis of saquinavir resistance and data from virus assays, confirming that
      Leu90-->Met and Gly48-->Val are the essential exchanges in the proteinase that
      determine loss of sensitivity to this inhibitor. Absence of genotypic resistance
      correlated with a sustained decrease in plasma viral RNA. There was a positive
      correlation between a Met90 mutation and some residues at natural polymorphic
      sites (positions 10, 36, 63, and 71).

PMID- 8648211
TI  - Seropositivities to human papillomavirus types 16, 18, or 33 capsids and to
      Chlamydia trachomatis are markers of sexual behavior.
AB  - The association of seropositivity to human papillomavirus (HPV) capsids of types
      11, 16, 18, or 33 with sexual behavior was investigated. Among 1002 women
      visiting family planning or youth clinics in Sweden, an age-matched subsample of
      274 women stratified according to lifetime number of sex partners was analyzed.
      The proportion of HPV-16-seropositive subjects increased linearly at
      approximately 4% per partner (P < .001), from 4% among those with 1 lifetime
      partner to 35% among those with >5 lifetime partners. Also, HPV-33 and HPV-18
      seroprevalences were linearly dependent on the number of partners (P < .001,
      increase with 4% per partner, and P = .008, increase with approximately 3% per
      partner, respectively), providing serologic confirmation that the important mode
      of transmission of HPV-16, -18, or -33 infection in women is sexual. HPV serology
      appears to be suitable as a marker of sexual behavior in populations.

PMID- 8648212
TI  - Streptococcal pyrogenic exotoxin A release, distribution, and role in a murine
      model of fasciitis and multiorgan failure due to Streptococcus pyogenes.
AB  - The role of streptococcal pyrogenic exotoxin A (SPEA) was evaluated in a murine
      model of fasciitis and multiorgan failure due to a toxigenic strain of
      Streptococcus pyogenes. Increased serum levels of SPEA at 15 and 21 h were
      associated with a survival time of <24 h. Levels of SPEA correlated with
      interleukin-6 levels. Immunostaining showed SPEA localized to renal and hepatic
      cells. Neutralizing rabbit antibody to SPEA was administered to mice challenged
      with S. pyogenes, but no effect on survival was observed. Vaccination of mice
      with recombinant SPEA enhanced mortality due to streptococcal infection, despite
      the development of neutralizing immunity to the toxin prior to infection. Hence,
      SPEA is produced systemically during S. pyogenes soft-tissue infection, and
      increased levels are associated with reduced survival. In this model, however,
      SPEA did not appear to play a dominant role in pathogenesis; passive immunization
      against SPEA was not protective, and active immunization enhanced mortality.

PMID- 8648213
TI  - phoP/phoQ-deleted Salmonella typhi (Ty800) is a safe and immunogenic single-dose
      typhoid fever vaccine in volunteers.
AB  - The phoP/phoQ virulence regulatory genes of Salmonella typhi Ty2 were deleted,
      and the resultant strain (Ty800) was tested as a live attenuated typhoid fever
      vaccine in human volunteers. Groups of 2 or 3 subjects received single oral doses
      of 10(7), 10(8), 10(9), or 10(10) cfu. Two volunteers who received the largest
      dose had self-limited side effects; no bacteremias were detected. Ten of 11
      subjects had evidence of intestinal immune responses to the vaccine as measured
      by increases in S. typhi lipopolysaccharide-specific IgA-secreting cells in
      peripheral blood samples. Humoral immune responses were measured and compared
      with those of control vaccinees who received 4 oral doses of S. typhi Ty21a. In
      the most sensitive assays, 9 of 11 volunteers and 5 of 8 Ty21a control vaccinees
      had evidence of IgG directed against S. typhi antigens. Ty800 is safe, and single
      oral doses are highly immunogenic in humans.

PMID- 8648214
TI  - Potential hazards of combination immunotherapy in the treatment of experimental
      septic shock.
AB  - Using an actual infection model of Pseudomonas aeruginosa sepsis in neutropenic
      rats, the potential utility of a combination anticytokine approach for the
      treatment of sepsis was tested. A dimeric tumor necrosis factor binding protein
      (TNF-BP) consisting of two soluble recombinant human TNF type 1 receptors linked
      with polyethylene glycol was used with recombinant human interleukin-1 receptor
      antagonist (IL-1ra). Despite having levels of bacteremia and endotoxemia similar
      to the control group (survivors, 0/18), 30% of IL-1ra-treated animals survived (P
      < .05); 31% of TNF-BP-treated animals survived (P < .01). Unexpectedly, the
      combination of IL-1ra plus TNF-BP proved to be uniformly fatal (survivors, 0/20).
      Endotoxin (P < .0001) and bacteremia (P < .01) levels were >10-fold higher than
      levels in animals treated with IL-1ra alone, TNF-BP alone, or placebo.
      Disseminated microabscesses in major organs were found in animals treated with
      combination immunotherapy. Combination anticytokine therapy may exacerbate
      systemic infection and worsen outcome in experimental sepsis.

PMID- 8648215
TI  - Sialylation lessens the infectivity of Neisseria gonorrhoeae MS11mkC.
AB  - In a human challenge experiment, the infectivity of gonococci with sialylated
      lipooligosaccharide (LOS) was compared with the infectivity of gonococci with
      unsialylated LOS. Volunteers were intraurethrally inoculated with approximately
      5000 sialylated or unsialylated piliated, non-opaque (P+Opa-, transparent) colony
      type gonococci, strain MS11mkC. Five (83%) of 6 volunteers inoculated with
      unsialylated gonococci became infected; however, only 1 of 5 volunteers became
      infected with sialylated gonococci. The unsialylated gonococcal infections, with
      a median incubation time of 62 h (range, 32-98), were similar to previously
      described experimental infections. Gonococci shed by infected volunteers showed a
      transition from the P+Opa- phenotype of the inoculation strain to the P+Opa+
      (piliated, opaque) phenotype 12-60 h before onset of disease. The subject with
      sialylated gonococcus infection had an extended incubation period, showing a
      progressive increase in the number of organisms shed until he became symptomatic
      on day 6 after inoculation. These results show that gonococci with sialylated LOS
      are less infective than gonococci with unsialylated LOS.

PMID- 8648216
TI  - Oral immunization with the B subunit of the heat-labile enterotoxin of
      Escherichia coli induces early Th1 and late Th2 cytokine expression in Peyer's
      patches.
AB  - The B subunit of heat-labile toxin (LT-B) from enterotoxigenic Escherichia coli
      has been shown to be a powerful mucosal immunogen. Oral immunization of mice with
      LT-B revealed that BALB/c (H-2d) and C57BL/6 (H-2b) mice gave high serum IgG and
      mucosal IgA responses specific for LT-B. However, ALY (H-2b) mice lacking
      intestinal Peyer's patches (PP) did not respond to oral LT-B with either serum or
      mucosal antibodies. These results indicate that PP lymphocytes supported both
      systemic and mucosal immune responses when the antigen was administered orally.
      Reverse transcription polymerase chain reaction analyses revealed that PP CD4 T
      cells expressed early Th1-type (interferon-gamma and interleukin [IL]-2) and late
      Th2-type (IL-4, -5, and -6) cytokine mRNA. These results suggest that the
      systemic and mucosal antibody responses induced by LT-B are regulated by a
      cooperation of PP Th1 and Th2 cells.

PMID- 8648217
TI  - Risk factors for Chlamydia trachomatis pelvic inflammatory disease among sex
      workers in Nairobi, Kenya.
AB  - Among 302 female sex workers in Nairobi, Kenya, who were followed for 17.6 +/-
      11.1 months, 146 had one or more infections with Chlamydia trachomatis; 102 had
      uncomplicated cervical infection only, 23 had C. trachomatis pelvic inflammatory
      disease (PID), and 21 had combined C. trachomatis and Neisseria gonorrhoeae PID.
      As determined by multivariate logistic regression analysis, risk factors for C.
      trachomatis PID included repeated C. trachomatis infection (odds ratio [OR], 1.8;
      95% confidence interval [CI], 1.3-2.4; P = .0004), antibody to C. trachomatis
      heat-shock protein 60 (OR, 3.9; CI, 1.04-14.5; P = .04), oral contraceptive use
      (OR, 0.28; 95% CI, 0.08-0.99; P = .048), and number of episodes of nongonococcal
      nonchlamydial PID (OR, 1.7; 95% CI, 1.1-2.7; P = .02). Among human
      immunodeficiency virus (HIV)-seropositive women, a CD4 lymphocyte count of
      <400/mm3 was an additional independent risk factor for C. trachomatis PID (OR,
      21.7; 95% CI, 1.2-383; P = .036); among HLA-typed women, HLA-A31 was
      independently associated with C. trachomatis PID (OR, 5.6; 95% CI, 1.1-29.4; P =
      .043). The results suggest an immune-mediated pathogenesis for C. trachomatis
      PID.

PMID- 8648218
TI  - Detection of Mycoplasma pneumoniae by two polymerase chain reactions and role of
      M. pneumoniae in acute respiratory tract infections in pediatric patients.
AB  - Mycoplasma pneumoniae and viruses in acute respiratory tract infections in
      children were studied during the winter of 1992-1993 in Antwerp, Belgium. M.
      pneumoniae was diagnosed in nasopharyngeal aspirates by culture and polymerase
      chain reaction (PCR). For this, amplification of a fragment of the PI adhesin
      gene in samples prepared by two methods was compared in two laboratories, and in
      one laboratory, a fragment of the 16S rRNA gene was amplified. The sensitivity of
      culture versus PCR was 61.5%. Provided a specific internal control is used,
      sample preparation by freeze-boiling combined with PCR for the PI gene and
      amplicon detection by visual inspection of the electrophoresis gel can be
      recommended, although maximal results are obtained after hybridization. M.
      pneumoniae was present in 0.5% of patients <2 years old and 6.9% of patients >2.
      M. pneumoniae was second to respiratory syncytial virus or detected equally in
      lower respiratory infections.

PMID- 8648219
TI  - The presence or absence of active infection, not clinical status, is most closely
      associated with cytokine responses in lymphatic filariasis.
AB  - Twenty-eight Brazilians from an area in which Wuchereria bancrofti is endemic
      were classified as asymptomatic microfilaremic or having clinical filariasis with
      active infection or without current active infection. Total accumulation of
      antigen-specific interleukin (IL)-4 and IL-5 in 48 h peripheral blood mononuclear
      cell supernatants was not significantly different between groups. However, when
      cytokine kinetics were examined, responses segregated according to infection
      status. Sustained production of IL-4 and IL-5 beyond the first 24 h of
      stimulation and production of interferon-gamma were seen only in the group with
      clinical filariasis without active infection. CD8 T cells were the major source
      of IL-5 production in this group, while CD8 production of IL-5 was undetectable
      in any subject with active infection (asymptomatic microfilaremic or with
      clinical filariasis and active infection). These findings indicate that active
      infection, rather than clinical status, is most closely associated with cytokine
      patterns in lymphatic filariasis.

PMID- 8648220
TI  - Enhancement of Schistosoma mansoni infectivity by intradermal injections of
      larval extracts: a putative role for larval proteases.
AB  - Extracts of Schistosoma mansoni cercariae caused increased vascular permeability
      and edema if administered to CBA/Ca mice by intradermal injection. Percutaneous
      infection with cercariae over the skin site at which cercarial homogenate (CH)
      had been injected intradermally resulted in a significant increase in the
      infectivity of S. mansoni compared with that shown by worm recovery from control
      animals (P < .05). This effect was abrogated by inhibition of protease activity
      prior to injection. Injection of inflammatory mediators (bradykinin or zymosan
      activated plasma) with or without prostaglandin E2 produced a similar amount of
      edema as did CH. Injection of these mediators did not, however, enhance
      infectivity of cercariae. Pancreatic elastase was found to induce edema and
      enhancement of infectivity comparable to those induced by CH. The protease(s)
      introduced into the site of infection may have facilitated larval migration
      directly by hydrolyzing host tissue or indirectly by inducing an inflammatory
      response (or both).

PMID- 8648221
TI  - Evaluation of a recombinant hemagglutinin expressed in insect cells as an
      influenza vaccine in young and elderly adults.
AB  - Healthy subjects <45 years old (young adults) or >65 (elderly adults) were
      randomized in double-blind fashion to receive intramuscularly subvirion trivalent
      influenza vaccine, placebo, or 15, 45, or 135 microgram of the hemagglutinin (HA)
      of the influenza A/Beijing/32/92 (H3N2) virus expressed in insect cells by a
      recombinant baculovirus (rHA0). All vaccines were well tolerated. Both young and
      elderly adults manifested serum hemagglutination-inhibition, virus neutralizing,
      and HA-specific IgG ELISA antibody responses to rHA0 vaccine. In young adults
      given 135 microgram of rHA0, the vaccine was significantly more immunogenic than
      subvirion influenza vaccine. Elderly adults also had increased antibody responses
      to 135 microgram of rHA0 compared with subvirion vaccine, but the difference was
      not statistically significant. These results demonstrate that high-dose rHA0
      vaccines are well tolerated and effectively induce both functional and binding
      serum HA-specific antibody in young and elderly adults.

PMID- 8648222
TI  - Comparative detection of measles-specific IgM in oral fluid and serum from
      children by an antibody-capture IgM EIA.
AB  - In vaccinated populations, the diagnosis of measles often requires laboratory
      confirmation. Serum tested by EIAs has proven sensitive and specific for
      diagnosing measles. For comparison of detection of measles-specific IgM in oral
      fluid and serum samples by an antibody-capture EIA, 163 Ethiopian infants who
      presented for routine measles vaccination were studied. Paired serum and oral
      fluid samples were collected before and 2 weeks after vaccination; 269 paired
      samples were adequate for analyses. Of the 104 serum samples that were IgM
      positive, 95 (91%) of the paired oral fluid samples were IgM-positive. Of the 165
      serum samples that were IgM-negative, 156 (95%) of the paired oral fluid samples
      were IgM-negative. The Pearson partial correlation coefficient for optical
      density readings from postvaccination oral fluid compared with serum was 0.81.
      Oral fluid appears to be an acceptable alternative to serum for measuring measles
      specific IgM antibodies by an antibody-capture EIA.

PMID- 8648223
TI  - Hepatitis B and C virus serologies among Japanese Americans with hepatocellular
      carcinoma.
AB  - A cohort of 5924 Japanese American men was examined between 1967 and 1970 for
      hepatocellular carcinoma (HCC). By 1992, 24 incident cases of HCC were
      histologically confirmed in the group. Frozen serum samples from the 24 men with
      HCC and 72 age-matched controls were tested for hepatitis B surface antigen
      (HBsAg), antibodies to hepatitis B core antigen, antibodies to HBsAg, and
      antibodies to hepatitis C virus. HBsAg was detected in 15 (62.5%) of 24 HCC cases
      compared with 2 (2.8%) of 72 controls (odds ratio, 43.0; 95% confidence interval,
      5.7-325.5). None of the cases and only 1 control had antibody to hepatitis C
      virus. This study demonstrates a strong association between hepatocellular
      carcinoma and hepatitis B virus infection, but not with hepatitis C virus
      infection, among men of Japanese ancestry in Hawaii.

PMID- 8648224
TI  - Use of antiherpes drugs and the risk of Kaposi's sarcoma: data from the
      Multicenter AIDS Cohort Study.
AB  - To determine if use of antiherpes drugs protects against the development of AIDS
      associated Kaposi's sarcoma (KS), data from 935 homosexual men with AIDS from the
      Multicenter AIDS Cohort Study were analyzed. In nested case-control analysis,
      neither acyclovir use for human immunodeficiency virus infection (odds ratio
      [OR], 0.84; 95% confidence interval [CI], 0.56-1.26; P = .39) nor acyclovir use
      for any indication (OR, 1.02; 95% CI, 0.76-1.38; P = .89) was associated with a
      reduced risk of KS as initial AIDS diagnosis. In longitudinal analysis, acyclovir
      was also not protective against developing KS as a late manifestation of AIDS
      (after initial non-KS AIDS diagnosis). Among men with cytomegalovirus disease,
      ganciclovir use (relative risk [RR], 0.56; 95% CI, 0.22-1.44; P = .23) and
      foscarnet use (RR, 0.40; 95% CI, 0.051-3.10; P = .38) were associated (although
      not significantly) with a reduced risk of KS. Thus, acyclovir use does not appear
      to reduce the risk of KS, but further study of other antiherpes drugs such as
      ganciclovir and foscarnet is warranted.

PMID- 8648226
TI  - Dynamics of virus versus host interaction in children with human immunodeficiency
      virus type 1 infection.
AB  - To investigate the dynamic interplay between human immunodeficiency virus type I
      (HIV-1) replication and the extent of immune destruction in HIV-1-infected
      children, virus burden in lymphoid tissues (LN) and peripheral blood was compared
      with changes in LN architecture and cytokine levels constitutively expressed in
      LN. In agreement with results of a preliminary study, the plasma HIV-1 RNA level
      correlated with the amount of provirus in LN. However, the level was also
      associated with a degree of destruction of lymphoid follicular architecture and
      an alteration of immune cytokine expression. Expression of interleukin (IL)-4 was
      higher in LN with higher virus replication. Reduction of plasma viremia was
      associated with an increase in IL-2 mRNA levels in LN. These findings suggest
      that measurable virus burden in the peripheral blood is not a simple reflection
      of viral replication in LN but is also influenced by the extent of progressive
      immune destruction.

PMID- 8648225
TI  - Polyradiculopathy associated with ganciclovir-resistant cytomegalovirus in an
      AIDS patient: phenotypic and genotypic characterization of sequential virus
      isolates.
AB  - To investigate the role of antiviral drug resistance in cytomegalovirus (CMV)
      disease progression, CMV cultured from an AIDS patient who developed progressive
      CMV disease despite continual anti- CMV treatment was characterized. In 7 CMV
      isolates, 1 ganciclovir-resistant strain predominated. Ganciclovir-resistant CMV,
      containing a UL97 mutation, was cultured from blood and urine before clinical
      indication of CMV central nervous system (CNS) disease, suggesting that the
      development of ganciclovir resistance preceded the dissemination of CMV to the
      CNS. Quantitative competitive polymerase chain reaction indicated that the
      isolation of ganciclovir-resistant CMV was concurrent with increased CMV DNA in
      plasma. The results suggest that antiviral resistance should be considered when
      selecting therapy for CMV CNS disease that develops in patients receiving
      treatment for CMV retinitis. In addition, plasma CMV DNA in AIDS patients
      receiving anti-CMV therapy may be a useful marker of disease progression and
      antiviral resistance.

PMID- 8648227
TI  - Seasonal variation of disseminated Penicillium marneffei infections in northern
      Thailand: a clue to the reservoir?
AB  - Disseminated Penicillium marneffei infections are common AIDS-defining
      opportunistic infections among persons with human immunodeficiency virus (HIV)
      infection in northern Thailand. Penicilliosis due to P. marneffei is the third
      most frequent AIDS-defining infection in this population, after tuberculosis and
      cryptococcosis. Very little is known about the epidemiology and natural reservoir
      of P. marneffei. The seasonal distribution of two common AIDS-defining fungal
      infections was compared among patients diagnosed between 1991 and 1994 at Chiang
      Mai University Hospital. There were 550 cases (492 male, 58 female patients) of
      P. marneffei and 793 cases (685 male, 108 female patients) of Cryptococcus
      neoformans infection diagnosed. In each year, P. marneffei but not C. neoformans
      infections were more frequent in the rainy than the dry season. Seasonal
      variation of P. marneffei infections in AIDS patients in northern Thailand may
      provide valuable information in determining the important reservoirs and
      exposures to this organism that lead to disseminated disease in these patients.

PMID- 8648228
TI  - Diphtheria antitoxin levels in US blood and plasma donors.
AB  - Plasma samples from 500 blood donors were titrated for diphtheria antitoxin (DAT)
      by the toxin neutralization (TN) test. Only 1.6% of donors had <0.01 IU/mL DAT,
      the minimum protective level against diphtheria; 15% had levels between 0.01 and
      <0.1 IU/mL, indicating basic protection, and 83.4% had levels > or =0.1 IU,
      indicating full protection. Three hundred fifty samples were studied by ELISA for
      diphtheria toxoid IgG antibodies to assess the utility of the assay as a quick,
      convenient method for evaluating diphtheria immunity. Although the correlation
      between TN and ELISA titers for the 350 samples was high (r = .80), there was no
      correlation (r = .07) for samples with antitoxin titers <0.1 IU/mL, the level of
      special interest for serosurveys for protection. Titration of 62 immune globulin
      samples (prepared from 1957 to 1994) showed that DAT levels in Massachusetts
      blood donors increased concurrently with increased use of tetanus-diphtheria
      vaccine in the state.

PMID- 8648230
TI  - Vitamin C for the treatment of recurrent furunculosis in patients with imparied
      neutrophil functions.
AB  - The effect of vitamin C treatment on 23 patients with a history of recurrent
      furunculosis with negative nasal cultures was studied. Neutrophil functions
      (chemotaxis, phagocytosis, or superoxide generation) of 12 patients were
      significantly lower than those of the matched controls. In this group, treatment
      with vitamin C (1 g/day) caused a dramatic clinical response as well as a
      significant improvement of neutrophil functions, reaching values similar to those
      of the controls. Two patients remained vitamin C-dependent. In the patients with
      normal neutrophil functions, vitamin C treatment neither affected neutrophil
      activity nor caused a clinical response. Therefore, patients suffering from
      recurrent furunculosis with defective neutrophil functions may be treated
      successfully with vitamin C, contributing to both neutrophil function recovery
      and a dramatic clinical response.

PMID- 8648229
TI  - Interleukin-10 and soluble tumor necrosis factor receptors in cerebrospinal fluid
      of children with bacterial meningitis.
AB  - The antiinflammatory mediators interleukin (IL)-10 and soluble tumor necrosis
      factor (TNF) receptors p55 (sTNFR-55) and sTNFR-75 in cerebrospinal fluid (CSF)
      from 37 children with bacterial meningitis were studied. CSF concentrations of IL
      10, sTNFR-55, and sTNFR-75 and of the proinflammatory cytokines TNF-alpha, IL-6,
      and IL-8 were markedly elevated and were, with the exception of the sTNFRs,
      significantly higher in CSF than in serum. CSF concentrations of sTNFR- 55 and
      sTNFR-75 were only associated positively with IL-10 levels. CSF glucose levels
      correlated highly with levels of IL-10, sTNFR-55, and sTNFR-75 and weakly with
      TNF-alpha and IL-6. Cytokine levels in CSF decreased rapidly, while sTNFR levels
      remained elevated for at least 24 h.

PMID- 8648231
TI  - Long-term malaria chemoprophylaxis with mefloquine in Dutch marines in Cambodia.
AB  - Three Dutch marine battalions (n=2289) serving in Western Cambodia during 1992
      1993 used mefloquine as weekly malaria chemoprophylaxis. One battalion started
      with a loading dose. Full compliance with prophylaxis was reported by 86.3%, and
      possible mefloquine-related adverse events were reported by 30.2%. Sixty-four
      periods of malaria were diagnosed in 59 marines. During deployment, 31 Plasmodium
      falciparum and no Plasmodium vivax infections occurred. After return, there were
      11 cases of falciparum malaria and 22 of vivax malaria, 16-72 days and 30-540
      days, respectively, after stopping prophylaxis. Mefloquine-resistant parasites
      were isolated from 4 Dutch and 4 Khmer patients. Long-term mefloquine prophylaxis
      was well tolerated but not totally effective.

PMID- 8648232
TI  - Evaluation of a polymerase chain reaction-based assay for diagnosis of Wuchereria
      bancrofti infection.
AB  - To assess the utility of a polymerase chain reaction (PCR)-based method for
      diagnosis of Wuchereria bancrofti infection, blood, plasma, and paraffin-embedded
      tissue samples were tested using a PCR-based assay that detects a W. bancrofti
      specific repetitive DNA sequence. The assay was positive in 100 microL of blood
      from 40 of 42 microfilaria-positive subjects, the 2 subjects with negative assays
      having microfilarial counts of 1. Samples from 127 uninfected subjects were PCR
      negative. The assay was also positive in 7 of 10 daytime samples in regions where
      infection is nocturnally periodic; PCR amplification from paraffin-embedded
      sections established the diagnosis of W. bancrofti infection in another 2 cases.
      A microtiter ELISA plate-based method was developed for rapid evaluation of large
      numbers of samples. These results suggest that this PCR-based assay will be
      useful in diagnosis of W. bancrofti infection in a variety of clinical settings.

PMID- 8648233
TI  - Interleukin-12 restores interferon-gamma production and cytotoxic responses in
      visceral leishmaniasis.
AB  - American visceral leishmaniasis (AVL) is associated with the absence of
      lymphocyte proliferative responses and interleukin (IL)-2 and interferon-gamma
      (IFN-gamma) production upon stimulation with Leishmania antigen. In contrast,
      cure of AVL is associated with restoration of these T cell functions. In the
      present study, the ability of IL-12, a cytokine that acts on NK and T cells to
      restore cellular immune responses in AVL, was evaluated. Participants of the
      study included 12 patients with AVL and 7 subjects cured of AVL. The
      [3H]thymidine uptake and IFN-gamma production in cultures of peripheral blood
      mononuclear cells (from AVL patients) stimulated with Leishmania chagasi antigen
      were 882 +/- 1393 cpm and zero, respectively. Addition of IL-12 enhanced the
      proliferative response to 5097 +/- 6429 cpm (P < .001) and IFN-gamma production
      to 305 +/- 325 pg/mL (P < .01). IL-12 also restored cytotoxic activity against
      the K562 cell line. These results indicate that IL-12 has an important role in
      the regulation of the cellular immune response in human leishmaniasis.

PMID- 8648234
TI  - Chlamydia pneumoniae and atherosclerotic plaque.

PMID- 8648235
TI  - Risk factors for susceptibility to heterosexual human immunodeficiency virus
      infection in women.

PMID- 8648236
TI  - Relationship between immune complex-dissociated p24 antigen and human
      immunodeficiency virus type 1 RNA titers in plasma.

PMID- 8648237
TI  - Relevance of plasma protein binding to antiviral activity and clinical efficacy
      of inhibitors of human immunodeficiency virus protease.

PMID- 8648238
TI  - Rapid progression to human immunodeficiency virus type 1 disease.

PMID- 8648239
TI  - Epidemiologic and diagnostic studies of patients with suspected early Lyme
      disease Missouri, 1990-1993.

PMID- 8648240
TI  - The ATM gene and the radiobiology of ataxia-telangiectasia.

PMID- 8648241
TI  - Induction of inositol 1,4,5 trisphosphate receptor genes by ionizing radiation.
AB  - We used differential display, a method designed to amplify partial cDNA sequences
      from subsets of mRNAs, to identify mRNAs induced by ionizing radiation in human
      Epstein Barr Virus (EBV)-transformed lymphoblastoid cells. Increased expression
      of a cDNA corresponding to the inositol 1,4,5 trisphosphate receptor (InsP3R)
      type 1 was observed after exposure of cells to 3Gy gamma-rays. This was confirmed
      by Northern blot analysis. The increase in mRNA for InsP3R type 1 was accompanied
      by a corresponding increase in the level of InsP3R type 1 protein as determined
      by Western blotting. Exposure of cells from patients with the human genetic
      disorder ataxia-telangiectasia (A-T), characterized by hypersensitivity to
      ionizing radiation, failed to change the levels of InsP3R type 1 mRNA and, as
      expected, there was no increase in InsP3R type 1 protein in A-T cells in response
      to radiation exposure. Protein levels for two other InsP3Rs, types 2 and 3, were
      observed to increase in control and A-T cells after exposure to ionizing
      radiation. The induction of the InsP3R type 1, which is primarily located in the
      endoplasmic reticulum, may play an important role in radiation signal
      transduction.

PMID- 8648242
TI  - Expression and localization of clusterin mRNA in the small and large intestine of
      the irradiated rat: its relationship with apoptosis.
AB  - Apoptotic elimination of intestinal cells following irradiation has been studied
      in the small and large intestine of the rat, and correlated with the level of
      expression and localization of clusterin mRNA. Clusterin was moderately expressed
      in normal intestine where only small levels of apoptosis were found. After
      irradiation, however, there was a temporal correlation between an increased
      apoptotic index and increased clusterin expression. Localization of clusterin
      mRNA by in situ hybridization identified extensive labelling in the lower part
      (Paneth cell region) of small intestinal crypt, whereas epithelial cells in the
      large intestine were diffusely labelled. Clusterin expression was not localized
      over apoptotic cells and its role may be as a cell protection factor for
      surviving cells, as had been suggested by others. Clusterin may also be involved
      in remodelling of the intestinal crypt after radiation damage, a process that
      includes altering cell-to-cell contact, apoptosis, and sloughing of the dead
      cells from the intestinal villi. Our results do show a close temporal link
      between apoptosis and clusterin expression, and, as such, expression of the gene
      may be a useful indicator of presence of apoptosis in the irradiated intestine.

PMID- 8648243
TI  - Inverse dose-rate effect for mutation induction by gamma-rays in human
      lymphoblasts.
AB  - In order to define further the effects of differences in recombinational
      proficiency on cell survival and mutation by ionizing radiation, we exposed the
      syngenic cell lines TK6 and WTK1 to continuous low dose-rate gamma-irradiation.
      We previously demonstrated that acute X-ray exposure results in lower survival
      and lower mutation induction at both the thymidine kinase (tk) and the
      hypoxanthine-guanine phosphoribosyltransferase (hprt) loci in TK6 cells compared
      with WTK1 cells. These differences were attributed in part to reduced levels of
      recombination in the TK6 line relative to WTK1. Using a low dose rate 137Cs
      irradiator, we exposed asynchronous growing populations of these cells to gamma
      rays at 14.3, 6.7 and 2.7 cGy/h. Both cell lines exhibited a dose-rate effect on
      survival. Compared with acute doses, the low dose-rates also protected against
      mutation induction at the hrpt locus in WTK1, but protection was inversely
      related to dose-rate. There was also a slight inverse dose-rate effect in TK6,
      with mutation induction at the lowest dose-rate exceeding that at acute
      exposures.

PMID- 8648244
TI  - Effect of B-type cyclin over-expression on radiation-induced mitotic delay in the
      fission yeast.
AB  - Exposure to ionizing radiation temporarily blocks eukaryotic cell cycle
      progression at the G2/M boundary (G2 delay). The delay probably provides time for
      repair of DNA damage before chromosome segregation and is thus an active
      response, indicative of a checkpoint control function. Transition from G2 into
      mitosis is normally controlled by the activity of a cyclin-dependent kinase, cdc2
      in the fission yeast (Schizosaccharomyces pombe). Genetic and cell kinetic
      evidence suggest that irradiation may impose mitotic delay by inactivation of the
      cdc2 product, p34cdc2. The activity of p34cdc2 in G2 is regulated by
      phosphorylation and association with a B-type cyclin, the product of the cdc13
      gene, p56cdc13. Previous work does not support a major role for changes in
      phosphorylation of p34cdc2 in the induction of mitotic delay. Alternatively the
      kinase may be regulated by changes in the activity/availability of p56cdc13. We
      have therefore tested the effect of high level, episomal expression of the cdc13
      gene on the induction of mitotic delay. No influence of this procedure on the
      duration of delay was detected, either in a wild-type cell cycle background, or
      the mutants wee1-50 and cdc2-3w, which show abnormal phosphorylation of p34cdc2.

PMID- 8648245
TI  - Reducing the radiation-induced G2 delay causes HeLa cells to undergo apoptosis
      instead of mitotic death.
AB  - Cells exposed to radiation may undergo death through apoptosis or mitotic death.
      HeLa cells predominantly undergo mitotic death after irradiation. Treatment of
      these cells with caffeine has been shown to shorten the G2 delay after
      irradiation, and to decrease their survival. The kinase inhibitor staurosporine
      also decreases the radiation-induced G2 delay in HeLa cells. Here we extend these
      findings to show that the decrease in radiation-induced G2 delay mediated by
      caffeine or staurosporine is accompanied by a shift in the pathway of cell death
      from mitotic death to apoptotic death. The increase in apoptosis is further
      accompanied by decreased clonogenic survival after irradiation. Based on these
      findings we propose the hypothesis that one mechanism of enhancing cell killing
      by radiation is to trigger apoptosis by decreasing the G2 delay induced by
      irradiation.

PMID- 8648246
TI  - Microdosimetry of haemopoietic stem cells irradiated by alpha particles from the
      short-lived products of 222Rn decays in fat cells and haemopoietic tissue.
AB  - The Monte Carlo method is used to model fat cells and the nuclei of stem cells in
      haemopoietic tissue where 222Rn is dissolved in different amounts in the fat and
      tissue. Calculations are performed for fat cells of diameters 50 and 100 microns
      and for stem cell nuclei of 8 and 16 microns diameters for various fractions of
      fat filling the volume. Average doses (and their distributions) to stem cell
      nuclei from single passages of alpha particles are presented. In addition to
      dose, the relationship between LET and dose is obtained, illustrating the
      importance of 'stoppers' in the calculations. The annual average dose equivalent
      for a concentration of 1 Bq/m3 in air agrees well with other authors at 12 mu
      Sv/year. The method also allows the calculation of the fraction of stem cell
      nuclei hit annually. Here for 1 Bq/m3, stem cell nuclei of diameter 8 microns and
      100% fat filing 15 x 10(-7) of the stem cell nuclei are hit.

PMID- 8648247
TI  - Effects of track structure and cell inactivation on the calculation of heavy ion
      mutation rates in mammalian cells.
AB  - It has long been suggested that inactivation severely effects the probability of
      mutation by heavy ions in mammalian cells. Heavy ions have observed cross
      sections of inactivation that approach and sometimes exceed the geometric size of
      the cell nucleus in mammalian cells. In the track structure model of Katz the
      inactivation cross section is found by summing an inactivation probability over
      all impact parameters from the ion to the sensitive sites within the cell
      nucleus. The inactivation probability is evaluated using the dose-response of the
      system to gamma-rays and the radial dose of the ions and may be equal to unity at
      small impact parameters for some ions. We show how the effects of inactivation
      may be taken into account in the evaluation of the mutation cross sections from
      heavy ions in the track structure model through correlation of sites for gene
      mutation and cell inactivation. The model is fit to available data for HPRT
      mutations in Chinese hamster cells and good agreement is found. The resulting
      calculations qualitatively show that mutation cross sections for heavy ions
      display minima at velocities where inactivation cross sections display maxima.
      Also, calculations show the high probability of mutation by relativistic heavy
      ions due to the radial extension of ions track from delta-rays in agreement with
      the microlesion concept. The effects of inactivation on mutations rates make it
      very unlikely that a single parameter such as LET or Z*2/beta(2) can be used to
      specify radiation quality for heavy ion bombardment.

PMID- 8648248
TI  - Radiation-induced structural modifications in dsDNA analysed by FT-Raman
      spectroscopy.
AB  - Structural changes of double stranded DNA in aqueous solution induced by ionizing
      radiation were studied by Fourier-Transform-Raman spectroscopy. In addition to
      base damage, strand breaks, structural changes, i.e. unstacking of the bases,
      premelting effects and disordering of the B-form backbone could be observed. The
      amount of these different kinds of damage depended on the concentration of the
      DNA solution. Specifically, the following modifications were found depending on
      the gamma-ray dose and DNA concentration. (1) Intensity increase of the lines of
      dT (1240 cm-1) and dA (729, cm-1) indicating unstacking of these bases. (2)
      Intensity and frequency changes of the marker bands of all four bases indicating
      structural modifications. (3) Intensity decrease of the sugar marker lines
      showing change of the bonds in the deoxyribose and of bonds between the sugar
      moiety and the phosphodiester. (4) Intensity decrease of the lines of the
      phosphodiester groups (1094 and 790 cm-1) with simultaneous appearance of a
      difference peak at 1080 cm-1 and a new peak at 980 cm-1 suggesting the presence
      of strand breaks. (5) Intensity decrease of the B-form marker band (approximately
      835 cm-1) and new lines at 876 cm-1), at approximately 660 cm-1 (C3'-endo/anti of
      dG) and at 1312 cm-1 (C3'endo/syn of dA) indicating decrease of the B-form
      conformation and the developing of partly new secondary forms of the DNA
      representing a helix-to-coil transition.

PMID- 8648249
TI  - Rejoining of DNA double-strand breaks in X-irradiated CHO cells studied by
      constant- and graded-field gel electrophoresis.
AB  - Induction and repair of double-strand breaks (dsb) were measured in exponentially
      growing CHO-10A cells using the constant- and graded-field gel electrophoresis.
      Dsb repair was studied after an X-ray dose of 60 Gy. The repair curve obtained
      was biphasic with the respective half-times of tau 1 = 3.8 +/- 0.9 and tau 2 =
      118 +/- 30 min. The number of non-reparable dsb was measured for X-ray doses up
      to 180 Gy and was found to be only a small fraction (14%) of all non-rejoinable
      breaks determined previously using the alkaline unwinding technique. The ratio of
      non-reparable dsb to the number of lethal events calculated from survival curves
      is 0.14:1. This result indicates that for CHO cells nonreparable dsb represent
      only a small fraction of lethal damage. This is in line with the cytogenetic
      observation that cell killing mainly results from mis-rejoined events (i.e.
      exchange aberrations, translocations, interstitial deletions). The kinetics of
      dsb rejoining were found to be independent of the size of the fragments involved
      (between 1 and 10 Mbp). In addition, the rejoining kinetics of DNA fragments < or
      = 1 Mbp did not show the formation of new DNA fragments with time after
      irradiation indicating the absence of programmed cell death in irradiated CHO
      cells.

PMID- 8648250
TI  - Concomitant low dose-rate irradiation and cisplatin treatment in ovarian
      carcinoma cell lines sensitive and resistant to cisplatin treatment.
AB  - Human ovarian carcinoma parental and cisplatin-resistant cells were evaluated for
      their radiation sensitivity to high and low dose-rate irradiation and for the
      effectiveness of cisplatin in radiosensitization. The cisplatin resistant variant
      A2780cp showed increased radiation resistance for both low dose-rate (LDRI) and
      high dose-rate irradiation. For cisplatin treatment for 1 h before and after HDRI
      there was radiosensitization in only the cisplatin-resistant variant. Concomitant
      cisplatin treatment during LDRI resulted in radiosensitization in both cell lines
      with dose-modifying factors ranging from 1.6 to 5.8. In this case greater
      radiosensitization was achieved in the parental cell line. In both cell lines the
      dose-modifying factors were larger when the cisplatin was refreshed every 6 h
      instead of 12 h during LDRI. These data show that cisplatin may be a very
      effective radiosensitizer when given during LDRI which is used in brachytherapy.

PMID- 8648251
TI  - Mechanisms of protection by buthionine sulphoximine against gamma-ray-induced
      micronuclei in polychromatic erythrocytes of mouse bone marrow.
AB  - The effect of pretreatment with buthionine sulphoximine (BSO) on the
      radiosensitivity of mouse bone marrow cells was studied using the in vivo
      micronucleus test. Varying concentrations of BSO were injected into mice by
      intraperitoneal injection 2 h before irradiation, and the frequency of
      micronuclei in polychromatic erythrocytes (MnPCEs) of bone marrow were scored.
      Treatment with BSO resulted in a significant reduction (41% at 20 mg/kg body
      weight) in the frequency of micronuclei induced by 1 Gy gamma-rays. Reduction was
      observed in cells sampled at 24, 30 and 48 h postirradiation with no apparent
      effect on the ratio of poly- to normo-chromatic erythrocytes in BSO-treated
      versus control groups. Glutathione levels in the bone marrow of BSO-treated
      animals 2 h after a single injection were found to be unaltered. The protective
      effect of BSO was not observed if it was given either immediately or 2 h after
      irradiation. Based on these and earlier findings it seemed as if BSO molecules
      may be involved in physicochemical reactions with reactive species generated in
      the system by irradiation. BSO showed relatively high reaction rate constants
      with hydroxyl radical (.OH, 2.5 x 10(9) dm3 mol-1s1, calculated on the basis of
      competition kinetics) and with singlet oxygen (1O2, 4.3 x 10(7) dm3 mol-1s-1 but
      a lower rate constant with hydrated electrons (< or = 5.0 x 10(6) dm3 mol-1s1).
      Based on half-life estimates, transients formed and potential for damage to
      biomolecules, .OH and 1O2 seemed to be the possible species responsible. In vitro
      studies reveal that BSO has significant abilities to protect DNA against single
      strand breaks and lipid peroxidation induced by 1O2 in microsomal membranes. This
      supports our hypothesis that BSO may be involved in scavenging the reactive
      species generated and that besides .OH, 1O2 may also be a major player in
      radiation damage.

PMID- 8648252
TI  - Comment on the paper: enhanced deposition of radon daughter nuclei in the
      vicinity of power frequency electromagnetic fields.

PMID- 8648253
TI  - Comment on the paper: enhanced deposition of radon daughter nuclei in the
      vicinity of power frequency electromagnetic fields.

PMID- 8648254
TI  - A model of osteoarthritis and a potential new therapy.

PMID- 8648255
TI  - Spotlight on DHEA: a marker for progression of HIV infection?

PMID- 8648256
TI  - Diversity of phenotype and function of vascular smooth muscle cells.
AB  - Recent observations indicate that cell-to-cell and segment-to-segment variation
      occur in the morphology and function of vascular smooth muscle (VSM) cells in
      pulmonary and systemic arteries. This diversity includes differences in cell
      phenotype and in expression of cytoskeletal proteins as well as heterogeneity of
      the number and activity of potassium (K) channel types. The concept of cell
      diversity indicates that the arterial media is a mosaic of cell populations that
      differ from each other in phenotype and function. The prevalence of various VSM
      populations varies from segment to segment within a single artery and also may
      contrast among vascular trees of different organs. The composition of the
      arterial media is plastic, changing with normal development from fetus to adult
      and in response to vascular injury. Diversity of cell function is important in
      physiology and pathophysiology, allowing localized responses to vasodilators,
      vasoconstrictors, and proliferative stimuli within a vascular segment. Diversity
      may also explain the divergent responses of vascular beds to a common stimulus,
      such as hypoxia.

PMID- 8648257
TI  - Inhalational nitric oxide in pulmonary parenchymal and vascular disease.

PMID- 8648258
TI  - Protein kinase C activator inhibits progression of osteoarthritis induced in
      rabbit knee joints.
AB  - To study the role of protein kinase C (PKC) in cartilage tissue in
      osteoarthritis, experimental osteoarthritis was induced in the knee joints of
      rabbits by resection of the anterior cruciate ligament (ACL). At 4 weeks after
      the operation, osteoarthritic changes varying from surface irregularities and
      cleft formation to loss of the tangential layer were observed, and cloning or
      hypocellularity of the chondrocytes was observed mainly in the transitional and
      radial layers. The PKC activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or
      non-PKC-activating phorbol ester 4 alpha-phorbol-12,13-didecanate (PDD) was
      administered intraarticularly once a week from the day of the operation for 3
      weeks. Histologic evaluation with a rating scale was carried out. In the TPA
      administered group, cartilage structures were preserved almost completely, and
      score of the cartilage lesion was significantly less than that in animals
      administered PDD or in nonadministered controls. A chondroprotective role of PKC
      under mechanical stress was suggested.

PMID- 8648259
TI  - Longitudinal study of adrenal steroids in a cohort of HIV-infected patients with
      hemophilia.
AB  - The objective of the study was to relate plasma dehydroepiandrosterone sulfate
      (DHEA-S) concentrations to the progression of HIV infection in individual HIV
      infected men with hemophilia and to obtain information on the cause of DH EA-S
      alterations. Blood samples were obtained from 16 men with hemophilia; in 9 men
      serial samples were available for up to 11 years after HIV-1 infection. Control
      samples were obtained from men of comparable ages without hemophilia or HIV
      infection. Measurements were made of CD4+ cell counts, plasma adrenocorticotropic
      hormone (ACTH), cortisol, DHEA, DHEA-S, and prolactin. Before HIV infection, men
      with hemophilia had significantly lower plasma levels of DHEA-S than control men.
      After infection, 3 of 9 subjects studied serially had little or no change in
      plasma DHEA-S levels or in CD4+ cell counts over 11 years. Four of the 9 i n whom
      AIDS developed had progressive decreases in plasma DHEA-S concentrations that, in
      some cases, preceded a precipitous fall in CD4+ cell counts. Major decreases in
      plasma DHEA-S levels before falls in CD4+ counts were observed in 2 ot her
      subjects who had other severe illnesses. None of the decreases in DHEA-S levels
      were associated with decreased concentrations of plasma cortisol, ACTH, or
      prolactin. We conclude that plasma DHEA-S is an indicator of general health
      rather than a specific indicator for progression of HIV. The decrease in plasma
      DHEA-S is not related to ACTH stimulation of the adrenal gland or to cortisol
      secretion, but it may be related to cytokines that can inhibit 17-hydroxylation
      of DH EA-S precursors.

PMID- 8648260
TI  - Specific measurement of hypocarboxylated prothrombin in plasma or serum and
      application to the diagnosis of hepatocellular carcinoma.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed for measuring human
      hypocarboxyprothrombin, a protein induced by vitamin K antagonists (PIV KA-II). A
      specific monoclonal antibody (P1-2-B9) was prepared and used for coating a
      microELISA plate, and revelation proceeded with a rabbit polyclonal anti-human
      prothrombin antibody-peroxidase conjugate. This assay allowed the measurement of
      PIVKA-II at concentrations ranging from 2 to 200 ng/ml, with an intraassay
      coefficient of variation of less than 5.2% and an interassay coefficient of
      variation of less than 7.4%. This assay permits the direct evaluation of PIVKA-II
      in citrated plasma as well as in serum. The concentration of PIVKA-II is
      expressed in nanograms per milliliter. It offers specific measurement of PIVKA-II
      without any cross-reactivity from native prothrombin: the specificity for PIVKA
      II respective to prothrombin is > 10(5). No reactivity was observed with other
      vitamin K-dependent proteins, whether fully active or decarboxylated.
      Complementary studies have demonstrated that the monoclonal antibody used was
      preferentially directed to 3 to 6 Gla hypocarboxylated prothrombin. PIVKA-II
      concentration was below 2.4 ng/ml in normal individuals (n = 59). In 61 patients
      given dicoumarol for more than 90 days (receiving a stable therapy), the measured
      concentrations of PIVKA-II ranged from 750 to 13,400 ng/ml. Combined with the
      assay of alpha-fetoprotein (AFP), measurement of PIVKA-II in patients with liver
      diseases introduces a complementary exploration for hepatocellular carcinoma
      (HCC). In a study in 59 patients with HCC, the assay sensitivity was 49.1% for
      PIVKA-II, 47.5% for AFP, and 71% for both markers combined.

PMID- 8648261
TI  - Inhibition of glycosylation decreases Na+/H+ exchange activity, blocks NHE-3
      transport to the membrane, and increases NHE-3 mRNA expression in LLC-PK1 cells.
AB  - Recent studies have shown that NHE-3 is the luminal Na+/H+ exchanger isoform in
      cultured renal proximal tubule cells LLC-PK1 and OK (J Biol Chem 1994; 269:15613
      8). The purpose of the current experiments was to study the role of NHE-3
      glycosylation on antiporter activity in LLC-PK1 cells. Treatment of LLC-PK, cells
      with 1.5 microgram/ml tunicamycin for 24 hours, which blocks glycosylation in the
      endoplasmic reticulum, significantly decreased antiporter activity as asses sed
      by acid-stimulated sodium 22 uptake (9.52 +/- 1.0 nmol/mg protein in control
      cells vs 5.85 +/- 0.7 nmol/mg protein in tunicamycin-treated cells, p < 0.01, n =
      4) and sodium-dependent pHi recovery from an acid load (0.46 +/- 0.05 pH/min in
      control cells vs 0.35 +/- 0.04 pH/min in tunicamycin-treated cells, p < 0.02, n =
      6). Lactate dehydrogenase (LDH) concentration in the medium was the same in both
      groups (p > 0.05), indicating that the inhibitory effect of tunicamycin was not
      caused by cell toxicity. Northern hybridization of poly(A)+ RNA from LLC-PK1
      cells illustrated that in tunicamycin-treated cells, NHE-3 mRNA expression
      increased threefold over control cells. Immunoblots of luminal membranes from
      control LLC-PK, cells with specific NHE-3 antiserum showed a doublet at 94 to 95
      kd and a band at 90 kd. Luminal membranes from tunicamycin-treated cells showed
      only one strong band at 95 kd. NHE-3 immunoblots of whole cell extract from
      tunicamycin-treated cells showed that in addition to the 95 kd protein, an 87 kd
      band was also detected. These results are consistent with the possibility that
      the two bands in the 94 and 90 kd areas became deglycosylated and did not reach
      the membrane in the presence of tunicamycin. We conclude that glycosylation of
      the Na+/H+ exchanger isoform NHE-3 is essential for antiporter activity in LLC
      PK, cells. The results further suggest that glycosylation of NHE-3 mediates the
      translocation and insertion of this exchanger in the plasma membrane.

PMID- 8648262
TI  - Mode of action of iron (III) chelators as antimalarials. IV. Potentiation of
      desferal action by benzoyl and isonicotinoyl hydrazone derivatives.
AB  - The antimalarial action of iron chelators is limited by factors related to drug
      permeation and parasite susceptibility to metal deprivation. In this study we
      applied iron-chelating isonicotinoyl and benzoyl hydrazones on Plasmodium
      falciparum cultures and assessed their antimalarial properties. The agents w ere
      used both individually and in combination with deferoxamine (DFO), a clinically
      approved iron chelator, and with hydroxyethyl-starch-DFO, a macromolecular
      carrier of DFO. Salicylaldehyde isonicotinoyl hydrazone (SIH) and 2-hydroxy-1
      naphthylaldehyde m-fluorobenzoyl hydrazone (HNFBH) were found to be highly
      efficient in suppressing parasite growth at all developmental stages (IC50 24 +/-
      6 micromol/L and 0.21 +/- 0.04 micromol/L, respectively, in a 36-to-42 hour
      test). In combination with impermeant DFO, SIH and HNFBH actions on ring forms
      were significantly potentiated in terms of speed of drug action and extent of
      inhibition. The combined effect of the hydrazones with DFO was greater than
      additive. Based on the capacity of SIH to extract iron from infected cells and to
      transfer the metal to extracellular DFOs, we propose a mechanism for a
      synergistic action of permeant hydrazones and impermeant (DFO) iron chelators.
      The application of a combination of iron chelators as antimalarials might be of
      therapeutic value.

PMID- 8648263
TI  - Interaction of low molecular weight heparin with ketorolac.
AB  - Postoperative patients may receive ketorolac, a nonsteroidal antiinflammatory
      drug that inhibits platelet function, for analgesia and may receive low-molecular
      weight heparin (LMWH) for thrombosis prevention. We investigated whether the
      combination of these two agents increases blood loss in a rabbit model of
      hemostasis. In a randomized, blinded study, animals received either intramuscular
      ketorolac (0.5 mg/kg or 1.0 mg/kg) and subcutaneous saline solution, subcutaneous
      LMWH (100 U/kg) and intramuscular saline solution, ketorolac (0.5 mg/kg or 1.0
      mg/kg) and subcutaneous LMWH (100 U/kg), or intramuscular and subcutaneous saline
      solution given 30 minutes before ear incision and measurement of blood loss.
      Collagen-induced platelet aggregation was examined and anti-Xa levels were
      determined by using a chromogenic substrate method. As compared with results in
      saline-treated controls, blood loss was significantly increased in animals
      receiving ketorolac in a dose of 1.0 mg/kg but not in those treated with 0.5
      mg/kg. The addition of LMWH did not further increase blood loss above that
      observed with either dose of ketorolac alone. Platelet aggregation was inhibited
      by both doses of ketorolac. The anti-Xa levels in the LMWH-treated animals were
      comparable to those measured in patients receiving these agents for prophylaxis
      (0.09 to 0.13 U/ml). We conclude that in the rabbit model, LMWH does not augment
      ketorolac-associated bleeding when both agents are used in doses comparable to
      those given to human patients.

PMID- 8648264
TI  - Glucose-6-phosphate dehydrogenase deficiency severely restricts the
      biotransformation of daunorubicin in human erythrocytes.
AB  - Recognition and analysis of distinct mechanisms by which primaquine and other
      hemolytic drugs activate the hexose monophosphate shunt (HMS) have suggested a
      hitherto unsuspected pharmacogenetic interaction between daunorubicin metabolism
      and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Because this deficiency
      is very common, and because anthracyclines are indispensable antitumor
      antibiotics that are biotransformed mainly by carbonyl reductase, we have
      compared the reductase-mediated conversion of daunorubicin to daunorubicinol and
      the conversion of doxorubicin to doxorubicinol in G6PD-deficient and nondeficient
      erythrocytes. We found that even without G6PD deficiency, the HMS dehydrogenases
      selectively limited daunorubicin metabolism, as contrasted with that of
      doxorubicin. The milder GdA- variety of G6PD deficiency restricted the
      biotransformation of daunorubicin at therapeutic levels, in hemolysates and
      intact erythrocytes, within 15 minutes, for at least 24 hours. The bioconversion
      defect was even more severe in Gd Mediterranean G6PD deficiency. Primaquine
      aldehyde competed with daunorubicin as a substrate for carbonyl reductase. These
      studies show that HMS dehydrogenase activity controls carbonyl reductase
      dependent biotransformation. New issues arise concerning possible effects of G6PD
      deficiency on the oncolytic and toxic properties of anthracyclines that are
      effective substrates for carbonyl reductase and also on non-xenobiotic reactions
      catalyzed by this enzyme.

PMID- 8648265
TI  - Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial
      cells: association with CREB transcription factor activation.
AB  - We assessed the effect of angiotensin II on fibronectin biosynthesis a nd
      transcription factor activation in adult human mesangial cells in culture. We
      found that 10(-5) mol/L angiotensin II tended to increase fibronectin mRNA
      expression within 1 hour (1.2-fold +/- 0.3-fold of that in controls), with a
      significant increase after 4 hours (0.3-fold +/- 0.1-fold of that in controls, p
      < 0.05) and 24 hours (1.9-fold +/- 0.3-fold of that in controls, p < 0.02). In
      conjunction with increased fibronectin mRNA levels, angiotensin II exposure
      resulted in a significant elevation in immunoreactive fibronectin concentrations
      and the incorporation of (35S)-labeled methionine into fibronectin after 2 hours
      (224% +/- 23% of controls, p < 0.05). Angiotensin II also induced mesangial cell
      activation of the cyclic adenosine monophosphate response element binding protein
      (CREB) transcription factor, a DNA binding protein known to recognize specific
      regulatory elements present on the fibronectin gene promoter. Using the
      electrophoretic mobility shift assay, we showed that angiotensin II increased
      mesangial cell expression of the activated form of CREB after 4 hours (1.2-fold
      +/- 0.04-fold of that in controls, p < 0.05). To determine the importance of the
      CREB regulatory elements in mediating angiotensin II induction of fibronectin
      gene transcription, JEG-3 cells were transfected with plasmids containing
      fibronectin promoter-chloramphenicol acetyltransferase (CAT) reporter gene
      constructs with (FN510) or without (FN122) the CREB regulatory motifs.
      Angiotensin II resulted in a significant increase in CAT activity in FN510
      transfectants (1.6-fold +/- 0.2-fold of that in controls, p < 0.05), but there
      was no effect of angiotensin II on FN122 transfected cells. These data
      demonstrate that angiotensin II stimulates fibronectin biosynthesis in adult
      human mesangial cells and suggest that the process may be regulated at the
      transcriptional level.

PMID- 8648266
TI  - Kallistatin, a novel human tissue kallikrein inhibitor: levels in body fluids,
      blood cells, and tissues in health and disease.
AB  - Kallistatin, a human serine proteinase inhibitor, is a newly identified tissue
      kallikrein inhibitor. It binds strongly to tissue kallikrein but weakly to other
      serine proteinases such as chymotrypsin and elastase. The tissue distribution and
      changes in kallistatin levels in human diseases were characterized by using
      specific monoclonal and polyclonal antibodies against kallistatin. Kallistatin
      antigen levels in blood cells, fluids, and tissues measured with a specific
      enzyme-linked immunosorbent assay showed displacement curves that were parallel
      with those in purified kallistatin, indicating their immunologic identity.
      Expression of kallistatin mRNA in platelets, neutrophils, lymphocytes, monocytes,
      endothelial cells, hepatocytes, and colon and prostate carcinoma cells was
      identified by reverse transcription-polymerase chain reaction followed by
      Southern blot analysis. Plasma kallistatin concentration was 22.1 +/- 3.5
      micrograms/ml in 30 normal subjects and 21.1 +/- 3.8 micrograms/ml in 5 patients
      with C1 inhibitor deficiency. A significantly reduced kallistatin level (7.2 +/-
      2.5 micrograms/ml, p < 0.001) was seen in plasma samples from 9 patients with
      liver disease and 10 patients with sepsis (7.7 +/- 3.5 micrograms/ml, p < 0
      .001). Further, kallistatin levels in 10 women taking oral contraceptives (19.8
      +/- 3.8 micrograms/ml) and 21 pregnant women (14.9 +/- 3.3 microg/ml) were
      significantly lower than those seen in healthy individuals. These data suggest
      that kallistatin is found in plasma, is produced mostly in the liver, and can be
      consumed during sepsis. Its consumption in sepsis may indicate a protective role
      to prevent blood pressure lowering.

PMID- 8648267
TI  - Cyclosporine-induced detachment of vascular endothelial cells initiates the
      intrinsic coagulation system in plasma and whole blood.
AB  - Cyclosporine A (CsA) is supposed to alter the metabolism of vascular endothelial
      cells, leading to a prothrombotic state. We examined by which mechanism human
      umbilical vein endothelial cells (HUVECs) treated with CsA would promote
      coagulation in human plasma and in whole blood. Treatment of HUVECs with CsA at
      concentrations clinically used led to dose-dependent cell detachment, with the
      subsequent exposure of the highly procoagulant connective tissue. As determined
      by scanning electron microscopy, cell counting of detached and adherent cells,
      and antigenic measurement of collagen exposure, HUVECs treated with 0.4
      micrograms/ml CsA (or more) for 4 days exhibited significant amounts of
      subendothelial areas. On CsA-treated HUVEC monolayers, the clotting time of
      recalcified citrated platelet-rich plasma (PRP), but not platelet-poor plasma
      (PPP), was dose-dependently shortened. Likewise, the onset of thrombin generation
      was significantly earlier. Except at a high concentration of 8.0 micrograms/ml
      CsA, there was no procoagulant effect when PPP was used. To investigate CsA
      treated HUVECs in whole blood, cells were cultivated on globular microcarriers
      and were incubated with nonanticoagulated whole blood. When untreated cells were
      used, generation of factor Xa, thrombin, and kallikrein was completely suppressed
      for 30 minutes. HUVEC beads treated with 0.4 and 0.8 micrograms/ml CsA, however,
      led to a dose-dependent generation of all three coagulation factors, with peak
      values at 2.5 to 5 minutes. Extrinsic activation was excluded, since CsA
      treatment did not induce tissue factor activity in HUVECs. Furthermore, the
      thrombomodulin activity of HUVECs w as not altered by CsA. In conclusion,
      treatment of HUVECs with CsA for 4 days at concentrations clinically used leads
      to the exposure of subendothelial areas that induce activation of the intrinsic
      coagulation in recalcified PRP and nonanticoagulated whole blood.

PMID- 8648268
TI  - Diaphragmatic paralysis following scalenotomy for thoracic outlet syndrome.
AB  - Potential phrenic nerve injury that results in diaphragmatic dysfunction and
      respiratory insufficiency has important implications for the anesthesiologist who
      must insure adequate ventilation and gas exchange. A variety of traumatic
      injuries as well as some surgical manipulations have been identified with an
      increased frequency of diaphragmatic paralysis. We have observed the occurrence
      of this sequelae after scalenotomy for thoracic outlet obstruction, a previously
      unreported association.

PMID- 8648269
TI  - Use of laparoscopy in the treatment of acute and chronic right lower quadrant
      pain.
AB  - Laparoscopy and the availability of procedures which can be easily performed
      through the laparoscope, including appendectomy, alter the surgeon's approach
      towards the management of right lower quadrant pain, both acute and chronic.
      Laparoscopy can be utilized in a variety of clinical settings, a number far
      greater than those patients which would otherwise be considered proper subjects
      for open appendectomy. Laparoscopy can be diagnostic, therapeutic, and also
      prophylactic. A two year experience of managing right lower quadrant pain in a
      rural hospital setting was reviewed; the procedure naturally lent itself to a
      variety of patients because of its ease, safety, and diagnostic accuracy. Chart
      review indicates an extraordinary degree of success in alleviating both acute and
      chronic symptoms; only one patient appears to have recurrent right lower quadrant
      pain out of our entire group. The use of laparoscopy in this manner creates a
      paradigm for a type of medical practice that is problem-oriented instead of
      specialty-oriented. The pathological status of the appendix was not the only
      factor that predicted patients' clinical response to the procedure.

PMID- 8648270
TI  - Dysphagia: diagnosis and treatment in Kentucky.

PMID- 8648271
TI  - Dyslexia: a validation of the concept at two age levels.
AB  - The 144 participants were administered tasks with a demonstrated relationship to
      reading. Both older students (8 to 10 years old) and younger students (6 to 7
      years old) included three groups of poor readers (matched on word reading but
      differing in the discrepancy from expected reading level) and age-matched average
      readers. Older poor readers also had a control group of reading-matched younger
      subjects. The study provided no support for the concept of dyslexia at age 6 to 7
      years. Among older participants there was support for the concept of dyslexia as
      a phonological deficit and of nondiscrepant garden-variety poor reading as a
      developmental lag. More discrepant participants with dyslexia exhibited
      orthographic and serial naming-speed deficits, as well as phonological deficits,
      and were a distinctive dyslexic group. Less discrepant participants with dyslexia
      were more similar to garden-variety poor readers than to the more discrepant
      participants with dyslexia.

PMID- 8648272
TI  - A status report on transition planning for individuals with learning
      disabilities.
AB  - The predominant focus of the transition movement has been on individuals with
      moderate and severe disabilities. Only recently have professionals begun to
      comprehensively address the transition needs of individuals with learning
      disabilities. Although certain transition planning components are applicable to
      all youth, regardless of disability, the unique needs of specific disability
      categories must be recognized. The purpose of this article is to provide a review
      of transition as it relates to students with learning disabilities. Specifically,
      it provides (a) an overview of state and federal mandates and initiatives that
      influence transition practices, and (b) a discussion of transition practices for
      individuals with learning disabilities.

PMID- 8648273
TI  - Transition to living: the neglected component of transition programming for
      individuals with learning disabilities.
AB  - The purpose of this article is to document the need for assisting individuals
      with learning disabilities (LD) to transition to adult life, with particular
      emphasis on aspects of adult life other than employment and postsecondary
      education. The adult roles emphasized are maintaining a home, becoming
      appropriately involved in the community (including recreation and leisure
      activities), and experiencing satisfactory personal and social relationships. The
      first section of this article reviews the results of major studies on the adult
      adjustment of individuals with LD, and discusses these individuals' learning
      characteristics. The second component briefly highlights existing models of
      career education and life skills education. The third section focuses on current
      practices in programming for adolescents with LD; and the final section proposes
      steps that must be taken if we are to more effectively help these individuals in
      their transition to all aspects of adult life.

PMID- 8648274
TI  - Comment on Eden et al. (1995)

PMID- 8648275
TI  - Self-determination instructional strategies for youth with learning disabilities.
AB  - The concept of self-determination is rapidly gaining attention and acceptance
      within the disability fields. The focus on self-determination is particularly
      strong in the transition-from-school-to-adulthood movement. The recent
      Individuals With Disabilities Education Act of 1990 mandated that students with
      disabilities be involved in the development of their transition plans and that
      students' preferences and interests be taken into account as transition plans are
      developed. This article describes four self-determination models and examines
      several instructional programs and strategies to promote self-determination in
      students with learning disabilities. Emerging issues in self-determination are
      examined, and the research and policy implications of these issues are discussed.
      These issues include (a) redefinition of roles, (b) the importance of taking
      risks, (c) individual versus group orientation for self-determination, and (d)
      the importance of early experiences.

PMID- 8648276
TI  - Life skills curricula for students with learning disabilities: a review of the
      literature.
AB  - This article presents a review of the current literature on life skills curricula
      and instruction as they relate to students with learning disabilities. The review
      of life skills literature is organized into two sections: intervention and follow
      up, follow-along studies. Based on the available research, several suggestions
      for designing research programs that address life skills curricula and
      instruction for students with learning disabilities are outlined.

PMID- 8648277
TI  - The positive force of vocational education: transition outcomes for youth with
      learning disabilities.
AB  - Successful transitions to postsecondary settings are associated with such adult
      outcomes as continuing education, independent living, and employment. The purpose
      of this article is to present research that supports the use of vocational
      education programs to improve the adult outcomes of students with learning
      disabilities as they transition to employment. The literature review focuses on
      four major topics: (a) data from follow-up and follow-along studies illustrating
      the relationship between vocational-technical education and adult outcomes; (b)
      recent program trends in vocational education; (c) current practices in
      vocational education regarding placement and access, instructional and setting
      demands, and teacher attitudes and preparation; and (d) speculations about the
      effects of school reform and pending legislation.

PMID- 8648278
TI  - Transition and students with learning disabilities: creating sound futures.
AB  - This article initiates a double issue that addresses a traditionally absent or
      rare piece in the system puzzle of preparing individuals with learning
      disabilities to meet the challenges of adulthood. Most professional efforts have
      focused on academic preparation for the 25 years or so that learning disabilities
      have been recognized. The rest of the person's adult adjustment (self
      determination, life skills and community living, vocational preparation and
      employment, etc.) is presented within the framework of vertical and horizontal
      transitions, to organize the reader to consider all the options that youth must
      consider and prepare for. Individualized transition planning is discussed as a
      dynamic vehicle by which to empower students and families to utilize strengths,
      set and reach short-term and long-range goals, and include community variables in
      the process. Finally, an overview of the two issues describes their creation,
      their core common themes, and highlights of each article.

PMID- 8648279
TI  - Transition planning assessment for secondary-level students with learning
      disabilities.
AB  - This article presents a survey of and recommendations for transition planning
      assessment for secondary teachers of students with learning disabilities. The
      author makes a case for redirecting assessment practices in secondary
      instructional programs to obtain present-level-of-functioning information for IEP
      planning that extends beyond high school graduation as a single outcome. Critical
      outcomes in adult adjustment requiring transition planning are presented. Current
      standardized and nonstandardized assessment procedures that focus on adult
      outcomes, as well as preferences and interests in planning for the future, are
      described. The author gives recommendations for planning and conducting
      transition-needs assessment for secondary schools.

PMID- 8648281
TI  - Reframing the learning disabilities experience.
AB  - Reframing the learning disabilities experience has been identified by researchers
      as a key variable in employment success and adjustment in adulthood. This article
      provides a discussion of theory, related literature, methods, and techniques
      related to the process of reframing--from recognition, to understanding, to
      acceptance of the learning disability, to the development of a plan of action. We
      argue that successful reframing is imperative if one is to take control of his or
      her learning disability in adult life. It is also necessary for the development
      and implementation of self-advocacy skills.

PMID- 8648280
TI  - Students with learning disabilities in Canadian colleges and universities: a
      primer for service provision.
AB  - The authors, both of whom are involved in providing support services to
      university students with learning disabilities, describe some of the current
      issues and challenges faced by students, staff, and faculty. Programs and
      initiatives in some Canadian institutions that have proven to be successful are
      described, such as a sequential five-step procedure model that directed the
      delivery of services at the university. Resource and reference lists are also
      provided.

PMID- 8648282
TI  - Word frequency effects on recall, recognition, and word fragment completion
      tests.
AB  - In 3 experiments, the effect of word frequency on an indirect word fragment
      completion test and on direct free-recall and Yes-no recognition tests was
      investigated. In Experiment 1, priming in word fragment completion was
      substantially greater for low-frequency words than for high-frequency words, but
      free recall was unaffected. Experiment 2 replicated the word fragment completion
      result and showed a corresponding effect in recognition. Experiment 3 replicated
      the low-frequency priming advantage in word fragment completion with the set of
      words that P.L. Tenpenny and E.J. Shoben (1992) had used in reporting the
      opposite pattern in word fragment completion. Using G. Mandler's (1980) dual
      process theory, the authors argue that recognition and word fragment completion
      tests both rely on within-item integration that influences familiarity, whereas
      recall hinges on elaboration that influences retrievability.

PMID- 8648283
TI  - Studies of directed forgetting in older adults.
AB  - Younger and older adults were compared in 4 directed forgetting experiments.
      These varied in the use of categorized versus unrelated word lists and in the use
      of item by item versus blocked remember-forget cueing procedures. Consistent with
      L. Hasher and R. T. Zacks's (1988) hypothesis of impaired inhibitory mechanisms
      in older adults, a variety of findings indicated that this age group is less able
      than younger adults to suppress the processing and retrieval of items designated
      as to be forgotten (TBF). Specifically, in comparison with younger adults, older
      adults produced more TBF word intrusions on an immediate recall test (Experiments
      1A and 1B), took longer to reject TBF items (relative to a neutral baseline) on
      an immediate recognition test (Experiment 3), and recalled (Experiments 1A, 1B,
      and 2) and recognized (Experiment 1B and 2) relatively more TBF items on delayed
      retention tests in which all studied items were designated as targets.

PMID- 8648284
TI  - Artificial grammar learning depends on implicit acquisition of both abstract and
      exemplar-specific information.
AB  - The contributions of exemplar-specific and abstract knowledge to artificial
      grammar learning were examined in amnesic patients and controls. In Experiment 1,
      grammatical rule adherence and chunk strength exerted separate effects on
      grammaticality judgments. Amnesic patients exhibited intact classification
      performance, demonstrating the same pattern of results as controls. In Experiment
      2, amnesic patients exhibited impaired declarative memory for chunks. In
      Experiment 3, both amnesic patients and controls exhibited transfer when tested
      with a letter set different than the one used for training, although performance
      was better when the same letter sets were used at training and test. The results
      suggest that individuals learn both abstract information about training items and
      exemplar-specific information about chunk strength and that both types of
      learning occur independently of declarative memory.

PMID- 8648285
TI  - Test question modulates cue competition between causes and between effects.
AB  - The research reported in this article replicated the well-established phenomenon
      of competition between causes (C) as well as the more controversial presence and
      absence of competition between effects (E). The test question was identified as a
      crucial factor leading to each outcome. Competition between causes was obtained
      when the test question asked about the probability of E given C, p(E/C),
      implicitly compared with the probability of E given some alternative cause,
      p(E/C'). competition between effects was obtained when the test question asked
      about p(C/E) implicitly compared with p(C/E'). Under these conditions, effects
      competed for diagnostic value just as causes competed for predictive value.
      Additionally, some conditions in which neither causes nor effects competed were
      identified. These results suggest a bidirectional and noncompetitive learning
      process, the contents of which can be used in different ways (competitively or
      noncompetitively and forward or backward) as a function of test demands.

PMID- 8648286
TI  - Mapping conceptual to spatial relations in visual reasoning.
AB  - In 3 experiments, the authors investigated the impact of goals and perceptual
      relations on graph interpretation when people evaluate functional dependencies
      between continuous variables. Participants made inferences about the relative
      rate of 2 continuous linear variables (altitude and temperature). The authors
      varied the assignments of variables to axes, the perceived cause-effect relation
      between the variables, and the causal status of the variable being queried. The
      most striking finding was that accuracy was greater when the slope-mapping
      constraint was honored, which requires that the variable being queried be
      assigned to the vertical axis, so that steeper lines map to faster changes in the
      queried variable. The authors propose that graphs provide external instantiations
      of intermediate mental representations, enabling people to move from visuospatial
      representations to abstractions through the use of natural mappings between
      perceptual and conceptual relations.

PMID- 8648287
TI  - Does recoding interfering material improve recall?
AB  - In 4 experiments, the authors attempted to replicate an improvement in recall of
      target memories produced by a post-learning clue enabling participants to
      reorganize and segregate interfering material, as shown by G. H. Bower and T.
      Mann (1992). The 1st three experiments studied retroactive interference (RI) in
      free recall of an initial word list after participants were informed post
      learning of a way to categorize a second, interfering list. In each case, the
      reorganizing clue failed to reduce RI. In the 4th experiment, interference during
      serial recall of an initial list of letters from a 2nd list was examined. Again,
      the reorganizing clue given after learning failed to reduce RI. Clearly, if the
      post-information effect is genuine, then better experimental arrangements will be
      required to demonstrate it more reliably.

PMID- 8648288
TI  - Visual memory for novel shapes: implicit coding without attention.
AB  - Implicit memory for novel shapes was explored with a negative priming paradigm.
      The results show that representations of shapes, formed in a single trial and
      without attention, can last without decrement across 200 intervening trials and
      with temporal delays of up to a month. No explicit memory of the shapes was
      available, either immediately or after a delay. There were consistent individual
      differences in the amount of negative priming shown, and some participants showed
      only facilitation. There was a trend toward increased facilitation across time,
      as if the memory of the shape survived longer than an "action tag" attached to
      it, which specified whether it should be attended or ignored. The results
      demonstrate a surprising combination of plasticity and permanence in the visual
      system and suggest that the roles of both attention and repetition may be to
      ensure voluntary retrievability rather than to form a lasting memory.

PMID- 8648289
TI  - Base rates in category learning.
AB  - Previous researchers have discovered perplexing inconsistencies in how people
      appear to utilize category base rates when making category judgments. In
      particular, D.L. Medin and S.M. Edelson (1988) found an inverse base-rate effect,
      in which participants tended to select a rare category when tested with a
      combination of conflicting cues, and M.A. Gluck and G.H. Bower (1988) reported
      apparent base-rate neglect, in which participants tended to select a rare
      category when tested with a single symptom for which objective diagnosticity was
      equal for all categories. This article suggests that common principles underlie
      both effects: First, base-rate information is learned and consistently applied to
      all training and testing cases. Second, the crucial effect of base rates is to
      cause frequent categories to be learned before rare categories so that the
      frequent categories are encoded by their typical features and the rare categories
      are encoded by their distinctive features. Four new experiments provide evidence
      consistent with those principles. The principles are formalized in a new
      connectionist model that can rapidly shift attention to distinctive features.

PMID- 8648290
TI  - Pseudohomophone effects and models of word recognition.
AB  - Two experiments examined factors that influence the processing of
      pseudohomophones (nonwords such as brone or joap, which sound like words) and
      nonpseudohomophones (such as brone and joap, which do not sound like words). In
      Experiment 1, pseudohomophones yielded faster naming latencies and slower lexical
      decision latencies than did nonpseudohomophones, replicating results of R. S.
      McCann and D. Besner (1987) and R. S. McCann, D. Besner, and E. Davelaar (1988).
      The magnitude of the effect was related to subjects' speed in lexical decision
      but not naming. In Experiment 2, both immediate and delayed naming conditions
      were used. There was again a significant pseudohomophone effect that did not
      change in magnitude across conditions. These results indicate that
      pseudohomophone effects in the lexical-decision and naming tasks have different
      bases. In lexical decision, they reflect the pseudohomophone's activation of
      phonological and semantic information associated with words. In naming, they
      reflect differences in ease of articulating familiar versus unfamiliar
      pronunciations. Implications of these results concerning models of word
      recognition are discussed, focusing on how pseudohomophone effects can arise
      within models that do not incorporate word-specific representations, such as the
      M. S. Seidenberg and J. L. McClelland (1989) model.

PMID- 8648291
TI  - Block of neuronal chloride channels by tetraethylammonium ion derivatives.
AB  - The block by the symmetric tetraethylammonium (TEA) ion derivatives
      tetrapropylammonium (TPrA), tetrabutylammonium (TBA), and tetrapentylammonium
      (TPeA) ions of fast chloride channels in acutely dissociated rat cortical neurons
      was studied with the excised inside-out configuration of the patch-clamp
      technique. When applied to the intracellular membrane surface, all three of the
      quaternary ammonium compounds (QAs) induced the appearance of short-lived closed
      states in a manner consistent with a blocking mechanism where the blocker
      preferentially binds to the open kinetic state and completely blocks ion current
      through the channel. The drug must leave the channel before the channel can
      return to a closed state. The mechanism of block was studied using one
      dimensional dwell-time analysis. Kinetic models were fit to distributions of open
      and closed interval durations using the Q-matrix approach. The blocking rate
      constants for all three of the QAs were similar with values of approximately 12
      20 x 10(6) M-1s-1. The unblocking rates were dependent on the size or
      hydrophobicity of the QA with the smallest derivative, TPrA, inducing a blocked
      state with a mean lifetime of approximately 90 microseconds, while the most
      hydrophobic derivative, TPeA, induced a blocked state with a mean lifetime of
      approximately 1 ms. Thus, it appears as though quaternary ammonium ion block of
      these chloride channels is nearly identical to the block of many potassium
      channels by these compounds. This suggests that there must be structural
      similarities in the conduction pathway between anion and cation permeable
      channels.

PMID- 8648292
TI  - The fusion kinetics of influenza hemagglutinin expressing cells to planar bilayer
      membranes is affected by HA density and host cell surface.
AB  - Time-resolved admittance measurements were used to follow formation of individual
      fusion pores connecting influenza virus hemagglutinin (HA)-expressing cells to
      planar bilayer membranes. By measuring in-phase, out-of-phase, and dc components
      of currents, pore conductances were resolved with millisecond time resolution.
      Fusion pores developed in stages, from small pores flickering open and closed, to
      small successful pores that remained open until enlarging their lumens to sizes
      greater than those of viral nucleocapsids. The kinetics of fusion and the
      properties of fusion pores were studied as functions of density of the fusion
      protein HA. The consequences of treating cell surfaces with proteases that do not
      affect HA were also investigated. Fusion kinetics were described by waiting time
      distributions from triggering fusion, by lowering pH, to the moment of pore
      formation. The kinetics of pore formation became faster as the density of active
      HA was made greater or when cell surface proteins were extensively cleaved with
      proteases. In accord with this faster kinetics, the intervals between transient
      pore openings within the flickering stage were shorter for higher HA density and
      more extensive cell surface treatment. Whereas the kinetics of fusion depended on
      HA density, the lifetimes of open fusion pores were independent of HA density.
      However, the lifetimes of open pores were affected by the proteolytic treatment
      of the cells. Faster fusion kinetics correlated with shorter pore openings. We
      conclude that the density of fusion protein strongly affects the kinetics of
      fusion pore formation, but that once formed, pore evolution is not under control
      of fusion proteins but rather under the influence of mechanical forces, such as
      membrane bending and tension.

PMID- 8648293
TI  - Comparison of transient and successful fusion pores connecting influenza
      hemagglutinin expressing cells to planar membranes.
AB  - Time-resolved admittance measurements were used to investigate the evolution of
      fusion pores formed between cells expressing influenza virus hemagglutinin (HA)
      and planar bilayer membranes. The majority of fusion pores opened in a stepwise
      fashion to semistable conductance levels of several nS. About 20% of the pores
      had measurable rise times to nS conductances; some of these opened to
      conductances of approximately 500 pS where they briefly lingered before opening
      further to semistable conductances. The fall times of closing were statistically
      similar to the rise times of opening. All fusion pores exhibited semistable
      values of conductance, varying from approximately 2-20 nS; they would then either
      close or fully open to conductances on the order of 1 microS. The majority of
      pores closed; approximately 10% fully opened. Once within the semistable stage,
      all fusion pores, even those that eventually closed, tended to grow.
      Statistically, however, before closing, transient fusion pores ceased to grow and
      reversed their conductance pattern: conductances decreased with a measurable time
      course until a final drop to closure. In contrast, pore enlargement to the fully
      open state tended to occur from the largest conductance values attained during a
      pore's semistable stage. This final enlargement was characterized by a stepwise
      increase in conductance. The density of HA on the cell surface did not strongly
      affect pore dynamics. But increased proteolytic treatment of cell surfaces did
      lead to faster growth within the semistable range. Transient pores and pores that
      fully opened had indistinguishable initial conductances and statistically
      identical time courses of early growth, suggesting they were the same upon
      formation. We suggest that transient and fully open pores evolved from common
      structures with stochastic factors determining their fate.

PMID- 8648294
TI  - K(+)- and HCO3(-)-dependent acid-base transport in squid giant axons. I. Base
      efflux.
AB  - We used microelectrodes to monitor the recovery (i.e., decrease) of intracellular
      pH (pHi) after using internal dialysis to load squid giant axons with alkali to
      pHi values of 7.7, 8.0, or 8.3. The dialysis fluid (DF) contained 400 mM K+ but
      was free of Na+ and Cl-. The artificial seawater (ASW) lacked Na+, K+, and Cl-,
      thereby eliminating effects of known acid-base transporters on pHi. Under these
      conditions, halting dialysis unmasked a slow pHi decrease caused at least in part
      by acid-base transport we refer to as "base efflux." Replacing K+ in the DF with
      either NMDG+ or TEA+ significantly reduced base efflux and made membrane voltage
      (Vm) more positive. Base efflux in K(+)-dialyzed axons was stimulated by
      decreasing the pH of the ASW (pHo) from 8 to 7, implicating transport of acid or
      base. Although postdialysis acidifications also occurred in axons in which we
      replaced the K+ in the DF with Li+, Na+, Rb+, or Cs+, only with Rb+ was base
      efflux stimulated by low pHo. Thus, the base effluxes supported by K+ and Rb+
      appear to be unrelated mechanistically to those observed with Li+, Na+, or Cs+.
      The combination of 437 mM K+ and 12 mM HCO3- in the ASW, which eliminates the
      gradient favoring a hypothetical K+/HCO3- efflux, blocked pHi recovery in K(+)
      dialyzed axons. However, the pHi recovery was not blocked by the combination of
      437 mM Na+, veratridine, and CO2/HCO3- in the ASW, a treatment that inverts
      electrochemical gradients for H+ and HCO3- and would favor passive H+ and HCO3-
      fluxes that would have alkalinized the axon. Similarly, the recovery was not
      blocked by K+ alone or HCO3- alone in the ASW, nor was it inhibited by the K-H
      pump blocker Sch28080 nor by the Na-H exchange inhibitors amiloride and
      hexamethyleneamiloride. Our data suggest that a major component of base efflux in
      alkali-loaded axons cannot be explained by metabolism, a H+ or HCO3- conductance,
      or by a K-H exchanger. However, this component could be mediated by a novel
      K/HCO3- cotransporter.

PMID- 8648295
TI  - K(+)- and HCO3(-)-dependent acid-base transport in squid giant axons II. Base
      influx.
AB  - We used microelectrodes to determine whether the K/HCO3 cotransporter tentatively
      identified in the accompanying paper (Hogan, E. M., M. A. Cohen, and W. F. Boron.
      1995. Journal of General Physiology. 106:821-844) can mediate an increase in the
      intracellular pH (pHi) of squid giant axons. An 80-min period of internal
      dialysis increased pHi to 7.7, 8.0, or 8.3; the dialysis fluid was free of K+,
      Na+, and Cl-. Our standard artificial seawater (ASW), which also lacked Na+, K+,
      and Cl-, had a pH of 8.0. Halting dialysis unmasked a slow pHi decrease.
      Subsequently introducing an ASW containing 437 mM K+ and 0.5% CO2/12 mM HCO3- had
      two effects: (a) it caused membrane potential (Vm) to become very positive, and
      (b) it caused a rapid pHi decrease, because of CO2 influx, followed by a slower
      plateau-phase pHi increase, presumably because of inward cotransport of K+ and
      HCO3- ("base influx"). Only extracellular Rb+ substituted for K+ in producing the
      plateau-phase pHi increase in the presence of CO2/HCO3-. Mean fluxes with Na+,
      Li+, and Cs+ were not significantly different from zero, even though Vm shifts
      were comparable for all monovalent cations tested. Thus, unless K+ or Rb+ (but
      not Na+, Li+, or Cs+) somehow activates a conductive pathway for H+, HCO3-, or
      both, it is unlikely that passive transport of H+, HCO3-, or both makes the major
      contribution to the pHi increase in the presence of K+ (or Rb+) and CO2/HCO3-.
      Because exposing axons to an ASW containing 437 mM K+, but no CO2/HCO3-, produced
      at most a slow pHi increase, K-H exchange could not make a major contribution to
      base influx. Introducing an ASW containing CO2/HCO3-, but no K+ also failed to
      elicit base influx. Because we observed base influx when the ASW and DF were free
      of Na+ and Cl-, and because the disulfonic stilbene derivatives SITS and DIDS
      failed to block base influx, Na(+)-dependent Cl-HCO3 exchange also cannot account
      for the results. Rather, we suggest that the most straightforward explanation for
      the pHi increase we observed in the simultaneous presence of K+ and CO2/HCO3- is
      the coupled uptake of K+ and HCO3-.

PMID- 8648296
TI  - Characterization of guanylate cyclase activity in single retinal rod outer
      segments.
AB  - cGMP mediates vertebrate phototransduction by directly gating cationic channels
      on the plasma membrane of the photoreceptor outer segment. This second messenger
      is produced by a guanylate cyclase and hydrolyzed by a light-activated cGMP
      phosphodiesterase. Both of these enzyme activities are Ca2+ sensitive, the
      guanylate cyclase activity being inhibited and the light-activated
      phosphodiesterase being enhanced by Ca2+. Changes in these activities due to a
      light-induced decrease in intracellular Ca2+ are involved in the adaptation of
      photoreceptors to background light. We describe here experiments to characterize
      the guanylate cyclase activity and its modulation by Ca2+ using a truncated rod
      outer segment preparation, in order to evaluate the enzyme's role in light
      adaptation. The outer segment of a tiger salamander rod was drawn into a suction
      pipette to allow recording of membrane current, and the remainder of the cell was
      sheared off with a probe to allow internal dialysis. The cGMP-gated channels on
      the surface membrane were used to monitor conversion of GTP, supplied from the
      bath, into cGMP by the guanylate cyclase in the outer segment. At nominal 0 Ca2+,
      the cyclase activity had a Km of 250 microM MgGTP and a Vmax of 25 microM cGMP s
      1 in the presence of 1.6 mM free Mg2+; in the presence of 0.5 mM free Mg2+, the
      Km was 310 microM MgGTP and the Vmax was 17 microM cGMP s-1. The stimulation by
      Mg2+ had an EC50 of 0.2 mM Mg2+ for MgGTP at 0.5 mM. Ca2+ inhibited the cyclase
      activity. In a K+ intracellular solution, with 0.5 mM free Mg2+ and 2.0 mM GTP,
      the cyclase activity was 13 microM cGMP s-1 at nominal 0 Ca2+; Ca2+ decreased
      this activity with a IC50 of approximately 90 nM and a Hill coefficient of
      approximately 2.0.

PMID- 8648297
TI  - The cGMP-phosphodiesterase and its contribution to sensitivity regulation in
      retinal rods.
AB  - We have used the truncated outer segment preparation to measure rod cGMP
      phosphodiesterase activity, as well as its modulation by Ca2+, in darkness and in
      light. The basal enzyme activity in darkness was approximately 0-3 s-1, and was
      largely independent of Ca2+ concentration from 10 nM to 10 microM. The steady
      state activity elicited by a step of light (lambda = 520 nm) was strongly
      enhanced by Ca2+, increasing from approximately 0.005 s-1/(h nu micron-2 s-1) at
      10 nM Ca2+ to approximately 0.16 s-1/h nu micron-2 s-1) at 10 microM Ca2+. Based
      on these measurements, as well as previous measurements on the effects of Ca2+ on
      rod guanylate cyclase and the cGMP-gated channel, we have calculated the step
      response-intensity relation for the rod cell in steady state. This relation
      agrees reasonably well with the relation directly measured from intact rods. We
      have also evaluated the relative contributions from the three Ca2+ effects to rod
      sensitivity. At low background light intensities, the Ca2+ modulation of the
      guanylate cyclase appears to be the most important for sensitivity regulation. At
      higher light intensities, especially above half-saturation of the response, the
      Ca2+ modulation of the light-stimulated phosphodiesterase shows a progressively
      important influence on the light response; it also extends the Weber-Fechner
      behavior of the cell to higher intensities. The contribution of the Ca2+
      modulation of the cGMP-gated channel is slight throughout.

PMID- 8648298
TI  - The mechanism of inward rectification of potassium channels: "long-pore plugging"
      by cytoplasmic polyamines.
AB  - The mechanism of inward rectification was examined in cell-attached and inside
      out membrane patches from Xenopus oocytes expressing the cloned strong inward
      rectifier HRK1. Little or no outward current was measured in cell-attached
      patches. Inward currents reach their maximal value in two steps: an instantaneous
      phase followed by a time-dependent "activation" phase, requiring at least two
      exponentials to fit the time-dependent phase. After an activating pulse, the
      quasi-steady state current-voltage (I-V) relationship could be fit with a single
      Boltzmann equation (apparent gating charge, Z = 2.0 +/- 0.1, n = 3). Strong
      rectification and time-dependent activation were initially maintained after patch
      excision into high [K+] (K-INT) solution containing 1 mM EDTA, but disappeared
      gradually, until only a partial, slow inactivation of outward current remained.
      Biochemical characterization (Lopatin, A. N., E. N. Makhina, and C. G. Nichols,
      1994. Nature. 372:366-396.) suggests that the active factors are naturally
      occurring polyamines (putrescine, spermidine, and spermine). Each polyamine
      causes reversible, steeply voltage-dependent rectification of HRK1 channels. Both
      the blocking affinity and the voltage sensitivity increased as the charge on the
      polyamine increased. The sum two Boltzmann functions is required to fit the
      spermine and spermidine steady state block. Putrescine unblock, like Mg2+
      unblock, is almost instantaneous, whereas the spermine and spermidine unblocks
      are time dependent. Spermine and spermidine unblocks (current activation) can
      each be fit with single exponential functions. Time constants of unblock change e
      fold every 15.0 +/- 0.7 mV (n = 3) and 33.3 +/- 6.4 mV (n = 5) for spermine and
      spermidine, respectively, matching the voltage sensitivity of the two time
      constants required to fit the activation phase in cell-attached patches. It is
      concluded that inward rectification in intact cells can be entirely accounted for
      by channel block. Putrescine and Mg2+ ions can account for instantaneous
      rectification; spermine and spermidine provide a slower rectification
      corresponding to so-called intrinsic gating of inward rectifier K channels. The
      structure of spermine and spermidine leads us to suggest a specific model in
      which the pore of the inward rectifier channel is plugged by polyamines that
      enter deeply into the pore and bind at sites within the membrane field. We
      propose a model that takes into account the linear structure of the natural
      polyamines and electrostatic repulsion between two molecules inside the pore.
      Experimentally observed instantaneous and steady state rectification of HRK1
      channels as well as the time-dependent behavior of HRK1 currents are then well
      fit with the same set of parameters for all tested voltages and concentrations of
      spermine and spermidine.

PMID- 8648299
TI  - Nucleotide turnover rate measured in fully relaxed rabbit skeletal muscle
      myofibrils.
AB  - Steady state measurements of the ATP turnover rate of myosin crossbridges in
      relaxed living mammalian muscle or in in vitro systems are complicated by other
      more rapid ATPase activities. To surmount these problems we have developed a
      technique to measure the nucleotide turnover rate of fully relaxed myosin heads
      in myofibrils using a fluorescent analogue of ATP (mant-ATP). Rabbit myofibrils,
      relaxed in 1.6 mM ATP, were rapidly mixed with an equal volume of solution
      containing 80 microM mant-ATP and injected into a fluorimeter. As bound ADP is
      released, a fraction of the myosin active sites bind mant-ATP and fluorescence
      emission rises exponentially, defining a rate of nucleotide turnover of 0.03 +/-
      0.001 s-1 at 25 degrees C (n = 17). This rate was approximately equal to one half
      that of purified myosin. The turnover rates for myosin and myofibrils increased
      between 5 degrees and 42 degrees C, reaching 0.16 +/- 0.04 s-1 and 0.06 +/- 0.005
      s-1, respectively, at 39 degrees C, the body temperature of the rabbit. If the
      rate observed for purified myosin occurred in vivo, it would generate more heat
      than is observed for resting living muscle. When myosin is incorporated into the
      myofilament lattice, its ATPase activity is inhibited, providing at least a
      partial explanation for the low rate of heat production by living resting muscle.

PMID- 8648301
TI  - Two functionally different Na/K pumps in cardiac ventricular myocytes.
AB  - The whole-cell patch-clamp technique was used to voltage clamp acutely isolated
      myocytes at -60 mV and study effects of ionic environment on Na/K pump activity.
      In quiescent guinea pig myocytes, normal intracellular Na+ is approximately 6 mM,
      which gives a total pump current of 0.25 +/- 0.09 pA/pF, and an inward background
      sodium current of 0.75 +/- 0.26 pA/pF. The average capacitance of a cell is 189
      +/- 61 pF. Our main conclusion is the total Na/K pump current comprises currents
      from two different types of pumps, whose functional responses to the
      extracellular environment are different. Pump current was reversibly blocked with
      two affinities by extracellular dihydro-ouabain (DHO). We determined dissociation
      constants of 72 microM for low affinity (type-1) pumps and 0.75 microM for high
      affinity (type-h) pumps. These dissociation constants did not detectably change
      with two intracellular Na+ concentrations, one saturating and one near half
      saturating, and with two extracellular K+ concentrations of 4.6 and 1.0 mM. Ion
      effects on type-h pumps were therefore measured using 5 microM DHO and on total
      pump current using 1 mM DHO. Extracellular K+ half-maximally activated the type-h
      pumps at 0.4 mM and the type-1 at 3.7 mM. Extracellular H+ blocked the type-1
      pumps with half-maximal blockade at a pH of 7.71 whereas the type-h pumps were
      insensitive to extracellular pH. Both types of pumps responded similarly to
      changes in intracellular-Na+, with 9.6 mM causing half-maximal activation.
      Neither changes in intracellular pH between 6.0 and 7.2, nor concentrations of
      intracellular K+ of 140 mM or below, had any effect on either type of pump. The
      lack of any effect of intracellular K+ suggests the dissociation constants are in
      the molar range so this step in the pump cycle is not rate limiting under normal
      physiological conditions. Changes in intracellular-Na+ did not affect the half
      maximal activation by extracellular K+, and vice versa. We found DHO-blockade of
      Na/K pump current in canine ventricular myocytes also occurred with two
      affinities, which are very similar to those from guinea pig myocytes or rat
      ventricular myocytes. In contrast, isolated canine Purkinje myocytes have
      predominantly the type-h pumps, insofar as DHO-blockade and extracellular K+
      activation are much closer to our type-h results than type-1. These observations
      suggest for mammalian ventricular myocytes: (a) the presence of two types of Na/K
      pumps may be a general property. (b) Normal physiological variations in
      extracellular pH and K+ are important determinants of Na/K pump current. (c)
      Normal physiological variations in the intracellular environment affect Na/K pump
      current primarily via the Na+ concentration. Lastly, Na/K pump current appears to
      be specifically tailored for a tissue by expression of a mix of functionally
      different types of pumps.

PMID- 8648302
TI  - Fixation for primary total knee arthroplasty: cemented.

PMID- 8648300
TI  - The relationship between depletion of intracellular Ca2+ stores and activation of
      Ca2+ current by muscarinic receptors in neuroblastoma cells.
AB  - The relationship between the depletion of IP3-releasable intracellular Ca2+
      stores and the activation of Ca(2+)-selective membrane current was determined
      during the stimulation of M1 muscarinic receptors in N1E-115 neuroblastoma cells.
      External Ca2+ is required for refilling Ca2+ stores and the voltage-independent,
      receptor-regulated Ca2+ current represents a significant Ca2+ source for
      refilling. The time course of Ca2+ store depletion was measured with fura-2
      fluorescence imaging, and it was compared with the time course of Ca2+ current
      activation measured with nystatin patch voltage clamp. At the time of maximum
      current density (0.18 + .03 pA/pF; n = 48), the Ca2+ content of the IP3
      releasable Ca2+ pool is reduced to 39 + 3% (n = 10) of its resting value. Calcium
      stores deplete rapidly, reaching a minimum Ca2+ content in 15-30 s. The
      activation of Ca2+ current is delayed by 10-15 s after the beginning of Ca2+
      release and continues to gradually increase for nearly 60 s, long after Ca2+
      release has peaked and subsided. The delay in the appearance of the current is
      consistent with the idea that the production and accumulation of a second
      messenger is the rate-limiting step in current activation. The time course of
      Ca2+ store depletion was also measured after adding thapsigargin to block
      intracellular Ca2+ ATPase. After 15 min in thapsigargin, IP3-releasable Ca2+
      stores are depleted by > 90% and the Ca2+ current is maximal (0.19 + 0.05 pA/pF;
      n = 6). Intracellular loading with the Ca2+ buffer EGTA/AM (10 microM; 30 min)
      depletes IP3-releasable Ca2+ stores by between 25 and 50%, and it activates a
      voltage-independent inward current with properties similar to the current
      activated by agonist or thapsigargin. The current density after EGTA/AM loading
      (0.61 + 0.32 pA/pF; n = 4) is three times greater than the current density in
      response to agonist or thapsigargin. This could result from partial removal of
      Ca(2+)-dependent inactivation.

PMID- 8648303
TI  - Fixation for primary total knee arthroplasty: cementless.

PMID- 8648304
TI  - Increasing incidence of femoral osteolysis in association with uncemented Harris
      Galante total hip arthroplasty. A follow-up report.
AB  - Sixty-nine consecutive uncemented total hip arthroplasties were performed in 59
      patients using the Harris-Galante prosthesis (Zimmer, Warsaw, IN). The patients
      were reviewed an average of 44 and 71 months after surgery. Patients in whom
      femoral osteolysis was identified at the time of the first review were again
      evaluated at the second review to determine if the size of the osteolytic lesion
      had increased over time. At the initial review an average of 44 months
      postsurgery, the overall incidence of femoral osteolysis was 22%. At the second
      review, the incidence of femoral osteolysis had increased from 22 to 52%. Two
      thirds of the lytic lesions diagnosed at the time of the first review had
      increased in size. This study demonstrated that the incidence of femoral
      osteolysis in cementless hip arthroplasties increases with time and that the
      majority of existing lesions enlarge over time. Once lesions are identified, more
      frequent follow-up evaluations are recommended. Revision surgery may be required
      for progressive femoral osteolysis, despite the absence of significant clinical
      symptoms.

PMID- 8648305
TI  - Osteolysis in cemented versus cementless acetabular components.
AB  - A prospective, randomized, double-blind, clinical trial comparing cemented with
      cementless total hip arthroplasty was performed to compare the prevalence and
      pattern of acetabular osteolysis. Both groups were similar before surgery.
      Acetabular components were metal-backed, titanium implants. Twenty-eight
      millimeter modular femoral heads with titanium femoral stems were used. At a
      minimum 2-year and mean 4-year follow-up period (range, 2-6 years), 224 patients
      had clinical and radiographic data available. There was no significant difference
      in the prevalence of acetabular osteolysis between cemented (5%) and cementless
      (9%) fixation. With or without cement, the use of a titanium femoral head led to
      osteolysis within a relatively short period after surgery in almost all of the
      cases, although this was not significant. The pattern of acetabular osteolysis
      was different. Progressive osteolysis occurred predominantly in acetabular zone 1
      in the cemented group and zone 2 in the cementless group. Cementless fixation of
      acetabular components has been advocated in an attempt to minimize osteolysis
      that may occur in cemented total hip arthroplasty. This study found no difference
      in the prevalence of acetabular osteolysis between the two groups.

PMID- 8648306
TI  - Long-term results of total knee arthroplasty in class 3 and 4 rheumatoid
      arthritis.
AB  - One hundred four total knee arthroplasties in 67 patients with class 3 and 4
      rheumatoid arthritis were reviewed clinically and radiographically at an average
      of 12.7 years. The Hospital for Special Surgery knee scores were good to
      excellent in 84 knees (81%). Seventeen knees (16%) were rated as fair, and three
      knees (3%) as poor. The average range of motion at follow-up examination was 95
      degrees. Six knees failed due to delayed sepsis (4.1%), and two failed due to
      aseptic loosening. At a follow-up period of 15 years, the survivorship analysis
      suggests a 91% probability of the arthroplasty remaining functional in situ.
      Cemented total condylar knee arthroplasties in severe rheumatoid arthritis
      provide durable pain relief and restoration of function.

PMID- 8648307
TI  - Removal and reinsertion of cemented femoral components during acetabular
      revision.
AB  - A retrospective review examined all patients who underwent removal and
      reinsertion of a cemented femoral component during isolated acetabular revision
      by one surgeon since 1981. All components were reinserted into the original,
      intact cement mantle. Forty-two hips with 2- to 10-year follow-up periods were
      reviewed. Average follow-up period since revision was 67 months. Average followup
      period since index procedure was 191 months. Average Harris hip score increased
      from 61 before surgery to 90 at follow-up examination. Two femurs are definitely
      loose by Harris criteria, but both are asymptomatic. One solidly fixed femoral
      component was revised because of joint instability. Two hips have postrevision
      cement fractures. One patient has mild thigh pain. In vitro testing of eight
      cadaver hips showed no increase in rotational micromotion following removal and
      reinsertion. It is concluded that this technique aids in isolated acetabular
      revision surgery by avoiding the complications of trochanteric osteotomy and
      femoral revision, improving acetabular exposure, and decreasing operative time
      with minimal risk of disrupting femoral component fixation.

PMID- 8648308
TI  - Cementless total knee arthroplasty in obese patients. A comparison with a matched
      control group.
AB  - The heaviest 45 patients (50 knees) who underwent cementless total knee
      arthroplasty were compared with a matched control group of 45 total knee
      arthroplasty patients (50 knees) with respect to clinical and radiographic data.
      Surgery was performed over a 10-year period (1980-1989) and follow-up evaluation
      averaged 7 years (range, 2-11 years). The control group consisted of nonobese
      patients matched to the obese group with respect to age, sex, diagnosis,
      preoperative deformity, and length of follow-up evaluation. Clinical evaluation
      was made using the Knee Society rating scale as well as an analysis of multiple
      other clinical parameters. Radiographically, each patient was evaluated with long
      standing anteroposterior views, lateral and patellar views, and spot fluoroscopic
      views of the involved knee. This evaluation included an analysis of lucencies,
      bead shedding, and prosthetic alignment. The final average clinical score in the
      obese group was 88 points with four revisions, and that for the control group was
      91 points with two revisions. There were no significant differences in the
      combined percentage of good and excellent results between the two groups. On the
      basis of the results of this study, it is believed that weight as a factor by
      itself should not compromise the early (7-year average follow-up period) results
      of total knee arthroplasty.

PMID- 8648309
TI  - Corrosion at the interface. A possible solution to cobalt-chrome heads on
      titanium alloy stems.
AB  - The low-wear characteristics of cobalt-chrome femoral heads matched with the
      excellent biocompatibility and low modulus of titanium alloy femoral stems
      constitute the preferred combination used by many orthopaedic surgeons performing
      total hip arthroplasty. The combination of these materials in a synovial fluid
      environment, however, has proven to result in extensive crevice corrosion and
      metallosis of the surrounding tissues. This study investigates an alternative to
      the conventional mating of dissimilar metals at the head-neck junction. Five
      cobalt-chrome heads premated with titanium alloy sleeves were investigated by
      gross examination, dissecting microscopy, and scanning electron microscopy.
      Examination by both gross examination and dissecting microscope revealed no signs
      of corrosion. Scanning electron microscope examination revealed slight crevice
      corrosion in the only head with a +15-mm neck length.

PMID- 8648310
TI  - Location of the femoral sulcus in the osteoarthritic knee.
AB  - Morphology of the distal femur is characterized in patients with osteoarthritis
      to identify an etiology for the high incidence of patellar till, subluxation, and
      failure noted in total knee arthroplasty. This study demonstrates that the sulcus
      of the trochlear groove is not located in the midline as traditionally
      represented, but is lateral to the midline in both osteoarthritic and normal
      knees. The significance of this is that the patella will presumably track lateral
      to the midline unless surgically realigned, contributing to the prevalence of
      patellar tracking problems associated with symmetric femoral components with
      centralized sulci used in contemporary total knee arthroplasty.

PMID- 8648311
TI  - Femoral articular shape and geometry. A three-dimensional computerized analysis
      of the knee.
AB  - An average, three-dimensional anatomic shape and geometry of the distal femur
      were generated from x-ray computed tomography data of five fresh asymptomatic
      cadaver knees using AutoCAD (AutoDesk, Sausalito, CA), a computer-aided design
      and drafting software. Each femur model was graphically repositioned to a
      standardized orientation using a series of alignment templates and scaled to a
      nominal size of 85 mm in mediolateral and 73 mm in anteroposterior dimensions. An
      average generic shape of the distal femur was synthesized by combining these
      pseudosolid models and reslicing the composite structure at different elevations
      using clipping and smoothing techniques in interactive computer graphics. The
      resulting distal femoral geometry was imported into a computer-aided
      manufacturing system, and anatomic prototypes of the distal femur were produced.
      Quantitative geometric analyses of the generic femur in the coronal and
      transverse planes revealed definite condylar camber (3 degrees-6 degrees) and toe
      in (8 degrees-10 degrees) with an oblique patellofemoral groove (15 degrees) with
      respect to the mechanical axis of the femur. In the sagittal plane, each condyle
      could be approximated by three concatenated circular arcs (anterior, distal, and
      posterior) with slope continuity and a single arc for the patellofemoral groove.
      The results of this study may have important implications in future femoral
      prosthesis design and clinical applications.

PMID- 8648312
TI  - Significance of the Trendelenburg test in total hip arthroplasty. Influence of
      lateral approaches.
AB  - The effects of lateral approaches to total hip arthroplasty on abductor weakness
      and limp were studied in 264 patients with primary osteoarthritis. The Hardinge
      approach was used in 82 patients, the transtrochanteric approach in 94, and the
      Liverpool approach in 88. There was no difference in functional level, range of
      movement, and limp among three lateral approaches. There was no increase in
      Trendelenburg gait after the Hardinge or Liverpool approach compared with the
      transtrochanteric approach. It is evident that the Trendelenburg test is a useful
      part of clinical examination if performed and interpreted correctly.

PMID- 8648313
TI  - Radiographic appearance and structural properties of proximal femoral bone in
      total hip arthroplasty patients.
AB  - The relationship between the morphology of the proximal femur and the physical
      properties of intertrochanteric trabecular bone was assessed in 26 patients
      undergoing total hip arthroplasty. Significant correlations were found between
      ash density and (1) Singh index, (2) "calcar-to-canal isthmus ratio," and (3) a
      modified "morphologic cortical index." Despite this, these radiographic indices
      accounted for only 30% of the variability in bone density and are therefore of
      limited predictive value in this context. Two indices of cortical morphology were
      at least as effective as the Singh index in predicting cancellous bone density.
      Surgeons using these indices to quantify the morphology and structure of proximal
      femoral bone should be aware of their limitations when selecting patients for
      cementless arthroplasty.

PMID- 8648314
TI  - Measurement of bone mineral density by dual-energy x-ray absorptiometry in
      patients with the Wisconsin hip, an uncemented femoral stem.
AB  - Although qualitative evidence of femoral bone remodeling, secondary to total hip
      arthroplasty (THA), is apparent on radiographs, quantification of change in bone
      mass from radiographs is limited. Dual-energy x-ray absorptiometry overcomes many
      of the limitations and yields accurate and precise bone mineral density (BMD)
      data. In this study, regional changes in femoral BMD were examined in 89 THA
      patients with a 2-year follow-up period. Thirty-two patients were evaluated
      initially before surgery and followed through the first 2 postoperative years. A
      second group was comprised of 57 patients whose surgery had been performed 1 to 6
      years prior to entry into the study; they were also followed for 2 years hence.
      Thus, both immediate and later bone responses were evaluated prospectively.
      Maximal bone remodeling was seen in the first 6 months after THA and with a near
      plateau by the end of the first year. A slow yearly decline in BMD appeared to
      occur as long as 8 years after THA, thus demonstrating the long-term effects of
      the introduction of a femoral stem. Variance in preoperative BMD was explained by
      disease only; no other factors (age, weight, sex) showed significant
      associations, and body weight was the only variable that affected rate of
      remodeling after THA (not age, weight, sex, prosthesis size, nor disease). All
      patients were healthy, relatively young individuals who were good candidates for
      uncemented implantation, and none showed evidence of clinical complications or
      surgical failure. It is therefore suggested that the patterns and results
      reported here be viewed as normative data, that is, the typical skeletal
      adaptation to THA. In future application, observation of disparate BMD results as
      compared with these "normal" data may be predictive of abnormal response to
      surgery and potential for later problems.

PMID- 8648315
TI  - Anterior cruciate-retaining total knee arthroplasty.
AB  - Fifty patients underwent bilateral total knee arthroplasty retaining both
      cruciate ligaments on one side and only the posterior cruciate ligament on the
      other. Patients were questioned about pain, instability, "feel," and ability to
      climb stairs. Seventy percent of patients stated that their anterior and
      posterior cruciate-retaining knee was their better knee overall. Ten percent
      stated that their posterior cruciate-only knee was better. Twenty percent could
      find no difference. There were no meaningful differences in inpatient care,
      physical therapy requirements, strength, range of motion, or component
      positioning. Fourteen patients handled stairs using each knee equally. Twenty
      nine climbed stairs leading with the anterior and posterior cruciate-retaining
      knee and seven patients led with the posterior cruciate-only knee. Complaints of
      clunks, pops, and clicks occurred in 11 patients with posterior cruciate-only
      knee arthroplasties and in 4 patients retaining both anterior and posterior
      cruciate ligaments. Retaining the anterior cruciate ligament can provide a knee
      that subjectively "feels" better.

PMID- 8648316
TI  - Patellar clunk syndrome in total knee arthroplasty without patellar resurfacing.
AB  - In a series of 647 total knee arthroplasties, the patella was not resurfaced if
      bony geometry of the patella was good enough to maintain good congruency of the
      patella undersurface to the femoral component and the patella was tracking
      normally at the femoral component groove at the time of surgery. Three hundred
      seventy-two total knee arthroplasties were done with a femoral component that had
      the same geometry as the original total condylar prosthesis. None of these knees
      resulted in patellar catching, whether the patella was resurfaced or not. Two
      hundred seventy-five total knee arthroplasties were done with a more contemporary
      femoral component with wider intercondylar space and shorter posterior extension
      of the intercondylar notch. Eleven of these 275 knees demonstrated catching of
      the patella at 60 degrees to 90 degrees of flexion when the knee was tested from
      flexion to extension during the surgery. All of these 11 knees did not have
      patellar resurfacing during surgery at first. Of these 11 knees with patellar
      catching noted during surgery, at first, patellar catching was eliminated with
      patellar resurfacing in 4 and by shaving of the superior pole of the patella in
      7. None of the knees with the patella resurfacing in this series showed patellar
      catching.

PMID- 8648317
TI  - Management of patellar clunk under local anesthesia.
AB  - Open resection through a limited lateral incision for the treatment of patellar
      clunk syndrome associated with patellar tilt in total knee arthroplasty is
      described. The procedure is done under local anesthesia. Dynamic flexion and
      extension of the knee during surgery ensures that correct patellar tracking has
      been restored.

PMID- 8648318
TI  - Intraoperative modular stem lengthening to treat periprosthetic femur fracture.
AB  - Fracture of the femur around a femoral prosthesis can be a difficult problem to
      manage. Treatment options consist of traction, allograft struts, or plating with
      cerclage fixation, and revision arthroplasty. Intramedullary stabilization is
      usually preferable to plating for treatment of diaphyseal femur fractures;
      however, for a fracture around a cementless stem, disruption of the biologically
      fixed proximal area of the implant and revision to a long-stem component are
      generally required to permit intramedullary fixation of the fracture. Many
      modular femoral stems are currently available. Some of these have both proximal
      and distal modular options. Distal modularity provides the surgeon treating a
      fracture around a femoral component with a unique opportunity to lengthen the
      stem during surgery by adding an attachment to the distal stem through the
      fracture site.

PMID- 8648319
TI  - Use of spontaneous electromyography during revision and complex total hip
      arthroplasty.
AB  - Intraoperative peripheral nerve injury is a serious potential complication of
      orthopaedic surgery and various intraoperative neurophysiologic monitoring
      techniques have been used to avoid this complication. Although somatosensory
      evoked potentials have been used effectively in spinal surgery, the efficacy of
      this technique has not been demonstrated in total hip arthroplasty. Spontaneous
      electromyography is a promising, alternative nerve monitoring technique. This
      technique was used in 44 consecutive revision and complex hip arthroplasty
      procedures. Five cases demonstrated sustained electromyography activity during
      surgery that subsided after retractors were removed and the limb brought into an
      anatomic position. In none of these five cases was there any evidence of clinical
      neurologic dysfunction after surgery. One patient developed causalgia without any
      motor deficit, but had no sustained electromyography activity during surgery.
      Spontaneous electromyography provides real-time monitoring of nerve function that
      allows immediate corrective action to be taken before nerve injury occurs.

PMID- 8648320
TI  - Use of a supracondylar nail for treatment of a supracondylar fracture of the
      femur following total knee arthroplasty.
AB  - Treatment of displaced or comminuted supracondylar fractures of the femur
      following total knee arthroplasty is challenging and problematic. Closed
      treatment has been associated with malunion, nonunion, and loss of motion,
      whereas early operative treatment has been associated with infection as well as
      nonunion. Intramedullary fixation of these fractures has the theoretical
      advantage of preserving periosteal blood supply while allowing early motion. The
      use of a nail specifically designed for supracondylar femur fractures to treat a
      a periprosthetic fracture about a well-fixed total knee arthroplasty is reported.
      This device provides a valuable treatment option to the surgeon treating this
      difficult problem.

PMID- 8648321
TI  - Condylar failure of the Lacey Rotating-Hinge total knee.
AB  - The Lacey Rotating-Hinge (Wright Medical, Arlington, TN) total knee is a
      constrained device for reconstruction of knees without collateral ligaments or to
      replace resected bone. Problems have been described with hinged total knees such
      as stem fracture, particulate synovitis, and stem loosening. A different mode of
      failure is described here. Two case histories are provided in which similar
      fractures occurred in the lateral condyle of Lacey Rotating-Hinge total knees.

PMID- 8648322
TI  - Periprosthetic infections due to Mycobacterium tuberculosis in patients with no
      prior history of tuberculosis.
AB  - Although uncommon, infection of prostheses with Mycobacterium tuberculosis can be
      managed successfully if it is diagnosed early and treated correctly. A case of M.
      tuberculosis infection of a prosthetic knee first diagnosed 4.5 years after
      initial arthroplasty is described. This case and a review of the literature led
      to the conclusion that there are two distinct patterns of M. tuberculosis
      infection following joint implant surgery in patients without a history of
      tuberculosis. (1) Mycobacterium tuberculosis infection may be an unexpected
      finding at the time of arthroplasty. These patients generally have favorable
      outcomes using standard antituberculous chemotherapy, without implant removal.
      (2) Late-onset M. tuberculosis joint infection may be identified in patients with
      painful, clinically infected, or malfunctioning prostheses. In these cases,
      medical treatment alone is usually unsuccessful; prosthesis removal is often
      required. With recent increases in the incidence of tuberculosis in the United
      States and the emergence of multidrug-resistant strains of M. tuberculosis,
      periprosthetic tuberculous infection is likely to become more common.

PMID- 8648323
TI  - Heterotopic ossification following primary total knee arthroplasty.

PMID- 8648324
TI  - Multifocal motor neuropathy.

PMID- 8648327
TI  - Risk of accidents in drivers with epilepsy.
AB  - OBJECTIVE: To estimate the risks of road traffic accidents over a period of three
      years in drivers with a history of single seizures or epilepsy, and to compare
      them with a cohort of drivers followed up by the Transport Research Laboratory
      (TRL). DESIGN: A retrospective survey of driving and accident experience by self
      completion questionnaire. SUBJECTS: 16,958 drivers with a previous history of
      epilepsy responding to the survey and 8888 non-epileptic drivers responding to a
      TRL survey. MAIN OUTCOME MEASURES: The risk of any accident, any accident
      producing an injury, and any accident producing a serious injury, over a three
      year period. RESULTS: After adjustment for differences in age, sex, driving
      experience, and mileage between the two populations there was no evidence of any
      overall increase in risk of accidents in the population of drivers with a history
      of epilepsy. However, there was evidence of an increased risk of more severe
      accidents in the population with epilepsy. The risk was increased by about 40%
      for serious injuries and there was evidence of a twofold risk of increase in non
      driver fatalities. These increases seem largely explicable by the occurrence of
      seizures in this population during the three years of driving that the survey
      covered. CONCLUSIONS: The acceptability of driving for people with a history of
      epilepsy should be determined by an acceptable risk of accidents resulting in
      injury or serious injury rather than overall accident rates. As people with
      epilepsy can now drive after a 12 month seizure free period rather than the
      required two year period when this survey was undertaken, it is important to
      ascertain whether there is any increased risk of injury associated accidents with
      this policy.

PMID- 8648326
TI  - Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski
      syndrome) and clinical predictors of survival: a clinicopathological study.
AB  - OBJECTIVE--To analyse the natural history of progressive supranuclear palsy (PSP
      or Steele-Richardson-Olszewski syndrome) and clinical predictors of survival in
      24 patients with PSP confirmed by necropsy, who fulfilled the NINDS criteria for
      a neuropathological diagnosis of typical PSP. METHODS--Patients were selected
      from the research and clinical files of seven medical centres involving tertiary
      centres of Austria, England, France, and the United States. Clinical features
      were analysed in detail. The patients' mean age at onset of PSP was 63 (range 45
      73) years. RESULTS--The most frequent clinical features (occurring in at least
      75% of the patients) were early postural instability and falls, vertical
      supranuclear palsy, akinetic-rigid predominant parkinsonian disorder
      characterised by symmetric bradykinesia and axial rigidity unrelieved by
      levodopa, pseudobulbar palsy, and frontal release signs. Occasionally, segmental
      dystonia or myoclonus were described, but neither aphasia nor alien limb syndrome
      was reported. Fractures occurred in 25% of the patients but were unrelated to the
      severity of the gait or to the presence of falls. Median survival time was 5.6
      (range 2-16.6) years. Onset of falls during the first year, early dysphagia, and
      incontinence predicted a shorter survival time. Age at onset, sex, early onset of
      dementia, vertical supranuclear palsy, or axial rigidity had no effect on
      prognosis of survival. Pneumonia was the most common immediate cause of death.
      PSP was most often clinically misdiagnosed as Parkinson's disease. Errors in
      diagnosis suggest that PSP is underdiagnosed. CONCLUSION--Progressive onset of
      early postural instability with falls or supranuclear vertical palsy in the fifth
      decade, should suggest the diagnosis of PSP. Onset of falls during the first year
      are emphasised, as they could lead to an early diagnosis and influence the
      prognosis of patients with PSP. Whether appropriate treatment of the dysphagia
      could prolong the survival of PSP patients needs to be explored.

PMID- 8648325
TI  - Schizophrenia.

PMID- 8648328
TI  - Prevalence of dementia in an elderly rural population: effects of age, sex, and
      education.
AB  - OBJECTIVES: To estimate the prevalence of dementia in an elderly rural population
      and to determine the effects of age, sex, and education. METHODS: To obtain
      prevalence estimates of both cognitive impairment and dementia a door to door two
      phase population survey was carried out in three rural villages in central Italy.
      Of 1147 inhabitants older than 64, 968 (84.4%) completed the protocol. RESULTS:
      The prevalence rates (cases per 100 population over 64) were 8.0 for dementia and
      27.3 for cognitive impairment. The prevalence rate for dementia did not differ
      between men and women (7.9 v 8.2), but increased with age (from 1.1 at age 65-69
      to 34.8 at age 90-96). Subjects with less than three years of schooling had a
      significantly higher prevalence of dementia (14.6; 95% confidence interval (95%
      CI) 10.2-19.1) than subjects with three or more years of schooling (5.9; 95% CI
      4.2-7.7). At the multivariate logistic analysis, the risk related with a low
      level of education was still present after adjustment for age and sex (OR = 2.0;
      95% CI 1.2-3.3). Alzheimer's disease was diagnosed in 64% of the 78 demented
      patients, vascular dementia in 27%, and other dementing diseases in 9%.
      CONCLUSIONS: In both Alzheimer and vascular dementia subtypes, the prevalence
      rates did not differ between men and women, but increased with age and were
      higher in subjects with a low level of education.

PMID- 8648329
TI  - Motor response to acute dopaminergic challenge with apomorphine and levodopa in
      Parkinson's disease: implications for the pathogenesis of the on-off phenomenon.
AB  - OBJECTIVES: To evaluate the contribution of postsynaptic changes to motor
      fluctuations, three groups of parkinsonian patients with differing responses to
      treatment were acutely challenged with two dopaminergic drugs-apomorphine and
      levodopa-having different mechanisms of action. METHODS: Forty two patients with
      Parkinson's disease (14 untreated, eight with a stable response to levodopa, and
      20 with levodopa induced motor fluctuations) were challenged on two consecutive
      days with apomorphine and levodopa. The latency, duration, and magnitude of motor
      response was measured. RESULTS: A progressive shortening of mean latency after
      levodopa challenge was found passing from the untreated to the stable and
      fluctuating groups; the difference between untreated and fluctuating patients was
      statistically significant (P < 0.01). Response duration after levodopa challenge
      was similar in untreated and stable patients, whereas it showed a significant
      shortening in patients with motor fluctuations (P < 0.05 v both untreated and
      stable patients). When subcutaneous apomorphine was given, untreated patients had
      a longer response duration than those who had developed motor fluctuations (P <
      0.05). Although baseline disability was significantly greater in the fluctuating
      patients than in the untreated and stable patients, the severity of residual
      parkinsonian signs after both apomorphine and levodopa challenge was similar for
      all three groups; as a result, the degree of improvement in parkinsonian signs
      after dopaminergic stimulation was substantially greater in more advanced than in
      early cases. Linear regression analysis also indicated that latency and duration
      after apomorphine challenge did not significantly correlate with those after
      levodopa challenge, whereas magnitude of response to apomorphine showed a strong
      positive correlation with that after levodopa challenge (r = 0.9, P < 0.001).
      CONCLUSION: The progressive shortening of motor response after both apomorphine
      and levodopa suggests that pharmacodynamic factors play an important part in
      determining the duration of motor response and argue against altered central
      pharmacokinetics of levodopa being principally responsible for the on-off effect.
      The widening response amplitude and increasing off phase disability occurring
      during disease progression are also critical factors in determining the
      appearance of motor fluctuations.

PMID- 8648330
TI  - Behavioural and electrophysiological chromatic and achromatic contrast
      sensitivity in an achromatopsic patient.
AB  - OBJECTIVES: In cases of incomplete achromatopsia it is unclear whether residual
      visual function is mediated by intact striate cortex or results from incomplete
      lesions to extrastriate cortical visual areas. A patient with complete cerebral
      achromatopsia was tested to establish the nature of his residual vision and to
      determine the integrity of striate cortex function. METHODS: Behavioural contrast
      sensitivity, using the method of adjustment, and averaged visually evoked
      cortical potentials were measured to sinusoidally modulated chromatic and
      achromatic gratings in an achromatopsic patient and a normal observer. Eye
      movements were measured in the patient using a Skalar infrared monitoring system.
      RESULTS: The patient's chromatic contrast sensitivity was normal, indicating that
      despite his dense colour blindness his occipital cortex still processed
      information about spatial variations in hue. His sensitivity to achromatic
      gratings was depressed particularly at high spatial frequencies, possibly because
      of his jerk nystagmus. These behavioural results were reinforced by the nature of
      visually evoked responses to chromatic and achromatic gratings, in which total
      colour blindness coexisted with an almost normal cortical potential to
      isoluminant chromatic gratings. CONCLUSIONS: The results show that information
      about chromatic contrast is present in some cortical areas, and coded in a colour
      opponent fashion, in the absence of any perceptual experience of colour.

PMID- 8648332
TI  - The F wave disappears due to impaired excitability of motor neurons or proximal
      axons in inflammatory demyelinating neuropathies.
AB  - OBJECTIVES: Investigation of pathophysiology of F wave disappearance in
      demyelinating neuropathies. METHODS: The peripheral motor nerve conduction was
      studied by motor evoked potential (MEP) on transcranial magnetic stimulation as
      well as conventional nerve conduction studies before and after the treatment in
      26 patients with inflammatory demyelinating neuropathies. In addition, serum
      antiganglioside antibodies in the acute or active stage were examined. RESULTS:
      The F wave was abolished in 10 patients. Seven of the 10 patients showed motor
      evoked potentials (MEPs) on transcranial magnetic stimulation that ranged from 1
      4 mV. In six of them the F wave reappeared in the recovery stage, but the MEP
      size did not change. This may be caused by humoral factors, because the F wave
      reappeared immediately after plasma exchange or intravenous immunoglobulin
      treatment. A correlation of F wave disappearance with the presence of serum
      antiganglioside antibodies was found. CONCLUSIONS: The major pathophysiology of F
      wave disappearance in demyelinating neuropathies is impairment of motor neuron
      excitability or prolonged refractoriness of the most proximal axon for
      backfiring. The conventional interpretation that absent F waves suggest a
      conduction block at the proximal site is often inadequate.

PMID- 8648331
TI  - SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E
      epsilon 4 allele.
AB  - OBJECTIVES: The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for
      late onset Alzheimer's disease. ApoE is present in senile plaques,
      neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in
      synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus,
      amygdala, and frontal lobe was studied. The hypothesis was that the patients with
      Alzheimer's disease carrying the epsilon 4 allele have more pronounced atrophy.
      The relation of ApoE and cerebral blood flow on cortical areas was also assessed.
      METHODS: Fifty eight patients with Alzheimer's disease at the early stage of the
      disease and 34 control subjects were studied. Patients with Alzheimer's disease
      were divided into subgroups according to the number of the epsilon 4 alleles.
      Volumes were measured by MRI and regional cerebral blood flow ratios referred to
      the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined
      by digestion of ApoE polymerase chain reaction products with the restriction
      enzyme Hha1. RESULTS: patients with Alzheimer's disease had smaller volumes of
      hippocampi and amygdala compared with control subjects, and the patients with
      Alzheimer's disease homozygous for the epsilon 4 allele had the most prominent
      volume loss in the medial temporal lobe structures. The frontal lobe volumes did
      not differ significantly. All patients with Alzheimer's disease had bilateral
      temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles
      also had frontal hypoperfusion compared with control subjects. The occipital
      perfusion ratios tended to decrease with increasing number of epsilon 4 alleles.
      CONCLUSIONS: Patients with Alzheimer's disease homozygous for the epsilon 4
      allele seem to have severe damage in the medial temporal lobe structures early in
      the disease process and differ from the patients with Alzheimer's disease with
      one or no epsilon 4 alleles.

PMID- 8648333
TI  - Myopathy in primary systemic amyloidosis.
AB  - OBJECTIVE: To define the natural history of primary systemic amyloidosis when
      muscle involvement is prominent at presentation. METHODS: A retrospective review
      was carried out of all patients seen at the tertiary referral practice of the
      Mayo Clinic between 1 January 1960 and 31 December 1994. All patients with
      primary systemic amyloidosis and proof of amyloid deposits by muscle biopsy were
      included for analysis. No patients were lost to follow up. RESULTS: Twelve
      patients were identified with amyloidosis in muscle. Muscle involvement was the
      most prominent symptom in patients who had widespread visceral involvement, which
      included the heart, peripheral nerve, and tongue. Of the 12, three had skeletal
      muscle pseudohypertrophy. All patients had a demonstrable dysproteinaemia by the
      finding of free light chain in the serum or urine, a discrete monoclonal peak on
      serum or urine protein electrophoresis, or a monoclonal population of plasma
      cells in the bone marrow. Measurement of creatine kinase was not a useful test.
      Of eight patients treated with chemotherapy based on alkylating agents, three
      responded. The median survival for the entire group was 12 months. CONCLUSIONS:
      The finding of a monoclonal protein in a patient with muscle weakness is an
      important clue to the diagnosis of primary systemic amyloidosis. Most patients
      have visceral involvement outside the musculoskeletal system. A subset of
      patients seems to respond to systemic chemotherapy. The overall survival,
      however, remains poor, with most patients dying of cardiac failure.
      Immunoelectrophoresis of serum and urine should be a routine diagnostic test
      during the evaluation of myopathy of unknown cause.

PMID- 8648334
TI  - Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role
      for hepatitis C virus infection?
AB  - BACKGROUND: The prevalence of hepatitis C virus (HCV) infection has been
      estimated at 43 to 84% in patients with essential mixed cryoglobulinaemia in
      recent large series. Some of these cases have been successfully treated with
      interferon-alpha. The objective was to evaluate the prevalence and the possible
      role of HCV infection in essential mixed cryoglobulinaemia. METHODS: Fifteen
      patients (eight men and seven women; mean age: 61.2 (SD 16.5) years) with
      peripheral neuropathy (10 polyneuropathies and five multifocal mononeuropathies)
      and essential mixed cryoglobulinaemia were tested for serum anti-HCV antibodies.
      RESULTS: Antibodies were found in 10 of 15 patients involving either
      polyneuropathies (seven patients) or multifocal mononeuropathies (three
      patients). Electrophysiological studies and teased nerve fibre studies (in seven
      patients) allowed neuropathies to be classified as predominantly sensory
      axonopathies. Compared with HCV-negative (HCV -) patients, HCV-positive (HCV +)
      patients had a more pronounced and more widespread motor deficit; motor nerve
      conduction velocities in peroneal and median nerves were more impaired in HCV +
      patients, although significance was not reached except for the mean value of the
      amplitude of the compound muscle action potentials of the median nerves (P <
      0.05); necrotising vasculitis was found in two of nine nerve biopsies from the
      HCV + patients studied and in none of the three HCV - patients. In addition, HCV
      + patients had more frequent cryoglobulin related cutaneous signs, higher
      aminotransferase and serum cryoglobulin concentrations, lower total haemolytic
      complement concentrations, and more frequent presence of rheumatoid factor. A
      liver biopsy performed in eight HCV + patients disclosed a range of lesions, from
      chronic active hepatitis (six patients) to persistent hepatitis (two patients).
      Lastly, treatment with interferon-alpha conducted over six months in two patients
      seemed to improve the peripheral neuropathy. CONCLUSIONS: Patients with
      peripheral neuropathy and essential mixed cryoglobulinaemia should be tested for
      anti-HCV antibodies to determine the appropriate treatment.

PMID- 8648335
TI  - Intra-arterial thrombolysis in acute ischaemic stroke: experience with a
      superselective catheter embedded in the clot.
AB  - OBJECTIVES: To report experience of intra-arterial thrombolysis for acute stroke,
      performed with a microcatheter navigated into the intracranial circulation to
      impale the clot. METHODS: Patients were selected on the following criteria: (1)
      clinical examination suggesting a large vessel occlusion in stroke patients
      between 18 and 75 years; (2) no radiographic signs of large actual ischaemia on
      CT at admission; (3) angiographically documented occlusion of the middle cerebral
      artery (MCA) stem or of the basilar artery (BA), without occlusion of the
      ipsilateral extracranial internal carotid artery or of both the vertebral
      arteries; (4) end of the entire procedure within six hours of stroke. 12 patients
      with acute stroke were recruited, eight of whom had occlusion of the MCA stem and
      four of the BA. Urokinase was used as the thrombolytic agent. RESULTS: Complete
      recanalisation in six MCA stem and in two BA occurred, and partial recanalisation
      in two MCA stem and one BA. There was no recanalisation in one BA. A clinically
      silent haemorrhage occurred in two patients, and a parenchymal haematoma in one
      patient, all in MCA occlusions. At four months five patients achieved self
      sufficiency (four with MCA and one with BA occlusion). Six patients were
      dependent (three totally), and one died. CONCLUSIONS: The strict criteria of
      eligibility allowing the enrollment of very few patients and the procedure
      itself, requiring particular neuroradiological expertise, make this procedure not
      routine. Nevertheless, the approach can be considered a possible option for
      patients with acute ischaemic stroke.

PMID- 8648336
TI  - Reduced bacterial adhesion to hydrocephalus shunt catheters mediated by
      cerebrospinal fluid proteins.
AB  - BACKGROUND: Prosthetic infections are a major problem, requiring complex and
      lengthy management. The role of blood proteins in the pathogenesis of implant
      infection has been investigated, but research into the role of CSF protein in
      shunt infections has not been undertaken, even though a high CSF protein has been
      assumed to increase the risk of such infections. METHODS: New shunt catheters
      were exposed to either CSF or individual protein solutions, and the numbers of
      radiolabelled staphylococci that adhered to them were compared with controls that
      had been exposed to saline only. RESULTS: A significant reduction in bacteria
      adhering to the test catheter was found in each instance. Furthermore, the CSF
      with the highest protein content, from a patient with intraventricular
      haemorrhage, had the greatest inhibitory effect on bacterial adhesion. The effect
      of the solutions on the hydrophobicity of the silicone rubber was also
      investigated. The silicone rubber was more hydrophilic, and bacterial adhesion
      was less, with solutions containing a higher protein content, and these findings
      were in keeping with the current theories on the mechanism of bacterial adhesion
      to polymers. CONCLUSIONS: A high CSF protein content does not predispose to the
      development of shunt infections.

PMID- 8648338
TI  - Substance P concentration and history of headache in relation to postlumbar
      puncture headache: towards prevention.
AB  - Medical treatment of postlumbar puncture headache (post-LP HA) is often difficult
      and ineffective. Prevention would be preferable to more invasive procedures,
      including blood patch. The aim was to determine the incidence of post-LP HA in
      two suspected high risk groups compared with the general outpatient population.
      Based on previous research, it was hypothesised that a low substance P
      concentration, or a history of chronic headache, or both would be associated with
      a higher risk of post-LP HA. A total of 310 randomly selected patients undergoing
      diagnostic lumbar puncture in the outpatient neurology clinic over 30 consecutive
      months were studied. Follow up was by headache questionnaire or phone survey
      after diagnostic lumbar puncture. Substance P was measured by radioimmunoassay on
      a subset of 102 samples of CSF. The overall incidence of post-LP HA was 38%.
      Patients with a measured substance P value < 1.3 pg/ml were three times as likely
      to have post-LP HA than those with a higher value. A history of chronic or
      recurrent headache was reported by 57% of those who developed post-LP HA. This
      group was also three times as likely to experience post-LP HA as those who did
      not have chronic headaches.

PMID- 8648339
TI  - Karl Rokitansky (1804-78).

PMID- 8648337
TI  - Cognitive impairments of alcoholic cirrhotic patients: correlation with
      endogenous benzodiazepine receptor ligands and increased affinity of platelet
      receptors.
AB  - OBJECTIVES: To determine whether differences in cognitive function between
      alcoholic and non-alcoholic cirrhotic patients relate to differences in
      endogenous ligands for the benzodiazepine receptor and/or benzodiazepine binding.
      METHODS: Seventeen grade-I hepatic encephalopathic patients (nine alcoholic,
      eight non-alcoholic) were compared with 10 matched controls on plasma
      concentrations of endogenous ligands for the neuronal benzodiazepine receptor,
      benzodiazepine binding in platelets, and performance on tests of cognitive
      function. RESULTS: Both groups of patients were impaired on verbal recall and on
      reaction time tasks compared with controls; alcoholic patients were also impaired
      on Reitan's trails test and digit cancellation. Four of the 17 patients had
      detectable concentrations of endogenous benzodiazepine ligands and they were more
      impaired than other patients on trails and cancellation tests. The groups did not
      differ in the density of benzodiazepine platelet receptors, but receptor affinity
      was higher in alcoholic patients than in controls; furthermore, receptor affinity
      correlated with the time to complete the cancellation task and with reaction
      time. CONCLUSION: Alcoholic cirrhotic patients may have enhanced concentrations
      of ligands for neuronal and peripheral benzodiazepine receptors and these may
      contribute to cognitive impairments in these patients.

PMID- 8648340
TI  - Lymphoma, paraproteinaemia, and neuropathy.

PMID- 8648341
TI  - Clinical, radiological, and therapeutic features of pleomorphic
      xanthoastrocytoma: report of three patients and review of the literature.
AB  - Two out of three patients with pleomorphic xanthoastrocytoma were initially
      misdiagnosed and correctly interpreted only at tumour recurrence, with
      progression to malignancy in one. The third patient presented with a remarkably
      long history of epilepsy. Pleomorphic xanthoastrocytoma is a low grade
      astrocytoma that is still confused with other tumours. Because pleomorphic
      xanthoastrocytoma can become malignant even after many years of benign behaviour,
      a long term follow up is necessary.

PMID- 8648342
TI  - Electroconvulsive therapy in Parkinson's disease: 30 month follow up.

PMID- 8648343
TI  - Pretarsal injections of botulinum toxin improve blepharospasm in previously
      unresponsive patients.

PMID- 8648345
TI  - Sixth nerve palsy from a CNS lesion in chronic inflammatory demyelinating
      polyneuropathy.

PMID- 8648344
TI  - Leucoencephalopathy after inhalation of heroin: a case report.

PMID- 8648346
TI  - Capture-recapture methods for precise measurement of the incidence and prevalence
      of stroke.

PMID- 8648347
TI  - Clinical and genetic evaluation of Japanese autosomal dominant cerebellar
      ataxias; is Machado-Joseph disease common in the Japanese?

PMID- 8648348
TI  - Amyotrophic lateral sclerosis after accidental injection of mercury.

PMID- 8648349
TI  - Intravenous immunoglobulin therapy in sensory neuropathy associated with
      Sjogren's syndrome.

PMID- 8648350
TI  - Diagnostic usefulness of apolipoprotein E epsilon 4 in the diagnosis of the
      dementias.

PMID- 8648351
TI  - Clinical evaluation of extracellular amino acids in severe head trauma by
      intracerebral in vivo microdialysis.

PMID- 8648352
TI  - Visually induced paroxysmal nausea and vomiting as presenting manifestations of
      multiple sclerosis.

PMID- 8648353
TI  - Persistent vegetative state.

PMID- 8648354
TI  - Pretarsal injection of botulinum toxin for blepharospasm and apraxia of eyelid
      opening.

PMID- 8648355
TI  - Chemotherapy as adjuvant therapy for completely resected non-small-cell lung
      cancer: have we made progress?

PMID- 8648356
TI  - Adjuvant chemotherapy after complete resection in non-small-cell lung cancer.
      West Japan Study Group for Lung Cancer Surgery.
AB  - PURPOSE: We performed a study to determine whether postoperative mild
      chemotherapy to maintain the patient's quality of life (QOL) and immunoactivity
      could also prolong survival. SUBJECT AND METHODS: From December 1985 to July
      1988, 323 patients with completely resected primary non-small-cell lung cancer
      (stage I to III) were enrolled. The subjects were randomized into three treatment
      groups, as follows: cisplatin (CDDP) 50 mg/m2 body surface, vindesine (VDS) 2 to
      3 mg/kg body weight for three courses, and 1-year oral administration of tegafur
      (FT) plus uracil (UFT) 400 mg/kg body weight (CVUft group, 115 patients); 1-year
      oral administration of UFT 400 mg/kg body weight (Uft group, 108 patients); or
      surgical treatment only (control group, 100 patients). RESULTS: The overall 5
      year survival rates were 60.6% for the CVUft group and 64.1% for the Uft group
      versus 49.0% for the control group. The results of statistical testing were P =
      .053 (log-rank test) and P = .044 (generalized Wilcoxon test) among the three
      groups, P = .083 (log-rank) and P = .074 (Wilcoxon) between the CVUft and the
      control groups, and P = .022 (log-rank) and P = .019 (Wilcoxon) between the Uft
      and the control groups, which indicates higher survival rates in the CVUft and
      the Uft groups compared with the control group. A multivariate statistical
      analysis on prognostic factors using Cox's proportional hazards model was
      performed with the following results: P = .037, hazards ratio = 0.64 with a 95%
      confidence interval (CI) of 0.42 to 0.97 (control v CVUft group); and P = .009,
      hazards ratio = 0.55 with a 95% CI of 0.36 to 0.86 (control v Uft group).
      CONCLUSION: Significantly favorable results were obtained in the CVUft and Uft
      groups compared with surgery alone. These data showed significant prognostic
      advantages in the postoperative adjuvant chemotherapy groups.

PMID- 8648357
TI  - Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally
      advanced inoperable non-small-cell lung cancer: radiation therapy oncology group
      protocol 91-06.
AB  - PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer
      (NSCLC) have a poor clinical outcome. We conducted a prospective study to
      evaluate the merit of chemotherapy administered concurrently with
      hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine
      patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of
      concurrent chemoradiation therapy. Treatment consisted of two cycles of oral
      etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous
      cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5
      days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS:
      Seventy-six assessable patients with a Karnofsky performance status > or = 60 and
      adequate organ function who had received no prior therapy were evaluated for
      clinical outcome and toxic effects. After a minimum follow-up duration of 21
      months, the 1- and 2-year survival rates and the median survival duration were
      67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for
      patients with weight loss of < or = 5%. Toxicity was significant; 57% developed
      grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4
      lung toxicity. However, only 6.6% of patients had grade 4 or lethal
      nonhematologic toxicity, which included three treatment-related deaths (two of
      pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation
      therapy with oral etoposide and cisplatin plus hyperfractionated radiation
      therapy is feasible. The survival outcome from this regimen compares favorably
      with that of other chemoradiation trials and even of multimodality trials that
      have included surgery.

PMID- 8648358
TI  - Hyperfractionated radiation therapy with or without concurrent low-dose daily
      carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized
      study.
AB  - PURPOSE: To investigate the efficacy of concurrent hyperfractionated radiation
      therapy (HFX RT) and low-dose daily chemotherapy (CHT) in stage III non-small
      cell lung cancer (NSCLC). PATIENTS AND METHODS: Between January 1990 and December
      1991, 131 patients with histologically or cytologically confirmed stage III
      NSCLC, Karnofsky performance status (KPS) > or = 50, and no previous therapy were
      randomly treated as follows: group I, HFX RT with 1.2 Gy twice daily to a total
      dose of 69.6 Gy (n = 66); and group II, same HFX RT with CHT consisting of 50 mg
      of carboplatin (CBDCA) and 50 mg of etoposide (VP-16) given on each RT day (n =
      65). RESULTS: Group II patients had a significantly longer survival time than
      group I patients, with a median survival of 22 versus 14 months and 4-year
      survival rates of 23% versus 9% (P = .021). The median time to local recurrence
      and 4-year local recurrence-free survival rate were also significantly higher in
      group II than in group I (25 v 20 months and 42% v 19% respectively, P = .015).
      In contrast, the distant metastasis-free survival rate did not significantly
      differ in the two groups (P = .33). The two groups showed similar incidence of
      acute and late high-grade toxicity (P = .44 and .75, respectively). No treatment
      related toxicity was observed. CONCLUSION: The combination of HFX RT and low-dose
      daily CBDCA plus VP-16 was tolerable and improved the survival of patients with
      stage III NSCLC as a result of improved local control.

PMID- 8648359
TI  - Severe lymphocytopenia and interstitial pneumonia in patients treated with
      paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer.
AB  - PURPOSE: In a phase II trial with paclitaxel and simultaneous radiotherapy in non
      small-cell lung cancer (NSCLC) patients, an unexpected high incidence of
      interstitial pneumonias was observed. The type of immunodeficiency associated
      with this treatment approach is characterized. PATIENTS AND METHODS: Fifteen
      patients with inoperable stage IIIA/B NSCLC were treated with paclitaxel as a 3
      hour infusion on day 1 in weeks 1 to 3 and 6 to 8 at dose levels between 50 mg/m2
      and 86 mg/m2 and with simultaneous radiotherapy in daily doses of 2 Gy, 5 days
      per week, in weeks 1 to 3 and 6 to 8 up to a total dose of 56 Gy. Hematologic
      parameters and lymphocyte subsets were monitored. RESULTS: Fourteen patients are
      assessable for response. The overall response rate was 78%, with four major
      responses, six partial remissions, and four minor responses. The major toxic
      effect observed was a moderate to severe protracted lymphocytopenia (380 +/-
      310/microL) in all patients. Seven patients developed moderate to severe
      interstitial pneumonia; one had an additional herpes zoster infection, while an
      eighth patient had a cytomegalovirus infection. During treatment, all lymphocyte
      subsets were reduced, as follows (n = 9, mean +/- SD): CD4+ T cells (100 +/-
      90/microL), CD8+ T cells (130 +/- 160/microL), natural killer (NK) cells (70 +/-
      80/microL), and B cells (20 +/- 10/microL). Thus, the most pronounced toxicity
      was seen in CD4+ T and B cells. There was no recovery of lymphocyte subsets
      during a 3-month follow-up period. CONCLUSION: Paclitaxel with simultaneous
      radiation induces lymphocytopenia and promotes opportunistic infections. Long
      term antibiotic and antimycotic prophylaxis is recommended. Whether the
      lymphocytopenia is an additive effect of paclitaxel and radiation or whether it
      can be induced by low-dose weekly paclitaxel alone remains to be determined.

PMID- 8648360
TI  - Effects of medroxyprogesterone acetate on appetite, weight, and quality of life
      in advanced-stage non-hormone-sensitive cancer: a placebo-controlled multicenter
      study.
AB  - PURPOSE: To investigate the effects of medroxyprogesterone acetate (MPA) on
      appetite, weight, and quality of life (QL) in patients with advanced-stage,
      incurable, non-hormone-sensitive cancer. PATIENTS AND METHODS: Two hundred six
      eligible patients were randomized between double-blind MPA 500 mg twice daily or
      placebo. Appetite (0 to 10 numerical rating scale), weight, and QL (European
      Organization for Research and Treatment of Cancer Quality of Life Questionnaire
      [EORTC-QLQ-C30]) were assessed before the start of treatment (t = 0), and 6 weeks
      (t = 6) and 12 weeks (t = 12) thereafter. RESULTS: One hundred thirty-four
      patients (68 MPA and 66 placebo) were assessable at t = 6 and 99 patients (53 MPA
      and 46 placebo) at t = 12. A beneficial effect of MPA on appetite was observed
      after both 6 weeks (P = .008) and 12 weeks (P = .01) of treatment. After 12
      weeks, a mean weight gain of 0.6 +/- 4.4 kg was seen in the MPA, versus an
      ongoing mean weight loss of 1.4 +/- 4.6 kg in the placebo group. This difference
      of 2.0 kg was statistically significant (P = .04). During the study, several
      areas of QL deteriorated in the total group of patients. With the exception of an
      improvement in appetite and possible also a reduction in nausea and vomiting, no
      measurable beneficial effects of MPA on QL could be demonstrated. The side
      effects profile of MPA was favorable: only a trend toward an increase in (usually
      mild) peripheral edema was observed. CONCLUSION: In weight-losing, advanced-stage
      non-hormone-sensitive cancer patients, MPA exhibits a mild side effects profile,
      has a beneficial effect on appetite, and may prevent further weight loss.
      However, general QL in the present study was not measurably influenced by MPA
      treatment.

PMID- 8648361
TI  - Linear accelerator-based stereotaxic radiosurgery for brain metastases:the
      influence of number of lesions on survival.
AB  - PURPOSE: To evaluate the influence of the number of brain metastases on survival
      after stereotaxic radiosurgery and factors that affect the risk of delayed
      radiation necrosis after treatment. MATERIALS AND METHODS: Between March 1989 and
      December 1993, 120 consecutive patients underwent linear accelerator-based
      stereotaxic radiosurgery for brain metastases identified by computed tomography
      (CT) or magnetic resonance imaging (MRI) scans. The influence of various clinical
      factors on outcome was assessed using Kaplan-Meier plots of survival from the
      date of radiosurgery, and univariate and multivariate analyses. RESULTS: The
      median survival time was 32 weeks. Progressive brain metastases, both local and
      regional, caused 25 of 104 deaths. Patients with two metastases (n = 30) or a
      solitary metastasis (n = 70) had equivalent actuarial survival times (P = .07;
      median, 37 weeks; maximum, 211+ weeks). Patients treated to three or more
      metastases (n = 20) had significantly shorter survival times (P < .002; median,
      14 weeks; maximum, 63 weeks). Prognostic factors associated with prolonged
      survival included a pretreatment Karnofsky performance status > or = 70% and
      fewer than three metastases. Delayed radiation necrosis at the treated site
      developed in 20 patients and correlated with prior or concurrent delivery of
      whole-brain irradiation and the logarithm of the tumor volume. CONCLUSION:
      Survival duration is equivalent for patients with one or two brain metastases and
      is similar to that reported for patients with a solitary metastasis managed by
      surgical resection and whole-brain irradiation. Survival after radiosurgery for
      three or more metastases was similar to that reported for whole-brain
      irradiation.

PMID- 8648362
TI  - Patterns-of-failure analysis of patients with high pretreatment prostate-specific
      antigen levels treated by radiation therapy: the need for improved systemic and
      locoregional treatment.
AB  - PURPOSE: The patterns of failure (local and/or regional v metastatic) have been
      determined for patients with prostate cancer and pretreatment prostate-specific
      antigen (PSA) levels > or = 20 ng/mL treated with radiation alone with the
      purpose to design appropriate multimodal treatments. MATERIALS AND METHODS: One
      hundred twenty patients with pretreatment PSA levels > or = 20 ng/mL were treated
      with external-beam radiation alone between February 1988 and October 1993. They
      were arbitrarily divided by PSA levels, 20 to 29.9 ng/mL, 30 to 49.9 ng/mL, and >
      or = 50 ng/mL, and analyzed in terms of freedom from any failure (no evidence of
      biochemical disease [bNED], and PSA level < 1.5 ngm/mL and not increasing), as
      well as freedom from imaging evidence of distant metastasis (fdm). RESULTS: There
      was no significant difference in short-term outcome by pretreatment PSA level,
      and thus all patients were pooled for analysis. At 4 years, 81% were fdm and 28%
      were free of any failure. This suggests that approximately 50% have recurred with
      local and/or regional disease or undetectable metastatic disease. Multivariate
      analysis indicated that low palpation stage and higher center of prostate dose
      were associated with better bNED survival. Multivariate analysis indicated that
      increasing stage and younger age are significantly associated with increasing
      distant metastasis. CONCLUSION: Patients with pretreatment PSA levels > or = 20
      ng/mL are not optimally treated by irradiation alone. The pattern of failure
      suggests improvement may come from systemic treatment of metastatic disease and
      high-dose radiation to improve locoregional disease. To evaluate this, we have
      begun a multimodal trial of chemohormonal therapy followed by extended-field
      irradiation.

PMID- 8648363
TI  - High-dose carboplatin, etoposide, and cyclophosphamide for patients with
      refractory germ cell tumors: treatment results and prognostic factors for
      survival and toxicity.
AB  - PURPOSE: The efficacy and toxicity of high-dose carboplatin, etoposide, and
      cyclophosphamide with autologous bone marrow transplantation (AuBMT) was
      investigated in a prospective trial for patients with cisplatin-refractory germ
      cell tumor (GCT). Prognostic factors for survival and treatment-related toxicity
      were identified. PATIENTS AND METHODS: Fifty-eight patients with refractory GCT
      were treated with high-dose carboplatin, etoposide, and cyclophosphamide plus
      AuBMT. Prognostic factors for toxicity and survival were examined in multivariate
      analyses. RESULTS: Twenty-three patients (40%) achieved a complete response and
      12 (21%) are alive and free of disease at a median follow-up time of 28 months.
      Myelosuppression was severe and there were seven (12%) treatment-related deaths.
      Independently predictive factors that resulted in faster blood count recovery
      were the use of granulocyte colony-stimulating factor (G-CSF) for the number of
      days to neutrophil count recovery (P = .013) and prior treatment with cisplatin
      limited to six cycles or less for the number of days to platelet count recovery
      (P = .0012). Both were predictive for the number of days of hospitalization (P =
      .04 and .03, respectively). The two independently predictive variables for
      survival were pretreatment level of HCG; human chorionic gonadotrophin (HCG; < or
      = 100 times the upper limit of normal [xnl] v > 100 xnl, P = .02) and the
      presence of retroperitoneal metastases (yes or no, P = .04). Patients grouped by
      HCG < or = 100 xnl with retroperitoneal metastases, HCG < or = 100 xnl without
      retroperitoneal metastases, and all patients with HCG more than 100 xnl had
      median survival times of 14, 11, and 3 months, respectively (P = .04).
      CONCLUSION: High-dose carboplatin, etoposide, and cyclophosphamide is an
      effective therapy for patients with refractory GCT, and results in a complete
      response proportion of 40% and a 2-year survival rate of 31% at a median follow
      up time of 28 months. This was accomplished in a group of patients with a dismal
      prognosis to conventional-dose therapy.

PMID- 8648364
TI  - Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell
      tumors of the testis: a Medical Research Council report.
AB  - PURPOSE: This United Kingdom Medical Research Council (UK-MRC) study
      prospectively evaluated efficacy and long-term toxicity of adjuvant chemotherapy
      in high-risk stage I nonseminomatous germ cell tumors of the testis (NSGCTT).
      PATIENTS AND METHODS: Eligible patients were those identified by the local
      histopathologist as having features confirmed in MRC surveillance studies to
      indicate an approximate 50% risk of relapse. Central histopathology review was
      undertaken. Chemotherapy consisted of two courses of cisplatin 100 mg/m2,
      bleomycin 30 mg weekly x 3, and etoposide 120 mg/m2 x 3, every 21 days (BEP).
      RESULTS: One hundred fourteen eligible cases were enrolled. Median time of follow
      up was 4 years, with 93 patients followed-up for at least 2 years. There have
      been two relapses, including one patient who did not have a germ cell tumor
      (GCT), according to the reference histopathologist. This patient is alive with
      active disease, the other has died. There was one death after a cerebrovascular
      accident during treatment. Assessment of fertility, lung function, and audiometry
      pretreatment and more than 9 months posttreatment indicated no clinically
      significant changes. A mean decrease in transfer factor coefficient (KCO) of 15%
      of the predicted value was noted, but no patient had symptomatic respiratory
      dysfunction. CONCLUSION: There have been only two relapses among 114 cases of
      high-risk stage I NSGCTT treated with two courses of adjuvant BEP chemotherapy.
      The 95% confidence interval (CI) excludes a true relapse rate of more than 5%. Of
      104 patients confirmed on histopathology review to have GCT, there has been only
      one relapse. Adjuvant chemotherapy is free from significant long-term toxicity,
      offering an effective alternative to surveillance or retroperitoneal lymph node
      dissection (RPLND) followed by surveillance, and may be preferred by some
      patients.

PMID- 8648365
TI  - Impact of preleukapheresis cell counts on collection results and correlation of
      progenitor-cell dose with engraftment after high-dose chemotherapy in patients
      with germ cell cancer.
AB  - PURPOSE: To identify predictive factors for a good leukapheresis yield and to
      determine peripheral-blood progenitor cell (PBPC) dose requirements for rapid
      hematopoietic engraftment. PATIENTS AND METHODS: Seventy-one patients with germ
      cell cancer (GCC) underwent PBPC harvest for autologous transplantation following
      high-dose therapy. Aphereses were performed after chemotherapy during granulocyte
      colony-stimulating factor (G-CSF) administration. RESULTS: A median of two
      aphereses (range, two to five) resulted in 4.6 x 10(8) mononuclear cells
      (MNC)/kg, 15.7 x 10(4) colony-stimulating units granulocyte-macrophage (CFU
      GM)/kg, and 6.0 x 10(6) CD34+ cells/kg. Peripheral blood MNC count correlated
      significantly with number of harvested CD34+ cells per kilogram (r = .49; P <
      .0001) and with CFU-GM count per kilogram (r = .35; P < .002). Circulating CD34+
      cells from peripheral blood gave the best correlations to collected CD34+ cells
      per kilogram (r = .92; P < .0001), as well as to harvested CFU-GM per kilogram (r
      = .48; P < .0001). A preleukapheresis number of CD34+ cells greater than 4 x
      10(4)/mL was highly predictive for a PBPC collection yield that contained more
      than 2.5 x 10(6) CD34+ cells/kg harvested by a single leukapheresis. After
      autologous transplantation, 41 patients were assessable for hematopoietic
      engraftment. They engrafted in a median time of 9 days (range, 7 to 18) to a WBC
      count greater than 1.0 x 10(9)/L, 10 days (range, 7 to 18) to an absolute
      neutrophil count (ANC) greater than 0.5 x 10(9)/L, and 11 days (range, 7 to 62)
      to a platelet (PLT) count greater than 20 x 10(9)/L. Good correlations were seen
      between reinfused CD34+ cell count and recovery of WBC count, ANC, and PLT count,
      with r values of .65 (P < .001), .65 (P < .001), and .45 (P < .03), respectively.
      Patients reinfused with a PBPC dose greater than 2.5 x 10(6) CD34+ cells/kg
      recovered hematopoiesis in a significantly shorter time than patients who
      received less than 2.5 x 10(6) CD34+ cells/kg. CONCLUSION: Rapid hematopoietic
      engraftment can be achieved by a PBPC dose of greater than 2.5 x 10(6) CD34+
      cells/kg. When circulating preleukapheresis CD34+ cell counts are greater than 4
      x 10(4)/mL, a PBPC autograft that contains more than 2.5 x 10(6) CD34+ cells/kg
      can be collected by a single leukapheresis.

PMID- 8648366
TI  - Expression of a CD44 variant containing exons 8 to 10 is a useful independent
      factor for the prediction of prognosis in colorectal cancer patients.
AB  - PURPOSE: To determine the expression of the CD44 variant containing a variant
      exon 8 to 10 product (CD44v8-10) in colorectal cancer and to evaluate its
      prognostic value. MATERIALS AND METHODS: CD44v8-10 was studied in resected tumors
      and normal mucosae obtained from 215 colorectal cancer patients (118 colon cancer
      and 97 rectal cancer). The expression of CD44v8-10 was analyzed
      immunohistochemically using the anti-CD44v8-10 monoclonal antibody (mAb) 44-1V.
      RESULTS: One hundred of 215 cancer tissues expressed CD44v8-10. Positive staining
      was intense mainly on the cell membranes. There was no significant correlation
      between expression of CD44v8-10 and histologic type, primary tumor, lymphatic
      invasion, venous invasion, or peritoneal invasion. There were significant
      correlations between CD44v8-10 immunoreactivity and both lymph node and
      hematogenous metastasis. Patients with CD44v8-10-positive tumors had a greater
      relative risk of death compared with those whose tumors were CD44v8-10-negative.
      Among 169 patients who underwent curative resection, CD44v8-10 expression
      correlated with a high recurrence rate. The 5- and 10-year survival rates were
      90.3% of patients with CD44v8-10-negative tumors, and 72.1% and 58.0% of those
      with CD44v8-10-positive tumors, respectively; these differences between the two
      groups of patients were significant (P < .01). In multivariate analysis using the
      Cox regression model, CD44v8-10 expression emerged as an independent prognostic
      indicator. CONCLUSION: The results suggest that CD44v8-10 plays a role in
      metastasis of colorectal cancer, and tha CD44v8-10 expression may be a biologic
      marker of prognostic significance.

PMID- 8648368
TI  - Adjuvant treatment of node-positive breast cancer with cyclophosphamide,
      doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate,
      and fluorouracil: final report after a 16-year median follow-up duration.
AB  - PURPOSE: To determine the long-term impact on disease-free survival (DFS) and
      overall survival (OS) of adjuvant anthracycline-based chemotherapy, when
      prospectively compared by random allocation with standard cyclophosphamide,
      methotrexate, and fluorouracil (CMF) in node-positive (N+) breast cancer
      patients. PATIENTS AND METHODS: Two hundred forty-nine patients with N+ breast
      cancer, recruited from eight French cancer centers, were randomized to receive 12
      monthly cycles of adjuvant chemotherapy, either CMF (n = 112) or doxorubicin,
      vincristine, cyclophosphamide, and fluorouracil (AVCF) (n = 136). All had a
      negative metastatic work-up before inclusion, which was stratified by accrual
      center, tumor stage (International Union Against Cancer [UICC]), and menopausal
      status. RESULTS: No severe adverse effect related to grade 4 (World Health
      Organization [WHO]) toxicity was observed. There was no difference in second
      primary tumor incidence between the two arms. The treatment given was 88% of
      planned for AVCF and 75% for CMF in both premenopausal and menopausal patients.
      With a median follow-up time of 16 years (range, 13 to 17), the OS and DFS rates
      are significantly longer in the AVCF arm (56% v 41% [P = .01] for OS, and 53% v
      36% [P = .006] for DFS). These differences are significant, irrespective of tumor
      stage (T1 to T2 v T3 to T4), and remain positive in patients with or without
      postoperative locoregional radiotherapy (55% of cohort). When analyzed according
      to menopausal status, the differences remain significant only for premenopausal
      patients. CONCLUSION: This set of mature controlled data confirms the added value
      of anthracycline-based combination adjuvant therapy for N+ breast cancer patients
      when compared with CMF, with both regimens given for 1 year.

PMID- 8648367
TI  - Phase II trial of irinotecan in patients with progressive or rapidly recurrent
      colorectal cancer.
AB  - PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients
      with metastatic colorectal carcinoma that had recurred or progressed following
      fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated
      with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks,
      followed by a 2-week rest. Forty-eight patients were entered onto the study and
      all were assessable for toxicity. Forty-three patients completed one full course
      of therapy and were assessable for response. RESULTS: One complete and nine
      partial responses were observed (response rate, 23%; 95% confidence interval
      [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13).
      The median survival time was 10.4 months and the 1-year survival rate was 46%
      (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine
      patients (44%) treated on this study at the 150-mg/m2 dose level. The study was
      amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose,
      nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration
      of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia
      occurred in eight of 48 patients (17%), but was associated with bacteremia and
      sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity
      against colorectal cancer that has progressed during or shortly after treatment
      with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by
      using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the
      earliest signs of diarrhea. These results warrant further clinical evaluation to
      define the role of irinotecan in the treatment of individuals with colorectal
      cancer.

PMID- 8648369
TI  - Dose-response relationship of epirubicin in the treatment of postmenopausal
      patients with metastatic breast cancer: a randomized study of epirubicin at four
      different dose levels performed by the Danish Breast Cancer Cooperative Group.
AB  - PURPOSE: To test for possible correlations between dose of single-drug epirubicin
      and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The
      study also included analysis of a correlation between pharmacokinetic and
      pharmacodynamic parameters. PATIENTS AND METHODS: Two hundred eighty-seven women
      were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin
      intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic
      therapy for metastatic disease. In patients with early progressive disease after
      either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full
      pharmacokinetic analysis was performed in 78 patients. RESULTS: Among 263
      eligible patients, an increase in response rate and time to progression was found
      with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was
      found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional
      hazards model with time to progression as the end point, confirmed that
      epirubicin dose more than 60 mg/m2 was an independent prognostic covariate.
      Furthermore, a significant association was established between randomized dose
      and both hematologic and nonhematologic toxicity. No association between
      pharmacokinetic parameters and efficacy parameters was demonstrated. On the other
      hand, a significant correlation between pharmacokinetic parameters and both
      hematologic and nonhematologic toxicity was found. CONCLUSION: An increase in
      dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy.
      Further increases in dose do not yield increased efficacy. A positive correlation
      between epirubicin dose and toxicity, as well as a correlation between
      pharmacokinetic parameters and toxicity, was also established.

PMID- 8648370
TI  - Minimal toxicity and mortality in high-risk breast cancer patients receiving high
      dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell
      transplantation and comprehensive supportive care.
AB  - PURPOSE: To assess the clinical toxicity and outcome associated with a
      comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients
      with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five
      consecutive patients with stages II, III or metastatic breast cancer received HDC
      between February 1992 and June 1994. Recipients received 4 days of continuous
      infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin
      200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells
      (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received
      similar supportive care that included administration of prophylactic antibiotics,
      management of neutropenic fevers, and transfusion support. RESULTS: There were 38
      women with stage II or III (27 patients with > or = 10 lymph nodes), four with
      stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years
      (range, 27 to 61). Grade II or greater nonhematologic toxicities included
      diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and
      pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between
      bone marrow and PBSC recipients (P > .1). Infectious complications were rare and
      consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%),
      fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There
      was one treatment-related death secondary to severe VOD. CONCLUSION: A
      comprehensive supportive care approach was associated with a low treatment
      related mortality rate of less than 1%. With the observed reduction in treatment
      related mortality, it is reasonable to evaluate the efficacy of HDC in women with
      less than 10 positive nodes and stage II disease in well-designed clinical
      trials.

PMID- 8648371
TI  - Lonidamine significantly increases the activity of epirubicin in patients with
      advanced breast cancer: results from a multicenter prospective randomized trial.
AB  - PURPOSE: Some evidence in vitro and in vivo shows that lonidamine (LND) can
      positively modulate the activity of doxorubicin and epirubicin (EPI). On this
      basis, a multicenter prospective randomized trial was performed in patients with
      advanced breast cancer (BC) to determine if the addition of LND to EPI could
      increase the response rate of EPI alone. PATIENTS AND METHODS: From May 1991 to
      May 1993, 207 patients were enrolled onto this study and randomized to receive
      intravenous (IV) EPI (60 mg/m2 on days 1 and 2) alone or with LND (600 mg orally
      daily). EPI administration was repeated every 21 days until tumor progression or
      for a maximum of eight cycles. LND was administered continuously until
      chemotherapy withdrawal. RESULTS: Response rate was significantly superior for
      the EPI plus LND scheme compared with the single-agent EPI either considering
      assessable patients (60.0% v 39.8%; P < .01) or including all registered patients
      according to an intention-to-treat analysis (55.3% v 37.5%; P < .02). The
      distribution of the response rate according to the site of disease did not show
      any significant difference between the treatment arms, except for the patient
      subgroup with liver metastases in which the combination EPI plus LND resulted in
      a significant improvement of responses than EPI alone. Toxicity was moderate, and
      except for myalgia, no adjunctive side effects were observed in the EPI plus LND
      arm. Overall survival and time to progression were similar in both groups.
      CONCLUSION: This study confirms in vivo that the administration of EPI is
      enhanced by the concomitant LND administration.

PMID- 8648372
TI  - Phase I crossover study of paclitaxel with r-verapamil in patients with
      metastatic breast cancer.
AB  - PURPOSE: We conducted a phase I crossover study of escalating doses of both
      paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the
      less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic
      breast cancer. PATIENTS AND METHODS: Twenty-nine patients refractory to
      paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours
      starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing
      for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination
      was determined, seven additional patients who had not been treated with either
      drug were evaluated to determine whether the addition of r-verapamil altered the
      pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P
      glycoprotein (Pgp) expression before receiving paclitaxel and after becoming
      refractory to paclitaxel therapy. RESULTS: The MTD of the combination was 225
      mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion.
      Dose-limiting hypotension and bradycardia were observed in three of five patients
      treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r
      verapamil at the MTD as outpatient therapy without developing cardiac toxicity.
      The median peak and trough serum verapamil concentrations at the MTD were 5.1
      micromol/L (range, 1.9 to 6.3), respectively, which are within the range
      necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR).
      Increased serum verapamil concentrations and cardiac toxicity were observed more
      frequently in patients with elevated hepatic transaminases and bilirubin levels.
      Hematologic toxicity from combined paclitaxel and r-verapamil was significantly
      worse compared with the previous cycle of paclitxel without r-verapamil. In the
      pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and
      increased mean peak paclitaxel concentrations. CONCLUSION: r-Verapamil at 225
      mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3
      hour infusion as outpatient therapy and is associated with serum levels
      considered active for Pgp inhibition. The addition of r-verapamil significantly
      alters the toxicity and pharmacokinetics of paclitaxel.

PMID- 8648373
TI  - Phase I/II trial of biweekly paclitaxel and cisplatin in the treatment of
      metastatic breast cancer.
AB  - PURPOSE: To determine the maximum-tolerated dose of escalating doses of
      paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly
      with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the
      activity of this combination in a phase I/II trial in metastatic breast cancer.
      PATIENTS AND METHODS: Twenty-nine women with metastatic breast cancer were
      enrolled; 27 were assessable for response and 29 for toxicity. All but two of the
      women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines
      and six previous cisplatin. RESULTS: The initial starting dose of paclitxel 90
      mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting
      neutropenia. Responses were seen in 85% of assessable patients, with three
      patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial
      response (PR), for an overall response rate of 85% (95% confidence interval [CI],
      66% to 96%). The time to disease progression for patients who achieved a CR was
      110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median
      time to progression of 7.1 months and a median response duration of 7.9 months.
      Sites of CR were skin, soft tissue, and lung, and all occurred in women with
      previous exposure to anthracyclines. Septic events were rare, with two grade 3
      infections (7%), only one of which required hospital admission. There were no
      grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251
      chemotherapy cycles were given -- 16 with paclitaxel alone in five patients.
      Forty-five percent of patients required dose reductions, while 52% had delays due
      to neutropenia. CONCLUSION: Biweekly paclitaxel and cisplatin is an active
      combination in the treatment of metastatic breast cancer, including for patients
      with previous exposure to anthracyclines.

PMID- 8648374
TI  - Intensive concomitant chemoradiotherapy in locally advanced unresectable squamous
      cell carcinoma of the head and neck: a phase II study of radiotherapy with
      cisplatin and 7-week continuous infusional fluorouracil.
AB  - PURPOSE: To evaluate an intensive concomitant chemoradiotherapy protocol of
      conventional radiotherapy with intermittent cisplatin (CDDP) and continuous
      infusion fluorouracil (5-FU) in unresectable, locally advanced squamous cell
      carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Fifty-seven
      patients with unresectable stage IV MO disease (International Union Against
      Cancer [UICC]/American Joint Committee on Cancer [AJCC], 1987) received
      radiotherapy 70 Gy followed by CDDP 80 mg/m2 and 5-FU 300 mg/m2/d. Response was
      assessed 2 months after treatment completion. RESULTS: Thirty patients (52%)
      received the full treatment schedule; 53 (93%) received full-dose radiotherapy,
      while 48 (84%) were given at least 75% of the planned chemotherapy doses. Severe
      mucositis (World Health Organization [WHO]) grade 3 to 4 was the limiting
      toxicity and was seen in 79% of patients. The median time for mucositis
      resolution was 8 weeks. Other toxicities were generally manageable, but there
      were four treatment related deaths (7%). Fifty patients were assessable for
      activity, with an overall response rate of 70% (95% confidence interval [CI], 58%
      to 82%). Complete response (CR) and partial response (PR) rates were 42% and 28%,
      respectively. CONCLUSION: This simultaneous combined-modality regimen was
      feasible at the cost of severe mucosal toxicity, which required hospitalization
      with nutritional, parenteral, and hydroelectrolytic support. The high response
      rate achieved (70%) did not translate into improved survival, probably due to
      patient eligibility. The likelihood of cure of this high-tumoral-volume patient
      population remains low (approximately 10%), despite the association of two
      therapeutic modalities at full standard therapeutic intensity.

PMID- 8648375
TI  - Synovial sarcoma: prognostic significance of tumor size, margin of resection, and
      mitotic activity for survival.
AB  - PURPOSE: The present study serves to describe outcomes-based prognostic variables
      characteristic of synovial cell sarcoma. PATIENTS AND METHODS: An analysis was
      performed of a prospectively compiled data base of 48 consecutive patients with
      extremity and truncal synovial sarcomas seen between 1966 and 1994. RESULTS: No
      local recurrences were observed among 27 patients who presented with localized
      primary disease. Patients with synovial sarcoma less than 5 cm in size has a
      cancer-specific survival rate at 10 years of 100%, compared with a 10-year
      survival rate of 32% and 0% for those with sarcoma 5 to 10 cm and greater than 10
      cm, respectively (P = .002). Patients with synovial sarcoma with less than 10
      mitoses per 10 high-power fields (hpf) had a 10-year cancer-specific survival
      rate of 46%, compared with a 10-year survival rate of 14% for those with sarcomas
      with greater than 10 mitoses per hpf (P = .04). Patients with a clean margin of
      excision were found to have a 10-year cancer-specific survival rate of 43%,
      compared with 0% for those with microscopic positive margins (P = .03). Among 14
      patients treated with neoadjuvant chemotherapy, seven (50%) had objective
      responses. CONCLUSION: Local control for patients with nonmetastatic disease was
      excellent. The overall cancer-specific survival rate for patients with localized
      synovial sarcoma was 34% at 10 years. Primary tumor size, margin of resection,
      and mean mitotic activity were prognostic factors for survival in synovial
      sarcoma. There was a high objective response rate to treatment with neoadjuvant
      chemotherapy; however, there was no detectable beneficial effects on survival in
      the subset of patients treated with chemotherapy versus nonrandomized patients
      who received no chemotherapy. Patients with synovial sarcoma > or = 5 cm in size,
      microscopic positive margins, and/or mean mitotic activity greater than 10
      mitoses per 10 hpf should be targeted for new therapeutic studies.

PMID- 8648376
TI  - Improved detection of medullary thyroid cancer with radiolabeled antibodies to
      carcinoembryonic antigen.
AB  - PURPOSE: This investigation was undertaken to assess the targeting of established
      and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies
      (MAbs) reactive with carcinoembryonic antigen (CEA). PATIENTS AND METHODS: Twenty
      six assessable patients with known (n = 17) or occult (n = 9) MTC were studied
      with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine
      targeting of tumor lesions. RESULTS: The targeting results of technetium 99m
      (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies
      (all directed against the same epitope of CEA) indicated that all these reagents
      were capable of detecting established and occult MTC. The sensitivity for
      detection of known sites of disease ranged from 76% to 100% for the various anti
      CEA MAbs used, when compared with computed tomography (CT), magnetic resonance
      imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody
      scan was positive in seven of nine patients with occult disease (patients with
      negative conventional imaging studies, but who had elevated calcitonin and/or CEA
      levels). Three of seven patients underwent surgery and the disease was confirmed
      by histopathology in all three. CONCLUSION: Anti-CEA MAbs are excellent agents
      for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity
      in patients with known lesions, combined with the ability to detect disease, may
      make these agents ideal for staging patients, monitoring disease pretherapy or
      posttherapy, and especially for evaluating patients with recurrent or persistent
      hypercalcitonemia or CEA elevations after primary surgery. Analogous to
      radioiodine in the evaluation of patients with differentiated thyroid cancer,
      radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and
      monitoring patients with MTC.

PMID- 8648377
TI  - Interobserver variability on the histopathologic diagnosis of cutaneous melanoma
      and other pigmented skin lesions.
AB  - PURPOSE: To assess the interobserver agreement on the diagnosis and
      classification of cutaneous melanoma. MATERIALS AND METHODS: A set of 140 slides
      of cutaneous melanoma, including a small subset of benign pigmented skin lesions,
      were circulated to four experienced histopathologists. The kappa statistic for
      multiple ratings per subject was calculated using the method described by Fleiss.
      RESULTS: The kappa value on the diagnosis of cutaneous melanoma versus benign
      lesions was 0.61. There was some discordance on the diagnosis in 37 of 140 cases
      (26%). For the histopathologic classification of cutaneous melanoma, the highest
      kappa values were attained for Breslow thickness (kappa = 0.76) and presence of
      ulceration (kappa = 0.87). The agreement was generally poor for other histologic
      features, such as level of dermal invasion (kappa = 0.38), presence of regression
      (kappa = 0.27), and lymphocytic infiltration (kappa = 0.27). CONCLUSION: Our
      study suggests considerable disagreement among pathologists on the diagnosis of
      melanoma versus other pigmented lesions. Tumor thickness and presence of
      ulceration are the most reproducible histologic features of cutaneous melanoma.

PMID- 8648378
TI  - Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor
      topotecan with granulocyte colony-stimulating factor in patients with solid
      tumors.
AB  - PURPOSE: To evaluate the feasibility of escalating doses of the topoisomerase I
      (topo I) inhibitor topotecan (TPT) with granulocyte colony-stimulating factor (G
      CSF) in minimally pretreated adults with solid tumors and to study whether G-CSF
      scheduling variably affects the ability to escalate TPT doses. MATERIALS AND
      METHODS: Thirty-six patients received 121 courses of TPT as a 30-minute infusion
      daily for 5 days every 3 weeks at doses that ranged from 2.0 to 4.2 mg/m2/d. G
      CSF 5 microg/kg/d subcutaneously (SC) was initiated concurrently with TPT
      (starting on day 1). Because the concurrent administration of TPT and G-CSF
      resulted in severe myelosuppression at the lowest TPT dose level, an alternate
      posttreatment G-CSF schedule in which G-CSF dosing began after TPT (starting on
      day 6) was subsequently evaluated. Plasma sampling was performed to characterize
      the pharmacologic behavior of high-dose TPT and to determine whether G-CSF
      altered the pharmacokinetic profile of TPT. RESULTS: Severe myelosuppression
      precluded the administration of TPT at the first dose, 2.0 mg/m2/d, with G-CSF on
      the concurrent schedule. However, dose escalation of TPT with G-CSF on a
      posttreatment schedule proceeded to 4.2 mg/m2/d. The dose-limiting toxicities
      (DLTs) were thrombocytopenia and neutropenia. One partial response was noted in a
      patient with colorectal carcinoma refractory to fluoropyrimidines.
      Pharmacokinetics were linear within the dosing range of 2.0 to 3.5 mg/m2/d, but
      TPT clearance was lower at the 4.2-mg/m2/d dose level. At 3.5 mg/m2/d, which is
      the maximum-tolerated dose (MTD) and recommended dose for subsequent-phase
      studies of TPT with G-CSF, the area under the concentration-versus-time curves
      (AUCs) for total TPT and lactone averaged 2.2- and 2.3-fold higher, respectively,
      than the AUCs achieved at the lowest TPT dose, 2.0 mg/m2/d. The pharmacologic
      behavior of high-dose TPT was not significantly altered by the scheduling of G
      CSF. CONCLUSION: G-CSF administered after 5 daily 30-minute infusions of TPT
      permits a 2.3-fold dose escalation of TPT above the MTD in solid-tumor patients,
      whereas concurrent therapy with G-CSF and TPT results in severe myelosuppression.

PMID- 8648379
TI  - Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion
      in adult cancer patients.
AB  - PURPOSE: To conduct a phase I and pharmacologic study of the new topoisomerase I
      inhibitor, 9-aminocamptothecin (9-AC). PATIENTS AND MATERIALS: A 72-hour infusion
      of 9-AC was administered every 14 days to 48 solid-tumor patients at doses of 5
      to 59 microg/m2/h without granulocyte colony-stimulating factor (G-CSF) and 47 to
      74 microg/m2/h with G-CSF. RESULTS: Without G-CSF, two of eight patients who
      received 47 microg/m2/h had dose-limiting neutropenia in their initial cycle, as
      did both patients who received 59 microg/m2/h (with a platelet count <
      25,000/microL in one). With G-CSF, zero of seven patients treated with 47
      microg/m2/h had dose-limiting neutropenia in their first cycle, while dose
      limiting neutropenia occurred in six of 14 patients (with platelet count <
      25,000/microL in five) entered at 59 microg/m2/h. Among 39 patients entered at >
      or = 25 microg/m2/h 9-AC with or without G-CSF, fatigue, diarrhea, and
      nausea/vomiting of grade 2 severity ultimately occurred in 54%, 30%, and 38%,
      respectively, while grade 3 toxicities of each type occurred in 8% of patients.
      Steady-state 9-AC lactone concentration (Css) increased linearly from 0.89 to
      10.6 nmol/L, and correlated strongly with leukopenia ( r = .85). CONCLUSION: The
      recommended phase II dose of 9-AC given by 72-hour infusion every 2 weeks is 35
      microg/m2/h without G-CSF or 47 microg/m2/h with G-CSF support. Dose escalation
      in individual patients may be possible according to their tolerance.

PMID- 8648380
TI  - Does expression of different EWS chimeric transcripts define clinically distinct
      risk groups of Ewing tumor patients?
AB  - PURPOSE: Because of the high heterogeneity of EWS gene fusions with FLI1 and ERG
      genes due to variable chromosomal breakpoint locations in Ewing tumors (ET) (14
      different chimeric transcripts identified so far), we evaluated the clinical
      impact of the expression of diverse fusion transcripts in ET patients. PATIENTS
      AND METHODS: In a European multicenter study, 147 ET were analyzed by reverse
      transcriptase polymerase chain reaction (RT-PCR) and the molecular data
      statistically compared with all clinical data available. RESULTS: Most tumors
      expressed chimeric transcripts with fusion of EWS exon 7 to FLI1 exon 6 (75 of
      147) (type I) or five (39 of 147) and EWS exon 10 to FLI1 exon 5 (eight of 147)
      or 6 (five of 147). In five cases, chimerism between EWS exon 9 and FLI1 exons 4
      and EWS exon 7 and FLI1 exon 7 or 8 was observed. Fifteen cases of EWS-ERG
      rearrangement were identified. In 85 of these patients treated in the European
      Cooperative Ewing Sarcoma Studies, molecular results were analyzed in comparison
      to age, sex, tumor localization, tumor volume, and disease extension. No
      significant correlation between the various fusion types and these features were
      observed. Relapse-free survival (RFS) for the 31 patients with localized disease
      and fusion type I tended to be longer compared with the 24 patients with
      localized tumors bearing other chimeric transcripts (P = .04). CONCLUSION:
      Results suggest a possible advantage in PFS for patients with localized disease
      and fusion type I transcripts, although this will require prospective validation
      with a larger number of patients and longer follow-up periods.

PMID- 8648382
TI  - Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for
      indolent lymphoma.
AB  - PURPOSE: Although most patients with indolent lymphomas respond to initial
      therapy, virtually all experience relapse. Secondary therapy is often beneficial,
      but responses are rarely, if ever, durable. We conducted this phase II trail to
      evaluate the therapeutic efficacy and toxicity of fludarabine, mitoxantrone, and
      dexamethasone (FND) in patients with relapsed indolent lymphoma. PATIENTS AND
      METHODS: Fifty-one patients with recurrent or refractory indolent lymphoma were
      treated with a regimen of fludarabine 25 mg/m2/d intravenously (IV) on days 1 to
      3, mitoxantrone 10 mg/m2 IV on day 1, and dexamethasone 20 mg/d IV or orally on
      days 1 to 5. Treatment was repeated at 4-week intervals for a maximum of eight
      courses. Late in the course of this trial, trimethoprim-sulfamethoxazole (TMP
      SMX) was incorporated for Pneumocystis carinii (PCP) prophylaxis. RESULTS:
      Responses were complete (CR) in 24 patients (47%) and partial (PR) in 24 (47%).
      The median failure-free survival time was 21 months for CR patients and 9 months
      for PR patients. Notable activity of FND was seen even in the elderly, in those
      with high serum lactate dehydrogenase (LDH) or beta2-microglobulin levels, and in
      those with multiple prior treatment regimens. The predominant toxic effects were
      myelosuppression and infections; other toxic effects were modest. Infections
      occurred in 12% of courses. Almost half of the infections were proven or
      suspected opportunistic infections, including six cases of dermatomal herpes
      zoster and two cases of proven PCP pneumonia. CONCLUSION: The FND combination is
      highly active in patients with recurrent or relapsed indolent lymphoma and
      results in a high percentage of CRs. Because of the risk of opportunistic
      infections, we currently recommend prophylaxis with TMP-SMX and advise deletion
      of corticosteroids for patients who develop opportunistic infections.

PMID- 8648381
TI  - Improved survival for children with B-cell acute lymphoblastic leukemia and stage
      IV small noncleaved-cell lymphoma: a pediatric oncology group study.
AB  - PURPOSE: In an effort to improve outcome for children with advanced B-cell
      malignancies, a treatment plan based on a published regimen that consists of four
      courses of fractionated cyclophosphamide (cyclo) given with doxorubicin (doxo)
      and vincristine (VCR) was intensified by alternating with sequential high-dose
      methotrexate (MTX) and cytarabine (Ara-C), given in conjunction with intrathecal
      (IT) MTX and Ara-C. PATIENTS AND METHODS: From October 1986 to October 1992, 133
      eligible patients were enrolled: 74 with B-cell (surface immunoglobulin-positive
      [Slg+] acute lymphoblastic leukemia (B-ALL) and 59 with stage IV small noncleaved
      cell lymphoma (SNCCL). The median age was 8 years; there were 103 males and 30
      females. Abdominal tumor masses were prominent in 63 cases (33 B-ALL and 30 stage
      IV SNCCL). RESULTS: Complete remission (CR) was achieved in 66 B-ALL and 57 stage
      IV patients (93% overall). At 4 years, the estimated event-free survival (EFS)
      rate is 65% +/- 8% for patients with B-ALL and 79% +/- 9% for those with stage IV
      SNCCL. Among patients with CNS involvement, 23 of 36 remain in CR (4-year EFS
      rate, 64% +/- 13%). Relapses occurred early; only 3 patients relapsed after
      completion of therapy. Thirteen relapses occurred in the marrow, three in the
      CNS, and six in other sites. Of 11 CNS-positive patients who relapsed, only two
      recurred primarily in the CNS. CONCLUSION: The results of this study indicate
      that with intensified chemotherapy an increasing potential for cure exists for
      patients with B-ALL and stage IV SNCCL.

PMID- 8648383
TI  - Mantle-cell lymphoma: a population-based clinical study.
AB  - PURPOSE: From a population-based non-Hodgkin's lymphoma (NHL) registry, 41
      patients with mantle cell lymphoma (MCL) -- a recently defined distinct B-cell
      NHL -- were selected and compared with patients with low- or intermediate-grade
      NHL from the same registry. PATIENTS AND METHODS: The incidence and behavior of
      MCL in the area of the Comprehensive Cancer Center West (CCCW) from 1981 to 1989
      were analyzed. Age, performance, tumor bulk, extranodal localization, stage,
      response to therapy, and survival were registered. Expression of cyclin D1
      protein and Ki-67 were measured in 29 patients. RESULTS: MCL made up 3.7% of
      NHLs. The median age was 68 years, and the male-to-female ratio was 1.6:1.
      Seventy-eight percent presented with stage IV, with the majority having bone
      marrow involvement. The complete response (CR) rate was 32% (13 of 41), with a
      median duration of 25 months. The median overall survival time was 31.5 months.
      The International Prognostic Index identified five patients with a low-risk score
      and a median survival time of 93+ months. In 23 of 29 patients, cyclin D1
      overexpression was present, without any relation to overall or disease-free
      survival. In contrast, a proliferative index less than 10% was significantly
      related to a better overall survival time (50 v 24 months). CONCLUSION: MCL is a
      disease of the elderly, who present with widespread disease and with a poor
      response to therapy. Although it harbors features of an indolent NHL, it behaves
      clinically as an aggressive NHL with a short overall survival time.

PMID- 8648384
TI  - Phase I trial of dose escalation with growth factor support in patients with
      previously untreated diffuse aggressive lymphomas: determination of the maximum
      tolerated dose of ProMACE-CytaBOM.
AB  - PURPOSE: The aim of this study was to determine the maximum-tolerated dose (MTD)
      of cyclophosphamide, doxorubicin, etoposide, prednisone, bleomycin, cytarabine,
      methotrexate, and leucovorin (ProMACE-CytaBOM) when the myelotoxic drugs
      cyclophosphamide, doxorubicin, etoposide, and cytarabine are escalated. PATIENTS
      AND METHODS: Thirty-eight eligible patients with diffuse aggressive non-Hodgkin's
      lymphoma were treated on a phase I trial of dose escalation using the ProMACE
      CytaBOM regimen and granulocyte-macrophage colony-stimulating factor (GM-CSF;
      Schering, Kenilworth, NJ). Patients were treated with recombinant (r)GM-CSF 10
      microg/kg/d subcutaneously from day 9 to 19. Twenty-seven patients had stage IV
      disease, four had stage III, and seven had bulky stage II. Half of the patients
      had bone marrow involvement. The median age was 45 years. RESULTS: We found that
      the MTD was 200% for the escalated drugs in this regimen (although we never
      escalated above the MTD or defined by dose-limiting toxicity) and that the
      normalized dose-intensity (NDI; defined as the ratio of the received dose
      intensity to the 100% dose-intensity of ProcMACE-CytaBOM) decreased with each
      cycle and was lower for the day-8 drug (cytarabine) than for the day-1 drugs. The
      complete response (CR) rate was 66%, and 92% of patients who achieved CR are
      alive without disease with a median follow-up time for survival of 3.6 years.
      CONCLUSION: The MTD of cyclophosphamide, doxorubicin, etoposide, and cytarabine
      in the ProMACE-CytaBOM regimen given with growth factor support is 200%, and this
      dose should be tested in larger phase II trials.

PMID- 8648385
TI  - Is radiotherapy curative for stage I and II low-grade follicular lymphoma?
      Results of a long-term follow-up study of patients treated at Stanford
      University.
AB  - PURPOSE: To evaluate retrospectively the results of radiotherapy for 177 patients
      with stage I (n = 73 [41%]) and II (n = 104 [59%]) follicular small cleaved-cell
      and follicular mixed small cleaved-cell and large-cell non-Hodgkin's lymphoma
      (NHL) treated in the Department of Radiation Oncology, Stanford University
      between 1961 and 1994. PATIENTS AND METHODS: Histology was follicular small
      cleaved-cell in 101 (57%) cases and follicular mixed small cleaved-cell and large
      cell in 76 (43%). Forty-five patients (25%) had staging laparotomy; 34 (19%) had
      extranodal involvement. All patients had received radiotherapy, either to one
      side of the diaphragm (involved or extended field) or to both sides (total
      lymphoid irradiation [TLI] or subtotal lymphoid irradiation [STLI]. Radiotherapy
      doses ranged from 35 to 50 Gy. RESULTS: The median follow-up duration was 7.7
      years. The longest follow-up duration was 31 years. Actuarial survival rates at
      5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. The median
      survival time was 13.8 years. At 5, 10, 15, and 20 years, 55%, 44%, 40%, and 37%
      of patients, respectively, were relapse-free. Only five of 47 patients who
      reached 10 years without relapse subsequently developed recurrence. Survival and
      freedom from relapse (FFR) were significantly worse for older patients. Relapse
      rates were lower following treatment on both sides of the diaphragm or staging
      laparotomy. Univariate analysis showed that youth and staging laparotomy were
      associated with significantly better survival and that FFR was better following
      treatment on both sides of the diaphragm or laparotomy. CONCLUSION: Radiotherapy
      remains the treatment of choice for early-stage low-grade follicular lymphomas.
      Patients who have remained free of disease for 10 years are unlikely to relapse.

PMID- 8648386
TI  - Allogeneic bone marrow transplant is not better than autologous transplant for
      patients with relapsed Hodgkin's disease. European Group for Blood and Bone
      Marrow Transplantation.
AB  - PURPOSE: To compare the results achieved with myeloablative therapy followed by
      either allogeneic bone marrow transplantation (alloBMT) or autologous bone marrow
      transplantation (ABMT) for patients with Hodgkin's disease (HD). PATIENTS AND
      METHODS: Of more than 1,200 patients with HD reported to the European Bone Marrow
      Transplantation (EBMT) registry, 49 underwent alloBMT. Of these, 45 with
      sufficient data were matched to 45 patients who underwent ABMT. The matching
      criteria were sex, age at time of transplantation, stage of disease at diagnosis,
      bone marrow involvement at diagnosis and at transplantation, year of
      transplantation, disease status at time of transplantation, time from diagnosis
      to transplantation, and conditioning regimen with or without total-body
      irradiation (TBI). RESULTS: The 4-year actuarial probabilities of survival,
      progression-free survival (PFS), relapse, and non-relapse mortality were 25%,
      15%, 61%, and 48% and 37%, 24%, 61%, and 27% after alloBMT and ABMT,
      respectively. The toxic death rate at 4 years was significantly higher for
      alloBMT patients (P = .04). For patients with sensitive disease at the time of
      transplantation, the 4-year actuarial probability of survival was 30% after
      alloBMT and 64% after ABMT (P = .007). This difference is mainly due to a higher
      transplant-related mortality rate after alloBMT (65% v 12%, P = .005). Acute
      graft-versus-host disease (aGVHD) > or = grade II was associated with a
      significantly lower risk of relapse, but also with a lower overall survival (OS)
      rate. CONCLUSION: Based on this study, alloBMT from a human leukocyte antigen
      (HLA)-identical sibling donor does not appear to offer any advantage when
      compared with ABMT. A graft-versus-Hodgkin effect is associated with > or = grade
      II aGVHD, but its positive effect on relapse is largely offset by its toxicity.
      In most circumstances, alloBMT cannot be recommended for patients with HD.

PMID- 8648387
TI  - Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on
      pulmonary function and symptoms in early-stage Hodgkin's disease.
AB  - PURPOSE: To evaluate the effect of doxorubicin, bleomycin, vinblastine, and
      dacarbazine (ABVD) chemotherapy alone and of ABVD with mantle or mediastinal
      irradiation (RT) on the pulmonary function of patients with early-stage Hodgkin's
      disease. PATIENTS AND METHODS: Between 1989 and 1993, 60 patients with clinical
      stage I to IIIA HD enrolled onto randomized trials at Memorial Sloan-Kettering
      Cancer Center (MSKCC) underwent prospective evaluation of pulmonary function. All
      patients received six cycles of ABVD, and 30 patients received mantle or
      mediastinal RT. Pulmonary function tests (PFTs) and symptom evaluation were
      conducted before, during, and after completion of chemotherapy and RT, and at
      various intervals thereafter. The median follow-up time was 30 months. RESULTS:
      During chemotherapy, symptoms of cough and dyspnea on exertion developed in 32 of
      60 patients (53%) and declines in pulmonary function occurred in 22 of 60
      patients (37%). Discontinuation of bleomycin was necessary in 14 of 60 patients
      (23%). Following chemotherapy, there was a significant decline in median forced
      vital capacity (FVC) and diffusing capacity of carbon monoxide (DLCO). In
      patients who received mantle or mediastinal RT, there was a further decline in
      FVC following radiation therapy. At the most recent follow-up evaluation, five of
      29 patients (18%) who received ABVD alone and nine of 30 (30%) who received ABVD
      and RT reported persistent mild pulmonary symptoms (P = .36), which did not
      significantly affect normal daily activity. CONCLUSION: ABVD chemotherapy induced
      acute pulmonary toxicity that required bleomycin dose modification in a
      substantial number of patients. The addition of RT resulted in a further decrease
      in FVC; however, this did not significantly affect the functional status of
      patients.

PMID- 8648388
TI  - Autologous peripheral-blood progenitor-cell support following high
      dosechemotherapy or chemoradiotherapy in patients with high-risk multiple
      myeloma.
AB  - PURPOSE: The aims of the current study were to evaluate in patients with high
      risk multiple myeloma (MM) the feasibility and usefulness of high-dose
      chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support
      with autologous peripheral-blood progenitor cells (PBPC) harvested after high
      dose cyclophosphamide (HDCYC). PATIENTS AND METHODS: Seventy-three patients with
      high-risk MM were entered onto the study. Before the procedure, all patients had
      received HDCYC to collect PBPC by leukapheresis. One patient died of infection
      after HDCYC. All other patients subsequently received high-dose melphalan (HDM)
      (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n
      = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of
      the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were
      reinfused either alone in 61 patients or together with back-up bone marrow cells
      in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM)
      cell content of the leukapheresis was low. RESULTS: One patient died of acute
      cardiac failure after reinfusion of PBPC; three patients did not respond after
      autologous blood progenitor cell transplantation (ABPCT), while the other 68
      patients achieved either a complete response (CR; n = 32) or partial response
      (PR; n = 36). Thirty-six patients relapsed or progressed after a median response
      duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four
      other patients died while still responsive of lung cancer (n = 1) or infection (n
      = 3). The remaining 28 patients are currently alive and still responding with a
      median follow-up duration of 27 months (range, 6 to 66). The 3-year probability
      of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/-
      51% (95% CI) from diagnosis. CONCLUSION: High-dose chemotherapy or
      chemoradiotherapy followed by autologous PBPC support in MM is feasible and
      efficient. Further studies are needed to confirm these encouraging, although
      preliminary, results and to compare this technique with other therapeutic
      strategies.

PMID- 8648389
TI  - Allogeneic blood cell transplantation without posttransplant colony-stimulating
      factors in patients with hematopoietic neoplasm: a phase II study.
AB  - PURPOSE: There is limited experience with allogeneic blood cell transplantation
      (BCT). In an earlier pilot study, the combination of bone marrow and blood did
      not produce severe acute graft-versus-host disease (GVHD). We now report the
      results of a phase II study using blood stem cells alone in 19 patients. PATIENTS
      AND METHODS: The median age was 40 years. All patients had hematopoietic
      malignancies and received transplants from HLA-identical sibling donors. GVHD
      prophylaxis consisted of cyclosporine plus prednisone. Posttransplant colony
      stimulating factors were not administered. Donors were mobilized with
      subcutaneous granulocyte colony-stimulating factor (G-CSF; 16 microg/kg/d) for 5
      days. Apheresis was performed on 2 consecutive days. RESULTS: The median cell
      content of the two apheresis was 11.9 x 10(8) WBC/kg, 3.2 x 10(8) CD3/kg, and 8.3
      x 10(6) CD34/kg. The median time to achieve an absolute neutrophil count (ANC) >
      or = 500/microL was 13 days, and 14 days to a platelet count > or =
      50,000/microL. All patients engrafted. Platelet recovery was faster in marrow
      historic control groups. Blood cells in all tested cases contained more than 95%
      donor cells on day 30. The actuarial incidence of acute GVHD was 37%, and 13% for
      grade II-IV GVHD. Limited, corticosteroid responsive, chronic GVHD developed in
      33% of assessable patients. At a median follow-up of 192 days, actuarial survival
      was 75%. CONCLUSION: Transplantation of a high number of stem cells may lead to
      rapid engraftment without the use of posttransplant colony-stimulating factors.
      GVHD does not appear to be more severe than in similarly treated patients
      undergoing bone marrow transplantation. For allogeneic transplantation, mobilized
      blood cell collections are an alternative to bone marrow collections.

PMID- 8648390
TI  - Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic
      malignancies.
AB  - PURPOSE: The phosphoprotein p53 is involved in transcriptional regulation and is
      detected in hematologic malignancies. In vitro incubation of acute myelogenous
      leukemia with OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary
      to p53 mRNA, results in leukemic cell death. A phase I dose-escalating trial was
      conducted to determine the toxicity of OL(1)p53 following systemic administration
      to patients with hematologic malignancies. PATIENTS AND METHODS: Sixteen patients
      with either refractory acute myelogenous leukemia (n = 6) or advanced
      myelodysplastic syndrome (n = 10) participated in the trial. Patients were given
      OL(1)p53 at doses of 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous
      infusion. RESULTS: No specific toxicity was directly related to the
      administration of OL(1)p53. One patient developed transient nonoliguric renal
      failure. One patient died of anthracycline-induced cardiac failure. Approximately
      36% of the administered dose of OL(1)p53 was recovered intact in the urine.
      Plasma concentrations and area under the plasma concentration curves were
      linearly correlated with dose. Leukemic cell growth in vitro was inhibited as
      compared with pretreatment samples. There were no clinical complete responses.
      CONCLUSION: A phosphorothioate oligonucleotide, OL(1)p53, can be administered
      systemically without complications. This type of modified oligonucleotide can be
      administered without complete degradation, as it was recovered from the urine
      intact. This oligonucleotide may be useful in combination with currently
      available chemotherapy agents for the treatment of malignancies.

PMID- 8648391
TI  - Impact of age on outcome of patients with cancer undergoing autologous bone
      marrow transplant.
AB  - PURPOSE: We examined the impact of age on outcomes in patients with cancer
      undergoing autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS:
      All 506 adult patients who underwent ABMT at the Johns Hopkins Oncology Center
      between January 1987 and January 1994 were studied. A total of 405 patients were
      aged 18 to 49 years and 101 were aged > or = 50. The effect of age and other
      prognostic variables on transplant-related mortality (TRM), relapse, and event
      free survival rates were analyzed. RESULTS: Patients aged > or = 50 years has a
      2.24-fold increased risk of TRM. Although relapse rates were not different based
      on age, the increased TRM rate resulted in a slight decrease in overall event
      free survival in the older patients. Causes of death were not different by age
      and were mainly related to preparative regimen toxicity. Length of hospital stay
      and hospitalization costs were not increased in the older patients. CONCLUSION:
      While the TRM rate was higher in older patients, relapse rates were not
      increased. Nearly 25% of older patients were expected to be cured of the disease.
      These data support the use of ABMT in eligible older patients, at least up to the
      age of 65.

PMID- 8648392
TI  - BCL-2/JH rearrangements in circulating B cells of healthy blood donors and
      patients with nonmalignant diseases.
AB  - PURPOSE: To answer the question whether t(14;18)-positive cells can be detected
      by polymerase chain reaction (PCR) in the peripheral blood of healthy blood
      donors and patients with nonmalignant diseases. PATIENTS AND METHODS: Peripheral
      blood mononuclear cells (PBMNC) from healthy donors (n = 36) and patients with
      nonmalignant diseases (n = 21) were examined by two-step PCR for the detection of
      t(14;18)-positive cells with a breakpoint within the major breakpoint region
      (MBR). Approximate numbers of t(14;18)-positive cells were determined using
      limiting dilution assays, as well as the stochastic multiple-tube approach.
      RESULTS: We were able to detect t(14;18)-positive cells in PBMNC of approximately
      50% of healthy donors and patients with nonmalignant diseases if DNA amounts up
      to 10 microg were tested. Compared with 17 t(14;18)-positive patients being in
      complete remission after radiotherapy for low-stage malignant follicular
      lymphoma, the majority of 26 healthy donors were found to have significantly
      lower numbers of t(14;18)-positive cells circulating in the peripheral blood. In
      the case of six healthy donors, more than one t(14;18) DNA fragment based on size
      and nucleotide sequence analysis was detected. In one healthy individual, four
      different t(14;18)-positive cell clones were found in nine samples found over 5
      years. CONCLUSION: The occurrence of the t(14;18) translocation is not restricted
      to follicular lymphoma cells. In healthy donors, long-lived t(14;18)-positive
      cells can be detected by PCR if the sensitivity is high enough. Based on
      nucleotide sequence analysis, the t(14;18) DNA fragments detected in healthy
      donors cannot be distinguished from those found in follicular lymphomas.

PMID- 8648393
TI  - Therapy of untreated acute myeloid leukemia in the elderly: remission-induction
      using a non-cytarabine-containing regimen of mitoxantrone plus etoposide.
AB  - PURPOSE: The University of Manitoba Adult Acute Leukemia Study Group sought to
      examine the safety, efficacy, and impact on quality of life of a non-cytarabine
      containing remission-induction regimen followed by intermediate-dose cytarabine
      (IDARA-C) postremission therapy for the management of untreated acute myeloid
      leukemia (AML) in patients age 60 to 80 years. PATIENTS AND METHODS: Eligible
      patients received mitoxantrone 10 mg/m2 and etoposide 100 mg/m2 on days 1 to 5.
      Complete remitters received a single course of cytarabine 0.5 mg/m2 every 12
      hours on days 1 to 6. Cytogenetic and immunophenotyping studies were performed at
      diagnosis and were examined for prognostic importance. The Functional Living
      Index-Cancer (FLI-C) was used in the longitudinal assessment of quality of life.
      RESULTS: A total of 37 (55%) of 67 eligible patients achieved remission, 34 (92%)
      of whom did so with a single course. The induction mortality rate was 12%. The
      median disease-free and overall survival times were 8.4 and 9.2 months,
      respectively. CD34 stem-cell phenotype, poor performance status, and high
      cytogenetic complexity score were independent covariates of failure to achieve
      remission. Very complex karotype combined with CD34 stem-cell phenotype to
      predict induction death in 67% of cases (P = .0003). Cytotoxic therapy-related
      gut epithelial damage was maximal during weeks 2 and 3 of therapy. Complete
      remitters and partial responders exhibited significantly improved global FLI-C
      scores following completion of therapy. CONCLUSION: Mitoxantrone plus etoposide
      was an effective and well-tolerated first-line induction regimen for AML in the
      elderly that should be studied further in comparison to the standard
      cytarabine/anthracycline-based therapy.

PMID- 8648394
TI  - Feasibility and results of bone marrow transplantation after remission induction
      and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group
      for Bone Marrow Transplantation.
AB  - PURPOSE: To evaluate prospectively the feasibility and results of bone marrow
      transplantation (BMT) after induction and intensification chemotherapy (CT) in
      patients with de novo acute myeloid leukemia (AML). PATIENTS AND METHODS: A total
      of 159 patients less than 51 years of age were treated. Induction CT consisted of
      daunorubicin 60 mg/m2 for 3 days, cytarabine (ARA-C) 100mg/m2 for 7 days, and
      etoposide 100 mg/m2 for 3 days. The first intensification therapy included
      mitoxantrone 10 mg/m2 for 3 days and ARA-C 1.2 g/m2 every 12 hours for 4 days.
      Amsacrine (100 or 150 mg/m2 for 3 days) and ARA-C (1.2 g/m2 every 12 hours for 2
      or 4 days) were given as the second intensification therapy. Depending on the
      availability of a human leukocyte antigen (HLA)-identical sibling, the intention
      of treatment after CT was allogeneic BMT (allo-BMT) or autologous BMT (ABMT).
      RESULTS: Complete remission (CR) was obtained in 120 patients (75%) and partial
      remission (PR) in 11 (7%), while 15 patients (10%) were refractory and 13 (8%)
      died during induction. There was a trend for better leukemia-free survival (LFS)
      at 4 years for patients assigned to the ABMT group (50% +/- 6%) compared with the
      allo-BMT group (31% +/- 7%) (P = .08). This difference in LFS reached statistical
      significance when considering only transplanted patients (63% +/- 3% at 4 years
      after ABMT and 38% +/- 11% after allo-BMT, P = .02). The favorable results in
      patients who received ABMT (no toxic deaths and 37% +/- 7% probability of relapse
      at 4 years) contrast with the poor outcome of allografted patients (11 patients
      with transplant-related mortality). CONCLUSION: Our study reflects the
      difficulties in the completion of a therapeutic strategy that include BMT and
      suggests that intensification before BMT may be useful in the setting of ABMT,
      but this approach was associated with a high mortality rate in allo-BMT patients.

PMID- 8648395
TI  - Reducing patient eligibility criteria in cancer clinical trials.
AB  - PURPOSE: To discuss patient eligibility criteria in phase III cancer clinical
      trials in the larger setting of the complexity of these trials, to review the
      various reasons for imposing restrictive eligibility requirements, to discuss the
      problems caused by these requirements, to argue that these requirements should be
      greatly relaxed in most cancer clinical trials, to provide some guiding
      principles and practical suggestions to facilitate such a relaxation, and to give
      an example of how eligibility requirements were reduced in a recent clinical
      trial in acute lymphocytic leukemia. METHODS: Implicit and explicit reasons for
      including eligibility criteria in clinical trials are reviewed. Safety concerns
      and sample size issues receive special attention. The types of problems
      restrictive eligibility criteria cause with respect to scientific interpretation,
      medical applicability, complexity, costs, and patient accrual are described.
      RESULTS: A list of three items that each eligibility criterion should meet in
      order to be included is proposed and applied to a recent trial in acute
      lymphocytic leukemia. CONCLUSION: Phase III clinical trials in cancer should have
      much broader eligibility criteria than the traditionally restrictive criteria
      commonly used. Adoption of less restrictive eligibility criteria for most studies
      would allow broader generalizations, better mimic medical practice, reduce
      complexity and costs, and permit more rapid accrual without compromising patient
      safety or requiring major increases in sample size.

PMID- 8648396
TI  - Use of cytokines in the treatment of acute myelocytic leukemia: a critical
      review.
AB  - PURPOSE: The colony-stimulating factors (CSFs) have been evaluated in patients
      with acute myelocytic leukemia (AML), both as potential priming agents and during
      and/or following induction chemotherapy to shorten the period of
      myelosuppression. The purpose of this review is to evaluate critically the safety
      and efficacy of the CSFs, primarily granulocyte-macrophage colony-stimulating
      factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF), in the
      treatment of patients with AML. METHODS: All phase III trials that have either
      been presented or published that used CSFs during and/or following induction
      chemotherapy in patients with de novo AML are discussed. Relevant background
      information and future directions are also addressed. RESULTS AND CONCLUSION:
      There have been six phase III trials that used either GM-CSF or G-CSF in
      induction therapy in patients with AML. It is difficult to compare these trials
      due to differences in patient age, induction therapy administered, disease
      characteristics, whether leukemia response or documentation of marrow hypoplasia
      was required before cytokine use, and the different cytokines administered during
      the study. In particular, the timing of CSF administration in relation to the
      chemotherapy may be important due to the different biologic effects these agents
      may have on leukemia cells, such as leukemia cell recruitment. Most of these
      studies administered either GM-CSF or G-CSF before or during induction therapy,
      as well as following completion of chemotherapy until neutrophil recovery. Only
      one of six trials required documentation of marrow hypoplasia before CSF use.
      Despite these differences, administration of either GM-CSF or G-CSF was found to
      be safe without an increase in acute toxicity or an increase in relapse rates. In
      addition, most trials demonstrated a significant improvement in neutrophil
      recovery, with several trials demonstrating an improvement in complete remission
      and overall survival rates. Therefore, the use of selected CSFs may be of benefit
      following induction chemotherapy in those patients with AML who are at increased
      risk for early morbidity and mortality.

PMID- 8648397
TI  - Radioimmunotherapy: recent results and future directions.
AB  - PURPOSE: To review antibody structure, function, and production; suitable
      radioisotopes for radioimmunotherapy; challenges facing the field; recent
      clinical results; toxicity; and future directions. DESIGN: The radioimmunotherapy
      literature was reviewed, with an emphasis on clinical results and future
      directions. RESULTS: The highest complete response rates (overall, approximately
      50%) have been achieved in patients with B-cell non-Hodgkin's lymphoma.
      Challenges that currently face radioimmunotherapy include circulating free
      antigen, binding of antibodies to nonspecific Fc receptors, insufficient tumor
      penetration, antigenic heterogeneity and insufficient antigen expression,
      antigenic modulation, and development of human antimouse antibodies. Possible
      approaches to these challenges, including high-dose radioimmunotherapy and
      chemotherapy followed by autologous bone marrow transplantation, the use of
      radionuclides such as yttrium 90 (90Y) and copper 67 (67Cu), and the development
      of humanized and bifunctional antibodies, are under investigation. CONCLUSION:
      Although radioimmunotherapy is a relatively new field, substantial progress has
      been made. Additional research will ultimately resolve many of the challenges
      that currently face radioimmunotherapy and hopefully lead to the cure of some
      currently incurable malignancies.

PMID- 8648398
TI  - Is oral ondansetron really efficacious in the control of cisplatin-induced
      delayed emesis?

PMID- 8648399
TI  - Combined modality therapy of lung cancer and lung tolerance.

PMID- 8648400
TI  - Paclitaxel and doxorubicin in metastatic breast cancer.

PMID- 8648401
TI  - Breast cancer: systemic benefit of locoregional treatment.

PMID- 8648402
TI  - Acute myeloid leukemia-type chemotherapy for myelodysplasia.

PMID- 8648403
TI  - Interleukin-10 and phenomena of tolerance in interleukin-2 therapy.

PMID- 8648404
TI  - Cessation of follow-up tests with limited utility: a patient's perspective.

PMID- 8648405
TI  - To test or not to test: where is the truth?

PMID- 8648406
TI  - Clinical assessment of the pumping technique in treating TMJ arthrosis with
      closed lock.
AB  - The treatment of closed jaw locking due to temporomandibular joint (TMJ)
      arthrosis is described. Conventional mandibular manipulation of the lower and/or
      upper joint compartments was performed using hydraulic pressure from an imaging X
      ray medium. The procedure was used in 40 patients with closed locking (5 acute
      and 35 chronic). The results of the treatment are evaluated and factors affecting
      the results are examined. In four of the five patients with acute closed locking,
      the lock was successfully released after use of the pumping technique on the
      lower joint compartment. In patients with chronic locking, an average improvement
      of 6.6 mm in the degree of interincisal opening was observed within 3-4 days of
      treatment with the pumping technique. In 13 of these patients, satisfactory
      opening (at least 40 mm) was achieved immediately. All the patients underwent
      further forward and contralateral manipulation to assist mouth opening, and after
      a period of 2-3 months 16 patients showed a further average improvement of 5.4 mm
      in interincisal opening.

PMID- 8648407
TI  - A finite element model of the human face. Stress distribution around the chin due
      to articulation of the five vowels in Japanese.
AB  - In this study the authors set out to investigate the stress distribution around
      the chin due to articulation, and to discuss whether the calculated stresses can
      cause bone remodeling. A finite element model of facial soft tissue was
      constructed and movements related to the articulation of the five basic Japanese
      vowel sounds were reproduced individually on the model. The stress distribution
      of each vowel depended on the shapes formed by the lips and the degree of
      mandibular opening. Stresses increased with the strain on the soft tissue of the
      lips. It seemed unlikely that the calculated stress alone was sufficient to
      produce a hypertrophic increase in modeling. However, it seemed that muscle
      forces might produce an effective strain load with a range sufficient to cause
      bone remodeling by accumulation of stresses around the chin.

PMID- 8648408
TI  - Hydroxyproline and total protein levels in gingiva from patients treated with
      phenytoin and cyclosporine-A.
AB  - Hydroxyproline (Hyp) and total protein levels were studied in gingiva from
      patients treated with phenytoin (PHT) and cyclosporine-A (CSA). The study
      included 5 groups of subjects: PHT and CSA groups with and without gingival
      overgrowth (PHT-GO+), (PHT-GO-), (CSA-GO+), (CSA-GO-), and periodontally healthy
      controls (C). After taking clinical measurements, gingival samples were harvested
      by gingivectomy or excising one or two papillae from the posterior areas. The
      samples were analyzed biochemically. In the PHT groups, both Hyp and total
      protein levels were significantly higher than in the C group. The differences
      between the PHT-GO+ and PHT-GO- groups were not statistically significant. In the
      CSA groups, total protein levels were significantly higher than in controls while
      no significant difference was found in Hyp levels. The differences between the
      CSA-GO+ and CSA-GO- groups were not statistically significant. When the PHT and
      CSA groups were compared, Hyp levels were significantly higher in the PHT-GO+
      group than in the CSA-GO+ group. Total protein level differences between the PHT
      and CSA groups were not statistically significant. Correlations between age,
      plaque index, gingival overgrowth index, Hyp and total protein levels were
      analyzed and most were found not to be statistically significant. PHT appears to
      stimulate both collagen and total protein synthesis in gingiva while CSA seems to
      have a stronger effect on total protein synthesis. This suggests that the
      mechanisms underlying PHT- and CSA-induced gingival overgrowth are different and
      further comparative studies are needed.

PMID- 8648409
TI  - Microstructure of etched "IPS Empress" heat-pressed ceramics observed by SEM.
AB  - A valuable characteristic of the "IPS Empress" used for producing all ceramic
      dental restorations is that it is a prefired ceramic ingot. The ingot is heated,
      softened and press-injected into the cavity, and ceramic restorations are
      fabricated by the lost wax casting method. The leucite crystal present in the
      ingot are scattered and distributed into the glassy phase in a more homogeneous
      manner through this pressing procedure, and the resulting ceramics are of higher
      flexural strength than conventional ones. The present study was carried out to
      clarify the microstructure of Empress ceramics by etching, and to observe the
      etched surface by scanning electron microscopy, in comparison with several other
      conventional ceramics. It was shown that the form and distribution of the leucite
      crystals in Empress ceramics are quite different before and after pressing, and
      that the staining and layering ceramics are also different from conventional
      ceramics. The method of surface treatment of ceramics prior to etching, such as
      fracturing or grinding, the kind of etching material used, the concentration and
      the etching time are important factors for revealing, observing and evaluating
      the microstructure of ceramics containing leucite crystals.

PMID- 8648410
TI  - Detection of Epstein-Barr virus early replicative phase using monoclonal antibody
      BZ-1 in oral hairy leukoplakia and other hyperkeratotic oral mucosal lesions: a
      retrospective study.
AB  - The early replicative phase of Epstein-Barr virus (EBV) was detected by
      immunohistochemistry, in addition to routine histology with hematoxylin eosin
      staining, in formalin fixed, paraffin-embedded archive specimens of 97
      hyperkeratotic lesions including oral hairy leukoplakia (HL) in order to assess
      whether EBV is specific to HL, or if it occurs in other hyperkeratotic lesions of
      the oral mucosa. Monoclonal antibody (MAb) BZ-1 directed against the BZLF-1 gene
      product of EBV was used for immunostaining by the avidin-biotin peroxidase
      technique. The reaction was visualized with DAB/H2O2 solution and counterstained
      with PAS stain to detect any coexisting of hyphae of Candida. Eight lesions were
      reactive with BZ-1, confirming a diagnosis of HL, although the total number of
      lesions with koilocytoid features was 33. Seventy percent of the patients with
      confirmed HL lesions were HIV-seropositive, and 50% of the HL lesions were
      associated with Candida hyphae. One third of the lesions with koilocytoid
      features were associated with hyphae of Candida. Only one renal transplant
      patient had HL, confirmed by a positive BZ-1 reaction, although 60% of the
      hyperkeratotic lesions showed koilocytoid features in a subgroup of 15 patients
      with renal transplants.

PMID- 8648411
TI  - Osseous choristoma of the tongue.
AB  - The term "choristoma" is used to describe a mass of histologically normal tissue
      presenting in an aberrant site. A rare case of osseous choristoma of the tongue
      is presented and the literature is briefly reviewed.

PMID- 8648412
TI  - An immunohistochemical study of two cases of either peripheral odontogenic
      fibroma (WHO type) or peripheral ameloblastoma.
AB  - Two cases of either peripheral odontogenic fibroma (POF) (WHO type) or peripheral
      ameloblastoma are reported. Their immunohistochemical characteristics were
      investigated in an attempt to clarify their histogenesis. The results showed that
      the epithelial component of this neoplasm tended to retain its distinct
      odontogenic character and expressed a keratin profile different from that of the
      overlying oral epithelium from which both cases most probably originated. The
      connective tissue element of these tumors was vimentin-positive and S-100 protein
      negative, confirming their mesodermal nature but precluding the possibility of
      ectomesenchymal derivation. No reactivity for desmin was noted.

PMID- 8648413
TI  - Impact of healthcare reform. Interview by Marie Manthey.

PMID- 8648414
TI  - JCAHO's management of information standards. The role of the informatics nurse
      specialist.

PMID- 8648415
TI  - Nursing education and administration in Nigeria. Progress and challenges.

PMID- 8648416
TI  - Graduate nursing education. What are the benefits and costs to hospitals?
AB  - In 1989, Hermann Hospital and University of Texas-Houston Health Science Center
      School of Nursing applied for and received approval to implement a 5-year
      demonstration project funded by the Health Care Finance Administration using
      Medicaid pass-through funds to educate nurses at the graduate level. The project
      aimed to evaluate the impact of advanced practice nurses and researchers on the
      practice of professional nursing at a 655-bed acute-care hospital in a large
      metropolitan area. The authors describe the factors that served to galvanize the
      two institutions to apply for such a grant, discuss the barriers encountered
      along the course of the project, and list the outcomes achieved by 1994 or
      project end. Predictions regarding the second 5-year segment (phase 2) are
      summarized as well. The article includes suggestions to other institutions
      interested in replicating such a project.

PMID- 8648417
TI  - Alta Bates responds.

PMID- 8648418
TI  - Project management. Lessons learned from introducing a multitask environmental
      worker program.
AB  - During a 13-month successful introduction of unit-based, multiskilled
      environmental workers at an academic medical center, responsibility for
      environmental support services migrated from centrally managed departments to
      more than 30 patient-care units. The authors discuss six project management
      lessons that may be used by clinicians and managers as they participate in
      service reorganization. Points related to the identification of committed
      leaders, exploration of barriers, planning, continuous training, negotiation, and
      communication are presented. Professional nurses who demonstrate their ability to
      work with these types of service innovations while clearly identifying clinical
      aspects best left unincorporated in such job descriptions will be in demand as
      participants in redesign efforts.

PMID- 8648419
TI  - Work group culture, stress, and hostility. Correlations with organizational
      outcomes.
AB  - Understanding your organizational culture is necessary if you are to be
      successful in making and surviving the necessary changes in current environments.
      Although organizational culture frequently has been studied in the business
      community, there are fewer studies of organizational or work group culture in
      hospital settings at the nursing unit level. The existing studies have emphasized
      the need to understand the individual work group culture before successfully
      implementing innovation and educational programs, or hiring and orienting new
      employees on nursing units. This descriptive, correlational study describes the
      relationships among work group culture, work-place stress, and hostility and
      nursing unit outcomes, specifically absenteeism and turnover. Implications of the
      findings include the idea that increasing decision latitude in workers may
      positively impact absenteeism.

PMID- 8648420
TI  - Using elements of the nursing minimum data set for determining outcomes.
AB  - To measure the contribution of nursing activities to patient outcome achievement
      requires a standardized language for documentation and retrieval of critical data
      elements. This pilot study explored the utilization of elements of the Nursing
      Minimum Data Set (NMDS) in a sample of patients undergoing parathyroidectomy.
      Results support the importance of nursing management's role in creating reliable
      systems that capture the critical elements of care delivery. The successful use
      of any system for documentation and for research will be dependent on education
      of the staff in the various taxonomies being used.

PMID- 8648421
TI  - The new reality.

PMID- 8648422
TI  - Clinical ladder to professional advancement program. An evolutionary process.
AB  - Since the early 1970s, clinical ladder programs have been a method of defining,
      recognizing, and rewarding nursing practice. As clinical practice in an
      institution grows and evolves, so must the program that supports the development
      of the practitioner. An in-depth evaluation of one clinical ladder program was
      conducted to determine if it was reflective of current practice. The authors
      discuss the method of evaluation, findings, and the revised program.

PMID- 8648423
TI  - The dilemma of the hasty discharge.

PMID- 8648424
TI  - Modulation of inflammation and cytokine production by dietary (n-3) fatty acids.
AB  - The production of pro-inflammatory cytokines, such as interleukin-1 and tumor
      necrosis factor, is pivotal in the response to infection. However, overproduction
      of these cytokines might be detrimental. It has been suggested that (n-3) fatty
      acids suppress inflammation and ameliorate the course of infection by decreasing
      the production of pro-inflammatory cytokines. We here, review these effects. Use
      of (n-3) fatty acids induced moderate clinical improvements in rheumatoid
      arthritis, psoriasis and colitis, but not in systemic lupus erythematosus. Data
      on critically ill burn or postoperative cancer patients are still inconclusive.
      The (n-3) fatty acids markedly inhibited sterile inflammation in animal studies
      and improved survival in some experimental infections. T cell responses decreased
      in healthy volunteers but remained unchanged or increased in certain patient
      groups. The production of pro-inflammatory cytokines decreased in most human
      studies. The (n-3) fatty acids increased cytokine production capacity in mice.
      Differences in cytokine-producing cell types studied may account for these
      paradoxical responses in humans and mice. Although the increased cytokine
      production in mice is partly mediated by effects on prostaglandins, mechanisms of
      action in other species remain to be elucidated. The (n-3) fatty acids may be of
      moderate benefit in some chronic inflammatory diseases. Their therapeutic value
      and possible hazards in critically ill patients remain to be established.

PMID- 8648425
TI  - Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4
      synthesis in rats and the effect is modified by dietary linoleic acid.
AB  - Eicosatrienoic acid (ETrA) is the (n-9) homologue of (n-6) arachidonic acid (AA)
      and (n-3) eicosapentaenoic acid (EPA). ETrA can be synthesized endogeneously, but
      tissue levels are normally undetectable except in essential fatty acid (EFA)
      deficiency. An ETrA-rich oil extracted from a cultured fungus was used to prepare
      diets which had varying levels of ETrA (0-8 g/kg diet) in combination with one of
      two levels of linoleic acid (LA, 2.2 or 9.5 g/kg diet). All diets were sufficient
      in essential fatty acids. Groups of rats were fed these diets for 4 wk after
      which leucocyte fatty acid content and leukotriene B4 (LTB4) synthesis were
      measured. The influence of dietary LA on ETrA accumulation in cells was studied
      and correlations with LTB4 synthesis determined. ETrA was efficiently
      incorporated into peritoneal exudate cell (PEC) phospholipids with no evident
      saturation being observed with levels up to 10 mol/100 mol total fatty acids in
      peritoneal exudate cells. Cellular ETrA levels were lower (P < 0.001) in rats fed
      the higher level of LA. ETrA accumulation in peritoneal exudate cells correlated
      (r(2) = 0.63, P < 0.05) with reduced LTB4 synthesis which was attributable to LTA
      hydrolase inhibition. Thus, dietary ETrA from a biological source can accumulate
      in leucocytes and suppress inflammatory eicosanoid synthesis. The findings
      justify further studies into the biochemical and anti-inflammatory effects of
      dietary ETrA, which could be incorporated into palatable food additives.

PMID- 8648426
TI  - Dietary polyunsaturated fatty acids modulate responses of pigs to Mycoplasma
      hyopneumoniae infection.
AB  - Polyunsaturated fatty acids (PUFA) are immunomodulators, but few studies have
      examined how these dietary components influence infectious respiratory disease.
      Groups of nine pigs were fed casein and corn starch-based diets containing 10.5
      g/100 g corn oil (CO), linseed oil (LO), menhaden oil (MO), linseed + corn oil
      (LC, 1:1) and menhaden + corn oil (MC, 1:1). As a methodological control, one
      group of pigs (n = 15) was fed a commercial ration (control diet; C). Pigs
      inoculated intratracheally with Mycoplasma hyopneumoniae after 4 wk of consuming
      the diets were killed 3 wk later. Gross lung lesions in MO-fed pigs were less (P
      < 0.05) than those in LC- and MC-fed pigs. Pigs fed MO had less peribronchial
      inflammation (P < 0.05) than all other groups. Gross lung lesions correlated
      negatively with basal in vitro alveolar macrophage tumor necrosis factor (TNF)
      production in pigs fed diets that contained negligible levels of (n-3) PUFA (C
      and CO). Basal macrophage TNF production did not correlate with lung lesion
      scores for diets containing more (n-3) PUFA than C or CO (LO, MO, LC and MC). For
      pigs fed the LO, MO, LC and MC diets, mean gross lung lesions increased as the
      mean ratio of (n-3):(n-6) PUFA in alveolar macrophage lipids decreased. Serum
      levels of alpha1 acid glycoprotein (AGP) were less (P < 0.05) in pigs fed MO, and
      there was a rise in mean lung lesions scores for each PUFA-fed group as mean AGP
      levels increased. These results indicate that dietary PUFA can affect disease
      pathogenesis and that the (n-3):(n-6) PUFA ratio may modulate the host response.

PMID- 8648427
TI  - Dietary fish oil enhances insulin sensitivity in miniature pigs.
AB  - The effects of dietary fish oil, MaxEPA, and corn oil on insulin sensitivity were
      examined in male miniature pigs. The pigs (20-35 kg) received 750 g of
      nonpurified diet per day (160 g/kg protein, 50 g/kg fat) with the addition of
      either 30 g corn oil or 30 g MaxEPA, resulting in 90 g total fat per kg diet for
      4-5 wk. The MaxEPA diet provided 12.6 g (n-3) polyunsaturated fatty acids per kg
      diet (6.7 g eicosapentaenoic acid, 4.8 g docosahexaenoic acid), 4.7 g (n-3)
      polyunsaturated fatty acids and 147 mg cholesterol. The corn oil diet provided
      22.7 g (n-6) polyunsaturated fatty acids per kg diet and no (n-3) polyunsaturated
      fatty acids; cholesterol was added to equal the amount in the MaxEPA. After
      overnight withdrawal of food, intravenous glucose tolerance tests were conducted
      in conscious pigs by using previously placed jugular vein catheters. Plasma
      glucose responses and the areas under the plasma glucose curves were similar in
      seven MaxEPA- and five corn oil-fed pigs. However, the incremental areas under
      the insulin curves were significantly lower for the pigs fed MaxEPA. Thus values
      for insulin sensitivity (SI), determined with Bergman's minimal model, were
      significantly higher for MaxEPA than for corn oil-fed pigs, whereas the rate of
      glucose disappearance (KG), did not differ between the two groups. Therefore,
      substitution of (n-3) for (n-6) polyunsaturated fatty acids in dietary lipids is
      associated with enhanced insulin sensitivity in male pigs.

PMID- 8648428
TI  - Brain neutral lipids and phospholipids are modified by long-term feeding of beef
      tallow vs. corn oil diets.
AB  - Previous studies examining the response of brain lipids to dietary fat
      modification have not quantified neutral lipids such as diacylglycerols (DG) and
      triacylglycerols (TG). In this study we measured the concentrations of neutral
      lipids and phospholipids, and their fatty acid profiles, in the cerebra of rats
      fed defined diets containing either beef tallow (BT) or corn oil (CO) at 12% or
      37% of energy. The diets were fed to rat pups beginning at 18 d of age and
      continued for 31 wk. The proportion of brain linoleic acid [18:2(n-6)] in TG from
      CO-fed rats was two- to fourfold greater than in BT-fed rats. Although 18:2(n-6)
      levels were higher in serum and brain TG of rats fed CO, differences in other TG
      fatty acid concentrations in serum were not reflected in the brain. Rats fed CO
      diets had higher concentrations of 18:2(n-6) in brain phospholipids as well as
      neutral lipids compared with rats fed BT diets, and the differences were greater
      in rats fed 37% rather than 12% of energy as fat. Differences in other
      polyunsaturated fatty acids associated with dietary fat composition were also
      found among the brain phospholipids. Most notably, the concentration of
      docosapentaenoic acid [22:5(n-6)] in brain phospholipids was highest in rats fed
      diets containing the lowest concentrations of alpha-linolenic acid [18:3(n-3)]. A
      concentration of 0.1 mg 18:3(n-3)/g diet appeared to be adequate to prevent
      elevation of 22:5(n-6) in brain phospholipids. These results demonstrate that
      consumption of a low fat diet (12% of energy) primarily comprised of saturated
      fats may potentiate an 18:3(n-3) deficiency in brain of rats.

PMID- 8648429
TI  - Dietary myristic acid alters acylated proteins in activated murine macrophages.
AB  - After stimulation with select activating agents such as lipopolysaccharide (LPS)
      or recombinant interferon-gamma (rIFNgamma), several macrophage proteins may be
      induced, acylated with myristic acid, or both. Our goal in this study was to
      determine whether altering the levels of myristic acid in the diet would modulate
      the levels of a specific acylated macrophage protein, MacMARCKS (myristoylated,
      alanine-rich C kinase substrate), because that fatty acid can be found in
      substantial quantities in some foods. Thioglycollate-elicited peritoneal
      macrophages from groups of mice fed diets with various levels of myristic acid
      (from 0.2 to 99 g/100 g fatty acids) were treated with LPS, phorbol myristate
      acetate (PMA), or rIFNgamma plus LPS, which are well-established macrophage
      activating agents. Levels of MacMARCKS were measured by enzyme-linked
      immunosorbent assay using a rabbit anti-mouse polyclonal antibody against the
      first 10 amino acids of murine MacMARCKS. A 42-kDa protein with the same
      molecular weight as MacMARCKS was identified in macrophage lysates by Western
      analysis using the antibody. Lipopolysaccharide- and PMA-activated macrophages
      from mice fed the trimyristin diet had significantly greater levels of MacMARCKS
      than LPS- and PMA-activated macrophages of mice fed the safflower oil-containing
      diet. The levels of MacMARCKS were also greater in lysates of LPS plus rIFNgamma
      stimulated macrophages from mice fed the trimyristin diet and mice fed a diet
      containing a moderate level of myristic acid (12 g/100 g fatty acids) compared
      with the lysates of macrophages from mice fed the safflower oil diet. These
      results indicate that altering the level of myristic acid in the diet may alter
      the production of specific proteins that may be involved in macrophage
      activation.

PMID- 8648430
TI  - A nucleoside-nucleotide mixture and its components increase lymphoproliferative
      and delayed hypersensitivity responses in mice.
AB  - We studied the effect of individual components of a nucleoside-nucleotide mixture
      on T cell-mediated immunity in BALB/c and DBA/2 mice. Mice were fed for 4 wk a
      nucleotide-free 20% casein diet (control) or this diet supplemented with 3 mol/kg
      of one of the following; inosine, guanosine monophosphate, uridine, cytidine,
      thymidine, or a mixture of these. In both strains of mice, popliteal lymph node
      immunoproliferative response to alloantigeneic (C57BL/6 splenic cells) challenge
      in mice fed the mixture and guanosine monophosphate was greater (P < 0.05) than
      in the mice fed the control diet. BALB/c mice fed inosine, uridine, and thymidine
      also showed greater (P < 0.05) responses compared with control fed mice. In the
      sheep red blood cells challenge assay, foot pad weight-gain in both strains of
      mice fed the mixture and the individual components supplemented diets was greater
      (P < 0.05) than in those fed the control diet. In both strains of mice,
      interleukin-2 secretion by popliteal lymph node lymphocytes in mice fed the
      mixture and thymidine was higher (P < 0.05) compared with the rest of the groups
      except BALB/c mice fed cytidine. Significantly higher than control secretions of
      interferon-gamma were observed only in BALB/c mice fed inosine, thymidine and the
      mixture. We conclude that mice fed the nucleoside-nucleotide mixture and the
      individual components of the mixture had greater responses in the T cell-mediated
      immune functions studied and that the responses in mice fed the mixture were not
      different from those in mice fed the individual components.

PMID- 8648431
TI  - Maternal protein restriction influences the programming of the rat hypothalamic
      pituitary-adrenal axis.
AB  - The role of glucocorticoids in the intrauterine programming of hypertension was
      assessed in the progeny of rats fed either 18 g casein/100 g diet (control diet)
      or 9 g casein/100 g diet (low protein diet), before conception and throughout
      pregnancy. Rats exposed to the low protein diet had significantly (P < 0.05)
      higher systolic blood pressures than control animals, when weaned. These rats had
      elevated brain and liver activities of specific glucocorticoid-inducible marker
      enzymes, relative to controls. Glycerol 3-phosphate dehydrogenase activity was
      also higher (377%) in whole brains of newborn rats exposed to low protein diet in
      utero, but no similar effect of corticosteroids was noted in brains of d 20
      fetuses. Weanling rats of the low protein group exhibited a blunted diurnal
      pattern of adrenocorticotrophin (ACTH) concentrations in plasma. Plasma
      corticosterone concentrations were unaltered by prenatal dietary experience and
      exhibited a normal pattern of diurnal variation. Brain regional 11beta
      hydroxysteroid dehydrogenase activities were unaltered by prenatal dietary
      experience, as was binding of 3H-corticosterone to type I glucocorticoid
      receptors in hippocampus, hypothalamus and liver. Type II glucocorticoid receptor
      binding capacity and receptor numbers in male rats were apparently elevated in
      hippocampus of low protein-exposed rats and were significantly lower in liver (P
      < 0.05), relative to control rats. Programming of the hypothalamic-pituitary
      adrenal axis is inferred, and the observation that binding of steroid to type II
      receptor sites in vascular tissue is increased in low protein exposed rats may
      provide a direct mechanism for modulation of blood pressure by glucocorticoids in
      this model.

PMID- 8648432
TI  - An orally supplemented mononucleotide mixture prevents the decrease in T cell
      dependent humoral immunity in C57BL/6 mice fed a nucleotide-free diet.
AB  - T-cell-dependent humoral immune responses are lower in mice fed a nucleotide-free
      (NF) diet. In a previous study, a mononucleotide and nucleoside mixture prevented
      the decrease in humoral immune responses in mice fed a NF diet when a total of
      seven doses [2100 micromol/(kg x dose)] were administered intraperitoneally. In
      the present study, C57BL/6 (B6) mice were fed a NF diet for 3 wk with or without
      mononucleotide mixture (MM) supplementation. The MM was given at the levels of 14
      or 70 micromol/(kg x d) by daily gavage feeding for 3 wk. Control mice were fed a
      NF diet without supplements (negative control) or a NF diet plus the
      mononucleotide/nucleoside mixture administered intraperitoneally (positive
      control). Both doses of MM prevented the decrease in T-dependent antibody (Ab)
      production in mice fed a NF diet as effectively as positive controls. T-helper
      (Th) spleen cells from mice of each diet group were enriched, mixed with Th cell
      depleted spleen cells from each diet group, and antigen-primed in the culture.
      The number of Ab-secreting cells formed was higher with Th cells from mice with
      oral MM supplements or from positive controls than with those from mice without
      nucleotide supplement. The source of Th cell-depleted spleen cells did not
      influence the number of Ab-secreting cells. Thus, orally supplemented nucleotides
      can prevent the suppression of Th cell-dependent humoral immunity in mice fed a
      NF diet with doses likely to be provided by dietary sources.

PMID- 8648434
TI  - D-tagatose is a bulk sweetener with zero energy determined in rats.
AB  - The ketohexose D-tagatose is readily oxidized but contributes poorly to lipid
      deposition. We therefore examined whether this sugar contributes to energy
      requirements by determining its net metabolizable energy value in rats. All
      substrate-induced energy losses from D-tagatose, with sucrose as reference
      standard, were determined as a single value accounting for the sum of the energy
      losses to feces, urine, gaseous hydrogen and methane and substrate-induced
      thermogenesis. A randomized parallel design involving two treatment periods
      (adaptation to D-tagatose and subsequent energy balance) and two control groups
      (to control for treatment effects in each period) was used. Rats consumed 1.8 g
      test carbohydrate daily as a supplement to a basal diet for a 40- or 41-d balance
      period after prior adaptation for 21 d. Growth, protein and lipid deposition were
      unaffected by supplementary gross energy intake from D-tagatose compared with an
      unsupplemented control, but sucrose significantly (P < 0.05) increased all three.
      Based on the changes induced in protein and fat gain during the balance period it
      was calculated that D-tagatose contributed -3 +/- 14% of its heat of combustion
      to net metabolizable energy, and therefore this ketohexose effectively has a zero
      energy value. D-Tagatose would potentially be helpful in body weight control,
      especially in diabetic subjects because of its antidiabetogenic effects.

PMID- 8648435
TI  - Relationship of protein synthesis to mRNA levels in the liver of chicks under
      various nutritional conditions.
AB  - The rate of liver protein synthesis in vivo and hepatic messenger ribonucleic
      acid (mRNA) levels were measured to examine the mechanisms regulating liver
      protein synthesis in chicks under various nutritional conditions. Fractional
      synthesis rate (FSR) of liver protein was measured by using a large dose
      injection of L-[4-3H]phenylalanine. Poly(A)+RNA was extracted as mRNA from total
      RNA using poly(U)-Sepharose 4B affinity chromatography. The influence of varying
      dietary protein levels (0-60%) on protein synthesis and mRNA concentration in the
      liver of chicks was examined. Both FSR (%/d) and absolute synthesis rate (ASR,
      mg/d) of liver protein increased with increasing dietary protein levels from 0 to
      20% (the dietary protein requirement), whereas when dietary protein increased
      from 20 to 40%, both rates decreased significantly. This change was accounted for
      by changes in RNA concentration (RNA:protein ratio) and hepatic mRNA content.
      Second, the time course of changes in liver protein synthesis and hepatic mRNA
      content were measured in force-fed chicks that had been deprived of food for 2 d.
      Liver protein synthesis (FSR) was significantly greater 30 min after refeeding
      compared with that of unfed chicks. Liver protein synthesis (FSR) correlated with
      the activity of RNA to synthesize protein (r = 0.61, P < 0.001), and ASR was
      correlated with hepatic mRNA content (r = 0.37, P = 0.030). Third, experimental
      diets containing individual nutrients were force-fed to chicks after 2 d of food
      deprivation. When chicks were refed carbohydrate and protein diets, liver protein
      synthesis (FSR) tended to be greater by 24% (P = 0.063) and 22% (P - 0.075) at 30
      min after refeeding compared with that of unfed chicks, respectively. These
      findings indicate that changes in the rate of liver protein synthesis in vivo due
      to the alteration in nutritional conditions are, at least partially, accounted
      for by not only RNA concentration and the activity of RNA synthesizing protein
      but also hepatic mRNA levels.

PMID- 8648433
TI  - Intake of rye bread ileostomists increases ileal excretion of fiber
      polysaccharide components and organic acids but does not increase plasma or urine
      lignans and isoflavonoids.
AB  - The excretion of starch, enzyme-resistant starch, dietary fiber components and
      organic acids (short-chain fatty acids plus lactic acid) as well as plasma and
      urine lignans and isoflavonoids was studied in eight ileostomists consuming mixed
      diets with wheat bread (low fiber diet) or rye bread (high fiber diet) in a
      crossover design. Average ileal excretions of enzyme-available starch were 3.5
      g/d during the low fiber period and 4.1 g/d during the high fiber period. The
      excretion of enzyme-resistant starch was approximately the same (2.3 g/d) in both
      periods. In comparison with intake, similar amounts of total fiber residues were
      excreted both by subjects receiving the low fiber diet (3.4 g/d) and by those
      receiving the high fiber diet (2.7 g/d). However, subjects excreted significantly
      more of certain polysaccharide residues (fucose, galactose, and uronic acids)
      than they ingested. On average, the excretion of organic acids was 18.6 mmol/d
      during the low fiber period and 30.2 mmol/d during the high fiber period. No
      significant differences in plasma lignans were observed between the high fiber
      and the low fiber dietary periods. The present findings indicate that enzyme
      available starch is highly digested and that a microbial breakdown of dietary
      fibers and probably other carbohydrates occurs in the small intestine. However,
      the bacterial activity in the ileostomists was not sufficient to cause an
      increased level in plasma lignans even when subjects consumed the high fiber rye
      diet.

PMID- 8648436
TI  - Retinol is sequestered in the bone marrow of vitamin A-deficient rats.
AB  - Retinoic acid bound to the nuclear retinoic acid receptor-alpha is required for
      the differentiation of promyelocytes to mature neutrophils. However, severely
      vitamin A-deficient rats have normal numbers of neutrophils in the blood and
      inflamed tissues. This paradox was explored using four dietary groups of rats: 1)
      vitamin A-deficient rats; 2) vitamin A-deficient rats subsequently receiving
      vitamin A; 3) weight-matched pair-fed rats; and 4) nonrestricted, vitamin A
      complete diet-fed rats. Plasma and liver retinol concentrations of the vitamin A
      deficient rats were < 1 % of those of the other three groups. In contrast, the
      bone marrow retinol concentrations of the vitamin A-deficient rats were fourfold
      higher than those in the other three groups. The distribution of myeloid-derived
      cells in the bone marrow was similar in all four groups of rats with the
      exception of a significantly greater (P < 0.05) occurrence of hypersegmented
      neutrophils (six or more lobes) in the vitamin A-deficient rats (2. 1 %) relative
      to the control groups (0-0.1%). The blood of the vitamin A-deficient rats also
      contained significantly higher numbers (P < 0.01) of hypersegmented neutrophils
      (67%) relative to those in the control groups (2-7%). The hypersegmentation of
      the neutrophils in this group of rats was not due to a concurrent deficiency of
      vitamin B-12 or folate. The importance of bone marrow-derived cells to the
      survival of the animal is suggested by retinol sequestration in the bone marrow
      of vitamin A-deficient rats, allowing the differentiation of myeloid cells to
      neutrophils.

PMID- 8648437
TI  - Rat plasma triglycerides and hepatic fatty acid synthetase mRNA, but not
      apolipoprotein B and A-IV mRNA, respond to dietary fat content.
AB  - The objective was to determine whether apolipoprotein B and A-IV mRNA abundance
      or plasma lipid concentrations would be altered by chronic or acute consumption
      of diets that differed in fat content. Forty Wistar male rats were fed either a
      low fat (5 g/ 100 g) or high fat (20 g/100 g) diet for 4 wk. Animals were killed
      unfed or 3 h after consumption of a test meal of the diet to which they had been
      adapted (n = 8). In addition, a low fat diet-adapted group was fed a high fat
      test meal and killed 3 h after the meal. Adaptation to the high or low fat diets
      did not result in differences in triglyceride or cholesterol concentrations in
      the plasma of unfed rats. In fed animals, plasma, VLDL, and LDL triglyceride
      concentrations were significantly higher in those fed the high fat test meal than
      in those fed the low fat test meal. Feeding did not alter plasma cholesterol
      concentrations; however, LDL cholesterol concentrations in the groups fed the
      high fat meals were significantly higher than in the group fed the low fat meal.
      There were no differences in plasma apolipoproteins B, A-IV, E, and A-I nor in
      the liver or intestinal apolipoprotein B and A-IV mRNA contents. Fatty acid
      synthetase (FAS) activity was significantly higher in rats adapted to the low fat
      diet, and no increase in activity due to feeding was observed. Hepatic FAS mRNA
      was higher in fed than unfed rats, and the low fat test meal resulted in a higher
      level than the high fat test meal. Plasma lipid concentrations were affected by
      the fat content of test meals rather than by the adaptation diet fat content.
      Apolipoprotein B and A-IV mRNA do not seem to respond to dietary fat or meal
      feeding.

PMID- 8648438
TI  - Dietary protein modifies oxidized cholesterol-induced alterations of linoleic
      acid and cholesterol metabolism in rats.
AB  - Effects of dietary protein on oxidized cholesterol-induced alterations in
      linoleic acid and cholesterol metabolism were studied in 4-wk-old male Sprague
      Dawley rats, using casein and soybean protein as dietary protein sources. The
      rats were fed one of the two proteins in cholesterol-free, 0.3% cholesterol or
      0.3% oxidized cholesterol mixture diets using a pair-feeding protocol for 3 wk.
      In the soybean protein-fed group, rats fed oxidized cholesterol did not have
      lower activity of liver microsomal delta6 desaturase, the rate-limiting enzyme in
      the metabolism of linoleic acid to arachidonic acid, compared with rats fed
      cholesterol-free diet, whereas in the casein-fed group the desaturase activity
      was significantly greater in rats fed oxidized cholesterol than in those fed
      cholesterol-free diet. This was in contrast to a significant reduction in liver
      microsomal delta6 desaturase activity by cholesterol, irrespective of protein
      source. In general, these changes were reflected in the desaturation indices of
      liver phospholipids. Furthermore, soybean protein significantly increased the
      fecal excretion of neutral and acidic steroids and tended to reduce (P = 0.082)
      the accumulation of oxidized cholesterols in the liver. Thus, soybean protein
      partly modified some of the undesirable effects of oxidized cholesterol through
      its hypocholesterolemic effect and possibly through the modulation of hepatic
      delta6 desaturase activity.

PMID- 8648439
TI  - Rates of lipid metabolism in adipose tissue of pigs adapt to lactational state
      and dietary energy restriction.
AB  - To define better the role of metabolism in adipose tissue during gestation and
      lactation, adaptations to gestation, lactation and to decreased energy intakes
      were determined using pigs as a model. The effects of energy restriction and the
      interactions of restriction during both periods were tested by feeding one of two
      rations during gestation to provide either 19.3 or 25.1 MJ of metabolizable
      energy per day (ME/d) and adequate amino acids, vitamins and minerals. Pigs from
      each gestation treatment then consumed 27.7, 48.6, or 69.0 MJ of ME/d during
      lactation. Body weight and subcutaneous fat thickness were lower in the energy
      restricted groups. Litter growth was slower only in the group receiving the
      lowest energy in gestation and lactation. During gestation, fatty acid synthesis,
      as measured in in vitro tissue incubations, was lower in subcutaneous adipose
      tissue of pigs consuming 19.3 compared with 25.1 MJ of ME/d. In pigs fed the
      highest energy, rates of lipogenesis and esterification were faster after
      parturition. Feeding 48.6 or 27.7 MJ of ME/d reduced lipogenesis during lactation
      by approximately 75 and 90% and rates of esterification by 35 and 60%,
      respectively, compared with controls fed 69.0 MJ of ME/d. Rates of lipid
      synthesis at d 7 of lactation were higher than at d 23. Lipolysis was
      approximately twofold higher due to energy restriction. Lactation alone did not
      alter lipolysis compared with during gestation. The first-committed step of
      glucose conversion to fatty acids was decreased in a manner sensitive to energy
      restriction. Recycling of fatty acids was maintained at a significant rate
      regardless of energy intake. Lipid metabolism in adipose tissue of pigs during
      lactation is regulated in a manner similar to that observed in humans.

PMID- 8648440
TI  - Recombinant bovine somatotropin decreases hepatic amino acid catabolism in female
      rats.
AB  - The effect of recombinant bovine somatotropin (rbST) on hepatic amino acid
      catabolism in female rats was investigated. Daily injections of rbST for 5 d
      decreased liver homogenate lysine alpha-ketoglutarate reductase (EC 1.5.1.8)
      activity (P < 0.05) and liver homogenate lysine oxidation (P < 0.05)
      approximately 35%. Liver homogenate methionine and valine oxidation were
      depressed approximately 20 (P = 0.13) and 35% (P < 0.05), respectively. These
      data show a decrease in hepatic capacity to oxidize amino acids in rats
      administered rbST. Whether depressed liver amino acid degrading enzyme activity
      plays a role in amino acid oxidation in vivo remains to be evaluated.

PMID- 8648441
TI  - Peptide-bound methionine can be a source of methionine for the synthesis of
      secreted proteins by mammary tissue explants from lactating mice.
AB  - Mammary tissue explants from d 10-11 of lactating CD-1 mice were used to study
      the ability of methionine-containing di- to octapeptides to substitute for free
      methionine for the synthesis of secreted proteins. Explants were incubated in a
      medium containing 3H-leucine and either L-methionine or one of 23 methionine
      containing peptides. The ability of methionine substrates to promote
      incorporation of 3H-leucine into secreted proteins was quantified. Mammary tissue
      explants were able to utilize methionine from all peptides tested. All of the
      peptides were at least as effective as free methionine in promoting 3H-leucine
      incorporation into secreted proteins. Most di- and tripeptides promoted 15-76%
      greater (P < 0.05) 3H-leucine incorporation than did free methionine. There was a
      negative correlation (r = -0.89, P < 0.01) between the rate of 3 H-leucine
      incorporation promoted by peptides and the number of amino acid residues in the
      peptides. The incorporation of 3H-leucine promoted by some dipeptides was reduced
      (P < 0.05) in the presence of a 200-fold higher concentration of glycylsarcosine
      or carnosine. The results indicate that peptide-bound methionine can serve as a
      source of methionine for the synthesis of secreted proteins by lactating mammary
      tissue. Mediated transport of some peptides is probably involved in peptide
      utilization.

PMID- 8648442
TI  - Milk carnitine affects organ carnitine concentration in newborn rats.
AB  - Previous studies suggest that exogenous milk carnitine may be necessary during
      the suckling period to maintain normal fat metabolism. To characterize the
      relationship between milk carnitine and carnitine in body organs, newborn rats
      were fed from birth a rat milk substitute with or without 300 micromol/L L
      carnitine, corresponding to the concentration present in rat milk, for either 2
      or 4 d. Carnitine concentrations in heart, skeletal muscle, liver and small
      intestine were compared with levels in rat pups that were never fed (d 0) and
      those that were nursed by their mothers for 4 d. Carnitine supplementation
      resulted in significantly higher concentrations of carnitine in all organs
      studied after 4 d compared with nursed controls. Relative intestinal carnitine
      pool size was 38.1 +/- 3.0, 22.6 +/- 1.0, 7.9 +/- 0.5 and 2.3 +/- 0.7 micromol/g
      body wt in supplemented, nursed, unsupplemented and never fed pups, respectively
      (P < 0.05, compared with one another). These results indicate that carnitine
      organ concentrations are related to dietary intake during the early suckling
      period and that the small intestine is a considerable and previously unrecognized
      proportion of the carnitine pool of suckling animals.

PMID- 8648444
TI  - Procyanidin from black beans (Phaseolus vulgaris) inhibits nutrient and
      electrolyte absorption in isolated rat ileum and induces secretion of chloride
      ion.
AB  - Dietary tannins are reported to impair the absorption of nutrients and minerals
      in whole animals and in semi-isolated intestinal preparations. The present
      studies investigated the effect of purified procyanidin from black beans
      (Phaseolus vulgarus) on tissue electrical parameters, isotopic Na+ and Cl- fluxes
      and Na+-dependent absorption of labeled glucose by isolated rat ileum. In short
      circuited ileal preparations, 0.5-2 g/L procyanidin (PC) inhibited Na+ and Cl-
      absorption and stimulated Cl- secretion, with consequent increases in short
      circuit current (Isc), total tissue conductance and transepithelial voltage. The
      effect was not blocked by indomethacin (20 micromol/L). Also, PC significantly
      inhibited the glucose-dependent and phlorizin-sensitive component of Isc; a
      similar result was obtained for the alanine-dependent fraction of Isc. In everted
      ileal sacs PC inhibited Na+-dependent uptake of labeled glucose, but not passive
      uptake, by a noncompetitive mechanism. The effects of PC are reminiscent of those
      of recognized intestinal secretagogues and suggest that the antinutrient effects
      of condensed tannins involve stimulation of intestinal secretion at the expense
      of absorption. The results argue against use of black bean broth or cooking
      liquor in rehydration media for treatment of secretory diarrhea.

PMID- 8648443
TI  - Pivalate affects carnitine status but causes no severe metabolic changes in rat
      liver.
AB  - To investigate the carnitine deficiency induced by pivalate, rats had free access
      to drinking water with or without pivalate. Consumption of 20 mmol/L pivalate for
      1 wk decreased the levels of both free and total carnitine in plasma to
      approximately 20% of levels before treatment. After 4 wk, the concentrations of
      free carnitine in the liver, heart and muscle of pivalate-treated rats were
      approximately 60-80% of the control, and in the kidney, 26% of the control.
      Fractional excretion of free carnitine (FEFC) in pivalate-treated rats was
      measured; however, the treatment for 3 or 8 d did not affect the values relative
      to those obtained before treatment. Treatment with pivalate for 4 wk did not
      affect plasma concentrations of glucose, ammonia and free fatty acids (FFA) in
      the rats; however, the concentration of 3-hydroxybutyrate (3-OHB) was higher, and
      the FFA/3-OHB ratio was lower than those of controls. In a liver perfusion study,
      ketogenesis from oleate and gluconeogenesis from lactate and pyruvate in rats
      treated with pivalate for 4 wk were not different from controls. These results
      suggest that administration of pivalate did not induce the excessive excretion of
      free carnitine in urine, and secondary carnitine deficiency induced by intake of
      20 mmol/L pivalate for 4 wk did not cause severe metabolic changes in rat liver.

PMID- 8648445
TI  - Dietary choline requirement of juvenile red drum (Sciaenops ocellatus).
AB  - A 6-wk feeding experiment was conducted to determine the maximal dietary choline
      requirement of juvenile red drum (Sciaenops ocellatus). Diets were formulated to
      provide 35 g crude protein/ 100 g dry weight from solvent-extracted lyophilized
      red drum muscle and an amino acid premix. This premix provided methionine
      precisely at the minimum requirement determined for red drum so that potential
      synthesis of choline from methionine would be limited. Menhaden oil and dextrin
      were added to all diets to provide 13.8 kJ metabolizable energy/g diet as
      estimated by physiological fuel values. The diets were supplemented with choline
      chloride to provide 0, 250, 500, 750, 1000 and 1500 mg choline/kg diet. Each diet
      was fed to triplicate groups of red drum initially averaging 5.5 g/fish in a
      closed, recirculating system consisting of 110-L glass aquaria. Dietary choline
      concentration significantly (P < 0.05) affected weight gain, feed efficiency,
      total lipid in liver and plasma, as well as plasma cholesterol ester,
      triglyceride, cholesterol and phosphatidylcholine concentrations. Least-squares
      regression of these responses yielded requirements ranging from 330 to 676 mg
      choline/kg diet. Based on weight gain data, a maximal requirement estimate (+/-
      SEM) of 588 (+/- 35) mg choline/kg diet was established. Red drum appear to
      differ from other animals in regard to the response of total lipid in liver
      because fish fed choline-deficient diets had reduced liver lipid rather than
      lipid accumulation. Cultured red drum normally store high levels of lipid in the
      liver.

PMID- 8648446
TI  - High zinc concentrations in culture media affect copper uptake and transport in
      differentiated human colon adenocarcinoma cells.
AB  - Previous studies suggest that high dietary zinc reduces the copper status of
      animals by reducing copper transport across the intestinal mucosa. The present
      study used an enterocyte mimic, the Caco-2 cell, grown on porus membranes as a
      model to assess the effects of various concentrations of zinc (6 to 200
      micromol/L) in the culture and assay media on 67Cu uptake and transport.
      Differentiated cells incubated for 7 d in a culture medium containing 50 micromol
      zinc + 0.7 micromol copper/L transported significantly less 67Cu across the
      monolayer than similar cells exposed to 6 micromol zinc/L. However, cells exposed
      to 200 micromol zinc/L for the same period transported significantly more 67Cu
      than those exposed to 6 micromol zinc/L. Cells exposed for only 1 h to 200
      micromol zinc/L in the uptake-transport medium alone did not show lower 67Cu
      uptake or transport, suggesting that time of exposure of the cells to high zinc
      was a contributing factor. Caco-2 cells exposed to 50 through 200 micromol zinc/L
      had higher cellular metallothionein (MT) than those exposed to 6 micromol zinc/L.
      As the amount of MT in cells increased upon exposure to 50 and 100 micromol
      zinc/L, the rate of 67Cu transport decreased. At higher zinc concentrations in
      the medium, there was even more MT in the cells, but a greater rate Of 67Cu
      transport. These studies demonstrate the use of the Caco-2 cell as a model for
      copper uptake-transport studies, but the conditions must be rigorously defined
      and controlled.

PMID- 8648447
TI  - Low-protein diet blocks development of hyperphagia and obesity in rats with
      hypothalamic knife cuts.
AB  - The objective of this study was to examine the influence of dietary protein
      levels on development of hyperphagia and obesity in rats that had been given
      surgical knife cuts between the ventromedial and lateral areas of the
      hypothalamus. Under normal conditions, rats with this type of surgery exhibit
      hyperphagia and become obese when given unlimited access to dietary energy.
      Earlier studies indicated impaired adaptive diet-induced thermogenesis in
      response to excess energy intake in this animal model of obesity. Because low
      protein diets can also stimulate diet-induced thermogenesis, we conducted four
      experiments which examined how diets containing different levels of protein
      affect development of hyperphagia and obesity in female rats given bilateral,
      parasagittal wire knife cuts between the ventromedial and lateral areas of the
      hypothalamus. For 28 d, knife-cut and sham-operated rats were given unlimited or
      restricted (1 79 or 1 80 kJ/d) access to diets containing protein at 5, 10 or 20%
      of total metabolizable energy. Knife-cut rats with unlimited access to 10 or 20%
      protein diets became obese, gaining 2-3 times more weight and 3-6 times more
      carcass energy while consuming 55-89% more energy than sham-operated rats. In
      contrast, energy consumed and gained by knife-cut rats with unlimited access to a
      5% protein diet was similar to that of rats given sham surgery. Results indicate
      that a low protein diet effectively blocks development of hyperphagia and obesity
      in rats with surgical knife cuts between the ventromedial and lateral regions of
      the hypothalamus.

PMID- 8648448
TI  - Meal patterns reveal differential effects of vagotomy and tropisetron on
      responses to indispensable amino acid deficiency in rats.
AB  - Rats offered an amino acid-imbalanced diet (IMB) respond to the ensuing amino
      acid deficiency rapidly with a decrease in food intake of at least 50%.
      Pretreatment with tropisetron (TROP), an antagonist at serotonin3 (5-HT3) and 5
      HT4 receptors, increases intake of IMB to approximately 85% of control. Vagotomy
      has two effects: it increases intake of an IMB to about 65%, and also blocks the
      increased response to tropisetron. This indicates that the greater IMB intake
      after tropisetron, approximately 20% more than in vagotomized rats, is dependent
      on an intact vagus. Rats were either 1) vagotomized or sham-operated, or 2) given
      tropisetron or saline injections. We then examined free-feeding meal patterns in
      rats fed an IMB to determine whether the microstructure of the feeding behavior
      differed, either between treatments, or by comparison with the meal patterns in
      rats fed the control diet. Vagotomy did not alter meal patterns in rats consuming
      the basal control diet. During the first 6 h after introduction of the IMB, the
      control rats showed significantly longer intermeal intervals (over twice the
      length of intervals recorded in those fed the basal diet), with corresponding
      effects on meal numbers, which were restored to basal values in tropisetron and
      vagotomized rats. Meal size was increased after vagotomy also. After 6 h, in
      intact tropisetron-treated rats only, a fourfold faster rate of eating throughout
      the late dark period accounted for the significantly greater intake of the IMB
      than in controls. The results demonstrated differential effects of the two
      treatments on the anorectic responses to amino acid deficiency.

PMID- 8648449
TI  - An evolutionary perspective enhances understanding of human nutritional
      requirements.

PMID- 8648450
TI  - LSRO Report: monosodium glutamate.

PMID- 8648451
TI  - From pilot tests to policy: the dilemma of extremely preterm infant viability.

PMID- 8648452
TI  - Evolution and variability of pulmonary mechanics during postnatal transition in
      term infants.
AB  - This study was designed to assess whether progressive changes related to the
      transition to extrauterine life explain in part the interassay variability of
      pulmonary mechanics in the immediate postnatal period. We performed sequential
      pulmonary function tests in 21 normal term infants with the use of a
      pneumotachometer and an esophageal balloon. The average percent increase in
      values from the first period (2 to 10 hours) to the last period of study (66 to
      78 hours) was 27% for tidal volume, 24% for minute ventilation, and 42% for
      dynamic compliance. The maximum difference between two pulmonary function
      measurements obtained within 30 minutes of each other ranged between 10% for
      dynamic compliance and 27% for minute ventilation. The coefficient of variation
      for dynamic compliance over a 2-hour period (12%) was less than half the 3-day
      coefficient of variation (31%). The reliability coefficient ranged between 0.72
      for tidal volume and 0.92 for dynamic compliance. We conclude that dynamic
      compliance in term infants increases progressively during the first 3 days of
      life, whereas tidal volume and minute ventilation increase mostly during the
      first day. The variability of pulmonary mechanics reflects in part those
      progressive physiologic changes during postnatal transition.

PMID- 8648453
TI  - Premature infant responses to noise reduction by earmuffs: effects on behavioral
      and physiologic measures.
AB  - The continuous high-intensity noise in the neonatal intensive care unit (NICU) is
      both stressful and harmful for the premature infant. Although some researchers
      have found evidence that loud noise can cause hearing loss and alter physiologic
      and behavioral responses, no study to date has investigated the benefits of noise
      reduction by the use of earmuffs. In this study earmuffs were placed over the
      premature infants' ears to reduce noise intensity in the NICU while physiologic
      and behavioral responses were measured. Two sites were used to collect data: in
      the first setting, 17 low birth weight infants were randomly assigned to an
      experimental and a control group, whereas 13 infants from a second hospital acted
      as their own controls and were tested with and without earmuffs. Earmuffs that
      reduced the intensity of noise by 7 to 12 dB were worn by infants in the
      experimental group only during the observation periods. Infants in the control
      group were exposed to the usual noise in the NICU. The infant's physiologic and
      behavioral responses were observed for four 2-hour intervals, morning and
      evening, on two consecutive days. Most of the significant results were from the
      site at which infants acted as their own controls. When infants wore the
      earmuffs, they had significantly higher mean oxygen saturation levels and less
      fluctuation in oxygen saturation. Furthermore, these infants had less frequent
      behavioral state changes, spent more time in the quiet sleep state, and had
      longer bouts in the sleep state. It is imperative that NICUs develop aggressive
      antinoise policies to substantially and consistently reduce noise.

PMID- 8648454
TI  - Effect of maternal illicit drug use on the mortality of very low birth weight
      infants.

PMID- 8648455
TI  - Low-dose aspirin and prednisone treatment of pregnancy loss caused by lupus
      anticoagulants.
AB  - The objective of this study was to ascertain the complications and the efficacy
      of low-dose aspirin (LDA) and prednisone therapy in women with pregnancy loss and
      "lupus anticoagulants" (LAC). During the period 1985 to 1993, 255 patients with
      two or more pregnancy losses (RPL) were tested for LAC with an activated partial
      thromboplastin time (aPTT) and a tissue thromboplastin inhibition index (TTI,
      normal value < 1.3). The diagnosis of LAC was established if two TTI values were
      > or = 1.3 or if a prolonged aPTT was measured in the patient's plasma that did
      not correct to normal by 1:1 mixing with normal plasma. We excluded patients with
      RPL who had only anticardiolipin antibodies. We treated 28 pregnancies in 21
      women with LDA/prednisone for RPL associated with LAC. Therapy with
      LDA/prednisone was initiated as soon as a viable pregnancy was diagnosed. Therapy
      was continued until delivery in all but one case. Prednisone dose was minimized
      by measuring TTI and aPTT every 2 weeks and adjusting the dosage to maintain a
      TTI < or = 1.2 and to correct the aPTT to less than 36 seconds. Among the 28
      pregnancies there were four (14%) first-trimester spontaneous abortions and four
      (14%) second-trimester fetal deaths. Of 20 surviving neonates (72%), seven were
      delivered after 37 weeks and 13 before 37 weeks (mean 35.9 +/- 2.3 weeks, range
      31.5 to 40.4 weeks). Pre-term premature rupture of membranes occurred in three
      pregnancies, hypertensive disorders in six, and four small-for-gestational-age
      neonates were delivered (two stillborn). Mean birth weight of 20 surviving
      neonates was 2736 +/- 763 gm (range 900 to 3920 gm). Mean daily prednisone dose
      in 20 live births was 24.1 +/- 8.5 (SD) mg (range 11.3 to 49.3 mg/day) with mean
      duration of LDA/prednisone therapy of 185 +/- 40 days (range 97 to 223 days).
      Maximum prednisone dose was 60 mg/day (mean 36.8 +/- 12.7 mg/day). Only one
      serious maternal complication of LDA/prednisone therapy was observed. One neonate
      had talipes equinovarus that resolved without surgical therapy. LDA/prednisone
      therapy seemed effective and reasonably well tolerated in this population. These
      findings should be confirmed in a prospective, controlled investigation if such a
      trial can be organized and performed.

PMID- 8648456
TI  - Determinants of blood pressure in infants admitted to neonatal intensive care
      units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure
      Study Group.
AB  - There are few blood pressure (BP) data reported for premature and term newborn
      infants after 24 hours of age. To determine BP levels and BP trends in a
      representative population of infants admitted to neonatal intensive care units
      (NICUs), this study was conducted in 14 NICUs in the greater Philadelphia area.
      All infants admitted to the 14 NICUs during a 3-month period were entered into
      the study. BP data, along with data on clinical conditions and therapeutic
      interventions (independent variables), were prospectively collected by a uniform
      protocol. Systolic BP (SBP) and diastolic BP (DBP) were measured indirectly by
      oscillometry and recorded every 8 hours. Data from 608 infants followed up for 1
      to 99 days after delivery generated 9911 infant-day records and 24,052 individual
      BP measurements. On day 1, birth weight and gestational age were strong
      correlates of SBP (r = 0.68, p < 0.0001 and r = 0.66, p < 0.0001, respectively)
      and DBP (r = 0.48, p < 0.0001 and r = 0.47, p < 0.001, respectively). During the
      first 5 days of life there was a progressive rise in SBP (2.23 to 2.67 mm Hg/day)
      and DBP (1.58 to 2.02 mm Hg/day) regardless of gestational age or weight at
      birth. After day 5 there was a more gradual increment in the daily SBP (0.24 to
      0.27 mm Hg/day) and DBP (0 to 0.15 mm Hg/day). Stepwise linear multiple
      regressions were used to examine the multiple correlations among the independent
      variables and to build a regression model for BP. Gestational age and day of life
      emerged in the first two steps of the multiple regression analysis (multiple R =
      0.463 and 0.655, respectively; p < 0.0001 for both). The multiple R values for
      day of life and gestational age were virtually identical to that for
      postconceptional age (day of life + gestational age at birth). Although other
      common diagnosis and treatment variables contributed a small amount to the total
      variance in BP, postconceptional age was the primary determinant of BP in this
      population of infants.

PMID- 8648457
TI  - Racial disparity in pregnancy outcomes: analysis of black and white teenage
      pregnancies.
AB  - The pregnancies of black women are complicated by adverse outcomes such as
      prematurity and low birth weight at twice the rate of complications in
      pregnancies of white women. Although the cause of this racial disparity is
      unknown, it is most likely multifactorial. The disparity in outcomes has been
      found in many studies despite implementation of controls for the factors of age,
      socioeconomic status, and access to health care. We hypothesized that the
      increased incidence of adverse outcomes may be strongly affected by adequacy of
      prenatal care. We investigated the effects of comprehensive prenatal care
      delivered at the University of North Carolina-Chapel Hill Teenage Obstetric
      Clinic. The gestational age at the onset of prenatal care and the mean number of
      prenatal visits were the same for black and white teenagers. Among 183 teenagers
      we found no significant difference between black and white pregnancies for the
      outcomes of premature labor, premature delivery, fetal death, neonatal mortality,
      or hypertensive diseases. The mean gestational age at delivery was 38.3 weeks and
      39.1 weeks for black and white women, respectively. The mean birth weight was
      3126 gm and 3272 gm for black and white women, respectively. There was a trend (p
      < 0.09) toward more low birth weight infants in white women: 7% for black infants
      and 12% for white infants. We believe that comprehensive prenatal care
      significantly lessens the racial disparity in pregnancy outcomes between black
      and white adolescent women.

PMID- 8648458
TI  - Pitfalls in the diagnosis of nonconjoined monoamniotic twins.
AB  - The morbidity and mortality of monoamniotic twins are high. Despite recent
      advances in imaging, the definitive diagnosis of monoamniotic twins remains
      elusive. When monoamniotic twins are suspected, the optimal antepartum management
      is uncertain. A false-positive diagnosis of monoamniotic twins by computed
      tomographic amniography was investigated. By a Medline search the literature on
      monoamnionicity from 1966 to January 1994 was reviewed. All reports including
      diagnostic methods and management of monoamniotic twins were reviewed. All five
      previous case reports of computed tomographic amniography correctly identified
      amnionicity in cases in which amnionicity was unclear. Four cases confirmed
      monoamnionicity and one case excluded monoamnionicity. Four recent series that
      used ultrasonography revealed a low predictive accuracy (9% to 25%) for the
      establishment of monoamnionicity when intervening membranes were absent. One
      recent prospective series revealed a positive predictive value of 80% among five
      monoamniotic twin pairs with the use of first-trimester ultrasonography. The
      methods available to diagnose monoamniotic twins are improving. The complications
      that result from a false-positive diagnosis are discussed and the management and
      diagnosis of monoamniotic twins are reviewed.

PMID- 8648459
TI  - Perceptions of the limit of viability: neonatologists' attitudes toward extremely
      preterm infants.
AB  - Although recent technologic advances have dramatically improved the survival of
      preterm infants, little information exists regarding the attitudes of
      neonatologists toward their smallest patients, infants born at the "limit of
      viability." In this pilot study we sent a single mailing of a 25-question survey
      designed to provide information about the medical treatment of extremely preterm
      infants (< 22 to 27 weeks' gestational age) to 3056 neonatologists practicing in
      the United States in September 1992. The 1131 (37%) respondents were well
      distributed geographically and by nature of practice (i.e., academic, academic
      affiliate, and community hospitals). Most of the respondents counseled parents
      that all infants < or = 22 weeks' gestational age die and that at least 75% of
      infants born at 23 weeks' gestation die. Only for infants born at > or = 26
      weeks' gestational age did most of the neonatologists counsel parents that
      mortality is < or = 50%. Nonintervention or compassionate care in the delivery
      room was believed to be appropriate for infants less than 23 weeks' gestational
      age by virtually all neonatologists, by 52% of respondents for infants 23 weeks'
      gestational age, and by only 1% of respondents for infants 25 weeks' gestational
      age. Approximately two thirds of neonatologists considered parental wishes
      regarding resuscitation, and one quarter considered parental parity/fertility
      history in their medical decision making for infants born at 23 to 24 weeks'
      gestation. If an infant who had been previously resuscitated decompensated in
      spite of maximal medical treatment, most of the neonatologists were not willing
      to provide full resuscitation for infants born at any gestation less than 27
      weeks. However, the number of neonatologists who would actively encourage
      withdrawal of support in a decompensating infant decreased markedly for infants
      born at > or equal 25 weeks' gestation. Neonatologists who responded to this
      survey in 1992 considered 23 to 24 weeks of gestation the limit of viability and
      had great concerns regarding medical decision making for these infants.

PMID- 8648461
TI  - Special imaging casebook. Neonatal dural sinus thrombosis.

PMID- 8648460
TI  - Fraser syndrome (cryptophthalmos [hidden eye]-syndactyly syndrome).

PMID- 8648462
TI  - Placental pathology casebook. Liveborn twin of an extramembranous pregnancy.

PMID- 8648463
TI  - Fetal heart rate monitoring casebook. Persistent bradycardia.

PMID- 8648464
TI  - Use of central venous catheters is common in neonatal intensive care units.

PMID- 8648465
TI  - Need exists for advance directives from parents.

PMID- 8648466
TI  - Need exists for advance directives from parents.

PMID- 8648467
TI  - Need exists for advance directives from parents.

PMID- 8648468
TI  - Providing a solid foundation for our specialty.

PMID- 8648469
TI  - Prospective study of the quality of life of cancer patients after intraoral tumor
      surgery.
AB  - PURPOSE: The aim of this prospective study was to determine the quality of life
      of patients with oral cancer after intraoral ablative surgery. PATIENTS AND
      METHODS: Eighty-five consecutive patients with squamous cell carcinoma of the
      floor of the mouth were enrolled in the study. Reconstruction of intraoral soft
      tissues was accomplished by local tissue (67.8%), jejunal grafts (16.9%), and
      cutaneous and myocutaneous flaps (15.3%). Soft tissue resections were combined
      with resections of the alveolar process of the mandible in 35.0% and mandibular
      discontinuity resections in 31.7% of the cases. A self-administered, standard
      questionnaire consisting of 22 visual analog scale items with a maximum index
      value of 154 was used to determine the physical functional status, the
      psychological status, and social functioning of cancer patients (Functional
      Living Index--Cancer). The questionnaire was administered preoperatively and 3,
      6, and 12 months postoperatively. RESULTS: The Functional Living Index score
      increased significantly toward the end of the first postoperative year because of
      an increase in all three factors of the scale. All modes of soft tissue
      reconstruction achieved nearly equal levels of life quality in patients with
      median or lateral defects at the end of the observation period. Only patients
      with large bilateral defects exhibited lower preoperative and postoperative
      values because of extensive loss of functionally important soft tissue. Patients
      with discontinuity resections of the mandible took longer to regain the same
      level of life quality as patients without bone resections. Persistence of
      dysphagia, reflux of liquids, limitations to liquid food, and sleep disorders had
      a significant negative effect on the score. CONCLUSIONS: It is concluded that
      rehabilitation of oral cancer patients is particularly difficult in the case of
      large soft tissue defects and is not always accomplished completely even with
      primary microsurgical tissue repair.

PMID- 8648470
TI  - Mandibular excursions and maximum bite forces in patients with temporomandibular
      joint disorders.
AB  - PURPOSE: This study evaluated mandibular motion and bite force in patients with
      temporomandibular joint disorders after joint surgery. PATIENTS AND METHODS:
      Maximum voluntary mandibular motion, maximum excursion during mastication, and
      maximum bite force were examined in 25 female patients before temporomandibular
      joint surgery. Their pretreatment performance was compared with that at 6 weeks,
      6 months, and 1 year after surgery, and with performance of 26 normal female
      volunteers. RESULTS: Before surgery, all of the patients' movements and bite
      forces were smaller than those of controls. One year after surgery, maximum
      interincisal opening increased significantly, but lateral excursion and
      protrusion remained unchanged. Maximum bite forces increased significantly and
      nearly reached control levels. CONCLUSIONS: Patients with severe restriction in
      temporomandibular joint function exhibit general improvements in some mandibular
      movements and in maximum bite force after surgical treatment.

PMID- 8648471
TI  - Induced hypotensive anesthesia for adolescent orthognathic surgery patients.
AB  - PURPOSE: This study compared blood loss, quality of surgical field, and duration
      of procedure with and without induced hypotensive anesthesia in adolescent
      orthognathic surgery patients. PATIENTS AND METHODS: Fifty orthognathic surgery
      patients were studied in a prospective, randomized, blocked, stratified, and
      single-blind fashion. All patients underwent either sagittal ramus split
      osteotomy or Le Fort I osteotomy or genioplasty. One group of patients (n = 25)
      had induced hypotension; the other group (n = 25) received anesthesia with no
      attempt to deliberately reduce blood pressure during the operation. The surgeon,
      unaware of to which group the patient had been assigned, rated the surgical field
      every 15 minutes. At completion of surgery, three different methods were used to
      estimate or calculate blood loss. Duration of the procedure was recorded from
      time of first incision to time of last suture placement. The data were analyzed
      using ANOVA, chi-squared, and linear regression, where appropriate. RESULTS:
      Estimated blood loss was significantly less when induced hypotensive anesthesia
      was used. The surgical field was better, but there was no significant difference
      in duration of the procedure with induced hypotensive anesthesia. CONCLUSION:
      Induced hypotensive anesthesia results in both reduced blood loss and improvement
      in surgical field.

PMID- 8648472
TI  - Sialolithectomy done with a CO2 laser: clinical and scintigraphic results.
AB  - PURPOSE: This study reviews the results of sialolithectomy performed with the CO2
      laser. PATIENTS AND METHODS: Forty-nine patients were treated under local
      anesthesia at initial presentation in the outpatient clinic. RESULTS: All
      patients had immediate relief after surgery. Clinical and scintographic follow-up
      of up to 28 months on 27 patients showed that all but 1 were asymptomatic. The
      single exception required excision of the submandibular gland because of two
      recurrences of sialoliths in Wharton's duct. Although some glands had no function
      clinically and scintigraphically, they were asymptomatic and needed no further
      treatment. CONCLUSIONS: Salivary glands that are nonfunctioning clinically and
      scintigraphically should only be removed when there is a recurrence of symptoms.

PMID- 8648474
TI  - Comparative evaluation of function after surgery for cancer of the alveolobuccal
      complex.
AB  - PURPOSE: The current study was undertaken to assess the functional deficit after
      hemiresection of the mandible and to determine whether lateral segment resection
      with reconstruction was a functionally superior alternative in the management of
      patients suffering from alveolobuccal cancer. PATIENTS AND METHODS: Eighty-three
      patients were assigned to one of two main groups: Group I, hemiresection of the
      mandible (n = 47), and group II, lateral segment defects (n = 36). Functional
      assessment of patients included subjective evaluation of overall well-being,
      feeding, and cosmesis, as well as objective assessment of mastication, speech,
      and cosmesis. Mean scores for each of these categories were compared across
      groups using the Duncan Multiple Range Test with .01 confidence intervals.
      RESULTS: Subjective assessment of overall well-being, feeding, and cosmesis did
      not yield statistically significant differences between groups. Objective
      evaluation of mastication showed significantly better function after
      hemiresection in dentate patients as compared with their edentulous counterparts.
      However, masticatory scores for hemimandibulectomy patients with intact residual
      dentition were not significantly different from those for patients whose lateral
      segmental defects had been reconstructed. Although objective cosmetic scores for
      reconstruction of lateral segment defects were significantly better than those
      for hemiresection of the mandible, most patients in the latter group accepted the
      resultant deformity as a consequence of their treatment and did not let it affect
      their routine activities. CONCLUSION: Until functional results in patients
      undergoing lateral segmental resection for alveolobuccal cancer can be improved
      by better prosthetic techniques, hemiresection of the mandible remains a simple,
      safe, reliable, and cost-effective option that produces acceptable postoperative
      function.

PMID- 8648473
TI  - Transalveolar fixation of the peri-implant soft tissue in the mandible: surgical
      method and clinical follow-up.
AB  - PURPOSE: Firm, immobile mucosa around endosteal implants is one prerequisite for
      a reliable long-term result. In the atrophic mandible, this may be achieved by a
      vestibuloplasty on the facial side. However, on the lingual side, the floor of
      the mouth is often high and the mucosa mobile, especially after unintentional
      detachment of the lingual flap during implant surgery. To overcome this problem,
      a surgical technique applying a transalveolar suture circumscribing the inserted
      implants was developed. PATIENTS AND METHODS: The operation was performed in six
      patients, and they were evaluated over a period of more than 18 months. RESULTS:
      There was a clinically significant increase in fixed mucosa behind the implants
      compared with a control group of six patients with a similar preoperative and
      intraoperative status. CONCLUSION: A localized lowering of the floor of the mouth
      limited to the peri-implant region using this technique can successfully improve
      the lingual mucosa around implants.

PMID- 8648475
TI  - Orthognathic surgery in patients with congenital myasthenia gravis.

PMID- 8648477
TI  - Effects of sex hormones on protein and collagen content of the temporomandibular
      joint disc of the rat.
AB  - PURPOSE: The effect of sex hormones on the protein and collagen content of the
      temporomandibular joint (TMJ) disc of adult male and female rats. MATERIALS AND
      METHODS: One hundred forty-four Wistar rats were assigned to 14 groups of 12
      each. Two groups, one female and one male, served as a control and received no
      treatment, and two other groups (one female and one male) received a sham
      gonadectomy and placebo hormone. The remaining 10 groups (five males and five
      females) received either orchiectomy or ovariectomy, followed by administration
      of estrogen, progesterone, combined estrogen and progesterone, or testosterone.
      The total protein and collagen content of the TMJ disc were determined using the
      calorimetric hydroxyproline method. RESULTS: The collagen content of TMJ discs of
      control males was statistically greater than the collagen content of the control
      female rats. This difference disappeared after ovariectomy of females and
      orchiectomy of males. Also, there was a general trend for a decrease in collagen
      and protein content to be produced by estrogen, progesterone, and by estrogen
      combined with progesterone in castrated male and female rats, and by orchiectomy
      of male rats. There was also a trend toward an increase in collagen and protein
      content after ovariectomy in female rats and administration of testosterone to
      castrated male and female rats. However, the only statistically significant
      effect of the drugs tested was that of estrogen combined with progesterone in
      ovariectomized female rats (a lowering effect on the total protein) and of
      estrogen alone in orchiectomized male rats (a lowering effect on the collagen
      content). CONCLUSION: Steroid sex hormones have an effect on the collagen and
      protein content of the TMJ disc of the rat as indicated by the difference in the
      values between control males and females and by the disappearance of this
      difference on castration of both male and female animals. This was also
      manifested by the significant effect of estradiol on collagen content of
      castrated males, by the effect of estrogen combined with progesterone on the
      protein content of castrated females.

PMID- 8648476
TI  - Maxillofacial fractures sustained during sports.
AB  - PURPOSE: This study investigated the number and type of maxillofacial fractures
      caused by various athletic activities. PATIENTS AND METHODS: The ninety-eight
      patients were treated between 1977 and 1993, and the type of sport involved,
      patient age and sex, cause of accident, site of injury, and mode of treatment
      were evaluated. RESULTS: Sports-related maxillofacial fractures accounted for
      10.4% of all patients with facial bone fractures. The number of different sports
      was 19, with the incidence of the fractures being most common in rugby and
      skiing, followed by baseball and soccer. The ratio of males to females was 5.5:1,
      and most of the patients were between 10 and 29 years of age. Total restriction
      from sports activity was between 8 and 12 weeks after initial treatment.
      CONCLUSION: The treatment for sports-related maxillofacial fractures is not
      different from that for fractures from other causes. However, it is important to
      establish some standard for deciding the time when it is possible to participate
      in sports after a fracture.

PMID- 8648478
TI  - Experimental study of combined hyperthermic and photodynamic therapy on carcinoma
      in the mouse.
AB  - PURPOSE: This study investigates the cytotoxic effect of photodynamic therapy
      using high-power laser irradiation on cancer cells. MATERIALS AND METHODS: High-
      or low-power irradiation from a pulsed Nd:YAG dye laser with or without a
      photosensitizer was administered to an NR-S1 carcinoma in the mouse dorsum.
      RESULTS: Photodynamic therapy with high-power laser irradiation yielded better
      results than conventional photodynamic therapy or hyperthermia with high-power
      laser irradiation. CONCLUSION: Photodynamic therapy with high-power laser
      irradiation is more effective because it generates both a hyperthermic and a
      photodynamic effect.

PMID- 8648479
TI  - Effects of multiple sterilization on surface characteristics and in vitro
      biologic responses to titanium.
AB  - PURPOSE: This study evaluates the surface changes and effects on in vitro cell
      attachment and spreading brought about on prepared commercially pure titanium by
      multiple exposures to common sterilization methods. MATERIALS AND METHODS: Discs
      of commercially pure titanium were prepared to approximate the surface roughness
      of commercially available bone miniplates. Samples underwent sterilization by
      exposure to ultraviolet light; ethylene oxide sterilization (1, 5, or 10 cycles);
      or by steam autoclaving (1, 5, or 10 cycles). Representative surfaces from these
      sterilization groups were examined using a series of surface analytical
      techniques including scanning electron microscopy (SEM), X-ray photoelectron
      spectroscopy (XPS), auger electron spectroscopy (AES), and contact angle
      measurements. Cell attachment assays using murine fibroblasts were then performed
      on titanium surfaces from each sterilization group and on tissue culture plastic
      controls. Sterilized surfaces contained O, C, and N contaminants, which affected
      surface energetics. Mean percent cell attachment values for each group were
      obtained for periods of up to 1 hour. Representative samples from each group were
      examined using SEM to ascertain cell spreading and morphology for each
      sterilization group. RESULTS: Ultraviolet (UV) sterilized surfaces showed no
      changes from the unsterilized state macroscopically or under SEM. UV surfaces
      showed cell attachment levels similar to control surfaces at all intervals, and a
      chronologic progression of cell spreading. Ethylene oxide-sterilized surfaces
      showed occasional bluish discoloration and a microscopic particulate contaminant,
      resulting in modest decreases in cell attachment levels without strong
      correlation to numbers of sterilization cycles. Autoclaved surfaces generally
      showed the greatest discoloration and heaviest particulate contamination. Cell
      attachment levels were lower, and cell spreading was diminished compared with the
      ethylene-oxide-treated group. CONCLUSIONS: Both ethylene oxide and steam
      autoclave sterilization contaminated and altered the titanium surface, resulting
      in decreased levels of cell attachment and spreading in vitro. Although
      corroborative in vivo experiments should be conducted, the results of this study
      indicate that some multiple sterilization regimens for metallic materials may
      pose serious biologic concerns.

PMID- 8648480
TI  - Autologous pericranial graft resurfacing after high condylectomy and discectomy
      of the temporomandibular joint in rabbits.
AB  - PURPOSE: This study tested the effects of an autologous pericranial graft placed
      over the condyle on healing after high condylectomy and discectomy. MATERIALS AND
      METHODS: Sixteen young adult New Zealand white rabbits were divided into four
      test groups and a control group. Three animals from the test group and one
      control animal were killed at 2, 4, 8, and 12 weeks postoperatively. Each
      experimental animal received a high condylotomy and discectomy bilaterally. In
      addition, on one side a pericranial graft was placed on the shaved bone and
      immobilized with a tissue adhesive. RESULTS: The results showed better healing of
      the articular defects in the joints where grafts had been placed, including
      earlier and more complete soft tissue covering, more substantial
      neochondrogenesis, and better organization of the regenerated articular
      cartilage. CONCLUSION: Pericranial grafts may be helpful in facilitating healing
      after high condylectomy. However, technical improvements in the method of tissue
      fixation may be necessary.

PMID- 8648481
TI  - Women in oral and maxillofacial surgery: factors affecting career choices,
      attitudes, and practice characteristics.
AB  - PURPOSE: This study analyzed the factors that attract women to the field of oral
      and maxillofacial surgery, their attitudes toward various aspects of the
      specialty, current practice patterns, and biases that may have been or are still
      being encountered. METHODS: Surveys were mailed to practicing female oral and
      maxillofacial surgeons, to oral and maxillofacial surgery residency programs to
      be distributed to their female residents, and to male and female dental students.
      RESULTS: A total of 107 surveys were sent to practicing female surgeons and 105
      to oral and maxillofacial surgery programs. There was a return rate of 71% and
      70%, respectively. Practicing female oral and maxillofacial surgeons tended to be
      young, Caucasian, and married. Fifty-nine percent were boarded, and 47% owned
      their own practices. Four of 76 had interrupted their residencies, and 18 had
      interrupted their practices at some point. More than 64% of practicing female
      oral and maxillofacial surgeons believed that there was a bias against women in
      this field. Female residents showed an overwhelming satisfaction with their
      career choice, but nearly half of them alluded to the need for dedication, a
      restriction of social life, or a concern for entering an male-dominated field.
      For students, the time commitment during residency and while in practice, and
      compromised family and social life, were the most commonly mentioned deterrents
      to entering oral and maxillofacial surgery, and lifestyle and the excitement of
      the field were its major attractions. CONCLUSION: Despite some biases in the
      field, women are practicing oral and maxillofacial surgery full time and are
      combining their career with full family lives. Among dental students, the time
      commitment and social compromise are the largest deterrents to entering the
      specialty of oral and maxillofacial surgery.

PMID- 8648482
TI  - Traumatic superior orbital fissure syndrome: report of two cases.

PMID- 8648483
TI  - Ehlers-Danlos syndrome: an approach to surgical management of temporomandibular
      joint dysfunction in two cases.

PMID- 8648484
TI  - Malignant peripheral nerve sheath tumor of the parotid gland: report of case.

PMID- 8648485
TI  - Inflammatory synovial cyst of the temporomandibular joint: a case report and
      review of the literature.

PMID- 8648486
TI  - Congenital unilateral fusion of the mandibular and maxillary alveolar ridges,
      temporomandibular joint, and coronoid process: a case report.

PMID- 8648487
TI  - Ultrasonic observation of facial bone fractures: report of cases.

PMID- 8648488
TI  - Fifteen-year follow-up of a family with inherited craniofacial fibrous dysplasia.

PMID- 8648489
TI  - Combined adenomatoid odontogenic tumor and calcifying epithelial odontogenic
      tumor: report of case and ultrastructural study.

PMID- 8648490
TI  - Modification of the temporalis muscle and fascia flap for the management of
      ankylosis of the temporomandibular joint.

PMID- 8648491
TI  - Osteomyelitis or abscess?

PMID- 8648492
TI  - Measuring outcomes.

PMID- 8648493
TI  - Development of a musculoskeletal extremity health status instrument: the
      Musculoskeletal Function Assessment instrument.
AB  - Despite an increasing reliance on the use of health status measures to assess and
      evaluate medical care, no single instrument is currently available for use with
      the broad range of patients with musculoskeletal disorders of the extremities
      that is commonly seen in clinical practice. In this paper, we report on the
      development of the Musculoskeletal Function Assessment instrument, a 100-item
      self reported health status instrument that is designed to meet this need. The
      instrument was developed in two phases. During the first phase, items were
      selected on the basis of interviews with 135 patients and 12 clinicians and from
      reviews of existing health status instruments. The items then were grouped into
      categories. During the second phase, the instrument was tested for reliability
      and content validity using a sample of 327 patients with one of five
      musculoskeletal disorders of the upper and lower extremities (fractures, soft
      tissue injuries, repetitive motion disorders, osteoarthritis, and rheumatoid
      arthritis). The patients were selected from both community and academic sites.
      Content validity also was demonstrated, based on a review of item selection
      procedures, expert opinion, and the distribution of scores on the instrument.

PMID- 8648494
TI  - Musculoskeletal Function Assessment instrument: criterion and construct validity.
AB  - The Musculoskeletal Function Assessment (MFA) instrument, a health status
      instrument with 100 self-reported health items, was designed for use with the
      broad range of patients with musculoskeletal disorders of the extremities
      commonly seen in clinical practice. In this paper, we report on its criterion and
      construct validity. Criterion validity was tested against physicians' ratings of
      patient functioning (e.g., upper functioning, lower functioning, daily
      activities, recreational functioning, emotional adjustment, and overall
      functioning) and standard clinical measures (e.g., grip strength, walking speed,
      fine motor skills, knee and elbow strength, and range of motion). Significant
      correlations (p < or = 0.05) between its scores, physicians' ratings, and
      clinical measures support the MFA's criterion validity. Construct validity was
      demonstrated against existing measures of health status (e.g., measures of lower
      and upper mobility, activity level and satisfaction, health status, social
      support, pain, emotional status, and quality of life), in accordance with
      clinical hypotheses about the effect of musculoskeletal disorders on functioning
      (e.g., type and number of problems, severity of illness or injury, and
      comorbidities) and by an analysis of demographic characteristics (e.g., sex,
      education, income, health insurance, and employment) against the MFA scores.
      Discriminant construct validity was supported in an analysis of MFA scores by
      patient disease groups (p < or = 0.01).

PMID- 8648495
TI  - Nerve regeneration during patellar tendon autograft remodelling after anterior
      cruciate ligament reconstruction: an experimental and clinical study.
AB  - The innervation of the rat and human anterior cruciate ligament, patellar tendon,
      and patellar tendon autograft after reconstruction of the anterior cruciate
      ligament was investigated by immunohistochemical and histological methods. A rat
      model of reconstruction with patellar tendon autograft was evaluated during
      active graft remodelling (2-16 weeks) and compared with normal ligament and
      tendon. The knees of 10 patients who had undergone reconstruction with patellar
      tendon autograft were examined 5-37 months postoperatively (remodeling fully
      completed) with arthroscopy and biopsy. As a control, biopsies from normal
      ligament and tendon were obtained from four patients. Nerve fibers were
      identified using antisera for protein gene product 9.5, a general neural marker.
      Neuronal regeneration was assessed by the expression of growth-associated protein
      43/B-50. The sensory type of innervation was characterized by assessing the
      distribution of nerves containing the sensory neuropeptides calcitonin gene
      related peptide and substance P. Immunoreactivity for all neural markers was
      found in both rat and human anterior cruciate ligament and patellar tendon. Two
      weeks after reconstruction, the rat autograft was acellular and no innervation
      could be identified. After 4 weeks, the grafts were viable, and immunoreactivity
      for protein gene product 9.5, growth associated protein 43/B-50, and calcitonin
      gene-related peptide was found until the 16th week postoperatively.
      Immunoreactivity for substance P was found in rat autografts at 4 weeks
      postoperatively only. All biopsies of human patellar tendon autograft showed
      signs of the remodelling process being fully completed, with revascularization
      and a sinusoidal collagen pattern with fibroblast repopulation. Neuropeptide
      immunoreactivity, however, was not found. The presence of immunoreactivity to
      sensory neuropeptides in the anterior cruciate ligament and patellar tendon may
      indicate a nociceptive and neuromodulatory function of these structures. The
      expression of sensory neuropeptides in the rat patellar tendon autograft suggests
      a possible involvement of sensory innervation during healing of the graft.

PMID- 8648496
TI  - Proliferative and matrix synthesis response of canine anterior cruciate ligament
      fibroblasts submitted to combined growth factors.
AB  - We investigated the effects of growth factors on the proliferation and matrix
      synthesis of anterior cruciate ligament fibroblasts. Fibroblasts from the
      anterior cruciate ligaments of dogs were transferred at the second passage in a
      defined medium. Epidermal growth factor, platelet-derived growth factor-AB,
      transforming growth factor-beta 1, insulin-like growth factor-1, and insulin,
      combined two by two following a 5 x 5 logarithmic concentration matrix, were
      added. Tridimensional curves showing cell proliferation at 24 hours against the
      concentration of two effectors were obtained for each combination. Collagen and
      proteoglycan productions were quantified using [14C]glycine and Na2[35S]O4.
      Ratios of type I:III collagen and hydrodynamic size distributions of
      proteoglycans were assayed, respectively, by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis and gel filtration chromatography. Epidermal
      growth factor had an effect nearly equivalent to that of platelet-derived growth
      factor-AB on cell proliferation. Both had a greater effect than insulin-like
      effect of transforming growth factor-beta 1. Neither platelet-derived growth
      factor-AB nor insulin has a significant effect by itself on collagen production.
      Epidermal growth factor slightly decreases collagen production as well as the
      type I:III collagen ratio; both transforming growth factor-beta 1 and insulin
      like growth factor-1 increase the same parameters. Epidermal growth factor
      inhibits the stimulation induced by transforming growth factor-beta 1. Similarly,
      insulin decreases the response to insulin-like growth factor-1. Proteoglycan
      production was significantly increased by all growth factors in this study, with
      transforming growth factor-beta 1 having the strongest effect. Small hydrodynamic
      size of proteoglycan was correlated to a high level of proteoglycan.
      biosynthesis. The results may be readily applied to tissue engineering or provide
      a basis for in vivo investigations.

PMID- 8648497
TI  - Intraoperative force-setting did not improve the mechanical properties of an
      augmented bone-tendon-bone anterior cruciate ligament graft in a goat model.
AB  - It has been hypothesized that load affects the mechanical properties of an
      anterior cruciate ligament graft while it remodels. The goal of this study was to
      use an existing goat model to evaluate the effect of intraoperative set force on
      the postoperative mechanical properties of an autograft that had been augmented
      with a synthetic segment. The following questions were addressed. Do augmented
      autografts set with a high force intraoperatively have improved structural and
      material graft properties and lower anterior-posterior knee laxity at 3 months
      after surgery, compared with autografts set with a low intraoperative force? How
      do the structural and material properties of these implanted autografts compare
      with the mechanical properties of an intact anterior cruciate ligament or an
      unimplanted control autograft? The anterior cruciate ligament was reconstructed
      in seven goats with use of a composite graft consisting of a bone-patellar tendon
      bone autograft and a synthetic augmentation device. A force-setting technique was
      used intraoperatively to establish the load-sharing between the autograft and
      augmentation segments such that the autograft carried either a high (16.5 N in
      four animals) or low (1.5 N in three animals) level of force, while the total
      force in the composite graft remained constant. Tensile testing was performed at
      3 months after surgery to determine the material and structural properties of the
      autograft, the intact anterior cruciate ligament from the normal contralateral
      knee, and a control bone-patellar tendon-bone graft of similar size that was
      harvested from the contralateral knee at the time of necropsy and had never been
      implanted in the joint. The structural and material properties of the autografts
      initially set to high or low loads at surgery were not significantly different
      after 3 months of implantation. The strength and stiffness of the implanted
      tendons were an average of 24 and 20% of the strength and stiffness of the normal
      anterior cruciate ligament and 31 and 62% of the control tendons, respectively.
      Intraoperative set force in an augmented anterior cruciate ligament graft at the
      levels chosen in this study did not significantly affect weakening of the
      autograft at 3 months.

PMID- 8648498
TI  - Subfailure injury of the rabbit anterior cruciate ligament.
AB  - Ligamentous injuries range in severity from a simple sprain to a complete
      rupture. Although sprains occur more frequently than complete failures, only a
      few studies have investigated the phenomena of these subfailure injuries. The
      purpose of our study was to document the changes in the load-deformation curve
      until the failure point, after the ligament has been subjected to an 80%
      subfailure stretch. Thirteen paired fresh rabbit bone-anterior cruciate ligament
      bone preparations were used. One of the pairs (control) was stretched until
      failure; the other (experimental) was first stretched to 80% of the failure
      deformation of the control and then stretched to failure. Comparisons were made
      between the load-deformation curves of the experimental and control specimens.
      The nonlinear load-deformation curves were characterized by eight parameters:
      failure load (Ffail), failure deformation (Dfail), energy until failure (Efail),
      deformations measured at 5, 10, 25, and 50% of the failure load (D5, D10, D25,
      and D50, respectively), and stiffness measured at 50% of the failure force (K50).
      There were no significant differences in the values for Ffail, Dfail, and Efail
      between the experimental and control ligaments (p > 0.33). In contrast, the
      deformation values were all larger for the experimental than the control
      ligaments (p > 0.01). The deformations D5, D10, D25, and D50 (mean +/- SD) for
      the control were 0.36 +/- 0.13, 0.49 +/- 0.23, 0.81 +/- 0.35, and 1.23 +/- 0.41
      mm. The corresponding deformations for the experimental ligaments were,
      respectively, 209, 186, 153, and 130% of the control values. K50 was also greater
      for the experimental ligament (125.0 +/- 41.7 N/mm compared with 108.7 +/- 31.4
      N/mm, p < 0.03). These findings indicate that even though the strength of the
      ligament did not change due to a subfailure injury, the shape of the load
      displacement curve, especially at low loads, was significantly altered. Under the
      dynamic in vivo loading conditions of daily living, this may result in increased
      joint laxity, additional loads being applied to other joint structures, and, with
      time, to joint problems.

PMID- 8648499
TI  - Medial collateral ligament healing one year after a concurrent medial collateral
      ligament and anterior cruciate ligament injury: an interdisciplinary study in
      rabbits.
AB  - The optimal treatment for concurrent injuries to the medial collateral and
      anterior cruciate ligaments has not been determined, despite numerous clinical
      and laboratory studies. The objective of this study was to examine the effect of
      surgical repair of the medial collateral ligament on its biomechanical and
      biochemical properties 52 weeks after such injuries. In the left knee of 12
      skeletally mature New Zealand White rabbits, the medial collateral ligament was
      torn and the anterior cruciate ligament was transected and then reconstructed.
      This is an experimental model previously developed in our laboratory. In six
      rabbits, the torn ends of the medial collateral ligament were repaired, and in
      the remaining six rabbits, the ligament was not repaired. Fifty-two weeks after
      injury, we examined varus-valgus and anterior-posterior knee stability;
      structural properties of the femur-medial collateral ligament-tibia complex; and
      mechanical properties, collagen content, and mature collagen crosslinking of the
      medial collateral ligament. We could not detect significant differences between
      repair and nonrepair groups for any biomechanical or biochemical property. Our
      data support clinical findings that when the medial collateral and anterior
      cruciate ligaments are injured concurrently and the anterior cruciate ligament is
      reconstructed, conservative treatment of the ruptured medial collateral ligament
      can result in successful healing.

PMID- 8648501
TI  - Stable partial debonding of the cement interfaces indicated by a finite element
      model of a total hip prosthesis.
AB  - A simplified three-dimensional finite element model of the femoral component of a
      cemented total hip prosthesis was used to investigate whether partial debonding
      at the stem-cement or bone-cement interfaces propagates in a stable or unstable
      manner, and to assess the resultant variation of the stresses within the cement
      layer. The likelihood of unstable debonding under tensile failure mode was
      assessed both by a conventional monotonic strength criterion and by a fracture
      mechanics approach that took into account debonding due to fatigue loading. The
      model predicted that partial debonding at the cement interfaces would be stable
      and would not precipitate complete debonding. Among the various bonding
      conditions that were investigated, the maximum tensile stress within the cement
      layer was least with a small amount of debonding rather than with complete
      bonding. These results were consistent with clinical observations of
      nonprogressive or slowly progressive separation at cement interfaces in cemented
      femoral components that were otherwise well functioning and asymptomatic.

PMID- 8648500
TI  - Myofibroblasts in the healing lapine medial collateral ligament: possible
      mechanisms of contraction.
AB  - The specific objective of this study was to determine the chronology of the
      appearance of the myofibroblast in the healing ligament. The overall goal of our
      work is to elucidate the cellular mechanism of contraction in this tissue. The
      myofibroblast has been found to be responsible for wound contraction in many
      tissues and to be the cause of the contracture in several pathological
      conditions. This cell type contains the actin isoform previously thought to be
      unique to smooth muscle cells and displays certain characteristic features at the
      ultrastructural level. In 26 New Zealand White male rabbits, the right medial
      collateral ligament was transected, whereas the left medial collateral ligament
      received a sham operation. The central third of the ligament (ligament scar
      tissue) was evaluated at 2, 3, 6, 8, 10, and 12 weeks postoperatively by
      immunohistochemical techniques, transmission electron microscopy, and Western
      blot analyses. Three other rabbits served as anatomic controls. During the early
      reparative phase (2 and 3 weeks after transection), there was an increase in the
      number of cells containing alpha-smooth muscle actin as well as augmentation of
      the alpha-smooth muscle actin content within each cell--a finding attributed to
      smooth muscle cells and pericytes associated with neovascularity. No
      myofibroblasts were detected at this stage, immediately postoperatively, or in
      the sham-operation controls. Ligaments in the remodeling phase of healing (6, 8,
      10, and 12 weeks) exhibited alpha-smooth muscle actin in fibroblasts
      (myofibroblasts) as well as in vascular pericytes and smooth muscle cells. During
      this stage of healing, transmission electron microscopy demonstrated an increase
      in the number of cells displaying myofibroblastic features. It was estimated that
      at 12 weeks of healing 10% of the cells at the site of injury were
      myofibroblasts. This is the first definitive finding of myofibroblasts in the
      injury site of the healing ligament, to our knowledge. The appearance of
      myofibroblasts in the 6-12 week healing period, the interval during which the
      ligament has been shown to contract in studies by other investigators, is a
      rationale for a hypothesis that a cellular contractile apparatus comprising alpha
      smooth muscle actin (i.e., the myofibroblast) may contribute to the recovery of
      original ligament length (and normal in situ strain).

PMID- 8648502
TI  - Trochanteric transfer in total hip replacement: effects on the moment arms and
      force-generating capacities of the hip abductors.
AB  - A three-dimensional computer model of the pelvis, femur, gluteus medius, and
      gluteus minimus was used to evaluate the changes in muscle moment arms and force
      generating capacities caused by alterations in the location of the greater
      trochanter. In the first part of this study, the hip center and all other aspects
      of joint geometry remained unaltered, while we examined changes in abduction
      moment arms that resulted from transfer of the trochanteric fragment to a wide
      variety of positions on the femur. The largest increase in average abduction
      moment arm was 11% (0.5 cm), which occurred with an anterolateral transfer. Most
      transfers resulted in moment arm changes of less than 5%. In the second part of
      this study, the hip center was displaced 2 cm superiorly, and the effects of a
      distal trochanteric transfer on the moment arms and force-generating capacities
      of the abductors were analyzed. The superior displacement caused a 13% decrease
      in the moment arm of the abductors and a 43% decrease in their force-generating
      capacity. The moment arm was not restored by distal transfer of the greater
      trochanter; however, distal transfer had the major advantage of restoring muscle
      lengths and force-generating capacities. These results suggest that trochanteric
      transfer should be considered primarily as a means to restore muscle length
      because it has limited potential to increase the moment arms of the two primary
      hip abductors.

PMID- 8648503
TI  - Removal of surface bacteria by irrigation.
AB  - We examined the efficacy of various irrigation solutions delivered through a
      power irrigator to remove bacteria from three different surfaces. Titanium,
      stainless-steel, and cortical bone surfaces were coated with three different
      bacterial species: Staphylococcus aureus, Pseudomonas aeruginosa, and
      Staphylococcus epidermidis. They were then irrigated with 1 L of fluid delivered
      by jet lavage. The fluids tested were normal saline and solutions of bacitracin,
      neomycin, and soap. One set of specimens was not irrigated, as a control. After
      irrigation, the specimens were sonicated to remove residual bacteria, and the
      sonicate was quantitatively cultured to allow evaluation of the amount of
      residual bacteria on the surface. The results showed that removal of bacteria
      reflects an interaction between bacterial species, surface characteristics, and
      irrigation solution. Fewer bacteria were present in all the irrigation groups
      than in the control. Soap solution was as good as or better than any other
      solution at removing all three types of bacteria from all three surfaces,
      although not all of the pairwise comparisons were statistically significant.
      There was a significant advantage to soap solution over antibiotic irrigant or
      saline alone in removing Staphylococcus epidermidis from metallic surfaces. The
      use of soap solution for irrigation seems to improve the removal of some bacteria
      from some surfaces in this experimental model and may represent a better type of
      irrigation additive.

PMID- 8648504
TI  - Assessment of donor cell and matrix survival in fresh articular cartilage
      allografts in a goat model.
AB  - The long-term survival of allografts of articular cartilage has been proposed to
      be dependent on the survival of the cells that maintain the unique structural and
      material properties of the allograft. In this study, we assessed cell survival in
      24 fresh articular cartilage allografts of the medial plateau in a Spanish-goat
      model. A DNA-probe technique was used to distinguish clearly between DNA from
      donor (allograft) and host cells. The intraarticular survival of viable allograft
      chondrocytes in the transplanted articular cartilage started to diminish as early
      as 3 weeks after transplantation; however, there was considerable variation in
      the amount of donor cell DNA detected in the allografts at 6 and 12 months
      following transplantation. This contrasts with our experience with fresh
      allografts of ligament, tendon, and meniscus, in which no donor DNA was detected
      4 weeks after transplantation. DNA from host cells was present in all articular
      cartilage allografts, as evidenced by detectable unique host DNA patterns.
      Histological and histochemical assays showed that none of the transplants
      demonstrated normal structure and composition at 1 year after transplantation.
      The grafts in which large quantities of donor DNA were present appeared grossly
      superior to those with no or reduced remaining demonstrable donor DNA.

PMID- 8648505
TI  - Basic fibroblast growth factor stimulates articular cartilage enlargement in
      young rats in vivo.
AB  - Basic fibroblast growth factor is a potent mitogen for chondrocytes and
      influences the protein synthesis of their extracellular matrix in vitro. To
      investigate its effect on normal developing articular cartilage in vivo, we
      injected basic fibroblast growth factor once into the knee joints of 4-week-old
      rats. Phosphate buffered saline was similarly injected into the contralateral
      knee joints as controls. A histological analysis showed that an injection of
      basic fibroblast growth factor induced enlargement of the articular cartilage
      area, especially in the condylar ridge region on day 7 after the injection. The
      extent of the enlargement was dose-dependent. The localization and amount of
      proliferating cells in the articular cartilage were analyzed
      immunohistochemically by the detection of proliferating cell nuclear antigen. On
      day 1 after the injection, the number of cells positive for proliferating cell
      nuclear antigen increased significantly in the joints that were injected compared
      with the controls, and Northern blot analysis showed that the level of messenger
      RNA for alpha 1(II) procollagen was lower in these joints than in the controls.
      The message in the joints that had been injected increased on day 7, and it was
      greater than that in the controls. This suggests that proliferating chondrocytes
      in developing articular cartilage respond to basic fibroblast growth factor with
      a resulting proliferation of chondrocytes followed by enlargement of cartilage.

PMID- 8648506
TI  - Articular chondrocyte tenascin-C production and assembly into de novo
      extracellular matrix.
AB  - Tenascin-C is an oligomeric glycoprotein of the extracellular matrix that is
      expressed in a variety of processes including development, tissue remodeling,
      wound healing, cell adhesion/antiadhesion, and cell/matrix interactions. Tenascin
      has recently been acknowledged as a component of the extracellular matrix of
      articular cartilage, but its function remains unclear. In this study, bovine
      articular chondrocytes were grown in alginate beads for 35 days to examine the
      kinetics of tenascin synthesis and incorporation into de novo extracellular
      matrix. During the culture period, 6 harvest days were established in which
      culture medium was recovered, alginate beads were dissociated with an EDTA
      solution, and chondrocytes were collected and lysed by sonication. Total DNA
      determination performed on the cell lysates demonstrated chondrocyte survival and
      proliferation. Western blotting performed on the medium, EDTA/alginate, and
      lysate samples demonstrated the production of both the 220 and 320 kDa tenascin
      size variants and their differential compartmentalization within the culture
      system. Tenascin was incorporated into the alginate bead matrix at a constant
      rate of 3.8 micrograms/day. The 320 kDa variant was produced in higher quantity,
      but the 220 kDa fragment was twice as likely to be incorporated into the de novo
      matrix. Methylene blue/acid fuchsin staining and tenascin immunohistochemistry
      demonstrated the incorporation of tenascin into a progressively expanding matrix
      surrounding the chondrocytes. The results suggest a role for tenascin in the
      assembly of the chondrocyte matrix and as a soluble mediator of chondrocytes with
      possible diverse functions for the tenascin size variants.

PMID- 8648507
TI  - Anterior glenohumeral stabilization factors: progressive effects in a
      biomechanical model.
AB  - The aim of this study was to evaluate the anterior stabilizing factors of the
      glenohumeral joint over a range of translations. The stabilizers examined
      included the capsular ligaments, the coracohumeral ligament, the rotator cuff
      muscles, and the long head of the biceps. Simulated muscle forces were applied to
      eight shoulder specimens to produce 90 degrees of total elevation of the arm in
      the scapular plane. Stability, defined as the force required to reach a specified
      subluxation, then was evaluated under varying configurations of capsule cuts,
      humeral rotation, and muscular loads. The overall force-displacement relationship
      of the subluxation was found to increase exponentially in external rotation to
      239 N at 10 mm of displacement and to level off in neutral rotation to 172 N at
      10 mm of displacement. Among the muscles, the biceps was the most important
      stabilizer in neutral rotation, providing more than 30 N of stabilization; the
      subscapularis provided the greatest degree of stabilization in external rotation,
      increasing to approximately 20 N. The subscapularis and supraspinatus were the
      most consistently important stabilizers in both types of rotation. In external
      rotation, the superior, middle, and inferior glenohumeral ligaments were the most
      effective ligamentous stabilizers, and all provided progressively more
      stabilization as higher displacements were reached. The stability provided by
      some of the ligaments reached nearly 50 N at 10 mm of displacement.

PMID- 8648508
TI  - Lower limb alignment and foot angle are related to stance phase knee adduction in
      normal subjects: a critical analysis of the reliability of gait analysis data.
AB  - Anatomic and mechanical factors that affect loading in the knee joint can
      contribute to pathologic changes seen at the knee in degenerative joint disease
      and should be considered in treatment planning. The objectives of this study were
      to quantify the relationships between the alignment of the bones of the lower
      extremity, foot progression angle, and knee adduction moment, and to determine
      the reliability of our gait measurements. Gait analysis and complete radiographic
      evaluation of the lower extremity were performed on 11 healthy subjects. The gait
      measurements were recorded with an optoelectronic digitizer and a multi-component
      force plate. The subjects who had radiographic measurements indicative of varus
      alignment of the lower extremity had statistically higher peaks in knee adduction
      moment in early stance. Conversely, those with valgus alignment of the lower
      extremity had statistically lower peaks in knee adduction moment in early stance.
      The subjects who had a large toe-out angle and low ankle inversion moment peaks
      in late stance had significantly lower peaks in knee adduction moment in late
      stance. These significant (low to moderate) correlations suggest that the limbs
      with more valgus alignment and those with a toe-out gait exhibited a reduced peak
      adduction moment at the knee. To verify the reproducibility of the data, gait
      analysis testing was performed on each lower limb on 2 separate days for each
      subject. Analysis of variance showed that there was no significant difference
      between test limbs or test days for each subject. Our results suggest that the
      alignment of the lower limb and the foot progression angle, which can be readily
      measured in a clinical setting, can serve as predictors of knee joint loading in
      healthy individuals. These findings may have important implications for both
      surgical and nonsurgical treatment of abnormalities of the knee joint.

PMID- 8648509
TI  - Effect of capacitive coupled electrical stimulation on regenerate bone.
AB  - An in vivo study was carried out to determine if capacitive coupled electrical
      stimulation increased the rate of recovery of strength of regenerate bone
      produced as a result of lengthening by the Ilizarov technique. Thirty-four adult
      male beagles underwent a right tibial mid-diaphyseal corticotomy, followed by a 5
      day delay, and then 21 days of lengthening (1 mm/day). At the start of the post
      distraction period (day 27), stimulation (3-6.3 V peak to peak, 5-10 mA root-mean
      square at 60 kHz) was applied for 28 days to one group. The nonstimulated group
      (n = 17) underwent a 28-day period with no stimulation. From each group, four
      tibiae were prepared for histology; both ends of the remaining bones were
      embedded in polymethylmethacrylate and tested in torsion (internal rotation at
      4.7 degrees/sec) until failure. Statistically significant changes included a 37%
      lower maximum torque capacity and a 40% decrease in strain energy to failure in
      the stimulated group compared with the nonstimulated group. The findings are
      supported by measured trends to a lower modulus of rigidity (37% decrease) and a
      smaller percentage of active osteoid perimeter (20% decrease) for the stimulated
      group. The experimental data suggest that when this dose of capacitive coupled
      electrical stimulation is applied to the regenerating bone created during
      distraction osteogenesis, it delays the recovery of bone strength compared with
      an untreated control.

PMID- 8648510
TI  - Intraosseous infusion of prostaglandin E2 prevents disuse-induced bone loss in
      the tibia.
AB  - We investigated whether intraosseous injection of prostaglandin E2 would preserve
      tibial bone mass in the skeletally unloaded limb of a large animal model.
      Skeletal unloading of one rear limb was produced by unilateral Achilles tenectomy
      in the goat. Prostaglandin E2 was injected at 0.5 or 1.0 mg (1 ml of volume)
      twice daily, beginning on day 7 and continuing for 10 days, through an implant
      that had been surgically placed in the proximal tibial metaphysis. Thirty-five
      days after surgery, the tibiae were harvested for measurement of static and
      dynamic bone parameters and mechanical characteristics using transmission
      ultrasound. Prostaglandin E2 produced a dose-dependent increase in the formation
      of woven new bone at all bone envelopes. The 1.0 mg dosage prevented and
      partially reversed the effects of skeletal unloading and added new bone (p <
      0.05) compared with the unloaded tibiae. Because prostaglandin E2 increased both
      bone formation and resorption and the new bone produced was primarily woven bone,
      the material properties of the tibiae infused with prostaglandin E2 did not
      increase significantly during the study compared with the unloaded and weight
      bearing tibiae.

PMID- 8648511
TI  - Activating mutations of Gs protein in monostotic fibrous lesions of bone.
AB  - Activating mutations of the alpha chain of the heterotrimeric signal transducer
      Gs disrupt the inherent guanosine triphosphatase activity of the alpha chain,
      stimulate adenylyl cyclase, and can result in independent cell proliferation.
      Such mutations are identified in a number of endocrine disorders, including
      McCune-Albright syndrome, which is a triad of endocrinopathy, cafe au lait spots,
      and polyostotic fibrous dysplasia. The mutation in this syndrome is a missense
      point mutation in exon 8 that results in the substitution of either histidine or
      cysteine for arginine at position 201. Monostotic fibrous dysplasia is a
      nonhereditary isolated bone lesion. Other isolated bone lesions that share some
      cytologic and clinical similarities to fibrous dysplasia are osteofibrous
      dysplasia and aggressive fibromatosis involving bone. Four cases of monostotic
      fibrous dysplasia, four cases of aggressive fibromatosis involving bone, and one
      case of osteofibrous dysplasia were studied to determine if a mutation was
      present in exon 8 of the alpha chain of Gs. A missense mutation was present in
      all of the fibrous dysplasias. The other fibrous lesions and uninvolved tissue
      did not contain a mutation. Somatic activating mutations of Gs differentiate
      fibrous dysplasia from the other lesions and may be responsible for the loss of
      control of local proliferation and growth factor expression.

PMID- 8648512
TI  - Basic fibroblast growth factor enhances bone-graft incorporation: dose and time
      dependence in rats.
AB  - In a previous study, we found that basic fibroblast growth factor could stimulate
      bone-graft incorporation. In the present study, the effects of different doses
      and implantation times were further studied, using the bone conduction chamber,
      in rats. Inside the chamber, the graft is isolated from the surrounding tissues
      except at one end, where small openings embedded in host bone allow ingrowth of
      tissue. The distance that new tissues had reached from the openings into the
      graft was measured on histological slides. Bone grafts were obtained from the
      proximal tibiae of donor rats, frozen at -70 degrees C, and lipid-extracted.
      Before implantation, they were soaked overnight in a hyaluronate gel with or
      without basic fibroblast growth factor and then were fitted into the chambers,
      which were implanted in the proximal tibiae of recipient rats. In a dose-response
      experiment, grafts containing 0.3, 8, 40, 200, or 1,000 ng of basic fibroblast
      growth factor were compared with grafts treated with carrier gel only, after an
      implantation time of 6 weeks. Fibrous tissue always penetrated the grafts further
      than the ingrown bone; the distance that it reached from the ingrowth openings
      (total ingrowth distance) was increased by all of the doses except 0.3 ng per
      implant. The distance of bone ingrowth was increased by 8, 40, and 200 ng. The
      increased total ingrowth with 1,000 ng was due to an increased amount of fibrous
      tissue ahead of the bone, whereas with the lower doses the increase was due to
      more bone. Thus, the dose had an effect on the type of ingrown tissue found in
      the graft. In a time-effect study, grafts treated with 40 ng of basic fibroblast
      growth factor had a higher uptake of [99mTc]MDP at 2 and 4 weeks and an increased
      bone ingrowth distance at 10 weeks. The radioactivity from [125I]basic fibroblast
      growth factor declined with a half-life of 17 hours. The results suggest that
      basic fibroblast growth factor may be beneficial for the incorporation of
      contained bone grafts; studies using more clinically relevant models are
      required.

PMID- 8648513
TI  - Functional degradation of the rabbit sciatic nerve during noncompressive
      segmental ischemia.
AB  - The purpose of this study was to evaluate functional degradation in a nerve with
      a local ischemic segment created without a direct compression effect. Ischemia of
      one segment of a rabbit sciatic nerve was induced by stripping the nerve's
      extrinsic blood supply along 15 cm. Blood flow of both in situ and ischemic
      nerves was quantitatively measured with radioactive microspheres in six serial
      segments in seven animals. The flow in one middle segment of the stripped nerve
      was significantly reduced to 0.1 ml/min per 100 g (p = 0.006). In another eight
      animals, both in situ and stripped nerves were metabolically challenged with
      repetitive stimuli (200 Hz). Conduction velocity and peak amplitude were measured
      before stimuli, after 30 and 60 minutes of stimuli, and after a 30-minute
      recovery period. Conduction velocity was reduced in both nonischemic and stripped
      nerves during prolonged repetitive stimulation. Peak amplitude was reduced
      slightly in the nonischemic group and markedly in the stripped group. Normal or
      higher values were seen again in both groups during the recovery period. It was
      demonstrated, therefore, that conduction properties of the nerve, especially
      amplitude, can be affected by localized ischemia in one segment.

PMID- 8648514
TI  - Effect of human adrenomedullin on vascular resistance of the canine tibia.
AB  - An ex vivo model of a perfused canine tibia was used to investigate the effect of
      human adrenomedullin, a novel peptide with known vasodilator properties, on the
      vascular resistance of bone. Human adrenomedullin has a potent and long-lasting
      vasodilator effect in the canine tibia following precontraction of vascular
      smooth muscle by infusion of prostaglandin F2 alpha. A 0.1 ml bolus injection of
      10(-5) M human adrenomedullin suppressed the pressor response of the canine tibia
      preparation to an infusion of norepinephrine by 43-52% for a duration of 100
      minutes. An injection of 10(-6) adrenomedullin suppressed the pressor response to
      an infusion of norepinephrine by 22-23% for a duration of 40 minutes. These data
      suggest that human adrenomedullin may be a potent and long-acting vascular smooth
      muscle relaxant in bone.

PMID- 8648515
TI  - Effect of link protein concentration on articular cartilage proteoglycan
      aggregation.
AB  - Previous work has shown that alterations in proteoglycan aggregates are among the
      first changes detected with aging, disuse, and degeneration of articular
      cartilage, yet the cause or causes of these alterations remain unknown. To
      determine if differences in link protein concentration can explain alterations in
      the assembly, size, and stability of articular cartilage proteoglycan aggregates,
      we isolated proteoglycan monomer (aggrecan) and link protein from adult bovine
      articular cartilage and then assembled proteoglycan aggregates from aggrecan and
      0.8% hyaluronan relative to aggrecan weight, in the presence of 0, 2, 4, 6, 8,
      10, 15, and 20% concentrations of link protein relative to aggrecan weight. We
      determined the amount, sedimentation coefficient, and stability of the aggregates
      by analytical ultracentrifugation and measured their dimensions by electron
      microscopy with use of the monolayer technique. Increased aggregate size, as
      determined by ultracentrifugation, was directly correlated with an increased
      number of aggrecans per aggregate and with increased hyaluronan length, as
      determined by electron microscopy. The concentration of link protein
      significantly influenced aggregation: concentrations of 6-8% produced maximum
      aggregation, aggregate stability, and uniformity of aggrecan spacing;
      concentrations greater than 10% led to the formation of superaggregates
      (aggregates with sedimentation velocities greater than 100 S that may result from
      linking two or more hyaluronan filaments) but decreased aggregate stability; and
      concentrations of less than 4% link protein significantly decreased aggregation,
      the size and stability of aggregates, and the regularity of aggrecan spacing. The
      latter observations suggest that a decline in the concentration of link protein
      could decrease the organization and stability of the articular cartilage matrix.

PMID- 8648516
TI  - Tolerability of continuous subcutaneous octreotide used in combination with other
      drugs.
AB  - Continuous subcutaneous infusion of octreotide combined with other drugs has
      proved to be useful in some circumstances in palliative care setting when theoral
      route is no longer available. Forty-four patients were administered octreotide
      alone or in combination with other drugs in the same syringe driver for symptom
      control in advanced cancer patients. Good tolerability and compatibility were
      observed without visual drug precipitation for a period of 48 hours at room
      temperature, the standard clinical situation in patients' homes. Such a
      combination of drugs administered by the subcutaneous route makes possible the
      adequate control of symptoms in the final days of life.

PMID- 8648517
TI  - The sensation of thirst in dying patients receiving i.v. hydration.
AB  - Cancer patients in the terminal phase of their disease often experience fluid
      deficits. This is mainly due to their inability to ingest adequate amounts of
      oral fluids to meet the body's physiological demands. In order to correct this
      deficit, intravenous (i.v.) fluid programs are often instituted. This pilot study
      was conducted on a group of terminal patients hospitalized in an oncology unit
      who died while receiving i.v. fluids. It sought to assess the effects of these
      fluids on their level of thirst. Data were collected on 30 patients in the last
      24 hours of life. However, of the 30 patients only 19 were sufficiently alert to
      be able to verbally evaluate their thirst intensity. Of the 19 patients, six
      experienced mild thirst, eight moderate thirst, and four severe thirst. This was
      in spite of IAV hydration regimens which ranged from 500 mL to 3000 mL. Little
      relationships was found between level of thirst and the amount of i.v. fluids
      received, blood urea nitrogen (BUN), or sodium blood levels. In addition,
      although 70% of the patients had fluid retention signs, there was little
      correlation between these signs and the amount of fluids received. Since the
      pilot study's sample was small, definitive conclusions could not be drawn.
      However, our results highlight the need for future research in this area.

PMID- 8648518
TI  - The promise of intimacy and the fear of our own undoing.

PMID- 8648519
TI  - Consumer participation in cancer system planning.

PMID- 8648520
TI  - Ethics and complexity in palliative care.

PMID- 8648521
TI  - Communication with cancer patients: does it matter?

PMID- 8648522
TI  - Hospice logos.

PMID- 8648523
TI  - Incorrect diagnosis and subsequent management of a patient labeled with
      cholangiocarcinoma.

PMID- 8648524
TI  - A prospective longitudinal investigation of spousal bereavement examining Parkes
      and Weiss' Bereavement Risk Index.
AB  - The purpose of this study was (a) to describe spousal bereavement both
      prospectively and longitudinally and (b) to examine the validity of the
      Bereavement Risk Index (BRI) published by Parkes and Weiss (1). Psychological
      distress was measured in 46 subjects across five time intervals beginning prior
      to a spousal death from lung cancer and ending 25 months after the death using
      the Brief Symptom Inventory (BSI) (2). The hypothesis that the BRI discriminates
      between bereaved spouses at high and low risk for psychological distress was
      supported by measurements taken within two months of the patient's diagnosis
      (prior to death), at 6 weeks following the death, and at 6 and 13 months
      thereafter. These findings support the need for early identification of
      individuals at high risk for negative bereavement outcomes even prior to the
      spousal death.

PMID- 8648525
TI  - The management of pain in patients with advanced cancer: the importance of
      multidimensional assessments.

PMID- 8648526
TI  - Futile care in the pediatric intensive care unit: ethical and economic
      considerations.

PMID- 8648527
TI  - Clinical heterogeneity in congenital sucrase-isomaltase deficiency.

PMID- 8648528
TI  - Resisting the urge to prescribe.

PMID- 8648529
TI  - Abnormal serum uric acid levels in children.
AB  - Measurement of the serum uric acid level, most commonly considered in adult
      patients, is frequently obtained inadvertently for pediatric patients because it
      is a standard component of many multichannel chemistry profiles offered by
      clinical laboratories. Most standard references for normal uric acid values do
      not take into account the impact of the metabolic changes in children at
      different ages on the uric acid level. A substantial number of childhood
      conditions may produce perturbations in the serum uric acid level. Knowledge of
      normal serum uric acid levels and of the conditions affecting those levels in
      children enables a more focused pursuit of underlying abnormalities.

PMID- 8648530
TI  - Resource consumption and the extent of futile care among patients in a pediatric
      intensive care unit setting.
AB  - OBJECTIVES: To estimate resource consumption and the extent of futile care among
      patients admitted to the pediatric intensive care unit (PICU). STUDY DESIGN: A
      prospective cohort study of 353 consecutive admissions followed for 1334 patient
      days during the PICU stay at the Texas Children's Hospital in Houston, Texas.
      Participants were 353 children and adolescents who were hospitalized in the PICU
      during September and October 1993. Three broad operational definitions of
      futility were developed to capture the maximum extent of resource consumption
      related to medical futility. Definition 1 (imminent demise futility) was
      developed by an objective, validated, severity of illness measure (Pediatric Risk
      of Mortality Score) to identify patients with high mortality risks. Definition 2
      (lethal condition futility) was used to identify patients in the PICU whose long
      term survival was unlikely. Definition 3 (qualitative futility) was used to
      identify patients with high morbidity. Resource consumption was measured
      according to the number of patient-days in the PICU and the Therapeutic
      Intervention Scoring System. RESULTS: Twenty-three (6.5%) patients representing
      36 (2.7%) patient-days met at least one of the definitions of medical futility
      for some of the days when they were in the PICU. None of the patient-days that
      met any of the definitions of medical futility were associated with high resource
      consumption compared with non-futile care patient-days. CONCLUSIONS: Despite our
      use of broad definitions of medical futility, relatively small amounts of
      resources were used in futile PICU care. This suggests that attempts to reduce
      resource consumption in the PICU by focusing on medical futility are unlikely to
      be successful.

PMID- 8648531
TI  - A prospective randomized trial comparing continuous versus intermittent feeding
      methods in very low birth weight neonates.
AB  - OBJECTIVE: To compare the effects of continuous versus intermittent feedings on
      physical growth, gastrointestinal tolerance, and macronutrient retention in very
      low birth weight infants ( < 1500 gm). STUDY DESIGN: Very low birth weight
      neonates stratified by birth weight were randomly assigned to either continuous
      (24-hour) or intermittent (every 3 hours) nasogastric feedings. Feedings with
      half-strength Similac Special Care formula were initiated between day 2 and 3 and
      were advanced isoenergetically to goal. Daily weights, volume/caloric intakes,
      weekly anthropometric and dynamic skin-fold thickness measurements, and data on
      feeding milestones and clinical complications were collected. Nitrogen,
      carbohydrate, and fat balance studies were performed on a subset of male
      subjects. RESULTS: Eighty-two neonates with birth weights between 750 and 1500 gm
      who were born between 27 and 34 weeks of gestation were randomly assigned to
      continuous (n = 42) and intermittent (n = 40) feeding groups. There were no
      significant differences in baseline demographics and severity of respiratory
      distress between groups. There were no significant differences in days to regain
      birth weight, days to full enteral feedings, days to discharge, and discharge
      anthropometric measurements between continuously fed and intermittently fed
      infants, both when evaluated together and according to 250 gm weight intervals.
      Retention rates of nitrogen, fat, total carbohydrate, and lactose were comparable
      in the continuously fed (n = 17) and intermittently fed (n = 13) male neonates.
      Very low birth weight neonates who were fed continuously did not have feeding
      related complications. CONCLUSION: Very low birth weight infants achieve similar
      growth and macronutrient retention rates and have comparable lengths of hospital
      stay whether they are fed with continuous or intermittent feedings.

PMID- 8648532
TI  - Glucose polymer as a cause of protracted diarrhea in infants with unsuspected
      congenital sucrase-isomaltase deficiency.
AB  - OBJECTIVE: To describe four infants with protracted diarrhea caused by glucose
      polymer intolerance resulting from congenital sucrase-isomaltase deficiency.
      METHODS: The diagnosis of congenital sucrase-isomaltase deficiency was
      established by mucosal disaccharidase assay. In each case the clinical response
      to discontinuation of glucose polymer was documented. RESULTS: The median age at
      the onset of symptoms was 3 weeks (range, 2 to 16 weeks). In three infants the
      formula had been prescribed for presumed postgastroenteritis diarrhea, and in a
      fourth it was begun after resection of a short-segment congenital ileal atresia.
      In each infant watery diarrhea occurred and persisted for many months, and it was
      assumed that the original gastrointestinal disorder was responsible. In two
      cases, parenteral nutrition was administered for persistent failure to thrive.
      Ultimately, investigation revealed the underlying congenital sucrase-isomaltase
      deficiency, and elimination of glucose polymer from the diet led to immediate
      recovery in each case. CONCLUSION: Congenital sucrase-isomaltase deficiency
      should be considered a possible cause of protracted diarrhea in infants receiving
      glucose polymer-based feedings.

PMID- 8648534
TI  - Granulocyte colony-stimulating factor as a marker for bacterial infection in
      neonates.
AB  - OBJECTIVE: To evaluate granulocyte colony-stimulating factor (G-CSF) as an early
      marker of bacterial or fungal infection in neonates. STUDY DESIGN: We measured G
      CSF levels in infants of varying gestational and postnatal ages. We separated the
      infants into three groups: group 1, positive bacterial or fungal blood culture
      result; group 2, negative blood culture result but evidence of clinical sepsis;
      and group 3, negative blood culture result and no or weak evidence of sepsis.
      Comparison of mean G-CSF levels by group was accomplished by an analysis of
      variance. RESULTS: One hundred seventy-six evaluations for sepsis were done for
      156 infants with gestational ages ranging from 24 to 43 weeks; 50% of these
      infants were less than 35 weeks of gestational age. The mean G-CSF levels of
      groups 1 and 2 were significantly higher than those of group 3. The mean G-CSF
      level of each group was 2278 pg/ml (group 1), 1873 pg/ml (group 2), and 280 pg/ml
      (group 3) (p < 0.001). On the basis of a cutoff level of 200 pg/ml, the
      sensitivity of the test was 95%, specificity 73%, positive predictive value 40%,
      and negative predictive value 99%. CONCLUSION: G-CSF levels represent a sensitive
      marker of infection in neonates of all gestational ages.

PMID- 8648533
TI  - Risk factors for carriage of drug-resistant Streptococcus pneumoniae among
      children in Memphis, Tennessee.
AB  - OBJECTIVES: To determine risk factors for carriage of drug-resistant
      Streptococcus pneumoniae to understand better the factors promoting spread of
      these isolates. STUDY DESIGN: We obtained medical and demographic information and
      nasopharyngeal swab specimens from 216 children less than 6 years old with upper
      respiratory tract infections, seeking medical care at five Memphis, Tenn, study
      sites. We evaluated risk factors for carriage of penicillin-nonsusceptible S.
      pneumoniae (NSSP) among 100 children with S. pneumoniae isolates. Patterns of
      antimicrobial prescription were recorded for enrolled children. RESULTS:
      Independent risk factors for carriage of NSSP included an increased number of
      antimicrobial treatment courses during the previous 3 months and white race. Day
      care attendance approached statistical significance (p = 0.07). Most children
      with upper respiratory tract infection received a prescription for antimicrobial
      drugs. These prescriptions were more common for white children than for black
      children. CONCLUSIONS: Increased use of antimicrobial drugs enhances the risk of
      carriage of NSSP. This may contribute to the higher risk among white children of
      NSSP infection; however, after control for antimicrobial use, white children were
      still at an increased risk of infection with NSSP, possibly through greater
      exposure to resistant strains.

PMID- 8648535
TI  - Maternal phenylketonuria: magnetic resonance imaging of the brain in offspring.
AB  - Phenylketonuria (PKU) produces white matter changes identifiable by magnetic
      resonance imaging. These changes occur postnatally. Offspring of untreated
      mothers with PKU also have a brain effect, expressed as microcephaly and mental
      retardation. This effect occurs prenatally. To determine whether the white matter
      changes seen in PKU are also present in maternal PKU offspring, despite the
      different developmental stages of exposure to PKU, we performed brain magnetic
      resonance imaging studies in seven maternal PKU offspring, five from essentially
      untreated pregnancies and two from treated pregnancies. None had white matter
      changes, although the one offspring with PKU had delayed myelination. However,
      hypoplasia of the corpus callosum was present in three of the four offspring from
      untreated pregnancies and in the offspring from a maternal PKU pregnancy not
      treated until the third trimester. Unlike PKU, white matter changes are not a
      feature of the brain effect in maternal PKU. However, hypoplasia of the corpus
      callosum is a feature of maternal PKU and is probably a result of inhibition of
      corpus callosum development at 8 to 20 weeks of gestation. The hypoplastic corpus
      callosum could be a marker for brain effect in maternal PKU and may have
      implications for the cognitive deficits in these offspring.

PMID- 8648536
TI  - Long-term sequelae of hearing impairment in congenital hypothyroidism.
AB  - Hearing loss and its functional consequences were evaluated retrospectively in
      children with congenital hypothyroidism. From a cohort of 101 children followed
      longitudinally to evaluate newborn screening, 75 with previous hearing tests were
      studied. Fifteen (20%) were found to have hearing problems. Of these, nine had
      unilateral or sensorineural loss mostly at high frequencies, five had a
      conductive loss, and one had both problems. Hearing impaired children differed
      from children with normal hearing in age of treatment onset (22 vs 14 days) but
      not disease severity or duration. A comparison of language and auditory
      processing skills at ages 3, 5, and 7 years revealed that early speech was
      delayed in hearing impaired children, whereas deficits persisted in later
      receptive language and auditory discrimination skills. Comparing hearing impaired
      children and children with normal hearing with matched control subjects at grade
      3 showed that hearing impaired children were poorer readers because of less
      adequate phonologic processing skills.

PMID- 8648537
TI  - Thyroid function and serum thyroid binding proteins in prepubertal and pubertal
      children with chronic renal insufficiency receiving conservative treatment,
      undergoing hemodialysis, or receiving care after renal transplantation.
AB  - OBJECTIVE: The abnormalities reported in some thyroid function tests in children
      with renal disease could be adaptive phenomena, shared by a variety of other
      nonthyroidal illnesses, or could reflect hypothyroidism. STUDY DESIGN: To answer
      this question, we studied thyroid function and serum thyroid binding proteins in
      36 prepubertal and 23 pubertal patients with renal disease receiving three
      different therapies: conservative treatment, hemodialysis, and care after renal
      transplantation. RESULTS: During prepuberty, the serum concentration thyroxine
      binding globulin (mean +/- SE) in the three groups of patients (294 +/- 18, 303
      +/- 18, and 323 +/- 16 nmol/L, respectively) was significantly lower than in
      prepubertal control subjects (451 +/- 71 nmol/L). Only in prepubertal patients
      after renal transplantation (3583 +/- 573 nmol/L) were serum thyroxine binding
      prealbumin values lower than in respective control subjects (5999 +/- 908
      nmol/L). The serum total thyroxine concentration in the three groups of patients
      (108 +/- 41.9, 121 +/- 5.7, and 123 +/- 5.5 nmol/L, respectively) was
      significantly lower than in prepubertal control subjects (149 +/- 10 nmol/L),
      whereas serum free thyroxine and serum albumin-bound thyroxine concentrations
      were similar to those in control subjects. The serum total triiodothyronine level
      in the three groups of patients (2.29 +/- 0.82, 2.13 +/- 0.13, and 2.01 +/- 0.20
      nmol/L respectively) was significantly lower than in prepubertal control subjects
      (3.04 +/- 0.24 nmol/L), whereas serum levels of free triiodothyronine and serum
      albumin-bound triiodothyronine were similar to those in prepubertal control
      subjects. During puberty, serum thyroxine binding globulin and serum thyroxine
      binding prealbumin levels in the three groups of patients were not statistically
      different from those in pubertal control subjects (309 +/- 47 and 4950 +/- 1230
      nmol/L, respectively). Serum levels of total thyroxine, free thyroxine, albumin
      bound thyroxine, total triiodothyronine, free triiodothyronine, and albumin-bound
      triiodothyronine were similar to those in pubertal control subjects except for
      pubertal patients undergoing hemodialysis. In all clinical groups the basal serum
      thyrotropin concentration was similar to those in respective control subjects.
      The frequency of goiter was increased in patients undergoing hemodialysis,
      probably as a result of iodide washout with dialysis. CONCLUSION: Children and
      adolescents with chronic renal insufficiency or endstage renal disease or after
      renal transplantation do not have a primary abnormality of thyroid function and
      therefore are not candidates for thyroid hormone treatment.

PMID- 8648538
TI  - Serum erythropoietin levels during infancy: associations with erythropoiesis.
AB  - OBJECTIVE: To determine plasma erythropoietin levels and their association with
      hemoglobin and reticulocyte counts in healthy term infants. DESIGN: We compared
      plasma erythropoietin levels measured in serial blood samples obtained every 4
      weeks during the first 6 months of life with one another and with levels in term
      fetuses and healthy adults. Correlation analysis was applied to examine for
      associations of erythropoietin with hemoglobin and with reticulocyte count.
      RESULTS: Plasma erythropoietin levels were lowest in the first and highest in the
      second postnatal months, a pattern reciprocal to that observed for hemoglobin
      during the period of physiologic anemia. The erythropoietin level was negatively
      correlated with hemoglobin (p < 0.0001) and positively correlated with
      reticulocytes (p < 0.0001). The slope of the inverse relationship of hemoglobin
      and plasma erythropoietin in infants was similar to those previously reported for
      anemic fetuses and premature infants, but much less steep than for anemic
      children and adults. CONCLUSION: This study is the first to report simultaneous
      patterns of change observed in plasma erythropoietin, hemoglobin, and
      reticulocytes during normal infancy. These patterns are consistent with postnatal
      perturbations in tissue oxygenation and suggest a major role for erythropoietin
      in the regulation of erythropoiesis during normal infancy, but at a lower
      hemoglobin concentration than for older children and adults with pathologic
      anemia.

PMID- 8648539
TI  - Effects of a school-based intervention to reduce cardiovascular disease risk
      factors in elementary-school children: the Cardiovascular Health in Children
      (CHIC) study.
AB  - OBJECTIVE: To test a classroom-based intervention to reduce cardiovascular
      disease risk factors in elementary school children. STUDY DESIGN: This was a
      randomized, controlled field trial in 12 schools across North Carolina,
      stratified by geographic region and urban/rural setting. Subjects were 1274 third
      and fourth graders (48% boys). The intervention, taught by regular classroom and
      physical education teachers, provided all children an 8-week exercise program and
      8 weeks of classes on nutrition and smoking. Data were analyzed at the school
      level with survey regression models and at the individual level with multivariate
      analysis of variance and analysis of covariance models; 95% confidence intervals
      were computed. RESULTS: Children in the intervention group had significantly
      greater knowledge (7.9% more correct) and a significant increase in self-reported
      physical activity than children in the control group. Trends for the intervention
      group were a reduction in total cholesterol level (-5.27 mg/dl), an increase in
      aerobic power, a reduction in body fat, and smaller rise in diastolic blood
      pressure than control children. CONCLUSIONS: This classroom-based, public health
      approach improved children's cardiovascular disease risk profiles; it is
      practical and fairly easy to incorporate into the school day. All children
      directly receive the potential benefits of the intervention without a risk of
      labeling. This program can improve health knowledge, habits, and health outcomes
      of young children at a time when health habits are being formed.

PMID- 8648540
TI  - Increased blood pressure in neonates and infants whose mothers smoked during
      pregnancy.
AB  - OBJECTIVE: To determine whether maternal smoking during pregnancy is associated
      with increased blood pressure (BP) in neonates. STUDY DESIGN: We measured BP in
      the following groups: (1) 73 neonates of mothers who smoked during pregnancy, (2)
      43 neonates of mothers who quit smoking early during pregnancy, (3) 83 neonates
      of passive smoking mothers, and (4) 170 neonates of nonsmoking parents. Three BP
      measurements were made at 1, 24, 48, and 72 hours of life. Some of the neonates
      were followed for 2 years. RESULTS: We observed a significant positive
      correlation between the number of cigarettes smoked by the mothers during
      pregnancy and the BP of the neonates. From the first to the seventy-second hour
      of life the BP in the infants of the mothers who smoked 15 or more cigarettes per
      day was significantly higher than in the infants of the nonsmoking mothers,
      whereas the increase in BP was intermediate when the mothers smoked 7 to 15
      cigarettes per day. The BP was similar to that of the control subjects when the
      mothers smoked 3 to 5 cigarettes per day, were passive smokers, or quit smoking
      during pregnancy. On reexamination between 4 and 9 months and at 12 months, in
      infants of mothers who smoked 15 or more cigarettes per day both the systolic and
      the diastolic BP were significantly higher than in the control subjects; at 12
      months 5 of the infants of mothers who smoked cigarettes had BP greater than the
      95th percentile for age and gender. At 24 months of life there was no significant
      difference in systolic or diastolic BP between infants of smoking and nonsmoking
      mothers. CONCLUSIONS: Neonates and infants of mothers who smoked during pregnancy
      have an elevation of BP that is related to the number of cigarettes smoked per
      day. Smoking 15 or more cigarettes per day may cause BP elevation in infancy, but
      the BP returns to normal during the second year of life.

PMID- 8648541
TI  - Relationship between Fc receptor IIA polymorphism and infection in children with
      sickle cell disease.
AB  - OBJECTIVE: Despite penicillin prophylaxis and vaccination, infection with
      encapsulated organisms remains a leading cause of morbidity and death in children
      with sickle cell disease. The role of Fc receptors in the clearance of
      encapsulated organisms is well documented. The His(H)-Arg(R) polymorphism at
      amino acid 131 of the Fc gamma RIIA receptor alters binding affinity for human
      IgG2 and influences infection with encapsulated organisms in children without
      sickle cell disease. We hypothesized that the genotype for high-affinity human
      IgG2 binding (H/H131) is underrepresented in children with sickle cell disease
      who had encapsulated organism infection. DESIGN: We studied 60 black children
      with sickle cell disease from four participating centers who had a history of
      encapsulated organism infection. Genomic DNA from peripheral blood was subjected
      to amplification by polymerase chain reaction and to sequence analysis for
      identification of the Fc gamma RIIA genotype, and the genotype distribution was
      then compared with our data from ethnically matched control subjects. RESULTS:
      Contrary to our hypothesis, the H/H131 genotype was overrepresented in all
      individuals (p = 0.046) and in particular in the 11 individuals with a history of
      Haemophilus influenzae type b infection (64% H/H131, 27% H/R131, 9% R/R131; p =
      0.002), in comparison with ethnically matched control subjects (14% H/H131, 60%
      H/R131, 26% R/R131). In the 51 individuals with a history of Streptococcus
      pneumoniae infection, the genotype distribution was not statistically
      significantly different from that of the control population. CONCLUSIONS: The
      H/H131 Fc gamma RIIA genotype is overrepresented in black children with sickle
      cell disease and a history of H. influenzae type b infection but not in those
      with S. pneumoniae infection.

PMID- 8648542
TI  - Hydroxyurea therapy in children severely affected with sickle cell disease.
AB  - HYPOTHESIS: The major clinical manifestations of sickle cell disease (SCD) are
      hemolytic anemia, predisposition to infection, and recurrent vaso-occlusive
      episodes resulting in pain, organ dysfunction, or both. There has been no
      satisfactory treatment for children with recurrent severe painful episodes caused
      by SCD. Hydroxyurea is an antimetabolite drug shown in adults with SCD to
      increase fetal hemoglobin levels and reduce the symptoms of SCD. We hypothesized
      that hydroxyurea therapy in children with severe (defined as > or = 3 vaso
      occlusive events per year) SCD could improve hematologic parameters and reduce
      vaso-occlusive events. OBJECTIVE: To assess the safety and efficacy of
      hydroxyurea for the treatment of severe SCD in children. STUDY DESIGN: After
      obtaining informed consent, we initiated hydroxyurea therapy at a dosage of 10 to
      20 mg/kg per day in 15 patients with severe SCD (hemoglobin SS, hemoglobin SS
      alpha thalassemia, or hemoglobin S-beta0-thalassemia). Doses were escalated as
      tolerated. Patients were monitored with bimonthly physical examinations and
      monthly laboratory measures. To assess the impact of hydroxyurea on clinical
      symptoms, we recorded the number of inpatient days for each patient during the
      period of treatment and compared it with the number of inpatient days for the 12-
      to 24-month period before institution of hydroxyurea therapy, using the subject
      as his or her own control subject. RESULTS: Thirteen patients received
      hydroxyurea for a median of 24 months (range, 6 to 39 months). The mean dose of
      hydroxyurea was 21.4 +/- 5.2 mg/kg. Treatment with hydroxyurea induced
      statistically significant increases in the total hemoglobin concentration, mean
      corpuscular volume, and percentage of hemoglobin F, and a decrease in the serum
      concentration of bilirubin. Toxic effects included three episodes of a reversible
      myelotoxic reaction, two of which required transfusion of packed erythrocytes.
      For the entire group, hospitalization decreased from a prehydroxyurea median of
      3.9 +/- 2.0 days per month to 1.1 +/- 2.1 days per month of therapy (p = 0.09).
      For those subjects (n = 10) completing at least 1 year of treatment, the decrease
      in hospitalization from 4.1 +/- 2.2 to 1.0 +/- 1.7 days per month was significant
      (p = 0.03). CONCLUSIONS: In this pilot trial, hydroxyurea treatment of severe SCD
      in children was associated with improved hematologic parameters, acceptable toxic
      effects, and a trend to reduced hospitalization. Hydroxyurea appears to be a safe
      and potentially effective agent for the treatment of severe SCD in children. A
      prospective, controlled trial to investigate the efficacy of hydroxyurea in
      children is therefore warranted.

PMID- 8648543
TI  - Efficacy of gabapentin therapy in children with refractory partial seizures.
AB  - Thirty-two children with refractory partial epilepsy received open-label
      gabapentin as an additional medication to their antiepileptic drug regimen.
      Gabapentin was given in a dose ranging from 10 to 50 mg/kg per day (mean dose,
      26.7 mg/kg daily). All patients had partial seizures with or without secondary
      generalization. Compared with baseline, 11 patients (34.4%) had a greater than
      50% decrease in seizure frequency, and 4 (12.5%) had a 25% to 50% decrease in
      seizure frequency. Of the seven children who received the medication for 6 months
      or longer, two were seizure free and four were almost seizure free (having one
      seizure every few months). Mean gabapentin concentration was 4.8 micrograms/ml,
      and mean apparent clearance was 372 ml/kg per hour. The major reported side
      effects were behavioral. These consisted of hyperactivity, irritability, and
      agitation that occurred in patients with baseline mental retardation with
      attention deficit. We conclude that gabapentin can be a useful adjunctive
      medication in the treatment of refractory partial epilepsy in children.

PMID- 8648544
TI  - Early detection of specific IgE antibody against house dust mite in children at
      risk of allergic disease.
AB  - OBJECTIVES: House dust mite (HDM) is a representative inhalant allergen that
      triggers allergic disease in childhood. The aim of this study is early detection
      of HDM-specific IgE antibody and prediction of the risk of a positive reaction to
      this antibody by in vitro parameters in infants with allergic manifestations.
      STUDY DESIGN: Levels of HDM IgE in a range below the standard cutoff point of
      0.35 U/ml, serum concentrations of IgE, and specific IgE antibodies against egg
      white, cow milk, and soybeans were determined in 108 infants with allergic
      manifestations at 6 months of age, and these infants were monitored for
      conversion of HDM IgE to positive levels greater than 0.35 U/ml up to 5 years of
      age. The presence of active allergic disease at 5 years of age in relation to HDM
      specific IgE was also examined. RESULTS: We were able to determine reliably the
      HDM IgE values between 0.23 and 0.35 U/ml, using a fluorescent enzyme immunoassay
      that measured the intensity of fluorescence. The HDM IgE levels increased,
      resulting in positive values, in 54 of 108 subjects during the first 5 years of
      life. In multiple regression analysis, an HDM IgE value between 0.23 and 0.35
      U/ml, a high serum IgE level, and a positive reaction to specific IgE antibody
      against egg white in infants at 6 months of age proved to be significant
      predictors of the future positive reaction to HDM IgE (p = 0.0006, 0.0043, and
      0.0001). In particular, the sensitivity and specificity of specific IgE antibody
      against egg white for the conversion of HDM IgE to positive values were the best
      among these indicators. Moreover, active allergic diseases were observed
      significantly more often in children with positive HDM IgE values than in
      children with negative HDM IgE values at 5 years of age (p < 0.001 for each).
      CONCLUSIONS: A determination of these predictors in infants at 6 months of age
      can be used for early detection of HDM IgE and would be valuable in a screening
      test for later allergic disease among infants with allergic manifestations.

PMID- 8648545
TI  - Right atrial thrombi in children with cancer and indwelling catheters.
AB  - OBJECTIVE: To determine the prevalence of right atrial thrombi in children with
      cancer and indwelling catheters. STUDY DESIGN: We systematically examined 156
      children with cancer and indwelling catheters for the presence of a right atrial
      thrombus when they underwent routine screening of cardiac function by two
      dimensional echocardiography. RESULTS: Thirteen children (8.8%) had right atrial
      thrombi. Of the 13 children, 6 had thrombi adherent to the right atrial wall, and
      in 5 of these 6 children the clots were considered large enough to require
      intervention: 2 children with obstruction of venous or tricuspid valve inflow
      underwent right atriotomy and thrombus removal; they recovered and remained well.
      The other 3 children had moderate-sized thrombi and were treated with oral
      anticoagulants; their clots stabilized (2 children) or regressed (1 child). The
      remaining 7 children had thrombus on the tip of the catheter: 5 of these children
      were observed; the thrombi spontaneously resolved in 2 of them and did not change
      in size in the other 3. In the sixth child, the catheter malfunctioned 2 weeks
      after discovery of the clot and the catheter was removed. The seventh child was
      treated with warfarin and the clot decreased in size. Thrombi were detected in a
      greater proportion of children with catheter tips in the right atrium versus the
      superior vena cava, and in a greater proportion of children with acute
      lymphoblastic leukemia versus other diagnoses. There was no association between
      the presence of a clot and duration of time the catheter was in place, the number
      of catheters placed, treatment with asparaginase, or treatment with total
      parenteral nutrition. CONCLUSION: The incidence of right atrial thrombi in
      children with indwelling catheters may be higher than was previously appreciated.

PMID- 8648546
TI  - A pilot study of outpatient management of febrile neutropenic children with
      cancer at low risk of bacteremia.
AB  - Febrile neutropenic children with cancer were eligible for outpatient management
      with intravenous ceftriaxone therapy if they displayed selected low-risk
      criteria. Nineteen children were enrolled. All patients had sterile blood
      cultures, and only one of them was hospitalized because of persistent fever. This
      pilot study suggests that selected children with febrile neutropenia might be
      successfully managed without hospitalization.

PMID- 8648547
TI  - Focal bacterial nephritis (lobar nephronia) in children.
AB  - We report 13 patients with 16 episodes of acute lobar nephronia diagnosed in a
      prospective study that was conducted among 210 hospitalized children with urinary
      tract infection. In 30 episodes of urinary tract infection, a hypoechogenic or
      hyperechogenic lesion was found. Twenty patients underwent computed tomography,
      and in 16 of them acute lobar nephronia was diagnosed. Evolution to renal abscess
      occurred in 25%. Prolonged intravenous antibiotic treatment was sufficient in all
      cases.

PMID- 8648548
TI  - Choledocholithiasis in a premature neonate.
AB  - Choledocholithiasis in neonates and infants has been reported only rarely.
      Infants with complications of prematurity are more predisposed to development of
      biliary calculi. With the current widespread use of diagnostic ultrasonography,
      more neonates may be found to have gallstones and common bile duct stones. We
      describe a case of choledocholithiasis and cholelithiasis in a premature neonate
      successfully treated by surgical placement of a cholecystotomy tube and
      irrigation of the biliary system.

PMID- 8648549
TI  - Effect of methimazole treatment of maternal thyrotoxicosis on thyroid function in
      breast-feeding infants.
AB  - In 35 infants of lactating mothers with thyrotoxicosis who were receiving 5 to 20
      mg methimazole daily, serum levels of thyroxine, triiodothyronine, thyrotropin
      were within normal ranges 1 month after the start of breast-feeding. Thyroid
      function in breast-feeding infants of six lactating mothers receiving
      methimazole, 20 mg for the first, 10 mg for the second, and 5 mg for an
      additional 4 months, remained normal. These results suggest the safety of
      methimazole therapy in lactating mothers.

PMID- 8648550
TI  - Nasal pyriform aperture stenosis and absence of the anterior pituitary gland:
      report of two cases.
AB  - We describe two female infants with congenital nasal pyriform aperture stenosis
      and severe pituitary insufficiency. The anterior pituitary gland was undetectable
      with magnetic resonance imaging. Consanguinity of parents in both cases suggests
      autosomal recessive inheritance of this disorder. An early fetal developmental
      defect may explain this syndrome, which affects midline craniofacial structures.
      In patients with congenital pyriform aperture stenosis, magnetic resonance
      imaging of the brain and endocrine investigations should be performed for rapid
      diagnosis and treatment of the latter to avoid major neurologic complications.

PMID- 8648551
TI  - Antibiotic-resistant pneumococci.

PMID- 8648552
TI  - Pathophysiology of spontaneous neonatal bilirubinemia associated with glucose-6
      phosphate dehydrogenase deficiency.

PMID- 8648553
TI  - Massive opioid requirements in children with disseminated central nervous system
      disease.

PMID- 8648554
TI  - Macroglossia: more than meets the eye.

PMID- 8648555
TI  - Error prone?

PMID- 8648556
TI  - Thirty years of human pineal research: do we know its clinical relevance?
AB  - A role for melatonin in humans is becoming evident in an increasing number of
      clinical situations. Marked variations in the magnitude of the nocturnal
      melatonin peak are observed throughout the human lifespan. The highest levels
      occur in children and then fall during puberty and further during adulthood. A
      negative correlation between circulating melatonin and sex steroids has been
      observed in a number of instances, and appears to be independent of concomitant
      gonadotrophins. No clear melatonin pattern has been observed in pituitary tumors,
      but in large lesions that involve the hypothalamus, a reduced nocturnal rise has
      been reported. Reported effects of exogenously administered melatonin are
      variable, probably reflecting differences in dose and timing; a slight
      stimulation of prolactin, as well as a partial inhibition of gonadotrophins, has
      been reported, which explains its utility as an oral contraceptive, associated
      with a progestogen. A potential clinical use of melatonin as an oncostatic drug
      still awaits confirmation, although experimental data firmly support this
      possibility. The indole has also been used to hasten entrainment of subjects
      travelling across various time zones, and has been found to be specially useful
      in eastward travel. Finally, changes in the normal melatonin circadian pattern
      have been reported in psychiatric diseases and in sudden infant death syndrome.

PMID- 8648558
TI  - Dithiothreitol treatment permits measurement of melatonin in otherwise unusable
      saliva samples.
AB  - Melatonin research has primarily utilized blood as the source of samples, but
      there is now increasing interest in measuring levels of the hormone found in
      saliva. One impediment to this approach is that several melatonin assays involve
      a column-extraction step that can prove very time-consuming or even impossible
      when salivary samples are excessively viscous. We have treated 67 samples with
      dithiothreitol to enhance their passage through the column. Following this
      treatment, all samples passed freely through the columns. The minimum and maximum
      values measured were 0.7 - 50.0 pg/ml for the untreated controls and 1.0 - 51.9
      pg/ml for the treated samples. The means (+/-SEM) for these groups were 9.5 +/-
      1.6 and 9.9 +/- 1.7, respectively, and were not significantly different from one
      another as assessed by Student's t-test (P = 0.08). In summary, we have found
      that this technique permits us to obtain values on samples which would otherwise
      be unusable and that such treatment does not alter the melatonin values yielded
      by RIA analysis.

PMID- 8648557
TI  - Beta-adrenergic receptor subtypes in human pineal gland.
AB  - The secretion of melatonin by the pineal has been promoted as a direct monitor of
      adrenergic function in depressive illness. However, discrepant findings have been
      reported, possibly reflecting a complex adrenergic regulation of pineal output.
      In order to clarify the anatomical localization and relative density of beta
      adrenergic receptors and their subtypes in human pineal, quantitative
      autoradiographic analysis was conducted of beta-adrenergic receptors in
      postmortem specimens using the high affinity radioligand 125I-pindolol. Dense
      specific binding was found throughout the gland. beta 1 -adrenergic receptors
      were more numerous, but beta 2-receptors were present in an overlapping
      anatomical distribution with beta 1-receptors.

PMID- 8648559
TI  - Exogenous melatonin entrains rhythm and reduces amplitude of endogenous
      melatonin: an in vivo microdialysis study.
AB  - The circadian rhythm of melatonin production was studied using on-line, in vivo
      microdialysis in the rat pineal gland. With this technique it was possible to
      record a pronounced melatonin rhythm with very high time resolution. Three phase
      markers of the rhythm were calculated from the data, indicating increase (IT50),
      decrease (DT50) and amplitude of the rhythm. Comparing these phase markers led to
      several conclusions. Entrainment of the rhythm under constant darkness was
      performed with melatonin administration at different circadian stages [circadian
      time (CT) 8 and CT12] and for different periods of time (2 weeks and 4 weeks).
      Also, entrainment was established by applying 15 min light pulses at CT0.
      Entrainment of IT50 with melatonin partially uncoupled it from DT50. Four weeks
      entrainment in constant darkness (DD) caused a phase-delay in DT50 of 2.2 hr.
      Entrainment of IT50 with light at CT0 for 2 weeks in DD caused a phase-advance in
      DT50 of 1.3 hr. The entrainment with melatonin was restricted to a narrow window
      for melatonin to be applied, since injections at CT8 did not result in
      entrainment. Exogenous melatonin reduced the amplitude of the rhythm of
      endogenous melatonin. This effect was not circadian time dependent, since
      administration at CT8 for 2 weeks and at CT12 for 4 weeks resulted in a highly
      significant decrease. Light did not seem to have an effect on the amplitude. The
      data presented here provide us with new information about the nature of
      entrainment by melatonin. Since the present development of melatonergic agents
      for clinical use focuses on the entrainment capacity, effects of these compounds
      on amplitude of circadian rhythms needs to be addressed. In vivo microdialysis
      seems to be a good technique for that.

PMID- 8648560
TI  - Specific binding of 2-[125I]iodomelatonin by rat spleen crude membranes: day
      night variations and effect of pinealectomy and continuous light exposure.
AB  - Melatonin binding sites were characterized in rat spleen crude membranes. The
      specific binding of 2-[125I]iodomelatonin by spleen crude membranes fulfills all
      the criteria for binding to a receptor site. Thus, binding was dependent on time
      and temperature, stable, specific, and increased under constant light exposure
      and after pinealectomy. In competition studies, the specific binding of 2
      [125I]iodomelatonin to spleen crude membranes was inhibited by increasing
      concentrations of native melatonin. Scatchard analysis showed that the data were
      compatible with the existence of two classes of binding sites: a high affinity
      site with a Kd of 0.53 nM and a binding capacity of 2.52 pM, and a low-affinity
      site with a Kd of 374 nM and binding capacity of 820 pM. Moreover, binding of 2
      [125I]iodomelatonin exhibited day-night variations with the highest binding
      observed late during the light period, and the lowest binding was observed late
      at night. However, binding of 2-[125I]iodomelatonin to membranes remained high
      when animals were kept under light exposure at night. Results support the
      hypothesis of a regulatory role of melatonin on the immune system in which
      melatonin downregulates its own binding site.

PMID- 8648561
TI  - Electron probe X-ray microanalysis of the elemental composition of the pineal
      gland of young adults and aged rats.
AB  - Fractures of deep-frozen and freeze-dried pineal glands were analysed for
      elemental composition by means of X-ray microanalysis with a scanning electron
      microscope. The results from young adults (3 months old) were compared with those
      from aged animals (24 months old); significant increases in S, Ca, Al, Si, and Fe
      were observed in aged animals when compared to young adults. There were no
      significant differences with Na, Mg, Cl, K, Ti, Cr, Mn, Ni, Cu, Zn, whereas a
      decrease of P was observed in aged animals when compared to young adults. Whether
      the changes observed in elemental composition have a direct effect on the
      activity and production of metalloenzymes and the overall physiology of the
      pineal gland are discussed.

PMID- 8648562
TI  - Twenty-four hour urinary excretion of 6-hydroxymelatonin sulfate in Down syndrome
      subjects.
AB  - Because of the overexpression of the enzyme superoxide dismutase, individuals
      with Down syndrome (DS) are believed to suffer from increased oxidative stress as
      a result of the excessive production of oxygen-based free radicals; their
      exposure to higher than normal free radical production may account in part for
      signs of premature aging, early onset of cataracts, and of Alzheimer's disease.
      Free radicals are normally neutralized by free radical scavengers and other
      antioxidants. The pineal hormone melatonin is a potent scavenger of both the
      hydroxyl and peroxyl radicals, both of which are highly toxic, and a stimulator
      of the antioxidative enzyme glutathione peroxidase. Considering this, we deemed
      it important to define the day/night rhythm and levels of melatonin production in
      DS subjects. To do this, we assessed the urinary excretion of the chief melatonin
      metabolite, 6-hydroxymelatonin sulfate, throughout a 24 hr period in DS subjects;
      comparisons were made with the metabolite levels in the urine of non-Down
      siblings and parents of the DS subjects. All 8 non-Down subjects exhibited what
      was classified as normal urinary excretion of 6-hydroxymelatonin sulfate with the
      usual low daytime and high night-time levels of the melatonin metabolite. Of 12
      DS subjects studied, 10 exhibited the normal day/night rhythm in urinary 6
      hydroxymelatonin sulfate levels; 2 subjects were devoid of a rhythm. However,
      when all the data from each group were averaged, there were no noticeable
      differences in the absolute levels or 24 hr variations in urinary 6
      hydroxymelatonin sulfate excretion between DS and non-Down subjects.

PMID- 8648564
TI  - Proceedings of the scientific meetings of the Physiological Society. University
      College Cork, 19-22 September 1995. Abstracts.

PMID- 8648563
TI  - Overnight human plasma melatonin, cortisol, prolactin, TSH, under conditions of
      normal sleep, sleep deprivation, and sleep recovery.
AB  - Early investigations of the effect of sleep deprivation on plasma melatonin
      reported no major changes. Recently, 36 hrs of sleep deprivation was reported to
      elevate melatonin levels on the post-sleep deprivation night. Given these
      contradictions melatonin, cortisol, prolactin, and thyroid stimulating hormone
      before, during, and, after sleep deprivation were examined in nine healthy young
      males following one night of sleep deprivation. Hormone levels at hourly
      intervals, for each night, were statistically analyzed by a repeated measures,
      two-way factorial ANOVA. ANOVA was also performed for measures of area under the
      curve (AUC). No significant differences were observed for melatonin levels.
      Cortisol was significantly higher on the sleep deprivation night presumably
      reflecting the aroused state accompanying being awake; however, there were
      several time points on the control night when it was elevated also. Prolactin was
      higher on the post-sleep deprivation and control nights but did not rise on the
      deprivation night, indicating a useful nonpolysomnographic index for
      discriminating overnight sleep and awake states. TSH levels showed a similar rise
      during the control and sleep deprivation nights, but remained flat on the post
      sleep deprivation night. It appears that the pineal is insulated against feedback
      from changes to the level of arousal accompanying sleep and wakefulness. In
      comparison, cortisol, prolactin, and TSH levels vary with these states and are,
      therefore, useful indices of arousal and sleep-wake.

PMID- 8648566
TI  - Placement of a custom implant provisional restoration at the second-stage surgery
      for improved gingival management: a clinical report.

PMID- 8648565
TI  - Ion Transport in Health and Disease. Symposium proceedings. University College
      Cork, 19-20 September 1995.

PMID- 8648567
TI  - Procedure to predictably seat multiple, hexed abutments onto endosseous implants:
      a clinical report.
AB  - The use of implants to restore the dentition of partially edentulous patients has
      increased over the past several years. Optimal esthetic results depend on
      satisfactory implant placement. Occasionally, implants are placed in less than
      optimal positions, which may require modification in the prosthesis design and
      increase the technical difficulty. In these instances, preangled or customized
      abutments can be used. If more than one of these abutments has to be used,
      accurate orientation of the hexed components to the implants and each other may
      be a problem. This clinical report illustrated a simple, inexpensive procedure to
      transfer the orientation of two or more hexed abutments from a master cast to the
      mouth. This procedure reduced the time needed to orient the hexed abutments
      correctly in laboratory and clinical situations. It may also reduce the chances
      of the patient aspirating or swallowing abutments or screws.

PMID- 8648568
TI  - Strategies for rehabilitation in the treatment of dentinogenesis imperfecta in a
      child: a clinical report.

PMID- 8648569
TI  - Tissue management with a new gingival retraction material: a preliminary clinical
      report.
AB  - A new retraction material (Merocel) was evaluated in a clinical trial with 10
      selected abutments. Each selected abutment required an anterior single unit. A
      comparison of probing attachment level, bleeding on probing, and plaque index
      demonstrated highly successful periodontal maintenance. The main advantage of
      Merocel retraction material is that it is capable of innocuously expanding the
      gingival sulcus. This preliminary study suggested that a Merocel strip was a
      predictable retraction material in conjunction with impression procedures. The
      material was also evaluated by scanning electron microscopy and demonstrated
      promise in this investigation. The Merocel strip shows potential for other
      applications, but limitations of this material indicated that evolution of
      atraumatic gingival retraction should continue.

PMID- 8648570
TI  - Risk of debonding in three-unit resin-bonded fixed partial dentures.
AB  - Resin-bonded fixed partial dentures are considered practical and conservative but
      have not always enjoyed longitudinal success. The long-term survival of 1637
      three-unit resin-bonded fixed partial dentures was analyzed. A multistate
      analysis that included parameters such as debonding, rebonding, or renewal of the
      restoration was used. Five years after insertion 66.1% (+/- 3.7%) of the
      originally inserted prostheses remained in place. If additional rebonding was
      computed, the probability of survival was 82.0% (+/- 3.0%). Reconstruction of the
      metal frame after one or more dislodgements raised the success rate to 87.1% (+/-
      2.6%). Rebonded resin-bonded fixed partial dentures developed a greater risk of
      debonding. The risk of failure for refabricated fixed partial dentures was
      similar to that of the originally inserted resin-bonded fixed partial dentures.
      There were no signs of greater caries incidence after multiple recementation
      procedures.

PMID- 8648571
TI  - Shear bond strengths of three resin cements used with three adhesive primers for
      metal.
AB  - This study compared the durability and shear bond strengths of combinations of
      three adhesive primers and three resin cements bonded to silver-palladium-copper
      gold (Ag-Pd-Cu-Au) and cobalt-chromium (Co-Cr) alloys. The adhesive luting
      cements Imperva Dual, Panavia 21, and Super-Bond C&B and the adhesive primers
      Metal Primer material, V-Primer material, and Cesead Opaque Primer material were
      used. The application of Metal Primer material was effective in improving the
      shear bond strengths between each of the three resin cements and Ag-Pd-Cu-Au
      alloy compared with nonprimed specimens. Co-Cr alloy primed with Cesead Opaque
      Primer, followed by cementation with Imperva Dual or Super-Bond C&B luting
      cements yielded the strongest shear bond strengths after 50,000 thermocycles, and
      Panavia 21 cement did not reveal any significant differences in bond strengths
      between nonprimed specimens and those primed with Cesead Opaque Primer at all
      thermocycles.

PMID- 8648572
TI  - Dimensional stability of occlusal splints.
AB  - Five fabrication techniques and two storage methods were used to construct and
      store specimens to investigate the dimensional stability of acrylic resin
      occlusal splints. A research model was developed to more closely approximate the
      tooth coverage limits of occlusal splints. Ten specimens were fabricated on
      individual stone casts for each of the five techniques. Four die pins were
      transferred to each specimen, and the distances between the inside diameters of
      the pins were measured over a 2-week period. After construction, initial
      measurement, and removal from the cast, each acrylic resin specimen was stored in
      either a wet or a dry environment. Measurements between pins were made and
      recorded at five time intervals. The sprinkle-on techniques resulted in less
      dimensional change than the dough application, the vacuum-adapted resin sheet and
      dough application, and the heat-cured denture processing techniques. Acrylic
      resin specimens stored in a wet environment showed less distortion 2 weeks after
      fabrication.

PMID- 8648573
TI  - Effects of improvements of poorly fitting dentures and new dentures on
      masticatory performance.
AB  - The effect of four modifications to improve the fit and maxillomandibular
      relationships of poorly fitting dentures and the insertion of new dentures on
      masticatory performance was assessed in 21 denture wearers. A 2-week adaptation
      period was allowed for each of the four modifications and 3 weeks and 12 weeks of
      adaptation for new dentures. The preferred side masticatory performances were not
      appreciably affected by either the modifications to improve the fit of the
      original dentures or the new dentures. In most instances there was a slight
      decline in performance. Three denture modifications caused significant declines
      in the carrot-swallowing threshold performances and the new dentures in the
      peanut-swallowing threshold performance. In other words, the denture wearers had
      a greater percentage of coarse particles in their bolus ready for ingestion when
      they chewed with altered or new dentures compared with original dentures.
      However, they chewed faster and applied fewer chewing strokes with their modified
      and new dentures. A steady but gradual improvement in the mean performance score
      with carrots was noted with time after the insertion of new dentures. Dentists
      and patients need to understand that adaptation to new or modified old dentures
      may be a long, drawn-out process for some patients.

PMID- 8648574
TI  - New design for an artificial saliva reservoir for the mandibular complete
      denture.
AB  - Wearing dentures can be an extremely uncomfortable experience for people with
      xerostomia. Despite several ingenious designs, the problem of combining saliva
      substitutes with a simple, effective, and readily cleanable dispensing system has
      not been satisfactorily resolved. The previous difficulties were analyzed and
      methods of overcoming them were devised. A new design for a reservoir denture is
      presented that maximizes capacity and is easily maintained by the wearer.

PMID- 8648575
TI  - Biometric design of complete dentures related to residual ridge resorption.
AB  - The aim of this study was to determine whether the location of the incisive
      papilla, the extent of the alveolar bone remaining on the facial side of the
      palatal-gingival margin in the canine region, and the height of the palatal vault
      in the molar region are associated with factors that may affect the volume of the
      residual ridges in an edentulous maxillae. Results suggest that duration of the
      edentulousness and skeletal mineral status are important factors in the
      resorption of the residual ridges in the maxillae. The location of the incisive
      papilla and the thickness of the ridge on the facial side of the palatal-gingival
      margin are associated with these two factors.

PMID- 8648576
TI  - Analysis of load transfer and stress distribution by an implant-supported fixed
      partial denture.
AB  - This study simultaneously examined the load transfer and stress distribution by
      an implant-supported fixed partial denture. A mandibular implant framework with
      implants connected to the abutments was embedded in a three-dimensional
      photoelastic model of a mandible. Strain gauges were attached on the superior
      surface of the framework, and a vertical load of 7.5 kg was applied to seven
      points on the framework. The measurements derived from this simulation revealed
      that (1) there was a direct proportion between the stress distribution in the
      metal framework and stresses created in the supporting structure around the
      implants; (2) the mode of load transfer and stress distribution was directly
      proportional to the distance of the components from the loading point; and (3)
      when the cantilever was loaded, the major part of the stress was distributed
      within the cantilever in the connection to the distal abutment. In this
      simulation, stress was distributed over the two, or maximum three, closest
      implants with the distal implant the most stressed.

PMID- 8648577
TI  - Technique for fabricating a mirror-image prosthetic ear.
AB  - A simple technique for producing a mirror image of a cast for sculpting an
      auricular prosthesis is described. A transparency copy of the cast assist the
      operator in sculpting the contours of the facial prosthesis.

PMID- 8648578
TI  - The relative value of provider work for maxillofacial prosthetic services.
AB  - The results of a national survey of members of the American Academy of
      Maxillofacial Prosthetics who estimated the relative value of provider work for
      nine existing and two proposed coded maxillofacial prosthetic services is
      reported. The work estimates are a necessary component of a larger effort by the
      Health Care Financing Administration to establish a resource-based relative value
      scale for reimbursement for all Medicare services. Analysis of the survey data
      reveals agreement regarding the relative value of work for maxillofacial services
      compared with other established medical procedures and that the median values for
      each service are acceptable initial estimates.

PMID- 8648579
TI  - Vertical distortion in distal extension ridges and palatal area of casts made by
      different techniques.
AB  - A coordinate measurement machine with laser probe was used to measure the
      vertical distortion of the casts produced by use of three types of impression
      materials (irreversible hydrocolloid, condensation silicone, and addition
      silicone) and two types of trays (stock and custom trays). Results indicated that
      all impression groups showed positive vertical distortion (ranging from 0.00566
      to 0.30299 mm) at the edentulous ridges and palatal area. The amount of the
      vertical distortion was greatest at the palatal area and was followed by the high
      edentulous ridge and the low edentulous ridge. Addition silicone, with either
      custom tray or stock tray, was the most accurate impression material.
      Condensation silicone was more accurate than irreversible hydrocolloid in custom
      tray impression. However, in stock tray impression the irreversible hydrocolloid
      was more accurate than the condensation silicone. The results suggest that, with
      careful manipulation, irreversible hydrocolloid with stock tray impression may
      provide a satisfactory cast for fabricating the framework of a distal extension
      removable partial denture.

PMID- 8648580
TI  - Effect of ultrasonic instrumentation on bond strength of three dental cements
      bonded to nickel-chromium alloy.
AB  - This study examined the effect of ultrasonic instrumentation on the bond strength
      of three types of luting material joined to a nickel-chromium alloy. Disk metal
      specimens were bonded together with zinc phosphate, glass ionomer, and adhesive
      resin luting agents. The bonded specimens were immersed in water, then vibrated
      with an ultrasonic unit for 0 to 5 minutes. The shear bond strength in the 0 or
      nonvibrated group was 50.1 MPa for adhesive resin, 18.4 MPa for glass ionomer,
      and 4.7 MPa for zinc phosphate cement. Vibration for a period of 5 minutes
      significantly diminished the bond strength of adhesive resin and glass ionomer
      materials, whereas the bond strength of zinc phosphate cement was affected after
      only 1 minute.

PMID- 8648581
TI  - Measuring fit at the implant prosthodontic interface.
AB  - Four centers in the United States and Sweden have been working for 2 years to
      develop systems and methods for measuring fit at the prosthodontic interface. Two
      systems are based on stylus contact techniques, one system uses a laser as its
      reader source, and one system is photogrammetric. All the systems are capable of
      providing data as three-dimensional x, y, and z axes coordinate values that can
      be transformed into linear and angular data that characterize the bearing
      surfaces of abutments or abutment replicas and their mating components in the
      prosthesis framework. The centroid, a single point computed from the collected
      data, was the measurement unit, derived for these bearing surfaces, that was used
      to compare the systems. All four methods can most likely detect misfits that are
      relevant in the clinical setting; however, only one system can be used
      intraorally. When any measurement system is assessed, the data should always be
      examined for repeatability to establish the reliability of the system. This
      investigation made comparisons among the measurement methods used at the four
      centers. It was apparent from this study that comparisons of data from
      measurement systems should be rounded to the nearest 10 microns. The SDs
      determined in the comparisons were larger than 5 microns and therefore misfits
      should be calculated in terms smaller than 10 microns. This final point is
      important to the clinician who relies on research reports about precision of fit
      when selecting treatment approaches in caring for the implant prosthodontic needs
      of their patients.

PMID- 8648582
TI  - Properties of a custom-made hinge clasp compared with a conventional
      circumferential clasp.
AB  - The use of the hinge clasp in removable partial denture design, together with the
      design of a custom-made hinge unit, is discussed in this article. Tests of the
      retention provided by these custom-made hinge clasps were made, together with
      conventional clasps, and the results were compared. Six custom-made hinge clasps
      were constructed and attached to blocks of acrylic resin. The forces required to
      open these clasps and the effect of wear on the clasps were measured. Six
      conventional cast clasping units were also constructed and tested. The results
      indicated that the average force required to open the hinge clasps was 8.13 N (SD
      1.99). After a period of simulated wear, the mean value of force required was
      7.70 N (SD 2.33) and there was no statistically significant deterioration caused
      by wear. The mean forces required to withdraw these clasps vertically from a
      tooth were 30.25 N (SD 6.51) for the conventional clasps and 49.67 N (SD 18.69)
      for the hinge clasps. It was also found that the hinge clasps had to be withdrawn
      further from their seated position than the conventional clasps before retention
      was finally lost. However, neither of these differences were statistically
      significant.

PMID- 8648583
TI  - Duration of induction melting of cobalt-chromium alloy and its effect on
      resistance to deflection fatigue of cast denture clasps.
AB  - This study determined the effect of various durations of induction melting of a
      cobalt-chromium alloy on resistance to deflection fatigue. Commercial cobalt
      chromium alloy was melted by high-frequency induction for various lengths of time
      before it was cast into the shape of a denture clasp. The test method used was a
      constant-deflection fatigue test. The fatigue fracture surface of the clasp was
      examined with a scanning electron microscope, and the surface hardness (Vickers
      hardness) of the clasps was measured. In clasps with greater fatigue resistance
      scanning electron microscope photomicrographs revealed a coarse grain structure.
      The surface hardness of the alloy was least in the group with the lowest fatigue
      resistance and was higher in groups with greater fatigue resistance. This study
      suggests that, although some porosities are formed in the middle of the clasps
      after the alloy is overheated, the fatigue resistance of cobalt-chromium alloy
      denture clasps can be increased by lengthening the induction melting period of
      the alloy.

PMID- 8648584
TI  - Improved method to construct an anterior deprogramming device.

PMID- 8648585
TI  - Maintaining immediate posterior disclusion on an occlusal splint for patient with
      severe bruxism habit.

PMID- 8648586
TI  - Improved resistance and retention of a short coronal tooth preparation for a
      complete crown.

PMID- 8648587
TI  - Transfer of gingival contours to a master cast.
AB  - This procedure provides a means for transferring intraorally formed gingival
      sulcular contours surrounding a single-tooth implant-supported provisional
      restoration to a master cast. When this procedure is used, the final fixed
      prosthesis may be made in the laboratory with gingival contours identical to
      those developed on the provisional restoration.

PMID- 8648588
TI  - Simplified procedure for making fixed partial dentures with a functionally
      generated path.

PMID- 8648589
TI  - Overdentures with roots or implants for elderly patients: a comparison.

PMID- 8648590
TI  - Overdentures with roots or implants for elderly patients: a comparison.

PMID- 8648591
TI  - Comparison of muscle activity between conventional and neuromuscular splints.

PMID- 8648592
TI  - The mandibular subperiosteal implant denture: a prospective survival study.

PMID- 8648593
TI  - The effects of vocal variation on listener recall.
AB  - The effects of variations in speaker rate and pitch on listener recall were
      studied. One hundred and twenty participants listened to an audiotape of one of
      two individuals speaking in one of four different styles--low variation in both
      rate and pitch, variation in rate but not in pitch, variation in pitch but not in
      rate, and variation in both rate and pitch. After hearing the audiotape,
      listeners were tested on the information in the presentation; they also completed
      questionnaires rating the speaker's benevolence and competence. Results indicated
      that the combined effect of pitch and rate variety significantly increased
      listener recall over no variety or pitch variety increased attributions of
      speaker competence over no variety or rate variety or rate variety alone.
      Additionally, pitch variety and combined pitch and rate variety significantly
      increased attributions of speaker competence over no variety or rate variety
      alone, but significantly decreased attributions of speaker benevolence.

PMID- 8648594
TI  - [JFR '95 book of abstracts].

PMID- 8648595
TI  - Conformationally restricted TRH analogs: a probe for the pyroglutamate region.

PMID- 8648596
TI  - Synthesis and biological evaluation of naphthyldesferrithiocin iron chelators.
AB  - The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'
      hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth
      1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2
      thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline
      (4S)-carboxylic acid are described. While the bile duct-cannulated rat model
      clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally
      active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl
      compounds are not, in the primate model none of the benz-fused
      desazadesferrithiocin analogues are active. Oral versus subcutaneous
      administration of these ligands strongly suggests that metabolism is a key issue
      in their iron-clearing properties and that these benz-fused desferrithiocins are
      not good candidates for orally active iron-clearing drugs.

PMID- 8648597
TI  - A 5'-(trifluoromethyl)anthracycline glycoside: synthesis of antitumor-active 7-O
      (2,6-dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyranosyl) adriamycinone.
AB  - 7-O-(2,6-Dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyranosyl)adriam ycinone (3),
      whose substituent at C-5' is a lipophilic trifluoromethyl group, has been
      prepared by coupling of 3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-alpha-L-lyxo
      hexopyran osyl bromide (20) with 14-O-(tert-butyldimethylsilyl)adriamycinone
      under the Koenigs-Knorr conditions. The key step in this synthesis was the C
      trifluoromethylation of 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-aldehydo-L-erythro
      pentose (10), derived from D-lyxose in 10 steps, with
      (trifluoromethyl)trimethylsilane in the presence of tetrabutylammonium fluoride,
      whereupon 1,1,1-trifluoro-L-arabino-hexitol (11) was obtained along with its 2
      epimer. The synthetic product 3 showed remarkable antitumor activity in vivo in a
      low dose range compared to the analogs including doxorubicin. The fact may be
      ascribed to the presence of a trifluoromethyl group at C-5', suggesting the
      importance of the group in view of biological activity.

PMID- 8648598
TI  - Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series
      reveal conformational changes relevant to the design of potent non-nucleoside
      inhibitors.
AB  - Crystal structures of HIV-1 reverse transcriptase (RT) complexed with a range of
      chemically diverse non-nucleoside inhibitors (NNIs) have shown a single pocket in
      which the inhibitors bind and details of the inhibitor-protein interactions. To
      delineate the structural requirements for an effective inhibitor, we have
      determined the structures of three closely related NNIs which vary widely in
      their potencies. Crystal structures of HIV-1 RT complexed with two very potent
      inhibitors, MKC-442 and TNK-651, at 2.55 angstroms resolution complement our
      previous analysis of the complex with the less effective inhibitor, HEPT. These
      structures reveal conformational changes which correlate with changes in potency.
      We suggest that a major determinant of increased potency in the analogues of HEPT
      is an improved interaction between residue Tyr181 in the protein and the 6-benzyl
      ring of the inhibitors which stabilizes the structure of the complex. This arises
      through a conformational switching of the protein structure triggered by the
      steric bulk of the 5-substituent of the inhibitor pyrimidine ring.

PMID- 8648599
TI  - Versatile approach to encoding combinatorial organic syntheses using chemically
      robust secondary amine tags.
AB  - Encoded combinatorial organic synthesis has recently emerged as a powerful tool
      for the discovery of biologically active compounds from complex chemical
      libraries. This report describes a new encoding methodology that uses chemically
      robust secondary amines as tags. These amines are incorporated into an N
      [(dialkylcarbamoyl)methyl]glycine-coding oligomer through simple chemistry that
      is compatible with a wide range of polymer-supported transformations useful in
      combinatorial synthesis. In the decoding process acidic hydrolysis of the tagging
      polymer regenerates the secondary amines, which after dansylation are resolved
      and detected at sub-picomole levels by reversed-phase HPLC. The versatility of
      this strategy is demonstrated here by encoded syntheses of members of several
      representative heterocyclic compound classes, including beta-lactams, 4
      thiazolidinones, and pyrrolidines.

PMID- 8648600
TI  - 6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]
      isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor
      activity, and quantitative structure-activity relationships.
AB  - New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with
      substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic
      displacement was a key reaction in the syntheses. Ten of the new compounds were
      more potent than the unsubstituted compound, azonafide, in a panel of tumor cells
      including human melanoma and ovarian cancer and murine sensitive and MDR L1210
      leukemia. They also were less cardiotoxic in cell culture. Four of these
      compounds were not cross-resistant with the MDR leukemia, and one of them, 6
      ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia
      cells. These compounds also had good potency against human breast, colon, and
      lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines.
      Advantages of the new analogues over azonafide were less in vivo, but 6
      ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16
      melanoma in mice. Although correlations of antitumor potency in cells and
      physicochemical properties of substituents were not found, there were
      statistically significant correlations of DNA melt transition temperature (delta
      Tm) with potency in solid tumor cells and sensitive and MDR resistant L1210
      leukemia cells for 6-substituted azonafides and with solid tumors for 7
      substituted azonafides.

PMID- 8648601
TI  - Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for
      central nervous system delivery. 3. 6-Amino prodrugs of 2'-beta-fluoro-2',3'
      dideoxyinosine.
AB  - A series of 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-beta-D-threo
      pentofuranosyl) purines (F-ddN) has been synthesized and characterized with the
      objective of finding compounds which might be superior to existing drugs for the
      treatment of HIV in the central nervous system. These compounds are intended to
      be more lipophilic than the currently approved anti-HIV drugs for better blood
      brain barrier penetration. Subsequent adenosine deaminase (ADA)-catalyzed
      hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV
      agent, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)hypoxanthine (F-ddI).
      The new compounds, synthesized from the corresponding 6-chloro analog, include F
      ddN which contain methylamino, ethylamino, dimethylamino, hydroxylamino,
      methoxyamino, benzyloxyamino, hydrazino, and nitro substituents in the 6
      position. The 6-nitro analog was isolated as an unexpected product during the
      preparation of the 6-chloro derivative. Among the analogs with anti-HIV activity,
      the ethylamino and dimethylamino compounds are ca. 100 times more lipophilic than
      ddI or F-ddI. As expected, 2'-fluoro substitution protects the compounds from
      acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs
      underwent any nonenzymatic hydrolysis at pH 1.0 or 7.4. This reaction, however,
      results in hydrolysis of the group in the 6-position rather than glycosylic bond
      cleavage. ADA catalyzes the hydrolysis of the 6-substituents at rates which vary
      from slightly slower (NO2, 1.7x) to much slower (NHEt, 5000x) than F-ddA. The 6
      dimethylamino analog is the only compound which possesses anti-HIV activity (ED50
      18 microM) without ADA hydrolysis. With the exception of the two inactive
      alkoxyamino compounds, the other prodrugs exhibited cellular protection in the
      HIV-1/PHA-PBM system with IC50 potencies of 7-40 microM.

PMID- 8648602
TI  - Polyanion inhibitors of human immunodeficiency virus and other viruses. Part 2.
      Polymerized anionic surfactants derived from amino acids and dipeptides.
AB  - A series of new polyanions was synthesized via gamma-polymerization, in aqueous
      micellar solution, of omega-unsaturated anionic surfactants whose polar head was
      derived from amino acids or dipeptides. The obtained polyanions were evaluated
      for their activity against human immunodeficiency virus (HIV-1, HIV-2) and
      various other RNA and DNA viruses. All the test compounds proved active against
      HIV-1 and HIV-2, their 50% inhibitory concentration (IC50) being in the range of
      0.04-7.5 micrograms/mL, while they were not toxic to the host cells (CEM-4 or MT
      4) at concentrations up to 100 micrograms/mL or higher. The HIV-inhibitory effect
      increased with the hydrophilic character of the amino acid moiety. The compounds
      were found to interact with both the viral envelope glycoprotein gp120 and the
      cellular CD4 receptor, thus blocking virus-cell binding and virus-induced
      syncytium formation. These polyanions also proved active against human
      cytomegalovirus at about the same IC50 as for HIV. In addition, they were also
      active, albeit at somewhat higher IC50 values (0.8-20 micrograms/mL), against
      other enveloped viruses such as respiratory syncytial virus and arenaviruses
      (Junin and Tacaribe). At yet higher IC50 values ( > or = 20 micrograms/mL), some
      of the compounds showed activity against influenza A virus. No activity was
      observed with any of the compounds against vesicular stomatitis virus, Sindbis
      virus, Semliki forest virus, influenza B, parainfluenza type 3, and the
      nonenveloped viruses Coxsackie type B4, polio type 1, and reovirus type 1.

PMID- 8648603
TI  - Synthesis and cyclic GMP phosphodiesterase inhibitory activity of a series of 6
      phenylpyrazolo[3,4-d]pyrimidones.
AB  - A series of 6-phenylpyrazolo[3,4-d]pyrimidones is described which are specific
      inhibitors of cGMP specific (type V) phosphodiesterase. Enzymatic and cellular
      activity as well as in vivo oral antihypertensive activity are evaluated. A n
      propoxy group at the 2-position of the phenyl ring is necessary for activity. A
      series of products substituted at the 5-position in addition to the 2-n-propoxy
      was prepared and evaluated. This position can accommodate many unrelated groups.
      Amino derivatives were very potent but lacked metabolic stability. Substitution
      by carbon-linked small heterocycles provided both high levels of activity and
      stability. Cellular activity very often correlated with in vivo activity. Among
      the compounds, 1,3-dimethyl-6(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydr
      opyrazolo[3,4-d]pyrimidin-4-one (38) and 1-ethyl-3-methyl-6-(2-propoxy-5-(4
      methylthiazol-2-yl)phenyl -1,5-dihy dropyrazolo[3,4-d]pyrimidin-4-one (59)
      displayed outstanding in vivo activities at 5 mg/kg/os and good metabolic
      stabilities.

PMID- 8648604
TI  - All-atom models for the non-nucleoside binding site of HIV-1 reverse
      transcriptase complexed with inhibitors: a 3D QSAR approach.
AB  - Several molecular modeling techniques were used to generate an all-atom molecular
      model of a receptor binding site starting only from Ca atom coordinates. The
      model consists of 48 noncontiguous residues of the non-nucleoside binding site of
      HIV-1 reverse transcriptase and was generated using a congeneric series of
      nevirapine analogs as structural probes. On the basis of the receptor-ligand atom
      contacts, the program HINT was used to develop a 3D quantitative structure
      activity relationship that predicted the rank order of binding affinities for the
      series of inhibitors. Electronic profiles of the ligands in their docked
      conformations were characterized using electrostatic potential maps and frontier
      orbital calculations. These results led to the development of a 3D
      stereoelectronic pharmacophore which was used to construct 3D queries for
      database searches. A search of the National Cancer Institute's open database
      identified a lead compound that exhibited moderate antiviral activity.

PMID- 8648605
TI  - CONCERTS: dynamic connection of fragments as an approach to de novo ligand
      design.
AB  - We have implemented and tested a new approach to de novo ligand design, CONCERTS
      (creation of novel compounds by evaluation of residues at target sites). In this
      method, each member of a user-defined set of fragments is allowed to move
      independently about a target active site during a molecular dynamics simulation.
      This allows the fragments to sample various low-energy orientations. When the
      geometry between proximal fragments is appropriate, bonds can be formed between
      the fragments. In this fashion, larger molecules can be built. The bonding
      arrangement can subsequently be changed-breaking bonds between chosen fragment
      pairs and forming them between other pairs-if the overall process creates lower
      energy molecules. We have tested this method with various mixes of fragments
      against the active sites of the FK506 binding protein (FKBP-12) and HIV-1
      aspartyl protease. In several cases, CONCERTS suggests ligands which are in
      surprisingly good agreement with known inhibitors of these proteins.

PMID- 8648606
TI  - Use of a dipeptide chemical library in the development of non-peptide tachykinin
      NK3 receptor selective antagonists.
AB  - The use of a dipeptide library as the source of a micromolar chemical lead
      compound for the human tachykinin NK3 receptor is described. The screening of a
      dipeptide library through a cloned human NK3 receptor binding assay resulted in
      the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been
      developed, following a 'peptoid' design strategy, into a series of high-affinity
      NK3 receptor selective antagonists. The structure-activity relationship of the C
      terminal portion of this dipeptide lead was first explored and led to the
      identification of the urea derivative Boc(S)Phe(R)alphaMePheNH(CH2)7NHCONH2 (41,
      PD157672). This modified dipeptide has a Ke of 7 nM in blocking senktide-induced
      increases in intracellular calcium levels in human NK3 receptors stably expressed
      in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the
      alphaMePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2
      (2,3-difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)ca r bamoyl]ethyl]carbamic acid
      2-methyl-1-phenylpropyl ester (60, PD161182), a non-peptide NK3 receptor
      selective antagonist. Compound 60 blocks the senktide-evoked increases in
      intracellular calcium levels in cloned human NK3 receptors stably expressed in
      CHO cells with Ke of 0.9 nM.

PMID- 8648607
TI  - Augmentation of human and rat lenticular glutathione in vitro by prodrugs of
      gamma-L-glutamyl-L-cysteine.
AB  - A marked age-related decrease in glutathione (GSH) levels as well as depression
      of gamma-glutamylcysteine synthetase activity are factors that are believed to
      render the aged lens more susceptible to oxidative stress and, therefore, to
      cataractogenesis. Providing gamma-L-glutamyl-L-cysteine, the dipeptide precursor
      of GSH, would effectively bypass the compromised first step in its biosynthesis
      and should protect the lens from GSH depletion. Accordingly, some bioreversible
      sulfhydryl-, amino-, and C-terminal carboxyl-protected prodrug forms of this
      dipeptide were prepared. Sulfhydryl protection was in the form of an acetyl
      thioester, while the carboxyl group was protected as the ethyl ester. These
      prodrugs were evaluated for their GSH-enhancing activity in cultured human and
      rat lenses in vitro using an assay that measured the incorporation of
      [14C]glycine into lens GSH. Ethyl S-acetyl-gamma-L-glutamyl-L-cysteinate (2)
      raised GSH levels in human lenses by 25% and in rat lenses by >150%. These data
      suggest that 2 may have potential as an anticataract agent since ethyl gamma-L
      glutamyl-L-cysteinate (1a), the des-S-acetyl analog of 2, had been shown (by
      others) to protect against experimental rodent cataracts. GSH augmentation by 1a
      was 2% in human lenses and 25% in rat lenses, considerably less than that shown
      by 2.

PMID- 8648608
TI  - Synthesis and pharmacology of highly selective carboxy and phosphono isoxazole
      amino acid AMPA receptor antagonists.
AB  - (RS)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 5) and the
      selective AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4
      isoxazolyl]propionic acid (AMOA, 7) have been used as leads for the design and
      synthesis of a number of potential AMPA receptor antagonists. Two parallel series
      of AMOA analogs were synthesized, containing either a distal carboxylic acid
      (compounds 8b-g and 11b) or a phosphonic acid (compounds 9a-g, 10c, and 11c).
      Pharmacological characterization of the synthesized compounds was carried out
      using a series of receptor binding assays and by in vitro electrophysiological
      experiments using the rat cortical slice model. The two analogs with a tert-butyl
      substituent, (RS)-2-amino-3-[5-tert-butyl-3-(carboxymethoxy)-4-isoxazolyl]pr opi
      onic acid (ATOA, 8b) and the corresponding phosphonic acid analog ATPO (9b), were
      the most potent and selective AMPA antagonists within each series. ATOA and ATPO
      showed IC50 values of 150 and 28 microM, respectively, toward AMPA-induced
      depolarizations in the cortical slice model compared to IC50 = 320 microM for the
      parent compound, AMOA. These two new competitive AMPA antagonists were
      significantly more selective than AMOA, showing no antagonism (up to 1 mM) toward
      NMDA-induced responses, whereas AMOA (at 1mM) showed weak (19%) inhibition toward
      NMDA-induced responses. The structure-activity relationships for the two series
      of compounds revealed considerable differences with respect to the substituents
      effects, and the phosphonic acid analogs generally exhibited significantly higher
      potencies compared to the carboxylic acid analogs.

PMID- 8648609
TI  - Design, synthesis, and biochemical evaluation of N-substituted maleimides as
      inhibitors of prostaglandin endoperoxide synthases.
AB  - N-(Carboxyalkyl)maleimides are rapid as well as time-dependent inhibitors of
      prostaglandin endoperoxide synthase (PGHS). The corresponding N-alkylmaleimides
      were only time-dependent inactivators of PGHS, suggesting that the carboxylate is
      critical for rapid inhibition. Several N-substituted maleimide analogs containing
      structural features similar to those of the nonsteroidal anti-inflammatory drug
      aspirin were synthesized and evaluated as inhibitors of PGHS. Most of the aspirin
      like maleimides inactivated the cyclooxygenase activity of purified ovine PGHS-1
      in a time- and concentration-dependent manner similar to that of aspirin. The
      peroxidase activity of PGHS was also inactivated by the maleimide analogs. The
      cyclooxygenase activity of the inducible isozyme, i.e., PGHS-2, was also
      inhibited by these compounds. The corresponding succinimide analog of N-5
      maleimido-2-acetoxy-1-benzoic acid did not inhibit either enzyme activity,
      suggesting that inactivation was due to covalent modification of the protein. The
      mechanism of inhibition of PGHS-1 by N-(carboxyheptyl)maleimide was investigated.
      Incubation of apoPGHS-1 with 2 equiv of N-(carboxyheptyl)[3,4-14C]maleimide led
      to the incorporation of radioactivity in the protein, but no adduct was detected
      by reversed-phase HPLC, suggesting that it was unstable to the chromatographic
      conditions. Furthermore, hematin-reconstituted PGHS-1, which was rapidly
      inhibited by N-(carboxyheptyl)maleimide, displayed spontaneous regeneration of
      about 50% of the cyclooxygenase and peroxidase activities, suggesting that the
      adduct responsible for the inhibition breaks down to regenerate active enzyme.
      ApoPGHS-1, inhibited by N-(carboxyheptyl)maleimide, did not display regeneration
      of enzyme activity, but addition of hematin to the inhibited apoenzyme led to
      spontaneous recovery of about 50% of cyclooxygenase activity. These results
      suggest that addition of heme leads to a conformational change in the protein
      which increases the susceptibility of the adduct toward hydrolytic cleavage.
      ApoPGHS-1, pretreated with N-(carboxyheptyl)maleimide, was resistant to trypsin
      cleavage, suggesting that the carboxylate functionality of the maleimide binds in
      the cyclooxygenase channel. A model for the interaction of N
      (carboxyheptyl)maleimide in the cyclooxygenase active site is proposed.

PMID- 8648610
TI  - Inhibitors of acyl CoA:cholesterol acyltransferase.
AB  - Conformational restriction of previously disclosed acyclic
      (diphenylethyl)diphenylacetamides led to the discovery of several potent
      inhibitors of acyl CoA:cholesterol acyltransferase (ACAT). cis-[2-(4
      Hydroxyphenyl)-1-indanyl]diphenylacetamide (4a) was the most potent ACAT
      inhibitor identified (IC50 = 0.04 microM in an in vitro rat hepatic microsomal
      ACAT assay, ED50 = 0.72 mg/kg/day in cholesterol-fed hamster.

PMID- 8648611
TI  - 6-Substituted and 5,6-disubstituted derivatives of uridine: stereoselective
      synthesis, interaction with uridine phosphorylase, and in vitro antitumor
      activity.
AB  - Stereoselective procedures are described for the synthesis of 6-alkyluridines by
      Lewis acid-catalyzed condensation of (a) trimethylsilylated 6-alkyl-4
      alkylthiouracils with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (ABR)
      and (b) trimethylsilylated 6-alkyl-3-benzyluracils with ABR. The 4-methylthio
      group was subsequently removed with the use of 1 N trifluoroacetic acid and the 3
      benzyl group by a new modified procedure with the use of the complex BBr3-THF.
      Furthermore, 6-(hydroxymethyl)uridine (39) and 5-fluoro-6-(hydroxymethyl)uridine
      (40) were obtained by sequential oxidation with SeO2 and reduction with
      tetrabutylammonium borohydride of the 6-methyl group of 6-methyluridine (5) and 5
      fluoro-6-methyluridine (35), and their corresponding 6-fluoromethyl congeners 41
      and 42 were obtained by DAST treatment of 39 and 40, respectively. For all the
      foregoing nucleosides in the fixed syn conformation about the glycosyl bond, 1H
      NMR spectroscopy further demonstrated that the pentose rings exist predominantly
      in the conformation N (3'-endo). Most of the nucleosides were weak substrates of
      Escherichia coli pyrimidine nucleoside phosphorylase. Enhanced susceptibility to
      phosphorolysis was exhibited by two of them, 39 and 41, with 6-CH2OH and 6-CH2F
      substituents capable of formation of an additional hydrogen bond with the enzyme.
      The 5-fluoro-6-substituted uridines were the poorest substrates. Cytotoxicities
      of the nucleosides were examined vs the human tumor cell lines MOLT-3, U-937, K
      562, and IM-9, as well as PHA-stimulated human lymphocytes. Two of the analogues,
      5-fluoro-6-(fluoromethyl)uridine (42) and 5-fluoro-6-(hydroxymethyl)uridine (40),
      exhibited cytotoxicities comparable to that of 5-fluorouracil.

PMID- 8648612
TI  - Arylacetamide-derived fluorescent probes: synthesis, biological evaluation, and
      direct fluorescent labeling of kappa opioid receptors in mouse microglial cells.
AB  - Fluorescein isothiocyanate isomer I (FITC-I) conjugates of 2-(3,4-dichlorophenyl)
      N-methyl-N-[1-(3- or 4-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (10 and 14)
      were prepared either without or with an intervening mono-, di-, or tetraglycyl
      linker. The 3-substituted fluorescent probes (2-5) were found to retain potent
      agonist activity in smooth muscle preparations as well as high kappa receptor
      affinity and selectivity in receptor binding assays. The 4-substituted series (6
      9) were substantially less potent than the corresponding 3-substituted compounds.
      Flow cytometric analysis demonstrated high levels of direct kappa-specific
      staining of mouse microglial cells by the fluorescent probe 5 containing a
      tetraglycyl linker, as indicated by a 41% decrease in percent cells positively
      labeled and a 61% decrease in mean fluorescence intensity in the presence of the
      kappa-selective antagonist, norbinaltorphimine (norBNI). In similar studies, the
      probe 2 without a linker exhibited only nonspecific binding. This is the first
      report of direct, selective staining of kappa opioid receptors by a fluorescent
      nonpeptide opioid ligand. The results of the present study illustrate the
      importance of introducing hydrophilic linkers to reduce nonspecific binding of
      fluorescent probes for opioid receptors.

PMID- 8648613
TI  - Design, synthesis, and evaluation of latent alkylating agents activated by
      glutathione S-transferase.
AB  - In search of compounds with improved specificity for targeting the important
      cancer-associated P1-1 glutathione S-transferase (GST) isozyme, new analogs 4 and
      5 of the previously reported glutathione S-transferase (GST)-activated latent
      alkylating agent gamma-glutamyl-alpha-amino-beta-[[[2-[[bis[bis(2
      chloroethyl)amino]ph osp horyl]oxy]ethyl]sulfonyl]propionyl]-(R)-(-)
      phenylglycine (3) have been designed, synthesized, and evaluated. One of the
      diastereomers of 4 exhibited good selectivity for GST P1-1. The tetrabromo analog
      5 of the tetrachloro compound 3 maintained its specificity and was found to be
      more readily activated by GSTs than 3. The GST activation concept was further
      broadened through design, synthesis, and evaluation of a novel latent urethane
      mustard 8 and its diethyl ester 9. Interestingly, 8 showed very good specificity
      for P1-1 GST. Cell culture studies were carried out on 4, 5, 8, and 9 using cell
      lines engineered to have varying levels of GST P1-1 isozyme. New analogs 4 and 5
      exhibited increased toxicity to cell lines with overexpressed GST P1-1 isozyme.
      The urethane mustard 8 and its diethyl ester 9 were found to be not as toxic.
      However, they too exhibited more toxicity to a cell line engineered to have
      elevated P1-1 levels, which was in agreement with the observed in vitro
      specificity of 8 for P1-1 GST isozyme. Mechanistic studies on alkaline as well as
      enzyme-catalyzed decomposition of latent mustard 3 provided experimental proof
      for the hypothesis that 3 breaks down into an active phosphoramidate mustard and
      a reactive vinyl sulfone. The alkylating nature of the decomposition products was
      further demonstrated by trapping those transient species as relatively stable
      diethyldithiocarbamic acid adducts. These results substantially extend previous
      efforts to develop drugs targeting GST and provide a paradigm for development of
      other latent drugs.

PMID- 8648614
TI  - Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue
      culture and may act by the generation of a novel intracellular metabolite.
AB  - New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared
      as potential membrane-soluble prodrugs of the bioactive free nucleotide. The
      enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads
      to an increase in selectivity relative to the parent nucleoside analogue.
      Moreover, the derivatives appear to bypass the dependence of the nucleoside on
      thymidine kinase-mediated activation, retaining full activity in thymidine kinase
      deficient cells. This strongly suggests the successful intracellular delivery of
      free nucleotides by the masked phosphate triester prodrugs. This is further
      confirmed by studies using radiolabeled compound which clearly demonstrate the
      generation of d4T mono-, di- and triphosphates from the prodrug, even in
      thymidine kinase-deficient cells. Moreover, we herein report the generation of a
      new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T
      monophosphate. We suggest that at least part of the antiviral action of the
      prodrugs derives from the intracellular generation of such novel diesters which
      may add considerable weight to the suggested further preclinical development of
      the phosphate prodrugs.

PMID- 8648615
TI  - The side-chain of the amino acid residue in position 110 of the Lac repressor
      influences its allosteric equilibrium.
AB  - Binding of the Lac repressor to its operator DNA controls the expression of the
      genes of the lac operon of Escherichia coli. Lac repressor's affinity for the lac
      operator is diminished by an inducer that affects the structure of the repressor
      tetramer. Here we report the cloning and sequencing of the mutant Lac repressor i
      t gene, whose product, the LacR-t repressor, shows a higher affinity for the
      inducer isopropyl-beta-D-thiogalactopyranoside (IPTG) and a lower affinity for
      the lac operator than the wild-type repressor. We show that the altered phenotype
      is due to a single amino acid residue replacement; the alanine residue at
      position 110 in the wild-type is replaced by threonine in i-t. Other amino acid
      residues in position 110 have been shown to result in an i-s phenotype. For the i
      s-substitution of alanine 110 with lysine we demonstrate an increase in the
      affinity for operator DNA and a decrease in the affinity for IPTG. Thus, A110-->
      K shows the opposite effect to A110-->T on the repressor protein. We explain the
      phenotype of the LacR mutants by displacements of the conformational equilibrium
      for the dimeric repressor unit between RR (high operator affinity, low inducer
      affinity) and R*R* (low operator affinity, high inducer affinity) towards R*R* in
      the i-t and towards RR in the i-s mutant in position 110 with respect to the wild
      type. The putative structures of the wild-type and mutant Lac repressors confirm
      this conclusion.

PMID- 8648616
TI  - A useful role for "static" models in elucidating the behaviour of DNA in
      solution.
AB  - Double-helical DNA is a long and flexible molecule that is in constant motion
      under thermal perturbations, more so in solution that in the crystal. Some
      workers, for example Olsen et al., have argued that the behaviour of this
      molecule in assays such as circularization or gel electrophoresis can only be
      understood properly by means of theories that take full account of its dynamical
      nature due to thermal motions. Other workers, per contra, have claimed success at
      explaining aspects of the behaviour of DNA in solution by means of "static"
      models that focus on "time-averaged" conformations. In these static models, the
      intrinsic curvature of DNA and its flexibility are both related to sequence
      dependent base-stacking effects, that are susceptible to study by the inherently
      static tools of X-ray crystallography and electron microscopy. Here we examine
      the question of whether such static models can, in practice, provide a clear
      understanding of what are generally acknowledged to be dynamic phenomena. Our
      investigation discusses some general principles of scientific method, and how
      suitable conceptual models are chosen; it describes the basic concept of
      "persistence length", and argues that long, superhelical DNA may be regarded at
      once as locally stiff yet globally flexible; it cites experimental evidence on
      gel-running which suggests that the flexibility of the molecule is not a crucial
      factor in relation to its mobility in electrophoretic gels; and it summarizes
      many data from gel-running, X-ray crystallography and electron microscopy, all of
      which provide a similar picture of DNA in solution as a stable, sequence
      dependent polymer. Therefore, our investigation clearly favours the use of static
      models to explain many important aspects of the behaviour of DNA in solution;
      while it accepts the use of "dynamic" models in certain specific cases, such as
      the kinetics of circularization, where the rate-limiting step is a high-energy
      thermal vibration away from the most-stable structure.

PMID- 8648617
TI  - A DNA sequence for positioning chromatosomes.
AB  - We have analysed the sequences of 280 chromatosomal DNA molecules. In
      approximately half the clones, a short DNA sequence of the preferred form NGGR is
      located at one, but not both, of the termini of the cloned DNA. We show that the
      clones lacking this signal possess a substantially stronger rotational
      positioning signal than those that contain it. These results indicate that the
      sequence organisation of chromatosomal DNA is asymmetric with respect to the
      midpoint and imply that the sequence NGGR may play a direct role in positioning
      chromatosomes in condensed chromatin.

PMID- 8648618
TI  - Deamidation in proteins: the crystal structure of bovine pancreatic ribonuclease
      with an isoaspartyl residue at position 67.
AB  - The non-enzymatic deamidation of asparagine residues in proteins is a widely
      occurring reaction, both in vivo and in vitro. Although the importance of this
      process is commonly recognised, only little structural information is available
      on it. In order to evaluate the structural effects of this reaction in proteins,
      we have determined the crystal structure of a ribonuclease A derivative in which
      asparagine 67 has been replaced by an isoaspartyl residue, as a consequence of an
      in vitro deamidation reaction. The overall structure of the model, refined to a
      crystallographic R-factor of 0.159 at a resolution of 1.9 A, is very similar to
      that of the native protein, but considerable deviations are observed in the
      region delimited by the disulphide bridge 65-72. In particular, the insertion of
      an extra methylene group in the main chain at residue 67 breaks up the hydrogen
      bond network that makes this region rather rigid in ribonuclease A. On the basis
      of the structure observed, some of the slightly but significantly different
      properties of this deamidated derivative, with respect to the native enzyme, can
      be explained.

PMID- 8648619
TI  - The M32L substitution of staphylococcal nuclease: disagreement between
      theoretical prediction and experimental protein stability.
AB  - The M32L substitution mutation of staphylococcal nuclease was made to test the
      theoretical prediction by Yamaotsu, Moriguchi and Hirono that it would be
      approximately 1.6 kcal/mol more stable than the wild-type protein. Instead M32L
      and the closely related M32I mutant were 0.8 and 0.6 kcal/mol less stable than
      the wild-type protein, respectively. The theoretical treatment had successfully
      predicted the stability effects of other mutations in staphylococcal nuclease.
      The discrepancy found here may be due to a general problem of the theoretical
      treatment, such as inadequate molecular dynamics simulation time, or possibly due
      to more specific difficulty in assessing the strength of the sulfur-aromatic
      interaction that is present in the wild-type.

PMID- 8648620
TI  - Involvement of C-terminal structural elements of equine infectious anemia virus
      reverse transcriptase in DNA polymerase and ribonuclease H activities.
AB  - In order to investigate the modes of DNA synthesis supported by the 66 and 51 kDa
      subunits of equine infectious anemia virus reverse transcriptase (EIAV RT),
      recombinant p66 polypeptides containing a modified ribonuclease H (RNase H)
      domain were purified and evaluated. Defined heteropolymeric template-primer
      combinations and high-resolution gel electrophoresis provided a qualitative
      evaluation of DNA polymerase and RNase H activities, while DNase I footprinting
      revealed features of replication complexes containing the truncated enzymes.
      Removal of alpha-helix E' and the conserved beta 5'-alphaE' "His-loop" in
      p66delta20 RT uncouples the RNase H activities, alters affinity for template
      primer and dictates how the replicating enzyme responds to secondary structure on
      both DNA and RNA templates. Despite these alterations, DNase I footprinting shows
      no major difference in the overall structure of DNA-directed DNA synthesis
      complexes. In contrast, removing 47 C-terminal residues, which includes alpha
      helix D', beta-strand 5' and alpha-Helix E', yields an enzyme with distributive
      DNA polymerase properties closely resembling the purified p51 subunit.

PMID- 8648621
TI  - A tyrosyl-tRNA synthetase protein induces tertiary folding of the group I intron
      catalytic core.
AB  - The Neurospora crassa mitochondrial tyrosyl-tRNA synthetase (CYT-18 protein)
      functions in splicing group I introns. We have used chemical-structure mapping
      and footprinting to investigate the interaction of the CYT-18 protein with the N.
      crassa mitochondrial large subunit ribosomal RNA (mt LSU) and ND1 introns, which
      are not detectably self-splicing in vitro. Our results show that both these non
      self-splicing introns form most of the short range pairings of the conserved
      group I intron secondary structure in the absence of CYT-18, but otherwise remain
      largely unfolded, even at high Mg2+ concentrations. The binding of CYT-18
      promotes the formation of the extended helical domains P6a-P6-P4-P5 (P4-P6
      domain) and P8-P3-P7-P9 (P3-P9 domain) and their interaction to form the
      catalytic core. In iodine-footprinting experiments, CYT-18 binding results in the
      protection of regions of the phosphodiester backbone expected for tertiary
      folding of the catalytic core, as well as additional protections that may reflect
      proximity of the protein. In both introns, most of the putative CYT-18 protection
      sites are in the P4-P6 domain, the region of the SU intron previously shown to
      bind CYT-18 as a separate RNA molecule, but additional sites are found in the
      other major helical domain in P8 and P9 in both introns and in L9 and P7.1/P7.1a
      in the mt LSU intron. Protease digestion of the CYT-18/intron RNA complexes
      results in the loss of CYT-18-induced RNA tertiary structure and splicing
      activity. Considered together with previous studies, or results suggest that CYT
      18 binds initially to the P4-P6 region of group I introns to form a scaffold for
      the assembly of the P3-P9 domain, which may contain additional binding sites for
      the protein. A three-dimensional model structure of the CYT-18 binding site in
      group I introns indicates that CYT-18 interacts with the surface of the catalytic
      core on the side opposite the active-site cleft and may primarily recognize a
      specific three-dimensional geometry of the phosphodiester backbone of group I
      introns.

PMID- 8648622
TI  - Assembly and orientation of Flp recombinase active sites on two-, three- and four
      armed DNA substrates: implications for a recombination mechanism.
AB  - The normal recombination reaction catalyzed by the Flp (pronounced flip) site
      specific recombinase between two full-site DNA substrates requires the action of
      four recombinase monomers in concert. Each monomer of the recombinase harbors an
      incomplete active site, and is hence chemically incompetent. In order to organize
      the strand cleavage pocket, it must accept the catalytic tyrosine (Tyr 343) from
      a second Flp monomer. We address the issue of the potential modes of assembling
      the shared active site in substrates containing two, three or four Flp binding
      arms. In normal full-sites (two Flp binding arms), strand cleavage occurs within
      a substrate and not across substrates. Flp is able to resolve a Y structure
      (three Flp binding arms) into linear plus hairpin recombinants. Strand cleavage
      by Flp in a Y structure and in a Holliday structure (four Flp binding arms)
      follows the trans rather than the cis mode. Within the context of two normal full
      sites, all of the strand cutting patterns are best accommodated by a single
      cleavage mode, namely the trans-horizontal mode. The assembly and orientation of
      a Flp active site is determined by whether two Flp-bound DNA arms have the
      stacking flexibility to accommodate the relevant protein-protein interactions.
      These results provide support for a model in which pairs of monomers bound within
      each of the two DNA partners contribute to the strand cleavage reactions that
      initiate and terminate a normal recombination event. Thus all four Flp monomers
      are required to mediate the cleavage/joining events at either end of the strand
      exchange region.

PMID- 8648623
TI  - Replication of plasmid R6K gamma origin in vivo and in vitro: dependence on IHF
      binding to the ihf1 site.
AB  - The gamma origin of plasmid R6K requires the specific initiator protein pi for
      initiation of replication. However, increased pi concentrations inhibit
      replication. The host-encoded integration host factor (IHF) protein permits gamma
      origin replication at otherwise inhibitory pi levels. IHF is thought to mediate
      this positive effect by directly binding to the gamma origin. In this study we
      demonstrate that IHF binding to one IHF site in the gama origin, ihf1, but not to
      the other side, ihf2, is necessary for the gamma origin to replicate at high pi
      protein levels. We also show that in vitro replication of the gamma origin
      plasmid requires IHF binding to the ihf1 site. Finally, we demonstrate both in
      vivo and in vitro that, when mutant pi proteins (hyperactive) are provided
      instead of wild-type pi, gamma origin plasmids can replicate in the absence of
      IHF. This supports a previously proposed hypothesis that the pi mutants can
      bypass the IHF requirement for gamma origin replication.

PMID- 8648624
TI  - Holliday junction resolvases encoded by homologous rusA genes in Escherichia coli
      K-12 and phage 82.
AB  - The RusA protein of Escherichia coli is an endonuclease that can resolve Holliday
      intermediates and correct the defects in genetic recombination and DNA repair
      associated with inactivation of RuvAB or RuvC. The structure of the rusA gene,
      its organisation in the genome, and its interaction with the Ruv and RecG
      proteins have been investigated. Recombinant plasmids carrying rusA were
      identified by their ability to make ruv mutants resistant to UV light. The gene
      was located to an open reading frame encoding a polypeptide of 120 amino acids.
      It forms the fifth gene in an operon containing a chain of short, interlinked
      open reading frames. A similar arrangement was found in the genome of the
      lambdoid bacteriophage, 82. The two rusA genes show 95% sequence identity. The E.
      coli operon forms part of the defective lambdoid prophage, DLP12, and is probably
      derived from a phage related to 82 and PA-2. rusA appears to be very poorly
      expressed in E. coli, but can be activated by insertion of IS2 or IS10 upstream
      of the coding sequence to promote transcription. These insertions arise
      spontaneously in ruv strains as suppressors of the mutant phenotype. Deletion of
      rusA from the chromosome of either wild-type or ruv mutant strains has no obvious
      effect on recombination or sensitivity to UV light. Multicopy plasmids expressing
      RusA alone make ruvA, ruvB, and ruvC mutants resistant to UV light. Suppression
      depends critically on RecG.

PMID- 8648625
TI  - Uneven distribution of GATC motifs in the Escherichia coli chromosome, its
      plasmids and its phages.
AB  - This work reconsiders the GATC motif distribution in a 1.6 Mb segment of the
      Escherichia coli genome, compared to its distribution in phages and plasmids. At
      first sight the distribution of GATC words looks random. But when a realistic
      model of the chromosome (made of average genes having the same codon usage as in
      the real chromasome), is used as a theoretical reference, strong biasesare
      observed. GATC pairs such as GATCNNGATC are under-represented while there is a
      strong positive selection for motifs separated by 10, 19, 70 and 1100 bp. The
      last class is the only one present in E. coli parasites. It can be ascribed to
      the triggering sequences of the long-patch mismatch repair system. The 6 bp class
      overlaps with the consensus of CAP (catabolite activator protein) and FNR
      (fumarate/nitrate regulator) binding sites, thus accounting for counter
      selection. The other classes, which could be targets for a nucleic acid-binding
      protein, are almost always present inside protein coding sequences, and are
      members of clusters of GATC motifs. Analysis of the genes containing these motifs
      suggests that they correspond to a regulatory process monitoring the shift from
      anaerobic to aerobic growth conditions. In particular this regulation, closing
      down transcription of a large number of genes involved in intermediary metabolism
      would be well suited for the cold and oxygen shift from the mammal's gut to the
      standard environmental conditions. In this process the methylation status of GATC
      clusters would be very important for tuning transcription, and a DNA binding
      protein, probably a member of the cold-shock proteins family would be needed for
      alleviating the effects mediated by slackening of the pace of methylation during
      the shift.

PMID- 8648626
TI  - Projection structure of the nicotinic acetylcholine receptor: distinct
      conformations of the alpha subunits.
AB  - The nicotinic acetylcholine (ACh) receptor is a neurotransmitter-gated ion
      channel consisting of a ring of five membrane-spanning subunits, including two
      (the alpha subunits) with identical amino acid sequences. To open the channel ACh
      has to bind at two sites, involving both alpha subunits, which have widely
      different affinities. An earlier three-dimensional electron microscopic study of
      the non-activated Torpedo receptor had suggested that these sites might be
      cavities with the alpha subunits, located 25 to 30 A from the membrane, and hence
      that the different affinities might be associated with alternative conformations
      of the alpha subunits. This paper compares the conformations of the alpha
      subunits by determining the projection structure of the non-activated receptor
      and correlating the projection and three-dimensional maps. The projection
      structure was calculated to 7.5 A resolution from images of ice-embedded "giant"
      tubular crystals of Torpedo membranes, which had been partially flattened to make
      pairs of two-dimensional sheets (rho 2 lattice: a=90.2 A, beta=162.3 A,
      gamma=121.7 degrees). Each subunit in projection occupied a sector of
      approximately 72 degrees, and had a peak of high density at a distance of 22 to
      25 A from the pseudo 5-fold axis. This peak in the single subunit between the
      alphas was approximately 3 A further from the axis than were the other peaks, and
      the projected density distributions composing the two alpha subunits were
      different. Close matching of the projected densities with the three-dimensional
      densities 25 to 35 A from the membrane, showed unequivocally that corresponding
      (alpha-helical) rods, which encircle the cavities in the two alpha subunits, are
      unequally inclined. Therefore, the cavities are indeed shaped by distinct
      conformations of the alpha subunits before ACh has bound. A model is proposed of
      how both alpha subunits participate concertedly to open the channel, assuming
      that ACh binds to these internal sites.

PMID- 8648627
TI  - Determination of DNA helical handedness by fluorescence resonance energy
      transfer.
AB  - Fluorescence resonance energy transfer (FRET) has been used to determine the
      helical handedness, twist and rise of different DNA conformations. The approach
      is based on the construction of a set of molecules consisting of two fused
      helical segments, one of which is in a known reference helical form. The duplexes
      are covalently labeled at one end with a donor and at the other with an acceptor.
      By systematically shifting the position of the junction while maintaining
      constant the total length in base-pairs, the variation in the efficiency of
      energy transfer can be shown to depend primarily and sensitively on the
      differences in helical twist and rise of the two constituent segments. If the
      latter have the same helical sense, one predicts a FRET signal that is a
      monotonic function of the junctional position. In contrast, a periodic function
      arises when two segments are of opposite handedness. The formalism includes
      explicit consideration of dye orientation (the dipole-dipole orientation factor
      kappa) and an implementation valid for single helix molecules, and introduces new
      functions of measured fluorescence signals for establishing the FRET efficiency.
      The method has been applied to a family of oligonucleotides forming hairpin
      duplexes containing an antiparallel-stranded (aps) d(m5C.G)m segment labeled at
      the 5' end with fluorescein (donor) and a second parallel- stranded d(A.T)N-m
      segment (psAt-DNA) labeled at the hairpin loop with the sulfoindocyanine dye Cy3.
      The segment lengths were in the range 4 to 12, but the total length N was
      maintained constant at 16. The d(m5C.G) sequence was chosen due to its capacity
      for adopting a B or a Z conformation at low and high concentrations of salt,
      respectively. The parallel-stranded d(A.T) sequence served as the second segment
      in order to determine the helical rise and twist of psAT-DNA, presumed to be
      right-handed from molecular modeling and a prior study of topologically
      constrained DNA. A Z-DNA/ps-DNA junction was created between the two segments by
      inducing a B-Z transition in d(m5C.G)m with MgCl2. The range of required salt
      concentration was established by circular dichroism measurements. FRET efficiency
      values of 0.38 to 0.41 were obtained for the oligonucleotides with the d(m5C.G)
      segment in the B conformation. In contrast, upon induction of the B-Z transition
      the FRET efficiency was a decreasing function of the d(m5C.G) content (0.38 to
      0.28 for m = 6 to 12). Helical parameters were estimated from functional fits of
      the data, and were consistent with the known properties of B- and Z-DNAs and with
      the conclusion that psAT-DNA has a helical rise and twist close to that of B-DNA.
      The approach outlined here is not restricted to DNA but can be applied to other
      helical structures, e.g. RNA, proteins, and protein-nucleic acid complexes.

PMID- 8648628
TI  - Three-dimensional structure of mammalian casein kinase I: molecular basis for
      phosphate recognition.
AB  - The three-dimensional structure for the catalytic region of the mammalian protein
      kinase, casein kinase I delta (CKI delta), has been solved by X-ray
      crystallography to a resolution of 2.3 A. A truncation mutant of CKI delta
      lacking the C-terminal autoinhibitory region was expressed in Escherichia coli,
      purified, and crystallized. The structure was solved by molecular replacement
      using the crystal structure of the catalytic domain of a CKI homolog from
      Schizosaccharomyces pombe, Cki1. A tungstate derivative confirmed the initial
      molecular replacement solution and identified an anion binding site which may
      contribute to the unique substrate specificity of CKI. Like other protein
      kinases, the catalytic domain of CKI is composed of two lobes with a cleft
      between them for binding ATP. Comparison of the mammalian and yeast CKI
      structures suggests that a rotation of the N-terminal domain occurs upon ATP
      binding. This domain motion is similar, but not identical, to that observed in
      cAMP-dependent protein kinase upon binding ATP. Although Cki1 has many
      similarities to CKI delta over the catalytic domain, these two forms of CKI
      likely perform different functions in vivo. Relating the primary sequences of
      other CKI enzymes to the three-dimensional architecture of CKI delta reveals a
      catalytic face that is especially conserved among the subset of CKI family
      members associated with the regulation of DNA repair.

PMID- 8648629
TI  - Crystal structure of P13K SH3 domain at 20 angstroms resolution.
AB  - The P13K SH3 domain, residues 1 to 85 of the P1-3 kinase p85 subunit, has been
      characterized by X-ray diffraction. Crystals belonging to space group P4(3)2(1)2
      diffract to 2.0 angstroms resolution and the structure was phased by single
      isomorphous replacement and anomalous scattering (SIRAS). As expected, the domain
      is a compact beta barrel with an over-all confirmation very similar to the
      independently determined NMR structures. The X-ray structure illuminates a
      discrepancy between the two NMR structures on the conformation of the loop region
      unique to P13K SH3. Furthermore, the ligand binding pockets of P13K SH3 domain
      are occupied by amino acid residues from symmetry-related P13K SH3 molecules: the
      C-terminal residues I(82) SPP of one and R18 of another. The interaction modes
      clearly resemble those observed for the P13K SH3 domain complexed with the
      synthetic peptide RLP1, a class 1 ligand, although there are significant
      differences. The solid-state interactions suggest a model of protein-protein
      aggregation that could be mediated by SH3 domains.

PMID- 8648630
TI  - Crystal structure of three consecutive laminin-type epidermal growth factor-like
      (LE) modules of laminin gamma1 chain harboring the nidogen binding site.
AB  - The structure of three consecutive laminin-type EGF-like (LE) modules of mouse
      laminin gammma1 chain, gamma1III3-5 (positions 738 to 899), has been determined
      by multiple isomorphous replacement in a crystal of space group p6(4)22
      (a=b=74.57 angstroms, c = 185.11 angstroms and gamma = 120 degrees). The crystal
      structure was refined using restrained crystallographic refinement to an R-factor
      of 19.72% for 14,983 independent reflections with intensities F(obs)> 0 at 2.1
      angstroms resolution, with root mean square deviation of 0.012 angstroms and
      1.690 degrees from ideal bond lengths and bond angles, respectively. The final
      model consisted of 1179 (non-hydrogen) protein atoms within 162 residues and 119
      water molecules. The molecule showed a rod-like structure of about 76 angstroms
      length with individual modules twisted relative to each other by about 70
      degrees. Each module has the same disulfide bond connections Cys1-Cys3 (loop a),
      Cys2-Cys4 (loop b), Cys5-Cys6 (loop c) and Cys7-Cys8 (loop d), the first three
      being identical to epidermal growth factor (EGF). All three LE modules showed
      little secondary structure which was mainly restricted to loop d, but they
      differed in several other details of their structure. The interface contacts
      between the LE modules are based on hydrogen bonds and hydrophobic interactions
      between the hydrophobic core of loop d of the preceding module and the first
      cysteine and an exposed residue in loop b of the following module. Module 4 was
      previously shown to contribute the major nidogen binding site of laminis and site
      directed mutagenesis demonstrated a specific binding role for Asp800, Asn802,
      Val804 and Tyr819 in loops a and c. The side-chain of these four residues are all
      located on the surface in a linear array and separated by a distance of 17
      angstroms between Tyr819 and Val804. The entire nidogen binding site is
      stabilized via main-chain hydrogen bonds which are in part derived from the link
      between loops b and c (residues Leu815 and Lys816). The data demonstrate the
      unique nature of the LE modules and only a remote similarity to EGF. They also
      indicate that the crucial residues in the binding loops provide direct contacts
      with nidogen and explain the synergism between loops a and c which is essential
      for binding.

PMID- 8648631
TI  - Structure of the nidogen binding LE module of the laminin gamma1 chain in
      solution.
AB  - The structure of the single LE module between residues 791 and 848 of the laminin
      gamma1 chain, which contains the high affinity binding site for nidogen, has been
      probed using NMR methods. The module folds into an autonomous domain which has a
      stable and unique three-dimensional (3D) structure in solution. The 3D structure
      was determined on the basis of 362 interproton distance constraints derived from
      nuclear Overhauser enhancement measurements and 39 phi angles, supplemented by 5
      psi and 22 chi1 angles. The main features of the NMR structures are two-stranded
      antiparallel beta-sheets which are separated by loops and cross-connected by four
      disulfide bridges. The N-terminal segment which contains the first three
      disulfide bridges is similar to epidermal growth factor. The C-terminal segment
      has an S-like backbone profile with a crossover at the last disulfide bridge and
      comprises two three-residue long beta-strands that form an antiparallel beta
      sheet. The LE module possesses an exposed nidogen binding loop that projects away
      from the main body of the protein. The side-chains of three amino acids which are
      crucial for binding (Asp, Asn, Val) are all exposed at the domain surface. An
      inactivating Asn-Ser mutation in this region showed the same 3D structure
      indicating that these three residues, and possibly an additional Tyr in an
      adjacent loop, provide direct contacts in the interaction with nidogen.

PMID- 8648632
TI  - Main-chain dynamics of a partially folded protein: 15N NMR relaxation
      measurements of hen egg white lysozyme denatured in trifluoroethanol.
AB  - 15N NMR relaxation measurements have been used to study the dynamic behaviour of
      the main-chain of hen lysozyme in a partially folded state, formed in a 70% (v/v)
      trifluoroethanol (TFE)/30% water mixture at 37 degrees C and pH 2. This state is
      characterised by helical secondary structure in the absence of extensive tertiary
      interactions. The NMR relaxation data were interpreted by mapping of spectral
      density functions and by derivation of segmental as well as global order
      parameters. The results imply that the dynamics of lysozyme in TFE can, at least
      for the great majority of residues, be adequately described by internal motions
      which are superimposed on all overall isotropic tumbling of the molecule.
      Although the dynamic behaviour shows substantial variations along the polypeptide
      chain, it correlates well with the conformational preferences identified in the
      TFE state by other NMR parameters. Segments of the polypeptide chain which are
      part of persistent helical structures are highly restricted in their motion (S2 >
      0.8 , with effective internal correlation times tau(e) < 200 ps) but are also
      found to experience conformational exchange on a millisecond timescale. Regions
      which are stabilised in less persistent helical structure possess greater
      flexibility (0.6 < S2 < 0.8, 200 ps < tau(e) < 1 ns) and those which lack defined
      conformational preferences are highly flexible (S2 < 0.6, tau(e) approximately 1
      ns). The dynamic behaviour of the main-chain was found to be correlated with
      other local features of the polypeptide chain, including hydrophobicity and the
      position of the disulphide bridges. Despite the absence of extensive tertiary
      interactions, preferential stabilisation of native-like secondary structure by
      TFE results in a pattern of main-chain dynamics which is similar to that of the
      native state.

PMID- 8648633
TI  - Solution structure of the superactive monomeric des-[Phe(B25)] human insulin
      mutant: elucidation of the structural basis for the monomerization of des
      [Phe(B25)] insulin and the dimerization of native insulin.
AB  - The three-dimensional solution structure of des-[Phe(B25)] human insulin has been
      determined by nuclear magnetic resonance spectroscopy and restrained molecular
      dynamics calculations. Thirty-five structures were calculated by distance
      geometry from 581 nuclear Overhauser enhancement-derived distance constraints,
      ten phi torsional angle restraints, the restraints from 16 helical hydrogen
      bonds, and three disulfide bridges. The distance geometry structures were
      optimized using simulated annealing and restrained energy minimization. The
      average root-mean-square (r.m.s.) deviation for the best 20 refined structures is
      1.07 angstroms for the backbone and 1.92 angstroms for all atoms if the less well
      defined N and C-terminal residues are excluded. The helical regions are more well
      defined, with r.m.s. deviations of 0.64 angstroms for the backbone and 1.51
      angstroms for all atoms. It is found that the des-[Phe(B25)] insulin is a monomer
      under the applied conditions (4.6 to 4.7 mM, pH 3.0, 310 K), that the overall
      secondary and tertiary structures of the monomers in the 2Zn crystal hexamer of
      native insulin are preserved, and that the conformation-averaged NMR solution
      structure is close to the structure of molecule 1 in the hexamer. The structure
      reveals that the lost ability of des-[Phe(B25)] insulin to self-associate is
      caused by a conformational change of the C-terminal region of the B-chain, which
      results in an intra-molecular hydrophobic interaction between Pro(B28) and the
      hydrophobic region Leu(B11)-Leu(B15) of the B-chain alpha-helix. This interaction
      interferes with the inter-molecular hydrophobic interactions responsible for the
      dimerization of native insulin, depriving the mutant of the ability to dimerize.
      Further, the structure displays a series of features that may explain the high
      potency of the mutant on the basis of the current model for the insulin-receptor
      interaction. These features are: a change in conformation of the C-terminal
      region of the B-chain, the absence of strong hydrogen bonds between this region
      and the rest of the molecule, and a relatively easy accessibility to the Val(A3)
      residue.

PMID- 8648634
TI  - Kinetic and structural consequences of replacing the aspartate bridge by
      asparagine in the catalytic metal triad of Escherichia coli alkaline phosphatase.
AB  - In each subunit of the homodimeric enzyme Escherichia coli alkaline phosphatase,
      two of the three metal cofactors Zn2+ and Mg2+, are bound by an aspartate side
      chain at position 51. Using site-specific mutagenesis, Asp51 was mutated both to
      alanine and to asparagine to produce the D51A and D51N enzymes, respectively.
      Over the range of pH values examined, the D51A enzyme did not catalyze phosphate
      ester hydrolysis above non-enzymic levels and was not activated by the addition
      of millimolar excess Zn2+ or Mg2+. Replacement of Asp51 by asparagine, however,
      resulted in a mutant enzyme with reduced activity and a higher pH optimum,
      compared with the wild-type enzyme. At pH 8.0 the D51N enzyme showed about 1% of
      the activity of the wild-type enzyme, and as the pH was raised to 9.2, the
      activity of the D51N enzyme increased to about 10% of the value for the wild-type
      enzyme. Upon the addition of excess Mg2+ at pH 9.2, the D51N enzyme was activated
      in a time-dependent fashion to nearly the same level as the wild-type enzyme. The
      affinity for phosphate of the D51N enzyme decreased tenfold as the concentration
      of Mg2+ increased. Under optimal conditions, the k(cat)/K(m) ratio for the D51N
      enzyme indicated that it was 87% as efficient as the wild-type enzyme. To
      investigate the molecular basis for the observed kinetic differences, X-ray data
      were collected for the D51N enzyme to 2.3 angstroms resolution at pH 7.5, and
      then to 2.1 angstroms resolution at pH 9.2 with 20 mM MgCl2. The two structures
      were then refined. The low magnesium, low pH D51N structure showed that the third
      metal site was unoccupied, apparently blocked by the amide group of Asn51. At
      this pH the phosphate anion was bound via one oxygen atom, between the zinc
      cations at the first and second metal sites, which strongly resembled the
      arrangement previously determined for the D153H enzyme at pH 7.5. In the high
      magnesium, high pH D51N structure, the third metal site was also vacant, but the
      phosphate anion bound closer to the surface of the enzyme, coordinated to the
      first metal site alone. Electron density difference maps provide evidence that
      magnesium activates the D51N enzyme by replacing zinc at the second metal site.

PMID- 8648635
TI  - Using a hydrophobic contact potential to evaluate native and near-native folds
      generated by molecular dynamics simulations.
AB  - There are several knowledge-based energy functions that can distinguish the
      native fold from a pool of grossly misfolded decoys for a given sequence of amino
      acids. These decoys, which are typically generated by mounting, or "threading",
      the sequence onto the backbones of unrelated protein structures, tend to be non
      compact and quite different from the native structure: the root-mean-squared
      (RMS) deviations from the native are commonly in the range of 15 to 20 angstroms.
      Effective energy functions should also demonstrate a similar recognition
      capability when presented with compact decoys that depart only slightly in
      conformation from the correct structure (i.e. those with RMS deviations of
      approximately 5 angstroms or less). Recently, we developed a simple yet powerful
      method for native fold recognition based on the tendency for native folds to form
      hydrophobic cores. Our energy measure, which we call the hydrophobic fitness
      score, is challenged to recognize the native fold from 2000 near-native
      structures generated for each of five small monomeric proteins. First, 1000
      conformations for each protein were generated by molecular dynamics simulation at
      room temperature. The average RMS deviation of this set of 5000 was 1.5
      angstroms. A total of 323 decoys had energies lower than native; however, none of
      these had RMS deviations greater than 2 angstroms. Another 1000 structures were
      generated for each at high temperature, in which a greater range of
      conformational space was explored (4.3 angstroms RMS deviation). Out of this set,
      only seven decoys were misrecognized. The hydrophobic fitness energy of a
      conformation is strongly dependent upon the RMS deviation. On average our
      potential yields energy values which are lowest for the population of structures
      generated at room temperature, intermediate for those produced at high
      temperature and highest for those constructed by threading methods. In general,
      the lowest energy decoy conformations have backbones very close to native
      structure. The possible utility of our method for screening backbone candidates
      for the purpose of modelling by side-chain packing optimization is discussed.

PMID- 8648636
TI  - Helix propensities of basic amino acids increase with the length of the side
      chain.
AB  - Helix formation in a 17-residue alanine-lysine peptide and analogous peptides
      with specific lysine --> X substitutions, where X is 2,3-diamino-L-propionic
      acid, 2, 4-diamino-L-butyric acid or L-ornithine, have been examined using
      circular dichroism measurements. The dependence of helix content on X, its
      position in the sequence, and the number of lysine --> X substitutions are
      reasonably well described by using the Lifson-Roig theory modified to include N
      capping, without explicitly considering charge-helix dipole interactions. The
      helix propensities for these basic amino acids increase with the length of the
      side-chain in the rank order 2,3-diamino-L-propionic acid < 2,4-diamino-L-butyric
      acid < ornithine < lysine. This parallels the increase in helix propensities with
      side-chain length of other polar and charged amino acids.

PMID- 8648637
TI  - Mutations in domain II of 23 S rRNA facilitate translation of a 23 S rRNA-encoded
      pentapeptide conferring erythromycin resistance.
AB  - Mutations in domain II of Escherichia coli 23 S rRNA that cause resistance to
      erythromycin do so in a manner fundamentally different from mutations at the drug
      binding site in domain V of the 23 S rRNA. The domain II mutations are located in
      a hairpin structure between nucleotides 1198 and 1247. This is close to a short
      open reading frame in the 23 S rRNA that encodes a pentapeptide (E-peptide) whose
      expression in vivo renders cells resistant to erythromycin. Therefore, a possible
      mechanism of resistance caused by domain II mutations may be related to an
      increased expression of the E-peptide. To test this hypothesis, a range of point
      mutations was generated in domain II of 23 S rRNA in the vicinity of the E
      peptide open reading frame. We find a correlation between erythromycin resistance
      of the mutant clones and increased accessibility of the ribosome binding site of
      the E-peptide gene. Furthermore, the erythromycin resistance determinant in the
      mutants was shown to be confined to a small 23 S rRNA segment containing the
      coding region and the ribosome binding site of the E-peptide open reading frame.
      It thus appears that the domain II mutations mediate erythromycin resistance by
      increasing expression of the 23 S rRNA-encoded E-peptide.

PMID- 8648638
TI  - Replication protein A induces the unwinding of long double-stranded DNA regions.
AB  - We have investigated nucleoprotein filaments composed of human replication
      protein A (RPA) and DNA by electron microscopy. At low ionic strengths, RPA
      complexes with single-stranded DNA are similar in length to protein-free DNA
      suggesting that RPA-bound DNA remains in an extended configuration under these
      conditions. However, severe compaction of RPA-DNA complexes occurs in buffers
      with > 2 mM MgCl2 or with 100 mM NaCl. At low ionic strengths, RPA binds to A + T
      rich internal regions of linear double-stranded simian virus 40 (SV40) DNA and
      induces separation of complementary DNA strands. RPA also binds to closed
      circular SV40 DNA, but requires the function of a DNA topoisomerase to invade and
      completely unwind duplex DNA regions. The ability of RPA to unwind long stretches
      of double-stranded DNA is not shared by the bacterial single-strand binding
      protein and the phage T4 gene 32 protein.

PMID- 8648639
TI  - Tandem arrangement of the human serum albumin multigene family in the sub
      centromeric region of 4q: evolution and chromosomal direction of transcription.
AB  - The albumin gene family is comprised of four genes encoding: serum albumin (ALB),
      alpha-fetoprotein (AFP), alpha-albumin (ALF), and vitamin D-binding protein (DBP;
      also known as GC). The genes are regulated developmentally, expressed in the
      liver, and the proteins are secreted into the bloodstream. The GC gene, and the
      tandemly linked ALB and AFP genes, have been previously localized to human
      chromosome 4q11-13. Using techniques of fluorescence in situ hybridization to
      chromatin fibres, chromosome walking and DNA sequencing of genomic clones, we now
      report on the chromosomal location of the ALF gene and the organization of the
      entire gene family. The four genes are tandemly linked in the 4q sub-centromeric
      region: 5'ALB-5'AFP-5'ALF-5'GC3'-centromere, and hence are transcribed in the
      same, centromere-bound, direction. The linear arrangement of the four genes along
      the chromosome is not correlated with their temporal expression in the human
      ontogeny. It appears that GC is very close (and may be the gene proximal) to the
      centromere. The linear chromosomal arrangement of the four genes and the
      structural differences between them are congruent with the following evolutionary
      divergence of the gene family. Starting with the first duplication of an
      ancestral progenitor gene, a single evolutionary line led to the contemporary GC,
      leaving ALB/AFP/ALF on the other line of descent. The second duplication occurred
      in this ALB lineage, giving rise to ALB and the AFP/ALF progenitor, and the
      third, most recent one, gave rise to the AFP-ALF pair.

PMID- 8648640
TI  - Synthesis and activity of piperazine-containing antirhinoviral agents and crystal
      structure of SDZ 880-061 bound to human rhinovirus 14.
AB  - A series of antipicornaviral agents containing piperazinyl moieties was
      synthesized with the objective of obtaining a compound with a broad spectrum of
      antirhinovirus activity, high potency (< or = 0.003 microgram/ml), and low
      cytotoxicity (> or = 30 micrograms/ml). Five compounds of this series were
      evaluated in detail for efficacy against various HRV serotypes. The agent SDZ 880
      061, containing the benzothiazine moiety SDZ 108-075, which is particularly
      active against HRV14, and the thiazolyl acetic acid ester group of SDZ 89-124,
      which is potent against HRV1B, indeed has a relatively broad antiviral spectrum.
      SDZ 880-061 inhibited 85% of 89 HRV serotypes tested at a concentration of < or =
      3 micrograms/ml. The 3.0 A resolution X-ray structure of SDZ 880-061 bound to
      HRV14 has revealed the binding characteristics of this potent compound. It binds
      in the same pocket as other capsid-binding antiviral agents characterized to
      date, leaving the innermost portion of the pocket vacant. The binding causes
      similar, although less extensive, alterations of the HRV14 VP1 backbone
      conformation (residues 100 to 110, 151 to 159, and 213 to 224) compared to other
      antiviral agents analyzed structurally. Although the contacts between SDZ 880-061
      and HRV14 are mostly of hydrophobic character, the inhibitor has three relatively
      short polar interactions with residues of VP1 that represent potential hydrogen
      bonds. The amount of solvent-accessible surface area of SDZ 880-061 buried in the
      complex (613 A2) is within the range of that observed in protein-protein
      interfaces. The observed influence of time of addition or removal of SDZ 880-061
      on virus yield and on the infectious-center formation indicates that the compound
      primarily interferes with HRV14 cellular attachment. Since it is assumed that
      uncoating requires virion instability and/or flexibility, the finding that SDZ
      880-061 has only a marginal effect on uncoating may be due to the fact that it
      does not completely fill the hydrophobic pocket.

PMID- 8648641
TI  - Conformation of a non-frameshifting RNA pseudoknot from mouse mammary tumor
      virus.
AB  - The solution conformation of an RNA pseudoknot, which is a mutant of the
      pseudoknot required for ribosomal frameshifting in mouse mammary tumor virus, has
      been determined by NMR. The 32-nucleotide RNA pseudoknot does not promote
      efficient frameshifting, although its sequence is very similar to the efficient
      frameshifting pseudoknot whose structure was recently determined by our group.
      13C-labeling of the RNA and 13C-edited NMR techniques were used to facilitate
      spectral assignment. The three-dimensional structure of the RNA pseudoknot was
      determined by restrained molecular dynamics based on NMR-derived interproton
      distances and torsion angle constraints. The conformation is very different from
      that previously determined for the efficient-frameshifting pseudoknot. Two
      unpaired nucleotides are stacked between stem 1 and stem 2, in contrast to the
      one unpaired nucleotide at the same junction region as found previously. The two
      stems of the pseudoknot are not coaxial, they are twisted and bent relative to
      each other. Loop 2 does not cross the shallow minor groove of stem 1, in contrast
      to the pseudoknots with one or no intervening nucleotides between the stems. The
      fact that a specific conformation is required for efficient frameshifting implies
      a specific interaction of the pseudoknot with the ribosome.

PMID- 8648642
TI  - Context dependence of mutational effects in a protein: the crystal structures of
      the V35I, I47V and V35I/I47V gene V protein core mutants.
AB  - The basis for the context dependence of the effects of core mutations on protein
      stability was investigated by comparing the structures of three gene V protein
      mutants with that of the wild-type protein. We previously examined a "swapped"
      mutant in which core residues Val35 and Ile47 were simply reversed so that the
      mutant had no hydrophobicity change from the native protein. The swapped mutant
      was destabilized by 3 kcal/mol per gene V protein dimer relative to the wild-type
      protein, demonstrating that factors other than hydrophobicity must make
      substantial contributions to the effects of mutations on the stability of the
      protein. Here we have determined the structure of this swapped mutant (V35I/I47V)
      as well as those of the two constituent mutants (V35I and I47V). We find that the
      structures of the mutant proteins are very similar to that of the wild-type
      protein except for the necessary addition or deletion of methylene groups and for
      slight positional shifts of atoms around each mutated residue. The structure of
      the double mutant is a composite of the structures of the two single mutants. In
      the mutant structures, the V35I mutation fills a cavity that exists in the wild
      type protein and the I47V mutation creates a new cavity. The structures of the
      mutants indicate further that the reason the V35I and I47V mutations do not have
      opposite effects on stability is that the cavity in the wild-type protein filled
      by the V35I mutation is not optimally shaped for accommodating the additional
      methylene group of the isoleucine. These results support the concepts that the
      details of core packing have substantial influence on the effects of core
      mutations on protein stability and that these packing effects are major
      determinants of the context dependence of core mutation effects on stability.

PMID- 8648643
TI  - DNA binding of PhoB and its interaction with RNA polymerase.
AB  - We have identified the DNA-binding domain (DBD) of an Escherichia coli activator
      protein PhoB as its C-terminal 91 residues. Four amino acid positions in the PhoB
      DBD are found important for interaction with the RNA polymerase holoenzyme that
      contains the sigma 70 subunit. Assuming that the PhoB DBD is structurally similar
      to the histone H5 DBD, the four positions are placed around the turn region that
      connects two putative helices, 2 and 3 (helix 3 is likely to be the recognition
      helix). The binding sites of PhoB, three with the sequence TGTCA and one of
      TTACA, are identified in the pstS promoter. The pstS promoter has intrinsic
      bending (or bendability), which is much enhanced upon binding PhoB. On the basis
      of the above, some aspects of the PhoB-DNA-RNA polymerase interaction are
      discussed.

PMID- 8648644
TI  - Large structures at high resolution: the 1.6 A crystal structure of spinach
      ribulose-1,5-bisphosphate carboxylase/oxygenase complexed with 2
      carboxyarabinitol bisphosphate.
AB  - Ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) from spinach is a
      hexadecamer (L8S8, Mr = 550,000) consisting of eight large (L, 475 residues) and
      eight small subunits (S, 123 residues). High-resolution data collection on
      crystals with large unit cells is not a trivial task due to the effect of
      radiation damage and the large number of overlapping reflections when
      conventional data collection methods are used. In order to minimise these
      effects, data on rubisco were collected with a giant Weissenberg camera at long
      crystal to image-plate distances at the synchrotron of the Photon Factory, Japan.
      Relative to conventional data sets, this experimental arrangement allowed a 20 to
      30-fold reduction of the X-ray dose/exposure time for data collection. This paper
      describes the refined 1.6 A crystal structure of activated rubisco complexed with
      a transition state analogue, 2-carboxyarabinitol-bisphosphate. The
      crystallographic asymmetric unit contains an L4S4 unit, representing half of the
      molecule. The structure presented here is currently the highest resolution
      structure for any protein of comparable size. Refinement of the model was carried
      out by restrained least squares techniques without non-crystallographic symmetry
      averaging. The results show that all L and S subunits have identical three
      dimensional structures, and their arrangement within the hexadecamer has no
      intrinsic asymmetry. A detailed analysis of the high-resolution maps identified
      30 differences in the sequence of the small subunit, indicating a larger than
      usual heterogeneity for this nuclear encoded protein in spinach. No such
      differences were found in the sequence of the chloroplast encoded large subunit.
      The transition state analogue is in the cis conformation at the active site
      suggesting a key role for the carbamate of Lys201 in catalysis. Analysis of the
      active site around the catalytically essential magnesium ion further indicates
      that residues in the second liganding sphere of the metal play a role in fine
      tuning the acid-base character and the position of the residues directly liganded
      to the metal.

PMID- 8648645
TI  - X-SITE: use of empirically derived atomic packing preferences to identify
      favourable interaction regions in the binding sites of proteins.
AB  - A new empirically based method for predicting favourable interaction regions
      within the binding sites of proteins is presented. The method uses spatial
      distributions of atomic contact preferences derived from a non-homologous dataset
      of 83 high-resolution protein structures. The contact preferences are obtained
      for 26 different atom types relative to 163 different types of three-atom
      fragments. Each fragment consists of a triplet of bonded atoms, 1-2-3, which
      defines a reference frame for the three-dimensional distributions. In this way,
      directional, as well as distance, information is retained. Once derived, the
      distribution can be applied in a predictive manner. Given a protein's binding
      site, each distribution is transformed on to the three-atom fragments of the
      constituent residues and, when combined, can identify the favourable interaction
      regions for each different atom type. These predicted regions can then form the
      basis either for the modification of known inhibitors or for the search and
      design of new ones. Five known protein-ligand complexes are used to demonstrate
      the validity and usefulness of the approach. The results show that the method
      provides a powerful tool both in understanding how a given ligand exploits the
      interactions available to it in an active site and in helping to design improved,
      or novel, protein ligands.

PMID- 8648646
TI  - Effects of Fis on ribosome synthesis and activity and on rRNA promoter activities
      in Escherichia coli.
AB  - The DNA-bending protein Fis of Escherichia coli is required for efficient
      initiation of chromosome replication and for activation of the P1 promoters of
      stable RNA (rRNA and tRNA) genes. Using fis+ and fis- bacterial strains, we have
      determined ribosome synthesis and activity, rRNA gene dosage, and transcript
      initiation rates at the rrnB P1 and P2 promoters. Different growth media were
      used to achieve growth rates between 0.7 and 2.7 doublings/hour for the fis+
      strain, and between 0.7 and 2.2 doublings/hour for the fis- strain. In minimal
      media, the Fis deficiency only reduced the DNA and rrn gene concentration (DNA,
      oriC copies and rrn genes per protein); in amino acid-supplemented media, it also
      reduced rRNA synthesis rates per protein. Under all conditions, the ribosome
      activity (protein synthesis rate/ribosome) remained unchanged by the absence of
      Fis. In the presence of Fis, the absolute activities of the isolated rrnB P1 and
      P2 promoters increased from 2 to 88 and 10 to 50 initiations/minute,
      respectively, with increasing growth-rate. In the absence of Fis, these
      activities increased from 3 to 70 and 10 to 80 initiations/minute, respectively.
      Relative to the isolated rrnB P2 promoter, the strength of the rrnB P1 promoter
      was found to increase with increasing growth rate tenfold (from 0.17 to 1.7) in
      the presence, but only fivefold (from 0.17 to 0.85) in the absence of Fis. An
      evaluation of the data leads us to propose estimates of kcat and relative KM
      values for the two rRNA promoters, and relative values for free RNA polymerase
      concentrations during growth in different media. The analysis suggests that the
      reduced strength of P1 promoters of stable RNA genes in the absence of Fis,
      together with the reduced rrn gene concentration, increases the concentration of
      free RNA polymerase. In addition, the lower rrn P1 promoter activity in the
      absence of Fis reduces the probability that the downstream P2 promoter is blocked
      ("occluded") by a transcription elongation complex originating at the P1
      promoter. The increased polymerase concentration and reduced P2 promoter
      occlusion both help to compensate for the Fis-deficiency, but during growth in
      rich media when the demand for ribosomes is high, this compensation is
      insufficient for fis- bacteria to achieve the wild-type level of ribosome
      synthesis and growth.

PMID- 8648647
TI  - Control of spoT-dependent ppGpp synthesis and degradation in Escherichia coli.
AB  - Escherichia coli has two ppGpp synthetases, PSI and PSII, encoded by the relA and
      spoT genes. The spoT gene also encodes a ppGpp hydrolase. During exponential
      growth and under various starvation conditions, the level of ppGpp depends on the
      balance of ppGpp synthetic and degradative activities of spoT gene products. To
      find out how these two activities respond to different physiological conditions
      and to learn about the signals involved in these responses, rates of ppGpp
      synthesis and degradation were determined in an E. coli B/r delta relA strain
      during: (1) multiple amino acid deprivation after a nutritional shift-down from
      glucose amino acids to glucose minimal medium; (2) carbon source starvation after
      a "glucose runout"; (3) energy starvation by treatment with sodium azide. To each
      of these conditions, bacteria responded with a similar gradual accumulation of
      ppGpp, occurring over a period of 20 to 40 minutes, from the basal level of 4 and
      24 pmol/OD460 in glucose amino acids and glucose minimal medium, respectively, to
      about 100 pmol ppGpp/OD460 unit of culture mass. After multiple amino acid
      deprivation and during azide treatment, the rate of ppGpp synthesis increased and
      the rate of ppGpp degradation decreased, but in different proportions by the two
      kinds of treatment. After glucose runout, both ppGpp synthesis and degradation
      immediately decreased, but the rate of degradation was reduced more, which caused
      the accumulation of ppGpp despite its reduced synthesis. ppGpp synthesis required
      continuous protein synthesis, but ppGpp hydrolysis and its control did not: the
      rate of ppGpp degradation could be instantly up or down-regulated in response to
      changes in exogenous amino acid or glucose levels in the absence of protein
      synthesis. The results suggest that PSII is unstable with an average functional
      lifetime of 40 seconds or less, and that its activity is generated during or
      shortly after spoT mRNA translation in response to the availability of amino
      acids. This regulation is responsible for the growth medium-dependent changes in
      basal levels of ppGpp. ppGpp hydrolysis is controlled, i.e. inhibited, mainly
      during conditions of physiological stress, such as multiple amino acid
      deprivation or energy deprivation. This inhibition can be correlated with an
      inferred accumulation of uncharged tRNA. Since previous reports have indicated
      that uncharged tRNA inhibits purified SpoT hydrolase in vitro, it is proposed
      that ppGpp hydrolase activity is, indeed, controlled by the concentration of
      uncharged tRNA in the cell. Finally, it was found that neither relC,
      transcriptional regulation of spoT, nor different translation starts of spoT mRNA
      are directly involved in the environmental control of SpoT hydrolase and PSII
      activities.

PMID- 8648648
TI  - Evidence that a kissing loop structure facilitates genomic RNA dimerisation in
      HIV-1.
AB  - Genomic RNA isolated from retroviral particles is a dimer composed of two
      identical strands. A region called the dimer linkage signal close to the 5' end
      of the RNA may be involved in forming the dimer. Several models for the formation
      of the HIV-1 RNA dimer have been proposed. In the kissing loop model,
      dimerisation results from base-pairing between homologous sequences in an RNA
      stem-loop. In the guanine tetrad model interstrand guanine contacts from the
      dimer. We have made mutations preventing the dimerisation of subgenomic RNAs in
      vitro by these mechanisms. To prevent the kissing loop dimer forming we changed
      the complementary loop sequence from 711GCGCGC716 to 711AAACGC716. To prevent the
      guanine tetrad dimer forming we changed G819 to U. These mutations were
      introduced into a clone of HIV-1NL4-3 separately and collectively. All three
      clones produced infectious virions. Dimeric RNA with similar thermal stabilities
      was isolated from viruses containing either the single or the double mutations.
      The results suggest that sequences involved in forming a guanine tetrad are not
      important for HIV-1 RNA dimerisation. In contrast sequences involved in forming a
      kissing loop complex are not absolutely required, but are important in forming a
      stable HIV-1 RNA dimer.

PMID- 8648649
TI  - The simian virus 40 packaging signal ses is composed of redundant DNA elements
      which are partly interchangeable.
AB  - Using the experimental system of simian virus 40 (SV40) pseudovirions we have
      previously shown that SV40 requires a specific DNA element for packaging, ses,
      which was mapped to the SV40 regulatory region. ses was previously found to play
      a role in facilitating the nucleosomal rearrangement required for chromatin
      condensation and viral packaging. Here, the fine structure of ses was
      investigated by genetic studies. Analyses of ses+ revertants indicated that in
      order to function, ses must be present in close proximity to the origin of
      replication (ori), supporting a role in the regulation of the viral life cycle.
      Fine dissection of ses was performed using a series of plasmids carrying
      mutations and deletions in this region. The results suggest that multiple DNA
      elements participate in the SV40 packaging process, including the GC-boxes and
      elements derived from the enhancer. The elements are redundant, and they can
      function in various combinations. Packaging efficiency correlated with the number
      of GC-boxes, known to bind Sp1. In addition, AP-2 binding elements appeared to
      more important than others. These findings were supported by experiments which
      showed that packaging was significantly enhanced by adding AP-2 binding sites to
      plasmids with large deletions and lacking those sites. The results imply that
      binding of Sp1 and/or AP-2 may participate in the packaging process.

PMID- 8648650
TI  - The hexameric E. coli DnaB helicase can exist in different Quaternary states.
AB  - The DnaB protein is the primary replicative helicase in Escherichia coli, and the
      active form of the protein is a hexamer. It has been reported that the protein
      forms a ring with strong 3-fold symmetry, which was suggested to be a trimer of
      dimers. We show that under different conditions, using either ATP, ATP gamma S,
      AMP-PNP or ADP as nucleotide cofactors, we always find two different forms of the
      DnaB ring; one with a 3-fold symmetry and one with 6-fold symmetry. We have used
      scanning transmission electron microscopy for mass analysis, and have found that
      both forms are hexamers, excluding the possibility that the 3-fold form is in
      fact a trimer of the 52 kDa monomer. We have also found rings that are in an
      intermediate state between these two. The existence of hexamers in discrete
      states shows that the transitions between these states must be cooperative. These
      observations suggest that there may be an equilibrium between two different
      conformations of the hexameric ring. The role of these two states in the
      mechanism of helicase action remains to be determined.

PMID- 8648651
TI  - Depurination of A4256 in 28 S rRNA by the ribosome-inactivating proteins from
      barley and ricin results in different ribosome conformations.
AB  - Ribosomal function in protein synthesis requires dynamic flexibility of the
      ribosomal structure. The two translational inhibitors derived from seeds of ricin
      and barley destroy the dynamic properties of the ribosome by selective
      depurination of A4256 in the phylogenetically conserved alpha-sarcin/ricin loop
      of mouse 28 S rRNA. As the alpha-sarcin/ricin loop is involved in binding of
      elongation factors to the ribosome, depurination blocks the protein synthesis
      elongation cycle. Depurination by the barley translational inhibitor (BTI) mainly
      effects eEF-1 alpha related functions, while ricin interferes with the
      interaction of eEF-2 with the ribosome. Analysis of the ribosomal structure after
      inhibitor shows that the accessibility of the rRNAs for single-strand-specific
      chemical modification was altered. Reactivity changes were seen in domains I, II
      and V of 28 S rRNA and in 5 S rRNA. A majority of the reactivity changes were
      found in putative functional regions of the rRNAs, such as the regions involved
      in peptidyltransferase activity, subunit interaction and in the binding of
      elongation factors. Most of the observed structural changes made the rRNAs less
      accessible for chemical modification, suggesting that the ribosomal particles
      became less flexible after inhibitor treatment. Moreover, the modification
      patterns obtained from the two inhibitor-treated ribosomal particles were only
      partly overlapping, indicating that the structure of the large ribosomal subunit
      differed after ricin and BTI treatment. Surprisingly, depurination in the alpha
      sarcin/ricin loop of 28 S rRNA also affected the structure of the 3' major domain
      in 18 S rRNA.

PMID- 8648652
TI  - Propeller-twisting of base-pairs and the conformational mobility of dinucleotide
      steps in DNA.
AB  - When DNA is bent around a protein, it must distort. The distortion occurs by
      changes in the conformation of successive dinucleotide steps. Bending does not
      necessarily occur uniformly: some steps might remain particularly rigid, i.e.
      they might deform relatively little, while others might take more than their
      proportional share of deformation. We investigate here the deformational capacity
      of specific dinucleotide steps by examining a database of crystallized oligomers.
      Dividing the steps into ten types by sequence (AA( = TT), AC( = GT), AG( = CT),
      AT, CA( = TG), CG, GA( = TC), GC, GG( = CC) and TA), we find that some step types
      are practically rigid, while others have considerable internal mobility or
      conformational flexibility. Now in general base-pairs are not planar, but have
      Propeller-Twist. We find a clear empirical correlation between the level of
      Propeller-Twist in the base-pairs and the flexibility of the dinucleotide step
      which they constitute. Propeller-Twist in the base-pairs makes stacking into a
      dinucleotide step more awkward than in plane base-pairs. In particular, it
      provides a stereochemical "locking" effect which can make steps with highly
      Propeller-Twisted base-pairs rigid. Although the origins of Propeller-Twist are
      not yet clearly understood, this result provides a key to understanding the
      flexibility of DNA in bending around proteins.

PMID- 8648653
TI  - Improving utilization of breast and cervical cancer screening.

PMID- 8648654
TI  - Mitral valve prolapse.

PMID- 8648655
TI  - African Americans and diabetes: reasons, rationale, and research.

PMID- 8648656
TI  - The perceptions of African-American physicians concerning their treatment by
      managed care organizations.

PMID- 8648657
TI  - Single-payer health insurance systems: national myths and immovable mountains.
AB  - Leaders in both government and the health-care industry have strong and varied
      opinions regarding the present US health-care system, but concur that health-care
      financing and organization need restructuring. The single-payer system offers the
      best framework for improving health-care universality, delivery, quality, access,
      choice, and cost effectiveness. However, the single-payer alternative often is
      dismissed early in debates on health-care reform. Popular aversion to collective
      governmental funding of health-care costs and the economic interests of the
      management, insurance, information, and profit sectors of the health-care
      industry are the critical impediments to adoption of single-payer insurance
      systems. This article examines the psychosocial and economic obstacles that
      prevent development of an efficient and effective health-care system and preclude
      recognition of the single-payer system as the best answer to health-care reform.

PMID- 8648658
TI  - Obesity and hypertension among African Americans: do African-American primary
      care providers address these conditions when secondary to primary illness?
AB  - This study examined the extent that black family medicine residents manage
      African-American patients with hypertension and obesity secondary to the primary
      health problem. A retrospective chart survey of 1806 outpatients was used to
      select a sample of 362 patients being treated by 12 African-American family
      medicine residents. Of the 362 patient charts, 31.2% of the patients had
      hypertension (ie, blood pressure > or = 140/90 mm Hg). A plan for managing
      hypertension was found in the charts for 77% of these patients. Obesity was
      present among 37% of the patients, and yet there was documentation of a treatment
      plan for managing this condition for only 38% of these patients. Black family
      medicine residents appear to be sensitized about addressing the problem of
      hypertension among African-American patients being treated for other illnesses.
      However, there is a vital need to teach family medicine physicians how to address
      and aggressively manage the problem of obesity among African-American patients,
      particularly those patients for whom obesity was not the primary reason for
      seeking medical care.

PMID- 8648659
TI  - Total joint arthroplasty in a predominantly African-American population. Part
      two: Hip arthroplasty.
AB  - This second part of a two-part series examines total hip arthroplasty in an
      African-American population. Total hip arthroplasty has revolutionized orthopedic
      surgery since it began more than two decades ago. The quality and durability of
      results have enabled patients to pursue a more normal lifestyle, greatly relieved
      of their pain. Although many studies have reviewed the long-term results of total
      hip arthroplasty, none have addressed the results in a predominantly African
      American population. This study retrospectively reviews the results of total hip
      arthroplasty in 62 African-American patients. Patients' attitudes toward this
      surgery, their co-morbid conditions, complications, and results were examined
      with regard to activity level and acceptance of the procedure.

PMID- 8648660
TI  - Attitudes of African Americans regarding screening for prostate cancer.
AB  - The purpose of this study was to identify attitudes associated with the
      willingness of African Americans to participate in prostate cancer screening.
      Subjects > or = 40 years were recruited from South Central Los Angeles. Fifty-six
      respondents were divided into low or middle socioeconomic groups based on
      education and occupation. Focus group discussions were conducted to assess
      knowledge, attitudes, and beliefs about prostate cancer screening and treatment,
      willingness to participate in screening, incentives and barriers toward
      participating in screening, and source of medical care. The middle socioeconomic
      respondents expressed a greater willingness to participate in prostate screening.
      This difference was attributed to their greater knowledge about the disease and
      screening procedures, enhanced access to health promotion activities, being less
      fearful of discovering abnormal results, exposure to more aggressive behavior on
      the part of the provider with respect to screening, and receiving medical care in
      an environment that is more respectful toward the consumer. Efforts to increase
      minority participation in prostate cancer screening or prevention studies must
      take these findings into consideration.

PMID- 8648661
TI  - Past quit smoking assistance and doctors' advice for white and African-American
      smokers.
AB  - Data for 473 African-American and white smokers showed that whites were more
      likely than African Americans to use formal cessation programs to quit smoking,
      to report that their doctor told them to stop smoking, and to use nicotine
      replacement therapy. While physicians advised a high proportion of smokers of
      each race group to quit smoking and were quite aggressive in prescribing nicotine
      replacement therapy, they were deficient in providing necessary behavioral
      support to their patients.

PMID- 8648662
TI  - Diversity of the envelope glycoprotein among human immunodeficiency virus type 1
      isolates of clade E from Asia and Africa.
AB  - Human immunodeficiency virus type 1 isolates of clade E, known to be largely
      responsible for the fulminating epidemic in Southeast Asia, have been derived
      exclusively from Asia and Africa. Here we provide full or partial sequences of
      the envelope glycoprotein gene from 13 additional clade E isolates from Asia
      representing patients in both early and late stages of disease. More extensive
      comparison of isolates within clade E by geographic locale, stage of disease, and
      year of isolation is now possible. The genetic diversity of clade E isolates from
      Asia, particularly among those derived from early-stage patients, is restricted
      compared with African isolates (mean interisolate distances in gp120, 5.4 and
      20.2%, respectively). However, patients hospitalized with AIDS-related illnesses
      in Thailand harbored clade E isolates exhibiting broader interisolate diversity
      and with highly heterogeneous third hypervariable loop sequences. An additional
      pair of cysteine residues, predicting a novel disulfide bridge and present in 80%
      of clade E isolates from Asia, was uniformly absent from six African isolates.
      Clade E isolates in Thailand from early-stage subjects continue to be genetically
      similar to potential vaccine prototype strains, providing a favorable environment
      for the evaluation of genotype E candidate vaccines. However, evidence of
      increasing interisolate diversity is appearing among late-stage patients in Asia.
      This diversification of the clade E virus, if sustained, may impact preventive
      vaccine development strategies.

PMID- 8648663
TI  - The human cytomegalovirus UL94 open reading frame encodes a conserved herpesvirus
      capsid/tegument-associated virion protein that is expressed with true late
      kinetics.
AB  - In this report, we provide a detailed characterization of the human
      cytomegalovirus (HCMV) UL94 gene product. Northern (RNA) blot analysis of
      infected cell RNA demonstrated that UL94 message was found only at late times of
      infection and was not synthesized in the presence of the viral DNA replication
      inhibitor ganciclovir. Expression of the UL94 open reading frame in vitro and in
      vivo yielded a protein with the predicted molecular mass of 36 kDa. A monoclonal
      antibody raised to a UL94-specific peptide reacted specifically with a 36-kDa
      protein in HCMV-infected fibroblasts. This protein was found only at late times
      of infection and was also present in purified HCMV virions. Fractionation of
      purified virions and HCMV-infected cells revealed an association of UL94
      immunoreactivity with the capsid/tegument and nuclear fractions, respectively.
      The evolutionary conservation of UL94 protein sequence and an analysis of
      potential functional regions of the protein are discussed.

PMID- 8648664
TI  - Genomic quasispecies associated with the initiation of infection and disease in
      ponies experimentally infected with equine infectious anemia virus.
AB  - Equine infectious anemia virus (EIAV) provides a uniquely dynamic system in which
      to study the mechanism and role of genomic variation in lentiviral persistence
      and pathogenesis. We have used a Shetland pony model of infection to investigate
      the association of specific long terminal repeat (LTR) and env gene genomic
      sequences with the initiation of infection and the onset of disease. We analyzed
      viral RNA isolated from a pathogenic stock of virus (EIAV PV) and from plasma
      taken during the first disease episode from two ponies infected with EIAV PV.
      Overall sequence variation within gp90 was low in EIAV PV and only slightly
      higher in plasma virus samples isolated from ponies during the first disease
      episode. However, a high proportion of mutations were localized to the principal
      neutralizing domain in EIAV PV and to the principal neutralizing domain and the
      gp90 hypervariable region in the two pony-derived samples. The rate of fixation
      of mutations was analyzed and determined to be approximately 4 x 10(-2) mutations
      per site per year. Sequence diversity within the U3 region of the LTR was
      extremely low, which suggested that the previously reported hypervariability of
      this region may be a consequence of selection for replication of EIAV in
      different host cells. The predominant EIAV PV env and LTR sequences were used to
      construct chimeric viruses so that the contribution of these sequences to viral
      pathogenicity could be examined. The chimeras replicated in cultured equine
      monocytes to the same extent as the parental nonpathogenic virus and did not
      cause disease in Shetland ponies by 120 days postinfection, suggesting that the
      EIAV genomic determinants of pathogenesis are complex.

PMID- 8648665
TI  - Transforming properties of the cottontail rabbit papillomavirus oncoproteins Le6
      and SE6 and of the E8 protein.
AB  - Cottontail rabbit papillomavirus induces on cottontail and domestic rabbits
      papillomas which progress at a high frequency to carcinoma. The virus encodes
      three transforming proteins; one is translated from open reading frame (ORF) E7
      and binds the retinoblastoma protein, and two, LE6 and SE6, are translated from
      the first and second ATGs of ORF E6, respectively. Here we show that neither of
      the E6 proteins coprecipitated with p53 in vitro, nor did they bind to a recently
      identified E6-binding protein (J. J. Chen, C. E. Reid, V. Band, and E. Androphy,
      Science 269:529-531, 1995). This protein was shown to bind to the E6 proteins of
      the high-risk human papillomairus types 16 and 18 but not to the low-risk human
      papillomavirus types VI and II. In-frame deletions cloned into the pZipNeo vector
      were used to identify structural features of SE6 and LE6 important for
      transformation of NIH 3T3 cells. Three deletions covering the amino-terminal half
      of SE6 did not transform cells. In two of the three deletions, two Cys-X-X-Cys
      motifs were deleted, each deletion preventing the formation of one of the
      potential small Zn fingers of SE6. Among the LE6 deletions, only one had a
      reduced transformation efficiency, while seven transformed cells at least as
      efficiently as wild-type LE6. In each of three of these seven mutants, two Cys-X
      X-Cys motifs were deleted. None of the three amino acid deletions which abolished
      transformation by SE6 reduced transformation by LE6. Furthermore, transformation
      did not correlate with the level of SE6 or LE6 proteins detectable. ORF E8
      colinear with ORF E6, which could generate a 50-amino-acid protein with a
      hydrophobic segment, did not transform cells when cloned into the pZipNeo vector.
      However, mutation of the E8 ATG, which did not alter the amino acid sequence of
      LE6, increased transformation by LE6 without affecting the level of LE6
      expression. The data suggest that transformation by the E6 proteins is not
      mediated by interfering with p53 function or through binding to the E6-binding
      protein. Furthermore, different structural features are important to maintain
      transformation functions and protein stability of LE6 and SE6. Finally, E8 seems
      not to be a transforming protein but rather appears to modulate transformation bv
      LE6.

PMID- 8648666
TI  - Identification of a highly conserved sequence element at the 3' terminus of
      hepatitis C virus genome RNA.
AB  - Previous reports suggest that the hepatitis C virus (HCV) genome RNA terminates
      with homopolymer tracts of either poly(U) or poly(A). By ligation of synthetic
      oligonucleotides followed by reverse transcription-PCR, cDNA cloning, and
      sequence analysis, we determined the 3'-terminal sequence of HCV genome RNA. Our
      results show that the HCV 3' nontranslated region consists of four elements
      (positive sense, 5' to 3'): (i) a short sequence with significant variability
      among genotypes, (ii) a homopolymeric poly(U) tract, (iii) a polypyrimidine
      stretch consisting of mainly U with interspersed C residues, (iv) a novel
      sequence of 98 bases. This latter nucleotide sequence is not present in human
      genomic DNA and is highly conserved among HCV genotypes. The 3'-terminal 46 bases
      are predicted to form a stable stem-loop structure. Using a quantitative
      competitive reverse transcription-PCR assay, we show that a substantial fraction
      of HCV genome RNAs from a high- specific-infectivity inoculum contain this 3'
      terminal sequence element. These results indicate that the HCV genome RNA
      terminates with a highly conserved RNA element which is likely to be required for
      authentic HCV replication and recovery of infectious RNA from cDNA.

PMID- 8648667
TI  - The vaccinia virus 4c and A-type inclusion proteins are specific markers for the
      intracellular mature virus particle.
AB  - Gel analysis of vaccinia virus particles purified by buoyant [correction of
      bouyant] density demonstrates a protein with an estimated molecular mass of 59
      kDa, which is apparently restricted to the intracellular mature virion (IMV)
      form. Western blotting (immunoblotting) and immunoprecipitation procedures
      identify the protein as the vaccinia virus 4c protein, which facilitates
      occlusion of poxvirus particles within cowpox cytoplasmic inclusions. Western
      blotting procedures also identify the truncated A-type inclusion protein of
      vaccinia virus as a specific marker for IMV particles. Kinetic analyses of virion
      maturation and 4c production suggest that peak enveloped virion production occurs
      before peak IMV production in the virus replication cycle and that 4c production
      is concomitant with maturation of IMV. The implications for a distinct and
      evolutionarily conserved function of IMV in viral pathogenesis are discussed.

PMID- 8648668
TI  - Inhibition of human and simian immunodeficiency virus protease function by
      targeting Vpx-protease-mutant fusion protein into viral particles.
AB  - The human immunodeficiency virus type I (HIV-1) Vpr and HIV-2 Vpx proteins
      package into virions through interactions with their cognate Gag polyprotein
      precursor. The targeting properties of Vpr and Vpx have been exploited to
      incorporate foreign proteins into virions by expression as heterologous fusion
      molecules (X. Wu, H.-M. Liu, H. Xiao, J. Kim, P. Seshaiah, G. Natsoulis, J. D.
      Boeke, B. H. Hahn, and J. C. Kappes, J. Virol. 69:3389-3398, 1995). To explore
      the possibility of utilizing Vpx and Vpr to target dominant negative mutants of
      the HIV Pol proteins into virions, we fused HIV-2 Vpx with an enzymatically
      defective protease (PR) mutant. Using a vector system to facilitate transient
      coexpression with HIV provirus, Vpx-PR-mutant (VpxPR(M)) fusion protein was
      expressed and packaged efficiently into HIV-2 and simian immunodeficiency virus
      virions. Immunoblot analysis of purified virions demonstrated that the packaging
      of VpxPR(M) interfered with the processing of the Gag and Gag/Pol precursor
      proteins, similar to that of a well-characterized active-site PR inhibitor. The
      incomplete processing of Gag and Gag/Pol was consistent with a 25-fold reduction
      in virion infectivity. The coexpression of a packaging defective VpxPR(M) fusion
      protein with HIV-2 provirus produced virions with fully processed Gag protein,
      similar to wild-type virions. Importantly, virions trans complemented with a Vpx
      chloramphenicol acetyltransferase fusion protein were normal with respect to the
      processing of Gag protein and the ability to infect and replicate in vitro. These
      results indicate that VpxPR(M) specifically inhibited the function of the viral
      protease and provide for the first time proof of principle that the incorporation
      of foreign proteins into virions via fusion with Vpx can inhibit HIV replication.
      The use of accessory proteins as vehicles to deliver deleterious proteins to
      virions, including dominant negative mutants of Pol proteins, may provide new
      opportunities for application of gene therapy-based antiretroviral strategies.
      The ability to package PR by expression in trans, independent of the Gag/Pol
      precursor, also represents a novel approach that may be exploited to study the
      function of the Pol proteins.

PMID- 8648669
TI  - Serine 3 is critical for phosphorylation at the N-terminal end of the
      nucleoprotein of influenza virus A/Victoria/3/75.
AB  - The influenza A virus nucleoprotein (NP) is a phosphoprotein that encapsidates
      the viral genomic RNA. To map the in vivo phosphorylation site(s) of this
      protein, 32P-labeled NP was purified from cell cultures infected with influenza
      virus A/Victoria/3/75 by immunoaffinity chromatography. The purified protein was
      then subjected to chemical digestion with formic acid, which cleaves proteins at
      Asp-Pro bonds, and the resulting products were analyzed by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis. Two of the phosphorylated products obtained
      were identified as fragments corresponding to the N-terminal 88 amino acids and
      to the C-terminal 196 residues of the NP. To identify the phosphate acceptor
      site(s) at the N-terminal phosphorylated region of NP, each of the seven serines
      within this region was individually changed to alanine by site-directed
      mutagenesis. The mutant proteins were then transiently expressed in mammalian
      cells and analyzed for their phosphorylation state. It was observed that the S-to
      A mutation at position 3 drastically reduced the amount of 32P label incorporated
      into NP, whereas the other substitutions did not have a discernible effect on the
      phosphorylation level of the protein. In addition, all serine-altered proteins
      were tested for their functionality in an artificial system in which expression
      of a synthetic chloramphenicol acetyl-transferase RNA molecule is driven by
      influenza virus proteins synthesized from cloned genes. The results obtained
      demonstrate that all mutant proteins were competent to cooperate with the
      subunits of the viral polymerase for expression of the synthetic virus-like
      chloramphenicol acetyltransferase RNA in vivo. These data are discussed regarding
      the possible roles of NP phosphorylation for the viral replicative cycle.

PMID- 8648670
TI  - Targeting human immunodeficiency virus type 1 reverse transcriptase by
      intracellular expression of single-chain variable fragments to inhibit early
      stages of the viral life cycle.
AB  - Novel molecular approaches to inhibit human immunodeficiency virus type 1 (HIV-1)
      infection have received increasing attention because of the lack of effective
      antiviral drug therapies in vivo. We now demonstrate that cells can be
      intracellularly immunized by cytoplasmic expression of single-chain variable
      antibody fragments (SFv) which bind to the HIV-1 reverse transcriptase (RT)
      enzyme. The expression of anti-RT SFv in T-lymphocytic cells specifically
      neutralizes the RT activity in the preintegration stage and affects the reverse
      transcription process, an early event of the HIV-1 life cycle. Blocking the virus
      at these early stages dramatically decreased HIV-1 propagation, as well as the
      HIV-1-induced cytopathic effects in susceptible human T lymphocytes, by impeding
      the formation of the proviral DNA. These data also demonstrate that
      intracellular, complete SFvs may gain access to viral proteins of the HIV-1
      preintegration complex. These SFvs will provide a tool with which to better
      understand the molecular mechanisms involved in restricting viral replication in
      HIV-1-infected cells.

PMID- 8648671
TI  - Sequences regulating tropism of human immunodeficiency virus type 1 for brain
      capillary endothelial cells map to a unique region on the viral genome.
AB  - Two infectious molecular clones of human immunodeficiency virus type 1, NL4-3 and
      JR-CSF, differ in their abilities to productively infect human brain capillary
      endothelial (HBCE) cells. The phenotypes of recombinants between these two
      molecular strains were examined to identify viral sequences responsible for the
      difference in HBCE cell tropism between the two parental strains. Our results
      indicate that HBCE cell tropism maps to a region that encompasses the C1 region
      of env and includes overlapping reading frames for the accessory genes vpr, vpu,
      tat, and rev. This region was unique for HBCE cell tropism and did not
      cosegregate with either macrophage or T-cell line tropism. However, several
      recombinant clones displayed dual tropism for both HBCE cells and macrophages.
      These endothelial cell- and macrophage-tropic strains may have a unique
      pathogenic advantage by entering the brain via HBCE cells and subsequently
      infecting microglial cells with high efficiency, leading to the induction of
      human immunodeficiency virus dementia.

PMID- 8648672
TI  - Folding, assembly, and intracellular trafficking of the human immunodeficiency
      virus type 1 envelope glycoprotein analyzed with monoclonal antibodies
      recognizing maturational intermediates.
AB  - Monoclonal antibodies (MAbs) that bind linear or conformational epitopes on
      monomeric or oligomeric human immunodeficiency virus type 1 (HIV-1) envelope
      glycoproteins were screened for their recognition of maturational intermediates.
      On the basis of reactivities with gp160 at different times after pulse-labeling,
      the MAbs were sorted into groups that exhibited binding which was immediate and
      constant, immediate but transient, delayed, late, or very late. This grouping was
      consistent with the selectivity of the MAbs for structural features of gp160.
      Thus, a MAb to the V3 loop reacted with envelope proteins at all times, in accord
      with the relative conformational independence and accessibility of the epitope.
      Several MAbs that preferentially react with monomeric gp160 exhibited diminished
      binding after the pulse. A 10-min tag occurred before gp160 reacted with
      conformational MAbs that inhibited CD4 binding. The availability of epitopes for
      other conformational MAbs, including some that react equally with monomeric and
      oligomeric gp160 and some that react better with oligomeric forms, was half
      maximal in 30 min and closely followed the kinetics of gp160 oligomerization.
      Remarkably, there was a 1- to 2-h delay before gp160 reacted with stringent
      oligomer-specific MAbs. After 4 h, approximately 20% of the gp160 was recognized
      by these MAbs. Epitopes recognized by monomerspecific or CD4-blocking MAbs but
      not by oligomer-dependent MAbs were present on gp160 molecules associated with
      the molecular chaperone BiP/GRP78. MAbs with a preference for monomers reacted
      with recombinant or HIV-1 envelope proteins in the endoplasmic reticulum, whereas
      the oligomer-specific MAbs recognized them in the Golgi complex. Additional
      information regarding gp160 maturation and intracellular trafficking was obtained
      by using brefeldin A, dithiothreitol, and a low temperature.

PMID- 8648673
TI  - Identification of Simian virus 40 promoter DNA sequences capable of conferring
      restriction endonuclease hypersensitivity.
AB  - The simian virus 40 (SV40) DNA sequences found in the enhancer domain,
      nucleotides (nt) 103 to 177, and the early domain, nt 5149 to 5232, of the SV40
      promoter have been analyzed for their ability to confer restriction endonuclease
      hypersensitivity in SV40 chromatin by using an SV40-based recombinant reporter
      system. The reporter system consists of a polylinker of various unique
      restriction endonuclease recognition sequences introduced into SV40 at nt 2666.
      We observed that the introduction of the enhancer domain at one end of the
      reporter and the early domain at the other end of the reporter resulted in a 20%
      increase in nuclease sensitivity within the reporter. In the enhancer domain, an
      element capable of conferring hypersensitivity was found between nt 114 and 124
      with the sequence 5'CTGACTAATTG3', which has previously been shown to be the SV40
      AP-1 binding site. In the early domain, an element capable of conferring
      hypersensitivity was localized to nt 5164 to 5187 and had the sequence
      5'CATTTGCAAAGCTTTTTGCAAAAGC3'.

PMID- 8648674
TI  - Plasmid-like replicative intermediates of the Epstein-Barr virus lytic origin of
      DNA replication.
AB  - During the lytic phase of herpesviruses, intermediates of viral DNA replication
      are found as large concatemeric molecules in the infected cells. It is not known,
      however, what the early events in viral DNA replication that yield these
      concatemers are. In an attempt to identify these early steps of DNA replication,
      replicative intermediates derived from the lytic origin of Epstein-Barr virus,
      oriLyt, were analyzed. As shown by density shift experiments with
      bromodeoxyuridine, oriLyt replicated semiconservatively soon after induction of
      the lytic cycle and oriLyt-containing DNA is amplified to yield monomeric plasmid
      progeny DNA (besides multimeric forms and high-molecular-weight DNA). A new class
      of plasmid progeny DNA which have far fewer negative supercoils than do plasmids
      extracted from uninduced cells is present only in cells undergoing the lytic
      cycle of Epstein-Barr virus. This finding is consistent with plasmid DNAs having
      fewer nucleosomes before extraction. The newly replicated plasmid DNAs are
      dependent on a functional oriLyt in cis and support an efficient marker transfer
      into Escherichia coli as monomeric plasmids. Multimeric forms of presumably
      circular progeny DNA of oriLyt, as well as detected recombination events,
      indicate that oriLyt-mediated DNA replication is biphasic: an early theta-like
      mode is followed by a complex pattern which could result from rolling-circle DNA
      replication.

PMID- 8648675
TI  - Exceptional fusogenicity of Chinese hamster ovary cells with murine retroviruses
      suggests roles for cellular factor(s) and receptor clusters in the membrane
      fusion process.
AB  - Chinese hamster ovary (CHO) cells are naturally resistant to infection by
      amphotropic and ecotropic murine retroviruses, but they become susceptible after
      expressing corresponding receptors rRAM-1 and mCAT-1, respectively, and they then
      form abundant syncytia when exposed to these viruses. The fusogenic activities of
      CHO cell clones increase much more strongly with levels of receptor expression
      than do their susceptibilities to infection, suggesting that the assembly of
      receptor clusters may limit syncytium formation. However, other cell lines are
      not fusogenic, even if they express larger amounts of receptors. Our results
      suggest that a factor that is relatively abundant or active in CHO cells may
      functionally interact with rRAM-1 and mCAT-1 in a pathway that enables receptor
      bearing membranes to fuse with membranes that contain viral envelope
      glycoproteins. In the case of CHO/rRAM-1 cells, syncytia form at foci of
      amphotropic 4070A virus infection by fusion-from-within of infected with
      uninfected cells. This fusogenic propensity is a sole property of the uninfected
      CHO/rRAM-1 cells, which fuse in cocultures with any cells infected with 4070A
      virus. With CHO/mCAT-1 cells, fusogenicity is even greater and involves fusion
      from-without by ecotropic virion particles. In contrast to infection, which
      behaves as expected for a process limited by ecotropic virus attachment to single
      receptors, fusion-from-without increases dramatically for cells that express the
      highest levels of mCAT-1. We propose that infection and syncytium formation are
      limited at distinct steps of a common pathway that requires virus binding to a
      single receptor, assembly of multivalent virus-receptor complexes, structural
      changes in viral envelope glycoproteins, and membrane fusion. The limiting step
      in syncytium formation is a cellular process that depends on receptor clustering
      and is relatively active in CHO cells.

PMID- 8648676
TI  - Mutations in the Ty3 major homology region affect multiple steps in Ty3
      retrotransposition.
AB  - The Saccharomyces cerevisiae retroviruslike element Ty3 encodes the major
      structural proteins capsid (CA) and nucleocapsid in the GAG3 open reading frame.
      The Ty3 CA protein contains a sequence (QGX2EX5FX3LX3H, where H is a hydrophobic
      residue) which has not been observed in other retrotransposons but which is
      similar to the major homology region (MHR) described for retrovirus CA. In this
      study the effects of mutations in the Ty3 MHR on particle formation, processing,
      DNA synthesis, and transposition were examined. Each of the mutations tested
      resulted in severe defects in transposition, with disruption occurring prior to
      or at particle formation, subsequent to particle formation and prior to
      completion of DNA synthesis, and subsequent to DNA synthesis. Changing the Q in
      the motif to R had relatively little effect on particle formation but decreased
      transposition to about 13% of that of a wild-type element. Changing G to A or V
      almost completely eliminated the formation of intracellular particles, possibly
      by disruption of CA-CA interactions. Changes introduced at the position of E
      resulted in blocked processing, blocked DNA synthesis, or a block at some post
      reverse transcription step, depending on the nature of the mutation introduced.
      These results showed that the integrity of the Ty3 MHR is required for multiple
      aspects of Ty3 replication involving CA. These functions are independent of
      extracellular budding and of infection, aspects of the retroviral life cycle
      which are not recapitulated in replication of the Ty3 retrotransposon.

PMID- 8648677
TI  - Nucleoplasmic and nucleolar distribution of the adenovirus IVa2 gene product.
AB  - Sequence elements (DE) located downstream of the adenovirus major late promoter
      start site have previously been shown to be essential for the activation of this
      promoter after the onset of viral DNA replication. Two proteins (DEF-A and DEF-B)
      bind to these elements in a late-phase-dependent manner and contribute to this
      activation. DEF-B corresponds to a dimer of the adenovirus IVa2 gene product
      (pIVa2, 449 residues), while DEF-A is a heteromeric protein also comprising
      pIVa2. As revealed by specific immunofluorescence staining of infected cells,
      pIVa2 is targeted to the nucleus, where it distributes to both nucleoplasmic and
      nucleolar structures. We have identified the pIVa2 nuclear localization signal
      (NLS) as a basic peptide element at the C terminus of the protein (residues 432
      to 449). An element essential for nucleolar localization (NuLS) has been mapped
      in the N-terminal part of pIVa2 (between residues 50 and 136). While NuLS
      activity is dependent upon an intact NLS, we show that both NLS and NuLS
      functions are independent of specific DNA-binding activity. As visualized by
      immunoelectron microscopy, pIVa2 is detected in the nucleoplasm at the level of
      the fibrillogranular network which is active in viral transcription. More
      surprisingly, pIVa2 accumulates within electron-dense amorphous inclusions found
      both in the nucleoplasm and in the nucleolus. Altogether, these results suggest
      that, besides controlling major late promoter transcription, pIVa2 serves
      additional, as yet unknown functions.

PMID- 8648678
TI  - Differences in the susceptibility of herpes simplex virus types 1 and 2 to
      modified heparin compounds suggest serotype differences in viral entry.
AB  - Although heparan sulfate (HS) serves as an initial receptor for the binding of
      both herpes simplex virus type 1 (HSV-1) and HSV-2 to cell surfaces, the two
      serotypes differ in epidemiology, cell tropism, and ability to compete for viral
      receptors in vitro. These observations are not necessarily contradictory and can
      be explained if the two serotypes recognize different structural features of HS.
      To compare the specific features of HS important for the binding and infection of
      HSV-1 and HSV-2, we took advantage of structural similarities between heparin and
      cell surface HS and compared the abilities of chemically modified heparin
      compounds to inhibit plaque formation. We found that the antiviral activity of
      heparin for both serotypes was independent of anticoagulant activity. Moreover,
      specific negatively charged regions of the polysaccharide, including N sulfations
      and the carboxyl groups, are key structural features for interactions of both HSV
      1 and HSV-2 with cell surfaces since N desulfation or carboxyl reduction
      abolished heparin's antiviral activity. In contrast, 6-O sulfations and 2-,3-O
      sulfations are important determinants primarily for HSV- 1 infection. The O
      desulfated heparins had little or no inhibitory effect on HSV-1 infection but
      inhibited HSV-2 infection. Using a series of intertypic recombinant mutant
      viruses, we found that susceptibility to O-desulfated heparins can be transferred
      to HSV-1 by the gene for glycoprotein C of HSV-2 (gC-2). This supports the notion
      that the envelope glycoproteins of HSV-1 and HSV-2 interact with different
      affinities for different structural features of heparin. To determine if the
      modified heparin compounds inhibited plaque formation by competing with cell
      surface HS for viral attachment, binding studies were also performed. As
      anticipated, most compounds inhibited binding and plaque formation in parallel.
      However, several compounds inhibited the binding of HSV-1 to cells during the
      initial attachment period at 4 degrees C; this inhibitory effect was reversed
      when the cells and inoculum were shifted to 37 degrees C. This temperature
      dependent differential response to modified heparin compounds was evident
      primarily when glycoprotein C of HSV-1 (gC-1) was present in the virion envelope.
      Minimal temperature-dependent differences were seen for HSV-1 with gC-1 deleted
      and for HSV-2. These results suggest differences in the interactions of HSV-1 and
      HSV-2 with cell surface HS that may influence cell tropism.

PMID- 8648679
TI  - Adenovirus uncoating and nuclear establishment are not affected by weak base
      amines.
AB  - We have used four established lysosomotropic agents, ammonium chloride,
      amantadine, chloroquine, and methylamine, to monitor the possible interference
      with an early low-pH-dependent step during adenovirus replication. Two
      concentrations of each of the different agents were selected; one was essentially
      nontoxic to uninfected HeLa cells, and the other resulted in some toxicity as
      measured by trypan blue staining and by interference with cell monolayer
      establishment, cell proliferation, and radioisotope labelling. It was separately
      determined that these concentrations displayed pH-raising effects of the same
      magnitude as higher concentrations previously used in similar studies. Adenovirus
      uncoating in vivo, normally reaching its maximum within 1 h after infection, was
      not affected by any of the agents. The subsequent levels of successful nuclear
      entry events by the parental genomes were monitored by measuring the extent of
      transcription of an mRNA species coding for the early 72-kDa DNA-binding protein
      at 10 to 12 h postinfection. In HeLa, KB, HEp-2, and A549 cells, none of the
      agents were able to affect the levels of early transcription after administration
      at the point of infection or at 3 h after infection. The cumulative synthesis of
      the hexon antigen was assessed late in infection, and inhibitory effects were
      revealed upon administration of 10, 20, and 40 mM ammonium chloride, 10 mM
      methylamine, and 0.5 mM amantadine, irrespective of the time point of addition.
      Ammonium chloride at 5 mM reduced the hexon yield by 20% at the most when added
      within 50 min after infection. Chloroquine at concentrations of 2.5 and 5 microM
      specifically reduced the hexon yields by 30 to 40% when administered within the
      first 50 min of infection. On the basis of the lack of effects of nontoxic
      concentrations of the four agents on the early virus-cell interactive event of
      uncoating and the early virus-specified transcription, we conclude that a low-pH
      dependent step early in the adenovirus replication cycle is not mandatory for a
      successful infection.

PMID- 8648680
TI  - Nucleotide sequence of classical swine fever virus strain Alfort/187 and
      transcription of infectious RNA from stably cloned full-length cDNA.
AB  - The complete nucleotide sequence of the genome of classical swine fever virus
      (CSFV) strain Alfort/187 was determined from three cDNA libraries constructed by
      cloning of DNA fragments obtained from independent sets of reverse transcription
      and PCR. The cDNA fragments were then assembled and inserted downstream of a T7
      promoter in a P15A-derived plasmid vector to obtain the full-length cDNA clone
      pA187-1. The first nucleotide of the CSFV genome was positioned at the
      transcription start site of the T7 promoter. Cleavage at an SrfI restriction site
      introduced at the exact 3' end of the cloned viral cDNA allowed the in vitro
      synthesis of full-length viral RNA by runoff transcription. This RNA proved to be
      infectious after transfection into porcine kidney cells. Infectivity was not
      increased after capping of the synthetic RNA. Virus recovered from transfected
      cells was titrated in porcine kidney cells by endpoint dilution using indirect
      immunofluorescence and a CSFV-specific monoclonal antibody. RNA transcripts
      generated from plasmid DNA isolated from bacteria which had been cultured and
      cloned 10 times remained infectious, indicating that the full-length clone is
      stable in bacterial cells. A silent point mutation introduced at position 11842
      of the genome was retained in the recombinant virus recovered from transfected
      cells. An infectious chimeric construct was obtained by replacing a 696-bp
      fragment in pA187-1 with the corresponding cDNA fragment from the CSFV strain
      CAP. The stably cloned full-length CSFV cDNA allows site-specific mutagenesis of
      the viral genome and thus will be useful for detailed molecular characterization
      of the virus as well as for studies of viral pathogenesis.

PMID- 8648681
TI  - Repression of the alpha0 gene by ICP4 during a productive herpes simplex virus
      infection.
AB  - During a productive infection by herpes simplex virus type 1 (HSV-1), ICP4, the
      major regulatory protein encoded by the alpha4 gene, binds to its transcription
      initiation site and represses the accumulation of alpha4 RNA. Evidence suggests
      that the degree of repression by ICP4 is a function of the absolute distance of
      an ICP4 binding site 3' from a TATA box. However, repression of HSV-1 gene
      expression by ICP4 through binding sites located 5' of TATA boxes, as in the case
      of the alpha0 gene, has not been adequately addressed. To this end, recombinant
      alpha0 promoters with various arrays of ICP4 binding sites flanking the alpha0
      TATA box were constructed and recombined into the HSV-1 genome. Our results
      demonstrate the following. (i) Destruction of the endogenous alphaO ICP4 binding
      site, located 5' of the TATA box, results in derepression of alpha0 protein and
      RNA accumulation in infected Vero cells. (ii) The degree of alpha0 derepression
      is equivalent to that reported for the alpha4 gene following destruction of the
      ICP4 binding site at the alpha4 mRNA cap site in HSV-1. (iii) Introduction of an
      ICP4 binding site at the alpha0 mRNA cap site represses the accumulation of
      alpha0 RNA greater than threefold relative to the wild type. (iv) Changes in the
      abundance of alpha0 protein and RNA in infected cells do not affect replication
      or growth of HSV-1 in tissue culture. Our findings are consistent with the
      conclusion that alpha0 transcription is repressed by ICP4. These results
      demonstrate that repression by ICP4 can occur through binding sites located 5' of
      virus gene TATA boxes in HSV-1. Thus, models addressing repression of HSV-1 gene
      expression by ICP4 should incorporate the role of binding sites located 5', as
      well as 3', of virus gene TATA boxes.

PMID- 8648682
TI  - Regulated, stable expression and nuclear presence of reovirus double-stranded RNA
      binding protein sigma3 in HeLa cells.
AB  - Reovirus genome segment S4 codes for polypeptide sigma3, a major outer capsid
      component of virions and a double-stranded RNA (dsRNA)-binding protein implicated
      in viral cytopathogenesis. We have constructed a stable HeLa cell line (S4tTA)
      that produces functional sigma3 under tetracycline transactivator control. In the
      absence of tetracycline, S4tTA cells synthesized stable dsRNA-binding sigma3 that
      accumulated in the nucleus as well as in the cytoplasm. However, in induced S4tTA
      cells also expressing reovirus outer shell polypeptide mu1/mu1C, migration of
      sigma3 into the nucleus was blocked, probably as a result of formation of a
      complex with mu1/mu1C which was exclusively in the cytoplasm. Mutant analyses
      indicated a correlation between dsRNA-binding activity and nuclear entry of
      sigma3, suggesting an additional role(s) for this capsid protein in virus-cell
      interactions.

PMID- 8648683
TI  - Mutational analysis of human papillomavirus type 11 E5a oncoprotein.
AB  - In this study, we investigated the structural basis of human papillomavirus type
      11 (HPV-11) E5a transforming activity at the amino acid level. The effects of
      insertion, deletion , and substitution mutations on teh E5a transforming activity
      were determined by the assay of anchorage-independent growth. In the conserved
      Cys-X-Cys structure, substitution of Ser for Cys-73 resulted in indistinguishable
      transforming activity, whereas substitution of Ser for Cys-75 or Ser for both Cys
      73 and Cys-75 retained 50 and 42% transformation, respectively. This suggests
      that Cys at position 75 may be important for transformation. Charge and
      structural changes at teh COOH termini of several mutants impaired transformation
      significantly, but those at the middle region did so only mildly. In addition,
      the 16,000-molecular-weight pore-forming protein (16K protein) is known to
      associate with BPV-1, HPV-6, and HPV-16 E5 proteins. In this study, we
      investigated the correlation between E5a-16K binding affinity and the
      transforming activity of E5a by the use of 11 E5a mutants. Results show that E5a
      and these 11 E5a mutants could bind to the 16K protein when these proteins were
      coexpressed in COS cells, suggesting that simple binding of the 16K protein by
      E5a may not be sufficient for cell transformation.

PMID- 8648684
TI  - An N-terminal deletion mutant of simian virus 40 (SV40) large T antigen
      oligomerizes incorrectly on SV40 DNA but retains the ability to bind to DNA
      polymerase alpha and replicate SV40 DNA in vitro.
AB  - A peptide encompassing the N-terminal 82 amino acids of simian virus 40 (SV40)
      large T antigen was previously shown to bind to the large subunit of DNA
      polymerase alpha-primase (I. Dornreiter, A. Hoss, A. K. Arthur, and E. Fanning,
      EMBO J. 9:3329-3336, 1990). We report here that a mutant T antigen, T83-708,
      lacking residues 2 to 82 retained the ability to bind to DNA polymerase alpha
      primase, implying that it carries a second binding site for DNA polymerase alpha
      primase. The mutant protein also retained ATPase, helicase, and SV40 origin DNA
      binding activity. However, its SV40 DNA replication activity in vitro was reduced
      compared with that of wild-type protein. The reduction in replication activity
      was accompanied by a lower DNA-binding affinity to SV40 origin sequences and
      aberrant oligomerization on viral origin DNA. Thus, the first 82 residues of SV40
      T antigen are not strictly required for its interaction with DNA polymerase alpha
      primase or for DNA replication function but may play a role in correct hexamer
      assembly and efficient DNA binding at the origin.

PMID- 8648685
TI  - Identification and characterization of the pseudorabies virus UL3.5 protein,
      which is involved in virus egress.
AB  - Alphaherpesvirus genomes exhibit a generally collinear gene arrangement, and most
      of their genes are conserved among the different members of the subfamily. Among
      the exceptions is the UL3.5 gene of pseudorabies virus (PrV) for which positional
      homologs have been detected in the genomes of varicella-zoster virus, equine
      herpesvirus 1, and bovine herpesvirus 1 but not in the genomes of herpes simplex
      virus types 1 and 2. To identify and characterize the predicted 224 amino acid
      UL3.5 protein of PrV, a rabbit antiserum was prepared against a UL3.5 fusion
      protein expressed in Escherichia coli. In Western blot (immunoblot) analyses the
      antiserum detected a 30-kDa protein in the cytoplasm of PrV infected cells which
      was absent from purified virions. For functional analysis, UL3.5-expressing cell
      lines were established and virus mutants were isolated after the rescue of
      defective, glycoprotein B-negative PrV by insertion of the complementing
      glycoprotein B-encoding gene of bovine herpesvirus 1 at two sites within the
      UL3.5 locus. A PrV mutant carrying the insertion at codon 159 and expressing a
      truncated UL3.5 protein was still capable of efficient productive replication in
      noncomplementing cells. In contrast, a PrV mutant carrying the insertion at codon
      10 of the UL3.5 gene did not express detectable UL3.5 protein and exhibited a
      dramatic growth deficiency on non-complementing cells with regard to plaque
      formation and one-step replication. Electron microscopical studies showed an
      accumulation of unenveloped capsids in the vicinity of the Golgi apparatus. This
      defect could be compensated by propagation on complementing UL3.5-expressing cell
      lines. Our results thus demonstrate that the PrV UL3.5 gene encodes a
      nonstructural protein which plays an important role in virus replication,
      presumably during virus egress. The functionally relevant domains appear to be
      located within the N-terminal part of the UL3.5 protein which also comprises the
      region exhibiting the highest level of homology between the predicted UL3.5
      homologous proteins of other alphaherpesviruses.

PMID- 8648686
TI  - Identification and characterization of murine gammaherpesvirus 68 gp150: a virion
      membrane glycoprotein.
AB  - Murine gammaherpesvirus 68 (MHV-68) is a naturally occurring virus of murid
      rodents which displays pathobiological characteristics similar to those of other
      gammaherpesviruses, including Epstein-Barr virus (EBV). However, unlike EBV and
      many other gammaherpesviruses, MHV-68 replicates in epithelial cells in vitro and
      infects laboratory strains of mice and therefore provides a good model for the
      study of gammaherpesviruses. Studies of sequences around the center of the MHV-68
      genome identified a gene (designated BPRF1 for BamHI P fragment rightward open
      reading frame 1) whose putative product had motifs reminiscent of a transmembrane
      glycoprotein. All other gammaherpesviruses have a glycoprotein in this genomic
      position, but the BPRF1 gene showed sequence homology with only the EBV membrane
      antigen gp340/220. Biochemical analysis showed that the product of BPRF1 was a
      glycoprotein present on the surface of infected cells, and immunoelectron
      microscopy showed that it was present in the virus particle. In addition,
      antibodies to the BPRF1 product raised by using a bacterial fusion protein
      neutralized the virus in the absence of complement. The predominant molecular
      weights of the protein were 150,000 and 130,000. Pulse-chase analysis and
      endoglycosidase-H digestion showed that the 130,000-molecular-weight form was a
      precursor of the 150,000-molecular-weight form, and cell surface labelling showed
      that the 150,000-molecular-weight form alone was on the cell surface. We
      therefore named the protein gp150. Since gp150 is the first virion-associated
      glycoprotein and neutralizing determinant of MHV-68 to be characterized, it
      provides a valuable tool for the future study of virus-host interactions.

PMID- 8648687
TI  - Spontaneous mutations in the human immunodeficiency virus type 1 gag gene that
      affect viral replication in the presence of cyclosporins.
AB  - Human immunodeficiency virus type 1 mutants that are resistant to inhibition by
      cyclosporins arise spontaneously in vitro during propagation in a HeLa-CD4+ cell
      line in the presence of a nonimmunosuppressive analog of cyclosporin A.
      Interestingly, the phenotype of all of the mutants examined is drug resistant and
      drug dependent, with both cyclosporin A and its analog. Four independently
      isolated mutants have been analyzed genetically by construction of recombinant
      proviruses in the NL4-3 parental strain background and subsequent testing of the
      chimeric viruses in HeLa cells. The cyclosporin-resistant, cyclosporin-dependent
      phenotype consistently transfers with a 1.3-kb fragment of gag, within which the
      four mutants share one of two possible single amino acid exchanges in a proline
      rich stretch in the capsid domain of Pr55gag. These mutants provide the first
      evidence that mutations in human immunodeficiency virus type 1 gag confer
      resistance to cyclosporins; however, replication is conditional on the presence
      of the drug. In the T-cell line CEM, replication of the recombinant mutant
      viruses is also cyclosporin dependent. The drug-dependent replication in HeLa
      cells is stringent, and in the absence of cyclosporin only revertant viruses with
      the parental phenotype grow out of cultures infected with cyclosporin-dependent
      virus. In at least one isolate examined, the revertant phenotype appears to be
      due to suppressor mutations near the proline-rich region.

PMID- 8648688
TI  - Intraepithelial gamma/delta T cells in duodenal mucosa are related to the immune
      state and survival time in AIDS.
AB  - The proportion of T-cell receptor gamma/delta+ cells and the CD4/CD8 ratio
      relative to all CD3+ intraepithelial lymphocytes (IEL) were determined by
      immunofluorescence in duodenal mucosa of late-stage (mostly CDC IVC1/D) subjects
      (n = 21) infected with human immunodeficiency virus type 1 (HIV-1). The
      gamma/delta fraction (median, 14.2%; range, 1.7 to 59.8%) was increased (P <
      0.03) compared with that in HIV- controls (n = 11; median 2.8%; range, 0.3 to
      38%). Also, the number of gamma/delta+ IEL per mucosal unit was increased (P <
      0.05) in the HIV+ subjects (median, 11.1/U) compared with the controls (3.2/U).
      Approximately 100% of the gamma/delta+ IEL were CD8-, and most expressed the
      Vdelta1vJdelta1-encoded epitope (median, 90.9%). The total number of CD3+ IEL
      tended to be lower than in the controls (67.4 versus 72.9/U). Both the epithelium
      and the lamina propria contained mainly CD8+ T cells, the median ratios of CD4+ T
      cells being 1 and 7.6%, respectively. This result accorded with the reduced CD4
      cell number in blood (median, 18 X 10(6)/liter). The HIV+ subjects had increased
      serum levels of neopterin and beta2-microglobulin (both P < 0.0001), probably
      reflecting immunostimulation. Serum neopterin and beta2-microglobulin were
      inversely related to duodenal gamma/delta IEL, particularly in the premortal
      group (r = -0.97 and r = -0.58, respectively). The increased gamma/delta IEL
      might reflect enhanced intestinal protection in late-phase HIV infection. Short
      survival expectancy (<7 months) was associated not only with high levels of
      neopterin and beta2-microglobulin but also with a reduced number of duodenal
      gamma/delta+ cells (P < 0.03).

PMID- 8648689
TI  - Cyclophilin A is required for an early step in the life cycle of human
      immunodeficiency virus type 1 before the initiation of reverse transcription.
AB  - Cyclophilin A (CyPA) is incorporated into human immunodeficiency virus type 1
      (HIV-1) virions via contact with the Gag polyprotein. Genetic or pharmacologic
      disruption of CyPA incorporation causes a quantitative reduction in virion
      infectivity with no discernible effects on virion assembly or on endogenous
      reverse transcriptase activity. Instead, the reduction of virion-associated CyPA
      is accompanied by a parallel, quantitative decrease in the initiation of viral
      DNA synthesis after infection of T cells. The infectivity of CyPA-deficient
      virions is not restored by pseudotyping with Env of amphotropic murine leukemia
      virus, demonstrating that CyPA is not required for the HIV-1-Env-CD4 interaction.
      These results indicate that CyPA is required for an early step in the HIV-1 life
      cycle following receptor binding and membrane fusion but preceding reverse
      transcription. CyPA is the first cellular protein other than the cell surface
      receptor shown to be required for an early event in the life cycle of a
      retrovirus.

PMID- 8648690
TI  - Transcription of the Epstein-Barr virus nuclear antigen 1 (EBNA1) gene occurs
      before induction of the BCR2 (Cp) EBNA gene promoter during the initial stages of
      infection in B cells.
AB  - The purpose of this study was to gain insights into the regulation of Epstein
      Barr virus (EBV) gene transcription during the establishment of viral latency in
      B cells. During the early stages of EBV infection in B lymphocytes, transcription
      of six viral nuclear antigens (EBNAs) is initiated from an early promoter (Wp).
      This is followed by a switch of promoter usage to an upstream promoter, Cp, whose
      activity is autoregulated by both EBNA1 and EBNA2. Previously it was demonstrated
      that infection of primary B cells with EBNA2-negative (EBNA2-) EBNA4-mutant
      (EBNA4mut) virus resulted only in the expression of mutant EBNA4 protein and
      failure to express the other EBNA gene products (C. Rooney H. G. Howe, S. H.
      Speck, and G. Miller, J. Virol. 63:1531-1539, 1989). We extended this research to
      demonstrate that Wp-to-Cp switching did not occur upon infection of primary B
      cells with an EBNA2- EBNA4mut virus (M. Woisetschlaeger, X. W. Jin, C. N.
      Yandara, L. A. Furmanski, J. L. Strominger, and S. H. Speck, Proc. Natl. Acad.
      Sci. USA 88:3942-3946, 1991). Further characterization of this phenomenon led to
      the identification of an EBNA2-dependent enhancer upstream of Cp. On the basis of
      these data, a model was proposed in which initial transcription from Wp gives
      rise to the expression of EBNA2 and EBNA4, and then transcription is upregulated
      from Cp via the EBNA2- dependent enhancer (Woisetschlaeger et al., as noted
      above). Implicit in this model is that transcription of the EBNA1 and EBNA3a to 
      3c genes is dependent on the switch from Wp to Cp, since primary cells infected
      with EBNA2- EBNA4mut virus fail to switch and also fail to express these viral
      antigens. Here we critically evaluate this model and demonstrate, in contrast to
      the predictions of the model, that transcription of both the EBNA1 and EBNA2
      genes precedes activation of Cp. Furthermore, the level of EBNA1 gene
      transcription was strongly reduced in primary B cells infected with EBNA2-
      EBNA4mut virus compared with that of cells infected with wild-type virus.
      Switching to Cp, as well as EBNA1 gene transcription, was observed upon infection
      of EBV-negative Burkitt's lymphoma (BL) cell lines with EBNA2- EBNA4mut virus,
      thus establishing a correlation between early EBNA1 gene transcription and
      upregulation of transcription initiation from Cp. However, in EBV-negative BL
      cell lines infected with EBNA2- EBNA4mut virus, transcription of the EBNA1 gene
      at early time points postinfection initiated from Qp, the EBNA1 gene promoter
      active in group I BL cells (B. C. Schaefer, J. L. Strominger, and S. H. Speck,
      Proc. Natl. Acad. Sci. USA 92:10565-10569, 1995), rather than from Wp. The data
      support a model in which EBNA1 plays an important role in the cascade of events
      leading to successful switching from Wp to Cp and subsequent immortalization of
      the infected B cell.

PMID- 8648691
TI  - Concerted integration of linear retroviral DNA by the avian sarcoma virus
      integrase in vitro: dependence on both long terminal repeat termini.
AB  - We have reconstituted integration reactions in vitro with specially designed
      donor DNAs, a supercoiled plasmid acceptor, purified bacterium-derived Rous
      sarcoma virus integrase (IN), and a host cell DNA-bending protein, HMG1. The
      duplex donor DNAs are approximately 300 deoxynucleotides in length and contain
      only 15 bp of the RSV U3 and U5 termini at the respective ends. The donor has
      blunt U3 and U5 termini which end with the sequence 5'CATT. Joining of the donor
      DNA to the acceptor DNA is detected by using a simple biochemical assay.
      Integration was found to be dependent on both U3 and U5 termini; mutations in
      either result in a significant decrease in the level of integration in vitro.
      Restriction digestion of the products is consistent with most integrants
      representing a concerted integration in which both long terminal repeat termini
      come from the same donor molecule. The U5 and U3 sequences in the substrate flank
      a supF tRNA gene, permitting biological selection of integrants. Many integrants
      have been sequenced, and have all of the hallmarks of authentic viral
      integration, including the removal of a terminal TT dinucleotide from each donor
      DNA end, and duplication of acceptor sequences at the integration site without
      introducing deletions into the acceptor. Target site selection in the acceptor
      plasmid was random except that the orientation of integrants selected was
      apparently influenced by supF transcription. Mutations which substituted the
      conserved CA dinucleotide with a GA pair led to a decreased rate of integration.
      In 2 of 14 mutant integrants sequenced, deoxynucleotides were deleted from either
      the U5 or U3 terminus. In one instance, an internal CA dinucleotide was used,
      which resulted in a 10-bp U5 donor deletion. In the other, an internal GA
      dinucleotide was used, which produced a 5-bp U3 donor deletion. Both of these
      integrants provide further evidence that concerted integration in this
      reconstituted system requires interactions between IN and the U3 and U5 termini
      from the same donor molecule.

PMID- 8648692
TI  - Genetic analysis of polyomavirus large T nuclear localization: nuclear
      localization is required for productive association with pRb family members.
AB  - Polyomavirus large T antigen (LT) is a multifunctional nuclear protein. LT has
      two nuclear localization signals (NLS2), one spanning residues 189 to 195 (NLS1)
      and another spanning residues 280 to 286 (NLS2). Site-directed mutagenesis showed
      that each signal contains at least two critical residues. The possibility of
      connections between NLSs and adjacent phosphorylations has attracted much
      attention. Cytoplasmic LT (CyT) mutants were underphosphorylated, particularly at
      sites adjacent to NLS2. However, since a nuclear LT bearing an inactivated NLS2
      was phosphorylated normally at adjacent sites, the signal was not directly
      required for phosphorylation. Conversely, LT could be translocated to the nucleus
      via NLS2 even when the adjacent phosphorylation sites were deleted. CyT was
      examined to probe the importance of LT localization. CyT was unable to perform LT
      functions related to interactions with retinoblastoma susceptibility gene (pRb)
      family members. Hence, CyT was unable to immortalize primary cells or to
      transactivate an E2F-responsive promoter. Consistent with these findings, CyT,
      though capable of binding pRb in vitro, did not cause relocalization of pRb in
      cells. Assays of transactivation of the simian virus 40 late promoter and of the
      human c-fos promoter showed that defects of CyT were not limited to functions
      dependent on pRb interactions.

PMID- 8648693
TI  - Longitudinal studies of viral sequence, viral phenotype, and immunologic
      parameters of human immunodeficiency virus type 1 infection in perinatally
      infected twins with discordant disease courses.
AB  - Perinatal human immunodeficiency virus type 1 (HIV-1) infections cause a broad
      spectrum of clinical disease and are variable in both the age of the patient at
      onset of serious disease and the progression of the clinical course.
      Heterozygotic perinatally infected twins with a marked difference in their
      clinical courses were monitored during the first 2 years of life. Twin B, the
      second-born twin, developed AIDS by 6 months of age and died at 22 months of age,
      while twin A remained minimally symptomatic through the first 2 years. Sequential
      blood specimens were obtained from the twins in order to characterize the
      immunologic properties of the children and the phenotypes and genotypes of the
      HIV-1 isolates at various times. Twin A developed neutralizing antibodies and a
      high-level antibody-mediated cellular cytotoxicity (ADCC) response, while twin B
      had no neutralizing antibody and a much lower ADCC response. The virus isolates
      obtained from the two children at various time points proliferated equally well
      in peripheral blood mononuclear cells, were nonsyncytium inducing, and could not
      infect established T-cell lines. They differed in their ability to infect primary
      macrophages. In parallel to the biological studies, the HIV-1 tat and part of the
      env gene sequences of the longitudinal isolates at four time points were
      determined. Sequences of virus from both twins at different time points were
      highly conserved; the viruses evolved at a similar rate until the last analyzed
      time point, at which there was a dramatic increase in sequence diversity for the
      sicker child, especially in the tat gene. Our results show that the viruses
      isolated at different times do not have significant changes in growth properties.
      The absence or low levels of neutralizing antibodies may correlate with disease
      progression in the twins.

PMID- 8648694
TI  - The human T-cell leukemia/lymphotropic virus type 1 p12I proteins bind the
      interleukin-2 receptor beta and gammac chains and affects their expression on the
      cell surface.
AB  - p12I is a small hydrophobic protein encoded by the human T-cell
      leukemia/lymphotropic virus type 1 (HTLV-1) that interacts with the 16-kDa
      component of the H+ vacuolar ATPase and cooperates with bovine papillomavirus 1
      E5 oncoprotein in cell transformation. Just as an important step in E5 action
      appears to be its binding to the platelet-derived growth factor receptor, it was
      found that p12I binds specifically to both the beta and gamma(c) chains of the
      interleukin-2 receptor (IL-2R). The IL-2R beta and gamma(c) chains associated
      with p12I are endoglycosidase-H sensitive, suggesting that their interaction
      occurs in a pre-Golgi compartment. p12I stabilizes the immature forms of the IL
      2R beta and gamma(c) chains and decreases their cell surface expression. The
      interactions of p12I with IL-2R beta and gamma(c) may have important implications
      in the immunosuppressive effect of HTLV-1 in vivo as well as in the ligand
      independent HTLV-1-mediated T-cell proliferation.

PMID- 8648695
TI  - Complete nucleotide sequence and transcriptional analysis of snakehead fish
      retrovirus.
AB  - The complete genome of the snakehead fish retrovirus has been cloned and
      sequenced, and its transcriptional profile in cell culture has been determined.
      The 11.2-kb provirus displays a complex expression pattern capable of encoding
      accessory proteins and is unique in the predicted location of the env initiation
      codon and signal peptide upstream of gag and the common splice donor site. The
      virus is distinguishable from all known retrovirus groups by the presence of an
      arginine tRNA primer binding site. The coding regions are highly divergent and
      show a number of unusual characteristics, including a large Gag coiled-coil
      region, a Pol domain of unknown function, and a long, lentiviral-like, Env
      cytoplasmic domain. Phylogenetic analysis of the Pol sequence emphasizes the
      divergent nature of the virus from the avian and mammalian retroviruses. The
      snakehead virus is also distinct from a previously characterized complex fish
      retrovirus, suggesting that discrete groups of these viruses have yet to be
      identified in the lower vertebrates.

PMID- 8648696
TI  - Genetic characterization of new West African simian immunodeficiency virus SIVsm:
      geographic clustering of household-derived SIV strains with human
      immunodeficiency virus type 2 subtypes and genetically diverse viruses from a
      single feral sooty mangabey troop.
AB  - It has been proposed that human immunodeficiency virus type 2 (HIV-2) originated
      from simian immunodeficiency viruses (SIVs) that are natural infections of sooty
      mangabeys (Cercocebus torquatus atys). To test this hypothesis, SIVs from eight
      sooty mangabeys, including six new viruses from West Africa, were genetically
      characterized. gag and env sequences showed that while the viruses of all eight
      sooty mangabeys belonged to the SIVsm/HIV-2 family, each was widely divergent
      from SIVs found earlier in captive monkeys at American primate centers. In two
      SIVs from sooty mangabeys discovered about 100 miles (ca. 161 Km) from each other
      in rural West Africa, the amino acids of a conserved gag p17-p26 region differed
      by 19.3%, a divergence greater than that in four of five clades of HIV-2 and in
      SIVs found in other African monkey species. Analysis of gag region sequences
      showed that feral mangabeys in one small troop harbored four distinct SIVs. Three
      of the newly found viruses were genetically divergent, showing as much genetic
      distance from each other as from the entire SIVsm/HIV-2 family. Sequencing and
      heteroduplex analysis of one feral animal-derived SIV showed a mosaic genome
      containing an env gene that was homologous with other feral SIVsm env genes in
      the troop but having a gag gene from another, distinct SIV. Surprisingly a gag
      phylogenetic tree based on nucleotide sequences showed that the African relatives
      closest to all three household-derived SIVs were HIV-2 subtypes D and E from
      humans in the same West African areas. In one case, the SIV/HIV-2 cluster was
      from the same village. The findings support the hypothesis that each HIV-2
      subtype in West Africans originated from widely divergent SIVsm strains,
      transmitted by independent cross-species events in the same geographic locations.

PMID- 8648698
TI  - Selection and characterization of replication-competent revertants of a Rous
      sarcoma virus src gene oversplicing mutant.
AB  - All retroviruses require both unspliced and spliced RNA for a productive
      infection. One mechanism by which Rous sarcoma virus achieves incomplete splicing
      involves suboptimal env and src 3' splice sites. We have previously shown that
      mutagenesis of the nonconsensus src polypyrimidine tract to a 14-nucleotide
      uninterrupted polypyrimidine tract results in an oversplicing phenotype and a
      concomitant defective replication in permissive chicken embryo fibroblasts. In
      this report, we show that splicing at the src 3' splice site (3'ss) is further
      negatively regulated by the suppressor of src splicing cis element which is
      located approximately 100 nucleotides upstream of the src 3'ss. The increase in
      splicing at the src 3'ss results in a corresponding increase in splicing at a
      cryptic 5'ss within the env gene. Two classes of replication-competent revertants
      of the src oversplicing mutant (pSAP1) were produced after infection, and these
      mutants were characterized by molecular cloning and sequence analysis. Class I
      revertants are transformation-defective revertants in which the src 3'ss and the
      src gene are deleted by homologous recombination at several different sites
      within the imperfect direct repeat sequences that flank the src gene. Cells
      infected with these transformation-defective revertants produce lower levels of
      virus particles than cells infected with the wild-type virus. Class II revertants
      bear small deletions in the region containing the branchpoint sequence or
      polypyrimidine tract of the src 3'ss. Insertion of these mutated sequences into
      pSAP1 restored inefficient splicing at the src 3'ss and efficient replication in
      chicken embryo fibroblasts. All of these mutations caused reduced splicing at the
      src 3'ss when they were tested in an in vitro splicing system. These results
      indicate that maintenance of a weak src 3'ss is necessary for efficient Rous
      sarcoma virus replication.

PMID- 8648697
TI  - Cellular or viral protein binding to a cytomegalovirus promoter transcription
      initiation site: effects on transcription.
AB  - We have previously shown that the IE2 protein of human cytomegalovirus (CMV)
      represses its own synthesis by binding to the major immediate-early promoter (M.
      P. Macias and M. F. Stinski, Proc. Natl. Acad. Sci. USA 90:707-711, 1993). The
      binding of a viral protein (IE2) and a cellular protein in the region of the
      transcription start site was investigated by site-specific mutational analysis
      and electrophoretic mobility shift assay. The viral protein and the cellular
      protein require different but adjacent core DNA sequence elements for binding. In
      situ chemical footprinting analysis of DNA-protein interactions with purified CMV
      IE2 protein or HeLa cell nuclear extracts demonstrated binding sites that overlap
      the transcription start site. The IE2 protein footprint was between bp -15 and
      +2, relative to the transcription start site, and the cellular protein was
      between bp -16 and +7. The ability of the unknown human cellular protein of
      approximately 150 kDa to bind the CMV major immediate-early promoter correlates
      with an increase in the level of transcription efficiency. Mutations in the core
      DNA sequence element for cellular protein binding significantly reduced the level
      of in vitro transcription efficiency. Mutations upstream and downstream of the
      core sequence moderately reduced the transcription efficiency level. Negative
      autoregulation of the CMV promoter by the viral IE2 protein may involve both
      binding to the DNA template and interference with the function of a cellular
      protein that binds to the transcription start site and enhances transcription
      efficiency.

PMID- 8648700
TI  - Identification of nuclear and cytoplasmic proteins that interact specifically
      with an AU-rich, cis-acting inhibitory sequence in the 3' untranslated region of
      human papillomavirus type 1 late mRNAs.
AB  - Expression of human papillomavirus late genes encoding L1 and L2 capsid proteins
      is restricted to terminally differentiated epithelial cells. We have previously
      identified and characterized an AU-rich, cis-acting negative regulatory element
      in the 3' untranslated region of human papillomavirus type 1 late mRNAs. This
      element acts posttranscriptionally to reduce mRNA levels and the translation
      efficiency of mRNAs. The experiments reported here are a continuation of our
      previous work. We have used RNA gel shifts and UV cross-linking assays to
      identify cellular proteins that interact with the inhibitory RNA sequence of
      human papillomavirus type 1. RNA gel shift assays established that cellular
      proteins interact with the AU-rich sequence. The binding of nuclear proteins was
      inhibited by competition with poly(U), whereas the binding of cytoplasmic
      proteins was inhibited by competition with poly(U) and also by competition with
      poly(A) and poly(G). Two nuclear proteins and two cytoplasmic proteins that bind
      specifically to the AU-rich RNA sequence were identified by UV cross-linking.
      These proteins did not bind to the 3' untranslated region of human papillomavirus
      type 1 early mRNAs, which does not show inhibitory activity. The cellular
      proteins identified in our experiments may therefore be involved in the
      inhibition of human papillomavirus type 1 late gene expression in
      nondifferentiated epithelial cells.

PMID- 8648699
TI  - Inhibitory activity of the equine infectious anemia virus major 5' splice site in
      the absence of Rev.
AB  - The major 5' splice site of equine infectious anemia virus (EIAV) conforms to the
      consensus 5' splice site in eight consecutive positions and is located
      immediately upstream of the gag AUG. Our results show that the presence of this
      5' splice site on the EIAV gag mRNA decreases Gag production 30- to 60-fold. This
      is caused by inefficient nuclear mRNA export and inefficient mRNA utilization.
      Inhibition could be overcome by providing human immunodeficiency virus type 1
      Rev/Rev-responsive element, human T-cell leukemia virus type 1 Rex/Rex-responsive
      element, or simian retrovirus type 1 constitutive transport element. In addition,
      inhibition could be abolished by introducing single point mutations in the 5'
      splice site or by moving the 5' splice site away from its natural position
      immediately upstream of the gag AUG. This demonstrates that both maintenance of a
      perfect consensus 5' splice site and its proper location on the mRNA are
      important for inhibitory activity of the EIAV major 5' splice site.

PMID- 8648701
TI  - Quantitative model of antibody- and soluble CD4-mediated neutralization of
      primary isolates and T-cell line-adapted strains of human immunodeficiency virus
      type 1.
AB  - Primary isolates (PI) of human immunodeficiency virus type 1 (HIV-1) are
      considerably less sensitive than T-cell line-adapted strains to neutralization by
      soluble CD4 and by most cross-reactive monoclonal antibodies to the viral
      envelope (Env) glycoprotein, as well as by postinfection and postvaccination sera
      (J. P. Moore and D. D. Ho, AIDS 9 [suppl. A]:5117-5136, 1995). We developed a
      quantitative model to explain the neutralization resistance of PI. The factors
      incorporated into the model are the dissociation constants for the binding of the
      neutralizing agent to native Env oligomers, the number of outer Env molecules on
      the viral surface (which decreases by shedding), and the minimum number of Env
      molecules required for attachment and fusion. We conclude that modest differences
      in all these factors can, when combined, explain a relative neutralization
      resistance of PI versus T-cell line-adapted strains that sometimes amounts to
      several orders of magnitude. The hypothesis that neutralization of HIV is due to
      the reduction below a minimum number of the Env molecules on a virion available
      for attachment and fusion is at odds with single- and few-hit neutralization
      theories. Our analysis of these ideas favors the hypothesis that neutralization
      of HIV is instead a competitive blocking of interactions with cellular factors,
      including adsorption receptors.

PMID- 8648702
TI  - Analysis of the complete nucleotide sequence and functional organization of the
      genome of Streptococcus pneumoniae bacteriophage Cp-1.
AB  - Cp-1, a bacteriophage infecting Streptococcus pneumoniae, has a linear double
      stranded DNA genome, with a terminal protein covalently linked to its 5' ends,
      that replicates by the protein-priming mechanism. We describe here the complete
      DNA sequence and transcriptional map of the Cp-1 genome. These analyses have led
      to the firm assignment of 10 genes and the localization of 19 additional open
      reading frames in the 19,345-bp Cp-1 DNA. Striking similarities and differences
      between some of these proteins and those of the Bacillus subtilis phage phi 29, a
      system that also replicates its DNA by the protein-priming mechanism, have been
      revealed. The genes coding for structural proteins and assembly factors are
      located in the central part of the Cp-1 genome. Several proteins corresponding to
      the predicted gene products were identified by in vitro and in vivo expression of
      the cloned genes. Mature major head protein from the virion particles results
      from hydrolysis of the primary gene product at the His-49 residue, whereas the
      phage gene is expressed in Escherichia coli without modification. We have also
      identified two open reading frames coding for proteins that show high degrees of
      similarity to the N- and C-terminal regions, respectively, of the single tail
      protein identified in phi 29. Sequencing and primer extension analysis suggest
      transcription of a small RNA showing a secondary structure similar to that of the
      prohead RNA required for the ATP-dependent packaging of phi 29 DNA. On the basis
      of its temporal expression, transcription of the Cp-1 genome takes place in two
      stages, early and late. Combined Northern (RNA) blot and primer extension
      experiments allowed us to map the 5' initiation sites of the transcripts, and we
      found that only three genes were transcribed from right to left. These analyses
      reveal that there are also noticeable differences between Cp-l and phi 29 in
      transcriptional organization. Considered together, the observations reported here
      provide new tangible evidence on phylogenetic relationships between B. subtilis
      and S. pneumoniae.

PMID- 8648703
TI  - Epitopes and hemagglutination binding domain on subgenus B:2 adenovirus fibers.
AB  - The adenovirus fiber serves as a ligand between the virus and the host cell
      receptor and manifests hemagglutination (HA) activity and antigenic domains. We
      have screened both the antigenic and immunogenic epitopes on the adenovirus
      fibers of subgenus B:2 by using recombinant fiber proteins (rfibers) expressed in
      Escherichia coli, synthesized peptides (P1 to P8), and the corresponding
      antisera. The results indicated that P4 (amino acids [aa] 201 to 220), P5 (aa 231
      to 250), and P7 (aa 275 to 295) presented both antigenic and immunogenic epitopes
      in adenovirus type 11 prototype (Ad11p), Ad34a, and Ad11a fibers. P6 (aa 251 to
      270) presented both epitopes in Ad11a fiber but only an antigenic epitope in
      other fibers. The C-terminal 20 amino acids of the fiber, corresponding to P8,
      manifested an epitope of low-level immunogenicity. P5, localized at the N
      terminal aa 231 to 250, displayed an epitope that reacted with fibers of all the
      members of subgenus B analyzed. The rfibers of Ad11p and Ad34a displayed HA
      activity with monkey erythrocytes, though those of Ad11a did not. Mutagenesis of
      the rfibers revealed that neither the fragment replacements, 11p20211a,
      llp26011a,and 11a28011p, nor the Ad11p rfiber with the substitutions of Tyr-260-
      >H (Tyr260H)and Arg279Q displayed HA activity. The Ad11a fiber knob was sensitive
      to proteolytic digestion, whereas that of Ad11p was resistant. The results
      demonstrated that the decisive HA binding domain was presented at aa 260 to 280
      and was conformation dependent. Nearby amino acids, aa 283 and 284, may also
      affect the HA function.

PMID- 8648704
TI  - (Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad
      spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant
      isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug
      resistant variants of HIV-1IIIB with reduced replication phenotypes.
AB  - The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class
      of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were
      identified by targeted screening of recombinant reverse transcriptase (RT)
      enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI)
      resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic
      profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in
      vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance
      conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed
      submicromolar 90% inhibitory concentration estimates for these compounds.
      Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF
      harboring the Pro-236->Leu RT substitution and significantly suppressed the
      replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U
      90152T) and zidovudine. Biochemical and phenotypic characterization of AAP
      BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP
      BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious
      effect on the integrity and enzymatic activity of virion-associated RT
      heterodimers, as well as the replication capacity of these resistant viruses.

PMID- 8648705
TI  - Synthesis and assembly of retrovirus Gag precursors into immature capsids in
      vitro.
AB  - The assembly of retroviral particles is mediated by the product of the gag gene;
      no other retroviral gene products are necessary for this process. While most
      retroviruses assemble their capsids at the plasma membrane, viruses of the type D
      class preassemble immature capsids within the cytoplasm of infected cells. This
      has allowed us to determine whether immature capsids of the prototypical type D
      retrovirus, Mason-Pfizer monkey virus (M-PMV), can assemble in a cell-free
      protein synthesis system. We report here that assembly of M-PMV Gag precursor
      proteins can occur in this in vitro system. Synthesized particles sediment in
      isopycnic gradients to the appropriate density and in thin-section electron
      micrographs have a size and appearance consistent with those of immature
      retrovirus capsids. The in vitro system described in this report appears to
      faithfully mimic the process of assembly which occurs in the host cell cytoplasm,
      since M-PMV gag mutants defective in in vivo assembly also fail to assemble in
      vitro. Likewise, the Gag precursor proteins of retroviruses that undergo type C
      morphogenesis, Rous sarcoma virus and human immunodeficiency virus, which do not
      preassemble capsids in vivo, fail to assemble particles in this system.
      Additionally, we demonstrate, with the use of anti-Gag antibodies, that this cell
      free system can be utilized for analysis in vitro of potential inhibitors of
      retrovirus assembly.

PMID- 8648706
TI  - Cell entry by measles virus: long hybrid receptors uncouple binding from membrane
      fusion.
AB  - The pH-independent fusion of membranes induced by measles virus (MV) requires, in
      addition to the fusion-competent protein F, hemagglutinin (H), and on the target
      membrane, the virus receptor CD46. We constructed hybrid receptors composed of
      different numbers and combinations of the four CD46 short consensus repeat (SCR)
      domains, followed by immunoglobulin-like domains of another cell surface protein,
      CD4. Hybrid proteins containing SCRs I and II bound MV particles and conferred
      fusion competence to rodent cells. SCRs III and/or IV strengthened MV binding.
      Increasing the distance between the MV binding site and the transmembrane domain
      enhanced virus binding but reduced fusion efficiency. A hybrid protein predicted
      to be about 120 Angstroms (12 nm) longer than the standard receptor lost fusion
      support function and was dominant negative over a functional receptor. These data
      indicate that receptor protein length influences virus binding and determines
      fusion efficiency.

PMID- 8648707
TI  - Vaccine protection by a triple deletion mutant of simian immunodeficiency virus.
AB  - Twelve rhesus monkeys were vaccinated with SIVmac316 delta nef (lacking nef
      sequences), and 12 were vaccinated with SIVmac239 delta3 (lacking nef, vpr, and
      upstream sequences in U3). SIVmac316 and SIVmac239 differ by only eight amino
      acids in the envelope; these changes render SIVmac316 highly competent for
      replication in macrophages. Seventeen of the animals developed persistent
      infections with the vaccine viruses. Seven of the 24 vaccinated animals, however,
      developed infections that were apparently transient in nature. Six of these seven
      yielded virus from peripheral blood when tested at weeks 2 and/or 3, three of the
      seven had transient antibody responses, but none of the seven had persisting
      antibody responses. The 24 monkeys were challenged in groups of four with 10
      rhesus monkey infectious doses of wild-type, pathogenic SIVmac251 at weeks 8, 20,
      and 79 following receipt of vaccine. None of the seven with apparently transient
      infections with vaccine virus were protected upon subsequent challenge. Analysis
      of cell-associated viral loads, CD4+ cell counts, and viral gene sequences
      present in peripheral blood in the remainder of the monkeys following challenge
      allowed a number of conclusions. (i) There was a trend toward increased
      protection with length of time of vaccination. (ii) Solid vaccine protection was
      achieved by 79 weeks with the highly attenuated SIV239 delta3. (iii) Solid long
      term protection was achieved in at least two animals in the absence of complete
      sterilizing immunity. (iv) Genetic backbone appeared to influence protective
      capacity; animals vaccinated with SIV239 delta3 were better protected than
      animals receiving SIV316 delta nef. This better protection correlated with
      increased levels of the replicating vaccine strain. (v) The titer of virus
      neutralizing activity in serum on the day of challenge correlated with protection
      when measured against a primary stock of SIVmac251 but not when measured against
      a laboratory-passaged stock. The level of binding antibodies to whole virus by
      enzyme-linked immunosorbent assay also correlated with protection.

PMID- 8648708
TI  - Measles virus infection of thymic epithelium in the SCID-hu mouse leads to
      thymocyte apoptosis.
AB  - Mortality from measles is caused mostly by secondary infections associated with
      the depression of cellular immunity. The mechanism of immune suppression and the
      role of virus strain differences on the immune system are incompletely
      understood. SCID-hu mice were used to determine the effects of virulent, wild
      type (Chicago-1) and avirulent, vaccine (Moraten) strains of measles virus (MV)
      on the human thymus in vivo. Chicago-1 replicated rapidly, with a 100-fold
      decrease in numbers of thymocytes, whereas Moraten replicated slowly, without
      significant thymocyte death. Productive MV infection occurred not in thymocytes
      but in thymic epithelial and myelomonocytic cells. Wild-type MV infection of
      thymic stromata leads to induction of thymocyte apoptosis and may contribute to a
      long-term alteration of immune responses. The extent of thymic disruption
      reflects the virulence of the virus, and therefore the SCID-hu mouse may serve as
      the first small animal model for the study of MV pathogenesis.

PMID- 8648710
TI  - Extracellular vaccinia virus envelope glycoprotein encoded by the A33R gene.
AB  - With the aid of three monoclonal antibodies (MAbs), a glycoprotein specifically
      localized to the outer envelope of vaccinia virus was shown to be encoded by the
      A33R gene. These MAbs reacted with a glycosylated protein that migrated as 23- to
      28-kDa and 55-kDa species under reducing and nonreducing conditions,
      respectively. The protein recognized by the three MAbs was synthesized by all 11
      orthopoxviruses tested: eight strains of vaccinia virus (including modified
      vaccinia virus Ankara) and one strain each of cowpox, rabbitpox, and ectromelia
      viruses. The observation that the protein synthesized by ectromelia virus
      infected cells reacted with only one of the three MAbs provided a means of
      mapping the gene encoding the glycoprotein. By transfecting vaccinia virus DNA
      into cells infected with ectromelia virus and assaying for MAb reactivity, we
      mapped the glycoprotein to the A33R open reading frame. The amino acid sequence
      and hydrophilicity plot predicted that the A33R gene product is a type II
      membrane protein with two asparagine-linked glycosylation sites. Triton X-114
      partitioning experiments indicated that the A33R gene product is an integral
      membrane protein. The ectromelia virus homolog of the vaccinia virus A33R gene
      was sequenced, revealing 90% predicted amino acid identity. The vaccinia and
      variola virus homolog sequences predict 94% identical amino acids, the latter
      having one fewer internal amino acid. Electron microscopy revealed that the A33R
      gene product is expressed on the surface of extracellular enveloped virions but
      not on the intracellular mature form of virus. The conservation of this protein
      and its specific incorporation into viral envelopes suggest that it is important
      for virus dissemination.

PMID- 8648709
TI  - Patterns of viral replication correlate with outcome in simian immunodeficiency
      virus (SIV)-infected macaques: effect of prior immunization with a trivalent SIV
      vaccine in modified vaccinia virus Ankara.
AB  - The dynamics of plasma viremia were explored in a group of 12 simian
      immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) that had
      received prior immunization with either nonrecombinant or trivalent (gag-pol,
      env) SIV-recombinant vaccinia viruses. Three distinct patterns of viral
      replication observed during and following primary viremia accounted for
      significant differences in survival times. High-level primary plasma viremia with
      subsequently increasing viremia was associated with rapid progression to AIDS (n
      = 2). A high-level primary plasma virus load with a transient decline and
      subsequent progressive increase in viremia in the post-acute phase of infection
      was associated with progression to AIDS within a year (n = 6). Low levels of
      primary plasma viremia followed by sustained restriction of virus replication
      were associated with maintenance of normal lymphocyte subsets and intact lymphoid
      architecture (n = 4), reminiscent of the profile observed in human
      immunodeficiency virus type 1-infected long-term nonprogressors. Three of four
      macaques that showed this pattern had been immunized with an SIV recombinant
      derived from the attenuated vaccinia virus, modified vaccinia virus Ankara. These
      data link the dynamics and extent of virus replication to disease course and
      suggest that sustained suppression of virus promotes long-term, asymptomatic
      survival of SIV-infected macaques. These findings also suggest that vaccine
      modulation of host immunity may have profound beneficial effects on the
      subsequent disease course, even if sterilizing immunity is not achieved.

PMID- 8648711
TI  - Second locus involved in human immunodeficiency virus type 1 resistance to
      protease inhibitors.
AB  - Protease inhibitors are potent antiviral agents against human immunodeficiency
      virus type 1. As with reverse transcriptase inhibitors, however, resistance to
      protease inhibitors can develop and is attributed to the appearance of mutations
      in the protease gene. With the substrate analog protease inhibitors BILA 1906 BS
      and BILA 2185 BS, 350- to 1,500-fold-resistant variants have been selected in
      vitro and were found not only to contain mutations in the protease gene but also
      to contain mutations in Gag precursor p1/p6 and/or NC (p7)/p1 cleavage sites.
      Mutations in cleavage sites give rise to better peptide substrates for the
      protease in vitro and to improved processing of p15 precursors in drug-resistant
      clones. Importantly, removal of cleavage site mutations in resistant clones leads
      to a decrease or even an absence of viral growth, confirming their role in viral
      fitness. Therefore, these second-locus mutations indicate that cleavage of p15 is
      a rate-limiting step in polyprotein processing in highly resistant viruses. The
      functional constraint of p15 processing also suggests that additional selective
      pressure could further compromise viral fitness and maintain the benefits of
      antiviral therapies.

PMID- 8648712
TI  - Tropism of human adenovirus type 5-based vectors in swine and their ability to
      protect against transmissible gastroenteritis coronavirus.
AB  - The infection of epithelia] swine testicle and intestinal porcine epithelial
      (IPEC-1) cell lines by adenovirus type 5 (Ad5) has been studied in vitro by using
      an Ad5-luciferase recombinant containing the firefly luciferase gene as a
      reporter. Porcine cell lines supported Ad5 replication, showing virus titers,
      kinetics of virus production, and luciferase expression levels similar to those
      obtained in human 293 cells, which constitutively express the 5'-end 11% of the
      Ad5 genome. The tropism of Ad5-based vectors in swine and its ability to induce
      an efficient immune response against heterologous antigens expressed by foreign
      genes inserted in these vectors has been determined. Ad5 vectors replicate and
      express heterologous antigens in porcine lungs and mediastinal and mesenteric
      lymph nodes. Significant levels of heterologous antigen expression were also
      demonstrated in the small intestine (jejunum and ileum), but Ad5 replication in
      this organ was very poor, suggesting that Ad vectors undergo an abortive
      replication in the porcine small intestine. The tissues infected by Ad5 were
      dependent on the inoculation route. The oronasal route appeared to be best for
      inoculation of bronchus-associated lymphoid tissue infection, while the
      intraperitoneal route was best for gut-associated lymphoid tissue infection.
      Epithelial cells of bronchioles, macrophages, type II pneumocytes, and follicular
      dendritic cells were identified as targets for Ad5, while epithelial cells of the
      intestine were not infected by Ad5. Viruses with a deletion from 79.5 to 84.8 map
      units in the E3 region, with or without heterologous inserted genes, replicated
      to lower levels in porcine tissues than did wild-type Ad5. It was also shown that
      an Ad5 recombinant expressing the four antigenic sites (A, B, C, and D) of
      transmissible gastroenteritis coronavirus (TGEV) spike protein induced in swine
      immune responses which neutralized TGEV infectivity. In addition, porcine serum
      from Ad-TGEV-immune animals provide passive protection when mixed with fully
      virulent TGEV and orally administered to highly susceptible newborn piglets.
      These results taken together indicate that swine may be a good animal model for
      human Ad5 lung infection to aid in the evaluation of candidate adenovirus
      vaccines and that Ad5 may be suitable as a recombinant viral vaccine or for other
      applications in swine.

PMID- 8648713
TI  - A viral vaccine vector that expresses foreign genes in lymph nodes and protects
      against mucosal challenge.
AB  - A candidate live-virus vaccine strain of Venezuelan equine encephalitis virus
      (VEE) was configured as a replication-competent vector for in vivo expression of
      heterologous immunogens. Three features of VEE recommend it for use as a vaccine
      vector. (i) Most human and animal populations are not already immune to VEE, so
      preexisting immunity to the vector would not limit expression of the heterologous
      antigen. (ii) VEE replicates first in local lymphoid tissue, a site favoring the
      induction of an effective immune response. (iii) Parenteral immunization of
      rodents and humans with live, attenuated VEE vaccines protects against mucosal
      challenge, suggesting that VEE vaccine vectors might be used successfully to
      protect against mucosal pathogens. Upon subcutaneous (s.c.) inoculation into the
      footpad of mice, a VEE vector containing the complete influenza virus
      hemagglutinin (HA) gene expressed HA in the draining lymph node and induced anti
      HA immunoglobulin G (IgG) and IgA serum antibodies, the levels of which could be
      increased by s.c. booster inoculation. When immunized mice were challenged
      intranasally with a virulent strain of influenza virus, replication of challenge
      virus in their lungs was restricted, and they were completely protected from
      signs of disease. Significant reduction of influenza virus replication in the
      nasal epithelia of HA vector-immunized mice suggested an effective immunity at
      the mucosal surface. VEE vaccine vectors represent an alternative vaccination
      strategy when killed or subunit vaccines are ineffective or when the use of a
      live attenuated vaccine might be unsafe.

PMID- 8648714
TI  - The structure of adenovirus type 12 DNA integration sites in the hamster cell
      genome.
AB  - Foreign DNA can integrate into the genomes of mammalian cells, and this process
      plays major roles in viral oncogenesis and in the generation of transgenic
      organisms and will be important in evolving regimens for human somatic gene
      therapy. In the present study, the insertion sites of adenovirus type 12 (Ad12)
      DNA genomes have been analyzed in detail in the Ad12-transformed hamster cell
      line T637, its revertants, which have lost most of the >20 Ad12 genome
      equivalents integrated chromosomally in cell line T637, and in the Ad12-induced
      tumor T191. Some of these junction sites have been molecularly cloned, and the
      nucleotide sequences at the sites of transition between viral and cellular DNAs
      have been determined. The sites of linkage between the hamster cellular and the
      foreign (viral) DNA are characterized by the frequent occurrence of patch
      homologies between the recombination partners. The cellular junction sites
      investigated here are not transcriptionally active. One of the cellular DNA
      sequences abutting the right Ad12 DNA terminus in cell line T637 (os2) is
      represented only once in the hamster genome and has a strikingly low abundance of
      5'-CG-3' dinucleotide sequences. One 5'-GCGC-3' sequence close to the Ad12 DNA
      integration site is heavily methylated in normal cells, Ad12-transformed cells,
      and Ad12-induced tumor cells. The second such sequence is more remote from the
      junction site, is partly methylated in BHK21 hamster cells, and shows differences
      in methylation in different Ad12-transformed cell lines. This site is
      unmethylated in liver DNA. The cellular DNA sequence at the site of Ad12 linkage
      in the tumor T191 exhibits homologies to highly repetitive sequences of the Alu
      family and to an origin of hamster DNA replication containing an Alu element. A
      number of junction sites between Ad12 DNA and hamster or mouse DNA in Ad12
      transformed cell lines or Ad12-induced tumor cell lines, investigated here and
      previously, are characterized by stem-loop structures encompassing the junction
      sites.

PMID- 8648715
TI  - Crystal structure of the top domain of African horse sickness virus VP7:
      comparisons with bluetongue virus VP7.
AB  - The baculovirus-expressed core protein VP7 of African horse sickness virus
      serotype 4 (AHSV-4) has been purified to homogeneity and crystallized in the
      presence of 2.8 M urea. The X-ray structure has been solved to a 2.3-Angstroms (1
      Angstrom = 0.1 nm) resolution with an Rfactor of 19.8%. The structure of AHSV VP7
      reveals that during crystallization, the two-domain protein is cleaved and only
      the top domain remains. A similar problem was encountered previously with
      bluetongue virus (BTV) VP7 (whose structure has been reported), showing that the
      connections between the top and the bottom domains are rather weak for these two
      distinct orbiviruses. The top domains of both BTV and AHSV VP7 are trimeric and
      structurally very similar. The electron density maps show that they both possess
      an extra electron density feature along their molecular threefold axes, which is
      most likely due to an unidentified ion. The characteristics of the molecular
      surface of BTV and AHSV VP7 suggest why AHSV VP7 is much less soluble than BTV
      VP7 and indicate the possibility of attachment to the cell via attachment of an
      Arg-Gly-Asp (RGD) motif in the top domain of VP7 to a cellular integrin for both
      of these orbiviruses.

PMID- 8648716
TI  - The latency-related gene of bovine herpesvirus 1 encodes a product which inhibits
      cell cycle progression.
AB  - Bovine herpesvirus 1 (BHV-1) establishes a latent infection in the sensory
      ganglionic neurons of cattle. The exclusive viral RNA expressed in a latent
      infection is the latency-related (LR) RNA, suggesting that it regulates some
      aspect of a latent infection. During the course of a productive infection,
      alphaherpesviruses induce certain events which occur during cell cycle
      progression. Consequently, we hypothesized that a BHV-1 infection might induce
      events in neurons which occur during cell cycle progression. In agreement with
      this hypothesis, cyclin A was detected in neurons of trigeminal ganglia when
      rabbits were infected. Neuronal cell cycle progression or inappropriate
      expression of cyclin A leads to apoptosis, suggesting that a viral factor
      inhibits the deleterious effects of cyclin A expression. The BHV-1 LR gene
      inhibited cell cycle progression and proliferation of human osteosarcoma cells.
      Antibodies directed against cyclin A or the LR protein coprecipitated the LR
      protein or cyclin A, respectively, suggesting that the two proteins interact with
      each other. We conclude that LR gene products inhibit cell cycle progression and
      hypothesize that this activity enhances the survival of infected neurons.

PMID- 8648717
TI  - Structure-function analysis of soluble forms of herpes simplex virus glycoprotein
      D.
AB  - Glycoprotein D (gD) of herpes simplex virus (HSV) is essential for virus entry.
      Truncated forms of gD lacking the transmembrane and cytoplasmic tail regions have
      been shown to bind to cells and block plaque formation. Using complementation
      analysis and a panel of gD mutants, we previously identified four regions of gD
      (regions I to IV) which are important for virus entry. Here, we used baculovirus
      vectors to overexpress truncated forms of wild-type gD from HSV type 1 (HSV-1)
      [gD-1(306t)] and HSV-2 [gD-2(306t)] and four mutants, gD-1(inverted delta 34t),
      gD-1(inverted delta 126t), gD-1(inverted delta 243t), and gD-1(delta 290-299t),
      each having a mutation in one of the four functional regions. We used an enzyme
      linked immunosorbent assay and circular dichroism to analyze the structure of
      these proteins, and we used functional assays to study the role of gD in binding,
      penetration, and cell-to-cell spread. gD-1 and gD-2 are similar in antigenic
      structure and thermal stability but vary in secondary structure. Mutant proteins
      with insertions in region I or II were most altered in structure and stability,
      while mutants with insertions in region III or IV were less altered. gD-1(306t)
      and gD-2(306t) inhibited both plaque formation and cell-to-cell transmission of
      HSV-1. In spite of obvious structural differences, all of the mutant proteins
      bound to cells, confirming that binding is not the only function of gD. The
      region I mutant did not inhibit HSV plaque formation or cell-to-cell spread,
      suggesting that this region is necessary for the function of gD in these
      processes. Surprisingly, the other three mutant proteins functioned in all of the
      in vitro assays, indicating that the ability of gD to bind to cells and inhibit
      infection does not correlate with its ability to initiate infection as measured
      by the complementation assay. The region IV mutant, gD-1(delta 290-299t), had an
      unexpected enhanced inhibitory effect on HSV infection. Taken together, the
      results argue against a single functional domain in gD. It is likely that
      different gD structural elements are involved in successive steps of infection.

PMID- 8648718
TI  - Interference to human immunodeficiency virus type 1 infection in the absence of
      downmodulation of the principal virus receptor, CD4.
AB  - It is thought that interference during human immunodeficiency virus type 1 (HIV
      1) infection is established by downmodulation of the principal virus receptor,
      CD4. Here we present evidence to the contrary. At various times after primary
      infection, we superinfected T cells in vitro by exposure to a genetically
      distinct viral clone or to a virus carrying the chloramphenicol acetyltransferase
      gene. Replication of each virus strain was determined by restriction enzyme
      analysis of total cellular DNA, by PCR amplification of viral DNA, or by assay of
      cell extracts for chloramphenicol acetyltransferase activity. We found that
      efficient viral interference is established within 24 h of infection at a
      multiplicity of infection of 1. At that time, expression of viral structural
      proteins was low and infected cells displayed undiminished levels of surface CD4
      and were fully susceptible to virus binding and fusion. Superinfection by either
      cell-free HIV-1 or cocultivation was blocked. Cells resistant to superinfection
      by HIV-1 remained susceptible to Moloney murine leukemia and vaccinia viruses. No
      interference was observed 4 h after primary infection or in cells infected with
      either UV-inactivated HIV-1 or a mutant virus defective in virus-cell fusion
      activity, indicating that binding of primary virus to CD4 is insufficient to
      prevent superinfection. The minimum viral requirements for this interference are
      that HIV-1 must be able to enter cells and synthesize viral DNA; Tat-mediated
      transcription is dispensable. Our results support the existence of a novel
      pathway to interference to HIV-1 infection, which we term postentry interference,
      which blocks superinfection during intracellular phases of the virus life cycle.

PMID- 8648719
TI  - Avian retroviral RNA element promotes unspliced RNA accumulation in the
      cytoplasm.
AB  - All retroviruses need mechanisms for nucleocytoplasmic export of their unspliced
      RNA and for maintenance of this RNA in the cytoplasm, where it is either
      translated to produce Gag and Pol proteins or packaged into viral particles. The
      complex retroviruses encode Rev or Rex regulatory proteins, which interact with
      cis-acting viral sequences to promote cytoplasmic expression of incompletely
      spliced viral RNAs. Since the simple retroviruses do not encode regulatory
      proteins, we proposed that they might contain cis-acting sequences that could
      interact with cellular Rev-like proteins. To test this possibility, we initially
      looked for a cis-acting sequence in avian retroviruses that could substitute for
      Rev and the Rev response element in human immunodeficiency virus type 1
      expression constructs. A cis-acting element in the 3' untranslated region of Rous
      sarcoma virus (RSV) RNA was found to promote Rev-independent expression of human
      immunodeficiency virus type 1 Gag proteins. This element was mapped between RSV
      nucleotides 8770 and 8925 and includes one copy of the direct repeat (DR)
      sequences flanking the RSV src gene; similar activity was observed for the
      upstream DR. To address the function of this element in RSV, both copies of the
      DR sequence were deleted. Subsequently, each DR sequence was inserted separately
      back into this deleted construct. While the viral construct lacking both DR
      sequences failed to replicate, constructs containing either the upstream or
      downstream DR replicated well. In the absence of both DRs, Gag protein levels
      were severely diminished and cytoplasmic levels of unspliced viral RNA were
      significantly reduced; replacement of either DR sequence led to normal levels of
      Gag protein and cytoplasmic unspliced RNA.

PMID- 8648720
TI  - Adenovirus E4 open reading frame 4 protein autoregulates E4 transcription by
      inhibiting E1A transactivation of the E4 promoter.
AB  - Here we show that the adenovirus early region 4 (E4) open reading frame 4 (ORF4)
      protein autoregulates its own transcription by inhibiting adenovirus E1A-induced
      activation of E4 transcription both in transient transfection experiments and
      during lytic virus growth. The inhibitory activity of E4-ORF4 was selective for
      E1A-CR3-dependent transactivation and had no effect on CR1 transactivation. The
      inhibitory activity of E4-ORF4 was relieved by okadaic acid treatment, which
      inhibits the cellular protein phosphatase 2A (PP2A), suggesting that E4-ORF4
      controls the phosphorylated status of transcription factors important for E4
      promoter activity. This conclusion agrees with previous demonstrations that E4
      ORF4 associates with PP2A and causes a partial dephosphorylation of certain
      transcription factors, including E1A (U. Muller, T. Kleinberger, and T. Shenk, J.
      Virol. 66:5869-5878, 1992; T. Kleinberger and T. Shenk, J. Virol. 67:7556-7560,
      1993). However, our results indicate that dephosphorylation of E1A itself might
      not be the primary target for E4-ORF4. Instead, the E4-ORF4-PP2A complex appears
      to work by dephosphorylation of multiple cellular transcription factors that are
      involved in E1A transactivation of the E4 promoter.

PMID- 8648721
TI  - A multistep process of leukemogenesis in Moloney murine leukemia virus-infected
      mice that is modulated by retroviral pseudotyping and interference.
AB  - Mixed retroviral infections frequently exhibit pseudotyping, in which the genome
      of one virus is packaged in a virion containing SU proteins encoded by another
      virus. Infection of mice by Moloney murine leukemia virus (M-MuLV), which induces
      lymphocytic leukemia, results in a mixed viral infection composed of the
      inoculated ecotropic M-MuLV and polytropic MuLVs generated by recombination of M
      MuLV with endogenous retroviral sequences. In this report, we describe
      pseudotyping which occurred among the polytropic and ecotropic MuLVs in M-MuLV
      infected mice. Infectious center assays of polytropic MuLVs released from
      splenocytes or thymocytes of infected mice revealed that polytropic MuLVs were
      extensively pseudotyped within ecotropic virions. Late in the preleukemic stage,
      a dramatic change in the extent of pseudotyping occurred in thymuses. Starting at
      about 5 weeks, there was an abrupt increase in the number of thymocytes that
      released nonpseudotyped polytropic viruses. A parallel increase in thymocytes
      that released ecotropic M-MuLV packaged within polytropic virions was also
      observed. Analyses of the clonality of preleukemic thymuses and thymomas
      suggested that the change in pseudotyping characteristics was not the result of
      the emergence of tumor cells. Examination of mice infected with M-MuLV, Friend
      erythroleukemia virus, and a Friend erythroleukemia virus-M-MuLV chimeric virus
      suggested that the appearance of polytropic virions late in the preleukemic stage
      correlated with the induction of lymphocytic leukemia. We discuss different ways
      in which pseudotypic mixing may facilitate leukemogenesis, including a model in
      which the kinetics of thymic infection, modulated by pseudotyping and viral
      interference, facilitates a stepwise mechanism of leukemogenesis.

PMID- 8648722
TI  - Human immunodeficiency virus type 1 replication is blocked prior to reverse
      transcription and integration in freshly isolated peripheral blood monocytes.
AB  - Peripheral blood monocytes are resistant to productive human immunodeficiency
      virus type 1 (HIV-1) infection in vitro immediately after isolation. No viral
      cDNA (either early or late transcripts) was detected by PCR in monocytes exposed
      to virus on the day of isolation. In contrast, in monocytes cultured for as
      little as 1 day, initiated and completed reverse transcripts were readily
      detectable within 24 h of infection with both HIV-1(Ba-L) and primary isolates.
      The levels of initiated, partially completed, and completed viral DNA copies
      found 24 h after infection increased progressively with time in culture before
      infection. Unlike quiescent T lymphocytes, there appeared to be no block or delay
      in the integration of viral DNA into the genome of susceptible cultured
      monocytes. With an Alu-PCR method designed to specifically detect proviral DNA
      being used, integration events were found within 24 h of infection in monocytes
      cultured for a day or more after isolation. No integration signal was found in
      freshly isolated monocytes up to 7 days following exposure to the virus. Cloning
      and sequencing of Alu-PCR-amplified DNA confirmed integration in HIV-1-infected
      cultured monocytes. Our finding that in vitro replication of HIV-1 is clearly
      blocked prior to the initiation of reverse transcription in freshly isolated
      peripheral blood monocytes suggests that these cells may not be susceptible to
      infection in vivo. Further studies to clarify this possibility and the nature of
      the block to infection should provide useful information for treatment strategies
      against HIV-1.

PMID- 8648723
TI  - Expression of human immunodeficiency virus type 1 reverse transcriptase in trans
      during virion release and after infection.
AB  - The normal reverse transcription of retroviral RNA is a complex process which
      depends on the orchestration of several steps throughout the virus life cycle.
      During the assembly of retroviruses, reverse transcriptase (RT) is directed into
      the virion as a component of the Gag-Pol polyprotein. In the maturation of the
      Gag-Pol polyprotein of human immunodeficiency virus type 1 (HIV-1), cleavage by
      the viral protease occurs during viral budding. After infection, reverse
      transcription of viral RNA into double-stranded DNA is completed in the cytoplasm
      of the infected cell. In this study, the processing and reverse transcription of
      HIV-1 have been examined by separate expression of mature HIV-1 RT and proviral
      molecules bearing RT mutations. The effects of RT expression in trans during
      virion release and after viral entry were investigated. Constitutive expression
      of HIV-1 RT was established in CD4- and non-CD4-expressing cells via the
      coexpression of its individual subunits, and three HIV-1 RT mutant constructs
      were generated. The results indicate that a bona fide RT trans complementation
      does not occur during virion release or after infection. However, after infection
      of an RT-expressing cell with a high titer RT-defective virus, intracellular
      reverse transcription can be detected.

PMID- 8648724
TI  - Coxsackie B3 virus protein 2B contains cationic amphipathic helix that is
      required for viral RNA replication.
AB  - Enterovirus protein 2B has been shown to increase plasma membrane permeability.
      We have identified a conserved putative amphipathic alpha-helix with a narrow
      hydrophilic face and an arrangement of cationic residues that is typical for the
      so-called lytic polypeptides. To examine the functional and structural roles of
      this putative amphipathic alpha-helix, we have constructed nine coxsackie B3
      virus mutants by site-directed mutagenesis of an infectious cDNA clone. Six
      mutants contained substitutions of the charged residues in the hydrophilic face
      of the alpha-helix. Three mutants contained insertions of leucine residues
      between the charged residues, causing a disturbance of the amphipathic character
      of the alpha-helix. The effect of the mutations on virus viability was assayed by
      transfection of cells with copy RNA transcripts. The effect on positive-strand
      RNA replication was examined by introduction of the mutations in a subgenomic
      luciferase replicon and analysis of luciferase accumulation following the
      transfection of BGM cells with RNA transcripts. It is shown that both the
      amphipathy of the domain and the presence of cationic residues in the hydrophilic
      face of the alpha-helix are required for virus growth. Mutations that disturbed
      either one of these features caused defects in viral RNA synthesis. In vitro
      translation reactions and the analysis of viral protein synthesis in vivo
      demonstrated that the mutations did not affect synthesis and processing of the
      viral polyprotein. These results suggest that a cationic amphipathic alpha-helix
      is a major determinant for a function of protein 2B, and possibly its precursor
      2BC, in viral RNA synthesis. The potential role of the amphipathic alpha-helix in
      the permeabilization of cellular membranes is discussed.

PMID- 8648725
TI  - Mechanisms of simian virus 40 T-antigen activation by phosphorylation of
      threonine 124.
AB  - Previous studies have shown that phosphorylation of simian virus 40 (SV40) T
      antigen at threonine 124 enhances the binding of T antigen to the SV40 core
      origin of replication and the unwinding of the core origin DNA via hexamer
      hexamer interactions. Here, we report that threonine 124 phosphorylation enhances
      the interaction of T-antigen amino acids 1 to 259 and 89 to 259 with the core
      origin of replication. Phosphorylation, therefore, activates the minimal DNA
      binding domain of T antigen even in the absence of domains required for hexamer
      formation. Activation is mediated by only one of three DNA binding elements in
      the minimal DNA binding domain of T antigen. This element, including amino acids
      167, 215, and 219, enhances binding to the unique arrangement of four
      pentanucleotides in the core origin but not to other pentanucleotide arrangements
      found in ancillary regions of the SV40 origin of replication. Interestingly, the
      same four pentanucleotides in the core origin are necessary and sufficient for
      phosphorylation-enhanced DNA binding. Further, we show that phosphorylation of
      threonine 124 promotes the assembly of high-order complexes of the minimal DNA
      binding domain of T antigen with core origin DNA. We propose that phosphorylation
      induces conformational shifts in the minimal DNA binding domain of T antigen and
      thereby enhances interactions among T-antigen subunits oriented by core origin
      pentanucleotides. Similar subunit interactions would enhance both assembly of
      full-length T antigen into binary hexamer complexes and origin unwinding.

PMID- 8648726
TI  - Characterization of the ZI domains in the Epstein-Barr virus BZLF1 gene promoter:
      role in phorbol ester induction.
AB  - Induction of the Epstein-Barr virus lytic cycle is mediated through the immediate
      early BZLF1 gene and the coordinately regulated BRLF1 gene. The BZLF1 gene
      product, Zta, transactivates its own promoter, as well as the promoters of a
      number of lytic genes, thereby initiating a cascade of viral gene expression.
      Previous work identified four related elements (ZIA, ZIB, ZIC, and ZID) and a
      cyclic AMP response element binding-AP-1 element (ZII) that are involved in the
      induction of the BZLF1 promoter (Zp) by the phorbol ester 12-O
      tetradecanoylphorbol-13-acetate (TPA) (E. Flemington and S. H. Speck, J. Virol.
      64:1217-1226, 1990). Here we report a detailed characterization of TPA induction
      mediated by the ZI domains. Mutation of individual ZI domains within the context
      of the intact promoter significantly diminished TPA induction. Cloning of
      individual ZI domains upstream of a minimal promoter demonstrated that the ZIA,
      ZIC, and ZID domains, but not the ZIB domain, are TPA responsive. Furthermore,
      cloning of the ZII domain downstream of the ZI domains significantly augmented
      TPA induction. The critical regions within the ZIA and ZIC elements involved in
      binding of cellular factors were identified by using methylation interference and
      electrophoretic mobility shift analyses of ZI domain mutants. Four specific
      complexes were observed with the ZIA and ZID domains, all of which could be
      specifically competed for by either the ZIA or ZID domain. Methylation
      interference analyses of bound complexes revealed the presence of two overlapping
      binding sites for cellular factors in the ZIA domain, and functional studies
      provided evidence that both of these sites are involved in TPA induction.
      Functional analyses of the ZIC domain revealed that the 5' region of this domain
      is largely responsible for mediating TPA induction. Binding data correlated well
      with functional activity and revealed that the ZIC domain binds only a subset of
      the cellular factors that bind to the ZIA and ZID domains. Analysis of factor
      binding to the ZIB domain revealed only a single shifted complex, which
      correlated with the most slowly migrating complex observed with the ZIA and ZID
      domains. These data provide a direct demonstration of TPA induction mediated by
      the ZIA, ZIC, and ZID domains and also provide the first evidence that the ZI
      domains exhibit distinct functional characteristics.

PMID- 8648727
TI  - The human foamy virus Bel-1 transcription factor is a sequence-specific DNA
      binding protein.
AB  - The Bel-1 transcriptional transactivator encoded by human foamy virus (HFV) can
      efficiently activate gene expression directed by both the HFV long terminal
      repeat (LTR) and internal (Int) promoter elements. By DNA footprinting and gel
      retardation analysis, we demonstrate that Bel-1 can specifically bind to discrete
      sites in both the LTR and Int promoter elements in vitro. However,
      transactivation of the HFV LTR by Bel-1 was observed to require not only the
      promoter-proximal Bel-1 binding site identified in vitro but also additional
      promoter-distal sequences. These data suggest that Bel-1 binding is necessary but
      not sufficient for efficient transactivation of Bel-1-responsive promoters in
      mammalian cells and therefore raise the possibility that Bel-1 function may
      require the action of a cellular DNA binding protein(s). Importantly, these data
      demonstrate that Bel-1 is unique among retroviral regulatory proteins in being a
      sequence-specific DNA binding protein.

PMID- 8648728
TI  - Coordinated disintegration reactions mediated by Moloney murine leukemia virus
      integrase.
AB  - The protein-DNA and protein-protein interactions important for function of the
      integrase (IN) protein of Moloney murine leukemia virus (M-MuLV) were
      investigated by using a coordinated-disintegration assay. A panel of M-MuLV IN
      mutants and substrate alterations highlighted distinctions between the
      intermolecular and intramolecular reactions of coordinated disintegration.
      Mispairing of the crossbone single-strand region and altered long terminal repeat
      (LTR) positioning affected the intermolecular, but not the intramolecular,
      reactions of coordinated disintegration. Partial components of the crossbone
      substrate were coordinated by M-MuLV IN, indicating a reliance on both LTR and
      target DNA determinants for substrate assembly. The intramolecular reaction was
      dependent on the presence of either the HHCC domain or a crossbone LTR 5' single
      stranded tail. An M-MuLV IN mutant without the HHCC domain (Ndelta105) catalyzed
      reduced levels of double disintegration but not single disintegration. A
      separately purified HHCC domain protein (Cdelta232) stimulated double
      disintegration mediated by Ndelta105, suggesting a role of the N-terminal HHCC
      domain in stable IN-IN and IN-DNA interactions. Significantly, crossbone
      substrates lacking the LTR 5' tails were not recognized by the fingerless
      Ndelta105 protein. Collectively, these data suggest similar roles of the HHCC
      domain and 5' LTR tail in substrate recognition and modulation of IN activity.

PMID- 8648729
TI  - Gene transfer into mammalian cells by a Rous sarcoma virus-based retroviral
      vector with the host range of the amphotropic murine leukemia virus.
AB  - We have constructed and characterized a Rous sarcoma virus-based retroviral
      vector with the host range of the amphotropic murine leukemia virus (MLV). The
      chimeric retroviral genome was created by replacing the env coding region in the
      replication-competent retroviral vector RCASBP(A) with the env region from an
      amphotropic MLV. The recombinant vector RCASBP-M(4070A) forms particles
      containing MLV Env glycoproteins. The vector replicates efficiently in chicken
      embryo fibroblasts and is able to transfer genes into mammalian cells. Vector
      stocks with titers exceeding 10(6) CFU/ml on mammalian cells can be easily
      prepared by passaging transfected chicken embryo fibroblasts. Since the vector is
      inherently defective in mammalian cells, it appears to have the safety features
      required for gene therapy.

PMID- 8648730
TI  - Dengue type 4 virus mutants containing deletions in the 3' noncoding region of
      the RNA genome: analysis of growth restriction in cell culture and altered
      viremia pattern and immunogenicity in rhesus monkeys.
AB  - The dengue type 4 virus (DEN4) genome contains a 384-nucleotide (nt) 3' noncoding
      sequence in which the last 81 nt, predicted to form a secondary structure, are
      thought to be essential for virus replication. Immediately upstream of the
      secondary structure, short RNA sequences that are conserved among mosquito-borne
      flaviviruses have been identified. A series of deletions that range from 30 to
      262 nt were introduced into this upstream region of full-length DEN4 cDNA to
      create viable deletion mutants, some of which might prove to be useful for
      inclusion in a live attenuated virus vaccine. When studied by an infectious
      center assay, most full-length RNA transcripts of the deletion constructs
      exhibited reduced infectivity when transfected into simian LLC-MK2 cells compared
      with the full-length RNA transcripts of wild-type parental virus. Deletion
      mutations that extended as far as the 5' boundary of the 3' noncoding region and
      whose 3' boundary did not extend beyond the last 113 nt of the 3' end were
      viable. With the exception of mutant 3'd 303-183, which contained a deletion of
      nt 303 to 183 from the 3' terminus, deletion mutants produced plaques that
      appeared late on simian LLC-MK2 cells or exhibited a small-plaque morphology on
      mosquito C6/36 cells compared with the wild-type virus. These mutants also
      replicated less efficiently and attained a lower titer in LLC-MK2 cells than
      parental wild-type virus. Significantly, mutant 3'd 303-183 grew to a high titer
      and was least restricted in growth. Mutant 3'd 303-183 and four other moderately
      to severely restricted mutants were selected for evaluation of infectivity and
      immunogenicity in rhesus monkeys. There was a suggestion that occurrence and
      duration of viremia were reduced for some of the deletion mutants compared with
      the wild-type virus. However, more convincing evidence for attenuation of some of
      the mutants was provided by an analysis of antibody response to infection. Mutant
      3'd 303-183 induced an antibody response equivalent to that stimulated by wild
      type virus, whereas other mutants induced low to moderate levels of antibodies,
      as measured by radioimmunoprecipitation and virus neutralization. The
      immunogenicity of these 3' DEN4 deletion mutants in monkeys appeared to correlate
      with their efficiency of growth in simian LLC-MK2 cells. One or more mutants
      described in this paper may prove to be useful for immunization of humans against
      disease caused by dengue virus.

PMID- 8648731
TI  - Properties of the protein encoded by the UL32 open reading frame of herpes
      simplex virus 1.
AB  - The functions previously assigned to the essential herpes simplex virus 1 UL32
      protein were in cleavage and/or packaging of viral DNA and in maturation and/or
      translocation of viral glycoproteins to the plasma membrane. The amino acid
      sequence predicts N-linked glycosylation sites and sequences conserved in
      aspartyl proteases and in zinc-binding proteins. We report the following. (i) The
      596-amino-acid UL32 protein accumulated predominantly in the cytoplasm of
      infected cells but was not metabolically labeled with glucosamine and did not
      band with membranes containing a known glycoprotein in flotation sucrose density
      gradients. The UL32 protein does not, therefore, have the properties of an
      intrinsic membrane protein. (ii) Experiments designed to demonstrate aspartyl
      protease activity in a phage display system failed to reveal proteolytic
      activity. Moreover, substitution of Asp-110 with Gly in the sequence Asp-Thr-Gly,
      the hallmark of aspartyl proteases, had no effect on viral replication in Vero
      and SK-N-SH cell lines or in human foreskin fibroblasts. Therefore, if the UL32
      protein functions as a protease, this function is not required in cells in
      culture. (iii) Both the native UL32 protein and a histidine-tagged UL32 protein
      made in recombinant baculovirus-infected insect cells bound zinc. The consensus
      sequence is conserved in the UL32 homologs from varicella-zoster virus and equine
      herpesvirus 1. UL32 protein is therefore a cysteine-rich, zinc-binding essential
      cytoplasmic protein whose function is not yet clear.

PMID- 8648732
TI  - Molecular anatomy of mouse hepatitis virus persistence: coevolution of increased
      host cell resistance and virus virulence.
AB  - Persistent infection of murine astrocytoma (DBT) cells with mouse hepatitis virus
      (MHV) has been established. From this in vitro virus-host system, persistence is
      mediated at the level of cellular MHV receptor (MHVR) expression and increased
      virus virulence. MHV persistence selects for resistant host cell populations
      which abate virus replication. Reductions in MHVR expression were significantly
      associated with increased host resistance, and transfection of MHVR into
      resistant host cells completely restored the capacity of cells to support
      efficient replication of MHV strain A59. The emergence of resistant host cells
      coselected for variant viruses that had increased avidity for MHVR and also
      recognized different receptors for entry into resistant cells. These data
      illustrate that MHV persistence in vitro provides a model to identify critical
      sites of virus-host interaction at the cellular level which are altered during
      the evolution of host cell resistance to viral infection and the coevolution of
      virus virulence.

PMID- 8648733
TI  - cis-Acting signals that promote genome replication in rotavirus mRNA.
AB  - A previous study has shown that rotavirus cores have an associated replicase
      activity which can direct the synthesis of double-stranded RNA from viral mRNA in
      a cell-free system (D. Y. Chen, C. Q.-Y. Zeng, M. J. Wentz, M. Gorziglia, M. K.
      Estes, and R. F. Ramig, J. Virol. 68:7030-7039, 1994). To define the cis-acting
      signals in rotavirus mRNA that are important for RNA replication, gene 8
      transcripts which contained internal and terminal deletions and chimeric
      transcripts which linked gene 8-specific 3'-terminal sequences to the ends of
      nonviral sequences were generated. Analysis of these RNAs in the cell-free system
      led to the identification of a cis-acting signal in the gene 8 mRNA which is
      essential for RNA replication and two cis-acting signals which, while not
      essential for replication, serve to enhance the process. The sequence of the
      essential replication signal is located at the extreme 3' end of the gene 8 mRNA
      and, because of its highly conserved nature, is probably a common feature of all
      11 viral mRNAs. By site-specific mutagenesis of the gene 8 mRNA, residues at
      positions -1, -2, -5, -6, and -7 of the 3' essential signal were found to be
      particularly important for promoting RNA replication. One of the cis-acting
      signals shown to enhance the replication in the cell-free system was located near
      the 5' end of the 3' untranslated region (UTR) of the gene 8 mRNA, while
      remarkably the other was located in the 5' UTR of the message. The existence of
      an enhancement signal in the 5' UTR raises the possibility that the 5' and 3'
      ends of the rotavirus mRNA may interact with each other and/or with the viral
      replicase during genome replication.

PMID- 8648734
TI  - Inhibition of nitric oxide synthesis increases mortality in Sindbis virus
      encephalitis.
AB  - Sindbis virus (SV) is an alphavirus that causes acute encephalomyelitis in mice.
      The outcome is determined by the strain of virus and by the age and genetic
      background of the host. The mortality rates after infection with NSV, a
      neurovirulent strain of SV, were as follows v: 81% (17 of 21) in BALB/cJ mice;
      20% (4 of 20) in BALB/cByJ mice (P < 0.001); 100% in A/J, C57BL/6J, SJL, and DBA
      mice; and 79% (11 of 14) in immunodeficient scid/CB17 mice. Treatment with Nomega
      nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthetase (NOS)
      inhibitor, increased mortality to 100% (P < 0.05) in NSV-infected BALB/cJ mice,
      to 95% (P < 0.001) in BALB/cByJ mice, and to 100% in scid/CB17 mice. BALB/cJ and
      BALB/cByJ mice had similar levels of inducible NOS mRNA in their brains, which
      were not affected by L-NAME or NSV infection. Brain NOS activity was similar in
      BALB/cJ and BALB/cByJ mice before and after infection and was markedly inhibited
      by L-NAME. NSV replication in the brains of BALB/cJ mice, BALB/cByJ mice, and
      mice treated with L-NAME was similar. Treatment of N18 neuroblastoma cells with
      NO donors S-nitroso-N-acetylpenicillamine or sodium nitroprusside in vitro before
      infection increased cell viability at 42 to 48 h compared with untreated NSV
      infected N18 cells with little effect on virus replication. These data suggest
      that NO protects mice from fatal encephalitis by a mechanism that does not
      directly involve the immune response or inhibition of virus growth but rather may
      enhance survival of the infected neuron until the immune response can control
      virus replication.

PMID- 8648735
TI  - Simian immunodeficiency virus DNA vaccine trial in macaques.
AB  - An experimental vaccine consisting of five DNA plasmids expressing different
      combinations and forms of simian immunodeficiency virus-macaque (SIVmac) proteins
      has been evaluated for the ability to protect against a highly pathogenic
      uncloned SIVmac251 challenge. One vaccine plasmid encoded nonreplicating
      SIVmac239 virus particles. The other four plasmids encoded secreted forms of the
      envelope glycoproteins of two T-cell-tropic relatives (SIVmac239 and SIVmac251)
      and one monocyte/macrophage-tropic relative (SIVmac316) of the uncloned challenge
      virus. Rhesus macaques were inoculated with DNA at 1 and 3, 11 and 13, and 21 and
      23 weeks. Four macaques were inoculated intravenously, intramuscularly, and by
      gene gun inoculations. Three received only gene gun inoculations. Two control
      monkeys were inoculated with control plasmids by all three routes of inoculation.
      Neutralizing antibody titers of 1:216 to 1:768 were present in all of the
      vaccinated monkeys after the second cluster of inoculations. These titers were
      transient, were not boosted by the third cluster of inoculations, and had fallen
      to 1:24 to 1:72 by the time of challenge. Cytotoxic T-cell activity for Env was
      also raised in all of the vaccinated animals. The temporal appearance of
      cytotoxic T cells was similar to that of antibody. However, while antibody
      responses fell with time, cytotoxic T-cell responses persisted. The SIVmac251
      challenge was administered intravenously at 2 weeks following the last
      immunization. The DNA immunizations did not prevent infection or protect against
      CD4+ cell loss. Long-term chronic levels of infection were similar in the
      vaccinated and control animals, with 1 in 10,000 to 1 in 100,000 peripheral blood
      cells carrying infectious virus. However, viral loads were reduced to the chronic
      level over a shorter period of time in the vaccinated groups (6 weeks) than in
      the control group (12 weeks). Thus, the DNA vaccine raised both neutralizing
      antibody and cytotoxic T-lymphocyte responses and provided some attenuation of
      the acute phase of infection, but it did not prevent the loss of CD4+ cells.

PMID- 8648736
TI  - Efficient retroviral infection of mammalian cells is blocked by inhibition of
      poly(ADP-ribose) polymerase activity.
AB  - Integration of proviral DNA into the host cell genome is a characteristic feature
      of the retroviral life cycle. This process involves coordinate DNA strand break
      formation and rejoining reactions. The full details of the integration process
      are not yet fully understood. However, the endonuclease and DNA strand-joining
      activities of the virus-encoded integrase protein (IN) are thought to act in
      concert with other, as-yet-unidentified, endogenous nuclear components which are
      involved in the DNA repair process. The nuclear enzyme poly(ADP-ribose)
      polymerase (PARP), which is dependent on DNA strand breaks for its activity, is
      involved in the efficient repair of DNA strand breaks, and maintenance of genomic
      integrity, in nucleated eukaryotic cells. In the present work, we examine the
      possible involvement of PARP in the retroviral life cycle and demonstrate that
      inhibition of PARP activity, by any one of three independent mechanisms, blocks
      the infection of mammalian cells by recombinant retroviral vectors. This
      requirement for PARP activity appears to be restricted to processes involved in
      the integration of provirus into the host cell DNA. PARP inhibition does not
      affect viral entry into the host cell, reverse transcription of the viral RNA
      genome, postintegration synthesis of viral gene products, synthesis of the viral
      RNA genome, or the generation of infective virions. Therefore, efficient
      retroviral infection of mammalian cells is blocked by inhibition or PARP
      activity.

PMID- 8648737
TI  - Costimulation of cytokine gene expression in T cells by the human T
      leukemia/lymphotropic virus type 1 trans activator Tax.
AB  - Many cell signals such as CD28 and CD4 binding can costimulate cytokine gene
      expression in activated T cells. We have found that the human T
      leukemia/lymphotropic virus type 1 viral protein Tax can also strongly
      costimulate expression of interleukin-2 (IL-2), IL-3, and granulocyte-macrophage
      colony-stimulating factor (GM-CSF) mRNA in T cells activated with the phorbol
      ester phorbol myristate acetate (PMA) and calcium ionophore, which can mimic
      activation through the antigen specific T-cell receptor. Reporter constructs also
      showed strong synergy between both stimuli and showed that Tax and the PMA-Ca2+
      ionophore act through different regions of the IL-2 and GM-CSF genes.
      Furthermore, the Tax-responsive regions (TxRR) from both GM-CSF and IL-2 respond
      to costimulation through the CD28 surface receptor. The GM-CSF and IL-2 TxRRs
      showed significantly higher levels of NF-kappaB/rel binding, following induction
      by Tax, compared with that of the PMA-Ca2+ ionophore with only Tax capable of
      inducing c-Rel binding to a Consensus kappaB element within the GM-CSF TxRR. Tax
      protein mutants, however, showed that a pathway(s) other than NF-kappaB/rel
      induction could also cooperate with the PMA-Ca2+ ionophore to activate the GM-CSF
      and IL-2 genes. This high-level costimulation by Tax, through multiple pathways,
      may be important in the early stages of leukemia and in the nervous system
      disorder tropical spastic paraparesis.

PMID- 8648739
TI  - A critical role for the TAR element in promoting efficient human immunodeficiency
      virus type 1 reverse transcription.
AB  - The regulation of human immunodeficiency virus type 1 (HIV-1) gene expression is
      dependent on the transactivator protein Tat and an RNA element extending from the
      transcription initiation site to +57 known as TAR. TAR forms a stable RNA
      secondary structure which is critical for high levels of HIV-1 gene expression
      and efficient viral replication. Using a genetic approach, we isolated HIV-1
      mutants in TAR that were competent for high levels of gene expression but yet
      were markedly defective for viral replication. Single-cycle infections with these
      viruses demonstrated that they were defective in the initiation of reverse
      transcription. Additional mutational analysis revealed a variety of other HIV-1
      TAR mutants with the same defective phenotype. Thus, in addition to the well
      characterized role of the primer binding site, other RNA elements within the HIV
      1 genome are also critical in the regulation of reverse transcription. These
      studies demonstrate that HIV-1 TAR RNA is a key regulator of the reverse
      transcription and illustrate how a unique RNA structure can modulate diverse
      regulatory processes in the HIV-1 life cycle crucial for efficient viral
      replication.

PMID- 8648738
TI  - Repression of human immunodeficiency virus type 1 long terminal repeat-driven
      gene expression by binding of the virus to its primary cellular receptor, the CD4
      molecule.
AB  - We have previously postulated that the binding of the human immunodeficiency
      virus type 1 (HIV-1) to cell surface CD4 induces signal transduction pathways
      that down-modulate production of progeny virions in acutely infected T cells (M.
      Tremblay, S. Meloche, S. Gratton, M. A. Wainberg, and R.-P. Sekaly, EMBO J.
      13:774-783, 1994). To evaluate the possibility that CD4 cross-linking might
      indeed affect viral gene expression, we have introduced a molecular construct
      made of the luciferase reporter gene placed under the control of the regulatory
      elements of HIV-1 in several CD4-positive T-cell lines. We found that cross
      linking of CD4 with defective HIV-1 particles and heat-inactivated viruses
      inhibits long terminal repeat-dependent luciferase expression. Experiments
      revealed that the gp120-CD4 interaction was necessary to repress HIV-1 long
      terminal repeat-dependent luciferase activity. The cytoplasmic domain of CD4 was
      also found to be required for this effect to occur. The virus-mediated signal
      transduction was shown to be mediated via p56lck-dependent and -independent
      pathways. These results indicate that the earliest event in the HIV-1 replicative
      cycle, namely, the binding of the virus to its cellular receptor, can lead to
      signal transduction culminating in down-modulation of viral gene expression. Thus
      we propose that defective viruses could regulate the pathogenesis of HIV disease
      as they constitute the vast majority of circulating HIV-1 particles.

PMID- 8648740
TI  - Human cytomegalovirus immediate-early 2 (IE2) protein can transactivate the human
      hsp70 promoter by alleviation of Dr1-mediated repression.
AB  - The immediate-early 1 and 2 (IE1 and IE2, respectively) proteins of human
      cytomegalovirus are known transcription factors, which regulate the expression of
      viral and cellular genes. Transcriptional activation by IE2 is dependent on the
      presence of a TATA motif in target promoters, and IE2 can interact directly with
      the TATA-binding protein (TBP) component of TFIID. TBP is known to be the target
      for transcriptional repression by the cellular Dr1 protein, and this factor has
      been shown to repress expression from the hsp70 promoter in vivo. Since this
      promoter is up-regulated by IE2, we asked whether the effects of Dr1 can be
      overcome by IE2. We report here that IE2 can overcome Dr1-mediated repression of
      the hsp70 promoter in vivo and that IE2 can interact with Dr1 in vivo and in
      vitro. We also demonstrate a previously unreported activity of Dr1, inhibition of
      DNA binding by TBP, and show that IE2 is able to overcome this inhibition in
      vitro, suggesting a mechanism for the TATA dependency of IE2-mediated trans
      activation.

PMID- 8648741
TI  - Human T-cell leukemia virus infection of human hematopoietic progenitor cells:
      maintenance of virus infection during differentiation in vitro and in vivo.
AB  - Human T-cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T
      cell leukemia and lymphoma and HTLV-1-associated myelopathy-tropical spastic
      paraparesis. We examined whether HTLV could productively infect human
      hematopoietic progenitor cells. CD34+ cells were enriched from human fetal liver
      cells and cocultivated with cell lines transformed with HTLV-1 and -2. HTLV-1
      infection was established in between 10 and >95% of the enriched CD34+ cell
      population, as demonstrated by quantitative PCR analysis. HTLV-1 p19 Gag
      expression was also detected in infected hematopoietic progenitor cells. HTLV-1
      infected hematopoietic progenitor cells were cultured in semisolid medium
      permissive for the development of erythbroid (BFU-E), myeloid (CFU-GM), and
      primitive progenitor (CFU-GEMM, HPP-CFC, or CFU-A) colonies. HTLV-1 sequences
      were detected in colonies of all hematopoietic lineages; furthermore, the ratio
      of HTLV genomes to the number of human cells in each infected colony was 1:1,
      consistent with each colony arising from a single infected hematopoietic
      progenitor cell. Severe combined immunodeficient mice engrafted with human fetal
      thymus and liver tissues (SCID-hu) develop a conjoint organ which supports human
      thymocyte differentiation and maturation. Inoculation of SCID-hu mice with HTLV-1
      infected T cells or enriched populations of CD34+ cells established viral
      infection of thymocytes 4 to 6 weeks postreconstitution. Thymocytes from two mice
      with the greatest HTLV-1 proviral burdens showed increased expression of the CD25
      marker and the interleukin 2 receptor alpha chain and perturbation of CD4+ and
      CD8+ thymocyte subset distribution profiles. Hematopoietic progenitor cells and
      thymuses may be targets for HTLV infection in humans, and these events may play a
      role in the pathogenesis associated with infection.

PMID- 8648742
TI  - Chimeric hepatitis B virus core particles as probes for studying peptide-integrin
      interactions.
AB  - An RGD-containing epitope from the foot-and-mouth disease virus (FMDV) VP1
      protein was inserted into the e1 loop of the hepatitis B virus core (HBc)
      protein. This chimeric protein was expressed at high levels in Escherichia coli
      and spontaneously assembled into virus-like particles which could be readily
      purified. These fusion particles elicited high levels of both enzyme-linked
      immunosorbent assay- and FMDV-neutralizing antibodies in guinea pigs. The
      chimeric particles bound specifically to cultured eukaryotic cells. Mutant
      particles carrying the tripeptide sequence RGE in place of RGD and the use of a
      competitive peptide, GRGDS, confirmed the critical involvement of the RGD
      sequence in this binding. The chimeric particles also bound to purified
      integrins, and inhibition by chain-specific anti-integrin monoclonal antibodies
      implicated alpha 5 beta 1 as a candidate cell receptor for both the chimeric
      particle and FMDV. Some serotypes of FMDV bound to beta 1 integrins in solid-
      phase assays, and the chimeric particles competed with FMDV for binding to
      susceptible eukaryotic cells. Thus, HBc particles may provide a simple, general
      system for exploring the interactions of specific peptide sequences with cellular
      receptors.

PMID- 8648743
TI  - Human immunodeficiency virus type 1 long terminal repeat variants from 42
      patients representing all stages of infection display a wide range of sequence
      polymorphism and transcription activity.
AB  - Despite extensive in vitro studies identifying a myriad of cellular transcription
      factors that bind the human immunodeficiency virus type 1 5' long terminal repeat
      (LTR), the relative contribution of these factors to human immunodeficiency virus
      type 1 replication in infected individuals remains obscure. To address this
      question, we investigated 478 proviral quasispecies derived from uncultured
      peripheral blood mononuclear cells of 42 patients representing all stages of
      infection. In addition to highly conserved TATA box, SP-1, and NF-kappaB sites,
      the Ets core and an adjacent 5'-ACYGCTGA-3' motif were extremely conserved.
      Importantly, the most frequent naturally occurring length polymorphism (MFNLP)
      duplicated 5'-ACYGCTGA-3' motifs in LTRs in which this same motif was disrupted
      or in LTRs in which a single point mutation to the Ets core ablated binding of c
      Ets 1 and another factor distinct from both c-Ets 1 and Elf 1. The MFNLP's
      location was precise (position -121) and surprisingly frequent (38% of patients)
      and demarcated LTR Nef-coding sequences from LTR noncoding sequences that appear
      to be evolving independently. Aside from these features, we found no definitive
      clinical or transcription phenotype common to all MFNLP LTRs. We also found
      previously described and novel point polymorphisms, including some conferring TAR
      dependent and TAR- independent Tat unresponsiveness, and showed that differential
      binding of nuclear factor(s) to a TCTAA TATA box variant may be the mechanism for
      the latter.

PMID- 8648744
TI  - Sequence tags of provirus integration sites in DNAs of tumors induced by the
      murine retrovirus SL3-3.
AB  - The murine retrovirus SL3-3 is a potent inducer of T-cell lymphomas when
      inoculated into susceptible newborn mice. The proviral integration site sequences
      were surveyed in tumor DNAs by a simple two-step PCR method. From 20 SL3-3
      induced tumors a total of 39 provirus-host junctions were amplified and
      sequenced. Seven showed homology to known sequences. These included the known
      common integration site c-myc as well as genes not previously identified as
      targets of provirus integration, namely N-ras and the genes coding for major
      histocompatibility complex class 11 E-beta, protein kinase C-eta, and T-cell
      receptor beta-chain. Among these genes, the integrations in c-myc as well as the
      one in N-ras were found to be clonal. One of the remaining 32 proviral
      integration site sequences that show no similarities to known sequences may
      represent a common integration site, as 2 of the 20 tumors demonstrated clonal
      provirus insertion into this region.

PMID- 8648746
TI  - A human cell line selected for resistance to adenovirus infection has reduced
      levels of the virus receptor.
AB  - To investigate determinants of host cell susceptibility to infection, cells
      partially resistant to infection were selected from the rare cells which remained
      adherent after infection of a culture of A549 cells with Ad2RAE, a mutant of
      adenovirus type 2 whose vertex capsomers lack an Arg-Gly-Asp (RGD) sequence which
      mediates binding of wild-type virus to integrins. Integrins promote the
      internalization of attached virions, whereas adsorption itself results from
      binding of the viral fibers to an unidentified cellular receptor. Following three
      rounds of selection, a persistently infected culture was established in which
      virus replication was detected in approximately 5% of the cells. Uninfected cells
      were readily cloned from the culture, indicating that at any particular time the
      majority of cells in the culture were uninfected. The resistance of one clone of
      uninfected cells to infection was correlated with a 10-fold reduction in the
      concentration of fiber receptors on these cells compared with the parental A549
      cell line, indicating that efficiency of virus adsorption depends on the receptor
      concentration. Surprisingly, the rate at which host cells internalized RGD
      negative virus also was strongly dependent on the fiber receptor concentration.
      While internalization of wild-type virus is promoted by the binding of integrins
      to the penton base RGD sequence, these results suggest that virus also can enter
      cells by an alternate pathway which requires binding of virions to multiple fiber
      receptors.

PMID- 8648745
TI  - mRNA export correlates with activation of transcription in human subgroup C
      adenovirus-infected cells.
AB  - To investigate the mechanisms by which viral mRNA species are distinguished from
      their cellular counterparts for export to the cytoplasm during the late phase of
      subgroup C adenovirus infection, we have examined the metabolism of several
      cellular and viral mRNAs in human cells productively infected by adenovirus type
      5 (Ad5). Several cellular mRNAs that were refractory to, or could escape from,
      adenovirus-induced inhibition of export of mRNA from the nucleus have been
      identified. This group includes Hsp70 mRNAs synthesized upon heat shock of Ad5
      infected 293 or HeLa cells during the late phase of infection. However,
      successful export in Ad5-infected cells is not a specific response to heat shock,
      for beta-tubulin and interferon-inducible mRNAs were also refractory to virus
      induced export inhibition. The export of these cellular mRNAs, like that of viral
      late mRNAs, required the E1B 55-kDa protein. Export to the cytoplasm during the
      late phase of Ad5 infection of several cellular mRNAs, including members of the
      Hsp70 family whose export was inhibited under some, but not other, conditions,
      indicates that viral mRNA species cannot be selectively exported by virtue of
      specific sequence or structural features. Cellular and viral late mRNAs that can
      be exported from the nucleus to the cytoplasm were expressed from genes whose
      transcription was induced or activated during the late phase of Ad5 infection.
      Consistent with the possibility that successful export is governed by
      transcriptional activation in the late phase of adenovirus infection, newly
      synthesized viral early E1A mRNA was subject to export inhibition during the late
      phase of infection.

PMID- 8648747
TI  - Synthesis of Semliki Forest virus RNA polymerase components nsP1 through nsP4 in
      Saccharomyces cerevisiae by expression of cDNA encoding the nonstructural
      polyprotein.
AB  - A Semliki Forest virus nonstructural polyprotein, P1234, expressed in the yeast
      Saccharomyces cerevisiae in the absence of a replicative RNA template appeared to
      be properly cleaved into nsP1 to nsP4. All nsPs were membrane associated, and
      nsP2 was also transported to the nucleus. The membrane fraction containing nsPs
      showed guanine-7-methyltransferase and guanylyltransferase-like activities,
      typical for Semliki Forest virus nsP1.

PMID- 8648748
TI  - Human isolates of dengue type 1 virus induce apoptosis in mouse neuroblastoma
      cells.
AB  - Human isolates of dengue (DEN) type 1 viruses FGA/89 and BR/90 differ in their
      membrane fusion properties in mosquito cell lines (P. Despres et al., Virology
      196:209-216, 1993). FGA/89 and BR/90 were assayed for their neurovirulence in
      newborn mice, and neurons were the major target cells for both DEN-1 virus
      strains within the central nervous system. To study the susceptibility of neurons
      to DEN virus infection, DEN virus replication was analyzed in the murine
      neuroblastoma cell line Neuro 2a. Infection of Neuro 2a cells with FGA/89 or
      BR/90 induced apoptotic DNA degradation after 25 h of infection. Studies of DEN
      protein synthesis revealed that accumulation of viral proteins leads to apoptotic
      cell death. The apoptotic process progressed more rapidly following BR/90
      infection than it did after FGA/89 infection. The higher cytotoxicity of BR/90
      for Neuro 2a cells was linked to an incomplete maturation of the envelope
      proteins, resulting in abortive virus assembly. Accumulation of viral proteins in
      the endoplasmic reticulum may induce stress and thereby activate the apoptotic
      pathway in mouse neuroblastoma cells.

PMID- 8648749
TI  - Oral inoculation with herpes simplex virus type 1 infects enteric neuron and
      mucosal nerve fibers within the gastrointestinal tract in mice.
AB  - Herpes simplex virus type 1 (HSV-1) is commonly encountered first during
      childhood as an oral infection. After this initial infection resolves, the virus
      remains in a latent form within innervating sensory ganglia for the life of the
      host. We have previously shown, using a murine model, that HSV-1 placed within
      the lumen of the esophagus gains access to nerves within the gut wall and
      establishes a latent infection in sensory ganglia (nodose ganglia) of the tenth
      cranial nerve (R. M. Gesser, T. Valyi-Nagy, S. M. Altschuler, and N. W. Fraser,
      J. Gen. Virol. 75:2379-2386, 1994). Peripheral processes of neurons in these
      ganglia travel through the vagus nerve and function as primary sensory receptors
      in most of the gastrointestinal tract, relaying information from the gut wall and
      mucosal surface to secondary neurons within the brain stem. In the work described
      here, we further examined the spread of HSV-1 through the enteric nervous system
      after oral inoculation. By immunohistochemistry, HSV-1 was found to infect
      myenteric ganglia in Auerbach's plexus between the inner and outer muscle layers
      of the gut wall, submucosal ganglia (Meisner's plexus), and periglandular
      ganglion plexuses surrounding submucosal glands. Virus-infected nerve fibers were
      also seen projecting through the mucosal layer to interact directly with surface
      epithelial cells. These intramucosal nerve fibers may be a conduit by which
      intraluminal virus is able to gain access to the enteric nervous system from the
      gastrointestinal lumen.

PMID- 8648750
TI  - N-acetyl-beta-glucosaminidase accounts for differences in glycosylation of
      influenza virus hemagglutinin expressed in insect cells from a baculovirus
      vector.
AB  - The hemagglutinin of fowl plague virus has been expressed in Spodoptera
      frugiperda (Sf9) cells and in Estigmene acrea cells by using a baculovirus
      vector. Structural analysis revealed that the endo-H-resistant N-glycans of HA
      from Sf9 cells were predominantly trimannosyl core oligosaccharides, whereas in
      E. acrea cells most of these cores were elongated by at least one terminal N
      acetylglucosamine residue. To understand the difference in carbohydrate
      structures, enzymes involved in N-glycan processing have been analyzed. The
      results revealed that the different glycosylation patterns observed are due to an
      N-acetyl-beta-glucosaminidase activity that was found in Sf9 cells but not in E.
      acrea cells. This enzyme specifically used the GlcNAcMan(3)GlcNAc(2)
      oligosaccharide as a substrate. When N-acetyl-beta-glucosaminidase or alpha
      mannosidase II was inhibited by specific inhibitors, the amount of terminal N
      acetylglucosamine in hemagglutinin from Sf9 cells was significantly enhanced.
      These results demonstrate that N glycosylation in both cell lines follows the
      classical pathway up to the stage of GlcNAcMan(3)GlcNAc(2) oligosaccharide side
      chains. Whereas these structures are the end product in E. acrea cells, they are
      degraded in Sf9 cells to Man(3)GlcNAc(2) cores by N-acetyl-beta-glucosaminidase.

PMID- 8648751
TI  - The equine herpesvirus 1 glycoprotein gp21/22a, the herpes simplex virus type 1
      gM homolog, is involved in virus penetration and cell-to-cell spread of virions.
AB  - Experiments to analyze the function of the equine herpesvirus 1 (EHV-1)
      glycoprotein gM homolog were conducted. To this end, an Rk13 cell line (TCgM)
      that stably expressed EHV-1 gM was constructed. Proteins with apparent M(r)s of
      46,000 to 48,000 and 50,000 to 55,000 were detected in TCgM cells with specific
      anti-gM antibodies, and the gM protein pattern was indistinguishable from that in
      cells infected with EHV-1 strain RacL11. A viral mutant (L11deltagM) bearing an
      Escherichia coli lacZ gene inserted into the EHV-1 strain RacL11 gM gene (open
      reading frame 52) was purified, and cells infected with L11deltagM did not
      contain detectable gM. L11deltagM exhibited approximately 100-fold lower titers
      and a more than 2-fold reduction in plaque size relative to wild-type EHV-1 when
      grown and titrated on noncomplementing cells. Viral titers were reduced only 10
      fold when L11deltagM was grown on the complementing cell line TCgM and titrated
      on noncomplementing cells. L11deltagM also exhibited slower penetration kinetics
      compared with those of the parental EHV-1 RacL11. It is concluded that EHV-1 gM
      plays important roles in the penetration of virus into the target cell and in
      spread of EHV-1 from cell to cell.

PMID- 8648752
TI  - Inactivated bovine herpesvirus 1 induces apoptotic cell death of mitogen
      stimulated bovine peripheral blood mononuclear cells.
AB  - Bovine herpesvirus 1 (BHV-1) is able to inhibit the proliferation of bovine
      peripheral blood mononuclear cells. Here, we have demonstrated that live BHV-1
      and, interestingly, inactivated BHV-1 can induce apoptosis of mitogen-stimulated
      bovine peripheral blood mononuclear cells in vitro.

PMID- 8648753
TI  - Induction of interleukin-12 (IL-12) by recombinant glycoprotein gp120 of human
      immunodeficiency virus type 1 in human monocytes/macrophages: requirement of
      gamma interferon for IL-12 secretion.
AB  - We studied the effects of the gp120 glycoprotein of human immunodeficiency virus
      type 1 on the expression of interleukin-12 (IL-12) in human monocytes and in
      monocyte-derived macrophages. Induction of the mRNA for both the p35 and p40
      subunits of IL-12 was observed in both cell types after gp120 treatment. We then
      evaluated cytokine secretion by using an enzyme-linked immunosorbent assay which
      recognizes only the IL-12 heterodimer. No IL-12 was detected in
      monocytes/macrophages treated with gp120 alone. A consistent IL-12 secretion was
      found in macrophages primed with gamma interferon (IFN-gamma) and subsequently
      treated with gp120. Low levels of IL-12 were occasionally observed in IFN-gamma
      primed monocytes stimulated with gp120. The greater response of macrophages than
      of monocytes to the priming effect of IFN-gamma was consistent with the finding
      that IFN-gamma induced a much stronger antiviral state to vesicular stomatitis
      virus in macrophages than in monocytes. These data indicate that gp120 is an
      inducer of IL-12 expression in monocytes/macrophages and that IFN-gamma is an
      essential cofactor for IL-12 secretion, especially in differentiated macrophages.

PMID- 8648754
TI  - Nondefective rotavirus mutants with an NSP1 gene which has a deletion of 500
      nucleotides, including a cysteine-rich zinc finger motif-encoding region
      (nucleotides 156 to 248), or which has a nonsense codon at nucleotides 153-155.
AB  - We isolated two nondefective bovine rotavirus mutants (A5-10 and A5-16 clones)
      which have nonsense mutations in the early portion of the open reading frame of
      the NSP1 gene. In the NSP1 gene (1,587 bases long) of A5-10, a nonsense codon is
      present at nucleotides 153 to 155 just upstream of the coding region (nucleotides
      156 to 230) of a cysteine-rich Zn finger motif. A5-16 gene 5 (1,087 bases long)
      was found to have a large deletion of 500 bases corresponding to nucleotides 142
      to 641 of a parent A5-10 NSP1 gene and to have a nonsense codon at nucleotides
      183 to 185, which resulted from the deletion. Expression of gene 5-specific NSP1
      could not be detected in MA-104 cells infected with the A5-10 or A5-16 clone or
      in an in vitro translation system using the plasmids with gene 5 cDNA from A5-10
      or A5-16. Nevertheless, both A5-10 and A5-16 replicated well in cultured cells,
      although the plaque size of A5-16 was extremely small.

PMID- 8648755
TI  - Processing in the pestivirus E2-NS2 region: identification of proteins p7 and
      E2p7.
AB  - The pestivirus genome encodes a single polyprotein which is subject to co- and
      posttranslational processing by cellular and viral proteases. The map positions
      of all virus-encoded proteins are known with the exception of a hypothetical
      peptide (p?) which interlinks the glycoprotein E2 and the nonstructural protein
      NS2-3 approximately between amino acid positions 1060 and 1130. Expression
      studies with recombinant vaccinia viruses bearing a set of C-terminally truncated
      E2-p?-NS2-encoding sequences derived from a bovine viral diarrhea virus (BVDV)
      strain led to the identification of a minor fraction of E2 which had an increased
      molecular mass due to a C-terminal extension. This larger form of E2 (E2p7) was
      specifically recognized by an antiserum raised against the amino acid sequence
      from 1065 to 1125. In addition, the antibodies revealed a BVDV-encoded 7-kDa
      protein (p7) in infected cells. By radiosequencing it was determined that Val
      1067 was the N-terminal amino acid of in vitro-synthesized p7. Analyses of BVDV
      and classical swine fever virus virions suggest that neither p7 nor E2p7 is a
      major structural constituent.

PMID- 8648756
TI  - Cloning, expression and characterization of the proteinase from human herpesvirus
      6.
AB  - After the U53 gene encoding the proteinase from human herpesvirus 6 (HHV-6) was
      sequenced, it was expressed in Escherichia coli, and the activity of the
      purified, recombinant HHV-6 proteinase was characterized quantitatively by using
      synthetic peptide substrates mimicking the release and maturation cleavage sites
      in the polyprotein precursors of HHV-6, human cytomegalovirus (CMV), murine CMV,
      and Epstein-Barr virus. Despite sharing 40% identity with other betaherpesvirus
      proteinases such as human CMV proteinase, the one-chain HHV-6 enzyme was
      distinguished from these two-chain proteinases by the absence of an internal
      autocatalytic cleavage site.

PMID- 8648757
TI  - Expression of the recombinant anchorless N-terminal domain of mouse hepatitis
      virus (MHV) receptor makes hamster of human cells susceptible to MHV infection.
AB  - Mouse hepatitis virus (MHV) receptor, the receptor for the murine coronavirus
      MHV, was expressed in MHV-resistant hamster and human cells as a series of
      mutant, recombinant glycoproteins with carboxy-terminal deletions lacking the
      cytoplasmic tail, transmembrane domain, and various amounts of the immunoglobulin
      constant-region-like domains. The soluble receptor glycoproteins containing the N
      terminal virus-binding domain were released into the supernatant medium and
      inactivated the infectivity of MHV-A59 virions in a concentration-dependent
      manner. Surprisingly, some of the anchorless glycoproteins were found on the
      plasma membranes of transfected cells by flow cytometry, and these cells were
      rendered susceptible to infection with three strains of MHV. Thus, in the cells
      in which the anchorless, recombinant receptor glycoprotein is synthesized, some
      of the protein is bound to an unidentified moiety on the plasma membrane, which
      allows it to serve as a functional virus receptor.

PMID- 8648758
TI  - Maintenance of pluripotency in mouse embryonic stem cells persistently infected
      with murine coronavirus.
AB  - A persistently coronavirus-infected embryonic stem (ES) cell line A3/MHV was
      established by infecting an ES cell line, A3-1, with mouse hepatitis virus type
      2. Although almost all A3/MHV cells were found infected, both A3/MHV and A3-1
      cells expressed comparable levels of cell surface differentiation markers. In
      addition, A3/MHV cells retained the ability to form embryoid bodies. These
      results suggest that persistent coronavirus infection does not affect the
      differentiation of ES cells.

PMID- 8648759
TI  - Evidence that replication of human neurotropic JC virus DNA in glial cells is
      regulated by the sequence-specific single-stranded DNA-binding protein Pur alpha.
AB  - Initiation of polyomavirus DNA replication in eukaryotic cells requires the
      participation of the viral early protein T antigen, cellular replication factors,
      and DNA polymerases. The human polyomavirus JC virus (JCV) is the etiologic agent
      of the fatal demyelinating disease progressive multifocal leukoencephalopathy in
      immunocompromised individuals. This virus exhibits a narrow host range and a
      tissue specificity that restricts its replication to glial cells of the central
      nervous system. Restriction of viral DNA replication due to species specificity
      of the DNA polymerase, coupled with glial cell-specific transcription of the
      viral early promoter, is thought to account for the brain-specific replication of
      JCV. In this report we demonstrate that overexpression of Pur alpha, a protein
      which binds to single-stranded DNA in a sequence-specific manner, suppresses
      replication of JCV DNA in glial cells. Results from footprinting studies indicate
      that Pur alpha and T antigen share a common binding region spanning the single
      stranded ori sequence of JCV. Further, T antigen was capable of stimulating the
      association of Pur alpha with the ori sequence in a band shift assay. Whereas no
      evidence for simultaneous binding of Pur alpha and T antigen to single-stranded
      DNA has been observed, results from coimmunoprecipitation and Western blot
      (immunoblot) analyses of proteins derived from cells producing JCV T antigen
      indicate a molecular association of JCV T antigen and Pur alpha. The binding of
      Pur alpha to the single-stranded ori sequence and its association with T antigen
      suggest that Pur alpha interferes with the activity of T antigen and/or other
      regulatory proteins to exert its negative effect on JCV DNA replication. The
      importance of these findings in the reactivation of JCV in the latently infected
      individual under immunosuppressed conditions is discussed.

PMID- 8648760
TI  - Requirements for lymphocyte activation by unusual strains of simian
      immunodeficiency virus.
AB  - When residues 17 and 18 in nef of simian immunodeficiency virus strain SIVmac239
      were changed from RQ to YE, the resultant virus was able to replicate in
      peripheral blood mononuclear cell cultures without prior lymphocyte activation
      and without the addition of exogenous interleukin-2, caused extensive lymphocyte
      activation in these cultures, and produced an acute disease in rhesus and pigtail
      macaques (Z. Du, S. M. Lang, V. G. Sasseville, A. A. Lackner, P. 0. Ilyinskii, M.
      D. Daniel, J. U. Jung, and R. C. Desrosiers, Cell 82:665-674, 1995). These
      properties are similar to those of the acutely lethal pathogen SIVpbj14 but
      dissimilar to those of the parental SIVmac239. We show here that the single
      change of R to Y at position 17 in nef of SIVmac239 is sufficient to confer the
      full, unusual phenotype. Conversely, the lymphocyte-activating properties of
      SIVpbj14 were lost by the single change of Y to R at position 17 of nef. The
      change of R17F or Q18E in SIVmac239 nef did not confer the unusual in vitro
      properties. Since SIVpbj14 has a duplication of the NF-kappaB binding sequence in
      the transcriptional control region, we also constructed and tested strains of
      SIVmac239/Rl7Y with zero, one, and two NF-kappaB binding elements. We found no
      difference in the properties of SIVmac239/R17Y, either in cell culture or in
      vivo, whether zero, one, or two NF-kappaB binding sites were present. Thus,
      tyrosine at position 17 of nef is absolutely necessary for the unusual phenotype
      of SIVpbj14 and is sufficient to convert SIVmac239 to a virus with a phenotype
      like that of SIVpbjl4. Multiple NF-kappaB binding sites are not required for the
      in vitro properties or for acute disease.

PMID- 8648761
TI  - Monkeys immunized with intertypic chimeric dengue viruses are protected against
      wild-type virus challenge.
AB  - Dengue epidemics caused by the four dengue virus serotypes continue to pose a
      major public health problem in most tropical and subtropical regions. A safe and
      effective vaccine against dengue is still not available. The current strategy for
      dengue immunization favors the use of a vaccine containing each of the four
      serotypes. We previously employed full-length dengue type 4 virus (DEN4) cDNA to
      construct a viable intertypic dengue virus of type 1 or type 2 antigenic
      specificity that contained the genes for the capsid-premembrane-envelope (C-pre-M
      E) structural proteins of DEN1 or pre-M and E structural proteins of DEN2
      substituting for the corresponding DEN4 genes. Chimeras DEN1/DEN4 and DEN2/DEN4,
      which express the nonstructural proteins of DEN4 and the C-pre-M-E structural
      proteins of DEN1 or the pre-M-E structural proteins of DEN2, and therefore the
      antigenicity of type 1 or type 2, were used to immunize rhesus monkeys. Other
      monkeys were inoculated with parental DEN1, DEN2, or cDNA-derived DEN4. Three of
      four monkeys immunized with DEN1/DEN4 developed neutralizing antibodies against
      DEN1 and were protected against subsequent DEN1 challenge. All four monkeys
      immunized with DEN2/DEN4 developed antibodies against DEN2 and were protected
      against subsequent DEN2 challenge. DEN1- and DEN2-immunized monkeys were
      protected against homologous virus challenge, but DEN4-immunized animals became
      viremic on cross-challenge with DEN1 or DEN2. In a second experiment, eight
      monkeys were immunized with equal mixtures of DEN1/DEN4 and DEN2/DEN4. Each of
      these monkeys developed neutralizing antibodies against both DEN1 and DEN2 and
      were protected against subsequent challenge with DEN1 or DEN2. Chimeric dengue
      viruses similar to those described here could be used to express serotype
      specific antigens in a live attenuated tetravalent human vaccine.

PMID- 8648762
TI  - Moloney murine leukemia virus activates NF-kappa B.
AB  - Nonacutely transforming retroviruses, such as Moloney murine leukemia virus (M
      MuLV), differ from transforming viruses in their mechanisms of tumor induction.
      While the transforming viruses cause tumors by transduction of oncogenes, the
      leukemia retroviruses, lacking oncogenes, employ other mechanisms, including
      promoter insertion and enhancer activation. Although these two mechanisms occur
      in many tumors induced by leukemia viruses, a substantial proportion of such
      tumors do not show site-specific proviral insertions. Thus, other, unidentified
      virus-driven mechanisms may participate in tumorigenesis. In these studies, we
      show that infection of cells by M-MuLV activates expression of Rel family
      transcription factors. In murine cells chronically infected with M-MuLV, gel
      shift analyses with kappaB DNA-binding motifs from the murine immunoglobulin
      kappa light chain enhancer demonstrated induction of at least two distinct kappaB
      enhancer-binding complexes. Supershifting and immunoblotting analyses defined
      p50, p52, RelB, and c-Rel subunits as constituents of these virus-induced protein
      complexes. Transient transfections performed with kappaB-dependent reporter
      plasmids showed transcriptional activation in M-MuLV-infected cells relative to
      uninfected cells. Induction of Rel/NF-kappaB transcription factor activity by M
      MuLV infection may prove relevant to the mechanism of M-MuLV-induced leukemia.

PMID- 8648763
TI  - Elimination of both E1 and E2 from adenovirus vectors further improves prospects
      for in vivo human gene therapy.
AB  - A novel recombinant adenovirus vector, Av3nBg, was constructed with deletions in
      adenovirus E1, E2a, and E3 regions and expressing a beta-galactosidase reporter
      gene. Av3nBg can be propagated at a high titer in a corresponding A549-derived
      cell line, AE1-2a, which contains the adenovirus E1 and E2a region genes
      inducibly expressed from separate glucocorticoid-responsive promoters. Av3nBg
      demonstrated gene transfer and expression comparable to that of Av1nBg, a first
      generation adenovirus vector with deletions in E1 and E3. Several lines of
      evidence suggest that this vector is significantly more attenuated than E1 and E3
      deletion vectors. Metabolic DNA labeling studies showed no detectable de novo
      vector DNA synthesis or accumulation, and metabolic protein labeling demonstrated
      no detectable de novo hexon protein synthesis for Av3nBg in naive A549 cells even
      at a multiplicity of infection of up to 3,000 PFU per cell. Additionally, naive
      A549 cells infected by Av3nBg did not accumulate infectious virions. In contrast,
      both Av1nBg and Av2Lu vectors showed DNA replication and hexon protein synthesis
      at multiplicities of infection of 500 PFU per cell. Av2Lu has a deletion in E1
      and also carries a temperature-sensitive mutation in E2a. Thus, molecular
      characterization has demonstrated that the Av3nBg vector is improved with respect
      to the potential for vector DNA replication and hexon protein expression compared
      with both first-generation (Av1nBg) and second-generation (Av2Lu) adenoviral
      vectors. These observations may have important implications for potential use of
      adenovirus vectors in human gene therapy.

PMID- 8648764
TI  - EBNA-2 and EBNA-3C extensively and mutually exclusively associate with RBPJkappa
      in Epstein-Barr virus-transformed B lymphocytes.
AB  - Although genetic and biochemical data indicate that the cell protein RBPJkappa is
      a mediator of EBNA-2 and EBNA-3C effects on transcriptional regulatory elements,
      the extent of association of these Epstein-Barr virus nuclear proteins with
      RBPJkappa in transformed B lymphocytes has not been determined. We now report
      that most of the EBNA-2 and at least 20% of the EBNA-3C coimmunoprecipitated with
      RBPJkappa from extracts of transformed B lymphocytes that contained most of the
      cellular EBNA-2 and EBNA3C. Both proteins are associated preferentially with the
      smaller of the two RBPJkappa isoforms. EBNA-2-RBPJkappa complexes do not contain
      EBNA-3C, and EBNA-3C-RBPJkappa complexes do not contain EBNA-2. Although EBNA-2
      and EBNA-3C are extensively associated with RBPJkappa, a fraction of RBPJkappa
      appears to be free of EBNAs after repeated immunoprecipitations with anti-EBNA,
      Epstein-Barr virus-immune, human antibody. Promoters with RBPJkappa sites in
      their regulatory elements are likely to be differentially regulated by these
      RBPJkappa-EBNA-2 and RBPJkappa-EBNA-3 complexes.

PMID- 8648765
TI  - The envelope gp120 gene of human immunodeficiency virus type 1 determines the
      rate of CD4-positive T-cell depletion in SCID mice engrafted with human
      peripheral blood leukocytes.
AB  - We have used envelope recombinant viruses generated between two molecular clones
      of human immunodeficiency virus type 1 (HIV-1), T-cell-tropic HIV-1SF2 and
      macrophage-tropic HIV-1SF162, to assess pathogenic potential in the human
      peripheral blood leukocyte-reconstituted severe combined immune deficiency mouse
      model. Recombinant HIV-1SF2 viruses expressing the envelope gp120 gene of HIV
      ISF162 caused as rapid a CD4+ T-cell depletion as did HIV-1SF162. The reciprocal
      HIV-1SF162 recombinant virus with the HIV-1SF2 envelope caused slower CD4+ T-cell
      loss. Although changing the V3 loop sequence of HIV-1SF162 to that of HIV-1SF2
      did not change the rate of CD4+ T-cell depletion, replacing the V3 of HIV-1SF2
      with the sequence of HIV-1SF162 resulted in virus that was poorly infectious in
      vivo but not in vitro. These studies suggest that the envelope gene determines
      properties important for pathogenesis in vivo as well as for cell tropism in
      vitro. HIV-1 infection in vivo may have more stringent requirements for envelope
      conformation.

PMID- 8648767
TI  - The effect of bicycle riding on serum prostate specific antigen levels.
AB  - PURPOSE: We determined if bicycle riding causes an increase in prostate specific
      antigen (PSA) levels. MATERIALS AND METHODS: Baseline PSA levels were measured
      from all 260 volunteers before a 250-mile bicycle ride. After this 4-day race PSA
      was again measured and this level was compared to the pre-race levels. RESULTS:
      The overall change from baseline to post-race PSA in all 260 men was 0.069
      ng./ml. The change for the 256 men with normal baseline PSA (0.0 to 4.0 ng./ml.)
      was 0.044 ng./ml. The 4 men with an already elevated PSA (more than 4.0 ng./ml.)
      showed a large change of 1.65 ng./ml. CONCLUSIONS: There is no statistically or
      clinically significant increase in PSA after bicycle riding. However, the few
      participants with an initially elevated PSA had an increase after bicycle riding,
      although this change does not represent the population and more research is
      warranted to define further its clinical implications.

PMID- 8648768
TI  - Endo-rectal coil magnetic resonance imaging in clinically localized prostate
      cancer: is it accurate?
AB  - PURPOSE: We assessed the staging accuracy of endo-rectal coil magnetic resonance
      imaging (MRI) in patients with clinically localized prostate cancer. MATERIALS
      AND METHODS: In a prospective study 56 consecutive patients underwent endo-rectal
      coil MRI before scheduled surgery. The ability of MRI to identify tumor
      involvement of the periprostatic soft tissue, seminal vesicles and pelvic lymph
      nodes was assessed by comparison with final pathological stage. RESULTS:
      Specificity of MRI was relatively high (84% for periprostatic soft tissue, 93%
      for seminal vesicles and 91% for pelvic lymph nodes) and sensitivity was low (22,
      23 and 0%, respectively). Accuracy was 64% for identification of periprostatic
      soft tissue invasion, 77% for seminal vesicle invasion and 86% for pelvic lymph
      node metastases. Had we excluded from surgery patients with MRI evidence of
      extraprostatic disease our organ confined disease rate would have improved by
      16.6%. However, this improvement would have been obtained at the expense of
      incorrectly excluding from surgery 21% of our patients with pathologically organ
      confined disease because of false-positive MRI predictions. CONCLUSIONS: Endo
      rectal coil MRI is not sufficiently accurate to influence the treatment of
      patients with clinically localized prostate cancer. Therefore, we advise against
      routine use of this imaging modality in staging such cases.

PMID- 8648766
TI  - A plasmid-based reverse genetics system for influenza A virus.
AB  - A reverse genetics system for negative-strand RNA viruses was first successfully
      developed for influenza viruses. This technology involved the transfection of in
      vitro-reconstituted ribonucleoprotein (RNP) complexes into influenza virus
      infected cells. We have now developed a method that allows intracellular
      reconstitution of RNP complexes from plasmid-based expression vectors. Expression
      of a viral RNA-like transcript is achieved from a plasmid containing a truncated
      human polymerase I (polI) promoter and a ribozyme sequence that generates the
      desired 3' end by autocatalytic cleavage. The polI-driven plasmid is
      cotransfected into human 293 cells with polII-responsive plasmids that express
      the viral PB1, PB2, PA, and NP proteins. This exclusively plasmid-driven system
      results in the efficient transcription and replication of the viral RNA-like
      reporter and allows the study of cis- and trans-acting signals involved in the
      transcription and replication of influenza virus RNAs. Using this system, we have
      also been able to rescue a synthetic neuraminidase gene into a recombinant
      influenza virus. This method represents a convenient alternative to the
      previously established RNP transfection system.

PMID- 8648769
TI  - Effect of the number of core biopsies of the prostate on predicting Gleason score
      of prostate cancer.
AB  - PURPOSE: We determined the effect of the number of core biopsies of the prostate
      on predicting the Gleason score of the prostatectomy specimen. MATERIALS AND
      METHODS: The Gleason scores from 124 radical prostatectomy specimens were
      compared to those from preoperative core needle biopsies of the prostate. The
      number of cores obtained and tumor stage were compared regarding agreement in
      prostate cancer score. RESULTS: Four to 6 core biopsies yielded the best results,
      with agreement within 1 Gleason score in 75% of the cases. Further increases in
      the number of core biopsies did not improve results. Additionally, 37% of the
      well differentiated tumors on core biopsy were stage C. CONCLUSIONS: Gleason
      score from the core biopsy has limitations in respect to predicting prostatectomy
      tumor score and stage and, therefore, it is problematic for use in therapeutic
      decision making.

PMID- 8648770
TI  - Preoperative diagnosis and staging of prostate cancer.

PMID- 8648771
TI  - Cryosurgical treatment of localized prostate cancer (stages T1 to T4):
      preliminary results.
AB  - PURPOSE: We determined the posttreatment biopsy results, prostate specific
      antigen (PSA) levels and complications associated with cryosurgical ablation of
      the prostate performed for localized prostate cancer. MATERIALS AND METHODS:
      Within 18 months 102 patients underwent cryosurgery as definitive therapy for
      localized prostate cancer. Mean patient age was 68 years and 57% had advanced
      local disease (stage T3 or T4). Mean preoperative PSA was 21.8 ng./ml. RESULTS:
      PSA was undetectable at 6 months in 48% of patients who received no androgen
      deprivation therapy following cryosurgery. Of 91 patients with postoperative
      biopsies 77% had no evidence of cancer but 71% had benign epithelial a elements.
      The complication rate (excluding impotence) was 51%. Biopsy and PSA results
      improved with experience and changes in technique, that is double freezing, more
      lateral placement of cryoprobes and more aggressive freezing beyond the prostatic
      capsule. The most recent cohort of 77 patients had a detectable PSA rate of 23%
      and a positive post-cryosurgical biopsy rate of 11%. The most common serious
      complication encountered was bladder outflow obstruction requiring transurethral
      resection in 23% of the patients. Impotence occurred in 84% of patients potent
      preoperatively. CONCLUSIONS: Cryosurgical ablation of the prostate can result in
      negative posttreatment biopsies and undetectable serum PSA levels. However, it is
      associated with significant side effects and the long-term durability of the
      procedure is unknown.

PMID- 8648772
TI  - The flare in serum alkaline phosphatase activity after orchiectomy: a valuable
      negative prognostic index for progression-free survival in prostatic carcinoma.
AB  - PURPOSE: We determined whether an early flare in serum alkaline phosphatase
      activity after orchiectomy was of prognostic value for progression-free survival
      in patients with advanced prostatic carcinoma. MATERIALS AND METHODS: A
      retrospective analysis of a data base from a Dutch multicenter study on prostatic
      carcinoma was done to determine the prognostic value of a flare in alkaline
      phosphatase activity after orchiectomy in 112 patients with metastatic (75%) or
      locally advanced (25%) disease. Cox's proportional hazards models and Kaplan
      Meier survival curves were used. RESULTS: Of the patients 50% had initially
      increased alkaline phosphatase levels and a flare in activity was demonstrated in
      87% 2 to 4 weeks after orchiectomy. The prostate specific antigen nadir (cutoff 4
      ng./ml.) 6 months after orchiectomy was of significant prognostic value for
      progression-free survival. A flare in alkaline phosphatase activity after
      orchiectomy demonstrated an early significant prognostic value for progression
      free survival, independent of the serum alkaline phosphatase activity.
      CONCLUSIONS: The simplicity, ready availability and cost-effectiveness of serum
      alkaline phosphatase activity as a prognostic index render it attractive to the
      clinician, particularly early in the course of prostatic carcinoma. Measuring the
      flare in alkaline phosphatase activity within 1 month of orchiectomy may permit
      early identification of patients in whom the disease is likely to progress
      rapidly and who would potentially benefit from aggressive treatment.

PMID- 8648773
TI  - The impact of co-morbidity on life expectancy among men with localized prostate
      cancer.
AB  - PURPOSE: We evaluated 3 indexes used to assess patient co-morbidities to
      determine whether they could predict mortality among men with clinically
      localized prostate cancer. MATERIALS AND METHODS: We measured the impact of co
      morbidity classifications on all cause mortality using a parametric proportional
      hazards model based on a retrospective cohort analysis. RESULTS: Each index
      tested is a highly significant predictor of mortality for patients dying of
      nonprostate cancer related causes after adjusting for age and Gleason score.
      CONCLUSIONS: Each co-morbidity index provides significant, independent predictive
      information concerning patient mortality beyond that provided by age, Gleason
      score and clinical stage alone.

PMID- 8648774
TI  - Survival in blacks and whites after treatment for localized prostate cancer.
AB  - PURPOSE: Racial differences were assessed in all cause and disease related
      actuarial survivals after treatment for localized prostate cancer. MATERIALS AND
      METHODS: We studied 148 black and 209 white men with clinical stages T1b to 4NXMO
      prostate cancer treated with surgery or radiation therapy between 1980 and 1991
      at a Veterans Affairs medical center. RESULTS: After a median potential followup
      of 96 months, there were no significant differences in the all cause, cause
      specific, metastases-free, clinical disease-free or prostate specific antigen
      disease-free survivals in 109 black and 167 white men with stages T1b to 2 cancer
      treated with surgery or radiation therapy, or in 39 black and 42 white men with
      stages T3 to 4 cancer treated with radiation therapy. CONCLUSIONS: Race appears
      to have no impact on the stage specific actuarial survivals in men with localized
      prostate cancer treated with surgery or radiation therapy in an equal access
      health care system.

PMID- 8648775
TI  - Analysis of risk factors for progression in patients with pathologically confined
      prostate cancers after radical retropubic prostatectomy.
AB  - PURPOSE: Up to 26% of patients with pathologically organ confined prostate cancer
      will experience clinical progression after radical prostatectomy. We attempted to
      identify patients at greatest risk for future clinical failure despite a
      favorable pathological outcome. MATERIALS AND METHODS: The study group included
      904 patients treated with bilateral pelvic lymphadenectomy and radical retropubic
      prostatectomy for disease confined to the prostate gland. Preoperative serum
      prostate specific antigen (PSA), clinical stage, pathological grade and stage,
      and deoxyribonucleic acid (DNA) ploidy were evaluated by multivariate analysis to
      determine relative value in predicting treatment failure. A prognostic scoring
      system was created using the regression coefficients from the Cox multivariate
      model to classify patients further according to risk of progression. RESULTS:
      Preoperative PSA concentration, clinical stage, grade and DNA ploidy were
      significant univariate predictors of progression (p < 0.0001), whereas
      pathological stage was not (p = 0.2). Multivariate analysis identified
      pathological grade (p < 0.0001), preoperative serum PSA concentration (p =
      0.0006) and DNA ploidy (p = 0.0089) as independent predictors of progression. The
      prognostic scoring system separated the patients into 5 distinct groups. Patients
      with the lowest score had a 92% progression-free survival rate at 5 years,
      compared to only 39% of those with the highest scores. CONCLUSIONS: Patients
      believed to be at higher risk for cancer progression despite having organ
      confined disease might be targeted for adjuvant therapy and closer surveillance,
      while those at low risk may be followed less often.

PMID- 8648776
TI  - Prostate cancer--the added factors.

PMID- 8648777
TI  - Oral fleroxacin prophylaxis in transurethral surgery.
AB  - PURPOSE: A prospective trial was done to test the efficacy of antimicrobial
      prophylaxis in patients undergoing transurethral surgery. MATERIALS AND METHODS:
      A total of 75 adults with preoperatively sterile urine was randomized to receive
      either 400 mg. oral fleroxacin once daily or placebo as long as the catheter was
      in place. Urine cultures were obtained preoperatively and after removal of the
      catheter just before hospital discharge. Growth of 10(4)/ml. or more bacteria was
      considered a positive urine culture. RESULTS: Postoperative urinary tract
      infection rates were significantly lower in the fleroxacin group (3%) than in the
      placebo group (23%). Our study demonstrated the benefit of antimicrobial
      prophylaxis in preventing urinary tract infection after transurethral surgery,
      including resection of the prostate, in patients with sterile urine. CONCLUSIONS:
      The oral administration of 1 daily tablet of fleroxacin for the duration of
      catheterization is a safe, efficacious and clinically feasible regimen.

PMID- 8648778
TI  - Tentative direct antimicrobial susceptibility testing in urine.
AB  - PURPOSE: Tentative direct disk susceptibilities in bacteriuria compared to
      standard techniques were reevaluated. MATERIALS AND METHODS: A sterile cotton
      swab was saturated with urine and uniformly streaked over the surface of a
      Mueller-Hinton agar plate. Susceptibility disks were added within 5 minutes and
      the zone of inhibition around the antibiotic disk was read after 16 to 18 hours
      of incubation. RESULTS: The tentative direct susceptibilities showed an accuracy
      of 98.2% compared to standard techniques in 2,906 positive pure cultures. The
      false-positive rate was 0.53% and the false-negative rate was 0.14%. CONCLUSIONS:
      Results of tentative direct antibiotic susceptibility in bacteriuria are
      comparable to those of standard techniques and are obtained 24 hours sooner.

PMID- 8648780
TI  - Micturition disturbances and human immunodeficiency virus infection.
AB  - PURPOSE: Human immunodeficiency virus (HIV) infections often lead to urological
      disorders, including tumors, infections and micturitional disturbances. It often
      is difficult to identify the origin of voiding disorders but the most frequent
      causes are infections (prostatitis and so forth), obstruction (cervico-prostatic
      or urethral) and neurological (encephalitis, myelitis, polyradiculoneuritis and
      so forth). We determined the etiologies, therapy and clinical outcome of
      micturitional disturbances in the acquired immunodeficiency syndrome. MATERIALS
      AND METHODS: Between February 1989 and September 1992 we studied prospectively 39
      HIV positive patients with voiding symptoms, such as straining, urinary
      retention, frequency and urgency. Each patient underwent a thorough neurological
      and urological examination, along with radiological evaluation of the urogenital
      tract and nervous system. Urodynamic evaluation was performed to specify the
      etiology and type of disturbance before treatment. The patients were followed for
      2 to 24 months (mean 9) and 34 (87%) had urodynamic abnormalities, including a
      hyperactive bladder, bladder sphincter dyssynergia and a hypoactive bladder.
      RESULTS: The cause of the voiding disorder was neurological in 61.5% of the
      cases, and the 2 most frequent disorders were cerebral toxoplasmosis and HIV
      encephalitis. Treatment was usually given to relieve symptoms with drugs acting
      on the detrusor-sphincter complex. A total of 22 patients (57%) had lasting
      improvement, while 17 (43%) died 2 to 24 months (mean 8) after onset of the
      voiding symptoms. CONCLUSIONS: A micturition problem is an unfavorable event
      since it usually indicates a neurological cause.

PMID- 8648779
TI  - Early identification of candiduria by polymerase chain reaction in high risk
      patients.
AB  - PURPOSE: Polymerase chain reaction amplification of Candida albicans
      deoxyribonucleic acid was evaluated as a diagnostic tool for candiduria.
      MATERIALS AND METHODS: Urine from 120 patients was tested for C. albicans 158
      base pair deoxyribonucleic acid by polymerase chain reaction. The study groups
      included 30 patients with positive urine cultures, 60 critically ill patients and
      30 healthy volunteers. RESULTS: All patients with proved candiduria had a
      positive polymerase chain reaction. Of the 60 critically ill patients 5 (8.3%)
      had a positive polymerase chain reaction for C. albicans 24 to 48 hours before
      identification with routine fungal culture. No healthy volunteer had a positive
      polymerase chain reaction. CONCLUSIONS: Polymerase chain reaction amplification
      is an effective laboratory tool for the early diagnosis of candiduria.

PMID- 8648781
TI  - Issues in infection.

PMID- 8648782
TI  - Fascial sling correction of kinked efferent limb in patients with continent
      diversion and catheterization difficulty.
AB  - PURPOSE: We determined the efficacy of using a rectus fascial sling to revise an
      angulated efferent limb in patients with continent urinary diversion and
      difficulty with intermittent catheterization. MATERIALS AND METHODS: Two spinal
      cord injured women who underwent modified Indiana pouch urinary diversion
      required revision of each efferent limb because of difficulty with
      catheterization. A strip section of anterior rectus sheath was harvested and used
      to fix the efferent limb in position, assuring freedom from angulation and
      facilitating catheterization. RESULTS: Both patients remained continent for more
      than 2 years postoperatively and neither had further difficulties with
      catheterization or required additional surgery. CONCLUSIONS: Use of the rectus
      fascial sling in continent urinary diversion enables fixation of the efferent
      limb to facilitate catheterization and enhance continence.

PMID- 8648783
TI  - The Glidewire technique for overcoming urethral obstruction.
AB  - PURPOSE: Using the hydrophilic Terumo Glidewire we developed a less traumatic,
      yet effective alternative method to filiforms and followers for cases of urethral
      obstruction. MATERIALS AND METHODS: The initial step and cornerstone of our
      method is the passage of the Glidewire per urethra in a manner similar to a
      filiform. After the appropriate intravesical location of the Glidewire is
      confirmed using a ureteral catheter, it is exchanged for a standard
      polytetrafluoroethylene (Teflon) coated guide wire. Urethral dilation and/or
      catheter placement is then performed. RESULTS: This technique was successful in
      19 of 20 attempts, several of which followed unsuccessful passage of filliform
      catheters. Urethral obstruction due to strictures, bladder neck contractures and
      benign prostatic hyperplasia in our group was treated effectively. Furthermore,
      no complications occurred due to the technique. CONCLUSIONS: The Glidewire method
      is safe and effective for treating most cases of urethral obstruction. Therefore,
      we recommend this technique over standard filiforms and followers when flexible
      or rigid cystourethroscopy is not immediately available.

PMID- 8648784
TI  - Vaginal wall sling for anatomical incontinence and intrinsic sphincter
      dysfunction: efficacy and outcome analysis.
AB  - PURPOSE: A prospective cohort study was done to determine the efficacy and
      clinical outcome of a new technique for anterior vaginal wall sling construction
      to treat urinary incontinence due to intrinsic sphincter dysfunction or
      anatomical incontinence. MATERIALS AND METHODS: Preoperative evaluation included
      lateral cystography, video urodynamics, cystoscopy and incontinence staging.
      Postoperative subjective and objective staging outcome measures were
      prospectively assigned at predetermined regular intervals by a third party.
      RESULTS: Of the patients 95 had intrinsic sphincter dysfunction and 65 had
      anatomical incontinence. The repair failed in 7% of the 160 patients who had
      recurrent incontinence during followup and 9% had de novo urgency incontinence.
      Time to failure comparing patients with intrinsic sphincter dysfunction and
      anatomical incontinence was modeled using Kaplan-Meier survival curves, and the
      log rank test showed no significant difference between the groups (p > 0.05).
      Logistic regression covariates revealed no significant predictive factors for
      postoperative failures. Preoperative patient age was the only predictive factor
      for de novo instability (logistic regression model p < 0.05). CONCLUSIONS: Our
      initial results indicate that the 2 groups are indistinguishable to date based on
      current clinical and experimental statistics except for time to full recovery of
      postoperative voiding and incidence of postoperative instability (regression
      model p < 0.05).

PMID- 8648785
TI  - Diagnosis of primary renal cell carcinoma in a left supraclavicular lymph node by
      chromosome analysis.

PMID- 8648786
TI  - Solitary contralateral psoas metastasis 14 years after radical nephrectomy for
      organ confined renal cell carcinoma.

PMID- 8648787
TI  - Verrucous carcinoma of a suprapubic cystostomy track.

PMID- 8648788
TI  - NonHodgkin's lymphoma arising in the urethra of a man.

PMID- 8648789
TI  - Penile denudation after adult circumcision.

PMID- 8648790
TI  - Glomangioma of the penile and scrotal median raphe.

PMID- 8648791
TI  - Immunochemotherapy for metastatic renal cell carcinoma using a regimen of
      interleukin-2, interferon-alpha and 5-fluorouracil.
AB  - PURPOSE: Promising results of recent clinical trials with a triple drug bio
      chemotherapy regimen encouraged its use in patients with renal cell carcinoma.
      MATERIALS AND METHODS: In a phase II study of patients with metastatic renal cell
      carcinoma the efficacy and toxicity of a treatment regimen were evaluated using
      interleukin-2 and interferon-alpha 2 subcutaneously in combination with
      intravenous 5-fluorouracil. The treatment protocol consisted of an 8-week cycle
      given on an outpatient basis, with 6 to 9 MU/m2. interferon-alpha given 1 to 3
      times a week during the 8 weeks, and sequentially combined with 5 to 20 MU/m2.
      interleukin-2, 3 times a week for 4 weeks and 750 mg./m.2 5-fluorouracil once a
      week for 4 weeks. RESULTS: Among 25 consecutive men and 9 women treated 3 (9%)
      had a complete and 10 (29%) had a partial remission (overall objective response
      rate 38%). Median response duration (complete plus partial) was 12.5 months
      (range 3 to 20+). Stable disease lasting 3 to 24+ months was noted in 12 patients
      (35%). There were only minor side effects, for a maximum toxicity grade of I in 3
      patients, II in 25 and III in 6 according to the World Health Organization
      classification. There were no dose limiting toxicities and no treatment related
      deaths. CONCLUSIONS: Triple drug immunochemotherapy resulted in a significant
      clinical effect comparable to an aggressive intravenous interleukin-2 treatment
      regimen but without significant toxicity.

PMID- 8648792
TI  - Striated pattern of the testicle on ultrasound: an appearance of testicular
      fibrosis.

PMID- 8648794
TI  - Seminal vesicle distension mimicking urinary retention.

PMID- 8648793
TI  - Osteitis pubis as a complication of prostate cryotherapy.

PMID- 8648795
TI  - Re: Extracorporeal shock wave lithotripsy in 5 patients with aortic aneurysm.

PMID- 8648796
TI  - Re: The nonrefluxing ileal conduit: a new form of urinary diversion.

PMID- 8648797
TI  - Re: Alpha-blockade in the treatment of symptomatic benign prostatic hyperplasia.

PMID- 8648798
TI  - Unilateral hydronephrosis in infants: are measurements of contralateral renal
      length useful?
AB  - PURPOSE: We investigated whether measurement of contralateral renal length in
      newborns with unilateral hydronephrosis may help to assess clinically significant
      hydronephrosis in the affected kidney. MATERIALS AND METHODS: We reviewed our
      experience with 53 newborns who had unilateral hydronephrosis presumed secondary
      to ureteropelvic junction obstruction. We divided the patients according to the
      presence of mild hydronephrosis and no obstruction on a furosemide renogram,
      severe hydronephrosis and obstruction on a furosemide renogram or a unilateral
      multicystic kidney. RESULTS: We found no significant correlation between findings
      on the affected and opposite normal sides. Contralateral hypertrophy, hypotrophy
      and normal sized kidneys were frequent findings. CONCLUSIONS: We conclude that
      measurement of contralateral renal length is not helpful in the evaluation of
      newborns with unilateral hydronephrosis.

PMID- 8648799
TI  - Can fetal renal artery Doppler studies predict postnatal renal function in
      morphologically abnormal kidneys? A preliminary report.
AB  - PURPOSE: The diagnosis of multicystic kidney in utero can be made with reasonable
      reliability with real-time sonography. However, a cystic hydronephrotic kidney
      may be difficult to distinguish from a multicystic kidney, necessitating
      postnatal renography. We report our preliminary observations of Doppler waveform
      variation in normal and cystic fetal kidneys. MATERIALS AND METHODS: Five
      consecutive fetuses with a unilateral cystic kidney, and one with a unilateral
      hydronephrotic duplex kidney and cystic upper moiety were evaluated in utero with
      color Doppler renal sonography. RESULTS: Doppler signal on serial ultrasound was
      consistently absent in the ipsilateral cystic kidney, while normal renal artery
      Doppler waveforms with a systolic and diastolic component were obtained from the
      contralateral and unaffected moieties. Postnatal renography confirmed nonfunction
      in all cystic moieties. The hydronephrotic noncystic moiety of the duplex kidney
      showed a normal Doppler waveform and good function. CONCLUSIONS: Absence of renal
      artery Doppler waveforms in fetal cystic kidneys correlates with renal
      nonfunction. If this observation can be further confirmed by additional cases,
      fetal Doppler sonography would become an additional tool to diagnose confidently
      a multicystic kidney in utero, which may allow us to dispense with postnatal
      renography.

PMID- 8648800
TI  - Renal tubular acidosis in children with vesicoureteral reflux.
AB  - PURPOSE: We evaluated renal tubular acidosis in children with primary
      vesicoureteral reflux. MATERIALS AND METHODS: We studied 18 children 4 to 15
      years old to determine age at onset, reflux intensity, and renal scars and volume
      as possible associated factors of renal tubular acidosis. Patients had normal
      glomerular filtration rates and no urinary infections for the last 12 weeks, and
      they had not undergone urological surgery. Urine acidification and alkalization
      tests were done, and the Mann-Whitney U test was used to assess differences
      between the groups with and without renal tubular acidosis. RESULTS: A total of
      14 patients had unilateral and 4 had bilateral reflux, which varied in severity.
      All children except 2 had renal scarring. Bilateral renal volume was smaller in
      the renal tubular acidosis group. Nine patients had distal renal tubular
      acidosis, including 4 with short stature. CONCLUSIONS: Several patients with
      vesicoureteral reflux had renal tubular acidosis and some had growth failure.
      Grades of reflux and renal scarring were similar in patients with and without
      renal tubular acidosis. A single evaluation of reflux is of slight value for
      predicting future functional tubular impairment, and the duration of reflux and
      other associated factors may be more important. Renal tubular acidosis was the
      main explanation for growth failure in these patients.

PMID- 8648801
TI  - Contralateral reflux after unilateral ureteral reimplantation.
AB  - PURPOSE: We analyzed the incidence and outcome of postoperative contralateral
      reflux after unilateral ureteral reimplantation by the Cohen and Glenn-Anderson
      techniques. MATERIALS AND METHODS: We retrospectively reviewed the records of 120
      patients 3 months to 21 years old in whom unilateral vesicoureteral reflux was
      treated by unilateral reimplantation. The incidence of postoperative
      contralateral reflux was documented by followup voiding cystourethrography.
      RESULTS: Overall 19% of patients who underwent unilateral reimplantation had
      contralateral vesicoureteral reflux postoperatively, including 21% after the
      Cohen and 17% after the Glenn-Anderson procedure. Of the cases 61% spontaneously
      resolved, 13% were surgically corrected and 26% continue to be followed.
      CONCLUSIONS: The rates of postoperative contralateral vesicoureteral reflux are
      not significantly different after Cohen and Glenn-Anderson repair. A majority of
      cases will resolve spontaneously within 2 years. The likelihood of trigonal
      distortion as the etiology of contralateral reflux is low given the similar
      incidence in cross-trigonal and ureteral advancement reimplantation.

PMID- 8648802
TI  - Endoscopic trigonoplasty in pediatric patients with primary vesicoureteral
      reflux: preliminary report.
AB  - PURPOSE: We investigated the preliminary surgical results of endoscopic
      trigonoplasty in pediatric patients with primary vesicoureteral reflux. MATERIALS
      AND METHODS: We performed endoscopic trigonoplasty in 6 pediatric patients (11
      refluxing ureters). Reflux was grade II in 4 reno-ureteral units, grade III in 5,
      grade IV in 1 and grade V in 1 (international classification). Surgery was done
      using laparoscopic and endoscopic instruments. RESULTS: Vesicoureteral reflux
      disappeared 3 to 12 months postoperatively. Analgesics were administered
      postoperatively to 4 patients for 24 hours and to 2 for 48 hours. No bladder
      irritability or postoperative upper urinary tract dilatation was observed in the
      early postoperative period. CONCLUSIONS: Minimally invasive endoscopic
      trigonoplasty can be an effective surgical procedure for pediatric patients with
      vesicoureteral reflux.

PMID- 8648803
TI  - A new treatment for clot retention: intravesical streptokinase instillation.

PMID- 8648804
TI  - Papillary transitional cell carcinoma of the bladder with lymphangiectasia in an
      8-year-old boy.

PMID- 8648805
TI  - Transitional cell carcinoma of the bladder in the pediatric patient.
AB  - PURPOSE: We report on 5 boys with transitional cell carcinoma of the bladder,
      describe the identifying characteristics, review the literature, and define the
      issues of diagnosis, treatment and followup in this rare disease in pediatric
      patients. MATERIALS AND METHODS: Five boys 11 to 18 years old were identified
      with transitional cell carcinoma of the bladder. Preoperative imaging and urinary
      cytology were correlated with cystoscopic and biopsy findings. RESULTS: In all
      patients evaluation was prompted by gross hematuria. Low grade lesions,
      definitive cystoscopic management and a low recurrence rate were uniform
      findings. Preoperative imaging identified the tumor in all cases and bladder
      ultrasound was the most sensitive scan with 4 of 4 cases identified. CONCLUSIONS:
      While rare, transitional cell carcinoma of the bladder in children presents a
      challenge in diagnosis and followup since cystoscopy typically requires general
      anesthesia in this age group. Bladder ultrasound was found to be extremely
      sensitive in identifying lesions, and it may be a valuable and minimally invasive
      surveillance tool.

PMID- 8648806
TI  - Demucosalized augmentation gastrocystoplasty with bladder autoaugmentation in
      pediatric patients.
AB  - PURPOSE: Potential metabolic complications in urinary reconstruction with bowel
      or stomach are due to the presence of the gastrointestinal mucosal layer. The
      advantage or disadvantage of each tissue has been debated. We report a procedure
      in which the mucosa of a gastric pedicle flap is removed and the remaining
      muscularis flap is transferred to an autoaugmented bladder. MATERIALS AND
      METHODS: Seven female and 4 male patients underwent the procedure at our
      institutions from October 1992 to November 1994. A retrospective chart review was
      performed to compare preoperative to postoperative urodynamic findings,
      continence status and complications. RESULTS: Mean followup was 23 months (range
      8 to 33). Preoperative urodynamics showed an average bladder capacity of 109 cc
      (range 45 to 200) and compliance of 3 ml./cm. water (range 1 to 6). Urinary
      continence was achieved in 10 patients on clean intermittent catherization every
      3 to 4 hours and 1 was wet due to low urethral resistance. All patients underwent
      postoperative urodynamics. Bladder capacity increased to 236 cc (range 150 to
      300) with an average compliance of 9 ml./cm. water (range 5 to 14). No metabolic
      complications were noted. CONCLUSIONS: The gastric muscularis appears to be
      preserved along with the native urothelium to provide a compliant tissue that can
      be an alternative to bowel and stomach for bladder augmentation. Because the
      procedure involves demucosalizing the gastric patch as well as performing bladder
      autoaugmentation, operative time is increased compared to normal
      gastrocystoplasty or enterocystoplasty. However, the lack of metabolic
      complications and mucus-free urine are important considerations and substantial
      advantages.

PMID- 8648807
TI  - Provoked enuresis-like episodes in healthy children 7 to 12 years old.
AB  - PURPOSE: We evaluated whether a water load before bedtime provoked enuresis
      episodes in healthy children with no previous enuresis. We also studied pelvic
      floor activity during an enuresis episode and the completeness of bladder
      emptying, attempted to identify a possible trigger mechanism for nocturnal
      enuresis, and investigated any age and sex differences regarding the frequency of
      provoked enuresis episodes. MATERIALS AND METHODS: We evaluated 55 healthy
      volunteers (22 girls and 33 boys) 7 to 12 years old who were dry from age 5 years
      and had no urological or other complaints. Subjects were admitted to the hospital
      for 4 consecutive nights. Night 1 was for adaptation without a water load. On
      nights 2 to 4, 25 ml./kg. body weight of water were given orally half an hour
      before bedtime. During the night pelvic floor activity was monitored, and the
      time and volume of enuresis and nocturia episodes were noted. RESULTS: In 17
      subjects 28 enuresis-like episodes were provoked, generally comprising incomplete
      voidings with large residual volumes mostly in younger children and in boys.
      Enuresis and nocturia episodes were provoked at a volume specific for each
      individual without a relation to the bladder filling rate. CONCLUSIONS: Our
      results support the hypotheses that nocturnal polyuria is an important
      pathogenetic factor in enuresis and that arousal failure can be provoked in
      nonenuretic subjects.

PMID- 8648808
TI  - Micropenis secondary to growth hormone deficiency: does treatment with growth
      hormone alone result in adequate penile growth?
AB  - PURPOSE: Congenital growth hormone deficiency is associated with aberrant
      androgen physiology and micropenis. We investigated whether treatment with growth
      hormone alone is adequate to restore normal phallic growth. MATERIALS AND
      METHODS: In all patients the diagnosis was isolated growth hormone deficiency and
      micropenis, and growth hormone was the only therapy. Stretched penile length, and
      somatic height and weight measurements were available from diagnosis through
      puberty for all patients. RESULTS: Eight patients diagnosed with isolated
      congenital growth hormone deficiency and micropenis were treated and evaluated.
      Mean z-score (number of standard deviations below mean stretched penile length)
      at diagnosis was -4.25 (range 3.1 to -6.6) with -2.5 representing micropenis. In
      adulthood mean final stretched penile length z-score was -1.73 (range -0.91 to 
      2.66). Seven of the 8 patients (87.5%) had stretched penile length within normal
      range. CONCLUSIONS: Our findings suggest that growth hormone therapy alone can
      result in normal phallic size in patients with micropenis secondary to isolated
      congenital growth hormone deficiency.

PMID- 8648809
TI  - Fertility potential after unilateral orchiopexy: an age independent risk of
      subsequent infertility when biopsies at surgery lack germ cells.
AB  - PURPOSE: We evaluated whether adult fertility potential was better when
      unilateral orchiopexy was done at ages 2 to 6 years or later, and we identified
      those at risk for infertility. MATERIALS AND METHODS: Unilateral orchiopexy was
      performed simultaneously with testicular biopsy in 11 patients 2.8 to 6.8 years
      old and in 54, 10.0 to 11.9 years old. In adulthood measurement of testicular
      volume, serum follicle-stimulating hormone, luteinizing hormone and testosterone
      was done, as well as analysis of semen specimens. RESULTS: At orchiopexy the 2
      groups were statistically similar, and statistically similar fertility potentials
      were found in adulthood. Five of the 65 patients (7.7%, 95% confidence limits 2.5
      to 17%) may experience infertility, representing 33% of both groups with less
      than 1% of the age matched number of spermatogonia per tubular transverse section
      (approximately no germ cells) in the biopsy specimen at orchiopexy. CONCLUSIONS:
      Between ages 2 and 12 years the timing of unilateral orchiopexy may vary without
      an effect on subsequent fertility potential. When biopsy at surgery lacks germ
      cells, there is an approximately 33% age independent risk of subsequent
      infertility. Otherwise patients may be fertile after unilateral orchiopexy
      between ages 2 and 12 years.

PMID- 8648810
TI  - Laparoscopic marsupialization of symptomatic polycystic kidney disease.
AB  - PURPOSE: Although laparoscopic unroofing of simple renal cysts has proved to be
      an effective form of therapy, its use for treatment of multiple renal cysts or
      symptomatic autosomal dominant polycystic kidney disease only recently has been
      investigated. MATERIALS AND METHODS: The results of laparoscopic marsupialization
      of symptomatic renal cysts in 13 patients was determined 12 to 28 months
      postoperatively by assessing subjective pain relief, and comparing preoperative
      and postoperative computerized tomography (CT). Eight patients had autosomal
      dominant polycystic kidney disease. Multiple dominant (more than 3 cm.) cysts
      were marsupialized in 11 patients and 1 dominant cyst was treated in 2. RESULTS:
      Of 13 patients with symptomatic renal cysts and 8 with autosomal dominant
      polycystic kidney disease 8 (62%) and 4, respectively, were pain-free 12 to 28
      months postoperatively. Two patients had persistent pain, while 3 had recurrent
      pain 7 to 16 months postoperatively. All 5 patients had persistent or recurrent
      dominant cysts on followup CT. Followup CT demonstrated resolution or a
      significant decrease of the largest and all or all but 1 of the other dominant
      cysts in 6 of 7 pain-free patients. Intraoperative ultrasound detected
      unidentified cysts during an open and laparoscopic procedure. No deleterious
      effects on serum creatinine were observed. CONCLUSIONS: Laparoscopic
      marsupialization is a safe, relatively successful technique for providing
      persistent pain relief in patients with autosomal dominant polycystic kidney
      disease. Although the 2-year pain-free rate approaches the 62% rate reported for
      open surgical cyst resection, continued efforts to improve current laparoscopic
      techniques are clearly indicated. Persistence or recurrence of dominant cysts on
      CT correlated with persistent or recurrent symptoms. Intraoperative ultrasound is
      effective in identifying dominant cysts.

PMID- 8648811
TI  - Solitary crossed renal ectopia associated with unicornuate uterus, imperforate
      anus and congenital scoliosis.

PMID- 8648812
TI  - Morphologic changes in intestinal mucosa with urinary contact--effects of urine
      or disuse?
AB  - PURPOSE: To evaluate the morphological changes induced in bypassed ileal and
      colonic segments and the influence of the urine on the mucosal histology.
      MATERIALS AND METHODS: In a rat model, an isolated ileocolonic segment was used
      for construction of an ileocolocystoplasty or an exteriorized blind loop. Sham
      operated animals were used for control. RESULTS: In ileal mucosa, villi and
      microvilli were better preserved when exposed to urine than when deprived of
      contact with luminal content. Numerical reduction of microvilli was found in
      colonic mucosa deprived of luminal content. In colonic mucosa exposed to urine
      some areas were denuded of microvilli and showed blebs. Findings of intact tight
      junctions in all specimens implied that an important morphological requirement of
      maintained epithelial barrier function is present in mucosa deprived of normal
      luminal stimulation and also after contact with urine. The intracellular
      ultrastructural changes in both colon and ileum were similar in the 2 groups.
      However, there were more solitary ribosomes lying free in the mucosa exposed to
      urine, indicating depressed or arrested protein synthesis. CONCLUSIONS: Mucosa in
      contact with urine seems to maintain surface characteristics better than mucosa
      deprived of luminal stimulation, indicating that factors present in the urine may
      be important for the epithelial cell physiology. Certain intracellular changes
      were found more often in mucosa exposed to urine, but there were no major
      differences. The changes noticed may indicate enterocyte adaptation to a new
      physiologic environment.

PMID- 8648813
TI  - Effects of anesthesia on urodynamic studies in the primate model.
AB  - PURPOSE: To elucidate the effect of anesthesia on bladder function and urodynamic
      studies by performing controlled comparisons of the effects of 2 anesthetics on
      urodynamics in a primate model. MATERIALS AND METHODS: Cystometrograms were
      performed in 4 awake adult female Rhesus monkeys (Macaca mulatta) via implantable
      transducer for continuous monitoring and compared with cystometrograms obtained
      under anesthetic agents. A total of 183 cystometric studies was performed (48 in
      the awake group, 74 under ketamine anesthesia and 61 under flurane anesthesia.
      RESULTS: Maximum detrusor contraction pressure [Pdet(max)] was significantly
      lower under flurane than under ketamine anesthesia (33.1 +/- 2.5 versus 49.1 +/-
      8.1 cm.H2O). In the awake state Pdet(max) (47.7 +/- 25.2 cm.H2O) was equal to
      that obtained under ketamine anesthesia. Cystometric bladder capacity was
      significantly larger under flurane (101.5 +/- 81.8 ml.) than under ketamine (70.3
      +/- 56.1 ml.) anesthesia. It was only (32.9 +/- 15.9 ml.) in the awake state.
      Cystometric bladder capacity under both anesthetics was larger than the mean
      voided volume (43.3 +/- 6.3 ml.), but was comparable to the largest voided volume
      (102.3 +/- 31 ml.). Cystometric reflex contractions with bladder filling occurred
      more frequently with ketamine (96%) than with flurane anesthesia (66%).
      CONCLUSIONS: These findings show that anesthesia has profound effects on the
      bladder, and careful interpretation of urodynamic data is suggested. These
      findings also suggest that ketamine is a suitable anesthetic for urodynamic
      studies in the subhuman primate.

PMID- 8648814
TI  - Characterization of nuclear oxalate binding protein of rat and human kidney.
AB  - PURPOSE: To characterize the nuclear oxalate binding protein and its involvement
      in hyperoxaluria. MATERIALS AND METHODS: Rat and human renal cortical epithelial
      cell nuclear protein was isolated and studied. Renal nuclear histones were
      isolated by acid extraction and purified by ion exchange column chromatography.
      RESULTS: Most of the 14C-oxalate binding was present in the histone-H1 fraction.
      The oxalate binding activity resided exclusively in the H1B fraction of H1. The
      protein was purified 13 to 16-fold with a specific activity of 940 to 1570
      pmol./mg. protein. Oxalate binding to rat or human kidney or calf thymus histone
      was rapid, reversible, pH dependent and saturable. Trypsin treatment abolished
      the binding activity. Scatchard plot analysis revealed the presence of 2 distinct
      oxalate binding sites, one with high affinity and the other with low affinity.
      Oxalate binding was inhibited by DIDS (4,4'-diisothio-cyanostilbene-2, 2'
      disulfonic acid) and other dicarboxylate transport inhibitors. The IC50 values
      for different substrate analogues were, in decreasing order, oxalate < oxamate <
      succinate < glyoxylate < malate < glycolate. In experimental urolithic rats,
      histone oxalate binding was increased by 50 to 70%. The higher oxalate binding
      activity in hyperoxaluric rats was due to increased formation of H1. Histone
      exhibited in vitro calcium oxalate crystal growth promoter activity. CONCLUSION:
      Oxalate binding activity resided in the H1B of histone H1. The protein promoted
      calcium oxalate crystal growth. This suggested a possible role for this protein
      in the retention of calcium oxalate in the nucleus.

PMID- 8648815
TI  - Increased phospholipid fatty acid remodeling in human and rat prostatic
      adenocarcinoma tissues.
AB  - PURPOSE: To study the mechanism of diminished arachidonic acid levels in
      malignant prostatic tissues. MATERIALS AND METHODS: Benign and malignant prostate
      tissues were obtained from human radical prostatectomy specimens and from rats
      using Pollard's Lobund/Wistar rat prostate cancer model. Fatty acid composition
      and a variety of enzyme activities involved in maintaining phospholipid fatty
      acid composition were compared in malignant and benign prostatic tissues.
      RESULTS: Decreased arachidonic acid levels, previously reported in human prostate
      cancer, were present in malignant rat as well as in human tissues. There were 21%
      and 26% decreases of arachidonic acid levels in the rat and human malignant
      tissues compared with benign tissues. Fatty acid desaturase activity was
      undetectable. Fatty acyl-CoA hydrolase and synthetase activities were not altered
      in the malignant tissues. However, there was a 2-fold increase in phospholipase
      A2 activity and a 4- to 12-fold increase in fatty acyl-CoA
      lysophosphatidylcholine acyltransferase activity in malignant rat and human
      prostatic tissues. CONCLUSIONS: These data indicate that, in malignant prostate
      tissues, the fatty acid remodeling mechanism is activated through the deacylation
      reacylation cycle. This process may be a result of increased use of arachidonic
      acid for the formation of prostaglandins that may be crucial for the further
      development and growth of the malignant tissues.

PMID- 8648816
TI  - Lovastatin has direct renal hemodynamic effects in a rodent model.
AB  - PURPOSE: Lovastatin, an HMG-CoA reductase inhibitor, has been shown to preserve
      renal function in models of chronic renal failure. We determined the effect of
      lovastatin on renal function and hemodynamics in normal nonpathologic kidneys in
      a rodent model. MATERIALS AND METHODS: Renal function was measured in
      anesthetized (Inactin) control rats (n = 13) and lovastatin-treated rats (15
      mg./kg./day, 3 weeks, orally, n = 17). Renal blood flow was measured with an
      ultrasonic flowprobe, and glomerular filtration rate was measured by inulin
      clearance. The effect of lovastatin on pre- and postglomerular vessel diameters
      was also observed in a hydronephrotic kidney preparation by videomicroscopy.
      RESULTS: Lovastatin significantly increased (p < 0.05) renal blood flow and
      glomerular filtration rate by 17% (3.4 +/- 0.2 ml./min./gram kidney weight (gKW)
      versus 2.9 +/- 0.2 ml./min./gKW) and 49% (0.67 +/- 0.04 ml./min./gKW versus 0.45
      +/- 0.06 ml./min./gKW). The increase in renal blood flow was mediated by
      preglomerular vasodilation (expressed as percent increase from baseline diameter,
      n = 20), 25% in the interlobular artery and 20% in the afferent arteriole (p <
      0.05). CONCLUSIONS: In addition to its known lipid-lowering properties,
      lovastatin has a direct renal hemodynamic effect, increasing renal blood flow and
      glomerular filtration rate in normal nonpathologic kidneys. Lovastatin's
      selective preglomerular vasodilation may account for the observed increase in
      renal blood flow and glomerular filtration rate. Accordingly, this additional
      hemodynamic effect may be useful in preserving renal function in models of
      chronic renal failure.

PMID- 8648817
TI  - Involvement of Epstein-Barr virus expression in testicular tumors.
AB  - PURPOSE: Because orchitis has been described as a symptom of infectious
      mononucleosis which is caused by Epstein-Barr virus (EBV), a human tumor virus,
      we tried to ascertain the relationship between EBV and testicular tumors.
      MATERIALS AND METHODS: Sixteen seminomas, 11 embryonal carcinomas and 25
      nonmalignant control testes were examined for persistence and expression of the
      EBV genome. To detect expression of EBV, mRNA in situ hybridization and
      immunofluorescence staining by monoclonal antibodies were performed. To confirm
      the EBV genome in testes, we used nested polymerase chain reaction (PCR).
      RESULTS: Messenger RNA in situ hybridization showed that all 27 seminomas and
      embryonal carcinomas expressed EB viral RNA, but the 25 nonmalignant testes did
      not. Monoclonal antibody staining showed EBV-related nuclear antigen (EBNA) 2 and
      latent membrane protein (LMP) 1 expression in testicular tumors. Nested
      polymerase chain reaction detected the EBV genome in normal testes as well as in
      testicular tumors. CONCLUSIONS: These results suggest that EBV is related to
      testicular tumors.

PMID- 8648818
TI  - Transperineal photodynamic ablation of the canine prostate.
AB  - PURPOSE: Experiments were undertaken to determine the effects of transperineal
      interstitial photodynamic therapy on the canine prostate. MATERIALS AND METHODS:
      Mongrel dogs were injected intravenously with the photosensitizer, tin (II) ethyl
      etiopurpurin dichloride. Twenty-four hours later, 2 optical fibers were implanted
      in 1 hemisphere of the prostate, which was then treated with red light (660 nm.).
      RESULTS: Acutely, the treated areas showed extensive hemorrhagic necrosis. At 3
      and 6 weeks, the treated lobes were largely replaced by fibrous connective
      tissue. CONCLUSION: Transperineal photodynamic therapy of the canine prostate is
      feasible. Further preclinical investigation is warranted to determine the
      applicability of this approach to the treatment of localized prostate cancer.

PMID- 8648819
TI  - TGF-beta mRNA expression in the renal pelvis after experimental and clinical
      ureteropelvic junction obstruction.
AB  - PURPOSE: The renal parenchymal expression of transforming growth factor-beta (TGF
      beta) is increased in experimental obstructive uropathy. To better understand the
      pathophysiology of hydronephrosis, we pursued this observation by determining if
      the expression of TGF-beta is also increased in the obstructed renal pelvis.
      MATERIALS AND METHODS: The expression of TGF-beta mRNA was evaluated in
      experimental and clinical ureteropelvic junction obstruction by reverse
      transcriptase polymerase chain reaction (RT-PCR). Southern blot analysis with
      labeled human cDNA probes for TGF-beta was then done to verify the results.
      RESULTS: Experimentally, pelves subjected to ureteral constriction showed
      significantly higher TGF-beta mRNA expression than normals. After reversal of
      obstruction, the expression of TGF-beta remained significantly higher than
      normals but was not different from pelves with ongoing obstruction. Clinically,
      there was a significantly higher level of TGF-beta mRNA expression in obstructed
      pelves than in nonobstructed ureters. High levels of TGF-beta mRNA expression
      correlated significantly with good clinical outcome, good renal function, muscle
      hypertrophy and acute onset of obstruction. CONCLUSIONS: There is increased TGF
      beta mRNA expression in the renal pelvis following clinical and experimental
      ureteropelvic junction obstruction. These data implicate TGF-beta in the adaptive
      molecular responses that increase muscle and collagen elaboration seen in
      hydronephrosis.

PMID- 8648820
TI  - Detrimental effect of left varicocele on the reproductive capacity of the early
      haploid male gamete.
AB  - PURPOSE: We evaluated the fertilizing capacity of round spermatids recovered from
      varicocelized rabbits. MATERIALS AND METHODS: A left varicocele model was created
      in 5 rabbits (Group A). Four rabbits underwent a sham operation (Group B). After
      3 months round spermatid nuclei were collected from the left testicle of each
      rabbit and injected into oocytes. Oocytes were cultured for 24 hours. RESULTS:
      The proportion of 2- to 4-cell stage embryos to the successfully injected oocytes
      was significantly lower in group A than in group B (p < 0.05). CONCLUSIONS: Our
      findings indicate a detrimental effect of varicocele on the fertilizing potential
      of round spermatid.

PMID- 8648821
TI  - Expression of MDR-1 gene in transitional cell carcinoma and its correlation with
      chemotherapy response.
AB  - PURPOSE: Expression of the mdr-1 gene has been correlated with the
      chemoresistance mechanisms of some cancer models. In the present study, we tried
      to evaluate mdr-1 gene expression in transitional cell carcinoma (TCC) in both
      cultured cells and clinical tumors. The expression status of mdr-1 was further
      correlated with the response to chemotherapy in both systemic and intravesical
      models. MATERIALS AND METHODS: We evaluated mdr-1 expression levels by reverse
      transcription polymerase chain reaction and Southern blotting (RT-PCR-SB) and the
      activity of P-glycoprotein (P-gp) by flow cytometric rhodamine-123 retention and
      efflux study in 10 TCC cell lines, 2 doxorubicin-resistant sublines (RLs), T24/A
      and NTUB1/A, and 2 cisplatin-RLs, T24/P and NTUB1/P. Eighty-eight clinical tumors
      with their benign counterparts were also assayed by RT-PCR-SB to determine mdr-1
      expression status. Of the 88 TCC cases, 28 were treated with systemic and 60 with
      intravesical chemotherapy. Response to chemotherapy in either form was correlated
      with mdr-1 expression status. RESULTS: By RT-PCR-SB, mdr-1 expression signals
      were observed in only 2 of the 10 TCC cell lines; only 1 of these had a strong
      signal and active P-gp function. The other, bearing a weak signal, was negative
      for active P-gp function. All of the 4 RLs studied showed elevated mdr-1
      transcript levels as compared with their mdr-1 negative parental cell lines.
      Doxorubicin-RLs showed much stronger expression signals than cisplatin-RLs.
      Active P-gp functions were observed in the 2 doxorubicin-RLs but not in the 2
      cisplatin-RLs. The efflux of rhodamine-123 in cells with active P-gp function can
      be significantly inhibited by 10 microM. verapamil. Of the 88 clinical tumors, 62
      (70.5%) were positive and 26 (29.5%) were negative for mdr-1 expression by RT-PCR
      SB. All benign counterparts of the 88 tumors were positive for mdr-1 expression.
      However, no differences in chemotherapy responses were found between the positive
      and negative mdr-1 expression groups in either systemic chemotherapy (p = 0.32,
      one-tailed Fisher's exact test) or intravesical chemotherapy (p = 0.52, Cox
      Mantel log rank test). CONCLUSIONS: Expression of mdr-1 was not commonly seen in
      TCC cell lines but can be significantly induced by chronic exposure to
      doxorubicin. Benign transitional cell epithelia seemed to universally express the
      mdr-1 gene. However, clinical TCCs lost mdr-1 transcript expressions in about 30%
      of cases. Most important, it appeared that mdr-1 expression status did not
      correlate with the response to chemotherapy in either systemic or intravesical
      models.

PMID- 8648822
TI  - Effects of potassium channel modulators cromakalim, tetraethylammonium and
      glibenclamide on the contractility of the isolated human ureter.
AB  - PURPOSE: Experiments were performed to assess the effect of the potassium channel
      modulators cromakalim, tetraethylammonium (TEA) and glibenclamide on the
      contractility of isolated human ureteric rings. MATERIALS AND METHODS: Segments
      of human distal ureter obtained from kidney donors (leftovers) were cut into
      rings and suspended in an organ bath filled with modified Tyrode solution for
      measurement of isometric contractile force. The ureter was stimulated
      electrically or with KCl, and the contractile activity recorded on a polygraph.
      RESULTS: The amplitude of the contraction induced by electrical stimulation was
      not changed by glibenclamide but was enhanced by tetraethylammonium. The resting
      tension of the ureter was not changed by either potassium channel inhibitor.
      Cromakalim did not change the resting tension of the human ureter per se but
      induced a concentration-dependent inhibition of the contractions induced by
      electrical stimulation. This inhibitory effect of cromakalim was not changed by
      tetraethylammonium but was inhibited by glibenclamide. A phasic and tonic
      contractile response in the isolated human ureteric ring was induced by 60 mM.
      KCl. The phasic contractions were abolished by cromakalim whereas the tonic
      contractions were unaffected. Following sustained contraction induced by 25 mM.
      KCl, the cumulative addition of cromakalim to the organ bath produced a
      concentration-dependent relaxation. However, in rings precontracted with 60 mM.
      KCl, cromakalim at a concentration as high as 10(-5) M. did not induce
      relaxation. The cromakalim-induced relaxation of rings precontracted with 25 mM.
      KCl was significantly inhibited by glibenclamide. CONCLUSION: These results
      suggest that potassium channels are important in the control of human ureter
      contractility and that potassium channel openers may be an alternative
      therapeutic indication in the treatment of human ureteric colic.

PMID- 8648823
TI  - Surgical management of complex renal cysts: a series of 32 cases.
AB  - PURPOSE: The differentiation between benign cysts of the kidney and those that
      require surgical exploration remains difficult. The accuracy of radiological
      techniques (ultrasound, computerized tomography [CT], angiography, magnetic
      resonance imaging, cyst puncture and intraoperative pathological examination) is
      analyzed. MATERIALS AND METHODS: Surgical exploration was performed in 30
      patients with 32 asymptomatic renal cysts, and the pathological specimens were
      compared retrospectively to the radiological findings. The classification of
      Bosnaik was used to categorize the ultrasound and CT findings. RESULTS: Of our
      complex renal cysts 41% proved to be malignant. Our results suggest that the
      radiological techniques are not well suited for characterization of these cysts.
      None of the Bosnaik types was sufficiently predictive of the lesion. Only a
      Bosnaik score of 4 (the sum of ultrasound and CT Bosnaik types) was not
      associated with renal cell carcinoma. According to the radiological findings, 1
      patient was under treated (recurrent renal cell carcinoma) and 4 were over
      treated (radical nephrectomy for benign lesions). CONCLUSIONS: A practical
      therapeutic strategy is described in which radical nephrectomy is performed when
      malignant lesions are detected either by preoperative or intraoperative
      techniques. Conservative surgery is indicated for benign cysts according to the
      clinical status and risks of nephron sparing surgery.

PMID- 8648824
TI  - Renal cell carcinoma genetic analysis by comparative genomic hybridization and
      restriction fragment length polymorphism analysis.
AB  - PURPOSE: To compare comparative genomic hybridization (CGH) with restriction
      fragment length polymorphism (RFLP) analysis in renal cell carcinoma (RCC).
      MATERIALS AND METHODS: Fifteen RCC specimens were analyzed by both CGH and RFLP
      analysis at 18 loci. RESULTS: Restriction fragment length polymorphism analysis
      was informative on 90 chromosomal arms. Allelic imbalance was identified on 27
      chromosomal arms by RFLP and on 26 arms by CGH. Data from CGH and RFLP
      demonstrated a high degree of concordance (p < 0.001). Comparative genomic
      hybridization identified previously documented areas of interest in RCC as well
      as potential new areas of interest including loss of genetic material on
      chromosome 2 and gains of genetic material on chromosome 16p. CONCLUSIONS:
      Comparative genomic hybridization can successfully be performed in RCC specimens.
      As it surveys the entire genome simultaneously, it may be more efficient than
      conventional cytogenetics or RFLP analysis in analyzing RCC.

PMID- 8648825
TI  - The role of ultraviolet light in the induction of cellular DNA damage by a spark
      gap lithotripter in vitro.
AB  - PURPOSE: The purpose of this study was to investigate the mechanisms for DNA
      damage induced by a spark-gap lithotripter. MATERIALS AND METHODS: Cultured
      Chinese hamster ovary cells suspended in phosphate buffered saline were exposed
      in small chambers placed at the focus of a lithotripter in a 37C water bath.
      Viability was checked by trypan blue exclusion, and DNA strand breaks were
      evaluated with the comet assay after exposure. RESULTS: About 50% cell lysis and
      significant DNA damage in surviving cells were found after 500 discharges. The
      strand break effect, but not the lysis, could be eliminated by blocking the light
      emitted by the discharge. The exposure chamber material influenced the results,
      and use of nutrient medium with serum reduced the observed effects. The DNA
      damage was eliminated by added novobiocin and enhanced by added aphidicolin, as
      expected for strand breaks associated with repair of ultraviolet light damage.
      The DNA strand-break effect of 500 spark-gap discharges approximated that
      obtained from a positive control treatment with 38 J/m2. of 254 nm. ultraviolet
      light. CONCLUSIONS: Thus, the observed DNA damage appears to result from exposure
      of cells to the ultraviolet light emissions of the spark-gap discharge, rather
      than to the shockwaves or shockwave induced cavitation, which causes the cell
      lysis. Exposure of the skin to this ultraviolet light during lithotripsy might
      have some clinical implications for prolonged or repeated treatment.

PMID- 8648826
TI  - Water channel protein subtype suggests the origin of renal cell carcinoma.
AB  - PURPOSE: Several subtypes of water selective channel protein have been cloned. In
      normal kidneys, CHIP-28 (channel forming integral protein of 28 kd) is expressed
      solely in the proximal tubules and descending thin limbs, and aquaporin-CD (AQP
      CD) expression is restricted to collecting ducts. We assessed expression of these
      2 distinct types of water channels in renal cancer tissues. MATERIALS AND
      METHODS: Expression of CHIP-28 and AQP-CD was examined in 12 samples of primary
      renal cell carcinoma by Northern blot, reverse transcriptase-polymerase chain
      reaction and immunohistochemistry. We also evaluated expression of these 2
      molecules immunohistochemically in 4 samples of Bellini duct tumor, which has
      been thought to arise from renal collecting ducts. RESULTS: Expression of CHIP-28
      was detected in all of the samples of primary renal cell carcinoma, whereas none
      of them expressed AQP-CD. None of 4 samples of Bellini duct tumor expressed CHIP
      28, although expression of AQP-CD was recognized in 2. CONCLUSIONS: Our current
      observation confirms the idea of the proximal or descending tubule origin of
      renal cell carcinoma.

PMID- 8648827
TI  - Female stress urinary incontinence due to intrinsic sphincteric deficiency:
      recognition and management.
AB  - PURPOSE: The recent literature on intrinsic sphincteric deficiency is reviewed.
      MATERIALS AND METHODS: We performed an extensive literature search related to the
      diagnosis, management and treatment of intrinsic sphincteric deficiency. RESULTS:
      Stress urinary incontinence results from insufficient urethral resistance and/or
      support during increases in intra-abdominal pressure. Since treatment of stress
      urinary incontinence is closely related to the mechanism of urinary leakage,
      recognition of intrinsic sphincteric deficiency is of the utmost importance in
      its evaluation. Furthermore, to date there is no consensus on the treatment of
      intrinsic sphincteric deficiency and various procedures may be considered.
      CONCLUSIONS: The pathophysiology of urinary incontinence in female patients is
      still controversial. Intrinsic sphincteric deficiency is best recognized by
      history and clinical examination in conjunction with documentation of severe
      stress urinary incontinence, a fixed urethra and a low Valsalva leak point
      pressure. The pubo-vaginal sling procedure still represents the most widely
      accepted treatment to correct intrinsic sphincteric deficiency.

PMID- 8648828
TI  - The definition and preoperative prediction of clinically insignificant prostate
      cancer.

PMID- 8648829
TI  - Follow-up prostate cancer treatments after radical prostatectomy: a population
      based study.

PMID- 8648830
TI  - Renal artery angioplasty: technical results and clinical outcome in 320 patients.

PMID- 8648831
TI  - Fluorescence in situ hybridization analysis of renal oncocytoma reveals frequent
      loss of chromosomes Y and 1.
AB  - PURPOSE: Cytogenetic studies of a small number of renal oncocytomas have
      indicated that loss of chromosomes 1 and Y may be involved in the pathogenesis of
      this tumor. To evaluate these observations further we selected paraffin embedded
      renal oncocytoma specimens from 20 male and 10 female patients for fluorescence
      in situ hybridization analysis. MATERIALS AND METHODS: Isolated nuclei were
      prepared from paraffin embedded specimens, and fluorescence in situ hybridization
      was performed with enumeration probes for chromosomes 1, 12, X and Y. RESULTS:
      Tumors from 10 male (50%) and 4 female (40%) patients demonstrated chromosomal
      alterations. Loss of chromosome Y was observed in specimens from all 10 male
      patients, and loss of chromosome 1 or gain of chromosome 12 was noted in 5 and 2
      of these specimens, respectively. Of the 4 female patients with chromosomal
      abnormalities 2 had loss of chromosome 1, 1 had gain of chromosome 1 and 1 had
      gain of chromosome 12. CONCLUSIONS: Our results confirm that loss of chromosomes
      Y and 1 is common in renal oncocytoma, and that the alterations are probably
      involved in the pathogenesis of this tumor.

PMID- 8648832
TI  - Nephron sparing surgery in patients with metastatic renal cell carcinoma.
AB  - PURPOSE: We evaluated the role of nephron sparing surgery in patients with
      metastatic renal cell carcinoma. MATERIALS AND METHODS: A total of 15 patients
      with metastatic renal cell carcinoma underwent nephron sparing surgery and
      treatment of metastases, including 4 who received adjunctive biological response
      modifier therapy. The 9 patients in group 1, who previously underwent
      contralateral nephrectomy for renal cell carcinoma and complete resection of all
      metastases, presented for treatment of localized renal cell carcinoma in the
      remaining kidney with no other evidence of disease. The 6 patients in group 2
      presented with localized renal cell carcinoma requiring nephron sparing surgery
      and concomitant distant metastases. Mean postoperative followup was 30.4 months.
      RESULTS: Of 9 patients in group 1, 6 (66.7%) were disease-free at a mean of 31.3
      months after nephron sparing surgery and 102.2 months after detection of
      metastatic disease, while 3 (33.3%) died at a mean of 53.3 and 73.0 months,
      respectively. Among the 6 patients in group 2, 4 (66.7%) were disease-free at a
      mean followup of 16.8 months and 2 (33.3%) died at a mean of 20.5 months
      postoperatively. Of the 4 patients who received adjunctive biological response
      modifier therapy 3 were disease-free at a mean of 12.7 months and 1 died 7 months
      after treatment. Satisfactory overall renal function was preserved in 14 of 15
      patients after nephron sparing surgery. CONCLUSIONS: We conclude that nephron
      sparing surgery can provide effective treatment for select patients with renal
      cell carcinoma and previously or recently treated metastatic disease.

PMID- 8648833
TI  - Certain subsets of renal neoplasms behave differently, but why?

PMID- 8648834
TI  - Nephrogenic adenoma of the bladder in renal transplant recipients: a report of 9
      cases with assessment of deoxyribonucleic acid ploidy and long-term followup.
AB  - PURPOSE: We evaluated the outcome of nephrogenic adenoma, a benign tumor rarely
      encountered in renal transplant recipients. MATERIALS AND METHODS: Between 1985
      and 1993, 9 renal transplant recipients with a nephrogenic bladder adenoma
      removed by endoscopic resection were followed for 24 to 88 months (mean 40).
      Tumor deoxyribonucleic acid ploidy was assessed by flow cytometry at diagnosis
      and/or relapse. RESULTS: The relapse rate was 88%. The tumors were diploid and of
      low proliferating potential, and showed no malignant transformation. CONCLUSIONS:
      Our study confirms the lack of premalignant potential of nephrogenic adenomas.
      However, since transplant recipients might be at increased risk for bladder
      cancer, they should be followed closely.

PMID- 8648835
TI  - Intravesical hyaluronic acid in the treatment of refractory interstitial
      cystitis.
AB  - PURPOSE: Based on the assumption that interstitial cystitis results from a
      defective mucous lining of the bladder epithelium, we investigated the activity
      of hyaluronic acid in the treatment of this disease. Hyaluronic acid is an
      important glycosaminoglycan present in all connective tissues, including the
      glycosaminoglycan layer of the vesical mucosa. It exhibits a variety of
      pharmacological properties that enhance its appeal for the therapy of
      interstitial cystitis. MATERIALS AND METHODS: A total of 25 patients with
      characteristic findings of interstitial cystitis refractory to other medical
      treatments participated in a trial of intravesical hyaluronic acid at a dose of
      40 mg. weekly for 4 weeks and then monthly. Response to therapy was evaluated by
      symptom score, voiding diaries and visual analog scales. RESULTS: An initial 56%
      positive (complete plus partial) response rate at week 4 increased to 71% by week
      12 and response was maintained until week 20. Beyond week 24 there was a moderate
      decrease in the effectiveness of the medication. There was no significant
      toxicity attributable to hyaluronic acid in the bladder. CONCLUSIONS: The
      response of patients with refractory interstitial cystitis to the intravesical
      administration of hyaluronic acid was gratifying. In the past many therapies for
      interstitial cystitis which were initially considered promising failed the test
      of a controlled study. Such a study to determine the activity of hyaluronic acid
      in patients with interstitial cystitis is currently under way.

PMID- 8648836
TI  - Ancillary techniques in the followup of transitional cell carcinoma: a comparison
      of cytology, histology and deoxyribonucleic acid image analysis cytometry in 91
      patients.
AB  - PURPOSE: Voided urine and bladder washing cytology are used frequently in the
      evaluation of transitional cell carcinoma of the bladder. As part of an ongoing
      investigation we report on the role of deoxyribonucleic acid (DNA) image analysis
      cytometry as an adjunct to cytology in the followup of patients with transitional
      cell carcinoma. MATERIALS AND METHODS: Urine cytology and image analysis
      cytometry were performed independently on aliquots of voided urine, catheterized
      urine or bladder washings from 91 patients with previous or active transitional
      cell carcinoma of the bladder, and the results were compared to those of
      concurrent biopsy and clinical followup. RESULTS: Of 75 recurrent transitional
      cell carcinomas 42 were detected by cytology, while 63 and 64 were identified by
      image analysis cytometry and biopsy, respectively, for a sensitivity of 57, 84
      and 85%, respectively. Combined cytology and image analysis cytometry detected 67
      recurrences, for an overall sensitivity of 89%. Of 11 cases undetected by
      concurrent biopsy 9 had abnormal DNA histograms with transitional cell carcinoma
      at followup and 2 were DNA diploid but with grade 1 transitional cell carcinoma
      at followup. Of 12 cases undetected by image analysis cytometry 8 were grade 1
      and 4 were grade 2 transitional cell carcinoma. CONCLUSIONS: Urine cytology and
      image analysis cytometry detect most recurrent tumors. Their combined use is
      indicated in the followup of patients with bladder transitional cell carcinoma.

PMID- 8648837
TI  - Alternating mitomycin C and bacillus Calmette-Guerin instillation prophylaxis for
      recurrent papillary (stages Ta to T1) superficial bladder cancer. Finnbladder
      Group.
AB  - PURPOSE: We attempted to prove if alternating chemoprophylactic and
      immunoprophylactic instillations improved efficacy and decreased toxicity in
      patients with recurrent superficial bladder cancer. MATERIALS AND METHODS: A
      total of 188 patients with rapidly recurring stage Ta or T1 cancer was randomly
      treated with mitomycin C (group 1) or alternating mitomycin C and Pasteur strain
      bacillus Calmette-Guerin (BCG) instillations (group 2) for 2 years. Mean followup
      was 34 months. RESULTS: Median times to initial recurrence were 12 months in
      group 1 and 7 months in group 2 (p = 0.976), and treatment failed in 21.5% and
      18.9%, respectively. Recurrence rates during the instillation period were 1.01 in
      group 1 and 0.86 in group 2 (p = 0.376). There was no difference in the disease
      free interval between the 2 groups (p = 0.976). Instillations were discontinued
      because of adverse effects in 6 cases (6%) in both groups. CONCLUSIONS: Efficacy
      of alternating mitomycin C and BCG was equal to mitomycin C monotherapy, and both
      methods were effective in prophylaxis of recurrent papillary bladder cancer. Less
      toxicity occurred in the alternating treatment group compared to earlier BCG
      monotherapy results.

PMID- 8648838
TI  - More is simply more and not necessarily better.

PMID- 8648839
TI  - Role of proliferative activity estimated by bromodeoxyuridine labeling index in
      determining predictive factors of recurrence in superficial intermediately
      malignant bladder tumors.
AB  - PURPOSE: Previous studies have shown that factors predictive of tumor recurrence
      include a history of the disease, multiple tumors at diagnosis, and high tumor
      grade and stage. Additional biological marker for predicting tumor recurrence
      could potentially be used in the decision making process and could alter the
      frequency of clinical cystoscopy. We attempted to clarify whether the tumor
      proliferative activity estimated by bromodeoxyuridine, which is believed to be a
      thymidine analogue, and deoxyribonucleic acid (DNA) ploidy status correlates well
      with tumor recurrence as an objective parameter. MATERIALS AND METHODS: We
      evaluated 103 patients with superficial grade 2 transitional cell carcinoma of
      the bladder treated with transurethral resection. Mean followup plus or minus
      standard deviation was 49.5 +/- 11.3 months (minimum 36). Tumor specimens were
      obtained by transurethral cold-cup biopsy, with bromodeoxyuridine in vitro pulse
      labeling then performed under hyperbaric oxygen. The flow cytometric
      determination of the bromodeoxyuridine labeled cell index and DNA ploidy were
      estimated. RESULTS: When the tumor was classified according to the
      bromodeoxyuridine labeled cell index the 5-year no recurrence rates were 82.0 and
      27.1% for an index of less than 5.3 and more than 5.3%, respectively.
      Furthermore, the 5-year no recurrence rates were 75.1% for DNA diploid compared
      to 29.3% for DNA aneuploid tumors, respectively. Multivariate analysis using
      Cox's proportional hazards model showed that the most important risk factor for
      tumor recurrence was a bromodeoxyuridine labeled cell index of more than 5.3%
      (risk ratio 5.31, p < 0.001), followed by DNA ploidy (risk ratio 2.61, p < 0.05).
      Tumor stage, initial lesion versus recurrence and single versus multiple tumors
      did not influence the risk factor for tumor recurrence. CONCLUSIONS: These data
      indicate that bromodeoxyuridine labeling status can be used as an objective risk
      factor for bladder cancer recurrence.

PMID- 8648840
TI  - Endoscopic management of the obliterated anastomosis following radical
      prostatectomy.
AB  - PURPOSE: We evaluated an endoscopic technique to treat the challenging problem of
      an obliterated anastomosis following radical prostatectomy. MATERIALS AND
      METHODS: Four men with a mean 2.25 cm. obliterative defect underwent visual
      internal urethrotomy along a sternal guide wire passed under direct antegrade and
      retrograde vision. Men then performed self-dilation according to an increasing
      interval protocol. RESULTS: All 4 men maintained anastomotic patency for a mean
      followup of 12.5 months and 1 no longer requires self-calibration. There were no
      complications of this procedure. CONCLUSIONS: Endoscopic management coupled with
      self-dilation offers a safe, minimally invasive option for difficult, long
      obliterative anastomotic defects following radical prostatectomy.

PMID- 8648841
TI  - Internal urethrotomy in the management of anterior urethral strictures: long-term
      followup.
AB  - PURPOSE: We evaluated the long-term results of internal urethrotomy for anterior
      urethral strictures. MATERIALS AND METHODS: Between 1975 and 1990, 224 patients
      underwent internal urethrotomy for anterior urethral strictures. Median followup
      was 98 months (range 60 to 216). RESULTS: The recurrence rate after 1 urethrotomy
      was 68% overall, and 58% for bulbar, 84% for penile and 89% for penile bulbar
      urethral strictures. Repeated urethrotomies did not improve the success rate.
      Prognostic characteristics of bulbar urethral strictures associated with good
      results included single or primary strictures, length shorter than 10 mm. and
      caliber wider than 15F. Preoperative infection and etiology of the strictures did
      not correlate with results. Multiple urethrotomies achieve only temporary
      improvement and can be compared to repeated dilations. CONCLUSIONS: Alternative
      treatments should be considered for penile strictures and after failure of
      initial urethrotomy.

PMID- 8648842
TI  - Reoperative surgery for recurrent strictures of the penile and bulbous urethra.
AB  - PURPOSE: We evaluated the outcome of reoperation for anterior urethral
      strictures. MATERIALS AND METHODS: Strictures that recurred after urethroplasty
      were repaired by various procedures in 20 patients (penile urethra in 8 and
      bulbous urethra in 12, mean followup 57 months). RESULTS: Of the recurrent penile
      urethral strictures 3 showed excellent and 5 satisfactory results, compared to 9
      and 3, respectively, for bulbous urethral strictures. Overall 60% of the cases
      had an excellent outcome and no failures were documented. CONCLUSIONS: Any type
      of urethroplasty may fail even after a considerable period but reoperation with
      proper indications can offer a lasting solution.

PMID- 8648843
TI  - Treatment of recurrent urethral strictures.

PMID- 8648844
TI  - Quality of life in patients using self-administered intracavernous injections of
      prostaglandin E1 for erectile dysfunction.
AB  - PURPOSE: We assessed changes in quality of life after 6 months of self-injections
      of prostaglandin E1 for the treatment of erectile dysfunction. MATERIALS AND
      METHODS: A prospective study was done at a university affiliated Veterans Affairs
      medical center of patients using prostaglandin E1 at home. Quality of life was
      assessed with the Case Western Reserve University sexual functioning
      questionnaire and the Duke health profile. These questionnaires were administered
      before initiation and after 6 months of prostaglandin E1 therapy. RESULTS: Of 16
      subjects injecting prostaglandin E1 at home 15 completed 6 months of therapy, and
      13 of them completed both questionnaires. While using prostaglandin E1 we found
      an increase in the frequency of sexual activity from 2.9 to 5.5 times during the
      prior month (p = 0.01), rigidity of erection scores from 3.8 to 7.6 (p = 0.002,
      score 0-no erection to 8-full erection) and sexual satisfaction scores from 2.5
      to 4.1 (p = 0.03, score 0-extremely unsatisfied to 5-extremely satisfied). We
      also found improvements in mental health scores from 80.0 to 92.3 (p = 0.007),
      social health scores from 61.5 to 80.8 (p = 0.004) and self-esteem scores from
      72.3 to 86.9 (p = 0.01) on a scale of 0 to 100, where a higher score indicates
      better health. CONCLUSIONS: Self-injection of prostaglandin E1 improves sexual
      satisfaction and quality of life in men with erectile dysfunction.

PMID- 8648846
TI  - Burned-out primary testicular cancer: sonographic and pathological
      characteristics.
AB  - PURPOSE: Rarely, a testicular scar is discovered in a patient with a presumed
      extragonadal germ cell tumor. Of 6 patients originally diagnosed with
      retroperitoneal extragonadal germ cell tumors who had echogenic foci on scrotal
      sonography 5 had definite histological evidence of a regressed primary testicular
      cancer. MATERIALS AND METHODS: Six men 21 to 36 years old presented with palpably
      normal testes and a presumed retroperitoneal extragonadal germ cell tumor. After
      chemotherapy each patient underwent retroperitoneal lymph node dissection and
      ipsilateral orchiectomy. The entire testis was submitted for histological
      evaluation and all calcifications were identified. RESULTS: Scrotal sonography
      revealed an echogenic focus or foci in all cases, which corresponded to
      intratubular hematoxyphilic bodies in 2. In 3 cases the echogenic foci were
      intratubular psammoma bodies close to a fibrous scar with hemosiderin deposition,
      1 of which contained a focus of intratubular germ cell neoplasia. The
      hematoxyphilic bodies appeared larger and more intensely echogenic on sonography
      than the psammoma bodies. The remaining case had stromal calcifications near the
      rete testis. CONCLUSIONS: The hematoxyphilic bodies and fibrosis with hemosiderin
      deposits are believed to represent remnants of testicular carcinoma. Our finding
      of intratubular germ cell neoplasia provides further proof that testicular
      carcinomas regress. In 5 of 6 patients (83%) with presumed extragonadal germ cell
      tumors we showed definite pathological evidence of a burned-out testicular
      carcinoma. With a presumed retroperitoneal germ cell tumor and palpably normal
      testes, sonographic demonstration of an echogenic lesion in the absence of a
      hypoechoic mass probably represents a burned-out primary neoplasm.

PMID- 8648845
TI  - Early treatment of cryptorchidism, semen quality and testicular endocrinology.
AB  - PURPOSE: We evaluated the effect of patient age at treatment of cryptorchidism in
      relation to subsequent semen quality. MATERIALS AND METHODS: Semen analyses and
      hormonal evaluations were performed in 51 men who were treated for cryptorchidism
      at ages 10 months to 12 years. RESULTS: Sperm concentration was normal in 90% of
      the patients with unilateral and 50% with bilateral cryptorchidism. No patient
      treated before age 4 years had severe sperm defects. Elevated follicle
      stimulating hormone levels indicated severe testicular damage. CONCLUSIONS:
      Fertility is better in patients with bilateral cryptorchidism if treated before
      age 4 years. Age at treatment did not have a significant effect on semen quality
      in patients with unilateral cryptorchidism.

PMID- 8648847
TI  - Retroperitoneal lymphadenectomy for clinical stage I nonseminomatous testicular
      tumor: laparoscopy versus open surgery and impact of learning curve.
AB  - PURPOSE: Laparoscopic retroperitoneal lymphadenectomy for clinical stage I
      nonseminomatous testicular tumors was compared to open surgery, taking into
      account the impact of the learning curve. MATERIALS AND METHODS: Between August
      1992 and September 1995, 29 consecutive patients underwent laparoscopic
      retroperitoneal lymphadenectomy. Open surgical retroperitoneal lymphadenectomy
      was performed on 30 patients between January 1988 and July 1992. RESULTS: A
      comparison of the 14 initial and 15 subsequent laparoscopies showed a steep
      learning curve (operative time shorter by 36%, blood loss decreased by 50% and
      postoperative hospital stay shorter by 27%). When comparing the last 15
      laparoscopic procedures to the open operations, the latter were superior only in
      terms of operative time (shorter by 18%). With regard to all other parameters
      open surgery was inferior (increased blood loss by 38%, longer postoperative
      hospital stay by 166%, more serious complications and a greater complication
      rate). Antegrade ejaculation was preserved after all laparoscopic and after 28 of
      the 30 open operations. There were no retroperitoneal recurrences in either group
      (mean followup 16 months after laparoscopy and 54 months after open surgery).
      CONCLUSIONS: Laparoscopic retroperitoneal lymphadenectomy is a demanding
      operation that is superior to open surgery once the learning curve has been
      overcome. However, this is possible only if laparoscopic retroperitoneal
      lymphadenectomy is performed on a regular basis.

PMID- 8648848
TI  - Analyses of indications for and outcomes of epididymectomy.
AB  - PURPOSE: We analyzed the contemporary indications for epididymectomy, and
      quantified outcomes in terms of symptom resolution, complications and patient
      satisfaction. MATERIALS AND METHODS: The indications for surgery and outcomes for
      57 patients who underwent epididymectomy between 1990 and 1994 were evaluated.
      RESULTS: A total of 30 patients (53%) underwent surgery for epididymal cysts and
      27 (47%) for chronic epididymitis or epididymalgia. There was greater patient
      satisfaction among the cyst group (92%) compared to the
      epididymitis/epididymalgia group (43%, p < 0.001). Furthermore, more patients in
      the latter group complained of subsequent problems that they considered related
      to the procedure. CONCLUSIONS: The outcome of epididymectomy, is significantly
      more favorable in patients with epididymal cysts than with chronic epididymitis
      or intractable epididymal pain. Epididymectomy should be reserved for the former
      group but avoided in the latter cases unless they have been carefully counseled
      regarding the likelihood of poor results.

PMID- 8648849
TI  - High energy thermotherapy in the treatment of benign prostatic hyperplasia:
      results of the European Benign Prostatic Hyperplasia Study Group.
AB  - PURPOSE: We documented the results of high energy transurethral microwave
      thermotherapy in the treatment of benign prostatic hyperplasia. MATERIALS AND
      METHODS: We evaluated 116 patients following transurethral microwave
      thermotherapy according to symptom scores, transrectal ultrasound, free voiding
      and pressure-flow study parameters. RESULTS: Significant improvement was noted in
      all objective and subjective parameters. Moreover, cavities in the prostatic
      urethra were observed in almost 40% of the patients. CONCLUSIONS: High energy
      transurethral microwave thermotherapy is an effective therapy for benign
      prostatic hyperplasia. Patients with larger prostates and moderate to severe
      bladder outlet obstruction seem to be the best candidates for this higher energy
      thermotherapy protocol, although morbidity is increased.

PMID- 8648850
TI  - When physicians ask, women tell about domestic abuse and violence.

PMID- 8648851
TI  - Psychiatry and primary care forge new bonds.

PMID- 8648852
TI  - Ethics consultation quality: is evaluation feasible?

PMID- 8648854
TI  - From the Centers for Disease Control and Prevention. Mosquito-transmitted malaria
      -Michigan, 1995.

PMID- 8648853
TI  - From the Centers for Disease Control and Prevention. Necrotic arachnidism-
      Pacific Northwest, 1988-1996.

PMID- 8648855
TI  - From the Centers for Disease Control and Prevention. Lake-associated outbreak of
      Escherichia coli O157:H7--Illinois, 1995.

PMID- 8648856
TI  - Contrast enhancement for cranial CT scanning.

PMID- 8648857
TI  - Voiding cystourethrography.

PMID- 8648859
TI  - Linguistic ability in early life and Alzheimer disease in late life.

PMID- 8648858
TI  - Linguistic ability in early life and Alzheimer disease in late life.

PMID- 8648860
TI  - Estrogen replacement therapy and endometrial hyperplasia.

PMID- 8648861
TI  - Estrogen replacement therapy and endometrial hyperplasia.

PMID- 8648862
TI  - Health effects in survivors of the Chernobyl disaster.

PMID- 8648863
TI  - Do heavy smokers need a higher replacement dose of nicotine to quit?

PMID- 8648864
TI  - Dietary fiber and coronary heart disease prevention.

PMID- 8648865
TI  - Treatment of chronic depression.

PMID- 8648866
TI  - Treatment of chronic depression.

PMID- 8648867
TI  - Treatment of chronic depression.

PMID- 8648868
TI  - BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective
      study of patient decision making and outcomes.
AB  - OBJECTIVES: To identify predictors of utilization of breast-ovarian cancer
      susceptibility (BRCA1 gene) testing and to evaluate outcomes of participation in
      a testing program. DESIGN: Prospective cohort study with baseline interview
      assessment of predictor variables (eg, sociodemographic factors, knowledge about
      hereditary cancer and genetic testing, perceptions of testing benefits,
      limitations, and risks). BRCA1 test results were offered after an education and
      counseling session in a research setting. Outcome variables (including
      depression, functional health status, and prophylactic surgery plans [follow-up
      only]) were assessed at baseline and 1-month follow-up interviews. PARTICIPANTS:
      Adult male and female members (n=279) of families with BRCA1-linked hereditary
      breast-ovarian cancer (HBOC). RESULTS: Of subjects who completed a baseline
      interview (n=192), 60% requested BRCA1 test results (43% of all study subjects
      requested results). Requests for results were more frequent for persons with
      health insurance (odds ration [OR], 3.74; 95% confidence interval [CI], 2.06
      6.80); more first-degree relatives affected with breast cancer (OR, 1.59; 95% CI,
      1.16-2.16); more knowledge about BRCA1 testing (OR, 1.85; 95% CI, 1.36-2.50); and
      indicating that test benefits are important (OR, 1.45; 95% CI, 1.13-1.86). At
      follow-up, noncarriers of BRCA1 mutations showed statistically significant
      reductions in depressive symptoms and functional impairment compared with
      carriers and nontested individuals. Individuals identified as mutation carriers
      did not exhibit increases in depression and functional impairment. Among
      unaffected women with no prior prophylactic surgery, 17% of carriers (2/12)
      intended to have mastectomies and 33% (4/12) to have oophorectomies. CONCLUSIONS:
      Only a subset of HBOC family members are likely to request BRCA1 testing when
      available. Rates of test use may be higher in persons of a higher socioeconomic
      status and those with more relatives affected with breast cancer. For some high
      risk individuals who receive test results in a research setting that includes
      counseling, there may be psychological benefits. More research is needed to
      assess the generalizability of these results and evaluate the long-term
      consequences of BRCA1 testing.

PMID- 8648869
TI  - Serum folate and risk of fatal coronary heart disease.
AB  - OBJECTIVE: To assess the relationship between serum folate level and the risk of
      fatal coronary heart disease (CHD) among men and women. DESIGN: Retrospective
      cohort study with serum folate levels measured from September 1970 to December
      1972, with follow-up through 1985. SETTING: Participants in the Nutrition Canada
      Survey. PARTICIPANTS: A total of 5056 Canadian men and women aged 35 to 79 years
      with no history of self-reported CHD. MAIN OUTCOME MEASURE: Fifteen-year CHD
      mortality. RESULTS: A total of 165 CHD deaths were observed. We found a
      statistically significant association between serum folate level and risk of
      fatal CHD, with rate ratios for individuals in the lowest serum folate level
      category (<6.8 nmol/L [3 ng/mL]) compared with the highest category (>13.6 nmol/L
      [6 ng/mL]) of 1.69 (95% confidence interval, 1.10-2.61). CONCLUSIONS: These data
      indicate that low serum folate levels are associated with an increased risk of
      fatal CHD.

PMID- 8648870
TI  - Initial antidepressant choice in primary care. Effectiveness and cost of
      fluoxetine vs tricyclic antidepressants.
AB  - OBJECTIVE: To compare the clinical, functional, and economic outcomes of
      initially prescribing fluoxetine with outcomes of initially selecting imipramine
      or desipramine. DESIGN: Randomized controlled trial. SETTING: Primary care
      clinics of a Seattle, Wash, area staff-model health maintenance organization from
      1992 through 1994. PATIENTS: A total of 536 adults beginning antidepressant
      treatment for depression. INTERVENTION: Random assignment of initial
      antidepressant prescription (desipramine, fluoxetine, or imipramine). Subsequent
      antidepressant treatment (doses, medication changes or discontinuation, specialty
      referral) was managed by the primary care physician. MAIN OUTCOME MEASURES:
      Assessments after 1, 3, and 6 months examined clinical outcomes (Hamilton
      Depression Rating Scale and the depression subscale of the Hopkins Symptom
      Checklist) and quality-of-life outcomes (Medical Outcomes Study SF-36).
      Medication use and health care costs were assessed using the health maintenance
      organization's computerized data. RESULTS: Patients assigned to receive
      fluoxetine reported fewer adverse effects, were more likely to continue the
      original medication, and were more likely to reach adequate doses than patients
      beginning treatment with either tricyclic drug. The fluoxetine group reported
      marginally better clinical outcomes after 1 month, but these differences were not
      statistically significant and disappeared by the 3-month assessment. Quality-of
      life outcomes in the 3 groups did not differ. Total health care costs over 6
      months were approximately equal for the 3 groups, with higher antidepressant
      costs in the fluoxetine group balanced by lower outpatient visit and inpatient
      costs. CONCLUSIONS: Clinical outcomes, quality-of-life outcomes, and overall
      treatment costs provide no clear guidance on initial selection of fluoxetine or
      tricyclic drugs. Thus, patients' and physicians' preferences are an appropriate
      basis for treatment selection.

PMID- 8648871
TI  - Personal exposure of faculty and medical students to family violence.
AB  - OBJECTIVE: To determine the prevalence of exposure to personal family violence
      among medical students and full-time faculty at a major medical center. DESIGN:
      Self-reported, double-mailing, anonymous survey conducted in September 1995.
      PARTICIPANTS: Of 406 medical students and 917 full-time faculty surveyed, 787
      (59%) responded, including 217 students and 559 faculty members who identified
      academic status and 292 women and 482 men who identified gender. MAIN OUTCOME
      MEASURE: Self-reported personal experience with partner abuse, child abuse,
      physical abuse, and sexual abuse. RESULTS: Response rates were higher for women
      (69%) than men (54%) (P<.001) and were higher for faculty (61%) than students
      (53%) (P=.01). Of the 787 respondents, 99 (12.6%; 95% confidence interval [CI],
      10.9%-15.6%) reported physical abuse, sexual abuse, or both by a partner during
      their adult life, 118 (15.0%; 95% CI, 12.8%-17.8%) reported physical abuse,
      sexual abuse, or both as a child, and 188 (23.9%; 95% CI, 22.0-28.1%) reported
      physical abuse, sexual abuse, or both in their lifetime. Based on positive
      responses, a minimum of 17% of the female medical students and faculty and 3% of
      the male medical students and faculty have experienced physical abuse or sexual
      abuse by a partner in their adult life. CONCLUSIONS: Family violence is a
      pervasive problem that crosses into the personal experience of medical
      professionals. The conservative estimate of partner abuse for female medical
      students and faculty appears comparable with the general population national
      estimates. The acknowledgment by physicians that family violence is a potential
      risk for everyone, physicians and patients alike, is a step toward enhancing the
      identification of abuse and initiating interventions on behalf of survivors of
      family violence.

PMID- 8648872
TI  - Cost savings at the end of life. What do the data show?
AB  - Medical care at the end of life consumes 10% to 12% of the total health care
      budget and 27% of the Medicare budget. Many people claim that increased use of
      hospice and advance directives and lower use of high-technology interventions for
      terminally ill patients will produce significant cost savings. However, the
      studies on cost savings from hospice and advance directives are not definitive.
      The 3 randomized trials show no savings from these interventions, but either they
      are too small for confidence in their negative results or their intervention and
      cost accounting are flawed. The nonrandomized trials of hospice and advance
      directives show a wide range of savings, from 68% to none. Five methodological
      issues obscure the assessment of these studies: (1) selection bias in those
      patients who use hospice and advance directives, (2) the different time frames of
      assessing the costs, (3) the limited types of medical costs evaluated, (4) the
      variability of reporting the savings, and (5) the lack of generalizability of the
      findings to other patient populations. A more definitive study that assessed
      patients' end-of-life care preferences, use of hospice and advance directives,
      and direct and indirect costs would be desirable. In the absence of such a study,
      the existing data suggest that hospice and advance directives can save between
      25% and 40% of health care costs during the last month of life, with savings
      decreasing to 10% to 17% over the last 6 months of life and decreasing further to
      0% to 10% over the last 12 months of life. These savings are less than most
      people anticipate. Nevertheless, they do indicate that hospice and advance
      directives should be encouraged because they certainly do not cost more and they
      provide a means for patients to exercise their autonomy over end-of-life
      decisions.

PMID- 8648873
TI  - Prevalence of violence against pregnant women.
AB  - OBJECTIVES: To summarize the methods and findings of studies examining the
      prevalence of violence against pregnant women and to synthesize these findings by
      comparing study characteristics for studies with similar and dissimilar results.
      DATA SOURCES: MEDLINE, POPLINE, Psychological Abstracts, and Sociological
      Abstracts databases were searched for all articles pertaining to violence during
      pregnancy for the period 1963 through August 1995. STUDY SELECTION: Thirteen
      studies were selected on the basis of specific criteria: a sample with initially
      unknown violence status; a clear statement of research question(s), with focus on
      measuring the prevalence of violence; descriptions of the sample, data source,
      and data collection methods; and data from the United States or another developed
      country. DATA EXTRACTION: Relevant data were extracted to compare studies by
      study description, methods, and results. DATA SYNTHESIS: Evidence from the
      studies we reviewed indicates that the prevalence of violence during pregnancy
      ranges from 0.9% to 20.1%. Measures of violence, populations sampled, and study
      methods varied considerably across studies, and these factors may affect
      prevalence estimates. Studies that asked about violence more than once during
      detailed in-person interviews or asked later in pregnancy (during the third
      trimester) reported higher prevalence rates (7.4%-20.1%). The lowest estimate was
      reported by women who attended a private clinic and responded to a self
      administered questionnaire provided to them by a person who was not a health care
      provider. CONCLUSIONS: Violence may be a more common problem for pregnant women
      than some conditions for which they are routinely screened and evaluated. Future
      research that more accurately measures physical violence during pregnancy would
      contribute to more effective design and implementation of prevention and
      intervention strategies.

PMID- 8648874
TI  - The public health information infrastructure. A national review of the law on
      health information privacy.
AB  - Our objectives were to review and analyze the laws in the 50 states, the District
      of Columbia, and Puerto Rico that regulate the acquisition, storage, and use of
      public health data and to offer proposals for reform of the laws on public health
      information privacy. Virtually all states reported some statutory protection for
      governmentally maintained health data for public health information in general
      (49 states), communicable diseases (42 states), and sexually transmitted diseases
      (43 states). State statutes permitted disclosure of data for statistical purposes
      (42 states), contact tracing (39 states), epidemiologic investigations (22
      states), and subpoena or court order (14 states). The survey revealed significant
      problems that affect both the development of fair and effective public health
      information systems and the protection of privacy. Statutes may be silent about
      the degree of privacy protection afforded, confer weaker privacy protection to
      certain kinds of information, or grant health officials broad discretion to
      disseminate personal information. Our proposals for law reform are based on a
      meeting of experts at the Carter Presidential Center under the auspices of the
      Centers for Disease Control and Prevention and the Council of State and
      Territorial Epidemiologists: (1) an independent data protection commission should
      be established, (2) health authorities should justify the collection of
      personally identifiable information, (3) subjects should be given basic
      information about data practices, (4) data should be held and used in accordance
      with fair information practices, (5) legally binding privacy and security
      assurances should attach to identifiable health information with significant
      penalties for breach of these assurances, (6) disclosure of data should be made
      only for purposes consistent with the original collection, and (7) secondary uses
      beyond those originally intended by the data collector should be permitted only
      with informed consent.

PMID- 8648875
TI  - Testing for inherited cancer susceptibility.

PMID- 8648876
TI  - Folate and cardiovascular disease. Why we need a trial now.

PMID- 8648877
TI  - Domestic violence in Mexico.

PMID- 8648878
TI  - Antisense approach to restenosis.

PMID- 8648879
TI  - Sympathetic hyperactivity in patients with vasospastic angina--assessment by
      spectral analysis of heart rate and arterial pressure variabilities.
AB  - The autonomic nervous system may play an important role in regulating coronary
      arterial tone. To evaluate the role of autonomic nervous activity in patients
      with vasospastic angina (VSA), we studied 10 VSA patients with patent coronary
      artery (mean; 56 yr, range; 44-66 yr) and 8 normal subjects (mean; 58 yr, range;
      35-71 yr). ECG and arterial pressure were continuously recorded for 4 min in a
      supine position at 7:30 am, 10:30 am, and 4:30 pm. Low-frequency (LF; 0.04-0.15
      Hz) and high-frequency (HF; 0.20 Hz) components of the beat-to-beat variabilities
      of the R-R interval (RRI) and systolic arterial pressure (SAP) were then
      estimated by autoregressive power spectral analysis. The LF-Normalized Power (LF
      NP; [LF Power]/[Total Power]-[Direct Current Power]) of both the RRI and SAP
      variabilities were greater in VSA patients than in normal subjects (RRI: 0.51 +/-
      0.07, 0.51 +/- 0.07, 0.53 +/- 0.06, vs 0.25 +/- 0.04, 0.31 +/- 0.05, 0.31 +/-
      0.06, at 7:30 am, 10:30 am, and 4:30 pm respectively: p = 0.010, 0.044, 0.018.
      SAP: 0.62 +/- 0.06, 0.53 +/- 0.06, 0.57 +/- 0.06 vs 0.37 +/- 0.04, 0.30 +/- 0.06,
      0.26 +/- 0.07, respectively: p = 0.006, 0.017, 0.003.). The LF-power of SAP
      variability also tended to be greater in VSA patients. There was no difference in
      the HF-component coefficient of variance (CCV (%) = 100 x (component power)
      (1/2)/ mean RR intervals) of the RRI variabilities between the 2 groups. These
      results indicate that increased sympathetic vasomotor tone and cardiac
      sympathetic predominance may play an important role in patients with VSA.

PMID- 8648880
TI  - Exercise beta-methyl iodophenyl acid (BMIPP) and resting thalium delayed single
      photon emission computed tomography (SPECT) in the assessment of ischemia and
      viability.
AB  - To clarify the significance of exercise BMIPP (beta-methyl iodophenyl
      pentadecanoic acid) and resting T1 delayed single photon emission computed
      tomography (SPECT) in the assessment of ischemia and viability, we studied
      maximal exercise-loading BMIPP SPECT following rest-injected T1 3 h SPECT in 11
      control subjects, 20 patients with effort angina and 38 patients with old
      myocardial infarction. The left ventricular wall on ECT was divided into 9
      segments. BMIPP and T1 uptake were scored as 0 = normal, 1 = reduced, 2 =
      severely reduced, or 3 = absent. Discordance was defined as when segments with a
      reduced BMIPP uptake had a better resting T1 uptake. Significant coronary artery
      stenosis was defined as stenosis of 75% or greater on coronary arteriogram. Left
      ventricular wall motion was assessed as either normokinesis, hypokinesis, severe
      hypokinesis, akinesis or dyskinesis on left ventriculogram. When discordance was
      considered to be a marker of ischemia, the sensitivity and specificity in effort
      angina and control subjects were 95.2% and 84.6% for patients and 83.9% and 94.4%
      for diseased vessels, respectively. There were no differences between the
      sensitivity and specificity in left anterior descending artery (LAD), left
      circumflex artery (LCx) and right coronary artery (RCA) lesions (83.3%, 95.5% in
      LAD, 83.3%, 95.5% in LCx, 85.7%, 92.6% in RCA, respectively). All of the patients
      with old myocardial infarction had reduced exercise BMIPP uptake in infarcted
      regions. In old myocardial infarction, 35 patients had segments with discordant
      uptake. Discordance was observed in 75 (91.5%) of 82 segments with hypokinesis,
      and in 24 (92.3%) of 26 segments with severe hypokinesis. Even among the 36
      segments with akinesis or dyskinesis, 25 (69.0%) had discordant uptake. When
      discordance in the infarcted region was considered to be a marker of viability,
      regions with severe asynergy showed a high possibility of viability. Thus,
      discordant uptake on exercise BMIPP and resting T1 delayed SPECT may be a useful
      marker of ischemia in effort angina and of viability in old myocardial
      infarction.

PMID- 8648881
TI  - Granulocyte activation in restenosis after percutaneous transluminal coronary
      angioplasty.
AB  - To examine whether or not granulocyte activation is involved in restenosis after
      percutaneous transluminal coronary angioplasty (PTCA), we prospectively followed
      the time course of the plasma level of granulocyte elastase, which is an index of
      granulocyte activation, before and after successful angioplasty in 43 consecutive
      patients. Restenosis was defined as a more than 50% loss of the initial gain in
      the coronary diameter achieved by PTCA with more than a 50% resultant stenosis in
      the follow-up coronary arteriography performed 3 months after PTCA. There was no
      difference in the level of granulocyte elastase between the 2 groups with (n =
      15) and without (n = 28) restenosis before, the day after and 1 month after PTCA.
      However, 3 months after PTCA, the level of granulocyte elastase was significantly
      higher in the group with restenosis than in that without restenosis (171 +/- 13
      vs 147 +/- 6 mg/l, P < 0.05). The level of granulocyte elastase at 3 months after
      PTCA also correlated significantly with the percent luminal stenosis at the
      angioplasty site (P < 0.05). These results suggest that granulocyte activation
      may be involved in restenosis after PTCA.

PMID- 8648882
TI  - The effect of nifedipine on ventriculoarterial coupling in old myocardial
      infarction.
AB  - The effect of nifedipine on ventriculoarterial coupling was examined in 8
      patients with old myocardial infarction who showed a depressed ejection fraction
      (37 +/- 7%). Left ventricular (LV) pressure and LV volume were determined
      simultaneously by micromanometer and conductance catheter, respectively. We
      measured the slope (Ees) of the end-systolic pressure-volume relation during
      transient inferior vena caval occlusion, the slope (Ea) of the end-systolic
      pressure-stroke volume relation, the ratio of Ea to Ees (Ea/Ees), and the work
      efficiency (the ratio of external work to the systolic pressure-volume area) at
      baseline and after the sublingual administration of nifedipine (10 mg).
      Nifedipine slightly increased the heart rate from 71 +/- 14 to 78 +/- 17
      beats/min. Although nifedipine had little effect on Ees (2.54 +/- 0.68 vs 2.47 +/
      0.62 mmHg/ml/m2, ns), it significantly decreased Ea from 3.47 +/- 1.16 to 2.37
      +/- 0.54 mmHg/ml/m2. Consequently, Ea/Ees decreased from 1.42 +/- 0.47 to 0.97 +/
      0.31 and work efficiency increased from 48 +/- 12 to 59 +/- 13% after nifedipine
      administration. These data suggest that nifedipine reduces afterload (Ea) and
      improves left ventriculoarterial coupling without depressing left ventricular
      contractility in patients with failing hearts due to old myocardial infarction.

PMID- 8648883
TI  - Augmented sympathoadrenal activity during treadmill exercise in patients with
      Wolff-Parkinson-White syndrome and atrial fibrillation.
AB  - It is believed that reciprocating tachycardia and accessory pathways play
      important roles in atrial fibrillation (AF) in patients with Wolff-Parkinson
      White (WPW) syndrome. However, the mechanism by which AF occurs is not yet fully
      understood. This study was performed to evaluate the contribution of
      sympathoadrenal activity to the onset of AF in patients with WPW syndrome.
      Symptom-limited treadmill exercise testing was performed and plasma
      norepinephrine and epinephrine concentrations were measured simultaneously in 27
      patients with WPW syndrome and 20 control subjects. In 13 patients with WPW
      syndrome and AF, plasma norepinephrine and epinephrine concentrations increased
      to 3.69 +/- 2.44 and 0.76 +/- 0.69 ng/ml at maximum exercise, respectively. These
      values were significantly higher (p < 0.001) than those in control subjects and
      in patients without AF. Pretreatment with 0.2 mg/kg of propranolol significantly
      reduced the incidence of exercise-induced atrial premature complexes (chi 2 =
      7.33, p < 0.05). With oral beta-blockade for an average of 22.8 months, the
      incidence of AF decreased significantly from 1.77 +/- 0.53/patient per year to
      0.33 +/- 0.57/patient per year (p < 0.001). Augmented sympathoadrenal activity in
      patients with WPW syndrome may contribute to AF.

PMID- 8648884
TI  - Effects of enalapril on the collagen matrix in cardiomyopathic Syrian hamsters
      (Bio 14.6 and 53.58).
AB  - The hereditary cardiomyopathic strain of Syrian hamster has been extensively
      studied as a model of cardiomyopathy of heart failure. We attempted to determine
      whether an angiotensin converting enzyme (ACE) inhibitor, enalapril, prevents the
      increase in extracellular collagen matrix which connects the myocytes in
      cardiomyopathy. Enalapril was administered at an average dosage of 10 mg/kg per
      day to 10- to 20-week-old hamsters with hypertrophic (Bio 14.6) and dilated (Bio
      53.58) cardiomyopathy, as well as to control Syrian hamsters (F1 beta). Collagen
      concentration estimated by hydroxyproline concentration and the collagen type
      III:I ratio significantly increased in the hearts of the Bio 14.6 and Bio 53.58
      strains at 20 and 40 weeks of age as, compared with those in age-matched F1 beta
      hamsters. When Bio 14.6 hamsters were given enalapril for 10 weeks from 10 to 20
      weeks of age, the collagen concentration, the collagen type III:I ratio and type
      III collagen mRNA expression were significantly decreased, compared with those in
      untreated animals of the same strain. After the administration of enalapril,
      scanning electron microscopic examination also revealed a decrease in fibrillar
      collagen accumulation in the interstitium and the network surrounding the cardiac
      myocytes. These prophylactic effects were not observed in the Bio 53.58 strain.
      These results indicate that the administration of ACE inhibitor prevents type III
      collagen production in the Bio 14.6 strain but not in the Bio 53.58 strain of
      Syrian hamster.

PMID- 8648885
TI  - Morphological study of vagal innervation in human semilunar valves using a
      histochemical method.
AB  - To determine the innervation of human semilunar valves, we examined the pulmonary
      and aortic valves of the normal autopsied hearts of 3 men (53 to 71 years old).
      Whole valve tissues with the aorta or pulmonary trunk were stained for
      acetylcholinesterase by a histochemical method. Acetylcholinesterase-positive
      nerve fibers with a diameter of 2 to 20 mm were located on the ventricular side
      of the semilunar valves. Innervation of the semilunar valves was extremely sparse
      compared with that of the atrioventricular valves and that of the aortic or
      pulmonary arterial wall. The nerves originated from the subendocardium of the
      ventricles and the adventitia of the arterial walls. The nerves were more
      distributed in the basal site than in the marginal site of the semilunar valve.
      The nerve fibers formed a network in basal two-thirds of the leaflet. Thick
      nerves ramified in the thin nerve plexus. The thick nerves had a varicose-like
      structure. Thin nerves had a dot- and brush-like ending. The nerves in human
      semilunar valves may play a role in valve motion.

PMID- 8648886
TI  - Use of intravenous dofetilide in atrial flutter with hemodynamic instability.
AB  - Paroxysmal atrial flutter is a drug-resistant supraventricular tachyarrhythmia
      that is often accompanied by hemodynamic instability due to an excessive
      ventricular response. We report here a case of atrial flutter with 1:1
      atrioventricular conduction, in which we were able to rescue the patient from a
      state of cardiogenic shock by using intravenous dofetilide, a new class III
      antiarrhythmic agent. Dofetilide was suitable for the treatment because it
      immediately increased atrioventricular nodal refractoriness without any negative
      inotropic action.

PMID- 8648888
TI  - [Frontal lobe dementia and Alzheimer type dementia].

PMID- 8648887
TI  - Long-term follow-up of an interatrial right-to-left shunt that appeared after
      cardiac surgery--evaluation by transesophageal Doppler echocardiography.
AB  - Two cases in which a right-to-left shunt appeared across a patent foramen ovale
      after mitral surgery were clinically and echocardiographically followed for a
      long period of time. The right-to-left shunt markedly decreased in the supine
      position on transesophageal Doppler echocardiography in both cases within 2 years
      after the cardiac surgery, which presumably corresponds to decreased risk of
      paradoxical embolism.

PMID- 8648889
TI  - [Problems in vascular dementia].
AB  - Vascular dementia (VD) and Alzheimer's type dementia are two main causes of
      dementia in the aged. Considering historical backgrounds and ethnic differences,
      a simplified classification of VD is suggested. First, poststroke dementia of
      acute onset associated with an infarct that is large enough to impair general
      cognitive functions, or strategically located. Second, multi-infarct dementia
      that develops incrementally with increasing numbers of infarcts, and which should
      be classified as multiple cortical infarct dementia and multiple small infarctor
      lacunar dementia. Third, vascular dementia of the Binswanger type (VDBT). We
      compared two types of white matter lesions, periventricular hyperintensity (PVH)
      and confluent centrum semiovale hyperintensity (CCSH) in lacunar stroke patients
      with regard to the cerebral blood flow (CBF). In patients with PVH, there was a
      significant positive correlation between the dementia scores and the CBF in the
      parietal and temporal areas but not in the frontal area. In CCSH patients, there
      was a significant positive correlation in the frontal area but not in the parieto
      temporal areas. Therefore, dementia in most patients with PVH may not be
      primarily related to the PVH, but may possibly be due to coexisting Alzheimer's
      type dementia, and dementia in most CCSH patients may be related to
      cerebrovascular disease. VDBT is unique clinically in its slowly progressive
      intellectual deterioration and pathologically in diffuse, confluent, and almost
      symmetrical white matter lesions. For the pathogenesis of VDBT, our studies
      suggest that hypertension, short-term variations in blood pressure, and a
      sustained nighttime elevation of blood pressure promote small vessel disease and
      cause ischemia of the cerebral white matter that is located in the end-fields of
      penetrating arteries; this leads to an imparied integrity of the blood-brain
      barrier and free radical generation, both of which may have important roles in
      producing diffuse white matter degeneration.

PMID- 8648890
TI  - [Problems of the amyloid beta precursor protein in pathogenesis of the Alzheimer
      type dementia].

PMID- 8648891
TI  - [Neurofibrillary changes and phosphorylated tau of Alzheimer's disease].

PMID- 8648892
TI  - [Apolipoprotein E polymorphism in Alzheimer's disease].

PMID- 8648893
TI  - [Prion diseases in dementia].

PMID- 8648895
TI  - [A case of diffuse idiopathic skeletal hyperostosis (DISH) with various
      neurological complications].
AB  - A 71-year-old female presented with a 10-year history of slowly progressive gait
      disturbance and dorsolumbar pain. Motion of he neck and trunk was severely
      restricted. She showed decreased sensation of vibration and position in the upper
      and lower limbs and had Romberg's sign. Hyperesthesia of touch sensation was
      distributed in a stocking pattern. She showed hyporeflexia and pathological
      reflexes in lower limbs. Her gait was ataxic and spastic. Laboratory examination
      of blood and urine revealed no remarkable findings. Radiographic examination
      revealed ligamentous calcification and ossification along the anterolateral
      aspect of the vertebral column at several levels, and there was ossification of
      hte ligament and tendon attachment to the bone at extraspinal sites. The
      radiographic features were characteristic of diffuse idiopathic skeletal
      hyperostosis (DISH). Computed tomography at lower thoracic and lumbar vertebral
      portions showed compression of the spinal cord by ossification of the flavatum
      ligament. The conduction velocity of tibial nerves and sural nerves were delayed,
      and the mechanism of the occurrence of peripheral nerve lesions in this patient
      could be explained by extrinsic compression by heterotopic calcification or some
      metabolic factor due to DISH.

PMID- 8648894
TI  - [Family history and the frequency of human leukocyte antigen (HLA-DR) in
      centenarians].
AB  - There are a few reports that associate several loci of the human leukocyte
      antigen (HLA) with longevity, such as DR1 which is significantly frequent in the
      very old, especially in Okinawa centenarians. In contrast DR9 is decreased. This
      report investigates 87 healthy Okinawan centenarians and 148 healthy Okinawan
      controls examined since 1987 with HLA phenotyping and family history
      questionnaires. The mean age in centenarians was 101.6 years, and that of
      controls was 66.4. We inquired the age and the cause of death of the parents of
      the subjects. Subjects whose parent's deaths were by suicide, homicide, accident,
      war or due to war trauma, were excluded and only those resulting from illness or
      natural causes were included. The relation between age of death of parents and DR
      types were studied. Compared to controls, DR1 was significantly increased in the
      centenarians (p = 0.036, RR 4.239), and DR8 was decreased (p = 0.012, RR =
      0.412). When the mean age of death of parents for each DR group and that of total
      was determined, the mean death age of those with DR9 was significantly lower than
      the mean of the total (p < 0.05). More over, when the frequency rate of the DR
      types were compared with the parents' death age, that of DR9 decreased as the age
      of death increased. It is suggested that some loci of HLA-DR relate to longevity
      and some genetic protection against immunorelated diseases contributes to long
      lived lineage.

PMID- 8648896
TI  - [An 85-year-old case of Basedow's disease associated with high output heart
      failure and angina pectoris].
AB  - We report a rare case of Basedow's disease associated with high output heart
      failure and angina pectoris over the age of 80 years. An 85-year-old woman was
      admitted with palpitation, finger tremor, hyperidrosis and weight loss. Basedow's
      disease was diagnosed by physical (diffuse goiter) and laboratory (free T3 19.4
      pg/ml, free T4 > 8.0 ng/dl, TSH < 0.1 microU/ml, TRAb positive, 123I uptake high)
      findings and was treated with methimazole. Chest oppression and dyspnea on
      exertion with negative T wave, cardiomegaly and pulmonary congestion appeared
      after methimazole. Cardiac catheterization showed a high cardiac output (CI
      5.01/min/m2, PCW 26 mmHg, PA 57/26 mmHg, RA 15 mmHg) and a significant coronary
      stenosis (LAD [symbol: see text] 99%). High output heart failure and angina
      pectoris responded to treatment. They subsequently worsened, because she stopped
      taking methimazole for a month and serum levels of thyroid hormones increased
      again. After retreatment with methimazole, serum levels of thyroid hormones
      decreased to within normal limits, and high output heart failure and angina
      pectoris also improved.

PMID- 8648897
TI  - [A case of multiple myeloma associated with abnormal plasma cells and M-protein
      in pleural effusion].
AB  - A 77-year-old woman with hypertension was admitted to our hospital because of
      exertional dyspnea end peripheral edema. Chest X-ray showed cardiomegaly,
      pulmonary congestion and right pleural effusion. Hypertensive heart failure was
      diagnosed and treated, and right pleural effusion disappeared in 2 weeks.
      Abnormalities on laboratory data, i.e. anemia and increased ESR et al. continued
      after the improvement of heart failure. Serum IgG was elevated (2570 mg/dl),
      while IgA and IgM were decreased. Immunoelectrophoresis indicated the presence of
      monoclonal IgG-lambda in the serum. Bone marrow puncture revealed an increase in
      atypical plasma cells (38.4%). Multiple myeloma was diagnosed from these findings
      and treated with melphalan and prednisolone. But increases in atypical plasma
      cells (43.2%) and serum IgG (2573 mg/dl) continued. During treatment, right
      pleural effusion increased again. Thoracocentesis showed bloody effusion with
      numerous atypical plasma cells, and the presence of monoclonal IgG-lambda was
      indicated by immunoelectrophoresis. The patient died of renal and heart failure 2
      months after the onset of malignant pleural effusion. Cytological examination and
      immunoelectrophoresis are necessary for pleural effusion in multiple myeloma.

PMID- 8648898
TI  - [Longevity science research retrieval system using the thesaurus specifically
      developed for the science].
AB  - Gerontology is a new field including various disciplines such as medicine,
      engineering science, social science etc, and is sometimes called as "longevity
      science". Because of the wide area of the field, it is important to show the
      scope of the science and the development of its thesaurus contributes to this
      end. We developed a relevant thesaurus based on the research funded by Longevity
      Science Promotion Organization, and using the thesaurus, we also developed a
      database and retrieval system of the gerontology research. This system can be
      accessed on the Internet.

PMID- 8648899
TI  - A reappraisal of immune-mediated glomerulosclerosis.

PMID- 8648900
TI  - Gene transfer into the kidney: promise for unravelling disease mechanisms,
      limitations for human gene therapy.

PMID- 8648901
TI  - Arachidonic acid protects against hypoxic injury in rat proximal tubules.
AB  - Free fatty acids (FFA) and lysophospholipids accumulate during hypoxia (H) in rat
      proximal tubular epithelial cells partly as a result of increased phospholipase
      A2 (PLA2) activity. The role of FFA in mediating hypoxic injury and modulating
      PLA2 activity is not clear. In the present study, the effect of several FFA
      including arachidonic acid (AA, 20:4) on hypoxia-induced injury and PLA2 activity
      was assessed in freshly isolated rat proximal tubules. Hypoxia (H) was induced in
      the presence of either an unsaturated free fatty acid (uFFA) [AA or linoleic acid
      (LA, 18:2)] or a saturated FFA (sFFA) [palmitic (PA, 16:0) or myristic acid (MA,
      14:0)]. Cell membrane injury was assessed by measuring lactate dehydrogenase
      release (LDH). AA markedly reduced LDH release during hypoxia in a dose dependent
      manner, while sFFA had no protective effect. LA showed similar protection to that
      observed with AA. AA did not affect buffer calcium concentration, buffer pH,
      intracellular pH or intracellular calcium concentration. Neither inhibiting the
      cyclooxygenase pathway with indomethacin, nor the lipoxygenase pathway with
      nordihydroguaiaretic acid (NDGA) had any effect on the AA observed
      cytoprotection. In vitro PLA2 activity in the control tubular extracts was
      compared to that following addition of AA or PA. PLA2 activity decreased
      significantly with AA but not with PA in a dose dependent manner. These data
      suggest that: (1) AA protects against hypoxic injury in rat proximal tubules. (2)
      This cytoprotection is not specific for AA and other uFFA have a similar effect.
      (3) AA significantly inhibits PLA2 activity, (4) AA induced cytoprotection may be
      related to a negative feedback inhibition of PLA2 activity.

PMID- 8648902
TI  - Regulation of renin release is impaired after nitric oxide inhibition.
AB  - The aim of the present study was dual: first to establish that a preparation of
      afferent arterioles freshly isolated from the rat kidney is a suitable model to
      study renin release and synthesis, and second to investigate the effect(s) of
      nitric oxide (NO) inhibition on renin release in this model. Purification of
      renal microvessels was based on iron oxide infusion into the kidneys and
      separation of the afferent arterioles from glomeruli and connective tissue with a
      magnet. These microvessels express preprorenin mRNA, contain renin granules and
      release renin as evidenced by RT-PCR, immunocytochemistry and measurement of
      renin activity, respectively. Renin secretion was increased in isolated afferent
      arterioles after in vivo treatment with the diuretic furosemide (+300%) or in
      vitro treatment with the adenylyl cyclase activator forskolin (+50%), indicating
      that this vascular preparation responds appropriately to regulators of the renin
      angiotensin system. Furthermore, in afferent arterioles isolated from control
      rats, renin release was positively correlated with total renin content (r =
      0.85). In afferent arterioles isolated from rats chronically treated with the NO
      synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), forskolin was
      ineffective in modifying renin release despite stimulation of cAMP levels. In
      addition, the correlation between renin release and tissue renin content was
      disrupted. Similar results were obtained when cortical slices were used instead
      of afferent arterioles, suggesting that this defect in the regulation of renin
      release is independent of the presence of macula densa cells. To verify that the
      lack of regulation of renin release after L-NAME treatment was due to NO
      inhibition, the NO donor 3-morpholino-syndonimin-hydrochloride (SIN-1) was
      administered in afferent arterioles or cortical slices from kidneys of L-NAME
      treated rats. In both preparations, SIN-1 reversed the L-NAME effect and re
      established the responsiveness of renin release to forskolin and the relationship
      between renin release and renin content. These data indicate that the adenylyl
      cyclase-mediated mechanism regulating renin release is impaired when NO synthesis
      is inhibited.

PMID- 8648903
TI  - Plasma clearance in the rat of a furan dicarboxylic acid which accumulates in
      uremia.
AB  - The furan dicarboxylic acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5
      propyl FPA) accumulates in the plasma of patients with chronic renal failure and
      has been implicated in several aspects of the uremic syndrome: the defective
      binding of organic acids in uremic plasma, inhibition of active tubular
      secretion, anemia and the severity of neurological symptoms. Evidence from
      experiments with rat kidney slices suggests that 5-propyl FPA undergoes active
      tubular secretion, and so its clearance after an intravenous bolus dose (5 mg/kg;
      21 mumol/kg) was investigated in anaesthetized female Wistar albino rats in vivo.
      The effects of intravenous bolus doses of p-aminohippuric acid (PAH) and
      probenecid on the clearance of this dose of 5-propyl FPA were also studied. The
      mean values (N = 16) for plasma half-life, plasma clearance and apparent volume
      of distribution of 5-propyl FPA were 3.6 hours, 2.4 ml . min(-1) . kg(-1) and
      0.69 liter . kg(-1), respectively. An equimolar dose of PAH did not affect the
      clearance of 5-propyl FPA, but a tenfold higher molar dose of PAH (40.4 mg/kg)
      increased the area under the plasma-concentration time curve of 5-propyl FPA, and
      there was a trend towards a decrease in the clearance and a prolongation of the
      half-life. Probenecid at a fivefold higher dose than 5-propyl FPA had a similar
      effect to PAH and increased the AUC of 5-propyl FPA. PAH and probenecid decreased
      the plasma clearance of 5-propyl FPA, which is evidence that this uremic
      metabolite undergoes active tubular secretion. It follows that 5-propyl FPA could
      therefore inhibit the secretion of other organic acids.

PMID- 8648904
TI  - Membrane damage and the Ca(2+)-paradox in the perfused rat kidney.
AB  - Lactate dehydrogenase (LDH) leaks from the perfused rat kidney under the
      artificial conditions of a Ca(2+)-paradox protocol, namely Ca(2+)-repletion
      following a 20 minute period of Ca(2+)-depletion. LDH leakage was markedly
      suppressed by perfusion at 25 degrees C or with 0.1 mM dibucaine or 2 mM
      lidocaine. Lidocaine inhibited leakage only during Ca(2+)-depletion. Lowering the
      perfusion rate significantly reduced LDH escape. No LDH loss occurred if the
      osmotic pressure of the perfusion fluid was raised by 420 mOsm during either
      Ca(2+)-depletion or Ca(2+)-repletion. Amiloride (2 mM) significantly reduced LDH
      leakage to 43%. Reduction of the pH of the perfusion fluid to 6.8 significantly
      inhibited LDH loss, and at pH 6.4 this leakage was almost completely suppressed.
      LDH loss was equally suppressed at pH 6.4 only during Ca(2+)-depletion, whereas
      pH 6.4 was markedly less effective when perfused only during Ca(2+)-repletion.
      Ouabain (5 x 10(-6) M) had only a limited effect in exacerbating LDH leakage.
      Raising [K+]o significantly protected against LDH leakage, which fell to 36% at
      16 mM [K+]. These features correspond with the Ca(2+)-paradox of the perfused rat
      heart an it is suggested that: (i) a Ca(2+)-paradox can be produced in the rat
      kidney; (ii) a similar mechanism governs the release of cytosolic proteins in
      these two preparations; and (iii) the damage mechanism of the plasmalemma is a
      transmembrane oxidoreductase-diaphorase molecular complex which generates H+ when
      activated by Ca(2+)-depletion.

PMID- 8648905
TI  - Polymorphonuclear leukocytes play a key role in the generation of "wire-loop"
      lesions induced by a murine IgG3 rheumatoid factor.
AB  - Murine IgG3 anti-IgG2a rheumatoid factor (RF) monoclonal antibodies (mAb) with
      cryoglobulin activity are able to induce skin leukocytoclastic vasculitis and
      glomerulonephritis resembling "wire-loop" glomerular lesions in normal mice.
      Since polymorphonuclear leukocyte (PMN) infiltration is one of the major
      pathological changes observed in both types of lesions, we determined the role of
      PMN and complement in the generation of these two different lesions, induced by 6
      19 IgG3 RF mAb, by interfering with adhesion molecules known for their
      involvement of PMN-endothelial cell interaction or by depleting mice of their PMN
      or C3. Our results have demonstrated that first, the PMN-endothelial cell
      interaction mediated by leukocyte function-associated antigen 1 (LFA-1) and
      intercellular adhesion molecule 1 (ICAM-1) was crucial for the generation of 6-19
      RF mAb-induced skin leukocytoclastic vasculitis, but not for glomerular lesions;
      second, PMN played an active role in the development of "wire-loop" glomerular
      lesions; in the absence of the PMN glomerular infiltration, 6-19 RF mAb induced a
      different type of glomerular lesions, characterized by voluminous intracapillary
      thrombi and mesangial deposits, but not subendothelial deposits; and third, the
      activation of the complement system did not appear to play a major role in both
      skin and glomerular lesions.

PMID- 8648906
TI  - Expression of epidermal growth factor and its receptor in normal and diseased
      human kidney: an immunohistochemical and in situ hybridization study.
AB  - The kidney is one of the major sites of EGF production and there it seems to play
      several biological functions, such as modulation of cell growth, renal repair
      following injury, regulation of cellular metabolism and glomerular haemodinamics.
      The present study was first aimed at localizing EGF and its receptor (R) in
      normal human kidney by immunohistochemical and in situ hybridization techniques.
      Then, the distribution of the growth factor and its R was explored in biopsy
      specimens from eight patients with acute tubulointerstitial damage. In the normal
      human kidney, both EGF immunoreactivity and EGF mRNA were localized in tubular
      profiles corresponding to Henle's loop and, although to a lesser intensity, to
      distal convoluted tubule. EGF immunostaining was remarkable mainly at the apical
      surface of tubular cells. EGF-R protein expression was detected in glomerular
      endothelial cells, in peritubular capillaries and arteriolar walls, as well as
      along the thick ascending limb of Henle's lop and distal convoluted tubule, where
      it colocalized with Tamm-Horsfall protein. Immunohistochemical analysis of
      tubular profiles revealed that EGF-R was located especially along the basolateral
      membrane of tubular cells and within the basal part of cytoplasm. Endogenous
      alkaline phosphatase and CHIP28 positive tubules did not show any signal for EGF
      and its receptor. Kidneys with acute tubulointerstitial injury exhibited a
      dramatic decrease of EGF expression, whereas EGF-R showed only minor
      modifications. Interestingly, EGF-R was localized to both apical and antiluminal
      membranes of positive tubular cells. It is concluded that EGF-EGF receptor loop
      may be relevant in the pathogenesis of acute tubulointerstitial damage and
      recovery from tubular injury, while its role in the physiological renewal of the
      urothelium remains speculative.

PMID- 8648907
TI  - Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6
      nephrectomized rats.
AB  - The 5/6 nephrectomy model is used to study pathogenetic mechanisms underlying
      chronic renal failure. We previously demonstrated that increased mesangial cell
      proliferation and glomerular PDGF B-chain expression precede glomerulosclerosis
      in this model. In the present study we have assessed the concomitant changes in
      the cortical tubulointerstitium. A wave of tubular and interstitial cell
      proliferation (as determined by immunostaining for PCNA) occurred at week 1 after
      5/6 nephrectomy. This wave preceded the peak glomerular cell proliferation by one
      week. Tubulointerstitial cell proliferation decreased thereafter and reached
      control values by week 10. In situ hybridization and immunostaining for PDGF B
      chain and beta-receptor in sham-operated controls showed labeling of distal
      tubules and collecting ducts, while no signal was present in the interstitium.
      PDGF B-chain mRNA and protein expression was markedly increased in tubules at
      weeks 2 and 4 after 5/6 nephrectomy and in the interstitium (particularly in
      areas of inflammatory infiltrates) at weeks 2 to 10. Similar changes occurred
      with PDGF receptor beta-subunit immunostaining. Interstitial expression of desmin
      and alpha-smooth muscle actin (markers of myofibroblasts) progressively increased
      after week 1. Interstitial influx of monocytes/macrophages with focal
      accentuation started at week 2. Counts of lymphocytes, neutrophils and platelets
      showed only minor changes. In parallel to the monocyte/macrophage influx,
      progressive interstitial accumulation of collagens I and IV, laminin, and
      fibronectin occurred. All of these changes were correlated with the increase in
      serum creatinine, proteinuria and an index of tubulointerstitial damage. We
      conclude that tubulointerstitial changes after 5/6 nephrectomy show similarities
      with those observed in the glomeruli. Tubular and interstitial overexpression of
      PDGF B-chain and its receptor may play a role in mediating fibroblast migration
      and/or proliferation in areas of tubulointerstitial injury.

PMID- 8648908
TI  - Glucocorticoids and acidosis stimulate protein and amino acid catabolism in vivo.
AB  - We have shown that chronic metabolic acidosis in awake rats accelerates whole
      body protein turnover using stochastic modeling and a continuous infusion of L-[1
      13C] leucine. To delineate the role that glucocorticoids play in mediating these
      catabolic responses, we measured protein turnover in awake, chronically
      catheterized, adrenalectomized rats in the presence or absence of glucocorticoids
      and/or a NH4Cl feeding regimen which induced chronic metabolic acidosis. In
      adrenalectomized rats receiving no glucocorticoids there was no statistical
      difference in amino acid oxidation, protein degradation or synthesis whether or
      not the rats had acidosis. In contrast, chronically acidotic, adrenalectomized
      rats receiving glucocorticoids demonstrated accelerated whole body protein
      turnover with a 84% increase in amino acid oxidation and a 26% increase in
      protein degradation, compared to rats not receiving glucocorticoids or those
      given the same dose of glucocorticoids but without acidosis. We conclude that
      metabolic acidosis accelerates amino acid oxidation and protein degradation in
      vivo, and that glucocorticoids are necessary but not sufficient to mediate the
      catabolic effects of metabolic acidosis.

PMID- 8648909
TI  - Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats.
AB  - It has become widely recognized that glycine (Gly) depletion predisposes isolated
      proximal tubules (PT) to necrotic cell damage induced by diverse insults and that
      Gly replacement in vitro is highly cytoprotective. However, the effectiveness of
      supplementation with Gly in vivo, where blood and tissue Gly normally are
      maintained at high levels, is incompletely defined. Our aim was to assess
      whether: (a) supplementation of Gly in drinking water of rats would attenuate the
      proximal tubule damage and the Fanconi syndrome (FS) induced by maleate (Mal), a
      classical proximal tubule toxin, or ifosfamide (IFO), an antineoplastic drug; and
      (b) to explore the mechanisms responsible for such effects, since Gly
      supplementation might be especially beneficial in treating the FS, where the
      kidney tends to waste amino acids. Rats received daily injection of Mal (2
      mmol/kg) for two days without or with oral supplementation of 2% Gly. IFO, 50
      mg/kg, was injected daily for five days without or with oral Gly. Control rats
      were injected with saline, without or with oral Gly. The results demonstrated
      that both Mal and IFO induced a FS characterized by wasting of amino and organic
      acids, glucose, and electrolytes, along with elevated plasma creatinine (Crn) and
      BUN, and decreased Crn clearance rate. Light microscopy revealed a necrotic
      lesion in the proximal tubules of the Mal group, but no necrosis after IFO. Gly
      strongly ameliorated the severity of renal necrosis and/or dysfunction induced by
      Mal or IFO, with significant decreases in total and fractional excretion of Na+,
      K+, PO4(3-) and glucose, decreased plasma BUN and Crn, and increased Crn
      clearance. Analysis of freeze-clamped cortical tissue showed substantial
      depletion of [Gly], [ATP] and [GSH] along with increased GSSG in Mal or IFO
      groups and correction of [Gly] and [ATP] with Gly supplementation, but no
      improvement with Gly of reduced gluthatione [GSH] or the ratio of reduced to
      oxidized gluthatione (GSH/GSSG). 31P-NMR analysis of the renal cortex indicated a
      decrease in Pi and various membrane phospholipids in Mal and IFO rats and
      prevention of this damage with Gly. These observations demonstrate that oral
      supplementation of Gly can provide protection against Mal or IFO-induced renal
      tubular cell dysfunction and structural damage. The lack of effect on glutathione
      oxidation and depletion suggests an action distal to toxin uptake and
      intracellular interactions, which is similar to the characteristics of Gly
      cytoprotection against diverse insults in vitro. The results also suggest
      modification by Gly of the primary toxicity of the agents and effects on
      phospholipid synthesis that could contribute to repair.

PMID- 8648910
TI  - Regulation of the renal Na-HCO3 cotransporter: VI. Mechanism of the stimulatory
      effect of protein kinase C.
AB  - We have previously shown that the activity of the Na-HCO3 cotransporter is
      stimulated by protein kinase C (PKC) activation, but the mechanism responsible
      for this effect is not clear. We have shown that cultured proximal tubule cells
      of the rabbit have DIDS-sensitive Na-HCO3 cotransporter activity as assessed by
      HCO3-dependent 22Na uptake or by measurement of intracellular pH. In cells loaded
      with BCECF and treated with the amiloride analogue, ethylisopropyl amiloride,
      removal of extracellular Na was associated with a rapid decrease in pH which
      returned to normal with re-addition of Na. This pH recovery was inhibited by DIDS
      and was used to quantify the activity of the Na-HCO3 cotransporter. In the
      present study, we utilized primary cultures of the proximal tubule of the rabbit
      to examine the effect of PKC activation on the activity of the Na-HCO3
      cotransporter. Short term incubation (5 min) with the active phorbol ester,
      phorbol 12-myristate, 13-acetate (PMA), 10(-7) M, caused a significant
      stimulation of the Na-HCO3 cotransporter activity as compared to controls.
      Incubation for two hours also caused a significant stimulation of the Na-HCO3
      cotransporter activity. The inactive analogue of PMA, 4-alpha phorbol, failed to
      alter the cotransporter. Similar results were observed when we examined the
      effect of PMA on HCO3-dependent 22Na uptake. The effect of PMA to stimulate the
      cotransporter was mediated by PKC activation since it could be prevented by the
      PKC inhibitors, calphostin C or sphingosine, or by prior PKC depletion. The long
      term but not the short term effect of PMA to stimulate the Na-HCO3 cotransporter
      activity was prevented by the protein synthesis inhibitors, actinomycin D or
      cycloheximide. The early effect of PKC to stimulate the cotransporter appeared to
      be associated with increased phosphorylation of a 56 kD protein band, while the
      late effect appeared to be associated with an increase in immunoreactive content
      of a 56 kD protein which is thought to be an active component of the
      cotransporter. Thus PKC stimulation activates the Na-HCO3 cotransporter by two
      distinct mechanisms: a long term effect which is protein synthesis-dependent and
      a short term effect which is protein synthesis-independent and is likely mediated
      by phosphorylation.

PMID- 8648911
TI  - Increased peritoneal permeability to albumin in streptozotocin diabetic rats.
AB  - The mechanism behind the increased peritoneal permeability to albumin in
      diabetics is still unclear. In this study, streptozotocin diabetic rats developed
      albuminuria and significantly increased D/P of albumin after the fourth week of
      disease, reaching peak levels at the end of the 24 week period of follow-up.
      Coincidentally, extravasation of albumin to the interstitial tissue was evaluated
      with the Evans-blue method. Age-matched control rats showed Evans-blue
      concentrations of 0.023 +/- 0.013 micrograms/100 mg of dry tissue, whereas in
      diabetics the numbers were 1.22 +/- 0.719 micrograms (P < 0.001). Perfusion with
      Ruthenium-Red (RR) done in control at zero time, and in age-matched intact as
      well as in diabetic rats after 24 weeks of disease showed that the density
      distribution of capillary subendothelial anionic sites was significantly lower
      for diabetics (13 +/- 3/microns basement membrane vs. 31 +/- 3 and 34 +/- 4 in
      control groups; P < 0.001). Similar findings were made on the mesenteric
      submesothelial basement membrane. Mean density of RR decorated anionic sites was
      12 +/- 2/microns basement membrane in diabetics, whereas those observed in both
      control groups were 31 +/- 2 and 31 +/- 3/microns (P < 0.001). Therefore, this
      reduced density of microvascular and submesothelial negative charges, equivalent
      to that induced by diabetes in other capillary beds, appears to be at the origin
      of the decreased permselectivity of the diabetic peritoneum for anionic serum
      albumin.

PMID- 8648912
TI  - Differential expression of macrophage inflammatory protein-2 and monocyte
      chemoattractant protein-1 in experimental glomerulonephritis.
AB  - We examined the relation between glomerular expression of chemokines from alpha
      subfamily (macrophage inflammatory protein-2, MIP-2) and beta-subfamily (monocyte
      chemoattractant protein-1, MCP-1) and infiltration of neutrophils and monocytes
      in antibody mediated glomerulonephritis in rats. In the accelerated model of
      nephrotoxic nephritis (NTN), glomerular expression of MIP-2 and MCP-1 genes
      correlated with the sequential migration of neutrophil and monocyte influx,
      respectively. These relationships were investigated further in the heterologous
      phase of NTN by applying various treatments known to modulate the severity of
      injury. Pretreatment with bacterial lipopolysaccharide resulted in greater
      injury, MIP-2 expression increased 25- to 50-fold, and the glomerular neutrophil
      count increased two- to fourfold. Both MIP-2 mRNA levels and neutrophil
      infiltration were reduced by additional pretreatment with IL-6, IL-1 receptor
      antagonist, soluble IL-1 receptor or soluble TNF receptor (Spearman correlation
      coefficient r = 0.897, P < 0.005). In the heterologous phase of NTN, different
      pre-treatments only resulted in trivial changes in MCP-1 expression and monocyte
      infiltration. In conclusion, glomerular MIP-2 gene expression correlates with
      neutrophil infiltration both temporally during the evolution of nephritis, and
      when glomerular injury is modified by treatment. Glomerular MCP-1 gene expression
      correlates with monocyte influx. The data show chemokines of alpha- and beta
      subfamilies co-operative to cause selective and sequential migration of different
      leukocyte subsets during development of antibody mediated glomerulonephritis.

PMID- 8648913
TI  - Vasodilation induced by vasopressin V2 receptor stimulation in afferent
      arterioles.
AB  - We have previously reported that vasopressin (AVP) V2 receptor stimulation
      increased renal blood flow in dogs anesthetized with pentobarbital. In this
      study, we examined the direct effects of AVP on afferent arterioles to clarify
      the role played by V2 receptors in regulating afferent arteriolar tone. We
      microdissected a superficial afferent arteriole with glomerulus from the kidney
      of a New Zealand White rabbit. Each afferent arteriole was cannulated with a
      pipette system and microperfused in vitro at 60 mm Hg. The effects of vasoactive
      substances were evaluated by changes in the lumen diameter of afferent
      arterioles. We found that AVP decreased the lumen diameter of microperfused
      afferent arterioles dose-dependently and that a V1 antagonist, OPC21268,
      inhibited the vasoconstrictor action of AVP. However, AVP 10(-8) M increased the
      lumen diameter of norepinephrine (NE)-constricted afferent arterioles pretreated
      with OPC21268 (OPC + NE, 8.2 +/- 0.7 microns; OPC + NE + AVP, 9.9 +/- 0.9
      microns*; *P < 0.05, N = 13). This vasodilatory effect of AVP was abolished by
      pretreatment with a V2 antagonist, OPC31260. Desmopressin (dDAVP), a V2 agonist,
      increased the lumen diameter of the NE-constricted afferent arterioles (NE, 7.4
      +/- 0.9 microns; NE + dDAVP, 10.1 +/- 0.7 microns*; *P < 0.05, N = 9). These
      results suggest that AVP V2 receptors are present in rabbit afferent arterioles
      and that V2 receptor stimulation induces vasodilation in rabbit afferent
      arterioles.

PMID- 8648914
TI  - Differential expression of complement components in human fetal and adult
      kidneys.
AB  - Various studies have shown that complement components are synthesized by renal
      cells and that mRNA for a number of complement components is detectable in renal
      tissue. The present study shows that complement proteins are present both in
      fetal and adult human kidneys. The localization of the complement components was
      compared with the localization of other proteins for which specific expression in
      defined renal cell types is known from the literature. In adult human kidneys C3,
      factor B and factor H were detected in the mesangial area by
      immunohistochemistry, whereas C2 and C4 were present in the proximal tubuli. In
      fetal kidneys C3 and factor B were expressed in glomeruli of kidneys of 11 weeks
      of gestation. In kidneys of 13 to 19 weeks of gestation no staining for C3 was
      found in the glomerulus, whereas for factor B glomerular staining was found in
      all fetal kidneys examined. Factor B was also detected in fetal tubuli and in the
      interstitium. Factor H was expressed in fetal tubuli starting at 13 weeks of
      gestation. For both C3 and C2 weak tubular staining was found in all fetal
      kidneys investigated. C4 could not be detected in any of the fetal kidneys. While
      not all the complement proteins investigated were detectable by
      immunohistochemistry, by RT-PCR analysis, mRNA expression for C3, factor B,
      factor H, C2 and C4 was found in all adult and fetal renal tissue. The finding of
      mRNA for the complement components in the fetal and the adult kidneys indicates
      that local synthesis of complement occurs both in the adult and in the fetal
      kidney. Next to the in situ expression of complement components in fetal kidneys
      the synthesis of complement proteins in vitro by fetal renal cells was
      investigated. Four different primary mesangial cell lines were shown to
      synthesize all complement proteins investigated. Although a specific role for
      complement during the development of the kidney is not known, it is possible that
      certain complement components may play a role during renal differentiation.

PMID- 8648915
TI  - Mitochondrial free radical production induces lipid peroxidation during
      myohemoglobinuria.
AB  - Iron catalyzed free radical formation and lipid peroxidation are accepted
      mechanisms of heme protein-induced acute renal failure. However, the source(s) of
      those free radicals which trigger lipid peroxidation in proximal tubular cells
      remains unknown. This study tested the potential involvement of mitochondrial
      electron transport, xanthine oxidase activity, and arachidonic acid metabolism in
      the heme-induced peroxidative state. The impact of cytosolic Ca2+ loading also
      was assessed. Rhabdomyolysis was induced in mice by glycerol injection, and two
      hours later heme-laden proximal tubular segments (PTS) were isolated for study.
      PTS from normal mice served as controls. During 30 to 60 minute incubations, heme
      loaded PTS developed progressive cytotoxicity (LDH release) and iron-dependent
      lipid peroxidation (malondialdehyde, MDA, generation; inhibited by deferoxamine).
      Site 2 (antimycin A) or site 3 (cyanide, hypoxia) mitochondrial respiratory chain
      inhibition completely blocked lipid peroxidation, whereas site 1 inhibition
      (rotenone) doubled its extent (presumably by shunting NADH through NADH
      dehydrogenase, a free radical generating system). Conversely, these agents did
      not substantially alter MDA in normal PTS. Normal and heme loaded PTS developed
      comparable degrees of LDH release during respiratory blockade irrespective of
      increased or decreased MDA production (indicating that lipid peroxidation was not
      a critical determinant of cell death). Neither increasing free arachidonic acid
      (PLA2 treatment) nor adding cyclooxygenase/lipoxygenase/cytochrome p450
      inhibitors conferred a consistent protective effect. Altering free Ca2+ status
      (chelators; ionophore addition) and xanthine oxidase inhibition had no
      discernible impacts. Despite mitochondrial free radical production, mitochondrial
      function, as assessed by the ATP/ADP ratio, seemingly remained intact. In
      conclusion, (1) the terminal mitochondrial respiratory chain is the dominant
      source of free radicals which trigger PTS lipid peroxidation; (2) iron is a
      required secondary factor; (3) although mitochondria fuel lipid peroxidation,
      they do not appear to be critical targets of the heme-induced oxidant attack.

PMID- 8648916
TI  - Carboxy terminal sequence and synthesis of rat kidney laminin gamma 1 chain.
AB  - We used antibodies against mouse Englebreth-Holm-Swarm (EHS) tumor laminin to
      screen a newborn rat kidney lambda gt11 expression library and isolated three
      overlapping cDNA clones, termed 2b-11 (401 bp), 10-b7 (779 bp), and 2a (2,095
      bp). DNA sequence analysis identified these cDNAs as encoding much of the carboxy
      terminal domain I/II of laminin gamma 1 chain (formerly referred to as B2e), and
      1436 bp of the 3' untranslated region. In situ hybridization of fetal (E15) rat
      sections localized laminin gamma 1 chain mRNA primarily to meninges of the brain,
      auditory and peripheral nerve fibers, gastrointestinal system, and developing
      lung airway epithelium. Intense hybridization was also found in early nephric
      structures and glomeruli of fetal kidneys. In kidneys of three-day-old rats,
      hybridization persisted over early nephric figures, developing glomeruli, and
      collecting ducts, but considerably less hybridization was seen over tubules. On
      Northern blots of neonatal kidney RNA, the three cDNA clones hybridized to two
      species of 7.5 and 5.5 kb, suggesting that developing rat kidney laminin gamma 1
      mRNAs are processed using two different polyadenylation signals.

PMID- 8648917
TI  - Monitoring urinary levels of monocyte chemotactic and activating factor reflects
      disease activity of lupus nephritis.
AB  - Monocytes/macrophages (M phi) have been implicated in the pathogenesis of lupus
      nephritis (LN), but the precise molecular mechanism of recruitment and activation
      of M phi in LN remains unclear. To clarify the involvement of chemotactic
      cytokines (chemokines) in those events, we measured levels of monocyte
      chemotactic and activating factor (MCAF, also termed monocyte chemoattractant
      protein-1, MCP-1) in urines and sera derived from 42 patients with LN. Both
      urinary and serum MCAF levels were significantly higher in patients with LN as
      compared with 22 healthy volunteers (10.3 +/- 3.2 vs. 1.0 +/- 0.1 pg/ml .
      creatinine, 212.2 +/- 75.8 vs. 66.1 +/- 15.5 pg/ml, respectively, P < 0.05, mean
      +/- SEM). Histological examination of renal lesions from 41 patients classified
      19 as active according to the WHO-defined classes IIIb, IVb and IVc, and 22 as
      inactive by the WHO-defined classes I, II, IIIc, IVd and V. Urinary MCAF levels
      in the patients with active lesions were significantly higher than those with
      inactive lesions (20.3 +/- 6.4 vs. 1.7 +/- 0.3 pg/ml . creatinine, P < 0.01).
      Moreover, elevated urinary MCAF levels were dramatically decreased during steroid
      therapy-induced convalescence in 29 patients examined serially (13.9 +/- 4.5 vs.
      5.3 +/- 1.7 pg/ml . creatinine, P < 0.001), whereas serum MCAF levels did not
      change significantly. Endothelial cells, renal epithelial cells and infiltrating
      mononuclear cells in the tubulointerstitial regions were MCAF-positive in
      immunohistochemical as well as in situ hybridization analysis. These observations
      suggest that MCAF is probably involved in the pathogenesis of LN with active
      lesions, possibly through the recruitment and activation of M phi, and that
      measurement of urinary MCAF levels may be a useful clinical tool for monitoring
      the disease activity of LN.

PMID- 8648918
TI  - OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: association
      with improvement in long-term survival.
AB  - The data on patients participating in two randomized, prospective studies with
      similar immunosuppressive regimens were updated and combined to evaluate the long
      term effects of OKT3 according to cold ischemia time (< or = or > 24 hr). Among
      159 patients in the OKT3 and 153 in the cyclosporine A (CsA) group, 8 and 12
      deaths occurred, respectively (P = NS). In patients with cold ischemia > 24
      hours, OKT3 prophylaxis resulted in a lower mean number of rejection episodes per
      patient than did CsA prophylaxis within one year (mean +/- SEM: 0.87 +/- 0.11 vs.
      1.35 +/- 0.14, respectively; P = 0.008) and within five years (1.07 +/- 0.12 vs.
      1.49 +/- 0.15, respectively; P = 0.032). In contrast, rejection incidences in
      patients with cold ischemia < or = 24 hours was not significantly different in
      the two groups. In all study patients, there was a trend towards higher graft
      survival rates in the OKT3 group versus the CsA group (at 5 years, 73% vs. 66%,
      respectively; P = 0.182). Among recipients of kidneys with cold ischemia times >
      24 hours, OKT3 patients had significantly higher graft survival than CsA patients
      at two years (84% vs. 64%, respectively) and at five years (71% vs. 56%,
      respectively; P = 0.045). Significant differences were not observed in recipients
      of kidneys with cold ischemia times < or = 24 hours. In conclusion, patients
      receiving renal grafts with long cold ischemia times strongly benefit from OKT3
      prophylaxis.

PMID- 8648919
TI  - Enhanced scavenger receptor expression in monocyte-macrophages in dialysis
      patients.
AB  - The macrophage scavenger receptor (SR), which has two isoforms named type I and
      II, plays a leading role in the atherosclerotic process. To elucidate the
      mechanism of atherosclerosis in dialysis patients, SR expression was studied in
      monocyte-macrophages from thirteen dialysis patients and eight healthy controls.
      SR mRNA expression was examined in four hemodialysis patients and four controls
      matched for age and sex. Monocytes were allowed to differentiate into macrophages
      in in vitro cultures for seven days and SR type I and II mRNA expression were
      analyzed with the reverse transcription-polymerase chain reaction and quantitated
      using radiation densities of Southern blots. Only SR type I expression increased
      during differentiation and was accelerated by one or two days and enhanced after
      five days in patients, as compared to controls. To detect SR protein expression,
      uptake of fluorescently labeled acetylated low-density lipoprotein (Ac-LDL) was
      evaluated by flow cytometry. The mean fluorescence intensity of labeled cells was
      significantly higher in hemodialysis and continuous ambulatory peritoneal
      dialysis patients than in controls, although the number of SR-positive cells
      remained constant. In conclusion, SR expression is enhanced in macrophages from
      dialysis patients, probably by up-regulation of type I, which may contribute to
      the development of atherosclerosis in these patients.

PMID- 8648920
TI  - Long-term treatment of growth retarded children with chronic renal insufficiency,
      with recombinant human growth hormone.
AB  - Long-term (5 years) treatment of 20 growth-retarded pre-pubertal children with
      chronic renal insufficiency (CRI) led to a significant (P < 0.00005) improvement
      in standardized height from -2.6 at baseline to -0.7 at five years. Eight
      patients were paused after reaching target height (50th centile midparental
      height) and 4 (50%) required re-initiation of recombinant human growth hormone
      (rhGH) because of a substantial decrease in standardized height. Growth potential
      was not adversely impacted with a delta height age (HA) minus delta bone age (BA)
      at five years of +0.5 (N = 8). The mean calculated CCr decreased from 32.2 +/-
      15.2 ml/min/1.73 m2 at baseline to 24.6 +/- 14.7 ml/min/1.73 m2 at five years (P
      = 0.04), which would be consistent with the natural history of CRI in children.
      Despite the absence of clinical consequences, the increase in the mean fasting
      and two-hour post-prandial plasma insulin levels during treatment compared to
      baseline requires further investigation. The only clinically significant adverse
      event potentially related to rhGH was the development of avascular necrosis of
      the femoral head during the fourth year of treatment in one patient. Long-term
      rhGH treatment in children with CRI improves the potential of children with CRI
      achieving target adult height.

PMID- 8648921
TI  - Early detection and the course of glomerular injury in patients with sickle cell
      anemia.
AB  - We performed a cross sectional analysis of glomerular function in 34 adult
      patients with sickle cell anemia (SSA). Patients were divided according to GFR
      and albumin excretion rate (AER): SSA controls (normal GFR and AER, N = 10),
      albuminuria (increased AER, but normal GFR, N = 7) and chronic renal failure
      (CRF, low GFR, N = 17). GFR did not correlate with age (that is, duration of
      disease), but was inversely related to AER and IgG excretion rates (r = -0.61 and
      -0.69, respectively, P < 0.001) and directly related to the hematocrit (r = 0.56,
      P < 0.001). Renal plasma flow was disproportionately higher than GFR, so that
      filtration fraction was low in all groups. Albuminuria was accompanied, even in
      patients with normal GFR, by a reduction in ultrafiltration coefficient (16 +/- 3
      in albuminuria vs. 25 +/- 3 in controls, P < 0.05). A more severe loss of
      ultrafiltration coefficient and glomerular permselectivity occurred in CRF. We
      conclude that renal failure in SSA occurs because of glomerular injury with loss
      of ultrafiltration coefficient and glomerular permselectivity. The earliest
      clinically detectable abnormality is an increase in albumin and IgG excretion.
      When albuminuria is present, the ultrafiltration coefficient is already
      diminished even if GFR is preserved. Detection of albuminuria can identify
      established glomerular injury in SSA.

PMID- 8648922
TI  - Apoptosis of monocytes cultured from long-term hemodialysis patients.
AB  - Monocyte apoptosis in vitro was studied in patients on long-term hemodialysis,
      CAPD, and in predialytic uremia to gain insight into the high susceptibility of
      these patients to infections. Monocytes from dialysis and control subjects were
      cultured for 24 to 120 hours in vitro to analyze the level and progression of DNA
      fragmentation as a hallmark of apoptosis. After an incubation time of 48 hours
      chromatin fragmentation of 48.5 +/- 7.7% was found in monocytes from dialysis
      patients, which significantly exceeded DNA fragmentation of control monocytes
      (23.1 +/- 9.1%; N = 12; P < 0.01). Over longer culture periods of up to 5 days, a
      continuous progression of apoptosis occurred with a similar slope of percent DNA
      fragmentation in the two studied groups. Monocyte viability was > 95% both in the
      dialysis and control group. Hemodialysis patients also showed elevated levels of
      monocyte apoptosis when programmed cell death was evaluated by transmission
      electron microscopy or DNA electrophoresis of cleaved chromatin. To test the
      functional relevance of monocyte apoptosis, a significant reduction of Candida
      growth inhibition by monocytes of dialysis patients was found with a strong
      linkage between percentage of DNA fragmentation and impaired microbicidal
      capacity. Monocytes obtained from patients after the hemodialysis session and
      from CAPD patients showed normal DNA fragmentation levels similar to controls.
      Differences of monocyte apoptosis between patients on cuprophane and high-flux
      polysulphone dialysis were not found. Uremic predialytic patients also exerted an
      increased monocyte DNA fragmentation of 44.2 +/- 1.5% (N = 7; P < 0.05 compared
      to controls). Enhanced apoptosis of uremic monocytes was accompanied by a reduced
      formation of TNF-alpha over 48 hours, revealing a significant negative
      correlation between chromatin fragmentation and monokine synthesis.
      Supplementation of monocyte cultures from dialysis patients with exogenous TNF
      alpha turned increased apoptosis back to baseline levels, suggesting that
      inflammatory mediators may modulate monocyte senescence. In summary, the elevated
      degree of monocyte apoptosis in end-stage renal failure may contribute to the
      impaired cellular host defense seen in these patients.

PMID- 8648923
TI  - Risk of developing end-stage renal disease in a cohort of mass screening.
AB  - The prognostic significance of abnormal findings has not been demonstrated in a
      setting of mass screening. To evaluate the relative risk of end-stage renal
      disease (ESRD) indicated by various results of community-based mass screening, we
      utilized the registries of both community mass screening and chronic dialysis
      programs. In 1983, a total of 107,192 subjects over 18 years of age (51,122 men
      and 56,070 women) participated in dipstick urinalysis and blood pressure
      measurement in Okinawa, Japan. During ten years of follow-up, we identified 193
      dialysis patients (105 men and 88 women) among them. Logistic regression analysis
      of clinical predictors of ESRD over 10 years was done and the adjusted odds ratio
      and 95% confidence interval were calculated in each of the predictors with
      adjustment to others. In the clinical predictors such as sex, age at screening,
      proteinuria, hematuria, systolic and diastolic blood pressure, proteinuria was
      the most potent predictor of ESRD (adjusted odds ratio 14.9, 95% confidence
      interval 10.9 to 20.2), and the next most potent predictor was hematuria
      (adjusted odds ratio 2.30, 95% confidence interval 1.62 to 3.28). Being of male
      gender was a significant risk factor for ESRD (adjusted odds ratio 1.41, 95%
      confidence interval 1.04 to 1.92). Diastolic blood pressure was also a
      significant predictor of ESRD (adjusted odds ratio 1.39, 95% confidence interval
      1.17 to 1.64), but systolic blood pressure was not. In a mass screening setting,
      positive urine test, high diastolic blood pressure, and male sex were identified
      as the significant predictors of ESRD. Effect of glycosuria and other possible
      predictors of ESRD remained to be determined.

PMID- 8648924
TI  - Citrate compared to low molecular weight heparin anticoagulation in chronic
      hemodialysis patients.
AB  - Citrate and nadroparin calcium, a low molecular weight heparin (LMWH), were
      compared in a randomized cross-over trial in 21 chronic hemodialysis patients
      regarding anticoagulation, calcium and magnesium kinetics, biocompatibility,
      dialysis efficiency, and aluminum contamination. Citrate was infused into the
      arterial line at a minimum rate of 0.68 mmol/min, combined with a calcium and
      magnesium-free dialysate and intravenous supplementation of calcium and magnesium
      at rates of 0.22 and 0.10 mmol/min, respectively. Seven patients with a dialysis
      session of six hours, received 2/3 of the nadroparin dose predialysis, and 1/3
      after 2.5 hours (divided dose (DD) group). A single predialysis bolus injection
      of nadroparin was administered to eight patients not on coumarins [single dose
      (SD) group] and to six patients on coumarins [single dose + coumarins (SD + C)
      group], all with a dialysis session of four hours. Nineteen patients received a
      nadroparin dose of 200 ICU/kg. Two patients with a single dose, one of them on
      coumarins, received a dose of 150 ICU/kg because of a hematocrit < 0.30. With
      citrate systemic whole blood activated clotting time (ACT) remained unchanged,
      indicating efficient regional anticoagulation. After two hours of dialysis with
      nadroparin, systemic ACT increments, that is, the increase compared to
      predialysis, of the DD, SD, and SD + C groups were 8.8 +/- 1.5, 18.7 +/- 4.7, and
      33.3 +/- 6.1 seconds, respectively (mean +/- SEM). Postdialysis ACT increments in
      these groups were 1.5 +/- 3.4, 17.7 +/- 6.8, and 30.3 +/- 8.0 seconds. Two hour
      increments of systemic activated partial thromboplastin time (APTT) of the DD,
      SD, and SD + C groups during nadroparin were 5.0 +/- 1.2, 15.1 +/- 2.7, and 32.2
      +/- 5.5 seconds, respectively, and the corresponding postdialysis APTT increments
      were 2.9 +/- 1.4, 7.8 +/- 2.4, and 15.8 +/- 2.6 seconds. Two-hour anti-Xa
      increments of the DD, SD, and SD + C groups amounted to 0.34 +/- 0.07, 0.67 +/-
      0.07, and 0.80 +/- 0.08 IU/ml. The respective postdialysis anti-Xa increments
      were 0.21 +/- 0.06, 0.58 +/- 0.06, and 0.71 +/- 0.08 IU/ml (All ACT, APTT and
      anti-Xa increments were significant; P < 0.05), except for the ACT increments and
      the postdialysis APTT increment of the DD group). These increments, together with
      unchanged prothrombin fragments 1 and 2 (PTF1 + 2), indicate systemic
      anticoagulation with nadroparin. The increments of serum calcium and magnesium
      during citrate were comparable to the increments observed with a dialysate
      containing 1.5 mmol/liter calcium and 0.75 mmol/liter magnesium used in
      combination with nadroparin. Ionized calcium increments during citrate were
      significant after the end of dialysis, while the dialysate containing 1.5
      mmol/liter calcium induced significant increments during and postdialysis. No
      differences were observed between citrate and nadroparin regarding
      biocompatibility), (expressed as dialysis-induced leukopenia and
      thrombocytopenia), and dialysis efficiency [measured as dialyzer urea and
      creatinine clearance, normalized weekly whole body urea clearance (Kt/Vurea) and
      time averaged urea concentration (TACurea)]. The citrate solution, if sterilized
      in glass bottles, contained 2 to 3 micrograms aluminum per mmol citrate, the
      nadroparin solution 0.009 microgram per 1,000 ICU. Aluminum contamination of the
      citrate solution was prevented by sterilizing the solution in polypropylene
      bottles. In conclusion, citrate anticoagulation is regional and is indicated for
      hemodialysis patients with an active or recently active bleeding focus. However,
      the citrate solution should be sterilized in polypropylene containers to prevent
      aluminum contamination. LMWHs induce systemic anticoagulation during
      hemodialysis, and this effect is enhanced by concomitant coumarin use and
      mitigated by a divided LMWH dose regimen. For hemodialysis patients not at risk
      of bleeding, LMWHs provide a simple anticoagulation regimen.

PMID- 8648925
TI  - The COL4A5 gene in Japanese Alport syndrome patients: spectrum of mutations of
      all exons. The Japanese Alport Network.
AB  - To determine the spectrum of mutations of the COL4A5 gene encoding type IV
      collagen among Japanese Alport syndrome (AS) patients, 60 unrelated patients (47
      males and 13 females) from all over the country were recruited. Screening for
      mutations in all the exons (1 to 51) of the COL4A5 gene was carried out by PCR
      SSCP analysis. A mobility shift was observed in 22 of 60 patients, and their
      genomic DNA were analyzed by the direct sequence method and using cloned ssDNA.
      Nine of these had missense mutations in the collagenous domain (in exons 39, 37,
      31, 29, 28, 27, 21, 20, 19). Eight of these mutations were observed in a codon of
      glycine residue. Two were altered to arginine, two to valine, two to glutamic
      acid and two to aspartic acid. The other missense mutation was a change from
      isoleucine to serine in a interruption region. Five patients had small size base
      deletions and one had a 4 bp insertion resulting in frameshift (in exons 49, 41,
      19, 14, 13). Three had a splice site mutation (in exons 49, 47, 27). One had a
      nonsense mutation (in exon 17). These mutations seemed to be pathogenic, but the
      phenotype, which includes extrarenal manifestations, can vary with respect to
      both expression and severity. The remaining mutations were three silent ones (in
      exons 19, 39, 46). In addition, major gene rearrangement seemed to be rare in
      Japanese AS patients.

PMID- 8648926
TI  - Quasi-steadiness approximation for the single-compartment urea kinetic model
      (SCUKM).
AB  - Using SCUKM, we constructed recurrence formulae expressing weekly pre- and post
      dialysis urea levels. Then we mathematically derived simple methods to estimate
      Kt/V0 and the urea generation rate (G) per unit urea distribution space post
      dialysis (V0), which only required the measurement of pre- (C) and post-dialytic
      blood urea concentrations (C0) of a single hemodialytic session (two-point
      method). Underlying fundamental assumptions were: (i) patients receive weekly
      scheduled hemodialysis; (ii) the ultrafiltration rate, intradialytic urea
      generation, interdialytic water increase rate, and residual renal function are
      small enough to be retained only as the leading term in the formulae. In the
      derivation, we proved relations: C = f(Kt/V0)G/V0, and C0 = g(Kt/V0)G/V0, which
      state that both C and C0 are directly proportional to G/V0, and that the
      proportional constants are functions of Kt/V0. Errors of the formulae were also
      checked to make the limitation of the approximations clear. The present formulae
      exactly reproduced Kt/V0 and G/V0 of virtual patients strictly obeying the SCUKM
      in a computer simulated model. Using the blood urea nitrogen concentration data
      of 20 actual patients, we compared our method with the usual three-point method
      and obtained substantial correlations between them (r = 1.00 for Kt/V0, r = 0.98
      for G/V0). Finally, we proposed convenient and easily calculable new formulae,
      which give sufficiently accurate Kt/V0 and G/V0.

PMID- 8648927
TI  - Beneficial effect of renal transplantation on cognitive brain function.
AB  - Cognitive brain dysfunction is a common complication of end-stage renal disease.
      To investigate the cerebral effect of renal transplantation, we studied P300
      event-related potentials--an objective marker of cognitive brain function-
      trailmaking test and Mini-mental state in 15 chronic hemodialysis patients and 45
      matched healthy subjects. Before transplantation, patients showed prolonged P300
      latency (364 vs. 337 ms, P < 0.01), smaller amplitude (15.2 vs. 19.1 microV) and
      scored lower (P < 0.05) in trailmaking test and Mini-mental state as compared to
      healthy subjects. Following renal transplantation (14 months), P300 latency
      decreased (337 ms, P < 0.01 vs. before) and amplitude increased (17.4 microV, P <
      0.05 vs. before), indicating improved cognitive brain function. The trailmaking
      test and Mini-mental state tended to improve. Following transplantation, P300
      findings, trailmaking test and Mini-mental state were not different from healthy
      subjects. Additional studies following erythropoietin treatment in 6 of the 15
      hemodialysis patients revealed decreased (improved) P300 latency (351 vs. 379 ms
      before, P < 0.05) with further decrease following transplantation (341 ms, P =
      0.06). Our findings indicate that cognitive brain dysfunction in hemodialysis
      patients may be fully reversed by successful renal transplantation.

PMID- 8648928
TI  - Increased binding of polymeric lambda-IgA to cultured human mesangial cells in
      IgA nephropathy.
AB  - IgA nephropathy (IgAN) is characterized by raised plasma lambda-IgA1 and
      mesangial polymeric lambda-IgA1 deposits. It remains uncertain whether the
      predominant glomerular lambda-IgA1 deposits represent a selective uptake of
      polymeric IgA or a non-specific uptake due to elevated circulating lambda-IgA1
      levels in response to an unidentified antigen. In this study, we explored whether
      there is an increased binding of monomeric IgA1 (mIgA1) or polymeric IgA1 (pIgA1)
      from patients with IgAN to cultured human mesangial cells (HMC). Total IgA1 in
      plasma from patients or healthy controls was isolated by jacalin-agarose column
      as jacalin-bound proteins (JBP). Monomeric IgA1 and pIgA1 were distinctly
      separated by FPLC. HMC were incubated with IgA preparations and IgA bound to HMC
      was determined by flow cytometry analysis using standard curves constructed by
      known concentrations of kappa-IgA1 or lambda-IgA1. In order to avoid any
      increased binding of IgA to HMC due to elevated kappa- or lambda-IgA
      concentrations in JBP samples from patients, JBP samples from patients or
      controls were appropriately diluted to achieve comparable levels of total IgA1.
      No differences in the total mIgA1 or pIgA1 concentration, percentage of mIgA1 or
      pIgA1, or the kappa/lambda ratio of mIgA1 or pIgA1 were found between adjusted
      JBP samples from patients or healthy controls. We found a sharp rise in
      percentage of pIgA1 among IgA1 bound to HMC (70%), despite the fact that only 3%
      of the IgA1 in the adjusted JBP samples were polymeric, suggesting that pIgA1 had
      a higher affinity to HMC than mIgA1. Furthermore, the kappa/lambda ratios of
      pIgA1 bound to HMC were significantly lower than the kappa/lambda ratios of pIgA1
      in adjusted JBP only with IgAN patients but not healthy controls (P = 0.0026).
      Our data suggest a preferential mesangial binding of polymeric lambda-IgA1 from
      patients with IgAN. These polymeric lambda-IgA immune complexes are likely to be
      "pathogenic" and are important in the pathogenesis of IgAN.

PMID- 8648929
TI  - Computed tomography-derived intrarenal blood flow in renovascular and essential
      hypertension.
AB  - The effect of renal artery stenosis on intrarenal perfusion and volume in
      renovascular hypertensive patients is unclear. Alterations in these attributes
      may ultimately be involved in deterioration of renal function. We measured whole
      kidney, cortical, and medullary perfusion and volume with electron beam computed
      tomography (EBCT) in 33 hypertensive patients, with well-preserved renal
      function, scheduled for renal angiography. EBCT-derived whole kidney perfusion
      was lower in patients with atherosclerotic renal artery stenosis (RAS; N = 20)
      than in fibromuscular dysplasia (FMD; N = 10) or essential hypertension (N = 28;
      P < 0.05), as was cortical perfusion (2.44 +/- 0.16 vs. 3.26 +/- 0.17 and 3.07 +/
      0.09 ml/min/cc tissue, respectively, P < 0.005), but medullary perfusion was
      similar. Whole kidney, cortical, and medullary perfusion correlated inversely
      with degree of stenosis in FMD, but not in atherosclerotic RAS. Renal volumes
      were similar. These results demonstrate that, in contrast to patients with FMD,
      in patients with atherosclerotic RAS the decrease in cortical perfusion is not
      directly related to the degree of stenosis in the main renal artery. Factors
      other than the stenosis itself may play a role in the pathophysiology of
      atherosclerotic RAS and associated renal failure.

PMID- 8648930
TI  - Gene expression of hepatic cholesterol 7 alpha-hydroxylase in the course of
      puromycin-induced nephrosis.
AB  - Cholesterol conversion to and biliary excretion of bile acids represents the
      principal pathway of cholesterol catabolism in mammals. Cholesterol 7 alpha
      hydroxylase (Ch-7 alpha-H) is the first and the rate limiting step in bile acid
      production. Recently, Ch-7 alpha-H enzymatic activity has been shown to be normal
      in rats with established puromycin aminonucleoside-induced nephrosis (NS). To our
      knowledge, the gene expression of Ch-7 alpha-H in NS has not been investigated.
      We measured hepatic Ch-7 alpha-H mRNA and protein (by Northern and Western blot
      analyses) in rats at baseline and longitudinally during the course of induction
      and chronic phase of puromycin (PAN) induced NS. Groups of placebo-treated
      (controls) and diet-induced hypercholesterolemic (DHC) rats were included for
      comparison. The NS and DHC animals exhibited severe hypercholesterolemia of
      similar magnitude. Hepatic Ch-7 alpha-H transcript and protein remained virtually
      unchanged throughout the study period in the NS group. In contrast, Ch-7 alpha-H
      gene expression was markedly up-regulated in the DHC group. These observations
      suggest that hepatic Ch-7 alpha-H gene expression may be inappropriately low for
      the degree of the associated hypercholesterolemia in the NS group. It should be
      noted, however, that hepatic tissue cholesterol concentration was normal in the
      NS group and greatly increased in the DHC group. This can account for the
      disparity in Ch-7 alpha-H mRNA levels between the two groups since intracellular
      rather than extracellular cholesterol modulates Ch-7 alpha-H gene expression. In
      conclusion, the present study revealed that hepatic Ch-7 alpha-H gene expression
      remains unchanged during the course of PAN-induced NS in rats. It thus appears
      that generation and maintenance of hypercholesterolemia in this model of NS does
      not involve significant alteration of Ch-7 alpha-H gene expression.

PMID- 8648931
TI  - Modification of beta 2m with advanced glycation end products as observed in
      dialysis-related amyloidosis by 3-DG accumulating in uremic serum.
AB  - beta 2microglobulin (beta 2m) isolated from the amyloid deposits in patients with
      dialysis-related amyloidosis (DRA) has been demonstrated to be modified with
      advanced glycation end products (AGEs). We demonstrated that AGE was localized to
      amyloid deposits in patients with DRA by immunohistochemistry using a monoclonal
      anti-AGE antibody. To clarify the mechanism of AGE modification of beta 2m
      amyloid, we studied the effects of 3-deoxyglucosone (3-DG), a potent protein
      crosslinking the intermediate of the Maillard reaction, on the AGE modification
      of beta 2m, and quantified the serum levels of 3-DG in patients undergoing
      hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD), and
      undialyzed patients. The serum levels of 3-DG were markedly increased in the
      dialyzed and undialyzed uremic patients. Although the serum level of 3-DG
      decreased after HD with a mean reduction rate of 67%, it was still significantly
      higher than in normal serum. Incubation of beta 2m with 3-DG at 37 degrees C
      emitted fluorescence characteristic for AGE, and caused AGE modification and
      dimer formation of beta 2m as demonstrated by Western blotting using the same
      monoclonal anti-AGE antibody used for immunohistochemical demonstration of AGE in
      DRA. The AGE-modified dimer of beta 2m could be extracted from the amyloid tissue
      of a patient with DRA. 3-DG showed more intense and faster reactivity with beta
      2m to form AGE and dimer as compared with glucose, and aminoguanidine suppressed
      the AGE and dimer formation of beta 2m by 3-DG. In conclusion, 3-DG accumulating
      in uremic serum may be involved in the AGE modification of beta 2m-amyloid.

PMID- 8648932
TI  - Inhibitory effect of calcium channel blockers on human mesangial cell growth:
      evidence for actions independent of L-type Ca2+ channels.
AB  - Calcium channel blockers (CCB) are known to affect the outcome of
      glomerulosclerosis in vivo and to suppress mesangial cell proliferation and
      cytokine production in vitro. It is uncertain, however, whether (i) human adult
      mesangial cells (HMC) express L-type Ca2+ channels and (ii) whether the effect of
      CCB on HMC is mediated by inhibition of L-type Ca2+ channels. In single cell
      preparations of HMC, the L-type Ca2+ channel agonist Bay K 8644 and K+
      depolarization of the cell membrane caused a transient increase of cytosolic free
      Ca2+ ([Ca2+]i) in 60 to 80% of the cells. The CCB verapamil and nifedipine
      partially inhibited the effect of Bay K 8644 and K+-depolarization on [Ca2+]i.
      Binding experiments confirmed these functional studies by showing specific
      binding at the phenylalkylamine binding site of L-Type Ca2+ channels. Quiescent
      HMC were stimulated with fetal calf serum (FCS) or growth factors (platelet
      derived growth factor A/B, epidermal growth factor, angiotensin II, endothelin 1)
      in the presence of various concentrations (10(-10) to 10(-5) M) of different CCB:
      either (R)-verapamil, (S)-verapamil or the raceme of verapamil, and nifedipine or
      diltiazem, respectively. In addition, the enantiomers of devapamil were studied,
      because their action on the L-type Ca2+ channel is more stereoselective than that
      of the enantiomers of verapamil. At high concentrations (10(-6) to 10(-5) M)
      (R,S)-verapamil decreased cell numbers in cultures of quiescent HMC, increased
      LDH in the supernatant, and caused loss of trypan blue exclusion (cytotoxicity).
      At lower concentrations (R,S)-verapamil showed no cytotoxicity, but had two
      effects: (1.) concentration dependent (down to 10(-8) M) inhibition of indices of
      cell proliferation, that is, (i) stimulated (FCS or growth factor) 3H-thymidine
      incorporation and (ii) increment in cell number; and (2.) inhibition of indices
      of cell or matrix protein synthesis, that is, (i) stimulated 3H-methionine
      incorporation and (ii) 3H-proline incorporation. At equimolar concentrations the
      dihydropyridine nifedipine was equipotent with verapamil, whereas the
      benzothiazepine diltiazem was conspicuously less effective. Even at the lowest
      effective concentration (10(-8) M) comparison of (R)- and (S)-verapamil showed no
      significant difference between the enantiomer with weak or with strong effect on
      L-type Ca2+ channels, and this was true even when the more stereoselective
      enantiomers of devapamil were tested. These observations argue against the notion
      that effects of CCB result from specific interaction with L-type Ca2+ channels.
      The data are more consistent with the idea that interactions with targets other
      than L-type Ca2+ channels are involved.

PMID- 8648933
TI  - Further evidence linking urolithiasis and blood coagulation: urinary prothrombin
      fragment 1 is present in stone matrix.
AB  - The fact that organic material is always present and distributed throughout each
      renal calculus suggests that it may play a role in stone formation. The organic
      matrix of calcium oxalate (CaOx) crystals freshly generated in urine in vitro
      contains urinary prothrombin fragment 1 (UPTF1) as the principal protein. In this
      initial study, matrix was extracted from 12 renal calculi and evaluated for the
      presence of UPTF1 using Western blotting. UPTF1 was present in all eight stones
      whose principal component was CaOx, and in one of two stones which consisted
      mainly of calcium phosphate (CaP). UPTF1 was absent from the two struvite calculi
      examined. The relationship between CaP and UPTF1 was explored further. Matrix
      harvested from CaP crystals freshly generated in urine in vitro was also shown to
      contain UPTF1 as its principal component. Our inability to detect UPTF1 in one
      mixed CaOx/CaP stone may be related to our methods of matrix retrieval, while its
      absence from two struvite stones argues against it being present in the other
      stones merely as a consequence of passive inclusion. This absence may be related
      to the alkaline environment typical of struvite stone growth. The finding that
      UPTF1 is present in some renal stones provides the first direct evidence that
      links blood coagulation proteins with urolithiasis.

PMID- 8648934
TI  - Hepatitis C virus in a hemodialysis unit: molecular evidence for nosocomial
      transmission.
AB  - Between February 1991 and January 1992, elevated alanine aminotransferase (ALT)
      levels were observed in several hemodialysis patients in a dialysis center in
      Dendermonde, Belgium. By the end of 1992, 25 out of 68 patients had seroconverted
      for HCV antibodies. The HCV strains from 23 of these seroconverters were
      genotyped and classified as genotype 1b. Sequence analysis of the HCV Core region
      was carried out in 12 patients, 9 of whom were infected with a strain bearing a
      unique sequence motif as compared with the currently known HCV 1b strains. A new
      5' UR/Core line probe assay was designed to screen for such variations. Twenty
      patients tested positively for this special sequence motif, while the other 3
      showed the regular subtype 1b sequence. Phylogenetic analysis of the Core
      sequences further revealed that the latter three were neither related to the main
      special strain of the infection, nor to each other. These three strains could be
      traced to two patients already infected at the time of residence in other
      dialysis units and to one patient who already showed ALT elevations in 1989.
      Epidemiological studies revealed no traceable source for this outbreak. In
      conclusion, molecular analysis demonstrates nosocomial transmissions by a
      peculiar genotype 1b strain in a dialysis center. Three other genotype 1b strains
      were also present in the unit, but were not responsible for the outbreak.

PMID- 8648936
TI  - Measuring flow in hemodialysis grafts by non-triggered 2DPC magnetic resonance
      angiography.

PMID- 8648935
TI  - Phylogenetic analysis of hepatitis C virus isolates from hemodialysis patients.
AB  - A high prevalence of hepatitis C virus (HCV) infection has been reported in
      hemodialysis patients. Main risk factors for transmission are previous blood
      transfusions and possibly nosocomial infections within the dialytic environment.
      In the present study 224 hemodialysis patients from the same department were
      tested for the presence of anti-HCV antibodies and HCV-RNA. The presence of anti
      HCV in hemodialysis patients was correlated with a history of more than 10 blood
      transfusions (P = 0.001) and with a duration of hemodialysis treatment for more
      than 10 years (P = 0.001). The issue of possible patient-to-patient infection was
      addressed by sequence analysis of all HCV-RNA positive hemodialysis patients (N =
      14) together with a control panel of HCV isolates from 56 unrelated non
      hemodialysis patients with hepatitis C from the same geographical area.
      Subsequent phylogenetic analysis of nucleotide sequences obtained from the 5'
      noncoding region and the nonstructural NS-5 region of the HCV genome revealed
      that only two hemodialysis patients were infected by a highly related HCV
      isolate. The remaining HCV-RNA positive hemodialysis patients including those
      without previous blood transfusions were all infected by phylogenetically-distant
      HCV isolates, providing evidence against a nosocomial transmission route. The
      data of the present study show that molecular epidemiological techniques are
      important to investigate the issue of nosocomial infection. In our hemodialysis
      unit patient-to-patient infection appears uncommon and draws attention towards
      other possible (such as, blood products such as human serum albumin,
      immunoglobulins) or even yet unrecognized transmission routes.

PMID- 8648937
TI  - The cellular basis of metabolic alkalosis.

PMID- 8648938
TI  - [Intraoperative anaphylactic shock following the percutaneous puncture of a
      hepatic echinococcal cyst].
AB  - This is a report on a case of severe intraoperative anaphylactic shock,
      developing within several hours of percutaneous puncture of a liver hydatid cyst,
      performed under echographic control, necessitating recovery from the shock state
      and discontinuation of the operative intervention. Inferences are reached
      regarding the most adequate treatment tactics to be adopted in handling such
      cases. Percutaneous puncture is discarded as a therapeutic approach because of
      the great risk of anaphylaxis with eventual lethal outcome, and the likelihood of
      severe abdominal echinococcosis development at a later period.

PMID- 8648939
TI  - [Vascular exclusion during liver resection--an experimental rabbit model].
AB  - Vascular exclusion of the liver (VEL) consists in clamping of the portal triad
      (VCI) below and above the liver. An experimental model of the technique is
      presented, accomplished in 20 rabbits divided in three groups according to
      vascular exclusion pattern. Complete VEL reduces the hazards of intraoperative
      hemorrhage and air embolism during major liver resections.

PMID- 8648940
TI  - [Electron microscopic changes in the liver of patients with calculosis of the
      extrahepatic bile ducts].
AB  - Thirty-four patients, operated for calculosis of extrahepatic bile ducts with
      obstructive jaundice, are studied. They are divided in two groups according to
      cholestasis duration-10 and 20 days respectively. Material from liver tissue,
      taken intraoperatively, is investigated light-and electron-microscopically. The
      statistical analysis shows a significant increase in cell count in either group,
      as compared to controls (2.0-controls, 4.2-group one, and 6.2-group two; P <
      0.05). There is electron microscope evidence of perisinusoidal fibrosis
      periportally, ito cell's fibroblastic transformation, and collagenogenesis phase
      II and III. In group one fibrogenesis is moderate, and in group two-markedly
      expressed. It is established that parallel to increase in cholestasis duration,
      fibrogenesis in zone 1 and 2 of the liver lobule intensifies. This explains the
      necessity of undertaking early surgical intervention.

PMID- 8648941
TI  - [The combination of chronic calculous cholecystitis and diabetes mellitus].
AB  - A total of 206 patients with chronic calculous cholecystitis (CCC) are subjected
      to operation in the surgical clinic of the Military Hospital--Plovdiv over the
      period 1991-1994 = Diabetes mellitus as a concomitant disease is discovered in 21
      cases (10.20 per cent). All of them have pain syndrome complaints, and during
      cholecystectomy concrements in the gallbladder are found. As shown by the
      results, the combination CCC and DM leads to aggravation of the disease.
      Destructive changes in the gallbladder in this combination are detected in 28.5
      per cent, whereas in patients free of DM they amount to 10.5 per cent.
      Presumably, removal of the gallbladder contributes to eliminate the persisting
      stress factor in terms of the insular apparatus of the pancreas. Assessment of
      the long-term results shows that the positive therapeutic effect of the operation
      is permanent.

PMID- 8648942
TI  - [A clinico-morphological study of cancer of the gastric stump following an
      operation for benign disease].
AB  - The study covers 108 patients with stomach resection (Billroth II), performed
      over a period of six years (1988-1993). Endoscopic and biopsy findings are
      described. Carcinoma of the gastric stump is established in 16 cases (14.8 per
      cent), high degree epithelial dysplasia-in six (5.5 per cent), and signs of acute
      or chronic anastomositis, superficial of atrophic gastritis, intestinal
      metaplasia, lipid islands and single hyperplastic polypoid lesions are present in
      all cases. Dysplasia III degree and carcinoma in the gastrojejunal junction are
      observed in the older age group with 10-15 years postoperative follow-up study.
      Patients with stomach resection should undergo check-ups and multiple biopsies at
      3-5 years intervals, especially those with high-degree epithelial dysplasia.

PMID- 8648943
TI  - [Laparoscopic vagotomy in the treatment of duodenal ulcer with a report of 3
      cases].
AB  - The report deals with posterior truncus and anterior supraselective vagotomy,
      performed laparoscopically for the first time in this country. Three patients-2
      women and one man-are operated on for duodenal ulcer,complicated with bleeding,
      controlled conservatively in the first stage. In one female patient the
      intervention described and cholecystectomy are simultaneously done. In none of
      the three patients is stenosis of the pylorus observed. A considerable reduction
      of operative time-to 95 and 83 minutes-is achieved when special instrumentation
      (Multifire Endo Gia) for automated linear resection of the anterior gastric wall
      is used. Emphasis is laid on a number of advantages of the technique described.

PMID- 8648944
TI  - [The endoscopic diagnostic and therapeutic procedure in acute peptic hemorrhages
      from the upper gastrointestinal tract].
AB  - Bleeding gastroduodenal ulcers continue to be a common complication of diseases
      involving the upper segment of the gastrointestinal tract. In the last few years,
      with the introduction of fiber gastroscopy as a routine method of study,
      diagnosing of the underlying cause of hemorrhages is no longer a problem. A total
      of 959 emergency fibro-gastroduodenoscopies are performed.

PMID- 8648945
TI  - [Our experience with the surgical treatment of complicated duodenal ulcer using
      truncal vagotomy].
AB  - Personal ten-year-long surgical and clinical experience with the application of
      truncal vagotomy in 51 patients with complicated duodenal ulcers-23 with
      hemorrhage, 19 with perforation and nine with stenosis, is shared. Emphasis is
      laid on the superiorities and comparatively low lethality (5.8 per cent) of the
      application of this type of vagotomy during the surgical management of
      complicated duodenal ulcers, as well as on the great diagnostic relevance of
      fiber gastroscopy applied on the apex of hemorrhage in case of bleeding duodenal
      ulcers.

PMID- 8648946
TI  - [The repair of extensive evisceration using an absorbable prosthesis].
AB  - The use of an absorbable material in the form of a permeable mesh of polyglactin
      910 is proposed for the treatment of extensive evisceration regardless of
      etiology. Its strength and excellent tolerance by the body even in the presence
      of infection justify its intraperitoneal placement on the deep surface of the
      peritoneum, in contact with the viscera and in reconstruction of the parietal
      wall. Perfect retention of the viscera in place is assured and the reconstructed
      parietal wall seems solid and stable, the absorbable mesh being rapidly replaced
      by host connective tissue of good quality. This technique, applicable to all
      cases of evisceration, is valuable in the surgical treatment of such patients,
      which is frequently difficult at best.

PMID- 8648947
TI  - [The determination of plasma malondialdehyde in patients with obstruction of the
      small intestine].
AB  - Plasma malonic dialdehyde (MDA) level is evaluated in 22 patients with small
      intestinal obstruction. Bowel strangulation is found in 14 cases-reversible in
      eight, and irreversible in six, and simple small-intestine obstruction-in eight.
      The plasma MDA level in this group of patients is compared with the one in a
      control group of twenty healthy individuals. In the control group MDA is 2.6 +/-
      0.5 nmol/ml, in strangulation obstruction-6.9 +/- 1.5 nmol/ml, and in those with
      simple obstruction-2.8 +/- 0.4 nmol/ml. The difference in MDA level between
      strangulation cases and the other groups under study is statistically significant
      plasma MDA increase in patients with small intestinal strangulation may be
      successfully used for the purpose of diagnosis.

PMID- 8648948
TI  - [Vascular exclusion of the liver].
AB  - Vascular exclusion of the liver (VEL) is a comparatively new and seldom used
      procedure. It is developed and practically implemented along with liver
      transplantation, and corresponds to the nonhepatic phase of the latter. VEL
      reduces considerably the risks of intraoperative hemorrhage, and is indicated in
      handling large and vascular tumors located in the vicinity of vessels. Its safe
      duration may reach up to 90 min, and is free of serious postoperative
      complications. VEL allows for broadening the scope of liver resection, and
      reduction of intra- and postoperative hemotransfusions.

PMID- 8648949
TI  - [New aspects in the etiopathogenesis of colorectal cancer].
AB  - Proceeding from a comprehensive literature review, the new aspects of the
      etiopathogenesis of colorectal carcinoma are presented for the first time in this
      country. The updated etiopathogenetic postulates in cancerogenesis are discussed,
      namely: the low calcium diet is associated with carcinoma of the colon,
      fecapentaens are mutagens found in the feces, produced by intestinal flora
      against the background of dysbacteriosis, triketosteroids at high concentrations
      are found in populations at risk of carcinoma of the colon, free bile acids in
      the faces play a major role in the genesis of carcinoma of the colon, serum
      cholesterol and beta-lipoproteins are directly linked to carcinoma of the colon-a
      decrease in serum, cholesterol level is noted in patients with colorectal
      carcinoma. The finding of a definite gen in 17 and 18 chromosomes, having a tumor
      suppressive and mutagenic effect, is the most important examination in the field
      of molecular biology.

PMID- 8648950
TI  - [Operations on the biliary system in liver damage].
AB  - Emphasis is laid on the correlation existing between liver and biliary apparatus
      pathology. On the one hand, attention is called to the development of reactive
      hepatitis in 60-75 per cent of patients presenting complicated cholelithiasis,
      and in nearly 30 per cent of the forms free of complications. Removal of the
      biliary pathology leads to complete regeneration of liver parenchyma in 80 per
      cent of the patients, especially in operation undertaken in opportune time. On
      the other hand, pathological conditions of the liver aggravate the developmental
      course and worsen the prognosis of biliary system diseases when operative
      management of the letter is necessitated. On the basis of personal experience,
      the unduely elevated risk in combining surgical intervention for biliary
      pathology with liver cirrhosis (27 observations), cholangiohepatitis (89
      observations), and obstructive jaundice conditioned by a benign underlying cause-
      usually concrement (164 observations), is underscored. In established
      cholelithiasis it is fully justified to advise early operation. Surgical
      intervention in liver cirrhosis should be done after adequate preparation only if
      absolutely necessary. Obstructive jaundice requires urgent operation, within 10
      days, as long as the pathomorphological changes are still reversible.

PMID- 8648951
TI  - [Biliary reoperation with the correction of portal hypertension in a female
      patient with a congenital anomaly].

PMID- 8648952
TI  - [A case of extensive resection of the small and large intestines].

PMID- 8648953
TI  - [Carcinoid of the major duodenal papilla].

PMID- 8648954
TI  - [2 cases of severe closed trauma to the duodenum].

PMID- 8648955
TI  - [A case of nongestational-type choriocarcinoma manifested as rectal hemorrhage
      and operated on as sigmoid carcinoma].

PMID- 8648956
TI  - [Phlegmon-exacerbated chronic calculous cholecystitis and its surgical
      treatment].
AB  - A series of 165 patients presenting chronic calculous cholecystitis (CCC),
      operated in the surgical clinic of the Military Hospital--Plovdiv over the period
      1991 through 1994, are analyzed. In twenty patients (10 men and 10 women) the
      disease a clinical course characterized by phlegmonous-purulent cholecystitis.
      All patients are subjected to operative management, and in all the clinical
      diagnosis is confirmed intraoperatively. Empyema of the gallbladder with
      concrements and purulent secretion is discovered in nine cases, and fragility of
      the gallbladder wall-in four. The histomorphological study reveals phlegmonously
      exacerbated CCC in 12 patients, walls totally replaced by granulation tissue--in
      three, and necrotic mucosa--in five. The early results of operative treatment are
      estimated as good. The long-term results are likewise very good. The positive
      effect of treatment is lasting, and persists for many years.

PMID- 8648957
TI  - [Anaerobic nonclostridial soft-tissue infection].
AB  - Over the period 1985 through 1994, observations are conducted on forty-eight
      patients, 35 men and 13 women, with age ranging from 11 to 56 years, presenting
      anaerobic non-spore-forming infection of the soft tissues (necrotizing fasciitis
      (3), postinjection nonclostridial myositis (7), crepitant cellulitis in diabetic
      gangrene (21), neck phlegmon (5), perineal phlegmon (9), and progressive
      bacterial synergistic gangrene against the background of chronic osteomyelitis
      (3). Infection development is characterized by local necrotic processes,
      intoxication, crepitations, fetor, fever, and in part of the patients--septic
      shock and DIC syndrome. The microbiological study shows presence of anaerobes, as
      mono- and polyinfection, aerobic-anaerobic associations, and gram-negative
      aerobes--in one patient alone. Invariably, the general condition is rather
      serious. Lethality amounting to 12.5 percent is ascribed to the late detection
      and unspecified and inadequate treatment protocol in the initial period of
      observation. The treatment is complex: incisions with successive many-staged
      necrectomies, antibiotics, metronidazole, hyperbaric oxygenation and
      hemadsorption. If several (2-3) of the aforementioned symptoms are present,
      evidence of anaerobic flora should be mandatory and purposefully seeked.

PMID- 8648958
TI  - [The systematization of APUD tumors].
AB  - The mechanisms involved in neuroendocrine transmission of peptides, underlying
      the so-called classification of multiple endocrine neoplasms (MEN), are
      described. Three cases from the clinical practice are followed up where
      facilitation of the diagnosis and the results of treatment are related to the
      tumor markers' values.

PMID- 8648959
TI  - [A 10-year follow-up study of bypass operations with double-velour dacron in the
      aortoiliofemoral position].
AB  - The results of the follow-up study of 271 bypass operations in aortoiliofemoral
      position are analyzed. The interventions are done using monotype double-velour
      dacron prosthesis, standard operative technique and tactics. At 5.4 percent
      operative lethality, the postoperative complications include infection (2%) and
      rethrombosis (4%), necessitating reoperation which is successful in 64 per cent.
      Secondary cumulative patency of the prostheses implanted, amounting to 90 percent
      at three years, 80 percent at 5 years, and 66 percent at ten years
      postoperatively, is recorded, with aortobifemoral bypasses yielding superior
      results. Serious late complications are registered, such as prosthesis infection,
      abnormal dilatation of the implant, periprosthetic seromas and aneurysms by
      anastomosis. The underlying causes of complications and the indications for
      reoperation are discussed. The role played by late reoperations, leading to a
      successful outcome in 63 percent of cases is underscored. Attention is called to
      a number of characteristic features of the prosthesis employed, including the
      need of precise preclotting, restrained post-implantation increase in its
      diameter up to 20 percent necessitating implantation of prostheses isodiametric
      to the recipient artery, high incidence of postoperative complications making
      mandatory, periodic check-ups of operated patients and the like. In conclusion,
      it is estimated that over the 10-year observation period, the prosthesis
      suggested yields satisfactory results upon implantation in the aortoiliofemoral
      segment, and these results may be accepted as a basis for comparison with new
      vascular prosthesis designs.

PMID- 8648960
TI  - [The lipid peroxidation level and antioxidant status of the plasma in patients
      operated on under propofol (Diprivan) anesthesia].
AB  - It has been investigated the level of lipid peroxidation and antioxidant status
      of blood plasma from patients operated under general anaesthesia with propofol
      (Diprivan). The following parameters have been registered: TBA-reactive
      substances (TBARS) and fluorescent lipofuscine-like lipid peroxidation products,
      before, directly after and 24 hours after anaesthesia. It was not shown
      statistically significant changes of TBARS before and after anaesthesia. The
      levels of TBARS were initially higher in comparison of referent levels. The
      fluorescent lipofuscine-like products were increased weakly after anaesthesia
      directly but the changes were not statistically significant, too. The antioxidant
      capacity of blood plasma was decreased weakly 24 hours after anaesthesia, in
      comparison of the levels, registered before anaesthesia. The good correlation
      between fluorescent products and antioxidant status of plasma was observed.

PMID- 8648961
TI  - [Controlled hypotension against a background of nimodipine during an operation on
      neurosurgical patients with hypertension].
AB  - Operative interventions in subarachnoid hemorrhages caused by brain vessel
      aneurysm require meticulous dissection of the latter. Regardless of the
      preoperative preparation of hypertensives, hypertension is a factor predisposing
      to intraoperative blood pressure fluctuation which, in turn, is extremely
      unfavourable and interferes with the operation proper on the aneurysm. What is
      more, it augments the spasm of cerebral vessels and brain edema. Any increase in
      blood pressure may result in a rupture of the aneurysm. As shown by a parallel
      study on two groups of patients with hypertension, following intraoperative
      administration of calcium antagonists having a preventive effect on brain, the
      stabilization of blood pressure attained is persistent, with the spasm of
      cerebral vessels and brain edema lending themselves more readily to control. The
      application of controlled hypotension is more easily effected, and administration
      of ganglioblocking agents is unnecessary.

PMID- 8648962
TI  - [Postoperative analgesia].
AB  - In a series of fifty-two patients undergoing abdominal surgery the listed below
      agents for postoperative analgesia are used: moradol (M), dipidolor (D),
      droperidol--DNBP, fentanyl (F). The control group is given analgin. During the
      first six hours, M and D show optimal effect in terms of postoperative pain
      syndrome relief, without suppression of the hemodynamics and respiration.

PMID- 8648963
TI  - [Combined spinal and epidural analgesia in urology].
AB  - Combined spinal and epidural analgesia is a new concept in the field of regional
      anesthesia. It combines the positive qualities of spinal and epidural analgesia,
      and is performed by the "needle-in-needle" technique, described in the paper.
      This type of analgesia is practically implemented in the Clinical Center of
      Urology over the past few months, and shows encouraging results. This is a report
      on clinical experience had with 10 combined analgesia procedures, running a
      course free of any complications against the background of stable hemodynamics
      and respiration of the patients. The block induced is with 4-hour duration, and
      lends itself to prolongation through an epidural catheter. This renders the
      method variable and suited for postoperative analgesia too. The Espokan set
      technical devices used make puncture of the spinal-epidural space readily
      practicable.

PMID- 8648964
TI  - [Ketamine at low doses + etomidate or diazepam--a comparative clinical study of
      anesthesia in urology].
AB  - Eighty urological patients, divided in two equal groups, are anesthesized using
      two anaesthetic combinations: small dose kaliposol + etomidate, or diazepam. The
      obtained results point to a stability of the arterial pressure and pulse rate and
      prompt recovery, rendering the kalipsol-etomidate combination an alternative to
      the kalipsol-diazepam one which is well affirmed in urological practice.

PMID- 8648965
TI  - [Anesthesia problems in patients with an infravesical obstruction].
AB  - The past few years mark an ever increasing interest in intravesical obstructions
      in urological practice. After clarifying issues relating to the role and type of
      the underlying disease leading to intravesical obstruction, 173 patients with
      such a condition, subjected to analgesia of varying type, are analyzed under the
      aspect of anesthesiology. In 98 cases (56.65 percent) the underlying cause of
      obstruction is adenoma of the prostate gland, in 60 men and 9 women (39.88
      percent)-carcinoma of the bladder, and in eight patients (3.47 percent)-sclerosis
      of the prostate gland. Preparation of the patients for anesthesia and operation
      is greatly interfered with by the concomitant polymorbidity, insofar as 83.5
      percent of the contingent are older than 60 years of age. Analgesia is secured by
      endotracheal anesthesia (96 cases), epidural analgesia (64) and spinal-epidural
      analgesia (13). A comprehensive analysis based on the type of anesthesia and
      condition of the patient during operation is done, leading to the inference that
      all three methods are individually indicated.

PMID- 8648967
TI  - [An orthotopic bladder from the ileum after total cystectomy--the technic of the
      operation].
AB  - This is a description of the operation proper with explanation of the motivation
      for giving preference to one or another technique of execution. Presumably,
      proceeding from experience accumulated hitherto, it will serve the purpose of
      instructions to Bulgarian urologists willing to implement in practice this
      difficult and complex operative procedure. After careful assessment of the
      methods existing, and in compliance with the logic of anatomy and physiology of
      the structures involved, two innovations concerning the formation of new urinary
      bladder and implantation of the ureters therein are introduced. The latter merit
      special attention since they contribute greatly to improve the functions of the
      new organ.

PMID- 8648966
TI  - [Cysts of the kidney--the clinical picture and diagnostic possibilities].
AB  - Malformations associated with the differentiation of kidneys are characterized by
      a great number of morphological sequels, most of them relating to cyst formation
      (A. Someren 1989). Over the period 1983 through 1992, a total of 400 patients
      presenting solitary cysts, multiple cysts and polycystic condition of the kidneys
      undergo treatment in the Clinical Center of Urology--Alexandrovska University
      Hospital. The symptomatology involves 19 single and combined symptoms, and
      independent and combined investigations, with echographies ranking first--400
      exams. Not a single of the symptoms is typical of cysts (with the exception of
      pain) with of the examinations the greatest diagnostic relevance is ascribed to
      echography and CAT.

PMID- 8648968
TI  - [Cysts of the kidney--their therapeutic management].
AB  - In patients presenting pain syndrome, hypertension obstruction of the
      pyelocaliceal system or kidney-cyst-induced ureteral compression, operative
      intervention should be by all means considered (A. Gelet 1990, L. Kavoussi 1991).
      Over the period 1983 through 1992, 400 patients with solitary and multiple cysts
      and polycystic condition of the kidneys (polycystosis) representing 1.13 percent
      of the total number of admissions, are subjected to treatment in the Clinical
      Center of Urology--Alexandrovska University Hospital. The series includes 196 men
      and 204 women; percutaneous puncture is performed in 245 cases, and operative
      intervention--in fifty-four. Twenty-five patients are reoperated, eight undergo
      three operations, and two--manifold repeated operations. Recurrent cysts are
      recorded in 35 instances. One patient of the contingent, admitted with ruptured
      cyst of the only kidney and peritonitis, dies after the operation.

PMID- 8648969
TI  - [Urethral stricture and chronic recurrent cystitis in women].
AB  - The study covers eighty-seven women, aged 21 to 68 years, presenting chronic
      recurrent cystitis. In 53 of the total number (60.92 percent) no evidence of
      intravesical obstruction is found. In the remainder 34 (39.08 percent), following
      urethral calibration and urodynamic investigations, direct and indirect data
      pointing to urethral stricture are established. Urethrotomy is done in thirteen
      women, and dilatation of the urethra (up to 30)-in twenty-one. After the
      manipulations described, a six-month antibiotic prophylaxis against urinary
      infection relapse is conducted. It is demonstrated that urethrotomy and
      dilatation of the urethra lead to normalization of the urodynamic indicators and
      subjective miction improvement. Within a year, one to several cystitis
      recurrences are recorded in all women documented.

PMID- 8648970
TI  - [The treatment of bladder tumors with the Nd:YAG laser].
AB  - This is a review of literature dealing with Nd:YAG laser application in the
      treatment of bladder tumors. The clinical characteristics of the laser, technique
      of application and the likely complications are described in details. The
      advantages and shortcomings of the method are also summed up. The updated
      clinical results are analyzed, and inferences on the effectiveness of Nd:YAG
      laser photocoagulation are reached, mainly with regard to reduction of the local
      recurrence rate.

PMID- 8648971
TI  - [Glutamate antagonists--a new stage in the development of cerebral protection?].
AB  - This is a survey of 35 papers, published in medical journals worldwide over the
      past 5 years, in an attempt to disclose the current level of understanding the
      fine biochemical mechanism underlying neuronal lesions, as well as to outline the
      possible trends of cerebroprotective therapy evolution, as put forward by the
      authors of the cited works. A number of researches demonstrate the role of
      glutamate and other excitatory amino acids in neuronal lesions' development
      during hypoxia, hypoglycemia, cranio-cerebral trauma and the like. It is logical
      to presume that the antagonists of glutamate receptors and their relationship to
      ionic canals may be considered as having an essential bearing on the build-up of
      a complex cerebroprotective strategy, corroborated in turn by a number of studies
      on cell cultures in vitro, and in numerous animal models as well. The already
      known and clinically used phencyclidine compounds, and first and foremost, the
      general anesthetic ketamine, spark a great surge of interest along these lines.

PMID- 8648972
TI  - [The TUR syndrome].
AB  - The incidence rate of transurethral resection (TUR) syndrome ranges from 1 to 7
      percent, although the mild cases may reach up to 10.25 per cent. Irrigation using
      nonelectrolyte fluid is associated with absorption of the latter. The prompt
      penetration of more than one liter distilled water into the circulation becomes
      manifest with a diversity of cardiovascular and neurological symptoms. In the
      event of persisting hypotension with bradycardia, the acute forms of TUR syndrome
      may result in a fatal outcome. The essence of TUR syndrome necessitates the
      undertaking of competent treatment, carried out by a team of specialists,
      including, apart from urologist and anesthesiologist, an intensive care
      therapist, neurologist, cardiologist, ophthalmologist and laboratory physician.
      In addition to general supporting treatment, it is mandatory to combat
      hypotension, hyponatremia, hypoosmolality and anuria. Monitoring the amount of
      fluid being absorbed has important practical implications on the prophylaxis. For
      the purpose ethanol (1 percent) as indicator is added to the wash-out fluid. By
      its concentration in the air exhaled by the patient it is possible to measure the
      quantity of fluid intake. In the survey presented the detrimental effects of
      glycine--the commonest osmotically active constituent of the wash-out fluid--is
      also discussed.

PMID- 8648973
TI  - [Endometriosis in the cicatrix after a cesarean section].

PMID- 8648974
TI  - [A case of gangrenous appendicitis complicated by an anaerobic gas infection in
      the retroperitoneal space and right thigh].

PMID- 8648975
TI  - [A nongerminal tumor of the testis--a Leydig-cell tumor clinically manifested by
      feminization--gynecomastia].

PMID- 8648976
TI  - [A case of a successfully conservatively treated ureterovaginal fistula of
      gynecological origin].

PMID- 8648977
TI  - [Anaerobic surgical infection].
AB  - The study covers 125 patients with anaerobic surgical infection, aged 7 to 82
      years. Of the total 27 cases are operated for acute cholecystitis, four--diffuse
      acute peritonitis, seventeen--acute appendicitis, and three--acute hematogenous
      osteomyelitis. In acute cholecystitis and acute appendicitis microbiological
      study is carried out of the content, organic wall and periorganic space. In acute
      cholecystitis patients anaerobic flora is found in 39.01 per cent, and gram
      negative--in 44.9 per cent, and in those presenting acute appendicitis--in 28.3
      per cent and 58 per cent, respectively. The clinical analysis results point to a
      severer clinical course in the patients presenting anaerobic flora. The letter
      becomes manifest as mono infection in 37.2 per cent. It is pointed out that in
      the presence of two or more signs, characteristic of anaerobic infection, namely:
      destructive early process, offensive odor and intoxication, anaerobic bacterial
      flora should be invariably considered. At each microbiological examination the
      results of staining according to Gram should be also demanded from the
      laboratory.

PMID- 8648978
TI  - [Surgery in the macular foramen--pro and contra].

PMID- 8648980
TI  - [Ophthalmoscopic study of the retinal nerve fiber layer].

PMID- 8648979
TI  - [Anterior ischemic optic neuropathy. Role of nocturnal arterial hypotension].

PMID- 8648981
TI  - [Information from the American Academy of Ophthalmology: how AIDS affects the
      eye].

PMID- 8648982
TI  - [Clinical measurement of intraocular gas].
AB  - BACKGROUND: Increased use of gases in retinal/vitreous surgery requires a good
      clinical estimate of intraocular gases. This is needed, if a supplement of gas is
      intended, its disappearance to be predicted (e.g. to 10% to permit travelling by
      plane) or the amount to be calculated to cover a break. Clinical estimation of
      gas in the pupil is limited by its size. Accuracy of pupil measurements will be
      tested and compared with experimental results obtained by estimating the level of
      gas meniscus at the retina. MATERIALS AND METHODS: Ten cadaver eyes (5 phakic, 4
      aphakic, 1 pseudophakic) were fixed in a plastic mold, vitrectomized and injected
      with multiple randomized volumes of air. Two observers measured the level of
      meniscus in disc diameters above or below the superior margin of disc and then
      anteriorly in the pupil in millimeters from the superior limbus. Measurements
      were converted to milliliters through tables constructed on mathematical models
      of the phakic and aphakic eye. RESULTS: Observations at the retina and in the
      pupil were equally accurate for intermediate gas volumes, for which the meniscus
      fell within the pupil (P = 0.372). Measurements at the retina proved less
      vulnerable to error induced by misalignment of the observer's eye. Above the
      pupil observations at the retina were still reliable for small bubbles up to 4 dd
      above the disc (error < 5% in the aphakic, < 10% in the phakic eye). Below the
      pupil observations at the retina yielded a result increasing less than the
      injected volume because of refraction at the anterior segment gas interface
      (error > 10% of the ocular volume). CONCLUSION: Observations of the level of gas
      meniscus at retina with indirect ophthalmoscopy is an accurate method for
      estimating intraocular gas volumes. It extends the range of measurement
      significantly beyond the pupil. Tables based on a mathematical model convert disc
      diameters to milliliters.

PMID- 8648983
TI  - [Hydroxyethyl starch for reversing edema in short-term culture media for donor
      corneas].
AB  - PURPOSE: To investigate the feasibility to use hydroxyethylstarch as an
      alternative deswelling additive in short-term preservation media. MATERIALS AND
      METHODS: Corneoscleral discs were prepared from pairs of eye balls of freshly
      slaughtered pigs. Corneas were stored in MEM-medium containing either 10% or 20%
      hydroxyethylstarch 450 000 at 4 degrees C in a refrigerator. Subsequently, the
      tissue was stored for 24 hours in organ culture at 37 degrees C in MEM-medium
      containing 10% fetal calf serum to detect latent endothelial cell damage. Mate
      corneas were treated the same except for being stored in Optisol GS during 4
      degrees C storage. We determined corneal endothelial cell density, stromal
      thickness, and glucose concentration in the medium directly after preparation,
      after short-term storage at 4 degrees C, and after subsequent organ culture at 37
      degrees C. Scanning electron microscopy of corneal endothelium was performed at
      each step during the experimental course. RESULTS: We did not observe any
      significant differences in endothelial-cell density between experimental groups
      and control groups. No decrease in endothelial-cell density was observed during
      the course of experiments. No increase in stromal thickness was determined in any
      group after short-term storage at 4 degrees C. Corneas stored in medium
      containing 20% hydroxyethylstarch showed a decrease in stromal thickness after
      short-term storage. After subsequent organ culture all corneas displayed a
      uniform stromal swelling. Glucose concentrations in the media decreased in all
      groups during the experiment. In scanning-electron microscopy we observed a
      reversible degeneration of cell borders after storage at 4 degrees C.
      Additionally, corneas stored in Optisol GS showed a reversible cobblestone
      appearance at this stage of the experiments. CONCLUSION: Hydroxyethylstarch
      appears to be an alternative to the use of dextran and chondroitin sulfate as a
      deswelling additive in corneal preservation media.

PMID- 8648984
TI  - [Thermo-mechanical behavior the the cornea].
AB  - BACKGROUND: Shrinkage of corneal collagen is used during thermokeratoplasty, a
      method to remodel the corneal curvature. The goals of our investigations were to
      determine the optimal temperature range for maximal shrinkage of the collagen
      fibers with minimal damage. MATERIALS AND METHODS: By means of a commercially
      available stress-strain-measuring device with a paraffin oil bath of temperatures
      varying from 35 degrees C to 120 degrees C strips of pig cornea 5 mm in width and
      9 mm in length were investigated in the physiological stress range from sigma =
      (0,5-12,5) . 10(4) N/m2 by stress-strain, stress relaxation and creep
      measurements. RESULTS: Biomechanical properties of the cornea remain unchanged in
      the temperature range from 30 to 50 degrees C. Starting at 60 degrees C shrinkage
      occurs that increases up to 90 degrees C. The maximal rate of shrinkage of (57 +/
      12)% was measured at temperatures of 75 to 80 degrees C. Above 100 degrees C
      this effect is reduced by the destruction of intermolecular bonds between the
      collagen fibers. The stress-strain curves of the shrunk corneas are flatter than
      that of native corneas, which means, the Young's modulus is significantly
      reduced. CONCLUSIONS: In order to realize optimal shrinkage during
      thermokeratoplasty temperatures of 65-85 degrees C should be achieved in the
      coagulated tissue. Higher temperatures cause also a shrinkage effect but also a
      destruction of tissue.

PMID- 8648986
TI  - [Descemetocele after Excimer laser phototherapeutic keratectomy in herpes simplex
      virus-induced keratitis: a clinico-pathologic correlation].
AB  - BACKGROUND: The indications for phototherapeutic keratectomy in superficial and
      deep corneal scars in Herpes simplex virus infections are controversial. Serious
      incidents after PTK have as yet not been reported. PATIENTS AND METHODS: A 62
      year-old patient had suffered from recurrent central herpetic keratitis since
      1948 and was treated for corneal scarring for the first time in 1992 by PTK. In
      1995, epithelial defects were noted and, since medical treatment was
      unsuccessful, repeat PTK was performed. Two weeks after the second PTK, stromal
      infiltration with a subsequent corneal ulcer was followed by a descemetocele and
      perforation. RESULTS: The recurrence of Herpes simplex keratitis was treated with
      systemic acyclovir, and the corneal perforation, the posterior synechiae and the
      complicated cataract were managed by a triple procedure a chaud (7.0 x 7.5 mm).
      The inflammation calmed down, and a significant improvement of vision was noted
      at dismissal. Histopathology of the corneal button showed no epithelial cells,
      endothelial cell rarefication, loss of Bowman's layer resulting from PTK, stromal
      edema, a descemetocele with perforation of 1.5 mm in diameter, and
      immunohistochemically Herpes simplex virus in the deep stroma and pre-Descemet.
      CONCLUSIONS: Considering the clinical data and the histopathology we conclude
      that repeat excimer laser phototherapeutic keratectomy of herpetic keratitis
      without antiviral coverage may result in complications.

PMID- 8648985
TI  - [Wyburn-Mason syndrome].
AB  - BACKGROUND: There are various malformations of retinal vessels. Some of them are
      associated with cerebral vascular anomalies. MATERIALS AND METHODS: This report
      is given on a girl 6 years of age with a retinal racemose angioma. RESULTS: The
      clinical examination showed a unilateral racemose angioma combined with
      retinachorioidal anastomosis and a hemifacial vascular malformation. We found
      teleangiectasia in this area. The ophthalmoscopy demonstrated a blurred border of
      optic disc on the right eye with forward protrusion of the disc about + 2.0
      dioptres. Large racemose lesions may be localized to the optic nerve and may
      involve segmental areas of the macula. The ultrasound showed a papillary stasis
      with highly reflective structures. The ultrasonic patterns are interpreted as a
      cholesterosis or fibrovascular tissue. This findings may belong to the rare
      Wyburn-Mason syndrome. Acute neurological symptoms by similar lesions the
      midbrain and hemorrhages during extraction of teeth are reported in literature.

PMID- 8648987
TI  - [Wound rupture 1 year after cataract operation with 7 mm scleral tunnel incision
      (no-stitch technique)].
AB  - BACKGROUND: Wound strength of the self-sealing tunnel technique is much higher
      than the former sutured corneoscleral incision, as many experimental
      investigations have shown. Therefore only a few cases of traumatic wound rupture
      after tunnel incision are published. We report on a traumatic wound rupture with
      loss of the IOL with capsular bag and iris. CASE REPORT: An 80-year-old patient
      suffered a traumatic wound rupture one year after cataract surgery with a 7-mm
      scleral self-sealing wound construction. The IOL with capsular bag and iris were
      expulsed and the wound construction was damaged. By gonioscopy a large irregular
      lesion of the inner lamella could be observed. After pars plana vitrectomy of the
      severe vitreous hemorrhage a visual acuity of 0.5 was achieved. The mechanism of
      the wound rupture is discussed. CONCLUSION: The loss of the iris and the IOL and
      the lesion of the inner lamella suggest a massive force. The yet existing
      relative wound stability after the trauma depends on the still working self
      sealing mechanism of the tunnel construction in spite of the lesion of the inner
      lamella.

PMID- 8648988
TI  - [Combined true exfoliation and pseudoexfoliation of the anterior lens capsule].
AB  - BACKGROUND: True exfoliation of the lens capsule is rare, and its occurrence with
      pseudoexfoliation in the same eye is very unusual. CASE REPORT: An 81-year-old
      female presented with bilateral cataracts and a history of working with ceramics
      in her home kiln. Slit-lamp examination revealed pseudoexfoliation. She underwent
      intracapsular cataract extraction and sector iridectomy in both eyes. Light and
      electron microscopy of the lenses revealed a central area of splitting of the
      anterior lens capsule into a thin anterior and a thicker posterior layer, and
      deposits pseudoexfoliation material on the anterior lens capsule, on the iris
      pigment epithelium, and in the iris stroma. CONCLUSIONS: We interpret our
      findings as representing a combination of true exfoliation and pseudoexfoliation,
      but we did not observe any signs that might indicate a correlation or a common
      pathogenesis of the two conditions. Although they may occur in one eye, true
      exfoliation of the lens capsule and pseudoexfoliation are two unrelated distinct
      entities.

PMID- 8648989
TI  - [Retinal tear in retinochoroiditis toxoplasmotica].
AB  - PATIENT: A 29-year-old white female presented with an episode of recurrent focal
      toxoplasmic retinochoroiditis in her right eye. Apart from a white active lesion
      between the temporal vascular arcades, marked vitreous opacification was present.
      Treatment with oral pyrimethamine and sulfadiazine led to resolution of
      retinochoroiditis activity including vitreous clearing within 10 weeks. Another 3
      weeks later, a fresh peripheral retinal tear was noted on routine fundus
      examination of the right eye. While the left eye showed no signs of vitreoretinal
      pathology, biomicroscopy revealed a posterior vitreous detachment and marked
      vitreous degeneration in the right eye of this emmetropic patient. Prophylactic
      laser treatment was performed. No further abnormalities were observed during a 5
      months follow-up period. CONCLUSION: Retinal tears (and rhegmatogenous retinal
      detachment) are rare complications of toxoplasmic retinochoroiditis. However, a
      tear may occur due to vitreoretinal traction following postinflammatory
      structural alteration of the vitreous. Thus, in toxoplasmic retinochoroiditis the
      diagnostic attention should not be limited to the evaluation of optical
      transparency of the vitreous. Vitreous structure should be assessed as well and
      if structural changes are noted, repeated ophthalmoscopy is mandatory in order to
      detect retinal tears and rhegmatogenous retinal detachment timely.

PMID- 8648991
TI  - [Risk factors for retinal redetachment by proliferative vitreoretinopathy after
      episcleral surgery for pseudophakic retinal detachment].
AB  - BACKGROUND: Conventional buckling procedures in pseudophakic eyes are more often
      than in phakic eyes complicated by proliferative vitreoretinopathy (PVR).
      PATIENTS: The records of 68 patients (68 eyes) suffering from pseudophakic retina
      detachment between January 1988 to March 1993 were evaluated. We analysed the
      frequency of PVR-redetachment and possible risk-factors. RESULTS: Thirteen eyes
      (19%) developed PVR-redetachment after external surgery. Within this group we
      were not able to find a retinal break before or during surgery in 70% of patients
      (9 eyes), compared to 25% of patients in the group without PVR complication.
      CONCLUSIONS: Uncertain visualisation of the retinal break prior to and during
      external surgery along with persistent retinal detachment represent risk factors
      for PVR. Also, extended indentation and cryotherapy during frustrane hole
      localisation is likely to reduce absorption of subretinal fluid and increase
      blood-ocular-breakdown. Both factors are known to raise the risk of PVR. Whether
      or not these severe disadvantages of "blind buckling" can be relieved by primary
      vitrectomy is subject of future investigations.

PMID- 8648990
TI  - [Autoimmune diseases of the peripheral cornea. Immunopathology, clinical aspects
      and therapy].
AB  - Noninfectious ulceration of the peripheral cornea remains a major diagnostic and
      therapeutic challenge. The pathogenesis in most of these disorders is unclear,
      however, on the basis of systemic connective tissue diseases, autoimmune
      mechanisms are most likely involved. The peripheral cornea has distinct
      morphological and immunological characteristics that predispose for inflammatory
      reactions. Major differences exist regarding humoral and cellular components of
      the immune system. In the peripheral cornea there is more high-molecular IgM and
      initial complement component C1 than in the central cornea and may predispose for
      immune complex formation. The close contact to the conjunctival vasculature
      provides the basis necessary to generate an immune response. Langerhans cells and
      macrophages as important antigen presenting and processing cells are present in
      higher number in the peripheral cornea. Autoimmune diseases that affect the
      peripheral cornea include collagen vascular diseases and Mooren's ulcer. Although
      this association is obvious in advanced rheumatoid arthritis more subtle forms of
      polyarteritis nodosa or systemic lupus erythematosus require careful medical
      evaluation and workup. Ocular manifestations may present as the initial clinical
      signs and require careful workup in these potentially lethal disorders.

PMID- 8648993
TI  - [Color Doppler ultrasound of the temporal arteries--a new method for diagnosing
      temporal arteritis].
AB  - BACKGROUND: Recently increasing attention has been paid to temporal arteritis
      which is not a very rare disease. Early establishment of the diagnosis and start
      of therapy can reduce serious visual complications. PATIENTS AND METHODS: The
      temporal arteries of 10 patients with temporal arteritis, 8 patients with
      polymyalgia rheumatica, and 23 controls were investigated with a high resolution
      ultrasound system, measuring size of lumen and wall as well as blood flow
      velocity. RESULTS: Colour doppler sonography of the superficial temporal artery
      showed a characteristic hypoechoic halo around the perfused lumen of an often
      stenosed or occluded artery. Neither patients with polymyalgia rheumatica nor
      controls had this hypoechoic halo. The halo disappeared 10-14 days after start of
      therapy with glucocorticoids. CONCLUSIONS: We think that colour doppler
      sonography of the temporal arteries is a simple, quick, and non-invasive method
      to diagnose temporal arteritis. When there will be more experience, sensitivity
      and specificity of the method can be defined. Perhaps sonography might replace
      biopsy in some cases in the future.

PMID- 8648992
TI  - [Glare sensitivity of phakic and pseudophakic eyes].
AB  - BACKGROUND: Glare disability and appearance of halos may be side-effects of
      cataract, but were also described in patients with multifocal IOLs. The aim of
      this study was to compare glare sensitivity and halo size in phakic and
      pseudophakic eyes. PATIENTS AND METHODS: Contrast sensitivity without and with
      glare and halos around a light source were measured by means of a new
      computerized test in patients with cataract, monofocal IOLs, multizonal
      progressive and diffractive multifocal IOLs as well as in a younger control group
      of subjects with clear lenses. Glare acuity was measured at three different
      luminance settings. RESULTS: Patients with cataract showed the most important
      reduction in contrast sensitivity, noticed significantly larger halos and were
      more impaired in glare acuity than patients with monofocal or multizonal
      progressive IOLs. There was no significant difference in any criteria between
      these two pseudophakic groups. Subjects with a clear cristalline lens had
      statistically significant better results compared with all other groups.
      CONCLUSION: An increase in glare sensitivity and the appearance of halos are more
      important in patients with even minor cataracts than in any pseudophakic
      population. As a consequence of this study, night driving ability should be
      carefully examined in any pseudophakic patient, but also in any subject with even
      beginning cataract.

PMID- 8648995
TI  - [Atrial natriuretic factor].

PMID- 8648994
TI  - [Psychosomatic aspects of patients with primary keratoconjunctivitis sicca].
AB  - PURPOSE: To evaluate the extent of psychosomatical complaints in patients with
      primary keratoconjunctivitis sicca (pKCS). METHODS: 20 patients (m:f = 1.19; mean
      age 49 +/- 7 years) with pKCS were rated according to the von Zerssen Symptom
      List (psychosomatical discomfort), the Maudsley Personality Inventory (MPI)-N
      (emotional status) and -E (extroverted-introverted) and to Beck Depression
      Inventory (BDI). 54 subjects (m:f = 35:17; mean age 46 +/- 17 years) without any
      ocular or general chronic disease were used as control group. RESULTS: In
      comparison to the control group the patients with pKCS showed significantly (p <
      0.0001) more complaints (von Zerssen Symptom List), were more (p < 0.0001)
      emotionally unstable (MPI-N) and more (p < 0.0001) depressive (BDI). No group
      differences were found regarding extroversion-introversion (MPI-E). CONCLUSION:
      Our results demonstrate that many patients with pKCS showed psychological
      problems and disturbances. We therefore recommend an additional psychological
      treatment (e.g. autogenic training) for these patients to stabilize their
      emotional condition, which may even have a positive effect on their dry eye
      problems.

PMID- 8648996
TI  - [Current and prospective uses of hyperthermia in medicine].

PMID- 8648997
TI  - [Assessment of the clinical course of chronic glomerulonephritis].
AB  - Clinical course of chronic glomerulonephritis (CG) with recognition of 4 types by
      frequency of exacerbations was investigated in 592 patients with morphologically
      verified diagnosis observed for a long time. The disease ran a stable course.
      Contrary to patients with mesangioproliferative CG who had rare or moderate
      frequency exacerbations, patients with membranoproliferative disease had
      exacerbations annually. This suggests correlation between the form of anatomical
      changes and the process activity. Irrespective of CG morphological form, the
      survival of CG patients is closely related to the disease course. Taken into
      account, this fact may serve the tool of prognosis, choice of treatment intensity
      and duration of follow-up.

PMID- 8648998
TI  - [Adenomas and adenomyomatosis of the gallbladder].

PMID- 8648999
TI  - [Outpatient treatment and follow-up of adolescents and adults with mucoviscidosis
      in a specialized center].
AB  - Of 49 mucoviscidosis patients benefited more those who received adequate home
      care. These patients had only 1-2 episodes of pulmonary inflammation aggravation
      a year, remained socially active, avoided hospitalization. It is emphasized that
      such patients need continuous follow-up and check-ups.

PMID- 8649000
TI  - [Prevalence of selective lactose malabsorption in Khants].
AB  - The aim of the study was to determine the prevalence of selective lactose
      malabsorption (SLM) in Khants, a small finno-ugric nation living in West Siberia.
      A total of 80 Khants from the Surgut region (Tyumen territory) were studied. The
      diagnosis of SLM was based on the evidence obtained at a 50 g lactose and, if
      possible, a 25 g + 25 g galactose-glucose loads. In 6 cases electron-microscopic
      examination of the duodenal mucosa was performed. The prevalence of SLM in the
      Khants reached 93-94% being the highest in CIS.

PMID- 8649001
TI  - [24-hour variations in cardiovascular and endocrine functions in patients with
      borderline arterial hypertension].

PMID- 8649002
TI  - [Hypoxic factor and its significance in the onset of gastroduodenal diseases].

PMID- 8649003
TI  - [Cardiovascular responses to feeding in patients with ischemic heart disease
      combined with duodenal ulcer].
AB  - Postprandial (after standard breakfast 590.1 kcal) hemodynamic response (PHR),
      vegetative reaction and cimetidine effect were registered in 120 coronary
      patients with duodenal ulcer, 126 patients with duodenal ulcer and 30 healthy
      controls. It was found that PHR is determined primarily by duodenal mucosa
      condition and is independent of baseline type of circulation and antral mucosa
      structure. In normal or slightly changed duodenal mucosa test meal induced
      positive inotropic reaction, a fall in total peripheral vascular resistance,
      cardiac performance index. In marked duodenitis cardiac output is reduced, total
      peripheral resistance and cardiac efficacy grows. Coronary patients with duodenal
      ulcer had duodenitis and more frequent associated severe angina pectoris,
      circulatory insufficiency and gastric acid hypersecretion. Cimetidine in a dose
      400 mg in patients with normal or slightly damaged duodenal mucosa had minimal
      effect on the PHR, whereas in duodenitis patients it prevented negative inotropic
      reaction and rise of the total resistance. Minor sympathetic effect on the sinus
      rhythm entails no increase in double product and cardiac performance efficacy.

PMID- 8649005
TI  - [Complications of food poisoning and salmonellosis].
AB  - During the follow-up of 32,448 patients with food poisoning and salmonellosis
      complications occurred in 665 (2.01%). Among them were general circulation
      disorders (shock), myocardial infarction, acute cerebral vascular accidents,
      mesenterial thromboembolism, pneumonia, acute renal failure (0.09, 0.4, 0.4, 0.1,
      0.5 and 0.6% of patients, respectively). Complications of food poisoning and
      salmonellosis caused lethal outcomes in 0.03% of cases. For the last 15 years
      acute adrenal insufficiency in patients with food poisoning and salmonellosis has
      not been reported.

PMID- 8649004
TI  - [Cerebral hemodynamics and bioelectric activity in patients with bronchial
      asthma].
AB  - Cerebral hemodynamics and bioelectric activity were studied in 40 asthmatic
      patients in remission and exacerbation. It was found that in remission cerebral
      circulation is normal, whereas in aggravation occipitotemporal circulation became
      subnormal. EEG provided evidence for typical for asthmatics rise in beta activity
      against attenuation of alpha activity. These phenomena occurred independently of
      the disease severity.

PMID- 8649007
TI  - [Laryngobronchofibroscopy in the diagnosis and treatment of acute purulent
      mediastinitis].
AB  - Laryngopharynx and tracheobronchial tree were examined in 20 patients with
      purulent mediastinitis (PM) of different origin. Endoscopically, upper posterior
      mediastinitis was characterized by swallowing of membraneous wall into the lumen
      due to pressure outside. The authors recommend diagnostic application of
      laryngobronchofibroscopy to verify PM following traumas of the respiratory tracts
      and therapeutic use of the above procedure to treat PM complications; propose to
      perform nasotracheal intubation using bronchofibroscope as a method of choice in
      prevention of asphyxia in PM patients provoked by laryngeal edema.

PMID- 8649006
TI  - [The hemostatic system in patients with viral hepatitis C].
AB  - Plasmic, platelet and fibrinolytic components of hemostasis were studied in 115
      patients with severe viral hepatitis C transmitted fecally and orally. Most
      informative for determination of the disease severity and prognosis of onset of
      acute hepatic encephalopathy within 1-2 days were plasmic factor II, V, VII, X.
      In genesis of hemorrhagic syndrome of importance is procoagulant deficiency as a
      result of detective synthesis and consumption due to DIC syndrome rather than
      platelet disorder. In addition to procoagulant disorders there were low levels of
      plasminogen and its inhibitors changing with the disease severity.

PMID- 8649008
TI  - [Effect of the antioxidant dibunol on hemostatic parameters in patients with non
      healing ulcers].
AB  - Dibunol, antioxidant drug, made in Russia was given to 42 patients aged 18-59
      with unhealing ulcer 0.64 c 0.06 cm in diameter treated previously without effect
      for 99.74 +/- 30.6 days. Scarring came in 99.6% of cases on treatment day 15.9 +/
      1.23 without appearance of a rough scar. Recurrences occurred 6 months later in
      7.1% of patients. Dibunol did not suppress antioxidant system of the serum,
      lowered serum level of lipid hydroperoxides, stimulated activity of natural
      antioxidants in the mucous gastroduodenal zone, had no effect on hormonal
      homeostasis and blood coagulation.

PMID- 8649009
TI  - [Clinical aspects of Kvamatel (famotidine) administration].

PMID- 8649010
TI  - [Clinical effectiveness of enterosorbents in patients with chronic bronchitis and
      gestational toxicosis].
AB  - The authors studied efficacy of enterosorption with activated coal KM in patients
      with exacerbation of chronic bronchitis and gestosis. The trend in clinical and
      laboratory characteristics of the exacerbation and gestosis, external
      respiration, cellular and humoral immunity gives grounds for validity of using
      enterosorbents in patients with chronic bronchitis and late gestosis.

PMID- 8649011
TI  - [Laser therapy in the comprehensive rehabilitation of patients after myocardial
      infarction].
AB  - The use of laser radiation in a complex of therapeutic measures after acute
      myocardial infarction promoted improvement in a clinical course of the disease,
      stabilization of coronary circulation as shown by ECG, intracardiac hemodynamics
      registered at echo-CG. The latter is able to identify early indications of
      hemodynamic defects. Basing on these data correction of rehabilitation plan is
      made.

PMID- 8649012
TI  - [Effect of low-intensity laser radiation on the metabolic and restorative
      processes of the body].

PMID- 8649013
TI  - [Healing of extensive acute gastric ulcer after chemical burn by Helium-Neon
      laser (endoscopic and morphologic investigation)].
AB  - The paper provides the results of endoscopic and morphologic follow-up of healing
      of extensive corrosive gastric ulcer in He-Ne laser therapy of 34 patients (512
      gastric biopsies). Laser radiation of ulcer reduces frequency of stenosis in
      healing outcome as well as treatment duration, creates conditions for healing
      without leukocytic fusion of necrotic tissues. Effectivity of laser therapy is
      determined by the time of its start and regularity.

PMID- 8649014
TI  - [Diagnostic and therapeutic aspects of B12-deficiency anemia].

PMID- 8649015
TI  - [A case of late syphilis with multisystem lesions].

PMID- 8649017
TI  - [A familial case of Ehlers-Danlos syndrome type VIII].

PMID- 8649016
TI  - [A case of multiple basalomas].

PMID- 8649018
TI  - [A rare case of malignant schwannoma of the small intestine].

PMID- 8649019
TI  - [Effect of pentagastrin in ulcer patients with postgastroresection syndrome].

PMID- 8649020
TI  - [Clinical assessment of autoimmune and immunocomplex reactions in patients with
      leptospirosis].

PMID- 8649021
TI  - [Diet therapy in diffuse progressive nephropathies].

PMID- 8649022
TI  - [Classification of erosive alterations of gastric and duodenal mucosa].

PMID- 8649023
TI  - [Robert Koch (1843-1910)].

PMID- 8649024
TI  - [Pathogenesis of heat inhalation injury in burn patients].

PMID- 8649025
TI  - The posttraumatic pulmonary mass.
AB  - Each year approximately 2 million people are seriously injured in traffic
      accidents. Injuries to the chest play a major role in the mortality and morbidity
      of these patients. One-third to one-half of motor vehicle crash victims suffer
      blunt thoracic trauma. The spectrum of injuries is broad but posttraumatic
      pulmonary masses are rarely noted. The proper use of radiographic imaging
      procedures allows documentation of pulmonary hematoma and exclusion of more
      ominous lesions.

PMID- 8649026
TI  - When Goody's Powder is not so good.

PMID- 8649028
TI  - The great imposter.

PMID- 8649029
TI  - Neck pain in a young woman.

PMID- 8649027
TI  - Penetrating wound to the shoulder: a case report that illustrates the need for a
      multisystem approach to injury.

PMID- 8649031
TI  - Maternal/fetal death.

PMID- 8649032
TI  - When the board comes a'callin'.

PMID- 8649030
TI  - Improving emergency medical care for pediatric patients.

PMID- 8649033
TI  - A need to study utilization of inhospital volunteer manpower for hospitalized
      adult cancer patients.

PMID- 8649034
TI  - Ramblings from an AMA ex-delegate.

PMID- 8649035
TI  - An HMO Christmas story.

PMID- 8649036
TI  - Oxygenation in tumors by modified hemoglobins.
AB  - The effect of systemic injection of modified hemoglobin (Hb) prepared from
      bovine, human, or mouse Hb on tumor oxygenation was investigated. Hb was modified
      by (1) diisothiocyanatobenzenesulfonate (DIBS) to yield cross-linking within a
      tetramer; (2) glycolaldehyde (Glyal) to yield cross-linking between and within
      tetramers; (3) carboxymethylation (Cm) to change oxygen affinity; or (4)
      poly(ethylene glycol) (PEG) to yield attachment between tetramers. HGL9 (human
      glioma) in nude mice and FSaII (mice fibrosarcoma) in C3H mice were used as tumor
      models. Dose and time dependency were detected in the oxygenation effect by
      bovine-PEG-Hb. Internal cross-linkage prolonged the half-life in the circulation,
      and thus showed a significant effect. Compared to bovine-CmHb, bovine-DIBS-Hb and
      bovine-DIBS-CmHb were more effective. Decreasing the oxygen affinity by Cm
      significantly enhanced tumor oxygenation. Human-DIBS-CmHb was more effective than
      human-DIBS-Hb. These effects were caused by oxygen carrying capacity of modified
      Hbs as well as hemodynamic factors, and the injection seemed to reduce both
      perfusion-limited (acute) and diffusion-limited (chronic) hypoxia.

PMID- 8649037
TI  - Postoperative recurrence of solitary small hepatocellular carcinoma.
AB  - The prognosis of hepatocellular carcinoma after hepatic resection remains poor.
      The major cause is postoperative recurrence, most frequently intrahepatic. During
      the past 7 years, we conducted a detailed study of recurrence after hepatectomy
      in 34 patients with solitary small hepatocellular carcinoma measuring no larger
      than 4 cm in diameter, in which 13 cases had postoperative recurrent tumors, and
      two cases were considered multicentric. Eighty-five percent of recurrences were
      diagnosed at 6-18 months after the operation. The cumulative recurrence rates
      were 61% at 5 years after operation. When analyzing the factors affecting
      recurrence, a significant difference was observed regarding tumor diameter. After
      recurrence, most patients underwent percutaneous ethanol injection treatment
      and/or transcatheter arterial chemoembolization and lipiodolization. Four
      patients died of progressive disease within 1 year after recurrence; the
      treatment thus seemed to have no effect. The other patients with recurrence
      remain alive with the disease. The overall cumulative survival rates in this
      series were 76% at 3 years and 60% at 5 years after operation. To obtain better
      results after hepatectomy, even for small hepatocellular carcinoma, careful, long
      term follow-up evaluation is therefore necessary for the multidisciplinary
      treatment of the postoperative recurrence, as well as the early diagnosis of
      tumors in high-risk patients.

PMID- 8649038
TI  - Fatal differentiated thyroid cancer.
AB  - Thirty-five patients who died of differentiated thyroid cancer were analyzed for
      factors affecting survival. The neck was the most common initial site of
      recurrence (62.0%). The lung was the most common metastatic site (56.7%). Major
      sites associated with death were locoregional recurrence (neck and mediastinum:
      48.6%) and bone metastases (22.9%). By univariate analysis, local tumor
      extension, type of initial surgery, and residual tumor and/or existence of
      distant metastases at the initial operation were significant factors affecting
      survival. Stepwise multivariate analysis revealed that invasion of the esophagus
      and/or carotid artery shortened survival and that multiple surgeries extended
      survival. Our results suggest that to improve survival in patients with
      differentiated thyroid cancer, better locoregional control, including multiple
      surgical resection, is necessary.

PMID- 8649039
TI  - Effect of intraperitoneal chemotherapy and fibrinolytic therapy on tumor
      implantation in wound sites.
AB  - Failure of surgical treatment for gastrointestinal cancers is often caused by
      recurrence of the tumor in traumatized peritoneal surfaces. This study examined
      the effect of intraperitoneal administration of doxorubicin and recombinant
      tissue plasminogen activator (rt-PA), a fibrinolytic agent, on incidence and
      volume of postoperative tumor implants in peritoneal wounds. Prior to
      randomization, a surgical wound was created on the right parietal peritoneum of
      110 BDIX rats and 6 x 10(5) DHD/K12 colon cancer cells were inoculated
      intraperitoneally (ip). The control group was given an intraperitoneal injection
      of saline. Five groups received 1 mg/kg of ip doxorubicin at different times
      postoperatively: at the end of surgery (D0), 3 hr after surgery (D + 3),
      postoperative day 1 (D1), postoperative day 3 (D3), and postoperative day 7 (D7).
      In a second set of experiments, five groups of rats received, in addition to
      postoperative doxorubicin, 5 mg/kg of intraoperative ip rt-PA. Incidence and
      volume of tumor implants in peritoneal wounds were assessed for each group 20
      days after the tumor inoculation. All rats of the control group (incidence =
      100%) developed tumor implants in peritoneal wounds. Mean (SD) volume was 16.2
      (4.7) mm3. When administered at D0, D + 3, and D1 intraperitoneal doxorubicin
      reduced significantly the incidence and volume of tumor implants in wounds.
      Postoperative administration of doxorubicin at D3 and D7 did not affect
      significantly the incidence and the volume of tumor implants in peritoneal
      wounds. When rt-PA was administered intraoperatively, ip injection of doxorubicin
      at any postoperative timing decreased significantly the incidence and volume of
      tumor implants. In conclusion, ip doxorubicin administered before postoperative
      D3 may act on tumor cell implanted in peritoneal wounds. Delayed (D3, D7) ip
      administration of doxorubicin does not prevent the development of tumor implants
      in peritoneal wounds. Intraoperative administration of rt-PA may significantly
      increase the efficacy of delayed ip chemotherapy.

PMID- 8649040
TI  - Pharmacokinetics of cis-diamminedichloroplatinum (II) given as low-dose and high
      dose infusions.
AB  - A pharmacokinetic analysis of cis-diamminedichloroplatinum (II) (DDP) was
      conducted comparing low-dose daily bolus infusions, and high-dose drip infusions.
      Eight patients with gastric cancer were treated with low-dose daily bolus
      infusions of DDP to a total daily dose of 75 mg/m2 bid for 5 days. Four patients
      with esophageal cancer and one patient with gastric cancer were treated with high
      dose drip infusions of DDP to a total daily dose of 70-80 mg/m2. Side effects
      were assessed in all the patients, and the platinum concentration in plasma was
      determined by an atomic absorption method. The peak plasma concentration (Cmax)
      and area under the curve (AUC) were calculated in four cases of the low-dose
      therapy, and three cases of the high-dose therapy. The side effects of DDP were
      evaluated according to the World Health Organization (WHO) grading, paying
      particular attention to nausea/vomiting, appetite loss, renal toxicity, and bone
      marrow suppression. The incidence of nausea/vomiting and appetite loss was
      significantly reduced with low-dose daily bolus infusions when compared to the
      high-dose drip infusions. Bone marrow toxicity and renal toxicity were similar
      with both administration methods, although hydration was required for the high
      dose drip infusions to prevent renal toxicity. The peak plasma concentration
      (Cmax) of total and free platinum, and the area under the curve (AUC) of total
      platinum, were similar with both administration methods, while the AUC of free
      platinum was higher with the low-dose daily bolus infusions compared to the high
      dose drip infusions. The time when the concentration of total platinum was > 1
      microgram per ml (holding time) was significantly longer with the high-dose drip
      infusions than with the low-dose daily bolus infusions. The present study
      suggests that low-dose daily bolus infusions of DDP would be useful in reducing
      gastrointestinal toxicity, without reducing the area under the curve which is
      important for antitumor activity.

PMID- 8649041
TI  - AgNORs and their relationship to cell size, histological grade, lymph node
      involvement, metastases, and survival pattern in carcinoma of the breast: a study
      from south India.
AB  - An AgNOR count using the Smith and Crocker [Histopathology 12:113-125, 1988]
      method of staining was performed on 200 cases of carcinoma of the breast. A count
      of coarse AgNORs per nucleus was made on 50 random cells and the mean of their
      number per nucleus calculated. The relationship of a single variable "AgNOR
      count" to other variables such as cell size, histological grade, number of
      positive ipsilateral axillary lymph nodes, and presence of metastasis in regions
      other than the ipsilateral axillary lymph nodes was found using a univariate
      method of analysis. Also, the effect of different independent variables, e.g.,
      number of AgNORs, cell size, histological grade, number of positive axillary
      lymph nodes, and metastasis on a single variable, i.e., 4-year period of
      survival, was also assessed by a univariate method of statistical analysis. It
      was found that the AgNOR count was significantly related to the cell size,
      histological grade, and presence of metastasis. Large cells, grade III tumors,
      and neoplasms with evidence of metastasis showed larger numbers of AgNORs in
      their nuclei. It was observed that the number of AgNORs significantly affected
      the 4-year survival of patients. The higher the AgNOR counts, the poorer were the
      chances of surviving for 4 years. The other factors that influenced survival in
      the present study were the number of positive axillary lymph nodes and metastasis
      to sites other than axillary lymph nodes.

PMID- 8649042
TI  - Cutaneous metastases from prostatic carcinoma.
AB  - Cutaneous metastasis from carcinoma of the prostate is a rare phenomenon. When it
      occurs, metastases usually appear as multiple nodules involving the suprapubic
      area and the anterior aspect of the thighs. We report on two cases of cutaneous
      metastases from prostatic carcinoma, one of them presenting the stereotypical
      clinical and histopathological findings, whereas in the other one cutaneous
      metastasis consisted of a morphea-like plaque on the chest. Histopathologically,
      the later case revealed accumulations of neoplastic cells distributed in a
      folliculotropic pattern. In both examples immunohistochemical study with
      prostatic specific antigen (PSA) confirmed the prostatic origin of the
      metastases. We review the literature on this subject.

PMID- 8649043
TI  - Primary leiomyosarcoma of the ureter.
AB  - We report the thirteenth case of primary leiomyosarcoma of the ureter, as well as
      a summary of previous cases. It is the first case reported to be studied by
      computer tomography and immunohistochemical procedure. Further evaluation
      included intravenous pyelogram, cystoscopy with retrograde pyelogram, cell block
      for cytology, and electron microscopy. Leiomyosarcoma is a very rare disease that
      is difficult to diagnose. It has a very poor 5-year disease-specific survival.

PMID- 8649044
TI  - Sentinel lymphadenectomy in primary breast carcinoma: an alternative to routine
      axillary dissection.

PMID- 8649045
TI  - A new model of active specific immunotherapy using interleukin-1 and sonicated
      tumor supernatant in murine tumor system.
AB  - The possibility of active specific immunotherapy using interleukin-1 (IL-1) plus
      sonicated tumor supernatant (SS) was examined in a murine tumor model. The growth
      of intraperitoneally or subcutaneously inoculated plasmacytoma MOPC104E, which is
      syngeneic to BALB/c mice, was significantly suppressed by intraperitoneal
      pretreatment with IL-1 and SS from MOPC104E cells (MOPC-SS), on days 10, 7, and 4
      before tumor inoculation. Pretreatment with IL-1 plus MOPC-SS or MethA-SS (SS
      from MethA cells) suppressed the growth of subcutaneous tumor of only the
      corresponding tumor cells, indicating the development of tumor-specific immunity
      in vivo. The splenic cells of immunized mice with IL-1 and MOPC-SS showed tumor
      neutralizing activity. However, their tumor neutralizing activity was abrogated
      when they were treated in vitro with anti-Thy1.2 or anti-L3T4 plus complement.
      Moreover, when combined with indomethacin per oral, IL-1 plus MOPC-SS
      significantly suppressed the growth of established subcutaneous tumor and
      prolonged survival of post-operative mice. These results suggest that this new
      type of active specific immunotherapy could be a useful method for cancer
      immunotherapy, especially when combined with oral indomethacin.

PMID- 8649047
TI  - High mortality after abdominal operation in patients with large-volume malignant
      ascites.
AB  - Advanced intra-abdominal cancers are frequently associated with malignant
      ascites. The aim of this study was to document the frequency and clinical course
      of patients found to have large-volume ( > or = 3 L) malignant ascites when
      undergoing a major abdominal operation. Between October 1, 1987 and September 1,
      1992, 385 patients with malignant ascites were admitted to hospitals associated
      with a university medical center. Seventeen with large volume ascites underwent
      exploration for palliation of bowel obstruction or debulking of tumor. Operative
      mortality was 41% and mortality correlated with the presence of a nonovarian
      primary and advanced age. We conclude that patients with large volume nonovarian
      malignant ascites have a high mortality rate following a major abdominal
      operation. New approaches such as neoadjuvant or intraperitoneal chemotherapy or
      possibly peritoneovenous shunt placement at the time of the abdominal operation,
      are needed to improve the dismal results in this subgroup of patients.

PMID- 8649046
TI  - Node negative breast carcinoma: hyperprolactinemia and/or overexpression of p53
      as an independent predictor of poor prognosis compared to newer and established
      prognosticators.
AB  - The purpose of this study was to investigate a prognostic indicator that can
      differentiate node negative breast cancer patients (N = 39, T2N0M0) with high
      risk and low risk for the development of recurrence or metastases. Preoperative
      plasma prolactin (PRL) was estimated by radioimmunoassay. The expression of PRL,
      p53, nm23, and c-erbB2 was investigated by immunohistochemical (IHC)
      localization; cathepsin D (CD, Enzyme Linked Sorbant Assay) and estrogen- and
      progesterone-receptors (ER and PR, Dextran coated charcoal method) were estimated
      in the tumor cytosols. The follow-up period was 2-6 years. Statistical
      comparisons were made between each marker for relapse-free survival (RFS) and
      overall survival (OS). Of the 39 patients, 18 had hyperprolactinemia (PRL > 20.0
      ng/ml plasma), whereas overexpression of p53 was observed in 55% (17/31) tumors.
      These were independently and in combination associated with a reduced RFS and OS.
      The rest of the investigated markers did not show promising results.
      Hyperprolactinemia and/or overexpression of p53 were associated with
      aggressiveness of the tumor, early disease relapse or metastases, and poor OS in
      patients with node negative breast cancer. These two markers may enhance our
      ability to identify node negative breast cancer patients with aggressive tumors,
      for whom the use of adjuvant chemo and/or endocrine therapy is unequivocally
      justified.

PMID- 8649048
TI  - Significance of spontaneous apoptosis during colorectal tumorigenesis.
AB  - To determine if apoptosis is involved in colorectal tumorigenesis and its
      progression, colorectal adenomas (n = 63), carcinomas (n = 49), and normal mucosa
      were investigated by using in situ end-labeling (TUNEL) method. The expression of
      Ki-67 was also analyzed immunohistochemically. TUNEL labeling index (TLI) and Ki
      67 labeling index (KLI) were determined. TLI/KLI was significantly higher in the
      adenomas of small size and/or of low and middle grade atypia than those of large
      size and/or of high grade atypia. No difference was observed in the indices
      between adenomas and carcinomas and among the cancer groups classified on the
      basis of their clinicopathological features. The results indicate that the
      reduction of susceptibility to apoptosis plays an important role in the early
      stage of the adenoma-carcinoma sequence. Apoptosis can explain the enormous cell
      loss thought to exist in normal colorectal mucosa and in the tumor growth
      process.

PMID- 8649049
TI  - The repression of apoptosis by activated abl oncogenes in chronic myelogenous
      leukaemia.
AB  - The formation of the unique fusion gene, bcr-abl, and the resultant increase in
      abl tyrosine kinase activity, is seen as the major driving force in the
      initiation of chronic myelogenous leukaemia (CML). The deregulation of abl
      tyrosine kinase activity, brought about by the binding of a portion of the Scr
      molecule to the SH2 regulatory domain of abl, appears to play a role in promoting
      resistance to drug-induced apoptosis. Thus the large increase In mature myeloid
      cells seen in CML could be the direct result of the suppression of apoptosis by
      the bcr-abl fusion protein. The role and contribution of apoptosis in the
      progression of CML and the possible role of antisense oligonucleotides to the bcr
      abl gene as therapeutic agents is discussed.

PMID- 8649050
TI  - Collection, analysis and transplantation of Ph-negative blood precursor cells in
      chronic myeloid leukemia.
AB  - This work represents an update of our experience on mobilization and
      transplantation of peripheral blood progenitor cells (PBPC) collected during the
      early recovery phase after chemotherapy in patients with chronic myelogenous
      leukemia. The collection of Ph-negative precursor cells occurred in 13/19 (68%)
      patients mobilized within the first year from diagnosis and not previously
      treated with interferon alpha (IFN-alpha). Fourteen out of 42 patients (33%)
      achieved Ph-negative precursors beyond 1 year from diagnosis. Eleven patients
      mobilized early after diagnosis were subsequently autografted with Ph-negative
      precursor cells. All patients are alive in hematologic remission and five of them
      maintain Ph-negativity in the marrow 7-15 months post-autograft. Four patients
      showed recurrence of Ph-positive cells (5 to 40%) within 4 to 8 months after
      autografting. Two patients became progressively Ph-positive after 6 months and
      are now 100% Ph-positive and in stable chronic phase. In the early stage of the
      disease the mobilization/transplantation procedure is safe and associated with
      very good compliance. However, occasional restoration of Ph-negative
      hematopoiesis could occur up to 45 months after autograft in patients undergoing
      the procedure beyond 1 year from diagnosis, and highly pretreated with IFN-alpha,
      but most patients revert to Ph-positive hematopoiesis. In an attempt to control
      the Ph-negative status and to prevent cytogeneic relapse, we are currently
      treating autografted patients with low doses of IFN-alpha and interleukin-2 (IL
      2). Whether and for how long Ph-negative status can be maintained is a matter for
      future observation and effort.

PMID- 8649051
TI  - Differentiating therapy in acute myeloid leukemia.
AB  - Differentiating therapy is a new antineoplastic strategy which has received
      increasing attention due to the remarkable activity of the vitamin A derivative,
      all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia
      (APL). Although it has been known for years that a variety of agents, including
      retinoids, could induce leukemic cells to differentiate in vitro, it was not
      until the initial report from Shanghai in 1988 that laboratory studies translated
      into clinical activity and benefit in patients. Since this initial report, a
      number of studies have confirmed that the majority of patients with both newly
      diagnosed and previously chemotherapy-treated patients with APL achieve complete
      remission (CR) with ATRA. In addition, the characteristic life-threatening
      coagulopathy resolves quickly. Several limitations to this approach have emerged,
      including the development of retinoid resistance, hyperleukocytosis and the
      retinoic acid syndrome, a constellation of findings including unexplained fever,
      fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although
      ATRA is very effective in inducing CR, its benefits compared to conventional
      chemotherapy are only now being addressed. The first prospective randomized trial
      comparing ATRA plus chemotherapy to chemotherapy alone was terminated early
      because of an improved event-free survival for patients receiving ATRA. The
      benefit was attributable to a difference in relapse rate. A large, intergroup,
      prospective, randomized trial comparing conventional chemotherapy to ATRA for
      induction and ATRA to observation for maintenance has recently completed accrual
      and will provide insight into the emerging role of ATRA in patients with APL.
      ATRA represents the first example of a specific form of antileukemic therapy
      targeting a specific genetic abnormality and may serve as a paradigm for the
      development of differentiating therapy for patients with other hematologic
      malignancies.

PMID- 8649052
TI  - Treatment of minimal residual disease in acute myelogenous leukemia (AML): focus
      on immunotherapeutic options.

PMID- 8649053
TI  - The role of anthracyclines in adult acute lymphoblastic leukaemia.
AB  - The role of anthracyclines (ANT) in the treatment of adult acute lymphoblastic
      leukaemia (ALL) is poorly defined as regards drug dosage, schedule, preferable
      compound, and indications for use in specific treatment phases or disease subset.
      We therefore reviewed ANT treatment results in adult ALL. Altogether, an early
      and intensive use of ANT would improve both initial response rate and long-term
      disease-free survival; idarubicin (IDR) exhibits a considerable antileukaemic
      activity deserving further evaluation as possible reference drug; and the
      prognosis of CD10+ t(9;22)/BCR-ABL- ALL can be particularly good following an
      early dose-intensive ANT consolidation program.

PMID- 8649054
TI  - Who are the high-risk patients with Hodgkin's disease?
AB  - The opinions concerning the prognosis of relapsing Hodgkin's disease (HD) are
      conflicting, although a number of clinical and biological parameters have been
      Identified. One reason is the rarity of large scale studies, another is the
      variability of populations and pretreatments In this particular disease, all
      factors that influence the relative weight of these parameters. Conversely, a
      large number of prognostic studies have been published in newly diagnosed HD,
      whether they concerned advanced or localized patients. Surprisingly, not so many
      parameters are common to these studies. Therefore, prognostic indexes are hardly
      usable, except if taken with great prudence. These uncertainties hamper the
      possibilities of conducting ample controlled studies designed to assess the best
      treatment modalities for high-risk HD, for both advanced or localized patients.

PMID- 8649055
TI  - Is ABVD the standard regimen for Hodgkin's disease based on randomized CALGB
      comparison of MOPP, ABVD and MOPP alternating with ABVD?

PMID- 8649056
TI  - High-dose therapy autologous stem cell transplantation vs conventional therapy
      for patients with advanced Hodgkin's disease responding to first-line therapy:
      analysis of clinical characteristics of 51 patients enrolled in the HD01
      protocol. EBMT/ANZLG/Intergroup HD01 Trial.
AB  - Whether high-dose therapy (HDT) plus autologous stem cell transplantation (ASCT)
      ought to be included in the initial treatment plan for those patients with
      unfavourable Hodgkin's disease, a wide cooperative study (HD01 protocol) was
      approved, comparing HDT followed by ASCT vs conventional chemotherapy (CT).
      Patients were eligible for the study if they had at least two of the following
      adverse prognostic factors: high serum LDH levels, mediastinal mass >0.45, more
      than one extranodal involved site, low hematocrit (<34% for women and <38% for
      men), and inguinal involvement. Those patients achieving complete or partial
      remission with four courses of ABVD or ABVD-containing chemotherapy were
      randomized to receive either HDT plus ASCT or four additional courses of
      chemotherapy, followed by ASCT in second remission, if appropriate. Between April
      1993 and September 1995, 55 patients from 14 different centers have been enrolled
      into the trial. Twenty patients (45%) were in stage IV, and 37 patients (84%) had
      systemic symptoms. Twenty-seven patients (61%) had two adverse prognostic
      factors, and 17 patients (39%) had three or more risk factors. After four cycles
      of ABVD-containing CT, 44 patients were assessable for response. Overall 12
      patients achieved CR (27%), 25 obtained a PR (57%) and seven patients failed to
      respond (16%). Thirty-six patients were randomized between ASCT (20 patients) or
      four additional cycles of conventional CT (16 patients). With a median follow-up
      after ASCT of 13 months (range 1-23 months), no major ASCT-related toxicity has
      been reported to the trial office. In conclusion, the first 44 patients
      registered in the HD01 trial and assessable for response, had a very aggressive
      disease and responded poorly to conventional CT, thus warranting a more
      aggressive approach, such as HDT followed by ASCT.

PMID- 8649057
TI  - Hodgkin's disease: chromosomes and genetics.

PMID- 8649058
TI  - Hodgkin's disease: from basic science to clinical application.
AB  - Although the pathogenesis of Hodgkin's disease is not clear, molecular analyses
      revealed characteristic features which proved the clonal origin of the disease.
      EBV injection can be demonstrated in more than 50% of cases at the DNA or protein
      level. Recently, immunoglobulin gone rearrangements were found in single Hodgkin
      and Reed-Sternberg cells. These rearrangements may be used as defined markers to
      detect residual disease after chemotherapy. This is of importance for the
      treatment of advanced stages, since about 50% of patients in this group will not
      be cured, and attempts are made to improve treatment results by high-dose
      chemotherapy. Salvage therapy for relapsed patients including high-dose
      chemotherapy with autologous stem cell support frequently results in remission
      although duration is generally short. New immunotherapy strategies with
      immunotoxins or bispecific antibodies are currently analyzed in clinical studies.

PMID- 8649059
TI  - Mantle cell lymphoma: a lymphoproliferative disorder associated with aberrant
      function of the cell cycle.
AB  - Mantle cell lymphoma is a B cell lymphoproliferative disorder cytogenetically
      characterized by the t(11;14)(q13;q32) which at molecular level involves the Bcl
      1/PRAD-1 gene. Immunophenotypically it is characterized by co-expression of
      CD5+/CD20+ and CD23- antigens. Histologic patterns are recognized as: diffuse,
      mantle zone and nodular. Diffuse mantle lymphoma is the most frequent and is
      associated with a poor prognosis. The rearrangement of the Bcl-1/PRAD-1 increases
      the synthesis of cyclin D1. Cyclin D1 binds to Cdk4 and forms a complex, then
      binds to and phosphorylates Rb protein thus triggering cells to progress from
      G0/G1 to S and thus drives cellular proliferation. The 5-year survival in the MD
      Anderson series was less than 30% and anthracycline regimens do not appear to
      have any major impact on the outcomes of cases with nodular or diffuse
      histopathological patterns. Intensive therapeutic programs and first line
      autologous or allogeneic bone marrow transplantation remains experimental.

PMID- 8649060
TI  - Epstein-Barr virus in T and natural killer (NK) cell non-Hodgkin's lymphomas.
AB  - Several studies using sensitive in situ hybridization techniques show that, in
      non-immunocompromised patients, Epstein-Barr virus (EBV) is more frequently
      detected in lymphomas expressing T cell markers than in B cell lymphomas. Among
      lymphomas expressing T cell markers, the presence of EBV is highly related to the
      site of origin of the tumor, being found in nearly all sinonasal lymphomas, in
      only a proportion of Waldeyer's ring, lung, gastrointestinal and nodal lymphomas,
      and undetectable in most primary cutaneous lymphomas. The role of EBV in their
      pathogenesis can be suggested in at least a proportion of extranodal lymphomas
      (nasal, lung, Waldeyer's ring, gastrointestinal) with T cell markers in which EBV
      genome is found in most if not all tumor cells (EBV-associated lymphomas) and the
      transforming LMP-1 protein is frequently expressed. Among these, sinonasal
      lymphomas constitute a distinct clinicopathologic entity which may present as
      lethal midline granuloma, are strongly associated with EBV and can be regarded in
      most cases as true NK cell lymphomas.

PMID- 8649062
TI  - Liposomal and lipid-based formulations of amphotericin B.
AB  - Encapsulating amphotericin B (AmB) into liposomes or binding of AmB to other
      lipid carriers results in a significant reduction of toxicity of AmB and possibly
      an increased therapeutic index. Following promising clinical results with
      investigational formulations, three industrial compounds have been developed:
      AmBisome, Amphocil (Amphotericin B Colloidal Dispersion) and Amphotericin B Lipid
      Complex (ABLC, Abelcet). These three formulations differ significantly in
      composition and pharmacokinetics. AmB serum levels after ABLC and Amphocil
      administration are low, but after AmBisome much higher. However, the
      interpretation of the pharmacokinetic data is hampered by the inability to
      separate free AmB fractions from tissue-, protein- and lipid carrier bound
      fractions. All three compounds share a considerable reduction of nephrotoxicity.
      However, the acute reaction rates differ among these compounds. Amphocil showing
      the highest and AmBisome the lowest rate. Unfortunately, efficacy data of ongoing
      trials comparing these formulations with conventional AmB are scarce. Therefore,
      for the moment we can recommend these compounds only in cases of intolerance to
      or failure on AmB therapy. The optimal therapeutic dosages have not been
      established, but dosages as low as 1 mg/kg should be avoided in the initial
      treatment of fulminant fungal infections, since efficacy may be inferior to equal
      doses of conventional AmB.

PMID- 8649061
TI  - Mobilization/transplantation of peripheral blood progenitor cells for aggressive
      non-Hodgkin's lymphoma with marrow involvement.
AB  - Thirty-five aggressive non-Hodgkin's lymphomas (NHL) with marrow involvement
      received high-dose cyclophosphamide (7 g/m2) and G-CSF in order to collect
      peripheral blood progenitor cells (PBPC). Fourteen patients were in partial
      remission, 16 patients were in relapse ('sensitive', 12; 'resistant', 4) and five
      patients were refractory to conventional treatment. A good yield of PBPC was
      obtained in 30 patients, while a low number of CD34+ cells and of CFU-GM was seen
      in two cases. Two patients entered progression and one patient died. Thirty
      patients underwent PBPC autografting. Twenty-nine out of 35 (83%) patients
      entered complete remission (CR). Two patients died in CR of infection following
      marrow aplasia 3 and 6 months after autografting. At 3 years the probability of
      survival and disease-free survival (DFS) are 62 and 51%, respectively.

PMID- 8649065
TI  - [How to distribute organs equally?].

PMID- 8649064
TI  - [A new clinical audit model for primary health care. Health centers are inspected
      for quality control].

PMID- 8649063
TI  - [Physicians at the top security criminal institution in the country. Feeling of
      safety may rapidly turn to fear].

PMID- 8649066
TI  - [Misleading information on pertussis vaccine].

PMID- 8649067
TI  - [Loyal to the physician or to ethics?].

PMID- 8649068
TI  - [The laser man returns, blushing].

PMID- 8649069
TI  - [Signing the prescriptions reduces the risk of errors].

PMID- 8649070
TI  - [Advertising of soap for feminine hygiene is being over-done].

PMID- 8649071
TI  - [It is incorrect to talk in absolute terms about the site of the arcuate
      nucleus].

PMID- 8649073
TI  - [Reperfusion in myocardial infarction: a two-edged sword].

PMID- 8649072
TI  - [Meningococcal infection is a threat to the community. The outbreak in Skane may
      serve as a warning].

PMID- 8649074
TI  - [Old principles for th treatment of obesity are still valid. Diet and exercise
      are still the most important factors].

PMID- 8649076
TI  - [An (inter)national resource. The Swedish registry on twins informs on the role
      of environment and heredity in diseases].

PMID- 8649075
TI  - [HIV is a threat even to eye-sight. Cooperation between clinics has improved
      diagnosis and treatment].

PMID- 8649077
TI  - [A warning in the Risk Registry: acute scrotal-testicular torsion--until
      something else is detected].

PMID- 8649078
TI  - [A study of children with retinoblastoma. Diagnosis is often delayed].
AB  - Retinoblastoma is an uncommon but highly malignant ocular tumour of the early
      childhood. The delay in diagnosis following presentation at a health care
      facility was studied for 22 consecutive cases derived from the National
      Retinoblastoma Center in Sweden. Four of the children were regularly examined
      owing to a family history of retinoblastoma, but among the remaining 18 children
      the delay in diagnosis exceeded one month in five cases (including all children
      presenting with squint). However, there was no appreciable delay once appropriate
      fundus examination had been performed, thus stressing the need of early
      ophthalmological assessment in all cases of children manifesting signs consistent
      with retinoblastoma.

PMID- 8649079
TI  - [Laboratory diagnosis of MS. Multiple sclerosis can be traced in the
      cerebrospinal fluid].

PMID- 8649080
TI  - ["Prao" at DN. Three weeks of training at the largest daily paper in Sweden
      financed by the medical research committee grant].

PMID- 8649081
TI  - [Euthanasia--an outdated idea?].

PMID- 8649082
TI  - [Patients' rights are too physician-oriented].

PMID- 8649083
TI  - [One third of the nursing education program is not on the university level].

PMID- 8649085
TI  - [Scrutinizing information:"Negative publicity is the best sanction". The text of
      FASS (a drug index) is not an absolute norm].

PMID- 8649084
TI  - [30 million dollars as the highest compensation so far. American hospitals salt
      the bills].

PMID- 8649086
TI  - [Problems will not be solved by abolishing forensic psychiatry. New problems will
      appear instead].

PMID- 8649087
TI  - [Death of two elderly physicians. Is euthanasia an expression of diminishing
      humanism?].

PMID- 8649088
TI  - [Health resources should be managed jointly. Prioritization should be decided by
      cooperation of responsible authorities].

PMID- 8649089
TI  - [Do cholesterol-lowering drugs cause cancer?].

PMID- 8649090
TI  - [Fibromyalgia and central sensitization].

PMID- 8649091
TI  - [An injectable nature product is condemned].

PMID- 8649092
TI  - [Hospital physicians--general practitioners and continuity of health care].

PMID- 8649093
TI  - [The physician-in-chief must follow the rules of the game].

PMID- 8649094
TI  - [Follow-up of colorectal polyps--is it really beneficial?].

PMID- 8649095
TI  - [Vaccination against hepatitis A gives protection fast. Combination with gamma
      globulin is probably unnecessary].

PMID- 8649096
TI  - [Anatomy and genetics of mental disorders. New findings in schizophrenia
      research].

PMID- 8649097
TI  - [Deficient care of children with functional disabilities. Insecure relationship
      between child health services and parents].

PMID- 8649098
TI  - [A case report on burns caused by ready-mixed cement. Need for emergency
      assessment in skin injury for possible referral].

PMID- 8649099
TI  - [Ophthalmology on CD-ROM. See more and better with new technology].

PMID- 8649100
TI  - [New discoveries on sex differences in the brain. Men lose their brain tissue
      earlier than women].

PMID- 8649101
TI  - [Unilateral injection with the patient in lateral position. Simpler pain blockade
      in pancreatic cancer].

PMID- 8649103
TI  - [Differentiate between individual and group insurance. The insurance premium is
      not to be used as a tool in insurance selection bias].

PMID- 8649102
TI  - [Utilization of patient questionnaires. A new promising method tested at three
      different ophthalmology clinics].

PMID- 8649104
TI  - [Depression in a child treated with Pulmicort Turbuhaler].

PMID- 8649105
TI  - [Salmeterol-induced enuresis in children].

PMID- 8649106
TI  - [An original Sida-project contributes to better drug control in Laos].

PMID- 8649107
TI  - [Can health services learn something from industry? Read issue 51-52/95! What
      happened since?].

PMID- 8649108
TI  - [Screening for breast cancer saves money].

PMID- 8649109
TI  - [Selenium toxicity].

PMID- 8649110
TI  - [A "loyal" chief physician is not very popular among the public].

PMID- 8649111
TI  - [The physician must not put himself before his patient].

PMID- 8649112
TI  - [How do we succeed in the fight against stomach cancer?].

PMID- 8649113
TI  - [Two different HIV types are known. The differences may explain mechanisms of the
      infection].

PMID- 8649114
TI  - [Mild mental retardation is very seldom discovered at child health care centers.
      Diagnosed in every fifth child prior to the compulsory schoolattendance].

PMID- 8649115
TI  - [A new course on global medicine. From relief work to pharmacological front line
      research].

PMID- 8649116
TI  - [Chronic renal failure prior to dialysis--a crisis. Patient groups give insight
      and life energy].

PMID- 8649117
TI  - [Drug induced tetraparesis and loss of myosin. Mild types are probably
      overlooked].

PMID- 8649119
TI  - [Expanded rehabilitation responsibility for insurance authorities. A new role of
      physicians employed by insurance authorities requires education].

PMID- 8649118
TI  - [Intestinal obstruction caused by Ascaris lumbricoides. A rare condition to be
      considered].

PMID- 8649120
TI  - [Lung X-ray as a control check-up after infection].

PMID- 8649121
TI  - [Lung X-ray is an efficient, cheap, simple and harmless method].

PMID- 8649122
TI  - [A study and treatment of a group of patients with electro-hypersensitivity. More
      than half of the patients were able to return to work].

PMID- 8649123
TI  - [A newly discovered biological clock. An internal stop-watch checks short time
      intervals].

PMID- 8649124
TI  - [Blood group antigen expression in papillary carcinoma of the thyroid gland. An
      immunohistochemical and clinical study of expression of Lewis, ABO and related
      antigens].
AB  - Nine monoclonal antibodies, lectin from Ulex europaeus and neuraminidase enzyme
      were employed to demonstrate the occurrence of type 1 and type 2 blood group
      antigens in 104 cases of papillary carcinoma of the thyroid. The reagents
      applied, recognize the following blood group related antigens: CA-50 (sialylated
      type 1 precursor), CA-19-9 (sialylated Le(a)), Le(a), Le(b), A, B, H, Le(x),
      sialylated Le(x), and Le(y). Immunohistochemical studies revealed that papillary
      carcinoma of the thyroid, in contrast to histologically normal thyroid tissue, is
      characterised by a progressive expression of blood group antigens. Most tumours
      (84%) reacted with C-50 antibody, whereas only a minority of the tissues
      demonstrated the CA-19-9 antigen (38%). Type 2 structures Le(x) (47%) and Le(y)
      (13%) were found less often than their corresponding type 1 isomers Le(a) (71%)
      and Le(b) (62%). Desialylation with neuraminidase increased the Le(a) and Le(x)
      staining intensity in 27 and 44 case, respectively. Of the A, B, H antigens the A
      determinants encountered most frequently (24%). Comparative examinations of
      sequential sections of the same tumour revealed coexpression of type 1 antigens
      in the same areas. In carcinomas showing type 1 and type 2 antigen reactivity, a
      complementary distribution of the structures in different tumour areas was often
      demonstrated. Some tumours presented combined type 1 and type 2 antigen
      expression in the same cells, however, in distinct areas within the cell. A
      follow-up examination was carried out in 68 of the 104 cases. The observation
      time ranged from 12 to 217 months. Thirteen patients suffered from recurrence, of
      which 7 died. While lymphatic metastases occurred in 39 tumours, distant
      metastases were detected in 6 patients. Most of the recurrences were found in
      patients with tumour classification pT4 (n = 19), whereas none of the pT1
      carcinomas (n = 20) showed recurrence. The clinical results were compared to the
      blood group antigen expression results. There was no correlation between antigen
      expression and differentiation degree of the tumour. The pT4 tumours showed a
      significant higher expression of the CA-50, CA-19-9, Le(a) and Sialyl Le(x)
      structures. Carcinomas expressing the Le(y) antigen were associated with a
      significant higher level of metastasizing capacity. The Le(y), H type 1 and H
      type 2 antigens occurred more frequently in recurrent tumours (n = 14). In
      contrast, none of the patients whose carcinomas expressed the A-antigens (n = 14)
      suffered from a recurrence or hematogenous metastasis. Multiple stepwise
      regression analysis was carried out to check the importance of each staining and
      clinical factor. In this analysis, "distant metastasis' was the most important
      parameter, whereas the staining results were of minor statistical importance.

PMID- 8649126
TI  - [Clinical standardization in acute abdominal pain].

PMID- 8649125
TI  - [Use of endoscopy in plastic surgery].
AB  - Now that endoscopic techniques have been established in visceral and trauma
      surgery under the concept of minimal invasive surgery, plastic surgery has also
      begun to accept these techniques since minimal invasive surgery is very important
      in this field. In contrast to abdominal and thoracic surgery, plastic surgery
      cannot be done in preformed cavities. Therefore, it was necessary to develop new
      techniques and instruments. We present the most important operations in the field
      of plastic surgery that can so far be carried out endoscopically. The development
      phase is only at the beginning, and new indications are being added daily since
      the technical equipment can also only be gradually adapted to the needs that
      arise.

PMID- 8649129
TI  - [Segmental displacement by callus distraction in extended tibial defects].
AB  - In open tibial fractures with defects over 4 cm, spongiosaplasty is considered to
      be insufficient. Since 1988 we have tried to apply Ilisarov's ideas of callus
      distraction in combination with modern external fixation devices and AO/ASIF
      implants. By August 1995, 15 patients with severe tibial fractures had been
      treated. The bone defect averaged 7 cm. Thus, more than 1 m of tubular bone was
      produced. Eleven male and 4 female patients, averaging 21.3 years in age, were
      given this treatment. The defect was caused by resection of a malignancy in 3
      cases and a second- or third-degree open fracture in 12 cases, accompanied by
      osteomyelitis in 6 cases. Reconstruction required an average of 5.3 operations.
      The complication rate was 53%, and the median duration of treatment was about 1
      year. The final results were excellent or good. Amputation could be avoided in
      all instances. This treatment is contra indicated if the patient exhibits a lack
      of compliance. There is a realistic chance of salvaging the limb in cases of
      severe soft tissue and bone defects. In terms of economical considerations, this
      treatment is cost effective. Physical integrity and mobility without aid is the
      important motivation for these patients.

PMID- 8649127
TI  - [Clinical standardization in acute abdominal pain].
AB  - The correct diagnosis in acute abdominal pain is necessary for adequate
      treatment. In several clinical studies it has been shown that, despite
      improvements in laboratory and technology medicine, errors occur in a
      considerable proportion of cases due to insufficient history-taking and clinical
      examination. By the introduction of a standardised and structured history and
      clinical examination, the diagnostic accuracy can be improved by at least 10%.
      The aim of this publication is to improve history-taking, clinical examination
      and diagnostic decision-making by exact definition of all relevant parameters.
      This was performed by a national clinical expert group, international
      standardisations were taken in consideration. The standardisation was based
      mainly on these existing international standardisations (World Organisation of
      Gastroenterology); however, revisions and corrections were necessary. In order to
      introduce the standardisation into clinical routine, a documentation form and a
      documentation program can be provided.

PMID- 8649130
TI  - [Modification of phagocytic microbicide function by antifungal agents--measuring
      luminol enhanced chemoluminescence in full blood].
AB  - Fungus infections are becoming more important in surgical intensive medicine, and
      various preparations are now available to treat them. The goal of our
      investigations was to determine the influence of the antimycotics in current use
      on the microbicide phagocytic function by measuring chemiluminescence. To this
      end the luminol-enhanced chemiluminescence in whole blood samples from a total of
      29 healthy donors was measured with a LKB 1251 Luminometer after stimulation with
      zymosan or a Canadida albicans preparation. We tested the substances amphotericin
      B, flucytosin (Ancotil), fluconazol (Diflucan) and itraconazol (Sempera), each in
      three different concentrations within the recommended dose range and compared the
      results with those in an untreated sample. For the insertions of amphotericin B
      or intraconazol after zymosan stimulation no significant differences in the
      measurements were found (50.84 vs 47.99 mV and 46.10 vs 47.89 mV) compared with
      the blank test. Similar situations revealed by the tests with C. albicans
      administration (15.21 vs 12.35 mV and 11.16 vs 11.91 mV). However, the tests with
      flucytosin in the higher concentration range, after stimulation with either
      zymosan or C. albicans, evidenced a significant reduction in the measurements
      (34.70 vs 52.74 mV, P<0.005, and 10.98 vs 14.57 mV, P<0.01). The tests with
      fluconazol showed a decrease of the chemiluminescence exclusively for the highest
      concentration in the C. albicans group (14.36 vs 17.20 mV, P<0.005). Our results
      indicate a negative influence of the phagocytes on the oxidative metabolism
      especially with flucytosin in the higher concentrations. This emphatically
      confirms demands for exact indications and dosage of antimycotics and their
      correct administration.

PMID- 8649128
TI  - [Primary pleomorphic rhabdomyosarcoma of the liver].
AB  - Two female adults with primary rhabdomyosarcoma of the liver were operated on in
      1981 and 1987 in the Department of Surgery in the University Hospital of Hamburg
      Eppendorf (Germany). In both cases a hemihepatectomy was performed.
      Postoperatively, the younger woman received adjuvant chemotherapy. Both patients
      are still alive. Both cases are reviewed with reference to the unusual findings
      in the liver combined with a really short history. In addition, the possibilities
      opened up by the diagnostic are measures discussed. Contrary to the literature,
      this rare malignant tumour seems to be curable if it is diagnosed early and
      treated while confined to the liver.

PMID- 8649132
TI  - Proceedings of the 2nd International Symposium on Intensive Care Medicine.
      Brijuni, Croatia, 26-29 June 1995.

PMID- 8649131
TI  - [Reperfusion shock after occlusion of the superior mesenteric artery and
      accumulation of leukocytes within the wall of the small intestine].
AB  - The epithelial damage and the accumulation of the leucocytes within intestinal
      wall layers after ischemia and reperfusion was investigated in a pig model.
      Superior mesenteric artery (SMA) was occluded for 1 h (group 2, n = 9), 2 h
      (group 3, n = 6) and 3 h (group 4, n = 7) with a consecutive 2 h reperfusion
      period. The histological evaluation was performed on hematoxylin-eosine and
      Naphtol AS-D chloracetate stained preparations. The intensity of reperfusion
      shock depended on the duration of the intestinal ischemia. After 1 h SMA
      occlusion systolic blood pressure stabilized at a lower level with a
      normalization of the serum lactate level and the intestinal intramural pHi within
      the reperfusion period. After 2 h SMA occlusion the decrease of the systolic
      blood pressure was intensified (54-69 mm Hg) with a persistent elevated serum
      lactate concentration and a delayed increase of the ischemic pHi values.
      Reperfusion after 3 h SMA occlusion caused an irreversible shock. The epithelial
      damage also depended on the duration of the SMA occlusion. There were no
      significant changes of the leucocytic accumulation within the submucosa. But a
      significant increase of the number of the leucocytes was seen within the inner
      and the outer layer of the muscularis after 1 h SMA occlusion (106+/-5/mm2 resp.
      280/mm2; p<0.05). This increase was less pronounced after 2 h (92+/-5/mm2*resp.
      189+/-4/mm2; *p<0.05) and 3 h of SMA occlusion (84+/-5/mm2 resp. 185+/-23/mm2).
      Intestinal ischemia and reperfusion caused no changes of the leucocytic
      accumulation within the submucosa but a significantly increased accumulation
      within the muscularis after 1 h SMA occlusion, which was not seen after a more
      elongated occlusion period. A reperfusion shock without normalization of the
      serum lactate level and the intramural pHi suggesting intestinal perfusion
      disturbances may also lead to a depression of the leucocytic accumulation within
      the muscularis.

PMID- 8649133
TI  - [Epidural anesthesia in vascular surgery in patients with chronic obstructive
      lung disease].
AB  - Epidural anaesthesia was determined in 29 patients with chronic obstructive
      pulmonary disease. Lidocaine 2% for vascular procedures such as embolectomy from
      the arteriae femoralis and arteriae poplitea was used as an anesthetic in 12
      patients and 0.5% bupivacaine for aortobitemoral or femoropopliteal bypass in 17
      patients. Thus possible complications in patients with obstructive chronic
      pulmonary disease were avoided as well as prolonged mechanical ventilation and
      endotracheal intubation. With the postoperative application of local anesthetic
      through a catheter into the epidural space, spontaneous breathing and good
      analgesia was achieved. Preoperatively all patients were administered
      bronchodilators, expetorants and they stopped smoking.

PMID- 8649134
TI  - [Hemodynamic effects of captopril, an ACE inhibitor, in patients after
      aortocoronary bypass].
AB  - During the last few years, the use of angiotensin converting enzyme (ACE)
      inhibitors in the treatment of patients with cardiovascular diseases has been
      increasing. Captopril is the earliest oral ACE inhibitor and was marketed in
      1977. The adverse effect most undesirable with vasodilators, particularly in
      patients with heart disease, is a reflex tachycardia. The absence of tachycardia
      with the possibility of binding free radicals is the comparative advantage of
      angiotensin converting enzyme inhibitors. Because of their positive hemodynamic
      effect, ACE inhibitors should be used as a supplement in the treatment of
      patients who need aortocoronary bypass. Their use does not exclude the
      intravenous administration of vasodilators, and only decreases the required
      therapeutic concentration of these drugs.

PMID- 8649135
TI  - The importance of glucose-insulin-potassium with cardiopulmonary bypass prior to
      cardioplegic arrest in open-heart surgery.
AB  - The benefit of a high dose glucose-insulin-potassium (33% glucose, 80 mmol KCl,
      120 units of insulin - 1 mL/kg) (GIK) with cardiopulmonary bypass support (CPB)
      prior to cardioplegic arrest in open-heart surgery has been evaluated in this
      article. Twenty non-diabetic patients (PTS) were selected upon their
      preoperatively impaired left ventricular ejection fraction (LVEF < 45%) and were
      divided into two groups. Group 1 was given GIK and 20 minutes of CPB prior to
      cardioplegic arrest; Group 2 was the control group with no GIK and no CPB
      support. Hemodynamics was measured prior to surgery, 30 minutes after weaning
      from CPB, and 12 and 24 hours postoperatively. There were less rhythm
      disturbances and need for intraoperative defibrillation in Group 1 (2:10 pts VS
      8:10 pts in the Group 2). There were significantly higher values of cardiac index
      (CI) in Group 1 30 minutes after weaning from CPB (2.5 +/- 0.28 VS 2.11 +/- 0.25:
      p < 0.01), while there was no significant difference in late postoperative
      course. Left ventricular stroke work index (LVSWI) in Group 2 was significantly
      higher 12 hours after the surgery (38.35 +/- 8.93 VS 29.76 +/- 8.17:p < 0.05). At
      30 minutes and 24 hours postoperatively there was no significant difference, but
      clinical difference was observed, probably due to necessary inotropic stimulation
      in Group 2. There was neither clinical nor statistical difference in right
      ventricular stroke work index (RVSWI) throughout the whole measurement. The
      authors emphasise the importance of GIK with CPB in myocardial protection in
      patients undergoing open-heart surgery.

PMID- 8649136
TI  - [The role of proteins and amino acids in acute phase response].
AB  - The acute phase response after severe trauma leads to the major changes in
      synthesis and levels of plasma proteins. Activation of humoral cascade system and
      activity of phagocytes accelerates healing. In the prospective study the levels
      of serum total proteins and albumin in relation to acute phase proteins,
      fibrinogen and CRP were measured in the group of 34 severe traumatized patients,
      age 31.21 +/- 1.52 yrs submitted to the standardized ICU treatment. An increase
      in the levels of serum total protein from 51.07 to 52.53 g/l was registered
      during the first week. The levels of albumin were below 30 g/l for most of the
      patients during the entire two-week examination. The initial levels of albumin
      were 26.40 +/- 6.13 g/l and at the end of the examination 29.60 +/- 2.97 g/l (p =
      0.008). The levels of fibrinogen showed the increase to 5.93 g/l during the
      entire examination. The rapid increase in the levels of CRP from 5 mg/l to 169.67
      mg/l 48 hours after trauma and were still high at the end of examination 45 mg/l.
      That implies the activity of inflammatory mediators. The role and supplement of
      certain amino acids in maintaining the integrity of intestinal mucosa and immune
      system during the acute response to stress is discussed.

PMID- 8649137
TI  - [The Q.E.D. test--possibility for rapid determination of ethanol levels in
      saliva].
AB  - The present study has been undertaken to compare the Q.E.D. test, a quantitative
      enzymatic method for the determination of ethanol concentration in the saliva,
      and quantitative methods for determination of ethanol serum concentrations: UV
      alcohol dehydrogenase method and gas chromatography. The results of the study
      demonstrated a statistically significant correlation between the methods
      compared. We conclude that Q.E.D. test is an effective, rapid and safe method for
      specific quantitative determination of ethanol levels in the blood defined by
      ethanol concentrations in the saliva, especially in outpatient departments,
      initial emergency treatment as well as in differential diagnosis. Sometimes, an
      increased salivary viscosity caused by dehydration of an acutely drunken man as
      well as insufficient cooperation of the examinee may, however, aggravate the test
      performance. We propose the use of a test that measures ethanol concentration in
      the saliva up to 3.5 g/L in order to avoid repetition of the test.

PMID- 8649138
TI  - [Pathogenic role of intracellular energy insufficiency (hypoenergy) in the
      development of circulatory collapse (hemodynamic shock)].
AB  - Hemodynamic shock syndrome represents an acute circulatory failure due to a
      decrease of arteriovenous pressure gradient. Three unrelated groups of processes,
      cardiogenic, vasohypotonic and hypovolemic mechanisms, are possible starting
      points of the shock syndrome pathogenesis. The basic features of those principal
      pathogenic steps are outlined in the paper. In addition, clinical practice very
      often encounters a complex forms of the syndrome, which include two or all three
      basic pathogenic mechanisms simultaneously. Direct consequence of arteriovenous
      pressure gradient loss is diminishing perfusion of tissues. Tissue hypoperfusion
      causes a progressive depletion of cellular energy rich compounds. Such lowering
      of cellular ATP concentration (cellular hypoenergosis), very often less than 0.1
      mmol/L, plays an important pathogenic role in the conversion of homeostatic
      regulation processes from a negative into a positive feedback mode. Positive
      feedback regulation amplifies deterioration of arteriovenous blood pressure
      gradient loss, which reversely intensifies the degree of energy depletion in
      tissues. Individual cell death decreases a tissue adjustment capacity to
      hypoperfusion. The critical step leading to a decompensation (systemic failure)
      or progressive phase of the shock is the reversal of the homeostasis into the
      positive feedback mode of action. Final outcome of the syndrome reflects a degree
      of compensation capacity loss as well as irreversible tissue alterations.
      Clinical manifestations correlate with the underlying pathogenic processes. Short
      summary of clinical correlative relations with the pathogenic processes, at the
      cellular, molecular and/or energy level, is given in the paper.

PMID- 8649139
TI  - Analgesia at the department of intensive care.
AB  - Analgesia at the Department of intensive care can be distributed into three
      groups, with respect to the patient's respiratory status: 1) analgesia in a
      patient on controlled ventilation; 2) analgesia in a patient who is being weaned
      from a respirator; 3) analgesia in a patient breathing spontaneously. In patients
      of group 1, analgesia, respiratory depression and sedation are achieved with
      morphine applied parenterally or epidurally. While patients on assisted
      ventilation (group 2) require good analgesia and sedation, they should remain
      cooperative; this is achieved with tramadol or ketamine. Spontaneously breathing
      patients are maintained on tramadol in combination with NSAID. In all patients
      the dosage needs to be adjusted with respect to the type of pain, age, nutrition
      status, and previous use of analgesics.

PMID- 8649140
TI  - [Treatment of septic shock in pediatrics].
AB  - A significant improvement has been noticed over the last 20 years in children in
      whom shock syndrome has developed. This has been attained through the application
      of technological advances in respiratory, cardiovascular, renal, nutritional
      support and improved antibacterial and antifungal therapy, but mostly through a
      better understanding of the physiology of shock. Newer concepts of the
      pathophysiology of sepsis and septic shock are presented, with clinical
      definitions referring to the pediatric patient. Innovative therapeutic modalities
      designed to modulate the systemic inflammatory response triggered by bacterial
      infection are discussed.

PMID- 8649141
TI  - Extracorporeal membrane oxygenation (ECMO) in children.
AB  - ECMO is the process of prolonged extracorporeal circulation in the treatment of
      respiratory and cardiovascular failure not responding to conventional therapy in
      neonates and children. Basic principles and techniques are discussed. After
      training ECMO on dogs ECMO was successfully introduced in clinical practice in
      Slovenia in 1994.

PMID- 8649143
TI  - Revising the ABCs of CPR: D and C now take the lead.

PMID- 8649142
TI  - Hemodynamic monitoring in the critically ill.
AB  - Monitoring of vital functions is one of the most important and essential tools in
      the management of critically ill patients in the ICU. Today it is possible to
      detect and analyze a great variety of physiological signals by various
      noninvasive and invasive techniques. An intensivist should be able to select and
      perform the most appropriate monitoring method for the individual patient
      considering risk-benefit ratio of the particular monitoring technique and the
      need for immediate therapy, specific diagnosis, continuous monitoring and
      evaluation of morphology should be included. Despite rapid development of
      noninvasive monitoring techniques, invasive hemodynamic monitoring in still one
      of the most basic ICU procedures. It enables monitoring of pressures, flow and
      saturation, pressures in the systemic and pulmonary circulation, estimation of
      cardiac performance and judgment of the adequacy of the cardiocirculatory system.
      Carefully and correctly obtained information are basis for proper hemodynamic
      assessment which usually effects the therapeutic decisions.

PMID- 8649144
TI  - [Oxygen delivery and tissue extraction in septic shock].
AB  - Hemodynamic and oxygen transport variables were evaluated in 34 patients with
      septic shock during fluid repletion and infusion of vasoconstricting and
      inotropic catecholamines (dopamine, dobutamine). Hypovolemia, increased cardiac
      output (CO), low pulmonary and systemic vascular resistance dominated in initial
      hypotensive status. Oxygen consumption (VO2) decreased despite increased oxygen
      delivery (DO2). Hypotension and hypovolemia were successfully corrected by
      therapeutic intervention and significantly higher values of CO and DO2 were
      obtained. However, VO2 remained low and oxygen extraction index declined from the
      initial level. THE CONCLUSION: The underlying pathophysiological defect in septic
      shock is not altered hemodynamics or low DO2 but impaired tissue oxygen
      extraction. The usual hemodynamic resuscitation does not improve tissue oxygen
      utilization and the results in the treatment of septic shock remain poor.

PMID- 8649145
TI  - [Comparison of clinical assessment and invasive evaluation of hemodynamic
      parameters in septic shock].
AB  - The authors compare, in this prospective study, the accuracy of their own
      clinical assessment of hemodynamic parameters and severity of disease with the
      findings obtained by right heart catheterization in 50 patients with septic
      shock. The purpose of the study was to determine whether Swan-Ganz catheter
      insertion was necessary in all patients with septic shock. As soon as the
      diagnosis was established, the value of pulmonary capillary wedge pressure was
      estimated, as well as presence or absence of pathological uptake/supply
      dependency in all patients. The latter is an excellent indicator of severity of
      disease. The accurate assessment was noted in 27 (54%) patients (1.
      investigator), and in 30 (60%) patients (2. investigator). The sensitivity of
      detection of pathological uptake/supply dependency amounted to 53% and 65%;
      specificity was 73% and 79%, respectively. The therapy was altered in 21 patients
      (42%) after catheter insertion. The results were tested with chi2-test (p <
      0.01). The findings of this study warrant catheter insertion in patients with
      septic shock.

PMID- 8649146
TI  - [Spinal shock. Diagnosis and therapy. Problems and dilemmas].
AB  - Spinal shock is the term used to signify the effect of sudden injury or
      transection of the spinal cord. It is characterized by sensory, motor and reflex
      loss occurring below the level of injury. High level spinal injuries are
      associated with loss of autonomous nerve system control. This condition still
      remains an enigma which challenges the neurophysiologists, clinical neurologists
      and the spinal surgeons. There are many different theories relating to the cause
      and nature of spinal shock as well as to the level of spinal injury that results
      in spinal shock. Duration of spinal shock varies from patient to patient, and
      some of the symptoms can last up to 12 weeks. Clinical presentation of spinal
      shock involves changes in skeletal muscles, sensory response, breathing, heart,
      blood vessels, vasomotor response, body temperature, GI tract, urinary bladder
      and genitalia. Somatosensory evoked potentials also reflect changes caused by
      spinal shock. The clinician's task is to treat clinical symptoms provoked by
      spinal shock in an attempt to reduce its intensity and duration. This can be
      achieved by operative and medicamentous therapy, promptness and efficacy being
      the treatment imperatives. The authors discuss diagnostic and therapeutic methods
      used in the treatment of spinal shock and present their own experience and
      viewpoints in terms of reduction of spinal shock intensity and duration.

PMID- 8649147
TI  - [Hemodynamic effects of amrinone, dobutamine and dopamine in the cardiac low
      output syndrome following open-heart surgery].
AB  - Low heart stroke volume syndrome is clinically manifested with hypoperfusion of
      all body systems. Inotropic or mechanical support is applied. Acute heart failure
      is one of the most important complications after open heart surgery.
      Catecholamines have been up to non considered as a therapy of choice for the
      acute heart failure. Effectiveness of catecholamines could be limited with some
      side effects. Phosphodiesterase inhibitors promise a new therapeutic approach.
      PDE III primary act through phosphodiesterase inhibition which leads to a rise of
      aAPM levels. Thus they show positive inotropic and lusitropic effects, which
      could be monitored by occlusive pulmonary capillary pressure values. Amrinone is
      obviously superior to inotropic catecholamines.

PMID- 8649148
TI  - [Treatment of acute loss of blood in major elective orthopedic surgery
      procedures].
AB  - Hypovolemia develops when volume of circulating fluid in the body during the
      surgical procedure and perioperative time is so depleted that effective tissue
      perfusion can not be maintained and generalized impairment of cellular function
      is possible. The study was designed to analyze, first, the perioperative acute
      blood loss in the course of implantation of hip endoprosthesis, and second, the
      prevention of hemorrhagic shock with regard to morbidity and mortality. In 35
      patients, a total hip endoprosthesis was implanted in spinal anesthesia. Prior to
      surgery and three days following operation, hemoglobin, hematocrit, thrombocyte
      and APTV analysis was done. Further evaluation included assessment of blood loss
      during the operation and within 48 h after the surgical procedure until the
      drainage was removed. The results showed that during the first day
      postoperatively, the average hemoglobin level was -18 g/L and that of hematocrit 
      8 vol/% (20%) with fluid substitution by means of blood transfusion and plasma
      volume expanders (Soludex 1 and 70) maintaining normovolemia. 73% of the patients
      were given 1270 ml of red blood cells on the first day after the operation, and,
      on the third day postoperatively, blood transfusion of about 450 ml was
      administered to 36% of the patients. No functional organ failure was observed. We
      conclude that the most effective way of treating hypovolemic shock is by the
      rapid infusion of volume-expanding fluids. There is no optimal level of
      hematocrit in critically ill patients, so transfusion should be given on
      individual basis combined with adequate monitoring.

PMID- 8649149
TI  - [Hemorrhagic shock--an emergency in extrauterine pregnancy].
AB  - A total of 59 female patients with suspected extrauterine pregnancy were admitted
      to the Department of Gynecology and Obstetrics of Zabok General Hospital from
      January 1, 1990 to December 31, 1994. The incidence of extrauterine pregnancies
      is 1.3% with regard to a total number of deliveries. Dominant clinical symptoms
      were amenorrhea, abdominal pain and abnormal bleeding from the uterus. Seven
      (14%) patients developed hemorrhagic shock. Resuscitation had not postponed the
      surgical procedure. The average value of serum beta HCG was 1700 IU/L. Amenorrhea
      was from 6-12 weeks. The age of patients ranged from 20 to 40 years. Seven (14%)
      patients had intrauterine device. There were 14 (27%) nulliparas, 15 (29%)
      primiparas, 20 (39%) secundiparas and two (4%) women had three pregnancies. The
      evaluation included ultrasound of the abdomen in 22 (37%) patients, culdocentesis
      in 31 (53%) of which 4 (13%) procedures were negative punctures. Laparoscopy was
      performed in 15 (25%) patients and exploration of the uterus in 36 (61%).
      Pathohistological finding of decidua was seen in 19 (53%) patients, Arias-Stella
      reaction in 3 (8%) and histological finding of the endometrium in secretion was
      obtained in 14 (39%) patients. Laparotomy was done in 44 (75%) patients;
      adnexectomy in 23 (39%), salpingectomy in 30 (51%), and expression of the ovum in
      3 (5%). One patient underwent laparoscopic administration of carboprost.
      Postoperative course was uneventful. Ectopic pregnancy is still the cause of 10%
      of the maternal deaths and is the leading cause of deaths in the first trimester
      of pregnancy of which more than 80% of deaths are due to massive hemorrhage. We
      have emphasized that efforts should be made to improve the diagnosis and, thus,
      the treatment.

PMID- 8649150
TI  - [Cardiogenic shock in acute myocardial infarct].
AB  - Cardiogenic shock is the most important fatal complication of acute myocardial
      infarction (AMI). This syndrome may be considered as a severe form of left
      ventricular failure and the mortality rate is very high. According to the
      clinical classification, Killip class IV ranges from 60 to 95%, depending on
      authors. Shock occurs in about 15-20% of patients with AMI and accounts for at
      least 70% of the in-hospital deaths. During 1994, 168 patients with AMI were
      treated at the Intensive Care Unit of the Zagreb General Hospital, of which 14
      (8.2%) developed cardiogenic shock. Ten patients experienced the first myocardial
      infarction, and 4 were admitted because of the second myocardial infarction, that
      time of anterior localization. Signs of cardiogenic shock were present in 8
      (57.1%) patients already on admission. Three patients developed cardiogenic shock
      during the first 10 hours of hospitalization and further 3 patients during the
      initial 4 to 15 days of treatment. Older age prevailed. Eleven (78.5%) persons
      were older than 60 years of age. Eight patients demonstrated anterior infarction,
      4 had inferior infarction and 2 non-Q-wave infraction. All patients had signs of
      left ventricular failure evidenced by pulmonary edema (Killip class IV) and later
      complicated by arrhythmia. Of the 14 patients who had AMI with the shock
      syndrome, 13 (92.8%) died; 5 (35.7%) patients during the first 2 hours, 3 (21.4%)
      within 24 hours of infarction, and 5 (35.7%) patients during the initial 4 to 25
      days of treatment. Patients were treated conservatively, and only 3 patients
      received thrombolytic therapy, namely, streptokinase.

PMID- 8649151
TI  - [Shock caused by electrical current].
AB  - The authors elaborate the most frequent causes of electroshock and consequences
      to the human body thereof. Recent advances in modern medical technology increase
      the hazard of the electroshock. Tissue burns, asphyxia, CNS destruction and
      ventricular fibrillation are possible consequences. Depending on the electric
      current strength, the organism may be a subject of either a macroshock or a
      microshock. The methods of microshock prevention in hospital environment are
      disclosed. Two patients are presented, being treated at the Institute of
      Anesthesiology and Intensive Care.

PMID- 8649152
TI  - Coma.

PMID- 8649153
TI  - Resuscitation: initial goal and steady state treatment in trauma and septic
      shock.

PMID- 8649154
TI  - [Disorders of consciousness as a manifestation of neurologic disease].
AB  - Seventy-nine patients admitted in the neurological Intensive care unit because of
      severe disturbances of consciousness has been evaluated. Protocol based on
      previous experiences in evaluation of unconsciousness patients was used. Forty
      four patients died and thirty-five survived. In 46 patients cause of illness was
      intracerebral hemorrhage. In 44 of them the cause of hemorrhage was arterial
      hypertension and in two of them rupture of a-v malformation. The majority of
      patients actually 41 of them showed hemispheral localization of intracerebral
      hematoma and five subtentorial. Pontien hemorrhages was found in three and
      cerebellar in two patients. In majority of 24 patients with hemispheral
      localization of intracerebral hematoma who showed progressive deterioration of
      consciousness the signs of descendent transtentorial herniation were found. The
      symptoms of uncal herniation were rare. In three patients with subtentorial
      localization of intracerebral hematoma who died signs of upward transtentorial
      herniation were observed. In 16 patients with ischemic cerebrovascular accident
      who showed disturbances of the consciousness at the admittance or soon after,
      nine patients died and seven survived. The cause of their condition were great
      hemispheral, smaller brain stem ischemic lesion, or deterioration of
      consciousness was related to the somatic illness. Patients with great ischemic
      lesions showed similar course of consciousness deterioration as it was observed
      in patients with hemispherical intracerebral hematomas with difference that
      biphasic course of illness characterized with temporary stagnation or even slight
      improvement of patients condition and than secondary progression of deterioration
      was seen only in patients with intracerebral hematoma, probably because of
      secondary ischemic complications. Ten patients were admitted because of
      subarachnoidal and two of them because of intraventricular hemorrhage. Six of
      them died and four survived. These patients has rupture of great sacular aneurysm
      with fast development of high intracranial pressure. In two of them the cause of
      death was rerupture of aneurysm. Stuporous patient with hemispheral neoplasm
      showed development of descendent transtentorial herniation which was stopped by
      anti oedematous and corticosteroid therapy. Comatose patient with brisk response
      on oculocephalic stimulation and normal papillary light reflexes was suspected on
      intoxication rather than structural brain lesion. He recovered by diuretics and
      forced rehydratation. After becoming conscious barbiturate intoxication was
      confirmed. Three patients were admitted in coma because of poisoning with CO, two
      patients died. Two patients admitted in epileptic status showed late diencephalic
      state of coma and they survived after anti epileptics and antioedematous
      treatment.

PMID- 8649155
TI  - Emergent evaluation of the comatose patient.

PMID- 8649156
TI  - [Causes of disorders of consciousness in internal medicine intensive care units].
AB  - The present study on 5330 patients admitted to the internal intensive care unit
      over the five year period (1990-1994) indicated that consciousness disorders are
      most frequently associated with poisoning. On admission, the state of
      consciousness of 665 of these 5330 patients was retrospectively evaluated.
      Poisoning by drugs was most common among intoxications (93 patients of 154 cases
      of poisoning). Coma, which is the most severe manifestation of consciousness
      disorder, occurred very often in these patients. Poisoning caused by other agents
      was connected with other forms of consciousness disorders. Low Glasgow Coma Score
      (GCS) was a severe predictor, while the number of deaths among patients with GCS
      > 10 was low. Sepsis was the next most common cause of consciousness disorder
      among our patients (88 patients). Death rate in these patients was high,
      amounting to almost 50%, regardless of GCS on admission, suggesting that the
      severity of main event determines the outcome. Glycemia disorders, including
      hypoglycemia, hyperglycemia as well as hyperosmotic state, did not result in
      lethal outcome, regardless of GCS on admission. The highest death rate was
      registered in patients with cardiopulmonary arrest and lowest GCS on admission.
      Patients with cardiogenic shock, despite high GCS on admission, had high death
      rate.

PMID- 8649157
TI  - [Intensive care of patients in a coma following severe craniocerebral injury].
AB  - During last 14 years 748 patients in coma according to the Glasgow Coma Scale
      (scores less than 8) were treated at Neurosurgical intensive care unit. All the
      patients were mechanically ventilated. In 354 patients intracranial pressure
      (ICP) was monitored using Leeds boult. From 1990 arterial pressure was monitored
      invasively in all patients. According to ICP and cerebral perfusion pressure
      (CPP) we used mannitol and/or thipental, trying to keep ICP below 20 mmHg, and
      CPP at least near 65 mmHG. From 1992 we started also with arteriojugular oxygen
      saturation monitoring. According to narrow, normal or wide cerebral extraction of
      oxygen range so called optimized hyperventilation can be achieved. Despite
      mortality rate in patients with severe head injury is still high, aggressive
      intensive management can reduce it.

PMID- 8649158
TI  - [Brain death--modern concepts].
AB  - Traditional definition of death-cessation of heart function-became obsolete,
      because it was indisputably ascertained that brain function may be totally an
      irreversibly destroyed, while other parts of the body continue to live including
      the heart. So the definition of death switched from the heart to brain function-
      a brain stem dead patient becomes'' a corps with a beating heart "(ghostly
      aspects of the medical progress). Early recognition of brain death before the
      unavoidable cessation of circulation is the basis of organ(s) transplantation.
      The tests necessary to show that the brain stem is not functioning take only a
      few minutes to carry out, but the moral and legal responsibility for such a
      diagnosis is tremendous. The best safeguards against suspicion of error are well
      written guidelines. Doctors involved with diagnosis of brain death must acquire
      clear and unambiguous criteria. The purpose of this presentation is to contribute
      to wider distribution of knowledge of brain death symptoms in our local situation
      where organ transplants, including the heart, have been achieved. During the year
      1994, 296 patients were admitted into the neurological intensive care unit, 32 of
      them in respiratory arrest. Ten were considered as potential organ donors but
      nine died during observation. However, one transplantation was performed: heart,
      kidneys, and corneae were donated and used.

PMID- 8649160
TI  - [Neuropsychologic examination in the evaluation of level of consciousness in
      patients with a craniocerebral injury associated with multiple injuries].
AB  - Today's way of life, with its high level of mechanization and need for speed
      brings a large number of injuries to the working population. There is usually a
      wide range of injuries, among which are very often closed head injuries. Until
      today the whole focus was on the restoration of organic systems and very little
      attention was given to subtle deficits in the area of cognition and higher
      intellectual functions. We wanted to point out that there is a great need for
      neuropsychological examination from the beginning of medical treatment, which
      will, with tests, point out disturbances which are not visible in the early post
      traumatic period, but which will get worse and prevent the normal resocialization
      and adaptation of the patient to their previous environment after being
      discharged from hospitals. After the research had been carried out it was obvious
      that these examinations, as well as the question of destroyed integrity, needed
      attention because such analyses can, in an early post-traumatic phase, show
      recovery or the existence of definite disability. We believe that
      neuropsychological examination needs to be equal to other forms of medical
      examination.

PMID- 8649159
TI  - [Disorders of consciousness in trauma patients].
AB  - 238 patients with multiple trauma hospitalized in the Intensive Care Unit of the
      Zagreb General Hospital during 1993 and 1994 were analyzed. They were grouped
      with respect to the type of their injury. The first group was composed of
      patients with isolated head injury. The second group was made up of patients with
      multiple trauma and head injury. Patients with multiple trauma but without head
      injury were inserted into group three. 138 patients were comatose (GCS < 8) and
      had to be reanimated. 143 patients underwent an urgent surgical procedure.
      Assisted ventilation over 24 hours needed 180 patients (average of 11,4 days).
      The most common complications were respiratory: pneumonia developed 60 and ARDS
      five patients. The rate of mortality was 35,9% (65 patients died.

PMID- 8649161
TI  - [Consciousness disorders in patients after carotid artery surgery].
AB  - The range of surgical management of the carotid arteries becomes every day wider.
      The most common cause of carotid arteries disease is atherosclerosis and its
      consequences for the brain, and more rarely anatomical anomalies. The majority of
      our patients had cerebral damage prior to the surgical procedure, so we have
      taken particular care to prevent cerebral perfusion disturbances following the
      operation. Consciousness disorders are not always the consequence of disturbed
      cerebral perfusion, but their cause may have effect on it. Our experience and
      observations are presented with the aim to alert those considered to the
      potential problems.

PMID- 8649162
TI  - [What is not revealed in the telephone call reporting "unconsciousness"].
AB  - Medical documentation of the Zagreb Emergency Medical Center was reviewed in the
      period between January 1 to December 31, 1994. 1352 telephone calls received by
      physician in charge related to the state of unconsciousness were processed. The
      state of unconsciousness was verified in 602 patients (44.52%). 315 patients
      (23.30%) were not unconscious. Insufficient evidence of the state of
      consciousness was provided in the case of 395 patients (29.22%). In the case of
      40 calls, patients were not found on the spot. Vasovagal syncope, death, acute
      alcoholism, epilepsy, trauma, stroke, hypoglycemia, psychoneurosis and
      intoxication represent the most usual diagnosis made by physicians who examined
      the patients.

PMID- 8649163
TI  - [Disorders of consciousness due to disorders of body fluid composition--case
      report of a female patient].
AB  - We report a female patient presenting with sepsis and multi-organ failure
      following eclampsia and intrauterine childdeath. In the phase of recovery, the
      patient developed consciousness disorder and coma characterized by fasciculation,
      generalized myoclonia and respiratory insufficiency. The clinical picture
      corresponded to that of Lance Adam's syndrome. A quick change in the composition
      of body fluids in the polyuric phase of renal insufficiency associated with an
      antidiuretic hormone deficit was a cause of that disorder. Metabolic dysfunction
      and hyperexcitability of neurons developed as a result. Hyperexcitability of the
      caudal part of the medulla oblongata was responsible for the development of
      myoclonia. Following the correction of that disorder, the patient completely
      improved.

PMID- 8649164
TI  - [Acute neuroleptic poisoning].
AB  - According to the record of the Poison Control Centre in Zagreb, drugs most
      frequently implicated in poisoning episodes were benzodiazepines, neuroleptics,
      anticonvulsants including barbiturates, fluorides and antidepressants, which
      comprised more than 40% of all drug poisonings. More than 90% of neuroleptic
      poisonings were symptomatic on admission, 19% were comatose, 45% were drowsy, in
      15% extrapyramidal symptoms were present, and only 9% were without symptoms.
      Severe poisonings in adults were almost all due to suicidal ingestion, while in
      children low to moderate doses of different neuroleptics caused severe poisoning
      in 13 cases, with coma, convulsions and most often with acute dystonic reactions.
      In 30 cases of neuroleptic ingestion more than one drug was involved. The usual
      combinations were with other neuroleptic or psychoactive drugs such as
      benzodiazepines, biperiden, carbamazepin and antidepressants. Therapeutic
      measures were gastric emptying in 32% of cases, biperiden when dystonia was
      present but only after consultation with the Centre and with 12-14 hours delay,
      and supportive treatment in all symptomatic patients.

PMID- 8649165
TI  - [Sepsis in surgery patients].
AB  - The aim of the study was to determine therapeutic possibilities in surgical
      patients with sepsis following gunshot wounds of the abdomen and lower
      extremities. Thirty patients who underwent repeated surgical procedures in
      general or peridural anesthesia were analyzed. Eleven patients developed ARDS, of
      which 7 also had acute renal insufficiency and required hemodialysis. Mechanical
      ventilatory support and PEEP therapy were instituted. In 4 cases, alprostidil at
      a dosage of 0.1 microgram/kg body weight/min over 2 days was given. Empirical use
      of antibiotics was at the beginning of the therapy carried out by penicillin,
      gentamicin and metronidazole and later according to the antibiogram. One patient
      presented with spinal meningitis after the insertion of peridural catheter.

PMID- 8649166
TI  - [Causes of complications in the early postoperative period after heart surgery].
AB  - In this study we have evaluated 32 patients who underwent open heart surgery with
      extracorporeal circulation. The aim of the study was to determine the influence
      of duration of surgical procedure, amount of bleeding after surgery, duration of
      assisted ventilation, need for mechanical and pharmacological assistance on the
      occurrence of complications in the early postoperative period. Sixteen patients
      who developed signs of systemic infection were evaluated. Other 16 patients had
      similar clinical characteristics and they were operated on the same day or within
      the same week as patients in the first group and they served as the controls.
      There was a statistically significant difference between those two groups in the
      duration of surgical procedure, amount of blood loss after surgery, amount of
      transfusions and duration of mechanical ventilation. The group of patients with
      systemic infection and other complications required in the majority cases left
      ventricular support and developed multiorgan system failure that resulted in a
      higher rate of mortality. In conclusion, this study shows that the causes of
      complications and systemic infection in the early postoperative period could be
      due to a greater blood loss following surgery, demand for blood transfusions and
      duration of mechanical ventilation.

PMID- 8649168
TI  - [How to evaluate and improve the effectiveness of intensive care].
AB  - Organizational problems regarding intensive care units (ICU) have become more and
      more significant. It is necessary to question the factors which can influence
      their effectiveness, and in this way ensure the high quality of intensive care. A
      grading of intensive care units through a quantitative method is necessary, and
      then a comparison of intensive care units with the same care level. In making a
      judgement of efficacy we need to follow the whole intensive care process, even
      after medical treatment. The time has come for establishing a national data base
      concerning the organization of ICU size, structure, technological capacity,
      staff, type and number of patients, mortality, length of stay, bed occupation,
      criteria for admission and discharge, interventions and procedures, etc. Future
      multidisciplinary units must employ educated and closely-specialized
      professionals. From the means of estimating the severity of sickness, the
      relationship between expected and real mortality should be used in judging
      efficacy. Measuring the burden of work, by using the TISS model, modified
      according to the conditions of our ICUs, will show the type and quality of the
      work done, and, in addition, can also determine cost. It points to a rational use
      of tests, the use of guidelines and recommendations and further recommends the
      making of our own protocols. Close professional links between ICUs are also
      necessary.

PMID- 8649167
TI  - [Immunotherapy of sepsis and septic shock].
AB  - An extraordinary advance in basic sciences and technology did not reduce high
      lethality rate of the septic shock patients. The lethality rate of those patients
      was and still is around 50%. A new knowledge about a role of an inflammatory
      response on the infection in the later fatal course of the septic patients, led
      to the new approach in the treatment. A trial to block an endotoxin, cytokines,
      especially TNF and IL-1, as well as some other substances, in experimental models
      of sepsis, in spite of inconsistent results, is promising. A clinical experiences
      are disappointing, at first because of our still poor knowledge about various
      cytokines cascade, feedback mechanisms, cellular protective mechanisms, etc. The
      new chapter on the treatment of that highly lethal syndrome is open, though a
      final achievement of that approach is not clear till now.

PMID- 8649169
TI  - Critical care medicine in cyperspace: Internet resources and techniques for the
      intensivist.
AB  - The internet, is an informational tool of impressive proportions and
      capabilities. New software developments puts the use of this informational
      technology into the hands of all physicians. The use of Internet informational
      resources allows the intensivist to stay abreast of new developments in critical
      care medicine, communicate in a matter of seconds with colleagues half a world
      away, acquire medically related software, access remote database structures,
      obtain continuing medical education, and in the near future to "see' patients and
      obtain physiological data in real time. This tutorial will introduce the Internet
      and it's current tool suite.

PMID- 8649170
TI  - [Multiorgan dysfunction syndrome (MODS) caused by long bone fractures in young
      persons].
AB  - In a prospective open study, the effect of continuous epidural analgesia by the
      0.5% bupivacaine-methadone mixture on the perfusion in the lower extremities was
      examined in a group of 34 patients (mean age 31.25-1.52 years). The patients were
      undergoing a standard intensive care treatment. The minimum analgetic dose was
      determined by means of an analogous-visual ten-point scale, and the minimum
      perfusion dose (MBD) by measuring the foot temperature on the injured side with
      electronic thermometer Genius 3000 (Sherwood, USA). Immediately, following the
      injury, the foot temperature on the involved side measured 27.40-2.20 (25.20
      31.30) degrees C. The temperature differences between the injured and healthy
      foot were 5.92-2.19 degrees C, p = 0.0000. Forty minutes after the induction of
      epidural analgesia, the temperature of the injured foot increased to 32.44-1.75
      degrees C, p = 0.0000. After 24 hours, it measured 32.44-1.27 degrees C, i.e.
      almost the same as in the healthy foot, with the auricle temperature being 36.20
      1.62 degrees C. The total dose of methadone during the first 24 hours was 20 mg,
      and the 0.5% bupivacaine dose was 133.00-48.80 mg/24 hrs.

PMID- 8649171
TI  - [Acute pancreatitis caused by Ascaris lumbricoides in acute renal failure: case
      report].
AB  - A 26-year-old female patient with severe acute pancreatitis caused by Ascaris
      lumbricoides and consecutive acute renal failure is described. Acute pancreatitis
      is mostly caused by gallstones and acute or chronic alcohol ingestion. Ascariasis
      as an etiologic factor of acute pancreatitis does not occur very often except in
      the tropical and subtropical regions, where it is widely distributed. The goal of
      this case report was to worn the clinicians to pay attention to this, in our
      country rarely occurring cause of acute pancreatitis. In special circumstances of
      great migration of refugees and displaced persons with very low hygienic
      standards this rare possibility should be taken into account.

PMID- 8649172
TI  - [Accidental hypothermia with cardiorespiratory arrest. Case report].
AB  - A case of an effective cardiopulmonary resuscitation in a 71-year-old woman
      following drowning in a cold water and cardiopulmonary arrest for at least 20
      minutes is presented. Intubation, ventilation with 100% oxygen, external cardiac
      massage and administration of adrenaline, 1 mg intravenously, were implemented.
      Ventricular fibrillation, which occurred after adrenaline therapy, responded to
      electrical defibrillation with 200 J and converted into a sinus rhythm. Metabolic
      acidosis was corrected by intravenous sodium bicarbonate administration. The
      patient became gradually conscious, and she was weaned from mechanical
      respiration after 12 hours. Subsequently, the patient was extubated. There were
      no neurological deficits.

PMID- 8649173
TI  - A case of fatal sepsis in a child due to highly resistant Streptococcus
      pneumoniae.
AB  - Infection with Streptococcus pneumoniae continues to be a significant cause of
      morbidity and mortality. Most of the pneumococci remain exquisitely sensitive to
      penicillin. However, S. pneumoniae with a reduced susceptibility to penicillin
      has been reported. To our knowledge, we present the first case in Croatia of
      fatal sepsis in a child due to Streptococcus pneumoniae that was highly resistant
      to penicillin.

PMID- 8649174
TI  - [Paracetamol poisoning--case report].
AB  - A case of paracetamol poisoning in 17-month-old girl is presented. Clinical
      features and therapeutic procedures are described. Differences in paracetamol
      metabolism between children and adults are compared. Differences in the incidence
      of paracetamol poisoning between Croatia and USA are surveyed. The role of a
      physician in the education of parents and medical stuff on paracetamol toxicity
      is emphasized.

PMID- 8649175
TI  - [Laparoscopic cholecystectomy: initial results].
AB  - Laparoscopic cholecystectomy, as the innovative surgical procedure of gallbladder
      removal was accepted in our Centre as a significant progress in the surgical
      treatment of gallbladder disease. Our experience, after the first thirty-two
      cases, is that a well prepared surgical team and trained surgeons provide
      procedure performance with insignificant number of complications.

PMID- 8649176
TI  - [Frequency of hospitalization in intensive care units of community hospitals].
AB  - One thousand eight hundred and eighty-eight patients were hospitalized and
      treated at the Intensive Care Unit, Department of Internal Medicine, Zabok
      General Hospital between January 1, 1990 and December 12, 1994. The majority of
      patients were admitted because of cardiovascular diseases (59.3%),
      gastrointestinal diseases (14.0%), metabolic diseases (5.1%), chronic obstructive
      lung disorders (4.6%), allergy and shock. The results show that the average
      treatment time of patients with cardiovascular diseases was 4.6 days,
      gastrointestinal diseases 3.2 days and metabolic diseases 4.2 days. The average
      age for males was 58 years and for females 64 years. We conclude that even
      hospitals with moderate equipment may provide a quick and proper medical care for
      critically ill patients.

PMID- 8649177
TI  - [Echocardiography in the diagnosis and therapy of pulmonary embolism].
AB  - A 58 year old woman was admitted to this hospital because of retrosternal pain
      followed by dyspnea which developed a few hours prior to admission, and two week
      history of progressive intolerance of physical effort. Echocardiography was done
      which revealed enlarged cavity of the right atrium (59 x 54 mm) and right
      ventricle (46 mm) of the heart. (Scintigraphy showed numerous triangular lung
      zones of sharply decreased or completely absent perfusion. After the diagnosis of
      recurrent pulmonary embolism, the patient was treated with intravenous heparin at
      a dosage of 25000 a day for 10 days. Dyspnea settled within 48 hours of starting
      heparin, analysis of arterial blood gases became normal and the general condition
      of the patient improved. A repeated echocardigram showed a significantly reduced
      dilatation of the right atrium from 59 x 45 mm to 47 x 43 mm and decreased
      pulmonary hypertension from 110 mmHg, on admission, to 65 mmHg.

PMID- 8649178
TI  - [Pulmonary hypertension in acute pulmonary embolism].
AB  - Twenty-five patients with acute pulmonary embolism without other pulmonary or
      heart diseases were analyzed for pulmonary hypertension. Doppler echocardiography
      was used to determine the systolic pressure of the pulmonary artery (PAPs) from
      the maximal velocity of the tricuspid regurgitation using corrected Bernoulli's
      formula (PAPs = 1.23 x 4 Vmax2 - 0.09). Pulmonary hypertension was found in 84%
      (21/25) of the patients with acute pulmonary embolism. PAPs values ranged between
      34 and 90 mmHg (X = 54 +/- 7.5 mmHg) and hypocapnia with carbon dioxide partial
      pressure, PaCO2, ranged from 26 to 34 mmHg (X = 30 +/- 2 mmHg). PAPs showed a
      significant negative correlation with oxygen partial pressure (r = -0.87, P <
      0.01). According to the findings of lung scintigraphy, all patients with
      pulmonary hypertension had submassive pulmonary embolism with perfusion
      abnormalities in two segments (X = 5 +/- 2 segments). It is concluded that
      pulmonary hypertension may be expected in more than 80% of the patients with
      submassive acute pulmonary embolism, and hypoxemia and hypocapnia. Doppler
      echocardiography is a noninvasive method useful in the diagnosis and follow-up of
      pulmonary hypertension in patients with acute pulmonary embolism.

PMID- 8649179
TI  - Immunity at the surface: homeostatic mechanisms of the skin immune system.
AB  - The coordinated function of multiple epidermal and dermal cell populations allows
      the skin immune system to respond rapidly and effectively to a wide variety of
      insults occurring at the interface of the organism and its environment.
      Keratinocytes are the first line of defense in the skin immune system, and
      keratinocyte-derived cytokines are pivotal in mobilizing leukocytes from blood
      and signaling other cutaneous cells. Cytokine-mediated cellular communication
      also enables dermal fibroblasts and endothelial cells lining the cutaneous
      vasculature to participate in immune and inflammatory responses. Skin is an
      important site for antigen presentation, and both epidermal Langerhans cells and
      dermal dendritic cells play pivotal roles in T cell-mediated immune responses to
      antigens encountered in skin. Proinflammatory signaling pathways are necessarily
      balanced by a variety of regulatory pathways that help maintain the homeostatic
      functioning of the skin immune system.

PMID- 8649180
TI  - Interleukin-2 inhibits 3T3 fibroblast proliferation.
AB  - In order to clarify the role played by interleukin-2 (IL-2) in the regulation of
      fibroblast function, we investigated the effect of rat IL-2 and human recombinant
      IL-2 on 3T3 fibroblast proliferation and collagen synthesis. Fibroblasts were
      incubated with various concentrations of IL-2 for different periods of time. IL-2
      was found to decrease in time- and dose-dependent manner the proliferation of 3T3
      fibroblasts. This effect correlated with ability of IL-2 to enhance PGE2
      production by 3T3 fibroblasts. When 3T3 fibroblasts were cocultured with rat
      peritoneal mast cells (MC), the growth-inhibiting effect of IL-2 was
      significantly less pronounced. Treatment of the cultures with IL-2 had no effect
      on collagen production by both 3T3 fibroblasts and fibroblasts cocultured with
      MC. In conclusion, in this study we provide evidence that IL-2, the key cytokine
      in T-cell growth and differentiation, can affect fibroblast functions.

PMID- 8649181
TI  - Force development with inosine triphosphate and uridine triphosphate in
      chemically skinned vascular smooth muscle.
AB  - The contraction of vascular smooth muscle is thought to be regulated by
      reversible phosphorylation of the 20,000 dalton light chains of myosin, catalyzed
      by myosin light chain kinase that is dependent on calcium and calmodulin. With
      phosphorylation, there is a coincident increase in the actin-activated myosin
      NTPase activity, cross bridge interaction and contractile activity. However, this
      myosin phosphorylation mechanism may not be the sole factor controlling actin
      myosin interaction in vascular smooth muscle. Other mechanisms may function in
      addition to this myosin-linked regulation. A calcium-insensitive regulation of
      contraction was observed in helical strips of chemically skinned (Triton X-100)
      arterial smooth muscle. Millimolar concentrations of inosine triphosphate and
      uridine triphosphate supported concentration dependent force development in the
      absence of calcium. Force development was a function of the MgNTP concentration.
      At high free calcium concentrations, an additional component of force was
      observed. ITP and UTP, in contrast to ATP, are less effective substrates for the
      myosin light chain kinase, and their effect on actin-myosin interaction is thus
      less than that of ATP. They are, however, utilized by the myosin NTPase after
      treatment by ATP-gamma-S. The efficacy of the substrate for the activated NTPase
      is greater for UTP than ITP than for ATP.

PMID- 8649182
TI  - Reduction of bile secretion by prostaglandins in the rat in vivo.
AB  - Bile secretion has been reported to be regulated by circulating hormones and by
      autonomic liver nerves. In the in situ perfused rat liver, prostaglandins reduce
      bile flow and bile acid secretion. The aim of this study was to investigate the
      regulation of bile secretion by prostaglandins in the in vivo situation. The bile
      duct and portal vein of anaesthetised Wistar rats were cannulated by polyethylene
      tubes. Bile flow was determined gravimetrically. Bile acids were quantified by
      the 3-alpha-hydroxy-steroid-dehydrogenase method and by high-pressure-liquid
      chromatography (HPLC) separation. Administration of 1 microM prostaglandin F2
      alpha into the portal vein over 5 minutes reduced bile flow from 1.57
      microliter/min.g liver to 0.95 microliter/min.g liver and bile acids secretion
      from 148 to 81 nmol/100g/min. The administration of different doses (0.1 microM,
      1 microM, 10 microM) of prostaglandin F2 alpha reduced hepatic bile secretion in
      a dose-dependent manner. Similar effects were observed after infusion of
      prostaglandin D2. However, the ratio of the bile acids (alpha-tauromuricholic
      acid), beta-tauromuricholic acid, taurocholic acid, taurochenodeoxycholic acid,
      and taurodeoxycholic acid) was unchanged by prostaglandin F2 alpha. In
      conclusion, infusion of prostaglandin F2 alpha into the portal vein results in a
      reduction of bile flow and bile acid secretion in a dose-dependent manner. These
      results suggest that the effect is linked to canicular bile secretion.

PMID- 8649183
TI  - Magnetic fields and pineal function in humans: evaluation of nocturnal acute
      exposure to extremely low frequency magnetic fields on serum melatonin and
      urinary 6-sulfatoxymelatonin circadian rhythms.
AB  - Exposure to a 50/60-Hz electromagnetic field can decrease the nocturnal
      production of melatonin in rodents. Melatonin is considered to be a marker of
      circadian rhythms, and abnormalities in its secretion are associated with
      clinical disorders, including fatigue, sleep disruption, mood swings, impaired
      performance, and depression, which are consequences of desynchronisation.
      Interestingly, some epidemiological studies have been reported finding most of
      these clinical disorders in individuals living or working in an environment
      exposed to electromagnetic fields. This experiment was designed to look for the
      possible effects of acute exposure (9 hours) to 50-Hz linearly polarized magnetic
      fields (10 mu T) on the pineal function. Thirty-two young men (20-30 years old)
      were divided into two groups (control group, i.e., sham-exposed: 16 subjects;
      exposed group: 16 subjects). All subjects participated in two 24-hour experiments
      to evaluate the effects of both continuous and intermittent exposure to linearly
      polarized magnetic fields. They were synchronized with a diurnal activity from
      08:00 to 23:00 and nocturnal rest. The experiment lasted two months (mid-February
      to mid-April). The subjects were exposed to the magnetic fields (generated by
      three Helmholtz coils per bed) from 23:00 to 08:00, while lying down. Blood
      samples were collected during each session at 3-hour intervals from 11:00 to
      20:00 and hourly from 22:00 to 08:00. Total urine was collected every 3 hours
      from 08:00 to 23:00 and once during the night, from 23:00 to 08:00. The levels of
      serum melatonin and its metabolite in urine (6-sulfatoxymelatonin) in exposed men
      did not differ significantly from those in control (sham-exposed) subjects. This
      study shows that nocturnal acute exposure to either continuous or intermittent 50
      Hz linearly polarized magnetic fields of 10 mu T does not affect melatonin
      secretion in humans.

PMID- 8649184
TI  - Effect of acute and chronic treatment with triiodothyronine on serotonin levels
      and serotonergic receptor subtypes in the rat brain.
AB  - Hyperthyroidism is often associated with behavioral disorders, and thyroid
      hormones modify receptor sensitivity as well as the synthesis and/or turnover
      rate of many neurotransmitters. We evaluated the influence in adult rats of
      triiodothyronine (T3), administered s.c. (100 micrograms/kg) acutely (once only)
      or chronically (once a day for 3 or 7 consecutive days), on brain serotonin
      concentration and on the density and affinity of two brain serotonin (5-HT)
      receptor subtypes mainly involved in behavioral effects. After both acute and
      chronic T3 treatment, serotonin levels increased in the cerebral cortex but not
      in the hippocampus. The density and affinity of 5-HT1A receptors (using [3H]-8-OH
      DPAT as ligand) were not affected, while there was a significant decrease in the
      number of 5-HT2 receptors in the cerebral cortex (using [3H]ketanserin as
      ligand). This observation might indicate that thyroid hormones enhance 5-HT
      concentration in certain brain areas, thus causing a down-regulation of 5-HT2
      receptors. The serotonergic system could be involved in the complex brain
      neurotransmitter imbalance underlying hyperthyroidism-linked behavioral changes.

PMID- 8649185
TI  - Metallothionein in the ovaries of laying hens exposed to cadmium.
AB  - The presence of metallothionein (MT) and its mRNA in the ovaries of laying hens
      is reported. In laying hens injected with cadmium (Cd), Cd accumulated in the
      follicle walls of the ovaries not in the follicle yolks. In the follicle walls,
      (Cd, Zn)-MT and its mRNA were found. This indicates that MT bound to Cd is
      biosynthesized in the follicle walls. We suggest that MT might play a role in
      sequestering Cd. On the other hand, zinc (Zn) was found in the follicle walls and
      yolks in the Cd-treated laying hens. The relationship between Zn and (Cd, Zn)-MT
      is also discussed.

PMID- 8649186
TI  - Effects of bradykinin on the intracellular calcium concentration of pancreatic
      acinar AR42J cells.
AB  - We examined the effects of bradykinin (BK) on the intracellular free calcium
      concentration ([Ca2+]i) in rat pancreatic acinar AR42J cells. BK induced a dose
      dependent rise in [Ca+2]i in AR42J cells between the concentrations of 10(-12)M
      and 10(-7)M. The BK-evoked response was not affected by the presence of Co2+ or
      the absence of extracellular calcium. This response was suppressed by neomycin or
      the B2 antagonist, but not by the B1 antagonist. The response was also attenuated
      by treatment with dexamethasone. These results suggest that BK increases [Ca2+]i
      through the B2 receptors by promoting the phosphatidyl inositol turn-over and
      that, in the process of azaserine-induced undifferentiation, the pancreatic
      acinar cells strongly express the BK receptors.

PMID- 8649187
TI  - Effects of cytochrome P450 2E1 modulators on the pharmacokinetics of
      chlorzoxazone and 6-hydroxychlorzoxazone in rats.
AB  - A previously observed correlation between the rate of 6-hydroxylation of
      chlorzoxazone (CZX), a potent skeletal muscle relaxant, and cytochrome P450 2E1
      activity in vitro led to the postulation that this drug may be used as a non
      invasive probe for P450 2E1 activity in vivo. In this study, comparative
      pharmacokinetics of CZX and 6-hydroxychlorzoxazone (OH-CZX) were conducted in
      rats pretreated with an inhibitor or inducer of P450 2E1. After administration of
      CZX (150 mumol/kg, i.v.) to rats, blood samples were taken at different time
      points and the plasma concentrations of CZX and OH-CZX were determined by HPLC.
      The concentrations for CZX and OH-CZX over time were simultaneously fitted to a
      model of first-order elimination of CZX and first-order formation and elimination
      of OH-CZX using the computer program PCNONLIN to give pharmacokinetic parameters.
      Diallyl sulfide, a P450 2E1 inhibitor, at an oral dose of 50 or 200 mg/kg 12 hr
      prior to the CZX dose markedly inhibited the hydroxylation of CZX. Pretreatment
      with ethanol (15% in the drinking water for six days), a condition known to
      induce P450 2E1, slightly enhanced the formation of OH-CZX. To observe possible
      involvement of enzymes other than P450 2E1 in CZX metabolism, dexamethasone and
      phenobarbital were also used. Pretreatment with dexamethasone (50 mg/kg, i.p.
      daily for four days) did not cause changes in CZX and OH-CZX pharmacokinetics.
      Pretreatment with phenobarbital (75 mg/kg, i.p. daily for three days) enhanced
      CZX metabolism slightly. Our results suggest that P450 2E1 plays a major role in
      CZX hydroxylation in rats, but other factors may also be involved in the
      metabolism in vivo.

PMID- 8649188
TI  - Stress and hypertension: role of serum, red cell and tissue electrolytes.
AB  - The role of stress in the precipitation of hypertension is often described in
      clinical studies, although the underlying mechanism remains unknown. The present
      study concerns the role of electrolytes in stress induced hypertension in rats.
      Acute immobilization stress of one hour elevated systolic blood pressure (SBP) in
      rats. Restraint induced blood pressure elevation was associated with increased
      sodium concentration in the red cells, heart and kidney, and decreased potassium
      in the red cells. Magnesium concentration increased and calcium concentration
      decreased in the serum. Increases of calcium and decreases of magnesium were also
      observed in the heart and kidney tissues. The results may help toward an
      understanding of the relationship between hypertension and electrolyte
      homeostasis. A possible role of Na(+)-K(+)-ATPase activity leading to observed
      changes of electrolytes or vice versa is discussed.

PMID- 8649190
TI  - In vitro pharmacological properties of 4-bromodexetimide for muscarinic
      receptors.
AB  - The decrease of m-AChR density observed in neurodegenerative disorders has
      generated considerable interest in non-invasive mapping of muscarinic
      acetylcholine receptors (m-AChR) in the central nervous system. The aim of our
      study was to evaluate the selectivity of 4-bromodexetimide for the M1, M2, M3 and
      M4 m-AChR subtypes using in vitro binding analysis to determine the potential use
      of the bromine-76 labelled 4-bromodexetimide in the investigation of m-AChR
      subtypes in human brain with Positron Emission Tomography. Subtype selectivity of
      4-bromodexetimide was determined in competition studies against tritiated subtype
      selective ligands using various rat or rabbit structure homogenates reflecting a
      single binding site and in optimal saturation and low non specific binding
      conditions. These conditions were reached for every subtype studied by analyzing
      the data from the saturation experiments of the tritiated ligands. 4
      bromodexetimide displayed nanomolar affinities for the four m-AChR subtypes and a
      preferential selectivity for the M1 and M4 subtypes. The saturation analysis of
      [76Br]4-bromodexetimide, performed with rat cortex membranes showed high affinity
      for m-AChR receptors (Kd = 1.8 nM). As in vivo studies of [76Br]4-bromodexetimide
      showed preferential localization in the cortex and the striatum which are M1 and
      M4 rich structures and since it binds preferentially to the M1 and M4 subtypes,
      this radiotracer can still allow a combined subtype specific measurement of these
      muscarinic receptors.

PMID- 8649189
TI  - Scavenging of reactive oxygen species and inhibition of arachidonic acid
      metabolism by silibinin in human cells.
AB  - The effects of the flavonoid silibinin, which is used for the treatment of liver
      diseases, on the formation of reactive oxygen species and eicosanoids by human
      platelets, white blood and endothelial cells were studied. Silibinin proved to be
      a strong scavenger of HOCI (IC50 7 microM), but not of O2- (IC50 > 200 microM)
      produced by human granulocytes. The formation of leukotrienes via the 5
      lipoxygenase pathway was strongly inhibited. In human granulocytes IC50-values of
      15 microM and 14.5 microM silibinin were detected for LTB4 and LTC4/D4/E4/F4
      formation, respectively. In contrast to this, three- to fourfold silibinin
      concentrations were necessary to half maximally inhibit the cyclooxygenase
      pathway. For PGE2 formation by human monocytes an IC50-value of 45 microM
      silibinin was found. IC50-values of 69 microM and 52 microM silibinin were
      determined for the inhibition of TXB2 formation by human thrombocytes and of 6-K
      PGF1 alpha formation by human omentum endothelial cells, respectively. Thus, the
      deleterious effects of HOCI that can lead to cell death, and those of
      leukotrienes that are especially important in inflammatory reactions, can be
      inhibited by silibinin in concentrations that are reached in vivo after the usual
      clinical dose. Silibinin is thought not only to display hepatoprotective
      properties but might also be cytoprotective in other organs and tissues.

PMID- 8649191
TI  - Inhibition of cell growth by accumulated spermine is associated with a transient
      alteration of cell cycle progression.
AB  - Exposure of HL-60 cells to millimolar levels of spermine resulted in the
      inhibition of cell growth. Flow cytometry revealed that the addition of exogenous
      spermine prevented the accumulation of cells in the S and G2/M phases of the cell
      cycle as observed in the control cells. High intracellular levels of spermine
      completely suppressed the early onset of ornithine decarboxylase activity and,
      consequently, the intracellular increase in spermidine and putrescine. On the
      other hand, the addition of exogenous spermidine or putrescine also abolished
      ornithine decarboxylase activity, but in this case neither the growth of
      spermidine- or putrescine-treated cells nor the cell cycle phase distribution was
      affected. In the latter cells, intracellular levels of spermidine were not
      significantly different from control ones. These results suggest that the
      addition of exogenous spermine inhibits cell proliferation by hindering the
      increase in cellular spermidine needed to accelerate the G1 to S phase
      transition.

PMID- 8649192
TI  - Eosinophil Charcot-Leyden crystal protein binds to beta-galactoside sugars.
AB  - The Charcot-Leyden crystal protein (CLC) found in human eosinophils and basophils
      has 43-48% amino acid sequence similarity to the galectin family of beta
      galactoside binding proteins. We show here that enzymatically active recombinant
      CLC binds to a lactose-conjugated agarose resin, and that binding is inhibited in
      a dose dependent fashion by both lactose (IC50 = 41 mM) and fucose (IC50 = 380
      mM), but not by arabinose. These results demonstrate that CLC has functional as
      well as structural homology to the galectins, and suggest that CLC may also
      participate, as do the galectins, in mediating cell-cell and cell-matrix
      interactions, and in activating the cellular immune response.

PMID- 8649193
TI  - AUUUA-specific mRNA binding proteins in astrocytes.
AB  - Binding of ribonucleoproteins to specific regions of mRNA can alter mRNA
      stability. This level of posttranscriptional regulation has been shown to play a
      major role in gene expression of eukaryotic cells. This process involves the
      binding of ribonucleoproteins to specific region(s) of unstable, rapidly
      degrading mRNAs such as those found in various cytokines, lymphokines, and
      oncogenes, thereby increasing the mRNA's stability. In many instances the
      instability of the mRNA has been mapped to an AU-rich motif in the 3'
      untranslated region. We transcribed RNA molecules containing four reiterations of
      an AUUUA motif, and demonstrated with RNA- band shift experiments that the AUUUA
      motif complexes with phosphorylated AUUUA-specific 43-47 kDa mRNA binding
      protein(s) found in the cytosol of both rat brain and cultured rat astrocytes.

PMID- 8649194
TI  - Opposite effects of metallothionein I and spermine on mitochondrial function.
AB  - Previously, we reported that the stress-induced protein metallothionein I (MT)
      modulated the oxygen consumption (VO2) of isolated rat liver mitochondria [Life
      Sci. 55 221-226, 1994]. We now present confirmation of this finding, and the
      additional observations that in rat liver mitochondria, MT caused swelling and
      depolarization. These actions of MT were inhibited by the aliphatic polyamine,
      spermine. Our findings suggest that mitochondrial function could be influenced by
      the balance between MT and spermine.

PMID- 8649195
TI  - Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the
      brain.
AB  - On the helical strip of a capacitance vessel, the pulmonary artery of the rabbit,
      phenylethylamine (PEA) and tyramine act solely via displacement of noradrenaline
      from their storage sites and this effect is inhibited by desmethylimipramine
      (DMI). In contrast, on a resistance vessel, the perfused central ear artery of
      the rabbit, PEA enhances stimulation induced contractions in 0.2-0.8 microgram/ml
      concentration [catecholaminergic activity enhancer (CAE) effect], and increases
      smooth muscle tone (noradrenaline displacing effect) in 4-6 micrograms/ml
      concentration. This latter effect only is blocked by DMI. Tyramine acts similarly
      and is more potent than PEA. On the isolated brain stem PEA, tyramine and (
      )methamphetamine are, in the presence of cocaine and DMI, highly potent enhancers
      of stimulation induced release of 3H-noradrenaline, 3H-dopamine and 3H-serotonin.
      Compounds with specific CAE effect in the brain, (-)deprenyl and 1-phenyl-2
      propylaminopentane [(-)PPAP], antagonize tetrabenazine-induced depression of
      performance of rats in the shuttle box. PEA and tyramine, which are rapidly
      metabolized in vivo, are ineffective in this test up to 40 mg/kg, whereas (
      )methamphetamine, the stable PEA derivative, is highly effective. Compounds with
      CAE effect enhance at low concentrations the slow inward Ca2+ current in the sino
      auricular fibers of the frog heart and inhibit it in high concentration. PEA and
      tyramine enhance Ca2+ influx from 0.05 to 4 micrograms/ml and inhibit it in 8
      micrograms/ml. In conclusion, PEA and tyramine stimulate primarily coupling of
      action potential to transmitter release in the catecholaminergic neurons in the
      brain and displace catecholamines in higher concentration only.

PMID- 8649196
TI  - Luminal exposure of oxidants alter colonic absorptive function.
AB  - The colonic lumen is likely to contain oxidants derived from unabsorbed dietary
      materials including transition metals, rancid fat, drugs and bacterial
      metabolites. The present study looks at the effect of luminal exposure of
      different oxidants on colonic mucosal lipid peroxidation and absorptive function.
      All the oxidants tested induced fluid and electrolyte secretion and indomethacin,
      a prostaglandin synthesis inhibitor reversed this effect. Oxidants did not induce
      mucosal lipid peroxidation. This study suggests that oxidants induce functional
      alterations in colon possibly through stimulation of prostaglandin generation
      without influencing mucosal lipid peroxidation.

PMID- 8649197
TI  - Selenium homeostasis in the central nervous system of the rat.
AB  - These experiments have investigated selenium movement between blood and CNS in
      anaesthetised rats. Each animal was surgically anaesthetised and the left femoral
      blood vessels cannulated for blood withdrawal and solute infusion. Each rat
      received 75-selenium as sodium selenite infused in normal saline and experiments
      lasted between 5 minutes and 5 hours during which blood samples were periodically
      taken. At termination, the CNS was removed, regionally dissected and analysed
      with the plasma samples for 75-Se radioactivity by gamma-counting. Data were
      analysed by graphical analysis. Results showed unidirectional uptake of 75-Se
      into the CNS and regional differences were not found except for the hypothalamus.
      On average the CNS influx rate constant (Kin) was about 7 +/- 1 x 10(-5)
      ml/min/g. Data suggest that the 75-Se most likely entered the CNS as a free ionic
      form.

PMID- 8649198
TI  - Natural immunity and chronic exercise in rats. The involvement of the spleen and
      the splenic nerves.
AB  - We have previously shown that voluntary running for 4-5 weeks in the
      spontaneously hypertensive rat (SHR) significantly increased in natural cytotoxic
      mechanism in vivo, measured as clearance of 51Cr YAC-1 lymphoma cells from the
      lungs. In the present study, we have studied the possible role of the spleen and
      the splenic nerves in this augmentation. The SHR were randomly allocated to
      either a voluntary exercise group or a sedentary control group. After four weeks
      of exercise the runners and sedentary control SHR were further assigned to one of
      four groups: 1) no surgery, 2) sham operation, 3) splenic nerve section and 4)
      splenectomy. Splenectomy drastically reduced in vivo cytotoxicity in both runners
      and sedentary controls, but in vivo cytotoxicity of splenectomized voluntary
      runners was significantly higher than that of splenectomized sedentary control
      animals. Selective denervation of the spleen did not affect the in vivo
      cytotoxicity. These results indicate that the enhanced in vivo natural cytotoxic
      mechanism following voluntary chronic exercise in SHR is partly dependent on
      intact splenic function. However, this enhancement does not seem to be mediated
      by the splenic sympathetic nerves.

PMID- 8649199
TI  - Synthesis, characterization and pharmacological profile of tropicamide
      enantiomers.
AB  - The synthesis, chemical characterization and antimuscarinic activity of the two
      enantiomers of tropicamide are reported. Functional (rabbit vas deferens, guinea
      pig heart (force) and ileum) as well as binding experiments (m1 and m4 human
      muscarinic receptors expressed in CHO-K1 cells: M2 and M3 receptors of rat heart
      and submaxillary gland membranes) were used to evaluate the antimuscarinic
      activity of the enantiomers. The results show that none of the enantiomers is
      able to significantly discriminate among the receptors studied and therefore do
      not support the proposal of tropicamide as an M4 (m4) selective agent.

PMID- 8649200
TI  - Involvement of somatostatin, bombesin and serotonin in the origin of the
      migrating myoelectric complex in sheep.
AB  - Antroduodenal myoelectric activity was recorded in conscious sheep by electrodes
      chronically implanted in the muscular wall. Furthermore, plasma immunoreactive
      (i.r.) motilin, somatostatin and bombesin concentrations were determined by RIA.
      The intravenous infusion of somatostatin (20 ng/kg/min), bombesin (10 ng/kg/min)
      or serotonin (5-HT, 4 micrograms/kg/min) for 5 min, induced a duodenal
      myoelectric activity front followed by a period of quiescence. These duodenal
      events were concomitant with an antral inhibition. This pattern resembled that
      observed in a spontaneous migrating myoelectric complex (MMC) in sheep. Bombesin
      and 5-HT evoked an additional and transient increase in antral activity
      simultaneously with the duodenal activity front. On the other hand, plasma i.r.
      motilin levels did not show any fluctuations during spontaneous MMC cycles or
      after somatostatin, bombesin or 5-HT infusions. Likewise, plasma i.r. bombesin
      levels remained unchanged during spontaneous MMC or after administration of
      somatostatin. However, 5-HT -induced duodenal activity fronts were closely
      associated with a sharp peak in plasma i.r. bombesin. Finally, plasma i.r.
      somatostatin concentrations rose at the end of spontaneous phase III and peaked
      in phase I. A similar pattern of somatostatin release in plasma was found while
      the duodenal activity front and quiescence period developed after either 5-HT or
      bombesin infusions. These results do not indicate a role for motilin in the
      control of MMCs in sheep, although a definitive conclusion cannot be drawn until
      synthetic sheep motilin is available. However, our data suggest that somatostatin
      and bombesin-like peptides as well as 5-HT, acting in a coordinated manner, could
      be involved in the regulation of cyclical antroduodenal motor events in sheep.

PMID- 8649201
TI  - Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human
      endothelial cells.
AB  - Leukocyte adhesion and transmigration through the endothelial cell (EC) layer
      plays a crucial role in inflammation. IL-1 alpha and TNF alpha increase EC
      adhesiveness for leukocytes by stimulating surface expression of ICAM-1
      (intercellular adhesion molecule 1, CD54), VCAM-1 (vascular cell adhesion
      molecule 1, CD106) and E-selectin (CD62E). In this study, the effects of
      ibuprofen on IL-1 alpha and TNF alpha-induced expression of ICAM-1, VCAM-1 and E
      selectin on cultured human umbilical vein EC (HUVEC) were analyzed. Exposure to
      IL-1 alpha or TNF alpha resulted in an increased expression of VCAM-1, ICAM-1,
      and E-selectin. Ibuprofen was identified as a potent inhibitor of IL-1 alpha and
      TNF alpha-induced surface expression of VCAM-1 and a less potent inhibitor of
      pyrogen-induced expression of ICAM-1, whereas no effect on E-selectin was found.
      The effects of ibuprofen on VCAM-1 expression were dose-dependent (IC50 [IL-1
      alpha]: 0.5 mM; IC50 [TNF alpha]: 0.5 mM) and time-dependent with maximum
      responses observed after 18 h. Moreover, ibuprofen abrogated pyrogen-dependent
      adhesion of leukocytes to HUVEC. Ibuprofen also inhibited VCAM-1 mRNA expression
      in pyrogen activated EC. VCAM-1-downregulation on EC by ibuprofen may contribute
      to the anti-inflammatory actions of the drug.

PMID- 8649202
TI  - Place preference and microdialysis studies with two derivatives of
      methylphenidate.
AB  - Conditioned place preference studies with derivatives of dl-threo-methylphenidate
      (Ritalin) which bear a bromine atom or a methoxy group on the para position of
      the phenyl ring are reported. Both derivatives, as well as methylphenidate
      itself, induced a significant increase in place preference when administered i/p
      to rats at 10 mg/Kg, compared with saline conditioned controls. The change for p
      bromomethylphenidate was slightly greater than that seen for methylphenidate or p
      methoxymethylphenidate. Extracellular dopamine in the striatum, and locomotor
      activity, were also increased by i/p administration of p-methoxymethylphenidate
      (20 mg/Kg) to a similar extent to the increases seen with this dose of
      methylphenidate or p-bromomethylphenidate in an earlier study (Pan et al. Eur. J.
      Pharmacol. 264: 177-182, 1994). Administration of p-methoxymethylphenidate failed
      to abolish increases in extracellular dopamine and locomotor activity induced by
      subsequent administration of cocaine (20 mg/Kg). It is concluded that the
      methylphenidate derivatives share the general pharmacological properties of other
      psychostimulant drugs.

PMID- 8649203
TI  - The interaction of clozapine with the meta-chlorophenylpiperazine (mCPP)
      discriminative stimulus.
AB  - The psychotropic effects of the 5-HT2C agonist mCPP in human subjects are blocked
      by the atypical antipsychotic clozapine, but not by typical antipsychotics. An
      understanding of the mechanistic basis for the interaction of clozapine and mCPP
      would provide further insight into the basis for its unique therapeutic effects
      in humans. Drug-induced stimulus control provides an animal model for the
      subjective effects of psychotropic agents in humans. In the present study, the
      interaction of the atypical antipsychotic clozapine and the typical antipsychotic
      fluphenazine with the mCPP-stimulus were defined. Neither drug antagonized the
      stimulus effects of mCPP in vivo. In contrast, clozapine fully antagonized the
      mCPP-stimulated phosphoinositide turnover at the 5-HT2C receptor in vitro. The
      present data indicate that the paradigm of mCPP-induced stimulus control does not
      facilitate the differentiation of atypical and typical antipsychotic activities.

PMID- 8649204
TI  - Estimation of oral drug absorption in man based on intestine permeability in
      rats.
AB  - Predicting the fraction of an oral dose absorbed in humans is of considerable
      interest at an early stage of a research program in the pharmaceutical industry.
      Models described in the literature to predict the oral absorption in man include:
      the permeability in Caco-2 cells, absorption from a perfused segment of rat
      intestinal lumen and uptake into everted rings. The present study used an
      isolated and vascularly perfused rat small intestine to determine the
      permeability values of eleven compounds across the intestinal epithelium. A good
      correlation was obtained between the permeability values determined in this model
      and the proportion of an oral dose absorbed in humans. Compared to the other
      models, the present one could allow the appearance in the artificial bloodstream
      and the intestinal metabolism of a compound to be studied simultaneously.

PMID- 8649205
TI  - Minireview. Galanin-acetylcholine interactions: relevance to memory and
      Alzheimer's disease.
AB  - The neuropeptide, galanin, and its receptors are localized in the cholinergic
      basal forebrain and its projection areas in mammalian brain. Centrally
      administered galanin inhibits acetylcholine release in the rat ventral
      hippocampus, and produces deficits in learning and memory tasks. In Alzheimer's
      disease, galanin is overexpressed in terminals innervating the nucleus basalis of
      Meynert cell bodies. Selective galanin receptor antagonists provide a novel
      approach for increasing cholinergic function, as a potential adjunct to the
      clinical treatment of dementias.

PMID- 8649207
TI  - Polyamine deprivation provokes an antalgic effect.
AB  - It is well established that inhibition of putrescine formation using D,L-2
      (difluoromethyl)ornithine and feeding a polyamine-deficient diet together with
      non-absorbable antibiotics (neomycin and metronidazole), prevent almost
      completely the growth of tumors in rats. A similar regimen given to patients with
      prostate cancer not only reduced the titer of prostate specific antigen in serum,
      but surprisingly provoked at the same time an antalgic effect. This observation
      led us to study the potentiation effect of polyamine deprivation on pain
      threshold in healthy rats. Animals were fed for 2 weeks with an artificial diet
      of known polyamine content, in combination with antibiotics and 2
      (difluoromethyl)ornithine, and were then submitted to pain stimuli using two
      models, the Randall-Selitto test and the Tail-Flick test. Polyamine deprivation
      produced in these models an increase in the latency of the response, even under
      conditions which did not produce significant changes of the polyamine
      concentrations in blood and brain. From these observations, we may conclude that
      the polyamines play a role in the perception of nociceptive stimuli under
      physiological conditions.

PMID- 8649206
TI  - Metabolism of [Des-Gly10,D-Trp6]LHRH ethylamide in rabbit nasal tissue.
AB  - The objective of this study was to determine whether [Des-Gly10, D-Trp6] LHRH
      ethylamide, a nonapeptide LHRH agonist known as deslorelin, is degraded by the
      rabbit nasal tissue. Deslorelin was incubated with nasal tissue either alone or
      in the presence of 0.1 mM ouabain, 0.1% 2,4-dinitrophenol, 0.1 mM phosphoramidon,
      0.1 mM N-tosyl-L-phenylalanine chloromethylketone (TPCK) or 2% EDTA at 37 degrees
      C. Furthermore, deslorelin alone was incubated with nasal tissue at 4 degrees C.
      All incubation solutions were adjusted to isotonicity and pH 5.0. At the end of
      90 min, the supernatants were analyzed using a reversed-phase HPLC. Metabolite
      peaks could be detected in all the above experiments except the low temperature
      study, suggesting inhibition of metabolism at low temperature. Intact drug
      remaining in the supernatant was elevated by about 32% by ouabain and
      dinitrophenol, suggesting that energy-dependent cellular uptake is likely for
      deslorelin. Phosphoramidon and TPCK failed to alter deslorelin levels, suggesting
      that phosphoramidon and TPCK sensitive endopeptidases did not contribute to the
      observed deslorelin metabolism. However, EDTA significantly elevated the intact
      deslorelin levels in a dose-dependent manner, with an elevation of 113% with 2%
      EDTA. With 2% EDTA, the metabolite peaks almost completely disappeared,
      indicating a possible role for either metal-activated peptidases or metallo
      endopeptidases in the nasal metabolism of deslorelin.

PMID- 8649208
TI  - Mechanisms of mechanical stress-induced Ca(2+)-mobilization sensitized by
      lysophosphatidic acid in cultured smooth muscle cells.
AB  - We have previously reported that lysophosphatidic acid (LPA) sensitizes
      mechanical stress-induced cytosolic free Ca2+ concentration ([Ca2+]i) response
      related to Ca2+ entry through Gd(3+)-sensitive ion channels (Biochem. Biophys.
      Res. Commun. 208 19-25 1995). Here we examined the contribution of Ca2 release
      from intracellular stores to the mechanical stress-induced [Ca2+]i response
      sensitized by LPA in cultured longitudinal muscle cells from guinea pig ileum.
      Although the percentage of responsive cells to the mechanical stress in the
      presence of 30 nM LPA declined by decreasing extracellular Ca2+ concentration to
      less than 20 microM, the amplitude of the mechanical stress-induced [Ca2+]i
      transient did not depend on extracellular Ca2+ concentrations (10 microM-1.8 mM).
      The [Ca2+]i transient was completely abolished by treatment with thapsigargin. In
      addition, the amplitude of the [Ca2+]i transient gradually decreased after
      ryanodine and caffeine treatment. These results indicate that the mechanical
      stress-induced [Ca2+]i transient in the presence of LPA is mainly due to Ca2+
      release from ryanodine-sensitive intracellular stores and may be triggered by
      Ca2+ influx through Gd(3+)-sensitive ion channels.

PMID- 8649209
TI  - Inhibition of cAMP mediated relaxation in rat coronary vessels by block of Ca++
      activated K+ channels.
AB  - The hypothesis for this study is that block of calcium activated potassium (KCa)
      channels inhibits cAMP induced relaxation in pressurized rat coronary resistance
      arteries. Pressure-diameter experiments with septal arteries (200-270 microns
      internal diameter at 60 mmHg and maximum dilation) showed significant basal tone
      over a range of pressure from 40-120 mmHg. The level of tone was increased with
      the thromboxane A2 analogue 9,11-dideoxy-11 alpha, 9 alpha-epoxy
      methanoprostaglandin F2 alpha (U46619) in all experiments. Receptor activation of
      the cAMP pathway was done with adenosine (ADO) and isoproterenol (ISO).
      Tetraethylammonium ion (TEA+), 1mM, significantly inhibited relaxation to ADO
      (10(-6)-10(-3)M) with a maximal inhibition of 75 +/- 7% (as a % of maximum
      diameter change with the vasodilator alone) at 10(-3)M ADO. TEA+ inhibited ISO
      (10(-6)M) relaxation by 63 +/- 9%. Direct activation of the cAMP pathway was done
      with forskolin and 8-bromo-cAMP. TEA+ significantly inhibited forskolin (10(-6)
      10(-4)M) induced relaxation with a maximal inhibition of 81.3 +/- 1.2% at 10(-4)M
      forskolin. TEA+ and iberiotoxin (10(-7)M) significantly inhibited 8- bromo-cAMP
      (10(-3)M) induced relaxation by 72 +/- 5% and 56 +/- 3% respectively. The effect
      of TEA+ on relaxation induced by nitroprusside (a cGMP dependent vasodilator) was
      not significant. The results show that rat coronary resistance arteries possess
      significant myogenic tone and modulation of Kca channels plays a major role in
      cAMP mediated relaxation.

PMID- 8649210
TI  - The role of vasopressin, somatostatin and GABA in febrile convulsion in rat pups.
AB  - In order to further elucidate a possible role of neuropeptides and GABA in the
      pathogenesis of febrile convulsions, we studied changes of immunoreactive
      arginine vasopressin (IR-AVP), IR-somatostatin (IR-SRIF) and gamma-aminobutyric
      acid (GABA) in the rat brain after febrile convulsions induced by ultra-red light
      (UR). Male Wistar rats at 16 days of age irradiated with UR developed generalized
      convulsions after 4.9 +/- 0.5 min irradiation. Six rats were killed by microwave
      irradiation 3 min after UR irradiation prior to convulsion development, and 29
      rats were killed either 0 min, 2 h, 6 h, 24 h or 48 h after febrile convulsions.
      Non-irradiated rats served as controls. The rat brain was dissected into 4
      regions; amygdala, hypothalamus, cortex and hippocampus, and subjected to
      radioimmunoassays. IR-AVP levels in hypothalamus were increased 3 min after UR
      and decreased at 2 h and 6 h after the convulsions. IR-SRIF levels were increased
      in cortex and hippocampus at 3 min after UR and 0 min after the convulsions. The
      GABA content increased in all regions tested at 2 h and 6 h after the
      convulsions. These results suggest that AVP, SRIF and GABA may be involved in the
      pathogenesis of febrile convulsions in different ways.

PMID- 8649211
TI  - Direct inhibitory effect of corticotropin releasing hormone on isolated caecal
      circular smooth muscle cells of guinea pig via adenylate cyclase system.
AB  - Smooth muscle cells isolated separately from the caecal circular smooth muscle
      layer of the guinea pig were used to investigate whether corticotropin releasing
      hormone (CRH) can inhibit directly the contraction produced by cholecystokinin
      octapeptide (CCK-8). In addition, the role of adenylate cyclase and guanylate
      cyclase in the direct inhibitory effect of CRH was examined. CRH inhibited the
      contractile response produced by 10(-9)M CCK-8 in a concentration-dependent
      manner, with an IC50 value of 0.16nM. An inhibitor of particulate guanylate
      cyclase and an inhibitor of soluble guanylate cyclase had no significant effect
      of the relaxation produced by CRH. In contrast, an inhibitor of adenylate cyclase
      and an inhibitor of cAMP-dependent protein kinase significantly inhibited the
      relaxation produced by CRH. This is the first report demonstrating the direct
      inhibitory action of CRH on the isolated caecal smooth muscle cells via adenylate
      cyclase system.

PMID- 8649212
TI  - Magnetic targeting of thermosensitive magnetoliposomes to mouse livers in an in
      situ on-line perfusion system.
AB  - We recently reported the preparation and in vitro targeting of dextran magnetite
      (DM)-incorporated thermosensitive liposomes, namely thermosensitive
      magnetoliposomes (TMs) [Viroonchatapan et al. Pharm. Res. 12 1176-1183 (1995)].
      The current study was designed to determine whether these novel liposomes can be
      targeted to the mouse liver with the aid of an extracorporeal magnet. An on-line
      liver perfusion system consisting primarily of a sample injector, permanent
      magnets, and a fluorescence detector was established for a real-time measurement
      of targeting efficiency of TMs containing calcein as a fluorescent marker. Normal
      and reticuloendothelial system (RES)-blocked livers from mice were used for the
      perfusion experiments. In the RES-blocked livers, percentage holdings of TMs were
      73-80% and 26-45% in the presence and absence of magnetic field, respectively,
      indicating an efficient targeting of TMs with a targeting advantage index (TAI)
      of 1.6-3.1. On the other hand, TAI in the normal livers was found to be 1.1-1.4
      and less than that in the RES-blocked livers, suggesting a role of RES uptake of
      TMs. The effects of DM concentrations in TM suspensions on the percentage holding
      of TMs were shown to be minor. Liposome concentration dependence was observed for
      hepatic uptake of TMs, possibly because of the saturation of phagocytosis by
      Kupffer cells. The present results suggest that TMs would be useful in future
      cancer treatment by magnetic targeting combined with drug release in response to
      hyperthermia.

PMID- 8649213
TI  - Liposomal Arg-Gly-Asp analogs effectively inhibit metastatic B16 melanoma
      colonization in murine lungs.
AB  - Analogs of a synthetic peptide having the L-arginine-L-glycine-L-aspartic acid
      (RGD) sequence have been found to decrease metastatic colonization. To enhance
      the metastasis-suppressing efficacy of these analogs, we sought to stabilize
      these analogs and to prolong their circulation time by incorporating them into a
      liposomal formulation. Various structures of RGD analogs grafted to hydrophobic
      groups were synthesized and then incorporated into liposomes. Liposomes composed
      of distearoylphosphatidylcholine, cholesterol, dipalmitoylphosphatidylglycerol
      and appropriate RGD analogs were injected intravenously along with B16BL6 murine
      melanoma cells into mice. Liposomal RGD (0.6 mumol of the analog equivalent to
      ca. 200 micrograms RGD peptides) inhibited lung colonization up to 76%. This dose
      is an order of magnitude lower than that for comparable inhibition reported for
      free RGD. Multi-dose administration of liposomal RGD (0.15 mumol of the analog)
      also inhibited the spontaneous lung metastasis of cells from a primary tumor site
      of B16BL6 cells subcutaneously implanted into the footpad of mice. Taken
      together, our data indicate that liposomal RGD may serve as a useful anti
      metastatic agent.

PMID- 8649214
TI  - Genetic differences in delta 9-tetrahydrocannabinol-induced facilitation of brain
      stimulation reward as measured by a rate-frequency curve-shift electrical brain
      stimulation paradigm in three different rat strains.
AB  - Lewis, Fischer 344, and Sprague-Dawley rats were implanted with electrodes in the
      medial forebrain bundle and trained to lever press for brain stimulation reward
      using a rate-frequency curve-shift electrical brain stimulation paradigm based on
      a series of 16 pulse frequencies ranging from 25 to 141 Hz in descending order.
      Once reward thresholds were stable, rats were given 1.0 mg/kg delta 9
      tetrahydrocannabinol (delta 9-THC), the psychoactive constituent in marijuana and
      hashish, or vehicle, by intraperitoneal injection. Lewis rats showed the most
      pronounced delta 9-THC-induced enhancement of brain reward functions. Sprague
      Dawley rats showed an enhancement of brain reward functions that was
      approximately half that seen in Lewis rats. Brain reward functions in Fischer 344
      rats were unaffected by delta 9-THC at the dose tested. These results are
      consistent with previous work showing Lewis rats to be highly sensitive to the
      rewarding properties of a variety of drugs of abuse, including opiates, cocaine,
      and alcohol, while Fischer 344 rats are relatively less sensitive. They extend
      such previous findings to cannabinoids, and further suggest that genetic
      variations to other cannabinoid effects may also exist.

PMID- 8649215
TI  - Interleukin-1 beta specifically stimulates nitric oxide production in the
      hypothalamus.
AB  - In previous experiments we have shown the role of nitric oxide (NO) in basal and
      interleukin-1 beta (IL-1 beta)-induced CRH and ACTH release in vitro. Now, we
      have studied the possible production of NO from hypothalamic cell cultures,
      particularly after IL-1 beta stimulation or L-NOArg inhibition, by high
      performance liquid chromatographic (HPLC) assay of L-citrulline production,
      adding further evidence for a role of NO in IL-1 beta activity in the
      hypothalamus.

PMID- 8649217
TI  - Allosteric and competitive interactions of 2 alpha-(2',2'-disubstituted- hydroxy
      ethoxy)tropane and its optical isomers at rat central muscarinic acetylcholine
      receptors.
AB  - Both allosteric and competitive interactions of 2 alpha-(2',2'-disubstituted
      hydroxy-ethoxy)tropane (2 alpha-DHET) and its four optical isomers with
      muscarinic acetylcholine receptors in rat cerebral cortex were investigated. 2
      alpha-DHET and its optical isomers allosterically decelerated the dissociation of
      bound [3H]N-methylscopolamine in a concentration-dependent manner, but these
      compounds failed to decelerate the dissociation of bound [3H]quinuclidinyl
      benzilate. The potencies of 2 alpha-DHET and its optical isomers to decelerate
      the dissociation of bound [3H]N-methylscopolamine were not differed
      significantly, but the competitive binding potencies of these compounds were
      significantly different. The order of potencies of 2 alpha-DHET and its four
      optical isomers to inhibit the binding of [3H]quinuclidinyl benzilate to central
      muscarinic acetylcholine receptors was 1S-2 alpha-2'R > 1R-2 alpha-2'R > 2 alpha
      DHET > 1S-2 alpha-2'S > 1R-2 alpha-2'S the isomer with 1S-2 alpha-2'R
      configuration was about two orders of magnitude more potent than the isomer with
      1R-2 alpha-2'S configuration. The allosteric potencies were found not to be
      correlated with their competitive binding potencies.

PMID- 8649216
TI  - Minireview. Emerging new functions of the glycolytic protein, glyceraldehyde-3
      phosphate dehydrogenase, in mammalian cells.
AB  - Recent evidence indicates new, intriguing roles for the glycolytic protein,
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in fundamental mammalian cell
      processes. These include its role in DNA repair, in the translational control of
      gene expression, in DNA replication and in endocytosis. These findings have the
      potential to alter our basic understanding of the molecular mechanisms through
      which human or mammalian cells utilize individual proteins in vital, yet
      unrelated, cell processes.

PMID- 8649218
TI  - Induction of immediate-early, ornithine decarboxylase and antizyme gene
      expression in the rat small intestine after transient ischaemia.
AB  - The expression of the immediate early genes (IEG)s c-fos, c-jun and zif/268, and
      the genes coding for ornithine decarboxylase (ODC) and its regulatory protein
      antizyme (AZ), was studied in rat small intestine following transient ischemia.
      The ischemic stimulus for 10 min alone did not alter the expression of these
      genes. A rapid and transitory induction of all IEG mRNAs occurred in a
      coordinated manner peaking at 30 min following recirculation and returned to
      basal levels 3 hr after recirculation. Protein products of the IEGs accumulated
      in the smooth muscle layer of the intestine by 2-3 hr after recirculation.
      Expression of both ODC and AZ mRNAs initially decreased to 70% of control levels
      1 hr after recirculation but markedly increased at 2 to 4 hr after recirculation.
      The functional significance of these changes in gene expression in relation to
      tissue integrity and function after the ischaemia/reperfusion is discussed.

PMID- 8649219
TI  - Central cholinergic antinociception induced by 5HT4 agonists: BIMU 1 and BIMU 8.
AB  - The antinociceptive effect of two 5-HT4 agonists, BIMU 1 and BIMU 8, were
      examined in mice and rats by using the hot-plate, abdominal constriction and paw
      pressure tests. In both species, BIMU 1 (10-20 mg kg-1 s.c. and 40-60 mg kg-1
      p.o. in mice; 20 mg kg-1 i.p. in rats) and BIMU 8 (20-30 mg kg-1 s.c. and 60 mg
      kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats), produced significant antinociception
      which was prevented by atropine (5 mg kg-1 i.p.), hemicholinium-3 (1 microgram
      per mouse i.c.v.), SDZ 205-557 (10 mg kg-1 i.p.), GR 125487 (20 mg kg-1 i.p.) but
      not by naloxone (1 mg kg-1 i.p.), CGP 35348 (100 mg kg-1 i.p.) and reserpine (2
      mg kg-1 i.p.). Moreover, BIMU 1 and BIMU 8 increase of pain threshold, is
      abolished by nucleus basalis magnocellularis (NBM) lesions in rats. SDZ 205-557
      and GR 125487 which totally antagonized BIMU 1 and BIMU 8 antinociception did not
      modify morphine (7 mg kg-1 s.c.) or baclofen (4 mg kg-1 s.c.) antinociception.
      Intracerebroventricular injection in mice of BIMU 1 (3 micrograms per mouse) and
      BIMU 8 (10 micrograms per mouse), doses which were largely ineffective by
      parenteral routes, induces an antinociception whose intensity equaled that
      obtainable s.c., i.p. or p.o. In the antinociceptive dose-range, neither 5HT4
      agonist impaired mice motor coordination evaluated by rota-rod test. On the basis
      of the above data, it can be postulated that BIMU 1 and BIMU 8 exerted an
      antinociceptive effect mediated by a central amplification of cholinergic
      transmission.

PMID- 8649220
TI  - Effects of luteolin 5-O-beta-rutinoside in streptozotocin-induced diabetic rats.
AB  - We have investigated the antidiabetic activity of luteolin 5-rutinoside in
      streptozotocin(STZ)-induced diabetic rats. Treatment for 20 days with 2 mg/kg
      increased both pancreatic insulin and DNA content. When both luteolin 5
      rutinoside (2 mg/kg) and glibenclamide (1 mg/kg) were administered concurrently
      to STZ-diabetic rats, a marked antidiabetic activity was achieved. This effect
      was evidenced by a significant decrease in glycemia levels (> 50%), a 2.5-fold
      increase in insulin blood levels and an increase in body and pancreas weight,
      compared to the diabetic control group.

PMID- 8649221
TI  - Decreased tumor incidence and increased survival by one year oral low dose
      arginine supplementation in the mouse.
AB  - The effects of arginine on tumor growth, antitumor mechanisms and a potential
      therapeutic role have been reviewed recently. In these studies, however
      controversial they were, high dose protocols for arginine treatment have been
      applied. Based upon own recent findings that low dose arginine stimulates the
      immune system and blocks lipid peroxidation, we performed preventive treatment
      with low dose (50 mg/kg body weight per day, orally administered) L-arginine in
      150 mice for a period of one year. We compared survival and total number of
      tumors at the end of the feeding period to that found in 150 mice given taurine
      in the same dosage and in 150 mice without treatment. Survival of the arginine
      treated group was statistically significant as compared to that of the control
      group without treatment (p < 0.05): 116 mice were alive in the control group, 122
      in the group administered taurine and 132 in the arginine treated group. The
      total number of tumors was significantly lower in the arginine treated group vs.
      the control group (p < 0.01). The total number of malign and benign tumors was
      significantly lower in the arginine treated group, whereas taurine significantly
      reduced the number of benign tumors only (p < 0.05). Arginine and taurine
      stimulate the immune system at the lymphocyte level. Arginine also acts at the
      macrophage level, inducing nitric oxide mediated cytotoxicity against tumor
      cells. Both compounds are known to block the formation of lipid peroxidation
      products. We therefore suggest that these two mechanisms are responsible for the
      decreased total number of tumors and the concomitant increase in survival.

PMID- 8649222
TI  - Plant alkaloids, tetrandrine and hernandezine, inhibit calcium-depletion
      stimulated calcium entry in human and bovine endothelial cells.
AB  - Depletion of internal Ca2+ stores causes capacitative Ca2+ entry which occurs
      through non-selective cation channels sensitive to blockade by SK&F 96365.
      Recently, alkaloids of Chinese herbal medicinal origin, tetrandrine and
      hernandezine, have been shown to possess actions including inhibition of Ca2+
      channels in non-excitable cell types. In this study, we compared the actions of
      these novel inhibitors to those of SK&F 96365 in fura-2-loaded endothelial cells
      from human umbilical vein and bovine pulmonary artery. Depletion of Ca2+ from the
      internal stores was accomplished in Ca(2+)-free medium using an endoplasmic
      reticulum Ca2+ pump inhibitor, cyclopiazonic acid (CPA) or receptor agonists,
      histamine and bradykinin. Stimulation with histamine or bradykinin caused a
      marked and rapid transient increase in Ca2+ signal whereas CPA caused a smaller
      amplitude increase of longer duration. Restoring Ca2+ to the medium caused marked
      and sustained increases in the fluorescence indicating movement of Ca2+ into the
      cytosol presumably stimulated by the emptied Ca2+ stores. SK&F 96365 as well as
      tetrandrine and hernandezine antagonized depletion-induced Ca2+ entry. The
      results suggest that these putative inhibitors interact with Ca2+ entry triggered
      by depletion of the internal Ca2+ stores and their action is presumed to be on
      the non-selective cation channels. Their effectiveness may be enhanced by the
      mechanisms which lead to the opening of the Ca2+ influx channel.

PMID- 8649223
TI  - 50-mile walking race suppresses neutrophil bactericidal function by inducing
      increases in cortisol and ketone bodies.
AB  - To examine the effect of intensive aerobic exercise on the interaction between
      endocrine and immune systems, we studied in ten normal healthy male subjects the
      effect of a 50-mile walking race on blood concentration of hormones (insulin, GH,
      ACTH, cortisol, adrenaline, noradrenaline, and dopamine), ketone bodies, specific
      immunological functions (IgG, IgM, and PHA/Con A-induced lymphocyte
      blastformation test), and nonspecific immune (CH50, and neutrophil bactericidal
      functions). Neutrophil bactericidal activity was measured as chemiluminescences
      amplified by luciferin analog (CLA-DCL) and luminol (L-DCL). The race increased
      cortisol and ketone bodies, and decreased insulin, CLA-DCL, and L-DCL (all
      parameters; P < 0.01). However, other parameters were not significantly changed.
      There were significant negative correlations between changes of ketone
      bodies/cortisol and CLA/L-DCL (P < 0.05), however there was no significant
      correlations between changes of insulin and CLA/L-DCL. These data indicate that
      extensive aerobic exercise causes impaired neutrophil bactericidal function,
      probably due to the induced increases in both cortisol and ketone bodies. This
      impaired neutrophil function may cause the susceptibility to infection after an
      extensive exercise.

PMID- 8649224
TI  - Specific potentiation by cyclic AMP of natriuretic peptide-mediated cyclic GMP
      production in adipose tissue.
AB  - Adipose tissue of the mesenteric territory contains large quantities of
      natriuretic peptide receptors (NPR) mainly of the NPR-C subtype. Guanylyl cyclase
      bound receptors are also present since atrial natriuretic peptide (ANP) and C
      type natriuretic peptide (CNP) are equally potent in activating this enzyme.
      While searching for a potential biological role for NP in adipocytes we observed
      that ANP-mediated generation of cyclic GMP (cGMP) was potentiated when the cells
      were simultaneously treated with isoproterenol. Indeed, isoproterenol, a beta
      adrenergic agonist, and forskolin, an activator of adenylyl cyclase, can both
      double or triple cGMP production in response to ANF stimulation. There was a
      direct correlation between the level of cyclic AMP (cAMP) generated and the level
      of NP-mediated cGMP production suggesting that a cAMP-dependent mechanism may be
      responsible of this potentiation. To determine whether or not this phenomenon was
      unique to adipocytes, NPR subtypes were characterized in 4 established cell lines
      and their cAMP-dependent cGMP behavior examined. A10 and A7r5 smooth muscle cells
      showed identical ratio of NPR subtypes with about 95% NPR-C and 5% NPR-B. PC12
      cells presented 100% NPR-A and NIH 3T3 fibroblasts 50% NPR-C and 50% NPR-B.
      Regardless of the NPR subtype, forskolin could not potentiate the cGMP generation
      in these cell lines. These data indicate that the cAMP-dependent potentiation of
      the NP-mediated cGMP production is unique to adipocytes, appears independent of
      the guanylyl cyclase-linked NPR subtypes and may be involved in the sensitization
      of the guanylyl cyclase domain of NPR for a potential biological role of NP in
      the adipose tissue.

PMID- 8649225
TI  - Formation of adducts between 13-oxooctadecadienoic acid (13-OXO) and protein
      derived thiols, in vivo and in vitro.
AB  - Linoleic acid is metabolized by numerous tissues to oxidized derivatives
      possessing biological activity. In the current experiments, we have investigated
      the reaction of 13-oxooctadecadienoic acid (13-OXO) and the metabolic precursor
      13-hydroxyoctadecadienoic acid (13-HODE) with cellular macromolecules and model
      cellular nucleophiles. Colonic mucosal explants from Sprague-Dawley rats were
      incubated in the presence of [1-14C]-13-OXO or [1-14C]-13-HODE. The binding of
      radiolabel to the protein and nucleic acid fractions was analyzed by isopycnic
      centrifugation in Cs2SO4. Cellular homogenates incubated with either 13-OXO or 13
      HODE resulted in the binding of radiolabel to cellular protein. No significant
      amounts of reaction with cellular RNA or DNA were observed. To assess possible
      modes of reaction with cellular constituents, the oxidized fatty acids were
      incubated in vitro with oxygen, sulfur, or nitrogen, nucleophiles including,
      serine, cysteine, glutathione, methionine, lysine, adenosine, and guanosine.
      Under physiologic conditions, in the absence of cellular homogenates, only 13-OXO
      was reactive. In addition, only the sulfur-containing compounds cysteine and
      glutathione showed significant rates of reaction. Furthermore, treatment of
      colonic homogenates with N-ethlymaleimide reduced the binding of [1-14C]-13-OXO
      to cellular protein. These data support the suggestion that 13-HODE requires
      metabolic activation, by dehydrogenation to 13-OXO, prior to binding to cellular
      protein and that protein-derived thiol groups are involved in the binding
      reactions.

PMID- 8649226
TI  - Changes in high density lipoprotein subfraction lipids during neutral lipid
      transfer in healthy subjects and in patients with insulin-dependent diabetes
      mellitus.
AB  - While it is known that the transfer of cholesteryl ester (CE) from high density
      lipoprotein (HDL) to the apo B-containing lipoproteins is increased in patients
      with diabetes, the extent to which the various lipoprotein fractions engage in
      neutral lipid exchange and the magnitude to which triglyceride (TG) is
      translocated is not known. To examine in greater detail neutral lipid net mass
      transfer in diabetes, the HDL subfractions and the apo B-containing lipoproteins
      were separated, and the net mass transfer of CE and TG was compared to that of
      control subjects. In both groups, bidirectional transfer of CE from HDL3 to very
      low density lipoprotein (VLDL) + low density lipoprotein (LDL) and of TG from
      VLDL + LDL to HDL3, took place, but this process was significantly greater (P <
      .01) in insulin-dependent diabetes mellitus (IDDM). In contrast, CE and TG
      accumulated in HDL2 to a similar degree in normal and IDDM subjects. In
      recombination experiments with each of the apo B-containing lipoproteins, IDDM
      VLDL had a greater capacity to facilitate the exchange of core lipids from both
      IDDM and control HDL3: on the other hand, LDL from IDDM and control subjects both
      donated TG and CE to HDL2 and affected little change in HDL3. These findings
      indicate that all the major plasma fractions normally participate in the
      trafficking of CE and TG among the lipoproteins during neutral lipid transfer and
      show that the principal perturbation in cholesteryl ester transfer in IDDM
      involves altered interaction between VLDL and the HDL3 subfraction.

PMID- 8649227
TI  - Biochemical effects of dietary linoleic/alpha-linolenic acid ratio in term
      infants.
AB  - Recent statements concerning linoleic (LA) and alpha-linolenic acid (LNA) intakes
      for infants include a desirable range of LA/LNA ratios. To evaluate several
      dietary LA/LNA ratios, the fatty acid patterns of plasma and erythrocyte
      phospholipid fractions, as well as plasma total lipid fractions, were determined
      shortly after birth and at 21, 60, and 120 d of age in term infants fed formula
      with 16% of fat as LA and either 0.4, 0.95, 1.7, or 3.2% as LNA (LA/LNA ratios of
      approximately 44, 18, 10, and 5). The content of all n-3 fatty acids in both
      plasma fractions was higher at all times in infants who received the highest LNA
      intake; however, the docosahexaenoic acid (DHA) content was only half that
      shortly after birth or reported in breast-fed infants of comparable ages. The LA
      content of plasma lipids of all groups was higher at all times than shortly after
      birth but did not differ among groups. The arachidonic acid (AA) content was
      higher in infants who received the lowest LNA intake, but only half that at birth
      or reported in breast-fed infants. In contrast, the DHA content of the
      erythrocyte phospholipid fraction did not differ among groups until 120 d of age
      when it was higher in those who received the highest LNA intake and the AA
      content of this fraction did not differ among groups at any time. These data
      demonstrate that dietary LA/LNA ratios between 5 and 44 do not result in plasma
      or erythrocyte lipid levels of DHA or plasma lipid levels of AA similar to those
      at birth or reported by others in breast-fed infants. However, the data indicate
      that the LA/LNA ratio of the formula is an important determinant of the amounts
      of DHA and AA required to achieve plasma and erythrocyte levels of these fatty
      acids similar to those of breast-fed infants.

PMID- 8649228
TI  - Is dietary docosahexaenoic acid essential for term infants?
AB  - There is a need to determine whether there is a dietary requirement for
      docosahexaenoic acid (DHA, 22:6 omega 3) by term infants to achieve their full
      developmental potential. Studies of brain fatty acid composition have
      demonstrated that infants who were breast fed have greater levels of cerebral
      cortex DHA than infants who were formula fed, suggesting that DHA in the cerebrum
      is dependent on a supply in the diet. Some physiological studies report that
      electrophysiological and behavioral assessments of visual function are improved
      in breast-fed infants relative to those fed formula, and that this is related to
      the level of DHA in their erythrocytes, whereas other studies demonstrate
      equivalent visual function between breast- and formula-fed infants. However,
      randomized studies of DHA supplementation of infant formula demonstrate that the
      visual function of formula-fed infants can be improved to breast-fed levels by
      adding DHA to formula. Further work is necessary to establish if there are long
      term benefits of dietary DHA to the term infant.

PMID- 8649229
TI  - Dietary modulation of phospholipid fatty acid composition and lipoxygenase
      products in mouse lung homogenates.
AB  - This study investigated the potential of dietary fats to modulate the arachidonic
      acid content of mouse lung phospholipids and the formation of lipoxygenase
      products from arachidonic and eicosapentaenoic acids. Prior to breeding, female
      mice were fed for five months diets with 10 wt% of either olive oil, safflower
      oil, fish oil, or linseed oil. The same diets were fed to the females during
      gestation and to the pups from day 18 to day 42 postpartum. On day 42, the
      phospholipids were extracted from fresh lung tissue and separated into classes
      [phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylcholine
      (PC), and phosphatidylinositol (PI)] by thin-layer chromatography. Methyl esters
      of phospholipid fatty acids and unesterified fatty acids were analyzed by gas
      chromatography. At comparable dietary n-3/n-6 ratios, arachidonic acid was
      reduced 85 and 75% in lungs from mice fed linseed oil and fish oil, respectively,
      compared to lungs of safflower oil-fed mice. Dietary fats affected the proportion
      of arachidonic acid in phospholipids in the order: PE > PC > PS > PI. Following
      incubation of homogenized lung tissue, the total amount of 12-lipoxygenase
      products was lowest in lungs from mice fed olive oil, and 12
      hydroxyeicosatetraenoic acid was lowest in incubated lungs from mice fed linseed
      oil. Comparison of the amounts of lipoxygenase substrate fatty acids in the
      individual phospholipids with the lipoxygenase products suggested that the major
      substrate pool for the 12-lipoxygenase pathway in mouse lung homogenates was PC.

PMID- 8649230
TI  - Separation and quantitation of mono-, di-, and triglycerides and free oleic acid
      using thin-layer chromatography with flame-ionization detection.
AB  - alpha-Monoolein was prepared from glycidol and oleic acid by the regioselective
      opening of glycidol in the presence of an anionic resin. During the reaction, the
      lipochemical synthesis medium becomes enriched in monoolein, the effective
      emulsifying agent. This mixture can be analyzed by thin-layer chromatography
      coupled with flame-ionization detection (FID). The products and reagents do not
      need to be derivatized. Diglyceride and triglyceride by-products affecting the
      selectivity of the reaction also could be detected using this technique.
      Cholesterol was used as an internal standard. The factors influencing the
      separation, including the hydrogen flow rate, scan speed, and the composition of
      the developing solvent, were investigated. The degree of separation is highly
      sensitive to the hexane/diethyl ether ratio of the developing solvent. Good
      separation of triglyceride, oleic acid, the two diglycerides, cholesterol, alpha
      monoolein, and glycidol was obtained with the mixture hexane/diethyl ether/formic
      acid (65:35:0.04, by vol). Detector response, detection limits, and rod-to-rod
      variations also were examined. A range of rod loads giving a straightforward
      relationship between FID response and amount of compound loaded (relative to
      oleic acid and alpha-monoolein) was defined. The accuracy of the quantification
      was illustrated by analysis of a mixture of oleic acid and alpha-monoolein
      standards of known composition.

PMID- 8649231
TI  - Optimization of the mass spectrometric analysis of triacylglycerols using
      negative-ion chemical ionization with ammonia.
AB  - Conditions for the mass spectrometric analysis of triacylglycerols, via direct
      exposure probe, with ammonia negative-ion chemical ionization were optimized.
      Triacylglycerols were most favorably ionized, using the reactant gas pressure of
      approximately 8500 mtorr at the ion source temperature of 200 degrees C with the
      instrumentation used. Abundant [M-H]- ions were produced under these conditions
      without the formation of [M + 35]- cluster ions, which would interfere with the
      molecular weight region of triacylglycerols in the spectra. A rapid desorption of
      the sample from the probe wire is recommended, using a relatively high heating
      rate (approximately 40 mA s-1), to minimize thermal degradation of unsaturated
      molecules and the reducing effect of double bonds on the mass spectrometric
      response of triacylglycerols. Furthermore, the abundance of [M-H]- ion was
      enhanced by rapid heating, which we found to be important to improve the
      sensitivity. The appropriate amount of sample applied to the rhenium wire was in
      the region of 50-300 ng for one determination, i.e., only a few nanograms of a
      single triacylglycerol is required for production of a reliable spectrum. The
      reproducibility of the method was good as demonstrated with standards and a
      raspberry seed oil sample. The described mass spectrometric method is a fast and
      potentially useful tool for semiquantitative determination of triacylglycerol
      mixtures of various fats and oils. The discrimination, caused by differences in
      molecular size and unsaturation of triacylglycerols with 50 to 56 acyl carbons,
      was negligible under our optimized ionization conditions, thus, no correction
      factors were needed. These findings have not yet been verified with instruments
      in other laboratories. However, the present study shows how the analysis of
      triacylglycerols can be improved, regardless of the instrument, by optimization
      of the analytical conditions.

PMID- 8649232
TI  - Vitamin E protects chick tissues against ex vivo oxidation of heme protein.
AB  - Protection by dietary vitamin E against ex vivo oxidation of heme proteins in
      liver and heart tissues of chicks was studied. A previously developed assay
      consisting of deconvoluting spectra obtained from tissue homogenates to measure
      oxidation of heme proteins proved successful. Compared to liver and heart from
      chicks fed the basal diet, the tissues from chicks receiving vitamin E exhibited
      less oxidation.

PMID- 8649233
TI  - Protection by multiple antioxidants against lipid peroxidation in rat liver
      homogenate.
AB  - The purpose of this study was to test the hypothesis that multiple antioxygenic
      nutrients provide increased protection against lipid peroxidative damage to rat
      liver. Rats were fed diets (i) deficient in vitamin E and selenium (Diet 1), (ii)
      supplemented with vitamin E and selenium (Diet 2), (iii) supplemented with (ii)
      and in addition trolox C, N-acetylcysteine, coenzyme Q0, and (+)-catechin (Diet
      3), or (iv) supplemented with (iii) and in addition beta-carotene, ascorbic acid
      palmitate, canthaxanthin, and coenzyme Q10 (Diet 4). Liver homogenates were
      obtained from three rats fed each of the diets for six weeks and were incubated
      at 37 degrees C up to two hours with and without exogenous tertiary-butyl
      hydroperoxide (TBHP) or Cu2+. Lipid peroxidation was determined by measurement of
      thiobarbituric acid substances. Diets 2 and 3 significantly protected against in
      vivo hepatic lipid peroxidation, and this protection was augmented by Diet 4.
      Diets 2, 3, and 4 were protective against mild oxidation induced by TBHP or Cu2+.
      During incubations with exogenous TBHP and Cu2+, there were only small
      differences between diets supplemented with antioxidants in inhibition of lipid
      peroxidation, indicating that diets supplemented with vitamin E and selenium
      (Diet 2) may have provided the maximal protection for liver. The possible
      mechanisms of protection provided by multiple antioxidants in diets were
      discussed. Protection by multiple antioxidants against lipid peroxidation may
      translate to prevention of peroxidative damage to human tissue, a factor in human
      disease.

PMID- 8649234
TI  - Retinal fatty acids of piglets fed docosahexaenoic and arachidonic acids from
      microbial sources.
AB  - Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) serve
      important roles in perinatal visual and neural development. A neonatal pig model
      was used to determine if dietary supplementation with DHA and AA at slightly
      greater concentrations than normally found in human milk would influence fatty
      acid accretion in retina. One-day-old piglets were assigned to one of four diets
      (n = 5/group): (i) STD, standard diet containing fat similar to infant formula;
      (ii) STD + DHA, 0.7% of fatty acids as DHA; (iii) STD + AA, 0.9% as AA; and (iv)
      STD + BOTH, 0.8% as DHA plus 1.0% as AA. After 25 d, fatty acids in retina
      phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were determined.
      Supplementation with DHA resulted in approximately twofold increases (P < 0.05)
      in PC-DHA (4.88% in STD vs. 10.03% in STD + DHA and 9.47% in STD + BOTH).
      Similarly, AA supplementation increased PC-AA 1.3-1.4-fold (4.47% in STD vs.
      6.19% in STD + AA and 5.70% in STD + BOTH). For PE, supplementation with either
      fatty acid or in combination resulted in no significant increases, except for a
      1.2-fold increase in DHA for STD + BOTH (32.66%) vs. STD (28.38%). Thus, PC
      responded to dietary supplementation, with addition of DHA, AA, or BOTH,
      resulting in increases in respective fatty acids; PE was less responsive, with
      only STD + BOTH resulting in increased DHA. No significant competition between
      DHA and AA in incorporation into phospholipids was observed. In conclusion,
      consumption of a combination of DHA and AA by neonatal pigs supported accretion
      of DHA in retina phospholipids, while simultaneously supplying the AA necessary
      for membrane phospholipids and eicosanoid biosynthesis.

PMID- 8649235
TI  - Relationship between dietary supply of long-chain fatty acids and membrane
      composition of long- and very long chain essential fatty acids in developing rat
      photoreceptors.
AB  - The present study was designed to determine if dietary supply of long-chain fatty
      acid (LCFA, C20:4n-6, and/or C22:6n-3), reflecting levels that might be
      incorporated into infant formulas, influences the fatty acid composition of the
      visual cell membrane. The rod outer segment (ROS) of the retina was analyzed from
      rats fed diets varying in the ratio of 18:2n-6 to 18:3n-3 with or without 20:4n-6
      [arachidonic acid (AA)] and 22:6n-3 (docosahexaenoic acid) from birth to six
      weeks of age. The level of very long chain fatty acids (VLCFA, C24-C36) was
      identified using gas chromatography and gas chromatography-mass spectrometry. In
      the ROS, the highest relative percent of AA was attained in phosphatidylcholine
      (PC) and phosphatidylethanolamine (PE) of animals fed 1% AA diet, whereas feeding
      0.7% docosahexaenoic acid (DHA) diet significantly increased the DHA level in PC,
      phosphatidylserine, and phosphatidylinositol compared to feeding diets containing
      AA. VLCFA of n-6 and n-3 up to C36 were found in PC, with the most abundant fatty
      acids being C32 and C34. In PC, phosphatidylserine and PE, the n-6 tetraenoic
      VLCFA level was highly increased in animals fed 1% AA compared to other dietary
      groups. This study suggests that dietary fat containing small amounts of AA or
      DHA is an important factor influencing membrane fatty acid composition of the
      visual cell during development.

PMID- 8649236
TI  - The effect of docosahexaenoic acid on the electroretinogram of the guinea pig.
AB  - Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is found in
      consistently high concentrations in the retinae of mammals, yet its role in
      vision remains unclear. In this study, a mammalian model of variable retinal DHA
      concentration has been developed, such that the retinal phospholipids of guinea
      pigs contained between 2.5 and 30.8% DHA. Visual function was assessed using full
      field flash electroretinography, over a range of exposure levels spanning six log
      units. Trend analysis indicated that retinal function was altered by the tissue
      DHA level, and was described by a second-order polynomial "inverted U-shaped"
      function. The results suggested that although some amount of DHA is essential for
      normal retinal function, increases in the DHA level past an optimal amount, found
      to be 19%, provided diminishing returns. In this study, manipulation of the
      retinal DHA level accounted for 21-35% of the electroretinographic variability.

PMID- 8649237
TI  - Artificial rearing of infant rats on milk formula deficient in n-3 essential
      fatty acids: a rapid method for the production of experimental n-3 deficiency.
AB  - Research into the function of docosahexaenoic acid (DHA; 22:6n-3), the
      predominant polyunsaturated fatty acid (PUFA) in the central nervous system
      (CNS), is often hindered by the difficulty in obtaining dramatic experimental
      decreases in DHA in the brain and retina of laboratory rats. In this study, the
      artificial rearing procedure, whereby infant rats are removed from their mothers,
      gastrostomized, and fed synthetic formula, was used in an attempt to produce
      rapid changes in CNS levels of DHA. Female rats were raised, from day 4-5 of
      life, on one of two formulas-one containing the essential fatty acids of both the
      n-6 and n-3 series in proportions approximately equal to those of rat milk, and
      the other containing high levels of 18:2n-6 but very little n-3 fatty acid. At
      weaning, both groups were given AIN-76A diets modified so that the PUFA content
      resembled that of the preweaning formula. At eight weeks of age, the n-3
      deficient group exhibited decreases of more than 50% in total DHA content in the
      brain, accompanied by increases in arachidonic acid (AA) (20:4n-6) and,
      especially, docosapentaenoic acid (22:5n-6). Other artificially-reared rats were
      mated and their offspring were also maintained on the respective diets. In spite
      of the fact that they had been reared artificially, the rats mated successfully
      and reared litters with no obvious abnormalities. At both ten days of age and
      again at eight weeks, offspring of the n-3-deficient mothers exhibited decreases
      of more than 90% in total DHA content. Again, the long-chain n-6 PUFA increased
      proportionately so that total PUFA levels in the brain were not lower. As these
      differences are greater than those commonly reported, even after 2-3 generations
      of normal dietary deprivation in rodents, this procedure may be an important tool
      in the study of the effects of n-3 deficiency on neural development and,
      subsequently, of the function of DHA in nervous tissue.

PMID- 8649238
TI  - Arachidonic acid supply and metabolism in human infants born at full term.
AB  - Infants need arachidonic acid (AA; C20:4n-6) for eicosanoid synthesis and
      deposition in growing tissues, including brain. Human milk supplies preformed AA
      in amounts considered to meet accretion in membrane-rich tissues, but vegetable
      oil-based infant formulas do not contain AA. We studied two groups of ten healthy
      infants, each fed human milk or formula, and analyzed plasma lipid composition.
      Percentage contributions of AA to plasma phospholipids were stable over two
      months after birth in breast-fed infants, but infants fed formula developed
      significantly (P < 0.05) lower levels at the ages of two weeks (formula 6.9% vs.
      breast 9.4%, w/w), one month (6.2 vs. 9.1%), and two months (5.7 vs. 8.4%). In a
      second trial, we randomized infants to receive (from birth to age four months)
      formula without or with both AA and docosahexaenoic acid (DHA; C22:6n-3) at
      levels typical for mature human milk. Infants fed conventional formula showed a
      continuous decrease of phospholipid AA over time, whereas feeding of formula
      supplemented with AA and DHA led to significantly higher AA levels, similar to
      those in breast-fed infants (two months: supplemented 9.6% vs. unsupplemented
      7.1%; four months: 8.7 vs. 6.6%). In order to estimate infantile capacity for
      endogenous synthesis of AA, we fed four term neonates with newly diagnosed
      phenylketonuria (mean age 18 d) a formula with all fat contributed by corn oil,
      which has a higher natural 13C-enrichment than European human milk or formula.
      Analysis of 13C-enrichment in plasma fatty acids over four days allowed us to
      estimate infantile AA synthesis. We found an increased 13C-value in plasma AA of
      all infants, which indicates that term neonates can synthesize AA. However, with
      a simplified isotope balance equation, we estimate that endogenous synthesis
      contributed only about 23% of total plasma arachidonic acid by day four. We
      conclude that full-term infants fed formula may require a dietary supply of some
      preformed AA if the biochemical status of breast-fed infants is to be achieved.

PMID- 8649239
TI  - A randomized trial of visual attention of preterm infants fed docosahexaenoic
      acid until two months.
AB  - This was a randomized, double-blind trial to determine if a nutrient-enriched
      (preterm) formula supplemented with 0.2% docosahexaenoic acid (DHA, 22:6n-3) from
      a low eicosapentaenoic acid (0.06%) source of marine oil would enhance visual
      novelty preference and attention of preterm infants. Both the standard and
      experimental formulas contained 3% of total fatty acids as linolenic acid (18:3n
      3) and were fed from approximately three days of age to two months past term.
      After two months, both diet groups were fed a commercially-available term formula
      with linolenic acid as the only source of n-3 fatty acid. At 12 mo visual
      recognition memory (novelty preference) and visual attention (number and duration
      of discrete looks) were determined with the Fagan Test of Infant Intelligence.
      The DHA-supplemented group compared with the control group had more and shorter
      duration looks in comparisons of familiar and novel stimuli, confirming earlier
      evidence that DHA can increase information processing speed of preterm infants
      who otherwise are receiving good intakes of linolenic acid. Because
      supplementation was stopped at two months and the effects seen at 12 mon, this
      study demonstrates for the first time that a relatively short period of DHA
      supplementation can produce significant effects on later visual attention.

PMID- 8649240
TI  - Hydrocarbon chain distribution of ether phospholipids of the ascidian Halocynthia
      roretzi and the sea urchin Strongylocentrotus intermedius.
AB  - The contents and compositions of the 1-O-alk-1'-enyl-2-acyl, 1-O-alkyl-2-acyl,
      and 1,2-diacyl glycerophospholipids in the muscle and viscera of the ascidian
      Halocynthia roretzi, and of the gonad of the sea urchin Strongylocentrotus
      intermedius, which are eaten to some extent in Alaska and in Asia, were analyzed
      by gas-liquid chromatography. 1-O-Alk-1'-enyl-2-acyl glycerophospholipids were
      found in all of the samples, accounting for 64.4-69.0% of the ethanolamine
      glycerophospholipid (EPL). By contrast, the levels of the 1-O-Alk-1'-enyl-2-acyl
      choline glycerophospholipids (CPL) were low (3.1-5.7%). CPL was rich in the 1-O
      alkyl-2-acyl subclass amounting to 12.5-23.9% in the ascidian sample. The level
      of CPL in the sea urchin gonad was extremely high, amounting to 46.1%. The most
      prominent alkyl chains in the sn-1 position of CPL from the ascidian muscle were
      16:0 (44.6%), 18:1 (26.5%), and 18:0 (10.7%), and of CPL from the sea urchin
      gonad were 18:0 (36.2%), 16:0 (33.0%), and 18:1 (17.8%). Unusually high levels of
      odd-numbered alkyl chains, e.g., 19:0 and anteiso 17:0, were detected in the CPL
      of all samples. The prominent alkenyl chains of EPL were 18:0 (69.4%), 16:0
      (10.0%), and 18:1 (8.54%) (not counting the vinyl double bond) for the sea urchin
      gonad. Relatively high levels of 20:1 alkenyl chains were also present. The
      glycerol sn-2 positions contained high proportions of polyunsaturated fatty
      acids. Thus, 20:5n-3 (43.6%) and 22:6n-3 (20.1%) were most abundant in the
      alkylacyl CPL from the ascidian muscle and 20:5n-3 (54.9%) and 20:4n-6 (30.1%) in
      alkylacyl CPL from the sea urchin gonad. Despite a possible interconversion of
      the alkyl and alkenyl chains of each class of the ether phospholipids, they
      showed few features in common.

PMID- 8649241
TI  - A randomized trial of visual attention of preterm infants fed docosahexaenoic
      acid until nine months.
AB  - This randomized, double-blind trial tested the hypothesis that the addition of
      0.2% docosahexaenoic acid (DHA, 22:6n-3) from marine oil to commercially
      available preterm and term formulas with > or = 3% linolenic acid (18:3n-3) would
      enhance novelty preference and visual attention of preterm infants. Among preterm
      infants cared for in our center, study infants were a select group considered to
      be at lower risk for developmental delay. Study infants received their assigned
      diet (control, DHA-supplemented) from a mean postnatal age of 25 d until 9 mon
      past term. At 6.5, 9, and 12 mon past term, they were tested for visual
      recognition memory (novelty preference) and attention with the Fagan Test of
      Infant Intelligence. The effects of DHA supplementation were analyzed by repeated
      measures analysis of variance. In paired comparisons of novel and familiar
      stimuli, DHA-supplemented and control infants had the same novelty preference,
      but supplemented infants had more discrete looks to both novel (P < 0.03) and
      familiar (P < 0.02) stimuli and a shorter overall look duration (P < 0.03). These
      data are analogous to those from n-3-deficient and n-3-fed monkeys in that the
      group with better DHA status had shorter overall look duration. Because shorter
      look duration has been associated with more rapid information processing, preterm
      infants fed formulas with only linolenic acid may have had slower information
      processing than those fed DHA.

PMID- 8649243
TI  - DNA technology in forensic applications.

PMID- 8649245
TI  - [Study of the impact of deltamethrin impregnated curtains on malaria morbidity in
      Ankazobe of the Madagascar highlands].

PMID- 8649244
TI  - [Experimental infections of Anopheles gambiae with Plasmodium falciparum
      gametocytes: epidemiology of malaria man-vector transmission in the urban
      milieu].

PMID- 8649242
TI  - Visual acuity and erythrocyte docosahexaenoic acid status in breast-fed and
      formula-fed term infants during the first four months of life.
AB  - It has been recognized that preterm infants have a more rapid development of
      visual acuity if fed human milk or a formula enriched with the long-chain
      polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) compared to a
      standard formula devoid of LCPUFA. Few studies have addressed whether the same is
      also true in term infants. The aim of the present study was to follow visual
      acuity and fatty acid composition in red blood cells (RBC) for the first 4 mon of
      life in 17 breast-fed and 16 formula-fed term infants. The formula used did not
      contain LCPUFA, but contained 1.7 wt% alpha-linolenic acid, and the
      linoleic/alpha-linolenic acid ratio was 8.5. The increase in visual acuity
      measured by Teller acuity cards developed more rapidly in breast-fed infants
      compared to formula-fed infants (P < 0.001). This was parallelled by a decrease
      in DHA of RBC in formula-fed infants, and with a significantly lower level at two
      and four months as compared to breast-fed infants. The content of DHA in milk
      from the breast-feeding mothers was high compared to other Western countries. The
      difference in visual acuity between the two feeding groups could be due to
      differences in DHA status as reflected by the RBC levels, but other explanations
      are possible. Intervention studies are required to verify if development of
      visual acuity in term formula-fed infants is dependent on the DHA level of
      formula.

PMID- 8649246
TI  - [Bred Anopheles gambiae infectivity of a population sample living in a malaria
      endemic zone].

PMID- 8649247
TI  - [Malaria typology in tropical Africa].

PMID- 8649248
TI  - [Acquisition of antimalarial immunity in infants and children in Cameroon: follow
      up of two cohorts. Presentation and preliminary results].

PMID- 8649249
TI  - [The role of nitric oxide in cerebral malaria].

PMID- 8649250
TI  - [Qinghao derivatives in the treatment of severe malaria].

PMID- 8649251
TI  - [Adjuvant treatments of cerebral malaria].

PMID- 8649252
TI  - [Reflections on past antimalarial molecules].

PMID- 8649253
TI  - [Immunological factors blocking transmission].

PMID- 8649254
TI  - [Vaccines blocking transmission].

PMID- 8649255
TI  - [Impact of insecticide impregnated bednets on malaria morbidity: preliminary
      results].

PMID- 8649256
TI  - Impregnated bednets trial in Kumba, Cameroon.

PMID- 8649257
TI  - [Individual and family protection against malaria].

PMID- 8649258
TI  - [Prophylaxis for travellers in Africa: new aspects].

PMID- 8649259
TI  - [Role of genetic epidemiology in the study of infectious diseases. The example of
      malaria].
AB  - Genetic epidemiology is a new tool for the study of malaria, with interesting
      incidence in the comprehension of host/parasite interrelations. The existence of
      a co-dominant major gene, with a mendelian transmission, controlling the levels
      of parasitemia has been found out. This allele has a frequency of 24% which means
      that about 6% of the population is predisposed to high parasitemias. These
      studies show the interest to integrate the existence of a genetical variability
      in the development and the evaluation of malaria control programmes. They are
      offering new perspectives in therapeutics and in the elaboration of vaccinal
      strategies.

PMID- 8649260
TI  - [Physiopathology of cerebral malaria].
AB  - Physiopathology of severe malaria is extremely complex and misappreciated.
      Sequestration of parasited red cells and role of cytokines are now accepted but
      we still have to discover why only a few people develop a severe malaria. A
      better knowledge of that physiopathology would allow the conception of new
      therapeutic strategies to reduce malaria mortality.

PMID- 8649261
TI  - [For new antimalarial drugs: the methods of fundamental research].
AB  - Research in new antimalarial drugs has too long been limited to a only
      pharmacological approach with its four main modalities: isolation of compounds
      from medicinal plants, oriented or not screening of varied molecules, molecular
      ingeniery modifying structure of wellknown drugs in order to improve their
      efficacy, products reversing resistance to antimalarial drugs (anti-Pfmdr).
      Important success has been obtained by these ways but the possibility of new
      discoveries seems to be limited. It is time certainly to concentrate efforts no
      more on the drug itself but on the real target i.e. Plasmodium or malaria
      disease. Our knowledge of Plasmodium biology and of pathophysiological mechanisms
      in malaria are still very limited. This kind of study comes up against many
      difficulties (plasmodial intracellular parasitism, parasitic specificity of
      Plasmodium parasites in Man, etc). Nevertheless, only a huge effort in
      fundamental research will open new perspectives in antimalarial therapeutics by
      identifying possible targets for new compounds from which pharmaccutal industry
      will be able to develop new medicines.

PMID- 8649262
TI  - [Role of modulators in Plasmodium falciparum resistance to antimalarials].
AB  - Modulating agents that circumvent the Plasmodium falciparum resistance to
      antimalarials are components without any intrinsic antimalarial activity but
      able, in association with a standard antimalarial drug, to restore the
      sensitivity of Plasmodium falciparum to this drug. Two hypotheses are forwarded
      about their possible mechanisms of action : the mechanisms involving the
      inhibition of the drug efflux and the mechanisms involving the inhibition of
      antimalarial drug metabolic degradation. None of these mechanisms is able to
      alone explain the effect of all modulating agents. The future use prospects of
      these compounds are limited by their in vivo toxicity. That relevant to the
      calcium channels blockers seems to be circumvented by the use of dextro
      enantiomers. A toxicity relevant to a possible accumulation of the antimalarial
      in healthy, non target cells must be also suspected. Moreover the use of these
      agents evidences a socio-economic problem : a complete new development of the
      association (antimalaria plus modulatin drugs) is needed and that, in developing
      countries. Nevertheless, the agents modulating the Plasmodium falciparum
      resistance are a new approach for the treatment of resistant malaria which might
      give a recrudescence of activity to the old antimalarials as chloroquine.

PMID- 8649263
TI  - Pharmacology and pharmacokinetics of new antimalarials.
AB  - Chloroquine-resistant Plasmodium falciparum is now widespread in Africa,
      requiring new drugs for the control of both non-severe and severe forms of the
      disease. For non-severe malaria, pyrimethamine-sulphadoxine, an antifolate
      combination antimalarial, is at present efficacious, single-dose and cheap;
      important characteristics for treatments in Africa. However, alternative
      combinations are being investigated which are intrinsically more active, less
      toxic and with shorter elimination half-lives. In theory, short half-life
      compounds reduce the selective pressure for resistance, which may be a major
      determinant of the useful therapeutic life of an antimalarial drug. The potential
      advantages/disadvantages of alternative antifolates is discussed. While the use
      of mefloquine and halofantrine in Africa is at present limited by cost, these
      drugs are likely replacements for the antifolates when parasite resistance
      arises. For severe, life-threatening falciparum malaria, quinine remains the
      treatment of choice. In contrast to quinine, artemether rapidly reduces the
      viability of circulating, ring-stage parasites, produces more rapid parasite
      clearance and may reduce the length of coma, but does not significantly reduce
      the mortality of severe malaria which remains at about 15% even with optimal
      management. It seems unlikely that chemotherapy, even with "new" antimalarials,
      will reduce this high figure. Other strategies are required.

PMID- 8649264
TI  - [Decision making policies on the utilization of antimalarials in response to a
      modification of chloroquine efficacity. Applications to Africa].
AB  - The strategy for malaria control in Africa is based on the association of malaria
      case management, selective and lasting vector control and prevention and control
      of outbreaks. Emergence and wide-spread of Plasmodium falciparum chloroquine
      resistance enjoins a change of the malaria case management. This change is
      difficult. It is function of the quality of health services, the epidemiological
      surveillance of malaria, the monitoring of drug efficacy and acceptability, the
      drug utilization policy, the time for reaction and adaptation to changes in new
      drug policy, the different epidemiological patterns. In Africa, alternatives to
      the loss of chloroquine efficacy are the implementation of public health
      performances, the control of the circulation of antimalarials, the training of
      health operators, the education of the beneficiary target populations and to draw
      up and implement strategies that are relevant, i.e. useful and usable.

PMID- 8649265
TI  - Randomised trial of SPf66 vaccine against Plasmodium falciparum malaria in
      children in southern Tanzania.
AB  - Malaria, especially that due to Plasmodium falciparum, is one of the most
      important parasitic disease in man. It causes more than 400 million cases per
      year and between 1 to 3 million deaths, mainly among young children and pregnant
      women in sub-Saharan Africa. The current malaria control strategies using rapid
      diagnosis and treatment as well as methods to reduce the man-vector contact have
      had limited success. In Kilombero district (Southern Tanzania), malaria
      transmission is perennial (parasite prevalence > or = 80% all year) and intense
      (approximatively 300 infectious bites per year). At the household level, each
      under-5 child suffers on average 3 clinical fever episodes per year. Minimum
      estimated community rates for serious malaria (cerebral malaria or malaria and
      anaemia) affect approximatively 5% of all children. Under conditions of a field
      experiment, the annual incidence of a febrile illness (axillary temperature > or
      = 37.5 degrees C) reported to the curative primary health services in each child
      was 0.86 of which 0,35 can be attributed to Plasmodium falciparum malaria. The
      best estimate of the SPf66 vaccine protective efficacy in the Kilombero was 31%
      (95% CI : 0.52).

PMID- 8649266
TI  - [Malaria vaccines: why, who and how?].
AB  - Although the search for a malaria vaccine has much progressed in recent years,
      all of the many vaccine candidates have still a long way to go before becoming
      available for clinical use. This paper reexamines the rationale of using a
      vaccine as an intervention tool against malaria, reviews the results recently
      obtained and discusses current trends of malaria vaccine research.

PMID- 8649268
TI  - [Vector control, perspectives and realities].
AB  - In the WHO Global Strategy for Malaria Control, selective and sustainable vector
      control is one of the measures to be implemented to complement case management
      and for the control of epidemics. Vector control can be targeted against larvae
      and adults, but two elements must be recognized: -vector control measures must be
      selected according to the existing eco-epidemiological diversity, which has to be
      well understood before embarking upon any extensive action; -efficient tools are
      currently available, both for large scale and household use. House spraying is
      still the method of choice for epidemic control but must be carefully considered
      and used selectively in endemic countries for various well known reasons. The
      promotion of personal protection measures for malaria prevention is advocated
      because insecticide-impregnated mosquito nets and other materials have proved to
      be effective in different situations. Implementation, sustainability and large
      scale use of impregnated nets implies a strong community participation supported
      by well motivated community health workers, the availability of suitable
      materials (insecticide, mosquito nets), intersectorial collaboration at all
      levels, well trained health workers from central to the most peripheral level and
      appropriate educational messages (Knowledge, Attitude and Practices) adapted and
      elaborated after surveys. It has to be kept in mind that the evaluation of the
      impact of vector control activities will be made in epidemiological terms such as
      the reduction of malaria morbidity and mortality.

PMID- 8649267
TI  - [The utilization of molecular biological tools in the study of malaria
      transmission: example of programs conducted in Senegal].
AB  - Some informations about malaria transmission, which has until nox difficult to
      get, can be obtained thanks to the use of molecular biology tools, PCR mainly. In
      Senegal, we use that technique to solve two kinds of problems: -Identification of
      species of the Anopheles gambiae complex: PCR technique is useful compared to
      other diagnostic methods (chromosome pattern, DNA probes, etc.) because it
      enables quickly and simply identification of captured anopheles from the DNA
      contained in their legs. The rest of the mosquito is tested by circumsporozoite
      protein antigen ELISA and blood meal ELISA. The data obtained are used to
      determine distribution, cycles, trophic preferences and comparative vectorial
      capacities of Anopheles gambiae, Anopheles arabiensis and Anopheles melas. 
      Identification in a mosquito blood meal of the individual bitten: we propose to
      evaluate factors (weight, age, sex, location of bedroom, etc.) which could
      explain why individuals are more, or less, bitten by a Plasmodium vector. Genetic
      typing is used on inhabitants'leukocytes DNA and on the leukocyte DNA extracted
      from the blood meal of resting anopheles. Through the high degree of polymorphism
      of three (AAAG)n microsatellites markers, we hope, using PCR, to attribute each
      blood meal to one individual. Statistical analysis will be used to identify
      attractivity factors and to determine more precisely the inoculation rates for
      each group rather than the classical rate calculated with male adults volunteers.

PMID- 8649269
TI  - [Immunological interactions between malaria and pregnancy].

PMID- 8649270
TI  - [Immune response against Plasmodium falciparum merozoite antigens and HLA
      restriction].

PMID- 8649271
TI  - [Study of premunition development in holo- and meso-endemic malaria areas in
      Dielmo and Ndiop (Senegal): preliminary results, 1990-1994[].

PMID- 8649272
TI  - [Epidemiological surveillance of Plasmodium falciparum sensitivity to chloroquine
      in Cameroon: necessity of public health policy adaptation].

PMID- 8649273
TI  - [The XVII Technical Conference of the OCEAC. Yaounde, Camaroun, 23-26 November
      1994. Proceedings].

PMID- 8649274
TI  - [Epidemiological surveillance of unstable malaria in Madagascar].

PMID- 8649275
TI  - [Heterogeneity of transmission and chemoresistance of Plasmodium falciparum to
      antimalarials in Madagascar : a relationship to watch].

PMID- 8649276
TI  - [Practical aspects of oral quinine utilization in french speaking Africa].

PMID- 8649277
TI  - [The status of malaria chemoresistance in Africa].
AB  - Chloroquine resistance of Plasmodium falciparum in Africa emerged two decades
      ago. Today, this resistance is wide-spread to the whole african continent and
      other resistances have appeared since. Mechanisms of resistance to lysosomotropes
      and to antimetabolites are described here, as also the epidemiology of these
      resistances in 1994.

PMID- 8649279
TI  - [Intensive care of severe cerebral malaria in the adult and the child].

PMID- 8649278
TI  - [Rectal quinine, an alternative to parenteral injections for the treatment of
      childhood malaria. Clinical, parasitological and pharmacological study].
AB  - In order to avoid the frequent side effects with injections of quinine in african
      children, empirical intrarectal administration of quinine (Quinimax, Sanofi
      Winthrop) has already been used successfully in Madagascar and Niger. In an
      attempt to optimise its use, a pharmacokinetic study was carried out with 66
      children, 2 to 15 years old, admitted in pediatric unit for acute uncomplicated
      Plasmodium falciparum malaria, but warranting parenteral therapy. Children
      received Quinimax intrarectally (20 mg/kg/12h), intravenously (12,5 mg/kg in a
      slow infusion over 4 hours/12h) or intramusculary (12,5 mg/kg/12h). Plasma
      quinine concentrations were determined by HPLC. In this study, temperature and
      parasite clearance were similar in the 3 groups. A second randomized study was
      performed with 3 different dosages of intrarectal Quinimax: 8 and 13 mg/kg/8h and
      20 mg/kg/12h. Temperature fell stably to normal at 36 hours with all regimens.
      Total clearance of parasitaemia was only obtained at 48 h with 30 mg/kg/12h
      regimen. Pharmacokinetic stimulation allowed to propose that intrarectal
      administration of Quinimax 20 mg/kg/8h would be a safe and effective regimen. A
      third approach studied the efficacy and pharmacokinetics of a new rectal quinine
      formulation (12,8 mg/kg/8h quinine gluconate) compared to IM and IV (8 mg/kg/8h)
      : at 36h, body temperature of all children was returned to normal and remained so
      until day 7. Parasitaemia expressed as a percentage of initial values was not
      different in the 3 groups after 48 h. At day 7, all the patients were
      aparasitaemics. The good tolerability and efficacy of this new intrarectal
      quinine formulation might allow to propose this route as an alternative to
      intramuscular route for the treatment of childhood malaria in Africa.

PMID- 8649280
TI  - [Plasmodium falciparum hematozoan morphological alterations in Gabon children
      treated with artemether].

PMID- 8649281
TI  - Pregnancy outcomes of Australian aboriginals and Torres Strait Islanders.

PMID- 8649282
TI  - The cardiovascular state of Australia: good or bad news?

PMID- 8649283
TI  - Migraine: then and now.

PMID- 8649284
TI  - Nurses in Australia: their role today and tomorrow.

PMID- 8649285
TI  - Pregnancy outcomes in urban aboriginal women.
AB  - OBJECTIVE: To assess Aboriginal women's access to antenatal care and their
      pregnancy outcomes in an urban setting. DESIGN: Retrospective descriptive study
      using an obstetric database. SETTING: King George V Memorial Hospital, Sydney.
      PATIENTS: All women who gave birth between 1 January 1992 and 31 December 1993.
      OUTCOME MEASURES: Age and parity, gestation at first antenatal visit and at
      delivery, antenatal complications, type of delivery, infant birthweights and
      perinatal mortality were compared between Aboriginal and non-Aboriginal women.
      Within the Aboriginal group, comparisons were made between those with and without
      poor pregnancy outcomes (low birthweight infants and perinatal deaths). RESULTS:
      Aboriginal women were younger and of higher parity than non-Aboriginal women and
      booked for confinement later in pregnancy, although nearly 80% were booked by 28
      weeks' gestation. There was more pregnancy-induced hypertension (P < 0.01;
      relative risk [RR], 1.66; 95% confidence interval [Cl], 1.17-2.37), urinary tract
      infection (P < 0.02; RR, 2.45; 95% Cl, 1.27-4.30) and need for methadone
      stabilisation in Aboriginal women (P < 0.001; RR, 5.88; 95% Cl, 2.99-11.57). In
      the Aboriginal group, there were higher preterm delivery rates (P < 0.001; 95%
      Cl, 1.31-2.74), more low birthweight babies (P < 0.001; 95% Cl, 1.67-3.33) and
      higher perinatal mortality rates. These findings applied to both Aboriginal women
      transferred from metropolitan district and country hospitals and those resident
      in central Sydney. Factors associated with low birthweight and perinatal deaths
      in Aboriginal infants included late antenatal booking, cigarette smoking,
      hypertension and urinary tract infection in pregnancy, and antepartum
      haemorrhage. CONCLUSION: Further efforts must be made to improve access of
      Aboriginal women to antenatal services in the Central Sydney Area to improve
      perinatal outcomes and maternal health.

PMID- 8649286
TI  - Anxiety and depression in general practice patients: prevalence and management.
AB  - OBJECTIVE: To determine the prevalence of anxiety and depression in general
      practice patients and assess management of these conditions by general
      practitioners (GPs). METHOD: A random sample of 212 GPs were approached to be
      interviewed and to conduct a patient survey and audit on 50 consecutive patient
      consultations during 1993. PARTICIPANTS: 117 GPs (55% response rate) and 4867
      patients (85%) who completed questionnaires suitable for analysis. SETTING:
      General practices in two areas (divisions of general practice) in Sydney, New
      South Wales. RESULTS: Thirty-six per cent of patients had abnormal scores on a
      General Health Questionnaire (GHQ-12); they were more likely to be women or to be
      unemployed. Twenty per cent of these patients had been treated for depression or
      anxiety in the previous 12 months; 52% were prescribed drug therapy, and were
      more likely to be older, male or unemployed. Seventy per cent of patients
      reported having been offered therapy by their GP that did not involve drugs.
      Twenty-four per cent had been referred to another health professional; they were
      more likely to be younger, or men, or patients attending their usual doctor.
      CONCLUSIONS: A brief screening instrument may improve GPs' detection rate of
      patients with anxiety or depression. The high prevalence of these conditions in
      unemployed people deserves particular attention by GPs. Both drug and non-drug
      therapies are being more appropriately applied in general practice than
      previously.

PMID- 8649287
TI  - Preventing falls in the elderly at home: a community-based program.
AB  - OBJECTIVE: To analyse the effectiveness of an ongoing program for reducing the
      risk of falls in the elderly in their homes. DESIGN: Retrospective questionnaire
      survey of the number of falls in the 12 months before home modifications were
      installed. Participants were followed up 12 months later to determine the number
      of falls since home modifications. SETTING: Major city, November 1993 to July
      1995. PARTICIPANTS: Healthy elderly people recruited at presentations made to
      gatherings of elderly people about the risks of falls in the home. INTERVENTION:
      A free home safety inspection and simple home modifications, such as grab-rails
      and non-slip floor surfaces, were offered at subsidized prices. MAIN OUTCOME
      MEASURES: Number of falls in the 12 months before and after home modifications.
      RESULTS: Nearly 4000 elderly people agreed to have a home safety inspection and,
      of these 90% agreed to have their homes modified. Of the first 305 participants
      (mean age 74 years) for whom it had been 12 months since modifications 69 (22.6%)
      had reported having fallen at least once in 12 months before modifications. In
      the 12 months after modifications, 29 participants (9.5% reported at least one or
      more falls--a 58% reduction (95% confidence interval [Cl], 37%-72%). The total
      number of falls decreased from 121 to 45--a 63% reduction (95% Cl, 50%-73%).
      There was a significant decrease in falls in the 61-65, 66-70, 71-75 and 81-85
      years age groups (P< 0.05). CONCLUSIONS: The risk of falling in the elderly can
      be lowered by more than a half by simple modifications to the home. Behavioural
      change, as well as environmental change, is important to the success of falls
      prevention programs.

PMID- 8649288
TI  - Reuse in sterile sites of single-use medical devices: how common is this in
      Australia?
AB  - OBJECTIVE: To determine to what extent Australian hospitals reuse in sterile
      sites medical devices labelled "single use only"; to assess the adequacy of
      cleaning and sterilising procedures before reuse; and to estimate the possible
      incidence of cross-infection and the costs of not reusing these devices. DESIGN:
      A self-administered questionnaire survey. SETTING: All Australian hospitals (419)
      with more than 45 beds and undertaking medical and surgical procedures. METHODS:
      Questionnaires were sent to hospital infection control practitioners in 1994
      requesting information about reuse in sterile sites of single-use medical
      devices, the extent of reuse, the cleaning and sterilising processes involved,
      and the reasons for reuse. RESULTS: Responses were received from 168 hospitals
      (40%). Reuse occurred in 64 (38%), and another 33 hospitals had been reusing
      medical devices 12 months before our survey (i.e., 97/168 hospitals [58%] were
      either reusing them at the time of our survey or had been doing so 12 months
      previously). More large (> 300 beds) metropolitan public hospitals (9/14; 64%)
      reported reusing than did smaller (50/143; 41%) or private hospitals (15/47;
      32%). At six of the 64 hospitals where reuse occurred, the process of cleaning
      and/or sterilization of these devices was not satisfactory; from the information
      we received, both cleaning and sterilization were satisfactory in only 38
      hospitals (59%). Examination of the 14 most commonly reuse devices showed that
      the structure of 13 of these may compromise cleaning (and therefore
      sterilization). The main reason given for reuse was cost saving. Assuming a 2%
      prevalence of transmissible infections in blood, and an infection transmission
      risk of 1/500, we estimate that each year in Australia there may be 40 cases of
      cross-infection for every one million procedures performed with reused devices
      (0.004%). CONCLUSIONS: Reuse of medical devices labelled "single use only" is
      common in Australian hospitals. Most devices appear to be unsuitable for reuse.
      Complete cessation of this practice of reusing single-use medical devices would
      stop potential cross-infection, but this would cost and estimated $2.5 million or
      more per case prevented

PMID- 8649289
TI  - Reuse of single-use medical devices: NHMRC deliberations.

PMID- 8649290
TI  - Reuse of single-use medical devices: who makes the decision?

PMID- 8649291
TI  - Managing HIV. Part 5: Treating secondary outcomes. 5.14 HIV and Kaposi's sarcoma.
AB  - The usual occurrence of Kaposi's sarcoma in otherwise healthy gay men in North
      America in the early 1980s was one of the first hints of the HIV epidemic.
      Kaposi's sarcoma remains a vexing problem. Existing treatments are not wholly
      satisfactory, but they can control the disease's unsightly appearance and the
      complications of visceral involvement.

PMID- 8649292
TI  - Managing HIV. Part 5: Treating secondary outcomes. 5.15 HIV and non-tuberculous
      mycobacterial infection.
AB  - About one in three patients with advanced immune deficiency will develop
      disseminated MAC infection. This incidence can be reduced with prophylactic drug
      therapy, and established infections can be effectively treated, with improved
      quality of life and lengthened survival.

PMID- 8649293
TI  - Managing HIV. Part 5: Treating secondary outcomes. 5.16 HIV and bacterial
      infections.
AB  - Patients with HIV infection have a high risk of bacterial infection. A high index
      of suspicion for common and less common bacterial infections is needed, together
      with a flexible approach to diagnosis and therapy. Many infections are
      characterized by relapse after therapy; long-term treatment is frequently
      required.

PMID- 8649295
TI  - Managing HIV. Recommendations for antimicrobial prophylaxis in HIV.
AB  - Much of the improvement n quality and length of life achieved by HIV medical
      science is due to primary and secondary prophylaxis for opportunistic infection.

PMID- 8649294
TI  - Manaing HIV. Part 5: Treating secondary outcomes. 5.17 HIV, weight loss and
      wasting syndrome.
AB  - Weight loss in HIV infection can be severe and distressing. Management must
      address the likely combination of causes by excluding opportunistic infection,
      monitoring drug effects, palliating diarrhoea, supporting a healthy diet and
      using drug therapy to improve appetite or weight gain.

PMID- 8649296
TI  - Tinea of the skin, hair and nails.

PMID- 8649297
TI  - Australian nursing: traditions and transitions.

PMID- 8649298
TI  - Selective serotonin reuptake inhibitors and SIADH. Adverse Drug Reactions
      Advisory Committee.

PMID- 8649299
TI  - Pertussis vaccines: acellular versus whole-cell.
AB  - Acellular pertussis vaccines containing purified Bordetella pertussis antigens
      have now been extensively field tested. They produce a significantly lower rate
      of reactions than whole-cell vaccines and their efficacy is either comparable or
      superior. At least three antigens appear necessary for good protection: pertussis
      toxoid, filamentous haemagglutinin and pertactin (an outer-membrane protein);
      fimbrial agglutinogens are probably not needed. It is hoped that a cellular
      pertussis vaccine will soon be licensed in Australia for both primary and booster
      vaccination.

PMID- 8649300
TI  - Multiple endoscopies in a Sydney blood donor found positive for hepatitis B and C
      antibodies.

PMID- 8649301
TI  - Diabetes and hypertension. Australian Diabetes Society position statement.

PMID- 8649302
TI  - Compensation, stress and the "V" code.

PMID- 8649303
TI  - Physical, sexual and emotional violence against women: a general practice-based
      prevalence study.

PMID- 8649304
TI  - An acute pain service and preventable deaths in hospitals.

PMID- 8649305
TI  - Heroin-related deaths in New South Wales, 1992: toxicological findings and
      circumstances.

PMID- 8649306
TI  - Safe sex information: getting it right.

PMID- 8649307
TI  - The phytoestrogen content of infant formulas.

PMID- 8649308
TI  - Urethral "discharge" from megadose ascorbic acid.

PMID- 8649309
TI  - Dermatological services for rural Victoria.

PMID- 8649310
TI  - Slip, slop, slap and wrap. Should we do more to prevent skin cancer?

PMID- 8649311
TI  - Submandibular calculus: who was teaching whom?

PMID- 8649312
TI  - Death after unlawful injury in utero can be murder.

PMID- 8649313
TI  - The preparation and use of dental evidence.

PMID- 8649314
TI  - Do victims become offenders?

PMID- 8649315
TI  - Legal protection of staff of mental hospitals--a note.

PMID- 8649316
TI  - A new hazard for engineers.

PMID- 8649317
TI  - Influence of antineoplastic therapy on function of the masticatory system, tooth
      development, and cariogenic status: a case report.
AB  - Antineoplastic therapy causes developmental disturbances in the dental enamel and
      root if children are treated during tooth development. Increased caries activity
      has also been reported. The effect of anticancer therapy on the function of the
      masticatory system (i.e. jaws, dentition, masticatory muscles) is not well known.
      A case report of a 9-year-old girl with right auricular rhabdomyosarcoma is
      presented. She received irradiation of 50 Gy to the right auricular area and
      chemotherapy. A year and a half after cessation of cancer therapy, she was
      disease free and the clinical stomatognathic examination combined with
      electromyogram (EMG) registration of the masseter and temporal muscles and
      magnetic resonance imaging (MRI) examination of the temporomandibular joints
      (TMJ) revealed a strongly restricted mouth opening capacity, painful right TMJ,
      and flattened head of the right mandibular condyle. Muscle atrophy in the right
      masseter muscle was clearly visible but EMG activities of the masseter and
      temporal muscles, however, were higher on the right than on the left. More severe
      developmental defects, and worse gingival and cariological health were observed
      on the right side than on the left side. She developed 12 carious lesions and all
      the lesions were on the right maxilla or mandible or on anterior teeth. The left
      side was not affected. Intensive prophylactic dental care after cancer treatment
      is important in order to prevent caries and gingival inflammation. Stomatognathic
      treatment (i.e. management of occlusal and dysfunctional problems) may improve
      the mouth opening capacity and relieve pain.

PMID- 8649319
TI  - Thomas Hodgkin (1798-1866): pathologist, social scientist, and philanthropist.

PMID- 8649318
TI  - Comparison of the antileukemic activity in vitro of dexamethasone and
      prednisolone in childhood acute lymphoblastic leukemia.
AB  - It is generally assumed that prednisolone (PRD) and dexamethasone (DXM) have
      equal glucocorticoid activity of PRD is given at sevenfold higher doses. Results
      of clinical studies of childhood acute lymphoblastic leukemia (ALL) suggested
      that DXM is more potent relative to PRD than assumed. The purpose of this study
      was to determine the relative antileukemic activity of PRD phosphate and DXM
      phosphate in 133 untreated childhood ALL samples in vitro, using the 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. There was a
      marked variation in antileukemic activity of both agents among the patient
      samples. The median LC50 (drug concentration lethal to 50% of the ALL cells) for
      PRD phosphate was 3.50 microM, for DXM phosphate 0.20 microM. The individually
      calculated ratios of the LC50 values for PRD and DXM phosphate showed a large
      range from 0.7 to >500, with a median of 16.2. This 16-fold difference could not
      be explained by differences between these glucocorticoids in stability,
      hydrolysis into unesterified drug, adhesion to the wall of the microculture
      plates, or protein binding. ALL cells were cross-resistant to PRD and DXM
      phosphate (correlation coefficient = 0.85, P<0.000001). We conclude that the in
      vitro antileukemic activity of DXM phosphate is median 16-fold higher than that
      of PRD phosphate, which contrasts to the generally assumed factor of 7. Based on
      the higher potency of DXM, and its more favorable pharmacokinetics as reported in
      the literature, DXM may be preferred to PRD as the glucocorticoid in the
      treatment of ALL.

PMID- 8649320
TI  - Moriz Kaposi (1837-1902): great master of the Viennese school of dermatology.

PMID- 8649321
TI  - Granulocytic sarcoma.

PMID- 8649322
TI  - Treatment of endodermal sinus tumor in children using a regimen that lacks
      bleomycin.
AB  - BACKGROUND: The EPO-VAC protocol was initiated to study 1) the efficacy of adding
      a cisplatin regimen (EPO) to VAC alone (the previous standard of care) and 2) the
      effect of replacing bleomycin with etoposide in the treatment of pediatric
      endodermal sinus tumors. METHODS: The eligibility requirements for entry included
      age <21 years at diagnosis, diagnosis of a primary gonadal or extragonadal tumor
      (excluding central nervous system tumors and stage I testicular tumors), and
      histological confirmation of endodermal sinus tumor. Children who met the
      eligibility criteria were treated with four courses of EPO (etoposide, cisplatin,
      vincristine) alternating with three courses of VAC (vincristine, dactinomycin,
      and cyclophosphamide). RESULTS: Eleven children were entered on the protocol. Six
      patients had extragonadal disease, five patients had ovarian primaries. Seven
      patients had low-stage tumor (I or II) and four had advanced-stage tumor (III or
      IV). Three of six evaluable patients attained a complete response at 21 weeks.
      Three patients with a residual soft tissue mass at restaging underwent further
      therapy. No patient has relapsed after a median of 51 (range 14-88) months of
      follow-up. CONCLUSIONS: The results of this protocol suggests that a cisplatin
      containing regimen that lacks bleomycin is active in childhood endodermal sinus
      tumors.

PMID- 8649323
TI  - Gonadal function following chemotherapy for childhood Hodgkin's disease.
AB  - Gonadal function was assessed in 101 postpubertal subjects after chemotherapy for
      childhood Hodgkin's disease. All had received ChlVPP (chlorambucil, vinblastine,
      procarbazine, and prednisolone) chemotherapy alone, with no radiotherapy below
      the diaphragm. Gonadotropin levels were available in 46 (79.3%) male and 32
      (74.4%) female subjects. The mean age at diagnosis in the male cohort was 12.2
      years (range 8.2-15.3) and in the females 13.0 years (9.0-15.2). The males and
      the females were studied at a median of 6 years (range 2.5-11.1) and 4.3 years
      (range 1.9-11.5) from diagnosis, respectively. Forty-one (89.1%) male subjects
      had elevated follicle-stimulating hormone (FSH) levels, confirming severe
      germinal epithelial damage. Germinal epithelial damage was seen in subjects up to
      10 years out of therapy. Subtle Leydig cell dysfunction was identified in 24.4%
      with raised luteinzing hormone (LH) levels. All subjects, however, progressed
      spontaneously through puberty. Seventeen (53%) women had raised gonadotropin
      levels, with variable estradiol levels. Of these, 10 subjects presented with
      symptomatic ovarian failure and 6 received hormone replacement therapy (HRT).
      Nine women had 11 successful pregnancies, two of whom had previously had symptoms
      of ovarian failure with one requiring HRT. A much higher prevalence of ovarian
      failure has been observed, than has previously been considered in the prepubertal
      and pubertal female following combination chemotherapy. These conclusions have
      important implications for future counseling, management, and research in this
      population.

PMID- 8649324
TI  - Pulmonary function in children treated for rhabdomyosarcoma.
AB  - Chemotherapy, radiation therapy, and surgical intervention have markedly improved
      the survival of patients treated for rhabdomyosarcoma. Unfortunately, the therapy
      may have deleterious effects on the lung. Pulmonary functions tests were obtained
      from 17 patients treated for rhabdomyosarcoma because of our concern regarding
      potential pulmonary dysfunction in this group of patients who had received
      bleomycin, which is known to be associated with lung injury. Mean age at the time
      of the diagnosis of rhabdomyosarcoma was 10.1 (+/- 7.2) years (range 0.01-23.5
      years). The mean age at the time of pulmonary function testing was 17.0 (+/- 7.5)
      years (range 5.8-34.0 years). Study patients reportedly had no pulmonary
      symptoms. Approximately 87% of study patients had a restrictive ventilatory
      impairment on pulmonary function testing as measured by total lung capacity (TLC)
      values less than the lower limit of normal. Approximately 70% of study patients
      had carbon monoxide diffusing capacity (DLCO) values less than the lower limit of
      normal. There were no significant differences in pulmonary function parameters
      when male study patients were compared to female study patients. There was a
      statistically significant lower forced expiratory volume in 1 second/forced vital
      capacity (FEV1/FVC) ratio (P=0.03) and percent predicted forced expiratory flow
      at 25-75% of the FVC (FEF25-75; P=0.03) in the group of patients diagnosed with
      rhabdomyosarcoma over 8 years of age as compared to those individuals diagnosed
      under 8 years of age. In addition, there were no statistically significant
      differences in pulmonary function when the variables of sex and age at diagnosis
      (as outlined above) were studied in combination. In summary, we identified a high
      incidence of restrictive ventilatory abnormalities in a group of individuals
      (predominantly children) treated for rhabdomyosarcoma as well as a significantly
      lower FEV1/FVC ratio and percent predicted FEF25-75 in the group of patients
      diagnosed with the neoplasm over 8 years of age. Individuals caring for such
      patients are encouraged to obtain pre- and sequential posttreatment pulmonary
      function tests.

PMID- 8649325
TI  - Long-term pulmonary toxicity of multiagent chemotherapy including bleomycin and
      cyclophosphamide in osteosarcoma survivors.
AB  - PURPOSE: To assess long-term pulmonary effects of multiagent chemotherapy, we
      studied serial pulmonary function tests (PFTs) of 35 children with osteosarcoma
      up to 12 years after diagnosis. PATIENTS AND METHODS: We analyzed 84 sets of PFTs
      from 35 patients diagnosed with osteosarcoma between 1981 and 1991. They received
      bleomycin, cyclophosphamide, methotrexate, doxorubicin, cisplatin, and
      actinomycin D over 9-12 months and we performed PFTs from 3 days to 152 months
      after diagnosis. Time period I included 36 PFTs (43%) performed between 1 and 5
      months from diagnosis, time period II included 20 PFTs (24%) performed between 8
      and 12 months from diagnosis, and time period III included 28 PFTs (33%)
      performed between 12 and 119 months from diagnosis. Total lung capacity (TLC),
      forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and
      carbon monoxide diffusing capacity (DLCO) were analyzed. Maximal respiratory
      pressures and arterial blood gases were measured to assess muscle weakness and
      gas exchange, respectively. Mean differences in PFTs were compared among the
      three time periods and between time period pairs. RESULTS: All mean PFT values
      showed significant differences among time periods. Significant decline in DLCO;
      (P=.012), TLC (P=.020), and FEV1 (P=.028) between time periods I and II were
      noted followed by a trend towards recovery between time periods II and III. Time
      periods I and III were not significantly different from one another. Mean PFTs
      performed after 2 years of diagnosis were not different from mean PFTs performed
      from diagnosis at 2 years. CONCLUSION: This dosage regimen of multi-agent
      chemotherapy for osteosarcoma patients caused a transient, but significant,
      decline in PFTs within 8-12 months after administration but appears to cause no
      significant long-term pulmonary function abnormalities.

PMID- 8649326
TI  - Influence of treatment modalities on body weight in acute lymphoblastic leukemia.
AB  - Weight for height of 92 patients (51 girls and 41 boys) treated for acute
      lymphoblastic leukemia (ALL) was evaluated in a longitudinal study. Fifty-four
      patients received cranial irradiation (CI) with a dose of 18 or 24 Gy and 38
      patients did not receive CI. Seventy-seven patients were treated according to a
      normal-risk protocol and 15 patients received more intensive chemotherapy
      according to a high-risk protocol. In most of the patients the duration of follow
      up was 12 years for irradiated patients and 4.5 years for the nonirradiated
      patients. Thirty of 92 patients were treated according to a protocol without CI,
      but with a difference in the use of corticosteroids: 19 patients received
      dexamethasone during the remission-induction and maintenance treatment and 11
      patients received prednisone. The influence of dexamethasone vs. prednisone, sex,
      CI and high-dose vs. low-dose chemotherapy on weight for height was evaluated.
      Patients who received dexamethasone showed a significant increase in weight for
      height immediately after the start of therapy. In patients who received CI,
      weight for height significantly increased after the first year of treatment. The
      overweight in these patients persisted during the whole follow-up period. The
      weight for height of patients treated with prednisone and of patients who did not
      receive CI was below the mean of the normal population during treatment but was
      not different from normal after cessation of therapy. No difference in weight
      gain was seen between boys and girls and between patients who were treated with
      high vs. normal-risk protocols.

PMID- 8649329
TI  - [Indication and limitation of interventional therapy in ischemic heart disease].

PMID- 8649327
TI  - Sibling adaptation to childhood cancer collaborative study: health outcomes of
      siblings of children with cancer.
AB  - OBJECTIVE: This seven-site study examined the overall health status, healthcare
      utilization, somatization, and health-risk behaviors of siblings of children with
      cancer compared to these factors in matched controls or normative data. The study
      also examined whether informants (i.e., siblings, parents, physicians) differed
      in their assessments of the above health domains. DESIGN: Subjects were 254
      siblings of children with cancer from seven different pediatric oncology
      treatment centers that participated in the Sibling Adaptation to Childhood Cancer
      Collaborative study group. Predictors of the siblings' health status, healthcare
      utilization, somatization, and health-risk behaviors were identified, and the
      relationship between these health domains and the siblings' resiliency vs.
      dysfunctionality were explored via interviews. RESULTS: Overall, siblings were
      found to be moderately healthy, although siblings report significant problems
      with sleeping and eating. Healthcare utilization appears to be reduced for
      siblings. Most importantly, the parents of these siblings are less likely to seek
      medical help for a variety of conditions for which parents of control children
      would bring their children to a doctor. A pattern emerged of parental
      underreporting of sibling health variables when compared to what the siblings
      themselves reported. When the relationship between health outcomes and the
      siblings' adaptation to their sick sibling's illness was examined, the resilient
      and dysfunctional groups significantly differed from each other. It appears that
      health outcomes are related to sibling adaptation to the changes brought about by
      their sick sibling's cancer diagnosis and treatment. CONCLUSIONS: The focus of
      care for families of children with cancer is often limited to the child with
      cancer. As indicated in this study, the "healthy" siblings may be overlooked in
      the process. While parents appear to recognize that their "healthy" children are
      complaining more about aches and pains, they may have little energy or time to
      attend to the needs of these other family members. It is the intent of this study
      to document what clinicians may expect and to highlight the need for evaluation
      of this otherwise neglected group.

PMID- 8649328
TI  - [Reasonable indication for PTCA or CABG in Japanese patients with coronary artery
      disease--on the basis of 11 years follow-up].
AB  - The principle of our treatment choices for either PTCA or CABG is as follows; 1)
      1VD is mainly indicated for PTCA or medical treatment except for very proximal or
      complicated LAD lesion, 2) 3VD is absolutely indicated for CABG, 3) 2VD involving
      LAD is positively indicated for CABG, 4) Special indications were set aside for
      critical lesion(s) in limited groups of patients such as those with prior CABG,
      and those with other serious or fatal disease, and also senile but active
      patients (male > 80 years old, female > 75 years old). Proper medial treatment
      was always conducted in all cases. During the period of 11 years between 1984 and
      1994, 1050 PTCA procedures (760 individual patients) and 1484 CABG's were done at
      our university hospital. The annual ratio between CABG and PTCA (CABG/PTCA) was
      higher than 2.0 in the first 4 years but it has settled on a level of 1.0 +/- 0.2
      in the last 5 years even with a significant increase in the number of PTCA
      patients. As to the characteristics of our PTCA group, patients with single
      vessel lesion comprised 57%, only single target PTCA did 78% and only LAD did
      47%. Patients with prior CABG and multi lesion PTCA comprised 10% and 22%,
      respectively. The lesion success rare was 89%. As the major complications in 1050
      PTCA's, one death (0.1%), seven (0.7%) emergency CABG's and eleven (1.0%) Q wave
      MI patients were recognized. The overall angiographical lesion restenosis rate
      was 44% of 657 lesions in 550 patients who underwent CAG within 6 months after
      PTCA. In 1484 CABG's, hospital mortality was 1.5% and non fatal major
      complications 6%. The survival rates (free of cardiac death) for PTCA patient
      appeared equivalent between single and multi vessel groups. However, their event
      free survival rates even for 1VD significantly dropped, from 99% to 68% in one
      year and below 60% at 5 years. For 3VD it became as low as 26% at 10 years. On
      the contrary, the even free survival rates for CABG patients with 3VD keep as
      high as 93% at 5 years and 75% at 10 years, respectively. As a conclusion, the
      timely use of PTCA considering an indication of CABG may be a wise and practical
      treatment choice for CAD, but the reasonable ratio of PTCA vs CABG seems to be
      about fifty-fifty as indicated in our study results. Our treatment decisions of
      either PTCA or CABG as mentioned above yielded acceptable outcomes in the
      prognosis of patients with CAD.

PMID- 8649330
TI  - [Ten-year survival and cardiac event-free rates in Japanese patients with the
      left anterior descending artery revascularized with internal thoracic artery or
      saphenous vein graft: a comparative study].
AB  - To evaluate the long-term results of surgical patients with coronary artery
      bypass grafting (CABG), we comparatively analyzed the 10-year survival and
      cardiac event-free rates between 713 patients group with at least one internal
      thoracic artery to the left anterior descending artery (LAD), (ITA-CABG) and 241
      patients group revascularized with vein grafts alone (SVG-CABG). ITA-CABG
      patients had more progressed diseases with a higher incidence of risk factors
      than SVG-CABG patients: number of vessel diseased 2.5 +/- 0.7 vs 2.3 +/- 0.7,
      LMTD 20.2% vs 14.1%, diabetes mellitus 37.3% vs 27.0% and hyperlipidemia 38.0% vs
      30.7%. The 10-year cumulative LAD graft patency and severe disease-free rate was
      90.3 and 67.0% for ITAs and vein grafts in this series. The 10-year overall
      actuarial survival, cardiac death-free and cardiac event-free rates for ITA and
      SVG groups were 88.8 vs 79.5%, 97.4 vs 92.6% and 84.1 vs 73.1%, all with a
      statistical significance (generalized Wilcoxon or logrank method). For the
      patients with reduced ventricular systolic function (EF < or = 0.4), ITA-CABG
      offered a significantly better 10-year cardiac death free rate. Also, for the
      diabetic patients, ITA-LAD offered a significantly better 10-year cardiac event
      free rate. In conclusion, the use of ITA graft can reduce postoperative cardiac
      events and enhance the long-term survival in Japanese patients. The ITA should be
      utilized at least for LAD in all CABG patients whenever feasible.

PMID- 8649331
TI  - [Indication of CABG as reflected in the late results--10 year follow-up 1344
      cases].
AB  - Because of the recent advancement and wide spread application of interventional
      cardiology, the indication and results of CABG have been more closely
      scrutinized. 10 year survival rate and cardiac event free rate of our 1344 cases
      pf CABG for the past 10 years was 79.3% and 69.8% respectively. Multivariate
      analysis revealed left ventricular dysfunction, old age, diabetes mellitus,
      severe symptom of angina, and no-use of ITA as variables influencing the late
      survival. These results are comparable to the published data from USA or European
      countries. The proper selection of patients in consultation with cardiologists
      may yield better surgical results.

PMID- 8649332
TI  - [Comparison of long-term prognosis between medical therapy PTCA and CABG for
      multiple coronary vessel disease].
AB  - Left main trunk disease is mainly treated by CABG, on the other hand, single
      vessel disease is applied by Simple Medical or PTCA. These concept is widely
      accepted, but, there were controversies about the treatment for multiple vessel
      disease. The purpose of this study was to clarify the long-term prognosis of
      different therapeutic means for multiple vessel diseases. In our center, 3635
      consecutive initial coronary angiography were done from September 1977 to
      December 1989. Of those, 1190 patients of multiple vessel diseases excluding
      those with left main trunk lesion, previous re-vascularization or acute
      myocardial infarction were served for this study. Double vessel disease (DVD) was
      727 patients, Triple vessel disease (TVD) was 455 patients. We divided these
      patients into three groups according to their initial therapy. A retrospective
      analysis was carried out on the follow-up patients from survival rate, cardiac
      death free rate and cardiac event free survival rate. The cardiac death were due
      to acute myocardial infarction, congestive heart failure and sudden death. The
      cardiac event including all death, acute myocardial infarction, PTCA and CABG.
      The statistical analysis was done by Kaplan-Meier and Cox Proportional Hazard
      Model. The survival rate in DVD and TVD, Medical was significantly lower than
      other groups. Survival curves of CABG and PTCA was quite similar. The survival
      rate at 5 years was 85 (M), 89 (C) and 89% (P), and at 10 years 67,78 and 76%,
      respectively in DVD, and the survival rate at 5 years was 57,91 and 90%, and at
      10-years, 57,77 and 78%, respectively. The cardiac death free rate in DVD and TVD
      showed same tendency. The cardiac event free survival in DVD, PTCA was
      significantly lower than other groups. This result was derived from high
      incidence of re-stenosis after PTCA. The cardiac event free survival rate were at
      5 years 79 (M), 86 (C) and 58% (P) and at 10 years 50, 58 and 30%, respectively.
      In TVD, CABG was significantly higher than other groups. The cardiac event free
      survival rate were at 5 years 72, 86 and 63% and 10 years 42,64 and 39%,
      respectively. In Summary, the survival rate and cardiac death free rate of
      Medical were significantly lower than those of CABG and PTCA. There were no
      significant differences between CABG and PTCA on the survival rate and cardiac
      death free rate. The cardiac event free survival rate of CABG was significantly
      higher than that of PTCA and Medical. In multiple vessel disease, CABG will bring
      the best long term prognosis. Even though the cardiac events were most frequent
      in PTCA, it's survival rate was quite similar to CABG. So, PTCA must be thought
      the second best method of the therapy of multiple vessel disease.

PMID- 8649333
TI  - [Multivessel coronary artery bypass grafting with arterial conduits].
AB  - With increased use of catheter intervention, candidates for coronary artery
      bypass grafting (CABG) have become more severely diseased. In the past 4 years
      with normothermic cardiopulmonary bypass technique, operative mortality was 1.5%
      (0.7% for elective and 5.6% for emergency) in 690 primary CABGs. The internal
      thoracic artery graft was used in 94% of the patients and the patency rate was
      98%. The gastroepiploic artery was used in 565 patients since 1986 with 2.3%
      operative mortality and the patency rate was 96% in early and 92% in mid-term
      angiography. The inferior epigastric artery was used in 48 patients with 2%
      operative mortality and 90% patency rate. The radial artery was used in 105
      patients with 0.9% operative mortality and patency rate was 88% at 1
      postoperative year. Surgical result and angiographic patency of the graft are
      acceptably good while candidates of CABG have become more severely diseased. With
      use of arterial conduits, better long term outcome can be expected.

PMID- 8649334
TI  - [Surgical treatment for ischemic cardiomyopathy].
AB  - From June 1970 to Aug. 1995. We were experienced 2,235 coronary surgical patients
      at the Heart Institute of Japan. Among them, the ischemic cardiomyopathy (ICM)
      was defined as the elective, isolated CABG with the EF of less than 20%. Among
      the 1,640 cases of elective, isolated CABG, the cases with the EF of less than
      20% were 29, 1.8% of the total. The hospital mortality was 2 cases (6.9%). The
      late mortality was 2 cases. The graft patency rate was 96.6%. An actuarial
      survival rates at 1 year, 3 years and 5 years were 93%, 93 and 87%. Operative
      mortality and 5-year survival rate of CABG for ICM are acceptable, and appear
      comparable to that achieved in similar patients after transplantation.

PMID- 8649335
TI  - [Current status and 21 century in the laser transmyocardial revascularization
      (LTMR)].
AB  - Recently, much attention has been paid to promote endovascular intervention for
      the patients with ischemic heart disease and occlusive peripheral arterial
      disease. There are a few patients for whom coronary artery bypass grafting and
      repeated PTCA can not be carried out, because small branches or diffuse stenoses
      of the coronary arteries. To resolve these problems author tried to supply
      arterial blood from the left ventricle into the ischemic myocardium through new
      channels created into the myocardium by CO2 laser. Consequently, it could be
      clarified that this procedure could be hemodynamically, or histologically used as
      an alternative transmyocardial revascularization (TMR) by laser. Finally, this
      TMR was clinically employed in 1985. Mechanism, technique and its results of TMR
      are discussed in detail.

PMID- 8649336
TI  - [Indication and clinical results of heart transplantation in the terminal stage
      of ischemic cardiomyopathy].
AB  - The results of medical therapy has been very poor for ischemic cardiomyopathy
      with inoperable coronary artery disease and left ventricular ejection fraction
      less than 20%, therefore, heart transplantation is considered to be definite
      indication for those patients. However, the limited supply of suitable donor
      organs imposes constraints upon the decision of whether patients are selected for
      transplantation or for alternative therapy including coronary artery bypass
      grafting (CABG), semipermanent use of implantable left ventricular assist device,
      or cardiomyoplasty even in the western countries. The heart transplantation
      therapy has not been accepted in Japan at the present time, therefore, such
      alternative therapy should be tried still more aggressively in our country. CABG
      is most established surgical technology among the alternative therapies for
      transplantation and realistic in availability. Many institutes in the western
      countries adopt the therapeutic strategy of aggressive trial of CABG for ischemic
      cardiomyopathy in the first stage and to use ventricular assist device as a
      bridge for heart transplantation in failure cases. Although the effects of CABG
      may not be permanent and ultimate heart transplantation may be required for those
      patients, still CABG therapy is considered reasonable, because of the shortage of
      supply of donor heart, rejection and the progression of coronary artery disease
      of transplanted heart in the chronic stage. The necessity and indication of heart
      transplantation for ischemic cardiomyopathy have not been discussed adequately in
      Japan, however, more than 5000 patients under 60-year-old are killed annually due
      to ischemic heart disease in our country. More hot discussion on heart
      transplantation is deems to be necessary for ischemic cardiomyopathy.

PMID- 8649337
TI  - [Surgical repair of atrial septal defect and tricuspid regurgitation in a 79-year
      old man: a case report].
AB  - A 79-year-old man with atrial septal defect (ASD) and tricuspid regurgitation was
      successfully operated upon. Preoperative examinations showed atrial fibrillation,
      moderate pulmonary hypertension and lung dysfunction. Direct closure of the ASD
      accompanying with tricuspid annuloplasty was performed. Postoperative
      administration of catecholamines continued for twenty-six days to maintain
      hemodynamics. An intratracheal tube was extubated two days after the operation.
      However, an additional respiratory support using a nasal continuous positive
      airway pressure method was required for six days. His postoperative physical
      activity has been improved with class I of the New York Heart Association
      classification. Surgical intervention may be the treatment of choice for aged
      patients over 70 years with an ASD.

PMID- 8649338
TI  - Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide
      analogs toward DNA polymerases alpha, delta and epsilon.
AB  - Based on the powerful virostatic potency and cytostatic activity of adenine, 2,6
      diaminopurine, and guanine derivatives of acyclic phosphonate nucleotide analog
      (S)-1-(3-hydroxy-2-phosphonomethoxypropyl) and 9-(2-phosphonomethoxyethyl)
      series, we examined the inhibitory potencies of their diphosphates [(S)-9-(3
      hydroxy-2-phosphonomethoxypropyl)adenine diphosphate (HPMPApp), 9-(2
      phosphonomethoxyethyl)adenine diphosphate, 9-(2-phosphonomethoxyethyl)-2,6
      diaminopurine diphosphate (PMEDAPpp), and 9-(2-phosphonomethoxyethyl)guanine
      diphosphate, analogs of nucleoside 5'-triphosphates] toward cellular DNA
      polymerases alpha, delta, and epsilon (isolated from tumors of T cell spontaneous
      acute lymphoblastic leukemia in Sprague-Dawley inbred rats). Kinetic measurements
      (K(m), K(i), and V(max)) of synthetic homopolymeric template primers have shown
      that HPMPApp is a selective and potent inhibitor of polymerase epsilon, whereas
      PMEDAPpp strongly inhibits polymerase delta. These two compounds may be useful
      for elucidating the roles of polymerases delta and epsilon. Of the nucleotide
      analogs tested, 9-(2-phosphonomethoxyethyl) guanine diphosphate is the most
      efficient inhibitor of polymerases alpha and epsilon, whereas the diphosphate of
      9-(2-phosphonomethoxyethyl) adenine, the therapeutically important agent
      adefovir, inhibits polymerases alpha and epsilon relatively poorly and exerts
      only moderate inhibition of polymerase delta. These data are quite consistent
      with previously reported cytostatic activity of these nucleotide analogs. All of
      the enzymes studied catalyze the incorporation of 9-(2
      phosphonomethoxyethyl)adenine, 9-(2-phosphonomethoxyethyl)-2, 6-diaminopurine,
      and (S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine into DNA chain. 9-(2
      Phosphonomethoxyethyl)adenine diphosphate and PMEDAPpp were confirmed to be DNA
      chain terminators. On the other hand, HPMPApp formed poly(dT)/oligo(dA(18)-[(S)-9
      (3-hydroxy-2-phosphonomethoxypropyl)a denine]2-4 structures.

PMID- 8649339
TI  - Buthionine sulfoximine induction of gamma-L-glutamyl-L-cysteine synthetase gene
      expression, kinetics of glutathione depletion and resynthesis, and modulation of
      carmustine-induced DNA-DNA cross-linking and cytotoxicity in human glioma cells.
AB  - Glutathione (GSH) depletion by buthioninine sulfoximine (BSO) is being explored
      clinically as a means of enhancing the efficacy of cancer chemotherapy. We
      investigated the kinetics of GSH depletion and altered gamma-L-glutamyl-L
      cysteine synthetase (gamma-GC-S) gene expression in two human malignant glioma
      cell lines, HBT5 and HBT28, and examined how these relate to GSH resynthesis and
      changes in DNA interstrand cross-link induction and cytotoxicity of 1,3-bis(2
      chloroethyl)-nitrosourea (BCNU). GSH content was 54 and 126 nmol/mg/protein in
      HBT 5 and HBT 28, respectively, and after a 24-hr exposure to 100 microM BSO was
      decreased by 95% in HBT 5 and 91% in HBT 28. Basal gamma-GC-S enzyme activity in
      HBT 28 was twice that in HBT 5, and steady state gamma-GC-S gene transcripts were
      2.6-fold higher in HBT 28 than in HBT 5, with no apparent amplification or
      rearrangement of the gene in either cell line. BSO exposure (100 microM) for 24
      hr increased gamma-GC-S gene transcripts by 1.7-fold in HBT 5 and 2.8-fold in HBT
      28. After BSO removal, the rate of GSH resynthesis in HBT 28 was twice that in
      HBT 5. Continuous BSO exposure increased the level of BCNU-induced DNA
      interstrand cross-links, and cytotoxicity was significantly higher in cells
      exposed continuously to BSO than in cells with only a 24-hr BSO preexposure. This
      increase was, however, greater in HBT 28 than in HBT 5. These findings indicate
      significant heterogeneity in the effects of BSO on gamma-GC-S gene expression and
      in the ability of BSO to sensitize tumors and cell lines to BCNU. The data also
      suggest that by preventing GSH resynthesis, a greater level of cytotoxicity is
      achieved with continuous BSO exposure than with BSO preexposure alone.

PMID- 8649340
TI  - Antagonist conformations with the beta(2)-adrenergic receptor ligand binding
      pocket.
AB  - The interactions between beta-adrenergic receptor (beta AR) antagonists and the
      beta(2)AR were studied with the use of photoaffinity labels. A proteolytic map of
      the receptor was made and confirmed through amino-terminal amino acid sequencing
      by locating sites of derivatization. [125I]Iodoazidothiophenylalprenolol (IAPTA)
      is a photoaffinity derivative of the beta AR antagonist alprenolol with a
      photoactivatable group on the aryloxy end of the molecule. IAPTA exclusively
      derivatizes a peptide consisting of transmembrane domains (TMs) 6 and 7 of the
      hamster lung beta(2)AR, supporting the contention that TMs 6 and 7 interact with
      the aryloxy portion of the beta AR antagonist pharmacophore. The beta AR
      antagonist photoaffinity labels [125I]iodoazidobenzylpindolol (IABP),
      [125I]iodoazidophenyl CGP-12177A (IAPCGP), and [125I]iodocyanopindololdiazarene
      (ICYPdz) are similar in that their photoactive moieties are attached to the amino
      end of the antagonist pharmacophore. IABP derivatized TMs 5-7 and a peptide
      containing TM 1 to approximately equal extents. IAPCGP derivatized Tms 6 and 7 >>
      TM 5 = TM 4 = TMs 2 and 3 = TM 1. ICYPdz derivatized TM 1 >> TMs 6 and 7 > Tm 4.
      We conclude that the aryloxy end of the beta AR antagonist pharmacophore is
      highly constrained within TMs 6 and 7, whereas the amino terminus is much less
      constrained and able to assume multiple conformations. Molecular dynamics
      simulations predict that IABP, IAPCGP, and ICYPdz favor a folded conformation,
      with both ends close together. Derivatization of TMs 6 and 7 by IABP, IAPCGP, and
      ICYPdz suggests the folded conformation of these compounds in the ligand binding
      pocket.

PMID- 8649341
TI  - A novel nonopioid action of enkephalins: competitive inhibition of the mammalian
      brain high affinity L-proline transporter.
AB  - The high affinity L-proline transporter (PROT) is a member of the family of Na+
      (and Cl-)-dependent plasma membrane transport proteins that comprises
      transporters for several neurotransmitters, osmolytes, and metabolites. The brain
      specific expression of PROT in a subset of putative glutamatergic pathways
      implies a specialized function for this novel transporter and its presumed
      natural substrate L-proline in excitatory synaptic transmission. However,
      definitive studies of the physiological role(s) of high affinity L-proline uptake
      have been precluded by the lack of specific uptake inhibitors. Here, we report
      that Leu- and Met-enkephalin and their des-tyrosyl derivatives potently and
      selectively inhibited high affinity L-proline uptake in rat hippocampal
      synaptosomes and in PROT-transfected HeLa cells. High concentrations of the
      opiate receptor antagonist naltrexone did not block the inhibitory actions of
      these peptides, arguing against an involvement of opioid receptors. Des-tyrosyl
      Leu-enkephalin elevated the apparent K(m) of L-proline transport in transfected
      HeLa cells without altering the V(max). PROT-transfected HeLa cells did not
      accumulate [3H]Leu-enkephalin above background levels, demonstrating that
      enkephalins are not substrates for PROT. These findings indicate that enkephalins
      competitively inhibit mammalian brain PROT through a direct interaction with the
      transporter protein at or near the L-proline binding site. The high potency and
      specificity of des-tyrosyl-Leu-enkephalin make this compound a useful tool for
      elucidating the structure-function properties and physiological role(s) of PROT.

PMID- 8649342
TI  - Regulation of 13(S)-hydroxyoctadecadienoic acid biosynthesis in Syrian hamster
      embryo fibroblasts by the epidermal growth factor receptor tyrosine kinase.
AB  - Metabolism of arachidonic and linoleic acid can be regulated by polypeptide
      growth factors in a variety of cell types. In Syrian hamster embryo (SHE)
      fibroblasts, epidermal growth factor (EGF) stimulates the conversion of exogenous
      linoleic acid to 13(S)-hydroxyoctadecadienoic acid (HODE). Inhibition of 13-HODE
      biosynthesis blocks the EGF-mitogenic response in SHE cells, and 13-HODE and its
      hydroperoxy precursor are potent and highly specific enhancers of EGF-dependent
      DNA synthesis. We demonstrated that EGF stimulates a biphasic production and
      release of endogenous 13-HODE. Through development of a stable isotope-dilution
      GC/MS assay for 13-HODE, we observed 13-HODE production as early as 5 min after
      EGF stimulation, and this initial phase peaked at 1 hr. A second rise in 13-HODE
      formation was seen at 2-4 hr, and this phase plateaued at 4-6 hr at a level of 30
      40 ng/10(6) cells. EGF stimulation of 13-HODE biosynthesis is not mediated by
      transcriptional or translational regulation of the inducible form of
      prostaglandin H synthase. Based on enzyme inhibitor studies and structural
      characterization of products, the linoleate metabolite is apparently formed by an
      n-6 lipoxygenase that remains to be characterized. EGF stimulation of 13-HODE
      formation is linked with activation of the EGF receptor tyrosine kinase.
      Inhibition of EGF receptor tyrosine kinase activity with methyl-2,5
      dihydroxycinnamate blocked EGF-dependent linoleic acid metabolism and EGF
      regulated DNA synthesis. Potentiation of the EGF receptor tyrosine
      phosphorylation cascade through treatment of SHE cells with the tyrosine
      phosphatase inhibitor vanadate resulted in a 3-fold increase in EGF-stimulated 13
      HODE production and a corresponding enhancement of the EGF mitogenic response.
      The coupling of EGF-regulated linoleic acid metabolism with the EGF receptor
      tyrosine kinase activity suggests the importance of specific linoleate compounds
      in mediating mitogenic signal transduction.

PMID- 8649343
TI  - Enhanced desensitization and phosphorylation of the beta 1-adrenergic receptor in
      rat adipocytes by peroxovanadate.
AB  - Peroxovanadate (PVN) is an insulin-like agent that inhibits the dephosphorylation
      of the insulin receptor kinase. PVN inhibited the lipolytic action of 0.1 microM
      isoproterenol by 88%, which is a relatively specific beta 1 catecholamine agonist
      at this concentration, but was largely ineffective against beta 3 agonists or
      forskolin. To determine whether PVN-mediated desensitization of the beta 1 AR was
      associated with enhanced phosphorylation, we immunoprecipitated the beta 1 AR
      from rat adipocytes that were metabolically labeled with 32PO4. Isoproterenol
      enhanced the net phosphorylation of the beta 1 AR by 8 +/- 2-fold over control.
      PVN increased the net phosphorylation of the beta 1 AR by 5 +/- 0.5-fold, and
      together with isoproterenol, they enhanced the phosphorylation of the beta 1 AR
      by 2-fold over isoproterenol alone. Phosphoamino acid analysis of the
      phosphorylated receptor revealed phosphate incorporation into serine that was
      proportional to the radioactivity incorporated into the immunoprecipitated
      receptor. PVN inhibited the serine/threonine phosphatase calcineurin, suggesting
      that inhibition of receptor dephosphorylation may play a role in the actions of
      PVN. Cyanogen bromide cleavage of the phosphorylated beta 1 AR generated a
      phosphoprotein with a molecular mass consistent with carboxyl-terminal
      phosphorylation. Furthermore, the magnitude of receptor phosphorylation by
      isoproterenol was 3-fold larger than that due to forskolin, suggesting that beta
      1 AR is a substrate for the beta AR kinase that phosphorylates carboxyl-terminal
      residues in the beta(2) AR. Our findings suggest that PVN may be a powerful new
      tool with which to study the phosphorylation of other G protein-coupled
      receptors.

PMID- 8649344
TI  - Effect of cyclic GMP-increasing agents nitric oxide and C-type natriuretic
      peptide on bovine chromaffin cell function: inhibitory role mediated by cyclic
      GMP-dependent protein kinase.
AB  - Both sodium nitroprusside (SNP), a nitric oxide (NO) generator, and C-type
      natriuretic peptide (CNP) have been found to raise cGMP levels in bovine
      chromaffin cells in a time- and concentration-dependent manner. The effect of
      these compounds on catecholamine secretion and calcium influx has also been
      studied, and both compounds were found to produce a slowly developing inhibitory
      effect on acetylcholine- or depolarization-stimulated catecholamine secretion and
      calcium increases without affecting the spontaneous release or the basal
      intracellular Ca2+ concentration. These inhibitory effects were observed only at
      high doses of acetylcholine or high levels of extracellular potassium and
      required concentrations of SNP or CNP very similar to those that increased cGMP
      levels. Preincubation with 100 microM zaprinast, a cGMP-phosphodiesterase
      inhibitor able to increase cGMP levels, mimicked the inhibitory effects of SNP
      and CNP. We investigated the effect of the soluble guanylate cyclase inhibitor
      methylene blue and the cGMP-dependent protein kinase (PKG) inhibitor 8-(4
      chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate, Rp isomer, on
      inhibition by SNP or CNP. Although methylene blue (10 microM) partially prevented
      the inhibitory effect of SNP, it did not do so for that produced by CNP, thus
      indicating that SNP acts through cGMP produced by the NO-activated guanylate
      cyclase. 8-(4-Chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate, Rp
      isomer totally reversed both the SNP and CNP inhibitory effects. These results
      suggest that the activation of PKG mediates the inhibition induced by SNP and
      CNP. We successfully measured the PKG activity from cells preincubated with SNP
      or CNP, and our results show that this enzymatic activity increased with a time
      dependence very similar to the increase in the cGMP levels. Our results indicate
      that NO and CNP peptide inhibit secretagogue-stimulated catecholamine release via
      activation of soluble and particulate isoforms of the guanylate cyclase,
      respectively, presumably by inhibition of calcium entry through voltage-activated
      calcium channels. This inhibitory effects seems to be mediated by activation of
      the PKG.

PMID- 8649345
TI  - Biological and molecular analyses of structurally reduced analogues of endothelin
      1.
AB  - Structurally reduced analogues of endothelin-1 (ET-1) were synthesized through
      linking with an aliphatic spacer [aminocaproic acid (Aca)], segment 3-11 of ET-1
      to carboxyl-terminal fragments of various lengths (16-21, 17-21,...,21). The
      peptides were prepared in their linear or cyclic form, and a formyl group was or
      was not introduced on the Trp21 side chain. Pharmacological studies were carried
      out with the guinea pig lung parenchyma paradigm and the rat thoracic aorta
      bioassay. In the rat aorta, an ET(A) receptor preparation, all of the analogues
      were inactive. However, in the lung parenchyma, we observed that among the linear
      formylated derivatives, [Cys(Acm)3,11,Trp(For)21]-(3-11)-Aca-(17-21)ET was a
      partial agonist. In this series, the presence of His16, as in
      [Cys(Acm)3,11,Trp(For)21]-(3-11)-Aca-(16-21)ET, caused a decrease in contractile
      activity, suggesting that the imidazole group disfavors the proper interaction of
      the linear molecule with the ETB receptors of the lung parenchyma. The loss of
      biological activity of the deformylated linear analogues strongly suggested that
      the formyl group played a stabilizing role in the structure of the linear
      molecules. Interestingly, molecular modeling studies indicated the adoption of
      different conformations by the formylated and the nonformylated analogues. In
      contrast, the stabilizing effect of the formyl group was not observed with the
      cyclic compounds. Furthermore, the presence of His16 favored the contractile
      activity of the cyclic peptides. Finally, the results demonstrated that the
      carboxyl-terminal residues 18-21 are required for the activity in the guinea pig
      lung parenchyma ETB receptors.

PMID- 8649347
TI  - Sparsomycin and its analogues: a new approach for evaluating their potency as
      inhibitors of peptide bond formation.
AB  - The ability of several sparsomycin analogues to inhibit peptide bond formation
      was studied in vitro. Peptide bonds are formed between puromycin (S) and the
      acetylPhe-tRNA of acetylPhe-tRNA/70 S ribosome/poly(U) complex (complex C),
      according to the puromycin reaction: [formula: see text] It was shown that the
      sparsomycin analogues, like sparsomycin itself, inhibit peptide bond formation in
      a time-dependent manner; they react with complex C according to the equation
      [formula: see text] where C*I is a conformationally altered species in which I is
      bound more tightly than in CI. The determination of the rate constant k(7) for
      the regeneration of complex C from the C*I complex allows evaluation of these
      analogues as inhibitors of peptide bond formation. According to their k7 values,
      these analogues are classified in order of descending potency as follows: n
      pentyl-sparsomycin (4) > n-butyl-sparsomycin (3) approximately n-butyl-deshydroxy
      sparsomycin (6) > benzyl-sparsomycin (2) > deshydroxy-sparsomycin (5)
      approximately sparsomycin (1) > n-propyl-desthio-deshydroxy-sparsomycin (7). The
      analogues with an aromatic or a larger hydrophobic side chain are stronger
      inhibitors of the puromycin reaction than are those with a smaller side chain or
      those lacking the bivalent sulfur atoms; replacement of the hydroxymethyl group
      with a methyl group does not affect the position of the compound in this ranking;
      compare the positions of compounds 1 and 3 with those of 5 and 6. In the case of
      compound 7, C*I adsorbed on cellulose nitrate disks was not sufficiently stable
      to allow examination by the method applied to the other analogues, probably due
      to a relatively large value of k7. This analogue showed also time-dependent
      inhibition, but after the isomerization of CI to C*I, the kinetics of inhibition
      become complex, and C*I interacted further with puromycin, either as C*I or after
      its dissociation to C*.

PMID- 8649346
TI  - Point mutations of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid(A) receptor
      affecting modulation of the channel by ligands of the benzodiazepine binding
      site.
AB  - Clinically relevant benzodiazepines allosterically stimulate neurotransmitter
      evoked chloride currents at the gamma-aminobutyric acid type A(GABAA) receptor.
      Rat wild-type or mutated alpha 1, beta 2, and gamma 2S subunits were coexpressed
      in Xenopus oocytes and investigated with electrophysiological techniques. Point
      mutations in two subunits were identified that affect the response of gamma
      aminobutyric acid (GABA)-induced currents by benzodiazepines. Mutation of one of
      three amino acid residues to alanine (alpha Tyr161 and alpha Thr206) or leucine
      (gamma Phe77) resulted in a approximately 3-fold increase in potentiation by
      diazepam. The response to zolpidem was increased in two mutant channels
      containing the mutated alpha subunit but was nearly absent in channels containing
      the mutated gamma subunit. In the former cases, methyl-6,7-dimethoxy-4-ethyl-beta
      carboline-3-carboxylate (DMCM) acted as a negative allosteric modulator of the
      channel, much stronger than in the wild-type channel, whereas there was no
      significant difference to the wild-type channel in the latter case. Thus, the
      mutant gamma subunit has different functional consequences for the various types
      of ligand of the benzodiazepine binding site. All three amino acid residues,
      alpha Tyr161, alpha Thr206, and gamma Phe77, are close or identical to homologous
      residues that are implicated in GABA binding. If the residues binding the channel
      agonist GABA are located at subunit interfaces, the residues influencing the
      benzodiazepine effects must also be located at subunit interfaces.

PMID- 8649348
TI  - Restricted analogues provide evidence of a biologically active conformation of
      thyrotropin-releasing hormone.
AB  - Thyrotropin-releasing hormone (TRH) is a tripeptide (< Glu-His-Pro-NH2) that
      signals through a G protein-coupled receptor. TRH is a highly flexible molecule
      that can assume many conformations in solution. To attempt to delineate the
      biologically active conformation of TRH, we synthesized a pair of
      conformationally restricted cyclohexyl/Ala2-TRH analogues. The diastereomeric
      analogues use a lactam ring to restrict two of the six free torsional angles of
      TRH and constrain the X-Pro-NH2 peptide bond to trans. Unrestricted
      cyclohexyl/Ala2-TRH exhibited a 650-fold lower affinity than TRH for TRH receptor
      and was 430-fold less potent than TRH in stimulating inositol phosphate second
      messenger formation. One diastereomer exhibited higher affinity and potency than
      the unrestricted analogue despite the presence of the methylene bridge and fused
      ring, whereas the other showed lower affinity and potency. Computer simulations
      predicted that the positions of the cyclohexyl/Ala2 and Pro-NH2 moieties relative
      to < glutamate were different in the two analogues and that the conformation of
      the higher affinity analogue is different from that of trans-TRH in solution but
      is superimposable on that of trans-TRH found in a model of the TRH/TRH receptor
      complex. These experimental findings identify a favored relative position of <
      glutamate and Pro-NH2 in the more active conformation of two diastereomeric
      analogues of TRH and provide independent support for the model of the TRH/TRH
      receptor complex.

PMID- 8649349
TI  - Reactive oxygen species mediate stem cell factor synergy with
      granulocyte/macrophage colony-stimulating factor in a subpopulation of primitive
      murine hematopoietic progenitor cells.
AB  - Reactive oxygen species (ROS) have been shown to stimulate proliferation and
      growth responses in a variety of mammalian cell types and to act as important
      mediators in many cellular processes, including hematolymphopoiesis. We examined
      the effect on primitive murine hematopoietic progenitor cells (HPC) of ROS
      generated by xanthine plus xanthine oxidase (xanthine/XO) and various
      antioxidants. Pretreatment of murine HPC (C57BL/6) with xanthine/XO produced a
      dose-dependent enhancement of clonogenic response to granulocyte/macrophage
      colony-stimulating factor (GM-CSF) but not to interleukin-3 or granulocyte colony
      stimulating factor. Stem cell factor (SCF), a potent comitogen for many
      hematopoietic growth factors, also synergized with GM-CSF. However, the
      synergistic enhancement of GM-CSF with xanthine/XO and SCF was not additive,
      indicating that xanthine/XO and SCF may target the same subpopulation of HPC.
      Support for this conclusion came from experiments demonstrating that 1) mutant
      mice strains constitutively lacking a SCF-responsive population of HPC [White
      spotted (W/WV) and Steel (SI/SId)] are unresponsive to xanthine/XO- and SCF
      induced enhancement of GM-CSF and 2) 3,4-epoxybutene, which selectively abrogates
      SCF synergy with GM-CSF, inhibits xanthine/XO-induced enhancement. As xanthine/XO
      can mimic SCF in this population of HPC, the possibility exists that ROS also
      play a role in normal SCF-mediated proliferation of these cells. To test this
      hypothesis, we used the antioxidants N-tert-butyl-alpha-phenylnitrone, exogenous
      superoxide dismutase, and catalase. Both N-tert-butyl-alpha-phenylnitrone and
      superoxide dismutase effectively inhibited SCF and xanthine/XO synergism with GM
      CSF, whereas catalase had no effect, indicating that the superoxide anion may be
      involved. Also, none of these compounds affected SCF synergism with other
      hematopoietic growth factors, such as interleukin-3 or granulocyte colony
      stimulating factor, suggesting a population-specific phenomenon. These findings
      indicate that xanthine/XO mimics SCF in stimulating a subpopulation of murine HPC
      to proliferate and that SCF synergy with GM-CSF in this population is sensitive
      to antioxidant inhibition.

PMID- 8649350
TI  - Thapsigargin modulates agonist-stimulated cyclic AMP responses through cytosolic
      calcium-dependent and -independent mechanisms in rat pinealocytes.
AB  - The role of mobilization of intracellular Ca2+ in the adrenergic-stimulated cAMP
      accumulation in rat pinealocytes was investigated with thapsigargin, an agent
      that inhibits endoplasmic reticulum Ca2+-ATPase. It was found that although
      thapsigargin alone had no effect on the basal cAMP accumulation, it potentiated
      the beta-adrenergic-stimulated cAMP response by isoproterenol in a dose-dependent
      manner. The potentiation was abolished with ethylene glycol bis(beta-aminoethyl
      ether)-N, N,N',N'-tetraacetic acid-acetoxymethyl ester (EGTA-AM) but persisted in
      the presence of isobutylmethylxanthine, indicating that thapsigargin enhances
      cAMP synthesis through elevation of cytosolic intracellular Ca2+ concentration
      ([Ca2+]i). However, when the pinealocytes were stimulated by norepinephrine, a
      mixed alpha 1- and beta-adrenergic agonist, thapsigargin dose-dependently
      inhibited the cAMP response. To investigate this inhibitory effect of
      thapsigargin, we substituted ionomycin, a [Ca2+]i-elevating agent, and 4 beta
      phorbol-12-myristate 13-acetate, an activator of protein kinase C, for the
      alpha(1)-adrenergic component of the norepinephrine-stimulated response. Although
      thapsigargin had no effect on the potentiation of the isoproterenol-stimulated
      cAMP accumulation by ionomycin, it significantly inhibited the potentiation by 4
      beta-phorbol-12-myristate 13-acetate. Furthermore, the inhibitory effect of
      thapsigargin was not affected by cotreatment with EGTA-AM or ionomycin,
      suggesting that this effect is independent of [Ca2+]i. Similar results were
      obtained when cyclopiazonic acid was used to inhibit the Ca(2+)-ATPase. Taken
      together, our results indicate that thapsigargin enhances the beta-adrenergic
      stimulated cAMP accumulation through its action in elevating [Ca2+]i but inhibits
      the potentiation of the beta-adrenergic-stimulated cAMP response by protein
      kinase C, as a consequence of Ca(2+)-ATPase inhibition.

PMID- 8649351
TI  - Metabolic activation of 2,6-dichlorobenzonitrile, an olfactory-specific toxicant,
      by rat, rabbit, and human cytochromes P450.
AB  - The herbicide 2,6-dichlorobenzonitrile (DCBN) is known to cause tissue-specific
      toxicity at very low doses in the olfactory mucosa of rodents. The toxicity of
      DCBN is reportedly cytochrome P450 (P450) dependent, but the isoforms involved
      have not been identified, and the effects of this agent on humans are not known.
      In the present study, DCBN metabolism was examined with microsomes and with
      purified P450s in a reconstituted system. Rat and rabbit olfactory microsomes act
      on DCBN to form DCBN-protein adducts as well as two metabolite peaks, designated
      M1 and M2, identified through high performance liquid chromatography with
      radiometric detection. The activity of rat olfactory microsomes in DCBN
      metabolism is much higher than that of liver or lung microsomes. Of seven
      purified rabbit P450s known to be expressed in the olfactory mucosa, including
      1A2, 2A10/11, 2B4, 2E1, 2G1, and 3A6, the 2A10/11 preparation is the most active,
      producing M2 as well as DCBN-protein adducts; P450 2E1 is the only other active
      isoform. The addition of purified epoxide hydrolase (EC 4.2.1.63) to the
      reconstituted enzyme system leads to the formation of M1 and decreased formation
      of M2. It seems that M1 and M2 are derived from an epoxide intermediate that also
      forms covalent protein adducts. Gas chromatography- and liquid chromatography
      mass spectrometry analyses of nasal microsomal DCBN metabolites and DCBN
      glutathione conjugates indicated that the major reactive intermediate may be 2,3
      oxo-DCBN and that M1 may be 2,3-dihydroxy-6-chlorobenzonitrile, whereas M2 may
      correspond to a monohydroxy-DCBN. Interestingly, heterologously expressed human
      P450s 2A6 and 2E1, but not 1A2, are active in the metabolism of DCBN, forming
      protein adducts as well as M2. Thus, the preferential expression of P450s of the
      2A subfamily in olfactory tissue suggests a molecular basis for the tissue
      specific toxicity of the herbicide and may have important implications for risk
      assessment in humans.

PMID- 8649352
TI  - Structural requirements for activity of propafenone-type modulators in P
      glycoprotein-mediated multidrug resistance.
AB  - The sodium channel blocker propafenone and a series of analogs have been
      identified as effective modulators of P-glyco-protein-mediated multidrug
      resistance in human tumor cells. A series of closely related structural
      homologues showed a highly significant correlation between lipophilicity and
      pharmacological effect. Reduction of the carbonyl group as well as conversion to
      a methylether led to a remarkable decrease in activity, whereby lipophilicity
      lost its predictive character as the main determinant for modulator potency.
      Similarly, the relative positioning of the acyl- and propanolamine side chains
      also influences activity, so the distance between carbonyl group and nitrogen
      atom seems important.

PMID- 8649353
TI  - An aspartate residue in the extracellular loop of the N-methyl-D-aspartate
      receptor controls sensitivity to spermine and protons.
AB  - To study the role of acidic residues in modulation of NMDA receptors by spermine,
      we used site-directed mutagenesis of receptor subunits and voltage-clamp
      recording in Xenopus oocytes. Sixteen glutamate and aspartate residues, located
      in the first two thirds of the putative extracellular loop of the NR1A subunit,
      were individually mutated. This region of NR1A shows homology with bacterial
      amino acid binding proteins, a bacterial polyamine binding protein, and a
      bacterial spermidine acetyltransferase. Mutation of D669 to asparagine (D669N),
      alanine (D669A), or glutamate (D669E) abolished the "glycine-independent" form of
      spermine stimulation in heteromeric NR1A/NR2B receptors. These mutations also
      markedly reduced inhibition by ifenprodil and by protons at NR1A/NR2B receptors.
      Mutations at the equivalent position (D690) in NR1B, which contains the insert
      encoded by exon 5, reduced the pH sensitivity of NR1B/NR2B receptors. Thus, the
      effects of mutations at D669 are not prevented by the presence of exon 5, and the
      influence of exon 5 is not prevented by mutations at D669 (D690 in NR1B).
      Mutations at NR1A (D669) had little or no effect on the potencies of glutamate
      and glycine and did not alter voltage-dependent block by Mg2+ or the "glycine
      dependent" form of spermine stimulation. Surprisingly, the D669N and D669A
      mutations, but not the D669E mutation, reduced voltage-dependent block by
      spermine at NR1A/NR2 receptors. Mutations in NR2B at a position (D668) equivalent
      to D669 did not alter spermine stimulation or sensitivity to pH and ifenprodil.
      However, mutations D668N and D668A but not D668E in NR2B reduced voltage
      dependent block by spermine. Screening of the negative charges at NR1A(D669) and
      NR2B(D668) may be involved in voltage-dependent block by spermine. D669 in NR1A
      could form part of a binding site for polyamines and ifenprodil and/or part of
      the proton sensor of the NMDA receptor. Alternatively, this residue may be
      critical for coupling of modulators such as spermine, protons, and ifenprodil to
      channel gating.

PMID- 8649354
TI  - High affinity open channel block by dofetilide of HERG expressed in a human cell
      line.
AB  - In the long QT syndrome, excessive prolongation of the cardiac action potential
      leads to polymorphic ventricular tachycardia (torsades de pointes) and sudden
      death. Mutations in HERG have been identified as one of the causes of the
      chromosome 7-linked form of congenital long QT syndrome. The biophysical
      properties of currents recorded from HERG expressing Xenopus oocytes are similar
      to those of a cardiac K+ current, I(Kr), but the characteristic nanomolar
      methanesulfonanilide sensitivity has not been demonstrated. To determine the
      biophysical and pharmacological properties of HERG under experimental conditions
      similar to those used to study native cardiac currents, we examined currents
      expressed after expression of HERG in a human cell line, human embryonic kidney
      293. Transfected cells display K+-selective outward currents that activated at
      membrane potentials positive to -50 mV with strongly voltage-dependent kinetics
      [time constant (tau) = 2 sec at -20 mV and 188 msec at +20 mV]. Marked inward
      rectification was observed for depolarizations positive to +0 mV, which was due
      to rapid channel inactivation (tau = 6 msec at +50 mV). The subsequent tail
      currents at -40 mV displayed an initial rising phase with tau = 10 msec, followed
      by a slow multiexponential decline. The EC50 for the methanesulfonanilide I(Kr)
      blocker dofetilide was 12 +/- 2 nM. Induction of block depended on depolarization
      beyond the threshold for channel opening. Time-dependent block developed slowly,
      with tau = 5.2 +/- 0.6 sec (300 nM) at +10 mV, and was delayed by stronger
      depolarizations. This pattern suggested that dofetilide preferentially blocks
      open (or activated) channels and that the fast inactivation may competitively
      slow the binding kinetics. The latter occurrence was further supported by a
      simplified mathematical model that addressed the impact on binding kinetics of
      fast inactivation. These results indicate that the HERG gene product encodes an
      alpha subunit that, when expressed in mammalian cells, displays both the major
      functional and pharmacological properties of native I(Kr). Dofetilide acts as a
      slow-onset/slow-offset open channel blocker of this current at nanomolar
      concentrations.

PMID- 8649355
TI  - A distinct G(i) protein-coupled receptor for sphingosylphosphorylcholine in human
      leukemia HL-60 cells and human neutrophils.
AB  - The sphingolipids, sphingosylphosphorylcholine (SPPC) and sphingosine-1-phosphate
      (SPP), induce a rapid and transient rise in intracellular free calcium
      concentration ([Ca2+]i) in a variety of cell lines via activation of pertussis
      toxin-sensitive G protein-coupled receptors. We investigated whether these
      sphingolipids act on different receptors by testing the effect of varying
      concentrations of SPPC on [Ca2+]i in human leukemia HL-60 cells, which have been
      found to be nonresponsive to SPP. SPPC potently (EC50 = 1.5 microM) and rapidly
      increased [Ca2+]i in HL-60 cells in a pertussis toxin-sensitive manner.
      Differentiation of HL-60 cells through treatment with dibutyryl cAMP into
      granulocyte-like cells did not change the magnitude or the pertussis toxin
      sensitivity of the SPPC-induced [Ca2+]i rise, indicating that the receptor for
      SPPC is constitutively expressed in HL-60 cells. SPPC did not activate
      phospholipase C or D in HL-60 cells. However, SPPC, but not SPP, stimulated the
      generation of superoxide anions in dibutyryl cAMP-differentiated HL-60 cells as
      well as in human neutrophils, suggesting that the SPPC receptor may play a role
      in the inflammatory defense against invading microorganisms. On the basis of
      these results, we conclude that there apparently is a heterogeneity of G protein
      coupled receptors for sphingolipids in mammalian cells.

PMID- 8649356
TI  - Structure and expression of the messenger RNA encoding the murine multidrug
      resistance protein, an ATP-binding cassette transporter.
AB  - In vitro, overexpression of the human multidrug-resistance protein (MRP) causes a
      form of multidrug resistance similar to that conferred by P-glycoprotein,
      although the two proteins are only very distantly related. Studies with MRP
      enriched membrane vesicles have demonstrated that the protein can bind and
      transport cysteinyl leukotrienes, as well as some other glutathione conjugates,
      with high affinity. In contrast, there is no direct evidence of the ability of
      MRP to bind or transport unmodified forms of the drugs to which it confers
      resistance. To facilitate studies of the physiological function(s) of MRP and its
      ability to cause multidrug resistance in vivo, we cloned and characterized the
      mRNA specifying its murine homolog. The murine MRP mRNA encodes a protein of 1528
      amino acids that is 88% identical to human MRP. Although detectable by Northern
      blotting at variable levels in a wide range of tissues, in situ hybridization
      experiments revealed that MRP mRNA expression in some tissues is cell-type
      specific. High levels of the mRNA were detected in epithelia lining bronchi and
      bronchioles, as well as stage-specific expression in the seminiferous epithelium
      of the testes. Comparison of the predicted hydropathy profiles of human and
      murine MRP suggests a highly conserved membrane topology, the most distinctive
      feature of which is an extremely hydrophobic NH2-terminal region containing five
      or six potential transmembrane sequences. This structural feature is shared with
      the sulfonylurea receptor and the yeast cadmium factor 1 but is not present in
      members of the superfamily, such as the cystic fibrosis transmembrane conductance
      regulator and P-glycoproteins. Finally, we used overlapping cDNAs to construct an
      episomally replicating murine MRP expression vector that was stably transfected
      into HeLa cells. MRP-Transfected cell populations expressed markedly elevated
      levels of a 180-190-kDa protein that cross-reacted with a polyclonal antiserum
      raised against a peptide that is completely conserved in murine and human MRPs.
      The MRP transfectants also displayed increased resistance to vincristine (5-6
      fold) and doxorubicin (< 2-fold).

PMID- 8649357
TI  - Phenylacetate inhibits protein isoprenylation and growth of the androgen
      independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene.
AB  - The refractoriness of prostate cancer to androgen suppression is the landmark of
      clinically aggressive disease. In this study, the androgen-dependent LNCaP
      prostate cancer cells were transfected with the mutated c-Ha-ras gene from the
      T24 human bladder cancer. The derivative clone overexpressing T24-ras (LNCaP(T24
      ras)) proliferated in androgen-depleted medium and showed increased growth.
      Protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells were
      tested in the presence of phenylacetate to document a possible relationship with
      the drug-induced inhibition of cell proliferation. Phenylacetate is a
      differentiation inducer that down-regulates in vitro the expression of the myc
      oncogene and activates the human peroxisome proliferator-activated nuclear
      receptor involved in cell growth regulation. The drug inhibited protein
      isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells; IC50 values were
      3.1 and 3.3 mM, respectively, compared with controls. The drug reduced the
      cellular levels of endogenous farnesyl-PP (mean IC50 = 3.5 mM) and inhibited
      activation of the p21ras downstream target, p42(MAPK)/ERK2. LNCaP(T24-ras) was
      more sensitive than the parental line to both growth inhibition (mean IC50 = 3.01
      and 7.1 mM, respectively) and apoptosis by phenylacetate. Exogenous farnesyl- and
      geranylgeranyl-PP indeed reduced the effects of the drug on proliferation and
      apoptosis in LNCaP(T24-ras) cells. In conclusion, the inhibition of protein
      isoprenylation and p21ras farnesylation by phenylacetate resulted in increased
      chemosensitivity of the androgen-independent LNCaP(T24-ras) cells compared with
      LNCaP, and this effect might contribute to the pharmacological activity of the
      drug.

PMID- 8649358
TI  - Transcriptional induction of the cytochrome P4501A1 gene by a thiazolium
      compound, YH439.
AB  - The molecular mechanism of induction of cytochromes P4501A1/2 (CYP1A1/2) by a
      synthetic compound YH439 was studied in rodents as well as in cultured hepatoma
      cells. CYP1A1-mediated ethoxyresorufin-O-deethylase activity and amounts of its
      immunoreactive protein were increased in a time- and concentration-dependent
      manner after a single dose of YH439 (150 mg/kg). Northern blot analyses revealed
      that YH439 rapidly increased (< or = 2 hr) the levels of CYP1A1/2 mRNAs,
      resulting in an increase in CYP1A protein level by > 6-fold at 8 hr after
      injection. After YH439 administration, the levels of CYP1A1 and CYP1A2 mRNAs
      peaked at 8 hr and 16 hr, respectively, before returning to control levels at 16
      and 24 hr. The CYP1A protein level, on the other hand, reached a maximum at 24 hr
      after YH439 treatment and returned to near-control levels at 72 hr. Nuclear run
      on analyses revealed that YH439 induces CYP1A1/2 gene transcription as early as 2
      hr after YH439 treatment. Cytosolic electrophoretic mobility shift assays
      suggested that YH439 activates the CYP1A1/2 genes through the aryl hydrocarbon
      (Ah) receptor and the xenobiotic response elements. The dependency on the Ah
      receptor for the induction of CYP1A1/2 by YH439 was confirmed by the lack of
      CYP1A1/2 induction in the Ah receptor knock-out mice (Ahr-1-) as well as in
      murine hepatoma cells without a functional Ah receptor. Molecular structural
      analysis of YH439 and several other compounds indicated that the planarity and
      size of a molecule are important in its interaction with the Ah receptor and
      subsequent CYP1A1/2 induction. YH439 is a thiazolium compound with little
      aromaticity and with a two-dimensional structure different from that of the Ahs.
      Therefore, it represents a new class of Ah receptor ligand and CYP1A inducer.

PMID- 8649359
TI  - Alteration by 2,3,7,8-Tetrachlorodibenzo-p-dioxin of CCAAT/enhancer binding
      protein correlates with suppression of adipocyte differentiation in 3T3-L1 cells.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit multiple
      effects on the function of adipose tissue and adipogenic cell lines, including
      the suppression of adipocyte differentiation. We began to examine the mechanism
      by which TCDD inhibits differentiation of the established preadipocyte cell line
      3T3-L1. Examination of the expression of several early marker genes of
      preadipocyte differentiation through Northern blot analysis and of
      differentiation-dependent mitosis showed that TCDD did not interfere with the
      earliest known responses of preadipocytes to inducers of differentiation.
      Analysis of mRNA for three isoforms of the CCAAT/enhancer binding protein (C/EBP)
      revealed that TCDD (5 nM) selectively inhibited the induction of C/EBP alpha mRNA
      but did not block the induction of C/EBP beta and C/EBP delta in response to
      differentiation inducers. The differentiation-dependent induction of PPAR gamma
      mRNA was also blocked by TCDD. Immunoblot analysis with specific antibodies to
      each C/EBP isoform demonstrated that the levels of C/EBP delta and C/EBP beta
      protein were rapidly induced (by day 1) and then abrogated by day 4 and 8,
      respectively, in solvent-treated (control) cells. In TCDD-treated cells, however,
      the levels of C/EBP beta and C/EBP delta protein persisted at these time points.
      In contrast, C/EBP alpha protein was markedly suppressed by TCDD in concordance
      with its level of RNA. Both translational products of C/EBP alpha, p30 and p42,
      were dose-dependently decreased by TCDD. Gel shift analysis of nuclear extract
      binding to an oligonucleotide containing a C/EBP DNA recognition sequence
      revealed no difference between extracts from control and TCDD-treated cells in
      the binding pattern at day 2 of differentiation. At days 4 and 8, the band
      corresponding to the C/EBP alpha/DNA complex (as determined with supershift
      assays) was dramatically decreased in the treated extracts in comparison to
      control extracts. In contrast, a band corresponding to a C/EBP beta/DNA complex
      was found to be enriched in the treated samples. These data indicate that
      suppression of differentiation in the 3T3-L1 preadipocyte cell line by TCDD
      occurs at a short but defined period, during the differentiation program, and
      involves altered regulation of C/EBP, including the inhibition of C/EBP alpha.

PMID- 8649360
TI  - D609, a phosphatidylcholine-specific phospholipase C inhibitor, blocks
      interleukin-1 beta-induced vascular cell adhesion molecule 1 gene expression in
      human endothelial cells.
AB  - At sites of inflammation, endothelial cells play a major role in defining the
      types of leukocytes that are recruited to a specific area. This is accomplished,
      at least in part, through the cytokine induction of cell surface adhesion
      molecules, including vascular cell adhesion molecule 1 (VCAM-1). We investigated
      the role of phosphatidylcholine-specific phospholipase C in the induction of VCAM
      1 gene expression by interleukin-1 beta. D609, a phosphatidylcholine-specific
      phospholipase C inhibitor, reduced VCAM-1 cell surface expression and VCAM-1
      promoter activity in human endothelial cells in a dose-dependent manner. D609 did
      not affect nuclear translocation of nuclear factor-kappa B but inhibited nuclear
      factor-kappa B-mediated transcription. The results of this study indicate that
      phosphatidylcholine-specific phospholipase C is required for activation of
      nuclear factor-kappa B and cytokine induction of VCAM-1 gene expression in
      endothelial cells.

PMID- 8649361
TI  - Functional analysis of histones H2A and H2B in transcriptional repression in
      Saccharomyces cerevisiae.
AB  - The presence of H2A-H2B dimers in nucleosomes can inhibit the binding of
      transcription factors to chromatin templates. To study the roles of histones H2A
      and H2B in transcriptional repression in vivo, mutant forms of these histones
      were analyzed in two different assay systems. Two repression domains were
      identified in H2A. One domain includes residues that fall in the beginning of the
      H2A-H2B dimerization region, and the second is in the H2A N terminus, a region of
      potential interactions with nonhistone proteins. The function of H2A and H2B in
      one repression assay was found to be dependent on three SPT (suppressor of Ty)
      genes whose products are important for chromatin-mediated repression. These
      results suggest that repressive chromatin structure may be established through
      the interactions of the Spt proteins with these histones. In contrast, other
      proteins, the products of the HIR (histone regulation) genes, may function to
      direct H2A and H2B to specific promoters.

PMID- 8649362
TI  - Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell
      cycle exit.
AB  - Cyclin D1 controls G1-associated processes, including G0-to-G1 and G1-to-S
      transitions. This study demonstrates a novel aspect of cyclin D1 as a regulator
      of the transition between G1 and G0. Overexpression of cyclin D1 in MCF7 breast
      tumor cells resulted in a continued proliferation under low-serum conditions,
      whereas nonoverexpressing cells ceased to grow. This difference in growth was due
      to a reduced exit from G1 to G0 in cyclin D1-overexpressing cells. Our data
      therefore suggest a model in which cyclin D1 overexpression in tumor cells is
      responsible for hyperproliferation under growth factor-deprived conditions.

PMID- 8649363
TI  - A Ras-GTPase-activating protein SH3-domain-binding protein.
AB  - We report the purification of a Ras-GTPase-activating protein (GAP)-binding
      protein, G3BP, a ubiquitously expressed cytosolic 68-kDa protein that
      coimmunoprecipitates with GAP. G3BP physically associates with the SH3 domain of
      GAP, which previously had been shown to be essential for Ras signaling. The G3BP
      cDNA revealed that G3BP is a novel 466-amino-acid protein that shares several
      features with heterogeneous nuclear RNA-binding proteins, including
      ribonucleoprotein (RNP) motifs RNP1 and RNP2, an RG-rich domain, and acidic
      sequences. Recombinant G3BP binds effectively to the GAP SH3 domain G3BP
      coimmunoprecipitates with GAP only when cells are in a proliferating state,
      suggesting a recruitment of a GAP-G3BP complex when Ras is in its activated
      conformation.

PMID- 8649365
TI  - The cap and the 3' splice site similarly affect polyadenylation efficiency.
AB  - The 5' cap of a mammalian pre-mRNA has been shown to interact with splicing
      components at the adjacent 5' splice site for processing of the first exon and
      the removal of the first intron (E. Izaurralde, J. Lewis, C. McGuigan, M.
      Jankowska, E. Darzynkiewicz, and I.W. Mattaj, Cell 78:657-668, 1994). Likewise,
      it has been shown that processing of the last exon and removal of the last intron
      involve interaction between splicing components at the 3' splice site and the
      polyadenylation complex at the polyadenylation signal (M. Niwa, S. D. Rose, and
      S.M. Berget, Genes Dev. 4:1552-1559, 1990; M. Niwa and S. M. Berget, Genes Dev.
      5:2086-2095, 1991). These findings suggest that the cap provides a function in
      first exon processing which is similar to the function of the 3' splice site at
      last exon processing. To determine whether caps and 3' splice sites function
      similarly, we compared the effects of the cap and the 3' splice site on the in
      vitro utilization of the simian virus 40 late polyadenylation signal. We show
      that the presence of a m7GpppG cap, but not a cap analog, can positively affect
      the efficiency of polyadenylation of a polyadenylation-only substrate. Cap
      analogs do not stimulate polyadenylation because they fail to bind titratable cap
      binding factors. The failure of cap analogs to stimulate polyadenylation can be
      overcome if a 3' splice site is present upstream of the polyadenylation signal.
      These data indicate that factors interacting with the cap or the 3' splice site
      function similarly to affect polyadenylation signal, along with m7GpppG cap, is
      inhibitory to polyadenylation. This finding suggests that the interaction between
      the cap-binding complexes and splicing components at the 5' splice site may form
      a complex which is inhibitory to further processing if splicing of an adjacent
      intron is not achieved.

PMID- 8649364
TI  - Id2 specifically alters regulation of the cell cycle by tumor suppressor
      proteins.
AB  - Cells which are highly proliferative typically lack expression of differentiated,
      lineage-specific characteristics. Id2, a member of the helix-loop-helix (HLH)
      protein family known to inhibit cell differentiation, binds to the retinoblastoma
      protein (pRb) and abolishes its growth-suppressing activity. We found that Id2
      but not Id1 or Id3 was able to bind in vitro not only pRb but also the related
      proteins p107 and p130. Also, an association between Id2 and p107 or p130 was
      observed in vivo in transiently transfected Saos-2 cells. In agreement with these
      results, expression of Id1 or Id3 did not affect the block of cell cycle
      progression mediated by pRb. Conversely, expression of Id2 specifically reversed
      the cell cycle arrest induced by each of the three members of the pRb family.
      Furthermore, the growth-suppressive activities of cyclin-dependent kinase
      inhibitors p16 and p21 were efficiently antagonized by high levels of Id2 but not
      by Id1 Id3. Consistent with the role of p16 as a selective inhibitor of pRb and
      pRb-related protein kinase activity, p16-imposed cell cycle arrest was completely
      abolished by Id2. Only a partial reversal of p21-induced growth suppression was
      observed, which correlated with the presence of a functional pRb. We also
      documented decreased levels of cyclin D1 protein and mRNA and the loss of cyclin
      D1-cdk4 complexes in cells constitutively expressing Id2. These data provide
      evidence for important Id2-mediated alterations in cell cycle components normally
      involved in the regulatory events of cell cycle progression, and they highlight a
      specific role for Id2 as an antagonist of multiple tumor suppressor proteins.

PMID- 8649366
TI  - BRO1, a novel gene that interacts with components of the Pkc1p-mitogen-activated
      protein kinase pathway in Saccharomyces cerevisiae.
AB  - Yeast cells with mutations in BRO1 display phenotypes similar to those caused by
      deletion of BCK1, a gene encoding a MEK kinase that functions in a mitogen
      activated protein kinase pathway mediating maintenance of cell integrity. bro1
      cells exhibit a temperature-sensitive growth defect that is suppressed by the
      addition of osmotic stabilizers or Ca2+ to the growth medium or by additional
      copies of the BCK1 gene. At permissive temperatures, bro1 mutants are sensitive
      to caffeine and respond abnormally to nutrient limitation. A null mutation in
      BRO1 is synthetically lethal with null mutations in BCK1, MPK1, which encodes a
      mitogen-activated protein kinase that functions downstream of Bck1p, or PKC1, a
      gene encoding a protein kinase C homolog that activates Bck1p. Analysis of the
      isolated BRO1 gene revealed that it encodes a novel, 97-kDa polypeptide which
      contains a putative SH3 domain-binding motif and is homologous to a protein of
      unknown function in Caenorhabditis elegans.

PMID- 8649367
TI  - Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of
      transcription by human progesterone and glucocorticoid receptors.
AB  - We have developed a system in Saccharomyces cerevisiae in which agonist-dependent
      transcriptional activity of the human progesterone receptor (hPR) is elevated to
      the point that it compromises cell growth. Screens for suppressors of this
      phenotype led to the demonstration that RSP5 is involved in hPR transactivation.
      Expression of RSP5 in yeast cells potentiated hPR and human glucocorticoid
      receptor (hGR) transcriptional activity and increased the efficacy of weak
      agonists of these receptors. Remarkably, expression of this yeast protein in
      mammalian cells had a similar effect on PR and GR transcriptional activity.
      Importantly, a human homolog of RSP5, hRPF1, functioned identically in mammalian
      cells. Previously, it has been demonstrated that RSP5 overexpression in yeast
      cells suppressed mutations within SPT3, a protein which interacts with the TATA
      box-binding protein (TBP), suggesting that RSP5 and SPT3 operate in the same
      regulatory pathway. In support of this observation, we have shown that SPT3
      enhances the activity of RSP5 on GR and PR when tested in yeast or mammalian
      cells. We conclude from these experiments that the regulatory pathways in which
      RSP5 and SPT3 operate in yeast cells are conserved in higher eukaryotes.
      Additionally, since SPT3 has been shown to contact yeast TBP directly and is the
      likely homolog of human TBP-associated factor TAFII18, we propose that RSP5/hRPF1
      and SPT3 establish a functional link between activated PR and GR and the general
      transcription apparatus.

PMID- 8649368
TI  - Introduction of p130cas signaling complex formation upon integrin-mediated cell
      adhesion: a role for Src family kinases.
AB  - Integrin-mediated cell adhesion triggers intracellular signaling cascades,
      including tyrosine phosphorylation of intracellular proteins. Among these are the
      focal adhesion proteins p130cas (Cas) and focal adhesion kinase (FAK). Here we
      identify the kinase(s) mediating integrin-induced Cas phosphorylation and
      characterize protein-protein interactions mediated by phosphorylated Cas. We
      found that expression of a constitutively active FAK in fibroblasts results in a
      consecutive tyrosine phosphorylation of Cas. This effect required the
      autophosphorylation site of FAK, which is a binding site for Src family kinases.
      Integrin-mediated phosphorylation of Cas was not, however, compromised in
      fibroblasts lacking FAK. In contrast, adhesion-induced tyrosine phosphorylation
      of Cas was reduced in cells lacking Src, whereas enhanced phosphorylation of Cas
      was observed Csk- cells, in which Src kinases are activated. These results
      suggest that Src kinases are responsible for the integrin-mediated tyrosine
      phosphorylation of Cas. FAK seems not to be necessary for phosphorylation of Cas,
      but when autophosphorylated, FAK may recruit Src family kinases to phosphorylate
      Cas. Cas was found to form complexes with Src homology 2 (SH2) domain-containing
      signaling molecules, such as the SH2/SH3 adapter protein Crk, following integrin
      induced tyrosine phosphorylation. Guanine nucleotide exchange factors C3G and Sos
      were found in the Cas-Crk complex upon integrin ligand binding. These
      observations suggest that Cas serves as a docking protein and may transduce
      signals to downstream signaling pathways following integrin-mediated cell
      adhesion.

PMID- 8649369
TI  - AKR1 encodes a candidate effector of the G beta gamma complex in the
      Saccharomyces cerevisiae pheromone response pathway and contributes to control of
      both cell shape and signal transduction.
AB  - Mating pheromones of Saccharomyces cerevisiae control both signal transduction
      events and changes in cell shape. The G beta gamma complex of the pheromone
      receptor-coupled G protein activates the signal transduction pathway, leading to
      transcriptional induction and cell cycle arrest, but how pheromone-dependent
      signalling leads to cell shape changes is unclear. We used a two-hybrid system to
      search for proteins that interact with the G beta gamma complex and that might be
      involved in cell shape changes. We identified the ankyrin repeat-containing
      protein Akr1p and show here that it interacts with the free G beta gamma complex.
      This interaction may be regulated by pheromone, since Akr1p is excluded from the
      G alpha beta gamma heterotrimer. Both haploid and diploid cells lacking Akr1p
      grow slowly and develop deformed buds or projections, suggesting that this
      protein participates in the control of cell shape. In addition, Akr1p has a
      negative influence on the pheromone response pathway. Epistasis analysis
      demonstrates that this negative effect does not act on the G beta gamma complex
      but instead affects the kinase cascade downstream of G beta gamma, so that the
      kinase Ste20p and components downstream of Ste20p (e.g., Ste11p and Ste7p) are
      partially activated in cells lacking Akr1p. Although the elevated signalling is
      eliminated by deletion of Ste20p (or components downstream of Ste20p), the growth
      and morphological abnormalities of cells lacking Akr1p are not rescued by
      deletion of any of the known pheromone response pathway components. We therefore
      propose that Akr1p negatively affects the activity of a protein that both
      controls cell shape and contributes to the pheromone response pathway upstream of
      Ste20p but downstream of G beta gamma. Specifically, because recent evidence
      suggests that Bem1p, Cdc24p, and Cdc42p can act in the pheromone response
      pathway, we suggest that Akr1p affects the functions of these proteins, by
      preventing them from activating mating-specific targets including the pheromone
      responsive kinase cascade, until G beta gamma is activated by pheromone.

PMID- 8649371
TI  - Developmental silencing of the embryonic zeta-globin gene: concerted action of
      the promoter and the 3'-flanking region combined with stage-specific silencing by
      the transcribed segment.
AB  - Globin gene switching is a well-described model of eucaryotic developmental
      control. In the case of the human alpha-globin gene cluster, migration of
      erythropoietic activity from the embryonic yolk sac to the fetal liver is
      parallaled by the zeta-globin gene silencing and enhanced expression of the alpha
      globin genes. To map critical cis determinants of this switch, the human zeta
      globin gene, the alpha-globin gene, and chimeric recombinants were introduced
      into the mouse genome. Consistent with previous studies, expression of the
      individual alpha- and zeta-globin transgenes was found to be developmentally
      appropriate. Contrary to current models, however, the alpha- and zeta-globin gene
      promoters were not sufficient to establish this control. Instead, full silencing
      of the zeta-globin gene required the combined activities of this promoter,
      transcribed region, and 3'-flanking sequences. Individually, the silencing
      activities of the zeta-globin gene promoter and 3'-flanking region were minimal
      but increased markedly when both regions were present. The zeta-globin
      transcribed region appeared to contribute to gene silencing by a mechanism
      specifically activated in definitive erythroblasts in the fetal liver. These data
      demonstrate that a complex set of controls, requiring at least three determinants
      and involving at least two independent mechanisms, is necessary for full
      developmental silencing of the human zeta-globin gene.

PMID- 8649370
TI  - Mutational analysis of the DNA binding, dimerization, and transcriptional
      activation domains of MEF2C.
AB  - There are four members of the myocyte enhancer factor 2 (MEF2) family of
      transcription factors in vertebrates, MEF2A, -B, -C, and -D, which have homology
      within a MADS box at their amino termini and an adjacent motif known as the MEF2
      domain. These factors activate muscle gene expression by binding as homo- and
      heterodimers to an A/T-rich DNA sequence in the control regions of muscle
      specific genes. To understand the mechanisms of muscle gene activation of MEF2
      factors, we generated a series of deletion and site-directed mutants of MEF2C.
      These mutants demonstrated that the MADS and MEF2 domains mediate DNA binding and
      dimerization, whereas the carboxyl terminus is required for transcriptional
      activation. Amino acids that are essential for MEF2 site-dependent transcription
      but which do not affect DNA binding were also identified in the MEF2 domain. This
      type of positive-control mutant demonstrates that the transcription activation
      domain of MEF2C, although separate from the MEF2 domain, is dependent on this
      domain for transcriptional activation through the MEF2 site. MEF2 mutants that
      are defective for DNA binding act as dominant negative mutants and can inhibit
      activation of MEF2-dependent genes by wild-type MEF2C.

PMID- 8649372
TI  - The Saccharomyces cerevisiae Start-specific transcription factor Swi4 interacts
      through the ankyrin repeats with the mitotic Clb2/Cdc28 kinase and through its
      conserved carboxy terminus with Swi6.
AB  - At a point in late G1 termed Start, yeast cells enter S phase, duplicate their
      spindle pole bodies, and form buds. These events require activation of Cdc28
      kinase by G1 cyclins. Swi4 associates with Swi6 to form the SCB-binding factor
      complex which activates G1 cyclin genes CLN1 and CLN2 in late G1. In G2 and M
      phases, the transcriptional activity of SCB-binding factor is repressed by the
      mitotic Clb2/Cdc28 kinase. Mbp1, a transcription factor related to Swi4, forms
      the MCB-binding factor complex with Swi6, which activates DNA synthesis genes and
      S-phase cyclin genes CLB5 and CLB6 in late G1. Clb2/Cdc28 kinase is not required
      for the repression of MCB-binding factor transcriptional activity in G2 and M
      phase. We show here that the Swi4 carboxy terminus is sufficient for interaction
      with Swi6 in vitro. A carboxy-terminal domain of Swi6 is required and sufficient
      for interaction with Swi4. The carboxy terminus of Mbp1 is sufficient for
      interaction with Swi6, and the carboxy terminus of Swi6 is required for
      interaction with Mbp1. By coimmunoprecipitation, we show that Swi4 but not Mbp1
      interacts with Clb2/Cdc28 kinase in vivo during the G2 and M phases of the cell
      cycle. We demonstrate that the ankyrin repeats of Swi4 mediate the interaction
      with Clb2/Cdc28 kinase. The ankyrin repeats constitute a domain by which a cell
      cycle-specific transcription factor can interact with cyclin-dependent kinase
      complexes, thus enabling it to link its transcriptional activity to cell cycle
      progression.

PMID- 8649373
TI  - Multiple single-stranded cis elements are associated with activated chromatin of
      the human c-myc gene in vivo.
AB  - Transcription activation and repression of eukaryotic genes are associated with
      conformational and topological changes of the DNA and chromatin, altering the
      spectrum of proteins associated with an active gene. Segments of the human c-myc
      gene possessing non-B structure in vivo located with enzymatic and chemical
      probes. Sites hypertensive to cleavage with single-strand-specific S1 nuclease or
      the single-strand-selective agent potassium permanganate included the major
      promoters P1 and P2 as well as the far upstream sequence element (FUSE) and CT
      elements, which bind, respectively, the single-strand-specific factors FUSE
      binding protein and heterogeneous nuclear ribonucleoprotein K in vitro. Active
      and inactive c-myc genes yielded different patterns of S1 nuclease and
      permanganate sensitivity, indicating alternative chromatin configurations of
      active and silent genes. The melting of specific cis elements of active c-myc
      genes in vivo suggested that transcriptionally associated torsional strain might
      assist strand separation and facilitate factor binding. Therefore, the
      interaction of FUSE-binding protein and heterogeneous nuclear ribonucleoprotein K
      with supercoiled DNA was studied. Remarkably, both proteins recognize their
      respective elements torsionally strained but not as liner duplexes. Single-strand
      or supercoil-dependent gene regulatory proteins may directly link alterations in
      DNA conformation and topology with changes in gene expression.

PMID- 8649374
TI  - The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins
      acts as a 4-amino-acid transcription repression and protein-protein interaction
      domain.
AB  - Hairy-related proteins include the Drosophila Hairy and Enhancer of Split
      proteins and mammalian Hes proteins. These proteins are basic helix-loop-helix
      (bHLH) transcriptional repressors that control cell fate decisions such as
      neurogenesis or myogenesis in both Drosophila melanogaster and mammals. Hairy
      related proteins are site-specific DNA-binding proteins defined by the presence
      of both a repressor-specific bHLH DNA binding domain and a carboxyl-terminal WRPW
      (Trp-Arg-Pro-Trp) motif. These proteins act as repressors by binding to DNA sites
      in target gene promoters and not by interfering with activator proteins,
      indicating that these proteins are active repressors which should therefore have
      specific repression domains. Here we show the WRPW motif to be a functional
      transcriptional repression domain sufficient to confer active repression to Hairy
      related proteins or a heterologous DNA-binding protein, Ga14. This motif was
      previously shown to be necessary for interactions with Groucho, a genetically
      defined corepressor for Drosophila Hairy-related proteins. Here we show that the
      WRPW motif is sufficient to recruit Groucho or the TLE mammalian homologs to
      target gene promoters. We also show that Groucho and TLE proteins actively
      repress transcription when directly bound to a target gene promoter and identify
      a novel, highly conserved transcriptional repression domain in these proteins.
      These results directly demonstrate that Groucho family proteins are active
      transcriptional corepressors for Hairy-related proteins and are recruited by the
      4-amino acid protein-protein interaction domain, WRPW.

PMID- 8649375
TI  - Repression by HoxA7 is mediated by the homeodomain and the modulatory action of
      its N-terminal-arm residues.
AB  - Hox genes encode homeodomain-containing proteins that are presumed to control
      spatial patterning during murine embryogenesis through their actions as
      transcriptional regulatory proteins. In this study, we have investigated the
      transcriptional function of a prototypic member of this family, HoxA7. We
      demonstrate that HoxA7 function as a potent transcriptional repressor and that
      its action as such requires several domains, including both activator and
      repressor regions. The repressor regions are contained within the homeodomain and
      a C-terminal acidic region, both of which are well conserved among members of the
      Hox family. Accordingly, we show that two other members of this family also
      function as repressors, although they vary in their relative repressor potency.
      Finally, we explore the novel observation that the homeodomain of HoxA7 functions
      as a transcriptional repressor domain. We show that the homeodomain compared with
      two other DNA-binding domains, is unique in its ability to function as a
      repressor domain and that repression requires conserved residues, in helix III.
      We further show that residues in the N-terminal arm of the homeodomain contribute
      to the differential repressor actions of various Hox proteins. These findings
      demonstrate that the transcriptional function of HoxA7 and possibility of Hox
      proteins in general is determined by their unique combination of conserved and
      nonconserved regions as well as through the complex actions of their
      homeodomains.

PMID- 8649376
TI  - Identification of a novel human Rho protein with unusual properties: GTPase
      deficiency and in vivo farnesylation.
AB  - We have identified a human Rho protein, RhoE, which has unusual structural and
      biochemical properties that suggest a novel mechanism of regulation. Within a
      region that is highly conserved among small GTPases, RhoE contains amino acid
      differences specifically at three positions that confer oncogenicity to Ras (12,
      59, and 61). As predicted by these substitutions, which impair GTP hydrolysis in
      Ras, RhoE binds GTP but lacks intrinsic GTPase activity and is resistant to Rho
      specific GTPase-activating proteins. Replacing all three positions in RhoE with
      conventional amino acids completely restores GTPase activity. In vivo, RhoE is
      found exclusively in the GTP-bound form, suggesting that unlike previously
      characterized small GTPases, RhoE may be normally maintained in an activated
      state. Thus, amino acid changes in Ras that are selected during tumorigenesis
      have evolved naturally in this Rho protein and have similar consequences for
      catalytic function. All previously described Rho family proteins are modified by
      geranylgeranylation, a lipid attachment required for proper membrane
      localization. In contrast, the carboxy-terminal sequence of RhoE predicts that,
      like Ras proteins, RhoE is normally farnesylated. Indeed, we have found that RhoE
      in farnesylated in vivo and that this modification is required for association
      with the plasma membrane and with an unidentified cellular structure that may
      play a role in adhesion. Thus, two unusual structural features of this novel Rho
      protein suggest a striking evolutionary divergence from the Rho family of
      GTPases.

PMID- 8649377
TI  - The newly identified yeast GRD genes are required for retention of late-Golgi
      membrane proteins.
AB  - Processing of A-ALP, a late-Golgi membrane protein constructed by fusing the
      cytosolic domain of dipeptidyl aminopeptidase A to the transmembrane and lumenal
      domains of alkaline phosphatase (ALP), serves as a convenient assay for loss of
      retention of late-Golgi membrane proteins in Saccharomyces cerevisiae. In this
      study, a large group of novel grd (for Golgi retention defective) yeast mutants,
      representing 18 complementation groups, were identified on the basis of their
      mislocalization of A-ALP to the vacuole, where it was proteolytically processed
      and thus became enzymatically activated. All of the grd mutants exhibited
      significant mislocalization of A-ALP, as measured by determining the kinetics of
      A-ALP processing and by analyzing its

PMID- 8649378
TI  - Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus
      development and a delay in Friend virus-induced erythroleukemia.
AB  - The proto-oncogene Fli-1 is a member of the ets family of transcription factor
      genes. Its activation by either chromosomal translocation or proviral insertion
      leads to Ewing's sarcoma in humans or erythroleukemia in mice, respectively, Fli
      1 is preferentially expressed in hematopoietic and endothelial cells. This
      expression pattern resembled that of c-ets-1, another ets gene closely related
      and physically linked to Fli-1. We also generated a germ line mutation in Fli-1
      by homologous recombination in embryonic stem cells. Homozygous mutant mice
      exhibit thymic hypocellularity which is not related to a defect in a specific
      subpopulation of thymocytes or to increased apoptosis, suggesting that Fli-1 is
      an important regulator of a prethymic T-cell progenitor. This phenotype was
      corrected by crossing the Fli-1 deficient mice expressing Fli-1 cDNA. Homozygous
      mutant mice remained susceptible to erythroleukemia induction by Friend murine
      leukemia virus, although the latency period was significantly increased.
      Surprisingly, the mutant Fli-1 allele was still a target for Friend murine
      leukemia virus integration, and leukemic spleens with a rearranged Fli-1 gene
      expressed a truncated Fli-1 protein that appears to arise from an internal
      translation initiation site and alternative splicing around the neo cassette used
      in the gene targeting. The fortuitous discovery of the mutant Fli-1 protein,
      revealed only as the result of the clonal expansion of leukemic cells harboring a
      rearranged Fli-1 gene, suggests caution in the interpretation of gene-targeting
      experiments that result in either no or only a subtle phenotypic alteration.

PMID- 8649379
TI  - The immunosuppressant SR 31747 blocks cell proliferation by inhibiting a steroid
      isomerase in Saccharomyces cerevisiae.
AB  - SR 31747 is a novel immunosuppressant agent that arrests cell proliferation in
      the yeast Saccharomyces cerevisiae, SR 31747-treated cells accumulate the same
      aberrant sterols as those found in a mutant impaired in delta 8- delta 7-sterol
      isomerase. Sterol isomerase activity is also inhibited by SR 31747 in in vitro
      assays. Overexpression of the sterol isomerase-encoding gene, ERG2, confers
      enhanced SR resistance. Cells growing anaerobically on ergosterol-containing
      medium are not sensitive to SR. Disruption of the sterol isomerase-encoding gene
      is lethal in cells growing in the absence of exogenous ergosterol, except in SR
      resistant mutants lacking either the SUR4 or the FEN1 gene product. The results
      suggest that sterol isomerase is the target of SR 31747 and that both the SUR4
      and FEN1 gene products are required to mediate the proliferation arrest induced
      by ergosterol depletion.

PMID- 8649381
TI  - Cell-specific transcriptional regulation and reactivation of galectin-1 gene
      expression are controlled by DNA methylation of the promoter region.
AB  - The galectin-1 gene is developmentally regulated gene whose activity is strongly
      modulated during cell differentiation and transformation. We have previously
      shown that galectin-1 promoter constructs are highly active when transiently
      transfected in cells both expressing and not expressing the endogenous gene and
      that the basal activity is determined by a small region encompassing the
      transcription start site (from positions -50 to +50). We have now investigated
      the role of DNA methylation in galectin-1 gene expression. Southern blot analysis
      with HpaII and MspI endonucleases and sodium bisulfite analysis of genomic DNA
      from expressing and nonexpressing cell lines and cell hybrids showed a close
      correlation between gene activity and demethylation of the 5' region of the
      galectin-1 gene. We found that the galectin-1 promoter region is fully
      methylated, at every CpG site on both strands, in nonexpressing differentiated
      rat liver (FAO) and thyroid (PC C13) cells and unmethylated in the expressing
      undifferentiated liver (BRL3A) and thyroid transformed (PC myc/raf) cell lines.
      In addition, reactivation of the silent FAO alleles in FAO-human osteosarcoma
      (143tk-) hybrid cells is accompanied by a complete demethylation of the promoter
      region. Finally, when galectin-1 chloramphenicol acetyltransferase (CAT) promoter
      constructs were methylated in vitro by SssI methylase at every cytosine residue
      of the CpG doublets and transfected into mouse fibroblasts, the transcription of
      the CAT reporter gene was strongly inhibited.

PMID- 8649380
TI  - Studies of partially transforming polyomavirus mutants establish a role for
      phosphatidylinositol 3-kinase in activation of pp70 S6 kinase.
AB  - Infection of mouse fibroblasts by wild-type polyomavirus results in increased
      phosphorylation of ribosomal protein S6 (D.A. Talmage, J. Blenis, and T.L.
      Benjamin, Mol. Cell. Biol. 8:2309-2315, 1988). Here we identify pp70 S6 kinase
      (pp70S6K) as a target for signal transduction events leading from polyomavirus
      middle tumor antigen (mT). Two partially transforming virus mutants altered in
      different mT signalling pathways have been studied to elucidate the pathway
      leading to S6 phosphorylation. An upstream role for mT-phosphatidylinositol 3
      kinase (PI3K) complexes in pp70S6K activation is implicated by the failure of
      315YF, a mutant unable to promote PI3K binding, to elicit a response. This
      conclusion is supported by studies using wortmannin, a known inhibitor of PI3K.
      In contrast, stable interaction of mT with Shc, a protein thought to be involved
      upstream of Ras, is dispensable for pp70S6K activation. 250YS, a mutant mT which
      retains a binding site for PI3K but lacks one for Shc, stimulates pp70S6K to wild
      type levels. Mutants 315YF and 250YS induce partial transformation of rats
      fibroblasts with distinct phenotypes, as judged from morphological and growth
      criteria. Neither mutant induces growth in soft agar, indicating that an increase
      in S6 phosphorylation, while necessary for cell cycle progression in normal
      mitogenesis, is not sufficient for anchorage-independent cell growth. In the
      polyomavirus systems, the latter requires integration of signals from mT
      involving both Shc and PI3K.

PMID- 8649382
TI  - The SAP, a new family of proteins, associate and function positively with the
      SIT4 phosphatase.
AB  - SIT4 is the catalytic subunit of a type 2A-related protein phosphatase in
      Saccharomyces cerevisiae that is required for G1 cyclin transcription and for bud
      formation. SIT4 associates with several high-molecular-mass proteins in a cell
      cycle-dependent fashion. We purified two SIT4-associated proteins, SAP155 and
      SAP190, and cloned the corresponding genes. By sequence homology, we isolated two
      additional SAP genes, SAP185 and SAP4. Through such an association is not yet
      proven for SAP4, each of SAP155, SAP185, and SAP190 physically associates with
      SIT4 in separate complexes. The SAPs function positively with SIT4, and by
      several criteria, the loss of all four SAPs is equivalent to the loss of SIT4.
      The data suggest that the SAPs are not functional in the absence of SIT4 and
      likewise that SIT4 is not functional in the absence of the SAPs. The SAPs are
      hyperphoshorylated in cells lacking SIT4, raising the possibility that the SAPs
      are substrates of SIT4. By sequence similarity, the SAPs fall into two groups,
      the SAP4/SAP155 group and the SAP185/SAP190 group. Overexpression of a SAP from
      one group does not suppress the defects due to the loss of the other group. These
      findings and others indicate that the SAPs have distinct functions.

PMID- 8649384
TI  - Inactivation of YME2/RNA12, which encodes an integral inner mitochondrial
      membrane protein, causes increased escape of DNA from mitochondria to the nucleus
      in Saccharomyces cerevisiae.
AB  - Inactivation of the yeast nuclear gene YMe2 causes an increased rate of DNA
      escape from mitochondria to the nucleus. Mutations in yme2 also show genetic
      interactions with yme1, a second gene that affects DNA escape from mitochondria
      to the nucleus. The yme1 cold-sensitive growth phenotype is suppressed by yme2
      mutations. In addition, yme1 yme2 double mutants exhibit a synthetic growth
      defect on ethanol-glycerol medium at 30 degrees C. YME2 was isolated by
      complementation of the synthetic growth defect of yme1 yme2 strains and was found
      to be identical with the previously cloned RNA12 gene. The dominant temperature
      sensitive mutation RNA12-1 prevents growth of yeast cells at 37 degrees C. YME2
      encodes a protein with a predicted molecular weight of 96,681 and is an integral
      inner mitochondrial membrane protein. The larger carboxyl-terminal domain of the
      YME2 gene product faces the intermembrane space. Null alleles of yme2 display the
      same genetic interactions with yme1 and high rate of DNA escape from mitochondria
      as do the originally isolated yme2 mutant strains. Disruption of yme2 causes a
      strain-dependent growth defect on nonfermentable carbon sources.

PMID- 8649383
TI  - A mouse Fas-associated protein with homology to the human Mort1/FADD protein is
      essential for Fas-induced apoptosis.
AB  - The Fas cell surface receptor belongs to the tumor necrosis factor receptor
      family and can initiate apoptosis in a variety of cell types. Using the Fas
      cytoplasmic domain as bait in a yeast two-hybrid screening, we isolated a mouse
      cDNA encoding a 205-amino-acid protein. Its predicted protein sequence shows 68%
      identity and 80% similarity with the sequence of recently described human
      Mort/FADD. This protein, most likely the mouse homolog of human FADD, associates
      with Fas in vivo only upon the induction of cell death. A fraction of this
      protein is highly phosphorylated at serine/threonine residues, with both
      phosphorylated and unphosphorylated forms being capable of binding to FAS. Stable
      expression of a truncated form of the Mort/FADD protein protects cells from Fas
      mediated apoptosis by interfering with the wild-type protein-Fas interaction.
      Thus, mouse Mort/FADD is an essential downstream component that mediates Fas
      induced apoptosis.

PMID- 8649385
TI  - Signals sufficient for 3'-end formation of yeast mRNA.
AB  - The following three elements were previously shown to be required for 3'-end
      formation of mRNA in the yeast Saccharomyces cerevisiae: (i) the efficiency
      element TATATA or related sequences, which function by enhancing the efficiency
      of downstream positioning elements; (ii) the positioning element AATAAA or
      related sequences, which position the poly(A) site; and (iii) the actual poly(A)
      site, which is usually Py(A)n. In this study, we synthesized a 39-pb poly(A)
      signal that contained the optimum sequences of these three elements. By inserting
      the synthetic 3'-end-forming signal into various positions of a CYC1-lacZ fusion
      gene, we showed that truncated transcripts of the expected sizes were generated.
      Furthermore, the poly(A) sites of the truncated transcripts were mapped to the
      expected poly(A) site within the synthetic signal. Our findings establish that
      the three elements are not only necessary but also sufficient for mRNA 3'-end
      formation in S. cerevisiae.

PMID- 8649386
TI  - Participation of the yeast activator Abf1 in meiosis-specific expression of the
      HOP1 gene.
AB  - The meiosis-specific gene HOP1, which encodes a component of the synaptonemal
      complex, is controlled through two regulatory elements, UASH and URS1H. Sites
      similar to URS1H have been identified in the promoter region of virtually every
      early meiosis-specific gene, as well as in many promoters of nonmeiotic genes,
      and it has been shown that the proteins that bind to this site function to
      regulate meiotic and nonmeiotic transcription. Sites similar to the UASH site
      have been found in a number of meiotic and nonmeiotic genes as well. Since it has
      been shown that UASH functions as an activator site in vegetative haploid cells,
      it seemed likely that the factors binding to this site regulate both meiotic and
      nonmeiotic transcription. We purified the factor binding to the UASH element of
      the HOP1 promoter. Sequence analysis identified the protein as Abf1 (autonomously
      replicating sequence-binding factor 1), a multifunctional protein involved in DNA
      replication, silencing, and transcriptional regulation. We show by mutational
      analysis of the UASH site, that positions outside of the proposed UASH consensus
      sequence (TNTGN[A/T]GT) are required for DNA binding in vitro and transcriptional
      activation in vivo. A new UASH consensus sequence derived from this mutational
      analysis closely matches a consensus Abf1 binding site. We also show that an Abf1
      site from a nonmeiotic gene can replace the function of the UASH site in the HOP1
      promoter. Taken together, these results show that Abf1 functions to regulate
      meiotic gene expression.

PMID- 8649387
TI  - Identification and characterization of a yeast gene encoding the U2 small nuclear
      ribonucleoprotein particle B" protein.
AB  - The inessential yeast gene MUD2 encodes a protein factor that contributes to U1
      small nuclear ribonucleoprotein particle (snRNP)-pre-mRNA complex (commitment
      complex) formation. To identify other genes that contribute to this early
      splicing step, we performed a synthetic lethal screen with a MUD2 deletion
      strain. The first characterized gene from this screen, MSL1 (MUD synthetic lethal
      1), encodes the yeast homolog of the well studied mammalian snRNP protein U2B".
      The yeast protein (YU2B") is a component of yeast U2 snRNP, and it is related to
      other members of the UIA-U2B" family, the human U2B" protein, the human U1A
      protein, and the yeast U1A protein. It binds in vitro to its RNA target, U2 snRNA
      stem-loop IV, without a protein cofactor, and the target resembles more closely
      the U1 snRNA binding site of the human U1A protein than it does the U2 snRNA
      binding site of human U2B". Surprisingly, the YU2B" protein lacks a C-terminal
      RNA binding domain, which is conserved in all other family members. Possible
      functional and evolutionary relationships among these proteins are discussed.

PMID- 8649388
TI  - Inhibition of cell proliferation by the Mad1 transcriptional repressor.
AB  - Mad1 is a basic helix-loop-helix-leucine zipper protein that is induced upon
      differentiation of a number of distinct cell types. Mad1 dimerizes with Max and
      recognizes the same DNA sequences as do Myc:Max dimers. However, Mad1 and Myc
      appear to have opposing functions. Myc:Max heterodimers activate transcription
      while Mad:Max heterodimers repress transcription from the same promoter. In
      addition Mad1 has been shown to block the oncogenic activity of Myc. Here we show
      that ectopic expression of Mad1 inhibits the proliferative response of 3T3 cells
      to signaling through the colony-stimulating factor-1 (CSF-1) receptor. The
      ability of over-expressed Myc and cyclin D1 to complement the mutant CSF-1
      receptor Y809F (containing a Y-to-F mutation at position 809) is also inhibited
      by Mad1. Cell cycle analysis of proliferating 3T3 cells transfected with Mad1
      demonstrates a significant decrease in the fraction of cells in the S and G2/M
      phases and a concomitant increase in the fraction of G1 phase cells, indicating
      that Mad1 negatively influences cell cycle progression from the G1 to the S
      phase. Mutations in Mad1 which inhibit its activity as a transcription repressor
      also result in loss of Mad1 cell cycle inhibitory activity. Thus, the ability of
      Mad1 to inhibit cell cycle progression is tightly coupled to its function as a
      transcriptional repressor.

PMID- 8649390
TI  - 2-Aminopurine selectively inhibits splicing of tumor necrosis factor alpha mRNA.
AB  - 2-Aminopurine (2-AP) inhibits specific kinases that phosphorylate the alpha
      subunit of eukaryotic translation initiation factor 2. One of these, PKR, is also
      involved in signal transduction. We show here that 2-AP selectively inhibits
      expression of tumor necrosis factor alpha (TNF-alpha) mRNA in primary human
      lymphoid cells. 2-AP does not inhibit transcription of the human TNF-alpha gene,
      nor does it affect mRNA stability. Instead, the flow of short-lived precursor
      transcripts into mature TNF-alpha mRNA is blocked. When 2-AP is present during
      induction, unspliced TNF-alpha precursor transcripts accumulate at the expense of
      mRNA. Using RNase protection analysis with genomic probes for different exon
      intron junctions, we show that 2-AP blocks splicing of TNF-alpha mRNA. Neither
      the TNF-beta nor the interleukin-1 beta gene shows such regulation. 2-AP also
      inhibits splicing of precursor RNA transcribed from an exogenous human TNF-alpha
      gene. Sequences within this gene thus confer sensitivity to 2-AP. Yet, control is
      not exerted at a specific splice site. Our results reveal the involvement of a 2
      AP-sensitive component, expressed in functional form before induction, in the
      splicing of TNF-alpha mRNA.

PMID- 8649389
TI  - An exceptionally conserved transcriptional repressor, CTCF, employs different
      combinations of zinc fingers to bind diverged promoter sequences of avian and
      mammalian c-myc oncogenes.
AB  - We have isolated and analyzed human CTCF cDNA clones and show here that the
      ubiquitously expressed 11-zinc-finger factor CTCF is an exceptionally highly
      conserved protein displaying 93% identity between avian and human amino acid
      sequences. It binds specifically to regulatory sequences in the promoter-proximal
      regions of chicken, mouse, and human c-myc oncogenes. CTCF contains two
      transcription repressor domains transferable to a heterologous DNA binding
      domain. One CTCF binding site, conserved in mouse and human c-myc genes, is found
      immediately downstream of the major P2 promoter at a sequence which maps
      precisely within the region of RNA polymerase II pausing and release. Gel shift
      assays of nuclear extracts from mouse and human cells show that CTCF is the
      predominant factor binding to this sequence. Mutational analysis of the P2
      proximal CTCF binding site and transient-cotransfection experiments demonstrate
      that CTCF is a transcriptional repressor of the human c-myc gene. Although there
      is 100% sequence identity in the DNA binding domains of the avian and human CTCF
      proteins, the regulatory sequences recognized by CTCF in chicken and human c-myc
      promoters are clearly diverged. Mutating the contact nucleotides confirms that
      CTCF binding to the human c-myc P2 promoter requires a number of unique contact
      DNA bases that are absent in the chicken c-myc CTCF binding site. Moreover,
      proteolytic-protection assays indicate that several more CTCF Zn fingers are
      involved in contacting the human CTCF binding site than the chicken site. Gel
      shift assays utilizing successively deleted Zn finger domains indicate that CTCF
      Zn fingers 2 to 7 are involved in binding to the chicken c-myc promoter, while
      fingers 3 to 11 mediate CTCF binding to the human promoter. This flexibility in
      Zn finger usage reveals CTCF to be a unique "multivalent" transcriptional factor
      and provides the first feasible explanation of how certain homologous genes
      (i.e., c-myc) of different vertebrate species are regulated by the same factor
      and maintain similar expression patterns despite significant promoter sequence
      divergence.

PMID- 8649391
TI  - Tyrosine phosphorylation of Grb2-associated proteins correlates with
      phospholipase C gamma 1 activation in T cells.
AB  - Ligation of the T-cell antigen receptor (TCR) results in the rapid activation of
      several protein tyrosine kinases, with the subsequent phosphorylation of numerous
      cellular proteins. We investigated the requirement for tyrosine phosphorylation
      of proteins which bind the Grb2 SH2 domain in TCR-mediated signal transduction by
      transfecting the Jurkat T-cell line with a cDNA encoding a chimeric protein
      designed to dephosphorylate these molecules. Stimulation of the TCR on cells
      expressing this engineered enzyme fails to result in sustained tyrosine
      phosphorylation of a 36-kDa protein likely to be the recently cloned pp36/Lnk.
      Interestingly, TCR ligation of the transfected cells also fails to induce soluble
      inositol phosphate production and intracellular calcium mobilization, although
      receptor-mediated tyrosine phosphorylation of phospholipase C gamma 1 still
      occurs. TCR-mediated Ras and mitogen-activated protein kinase activation remain
      intact in cells expressing the engineered phosphatase. These data demonstrate
      that tyrosine phosphorylation of a protein(s) which binds the SH2 domain of Grb2
      correlates with phospholipase C gamma 1 activation and suggest that such a
      phosphoprotein(s) plays a critical role in coupling the TCR with the
      phosphatidylinositol second-messenger pathway.

PMID- 8649392
TI  - Ste12 and Mcm1 regulate cell cycle-dependent transcription of FAR1.
AB  - The transcripts of many genes involved in Saccharomyces cerevisiae mating were
      found to fluctuate during the cell cycle. In the absence of a functional Ste12
      transcription factor, both the levels and the cell cycle pattern of expression of
      these genes were affected. FUS1 and AGA1 levels, which are maximally expressed
      only in G1-phase cells, were strongly reduced in ste12- cells. The cell cycle
      transcription pattern for FAR1 was changed in ste12- cells: the gene was still
      significantly expressed in G2/M, but transcript levels were strongly reduced in
      G1 phase, resulting in a lack of Far1 protein accumulation. G2/M transcription of
      FAR1 was dependent on the transcription factor Mcm1, and expression of a gene
      with Mcm1 fused to a strong transcriptional activation domain resulted in
      increased levels of FAR1 transcription. The pattern of cell cycle-regulated
      transcription of FAR1 could involve combinatorial control of Ste12 and Mcm1.
      Forced G1 expression of FAR1 from the GAL1 promoter resorted the ability to
      arrest in response to pheromone in ste12-cells. This indicates that transcription
      of FAR1 in the G1 phase is essential for accumulation of the protein and for
      pheromone-induced cell cycle arrest.

PMID- 8649393
TI  - Faithful chromosome transmission requires Spt4p, a putative regulator of
      chromatin structure in Saccharomyces cerevisiae.
AB  - A chromosome transmission fidelity (ctf) mutant, s138, of Saccharomyces
      cerevisiae was identified by its centromere (CEN) transcriptional readthrough
      phenotype, suggesting perturbed kinetochore integrity in vivo. The gene
      complementing the s138 mutation was found to be identical to the S. cerevisiae
      SPT4 gene. The s138 mutation is a missense mutation in the second of four
      conserved cysteine residues positioned similarly to those of zinc finger
      proteins, and we henceforth refer to the mutation of spt4-138. Both spt4-138 and
      spt4 delta strains missegregate a chromosome fragment at the permissive
      temperature, are temperature sensitive for growth at 37 degrees C, and upon a
      shift to the nonpermissive temperature show an accumulation of large budded
      cells, each with a nucleus. Previous studies suggest that Spt4p functions in a
      complex with Spt5p and Spt6p, and we determined that spt6-140 also causes
      missegregation of a chromosome fragment. Double mutants carrying spt4 delta
      2::HIS3 and kinetochore mutation ndc10-42 or ctf13-30 show a synthetic
      conditional phenotype. Both spt4-138 and spt4 delta strains exhibit synergistic
      chromosome instability in combination with CEN DNA mutations and show in vitro
      defects in microtubule binding to minichromosomes. These results indicate that
      Spt4p plays a role in chromosome segregation. The results of in vivo genetic
      interactions with mutations in kinetochore proteins and CEN DNA and of in vitro
      biochemical assays suggest that Spt4p is important for kinetochore function.

PMID- 8649394
TI  - Identification and analysis of a functional human homolog of the SPT4 gene of
      Saccharomyces cerevisiae.
AB  - Spt4p is a nonhistone protein of Saccharomyces cerevisiae that is believed to be
      required for normal chromatin structure and transcription. In this work we
      describe the isolation and analysis of a human gene, SUPT4H, that encodes a
      predicted protein 42% identical to Spt4p. When expressed in S. cerevisiae, SUPT4H
      complemented all spt4 mutant phenotypes. In human cells SUPT4H encodes a nuclear
      protein that is expressed in all tissues tested. In addition, hybridization
      analyses suggest that an SUPT4H-related gene is also present in mice. SUPT4H was
      localized to human chromosome 17 by PCR analysis of a human-rodent somatic cell
      hybrid panel. Thus, like other proteins that are components of or control the
      structure of chromatin, Spt4p appears to be conserved from S. cerevisiae to
      mammals.

PMID- 8649395
TI  - Stimulation of protein synthesis, eukaryotic translation initiation factor 4E
      phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor
      substrate 1 and phosphatidylinositol 3-kinase.
AB  - Insulin rapidly stimulates protein synthesis in a wide variety of tissues. This
      stimulation is associated with phosphorylation of several translational
      initiation and elongation factors, but little is known about the signaling
      pathways to these events. To study these pathways, we have used a myeloid
      progenitor cell line (32D) which is dependent on interleukin 3 but insensitive to
      insulin because of the very low levels of insulin receptor (IR) and the complete
      lack of insulin receptor substrate (IRS)-signaling proteins (IRS-1 and IRS-2).
      Expression of more IR permits partial stimulation of mitogen-activated protein
      kinase by insulin, and expression of IRS-1 alone mediates insulin stimulation of
      the 70-kDa S6 kinase (pp70S6K) by the endogenous IR. However, expression of both
      IR and IRS-1 is required for stimulation of protein synthesis. Moreover, this
      effect requires activation of phosphatidylinositol 3-kinase (PI3K), as determined
      by wortmannin inhibition and the use of an IRS-1 variant lacking all Tyr residues
      except those which activate PI3K. Stimulation of general protein synthesis does
      not involve activation by IRS-1 of GRB-2-SOS-p21ras or SH-PTP2, since IRS-1
      variants lacking the SH2-binding Tyr residues for these proteins are fully
      active. Nor does it involve pp70S6K, since rapamycin, while strongly inhibiting
      the synthesis of a small subset of growth-regulated proteins, only slightly
      inhibits total protein synthesis. Recruitment of mRNAs to the ribosome is
      enhanced by phosphorylation of eIF4E, the cap-binding protein, and PHAS-I, a
      protein that specifically binds eIF4E. The behavior of cell lines containing IRS
      1 variants and inhibition by wortmannin and rapamycin indicate that the
      phosphorylation of both proteins requires IRS-1-mediated stimulation of PI3K and
      pp70S6K but not mitogen-activated protein kinase or SH-PTP2.

PMID- 8649396
TI  - Accessibility of alpha 2-repressed promoters to the activator Gal4.
AB  - It has been proposed that eukaryotic repressors of transcription can act by
      organizing chromatin, thereby preventing the accessibility of nearby DNA to
      activator proteins required for transcription initiation. In this study, we test
      this idea for the yeast alpha 2 repressor using a simple, artificial promoter
      that contains a single binding site for the activator protein Gal4 and a single
      binding site for the repressor alpha 2. When both the repressor and the activator
      are expressed in the same cell, the artificial promoter is efficiently repressed.
      In vivo footprinting experiments demonstrate that Gal4 can occupy its binding
      site even when the promoter is repressed. This result indicates that alpha 2
      directed repression must result from interference with some stage in
      transcription initiation other than activator binding to DNA.

PMID- 8649397
TI  - Activation and regulation of the Spc1 stress-activated protein kinase in
      Schizosaccharomyces pombe.
AB  - Spc1, an osmotic-stress-stimulated mitogen-activated protein kinase (MAPK)
      homolog in the fission yeast Schizosaccharomyces pombe, is required for the
      induction of mitosis and survival in high-osmolarity conditions. Spc1, also known
      as Sty1, is activated by Wis1 MAPK kinase and inhibited by Pyp1 tyrosine
      phosphatase. Spc1 is most closely related to Saccharomyces cerevisiae Hog1 and
      mammalian p38 kinases. Whereas Hog1 is specifically responsive to osmotic stress,
      we report here that Spc1 is activated by multiple forms of stress, including high
      temperature and oxidative stress. In this regard Spc1 is more similar to
      mammalian p38. Activation of Spc1 is crucial for survival of various forms of
      stress. Spc1 regulates expression of genes encoding stress-related proteins such
      as glycerol-3-phosphate dehydrogenase (gpd1+) and trehalose-6-phosphate synthase
      (tps1+). Spc1 also promotes expression of pyp2+, which encodes a tyrosine
      phosphatase postulated as a negative regulator of Spc1. This proposal is
      supported by the finding that Spc1 associates with Pyp2 in vivo and that the
      amount of Spc1 tyrosine phosphorylation is lower in a Pyp2-overproducing strain
      than in the wild type. Moreover, the level of stress-stimulated gpd1+ expression
      is higher in delta pyp2 mutants than in the wild type. These findings demonstrate
      that Spc1 promotes expression of genes involved in stress survival and that of
      regulation may be commonly employed to modulate MAPK signal transduction pathways
      in eukaryotic species.

PMID- 8649398
TI  - Either of the major H2A genes but not an evolutionarily conserved H2A.F/Z variant
      of Tetrahymena thermophila can function as the sole H2A gene in the yeast
      Saccharomyces cerevisiae.
AB  - H2A.F/Z histones are conserved variants that diverged from major H2A proteins
      early in evolution, suggesting they perform an important function distinct from
      major H2A proteins. Antisera specific for hv1, the H2A.F/Z variant of the
      ciliated protozoan Tetrahymena thermophila, cross-react with proteins from
      Saccharomyces cerevisiae. However, no H2A.F/Z variant has been reported in this
      budding yeast species. We sought to distinguish among three explanations for
      these observations: (i) that S. cerevisiae has an undiscovered H2A.F/Z variant,
      (ii) that the major S. cerevisiae H2A proteins are functionally equivalent to
      H2A.F/Z variants, or (iii) that the conserved epitope is found on a non-H2A
      molecule. Repeated attempts to clone an S. cerevisiae hv1 homolog only resulted
      in the cloning of the known H2A genes yHTA1 and yHTA2. To test for functional
      relatedness, we attempted to rescue strains lacking the yeast H2A genes with
      either the Tetrahymena major H2A genes (tHTA1 or tHTA2) or the gene (tHTA3)
      encoding hv1. Although they differ considerably in sequence from the yeast H2A
      genes, the major Tetrahymena H2A genes can provide the essential functions of H2A
      in yeast cells, the first such case of trans-species complementation of histone
      function. The Tetrahymena H2A genes confer a cold-sensitive phenotype. Although
      expressed at high levels and transported to the nucleus, hv1 cannot replace yeast
      H2A proteins. Proteins from S. cerevisiae strains lacking yeast H2A genes fail to
      cross-react with anti-hv1 antibodies. These studies make it likely that S.
      cerevisiae differs from most other eukaryotes in that it does not have an H2A.F/Z
      homolog. A hypothesis is presented relating the absence of H2A.F/Z in S.
      cerevisiae to its function in other organisms.

PMID- 8649399
TI  - Role of amino-terminal histone domains in chromatin replication.
AB  - Simian virus 40 minichromosomes were treated with trypsin to specifically remove
      the amino-terminal histone domains (tails). Trypsin treatment does not affect the
      spacing and the number of nucleosomes on minichromosomes but indices a more
      extended conformation, as shown by the reduced sedimentation coefficient of
      trypsinized minichromosomes compared with the untreated controls. Trypsinized
      minichromosomes replicate more efficiently than control minichromosomes in in
      vitro replication assays. The increased template efficiency appears to be due to
      higher rates of replicative fork movement. In vitro replication in the presence
      of protein-free competitor DNA shows that replicating trypsinized minichromosomes
      do not lose nucleosomes and replicating competitor DNA does not gain nucleosomes.
      This finding suggests that tailless nucleosomes are transferred from the
      unreplicated prefork stem to replicated DNA branches and excludes a participation
      of the basic histone domains in nucleosome transfer.

PMID- 8649400
TI  - B-lymphocyte development is regulated by the combined dosage of three basic helix
      loop-helix genes, E2A, E2-2, and HEB.
AB  - B-lymphocyte development requires the basic helix-loop-helix proteins encoded by
      the E2A gene. In this study, the control mechanism of E2A was further explored by
      disruption of the E2A-related genes, E2-2 and HEB. In contrast to E2A, E2-2 and
      HEB are not essential for the establishment of the B-cell lineage. However, both
      E2-2 and HEB are required for the generation of the normal numbers of pro-B cells
      in mouse embryos. Breeding tests among mice carrying different mutations revealed
      that E2-2 and HEB interact with E2A in many developmental processes including
      generation of B cells. Specifically, mice transheterozygous for any two mutations
      of these three genes produced fewer pro-B cells than the singly heterozygous
      littermates. This study indicates that B-cell development is dependent not only
      on an essential function provided by the E2A gene but also on a combined dosage
      set by E2A, E2-2, and HEB.

PMID- 8649401
TI  - Analysis of mice containing a targeted deletion of beta-globin locus control
      region 5' hypersensitive site 3.
AB  - To examine the function of murine beta-globin locus region (LCR) 5'
      hypersensitive site 3 (HS3) in its native chromosomal context, we deleted this
      site from the mouse germ line by using homologous recombination techniques.
      Previous experiments with human 5' HS3 in transgenic models suggested that this
      site independently contains at least 50% of total LCR activity and that it
      interacts preferentially with the human gamma-globin genes in embryonic erythroid
      cells. However, in this study, we demonstrate that deletion of murine 5' HS3
      reduces expression of the linked embryonic epsilon y- and beta H 1-globin genes
      only minimally in yolk sac-derived erythroid cells and reduces output of the
      linked adult beta (beta major plus beta minor) globin genes by approximately 30%
      in adult erythrocytes. When the selectable marker PGK-neo cassette was left
      within the HS3 region of the LCR, a much more severe phenotype was observed at
      all developmental stages, suggesting that PGK-neo interferes with LCR activity
      when it is retained within the LCR. Collectively, these results suggest that
      murine 5' HS3 is not required for globin gene switching; importantly, however, it
      is required for approximately 30% of the total LCR activity associated with adult
      beta-globin gene expression in adult erythrocytes.

PMID- 8649402
TI  - Activation of the mitogen-activated protein kinase pathway induces transcription
      of the PAC-1 phosphatase gene.
AB  - PAC-1, an early-response gene originally identified in activated T cells, encodes
      a dual-specificity mitogen-activated protein kinase phosphatase. Here we report
      on the regulation of PAC-1 expression in murine hemopoietic cells. PAC-1 mRNA
      levels rapidly increase in mitogen-stimulated lymphocytes, with the induced
      expression being transient in B cells but sustained in activated T cells.
      Transfection analysis of murine PAC-1 promoter-reporter constructs established
      that in T cells, sequences necessary for basal and induced transcription reside
      within a 200-bp region located immediately upstream of the transcription
      initiation sites. Basal transcription is regulated in part by an E-box element
      that binds a 53-kDa protein. PAC-1 transcription induced by phorbol myristate
      acetate stimulation and the expression of the v-ras or v-raf oncogene is mediated
      via the E-box motif and an AP-2-related site and coincides with increased binding
      activity of the constitutive 53-kDa E-box-binding protein and induced binding of
      AP-2. The ability of an interfering ERK-2 mutant to block phorbol myristate
      acetate and v-ras-dependent PAC-1 transcription indicates that mitogen-activated
      protein kinase activation is necessary for these stimuli to induce transcription
      of the PAC-1 gene in T cells.

PMID- 8649404
TI  - Regulation of telomerase activity in immortal cell lines.
AB  - Telomerase is a ribonucleoprotein whose activity has been detected in germ line
      cells, immortal cells, and most cancer cells. Except in stem cells, which have a
      low level of telomerase activity, its activity is absent from normal somatic
      tissues. Understanding the regulation of telomerase activity is critical for the
      development of potential tools for the diagnosis and treatment of cancer. Using
      the telomeric repeat amplification protocol, we found that immortal, telomerase
      positive, pseudodiploid human cells (HT1080 and HL60 cells) sorted by flow
      repressed in quiescent cells. This was true whether quiescence was induced by
      contact inhibition (NIH 3T3 mouse cells), growth factor removal
      (bromodeoxyuridine-blocked mouse myoblasts), reexpression of cellular senescence
      (the reversibly immortalized IDH4 cells), or irreversible cell differentiation
      (HL60 promyelocytic leukemia cells and C2C12 mouse myoblasts). Taken together,
      these results indicate that telomerase is active throughout the cell in dividing,
      immortal cells but that its activity is repressed in cells that exit the cell
      cycle. This suggests that quiescent stem cells that have the potential to express
      telomerase may remain unaffected by potential antitelomerase cancer therapies.

PMID- 8649403
TI  - The REG2 gene of Saccharomyces cerevisiae encodes a type 1 protein phosphatase
      binding protein that functions with Reg1p and the Snf1 protein kinase to regulate
      growth.
AB  - The GLC7 gene of Saccharomyces cerevisiae encodes the catalytic subunit of type 1
      protein phosphatase (PP1) and is essential for cell growth. We have isolated a
      previously uncharacterized gene, REG2, on the basis of its ability to interact
      with Glc7p in the two-hybrid system. Reg2p interacts with Glc7p in vivo, and
      epitope-tagged derivatives of Reg2p and Glc7p coimmunoprecipitate from cell
      extracts. The predicted protein product of the REG2 gene is similar to Reg1p, a
      protein believed to direct PP1 activity in the glucose repression pathway.
      Mutants with a deletion of reg1 display a mild slow-growth defect, while reg2
      mutants exhibit a wild-type phenotype. However, mutants with deletions of both
      reg1 and reg2 exhibit a severe growth defect. Overexpression of REG2 complements
      the slow-growth defect of a reg1 mutant but does not complement defects in
      glycogen accumulation or glucose repression, two traits also associated with a
      reg1 deletion. These results indicate that REG1 has a unique role in the glucose
      repression pathway but acts together with REG2 to regulate some as yet
      uncharacterized function important for growth. The growth defect of a reg1 reg2
      double mutant is alleviated by a loss-of-function mutation in the SNF1-encoded
      protein kinase. The snf1 mutation also suppresses the glucose repression defects
      of reg1. Together, our data are consistent with a model in which Reg1p and Reg2p
      control the activity of PP1 toward substrates that are phosphorylated by the
      Snf1p kinase.

PMID- 8649405
TI  - Sp1 binds two sites in the CD11c promoter in vivo specifically in myeloid cells
      and cooperates with AP1 to activate transcription.
AB  - The leukocyte integrin gene, CD11c, is transcriptionally regulated and is
      expressed predominantly on differentiated cells of the myelomonocytic lineage. In
      this study we have demonstrated that the regions -72 to -63 and -132 to -104 of
      the CD11c promoter contain elements responsible for phorbol ester-induced
      differentiation of the myeloid cell line HL60. DNase I footprinting analysis
      revealed that these regions can bind purified Sp1, and supershift analysis with
      Sp1 antibody confirmed that Sp1 in HL60 nuclear extracts could bind these
      regions. Transfection analysis of CD11c promoter-chloramphenicol
      acetyltransferase constructs containing deletions of these Sp1-binding sites
      revealed that these sites are essential for expression of the CD11c gene in HL60
      cells but not in the T-cell line Molt4 or the cervical carcinoma cell line HeLa.
      Moreover, cotransfection of pPacSp1 along with these CD11c promoter
      chloramphenicol acetyltransferase constructs into Sp1-deficient Drosophila
      Schneider 2 cells verified that these sites are essential for Sp1-dependent
      expression of the CD11c promoter. In vivo genomic footprinting revealed that Sp1
      contacts the CD11c promoter within the regions -69 to -63 and -116 to -105 in
      phorbol 12-myristate 13-acetate-differentiated HL60 cells but not in
      undifferentiated HL60 cells or in Molt4 or HeLa cells. Cotransfection assays in
      HL60 cells revealed that Sp1 acts synergistically with Ap1 to activate CD11c.
      Further, both Sp1 sites are capable of cooperating with AP1. In vitro DNase I
      footprinting analysis with purified Sp1 and c-jun proteins showed that Sp1
      binding could facilitate binding of c-jun. We propose that myeloid-specific
      expression of the CD11c promoter and is facilitated by cooperative interaction
      between the Sp1- and Ap1-binding sites.

PMID- 8649406
TI  - Effects of terminal nonhomology and homeology on double-strand-break-induced gene
      conversion tract directionality.
AB  - Double-strand breaks (DSBs) greatly enhance gene conversion in the yeast
      Saccharomyces cerevisiae. In prior plasmid x chromosome crosses, conversion
      tracts were often short ( < 53 bp) and usually extended in only one direction
      from a DSB in an HO recognition sequence inserted into ura3. To allow fine
      structure analysis of short and unidirectional tracts, phenotypically silent
      markers were introduced at 3- and 6-bp intervals flanking the HO site. These
      markers, which created a 70-bp homeologous region (71% homology), greatly
      increased the proportion of bidirectional tracts. Among products with short or
      unidirectional tracts, 85% were highly directional, converting markers on only
      one side (the nearest marker being 6 bp from the HO site). A DSB in an HO site
      insertion creates terminal nonhomologies. The high degree of directionality is a
      likely consequence of the precise cleavage at homology/nonhomology borders in
      hybrid DNA by Rad1/10 endonuclease. In contrast, terminal homeology alone yielded
      mostly unidirectional tracts. Thus, nonhomology flanked by homeology yields
      primarily bidirectional tracts, but terminal homeology or nonhomology alone
      yields primarily unidirectional tracts. These results are inconsistent with uni-
      and bidirectional tracts arising from one- and two-ended invasion mechanisms,
      respectively, as reduced homology would be expected to favor one-ended events.
      Tract spectra with terminal homeology alone with similar in RAD1 and rad1 cells,
      indicating that the high proportion of bidirectional tracts seen with homeology
      flanking nonhomology is not a consequence of Rad1/10 cleavage at
      homology/homeology boundaries. Instead, tract directionality appears to reflect
      the influence of the degree of broken-end homology on mismatch repair.

PMID- 8649407
TI  - cis-acting sequences located downstream of the human immunodeficiency virus type
      1 promoter affect its chromatin structure and transcriptional activity.
AB  - We have examined the roles of AP-1, AP-3-like, DBF1, and Sp1 binding sites, which
      are located downstream of the human immunodeficiency virus type 1 (HIV-1)
      promoter, in regulating basal transcriptional activity directed by the integrated
      viral long terminal repeat (LTR). Point mutations affecting all four of these
      elements functionally inactivated the HIV-1 LTR when it was constrained in a
      chromatin configuration. Analyses of the chromatin structures of the
      transcriptionally active wild-type and inactive mutated HIV-1 promoters revealed
      several differences. In the active promoter, the 3' half of the U3 region,
      including the basal promoter, the enhancer, and the putative upstream regulatory
      sequences are situated within a nuclease-hypersensitive region. However, the far
      upstream U3 region appears to be packaged into a nuclease-resistant nucleosomal
      structure, whereas the R, U5, and gag leader sequences are associated with a
      region of altered chromatin that is sensitive to restriction endonucleases. In
      the inactive template, only the basal promoter and enhancer element remain
      sensitive to nucleases, and the adjacent upstream and downstream regions are
      incorporated into nuclease-resistant nucleosomal structures. Taken together,
      these results indicate that the chromatin structure of the integrated HIV-1 LTR
      plays a critical role in modulating basal transcriptional activity.

PMID- 8649408
TI  - Differential control of transcription by homologous homeodomain coregulators.
AB  - The human herpes simplex virus type 1 (HSV-1) transactivator VP16 and its homolog
      from bovine herpes-virus 1 (BHV-1) can each recruit the human homeodomain protein
      Oct-1 into a transcriptional regulatory complex. Here, we show that these two Oct
      1 coregulators possess similar, if not identical, homeodomain recognition
      properties but possess different virus-specific cis-regulatory specificities: the
      HSV-1 VP-16 protein activates transcription from the HSV-1 VP16 response element,
      and the BHV-1 VP16 protein activates transcription from the BHV-1 VP16 response
      element. A distinct 3-bp segment, the D segment, lying 3' of the canonical
      TAATGARAT motif (where R is a purine) in the VP16 response element is responsible
      for the differential cis element recognition and transcriptional activation by
      these two homeodomain coregulators. These results demonstrate how a single
      homeodomain protein can direct differential transcriptional regulation by
      selective association with homologous homeodomain coregulators.

PMID- 8649409
TI  - Direct repeats bind the EcR/USP receptor and mediate ecdysteroid responses in
      Drosophila melanogaster.
AB  - The steroid hormone 20-hydroxyecdysone plays a key role in the induction and
      modulation of morphogenetic events throughout Drosophila development. Previous
      studies have shown that a heterodimeric nuclear receptor composed of the EcR and
      USP proteins mediates the action of the hormone at the transcriptional through
      binding to palindromic ecdysteroid mediates the action of the hormone at the
      transcriptional level through binding to palindromic ecdysteroid response
      elements (EcREs) such as those present in the promoter of the hsp27 gene or the
      fat body-specific enhancer of the Fbp1 gene. We show that in addition to
      palindromic EcREs, the EcR/USP heterodimer can bind in vitro with various
      affinities to direct repetitions of the motif AGGTCA separated by 1 to 5
      nucleotides (DR1 to DR5), which are known to be target sites for vertebrate
      nuclear receptors. At variance with the receptors, EcR/USP was also found to bind
      to a DR0 direct repeat with no intervening nucleotide. In cell transformation
      assays, direct repeats DR0 to DR5 alone can render the minimum viral tk or
      Drosophila Fbp1 promoter responsive to 20-hydroxyecdysone, as does the
      palindromic hsp27 EcRE. In a transgenic assay, however, neither the palindromic
      hsp27 element nor direct repeat DR3 alone can make the Fbp1 minimal promoter
      responsive to premetamorphic ecdysteroid peaks. In contrast, DR0 and DR3
      elements, when substituted for the natural palindromic EcRE in the context of the
      Fbp1 enhancer, can drive a strong fat body-specific ecdysteroid response in
      transgenic animals. These results demonstrate that directly repeated EcR/USP
      binding sites are as effective as palindromic EcREs in vivo. They also provide
      evidence that additional flanking regulatory sequences are crucially required to
      potentiate the hormonal response mediated by both types of elements and specify
      its spatial and temporal pattern.

PMID- 8649410
TI  - Inhibition of E2F activity by the cyclin-dependent protein kinase inhibitor p21
      in cells expressing or lacking a functional retinoblastoma protein.
AB  - p21Sdi1/WAF1/Cip1 inhibits cyclin-dependent protein kinases and cell
      proliferation. p21 is presumed to inhibit growth by preventing the
      phosphorylation of growth-regulatory proteins, including the retinoblastoma tumor
      suppressor protein (pRb). The ultimate effector(s) of p21 growth inhibition,
      however, is largely a matter of conjecture. We show that p21 inhibits the
      activity of E2F, an essential growth-stimulatory transcription factor that is
      negatively regulated by unphosphorylated pRb. p21 suppressed the activity of E2F
      responsive promoters (dihydrofolate reductase and cdc2), but E2F-unresponsive
      promoters (c-fos and simian virus 40 early) were unaffected. Moreover, the simian
      virus 40 early promoter was rendered p21 suppressible by introducing wild-type,
      but not mutant, E2F binding sites; p21 deletion mutants showed good agreement in
      their abilities to inhibit E2F transactivation and DNA synthesis; and E2F-1
      (which binds pRb), but not E2F-4 (which does not), reversed both inhibitory
      effects of p21. Despite the central role for pRb in regulating E2F, p21
      suppressed growth and E2F activity in cells lacking a functional pRb. Moreover,
      p21 protein (wild type but not mutant) specifically disrupted an E2F-cyclin
      dependent protein kinase 2-p107 DNA binding complex in nuclear extracts of
      proliferating cells, whether or not they expressed normal pRb. Thus, E2F is a
      critical target and ultimate effector of p21 action, and pRb is not essential for
      the inhibition of growth or E2F-dependent transcription.

PMID- 8649411
TI  - Germ line and embryonic expression of Fex, a member of the Drosophila F-element
      retrotransposon family, is mediated by an internal cis-regulatory control region.
AB  - The F elements of Drosophila melanogaster belong to the superfamily of long
      interspersed nucleotide element retrotransposons. To date, F-element
      transcription has not been detected in flies. Here we describe the isolation of a
      member of the F-element family, termed Fex, which is transcribed in specific
      cells of the female and male germ lines and in various tissues during
      embryogenesis of D. melanogaster. Sequence analysis revealed that this element
      contains two complete open reading frames coding for a putative nucleic acid
      binding protein and a putative reverse transcriptase. Functional analysis of the
      5' region, using germ line transformation of Fex-lacZ reporter gene constructs,
      demonstrates that major aspects of tissue-specific Fex expression are controlled
      by internal cis-acting elements that lie in the putative coding region of open
      reading frame 1. These sequences mediate dynamic gene expression in eight
      expression domains during embryonic and germ line development. The capacity of
      the cis-regulatory region of the Fex element to mediate such complex expression
      patterns is unique among members of the long interspersed nucleotide element
      superfamily of retrotransposons and is reminiscent of regulatory regions of
      developmental control genes.

PMID- 8649412
TI  - Saccharomyces cerevisiae pms2 mutations are alleles of MLH1, and pms2-2
      corresponds to a hereditary nonpolyposis colorectal carcinoma-causing missense
      mutation.
AB  - A number of mutant Saccharomyces cerevisiae strains having phenotypes consistent
      with defects in DNA mismatch repair have been described, but not all have been
      extensively characterized. In this study we demonstrate that the pms2-1 and pms2
      2 alleles arise from missense mutations in the MLH1 gene which inactivate MLH1.
      One of these alleles, pms2-2, causes the same amino acid substitution in a highly
      conserved region of the known MutL homologs as that caused by a proposed missense
      mutation observed in a Swedish hereditary nonpolyposis colorectal carcinoma
      kindred. This observation supports the functional significance of missense
      mutations found in hereditary nonpolyposis colorectal carcinoma kindreds and
      indicates that in some cases S. cerevisiae can serve as a useful model system for
      the analysis of such mutations.

PMID- 8649413
TI  - Base pairing at the 5' splice site with U1 small nuclear RNA promotes splicing of
      the upstream intron but may be dispensable for slicing of the downstream intron.
AB  - We previously reported that exon skipping in vivo due to point mutations in the
      5' splice site (5'ss) signal of an internal mammalian exon can be prevented by
      coexpression of U1 small nuclear RNAs, termed shift-U1s, with complementarity to
      sequence upstream or downstream of the mutated site. We now show by S1 nuclease
      protection experiments that a typical shift-U1 restores splicing of the upstream
      intron, but not necessarily of the down stream intron. This indicates that the
      normal 5'ss sequence acts as an enhancer for splicing of the upstream intron,
      that it owes this activity to base pairing with U1, and that the enhancer
      activity is reproduced by base pairing of U1 with other sequences in the area.
      Shift-U1s are dispensable when the 3'ss sequence of the upstream intron is
      improved, which suggests that base pairing of U1 with sequences at or near the
      downstream end of the exon normally functions by compensating for a weakness in
      the upstream 3'ss. Accordingly, U1 appears to be involved in communication across
      the exon, but our data indicate at the same time that extensive base pairing
      between U1 and the 5'ss sequence is not necessary for accurate splicing of the
      downstream intron. These findings are discussed in relation to the coordinate
      selection exon termini proposed by the exon definition model.

PMID- 8649414
TI  - A testis cytoplasmic RNA-binding protein that has the properties of a
      translational repressor.
AB  - Translation of the mouse protamine 1 (Prm-1) mRNA is repressed for several days
      during male germ cell differentiation. With the hope of cloning genes that
      regulate the translational repression of Prm-1, we screened male germ cell cDNA
      expression libraries with the 3' untranslated region of the Prm-1 RNA. From this
      screen we obtained two independent clones that encode Prbp, a Prm-1 RNA-binding
      protein. Prbp contains two copies of a double-stranded-RNA-binding domain. In
      vitro, the protein binds to a portion of the Prm-1 3' untranslated region
      previously shown to be sufficient for translational repression in transgenic
      mice, as well as to poly(I). poly(C). Prbp protein is present in multiple forms
      in cytoplasmic extracts prepared from wild-type mouse testes and is absent from
      testes of germ cell-deficient mouse mutants, suggesting that Prbp is restricted
      to the germ cells of the testis. Immunocytochemical localization confirmed that
      Prbp is present in the cytoplasmic compartment of late-stage meiotic cells and
      haploid round spermatids. Recombinant Prbp protein inhibits the translation of
      multiple mRNAs in a wheat germ lysate, suggesting that Prbp acts to repress
      translation in round spermatids. While this protein lacks complete specificity
      for Prm-1-containing RNAs in vitro, the properties of Prbp are consistent with it
      acting as a general repressor of translation.

PMID- 8649415
TI  - Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta
      chain heterodimerization, which is required for receptor activation but not high
      affinity binding.
AB  - The human interleukin-3 receptor (IL-3R) is a heterodimer that comprises an IL-3
      specific alpha chain (IL-3R alpha) and a common beta chain (beta C) that is
      shared with the receptors for granulocyte-macrophage colony-stimulating factor
      (GM-CSF) and IL-5. These receptors belong to the cytokine receptor superfamily,
      but they are structurally and functionally more related to each other and thus
      make up a distinct subfamily. Although activation of the normal receptor occurs
      only in the presence of ligand, the underlying mechanisms are not known. We show
      here that human IL-3 induces heterodimerization of IL-3R alpha and beta c and
      that disulfide linkage of these chains is involved in receptor activation but not
      high-affinity binding. Monoclonal antibodies (MAb) to IL-3R alpha and beta c were
      developed which immunoprecipitated, in the absence of IL-3, the respective chains
      from cells labelled with 125I on the cell surface. However, in the presence of IL
      3, each MAb immunoprecipitated both IL-3R alpha and beta c. IL-3-induced receptor
      dimers were disulfide and nondisulfide linked and were dependent on IL-3
      interacting with both IL-3R alpha and beta c. In the presence of IL-3 and under
      nonreducing conditions, MAb to either IL-3R alpha or beta c immunoprecipitated
      complexes with apparent molecular weights of 215,000 and 245,000 and IL-3R alpha
      and beta c monomers. Preincubation with iodoacetamide prevented the formation of
      the two high-molecular-weight complexes without affecting noncovalent dimer
      formation or high-affinity IL-3 binding. Two-dimensional gel electrophoresis and
      Western blotting (immunoblotting) demonstrated the presence of both IL-3R alpha
      and beta c in the disulfide-linked complexes. IL-3 could also be
      coimmunoprecipitated with anti-IL-3R alpha or anti-beta c MAB, but it was not
      covalently attached to the receptor. Following IL-3 stimulation, only the
      disulfide-linked heterodimers exhibited reactivity with antiphosphotyrosine
      antibodies, with beta c but not IL-3R alpha being the phosphorylated species. A
      model of IL-3R activation is proposed which may be also applicable to the related
      GM-CSF and IL-5 receptors.

PMID- 8649416
TI  - Determinants of Drosophila fushi tarazu mRNA instability.
AB  - The fushi tarazu gene is essential for the establishment of the Drosophila
      embryonic body plan. When first expressed in early embryogenesis, fushi tarazu
      mRNA is uniformly distributed over most of the embryo. Subsequently, fushi tarazu
      mRNA expression rapidly evolves into a pattern of seven stripes that encircle the
      embryo. The instability of fushi tarazu mRNA is probably crucial for attaining
      this localized pattern of expression. mRNA stability in transgenic embryos was
      measured by a new method that does not use drugs or external interference.
      Experiments using hybrid genes that fuse fushi tarazu sequences to those of the
      stable ribosomal protein A1 mRNA provide evidence for at least two destabilizing
      elements in the fushi tarazu mRNA, one located within the 5' one-third of the
      mRNA and the other near the 3' end (termed FIE3 for ftz instability element 3').
      The FIE3 lies within a 201-nucleotide sequence just upstream of the
      polyadenylation signal and can act autonomously to destabilize a heterologous
      mRNA. Further deletion constructs identified an essential 68-nucleotide element
      within the FIE3. Lack of homology between this element and other previously
      identified destabilization sequences suggests that FIE3 contains a novel RNA
      destabilization element.

PMID- 8649417
TI  - Methylation of DNA repeats of decreasing sizes in Ascobolus immersus.
AB  - In Ascobolus immersus, DNA duplications are subject to the process of methylation
      induced premeiotically (MIP), which methylates the cytosine residues within the
      repeats and results in reversible gene silencing. The triggering of MIP requires
      pairing of the repeats, and its detection requires maintenance of the resulting
      methylation. MIP of kilobase-size duplications occurs frequently and leads to the
      methylation of all C residues in the repeats, including those belonging to non
      CpG sequences. Using duplications of decreasing sizes, we observed that tandem
      repeats never escaped MIP when larger than 630 bp and showed a sudden and drastic
      drop in MIP frequencies when their sizes decreased from 630 to 317 bp. This
      contrasted with the progressive decrease of MIP frequencies observed with ectopic
      repeats, in which apparently the search for homology influences the MIP
      triggering efficiency. The minimal size actually required for a repeat to undergo
      detectable MIP was found to be close to 300 bp. Genomic sequencing and Southern
      hybridization analyses using restriction enzymes sensitive to C methylation
      showed a loss of methylation at non-CpG sites in short DNA segments, methylation
      being restricted to a limited number of CpG dinucleotides. Our data suggest the
      existence of two distinct mechanisms underlying methylation maintenance, one
      responsible for methylation at CpG sites and the other responsible for
      methylation at non-CpG sites.

PMID- 8649418
TI  - Interaction of Vav with ENX-1, a putative transcriptional regulator of homeobox
      gene expression.
AB  - The proto-oncogene product Vav plays a critical role in hematopoietic signal
      transduction. By using the yeast two-hybrid system, we identified a novel human
      protein, ENX-1, which interacts specifically with Vav both in vitro and in vivo.
      ENX-1 represents the human homolog of the Drosophila Enhancer of zeste gene, a
      member of the Polycomb group of genes, which are transcriptional regulators of
      homeobox gene expression. Interaction with ENX-1 suggests that Vav functions as
      an upstream element in the transcriptional regulation of homeobox genes, known to
      be important effectors in the hematopoietic system.

PMID- 8649419
TI  - Insulin signalling and insulin actions in the muscles and livers of insulin
      resistant, insulin receptor substrate 1-deficient mice.
AB  - We and others recently generated mice with a targeted disruption of the insulin
      receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth
      retardation and had resistance to the glucose-lowering effect of insulin. Insulin
      initiates its biological effects by activating at least two major signalling
      pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other
      involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this
      study, we investigated the roles of IRS-1 and IRS-2 in the biological action in
      the physiological target organs of insulin by comparing the effects of insulin in
      wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the
      responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6
      kinase and MAP kinase activation, mRNA translation, and protein synthesis were
      significantly impaired compared with those in wild-type mice. Insulin-induced
      protein synthesis was both wortmannin sensitive and insensitive in wild-type and
      IRS-1 deficient mice. However, in another target organ, the liver, the responses
      to insulin-induced PI3-kinase and MAP kinase activation were not significantly
      reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice)
      was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it
      only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays
      central roles in two major biological actions of insulin in muscles, glucose
      transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient
      mice is mainly due to resistance in the muscles; and (iii) the degree of
      compensation for IRS-1 deficiency appears to be correlated with the amount of
      tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1
      (in wild-type mice).

PMID- 8649422
TI  - Sex-specific and non-sex-specific oligomerization domains in both of the
      doublesex transcription factors from Drosophila melanogaster.
AB  - The doublesex gene of Drosophila melanogaster encodes the alternatively spliced,
      sex-specific transcription factors DSXM and DSXF. These factors regulate male-
      and female-specific transcription of many genes. For example, female-specific
      transcription of the yolk protein 1 gene is regulated by DSXM repression in males
      and DSXF activation in females. In this study we used in vitro interaction assays
      and the in vivo yeast two-hybrid method to identify and examine oligomerization
      domains of the DSX proteins. A 66-amino-acid segment common to both proteins
      (amino acids 39 to 104) contains a sequence-specific DNA binding domain and an
      oligomerization domain (OD1). The OD1 domain oligomerizes up to at least a
      pentamer, but only dimers bound to a palindromic regulatory site in the yolk
      protein 1 gene are detected. Both subunits of the OD1 dimer are in contact with
      DNA. Another segment of each protein (amino acids 350 to 412 for DSXF and 350 to
      427 for DSXM) contains a second oligomerization domain (OD2F and OD2M,
      respectively). The OD2 domains have both sex-specific and non-sex-specific
      sequences which are necessary for oligomerization. On the basis of sequence
      analysis, we predict that OD2 oligomerizes through coiled-coil interactions. We
      speculate that the common function of OD1 and OD2 is to oligomerize the full
      length proteins, whereas their specialized functions are to form a dimeric DNA
      binding unit and a sex-specific transcriptional activation or repression unit.

PMID- 8649420
TI  - Interaction of the viral activator protein ICP4 with TFIID through TAF250.
AB  - ICP4 of herpes simplex virus is responsible for the activation of viral
      transcription during infection. It also efficiently activates and represses
      transcription in vitro depending on the promoter context. The contacts made
      between ICP4 and the cellular proteins that result in activated transcription
      have not been identified. The inability of ICP4 to activate transcription with
      TATA-binding protein in place of TFIID and the requirement for an initiator
      element for efficient ICP-4-activated transcription suggest that coactivators,
      such as TBP-associated factors, are involved (B. Gu and N. DeLuca, J. Virol.
      68:7953-7965, 1994). In this study we showed that ICP4 activates transcription in
      vitro using an immunopurified TFIID, indicating that TBP-associated factors may
      be a sufficient subset of coactivators for ICP4-activated transcription. Similar
      to results seen in vivo, the presence of the ICP4 C-terminal region (amino acids
      774 to 1298) was important for activation in vitro. With epitope-tagged ICP4
      molecules in immunoaffinity experiments, it was shown that the C-terminal region
      was also required for ICP4 to interact with TFIID present in a crude
      transcription factor fraction. In the same assay, ICP4 was unable to interact
      with the basal transcription factors, TFIIB, TFIIE, TFIIF, and TFIIH and RNA
      polymerase II. ICP4 could also interact with TBP, independent of the C-terminal
      region. However, reflective of the interaction between ICP4 and TFIID, the ICP4 C
      terminal region was required for an interaction with FAF250-TBP complexes and
      with TAF250 alone. Therefore, the interfaces or conformation of TBP mediating the
      interaction between ICP4 and TBP in solution is probably masked when TBP is bound
      to TAF250. With a series of mutant ICP4 molecules purified from herpes simplex
      virus-infected cells, it was shown that ICP4 molecules that can bind DNA and
      interact with TAF250 could activate transcription. Taken together, these results
      demonstrate that ICP4 interaction with TFIID involves the TAF250 molecule and the
      C-terminal region of ICP4 and that this interaction is part of the mechanism by
      which ICP4 activates transcription.

PMID- 8649421
TI  - TEL2, an essential gene required for telomere length regulation and telomere
      position effect in Saccharomyces cerevisiae.
AB  - The DNA-protein complexes at the ends of linear eukaryotic chromosomes are called
      the telomeres. In Saccharomyces cerevisiae, telomeric DNA consists of a variable
      length of the short repeated sequence C1-3A. The length of yeast telomeres can be
      altered by mutation, by changing the levels of telomere binding proteins, or by
      increasing the amount of C1-3A DNA sequences. Cells bearing the tel1-1 or tel2-1
      mutations, known previously to have short telomeres, did not respond to
      perturbations that caused telomere lengthening in wild-type cells. The
      transcription of genes placed near yeast telomeres is reversibly repressed, a
      phenomenon called the telomere position effect. The tel2-1 mutation reduced the
      position effect but did not affect transcriptional repression at the silent
      mating type cassettes, HMRa and HML alpha. The TEL2 gene was cloned, sequenced,
      and disrupted. Cells lacking TEL2 function died, with some cells arresting as
      large cells with three or four small protrusions or "blebs."

PMID- 8649423
TI  - Drosophila NAP-1 is a core histone chaperone that functions in ATP-facilitated
      assembly of regularly spaced nucleosomal arrays.
AB  - We describe the cloning and analysis of Drosophila nucleosome assembly protein 1
      (dNAP-1), a core histone-binding protein that functions with other chromatin
      assembly activities in a Drosophila chromatin assembly factor 1-containing
      fraction (dCAF-1 fraction) in the ATP-facilitated assembly of regularly spaced
      nucleosomal arrays from purified core histones and DNA. Purified, recombinant
      dNAP-1 acts cooperatively with a factor(s) in the dCAF-1 fraction in the
      efficient and DNA replication-independent assembly of chromatin. In the presence
      of histone H1, the repeat length of the chromatin is similar to that of native
      chromatin from Drosophila embryos. By coimmunoprecipitation analysis, dNAP-1 was
      found to be associated with histones H2A and H2B in a crude whole-embryo extract,
      which suggests that dNAP-1 is bound to the histones in vivo. Studies of the
      localization of dNAP-1 in the Drosophila embryo revealed that the factor is
      present in the nucleus during S phase and is predominantly cytoplasmic during G2
      phase. These data suggest that NAP-1 acts as a core histone shuttle which
      delivers the histones from the cytoplasm to the chromatin assembly machinery in
      the nucleus. Thus, NAP-1 appears to be one component of a multifactor chromatin
      assembly machinery that mediates the ATP-facilitated assembly of regularly spaced
      nucleosomal arrays.

PMID- 8649424
TI  - The activity of the highly inducible mouse phenylalanine hydroxylase gene
      promoter is dependent upon a tissue-specific, hormone-inducible enhancer.
AB  - Expression of the phenylalanine hydroxylase gene in livers and kidneys of rodents
      is activated at birth and is induced by glucocorticoids and cyclic AMP in the
      liver. Regulatory elements in a 10-kb fragment upstream of the mouse gene have
      been characterized. The promoter lacks TAATA and CCAAT consensus sequences and
      shows only extremely weak activity in transitory expression assays with
      phenylalanine hydroxylase-producing hepatoma cells. No key elements for
      regulation of promoter activity are localized within 2 kb of upstream sequences.
      However, a liver-specific DNase I-hypersensitive site at kb -3.5 comprises a
      tissue-specific and hormone-inducible enhancer. This enhancer contains multiple
      protein binding sites, including sites for ubiquitous factors (NF1 and AP1), the
      glucocorticoid receptor, and the hepatocyte-enriched transcription factors
      hepatocyte nuclear factor 1 (HNF1) and C/EBP. Mutation revealed that the last two
      sites are critical not only for basal activity but also for obtaining a maximal
      hormone response. Efficient transcription from the highly inducible promoter
      shows absolute dependence upon the enhancer at kb - 3.5, which in turn requires
      HNF1 and C/EBP as well as hormones. The regulatory region of the mouse
      phenylalanine hydroxylase gene differs totally from that of humans, even though
      the genes of both species are expressed essentially in the liver. Furthermore,
      the phenylalanine hydroxylase gene of mice shows an expression pattern very
      similar to those of the rodent tyrosine aminotransferase and phosphoenolpyruvate
      carboxykinase genes, yet each shows a different organization of its regulatory
      region.

PMID- 8649425
TI  - A developmentally modulated chromatin structure at the mouse immunoglobulin kappa
      3' enhancer.
AB  - Transcription of the mouse immunoglobulin kappa gene is controlled by two
      enhancers: the intronic enhancer (Ei) that occurs between the joining (J kappa)
      and constant (C kappa) exons and the 3' enhancer (E3') located 8.5 kb downstream
      of the gene. To understand the role of E3' in the activation of the mouse
      immunoglobulin kappa gene, we studied its chromatin structure in cultured B-cell
      lines arrested at various stages of differentiation. We found that 120 bp of the
      enhancer's transcriptional core becomes DNase I hypersensitive early in B-cell
      development. Genomic footprinting of pro-B and pre-B cells localized this
      chromatin alteration to B-cell-specific protections at the region including the
      direct repeat (DR) and the sequence downstream of the DR (DS), the PU.1-NFEM-5
      site, and the core's E-box motif, identifying bound transcription factors prior
      to kappa gene rearrangement. Early footprints were, however, not detected at
      downstream sites proposed to play a negative role in transcription. The early
      chromatin structure persisted through the mature B-cell stage but underwent a
      dramatic shift in plasma cells, correlating with the loss of guanosine protection
      within the DR-DS junction and the appearance of novel footprints at a GC-rich
      motif upstream and the NF-E1 (YY1/delta)-binding site downstream. Gel shift
      analysis demonstrated that the DR-DS junction is bound by a factor with
      properties similar to those of BSAP (B-cell-specific activator protein). These
      results reveal developmental-stage-specific changes in the composition of nuclear
      factors bound to E3', clarify the role of factors that bind constitutively in
      vitro, and point to the differentiation of mature B cells to plasma cells as an
      important transitional point in the function of this enhancer. The observed
      changes in nuclear factor composition were accompanied by the rearrangement of
      positioned nucleosomes that flank the core region, suggesting a role for both
      nuclear factors and chromatin structure in modulating kappa E3' function during B
      cell development. The functional implications of the observed chromatin
      alterations are discussed in the context of recent studies on kappa E3' and the
      factors that bind to it.

PMID- 8649426
TI  - Complex formation between CREB and Tax enhances the binding affinity of CREB for
      the human T-cell leukemia virus type 1 21-base-pair repeats.
AB  - The regulation of human T-cell leukemia virus type 1 (HTLV-1) gene expression is
      dependent on three cis-acting elements, known as the 21-bp repeats, in the long
      terminal repeat. Each of the 21-bp repeats contains a nonpalindromic cyclic AMP
      response element (CRE) sequence which is capable of binding members of the
      ATF/CREB family of transcription factors. The HTLV-1 transactivator protein Tax
      is able to markedly stimulate the in vitro binding of CREB to the CRE sites
      present in each of the 21-bp repeats but not to CRE sites present in cellular
      promoters. The ability to Tax to stimulate CREB binding to different CRE sites
      correlates with the ability of Tax to activate gene expression from these sites.
      We wished to determine how sequence differences between the somatostatin CRE and
      the 21-bp repeat were involved in this different response to Tax. Scatchard
      analysis indicated that CREB bound to the somatostatin CRE with a single class of
      high-affinity binding while CREB bound to the 21-bp repeats with a biphasic
      binding pattern, indicating the presence of both low- and high-affinity binding.
      Tax increased the affinity of CREB binding but not that of another ATF/CREB
      protein, CREB2, to the 21-bp repeat. However, Tax did not increase affinity of
      binding of CREB to the somatostatin CRE. To determine the mechanism by which Tax
      increased dCREB binding affinity, immobilized oligonucleotides corresponding to
      either the 21-bp repeat or the somatostatin CRE were used to demonstrate that Tax
      formed a highly specific complex with CREB on the 21-bp repeat but not on the
      somatostatin CRE. These results indicate that formation of a complex between Tax
      and CREB results in specific high-affinity binding of this ternary complex to the
      HTLV-1 21 bp repeats.

PMID- 8649427
TI  - An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates
      with focal adhesion kinase.
AB  - The integrin family of cell surface receptors mediates cell adhesion to
      components of the extracellular matrix (ECM). Integrin engagement with the ECM
      initiates signaling cascades that regulate the organization of the actin
      cytoskeleton and changes in gene expression. The Rho subfamily of Ras-related low
      molecular-weight GTP-binding proteins and several protein tyrosine kinases have
      been implicated in mediating various aspects of integrin-dependent alterations in
      cell homeostasis. Focal adhesion kinase (FAK or pp125FAK) is one of the tyrosine
      kinases predicted to be a critical component of integrin signaling. To elucidate
      the mechanisms by which FAK participates in integrin-mediated signaling, we have
      used expression cloning to identify cDNAs that encode potential FAK-binding
      proteins. We report here the identification of a cDNA that encodes a new member
      of the GTPase-activating protein (GAP) family of GTPase regulators. This GAP,
      termed Graf (for GTPase regulator associated with FAK), binds to the C-terminal
      domain of FAK in an SH3 domain-dependent manner and preferentially stimulates the
      GTPase activity of the GTP-binding proteins RhoA and Cdc42. Subcellular
      localization studies using Graf-transfected chicken embryo cells indicates that
      Graf colocalizes with actin stress fibers, cortical actin structures, and focal
      adhesions. Graf mRNA is expressed in a variety of avian tissues and is
      particularly abundant in embryonic brain and liver. Graf represents the first
      example of a regulator of the Rho family of small GTP-binding proteins that
      exhibits binding to a protein tyrosine kinase. We suggest that Graf may function
      to mediate cross talk between the tyrosine kinases such as FAK and the Rho family
      GTPase that control steps in integrin-initiated signaling events.

PMID- 8649428
TI  - The Ras-GTPase-activating protein SH3 domain is required for Cdc2 activation and
      mos induction by oncogenic Ras in Xenopus oocytes independently of mitogen
      activated protein kinase activation.
AB  - The Ras-GTPase-activating protein (RasGAP) is an important modulator of p21ras -
      dependent signal transduction in Xenopus oocytes and in mammalian cells. We
      investigated the role of the RasGAP SH3 domain in signal transduction with a
      monoclonal antibody against the SH3 domain of RasGaP. This antibody prevented the
      activation of the maturation-promoting factor complex (cyclin B-p34cdc2) by
      oncogenic Ras. The antibody appears to be specific because as little as 5 ng
      injected per oocyte reduced the level of Cdc2 activation by 50% whereas 100 ng of
      nonspecific immunoglobulin G did not affect Cdc2 activation. The antibody blocked
      the Cdc2 activation induced by oncogenic Ras but not that induced by
      progesterone, which acts independently of Ras. A peptide corresponding to
      positions 317 to 326 of a sequence in the SH3 domain of human RasGAP blocked Cdc2
      activation, whereas a peptide corresponding to positions 273 to 305 of a sequence
      in the N-terminal moiety of the SH3 domain of RasGAP had no effect. The antibody
      did not block the mitogen-activated protein (MAP) kinase cascade (activation of
      MAPK/ERK kinase [MEK], MAP kinase, and S6 kinase p90rsk). Surprisingly, injection
      of the negative MAP kinase mutant protein ERK2 K52R (containing a K-to-R mutation
      at position 52) blocked the Cdc2 activation induced by oncogenic Ras as well as
      blocking the activation of MAP kinase. Thus, MAP kinase is also implicated in the
      regulation of Cdc2 activity. In this study, we further investigated the
      regulation of the synthesis of the c-mos oncogene product, which is necessary for
      the activation of Cdc2. We report that the synthesis of the c-mos oncogene
      product, which is necessary for the activation antibody to the SH3 domain of
      RasGAP and by injecting the negative MAP kinase mutant protein ERK2 K52R. These
      results suggest that oncogenic Ras activates two signaling mechanisms: the MAP
      kinase cascade and a signaling pathway implicating the SH3 domain of RasGAP.
      These mechanisms might control Mos protein expression implicated in Cdc2
      activation.

PMID- 8649429
TI  - Activation mechanism of the multifunctional transcription factor repressor
      activator protein 1 (Rap1p).
AB  - Transcriptional activation in eukaryotic organisms normally requires
      combinatorial interactions of multiple transcription factors. In most cases, the
      precise role played by each transcription factor is not known. The upstream
      activating sequence (UAS) elements of glycolytic enzyme genes in Saccharomyces
      cerevisiae are excellent model systems for the study of combinatorial
      interactions. The yeast protein known as Rap1p acts as both a transcriptional
      repressor and an activator, depending on sequence context. Rap1p-binding sites
      are found adjacent to Gcr1p-binding sites in the UAS elements of glycolytic
      enzyme genes. These UAS elements constitute some of the strongest activating
      sequences known in S. cerevisiae. In this study, we have investigated the
      relationship between Rap1p- and Gcr1p-binding sites and the proteins that bind
      them. In vivo DNA-binding studies with rap1ts mutant strains demonstrated that
      the inability of Rap1p to bind at its site resulted in the inability of Gcr1p to
      bind at adjacent binding sites. Synthetic oligonucleotides, modeled on the UAS
      element of PYK1, in which the relative positions of the Rap1p- and Gcr1p-binding
      sites were varied prepared and tested for their ability to function as UAS
      elements. The ability of the oligonucleotides to function as UAS elements was
      dependent not only on the presence of both binding sites but also on the relative
      distance between the binding sites. In vivo DNA-binding studies showed that the
      ability of Rap1p bind its site was independent of Gcr1p but that the ability of
      Gcr1p to bind its site was dependent on the presence of an appropriately spaced
      and bound Rap1p-binding site. In vitro binding studies showed Rap1p-enhanced
      binding of Gcr1p on oligonucleotides modeled after the native PYK1 UAS element
      but not when the Rap1p- and Gcr1p-binding sites were displaced by 5 nucleotides.
      This work demonstrates that the role of the Rap1p in the activation of glycolytic
      enzyme genes is to bind in their UAS elements and to facilitate the binding of
      Gcr1p at adjacent binding sites.

PMID- 8649430
TI  - ADA5/SPT20 links the ADA and SPT genes, which are involved in yeast
      transcription.
AB  - In this report we described the cloning and characterization of ADA5, a gene
      identified by resistance to GAL4-VP16-mediated toxicity. ADA5 binds directly to
      the VP16 activation domain but not to a transcriptionally defective VP16 double
      point mutant. Double mutants with mutations in ada5 and other genes (ada2 or
      ada3) isolated by resistance to GAL4-VP16 grow like ada5 single mutants,
      suggesting that ADA5 is in the same pathway as the other ADA genes. Further, ADA5
      cofractionates and coprecipitates with ADA3. However, an ada5 deletion mutant
      exhibits a broader spectrum of phenotypes than mutants with null mutations in the
      other ADA genes. Most interestingly, ADA5 is identical to SPT20 (S.M. Roberts and
      F. Winston, Mol. Cell. Biol. 16: 3206-3213, 1996), showing that it shares
      phenotypes with the ADA and SPT family of genes. Of the other SPT genes tested,
      mutants with mutations in SPT7 and, strikingly, SPT15 (encoding the TATA-binding
      protein) show resistance to GAL4-VP16. We present a speculative pathway of
      transcriptional activation involving the ADA2-ADA3-GCN5-ADA5 complex and the TATA
      binding protein.

PMID- 8649432
TI  - Ligand-induced assembly and activation of the gamma interferon receptor in intact
      cells.
AB  - Functionally active gamma interferon (IFN-gamma) receptors consist of an alpha
      subunit required for ligand binding and signal transduction and a beta subunit
      required primarily for signaling. Although the receptor alpha chain has been well
      characterized, little is known about the specific role of the receptor beta chain
      in IFN-gamma signaling. Expression of the wild-type human IFN-gamma receptor beta
      chain in murine L cells that stably express the human IFN-gamma receptor alpha
      chain (L.hgR) produced a murine cell line (L.hgR.myc beta) that responded to
      human IFN-gamma. Mutagenesis of the receptor beta-chain intracellular domain
      revealed that only two closely spaced, membrane-proximal sequences (P263PSIP267
      and I270EEYL274) are required for function. Coprecipitation studies showed that
      these sequences are necessary for the specific and constitutive association of
      the receptor beta chain with the JAK-2 tyrosine kinase. These experiments also
      revealed that the IFN-gamma receptor alpha and beta chains are not preassociated
      on the surface of unstimulated cells but rather are induced to associate in an
      IFN-gamma-dependent fashion. A chimeric protein in which the intracellular domain
      of the beta chain was replaced by JAK-2 complemented human IFN-gamma signaling
      and biologic responsiveness in L.hgR. In contrast, a c-src-containing beta-chain
      chimera did not. These results indicate that the sole obligate role of the IFN
      gamma receptor beta chain in signaling is to recruit JAK-2 into the ligand
      assembled receptor complex.

PMID- 8649431
TI  - SPT20/ADA5 encodes a novel protein functionally related to the TATA-binding
      protein and important for transcription in Saccharomyces cerevisiae.
AB  - Mutations selected as suppressors of Ty and solo delta insertion mutations is
      Saccharomyces cerevisiae have identified a number of genes important for
      transcription initiation. One of these gens, SPT15, encodes the TATA-binding
      protein, and three others, SPT3, SPT7, and SPT8, encode proteins functionally
      related to the TATA-binding protein. To identify additional related functions, we
      have selected for new spt mutations. This work has identified one new gene,
      SPT20. Null mutations in SPT20 cause poor growth and a set of severe
      transcriptional defects very similar to those caused by null mutations in SPT3,
      SPT7, and SPT8 and also very similar to those caused by certain missense
      mutations in SPT15. Consistent with its having an important function in
      transcription in vivo, SPT20 was also recently identified as ADA5 and has been
      shown to be important for transcriptional activation (G.A. Marcus, J. Horiuchi,
      N. Silverman, and L. Guarente, Mol. Cell. Biol. 16:3197-3205, 1996.

PMID- 8649434
TI  - Regulation of the leukocyte integrin gene CD11c is mediated by AP1 and Ets
      transcription factors.
AB  - The leukocyte integrin gene, CD11c, encodes the chi subunit of the p150,95
      (CD11c.CD18) receptor. Expression of the CD11c gene is predominately seen in
      monocytes, but has also been detected in some B- and T-cell neoplasms and in some
      large-cell lymphomas of uncertain origin. To elucidate the molecular mechanisms
      that govern the expression of CD11c, we have cloned and characterized the
      promoter region of this gene. The DNase I footprint and mobility shift analyses
      revealed five sites within the -86 to +40 region that interact with nuclear
      proteins. The -62 to -44 region contains two consensus sequences for AP1
      (referred to as AP1-1 and AP1-2) and were shown to bind purified c-jun protein.
      Co-transfection of c-fos and c-jun expression constructs with a CD11c promoter
      CAT fusion into HL60 cells led to a 6.7-fold increase in CD11c promoter activity.
      We show that c-fos and c-jun mediate their effects through both AP1-1 and AP1-2
      which function in an additive manner. Regions -42 to -34 and -13 to -5 contain
      consensus sequences for Ets factors (referred to as Ets C and Ets A,
      respectively). Deletion of Ets resulted in a significant reduction in phorbol
      ester-induced expression of CD11c, whereas deletion of Ets A led to only a modest
      loss in CD11c expression. We show that Ets C cooperates with the AP1 sites to
      regulate CD11c expression.

PMID- 8649435
TI  - Heteroligation of a mouse monoclonal IgE antibody (La2) with small molecules,
      analysed by computer-aided automated docking.
AB  - A mouse monoclonal anti-TNP IgE antibody (IgE-La2) was screened by a competitive
      binding ELISA with a random pool of over 2000 small molecules, mostly drugs, drug
      derivatives and metabolites. Thirteen of these (naproxene, beta-carboxy-chi
      naphthol, oxolinic acid, hymecromone, 8-aminoquinoline, beta-naphthylamine, chi
      nitrilo-cinnamic acid, 1,5-diaminonaphthaline, prolonium iodide, diaspirin, 3,4,5
      trimethoxy-cinnamic acid, cycrimine, hemimellitic acid) were found to bind as
      strongly, or stronger, to the antibody as the immunizing hapten. We have used a
      Monte Carlo search technique for simulated docking of the DNP and non-DNP ligands
      to a model of the Fv region of IgE(La2). The validity of structural predictions
      made by the AutoDock program were tested on IgG(ANO2), the three-dimensional
      structure of which had been obtained previously by X-ray crystallography and 2D
      NMR. The rms differences between the experimentally determined and auto-docked
      complexes in the energetically most favored binding modes were 0.31-0.44 A.
      Evaluation of structures of IgE(La2)-ligand complexes [including 2,4
      dinitrophenol (DNP), 16 DNP amino acids, and the 13 non-DNP ligands listed above]
      obtained by computer-aided automated docking, suggested the existence of two
      subsites within an approximately 12 x 18 A2 groove extending between the H and L
      CDRs. Some of the ligands (DNP-Glu, 8-aminoquinoline, prolonium-I, beta
      naphthylamine) were found to bind exclusively to subsite 1, others (DNP-Ala, chi
      nitrilo-cinnamic acid, hemimellitic acid, beta-carboxy-chi-naphthol) to subsite
      2. The majority of DNP amino acids and other ligands (oxolinic acid, 3,4,5
      trimethoxy-cinnamic acid, diaspirin, [R]-cycrimine) were found to occupy an
      overlapping area including subsites 1 and 2, while some of the compounds (DNP
      Asn, DNP-Pro, hymecromone, 1,5-naphthylenediamine) were predicted to interact
      with either of these subsites with comparable probabilities. When all of the
      docked La2-ligand complexes were taken into account, five tyrosine residues (H33,
      L32, L91, L92, L96) were found to provide the majority (53.4%) of all observed
      contact points. Thus, a multitude of interactions with aromatic residues, and a
      combinatorial type of interaction within the binding region, seem to be the major
      factors to explain the mechanism of heteroligation by IgE(La2).

PMID- 8649436
TI  - Statistical comparison of established T-cell epitope predictors against a large
      database of human and murine antigens.
AB  - Identification of T-cell epitopes within a protein antigen is an important tool
      in vaccine design. The T-cell epitope prediction schemes often are exploited by
      workers but have proved unreliable in comparison with experimental techniques. We
      compared published T-cell epitope predictors against two databases of human and
      murine T-cell epitopes. Each predictor was assessed against random cyclic
      permutations of epitopes in order to determine significance. Predictor
      performance was expressed in terms of two parameters, specificity and
      sensitivity. Specificity is an expression of the quality of predictions, whereas
      sensitivity is an expression of the quantity of epitopes predicted. Against the
      human data set, the strip-of-hydrophobic helix algorithm [Stille et al., Molec.
      Immun. 24, 1021-1027 (1987)] was the only significant predictor (p < 0.05),
      whereas against murine data only, the Roth2 pattern [Rothbard and Taylor, EMBO J.
      7, 93-100 (1988)] was significant (p < 0.05). Not only were the majority of
      algorithms no better than random against both data sets, against the murine data
      two schemes were significant (p < 0.05) anti-predictors. This report indicates
      which predictors are relevant statistically and is the first to describe anti
      predictors which can themselves be useful in the identification of T-cell
      epitopes.

PMID- 8649433
TI  - Nutritional regulation of late meiotic events in Saccharomyces cerevisiae through
      a pathway distinct from initiation.
AB  - The IME1 gene is essential for initiation of meiosis in the yeast Saccharomyces
      cerevisiae, although it is not required for growth. Here we report that in
      stationary-phase cultures containing low concentration of glucose, cells
      overexpressing IME1 undergo the early meiotic events, including DNA replication,
      commitment to recombination, and synaptonemal complex formation and dissolution.
      In contrast, later meiotic events, such as chromosome segregation, commitment to
      meiosis, and spore formation, do not occur. Thus, nutrients can repress the late
      stages of meiosis independently of their block of initiation. Cells arrested at
      this midpoint in meiosis are relatively stable and can resume meiotic
      differentiation if transferred to sporulation conditions. Resumption of meiosis
      does not require repression of IME1 expression, since IME1 RNA levels stay high
      after transfer of the arrested cells to sporulation medium. These results suggest
      that meiosis in S. cerevisiae is a paradigm of a differentiation pathway
      regulated by signal transduction at both early and late stages.

PMID- 8649437
TI  - Characterization of an endonuclease activity which preferentially cleaves the G
      rich immunoglobulin switch repeat sequences.
AB  - B lymphocytes can alter selectively their immunoglobulin (Ig) isotype expressed
      by deletional rearrangement of the first active immunoglobulin heavy-chain (IgH)
      constant region (C mu) gene with one of six other constant region genes.
      Recombination breakpoints occur within highly repetitive "switch" (S) regions
      located upstream of each IgH constant region gene except C delta. Analysis of
      rearranged switch DNA junctions has not detected a consensus sequence, although
      the predominance of two pentamer motifs (TGGGG and TGAGC) at or near these
      breakpoints and throughout all murine S region sequences has led to their
      advocacy as the S recombination signals. In this paper, we describe the
      characterization and partial purification of a lymphoid-specific endo-nuclease
      activity which cleaves preferentially murine S region DNA. Enzyme activity
      selectively produced single- and double-stranded breaks at TGAGC and TGGG motifs
      within murine S mu and S alpha DNA. Rare cryptic cleavage sites were detected
      also within non-switch sequences, although cleavage intensities at these sites
      were reduced greatly, relative to consensus S region cleavages. Analogous
      activity was found in murine tissue extracts, although among the tissues assayed
      only spleen and thymus contained detectable activity. Subsequent biochemical
      characterization of this activity demonstrated that the responsible enzyme (Endo
      SR) represented a previously unreported tissue-specific mammalian endonuclease.
      Endo-SR-specific activity could be enhanced by addition of Mg2+ or Ca2+ and
      inhibited by addition of Zn2+. Maximal specific activity was detected at pH 5.5
      and sharply declined within +/- 0.5 pH units. In view of this enzyme's sequence-
      and tissue-specificity, we propose that Endo-SR is a strong candidate for an
      endonuclease activity associated with the switch recombination process.

PMID- 8649438
TI  - Design and synthesis of a highly immunogenic, discontinuous epitope of HIV-1
      gp120 which binds to CD4+ve transfected cells.
AB  - Here we report the design and synthesis of a novel 32-mer peptide, Lys364
      378Val445-459.oxidized (named GC-1), which represents a discontinuous epitope
      from the C3 and C4 domains of gp120 from the HIV-1 IIIB isolate. This peptide
      induces high titre IgG antibody responses in mice, indicating that it has both B
      and T cell epitopes. Epitope mapping using reduced GC-1 and appropriate linear
      peptides demonstrated that a large proportion of the antibodies raised in mice
      were directed against discontinuous epitope(s). Furthermore, antibodies to GC-1
      peptide cross-reacted with purified HIV-1 strain IIIB gp120, indicating the GC-1
      mimicked at least one epitope of the native protein. The peptide, which
      incorporates three gp120 residues Asp 368, Glu 370 and Asp 457, previously shown
      to be critical for CD4 ligation, bound to the surface of a CD4 transfected human
      epithelial cell line HeLa, but not to the parent cell line and inhibited binding
      of recombinant HIV-1 gp120 to recombinant soluble CD4. We have synthesized the
      first of a series of discontinuous peptides which will be useful for the probing
      of interactions of HIV-1 gp120 with the CD4 molecule.

PMID- 8649439
TI  - Structural features of the extracellular portion of membrane-anchoring peptides
      on membrane-bound immunoglobulins.
AB  - Membrane-bound immunoglobulins, mIgs, are displayed as transmembrane proteins on
      the surface of B cells, where they serve as antigen receptors. The mIgs are
      anchored to the membrane through a carboxy-terminal extension of the
      immunoglobulin heavy chain. Three distinct structural regions of these membrane
      anchor peptides, of mouse and human mIgs, have been delineated: (1) a central
      conserved stretch of 25 hydrophobic, unchanged amino acid residues, which spans
      the membrane lipid bilayer; (2) a C-terminal hydrophilic region of 3-28 amino
      acids, which is intracytoplasmic; and (3) an N-terminal extracellular hydrophilic
      region of 13-67 amino acids, which is isotype-specific. Here we report predicted
      secondary and tertiary structures of the third structural region of the membrane
      anchoring peptide along with corroborating experimental evidence. The predictions
      of secondary and tertiary structure indicate that most of these regions can
      assume an chi-helical conformation. Circular dichroism spectroscopy of
      corresponding synthetic peptide confirms this essential feature. The choice of
      solvent and pH have dramatic effects on peptide helicity; solvent conditions
      consistent with a membrane-proximal environment promote helicity. Additional
      studies suggest that the two adjacent extracellular peptides may be stabilized
      through coiled-coil interactions similar to those described for some other
      transmembrane proteins.

PMID- 8649440
TI  - The heterogeneity of bovine IgG2--VIII. The complete cDNA sequence of bovine
      IgG2a (A2) and an IgG1.
AB  - The complete cDNA sequences of two bovine IgGs were obtained by RT-PCR cloning.
      The first-strand cDNA was prepared from an animal homozygous (A2/A2) for IgG2a;
      the resulting sequences of the two bovine IgGs reported here were identified as
      IgG2a(A2) and IgG1. These sequences, and their deduced amino acid sequences, are
      compared to the previously reported partial protein sequences of IgG2a(A2) and
      IgG2(A1), two genomic DNA sequences of IgG2a and one genomic DNA sequence of
      IgG1. Data show that the two IgG2a allotypes (A1 and A2) differ in four regions:
      (a) region I-the site of the L-H bond in CH1; (b) region II-the middle hinge; (c)
      region III-a seven amino acid region at the beginning of the intradomain loop in
      CH3; and (d) region IV-an Arg-to-Glu exchange at the end of the same intradomain
      loop. The A1 allotype, which so remarkably distinguishes these allotypic
      variants, must result from differences in regions III and IV. The IgG1 sequence
      differs in the hinge region from the sequence reported previously and may
      represent an allotypic variant. We found no evidence to support the hypothesis
      that similarities between the CH3 domains of IgG2a(A2) and IgG1 result from gene
      conversion in the C-region of the bovine heavy chain locus.

PMID- 8649441
TI  - Heavy chain dominance in the binding of DNA by a lupus mouse monoclonal
      autoantibody.
AB  - Antibodies H241 and 2C10 are lupus mouse IgG autoantibodies that bind native DNA.
      In previous experiments, oligonucleotide antigens affinity-labeled both H and L
      chains of H241 but only the H chain of antibody 2C10. Primary structures of the V
      regions of the 2C10 H and L chains and the H241 L chain, determined from cDNA,
      help to explain the previous affinity-labeling experiments. The 2C10 L chain CDRs
      had several Asp residues and a net negative charge of five, whereas the 2C10 H
      chain CDRs had four Arg residues and a net positive charge of five. The L chain
      CDRs of H241 had a net positive charge of one. [The H241 H chain cDNA sequence
      was published previously by Gangemi et al. (1993) J. Immun. 151, 4660-4671].
      Plasmid vectors were used for bacterial expression of H and L chains of 2C10
      alone and in combinations in single chain Fv (scFv) molecules. The H chain alone
      bound native DNA as well as or better than the H-plus-L chain scFv. The H chain
      alone also bound Z-DNA. Combination of the 2C10 H chain with the L chain of an
      anti-Z-DNA antibody maintained the selectivity for Z-DNA, whereas its combination
      with the 2C10 L chain (in the 2C10 Fab) yielded selective B-DNA binding. The
      results with 2C10 match other examples in which the H chain is sufficient for DNA
      binding but selectivity is modulated by the L chain. The H chain binding to
      autoantigen may reflect selective events in early stages of B cell development.

PMID- 8649442
TI  - A single-chain bispecific Fv2 molecule produced in mammalian cells redirects
      lysis by activated CTL.
AB  - Single-chain Fv (sFv) molecules consist of the two variable domains of an
      antibody (Ab) connected by a polypeptide spacer and contain the binding
      activities of their parental antibodies (Abs). In this paper we have attached the
      C-terminus of 2C11-sFv (anti-mouse CD3 epsilon-chain) to the N-terminus of OKT9
      sFv (anti-human transferrin receptor [TfR]) through a 23 amino acid inter-sFv
      linker consisting primarily of CH1 region residues from 2C11, to form a single
      chain bispecific Fv2 [bs(sFv)2] molecule. The bs(sFv)2 was expressed in COS-7
      cells, and was secreted at the same rate as the two parental sFvs. The secreted
      protein had both anti-CD3 and anti-TfR binding activities. Essentially all of the
      secreted bs(sFv)2 molecules bound TfR and the binding affinity of the bs(sFv)2
      was comparable to that of OKT9 sFv and Fab. Thus, the attachment of the inter-sFv
      linker to the N-terminus of OKT9-sFv did not impair its binding function. The
      bs(sFv)2 retained both binding specificities after long-term storage at 4 degrees
      C or overnight incubation at 37 degrees C. It redirected activated mouse CTL to
      specifically lyse human TfR+ target cells at low (ng/ml) concentrations and was
      much more active than a chemically cross-linked heteroconjugate prepared from the
      same parental mAbs. Because bs(sFv)2 molecules secreted by mammalian cells are
      homogeneous proteins containing two binding sites in a single polypeptide chain,
      they hold great promise as an easily obtainable, economic source of a bispecific
      molecule suitable for in vivo use.

PMID- 8649443
TI  - Selection of peptides that bind to the HLA-A2.1 molecule by molecular modelling.
AB  - Cytotoxic T lymphocytes recognize antigenic peptides in association with major
      histocompatibility complex class I proteins. Although a large set of class I
      binding peptides has been described, it is not yet easy to search for potentially
      antigenic peptides without synthesis of a panel of peptides, and subsequent
      binding assays. In order to predict HLA-A2.1-restricted antigenic epitopes, a
      computer model of the HLA-A2.1 molecule was established using X-ray
      crystallography data. In this model nonameric peptide sequences were aligned. In
      a molecular dynamics (MD) simulation with two sets of peptides known to be
      presented by HLA-A2.1, it was important to know the anchor amino acid residue
      preference and the distance between the anchor residues. We show here that the
      peptides bound to the HLA-A2.1 model structure possess a side chain of C-terminal
      anchor residue oriented into the binding groove with different distances between
      the two anchor residues from 15 to 21A. We also synthesized a set of nonamer
      peptides containing amino acid sequences of Hepatitis B virus protein that were
      selected on the basis of previously described HLA-A2.1 specific motifs. When
      results obtained from the MD simulation were compared with functional binding
      assays using the TAP-deficient cell line T2, it was evident that the MD
      simulation method improves prediction of the HLA-A2.1 binding epitope sequence.
      These results suggest that this approach can provide a way to predict peptide
      epitopes and search for antigenic regions in sequences in a variety of antigens
      without screening a large number of synthetic peptides.

PMID- 8649444
TI  - A DNA repair abnormality specific for rearranged immunoglobulin variable genes in
      germinal center B cells.
AB  - The somatic hypermutation mechanism produces high-rate mutagenesis specifically
      targeted to rearranged immunoglobulin (Ig) variable (V) gene segments during the
      germinal center (GC) stage of B lymphocyte differentiation. The mechanism of this
      process remains uncertain, partly due to the lack of a direct assay for
      hypermutation activity. In this study, a gene-specific DNA repair assay was used
      to compare the rate and quality of DNA repair in the mantle zone (MZ) and GC B
      cells at rearranged and unrearranged Ig V genes. GC B cells were distinguished
      from MZ B cells by a retarded repair rate specific for rearranged Ig V genes. In
      addition, a unique feature of GC cells after DNA repair was the appearance of
      predominant mutations in rearranged Ig VH5 gene PCR products. These predominant
      mutations also occurred in natural mutants of VH5 genes. However, repair
      associated mutations reflected, at least in part, "template-jumping" during
      amplification of the residually damaged genomic template. Overall, these findings
      reflect a repair abnormality associated with the hypermutation process by the
      criteria of sequence- and B cell stage-specificity. We conclude that locus
      specific retardation of DNA repair is a component of the hypermutation mechanism.
      RFLP or SSCP analysis provides a simple assay to monitor this repair abnormality
      as a surrogate biochemical marker for hypermutation during B cell
      differentiation.

PMID- 8649445
TI  - Prolonged inhibition of IgE production in mice following treatment with an IgE
      specific immunotoxin.
AB  - The synthesis of IgE antibodies by B cells is the first in a series of steps
      resulting in an allergic response. To eliminate IgE-bearing B cells and thereby
      prevent IgE production, we have developed an immunotoxin (ITA) composed of the
      non-anaphylactic 84.1c anti-mouse IgE mAb and the A chain of ricin (ricin A).
      This ITA specifically inhibited the induction of IgE synthesis by
      lipopolysaccharide plus interleukin-4 (LPS + IL-4) in vitro, and antigen-specific
      IgE production in vivo in adult mice. A single dose of anti-IgE ITA, given within
      a week (either before or after) of antigen challenge completely abolished antigen
      specific primary IgE responses. No IgE production was seen for 2 months after ITA
      treatment. Following antigenic re-challenge, a suppressed secondary response
      (over 50% reduction) was still seen in the ITA-treated mice, 100 days after
      immunization. The results of this study demonstrate the potential use of anti-IgE
      toxin conjugates for the suppression of periodic (seasonal) allergic outbreaks.

PMID- 8649446
TI  - Reactivity and epitope mapping of single-chain T cell receptors with monoclonal
      antibodies.
AB  - To examine further the structure of the T cell receptor (TCR) and the specificity
      of mAbs generated against the native protein, the TCR was expressed in
      Escherichia coli as a single chain in which the variable regions of the alpha and
      beta chains are joined by a 25 amino acid linker. Five single-chain TCR that have
      different alpha and/or beta variable (V) regions were examined with the anti-V
      beta 8 region mAbs KJ16 and F23.1 and the anti-V alpha 8 mAbs KT50, KT65 and
      B21.14. Each of the mAbs reacted with one or more of the single-chain receptors.
      Western blot analysis demonstrated that the intrachain disulfide bonds were
      required for proper epitope conformation and recognition of the TCR by the
      antibodies. KT50, KT65 and B21.14 antibodies distinguished between two related V
      alpha regions that differed at only six residues. A model of the V regions of the
      TCR based on immunoglobulin (Ig) structure suggests that three of these six
      variant residues are in the putative CDR1 of the receptor and possibly accessible
      to antibody. To test this possibility, site-directed mutagenesis of the
      unreactive V alpha region demonstrated that the combination of all three residues
      restored binding by the anti-V alpha 8 antibodies. In addition, these three
      complimentarity determining regions (CDR) residues are likely to be in close
      proximity to the putative CDR3 which also influenced binding of the antibodies.
      The epitopes recognized by the V alpha-specific antibodies are thus predicted to
      reside closer to the putative binding site than the epitopes previously
      determined to be recognized by the anti-V beta 8 antibodies, KJ16 and F23.1.
      Finally, the specificities of KT50 and KT65 as determined with the E. coli
      expression system suggests an explanation for previous observations about the
      differences in the T cell populations that are recognized by these antibodies.

PMID- 8649447
TI  - Structural analysis of human natural resistance-associated macrophage protein 1
      promoter.
AB  - Natural resistance-associated macrophage protein gene 1 (Nramp1) was isolated as
      a candidate for the mouse gene locus Lsh/Ity/Bcg, which regulates macrophage
      activation for antimicrobial activity against intracellular pathogens. To
      investigate the structural and functional organization of the human homologue,
      NRAMP1, the overlapping genomic clones encompassing NRAMP1 were isolated. These
      clones spanned approximately 35 kb in size and the nucleotide sequence of 3779 bp
      of the 5' flanking region has been determined. The transcription start site was
      mapped by primer extension analysis. A TATA box element and the transcription
      regulatory elements in the acute phase reaction were found.

PMID- 8649448
TI  - Selective association of a 22-38 kDa glycoprotein with MHC class II DP antigen on
      activated human lymphocytes at the plasma membrane.
AB  - Two-dimensional electrophoretic analysis (2D-PAGE) of cell surface human DP and
      DR class II antigens identified a glycoprotein, designated pX, that is associated
      at the cell surface with DP but not DR class II antigen in activated T, B and NK
      lymphocytes but not in resting B lymphocytes, Raji B lymphoma cells, activated
      thymic epithelial cells or activated monocytes. pX is a heavily glycosylated
      protein with an apparent molecular mass spanning between 38 kDa and 22 kDa, that
      is reduced, after deglycosylation with Endo-F, to 22 kDa. The pX structure
      appears nonpolymorphic and independent of DP polymorphism, as suggested by 2D
      PAGE migrational pattern of 125I-labelled Endo-F deglycosylated DP
      immunoprecipitates from T cells blasts derived from four donors with different DP
      allotypes. The apparent absence of polymorphism of pX is further suggested by two
      dimensional peptide mapping of a single spot derived from 2D-PAGE of 125I
      labelled DP deglycosylated immunoprecipitates from two donors.

PMID- 8649449
TI  - Selection of phage displayed antibodies based on kinetic constants.
AB  - The display of antibody fragments on the surface of filamentous bacteriophages
      and the selection of binders from antibody libraries have provided powerful tools
      to generate human antibodies. We reported recently a new concept (SAP system) for
      the selection of specific phages by linking antigenic recognition and phage
      replication, using a soluble fusion protein containing the antigen and a fragment
      of the M13 coat protein 3. In this investigation, a model library has been
      composed using six different antibody fragments which were characterized
      individually regarding their kass, kdiss and Ka. All Fab fragments were specific
      for a 15 amino acid region of the V3 loop of gp120 (HIV-1). We demonstrated that
      the SAP system could discriminate between the kinetic parameters of each clone,
      using different selection strategies. Phages expressing high affinity clones were
      selected preferentially using low doses of antigen but clones of lower affinity
      also could be selected by increasing the antigen concentration or using a
      preselection procedure. Phages expressing antibody fragment with high association
      or low dissociation rate constants were retrieved by utilizing short contact
      times between antigen and antibody or antigen-chase conditions.

PMID- 8649451
TI  - Mouse complement component C4 is devoid of classical pathway C5 convertase
      subunit activity.
AB  - It has long been known that mouse C4 has unusually low hemolytic activity
      relative to the C4 of other mammalian species (e.g. human and guinea pig), the
      measurements being done in most cases using a C4-deficient guinea pig serum
      reagent in a one-step assay with EA. This low activity for mouse C4 previously
      had been attributed to "technical" difficulties such as lability of the protein
      during blood collection and partial species incompatibilities with guinea pig
      components. Recently, we presented evidence for the involvement of human C4 beta
      chain residues 455-469, a putatively exposed hydrophilic segment, in contributing
      to a C5 binding site in the C4b subunit of the classical pathway C5 convertase,
      C4b3b2a. Given that there were five sequence differences between the human and
      mouse protein within this segment, we hypothesized that these substitutions may
      have compromised the C5 convertase subunit activity of mouse C4, thereby
      resulting in its low hemolytic activity. Using a multi-step hemolytic assay which
      was totally dependent upon C5 cleavage by the classical pathway, we found that
      mouse C4 was completely devoid of classical pathway C5 convertase subunit
      activity. We have been able to rule out the most obvious potential species
      incompatibilities (e.g. between C4mo and C5gp) as being responsible for this lack
      of activity. Moreover, we found that the low level of hemolytic activity of mouse
      C4 measured in the one-step assay can be ascribed totally to C5 cleavage, and
      subsequent terminal component assembly, by the alternative pathway C5 convertase,
      (C3b)2Bb. However, the assembly of the latter enzyme complex is dependent upon
      the presence of C3b molecules deposited initially via the classical pathway C3
      convertase in which mouse C4b is a subunit. Finally, whereas conversion of human
      residues 458RP to the mouse-like sequence PL was sufficient to abrogate classical
      pathway C5 convertase subunit activity in human C4, the five substitutions which
      "humanized" the 452-466 segment of mouse C4 (corresponding to human residues 455
      469) were on their own insufficient to impart this activity to mouse C4. This
      implies that, in addition to the 455-469 beta-chain segment of human C4, there
      are other regions of the molecule contributing to C5 binding which are also non
      conserved between human and mouse C4.

PMID- 8649450
TI  - Regulation of BCR- and PKC/Ca(2+)-mediated activation of the Raf1/MEK/MAPK
      pathway by protein-tyrosine kinase and -tyrosine phosphatase activities.
AB  - Ligation of the B cell Ag receptor (BCR) activates a protein-tyrosine kinase
      (PTK) and CD45 protein-tyrosine phosphatase (PTPase)-dependent signaling cascade
      that results in the activation of Ras. This pathway of Ras activation can operate
      independently of protein kinase C (PKC) activity. Activation of Ras may lead to
      two distinct Ras-dependent pathways involving either a Raf1/MEK/MAPK module or a
      MEKK/SEK/SAPK module; however, it is unclear as to how Ras controls the
      independent activation of either of these pathways. We have used genistein and
      phenylarsine oxide (PAO) as inhibitors of PTK and PTPase, respectively, to
      investigate whether they regulate the BCR- and Ca2+/PKC-dependent activation of
      the Ras/Raf1/MEK/MAPK module. Assays of phosphotransferase activities conducted
      with Ag (TNP6-OVA)-specific 7.9 murine B lymphoma cells demonstrated that BCR
      mediated stimulation of the Raf1/MEK/MAPK module is controlled by PTK and PTPase
      activities. An elevation in [Ca2+]i was required to optimally activate Raf1 and
      MEK through the BCR. However, when signaling through the BCR was bypassed by
      direct stimulation of the Raf1/MEK/MAPK module via a rise in [Ca2+]i and phorbol
      ester-induced PKC activation, the phosphotransferase activities of Raf1, MEK and
      MAPK were still regulated in a PTK-dependent manner that was also partially
      sensitive to the PTPase inhibitor PAO. Thus, at least two alternate routes, i.e.
      a BCR/PTK/Ras-dependent route and another PKC/Ca(2+)-dependent route, may
      converge at the level of Raf1 for activation of the Raf1/MEK/MAPK module in B
      cells.

PMID- 8649452
TI  - Cloning and characterization of a new allergen, Mag 3, from the house dust mite,
      Dermatophagoides farinae: cross-reactivity with high-molecular-weight allergen.
AB  - A new immunoreactive clone whose sequence is not homologous to that of any of the
      previously identified mite allergens was isolated by successive immunoscreening
      of a Dermatophagoides farinae cDNA library with rabbit antisera to an extract of
      the house dust mite and IgE in pooled sera from patients allergic to mites.
      Rabbit antibodies specific for the recombinant protein recognized a 177 kD
      protein in a mite body extract. This immunoreactive protein was located in the
      circumferential tissues of esophagus, gut and the other internal organs in mites.
      The reaction of human IgE to the purified natural antigen was inhibited
      competitively to 30% by the recombinant antigen. In terms of the frequency and
      the intensity of response to specific IgE in sera from asthmatic patients, the
      natural protein was similar to Der f2, while the recombinant protein was slightly
      less allergenic by these criteria. We conclude that the natural protein from the
      house dust mite, D. farinae, is an important allergen.

PMID- 8649453
TI  - Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and
      B70 (B7.2): analysis by site directed mutagenesis.
AB  - CD28, which is a member of the immunoglobulin superfamily of molecules (IgSF), is
      a homodimer of two polypeptides containing a single V-like domain with short
      transmembrane and cytoplasmic regions. It serves as a co-signalling molecule for
      T cell activation through binding to its cognate counter-receptors CD80 and B70,
      expressed on antigen presenting cells. In the current study, we investigated the
      regions of CD28 which are involved in its interactions with CD80 and B70, using
      site directed mutagenesis, CD28 mAb epitope mapping, receptor based adhesion
      assays and direct binding of Ig-fusion proteins to cell surface receptors.
      Truncation or substitution of a stretch of a proline rich "hallmark" sequence,
      "MYPPPY", abrogates binding to CD80 or B70, while retaining CD28 mAb epitopes and
      cell surface expression. On an Ig-fold model of the CD28 V-domain, this fully
      conserved motif localizes to a CDR3-like region. Mutations introduced into other
      loops, including the CDRI-like and CDR2-like regions, had very little effect on
      CD80 or B70 binding. Mutations introduced within the predicted beta-strand
      regions caused loss of receptor expression. Conservative substitution of both the
      flanking tyrosine residues within the "MYPPPY" motif with phenylalanine, caused
      loss of binding to B70 but not to CD80. These results show that, although the
      same overall region on CD28 may be involved in the interactions with CD80 and
      B70, subtle but important differences distinguish recognition by the two
      molecules. These finding, along with previous observations on the differential
      pattern of expression and tissue distribution of CD80 and B70, support the
      contention that these molecules play distinct roles in the regulation of immune
      responses in vivo.

PMID- 8649454
TI  - Telomere length does not change during senescence of the ascomycete Podospora
      anserina.
AB  - All strains of the filamentous fungus Podospora anserina are characterized by a
      well defined life span. Senescence is controlled by nuclear and extranuclear
      genetic traits. In order to test whether or not the ends of the chromosomes of
      this ascomycete shorten during senescence and thus telomere shortening may be
      linked to the well analyzed, age-related reorganizations of the mitochondrial DNA
      (mtDNA), we analyzed the genomic DNA of P. anserina wild-type strain s. We found
      that, although the mtDNA becomes reorganized when cultures age, the telomeres
      remain constant suggesting that telomere shortening does not play a major role in
      normal aging of this particular biological system.

PMID- 8649455
TI  - Correlation between age and DNA damage detected by FADU in human peripheral blood
      lymphocytes.
AB  - Fluorometric analysis of DNA unwinding (FADU) is a fast and reliable method for
      detecting single strand DNA breaks as an index of DNA damage induced by
      clastogenic agents. A study of damage detected by FADU was conducted on DNA
      extracted from peripheral blood lymphocytes of 128 healthy nonsmoking regular
      donors (ranging in age from 19 to 67 years) and from 5 umbilical cord blood
      samples. DNA damage was measured as percentage of unwound DNA after
      alkalinization. Statistical analyses, both parametric (Pearson r correlation
      coefficient, b regression coefficient, ANOVA) and nonparametric (Kruskal-Wallis H
      test, Spearman rs rank correlation coefficient), support a significant
      correlation between age of donors and amount of DNA damage. The same results are
      found when adult donors are divided in four age classes and the ANOVA test
      performed among the mean percentages of unwound DNA of each class. Furthermore,
      donors of the same age belonging to different blood groups (A, B, AB and O) do
      not show any difference in DNA damage detected by FADU.

PMID- 8649456
TI  - A network theory of ageing: the interactions of defective mitochondria, aberrant
      proteins, free radicals and scavengers in the ageing process.
AB  - Evolution theory indicates that ageing is caused by progressive accumulation of
      defects, since the evolutionary optimal level of maintenance is always below the
      minimum required for indefinite survival. Evolutionary theories also suggest that
      multiple processes are operating in parallel, but unfortunately they make no
      predictions about specific mechanisms. To understand and evaluate the many
      different mechanistic theories of ageing which have been proposed, it is
      therefore important to understand and study the network of maintenance processes
      which control cellular homeostasis. In this paper we describe a Network Theory of
      Ageing which integrates the contributions of defective mitochondria, aberrant
      proteins, and free radicals to the ageing process, and which includes the
      protective effects of antioxidant enzymes and proteolytic scavengers. The model
      simulations not only confirm and explain many experimental, age related findings
      like an increase in the fraction of inactive proteins, a significant rise in
      protein half-life, an increase in the amount of damaged mitochondria, and a drop
      in the energy generation per mitochondrion, but they also show interactions
      between the different theories which could not have been observed without the
      network approach. In some simulations, for example, the mechanism of the final
      breakdown seems to be a consequence of the cooperation of mitochondrial and
      cytoplasmic reactions, the mitochondria being responsible for a long term,
      gradual change which eventually triggers a short lived cytoplasmic error loop.

PMID- 8649457
TI  - An accessory protein enhances both DNA binding and activity of DNA polymerase
      alpha isolated from normal, but not transformed, human fibroblasts.
AB  - DNA polymerase alpha/primase (pol alpha) isolated from fibroblasts established
      from a 66-year-old human donor (GM3529) exhibited decreased specific activity
      compared with pol alpha from either fetal-derived fibroblasts (WI38), or pSV3.neo
      transformed GM3529 fibroblasts. The pol alpha specific activity decrease was
      correlated with a decreased proliferative capacity frequently seen in cells from
      aged donors. Pol alpha isolated from pSV3.neo-transformed GM3529 cells (GM3529T)
      exhibited a single isoform with about 10-fold higher specific activity than pol
      alpha from GM3529 cells. GM3529T pol alpha was immunoreactive with both anti-pol
      alpha and anti-SV40 large tumor antigen. Polymerases from GM3529 and GM3529T
      cells were treated with a pol alpha accessory protein, alpha AP, isolated from
      L1210 cells. Pol alpha from GM3529T cells showed no increase in activity in the
      presence of alpha AP, while pol alpha isolated from GM3529 cells exhibited about
      an 8-fold increase in activity after treatment with alpha AP. Double stranded
      SV40 DNA containing multiple ori sequences exhibited a greater decrease in
      electrophoretic mobility in the presence of GM3529T pol alpha than when treated
      with GM3529 pol alpha. In the presence of pol alpha from either GM35229 or
      GM3529T cells SV40 dsDNA exhibited a decrease in electrophoretic mobility, and in
      each instance addition of alpha AP resulted in an even greater decrease in DNA
      mobility. These data indicate that alpha AP increased pol alpha binding to SV40
      dsDNA, or that alpha AP bound the DNA in addition to previously bound pol alpha.
      GM3529 pol alpha also bound non-specific, non-SV40, dsDNA, whereas GM3529T pol
      alpha with associated TAg did not bind the non-viral dsDNA unless alpha AP was
      added to the preparation. While not all human diploid fibroblast cell lines
      derived from aged human donors necessarily exhibit decreased proliferative
      capacity compared with cells from young donors, decreased specific activity
      associated with a decline in cellular DNA synthesis is typical of pol alpha from
      cells derived from aged human donors. We suggest that a decrease in endogenous
      alpha AP interaction with pol alpha may account, in part, for the loss of DNA
      binding affinity and specific activity of pol alpha from GM3529 cells derived
      from an aged donor.

PMID- 8649458
TI  - Differences in the spectrum of spontaneous mutations in the hprt gene between
      tumor cells of the microsatellite mutator phenotype.
AB  - We have determined the frequency and spectrum of spontaneous mutations at the
      hprt locus in LoVo, HCT116, LS180 and DLD-1 colon carcinoma cell lines exhibiting
      microsatellite genetic instability. Each cell line has a different mutator gene.
      LoVo and HCT116 cells have mutated hMSH2 and hMLH1 genes, respectively, which
      account for the majority of hereditary non-polyposis colorectal cancer (HNPCC).
      LS180 cells are wild type for these genes and also for hPMS1 and hPMS2 mismatch
      repair genes. DLD-1 cells harbor a mutated GTBP mismatch binding factor and a
      mutated DNA Polymerase delta. The mutation rate at the hprt locus was several
      hundred fold higher in these cell lines relative to control cell lines without
      microsatellite instability. The mutations were frameshifts (deletions and
      insertions of a single nucleotide in short repeats) and single base substitutions
      (transversions and transitions). Some mutations were shared by these four cell
      lines. However, every cell line also exhibited a distinctive spectrum of
      mutations suggesting that each mutator gene induces a particular mutator
      phenotype. These results also suggest that the frequency and spectrum of somatic
      mutations in tumor cells of the microsatellite mutator phenotype may have
      diagnostic applications to discriminate among the diverse underlying mutator
      genes.

PMID- 8649459
TI  - Spermatid micronucleus analysis of aging effects in hamsters.
AB  - Spermatid micronuclei (MN) from Armenian hamsters in different age groups were
      compared with regard to frequencies and kinetochore status (presence or absence)
      as determined with immunofluorescent staining. Six thousand cells analyzed from
      each of fifteen young animals (3 months) revealed a group mean frequency of 0.45
      MN/1000 spermatids; kinetochore staining was uniformly negative. Six thousand
      cells scored from each of fifteen older animals (2 years) revealed a group mean
      frequency of 1.00 MN/1000 spermatids. Most of the MN in these animals were
      negative for kinetochore staining, although a significant representation of MN
      with positive kinetochore staining was also observed. The results indicate that
      frequencies of spermatid MN increase with advancing age, and suggest that the
      increase is due to significant elevations in both chromosome breakage and
      chromosome loss.

PMID- 8649461
TI  - Non-linear accumulation of 8-hydroxy-2'-deoxyguanosine, a marker of oxidized DNA
      damage, during aging.
AB  - Damage to DNA seems to be involved in aging and the etiology of age-associated
      degenerative diseases. The purpose of this study is to examine changes in DNA
      damage during aging. An oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (8
      OHdG), is a proposed biomarker for DNA damaged by oxidative stress. The content
      of 8-OHdG in nuclear DNA isolated from brain, heart, liver, and kidneys of male
      Fischer 344 rats of different ages was measured, 8-OHdG can be detected
      selectively and sensitively at the fmol level by high performance liquid
      chromatography-electrochemical detection at an applied potential of +350 mV. The
      amount of 8-OHdG, expressed as the ratio to deoxyguanosine in nuclear DNA, in
      heart, liver, and kidney remained steady from 2 to 24 months and then increased
      progressively. The content of 8-OHdG in the DNA in brain showed no changes from 2
      to 27 months, but was significantly higher in 30 month-old rats. There was a
      significant 2-fold increase in the amount of 8-OHdG in the nuclear DNA of all
      organs tested in 30 month-old rats as compared to 2-24 month-old rats. These
      results indicate that the accumulation of 8-OHdG in the DNA of rat organs begins
      at ages above 24 months.

PMID- 8649460
TI  - Differential expression of DNA polymerase alpha in normal and transformed human
      fibroblasts.
AB  - The expression of DNA polymerase alpha (pol alpha) was studied in human
      fibroblast lines W138 (fetal lung) and GM3529 (skin, established from a 66 yr old
      donor), and their Simian virus 40 (SV40) large tumor antigen (TAg)-transformed
      corollaries, 2RA and 2-1 respectively. Both SV40-transformed and pSV3.neo (SV40
      derived plasmid)-transformed cells express TAg, a virally encoded protein not
      expressed by the normal parent cell lines. Northern blot hybridization studies
      showed increased recovery of pol alpha mRNA from transformed cells compared with
      normal cells. This increase was correlated with increased pol alpha mRNA
      transcription as determined by nuclear run-on assays. Northern blot analyses also
      showed an increase in the instability of translationally active pol alpha mRNA in
      transformed cells. The results suggest that TAg, in addition to its dsDNA
      binding, pol alpha binding, retinoblastoma protein binding and helicase
      activities, may be involved either directly or indirectly in regulation of the
      steady state mRNA levels of pol alpha at the transcriptional level in both fetal
      and aged donor-derived transformed fibroblasts.

PMID- 8649462
TI  - Comparison of the X-gal- and P-gal-based systems for screening of mutant lambda
      lacZ phages originating from the transgenic mouse strain 40.6.
AB  - The recent introduction of the phenyl-beta-D-galactopyranoside (P-gal)-based
      positive-selection system for screening of lambda lacZ phages originating from
      the lambda lacZ transgenic mouse (Muta Mouse) has made the determination of
      mutant frequencies (MF) a much simpler task. Previously, MF data from these mice
      have been collected by means of the 5-bromo-4-chloro-3-indolyl-beta-D
      galactopyranoside (X-gal) colour-screening procedure. To determine whether data
      obtained with the two systems are comparable, the MF in lambda phages recovered
      from liver and brain of transgenic mice treated with N-ethyl-N-nitrosourea (ENU)
      and liver of benzo(a)pyrene (B(a)P)-treated mice was determined with both
      procedures. For the livers of mice treated with ENU, both methods yielded
      approximately the same MF values. No induction of mutants, relative to the
      control animals, was seen after 1.5 h, but a clear 4-fold increase was measured
      with both assays at the 14-day time point. No induction of mutants was found in
      the brain with either method. In the B(a)P-treated mice, both methods showed a
      substantial induction in MF after 21, 28 and 35 days. The values generated by the
      X-gal and P-gal methods were not significantly different, with the exception of
      the 35-day post-treatment point that appeared higher in the X-gal assay. When the
      mutants isolated by use of the X-gal method were tested in the P-gal assay, a
      number of these did not turn up as mutants, and the significance disappeared. In
      conclusion, the data obtained with the two screening procedures agree to such an
      extent as to permit a direct comparison between the earlier results generated
      with X-gal and P-gal values generated with the new positive-selection method.
      This is likely to apply also to other organs and mutagens than those studied
      here.

PMID- 8649463
TI  - Cytogenetic study of radiation burden in thyroid disease patients treated with
      external irradiation or radioiodine.
AB  - Where clinically permitted, either external irradiation or radioiodine therapy is
      usually recommended for the treatment of differentiated thyroid cancer patients.
      The choice depends on the treatment philosophy of the responsible physician. This
      paper describes an attempt to clarify the radiation burden on the lymphocytes in
      consequence of these two therapeutic modalities. An analysis was made of the
      extent to which exposure to local neck irradiation (25 x 2 Gy) or radioiodine
      therapy (1734-2600 MBq) causes chromosomal aberrations in the lymphocytes of
      thyroid disease patients after total or subtotal thyroidectomy. External
      irradiation caused many more chromosomal aberrations than 131I therapy did, but
      analysis of the distribution of the aberrations suggested a homogeneous dose
      distribution only in 131I-treated and thyroidectomized cancer patients. In
      thyrotoxic patients with intact thyroid glands, the lower therapy doses (185-595
      MBq) caused a significantly higher frequency of aberrations than that observed in
      thyroid cancer patients, and the dose distribution in the lymphocytes was
      inhomogeneous. Thus, in the modelling of accidental environmental radioiodine
      exposure, thyroid patients with small if any residual thyroids are not a suitable
      group.

PMID- 8649465
TI  - Effect of dietary casein levels on activation of promutagens in the spiral
      Salmonella mutagenicity assay. II. Studies with induced rat liver S9.
AB  - In the previous study (Mutation Res., this issue), we showed that increased
      levels of dietary casein as the sole protein source for male F344 rats decreased
      the ability of the uninduced liver S9s to activate 2-aminoanthracene (2AN) to a
      mutagen in strain TA98 using the spiral Salmonella mutagenicity assay. No effects
      of dietary casein levels were noted for the ability of uninduced liver S9s to
      activate the promutagens aflatoxin B1 (AFB) and benzo[a]pyrene (BAP). In the
      present study, we have extended this study to include liver S9s induced with
      either Aroclor 1254, phenobarbital or 3-methylcholanthrene (3MC). S9s were
      derived from individual male F344 rats fed for 6 weeks on semisynthetic diets
      containing 8%, 12% or 22% methionine-supplemented casein as the sole source of
      protein (diets were made isocaloric by adjusting the corn starch content). Rats
      were housed in large, raised-bed cages by groups of three/diet/inducing agent. S9
      activation mixtures were prepared at 5 mg of S9 protein/ml of S9 mix. Slopes from
      the linear portions of the mutagenicity dose-response curves were analyzed by
      ANOVA comparisons. Assays used to elucidate the phase I activities of microsomal
      preparations were cytochrome P-450 content, cytochrome-c reductase activity,
      flavin-containing monooxygenase activity, 7-ethoxyresorufin O-deethylation (EROD)
      activity, N-demethylation of benzphetamine, and para-nitrophenol O-deethylation.
      Phase II activities were assayed by estimating glutathione (GSH) content and
      measuring the metabolism of 1-chloro-2,4-dinitrobenzene (CDNB) by glutathione S
      transferase in cytosolic preparations. None of the phase I or phase II endpoints
      were significantly affected by dietary casein levels. In general, increasing
      levels of dietary casein resulted in increased body and liver wet weight and
      amount of S9 protein. Aroclor-induced S9s from rats fed the 22% or 12% casein
      diet were most effective at activating AFB, depending on the lot of Aroclor used
      for induction; these divergent results were replicated with two groups of rats
      for each lot of Aroclor. The observed differences between Aroclor lots are
      assumed to arise from variation in the mix of PCB isomers. The Aroclor-induced
      S9s did not exhibit any casein-related effects for the activation of BAP or 2AN.
      For 3MC-induced S9s, the 12% casein diets produced S9s with the highest ability
      to activate AFB and BAP when standardized for protein content. Phenobarbital
      induced S9s did not demonstrate any dietary casein-related effects on the
      activation of the three model promutagens. These results illustrate the complex
      interaction between dietary levels of casein, enzyme inducing agent and
      promutagen.

PMID- 8649464
TI  - Effect of dietary casein levels on activation of promutagens in the spiral
      Salmonella mutagenicity assay. I. Studies with noninduced rat liver S9.
AB  - Xenobiotic metabolism can be influenced by various nutritional factors, including
      protein. In the present study, we have examined the effect of dietary protein
      (casein) levels on the ability of rat liver S9 to activate the promutagens
      aflatoxin B1 (AFB), 2-aminoanthracene (2AN) and benzo[a]pyrene (BAP) in strain
      TA98 using the spiral Salmonella mutagenicity assay. S9s were derived from
      individual male F344 rats fed for 6 weeks on semisynthetic diets containing 8%,
      12% or 22% methionine-supplemented casein as the sole source of protein (diets
      were made isocaloric by adjusting the corn starch content). Rats were housed in
      large, raised-bed cages by groups of three per diet. S9 activation mixtures were
      prepared at 5 mg of S9 protein/ml of S9 mix. Slopes from the linear portions of
      the mutagenicity dose-response curves were analyzed by ANOVA comparisons. Assays
      used to elucidate the phase I activities of microsomal preparations were
      cytochrome P450 content, cytochrome-c reductase activity, flavin-containing
      monooxygenase activity, 7-ethoxyresorufin O-deethylation (EROD) activity, N
      demethylation of benzphetamine and para-nitrophenol O-deethylation. Phase II
      activities in cytosolic preparations were assayed by estimation of glutathione
      (GSH) content and glutathione S-transferase activity through metabolism of 1
      chloro-2,4-dinitrobenzene (CDNB). Increased levels of dietary casein increased
      liver wet weights and decreased the ability of the S9 to activate 2AN. Dietary
      casein levels did not influence the S9-mediated activation of BAP; and consistent
      but nonsignificant increases in activation of AFB were produced by S9 from
      animals fed the 22% casein diet. The phase I and phase II activities measured
      here were not altered significantly by dietary casein levels; thus, other, more
      specific enzymatic activities may account for the mutagenesis data. These results
      illustrate the complex interaction between dietary levels of casein and
      promutagen activation mechanisms, which prevents drawing broad generalizations
      regarding the influence of dietary casein levels on the capacity of hepatic S9s
      to activate promutagens.

PMID- 8649466
TI  - The w/w+ somatic mutation and recombination test (SMART) of Drosophila
      melanogaster for detecting reactive oxygen species: characterization of 6
      strains.
AB  - The w/w+ somatic mutation and recombination test (SMART) of Drosophila
      melanogaster is a fast and low cost in vivo assay that has shown excellent
      results in the assessment of genotoxicity of a large number of compounds.
      However, recent studies have revealed that, when procarcinogens are to be
      evaluated, the performance of the assay is largely dependent on the genetic
      background of the strains used. To determine which one of the strains available
      for this test would be advisable to evaluate agents producing reactive oxygen
      species we have used two approaches. Firstly, the w/w+ assay was carried out
      using 6 different strains and two compounds: menadione and paraquat. Secondly, 3
      biochemical traits were determined for the 6 strains: superoxide dismutase and
      catalase activities, and their capacity to induce reactive oxygen species. The
      results suggest that the strains Oregon K and Haag 79 would be usable when
      potential inducers of reactive oxygen species are to be investigated.

PMID- 8649467
TI  - A cytogenetic study of radiological workers: effect of age, smoking and radiation
      burden on the micronucleus frequency.
AB  - A large scale cytogenetic study of the radiation damage in nuclear power plant
      workers and medical workers handling X-ray machines (269 individuals) was
      undertaken using the micronucleus assay for peripheral blood lymphocytes. The
      micronucleus frequency was found to increase systematically with donor age. After
      correction for the age-dependence, no correlation of the micronucleus frequency
      with smoking habits, expressed as cigarette-years and cigarette consumption per
      day, could be observed. Compared to the group of administrative workers receiving
      doses below 1 mSv/year, limit recommended by the ICRP for public exposure, the
      micronucleus frequency was slightly increased in the group of radiation workers,
      exposed occupationally. However, applying the Mann-Whitney test, the observed
      differences are not statistically significant. After correction of the dose
      accumulation pattern for the turn-over of the lymphocyte pool, a weak correlation
      between the micronucleus frequency and the equivalent dose accumulated over the
      10 years preceding the study was obtained. For clear-cut conclusions on the
      radiation damage of low-dose worker cohorts, an increase in the sensitivity of
      the assay, e.g., by analysis of the micronuclei for the presence of centromeres
      is necessary.

PMID- 8649468
TI  - Tissue-specific induction of mutations by acute oral administration of N-methyl
      N'-nitro-N-nitrosoguanidine and beta-propiolactone to the Muta Mouse: preliminary
      data on stomach, liver and bone marrow.
AB  - We used the positive selection Muta Mouse model to detect organ-specific activity
      of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and beta-propiolactone (BPL), two
      highly reactive alkylating agents known to induce genetic damage and tumors in
      rodent stomach when administered orally. Seven days after a single oral
      administration of MNNG (100 mg/kg) or BPL (150 mg/kg), the mutation frequency in
      the Muta Mouse stomach increased significantly by 6.4-fold and 8.8-fold,
      respectively. A slight (1.8-fold) but significant increase in mutation frequency
      was also observed in the livers of BPL-treated mice, but not in the livers of
      MNNG-treated mice or the bone marrow of MNNG- and BPL-treated animals. These data
      indicate that the Muta Mouse model can be used to predict the gastric specificity
      of genotoxic carcinogens.

PMID- 8649469
TI  - Antigenotoxic spinasterol from Cucurbita maxima flowers.
AB  - The antigenotoxic constituent of squash flowers was isolated by solvent
      partitioning and repeated vacuum liquid chromatography. The micronucleus test, an
      in vivo method, was used to monitor the antigenotoxicity of the various fractions
      during the isolation process. Isolate SQFwB2D from the chloroform extract of
      squash flowers is the most antigenotoxic isolate. It decreased the mutagenicity
      of tetracycline by 64.7% at a dosage of 100 mg/kg mouse. Statistical analysis
      using Kruskall Wallis one-way analysis of variance by Ranks showed that SQFw2D is
      different from the control group (tetracycline + corn oil) at alpha = 0.001. GC
      MSD of isolate SQFwB2D shows 2 peaks at Rt = 19.860 (SQFwB2D-1) and 20.242 min
      (SQFwB2D-2) with relative peak heights of 16:1, respectively. Spectral analyses
      show that SQFwB2D-1 is 24 alpha-ethyl-5 alpha-cholesta-7,trans-22-dien-3 beta-ol
      or spinasterol.

PMID- 8649470
TI  - DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-L-norleucine.
AB  - A tumor-inhibiting antibiotic, 6-diazo-5-oxo-L-norleucine (DON), caused DNA
      single-strand breaks. Thus, supercoiled plasmid DNA was transformed into an open
      circular relaxed form DNA by incubation with DON at pH 7.4. DNA strand cleavage
      by DON was not inhibited by superoxide dismutase, but inhibited by catalase. The
      inhibition by catalase may not be due to the destruction of hydrogen peroxide,
      but to the masking DON by the interaction with the heme moiety of the enzyme. DNA
      strand cleavage by DON was inhibited by azide, mannitol, ethanol, cysteine and 2
      mercaptoethanol, suggesting the involvement of radical species in the cleavage.
      The cleavage, however, was not suppressed by removal of dissolved oxygen from the
      reaction mixture, indicating that no oxygen-derived radicals participated in the
      cleavage. Electron spin resonance spin-trapping technique using 5,5-dimethyl-1
      pyrroline N-oxide (DMPO) and N-tert-butyl-alpha-phenylnitrone (PBN) elucidated
      the generation of a carbon-centered radical from DON. Hence, the carbon-centered
      radical may participate in DNA strand cleavage by DON.

PMID- 8649471
TI  - Venous thromboembolism during pregnancy.

PMID- 8649472
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 21-1996. A 52-year-old man with back pain, fever, and abnormal
      imaging studies.

PMID- 8649473
TI  - Artemether in severe malaria--still too many deaths.

PMID- 8649474
TI  - Killing heat.

PMID- 8649475
TI  - Molecular mechanisms of cocaine addiction.

PMID- 8649476
TI  - Living with Parkinson's disease.

PMID- 8649477
TI  - Living with Parkinson's disease.

PMID- 8649478
TI  - Electrocardiographic diagnosis of acute myocardial infarction in the presence of
      left bundle-branch block.

PMID- 8649479
TI  - Electrocardiographic diagnosis of acute myocardial infarction in the presence of
      left bundle-branch block.

PMID- 8649480
TI  - Electrocardiographic diagnosis of acute myocardial infarction in the presence of
      left bundle-branch block.

PMID- 8649481
TI  - Electrocardiographic diagnosis of acute myocardial infarction in the presence of
      left bundle-branch block.

PMID- 8649482
TI  - Systemic granulomatous reaction to a foreign body after hip replacement.

PMID- 8649483
TI  - Secrecy in research.

PMID- 8649484
TI  - Secrecy in research.

PMID- 8649485
TI  - Secrecy in research.

PMID- 8649486
TI  - Barriers to patients' rights.

PMID- 8649487
TI  - Barriers to patients' rights.

PMID- 8649488
TI  - Barriers to patients' rights.

PMID- 8649489
TI  - Patient advocacy in the 1990s.

PMID- 8649490
TI  - Patient advocacy in the 1990s.

PMID- 8649491
TI  - Availability of intravenous quinidine for falciparum malaria.

PMID- 8649492
TI  - A trial of artemether or quinine in children with cerebral malaria.
AB  - BACKGROUND: Cerebral malaria has a mortality rate of 10 to 30 percent despite
      treatment with parenteral quinine, a situation that may worsen with the spread of
      quinine resistance. Artemether is a new antimalarial agent that clears parasites
      from the circulation more rapidly than quinine, but its effect on mortality is
      unclear. METHODS: We conducted a randomized, unblinded comparison of
      intramuscular artemether and intramuscular quinine in 576 Gambian children with
      cerebral malaria. The primary end points of the study were mortality and residual
      neurologic sequelae. RESULTS: Fifty-nine of the 288 children treated with
      artemether died in the hospital (20.5 percent), as compared with 62 of the 288
      treated with quinine (21.5 percent). Among the 418 children analyzed at
      approximately five months for neurologic disease, residual neurologic sequelae
      were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11
      of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment
      for potential confounders, the odds ratio for death was 0.84 (95 percent
      confidence interval, 0.53 to 1.32) in the artemether group, and for residual
      neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There
      were fewer local reactions at the injection site with artemether than with
      quinine (0.7 percent vs. 5.9 percent, P = 0.001). CONCLUSIONS: Artemether is as
      effective as quinine in the treatment of cerebral malaria in children.

PMID- 8649493
TI  - A controlled trial of artemether or quinine in Vietnamese adults with severe
      falciparum malaria.
AB  - BACKGROUND: Artemisinin (qinghaosu) and its derivatives are rapidly effective
      antimalarial drugs derived from a Chinese plant. Preliminary studies suggest that
      these drugs may be more effective than quinine in the treatment of severe
      malaria. We studied artemether in Vietnam, where Plasmodium falciparum has
      reduced sensitivity to quinine. METHODS: We conducted a randomized, double-blind
      trial in 560 adults with severe falciparum malaria. Two hundred seventy-six
      received intramuscular quinine dihydrochloride (20 mg per kilogram of body weight
      followed by 10 mg per kilogram every eight hours), and 284 received intramuscular
      artemether (4 mg per kilogram followed by 2 mg per kilogram every eight hours).
      Both drugs were given for a minimum of 72 hours. RESULTS: There were 36 deaths in
      the artemether group (13 percent) and 47 in the quinine group (17 percent; P =
      0.16; relative risk of death in the patients given artemether, 0.74; 95 percent
      confidence interval, 0.5 to 1.11). The parasites were cleared more quickly from
      the blood in the artemether group (mean, 72 vs. 90 hours; P < 0.001); however, in
      this group fever resolved more slowly (127 vs. 90 hours, P < 0.001), the time to
      recovery from coma was longer (66 vs. 48 hours, P = 0.003), and the
      hospitalization was longer (288 vs. 240 hours, P = 0.005). Quinine treatment was
      associated with a higher risk of hypoglycemia (relative risk, 2.7; 95 percent
      confidence interval, 1.7 to 4.4; P < 0.001), but there were no other serious side
      effects in either group. CONCLUSIONS: Artemether is a satisfactory alternative to
      quinine for the treatment of severe malaria in adults.

PMID- 8649494
TI  - Heat-related deaths during the July 1995 heat wave in Chicago.
AB  - BACKGROUND: During a record-setting heat wave in Chicago in July 1995, there were
      at least 700 excess deaths, most of which were classified as heat-related. We
      sought to determine who was at greatest risk for heat-related death. METHODS: We
      conducted a case-control study in Chicago to identify risk factors associated
      with heat-related death and death from cardiovascular causes from July 14 through
      July 17, 1995. Beginning on July 21, we interviewed 339 relatives, neighbors, or
      friends of those who died and 339 controls matched to the case subjects according
      to neighborhood and age. RESULTS: The risk of heat-related death was increased
      for people with known medical problems who were confined to bed (odds ratio as
      compared with those who were not confined to bed, 5.5) or who were unable to care
      for themselves (odds ratio, 4.1). Also at increased risk were those who did not
      leave home each day (odds ratio, 6.7), who lived alone (odds ratio, 2.3), or who
      lived on the top floor of a building (odds ratio, 4.7). Having social contacts
      such as group activities or friends in the area was protective. In a multivariate
      analysis, the strongest risk factors for heat-related death were being confined
      to bed (odds ratio, 8.2) and living alone (odds ratio, 2.3); the risk of death
      was reduced for people with working air conditioners (odds ratio, 0.3) and those
      with access to transportation (odds ratio, 0.3). Deaths classified as due to
      cardiovascular causes had risk factors similar to those for heat-related death.
      CONCLUSIONS: In this study of the 1995 Chicago heat wave, those at greatest risk
      of dying from the heat were people with medical illnesses who were socially
      isolated and did not have access to air conditioning. In future heat emergencies,
      interventions directed to such persons should reduce deaths related to the heat.

PMID- 8649495
TI  - A prospective, randomized trial of autologous bone marrow transplantation and
      chemotherapy in multiple myeloma. Intergroupe Francais du Myelome.
AB  - BACKGROUND: The median survival of patients with myeloma after conventional
      chemotherapy is three years or less. Promising results have been reported with
      high-dose therapy supported by autologous bone marrow transplantation. We
      conducted a randomized study comparing conventional chemotherapy and high-dose
      therapy. METHODS: Two hundred previously untreated patients under the age of 65
      years who had myeloma were randomly assigned at the time of diagnosis to receive
      either conventional chemotherapy or high-dose therapy and autologous bone marrow
      transplantation. RESULTS: The response rate among the patients who received high
      dose therapy was 81 percent (including complete responses in 22 percent and very
      good partial responses in 16 percent), whereas it was 57 percent (complete
      responses in 5 percent and very good partial responses in 9 percent) in the group
      treated with conventional chemotherapy (P < 0.001). The probability of event-free
      survival for five years was 28 percent in the high-dose group and 10 percent in
      the conventional-dose group (P = 0.01); the overall estimated rate of survival
      for five years was 52 percent in the high-dose group and 12 percent in the
      conventional-dose group (P = 0.03). Treatment-related mortality was similar in
      the two groups. CONCLUSIONS: High-dose therapy combined with transplantation
      improves the response rate, eventfree survival, and overall survival in patients
      with myeloma.

PMID- 8649496
TI  - Images in clinical medicine. Placental malaria.

PMID- 8649497
TI  - Chronic autoimmune thyroiditis.

PMID- 8649498
TI  - NIH bucks political trend to win increased funds from Congress.

PMID- 8649499
TI  - UK scheme aims to make biotech pay.

PMID- 8649500
TI  - US bid to eliminate gene therapy panel under fire.

PMID- 8649501
TI  - US panel backs new approach to risk.

PMID- 8649503
TI  - Rockefeller link for AIDS centre.

PMID- 8649502
TI  - Hostile reception to US misconduct report.

PMID- 8649504
TI  - Chernobyl legacy.

PMID- 8649505
TI  - Cell-cycle control and its watchman.

PMID- 8649506
TI  - Hot fusion of HIV.

PMID- 8649507
TI  - Evolutionary genetics...and scandalous symbionts.

PMID- 8649508
TI  - Bacterium genome sequence.

PMID- 8649509
TI  - Contamination of drinking water.

PMID- 8649510
TI  - Protein-RNA molecular recognition.

PMID- 8649511
TI  - Identification of a major co-receptor for primary isolates of HIV-1.
AB  - Entry of HIV-1 into target cells requires cell-surface CD4 and additional host
      cell cofactors. A cofactor required for infection with virus adapted for growth
      in transformed T-cell lines was recently identified and named fusin. However,
      fusin does not promote entry of macrophage-tropic viruses, which are believed to
      be the key pathogenic strains in vivo. The principal cofactor for entry mediated
      by the envelope glycoproteins of primary macrophage-tropic strains of HIV-1 is CC
      CKR-5, a receptor for the beta-chemokines RANTES, MIP-1alpha and MIP-1beta.

PMID- 8649512
TI  - HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.
AB  - The beta-chemokines MIP-1alpha, MIP-1beta and RANTES inhibit infection of CD4+ T
      cells by primary, non-syncytium-inducing (NSI) HIV-1 strains at the virus entry
      stage, and also block env-mediated cell-cell membrane fusion. CD4+ T cells from
      some HIV-1-exposed uninfected individuals cannot fuse with NSI HIV-1 strains and
      secrete high levels of beta-chemokines. Expression of the beta-chemokine receptor
      CC-CKR-5 in CD4+, non-permissive human and non-human cells renders them
      susceptible to infection by NSI strains, and allows env-mediated membrane fusion.
      CC-CKR-5 is a second receptor for NSI primary viruses.

PMID- 8649513
TI  - Estimate of the genomic mutation rate deleterious to overall fitness in E. coli.
AB  - Mutations are a double-edged sword: they are the ultimate source of genetic
      variation upon which evolution depends, yet most mutations affecting fitness
      (viability and reproductive success) appear to be harmful. Deleterious mutations
      of small effect can escape natural selection, and should accumulate in small
      population. Reduced fitness from deleterious-mutation accumulation may be
      important in the evolution of sex, mate choice, and diploid life-cycles, and in
      the extinction of small populations. Few empirical data exist, however. Minimum
      estimates of the genomic deleterious-mutation rate for viability in Drosophila
      melanogaster are surprisingly high, leading to the conjecture that the rate for
      total fitness could exceed 1.0 mutation per individual per generation. Here we
      use Escherichia coli to provide an estimate of the genomic deleterious-mutation
      rate for total fitness in a microbe. We estimate that the per-microbe rate of
      deleterious mutations is in excess of 0.0002.

PMID- 8649514
TI  - Visual feature selectivity in frontal eye fields induced by experience in mature
      macaques.
AB  - When examining a complex image, the eye movements of expert observers differ from
      those of novices; experts have learned to ignore features that are visually
      salient but are not relevant to the interpretation of the image. We have studied
      the neural basis of this form of perceptual-motor learning using monkeys that
      have learned to search for a visual target among distractors. Monkeys trained to
      search only for, say, a red stimulus among green distractors will ignore green
      stimuli even if they subsequently appear as targets in a complementary search
      array, that is, among red distractors. We recorded from neurons in the frontal
      eye field (FEF), a cortical area that responds to visual stimuli and controls
      purposive eye movements. Normally, FEF neurons do not exhibit feature
      selectivity, but their activity evolves to signal the target for an incipient eye
      movement. In monkeys trained exclusively on targets of one colour, however, FEF
      neurons show selectivity for stimuli of that colour. Because this selective
      response occurs so soon after presentation of the stimulus array, and is
      independent of location within the visual field, we propose that it reflects a
      form of experience-dependent plasticity that mediates the learning of arbitrary
      stimulus-response associations.

PMID- 8649515
TI  - The neurobiology of sign language and its implications for the neural basis of
      language.
AB  - The left cerebral hemisphere is dominant for language, and many aspects of
      language use are more impaired by damage to the left than the right hemisphere.
      The basis for this asymmetry, however, is a matter of debate; the left hemisphere
      may be specialized for processing linguistic information or for some more general
      function on which language depends, such as the processing of rapidly changing
      temporal information or execution of complex motor patterns. To investigate these
      possibilities, we examined the linguistic abilities of 23 sign-language users
      with unilateral brain lesions. Despite the fact that sign language relies on
      visuospatial rather than rapid temporal information, the same left-hemispheric
      dominance emerged. Correlation analyses of the production of sign language versus
      non-linguistic hand gestures suggest that these processes are largely
      independent. Our findings support the view that the left-hemisphere dominance for
      language is not reducible solely to more general sensory or motor processes.

PMID- 8649516
TI  - RAPID and opposite effects of BDNF and NGF on the functional organization of the
      adult cortex in vivo.
AB  - The adult cortex is thought to undergo plastic changes that are closely dependent
      on neuronal activity (reviewed in ref. 1), although it is not yet known what
      molecules are involved. Neurotrophins and their receptors have been implicated in
      several aspects of developmental plasticity, and their expression in the adult
      cortex suggests additional roles in adult plasticity. To examine these potential
      roles in vivo, we used intrinsic-signal optical imaging to quantify the effects
      of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) on the
      functional representation of a stimulated whisker in the 'barrel' subdivision of
      the rat somatosensory cortex. Topical application of BDNF resulted in a rapid and
      long-lasting decrease in the size of a whisker representation, and a decrease in
      the amplitude of the activity-dependent intrinsic signal. In contrast, NGF
      application resulted in a rapid but transient increase in the size of a
      representation, and an increase in the amplitude of the activity-dependent
      intrinsic signal. These results demonstrate that neurotrophins can rapidly
      modulate stimulus-dependent activity in adult cortex, and suggest a role for
      neurotrophins in regulating adult cortical plasticity.

PMID- 8649517
TI  - Regulation of synaptic responses to high-frequency stimulation and LTP by
      neurotrophins in the hippocampus.
AB  - Neurotrophins promote neuronal survival and differentiation, but the fact that
      their expression is modified by neuronal activity, suggests a role in regulating
      synapse development and plasticity. In developing hippocampus, the expression of
      brain derived neurotrophic factor (BDNF) and its receptor TrkB increases in
      parallel with the ability to undergo long-term potentiation (LTP). Here we report
      a mechanism by which BDNF modulates hippocampal LTP. Exogenous BDNF promoted the
      induction of LTP by tetanic stimulation in young (postnatal day 12-13)
      hippocampal slices, which in the absence of BDNF show only short-term
      potentiation (STP). This effect was due to an enhanced ability of hippocampal
      synapses to respond to tetanic stimulation, rather than to a direct modulation of
      the LTP-triggering mechanism. A TrkB-IgG fusion protein, which scavenges
      endogenous BDNF, reduced the synaptic responses to tetanus as well as the
      magnitude of LTP in adult hippocampus. Our results suggest that BDNF may regulate
      LTP in developing and adult hippocampus by enhancing synaptic responses to
      tetanic stimulation.

PMID- 8649518
TI  - An RNA-dependent ATPase associated with U2/U6 snRNAs in pre-mRNA splicing.
AB  - The hydrolysis of ATP by a group of RNA-dependent ATPases (DEAD/H proteins) is
      required for spliceosome assembly, but not for the subsequent transesterification
      reactions. Little is known about the function of these ATPases in relation to the
      RNA conformational changes that occur in formation of active structures, in which
      U2/U6 small nuclear RNA (snRNA) interactions are essential for splicing to take
      place. Using a synthetic lethal genetic screen, we have isolated four yeast
      splicing factors involved in U2/U6 snRNA interactions (D.X. et al., manuscript in
      preparation). The RNA-dependent ATPase activity associated with one such factor,
      the Slt22 protein, is stimulated preferentially by annealed U2/U6 snRNAs. Both
      mutant slt22-1 and U2 snRNA cause a reduction in stimulation. The slt22-1
      mutation blocks splicing at or before the first step, resulting in the
      accumulation of an unusual complex which lacks U5 snRNA. Our results indicate
      that the U2/U6 snRNA interactions facilitated by Slt22 are also involved in the
      interaction of U5 snRNA with the spliceosome.

PMID- 8649520
TI  - [Request for late pregnancy interruption in severe congenital anomalies].

PMID- 8649519
TI  - Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking
      p21.
AB  - Precise coordination of the S and M phases of the eukaryotic cell cycle is
      critical not only for normal cell division, but also for effective growth arrest
      under conditions of stress. When damaged, a cell must communicate signals to both
      the mitotic and DNA synthesis machineries so that a mitotic block is not followed
      by an extra S phase, or vice versa. The biochemical mechanisms regulating this
      coordination, termed checkpoints, have been identified in lower eukaryotes, but
      are largely unknown in mammalian cells. Here we show that p21 WAF1/CIP1, the
      prototype inhibitor of cyclin-dependent kinases (CDKs), is required for this
      coordination in human cells. In the absence of p21, DNA-damaged cells arrest in a
      G2-like state, but then undergo additional S phases without intervening normal
      mitoses. They thereby acquire grossly deformed, polyploid nuclei and subsequently
      die through apoptosis. Perhaps not by coincidence, the DNA-damaging agents that
      can cause S/M uncoupling are used in the clinic to kill cancer cells
      preferentially.

PMID- 8649521
TI  - [Deep venous thrombosis: does recently improved knowledge lead to a real advance
      in the direction patient care?].

PMID- 8649522
TI  - [Late pregnancy interruption].

PMID- 8649523
TI  - [Fetal alcohol syndrome: an unrecognized cause of intellectual handicap and
      problem behavior in The Netherlands].

PMID- 8649524
TI  - [Consensus 'Basic Resuscitation' from the Nederlandse Reanimatie Raad].

PMID- 8649525
TI  - [Late pregnancy interruption in Noord-Holland. I. Incidence and abnormalities].
AB  - OBJECTIVE: To gain insight into the extent to which late termination of pregnancy
      (gestational age > 24 weeks) is practised and to find out what foetal diseases
      and abnormalities lead to termination. DESIGN: An exploratory, descriptive,
      retrospective study. SETTING: Province of North Holland, the Netherlands.
      METHODS: An investigation, based on an anonymous printed questionnaire, was
      conducted among all associations/departments of gynaecologists in the 21
      hospitals in North Holland. The period of study covered the years 1990 to 1994
      inclusive. RESULTS: Replies, in the form of completed questionnaires, were
      received from 19 associations/departments in the 21 hospitals (90% response). In
      the five-year period under study 103 pregnancies in 14 of the hospitals were
      terminated beyond the 24th week. In 21% of the cases anencephaly was diagnosed
      prior to the termination; another 21% of the foetuses were diagnosed as having
      severe chromosomal defects. Other severe abnormalities were neural groove defects
      like hydrocephaly and/or spina bifida (16%), no renal function (12%) and skeletal
      abnormalities (11%). CONCLUSION: Late termination of pregnancy appears to be
      practised on a substantial scale, at any rate in North Holland. The reasons for
      termination are severe structural abnormalities which in most of the cases are
      not compatible with extrauterine survival.

PMID- 8649526
TI  - [Late pregnancy interruption in Noord-Holland. II. Carefulness before and review
      afterwards].
AB  - OBJECTIVE: To gain insight into the carefulness of medical activity in late
      termination of pregnancy, and into gynaecologists' relevant views. DESIGN: A
      descriptive, partly cross-sectional, partly retrospective study. SETTING:
      Province of North Holland, The Netherlands. METHOD: An anonymous written inquiry
      was conducted among all individual obstetrically active gynaecologists and all
      associations/departments of gynaecology in the 21 hospitals in North Holland. The
      study period covered the years 1990-1994 inclusive. RESULTS: Replies were
      obtained from 19 associations/departments of the 21 hospitals and from 83% of the
      obstetrically active gynaecologists (77/93). Activity had been careful in the
      vast majority (93%) of the 103 reported cases of late termination of pregnancy:
      the diagnosis was definite prenatally and verified postnatally; consultation
      about termination was conducted in 91%; reports were made in all cases. Most
      responding gynaecologists had performed late termination of pregnancy (44/77).
      Sixty-eight percent of these were of the opinion that a death certificate had to
      be issued, as against 30% of those who had not performed late terminations of
      pregnancy (9/30). A death certificate was issued in 88% of the cases of
      termination. Sixty-eight percent of the respondents with a view to external
      quality control and subsequent review had opted for a national committee of
      experts from the profession, in some cases supplemented with experts from outside
      the profession, plus supervision by the Health Care Inspectorate. CONCLUSION:
      Gynaecologists in North Holland in general acted carefully regarding late
      termination of pregnancy, although they did not always observe the guidelines
      issued by their professional association.

PMID- 8649527
TI  - [Poor prognosis in children with ultrasonographically diagnosed abnormalities of
      the central nervous system].
AB  - OBJECTIVE: Long-term follow-up of children with a prenatally diagnosed
      malformation of the central nervous system. DESIGN: Descriptive study. SETTING:
      Department of prenatal diagnosis, Academic Medical Center, Amsterdam, the
      Netherlands. METHODS: Evaluation of all documented ultrasound examinations
      between 1985 and 1990 (6 years). These ultrasound examinations were performed in
      women with an increased risk for a foetal malformation, because of obstetrical
      complications or when a foetal malformation was suspected on ultrasound
      examination performed elsewhere. Paediatricians and general practitioners were
      asked to provide follow-up data on the children who were still alive. RESULTS:
      Seven out of 67 foetuses with a prenatally diagnosed malformation of the central
      nervous system lived longer than one month. Two out of these 7 children developed
      normally, one child died after several years and four children were severely
      retarded. The two children who developed normally both had mild hydrocephaly.
      CONCLUSION: Prognosis of children with a prenatally diagnosed malformation of the
      central nervous system is poor. Children with mild hydrocephaly may have a better
      prognosis.

PMID- 8649528
TI  - [Transient erythroblastopenia in children; a harmless form of anemia].
AB  - In three children presenting with anaemia, transient erythroblastopenia of
      childhood (TEC) was diagnosed. This is a harmless disorder in which
      erythropoiesis is temporarily suppressed by some unknown cause. TEC mostly
      affects young children between the age of 1 and 4 years. Apart from the anaemia
      symptoms are rare. Children with TEC recover spontaneously but sometimes one or
      more packed red cell transfusions may be necessary. It is easy to distinguish TEC
      from other causes of anaemia by history, physical examination and limited blood
      testing. Awareness of the existence of TEC can prevent unnecessary diagnostic
      procedures and treatment.

PMID- 8649530
TI  - [Post-marketing surveillance].

PMID- 8649529
TI  - [History of healing; trachoma, the scourge of the Jewish district in Amsterdam].

PMID- 8649531
TI  - [Late pregnancy interruption: how tough is the law?].

PMID- 8649532
TI  - [Alarming increase in deptropine poisonings].

PMID- 8649533
TI  - [Alarming increase in deptropine poisonings].

PMID- 8649534
TI  - [Alarming increase in deptropine poisonings].

PMID- 8649535
TI  - [Glucose intolerance in the elderly in The Netherlands; the Twello Study].

PMID- 8649536
TI  - [TIA... An aspirin?].

PMID- 8649537
TI  - Psychogenic seizures.

PMID- 8649538
TI  - Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic
      Paraplegia Working group.
AB  - Hereditary spastic paraplegia (HSP) is a diverse group of inherited disorders
      characterized by progressive lower-extremity spasticity and weakness. Insight
      into the genetic basis of these disorders is expanding rapidly. Uncomplicated
      autosomal dominant, autosomal recessive, and X-linked HSP are genetically
      heterogeneous: different genes cause clinically indistinguishable disorders. A
      locus for autosomal recessive HSP is on chromosome 8q. Loci for autosomal
      dominant HSP have been identified on chromosomes 2p, 14q, and 15q. One locus
      (Xq22) has been identified for X-linked, uncomplicated HSP and shown to be due to
      a proteolipoprotein gene mutation in one family. The existence of HSP families
      for whom these loci are excluded indicates the existence of additional, as yet
      unidentified HSP loci. There is marked clinical similarity among HSP families
      linked to each of these loci, suggesting that gene products from HSP loci may
      participate in a common biochemical cascade, which, if disturbed, results in
      axonal degeneration that is maximal at the ends of the longest CNS axons.
      Identifying the single gene defects that cause HSPs distal axonopathy may provide
      insight into factors responsible for development and maintenance of axonal
      integrity. We review clinical, genetic, and pathologic features of HSP and
      present differential diagnosis and diagnostic criteria of this important group of
      disorders. We discuss polymorphic microsatellite markers useful for genetic
      linkage analysis and genetic counseling in HSP.

PMID- 8649539
TI  - Phobic postural vertigo.

PMID- 8649540
TI  - Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic
      cases.
AB  - We analyzed our experience with cough, exertional, and vascular sexual headaches,
      evaluated the interrelationships among them, and examined the possible
      symptomatic cases. Seventy-two patients consulted us because of headaches
      precipitated by coughing (n = 30), physical exercise (n = 28), or sexual
      excitement (n = 14). Thirty (42%) were symptomatic. The 17 cases of symptomatic
      cough headache were secondary to Chiari type I malformation, while the majority
      of cases of symptomatic exertional headaches and the only case of symptomatic
      sexual headache were secondary to subarachnoid hemorrhage. Although the
      precipitant was the same, benign and symptomatic headaches differed in several
      clinical aspects, such as age at onset, associated clinical manifestations, or
      response to pharmacologic treatment. Although sharing some properties, such as
      male predominance, benign cough headache and benign exertional headache are
      clinically separate conditions. Benign cough headache began significantly later,
      43 years on average, than benign exertional headache. By contrast, our findings
      suggest that there is a close relationship between benign exertional headache and
      benign vascular sexual headache. We conclude that benign and symptomatic cough
      headaches are different from both benign and symptomatic exertional and sexual
      headaches.

PMID- 8649541
TI  - Lumboperitoneal shunt for the treatment of pseudotumor cerebri.
AB  - We conducted a retrospective study of 27 patients with pseudotumor cerebri (PTC)
      treated with at least one lumboperitoneal shunt (LPS) to ascertain the efficacy
      of this treatment. The average duration of follow-up for this population was 77
      months (median, 47 months), with a range of 21 to 278 months. A functioning LPS
      was successful in alleviating symptoms in all patients studied, and no patient
      with a functioning shunt complained of shunt-related symptoms, such as low
      pressure headache or abdominal pain, within 2 months after the shunt was
      performed. Twelve patients (44%) required no revisions. The number of revisions
      among the 15 patients (56%) who required them ranged from 1 (5 patients) to 13 (1
      patient). Three of these patients required 35 of the 66 total shunt revisions
      (53%). There were no major complications from LPS, other than failure of the
      shunt, even in patients who required multiple shunts. We conclude that placement
      of a lumboperitoneal shunt is satisfactory treatment for the majority of patients
      with PTC who require surgical therapy for the disorder, even though some patients
      ultimately require multiple shunt revisions.

PMID- 8649542
TI  - Clinical profile of patients with epileptic and nonepileptic seizures.
AB  - Epileptic seizures (ES) and nonepileptic seizures (NES) often coexist in patients
      with treatment-refractory seizures. There are few data on ictal features of these
      different seizure types in the same patient. We identified 20 patients with ES
      from a group of 99 NES patients (ES/NES) and compared this group with patients
      with only ES or NES. All 20 ES/NES patients developed NES after ES. Clinical
      features of NES clearly differed from ES in 18 of 20 cases. In patients with
      ES/NES their ES were similar to seizures in patients with only ES, and their NES
      were similar to spells in patients with only NES. ES/NES patients were similar to
      ES patients in electrodiagnostic and neuroimaging studies, and similar to NES
      patients in psychiatric interviews and inventories. The clinical manifestations
      of ES and NES in the same patient are usually different. Both types of events may
      be stereotypic and can be distinguished and characterized during video-EEG
      recording. Determining what events are more prevalent or disturbing is critical.
      Psychiatric and antiepileptic drug treatment may be provided accordingly.

PMID- 8649544
TI  - Photosensitive temporal lobe epilepsy.
AB  - Photic-induced seizures are usually generalized. There are several cases of focal
      seizures reported, and all have been shown to arise from the visual cortex. We
      report an unusual case of temporal lobe epilepsy, supported by electroclinical
      data and confirmed by a successful temporal lobectomy, with seizures induced by
      photic stimulation.

PMID- 8649543
TI  - Antiepileptic medication and oral contraceptive interactions: a national survey
      of neurologists and obstetricians.
AB  - Hepatic enzyme-inducing antiepileptic drugs (AEDs) lower oral contraceptive (OC)
      sex hormone levels approximately 40% and increase the risk of unplanned
      pregnancies in women with epilepsy. AEDs also increase the risk of birth defects
      in offspring of women with epilepsy. We performed a national survey to determine
      obstetricians' and neurologists' knowledge of OC and AED interactions and the
      risk of birth defects for women with epilepsy taking AEDs. We received responses
      to a mailed questionnaire from 160 of 1,000 neurologists (16%) and 147 of 1,000
      obstetricians (15%) from 47 states. Practice demographics and ages of responders
      were typical for U.S. neurologists and obstetricians. Ninety-one percent of
      neurologists and 75% of obstetricians said they treat women with epilepsy of
      child-bearing age. Only 4% of the neurologists and none of the obstetricians,
      however, knew the effects of the six most common AEDs on OCs, even though 27% of
      neurologists and 21% of obstetricians reported OC failures in their patients
      taking AEDs. Although increasing OC doses can compensate for insufficient OC sex
      hormone levels due to AEDs, most physicians do not increase the doses. Even
      though the risk of birth defects for the offspring of women with epilepsy is 4 to
      6%, up from the background level of 2%, 44% of neurologists thought the risk was
      lower (0 to 3%), and some of the respondents guessed that it was as high as 50%.
      Many neurologists and obstetricians do not have accurate information to counsel
      women with epilepsy properly about their contraceptive and pregnancy choices.

PMID- 8649545
TI  - Chemosensitive epidural spinal cord disease in non-Hodgkins lymphoma.
AB  - Epidural spinal cord disease (ESCD), an infrequent complication of systemic non
      Hodgkins lymphoma (NHL), can occur at diagnosis or at relapse, and is usually
      treated with radiotherapy, or infrequently surgical decompression. We
      retrospectively analyzed 140 patients with intermediate-grade NHL (IG-NHL) who
      were treated on a dose-intense protocol using doxorubicin, vincristine, and high
      dose cyclophosphamide (NHL-15). There were seven episodes of ESCD in six (4.3%)
      patients. Five episodes were asymptomatic at presentation; one patient had back
      pain, leg numbness, and tingling; and one had radicular pain and mild leg
      weakness. None had malignant cells in the CSF. One patient received high-dose
      dexamethasone after laminectomy for diagnostic biopsy; otherwise, dexamethasone
      was used only as an anti-emetic prior to chemotherapy. Patients who developed
      ESCD at diagnosis received the planned course of NHL-15 chemotherapy as treatment
      for ESCD, and those treated with NHL-15 who developed ESCD at relapse were given
      a regimen containing ifosfamide, carboplatin, and etoposide (ICE). After
      chemotherapy alone, five of seven episodes showed radiographic resolution of ESCD
      and improvement of neurologic deficits. One patient received consolidation
      radiotherapy (2,700 cGy) to the spine after ICE for relapsed ESCD and had a
      complete response. One patient had progression of systemic lymphoma and ESCD
      despite chemotherapy. These data suggest that chemotherapy may be effective as
      initial treatment of ESCD in IG-NHL and may reduce the potential complications of
      spinal surgery and radiotherapy.

PMID- 8649546
TI  - Improvement of levodopa-induced dyskinesia by propranolol in Parkinson's disease.
AB  - Seven patients suffering from Parkinson's disease (PD) with severely disabling
      dyskinesia received low-dose propranolol as an adjunct to the currently used
      medical treatment. There was a significant 40% improvement in the dyskinesia
      score without increase of parkinsonian motor disability. Ballistic and choreic
      dyskinesia were markedly ameliorated, whereas dystonia was not. This study
      suggests that administration of low doses of beta-blockers may improve levodopa
      induced ballistic and choreic dyskinesia in PD.

PMID- 8649547
TI  - Amantadine treatment is an independent predictor of improved survival in
      Parkinson's disease.
AB  - Amantadine has been used for more than 20 years in the symptomatic treatment of
      Parkinson's disease (PD). Several recent discoveries suggest that amantadine
      could also have a neuroprotective effect in PD. We studied survival in all
      parkinsonism (including PD and other parkinsonian syndromes) patients attending a
      single clinic, employing standard survival curves and a Cox regression model, to
      identify independent predictive variables for survival (while taking into account
      factors potentially associated with both outcome and treatment selection).
      Amantadine-treated patients (n = 250) were similar to the patients not treated
      with amantadine (n = 586) in terms of age, gender, type of parkinsonism, Hoehn
      and Yahr stage and dementia status at initial neurological visit. Amantadine use
      was an independent predictor of improved survival (p < 0.01). Improved survival
      was also associated with a higher 10-year expected survival (based on age,
      gender, and birth year), absence of dementia, type of parkinsonism = PD, and low
      Hoehn and Yahr stage (I or II) at initial neurologic visit (all p < 0.01); these
      additional factors occurred in statistically similar proportions in the groups
      that were and were not treated with amantadine. The association of improved
      survival with amantadine use may stem from symptomatic benefit or may reflect a
      "neuroprotective" effect, mediated through N-methyl-D-aspartate (NMDA) receptor
      antagonism, dopamine uptake blockade activity, or other mechanisms. Our
      preliminary findings suggest that a prospective, controlled, randomized trial of
      amantadine's effects on PD progression is warranted.

PMID- 8649548
TI  - Neurologic consequences of HTLV-II infection in injection-drug users.
AB  - Several case reports have suggested an association between human T-cell
      lymphotropic virus type II (HTLV-II) infection and chronic neurologic disease. We
      performed serial neurologic examinations in injection-drug users (IDU), a group
      known to be at increased risk for HTLV-II infection. At baseline, those infected
      with HTLV-II alone, human immunodeficiency virus (HIV) alone, or both were
      significantly more likely to have neurologic disability than uninfected subjects.
      Longitudinally, HTLV-II infection was independently associated with the
      development of global neurologic disability and neuropathy, suggesting that HTLV
      II causes neurologic disease.

PMID- 8649550
TI  - MRI and neuropsychological differences in early- and late-life-onset geriatric
      depression.
AB  - We sought to determine whether geriatric patients with late-life-onset major
      depression have more subcortical hyperintensities on MRI and greater cognitive
      impairment than age-matched geriatric patients with early-life-onset major
      depression, suggesting that subcortical disease may be etiologic in late-life
      depression. Most negative studies of the clinical significance of subcortical
      hyperintensities on MRI in geriatric patients have sampled from a restricted
      range of subjects, have employed limited batteries of neuropsychological tests,
      or have not quantified MRI changes; the present study attempted to address these
      limitations. Thirty subjects from a geriatric psychiatry inpatient service who
      were over 60 years of age and presented with major depression were divided into
      groups with onset of first depression after age 60 (mean = 72.4 years, 15 women,
      0 men), and onset of first depression before age 60 (mean = 35.8 years, 12 women,
      3 men). Quantitative analysis of MRI yielded the volume of: periventricular
      hyperintensities (PVH) and deep white-matter hyperintensities (DWMH). Subjects
      were administered a neuropsychological battery and measures of depression by
      raters blind to age of onset. The late-onset group had significantly more PVH and
      DWMH. They were also more impaired on executive and verbal and nonverbal memory
      tasks. Discriminant analysis using the severity or subcortical signal
      hyperintensities on MRI, cognitive index, and depression scores correctly
      predicted late versus early onset of depression in 87% of the early-onset group
      and 80% of the late-onset group. These findings suggest that late-life-onset
      depression may be associated with an increased severity of subcortical vascular
      disease and greater impairment of cognitive performance.

PMID- 8649549
TI  - Aortic atheromas and acute ischemic stroke: a transesophageal echocardiographic
      study in an ethnically mixed population.
AB  - PURPOSE: Proximal aortic atheromas have been suggested as a potential ischemic
      stroke determinant in the elderly, especially in cases of unexplained
      (cryptogenic) stroke. Our aim was to assess the potential role of proximal aortic
      atheromas as an independent risk factor for stroke by comparing their frequency
      in patients with acute ischemic stroke and in stroke-free control subjects. The
      frequency of atheromas was also compared among different ethnic groups. PATIENTS
      AND METHODS: A case-control study was conducted in 106 patients with acute
      ischemic stroke and 114 stroke-free control subjects. The presence of atheromas
      of the proximal portion of the aorta was assessed by biplane transesophageal
      echocardiography. Atheromas were categorized on the basis of their thickness (0.2
      to 0.4 cm, small; > or = 0.5 cm, large) and complexity (i.e., ulceration or
      mobility). The association between aortic atheromas and ischemic stroke was
      tested, controlling for patients' demographic variables and stroke risk factors.
      In stroke patients, subgroup analyses were performed to test the associations
      between aortic atheromas and stroke diagnostic subtypes (determined cause versus
      cryptogenic) and presence and degree of carotid stenoses by duplex Doppler
      examination. RESULTS: The frequency of large aortic atheromas was greater in
      stroke patients than in controls (26% versus 13%; crude odds ratio [OR] 2.4, 95%
      CI 1.2 to 4.7); ulcerated or mobile atheromas also tended to be more frequent in
      stroke patients (12% versus 5%; OR 2.5, 95% CI 1.0 to 6.8). Differences were
      entirely attributable to the subgroup of patients aged 60 years or older, in whom
      the frequency of ulcerated or mobile atheromas was particularly high among
      cryptogenic stroke patients (22% versus 8% in control subjects; OR 3.4, 95% CI
      1.1 to 11.2). Multivariate analysis showed the presence of large atheromas to be
      independently associated with stroke in the entire study group (adjusted OR 2.6,
      95% CI 1.1 to 5.9) and in the older subgroup (OR 2.4, 95% CI 1.1 to 5.7). Carotid
      stenosis > or = 60% was more frequent with increasing size and complexity of
      aortic atheromas but had low predictive value (16%) for presence of large
      atheromas; moreover, 36% of patients with mild or no carotid stenosis had large
      or complex aortic atheromas. No significant differences were found in the
      frequency of atheromas by ethnic group. CONCLUSIONS: Proximal aortic atheromas >
      or = 0.5 cm in size are a risk factor for ischemic stroke in patients aged 60
      years or older. Ulcerated or mobile atheromas may play a role in explaining some
      cryptogenic strokes in the elderly. The risk for stroke of patients with aortic
      atheromas may be similar across different ethnic groups. The absence of carotid
      stenosis does not exclude aortic atheromas as a potential cause for ischemic
      stroke.

PMID- 8649551
TI  - Alzheimer's disease: interaction of apolipoprotein E genotype, family history of
      dementia, gender, education, ethnicity, and age of onset.
AB  - We evaluated 197 patients with predominantly late-onset Alzheimer's disease (AD)
      who belonged to several ethnic groups and analyzed the relationship of age of
      onset of AD to the presence or absence of several risk factors in this entire
      group of patients. The apolipoprotein E (apoE) epsilon 4 allele frequency, which
      was 29% in all patients (compared with the reported population mean of 13.7%, p <
      0.001, did not vary significantly between ethnic groups but declined
      significantly with increasing age. The apoE epsilon 2 allele frequency was 3%,
      compared with the reported population mean of 7.4% (p = 0.001). The frequency of
      a positive family history of dementia in first-degree relatives (FH +) (overall
      45%) did not vary significantly between ethnic groups. ApoE epsilon 4-positive
      (epsilon 4+) patients tended to have a higher FH + rate (58%) than apoE epsilon 4
      negative (epsilon 4-) patients (40%) (p = 0.02). When the potential risk factors
      of gender, education, FH+ status, and epsilon 4+ status were examined together in
      a multiple linear-regression analysis, FH+ and epsilon 4+ status (but not gender
      or education) were significant (they were both associated with an earlier age of
      onset of AD). In a post-hoc analysis, we found a reduced age of onset in women,
      but not men, who were both FH + and epsilon 4+. Additionally, those probands who
      were epsilon 4+ were more likely to inherit the disease from their mothers than
      their fathers. The mechanism by which epsilon 4+ and FH+ status operate as risk
      factors may be by their effect on the age of onset of AD.

PMID- 8649553
TI  - Low body weight in Alzheimer's disease is associated with mesial temporal cortex
      atrophy.
AB  - There are reports of weight loss and low body mass index (BMI) in patients with
      AD. The mesial temporal cortex (MTC) is involved in feeding behavior and memory
      and is preferentially involved in AD. We studied 74 subjects, including 58 AD
      patients and 16 control subjects, to determine whether BMI is associated with
      atrophy of the MTC or other brain regions. We used MRI morphometric analysis to
      provide measures of regional brain atrophy. AD patients had significant brain
      atrophy in all measured brain regions, except the white matter, compared with
      normal control subjects. The MTC was the only brain region significantly
      associated with BMI in AD patients (r = 0.39, p = 0.003). Multiple-regression
      analysis indicated that addition of brain regions other than the MTC to the model
      did not significantly add to the prediction of BMI. We conclude that low BMI
      correlates best and specifically with MTC atrophy. This finding supports a
      connection between limbic system damage and low body weight in AD.

PMID- 8649552
TI  - Effects of estrogen replacement therapy on response to tacrine in patients with
      Alzheimer's disease.
AB  - OBJECTIVE: To examine whether estrogen replacement therapy (ERT) affects clinical
      and cognitive responses to tacrine in women with Alzheimer's disease (AD).
      DESIGN: A 30-week, randomized, double-blind, placebo-controlled, parallel-group,
      multicenter clinical trial of tacrine in which a subgroup of women were receiving
      ERT prior to randomization. PATIENTS: Women with mild to moderate-stage AD, at
      least 50 years of age, who were enrolled in the previously reported trial.
      INTERVENTIONS: Randomized assignment to placebo or to one of three ascending
      dosage regimens of tacrine: maximum dosages of 80 mg/d, 120 mg/d or 160 mg/d.
      OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-Cognitive Scale (ADASc),
      Clinician Interview-Based Impression of change (CIBI), Mini-Mental State
      Examination (MMSE), Caregiver's Impression of Change (CIC). RESULTS: Of 318 women
      with evaluable data 14.5% were receiving ERT. Women completing the trial taking
      ERT and tacrine improved more than women not receiving ERT who were randomly
      assigned to tacrine or to placebo as assessed by the ADASc (p < 0.01), the CIBI
      (p = 0.02), the CIC (p = 0.006), and the MMSE (p = 0.07). They improved
      significantly on the ADASc (p = 0.01) using an intent-to-treat analysis.
      CONCLUSIONS: Prior and continuing ERT may enhance response to tacrine in women
      with AD. Randomized trials are needed.

PMID- 8649554
TI  - Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease:
      the CERAD experience, Part XV.
AB  - We studied the frequency, severity, and clinical correlations of cerebral amyloid
      angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three
      percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains
      (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or
      more cortical regions. These brains also showed a significantly higher frequency
      of hemorrhages or ischemic lesions than those of subjects with little or no
      amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2)
      High CAA scores also correlated with the presence of cerebral arteriosclerosis
      and with older age at onset of dementia. Our findings suggest that factors
      contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may
      play a role in amyloid deposition in cerebral vessels in AD.

PMID- 8649555
TI  - Transient encephalopathy after paclitaxel (Taxol) infusion.
AB  - Paclitaxel (Taxol) is a novel antineoplastic agent that acts by promoting
      microtubule polymerization. Although myelosuppression and peripheral
      neurotoxicity are well known and dose limiting, there have been no reports of CNS
      toxicity apart from two patients with seizures. This may reflect that paclitaxel
      has little or no blood-brain barrier penetration. We report two women treated
      with paclitaxel who developed a clinical state characterized by confusion, word
      finding difficulty, and behavioral changes. One had bilateral extensor plantar
      responses. These symptoms appeared 1 week after paclitaxel infusion and resolved
      spontaneously. Subsequent infusions were associated with a similar self-resolving
      encephalopathy in one patient and recurrent headache and ataxia in the other.
      Neuroimaging (including enhanced MRI), LP, and laboratory investigations did not
      reveal other causes. Electroencephalography showed diffuse nonspecific slowing.
      One MRI had prominent but nonspecific high signal intensity abnormalities in the
      deep white matter of the cerebral hemispheres. Based on temporal association,
      diagnostic exclusion, and repeated episodes with subsequent challenges, we
      believe these patients may have experienced CNS toxicity from paclitaxel. The
      mechanism for this self-resolving encephalopathic process is unclear.

PMID- 8649556
TI  - Reversible dementia and chorea in a young woman with the lupus anticoagulant.
AB  - A 22-year-old woman gradually developed depression, dementia, and chorea over an
      8-month period. She fulfilled the criteria for the primary antiphospholipid
      antibody syndrome but not those for systemic lupus erythematosus. Her chorea and
      neurobehavioral deficits responded favorably to a regimen of prednisone,
      hydroxychloroquine, and aspirin. This appears to be the first report of a patient
      with a lupus anticoagulant and reversible dementia. The response to
      immunosuppressive therapy implies an antibody-mediated condition similar to
      Sydenham's chorea.

PMID- 8649557
TI  - Delayed radiation-induced bulbar palsy.
AB  - We report a man with a slowly progressive bulbar palsy 14 years after radiation
      therapy for nasopharyngeal carcinoma. Electromyography demonstrated prominent
      myokymic and neuromyotonic discharges in muscles innervated by the lower cranial
      nerves. Late effects of radiation therapy can occur in the cranial nerve
      musculature that are similar to well-recognized syndromes affecting the brachial
      plexus and spinal cord.

PMID- 8649558
TI  - Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control
      study.
AB  - An increased risk of cancer has been reported in patients treated with
      azathioprine. To assess the long-term risk of neoplasia in azathioprine-treated
      multiple sclerosis (MS) patients, we conducted a case-control study using the
      Lyon Multiple Sclerosis Database. From the 1,191 MS patients included in the
      database, we identified patients who developed cancer before December 31, 1991.
      Each case was then matched to three cancer-free MS controls by gender, date of
      birth, and date of MS onset. A matched analysis was performed to compare cases
      and controls for exposure to azathioprine therapy during the same follow-up
      period. Twenty-three MS patients with cancer were identified: 17 solid tumors, 2
      skin carcinomas, 4 hematopoietic cancers. Cases had a mean age of 34.5 years +/-
      10.2 (+/- SD) at clinical onset of MS and have been followed up for an average
      13.8 years +/- 8.1 before being diagnosed with cancer. Fourteen cases (61%) and
      34 controls (49%) had been treated with azathioprine for at least 1 month after
      being diagnosed with MS (adjusted odds ratio = 1.7; 95% confidence interval [CI],
      0.6 to 4.6). When assessing risk associated with different durations of
      azathioprine therapy compared with no treatment at all, we found that MS patients
      had an increase in cancer risk of 1.3 (95% CI, 0.4 to 4.0) when treated less than
      5 years, of 2.0 (95% CI, 0.4 to 9.1) when treated 5 to 10 years, and of 4.4 (95%
      CI 0.9 to 20.9) when treated more than 10 years. Similar results were obtained
      when assessing cancer risk associated with cumulative doses of azathioprine ever
      taken. This case-control study suggests that the overall long-term risk of cancer
      from azathioprine is low in MS patients. The results are suggestive of a dose
      response relationship with no significant risk during the first years of
      treatment and a possible increased risk after about 10 years of continuous
      therapy. Further studies are needed to better assess the risk-benefit ratio of
      azathioprine in MS.

PMID- 8649559
TI  - Meta-analysis of the placebo-treated groups in clinical trials of progressive MS.
AB  - The behavior of the control groups can substantially affect the power and outcome
      of a clinical trial. We report a meta-analysis of the control groups of four
      large, double-blind, placebo-controlled clinical trials of immuno-suppressive
      treatment of progressive MS to address the sensitivity of five hypothetical
      definitions of treatment failure (TF). The rate of TF in the aggregate control
      groups (n = 427) was 31% when a confirmed increase of 1.0 expanded disability
      status scale (EDSS) point was required at the end of the trial; it was 51% when
      confirmation was not required and TF was allowed at the first point where the
      criteria for TF were met. The rate of confirmed TF was 45% when the TF criteria
      were indexed to baseline EDSS, accounting for the observed differences in staying
      times at different EDSS levels. We developed models predicting TF in progressive
      MS. In addition to baseline EDSS, the pyramidal functional score and, for one
      definition, brainstem functional score were associated with probability of TF.

PMID- 8649560
TI  - Plasma exchange combined with azathioprine in multiple sclerosis using serial
      gadolinium-enhanced MRI to monitor disease activity: a randomized single-masked
      cross-over pilot study.
AB  - We enrolled 11 patients with secondary progressive MS in a randomized single
      masked cross-over study of plasma exchange (PE) in combination with azathioprine
      2 mg/kg. PE was performed once a week for 4 weeks and thereafter every second
      week for 20 weeks (14 treatments). Eight patients completed the whole trial, and
      three patients discontinued the trial, two during the run-in period of
      azathioprine treatment and one at the introduction of PE. The primary efficacy
      variables were the number of gadolinium-enhancing lesions and the occurrence of
      new enhancing lesions on serial MRI performed every 3 weeks during the PE and the
      control period. Secondary efficacy variables were the total MS lesion load on T2
      weighted MRI, multimodal evoked potentials, and clinical neurologic ratings. No
      significant differences were found regarding the number of enhancing lesions or
      occurrence of new enhancing lesions in the two periods. Although the total MS
      lesion load on MRI was significantly lower (p < 0.02) and central motor
      conduction times decreased significantly (p < 0.05) during PE, this small study
      did not provide sufficient evidence for a significant beneficial effect of PE or
      encourage a subsequent large randomized parallel group study.

PMID- 8649561
TI  - Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis:
      relation to blood-brain barrier injury.
AB  - Contrast-enhanced MRI in patients with MS shows that increased permeability of
      the blood-brain barrier (BBB) commonly occurs. The changes in capillary
      permeability often precede T2-weighted MRI evidence of tissue damage. In animal
      studies, intracerebral injection of the matrix metalloproteinase (MMP) 72-kDa
      type IV collagenase (gelatinase A) opens the BBB by disrupting the basal lamina
      around capillaries. Steroids affect production of endogenous MMPs and tissue
      inhibitors to metalloproteinases (TIMPs). To determine the role of MMP activity
      in BBB damage during acute exacerbations of MS, we measured MMPs in the CSF of
      patients with MS. Patients (n = 7) given steroids to treat an acute episode of MS
      had CSF sampled before and after 3 days of methylprednisolone (1 g/day). Patients
      had a graded neurologic examination and gadolinium-enhanced MRI before treatment.
      CSF studies included total protein, cell count, and a demyelinating profile. We
      measured levels of MMPs, urokinase-type plasminogen activator (uPA), and TIMPs by
      zymography, reverse zymography, and Western blots. The MMP, 92-kDa type IV
      collagenase (gelatinase B), fell from 216 +/- 70 before steroids to 54 +/- 26
      relative lysis zone units (p < 0.046) after treatment. Similarly, uPA dropped
      from 3880 +/- 800 to 2655 +/- 353 (p < 0.03). Four patients with gadolinium
      enhancement on MRI had the most pronounced drop in gelatinase B and uPA. Western
      immunoblots showed an increase in a complex of gelatinase B and TIMPs after
      treatment, suggesting an increase in a TIMP (p < 0.05). Reverse zymography of CSF
      samples showed that steroids increased a TIMP with a molecular weight similar to
      that of mouse TIMP-3 (p = 0.053). Our results suggest that increased gelatinase B
      is associated with an open BBB on MRI. Steroids may improve capillary function by
      reducing activity of gelatinase B and uPA and increasing levels of TIMPs.

PMID- 8649562
TI  - Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases
      interleukin-6 production in multiple sclerosis.
AB  - MS is presumed to be a T-cell-mediated chronic inflammatory disease of the CNS.
      We examined proliferation and cytokine secretion of mononuclear cells after
      stimulation with OKT3 [anti-CD3] monoclonal antibody (MAb) or concanavalin A (Con
      A) in subjects with stable relapsing-remitting MS (RR MS) before and after
      initiating interferon (IFN)-beta 1b treatment. There was no significant
      difference in pretreatment to on-treatment anti-CD3 mAb or Con A-induced
      proliferation in RR MS patients. There was significantly increased Con A-induced
      secretion of tumor necrosis factor (TNF)-alpha, IFN-gamma, interleukin (IL)-2, IL
      6, and IL-10 and decreased IL-4 secretion in on-treatment compared with
      pretreatment peripheral blood mononuclear cell samples. However, on-treatment CD3
      mediated secretion of TNF-alpha was significantly decreased, and IL-6 secretion
      was significantly increased compared with pretreatment values. IFN-gamma was also
      decreased in on-treatment cultures stimulated with anti-CD3 MAb, but these values
      did not reach statistical significance. Systemic side effects from IFN-beta 1b
      were associated with increased IL-6 secretion. There were no significant changes
      in CD3-mediated IL-4, IL-10, transforming growth factor (TGF)-beta, or IL-2
      secretion or Con A-induced TGF-beta secretion. IFN-beta 1b (Betaseron) decreases
      CD3-mediated TNF-alpha secretion but increases another inflammatory cytokine, IL
      6, that could potentially counteract its beneficial immunomodulatory effects.

PMID- 8649563
TI  - Interferon beta-1b serum levels in multiple sclerosis patients following
      subcutaneous administration.
AB  - Recombinant interferon beta-1b (rIFNbeta) reduces the frequency of exacerbations
      in relapsing-remitting MS when administered subcutaneously on alternate days.
      However, the pharmacokinetics of rIFNbeta are not well understood and there are
      scant data on the detectability of rIFNbeta in the serum of MS patients following
      subcutaneous administration. Moreover, existing assays for detecting IFNbeta are
      biologic, time-consuming, and require handling of infectious agents. We developed
      and standardized an ELISA specific for measuring rIFNbeta with a detection range
      of 40 to 1,000 IU/ml. The specificity of our ELISA was confirmed by the lack of
      cross-reactivity with other cytokines, including IFNalpha, IFNgamma, IFN
      Consensus-1, and TNFalpha. We screened serum from 34 MS patients drawn within 12
      36 hours of treatment: 15 patients taking 8 MIU, four patients taking 1.6 MIU,
      and 15 patients taking placebo. Eleven of the 15 patients in the 8-MIU treatment
      group had measurable rIFNbeta serum levels ranging from 120 to 475 MIU/ml. Two of
      four patients in the 1.6-MIU treatment group, but none of the placebo group, had
      detectable serum rIFNbeta levels. A small prospective time-course study was
      carried out in four MS patients receiving rIFNbeta. Serial blood samples were
      obtained prior to and 4, 8, 24, and 48 hours after rIFNbeta injection. A peak
      serum rIFNbeta level was observed between 8 and 24 hours after rIFNbeta injection
      and tended to decline to near preinjection levels at 48 hours postinjection.
      These results are consistent with the rationale of alternate-day, subcutaneous
      administration of rIFN beta. In addition, the ELISA described might be a useful
      tool to study the pharmacokinetics and the relationship of rIFN beta serum levels
      to clinical efficacy.

PMID- 8649564
TI  - Tryptophan-immobilized column adsorbs immunoglobulin G anti-GQ1b antibody from
      Fisher's syndrome: A new approach to treatment.
AB  - Sera from patients with Fisher's syndrome in the acute phase contain
      immunoglobulin (Ig)G anti-GQ1b ganglioside antibody. Removal of the autoantibody
      should lead to earlier recovery with less residual neurologic involvement. A
      tryptophan- or phenylalanin-immobilized polyvinyl alcohol gel column (IM-TR 350
      or IM-PH 350) semiselectively adsorbs such autoantibodies as rheumatoid factor,
      anti-DNA antibody, or anti-acetylcholine receptor antibody. A batchwise
      adsorption test showed that an IM-TR gel adsorbed a larger amount of the IgG anti
      GQ1b antibody than did an IM-PH column. Several patients with Fisher's syndrome
      therefore were given immunoadsorbent therapy using the IM-TR column without
      adverse reactions. An ex vivo plasma perfusion study done with the IM-TR column
      confirmed that it effectively adsorbs the IgG anti-GQ1b antibody. Results of
      adsorption tests done with various amino acid-immobilized gels suggest that both
      the hydrophobic force of the side chain and the anionic charge of the carboxylic
      acid in tryptophan are important in the adsorption of the autoantibody by the IM
      TR gel. Immunoadsorption using the IM-TR column, which does not need replacement
      fluids, offers an alternative type of plasmapheresis for Fisher's syndrome.

PMID- 8649566
TI  - Neuropsychological significance of areas of high signal intensity on brain MRIs
      of children with neurofibromatosis.
AB  - Of children with neurofibromatosis (NF), 40% have a cognitive or learning
      impairment. Approximately 60% also have anomalous areas of high signal intensity
      on T2-weighted brain MRIs. The association of these hyperintensities and
      neuropsychological status is not fully understood. We administered a battery of
      neuropsychological tests and a standard clinical MRI to determine the impact of
      hyperintensity presence, number, and location on cognitive status in 84 children
      (8 to 16 years) with NF type 1. These children underwent standard clinical MRI
      using a GE 1.5-tesla scanner (except one child who was examined with a 1.0-tesla
      scanner). We conducted three types of analyses: Hyperintensity presence or
      absence.-Scores of children with (55%) and without hyperintensities (45%) were
      compared using t tests. No statistically significant differences between groups
      in intellectual functioning or any neuropsychological variable were found. Number
      of hyperintensities-The number of hyperintensity locations per child ranged from
      one to five (mean = 2.22). Pearson correlations revealed no significant
      association between the number of hyperintensities and neuropsychological
      performance. Location of hyperintensities-In four of the five locations studied,
      no statistically significant differences were found between scores of children
      with a hyperintensity in an area and those with one elsewhere. However, mean
      scores for IQ, Memory, Motor, Distractibility, and Attention domains for children
      with hyperintensities in the thalamus were significantly lower than scores for
      those with hyperintensities elsewhere. These results suggest that the simple
      presence or absence of hyperintensities, or their total number, is not as
      important as their anatomic location for detecting their relationship with
      neuropsychological status. Taking location into account, hyperintensities in the
      cerebral hemispheres, basal ganglia, brainstem, or cerebellum seem to have no
      impact on neuropsychological functioning, whereas hyperintensities in the
      thalamus do.

PMID- 8649565
TI  - The management of brainstem gliomas in patients with neurofibromatosis 1.
AB  - The appropriate management of brainstem tumors in patients with neurofibromatosis
      1 (NF1) has been problematic because the natural history of these lesions remains
      poorly defined. To formulate rational guidelines for the evaluation and treatment
      of these tumors, we reviewed the outcome of 21 patients with brainstem mass
      lesions followed in our NF clinic during the last 9 years. We subdivided the
      imaging features of these lesions into four groups: (1) diffuse enlargement of
      the brainstem with hypointensity on T1-weighted MR images and hyperintensity on
      T2-weighted images (n = 9); (2) focal enhancing masses (n = 7); (3) intrinsic
      tectal tumors (n = 5); and (4) focal nonenhancing areas of hypointensity on T1
      weighted MR images (n = 2). Two cases exhibited two types of lesions. Twelve
      patients presented with, or developed, symptoms that were referable to the mass;
      in nine, the lesion was asymptomatic. A distinguishing feature of these tumors
      was their generally indolent biological behavior. With a median follow-up of 3.75
      years, only 10 patients have had radiographic (n = 9) or clinical (n = 3)
      evidence of disease progression. In seven of these patients, the tumor
      subsequently stabilized in size or regressed without intervention. Only four
      patients, each with a focal enhancing tumor, received specific therapy for the
      tumor; this consisted of biopsy (n = 1), excision (n = 3), and adjuvant
      radiotherapy (n = 2). Each of these lesions was a low-grade glioma histologically
      and each remained stable in size after treatment (median follow-up = 4.25 years).
      Four patients with tectal tumors underwent insertion of a CSF shunt for
      hydrocephalus, but required no specific treatment for the tumor. None of the
      patients with diffuse brainstem lesions or focal areas of hypointensity required
      any intervention for the tumor. All 21 patients are presently alive and well. We
      conclude that the biological behavior of brainstem lesions in patients with NF1
      differs significantly from that of lesions with a similar appearance in patients
      without this disorder. Although these lesions may at some time in their course
      exhibit clinical and radiographic progression, most do not require specific
      intervention. The lesions that are most likely to progress and require therapy
      are focal enhancing tumors; however, even lesions in this subgroup may stabilize
      in size or regress spontaneously without intervention. Based on these results, we
      recommend that intervention be limited to those lesions that exhibit rapid or
      unrelenting growth on serial images or that produce significant clinical
      deterioration.

PMID- 8649567
TI  - Gangliogliomas involving the optic chiasm.
AB  - We report three patients with gangliogliomas involving the optic chiasm via
      distinct mechanisms. The ganglioglioma in one patient likely originated in the
      temporal lobe and spread medially to involve the chiasm, and diffuse spinal cord
      dissemination also occurred. Chiasmal involvement in this manner and
      dissemination at presentation are unusual for gangliogliomas. The tumor in a
      second patient was intrinsic to the hypothalmus and chiasm, while in the third
      patient, it involved both optic tracts, and a cyst compressed the chiasm
      laterally. Two patients developed severe bilateral visual loss, while the other
      had a stable bitemporal hemianopsia. Two patients received radiotherapy, but one
      continued to lose vision. Although gangliogliomas rarely involve chiasm, the
      mechanisms by which they produce chiasmal visual loss may be diverse, and the
      long-term visual prognosis is variable.

PMID- 8649568
TI  - Prognostic significance of 111indium-DTPA CSF flow studies in leptomeningeal
      metastases.
AB  - We assessed the clinical significance of interruption of CSF flow documented by
      radionuclide ventriculography (111Indium-DTPA CSF flow study) in patients with
      leptomeningeal metastases. Forty patients (25 men and 15 women) ranging in age
      from 6 to 70 years (median 38.5 years) with cytologically documented
      leptomeningeal metastases were demonstrated to have interruption of CSF flow by
      radionuclide ventriculography. All patients were treated with radiotherapy (30 Gy
      in 10 fractions) to the site of CSF obstruction after which intra-CSF
      chemotherapy (methotrexate or cytarabine followed by cytarabine or thio-TEPA if
      clinically indicated) was administered. Twenty patients (group 1) after
      radiotherapy to the site of CSF flow block demonstrated reestablishment of normal
      CSF flow. By contrast, 20 patients (group 2) treated in a similar manner had
      persistent CSF flow obstruction. All patients were treated with intraventricular
      chemotherapy. Median survival was 6 months in group 1 (range 3 to 15 months)
      compared with 1.75 months in group 2 (range 1 to 4 months) (p < 0.0001). Cause of
      death differed between groups with 20% of group 1 patients dying of progressive
      leptomeningeal disease compared with 70% of group 2 patients (p < 0.0006). In
      patients with leptomeningeal metastases and CSF flow obstruction, 111Indium-DTPA
      CSF flow studies predict patient survival and are useful in determining which
      patients would be candidates for intra-CSF chemotherapy administration.

PMID- 8649569
TI  - Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy
      using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study Group.
AB  - We conducted a multicenter, double-blind, randomized, parallel, placebo
      controlled trial in 190 patients to evaluate the safety and efficacy of three
      dosages of topiramate (600, 800, and 1,000 mg/day) as adjunctive therapy for
      patients with refractory partial epilepsy. During an 18-week double-blind
      treatment period, median percent reductions from baseline in average monthly
      seizure rates were 1% for placebo, 41% for topiramate 600 mg/day and topiramate
      800 mg/day, and 38% for topiramate 1,000 mg/day. There was a 50% or greater
      reduction from baseline in seizure frequency in 9% of patients in the placebo
      group and in 44% for topiramate 600 mg/day, 40% for topiramate 800 mg/day, and
      38% for topiramate 1,000 mg/day. No placebo patients were improved by 75 to 100%
      in seizure frequency, whereas 20% of the topiramate patients were improved to
      this degree. All intent-to-treat drug-placebo comparisons including seizure
      reduction, percent responders, and investigator and patient global evaluations
      significantly (p < or = 0.02) favored topiramate. Treatment-emergent adverse
      events consisted mainly of neurologic symptoms commonly observed during
      antiepileptic drug (AED) therapy. Sixteen percent of patients on topiramate
      discontinued therapy due to adverse events. Results of this study indicate that
      topiramate is a highly efficacious and generally well tolerated new AED. When
      large groups of patients are compared, incremental efficacy in the add-on setting
      is not observed at topiramate dosages above 600 mg/day; however, higher doses may
      prove beneficial to individual patients who tolerate them.

PMID- 8649570
TI  - Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy
      using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group.
AB  - We conducted a randomized double-blind comparison of three doses of the novel
      antiepileptic drug (AED) topiramate (200, 400, and 600 mg/day) and placebo as
      adjunctive therapy in patients with refractory partial onset epilepsy receiving
      one or two other AEDs at therapeutic concentrations. A total of 181 patients
      completed the 12-week baseline phase and were randomized to double-blind therapy.
      Median percent reductions from baseline in average monthly seizure rate, the
      principal efficacy evaluation, were 13% for placebo, 30% for topiramate 200
      mg/day, 48% for topiramate 400 mg/day, and 45% for topiramate 600 mg/day. For the
      seizure rate comparison of active drug to placebo p values were: topiramate 200
      mg/day, p = 0.051; topiramate 400 mg/day, p = 0.007; topiramate 600 mg/day, p <
      0.001. Percent responders ( > or = 50% reduction in seizure rates) were 18% for
      placebo, 27% for topiramate 200 mg/day, 47% for topiramate 400 mg/day (p =
      0.013), and 46% for topiramate 600 mg/day (p = 0.027). A significant (p = 0.003)
      reduction in secondarily generalized seizures compared with placebo treatment was
      also documented with topiramate. Topiramate plasma concentrations were closely
      related to dosage, and there were no significant interactions between topiramate
      and other AEDs. The minimal effective dose of topiramate in this study population
      was approximately 200 mg/day. Mild or moderate CNS symptoms were the primary
      treatment-emergent adverse events, but treatment-limiting adverse events occurred
      in only 9% of patients given topiramate compared with 7% given placebo. Results
      of this initial well-controlled study in patients indicate that topiramate is a
      very promising new AED.

PMID- 8649571
TI  - Early pathologic and biochemical changes in Creutzfeldt-Jakob disease: study of
      brain biopsies.
AB  - We examined brain biopsy tissue from five patients with a neurologic syndrome
      consistent with Creutzfeldt-Jakob disease using Western blot analysis and
      immunohistochemistry for the detection of protease-resistant prion protein, in
      addition to histopathologic examination. Our results indicate that the formation
      of protease-resistant prion protein is an early event in disease pathogenesis and
      Western blot analysis can detect protease-resistant prion protein in the absence
      of structural lesions using a small amount of brain biopsy tissue.

PMID- 8649572
TI  - Large neurons in the tuberomammillary nucleus in patients with Parkinson's
      disease and multiple system atrophy.
AB  - To investigate whether the histaminergic neurons degenerate in Parkinson's
      disease (PD) and multiple system atrophy (MSA), we studied the number of large
      sized neurons in the tuberomammillary nucleus in patients with PD, patients with
      MSA, and age-matched controls. The number of large-sized neurons in the
      tuberomammillary nucleus in PD patients was not altered compared with controls,
      and Lewy bodies were rarely present in the tuberomammillary nucleus. In contrast,
      the number of large-sized neurons in the tuberomammillary nucleus in MSA patients
      was significantly decreased compared with controls. Thus, the central
      histaminergic neurons are affected in MSA and preserved in PD.

PMID- 8649574
TI  - Electrophysiologic evidence for extremely late sensory collateral reinnervation
      in humans.
AB  - We present a patient in whom unexpectedly late sensory recovery occurred over 5
      years after removal of a 3-cm piece of the right inferior alveolar nerve (IAN) in
      tumor surgery of the mandible. For a year after surgery, the distribution of the
      mental nerve, the terminal branch of the IAN, was totally anesthetic. Thereafter,
      a gradual subjective sensory recovery occurred centripetally from the surrounding
      skin distributions. Five years after surgery, findings in electrophysiologic
      tests were consistent with a total lesion of the right IAN. Two years later,
      electrophysiologic tests gave, for the first time in humans, objective evidence
      for sensory collateral sprouting in trigeminal distribution.

PMID- 8649573
TI  - The correlation between neuropsychological and neuroanatomic changes over time in
      asymptomatic and symptomatic HIV-1-infected individuals.
AB  - To determine the relationship between neuroanatomic and neuropsychological
      changes in both asymptomatic and symptomatic HIV-1-infected individuals, we
      conducted a longitudinal study of 47 HIV-infected individuals, 15 of whom were
      asymptomatic and 32 of whom had either AIDS-related complex or AIDS. To measure
      neuroanatomic change over a 30-month period, we conducted quantitative MRI
      measures of bicaudate/brain ratio (BCR) and bifrontal/ brain ratio. A comparison
      of change over time between BCR and neuropsychological performance showed a
      correlation between increase in atrophy and worsening in certain cognitive
      functions. The correlation held for both asymptomatic and symptomatic groups,
      with more pronounced changes in the symptomatic group.

PMID- 8649575
TI  - Spinal responses to median and tibial nerve stimulation and magnetic resonance
      imaging in intramedullary cord lesions.
AB  - We recorded median and tibial nerve somatosensory evoked potentials (SEPs) in 18
      patients with intramedullary lesions of the cord (intramedullary tumors in 14
      patients and syringomyelia cavitations in 4). Patients were divided into four
      groups on the basis of the longitudinal extension of the lesions as revealed by
      magnetic resonance imaging. The lesions involved the cervical cord in nine
      patients (group 1), both cervical and lumbar cord ("holocord" lesion) in two
      (group 2), the dorsal cord in one (group 3), and the lumbar cord in six (group
      4). The recording technique enabled us to analyze clearly the spinal SEPs,
      labeled for the median nerve as N13, and for the tibial nerve as N24. Both spinal
      responses are probably generated by the activation of dorsal horn cells and
      proved useful in revealing focal lesions of the cervical or lumbar cords. Median
      nerve N13 was abnormal in all group 1 and group 2 patients; in three patients,
      this was the only median SEP abnormality, suggesting that the dysfunction was
      limited to the cervical grey matter. Tibial nerve N24 was abnormal in all group 2
      and group 4 patients. The abnormality of both cervical and lumbar segmental
      responses in patients with holocord lesions strongly suggested that both the
      cervical and lumbar cords were involved. The SEP study was often more effective
      than the clinical examination in revealing cord involvement and the actual
      extension of damage. The recording of the spinal SEPs is thus highly sensitive in
      assessing cord dysfunction in intramedullary lesions, providing that specific
      recording techniques are used.

PMID- 8649576
TI  - CSF excitatory amino acids and severity of illness in Alzheimer's disease.
AB  - Researchers have proposed that increased release of excitatory amino acids (EAAs)
      is involved in the pathogenesis of dementia of the Alzheimer type (DAT), and CSF
      EAA concentrations have been measured to obtain evidence in support of this
      hypothesis. However, previous comparisons of CSF EAA concentrations in patients
      with DAT and in controls have yielded inconsistent results, perhaps because
      patient samples have been heterogeneous as to dementia severity. To determine
      whether there are changes in CSF concentrations of EAAs related to severity of
      illness in patients with DAT, we measured CSF concentrations of glutamate,
      aspartate, and taurine in 32 subjects with DAT, in whom we also assessed the
      severity of illness using clinical and neuropsychological measures, and 11 age
      matched controls. The results suggested that increased CSF aspartate and
      glutamate concentrations, as well as decreased taurine concentrations, may occur
      in some persons with more advanced symptoms of DAT.

PMID- 8649577
TI  - Japanese siblings with missense mutation (717Val --> Ile) in amyloid precursor
      protein of early-onset Alzheimer's disease.
AB  - We report Japanese siblings with the missense mutation 717Val --> Ile in the
      amyloid precursor protein. The maternal grandmother died of an unknown dementing
      disorder. The proband's mother had gradually increasing amnesia beginning at age
      64, which was diagnosed as Alzheimer's disease (AD). She died in a psychiatric
      hospital (duration of illness: 16 years). Both the proband and her elder sister
      were affected at about age 55 years. Disturbances of memory, judgment, and
      emotion, as well as personality changes, occurred first, with dementia eventually
      predominating. The elder sister died of pneumonia (duration of illness: 9 years).
      The amyloid precursor protein (APP) gene was analyzed from each sibling. Genomic
      DNAs obtained from blood samples were amplified by the polymerase chain reaction
      (PCR) method. PCR products were digested with the restriction enzyme Bcl I. The
      resulting restriction fragment length polymorphisms (RFLPs) showed the missense
      mutation 717Val --> Ile in both patients, but not in a normal control. DNA
      sequencing showed the presence of the 2149G --> A missense mutation only in the
      patients. We conclude that this familial AD may originate from the missense
      mutation 717Val --> Ile in the amyloid precursor protein gene and that the
      clinical picture is typical of AD, except for normal-pressure hydrocephalus and
      psychiatric phenomena.

PMID- 8649578
TI  - Severity of hippocampal atrophy correlates with the prolongation of MRI T2
      relaxation time in temporal lobe epilepsy but not in Alzheimer's disease.
AB  - We analyzed hippocampal volumes and T2 relaxation times by MRI from 78 control
      subjects, 24 patients with temporal lobe epilepsy, and 55 patients with
      Alzheimer's disease (AD). In the epilepsy group, the hippocampal volumes were 27%
      smaller than in control subjects (p < 0.001). The T2 relaxation times were
      prolonged (8 to 20 ms compared with control subjects) in the head, body, and tail
      portions of the hippocampus on the focal side (p < 0.01) and also on the
      contralateral side (p < 0.05) compared with control subjects. In the epilepsy
      group, the prolongation of T2 relaxation time correlated inversely with the
      hippocampal volume (p < 0.05). In the AD group, the hippocampal volumes were 35%
      smaller than in control subjects (p < 0.01). The T2 relaxation times were
      slightly prolonged (5 to 6 ms) in the head and tail portions of the right
      hippocampus (p < 0.01), but the T2 relaxation times did not correlate with the
      hippocampal volumes. These data show that the degree of prolongation of T2
      relaxation time is associated with severity of hippocampal atrophy in temporal
      lobe epilepsy but not in AD.

PMID- 8649579
TI  - Genetic mapping of the spinocerebellar ataxia type 2 gene on human chromosome 12.
AB  - The dominant spinocerebellar ataxias are a genetically heterogeneous group of
      diseases leading to premature death of neurons in the cerebellum and other parts
      of the nervous system. The mutation causing SCA1 is on human chromosome (CHR) 6p
      and SCA3 is on CHR 14q. To refine the location of the SCA2 gene on CHR 12q, we
      performed genetic linkage analysis between the SCA2 locus and nine Ioci (D12S58,
      D12S78, D12S317, D12S330, D12S353, D12S84, D12S105, D12S79, and PLA2) in three
      SCA2 families. The highest pairwise lod scores were obtained between SCA2 and
      D12S84/D12S105 and D12S79. We determined the best order and genetic distances
      among these loci in ten multigenerational families by multipoint linkage analysis
      and established the following order: D12S101-D12S58/IGF1- D12S78-D12S317
      D12S330/D12S353-D12S84/D 12S105-D12S79-PLA2. Using this genetic map, multipoint
      linkage analysis placed SCA2 between D12S84/D12S105 and D12S79.

PMID- 8649580
TI  - Mitochondrial DNA in migraine with aura.
AB  - Migraine and the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis,
      and stroke-like episodes) syndrome have some clinical features in common. First,
      cerebral infarctions, most often in the posterior cerebral regions, which are a
      main symptom of MELAS, may complicate migraine. Second, migrainous headache with
      vomiting is also a characteristic feature of the MELAS syndrome. Less frequently,
      hemicranial headache is present in another mitochondrial disease, myoclonic
      epilepsy with ragged-red fibers (MERRF). Moreover, there is a mild bias toward
      maternal transmission in migraine. Apart from clinical resemblance, there is some
      experimental evidence for mitochondrial dysfunction in migraine. There may be
      depression of respiratory chain enzyme activity in muscle and platelets, and
      magnetic resonance spectroscopy has revealed a defective energy metabolism in
      brain and muscle of migraine patients. There has not been a systematic study of
      mitochondrial DNA in migraine, however. We therefore analyzed the mitochondrial
      DNA in lymphocytes of 23 migraine patients with aura. Southern blot and
      polymerase chain reaction analysis of mitochondrial DNA failed to detect any
      large-scale deletions or point mutations at base pair 3243 (MELAS) and base pair
      8344 (MERRF). Our data show that deletions of mitochondrial DNA and the most
      frequent point mutations of MELAS and MERRF syndromes are not common in migraine
      with aura. In particular, these data do not support the hypothesis that some
      cases of migraine may be monosymptomatic forms of a MELAS syndrome. We cannot
      exclude, however, that migraine may be associated with different point mutations
      of mitochondrial DNA or with mutations of autosomally coded respiratory chain
      subunit genes.

PMID- 8649581
TI  - Pitfalls in the diagnosis of autoantibodies associated with paraneoplastic
      neurologic disease.
AB  - We studied the sera of 15 patients with Sjogren's syndrome using the Western blot
      technique for the presence of anti-Ro and anti-Hu (type 1 antineuronal nuclear
      autoantibody [ANNA-1]). All sera reacted with Ro-52 protein. Two of the Sjogren
      sera reacted with 38-kd bands on Western blots of rat cerebellar homogenate,
      resembling anti-Hu immunoreactivity. However, when reacted with purified human
      Purkinje cells or purified recombinant HuD protein, none of the sera
      immunoreacted with the Hu antigens. We recommend the use of either a recombinant
      Hu protein or the combination of immunohistochemistry and Western blot of
      purified human neuronal preparations to identify paraneoplastic antibodies. This
      approach will prevent the unnecessary workup for suspected lung cancer.

PMID- 8649583
TI  - Lyme neuroborreliosis disguised as normal pressure hydrocephalus.
AB  - A 74-year-old woman presented with gait impairment, urinary incontinence, and
      dementia. She showed lymphocytic CSF pleocytosis and pronounced intrathecal
      Borrelia burgdorferi antibody production, indicating active Lyme
      neuroborreliosis. The syndrome of normal-pressure hydrocephalus (NPH) fully
      remitted after ceftriaxone treatment. Lyme neuroborreliosis may cause NPH by
      interfering with subarachnoid CSF flow.

PMID- 8649582
TI  - Cocaine-associated intracranial hemorrhage: absence of vasculitis in 14 cases.
AB  - Complications associated with the use of cocaine are varied, and include cerebral
      hemorrhage and ischemia, with vasculitis and vasospasm as possible etiologies. We
      reviewed selected brain samples from 14 autopsy cases of cocaine-related
      cerebrovascular disease. Intracerebral or subarachnoid hemorrhage was present in
      12 cases. Intracranial arterioles were either normal or showed nonspecific
      changes. From these observations, we suggest that intracranial hemorrhages occur
      in the absence of readily detectable vascular abnormalities.

PMID- 8649584
TI  - The Clinical Dementia Rating scale: community-based validation of "profound' and
      "terminal' stages.
AB  - The original version of the Clinical Dementia Rating (CDR) scale correlates with
      other dementia rating scales, and predicts nursing home (NH) admission and death.
      To validate the extended components of the scale, we analyzed data from subjects
      participating in a community-based study of dementia. The extended CDR scale also
      correlated with measures of dementia severity and NH residence. "Profound" and
      "terminal" stages predicted shortened survival. The extended CDR scale should be
      useful in studies of the later stages of dementia.

PMID- 8649585
TI  - Epsilon 4 allele of apolipoprotein E increases risk of Alzheimer's disease in a
      Chinese population.
AB  - We examined the apolipoprotein E genotype in 56 Chinese patients with late-onset
      sporadic Alzheimer's disease (AD) and 57 Chinese control subjects of similar age.
      The frequency of epsilon 4 in the AD group was significantly higher than that in
      the control group (23.2% versus 7.9%, p = 0.003). The odds ratio for AD in
      individuals with either one or two epsilon 4 was 2.96 (95% CI 1.11 to 8.03). The
      linear trend for AD in proportion to alleles of epsilon 4 was also significant
      (chi 2 = 8.2, p = 0.004). Our results support the association between epsilon 4
      and AD in the Chinese.

PMID- 8649586
TI  - Petechial hemorrhages accompanying lobar hemorrhage: detection by gradient-echo
      MRI.
AB  - Based on the pathologic observation that severe cerebral amyloid angiopathy is
      often accompanied by multiple petechial hemorrhages, we prospectively obtained
      gradient-echo MRI on 15 elderly patients with lobar hemorrhage on CT. Nine of the
      15 demonstrated accompanying petechial hemorrhages restricted to the cortical or
      corticosubcortical regions. No similar lesions were present on gradient-echo MRI
      in 10 elderly control patients. These findings suggest that cerebral amyloid
      angiopathy might be neuroradiologically diagnosed and staged during life.

PMID- 8649587
TI  - Bromocriptine and postpartum cerebral angiopathy: a causal relationship?
AB  - We describe a postpartum 30-year-old woman who developed headaches, hypertension,
      and speech disturbances after bromocriptine treatment to suppress lactation.
      Brain MRI revealed intraparenchymal hematomas, and an angiographic study showed
      multiple arterial segmental narrowings compatible with postpartum cerebral
      angiopathy. We also comment on other cases of postpartum cerebral angiopathy.

PMID- 8649588
TI  - Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred
      radiotherapy: preliminary results.
AB  - Disease-free survival in primary CNS lymphoma has improved with the advent of
      methotrexate-based pre-irradiation chemotherapy. Prolonged response durations
      have been noted in six of eight patients refusing radiation therapy in two of our
      prior series. We have treated an additional 11 patients with methotrexate-based
      chemotherapy without subsequent planned irradiation. Some received maintenance
      chemotherapy. Most have had durable responses with little or no toxicity.
      Prolonged responses can be maintained without radiation therapy, thus avoiding
      potential long-term radiation toxicity.

PMID- 8649589
TI  - Meningeal gliomatosis presenting as multiple cerebral infarcts: a case report.
AB  - A 70-year-old man presented to the hospital with a history of progressive
      cognitive decline, and shortly after admission he developed sudden neurologic
      deterioration leading to coma. CT revealed multiple contrast-enhancing lesions
      within the cerebral hemispheres and midbrain tectum. Autopsy revealed a left
      occipital glioblastoma associated with widespread meningeal dissemination of
      tumor, occlusive vasculopathy, and multifocal infarcts.

PMID- 8649590
TI  - Assessment: electronystagmography. Report of the Therapeutics and Technology
      Assessment Subcommittee.

PMID- 8649591
TI  - Brueghel syndrome: its distinction from Meige syndrome.
AB  - A critical historical evaluation of the cranial dystonias supports the separation
      of the dystonia of the motor trigeminal nerve producing a widely opened mouth
      (Brueghel syndrome) from the more common facial dystonias with blepharospasm
      (Meige syndrome). In a patient with Brueghel syndrome, paroxysmal hyperpnea
      coincided with dystonic gaping; the finding of upbeating nystagmus suggests
      pontine localization in the pathogenesis of this rare disorder.

PMID- 8649592
TI  - Temporomandibular joint compression in coma.

PMID- 8649593
TI  - Cranial neuropathies and liver failure due to hepatitis A.

PMID- 8649594
TI  - Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba
      ingestion.

PMID- 8649595
TI  - Pure cerebellar ataxia phenotype in Machado-Joseph disease.

PMID- 8649596
TI  - Anti-Yo antibody binding to 62-, 52-, or 58-kd protein recognizes a single
      molecule.

PMID- 8649597
TI  - Fever, convulsions and coma in scleromyxedema: a "dermato-neuro syndrome".

PMID- 8649598
TI  - Serum NSE in status epilepticus.

PMID- 8649599
TI  - Warfarin in Sneddon's syndrome.

PMID- 8649600
TI  - Primary care neurologists.

PMID- 8649601
TI  - Primary care neurologists.

PMID- 8649602
TI  - Primary care neurologists.

PMID- 8649603
TI  - Adhalin deficiency.

PMID- 8649604
TI  - Ictus emeticus.

PMID- 8649605
TI  - Niemann-Pick; type C.

PMID- 8649606
TI  - Psychogenic basilar migraine.

PMID- 8649607
TI  - Use of parenteral antiepileptic drugs and the role for fosphenytoin.

PMID- 8649608
TI  - Fosphenytoin use in children.
AB  - Phenytoin is widely used for the prevention and treatment of acute seizures in
      children. Although it has the advantage of being available in parenteral form, it
      cannot be given through the i.m. route. Furthermore, problems with venous
      accessibility and maintenance may complicate i.v. administration of phenytoin in
      newborns and very sick infants. Fosphenytoin, a new phenytoin prodrug, can be
      safely administered through the i.m. route, and, because of the physical
      characteristics of its formulation, it offers advantages over phenytoin for i.v.
      administration. Clinical studies with i.v. and i.m. fosphenytoin demonstrate that
      the efficacy, safety, and pharmacokinetics of this drug are similar in 5- to 18
      year-old children and in young adults. The safety and pharmacokinetic profile of
      i.v. and i.m. fosphenytoin in younger children and infants is currently being
      investigated.

PMID- 8649609
TI  - Intravenous administration of fosphenytoin: options for the management of
      seizures.
AB  - Fosphenytoin is a water-soluble disodium phosphate ester of phenytoin that is
      converted in plasma to phenytoin. Fosphenytoin is compatible with most common
      i.v. solutions and can be administered safely through the i.m.route. An
      additional safety factor is the absence of propylene glycol in the fosphenytoin
      formulation. Propylene glycol is used as a vehicle in the i.v. phenytoin
      preparation and by itself may produce serious cardiovascular complications.
      Studies of the pharmacokinetics, safety, and tolerance of i.v. fosphenytoin have
      demonstrated that fosphenytoin produces phenytoin plasma concentrations similar
      to those achieved with oral and i.v. phenytoin, but without significant
      cardiovascular effects and only minimal discomfort at the injection site. Aside
      from local reactions, the most common adverse events associated with fosphenytoin
      have been pruritus and reactions typical of phenytoin (e.g., dizziness,
      somnolence, and ataxia). Fosphenytoin represents a significant advance in the
      treatment of patients with seizures who require parenteral therapy.

PMID- 8649610
TI  - Emergency treatment of status epilepticus.
AB  - Status epilepticus occurs in more than 50,000 people in the United States each
      year and should be considered a neurologic emergency. A variety of drugs are used
      to treat status epilepticus, including i.v. benzodiazepines, phenytoin, and
      barbiturates. They are all short of being ideal, primarily because of
      difficulties with administration or associated toxicity. Fosphenytoin, a prodrug
      and phosphate ester of phenytoin, was developed to overcome the drawbacks
      associated with i.v. phenytoin. With its efficacy, safety, and ease of
      administration, fosphenytoin is a valuable option for the treatment of status
      epilepticus.

PMID- 8649611
TI  - Intramuscular use of fosphenytoin: an overview.
AB  - Phenobarbital, diazepam, lorazepam, and phenytoin are all currently used for the
      treatment of acute seizures, including status epilepticus. None of these drugs is
      considered ideal. Fosphenytoin is a new phenytoin prodrug that fulfills many of
      the properties of an ideal anticonvulsant drug. The safety, tolerance, and
      pharmacokinetics of intramuscularly administered fosphenytoin have been evaluated
      in three clinical trials involving patients requiring loading or maintenance
      doses of phenytoin. These investigations demonstrated that fosphenytoin is
      rapidly and completely absorbed after injection into muscle and is quickly
      converted to produce therapeutic phenytoin plasma concentrations within 30 min of
      administration. Plasma concentrations of phenytoin achieved with i.m.
      fosphenytoin exceeded those associated with an equimolar dose of oral phenytoin.
      i.m. fosphenytoin was well tolerated both locally and systemically. Only mild and
      transient reactions occurred at the injection site. The most common systemic
      adverse events reported--somnolence, nystagmus, dizziness, and ataxia--are side
      effects commonly seen with phenytoin and tended to be mild. Preexisting seizure
      disorders remained stable. Combination treatment with i.v. diazepam or lorazepam
      to attain rapid seizure control and i.m. fosphenytoin to maintain the
      anticonvulsant effect theoretically offers many advantages for control of acute
      seizures and should be studied.

PMID- 8649612
TI  - Pharmacology and pharmacokinetics of fosphenytoin.
AB  - Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a
      replacement for parenteral phenytoin sodium. Unlike phenytoin, fosphenytoin is
      freely soluble in aqueous solutions, including standard i.v. solutions, and is
      rapidly absorbed by the i.m. route. Fosphenytoin is metabolized (conversion half
      life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free
      (unbound) and total plasma phenytoin concentrations are consistently attained
      after i.m. or i.v. administration of fosphenytoin loading doses. Fosphenytoin has
      fewer local adverse effects (e.g., pain, burning, and itching at the injection
      site) after i.m. or i.v. administration than parenteral phenytoin. Systemic
      effects related to the CNS are similar for both preparations, but transient
      paresthesias are more common with fosphenytoin.

PMID- 8649613
TI  - Parenteral antiepileptic/anticonvulsant drugs.
AB  - A large number of drugs can be given parenterally for the control of acute
      seizures, although many of these compounds are associated with serious adverse
      effects. Phenobarbital, the first antiepileptic drug (AED), has long been
      available in an injectable formulation. The sodium salt of phenobarbital is water
      soluble, and its parenteral formulation can be given for maintenance therapy or
      treatment of acute seizures. The introduction of phenytoin in 1938, and its
      subsequent parenteral formulation, represented a significant advance in AED
      therapy owing to its relative absence of sedation. However, the risk of adverse
      effects necessitates that the rate of phenytoin administration usually be limited
      to 50 mg/min. I.v. valproate has been used extensively but has not been approved
      for use in the United States, and its value for treating acute seizures is
      unclear. Several benzodiazepines have been used as adjunctive drugs for the
      treatment of epilepsy; given parenterally, they provide rapid CNS entry and
      prompt control of seizures, but their effect is short lived. Agents that have
      more hypnotic anesthetic properties are often used when the benzodiazepines or
      phenytoin alone or in combination fails.

PMID- 8649614
TI  - Towards understanding the pathogenesis of SLE.

PMID- 8649615
TI  - Induction of interleukin-1 and interleukin-1 receptor antagonist during
      contaminated in-vitro dialysis with whole blood.
AB  - BACKGROUND: Previous studies on the permeability of cellulosic and synthetic
      dialysers for bacterial-derived cytokine-inducing substances gave conflicting
      results. We tried to study this issue as close to the in-vivo situation as
      possible. METHODS: An in-vitro dialysis circuit with whole human blood present in
      the blood compartment of cuprophane (Cup), polysulphone (PS), and polyamide (PA)
      dialysers was employed; sterile filtrates derived from Pseudomonas aeruginosa
      cultures were added to the dialysate. We studied the induction of interleukin-1
      beta (IL-1 beta) by plasma samples taken from the blood compartment as well as
      the induction of IL-1 beta and interleukin-1 receptor antagonist (IL-1Ra) in
      mononuclear cells separated from whole blood after circulation by
      radioimmunoassay and polymerase chain reaction. RESULTS: Plasma samples from the
      blood side of all dialysers induced IL-1 beta from non-circulated mononuclear
      cells after addition of pseudomonas filtrates to the dialysate; the maximal
      amount of IL-1 beta induced by samples from the blood compartment was 4.8 +/- 1.2
      ng/ml for Cup, 1.9 +/- 0.5 ng/ml for PS, and 2.0 +/- 0.6 ng/ml for PA.
      Mononuclear cells separated after contaminated dialysis will all types of
      dialysers expressed increased mRNA levels for IL-1 beta and IL-1Ra. Production of
      IL-1Ra by cells separated after contaminated dialysis was determined after Cup
      and PS dialysis; there was increased production of IL-1Ra by these cells (Cup,
      10.3 +/- 4.2; PS, 7.3 +/- 2.5 ng/ml) compared to cells separated after sterile
      dialysis (Cup, 5.6 +/- 2.1, P < 0.05; PS, 4.5 +/- 1.1 ng/ml, n.s.) or from non
      circulated blood (Cup experiments, 4.7 +/- 1.5, P < 0.05; PS experiments, 4.1 +/-
      1.2 ng/ml, n.s.). CONCLUSIONS: These data suggest penetration of cytokine
      inducing substances through both cellulosic and synthetic dialysers. Differences
      between dialysers may exist regarding extent and time course of penetration. The
      detection of cytokine mRNA as well as the measurement of IL-1Ra synthesis is a
      more sensitive marker for the transfer of cytokine-inducing substances through
      dialyser membranes than the measurement of IL-1 beta protein synthesis.

PMID- 8649616
TI  - Haemodialysis activates phospholipase A2 enzyme.
AB  - BACKGROUND: Clinical and experimental evidence suggest that haemodialysis (HD)
      procedure is an inflammatory process. For the production of proinflammatory lipid
      mediators in many inflammatory reactions, the release of arachidonic acid by
      phospholipase A2 (PLA2) enzyme is a prerequisite. Therefore, the purpose of the
      present investigation was to establish whether the activity of PLA2 increases
      during HD and whether the increase depends on the type of dialyser used. METHODS:
      We performed dialysis in eight chronic HD patients. Blood samples entering and
      leaving the dialyser were obtained before and at 15, 60, 120 and 180 min after
      the dialysis was started, on one occasion using a cuprophane and on another
      occasion a cellulose triacetate dialyser. PLA2 activity was assessed in crude
      plasma and in plasma extract. RESULTS: PLA2 activity in plasma extract exhibited
      similar biochemical properties to that of inflammatory human synovial fluid PLA2
      enzyme which is of group II PLA2. PLA2 activity in crude plasma represents a type
      of PLA2 other than the synovial type. In HD patients, baseline PLA2 activities in
      a crude plasma and plasma extract were significantly increased when compared to
      normal subjects. An increase in PLA2 activity was observed in crude plasma with a
      peak appearing at 15 min when the patients were dialysed with cuprophane and
      cellulose triacetate membranes. This increase was observed in both arterial and
      venous blood samples and was more pronounced when the patients were dialysed with
      cuprophane than with cellulose triacetate membranes. When PLA2 was assessed in
      plasma extract, the activity increased only with cuprophane but not with
      cellulose triacetate membranes. CONCLUSION: PLA2 activity in plasma is increased
      in HD patients and increases during the dialysis procedure to a greater extent
      with a less biocompatible membrane. Continuous activation of PLA2 might be
      relevant for long-term deleterious consequences of HD.

PMID- 8649618
TI  - The nephrotic syndrome: does renal biopsy affect management?

PMID- 8649617
TI  - Complement depletion during haemofiltration with polyacrilonitrile membranes.
AB  - BACKGROUND: Polyacrylonitrile (PAN, AN69) dialysis membranes have been shown to
      improve the outcome of critically ill patients. Factor D is an essential enzyme
      of the alternative pathway of complement and is increased during renal failure.
      On the other hand the contact of blood with biomaterials activates the complement
      cascade through the alternative pathway. PAN filters adsorb factor D which looses
      its enzymatic activity whilst bound to the membrane [1]; the complement
      alternative pathway function of serum exposed to PAN filters is greatly
      diminished and restored after addition of purified factor D [1]. The aim of our
      study was to measure the time course of factor D adsorption and its blood
      concentration during CVVH in critically ill patients with acute renal failure.
      METHODS: We studied seven critically ill patients with ARF before, during and
      after continuous veno-venous haemofiltration (CVVH) with AN69. RESULTS: There was
      a rapid decrease of factor D levels to 62(+/-6%) of the pre-CVVH value during the
      first 2 h, which continued to 51(+/-7.3%) after 12 h; at 24 h there was a slight
      rise to 62 +/- 12%. Sequential use of Polyacrylonitrile (AN69) filters lowered
      factor D levels below the normal plasma concentration in three patients, thus
      producing a state of factor D depletion. CONCLUSION: The significant reduction of
      factor D levels during CVVH with PAN filters suggests that frequent changes of
      PAN filters may reduce alternative pathway function by lowering factor D levels.
      CVVH (as opposed to intermittent dialysis) with PAN membranes may further improve
      the outcome of critically ill patients.

PMID- 8649619
TI  - Helicobacter pylori-specific IgG in chronic haemodialysis patients: relationship
      of hypergastrinaemia to positive serology.
AB  - BACKGROUND: Chronic haemodialysis (HD) patients frequently suffer from dyspeptic
      symptoms and hypergastrinaemia is a common finding in these patients.
      Helicobacter pylori (H. pylori) infection is associated with dyspepsia and
      hypergastrinaemia. METHODS: The aim of this study was to determine whether H.
      pylori is frequently found in HD patients and to explore the relationship of H.
      pylori with dyspeptic symptoms and/or hypergastrinaemia in these patients. Serum
      H. pylori specific IgG were measured by an in-house enzyme-linked immunosorbent
      assay (sensitivity and specificity is 97% and 91% respectively) in 103 chronic HD
      patients. The patients (53 M, 50 F, mean age f60 +/- 13 years) completed a
      questionnaire exploring the type, frequency and intensity of dyspeptic symptoms.
      Fasting plasma gastrin levels were also measured. Serum and plasma samples from
      103 hospital patients matched for age, sex and dyspepsia were use as controls.
      RESULTS: There was no significant difference in terms of serum H. pylori IgG
      between HD patients and controls (0.977 +/- 0.295 vs 1.046 +/- 0.306 OD
      respectively). The prevalence of subjects with positive serology was relatively
      high in both groups, but did not differ between HD patients (73%) and controls
      (78%). Dyspepsia was reported in 72 (70%) cases. There was no relationship
      between presence (and grading) of dyspepsia or type of dyspeptic symptoms and H.
      pylori serology. In the HD group, patients seropositive for H pylori had a
      significantly higher gastrinaemia than those who were seronegative: 598 +/- 413
      ng/ml vs 309 +/- 252 ng/ml (P < 0.0001). The relationship between seropositivity
      for H. pylori and hypergastrinaemia was significant (P = 0.00038), after
      adjustment by multiple regression analysis for sex, age, smoking, alcohol, months
      on dialysis, renal function, drugs, and dyspepsia. CONCLUSIONS: Data of this
      study suggest that H. pylori may play a role in contributing to hypergastrinaemia
      of HD patients.

PMID- 8649620
TI  - Low-dose (5 mg/kg) desferrioxamine treatment in acutely aluminium-intoxicated
      haemodialysis patients using two drug administration schedules.
AB  - BACKGROUND: According to the recommendations proposed at The Consensus Conference
      on Diagnosis and Treatment of Aluminium Overload in End-Stage Renal Failure
      Patients, Paris, 1992 low-dose desferrioxamine (DFO) treatment was applied for
      the first time in 41 acutely aluminium-intoxicated patients. METHODS AND RESULTS:
      DFO-related neurological/ophthalmological side-effects were observed in nine of
      11 patients with a post-DFO serum aluminium level > 300 micrograms/litre and in
      two patients of 30 below this level after a single administration of a 5-mg/kg
      dose of the chelator in the conventional way (i.e. the last hour of a dialysis
      session). They were no longer observed after introducing an alternative DFO
      administration schedule (i.e. administration of the chelator 5 h prior to the
      start of a haemodialysis session; group I: n = 14). A significant decrease in the
      serum aluminium levels as well as in the post-DFO serum aluminium increment
      (delta s A1) was observed during the first 6 months, course of low-dose DFO
      treatment in group I as well as group II (which consisted of patients receiving
      DFO in the conventional way; n = 27). Low-dose DFO treatment was accompanied by a
      significant increase in the mean +/- SD serum iPTH levels (group I: 174 +/- 245
      up to 286 +/- 285 ng/litre; group II: 206 +/- 272 up to 409 +/- 424 ng/litre; P <
      0.005) and the mean corpuscular volume (group I: 80 +/- 6.4 up to 85 +/- 3.7 fL,
      P < 0.005; group II: 76 +/- 5.0 up to 87 +/- 4.3 fL, (P < 0.0001). Serum ferritin
      levels significantly decreased in both groups. No further side-effects were
      observed during the DFO course. Patients in which DFO treatment could be stopped
      (i.e. subjects in which both serum aluminium and delta sA1 were below 50
      micrograms/litre at two successive occasions) before the end of the 6 months'
      treatment course had a significantly greater residual diuresis (700 +/- 682
      ml/min vs 84 +/- 109 ml/24 h). Also, residual diuresis was found to protect
      against aluminium intoxication as reflected by the values noted in group I versus
      those in group II. CONCLUSION: The 5-mg/kg DFO treatment provides a safe and
      adequate therapy for aluminium overload. In severely aluminium-intoxicated
      patients presenting post-DFO serum aluminium levels above 300 micrograms/litre
      DFO should be given once weekly 5 h prior to high-extraction dialysis ensuring
      (i) maximal chelation of aluminium (ii) limited exposure to circulating aluminium
      noxamine levels, and (iii) adequate removal of the latter compound. Finally, the
      necessity for a better communication between the local water distribution
      companies and the dialysis centres is a major lesson that can be drawn from this
      dramatic intoxication.

PMID- 8649621
TI  - Withdrawal of renal replacement therapy in Newcastle upon Tyne: 1964-1993.
AB  - BACKGROUND: Termination of renal replacement therapy (RRT) is common in North
      America and Australia but is considered to be rare in Europe. METHODS: In order
      to review the phenomenon of RRT termination in all patients treated in Newcastle
      upon Tyne between 1964 and 1993 a retrospective study of clinical case notes was
      undertaken. In all RRT patients sex, age at start of RRT, renal diagnosis and
      history of RRT were recorded. In addition, mortality data and marital and
      residential status were recorded in all patients who died, and Karnofsky index,
      bodyweight, complications, history of bereavement, place of death, overall
      survival, survival after withdrawal of treatment, other medical problems, higher
      mental function and surgical history in all patients stopping treatment. RESULTS:
      1639 patients started RRT between 1964 and September 1993 inclusive. Eighty-eight
      patients were identified in whom death was a result of treatment being stopped
      (17% of all deaths). The first was in 1985. In these patients, age was greater
      (62 vs 47 years, P < 0.001) and diabetes was more prevalent (15 vs 7%, P < 0.03)
      than in the total RRT population. The Karnofsky index was 70 at the start and 33
      at withdrawal of treatment (P < 0.001). The Karnofsky index at the start of RRT
      was weakly related to that at withdrawal and overall survival (r = 0.36 and 0.28
      respectively, P < 0.01). The Karnofsky index at treatment withdrawal correlated
      with the following survival (r = 0.40, P < 0.001). The median survival of
      patients stopping treatment was significantly lower than in all RRT patients (16
      vs 74 months, P < 0.001) and the majority survived less than 2 years. After
      dialysis withdrawal the median survival was 8 days, 15 patients survived 3 days
      or less and 19 more than 10 days. The majority (80%) received terminal care in
      hospital. At treatment withdrawal 11 patients were demented and 34 showed signs
      of early dementia. Seventy-eight patients (89%) stopped treatment as a
      consequence of multiple medical problems. The possibility of dialysis withdrawal
      was raised by physicians in 50.5%, the patient in 23.8% and the patients'
      relatives in 21.9% of cases. Four patients (3.8%) committed suicide. CONCLUSIONS:
      Death from dialysis termination is a relatively common cause of death in RRT
      patients in Newcastle upon Tyne. These patients are older with a higher
      prevalence of diabetes. In 89% of cases the decision to stop treatment was
      related to multiple medical problems with a recent deterioration. Physicians
      raised the issue of withdrawal in the majority of cases and most patients
      subsequently received terminal care in hospital.

PMID- 8649622
TI  - Does the modality of haemodialysis treatment affect lipoprotein composition?

PMID- 8649623
TI  - Primary renal graft thrombosis.
AB  - BACKGROUND: Renal allograft thrombosis is a serious complication of kidney
      transplantation that ultimately leads to graft loss. Its association with acute
      and hyperacute rejection is well documented; however, in a large proportion of
      patients the precise cause remains obscure. The exact incidence and the
      associated risk factors for those episodes of graft thrombosis lacking evidence
      of rejection have not yet been clearly established. METHODS: All reported
      episodes of graft thrombosis in 558 consecutive cadaveric kidney transplants
      performed in a single centre were examined to identify those without
      histopathological evidence of rejection, i.e. primary renal graft thrombosis.
      Univariate and multivariate types of analysis were applied to study the possibly
      related risk factors and any associated morbid event(s) of those episodes.
      Recipients without reported episodes of primary renal graft thrombosis (n = 493)
      represented the control group for the 34 identified cases. RESULTS: The
      calculated incidence of primary renal graft thrombosis was 6% (1.9% arterial,
      3.4% venous and 0.7% both), comprising 45% of early (90 days) and 37% of 1-year
      graft losses in our centre. The multivariate analysis identified five independent
      risk factors for primary renal graft thrombosis: donor's right kidney P < 0.007,
      past history of venous thrombosis (renal or extrarenal) P = 0.000, and diabetic
      nephropathy P = 0.000 of the recipient, technical surgical problems P = 0.000,
      and recipient's haemodynamic status peri and early postoperatively P < 0.001.
      Primary renal graft thrombosis was related to the presentation with delayed graft
      function (DGF) P < 0.0005 and was significantly associated with extrarenal
      thromboembolic manifestations P < 0.0005. There was no association between
      primary renal graft thrombosis and recipient's age, sex, number of previous
      transplants, type of dialysis, pretransplant treatment with erythropoietin,
      antiplatelet agents, or oral anticoagulants, donor's age, sex, number or graft
      vessels, warm and cold ischaemia times, site of transplant (R/L iliac fossa) and
      type of immunosuppressive agent used for induction whether cyclosporin A (CsA) or
      OKT3. CONCLUSIONS: Primary renal graft thrombosis is an important cause of graft
      loss that may be accompanied by thrombosis of extrarenal sites and effective,
      safe prophylactic regimens are needed, especially for those at high risk.

PMID- 8649624
TI  - HLA-DR class II and ICAM-1 expression on tubular cells taken by fine-needle
      aspiration biopsy in renal allograft dysfunction.
AB  - BACKGROUND: Percutaneous biopsy is the method of choice for differential
      diagnosis of renal allograft dysfunction, although it is not risk-free. The use
      of less aggressive methods for diagnosis should limit the need for percutaneous
      biopsy to some specific situations. METHODS: We analysed 42 fine-needle
      aspiration biopsies from 36 kidney allograft recipients immunosuppressed with
      quadruple sequential therapy who suffered renal allograft dysfunction. Seven
      cases with stable renal function were used as controls and included as non
      rejection cases in the analysis. In all aspirates the Corrected Increment was
      calculated and an immunocytochemical analysis of renal tubular cells with the
      monoclonal antibodies HLA-DR and ICAM-1 was performed. RESULTS: The Corrected
      Increment was increased in 13 out of 18 acute rejection cases and in one out of
      31 non-rejection cases. HLA-DR expression was found in more than 30% of tubular
      cells from the aspirates in 16 out of 18 acute rejection cases and in eight out
      of 31 cases without rejection (P < 0.001). ICAM-1 expression was detected in more
      than 30% of tubular cells in 14 out of 18 cases with acute rejection, and in four
      out of 31 cases without acute rejection (P < 0.001). Interestingly, all acute
      vascular rejection cases (n = 6), and six out of 12 acute cellular rejection
      cases expressed both, HLA-DR and ICAM-1, in more than 30% of tubular cells. On
      the other hand, none of the non-rejection allograft dysfunctions or control
      samples showed more than 30% of tubular cells immunostained with both HLA-DR and
      ICAM-1 antibodies. CONCLUSIONS: The immunocytochemical analysis of HLA-DR and
      ICAM-1 on renal tubular cells taken by fine-needle aspiration biopsy, allows the
      diagnosis of acute cellular rejection and acute vascular rejection even when the
      Corrected Increment is not increased. Moreover, the risk of a core renal biopsy
      can be avoided when both tests are negative since an acute rejection is a remote
      possibility.

PMID- 8649625
TI  - Hyperuricaemia in cyclosporin-treated patients: GFR-related effect.
AB  - BACKGROUND: Hyperuricaemia is a well known side-effect of cyclosporin A (CsA)
      treatment. The pathogenic mechanisms, however, remain controversial. There is no
      convincing evidence that hyperuricaemia is due to CsA-induced, impaired tubular
      handling of uric acid. The impact of diminished GFR in this particular context
      has never been investigated. METHODS: We prospectively studied plasma uric acid,
      inulin clearances, and fractional clearances of uric acid in two groups of CsA
      treated patients (bone-marrow transplant patients, n = 50; renal transplant
      patients, n = 32), and one healthy control group without CsA (living related
      kidney donors, n = 28). Bone-marrow transplant patients were examined before
      transplantation and 6, 12, 18, 24 months after transplantation, renal transplant
      patients 1 year after transplantation, and living related kidney donors before
      and 1 year after unilateral nephrectomy. RESULTS: After 1 year of CsA treatment,
      hyperuricaemia was found in 36% of bone-marrow transplant patients and in 53% of
      renal transplant patients. Thirty per cent of living related kidney donors were
      borderline hyperuricaemic 1 year after unilateral nephrectomy. The fractional
      clearance of uric acid, measured serially in bone-marrow transplant patients did
      not change significantly over time; it was, however, slightly higher during CsA
      treatment than after CsA withdrawal. Moreover, the bone-marrow transplant
      patients' fractional clearance of uric acid was not statistically different from
      the renal transplant patients' and the living related kidney donors' (values 1
      year after transplantation/unilateral nephrectomy: bone-marrow transplant
      patients, 15.3 +/- 2.3%; renal transplant patients, 11.9 +/- 0.9%; living related
      kidney donors, 11.1 +/- 0.8%). The GFR at 1 year measured by inulin clearance,
      was identical in the CsA-treated groups and slightly higher in the living related
      kidney donors (bone-marrow transplant patients, 51 +/- 6 ml/min per 1.73 m2;
      renal transplant patients, 49 +/- 3 ml/min per 1.73 m2; living related kidney
      donors, 61 +/- 2 ml/min per 1.73 m2). CONCLUSION: There is no evidence for
      impaired tubular handling of uric acid, induced by a CsA-specific tubulotoxic
      effect. Hyperuricaemia in CsA-treated transplant patients can therefore be
      attributed to the cyclosporin-associated decrease of GFR.

PMID- 8649626
TI  - Virological and histological features of hepatitis C virus (HCV) infection in
      kidney transplant recipients.
AB  - BACKGROUND: Although there are some reports regarding prevalence of anti-HCV
      antibodies in kidney transplant patients, there are scarce data about viraemia,
      genotyping and liver histology of HCV infection in kidney transplant recipients.
      METHODS: We studied the prevalence of anti-HCV antibodies by second-generation
      screening and confirmatory assays in a cohort of 73 renal allograft recipients.
      All patients were tested for serum HCV RNA using reverse transcription polymerase
      chain reaction in the 5'-untranslated region (UTR) of the viral genome. HCV RNA
      positive patients were subjected to genotype analysis using biotinylated type
      specific oligonucleotide probes after hybridization with amplified sample
      material. Eleven of 73 patients showing raised aminotransferase levels underwent
      hepatic biopsy. RESULTS: Fifteen of 73 (20%) patients were determined anti-HCV
      positive. Eleven of 73 (15%) showed detectable serum HCV RNA; no viraemic,
      seronegative patients were identified. Genotyping showed that HCV subtype 2a was
      dominant (64%), followed by HCV subtypes 1b (27%) and 1a (9%). Six of 11 (54%)
      HCV RNA patients and 12 of 62 (19%) HCV RNA negative patients showed raised
      aminotransferase levels (P = 0.03). Liver biopsies showed histological features
      of chronic hepatitis with mild or moderate degrees of activity. CONCLUSIONS: The
      prevalence of anti-HCV antibodies and HCV viraemia was 20% and 15% respectively;
      there was a good association between anti-HCV anti-bodies and HCV viraemia;
      hepatic enzyme levels were good indicators of ongoing HCV infection; HCV subtype
      2a was prevalent; liver histology showed histological characteristics of chronic
      hepatitis with mild or moderate degrees of activity.

PMID- 8649627
TI  - Parathyroid gland function and the set point for PTH release: understanding the
      available data.

PMID- 8649628
TI  - Substitution of conventional cyclosporin with a new microemulsion formulation in
      renal transplant patients: results after 1 year.
AB  - BACKGROUND: A new galenic form of cyclosporin A has been developed, based on
      microemulsion technology. The bioavailability of the compound is relatively
      independent of food intake and bile flow. It was the purpose of this prospective
      clinical trial to study the safety of the microemulsion form of cyclosporin A.
      METHODS: Three hundred and two renal transplant patients, stratified according to
      transplant age, were switched from the conventional to the new microemulsion
      formulation of cyclosporin A. A 1:1 conversion ration was used. Measurements
      included CsA levels, S-creatinine, liver enzymes, uric acid, and blood pressure.
      Measurements were performed at baseline and on days 4, 8, 15, 29 and months 3, 6
      and 12 after conversion. Dose adjustments were performed to achieve through
      levels of 80-120 ng/ml. RESULTS: Within the 12-month observation period the
      cyclosporin dose was reduced by 14.7% (from 204 +/- 60 mg/day at baseline to 174
      +/- 51 mg/day after conversion, P < 0.001). Acutely, i.e. by day 8, 1:1 dose
      conversion resulted in a modest increase of mean drug through levels (from 114
      ng/ml at baseline to 120 ng/ml, P < 0.01). This increase was accompanied by an
      increase in serum creatinine concentration, a decrease in calculated creatinine
      clearance, and an increase in uric acid values (P < or = 0.05). Liver enzymes
      remained unchanged while systolic and mean arterial blood pressure decrease (P <
      0.05). After 1 month, drug through levels had decreased to baseline (112 ng/ml)
      and remained there until month 6. They were significantly lower after 12 months
      (102 +/- 33 ng/ml), P <0.001). Creatinine clearance values increased to above
      baseline at 6 and 12 months. Within the 1-year period there occurred 24 (= 8%)
      episodes of biopsy proven rejection and seven episodes of cyclosporin-attributed
      nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A
      to the microemulsion formulation s efficacious and safe, but an initial dose
      reduction of 10% is advised in patients with through levels in the high-normal
      range.

PMID- 8649629
TI  - Effect of desmopressin substitution during organ procurement on early renal
      allograft function.
AB  - BACKGROUND: As diabetes insipidus in brain-dead organ donors leads to
      hypovolaemia, hyponatraemia, and hypotension, desmopressin is recommended for
      treatment of diabetes insipidus. As its effect on early renal allograft function
      remains unclear, we conducted a study to evaluate the effect of desmopressin on
      renal-graft survival. METHODS: We report the results of a prospective study in 41
      brain-dead organ donors (mean age 45 +/- 12 years) with diabetes insipidus, who
      were treated either with adequate fluid substitution and bolus application of
      desmopressin (desmopressin group; n = 22) or with volume substitution along
      (control group; n = 19). Donors as well as recipients of both groups were well
      matched with respect to age, sex, dopamine dosage, serum electrolytes, cold
      ischaemic time, HLA match, number of prior transplantations, and current
      cytotoxic antibodies. Early renal allograft function was evaluated in 71
      recipients (mean age 48 +/- 4 years within 3 days after transplantation. RESULTS:
      Overall, primary non-function was observed in 26 (36.6%) of 71 recipients. The
      rate of primary non-function was significantly higher in the desmopressin group
      compared to the control group (desmopressin group 48.6%; control group 23.5%; P =
      0.28). CONCLUSION: The use of desmopressin during organ procurement is associated
      with a higher rate of primary non-function of renal allografts.

PMID- 8649630
TI  - Erythropoietin deficiency and relative resistance cause anaemia in post-renal
      transplant recipients with normal renal function.
AB  - BACKGROUND: Following successful renal transplantation, blood erythropoietin
      (Epo) levels peak in two phases during the first 2-3 months, and blood
      haemoglobin/haematocrit (HB/Hct) levels are restored to normal in a period of 2-6
      months. However, some transplant recipients continue to remain anaemic in spite
      of normal graft function and in the absence of recognizable causes. The role of
      endogenous Epo production in the causation of anaemia in such patients is poorly
      understood and has been investigated in this study. METHODS: Twenty-three post
      renal transplant recipients with stable normal renal function were studied.
      Eleven of these patients had normal HB/Hct levels (group 1) and served as control
      for the rest 12 patients with anaemia (group 2). Patients included in group 2 had
      no readily recognizable cause for their anaemia. Other laboratory and clinical
      findings were similar in both groups. Patients with erythrocytosis were excluded.
      Serum Epo levels were measured in all patients. Five patients in group 2 were
      treated with recombinant human erythropoietin (rHuEpo) and their erythropoietic
      response was assessed. rHuEpo was discontinued when the target Hb/Hct levels
      (lowest normal range) were achieved and the patients were followed up for a
      further period of 9-12 months. RESULTS: Five patients in group 1 had normal
      expected serum Epo levels whereas the other six patients had inappropriately high
      serum Epo levels with respect to their Hb/Hct status suggestive of relative ?EPO
      resistance'. Serum Epo levels in all patients except two in group 2 were low
      indicative of 'Epo deficiency'. The two exceptional patients in group 2 had
      higher serum Epo levels in the presence of anaemia suggestive of relative ?Epo
      resistance'. All five patients treated with rHUEpo responded adequately by
      achieving normal Hb/Hct levels. Three of them were originally ?Epo deficient' and
      they reached target Hb/Hct levels in a mean period of 4 weeks, requiring a mean
      cumulative rHuEpo dose of 428.3 units/kg. The other two patients with higher
      initial serum Epo levels, and considered to be ?Epo resistant' required an
      average of 11 weeks of treatment and a mean cumulative rHuEpo dose of 1582.5
      units/kg, indicating an increased Epo demand. On cessation of therapy the Hb/Hct
      levels fell in all five patients to pretreatment values in 6 months. CONCLUSIONS:
      There are important variations in the endogenous Epo production in renal
      transplant patients with normal renal function, the cause of which is not clear.
      Epo deficiency and relative Epo resistance play a causative role for anaemia in
      some post-renal transplant recipients with stable normal renal function. They
      respond adequately to rHuEpo administration.

PMID- 8649631
TI  - Effect of sulphated glycosaminoglycans on albuminuria in patients with overt
      diabetic (type 1) nephropathy.
AB  - Decreased expression of heparan sulphate has been shown in the glomerular
      basement membrane of patients with over diabetic nephropathy. Low- molecular
      weight heparin (LMWH) is a highly sulphated glycosaminoglycan with strong
      structural and functional similarities to heparan sulphate. In a first study, we
      set out to assess if LMWH could decrease the urinary albumin excretion rate (AER)
      in diabetic patients with over nephropathy. Six patients entered a randomized,
      double-blind, placebo-controlled crossover study with treatment episodes of 1
      month, separated by a 1-month wash-out. Patients self-administered prefilled
      syringes with either placebo or LMWH (enoxaparin 40 mg/0.4 ml) at bedtime.
      Baseline AER levels before either treatment period were similar. In contrast to
      placebo, AER significantly decreased from 447 (181-1102) to 295 (100-873)
      micrograms/min after 1 month treatment with LMWH (P < 0.05). Compared to placebo,
      the effect of LMWH did not reach statistical significance in these six patients
      after 1 month treatment (P = 0.16). Haemodynamic variables including glomerular
      filtration rate and filtration fraction did not change during enoxaparin
      treatment. We observed a favourable effect on AER during LMWH treatment in
      diabetic patients with over nephropathy. These data suggest that long-term
      treatment trials in a larger group of patients may potentially demonstrate a new
      therapeutic option for patients with over diabetic nephropathy.

PMID- 8649632
TI  - The effect of rhubarb extract on experimental renal fibrosis.
AB  - In order to explore the therapeutic potential of traditional Chinese medicinal
      herbs on the progression of experimental chronic renal failure (CRF), we have
      studied the effect of orally administered rhubarb extract on the course of CRF in
      rats submitted to subtotal nephrectomy (SNx). Adult male Wistar rats were
      submitted to either a SNx (n = 18) or a sham operation (n = 10). Thirty days
      after SNx, nine SNx and five sham operated rats were given aqueous rhubarb roots
      extract (150 mg/day) in drinking water. The rats were followed up for 120 days.
      Rhubarb treatment had no effect on the systemic hypertension observed in SNx
      rats. Rhubarb-tested SNx rats had significantly less proteinuria 90 days (172 +/-
      63 mg/24 h) and 120 days (228 +/- 92 mg/24 h) after SNx when compared to
      untreated SNx controls (day 90, 246 +/- 80 mg/24 h; day 120, 335 +/- 113 mg/24 h,
      P < 0.05). Renal function was comparable in rhubarb-treated and untreated SNx
      rats. However, at sacrifice the severity of glomerulosclerosis was significantly
      reduced in SNx rats treated with rhubarb (2.03 +/- 0.44; SNx controls, 2.58 +/-
      0.53, P < 0.05). The difference in tubulointerstitial scarring between the two
      groups did not reach significance. Our results suggest that rhubarb extract
      reduces proteinuria and the severity of glomerulosclerosis in rats with remnant
      kidneys.

PMID- 8649633
TI  - Cyclosporin as microemulsion--is it a new drug?

PMID- 8649634
TI  - Intracutaneous versus intramuscular hepatitis B vaccination in primary non
      responding haemodialysis patients.
AB  - OBJECTIVE: To determine whether hepatitis B vaccination given intracutaneously
      (i.c.) is more effective than intramuscularly (i.m.) in primary non-responding
      haemodialysis patients. DESIGN: A prospective, randomized study of antibody
      responses to hepatitis B vaccine given i.c. or i.m., in 25 haemodialysis
      patients. Outcome measures were rates of seroconversion, mean and geometric mean
      levels of antibody achieved, and antibody levels 1 year after vaccination.
      RESULTS: With a dosing schedule of 10 micrograms vaccine once a week i.c. in the
      skin overlying the deltoideus muscle of the non-dominant arm during 12
      consecutive weeks, antibody levels to hepatitis B surface antigen (anti-HBsAg) of
      10 IU/1 or more were achieved in nine of 10 evaluable patients, with a geometric
      mean of 70 IU/1. Nine months after the end of the vaccination anti-HBsAg levels
      had dropped to 9 +/- 4 IU/1 (M +/- SE), with a geometric mean of 5 IU/1, in the
      nine remaining evaluable patients. With a dosing schedule of 40 micrograms
      vaccine i.m. in the deltoideus muscle of the non-dominant arm at 0, 1, and 3
      months, anti-HBsAg levels of at least 10 IU/1 were achieved in eight of 14
      evaluable patients, with a geometric mean of 94 IU/1. Nine months after the end
      of the vaccination anti-HBsAG levels had dropped to 16 +/- 7 IU/1, with a
      geometric mean of 9 IU/1, in the nine remaining evaluable patients. Anti-HBsAg
      levels at 8 and 12 weeks were higher in the i.c. than in the group receiving
      vaccine i.m. (at 8 weeks 134 +/- 76 vs 39 +/- 20 IU/1, P < 0.05, and at 12 weeks
      188 +/- 98 vs 47 +/- 18 IU/1 P < 0.01). The half-time of anti-HBsAg is about 13
      weeks, both when the averaged absolute and when the geometric mean levels are
      used for the estimate. CONCLUSION: intracutaneous route is a less practical but
      effective method of vaccination against hepatitis B in primary non-responding
      haemodialysis patients. The weekly 10 micrograms vaccine i.c. scheme resulted in
      the fastest development of protective antibody levels, within 8 weeks, which may
      be useful in previously non-immune persons who may be infected with hepatitis B
      virus (e.g. needle-stick accidents).

PMID- 8649635
TI  - Acute nephritis by Aspergillus in a patient with AIDS.

PMID- 8649636
TI  - Relapsing pyrogenic reactions due to Xanthomonas maltophilia in a dialysis
      patient with a long-term central venous catheter.

PMID- 8649637
TI  - Haemophilus influenzae: a cause of peritonitis in peritoneal dialysis.

PMID- 8649638
TI  - Rhodococcus peritonitis in continuous ambulatory peritoneal dialysis.

PMID- 8649639
TI  - View from across the Atlantic. America struggles with health care reform.

PMID- 8649640
TI  - Treatment of primary graft dysfunction after kidney transplantation by renal
      artery stent.

PMID- 8649641
TI  - Is there a rationale to combine cyclosporin and sirolimus?

PMID- 8649642
TI  - Ocular complications of type 2 membranoproliferative glomerulonephritis.

PMID- 8649643
TI  - Nitric oxide synthases: regulation in disease.

PMID- 8649644
TI  - Acute renal failure associated with foscarnet therapy.

PMID- 8649645
TI  - Control of severe hyperparathyroidism and regression of a brown tumour after
      treatment with i.v. alfacalcidol in a uraemic patient.

PMID- 8649647
TI  - Simplified approaches to calculate Kt/V. It's time for agreement.

PMID- 8649646
TI  - Successful treatment of Kaposi's sarcoma in a renal allograft recipient.

PMID- 8649648
TI  - Renal failure and transplantation activity in the Arab world. Arab Society of
      Nephrology and Renal Transplantation.

PMID- 8649649
TI  - Nephrology in South Africa.

PMID- 8649650
TI  - Effect of antiproteolytic drugs: epsilon-aminocaproic acid (EACA) and aprotinin
      on experimental anti-GBM nephritis.
AB  - BACKGROUND: Given the evidence accrued by other authors on beneficial effect of
      protease inhibitors on experimental immune nephritis, and following our
      preliminary report on abrogation of immune glomerulopathy in the rat by
      antifibrinolytic and antiproteolytic drug, epsilon-aminocaproic acid (EACA), we
      investigated the effect of this drug on the rat autologous anti-GBM nephritis.
      Along with the EACA we evaluated another protease inhibitor, aprotinin, an
      antagonist of serine proteases. METHODS: EACA (0.3g/kg) or aprotinin (5000
      kallkrein inhibition units, KIU/kg) was administered intraperitoneally (t.i.d.)
      from day 0 (preventive protocol) or day 3 (therapeutic protocol) of autologous
      anti-GBM nephritis induced in Wistar rats. Proteinuria, creatinine clearance and
      renal histopathology were assessed as markers of disease activity, while
      glomerular fibrin deposits (immunoperoxidase staining) and standard parameters of
      coagulation/fibrinolysis of peripheral blood enabled insight into local and
      systemic haemostatic mechanisms. Glomerular binding of anti-GBM antibodies
      (immunofluorescence) and serum titres of autologus nephrotoxic antibodies
      (haemagglutination assay) represented conditions of immune induction of
      glomerulopathy. RESULTS: Our experiments indicated that EACA, and to a lesser
      extent also aprotinin, are capable of preventing proteinuria (EACA, reduction by
      57.6%; aprotinin, reduction by 26.8%, compared to untreated nephritic rats, day 3
      post-induction) and glomerular histopathological changes, without affecting
      endogenous creatinine clearance, otherwise depressed in this model of
      glomerulonephritis. More importantly, both drugs significantly ameliorated
      glomerular lesions and proteinuria, even when the treatment was initiated on day
      3 post-induction, after the injury has begun (EACA reduced proteinuria by 32.0%,
      and aprotinin reduced it by 20.9% day 7). Administration of EACA and aprotinin at
      doses reducing glomerular injury did not cause appreciable fibrin deposition in
      glomeruli of nephritic rats, nor did it modify parameters of systemic coagulation
      and fibrinolysis in these animals, EACA and aprotinin did not interfere with
      serum titres of nephrotoxic antibody, nor with the intensity of its binding to
      the glomerular basement membrane in vivo. CONCLUSIONS: Antiproteolytic drugs
      utilized in our studies exert their beneficial effect on autologous anti-GBM
      nephritis through interference with inflammatory phase of the disease, while
      sparing its immune induction and mechanisms of coagulation/fibrinolysis.

PMID- 8649651
TI  - Angiotensin-converting enzyme inhibition in experimental in-situ immune complex
      glomerulonephritis: influence on renal function, proteinuria, and morphology.
AB  - BACKGROUND: Converting enzyme inhibition (CEI) ameliorates progressive loss of
      function in non-immune-mediated renal diseases and experimental hypertension.
      Little, however, is known on the potential role of CEI in established
      experimental chronic glomerular immune injury. We therefore studied the effect of
      the CEI ramipril on renal function and morphology in a model of immune mediated
      glomerular injury. METHODS: The immune complex glomerulonephritis was induced in
      uninephrectomized rats by intrarenal perfusion with the cationized antigen
      followed by an intravenous application of the antibody. This disease is
      characterized by the development of progressive albuminuria and a nephrotic
      syndrome (albuminuria: immune complex glomerulonephritis 342 +/- 58, control 76
      +/- 18 mg/24h; P < 0.001). The CEI by ramipril, dissolved in the drinking water,
      was given 28 weeks after induction of the disease and treatment was continued for
      12 weeks. RESULTS: In these experiments ramipril significantly reduced albumin
      excretion (immune complex glomerulonephritis + CEI 109 +/- 16 mg/24h; P < 0.01)
      when compared with untreated nephritic rats. Ramipril, however, did not
      significantly change inulin clearances (immune complex glomerulonephritis 224 +/-
      67, immune complex glomerulonephritis + CEI 278 +/- 48 microliters/min/100 g bw).
      Glomerular structural damage expressed as glomerular damage index was
      significantly greater in rats with immune complex glomerulonephritis when
      compared with controls (immune complex glomerulonephritis 0.91 +/- 0.13; control
      0.60 +/- 0.08; P < 0.05), but was uneffected by the treatment with the CEI
      (immune complex) glomerulonephritis + CEI 1.02 +/- 0.26; control + CEI 0.63 +/-
      0.11). CONCLUSIONS: These data demonstrate that ramipril reduced albuminuria in a
      model of immune complex glomerulonephritis; however, it failed to alter GFR and
      glomerular damage index. The study suggests that ramipril ameliorates proteinuria
      independently of obvious glomerular histological changes. The reduction of
      proteinuria is, however, associated with a significant decrease in filtration
      fraction and therefore is at least partially haemodynamically mediated.

PMID- 8649652
TI  - Stimulatory effect of insulin on tubular sodium reabsorption in normotensive
      subjects with a positive family history of hypertension.
AB  - BACKGROUND: Insulin resistance and hyperinsulinaemia has been suggested as a
      pathogenetic mechanism in hypertension. METHODS: In this investigation the renal
      response to insulin was studied in normotensive subjects with a positive family
      history of hypertension in two generations (n = 14), in one weight-matched (n =
      11) and one lean (n = 13) control group. During hyperinsulinaemia (euglycaemic
      hyperinsulinaemic clamp technique) we determined renal haemodynamics (clearances
      of 51Cr-EDTA and PAH) and urinary sodium excretion. Lithium clearance was used to
      estimate the segmental tubular reabsorption of sodium. RESULTS: In subjects with
      a positive family history of hypertension, hyperinsulinaemia did not influence
      renal plasma flow (RPF) or glomerular filtration rate (GFR) but urinary sodium
      excretion decreased by 50%. Estimated proximal tubular sodium reabsorption was
      unaffected by insulin while estimated distal fractional sodium reabsorption
      increased, P < 0.01. At the end of the clamp a low-dose infusion of angiotensin
      II (0.1 ng/kg per min) was superimposed. GFR and RPF then decreased significantly
      concomitant with urinary excretion of sodium. In control subjects
      hyperinsulinaemia caused an unchanged GFR in both groups, increased RPF in the
      lean control group and 15-25% reduction in sodium excretion. No alteration was
      seen in estimated proximal tubular sodium reabsorption, but estimated distal
      tubular sodium reabsorption increased (P < 0.05) in the lean control group.
      Angiotensin II elicited a further increase in distal fractional tubular sodium
      reabsorption in both groups (P < 0.05). CONCLUSION: In normotensive subjects with
      a positive family history of hypertension, in contrast to control subjects
      without such history, hyperinsulinaemia caused a marked decrease in urinary
      sodium excretion in presence of unchanged RPF and GFR indicating a renal tubular
      effect of insulin located at distal site of the renal tubules. Angiotensin II
      caused further sodium retention, probably due to an effect on renal
      haemodynamics.

PMID- 8649653
TI  - Cisplatin nephrotoxicity and protection by silibinin.
AB  - BACKGROUND: The anticancer drug cisplatin is know to have toxic side-effects on
      different segments of the nephron. The flavonoid silibinin has previously been
      shown to be protective in models of hepatotoxicity. The aim of the present study
      was to evaluate, whether silibinin can also ameliorate alterations in renal
      glomerular and tubular function and tubular morphology induced by cisplatin.
      METHODS: In a rat model renal damage was induced by a single injection of
      cisplatin (5 mg/kg body weight). The protective effects of silibinin were studied
      in rats that received the flavonoid (200 mg/kg body weight, i.v.) 1 h prior to
      the administration of cisplatin. Kidney function was monitored by analysing
      urinary markers of glomerular and tubular function over a period of 11 days.
      Animals of a second group, with identical treatment, were sacrificed 4 days after
      drug application for an evaluation of tubular morphology at the light
      microscopical level. RESULTS: Administration of cisplatin caused a decline in
      kidney function within a day following treatment. Symptoms observed were for
      example decreases in creatinine clearance and increases in proteinuria, in the
      urinary activity of the proximal tubular enzymes alanine aminopeptidase and N
      acetyl-beta-D-glucosaminidase and in renal magnesium wasting. The effects of
      cisplatin on creatinine clearance and proteinuria were totally prevented by a
      pretreatment of the animals with silibinin. Impairment of proximal tubular
      function was ameliorated, that is enzymuria and magnesium wasting was less
      pronounced. Silibinin alone had no effect on kidney function. Treatment with
      silibinin distinctly diminished morphological alterations observed in the S3
      segment of the proximal tubule 4 days after cisplatin administration. CONCLUSION:
      The effects of cisplatin on glomerular and proximal tubular function as well as
      proximal tubular morphology could totally or partly be ameliorated by silibinin.
      It is concluded the silibinin can act as a nephroprotectant and it is suggested
      that it could have beneficial effects on the kidney in clinical settings.

PMID- 8649654
TI  - Abnormal lipid and apolipoprotein composition of major lipoprotein density
      classes in patients with chronic renal failure.
AB  - BACKGROUND AND METHODS: To characterize the abnormalities of lipoprotein
      composition in patients with chronic renal failure (CRF), the lipid and
      apolipoprotein (apo) concentrations and compositions of major lipoprotein density
      classes were determined in 20 subjects with moderate to advanced renal failure
      (GFR 5-59 ml/min) and nine controls. Patients were divided in 14
      normotriglyceridaemic (NTG) subjects with triglyceride (TG) levels < or = 1.7
      mmol/l (150 mg/dl) and six hypertriglyceridaemic (HTG) subjects with TG > or =
      1.7 mmol/l. Lipoproteins were isolated by preparative ultracentrifugation: very
      low density (VLDL), intermediate density (IDL), low density (LDL) and high
      density (HDL) lipoproteins. RESULTS: Although all density classes were
      characterized by abnormal concentration and composition of some lipid and apo
      constituents, the most profound changes occurred in IDL and HDL. Cholesterol
      levels were elevated in VLDL and IDL with little change in LDL and reduced in
      HDL. TG levels were increased in all density classes. ApoB levels were increased
      in VLDL, IDL and LDL of all CRF patients reaching the significance levels in VLDL
      and IDL of HTG (P < 0.01). In IDL, the levels of apoC-peptides and apoE were
      increased (P < 0.01). ApoC-peptides and apo E were also elevated in VLDL of NTG
      and HTG, but their increase was only significant in HTG (P < 0.01). In LDL, the
      concentration of apoC-II and apoC-III was significantly increased (P < 0.05).
      However, in HDL there was significant (P < 0.01) reduction of apoA-I, apoA-II and
      apoC-peptides in both patient groups. The major compositional change was a
      significant increase in the relative contents of apoC-II and apoC-III in VLDL,
      IDL and LDL (P < 0.01). CONCLUSIONS: Results indicate that the characteristic
      feature of dyslipoproteinemia in CRF is the accumulation of partially delipidized
      TG-rich apoB-containing lipoproteins enriched in apoC-peptides and distributed
      characteristically in the IDL density-range irrespective of fasting TG
      concentrations. Increased levels of these ?remnant lipoproteins' and reduced
      levels of HDL may represent risk factors for atherogenesis and progressive renal
      disease.

PMID- 8649655
TI  - Effect of calcium-channel blockers on calcium-phosphate metabolism in patients
      with end-stage renal disease.
AB  - BACKGROUND: After EDTA-induced hypocalcaemia, healthy volunteers treated with
      diltiazem display more severe hyperparathyroidism than subjects on felodipine
      studied under identical conditions. Therefore patients with end-stage renal
      disease (ESRD) and severe secondary hyperparathyroidism might be particularly
      sensitive to this side-effect. METHODS: To test this hypothesis, seven patients
      with ESRD on chronic haemodialysis (3 women and 4 men) with serum levels of
      intact PTH ranging from 204 to 675 pg/ml were studied both before and during the
      first 180 min of haemodialysis against a dialysate with low calcium concentration
      (0.75 mmol/l, n = 6 and 1 mmol/l, n = 1) under the following three experimental
      conditions: control, felodipine (10 mg/day) and diltiazem (120 mg b.i.d.).
      RESULTS: At onset of dialysis, plasma phosphorus level was higher on diltiazem
      (2.03 +/- 0.08 mM) than on felodipine (1.64 +/- 0.10, P < 0.02), and on the
      latter it was lower than in control condition (1.88 +/- 0.16, P < 0.02). As a
      probable consequence, blood ionized calcium concentration was lower on diltiazem
      (1.14 mM +/- 0.02, mean +/- SEM) than on felodipine (1.2 +/- 0.03, P < 0.05) or
      in control condition (1.17 +/- 0.01, NS). There was a trend for intact PTH to be
      higher on diltiazem (324 +/- 47 pg/ml) than on felodipine (246 +/- 55) or in
      control condition (305 +/- 49) and 1,25-dihydroxyvitamin D was higher indeed on
      diltiazem (6.70 +/- 0.92 pg/ml) than on felodipine (4.75 +/- 0.91, P < 0.02) or
      control (3.87 +/- 0.62, P < 0.05). Area under the curve PTH over the first 60 min
      of dialysis was higher by 16 +/- 7% on diltiazem than on felodipine (P < 0.05).
      CONCLUSIONS: While on diltiazem rather than on felodipine, patients with ESRD
      display higher plasma phosphorus levels, and slightly aggravate the degree of
      severity of hyperparathyroidism recorded during haemodialysis against low-calcium
      dialysate. The long-term effect of this new observation remains to be evaluated.

PMID- 8649656
TI  - Assessment of total body water in paediatric patients on dialysis.
AB  - BACKGROUND: Various anthropometric techniques are used to assess total body water
      in children on dialysis; however, their predictive accuracy and precision has not
      been validated. METHODS: We compared total body water measurements obtained by
      deuterium oxide (D2O) dilution with predictions of total body water from (1)
      height and weight, (2) skinfold measurements, and (3) bioelectrical impedance
      analysis, using previously published formulae for healthy children. Measurements
      were performed in 14 patients on peritoneal and in nine patients on
      haemodialysis, aged 4-22 years. RESULTS: In the total population of dialysed
      patients, weight was the strongest single predictor of total body water (R2 =
      0.93), followed by the resistance index (RI = height2/impedance; R2 = 0.85) and
      height (R2 = 0.93). A prediction formula based on height and weight predicted
      total body water with a residual mean square error (RMSE) of 1.97 1 (coefficient
      of variation (CV) = 10.0%) and with a systematic overestimation of true total
      body water by 0.4%. A prediction equation based on skinfold measurements yielded
      a total body water estimate with an RMSE of 2.15 1 (CV = 10.5%) and overpredicted
      true total body water by an average of 2.2%. Using three published prediction
      equations incorporating RI, RMSEs of 2.78 1 (CV = 14.1%) with a mean under- or
      overestimation of true total body water by 6.9, 7.1, and 0.8% respectively, were
      achieved. The prediction of total body water was optimized by linear combinations
      of RI or the log-transformed sum of four skinfolds (logsum) with weight by the
      following equations: total body water (1) = 9.97 - 3.13 x logsum (1) +0.59 x
      weight (kg) (R2 = 0.951; RMSE = 1.67 1; CV = 8.17%). total body water (1) = 1.99
      + 0.144 x RI (Ohm/cm2) (2) + 0.40 x weight (kg) (R2 = 0.949; RMSE = 1.67 1; CV =
      8.53%). The fit of these prediction formulae, which were derived from the total
      population, did not differ significantly between haemo- and peritoneal dialysis
      patients or between boys and girls. CONCLUSIONS: Both skinfold measurements and
      bioelectrical impedance analysis can be used to improve the height- and weight
      based prediction of total body water in children on dialysis.

PMID- 8649657
TI  - Different effects of calcitriol and parathyroidectomy on the PTH-calcium curve in
      dialysis patients with severe hyperparathyroidism.
AB  - BACKGROUND: The PTH-calcium sigmoidal curve is shifted to the right, the slope of
      the curve is steeper, and the set point of calcium is increased in dialysis
      patients with secondary hyperparathyroidism, compared to patients with low
      turnover bone disease. These findings could be related to increased parathyroid
      cell mass and increased sensitivity of parathyroid cells to serum calcium
      variations in these patients. Calcitriol therapy has been documented to reduce
      PTH levels by shifting the curve to the left and downward. The effect of a
      surgical reduction of parathyroid gland mass on the PTH-calcium curve has not yet
      been investigated. In this study we compared the effects of calcitriol and
      subtotal parathyroidectomy (PTH) on the dynamics of PTH secretion in response to
      acute changes of serum calcium in two groups of dialysis patients with severe
      hyperparathyroidism. METHODS: Fourteen dialysis patients treated for 6 months
      with high-dose i.v. calcitriol (1-2 micrograms thrice weekly, and 10 dialysis
      patients who underwent subtotal PTx were studied. The PTH-calcium relationship
      obtained by inducing hypo- and hypercalcaemia means of low and high calcium
      dialysis was evaluated before and 2-6 months after treatment. RESULTS: Both
      calcitriol and subtotal PTx significantly decreased PTH (respectively from 797 +/
      595 to 380 +/- 244 and from 1036 +/- 250 to 70 +/- 34 pg/ml), as well as maximal
      PTH response to hypocalcaemia (PTHmax), and maximal PTH suppression during
      hypercalcaemia ( PTHmin). When the PTH-calcium curves were constructed using
      PTHmax as 100% to factor for differences in absolute PTH levels and to provide an
      assessment of individual parathyroid cell function, a shift of the sigmoidal
      curve to the left and downward, and a significant decrease in the set point of
      ionized calcium (from 1.31 +/- 0.05 to 1.26 +/- 0.05 and from 1.36 +/- 0.09 to
      1.22 +/- 0.07 mmol/l) was documented with both treatments. However, the slope of
      the PTH-calcium curve increased after subtotal PTx indicating that the
      sensitivity of the parathyroid cell to serum calcium changes increased with PTx,
      while on the contrary it decreased with calcitriol. CONCLUSIONS: PTH secretion
      decreases proportionally more with calcitriol than with surgery for a given
      decrease in the functional mass of parathyroid cells. The change in the PTH-ICa
      sigmoidal curve induced by subtotal PTx is due to the removal of a large mass of
      parathyroid tissue with advanced hyperplasia.

PMID- 8649658
TI  - A randomized trial comparing 1.25 mmol/l calcium dialysate to 1.75 mmol/l calcium
      dialysate in CAPD patients.
AB  - BACKGROUND: Effective control of hyperparathyroidism and renal osteodystrophy in
      CAPD patients requires a combination of calcitriol and calcium carbonate (CaCO3),
      but is frequently limited by hypercalcaemia. Reducing dialysate calcium (Ca)
      concentration may overcome this problem, but had not been examined in a
      controlled trial. METHODS: 45 stable CAPD patients were randomly assigned in a
      prospective double-blind trial to either a study group (1.25 mmol/l Ca dialysate)
      or a control group (1.75 mmol/l Ca dialysate) for 12 months. Clinical,
      biochemical and radiological parameters of secondary hyperparathyroidism were
      followed. RESULTS: Twenty-three patients did not complete the study due to death
      (9), transplantation (7) or conversion to haemodialysis (7). Eleven patients in
      each group completed the study. Mean serum Ca, phosphate, ionized Ca, aluminium,
      alkaline phosphatase (AP), and bone mineral density (BMD) Z-scores did not differ
      significantly at any time within or between the two groups. Severe hypercalcaemia
      was more common in the control group (11 vs. 2, P = 0.027). Mean serum intact
      parathyroid hormone (PTH) and osteocalcin (OCN) initially rose in the study group
      relative to controls at 3 months (40 +/- 7 vs 12 +/- 3 pmol/l, P = 0.004, and 33
      +/- 5 vs 15 +/- 2 micrograms/l, P = 0.002 respectively), but were not sustained.
      Median weekly dosages of calcitriol and daily dosages of CaCO3 increased
      significantly in the study group (O microgram to 1 microgram P = 0.014 and 1260
      mg to 2520 mg P = 0.002 respectively), but not in the control group.
      Supplementary aluminium hydroxide (A1, (OH)3) was required for phosphate control
      in both study (n = 5) and control patients (n = 4). CONCLUSIONS: Lowering
      dialysate calcium concentration reduced the frequency of severe hypercalcaemia
      and allowed prescription of larger quantities of calcitriol and CaCO3. However,
      in this study it offered no advantage in terms of A1(OH)3 requirement, while bone
      mass density did and may have initially exacerbated secondary hyperparathyroidism
      not change.

PMID- 8649659
TI  - Haemodialysis arteriovenous access--a prospective haemodynamic evaluation.
AB  - BACKGROUND: Factors affecting cardiac function in dialysis patients include
      arterial blood pressure, anaemia, intravascular volume, and the arteriovenous (a
      v) access. Cardiac failure has been directly attributed to dialysis a-v access in
      several cases. The contribution of the a-v access to cardiac performance has been
      tested, in the past, by a short manual compression on the fistula, but this
      technique has obvious limitations. METHODS: The present study examined
      prospectively the effect of dialysis a-v access on both cardiac function and
      various hormonal responses. Ten patients (age, mean +/- SD, 59.6 +/- 12.3) with
      end-stage renal failure being prepared for chronic dialysis therapy were
      included. All patients underwent an echocardiographic study before and 2 weeks
      after the creation of the a-v access. Plasma atrial natriuretic peptide (ANP),
      plasma renin activity (PRA), and plasma aldosterone were measured at the same
      time periods. RESULTS: Following the creation of the a-v fistula or graft,
      shortening fraction increased by 15.8 +/- 6.3% (P < 0.01), stroke volume
      increased by 21.9 +/- 5.3% (P < 0.01), ejection fraction increased by 10.6 +/-
      4.5% (P < 0.02), cardiac output increased by 19.0 +/- 6.9% (P < 0.02), and
      cardiac index increased by 18.3 +/- 7.1% (P = 0.05). Systemic vascular resistance
      decreased by 23.5 +/- 7.1% (P < 0.01). There was no change in blood pressure,
      heart rate, weight, haemoglobin or serum creatinine. ANP increased by 83.7 +/-
      17.0% following the a-v access operation (P < 0.001), PRA decreased by 41.2 +/-
      10.0% (P < 0.05), and plasma aldosterone did not change. None of the patients
      developed overt high-output cardiac failure. CONCLUSIONS: This study shows that
      at least in the short term following the creation of a dialysis a-v access, a
      mild state of volume overload develops, which is offset by the ?unloading' effect
      of the decreased peripheral vascular resistance; the latter is probably mediated
      by secretion of ANP in response to atrial stretching.

PMID- 8649660
TI  - Serum hyaluronan concentrations predict survival in patients with chronic renal
      failure on maintenance haemodialysis.
AB  - BACKGROUND: Malnutrition and wasting are common in chronic renal failure and are
      adverse prognostic features. The underlying mechanisms are complex and not fully
      understood. Hyaluronan is present in increased concentrations in chronic renal
      failure and may be associated with adverse features of chronic renal failure.
      METHODS: We have investigated the relationship of this abnormality to long-term
      survival. Outcome of 81 patients of median of 5.6 years (3.9-6.8) after
      measurement of hyaluronan was determined. RESULTS: Survival analysis by the Cox
      regression model showed that increased concentrations of hyaluronan (P < 0.0001).
      There was also a weak but significant negative correlation between hyaluronan
      concentrations and serum albumin concentrations (rs = - 0.27, P = 0.02).
      CONCLUSIONS: We conclude that serum hyaluronan is a strong independent predictor
      of long-term survival in CRF may reflect abnormal connective tissue metabolism in
      this condition.

PMID- 8649661
TI  - The effect of local application of chlorhexidine on plaque and gingivitis.
AB  - This study compared the effects on plaque accumulation and gingival inflammation,
      of a 0.2 percent chlorhexidine solution applied with an interdental brush, with
      the effects of the interdental brush with control solution. Thirty-three subjects
      with at least one tooth-bounded edentulous space were chosen. The trial was of a
      double-blind, cross-over design with two, 28-day active periods separated by a 21
      day rest period. The experimental solution was 0.2 percent aqueous
      chelorhexidine, and 0.1 percent quinine solution was used as the control. Prior
      to the commencement of the trial, plaque accumulation at the sites to be tested
      was recorded using the Plaque Index. Gingival condition was recorded using the
      Gingival Index. The surfaces were carefully scaled and cleaned to reduce the
      Plaque Index to 0. Subjects cleaned the selected tooth surfaces on a day using
      the interdental brush with the appropriate solution. After 28 days, the Plaque
      and Gingival Indices were recorded again. Normal oral hygiene was resumed during
      the rest period. The second trial followed the same format as the first, but with
      each subject using the alternative solution. Results were analysed using Wilcoxon
      signed-rank tests for matched pairs. 1. The mean Plaque and Gingival Index scores
      were reduced over the 28-day trial period for both experimental and control
      groups. 2. Although the Plaque Index scores were slightly lower after treatment
      with chlorhexidine when compared with the control, the difference was not
      statistically significant. 3. The reduction in Gingival Index was significantly
      greater for the chlorhexidine group than for the control group. The results
      indicated that 0.2 percent aqueous chlorhexidine, applied with an interdental
      brush to tooth surfaces adjacent to edentulous spaces, produced a significantly
      greater improvement in gingival health than the interdental brush with a placebo
      quinine solution, but the reductions in plaque accumulation were similar with the
      two solutions.

PMID- 8649662
TI  - Naught for your comfort.
AB  - A review of 51 children enrolled consecutively under the Dental Benefit Scheme in
      a private practice has shown that some children would have benefited from having
      bitewing radiographs at a much earlier age. Differences in dental development
      between girls and boys, and between children of European and Polynesian
      background mean that children vary greatly in the dental age when the first
      bitewing radiograph is taken, generally at enrollment in the General Dental
      Benefit Scheme. The decline in dental caries has made diagnosis and treatment
      planning more demanding, and this has exposed the deficiencies of the public
      programmes.

PMID- 8649663
TI  - The dental student profile.

PMID- 8649664
TI  - Survey of anomalies in primary teeth and their correlation with the permanent
      dentition.
AB  - The purpose of the study was to investigate primary and permanent tooth anomalies
      of 5-year-old children in Taranaki; 1,680 children were examined by school dental
      therapists, and the presence of hypodontia, hyperdontia, and double teeth
      recorded. Panoramic radiographs were taken of those children with anomalies of
      the primary teeth. Anomalies of the primary teeth were detected in 23 children
      (1.4 percent). Six children (3 boys and 3 girls) had hypodontia, 3 children (2
      boys and 1 girl) had a supernumerary tooth, and 14 children (9 boys and 5 girls)
      had double teeth. Six of the affected teeth (in 4 boys and 2 girls) were
      diagnosed as fusion, and 8 (5 boys and 3 girls) as gemination. The panoramic
      radiographs of the 23 children with anomalies of the primary teeth revealed that
      14 (60.9 percent) also had anomalies of the succedaneous permanent teeth.
      Children with hypodontia in the primary dentition all had corresponding permanent
      teeth missing. In all but three children, only one tooth was involved. Nineteen
      of the 30 primary teeth (63 percent) and 12 of the 15 permanent teeth (80
      percent) affected by hypodontia, gemination, or fusion were lateral incisors. For
      each type of anomaly, boys were affected more often than girls. The results of
      the study confirm that, when there is hypodontia, hyperdontia, gemination, or
      fusion of teeth in the primary dentition, there is an increased likelihood of
      anomalies of the succedaneous permanent teeth. Because of this close relationship
      between the dentitions, early identification of anomalies of the primary teeth
      can allow the dentist to investigate further and plan for treatment at the
      appropriate time.

PMID- 8649666
TI  - Epithelial ovarian cancer: future prospects for treatment.

PMID- 8649665
TI  - The changing profile of undergraduate dental students at the University of Otago
      1992-1994.
AB  - Incoming students to the School of Dentistry, University of Otago, were surveyed
      in 1992, 1993, and 1994. Since 1992 there has been a marked trend for the
      students to originate from an overseas culture, to have more wealthy parents who
      support their education, and an increase in the numbers who expect to practice
      overseas upon graduation. This has implications for workforce planning in New
      Zealand and raises issues relating to equality of access to tertiary education.

PMID- 8649667
TI  - New Zealand guidelines for the management of dyslipidaemia: implications for
      treatment in an urban New Zealand population.
AB  - AIMS: The paper uses coronary heart disease risk factor prevalence data from a
      defined urban population to assess the potential impact of implementing the New
      Zealand National Heart Foundation "Guidelines for detection and management of
      dyslipidaemia" on the treatment of dyslipidaemia in New Zealand. METHODS:
      Coronary heart disease risk factor data was collected on an age stratified random
      sample of Auckland residents aged 35-74 years. The 10 year absolute risk of
      coronary heart disease was calculated for each participant aged between 35-64
      years and management options determined from the National Heart Foundation
      guidelines. The Framingham equation used in these guidelines was used to
      extrapolate the 10 year risk of a coronary event in the 65-74 year age group. The
      proportions of participants potentially requiring treatment with lipid modifying
      medication were identified and extrapolated to the New Zealand European
      population. A sensitivity analysis was undertaken to assess the impact of 5% and
      10% reductions in total cholesterol following dietary intervention on numbers
      meeting the drug treatment criteria. RESULTS: The proportion of participants
      potentially requiring lipid modifying treatment based on the guidelines was
      considerably higher than estimates of current treatment rates in each age group.
      The number meeting the treatment criteria increased dramatically with age. By the
      age of 65-74 years one in five participants met the drug treatment criteria. A 5%
      and 10% reduction in total cholesterol following dietary intervention reduced the
      proportion of participants potentially requiring drugs by almost one quarter and
      one half respectively. CONCLUSION: The approach taken by the New Zealand National
      Heart Foundation guidelines appropriately gives highest priority to patients at
      highest risk of a coronary event. If this high risk approach is extrapolated to
      older age groups, it will lead to more drug treatment among the elderly. Further
      evidence from randomised controlled trials on benefits of using cholesterol
      modifying medication in older age groups is required. Future guidelines need to
      address specifically criteria for use of lipid modifying medications in older age
      groups. Reductions in the numbers meeting drug treatment criteria following 5%
      and 10% reductions in total cholesterol reinforces the importance of dietary
      management.

PMID- 8649668
TI  - Management of severe bronchiolitis: indications for ventilator support.
AB  - AIM: Bronchiolitis is a common respiratory illness in children. We reviewed our
      experience of children under one year presenting to an intensive care unit with a
      clinical diagnosis of bronchiolitis in order to determine if ethnicity,
      prematurity, arterial carbon dioxide tension or nasopharyngeal aspirates positive
      for respiratory syncytial virus were related to the need for ventilator
      assistance. METHOD: A review of the charts of all infants with bronchiolitis
      admitted to the paediatric intensive care unit from December 1991 to February
      1994 was undertaken. RESULTS: There were 94 infants. Ventilator assistance was
      given to 24 children--nine children had nasopharyngeal continuous positive airway
      pressure and 15 children required intermittent positive pressure ventilation.
      There was no difference in ethnic mix between the respiratory support group
      (Maori 45%, Pacific Islands 30%, other 25%) and those children managed
      conservatively (Maori 40%, Pacific Islands 36%, other 24%). Fifteen of the 24
      infants who needed ventilator support were born prematurely. The mean (corrected)
      age of infants who required respiratory support was 1.79 (SD2.98) months compared
      to 3.32 (SD2.58) months for those infants who did not (p < 0.01). We were able to
      match 19 of the 24 infants who required ventilator support by age, sex and
      ethnicity with a nonventilated child. There was no significant difference in
      admission PaCO2 between groups (7.7 SD 1.5 vs 8.1 SD 1.5 kPa) or highest PaCO2 in
      the first 24 hours for nonventilated children and preintubation PaCO2 in
      ventilated children (8.6 SD1.3 vs 8.9 SD 1.9kPa). Nasopharyngeal aspirates were
      positive for respiratory syncytial virus in 39 patients. Respiratory support was
      required for 13 children who had positive RSV aspirates and for nine children who
      were not RSV positive (NS). CONCLUSION: Infants with bronchiolitis that were
      premature were not likely to need respiratory support. Ethnicity, arterial PaCO2
      and positivity for RSV were not related to the need for ventilator assistance.

PMID- 8649669
TI  - Proposals for standards of cystic fibrosis management in New Zealand. A position
      statement by the Respiratory Committee of the Paediatric Society of New Zealand.

PMID- 8649670
TI  - Compliance with guidelines results in appropriate ondansetron prescribing at
      Christchurch Hospital.
AB  - AIM: To assess compliance with established consensus derived guidelines for
      ondansetron therapy and to estimate the cost of any non-guideline use. METHODS:
      All inpatients (including paediatric patients) at Christchurch Hospital who
      received ondansetron during August 1993 were identified by daily review of
      medication charts. Outpatients who received ondansetron prescriptions were
      identified from pharmacy records. All patients' medical records were then
      examined and ondansetron therapy was compared with the guideline recommendations
      for indication and dosage. The total cost of ondansetron for each patient was
      also calculated. RESULTS: Ondansetron was prescribed for 64 patients (41 female,
      23 male) during the one month period. Fifty patients received ondansetron therapy
      in accordance with all indication and dosage aspects of the guidelines. The main
      guideline indication for use was highly emetogenic chemotherapy with 28 patients.
      Fifteen patients received ondansetron because of failure of standard antiemetic
      therapy and nine because they were paediatric chemotherapy patients. Of the 12
      patients who received ondansetron outside the guidelines indications, nine had
      received 'moderately highly' emetogenic chemotherapy (whereas the guidelines
      state 'highly' only), two had severe asthma, one received radiotherapy. Two
      patients did not comply with the dosage recommendations as they received
      ondansetron more than 24 hours after the initial cytotoxic dose. Total
      ondansetron expenditure for the period was $12,789 (inpatient $8492 outpatient
      $4297). Expenditure related to the nonguideline usage was $536 (4.2% of the total
      monthly ondansetron expenditure). CONCLUSION: There was high compliance with the
      guidelines. This supports the use of guidelines in encouraging appropriate
      prescribing.

PMID- 8649671
TI  - Child care practices and cot death in Hong Kong.
AB  - AIMS: To document child care practices in Hong Kong which has a very low SIDS
      rate of 0.3/1000 live births. METHODS: Data were collected by interview and
      postal questionnaires using a protocol developed in southern New Zealand. 195
      mothers were recruited at the Prince of Wales Hospital and 100 completed the
      study. RESULTS: 81% babies slept in the parents room. 32% shared a bed with
      parents but only a third were described as being "in direct contact". Only 9% of
      infants were still breast feeding by 4 weeks of age. 78% of babies slept on their
      backs, 18% on their sides and 3% on the fronts. Sheepskins were not used and
      56/58 described underbedding as firm or moderately firm. At the time of birth
      only 3% of mothers smoked. CONCLUSIONS: Certain SIDS risk factors (bedsharing,
      lack of breast feeding) are common in Hong Kong, whereas others (prone sleep
      position, soft underbedding, maternal smoking) appear uncommon.

PMID- 8649672
TI  - Forearm and wrist fractures in mountain bike riders.
AB  - AIMS: To identify the different types of fractures of the forearm caused by
      mountain bike accidents, and to assess the physical and social consequences of
      these injuries. METHODS: All the forearm fractures recorded in the Wellington
      Hospital fracture logs between July 1992 and July 1994 were reviewed in December
      1994. Mountain bike accidents were identified in 37 patients. 11 patients could
      not be contacted and one patient declined participation, leaving 25 patients who
      participated in the study. Those who took part each completed a questionnaire and
      were examined. The radiographs of each patient were also reviewed. RESULTS: Nine
      of the fractures occurred in the proximal third of the forearm and 16 occurred in
      the distal third. The most common fracture was that of the radial head (9). When
      functionally assessed 15 patients were graded excellent, 5 satisfactory, 4
      unsatisfactory, and 1 patient was graded as poor. The average time off work was
      28 days, with no change of occupation being necessitated in any of the patients.
      Eight patients had to make changes to their recreational activities. CONCLUSIONS:
      The results of the study suggest that mountain bike accidents can result in
      significant injury. With adequate medical attention it appears that the majority
      of cases recover well, and experience only minimal discomfort without significant
      long term physical and social consequences.

PMID- 8649673
TI  - The weight of the lighter twin is more important than twin growth discordancy in
      assessing perinatal mortality.

PMID- 8649674
TI  - Medical discipline and sexual activity between doctors and patients.

PMID- 8649675
TI  - Medical discipline and sexual activity between doctors and patients.

PMID- 8649677
TI  - Maharishi Vedic Health Science.

PMID- 8649676
TI  - Acute hepatitis B in New Zealand.

PMID- 8649678
TI  - New definition of still-birth.

PMID- 8649679
TI  - Factors associated with the use of episiotomy during vaginal delivery.
AB  - OBJECTIVE: To examine factors associated with the performance of episiotomy.
      METHODS: A retrospective review was performed on 8647 deliveries during 1991 and
      1992 at five medical centers. Episiotomy rates were compared based on variables
      involving patient demographics, obstetric condition, and physician factors for
      the 6458 vaginal deliveries in the sample. Logistic regression modeling using
      variables associated in bivariate analysis was performed to examine independent
      effects of each variable. RESULTS: Several characteristics of the patient, her
      clinical status, and physician factors were all associated with episiotomy use.
      The strongest independent predictors of episiotomy were nulliparity (odds ratio
      [OR] 4.10, 95% confidence interval [CI] 3.59-4.68) and the use of forceps (OR
      5.03, 95% CI 3.39-7.46) or vacuum extraction (OR 3.78, 95% CI 2.36-6.04).
      Provider specialty and the site of care were also associated independently with
      episiotomy. Episiotomy use was also associated with major perineal lacerations
      and an increased length of hospital stay. CONCLUSION: Although differences in
      episiotomy rates mainly reflect clinical circumstances, important site-to-site
      variations and interspecialty differences point to potential areas where
      physician behaviors influence the performance of episiotomy.

PMID- 8649680
TI  - Early oral feeding after cesarean delivery.
AB  - OBJECTIVE: To assess the gastrointestinal function and patient acceptability of
      early initiation of oral feeding after cesarean delivery. METHODS: Two hundred
      twenty-one healthy women delivered by cesarean were assigned in an alternating
      manner to receive either a high-protein, low-residue pudding initiated within 6
      hours of delivery and given every 6 hours thereafter (n = 108), or a standard
      postoperative diet, consisting of sips of water 12 hours after surgery and a
      liquid diet permitted only after bowel sounds returned and flatus passed (n =
      113). RESULTS: Compared with the control group, the early-feeding group had a
      shorter mean (+/- standard deviation) duration of intravenous fluid
      administration, 18.6 +/- 6.3 versus 30.5 +/- 8.1 hours (P < .001); more rapid
      return to regular oral diet, 26.8 +/- 6.3 versus 39.7 +/- 8.8 hours (P < .001);
      and a shorter time to first bowel movement, 30.0 +/- 10.0 versus 43.3 +/- 11.7
      hours (P < .001). There was no significant increase in gastrointestinal
      morbidity: 17.4 versus 15.6%, respectively. CONCLUSION: Early feeding after
      cesarean delivery was well tolerated and was associated with a more rapid return
      to a normal diet. This approach may facilitate early hospital discharge.

PMID- 8649681
TI  - A comparative study of laparoscopy and colpotomy for the removal of ovarian
      dermoid cysts.
AB  - OBJECTIVE: To compare laparoscope-assisted transvaginal removal of dermoid cysts
      to more standard laparoscopic cystectomy techniques. METHODS: We conducted a
      retrospective review of 44 laparoscopic dermoid removals performed at Olive View
      UCLA Medical Center between 1992 and 1995. Cases were divided into three groups
      based on surgical approach: 1) conventional laparoscopic ovarian cystectomy, 2)
      laparoscopic ovarian cystectomy and removal of the freed mass via colpotomy, and
      3) laparoscopic inspection, then transvaginal cystectomy via colpotomy. Surgical
      time, estimated blood loss, cyst spillage, and complications were compared.
      RESULTS: There were 11-19 patients in each group. The groups were similar in
      patient age, parity, and weight. Larger cysts tended to be removed by the
      laparoscopy-colpotomy techniques (mean diameter 10 cm) rather than by the purely
      laparoscopic approach (mean diameter 7 cm, P < .05). Cyst spillage occurred less
      often (43%, P < .05) and surgical time was shortest (mean 81 minutes, P < .05)
      with laparoscope-assisted transvaginal ovarian cystectomy compared with
      conventional laparoscopic techniques. Disposable laparoscopic instruments were
      used less often with transvaginal cystectomy (7%) than with conventional
      laparoscopic cystectomy (77%, P < .01). The difference in mean estimated blood
      loss in the cases using colpotomy (89 mL) compared with cases that did not (65
      mL) was not statistically significant. Among the three groups, there were four
      major operative complications related to blood loss and infection. CONCLUSION:
      Laparoscope-assisted transvaginal ovarian cystectomy allows the removal of larger
      dermoid cysts, with less cyst spillage and savings in operative time and
      equipment compared with conventional laparoscopic cystectomy.

PMID- 8649682
TI  - A randomized comparison of vasopressin and tourniquet as hemostatic agents during
      myomectomy.
AB  - OBJECTIVE: To assess the comparative efficacy of perivascular vasopressin and
      tourniquet in minimizing bleeding and its sequelae at myomectomy. METHODS:
      Between March 1994 and February 1995, 52 women with symptomatic uterine
      leiomyomas scheduled for myomectomy were entered into a randomized trial
      comparing vasopressin (26 patients) and tourniquet (26 patients) for hemostasis.
      Myomectomy was performed after either the perivascular injection of 20 U of
      vasopressin diluted to 20 mL with normal saline or with the use of a Foley
      catheter tourniquet around both uterine vessels. The efficacy of each method was
      measured by comparing differences in pre- and postoperative hemoglobin levels,
      intraoperative blood pressure, measured blood loss, need for blood transfusion,
      evidence of postoperative febrile morbidity, complications, and length of
      hospital stay. RESULTS: Vasopressin resulted in less blood loss (mean 287.3 mL
      [standard deviation (SD) 195] versus 512.7 mL [SD 400] for tourniquet [P =
      .036]). Six of 26 patients in the tourniquet group lost more than 1000 mL of
      blood, whereas all of the vasopressin subjects lost less than this amount (P =
      .023). However, there were no significant differences between the two groups in
      the fall in the hemoglobin level, number of blood transfusions given,
      intraoperative blood pressure, highest postoperative pulse and temperature, or
      other complications. CONCLUSION: Vasopressin prevents blood loss better than
      using the tourniquet during myomectomy.

PMID- 8649683
TI  - Intratumoral blood flow in uterine myoma correlated with a lower tumor size and
      volume, but not correlated with cell proliferation or angiogenesis.
AB  - OBJECTIVE: To investigate the correlation of intratumoral blood flow in uterine
      myoma with cell proliferation, angiogenesis, tumor size, and tumor volume.
      METHODS: Thirty-nine patients who had been scheduled for surgery because of
      symptomatic uterine myomas were evaluated by transvaginal sonography and color
      Doppler ultrasound before surgery. The largest dimension of each tumor and the
      volumes of myomas were determined ultrasonographically. Pulsatility index (PI)
      was determined by color Doppler ultrasound according to the maximum systolic, end
      diastolic, and the mean flow velocities measured within the uterine nodules.
      After surgery, the paraffin-embedded slides containing representative leiomyoma
      tissues were stained with hematoxylin and eosin, proliferating cell nuclear
      antigen for measurement of cell proliferation, and factor VIII for quantitation
      of microvessel density. The ultrasonographic findings were correlated
      postoperatively with pathologic findings, and the data were analyzed by simple
      linear regression and Fisher r to z transformation. RESULTS: Simple regression
      analysis of the intratumoral PI values on the sizes of myomas showed a negative
      correlation (r = -0.47, P = .003; n = 39), whereas a less significant correlation
      between PI values and tumor volumes was observed (r = -0.42, P = .008). In
      contrast, no statistically significant correlation was observed between the
      intratumoral PI values and the values of the proliferating cell nuclear antigen
      index (r = 0.10, P = .547) or microvessel density counts (r = 0.18, P = .282).
      CONCLUSION: The intratumoral blood flow by transvaginal color Doppler ultrasound
      correlated with a reduced tumor size and tumor volume, but did not correlate with
      cell proliferation or angiogenesis.

PMID- 8649684
TI  - The effect of intracervical vasopressin on the systemic absorption of glycine
      during hysteroscopic endometrial ablation.
AB  - OBJECTIVE: To examine the effect of paracervical injection of vasopressin on the
      absorption of glycine during transcervical endometrial ablation. METHODS: Thirty
      three consecutive women scheduled for elective hysteroscopic endometrial ablation
      were randomized to either the study or control group. All procedures were
      performed with a myoma resectoscopy using 1.5% glycine as the irrigating medium
      at a flow rate of 100 mL/minute. In the study group, a solution of 0.2 mg
      vasopressin diluted with 20 mL saline was injected paracervically. Blood samples
      were obtained through an indwelling intravenous catheter every 5 minutes until
      the completion of the operation. Serum sodium, potassium, and magnesium levels
      were measured at 20-minute intervals. In addition, glycine concentrations were
      determined by both rapid screening and quantitative amino acid analysis. RESULTS:
      Plasma glycine maximal concentrations were significantly lower (P < .001) in
      patients who received vasopressin, compared with controls (8.8 +/- 4.5 versus
      16.0 +/- 6.3 mmol/L, respectively). The calculated extent of glycine absorption
      within the first 20 minutes of the procedure was 59.6 +/- 30.0 versus 179.8 +/-
      66.2 mmol/L.minute in the study and control groups, respectively (P < .001). The
      differences in plasma sodium, potassium, and magnesium levels were not
      significant. CONCLUSION: Intracervical vasopressin administration significantly
      decreased systemic glycine absorption in patients undergoing hysteroscopic
      endometrial ablation.

PMID- 8649685
TI  - Characteristics of menstruation in women infected with human immunodeficiency
      virus.
AB  - OBJECTIVE: To determine the characteristics of menstruation in women infected
      with human immunodeficiency virus (HIV) and the impact of immunosuppression on
      menstruation in HIV-infected women. METHODS: In this cross-sectional study, 197
      HIV-infected and 189 HIV-uninfected women were interviewed about menstruation and
      abnormal vaginal bleeding during the previous 12 months. Information was also
      obtained about CD4+ T-lymphocyte levels of HIV-infected women and other factors,
      including drug use and weight loss, that might affect menstruation. RESULTS: The
      number and duration of menses in HIV-infected women were not significantly
      different from those of uninfected women. During a 12-month period, 154 (78%) of
      197 HIV-infected women and 150 (80%) of 188 uninfected women had 10-14 menses (P
      = .74). The proportions of women in the two groups with intermenstrual bleeding,
      postcoital bleeding, or no bleeding were also similar. In HIV-infected women,
      menstruation and the prevalence of abnormal vaginal bleeding were not
      significantly different by CD4+ T-lymphocyte level. By multiple logistic
      regression analysis, neither HIV infection nor CD4+ T-lymphocyte level less than
      200 cells/microL was associated with intermenstrual bleeding, postcoital
      bleeding, or no bleeding. CONCLUSION: The results of this study suggest that
      neither HIV infection nor immunosuppression has a clinically relevant effect on
      menstruation or other vaginal bleeding. Most HIV-infected women menstruate about
      every 25-35 days, suggesting monthly ovulation and an intact hypothalamic
      pituitary-ovarian axis.

PMID- 8649686
TI  - The effect of estrogen replacement therapy on zinc in serum and urine.
AB  - OBJECTIVE: To ascertain the influence of estrogen replacement therapy (ERT) on
      blood and urinary zinc in postmenopausal women. METHODS: Thirty-seven
      postmenopausal women aged 53.2 +/- 3.7 years were examined. All were treated with
      conjugated estrogens 0.625 mg and medroxyprogesterone acetate 5 mg. Zinc,
      magnesium, calcium, phosphate, and alkaline phosphatase levels in blood were
      measured before and after 6 and 12 months of treatment. Urinary excretion of
      zinc, magnesium, calcium, phosphate, and hydroxyproline were evaluated before and
      after 3, 6, and 12 months of therapy. Bone mineral density was examined before
      treatment and after 1.7 +/- 0.3 years of ERT. Subjects were classified by 1)
      initial bone mineral density values (osteoporotics less than 0.850 g/cm2) and 2)
      zinc excretion as elevated (greater than 600 micrograms/g creatinine). RESULTS:
      At baseline, the values of most markers of bone turnover were higher in the
      osteoporotic women (Hotelling test, P = .06). After 1 year of treatment, a higher
      decrease of most indices was observed in the osteoporotic patients, and no
      statistical difference was found between the osteoporotic and the normal groups
      (Hotelling test, P = .31). A consistent negative association was observed between
      changes in bone mineral density and urinary zinc excretion in the osteoporosis
      group. Estrogen replacement therapy reduced excretion of zinc, magnesium, and
      hydroxyproline in the elevated zinc excretion group. Zinc excretion decreased 35%
      after 3 months and 26% after 1 year of treatment. The serum tests, with the
      exception of alkaline phosphatase, showed only negligible changes during ERT.
      CONCLUSION: A significant decrease in zinc excretion was observed after 3 months
      of ERT. This change was more pronounced in women with osteoporosis and elevated
      zinc excretion. Because zinc excretion is almost uninfluenced by variation in
      diet, it may be used as an additional marker of changes in bone metabolism.

PMID- 8649687
TI  - Surgical staging and high dose rate brachytherapy for endometrial cancer:
      limiting external radiotherapy to node-positive tumors.
AB  - OBJECTIVE: To evaluate the efficacy and morbidity of surgical staging and high
      dose rate brachytherapy for women with stage I-IIIA endometrial cancer. METHODS:
      Sixty consecutive patients underwent surgical staging consisting of total
      abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology,
      bilateral pelvic lymphadenectomy, periaortic lymphadenectomy, and omentectomy.
      High dose rate brachytherapy was delivered postoperatively in three fractions for
      a total of 2100 cGy. Only patients with nodal metastasis received external
      radiotherapy. RESULTS: Twenty-two tumors (37%) were considered high-risk uterine
      disease because of deep invasion (stage IC), cervical involvement (stage II),
      positive peritoneal cytology (stage IIIA), or poor differentiation (grade 3).
      Lymph node metastases were detected in five patients. There was no surgical
      mortality, and morbidity from surgery and high dose rate brachytherapy was
      minimal. At a median follow-up of 3 years, there has been one recurrence. The
      conventional practice of postoperative external radiotherapy was altered in 23 of
      60 patients (38%): 22 women with high-risk uterine factors did not receive
      external radiotherapy, and one patient with low-risk uterine factors (less than
      50% myometrial invasion, grade 2) received external radiotherapy because of
      microscopic pelvic lymph node metastasis. CONCLUSION: Surgical staging and high
      dose rate brachytherapy without external radiotherapy for stage I-IIIA
      endometrial cancer were associated with minimal morbidity and produced excellent
      survival.

PMID- 8649689
TI  - Relationship between foot flexibility and urinary incontinence in nulliparous
      varsity athletes.
AB  - OBJECTIVE: To explore the relationship between urinary incontinence in elite
      nulliparous athletes and force absorption on impact, as assessed by foot arch
      flexibility. METHODS: One investigator measured medial longitudinal arch height
      in two gait stances (neutral and maximally dorsiflexed ankle positions) in 47
      female varsity athletes representing five sports. Each athlete completed a
      questionnaire about urinary incontinence prevalence. We compared the change in
      arch height between the two gait stances with the prevalence of urinary
      incontinence. RESULTS: There was a statistically significant association between
      decreased foot flexibility and urinary incontinence; the mean percent change in
      arch height was 8.94 +/- 0.08% (standard deviation) in incontinent women and
      13.70 +/- 0.09% in continent women (P = .03). CONCLUSION: How impact forces are
      absorbed may be one potential etiology for stress incontinence. An improved
      understanding of how impact forces are transmitted to the pelvic floor could
      provide important information about potential preventive interventions for
      urinary incontinence and other pelvic floor disorders, such as genital prolapse.

PMID- 8649688
TI  - Nitrous oxide inhalation: effects on maternal and fetal circulations at term.
AB  - OBJECTIVE: To evaluate the hemodynamic effects of nitrous oxide inhalation in
      normal term pregnancy. METHODS: Twenty healthy term pregnant women were given 30%
      nitrous oxide in pure oxygen for 2 minutes, and the hemodynamics were assessed by
      pulsed-wave color Doppler velocimetry of the uterine and internal carotid artery
      of the mother and the umbilical and middle cerebral artery of the fetus. Each
      vessel was assessed separately, allowing a 5-minute wash-out period between the
      inhalations. The measurements were continued for 2 minutes after the inhalation,
      and the pulsatility index (PI) was determined at 1-minute intervals. The maternal
      heart rate and blood pressure (BP) were recorded before and after inhalation;
      fetal well-being was confirmed with cardiotocography. Analysis of variance for
      repeated measurements and paired-sample t test were used for statistical
      analysis. RESULTS: A significant decrease in the PI of the maternal internal
      carotid artery was observed after 2-minutes of inhalation (from 0.83 +/- 0.22 to
      0.71 +/- 0.20; P < .001). The uterine artery PI and maternal BP and heart rate
      were not affected by nitrous oxide. A significant decrease was evident even in
      the fetal middle cerebral artery PI (from 1.37 +/- 0.27 to 1.22 +/- 0.17; P =
      .02). The umbilical artery PI remained unchanged. CONCLUSION: Both maternal and
      fetal central vascular resistance were decreased by 30% nitrous oxide inhalation.
      So far, no adverse effects to mother or fetus have been demonstrated in clinical
      practice. However, preterm fetuses are susceptible to intracranial hemorrhage,
      and the cerebral hyperemia by nitrous oxide might increase the risk of hemorrhage
      in these fetuses. This hypothesis requires further investigation.

PMID- 8649690
TI  - Stage IA carcinoma of the cervix revisited.
AB  - OBJECTIVE: To examine some of the controversy that still exists regarding the
      definition and management of microinvasive or early invasive cervical carcinoma,
      in particular, the current concepts regarding the definition of these conditions
      and their inclusion into the staging system for cervical cancer. DATA SOURCES: A
      MEDLINE search was used to identify English-language reports of clinical and
      pathologic information on cervical cancer. Articles published during 1970-1993
      were reviewed. METHODS OF STUDY SELECTION: Articles were selected for review if
      the information published contained data regarding measured depth of invasion,
      histologic examination of lymph nodes, and lymphatic vascular space status with
      these tumors. TABULATION, INTEGRATION, AND RESULTS: Results from the studies were
      pooled to determine the correlation between depth of invasion with the likelihood
      of nodal disease and recurrence, both with and without lymphatic vascular space
      involvement. These studies indicated that the likelihood of recurrence and death
      from cancer, together with the presence of nodal metastasis, appears to be
      directly related to the depth of tumor invasion. The relative importance of
      factors such as lymphatic space involvement will likely remain controversial
      because they may not be independent prognostic factors. CONCLUSION: Review of the
      literature suggests that although no uniform opinion exists as to how these
      conditions should be described or managed, the evidence indicates that some
      modifications to the 1985 staging system for cervical cancer could be made to
      better categorize patients with these conditions and also, perhaps, provide
      guidelines for management.

PMID- 8649691
TI  - Adolescence and very low birth weight infants: a disproportionate association.

PMID- 8649692
TI  - Urinary calcium in asymptomatic primigravidas who later developed preeclampsia.

PMID- 8649693
TI  - Lactation after augmentation mammoplasty.

PMID- 8649694
TI  - Do growth-retarded premature infants have different rates of perinatal morbidity
      and mortality than appropriately grown infants?

PMID- 8649695
TI  - Acyclovir suppression to prevent cesarean delivery after first-episode genital
      herpes.

PMID- 8649696
TI  - The intergenerational predisposition to operative delivery.
AB  - OBJECTIVE: To determine the risk of cesarean delivery for women who themselves
      were born via operative delivery. METHODS: A linked data base was constructed
      between the birth certificates of individuals born in Utah during 1947-1957
      (parental cohort) and who subsequently became a parent of offspring born in Utah
      between 1970-1991 (offspring cohort). Parental cohort women (cases) who had been
      delivered operatively (cesarean delivery, mid- or high forceps) as well as women
      who had a sibling delivered by an operative procedure were matched (1:2) with
      parental-cohort women born by spontaneous vaginal delivery (controls). Both cases
      and controls were selected based on having a record of at least one delivery in
      Utah during 1970-1991. RESULTS: Women who were delivered by cesarean were at
      increased risk of subsequently delivering their children by cesarean (odds ratio
      [OR] 1.41, 95% confidence interval [CI] 1.18-1.70; P < .001). Progressive risk
      was associated with parental delivery by mid- or high forceps (OR 1.72, 95% CI
      1.20-2.47; P = .004), parental cesarean because of cephalopelvic disproportion
      alone (OR 1.83, 95% CI 1.16-2.88; P = .01), or parental cesarean for
      dysfunctional labor (OR 5.97, 95% CI 1.5-23.6; P < .001). The attributable risk
      for cesarean delivery to the contemporary population is 3.5%. CONCLUSION: An
      intergenerational predisposition to cesarean delivery exists.

PMID- 8649697
TI  - Pre-cesarean blood bank orders: a safe and less expensive approach.
AB  - OBJECTIVES: To 1) characterize pre-cesarean blood bank testing, 2) describe the
      transfusion experience in a large series of cesarean patients, and 3) evaluate
      safety and cost implications of a "hold clot" order for patients at low risk for
      transfusion. METHODS: A review of 1111 consecutive cesarean patients used
      computerized perinatal and blood bank data bases and a detailed chart review of
      all cross-matched patients. Information collected included indications for
      cesarean and transfusion, etiology of hemorrhage, transfusion number and type,
      admission and lowest hemoglobin level, and information regarding the events
      leading to transfusion. A blinded review of the cross-matched patient's
      information assessed whether a cross-match was appropriate or could have been
      replaced safely by a "hold clot" (current clot tube in blood bank) order.
      RESULTS: Nineteen patients (1.7%) were transfused. The only patients requiring a
      transfusion were diagnosed with placenta previa, placenta accreta, anemia,
      preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP syndrome),
      or hemorrhage. A comparison of two blood banking approaches (routine pre-cesarean
      type and screen testing versus a "hold clot" order for cesarean patients at low
      risk for transfusion) indicated that the latter would reduce costs by $45 per
      cesarean, or $95,000 annually. CONCLUSIONS: The incidence of transfusion was low
      (1.7%) and associated with specific diagnoses (previa, accreta, anemia,
      preeclampsia/HELLP, or hemorrhage). The data support the replacement of pre
      cesarean type and screen testing with a "hold clot" order for patients at low
      risk for transfusion with negative prenatal antibody screen. This approach is
      safe and would reduce cost substantially.

PMID- 8649698
TI  - Pregnancy outcome at age 40 and older.
AB  - OBJECTIVE: To examine pregnancy outcome among women age 40 years and older.
      METHODS: A retrospective cohort study, including 1404 pregnant women at least 40
      years of age and 6978 controls age 20-29 years, was conducted. The two groups
      were stratified, according to parity, to facilitate separate analysis.
      Associations between maternal age and pregnancy outcomes were assessed with the
      contingency chi 2 or two-tailed Fisher exact test. Multiple logistic regression
      was used to evaluate these associations and allowed for calculation of adjusted
      odds ratios (OR). RESULTS: Older gravidas were more likely to develop gestational
      diabetes (nulliparas: OR 2.7, 95% confidence interval [CI] 1.9-3.7; multiparas:
      OR 3.8, 95% CI 2.7-5.4), preeclampsia (nulliparas: OR 1.8, 95% CI 1.3-2.6;
      multiparas: OR 1.9, 95% CI 1.2-2.9), and placenta previa (nulliparas: OR 13.0,
      95% CI 4.8-35.0; multiparas: OR 6.4, 95% CI 2.6-15.6). Older women were also at
      increased risk for cesarean delivery (nulliparas: OR 3.1, 95% CI 2.6-3.7;
      multiparas: OR 3.3, 95% CI 2.6-4.1), operative vaginal delivery (nulliparas: OR
      2.4, 95% CI 1.9-2.9; multiparas: OR 1.5, 95% CI 1.2-1.9), and induction of labor
      (nulliparas: OR 1.5, 95% CI 1.2-1.8; multiparas: OR 1.4, 95% CI 1.1-1.7). Older
      nulliparas had an increased incidence of abnormal labor patterns (OR 1.4, 95% CI
      1.2-1.7), neonatal intensive care unit admissions (OR 1.6, 95% CI 1.2-2.2), and
      low 1-minute Apgar scores (OR 2.3, 95% CI 1.1-4.9). Older multiparas were more
      likely to experience fetal distress (OR 2.0, 95% CI 1.4-2.8), antepartum vaginal
      bleeding (OR 1.8, 95% CI 1.1-3.1), and preterm premature rupture of membranes (OR
      1.7, 95% CI 1.1-2.9). CONCLUSION: Although maternal morbidity was increased in
      the older gravidas, the overall neonatal outcome did not appear to be affected.

PMID- 8649699
TI  - Cervical priming with oral misoprostol in pre-labor rupture of membranes at term.
AB  - OBJECTIVE: To investigate the effectiveness of oral misoprostol as a cervical
      priming agent for patients presenting with pre-labor rupture of membranes at
      term. METHODS: Eighty patients presenting with pre-labor rupture of membranes at
      term were randomized to receive either 200 micrograms of misoprostol or 50 mg of
      vitamin B6 orally 1 hour after admission. Labor was induced with intravenous
      oxytocin infusion 12 hours after oral medication if the patient did not go into
      labor. We compared the induction rate, duration of labor, mode of delivery, and
      leaking-to-delivery interval in the two groups. RESULTS: The cervical score was
      significantly improved and the induction rate was also reduced in the misoprostol
      group when compared with the control group. The interval from recruitment to
      onset of labor, duration of labor, and the interval from recruitment to delivery
      were significantly shorter in the misoprostol group. The mode of delivery and the
      perinatal outcome were similar for the two groups. CONCLUSION: Oral misoprostol
      is an effective agent for cervical priming and labor induction in patients with
      pre-labor rupture of membranes at term.

PMID- 8649700
TI  - Stripping of membranes as a safe method to reduce prolonged pregnancies.
AB  - OBJECTIVE: To evaluate weekly stripping of membranes at term to determine its
      safety and effectiveness in reducing the incidence of prolonged and postterm
      pregnancies. METHODS: One hundred forty-two pregnant women with certain
      gestational dates were randomly selected to receive, starting at 38 weeks, either
      weekly stripping of membranes (73 patients) or weekly gentle cervical
      examinations (69 patients). RESULTS: Women who received stripping had earlier
      delivery (8.2 versus 12.2 days; P < .005) and less incidence of delivery at 41
      weeks or greater (three versus 13 patients; P < .01). The reduction remained
      consistent for favorable and unfavorable Bishop scores, and for nulliparas and
      multiparas. Only three subjects in the study delivered at 42 weeks or greater. No
      woman reported rupture of membranes after stripping. CONCLUSION: Stripping of
      membranes is a safe method to reduce the incidence of prolonged pregnancies and
      the length of term gestations. Larger trials on populations with a higher
      incidence of postterm pregnancies are needed to evaluate its efficacy in reducing
      the incidence of postterm pregnancies.

PMID- 8649701
TI  - Management of the presumed susceptible varicella (chickenpox)-exposed gravida: a
      cost-effectiveness/cost-benefit analysis.
AB  - OBJECTIVE: To compare the cost-effectiveness and cost-benefit of different
      strategies for managing the presumed susceptible varicella (chickenpox)-exposed
      gravida. METHODS: Three strategies were evaluated: 1) a do-nothing or observation
      strategy; 2) a testing strategy, in which immune status was assessed and
      varicella-zoster immune globulin was administered to those who tested nonimmune;
      and 3) a universal-administration strategy, in which varicella-zoster immune
      globulin was given to all exposed, presumed susceptible gravidas. Because precise
      data are unavailable about varicella mortality and hospitalization rates in
      pregnancy, a range of potential rates was evaluated, from one to greater than 20
      times healthy nonpregnant adult rates. The potential efficacy of varicella-zoster
      immune globulin varied from 1 to 99%. A strategy was defined as cost-effective if
      it cost less than $50,000 per life-year gained. RESULTS: If the mortality rate
      from varicella infection in pregnancy was increased fivefold over the nonpregnant
      healthy adult rate (ie, from 31/100,000 to 155/100,000 cases), efficacy would
      have to be at least 49% for the immune-testing strategy to be cost-effective. If
      pregnancy only doubled the varicella mortality rate, then even with perfect
      efficacy, the immune-testing strategy would not be cost-effective. Under most
      assumptions, the universal-administration strategy was cost-ineffective when
      compared with the immune-testing strategy. Similar results were obtained in the
      parallel cost-benefit analysis, which considered hospitalization costs and rates.
      The analysis was sensitive to the varicella transmission rate and the discount
      rate. CONCLUSION: From a cost-effectiveness/cost-benefit standpoint, management
      based on immune testing is preferable to universal varicella-zoster immune
      globulin administration when caring for the varicella-exposed gravida with a
      negative or indeterminate infection history.

PMID- 8649703
TI  - Down syndrome screening in an Asian population using alpha-fetoprotein and free
      beta-hCG: a report of the Taiwan Down Syndrome Screening Group.
AB  - OBJECTIVE: To evaluate whether the strategy of maternal serum screening for Down
      syndrome, using alpha-fetoprotein (AFP) and free beta-hCG in combination with
      maternal age, a technique developed in western countries, is applicable to an
      Asian population. METHODS: Alpha-fetoprotein and beta-hCG were measured in serum
      samples from 23 Down syndrome pregnancies and 1748 unaffected singleton Taiwanese
      (ethnically Chinese) pregnancies at 14-22 weeks' gestation. Gestational age
      specific medians and a maternal weight correction formula were established for
      our own population. Likelihood ratio for Down syndrome pregnancies in relation to
      multiples of the median (MoM) levels of these analytes were derived from the
      overlapping gaussian frequency distribution curves for Down syndrome and
      unaffected pregnancies. RESULTS: The serum AFP and free beta-hCG median MoM
      values of Down syndrome pregnancies were significantly abnormal in Asian subjects
      (0.77 and 2.91, respectively), and similar to those of affected pregnancies in
      white women. The median value of free beta-hCG:AFP MoM ratio (2.97) in Down
      syndrome pregnancies was significantly higher than that of unaffected pregnancies
      (1.09). The mean maternal weight during the second trimester in pregnant Asian
      women (55.2 kg) was markedly lighter than that of white women. At a 5.8% false
      positive rate, free beta-hCG identified 47.8% of Down syndrome pregnancies
      (likelihood ratio 8.2), AFP detected only 13% of the cases (likelihood ratio
      2.2), and free beta-hCG:AFP MoM ratio detected 43.5% of the cases (likelihood
      ratio 7.4). By using a multivariate risk algorithm involving the combination of
      AFP, free beta-hCG, and maternal age, 56.5% of Down syndrome cases could be
      detected with a 5.3% false-positive rate (likelihood ratio 10.7). CONCLUSION:
      Maternal serum screening strategy using AFP and free beta-hCG in combination with
      maternal age is feasible in the detection of fetal Down syndrome among Asian
      women.

PMID- 8649702
TI  - The impact of gestational age and fetal growth on the maternal-fetal glucose
      concentration difference.
AB  - OBJECTIVE: To test whether the human fetus accommodates to the increasing glucose
      requirements of late pregnancy with an increased maternal-fetal glucose
      concentration gradient and whether there are differences in pregnancies with
      fetal growth restriction (FGR) according to clinical severity. METHODS: Umbilical
      venous glucose concentration was measured in 77 normal pregnancies (appropriate
      for gestational age [AGA]) and 42 pregnancies complicated by FGR at the time of
      fetal blood sampling. In 40 AGA and in all FGR cases, a maternal "arterialized"
      blood sample was collected simultaneously. Growth-restricted fetuses were
      subdivided into three groups according to fetal heart rate (FHR) recordings and
      Doppler measurements of the umbilical artery pulsatility index (PI): group 1
      (normal FHR and PI; 12 cases), group 2 (normal FHR, abnormal PI; 17 cases) and
      group 3 (abnormal FHR and PI; 13 cases). RESULTS: In normal pregnancies with
      increasing gestational age, there was a significant decrease (P < .001) of
      umbilical venous glucose concentration and a significant increase of the maternal
      fetal glucose concentration difference (P < .001). In addition, there was a
      significant relation between fetal and maternal glucose concentrations (P <
      .001). In FGR pregnancies, the maternal-fetal glucose concentration difference
      was significantly higher in fetuses of groups 2 and 3 compared with normal
      pregnancies and FGR pregnancies of group 1. CONCLUSION: In human pregnancy, the
      fetal glucose concentration is a function of both gestational age and the
      maternal glucose concentration. In FGR pregnancies, as an accommodation of the
      fetus to a restricted placental size and placental glucose transport capacity,
      the maternal-fetal glucose concentration difference is increased, and this
      increase is a function of the clinical severity.

PMID- 8649704
TI  - The use of second-trimester genetic sonogram in guiding clinical management of
      patients at increased risk for fetal trisomy 21.
AB  - OBJECTIVE: To test the efficacy of ultrasound in detecting fetuses with trisomy
      21. METHODS: From November 1, 1992, to December 31, 1995, a second-trimester
      genetic sonogram was offered to all women with singleton fetuses at increased
      risk (at least 1:274) for trisomy 21, who had either declined genetic
      amniocentesis or chose to have a sonogram before deciding whether to undergo an
      amniocentesis. In addition to standard fetal biometry, the following ultrasound
      markers for aneuploidy were evaluated: structural anomalies (including face,
      hands, and cardiac [four-chamber view and outflow tracts]), short femur, short
      humerus, pyelectasis, nuchal fold thickening, echogenic bowel, choroid plexus
      cysts, hypoplastic middle phalanx of the fifth digit, wide space between the
      first and second toes, and two-vessel umbilical cord. Outcome information
      included the results of genetic amniocentesis, if performed, or the results of
      postnatal pediatric assessment and follow-up. RESULTS: Five hundred seventy-three
      patients had a genetic sonogram between 15 and 23 weeks' gestation: 378 patients
      had advanced maternal age (at least 35 years), 141 had abnormal serum
      biochemistry, and 54 had both. The majority (495, or 86.3%) had a normal genetic
      sonogram (absence of abnormal ultrasound markers); 51 (9%) had one marker
      present, and 27 (4.7%) had two or more markers present. Outcome was obtained on
      422 patients (the remaining were ongoing pregnancies or were lost to follow-up).
      Twelve of 14 fetuses with trisomy 21, one fetus with trisomy 13, and one fetus
      with triploidy had two or more abnormal ultrasound markers present; one fetus
      with trisomy 21 had one abnormal marker and one had a completely normal
      ultrasound. When one or more abnormal ultrasound markers were present, the
      sensitivity, specificity, and positive and negative predictive values for trisomy
      21 were 92.8%, 86.7%, 19.4%, and 99.7%, respectively. When two or more abnormal
      ultrasound markers were present, the corresponding values were 85.7%, 96.8%, 48%,
      and 99.5%. In the study population, the amniocentesis rate was 12.7% overall and
      17.3% in cases with known outcome. CONCLUSION: Second-trimester genetic sonogram
      may be a reasonable alternative for patients at increased risk for fetal trisomy
      21 who wish to avoid amniocentesis. In experienced hands, this approach may
      result in a high detection rate of trisomy 21 (93%), with an amniocentesis rate
      of less than 20%.

PMID- 8649705
TI  - Adjusting the risk for trisomy 21 by a simple ultrasound method using fetal long
      bone biometry.
AB  - OBJECTIVE: To establish the efficacy of second-trimester fetal long-bone biometry
      (femur, humerus, tibia, and fibula length) in detecting trisomy 21 and to
      generate tables for adjusting the risk of trisomy 21 according to long-bone
      biometry. METHODS: Four long-bones--femur, humerus, tibia, and fibula--were
      measured ultrasonically in singleton fetuses before genetic amniocentesis.
      Fetuses with normal karyotypes were used to derive regression equations
      describing predicted lengths on the basis of the biparietal diameter measurement.
      The efficacy of each abnormally short bone, alone and in combination, was
      determined in 22 fetuses with trisomy 21 encountered during the study period.
      After the sensitivity and specificity of long-bone biometry were established,
      appropriate tables were generated by Bayes' theorem to adjust the risk of trisomy
      21 in the second trimester depending on long-bone biometry. RESULTS: Of 515
      patients between 14 and 23 weeks' gestation, 493 had normal fetal karyotypes and
      22 had trisomy 21. The sensitivity of an abnormal ultrasound, as defined by the
      presence of one or more short bones, was 63.6% and the specificity was 78.5%.
      According to Bayes' theorem, genetic amniocentesis may not be recommended for
      women less than 40 years old in the presence of normal long-bone biometry (ie,
      all four bones normal). CONCLUSION: Second-trimester fetal long-bone biometry is
      useful in detecting trisomy 21 and may be used to adjust the a priori risk of
      both high- and low-risk women for trisomy 21 and, therefore, the need for genetic
      amniocentesis.

PMID- 8649706
TI  - A population-based study of congenital diaphragmatic hernia in Utah: 1988-1994.
AB  - OBJECTIVE: To define the natural history of congenital diaphragmatic hernia and
      to determine the potential impact of fetal therapy. METHODS: This retrospective
      case series consisted of all fetuses and neonates with congenital diaphragmatic
      hernia born between 1988 and 1994 in the state of Utah that could be identified
      through genetic counseling referrals, delivery logs, and neonatal intensive care
      unit discharge diagnosis records. Maternal and neonatal hospital records were
      reviewed for antepartum, intrapartum, and postpartum variables. Based on existing
      recommendations, fetuses who might have benefited from fetal therapy were
      identified. RESULTS: Ninety-six cases were identified, for a frequency of one
      case in 2710 live births per year. Five pregnancies were terminated before 21
      weeks' gestation. The overall survival rate excluding these five cases was 58.2%.
      Among the remaining 91 cases, survival was significantly better for infants
      diagnosed in the neonatal period than for those diagnosed prenatally (78% versus
      35%; P < .001). The frequency of associated anomalies was similar for antepartum
      and postpartum cases. Sixty-two percent of nonsurvivors had some type of other
      anomaly, but no pattern was apparent. There were no accurate prenatal predictors
      for lethal pulmonary hypoplasia, but preterm birth and the presence of severe
      cardiac anomalies were predictors of neonatal death. Only two of 96 fetuses would
      have potentially benefited from fetal therapy. CONCLUSION: The outcome of infants
      with congenital diaphragmatic hernia is worse with preterm birth and if diagnosed
      prenatally. The survival rate we found was better than that reported in earlier
      studies, suggesting improved perinatal and neonatal management. Fetal therapy
      based on current eligibility criteria would have a minimal impact on survival of
      fetuses with congenital diaphragmatic hernia.

PMID- 8649707
TI  - Effects of fetal number and multifetal reduction on length of in vitro
      fertilization pregnancies.
AB  - OBJECTIVE: To determine the effects of multifetal reduction and other variables
      on the duration of gestation of in vitro fertilization (IVF) pregnancies.
      METHODS: All 274 IVF pregnancies from the inception of the Women and Infants'
      Hospital IVF Program on May 26, 1988, until December 31, 1993, were evaluated.
      RESULTS: Spontaneous reduction occurred in ten pregnancies, and multifetal
      reduction was elected in 28 multiple gestations. Among 260 pregnancies that
      remained viable beyond 20 weeks, 162 singletons (37.9 +/- 0.29 weeks; mean +/-
      standard error) had a longer mean gestation than did 64 twins (34.6 +/- 0.61
      weeks), 25 pregnancies reduced to twins (33.4 +/- 1.0 weeks), or nine triplets
      (29.7 +/- 1.9 weeks). Triplets delivered 4.9 weeks earlier than nonreduced twins
      (P < .05) and 3.7 weeks before twins resulting from multifetal pregnancy
      reduction (P < .05). Regression analysis showed that at the 8-week ultrasound,
      each viable fetus could be expected to reduce the duration of the gestation by
      about 3.6 weeks, and each fetus reduced medically or as a result of natural
      causes could be expected to prolong the gestation by approximately 3.0 weeks.
      Only 14% of triplet pregnancies underwent spontaneous multifetal reduction.
      CONCLUSION: Multifetal reduction of pregnancies with three or more fetuses was
      beneficial and increased the duration of gestation.

PMID- 8649708
TI  - The efficacy of individual computer heart rate indices in detecting acidemia at
      birth in growth-restricted fetuses.
AB  - OBJECTIVE: To determine the efficacy of individual fetal heart rate (FHR)
      indices, as determined by computer analysis of the FHR tracing, in detecting
      fetal acidemia at birth in growth-restricted fetuses. METHODS: The study
      population consisted of 38 growth-restricted fetuses at 26-37 weeks' gestation
      from pregnancies with abnormal uterine and/or umbilical artery Doppler
      velocimetry. The 1-hour FHR tracing was analyzed by computer within 4 hours of
      cesarean birth before the onset of labor. Umbilical artery cord blood was
      collected at birth, and pH was determined within 5 minutes of collection.
      RESULTS: On linear regression, the duration of episodes of low variation in
      minutes (r = -0.77, r2 = 0.59) and short-term (r = 0.72, r2 = 0.52) and long-term
      (r = 0.69, r2 = 0.47) variation in milliseconds were significantly related to
      umbilical artery pH at birth, and more so than the number of accelerations of ten
      (r = 0.57, r2 = 0.32) and 15 (r = 0.38, r2 = 0.14) beats per minute. There were
      significant differences in computer measurements of FHR accelerations and
      variation between the umbilical artery pH categories of acidemia (pH less than
      7.20), preacidemia (7.20-7.25), and nonacidemia (greater than 7.25). Stepwise
      regression revealed that episodes of low variation best described the model for
      predicting umbilical artery pH at birth (P < .001), with no improvement provided
      by the addition of other computer-analyzed FHR characteristics. CONCLUSION: In
      this population of growth-restricted fetuses delivered by elective cesarean, the
      computer indices of duration of episodes of low variation and short-term and long
      term variation were significantly associated with umbilical artery pH and
      predicted umbilical artery acidemia at birth.

PMID- 8649709
TI  - Aspects of fetal physiology from 18 to 37 weeks' gestation as assessed by blood
      sampling.
AB  - OBJECTIVE: To construct reference ranges for fetal pH, oxygen pressure (PO2), and
      hematologic and biochemical blood constituents, which can be used to analyze
      changes with gestation and differences with maternal values, thus elucidating
      some aspects of fetal biology and the effects of the maternal and placental
      environments. METHODS: We assayed venous pH, PO2, hematocrit, glucose, uric acid,
      urea, creatinine, total protein, total and direct bilirubin, aspartate
      aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline
      phosphatase, lactic dehydrogenase, amylase, pseudocholinesterase, creatine
      kinase, triglycerides, and cholesterol concentrations in 157 fetuses and 134
      mothers who underwent fetal blood sampling from 18 to 37 weeks' gestation. None
      of the fetuses was infected or had chromosomal, hematologic, or hormonal
      abnormalities. RESULTS: All the variables analyzed were similar in fetuses
      sampled at the placental cord insertion (n = 125) or at the intrahepatic vein (n
      = 32). Maternal and fetal concentrations of glucose (r = 0.79, P < .001), urea (r
      = 0.96, P < .001), creatinine (r = 0.83, P < .001), and uric acid (r = 0.94, P <
      .001) correlated significantly, and their differences exhibited significant
      changes: the maternal-fetal differences of glucose and urea increased, whereas
      those of uric acid and creatinine decreased with advancing gestation. Fetal pH
      and PO2 decreased with gestational age, whereas hematocrit increased, similar to
      what has been described previously. All of the other variables, with the
      exception of amylase and cholesterol, changed significantly during the
      investigated period of pregnancy. Gestational age explained at least 40% of the
      variance in values of fetal total protein, pseudocholinesterase, alanine
      aminotransferase, creatine kinase, and triglycerides, but only 3-25% of the
      variation in the remainder. Most enzymes were higher in the fetus than in the
      maternal circulation, and all except alkaline phosphatase increased with
      gestational age. The maternal-fetal glucose difference correlated significantly
      with hematocrit, pH, and PO2, independent of gestational age and independent of
      each other. CONCLUSION: With the exception of aspartate aminotransferase, all of
      the analyzed fetal variables were different from the maternal values, and most
      changed with gestational age. The mechanisms leading to these fetal specificities
      remain mostly uncertain, but the provision of reference ranges for several blood
      constituents may be useful in the differential diagnosis of fetal disease.

PMID- 8649710
TI  - Fetal cerebral Doppler studies as a predictor of perinatal outcome and subsequent
      neurologic handicap.
AB  - OBJECTIVE: To study the use of middle cerebral arterial Doppler findings in a
      group of high-risk fetuses as a predictor of adverse perinatal outcome, including
      subsequent neurologic handicap. METHODS: A group of very high-risk fetuses was
      recruited over a 2-year period for study. Weekly fetal biometries and Doppler
      studies of the umbilical artery and middle cerebral arteries were carried out
      until delivery. Main outcome indices analyzed included birth weight ratio (ratio
      of observed birth weight to mean birth weight for gestation), days of ventilator
      requirement, neonatal intracranial hemorrhage or periventricular leukomalacia,
      necrotizing enterocolitis, and follow-up data on major neurologic handicap and
      death. RESULTS: Seventy-four patients were recruited. One hundred thirty-four
      sets of examinations were made and prospective follow-up data were available for
      up to 2 years. The ratio of the umbilical and middle cerebral arterial resistance
      index was found to be inversely proportional to the birth weight ratio. Fetuses
      who had a high prenatal umbilical-cerebral Doppler ratio had significantly lower
      birth weight ratios than those with normal findings (0.72 versus 0.92; P < .001).
      The ratio was a more sensitive marker for growth restriction (sensitivity 78%)
      than conventional fetal biometry and umbilical arterial systolic-diastolic ratio.
      However, fetuses with high ratios did not have higher incidences of perinatal
      complications or subsequent neurologic handicap. CONCLUSION: Prenatal cerebral
      vasodilation is a sensitive marker for growth restriction and it seems to be a
      physiologic response to hypoxia. Fetuses with intrauterine cerebral vasodilation
      do not have increased risk for subsequent gross neurologic damage.

PMID- 8649711
TI  - Cerebellar Doppler velocimetry in the appropriate- and small-for-gestational-age
      fetus.
AB  - OBJECTIVE: To compare superior cerebellar artery flow velocity waveforms in the
      appropriate-for-gestational-age (AGA) and the small-for-gestational-age (SGA)
      fetus. METHODS: Superior cerebellar artery velocity waveforms were obtained
      prospectively from 172 AGA fetuses at 17-41 weeks' gestation. The pulsatility
      index (PI) was used to quantify the waveforms. Superior cerebellar artery
      velocity waveforms were also obtained from 30 SGA fetuses divided into group A (n
      = 15), with a normal umbilical artery PI, and group B (n = 15), with an abnormal
      umbilical artery PI. The transverse cerebellar diameter was measured in all SGA
      fetuses. RESULTS: The superior cerebellar artery PI was best represented by a
      second-order polynomial equation [PI = 0.145 + 0.101 x (gestational age) -
      0.00197 (gestational age)2]. Small-for-gestational-age fetuses of group A had a
      superior cerebellar artery PI in the normal range, whereas 13 of 15 fetuses of
      group B (86.7%) had a PI value less than the individual 95% confidence interval.
      The transverse cerebellar diameter in group A fetuses was in the normal range in
      ten of 15 cases, whereas it was in the normal range for all group B fetuses.
      CONCLUSION: Small-for-gestational-age fetuses with an abnormal umbilical artery
      PI have "cerebellar-sparing effect," as suggested by a superior cerebellar artery
      PI less than the normal range and a normal transverse cerebellar diameter.

PMID- 8649713
TI  - Q.E.D. saliva testing isn't flawed.

PMID- 8649714
TI  - Medical monitoring: can we do better?

PMID- 8649712
TI  - A comparison of once-daily and 8-hour gentamicin dosing in the treatment of
      postpartum endometritis.
AB  - OBJECTIVE: To evaluate whether once-daily gentamicin dosing is as effective as
      the traditional 8-hour regimen for the treatment of postpartum endometritis.
      METHODS: Postpartum women with endometritis were randomized to receive gentamicin
      5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also
      received clindamycin. Each participant had a peak serum gentamicin level of at
      least 5.0 micrograms/mL within the first 24 hours. The dosing regimens were
      compared by analyzing the number of hours that patients were febrile, the length
      of hospital stay, occurrence of complications, pharmacy costs, and nursing time
      required to administer the regimens. RESULTS: The study group (n = 62) and the
      control group (n = 65) were similar in demographic characteristics and the
      presence of endometritis risk factors. No differences were found between the
      groups in the number of patients who completed therapy without complications,
      required changes in antibiotics, or required readmission for endometritis. The
      groups did not differ in the number of hours that patients remained febrile after
      the start of therapy or in the length of hospital stay. No patient in the study
      group had an initial peak serum concentration less than 5.0 micrograms/mL,
      whereas 24 patients in the control group had initial peak serum concentrations
      less than 5.0 micrograms/mL and required dose adjustment, a statistically
      significant difference (P < .001). Pharmacy costs averaged $16.12 +/- 5.68 for
      the study group and $41.75 +/- 17.41 for the control group, also a significant
      difference (P < .001). Nurse tasking time averaged 13.62 +/- 2.56 minutes for the
      study group and 28.06 +/- 8.77 minutes for the control group (P < .001).
      CONCLUSION: In patients with postpartum endometritis, once-daily gentamicin
      dosing provides consistently high peak serum levels of gentamicin, requires less
      nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

PMID- 8649715
TI  - Dispelling the myths of toxicology.

PMID- 8649716
TI  - Dangerous atmospheres: IH concerns in confined spaces.

PMID- 8649717
TI  - Respirator fit testing.

PMID- 8649718
TI  - Selecting personal protective apparel.

PMID- 8649719
TI  - Office ergonomics: focusing on the problem.

PMID- 8649720
TI  - [The participation of retinoic acid in embryonic and postembryonic development].
AB  - Retinoids are low molecular weight, lipophilic derivatives of vitamin A which
      have profound effects upon the development of various embryonic systems. Here I
      review the these effects on developing and regenerating limbs, regenerating
      amphibian tails and the developing central nervous system (CNS). In the
      regenerating amphibian limb, retinoids can proximalise, posteriorise and
      ventralise the axes. In the chick limb bud retinoids can only posteriorise the
      tissue. In the regenerating amphibian tail retinoids can homoetically transform
      tail tissue into hindlimb tissue. In the developing and regenerating limb
      retinoic acid has been detected endogenously, confirming that this molecule plays
      a role in the generation of pattern and limbs cannot develop in the absence of
      retinoic acid. In the developing CNS retinoic acid specifically affects the
      hindbrain where it causes a transformation of anterior rhombomeres into more
      posterior ones. Again, endogenous retinoic acid has been detected in the CNS and
      in the absence of retinoids the posterior hindbrain has been found to be
      affected. The effects of retinoids on the CNS are most likely to be mediated via
      the Hox genes acting in the mesoderm after gastrulation. It has also been
      proposed that the establishment of the head-to-tail axis in the mesoderm is
      established by retinoic acid. These data show that retinoids play an important
      role in both the development and regeneration of various systems in the embryo
      and post-embryonically.

PMID- 8649721
TI  - [Protein synthesis in the liver and cerebellum of rats growing at different rates
      of intensity].
AB  - Newborn rats were grown in litters of 8 (control), 4, or 16 individuals up to the
      day 21 of postnatal development and then transferred to usual keeping and feeding
      conditions similar for all groups. Liver and cerebellum were removed for the
      study at days 18, 45, and 90. At day 28, the body weight of animals from
      experimental groups differed by approximately three-fold, weight of liver, almost
      five-fold, and weight of the cerebellum, by 1.4 times. The body weight of animals
      also showed significant differences at day 90, however, the weight of the liver
      and cerebellum differed from the control only in animals that received excessive
      feeding. We demonstrate that in the control and in experimental rats, the
      intensity of the protein synthesis during the period from day 18 to day 90 shows
      similar changes, and it is always higher in the liver as compared with the
      cerebellum. Differences between fasting animals and animals given excess food
      generally were apparent mainly at day 90. Thus, feeding disturbances during the
      first weeks after birth result in uncompensated changes of animal growth and of
      the studied animal organs. These data are discussed in connection with
      perspectives of using this model to study specific aspects of three-dimensional
      organization of the nucleolar complex of hepatocytes and cerebellar neurons.

PMID- 8649722
TI  - [The nuclei of the follicular cells regulate steroidogenesis stimulated by a
      pituitary suspension in the follicles of the common frog in vitro].
AB  - It has already been shown that the follicle cell nuclei are not involved in
      regulation of amphibian oocyte maturation stimulated by the gonadotropic hormones
      (Skoblina and Kondrat'eva, 1992). In order to elucidate their involvement in
      regulation of steroidogenesis, we determined changes in the content of
      progesterone, testosterone, and estradiol-17beta in the common frog follicles
      stimulated by the pituitary suspension after preliminary treatment with
      actinomycin D and without it. Treatment with actinomycin D (5 micrograms/ml)
      reliably decreased the content of progesterone and increased that of
      testosterone. The content of estradiol-17beta in the control and actinomycin
      treated follicles was below the method sensitivity. Treatment of the follicles
      with the inhibitor of chloride channels SITS (10 microM) reduced the progesterone
      content to the initial level, did not affect the testosterone content and
      suppressed oocyte maturation.

PMID- 8649723
TI  - [The effect of a synthetic analog of the gonadotropin-releasing hormone and of
      dopamine antagonists on the maturation and quality of loach ova].
AB  - We studied the effects of a synthetic analog of the gonadotropin-releasing
      hormone (aGnRH) and dopamine antagonists on oocyte maturation and ovulation in
      the loach Misgurnus fossilis L. under the conditions of artificial wintering.
      Marked differences in sensitivity of different fish to these drugs were found.
      The use of dopamine antagonists markedly (tens of times) decreased the effective
      dose of aGGGnRH. The sequence of efficiency of the dopamine antagonists was
      determined. Pimozide was most active and Sulpirid followed it. Haloperidol and
      Metaclopromide are markedly less active and they little differ from each other.
      When using little effective drugs or doses including little effective drugs or
      doses inducing a low percentage of ovulation, the time of ovulation was usually
      longer. No essential differences were found in the quality of eggs, obtained
      through stimulation with chorionic gonadotropin or aGnRH injected together with
      Pimozide or Sulpirid at the optimal doses.

PMID- 8649724
TI  - [The ballistic transfection of mammalian cells in vivo].
AB  - The method of ballistic transfection initially proposed for genetic
      transformation of plants was used for animal cells in vitro and in situ. The
      method consists in bombarding the transfected cells with microparticles of heavy
      metals carrying foreign DNA. Having penetrated in the cell nucleus, the
      microparticles transport the introduced gene. Successful genetic transformation
      of the cultured mouse cells and fish embryos was realized and this allowed to
      study mammalian cells in situ. The studies performed allowed us to demonstrate
      expression of the reporter genes of chloramphenicol acetyltransferase,
      galactosidase and neomycin phosphotransferase in the mouse liver, mammary gland
      and kidney explants, in the liver and cross-striated muscle of mouse and rat in
      situ and in developing mouse embryos at the stages of two-cell embryo, morula and
      blastocyst. All these genes were introduced by ballistic transfection. In the
      liver and cross-striated muscle the transgene activity was found within two-three
      months after transfection. Thus, the ballistic introduction of the foreign genes
      in the cells in situ was demonstrated and this opens possibilities for the use of
      this method in gene therapy. Methodical aspects of the bombarding and
      transfection are considered in detail and the published data on transfection and
      genetic transformation of mammalian cells are discussed.

PMID- 8649725
TI  - [The mechanisms of onto- and gerontogenesis].
AB  - The idea that processes in the non-living systems lead, as a result of evolution,
      to the state of thermodynamic equilibrium was almost fully taken up in biology
      (Arshavskii, 1982). The entropic theories of development appeared in this way,
      which dominated until recently. These theories take their origin from the studies
      of Weismann (1882), who noted that the zygote can realize only a certain number
      of divisions during the life cycle due to diminution of chromatin. According to
      this author, this determines ageing starting from the zygote and gradually
      leading to death.

PMID- 8649726
TI  - Molecular biology of sarcomas.
AB  - There has been a virtual explosion of information relating to the biology of
      sarcomas with which we as orthopaedists deal. Much more is yet to be learned.
      These findings will teach us more about the etiology of these tumors. More
      important, the findings will alter the way in which these tumors are treated. It
      is unlikely that we will continue to treat osteosarcoma or Ewing's sarcoma
      patients with currently available drug regimens and surgery or make treatment
      decisions based on the histologic classification of tumors we know today. If we
      are to remain active in the management of these patients we must be aware of the
      findings as they occur. That will ensure both that we remain the primary
      caretakers of these patients, and that we will continue to be stimulated
      intellectually by these intriguing scientific investigations.

PMID- 8649727
TI  - Evaluation of the child with a bone or soft-tissue neoplasm.
AB  - The prebiopsy evaluation of a child with a musculoskeletal neoplasm is the
      cornerstone for all subsequent treatment. A better understanding of the natural
      history of pediatric musculoskeletal tumors and an explosion in the development
      of sensitive new imaging modalities have significantly advanced the care of the
      child with a musculoskeletal pathologic condition. This article details the
      prebiopsy clinical and radiographic evaluation of the child or adolescent with a
      musculoskeletal neoplasm.

PMID- 8649728
TI  - Making the diagnosis: keys to a successful biopsy in children with bone and soft
      tissue tumors.
AB  - A well-planned and -executed biopsy is critical in the management of a child with
      either a bone lesion or a soft-tissue mass. A biopsy is necessary when the
      orthopedic surgeon, in conjunction with the radiologist, believes that the
      radiographic studies or patient history indicate a progressive process that
      requires intervention. Biopsies may be open (incisional or excisional) or closed
      (needle or trephine). Careful attention to biopsy site and technique is important
      to avoid complications that may compromise the ability to preserve a limb.

PMID- 8649729
TI  - Laboratory evaluation of pediatric bone and soft-tissue tumors.
AB  - This article discusses how specimens are approached and handled by the
      laboratory. Basic histology is reviewed. Contributions by electron microscopy and
      immunoperoxidase staining are briefly discussed. Current uses of DNA indices,
      cytogenetic analysis, and new molecular diagnostic advances are highlighted.
      Proper communication between the pathologist and the orthopedist is the
      cornerstone for optimal use of laboratory resources.

PMID- 8649730
TI  - The staging and surgery of musculoskeletal neoplasms.
AB  - This review has outlined the surgical staging of benign and malignant
      musculoskeletal neoplasms. Based on their unique natural history, these neoplasms
      behave in a predictable fashion. The surgical staging system assigns
      progressively higher degrees of risks to the neoplasms based on their surgical
      grade, their anatomic location, and the presence or absence of metastases. The
      staging system articulates well with preoperative planning, defining the margins
      needed for local tumor control. Because surgery distorts most of the imaging
      modalities available, all clinical staging studies must be completed before
      surgical intervention. As more data accrue as to the importance of DNA ploidy,
      genetic markers, and other characteristics, it is likely they will play an
      important role in the diagnosis and treatment of musculoskeletal neoplasms in the
      future.

PMID- 8649731
TI  - Autograft reconstructions.
AB  - Autogenous bone and cartilage grafts provide the optimal material to be used in
      reconstruction of the skeleton. If there were an adequate supply of autogenous
      bone grafts of ideal size and shape, there would be no need for allograft or
      endoprosthetic replacements. Unfortunately, the major limitation to the use of
      autografts is their short supply. This is especially true when articular
      cartilage is needed. The other shortcoming of autogenouus grafts is the donor
      site morbidity, which, although modest, is of concern to the patient and, on rare
      occasions can lead to a significant complication. In the future, we may be able
      to have patients make their own autogenous bone and cartilage grafts, but for now
      we are limited to small corticocancellous grafts, strips of tibia or iliac crest,
      a rib, or the fibula. Clinically useful cartilage grafts can be obtained only
      from the proximal fibula or patella.

PMID- 8649732
TI  - Endoprosthetic bone reconstruction following malignant tumor resection in
      skeletally immature patients.
AB  - Modular and expandable endoprosthetic reconstruction of the child's extremity
      following bone tumor resection affords an opportunity for both limb salvage and
      progressive limb length equalization. This article discusses the rationale,
      advantages, disadvantages, and results of endoprosthetic bone reconstruction
      following tumor resections in the skeletally immature patient. In addition to an
      extensive literature review, an overview of the authors' results with this
      reconstructive option in 31 patients over the past 14 years is presented. This
      article will inform the reader of the current state of the art in endoprosthetic
      reconstruction of the immature patient and should allow clinicians to make more
      informed decisions regarding treatment options for their patients.

PMID- 8649733
TI  - Rotationplasty.
AB  - Today rotationplasty is well established as an acceptable procedure for limb
      salvage in patients who have a malignant tumor in the femur or tibia. The main
      indication is that it is the alternative to amputation. Rotationplasty should
      further be used in the very young child because of growth-dependent complications
      that can be expected after tumor resection and any kind of reconstruction. This
      article covers the classification of the different types of rotationplasties, the
      operative procedure, prosthetic care, and the functional results.

PMID- 8649734
TI  - Amputation surgery and prostheses.
AB  - Wide surgical margins in surgery for a bone tumor can be accomplished either by
      local excision or by amputation surgery. Amputation surgery has less morbidity
      than limb salvage surgery. Prosthetic replacement in the lower-extremity
      amputation should provide an artificial limb that will be comfortable and stable
      for weight bearing. Retention of the anatomic knee joint is critical for better
      ambulation and less energy expenditure. Upper-extremity prosthesis should be
      functional and cosmetically acceptable.

PMID- 8649735
TI  - The evolution of chemotherapeutic agents for the treatment of pediatric
      musculoskeletal malignancies.
AB  - The incorporation of antineoplastic agents in the treatment of pediatric
      musculoskeletal malignancies and their impact in the management and outcome of
      patients with these types of malignancies are briefly reviewed. The role of
      chemotherapy in the management of these tumors with special emphasis on
      osteosarcoma, Ewing's sarcoma family of tumors, and rhabdomyosarcoma and
      undifferentiated sarcomas is discussed. Also included are complications and side
      effects of the antineoplastic agents.

PMID- 8649736
TI  - Current controversies in pediatric radiation oncology.
AB  - Radiotherapy is commonly used in Ewing's sarcoma and pediatric soft-tissue
      sarcomas. In Ewing's sarcoma, radiotherapy appears to produce survival rates
      similar to surgery if used to treat the primary lesion, though the data remain
      subject to interpretation. When surgery is used to treat the primary lesions,
      postoperative irradiation should be given if the margins are less than wide,
      though the response to chemotherapy may also influence local control. In
      nonrhabdomyosarcoma soft tissue sarcomas, postoperative irradiation should be
      given if the margins are less than wide, with doses of 54 Gy at 1.8 Gy per day;
      this provides excellent local control.

PMID- 8649737
TI  - Clinicopathologic features and treatment of osteoid osteoma and osteoblastoma in
      children and adolescents.
AB  - Benign bone-forming tumors are common in children. Careful radiographic imaging
      is necessary to plan surgical treatment. Careful histologic study is necessary to
      distinguish osteoblastoma from more aggressive tumors. Osteoid osteoma should be
      considered when the child or adolescent presents with pain in an extremity or
      along the spine.

PMID- 8649738
TI  - Osteosarcoma and its variants.
AB  - Osteosarcoma is the most common primary malignant tumor of bone. The variability
      of this tumor and its histologic variants in presentation, location, and biologic
      behavior has an influence on the prognosis and determines treatment options.
      Despite improvements in both survival and function due to limb salvage techniques
      and adjuvant chemotherapy, osteosarcoma continues to be a major challenge for the
      medical and surgical oncologist.

PMID- 8649739
TI  - Benign cartilage tumors.
AB  - Benign cartilaginous tumors are some of the most common lesions affecting the
      skeleton of children. These include exostoses, enchondromas, periosteal
      chondromas, chondromyxoid fibroma, and chondroblastoma. The clinicopathologic
      features of these conditions and their treatment is discussed.

PMID- 8649740
TI  - Ewing's sarcoma.
AB  - Ewing's sarcoma is the second most common primary malignant bone tumor of
      children. Tremendous strides in the multidisciplinary treatment of Ewing's
      sarcoma have been made over the past 25 years. Aggressive chemotherapy has
      increased the 5-year survival rates from 10% to over 70%. The role of surgery for
      local control has gained importance. These advances in the diagnosis, staging,
      and treatment of Ewing's sarcoma are discussed in detail.

PMID- 8649741
TI  - Unicameral and aneurysmal bone cysts.
AB  - Unicameral and aneurysmal bone cysts are considered tumorlike conditions of
      unclear origin. The diagnosis of unicameral bone cysts is almost always based on
      the radiographic appearance, whereas aneurysmal bone cyst imaging may sometimes
      mimic a sarcomatous lesion. Several pathogenetic hypotheses [correction of
      hypothesis] reported in literature have been described. Classifications have been
      proposed to detect the activity of the cysts and to predict the prognostic
      behavior. The results observed with different options of treatment have been
      discussed.

PMID- 8649742
TI  - Langerhans' cell histiocytosis.
AB  - Langerhans' Cell Histiocytosis, formerly known as Histiocytosis X, and its
      related syndromes (i.e., eosinophilic granuloma, Hand-Schuller-Christian disease,
      and Letterer-Siwe disease) are briefly reviewed. The biology, clinical
      manifestations, and treatment options of the localized, single form and the
      disseminated, multisystem form are also discussed.

PMID- 8649743
TI  - Pediatric osteomyelitis masquerading as skeletal neoplasia.
AB  - Osteomyelitis has many forms of presentation in the pediatric age group. From
      neonatal osteomyelitis, with a paucity of clinical symptoms and signs, to the
      more typical acute hematogenous form or even the subacute or chronic
      presentations, a high index of suspicion is needed to institute appropriate
      investigations and treatment.

PMID- 8649744
TI  - Orthopedic manifestations of acute pediatric leukemia.
AB  - The variety and distribution of skeletal lesions in children with acute
      lymphoblastic leukemia is rarely seen in other diseases. Skeletal radiographic
      changes that can occur in a child with acute leukemia include diffuse osteopenia,
      metaphyseal bands, periosteal new bone formation, geographic osteolysis,
      osteosclerosis, mixed osteolysis and sclerosis, and permeative destruction. It is
      important for orthopedic surgeons to recognize the skeletal manifestations of
      acute leukemia of childhood because the physician who initially evaluates the
      child will often be an orthopedic surgeon, and a delay in diagnosis has an
      adverse affect on survival.

PMID- 8649745
TI  - Benign soft-tissue lesions in children.
AB  - This article is a review of the common benign soft-tissue lesions of the spine
      and extremities. Reviewed are the pathophysiology, natural history, appropriate
      work-up, and treatment options. A recommendation is given to consider the
      diagnosis as possible malignancy and approach such lesions with caution.

PMID- 8649746
TI  - Pediatric soft-tissue sarcomas.
AB  - Pediatric soft-tissue sarcomas represent a relatively common problem in pediatric
      oncology. The evaluation of these lesions has contributed significantly to the
      understanding of the molecular basis of sarcomas, and the adjuvant treatment of
      these tumors has resulted in improved local control and significant improvements
      in long-term survival. The essence of successful treatment involves preoperative
      imaging, followed by needle biopsy, preoperative neoadjuvant chemotherapy, and
      well-documented surgical resection. Indications for radiation therapy and the
      adequacy of surgical margins remain areas of further investigation. The
      identification and treatment of well-defined histologic and molecular subtypes
      will allow further improvements in treatment decisions and clinical results.

PMID- 8649747
TI  - [Intrauterine management of Rh-alloimmunization].
AB  - The authors report the strategy of invasive management of Rh alloimmunisation in
      pregnancy. From the 34 pregnancies 6 were monitored by amniocenteses, 11 by fetal
      blood sampling, and 4 with combination of the two above mentioned diagnostic
      procedures. In 13 cases the fetuses were treated with intrauterine intravascular
      blood transfusions. All the procedures were ultrasound guided. The fetal blood
      sampling and the transfusions were carried out by puncturing the umbilical vein
      or artery. For transfusions, maternal blood was used in case of identical blood
      type, otherwise adult Rh negative, filtered, washed, irradiated blood was
      transfused. They report the complications as well, giving the cause of their
      fetal losses in details. There were no maternal complications observed. Out of
      the 34 pregnant women 25 had healthy newborns, which number is acceptable in this
      disease with a very high mortality rate. The authors underline that the technique
      of fetal blood sampling and intrauterine transfusion if needed is necessary in
      the management of Rh alloimmunised pregnancies.

PMID- 8649749
TI  - [Sinoatrial block caused by gastroesophageal reflux. The role of simultaneous 24
      hr. esophageal pH-metry and Holter-ECG in the differential diagnosis of angina
      pectoris].
AB  - The authors report on a 61-year-old female patient, who has suffered from
      recurrent angina-like chest pain for 30 years. The patient's complaints became
      intolerable, in spite of therapy with nitroglycerin, H2 receptor blockers and
      sedative medication. The echocardiography, the ECG exercise testing and Thallium
      scintigraphy were normal, the upper gastrointestinal endoscopy did not prove
      oesophagitis either macroscopically or microscopically. The simultaneous 24-hr
      Holter ECG monitoring and esophageal pH-metry demonstrated pathological acid
      gastro-oesophageal reflux and frequent sinoatrial blocks (Mobitz I) in painful
      periods. After monotherapy with proton pump inhibitor (omeprazole) the patient
      became complaint-free. Repeated combined 24-hr oesophageal pH-metry and Holter
      ECG monitoring indicated nonpathological acid reflux and insignificant number of
      sinoatrial blocks. During the course of 19 months the patient was asymptomatic.
      The acid pump inhibitor was stopped for a 10 day-period, while the chest pain
      returned. The combined 24-hr Holter ECG and esophageal pH-metry proved
      pathological acid gastro-oesophageal reflux and frequent sinoatrial blocks during
      chest pain period. After treatment with acid pump inhibitor the patient became
      asymptomatic again. CONCLUSIONS: 1. The acid gastro-oesophageal reflux may be a
      provocative factor of sinoatrial blocks and it can be influenced by proton pump
      inhibitor successfully. 2. Simultaneous 24-hr oesophageal pH-metry and Holter ECG
      monitoring can be contribute to the differentiation among causes of atypical
      chest pain.

PMID- 8649748
TI  - [Effect of vaccination on the risk of hepatitis B infection in hospital
      personnel].
AB  - The effect of vaccination on acute B hepatitis, on HBsAg carrier state and on the
      seropositivity of hepatitis B virus was examined in the personnel of the St.
      Laszlo Hospital in two periods. Human plasma origin vaccine was introduced
      gradually from 1985 to 1989. From 1989 till the end of 1994 recombinant vaccines
      were provided for all workers. A total of 10577 tests were done from 3524 sera of
      2019 hospital workers. A total of 2.4% of the workers developed acute hepatitis.
      Hepatitis B was confirmed most frequently (29%) of hepatitis cases. In the first
      and second period HBsAg positivity was 4.1% and 2.1% (P = 0.1), respectively.
      Although the annual frequency of acute hepatitis has not changed, that of HBsAg
      positivity showed a decreasing tendency during the nine years of the study. The
      prevalence of hepatitis B markers could be characterized by a significant rise in
      close correlation with age. The protective effect of vaccination is markedly
      reflected by the altered prevalence of hepatitis B virus markers in the different
      age groups. At the age of fifty and above hepatitis B seropositivity was 47.2%
      and 36.4% in the first and second period (P = 0.1), respectively. The frequency
      of seropositivity was the highest among the workers of surgical, pathological,
      hepatological departments and ICU. Our results show that vaccination is an
      effective tool in hepatitis B prevention. Every effort has to be made to promote
      hepatitis B immunity to all health care workers and strictly follow hygienic
      preventive measures.

PMID- 8649750
TI  - [Mainz pouch II, a modified method of ureterosigmoidostomy].
AB  - The authors applied a new method, the low pressure ureterosigmoidostomy, namely
      the Mainz pouch II. The essence of the operation was a reverse "U" shape opening
      of the sigma, detubularization, then suturing together, so a diverticulum like
      cavity was created, and the ureters were implanted here. The detubularization
      broke the peristaltic pressure wave in the bowel and protected the kidneys from
      reflux, inflammation and stone formation. From early complications the suture
      insufficiency and sterile disruption of the abdominal wall emerged. The former
      was solved with conversion to rectal bladder, the latter with special stitches.
      Hyperchloraemic acidosis manifested in every case and it was compensated with
      medicines. For the 23 tumour free patients the operation brought daytime
      continency, a good quality of life, and as a palliation diminished the
      complaints. There were no inflammatory complications and only one ureter
      stricture and one fistula developed. The operation technically was simple and
      united the advantages of the ureterosigmoidostomy and the low pressure reservoir.

PMID- 8649751
TI  - [Cardiogenic shock and ventricular fibrillation induced by prajmalium and
      metoprolol poisoning].
AB  - Prajmaline is not a relatively well known and frequently used antiarrhythmic
      belonging to Class IA group of antiarrhythmics, which was administered to a young
      male with metoprolol for the treatment of parasystole. The patient took in 120
      mgs prajmaline and 600 mgs metoprolol during the day of the case, which leads to
      cardiogenic shock, ventricular tachycardia and ventricular fibrillation. The
      patient's parameters were normalized after successful resuscitation, temporary
      pacemaker and two days long Dopamin therapy. Therapy was not regarded to be
      necessary for a few ventricular premature beats detected during a week
      observation period. The patient is without complaints now, and significant
      ventricular arrhythmias, or malignant ventricular ectopy hasn't been proved with
      ECG tests and Holter monitoring for more than three months. Due to adverse effect
      profile of prajmaline, even at commonly used doses it should be administered
      carefully and other agents should probably be considered first before beginning
      long term treatment with prajmaline.

PMID- 8649752
TI  - [Analysis of five mutations of cystic fibrosis occurring in the Hungarian
      population].
AB  - The authors screened 374 patients clinically diagnosed be affected by cystic
      fibrosis. Mutations delta F508, G542X, G551D, R553X, N1303K were analysed to
      obtain genetic diagnosis. The large number of patients involved in this study
      allowed for authors to present precise data of the frequencies of these mutations
      in Hungary. The frequency of mutation delta F508 is found to be significantly
      less then the numbers reported in other studies. This is due to sampling bias
      occurring at little sample sizes. Mutational analysis has been used as a tool of
      prenatal diagnosis.

PMID- 8649753
TI  - [Malignant thyroid tumors in Hungary: morbidity and mortality].
AB  - In 1993, 181 new cases (36 men and 145 women) of thyroid cancer were diagnosed
      pathologically in Hungary, i.e. a morbidity of 1.8/100,000 for the total
      population, and of 0.7/100,000 and 2.7/100,000 for men and women, respectively.
      The distribution of the histological diagnoses: 61% papillary, 25% follicular, 5%
      medullary and 3% anaplastic carcinomas, and 6% others. In the same year, 125
      patients (31 men and 94 women) died from thyroid cancer, i.e. a mortality rate of
      1.2/100,000 for the total population, and of 0.6/100,000 and 1.8/100,000 for men
      and women, respectively. The relatively low morbidity reflects the fact that no
      new strong aetiological factor is operative in Hungary. The substantial mortality
      rate, however, is influenced by the geographically determined aggressivity of the
      disease, the inadequacy of the diagnostic procedures and therapeutic measures,
      and lack of the active follow-up. The latter facts are especially prominent in
      centres with a low patient turnover. In the field of health care, various
      measures must be introduced to prevent an increase in the morbidity and to
      diminish the mortality. Reduction of the iodine deficiency, rationalization of
      the medical use of ionizing irradiation, and implementation of the necessary
      hormonal medication for all patients operated by resection for thyroid diseases
      are needed for tumour prophylaxis. Before any medical decision-making, the
      achievement of complete diagnostic information, including the pathological
      revision of clinically questionable cases, is of paramount importance. The
      fundamental goals as concerns the treatment modalities are as follows: increased
      surgical skill and level of performance of external irradiation, the availability
      of radionuclide therapy, and guidance of all types of thyroxine medication by
      endocrine experts.

PMID- 8649755
TI  - [Papillary cystic neoplasms in the ectopic pancreas].
AB  - The authors reported a case of a young woman. From her omentum a clinically and
      radiologically benign tumour was removed that had been observed for years and
      caused minor symptoms. Histologically the tumour proved to be a so called
      papillary and cystic tumour that originated from ectopic pancreatic tissue. The
      histological diagnosis was justified by immunohistochemical and
      electronmicroscopical examinations. Reports of this type of tumour evolving in an
      ectopic pancreas appeared only twice in the world literature to the knowledge of
      the authors.

PMID- 8649754
TI  - [Emergency situations in hypertension].
AB  - Hypertensive emergency is an acute, perilous state connected with a marked
      increase of peripheral vascular resistance and the decrease of tissue perfusion.
      Its development depends on the rate of blood pressure elevation, on the severity
      of developed hypertension and the state of the vascular system. Although
      hypertensive emergencies can be grouped also on symptomatological and etiological
      basis, regarding the therapeutic measures to be taken, they appear in two well
      distinguishable forms. In case of hypertensive crisis treatment has to be started
      without delay, possibly in a few minutes, in states involving the risk of
      hypertensive crisis treatment has to be initiated within a few hours to avoid
      extensive damage of the vital organs or fatal outcome. The acute, but controlled
      reduction of blood pressure must not surpass 15-25% of the medium value. In
      hypertensive crisis, if possible, parenteral medication--as first aid--urapidil,
      verapamil, in states with endangering hypertensive crisis sublingual nifedipine,
      captopril, nitroglycerin may be applied, however in the different emergency
      states therapeutic intervention has to be individually determined.

PMID- 8649756
TI  - [Milestones in the fight against nosocomial infections in Hungary].
AB  - The world-wide struggle against nosocomial infections began with the work of the
      well known Hungarian physician, Ignac Semmelweis, in the middle of the 19th
      century. His activity is the milestone in the fight against the nosocomial
      infections not only in Hungary but internationally, as well. The recognition made
      in the 1950-s, of more than sixty different sorts of hospital-acquired infections
      frequently occurring in almost all departments of Hungarian hospitals formed a
      major momentum. The acknowledgement of this situation by the highest National
      medical professional council, with all the favourable consequences for future
      solutions, can be taken as the third historical continuation. The next important
      step was the recognition that the immunocompromised state of the hospitalized
      patients is the basis of becoming a victim of a nosocomial infection. The
      epidemiology of these diseases should be called "clinical epidemiology" and may
      be considered as an independent discipline. The major step against the struggle
      of nosocomial infections was the introduction of antibiotic prophylaxis. The
      following step was the construction of a special informatical, preventive and
      control system, collectively called "surveillance". The institutional and
      professional bases of all these activities were provided by the Central Municipal
      Hospital for Infectious Diseases and the National Institute of Traumatology at
      Budapest.

PMID- 8649757
TI  - [Laparoscopic cholecystectomy causing injury to biliary tracts. Analysis of the
      results of 26,440 operations in Hungary].
AB  - The authors analyse the etiology, diagnosis, treatment and outcome of 148 biliary
      tract injuries in connection with 26,440 laparoscopic cholecystectomies performed
      in 89 domestic institutes between January 1st, 1991, and December 31st, 1994.
      There was no significant correlation between the amount of laparoscopic
      cholecystectomies performed in one institute and the incidence of biliary tract
      injuries and postoperative bile leakage (wide range of figures were found in
      different institutes), but in the second year of practice, the incidence of both
      complication decreased (there was statistically significant difference between
      the regression co-efficients). There was no significant correlation between the
      laparoscopic cholecystectomies performed and the rate of conversion, but the co
      efficient of the regression curve showing the correlation of the absolute number
      of laparoscopic cholecystectomies and conversions significantly decreased in the
      second year of practice. In institutes having significantly more conversions,
      more cases of bile leakage was found also. There is a significantly positive
      relationship between biliary tract injuries and postoperative bile leakage; the
      more lesions are found in an institute, the more cases of bile leakage they have.
      There was no significant relationship between the incidence biliary tract
      injuries and postoperative bile leakage and the usage of intraoperative
      cholangiography, preoperative intravenous cholangiography and/or ERCP. The
      partial and complete injuries of main bile ducts were detected intraoperatively
      significantly more often while most of the lesions of the area of cystic duct
      were detected postoperatively. There was no significant difference between the
      types of the only postoperative recognized injuries and the time of establishing
      the diagnosis. Simple suture was performed in 69.2% of the partial injuries (with
      or without T-tube or other drainage), while 63.3% of the complete transsections
      were treated with biliodigestive anastomosis. In univariant analysis the type of
      injury, the primary treatment modality did not affect on the outcome (the ratio
      of cured and expired), but significantly more patients continue to have
      complaints following biliodigestive anastomosis than following the treatment of
      lesions around the cystic duct. The older the patient is, the worse the prognosis
      is. The primary treatment modality (biliodigestive anastomosis or biliary tract
      reconstruction with or without drain) did not significantly altered the necessity
      of reoperation. Thermic injury caused significantly more partial than complete
      lesion. Disturbance in identification of the anatomic structures leads
      significantly more partial or complete main bile duct injuries than lesion in
      region of the cystic duct and causes more complete transsections than partial
      lesions. According to multivariant analysis the outcome is significantly
      influenced in an adverse way by the necessity of repeated interventions and
      higher age.

PMID- 8649758
TI  - [Theoretical and practical problems concerning therapeutic drug monitoring from
      the viewpoint of the pharmacologist].
AB  - Drug treatment is aimed at achieving a maximum therapeutic benefit while
      minimizing unwanted side-effects. The recognition that drug doses administered to
      patients were often inadequate or excessive has highlighted the importance of
      measuring serum levels of drugs - by the methods of Therapeutic Drug Monitoring, 
      for effective patient care. The clinical usefulness of TDM has been undoubtedly
      demonstrated for a number of drugs. During 1990-1995 four commonly used
      anticonvulsive drugs, - carbamazepine, phenytoin, primidone and valproic acid -
      were monitored by an Abbott TDx machine, and the usefulness of TDM was further
      strengthened. In spite of some difficulties the number of samples located in the
      therapeutic range gradually elevated, assuring a better individual therapy and
      cost-benefit ratio. During the last 18 months similar results were obtained with
      theophylline and digoxin as well.

PMID- 8649759
TI  - [Incidence of scurvy in Hungary today].
AB  - The author reports the medical history of a 63-year-old woman. The patient
      collapsed on the street, and the National Ambulance Service transported her to
      the hospital. The clinical picture was characterized by serious anaemia and
      haemorrhagic diathesis. Scurvy has been identified by the measurement of low
      leucocyte-vitamin-C level. While in the last 20-30 years scurvy was not diagnosed
      in Hungary, one cannot easily recognize it. The author thinks necessary to report
      this case, because of its recent infrequency.

PMID- 8649760
TI  - [A case of detection of pulmonary sequestration during the early stage of
      pregnancy and subsequent successful therapy].
AB  - As result of routine ultrasound screening during the pregnancy, the number of
      congenital abnormalities causes severe perinatal respiratory or circulatory
      failure detected antenatally is rising. The severity of the extralobar pulmonary
      sequestration is variable. The intrauterine diagnosis and the proper prognosis is
      difficult because of the rarity of this abnormality. The Color-Doppler ultrasound
      method has a great importance in the diagnosis. With our case report we would
      like to help in the better understanding of this rare abnormality.

PMID- 8649761
TI  - [Free radical reactions in juvenile rats treated with streptozotocin].
AB  - Male, weaned Wistar albino rats (n = 8) were treated by single dose of
      intravenous 50 mg/bodyweight-kg streptozotocin (STZ) injection. Changes in
      carbohydrate and lipid metabolism, and scavenger capacity of red blood cells and
      liver homogenates were evaluated and compared to the respective values of the
      control group (n = 9) after 3 weeks. HbAlc was significantly higher (p < 0.005)
      in the STZ treated group. Plasma triglyceride also showed a marked elevation
      compared to the control group (p < 0.05). Scavenger capacity in erythrocytes was
      significantly (p < 0.05) higher in treated animals while no change was observed
      in liver homogenates. No alteration was observed in the superoxide dismutase
      activity of treated animals, but catalase activity was weaker (p < 0.05).
      Thiobarbituric acid reactive substances were in higher concentration in plasma of
      STZ treated animals (p < 0.01) and were in comparable amount in homogenates. The
      results suggest that 3 weeks after STZ treatment of rats, alterations can be
      observed in the scavenger system and of the examined tissues changes are most
      prominent in erythrocytes.

PMID- 8649762
TI  - [Remembering Georgius Agricola].

PMID- 8649763
TI  - [The naming of "scurvy"].

PMID- 8649764
TI  - Bcl-2 expression prevents activation of the ICE protease cascade.
AB  - The Bcl-2 family and the ICE family of cysteine proteases play important roles in
      regulating cell death. We show here that induction of cell death by a Ca2+
      ionophore or hypoxia results in increased levels and activity of active ICE(
      like) proteases and the subsequent activation of CPP32/Yama(-like) proteases, and
      that inhibition of these protease activities reduces the extent of cell death.
      Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-xL inhibits the cell
      death and the activation of ICE(-like) and CPP32/Yama(-like) proteases,
      indicating that Bcl-2 and Bcl-xL act upstream of these proteases. We also show
      that specific inhibition of ICE(-like) proteases in vivo prevents activation of
      CPP32/Yama(-like) proteases, whereas inhibition of CPP32/Yama(-like) proteases
      does not prevent activation of ICE(-like) proteases, suggesting the existence of
      a protease cascade in vivo that requires ICE(-like) proteases for activation of
      CPP32/Yama(-like) proteases. Induction of necrotic cell death by KCN also induces
      activation of ICE(-like) proteases but not of CPP32/Yama(-like) proteases, and
      Bcl-2 and Bcl-xL inhibit the activation and the cell death, suggesting that the
      functional site of Bcl-2 and Bcl-xL is also upstream of ICE(-like) proteases in
      at least some forms of necrosis.

PMID- 8649765
TI  - Apoptosis suppression by bcl-2 is correlated with the regulation of nuclear and
      cytosolic Ca2+.
AB  - Bcl-2 expression is associated with the progression of prostate cancer from
      androgen-dependence to androgen-independence. Bcl-2 is an integral membrane
      protein which localizes to mitochondria, endoplasmic reticulum, and the nuclear
      envelope. Using spectrofluorometry and laser confocal microscopy, the ability of
      bcl-2 to modulate intracellular Ca2+ was examined in the Dunning G prostate
      carcinoma cell line following apoptosis induction by adriamycin. Adriamycin and
      thapsigargin, an endoplasmic reticulum Ca2+-pump inhibitor, were effective
      inducers of apoptosis in control, but not bcl-2 transfected, cells. Treatment
      with adriamycin was accompanied by a sustained rise in cytoplasmic Ca2+ in
      control and bcl-2 transfected cells. An increase in intranuclear Ca2+ was
      observed in control cells only. Apoptosis induction by thapsigargin was
      associated with an increase in cytoplasmic Ca2+ in control cells that was not
      detected in the resistant bcl-2 transfectants. Ca2+ was excluded from nuclei
      isolated from bcl-2 expressing cells, but was sequestered in control nuclei,
      following the addition of ATP. These findings suggest that bcl-2 may regulate
      levels of intranuclear Ca2+ independently of cytosolic Ca2+ levels. The ability
      of bcl-2 to modulate, directly or indirectly, sustained increases in both
      cytosolic and intranuclear Ca2+ may provide a common basis for bcl-2 function in
      different subcellular compartments.

PMID- 8649766
TI  - Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53
      mutations.
AB  - Germline p53 mutations are frequently observed in the normal DNA of cancer-prone
      patients with Li-Fraumeni syndrome (LFS). Fibroblasts from LFS patients develop
      chromosomal aberrations, loss of cell cycle control, and spontaneous
      immortalization. We transfected four different mutant p53 genes into human skin
      fibroblasts from normal donors with two copies of wild-type p53 (p53(wt/wt)).
      Each mutant p53 expression-plasmid induced genomic instability equivalent to that
      seen in LFS cells. To test the role of wild-type and mutant p53 alleles in DNA
      replication and fidelity in LFS cells, we analysed the replication of the SV40
      based shuttle vector pZ189 in four types of cells. We used p53(wt/mut) and
      p53(mut/-) LFS fibroblasts, and p53(-/-) non-LFS cells. Replication of pZ189 in
      vivo was significantly reduced by the presence of a p53(wt) allele. To show that
      this was not just due to inhibition of the function of T-antigen in SV40-based
      replication, we constructed a shuttle vector, pZ402, that contains a mutation in
      SV40 T-antigen which blocks its ability to interact with p53. Replication of
      pZ402 in LFS cells was also reduced by the presence of p53(wt), indicating that
      p53 can inhibit replication by interacting with proteins within the cellular
      replication machinery. Replicative errors in this shuttle vector are detected as
      mutations in a marker gene, supF. In addition to supF mutations, we observed
      deletion of a portion of the SV40 T-antigen gene in 100% of replicated plasmid
      pZ189 mutants (supF-) from the p53(wt/mut) fibroblasts and in 88% of the supF
      mutants from the p53(mut/-) (amino acid 175 arg to his) LFS cells. In one cell
      strain of immortal LFS cells, P53(mut/-) , containing a p53 frameshift mutation
      at amino acid 184, pZ189 replication yielded very few of these deleted shuttle
      vector plasmids (15%). These large deletions were not detected in plasmids
      replicated in p53(-/-) non-LFS cells, Saos-2 cells. Replicated plasmids with a
      normal supF gene were never found to have this large deletion regardless of the
      cell from which they were derived. Because the supF gene is not in the same
      region of the shuttle vector as the T-antigen gene it appears that second,
      independent gene deletions are frequent when replicative errors in supF occur in
      cells with a mutant p53. We conclude, therefore, that p53(wt/mut) LFS cells
      contain an activity that promotes mutations. Such an activity, which is likely to
      be due to the p53(mut), could result in the high rate of chromosomal instability
      and allelic loss of the wild-type p53 observed as these cells spontaneously
      immortalize.

PMID- 8649767
TI  - Analysis of the proportion of p53 bound to mdm-2 in cells with defined growth
      characteristics.
AB  - A critical parameter affecting cell growth properties is the relative levels of
      the p53 tumor suppressor protein and the mdm-2 oncoprotein. Because mdm-2
      overexpression is observed in several types of human cancers and its physical
      association with p53 appears essential for down-regulating p53 activity the
      proportion of p53 bound to mdm-2 was examined in four types of cells with
      divergent growth properties: (1) Growth arrested cells (Al) expressing high
      levels of wild-type p53 activity; (2) Tumorigenic cells (3T3DM) expressing high
      levels of mdm-2; (3) Immortalized non tumorigenic cells (Swiss3T3 and Balb/c3T3);
      and (4) Normal murine fibroblasts. In Al cells, greater than 78% of the p53 was
      not bound to mdm-2, demonstrating that excess free p53 is available for cell
      cycle arrest. In 3T3DM cells 100% of the p53 was bound to mdm-2 and these cells
      were unable to support p53-mediated transactivation, a p53 function essential for
      cell growth inhibition. In Swiss3T3 cells 75% of the p53 was bound to mdm-2. In
      Balb/c3T3 cells and normal cells no detectable mdm-2 was bound to p53. Since free
      p53 was detected in several of these cell lines the possibility that mdm-2 is
      completely titrated by p53 was investigated. However, free mdm-2 was present in
      all these cells. Phosphorylation of p53 does not appear to control complex
      formation since the free and the mdm-2-bound form of p53 from Al cells had
      identical phosphorylation maps. These data suggest that a high proportion of p53
      bound to mdm-2 is observed in some cells with a more transformed phenotype and
      that p53-mdm-2 complex formation is controlled by a posttranslational event other
      than p53 phosphorylation.

PMID- 8649768
TI  - A 15 amino acid stretch close to the Grb2-binding domain defines two
      differentially expressed hSos1 isoforms with markedly different Grb2 binding
      affinity and biological activity.
AB  - We compared structure, expression and functional properties of two hSos1 cDNA
      isoforms (IsfI and Isf II) isolated, respectively, from human fetal brain and
      adult skeletal muscle libraries. IsfI and IsfII nucleotide sequences differ only
      by the presence in IsfII of an inframe 45 hp insertion located near the first
      proline-rich motif required for Grb2 binding. Some human tissues express only one
      isoform whereas others express different proportions of both in fetal and adult
      stages. In vitro binding assays and in vivo functional studies showed that MI
      exhibits significantly higher Grb2 binding affinity and biological activity than
      IsfI. These results suggest that functionally different hSos1 isoforms, with
      differential tissue expression and distribution, play important regulatory roles
      in the mechanisms controlling Ras activation in different tissues and/or
      developmental stages.

PMID- 8649769
TI  - Okadaic acid stimulated TRE binding activity in a papilloma producing mouse
      keratinocyte cell line involves increased AP-1 expression.
AB  - The effects of the non-phorbol ester type tumor promoter okadaic acid, a serine
      threonine phosphatase inhibitor, on activator protein 1 (AP-1) DNA binding
      activity were studied in papilloma producing 308 mouse keratinocytes. Okadaic
      acid increased AP-1 binding to a consensus TPA responsive element (TRE) within 2
      h; maximum stimulation was observed at 6 h followed by a gradual decrease to
      basal levels within 24 h. Jun B, Jun D and Fos B proteins were identified as the
      major components of the AP-1 complex binding to the TRE element at 6 h.
      Inhibition of transcription with actinomycin D and inhibition of protein
      synthesis with cycloheximide abrogated the okadaic acid effect on AP-1 DNA
      binding, indicating that transcription and translation are required for okadaic
      acid increased TRE binding activity. Northern and Western blot analyses revealed
      a correlation between increased AP-1 binding activity and accumulation of jun B,
      jun D and fos B mRNAs and proteins. These data suggest increased AP-1 expression
      as principal mechanism of okadaic acid stimulated AP-1 activation in the mouse
      keratinocytes studied.

PMID- 8649770
TI  - Overexpression of CD44 in pl85(neu)-transfected NIH3T3 cells promotes an up
      regulation of hyaluronic acid-mediated membrane-cytoskeleton interaction and cell
      adhesion.
AB  - CD44 is a transmembrane glycoprotein known to bind hyaluronic acid (HA) in its
      extracellular domain and to contain at least one ankyrin-binding site in its
      cytoplasmic domain. In this study we have examined CD44 expression in a mouse
      fibroblast cell line transfected with the pl85(neu) oncogene cDNA. The results of
      RT-PCR and Southern blot analyses reveal that CD44s (CD44 standard form)
      transcript is expressed in both pl85(neu)-transfected cells and untransfected
      cells. Using surface iodination, anti-CD44 immunoprecipitation and immuno-binding
      assays, we have found that the number of CD44s molecules expressed on the surface
      of pl85(neu)-transfected cells are at least 4.5-fold higher than those detected
      on untransfected cells. Overexpression of surface CD44s in pl85(neu)-transfected
      cells results in a dramatic enhancement of HA-mediated cell adhesion. Scatchard
      plot analysis indicates that CD44s in pl85(neu) transfected cells binds directly
      and specifically to ankyrin. The binding affinity between CD44s and ankyrin in
      p185(neu)-transfected cells approximately 0.19 nM) appears to be somewhat higher
      than that found in the untransfected cells (K(p) approximately 0.30 nM). Double
      immunofluorescence staining and confocal microscopic analyses indicate that HA
      induces the HA receptor (i.e. CD44s) to form adhesion plaque-like structures, and
      causes an accumulation of intracellular ankyrin directly underneath HA receptor
      (CD44s)-adhesion plaque-like structures in pl85(neu)-transfected cells (but not
      in untransfected cells). These findings suggest that overexpression of CD44s and
      up-regulation of CD44s-ankyrin interaction by pl85(neu) oncogene may be one of
      the pre-requisite steps in regulating tumor cell behavior.

PMID- 8649771
TI  - 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex
      activation and p105Rb phosphorylation during mitogenic stimulation of G(1)
      arrested human breast cancer cells.
AB  - MCF-7 human breast cancer cells express functional estrogen receptor and grow in
      response to estrogen stimulation. G(1)-synchronized MCF-7 cells, made quiescent
      by exposure to the HMG-CoA reductase inhibitor Simvastatin in estrogen-free
      medium, readily resume cell cycle progression upon stimulation with 17beta
      estradiol (E(2)), even under conditions where polypeptide growth factor-triggered
      signal transduction pathways are inhibited by the continuous presence of
      Simvastatin in the culture medium. Under these conditions, cyclin D(1) gene
      transcription is transiently induced within the first 1-9 h of stimulation, as
      shown by the accumulation of cyclin D(1) mRNA and protein (p36(D(1))) in the cell
      and by enhanced expression of stably transfected D(1) promoter-luciferase hybrid
      genes. Estrogen-induced p36(D(1)) associates readily with p32(cdk2) and
      p34(cdk4), but not with p31(cdk5), which is however abundantly expressed in these
      cells. Only p36(D(1))-p34(cdk4) complexes are activated by E(2), as detected in
      cell extracts by immunoprecipitation with anti-D(1) antibodies followed by
      assessment of phosphotransferase activity toward the retinoblastoma (Rb) gene
      product and by analysis of p105(Rb) phosphorylation in vivo. An estrogen
      responsive regulatory region has been mapped within the first 944 bp upstream of
      the transcriptional startsite of the human D(1) gene. Sequence analysis of this
      DNA region reveals that the cis-acting elements responsive to estrogen are likely
      to be different in this case from the canonical EREs.

PMID- 8649772
TI  - HPV-16 E7 and adenovirus E1a complex formation with TATA box binding protein is
      enhanced by casein kinase II phosphorylation.
AB  - The major transforming protein of HPV-16 is encoded by the E7 gene. This has been
      shown to cooperate with EJ-ras in the immortalisation of primary rodent cells and
      with the viral E6 gene in the immortalisation of primary human keratinocytes. HPV
      16 E7 protein has been shown to bind to a number of cellular proteins involved in
      the control of cell growth; including pRB, p107 and cyclin A. Loss of pRb or p107
      binding results in the loss of transforming activity. In this paper we
      demonstrate that HPV-16 E7 can also complex with the core component of TFIID, the
      TATA Box Binding Protein (TBP). This interaction is partly dependent upon
      phosphorylation of the E7 protein by cellular casein kinase II (CKII), since
      phosphorylation of E7 by CKII increases the affinity with which E7 binds TBP.
      Similar results are also obtained with the Adenovirus Ela protein, indicating a
      conservation of function between these two viral oncoproteins. Mutation of the
      CKII site to two acidic amino acids significantly increases the affinity of E7
      for TBP, indicating that the incorporation of two negative charges at this region
      of E7 is important in regulating the interaction with TBP.

PMID- 8649773
TI  - Transcriptional repression by the proto-oncogene BCL-6.
AB  - In up to 45% of reported cases of the non-Hodgkin's lymphoma, diffuse large cell
      lymphoma, there are translocations of the BCL-6 gene, which are presumed to
      deregulate its expression. The BCL-6 protein, which is unmutated in these
      lymphomas, contains six Kruppel-like zinc fingers at its carboxy terminus and a
      121 amino acid domain at its amino terminus, termed the POZ domain, which bears
      homology with amino terminal domains in a subset zinc finger transcription
      factors. In this study, we tested whether BCL-6 regulates transcription and if
      the POZ domain has a role in this function. The BCL-6 POZ domain, when fused to
      the GAL4 DNA binding domain, strongly repressed transcriptional activation
      initiated from several different promoters including the SV40 enhancer/promoter.
      Repression was also observed when the fusion protein was bound at a distance of
      200 bp 5' of the promoter. When the GAL4/BCL6 POZ domain fusion protein was
      expressed in yeast, it was able to homodimerize in the nucleus. Nevertheless, in
      contrast with mammalian cells, the fusion protein did not repress transcription.
      To test the ability of the full length BC1-6 protein to repress transcription
      when bound to DNA through its zinc finger DNA binding domain, high affinity BCL-6
      binding sites were selected from a pool of random oligonucleotides. Full length
      BCL-6 was able to strongly repress transcription when bound to its cognate site
      cloned upstream of the thymidine kinase promoter. This repression was mediated,
      in large measure, by the POZ domain, although a variant of BCL-6 lacking the POZ
      domain was able to repress transcription modestly. The ability of BCL-6 to
      function as a transcriptional repressor may contribute to its ability to
      transform B lymphocytes in diffuse large cell lymphoma.

PMID- 8649774
TI  - Association of a novel GTP binding protein, DRG, with TAL oncogenic proteins.
AB  - TAL1 is a basic helix-loop-helix (bHLH) protein involved in hematopoietic
      development. In T cell acute lymphoblastic leukemic cells, TAL1 is aberrantly
      overexpressed and is thought to contribute to oncogenesis. To identify proteins
      that interact with TAL1 in mediating leukemogenesis, we used TAL1 as a bait in a
      two-hybrid interaction screen, and isolated a cDNA clone that encodes a unique
      GTP binding protein, DRG. The interaction between DRG and TAL1 was confirmed both
      in vitro and in vivo. DRG was also shown to bind in vitro to two TAL1-related
      proteins, TAL2 and Lyl1. Mutational analyses showed that the HLH domain of TAL1
      was necessary and sufficient for its interaction with the C-terminus of DRG.
      Furthermore, while DRG and E47 compete to interact with TAL1, TAL1 binds to DRG
      and E47 in a mutually exclusive manner. In rat embryonic fibroblast
      transformation assays, DRG stimulated the cotransforming activity of c-myc and
      ras. Based on these results, DRG appears to be a potential target for TAL-like
      oncoproteins.

PMID- 8649775
TI  - Nck inhibits NGF and basic FGF induced PC12 cell differentiation via mitogen
      activated protein kinase-independent pathway.
AB  - Proto-oncogene Nck, an adapter molecule containing three SH3 and one SH2 domains,
      binds to cell surface receptors and mediates mitogenic effects in the cells.
      Overexpression of Nck caused cell transformation in vitro and tumor formation in
      the nude mice. The mechanism of this action by Nck, however, remained unclear.
      Rat adrenal pheochromocytoma cell line PC12 provides a useful system for studying
      growth factor-regulated cell proliferation and differentiation. Serum and
      epidermal growth factor (EGF) stimulate proliferation, whereas nerve growth
      factor (NGF) and basic fibroblast growth factor (bFGF) cause growth arrest and
      sympathetic neurite outgrowth in these cells. To study the function of Nck, we
      generated stable clones of PC12 cells overexpressing the human Nck. We report
      here that the overexpressed Nck caused continued proliferation of PC12 cells even
      in the presence of NGF and blocked both the NGF- and bFGF-induced neurite
      outgrowth. Anti-sense but not sense oligonucleotides to the human Nck resumed the
      NGF-induced differentiation, indicating the specific inhibitory effect of Nck.
      Interestingly, Nck did not interfere with the kinetics of NGF- and EGF-stimulated
      protein tyrosine phosphorylation and the mitogen-activated protein kinase (MAPK)
      activation, suggesting that Nck inhibited the induced PC12 cell differentiation
      via a MAPK-independent mechanism. This study has provided a useful system for
      further understanding the function of Nck.

PMID- 8649776
TI  - The 273rd codon mutants of p53 show growth modulation activities not correlated
      with p53-specific transactivation activity.
AB  - Cancer-related mutations of the p53 tumor suppressor gene are clustered in the
      four so-called 'hot spots', codons 175, 248, 273 and 281/282. By using
      recombination PCR in vitro mutagenesis, we introduced point mutations into the
      codon 273 of wild-type (wt) p53 (pC53-SN3) from Arg to His (pC53-273H [273H]),
      Asp (273D), Pro (273P), Lys (273K), Leu (273L) or Thr (273T), and compared their
      biological and biochemical activities with wt p53 and cancer-derived 175H, 248W
      and 273H/309S. Among them, 273H/309S, 273H and 273D as well as wt p53
      transactivated the chloramphenicol acetyltransferase (CAT) gene placed downstream
      of the p53 binding consensus, while none of the other mutants including 273L did.
      Transcriptions from human c-fos and rat PCNA promoters were suppressed by wt p53
      and 273D, while they were enhanced variously by all other mutants in Saos-2
      and/or NIH3T3 cells. On the other hand, growth of human squamous carcinoma cell
      lines measured by the plating efficiency of G418-resistant colonies was enhanced
      by transfection of 175H, 248W, 273H/309S and 273P, while suppressed by not only
      wt p53, 273D and 273H but also 273L. Thus, 273H/309S enhanced cell growth in
      spite of its p53-specific transactivation activity, while 273L suppressed cell
      growth in spite of its complete loss of the p53-specific transactivation. We
      concluded that the sequence-specific transactivation of p53 is not always
      correlated with its growth inhibitory activity.

PMID- 8649777
TI  - Growth inhibitory concentrations of EGF induce p21 (WAF1/Cip1) and alter cell
      cycle control in squamous carcinoma cells.
AB  - Previous studies have reported inhibition of A431 squamous carcinoma cell growth
      by nanomolar concentrations of epidermal growth factor (EGF), a potent mitogen
      for cells of epithelial origin. In this study, we examined potential mechanisms
      through which inhibition of keratinocyte growth mediated by EGF might occur by
      analysing components of the cell cycle regulatory machinery in A431, HN6 and HN30
      keratinocytes in the presence of growth inhibitory or growth stimulatory doses of
      EGF. Treatment of cells with 25 pM EGF produced an increase in [3H]thymidine
      incorporation in A431, HN6 and HN30 cells, with respect to control cultures.
      Exposure to 2.5 nM EGF reduced [3H]thymidine incorporation in A431 cells and HN6
      cells to 11% and 70% of control levels, respectively, whereas HN30 cells
      continued to proliferate in the presence of EGF. [3H]thymidine incorporation
      assays carried out over 24 h revealed repression of DNA synthesis in A431 cells
      after 12 h exposure to 2.5 nM EGF compared to untreated cells. Flow cytometry
      studies demonstrated accumulation of cells in G0/G1 after addition of 2.5 nM, but
      not 25 pM EGF. Western blot analysis revealed elevation of p21 (WAF1/CIP1/SDI1)
      protein levels in A431 and HN6 cells under growth-inhibitory conditions.
      Stimulatory doses of EGF did not induce p21 in these cells. Northern blot
      hybridization demonstrated elevated levels of p21 mRNA within 4 h of exposure of
      A431 cells to 2.5 nM EGF, which remained elevated above basal levels at 24 h. In
      vitro kinase assays demonstrated temporal differences in CDK2 and CDK6 activities
      which were related to EGF concentration. Immunocomplex Western blotting
      demonstrated increased association of p21 with CDK2 and CDK6 in A431 cells
      treated with 2.5 nm EGF. Furthermore, temporal alterations in the association of
      PCNA with p21 and with CDK6 were observed. The data indicate that p21 is a likely
      mediator of EGF-induced growth-inhibition, probably through mechanisms involving
      sequestration of PCNA and inhibition of CDK activity.

PMID- 8649778
TI  - Synergism between two growth regulatory pathways: cooperative transformation of
      NIH3T3 cells by G alpha 12 and c-raf-1.
AB  - The alpha-subunit of the heterotrimeric G-protein, G12, has been shown to induce
      cellular transformation when overexpressed or oncogenically activated in rodent
      fibroblasts. To investigate the interaction between Galpha12 transforming pathway
      and the Ras-Raf-MAPK pathway, we examined the ability of mitogenic signaling
      molecules in cooperating with Galpha12 in transforming NIH3T3 fibroblasts. We
      observed a striking cooperative effect on focus-forming ability when Galpha12 and
      c-raf-1 cDNAs were co-transfected into NIH3T3 cells. NIH3T3 cells coexpressing
      both Galpha12 and c-raf-1 resulted in the constitutive activation of the
      mitogenic-activated protein kinase (MAPK). In addition, the levels of GTP-bound
      Ras were elevated in Galpha12 transformed NIH3T3 cells. Our results provide a
      model for studying the effects of simultaneous activation of two distinct growth
      regulatory pathways in cellular transformation.

PMID- 8649780
TI  - The retinoblastoma protein modulates expression of genes coding for diverse
      classes of proteins including components of the extracellular matrix.
AB  - The product of the retinoblastoma susceptibility gene, pRb, is a negative
      regulator of cell growth. It functions by regulating the activity of
      transcription factors. Rb represses some genes by sequestering or inactivating
      the positive transcription factor E2F and seems to activate some others by
      interacting with factors like Sp1 or ATF-2. However, there are only a few
      examples of genes which are positively regulated by pRb. In order to find out if
      there are common mechanisms for promoter regulation by pRb, we were interested to
      identify more genes which are either stimulated or repressed by pRb. Using the
      method of differential display (DDRT-PCR) in combination with nuclear run-on
      analyses we were able to detect a number of genes which are upregulated by
      ectopic expression of the Rb gene in Rb-deficient mammary carcinoma cells. We
      could demonstrate not only stimulation of the endogenous mutant Rb gene but also
      positive regulation of genes coding for diverse classes of proteins, including
      the endothelial growth regulator endothelin-1 and the proteoglycans versican and
      PG40. As a second approach, we investigated gene expression in cell lines
      established from Rb deficient heterozygous and homozygous knockout mouse embryos
      and normal mice. We have identified several genes the expression of which
      correlates positively or negatively with the presence of Rb. These data provide
      further evidence for pRb being a master regulator of a complex network of gene
      activities defining the difference between dividing and resting or differentiated
      cells.

PMID- 8649779
TI  - Inhibition of p105 processing by NF-kappaB proteins in transiently transfected
      cells.
AB  - Regulation of the transcription factor NF-kappaB involves proteasome-mediated
      processing of the NF-kappaB1 p105 precursor protein, which generates the p50
      subunit of NF-kappaB. The processing of p105 occurs constitutively in vivo but
      can be markedly enhanced by various cellular activation agents, although the
      underlying regulatory mechanism is not yet clear. In the present study, we
      demonstrate that signal-mediated induction of p105 processing in human T cells is
      associated with de novo synthesis of this precursor protein. Transient
      transfection studies performed in COS7 cells revealed that the newly synthesized
      p105 protein appears to be more rapidly processed compared to its accumulated
      form that is already associated with the processed product p50. Interestingly,
      the processing rate of p105 is markedly inhibited in cells co-transfected with
      p50 or other NF-kappaB subunits, including RelA and c-Rel, that physically
      interact with p105. These findings suggest that the processing of p105 is subject
      to negative regulation by the various NF-kappaB subunits. We further demonstrate
      that p105 undergoes degradation in lipopolysaccharide-stimulated human monocytic
      cells. However, the inducible degradation of p105 is not coupled with the
      generation of p50. Together, these studies demonstrate that the processing and
      inducible degradation of p105 are differentially regulated.

PMID- 8649781
TI  - Selective cooperation of HTLV-1-encoded p40tax-1 with cellular oncoproteins in
      the induction of hematopoietic cell proliferation.
AB  - Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T
      cell leukemia (ATL). The virus-encoded p40tax-1, a nuclear oncoprotein, is known
      to promote transcription of its own as well as a variety of cellular genes.
      However, the mechanism by which p40tax-1 promotes lymphocyte transformation is
      not fully understood. In the present study, we examined whether p40tax-1 can
      induce hematopoietic cell proliferation by cooperating with the products of
      cellular proto-oncogenes; i.e. an activated form of the src-family protein
      tyrosine kinase p56lck (lck F505), c-Myc or Bcl-2. These oncoproteins are
      critical mediators of interleukin 2 (IL-2)-induced proliferative signals. We show
      that p40tax-1 alone cannot render the hematopoietic cell line, BAF-B03, able to
      proliferate in the absence of cytokines, but it can do so in cooperation with
      lckF505, or c-Myc but not with Bcl-2.

PMID- 8649782
TI  - The v-Jun oncoprotein replaces p39 c-Jun as the predominant AP-1 constituent in
      ASV17-transformed fibroblasts: implications for SAPK/JNK-mediated signal
      transduction.
AB  - We have investigated the expression of Jun family proteins and composition of AP
      1 in chicken embryo fibroblasts before and after transformation by the v-Jun
      oncoprotein of ASV17. We show that p39 c-Jun is the predominant Jun family
      protein expressed in normal fibroblasts, and that heterodimers of c-Jun and Fos
      related partners (Fra's) account for the majority of the AP-1 DNA binding
      activity. Unexpectedly, because ASV17-transformed fibroblasts do not express p39
      c-Jun, v-Jun replaces c-Jun as the predominant AP-1 constituent in association
      with similar or identical Fra's. This substitution has little effect on the
      overall level of TRE-specific DNA binding activity, however it results in a
      profound reduction in TRE-dependent transcriptional activity and a striking
      defect in signal-regulated phosphorylation of the Jun component of AP-1; whilst
      agonists of SAPK/JNK kinases trigger transient N-terminal phosphorylation of c
      Jun in normal fibroblasts, no corresponding modification of v-Jun occurs in ASV17
      transformed cells. Because SAPK/JNK-mediated phosphorylation is thought to
      regulate c-Jun transcriptional activity and thereby cellular gene expression in
      response to extracellular signals, we propose that subversion of this signal
      transduction process by v-Jun is likely to contribute to oncogenesis by ASV17.

PMID- 8649783
TI  - Proliferation of HTLV-1 infected circulating cells in vivo in all asymptomatic
      carriers and patients with TSP/HAM.
AB  - Assuming that the clonal expansion of T cells harbouring the human T-cell
      leukemia virus type 1 (HTLV-1) provirus is a central feature of HTLV-1 infection,
      the identification of such cells was sought among a series of 19 asymptomatic
      carriers and 19 cases of tropical spastic paraparesis/HTLV-1 associated
      myelopathy (TSP/HAM) devoid of malignancy. Two PCR based protocols designed to
      amplify the host cell-HTLV-1 proviral integration sites were used. In all cases
      large numbers of proliferating clones could be identified. The proportion of some
      clones was > 1/1500 peripheral blood mononuclear cells (PBMCs) with the
      suggestion that their number increased as a function of age among asymptomatic
      carriers.

PMID- 8649784
TI  - Identification of lysine residues required for signal-induced ubiquitination and
      degradation of I kappa B-alpha in vivo.
AB  - Activation of transcription factor NF-kappaB involves signal-induced degradation
      of the protein inhibitor IkappaB-alpha and release of NF-kappaB which
      translocates to the nucleus where it influences transcription of responsive
      genes. Although multiple regions of IkappaB-alpha are involved in this process,
      the N-terminal region of the protein has been identified as a regulatory region
      that is required for signal induced phosphorylation and degradation. The
      sensitivity of IkappaB-alpha degradation to peptide aldehydes which inhibit
      components of the proteasome and the detection of ubiquitinated forms of IkappaB
      alpha indicate that IkappaB-alpha is degraded by the ubiquitin-proteasome
      pathway. To identify lysine residues that represent the sites of ubiquitin
      addition, a series of lysine to arginine mutations were introduced into IkappaB
      alpha and the mutant proteins tested for their ability to function in vivo.
      Exposure of COS7 cells, cotransfected with IkappaB-alpha and a TNF-responsive NF
      kappaB reporter gene, resulted in stimulation of reporter activity as a
      consequence of IkappaB-alpha degradation. In contrast, this effect was
      drastically reduced when an IkappaKB-alpha mutant carrying serine to alanine
      changes at amino-acids, 32 and 36, which blocks both signal-induced
      phosphorylation and ubiquitin conjugation of the protein, was co-transfected with
      the reporter gene. Likewise, a mutant form of IkappaB-alpha containing lysine to
      arginine changes at positions 21 and 22 (K21R, K22R) severely reduces TNF-induced
      activation of the NF-kappaB-dependent reporter gene. Examination of the
      metabolism of mutant IkappaB-alpha molecules reveals that, while the K21R, K22R
      mutant inhibits the DNA-binding activity of NF-kappaB and undergoes signal
      induced phosphorylation, it is neither ubiquitinated nor degraded in response to
      TNF. Thus, it is likely that after signal-induced phosphorylation Of IkappaB
      alpha on serine residues 32 and 36, lysine residues 21 and 22 are major sites of
      ubiquitin ligation which target the protein for rapid degradation by the
      proteasome.

PMID- 8649785
TI  - A previously undescribed mutation within the tetramerisation domain of TP53 in a
      family with Li-Fraumeni syndrome.
AB  - We report details of a family with classic Li-Fraumeni syndrome in which there is
      a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key
      residue within the tetramerisation domain, and the amino acid substitution of a
      proline for a leucine is predicted to have profound implications for
      tetramerisation and potentially DNA binding. This is the first report of a
      mutation at this residue in either sporadic tumours or in the germline and the
      first report of a germline mutation within the tetramerisation domain. The family
      does not appear to be remarkable in the spectrum of tumours, and there is loss of
      the wild-type allele in a leiomyosarcoma from the proband. A cell line has been
      established from the tumour of the proband and cytogenetic and molecular studies
      carried out, providing an extensive analysis in this family.

PMID- 8649786
TI  - Differential changes of retinoid-X-receptor (RXR alpha) and its RAR alpha and PML
      RAR alpha partners induced by retinoic acid and cAMP distinguish maturation
      sensitive and resistant t(15;17) promyelocytic leukemia NB4 cells.
AB  - The expression of retinoid receptors (RXRalpha, RARalpha and the chimeric form
      PML-RARalpha) was analysed both at the mRNA and protein level in the maturation
      sensitive NB4 and resistant NB4-R1 cell lines of t(15;17) promyelocytic leukemia
      (APL). All-trans RA and cAMP which show synergistic activity in inducing
      maturation of NB4 cells and maturation triggering of the RA 'primed' NB4-R1
      resistant cells, distinctly modulate RXRalpha, RARalpha and PML-RARalpha mRNA. In
      the NB4 and NB4-R1 cells, RXRalpha mRNA was downregulated by RA, but only in RA
      primed NB4-R1 cells a release from RXRalpha mRNA downregulation was obtained by
      cAMP treatment. RXRalpha protein (53 kDa) was decreased to the western-blot
      detection limit (97.5%) by RA in NB4 cells, but in NB4-R1 cells although it was
      frankly decreased (85%), the signal for RXRalpha protein remained very
      significant. More importantly, while cAMP slightly upregulated RXRalpha protein
      in RA-treated NB4 cells, it caused an increase of RXRalpha protein in RA-treated
      NB4-R1 cells bringing RXRalpha to the initial control level. RXRalpha partners in
      heterodimers (PML-RARalpha, RARalpha) were also analysed. In contrast to
      RXRalpha, RARalpha and PML-RARalpha mRNA were not modulated by RA and/or cAMP,
      while significant changes were observed at the protein levels. A putatively
      phosphorylated form of RARalpha (52 kDa) decreased during maturation of NB4
      cells, but was unchanged in resistant NB4-R1 cells. Conversely, while PML
      RARalpha remained stable during RA-induced NB4 maturation, RA treatment which
      failed to induce maturation of NB4-R1 cells significantly down-regulated the
      chimeric receptor (120 kDa). These differences most likely results from
      translational and post-translational regulation. This work reveals complex
      pattern of subtle changes at the protein level distinguishing RA-sensitive and RA
      resistant cells. Our data show that the RA-cAMP synergistic effect on NB4 cell
      maturation and cooperation in triggering maturation of RA-primed NB4-R1 cells
      operate changes in the RXR/PML-RARalpha ratio which are both favouring RXRalpha.
      In both cell lines, variations of PML-RARalpha and RXRalpha may result in a
      decrease in the formation of the PML-RARalpha/RXRalpha heterodimers which are
      supposed involved in the block of maturation. This may prove crucial to embark
      cells on maturation.

PMID- 8649788
TI  - Epitope analysis of the murine p53 tumour suppressor protein.
AB  - The identification and characterisation of the p53 tumour suppressor has relied
      extensively on the use of immunological reagents. To facilitate further
      characterisation of the murine p53 protein (Mp53), and its interaction with other
      proteins, we have characterised the antigenic sites of Mp53 in fine detail. Using
      an overlapping Mp53 peptide library we report the identification by Pepscan ELISA
      of the epitopes of nine antibodies. We have also used this technique to determine
      whether corresponding epitopes were present in a human p53 (Hp53) peptide
      library. This comparison was extended to include polyclonal sera of mice
      immunized with either Mp53 or Hp53, to compare the overall range of antigenic
      sites. The range of antigenic sites identified by polyclonal sera is very
      similar, although the N-terminus of Mp53 is clearly not an immunodominant region,
      in contrast to the N-terminus of Hp53. However, the N-terminus of Mp53 is
      immunogenic in rabbits as demonstrated by the Pepscan ELISA of CM5 serum (a
      rabbit anti-Mp53 serum used in analysing p53 expression in mice). Since, very few
      new antigenic sites were identified in either Mp53 or Hp53, new approaches will
      have to be employed to identify novel immunological reagents against human and
      murine p53.

PMID- 8649787
TI  - cAMP signalling is decisive for recovery of nuclear bodies (PODs) during
      maturation of RA-resistant t(15;17) promyelocytic leukemia NB4 cells expressing
      PML-RAR alpha.
AB  - We analysed the expression of retinoid receptors and PML in relation to the
      morphology of PML-containing nuclear bodies (PODs) in maturation sensitive (NB4)
      and resistant subclones (NB4-R1 and R2) of the promyelocytic NB4 cell line. The
      basal level of RARalpha, RXRalpha and PML mRNA and protein were roughly the same
      in the three cell lines. While NB4 and NB4-R1 cells express comparable amounts of
      PM-RARalpha mRNA and 120 kDa protein, NB4-R2 cells despite normal mRNA levels the
      120 kDa protein was not detectable. In NB4-R2 cells however, two novel PML
      related entities of 65 kDa and 85 kDA were detected with a anti-PML antibody, in
      addition to the two PML isoforms of 78 and 97 kDa found in any NB4 cells. Despite
      the 120 kDa PML-RARalpha defect, NB4-R2 cells show micropunctuated nuclear bodies
      typical of APL cells. Contrasting with NB4 cells, neither NB4-R1 cells which
      express PML-RARalpha, nor NB4-R2 cells lacking the 120 kDa PML-RARalpha
      reorganised nuclear bodies (PODs) in response to RA. Importantly, in RA-primed
      NB4-R1 cells, a secondary event triggered by cAMP restored PODs, concomitant to
      maturation. This indicates that the recovery of nuclear bodies in APL is
      dissociated from the early action of RA in cell maturation. Finally, the key
      finding of this work is that cAMP signalling ultimately determines the recovery
      of nuclear bodies associated to cell maturation.

PMID- 8649789
TI  - The identification of p130cas-binding proteins and their role in cellular
      transformation.
AB  - Adaptor proteins play an important role in signal transduction by regulating the
      establishment and maintenance of functionally important protein complexes. A
      recently described member of this group of proteins is p130cas (CAS), which
      contains numerous sequence motifs predicted to be involved in mediating protein
      protein interactions. We propose that adaptor molecules like CAS may help
      determine the response of a cell to a particular signal by interacting with
      specific subsets of cellular proteins. To test this hypothesis, we have
      identified potential binding partners of CAS that may play a rote in cellular
      transformation by the oncoproteins v-SRC and/or v-CRK. We show that individual
      domains of CAS associate with specific subsets of proteins in vitro, and that
      many of these interactions are dependent on the state of tyrosine-phosphorylation
      of CAS. Sequences necessary for interacting with the focal adhesion kinase
      pp125FAK (FAK), v-SRC and v-CRK have been mapped to distinct regions of CAS. In
      addition, the identification of a number of putative CAS-binding partners that
      are present in crk-transformed cell extracts but undetectable in normal and src
      transformed cell extracts supports a model in which unique protein complexes are
      formed in response to different signals.

PMID- 8649790
TI  - Heregulin is rapidly translocated to the nucleus and its transport is correlated
      with c-myc induction in breast cancer cells.
AB  - Heregulins (neuregulins) are a family of proteins known to interact and activate
      the receptor tyrosine kinases ErbB2 in association with ErbB3 or ErbB4. Using
      immunofluorescence microscopy, electron microscopy autoradiography, and SDS-PAGE
      analysis of nuclear fractions, we show that the heregulin-beta1(1-244) isoform is
      rapidly internalized and translocated to the nucleus of SK-BR-3 breast cancer
      cells as an intact molecule. Heregulin-beta 1(1-244) treatment up-regulated
      expression of c-myc mRNA and protein, which was also observed to undergo its own
      translocation from the cytosol to the nucleus. c-myc thus appears to be a
      cellular target gene of HRGbeta 1(1-244), and its induction may be related to the
      nuclear translocation of heregulin.

PMID- 8649791
TI  - A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in
      myeloid leukaemia cell lines.
AB  - The response of the CML-BC cell line, K562, the myelomonocytic cell line MM6 and
      the promyelocytic leukaemia cell line HL-60, to a 15 mer WT1 antisense
      oligonucleotide, targeted to the translation initiation site of the WT1 mRNA was
      examined. K562 cells exposed to 0.4 microM antisense oligonucleotide showed
      markedly reduced proliferation which was associated with reduced cell viability.
      Sense, scrambled and mutant antisense oligonucleotides had no effect on the
      proliferation of K562 cells. MM6 cells exposed to 0.4 microM antisense
      oligonucleotide also showed significantly reduced cellular proliferation which
      was also accompanied by loss of cell viability. In the K562 and MM6 antisense
      cultures that exhibited reduced cell viability, both DNA fragmentation and
      morphological features consistent with apoptosis could be identified. In contrast
      the growth of HL-60 cells was unaffected by exposure to 0.4 microM antisense
      oligonucleotide. In each of the cell lines examined, WT1 antisense
      oligonucleotide abrogated WT1 protein expression, and analysis of WT1 coding
      sequence in these cells showed that no oncogenic point mutations in the gene were
      present. We propose therefore that in some myeloid leukaemia cell lines, the
      expression of a normal WT1 protein is necessary for cell proliferation and that
      it plays a role in maintaining the viability of some leukaemia cells.

PMID- 8649793
TI  - Altered AP-1/ATF complexes in adenovirus-E1-transformed cells due to EIA
      dependent induction of ATF3.
AB  - The adenovirus (Ad) E1A proteins alter the expression level and activity of AP
      1/ATF transcription factors. Previously we have shown that in AdE1-transformed
      cells cJun is hyperphosphorylated in its N-terminal transactivation domain, which
      parallels enhanced transactivation function. To find out whether the interaction
      between cJun and other cellular proteins is altered, we have searched for
      proteins which would physically associate with cJun. In this report we show that
      in AdE1-transformed cells cJun specifically associates with two proteins of 21
      and 23 kD. These proteins are not expressed at detectable levels in the parental
      cells or in cells transformed by oncogenes other than AdE1. The cJun-associated
      proteins represent different forms of the bZIP transcription factor ATF3, the
      human homolog of rat LRF1. The expression of ATF3 is induced in AdE1-transformed
      cells and is a direct effect of the expression of E1A. Through induction of ATF3
      expression and the subsequent formation of cJun/ATF3 heterodimers, E1A alters the
      repertoire of AP-1/ATF factors and may thereby redirect the corresponding gene
      expression program. Since the induction of ATF3 is a function of sequences within
      the transforming 12S-ElA protein, cJun/ATF3 complexes might be involved in
      establishing cellular transformation by AdE1A.

PMID- 8649792
TI  - IL2 triggers a tumor progression process in a melanoma cell line MELP derived
      from a patient whose metastasis increased in size during IL2/INFalpha biotherapy.
AB  - Human melanomas may express both in vivo and in vitro functional IL-Rs and may be
      expected to directly respond to injected IL2. This may generate biological
      situations which may be favourable for the patient, but also for tumor
      progression. Here, we analyse the latter hypothesis. MELP is a melanoma cell line
      derived from a patient whose metastasis increased in size during IL2/IFN alpha
      biotherapy [correction of biotheraphy]. These cells have been characterized in
      vitro for their phenotype and for their sensitivity to IL2. In vitro MELP cells
      express an IL2-R alpha(+) beta(+) gamma(-) phenotype and IL2 treatment induces
      the acquisition of new functional characteristics represented (i) by the
      increased surface expression of two markers of metastatic evolution (ICAM-1 and
      CD44); (ii) by the stable induction of the IL2-R gamma with the appearance of
      functional IL2-R beta complex, which are also recognized by GM-CSF; (iii) by the
      inhibition of transcription of a regulatory cytokine such as IL6; (iv) by a
      differential effect of IL6 on CD44 surface expression in MELP cells treated or
      not with IL2 (MILG cells); (v) by the acquisition of faster growth rates and
      appearance of piling up and multilayer cellular organization; (vi) by the
      development of rapidly growing tumors in nude mice. IL2 induces in MELP cells a
      tumor progression process that could mimic the metastatic evolution observed in
      vivo during biotherapy. Therefore, MELP phenotype may help to define a subset of
      patients in which IL2 therapy may trigger unfavourable evolution.

PMID- 8649794
TI  - Tyrosine phosphorylation at the membrane-microfilament interface: a p185neu
      associated signal transduction particle containing Src, Abl and phosphorylated
      p58, a membrane- and microfilament-associated retroviral gag-like protein.
AB  - Microfilaments are associated with the microvillar membrane in the 13762 ascites
      rat mammary carcinoma cells by stable interaction with a large, multimeric signal
      transduction particle (STP) containing the (proto)oncogene receptor p185(neu). In
      vitro kinase assays on isolated microvilli and microvillar fractions enriched in
      the putative signal transduction particle showed a high specific activity of
      tyrosine kinase activity compared to that of membranes from EGF receptor
      overexpressing A431 cells maximally activated by EGF. Assays of velocity
      sedimentation fractions from microvillar lysates in the presence and absence of
      the exogenous tyrosine kinase substrate poly-glu-tyr polypeptide (poly-E(4)Y)
      suggested association of the tyrosine kinase activity with STP-enriched
      microvillar fractions. The particulate fractions also contained discrete
      endogenous tyrosine-phosphorylated proteins, including prominent bands of
      approximately 42 and 58 kDa. Addition of ATP to these fractions resulted in a
      rapid increase in tyrosine phosphorylation of these and several other proteins,
      as detected by anti-phosphotyrosine blots. Immunoprecipitation and immunoblotting
      with anti-phosphotyrosine antibody of SDS-solubilized ascites cells and
      microfilament core fractions showed nine major bands; the electrophoretic
      mobilities of most of these in the cell immunoprecipitate and microfilament core
      were the same. In vivo and in situ phosphorylation, phosphoamino acid analysis,
      immunoprecipitation, 2-dimensional isoelectric focusing/SDS PAGE and immunoblot
      analysis showed that one of the prominent substrates is p58(gag), a retroviral
      Gag-like cytoplasmic STP component implicated in stabilizing microfilament
      membrane interactions. Immunoblotting identified two peripheral membrane tyrosine
      kinases, p6O(src) and p120(abl), stably associated with the p185(neu)-containing
      signal transduction particle. These results provide further evidence for the
      constitutive activation of this aggressive mammary tumor and suggest a rote for
      phosphorylation of p58(gag) in organization of the STP at the membrane
      microfilament interface in these cells.

PMID- 8649795
TI  - The inhibitory activity of a transdominant c-jun mutant fused to the ligand
      binding domain of the estrogen receptor.
AB  - Tam-67 is an amino-terminal deletion mutant of c-Jun (delta3-122) lacking most of
      the c-Jun transactivation domain, which has been shown previously to function in
      a transdominant fashion to inhibit c-Jun-induced transactivation and cellular
      transformation. In order to create a ligand-dependent dominant negative repressor
      of AP-1, we have constructed a fusion of the TAM-67 gene with the ligand binding
      domain of the estrogen receptor. Fusion of TAM-67 with the ligand binding domain
      of the estrogen receptor produced a 68 kD protein (TAM-67ER) which was
      immunoprecipitated by c-Jun-specific and estrogen receptor-specific antisera and
      shown by gel retardation assay to bind oligonucleotides containing an AP-1
      sequence. Cotransfection of TAM-67ER and an AP-1-dependent reporter construct
      into rat embryo cells demonstrated ligand specific inhibition of AP-1
      transactivation. In the absence of hormone, TAM-67ER produced complete inhibition
      of c-Jun-induced AP-I transactivation. This inhibition was relieved by treatment
      with estradiol but not by treatment with tamoxifen. In addition, TAM-67ER
      inhibited activated c-Ha-ras- or c-raf-induced transformation of NIH3T3 cells.
      However, this inhibition of transformation was not relieved by the addition of
      estrogen. Thus, TAM-67ER inhibits transactivation in a ligand-dependent manner,
      but inhibits transformation in a ligand-independent manner. The results suggest
      that the ligand-dependent transactivation domain of the estrogen receptor (TAF-2)
      can substitute for the c-Jun transactivation domain absent in TAM-67 to stimulate
      transactivation. However, TAF-2 cannot substitute for the missing c-Jun
      transactivation domain to induce cellular transformation.

PMID- 8649797
TI  - Insulin-induced dissociation of Sos from Grb2 does not contribute to the down
      regulation of Ras activation.
AB  - Activation of Ras by a number of receptor tyrosine kinases is mediated by the
      guanine nucleotide exchange factor Sos. This activation is thought to occur as a
      result of the recruitment to the plasma membrane of a complex consisting of Sos
      and the adaptor molecule Grb2. Growth factor stimulation has been shown to induce
      the rapid phosphorylation of Sos on serine and threonine residues. In rat L6
      cells, insulin-induced Sos phosphorylation is accompanied by a partial
      dissociation of the Grb2-Sos complex. In this study we have investigated the
      relationship between Sos phosphorylation and Grb2 association. To this end, we
      have utilized cAMP because it has been demonstrated that elevation of cytoplasmic
      levels of cAMP inhibits growth factor-induced Sos phosphorylation. We show that
      in rat L6 cells, cAMP treatment prevents both the insulin-stimulated Sos
      phosphorylation and Grb2 dissociation. However, cAMP treatment has no effect on
      the duration of insulin-induced Ras activation. These results suggest that the
      kinetics of Ras activation are independent of the phosphorylation-induced
      dissociation of Sos from Grb2.

PMID- 8649796
TI  - Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship
      between p53 gene mutation and bcl-2/bax proteins in drug resistance.
AB  - We investigated the relationship among chemosensitivity to drug-induced apoptosis
      in vitro, the presence of p53 gene mutations, and the expression of bcl-2 and bax
      proteins in B-cells from B-cell chronic lymphocytic leukemia (B-CLL) patients.
      Apoptosis was induced with a camptothecin analogue, 9-amino-20(s)-camptothecin,
      or a purine analogue, fludarabine. Cell death was monitored by propidium iodide
      staining and FACS analysis. Drug-induced apoptosis in B-CLL cells was p53
      independent. Immunoblot analysis of bcl-2 and bax expression revealed a
      correlation between drug-induced apoptosis and the ratio of endogenous levels of
      bcl-2 to bax proteins. B-CLL cells with none to low bcl-2/bax ratios were drug
      sensitive as compared to cells with intermediate to high ratios that were drug
      resistant (P = 0.015). Prior to drug treatment, bax protein migrated as a single
      species of 21 kDa. Following drug-induced apoptosis, anti-bax specific protein
      complexes of 36-42 kDa were up-regulated. Using two-dimensional gel
      electrophoresis, bax complexes were disrupted under reducing conditions to reveal
      homo- and heterodimers of 18 and 21 kDa suggesting that disulfide interactions
      were required for complex formation. The de novo appearance of the 18 kDa anti
      bax specific protein together with its increased expression in drug-sensitive B
      CLL B-cells undergoing cell death suggests a role for this protein in the
      regulation of apoptosis.

PMID- 8649798
TI  - Differential expression of the cyclin-dependent kinase inhibitors p16 and p21 in
      the human melanocytic system.
AB  - To determine whether loss or inactivation of the putative tumor-suppressor gene,
      p16, represents an initiating or a secondary event in the progression of human
      melanoma, we evaluated the status of this gene in early and advanced-stage
      melanomas of sporadic origin. The results of this analysis revealed p16 deletions
      in 4/6 primary and 6/14 metastatic melanoma cell lines but not in 3/3 metastatic
      melanoma specimens. Surprisingly, p16 deletions were also detected in 8/8 benign
      compound nevi and in 1/3 normal human melanocyte isolates. To investigate whether
      these deletions in benign and malignant stages of the human melanocytic system
      were specific for p16, we analysed the same specimens and cell lines for
      expression of p21, another cyclin-dependent kinase inhibitor and potential tumor
      suppressor. In contrast to p16, expression of p21 was detected in 3/3
      melanocytes, in 3/3 benign nevi, and in greater than 50% of malignant melanoma
      cell lines and specimens. Finally, because of the recently documented inverse
      relationship between expression of p16 and pRb protein in a variety of tumor cell
      lines, we analysed some of the p16-positive and negative melanoma cell lines for
      the presence of pRb protein. The results demonstrated pRb protein in each of
      these cell lines. Taken together, although this study revealed deletions of the
      p16 gene in a significant number of sporadic primary and metastatic melanoma cell
      lines, they were also detected in benign nevus specimens and in some normal human
      melanocyte isolates. Thus, these findings cast some doubt on the role of this
      gene as being causal to the onset and progression of human melanoma, in
      particular, sporadic melanoma.

PMID- 8649799
TI  - S phase cell-cycle arrest following DNA damage is independent of the
      p53/p21(WAF1) signalling pathway.
AB  - It is now likely that the cyclin-kinase inhibitor, p21(WAF1/SD11), is a key
      effector of p53-mediated cell-cycle arrest at the G(1)/S checkpoint following DNA
      damage. More recently, however, in vitro data has suggested that this pathway may
      also mediate the acute inhibition of DNA synthesis seen in cells already in S
      phase. Here we address this question in an intact cell system using normal human
      diploid fibroblasts in which p53 function is manipulated by expression of a
      dominant-negative mutant (ala(143)) introduced by a retroviral vector. Induction
      of DNA strand breaks in normal control fibroblasts by exposure to bleomycin led
      as expected to G(1)/S cell cycle arrest, induction of p2l(WAF1) and a rapid
      reduction in the rate of DNA synthesis in cells already in S phase. Stable
      expression of mutant p53 abrogated the G(1)/S (but not the G(2)/M) cell cycle
      checkpoint and abolished the induction of p21(WAF1), but had no significant
      effect on the inhibition of DNA replication in S phase nuclei. We conclude that,
      despite the in vitro evidence for inhibitory activity on PCNA/polymerase delta,
      p21(WAF1) induction does not appear to be essential for the acute inhibition of
      DNA synthesis in the intact cell following strand-break damage in S phase.

PMID- 8649800
TI  - Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the
      development of bladder cancer.
AB  - Chromosome 8 loss of heterozygosity (LOH) in cancer of the urinary bladder is
      associated with high tumour grade and stage. We have screened 193 cases of
      transitional cell carcinoma (TCC) of the bladder using 30 microsatellite
      polymorphisms on chromosome 8. Forty three cases (22%) showed LOH on 8p, the
      majority of which (72%) had lost the entire short arm. Using 12 tumours with
      partial deletions of 8p, we have defined a minimum telomeric region of deletion
      between D8S264 and D8S133 (8p2l.1-pter). We also found LOH in the region 8pl1.2
      12, where we have defined at least one centromeric target for deletion within a 4
      cM interval. Two tumours were identified with loss of the telomeric region only,
      whereas all cases with loss in the centromeric region also had telomeric
      deletion. Chromosome 8p deletions have also been described in prostate,
      colorectal, hepatocellular, lung and endometrial carcinoma and collecting duct
      carcinoma of the kidney. It has been postulated that loss or inactivation of at
      least 2 tumour suppressor genes on 8p may play an important role in progression
      of both prostate and colorectal carcinomas. The regions of deletion we have
      identified in bladder tumours are compatible with these, suggesting that at least
      two genes on 8p may play a role in the development of many common solid tumours.
      Our findings significantly refine the localisation of the more centromeric of
      these loci.

PMID- 8649801
TI  - Oncogenic transformation of HPV-immortalized human oral keratinocytes is
      associated with the genetic instability of cells.
AB  - HPV-immortalized human oral keratinocytes can convert to tumorigenic cells when
      exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but normal human oral
      keratinocytes cannot transform with a similar exposure. The different responses
      of these cells could be due to different genetic stability of cells. In as much
      as genetic stability is determined by cell cycle control and of repair of damaged
      DNA, we studied the effect of MNNG exposure upon cell cycle progression,
      expression of p53, WAF1/CIP1 and gadd45, and the mutation frequency of a shuttle
      vector pS189 in normal human oral keratinocytes, in HPV-immortalized oral
      keratinocytes, and in an oral cancer cell line expressing mutant p53. Normal
      cells demonstrated transient cell cycle arrest after exposure to MNNG, but the
      other tested cells did not. While MNNG exposure significantly increased the
      levels of intranuclear wt p53 protein and the expression of WAF1/CIP1 and gadd45
      genes in normal cells, it did not alter them in the immortalized and cancer
      cells. The mutation frequency of pS189 plasmid was significantly lower in normal
      cells than in the other tested cells. These data indicate that malignant
      conversion of HPV-immortalized oral keratinocytes may, in part, be associated
      with the cells' genetic instability. The genetic instability may be due to cells'
      (1) inability to accumulate intranuclear wt p53 to a threshold level at which p53
      upregulates the transcription of WAF1/CIP1 and gadd45, resulting in the loss of
      cell cycle control and (2) inefficient repair of DNA damage caused by genotoxic
      agents.

PMID- 8649802
TI  - Expression of alternative forms of Ras exchange factors GRF and SOS1 in different
      human tissues and cell lines.
AB  - DNA probes and antibodies specific for different coding regions of human SOS1 and
      GRF genes were used to screen expression of these genes in a variety of adult and
      fetal human tissues and cell lines. Despite previous reports of the exclusive
      expression of hGRF RNA in brain, we also observed expression of this gene in
      various other tissues including lung and pancreas, as well as several tumor cell
      lines. At least three different hGRF mRNA transcripts were observed depending on
      the probe used, with the larger transcripts being detected by probes
      corresponding to the 5' end of the gene while smaller transcripts were detected
      by probes corresponding to the 3' end. Expression of hSOS1-related transcripts
      was more ubiquitous and homogeneous than with hGRF, with similar levels of
      specific transcripts being detected in most tissues and cell fines tested. Three
      to five different transcripts were detected in human tissues when using probes
      for the 5' end and middle regions of this gene, whereas only two were detected
      with probes corresponding to the 3' end. Screening of multiple human tumor cell
      lines showed ubiquitous expression of three specific transcripts, although the
      level and ratio of each of these transcripts varied widely among individual cell
      lines. Consistent with the variety of transcripts detected, several protein forms
      were also identified in Western immunoblots with antisera raised against specific
      domains of hSOS1 and human Ras-GRF gene products. Fluorescence in situ
      chromosomal hybridization suggested that, in both cases, the multiple forms arise
      from single chromosomal loci. The heterogeneity of hGRF and hSOS1 gene products
      detected (which appear to retain in most cases a functional catalytic domain),
      suggests that differentially expressed, alternatively spliced hSOS1 and hGRF
      forms may contribute to fine regulation of Ras activation in different tissues or
      at different stages of development.

PMID- 8649803
TI  - Activation of Mil/Raf protein kinases in mitotic cells.
AB  - The c-Raf-1 protein kinase is a major element of several signal transduction
      pathways and thought to be involved in entry into the S phase of the cell cycle.
      Here we show that c-Raf-1 as well as the transforming viral fusion protein Gag
      Mil, in which most of the amino terminal regulatory region of the avian Raf
      homologue Mil is deleted, are activated five- to sixfold in mitotic cells.
      Mitotic activation of Mil/Raf kinase activity correlates with reduced
      electrophoretic mobility caused by hyperphosphorylation at serine/threonine
      residues located in the carboxy terminal part of c-Raf-1. Mitotic
      hyperphosphorylation occurs in various cell-lines indicating that it is
      ubiquitous. Our data suggest a novel function for Mil/Raf kinases in late stages
      of the cell cycle.

PMID- 8649804
TI  - Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to
      other ErbB proteins.
AB  - The ErbB family of transmembrane tyrosine kinases includes the receptor for EGF
      (ErbB-1), two receptors for NDF/heregulin (ErbB-3 and ErbB-4) and an orphan
      receptor (ErbB-2). In order to examine the possibility that distinct signal
      transduction pathways are coupled to each ErbB protein, we examined the
      interaction of individual ligand-stimulated receptors with the c-Cbl protein, a
      protooncogene-encoded signaling molecule previously identified in hematopoietic
      cells. We report that c-Cbl undergoes rapid and sustained phosphorylation on
      tyrosine residues upon stimulation of fibroblast and epithelial cell lines with
      ligands of ErbB-1. By contrast, activation of either ErbB-3 or ErbB-4 by NDF did
      not affect tyrosine phosphorylation of c-Cbl. Likewise, activation of a chimeric
      ligand-stimulatable ErbB-2 by a heterologous ligand was ineffective. Despite
      rapidity of the EGF effect, we observed no association of c-Cbl with activated
      ErbB-1, implying that the interaction is indirect. Our in vitro experiments
      suggest that a candidate mediator of the interaction is the Grb-2/Ash adaptor
      protein, which is constitutively bound to c-Cbl. These results indicate that
      different ErbB proteins can couple to distinct signaling pathways, and therefore
      their physiological functions are probably non-redundant.

PMID- 8649805
TI  - Decreased Fas antigen receptor expression in testicular tumor cell lines derived
      from polyomavirus large T-antigen transgenic mice.
AB  - MT-PVLT-10 transgenic mice express large T-antigen of polyomavirus under the
      control of the mouse metallothionein-1 promoter and mates of this transgenic line
      develop testicular tumors at advanced ages. The differential display technique
      was employed to compare mRNA expression from immortalized cell lines derived from
      normal or adenomatous testis from MT-PVLT-10 transgenic males. Using this
      technique, a complementary DNA fragment corresponding to the mouse Fas antigen
      receptor was recovered from normal testicular cells but not from tumor cells.
      RNAse protection assays with the Fas antigen specific fragment confirmed its
      differential expression. Normal testicular cells from the transgenic animals
      responded to treatment of interferon-gamma by increasing the expression of Fas
      antigen specific mRNA and were sensitive to the proliferative inhibitory effect
      of anti-Fas antibody in vitro. This proliferative inhibition was characterized by
      an accumulation of cells in S phase of the cell cycle. In contrast, the
      testicular tumor cells did not respond to either interferon-gamma or to anti-Fas
      antibody in vitro. These results suggest that the toss of proliferative
      inhibitory effect mediated by the Fas antigen pathway in tumor cells may be an
      important step in testicular tumor progression in the MT-PVLT-10 transgenic mice.

PMID- 8649806
TI  - Expression of CD44 splice variants in normal respiratory epithelium and bronchial
      carcinomas: no evidence for altered CD44 splicing in metastasis.
AB  - Expression of alternatively spliced CD44 adhesion molecules has been implicated
      in metastatic spread of various rodent and human tumors. To determine whether
      specific CD44 splice variants contribute to metastatic spread of bronchial
      cancers, we compared the expression of CD44 splice variants in normal bronchial
      epithelium and bronchial cancers, including tumors which already spread to
      regional lymph nodes or distant organs. Variant CD44 expression was analysed by
      immunohistochemistry using variant exon-specific monoclonal antibodies. The
      precise composition of CD44 transcripts was delineated by exon-specific RT-PCR.
      The concurring data obtained by both methods revealed that high levels of
      standard CD44 and variants v5 and v6 as well as low levels of variants v7 and v10
      are expressed both in normal bronchial epithelium and squamous cell lung cancers.
      No CD44 expression was observed in the highly metastatic small cell lung cancers
      and adenocarcinomas with the exception of bronchioalveolar cancers showing weak
      expression of standard CD44. These data suggest that expression of alternatively
      spliced CD44 molecules in the bronchial tract is related to the distinct
      differentiation of the respiratory epithelium. No correlation between expression
      of specific CD44 splice variants and metastasis of bronchial cancers was
      observed.

PMID- 8649807
TI  - Specific association of Mil/Raf proteins with a 34 kDa phosphoprotein.
AB  - Mil/Raf protein kinases are intermediates in signaling pathways leading to
      differentiation, mitogenesis and cellular transformation. To gain insight into
      the activity of Mil/Raf kinases at the molecular level we aimed to identify
      proteins specifically interacting with Mil/Raf proteins. A phosphoprotein of 34
      kDa (pp34) was found to be associated with c-Raf as well as with viral and
      activated forms of Mil/Raf proteins in exponentially growing interphase cells.
      pp34 association was not detectable in mitotic cells. Serum stimulation or
      coexpression of activated Ras led to decreased electrophoretic mobility of pp34
      complexed to Mil/Raf proteins while serum starvation rendered pp34 undetectable.
      Moreover, the association with pp34 became undetectable in parallel with the
      onset of morphological cellular transformation caused by overexpression of a
      constitutively activated mutant of c-Raf in an inducible expression system. Thus,
      the association of Mil/Raf proteins with pp34 is altered in the course of cell
      cycle progression, serum stimulation and cellular transformation. These events
      represent hallmarks of cellular Mil/Raf functions, rendering pp34 a candidate
      protein involved in Mil/Raf function

PMID- 8649808
TI  - v-rel and c-rel induce a membrane protein, p75, on avian hematopoietic cells.
AB  - v-rel-induced neoplasias are thought to be caused by the aberrant expression of
      cellular genes. Using a monoclonal antibody we detected a 75 kDa-protein (p75) on
      v-rel-transformed chicken hematopoietic cells. This protein is normally expressed
      only on a certain type of non-T, non-B cells in the chicken caecal tonsils.
      Overexpression of v-rel in two B-cell lines and in splenic cells induced the
      expression of p75. In contrast, overexpression of c-rel in these cells resulted
      in variable expression of p75. These data indicated that p75 is ectopically
      expressed on v-rel-transformed hematopoietic cells and that it responds
      differently to v-rel and c-rel induction.

PMID- 8649809
TI  - The ankyrin repeats but not the PEST-like sequences are required for signal
      dependent degradation of IkappaBalpha.
AB  - The nuclear activity of Rel/NFkappaB transcription factors is tightly regulated
      from the cytoplasmic compartment by an inhibitory subunit called IkappaBalpha.
      IkappaBalpha is rapidly phosphorylated and degraded in response to the
      stimulation through tumor necrosis factor alpha (TNFalpha) receptor, interleukin
      1 receptor or CD40. To explore the molecular mechanisms of signal-induced
      depletion of IkappaBalpha, we have delineated the domain in IkappaBalpha that is
      required for TNFalpha-induced phosphorylation and rapid degradation of
      IkappaBalpha. In contrast to the previous reports, the PEST-like sequences, which
      are present in the carboxyl-terminal region of IkappaBalpha, are demonstrated
      here to be dispensable for TNFalpha-induced degradation but could be required for
      signal-independent degradation, as in the case of Cactus, Drosophila homologue of
      IkappaB. Furthermore, the ankyrin repeats, which are essential for forming a
      complex with Rel and RelA, are required for TNFalpha-induced degradation
      suggesting that the putative IkappaB protease could interact with IkappaBalpha in
      complex with RelA or could recognize the structure of ankyrin repeats. Our data
      also indicate that neither the ankyrin repeats nor the PEST-like sequences, are
      essential for TNFalpha-induced phosphorylation.

PMID- 8649810
TI  - Mouse Sin3A interacts with and can functionally substitute for the amino-terminal
      repression of the Myc antagonist Mxi1.
AB  - Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in
      association with Max, antagonizes Myc oncogenic activities. A possible
      mechanistic basis for Mxi1-mediated repression was provided by the recent
      demonstration that the repressive potential of Mxi1 correlates with its ability
      to physically associate with mSin3B, one of two mammalian homologues of the yeast
      transcriptional repressor SIN3. Here, we sought to characterize more fully the
      physical properties of the second homologue, mSin3A and to determine whether the
      recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity. Transient
      transfection of mammalian cells showed that the mSin3A protein can associate with
      the strong repressive isoform of Mxi1 (Mxi1-SR) and that, like other Myc
      superfamily members, both mSin3A and Mxi1-SR localize to the nucleus. From a
      developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A
      expression during postnatal mouse development and in differentiating mouse
      erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc
      and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in
      mSin3A gene expression. This constant expression profile, coupled with the
      observation that over-expression of mSin3A does not augment the anti-Myc activity
      of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that
      mSin3A is not a limiting factor in the regulation of Myc superfamily function.
      Finally, a mSin3A-Mxi1 fusion protein, in which the amino terminal mSin3
      interacting domain of Mxi1-SR was replaced with the full-length mSin3A, exhibited
      a level of repression activity equivalent to, or greater than, the level of
      repression obtained with Mxi1-SR. Taken together, these observations directly
      demonstrate that the amino-terminal repression domain of Mxi1-SR functions solely
      to recruit mSin3A and possibly other proteins like mSin3A and this association is
      necessary for the anti-Myc activity of Mxi1-SR.

PMID- 8649811
TI  - Identification of a novel Bcl-2 related gene, BRAG-1, in human glioma.
AB  - Programmed cell death (apoptosis) plays a major role in embryogenesis, in mature
      organ homeostasis and in many disease states including cancer. Apoptosis occurs
      as an orderly cell-intrinsic suicide program regulated by a family of genes
      related to Bcl-2. Here, we describe the cloning and molecular characterization of
      a gene homologous to Bcl-2 from a human glioma. This gene named BRAG-1 (for brain
      related apoptosis gene) has an open reading frame that encodes for a protein of
      31 kDa sharing significant sequence homology with the Bcl-2 family of genes in
      the BH1 and BH2 regions. Northern blot analyses revealed that BRAG-1 is expressed
      in human gliomas as a 1.8 kb message. This gene, interestingly, was found to be
      expressed predominantly in normal human brain as a 4.5 kb transcript which is
      different in size from the message found in tumor tissues. These results suggest
      that BRAG-1 may be rearranged in human gliomas leading to its over-expression as
      a truncated transcript. Utilizing a bacterial expression vector, we produced BRAG
      1 protein which was found to cross-react with a Bcl-2 monoclonal antibody,
      further suggesting structural and immunological similarity to Bcl-2.

PMID- 8649812
TI  - Complex regulation of the DNA-binding activity of p53 by phosphorylation:
      differential effects of individual phosphorylation sites on the interaction with
      different binding motifs.
AB  - The tumor suppressor protein p53 exists in different phosphorylation states
      depending on the cellular environment and perhaps the stage of the cell cycle.
      These different phosphorylation states can be mimicked in the baculovirus
      expression system by employing the phosphatase inhibitor okadaic acid.
      Hyperphosphorylation of p53, particularly of Ser313 and/or Ser309, stimulated its
      DNA binding activity (Fuchs, Hecker and Scheidtmann, Eur. J. Biochem. 228, 625,
      1995). Here we show that hyperphosphorylation of p53 has different effects on its
      DNA-binding activity, depending on the phosphorylation sites and the binding
      motif: (i) Phosphorylation of amino-terminal sites appeared to reduce binding to
      the RGC consensus motif, whereas additional phosphorylation of both, Ser313 and
      Ser309 led to enhanced binding. (ii) Upon hyperphosphorylation, binding to the
      RGC motif was enhanced whereas binding to the p53 response element of the bax1
      gene promoter was diminished. (iii) DNA binding was also greatly enhanced by
      antibodies Pab 122 and 421 directed against the carboxyl terminus, but this
      latter effect was superimposed by the phosphorylation state of p53. Thus, the DNA
      binding activity of p53 appears to be regulated in a complex way in that (i)
      binding to a given sequence motif may be regulated by differential
      phosphorylation and/or by interaction with other factors; (ii) binding to
      different motifs may be modulated in opposite ways. Thus, the different genes
      that are regulated by p53 may be differently affected by these parameters.

PMID- 8649813
TI  - Mader: a novel nuclear protein over expressed in human melanomas.
AB  - Mader is a novel delayed early response gene encoding a nuclear protein.
      Upregulation of the Mader 2.7 kb mRNA requires protein synthesis and can be
      induced in a variety of human cell lines by serum stimulation and in freshly
      isolated lymphocytes by mitogens. mRNA levels reach a maximum by 2 h and return
      to basal levels by 6 h. Mader is highly conserved as cross-hybridizing DNA
      sequences were observed in species as diverse as Rhesus and S. cerevisiae. The
      Mader protein of approximately 55 kD has two proline rich domains and contains 15
      potential phosphorylation sites, a nuclear localization signal, and multiple
      S(T)PXX motifs that are characteristic of regulatory DNA binding proteins.
      Monoclonal antibodies produced against Mader confirm that it is localized to the
      nucleus. These features of Mader suggest that it may play a role in growth
      regulation. Although Mader mRNA can be detected in most cell lines, only
      occasional immunoreactive cells were detected in normal human tissues. In
      contrast, uniform strong nuclear staining was observed in all malignant melanomas
      examined. The fact that only one of six benign melanocytic nevi examined showed
      evidence of Mader expression suggests that over-expression of Mader protein may
      be associated with the malignant transformation of melanocytes.

PMID- 8649814
TI  - Evidence for a novel tumor suppressor gene on chromosome 15 associated with
      progression to a metastatic stage in breast cancer.
AB  - Loss of heterozygosity (LOH) studies have emerged as a valuable indicator for
      tumor suppressor genes involved in the formation or progression of carcinomas. We
      here present data indicating that human chromosome 15 harbours a novel putative
      tumor suppressor gene which appears to play a role during later stages of
      carcinogenesis and which may be associated with metastasis in breast cancer. In
      this study, 153 primary and metastatic carcinomas from 101 patients have been
      analysed for LOH with 13 polymorphic microsatellite markers on chromosome 15. The
      tumors included carcinoma of the lung in 49 patients, breast carcinoma in 29,
      colorectal carcinoma in nine, renal carcinoma in five, pancreatic carcinoma in
      five, urinary bladder carcinoma in two and prostate carcinoma and ovarial
      carcinoma in one patient each. LOH15 was seen in 42/99 (42%) informative
      patients. In metastatic tumors, LOH15 was observed in 37/68 (54%). High
      incidences of allelic losses were detected in metastases from lung (56%), breast
      (70%) and colorectal (67%) carcinomas. In carcinomas of the breast, there was a
      significant difference (P<0.01) in LOH15 frequencies between non-metastatic
      tumors (11%) and brain metastases (70%). Such a difference was not observed on
      the chromosomal arm 17p which yielded high proportions of LOH in both non
      metastatic breast tumor (73%) and breast carcinoma metastases (90%). In 16
      patients, interstitial deletions could be detected. The common region of overlap
      extended from D15S231 to D15S641, thus mapping this putative tumor suppressor
      gene to chromosome 15q14. Our data indicate that a gene on chromosome 15
      contributes to the pathogenesis of metastatic carcinoma.

PMID- 8649815
TI  - Germ-line inactivation of the murine Eck receptor tyrosine kinase by gene trap
      retroviral insertion.
AB  - The present study characterized a mutation in the Eck receptor tyrosine kinase
      gene induced by the U3betageo gene trap retrovirus. The mutation (eck(i)) was
      identified during an in vitro screen for proviruses that disrupt developmentally
      regulated genes in cultured ES cells. The germ-line eck(i) fusion gene was
      expressed in blastocyst and later restricted to the primitive streak, node and to
      regions of the hindbrain in 6.5-10.5 day embryos. This is identical to the
      pattern of Eck gene expression as determined by either in situ hybridization or
      immunostaining, suggesting that expression of the Eck promoter was not affected
      by provirus integration. The provirus inserted approximately 8 kb upstream of the
      5' end of the published cDNA sequence, and 1.8 kb downstream of an alternatively
      spliced 5' exon. The eck(i) allele is essentially a null mutation since mutant
      mice are severely deficient for Eck protein as determined by Western blot
      analysis and in vitro kinase assays. Nevertheless, mice homozygous for the
      mutation did not exhibit any discernable phenotype. These results suggest that
      other members of the Eph family of receptor tyrosine kinases can functionally
      compensate for loss of Eck.

PMID- 8649816
TI  - Src-homology domain 2 is responsible for transcriptional suppression induced by
      expression of Lck.
AB  - Overexpression of Lck was shown, by our previous study, to suppress gene
      transcription from various viral and cellular promoters. The suppression of
      transcription from human T-cell leukemia virus promoter by Lck was independent of
      the presence of the enhancer core sequences within the long terminal repeat. The
      suppression of transcription was observed with Lck mutants that had either
      diminished or enhanced tyrosine-kinase activity. A mutant lacking the
      myristylation site also suppressed transcription. From the analysis with various
      deletion mutants of Lck, it was suggested that Src-homology domain 2 (SH2) is
      both necessary and sufficient for the suppression of transcription. A similar
      effect was also observed with the SH2 domain of the v-src gene. Thus,
      overexpression of Lck could suppress gene expression through a unique function of
      the SH2 domain.

PMID- 8649817
TI  - Response of human ovarian carcinoma cell lines to antiprogestin mifepristone.
AB  - The effects of antiprogestin mifepristone (MF) on the growth, progesterone
      receptor expression and cell cycle kinetics of several human ovarian epithelial
      carcinoma (OEC) cell lines were evaluated. MF, a synthetic antiprogestin, has
      been shown to have some antiproliferative activity in breast tumors and in the
      endometrium, but its efficacy in ovarian carcinomas has not been explored
      previously. Continuous exposure of OEC cells to MF resulted in a dose- and time
      dependent growth inhibition, as determined by MTT assay. Growth inhibition was
      apparent by day three following addition of MF to cultures in vitro. All cell
      lines used in this study expressed a progesterone receptor (PR). MF down
      regulated PR expression on these cells. Changes in the cell cycle kinetics of OEC
      cells exposed to MF correlated with the observed antiproliferative effects. MF
      blocked cells in a G0/G1 phase of the cell cycle and thus reduced the number of
      cells in the S phase. The efficacy of MF was compared with that of taxol and
      tamoxifen in the same human OEC cell lines. Continuous exposure of OEC cells to
      tamoxifen resulted in a varied cytostatic response and a transient change in the
      cell cycle. Taxol inhibited growth of some but not all of the cell lines. These
      results indicate that PR-positive human OEC cells are sensitive to MF in vitro
      and that MF may be an active agent against ovarian epithelial tumors.

PMID- 8649818
TI  - Regulation of cyclin E transcription by E2Fs and retinoblastoma protein.
AB  - Cyclin E is critical for the advance of cells through the G1 phase of their
      growth cycle. Transcription of the cyclin E gene is known to be cell cycle
      dependent. We have shown previously that mRNA levels of cyclin E are regulated
      positively by mitogens and negatively by TGF-beta. Much circumstantial evidence
      implicates both E2F transcription factors and the retinoblastoma protein (pRB) in
      the control of cyclin E expression. However, the molecular basis of this control
      has remained unclear. We report here the cloning of the cyclin E promoter and the
      identification of several putative E2F binding sites within the promoter
      sequence. We have found that cell cycle regulation of cyclin E transcription is
      mediated by E2F binding sites present in the promoter. The activity of this
      promoter can be regulated negatively by pRB. Our results suggest the operation of
      a positive-feedback loop in late G1 that functions to ensure continued cyclin E
      expression and pRB inactivation.

PMID- 8649819
TI  - Identification and cloning of EI24, a gene induced by p53 in etoposide-treated
      cells.
AB  - To search for candidate genes involved in p53-mediated apoptosis, the
      differential display technique was used to identify RNA species whose expression
      was altered in murine NIH3T3 cells treated with the cytotoxic drug etoposide. We
      report here the isolation and characterization of EI24, a novel gene whose 2.4 kb
      mRNA is induced following etoposide treatment. Induction of EI24 mRNA by
      etoposide required expression of wild-type p53 in murine embryonic fibroblasts
      which had been transformed with the oncogenes E1A and T24 H-ras; and
      overexpression of functional p53 in these cells was sufficient to induce
      expression of the EI24 mRNA. The EI24 mRNA was also induced in a p53-dependent
      manner by ionizing irradiation of primary murine thymocytes. Isolation of a full
      length EI24 cDNA revealed that its protein product bears homology to CELF37C12.2,
      a Caenorhabditis elegans protein of unknown function.

PMID- 8649820
TI  - Apoptosis in v-myc transformation of myelomonocytic cells and its modulation by
      CSF-1.
AB  - c-myc is a proto-oncogene essential for cell growth. When activated, its
      expression can lead to uncontrolled cell proliferation, transformation and
      tumorigenesis. The cell line tEMmyc4 is a murine myelomonocytic cell line that
      was established following transformation by v-myc. It has a high level of v-myc
      expression and constitutively expresses endogenous CSF-1, the monocytic growth
      and viability factor. Under growth restricting conditions (high cell density
      serum deprivation, heat shock, or dexamethasone addition) cells of this line were
      found to undergo cell death through apoptosis. The induction of apoptosis by
      dexamethasone was associated with a decrease in constitutive CSF-1 expression
      without significant change in v-myc expression. Exogenous CSF-1 rescued these
      cells from dexamethasone induced-apoptosis. In vivo studies showed that tEMmyc4
      cells were tumorigenic in syngeneic animals despite exhibiting some spontaneous
      apoptosis within the tumour mass. Co-administration of dexamethasone with the
      tumour cells significantly inhibited tumor development and the administration of
      dexamethasone to mice with established tumors resulted in tumor regression in all
      mice. This regression was associated with a high level of apoptosis and necrosis
      in the tumors. This study shows a correlation between the in vitro and in vivo
      induction of apoptosis and indicates that cancer cells bearing activated
      oncogenes may be more sensitive to apoptosis induction by chemotherapeutic
      agents.

PMID- 8649821
TI  - ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS)
      modulate protein: DNA interaction.
AB  - p53 is an extensively studied tumor suppressor gene implicated in the genesis of
      a large number of varied tumors. However, the pathways of regulation for the wild
      type p53 gene and its product are as yet unknown. In situ hybridization analyses
      of ETS1 and ETS2 expression during mouse embryogenesis, have shown a pattern
      similar to that of p53 gene expression. Significantly, we have identified several
      ETS-binding sites (EBS) in the promoter regions of the human and mouse p53 genes.
      In the human promoter two of these EBS are present in the form of a palindrome,
      with the two EBS cores being separated by four nucleotides. This report shows
      that the EBS palindrome of the human p53 promoter has a high affinity for ETS1
      and ETS2 and that such binding interaction intracellularly is able to activate
      the transcription of a CAT reporter gene by 5-10-fold using COS cells. To
      investigate whether the spacing between the two EBS cores influences the DNA
      binding activity, we synthesized oligonucleotides with increasing distances
      (4,12,16, and 20 bases respectively) between the two EBS cores of the palindrome.
      We observed an inverse correlation between an increasing distance in the two EBS
      cores of the palindrome and the ETS1 and ETS2 DNA binding activity respectively.
      Interestingly, optimal DNA binding activity was observed when the distance
      between the two EBS cores was four bases, identical to that which occurs in the
      natural promoter. Furthermore we show that the p53 mRNA is expressed at higher
      levels in NIH3T3 cells overexpressing ETS2 gene product, suggesting that the ETS2
      transcription factor is a likely candidate for regulating the expression of p53
      in vivo.

PMID- 8649823
TI  - A role for activated p21 ras in inhibition/regulation of platelet-derived growth
      factor (PDGF) type-beta receptor activation.
AB  - Ligand-stimulated Platelet-Derived Growth Factor (PDGF) type-beta receptor
      autophosphorylation, and tyrosine phosphorylation of receptor-associated
      signalling proteins, is blocked in cells expressing activated Ras genes. A factor
      present in membrane fractions of v-ras-expressing fibroblasts (Kbalb cells)
      dominantly inhibits the autophosphorylation of the PDGF type-beta receptor.
      Purification of this factor, via ion exchange, reveals that the inhibitor can be
      physically separated from the PDGF type-beta receptor, with reconstitution of
      PDGF type-beta receptor kinase activity in response to ligand binding. The
      inhibitor exhibited specificity for the PDGF type-beta receptor, and consistently
      co-purified with activated p21 ras, with Syp/PTP-2, and with Grb2. Neutralization
      of the p21 ras protein from the Kbalb cell membranes by p21 ras-specific
      monoclonal antibodies, however, completely removed the inhibition of PDGF type
      beta receptor, rendering the PDGF type-beta receptor molecule capable of
      autophosphorylation in response to ligand. These results indicate that activated
      p21 ras either interacts directly with the PDGF type-beta receptor to inhibit
      autokinase activity, or complexes with different molecules such as Syp and/or
      Grb2 at the cell membrane to act on another effector which then inhibits PDGF
      type-beta receptor function.

PMID- 8649822
TI  - Identification of a human LIM-Hox gene, hLH-2, aberrantly expressed in chronic
      myelogenous leukaemia and located on 9q33-34.1.
AB  - We describe the isolation of human LH-2, a putative transcription factor
      containing two cysteine-rich regions (LIM domains) and a homeobox (Hox) DNA
      binding domain. High levels of hLH-2 expression were observed in all cases of
      chronic myelogenous leukaemia (CML) tested, regardless of disease status. hLH-2
      was mapped to chromosome 9Q33-34.1, in the same region as the reciprocal
      translocation that creates the BCR-ABL chimera of the Philadelphia chromosome
      (Ph'), the hallmark of CML; hLH-2 was retained on the derivative 9 chromosome and
      is therefore centromeric of c-ABL. The proximity of hLH-2 to the breakpoint on
      chromosome 9 raises the possibility of cis-activation by the t(9;22)(q34;q11)
      translocation. In addition to finding hLH-2 expression in all cases of CML,
      expression was observed in lymphoid malignancies and myeloid cell lines, but not
      in primary cases of acute myelogenous leukaemia. The role of hLH-2 in the
      development or progression of leukaemia is not known. However, hLH-2 may prove
      useful as a marker of CML for monitoring residual disease.

PMID- 8649824
TI  - Effects of c-myc first exons and 5' synthetic hairpins on RNA translation in
      oocytes and early embryos of Xenopus laevis.
AB  - Mammalian c-myc transcripts have long G/C-rich 5' untranslated regions (UTRs)
      that may fold into secondary structural elements that may impede translation. We
      have examined the effects of different c-myc first exons, which produce most of
      the 5' UTR of c-myc transcripts, on translation in Xenopus oocytes and embryos,
      by placing these structures upstream of a chloramphenicol acetyltransferase (CAT)
      reporter. Our results demonstrate that the human c-myc first exon inhibits
      reporter translation in both oocytes and embryos. Unlike their mammalian
      counterparts, Xenopus c-mycI first exons initiated at either promoter 1 or
      promoter 2 do not impede translation. We conclude that translation inhibition
      reported in a previous investigation (Lazarus, 1992. Oncogene, 7:1037) utilizing
      Xenopus c-mycI 5' non-coding elements was due to the inclusion of nonrelevant non
      transcribed sequences. Previous investigators have reported that inhibition of
      translation in Xenopus oocytes by 5' secondary structure is alleviated after
      fertilization (Lazarus et al., 1988. Oncogene 3:517; Fu et al., 1991, Science
      251:807). We repeated the experiments of Fu et al., examining the effects on
      translation by a highly stable synthetic hairpin. The hairpin severely
      [correction of severly] restricted translation in both oocytes and embryos,
      indicating that highly stable 5' secondary structure is equally inhibitory in
      oocytes and embryos.

PMID- 8649825
TI  - Mutational analysis of the mitogenic and transforming activities of the insulin
      like growth factor I receptor.
AB  - THe type 1 insulin-like growth factor receptor (IGF-IR) plays an important role
      in mitogenesis and transformation. It has been previously shown that mitogenic
      signaling and transforming activity of the IGF-IR can be dissociated: a receptor
      truncated at residue 1229 (C-terminus) is fully mitogenic, in terms of its
      response to IGF-I, but cannot transform 3T3-like cells that are devoid of
      endogenous IGF-IRs (R- cells). We have extended our mutational analysis of the C
      terminus of the human IGF-IR, by stably transfecting several mutant receptors
      into R- cells, and testing the resulting cell lines for IGF-I-mediated mitogenic
      response and formation of colonies in soft agar. The results indicate that the
      transforming domain of the IGF-IR can be localized between residues 1245 and
      1310, these sequences being not required for mitogenic signaling. Within these
      residues, there are at least two areas that contribute to the transforming
      activity of the receptor.

PMID- 8649826
TI  - p16 inhibition of transformed and primary squamous epithelial cells.
AB  - We and others have recently shown that p16 can potently and specifically inhibit
      progression through the G1 phase of the replicative cycle in cells that express
      the retinoblastoma protein (pRB). However, none of these studies examined cell
      types in which p16 has been firmly implicated in tumorigenesis. We predicted that
      such cells would show sensitivity to p16 inhibition, perhaps conferred by
      proteins in addition to or other than pRB. Intragenic, inactivating mutations of
      p16 have been found at significant frequency in primary tumors derived from
      squamous epithelial cells of the esophagus (ESCC). We therefore examined p16
      function in ESCC lines and in primary squamous epithelial cells cultured from
      mouse skin. We find that seven of eight ESCC lines tested are inhibited by p16
      and fail to express the protein endogenously. The lone p16-resistant line
      expresses endogenous p16 but lacks functional pRB. Primary squamous epithelial
      cells are also inhibited by p16. These data suggest that squamous epithelial
      cells are generally sensitive to inhibition by a regulatory pathway that involves
      p16 and pRB, and that, by the time of establishment in culture, there is nearly
      universal inactivation of this pathway in ESCCs.

PMID- 8649828
TI  - Isolation of a novel oncogene, NET1, from neuroepithelioma cells by expression
      cDNA cloning.
AB  - We generated a cDNA expression library from a human neuroepithelioma cell line
      for detection of novel oncogenes by focus formation assay in NIH3T3 cells. A
      morphologically unique focus was identified upon transfection and the
      transforming plasmid was isolated. The transforming gene, designated NET1,
      encoded a predicted protein species of 54 kDa containing the Dbl-Homology (DH)
      motif. This motif is also present in other growth regulatory molecules including
      Bcr, Cdc24, Vav, Ras-Grf, Ect2, Ost, Tim and Tiam1, which have been implicated as
      regulators of small GTP-binding proteins. NIH3T3 cells transfected with NET1
      expression plasmid showed altered growth properties in vitro and were tumorigenic
      when injected into nude mice. In addition, a 2.5 kb cDNA was isolated from a
      normal human cDNA library which represented the NET1 proto-oncogene contained a
      5' extended open reading frame. The fact that the proto-oncogene failed to induce
      transformation in NIH3T3 cells suggested that the original NET1 oncogene was
      activated by 5'-truncation. The 3.0 and 2.4 kilobasepair (kb) transcripts of the
      NET1 gene was ubiquitously expressed in all tissues examined. Using fluorescence
      in situ hybridization, we localized the NET1 gene to the short arm of human
      chromosome 10 at band p15.

PMID- 8649827
TI  - Expression of the jun family of genes in human ovarian cancer and normal ovarian
      surface epithelium.
AB  - The jun genes (c-jun, jun-B and jun-D) play a role in critical cell functions
      such as proliferation, differentiation and apoptosis. We documented jun
      expression at the mRNA and protein level in human ovarian cancer tissues (n=28),
      surface epithelial cells of normal ovaries (n=14) and ovarian cancer cell lines
      (n=6). Almost all of ovarian tumors as well as normal ovaries concomitantly
      express c-jun, jun-B, and jun-D mRNA. Immunohistochemistry was less sensitive and
      revealed nuclear c-Jun and Jun-B proteins in the malignant epithelial cells of
      respectively 38% and 11% of ovarian tumors and in the surface epithelium of a
      normal premenopausal ovary. In cultured ovarian cancer cells, c-jun and jun-B
      expression is inducible by serum and TPA and is therefore not constitutive. The c
      jun and jun-B proteins therefore play a role both in differentiation of the
      normal ovarian surface epithelium, as well as in the proliferation of epithelial
      ovarian cancer cells. High jun-B expression relates to a more malignant phenotype
      both in vitro and in vivo. The jun-D gene is suppressed in ovarian cancer cells
      as compared to normal ovarian surface epithelial cells in situ and in vitro.
      Downregulation of jun-D might therefore be part of the malignant ovarian
      epithelial cell phenotype.

PMID- 8649830
TI  - Evidence for GEAPS, novel Glial E2F1-Associated Proteins in hamster glioma cells
      induced by the human neurotropic polyomavirus, JCV.
AB  - Injection of the human neurotropic polyomavirus, JCV, into neonatal hamsters
      causes tumors of glial origin. Previously, a rapidly proliferating cell line, HJC
      15, which expresses high levels of the viral T-antigen, had been established from
      JCV-induced hamster glial tumors. In our analyses of the mechanisms involved in
      the control of glial cell proliferation in these tumor cells, we have focused our
      attention on E2F1, a DNA-binding transcription factor which modulates the
      activity of genes involved in the S-phase of the cell cycle. Here, we report the
      identification of a novel nucleo-protein complex that forms between select E2F1
      binding sites and nuclear proteins from HJC-15 and normal hamster glial cells. In
      comparison to the previously characterized E2F1 complexes, this complex exhibited
      distinct mobility, binding and biochemical characteristics. This slower migrating
      complex also contained several unique Glial E2F1-associated proteins, (GEAP),
      which have a distinct molecular mass. Of particular, unlike the classical E2F1
      whose DNA binding activity is increased during S-phase, the level GEAPs remained
      constant throughout the cell cycle. GEAPs appeared to confer an increased basal
      transcriptional activity of promoters containing select E2F1 sites in HJC-15
      cells. Interestingly, the increased transcriptional activity modulated by GEAPs
      in HJC-15 cells was overcome by overexpression of E2F1 in these cells. These data
      point to the presence of novel members of the E2F family in hamster glial cells
      with the potential to regulate expression of S-phase specific genes in glial
      tumors obtained upon intracerebral injection of JCV. The importance of these
      findings in the pathogenesis of viral-induced tumors and the role of cell cycle
      regulatory proteins in brain tumor formation is discussed.

PMID- 8649829
TI  - Induction of expression of growth-related genes by FGF-4 in mouse fibroblasts.
AB  - Cells monitor and respond to extracellular signals from polypeptide growth
      factors by the induction of a genetic program. Although poorly understood at the
      molecular level, the biological activity of growth factors is believed to be
      mediated by the regulation of specific sets of genes. We have isolated a number
      of cDNAs, the expression of whose corresponding RNAs is induced by FGF-4 (K-FGF)
      in murine NIH3T3 fibroblasts. The cDNAs (FIN, for FGF-inducible) were isolated
      using a strategy of subtractive hybridization designed to yield 'late' genes
      which compared transformed 3T3 cells that constitutively produce FGF-4 with their
      normal counterpart. The 21 independent cDNAs isolated were found to correspond to
      known genes (FIN1-12), or novel genes (FIN13-21). Expression of the FIN genes is
      induced in response to FGF-4 as well as to serum in NIH3T3 cells with delayed
      kinetics, with maximum stimulation occurring 12-18h after growth factor
      treatment. Induction requires protein synthesis and is mostly transcriptional.
      FIN1-12 encode a broad range of previously described genes, some of which are
      proposed to have an important role in cell proliferation. The novel clones
      include a putative serine-threonine phosphatase (FIN13) and a gene with homology
      to NTP-binding proteins (FIN16). The distribution of expression of the novel FIN
      clones in adult mouse tissues was highly restricted, although most were expressed
      in embryos. While expression of novel FIN cDNAs was strongly regulated in NIH3T3
      cells, induction of differentiation in PC-12 cells by FGF-4 (as well as by NGF)
      did not result in significant induction of expression, suggesting that most of
      the FIN genes are proliferation-specific. Chromosomal localization of novel FIN
      clones indicated that each segregated independently to separate mouse
      chromosomes.

PMID- 8649831
TI  - Distinct 3p21.3 deletions in lung cancer and identification of a new human
      semaphorin.
AB  - Loss of chromosome 3p is a critical event in the pathogenesis of lung cancer.
      Overlapping homozygous 3p21.3 deletions in lung cancer cell lines involving GNAI2
      were characterized and found to involve a region of genomic instability. A new
      widely expressed Semaphorin, H.SemaIV, was isolated from the GNAI2 deletion
      region. Reduced H.SemaIV expression allowed identification of additional cell
      lines with submicroscopic or larger deletions of the locus which occurred in a
      heterogeneous manner. We also demonstrate the presence of a distinct 3p21.3
      homozygous deletion region, adjacent to the DNA mismatch repair gene, hMLH1, and
      identified deletions in direct tumors. This appears to represent one of the first
      demonstrations of homozygous deletions affecting 3p in direct lung tumors.

PMID- 8649832
TI  - c-myc expression is activated by the immunoglobulin kappa-enhancers from a
      distance of at least 30 kb but not by elements located within 50 kb of the
      unaltered c-myc locus in vivo.
AB  - 50 kb of contiguous DNA sequences covering the human c-myc coding region and
      approximately 20 kb of flanking upstream and downstream sequences were cloned
      onto a prokaryotic F-factor derived plasmid, which also contains a selectable
      marker and the plasmid origin of DNA replication oriP of Epstein Barr virus
      (EBV). Since these plasmids replicate extrachromosomally after stable
      transfection into EBV-positive B-cell lines, the gene regulation of c-myc can be
      analysed independent from chromosomal integration positions. Despite the presence
      of all known c-myc regulatory elements on these constructs, expression from the
      stably transfected c-myc gene was barely detectable in either cell line.
      Hypermethylation of these plasmids could be excluded as a mechanism for the lack
      of gene expression. Insertion of the immunoglobulin kappa-intron and 3'
      enhancers, however, activated c-myc transcription, when placed adjacent to or
      separated from the c-myc promoters by as far as 30 kb. These results indicate
      that transcription of c-myc in vivo requires additional and still unidentified
      control elements located outside this 50 kb fragment, and experimentally
      demonstrate long range enhancer function in vivo.

PMID- 8649833
TI  - Wild type neu transgene counteracts mutant homologue in malignant transformation
      of rat Schwann cells.
AB  - Mutational activation of the neu (erbB-2) receptor protein tyrosine kinase gene
      appears to be the triggering event in the process of oncogenesis induced by N
      ethyl-N-nitrosourea (EtNU) in immature Schwann cells of the rat peripheral
      nervous system. Subsequent loss of the wild-type neu allele may represent a
      critical secondary step towards malignancy. Developmentally-regulated expression
      of a wild-type rat neu transgene (neu cDNA under the control of the rat Po
      promoter) in the Schwann cells of transgenic BDIX and Sprague-Dawley rats exposed
      to EtNU on postnatal day 1 results in a lower incidence of early atypical
      proliferates in the trigeminal nerve. Furthermore, re-introduction of the wild
      type neu gene into homozygous neu mutant schwannoma cells counteracts the
      expression of the tumorigenic phenotype. The suppressive action of the wild-type
      gene over its mutationally activated oncogenic homologue underlines the critical
      function of the neu gene in the control of differentiation in the Schwann cell
      lineage, and provides evidence for the responsiveness of cellular phenotypes
      towards quantitative shifts in the dosage of wild-type vs mutant signal
      transducing molecules.

PMID- 8649834
TI  - p21 RNA and protein expression in non-small cell lung carcinomas: evidence of p53
      independent expression and association with tumoral differentiation.
AB  - p21, the product of the WAF1/CIP1/SDI1/mda-6 gene, is an inhibitor of cyclin
      dependent kinases. In cell cultures p21 is induced by p53-dependent and p53
      independent pathways by DNA damage and induction of differentiation. We
      investigated p21 RNA and immunohistochemical expression in 43 non-small cell lung
      carcinomas and corresponding normal lung samples previously investigated for p53
      and WAF1 gene status and p53 protein expression. p21 RNA and protein expression
      in normal and neoplastic tissues were strictly associated (p-0.0001). In normal
      tissue p21 RNA was expressed at low levels and p21 immunoreactivity was seen in
      scattered differentiated bronchial, alveolar and stromal cells. In the majority
      of neoplasms p21 protein and RNA were expressed at higher levels than in the
      corresponding normal tissues: p21 overexpression was seen in 27 (63%) and 28
      (65%) cases respectively. p21 was expressed independently from p53 gene/protein
      alterations. p21 overexpression was more frequent in well differentiated tumors
      (P=0.01 and P=0.022 for RNA and protein respectively), and p21 immunoreactivity
      was usually seen in foci of more pronounced differentiation. We conclude that p21
      expression is related to tumor differentiation, and that p53-independent p21
      expression is a common feature of in vivo neoplasms.

PMID- 8649835
TI  - Two functionally distinct domains responsible for transactivation by the Ets
      family member ERM.
AB  - The recently cloned human Ets transcription factor ERM is closely related to the
      ER81 and PEA3 genes. Here, we report the functional analysis of the DNA-binding
      and transactivation properties of ERM. Specific DNA-binding by ERM requires the
      ETS domain, conserved in all members of the Ets family and is inhibited by an 84
      residue long central region and the carboxy-terminal tail. Two fragments of ERM
      are transferrable activation domains: alpha, which sits in the 72 first residues
      and encompasses the acidic domain conserved between ERM, ER81 and PEA3, and the
      carboxy-terminal tail which also bears a DNA-binding inhibition function.
      Deletion of alpha strongly reduces transactivation by ERM. Moreover, alpha and
      the carboxy-terminal tail exhibit functional synergism, suggesting that they
      activate transcription through different mechanisms. In support of this idea, we
      demonstrate that VP16 squelches transactivation by alpha but not by the carboxy
      terminal tail. This result also indicates that alpha and VP16 may share common
      limiting cofactors. alpha and the carboxy-terminal tail do not seem to be
      conserved within the whole Ets family, indicating that the specificity of ERM may
      rely on interactions with distinct cofactors.

PMID- 8649836
TI  - The bombesin/GRP receptor transfected into Rat-1 fibroblasts couples to
      phospholipase C activation, tyrosine phosphorylation of p125FAK and paxillin and
      cell proliferation.
AB  - Bombesin elicits multiple signalling pathways in various cell types. It is not
      clear, however, whether these responses are mediated by a single receptor subtype
      or by different subtypes that couple preferentially to specific pathways. To
      resolve this we transfected the mouse bombesin/GRP receptor into Rat-1
      fibroblasts and investigated the pathways activated by bombesin. Expression of
      the transfected receptors was verified by binding of (125I)GRP and two clones
      were selected, BOR5 and BOR15. Bombesin stimulation of BOR5 and BOR15 cells
      caused intracellular Ca2+ mobilisation and increased the phosphorylation of
      80K/MARCKS, a prominent protein kinase C substrate. The transfected receptor
      conferred a proliferative response to bombesin demonstrated by incorporation of
      (3H) thymidine after 18 h and an increase in total cell numbers after 1-2 days.
      In BOR5 and BOR15 cells, bombesin rapidly stimulated the tyrosine phosphorylation
      of multiple proteins Mr 110 000-130 000 and 70 000-80 000 including p125fak and
      paxillin, at low concentrations (half maximum 0.3 nM). The specific bombesin/GRP
      receptor antagonist, D-F5-Phe6, D-Ala11-Bombesin (6-13)OMe, inhibited all the
      above responses. These results show that phospholipase C activation, cell growth
      and tyrosine phosphorylation emanate from a single class of bombesin receptor.

PMID- 8649837
TI  - Effect of nerve growth factor on the expression of cell cycle regulatory proteins
      in PC12 cells: dissection of the neurotrophic response from the anti-mitogenic
      response.
AB  - PC12 cells treated with nerve growth factor (NGF) undergo a G1 block and
      differentiate. Expression of selected cell cycle regulatory proteins was studied
      under culture conditions which permit observation of a differentiation response
      independently from a mitogenic or anti-mitogenic response. The expression of all
      cell cycle regulatory proteins studied is modulated by NGF addition to
      exponentially-growing cultures in the presence of serum. While levels of most of
      these proteins decrease, accumulation of cyclin D1 and the cyclin-dependent
      kinase inhibitor p21 Cip1/WAF1 is observed. Cyclin D1 associated kinase activity
      is inhibited, correlating with an increase in p21 protein. PC12 cells,
      synchronized by serum starvation, undergo morphological and functional
      differentiation in the presence of NGF. Neither cyclin D1 nor p21 are present in
      such cultures, nor is their expression upregulated by NGF, indicating that they
      are not required for this process. Removal of serum from differentiated PC12
      cells results in loss of these proteins, but has no effect on differentiation or
      the nonproliferative state in presence of NGF. Together, the results indicate
      that cyclin D1 and p21 are not necessary for differentiation per se, nor are they
      required for maintenance of the differentiated state in the absence of serum.

PMID- 8649838
TI  - Cholecystokinin-B/gastrin receptors mediate rapid formation of actin stress
      fibers.
AB  - Specific receptors for brain-gut peptide hormones, cholecystokinin (CCK) and
      gastrin, are expressed in a variety of human tumor cells. CCK and gastrin promote
      the growth of NIH3T3 cells into which the CCK-B/gastrin receptor had been
      introduced via a eukaryotic expression vector. In this study, we have examined
      the effect of CCK-8 on the actin cytoskeleton by using two mouse fibroblast cell
      lines expressing human CCK-B/gastrin receptors. Treatment with very low
      concentration of CCK-8 (10(-10) M) induced the formation of actin stress fibers
      within one minute. Stress fiber formation increased for 30 min. In contrast, a
      potent mitogen for fibroblasts, platelet-derived growth factor (PDGF), initially
      induced membrane ruffling and, later, a weak formation of stress fibers.
      Microinjection of rho GDP dissociation inhibitor or Clostridium botulinum ADP
      ribosyltransferase C3 which is known to impair the function of a small GTP
      binding protein, rho p21, inhibited the stress fiber formation by CCK-8 as well
      as by PDGF. These results indicate that CCK-B/gastrin receptor could regulate
      stress fiber formation in a rho p21-dependent manner. The signals from CCK
      B/gastrin receptor might affect cell growth as well as cell motility or adhesion
      by regulating the actin cytoskeleton.

PMID- 8649839
TI  - A follistatin-like gene, mac25, may act as a growth suppressor of osteosarcoma
      cells.
AB  - mac25, a retinoic acid-inducible gene that is expressed at high levels in
      senescent epithelial cells, was initially cloned as a gene that is differentially
      expressed in meningioma. Although the homology of its product with members of
      family of insulin-like growth factor-binding proteins was suggested, the product
      also exhibits strong homology to follistatin, an activin-binding protein.
      However, a domain corresponding to the carboxyl terminus of follistatin is not
      found in mac25. The carboxyl-terminally truncated form of follistatin, generated
      by alternative splicing, has stronger activin-binding activity than the complete
      form. This result suggests that mac25 might act as an activated follistatin.
      Clonal growth of a p53-deficient osteosarcoma cell line was strongly inhibited
      when the murine mac25 gene, as well as the p53 gene, was introduced. Resembling
      activins that belong to the transforming growth factor-beta (TGF-beta)
      superfamily, mac25 and p53 might associate with similar but distinct targets,
      namely cyclin-dependent kinase inhibitors. However, there is no evidence for
      compensation of p53 function by mac25 in the development of p53-deficient mice,
      as judged from the pattern of expression of mac25 in mice. mac25 might act as a
      tumor suppressor, modulating signaling of the TGF-beta family, as does alpha
      inhibin.

PMID- 8649840
TI  - Selective maternal-allele loss in human lung cancers of the maternally expressed
      p57KIP2 gene at 11p15.5.
AB  - Genomic imprinting at 11p15 is suggested to play a role in certain pediatric
      tumors such as Wilms' tumor, based on the findings of selective maternal loss of
      this chromosomal region. Although the allele loss at 11p15 is also frequent in a
      number of cancers of adults including lung, breast, and bladder cancers, possible
      involvement of genomic imprinting in these tumors has not been investigated
      extensively. p57KIP2, a newly described member of the p21 cyclin-dependent kinase
      (CDK) inhibitor family which is thought to negatively regulate the cell cycle at
      the G1 checkpoint, has been mapped to 11p15. In the present study, we searched
      for somatic p57KIP2 mutations in lung cancer, but failed to find such
      alterations. Interestingly, however, we found that the p57KIP2 gene is imprinted
      with maternal expression and that the maternal alleles had been selectively lost
      in 11 of 13 (85%) lung cancer cases carrying 11p15 deletions, this being a
      significant bias (p=0.01). These data provide the first evidence that genomic
      imprinting may play a role in the oncogenesis of not only rare pediatric tumors
      but also this common cancer of adults, suggesting that the imprinted p57KIP2 CDK
      inhibitor gene is a potential target for maternally biased 11p15 deletions.

PMID- 8649841
TI  - A cis-acting element in the BCL-2 gene controls expression through translational
      mechanisms.
AB  - The bcl-2 gene becomes activated in many types of human cancers and contributes
      to neoplastic cell expansion, as well as to resistance to radiation and
      chemotherapy, by blocking programmed cell death or apoptosis. The expression of
      this proto-oncogene is regulated at both the transcriptional and post
      transcriptional levels. DNA sequence comparisons of human, mouse, rat and chicken
      bcl-2 cDNAs revealed the presence of an open reading frame (ORF) [correction of
      (OFR)] located upstream of the normal coding region. Because upstream ORFs
      (uORFs) have been associated with translational repression, we analysed the
      functional significance of the 11 amino-acid uORF in the human BCL-2 gene (-119
      to -84 bp). Deletion of this uORF from chloramphenicol acetyltransferase (CAT)
      reporter gene constructs that contained the bcl-2 promoter and entire 5'
      untranslated region (5'-UTR), as well as introduction of an A-->T mutation at
      position -119 bp that destroyed the AUG-initiation codon, significantly increased
      CAT activity in HeLa, CEM, and other cell lines, without producing a
      corresponding elevation in CAT mRNA levels. Positioning this uORF, together with
      its accompanying Kozak sequences, between a heterologous promoter from SV40 and a
      CAT reporter gene resulted in marked inhibition of CAT protein production without
      a decrease in CAT mRNA. Mutation of the start codon (ATG-->TTG) of this uORF
      completely abolished its inhibitory activity, consistent with a translational
      mechanism. Taken together, these findings suggest that the uORF located within
      the 5'UTR of the bcl-2 gene is necessary and sufficient for translational
      regulation of bcl-2 gene expression.

PMID- 8649842
TI  - The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour
      suppressor gene involved in the development of cylindromas.
AB  - Hereditary cylindromatosis is a rare autosomal dominant disease characterised by
      the development of multiple benign neoplasms of the skin. We recently localised
      the gene responsible for this disease (cyld1) to chromosome 16q12-q13 and
      provided evidence that it is a tumour suppressor gene (Biggs et al., 1995). We
      have now examined polymorphic markers on every chromosome, some of which are
      close to known tumour suppressor genes, in 25 tumours from 4 individuals with
      familial cylindromatosis. No loss of heterozygosity (LOH) was detected other than
      at loci on chromosome 16q. This observation suggests that the cyld1 gene may be
      the only tumour suppressor gene implicated in the development of cylindromas. We
      have also demonstrated LOH using markers on chromosome 16q in 8/14 (57%) sporadic
      cylindromas, indicating that the cyld1 gene is likely to be involved in the
      genesis of both familial and sporadic cylindromas.

PMID- 8649843
TI  - Activation of the retinoblastoma gene expression by Bcl-3: implication for muscle
      cell differentiation.
AB  - The retinoblastoma (Rb) protein is a master regulator of cell cycle. Accumulating
      evidence suggests that elevation of Rb expression is a key event in
      differentiation of various cell types. However the mechanism of regulation of Rb
      expression is poorly understood. Here we report that the candidate oncoprotein
      Bcl-3, previously characterized as a member of the IkappaB family, activates
      transcription of the Rb gene, whose promoter has no typical kappaB sites. A
      target element for Bcl-3 that matches the consensus for the E4TF1/GABP
      transcription factor was identified. Bcl-3 was shown to promote tetramer
      formation of E4TF1. During muscle cell differentiation, increased bcl-3
      expression was observed before the induction of the Rb mRNA. Transient expression
      of Bcl-3 in myoblasts was shown to induce expression of the endogenous Rb.
      Furthermore, expression of the antisense bcl-3 RNA in myoblasts suppressed
      induction of Rb and myogenic differentiation. These results suggest that Bcl-3 is
      an upstream regulator of Rb expression during differentiation of muscle cells.

PMID- 8649844
TI  - Induction of c-myc mediated apoptosis in SV40-transformed rat fibroblasts.
AB  - The ability of SV40 T antigen to block apoptosis was investigated in Rat1-A
      fibroblasts expressing an estrogen-dependent c-myc construct, mycER (Eilers et
      al., 1989). These RatmycER cells undergo apoptosis upon activation of c-myc by
      estradiol under conditions of serum deprivation. Under such conditions SV40
      transfected derivatives of RatmycER undergo apoptosis as evidenced by rapid cell
      death, characteristic morphological changes and DNA fragmentation in a manner
      indistinguishable from the parental cell line, indicating that T antigen is not
      able to protect against myc-induced apoptosis. In as much as it had been reported
      that myc-mediated apoptosis involves wild-type p53 in other systems and T antigen
      is known to bind and inhibit p53 function, we examined these two polypeptides
      under different experimental conditions. In all cases, the great majority of the
      p53 in the SV40 transfectants was found to be in complexes with T antigen.
      Furthermore, the residual p53 in the uncomplexed state was not sufficient to
      transactivate an endogenous promoter, WAF1/p21. These data indicate that the
      failure of T antigen to block apoptosis cannot be attributed to defective
      function of T antigen and suggest that myc-mediated apoptosis may involve a p53
      independent pathway in these cells.

PMID- 8649845
TI  - Cell-cycle regulation of B-Myb protein expression: specific phosphorylation
      during the S phase of the cell cycle.
AB  - Previous studies revealed that transcription of B-Myb, which encodes a
      transcription factor related to the c-Myb proto-oncoprotein, is cell-cycle
      regulated by an E2F transcription factor-mediated repression mechanism operating
      in G0/G1. To begin to determine the consequences of transcriptional regulation on
      B-Myb function, we report here further studies of B-Myb protein expression in the
      cell cycle. We found that G0-arrest of serum-deprived mouse fibroblasts was
      achieved without significant reduction in B-Myb levels, moreover, over-expression
      of B-Myb in stably transfected cells did not prevent their entry into G0.
      Following serum-induction of arrested fibroblasts, B-Myb abundance increased as
      cells entered S phase to levels significantly greater than found in cycling
      cells. This was accompanied by the appearance of a novel phosphorylated form of B
      Myb (112 kDa) of distinctly lower electrophoretic mobility than B-Myb present in
      G1 (110 kDa). The 112 kDa species was S phase-specific even in transfected cells
      overexpressing B-Myb. Consistent with modification in the S phase of the cell
      cycle, preliminary evidence suggested that a cyclin A/cdk2, but not cyclin E/cdk2
      or cyclin D1/cdk4, complex could induce a similar electrophoretic mobility change
      in baculovirus-specified B-Myb. These findings show that B-Myb expression may be
      subject to two levels of control during the cell cycle, transcription and protein
      phosphorylation.

PMID- 8649846
TI  - Sos1 rapidly associates with Grb2 and is hypophosphorylated when complexed with
      the EGF receptor after EGF stimulation.
AB  - The Son of sevenless (Sos) protein, a guanine nucleotide exchange factor for ras
      proteins, appears to play a central role in signalling between protein tyrosine
      kinase receptors and ras. The C-terminal region of Sos binds an adaptor protein,
      Grb2, which in turn binds to activated receptors including the EGF receptor
      (EGFR). Although the Sos protein is rapidly phosphorylated following cytokine
      stimulation, there is no evidence that this alters the enzymatic activity of Sos
      for ras proteins. Therefore, we investigated whether the ability of Sos1 to form
      complexes with Grb2 and with the EGF receptor (EGFR) changes following EGF
      stimulation, as a possible mechanism for regulating Sos activity. In contrast to
      earlier findings, we find that both the association and dissociation of Sos1 with
      Grb2 is responsive to EGF. Whilst the association of Sos1 and Grb2 following EGF
      stimulation is not cell type specific, we find that it is dependent on cell
      density and that the response to EGF differs to that induced by NGF. We find that
      following EGF stimulation, the Sos1 protein associated with the EGFR is markedly
      less phosphorylated than the majority of the Sos1 within the cell and there was
      reduced binding of Grb2 with phosphorylated Sos1 protein in a direct binding
      assay. A time course analysis showed that Sos1 dissociates from the EGFR more
      rapidly than does Grb2 following EGF stimulation. Collectively our findings are
      consistent with the notion that the phosphorylation of Sos1 affects its ability
      to complex with the EGFR and Grb2.

PMID- 8649847
TI  - Determination of the frequency of loss of heterozygosity in esophageal
      adenocarcinoma by cell sorting, whole genome amplification and microsatellite
      polymorphisms.
AB  - It is well established that the progression to human cancer is characterized by
      the evolution of clones of cells with accumulated genetic abnormalities. However,
      technical difficulties limit the ability to study this process in some
      premalignant and malignant conditions. For example, the progression to esophageal
      adenocarcinoma in the premalignant condition Barrett's esophagus is characterized
      by the evolution of genetic and cell cycle abnormalities, but it has been
      difficult to characterize this process completely because of the small size of
      biopsies and the relative abundance of genetically normal stromal cells in some
      esophageal adenocarcinomas and premalignant mucosa. We have combined flow
      cytometric cell sorting to obtain purified populations of neoplastic cells with
      whole genome amplification and analysis of microsatellite polymorphisms to
      determine the frequency of allelic loss on every nonacrocentric autosomal arm in
      20 esophageal adenocarcinomas and two high-grade dysplasias. DNA samples of
      purified flow-sorted aneuploid and corresponding normal tissue were amplified
      with a degenerate 15mer primer. Aliquots of these reactions were then screened
      with forty-three highly polymorphic simple sequence repeat markers in PCR-based
      assays. Allelic losses were observed at polymorphic loci in 38 of the 40
      chromosome arms that were analysed and the median fractional allelic loss (FAL)
      observed in the samples was 0.28. The background allelic loss frequency was
      estimated at 0.23 with the highest rates of loss observed at 17p (100%), 5q
      (80%), 9p (64%), 13q (43%), 18q (43%) and 1p (41%). These data represent the
      first comprehensive allelotype of esophageal adenocarcinoma and show the
      feasibility of multiloci analyses with small highly purified human biopsy
      material.

PMID- 8649848
TI  - The v-erbA oncogene selectively inhibits iodide uptake in rat thyroid cells.
AB  - v-erbA is the oncogenic form of the c-erbA proto-oncogene, which encodes the
      receptor for thyroid hormones. The expression of the v-erbA oncogene in thyroid
      differentiated cells, PC Cl 3, inhibits iodide uptake and thyrotropin-dependent
      growth, whereas it has no effect on the expression of the other thyroid specific
      markers, i.e. thyroglobulin, thyroperoxidase and thyrotropin receptor. The
      activity of transcription factor AP-1, evaluated by a specific DNA binding assay
      and by transcription of AP-induced promoter (TRE) is enhanced in PC v-erbA cells.
      v-erbA mutants in the DNA binding domain do not affect the iodide uptake of
      thyroid cells nor AP-1 activity. We suggest that this transcriptional activation
      mediates the selective effects of v-erbA on the expression of thyroid specific
      markers.

PMID- 8649849
TI  - Expression of B-Myb during mouse embryogenesis.
AB  - B-myb is a member of the myb family of nuclear sequence-specific DNA-binding
      proteins which has been highly conserved among vertebrates. B-myb has been
      implicated in the control of cell proliferation, particularly at the G1/S
      transition of the cell cycle. So far, most of the work on B-myb has been
      performed in immortalized cell lines. Since these cells might show aberrant
      behavior of genes involved in proliferation control we have begun to investigate
      the role of B-myb in normal cells. As a first step, we have studied the
      expression of B-myb during mouse development. Here, we show the B-myb is
      expressed at similar levels during all stages of embryogenesis. In situ
      hybridization reveals a tight linkage between B-myb expression and proliferative
      activity (as assessed by the expression of the S-phase specific histone H4 gene)
      in most tissues and throughout embryonic development. However, B-myb and histone
      H4 expression are uncoupled during spermatogenesis in the adult mouse. Histone H4
      is expressed at high levels in the early spermatogenic progenitor cells but not
      in successive stages of sperm cell development. By contrast, the highest levels
      of B-myb expression are found during the intermediate stages of spermatogenesis.
      Furthermore, we have found that B-myb mRNA isolated from the testis differs in
      size from that of other tissues. The data presented here strongly support the
      notion that B-myb plays a general role during proliferation of most cells.
      Furthermore, our results raise the possibility that the function of B-myb in
      cells undergoing meiosis may be different from its role in cells dividing
      mitotically.

PMID- 8649850
TI  - SPARC, an extracellular matrix protein with tumor-suppressing activity in human
      ovarian epithelial cells.
AB  - SPARC, also termed osteonectin, BM-40 and 43K protein, is an acidic, cysteine
      rich component of the extracellular matrix that has been shown to be directly
      regulated by progesterone and dexamethasone and indirectly by cytokines. By RNA
      fingerprinting technique, we cloned a SPARC homolog from the normal human ovarian
      surface epithelial (HOSE) cells and demonstrated that it is expressed at high
      levels in the normal HOSE cells but at much lower levels in ovarian carcinoma
      cells in vitro and in vivo. Subsequently, we transfected the full length SPARC
      cDNA into an ovarian carcinoma cell line SKOV3 and showed that it reduced the
      growth rate of the cancer cell line in culture and reduced the cell's ability to
      induce tumours in nude mice. These results suggest that SPARC may play an
      important role in growth and and differentiation of the HOSE cells and support
      the hypothesis that SPARC functions as a tumor suppressor.

PMID- 8649851
TI  - Increased expression of cyclin D1 and the Rb tumor suppressor gene in c-K-ras
      transformed rat enterocytes.
AB  - Activating mutations in the c-K-ras gene occur in about 40% of human colorectal
      carcinomas, yet the role of this oncogene in tumorigenesis is not known. We have
      developed a model cell culture system to study this problem, utilizing the
      immortalized but non-tumorigenic epithelial cell line IEC18, originally derived
      from normal rat intestine epithelium. These cells were cotransfected with the
      drug resistance selectable marker tk-neo and the plasmid pMIKcys, which encodes a
      mini human c-K-ras gene (15 kb) containing a cysteine mutation at codon 12. Drug
      resistant clones were isolated. Clones which also expressed the activated c-K-ras
      gene displayed a transformed morphology, decreased doubling time, increased level
      of diacylglycerol, anchorage independent growth in soft agar and an aneuploid
      karyotype and they were also tumorigenic when injected into nude mice. These
      clones also displayed increased expression, at both the mRNA and protein levels,
      of cyclin D1 and Rb. These findings may be of clinical relevance since human
      colorectal tumors also frequently display increased expression of both cyclin D1
      and Rb. This model system may be useful for understanding the role and
      interrelationship between activation of the c-K-ras oncogene and increased
      expression of cyclin D1 and Rb in colorectal tumorigenesis.

PMID- 8649852
TI  - The retinoblastoma gene product inhibits TGF-beta1 induced apoptosis in primary
      rat hepatocytes and human HuH-7 hepatoma cells.
AB  - Transforming growth factor-beta1 (TGF-beta1) can induce rapid growth arrest and
      apoptosis in hepatic cells. Its growth suppressive effects appear to be linked to
      decreased phosphorylation of the protein product of the retinoblastoma gene, pRb.
      To characterize the role of pRb in apoptosis, we examined endogenous
      retinoblastoma gene (Rb) expression following treatment with TGF-beta1, okadaic
      acid, or antisense Rb S-oligonucleotides in cultured primary rat hepatocytes and
      human hepatoma HuH-7 cells. We also investigated the effects on apoptosis of Rb
      overexpression following transfection with vectors containing wild-type Rb in HuH
      7 cells. Our results indicated that transfection with Rb antisense S
      oligonucleotides blocked the expression of pRb in cultured primary hepatocytes
      and induced apoptosis. Treatment of HuH-7 cells with TGF-beta1 inhibited
      expression and phosphorylation of pRb, and also induced apoptosis. Furthermore,
      93% of viable preapoptotic cells were arrested in the G1 phase of the cell cycle.
      Incubation with the phosphatase inhibitor okadaic acid maintained pRb in its
      phosphorylated state, and resulted in significant apoptosis. Overexpression of
      wild-type Rb inhibited TGF-beta1 induced apoptosis in HuH-7 cells. In contrast,
      overexpression of transcription factor E2F-1, a known target for the activity of
      pRb, caused significant apoptosis. However, coexpression of Rb suppressed E2F-1
      induced apoptosis in HuH-7 cells. Our results suggest that inhibition of pRb
      expression is associated with hepatocyte apoptosis. Furthermore, E2F-1 appears to
      be a target in the pathway through which pRb modulates the apoptotic threshold in
      hepatic cells. Finally, the data suggest that these cells exit the cell cycle
      during the G1 phase before progressing into apoptosis and pRb may be a negative
      regulator of this process.

PMID- 8649854
TI  - A gene from human chromosomal band 3p21.1 encodes a highly conserved arginine
      rich protein and is mutated in renal cell carcinomas.
AB  - We have identified a gene, called ARP for Arginine-rich protein, in human
      chromosomal band 3p21. It is approximately 600 Kb telomeric to the ACY1 locus
      (Miller et al., 1989) and encodes a previously unidentified 234 amino acid long,
      highly basic protein. This gene is highly conserved at the DNA and RNA level. It
      is found in all species including hamster, rat, mouse, bovine and yeast. We have
      detected a point mutation (ATG50 to AGG) or deletion of ATG50 in 10 of 21
      sporadic renal cell carcinomas. The mutable region is in an imperfect
      trinucleotide repeat in the coding region which is non-polymorphic among 50
      normal individuals examined. The point mutation (ATG50 to AGG) or deletion of
      codon 50 removes a methionine and increases the stretch of arginines encoded by
      the AGG repeats in the ARP gene.

PMID- 8649853
TI  - Identification of ArgBP1, an Arg protein tyrosine kinase binding protein that is
      the human homologue of a CNS-specific Xenopus gene.
AB  - Arg and c-Abl represent the mammalian members of the Abelson family of
      nonreceptor protein-tyrosine kinases. To gain insight into the biological role of
      Arg we used the two-hybrid approach to identify interacting proteins. Using a C
      terminal segment of Arg we identified a novel protein, ArgBP1 (Arg binding
      protein 1). ArgBP1 contains a C-terminal SH3 domain, several PEST sequences, a
      serine rich domain and an SH3 binding site. ArgBP1 is ubiquitously expressed as
      two transcripts of approximately 2.2 kb and approximately 8 kb with highest
      levels in brain, heart and testis. The association of ArgBP1 with Arg in living
      cells was confirmed by coimmunoprecipitation in cotransfected COS cells. Analysis
      of the mechanism of association indicated that the ArgBP1 SH3 domain binds to a C
      terminal Arg SH3-binding site, and that an N-terminal ArgBP1 proline-rich
      sequence binds to the Arg SH3 domain. Immunostaining indicated that the
      subcellular localization of ArgBP1 is cytoplasmic. The similarity of the ArgBP1
      expression pattern and subcellular localization to those of Arg and the potential
      for a highly specific and potentially strong association mediated by two pairs of
      SH3 domain/proline-rich motif interactions, suggest that ArgBP1 is likely to be a
      regulator and/or effector of Arg function.

PMID- 8649855
TI  - Specific binding of MAR/SAR DNA-elements by mutant p53.
AB  - Inactivation of the tumor suppressor p53 by single missense point mutations
      characterizes a large number of human tumors. At least some mutant p53 proteins
      not only have lost the tumor suppressor function, but at the same time reveal a
      variety of dominant oncogenic properties. The molecular basis of this 'gain of
      function' is still unknown. In this report we describe a new biochemical activity
      of mutant p53, the specific high-affinity interaction with MAR/SAR DNA-elements
      (nuclear matrix/scaffold attachment regions). This DNA-binding activity can be
      distinguished from the previously reported DNA-binding activities of p53 by its
      specificity for mutant p53, the high binding affinity, and the domains of the
      mutant p53 molecule involved in MAR/SAR DNA-binding. The MAR/SAR-binding region
      of mutant p53 maps to a bipartite domain consisting of the mutated core region
      and the C-terminal 60 amino acids, carrying the unspecific DNA-binding domain and
      the oligomerization motif. MAR/SAR elements are considered as important
      regulatory elements in a variety of nuclear processes. We propose a model
      according to which the specific interaction of mutant p53 with MAR/SAR elements
      might interfere with these processes, thereby exerting pleiotropic oncogenic
      effects.

PMID- 8649856
TI  - Characterization of the APC gene in sporadic gastric adenocarcinomas.
AB  - The prominent role of the APC gene in colorectal tumor development is well
      established. However, its role in tumorigenesis in other tissues is not clear.
      Hence, DNA from 30 primary sporadic gastric adenocarcinomas was obtained from
      patients living in a high risk area of the world (North-Central Italy) in order
      to further define APC's role in gastric tumorigenesis. We thoroughly examined
      that region of APC which is commonly mutated in colorectal tumors using proven
      sensitive methods. The IVS protein assay and DNA sequence analysis of APC codons
      686 through 1693 revealed no intragenic mutations. However, allelic loss of loci
      near APC was detected in 7 (28%) of 25 informative gastric adenocarcinomas using
      two 5q dinucleotide repeat markers for LOH analysis. These results suggest that
      genetic alteration of a region of APC commonly mutated in colorectal cancer is
      not a common event during sporadic gastric tumor development, at least in
      patients from North-Central Italy. Further analysis of chromosome 5q might
      identify another gene to be significantly altered in these gastric cancers.

PMID- 8649857
TI  - Regulation of the c-fos promoter by the ternary complex factor Sap-1a and its
      coactivator CBP.
AB  - The c-fos proto-oncogene is activated by a plethora of signals via the
      transcription factors Sap-1a and CREB. Recently, the coactivator CBP has been
      demonstrated to act in concert with CREB when CREB is phosphorylated by protein
      kinase A. We show that CBP also binds directly to Sap-1a. While phosphorylation
      of Sap-1a by mitogen-activated protein kinases is not necessary for CBP/Sap-1a
      interaction, functional cooperation between these two proteins requires Sap-1a to
      become phosphorylated. CBP-antagonists impair Sap-1a-mediated transactivation.
      Similarly, the CBP antagonist E1A suppresses c-fos upregulation by phosphorylated
      CREB, indicating that CBP is a central component of c-fos regulation.
      Furthermore, CBP is phosphorylated by protein kinase A in vitro and the
      transactivation potential of the carboxy-terminal region of CBP is enhanced in
      the presence of active protein kinase A in vivo. Thus, CBP, in addition to CREB,
      is a target for cAMP-dependent signaling. However, combined phosphorylation of
      CBP by protein kinase A and mitogen-activated protein kinases appears to be non
      cooperative, suggesting that CBP serves the function of a dampening integrator of
      two different signaling pathways.

PMID- 8649858
TI  - In vivo association of ATFa with JNK/SAP kinase activities.
AB  - The human ATFa proteins belong to the CREB/ATF family of transcription factors.
      We have previously shown that the ATFa proteins may contribute to the modulation
      of the transcriptional activity of the Jun/Fos complexes (Chatton et al. (1994).
      Oncogene, 9, 375-385). We now show that a protein kinase activity is strongly
      associated with ATFa in vivo, as revealed by coimmunoprecipitation of ATFa/kinase
      complexes from whole cell extracts, with antibodies against ATFa. Two independent
      regions were found to be implicated in kinase binding: a major interaction site
      is located within the N-terminal 82 residues comprising an important metal
      chelating element; a weaker binding site corresponds to the basic sequence
      element preceding the C-terminal leucine-zipper of ATFa. Induction experiments
      suggest that each of these ATFa domains may interact with different kinases. The
      major activity is associated with the ATFa N-terminal domain. Based on its
      response to various inducers, on both in vitro and in vivo binding assays, and on
      its immunological properties, this activity most likely corresponds to the 54/55
      kDa JNK2 protein. Taken together, these observations suggest that the ATFa
      proteins, among other CREB/ATF proteins, may be important effectors of cell
      signalling pathways.

PMID- 8649859
TI  - The two major sites of cbl tyrosine phosphorylation in abl-transformed cells
      select the crkL SH2 domain.
AB  - We recently found that the 120-kD protein product of the c-cbl oncogene is
      tyrosine phosphorylated in tumor cells generated by bcr-abl or v-abl and that
      p120cbl will associate with these proteins in vivo. We also found an oncogenic
      form of cbl protein in the 70Z/3 pre-B cell lymphoma which exhibits deregulated
      tyrosine phosphorylation. These findings have led us to broaden our study of
      cbl's involvement in abl-mediated tumorigenesis. Here we show by immunodepletion
      that cbl is the major 120-kD tyrosine phosphorylated protein in cells which
      express activated forms of the abl oncogene. We also demonstrate that tyrosine
      phosphorylation of pl20cbl in bcr-abl transformed cells does not alter its
      subcellular localization. In addition we show that the oncogenic 7OZ/3 form of
      cbl exhibits enhanced tyrosine phosphorylation in v-abl infected cells and that
      cbl is heavily tyrosine phosphorylated in hemopoietic cells transformed by v-src.
      Finally this study identifies two sites that are essential for the tyrosine
      phosphorylation of cbl in abl-transformed cells. These sites conform to the
      preferred abl kinase substrate sequence of YXXP and we show that following
      phosphorylation they mediate an association with the crkL SH2 domain.

PMID- 8649860
TI  - Transcriptional and post-transcriptional induction of the TGFalpha gene in
      transformed rat liver epithelial cells.
AB  - Although TGFalpha mRNA and protein are frequently elevated in neoplastic cells,
      neither the level at which deregulation occurs nor the mechanism(s) responsible
      have been well characterized. As a first step, we examined the induction of
      TGFalpha mRNA in two series of clonally-derived rat liver epithelial cell lines
      that were transformed either by exposure to chemical carcinogen or stable
      transfection of activated Ha-ras. We found that steady-state levels of TGFalpha
      mRNA in both series of transformed lines were induced 25- to 50-fold over those
      in the respective normal parental cells. This induction, which occurred without
      amplification of the TGF alpha gene, was accompanied by at least a five- to 10
      fold increase in transcription along the entire length of the gene with no
      evidence of a transcriptional attenuation or arrest mechanism in the normal
      cells. Analysis of the TGFalpha promoter and flanking regions did not support a
      correlation between the extent of methylation and the level of expression, but
      did reveal several DNase I hypersensitive sites spanning from -14 to +8
      kilobases. Two of these sites were differentially observed in cells displaying
      high and low TGFalpha gene transcription, while a third site correlated with TPA
      induced expression. Finally, measurement of TGFalpha mRNA decay in the presence
      of Actinomycin D revealed a consistent 1.5- to 3.2-fold increase in the half-life
      of the TGFalpha transcript in the various transformed cell lines. These results
      indicate that transformation-mediated induction of TGFalpha gene expression in
      rat liver epithelial cells occurs through both transcriptional and post
      transcriptional mechanisms, but is primarily the result of TGFalpha promoter
      activation.

PMID- 8649861
TI  - M6P/IGF2 receptor: a candidate breast tumor suppressor gene.
AB  - The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r)
      functions in the activation of TGFbeta, a potent growth inhibitor for most cell
      types, the degradation of the mitogen, IGF2, and the intracellular trafficking of
      lysosomal enzymes. We have found its expression to be significantly reduced in
      both rat and human hepatocellular carcinomas (HCCs) and recently reported loss of
      heterozygosity (LOH) at this locus with mutations in the remaining allele in
      human liver tumors. Using the polymerase chain reaction, we utilized two
      polymorphisms in the 3' untranslated region of M6P/IGF2r to screen breast tumors
      for LOH. Forty of 62 (65%) patients were informative (heterozygous) and 12/40
      (30%) breast tumors had LOH; 5/19 (26%) carcinomas in situ (CIS) and 7/21 (33%)
      invasive carcinomas. To investigate the early molecular genetic events in breast
      carcinogenesis, we screened the CIS with LOH for mutations. In 2/5 (40%) of these
      tumors, missense mutations were found in the remaining allele that gave rise to
      significant amino acid substitutions. These findings provide evidence that
      M6P/IGF2r allelic loss is an early event in the etiology of breast cancer, that
      this gene functions as a tumor suppressor gene in the breast.

PMID- 8649862
TI  - A functional N-myc2 retroposon in ground squirrels: implications for hepadnavirus
      associated carcinogenesis.
AB  - Three hepatitis B viruses infecting humans, woodchucks and ground squirrels
      increase the risk of hepatocellular carcinoma in their respective hosts. The
      woodchuck hepatitis B virus (WHV), unlike the two other viruses, induces a rapid
      carcinogenic process characterized by direct activation of myc proto-oncogenes by
      insertion of viral DNA. The highly preferred target of insertional mutagenesis in
      woodchucks is N-myc2, an intronless N-myc gene. Strikingly, N-myc2 has no human
      homolog and the homologous N-myc2 locus previously detected in the ground
      squirrel genome, remains silent during hepatocarcinogenesis. Therefore, N-myc2
      may represent a critical host determinant in the evolution of the disease
      associated with hepadnavirus infection. To address this question, we performed a
      structural and functional analysis of the ground squirrel N-myc2 locus. We show
      that ground squirrel N-myc2 is highly homologous to its woodchuck counterpart and
      is a functional proto-oncogene. Existence of a functional N-myc2 gene as a
      potential target for insertional activation by viral DNA is therefore not
      restricted to the woodchuck species. This suggests that viral rather than host
      factors determine the higher oncogenic phenotype of WHV as compared to the two
      other mammalian hepadnaviruses.

PMID- 8649864
TI  - Deletions and rearrangements inactivate the p16INK4 gene in human glioma cells.
AB  - Structural alterations in the p16INK4 gene were examined in early passage human
      glioma cell lines and related to the expression of p16 transcripts and protein.
      Using the Southern blot approach, we observed both homozygous and hemizygous
      deletions, as well as rearrangements of the p16 and p15 genes in 5 of the 7 cell
      lines (71%). Two cell lines, MGR3 and HBT28, revealed hemizygous deletion of the
      p16 and p15 genes combined with indistinguishable rearrangements of the remaining
      p15-p16 locus that resulted in loss of exon 2 sequences for p15 and p16, but
      retention of p16 exon 1; neither of these cell lines expressed p16 mRNA. Data for
      a third cell line, MGR2, indicated a similar, but unique rearrangement involving
      the p15 and p16 genes. MGR2, which retained a single wild-type p15-p16 locus,
      showed expression of p16 transcript, but not of p16 protein as indicated by
      Western blot analysis. All the glioma cell lines expressed similar levels of the
      retinoblastoma protein and no amplification of the cyclin-dependent kinase 4
      gene. These results demonstrate that human glioma cells contain p16 gene
      microdeletions and rearrangements that contribute to inactivation of the cell
      cycle regulatory protein.

PMID- 8649865
TI  - Soft tissue sarcoma metastasis from clonal expansion of p53 mutated tumor cells.
AB  - Although soft tissue sarcoma has a high incidence of p53 mutations, it is not
      clear if such alterations facilitate tumor growth and metastasis. In this study,
      fresh autologous normal lymphocytes, normal muscle, primary and metastatic
      sarcoma tissues from a single synovial sarcoma patient were examined for p53
      related alterations that potentially associated with sarcoma tumor development
      and metastasis. Normal tissues contain two wild-type p53 alleles. Primary sarcoma
      had one chromosome 17p p53 allelic deletion without apparent p53 mutation in the
      other allele. However, metastatic tumor had deletion of one p53 allele with an
      exon 5 codon 135 missense mutation in the other allele. This p53 gene point
      mutation in the metastasis was associated with the production of mutated p53
      protein. A small clone of cells harboring the identical p53 gene point mutation
      was identified in the primary tumor using mutant allele specific PCR
      amplification, albeit at levels much less than in the metastatic sarcoma. This
      single patient example indicate that soft tissue sarcoma metastasis can develop
      from clonal expansion of primary tumor cells bearing p53 mutations.

PMID- 8649866
TI  - The history of laryngology: a centennial celebration.

PMID- 8649863
TI  - Implication of retinoic acid receptor gamma in squamous differentiation and
      response to retinoic acid in head and neck SqCC/Y1 squamous carcinoma cells.
AB  - Nuclear retinoic acid receptors are considered to be the mediators of most of the
      effects of retinoic acid (RA) on gene expression. To explore the role of RA
      receptor gamma (RARgamma) in the growth and differentiation of SqCC/Y1 head and
      neck squamous carcinoma cells, they were transfected with RARgamma sense and
      antisense expression vectors and stable clones in which RARgamma expression was
      either increased or blocked were isolated. The growth inhibitory effect of RA in
      monolayer culture was enhanced in the sense transfectants and decreased in the
      antisense ones. The ability to form colonies in semisolid medium was abolished by
      RA in the sense transfectants, while the antisense transfected clones exhibited
      heterogeneous responses. The expression the squamous differentiation markers
      cytokeratin K1 transglutaminase type I, and involucrin was increased in the
      absence of exogenous retinoid in a sense transfected clone and decreased in an
      antisense transfected clone. RA suppressed squamous differentiation in both types
      of transfectant. The expression of epidermal growth factor receptor (EGFR) was
      higher in the antisense and lower in the sense transfectant than in the parental
      cells and RA decreased EGFR mRNA level in the parental and the sense transfectant
      but not in the antisense transfectant. In addition activator protein-1 (AP-1)
      binding activity was decreased by the RA treatment in the sense clones, but not
      in the antisense ones. These results suggest that RARgamma mediates the effects
      of RA on the cell growth both in monolayer culture and in semisolid medium
      possibly through AP-1 suppression.

PMID- 8649867
TI  - Ambulatory vs. in-patient stapedectomy: a randomized twenty-patient pilot study.
AB  - A prospective study was undertaken to determine whether stapedectomy can safely
      be performed in an outpatient setting. Twenty patients with otosclerosis amenable
      to surgical treatment were divided into two groups; those in the hospitalized
      group were admitted the day before surgery and discharged 24 hours after the
      procedure. The patients in the ambulatory group were admitted on the day surgery
      was scheduled and released 1 or 2 hours after the procedure. We analyzed the
      intensity and duration of postoperative vertigo, and the hearing gain obtained,
      studying the speech frequencies(500 to 2000 Hz) separately from the high
      frequencies (4000 to 8000 Hz). No significant difference was found at 1, 3, and 6
      months of follow-up in any of the parameters studied, concluding that small
      fenestra stapedectomy can safely be performed as an outpatient procedure.

PMID- 8649868
TI  - Allergic and immunologic aspects of Meniere's disease.
AB  - Meniere's disease, although idiopathic by definition, has been ascribed to a
      variety of causes, which more recently include autoimmune factors. Interest in
      the role of allergy in Meniere's disease has also increased. Studies from this
      institution and elsewhere provide evidence that allergy and immunologic factors
      play a role in Meniere's disease in at least some patients. The symptoms of
      Meniere's disease are thought to be produced by a sudden influx of fluid into the
      endolymphatic sac, producing a rupture of Reissner's membrane in the cochlea. The
      endolymphatic sac is capable of trapping antigen and generating its own immune
      response. It has a highly vascular subepithelial space containing numerous
      fenestrated blood vessels that are peripheral and "leaky." At least three
      mechanisms by which allergy may play a role in the production of fluid in the
      endolymphatic sac are described: the endolymphatic sac itself might be a "target
      organ" of mediator released from systemic inhalant or food reactions; deposition
      of circulating immune complex may produce inflammation and interfere with the
      sac's filtering capability; and a predisposing viral infection in childhood that
      produces a mild impairment of endolymphatic sac function may interact with
      allergies in adulthood and cause the endolymphatic sac to decompensate, resulting
      in endolymphatic hydrops. The endolymphatic sac is the seat of immune reactivity
      in the inner ear. Repeated inflammatory reactions can produce sac dysfunction and
      eventual production of Meniere's disease.

PMID- 8649869
TI  - Tympanic membrane reconstruction using formaldehyde-formed autogenous temporalis
      fascia: twenty years' experience.
AB  - This study describes 20 years' experience with autogenous temporalis fascia that
      is formed and shaped by formaldehyde cross-linking with special Fasciaform (Hear
      America, Palo Alto, Calif.) molds in the repair of large tympanic membrane
      perforations. One hundred twenty operations in 113 patients were performed
      between 1973 and 1993 to close large perforations in patients with intact
      ossicular chains. All perforations were successfully closed by this technique.
      Audiometric studies indicated that the postoperative air-borne gap was closed to
      within 0 to 10 dB in 63% and to within 0 to 20 dB in 97%. One patient had a 15-dB
      sensorineural hearing impairment. Graft lateralization requiring revision
      occurred in three patients, two of whom had previous unsuccessful
      tympanoplasties. Comparisons of adult vs. pediatric groups and primary vs.
      revision groups were made. The technique ensures the removal of any ectopic
      epithelium on the medial surface of the tympanic membrane remnant and provides
      for easy graft placement and stability during healing without the use of middle
      ear Gelfoam (Upjohn Co., Kalamazoo, Mich.). The formaldehyde-formed fascia graft
      or Fasciaform graft technique provides an effective method of closing large
      perforations with excellent functional results and minimal complications.

PMID- 8649870
TI  - Development of a sensitive clinical facial grading system.
AB  - Clinicians require a reliable and valid method of evaluating facial function
      after facial nerve injury. This tool should be clinically relevant and easy to
      administer, provide a quantitative score for reporting purposes, and be sensitive
      enough to detect clinically important change over time or with treatment. The
      proposed facial grading system has all essential information, including precise
      definitions for each item, presented on one page. The facial grading system is
      based on the evaluation of resting symmetry, degree of voluntary excursion of
      facial muscles, and degree of synkinesis associated with specified voluntary
      movement. Different regions of the face are examined separately with the use of
      five standard expressions. All items are evaluated on point scales, and a
      cumulative composite score is tabulated. Construct validity was addressed by
      comparing the proposed facial grading system to prerehabilitation and
      postrehabilitation treatment scores of 19 patients with varying degrees of facial
      nerve injury. All patients had documented change in a controlled study of
      feedback training. The proposed system reports results in a more continuous
      manner with a wider response range than the House-Brackmann grades. Each
      component of the grading system is sensitive to change and individually
      contributes to a change in the composite score. Tests of interrater reliability
      are currently near completion.

PMID- 8649871
TI  - Unique nuclear matrix protein alterations in head and neck squamous cell
      carcinomas: intermediate biomarker candidates.
AB  - The progression of normal squamous epithelium to a malignant metastatic phenotype
      may depend on cellular genetic events and the failure of host mechanisms.
      Intermediate biomarkers are needed to more effectively identify and quantify
      malignant progression and develop the potential for specific treatments and
      prevention strategies. The nuclear matrix is the RNA-protein scaffold of the
      nucleus, which controls in part nuclear shape, DNA organization, and DNA
      function. Nuclear matrix proteins in all previously studied cell types show a
      common set of nuclear matrix proteins and a subset of tissue- and cell type
      specific proteins. In every system studied to date, the nuclear matrix has been
      demonstrated to undergo quantifiable alterations in its protein composition with
      transformation to the malignant phenotype. The loss and gain of nuclear matrix
      proteins are being investigated as biomarkers for malignant transformation in
      breast, colon, and prostate carcinoma. We have investigated nuclear matrix
      protein composition in laryngeal and oral cavity primary squamous cell tumors and
      metastatic cervical lymph nodes. Laryngeal carcinoma demonstrated the gain of two
      specific nuclear matrix proteins in comparison with noncancerous squamous
      epithelium. Squamous cell carcinoma matrixes demonstrate greater heterogeneity
      than do previously studied adenocarcinoma matrixes, and yet they display specific
      matrix proteins that may represent important potential biomarkers.

PMID- 8649872
TI  - Paranasal sinus computed tomography scan findings in patients with cystic
      fibrosis.
AB  - Seventy paranasal sinus computed tomography scans of patients with cystic
      fibrosis were compared with those of age-matched control groups of randomly
      selected chronic sinusitis patients without cystic fibrosis to determine whether
      differences in disease patterns existed. In patients older than 10 years, frontal
      sinus agenesis and maxilloethmoid sinus opacification were significantly more
      prevalent in patients with cystic fibrosis than in chronic sinusitis patients
      without cystic fibrosis. Medial bulging of the lateral nasal wall was
      significantly greater in patients with cystic fibrosis than in chronic sinusitis
      patients without cystic fibrosis in patients older than 5 years. On the basis of
      these findings, a diagnostic triad of radiologic findings for cystic fibrosis
      detection is presented, as well as its clinical implications.

PMID- 8649873
TI  - Glottic carcinoma with a fixed true vocal cord: outcomes after neoadjuvant
      chemotherapy and supracricoid partial laryngectomy with cricohyoidoepiglottopexy.
AB  - Twenty patients with glottic squamous cell carcinoma and a fixed true vocal cord
      underwent neoadjuvant chemotherapy followed by supracricoid partial laryngectomy
      with cricohyoidoepiglottopexy. Phonation, respiration, and deglutition were
      preserved. Local control was better than has been previously reported for either
      extended vertical partial laryngectomy or radiation therapy. All patients were
      monitored for at least 3 years or until death. The Kaplan-Meier 3-year survival,
      local recurrence, nodal recurrence, distant metastasis, and second primary rates
      were 75%, 10.8%, 5%, 10.8%, and 10.8%, respectively. Overall local control was
      achieved in all cases, and laryngeal preservation in 90%. Our experience
      suggested that neoadjuvant chemotherapy with supracricoid partial laryngectomy
      with cricohyoidoepiglottopexy deserves further consideration in the treatment of
      glottic tumors with a fixed true vocal cord.

PMID- 8649874
TI  - Quantitative evaluation of fine-needle aspiration.
AB  - A protocol was developed to obtain mature lymphocytes from freshly harvested
      tonsils by a combination of 5-, 10-, and 20-cm3 syringes and 21-, 23-, and 27
      gauge needles. The cells were then suspended in Earle's balanced salt solution
      and counted with an automated cell counter. Cell counts for each study group was
      compared as a function of needle and syringe size. The range of harvested cells
      was 900 to 2800 cells per cubic millimeter, allowing adequate cellular material
      for diagnostic purposes. The amount of negative pressure for each syringe/needle
      combination was measured with a manometer. Pressures ranged from -500 to -700 cm
      of H2O pressure. In this particular study, fine-needle aspiration with a 20-cm3
      syringe and 21-gauge needle yielded the best results.

PMID- 8649875
TI  - Pediatric fiberoptic laser rigid bronchoscopy.
AB  - Use of the fiberoptic laser for treatment of tracheobronchial lesions in the
      adult is well established. However, there is a paucity of experience with the
      fiberoptic laser in the pediatric airway. Tracheal obstruction caused by
      granulation tissue or stenosis, as is often seen in children, may be effectively
      treated with this approach. This article documents the successful use as well as
      the technologic advantage of the flexible fiberoptic laser systems, primarily the
      potassium titanyl phosphate (KTP) laser, combined with standard pediatric rigid
      bronchoscopic equipment in 73 procedures involving 52 children (43 children
      younger than five years. with an average age of 21 months). Visualization was
      excellent, assisted or spontaneous ventilation was well maintained, and
      complications were few.

PMID- 8649876
TI  - Role of tumor necrosis factor and granulocyte-macrophage colony-stimulating
      factor in the late allergic response in human nasal mucosa.
AB  - Cytokines play an integral role in the allergic response of the nasal mucosa. The
      ideal model for analysis of this interaction has yet to be perfected. We present
      a model for such evaluation and present results of experiments on the release of
      several cytokines. Freshly harvested human nasal turbinate mucosa was placed on a
      Gelfoam (Upjohn Co., Kalamazoo, Mich.) raft in a liquid medium to simulate the in
      situ environment. The allergic response was initiated by exposing the nasal
      mucosa to various combinations and amounts of human immunoglobulin E and
      antihuman immunoglobulin E antibody. The supernatants were collected and analyzed
      by enzyme-linked immunosorbent assay techniques for various cytokines.
      Histopathologic evaluation of the mucosa was performed throughout the exposure
      period, confirming normal cellular and tissue architecture and viability. This
      model was used to monitor the release of interleukin-3, granulocyte-macrophage
      colony-stimulating factor, tumor necrosis factor-alpha, and soluble tumor
      necrosis factor receptors after exposure to immunoglobulin E and immunoglobulin E
      antibody. Interleukin-3 did not show significant increases during the experiment
      testing period of 48 hours. Tumor necrosis factor-alpha and soluble tumor
      necrosis factor receptors demonstrated time-dependent increases in concentration
      after immunoglobulin E stimulation. Granulocyte-macrophage colony-stimulating
      factor showed the greatest time-dependent increases. Their impact on the
      understanding of the allergic response will be discussed.

PMID- 8649878
TI  - Sharp dissection, electrosurgery, and argon-enhanced electrosurgery in porcine
      skin flaps.
AB  - Sharp scalpel dissection, electrosurgery, and argon-enhanced electrosurgery
      (argon beam coagulation) were used to elevate random pedicled skin flaps in a
      randomized blinded fashion with a porcine model. A total of 72 flaps on 9 pigs
      were examined. Flap survival was quantified, and histology was also reviewed 2
      and 6 weeks after surgery. No significant difference among the three techniques
      was noted in terms of area or length of surviving flaps. There were also no
      histologic differences noted with regard to fibrosis, inflammatory infiltrate, or
      necrosis. We conclude that the use of electrosurgery during surgical dissection
      of random pedicled skin flaps is not detrimental to wound healing or tissue
      survival, and it provides benefits such as decreased blood loss, absence of the
      need for sharp instruments in the surgical field and faster operative times.

PMID- 8649877
TI  - Hyperbaric oxygen treatment after rat peroneal nerve transection and
      entubulation.
AB  - Rat peroneal nerves were transected and entubulated with a Silastic channel. The
      experimental group was treated with hyperbaric oxygen to evaluate changes in
      acute edema, functional recovery, and histology. Hyperbaric oxygen was
      administered with 100% O2 at 2.5 atmospheres absolute for 90 minutes twice a day
      for 1 week and then four times a day for 1 week. Acute edema changes based on
      nerve water weight and transfascicular area measurements were greater in injured
      than in uninjured nerves but demonstrated no differences between hyperbaric
      oxygen-treated and -untreated groups 2, 8 and 16 days after surgery. Functional
      evaluation with gait analysis demonstrated significant changes between injured
      and uninjured group 1, 3, 7, and 13 weeks after injury but no differences between
      hyperbaric oxygen-treated and -untreated groups. Thirteen weeks after the initial
      injury, elicited muscle force measurements demonstrated no significant
      improvement from hyperbaric oxygen treatment of injured nerves. Histologic
      evaluation of nerve area, myelinated axon number, myelinated axon area, myelin
      thickness, and blood vessel number and area revealed no significant differences
      between hyperbaric oxygen-treated and -untreated groups. Hyperbaric oxygen was
      not associated with improvement of nerve regeneration with any of the outcome
      variables in this model.

PMID- 8649879
TI  - Bacillary angiomatosis presenting as a nasal mass with epistaxis.

PMID- 8649880
TI  - Squamous cell carcinoma arising in a benign teratoma of the maxilla.

PMID- 8649882
TI  - Upper airway resistance syndrome after uvulopalatopharyngoplasty for obstructive
      sleep apnea syndrome.

PMID- 8649881
TI  - Pseudoaneurysm of the descending palatine artery presenting as epistaxis.

PMID- 8649883
TI  - Acute suppurative thyroiditis in children.

PMID- 8649884
TI  - Orbitoethmoid aneurysmal bone cyst.

PMID- 8649885
TI  - Invasive aspergillosis of the larynx: case report and review of the literature.

PMID- 8649887
TI  - Lower cervical cutaneous sensory nerves: an alternative for facial nerve cable
      grafting.

PMID- 8649886
TI  - Large oral ulcers leading to the destruction of the tonsils in patients with
      AIDS.

PMID- 8649888
TI  - Audiologic findings in unilateral deafness resulting from contralateral pontine
      infarct.

PMID- 8649889
TI  - Condyloma acuminatum presenting as a base-of-tongue mass.

PMID- 8649891
TI  - Insulated Fisch dissector in acoustic neuroma surgery.

PMID- 8649890
TI  - Chloroquine ototoxicity: an idiosyncratic phenomenon.

PMID- 8649892
TI  - ASAP18 core biopsy needle for the diagnosis of head and neck cancer.

PMID- 8649893
TI  - Hypopharyngeal liposarcoma.

PMID- 8649894
TI  - Macroglossia.

PMID- 8649895
TI  - Canalith repositioning procedure.

PMID- 8649896
TI  - Decompression of the paralyzed recurrent laryngeal nerve.

PMID- 8649897
TI  - Clinical ecology.

PMID- 8649898
TI  - Speaking tubes for bedside use.

PMID- 8649899
TI  - Botulinum toxin and rhinorrhea.

PMID- 8649900
TI  - Autoimmune inner ear disease.

PMID- 8649901
TI  - Interpretation of the complete blood count.
AB  - The authors' impression is that the CBC provides much more information than is
      routinely used. When anemia is present, the CBC contains considerable information
      regarding its cause, which can assist in formulating a differential diagnosis and
      directing further evaluation. White blood cell and platelet count levels may
      similarly direct practitioners to consider or dismiss underlying conditions. This
      article assists the pediatrician in optimizing use of this familiar diagnostic
      tool.

PMID- 8649902
TI  - The anemia of inflammation. A common cause of childhood anemia.
AB  - Pediatricians should understand that the anemia of inflammation is second only to
      iron deficiency in overall incidence. When evaluating a child for mild to
      moderate anemia, one should always consider hemolytic anemia, both immune and
      congenital, and blood loss. Careful scrutiny of the peripheral blood smear is
      always helpful and can assist in minimizing expensive and unnecessary
      evaluations. When the anemia of inflammation is suggested by history or physical
      examination and the CBC reveals a normocytic, or possibly microcytic, mild to
      moderate anemia with a normal peripheral blood smear, it is prudent to not embark
      on an extensive evaluation for the anemia but instead wait for the inflammation
      to resolve. This may take as many as 3 months, depending on the degree of
      inflammation. Because the anemia resolves with subsiding inflammation, it is best
      to avoid treatment with iron or RBC transfusions. More studies need to be
      performed concerning the pathogenesis of the anemia of acute inflammation in
      children and the best course of treatment, if needed. The role of erythropoietin
      in the treatment of this form of anemia, though promising in some adult models of
      inflammation, awaits exploration in pediatric patients.

PMID- 8649904
TI  - Hematologic disorders in children from southeast Asia.
AB  - The overall laboratory features of the common RBC disorders occurring in
      Southeast Asians is summarized in Table 4. These erythrocyte disorders will
      continue to be important public health issues, and it has been predicted that
      most new cases of thalassemia in the United States will occur in this population
      group. The fertility rate in Southeast Asian families is very high, with an
      average of more than five children delivered by each married woman. This number
      of children is consistent with perceptions of ideal family size, and, to date, no
      evidence suggests any change in the size of Southeast Asian families who now
      reside in the United States. Moreover, attitudes about health care, reasons why
      one seeks medical attention, and a variety of other cultural issues may impair
      the effectiveness of genetic counseling and other preventive measures designed to
      reduce the incidence of serious blood diseases. Genetic screening and prenatal
      diagnosis clearly have led to a markedly decreased incidence of homozygous
      thalassemia disorders in high-risk Mediterranean populations throughout the
      world. With further assimilation into Western culture, a similar disease may
      occur in the Southeast Asian population also.

PMID- 8649903
TI  - Sickle cell disease.
AB  - The identification of genetic mutation that causes sickle cell disease 35 years
      ago has not yet led to a widely applicable, specific therapy that corrects the
      underlying abnormality of hemoglobin. Nevertheless, recent progress in
      understanding the pathophysiology and natural history of sickling disorders has
      led directly to important prophylactic and supportive therapies that have
      markedly reduced morbidity and prolonged life expectancy. This is particularly
      true for manifestations of sickle cell disease that result from damage to the
      spleen, lungs, and brain. New strategies for specific therapy, including expanded
      use of chronic transfusions, bone marrow transplantation, and hydroxyurea, now
      offer hope for prevention of many or all of the hemolytic and vaso-occlusive
      manifestations of sickle cell disease.

PMID- 8649905
TI  - von Willebrand disease in children and adolescents.
AB  - The term von Willebrand disease includes many bleeding disorders caused by
      abnormalities of vWF. Frequent or severe bleeding may be indicative of vWD or
      other bleeding conditions. Primary care practitioners need to be familiar with
      vWD and evaluate possibly affected individuals with appropriate laboratory
      studies. Patients with vWD should be educated about their disorder and preventive
      measures to limit its effect. Medications are available that can treat or prevent
      bleeding complications for most patients with vWD. Intervention with blood
      products is occasionally necessary.

PMID- 8649906
TI  - Hemophilia 1996. New approach to an old disease.
AB  - The history of hemophilia diagnosis and therapy has been a turbulent one. We are
      coming full circle, back to the use of genetics as the main diagnostic tool for
      this disease. Therapeutically, the retroviruses that ravaged one generation of
      hemophiliac patients now may participate in the cure for the next generation. The
      hemophilia community hopes that the future of hemophilia care will follow a
      course guided by this modified quote from James Russell Lowell: "New times demand
      new measures, and men [and women]. As the world advances and in time outgrows the
      laws that in our fathers' [and mothers'] days were the best, doubtless after us
      some purer scheme will be shaped out by wiser men [and women] than we, made wiser
      by the steady growth of truth."

PMID- 8649908
TI  - Current controversies in the management of idiopathic thrombocytopenic purpura
      during childhood.
AB  - Both acute and chronic ITP in children are generally benign conditions. Few
      patients develop serious complications or long-term sequelae. Therefore, most
      patients require little or no specific therapy. IVIG or high-dose steroids may
      benefit some patients who have evidence of clinical bleeding, and splenectomy may
      be of value in patients with chronic ITP whose lives are altered by low platelet
      counts or bleeding. It is difficult to predict which patients are at risk for the
      development of ICH, and severe hemorrhage is not always curtailed by prior or
      concomitant therapy. The decision to treat a child with ITP should be based on
      the entire clinical picture rather than on the platelet count alone.

PMID- 8649907
TI  - Thrombocytopenia in the neonate.
AB  - Pediatricians caring for newborns will eventually be confronted with the problem
      of thrombocytopenia in the neonatal period. Familiarity with the differential
      diagnosis of neonatal thrombocytopenia and understanding the pathogenesis of the
      more common entities allows physicians to design a selective diagnostic and
      therapeutic plan to benefit these thrombocytopenic infants.

PMID- 8649909
TI  - Diagnosis and management of chronic neutropenia during childhood.
AB  - The approach to the diagnostic evaluation of a patient with neutropenia can be
      guided largely by clinical history and physical examination and does not always
      require an extensive laboratory evaluation. Based on the history and bone marrow
      morphology, most children with chronic neutropenia can be classified and managed.
      Most patients with chronic neutropenia are free of infections and are able to
      maintain a normal lifestyle with no or minimal medical intervention. On the other
      hand, for patients with recurrent or severe infections, careful follow-up and
      institution of treatment are mandatory. The Food and Drug Administration has
      approved the use of rhG-CSF in patients with chronic neutropenia. As mentioned
      previously, the use of colony-stimulating factors has dramatically improved the
      outcome for many patients with the more severe neutropenia; however, this
      cytokine is expensive, so treatment should be reserved for more severely affected
      patients and not given just because the ANC is low. Although concerns exist
      regarding leukemogenic effects or eventual loss of the progenitor cell
      compartment driven by the continuous stimulation of rhG-CSF, at this moment, the
      long-term data available suggest that the chronic administration of rhG-CSF is
      safe.

PMID- 8649910
TI  - What's new in transfusion medicine?
AB  - The safety of the blood supply has increased tremendously in the past decade.
      Donor screening and improved infectious disease testing of units for transfusion
      have contributed to the decreased risk of transfusion-transmitted diseases.
      Reduction of the number of passenger leukocytes from RBC and platelet
      transfusions decreases the rate of febrile transfusion reactions and
      alloimmunization. Irradiation of cellular products helps prevent TA-GVHD. The
      practice of obtaining an informed consent prior to transfusion helps patients and
      families understand the risks and benefits of and alternatives to transfusion
      therapy.

PMID- 8649911
TI  - Diverse hematologic effects of parvovirus B19 infection.
AB  - Human parvovirus B19 is linked with a broadening spectrum of hematologic
      disorders, including aplastic crises in the context of hemolytic anemias,
      neutropenia, thrombocytopenia, and hemophagocytic syndromes. Children with any of
      these cytopenias should be screened for the presence of B19 because treatment
      with intravenous gamma globulin may provide resolution of abnormal blood counts
      if other therapeutic options, such as transfusion, are not adequate or desired.

PMID- 8649912
TI  - Deep venous lines and thromboembolism.

PMID- 8649913
TI  - Venous catheter thrombus formation and pulmonary embolism in children.
AB  - Central venous catheter (CVC)-related thrombus formation has been increasingly
      recognized as a complication in adults and somewhat less frequently in children
      and neonates. However, the association of CVC thrombus and pulmonary embolism
      (PE) has rarely been reported in infants or children, and the few existing
      reports primarily involve chronic, indwelling CVCs such as Broviac or Hickman
      catheters. During an 18-month-period of autopsy review, we found that 5 of our
      pediatric intensive care unit patients had autopsy-proven CVC thrombus and
      pulmonary embolism. All of them had prolonged mechanical ventilation for
      respiratory failure and required insertion of one or more short-term, temporary
      CVCs during the course of routine critical care management. In retrospect, signs
      related to CVC thrombus were present in 4 patients (3 had positive blood cultures
      and 1 had persistent hypertension). PE was not diagnosed until autopsy in every
      case. The diagnosis may have been missed because the symptoms of PE are the same
      as those of severe lung disease. We, therefore, advocate a heightened suspicion
      of CVC thrombus formation and PE in critically ill children with respiratory
      failure and temporary CVCs and recommend early diagnostic ultrasound to confirm
      the diagnosis. Once a CVC thrombus is found, subsequent pulmonary deterioration
      may necessitate evaluation for acute PE.

PMID- 8649914
TI  - Oral and inhaled steroids in croup: a randomized, placebo-controlled trial.
AB  - It was the objective of this study to compare the efficacy of oral dexamethasone
      and inhaled budesonide in children hospitalized with croup, using a three-way,
      double blind, randomized, placebo-controlled clinical trial design. The trial was
      carried out in the Emergency Department Observation Ward of a tertiary pediatric
      hospital. The subjects for the study were 80 children (age range 5 to 158 months)
      who were hospitalized with croup. Children received either 2 mg of nebulised
      budesonide, dexamethasone syrup (0.6 mg/kg) or a placebo. Median duration of
      hospitalization was shorter for children treated with dexamethasone (12 hr) and
      budesonide (13 hr) compared to placebo (20 hr) (P < 0.03). There was no
      significant difference in hospitalization time between children treated with
      dexamethasone and budesonide. Median time to a croup score of < or = 1 was
      shorter for children treated with dexamethasone (2 hr) or budesonide (3 hr)
      compared to those who received placebo (8 hr) (P < 0.01). Croup scores for both
      steroid groups were significantly lower than the placebo group by 1 hr and
      remained so subsequently. The croup scores did not differ significantly in the 2
      steroid treated groups. Six of the 30 children (20%) in the placebo group
      required adrenaline after the first hour compared to none of the 50 children in
      the steroid treated groups (P < 0.02). We conclude that oral dexamethasone and
      inhaled budesonide are both effective in reducing symptoms and duration of
      hospitalization in children with croup.

PMID- 8649915
TI  - Oral dexamethasone in the treatment of croup: 0.15 mg/kg versus 0.3 mg/kg versus
      0.6 mg/kg.
AB  - The objective of this study was to compare the efficacy of a single dose of oral
      dexamethasone of varying sizes in 120 children hospitalized with croup in two
      sequential double blind, randomized, controlled clinical trials (Trials A and B).
      The study was conducted in the Emergency Department Observation Ward of a
      tertiary pediatric hospital. One hundred and twenty children (age range 6 to 160
      months) hospitalized with croup participated. Baseline characteristics for the
      two groups in each trial were similar. In Trial A 60 children received either 0.6
      or 0.3 mg/kg dexamethasone syrup; in Trial B 60 children received either 0.3 or
      0.15 mg/ kg dexamethasone syrup. Duration of hospitalization, reduction in croup
      scores, and adrenaline usage were evaluated. Median duration of hospitalization
      was similar for children in Trial A (7 and 8 hr), and in Trial B (9 and 9 hr).
      Croup scores following treatment did not differ and were significantly lower than
      initial scores for all groups and in each trial. Other outcome measures were
      similar for the two groups in each trial, including need for nebulized
      adrenaline, numbers of patients admitted to intensive care, rate of return to
      medical care with reoccurrence of croup, and readmission to hospital with croup
      following discharge from hospital. We conclude that oral dexamethasone in a dose
      of 0.15 mg/kg is as effective as 0.3 or 0.6 mg/kg in relieving symptoms and
      results in a similar duration of hospitalization in children with croup.

PMID- 8649916
TI  - The significance of sweat Cl/Na ratio in patients with borderline sweat test.
AB  - Recently a few cystic fibrosis (CF) patients with borderline or normal sweat
      tests have been reported. These patients present a diagnostic challenge. We aimed
      to study the sweat Cl/Na ratio in cystic fibrosis patients and to assess whether
      this ratio could be used as a diagnostic criteria. The mean sweat Cl/Na ratio of
      3 groups was compared: Group A: 71 CF patients carrying 2 mutations known to be
      associated with severe disease presentation (delta F508, W1282X, G542X, N1303K,
      1717-1G --> A). Group B: 10 compound heterozygous patients who carry one mutation
      associated with mild clinical disease (3849 + 10 kb --> T). Group C: 142 normal
      subjects. Sweat chloride levels higher than those of sodium were found in 96% of
      patients in Group A as compared to 3% of patients in Group C. In Group B 40% of
      the patients had sweat chloride levels higher than or equal to sodium levels. The
      mean Cl/Na ratio of Group A (1.2 +/- 0.1) differed significantly from that of
      Group B (0.94 +/- 0.1) and both groups had significant higher mean Cl/Na ratio
      compared to Group C (0.7 +/- 0.4) (P < 0.001). Thus in individuals with a
      borderline sweat test and a Cl/Na ratio > or = 1 the diagnosis of CF should be
      considered. However, a Cl/Na ratio < 1 does not exclude CF, since patients
      carrying mild mutations may have sweat sodium levels higher than those of
      chloride. Our findings suggest that the sweat Cl/Na ratio in CF is genetically
      determined and it may be of help in establishing the diagnosis of CF in patients
      with a borderline sweat test.

PMID- 8649917
TI  - Spirometric patterns in childhood asthma: peak flow compared with other indices.
AB  - The objective of this study was to determine patterns of pulmonary function
      abnormalities and to evaluate how adequately peak flow monitoring was correlated
      to other spirometric indices in childhood asthma. Ninety-one children, aged 8-15
      years, with moderate-to-severe asthma were repeatedly tested in a summer camp. On
      site medical staff permitted 24-hour-a-day supervision. Subjective and objective
      clinical evaluations of asthma status were made over 14 consecutive days.
      Detailed clinical history and clinical observations were made by an experienced
      staff, and a total of 2,663 pulmonary function tests were performed regularly
      three times daily and whenever a child sensed asthma symptoms. Patterns of
      obstruction were divided into large airway abnormalities and small airway
      abnormalities. There was a low concordance between standard large airway
      measures, such as the peak expiratory flow rate (PEFR) or the forced expiratory
      volume in 1 second (the FEV1), and measures of small airway obstruction, such as
      the forced expiratory flow rate 25-75% (FEF25-75). Normal PEFR measurements do
      not always indicate that all other pulmonary function measures are normal. In
      fact, 18% of children with a normal PEFR had abnormal FEF25-75 values. Results
      demonstrated that the FEF25-75 was the most specific and sensitive measure of
      airway obstruction. PEFR is widely used to monitor asthma symptoms objectively
      because it is technically simple to perform, relatively inexpensive, and helpful
      in most cases. It is, therefore, appropriate for asthma education programs to
      recommend PEFR as an objective measure to guide in making therapeutic decisions.
      Our data and clinical observations support the "Guidelines for the Diagnosis and
      Management of Asthma" of the NIH Health Asthma Education Program that suggest
      that children have more complete pulmonary function testing along with frequent
      PEFR measures. Many children may appear asymptomatic, while recording normal PEFR
      measures, and still having significant asthma. Repeated pulmonary function
      testing and evaluation of the pattern of respiratory obstruction aids in managing
      this challenging group. We recommend that efforts be made to develop a simple and
      inexpensive method of measuring FEF25-75 that will allow this measurement to be
      made even at home.

PMID- 8649918
TI  - Effect of neck rotation on the timing and pattern of infant tidal breathing.
AB  - While neck flexion and extension are known to influence the patency of the upper
      airway, far less information is available regarding the effects of neck rotation.
      The effect of neck rotation on respiratory rate (RR), expiratory time (tE), and
      phase angle (phi) was assessed in 17 healthy infants aged between 1 and 4 months.
      An inclinometer was used to measure neck rotation and uncalibrated Respiratory
      inductive Plethysmography to measure the dependent variables while the infants
      were in natural, quiet sleep. Baseline measurements were made with the head
      positioned centrally (0 degree rotation); further measurement positions included
      30 degrees, 60 degrees, 90 degrees rotation, and repeat measurement at 0 degree
      (0r degree) in randomized order. Mean RR, tE, and phi were determined for each
      infant in each position. Using the paired t-test, RR at 0 degree rotation was
      significantly higher than that at 0r degree rotation (mean difference, 5 bpm; 95%
      CI, 2.1, 8.1; P = 0.0023); mean tE at 0 degree rotation was significantly shorter
      than at 0r degree rotation (mean difference, -0.18s; 95% CI, -0.27, -0.07; P =
      0.002); whereas phi remained similar (mean difference, 10 degrees; 95% CI, -2.2,
      22.3; P = 0.10. These changes probably reflect the slowing of metabolism that
      occurs after the onset of quiet sleep, and they emphasize the importance of
      randomization. Measurements at 0r degree were randomized and hence were most
      likely to reflect the true basal condition of the infant with the head in a
      neutral position. Consequently, these data, rather than those collected at 0
      degree at the onset of quiet sleep, were used for comparisons with all subsequent
      positional changes. When comparing the positions whose order was randomized, neck
      rotation did not significantly affect RR (P = 0.445), tE (P = 0.272), or phi (P =
      0.169). However, two infants demonstrated marked changes in respiratory pattern
      with decreases in RR and increases in tE at 90 degrees rotation, suggesting that
      some infants may be susceptible to obstruction in this position.

PMID- 8649919
TI  - Evaluation of the interrupter technique for measuring change in airway resistance
      in 5-year-old asthmatic children.
AB  - The interrupter technique is a noninvasive method for measuring airway resistance
      during quiet breathing which requires minimal subject cooperation. It, therefore,
      has enormous potential for use in young children unable to cooperate with
      conventional lung function tests. We evaluated the interrupter technique during
      bronchial challenge with methacholine administered by the tidal breathing method
      in 10 5-year-old asthmatic children. The mouth pressure/time [P mo(t)] curve
      obtained following brief airflow interruption during the expiratory phase of
      quiet breathing was analyzed to determine the interrupter resistance (Rint) using
      four different methods: RintC, a smooth curve fit with back-extrapolation;
      RintEO, calculated from the pressure change after the postinterruption
      oscillations had decayed (end-oscillation); RintL, two-point linear fit with back
      extrapolation; and RintEI, calculated from the pressure change at the end of the
      period of interruption. The four Rint methods were compared for repeatability and
      sensitivity with the direct measurement of resistance by the forced oscillation
      technique (Rrs), and with an independent method of measuring the response to
      challenge, utilizing the change in transcutaneous oxygen tension (PtcO2). The
      sensitivity of the methods was defined by a sensitivity index (SI), the change
      after challenge expressed in multiples of the baseline standard deviation. The
      PtcO2 method had the lowest variability and was by far the most sensitive method
      (geometric mean SI 18.9), at least 1 doubling concentration more sensitive than
      the other techniques in every subject (P < 0.05). RintL was more sensitive than
      the other interrupter methods (geometric mean SI: RintL 4.2; RintC 1.0; RintEO
      2.7; RintEI 3.1; P < 0.05) and similar in sensitivity to Rrs (geometric mean SI
      4.6) in 7 out of 10 children in which this could be measured. We conclude that
      the interrupter method provides a simpler method than the oscillation technique
      for assessing airway obstruction in this age group.

PMID- 8649920
TI  - Respiratory inductive plethysmography in the evaluation of lower airway
      obstruction during methacholine challenge in infants.
AB  - Respiratory inductive plethysmography (RIP) is a simple technique for an
      objective, noninvasive assessment of thoracoabdominal asynchrony, which in turn
      is an indirect measure of airway obstruction. We evaluated different indices of
      asynchrony obtained by RIP before and after methacholine-induced airway
      obstruction. Bronchial obstruction was elicited by progressive doubling
      concentrations of methacholine until a > 15% fall in the transcutaneous oxygen
      tension (PtcO2) had developed. Maximal expiratory flow rates at functional
      residual capacity (FRC) (VmaxFRC) was obtained by the squeeze technique before
      and after the challenge. Fifteen infants with a history of wheezing were studied
      after sedation. Thoracoabdominal movements were recorded with RIP bands placed
      around either the upper or the lower ribcage (RC) and around the abdomen (AB). An
      inspiratory asynchrony index (IAI) and an expiratory asynchrony index (EAI) were
      calculated as determined by the lag of RC relative to AB at start of inspiration
      and of expiration, respectively. The total time in asynchrony (TTA: the
      percentage of time in which the RC and the AB signals were in opposite direction)
      and phi (an angle derived from a Lissajous loop) were also calculated. All
      subjects responded to the challenge. The median fall in PtcO2 following
      methacholine challenge was 23.6% and in VmaxFRC was 43%. A large scatter of
      baseline values was found for all indices with the exception of TTA. There was no
      correlation between TTA and age, length, or VmaxFRC. The IAI and EAI with the RC
      band in the upper position were the most sensitive indices, both within subjects
      (65% of the subjects had a significant change in IAI and 80% in EAI) and for the
      group as a whole (median values increased for IAI, P = 0.007, and for EAI, P =
      0.017). TTA and phi were less sensitive, and a great discrepancy was observed
      between the two measurements. Poor results were obtained with the RC band in the
      lower position. No correlations were found between the changes in IAI and EAI,
      with the RC band around the lower chest and VmaxFRC. We conclude that IAI and
      EAI, measured with the RC band in the upper position and another band around the
      abdomen, can detect changes in thoracoabdominal asynchrony in most infants. The
      usefulness of assessing IAI and EAI in infants with acute lower airway
      obstruction needs to be determined.

PMID- 8649922
TI  - Recurrent venous thrombosis in a patient with cystic fibrosis.

PMID- 8649921
TI  - Validation of a nitrogen washout system to measure functional residual capacity
      in premature infants with hyaline membrane disease.
AB  - A multiple-breath nitrogen washout system designed to measure lung volume in
      mechanically ventilated infants was validated by assessing three performance
      criteria: 1) accuracy of lung volume measurements in the presence of an
      endotracheal tube leak was assessed by comparing the measurements of functional
      residual capacity (FRC) in a mechanical lung model with and without airway leak;
      2) in vivo accuracy was assessed in rabbits by comparing FRC measurements
      obtained by this system with measurements obtained by helium dilution; and 3) in
      vivo precision was assessed by analyzing measurements of FRC obtained in
      replicate measurements at different times in ventilator-dependent premature
      infants with hyaline membrane disease. The average difference between the
      measurements of FRC in a mechanical lung model with airway leak and without leak
      was 3.0 +/- 9.4% (mean +/- SD, P > 0.2), and no difference was greater than 20%.
      There was a significant correlation between the measurements of FRC in rabbits by
      nitrogen washout and by helium dilution (r = 0.93, P < 0.0001), and 65.4% of the
      paired measurements were within 20% of their average. The 95% limits of agreement
      within pairs of measurements by the two techniques ranged from -4.0 to + 6.5
      mL/kg. FRC measured by helium dilution was slightly higher (1.3 +/- 2.7 mL/kg, P
      < 0.01) than FRC measured by nitrogen washout, and positive end-expiratory
      pressure was a significant predictor of this difference (P < 0.0001). The
      regression between the individual FRC measurements obtained in premature infants
      and the average of the other replicates was significant (r2 > 0.98, P < 0.0001).
      The coefficient of variation was 12.3%. These findings provide further validation
      of this multiple-breath nitrogen washout system for measuring FRC in premature
      infants during mechanical ventilation.

PMID- 8649923
TI  - Tracheal bronchus associated with congenital cystic adenomatoid malformation.

PMID- 8649924
TI  - [Acute pancreatitis in children. Diagnosis and procedures].

PMID- 8649925
TI  - [The importance of free oxygen radicals in perinatal medicine].
AB  - A review of free oxygen radicals and their role in the perinatal period is
      presented. Basic problems related to their formation, defence systems, pregnancy,
      delivery and the postnatal period are addressed. Special attention is given to
      acute and chronic diseases typical for prematurity. Current therapy and future
      prospects are discussed.

PMID- 8649927
TI  - [Noonan syndrome in clinical practice].
AB  - The author presents the basic criteria for clinical recognition of Noonan
      syndrome. The hypothetical pathogenesis, differential diagnosis and risk of
      recurrence of this syndrome are also discussed.

PMID- 8649926
TI  - [Reliability of cytogenetic and clinical diagnostic studies. Results of analyzing
      1621 pre- and postnatal studies].
AB  - Systematic quality assessment of cytogenetic studies is very important for
      maintaining high standards of diagnostic testing and adequate genetic service.
      Results of quality assessment for 714 pre- and 907 postnatal cytogenetic studies
      performed in the Genetic Department of the National Research Institute of Mother
      and Child are presented. The assessment included: reporting time, quality of
      chromosome preparations, reliability and success rate of the studies. Mean
      reporting time for blood samples was 20 days and for amniotic fluid 23 days.
      Chromosome banding quality was adequate to reasons for referral in 86.9% of blood
      samples and in 100% of amniotic fluids. The success rate for pre- and postnatal
      studies was 99.4 and 96.6%, respectively. The need to develop a quality
      assessment scheme for clinical cytogenetics in Poland is discussed.

PMID- 8649929
TI  - [Use of polymerase chain reaction for detection of human cytomegalovirus in blood
      samples of children with suspected active infection with cytomegalovirus].
AB  - The aim of our study was to assess the applicability of the PCR technique for
      detecting HCMV DNA in blood and urine samples from infected children. The
      sensitivity of agarose gel electrophoresis (ethidium bromide staining) and RNA
      hybridization (DSSS system), the two methods used to detect PCR products, were
      compared. HCMV DNA was detected by the DSSS system and gel electrophoresis in 31
      and 29 blood samples, respectively, taken from children with suspected infection.
      HCMV DNA was also detected in 29 urine samples of 31 tested children, including 5
      newborns (not older than 14 days) excreting HCMV in urine and manifesting
      clinical signs of infection. Specific anti-HCMV antibodies were detected in 22
      (71%) of the tested children.

PMID- 8649928
TI  - [Alpha-1-antitrypsin, albumin and whole protein in meconium and stools during the
      first days of life in the neonate].
AB  - Samples of meconium and first stools were taken prospectively over the first 3
      days of life from healthy, term neonates from uncomplicated deliveries (control
      group) and from neonates that were hypertrophic, premature, delivered through a
      Cesarian section or born to diabetic mothers. The variability and diagnostic
      value of determining alpha-1-antitrypsin (AAT), albumin and total protein in
      these samples was analyzed. Both the level and dynamics of AAT in the first three
      days of life differed between the study and control groups. No correlation was
      found between the AAT and albumin concentrations in the studied material. An
      increase in total protein content over control values was found in the same
      neonates that showed elevated AAT concentration in meconium and stools. The
      concomitant determination of AAT, albumin and total protein in stool makes it
      possible to discriminate between these groups of neonates with a 91.7% accuracy.

PMID- 8649931
TI  - [Complications of mumps in children in light of personal observations].
AB  - The clinical manifestation and course of mumps-related complications in 183
      children among 214 patients hospitalized due to mumps were analysed. Meningitis
      was diagnosed in 78% of cases, pancreatitis in 48% and unilateral orchitis was
      observed in 1.6%. More than one complication was noted in 27% of patients.
      Usually mumps-related complications occurred between the second and fifth day
      after the appearance of salivary gland involvement. Their course was fairly
      grave. Boys were afflicted twice as often as girls. No correlation between the
      severity of the disease and pleocytosis in cerebro-spinal fluid was observed. The
      authors discussed a necessity to introduce mass vaccinations against mumps.

PMID- 8649930
TI  - [Acute neurologic rubella complications observed in children of southeastern
      Poland during rubella epidemics in 1986 and 1992].
AB  - During the last two rubella epidemics in 1985-1986 and 1992, 24 children (15 boys
      and 9 girls) were hospitalized with acute neurological complications manifested
      in the first week of clinical symptoms of rubella. Average age of patients was 9
      years (3-15 years). Acute rubella encephalitis (ARE) was diagnosed in 22 cases.
      Most of these patients had sudden loss of consciousness lasting from several
      hours to 12 days and convulsions during the first stage of the illness. Two
      patients developed retrobulbar neuritis which led to a significant impairment of
      sight in one of them. One child suffers epilepsy as a result of ARE. The
      remaining children did not develop lasting complications. During hospitalization,
      active infection by the rubella virus was confirmed in 20 children by detecting
      specific IgM antibodies in serum using the ELISA method. Comparing the ARE cases
      in 1986 and 1992 rubella epidemics revealed a change in clinical course. Earlier
      manifestations of neurological symptoms and more marked changes in CSF were
      observed. The issue of immunoprophylaxis is discussed; these measures only
      started in 1989 by vaccinating 13 and 14 year old girls. This method of
      prophylaxis will neither stop the transmission of the virus among children nor
      prevent the occurrence of periodic epidemics and rubella-related complications.

PMID- 8649932
TI  - [Thin-layer chromatography of urine oligosaccharides in diagnosis of some
      lysosomal storage disorders].
AB  - Inherited lysosomal storage disorders are caused by the deficiency or importantly
      lowered activity of one of the lysosomal enzymes, leading to the storage in the
      lysosomes the not degraded high-molecular substrates, among others:
      mucopolysaccharides, glycolipids, oligosaccharides and glycoproteins. Thin-layer
      chromatography of urine oligosaccharides allows reliable and fast diagnosis of
      some lysosomal storage disorders e.g. alpha-mannosidosis, fucosidosis,
      sialidosis, galactosialidosis, Schindler disease, GM1-gangliosidosis, GM2
      gangliosidosis (Sandhoff type), Pompe disease, Salla disease, mucolipidosis II
      and III. We are presenting a modification of the Humbel and Collart's method of
      TLC of urine oligosaccharides. The principle of our modification is to introduce
      of the preliminary desalting step of the urine on the columns containing anionit
      BioRad AG 1 x 8 and cationit Dowex 50 x 8-200.

PMID- 8649933
TI  - [Pseudodeficiency of lysosomal enzymes].

PMID- 8649935
TI  - [Retinitis pigmentosa and associated hearing loss (Usher's syndrome type I) in a
      12 year old boy].

PMID- 8649934
TI  - [Diagnosis of Edwards syndrome in newborns].
AB  - Congenital malformations most useful for the diagnosis of trisomy 18 in the first
      days of life were defined based on observations of newborns with Edwards syndrome
      treated at the Child Health Center in 1992-1994. Intrauterine growth retardation,
      facial skeleton dysmorphy, congenital heart malformation, mainly VSD, extremity
      malformations, especially of the palms and feet found in the newborn suggest a
      diagnosis of Edwards syndrome. The need to differentially diagnose trisomy 18
      with autosomal recessive syndrome TAR, Roberts and Smith-Lemli-Opitz is stressed.

PMID- 8649936
TI  - [Spondylo-metaphyseal dysplasia type I (Kozlowski)].

PMID- 8649937
TI  - [Renal tubular acidosis: pathomechanism, clinical diagnosis and treatment].

PMID- 8649938
TI  - [Therapeutic approach to steroid resistant idiopathic nephrotic syndrome in
      childhood].

PMID- 8649939
TI  - [Correlation between osteocalcin and bone histomorphometry in children with
      chronic renal failure].
AB  - The study was performed in 17 children with chronic renal failure, 7 were on
      hemodialysis, 6 on continuous ambulatory peritoneal dialysis, 4 were treated
      conservatively. In all, serum levels of alkaline phosphatase, PTH intact and
      osteocalcin were measured and bone biopsy was performed. We analyzed correlations
      between biochemical markers of bone metabolism and histomorphometric parameters.
      The lowest mean serum osteocalcin levels were found in children with adynamic
      bone disease, the highest with osteitis fibrosa. The serum osteocalcin level was
      significantly correlated with the dynamic parameter of bone formation rate (BFR),
      which suggests that this biochemical marker can be of use in discriminating
      between renal osteopathy with low and high bone turnover. Lack of correlation
      between serum osteocalcin level and mineralizing surface confirms it significance
      as a good marker of osteoblastic activity in bone formation but not in bone
      mineralization.

PMID- 8649940
TI  - [The effect of decreasing serum calcium in serum during hemodialysis on PTH
      levels in children with end stage renal disease].
AB  - The aim of our study was to evaluate serum Ca and PTH intact levels in children
      during one hemodialysis session using a low calcium level dialysate (1.25 mEq/l).
      The study was performed in 6 children with end-stage renal disease. We analysed
      the parameters of calcium-phosphorus metabolism in children 18 months before the
      test. In 5 of children the increase of PTH level during hemodialysis was lower
      than in healthy people. In 3 patients with hyperparathyroidism the basal PTH
      (PTHb) level before the test was high and increased by 45%, 67% and 118% during
      hypocalcemic stimulation. In 2 patients suppression of parathyroid function was
      diagnosed due to low serum PTHb level and small increase during hypocalcemic
      stimulation. Despite low basal PTH level, one of the patients respond to
      hypocalcemic stimulation like healthy subjects. Dynamic monitoring of the PTH
      level during hypocalcemic stimulation is a very useful method of estimation
      parathyroid gland function and adjusting doses of vitamin D metabolites.

PMID- 8649941
TI  - [Dosage of erythropoietin in children treated with hemodialysis and continuous
      ambulatory peritoneal dialysis].
AB  - The authors compared the efficacy of erythropoietin (EPO) in a standard dose of
      50 U/kg/week used in children undergoing haemodialysis (HD) and continuous
      ambulatory peritoneal dialysis (CAPD). It was concluded that this dose is
      suitable for children on CAPD. Hemoglobin increased to > 10 g% and Ht > 30% after
      8 weeks in 83% of patients and in all of the treated patients after 12 weeks.

PMID- 8649942
TI  - [Molecular markers of hemostasis activation in children with nephrotic syndrome].
AB  - Vein and arterial thrombosis is a rather rare but potentially life-threatening
      complication of nephrotic syndrome (n.s.). None of the specific markers of
      hypercoagulability state in n.s. have been identified. The aim of the study was
      to estimate plasma parameters of prothrombic state in children with n.s. Ten
      children aged from 3 to 10 yrs (mean 5.7 +/- 2.5) with recurrence of n.s. and 10
      healthy controls matched for age and sex were studied. In all children with n.s.
      prothrombin fragments F 1+2, D-dimers (D-d), thrombin-antithrombin III complexes
      (TAT) and whole blood clotting time thrombin time, prothrombin time, plasma
      fibrinogen and platelet count were determined in the hypovolemic state (before
      therapy was started), in the normovolemic state (after plasma expander was used)
      and in the course of anticoagulation treatment (two week dicumarol therapy). In
      comparison with healthy controls all children with recurrence of n.s. in the
      hypovolemic state showed a significant (p < 0.05) increase of D-d (910 vs 500
      ng/ml), TAT (14.26 vs 2.6 ng/ml), F 1+2 (5.68 vs 0.79 nmol/l), plasma fibrinogen
      (592 vs 272 mg/dl), platelet count (632 vs 275 x 10(9)/l) and shortening of WBCT
      (30.0 vs 35 s). Plasma volume expansion produced by dekstran was followed by a
      moderate decrease of all parameters. Two-week anticoagulant treatment had no
      impact on estimated haemostasis parameters.

PMID- 8649943
TI  - [Evaluation of the efficacy of levamisole in corticosteroid-dependent nephrotic
      syndrome in children].
AB  - The efficacy of levamisole was evaluated in 22 steroid-dependent nephrotic
      children. All of them were treated before with glucocorticoids. In 45.5% of
      children, prednisone was with-drawn after levamisole treatment and the remissions
      obtained lasted more than six months, 18.2% of the children relapsed after
      prednisone withdrawal and 36.4% children did not respond to levamisole treatment.
      Levamisole could be recommended for steroid-dependent patients with recurrent
      infections, in which alkylating agents are contraindicated.

PMID- 8649944
TI  - [Evaluation of the efficacy, tolerance and safety of Biotrakson use in patients
      with kidney failure].
AB  - Increased susceptibility to infection is observed in patients with chronic renal
      failure (CRF). Therefore, when antibiotic therapy is indicated, it is reasonable
      to use a drug which is usually reserved as a second-choice antibiotic in other
      patients. Antibiotic prevention before surgical procedures with a high risk of
      infection, especially before renal transplantation is also often necessary.
      Evaluation of Biotrakson (ceftriakson) (produced in Poland) efficacy in patients
      with CRF was the aim of this study. The antibiotic was administered in a single,
      complete prophylactic dose or once daily when given therapeutically in 25
      patients: 13 with end-stage renal disease treated with hemodialysis, 5 with end
      stage renal disease treated with peritoneal dialysis, 4 with chronic renal
      failure, 1 with acute renal failure treated with peritoneal dialysis, 2 after
      renal transplantation. The antibiotic was given for local and generalised
      bacterial infections in 10 patients; in 15 the drug was administered
      prophylactically before serious surgical procedures (including 10 patients before
      renal transplantation). Resolution of infection was observed in 9 out of 10
      treated patients (90%). When the antibiotic was given prophylactically, its
      efficacy was assessed as good in 8 of 10 patients (80%) after renal
      transplantation and in 4 of 5 patients (80%) after other surgical procedures.
      There were no significant adverse side effects in any patient. Biotrakson is,
      therefore, an effective drug for therapeutic and preventive use in patients with
      renal failure.

PMID- 8649945
TI  - [Clinical evaluation of Uro-Vaxom in treatment of recurrent urinary tract
      infections in girls].
AB  - Uro-Vaxom was used in the treatment of recurrent urinary tract infections in 28
      girls. Most of them (27/28) tolerated the drug very well, no side effects were
      observed. We stopped administration of the Uro-Vaxom in one girl during the first
      month of treatment because of vomiting. Uro-Vaxom efficiency was, therefore,
      evaluated in 27 girls. Uro-Vaxom was found to be a valuable drug, supplementing
      antibiotic therapy in recurrent urinary tract infections caused by E. coli.

PMID- 8649946
TI  - [Renal tubular acidosis].

PMID- 8649947
TI  - [Diagnostic and therapeutic problems in a newborn with aortic coarctation,
      adrenal and intracranial hemorrhages and renal failure].
AB  - We report on a 3-day-old newborn with critical coarctation of the aorta,
      coexisting adrenal and intracranial hemorrhages and acute renal failure requiring
      dialysis. Severe hypoglycemia, hyperbilirubinemia, mounting anemia and
      thrombocytopenia, clotting disturbances suggesting DIC, pneumonia, hypertension,
      increasing circulatory failure and repeated intracranial hemorrhage were observed
      and were the reason for postponing heart surgery. The child was operated on
      during the third week of hospitalisation on an emergency basis. The cardiac
      surgery procedure was performed successfully.

PMID- 8649948
TI  - [Specialist care in the field of pediatric orthopedics].

PMID- 8649949
TI  - [Polish Society of Endocrinology declares the Merck Company as a friend of Polish
      endocrinology].

PMID- 8649951
TI  - [Intestinal microflora and antibiotic therapy].
AB  - Antibiotic therapy is one of the major factors leading to disturbances in the
      intestinal flora. This can lead to chronic diarrhea and life threatening
      pseudomembranous colitis. Much attention had recently been focused on so-called
      translocation of endotoxins and bacteria through the intestinal wall which lead
      to systemic infection, shock and multiorgan failure. Prevention is based on the
      proper choice of antibiotic and administration of lactic-acid bacteria.

PMID- 8649950
TI  - [Daily nutritional recommendations for children and adolescents].

PMID- 8649952
TI  - [Bacterial flora in the digestive tract during diarrhea in infants upon hospital
      admission and at the end of hospitalization].
AB  - The stools of 23 children aged from 14 days to 18 months were analysed
      (qualitatively and quantitatively) for some genera of bacteria which could be the
      cause of diarrhea. Feces were collected at the beginning and the end of
      hospitalisation. The results were evaluated and referred to five age subgroups
      and duration of hospitalization. The presence of potentially enteropathogenic
      bacteria was noted in 87 per cent of children in widely varying quantities. In
      the most numerous group of children the same bacteria were revealed at the
      beginning and at the end of hospitalization. The microorganisms were most
      frequently present at the moment of hospitalisation in newborn children. Complete
      elimination during stay in hospital occurred mainly in the youngest children, who
      did not acquire these bacteria during their stay in hospital. Colonisation with
      potentially pathogenic strains in hospital affected mainly children aged 7 to 12
      months. EPEC prevailed among the strains isolated in both analyses.

PMID- 8649953
TI  - [Carcinoembryonic antigen and immunoglobulin IgE in duodenal ulcer disease in
      children].
AB  - The aim of this study was to monitor the behaviour of carcinoembryonic antigen
      (CEA) and immunoglobulin IgE level in children with duodenal ulcer disease. No
      sex-dependent differences were found in mean values of CEA, whereas the mean IgE
      level in boys was twice as high as in girls. No seasonal differences in CEA and
      IgE levels were found. The IgE concentration increased during exacerbations, and
      this difference was statistically significant. CEA levels changed according to a
      similar pattern during exacerbation and remission, but remained within normal
      limits.

PMID- 8649954
TI  - [Helicobacter pylori--an etiopathogenic factor of stomach and duodenal diseases
      among children].
AB  - One of the newest conceptions on the causes of gastritis, duodenitis, peptic and
      duodenal ulcers states that an infectious factor--Helicobacter pylori is
      responsible. The purpose of the this study was to estimate the frequency of
      Helicobacter pylori among children and the correlation between its presence and
      gastritis, duodenitis, peptic and duodenal ulcers and biliary reflux.
      Helicobacter pylori infection seems to be a serious etiopathogenic factor of
      stomach and duodenal diseases among children. Inflammatory changes of the gastric
      mucosa, as well as peptic and duodenal ulcers more frequent in children with H.
      pylori.

PMID- 8649955
TI  - [Evaluation of nonspecific inflammatory bowel disease in children using disease
      activity scoring systems].
AB  - Scoring systems for assessment of clinical activity of IBD were used to evaluate
      62 children with IBD (14 with CD, 35 with CU and 13 with CNS). The PCDAI system
      was most effective in children with CD. In children with CU, both modified
      Truelove-Witts and Rachmilewitz indexes are equally effective, however use of the
      Truelove-Witts scale is simpler. The Rachmilewitz scale is better in
      distinguishing between UC and CNS.

PMID- 8649956
TI  - [The value of IgA endomysium antibodies in diagnosis of coeliac disease among
      short children].
AB  - In recent years a shift in incidence of coeliac disease from the classical to
      late-onset form has been observed. The main, and often only, symptom of late
      onset coeliac disease is short stature. The presence of antiendomysial antibodies
      was found in 14 of 115 children with statural height below the third percentile
      from randomly chosen kindergartens and schools in Bydgoszcz. Severe atrophy of
      the intestinal villi in a biopsy specimen confirmed the suspicion of coeliac
      disease in these children. IgA-EmA are markers of coeliac disease in children
      with short stature and should be used as a screening test in looking for the
      causes of short stature.

PMID- 8649957
TI  - [Effect of feeding methods in infants on serum lipid profile].
AB  - Mothers very often do not start to breast feed their children, or stop very
      quickly and introduce various formulas based either on modified or unmodified
      cow's milk. These infant formulas differ from human milk in their chemical
      composition. Breast milk is the most suitable source of all nutrients required
      for the development of a newborn or infant. The serum levels of total
      cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and phospholipids
      were determined. The influence of the type of feeding on the levels of the above
      mentioned lipids was analyzed. Higher serum levels of triglycerides in babies fed
      formulas based on modified cow's milk than in those fed formulas based on
      unmodified milk were found. Higher serum levels of phospholipids were found in
      breast-fed babies than in those fed formulas based on unmodified cow's milk.

PMID- 8649958
TI  - [Use of a scoring index for evaluating disease activity of Lesniowski-Crohn
      disease and ulcerative colitis in children].

PMID- 8649959
TI  - [New soy-based formulas].

PMID- 8649960
TI  - [Is a fish oil enriched diet therapeutically beneficial?].
AB  - The metabolism of arachidonic acid (AA) and significance of leukotrienes in the
      pathogenesis of asthma are presented in this article. The effect of a diet
      containing eicosapentaenoic acid in the treatment of a variety of diseases is
      discussed as well.

PMID- 8649961
TI  - [Curling's ulcer in a 9-month-old infant].
AB  - Burns are the most frequent severe trauma in childhood. Curling's ulcer is a
      complication of burn shock which occurs in the gastrointestinal tract in burned
      children. Prognosis in Curling's ulcer is always serious. A rare case of acute
      duodenal ulcer in a nine-month-old infant after deep burns of both lower
      extremities is described. It seems that it is necessary to take into
      consideration the possibility of Curling's ulcer in every case of deep and
      extensive burns in children.

PMID- 8649962
TI  - [Splenic necrosis during meningococcal sepsis treated with splenectomy].
AB  - The authors present rare case of splenic necrosis during meningococcal sepsis in
      an eight-month-old infant. The diagnosis was based on ultrasonographic
      examination and confirmed by CT. These investigations were conducted because of
      splenomegaly and gastrointestinal tract disturbances. Splenectomy gave good
      results.

PMID- 8649963
TI  - [Specialist care of children with diabetes].

PMID- 8649964
TI  - [Decreasing the risk of sudden infant death syndrome--SIDS. Recommendations of
      the Polish Occupational Group on sudden infant death syndromes and the Kracow
      Team of Medical Consultants in pediatrics and school medicine].

PMID- 8649965
TI  - [About specialist care for children with neoplasms].

PMID- 8649966
TI  - [How can Scandinavian countries with antibiotics resistance?].

PMID- 8649967
TI  - [Epidemiology of penicillin-resistant pneumococci].
AB  - Penicillin-resistant and multiresistant pneumococci occur throughout the world
      and at high prevalence in certain areas. Pneumococci resistant of cefotaxime and
      ceftriaxone have so far become established in Spain, South Africa and the USA,
      and the occurrence of such strains was recently reported in the UK. In Iceland,
      the first penicillin-resistant pneumococci were identified in December 1988, and
      by 1993 the prevalence was 20 percent. The risk factors appear to be the
      congregation of children at day-care centres, excessive consumption of
      antibiotics, and the common use of the sulphamethoxazole-trimethoprim combination
      (co-trimoxazole). The consumption of antibiotics in Iceland has been reduced, and
      the incidence of resistant pneumococci is somewhat lower than formerly.

PMID- 8649968
TI  - [Sick of food? Knowledge and hypothesis on food intolerance].
AB  - Food intolerance is frequently reported by patients and represent a diagnostic
      and therapeutic challenge. We review the nomenclature and report on symptoms,
      diagnostic tests and treatment. The nomenclature presented is based on the
      primary events such as toxic reactions, allergy or an undefined mechanism,
      including psychosomatic, although these subgroups may involve common pathogenetic
      mechanism. Double blind placebo controlled food challenge is the golden standard
      in the diagnostic workup and the importance of elimination diets--individually
      tailored to each patients requirements in cooperation with a nutritionist--is
      stressed. Through strict adherence to diagnostic and therapeutical guidelines,
      therapy may resolve food induced symptoms. Based on preliminary findings of
      signal transduction, we propose that symptoms in some patients may depend on an
      allergy type IV reaction. This working hypothesis forms the basis for further
      accumulation of knowledge of food intolerance reactions.

PMID- 8649970
TI  - [Who is not sick? One of health care's major problems].

PMID- 8649969
TI  - [Was Illich right? Is ill health created by focusing on risks?].

PMID- 8649971
TI  - [Hurricane shelter--a safe retreat].

PMID- 8649972
TI  - [Does learning new knowledge and discarding old knowledge go too slowly?].

PMID- 8649973
TI  - A novel DNA damage-inducible transcript, gadd7, inhibits cell growth, but lacks a
      protein product.
AB  - gadd7 cDNA was isolated from Chinese hamster ovary (CHO) cells on the basis of
      increased levels of RNA following treatment with UV radiation. The transcript for
      gadd7, as well as for four other gadd genes, was found to increase rapidly and
      coordinately following several different types of DNA damage and more slowly
      following other stresses that elicit growth arrest. Agents that induce gadd7 RNA
      include alkylating agents, such as methyl methanesulfonate (MMS), N-methyl-N'
      nitro-N-nitrosoguanidine (MNNG) and mechlorethamine HCl (HN2), oxidizing agents,
      such as hydrogen peroxide, and growth arrest signals, such as medium depletion
      (starvation). Since growth arrest is a cellular consequence of many types of DNA
      damage in normal cells, it was thought that gadd7 may play a role in the cellular
      response to DNA damage. Indeed, overexpression of gadd7 led to a decrease in cell
      growth. Interestingly, gadd7 cDNA does not contain an appreciable open reading
      frame and does not appear to encode a protein product, but instead may function
      at the RNA level.

PMID- 8649974
TI  - The structure of 4-way DNA junctions: specific binding of bis-intercalators with
      rigid linkers.
AB  - During replication and recombination, two DNA duplexes lie side by side. We have
      developed reagents that might be used to probe structure during these critical
      processes; they contain two intercalating groups connected by a rigid linker that
      forces those groups to point in opposite directions. If their stereochemistry
      proves appropriate, such structure-specific agents should intercalate
      specifically into adjacent duplexes in the Y- and X-shaped structures (i.e. 3-
      and 4-way junctions, now known as 3H and 4H junctions) found at replication and
      recombination sites. We prepared DNA structures in which four duplexes were
      arranged in all possible combinations around 2- and 4-way junctions and then
      probed the accessibility to DNase I of all their phosphodiester bonds. In the
      absence of any bis-intercalators, 7-9 nucleotides (nt) in each of the strands in
      4-way junctions were protected from attack; protected regions were significantly
      offset to the 3' side of the junction in continuous strands, but only slightly
      offset, if at all, in exchanging strands. All the intercalators decreased
      accessibility throughout the structure, but none did so at specific points in the
      two adjacent arms of 4-way junctions. However, one bis-intercalator--but not its
      sister with a shorter linker--strikingly increased access to a particular CpT
      bond that lay 9 nt away from the centre of some 4-way junctions without reducing
      access to neighbouring bonds. Binding was both sequence and structure specific,
      and depended on complementary stereochemistry between bis-intercalator and
      junction.

PMID- 8649975
TI  - Use of 1,2,4-dithiazolidine-3,5-dione (DtsNH) and 3-ethoxy-1,2,4-dithiazoline-5
      one (EDITH) for synthesis of phosphorothioate-containing
      oligodeoxyribonucleotides.
AB  - Previous methods for the preparation of phosphorothioate-containing
      oligodeoxyribonucleotides rely on the reaction of phosphite triesters with
      sulfurizing reagents such as tetraethylthiuram disulfide (TETD) and 3H-1,2
      benzodithiol-3-one 1,1-dioxide (Beaucage reagent). However, these and other
      sulfurizing reagents suffer from several disadvantages, and there is great
      impetus for the development of improved methods for sulfur transfer that are
      fully compatible with standard automated DNA synthesis. The present report
      describes the use of 1,2,4-dithiazolidine-3,5-dione (DtsNH) and 3-ethoxy-1,2,4
      dithiazoline-5-one (EDITH) as effective sulfurizing reagents that meet these
      needs. Both reagents are easily prepared, and are stable upon prolonged room
      temperature storage in acetonitrile solution. The reagents are used at low
      concentrations (0.05 M) and for short reaction times (30 s). The methodology has
      been proven for the automated synthesis on 0.2-1.0 micromol scales of
      oligodeoxyribonucleotides, of length 6-20 bases, containing the phosphorothioate
      substitution at either a single site or at all positions.

PMID- 8649976
TI  - The polypyrimidine tract binding (PTB) protein interacts with single-stranded DNA
      in a sequence-specific manner.
AB  - Polypyrimidine tract binding (PTB) protein is a cellular factor whose function is
      unknown. Various RNA or single-stranded DNA sequences have been shown to interact
      with PTB. In this paper, using laser UV crosslinking and electrophoretic mobility
      shift assays to probe DNA-protein interactions, we demonstrate that PTB binding
      at a single-stranded DNA target is highly sequence-specific. We provide data
      showing that PTB interacts with the top strand of the adenovirus major late
      promoter transcriptional initiator, a sequence rich in pyrimidine residues. We
      also demonstrate that PTB is organised into at least two different binding
      domains.

PMID- 8649977
TI  - On the use of double FLP recognition targets (FRTs) in the LTR of retroviruses
      for the construction of high producer cell lines.
AB  - A pilot experiment for the construction of a hamster derived, high producer cell
      line using site specific recombination is described. In the experiment
      chromosomal loci with intrinsic high expression characteristics were sought via
      infection with a retroviral construct, containing double FRT sites and subsequent
      screening for overproduction of an encoded markergene. These sites were then
      targeted with a second vector, that recombined via the FLP/FRT system from
      Saccharomyces cerevisiae yielding cells that had the second construct at exactly
      the same position as the first. By using retroviral vectors with double and
      single FRT sites, respectively, stable clones can be created that can no longer
      be excised with FLP.

PMID- 8649978
TI  - Photolysis of N-hydroxpyridinethiones: a new source of hydroxyl radicals for the
      direct damage of cell-free and cellular DNA.
AB  - N-Hydroxypyridine-2-thione (2-HPT), known to release hydroxyl radicals on
      irradiation with visible light, and two related compounds, viz. N-hydroxypyridine
      4-thione (4-HPT) and N-hydroxyacridine-9-thione (HAT), were tested for their
      potency to induce DNA damage in L1210 mouse leukemia cells and in isolated DNA
      from bacteriophage PM2. DNA single-strand breaks and modifications sensitive to
      various repair endonucleases (Fpg protein, endonuclease III, exonuclease III, T4
      endonuclease V) were quantified. Illumination of cell-free DNA in the presence of
      2-HPT and 4-HPT gave rise to damage profiles characteristic for hydroxyl
      radicals, i.e. single-strand breaks and the various endonuclease-sensitive
      modifications were formed in the same ratios as after exposure to established
      hydroxyl radical sources. In contrast, HAT plus light gave rise to a completely
      different DNA damage profile, namely that characteristic for singlet oxygen.
      Experiments with various scavengers (t-butanol, catalase, superoxide dismutase)
      and in D2O as solvent confirmed that hydroxyl radicals are directly responsible
      for the DNA damage caused by photoexcited 2-HPT and 4-HPT, while the damage by
      HAT plus light is mediated by singlet oxygen and type I reactions. The type of
      DNA damage characteristic of hydroxyl radicals was also observed in L1210 mouse
      leukemia cells when treated with 2-HPT plus light or with H2O2 at 0 degrees C. t
      Butanol (2%) inhibited the cellular DNA damage by approximately 50%. A dose of 2
      HPT plus light that generated single-strand breaks at a frequency of 5 x 10(
      7)/bp was associated with 50% cell survival. No DNA damage and cytotoxicity was
      observed after treatment with 2-HPT in the dark. We propose that 2-HTP and 4-HTP
      may serve as new agents to study the consequences of DNA damage induced by
      hydroxyl radicals in cells. In addition, the data provide direct evidence that
      hydroxyl radicals are ultimately responsible for the genotoxic effects caused by
      H2O2 in the dark.

PMID- 8649979
TI  - Molecular modelling of (A4T4NN)n and (T4A4NN)n: sequence elements responsible for
      curvature.
AB  - The molecular modelling program JUMNA has been used to investigate the origins of
      the strikingly different curvature of the two sequences, (A4T4NN)n and (T4A4NN)n.
      Gel electrophoresis and cyclisation studies have shown that only the former of
      these two sequences is significantly curved. By developing novel superhelical
      symmetry constraints we were able to study the energetic and structural aspects
      of polymeric DNA having a controlled curvature. The results obtained (which do
      not take into account specific hydration effects) correlate well with the
      experimental data and offer a molecular level explanation of curvature. Although
      curvature is found to be initiated by specific dinucleotide junctions,
      deformations spread to surrounding dinucleotide steps and, moreover, sequence
      effects beyond the dinucleotide level are observed.

PMID- 8649980
TI  - The 5' and 3' splice sites come together via a three dimensional diffusion
      mechanism.
AB  - We present evidence that the splice sites in mammalian pre-mRNAs are brought
      together via a three dimensional diffusion mechanism. We tested two mechanisms
      for splice site pairing: a lateral diffusion ('scanning') model and the currently
      favored three dimensional diffusion ('jumping') model. Two lines of evidence that
      distinguish between these two models are presented. The first utilized bipartite
      splicing substrates tethered by double-stranded RNA stems predicted to provide
      either a moderate or severe block to splice site pairing via a scanning
      mechanism. Splice site pairing via a jumping mechanism was expected to be
      unaffected or affected minimally. The second approach utilized a flexible
      poly(ethylene glycol) moiety within the intron. This insertion was predicted to
      reduce scanning efficiency but not the efficiency of a three dimensional
      diffusion mechanism. The best explanation for the data with the bipartite RNAs is
      that splice site pairing occurs through three dimensional diffusion. Kinetic
      analysis of the poly(ethylene glycol) containing substrate showed that neither
      the lag phase nor the initial rates of mRNA production and spliceosome assembly
      were affected by this insertion. Therefore, both experimental approaches
      supported the three dimensional diffusion model of splice site pairing.

PMID- 8649981
TI  - Molecular and functional analysis of the utrophin promoter.
AB  - Utrophin is a ubiquitously expressed cytoskeletal protein which is an important
      structural component of the mammalian neuromuscular junction. It shows extensive
      sequence similarity to dystrophin leading to postulation that utrophin may be
      able to compensate for the absence of dystrophin in Duchenne muscular dystrophy
      (DMD) patients. In order to study the transcriptional control of utrophin
      expression including its regulation at the neuromuscular junction, and as a first
      step in the development of a potential DMD therapy, we have cloned the utrophin
      promoter region from human and mouse. The utrophin promoter is associated with a
      CpG island at the 5'-end of the gene, and sequence analysis of the 5'-UTR reveals
      several Sp1 binding sites and the absence of TATA or CAAT motifs. Transcription
      is initiated at one major and three minor sites. Using deletion constructs, we
      have defined an active promoter region of 155 bp. The first exon and 900 bp
      upstream display limited sequence conservation between human and mouse. The core
      sequence TTCCGG of the N box which regulates synaptic expression of other genes
      is also present and may be involved in regulating the specific expression of
      utrophin at the postsynaptic membrane. This study provides the basis for the
      understanding of the regulatory mechanism that controls utrophin expression and
      provides the data needed to develop methods for the upregulation of utrophin in
      DMD patients.

PMID- 8649982
TI  - Trans-splicing and alternative-tandem-cis-splicing: two ways by which mammalian
      cells generate a truncated SV40 T-antigen.
AB  - The early SV40 BstXI-BamHI (Bst/Bam) DNA fragment encodes exclusively for the
      second exon of the large T-antigen and contains the intact small t-antigen
      intron. Rat cells transformed by the p14T, a construct that carries the Bst/Bam
      DNA fragment as a tail-to-head tandem duplication, synthesize a truncated T
      antigen (T1-antigen) without having a direct equivalent at the DNA level.
      Formation of the T1-mRNA occurs by means of two distinct mechanisms: alternative
      tandem-cis-splicing and trans-splicing. To generate the T1-mRNA the cells utilize
      a cryptic 5' splice site, located within the second exon of the large T-antigen
      and the regular small t-antigen 3' splice site. Since these splice sites are in
      an inverted order two Bst/Bam transcripts are required to generate one T1-mRNA
      molecule. For alternative-tandem-cis-splicing the cells utilize a 4.4 kb pre-mRNA
      that contains the sequence of the entire Bst/Bam tandem repeat. The proximal
      Bst/Bam segment provides the 5' donor splice site and the distal segment the 3'
      acceptor site. This requires that the pre-mRNA not be cleaved after the RNA
      polymerase II has passed the polyadenylation signal of the proximal Bst/Bam DNA
      segment. Synthesis of the 4.4 kb pre-mRNA was demonstrable by RT-PCR but not by
      Northern blot analysis. For trans-splicing, the cells utilize two separate pre
      mRNA molecules. One transcript provides the cryptic 5' splice donor site and the
      other the 3' splice acceptor site. To demonstrate this a three base pair deletion
      was introduced into the proximal Bst/Bam segment of the p14T DNA (p14Tdelta-3) as
      a marker, destroying the recognition site for Pf/MI restriction enzyme. This
      deletion allowed the differentiation between the proximal and distal Bst/Bam
      segment. RT-PCR analysis and DNA sequencing confirmed that the p14Tdelta-3
      transformed cells generate the T1-mRNA by intra- and inter-molecular RNA
      splicing.

PMID- 8649985
TI  - Lack of biological significance in the 'linguistic features' of noncoding DNA--a
      quantitative analysis.
AB  - Recently, the application of two statistical methods (related to Zipf's
      distribution and Shannon's redundancy), called 'linguistic' tests, to the primary
      structure of DNA sequences of living organisms has excited considerable interest.
      Of particular importance is the claim that noncoding DNA sequences in eukaryotes
      display specific 'linguistic' features, being reminiscent of natural languages.
      Furthermore, this implies that noncoding regions of DNA may carry some new, thus
      far unknown, biological information which is revealed by these tests. In this
      paper these claims are tested quantitatively. With the aid of computer
      simulations of natural DNA sequences, and by applying the same 'linguistic' tests
      to both natural and artificial sequences, we investigate in detail the reasons of
      the appearance of the claimed 'linguistic' features and the associated
      differences between coding and noncoding DNAs. The presented results show
      quantitatively that the 'linguistic' tests failed to reveal any new biological
      information in (noncoding or coding) DNA.

PMID- 8649983
TI  - Centromeric polymerase III transcription units in Chironomus pallidivittatus.
AB  - Cp1 is a polymorphic short interspersed repeat (SINE) which is distributed over
      the whole genome of the dipteran Chironomus pallidivittatus, and is particularly
      abundant in the centromeres. It contains two different sequence modules, one of
      which, the B module, has a polymerase III internal control region (ICR) typical
      for tRNA genes (A and B box). Such sequence motifs are common in SINEs and
      assumed to function in RNA-mediated transposition. In the present case, however,
      several structural features speak for another role. An investigation of the
      transcription of the B module shows that it encodes a 99 nt RNA species in vivo,
      Cp1-RNA, terminating within the module. The transcription unit is likely to have
      evolved from a pre-tRNA gene and the transcript has sequence similarities to non
      processed pre-tRNA. Most of the in vitro transcription is eliminated by deletion
      or substitution mutation of an upstream TATA box, present within the B module, as
      well as by changing either the A or B box. The properties of the transcript
      suggest that it does not have a role in transposition but may have some other
      function, perhaps in the centromere.

PMID- 8649984
TI  - Cloning and characterization of RAD17, a gene controlling cell cycle responses to
      DNA damage in Saccharomyces cerevisiae.
AB  - Mutants of the yeast Saccharomyces cerevisiae defective in the RAD17 gene are
      sensitive to ultraviolet (UV) and gamma radiation and manifest a defect in G2
      arrest following radiation treatment. We have cloned the RAD17 gene by
      complementation of the UV sensitivity of a rad17-1 mutant and identified an ORF
      of 1.2 kb encoding a predicted gene product of 45.4 kDa with homology to the
      Schizosaccharomyces pombe rad1+ gene product and to Ustilago maydis Rec1, a known
      3'->5'exonuclease. The RAD17 transcript is cell cycle regulated, with maximum
      steady-state levels during late G1. The rad17-1 mutation represents a missense
      mutation that maps to a conserved region of the gene. A rad17 disruption mutant
      grows normally and manifests levels of UV sensitivity similar that of the rad17-1
      strain. As previously observed with other genes involved in G2 arrest (such as
      RAD9 and RAD24), RAD17 regulates radiation-induced G1 checkpoints at at least two
      possible arrest stages. One is equivalent to or upstream of START, the other at
      or downstream of the Cdc4 execution point. However, the temperature sensitivity
      of the cell cycle mutant dna1-1 (a G1 arrest mutant) is not influenced by
      inactivation of RAD17.

PMID- 8649986
TI  - In vivo footprinting of the mouse inducible nitric oxide synthase gene: inducible
      protein occupation of numerous sites including Oct and NF-IL6.
AB  - A wide variety of cells usefully but sometimes destructively produce nitric oxide
      via inducible nitric oxide synthase (iNOS). Data obtained by gel shift analysis
      and reporter assays have linked murine iNOS gene induction by cytokines and
      bacterial products with the binding of a number of proteins to a proximal
      promoter, as well as to a distal enhancer of the iNOS gene. Nevertheless, these
      techniques do not necessarily reflect protein occupation of sites in vivo. To
      address this, we have used dimethyl sulphate in vivo footprinting to determine
      binding events in the two murine iNOS transcription control regions, using a
      classical lipopolysaccharide induction of RAW 264.7 macrophages. Protein-DNA
      interactions are absent before activation. Exposure to lipopolysaccharide induces
      protection at a NF-kappaB site and hypersensitivity at a shared gamma-activated
      site/interferon-stimulated response element within the enhancer. Protections are
      seen at a NF-IL6, and an Oct site within the promoter. We also observe
      modulations in guanine methylation at two regions which do not correspond to any
      known putative binding elements. Furthermore, we confirm the probable involvement
      of interferon regulatory factor-1 (binding to its -901 to -913 site) and the
      binding of NF-kappaB to its proximal site. Our data demonstrate an abundance of
      hitherto-unrecognised protein-DNA binding events upon simple lipopolysaccharide
      activation of the iNOS gene and suggests a role for protein-protein interactions
      in its transcriptional induction.

PMID- 8649987
TI  - The Leishmania genome comprises 36 chromosomes conserved across widely divergent
      human pathogenic species.
AB  - All the physical linkage groups constituting the genome of Leishmania infantum
      have been identified for the first time by hybridization of specific DNA probes
      to pulsed field gradient-separated chromosomes. The numerous co-migrating
      chromosomes were individualised using the distinctive size polymorphisms which
      occur among strains of the L. infantum/L. donovani complex as a tool. A total of
      244 probes, consisting of 41 known genes, 66 expressed sequence tags (ESTs) and
      137 anonymous DNA sequences, were assigned to a specific linkage group. We show
      that this genome comprises 36 chromosomes ranging in size from 0.35 to -3 Mb.
      This information enabled us to compare the genome structure of L. infantum with
      those of the three other main Leishmania species that infect man in the Old
      World, L. major, L. tropica and L. aethiopica. The linkage groups were
      consistently conserved in all species examined. This result is in striking
      contrast to the large genetic distances that separate these species and suggests
      that conservation of the chromosome structure may be critical for this human
      pathogen. Finally, the high density of markers obtained during the present study
      (with a mean of 1 marker/130 kb) will speed up the construction of a detailed
      physical map that would facilitate the genetic analysis of this parasite, for
      which no classical genetics is available.

PMID- 8649988
TI  - Repression by a differentiation-specific factor of the human cytomegalovirus
      enhancer.
AB  - We detected a novel nuclear protein, MRF, that binds to multiple sites on the
      modulator which is located upstream of the human cytomegalovirus major immediate
      early gene enhancer. The expression of MRF is differentiation specific; the DNA
      binding activity is present in nuclear extracts from undifferentiated Tera-2 and
      THP-1 cells, but significantly reduced after these cells are induced to
      differentiate. In undifferentiated cells the enhancer activity is repressed by
      the modulator and upon differentiation the enhancer becomes active. Competitive
      binding assays demonstrate that MRF requires the presence of multiple A+T
      stretches for binding to DNA, rather than binding to a specific DNA sequence.
      Mutations of these stretches in the modulator reduce the binding activity of MRF,
      as well as the repressing activity on the enhancer. These results suggest that
      MRF may act as a repressor of enhancer function. We propose that MRF binds over
      the entire modulator and exerts repressor activity.

PMID- 8649989
TI  - Sequence-specific labeling of superhelical DNA by triple helix formation and
      psoralen crosslinking.
AB  - Site-specific labeling of covalently closed circular DNA was achieved by using
      triple helix-forming oligonucleotides 10, 11 and 27 nt in length. The sequences
      consisted exclusively of pyrimidines (C and T) with a reactive psoralen at the 5'
      end and a biotin at the 3'-end. The probes were directed to different target
      sites on the plasmids pUC18 (2686 bp), pUC18/4A (2799 bp) and pUC1 8/4A-H 1 (2530
      bp). After triple helix formation at acid pH the oligonucleotides were
      photocrosslinked to the target DNAs via the psoralen moiety, endowing the
      covalent adduct with unconditional stability, e.g. under conditions unfavorable
      for preservation of the triplex, such as neutral pH. Complex formation was
      monitored after polyacrylamide gel electrophoresis by streptavidin-alkaline
      phosphatase (SAP)-induced chemiluminescence. The yield of triple helix increased
      with the molar ratio of oligonucleotide to target and the length of the probe
      sequence (27mer > 11mer). The covalent adduct DNA were visualized by scanning
      force microscopy (SFM) using avidin or streptavidin as protein tags for the
      biotin group on the oligonucleotide probes. We discuss the versatility of triple
      helix DNA complexes for studying the conformation of superhelical DNA.

PMID- 8649990
TI  - Differences in mutagenesis during minus strand, plus strand and strand transfer
      (recombination) synthesis of the HIV-1 gene in vitro.
AB  - We have developed an HIV nef-Escherichia coli lacZ fusion system in vitro that
      allows the detection of low frequency mutations, including frameshifts, deletions
      and insertions. A portion of the nef gene that encompasses a hypervariable region
      was fused in-frame with a downstream lacZalpha peptide coding region. The
      resulting lacZalpha peptide fusion protein remained functional. Any frameshift
      mutations in the nef insert would put the downstream lacZ alpha peptide gene out
      of frame, eliminating alpha complementation. With this system we compared the
      error rates of frameshift mutations that arise during DNA-directed and RNA
      directed DNA synthesis. Results showed that DNA-directed and RNA-directed DNA
      synthesis did not contribute equally to the generation of mutations. DNA-directed
      DNA synthesis generated frameshift mutations at a frequency approximately 10-fold
      higher than those arising from RNA-directed DNA synthesis. RNA-directed DNA
      synthesis in the presence of acceptor templates showed an increase in mutation
      rate and differences in the mutation spectrum. The enhancement of mutation rate
      was caused by the appearance of mutations at three new locations that correlated
      with likely recombination sites. Results indicate that recombination is another
      source of mutations during viral replication.

PMID- 8649991
TI  - Relationship between plus strand DNA synthesis removal of downstream segments of
      RNA by human immunodeficiency virus, murine leukemia virus and avian
      myeloblastoma virus reverse transcriptases.
AB  - During retroviral reverse transcription the genomic RNA is degraded by the RNase
      H activity of reverse transcriptase (RT). Previous results suggest that after RNA
      directed DNA synthesis, fragments of RNA remain annealed to the newly synthesized
      DNA [DeStefano et al.(1991) J. Biol.Chem. 266, 7423-7431]. These must be removed
      to allow synthesis of the second DNA strand. We measured the ability of HIV-, AMV
      and MuLV-RT to coordinate DNA-dependent DNA synthesis and removal of downstream
      segments of RNA. The substrates employed were DNA templates having upstream DNA
      and downstream RNA primers. We found that none of the wild type RTs elongated the
      upstream DNA without simultaneous degradation of the RNA. Consistent with these
      results, HIV-, AMV- and MuLV-RT showed relatively higher affinity for RNA than
      for DNA oligonucleotides bound to a DNA template. Differences were observed in
      the RNA degradation and DNA extension patterns generated by the different RTs.
      AMV-RT degraded the RNA to segments 11-12 nt long, and readily elongated the
      upstream DNA to the end of the template. MuLV- and HIV-RT degraded the RNA
      primarily to segments 15-16 nt long. At low concentrations of the latter two RTs,
      the DNA primer stalled when it encountered the 5'-end of the RNA. In sufficient
      excess, all of the RTs elongated the upstream primer without stalling. Even
      though we were unable to detect displacement of the downstream RNA by the wild
      type RTs, MuLV- and HIV-RT lacking RNase H, were able to elongate the upstream
      DNA to the end of the template without degradation of the RNA. This suggests that
      degradation of downstream pieces of RNA is not absolutely required before
      synthesis of the plus strand DNA. The implications of these findings for viral
      replication are discussed.

PMID- 8649992
TI  - A 39 amino acid fragment of the cell cycle regulator p21 is sufficient to bind
      PCNA and partially inhibit DNA replication in vivo.
AB  - The cell cycle regulator p21 interacts with and inhibits the DNA replication and
      repair factor proliferating cell nuclear antigen (PCNA). We have defined a 39
      amino acid fragment of p21 which is sufficient to bind PCNA with high affinity
      (Kd 10-20 nM). This peptide can inhibit DNA replication in vitro and
      microinjection of a GST fusion protein containing this domain inhibited S phase
      in vivo. Despite its high affinity for PCNA, the free 39 amino acid peptide does
      not have a well-defined structure, as judged from circular dichroism and nuclear
      magnetic resonance measurements, suggesting an induced fit mechanism for the PCNA
      p21 interaction. The association of the small peptide with PCNA was thermolabile,
      suggesting that portions of p21 adjoining the minimal region of contact stabilize
      the interaction. In addition, a domain containing 67 amino acids from the N
      terminus of PCNA was defined as both necessary and sufficient for binding to p21.

PMID- 8649993
TI  - Contribution of ultra-short invasive elements to the evolution of the
      mitochondrial genome in the genus Podospora.
AB  - In the filamentous fungus Podospora anserina, senescence is associated with major
      rearrangements of the mitochondrial DNA. The undecamer GGCGCAAGCTC has been
      described as a preferential site for these recombination events. We show that:
      (i) copies of this short sequence GGCGCAAGCTC are present in unexpectedly high
      numbers in the mitochondrial genome of this fungus; (ii) a short cluster of this
      sequence, localised in a group II intronic ORF, encodes amino acids that disrupt
      a protein domain that is otherwise highly conserved between various species;
      (iii) most of the polymorphisms observed between three related species,
      P.anserina, P.curvicolla and P.comata, are associated with the presence/absence
      of this sequence; (iv) this element lies at the boundaries of major
      rearrangements of the mitochondrial genomes; (v) at least two other short
      elements in the Podospora mitochondrial genomes display similar features. We
      suggest that these short elements, called MUSEs (mitochondrial ultra-short
      elements), could be mobile and that they contribute to evolution of the
      mitochondrial genome in the genus Podospora. A model for mobility involving a
      target DNA-primed reverse transcription step is discussed.

PMID- 8649994
TI  - Reduction of the toxicity and mutagenicity of aziridine in mammalian cells
      harboring the Escherichia coli fpg gene.
AB  - Aziridine (ethyleneimine) reacts with DNA in vitro, mainly at the N7 position of
      guanine and N3 of adenine, then imidazole ring opening of the modified guanine
      results in formation of formamidopyrimidine (FaPy) residues. The Escherichia coli
      fpg gene encodes a DNA glycosylase that removes FaPy residues from DNA. To
      determine whether aziridine produces FaPy lesions in mammalian cells we have
      expressed the E.coli fpg gene in CHO cells. The transfected cells, expressing
      high levels of the bacterial protein, are more resistant to the toxic and
      mutagenic effects of aziridine than the control population. Less DNA damage was
      measured by quantitative PCR analysis in transfected than in control cells
      treated with equimolar concentrations of aziridine. The results suggest that
      aziridine produces in vivo FaPy residues that could account for the deleterious
      effects of this compound.

PMID- 8649996
TI  - Accumulation of a mRNA decay intermediate by ribosomal pausing at a stop codon.
AB  - A RNA fragment which is protected from degradation by ribosome pausing at a stop
      codon has been identified in growing Escherichia coli. The fragment is 261 nt
      long and corresponds to the 3'-end of the mRNA expressed from a semi-synthetic
      model gene. The 5'-end of the RNA fragment, denoted rpRNA (ribosomal pause RNA),
      is located 13 bases upstream of the stop codon. In vivo decay of the complete
      mRNA and accumulation of rpRNA are dependent on the nature of the stop codon and
      its codon context. The data indicate that the rpRNA fragment arises from
      interrupted decay of the S3A'mRNA in the 5'-->m3'direction, in connection with a
      ribosomal pause at the stop codon. RF-2 decoding of UGA is less efficient than RF
      1 decoding of UAG in identical codon contexts, as judged from rpRNA steady-state
      levels. The half-life of UGA-containing rpRNAs is at least 5 min, indicating that
      ribosomal pausing can be a major factor in stabilising downstream regions of
      messenger RNAs.

PMID- 8649995
TI  - Identification of promoter and stringent regulation of transcription of the fabH,
      fabD and fabG genes encoding fatty acid biosynthetic enzymes of Escherichia coli.
AB  - In Escherichia coli, amino acid starvation results in the coordinate inhibition
      of a variety of metabolic activities, including fatty acid and phospholipid
      biosynthesis. By using primer extension analysis we identified the fabH promoter
      responsible for transcription of the fabH, fabD and fabG genes encoding fatty
      acid biosynthetic enzymes. The response of the fabH promoter to amino acid
      starvation was determined in vivo. Transcripts originating from the fabH promoter
      were quantified by employing a ribonuclease protection assay. The fabH promoter
      was subject to relA-dependent stringent control and was repressed approximately 4
      fold upon amino acid starvation. The results suggest that inhibition of
      transcription initiation of lipid biosynthetic genes in starved cells contributes
      to the stringent control of lipid biosynthesis.

PMID- 8649997
TI  - Binding of DNA oligonucleotides to sequences in the promoter of the human bc1-2
      gene.
AB  - Duplex DNA recognition by oligonucleotide-directed triple helix formation is
      being explored as a highly specific approach to artificial gene repression. We
      have identified two potential triplex target sequences in the promoter of the
      human bcl-2 gene, whose product inhibits apoptosis. Oligonucleotides designed to
      bind these target sequences were tested for their binding affinities and
      specificities under pseudo-physiological conditions. Electrophoretic mobility
      shift and dimethyl sulfate footprinting assays demonstrated that an
      oligonucleotide designed for simultaneous recognition of homopurine domains on
      alternate duplex DNA strands had the highest affinity of any oligonucleotide
      tested. Modifications to render this oligonucleotide nuclease-resistant did not
      reduce its binding affinity or specificity. In additional studies under various
      pH conditions, pyrimidine motif complexes at these target sequences were found to
      be stable at pH 8.0, despite the presumed requirement for protonation of
      oligonucleotide cytidines. In contrast, purine motif complexes, typically
      considered to be pH independent, were highly destabilized at decreasing pH
      values. These results indicate that a natural sequence in the human bcl-2
      promoter can form a stable triplex with a synthetic oligonucleotide under pseudo
      physiological conditions, and suggest that triple helix formation might provide
      an approach to the artificial repression of bcl-2 transcription.

PMID- 8649998
TI  - Sequence of the polypyrimidine tract of the 3'-terminal 3' splicing signal can
      affect intron-dependent pre-mRNA processing in vivo.
AB  - Most pre-mRNAs require an intron for efficient processing in higher eukaryotes.
      However, not all introns can provide this function. For example, transcripts
      synthesized from a variant of the human beta-globin gene lacking its second
      intervening sequence (IVS2), yet retaining its first intervening sequence (IVS1),
      exhibit multiple defects in mRNA biogenesis. To investigate why, we transfected
      into monkey cells plasmids containing the human beta-globin gene and variants of
      it altered in (i) IVS1, (ii) the 3'-terminal exon, and (iii) the polyadenylation
      signal. The beta-globin RNAs accumulated in these cells were analyzed by
      quantitative S1 nuclease mapping for nuclear accumulation, intron excision,
      polyadenylation and cytoplasmic accumulation. We found that the 3' splicing
      signal of IVS1, with multiple purines interrupting its polypyrimidine tract,
      could efficiently function as an internal 3' splicing signal; however, it could
      not efficiently function as the 3'-terminal 3' splicing signal for any of these
      steps in intron-dependent mRNA biogenesis unless (i) its polypyrimidine tract was
      made uninterrupted in pyrimidines, or (ii) specific sequences were deleted from
      the 3'-terminal exon. We conclude that whether an intron can provide the function
      necessary for efficient processing of intron-dependent pre-mRNA is dependent upon
      the ability of its 3' splicing signal to define the 3'-terminal exon. On the
      practical side, this finding means one needs to consider both the sequence and
      location of the intron to be included in an intron-dependent gene to obtain
      efficient expression in vivo.

PMID- 8649999
TI  - High-level production of recombinant proteins in CHO cells using a dicistronic
      DHFR intron expression vector.
AB  - We have constructed expression vectors for Chinese hamster ovary (CHO) cells that
      produce both selectable marker and recombinant cDNA from a single primary
      transcript via differential splicing. These vectors produce stable CHO cell
      clones that, when pooled, produce abundant amounts of secreted recombinant
      proteins compared with the amounts produced by conventional expression approaches
      that have selectable marker and the cDNA of interest under control of separate
      transcription units. Our vectors divert most of the transcript to product
      expression while linking it, at a fixed ratio, to dihydrofolate reductase (DHFR)
      expression to allow selection of stable transfectants. Pools of clones with
      increased expression of the product gene can be efficiently generated by
      selection in methotrexate. The high level of expression from pools allows
      convenient and rapid production of milligram amounts of recombinant proteins.

PMID- 8650001
TI  - The human ubiquitin C promoter directs high ubiquitous expression of transgenes
      in mice.

PMID- 8650000
TI  - Examining the contribution of a dA+dT element to the conformation of Escherichia
      coli integration host factor-DNA complexes.
AB  - DNA binding proteins that induce structural changes in DNA are common in both
      prokaryotes and eukaryotes. Integration host factor (IHF) is a multi-functional
      DNA binding and bending protein of Escherichia coli that can mediate protein
      protein and protein-DNA interactions by bending DNA. Previously we have shown
      that the presence of a dA+dT element 5'-proximal to an IHF consensus sequence can
      affect the binding of IHF to a particular site. In this study the contribution of
      various sequence elements to the formation of IHF-DNA complexes was examined. We
      show that IHF bends DNA more when it binds to a site containing a dA+dT element
      upstream of its core consensus element than to a site lacking a dA+dT element. We
      demonstrate that IHF can be specifically crosslinked to DNA with binding sites
      either containing or lacking this dA+dT element. These results indicate the
      importance of flanking DNA and a dA+dT element in the binding and bending of a
      site by IHF.

PMID- 8650002
TI  - Controlled ribonucleotide tailing of cDNA ends (CRTC) by terminal
      deoxynucleotidyl transferase: a new approach in PCR-mediated analysis of mRNA
      sequences.
AB  - Controlled ribonucleotide tailing of cDNA ends (CRTC) by terminal
      deoxynucleotidyl transferase is a polymerase chain reaction (PCR)-mediated
      technique that was developed to facilitate cloning and direct sequence analysis
      of complete 5'-terminal unknown coding regions of rare RNA molecules. In contrast
      with standard tailing protocols using dNTPs as the substrate, ribo-tailing of
      cDNA ends is easily controllable, self-limited (from two to four rNMP
      incorporations) and highly efficient (>98%). By virtue of the homopolymeric ribo
      tail, the modified cDNA is anchored to the 3' overhang of a double-stranded DNA
      adaptor in a T4 DNA ligase-dependent ligation. PCR amplification, mediated by two
      sequence-specific primers, yields the desired unique product suitable for cloning
      and dideoxy-sequencing.

PMID- 8650003
TI  - Federal support of graduate nursing education: rationale and policy options.

PMID- 8650004
TI  - Cancer fatalism among African-Americans: a review of the literature.
AB  - Historically, the health status of African-Americans has been significantly lower
      when compared with the general population. Too often, attempts to explain and
      understand this occurrence have focused on factors such as poverty, decreased
      access, under-education, and decreased knowledge of cancer. Despite the providing
      of screening at reduced costs or educational interventions, the screening rates
      for African-Americans remains lower than that of the general population. Cancer
      fatalism is believed to be an additional barrier to participation in screening
      for this population. Previous research findings can raise the consciousness of
      nursing professionals about the influence of cancer fatalism. There are no easy
      solutions, and much additional research is needed.

PMID- 8650005
TI  - Men researching women working.

PMID- 8650006
TI  - Students' perceptions of ideal and nursing career choices.

PMID- 8650007
TI  - Public policy and adolescent pregnancy: a reexamination of the issues.

PMID- 8650008
TI  - Does every patient deserve a nurse?

PMID- 8650009
TI  - Interdisciplinary education for professionals.

PMID- 8650010
TI  - Nursing in the political and economic marketplace: challenges for the 21st
      century.

PMID- 8650012
TI  - Factors associated with stroke following the Fontan procedure.
AB  - We reviewed the results of 68 consecutive Fontan procedures from 1978 to 1993 to
      determine the frequency of late central neurologic complications of the Fontan
      procedure in patients living at a mean altitude of 4500 feet. Two surviving
      patients had transient neurologic symptoms or signs with no corresponding
      evidence of brain injury by magnetic resonance imaging (MRI), whereas six
      surviving patients had strokes defined by sustained neurologic symptoms or signs
      with areas of brain injury identified by MRI [8.8% (6.0-13.0%; 70% confidence
      limits)]. Collectively, patients with neurologic symptoms had normal hemoglobin
      values, platelet counts, partial thromboplastin times, and prothrombin times at
      the onset of clinical neurologic findings. Two patients were taking antiplatelet
      agents, and one patient was taking warfarin. One of the patients with transient
      neurologic findings and all of the stroke patients had residual right-to-left
      shunts. Thus strokes were not uncommon in our patients after the Fontan
      procedure. Brain injury may result from thromboembolic events associated with
      residual right-to-left shunts, but our total number of asymptomatic patients with
      a residual shunt or brain abnormalities by MRI is not known.

PMID- 8650011
TI  - Validity of electrocardiographic criteria for left ventricular hypertrophy in
      children with pressure- or volume-loaded ventricles: comparison with
      echocardiographic left ventricular muscle mass.
AB  - To determine the correlation between electrocardiographic (ECG) findings and
      anatomy utilizing echocardiography in children with pressure- or volume-loaded
      left ventricles, we analyzed the preoperative ECG tracings of 19 patients who
      underwent surgery for significant aortic stenosis and 12 patients who underwent
      cardiac catheterization or surgery for clinically significant ventricular septal
      defects. We then compared them with a group of 21 normal controls. The left
      ventricular muscle mass in these patients was calculated from echocardiograms
      using the simplified cubed formula. Posterior and septal wall thickness and
      cavity size were significantly greater in the aortic stenosis group than in the
      normal group. Only cavity size was significantly greater in the ventricular
      septal defect group than in the normal group. Eighteen aortic stenosis patients
      (95%) and ten ventricular septal defect patients (83%) had a left ventricular
      muscle mass greater than 2 standard deviations above the mean for the normal
      group. Significant differences were found in the voltages of SV1 + RV6 and in the
      voltage of RV6 alone between normals, aortic stenosis patients, and ventricular
      septal defect patients regardless of age. Using conventional ECG criteria for
      left ventricular hypertrophy, the highest sensitivity in aortic stenosis patients
      (67%) and ventricular septal defect patients (60%) was modest. The likelihood
      ratio for a positive test in either group was the best for SV1 + RV6 > 98th
      centile for age; RV6 > 98th centile for age was the best single measurement. No
      correlation was found between voltage and any measurable hemodynamic or anatomic
      data. Conventional pediatric ECG criteria for left ventricular hypertrophy have
      only modest sensitivity regardless of whether the heart is under pressure or
      volume load. Because left ventricular muscle mass can be precisely determined by
      echocardiography, these ECG criteria should be applied cautiously.

PMID- 8650013
TI  - Outcome of pulmonary atresia and ventricular septal defect during infancy.
AB  - We evaluated 54 patients with pulmonary atresia and ventricular septal defect who
      were referred during the first year of life between 1972 and 1992. Particular
      emphasis was given to the nature of the pulmonary blood supply and its influence
      on outcome. Ductal supply of confluent pulmonary arteries was present in 30
      patients (55.6%, group I), whereas 24 patients (44.4%, group II) had a pulmonary
      blood supply that was entirely (31.4%) or predominantly (13.0%) dependent on
      systemic collateral arteries. Over the 20 years there was no significant
      difference in actuarial survival between the two groups. Corrective surgery was
      performed in 8 of 30 patients in group I (26.7%)-significantly more than in group
      II (4 of 24, 16.7%). Arborization abnormalities of the pulmonary arteries
      (stenosis of unbranched and intrapulmonary arteries) were almost exclusively
      present in patients with systemic collateral arteries (p < 0.03), accounting for
      the lower probability of undergoing corrective surgery in group II patients.
      During the first decade of this study (1973-1983) corrective surgery was
      attempted in 9.6% of patients, with 42% mortality; and during the second decade
      (1983-1993) surgery was performed in 39.1% of patients, with 26% mortality, a
      significantly lower figure. Improving surgical results, complete preoperative
      demarcation of the pulmonary blood supply, and a more aggressive approach with
      early unifocalization of the pulmonary blood supply may invalidate comparison
      with retrospective data on the advisability of attempting to correct this
      anomaly. The present paper provides data against which treatment of infants with
      pulmonary atresia and ventricular septal defect presenting during the next decade
      can be compared.

PMID- 8650014
TI  - Scimitar syndrome: five cases examined with two-dimensional and Doppler
      echocardiography.
AB  - Five patients with scimitar syndrome (three boys, two girls) with a mean age of
      3.4 years (range 6 months to 11 years) were studied with two-dimensional and
      Doppler echocardiography. Four-chamber apical and parasternal short- and long
      axis views were obtained, in addition to subcostal views. The anomalous drainage
      was seen entering the inferior vena cava below the diaphragm in three patients,
      and in two cases the inferior vena cava was considered normal (both patients had
      supradiaphragmatic drainage). The anomalous flow velocity pattern was monophasic
      without reverse flow at atrial contraction. The peak velocity ranged from 0.6 to
      1.0 m/s (mean 0.8 m/s). In one case an ostium secundum atrial septal defect was
      detected. It is concluded that two-dimensional and Doppler echocardiography
      permit demonstration of the anomalous drainage, analyze the anomalous flow
      velocity pattern, and detect other associated cardiac abnormalities.

PMID- 8650015
TI  - Innominate artery enlargement in congenital arteriovenous fistula with subsequent
      tracheal compression and stridor.
AB  - To demonstrate that airway obstruction may be the first manifestation of a
      congenital fistula, a female newborn is reported who presented with increasing
      stridor during her first 23 months of life. Magnetic resonance imaging and
      Doppler echocardiography revealed an enlarged innominate artery with turbulent
      flow. Angiography demonstrated an arteriovenous fistula between the right
      subclavian artery and right subclavian vein and an abnormal origin of the right
      internal thoracic artery. Bronchoscopy showed a pulsating compression of the
      middle section of the trachea. Closure and division of the fistula and
      aortotruncopexy were performed. The stridor disappeared, and there was marked
      relief of the tracheal obstruction, confirmed by bronchoscopy. It is concluded
      that, a search for enlarged vessels is necessary in cases of airway obstruction.

PMID- 8650016
TI  - Left innominate vein compression by a brachiocephalic artery anomaly.
AB  - An unique case of left innominate vein compression by a leftward origin of a
      brachiocephalic artery in conjunction with an aberrant right subclavian artery
      anomaly occurred in a young patient. Aortography and magnetic resonance imaging
      were invaluable in arriving at a diagnosis.

PMID- 8650017
TI  - Fatal pneumonia complicating hypothermia for the treatment of postoperative
      junctional ectopic tachycardia.
AB  - A 5-month-old male infant developed junctional ectopic tachycardia after surgical
      repair for ventricular septal defect. Management with sotalol and moderate
      hypothermia was initially successful, but he died from Pseudomonas aeruginosa
      pneumonia. The safety of treatment with hypothermia is discussed.

PMID- 8650018
TI  - Acute pulmonary hypertension complicating the arterial switch procedure.
AB  - Two neonates undergoing arterial switch procedure developed life-threatening
      pulmonary hypertension intraoperatively. In one patient, bradycardia,
      hypotension, and electrocardiographic (ECG) evidence of myocardial ischemia
      suddenly occurred 20 minutes after uneventful weaning from cardiopulmonary
      bypass. Lifting a palpably hypertensive main pulmonary artery (MPA) resulted in
      reproducible hemodynamic improvement. Because the patient was already on full
      ventilatory support and a nitroglycerin infusion, the MPA was suspended onto the
      anterior chest wall. In the other patient, after removal of intraoperative
      drapes, severe generalized swelling and cyanosis were noted. The central venous
      pressure had risen to 25 mmHg, and the PO2 had dropped to 52 mmHg on 100% FIO2.
      The systolic arterial pressure and ECG remained normal. Immediate reexploration
      revealed a palpably hypertensive MPA. The coronary arteries implanted more
      laterally on the neoaorta were uncompromised. Amrinone loading and infusion
      produced immediate improvement. We believe that surgeons should be aware that
      pulmonary hypertension can cause coronary artery compression and right heart
      failure in neonates undergoing the arterial switch procedure. Lateral placement
      of the coronary artery and aggressive use of pulmonary vasodilators can minimize
      the problem.

PMID- 8650019
TI  - Unusual form of total anomalous pulmonary venous connection with double drainage.
AB  - A patient with complex congenital heart disease was diagnosed by two-dimensional
      echocardiography. Total anomalous pulmonary venous connection (TAPVC) was
      suspected because of the results of two-dimensional echocardiography, but the
      exact anatomy was delineated by cineangiocardiography as an unusual form of TAPVC
      with double drainage or connections to the left superior vena cava at nearly the
      same level. The clinical implications and possible embryogenesis for such a
      condition are discussed.

PMID- 8650020
TI  - Interruption of aortic arch and hypoplastic left heart syndrome.
AB  - Interruption of the aortic arch and hypoplastic left heart syndrome in the same
      patient is exceptional. In the combined collections of the Registry of
      Cardiovascular Disease (St. Paul, Minnesota, U.S.A.) and the Registry of
      Congenital Heart Defects of the Rijksuniversiteit Gent (Gent, Belgium) three
      specimens were found with this unusual combination. These cases are herein
      described and compared with four similar cases previously reported in the
      literature.

PMID- 8650021
TI  - [Activity of plasminogen activator inhibitor (PAI-1) in plasma of women treated
      after menopause with hormone replacement therapy].
AB  - Prospective studies that included 48 postmenopausal women on hormonal replacement
      therapy (transdermal estradiol and medroxyprogesterone acetate orally) was
      performed. Plasma activity of plasminogen activator inhibitor (PAI-1), levels of
      fibrinogen and serum lipids profile was measured before, after 6 and 12 months of
      continuous treatment. Plasma activity of PAI-1 showed significant decrease after
      6 month of therapy. Plasma fibrinogen concentration significantly decreased (p <
      0.05) after 12 months of treatment (271.27 +/- 71.08 vs. 238.33 +/- 34.48 mg/dl).

PMID- 8650023
TI  - [Late complications of subarachnoid hemorrhage from ruptured aneurysms treated
      with early and delayed surgery].
AB  - Result of studies on remote sequele of SAH from ruptured brain aneurysms are
      presented. The investigation have been pointed at the character, range and
      intensity of some changes in CNS initiated by SAH and resulting from this
      bleeding. The material comprised of 110 patients: 48 out of this number having
      been operated on within 72 hours from initial bleed, while 62 have had surgery in
      delayed term. Three methods of investigations were applied: 1. Angioscintigraphy
      of the brain. 2. Computerized tomography. 3. Clinical evaluation according to GOS
      (Glasgow Outcome Scale). The results obtained seem to give reasons to assumption
      that SAH initiates the gradual process of degradation of the CNS tissues. The
      blood extravasated to the subarachnoid space following aneurysm burst sets in
      motion a chain of events leading to: 1) impairment of brain arteries reactivity
      on elevation of pCO2, 2) intensification of brain atrophy. The intensity of the
      above mentioned phenomena is proportional to the severity of clinical course of
      SAH. It came out that timing of surgery has influenced the remote postoperative
      results less than it had been expected.

PMID- 8650022
TI  - [Identification analysis using PCR of fresh or fixed and paraffin wax embedded
      tissue].
AB  - The aim of the work was a selection of the best method of DNA extraction from
      soft tissues, and than application of this method to the fixed and paraffin wax
      embedded tissue. Isolated DNA was amplified using PCR method. Amplification was
      done for amelogenin locus (sex specific sequences) and some polymorphic systems
      like mini- and microsatellites. It was found that it is possible to amplify 788
      and 977 bp long amelogenin fragments, using DNA isolated from fixed and paraffin
      wax embedded tissue stored for two years. The case of identification of unknown
      person (victim of fire at Gdansk Shipyard show room) on basis of DNA isolated
      from soft tissue was presented.

PMID- 8650024
TI  - [Evaluation of long term results of surgery for myasthenia gravis (with regard to
      electrophysiological studies)].
AB  - The study aimed to quantify clinical and electrophysiological results of
      thymectomy. The study included 43 patients (14 men and 29 female) with the peak
      age of onset of symptoms between 20 to 40 years. The mean duration time after the
      thymectomy was 36 months. In all the patients the supramaximal repetitive nerve
      stimulation was performed. In 31 patients the clinical results of thymectomy were
      good (remission or reduced post operative dosage of drugs). The abnormal
      decrement in repetitive nerve stimulation was detected in 38 patients. The study
      demonstrates that clinical improvement after thymectomy is not equal to
      normalization of neuromuscular junction and clinical remission did not predict
      the final course of myasthenia.

PMID- 8650027
TI  - [History of medicine in the postgraduate education of physicians--practical
      probes to realization].

PMID- 8650026
TI  - [Clinical usefulness of auditory brainstem responses in patients with
      sensorineural and mixed hearing loss].
AB  - The brain stem response (ABR) and pure tone audiometry was recorded in to
      patients: 23 with sensorineural and 17 with mixed hearing loss. The control group
      included 10 males and 10 females. The presented method (ABR) shows to be very
      useful for objective estimating the level of hearing lose and location of failure
      in auditory pathways. Particular statistics analysis of obtained results (wave V
      latency-intensity function) shows high correlation with a pure tone audiometry.

PMID- 8650025
TI  - [Results of conservative treatment for regressive vesicoureteral reflux in
      childhood].
AB  - The study involved 112 children with 169 confirmed vesicoureteric reflux grades
      I, II, III. During anti-bacterial treatment which lasted at last two years,
      spontaneous regression occurred in 82% of the vesicoureteral reflux. Renal scars
      were observed in 8% of the cases. Initially urinary tract infection was diagnosed
      in 84% of the children. This figure was reduced to 8% after anti-bacterial
      treatment. 54% of the observed children had associated diseases (anaemia, chronic
      enteropathy, bronchitis and pneumonia). The results confirmed the efficiency of
      anti-bacterial treatment in children with vesicoureteral reflux grades I, II,
      III.

PMID- 8650028
TI  - [Thyroid cancer in material of the II Department of Surgery, Medical University
      of Gdansk].
AB  - The aim of study is an evaluation of the diagnostic methods and results of
      surgical treatment 202 patients suffered from thyroid cancer. Those patients were
      operated on in II Department of Surgery Medical University of Gdansk in the years
      1950-1993. There were 146 female and 56 males. Most frequently histological
      finding was papillar cancer--71 cases, follicular cancer in 57 cases, medullar
      cancer in 31 cases and anaplastic cancer in 43 cases. FNB diagnosis of the cancer
      was established 89% of the patients before operation, during operation in 96%
      cases. In the majority of the patients with papillar cancer total thyroidectomy
      were carried out but the medullar and anaplastic cancer this treatment was
      possible only in small numbers of cases. In majority of those patients adjuvant
      treatment was performed. 128 patients with well-differentiated thyroid cancer was
      treated 131. Radiotherapy have been applied in all patients with medullar and
      anaplastic cancer. In cases of well-differentiated thyroid cancer the serum
      thyroglobulin level was also determined.

PMID- 8650030
TI  - [Gdansk HIV-AIDS project, yesterday, today and future].
AB  - Medical care project for HIV positive and AIDS patients in Gdansk voivodship was
      established in 1988 in the Clinic for Infectious Diseases of Gdansk Medical
      University. The aim of this modern and multidirectional program was to provide
      full medical care for HIV/AIDS patients and introduce effective prophylaxis
      against spread of HIV infection. According to the project-clinical ward,
      outpatient clinic for HIV positive and AIDS patients, diagnostic and laboratory
      units, were established. Close cooperation including specialistic and general
      medical care, was set with detoxication ward, rehabilitation centers for drug
      addicts, prison medical services and the Korczak Orphanage. Education of medical
      staff and some social groups was provided (teachers, teenagers of secondary
      schools, journalists, police employees). Clinical ward for HIV positive patients
      who are in need of inpatient medical care is localized in the Clinic for
      Infectious Diseases of Gdansk Medical University. The ward has 16 double - bed
      Melcer's boxes which are used for other HIV/AIDS patients according to present
      needs. Free beds are used for HIV negative patients. HIV/AIDS Outpatient Clinic
      is localized in Venerologic Outpatient Unit. This was because of some
      psychological, social, professional and organization aspects. Outpatient Clinic
      staff is responsible for first patients' examination. Serological diagnostics of
      HIV infection is follow up for everyone (anonymous testing is possible); testing
      for STD is available also. Diagnostic laboratory base for clinical ward and other
      units are the laboratories of Gdansk Voivodship Hospital for Infectious Diseases.
      Clinic for Infectious Diseases supervises all co-operating units. These are the
      following: 10-beds detoxication ward for drug addicts in Psychiatric -
      Neurological Hospital "Srebrzysko", 70-80 places in rehabilitation centers for
      drug addicts in Zapowiednik and Smazyno, remand prison ward for HIV positive
      patients (this is the first ward established in Poland, thanks to our initiative,
      in 1990). One of very important units of our Center is the Korczak Orphanage for
      children aged 0-7 years, which is subjected to Voivodship Health Department. This
      orphanage is the place for children with positive HIV serology from the whole
      Poland. Children who need inpatient medical care, among them AIDS children, are
      admitted to the Clinic for Infectious Diseases and can be diagnosed and consulted
      in all units of Gdansk Medical University. In 1992 the co-operation with Gdansk
      homosexual society represented by the Gdansk Initiative (a submit of Lambda
      organization), was established. Education program is the next very important part
      of the Clinical and Diagnostic HIV/AIDS Center work. Until now medical staff and
      Education Department staff were mainly concerned. It is planned to establish
      Voivodship Social Needs Outpatient Clinic which would continue all hitherto
      activities, which would be extended by social law counseling. Such outpatient
      clinic would facilitate education activity. It would be the base for medical
      research on social pathology and HIV/AIDS related problems.

PMID- 8650029
TI  - [Evaluation of acceptance rate and outcome of renal replacement therapy in
      patients with diabetic nephropathy--multicenter study].
AB  - Development of dialysis methods and progress in kidney and pancreas
      transplantation allowed to treat an increasing number of patients suffering from
      diabetic nephropathy (D.N.). This report evaluates availability and results of
      treatment in these patients. 31.12.93 in Gdansk and Bydgoszcz area there were
      treated 519 patients, including 43 (8.2%) with D.N. It is impossible to evaluate
      the demand for renal replacement therapy in patients with D.N., because there is
      no exact data concerning diabetic patients with progressing renal failure. Up to
      now 88 patients with D.M. (68 with IDDM, 20 with NIDDM) were treat in this area.
      Most of them (92%) were treated with hemodialysis is and only a few with CAPD, 13
      patients received a kidney graft. The average patient survival on dialysis
      treatment in NIDDM patients was 15 months and in IDDM patients was 11 months.
      Deaths were mainly caused by cardiovascular complications. The results of renal
      replacement therapy in these patients cannot be compared with data from other re
      ports, because the treatment was introduced at advanced stage of D.N. in patients
      with systemic complications (serum creatinine in IDDM was 9.7 md% and in NIDDM
      was 6.2% mg%). Following conclusions can be drawn from our observations: 1. There
      is a need for close cooperation between diabetologist and nephrologist in repeat
      of evaluation of the demand for renal replacement therapy and time for its
      institution in a particular patient. 2. The choice of method of renal replacement
      therapy depends on clinical findings in a particular patient but also on methods
      available in a particular center. 3. Improvement of therapy outcome can be
      achieved primarily by earlier institution of dialysis (serum creatinine below 5
      m5%).

PMID- 8650031
TI  - [Clearance, reabsorption and excretion of free and bound L-carnitine in
      children].
AB  - Acylcarnitines are by-products of fatty acid, pyruvate and some xenobiotics
      metabolism excreted in urine. We compare the renal handling of free and
      acylcarnitine in a group of 15 healthy children in relation to sodium and urea
      excretion and to sodium fractional tubular reabsorption (FTR%) and fractional
      excretion (FE%). Urea and sodium were determined by routine laboratory method;
      free and acylcarnitines by enzymatic one. FTR% and FE% were determined as a % of
      filtration load. Linear regression was used for calculation of correlation
      coefficient "r" from paired data. Low correlation (r = 0.25; p = 0.42) between
      urea and free carnitine excretion was observed; for excretion of acylcarnitine
      and urea correlation was much higher (r = 0.61; p < 0.03). Excretion of free
      correlation was negatively correlated with sodium FTR (r = -0.86; p < 0.001) and
      there was no correlation at all for acylcarnitine excretion and sodium FTR. It
      can be assumed:-neither excretion nor reabsorption of acylcarnitines are Na
      dependent;-renal handling of free and total carnitines proceeds on different
      mechanisms.

PMID- 8650032
TI  - [Antibiotic-associated diarrhea in light of personal observations].
AB  - Examination was performed in a group of 539 adult patients with diarrhea admitted
      to the Department of Infectious Diseases in Gdansk from 1991 to 1994. The group
      of 17 patients with antibiotic-associated colitis (AAC) was analysed. The
      antibiotics responsible for AAC were lincosamides, cephalosporins and
      penicillins. AAC was diagnosed by anamnesis, medical examination and detection of
      toxin A Clostridium difficile in stool samples. The contrast enema, colonoscopy
      and histopathological examination of colon mucosa were performed only in severe,
      protracted cases. The course of disease was mild in 2 cases, moderate in 13 and
      severe in 2 patients. Relapses of AAC were observed in 2 cases. Initial treatment
      of AAC included discontinuation of the antibiotic therapy that precipitated the
      disease and the replacement of fluid and electrolyte losses. Moreover, oral
      metronidazole and oral vancomycin were administered. All patients made a complete
      recovery.

PMID- 8650033
TI  - [Mini mental state as a method of diagnosing early dementia].
AB  - The aim of the present paper was to evaluate the validity of the Mini Mental
      State as a screening instrument for the diagnosis of dementia in comparison with
      the DSWM III R criteria for dementing syndromes. We conducted a case-control
      study of 335 person--89 had a diagnosis of primary progressive dementia, 76 had a
      diagnosis of vascular dementia. The data show that the Mini Mental State is
      useful clinical instrument for the preliminary screening for the diagnosis of
      dementia.

PMID- 8650034
TI  - [Renin subgroups in borderline hypertension].
AB  - The study was carried out in 42 healthy men--control group and in 21 patients
      with borderline essential hypertension. It was found that the patients differ in
      hemodynamics from the control group. The group patients as a whole show
      significantly higher blood pressure, lower plasma volume and shorter total
      transit time compared with normotensive men. Division the patients on the renin
      subgroups revealed significant difference. High renin patients had hyperkinetic
      circulation. Patients with normal renin had significantly elevated total
      peripheral resistance. These results suggest that renin-angiotensin system no
      played an essential role in pathogenesis of borderline hypertension.

PMID- 8650035
TI  - [Advantages and controversies regarding physiologic electrostimulation of the
      heart in sinus node disease].
AB  - Pacing mode in sinus node disease (SND) is one of controversies in cardiac
      pacing. We evaluated atrial pacing mode (AAI) in SND patients (pts). Between 1985
      and 1994 AAI pacemaker was inserted in 179 pts due to symptomatic SND of varied
      etiology. RESULTS: The majority of pts (91.6%) were free from syncopal episodes
      after AAI implantation, in 15 pts (8.4%) syncopes were occasionally observed due
      to disturbances in pacemaker function, AVB III degrees, vaso-vagal syndrome,
      orthostatic hypotonia or atherosclerotic insufficiency of the cerebral
      circulation. In 49 (51%) out of 96 pts with brady-tachy syndrome (BTS), episodes
      of supraventricular tachyarrhythmia were not observed after AAI insertion and in
      the majority of the remaining pts the frequency of the episodes decreased
      significantly. Chronic atrial fibrillation developed in 5 (5.2%) pts. In some of
      the pts the symptoms related to chronic heart failure decreased or disappeared. A
      reoperation was performed in 44 (24%) pts due to electrode dislocation or
      fracture, atrio-ventricular conduction disturbances, an increase in pacing
      threshold or due to local infections. During the follow-up period 13 (7.3%) pts
      died of reasons unrelated to cardiac pacing therapy. CONCLUSION: In the majority
      of SND pts AAI pacing mode prevents from syncopal episodes caused by sinus node
      disfunction. It decreases the symptoms of heart failure in SND pts and stabilizes
      the sinus rhythm in the majority of BTS pts. Complications accompanying AAI do
      not post a major threat for the pts and can be easily resolved. They should by no
      means discourage from AAI implantation in SND.

PMID- 8650036
TI  - [Myocardial infarction in children].
AB  - Twenty nine patients with myocardial infarction (MI) of different etiology were
      analysed. The diagnosis was based on routine clinical examination with ECG
      predominance. In certain cases cardiac catheterisation with cineangiography and
      scintigraphy were performed. Myocardial infarction the most often was observed in
      Bland-White-Garland syndrome (15 cases). In 5 cases MI was found in heart muscle
      disease, in 3 cases in critical aortic stenosis, and in singular cases in
      progeria syndrome, bacterial endocarditis and after surgical procedure. In 2
      older children the etiology of MI was difficult to establish. Clinical picture of
      MI in children is different in comparison with adult person. Chest pain, typical
      for MI in adults, is difficult to diagnose particularly in infants. Localisation
      of MI is also different, predominant is anteroseptal, lateral, subendocardial and
      papillary muscle infarction. Relative small number of MI in children is due to
      difficulty in interpretation of clinical picture and to low popularity of ECG
      examination in this group of age.

PMID- 8650037
TI  - [Reference values for peripheral blood morphology in countryside population of
      northern Poland].
AB  - Reference values for hematological parameters were determined in countryside
      population living in the area surrounding Zarnowieckie Lake. Randomly selected
      population of 1065 individuals were divided into 11 groups: children from 0 to 3
      years, 4 to 7 years and 8 to 11 years; and males and females from 12 to 20 years,
      21, to 40 years, 41 to 55 years and older than 56 years. In the paper are
      presented reference values estimated on Technicon H1 analyser for 8 red cells
      parameters, 3 platelets parameters and absolute values for white blood cell and
      differential counts. Red cell parameters values were changing with age and sexes,
      and were similar to determined by the others. In examined population white blood
      cell counts were higher then in earlier reports. Moreover in males over 40 WBC
      were higher than in females. Neutrophil counts were parallel to white blood
      cells. Lymphocyte and eosinophil counts were decreasing with age, and were not
      depending on sex. Platelet counts were decreasing with age, with concommitant MPV
      increase.

PMID- 8650038
TI  - [Heart conduction system in the human in light of personal research].
AB  - A new model of the atrioventricular junction was developed by Anderson et al, of
      which each element has clinical significance and requires more specific research
      into its morphology and topography. Observations were carried out on materials
      consisting of 200 human hearts of both sexes of various ages (from 16 weeks of
      fetal life to 97 years of age). Histological slides were stained by Masson's
      method in Goldner's modification. It was concluded that the atrioventricular node
      consisted of two layers in all groups of examined hearts: cells of the compact
      area and transitional cells. With age, these cells change their morphology,
      especially in the transitional layer. Morphologically, within the
      atrioventricular bundle were differentiated. The topography of the
      atrioventricular node is dependent on the age of the examined heart. As much as
      in human adults it is found entirely within the triangle of Koch, in fetal and
      children's hearts its elements of its left branch were found in the false chordae
      tendinae of the left ventricle. The above observations suggest that in the case
      of younger hearts the triangle of Koch does not represent an absolute margination
      for the elements of the conductive system of the heart, which in the case of
      cardiac surgical procedures and ablations can in some percent, be the cause of
      iatrogenic complications.

PMID- 8650039
TI  - [Clinical course and risk of fungal infections development in children with
      treated with chemo- and radiotherapy for solid tumors].
AB  - The authors estimated the incidence of mycotic infections among children patients
      with histological diagnosis of solid tumors during the period of neutropenia.
      Superficial mycoses including mucoses were observed in 35.3% of analysed
      patients, while a disseminated mycotic infections of a severe clinical course
      were seen in 2.9% neutropenic patients. Prophylactic administration of Diflucan
      (1-2 mg/kg/24h)(fluconazole) in neutropenic patients proved efficient in great
      majority of children, preventing the occurrence of severe mycotic complications.

PMID- 8650040
TI  - [Evaluation of bone marrow grafts and hemopoietic chimerism using PCR
      hypervariable sequencing with variable number tandem repeat sequences].
AB  - PCR amplification of highly polymorphic variable number of tandem repeat (VNTR)
      sequences could be particularly useful in documentation of engraftment and
      characterization of chimerism following allogeneic bone marrow transplantation
      (BMT). We have monitored a 31-year old male patient treated with allogeneic BMT
      for chronic myeloid leukaemia. The recipient's DNA samples were obtained before
      the transplant and on day 28, 100 and 150 after BMT. The donor's DNA (patient's
      sister) was also obtained as a reference. ACT B2 locus on chromosome 6 was chosen
      for the analysis. In addition a deletion polymorphism locus within the
      pseudoautosomal region of chromosome X and Y (amelogenin gene) was also analysed.
      On day 28 after BMT both donor and recipient specific alleles were detected in
      the recipient's sample. However, on day 100 and 150 the recipient specific
      alleles were no longer detectable. The aforementioned pattern was observed for
      both markers analysed. The disappearance of recipient specific alleles correlated
      with clinical symptoms of chronic graft-versus host disease.

PMID- 8650041
TI  - [Longitudinal studies on the effect of fluorine in drinking water on the
      periodontium during development and maturity].
AB  - Longitudinal clinical studies of the periodontium have been carried out in the
      same subjects aged 14 and again 26 years old who-since their birth till the time
      of maturity-were drinking water with a trace, overoptimal amount of fluorine.
      Fluorine has been shown to decrease susceptibility of the periodontium tissues to
      pathogenic factors.

PMID- 8650042
TI  - [Wilson's disease in personal material--disturbances in hemostasis].
AB  - Genetically determined impairment of copper excretion from the liver into the
      bile in Wilson's disease (WD) cause that "free copper" is accumulated in toxic
      amounts not only in the liver, but also in other organs. In WD liver biopsy often
      could not be made because of serious disturbances in hemostasis. The aim of the
      study was: a) to demonstrate our 9 patients with various form of WD. b) to
      examine some blood clotting factors and compare the results with these obtained
      in other liver diseases. The diagnosis of Wilson's disease was made on the basis
      of disturbed copper metabolism. Among our 9 patients (8 women and 1 man, between
      17-33 years old) we diagnosed: 3 patients with fulminant Wilson's disease with
      all day deep jaundice, hemolytic anemia, haemorrhagic diathesis and liver
      failure, died, 2 patients with active chronic hepatitis, hemolytic anemia and
      haemorrhagic diathesis, 2 patients with liver cirrhosis, haemorrhagic diathesis,
      Kayser-Fleisher ring, neuropsychiatric syndrome, 2 asymptomatic patients without
      haemorrhagic diathesis. The prothrombin index and the factors of prothrombin stem
      (II, V, VII, X) were lower than in other kinds of cirrhosis. After treatment with
      d-penicillamine the clothing factors returned near to the norm, similar as the
      biochemical and immunological results.

PMID- 8650043
TI  - [Diagnostic difficulties in the case of a brain tumor of embryonic origin in an
      18-year old man].
AB  - A case of an 18-year-old man with symptoms of diabetes insipidus and signs of
      hypothalamus injury was presented. The computerized tomography of the head and
      the examination of the cerebrospinal fluid suggested an inflammatory process.
      After a few-month observation, due to the increased level of tumor markers (human
      chorionic gonadotropin-HCG) and the results of the MR imaging, a tumor of an
      embryonic origin was recognized. The type of the tumor is unknown because a
      biopsy specimen for the histopathology could not have been taken.

PMID- 8650044
TI  - [Specific chromosome aberrations in human soft-tissue tumors and their diagnostic
      significance].
AB  - Recent cytogenetic studies have revealed that several types of benign and
      malignant human soft tissue tumors are characterized by highly specific
      chromosome abnormalities. In this article, we review the primary and secondary
      chromosome aberrations detected in lipoma, uterine leiomyoma, Ewing sarcoma,
      rhabdomyosarcoma, myxoid liposarcoma, synovial sarcoma, and clear cell sarcoma of
      tendons and aponeuroses. The primary aberrations are unique for the particular
      tumor type and therefore are of diagnostic value. Most recent molecular studies
      indicate that several sarcoma-specific translocations result in the gene fusion
      and creation of tumor-specific proteins that are novel DNA transcription factors.

PMID- 8650045
TI  - [Development of renal transplantation in the Gdansk center].
AB  - The kidney transplantation is one of the renal replacement therapy methods, which
      prolongs live of the patients with the end stage renal disease for many years.
      Moreover, this method is well known, safe and not so expensive as dialysotherapy.
      Our purpose was to present the 15-year activity of the transplantation center in
      Gdansk. The first renal transplantation took place on the 31st of March 1980 and
      there have been 137 renal transplantations in Gdansk until now. We can divide the
      time between the 31st of March 1980 and the end of 1994 into two periods: I from
      31.03.80 to 31.12.89 and II from 1991 to 1994. During the first were 46, and
      during the second were 91 renal transplantations performed. It means that since
      the second half of 1991 the activity of the center in Gdansk has increased. The
      graft function was noted in 29 patients (63%) during the first period and in 75
      (82%) during the second. The acute graft failure was observed in the most of the
      cases mentioned above. The 5-year living of the transplanted patients and the
      dialysed patients is comparable and amounts to 90%. Infections were the main
      reason of death during the first period, and cardiovascular complications during
      the second. The 5-year graft's functioning is 60%. Nowadays the results of the
      kidney transplantation center in Gdansk are good and comparable with the results
      of other centers in Poland and Europe. Our center, as similar ones in Poland is
      prepared to extend the kidney transplantation activity. So it is necessary to
      intensify an effort to gain more organs for transplantations.

PMID- 8650046
TI  - [Biophysical basis and clinical use of catheter guided electric high frequency
      ablation in treatment of cardiac arrhythmias].

PMID- 8650047
TI  - [Deontology of the medical expert].
AB  - The authority of prosecuting organ to choose the expert, set his task and verify
      the following opinion is defined. The qualities of the medical expert and his
      duties are described, referring to: -his expertise; -his morality; -his ability
      to issue an independent (objective) opinion. Detailed rules, which can be
      ascribed to a specific medical expert's deontological code, are listed and
      explained.

PMID- 8650048
TI  - [Allotransplantation of the parathyroid in patients without immunosuppression].
AB  - Eighteen patients with postoperative insufficiency (after thyroid operations)
      have been treated with cultured, hormonally active, living and ABO the same group
      type parathyroid cells. Explants had been taken from 2 operated patients with
      secondary hyperparathyroidism. Hormonal activity of the transplanted parathyroid
      cells under the fascia of the brachio-radialis muscle has been confirmed by
      clinical, biochemical tests and the level of PTH in blood serum from the vein of
      non-grafted arm. Hormonal activity of the graft was variable but lasted up to 14
      months.

PMID- 8650049
TI  - [Chronic lymphatic leukemia from B CD5+ cells: characteristics, clinical and
      laboratory features, and immunophenotyping].
AB  - Fifty four cases of CLLB were studied from 1st of April. 1990 to October 30,
      1993; 35 male and 19 female (M:F = 1.8:1) in age 39-76 years (median age = 62
      years). 81% patients had lymphadenopathy, 30%--hepatomegaly, 31% splenomegaly,
      24% had allergic symptoms, 24% had anaemia (7% AINH). 13% thrombopoenia (2%
      autoimmunologic thrombopoenia). In all cases immunological phenotype of
      peripheral blood lymphocytes was determined, 100% patients had B cells CD5+, 70%
      lymphocytes sIg+, 97%-CD19+, 73%-CD23+, 67%-CD22+, 82%-HLADr, 10%-71(TR90), CD10
      was negative. There was negative correlation between B CD5+ cells and life span
      (p < 0.03). There was positive correlation, between CD23 and bulky diseases (p <
      0.01). Percentage of T cells with CD2+, CD3+, CD4+, CD8+ and CD4:CD8 was
      diminished. Lymphocytosis T with antigens CD2+, CD3+, CD4+, CD8+ was enhanced.
      There was found a positive correlation between lymphocytosis CD2+ (p < 0.00009),
      CD4+ (p < 0.008), CD8+ (p < 0.0008) and blood lymphocytosis and positive
      correlation between T lymphocytosis CD2+ (p < 0.02), CD4+ (p < 0.002) and
      lymphocytosis bone marrow.

PMID- 8650050
TI  - [Evaluation of treating anemia in patients undergoing chronic dialysis with small
      doses of human recombinant erythropoietin].
AB  - The aim of the study was to assess the efficacy of low dose subcutaneous (sc)
      recombinant human erythropoietin (rHuEpo) therapy in hemodialysis (hd) patients,
      with particular emphasis on their quality of life. 25 anemic (Ht < 25%) hd
      patients with end-stage renal disease were given small sc doses of rHuEpo once or
      twice weekly for 12 months. During first 4 months of the therapy there was a
      significant increase of Ht (21.1 +/- 0.5 vs 28.5 +/- 0.6%; p < 0.0001) and serum
      hb (6.68 +/- 0.12 vs 8.51 +/- 0.18 g/dl; p < 0.0001) at mean induction dose of
      52.5 +/- 2.5 IU/kg/week and this was maintained with a mean dose 67.0 +/- 10.5
      IU/kg/week. RHuEpo was effective in 24 patients; all of them required no blood
      transfusions after starting the therapy. In majority of patients an substantial
      (p < 0.01) improvements in exercise tolerance, well-being, cold tolerance, sexual
      satisfaction and libido were observed, although sexual hormones profile revealed
      no significant changes during the treatment. Within first 6 months of the study
      cardiac index decreased substantially (p < 0.01), mainly because of stroke volume
      reduction, but after one year this hemodynamic improvement was noted only in
      patients who maintained a stable blood pressure. Hypertension worsened in 31% of
      patients. Low-dose s.c. rHuEpo: (1) is effective and safe treatment for anemia in
      hds patients, sufficient to abolish blood transfusion requirements; (2) produces
      significant improvements in quality of life; and (3) allows for 50% costs
      reduction.

PMID- 8650051
TI  - [Transcutaneous balloon angioplasty in the treatment of subclavian steal
      syndrome. Characteristics of vertebral basal flow with transcranial Doppler
      technique].
AB  - Subclavian steal syndrome (SSS) appears when the origin of the subclavian artery
      (SA) is occluded or stenosed. Introduction of transcranial Doppler sonography
      (TCD) provided an opportunity to evaluate parameters of the blood flow in the
      vertebral (VA) and basilar artery (BA). Measurements of blood flow velocities
      performed at rest and after the brachial hyperemia test allow one to classify
      hemodynamic types of SSS. The aim of the study was to categorize types of steal
      and to compare the differences of flow patterns before and after percutaneous
      transluminal SA balloon angioplasty (SA-PTA). Fourty-eight patients with
      angiographically confirmed SSS (aged from 27 to 68 years, mean 53; 2/1 f/m ratio)
      were examined with 2 MHz range-gated, pulsed transcranial Doppler device (TC 2
      64B EME). Both VA and BA were evaluated by the transoccipital approach at rest
      and during the brachial hyperemia. In 5 cases (10.4%) permanent reversal blood
      flow in the BA was observed (complete basilar steal). In flow in the BA blood
      flow was in the normal direction at rest and altered (reversed or decreased) when
      induced with brachial hyperemia test (transient basilar steal). In the next 14
      patients (29.2%) permanently reversed VA blood flow was observed with only a
      slight or no alterations of the BA flow after the hyperemia test (complete
      vertebral steal). In the last 19 cases (39.6%) alterations of the VA blood flow
      without changes in BA flow were observed (latent vertebral steal). Between 1991
      and 1994 twenty seven symptomatic patients with different hemodynamic types of
      SSS were treated with SA-PTA. TCD evaluation of VA's and BA using the hyperemia
      test was performed before, 3 to 7 days and 3 months after morphologically and
      hemodynamically successful subclavian artery balloon PTA. Normal results of
      vertebrobasilar examinations were obtained in 26 cases after this procedure. In
      one case the latent vertebral steal was detected. The 28 months mean follow-up
      revealed no significant changes in TCD flow patterns recorded from VA's and BA.
      After collecting data of about 60 patients with SSS we examined with TCD we
      conclude that: in patients with a hemodynamically significant SA stenosis the
      presence of reversed ipsilateral VA blood flow (a radiologic steal) its not a
      good determinant of either the presence or type of presenting symptoms and after
      successful PTA or recanalisation and PTA of SA in almost all cases we examined
      close to normal TCD recordings in BA and VA.

PMID- 8650052
TI  - [Usefulness of scintigraphy using 99mTc-MIBI for localization of parathyroid
      adenoma].
AB  - Aim of this study was to evaluate the significance of 99mTc-MIBI scintigraphy in
      detection of parathyroid adenomas in patients with primary and primary recurrent
      or persistent hyperparathyroidism after surgical treatment. The images of the
      neck and mediastinum were taken 20 minutes and 2 hours after i.v. injection of
      the radiopharmaceutic. Result of the scintigraphy was defined as positive when
      the initial high 99mTc-MIBI uptake persistent in the region of the neck or
      mediastinum. At this time the radioactivity from thyroid gland declined
      significantly. Parathyroid adenoma was confirmed by surgery in 10 out of 12 cases
      diagnosed by scintigraphy. Parathyroid imaging using 99mTc-MIBI is a promising
      procedure in the preoperative localisation of parathyroid adenomas in patient
      with hyperparathyroidism.

PMID- 8650053
TI  - [Embolization of carotid-cavernous fistulae. Technique and results of surgery].
AB  - Seventy two patients with carotid cavernous fistula (CCFs) were managed at our
      hospital during fifteen year period. Transarterial treatment of CCFs using the
      detachable balloon technique was performed in all patients resulting in clinical
      and angiographic cure in 68 patients. Fatal outcome in two patients. Surgical
      ligation of the internal carotid artery was needed also in two patients.

PMID- 8650054
TI  - [Diagnosis and treatment of Cushing's disease].
AB  - Authors present the results of surgical treatment of 63 patients with Cushing's
      disease. They evaluate various diagnostic procedures, applied to define the
      aetiology of endogenous hypercortisol. The petrosal sinus sampling for ACTH level
      is described. In the series in only 32% of patients; radiological examinations
      (including CT and MRI) showed the pituitary adenoma. Among 63 operated persons-
      43 were subjected to surgery based on endocrinological data alone. All the
      patients were operated by transsphenoidal route. Good result--endocrinological
      recovery in the treatment of Cushing's disease was achieved in 80% of patients.

PMID- 8650055
TI  - [Correlation among clinical and histopathologic criteria in selection of donors
      for orthotopic liver transplantation].
AB  - The aim of this work is to present the correlation between the initial
      microscopic pattern of the liver graft and clinical and laboratory findings. In
      the Department of General Surgery and Liver Diseases 6 specimens were taken from
      4 livers destined for planned liver transplantations. They were taken from the
      organ rinsed in UW solution, processed and stained extemporaneously. Quick HE
      staining was performed in some cases. Two livers were qualified for
      transplantation although they showed negligible histopathological changes. In one
      of these cases there was a clinical and pathological disagreement. The results of
      histological examination were crucial in qualification of the liver for grafting.
      One organ was disqualified because of negative clinical and pathological
      findings, while two other livers were disqualified after clinical examination. We
      resigned from the transplantation of liver of the last donor, who exhibited
      unsatisfactory clinical tests in spite of good pathological results.

PMID- 8650056
TI  - [Personal experience with simultaneous transplantation of pancreas segment and
      kidney].
AB  - Between February 1988 and December 1994, 25 patients underwent simultaneous
      kidney and segmental pancreatic transplantation. Diabetes type I with the end
      stage renal disease secondary to the diabetic nephropathy was the indication for
      this procedure. The original method of the four vascular anastomoses was
      introduced to prevent early pancreatic graft thrombosis. The cross section of the
      pancreatic segment was anastomosed to Roux--en Y loop in 80% cases and in 20%
      ductal occlusion with Ethiblock was performed. One-year survival rate for kidney
      and the pancreas was 81% and 57% and five - years survival rate 57% and 42%,
      respectively. One - year and five - year survival rate for the patients was 72%
      and 68%, respectively. The most serious complication leading to the graft removal
      was intrapancreatic abscess. Sepsis was the main cause of the death among
      transplant patients.

PMID- 8650057
TI  - [P-wave ekg averaging technique--a new method of selecting patients with
      paroxysmal atrial fibrillation].
AB  - The aim of study was to assess the value of signal averaged ecg for detection of
      patients (pts) at risk for paroxysmal atrial fibrillation (paf). We examined
      three groups of pts: group I-41 pts with nonvalvular paf, group II-20 pts with
      hypertension and/or ischemic heart disease without paf and group 3-26 health
      persons, without organic heart disease. In all pts the signal-averaged
      electrocardiogram triggered by P waves was recorded. Seven parameters of the
      spatial magnitude of filtered P wave were measured. Significant difference
      between group I and group II or III was found in most parameters. Using the
      method of multidimensional variance analysis we constructed "the diagnostic
      vector" in multidimensional parameters space, which was used to determine
      patients belonging to group. Total percent of right decision was 85%. These
      findings suggest that pts at risk for paf could be detected while in sinus rhythm
      by using the P wave-triggered signal-averaged ecg.

PMID- 8650058
TI  - [Transferrin and ferritin as laboratory indices of body iron deposits].
AB  - The aim of the study was to present the relation between serum parameters
      connected with iron metabolism; serum iron, transferrin and ferritin. Biochemical
      data in 126 patients were not compared with microscopic evaluation of
      erythrocytes. The tendency to decrease of serum transferrin with increased of
      serum ferritin was found. Significant relations between those proteins and serum
      iron were observed only in patients with very low ferritin values. It can be
      concluded that ferritin and transferrin may be considered as independent
      diagnostic in differential diagnosis of real (latent) and false iron depletion.

PMID- 8650059
TI  - [Parenteral nutrition at home].
AB  - Development of home parenteral nutrition (HPN) allowed for long term survival for
      patients with chronic intestinal failure, followed mainly total or near total
      small bowel resection. Own 11 years long experience with 49 HPN patients treated
      for 98 patients years with a HPN model adapted to polish conditions is presented.
      Long term survival (4 patients over 10 years) and low complications rate,
      comparable to reported from West European countries and USA, shows HPN possible
      in Poland and developed HPN model is efficient and safe method of life-restoring
      therapy with long term survival of patients with severe disturbances of
      absorption otherwise leading to death by starvation.

PMID- 8650061
TI  - [20 Years at the Central Clinical Hospital of the Medical Academy in Warsaw].

PMID- 8650060
TI  - [Effect of 16-week use of salmeterol on ECP levels, pulmonary function tests and
      bronchial hyperreactivity in patients with chronic obstructive lung disease].
AB  - The aim of the study was to compare the influence of salmeterol on lung function
      tests (VC, FEV1), bronchial hyperreactivity (PC20) and eosinophil cationic
      protein (ECP) level in serum and in sputum in 10 patients with COPD. FEV1 was
      less than or equal 70% of predicted values but greater than 0.6 L. FEV1%VC less
      or equal 60% (reversibility after 200 micrograms salbutamol between 5-15%.
      Patients were treated with 2 x 50 micrograms salmeterol for 16 weeks. Lung
      function test didn't change during the observation but hyperreactivity had
      decreased (0.08 + 0.1 microgram/ml before, 0.24 + 0.2 microgram/ml after 4 weeks
      and 0.4 + 0.16 microgram/ml after 16 weeks) ECP level had decreased in serum (53
      +/- 24 micrograms/l before, 32 +/- 12 micrograms/l after 4 weeks and 36 +/- 13
      micrograms/l after 16 weeks) and in sputum (2345 +/- 789 micrograms/g before 1342
      +/- 894 micrograms/g after 4 weeks, 1742 mu 698 micrograms/g after 16 weeks). We
      concluded that salmeterol didn't change lung function test but decreased
      bronchial hyperreactivity and decreased ECP level in serum and sputum.

PMID- 8650062
TI  - [Myasthenic crisis during pregnancy: case report and literature survey].
AB  - We report the successful use of high-dose intravenous immunoglobulins during
      pregnancy in a young woman with myasthenic crisis. To our knowledge,
      immunoglobulins in the management of myasthenic crisis during pregnancy have not
      been previously described. It is emphasized that both the patient and her fetus
      tolerated the treatment well.

PMID- 8650063
TI  - [Orthotopic liver transplantation in a patient with primary biliary cirrhosis].
AB  - In December 1994 an orthotopic liver transplantation was performed in a 46-year
      old female patient with liver failure due to primary biliary cirrhosis. The
      patient was discharged on the 31-st postoperative day. The graft was obtained at
      the multi-organ harvesting. The results of the donor's biochemical tests and the
      histological estimation of the graft tissue allowed to prognose a successful
      postoperative course.

PMID- 8650064
TI  - [Advances in liver surgery].

PMID- 8650065
TI  - [Evaluation of imaging methods used for diagnosis of abdominal aorta aneurysm].

PMID- 8650066
TI  - [Use of electrophysiologic hearing tests in clinical practice].

PMID- 8650067
TI  - [Franciszek Neugebauer's contribution to hermaphroditism studies in the human].

PMID- 8650068
TI  - [Surgical treatment of tracheal stenosis].
AB  - In the Department of General and Thoracic Surgery between 1981 and 1992 497
      patients with tracheal stenosis were treated surgically. In 19 (3.8%) cases the
      stenosis was after previous tracheostomy. In 469 patients (94.4%) the stenosis
      was caused as the result of compression by goitre and in 9 (1.8%) by neoplastic
      tumors of mediastinum. Most patients with tracheal stenosis were treated
      surgically. In 13 cases the stenosis was resected, in 3 cases T-tube was inserted
      and in 3 cases the stenosis was dilated. In patients with secondary stenosis due
      to compression by goitre subtotal thyroidectomy was performed. Early good
      immediate results in both groups of tracheal stenosis were obtained in 90% of
      cases. Late results obtained 12 months after treatment of primary tracheal
      stenosis and 4 to 48 months after treatment of secondary tracheal stenosis (due
      to goitre) revealed 90% of good results.

PMID- 8650069
TI  - Ultrastructural study of the coagulating gland of Wistar rats submitted to
      experimental chronic alcohol ingestion.
AB  - Morphological changes of coagulating gland of Wistar rats submitted to the
      experimental chronic alcoholism were noted. Ultrastructurally, it was observed
      reduction of the granular endoplasmic reticulum cisternae and nuclei with basal
      position and irregular shape. The epithelial cells presented pycnotic nuclei and
      the mitochondrial cristae disappeared, characteristic of cellular degeneration.

PMID- 8650070
TI  - Concentration of the endogenous antiandrogen epitestosterone and androgenic C19
      steroids in hyperplastic prostatic tissue.
AB  - Epitestosterone (epiT, 17 alpha-hydroxy-4-androsten-3-one), an endogenous C19
      steroid in humans, was considered for a long time as a physiologically inactive
      steroid. Recently, its antiandrogenic properties have been discovered. For the
      evaluation of its biological availability in the target organs the tissue
      concentration is of importance. EpiT, testosterone, dihydrotestosterone, and
      androstenedione concentrations in prostatic tissue were determined in 15 prostate
      samples obtained by suprapubic prostatectomy for benign prostatic hyperplasia.
      The steroids were extracted and separated by high-pressure liquid chromatography
      and determined by specific radioimmunoassay (RIA) methods. The concentration of
      epiT (mean 58.4 +/- 40.4 SD, range 14.0-144.0 fmol/mg protein) exceeded that of
      testosterone and was approximately as high as that of dihydrotestosterone. EpiT
      level increased with age and the correlation was significant (P < 0.05). It did
      not correlate significantly with testosterone but did with androstenedione and
      dihydrotestosterone (P < 0.05, each). As expected, a positive correlation was
      found between testosterone and dihydrotestosterone levels.

PMID- 8650071
TI  - Effect of prostatic growth factor, basic fibroblast growth factor, epidermal
      growth factor, and steroids on the proliferation of human fetal prostatic
      fibroblasts.
AB  - To study the relationship between androgen metabolism and the pathogenesis of
      benign prostatic hypertrophy, we purified a growth factor from benign
      hyperplastic tissue of human prostates and assayed the proliferative responses of
      human fetal prostatic fibroblasts to the purified growth factor (hPGF), basic
      fibroblast growth factor (bFGF), epidermal growth factor (EGF),
      dihydrotestosterone (DHT), and estradiol (E2). Prostatic tissue extracts were
      fractionated using heparin-Sepharose chromatography. The fraction that eluted
      with 1.3-1.7 M NaCl contained the majority of mitogenic activity. Sodium dodecyl
      sulfate polyacrylamide gel electrophoresis (SDS/PAGE) of the lyophilyzed active
      fraction showed a band at 17,000 daltons. Human prostatic fibroblasts were
      isolated from fetal prostate and tested for their proliferative responses to
      hPGF, bFGF, EGF, DHT, and E2. hPGF, as well as bFGF and EGF, did increase
      tritiated thymidine incorporation into the cultured fibroblasts. DHT(10(-7) M)
      had a significant stimulatory effect on cell growth in serum-free media after 6
      days of culture. E2(10-7 M) had no effect on cell proliferation. The combination
      of DHT and E2 showed no synergistic effect. We conclude that our purified hPGF,
      bFGF, and EGF promote cell growth directly, DHT indirectly, while E2 does not.
      The effect of DHT appears to be mediated via the increased production and/or
      secretion of growth factor(s). Possibly, the bFGF-like hPGF purified from human
      benign hyperplastic prostatic tissue is such a mediator.

PMID- 8650072
TI  - Microvascular invasion of the seminal vesicles in adenocarcinoma of the prostate.
AB  - The objective of this article is to determine the relationship between
      microvascular invasion and seminal vesicle invasion in prostatic adenocarcinoma.
      Radical prostatectomies with seminal vesicle involvement were examined
      histologically and immunohistochemically with antibodies directed against S-100
      protein and factor VIII. Microvascular invasion of the seminal vesicles showed a
      positive correlation with microvascular and capsular invasion of the prostate (P
      = 0.006 and 0.048, respectively) and lymph node metastases. Tumor progression was
      found in 8 of 14 (57%) patients with microvascular invasion of the seminal
      vesicles, compared with 3 of 22 (14%) without microvascular invasion (P = 0.001).
      Microvascular invasion of the seminal vesicles is predictive of tumor progression
      and lymph node metastases in prostatic adenocarcinoma.

PMID- 8650073
TI  - Selection toward diploid cells in prostatic carcinoma derived cell cultures.
AB  - For elucidation of the growth-regulatory mechanisms in prostatic carcinoma, in
      vitro investigations on prostatic cell cultures are required. However, one major
      problem of cell culturing is the selection of particular cell types such that the
      cell lines representing only some of the features as compared with the tumor of
      origin. We studied the chromosomal composition of 20 prostatic tissue-derived
      cell cultures and 12 original (fresh) tissue specimens that were obtained from 13
      patients with prostatic adenocarcinoma. Using fluorescence in situ DNA
      hybridization (FISH), evident clonal abnormalities were detected in 78% of the
      fresh cancer samples and in 47% of the cultured cancer samples. Of the seven
      cases revealing clonal abnormalities in the fresh cancer specimen, aneuploidy was
      detected in only two samples after cell culturing at the earliest passage
      studied. The aneuploid cell populations in the cultured samples were all lost
      during progressive subcultivation (after passage 4). Interestingly, by performing
      FISH on cytogenetic preparations aneuploidy was confined to the interphases, with
      the metaphases being found to be diploid. This finding indicates that the
      aneuploid cells have a proliferation disadvantage in cell culture resulting in an
      overgrowth of diploid cells.

PMID- 8650074
TI  - There are multiple forms of glyceraldehyde-3-phosphate dehydrogenase in prostate
      cancer cells and normal prostate tissue.
AB  - We analyzed glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in normal
      and malignant human prostate tissues, normal rat prostate, and Dunning R-3327 rat
      prostate cancer cell lines. We detected multiple forms of GAPDH in Dunning cell
      lines by two-dimensional protein electrophoresis and Western analysis. Five forms
      of GAPDH that differed by isoelectric point were detected for each of the two
      metastatic Dunning cell lines, while four or fewer forms were detected for
      Dunning cell lines with low metastatic ability. We also detected multiple forms
      of GAPDH in normal and malignant human prostate specimens by two dimensional
      protein electrophoresis and immunohistochemical analysis. GAPDH was undetectable
      in normal human prostate secretory epithelium by immunohistochemistry, but was
      abundant in nuclei of normal basal cells and stromal cells. In human prostate
      cancer specimens, there was a rough correlation between cytoplasmic staining for
      GAPDH and tumor grade, but GAPDH staining was extremely heterogeneous. GAPDH was
      abundant in nuclei of some high-grade human prostate tumors. Both of the human
      prostate cancer bone metastases analyzed with immunohistochemistry had markedly
      elevated cytoplasmic GAPDH expression. We conclude that multiple forms of GAPDH
      may play diverse roles in normal prostate tissue and in prostate cancer.

PMID- 8650075
TI  - Identification of endothelin receptors in normal and hyperplasic human prostate
      tissues.
AB  - Specific endothelin-1 (ET1) binding sites have been demonstrated in membranes
      derived form normal (NP) and benign hyperplasic (BPH) human prostate using an
      125I-ET1 binding assay. 125I saturation experiments and Scatchard analysis
      demonstrated the existence of a homogeneous population of binding sites with high
      affinity (Kd(app)) and density (B(max)), respectively, 106 +/- 15 pM and 1086 +/-
      399 fmol/mg protein for NP (n = 5) and 168 +/- 26 pM and 964 +/- 445 fmol/mg
      protein for BPH (n = 5). We demonstrated the presence of two subtypes of ET1
      receptors, ETA and ETB, by means of the following ET1 competitors: ET2, ET3, and
      BQ123 (which is selective for the ETA receptor), and IRL1620 and sarafotoxine c
      (S6c) (which are selective for the ETB receptor). The displacement curves allowed
      us to conclude that the large majority (85%) of the ET1 receptors in normal and
      hyperplasic human prostate are of the A subtype.

PMID- 8650076
TI  - Correlation between morphometric differences and norepinephrine content in benign
      prostatic hyperplasia.
AB  - Tissue norepinephrine (NE) content and quantitative morphometric analysis of
      benign prostatic hyperplasia (BPH) were evaluated in 30 patients with symptomatic
      BPH. BPH specimens were obtained by transurethral resection, and NE content was
      evaluated by high-performance liquid chromatography. The proportions of smooth
      muscle fibrous, and glandular elements were determined by the light microscopic
      stereological method. Norepinephrine content of the prostate correlated well with
      the proportion of smooth muscle component (r = 0.749, P < 0.0001). The percentage
      of fibrous tissue element was positively correlated with prostate size (r =
      0.459, P = 0.0099). Norepinephrine content and histological components did not
      correlate with subjective symptom score. Morphometrical findings and NE content
      did not correlate with uroflowmetry parameters and postvoid residual urine rate.
      In conclusion, NE content of the prostate was probably determined by the amount
      of smooth muscle element in BPH tissue. The fibrous tissue element was increased
      in large hyperplastic tissue. The severity of BPH could not be explained by
      differences in histological composition alone.

PMID- 8650077
TI  - Regulation of prostatic growth and function by peptide growth factors.
AB  - Polypeptide growth factors are positive and negative regulators of prostatic
      growth and function. Expression and biological effects of epidermal growth factor
      (EGF), transforming growth factors (TGFs) alpha and beta, fibroblast growth
      factors (FGFs), and insulin-like growth factors (IGFs) in the prostate have been
      extensively studied. EGF and TGF alpha, which share the same receptor, are strong
      mitogens for prostatic epithelial and stromal cells. Their paracrine mode of
      action in normal tissue and early-stage tumors is apparently altered towards an
      autocrine stimulation in hormone-independent tumors, which gain the ability to
      produce TGF alpha by themselves. TGF beta has a dual role in the regulation of
      prostatic growth. It inhibits growth of prostatic epithelial cells in culture and
      mediates programmed cell death after androgen withdrawal. However, advanced
      prostatic carcinomas become insensitive to the inhibitory effect of TGF beta.
      Several members of the FGF family have been identified in the prostate. They are
      mainly or exclusively expressed in the stromal cells, and stimulate the
      epithelial cells. In the rat Dunning tumor model, progression is accompanied by
      distinct changes in the expression of FGFs and their receptors. In the
      hyperplastic tissue, basic FGF (bFGF) is accumulated. This growth factor is also
      a potent angiogenic inducer, expression of which may determine the metastatic
      capability of a tumor. IGFs are paracrine growth stimulators in the normal and
      hyperplastic prostate. It is still under consideration whether prostatic cancer
      cells gain the ability to produce IGF-I by themselves and thus shift to an
      autocrine mode of IGF-I stimulation. Growth factors also interact with the
      androgen-signaling pathway. IGF-I in particular, other growth factors as well,
      can activate the androgen receptor.

PMID- 8650078
TI  - Functional assessment in older patients. Key to improving quality of life.
AB  - Functional assessment in older patients focuses on their level of functioning
      rather than on medical diagnoses alone. Patients who have multiple medical
      problems also have functional and support issues that affect their quality of
      life. Areas of concern include basic and instrumental activities of daily living,
      balance and mobility, mental ability, vision and hearing, bowel and bladder
      function, nutritional status, and environmental factors. Formal geriatric
      evaluation and management units composed of a physician, a social worker, and a
      nurse have been developed to address the functional needs in this population.
      However, primary care physicians can effectively apply the functional assessment
      approach in evaluation of their older patients with the help of the three-part
      problem list, along with selected tests and rating scales.

PMID- 8650079
TI  - The aging process. Physiologic changes and pharmacologic implications.
AB  - Age-related physiologic changes are important to consider when making diagnostic
      and therapeutic decisions. Such changes begin in the fifth decade and continue at
      varying rates depending on the organ system involved. Physicians need to be aware
      of the ramifications of the aging process, especially with regard to decreased
      functional reserve and changes in drug actions. The concept of homeostenosis
      implies that a functional elderly person may maintain health into old age but
      become increasingly vulnerable to stress and illness because of a lack of
      physiologic reserve. Thoughtful clinical application of this concept improves
      purely medical outcomes and surely enhances patients' quality of life in their
      later years.

PMID- 8650080
TI  - Brain failure in older patients. Uncovering treatable causes of a diminished
      ability to think.
AB  - The term "brain failure" implies only dysfunction of a major organ system, not
      that an exact diagnosis has been made. Assessment and treatment of older patients
      with diminished cognitive ability can be challenging; however, the experience can
      also be extremely rewarding when a reversible condition is alleviated and the
      patient is given added years of productive life. The first step in patient
      evaluation is to rule out delirium. The presence of delirium is a medical
      emergency in a patient of any age. Abrupt onset of cognitive deficit, waxing and
      waning of symptoms, and worsening of symptoms at night are the hallmarks of
      delirium. The second step is careful history taking and physical examination to
      rule out "apparent dementia," a potentially reversible form of brain failure that
      can mimic irreversible dementia. The third step is to treat what is treatable.
      Finally, extreme care must be taken in making the diagnosis of true dementia.
      Diagnosis of such a condition (eg, Alzheimer's disease, multi-infarct dementia,
      dementia of Parkinson's disease) has a profound effect on the patient and the
      family. These conditions are largely nontreatable, but physicians still have an
      important role in helping caregivers find appropriate assistance and support.

PMID- 8650081
TI  - Urinary incontinence. Basic types and their management in older patients.
AB  - Current guidelines for evaluation and management of urinary incontinence in older
      patients advise thorough history taking, physical examination, and limited
      laboratory workup. Most patients with urinary incontinence can be treated
      successfully with behavior modification, muscle exercises, and medications.
      Surgery should be reserved for patients who are not relieved by conservative
      therapy or who have obvious anatomical abnormalities amenable to repair.

PMID- 8650082
TI  - Do we really have a doctor glut? Or is it a question of guiding students to where
      they're needed?

PMID- 8650083
TI  - Otitis externa. Management in the primary care office.
AB  - Otitis externa is a widespread problem that is most commonly caused by
      Pseudomonas aeruginosa. Pain, ear discharge, and edema of the ear canal are the
      main manifestations. The presence of granulation tissue is an ominous sign that
      usually indicates necrotizing otitis externa or even a neoplastic process. It is
      important for primary care physicians to be familiar with methods of ear cleaning
      and use of topical medications for otitis externa. It is equally vital to be
      aware of the importance of a timely referral to an otolaryngologist when a
      serious underlying cause is suspected.

PMID- 8650084
TI  - Nasogastric and feeding tubes. The importance of proper placement.
AB  - The authors' experience in a radiology department suggested to them that there is
      a wide range of beliefs among practitioners regarding proper placement of
      nasogastric and feeding tubes. Improper positioning can cause serious problems,
      as they explain. Indications for different tube positions, complications of
      incorrect tube placement, and directions for proper positioning are discussed and
      illustrated.

PMID- 8650085
TI  - Management of depression. Current trends in primary care.
AB  - Depression is a common illness that may be difficult to detect, especially in
      patients with concurrent illness. Fortunately, depression is usually treatable.
      Identifying the optimal antidepressant agent requires careful consideration of
      the patient's age, health status, and history of response to antidepressants.
      Other considerations include the potential for drug interactions, adverse
      effects, and cost of drug therapy. Selective serotonin reuptake inhibitors are
      well tolerated and are considered by many to be the agents of choice in primary
      care treatment of depression because of their favorable adverse-effect profile.
      Lifelong treatment may be required because of the risk of recurrence. Primary
      care physicians may wish to collaborate with psychiatrists or psychologists when
      treating atypical depression.

PMID- 8650086
TI  - Interstitial cystitis. When urgency and frequency mean more than routine
      inflammation.
AB  - Interstitial cystitis is fairly common in primary care practices and very common
      in urology practices. Still, it is probably underdiagnosed. Because symptoms can
      be confusing, patients are sometimes thought to have psychogenic problems or are
      treated repeatedly with antibiotics, despite the absence of evidence of bacterial
      infection. The key to correct diagnosis is awareness of the condition and its
      characteristics. In patients who have symptoms that resemble routine cystitis but
      normal results on urinalysis, interstitial cystitis should be considered as the
      working diagnosis. This is especially applicable in women, who are affected far
      wore often than men. Various therapies have been tried, but the cure, like the
      cause, remains unknown. Many patients respond to some form of therapy and may
      even have long-term remissions. However, arriving at the form of therapy that
      relieves symptoms in a given patient is often a trial-and-error process. A short
      term trial of various methods is warranted initially. Ultimately, however,
      referral to a urologist may be necessary for definite diagnostic testing and
      additional therapy.

PMID- 8650087
TI  - Hepatotoxic effects of tuberculosis therapy. A practical approach to a tricky
      management problem.
AB  - Side effects of the most commonly used first-line antituberculosis drugs range
      from minor gastrointestinal symptoms to severe hepatotoxicity. If unrecognized,
      they can lead to increased morbidity and mortality as well as to higher
      healthcare costs. Side effects are most evident in patients with underlying
      compromise in hepatic function. Erratic treatment protocols not only promote
      secondary drug resistance but also offset all gains in tuberculosis control.
      Recognition of this problem, mandatory directly observed therapy, judicious
      standardized follow-up planning, and implementation of modified treatment
      protocols when needed may play a dominant role in treating and controlling
      tuberculosis and may also prevent the morbidity and mortality sometimes
      associated with tuberculosis treatment. In view of the changing epidemiology of
      tuberculosis and its global impact, the American Thoracic Society and the Centers
      for Disease Control and Prevention may need to look closely into the issues
      outlined here to develop a consensus and establish more specific guidelines.

PMID- 8650088
TI  - Helping smokers quit.

PMID- 8650089
TI  - Ready, set, go! Sports medicine on and off the field.
AB  - Team and event physicians can play an important role in ensuring the medical
      safety of a sports event by several actions: analyzing common injuries particular
      to a sport and planning accordingly in terms of equipment and procedures,
      establishing a hierarchy of the team's staff (ie, who has the authority to take a
      player out of the game), organizing medical equipment, establishing communication
      among the support personnel, considering crowd-control techniques for large
      events, arranging accessible transportation to a nearby medical facility, and
      being alert to possible dangerous weather conditions. Athletes will be safer,
      physicians more secure, and sports events more successful if these precautions
      are primary.

PMID- 8650090
TI  - Recognizing glaucoma. A guide for the primary care physician. .
AB  - Glaucoma is a group of diseases leading to characteristic cupping and damage of
      the optic nerve head associated with progressive visual loss. The exact mechanism
      of damage is unknown, but current research is pointing toward a multifactorial
      disease process, in which elevated intraocular pressure is just one of the
      factors. Early detection and proper management are imperative because of the
      disease's prevalence, progressive and often insidious nature, and significant
      associated morbidity.

PMID- 8650091
TI  - Hyperprolactinemia. Causes, consequences, and treatment options.
AB  - Hyperprolactinemia is one of the most common pituitary abnormalities. The cause
      can usually be determined by review of the patient's history, physical
      examination, selected laboratory tests and, when indicated, magnetic resonance
      imaging scans of the sella. Pituitary tumors and medications are the most common
      causes of hyperprolactinemia. Appropriate treatment is determined by the cause
      and by the patient's tolerance of the clinical consequences.

PMID- 8650092
TI  - Use of urokinase in pregnancy. Two success stories.
AB  - Use of urokinase in treatment of deep venous thrombosis in pregnancy has been
      limited because of concerns about teratogenic effects and potential hemorrhage
      before and after delivery. However, reports to date have been encouraging and our
      experience is supportive. In the cases described here, urokinase thrombolytic
      therapy was effectively used to treat deep venous thrombosis in two pregnant
      patients without any apparent complications.

PMID- 8650093
TI  - Bringing your office into the computer age. Do you really need all the bells and
      whistles?

PMID- 8650094
TI  - The business side of healthcare.

PMID- 8650095
TI  - The business side of healthcare.

PMID- 8650096
TI  - Vancomycin-resistant enterococci. The 'superbug' scourge that's coming your way.
AB  - Strains of vancomycin-resistant enterococci (VRE) have emerged and spread widely
      throughout the United States during the last few years. Multiply-resistant
      strains of Enterococcus faecium are especially troublesome because they are often
      resistant to all commercially available antimicrobial agents. At present, VRE
      infections occur most often in hospitalized patients with severe underlying
      disease who have undergone invasive procedures and received prolonged courses of
      broad-spectrum antimicrobial therapy. Because therapeutic options are limited,
      prevention of spread from patients with known cases to other vulnerable patients
      is essential.

PMID- 8650097
TI  - Ebola virus disease. Recognizing the face of a rare killer.
AB  - Because of international travel and immigration, US physicians should be aware of
      the signs and symptoms of Ebola virus disease. It should be suspected in any
      recent traveler who presents with manifestations of viral hemorrhagic fever and
      in laboratory workers exposed to animals from endemic areas who show symptoms.
      Infected persons should be given supportive care to help them survive the acute
      phase of infection. Fortunately, adequate preventive measures are already in
      place in US hospitals and laboratories because of the prevalence of AIDS and
      hepatitis. However, aid should be provided to the World Health Organization and
      developing countries such as Zaire to support further research into the
      epidemiology and natural history of the virus, which may help prevent future
      deadly epidemics.

PMID- 8650098
TI  - Acute epistaxis. How to spot the source and stop the flow.
AB  - The goals of epistaxis treatment are control of hemorrhage, prevention of
      cardiovascular and airway compromise, and determination of the cause and the
      source of bleeding. Distinguishing anterior from posterior epistaxis is important
      because therapeutic approaches differ. Epistaxis can usually be managed
      nonsurgically, but a surgical procedure is sometimes necessary. Cauterization,
      nasal packing, and use of an intranasal tampon or balloon catheter are effective
      nonsurgical interventions, but they may cause sinusitis, middle ear effusion,
      patient discomfort, and hypoxia. Surgical interventions include arterial
      ligation, endoscopic cauterization, and angiographic embolization. These highly
      effective methods incur the risks of general anesthesia and require technical
      expertise. A thorough and methodical approach to epistaxis is necessary, with
      otolaryngologic consultation when appropriate.

PMID- 8650099
TI  - Hematocrit values and mortality from ascites in cold-stressed broilers from
      parents selected by hematocrit.
AB  - A hypothesis that the relative hematocrit value of broilers is inherited and can
      serve as an indicator of partial resistance to the ascites syndrome in cold
      stressed broilers was shown to be valid in a field trial. Hematocrits were
      determined for male and female grandparent breeding stocks. Matings were then
      made between low (LL), low-medium (LM), medium-high (MH), and high (HH)
      hematocrit parents: LL x LL, LM x LM, MH x MH, and HH x HH. The progeny of HH
      parents had higher hematocrit values than the progeny of lower hematocrit parents
      (P < 0.0001). Exposure of the progeny from all the parental groups to an ascites
      predisposing cold environment caused higher losses from ascites in the progeny of
      the HH parents (P < 0.0001). The progeny of LH parents had an increased mortality
      from causes other than ascites (P < 0.0001). This work suggests that elimination
      of birds with HH in broiler breeding programs may be desirable where cold-induced
      ascites is an important problem.

PMID- 8650100
TI  - Additive effects of 1,25-dihydroxycholecalciferol and phytase on phytate
      phosphorus utilization and related parameters in broiler chickens.
AB  - Two experiments were conducted to compare the effects of supplementation with
      1,25-dihydroxycholecalciferol [1,25-(OH)2D3] and a commercial phytase on P
      utilization by broiler males. Experiment 1 was conducted with three levels of
      total dietary P (0.45,0.55, and 0.65%) in corn-soybean meal diets supplemented
      with 5 micrograms/kg of 1,25-(OH)2D3, 600 units/kg of phytase, or the combination
      of these supplements in a factorial arrangement from 0 to 21 d in battery
      brooders. A second experiment was conducted with a similar design except that it
      was carried out in floor pens for a period of 35 d. In Experiment 1, maximal BW
      was obtained at 0.65% P in chicks receiving the basal diet, 0.55% P in chicks
      receiving phytase or 1,25-(OH)2D3, and 0.45% P in chicks fed both supplements.
      Bone ash for chicks receiving the basal, phytase, 1,25-(OH)2D3, and combination
      treatments at 0.45% total dietary P were 26.6, 34.9, 35.1, and 38.8%. There were
      significant interactions between phytase and 1,25-(OH)2D3 for BW, bone ash, and
      incidence of rickets. Similar results were noticed in Experiment 2, with the
      exception that 1,25-(OH)2D3 had little influence on BW from 0 to 3 wk, likely due
      to slightly higher dietary P. From 3 to 5 wk, BW and bone ash were increased by
      each supplement and further increased by their combination. These interactions
      suggest different mechanisms of action for these supplements in influencing
      phytate P utilization.

PMID- 8650101
TI  - Effect of glutamic acid on broilers given submarginal crude protein with adequate
      essential amino acids using feeds high and low in potassium.
AB  - Broiler males were examined for their response to feeds containing CP 1 to 2%
      below levels advocated by NRC (1994) and when supplemented with L-glutamic acid.
      Crude protein and glutamic acid treatments were imposed in starting, growing, and
      finishing feeds over 7 wk with K at high and low levels likely to occur in
      practice (0.80 vs 0.65 to 0.55%). All feeds were formulated to be isocaloric
      (3.20 kcal ME/g) and satisfy NRC (1994) essential amino acid (EAA) minimum
      requirements. Improved live weight gain occurred during the first 6 wk with
      supplementation of glutamic acid to the low CP feed but not when intact protein
      per se was used to increase CP. A similar advantage in growth was obtained from
      glutamic acid in response to its addition at equivalence of 1 to 2% CP as well as
      when dietary adjustments maintained low CP. Response to altered K could not be
      interpreted because of concurrent differences in glutamic acid and AMEn intakes.
      High glutamic acid levels did not decrease abdominal fat unless CP increased
      concurrently, whereas carcass back bruising and drumstick deformations were
      relieved by supplemental glutamic acid independent of CP. Increased weight gain
      from glutamic acid was only evident with drumsticks and debris that included the
      back when carcasses were cone-deboned. Supplemental glutamic acid is believed to
      improve the rate of connective tissue formation during rapid growth.

PMID- 8650102
TI  - Effects of sex-linked imperfect albinism (sal-s) in the chicken on the
      relationships of plasma concentrations of progesterone and 17 beta-estradiol with
      egg production.
AB  - Effects of the sal-s gene for sex-linked imperfect albinism on the relationships
      of plasma concentrations of progesterone (P4) and estradiol (E2) with egg
      production were investigated during the laying period. Egg production of 17
      albino and 16 nonalbino hens was recorded from 19 to 60 wk of age. Blood samples
      of these hens were taken between 1330 and 1500 h at 19 and 20 wk of age and every
      4 wk until 60 wk of age. At 61 wk, blood samples were taken 6, 5, and 4 h before
      a midsequence ovulation. Plasma P4 and E2 were measured by RIA. There was no
      difference between genotypes in days to first egg (157.8 vs 158.1 d). Hen-day egg
      production of albinos was greater (P < 0.05) than that of nonalbinos in the 4-wk
      periods between 52 and 56 wk (83.8 vs 69.2%) and 56 and 60 wk (81.3 vs 64.3%).
      Egg production for the entire laying cycle was not different between genotypes
      (81.0 vs 73.0%, P = 0.08). Plasma P4 and E2 concentrations were not different
      between albino and nonalbino hens. From 28 to 60 wk of age, partial correlation
      coefficients between P4 and egg production, and E2 and egg weight were
      significant for albino hens (r = 0.15 and 0.16, respectively) but not for
      nonalbinos (r = -0.03 and -0.1, respectively), and age and P4 concentrations were
      negatively correlated for both albinos (r = -0.22, P < 0.01) and nonalbinos (r = 
      0.32, P < 0.01). Preovulatory levels of P4 in albino hens were higher (P < 0.05)
      than those in nonalbinos. Plasma E2 was higher in albinos than in nonalbinos 5 h
      before ovulation (P < 0.05). These data suggest that increased egg production of
      albino hens is associated with differences in P4 and E2 metabolism.

PMID- 8650103
TI  - Immunolocalization of basic fibroblastic growth factor in avian tibial
      dyschondroplastic cartilage.
AB  - Recent research in our laboratory has demonstrated that basic fibroblast growth
      factor (bFGF) is a permissive mitogen for epiphyseal growth plate chondrocytes.
      Immunocytochemistry demonstrated the presence of bFGF in the proliferative and
      hypertrophic zones of normal epiphyseal growth plates of 4-wk-old broiler
      chickens. The purpose of this investigation was to extend this research to
      include examination of the status of bFGF in the cartilage lesion associated with
      tibial dyschondroplasia (TD). Immunocytochemistry revealed that the distribution
      of bFGF in the growth plate proximal to the TD lesion was similar to that
      observed with normal growth plate. However, the intensity of immunofluorescence
      was greatly diminished in the TD lesion. The number of chondrocytes staining
      positive for bFGF was also reduced. In the peripheral edges of the lesion where
      cartilage was being actively resorbed, the staining intensity was greatly
      increased when compared to the rest of the TD lesion. Similar patterns were
      observed in all TD tissues examined whether the lesions were spontaneous or
      induced by dietary treatments or genetic selection. It is hypothesized that the
      decrease in bFGF, a potent angiogenic factor, may be responsible for the poor
      vascularization of the TD lesion.

PMID- 8650104
TI  - Analysis of poultry fertility data. 3. Analysis of the duration of fertility in
      naturally mating Japanese quail.
AB  - The purpose of the present study was to test the appropriateness of iterative
      least squares regression for the evaluation of fertility data in naturally mating
      quail. In each of four trials, 20 male and 200 female randombred Japanese quail
      were housed in stacked breeder cages. Paired females were exposed to their
      assigned male for a single 48-h period. Eggs were collected for 2 wk following
      removal of the male, incubated, and fertility determined by visual inspection at
      egg breakout. In Trials 1 and 3, sexually experienced males were placed with
      experienced and inexperienced females, respectively. In Trials 2 and 4,
      inexperienced males were placed with experienced and inexperienced females,
      respectively. Duration of fertility, by male, was analyzed by iterative least
      squares, using the model y(x) = gamma/(1 + e beta(tau - x)). Overall fertility
      was analyzed with a log odds model following transformation to logits. Iterative
      least squares provided estimates of fertility duration of 3.75 to 9.18 d, with
      significant (P < 0.05) differences in the duration of fertility observed between
      individual males as well as between the trials. Differences (P < 0.05) in overall
      fertility (17.7 to 58.3%) were also observed, with inexperienced males paired
      with experienced females exhibiting the lowest overall means. Taken together,
      these results suggest that iterative least squares may be used to evaluate
      fertility in naturally mating populations and that reproductive experience can
      have a profound effect on the interpretation of fertility in naturally mating
      quail.

PMID- 8650105
TI  - Heterosis in egg-laying lines under divergent selection for residual feed
      consumption.
AB  - Two lines selected since 1976 for high (R+) or low (R-) residual feed consumption
      (RFC) from a common genetic base were compared with one another and with their F1
      reciprocal crosses for traits of egg production and quality, for morphological
      traits, body weights, and feed consumption. Heterosis was 11, -2.5, 8, and 2%,
      respectively, for egg number, age at first egg, egg laying rate, and egg weight,
      with marked differences between reciprocal crosses for all those traits but egg
      number. Heterosis for wattle length and shank length was 3.8 and 1.3%,
      respectively, essentially because R+ x R- crossbreds, with larger mean values,
      resembled the R+ line for those traits, which may therefore be associated with
      the presence of genes linked to the Z chromosomes. On the other hand, heterosis
      for RFC (-3.6%) originated from similar crossbred advantage in both reciprocal
      crosses, thereby suggesting that RFC is not determined by sex-linked genes.

PMID- 8650106
TI  - Relationship between band sharing levels of DNA fingerprints and inbreeding
      coefficients and estimation of true inbreeding in turkey lines.
AB  - A regression analysis between band sharing of DNA fingerprints and calculated
      inbreeding coefficients was conducted using six experimental turkey lines. The
      DNA fingerprints were produced from 18 individual DNA samples per line
      representing different families. The DNA was digested with a HaeIII restriction
      enzyme and hybridized with Jeffreys' 33.6 probe. The band sharing within lines
      ranged from 0.42 to 0.62. The inbreeding coefficients of the lines were
      calculated based on population sizes and variation in family sizes. The
      inbreeding coefficients varied from 2.5 to 45%. Regression analysis between the
      two variables yielded a highly significant (P < or = 0.0001) linear model with a
      correlation coefficient of 0.992. The linear model was used to estimate the
      actual inbreeding in these lines.

PMID- 8650107
TI  - The influence of major histocompatibility complex genotypes on resistance to
      Pasteurella multocida and Newcastle disease virus in turkeys.
AB  - Sublines homozygous for each of four MHC haplotypes were developed from
      randombred control populations of turkeys and challenged with Pasteurella
      multocida (capsular serogroup a, somatic serotype 3, 4) at 6 wk of age or
      Newcastle disease virus (NDV; Texas GB strain) at 4 wk of age. In addition,
      individuals from a randombred control line (RBC2) and a subline (F) of RBC2 long
      term selected for increased 16-wk BW were included in most of the challenge
      trials. The duration of the challenge trials was 2 wk for both organisms.
      Mortality following challenge with P. multocida or NDV was higher in the F line
      than in its randombred control. The MHC genotypes differed in mortality following
      exposure to both organisms but the rankings of the genotypes were not the same
      for P. multocida and NDV. The increased susceptibility of the F line to both
      organisms could not be explained by known changes in the frequency of the MHC
      haplotypes.

PMID- 8650108
TI  - Interaction of feeding time and temperature and their relationship to performance
      of the broiler breeder hen.
AB  - Experiments with broiler breeder hens were undertaken to determine effect of
      feeding time and environmental temperature on various production variables, body
      weight, and feed consumption. Two temperature treatments were used: low cyclic
      temperature (10 to 25 C), and high cyclic temperature (21 to 39 C). The three
      feeding treatments were: fed one daily meal either at 0700 h (Treatment 1) or
      1800 h (Treatment 2), or one-half the daily amount at 0700 h and the other half
      at 1800 h (Treatment 3). In another experiment, hens were assigned to feeding
      times of either 0700 or 1800 h. Feeding time and temperature did not markedly
      affect rate of egg production; however, hens at high temperature fed two meals
      per day produced the fewest eggs. High temperature caused significant reductions
      in egg weight, specific gravity, and shell thickness. Feeding time and
      temperature had no effect on time of oviposition, ovulation, or the transit time
      of the egg through the oviduct. Significant body weight loss occurred in hens at
      high temperature and fed at 0700 h. Both high temperature and feeding one-half of
      the daily feed at 0700 and the other half at 1800 h caused a reduction in feed
      consumption.

PMID- 8650109
TI  - Sensitivity of Escherichia coli O157:H7 strain 932 to selected anticoccidial
      drugs in broiler chicks.
AB  - The ability of selected anticoccidial drugs to inhibit the colonization of day
      old male broiler chicks (Cornish Rocks) by Escherichia coli O157:H7, strain 932
      was examined. Chicks were challenged with 1.8 x 10(9) E. coli O157:H7 on Day 1,
      and fed diets supplemented with three selected anticoccidial drugs; monensin,
      nicarbazin, or robenidine. The cecal and colon fecal contents of the chicks were
      removed on Day 7, 14, and 21 postinoculation and examined for the concentration
      of E. coli O157: H7 per gram of contents. Monensin effectively reduced cecal and
      colon colonization of the chicks by E. coli O157:H7. By Day 7, there were
      significant reductions in the bacterial population of the cecal contents of
      chicks receiving the monensin-medicated feed, and by Day 21 no E. coli O157:H7
      was recovered from the cecal and colon contents. The bacterial counts in the
      colon contents of the nicarbazin- and robenidine-medicated and unmedicated chicks
      were significantly higher than the monensin-treated chicks. Bacterial populations
      in the colon contents were high only when there were high bacterial
      concentrations in the cecal contents.

PMID- 8650110
TI  - The long-term productivity of hens housed in battery cages and an aviary.
AB  - This study examined the long-term effects of housing system on several aspects of
      laying hen production. At 19 wks of age, 336 White Leghorn hens were placed, 3
      birds per cage, into battery cages; 437 birds were assigned to an aviary with
      communal nests, ambulation areas, and three raised tiers with feeders and
      drinkers. Family groups were split between the two housing systems. The hens were
      housed in such a manner for over 3 yr (until the end of the 168th wk of age),
      with forced molts between 66 and 74 and between 119 and 125 wk of age. Feed
      consumption and conversion, egg weight, eggshell deformation, and hen-day
      productivity were assessed monthly in both systems. Although feed consumption and
      conversion tended to be higher in the aviary throughout the study, these
      variables differed significantly due to housing system only in Year 2 (P = 0.04).
      There were no differences in egg weight (P = 0.7), eggshell deformation (P =
      0.85), egg cracking during shaking (P = 0.34), total hen-day productivity (P =
      0.55), or egg mass produced per hen per month (P = 0.4). Although aviary systems
      have been criticized for egg losses due to floor laying, only 2.5% of eggs in the
      current study were laid on the floor in Year 1, and 0.3% in Years 2 and 3; 1.7%
      across all years. Hen mortality was variable across production and molt periods,
      and did not differ due to housing system (P > 0.05). The results of this study
      confirm that hen productivity in well-managed alternative housing systems can
      compare favorably with that in battery cages.

PMID- 8650111
TI  - Degradation of aflatoxin by poultry litter.
AB  - Two trials were conducted to determine whether deep stacking of contaminated corn
      with poultry litter destroys aflatoxin. Contaminated corn was ground and mixed
      with litter to carbon:nitrogen ratios of 30:1. Moistures were adjusted by adding
      tap water just prior to incubation or stacking. The initial laboratory trial
      included only broiler litter at 40% moisture, whereas the subsequent field trial
      involved a 2 x 2 factorial design with litter type (turkey or broiler) and
      moisture (20 or 40%) as main effects. Aflatoxin assays were reduced in the
      laboratory trial from 433 and 402 to 54 and 8 ppb in Containers 1 and 2,
      respectively, after 35 d of incubation at 28 C. In the field trial, aflatoxin
      disappeared from broiler and turkey litter mixtures with projected moistures of
      20% after 10 and 6 wk of storage, respectively, whereas disappearance in mixtures
      containing projected moistures of 40% required 5 and 3 wk, respectively.
      Differences in moisture appear to account for differences in the ability of
      turkey and broiler litter to detoxify aflatoxin. Hence, turkey and broiler litter
      would appear equal with respect to the ability to detoxify aflatoxin-contaminated
      corn. Disappearance of aflatoxin during storage with litter could have occurred
      as a result of ammonia release during storage or microbial detoxification
      mechanisms. However, nitrogen values suggest that microbial action was
      responsible for much of the detoxification, as aflatoxin disappeared from
      mixtures with little apparent ammonia release.

PMID- 8650112
TI  - Effect of feed and water withdrawal on green liver discoloration, serum
      triglycerides, and hemoconcentration in turkeys.
AB  - Turkey poults at 1 d of age were obtained from a local hatchery (Experiment 1),
      or at 14 wk of age from a local grower (Experiment 2), and kept in floor pens
      with feed and water available for ad libitum consumption. When the turkeys
      reached 16 wk of age (Experiment 1) and 18 wk of age (Experiment 2), the
      treatments were established within a 2 x 2 factorial arrangement and consisted of
      ad libitum consumption of feed and water (control), or feed, water, or both feed
      and water withdrawal. In Experiment 1, 1 turkey per pen, 6 turkeys per treatment,
      were killed every 4 h for 32 h, and in Experiment 2, 10 turkeys per treatment
      were killed at 24, 30, 36, 42, 48, and 54 h after feed, or water, or both had
      been withdrawn. The turkeys were bled at sampling times 16 and 32 h in Experiment
      1 and at each sampling time in Experiment 2. Serum was collected and
      hematological and clinical chemistries performed. The turkeys were examined for
      green liver discoloration and turkey osteomyelitis complex lesions. Withdrawal of
      feed, water, or both feed and water for up to 54 h did not affect the incidence
      of green liver discoloration in these studies. Serum triglyceride concentrations
      were the most sensitive blood constituent to either water or feed withdrawal,
      with reductions (P < or = 0.05) occurring at 16 h after feed withdrawal.
      Hemoconcentration resulted in an increase in hematocrit and hemoglobin levels 30
      h after water withdrawal.

PMID- 8650114
TI  - Influence of calcium and environmental temperature on performance of first-cycle
      (phase 1) commercial leghorns.
AB  - An experiment was conducted to determine whether optimizing profits, as well as
      eggshell and skeletal strength, by manipulation of dietary Ca level has any
      influence on either egg weight, egg production or feed consumption during the
      first 12 wk of production (Weeks 20 to 32, Phase 1). Hens were housed at two
      environmental temperatures (15.6 to 23.3 and 21.1 to 28.9 C) and fed six diets
      from 20 to 32 wk of age containing 2.5 to 5.0% Ca with increments of 0.5% and
      with ME levels ranging from 2,719 to 2,950 kcal/kg, respectively. Egg specific
      gravity, egg production, egg weight, and feed consumption were determined at
      weekly or biweekly intervals. At 32 wk of age, plasma Ca, bone density, and bone
      breaking strength were determined. Results indicated that environmental
      temperature had no influence on egg production but hens housed at the lower
      environmental temperature had an increase in egg weight, egg specific gravity,
      and feed consumption. Increasing dietary Ca level increased egg production, egg
      specific gravity, feed consumption, ionic plasma Ca, bone density, and bone
      breaking strength and had no adverse effect on egg weight. It was concluded that
      Hy-Line W-36 hens could be fed diets containing as much as 5% Ca with no adverse
      effect on egg production, egg weight, or feed consumption and that Hy-Line W-36
      hens (Phase 1) under conditions described should be fed diets containing a
      minimum of 4.25% Ca (3.4 to 3.6 g per hen per d) to 4.5% Ca (3.6 to 3.8 g per hen
      per d). Calcium intake should range from 3.0 g per hen per d at 21 wk of age to
      4.2 g per hen per d at 32 wk of age.

PMID- 8650113
TI  - Gene mapping by chromosome microdissection and microisolation in the chicken.
AB  - A chromosome microdissection and microisolation technique in combination with
      filter hybridization was developed for chromosomal localization of cloned chicken
      genes. The DNA was obtained from microdissected chromosome regions of metaphase
      spreads. Dissected DNA was amplified by polymerase chain reaction (PCR). The
      chicken MHC gene located on the nucleolar chromosome and beta-actin gene located
      on chromosome 2q were chosen as tests for the procedure and then detected by dot
      blot analysis using amplified chromosomal DNA probed with biotinylated DNA. The
      study establishes the technique of using chromosome microdissection and
      microisolation for localization of cloned genes as a complementary or alternative
      approach to both in situ DNA/chromosome hybridization and fluorescent in situ
      hybridization.

PMID- 8650116
TI  - Effect of diet on growth and plasma ascorbic acid in chicks.
AB  - Six experiments were conducted to study the effect of diet on growth and plasma
      ascorbic acid in chickens. D-Glucuronolactone failed to improve growth with
      either a crude yeast-fish meal diet or a purified diet based on casein and
      gelatin. With the purified diet, D-glucuronic acid and L-gulonolactone also
      failed to improve growth and did not influence plasma ascorbic acid levels.
      Dietary ascorbic acid improved growth of chicks with a purified diet in most
      cases, but not with a corn-soybean diet. Meat meal and fish meal caused slight
      increases in plasma ascorbic acid, whereas soybean meal, safflower meal, and
      cottonseed meal caused greater increases when used in a purified diet.
      Gulonolactone oxidase activity in the kidney was not different between chicks fed
      the purified or the corn-soybean diets, but was reduced by 0.1% dietary ascorbic
      acid. The mechanism for the increase in plasma ascorbic acid with the addition of
      soybean meal and other plant protein sources to the diet is not known.

PMID- 8650117
TI  - Effect of dietary 1,25-dihydroxycholecalciferol level on broiler performance.
AB  - Studies were conducted to evaluate the level of dietary 1,25
      dihydroxycholecalciferol [1,25-(OH)2D3] required to decrease the incidence of
      tibial dyschondroplasia (TD) in male broilers at 3 and 5 wk of age. The birds
      were reared in floor pens with wood shavings and fed a corn-soybean meal diet
      supplemented with 0, 3, 6, or 9 micrograms/kg 1,25-(OH)2D3. The diet contained,
      by averaged analyses, 0.73% calcium, 0.74% total phosphorus, and 0.22% phytate
      phosphorus. There was no treatment effect on body weight or gain: feed at either
      age. The incidence and severity of TD and the percentage of severe lesions were
      decreased and bone ash was increased by 6 micrograms/kg 1,25-(OH)2D3 at 3 wk of
      age. At 5 wk of age, the incidences of TD and severe lesions were decreased when
      6 micrograms/kg 1,25-(OH)2D3 was fed. Bone ash was increased by this level in one
      of the two experiments. Plasma calcium was increased at 5 wk when 9 micrograms/kg
      1,25-(OH)2D3 was fed, but there was no treatment effect on plasma dialyzable
      phosphorus or 1,25-(OH)2D3. The results indicate that 6 micrograms/kg 1,25
      (OH)2D3 is effective for decreasing TD under practical rearing conditions.

PMID- 8650115
TI  - Phosphorus equivalence of microbial phytase in turkey diets as influenced by
      calcium to phosphorus ratios and phosphorus levels.
AB  - Male day-old turkey poults (n = 768) were fed 0, 300, 600, or 900 U of phytase/kg
      of a corn-soybean diet in combination with four Ca:total P (tP) ratios of 1.1,
      1.4, 1.7, and 2.0:1, and two levels of nonphytate P (nP) of 0.27 and 0.36% in a
      21-d trial. Dietary Ca:tP ratios were obtained by varying defluorinated phosphate
      and limestone at the expense of cornstarch. The calculated dietary percentage of
      phytate P was 0.266 for all diets. Phytase additions linearly increased (P <
      0.05) BW gain, feed intake, gain:feed, toe ash content, and apparent retentions
      of Ca and P at each Ca:tP ratio and nP level, but the response was influenced by
      dietary Ca:tP ratios and P levels. The detrimental effect (P < 0.02) of widening
      the Ca:tP ratio was observed for all measurements at each phytase and P level,
      and was greatest at lower phytase and P levels. Widening the Ca:tP ratio from 1.4
      to 2.0 decreased the phytase efficacy by 7.4 and 4.9%, respectively, for 0.27 and
      0.36% nP diets, which was close to the decrease in the phytase activity in vitro
      by 7.5 and 6.7%, respectively. The largest responses to supplemental phytase were
      achieved when poults were fed diets with 600 and 900 U of phytase/kg diet,
      respectively, for 0.36 and 0.27% nP, and for Ca:tP ratios ranging from 1.1 to
      1.4:1. Second-order translog equations were generated for the phytase, Ca:tP
      ratio, and P effect, and nonlinear and linear equations for the phytase and Ca:tP
      ratio effect. Based on an assessment for the R2 and P values of equations, BW
      gain, feed intake, toe ash content, and P retention were sensitive measurements
      of the response to phytase addition. Equivalent equations were developed to
      determine the P equivalency of supplemental phytase. About 652 and 963 U of
      phytase were equivalent to 1 g nP, respectively, for 0.27 and 0.36% nP diets in
      turkey poults from hatch to 21 d of age.

PMID- 8650118
TI  - Effects of phytase and 1,25-dihydroxycholecalciferol on phytate utilization and
      the quantitative requirement for calcium and phosphorus in young broiler
      chickens.
AB  - Three experiments were conducted to determine the effects of supplementing 1,25
      dihydroxycholecalciferol [1,25-(OH)2D3] and a commercial phytase product on Ca
      and P requirements of 0- to 21-d-old broiler males. These experiments were
      conducted with four levels of dietary Ca and P in corn-soybean diets with and
      without supplementation of 5 micrograms/kg of 1,25-(OH)2D3, 600 units/kg of
      phytase, and the combination of these supplements. The results show that these
      levels of phytase and 1,25-(OH)2D3 can replace up to 0.1% of the inorganic P for
      criteria such as BW, bone ash, and plasma P. Both supplements increased phytate P
      retention, whereas higher levels of Ca and P decreased phytate P retention. The
      addition of 1,25-(OH)2D3, but not phytase, reduced Ca requirements and decreased
      the incidence of tibial dyschondroplasia. The combination of these levels of
      phytase and 1,25-(OH)2D3 replaced 0.2% inorganic P for criteria such as BW, bone
      ash, and P rickets. Total dietary P requirements are estimated to be between 0.55
      and 0.60% at the levels of phytase and 1,25-(OH)2D3, listed above, or 0.45% when
      the combination is added. The Ca requirements are estimated to be 0.77% when 1,25
      (OH)2D3 is added to the diet and 0.9 to 0.95% when phytase is added.

PMID- 8650119
TI  - Prenatal diagnosis of glycogen storage disease type 1a by direct mutation
      detection.
AB  - Current laboratory diagnosis for glycogen storage disease type 1a (GSD 1a) is
      established by functional enzyme assay to demonstrate the deficiency of glucose-6
      phosphate phosphatase (G6Pase). This procedure requires liver biopsy and is
      impractical for routine prenatal diagnosis owing to the high morbidity of fetal
      liver biopsy. The accuracy of test results is dependent on the stability of the
      enzyme during specimen collection, shipment, and storage. Recently the gene for
      G6Pase has been cloned and the prevalent mutations in different ethnic groups
      have been identified. We have developed an allele-specific oligonucleotide (ASO)
      method to detect mutations in a large number of GSD 1a patients. In this paper we
      report the prenatal detection of mutations in the G6Pase gene using this simple,
      dependable, rapid, and non-invasive procedure. The turnaround time of this test
      can be as short as 48 h. A fetus was found to be a carrier using the ASO method
      and this was confirmed after birth. To our knowledge, this is the first GSD 1a
      prenatal case diagnosed by a DNA molecular method.

PMID- 8650120
TI  - Prenatal cytogenetic results from cases referred for 44 different types of
      abnormal ultrasound findings.
AB  - During the period 1987 through mid-1993, 118 490 chromosome analyses from
      amniocytes were performed at the Integrated Genetics Laboratories in Santa Fe,
      New Mexico (formerly Vivigen Laboratories). This report summarizes the data for
      all specimens submitted because of anomalies seen during ultrasound examination;
      this includes 44 different categories of anomalies. There were 3177 cases
      referred because of at least one structural abnormality; 494 (15.5 per cent) of
      the cases had an abnormal karyotype. Our cytogenetic findings are summarized for
      the different types of anomalies and the corresponding empirical risks are given
      for abnormal cytogenetic results.

PMID- 8650121
TI  - Prenatal diagnosis of mitochondrial fatty acid oxidation defects.
AB  - Amniocytes isolated from two pregnancies at risk for fatty acid oxidation defects
      were incubated with stable isotopically labelled palmitate, in the presence of L
      carnitine, to probe that pathway. The labelled acylcarnitines were then
      quantitated using tandem mass spectrometry. Amniocytes from a pregnancy at risk
      for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency produced a
      characteristic acylcarnitine profile with increased levels of octanoylcarnitine
      and decanoylcarnitine, indicative of MCAD deficiency. DNA analysis confirmed that
      the fetus was homozygous for the MCAD A985G mutation. Acylcarnitine and DNA
      analysis of the infant's blood obtained post-partum confirmed MCAD deficiency.
      Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect
      produced increased levels of long-chain acylcarnitines consistent with a
      deficiency in very-long-chain acyl-CoA dehydrogenase (VLCAD). Measurements of the
      enzymatic activity confirmed VLCAD deficiency in amniocytes. Acylcarnitine
      profiles of the infant's blood obtained post-partum in addition to enzyme
      activities measured in fibroblasts confirmed VLCAD deficiency. The successful
      prenatal diagnosis of VLCAD and MCAD deficiencies using in vitro probes of fatty
      acid oxidation in fibroblasts suggests that this approach can potentially
      recognize many mitochondrial fatty acid oxidation defects even if no prior
      diagnosis is determined in the family at risk.

PMID- 8650122
TI  - Prenatal diagnosis of Roberts syndrome: two new cases.
AB  - We report two fetuses with typical anomalies of Roberts syndrome. Prenatal
      diagnosis was confirmed by the characteristic disjunction of centromeres in
      amniocytes. We compare these cases with a child who presented with severe Roberts
      syndrome. We attempted to evaluate quantitatively the centromeric abnormality and
      the chromosome separation in the different cultures and with different methods.
      The variability of the clinical manifestations and cytogenetic investigations of
      this syndrome are reviewed.

PMID- 8650123
TI  - Multiple fetal intracardiac echogenic foci: not always a benign sonographic
      finding.
AB  - Isolated left-sided echogenic foci in the fetal heart are considered as a benign
      condition, probably representing a normal variant of the development of papillary
      muscles. The objective of the present study was to evaluate the incidence and
      significance of multiple or diffuse echogenic foci in the fetal heart. We
      analysed retrospectively 25 725 ultrasound examinations conducted for fetal
      malformations between 12 and 24 weeks' gestation. In the study group, echogenic
      intracardiac foci were observed in 44 cases (0.17 per cent). In 35 fetuses, these
      foci were confined to the region of the papillary muscles/chordae tendinae as an
      isolated finding in the left side of the heart. All these fetuses had an
      uneventful neonatal follow-up. However, in nine of these cases, diffuse echogenic
      foci were demonstrated in various regions of the fetal heart, five of them with
      involvement of the right ventricle. In five of the nine cases, other major
      pathologies were found. In one case, a missed abortion occurred and in one case
      of early termination of pregnancy, calcifications were demonstrated in the
      endocardium on histological examination. Only in two of the nine fetuses was the
      outcome uneventful. Our findings suggest that diffuse echogenicity in the fetal
      heart, especially when the right ventricle is also involved, may signal a poor
      prognosis and deserves a further search for associated pathologies. This is in
      contrast to the benign character of an isolated left-sided echogenic focus.

PMID- 8650124
TI  - Clinical experience with preimplantation genetic diagnosis of cystic fibrosis
      (delta F508).
AB  - Preimplantation genetic diagnosis (PGD) was attempted in 12 couples in whom both
      parents carry the common delta F508 deletion causing cystic fibrosis (CF). In
      vitro fertilization (IVF) was followed by cleavage stage biopsy on days 2 and 3
      and removal of one or two cells for genetic analysis by nested polymerase chain
      reaction (PCR) and heteroduplex formation. A total of 18 cycles resulted in 137
      normally fertilized embryos, of which 115 developed to cleavage stages and 114
      were successfully biopsied. Genetic analysis was successful in 83 embryos (73 per
      cent). With the remaining embryos, either results from two or more cells were
      discordant or amplification failed. In 15 cycles, one or two either normal or
      carrier embryos were transferred and five (33 per cent) clinical pregnancies were
      established. Five singletons have been born and at birth all five babies have
      been confirmed as homozygous for the normal allele. Our experience demonstrates
      that IVF and cleavage stage biopsy consistently provides sufficient embryos,
      diagnosed as unaffected, for transfer in this autosomal recessive disease and
      that pregnancy rates are comparable to those following IVF.

PMID- 8650125
TI  - Prenatal screening for Down's syndrome using inhibin-A as a serum marker.
AB  - The value of measuring inhibin-A (a beta A dimer) with human chorionic
      gonadotrophin (total or the sub-units free a-hCG and free beta-hCG separately),
      alpha-fetoprotein (AFP), and unconjugated oestriol (uE3) was examined to
      determine the effect on the performance of serum screening for Down's syndrome
      between 15 and 22 weeks of pregnancy. The study was based on stored serum samples
      from 77 Down's syndrome singleton pregnancies and 385 unaffected singleton
      pregnancies, matched for maternal age, gestational age, and duration of storage
      of the sample, supplemented by data from 970 white women with unaffected
      pregnancies. Inhibin-A was elevated in the serum of women with Down's syndrome
      pregnancies with a median of 1.79 multiples of the median (MOM). Using the four
      serum markers AFP, uE3, total hCG, and inhibin-A, in addition to maternal age, 70
      per cent of Down's syndrome pregnancies were detected for a 5 per cent false
      positive rate compared with 59 per cent with the conventional triple test (AFP,
      uE3, and total hCG with maternal age). If the estimate of gestational age were
      based on an ultrasound scan examination, the detection rate would be 77 per cent
      [95 per cent confidence interval (CI) 69-85 per cent] using the four serum
      markers including inhibin-A, compared with 67 per cent with the triple test or 79
      per cent (95 per cent CI 71-87 per cent) if marker values were adjusted for
      maternal weight. If the detection rate were kept at 70 per cent and the
      gestational age were estimated by an ultrasound scan examination, the four-marker
      test would reduce the false-positive rate from 6-1 per cent using the triple test
      to 2-9 per cent. The results were virtually the same if free beta-hCG was used
      instead of total hCG. The inhibin-A-based four-marker test is the most effective
      method of prenatal screening for Down's syndrome suitable for routine use. If the
      extra cost required to carry out the inhibin-A test were less than about [symbol:
      see text]3 per woman screened, the four-marker test including inhibin-A would be
      financially cost-effective.

PMID- 8650126
TI  - First-trimester prenatal diagnosis of Crouzon syndrome.
AB  - Crouzon syndrome, one of the best known of many craniofacial syndromes, is an
      autosomal dominant disorder characterized by craniosynostosis, prominent eyes,
      and midfacial hypoplasia due to abnormal development and premature fusion of the
      skull. Recently mutations in the fibroblast growth factor receptor 2 gene (FGFR2)
      were found to cause Crouzon. We have identified the recurrent mutation C342Y in
      two unrelated patients with Crouzon syndrome. One patient (A) belongs to a family
      in which Crouzon could be followed in three generations, while the other patient
      (B) represents a sporadic case. The identification of the disease-causing
      mutation allowed first-trimester prenatal diagnosis as requested by both patients
      in their subsequent pregnancies. A chorionic villus biopsy was performed in the
      11th gestational week of patient A's pregnancy. DNA isolated from the biopsy
      revealed a fetus heterozygous for the C342Y mutation, i.e., having Crouzon
      syndrome. The pregnancy was terminated and the molecular diagnosis was confirmed
      later by analysis of fetal and placental tissue. Patient B had a missed abortion
      before the scheduled chorionic villus biopsy was performed. Mutation analysis of
      the aborted fetal tissue did not show the C342Y mutation.

PMID- 8650127
TI  - Distribution of abnormal karyotypes among malformed fetuses detected by
      ultrasound throughout gestation.
AB  - A karyotype was obtained from 755 fetuses with structural anomalies detected by
      sonography between 13 and 40 weeks' gestation. Gestational age was found to have
      no influence on the prevalence of chromosomal aberrations. The incidence in the
      second and third trimesters of pregnancy was 15.7 and 17.5 per cent,
      respectively. The contribution of the different malformations to such proportions
      did, however, change throughout gestation. Cystic hygroma was by far predominant
      in the early second trimester, cardiac defects in the late second trimester, and
      duodenal atresia in late pregnancy. Our findings confirm that karyotyping of
      malformed fetuses is highly advisable; the importance of chromosomal
      investigation is not dependent on the gestational age at detection of the
      structural defect as the likelihood of finding a chromosomal anomaly during the
      second and third trimesters is quite similar. Spontaneous intrauterine selection
      of chromosomally abnormal fetuses is most likely counterbalanced by the limited
      accuracy of prenatal ultrasound in recognizing many fetal anomalies early in
      pregnancy.

PMID- 8650128
TI  - Cytogenetic analysis of fetal chondrocytes: a comparative study.
AB  - Progress in the prevention and prenatal detection of birth defects has led to a
      relative increase in the number of interruption of pregnancies associated with
      chromosomal abnormalities. There is an inverse relationship between the rate of
      success of fetal cell cultures and the interval between fetal demise and the
      initiation of culture. This report describes the cytogenetic analyses of cultured
      fetal chondrocytes compared with tissue cultures of fetal skin, fetal membranes,
      and placenta. The results show that cells obtained from the fetal chondrocostal
      junction and/or patella from missed abortions, intrauterine fetal deaths, or
      stillbirths can be cultured and successfully karyotyped. Since cartilage cells
      remain viable for some time after fetal demise, the culture of fetal chondrocytes
      is a complementary method for fetal chromosome analysis, especially in cases of
      tissue maceration after fetal demise. The success rate of chondrocyte cultures is
      similar to that of conventional fetal tissue cultures.

PMID- 8650129
TI  - Prenatal detection of two different monosomic cell lines by chorionic villus
      sampling.
AB  - We present a prenatal case of mosaicism with at least two monosomy cell lines:
      one with monosomy 21 (45,XY,-21) and one missing the Y (45,X) and a possible
      third 46,XY in chorionic villus cell culture. Cytogenetic studies were initiated
      following the ultrasound detection at 11 weeks of a large cystic hygroma and in
      utero growth retardation. Spontaneous fetal demise occurred at 12 weeks and the
      pregnancy was terminated. To our knowledge, this is the first report of two
      different monosomic cell lines found in chorionic villus cells.

PMID- 8650130
TI  - Prenatal ultrasound findings in hydrolethalus: continuing difficulties in
      diagnosis.
AB  - We present the prenatal ultrasound findings in a case of hydrolethalus. This case
      illustrates ongoing problems in differentiating hydrolethalus, both pre- and
      postnatally, from other midline malformation syndromes including Pallister-Hall,
      Smith-Lemli-Opitz, pseudo-trisomy 13, oral facial-digital syndrome, and Meckel
      syndrome. Hydrolethalus can also be difficult to distinguish from certain
      skeletal dysplasias such as the short rib-polydactyly syndromes and campomelic
      dysplasia. Tests which can aid in diagnosis are presented.

PMID- 8650132
TI  - Multiple-marker screen positive results in Noonan syndrome.

PMID- 8650131
TI  - Blood contamination of amniotic fluid after amniocentesis in relation to
      placental location.
AB  - The aim of the present study was to evaluate blood contamination of the amniotic
      fluid collected in 20 patients undergoing a second amniocentesis performed 2
      weeks after a first procedure that had failed due to Pseudomonas aeruginosa
      contamination of the cell cultures. Red blood cell and haemoglobin concentrations
      in the amniotic fluid were significantly higher in patients who had undergone a
      transplacental procedure compared with patients in whom the placenta was not
      traversed with the needle. For both groups, blood contamination of the amniotic
      fluid was significantly higher compared with a control group of 20 patients
      undergoing amniocentesis for the first time. Significant blood contamination of
      the amniotic fluid after amniocentesis occurs in every instance if evaluated at a
      "second-look' procedure; the blood contamination is higher when an anterior
      placenta is traversed with the needle. The clinical significance of these
      findings needs to be further evaluated.

PMID- 8650133
TI  - Current awareness in prenatal diagnosis.

PMID- 8650134
TI  - PK Mondor: prenatal diagnosis of a frameshift mutation in the LR pyruvate kinase
      gene associated with severe hereditary non-spherocytic haemolytic anaemia.
AB  - A mutant form of pyruvate kinase (PK) from the red blood cells of a
      consanguineous family with severe non-spherocytic haemolytic anaemia has been
      characterized by polymerase chain reaction (PCR) amplification and sequencing.
      The variant enzyme was named PK Mondor, according to the recommendations of the
      International Committee for Standardisation in Haematology. The propositus lacked
      PK activity and the low level of PK activity found resulted more likely from PK
      M2 (fetal isozyme) expression in the red blood cells of the propositus. PK Mondor
      corresponds to a frameshift mutation with deletion of one G in a repetition of
      four Gs in positions 1231-1234. This family, whose first child was stillborn and
      whose second was homozygous for the frameshift mutation, requested prenatal
      diagnosis during the third pregnancy. Diagnosis was made after chorionic biopsy
      by a specific approach combining PCR amplification and restriction enzyme
      digestion.

PMID- 8650135
TI  - [Pathology of autoimmune diseases. On the 80th Congress of the German Society of
      Pathology in Dresden 27 May - 1 June 1996].

PMID- 8650137
TI  - [Detection of atypical mycobacterial endophthalmitis by PCR].

PMID- 8650136
TI  - [Hyalinizing clear cell carcinoma of the salivary glands].
AB  - Many cell types of the salivary glands have clear cytoplasm. Causes of clear
      cytoplasmic quality in light microscopy are loss of organelles, storage of
      substances or fixation artefacts. Differential diagnosis of the different clear
      cell types requires special staining techniques, immunocytochemistry and electron
      microscopy. A new and distinct salivary gland neoplasm is hyalinizing clear cell
      carcinoma, which was not included in the second edition of the WHO Classification
      of Salivary Gland Tumors. Analysis of the collected cases of the Salivary Gland
      Register Hamburg and recent reports in the literature reveal that this carcinoma
      shows low-grade malignancy with localization usually in the minor salivary
      glands. Most cases occur in women. The pathohistology is characterized by solid
      or trabecular formations of polygonal clear cells which are surrounded by a broad
      hyalinized desmoplastic connective tissue stroma. The clear cells are mucin
      negative and express cytokeratin and EMA, in some cases also CEA, but not S-100
      protein, actin or other markers of myoepithelial cells. Ultrastructural findings
      are undifferentiated duct cells with only few organelles and inclusion of
      glycogen granules. The differential diagnosis includes other clear cell tumours,
      especially epithelial-myoepithelial carcinoma and the clear cell variants of
      myoepithelial carcinoma and acinic cell or mucoepidermoid carcinoma.

PMID- 8650138
TI  - [Low malignancy myxofibrosarcoma versus low malignancy fibromyxoid sarcoma.
      Distinct entities with similar names but different clinical course].
AB  - Low-grade myxofibrosarcoma (MFS) and low-grade fibromyxoid sarcoma (FMS) are two
      distinct entities in the spectrum of myxoid mesenchymal sarcomas with
      fibroblastic differentiation. Low-grade MFS is seen often in the extremities of
      elderly patients, subcutaneously more frequent than in deep soft tissues, whereas
      the majority of cases of low-grade FMS occur in young to middle-aged adults,
      commonly in deep soft tissues of the shoulder region, the extremities and the
      trunk. Histologically, low-grade MFS shows a multinodular growth pattern and is
      composed of round or polygonal tumour cells mixed with elongated, curvilinear,
      thin-walled blood vessels in a myxoid matrix. The tumour cell nuclei in low-grade
      MFS display at least moderate nuclear pleomorphism and hyperchromasia. Low-grade
      FMS, however, is composed of bland fusiform tumour cells arranged in a whorled or
      swirling pattern, or occasionally more linear, and set characteristically in an
      alternating fibrous and myxoid stroma. Low-grade MFS recurs frequently but has a
      very low metastatic potential, whereas low-grade FMS is characterised by an
      indolent but ultimately malignant clinical course with metastases in more than
      half of the cases, which underlines the importance of distinguishing between the
      two entities.

PMID- 8650139
TI  - [Tubular differentiated stomach carcinoma of the (Ming) infiltrating type].
AB  - Gastric carcinoma of the infiltrative type (according to Ming) occasionally shows
      adenomatous differentiation only. Over the past 18 years, we have observed 23
      cases of this tumour type, accounting for 3.6% of all surgically treated gastric
      carcinomas. Macroscopically they were classified as Borrmann IV or III, while
      histologically most of them were well differentiated. Histologically, these
      tumours retained the pre-existing structures of the stomach, most readily
      observable at the tunica muscularis propria; a pronounced desmoplasia was also
      characteristic, particularly in the submucosal and subserosal layers. In all
      cases the tumour tissue spread inside lymphatic vessels. All but 2 cases with
      metastatically involved lymph nodes, often small, showed infiltration of the
      lymph node sinus; in three quarters of cases the serosa was infiltrated by the
      tumour. Significant findings among the patients under observation for extended
      periods included bilateral ovarian metastases in 4 of 5 women examined and tumour
      recurrence at the anastomosis in 6 of 9 patients in whom Billroth II operation
      had been performed. The mean survival time of 16 patients was 14.9 months. Owing
      to the diffuse type of tumour growth, extensive surgery is recommended as in
      cases of signet ring cell cancer. The high incidence of small lymph node
      metastases from this type of tumour should also be taken in account preoperative
      staging. Preoperative diagnosis of this tumour subtype is difficult, because
      histological criteria alone do not allow clear identification. Close cooperation
      with clinical investigators is necessary, and intraoperative assessment of the
      tumour--including frozen section of necessary--in particular is of the utmost
      importance.

PMID- 8650140
TI  - [A histological technique for processing excised skin tumors for continuous tumor
      margin control].
AB  - In the treatment of basal cell carcinoma, squamous cell carcinoma and a number of
      other tumors of the skin, the recurrence rate is tenfold lower if they are
      treated with micrographic surgery in comparison with tumors, assessed by parallel
      histological sections. We demonstrated this in our investigations including over
      5900 cases. The rate of local recurrences in under 1%. The difference can be
      explained by the typical growth pattern of skin tumors. In the following article
      two simple methods of tissue processing are described, which can be used for
      formalin-fixed tissues and for fresh tissues.

PMID- 8650141
TI  - [Experiences with the NoToX formalin substitute solution].
AB  - "NoToX Histological Fixative" is a formaldehyde substitute for the fixation of
      tissues prior to histological investigation. Intraoperative samples and necropsy
      tissue were tested. NoToX was substituted for formaldehyde in the fixation step,
      otherwise the same manufacturer-specified protocols were used for all reagents.
      Conventional histological and accepted immunohistological investigations,
      especially for tumour diagnosis, were used. In all tests, results with NoToX
      fixated tissue were similar to those with tissue fixed with formaldehyde
      regarding both staining and diagnosis. NoToX is a useful substitute for
      formaldehyde.

PMID- 8650142
TI  - [Involvement of the large intestine in neurofibromatosis type 1].
AB  - This report presents the cases of two female patients aged 54 and 57 years, both
      with colon involvement of type 1 neurofibromatosis. The first woman had a
      polypoid neuronal hyperplasia containing small Wagner-Meissner corpuscles, which
      had allowed identification of the neuronal nature of the lesion in a small
      mucosal biopsy specimen taken previously. The second patient had an idiopathic
      megacolon of the sigmoid, which had to be extirpated because of acute obstruction
      and ileus. Morphological examination revealed a typical plexiform neurofibroma of
      the bowel wall and neuronal hyperplasia of the colonic mucosa and submucosa,
      which had obviously caused disordered gut mobility leading to functional stenosis
      and extreme dilatation of prestenotic bowel parts. Gastrointestinal
      neurofibromatosis is rare and is characterized morphologically by neuronal
      hyperplasia of the mucosa and submucosa, sometimes containing small aggregates of
      ganglion cells by which it can easily be identified. However, in the majority of
      cases the increase of proliferating mucosal nerve fibres can only be confirmed by
      S-100 protein immunostaining. Furthermore, solitary, multiple and plexiform
      neurofibromas are found, but only the last, which arises from mesenteric or
      subserosal nerves, is virtually pathognomonic for neurofibromatosis.
      Gastrointestinal neurofibromas are usually late manifestations of the disease,
      but in exceptional cases they can be the initial sign of neurofibromatosis in
      patients who have no external stigmata that arouse suspicion. The occurrence of
      gastrointestinal neurofibromas should therefore lead to a careful search for
      other features of NF-1 in the affected patients and in their families.

PMID- 8650143
TI  - [Solitary fibrous tumor of the epicardium].
AB  - A giant Solitary Fibrous Tumor (SFT) arising in the pericardium is described. A
      53 year old woman was suspected to have a lung tumor and thoracotomy was
      performed. Intraoperatively the child-head sized mass was found to be localized
      in the pericardial sac. The histopathological interpretation of a small wedge
      biopsy was 'endothelioma of uncertain malignancy' and heart-transplantation was
      performed two months later. The patient died of postoperative infection. Post
      mortem examination could exclude tumor rest or metastasis. The explanted heart
      revealed a large bulk of 2800 grams arising from the epicardium of the left
      chamber and enveloping the heart without invading the underlying myocardium. The
      histopathological pattern varied between cell-rich and -poor fibromatous areas
      and well capillarized endothelioma-like zones. Immunohistochemistry revealed
      positive reactions with monoclonal antibodies against Vimentin and CD 34 and no
      reactions against Cytokeratins and Faktor VIII. This pattern was confirmed in 7
      SFT's of the pleura from our archives. A second control group of 7 mesotheliomas
      was positive for cytokeratins and vimentin but not for CD 34 and Faktor VIII.
      Diagnosis of SFT might be difficult because of its variability in histopathology,
      sometimes mimicking a hemangiopericytoma or endothelioma. Recent reports of tumor
      localizations devoiding serosal surfaces illustrate the diagnostic and
      histogenetic dilemma of this tumor. The differentiation of SFT from mesothelioma
      and endothelioma can be achieved by immunophenotyping including CD 34.

PMID- 8650144
TI  - [Disseminated lipogranulomatosis (Farber disease) with hydrops fetalis].
AB  - We report on a female preterm infant of 29 weeks' gestation with severe hydrops
      fetalis who died 3 days post natum as a result of disseminated intravascular
      coagulation. Autopsy findings included anasarca, bilateral pleural effusions,
      ascites and hepatosplenomegaly as well as multiple, up to pinhead sized, white
      granulomas on the surface of liver, spleen and lungs. Microscopy revealed storage
      macrophages of the reticuloendothelial system, especially in liver, spleen and
      bone marrow, the lymphatic organs, the salivary glands, the thyroid gland and the
      suprarenal medulla. Cerebrum, heart, kidneys, intestines and placenta were not
      afflicted. Atrophy of the lymphatic compartments in the spleen, lymph nodes and
      thymus, as well as disorder of the liver texture, are presumably a secondary
      result. The diagnosis of Farber's disease was established biochemically by the
      demonstration of ceramide depositions in the spleen, and in fibroblast cultures
      in situ by the accumulation of ceramide released from loaded radioactive
      glucosylceramide. Ultrastructurally, corresponding storage lysosomes were found
      in macrophages. To our knowledge this is the first account of Farber's disease in
      a preterm infant with hydrops fetalis.

PMID- 8650145
TI  - [Alveolar adenoma of the lung. Immunohistochemical characterization of type II
      pneumocytes].
AB  - The alveolar adenoma of the lung is a rare benign tumor in which the normal
      parenchymal architecture is imitated by a proliferation of both the alveolar
      epithelial cells and the mesenchymal septal cells. The first description, based
      on six cases, was published in 1986 by Yousem and Hochholzer. From their
      ultrastructural findings they presumed a type II pneumocytes differentiation of
      the epithelial cells. We investigated an alveolar adenoma of the lung
      immunohistochemical by means of antibodies against apoprotein B and C of human
      surfactant. Both the lining cells and the macrophages in the alveolar-like spaces
      were stained. The septal connection tissue cells did not react. These findings
      confirm the expression of surfactant constituents and, hence, the differentiation
      into type II pneumocytes of the epithelial cells of the alveolar adenoma.

PMID- 8650146
TI  - [An unusual form of a pulmonary fat embolism in fulminant viral hepatitis].
AB  - A 28-year-old drug addict who had injected intravenously died of hepatic failure
      and coma caused by fulminant hepatitis (simultaneously: hepatitis A, persistent
      hepatitis B, hepatitis C and superinfection by delta hepatitis). Liver histology
      disclosed cirrhosis with severe necrotizing hepatitis and extensive
      microvesicular steatosis, compatible with a delta virus infection. Moderate
      pulmonary fat embolism (grade I-II according to Falzi) was accompanied by fat
      deposits in alveolar macrophages. It is postulated that protracted fat
      mobilization from necrotizing hepatocytes may be the cause of pulmonary fat
      embolism; the extravasation of fat from the vessels into the alveoli results in
      phagocytosis by alveolar macrophages.

PMID- 8650147
TI  - [Sclerosing adenosis of the prostate. Carcinoma simulation].
AB  - Sclerosing adenosis of the prostate is a benign lesion, which was not recognized
      until a few years ago. As in sclerosing adenosis of the breast, a background of
      various hyperplastic changes is commonly also present in the prostate. An
      incidence of 2.8% was reported in one series of resected hyperplastic prostatic
      glands. As demonstrated in this case report, the main problem lies in the
      differential diagnosis between sclerosing adenosis and highly differentiated
      adenocarcinoma of the prostate. Histological diagnosis of sclerosing adenosis
      based on routine HE sections is supplemented by immunohistochemical methods.
      Important diagnostic criteria of sclerosing adenosis are the presence of basal
      cell differentiation, which is demonstrated by cytokeratin 903, and signs of
      possible myoepithelial differentiation, with expression of S-100 and/or smooth
      muscle actin. These antibody expressions are lacking with in the presence of
      adenocarcinoma of the prostate. Nevertheless, in a small number of cases this
      differential diagnosis remains impossible, even after the application of
      immunohistochemical methods. Further studies are needed to shed some light on the
      relations between sclerosing adenosis, atypical adenomatous hyperplasia and
      adenocarcinoma of the prostate. So far, there appears to be no evidence of a
      direct relationship between sclerosing adenosis of the prostate and an elevated
      risk of carcinoma.

PMID- 8650148
TI  - [Proliferation kinetics of bronchioloalveolar tumorlets].
AB  - Bronchiolo-alveolar tumorlets--mostly clinically asymptomatic--generally are
      noticed as "contingent findings" in the diagnoses of interstitial fibrosing lung
      diseases. The growth fraction of these epithelial proliferates in the WHO
      classification summarized in the group of tumor like lesions was explored by
      immunohistochemical stainings with the PCNA and Ki67 (MIB1) antibodies and
      correlated with (pre-) neoplastic lesions of the lung. The proliferation indices
      varied between 0.029 to 0.67 (MIB1) and 0.057 to 0.81 (PCNA). Depending on the
      main disease the observation of cuboid metaplasias, areas of bronchiolization via
      tumorlets in inactive interstitial lung fibrosis up to bronchiolo alveolar
      tumorlets following interstitial lung disease after cytostatic treatment showed
      increasing proliferation indices. Accordingly to prencoplastic changes of the
      bronchial epithelium the findings suggest that interpretation of bronchiolo
      alveolar tumorlets as basic cells of malignant peripheral lung tumors seems to be
      possible. The value of these findings in relationship to the associated
      interstitial lung disease is discussed in the context of reflections related to
      the formal pathogenesis of so called scar cancer.

PMID- 8650150
TI  - A brief history of hemoglobins: plant, animal, protist, and bacteria.

PMID- 8650149
TI  - [Consensus report: tissue handling in suspected Creutzfeldt-Jakob disease and
      other spongiform encephalopathies (prion diseases) in the human. European Union
      Biomed-1 Concerted Action].
AB  - Despite many sensational and intimidating reports in the mass media,
      transmissible spongiform encephalopathies (prion diseases) are not contagious in
      the usual sense. Successful transmission requires both specific material (an
      affected individual's tissue, from or adjacent to CNS) and specific modes (mainly
      penetrating contact with the recipient). Nevertheless, specific safety
      precautions are mandatory to avoid accidental transmission and to decontaminate
      any infectivity. The autopsy is essential for definite diagnosis of these
      disorders. Recommendations are given here for safe performance of the autopsy,
      for neuropathology service and appropriate decontamination; they are based on the
      current literature and on precautions taken in most laboratories experienced in
      handling tissue from transmissible spongiform encephalopathies. In essence,
      special care must be taken to avoid penetrating wounds, possible contamination
      should be kept to a minimum, and potentially infectious material must be
      adequately decontaminated by specific means. The full English text of this
      Consensus Report was published in Brain Pathology 5: 319-322 (1995).

PMID- 8650151
TI  - Protein minimization: downsizing through mutation.

PMID- 8650152
TI  - A new hemoglobin gene from soybean: a role for hemoglobin in all plants.
AB  - We have isolated a new hemoglobin gene from soybean. It is expressed in
      cotyledons, stems of seedlings, roots, young leaves, and in some cells in the
      nodules that are associated with the nitrogen-fixing Bradyrhizobium symbiont.
      This contrasts with the expression of the leghemoglobins, which are active only
      in the infected cells of the nodules. The deduced protein sequence of the new
      gene shows only 58% similarity to one of the soybean leghemoglobins, but 85-87%
      similarity to hemoglobins from the nonlegumes Parasponia, Casuarina, and barley.
      The pattern of expression and the gene sequence indicate that this new gene is a
      nonsymbiotic legume hemoglobin. The finding of this gene in legumes and similar
      genes in other species strengthens our previous suggestion that genomes of all
      plants contain hemoglobin genes. The specialized leghemoglobin gene family may
      have arisen from a preexisting nonsymbiotic hemoglobin by gene duplication.

PMID- 8650153
TI  - Minimizing a binding domain from protein A.
AB  - We present a systematic approach to minimizing the Z-domain of protein A, a three
      helix bundle (59 residues total) that binds tightly (Kd = 10 nM) to the Fc
      portion of an immunoglobin IgG1. Despite the fact that all the contacts seen in
      the x-ray structure of the complex with the IgG are derived from residues in the
      first two helices, when helix 3 is deleted, binding affinity is reduced > 10(5)
      fold (Kd > 1 mM). By using structure-based design and phage display methods, we
      have iteratively improved the stability and binding affinity for a two-helix
      derivative, 33 residues in length, such that it binds IgG1, with a Kd of 43 nM.
      This was accomplished by stepwise selection of random mutations from three
      regions of the truncated Z-peptide: the 4 hydrophobic residues from helix 1 and
      helix 2 that contacted helix 3 (the exoface), followed by 5 residues between
      helix 1 and helix 2 (the intraface), and lastly by 19 residues at or near the
      interface that interacts with Fc (the interface). As selected mutations from each
      region were compiled (12 in total), they led to progressive increases in affinity
      for IgG, and concomitant increases in alpha-helical content reflecting increased
      stabilization of the two-helix scaffold. Thus, by sequential increases in the
      stability of the structure and improvements in the quality of the intermolecular
      contacts, one can reduce larger binding domains to smaller ones. Such mini
      protein binding domains are more amenable to synthetic chemistry and thus may be
      useful starting points for the design of smaller organic mimics. Smaller binding
      motifs also provide simplified and more tractable models for understanding
      determinants of protein function and stability.

PMID- 8650154
TI  - Modifications of RNA processing modulate the expression of hemoglobin genes.
AB  - The developmental changes in hemoglobin gene expression known as "switching"
      involve both the sequential activation and silencing of the individual globin
      genes. We postulated that in addition to changes in transcription,
      posttranscriptional mechanisms may be involved in modulating globin gene
      expression. We studied globin RNA transcripts in human adult erythroid cells
      (hAEC to analyze the mechanism of silencing of the embryonic epsilon-globin gene
      in the adult stage and in K562 erythroleukemic cells to analyze the inactive
      state of their adult beta-globin genes. In hAEC, which express primarily the beta
      globin gene, quantitative PCR analysis shows that beta-mRNA exon levels are high
      and comparable among the three exons; the RNA transcripts corresponding to exons
      of the gamma-globin gene are low, with slight differences among the three exons.
      Although epsilon-globin is not expressed, epsilon-globin RNA transcripts are
      detected, with exon I levels comparable to that of gamma-globin exon I and much
      higher than epsilon-exons II and III. As expected, in K562 cells that express
      high levels of epsilon- and gamma-globin, epsilon- and gamma-mRNA levels are
      high, with comparable levels of exons I, II, and III. In K562 cells beta-mRNA
      levels are very low but beta-exon I levels are much higher than that of exons II
      or III. Moreover, all or most of the globin transcripts for the highly expressed
      globin genes in both cell types (gamma and beta in hAEC, epsilon and gamma in
      K562 cells) found in the cytoplasm or nucleus are correctly processed. The globin
      transcripts that are detected both in the cytoplasm and nucleus of cells without
      expression of the corresponding protein are largely unspliced (containing one or
      two intervening sequences). These studies suggest that in addition to changes in
      transcription rates, changes in completion or processing of globin RNA
      transcripts may contribute to the developmental regulation of the hemoglobin
      phenotype.

PMID- 8650155
TI  - Activation and phosphorylation of a pleckstrin homology domain containing protein
      kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors.
AB  - Treatment of quiescent Swiss 3T3 fibroblasts with serum, or with the phosphatase
      inhibitors okadaic acid and vanadate, induced a 2- to 11-fold activation of the
      serine/ threonine RAC protein kinase (RAC-PK). Kinase activation was accompanied
      by decreased mobility of RAC-PK on SDS/PAGE such that three electrophoretic
      species (a to c) of the kinase were detected by immunoblot analysis, indicative
      of differentially phosphorylated forms. Addition of vanadate to arrested cells
      increased the RAC-PK phosphorylation level 3-to 4-fold. Unstimulated RAC-PK was
      phosphorylated predominantly on serine, whereas the activated kinase was
      phosphorylated on both serine and threonine residues. Treatment of RAC-PK in
      vitro with protein phosphatase 2A led to kinase inactivation and an increase in
      electrophoretic mobility. Deletion of the N-terminal region containing the
      pleckstrin homology domain did not affect RAC-PK activation by okadaic acid, but
      it reduced vanadate-stimulated activity and also blocked the serum-induced
      activation. Deletion of the serine/threonine rich C-terminal region impaired both
      RAC-PKalpha basal and vanadate-stimulated activity. Studies using a kinase
      deficient mutant indicated that autophosphorylation is not involved in RAC
      PKalpha activation. Stimulation of RAC-PK activity and electrophoretic mobility
      changes induced by serum were sensitive to wortmannin. Taken together the results
      suggest that RAC-PK is a component of a signaling pathway regulated by
      phosphatidylinositol (PI) 3-kinase, whose action is required for RAC-PK
      activation by phosphorylation.

PMID- 8650156
TI  - Second generation hybrid polar compounds are potent inducers of transformed cell
      differentiation.
AB  - Hybrid polar compounds, of which hexamethylenebisacetamide (HMBA) is the
      prototype, are potent inducers of differentiation of murine erythroleukemia (MEL)
      cells and a wide variety of other transformed cells. HMBA has been shown to
      induce differentiation of neoplastic cells in patients, but is not an adequate
      therapeutic agent because of dose-limiting toxicity. We report on a group of
      three potent second generation hybrid polar compounds, diethyl bis
      (pentamethylene-N,N-dimethylcarboxamide) malonate (EMBA), suberoylanilide
      hydroxamic acid (SAHA), and m-carboxycinnamic acid bis-hydroxamide (CBHA) with
      optimal concentrations for inducing MEL cells of 0.4 mM, 2 microM, and 4 microM,
      respectively, compared to 5 mM for HMBA. All three agents induce accumulation of
      underphosphorylated pRB; increased levels of p2l protein, a prolongation of the
      initial G1 phase of the cell cycle; and accumulation of hemoglobin. However,
      based upon their effective concentrations, the cross-resistance or sensitivity of
      an HMBA-resistant MEL cell variant, and differences in c-myb expression during
      induction, these differentiation-inducing hybrid polar compounds can be grouped
      into two subsets, HMBA/EMBA and SAHA/CBHA. This classification may prove of value
      in selecting and planning prospective preclinical and clinical studies toward the
      treatment of cancer by differentiation therapy.

PMID- 8650157
TI  - A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn
      superoxide dismutase mutant: An enhancement of free radical formation due to a
      decrease in Km for hydrogen peroxide.
AB  - Cu,Zn-superoxide dismutase (SOD) is known to be a locus of mutation in familial
      amyotrophic lateral sclerosis (FALS). Transgenic mice that express a mutant Cu,Zn
      SOD, Gly-93--> Ala (G93A), have been shown to develop amyotrophic lateral
      sclerosis (ALS) symptoms. We cloned the FALS mutant, G93A, and wild-type cDNA of
      human Cu,Zn-SOD, overexpressed them in Sf9 insect cells, purified the proteins,
      and studied their enzymic activities for catalyzing the dismutation of superoxide
      anions and the generation of free radicals with H2O2 as substrate. Our results
      showed that both enzymes contain one copper ion per subunit and have identical
      dismutation activity. However, the free radical-generating function of the G93A
      mutant, as measured by the spin trapping method, is enhanced relative to that of
      the wild-type enzyme, particularly at lower H2O2 concentrations. This is due to a
      small, but reproducible, decrease in the value of Km for H2O2 for the G93A
      mutant, while the kcat is identical for both enzymes. Thus, the ALS symptoms
      observed in G93A transgenic mice are not caused by the reduction of Cu,Zn-SOD
      activity with the mutant enzyme; rather, it is induced by a gain-of-function, an
      enhancement of the free radical-generating function. This is consistent with the
      x-ray crystallographic studies showing the active channel of the FALS mutant is
      slightly larger than that of the wild-type enzyme; thus, it is more accessible to
      H2O2. This gain-of-function, in part, may provide an explanation for the
      association between ALS and Cu,Zn-SOD mutants.

PMID- 8650158
TI  - Mutation of a conserved serine in TM4 of opioid receptors confers full agonistic
      properties to classical antagonists.
AB  - The involvement of a conserved serine (Ser196 at the mu-, Ser177 at the delta-,
      and Ser187 at the kappa-opioid receptor) in receptor activation is demonstrated
      by site-directed mutagenesis. It was initially observed during our functional
      screening of a mu/delta-opioid chimeric receptor, mu delta2, that classical
      opioid antagonists such as naloxone, naltrexone, naltriben, and H-Tyr
      Tic[psi,CH2NH]Phe-Phe-OH (TIPPpsi; Tic = 1,2,3,4-tetrahydroisoquinoline-3
      carboxylic acid) could inhibit forskolin-stimulated adenylyl cyclase activity in
      CHO cells stably expressing the chimeric receptor. Antagonists also activated the
      G protein-coupled inward rectifying potassium channel (GIRK1) in Xenopus oocytes
      coexpressing the mu delta2 opioid receptor and the GIRK1 channel. By sequence
      analysis and back mutation, it was determined that the observed antagonist
      activity was due to the mutation of a conserved serine to leucine in the fourth
      transmembrane domain (S196L). The importance of this serine was further
      demonstrated by analogous mutations created in the mu-opioid receptor (MORS196L)
      and delta-opioid receptor (DORS177L), in which classical opioid antagonists could
      inhibit forskolin-stimulated adenylyl cyclase activity in CHO cells stably
      expressing either MORS196L or DORS177L. Again, antagonists could activate the
      GIRK1 channel coexpressed with either MORS196L or DORS177L in Xenopus oocytes.
      These data taken together suggest a crucial role for this serine residue in
      opioid receptor activation.

PMID- 8650160
TI  - Maternal effort mediates the prevalence of trypanosomes in the offspring of a
      passerine bird.
AB  - The relationships between parental effort, offspring growth, and offspring blood
      parasitemias are poorly known. We examined the effect of parental effort on
      offspring size and prevalence of trypanosomes in peripheral blood of nestling
      Pied Flycatchers Ficedula hypoleuca aged 13 days. Trypanosome infections were
      likely to be shared by siblings, indicating the role of a common environment
      and/or shared genes in the susceptibility to infection. Broods infected by
      trypanosomes had reduced growth, but this was due to decreased parental,
      especially maternal, energy expenditure in broods with nestlings infected by
      trypanosomes. There was no association between parental infection with
      trypanosomes and both their energy expenditure and the infection of their broods.
      Under stressful conditions caused by low maternal energy expenditure, the immune
      response of nestlings during growth was probably impaired, in a way analogous to
      the relapses of blood parasitemias with reproductive effort in breeding animals.

PMID- 8650159
TI  - Adenylate kinase complements nucleoside diphosphate kinase deficiency in
      nucleotide metabolism.
AB  - Nucleoside diphosphate (NDP) kinase is a ubiquitous nonspecific enzyme that
      evidently is designed to catalyze in vivo ATP-dependent synthesis of ribo- and
      deoxyribonucleoside triphosphates from the corresponding diphosphates. Because
      Escherichia coli contains only one copy of ndk, the structural gene for this
      enzyme, we were surprised to find that ndk disruption yields bacteria that are
      still viable. These mutant cells contain a protein with a small amount NDP kinase
      activity. The protein responsible for this activity was purified and identified
      as adenylate kinase. This enzyme, also called myokinase, catalyzes the reversible
      ATP-dependent synthesis of ADP from AMP. We found that this enzyme from E. coli
      as well as from higher eukaryotes has a broad substrate specificity displaying
      dual enzymatic functions. Among the nucleoside monophosphate kinases tested, only
      adenylate kinase was found to have NDP kinase activity. To our knowledge, this is
      the first report of NDP kinase activity associated with adenylate kinase.

PMID- 8650161
TI  - A new adenoviral vector: Replacement of all viral coding sequences with 28 kb of
      DNA independently expressing both full-length dystrophin and beta-galactosidase.
AB  - Adenoviral vector-mediated gene transfer offers significant potential for gene
      therapy of many human diseases. However, progress has been slowed by several
      limitations. First, the insert capacity of currently available adenoviral vectors
      is limited to 8 kb of foreign DNA. Second, the expression of viral proteins in
      infected cells is believed to trigger a cellular immune response that results in
      inflammation and in only transient expression of the transferred gene. We report
      the development of a new adenoviral vector that has all viral coding sequences
      removed. Thus, large inserts are accommodated and expression of all viral
      proteins is eliminated. The first application of this vector system carries a
      dual expression cassette comprising 28.2 kb of nonviral DNA that includes the
      full-length murine dystrophin cDNA under control of a large muscle-specific
      promoter and a lacZ reporter construct. Using this vector, we demonstrate
      independent expression of both genes in primary mdx (dystrophin-deficient) muscle
      cells.

PMID- 8650162
TI  - Independent determination of symmetry and polarity in the Drosophila eye.
AB  - In each facet of the Drosophila compound eye, a cluster of photoreceptor cells
      assumes an asymmetric trapezoidal pattern. These clusters have opposite
      orientations above and below an equator, showing global dorsoventral mirror
      symmetry. However, in the mutant spiny legs, the polarization of each cluster
      appears to be random, so that no equator is evident. The apparent lack of an
      equator suggests that spiny legs+ may be involved in the establishment of global
      dorsoventral identity that might be essential for proper polarization of the
      photoreceptor clusters. Alternatively, a global dorsoventral pattern could be
      present, but spiny legs+ may be required for local polarization of individual
      clusters. Using an enhancer trap strain in which white+ gene expression is
      restricted to the dorsal field, we show that white+ expression in spiny legs
      correctly respects dorsoventral position even in facets with inappropriate
      polarizations; the dorsoventral boundary is indeed present, whereas the mechanism
      for polarization is perturbed. It is suggested that the boundary is established
      before the action of spiny legs+ by an independent mechanism.

PMID- 8650163
TI  - The nu gene acts cell-autonomously and is required for differentiation of thymic
      epithelial progenitors.
AB  - The nude mutation (nu) causes athymia and hairlessness, but the molecular
      mechanisms by which it acts have not been determined. To address the role of nu
      in thymogenesis, we investigated whether all or part of the nude thymic
      epithelium could be rescued by the presence of wild-type cells in nude <--> wild
      type chimeric mice. Detailed immunohistochemical analyses revealed that nude
      derived cells could persist in the chimeric thymus but could not contribute to
      cortical or medullary epithelial networks. Nude-derived cells, present in few
      clusters in the medulla, expressed markers of a rare subpopulation of adult
      medullary epithelium. The thymic epithelial rudiment of nude mice strongly
      expressed these same markers, which may therefore define committed immature
      thymic epithelial precursor cells. To our knowledge, these data provide the first
      evidence that the nu gene product acts cell-autonomously and is necessary for the
      development of all major subpopulations of mature thymic epithelium. We propose
      that nu acts to regulate growth and/or differentiation, but not determination, of
      thymic epithelial progenitors.

PMID- 8650164
TI  - Miniature endplate current rise times less than 100 microseconds from improved
      dual recordings can be modeled with passive acetylcholine diffusion from a
      synaptic vesicle.
AB  - We recorded miniature endplate currents (mEPCs) using simultaneous voltage clamp
      and extracellular methods, allowing correction for time course measurement
      errors. We obtained a 20-80% rise time (tr) of approximately 80 micros at 22
      degrees C, shorter than any previously reported values, and tr variability (SD)
      with an upper limit of 25-30 micros. Extracellular electrode pressure can
      increase tr and its variability by 2- to 3-fold. Using Monte Carlo simulations,
      we modeled passive acetylcholine diffusion through a vesicle fusion pore
      expanding radially at 25 nm x ms(-1) (rapid, from endplate omega figure
      appearance) or 0.275 nm x ms(-1) (slow, from mast cell exocytosis). Simulated
      mEPCs obtained with rapid expansion reproduced tr and the overall shape of our
      experimental mEPCs, and were similar to simulated mEPCs obtained with instant
      acetylcholine release. We conclude that passive transmitter diffusion, coupled
      with rapid expansion of the fusion pore, is sufficient to explain the time course
      of experimentally measured synaptic currents with trs of less than 100 micros.

PMID- 8650166
TI  - Direct observation of fast protein folding: the initial collapse of apomyoglobin.
AB  - The rapid refolding dynamics of apomyoglobin are followed by a new temperature
      jump fluorescence technique on a 15-ns to 0.5-ms time scale in vitro. The
      apparatus measures the protein-folding history in a single sweep in standard
      aqueous buffers. The earliest steps during folding to a compact state are
      observed and are complete in under 20 micros. Experiments on mutants and
      consideration of steady-state CD and fluorescence spectra indicate that the
      observed microsecond phase monitors assembly of an A x (H x G) helix subunit.
      Measurements at different viscosities indicate diffusive behavior even at low
      viscosities, in agreement with motions of a solvent-exposed protein during the
      initial collapse.

PMID- 8650165
TI  - Stimulation of new bone formation by direct transfer of osteogenic plasmid genes.
AB  - Degradable matrices containing expression plasmid DNA [gene-activated matrices
      (GAMs)] were implanted into segmental gaps created in the adult rat femur.
      Implantation of GAMs containing beta-galactosidase or luciferase plasmids led to
      DNA uptake and functional enzyme expression by repair cells (granulation tissue)
      growing into the gap. Implantation of a GAM containing either a bone
      morphogenetic protein-4 plasmid or a plasmid coding for a fragment of parathyroid
      hormone (amino acids 1-34) resulted in a biological response of new bone filling
      the gap. Finally, implantation of a two-plasmid GAM encoding bone morphogenetic
      protein-4 and the parathyroid hormone fragment, which act synergistically in
      vitro, caused new bone to form faster than with either factor alone. These
      studies demonstrate for the first time that repair cells (fibroblasts) in bone
      can be genetically manipulated in vivo. While serving as a useful tool to study
      the biology of repair fibroblasts and the wound healing response, the GAM
      technology may also have wide therapeutic utility.

PMID- 8650167
TI  - Segregation of DNA polynucleotide strands into sister chromatids and the use of
      endoreduplicated cells to track sister chromatid exchanges induced by crosslinks,
      alkylations, or x-ray damage.
AB  - The method of Matsumoto and Ohta [Matsumoto, K. & Ohta, T. (1992) Chromosoma 102,
      60-65; Matsumoto, K. & Ohta, T. (1995) Mutat. Res. 326, 93-98] to induce large
      numbers of endoreduplicated Chinese hamster ovary cells has now been coupled with
      the fluorescence-plus-Giemsa method of Perry and Wolff [Perry, P. & Wolff, S.
      (1974) Nature (London) 251, 156-158] to produce harlequin endoreduplicated
      chromosomes that after the third round of DNA replication are composed of a
      chromosome with a light chromatid and a dark chromatid in close apposition to its
      sister chromosome containing two light chromatids. Unless the pattern is
      disrupted by sister chromatid exchange (SCE), the dark chromatid is always in the
      center, so that the order of the chromatids is light-dark light-light. The advent
      of this method, which permits the observation of SCEs in endoreduplicated cells,
      makes it possible to determine with great ease in which cell cycle an SCE
      occurred. This now allows us to approach several vexing questions about the
      induction of SCEs (genetic damage and its repair) after exposure to various types
      of mutagenic carcinogens. The present experiments have allowed us to observe how
      many cell cycles various types of lesions that are induced in DNA by a
      crosslinking agent, an alkylating agent, or ionizing radiation, and that are
      responsible for the induction of SCEs, persist before being repaired and thus
      lose their ability to inflict genetic damage. Other experiments with various
      types of mutagenic carcinogens and various types of cell lines that have defects
      in different DNA repair processes, such as mismatch repair, excision repair,
      crosslink repair, and DNA-strand-break repair, can now be carried out to
      determine the role of these types of repair in removing specific types of
      lesions.

PMID- 8650168
TI  - Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the
      multistress response in Saccharomyces cerevisiae.
AB  - The stress response promoter element (STRE) confers increased transcription to a
      set of genes following environmental or metabolic stress in Saccharomyces
      cerevisiae. A lambda gt11 library was screened to isolate clones encoding STRE
      binding proteins, and one such gene was identified as MSN2, which encoded a zinc
      finger transcriptional activator. Disruption of the MSN2 gene abolished an STRE
      binding activity in crude extracts as judged by both gel mobility-shift and
      Southwestern blot experiments, and overexpression of MSN2 intensified this
      binding activity. Northern blot analysis demonstrated that for the known or
      suspected STRE-regulated genes DDR2, CTT1, HSP12, and TPS2, transcript induction
      was impaired following heat shock or DNA damage treatment in the msn2-disrupted
      strain and was constitutively activated in a strain overexpressing MSN2.
      Furthermore, heat shock induction of a STRE-driven reporter gene was reduced more
      than 6-fold in the msn2 strain relative to wild-type cells. Taken together, these
      data indicate that Msn2p is the transcription factor that activates STRE
      regulated genes in response to stress. Whereas nearly 85% of STRE-mediated heat
      shock induction was MSN2 dependent, there was significant MSN2-independent
      expression. We present evidence that the MSN2 homolog, MSN4, can partially
      replace MSN2 for transcriptional activation following stress. Moreover, our data
      provides evidence for the involvement of additional transcription factors in the
      yeast multistress response.

PMID- 8650169
TI  - Granzyme A is critical for recovery of mice from infection with the natural
      cytopathic viral pathogen, ectromelia.
AB  - Cytolytic lymphocytes are of cardinal importance in the recovery from primary
      viral infections. Both natural killer cells and cytolytic T cells mediate at
      least part of their effector function by target cell lysis and DNA fragmentation.
      Two proteins, perforin and granzyme B, contained within the cytoplasmic granules
      of these cytolytic effector cells have been shown to be directly involved in
      these processes. A third protein contained within these granules, granzyme A, has
      so far not been attributed with any biological relevance. Using mice deficient
      for granzyme A, we show here that granzyme A plays a crucial role in recovery
      from the natural mouse pathogen, ectromelia, by mechanisms other than cytolytic
      activity.

PMID- 8650170
TI  - Purification of the Drosophila RNA polymerase II general transcription factors.
AB  - We describe a fractionation and purification scheme for the Drosophila RNA
      polymerase II general transcription factors. Drosophila TFIIE, TFIIF, TFIIH, and
      RNA polymerase II have been purified to greater than 50% homogeneity from
      Drosophila embryo nuclear extracts. TFIID has been purified 80-fold and is not
      significantly contaminated with any of the other general factors. This is the
      first reported identification and purification of Drosophila TFIIH and TFIIE.
      Further analysis shows that, similar to their mammalian counterparts, Drosophila
      TFIIH is composed of eight polypeptides sized between 30 and 100 kDa, and
      Drosophila TFIIE is composed of two polypeptides sized at 34 and 60 kDa. When all
      of these fractions are combined with recombinant Drosophila TFlIB, a highly
      purified in vitro transcription system is generated that has not previously been
      available in Drosophila. The TFIID fraction can be replaced with recombinant
      Drosophila TBP to give a transcription system that is nearly free of
      contaminating proteins.

PMID- 8650172
TI  - Behavior predicts genes structure in a wild primate group.
AB  - The predictability of genetic structure from social structure and differential
      mating success was tested in wild baboons. Baboon populations are subdivided into
      cohesive social groups that include multiple adults of both sexes. As in many
      mammals, males are the dispersing sex. Social structure and behavior successfully
      predicted molecular genetic measures of relatedness and variance in reproductive
      success. In the first quantitative test of the priority-of-access model among
      wild primates, the reproductive priority of dominant males was confirmed by
      molecular genetic analysis. However, the resultant high short-term variance in
      reproductive success did not translate into equally high long-term variance
      because male dominance status was unstable. An important consequence of high but
      unstable short-term variance is that age cohorts will tend to be paternal
      sibships and social groups will be genetically substructured by age.

PMID- 8650171
TI  - Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1
      adipocytes.
AB  - Lack of leptin (ob) protein causes obesity in mice. The leptin gene product is
      important for normal regulation of appetite and metabolic rate and is produced
      exclusively by adipocytes. Leptin mRNA was induced during the adipose conversion
      of 3T3-L1 cells, which are useful for studying adipocyte differentiation and
      function under controlled conditions. We studied leptin regulation by
      antidiabetic thiazolidinedione compounds, which are ligands for the adipocyte
      specific nuclear receptor peroxisome proliferator-activated receptor gamma
      (PPARgamma) that regulates the transcription of other adipocyte-specific genes.
      Remarkably, leptin gene expression was dramatically repressed within a few hours
      after thiazolidinedione treatment. The ED50 for inhibition of leptin expression
      by the thiazolidinedione BRL49653 was between 5 and 50 nM, similar to its Kd for
      binding to PPARgamma. The relatively weak, nonthiazolidinedione PPAR activator WY
      14,643 also inhibited leptin expression, but was approximately 1000 times less
      potent than BRL49653. These results indicate that antidiabetic thiazolidinediones
      down-regulate leptin gene expression with potencies that correlate with their
      abilities to bind and activate PPARgamma.

PMID- 8650173
TI  - The embryonic transcription factor stage specific activator protein contains a
      potent bipartite activation domain that interacts with several RNA polymerase II
      basal transcription factors.
AB  - Stage specific activator protein (SSAP) is a member of a newly discovered class
      of transcription factors that contain motifs more commonly found in RNA-binding
      proteins. Previously, we have shown that SSAP specifically binds to its
      recognition sequence in both the double strand and the single strand form and
      that this DNA-binding activity is localized to the N-terminal RNA recognition
      motif domain. Three copies of this recognition sequence constitute an enhancer
      element that is directly responsible for directing the transcriptional activation
      of the sea urchin late histone H1 gene at the midblastula stage of embryogenesis.
      Here we show that the remainder of the SSAP polypeptide constitutes an extremely
      potent bipartite transcription activation domain that can function in a variety
      of mammalian cell lines. This activity is as much as 3 to 5 times stronger than
      VP16 at activating transcription and requires a large stretch of amino acids that
      contain glutamine-glycine rich and serine-threonine-basic amino acid rich
      regions. We present evidence that SSAP's activation domain shares targets that
      are also necessary for activation by E1a and VP16. Finally, SSAP's activation
      domain is found to participate in specific interactions in vitro with the basal
      transcription factors TATA-binding protein, TFIIB, TFIIF74, and dTAF(II) 110.

PMID- 8650175
TI  - Global properties of the mapping between local amino acid sequence and local
      structure in proteins.
AB  - Local protein structure prediction efforts have consistently failed to exceed
      approximately 70% accuracy. We characterize the degeneracy of the mapping from
      local sequence to local structure responsible for this failure by investigating
      the extent to which similar sequence segments found in different proteins adopt
      similar three-dimensional structures. Sequence segments 3-15 residues in length
      from 154 different protein families are partitioned into neighborhoods containing
      segments with similar sequences using cluster analysis. The consistency of the
      sequence-to-structure mapping is assessed by comparing the local structures
      adopted by sequence segments in the same neighborhood in proteins of known
      structure. In the 154 families, 45% and 28% of the positions occur in
      neighborhoods in which one and two local structures predominate, respectively.
      The sequence patterns that characterize the neighborhoods in the first class
      probably include virtually all of the short sequence motifs in proteins that
      consistently occur in a particular local structure. These patterns, many of which
      occur in transitions between secondary structural elements, are an interesting
      combination of previously studied and novel motifs. The identification of
      sequence patterns that consistently occur in one or a small number of local
      structures in proteins should contribute to the prediction of protein structure
      from sequence.

PMID- 8650174
TI  - HslV-HslU: A novel ATP-dependent protease complex in Escherichia coli related to
      the eukaryotic proteasome.
AB  - We have isolated a new type of ATP-dependent protease from Escherichia coli. It
      is the product of the heat-shock locus hslVU that encodes two proteins: HslV, a
      19-kDa protein similar to proteasome beta subunits, and HslU, a 50-kDa protein
      related to the ATPase ClpX. In the presence of ATP, the protease hydrolyzes
      rapidly the fluorogenic peptide Z-Gly-Gly-Leu-AMC and very slowly certain other
      chymotrypsin substrates. This activity increased 10-fold in E. coli expressing
      heat-shock proteins constitutively and 100-fold in cells expressing HslV and HslU
      from a high copy plasmid. Although HslV and HslU could be coimmunoprecipitated
      from cell extracts of both strains with an anti-HslV antibody, these two
      components were readily separated by various types of chromatography. ATP
      stimulated peptidase activity up to 150-fold, whereas other nucleoside
      triphosphates, a nonhydrolyzable ATP analog, ADP, or AMP had no effect. Peptidase
      activity was blocked by the anti-HslV antibody and by several types of inhibitors
      of the eukaryotic proteasome (a threonine protease) but not by inhibitors of
      other classes of proteases. Unlike eukaryotic proteasomes, the HslVU protease
      lacked tryptic-like and peptidyl-glutamyl-peptidase activities. Electron
      micrographs reveal ring-shaped particles similar to en face images of the 20S
      proteasome or the ClpAP protease. Thus, HslV and HslU appear to form a complex in
      which ATP hydrolysis by HslU is essential for peptide hydrolysis by the
      proteasome-like component HslV.

PMID- 8650176
TI  - Receptor stimulation causes slow inhibition of IRK1 inwardly rectifying K+
      channels by direct protein kinase A-mediated phosphorylation.
AB  - Strongly rectifying IRK-type inwardly rectifying K+ channels are involved in the
      control of neuronal excitability in the mammalian brain. Whole-cell patch-clamp
      experiments show that cloned rat IRK1 (Kir 2.1) channels, when heterologously
      expressed in mammalian COS-7 cells, are inhibited following the activation of
      coexpressed serotonin (5-hydroxytryptamine) type 1A receptors by receptor
      agonists. Inhibition is mimicked by internal perfusion with GTP[gamma-S] and
      elevation of internal cAMP concentrations. Addition of the catalytic subunits of
      protein kinase A (PKA) to the internal recording solution causes complete
      inhibition of wild-type IRK1 channels, but not of mutant IRK1(S425N) channels in
      which a C-terminal PKA phosphorylation site has been removed. Our data suggest
      that in the nervous system serotonin may negatively control IRK1 channel activity
      by direct PKA-mediated phosphorylation.

PMID- 8650177
TI  - A single mutation that increases maize seed weight.
AB  - The maize endosperm-specific gene shrunken2 (Sh2) encodes the large subunit of
      the heterotetrameric starch synthetic enzyme adenosine diphosphoglucose
      pyrophosphorylase (AGP; EC 2.7.7.27). Here we exploit an in vivo, site-specific
      mutagenesis system to create short insertion mutations in a region of the gene
      known to be involved in the allosteric regulation of AGP. The site-specific
      mutagen is the transposable element dissociation (Ds). Approximately one-third (8
      of 23) of the germinal revertants sequenced restored the wild-type sequence,
      whereas the remaining revertants contained insertions of 3 or 6 bp. All
      revertants retained the original reading frame 3' to the insertion site and
      involved the addition of tyrosine and/or serine. Each insertion revertant reduced
      total AGP activity and the amount of the SH2 protein. The revertant containing
      additional tyrosine and serine residues increased seed weight 11-18% without
      increasing or decreasing the percentage of starch. Other insertion revertants
      lacking an additional serine reduced seed weight. Reduced sensitivity to
      phosphate, a long-known inhibitor of AGP, was found in the high seed-weight
      revertant. This alteration is likely universally important since insertion of
      tyrosine and serine in the potato large subunit of AGP at the comparable position
      and expression in Escherichia coli also led to a phosphate-insensitive enzyme.
      These results show that single gene mutations giving rise to increased seed
      weight, and therefore perhaps yield, are clearly possible in a plant with a long
      history of intensive and successful breeding efforts.

PMID- 8650178
TI  - Activating transcription from single stranded DNA.
AB  - Sequence specific regulators of eukaryotic gene expression, axiomatically, act
      through double stranded DNA targets. Proteins that recognize DNA cis-elements as
      single strands but for which compelling evidence has been lacking to indicate in
      vivo involvement in transcription are orphaned in this scheme. We sought to
      determine whether sequence specific single strand binding proteins can find their
      cognate elements and modify transcription in vivo by studying heterogeneous
      nuclear ribonucleoprotein K (hnRNP K), which binds the single stranded sequence
      (CCCTCCCCA; CT-element) of the human c-myc gene in vitro. To monitor its DNA
      binding in vivo, the ability of hnRNP K to activate a reporter gene was amplified
      by fusion with the VP16 transactivation domain. This chimeric protein was found
      to transactivate circular but not linear CT-element driven reporters, suggesting
      that hnRNP K recognizes a single strand region generated by negative supercoiling
      in circular plasmid. When CT-elements were engineered to overlap with lexA
      operators, addition of lexA protein, either in vivo or in vitro, abrogated hnRNP
      K binding most likely by preventing single strand formation. These results not
      only reveal hnRNP K to be a single strand DNA binding protein in vivo, but
      demonstrate how a segment of DNA may modify the transcriptional activity of an
      adjacent gene through the interconversion of duplex and single strands.

PMID- 8650179
TI  - Voltage gating and permeation in a gap junction hemichannel.
AB  - Gap junction channels are formed by members of the connexin gene family and
      mediate direct intercellular communication through linked hemichannels
      (connexons) from each of two adjacent cells. While for most connexins, the
      hemichannels appear to require an apposing hemichannel to open, macroscopic
      currents obtained from Xenopus oocytes expressing rat Cx46 suggested that some
      hemichannels can be readily opened by membrane depolarization [Paul, D. L.,
      Ebihara, L., Takemoto, L. J., Swenson, K. I. & Goodenough, D. A. (1991), J. Cell
      Biol. 115, 1077-1089]. Here we demonstrate by single channel recording that
      hemichannels comprised of rat Cx46 exhibit complex voltage gating consistent with
      there being two distinct gating mechanisms. One mechanism partially closes Cx46
      hemichannels from a fully open state, gammaopen, to a substate, gammasub, about
      one-third of the conductance of gammaopen; these transitions occur when the cell
      is depolarized to inside positive voltages, consistent with gating by
      transjunctional voltage in Cx46 gap junctions. The other gating mechanism closes
      Cx46 hemichannels to a fully closed state, gammaclosed, on hyperpolarization to
      inside negative voltages and has unusual characteristics; transitions between
      gammaclosed and gammaopen appear slow (10-20 ms), often involving several
      transient substates distinct from gammasub. The polarity of activation and
      kinetics of this latter form of gating indicate that it is the mechanism by which
      these hemichannels open in the cell surface membrane when unapposed by another
      hemichannel. Cx46 hemichannels display a substantial preference for cations over
      anions, yet have a large unitary conductance (approximately 300 pS) and a
      relatively large pore as inferred from permeability to tetraethylammonium
      (approximately 8.5 angstroms diameter). These hemichannels open at physiological
      voltages and could induce substantial cation fluxes in cells expressing Cx46.

PMID- 8650180
TI  - A JAK-STAT pathway regulates wing vein formation in Drosophila.
AB  - We present evidence that the JAK-STAT signal transduction pathway regulates
      multiple developmental processes in Drosophila. We screened for second-site
      mutations that suppress the phenotype of the hyperactive hopTum-1 Jak kinase, and
      recovered a mutation that meiotically maps to the known chromosomal position of D
      Stat, a Drosophila stat gene. This hypomorphic mutation, termed statHJ contains a
      nucleotide substitution in the first D-Stat intron, resulting in a reduction in
      the number of correctly processed transcripts. Further, the abnormally processed
      mRNA encodes a truncated protein that has a dominant negative effect on
      transcriptional activation by the wild-type cDNA in cell culture. statHJ mutants
      exhibit patterning defects that include the formation of ectopic wing veins,
      similar to those seen in mutants of the epidermal growth factor/receptor pathway.
      Abnormalities in embryonic and adult segmentation and in tracheal development
      were also observed. The hopTum-1 and statHJ mutations can partially compensate
      for each other genetically, and Hop overexpression can increase D-Stat
      transcriptional activity in vitro, indicating that the gene products interact in
      a common regulatory pathway.

PMID- 8650181
TI  - Two genes abrogate the inhibition of murine hepatocarcinogenesis by ovarian
      hormones.
AB  - Hormonal and genetic factors strongly influence the susceptibility of inbred mice
      to hepatocarcinogenesis. Female C57BR/cdJ (BR) mice are extremely susceptible to
      liver tumor induction relative to other strains because they are genetically
      insensitive to the inhibition of hepatocarcinogenesis by ovarian hormones. To
      determine the genetic basis for the sensitivity of BR mice relative to resistant
      C57BL/6J (B6) mice, we treated 12-day-old B6BRF1 x B6 and B6BRF1 x B6BRF1 (F2)
      animals with N,N-diethylnitrosamine (0.1 micromol/g of body weight) and
      enumerated liver tumors at 32 weeks of age in males and at 50 weeks in females.
      Genomic DNA samples from backcross and F2 mice were analyzed for 70 informative
      simple sequence length polymorphism markers. Genetic markers on chromosome 17
      (D17Mit21) and chromosome 1 (D1Mit33) cosegregated with high tumor multiplicity
      in both sexes. Together, these loci [designated Hcf1 and Hcf2
      (Hepatocarcinogenesis in females), respectively] account for virtually all of the
      difference in sensitivity between BR and B6 mice. The Hcf1 locus accounts for a
      majority of the higher susceptibility of BR mice of both sexes. Backcross female
      mice heterozygous at both loci (33 +/- 23 tumors per mouse) and at Hcf1 only (17
      +/- 18) were 15- and 8-fold more sensitive, respectively, than mice homozygous
      for the B6 alleles at Hcf1 and Hcf2 (2.2 +/- 3.9). In backcross male mice, the
      double heterozygotes (35 +/- 22) and Hcf1 heterozygotes (28 +/- 12) were 5.4- and
      4.3-fold more sensitive than mice homozygous for B6 alleles at both loci (6.5 +/-
      5.4).

PMID- 8650182
TI  - Similarities and dissimilarities of phage genomes.
AB  - Genomic similarities and contrasts are investigated in a collection of 23
      bacteriophages, including phages with temperate, lytic, and parasitic life
      histories, with varied sequence organizations and with different hosts and with
      different morphologies. Comparisons use relative abundances of di-, tri-, and
      tetranucleotides from entire genomes. We highlight several specific findings. (i)
      As previously shown for cellular genomes, each viral genome has a distinctive
      signature of short oligonucleotide abundances that pervade the entire genome and
      distinguish it from other genomes. (ii) The enteric temperate double-stranded
      (ds) phages, like enterobacteria, exhibit significantly high relative abundances
      of GpC = GC and significantly low values of TA, but no such extremes exist in ds
      lytic phages. (iii) The tetranucleotide CTAG is of statistically low relative
      abundance in most phages. (iv) The DAM methylase site GATC is of statistically
      low relative abundance in most phages, but not in P1. This difference may relate
      to controls on replication (e.g., actions of the host SeqA gene product) and to
      MutH cleavage potential of the Escherichia coli DAM mismatch repair system. (v)
      The enteric temperate dsDNA phages form a coherent group: they are relatively
      close to each other and to their bacteria] hosts in average differences of
      dinucleotide relative abundance values. By contrast, the lytic dsDNA phages do
      not form a coherent group. This difference may come about because the temperate
      phages acquire more sequence characteristics of the host because they use the
      host replication and repair machinery, whereas the analyzed lytic phages are
      replicated by their own machinery. (vi) The nonenteric temperate phages with
      mycoplasmal and mycobacterial hosts are relatively close to their respective
      hosts and relatively distant from any of the enteric hosts and from the other
      phages. (vii) The single-stranded RNA phages have dinucleotide relative abundance
      values closest to those for random sequences, presumably attributable to the
      mutation rates of RNA phages being much greater than those of DNA phages.

PMID- 8650183
TI  - Efficient in vivo manipulation of mouse genomic sequences at the zygote stage.
AB  - We describe a transgenic mouse line carrying the cre transgene under the control
      of the adenovirus EIIa promoter that targets expression of the Cre recombinase to
      the early mouse embryo. To assess the ability of this recombinase to excise loxP
      flanked DNA sequences at early stages of development, we bred EIIa-cre transgenic
      mice to two different mouse lines carrying loxP-flanked target sequences: (i) a
      strain with a single gene-targeted neomycin resistance gene flanked by 1oxP sites
      and (ii) a transgenic line carrying multiple transgene copies with internal loxP
      sites. Mating either of these loxP-carrying mouse lines to EIIa-cre mice resulted
      in first generation progeny in which the loxP-flanked sequences had been
      efficiently deleted from all tissues tested, including the germ cells.
      Interbreeding of these first generation progeny resulted in efficient germ-line
      transmission of the deletion to subsequent generations. These results demonstrate
      a method by which loxP-flanked DNA sequences can be efficiently deleted in the
      early mouse embryo. Potential applications of this approach are discussed,
      including reduction of multicopy transgene loci to produce single-copy transgenic
      lines and introduction of a variety of subtle mutations into the line.

PMID- 8650184
TI  - Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and
      neural crest development.
AB  - Factors that regulate cellular migration during embryonic development are
      essential for tissue and organ morphogenesis. Scatter factor/hepatocyte growth
      factor (SF/HGF) can stimulate motogenic and morphogenetic activities in cultured
      epithelial cells expressing the Met tyrosine kinase receptor and is essential for
      development; however, the precise physiological role of SF/HGF is incompletely
      understood. Here we provide functional evidence that inappropriate expression of
      SF/HGF in transgenic mice influences the development of two distinct migratory
      cell lineages, resulting in ectopic skeletal muscle formation and melanosis in
      the central nervous system, and patterned hyperpigmentation of the skin.
      Committed TRP-2 positive melanoblasts were found to be situated aberrantly within
      defined regions of the transgenic embryo, including the neural tube, which
      overproduced SF/RGF. Our data strongly suggest that SF/HGF possesses
      physiologically relevant scatter activity, and functions as a true morphogenetic
      factor by regulating migration and/or differentiation of select populations of
      premyogenic and neural crest cells during normal mammalian embryogenesis.

PMID- 8650185
TI  - Conformational trapping in a membrane environment: a regulatory mechanism for
      protein activity?
AB  - Functional regulation of proteins is central to living organisms. Here it is
      shown that a nonfunctional conformational state of a polypeptide can be
      kinetically trapped in a lipid bilayer environment. This state is a metastable
      structure that is stable for weeks just above the phase transition temperature of
      the lipid. When the samples are incubated for several days at 68 degrees C, 50%
      of the trapped conformation converts to the minimum-energy functional state. This
      result suggests the possibility that another mechanism for functional regulation
      of protein activity may be available for membrane proteins: that cells may insert
      proteins into membranes in inactive states pending the biological demand for
      protein function.

PMID- 8650187
TI  - Calcium-dependent oligonucleotide antagonists specific for L-selectin.
AB  - The selectins are calcium-dependent C-type lectins that recognize complex anionic
      carbohydrate ligands, initiating many cell-cell interactions in the vascular
      system. Selectin blockade shows therapeutic promise in a variety of inflammatory
      and postischemic pathologies. However, the available oligosaccharide ligand
      mimetics have low affinities and show cross-reaction among the three selectins,
      precluding efficient and specific blockade. The SELEX (systematic evolution of
      ligands by exponential enrichment) process uses combinatorial chemistry and in
      vitro selection to yield high affinity oligonucleotides with unexpected binding
      specificities. Nuclease-stabilized randomized oligonucleotides subjected to SELEX
      against recombinant L-selectin yielded calcium-dependent antagonists with
      approximately 10(5) higher affinity than the conventional oligosaccharide ligand
      sialyl LewisX. Most of the isolated ligands shared a common consensus sequence.
      Unlike sialyl LewisX, these antagonists show little binding to E- or P-selectin.
      Moreover, they show calcium-dependent binding to native L-selectin on peripheral
      blood lymphocytes and block L-selectin-dependent interactions with the natural
      ligands on high endothelial venules.

PMID- 8650186
TI  - The recombinant proregion of transforming growth factor beta1 (latency-associated
      peptide) inhibits active transforming growth factor beta1 in transgenic mice.
AB  - All three isoforms of transforming growth factors beta (TGF-betal, TGF-beta2, and
      TGF-beta3) are secreted as latent complexes and activated extracellularly,
      leading to the release of the mature cytokines from their noncovalently
      associated proregions, also known as latency-associated peptides (LAPs). The LAP
      region of TGF-beta1 was expressed in a baculovirus expression system and purified
      to homogeneity. In vitro assays of growth inhibition and gene induction mediated
      by TGF-beta3 demonstrate that recombinant TGF-beta1 LAP is a potent inhibitor of
      the activities of TGF-betal, -beta2, and -beta3. Effective dosages of LAP for 50%
      neutralization of TGF-beta activities range from 4.7- to 80-fold molar excess
      depending on the TGF-beta isoform and activity examined. Using 125I-labeled LAP,
      we show that the intraperitoneal application route is effective for systemic
      administration of LAP. Comparison of concentrations of LAP in tissues shows a
      homogenous pattern in most organs with the exception of heart and muscle, in
      which levels of LAP are 4- to 8-fold lower. In transgenic mice with elevated
      hepatic levels of bioactive TGF-betal, treatment with recombinant LAP completely
      reverses suppression of the early proliferative response induced by TGF-beta1 in
      remnant livers after partial hepatectomy. The results suggest that recombinant
      LAP is a potent inhibitor of bioactive TGF-beta both in vitro and in vivo, after
      intraperitoneal administration. Recombinant LAP should be a useful tool for novel
      approaches to study and therapeutically modulate pathophysiological processes
      mediated by TGF-beta3.

PMID- 8650188
TI  - Enhanced green fluorescence by the expression of an Aequorea victoria green
      fluorescent protein mutant in mono- and dicotyledonous plant cells.
AB  - The expression of the jellyfish green fluorescent protein (GFP) in plants was
      analyzed by transient expression in protoplasts from Nicotiana tabacum,
      Arabidopsis thaliana, Hordeum vulgare, and Zea mays. Expression of GFP was only
      observed with a mutated cDNA, from which a recently described cryptic splice site
      had been removed. However, detectable levels of green fluorescence were only
      emitted from a small number of protoplasts. Therefore, other mutations in the GFP
      cDNA leading to single-amino acid exchanges in the chromophore region, which had
      been previously studied in Escherichia coli, were tested in order to improve the
      sensitivity of this marker protein. Of the mutations tested so far, the exchange
      of GFP amino acid tyrosine 66 to histidine (Y66H) led to detection of blue
      fluorescence in plant protoplasts, while the exchange of amino acid serine 65 to
      cysteine (S65C) and threonine (S65T) increased the intensity of green
      fluorescence drastically, thereby significantly raising the detection level for
      GFP. For GFP S65C, the detectable number of green fluorescing tobacco (BY-2)
      protoplasts was raised up to 19-fold, while the fluorimetricly determined
      fluorescence was raised by at least 2 orders of magnitude.

PMID- 8650189
TI  - Intercellular transfer of a glycosylphosphatidylinositol (GPI)-linked protein:
      release and uptake of CD4-GPI from recombinant adeno-associated virus-transduced
      HeLa cells.
AB  - A diverse group of GPI-anchored protein structures are ubiquitously expressed on
      the external cell membranes of eukaryotes. Whereas the physiological role for
      these structures is usually defined by their protein component, the precise
      biological significance of the glycolipid anchors remains vague. In the course of
      producing a HeLa cell line (JM88) that contained a recombinant adeno-associated
      virus genome expressing a GPI-anchored CD4-GPI fusion protein on the surface of
      the cells, we noted the transfer of CD4-GPI to native HeLa cells. Transfer
      occurred after direct cell contact or exposure to JM88 cell supernatants. The
      magnitude of contact-mediated CD4-GPI transfer correlated with temperature.
      Supernatant CD4-GPI also attached to human red blood cells and could be cleaved
      with phosphatidylinositol-specific phospholipase C. The attached CD4-GPI remained
      biologically active after transfer and permitted the formation of syncytium when
      coated HeLa cells were incubated with glycoprotein 160 expressing H9 cells. JM88
      cells provide a model for the production, release, and reattachment of CD4-GPI
      and may furnish insight into a physiologic role of naturally occurring GPI
      anchored proteins. This approach may also allow the production of other
      recombinant GPI-anchored proteins for laboratory and clinical investigation.

PMID- 8650190
TI  - Urokinase-type plasminogen activator is effective in fibrin clearance in the
      absence of its receptor or tissue-type plasminogen activator.
AB  - The availability of gene-targeted mice deficient in the urokinase-type
      plasminogen activator (uPA), urokinase receptor (uPAR), tissue-type plasminogen
      activator (tPA), and plasminogen permits a critical, genetic-based analysis of
      the physiological and pathological roles of the two mammalian plasminogen
      activators. We report a comparative study of animals with individual and combined
      deficits in uPAR and tPA and show that these proteins are complementary
      fibrinolytic factors in mice. Sinusoidal fibrin deposits are found within the
      livers of nearly all adult mice examined with a dual deficiency in uPAR and tPA,
      whereas fibrin deposits are never found in livers collected from animals lacking
      uPAR and rarely detected in animals lacking tPA alone. This is the first
      demonstration that uPAR has a physiological role in fibrinolysis. However, uPAR-/
      /tPA-/- mice do not develop the pervasive, multi-organ fibrin deposits, severe
      tissue damage, reduced fertility, and high morbidity and mortality observed in
      mice with a combined deficiency in tPA and the uPAR ligand, uPA. Furthermore,
      uPAR-/-/tPA-/- mice do not exhibit the profound impairment in wound repair seen
      in uPA-/-/tPA-/- mice when they are challenged with a full-thickness skin
      incision. These results indicate that plasminogen activation focused at the cell
      surface by uPAR is important in fibrin surveillance in the liver, but that uPA
      supplies sufficient fibrinolytic potential to clear fibrin deposits from most
      tissues and support wound healing without the benefit of either uPAR or tPA.

PMID- 8650191
TI  - Complementation of the beige mutation in cultured cells by episomally replicating
      murine yeast artificial chromosomes.
AB  - Chediak-Higashi syndrome in man and the beige mutation of mice are phenotypically
      similar disorders that have profound effects upon lysosome and melanosome
      morphology and function. We isolated two murine yeast artificial chromosomes
      (YACs) that, when introduced into beige mouse fibroblasts, complement the beige
      mutation. The complementing YACs exist as extrachromosomal elements that are
      amplified in high concentrations of G418. When YAC-complemented beige cells were
      fused to human Chediak-Higashi syndrome or Aleutian mink fibroblasts,
      complementation of the mutant phenotype also occurred. These results localize the
      beige gene to a 500-kb interval and demonstrate that the same or homologous genes
      are defective in mice, minks, and humans.

PMID- 8650193
TI  - Serological analysis of Melan-A(MART-1), a melanocyte-specific protein
      homogeneously expressed in human melanomas.
AB  - Recent progress in the structural identification of human melanoma antigens
      recognized by autologous cytotoxic T cells has led to the recognition of a new
      melanocyte differentiation antigen, Melan-A(MART-1). To determine the properties
      of the Melan-A gene product, Melan-A recombinant protein was produced in
      Escherichia coli and used to generate mouse monoclonal antibodies (mAbs). Two
      prototype mAbs, A103 and A355, were selected for detailed study. Immunoblotting
      results with A103 showed a 20-22-kDa doublet In Melan-A mRNA positive melanoma
      cell lines and no reactivity with Melan-A mRNA-negative cell lines. A355, in
      addition to the 20-22-kDa doublet, recognized several other protein species in
      Melan-A mRNA-positive cell lines. Immunocytochemical assays on cultured melanoma
      cells showed specific and uniform cytoplasmic staining in Melan-A mRNA-positive
      cell lines. Immunohistochemical analysis of normal human tissues with both mAbs
      showed staining of adult melanocytes and no reactivity with the other normal
      tissues tested. Analysis of 21 melanoma specimens showed homogenous staining of
      tumor cell cytoplasm in 16 of 17 Melan-A mRNA-positive cases and no reactivity
      with the three Melan-A mRNA-negative cases.

PMID- 8650192
TI  - RIG-E, a human homolog of the murine Ly-6 family, is induced by retinoic acid
      during the differentiation of acute promyelocytic leukemia cell.
AB  - In vivo all-trans-retinoic acid (ATRA), a differentiation inducer, is capable of
      causing clinical remission in about 90% of patients with acute promyelocytic
      leukemia (APL). The molecular basis for the differentiation of APL cells after
      treatment with ATRA remains obscure and may involve genes other than the known
      retinoid nuclear transcription factors. We report here the ATRA-induced gene
      expression in a cell line (NB4) derived from a patient with APL. By differential
      display-PCR, we isolated and characterized a novel gene (RIG-E) whose expression
      is up-regulated by ATRA. The gene is 4.0 kb long, consisting of four exons and
      three introns, and is localized on human chromosome region 8q24. The deduced
      amino acid sequence predicts a cell surface protein containing 20 amino acids at
      the N-terminal end corresponding to a signal peptide and an extracellular
      sequence containing 111 amino acids. The RIG-E coded protein shares some homology
      with CD59 and with a number of growth factor receptors. It shares high sequence
      homology with the murine LY-6 multigene family, whose members are small cysteine
      rich proteins differentially expressed in several hematopoietic cell lines and
      appear to function in signal transduction. It seems that so far RIG-E is the
      closest human homolog of the LY-6 family. Expression of RIG-E is not restricted
      to myeloid differentiation, because it is also present in thymocytes and in a
      number of other tissues at different levels.

PMID- 8650194
TI  - Presynaptic association of Rad51 protein with selected sites in meiotic
      chromatin.
AB  - Eukaryotic homologs of Escherichia coli Rec-A protein have been shown to form
      nucleoprotein filaments with single-stranded DNA that recognize homologous
      sequences in duplex DNA. Several recent reports in four widely diverse species
      have demonstrated the association of RecA homologs with meiotic prophase
      chromatin. The current immunocytological study on mouse spermatocytes and oocytes
      shows that a eukaryotic homolog, Rad5l, associates with a subset of chromatin
      sites as early as premeiotic S phase, hours before either the appearance of
      precursors of synaptonemal complexes or the initiation of synapsis. When
      homologous chromosomes do begin to pair, the Rad5l-associated sequences are sites
      of initial contact between homologues and of localized DNA synthesis.
      Distribution of Rad5l foci on the chromatin of fully synapsed bivalents at early
      pachynema corresponds to an R-band pattern of mitotic chromosomes. R-bands are
      known to be preferred sites of both synaptic initiation and recombination. The
      time course of appearance of Rad51 association with chromatin, its distribution,
      and its interaction with other Rad5l-associated sequences suggests that it plays
      an important role preselection of sequences and synaptic initiation.

PMID- 8650195
TI  - Cloning of a novel receptor expressed in rat prostate and ovary.
AB  - We have cloned a novel member of the nuclear receptor superfamily. The cDNA of
      clone 29 was isolated from a rat prostate cDNA library and it encodes a protein
      of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone
      29 protein is unique in that it is highly homologous to the rat estrogen receptor
      (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal
      ligand-binding domain (55%). Expression of clone 29 in rat tissues was
      investigated by in situ hybridization and prominent expression was found in
      prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells
      of the secretory alveoli, whereas in the ovary the granuloma cells in primary,
      secondary, and mature follicles showed expression of clone 29. Saturation ligand
      binding analysis of in vitro synthesized clone 29 protein revealed a single
      binding component for 17beta-estradiol (E2) with high affinity (Kd= 0.6 nM). In
      ligand-competition experiments the binding affinity decreased in the order E2 >
      diethylstilbestrol > estriol > estrone > 5alpha-androstane-3beta,17beta-diol >>
      testosterone = progesterone = corticosterone = 5alpha-androstane-3alpha,17beta
      diol. In cotransfection experiments of Chinese hamster ovary cells with a clone
      29 expression vector and an estrogen-regulated reporter gene, maximal stimulation
      (about 3-fold) of reporter gene activity was found during incubation with 10 nM
      of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all
      trans-retinoic acid, nor 5alpha-androstane-3alpha,I7beta-diol could stimulate
      reporter gene activity, whereas estrone and 5alpha-androstane-3beta,17beta-diol
      did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be
      named rat ERbeta to distinguish it from the previously cloned ER (ERalpha) from
      rat uterus.

PMID- 8650197
TI  - Structure and conformational changes of DNA topoisomerase II visualized by
      electron microscopy.
AB  - Type II DNA topoisomerases, which create a transient gate in duplex DNA and
      transfer a second duplex DNA through this gate, are essential for topological
      transformations of DNA in prokaryotic and eukaryotic cells and are of interest
      not only from a mechanistic perspective but also because they are targets of
      agents for anticancer and antimicrobial chemotherapy. Here we describe the
      structure of the molecule of human topoisomerase II [DNA topoisomerase (ATP
      hydrolyzing), EC 5.99.1.3] as seen by scanning transmission electron microscopy.
      A globular approximately 90-angstrom diameter core is connected by linkers to two
      approximately 50-angstrom domains, which were shown by comparison with
      genetically truncated Saccharomyces cerevisiae topoisomerase II to contain the N
      terminal region of the approximately 170-kDa subunits and that are seen in
      different orientations. When the ATP-binding site is occupied by a
      nonhydrolyzable ATP analog, a quite different structure is seen that results from
      a major conformational change and consists of two domains approximately 90
      angstrom and approximately 60 angstrom in diameter connected by a linker, and in
      which the N-terminal domains have interacted. About two-thirds of the molecules
      show an approximately 25 A tunnel in the apical part of the large domain, and the
      remainder contain an internal cavity approximately 30 A wide in the large domain
      close to the linker region. We propose that structural rearrangements lead to
      this displacement of an internal tunnel. The tunnel is likely to represent the
      channel through which one DNA duplex, after capture in the clamp formed by the N
      terminal domains, is transferred across the interface between the enzyme's
      subunits. These images are consistent with biochemical observations and provide a
      structural basis for understanding the reaction of topoisomerase II.

PMID- 8650196
TI  - Leukotriene A4 hydrolase: protection from mechanism-based inactivation by
      mutation of tyrosine-378.
AB  - Leukotriene A4 (LTA4) hydrolase [(7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,
      9,11,14-tetraenoate hydrolase; EC 3.3.2.6] is a bifunctional zinc metalloenzyme
      that catalyzes the final step in the biosynthesis of the potent chemotactic agent
      leukotriene B4 (LTB4). LTA4 hydrolase/aminopeptidase is suicide inactivated
      during catalysis via an apparently mechanism-based irreversible binding of LTA4
      to the protein in a 1:1 stoichiometry. Previously, we have identified a
      henicosapeptide, encompassing residues Leu-365 to Lys-385 in human LTA4
      hydrolase, which contains a site involved in the covalent binding of LTA4 to the
      native enzyme. To investigate the role of Tyr-378, a potential candidate for this
      binding site, we exchanged Tyr for Phe or Gln in two separate mutants. In
      addition, each of two adjacent and potentially reactive residues, Ser-379 and Ser
      380, were exchanged for Ala. The mutated enzymes were expressed as (His)6-tagged
      fusion proteins in Escherichia coli, purified to apparent homogeneity, and
      characterized. Enzyme activity determinations and differential peptide mapping,
      before and after repeated exposure to LTA4, revealed that wild-type enzyme and
      the mutants [S379A] and [S380A]LTA4hydrolase were equally susceptible to suicide
      inactivation whereas the mutants in position 378 were no longer inactivated or
      covalently modified by LTA4. Furthermore, in [Y378F]LTA4 hydrolase, the value of
      kcat for epoxide hydrolysis was increased 2.5-fold over that of the wild-type
      enzyme. Thus, by a single-point mutation in LTA4 hydrolase, catalysis and
      covalent modification/inactivation have been dissociated, yielding an enzyme with
      increased turnover and resistance to mechanism-based inactivation.

PMID- 8650198
TI  - G1 arrest and down-regulation of cyclin E/cyclin-dependent kinase 2 by the
      protein kinase inhibitor staurosporine are dependent on the retinoblastoma
      protein in the bladder carcinoma cell line 5637.
AB  - The protein kinase inhibitor staurosporine has been shown to induce G1 phase
      arrest in normal cells but not in most transformed cells. Staurosporine did not
      induce G1 phase arrest in the bladder carcinoma cell line 5637 that lacks a
      functional retinoblastoma protein (pRB-). However, when infected with a pRB
      expressing retrovirus [Goodrich, D. W., Chen, Y., Scully, P. & Lee, W.-H. (1992)
      Cancer Res. 52, 1968-1973], these cells, now pRB+, were arrested by staurosporine
      in G1 phase. This arrest was accompanied by the accumulation of
      hypophosphorylated pRB. In both the pRB+ and pRB- cells, cyclin D1-associated
      kinase activities were reduced on staurosporine treatment. In contrast, cyclin
      dependent kinase (CDK) 2 and cyclin E/CDK2 activities were inhibited only in pRB+
      cells. Staurosporine treatment did not cause reductions in the protein levels of
      CDK4, cyclin D1, CDK2, or cyclin E. The CDK inhibitor proteins p21(Waf1/Cip1) and
      p27 (Kip1) levels increased in staurosporine-treated cells. Immunoprecipitation
      of CDK2, cyclin E, and p2l from staurosporine-treated pRB+ cells revealed a 2.5-
      to 3-fold higher ratio of p2l bound to CDK2 compared with staurosporine-treated
      pRB- cells. In pRB+ cells, p2l was preferentially associated with Thrl6O
      phosphorylated active CDK2. In pRB- cells, however, p2l was bound preferentially
      to the unphosphorylated, inactive form of CDK2 even though the phosphorylated
      form was abundant. This is the first evidence suggesting that G1 arrest by 4 nM
      staurosporine is dependent on a functional pRB protein. Cell cycle arrest at the
      pRB- dependent checkpoint may prevent activation of cyclin E/CDK2 by stabilizing
      its interaction with inhibitor proteins p2l and p27.

PMID- 8650199
TI  - Modulation of growth factor receptor function by isoform heterodimerization.
AB  - Activation of prolactin (PRL)-dependent signaling occurs as the result of ligand
      induced dimerization of receptor (PRLr). Although three PRLr isoforms (short,
      intermediate, and long) have been characterized and are variably coexpressed in
      PRL-responsive tissues, the functional effects of ligand-induced PRLr isoform
      heterodimerization have not been examined. To determine whether heterodimeric
      PRLr complexes were capable of ligand-induced signaling and cellular
      proliferation, chimeras consisting of the extracellular domain of either the
      alpha or beta subunit of human granulocyte-macrophage colony-stimulating factor
      receptor (GM-CSFr) and the intracellular domain of the rat intermediate or short
      PRLr isoforms (PRLr-I or PRLr-S) were synthesized. Because high affinity binding
      of GM-CSF is mediated by the extracellular domain of one alpha and beta GM-CSFr
      pair, use of GM-CSFr/PRLr chimera specifically directed the dimerization of the
      PRLr intracellular domains within ligand-receptor complexes. Stable transfection
      of these constructs into the Ba/F3 line was demonstrated by Northern blot and
      immunoprecipitation analyses. Flow cytometry revealed specific binding of a
      phycoerythrin-conjugated human GM-CSF to the transfectants, confirming cell
      surface expression of the chimeric receptors. When tested for their ability to
      proliferate in response to GM-CSF, only chimeric transfectants expressing GM
      CSFr/PRLr-I homodimers demonstrated significant [3H]thymidine incorporation. GM
      CSF stimulation of transfectants expressing either GM-CSFr/PRLr-S homodimers or
      GM-CSFr/PRLr-S+1 heterodimers failed to induce proliferation. Consistent with
      these data, the GM-CSF-induced activation of two phosphotyrosine kinases, Jak2
      and Fyn, was observed only in homodimeric GM-CSFr/PRLr-I transfectants. These
      results show that the PRLr-S functions as a dominant negative isoform, down
      regulating both signaling and proliferation mediated by the receptor complex.
      Thus, structural motifs necessary for Jak2 and Fyn activation within the carboxy
      terminus of the PRLr-I, absent in the PRLr-S, are required in each member of the
      dimeric PRLr complex.

PMID- 8650200
TI  - prlA suppressors in Escherichia coli relieve the proton electrochemical gradient
      dependency of translocation of wild-type precursors.
AB  - The SecY protein of Escherichia coli is an integral membrane component of the
      protein export apparatus. Suppressor mutations in the secY gene (prlA alleles)
      have been isolated that restore the secretion of precursor proteins with
      defective signal sequences. These mutations have never been shown to affect the
      translocation of wild-type precursor proteins. Here, we report that prlA
      suppressor mutations relieve the proton-motive force (pmf) dependency of the
      translocation of wild-type precursors, both in vivo and in vitro. Furthermore,
      the proton-motive force dependency of the translocation of a precursor with a
      stably folded domain in the mature region was suppressed by prlA mutations in
      vitro. These data show that prlA mutations cause a general relaxation of the
      export apparatus rather than a specific change that results in bypassing of the
      recognition of the signal sequence. In addition, these results are indicative for
      a mechanism in which the proton-motive force stimulates translocation by altering
      the conformation of the translocon.

PMID- 8650202
TI  - Molecular cloning of the Golgi apparatus uridine diphosphate-N-acetylglucosamine
      transporter from Kluyveromyces lactis.
AB  - The mannan chains of Kluyveromyces lactis mannoproteins are similar to those of
      Saccharomyces cerevisiae except that they lack mannose phosphate and have
      terminal alpha1-->2-linked N-acetylglucosamine. The biosynthesis of these chains
      probably occurs in the lumen of the Golgi apparatus, by analogy to S. cerevisiae.
      The sugar donors, GDP-mannose and UDP-GlcNAc, must first be transported from the
      cytosol, their site of synthesis, via specific Golgi membrane transporters into
      the lumen where they are substrates in the biosynthesis of these mannoproteins. A
      mutant of K. lactis, mnn2-2, that lacks terminal N-acetylglucosamine in its
      mannan chains in vivo, has recently been characterized and shown to have a
      specific defect in transport of UDP-GlcNAc into the lumen of Golgi vesicles in
      vitro. We have now cloned the gene encoding the K. lactis Golgi membrane UDP
      GlcNAc transporter by complementation of the mnn2-2 mutation. The mnn2-2 mutant
      was transformed with a genomic library from wild-type K. lactis in a pKD1-derived
      vector; transformants were isolated and phenotypic correction was monitored
      following cell surface labeling with fluorescein isothiocyanate conjugated to
      Griffonia simplicifolia II lectin, which binds terminal N-acetylglucosamine, and
      a fluorescent activated cell sorter. A 2.4-kb DNA fragment was found to restore
      the wild-type lectin binding phenotype. Upon loss of the plasmid containing this
      fragment, reversion to the mutant phenotype occurred. The above fragment
      contained an open reading frame for a multitransmembrane spanning protein of 328
      amino acids. The protein contains a leucine zipper motif and has high homology to
      predicted proteins from S. cerevisiae and C. elegans. In an assay in vitro, Golgi
      vesicles isolated from the transformant had regained their ability to transport
      UDP-GlcNAc. Taken together, the above results strongly suggest that the cloned
      gene encodes the Golgi UDP-GlcNAc transporter of K. lactis.

PMID- 8650201
TI  - A tyrosine kinase profile of prostate carcinoma.
AB  - Tyrosine kinases play central roles in the growth and differentiation of normal
      and tumor cells. In this study, we have analyzed the general tyrosine kinase
      expression profile of a prostate carcinoma (PCA) xenograft, CWR22. We describe
      here an improved reverse transcriptase-PCR approach that permits identification
      of nearly 40 different kinases in a single screening; several of these kinases
      are newly cloned kinases and some are novel. According to this, there are 11
      receptor kinases, 9 nonreceptor kinases, and at least 7 dual kinases expressed in
      the xenograft tissue. The receptor kinases include erbB2, erbB3, Ret, platelet
      derived growth factor receptor, sky, nyk, eph, htk, sek (eph), ddr, and tkt. The
      nonreceptor kinases are lck, yes, abl, arg, JakI, tyk2, and etk/bmx. Most of the
      dual kinases are in the mitogen-activating protein (MAP) kinase-kinase (MKK)
      family, which includes MKK3, MKK4, MEK5, and a novel one. As a complementary
      approach, we also analyzed by specific reverse transcriptase-PCR primers the
      expression profile of erbB/epidermal growth factor receptor family receptors in a
      variety of PCA specimens, cell lines, and benign prostatic hyperplasia. We found
      that erbB1, -2, and -3 are often coexpressed in prostate tissues, but not in
      erbB4. The information established here should provide a base line to study the
      possible growth and oncogenic signals of PCA.

PMID- 8650203
TI  - Functional expression of mouse Mdr1 in an outer membrane permeability mutant of
      Escherichia coli.
AB  - Functional expression of the multidrug resistance protein P-glycoprotein (P-gp)
      in Escherichia coli is providing an appropriate system for structure/function
      studies and might provide an invaluable tool to screen potential P-gp substrates
      and inhibitors. The major problem encountered in such studies, however, is the
      impermeability of the outer membrane of Gram-negative bacteria, which protects
      microorganisms against the cytotoxic effects of many lipophilic cancer drugs and
      blocks accessibility of P-gp reversal agents. In the present study we have
      constructed, by mutagenesis, a "leaky" (containing a permeable outer membrane)
      strain of E. coli, which is significantly more susceptible to the toxic effect of
      known P-gp substrates and cytotoxic agents. Expression of mouse Mdr1 in the
      mutant confers cross-resistance to daunomycin, quinidine, chloroquine, rhodamine
      6G, and puromycin. Most importantly, reserpine and doxorubicin completely abolish
      Mdr1-mediated rhodamine resistance. The results provide strong support for
      previous observations, suggesting that Mdr1 can be expressed functionally in E.
      coli and indicate that the leaky mutant will be useful for further
      structure/function studies of the heterologously expressed eukaryotic drug efflux
      protein.

PMID- 8650204
TI  - Kinetics of self-assembling microtubules: an "inverse problem" in biochemistry.
AB  - Experimental time series for a nonequilibrium reaction may in some cases contain
      sufficient data to determine a unique kinetic model for the reaction by a
      systematic mathematical analysis. As an example, a kinetic model for the self
      assembly of microtubules is derived here from turbidity time series for solutions
      in which microtubules assemble. The model may be seen as a generalization of
      Oosawa's classical nucleation-polymerization model. It reproduces the
      experimental data with a four-stage nucleation process and a critical nucleus of
      15 monomers.

PMID- 8650205
TI  - Promotion of sleep mediated by the A2a-adenosine receptor and possible
      involvement of this receptor in the sleep induced by prostaglandin D2 in rats.
AB  - A 6-hr continuous infusion of 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N
      ethylcarboxamidoadenos ine (CGS21680), a selective A2a-adenosine agonist, into
      the subarachnoid space underlying the ventral surface region of the rostral basal
      forebrain, which has been defined as the prostaglandin (PG) D2-sensitive sleep
      promoting zone, at rates of 0.02, 0.2, 2.0, and 12 pmol/min increased slow-wave
      sleep (SWS) and paradoxical sleep (PS) in a dose-dependent manner up to 183% and
      202% of their respective baseline levels. The increments produced by the infusion
      of CGS21680 at 0.2 and 2.0 pmol/min were totally diminished when the rats had
      been pretreated with an i.p. injection of (E)-1,3-dipropyl-7-methyl-8-(3,4
      dimethoxystyryl)xanthine (KF17837; 30 mg/kg of body weight), a selective A2
      adenosine antagonist. In contrast, the infusion of N6-cyclohexyladenosine (CHA),
      a selective A1-adenosine agonist, at 2 pmol/min significantly suppressed SWS
      before causing an increase in SWS, and a decrease in PS was also markedly
      visible. Essentially the same effects of CGS21680 and CHA were observed when
      these compounds were administered to the parenchymal region of the rostral basal
      forebrain through chronically implanted microdialysis probes. Thus, we clearly
      showed that stimulation of A2a-adenosine receptors in the rostral basal forebrain
      promotes SWS and PS. Furthermore, i.p. injections of KF17837 at 30 and 100 mg/kg
      of body weight dose-dependently attenuated the magnitude of the SWS increase
      produced by the infusion of PGD2 into the subarachnoid space of the sleep
      promoting zone, thus indicating that the A2a-adenosine receptors are crucial in
      the sleep-promoting process triggered by PGD2.

PMID- 8650206
TI  - Substrate-bound agrin induces expression of acetylcholine receptor epsilon
      subunit gene in cultured mammalian muscle cells.
AB  - Expression of the epsilon-subunit gene of the acetylcholine receptor (AChR) by
      myonuclei located at the neuromuscular junction is precisely regulated during
      development. A key role in this regulation is played by the synaptic portion of
      the basal lamina, a structure that is also known to contain agrin, a component
      responsible for the formation of postsynaptic specializations. We tested whether
      agrin has a function in synaptic AChR gene expression. Synaptic basal lamina from
      native adult muscle and recombinant agrin bound to various substrates induced in
      cultured rat myotubes AChR clusters that were colocalized with epsilon-subunit
      mRNA. Estimation of transcript levels by Northern hybridization analysis of total
      RNA showed a significant increase when myotubes were grown on substrate
      impregnated with agrin, but were unchanged when agrin was applied in the medium.
      The effect was independent of the receptor aggregating activity of the agrin
      isoform used, and agrin acted, at least in part, at the level of epsilon-subunit
      gene transcription. These findings are consistent with a role of agrin in the
      regulation of AChR subunit gene expression at the neuromuscular junction, which
      would depend on its binding to the synaptic basal lamina.

PMID- 8650207
TI  - Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2
      domain.
AB  - A novel human cDNA encoding a cytosolic 62-kDa protein (p62) that binds to the
      Src homology 2 (SH2) domain of p56lck in a phosphotyrosine-independent manner has
      been cloned. The cDNA is composed of 2074 nucleotides with an open reading frame
      encoding 440 amino acids. Northern analysis suggests that p62 is expressed
      ubiquitously in all tissues examined. p62 is not homologous to any known protein
      in the data base. However, it contains a cysteine-rich region resembling a zinc
      finger motif, a potential G-protein-binding region, a PEST motif, and several
      potential phosphorylation sites. Using T7-epitope tagged p62 expression in HeLa
      cells, the expressed protein was shown to bind to the lck SH2 domain. Deletion of
      the N-terminal 50 amino acids abolished binding, but mutagenesis of the single
      tyrosine residue in this region had no effect on binding. Thus, the cloned cDNA
      indeed encodes the p62 protein, which is a phosphotyrosine-independent ligand for
      the lck SH2 domain. Its binding mechanism is unique with respect to binding modes
      of other known ligands for SH2 domains.

PMID- 8650208
TI  - Membrane healing and restoration of contractility after mechanical injury in
      isolated skeletal muscle fibers of the frog.
AB  - In single isolated skeletal muscle fibers of the frog, we studied (i) the
      recovery from large sarcolemmal mechanical injuries of the response to electric
      stimulation and (ii) the integrity of the sarcolemma under the light microscope.
      In Ringer's solution, the damaged cells stopped contracting and deteriorated
      completely within 1 hr. In the presence of phosphatidylcholine (0.025 g/ml in
      Ringer's solution), the injured cells initially responded with local twitches.
      Within 0.5 hr, contractility and membrane integrity started to recover and both
      were back to control levels within 3 hr. When these cells were placed back in
      normal Ringer's solution, they remained viable and active for several hours. Our
      results suggest that phosphatidylcholine can protect muscle fibers from the
      effects of sarcolemmal injury.

PMID- 8650209
TI  - A new endogenous natriuretic factor: LLU-alpha.
AB  - For over three decades, renal physiology has sought a putative natriuretic
      hormone (third factor) that might control the body's pool of extracellular fluid,
      an important determinant in hypertension, congestive heart failure, and
      cirrhosis. In our search for this hormone, we have isolated several pure
      natriuretic factors from human uremic urine that would appear, alone or in
      combination, to mark a cluster of phenomena previously presumed to be that of a
      single "natriuretic hormone." This paper reports the purification, chemical
      structure, and total synthesis of the first of these compounds, LLU-alpha, which
      proved to be 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman, presumably a
      metabolite of gamma-tocopherol. Both natural LLU-alpha and synthetic material are
      identical (except for optical activity) with respect to structure and biological
      activity. It appears that the natriuretic activity of LLU-alpha is mediated by
      inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending
      limb of the kidney.

PMID- 8650211
TI  - PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase
      activity by binding to Src homology 3 domains of p47 phox.
AB  - Reactive oxygen intermediates generated by the phagocyte NADPH oxidase are
      critically important components of host defense. However, these highly toxic
      oxidants can cause significant tissue injury during inflammation; thus, it is
      essential that their generation and inactivation are tightly regulated. We show
      here that an endogenous proline-arginine (PR)-rich antibacterial peptide, PR-39,
      inhibits NADPH oxidase activity by blocking assembly of this enzyme through
      interactions with Src homology 3 domains of a cytosolic component. This
      neutrophil-derived peptide inhibited oxygen-dependent microbicidal activity of
      neutrophils in whole cells and in a cell-free assay of NADPH oxidase. Both
      oxidase inhibitory and direct antimicrobial activities were defined within the
      amino-terminal 26 residues of PR-39. Oxidase inhibition was attributed to binding
      of PR-39 to the p47phox cytosolic oxidase component. Its effects involve both a
      polybasic amino-terminal segment and a proline-rich core region of PR-39 that
      binds to the p47phox Src homology 3 domains and, thereby, inhibits interaction
      with the small subunit of cytochrome b558, p22phox. These findings suggest that
      PR-39, which has been shown to be involved in tissue repair processes, is a
      multifunctional peptide that can regulate NADPH oxidase production of superoxide
      anion O2-. thus limiting excessive tissue damage during inflammation.

PMID- 8650210
TI  - Evidence from disruption of the lmcpb gene array of Leishmania mexicana that
      cysteine proteinases are virulence factors.
AB  - The mammalian form of the protozoan parasite Leishmania mexicana contains high
      activity of a cysteine proteinase (LmCPb) encoded on a tandem array of 19 genes
      (lmcpb). Homozygous null mutants for lmcpb have been produced by targeted gene
      disruption. All life-cycle stages of the mutant can be cultured in vitro,
      demonstrating that the gene is not essential for growth or differentiation of the
      parasite. However, the mutant exhibits a marked phenotype affecting virulence--
      its infectivity to macrophages is reduced by 80%. The mutants are as efficient as
      wild-type parasites in invading macrophages but they only survive in a small
      proportion of the cells. However, those parasites that successfully infect these
      macrophages grow normally. Despite their reduced virulence, the mutants are still
      able to produce subcutaneous lesions in mice, albeit at a slower rate than wild
      type parasites. The product of a single copy of lmcpb re-expressed in the null
      mutant was enzymatically active and restored infectivity toward macrophages to
      wild-type levels. Double null mutants created for lmcpb and lmcpa (another
      cathepsin L-like cysteine proteinase) have a similar phenotype to the lmcpb null
      mutant, showing that LmCPa does not compensate for the loss of LmCPb.

PMID- 8650212
TI  - Novel unconventional binding site in the variable region of immunoglobulins.
AB  - The variable immunoglobulin (Ig) domains contain hypervariable regions that are
      involved in the formation of the antigen binding site. Besides the canonical
      antigen binding site, so-called unconventional sites also reside in the variable
      region that bind bacterial and viral proteins. Docking to these unconventional
      sites does not typically interfere with antigen binding, which suggests that
      these sites may be a part of the biological functions of Igs. Herein, a novel
      unconventional binding site is described. The site is detected with 8-azidopurine
      nucleotide photoaffinity probes that label antibodies efficiently and under mild
      conditions. Tryptic peptides were isolated from photolabeled monoclonal
      antibodies and aligned with the variable antibody domains of heavy and light
      chains. The structure of a variable Ig fragment was used to model the binding of
      the purine nucleotide to invariant residues in a hydrophobic pocket of the Ig
      molecule at a location distant from the antigen binding site. Monoclonal and
      polyclonal antibodies were biotinylated with the photoaffinity linker and used in
      fluorescence-activated cell sorter and ELISA analyses. The data support the
      utility of this site for tethering diagnostic and therapeutic agents to the
      variable Ig fragment region without impairing the structural and functional
      integrity of antibodies.

PMID- 8650213
TI  - Suppression subtractive hybridization: a method for generating differentially
      regulated or tissue-specific cDNA probes and libraries.
AB  - A new and highly effective method, termed suppression subtractive hybridization
      (SSH), has been developed for the generation of subtracted cDNA libraries. It is
      based primarily on a recently described technique called suppression PCR and
      combines normalization and subtraction in a single procedure. The normalization
      step equalizes the abundance of cDNAs within the target population and the
      subtraction step excludes the common sequences between the target and driver
      populations. In a model system, the SSH technique enriched for rare sequences
      over 1,000-fold in one round of subtractive hybridization. We demonstrate its
      usefulness by generating a testis-specific cDNA library and by using the
      subtracted cDNA mixture as a hybridization probe to identify homologous sequences
      in a human Y chromosome cosmid library. The human DNA inserts in the isolated
      cosmids were further confirmed to be expressed in a testis-specific manner. These
      results suggest that the SSH technique is applicable to many molecular genetic
      and positional cloning studies for the identification of disease, developmental,
      tissue-specific, or other differentially expressed genes.

PMID- 8650214
TI  - The glycine binding site of the N-methyl-D-aspartate receptor subunit NR1:
      identification of novel determinants of co-agonist potentiation in the
      extracellular M3-M4 loop region.
AB  - The N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors is a
      heterooligomeric membrane protein composed of homologous subunits. Here, the
      contribution of the M3-M4 loop of the NR1 subunit to the binding of glutamate and
      the co-agonist glycine was investigated by site-directed mutagenesis.
      Substitution of the phenylalanine residues at positions 735 or 736 of the M3-M4
      loop produced a 15- to 30-fold reduction in apparent glycine affinity without
      affecting the binding of glutamate and the competitive glycine antagonist 7
      chlorokynurenic acid; mutation of both residues caused a >100-fold decrease in
      glycine affinity. These residues are found in a C-terminal region of the M3-M4
      loop that shows significant sequence similarity to bacterial amino acid-binding
      proteins. Epitope tagging revealed both the N-terminus and the M3-M4 loop to be
      exposed extracellularly, whereas a C-terminal epitope was localized
      intracellularly. These results indicate that the M3-M4 loop is part of the ligand
      binding pocket of the NR1 subunit and provide the basis for a refined model of
      the glycine-binding site of the NMDA receptor.

PMID- 8650215
TI  - Magnetic resonance imaging (MRI) detection of the murine brain response to light:
      temporal differentiation and negative functional MRI changes.
AB  - Using a 9.4 T MRI instrument, we have obtained images of the mouse brain response
      to photic stimulation during a period between deep anesthesia and the early
      stages of arousal. The large image enhancements we observe (often >30%) are
      consistent with literature results extrapolated to 9.4 T. However, there are also
      two unusual aspects to our findings. (i) The visual area of the brain responds
      only to changes in stimulus intensity, suggesting that we directly detect
      operations of the M visual system pathway. Such a channel has been observed in
      mice by invasive electrophysiology, and described in detail for primates. (ii)
      Along with the typical positive response in the area of the occipital portion of
      the brain containing the visual cortex, another area displays decreased signal
      intensity upon stimulation.

PMID- 8650217
TI  - Mutations in the rotated abdomen locus affect muscle development and reveal an
      intrinsic asymmetry in Drosophila.
AB  - In bilateral animals, the left and right sides of the body usually present
      asymmetric structures, the genetic bases of whose generation are still largely
      unknown [CIBA Foundation (1991) Biological Asymmetry and Handedness, CIBA
      Foundation Symposium 162 (Wiley, New York), pp. 1-327]. In Drosophila
      melanogaster, mutations in the rotated abdomen (rt) locus cause a clockwise
      helical rotation of the body. Even null alleles are viable but exhibit defects in
      embryonic muscle development, rotation of the whole larval body, and helical
      staggering of cuticular patterns in abdominal segments of the adult. rotated
      abdomen is expressed in the embryonic mesoderm and midgut but not in the
      ectoderm; it encodes a putative integral membrane glycoprotein (homologous to key
      yeast mannosyltransferases). Mesodermal cells defective in O-glycosylation lead
      to an impaired larval muscular system. We propose that the staggering of the
      adult abdominal segments would be a consequence of the relaxation of intrinsic
      rotational torque of muscle architecture, preventing the colateral alignment of
      the segmental histoblast cells during their proliferation at metamorphosis.

PMID- 8650216
TI  - A specific protein carboxyl methylesterase that demethylates phosphoprotein
      phosphatase 2A in bovine brain.
AB  - Phosphoprotein phosphatase 2A (PP2A) is one of the four major protein
      serine/threonine phosphatases found in all eukaryotic cells. We have shown that
      the 36-kDa catalytic subunit of PP2A is carboxyl methylated in eukaryotic cells,
      and we have previously identified and purified a novel methyltransferase (MTase)
      that is responsible for this modification. Here, we describe a novel protein
      carboxyl methyl-esterase (MEase) from bovine brain that demethylates PP2A. The
      enzyme has been purified to homogeneity as a monomeric 46-kDa soluble protein.
      The MEase is highly specific for PP2A. It does not catalyze the demethylation of
      other protein or peptide methylesters. Moreover, MEase activity is dramatically
      inhibited by nanomolar concentrations of okadaic acid, a specific inhibitor of
      PP2A. From these results, we conclude that PP2A methylation is controlled by two
      specific enzymes, a MTase and a MEase. Since PP2A methylation is highly conserved
      in eukaryotes ranging from human to yeast, it is likely that this system plays an
      important role in phosphatase regulation.

PMID- 8650218
TI  - The association between glycosylphosphatidylinositol-anchored proteins and
      heterotrimeric G protein alpha subunits in lymphocytes.
AB  - Glycosylphosphatidylinositol (GPI)-anchored proteins are nonmembrane spanning
      cell surface proteins that have been demonstrated to be signal transduction
      molecules. Because these proteins do not extend into the cytoplasm, the mechanism
      by which cross-linking of these molecules leads to intracellular signal
      transduction events is obscure. Previous analysis has indicated that these
      proteins are associated with src family member tyrosine kinases; however, the
      role this interaction plays in the generation of intracellular signals is not
      clear. Here we show that GPI-anchored proteins are associated with alpha subunits
      of heterotrimeric GTP binding proteins (G proteins) in both human and murine
      lymphocytes. When the GPI-anchored proteins CD59, CD48, and Thy-1 were
      immunoprecipitated from various cell lines or freshly isolated lymphocytes, all
      were found to be associated with a 41-kDa phosphoprotein that we have identified,
      by using specific antisera, as a mixture of tyrosine phosphorylated G protein
      alpha subunits: a small amount of Gialpha1, and substantial amounts of Gialpha2
      and Gialpha3. GTP binding assays performed with immunoprecipitations of CD59
      indicated that there was GTP-binding activity associated with this molecule.
      Thus, we have shown by both immunochemical and functional criteria that GPI
      anchored proteins are physically associated with G proteins. These experiments
      suggest a potential role of G proteins in the transduction of signals generated
      by GPI-anchored molecules expressed on lymphocytes of both mouse and human.

PMID- 8650219
TI  - An Escherichia coli chromosomal "addiction module" regulated by guanosine
      [corrected] 3',5'-bispyrophosphate: a model for programmed bacterial cell death.
AB  - "Addiction modules" consist of two genes. In most of them the product of one is
      long lived and toxic while the product of the second is short lived and
      antagonizes the toxic effect; so far, they have been described mainly in a number
      of prokaryotic extrachromosomal elements responsible for the postsegregational
      killing effect. Here we show that the chromosomal genes mazE and mazF, located in
      the Escherichia coli rel operon, have all of the properties required for an
      addiction module. Furthermore, the expression of mazEF is regulated by the
      cellular level of guanosine [corrected] 3',5'-bispyrophosphate, the product of
      the RelA protein under amino acid starvation. These properties suggest that the
      mazEF system may be responsible for programmed cell death in E. coli and thus may
      have a role in the physiology of starvation.

PMID- 8650220
TI  - An axoplasmic myosin with a calmodulin-like light chain.
AB  - Organelles in the axoplasm from the squid giant axon move along exogenous actin
      filaments toward their barbed ends. An approximately 235-kDa protein, the only
      band recognized by a pan-myosin antibody in Western blots of isolated axoplasmic
      organelles, has been previously proposed to be a motor for these movements. Here,
      we purify this approximately 235-kDa protein (p235) from axoplasm and demonstrate
      that it is a myosin, because it is recognized by a pan-myosin antibody and has an
      actin-activated Mg-ATPase activity per mg of protein 40-fold higher than that of
      axoplasm. By low-angle rotary shadowing, p235 differs from myosin II and it does
      not form bipolar filaments in low salt. The amino acid sequence of a 17-kDa
      protein that copurifies with p235 shows that it is a squid optic lobe calcium
      binding protein, which is more similar by amino acid sequence to calmodulin (69%
      identity) than to the light chains of myosin II (33% identity). A polyclonal
      antibody to this light chain was raised by using a synthetic peptide representing
      the calcium binding domain least similar to calmodulin. We then cloned this light
      chain by reverse transcriptase-PCR and showed that this antibody recognizes the
      bacterially expressed protein but not brain calmodulin. In Western blots of
      sucrose gradient fractions, the 17-kDa protein is found in the organelle
      fraction, suggesting that it is a light chain of the p235 myosin that is also
      associated with organelles.

PMID- 8650221
TI  - Human immunodeficiency virus tat gene transfer to the murine central nervous
      system using a replication-defective herpes simplex virus vector stimulates
      transforming growth factor beta 1 gene expression.
AB  - The high incidence of neurological disorders in patients afflicted with acquired
      immunodeficiency syndrome (AIDS) may result from human immunodeficiency virus
      type 1 (HIV-1) induction of chemotactic signals and cytokines within the brain by
      virus-encoded gene products. Transforming growth factor beta1 (TGF-beta1) is an
      immunomodulator and potent chemotactic molecule present at elevated levels in HIV
      1-infected patients, and its expression may thus be induced by viral trans
      activating proteins such as Tat. In this report, a replication-defective herpes
      simplex virus (HSV)-1 tat gene transfer vector, dSTat, was used to transiently
      express HIV-1 Tat in glial cells in culture and following intracerebral
      inoculation in mouse brain in order to directly determine whether Tat can
      increase TGF-beta1 mRNA expression. dSTat infection of Vero cells transiently
      transfected by a panel of HIV-1 long terminal repeat deletion mutants linked to
      the bacterial chloramphenicol acetyltransferase reporter gene demonstrated that
      vector-expressed Tat activated the long terminal repeat in a trans-activation
      response element-dependent fashion independent of the HSV-mediated induction of
      the HIV-1 enhancer, or NF-kappaB domain. Northern blot analysis of human
      astrocytic glial U87-MG cells transfected by dSTat vector DNA resulted in a
      substantial increase in steady-state levels of TGF-beta1 mRNA. Furthermore,
      intracerebral inoculation of dSTat followed by Northern blot analysis of whole
      mouse brain RNA revealed an increase in levels of TGF-beta1 mRNA similar to that
      observed in cultured glial cells transfected by dSTat DNA. These results provided
      direct in vivo evidence for the involvement of HIV-1 Tat in activation of TGF
      beta1 gene expression in brain. Tat-mediated stimulation of TGF-beta1 expression
      suggests a novel pathway by which HIV-1 may alter the expression of cytokines in
      the central nervous system, potentially contributing to the development of AIDS
      associated neurological disease.

PMID- 8650222
TI  - Behavioral genetics of thermosensation and hygrosensation in Drosophila.
AB  - Whereas temperature and humidity are critical variables affecting physiology,
      behavior, and evolution, the genetic and neuronal underpinnings of
      thermosensation and hygrosensation remain poorly understood. We have initiated a
      behavioral-genetic investigation of these sensory systems in Drosophila.
      Behavioral tests are described for the rapid screening of mutants defective in
      thermosensation and hygrosensation. We demonstrate the strong responses of normal
      flies to temperature and humidity. Two mutants were found with defects in
      thermosensation, only one of which is also defective in hygrosensation,
      indicating that they involve different sensory mechanisms. Ablation experiments
      further separate these sensory systems by showing that thermoreceptors are housed
      in the third antennal segment, whereas hygroreceptors are located more distally
      in the antennal arista.

PMID- 8650223
TI  - Different cleavage sites are aligned differently in the active site of M1 RNA,
      the catalytic subunit of Escherichia coli RNase P.
AB  - We have studied RNase P RNA (M1 RNA) cleavage of model tRNA precursors that are
      cleaved at two independent positions. Here we present data demonstrating that
      cleavage at both sites depends on the 2'-OH immediately 5' of the respective
      cleavage site. However, we show that the 2-amino group of a guanosine at the
      cleavage site plays a significant role in cleavage at one of these sites but not
      at the other. These data suggest that these two cleavage sites are handled
      differently by the ribozyme. This theory is supported by our finding that the
      cross-linking pattern between Ml RNA and tRNA precursors carrying 4-thioU showed
      distinct differences, depending on the location of the 4-thioU relative to the
      respective cleavage site. These findings lead us to suggest that different
      cleavage sites are aligned differently in the active site, possibly as a result
      of different binding modes of a substrate to M1 RNA. We discuss a model in which
      the interaction between the 3'-terminal "RCCA" motif (first three residues
      interact) of a tRNA precursor and M1 RNA plays a significant role in this
      process.

PMID- 8650224
TI  - Cell cycle-dependent modulation of telomerase activity in tumor cells.
AB  - Telomerase is a ribonucleoprotein complex that is thought to add telomeric
      repeats onto the ends of chromosomes during the replicative phase of the cell
      cycle. We tested this hypothesis by arresting human tumor cell lines at different
      stages of the cell cycle. Induction of quiescence by serum deprivation did not
      affect telomerase activity. Cells arrested at the G1/S phase of the cell cycle
      showed similar levels of telomerase to asynchronous cultures; progression through
      the S phase was associated with increased telomerase activity. The highest level
      of telomerase activity was detected in S-phase cells. In contrast, cells arrested
      at G2/M phase of the cell cycle were almost devoid of telomerase activity.
      Diverse cell cycle blockers, including transforming growth factor beta1 and
      cytotoxic agents, also caused inhibition of telomerase activity. These results
      establish a direct link between telomerase activity and progression through the
      cell cycle.

PMID- 8650225
TI  - Expression of corticotropin-releasing factor in inflamed tissue is required for
      intrinsic peripheral opioid analgesia.
AB  - Immune cell-derived opioid peptides can activate opioid receptors on peripheral
      sensory nerves to inhibit inflammatory pain. The intrinsic mechanisms triggering
      this neuroimmune interaction are unknown. This study investigates the involvement
      of endogenous corticotropin-releasing factor (CRF) and interleukin-1beta (IL-1).
      A specific stress paradigm, cold water swim (CWS), produces potent opioid
      receptor-specific antinociception in inflamed paws of rats. This effect is dose
      dependently attenuated by intraplantar but not by intravenous alpha-helical CRF.
      IL-1 receptor antagonist is ineffective. Similarly, local injection of antiserum
      against CRF, but not to IL-1, dose-dependently reverses this effect. Intravenous
      anti-CRF is only inhibitory at 10(4)-fold higher concentrations and intravenous
      CRF does not produce analgesia. Pretreatment of inflamed paws with an 18-mer 3'
      3'-end inverted CRF-antisense oligodeoxynucleotide abolishes CWS-induced
      antinociception. The same treatment significantly reduces the amount of CRF
      extracted from inflamed paws and the number of CRF-immunostained cells without
      affecting gross inflammatory signs. A mismatch oligodeoxynucleotide alters
      neither the CWS effect nor CRF immunoreactivity. These findings identify locally
      expressed CRF as the predominant agent to trigger opioid release within inflamed
      tissue. Endogenous IL-1, circulating CRF or antiinflammatory effects, are not
      involved. Thus, an intact immune system plays an essential role in pain control,
      which is important for the understanding of pain in immunosuppressed patients
      with cancer or AIDS.

PMID- 8650226
TI  - The molecular basis of Sanfilippo syndrome type B.
AB  - The Sanfilippo syndrome type B is a lysosomal storage disorder caused by
      deficiency of alpha-N-acetylglucosaminidase; it is characterized by profound
      mental deterioration in childhood and death in the second decade. For
      understanding the molecular genetics of the disease and for future development of
      DNA-based therapy, we have cloned the cDNA and gene encoding alpha-N
      acetylglucosaminidase. Cloning started with purification of the bovine enzyme and
      use of a conserved oligonucleotide sequence to probe a human cDNA library. The
      cDNA sequence was found to encode a protein of 743 amino acids, with a 20- to 23
      aa signal peptide immediately preceding the amino terminus of the tissue enzyme
      and with six potential N-glycosylation sites. The 8.5-kb gene (NAGLU),
      interrupted by 5 introns, was localized to the 5'-flanking sequence of a known
      gene, EDH17B, on chromosome 17q21. Five mutations were identified in cells of
      patients with Sanfilippo syndrome type B: 503del10, R297X, R626X, R643H, and
      R674H. The occurrence of a frameshift and a nonsense mutation in homozygous form
      confirms the identity of the NAGLU gene.

PMID- 8650228
TI  - Inhibition of sustained gamma oscillations (35-80 Hz) by fast transient responses
      in cat visual cortex.
AB  - Interactions between stimulus-induced oscillations (35-80 Hz) and stimulus-locked
      nonoscillatory responses were investigated in the visual cortex areas 17 and 18
      of anaesthetized cats. A single square-wave luminance grating was used as a
      visual stimulus during simultaneous recordings from up to seven electrodes. The
      stimulus movement consisted of a superposition of a smooth movement with a
      sequence of dynamically changing accelerations. Responses of local groups of
      neurons at each electrode were studied on the basis of multiple unit activity and
      local slow field potentials (13-120 Hz). Oscillatory and stimulus-locked
      components were extracted from multiple unit activity and local slow field
      potentials and quantified by a combination of temporal and spectral correlation
      methods. We found fast stimulus-locked components primarily evoked by sudden
      stimulus accelerations, whereas oscillatory components (35-80 Hz) were induced
      during slow smooth movements. Oscillations were gradually reduced in amplitude
      and finally fully suppressed with increasing amplitudes of fast stimulus-locked
      components. It is argued that suppression of oscillations is necessary to prevent
      confusion during sequential processing of stationary and fast changing retinal
      images.

PMID- 8650227
TI  - Recombination leads to the rapid emergence of HIV-1 dually resistant mutants
      under selective drug pressure.
AB  - The potential contribution of recombination to the development of HIV-1
      resistance to multiple drugs was investigated. Two distinct viruses, one highly
      resistant to a protease inhibitor (SC-52151) and the other highly resistant to
      zidovudine, were used to coinfect T lymphoblastoid cells in culture. The viral
      genotypes could be distinguished by four mutations conferring drug resistance to
      each drug and by other sequence differences specific for each parental virus.
      Progeny virions recovered from mixed infection were passaged in the presence and
      absence of both zidovudine and SC-52151. Dually resistant mutants emerged rapidly
      under selective conditions, and these viruses were genetic recombinants. These
      results emphasize that genetic recombination could contribute to high-level
      multiple-drug resistance and that this process must be considered in
      chemotherapeutic strategies for HIV infection.

PMID- 8650229
TI  - A single residue in the M2-M3 loop is a major determinant of coupling between
      binding and gating in neuronal nicotinic receptors.
AB  - Binding of agonists to nicotinic acetylcholine receptors generates a sequence of
      changes that activate a cation-selective conductance. By measuring
      electrophysiological responses in chimeric alpha7/alpha3 receptors expressed in
      Xenopus oocytes, we have showed the involvement of the M2-M3 loop in coupling
      agonist binding to the channel gate. An aspartate residue therein, Asp-266 in the
      alpha7 subunit, was identified by site-directed mutagenesis as crucial, since
      mutants at this position exhibited very poor functional responses to three
      different nicotinic agonists. We have extended this investigation to another
      neuronal nicotinic receptor (alpha3/beta4), and found that a homologous residue
      in the beta4 subunit, Asp-268, played a similar role in coupling. These findings
      are consistent with a hypothesis that the aspartate residue in the M2-M3 loop,
      which is conserved in all homomer-forming alpha-type subunits and all neuronal
      beta-type subunits that combine to form functional receptors, is a major
      determinant of information transmission from binding site to channel gate in all
      neuronal nicotinic receptors.

PMID- 8650230
TI  - Novel human DNA alkyltransferases obtained by random substitution and genetic
      selection in bacteria.
AB  - DNA repair alkyltransferases protect organisms against the cytotoxic, mutagenic,
      and carcinogenic effects of alkylating agents by transferring alkyl adducts from
      DNA to an active cysteine on the protein, thereby restoring the native DNA
      structure. We used random sequence substitutions to gain structure-function
      information about the human O6-methylguanine-DNA methyltransferase (EC 2.1.1.63),
      as well as to create active mutants. Twelve codons surrounding but not including
      the active cysteine were replaced by a random nucleotide sequence, and the
      resulting random library was selected for the ability to provide alkyltransferase
      deficient Escherichia coli with resistance to the methylating agent N-methyl-N'
      nitro-N-nitrosoguanidine. Few amino acid changes were tolerated in this
      evolutionarily conserved region of the protein. One mutation, a valine to
      phenylalanine change at codon 139 (V139F), was found in 70% of the selected
      mutants; in fact, this mutant was selected much more frequently than the wild
      type. V139F provided alkyltransferase-deficient bacteria with greater protection
      than the wild-type protein against both the cytotoxic and mutagenic effects of N
      methyl-N'-nitro-N-nitrosoguanidine, increasing the D37 over 4-fold and reducing
      the mutagenesis rate 2.7-5.5-fold. This mutant human alkyltransferase, or others
      similarly created and selected, could be used to protect bone marrow cells from
      the cytotoxic side effects of alkylation-based chemotherapeutic regimens.

PMID- 8650231
TI  - Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus
      adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma.
AB  - Analyses of the human PAX-5 locus and of the 5' region of the mouse Pax-5 gene
      revealed that transcription from two distinct promoters results in splicing of
      two alternative 5' exons to the common coding sequences of exons 2-10.
      Transcription from the upstream promoter initiates downstream of a TATA box and
      occurs predominantly in B-lymphocytes, whereas the TATA-less downstream promoter
      is active in all Pax-5-expressing tissues. The human PAX-5 gene is located on
      chromosome 9 in region p13, which is involved in t(9;14)(pl3;q32) translocations
      recurring in small lymphocytic lymphomas of the plasmacytoid subtype and in
      derived large-cell lymphomas. A previous molecular analysis of a t(9;14)
      breakpoint from a diffuse large-cell lymphoma (KIS-1) demonstrated that the
      immunoglobulin heavy-chain (IgH) locus on 14q32 was juxtaposed to chromosome 9p13
      sequences of unknown function [Ohno, H., Furukawa, T., Fukuhara, S., Zong, S. Q.,
      Kamesaki, H., Shows, T. B., Le Beau, M. M., McKeithan, T. W., Kawakami, T. &
      Honjo, T. (1990) Proc. Natl. Acad. Sci. USA 87,628-632]. Here we show that the
      KIS-1 translocation breakpoint is located 1807 base pairs upstream of exon 1A of
      PAX-5, thus bringing the potent Emu enhancer of the IgH gene into close proximity
      of the PAX-5 promoters. These data suggest that deregulation of PAX-5 gene
      transcription by the t(9;14)(pl3;q32) translocation contributes to the
      pathogenesis of small lymphocytic lymphomas with plasmacytoid differentiation.

PMID- 8650232
TI  - Isolation of an immunodominant viral peptide that is endogenously bound to the
      stress protein GP96/GRP94.
AB  - Heat shock protein gp96 primes class I restricted cytotoxic T cells against
      antigens present in the cells from which it was isolated. Moreover, gp96 derived
      from certain tumors functions as an effective vaccine, causing complete tumor
      regressions in in vivo tumor challenge protocols. Because tumor-derived gp96 did
      not differ from gp96 isolated from normal tissues, a role for gp96 as a peptide
      carrier has been proposed. To test this hypothesis, we analyzed whether such an
      association of antigenic peptides with gp96 occurs in a well-defined viral model
      system. Here we present the full characterization of an antigenic peptide that
      endogenously associates with the stress protein gp96 in cells infected with
      vesicular stomatitis virus (VSV). This peptide is identical to the immunodominant
      peptide of VSV, which is also naturally presented by H-2Kb major
      histocompatibility complex class I molecules. This peptide associates with gp96
      in VSV-infected cells regardless of the major histocompatibility com- plex
      haplotype of the cell. Our observations provide a biochemical basis for the
      vaccine function of gp96.

PMID- 8650233
TI  - Age-specific inbreeding depression and components of genetic variance in relation
      to the evolution of senescence.
AB  - Two major theories of the evolution of senescence (mutation accumulation and
      antagonistic pleiotropy) make different predictions about the relationships
      between age, inbreeding effects, and the magnitude of genetic variance components
      of life-history components. We show that, under mutation accumulation, inbreeding
      decline and three major components of genetic variance are expected to increase
      with age in randomly mating populations. Under the simplest version of the
      antagonistic pleiotropy model, no changes in the severity of inbreeding decline,
      dominance variance, or the genetic variance of chromosomal homozygotes are
      expected, but additive genetic variance may increase with age. Age-specific
      survival rates and mating success were measured on virgin males, using lines
      extracted from a population of Drosophila melanogaster. For both traits,
      inbreeding decline and several components of genetic variance increase with age.
      The results are consistent with the mutation accumulation model, but can only be
      explained by antagonistic pleiotropy if there is a general tendency for an
      increase with age in the size of allelic effects on these life-history traits.

PMID- 8650234
TI  - Selenocysteine, identified as the penultimate C-terminal residue in human T-cell
      thioredoxin reductase, corresponds to TGA in the human placental gene.
AB  - The possible relationship of selenium to immunological function which has been
      suggested for decades was investigated in studies on selenium metabolism in human
      T cells. One of the major 75Se-labeled selenoproteins detected was purified to
      homogeneity and shown to be a homodimer of 55-kDa subunits. Each subunit
      contained about 1 FAD and at least 0.74 Se. This protein proved to be thioredoxin
      reductase (TR) on the basis of its catalytic activities, cross-reactivity with
      anti-rat liver TR antibodies, and sequence identities of several tryptic peptides
      with the published deduced sequence of human placental TR. Physicochemical
      characteristics of T-cell TR were similar to those of a selenocysteine (Secys)
      containing TR recently isolated from human lung adenocarcinoma cells. The
      sequence of a 12-residue 75Se-labeled tryptic peptide from T-cell TR was
      identical with a C-terminal-deduced sequence of human placental TR except that
      Secys was present in the position corresponding to TGA, previously thought to be
      the termination codon, and this was followed by Gly-499, the actual C-terminal
      amino acid. The presence of the unusual conserved Cys-Secys-Gly sequence at the C
      terminus of TR in addition to the redox active cysteines of the Cys-Val-Asn-Val
      Gly-Cys motif in the FAD-binding region may account for the peroxidase activity
      and the relatively low substrate specificity of mammalian TRs. The finding that T
      cell TR is a selenoenzyme that contains Se in a conserved C-terminal region
      provides another example of the role of selenium in a major antioxidant enzyme
      system (i.e., thioredoxin-thioredoxin reductase), in addition to the well-known
      glutathione peroxidase enzyme system.

PMID- 8650235
TI  - Application of capillary electrophoresis-electrospray ionization mass spectometry
      in the determination of molecular diversity.
AB  - By means of capillary electrophoresis coupled online to electrospray ionization
      MS, a library of theoretically 171 disubstituted xanthene derivatives was
      analyzed. The method allowed the purity and makeup of the library to be
      determined: 160 of the expected compounds were found to be present, and 12 side
      products were also detected in the mixture. Due to the ability of capillary
      electrophoresis to separate analytes on the basis of charge, most of the xanthene
      derivatives could be resolved by simple capillary electrophoresis-MS procedures
      even though 124 of the 171 theoretical compounds were isobaric with at least one
      other molecule in the mixture. Any remaining unresolved peaks were resolved by
      MS/MS experiments. The method shows promise for the analysis of small
      combinatorial libraries with fewer than 1000 components.

PMID- 8650236
TI  - Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre
      recombinase-mediated site-specific recombination in embryonic stem cells.
AB  - Gene disruptions and deletions of up to 20kb have been generated by homologous
      recombination with appropriate targeting vectors in murine embryonic stem (ES)
      cells. Because we could not obtain a deletion of about 200 kb in the mouse
      amyloid precursor protein gene by the classical technique, we employed strategies
      involving the insertion of loxP sites upstream and downstream of the region to be
      deleted by homologous recombination and elicited excision of the loxP-flanked
      region by introduction of a Cre expression vector into the ES cells. In the first
      approach, the loxP sequences were inserted in two successive steps and after each
      step, ES cell clones were isolated and characterized. Deletion of the loxP
      flanked sequence was accomplished by introducing the cre gene in a third step. In
      the second approach, ES cells containing the upstream loxP cassette were
      electroporated simultaneously with the downstream loxP targeting vector and the
      Cre expression plasmid. ES cells were obtained that gave rise to chimeric mice
      capable of germ-line transmission of the deleted amyloid precursor protein
      allele.

PMID- 8650237
TI  - Centromere mapping and orientation of the molecular linkage map of rice (Oryza
      sativa L.).
AB  - Rice has become a model cereal plant for molecular genetic research. Rice has the
      most comprehensive molecular linkage maps with more than 2000 DNA markers and
      shows synteny and colinearity with the maps of other cereal crops. Until now,
      however, no information was available about the positions of centromeres and arm
      locations of markers on the molecular linkage map. Secondary and telotrisomics
      were used to assign restriction fragment length polymorphism markers to specific
      chromosome arms and thereby to map the positions of centromeres. More than 170
      restriction fragment length polymorphism markers were assigned to specific
      chromosome arms through gene dosage analysis using the secondary and
      telotrisomics and the centromere positions were mapped on all 12 linkage groups.
      The orientations of seven linkage groups were reversed to fit the "short arm on
      top" convention and the corrected map is presented.

PMID- 8650238
TI  - Modulation of AP-1 activity by the human progesterone receptor in endometrial
      adenocarcinoma cells.
AB  - The composite transcription factor activating protein 1 (AP-1) integrates various
      mitogenic signals in a large number of cell types, and is therefore a major
      regulator of cell proliferation. In the normal human endometrium, proliferation
      and differentiation alternate in a cyclic fashion, with progesterone being
      largely implicated in the latter process. However, the effects of progesterone
      and the progesterone receptor (hPR) on AP-1 activity in the human endometrium are
      not known. To address this issue, HEC-1-B endometrial adenocarcinoma cells, which
      are devoid of hPR, were transfected with luciferase reporter constructs driven by
      two different AP-1-dependent promoters. Unexpectedly, cotransfection of hPR
      caused a marked induction of luciferase activity in the absence of ligand on both
      promoters. The magnitude of this induction was similar to that observed in
      response to the phorbol ester TPA. Addition of ligand reversed the stimulating
      effect of the unliganded hPR on AM activity in these cells. These effects were
      specific for hPR, and were not observed with either human estrogen receptor or
      human glucocorticoid receptor. Furthermore, they strictly depended on the
      presence of AP-1-responsive sequences within target promoters. Finally, the
      described effects of hPR on AP-1 activity were shown to be cell-type specific,
      because they could not be demonstrated in SKUT-1-B, JEG-3, and COS-7 cells. To
      our knowledge this is the first report of an unliganded steroid receptor
      stimulating AP-1 activity. This effect and its reversal in the presence of ligand
      suggest a novel mechanism, through which hPR can act as a key regulator of both
      proliferation and differentiation in the human endometrium.

PMID- 8650239
TI  - Introduction of asymmetry in the naturally symmetric restriction endonuclease
      EcoRV to investigate intersubunit communication in the homodimeric protein.
AB  - Type II restriction endonucleases are dimers of two identical subunits that
      together form one binding site for the double-stranded DNA substrate. Cleavage
      within the palindromic recognition site occurs in the two strands of the duplex
      in a concerted manner, due to the action of two catalytic centers, one per
      subunit. To investigate how the two identical subunits of the restriction
      endonuclease EcoRV cooperate in binding and cleaving their substrate,
      heterodimeric versions of EcoRV with different amino acid substitutions in the
      two subunits were constructed. For this purpose, the ecorV gene was fused to the
      coding region for the glutathione-binding domain of the glutathione S-transferase
      and a His6-tag, respectively. Upon cotransformation of Escherichia coli cells
      with both gene fusions stable homo- and heterodimers of the EcoRV variants are
      produced, which can be separated and purified to homogeneity by affinity
      chromatography over Ni-nitrilotriacetic acid and glutathione columns. A steady
      state kinetic analysis shows that the activity of a heterodimeric variant with
      one inactive catalytic center is decreased by 2-fold, demonstrating that the two
      catalytic centers operate independently from each other. In contrast,
      heterodimeric variants with a defect in one DNA-binding site have a 30- to 50
      fold lower activity, indicating that the two subunits of EcoRV cooperate in the
      recognition of the palindromic DNA sequence. By combining a subunit with an
      inactive catalytic center with a subunit with a defect in the DNA-binding site,
      EcoRV heterodimers were produced that only nick DNA specifically within the EcoRV
      recognition sequence.

PMID- 8650240
TI  - Pantropic retroviral vectors integrate and express in cells of the malaria
      mosquito, Anopheles gambiae.
AB  - The lack of efficient mechanisms for stable genetic transformation of medically
      important insects, such as anopheline mosquitoes, is the single most important
      impediment to progress in identifying novel control strategies. Currently
      available techniques for foreign gene expression in insect cells in culture lack
      the benefit of stable inheritance conferred by integration. To overcome this
      problem, a new class of pantropic retroviral vectors has been developed in which
      the amphotropic envelope is completely replaced by the G glycoprotein of
      vesicular stomatitis virus. The broadened host cell range of these particles
      allowed successful entry, integration, and expression of heterologous genes in
      cultured cells of Anopheles gambiae, the principle mosquito vector responsible
      for the transmission of over 100 million cases of malaria each year. Mosquito
      cells in culture infected with a pantropic vector expressing hygromycin
      phosphotransferase from the Drosophila hsp70 promoter were resistant to the
      antibiotic hygromycin B. Integrated provirus was detected in infected mosquito
      cell clones grown in selective media. Thus, pantropic retroviral vectors hold
      promise as a transformation system for mosquitoes in vivo.

PMID- 8650241
TI  - Subunit cleavage of mosquito pro-vitellogenin by a subtilisin-like convertase.
AB  - The eukaryotic convertase family plays an important role in posttranslational
      proteolytic processing and activation of many pro- and polypeptides that have at
      their cleavage sites the paired basic motif, RX(K/R)R. Recent studies have
      revealed that the cleavage site of insect pro-vitellogenins (pro-Vg) also
      contains this motif. To identify and characterize the insect pro-Vg processing
      enzyme, Vg convertase (VC), its cDNA was cloned from a vitellogenic female fat
      body cDNA library of the mosquito, Aedes aegypti. The 3735-bp-long VC cDNA has an
      open reading frame encoding a 115-kDa protein. In vitro transcription/translation
      of VC cDNA revealed that this 115-kDa protein becomes 140 kDa after co- and
      posttranslational modifications. The VC deduced amino acid sequence has high
      similarity to and a domain structure characteristic of furin-like convertases.
      Northern blot analysis showed that a single 4.2-kb transcript was expressed in
      the fat body during the first 18 hr of the Vg synthetic period. Coexpression of
      VC cDNA with mosquito Vg cDNA resulted in correct cleavage of pro-Vg. Thus, this
      newly identified convertase is, indeed, a functional fat body-specific enzyme for
      pro-Vg cleavage.

PMID- 8650242
TI  - Flp recombinase promotes site-specific DNA recombination in embryonic stem cells
      and transgenic mice.
AB  - Site-specific recombinases are being developed as tools for "in vivo" genetic
      engineering because they can catalyze precise excisions, integrations,
      inversions, or translocations of DNA between their distinct recognition target
      sites. Here it is demonstrated that Flp recombinase can effectively mediate site
      specific excisional recombination in mouse embryonic stem cells, in
      differentiating embryonal carcinoma cells, and in transgenic mice. Broad Flp
      expression is compatible with normal development, suggesting that Flp can be used
      to catalyze recombination in most cell types. These properties indicate that Flp
      can be exploited to make prescribed alterations in the mouse genome.

PMID- 8650243
TI  - Cell-type and promoter-context dependent retinoic acid receptor (RAR)
      redundancies for RAR beta 2 and Hoxa-1 activation in F9 and P19 cells can be
      artefactually generated by gene knockouts.
AB  - By using RAR type (alpha, beta, or gamma)-specific synthetic retinoids and a pan
      retinoic X receptor (RXR)-specific ligand, we have investigated the contribution
      of RARs and RXRs in the activation of RA target genes and the differentiation of
      embryonal carcinoma cells. We demonstrate cell-type- and promoter context
      dependent functional redundancies that differ between the three RAR types for
      mediating the induction of RARbeta2 and Hoxa-1 in wild-type, RARgamma-/- and
      RARalpha-/- F9 cells and in P19 cells. The extent of redundancy between RARs is
      further modulated by the synergistic activation of RXRs with a pan-RXR agonist.
      We also demonstrate that the expression of RARbeta2 is auto-inducible in RARgamma
      /- but not in wild-type F9 cells, indicating that the functional redundancies
      observed between RARs in gene disruption studies can be artefactually generated.
      Thus, even though all three RARs can functionally substitute each other for
      inducing the expression of RA target genes and cell differentiation, one RAR can
      cell-specifically override the activity of the other RARs. Interestingly, only
      RARgamma can mediate the retinoic acid-induced differentiation of wild-type F9
      cells, whereas the differentiation of P19 cells can be mediated by either
      RARalpha or RARgamma.

PMID- 8650244
TI  - Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme
      deficient in multiple different cancers.
AB  - 5'-Deoxy-5'-methylthioadenosine phosphorylase (methylthioadeno-sine: ortho
      phosphate methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine
      and polyamine metabolism and in the regulation of transmethylation reactions.
      MTAP is abundant in normal cells but is deficient in many cancers. Recently, the
      genes for the cyclin-dependent kinase inhibitors p16 and p15 have been localized
      to the short arm of human chromosome 9 at band p21, where MTAP and interferon
      alpha genes (IFNA) also map. Homozygous deletions of p16 and p15 are frequent
      malignant cell lines. However, the order of the MTAP, p16, p15, and IFNA genes on
      chromosome 9p is uncertain, and the molecular basis for MTAP deficiency in cancer
      is unknown. We have cloned the MTAP gene, and have constructed a topologic map of
      the 9p21 region using yeast artificial chromosome clones, pulse-field gel
      electrophoresis, and sequence-tagged-site PCR. The MTAP gene consists of eight
      exons and seven introns. Of 23 malignant cell lines deficient in MTAP protein,
      all but one had complete or partial deletions. Partial or total deletions of the
      MTAP gene were found in primary T-cell acute lymphoblastic leukemias (T-ALL). A
      deletion breakpoint of partial deletions found in cell lines and primary T-ALL
      was in intron 4. Starting from the centromeric end, the gene order on chromosome
      9p2l is p15, p16, MTAP, IFNA, and interferon beta gene (IFNB). These results
      indicate that MTAP deficiency in cancer is primarily due to codeletion of the
      MTAP and p16 genes.

PMID- 8650245
TI  - Perpetuation of the agent of human granulocytic ehrlichiosis in a deer tick
      rodent cycle.
AB  - A human-derived strain of the agent of human granulocytic ehrlichiosis, a
      recently described emerging rickettsial disease, has been established by serial
      blood passage in mouse hosts. Larval deer ticks acquired infection by feeding
      upon such mice and efficiently transmitted the ehrlichiae after molting to
      nymphs, thereby demonstrating vector competence. The agent was detected by
      demonstrating Feulgen-positive inclusions in the salivary glands of the
      experimentally infected ticks and from field-derived adult deer ticks. White
      footed mice from a field site infected laboratory-reared ticks with the agent of
      human granulocytic ehrlichiosis, suggesting that these rodents serve as
      reservoirs for ehrlichiae as well as for Lyme disease spirochetes and the
      piroplasm that causes human babesiosis. About 10% of host-seeking deer ticks were
      infected with ehrlichiae, and of these, 20% also contained spirochetes.
      Cotransmission of diverse pathogens by the aggressively human-biting deer tick
      may have a unique impact on public health in certain endemic sites.

PMID- 8650246
TI  - The heart communicates with the kidney exclusively through the guanylyl cyclase-A
      receptor: acute handling of sodium and water in response to volume expansion.
AB  - Disruption of guanylyl cyclase-A (GC-A) results in mice displaying an elevated
      blood pressure, which is not altered by high or low dietary salt. However, atrial
      natriuretic peptide (ANP), a proposed ligand for GC-A, has been suggested as
      critical for the maintenance of normal blood pressure during high salt intake. In
      this report, we show that infusion of ANP results in substantial natriuresis and
      diuresis in wild-type mice but fails to cause significant changes in sodium
      excretion or urine output in GC-A-deficient mice. ANP, therefore, appears to
      signal through GC-A in the kidney. Other natriuretic/diuretic factors could be
      released from the heart. Therefore, acute volume expansion was used as a means to
      cause release of granules from the atrium of the heart. That granule release
      occurred was confirmed by measurements of plasma ANP concentrations, which were
      markedly elevated in both wild-type and GC-A-null mice. After volume expansion,
      urine output as well as urinary sodium and cyclic GMP excretion increased rapidly
      and markedly in wild-type mice, but the rapid increases were abolished in GC-A
      deficient animals. These results strongly suggest that natriuretic/diuretic
      factors released from the heart function exclusively through GC-A.

PMID- 8650247
TI  - Vitamin D in the treatment of osteoporosis revisited.
AB  - Interest in vitamin D treatment for osteoporosis has recently been revived
      because of the focus in various parts of the world on the elderly population,
      which is predominantly vitamin D deficient, in addition to postmenopausal
      osteoporosis due to estrogen withdrawal, which has been the central theme of
      osteoporosis research for many years. Combined use of other agents along with
      vitamin D has fortified the therapeutic armory against osteoporosis. The recent
      suggestion of a role of vitamin D receptor polymorphism in the development and
      progress of osteoporosis, possibly by interfering with its expected action,
      provoked intense discussions on the role of vitamin D in the pathogenesis and
      treatment of osteoporosis. Vitamin D receptor polymorphism may explain some of
      the racial differences in the incidence of osteoporosis and its complications.
      Responses to vitamin D treatment may also be predicted by vitamin D receptor
      allelic analysis, though the currently proposed allelic patterns are yet far from
      being widely accepted. The outlook for vitamin D treatment for osteoporosis may
      require insight into vitamin D receptor, not only for vitamin D's given form, but
      also for a possible future form designed to intervene at the genomic level.

PMID- 8650248
TI  - Regulation of the hypoxanthine phosphoribosyltransferase gene: in vitro and in
      vivo approaches.
AB  - The hypoxanthine phosphoribosyltransferase (HPRT) locus is a constitutively
      expressed housekeeping gene characterized by a notably higher level of expression
      in the mammalian brain. The enzyme it encodes is key to purine salvage in humans
      and is the basis for the X-linked recessive disorder, Lesch-Nyhan syndrome (LNS).
      Methylation in the promoter plays a critical, if not fully understood, role in
      transcriptional silencing of the locus on the inactive chromosome, possibly by
      conferring structural stability. In vivo footprinting assays of the promoter
      region have shown protein interaction with multiple Spl-binding sites, a possible
      AP2 site, and a potentially novel binding site. In vitro studies of HPRT promoter
      deletion constructs have identified a minimal promoter element necessary for
      maximal transcription and a position-dependent, orientation-independent repressor
      element (HPRT-NE) that functions on heterologous promoters. Regulatory intron
      elements have also been observed. Studies on transgenic mice bearing HPRT
      promoter constructs have shown that the minimal promoter element is insufficient
      for in vivo expression and that HPRT-NE is responsible for conferring neuronal
      specificity. HPRT-mice possess metabolic defects similar to LNS patients, but
      fail to develop human behavioral abnormalities, perhaps because of species
      differences in purine metabolism. A neuronal-specific protein complex appears to
      be necessary for activator function of HPRT-NE, while a ubiquitously expressed
      complex may be responsible for repression. Sequence analysis Indicates that the
      latter complex may depend on the multifunctional transcription factor YY1 for
      binding. A fuller understanding of HPRT gene regulation will hopefully provide
      insight into the transcriptional mechanisms controlling the expression of
      housekeeping and brain-specific genes.

PMID- 8650249
TI  - A fragment of human kininogen containing bradykinin blunts the diuretic effect of
      atrial natriuretic peptide.
AB  - A synthetic 15 aminoacids kinin, named PU-15, is able to block the diuretic
      natriuretic action of Atrial Natriuretic Peptide (ANP). The structure of PU-15 is
      Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-Iso, having the aminoacid
      sequence of a fragment of human kininogens. The increase in the urinary excretion
      of sodium, potassium, and water, elicited by a bolus of 0.5 microg of ANP in
      anesthetized rats, is blocked by PU-15 (100-150 ng) given either intravenously 3
      min before ANP injection, or injected intraperitoneally or in the duodenal lumen,
      40 min before ANP. This ANP blockade, which mimics the action of pepsanurin, is
      only obtained with doses of PU-15 in a narrow range around 100 picomol/rat, and
      do not modify blood pressure. Larger doses, 2- to 8-fold the effective dose,
      either do not change the response to ANP or raise the excretion of sodium and
      water. The administration of HOE-140, a bradykinin B2 receptor blocker, prior to
      PU-15, completely abolishes the anti-ANP action of PU-15. These findings lend
      support to the proposal that kinins released from the intestinal tract during
      prandial period can modulate renal excretory function.

PMID- 8650250
TI  - Relationship between opioids and prostaglandins in hypoxia-induced vasodilation
      of pial arteries in the newborn pig.
AB  - Previously, it has been observed that methionine enkephalin and leucine
      enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig.
      It has also been observed that the cyclooxygenase inhibitor indomethacin
      attenuates hypoxic hyperemia in piglets. The present study was designed to
      determine the relationship between opioids and prostaglandins in hypoxia-induced
      pial artery dilation. Newborn pigs equipped with closed cranial windows were used
      to measure pial artery diameter and collect cortical periarachnoid cerebrospinal
      fluid (CSF) for assay of opioids and prostaglandins. Hypoxia-induced artery
      vasodilation was mildly attenuated during moderate hypoxia (PaCO2 approximately
      35 mm Hg), while this response was blunted during severe hypoxia (PaO2
      approximately 25 mm Hg) by indomethacin, 5 mg/kg iv (23% +/- 1 % vs 18% +/- 1%
      and 33% +/- 2% vs 21% +/- 2% for moderate and severe hypoxia in the absence and
      presence of indomethacin, respectively). Hypoxic dilation was accompanied by
      increased CSF prostaglandin E2 (PGE2) concentration (1260 +/- 37 vs 1734 +/- 67
      and 1256 +/- 33 vs 2859 +/- 189 pg/ml for moderate and severe hypoxia,
      respectively). Similar changes in CSF 6 keto PGF1alpha concentration during
      hypoxia were also observed. Topical PGE2 (10,100 ng/ml) increased CSF methionine
      enkephalin (874 +/- 35, 1290 +/- 44, and 1791 +/- 143 pg/ml for control, 10 and
      100 ng/ml PGE2 respectively). Similar increases in CSF methionine enkephalin
      concentration were observed for topical PGI2. Additionally, these two
      prostaglandins also increased CSF leucine enkephalin concentration. Furthermore,
      while indomethacin had no effect on the release of CSF methionine enkephalin
      during moderate hypoxia, it attenuated the release of this opioid during severe
      hypoxia (786 +/- 27 and 2633 +/- 74 vs 781 +/- 51 and 2467 +/- 52; 926 +/- 15 and
      3489 +/- 156 vs 898 +/- 11 and 2314 +/- 124 pg/ml for control and moderate/severe
      hypoxia before and after indomethacin, respectively). Similar effects of
      indomethacin on hypoxic release of leucine enkephalin were also observed. These
      data indicate that prostaglandins contribute to hypoxic pial dilation.
      Additionally, these data show that prostaglandins release the opioids methionine
      enkephalin and leucine enkephalin. Finally, these data suggest that elevated
      prostaglandin concentrations during severe hypoxia release opioids which in turn
      contribute to hypoxic pial dilation.

PMID- 8650251
TI  - Characteristics of the prolactin stimulation of c-fos mRNA levels in mouse
      mammary gland explants.
AB  - The signal transduction pathway(s) for the prolactin (PRL) regulation of
      lactogenic processes in the mammary are not fully known. Recent studies indicate
      that the PRL occupancy of its receptor activates a tyrosine kinase (JAK-2), which
      is constitutively associated with the receptor. In the present studies, we have
      characterized the PRL stimulation of c-fos mRNA accumulation in mouse mammary
      gland explants that were precultured with insulin and cortisol for 36 hr. In time
      course studies, an initial effect (2-fold increase) of PRL was apparent after 15
      min, a 4-fold increase occurred after 60 min, and a 2-fold increase was apparent
      after 2 hr. Dose-response experiments indicated an initial effect with 5 ng/ml
      PRL and a maximum effect with 500 ng/ml PRL. The accumulation of c-fos; mRNA in
      the cultured mammary tissues was also increased by human GH, recombinant bovine
      PRL, cycloheximide, and phorbol 12-myristate 13-acetate (TPA). The cycloheximide
      and PRL responses were additive, thus indicating that cycloheximide did not
      "superinduce" the PRL stimulation of c-fos mRNA accumulation. Downregulation of
      protein kinase C (PKC) by pretreating mammary tissues for 1 day with TPA did not
      affect the magnitude of the PRL stimulation of c-fos mRNA accumulation. The
      findings from these studies are consistent with c-fos playing a role in the PRL
      stimulation of lactogenic processes in the mammary gland. PRL had no effect on c
      jun mRNA accumulation under any of the experimental conditions employed in the c
      fos studies.

PMID- 8650252
TI  - Increase of aldosterone secretion in adrenal cortex suspensions derived from
      pregnant rats.
AB  - Plasma aldosterone levels increase markedly during pregnancy, but not in
      proportion to the rise in plasma renin activity (PRA). We have developed a
      reliable in vitro method to investigate aldosterone secretion during pregnancy.
      With this method, we have assessed the potency and effectiveness of ACTH and
      potassium to stimulate this secretion during pregnancy. Adrenal capsules from
      pregnant and nonpregnant rats were incubated in 1 ml of culture medium within
      wells of tissues culture plates. The cortex was transferred every 20 min to
      another well containing fresh medium with or without ACTH or potassium. Basal and
      stimulated aldosterone secretions were not significantly affected by time under
      our experimental conditions. The glands remained responsive to stimulants
      throughout the study period (360 min). Plasma aldosterone levels and PRA were
      increased during pregnancy. Basal aldosterone secretion in adrenal cortex
      suspensions from pregnant rats showed a 1.6-fold increment (P < 0.001) in
      comparison with nonpregnant controls. The dose-response curves of ACTH were not
      significantly different between pregnant and nonpregnant animals. However,
      sensitivity to potassium was significantly reduced during pregnancy, as
      demonstrated by an elevated ED50 (4.01 +/- 0.08 vs 4.71 +/- 0.07 mM for
      nonpregnant versus pregnant rats respectively, P < 0.001). These data indicate
      that adrenal cortex suspensions are a reliable and reproducible way to study
      aldosterone secretion during pregnancy. They reveal that, during pregnancy,
      sensitivity of potassium to stimulate aldosterone secretion is decreased while
      the response to ACTH is not affected.

PMID- 8650253
TI  - Linoleate impairs collagen synthesis in primary cultures of avian chondrocytes.
AB  - The effects of supplemental fatty acids, vitamin E (VIT E), and iron-induced
      oxidative stress on collagen synthesis, cellular injury, and lipid peroxidation
      were evaluated in primary cultures of avian epiphyseal chondrocytes. The
      treatments included oleic and linoleic acids (O or 50 microM) complexed with BSA
      and dl-alpha-tocopheryl acetate (VIT E at 0 or 100 microM). After 14 days of
      preculture, the chondrocytes were enriched with fatty acids for 8 days then
      cultured with VIT E for 2 days. The chondrocytes were then treated with ferrous
      sulfate (O or 20 microM) for 24 hr to induce oxidative stress. Collagen synthesis
      was the lowest and the activity of lactate dehydrogenase (LDH) was the highest in
      chondrocyte cultures treated with 50 microM linoleic acid and 0 VIT E. In
      contrast, VIT E supplemented at 100 microM partially restored collagen synthesis
      in the chondrocytes enriched with linoleic acid and lowered LDH activity in the
      media. The iron oxidative inducer significantly increased the values of
      thiobarbituric acid-reactive substances (TBARS) in the culture medium. The data
      showed that linoleic acid impaired chondrocyte cell function and caused cellular
      injury but that VIT E reversed these effects. Results from a previous study
      demonstrated that VIT E stimulated bone formation in chicks fed unsaturated fat,
      and the present findings in cultures of epiphyseal chondrocytes suggest that VIT
      E is important for chondrocyte function in the presence of polyunsaturated fatty
      acids. VIT E appears to be beneficial for growth cartilage biology and in
      optimizing bone growth.

PMID- 8650254
TI  - Transplantation of immortalized, nontumorigenic parotid acinar cells into the
      allogeneic rat parotid gland and oral submucosa.
AB  - The recent establishment of an immortalized clonal cell line of rat parotid
      acinar cells (2RSG) by transfecting isoproterenol-stimulated parotid cells with a
      plasmid vector, pSV3neo which carries the large T-antigen gene from SV40 virus,
      afforded the opportunity to develop a model for parotid acinar cell
      transplantation. Single cell suspensions of 2RSG cells labeled with a fluorescent
      tracer, DiI, were injected into the parotid gland or oral submucosa of allogeneic
      adult rats. The grafted cells survived and were functionally viable for at least
      30 days. Histological sections revealed no evidence of infiltration of leukocytes
      or lymphocytes. Grafted cells did not form tumors. Results suggest that
      allogeneic parotid acinar cell transplantation is a feasible technique in the
      animal model.

PMID- 8650255
TI  - PGF2alpha-induced signaling events in glomerular mesangial cells.
AB  - Of the various arachidonate cyclooxygenation eicosanoids synthesized in the
      normal and injured renal glomerular capillary, prostaglandin F2alpha (PGF2alpha)
      is the most abundant and potent in eliciting signaling events and biologic
      responses including contraction and proliferation of glomerular capillary
      pericytes known as mesangial cells. The regulation of PGF2alpha-induced signaling
      in these cells is unknown. The present studies assessed two key signaling events
      in response to PGF2alpha in mesangial cells; activation of phospholipase C (PLC)
      and protein kinase C (PKC). Mechanisms regulating PLC activation were also
      explored. Incubation of cultured growth arrested rat mesangial cells with
      PGF2alpha (1 microM) resulted in activation of a phosphatidyl inositol-specific
      phospholipase C (PI-PLC) assessed as increased generation of polyphosphates in
      myo-[3H]-inositol-labeled cells and as increased diacylglycerol (DAG) mass levels
      measured by a radioenzymatic assay. Generation of both inositol 1,4,5
      trisphosphate and inositol 1,3,4-trisphosphate occurred, the former constituting
      70% of total inositol trisphosphates. Enhanced generation of inositol 1,4
      bisphosphate (IP2) also occurred and was greater than that of inositol 1,4,5
      trisphosphate (IP3), indicating that PI-PLC utilized the phosphatidyl inositol
      monophosphate (PIP) to a greater extent than the phosphatidyl inositol
      bisphosphate (PIP2) substrate. Generation of DAG in response to PGF2alpha
      occurred in a biphasic pattern characterized by an early transient rise that
      peaked concomitantly with IP3 at 15 sec, and a late sustained increase at 2, 5,
      and 15 min that was not associated with an increase in IP3. PGF2alpha also
      activated PKC assessed as translocation of enzyme activity from cytosolic to
      membrane fractions. Inhibition of PKC using H-7 enhanced PGF2alpha-induced
      generation of IP3 at 15 sec but attenuated generation of DAG at 15 min. A more
      selective PKC inhibitor, Calphostin C, dose-dependently increased basal IP3
      generation and also attenuated generation of DAG in response to PGF2alpha. This
      indicates that PKC negatively modulates PGF2alpha-induced PI-PLC activation, and
      that the late sustained DAG generation in response to PGF2alpha is regulated by a
      PKC-dependent phospholipase other than PLC. The mechanisms of PI-PLC stimulation
      in response to PGF2alpha were further explored using inhibitors of protein
      tyrosine phosphorylation and of guanine nucleotide-binding (G) protein
      activation. Inhibition of protein tyrosine phosphorylation using genistein had no
      effect on IP3 or DAG generation. ADP ribosylation of Gi using pertussis toxin
      (PTx) had no effect on IP3 generation in response to PGF2alpha. The inhibitor of
      receptor-coupled PI-PLC activation aminosteroid compound U-73122 that blocks
      G(PLC) was also ineffective. The observations indicate that PGF2alpha stimulates
      a PI-PLC which is under negative feedback regulatory control by PKC, and a
      phospholipase other than PLC which is under positive regulatory control by PKC.
      PGF2alpha-induced PI-PLC activation is independent of protein tyrosine
      phosphorylation and of PTx-sensitive G proteins.

PMID- 8650256
TI  - The regulation of phospholipase-A2 (PLA-2) by cytokines expressing hematopoietic
      growth-stimulating properties.
AB  - Various growth factors released by macrophages and other cell types modulate
      normal hematopoiesis. The physiological mechanisms whereby these molecules
      interact with specific target cells are ill defined. Eicosanoids, the products of
      fatty acid metabolism, are known to regulate cell proliferation and
      differentiation. The release of membrane-bound phospholipid by phospholipase-A2
      (PLA-2) is the first critical step in the initiation of membrane remodeling and
      eventually eicosanoid synthesis. We report here data that demonstrates how
      various cytokines exhibit a marked hydrolytic activity mediated through PLA-2
      against both [1-14C] oleic acid- and [1-14C] arachidonic acid-labeled Escherichia
      coli (micelle) substrates. PLA-2 extracts were prepared from neutrophils elicited
      by injecting rats ip with 8% glycogen. The rate of hydrolysis of free fatty acids
      from the phospholipid substrate was found to be linear, rapid, and pH dependent
      and was calculated to be 30 nmoles of phospholipid/hr/mg protein lysate.
      Cytokines (i.e., interleukin-1 [IL-1, human and murine recombinant, alpha], mouse
      lung cell-derived colony-stimulating factor [L-CSF], granulocyte-macrophage
      colony-stimulating factor [murine recombinant GM-CSF], tumor necrosis factor
      [murine recombinant TNF-alpha], and granulocyte colony-stimulating factor [human
      recombinant, G-CSF] all induced PLA-2 activity with the release of free fatty
      acids above basal levels. In contrast, lipopolysaccharide (LPS), interleukin-2,
      (IL-2, human recombinant), and macrophage colony-stimulating factor (M-CSF) did
      not significantly activate PLA-2 hydrolysis. The activation of this membrane
      bound enzyme-substrate complex by these growth factors may serve as a mechanism
      whereby the appropriate target cells expressing receptors respond through either
      direct or secondary signals leading to the formation of free fatty acids with the
      eventual synthesis of prostanoid or lipoxygenase products, resulting in cellular
      proliferation and differentiation.

PMID- 8650258
TI  - The regulation of AP-1 activity by mitogen-activated protein kinases.
AB  - AP-1 is a collection of dimeric sequence specific, DNA binding, transcriptional
      activators composed of Jun and Fos subunits. The composition, the level and the
      activity of AP-1 complexes are regulated in response to extracellular stimuli. An
      important role in this regulation is played by mitogen-activated protein kinases
      (MAPKs). The specific roles of three MAPKs, namely ERK, JNK and FRK, in
      modulation of both the level and activity of AP-1, are discussed.

PMID- 8650257
TI  - Superantigens: structure and relevance to human disease.
AB  - Superantigens are a class of immunostimulatory molecules produced by bacteria and
      viruses. Their potent immune effects are due to their unique ability to bind to
      the major histocompatibility complex (MHC) outside the antigen-binding cleft and
      to stimulate T cells in a T-cell receptor (TCR) Vbeta-specific manner. Structural
      studies have revealed the binding sites involved in the MHC/superantigen/TCR
      complex. The bacterial superantigens are responsible for a number of syndromes,
      including food poisoning and toxic shock syndrome, but their effects may be not
      only acute but also chronic and complex. Recent evidence suggests that
      superantigens may be relevant to the pathogenesis of autoimmune and
      immunodeficiency disorders. To illustrate the detrimental effects of
      superantigens on disease outcome, evidence demonstrating the modulation of
      experimental allergic encephalomyelitis, an animal model for multiple sclerosis,
      by superantigen, as well as the potential role of superantigens in HIV
      pathogenesis of AIDS, will be presented. The information presented may provide
      valuable insight into the role of superantigens in autoimmunity and HIV
      infection.

PMID- 8650259
TI  - Reconstitution of novel signalling cascades responding to cellular stresses.
AB  - Mammalian cells respond to their immediate environment by inducing signal
      transduction cascades that regulate metabolism, secretion and gene expression.
      Several of these signalling pathways are structurally and organizationally
      related insofar as they require activation of a protein-serine kinase via it's
      phosphorylation on tyrosine and threonine; the archetype being mitogen-activated
      protein kinase (MAPK) which responds primarily to mitogenic stimuli via Ras. In
      contrast, two more recently identified cascades are responsive to cellular
      stresses such as heat, inflammatory cytokines, ischaemia and metabolic poisons.
      The recent identification of the components of these pathways has allowed
      manipulation of the stress-responsive pathways and evaluation of their
      physiological roles. These studies reveal a high degree of independence between
      the pathways not apparent from in vitro studies. Manipulation of the pathways in
      vivo will likely result in novel therapies for inflammatory disease and
      reperfusion injury.

PMID- 8650260
TI  - Feedback regulation of map kinase signal pathways.
AB  - Ste7 is a MEK (MAPK/ERK kinase) family member that functions in the pheromone
      induced mating response pathway of Saccharomyces cerevisiae. We analysed the
      catalytic competence and in vivo function of Ste7 variants that have alterations
      of stimulatory and feedback phosphorylation sites. These analyses led us to
      unanticipated insights into two separate feedback mechanisms that impede the
      output of the mating response MAPK activation pathway.

PMID- 8650261
TI  - Interleukin 1 (IL1) and tumour necrosis factor (TNF) signal transduction.
AB  - The inflammatory cytokines interleukin 1 (IL1) and tumour necrosis factor (TNF)
      have a broad range of physiological effects. Whereas their immediate post
      receptor events are not well understood, both have the potential to activate a
      range of protein kinases. These include the three types of mitogen activated
      protein (MAP) kinase (ERK, JNK/p54 and p38) and a beta-casein kinase. The
      mechanisms by which these kinases are activated is discussed and the significance
      of their activation for particular biological responses is assessed.

PMID- 8650262
TI  - Janus kinases in cytokine signalling.
AB  - Hematopoiesis is largely regulated by the binding of cytokines to receptors of
      the cytokine receptor superfamily. Although lacking catalytic domains, members of
      the cytokine receptor superfamily mediate ligand dependent activation of tyrosine
      phosphorylation which is critical for all receptor functions. Recent studies have
      demonstrated that this is mediated through the association and activation of
      members of the Janus kinase (Jak) family of protein tyrosine kinases. The
      activated Jaks phosphorylate the receptors, creating docking sites for SH2
      containing signalling proteins which are tyrosine phosphorylated following their
      association with the receptor complex. Among the substrates of tyrosine
      phosphorylation are members of the signal transducers and activators of
      transcription family of proteins (Stats). Various cytokines induce the tyrosine
      phosphorylation and activation of one or more of the six family members. The
      pattern of Stat activation provides a level of cytokine individuality that is not
      observed in the activation of other signalling pathways. Although not required
      for mitogenic responses, it is speculated that the Stats may mediate many of the
      cytokine specific functional responses of hematopoietic cells.

PMID- 8650263
TI  - JAKs, STATs and signal transduction in response to the interferons and other
      cytokines.
AB  - The isolation and complementation of mutant human cell lines has established an
      essential role for the JAK (Janus kinase) family of protein tyrosine kinases and
      STAT (signal transduction and transcription) factors in the Interferon response
      pathways. Activation of STATs by JAKs occurs in receptor complexes at the cell
      membrane. Activated STATs form homo- or heterodimers and, with or without
      additional factors, migrate to the nucleus to initiate transcription. Different
      STAT combinations interact differentially with related DNA response elements.
      Signalling pathways of this novel type are likely utilized by a wide variety of
      polypeptide ligands. Data from the IL2, IL6 and IFN systems indicate a major role
      for the tyrosine phosphorylated receptor/JAK complexes (rather than substrate
      specificity of the JAKs per se) in STAT selection. The mutant cell lines lacking
      individual JAKs and STATs are being used together with kinase-negative JAK
      mutants which differentially affect the IFN-gamma, and IFN-alpha beta and IL-6
      pathways in the further analysis of these and additional systems.

PMID- 8650264
TI  - DNA-dependent protein kinase defects are linked to deficiencies in DNA repair and
      V(D)J recombination.
AB  - DNA-dependent protein kinase is a nuclear serine/threonine kinase whose catalytic
      properties are expressed only when the enzyme is bound to DNA ends or other
      discontinuities in the DNA. DNA-PK comprises two components: one mediates binding
      to DNA and corresponds to the heterodimeric human autoimmune antigen Ku; the
      other, DNA-PK catalytic subunit (DNA-PKcs), is a polypeptide of approximately 450
      kDa. DNA-PK deficiencies are associated with certain mutant rodent cell lines
      that display defects in DNA double strand break repair and V(D)J recombination.
      Specifically, hamster xrs-6 cells lack Ku function, whereas murine scid and
      hamster V3 cells lack functional DNA-PKcs. Furthermore, the phenotypes of xrs-6
      and V3 cells can be corrected by the expression of the genes encoding the 80 kDa
      component of Ku or DNA-PKcs, respectively. These results imply that DNA-PK is an
      important component of the DNA double strand break repair/recombination
      apparatus. Possible roles for DNA-PK in these processes are discussed.

PMID- 8650265
TI  - The IRS-signalling system in insulin and cytokine action.
AB  - IRS-signalling proteins are engaged and phosphorylated on tyrosine residues by
      the receptors for insulin and IGF-1, and various classes of cytokine receptors,
      including IL-4, IL-9, and IL-13; IFN alpha/beta and IFN gamma; and growth hormone
      and LIF. IRS-proteins provide an interface between these receptors and signalling
      proteins which contain Src homology-2 domains (SH2-proteins). The recent
      identification of IRS-2 provides new insight into the modular structure and
      function of the IRS-proteins. The IRS-proteins provide a means for signal
      amplification by eliminating the stoichiometric constraints encountered by most
      receptors which directly recruit SH2-proteins to their autophosphorylation sites.
      Moreover, IRS-proteins dissociate the intracellular signalling complex from the
      endocytic pathways of the activated receptor. The shared use of IRS-proteins by
      multiple receptors is likely to reveal important connections between various
      hormones and cytokines that were previously unrecognized,or observed but
      unexplained. The existence of additional signalling molecules based on the IRS
      paradigm is likely.

PMID- 8650266
TI  - New connections in the regulation of PEPCK gene expression by insulin.
AB  - Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the rate-limiting step in
      hepatic gluconeogenesis. Glucagon (via the second messenger cAMP) and
      glucocorticoids stimulate transcription of the PEPCK gene whereas insulin and
      phorbol esters have a dominant inhibitory effect. Wortmannin, an inhibitor of 1
      phosphatidylinositol 3-kinase (PI 3-kinase), blocks the inhibition of
      glucocorticoid- and cAMP-stimulated PEPCK gene transcription by insulin. By
      contrast, although phorbol esters mimic the action of insulin on the regulation
      of PEPCK gene transcription, wortmannin does not block the effect of these
      agents. Thus PI 3-kinase is required for the regulation of PEPCK gene expression
      by insulin but not by phorbol esters. In liver cells, insulin administration
      stimulates the activity of multiple protein kinases, including the p42/p44
      Mitogen Activated Protein (MAP) kinase and the p70/p85 ribosomal protein S6
      kinase. Selective inhibition of the activation of either kinase, utilizing the
      compounds PD98059 and rapamycin respectively, does not affect insulin regulation
      of PEPCK gene transcription. Thus regulation of PEPCK gene transcription requires
      PI 3-kinase but does not require the activation of either p42/p44 MAP kinase or
      p70/p85 ribosomal protein S6 kinase.

PMID- 8650267
TI  - The nuclear response to cAMP: role of transcription factor CREM.
AB  - In eukaryotes, transcriptional regulation upon stimulation of the adenylate
      cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear
      factors. This family consists of a large number of members which may act as
      activators or repressors. These factors contain the basic domain/leucine zipper
      motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE
      binding proteins is modulated by phosphorylation by several kinases. The ICER
      (inducible cAMP early repressor) protein is the only inducible member of this
      family. The induction of this powerful repressor is likely to be important for
      the transient nature of cAMP-induced gene expression. CRE-binding proteins have
      been found to play an important role in the physiology of the pituitary gland, in
      regulating spermatogenesis, in the response to circadian rhythms and in the
      molecular basis of memory.

PMID- 8650268
TI  - A heterotrimeric GTPase-regulated isoform of PI3K and the regulation of its
      potential effectors.
AB  - We have purified two forms of phosphoinositide 3-kinase (PI3K) that are activated
      by heterotrimeric G-protein beta gamma-subunits. These novel isoforms of PI3K are
      structurally distinct to those forms of PI3K which have already been cloned. They
      are both heterodimers made up of a p120 and a p101 and a p117 and a p101 protein.
      The p101 species in both heterodimers are identical and show no substantial
      homology with any other proteins or DNA sequences. The p117 and p120 are highly
      related. The p101 and p120 species have been cloned from a pig neutrophil mRNA
      library. The p120 has similarities with other known PI3K catalytic subunits. They
      may be responsible for conferring cells with the capacity to produce
      phosphatidylinositol (3,4,5)-trisphosphate in response to activation of G-protein
      coupled receptors. Activation of both the monomeric G-protein rac and PI3K(s)
      have been implicated in receptor-stimulated membrane-ruffling. We have observed
      that agonist-stimulated guanine nucleotide exchange on rac can be inhibited by a
      variety of PI3K inhibitors. This suggests PI3K may lie upstream of rac in
      receptor-driven pathways regulating cell movement.

PMID- 8650269
TI  - Structural and functional diversity of phosphoinositide 3-kinases.
AB  - Phosphoinositide 3-kinases (PI3-kinases) have been shown to be recruited to cell
      surface receptor signal complexes whose formation is triggered by growth factors,
      cytokines and other ligands. PI3-kinases are also involved in protein sorting
      phenomena. A number of PI3-kinase isotypes have been characterised in several
      laboratories. Here the relations between the PI3-kinases, PI4-kinases and PI5
      kinases and other potential phosphoinositide kinases are analysed. A study of the
      relation of structure to function for sequence motifs defined through the use of
      homology searches and protein modelling techniques is described and used to
      assign the family of phosphoinositide kinases to subgroups.

PMID- 8650270
TI  - Phosphatidylinositol 3' kinase: one of the effectors of Ras.
AB  - Ras proteins are proto-oncogene products that are critical components of
      signalling pathways leading from cell surface receptors to control of cellular
      proliferation, morphology and differentiation. the ability of Ras to activate the
      MAP kinase pathway through interaction with the serine/threonine kinase Raf is
      now well established. However, recent work has shown that Ras can also interact
      directly with the catalytic subunit of phosphatidylinositol 3' kinase and is
      involved in control of the lipid kinase in intact cells. A model is presented in
      which both tyrosine phosphoprotein interaction with the regulatory p85 subunit
      and Ras. GTP interaction with the catalytic p110 subunit is required to achieve
      optimal activation of phosphatidylinositol 3'kinase in response to extracellular
      stimuli. The ability of Ras to regulate phosphatidylinositol 3' kinase may be
      important both in Ras control of cellular morphology through the actin
      cytoskeleton and also in Ras control of DNA synthesis.

PMID- 8650271
TI  - Ceramide: an intracellular mediator of apoptosis and growth suppression.
AB  - Ceramide is an endogenous lipid molecule generated by hydrolysis of membrane
      sphingomyelin, in response to cellular stimulation by hormones and cytokines.
      Ceramide appears to have a role in mediating biological responses in a wide
      variety of cell types. These responses are generally considered anti
      proliferative, but endpoints are varied and include differentiation, growth
      inhibition, senescence and apoptotic cell death. Mechanisms for ceramide action
      involve regulation of protein phosphorylation via stimulation of a
      serine/threonine protein phosphatase, a proline-directed kinase and possibly
      other direct and/or indirect targets.

PMID- 8650272
TI  - Romance, reality, and managed care.

PMID- 8650273
TI  - Use of the Berg Balance Test to predict falls in elderly persons.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to determine whether the
      Berg balance test could be used to predict an elderly person's risk of falling.
      SUBJECTS: Sixty-six residents of two independent life-care communities, aged 69
      to 94 years (X = 79.2, SD = 6.2), participated. METHODS: Subjects completed a
      questionnaire pertaining to their fall history and activity level. The Berg
      balance test, consisting of 14 functional subtests, was then administered. Six
      months later, subjects again completed the questionnaire. RESULTS: Performance of
      activities of daily living predicted 43% of the subjects' scores. There was a
      difference between the subjects who were prone to falling and those who were not
      prone to falling, but the test demonstrated poor sensitivity for predicting who
      would fall. The specificity of the test was very strong. The use of an assistive
      device was a strong predictor of performance on the Berg balance test. No
      relationship was noted between increasing age and decreasing performance on the
      Berg balance test. CONCLUSION AND DISCUSSION: Although the Berg balance test
      demonstrated only 53% sensitivity, the results support the test developers' use
      of 45 (out of 56) as a generalized cutoff score. Older adults who scored higher
      than the cutoff score on the test were less likely to fall than were those adults
      who scored below the cutoff score. Decreased scores, however, did not predict
      increased frequency of falls. Results must be viewed cautiously because self
      report was the sole means of documenting fall history.

PMID- 8650274
TI  - Determining consistency of elbow joint threshold angle in elbow flexor muscles
      with spastic hypertonia.
AB  - BACKGROUND AND PURPOSE: Threshold angle, the point in passive range of motion
      where a muscle response or torque change is elicited, may be a potentially valid
      measure of hypertonus. Because the relationship of initial muscle length to
      threshold angle has not been addressed previously, this preliminary study
      examined whether starting elbow joint position and speed of stretch to elbow
      flexor muscles affect threshold angle. SUBJECTS: Five subjects with stroke
      induced hypertonia of the elbow flexor muscles participated. METHODS: Two
      starting angles and two designated stretch speeds were applied randomly by a
      torque motor at each of three testing sessions. RESULTS: Starting angle, subject,
      and session affected threshold angle. A 90-degree starting angle at a stretch
      speed of approximately 1.0 radian/s produced the most consistent threshold angles
      between sessions within subjects, and threshold angle was relatively consistent
      for some subjects, irrespective of speed. CONCLUSION AND DISCUSSION: If future
      research indicates that these data can be generalized, the use of threshold angle
      as a consistent measure of hypertonia will require comparison within individuals,
      use of a consistent starting angle, and a movement condition of a 90-degree
      starting angle and an approximate movement speed of 1.0 radian/s across sessions.

PMID- 8650275
TI  - The relationship between symptoms and abnormal magnetic resonance images of
      lumbar intervertebral disks.

PMID- 8650276
TI  - Chest physical therapy for patients in the intensive care unit.
AB  - Chest physical therapy is used in the intensive care unit (ICU) to minimize
      pulmonary secretion retention, to maximize oxygenation, and to reexpand
      atelectatic lung segments. This article reviews how chest physical therapy is
      used with patients who are critically ill. A brief historical review of the
      literature is presented. Chest physical therapy treatments applicable to patients
      in the ICU are discussed. Postural drainage, percussion, vibration, breathing
      exercises, cough stimulation techniques, and airway suctioning are described in
      detail, with current references. The importance of patient mobilization is
      emphasized. The advantages of chest physical therapy over therapeutic
      bronchoscopy also are discussed. Two patient examples are used to demonstrate the
      beneficial effects that may be obtained with chest physical therapy. Following
      the removal of retained secretions, arterial oxygenation and partial pressure of
      arterial oxygen/fraction of inspired oxygen concentration ratios improved, and
      atelectasis resolved without the negative hemodynamic side effects of therapeutic
      bronchoscopy. Physical therapists trained in the ICU can safely perform chest
      physical therapy with the majority of patients who are critically ill.

PMID- 8650277
TI  - Physical therapy in lung transplantation.
AB  - Lung transplantation requires the skillful attention of a health care team to
      provide optimal results. The physical therapist is an integral part of this team,
      providing expertise in exercise testing and prescription in all phases, from
      initial evaluation through postoperative rehabilitation and beyond. In addition,
      the physical therapist promotes effective ventilation, offers techniques for
      enhanced coughing and mucociliary clearance, and provides treatment of the
      musculoskeletal system. Lung transplantation is reserved for patients in whom all
      other treatments have been exhausted. It is important for the physical therapist
      to stay abreast of the evolving field of lung transplantation, including
      medications and complications. The physical therapist has a critical role in
      helping lung transplant recipients achieve optimal function, increased survival,
      and improved quality of life.

PMID- 8650278
TI  - Outcomes in cardiopulmonary rehabilitation.
AB  - Physical therapists, as integral members of the multidisciplinary team in cardiac
      and pulmonary rehabilitation, should be knowledgeable about methods for assessing
      outcomes for their patients, and they need to understand the value of aggregated
      data in improving interventions. Definitions are discussed, and appropriate data
      used to monitor function are identified, including data used in the assessment of
      well-being. Results of outcome studies from current cardiac and pulmonary
      literature are presented. A discussion of how to select outcomes to assess and
      the value of outcome information for program management is included. Therapists
      are in a position to encourage and participate in widespread, collaborative
      measurement of disease-specific clinical outcomes, patient functioning, and well
      being, which should improve the effectiveness and efficiency of cardiopulmonary
      rehabilitation.

PMID- 8650279
TI  - Be not content to "sleep and feed".

PMID- 8650280
TI  - Critiquing treatment for scientific merit.

PMID- 8650281
TI  - [Obsessive-compulsive disorder in girls with eating disorders].
AB  - 30 girls aged 13-19 who met criteria DSM-IV for anorexia nervosa were
      investigated by using a semistructured diagnostic interview assessing general
      psychopathology as well as anorectic and bulimic behavior, The Yale-Brown
      Obsessive-Compulsive Scale. The Eating Disorder Inventory, The Anxiety Hamilton
      Scale, The Depression Hamilton Scale. The comparison group consisted of 30
      healthy girls aged 13-19. 1/3 of the girls with anorexia nervosa met the DSM-IV
      criteria for OCD, 1/10 subjects had OCD and depressive disorder. The comorbidity
      of eating disorder and OCD or OCD and depressive disorder worsened the course of
      anorexia nervosa and prognosis.

PMID- 8650282
TI  - [Depressive disorders in mentally retarded children. A review of selected
      literature. Part I].
AB  - This article is a review of the results of the empirical research concerning
      depressive disorders in children and adults with mental retardation. The author
      presents diagnostic criteria for major depressive disorders. Similarities and
      differences in manifestation of major depression in children with and without
      mental retardation are discussed.

PMID- 8650283
TI  - [Depressive disorders in mentally retarded children. A review of selected
      literature. Part II].
AB  - This article is a review of the results of empirical research concerning reactive
      depression in children with mild mental retardation. The reactive depression is
      understood as a childs' reaction to important losses. The author presents a
      review concerning epidemiology and symptomatology of dystimic disorders in
      children with mental retardation. The article shows similarities and differences
      in manifestation of reactive depression in children with mild mental retardation
      and children without mental retardation.

PMID- 8650284
TI  - [Coping strategies and psychological well-being in mothers of children with
      disabilities].
AB  - The purpose of the study was to determine relationships between coping with
      stress and well-being in mothers of developmentally disabled children. Marital,
      parenthood and global life satisfaction were analyzed. Two interesting
      relationships between coping strategies and well-being (marital and global life
      satisfaction) were found. The results are discussed in terms of parental stress
      experienced by mothers of children with disabilities.

PMID- 8650285
TI  - [Elective mutism in children: literature review].
AB  - This paper presents contemporary opinions about selective mutism in children,
      including epidemiology, etiology, clinical features and therapy. This is the
      first extensive review on this topic in Polish literature. The essential feature
      of selective mutism is persistent failure to speak in social situations, where
      speaking is expected (e.g., in school), despite speaking in other situations
      (e.g., at home). The authors present the diagnostic criteria according do DSM-IV
      and suggested by other authors. Clinical characteristics of this disorder were
      also presented, including personality traits and behaviour of mutistic children
      (different at home and in unfamiliar environment) and comorbidity of selective
      mutism. Etiology of this disorder seems to be multifactorial. The important
      etiological factors are: minimal brain dysfunction, somatic or psychological
      trauma, particularly during the speech development and a family structure,
      especially the mother-child relation. The authors emphasize that mutism in
      children is a heterogeneous symptom and present several models of mutism. The
      paper describes also different methods of treatment (e.g., behavioral,
      psychodynamic, family therapy and some case reports on pharmacotherapy); and long
      term prognosis.

PMID- 8650286
TI  - [Art therapy as an assisting psychotherapeutic method for adolescents].
AB  - The report deals with psychoprophylaxis of children and youth being in danger of
      alcoholism, drug addiction, juvenile delinquency and suicide. In the Psychiatric
      Out-patient Department in Gdynia we have been practising psychological, social
      and art-therapeutic care to the youth, and rendering training to their families
      and tutors (Consulting-Psychoprophylactic Club). The authoresses describe one
      example of art-therapeutic expression included in two series of pictures made by
      a girl (4 years old) and her brother (9 years old) after the tragedy of their
      mother's being killed by their father. CONCLUSIONS: This type of therapy
      facilitates the experience and release of stress is helpful in improving the
      relationship between the child and his frequently awkward tutors.

PMID- 8650287
TI  - [The world of computer games I: a new entertainment medium and new danger.
      Description of a technique].
AB  - The paper presents a psychiatric description of the phenomenon of computer games
      as a new entertainment medium. The possibilities and impedences of this technique
      are described.

PMID- 8650288
TI  - [The world of computer games II: a demographic study on prevalence of computer
      players in secondary school students].
AB  - The article presents the results of the first stage of our own research on the
      popularization of computer games among adolescents. A questionnaire was filled by
      2678 class one pupils of secondary schools (born in 1979). The investigations
      were aimed at selecting a group of secondary school pupils particularly
      interested in computers and computer games. The investigations proved that the
      problem of computer games playing regards more than a half of the school pupils
      population we examined. There are twice as many boys as girls among the computer
      games players. Also, boys have better knowledge of computer games, they start to
      play at a younger age, devote more time to playing these games. The most popular
      hardware are Amiga or IBM compatible PCs. As many as 3/4 of computer games
      players have their own computers. The most significant information was the data
      concerning the time devoted to playing, both daily and weekly. The investigations
      show that boys spend much more time playing computer games than girls do. The
      selected group of pupils will undergo detailed clinical as well as psychological
      examination.

PMID- 8650289
TI  - [Depression and alcoholism: a potential familial-genetic relationship].
AB  - In the paper, a review of literature was done for a potential familialgenetic
      relationship between alcohol dependence and depression. The incidence of
      secondary alcoholism in patients with depression may have different pathogenesis
      depending on gender: men with primary depression and alcoholism may exhibit two
      distinct illnesses, while in women secondary alcoholism may be a form of
      affective disorder (depression spectrum disease). Studies on the prevalence of
      alcohol dependence in families of depressive patients are inconsistent: some
      authors observed an increased risk of alcohol dependence while others did not.
      Secondary depression in alcohol dependent patients usually results from the
      pharmacological effect of alcohol, is concommittant with withdrawal syndrome or
      may be connected with psychological problems related to alcohol abuse. Usually,
      such depressive symptoms improve within 2-4 weeks after cessation of drinking and
      do not require additional treatment. However, the risk of major depression in
      alcohol-dependent persons is twice as high as in general population. Among
      various contemporary hypotheses about the genetic link between alcohol dependence
      and depression, a conception of "depressive spectrum", formulated by Winokur,
      received the strongest support from clinical and familial studies.

PMID- 8650290
TI  - [Evaluation of selected immunological and biochemical parameters of blood in
      alcohol dependency].
AB  - The aim of this study was evaluation of selected immune humoral indicators in
      connection with biochemical parameters of blood in 28 alcohol dependent men.
      Increased activity of liver enzymes: AspAT in 53,6% of patients, A1AT in 46,4%,
      GGTP in 25% were found. Macrocytosis in 29% of patients was observed. There were
      also abnormal changes of immune proteins concentration: IgM, IgG, IgA, C3, C4
      respectively in 60,7%, 46,4%, 21,4%, 42,9%, 10,7% of patients. In the group of
      patients with normal values of AspAT, GGTP, MCV; abnormal levels of humoral
      indicators concentration were observed. The correlation between immune proteins
      concentration and biochemical parameters was not found. The authors conclude that
      changes of determined immunological parameters may be used as prognostic
      indicators in disturbances in the alcoholics' immunity system.

PMID- 8650291
TI  - [The effect of nifedipine and chlordiazepoxide on alcohol withdrawal syndrome].
AB  - The aim this study was to evaluate the efficacy and tolerability of DHP calcium
      channel antagonist-nifedipine in human AWS in comparison to conventional
      treatment with chlordiazepoxide. Fifty nine hospitalized alcoholics of both sexes
      with diagnosis of AWS according to DSM-III-R criteria were treated for 2 weeks in
      monotherapy with nifedipine (Cordafen-Polfa)-60 mg/d. or with chlordiazepoxide
      (Elenium-Polfa)-150 mg/d. Evaluation of AWS symptoms was performed at baseline
      and after 3, 7, 14 days using Sandowal-Wang scale. Our original scales (37 items)
      were designed for measuring the depth of dependence (WGU) and the velocity of
      dependence syndrome appearance (WWO). The results show that both groups were
      similar regarding WGU and WWO before treatment. Both drugs caused an improvement
      of AWS symptoms after 3 and 7 days lasting till the end of hospitalization.
      Nifedipine was well tolerated and no side effects were observed or reported. The
      group and multidimensional analyses were performed using original computer
      program. The patients were divided into 3 subgroups. Comparison of mean values of
      improvement index between both drugs in those subgroups of patients according to
      WGU criteria, revealed that nifedipine was more effective on the 3-rd and 7-th
      day in 3 groups and 2 groups resp. According to WWO criteria the improvement
      index was significantly higher on the 3-rd and 7-th day in two groups whereas in
      one group chlordiazepoxide and nifedipine action was equal. The proposed method
      of group and multidimensional analysis enable us to compare the effectiveness of
      different kinds of AWS treatment. It is an useful aid of choosing the best drug
      treatment for a new patient.

PMID- 8650292
TI  - [Class I and II alcohol dehydrogenase isoenzymes as biochemical markers of
      alcoholism].
AB  - The activity of class I and II of alcohol dehydrogenase isoenzymes was tested in
      the sera of alcoholics using specific and fluorogenic substrates. Almost 3-fold
      increase of the activity of class I isoenzymes was found in developed alcoholism.

PMID- 8650293
TI  - [Personality determinants of effectiveness in performing duties by soldiers in
      active service in the landing-shock brigade].
AB  - After studies in the Brigade the authors identified and qualified personality
      traits which co-determine effectiveness in performing duties in active service.
      The efficiency of performing duties is determined by: high emotional resistance,
      high level of ability to logical conclusion, high level of self-control, low
      extroversion level, lack of antisocial tendencies. The authors worked out some
      indications concerning choice and selection for this military formation.

PMID- 8650294
TI  - [Room for the improvement of soldier selection for the landing brigade].
AB  - After realization of psychological examinations the authors identified and
      qualified personality traits which co-determine effectiveness in performing
      duties by soldiers in the Brigade. The authors worked out a set of psychological
      tests which facilitate for selection and classification of recruits to the
      Brigade.

PMID- 8650295
TI  - Queueing network modeling of elementary mental processes.
AB  - This article examines the use of reaction time (RT) to infer the possible
      configurations of mental systems and presents a class of queueing network models
      of elementary mental processes. The models consider the temporal issue of
      discrete versus continuous information transmission in conjunction with the
      architectural issue of serial versus network arrangement of mental processes.
      Five elementary but important types of queueing networks are described in detail
      with regard to their predictions for RT behavior, and they are used to re-examine
      existing models for psychological processes. As continuous-transmission networks
      in the general form, queueing network models include the existing discrete and
      continuous serial models and discrete network models as special cases, cover a
      broader range of temporal and architectural structures that mental processes
      might assume, and can be subjected to empirical tests.

PMID- 8650296
TI  - An auditory illusion predicted from a weighted cross-correlation model of
      binaural interaction.
AB  - In humans, the lateral movement of an acoustic source produces dynamic changes in
      the relative sound-pressure level and time of arrival of the acoustic wave at the
      2 ears. The dynamic nature of these cues is assumed to play an important role in
      the perception of lateral motion. A phenomenon of auditory motion is reported
      whose lateral direction and relative velocity may be specified while interaural
      differences are kept constant. The stimulus producing this percept is a
      narrowband wave-form whose instantaneous bandwidth is a cosine function of time.
      This phenomenon is predicted from a model of cross-correlation that estimates the
      running position of an image from a weighted combination of 2 variables: (a)
      magnitude of interaural delay, with smaller delays receiving more weight, and (b)
      consistency of interaural information across frequency.

PMID- 8650297
TI  - A formal theory of feature binding in object perception.
AB  - Visual objects are perceived correctly only if their features are identified and
      then bound together. Illusory conjunctions result when feature identification is
      correct but an error occurs during feature binding. A new model is proposed that
      assumes feature binding errors occur because of uncertainty about the location of
      visual features. This model accounted for data from 2 new experiments better than
      a model derived from A. M. Treisman and H. Schmidt's (1982) feature integration
      theory. The traditional method for detecting the occurrence of true illusory
      conjunctions is shown to be fundamentally flawed. A reexamination of 2 previous
      studies provided new insights into the role of attention and location information
      in object perception and a reinterpretation of the deficits in patients who
      exhibit attentional disorders.

PMID- 8650298
TI  - Silence is liberating: removing the handcuffs on grammatical expression in the
      manual modality.
AB  - Grammatical properties are found in conventional sign languages of the deaf and
      in unconventional gesture systems created by deaf children lacking language
      models. However, they do not arise in spontaneous gestures produced along with
      speech. The authors propose a model explaining when the manual modality will
      assume grammatical properties and when it will not. The model argues that two
      grammatical features, segmentation and hierarchical combination, appear in all
      settings in which one human communicates symbolically with another. These
      properties are preferentially assumed by speech whenever words are spoken,
      constraining the manual modality to a global form. However, when the manual
      modality must carry the full burden of communication, it is freed from the global
      form it assumes when integrated with speech--only to be constrained by the task
      of symbolic communication to take on the grammatical properties of segmentation
      and hierarchical combination.

PMID- 8650299
TI  - Relation of threatened egotism to violence and aggression: the dark side of high
      self-esteem.
AB  - Conventional wisdom has regarded low self-esteem as an important cause of
      violence, but the opposite view is theoretically viable. An interdisciplinary
      review of evidence about aggression, crime, and violence contradicted the view
      that low self-esteem is an important cause. Instead, violence appears to be most
      commonly a result of threatened egotism--that is, highly favorable views of self
      that are disputed by some person or circumstance. Inflated, unstable, or
      tentative beliefs in the self's superiority may be most prone to encountering
      threats and hence to causing violence. The mediating process may involve
      directing anger outward as a way of avoiding a downward revision of the self
      concept.

PMID- 8650300
TI  - Understanding normal and impaired word reading: computational principles in quasi
      regular domains.
AB  - A connectionist approach to processing in quasi-regular domains, as exemplified
      by English word reading, is developed. Networks using appropriately structured
      orthographic and phonological representations were trained to read both regular
      and exception words, and yet were also able to read pronounceable nonwords as
      well as skilled readers. A mathematical analysis of a simplified system clarifies
      the close relationship of word frequency and spelling-sound consistency in
      influencing naming latencies. These insights were verified in subsequent
      simulations, including an attractor network that accounted for latency data
      directly in its time to settle on a response. Further analyses of the ability of
      networks to reproduce data on acquired surface dyslexia support a view of the
      reading system that incorporates a graded division of labor between semantic and
      phonological processes, and contrasts in important ways with the standard dual
      route account.

PMID- 8650301
TI  - Uracil metabolism--UMP synthesis from orotic acid or uridine and conversion of
      uracil to beta-alanine: enzymes and cDNAs.

PMID- 8650302
TI  - Chemical and computer probing of RNA structure.

PMID- 8650303
TI  - Transcriptional activation of thymidine kinase, a marker for cell cycle control.

PMID- 8650304
TI  - Eukaryotic gene expression: metabolite control by amino acids.
AB  - Our understanding of the metabolite control in mammalian cells lags far behind
      that in prokaryotes. This is particularly true for amino-acid-dependent gene
      expression. Few proteins have been identified for which synthesis is selectively
      regulated by amino-acid availability, and the mechanisms for control of
      transcription and translation in response to changes in amino-acid availability
      have not yet been elucidated. The intimate relationship between amino-acid supply
      and the fundamental cellular process of protein synthesis makes amino-acid
      dependent control of gene expression particularly important. Future studies
      should provide important insight into amino-acid and other nutrient signaling
      pathways, and their impact on cellular growth and metabolism.

PMID- 8650305
TI  - Molecular recognition in the assembly of the segmented reovirus genome.

PMID- 8650306
TI  - Alu: structure, origin, evolution, significance and function of one-tenth of
      human DNA.

PMID- 8650307
TI  - Recent advances in the molecular biology of vitamin D action.
AB  - Following the cloning and deletion analysis of the vitamin D receptor, most
      recent advances have been in the isolation and characterization of the DNA
      response elements found in the promoter region of target genes of vitamin D.
      Vitamin D, like the thyroid and retinoid hormones, binds to repeat sequences, but
      the repeats are separated by three nonspecified bases. The action of the VDR
      requires the presence of the RXR proteins and evidently other proteins that are
      involved in regulating transcriptions. A possible role of phosphorylation of the
      ligand binding domain of the VDR in transcription has also appeared. Very likely,
      the molecular events involved in vitamin D stimulation or suppression of a target
      gene will include its interaction with a number of transcription factors, both in
      the regulation of transcription and in the actual machinery involved in the
      transcription process through polymerase II. Although likely, it is not entirely
      clear whether the genomic action of vitamin D can account for all of its
      biological activities. Nongenomic actions of the vitamin D hormone have been
      reported, but convincing evidence that this is of biological importance in vivo
      is lacking. Advances in our understanding of the vitamin D mechanism of action
      can clearly be expected from physical studies of cloned and expressed vitamin D
      receptor and its subdomains, elucidation of the transcription factors in vitamin
      D-modulated transcription of target genes, elucidation of the role of
      phosphorylation in the transcription process, and the identification of important
      genes that are regulated in the specific target tissues responsive to vitamin D.
      This will definitely remain as a very active field of investigation well into the
      future.

PMID- 8650308
TI  - Regulation of synthesis of ribonucleotide reductase and relationship to DNA
      replication in various systems.

PMID- 8650309
TI  - The importance of being modified: roles of modified nucleosides and Mg2+ in RNA
      structure and function.

PMID- 8650310
TI  - [Principles of PCR-based technologies].

PMID- 8650311
TI  - [Reaction conditions of PCR].

PMID- 8650312
TI  - [Thermostable DNA Polymerases and PCR].

PMID- 8650313
TI  - [PCR primer].

PMID- 8650314
TI  - [Method of determining optimal PCR primers].

PMID- 8650315
TI  - [Primer for PCR method, synthesis and purification].

PMID- 8650316
TI  - [Isolation of DNA from cells and tissues for PCR].

PMID- 8650317
TI  - [Treatment of clinical specimens for PCR].

PMID- 8650318
TI  - [Methods of DNA extraction from cells obtained by cytological techniques].

PMID- 8650319
TI  - [PCR application for paraffin-embedded tissues].

PMID- 8650321
TI  - [Hot start method].

PMID- 8650320
TI  - [Extraction of DNA from pancreatic and/or duodenal juice].

PMID- 8650322
TI  - [Hot-start PCR by using antibody].

PMID- 8650323
TI  - [Agarose gel electrophoresis].

PMID- 8650324
TI  - [Polyacryl amide gel electrophoresis].

PMID- 8650325
TI  - [Dot hybridization].

PMID- 8650326
TI  - [Detection of gene expression using digoxigenin-labeled probes].

PMID- 8650327
TI  - [Analysis of PCR products using silver staining].

PMID- 8650328
TI  - [Labelling of PCR products].

PMID- 8650329
TI  - [Quantitative PCR: DNA quantification by PCR].

PMID- 8650330
TI  - [Quantitative PCR].

PMID- 8650331
TI  - [Problems in PCR].

PMID- 8650332
TI  - [PCR machine].

PMID- 8650333
TI  - [TA cloning: a rapid and efficient method for cloning of the PCR products].

PMID- 8650334
TI  - [PCR and DNA sequencing].

PMID- 8650335
TI  - [Gamma exonuclease method].

PMID- 8650336
TI  - [Site-directed mutagenesis by PCR].

PMID- 8650337
TI  - [Single-strand conformation polymorphism (SSCP) analysis: a convenient, rapid
      method for detection of single-base changes in DNA].

PMID- 8650338
TI  - [Mutant allele specific amplification (MASA)].

PMID- 8650339
TI  - [Detection of rare target gene with a point mutation by improved PCR].

PMID- 8650340
TI  - [PCR-SSOP (sequence specific oligonucleotide probe) method].

PMID- 8650341
TI  - [Denaturing gradient gel electrophoresis of DNA fragments attached with a GC
      clamp].

PMID- 8650342
TI  - [RNase protection analysis].

PMID- 8650343
TI  - [PCR-RFLP analysis].

PMID- 8650344
TI  - [Arbitrarily primed PCR: an unique technique for molecular genetical analysis].

PMID- 8650345
TI  - [Representational difference analysis: identification of the differences between
      genomes].

PMID- 8650346
TI  - [Differential display analysis of mRNA].

PMID- 8650347
TI  - [LA PCR].

PMID- 8650348
TI  - [Reverse transcriptase-polymerase chain reaction].

PMID- 8650349
TI  - [Isolation of mRNA 5'-end using oigo-capping].

PMID- 8650350
TI  - [In situ PCR: principles, problems and application to molecular biology].

PMID- 8650351
TI  - [Immuno-PCR: a sensitive method for detecting antigen].

PMID- 8650352
TI  - [Analysis of STS (sequence tagged site): microsatellite marker].

PMID- 8650353
TI  - [Application of PCR technique to mouse genetics].

PMID- 8650354
TI  - [AP-PCR genomic fingerprinting].

PMID- 8650356
TI  - [Molecular diagnosis of cancer by non-radioisotopic PCR/SSCP analysis].

PMID- 8650355
TI  - [Detection of DNA aberrations in human cancers by AP-PCR-SSCP analysis].

PMID- 8650357
TI  - [Triplet repeat disorders].

PMID- 8650358
TI  - [Slide PCR for gene mapping].

PMID- 8650359
TI  - [In situ PCR detection of HTLV-1 provirus in spinal cord lesions with HAM/TSP].

PMID- 8650361
TI  - [Detection and typing of HPV genome: consensus PCR method].

PMID- 8650360
TI  - [Histopathological application of in situ PCR (in situ hybridization after
      amplification by PCR)].

PMID- 8650362
TI  - [Detection and analysis of human herpesvirus genomes by polymerase chain
      reaction].

PMID- 8650363
TI  - [Hepatitis C virus].

PMID- 8650364
TI  - [Analysis of HTLV-1 expression in vivo].

PMID- 8650365
TI  - [Novel molecular technology for HIV detection and analysis].

PMID- 8650366
TI  - [Hemorrhagic fever renal syndrome-associated virus].

PMID- 8650367
TI  - [Detection of Borna disease virus RNA by RT-PCR in PBMC].

PMID- 8650368
TI  - [Application of PCR to hospital epidemiology].

PMID- 8650369
TI  - [Gene expression analysis by random cDNA sequencing].

PMID- 8650370
TI  - [Large scale analysis of C. elegans cDNA].

PMID- 8650371
TI  - [Molecular cloning of differentially expressed genes during plant somatic
      embryogenesis].

PMID- 8650372
TI  - [Origin of modern humans revealed by complete sequences of hominoid mitochondrial
      DNAs].

PMID- 8650373
TI  - [Ancient DNA].

PMID- 8650374
TI  - [PCR amplification on forensic science].

PMID- 8650375
TI  - [Oral hygiene of handicapped subjects in Flanders].
AB  - As part of an epidemiology survey within the population of handicapped 12-year
      old in Flanders this article describes several parameters related to oral health.
      On the average, it became obvious that oral hygiene had to be seriously
      increased. The presence of plaque and calculus is very typical for types 1, 2, 4
      and 8. In addition, it is most striking to conclude that groups where a maximum
      of self-handiness is expected, do not score any better. The application of
      chemical controlling agents and the use of fluoride supplements is found
      extremely low. Finally, a lack was found, with respect to adequate oral hygiene
      instructions. There is a real need for in-service training programs for educators
      as well as for parents.

PMID- 8650376
TI  - [Medical symptomatology and integrated therapeutic planning at the level of
      handicapped children].
AB  - The knowledge of the neurological diseases is an essential factor to establish a
      relation between the practitioner and the child or the handicapped adult. The
      authors suggest to describe some pathologies with a particular attention for the
      keywords to realize a concerted management.

PMID- 8650377
TI  - [Down syndrome: 1. Medical aspects].
AB  - Each organ of a patient with the Down's Syndrome (trisomy 21) shows the
      pathology. One notices the specific features already with an infant. The life
      expectation of these children has increased considerably and it depends upon the
      appearance or not of a heart defect. The ventricular septum defect is most
      frequent but a small number of these patients show a complex cardiopathy. The
      incidence of pulmonary hypertension is also high. The obstruction of
      gastroenteric tract can cause problems from the prenatal phase onwards. The main
      endocrinological difficulties are dysfunction of the thyroid gland and also
      infertility. Ocular disorders like refraction disorders occur frequently. Due to
      decreased conduction, there is a hearing loss. The cellular immunity is clearly
      reduced, hence, the susceptibility to infections like hepatitis B, increases. The
      major oral problems are apparently oversized tongue and a high sensitivity to
      gingivitis.

PMID- 8650378
TI  - [Down syndrome--2. Orofacial aspects].
AB  - Because of the higher life expectancy and the ambulant care facilities, the
      general dentist will be more and more confronted with patients suffering from
      Down's syndrome. Of major importance are the associated heart and vascular
      diseases and hypothyroidism, accentuating even more the retarded growth. These
      patients also show a decrease in resistance, which frequently (50%) results into
      periodontal disease. Apart from the typical bone "growth" changes, the
      hypotonicity of the masticatory musculature and the tongue are key factors
      determining the typical expression. The eruption time and, to a lesser extent,
      the age of the final teeth is slowed down. When in addition hypothyroidism is
      observed, this results in a typical radiographic image of the mandible (apices
      against bottom corticalis). When merely considering the microdontics, the
      agenesis and the more favourable composition of saliva, caries should be less
      frequent. However, for techno-hygienic reasons this is often not the case. When
      the gingiva is affected by a rapidly progressing periodontal disease, it should
      be frequently cleaned, supported by a chemical plaque treatment. The author
      emphasizes that on no account prevention can be left to the patient. The patients
      always need to be helped. Finally the logopaedic purpose of the Castillo-Moralis
      palatal plate, as well as the functional use of the surgical tongue reduction,
      are discussed.

PMID- 8650379
TI  - [Status of the teeth and degree of care in handicapped in Flanders].
AB  - In general, handicapped 12-year old do not show statistical relevant differences
      with non-handicapped age-matched children in Flanders regarding general caries
      prevalence, caries distribution and total caries experience. However, important
      differences were found for the restorative index showing a higher caries
      treatment need in handicapped children. When the results were analysed according
      to the type of handicapping condition, it was seen that children with borderline
      and mild mental handicap and children with speech-, language and/or learning
      difficulties show the most unfavorable picture. They have a high caries
      prevalence and caries experience and a low restorative index. Additional analysis
      of the results can throw some light on the presence of additional caries risk
      indicators and contributing caries risk factors.

PMID- 8650380
TI  - [Intoxications: current issues].

PMID- 8650381
TI  - [Bronchial hyperreactivity and occupational asthma].

PMID- 8650382
TI  - [Poisoning caused by organophosphate insecticides. Study of 506 cases].
AB  - A total of 506 cases of acute poisoning with organophosphorus insecticides
      attended at Hospital Torrecardenas, Almeria, from 1981 to 1992 were prospectively
      studied. In all cases a predetermined clinical and therapeutical protocol was
      followed. Eighty per cent of poisoning events were accidental in nature, most
      occurred in males, greenhouse workers, and the toxic agents was most commonly
      absorbed through the skin and airways. All patients presented initially with
      overt cholinergic symptoms. The presence of bronchorrhea, tremor-fasciculations,
      respiratory depression and a lower level of consciousness was associated with
      severe poisonings. Uncommon and exceptional complications included: 5 cases with
      complete atrio-ventricular block, 3 cases with pancreatitis, 17 cases with
      endogenous re-intoxications and 3 patients with central diabetes insipidus.

PMID- 8650383
TI  - [Epidemiology of acute poisoning: study of 613 cases in the Community of Madrid
      in 1994].
AB  - Following a determined protocol, 613 acute poisonings (AP) attended at the
      Emergency Department of Internal Medicine, Hospital Doce de Octubre, Madrid, in
      1994, were studied. The incidence was 90/100,000 inhabitants. The number of cases
      was similar among sexes. The mean age of patients was 32 years and the median 29
      years. Most poisonings were voluntary in nature (601, 98%); overall, suicide
      attempts accounted for the most frequent type of AP (354, 58%), but among male
      patients the alcoholic intoxication predominated (148, 48%). Among accidental
      APs, domestic accidents were most common and only one was occupational in nature.
      Poisoning agents: 1) pharmaceuticals: 96% for suicide attempts, particularly
      among females). The relative incidence of pharmaceuticals was consistent with
      data reported in other studies; benzodiazepines, 39%; antidepressants, 14%;
      pharmaceutical/patient ratio 1.4. Alcohol and to a lesser extent drugs, were the
      most common non-pharmaceutical toxic agents. The most common background for
      suicide attempts included depression and previous attempts. In alcoholism cases,
      alcohol and AP caused by drugs were observed in non drug-abusers. Three per cent
      of patients were admitted to the ICU and the mortality rate fell to 0.1%.

PMID- 8650384
TI  - [Adverse effects on the respiratory system in textile printing sprayers].
AB  - OBJECTIVE: To study the initial respiratory effects and those observed 18 months
      later after the inhalation of toxic and irritant substances in textile aerography
      workers. SUBJECTS: Seventeen patients (14 women and 3 men), with a mean age of 21
      years (range: 18-38). METHODS: Initially, pulmonary effects were assessed by
      pathological (transbronchial biopsy and/or video-thoracoscopy) and functional
      findings [spirometry with lung volumes and study of diffusion capacity of CO
      (DLCO)]. Eighteen months later a challenge bronchial test with histamine was
      performed. RESULTS: Forty-one per cent of patients had pathologic lesions with
      intraalveolar fibrin, 35% had minimal non-specific lesions, 18% bronchiolitis
      obliterans with organized pneumonia (BOOP) and 6% pulmonary fibrosis and BOOP.
      Functional respiratory test showed two patients with a slight restrictive
      pattern, one patient with very severe restriction and six patients with low DLCO.
      The challenge tests was positive for 59% of patients. CONCLUSION: After the
      massive inhalation of irritant and/or toxic substances, patients presented
      different types of pathological response at pulmonary level. In our workers
      histological repairing lesions--of high or low degree--were found, BOOP being the
      lesions observed most frequently, and different patterns of functional
      involvement. Fifty-nine per cent of cases developed non-specific bronchial
      hyperreactivity consistent with a reactive airways dysfunction syndrome.

PMID- 8650385
TI  - [A comparative study of the effects on the left ventricular function of 2 methods
      of noninvasive ventilation: NIPPV and EFHO-NB].
AB  - BACKGROUND: Among the non-invasive ventilatory methods, the Nasal Intermittent
      Positive Pressure Ventilation (NIPPV) can cause important effects on circulation
      since a positive intrathoracic pressure is obtained and thus in the transmural
      cardiac pressure. In contrast, the External High Frequency Oscillation around a
      Negative Baseline (EHFO-NB) obtains a negative thoracic pressure. Therefore, the
      opposite circulatory changes should be expected. OBJECTIVE: To study and compare
      the effects on the left systolic and diastolic ventricular functions derived from
      the application of both NIPPV and EHFO-NB ventilatory support methods in patients
      with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Nine
      patients with COPD were studied. The investigation was carried out from the third
      to the seventh day of follow-up at the ICU. For each patient three equilibrium
      radionuclide angiocardiography (ERA) were performed. With the patient breathing
      room air spontaneously, 45 minutes after ventilatory support with NIPPV and also
      45 minutes after ventilatory support with EHFO-NB. Measurements of radionuclide
      activity (counts) and derived parameter of left systolic and ventricular
      functions were determined following a previously reported protocol. RESULTS:
      During ventilatory support with NIPPV a significant increase in the time elapsed
      since the end of the diastole to the peak systolic ejection was observed. During
      ventilatory support with EHFO-NB a significant decrease in cardiac radioactivity
      (counts) in tele-systole was observed together with an increase in the ejection
      velocity measured in the first third of the systolic phase. These findings
      occurred both with respect to the basal situation and to the ventilatory phase
      with NIPPV: CONCLUSIONS: Under the study conditions, none of the non-invasive
      ventilatory support methods compromised hemodynamic parameters in patients
      studied. Ventilation with EHFO-NB improved the left ventricular function.

PMID- 8650386
TI  - [Low-dose desmopressin (DDAVP) and blood levels of FSH, LH and testosterone in
      men].
AB  - The effect of desmopressin (DDAVP) administration (2.5 micrograms/12 hours) on
      serum concentrations of FSH, LH and testosterone was studied in six men. No
      significant changes were observed in serum concentrations of FSH and LH after 9
      days with DDAVP therapy. Nevertheless, serum concentrations of testosterone after
      12 hours of DDAVP administration were significantly higher than basal
      concentrations. Three hours after the administration of DDAVP, serum testosterone
      concentrations decreased significantly. The conclusion reached was that low doses
      of desmopressin do not change serum concentrations of FSH and LH, but serum
      concentration of testosterone is decreased within three hours after the
      administration, although an increase is observed 12 hours later possibly due to a
      "rebound effect". Desmopressin would therefore directly act upon human testicle.

PMID- 8650387
TI  - [Aneurysms of the splenic artery in patients with liver transplantation].
AB  - Splenic artery aneurysms (SAA) are not uncommon in patients with hepatic
      transplant (HT). Three in 150 transplanted patients in our institutions were
      diagnosed with SAA and two of them had a spontaneous rupture. In two patients
      embolization with interventionist radiology was performed with excellent results.
      SAA should be investigated before and after HT and be treated with embolization
      as soon as possible because of the high risk of rupture.

PMID- 8650388
TI  - [A practical approach to health information in Spain].

PMID- 8650389
TI  - [Immunopathogenic aspects of chronic viral hepatitis].

PMID- 8650390
TI  - [Abdominal colics and polyarthralgias. Saturnism (lead poisoning)].

PMID- 8650391
TI  - [Digital ischemia, renal failure and livedo reticularis after fibrinolysis.
      Cholesterol embolism].

PMID- 8650392
TI  - [25-year-old women with epileptic crisis. Neuronal migration anomaly].

PMID- 8650393
TI  - [Arthritis and characteristic images of abdominal magnetic resonance. Idiopathic
      hemochromatosis].

PMID- 8650394
TI  - [Fever, cough and x-ray pulmonary condensation in an HIV-positive patient.
      Kaposi's sarcoma].

PMID- 8650395
TI  - [72-year-old diabetic patient with a month-long progressive deterioration and
      acute hypotension and coma].

PMID- 8650396
TI  - [Aneurysm of the hepatic artery as a rare cause of obstructive jaundice].

PMID- 8650397
TI  - [Paralysis of the 6th cranial nerve secondary to spontaneous intracranial
      hypotension].

PMID- 8650398
TI  - [Non-imported acute hepatitis E in Western countries C].

PMID- 8650399
TI  - [Neurohormonal factors in heart failure. I].
AB  - Heart failure is a physiopathological condition, with an increasing incidence and
      prevalence, involving the action of a series of mechanisms known as
      'compensators', which are phylogenetically ready to normalize minute volume and
      blood pressure. These mechanisms include the activation of a series of
      neurohormonal systems: the sympathetic nervous system, the aldosterone renin
      angiotensin system, vasopressin arginine, endothelin, which are basically
      vasoconstrictors, with the counterpoint of other vasodilator systems, such as the
      endothelial relaxation factor, certain prostaglandins and the bradykinin
      kallikrein system, which modulate global response. The authors review the
      physiopathology of each of these systems, as well as their significance in the
      diagnosis and prognostic evaluation of heart failure. We analyze the possible
      deleterious effects of neurohormonal activation, anatomically and at the
      cardiovascular function level, and try to determine if they are capable of
      explaining the evolution and progression of heart failure, in a truly vicious
      circle, up until the irreversible heart failure phase. We review the current
      importance of the inhibition of the aldosterone renin-angiotensin system in the
      prophylaxis and treatment of heart failure. Furthermore, we describe the present
      day value of the inhibition of the sympathetic nervous system in some forms of
      heart failure. We also analyze the different pharmacological treatment for heart
      failure: diuretics, inotropic agents, vasodilators (in their different
      pharmacological types), paying particular attention to their action on
      neurohormonal systems and their implications in the prognosis and evolution of
      heart failure.

PMID- 8650401
TI  - [Studies of cardiovascular autonomic function and duration of QTc interval in
      smokers].
AB  - OBJECTIVES: A total of 97 apparently healthy subjects were studied in order to
      establish the influence of smoking habits in studies on neurocardiovascular
      control and the QTc interval duration. MATERIAL AND METHODS: The study group
      consisted of 37 smokers and 60 non-smokers as the control. A 12-lead
      electrocardiogram was performed on all subjects to determine the duration of the
      QTc interval. Other aspects studied include heart rate variability at rest during
      150 cardiac cycles using time domain: coefficient of variation and root mean
      squared successive difference; and frequency domain: low frequency band (0.04
      0.15 Hz) and high frequency band (0.15-0.50 Hz), to determine total energy
      logarithm and maximum energy frequency. Additionally, conventional cardiovascular
      autonomic function tests, such as orthostasis, Valsalva maneuver and deep
      breathing were performed. RESULTS: No significant differences were observed in
      the duration of the QTc interval nor in time and frequency domain parameters,
      except in the maximum frequency in the high frequency band, which appeared
      significantly lower (p < 0.05) in smokers when compared to non-smokers (0.28 +1-
      0.1 vs 0.33 +/- 0.1 Hz). No modifications were noted in the cardiovascular
      autonomic function tests applied to smokers and non-smokers, and the QTc interval
      was not linked to the rest of the variables studied. CONCLUSIONS: To conclude,
      smoking habits do not seem to have a significant influence in studies addressed
      to determine the impact of the autonomic nervous systems on cardiovascular
      control.

PMID- 8650400
TI  - [Characteristics and course of patients over 65 years of age with severe heart
      failure].
AB  - INTRODUCTION AND OBJECTIVES: Although there have been many studies on the
      prognosis of congestive heart failure, most of them have not provided specific
      data about older patients. The aim of our study is to evaluate general
      characteristics and short and medium-term evolution of patients older than 65
      years with severe heart failure. PATIENTS AND METHODS: We have carried out a
      prospective study of all patients older than 65 years admitted to our Department
      during 1993 due to severe heart failure (functional class III or IV of the NYHA
      classification), regardless of the etiology. In that year, 84 patients who
      fulfilled those criteria were admitted. RESULTS: The mean age was 72 +/- 6 years,
      56% were male and 44% female. Age distribution was as follows: 36 patients were
      between 65 and 70 years, 27 between 70 and 75, 8 between 75 and 80, and 13 older
      than 80. The etiology of heart failure was: ischemic heart disease 44%, valvular
      heart disease 36%, idiopathic dilated cardiomyopathy 8%, systemic arterial
      hypertension 7% and other etiologies 5%. Significant systolic dysfunction (left
      ventricular ejection fraction < 0.45) was present in 36% of the patients. Ten
      percent of the patients suffered from severe ventricular arrhythmias (ventricular
      tachycardia or fibrillation). Regarding treatment, 24% underwent valvular
      surgery, 74% received only medical treatment and coronary angioplasty was
      performed in one patient. In hospital mortality was 9% (8 patients). After a mean
      follow-up of 8 +/- 4 months, the probability of survival was 78% at 1 month, 71%
      at 6 months and 63% at 1 year. The survival rate was better in patients with
      higher ejection fraction (53% for patients with ejection fractions of less than
      0.45, 64% for those with ejection fractions between 0.45 and 0.60 and 79% for
      those with ejection fractions greater than 0.60). Considering etiology, the
      survival rate was worse for patients with acute myocardial infarction (30%) and
      aortic valve stenosis (58%). CONCLUSIONS: Patients older than 65 years admitted
      to the hospital for severe congestive heart failure represent a heterogeneous
      population in respect to etiology, systolic function and prognosis. Nevertheless,
      from this study it appears that a worse prognosis was associated with the lower
      left ventricular ejection fractions and with certain etiologies; such as acute
      myocardial infarction or aortic stenosis.

PMID- 8650402
TI  - [Directional coronary atherectomy in ostial lesions of the anterior descending
      coronary artery].
AB  - INTRODUCTION AND OBJECTIVES: Coronary stenoses at ostial level, when treated by
      balloon angioplasty, show a primary success rate much lower than those located in
      other parts of the coronary tree. Balloon dilation of lesions located at the left
      anterior descending ostium is associated with a high degree of restenosis,
      elastic recoil and the possibility of retrograde dissection to the left main
      coronary artery. Simpson atherectomy may be considered a percutaneous alternative
      in this particular location, since this technique produces fewer incidents of
      elastic recoil than balloon dilation. The purpose of the present study is to
      evaluate directional atherectomy in the treatment of patients with symptoms
      deriving from severe to stenosis at the origin of the left anterior descending
      artery. MATERIAL AND METHODS: From a total number of 302 patients treated by
      Simpson atherectomy, we have analyzed 45 with severe stenosis at the left
      anterior descending ostium (less than 3 mm from its origin). The mean age was 54
      +/- 12 years. Eighty two percent of the patients were male. The clinical
      condition was stable in unstable in 34; eleven had had a previous myocardial
      infarction. Six had multivessel coronary disease, all of them underwent combined
      balloon angioplasty of other segments. The treated lesion was native in 41
      patients and previously dilated by balloon (restenosis) in 4. Two patients needed
      balloon predilation with 2 and 2.5 mm to facilitate the pass of the
      atherocatheter. The size of the Simpson atherocatheter was mainly 7F (78%). The
      weight of the resected arteriosclerotic material was 11 +/- 7 mg. RESULTS:
      Primary success (residual stenosis < 40% without major complications) was
      obtained in 42 out of 45 patients (93%); 3 patients (7%) had major complications
      (1 death, 1 emergency surgery, and 1 non-Q wave myocardial infarction). A follow
      up angiography study was available in 31 patients 7 +/- 8 months later.
      Restenosis was evidenced in 12 (39%). CONCLUSIONS: Simpson atherectomy for left
      anterior descending artery ostial lesions is an effective transluminal
      alternative in selected patients providing a high rate of primary success (93%)
      and an acceptable restenosis rate (39%).

PMID- 8650403
TI  - [LDL apheresis using a double filtration technique. Results after a 6-to-12 month
      follow-up in patients with refractory hyperlipemia and ischemic heart disease].
AB  - METHODS: Five patients with a family history of hypercholesterolemia were treated
      for one year with double filtered technique of LDL-apheresis: heterozygotic in
      four patient and homozygotic in one. All patients presented documented
      cardiovascular disease and had been treated unsuccessfully with lipid lowering
      drugs. RESULTS: Plasmatic cholesterol was significantly reduced from 463.8 +/-
      60.9 mg/dl to 326.36 +/- 36 mg/dl at 6 months after treatment and 347.56 +/- 68.1
      mg/dl at 12 months (p < 0.05). LDL was also reduced from 407.92 +/- 69.39 mg/dl
      to 294.04 +/- 62.02 mg/dl and 296.6 +/- 82.42 mg/dl respectively (p < 0.05) and
      Apo B was reduced from 291.84 +/- 28.97 mg/dl to 224.5 +/- 47.11 mg/dl at 6 and
      12 months respectively, without significant modifications of other lipidic
      parameters and without adverse events. CONCLUSIONS: LDL-apheresis is a
      therapeutic approach effective in the reduction of total plasmatic cholesterol,
      in conjunction with to LDL and APO B in patients refractory to lipid lowering
      agents.

PMID- 8650404
TI  - [Aortic balloon valvuloplasty in critical aortic stenosis in the newborn and
      infants].
AB  - INTRODUCTION: Balloon valvuloplasty in neonates and small infants with critical
      aortic stenosis is a palliative procedure. The present report describes the
      results of the technique in our center. METHODS: From April 1993 to March 1995,
      six consecutive patients with critical aortic valve stenosis underwent catheter
      balloon valvuloplasty. Their ages ranged from 2 to 120 days old (45.5 +/- 47.5
      days). Four patients had associated lesions: 2 had coarctation of the aorta, 1
      had ischemic dilated cardiomyopathy and 1 had endocardial fibroelastosis.
      Percutaneous femoral artery access was used in four cases and axillary artery
      dissection in two. RESULTS: The balloon-annulus diameter ratio was 0.92 +/- 0.12.
      The peak systolic ejection gradient decreased from 66.1 +/- 26.4 to 38 +/- 15.7
      mmHg (p < 0.05) and the left ventricle systolic pressure decreased from 136.3 +/-
      26.8 to 115 +/- 22.5 mmHg (p < 0.05). There were no mortalities related to the
      procedure. Both patients who had aortic coarctation developed aortic
      regurgitation and died after repairing of the coarctation. The patient with
      endocardial fibroelastosis died during an attempt to perform the Norwood
      operation (Stage I) and the other patient with ischemic dilated cardiomyopathy
      survived after cardiac transplantation. The remaining two patients with isolated
      aortic valve stenosis are currently asymptomatic. CONCLUSIONS: Catheter-balloon
      valvuloplasty is an effective procedure in the initial treatment of critical
      aortic stenosis and may be life saving.

PMID- 8650405
TI  - [Urate production in a porcine model of myocardial ischemia-reperfusion].
AB  - OBJECTIVE: This study was designed to investigate urate production by swine
      hearts using an in vivo regionally ischemic-reperfused model. ANIMALS AND
      METHODS: Ten female pigs underwent 60 minutes of myocardial ischemia by clamping
      of the left anterior descending artery and afterwards 120 minutes of reperfusion.
      Epicardial biopsies and blood samples from coronary sinus were taken before
      ligation, at the end of ischemic period and 5, 30, 60 and 120 minutes upon
      reperfusion. RESULTS: During ischemia, tissue levels of ATP and ADP greatly
      declined with a subsequent increase in the concentration of AMP, inosine and
      hypoxanthine (33 +/- 12 vs 93 +/- 17, 26 +/- 8 vs 768 +/- 86 and 32 +/- 10 vs 219
      +/- 26 nmol/g dry weight, p < 0.01 for each). Despite the great increase in the
      hypoxanthine levels, uric acid concentration remained constant (69 +/- 9 vs 32 +/
      12 nmol/g dry weight, NS). Hypoxanthine, xanthine and uric acid concentrations
      increased in blood samples obtained from the coronary sinus at the end of
      ischemic period (17.99 vs 31.03 nmol/ml, p < 0.01, 0.29 vs 1.45 nmol/ml, p < 0.05
      and 1.20 vs 2.31 nmol/ml, p < 0.01 respectively) and were enhanced upon
      reperfusion (35.8 and 3.89 nmol/ml for hypoxanthine and uric acid respectively, p
      < 0.05) without any significant modifications in their concentrations at the
      arterial level. CONCLUSION: These results demonstrate that the ischemic
      reperfused swine heart produces urate probably outside the myocardium.

PMID- 8650406
TI  - [Cardiomyopathies. VIII. Sudden death in hypertrophic cardiomyopathy].
AB  - The natural history of patients with hypertrophic cardiomyopathy (HCM) may be
      shadowed by the appearance of sudden death (SD). The identification and
      management of patients with HCM who are at increased risk of SD remains a major
      problem and a clinical challenge. Several mechanisms have been implicated in the
      pathogenesis of the disease, its symptomatic status and prognosis. However, the
      definitive cause of SD in HCM is rarely ascertainable. Genetic factors are
      emerging as new and important determinants of life expectancy among affected
      individuals. Conversely, ventricular arrhythmias remain the most useful single
      factor in the prediction of SD. In this review we highlight the assessment of
      patients at high risk, potential mechanisms of SD and major unanswered issues
      concerning prevention and treatment.

PMID- 8650407
TI  - [Cardiac angiosarcoma].
AB  - We report a case of a 29-year-old patient with recurrent hemorrhagic pericardial
      effusion secondary to a right atrial mass detected by transthoracic
      echocardiography. A more detailed anatomic study was provided by transesophageal
      echocardiogram and nuclear magnetic resonance imaging. During surgery, a biopsy
      confirmed the diagnosis of angiosarcoma. We discuss the contribution of
      echocardiography and other noninvasive methods to evaluate intracardiac tumors. A
      brief review of treatment and prognosis is made.

PMID- 8650408
TI  - [Left coronary artery with anomalous origin and course].
AB  - We report a 45 year-old patient with angina and positive exercise test. In the
      coronary arteriography that left coronary artery rose from a vascular structure
      that connected the aorta to the middle of the left anterior descending coronary
      artery. In the right coronary artery there was a 90% stenosis. An ACTP was made
      in this stenosis. The patient displayed no symptoms eight months after the
      procedure. We have not found in the literature and anomaly of the left coronary
      artery similar to what was found in this patient.

PMID- 8650409
TI  - [Severe digoxin intoxication in a 15-year-old girl treated with Fab antidigoxin].
AB  - A 15-year-old-female admitted after ingesting 5 milligrams of digoxin, presented
      atrial tachycardia with 2.0 degree atrioventricular block and frequent
      ventricular premature complexes. Serum digoxin determination at admission was 16
      ng/ml. Two hours following the administration of 2 amp of Fab antidigoxin (160
      milligrams) the arrhythmias disappeared and remained asymptomatic until
      discharge.

PMID- 8650410
TI  - [Mortality by respiratory diseases in ten European and North American countries
      (1979-1990)].

PMID- 8650411
TI  - [Scleroderma and alveolar inflammation].
AB  - Pulmonary fibrosis is a frequent and serious complication of scleroderma whose
      pathophysiology remains poorly understood. The alveolar structures are
      infiltrated by activated chronic inflammatory cells, alveolar macrophages and
      polymorphonuclear neutrophils in particular and these could play a determining
      role. We have studied the state of activation of alveolar macrophages and
      monocytes circulating in these patients who presented with scleroderma and
      interstitial pulmonary involvement and also in healthy subjects. The neutrophil
      alveolitis observed in the patients is accompanied by a raised level of
      interleukin-8 secretion by the alveolar macrophages compared to the healthy
      subjects. Interleukin-8 is an important chemotactic molecule for
      polymorphonuclear neutrophils in the lung. The neutrophil alveolitis is
      accompanied by a breakdown in the equilibrium of elastase-antielastase which
      could participate in the development of alveolar lesions leading to fibrosis. In
      addition to the activation of macrophages, there is an activation of monocytes
      marked by the increase in secretion of interleukin-6 and interleukin-8 in vitro
      during the progression of the disease of scleroderma. Thus, alveolar inflammation
      is integrated with the overall systemic inflammation whose causes remain unknown.

PMID- 8650412
TI  - [Therapeutic role of coagulation in small cell lung cancers].
AB  - Biological data and several experimental works have shown evidence of the
      important relationship that exists between the development of the neoplastic
      process and phenomena linked to blood coagulation. This relationship would appear
      particularly important in small cell bronchopulmonary cancer. Several therapeutic
      trials are attached to confirming in vivo the hopes furnished by the series on
      the mechanism of thrombosis in associating chemotherapy with coagulation therapy.
      If Aspirin used in a dose for anti-platelet aggregation is revealed as being
      insufficient then anti-Vitamin K and standard Heparin have brought an undeniable
      benefit to the level of response and survival in phase three randomised trials.
      Urokinase also brings a promising improvement in an open phase two trial but has
      to be confirmed.

PMID- 8650413
TI  - [Immunoglobulins E and inflammatory cells].
AB  - Immunoglobulins E (IgE) have a privileged relationship with inflammatory cells
      due to the fact that there are different receptors for their Fc fragment
      expressed on the cell's surface. Currently one recognises at least three types of
      receptor: high affinity receptors (Fc epsilon RI) which are present on the
      surface of mast cells, basophils, and Langerhans cells. The receptors of low
      affinity (Fc epsilon RII) are represented on the surface of numerous inflammatory
      cells (eosinophils, lymphocytes, platelets...) and some lectine type (epsilon BP)
      receptors which are present on polymorpho-nuclear neutrophils and activated
      macrophages. The IgE interaction in the presence of specific antigens on the
      receptor may lead to cellular activation by transduction mechanism which are
      becoming better understood. This sequence of events, combined with the mechanisms
      of immediate hypersensitivity lead to the liberation of mediators and cytokines
      which nature varies according to the cell type and its environment. Polymorpho
      nuclear eosinophils, mast cells, basophils and many other cells comply with this
      type of activation. However, the relationship between IgE and cells is not
      limited to this type of activation response. In the absence of specific antigen,
      IgE may sometimes play an inhibitory role on cellular functions; it is the case
      of blood platelets and polymorpho-nuclear neutrophils. Finally, IgE also
      participates in normal mechanisms of immune defence and may perhaps, by their
      presence on the surface of the dentritic cells, be determining factors in the
      function of antigen presentation. The diversity of IgE action at cellular level
      may equally be observed at the level of the bronchus, on organ which is
      implicated in allergic pathology. Passive sensitisation of the human bronchus by
      IgE may have at least two types of effect on the contractile response observed in
      vivo: in the presence of specific antigen it enables the contraction of bronchial
      smooth muscles and in the absence of antigen it could change the contractile
      response to non-specific agonists as it is observed in vivo in bronchial hyper
      reactivity.

PMID- 8650414
TI  - [Inhaled nitric oxide test for patients with stable chronic obstructive pulmonary
      disease: value and feasibility].
AB  - Patients suffering from chronic lung disease (CLDP) often develop secondary
      pulmonary hypertension (HP), which contributes to right ventricular dysfunction
      and worsens their prognosis. In order to evaluate the severity of this HP,
      pharmacodynamics tests are periodically proposed to these patients. Therefore,
      the administration of vasodilators is limited by systemic and pulmonary side
      effects. Inhaling nitric oxide gas (NO) has been reported to induce a selective
      pulmonary vasodilation. The purpose of this study was to evaluate the safety and
      efficacy of an inhaled NO test perfected in our service. Sixteen CLDP were
      investigated in the absence of acute pulmonary failure. All had severe pre
      capillary HP, confirmed after placement of a thermodilution pulmonary-artery
      catheter (mean pulmonary artery pressure >20 mmHg, pulmonary capillary wedge
      pressure >12 mmHg). Each subject breathed spontaneously NO in a concentration of
      10 ppm for 15 minutes. They were connected through a facial mask and a one-way
      valve put on the inspiratory connection of a ventilator (Drager-Evita), to a tank
      of nitrogen with a NO concentration of 900 ppm. Hemodynamic variables and gas
      exchange were measured before, during and after gas inhalation. The inspired
      fractions of NO and NO2 were determined using a Polytron analyser (Drager). The
      methemoglobin levels were measured with spectrophotometry (OSM3). Inhaled NO acts
      as a selective pulmonary arterial vasodilator, without systemic effect. The
      action on the shunt is variable. Methemoglobin levels are remained <0.01%. All
      the patients were satisfied with the way of NO administration. In view of the
      lack of systemic effects, its seems that the NO inhaled test proposed in this
      study may be used accurately to evaluate the HP of chronic lung disease patients.

PMID- 8650415
TI  - [Validation of the St George's questionnaire for measuring the quality of life in
      patients with chronic obstructive pulmonary disease].
AB  - The validity of a French version of a disease specific quality of life
      instrument, the St George's Respiratory Questionnaire, has been assessed in a
      sample of 64 patients with chronic respiratory disease undergoing oxygen therapy.
      The studied properties were internal consistency, test-retest reproducibility and
      criterion validity. The St George's showed a good internal consistency with
      Cronbach's alpha coefficients from 0.61 to 0.95 and a good reproducibility with
      Intraclass Correlation Coefficients (ICC) from 0.67 to 0.95. High correlation
      with dyspnea (p=0.0004 to 0.01) showed a correct criterion validity. So
      psychometric properties of the French version of the questionnaire are good.
      However, its administration caused a few problems, and we advice it to be
      administered by a trained interviewer in such patients.

PMID- 8650416
TI  - [Mortality by respiratory disease in ten European and North American countries
      (1979-1990)].
AB  - The aim of this paper is to compare respiratory mortality, cancer and
      tuberculosis excluded, in 10 countries during 12 years. Mortality data came from
      World Health Statistics Annual of the WHO and age adjusted rates were calculated.
      For all causes respiratory mortality, acute pathologies and chronic obstructions
      not elsewhere classified, United Kingdom and above all Eire have the highest
      rates; Italy, France and Germany have the lowest rates; the other countries
      (Belgium, Denmark, Netherlands, Canada, United States) have rates similar,
      sometimes equal). For chronic conditions, Denmark has the highest rates, Canada
      and United States the lowest; Eire and United Kingdom begin a great decrease from
      1983. On the whole, differences between countries do not vary very much with the
      years or the pathologies and the evolution over the time is not very marked apart
      from some countries.

PMID- 8650417
TI  - [Rehabilitation exercise training in chronic obstructive pulmonary disease].

PMID- 8650418
TI  - [Pulmonary deposition of colistin aerosols in cystic fibrosis. Comparison of an
      ultrasonic nebulizer and a pneumatic nebulizer].
AB  - The objective of this study was to quantify the deposition in the lung of a
      Colistine aerosol generated using a pneumatic nebuliser (Pari LL(R) equipped with
      a Pari Master, Pari, Germany) and to compare this with the results obtained with
      an ultrasonic nebuliser (DP100, DP Medical, France) in four subjects suffering
      from cystic fibrosis being colonised with Pseudomonas aeruginosa. To quantify the
      pulmonary deposition of the aerosols we have used an indirect isotopic method
      which consists in assimilating the kinetics of the molecules studied with a serum
      albumin tagged with Technetium 99m (Tc99mm) and added to a preparation of
      Colistine. We have previously verified that the addition of a radioactive tracer
      does not change the normal distribution or dynamics of the medication within the
      aerosol and the radioactive counter linked to the tracer reflects the mass of the
      medicament. The pulmonary deposition was expressed as a percentage of the
      nebuliser dose. A regional analysis of the deposition (central, peripheral,
      superior and inferior) was carried out and in central deposition compared to the
      periphery (C/P) and superior compared to inferior (S/I) were calculated. With the
      DP100 nebuliser the pulmonary deposition of the aerosol was very reproducible
      from one patient to another, varying only between 9.5 to 14 percent of the
      nebuliser dose. With the Pari LL the fraction deposited varied more from one
      patient to another from 5.6 to 27% of the nebuliser dose. In three of four
      patients, the pulmonary deposition was superior or equal to that obtained with
      the ultrasonic nebuliser. The patients whose pulmonary deposition was inferior,
      using the pneumatic nebuliser, was the youngest in the group and co-ordinately
      poorly the triggering of the nebuliser with the beginning of inspiration. With
      the two nebulisers, the pulmonary deposition of Colisitine was very heterogeneous
      throughout the pulmonary parenchyma. The mean of the ratio C/P and S/I obtained
      in all four patients was identical (1.35 an 0.86 respectively), indicating a
      deposition of the aerosol which was predominantly central and inferior but was
      distributed equally in the peripheral parts of the lung. Pneumatic nebulisers
      offer a reliable alternative notably for domiciliary treatment for Colistine
      aerosols in patients suffering from cystic fibrosis. In younger patients who have
      not yet acquired good motor co-ordination, nebulisers which function continuously
      or are triggered by inspiration seem to be the preferred choice.

PMID- 8650419
TI  - [Effects of ambulatory respiratory rehabilitation on exercise tolerance and
      quality of life in chronic obstructive lung disease patients].
AB  - Respiratory rehabilitation is a multidisciplinary medical approach which allows a
      total care of patients suffering from COPD. Optimisation of bronchodilator
      treatment, health education, cessation of smoking, dietetic, relaxation and re
      entrainment to effort. We report out experience concerning 88 BPCO (mean age
      62.1, FEV1 of 1.4 litres; or 48% of predicted normal); these 88 patients were
      cared for on an ambulatory basis at our centre for two hours per session, three
      times per week for seven weeks. The objective results were analysed on exercise
      tests before and after treatment. For ventilation, there was a significant
      improvement in the power developed (from 45.5+/-17.1 to 53.4+/-23 watts; p<0.001)
      without any change in the oxygen consumption (VO2), ventilation (VE) or heart
      rate (FC) and of oxygen pulse (VO2/FC). For the same level of power (80% of
      maximum power for the initial exercise test) there was a significant lowering of
      ventilation (V=33.5+/-9.4 to 30.7+/-7.4 litres per minute, p<0.001), cardiac
      frequency (FC: from 116.9+/-16 to 111.1+/-13.1 beats per minute, p<0.001) as well
      as the oxygen pulse (VO2/FC: from 7.9+/-2.7 to 8.3+/-3.7). At the maximum on the
      exercise test all the parameters studied were significantly better: watts, VO2,
      VE, cardiac frequency and VO2/FC. A study of the visual analogue scale (EVA),
      analysing sleep, anxiety, dyspnoea and the physical aspects showed a significant
      improvement in the four subjective parameters. Respiratory rehabilitation of BPCO
      practiced as an out patient has shown an improvement in exercise tolerance in
      every day activities and improvement in dyspnoea and in the quality of life.

PMID- 8650420
TI  - [Acute pleurisy secondary to ovarian hyperstimulation after in vitro
      fertilization].
AB  - Pleurisies due to the syndrome of ovarian hyperstimulation typically accompany
      ascites and in their most severe form are associated with haemoconcentration,
      hypovolaemia and thromboembolic phenomena. It is not unusual in this context for
      pleural effusions to be isolated. They may occur during treatment for sterility
      by inducing ovulation, they are exudates and predominantly right sided. The
      pathophysiology is not clear and results in vascular hyperpermeability.
      Currently, no treatment aimed at the aetiology has proven its own efficacy.
      Spontaneous regression of the effusion is the rule but in severe forms, where the
      prognosis is uncertain, correction of hypovolaemia is a priority.

PMID- 8650421
TI  - [Gene therapy for alpha 1-antitrypsin deficiency. Hopes, realities and
      perspectives].
AB  - Alpha 1 antitrypsin deficiency (alpha 1 AT) is an autosomal recessive disease due
      to mutations in the gene coding for alpha 1 antitrypsin and characterised by very
      reduced serum levels of the anti-protease. Alpha 1 antitrypsin is primarily
      produced in the liver by hepatocytes and then passes into the general circulation
      to diffuse into the pulmonary tissue. Its function is to inhibit the elastase
      secreted by the polymorpho-nuclear neutrophils. When the quantity of alpha 1
      antitrypsin secreted into the circulation is insufficient to inhibit the
      elastase, the pulmonary tissue is progressively destroyed, leading to the
      appearance of emphysema around 30 to 40 years of age. Gene therapy in alpha 1
      antitrypsin deficiency rests on the transfer and the expression of a copy of the
      normal human alpha 1 antitrypsin gene by the cells of an organism of a subject
      suffering from the disease. The aim is to restore a sufficient level of alpha 1
      antitrypsin to inactivate the elastase in the pulmonary tissue and thus prevent
      the appearance of emphysema. Numerous experimental protocols have been developed
      in vivo in animals since 1987. They identify the two principal current
      difficulties for the development of clinical trials: the brevity of the duration
      of expression of the transferred gene which does not last more than a few months,
      and insufficient levels of alpha 1 antitrypsin which are obtained, usually less
      than the therapeutic level required.

PMID- 8650422
TI  - [Mediastinal adenopathies metastatic from a basocellular skin carcinoma].
AB  - Skin basocellular carcinoma is very frequent, and does not usually cause distant
      metastasis. However, a few cases of distal lymph node, pulmonary, bone metastasis
      have been described in the literature. In the present case, we report a
      basocellular mediastinal lymph node metastasis. Some precise histological
      characteristics described by Lattses must be present to admit authenticity of
      these metastasis. The treatment of such cases is based on surgery, radiotherapy
      and chemotherapy containing cisplatinum. However, the overall prognosis of these
      metastases remains poor.

PMID- 8650423
TI  - [A case of thoracic pain].

PMID- 8650424
TI  - [Bronchial dilatations with inflatable balloon].

PMID- 8650425
TI  - [Outcome of cystic fibrosis children screened at birth].

PMID- 8650426
TI  - [Treatment of non-tuberculous mycobacterial infections].

PMID- 8650427
TI  - [Debate on the treatment of small cell cancers. Utilization of hematopoietic
      growth factors: necessity for a new trial].

PMID- 8650429
TI  - [Usefulness of computerized dynamic capillaroscopy in the monitoring of treatment
      of progressive systemic sclerosis with synthetic prostacyclin].
AB  - The aim of this study was to evaluate the variations of blood flow velocity in
      the skin microcirculation before and after vasoactive drugs' administration.
      Eight patients affected by progressive systemic sclerosis have been treated with
      synthesis prostacyclin for six hours during a period of fifteen days at the
      standard dosage of 0.5-2 ng/kg/min. We used computerized dynamic capillaroscopy
      with Capiflow technique to evaluate cutaneous microcirculation before and after
      the treatment. The Capiflow technique is a new videophotometric technique to
      study and quantify the diameter, density and velocity blood flow in the
      nutritional skin capillary. The quantitative analysis of blood flow velocity
      detected an increase, statistically significant, at the end of the treatment. The
      statistic analysis was performed by "t Student" test.

PMID- 8650428
TI  - Fish oil supplementation in patients with heterozygous familial
      hypercholesterolemia.
AB  - Familial hypercholesterolemia is associated with premature coronary heart
      disease. In patients with familial hypercholesterolemia, monotherapy with
      hydroxymethylglutaril coenzyme. A reductase inhibitors rarely achieves the goal
      of desirable low-density lipoprotein levels. Epidemiological studies suggest that
      populations with a high dietary intake of marine n3 fatty acids are protected
      against coronary heart disease. Hepatic synthesis and secretion of very low
      density lipoproteins are reduced during fish oil supplementation while other
      effects on lipid and lipoprotein metabolism are controversial. Fourteen patients
      affected by familial heterozygous hypercholesterolemia on chronic treatment with
      simvastatin were enrolled in a double blind, placebo controlled, randomized
      crossover trial that evaluated the effect of fish oil ethyl ester (Esapent, 5.1
      g/day) on lipid and lipoprotein serum concentrations. Total cholesterol, low
      density lipoprotein cholesterol, high density lipoprotein cholesterol,
      triglycerides, apoprotein B, apoprotein AI, lipoprotein (a) did not show any
      significant variation during the four week treatment period with fish oil ethyl
      ester. The present data suggest that the possible favourable influence of fish
      oil on the progression of atherosclerosis in these high-risk patients might
      involve mechanisms which are different from lipid metabolism.

PMID- 8650431
TI  - [Current controversies concerning the use of calcium antagonists].

PMID- 8650430
TI  - [Cerebrotendinous xanthomatosis. A case report].
AB  - We describe a patient with cerebrotendinous xanthomatosis (CTX) who saw a
      Rheumatologist because of joint and muscle pain in the lower limbs. Clinical
      examination did not reveal any classic joint disease; however, tendon lesions and
      clumsy gait were noted. The patient presented with a swollen Achilles tendon
      bilaterally and a parapareto-spastic gait; Babinski sign was positive on the
      right side, and hyperreflexia of both lower limbs could be demonstrated. As
      bilateral cataracts were present, we have interpreted the aforementioned signs as
      CTX with spinal involvement; mean plasma cholesterol was increased, thus
      confirming the diagnosis. The primary biochemical abnormality of this disease is
      a defect in the synthesis of bile acids; therefore, chenodeoxycholic acid (CDCA)
      has been tried, and beneficial effects following CDCA treatment, especially in
      the early stages of CTX, have been reported in the literature. We report this
      case because of the severity and the rarity of this disease, and also because of
      its hereditary transmission. Our aim is to underline the need of a precocious
      diagnosis, in order to prevent a further progression of the disease; this
      therapeutic goal can now be achieved, thanks to the therapeutic regimens recently
      developed.

PMID- 8650432
TI  - [Genetic hemochromatosis: importance of population screening?].
AB  - Genetic hemochromatosis is a metabolic autosomal-recessive disease characterized
      by an iron excessive absorption; its subsequent accumulation in the liver,
      hearth, pancreas and endocrine glands, gives rise to organ damage and
      dysfunction. Recent studies of both screening tests and natural history have
      shown that the illness, once thought to be rare and fatal, is quite frequent (up
      to 2-5 homozygotes for 1000 inhabitants) and when recognized and treated before
      onset of cirrhosis, subjects affected have a normal life expectancy.
      Consequently, in order to reduce mortality from genetic hemochromatosis, mainly
      due to liver cirrhosis, frequently complicated with hepatocellular carcinoma, or
      congestive hearth failure, early diagnosis and therapeutic phlebotomy are
      essential. In order to achieve these aims, besides high clinical suspicion and
      familiar study, is fundamental to conduct systematic screening since, at present,
      little use is being made of this, even though numerous studies have recently
      shown its low cost and efficacy. The Authors, after an extensive review of the
      literature, underline the feasibility of screening on the general population and
      its extremely advantageous cost/benefit ratio.

PMID- 8650434
TI  - [Blastocystis hominis in a zone of Northern Italy].

PMID- 8650433
TI  - [Immunosuppressive therapy of vasculitis: current aspects and perspectives].
AB  - Vasculitides are a set of serious diseases of unknown aetiology with various
      immunopathogenetic mechanisms, characterized by inflammation and necrosis of the
      vessel wall with consequent lumen obliteration. They may be primitive or
      associated with other diseases, have heterogeneous clinical manifestations and
      different degrees of severity which may be related to the localization of the
      interested vessels. Although in the last years many classifications have been
      proposed, a standardized nomenclature of vasculitides is unquestionably still
      needed to facilitate the diagnosis and management of patients with the disease.
      Steroids and immunosuppressant are the conventional therapy, whereas other
      therapeutic strategies are reserved for the refractory vasculitides to
      conventional therapies or for intolerant recipients to cytotoxic drugs. New
      approaches are represented by monoclonal antibodies and drugs which could be
      effective in the treatment of the trigger factors which activate the
      immunopathological mechanisms. Current data suggest that, rather than pursuing
      the idea of a single therapy for vasculitides, an oncological model of combined
      therapy, to induce both the disease control and maintenance of remission, might
      be adopted. An improvement of our knowledges on the mechanisms underlying the
      different entities associated to standardized criteria of activity and remission
      of disease will lead to an improvement of our therapeutic strategies.

PMID- 8650435
TI  - Possible interactions between antiblastic agents and warfarin inducing
      prothrombin time abnormalities.

PMID- 8650436
TI  - [Considerations on the methodology of evaluation of scientific activities in
      contests at internal medicine departments].

PMID- 8650438
TI  - Platelet-associated bleeding disorders.
AB  - OBJECTIVE: To provide a review of platelet disorders, treatment, and nursing
      care. DATA SOURCES: Review articles and book chapters pertaining to quantitative
      and qualitative platelet disorders. CONCLUSIONS: Platelet-associated bleeding
      disorders are classified as quantitative (abnormal number), qualitative (abnormal
      function), or hypercoagulable states (errors in hemostasis). The resulting
      complications include thrombocytosis, thrombocytopenia, hypercoagulation, or
      bleeding dyscrasias. The administration of drugs, plasma, or platelet therapy may
      be beneficial to these patients. IMPLICATIONS FOR NURSING PRACTICE: Patients with
      platelet disorders are at great risk of life-threatening hemorrhage and require
      close monitoring to prevent unnecessary sequelae. Patient instruction to prevent
      trauma is required.

PMID- 8650437
TI  - [Arrhythmias in the aged: prevalence and correlation with symptoms].
AB  - Objective of our study was to evaluate the prevalence of arrhythmias as well as
      their correlation with the reported anamnestic symptomatology in the elderly
      population. With 24 hour ambulatory electrocardiography (Holter ECG) 913
      patients, (440 males and 473 females, range 60-89 years, mean age 71) were
      consecutively studied and subdivided according to the following criteria: (1) age
      (3 classes: 60-69 [I], 70-79 [II], > or = 80 [III]; (2) presence/absence of
      "guide" symptoms (syncope/faintness, chest pain, palpitation), and (3) Holter
      electrocardiography results. We have demonstrated a high prevalence of
      arrhythmias: 72% (657), which was significantly higher in age classes II (80.5%)
      and III (79.1%) in comparison to class I (60.6%). A notably higher prevalence of
      tachyarrhythmias is documented compared to bradyarrhythmias (5:1). With a higher
      age the prevalence of supraventricular tachyarrhythmias increases significantly,
      while bradyarrhythmias do not have the same trend. We have a similar prevalence
      of arrhythmias between symptomatic (77.4%) and asymptomatic patients (63.6%) and
      no significant correlation between anamnestic symptoms and presence of
      arrhythmias are observed. Considering the high prevalence of arrhythmias during
      Holter ECG we think that the clinical importance and prognosis should be
      evaluated with caution.

PMID- 8650439
TI  - Anemia.
AB  - OBJECTIVES: To provide an overview of the disorders that cause anemia and to
      review clinical and laboratory assessment and medical and nursing management of
      the anemic patient. DATA SOURCES: Published articles and book chapters that
      pertain to red blood cell physiology and the major causes and types of anemia.
      CONCLUSIONS: Advances in molecular and genetic aspects of anemia are leading to
      new developments in the diagnosis and management of all types of anemia.
      Symptomatic relief to maintain quality of life is essential for all anemic
      patients. IMPLICATIONS FOR NURSING PRACTICE: Nurses can play a major role in the
      supportive care of patients with anemia through interventions related to
      pharmacological therapy, blood transfusions, nutritional counseling, and symptom
      management.

PMID- 8650440
TI  - Benign lymphoproliferative disorders.
AB  - OBJECTIVE: To provide a review of three benign lymphoproliferative disorders
      commonly encountered in nursing practice: (1) infectious mononucleosis, (2) cat
      scratch disease, and (3) sarcoidosis. DATA SOURCES: Research studies, review
      articles, and book chapters pertaining to benign lymphoproliferative disorders.
      CONCLUSIONS: Benign lymphoproliferative disorders may be associated with
      infections, autoimmune disorders, hypersensitivity reactions, and unknown causes.
      Most of these disorders are self-limiting; however, some are associated with
      significant morbidity and mortality. IMPLICATIONS FOR NURSING PRACTICE: Benign as
      well as malignant lymphoproliferative disorders will be encountered with
      increasing frequency by nurses in ambulatory settings. Nurses need to have a
      basic knowledge of these disorders that present a diagnostic and management
      challenge.

PMID- 8650441
TI  - Hematologic problems in pediatric patients.
AB  - OBJECTIVE: To provide a review of the common hematologic disorders of childhood:
      iron deficiency anemia, aplastic anemia, sickle cell disease, and hemophilia.
      DATA SOURCES: Review articles and book chapters pertaining to the care and
      treatment of children with hematologic disorders. CONCLUSIONS: These common
      hematologic disorders of childhood have the potential to cause not only acute
      illness but chronic medical problems, particularly in the growing child.
      Anticipating and preventing the long-term effects of the illness and treatment
      are the primary goals of care. IMPLICATIONS FOR NURSING PRACTICE: Nursing
      assessment, patient education, and long-term follow-up are major factors in the
      care of children with hematologic disorders. Nurse-managed comprehensive care
      clinics have provided successful programs directed at acute care and maintenance
      care for these children and their families.

PMID- 8650442
TI  - Myelodysplastic syndromes.
AB  - OBJECTIVES: To provide a framework of information from which the nurse can
      collaborate with the health care team to plan, coordinate, and deliver care to
      persons with myelodysplastic syndromes (MDS) and their families. DATA SOURCES:
      Research studies, book chapters, and review articles pertaining to the
      classification, pathogenesis, manifestations, diagnosis, treatment, and prognosis
      of MDS. CONCLUSIONS: The MDS are a group of hematologic disorders characterized
      by ineffective hematopoiesis, peripheral blood cytopenias, and a propensity to
      transform into acute myelogenous leukemia. The primary treatment is supportive
      care; however, chemotherapy, bone marrow transplant, and hematopoietic growth
      factors are also used. IMPLICATIONS FOR NURSING PRACTICE: Assessment, education,
      emotional support, monitoring of complications, and provision of help to the
      patient with fatigue to prioritize activities and plan periods of rest are
      important supportive care measures.

PMID- 8650443
TI  - Multiple myeloma.
AB  - OBJECTIVES: To review the epidemiology, pathogenesis, clinical features,
      diagnosis, treatment, and nursing management of multiple myeloma. DATA SOURCES:
      Review articles, research studies, and book chapters related to multiple myeloma.
      CONCLUSIONS: Despite insights into the immunobiology of multiple myeloma and the
      advances in intensive therapy and supportive care, multiple myeloma remains an
      incurable disease. Patients will experience chronic and acute symptomatic
      episodes throughout the course of their disease. IMPLICATIONS FOR NURSING
      PRACTICE: Oncology nurses can assist patients with multiple myeloma and their
      families to manage both the disease and treatment related symptoms and to improve
      their overall quality of life. Specific nursing assessments can provide early
      recognition of complications, such as hypercalcemia and spinal cord compression.

PMID- 8650444
TI  - Polycythemia vera.
AB  - OBJECTIVES: To review the proliferative nature of polycythemia vera (PV),
      clinical features, laboratory findings, treatment options and controversies, and
      nursing management. DATA SOURCES: Textbook chapters and review articles that
      pertain to polycythemia vera. CONCLUSIONS: Polycythemia vera is a chronic
      myeloproliferative disorder that can evolve into acute leukemia. Treatment
      options include phlebotomy, myelosuppressive agents, interferon, and platelet
      inhibitors. IMPLICATIONS FOR NURSING PRACTICE: Nursing management of the patient
      with PV is challenging because of the evolving nature of the disease and
      treatment-related complications. Close monitoring and compliance with the
      treatment plan is necessary.

PMID- 8650445
TI  - On content of practice. The advantage of computerized information systems in
      family practice.
AB  - BACKGROUND: Computerized medical records have been widely used in family practice
      in Iceland for several years. Extensive data have been accumulated; however, how
      best to use and implement these data has been debated. OBJECTIVES: The main
      objectives of this study was to determine the advantage of computerized
      information systems in family practice. MAIN RESULTS: The results provided broad
      epidemiological information on the content of family practice in Iceland. The
      study population consisted of 50,865 Icelanders and their 257,188 contacts with
      17 community health centres over one whole year, 1988. Services were provided by
      50 doctors, 43 nurses and nurses' assistants, and 7 midwives. Almost 90% of the
      rural population made at least one contact over the year of study; the mean rate
      of contacts per individual was 5.1, office visit 2.8-3.3, phone calls 1.1-1.6,
      and home-visits 0.4, females (40%) more often than males, increasing in number
      with increasing age. Disease symptoms were the reason for contact in 35-39% of
      cases, the initiative of the health care provider in 44-50%, and administration
      in 9-12%. The mean number of health problems recorded were 2.3 per individual per
      year. Extensive prevalence numbers are provided by age and sex. The largest
      categories were respiratory, injuries and musculoskeletal with a prevalence of
      over 200/1000 individuals per year. The most frequent contacts were made by
      persons with cancer and mental problems. The actions taken (processes) as a
      result of these contacts were numerous, an average of 1.6 per contact; 648
      medications/1000 contacts, 141 laboratory tests, 126 surgical procedures, 15-24
      referrals, and 15-26 hospital admissions. Prescriptions were most frequently for
      central nervous system medication (93-117/1000 contacts), for anti-infectives
      (100-106), and for cardiovascular (58-99). The cost of x-rays was shown to be
      $866 per 1000 contacts, and the odds for having an x-ray decreased by 18% for
      every 1000 individuals added to a practice. A quality study showed 16% of x-ray
      requests and 13% of office prescriptions were lacking. CONCLUSION: The
      information obtained reflects health problems of the population as observed by
      family doctors. The information is useful for observing and influencing the
      health of a nation, the practices of health care providers, the generation of
      cost in the health system, and the use of appropriate health services. It is also
      useful to health care planners and researchers, as well as educators of health
      care providers. This study serves as a baseline for these tasks.

PMID- 8650446
TI  - [Pharma-clinics. How I treat.... Ventricular tachycardia in children].

PMID- 8650447
TI  - [Clinical case of the month. Hereditary hemochromatosis].

PMID- 8650448
TI  - [Drug addiction: pregnancy and newborn infant].

PMID- 8650449
TI  - [Topical antibiotic therapy and skin infections].

PMID- 8650450
TI  - [[Wallonian general physicians. Which prescriptions should be given to elderly
      persons over 75 years?].

PMID- 8650452
TI  - [Pitfalls and difficulties in medical terminology].

PMID- 8650451
TI  - [Renal revascularization for kidney salvage or preservation].

PMID- 8650453
TI  - [How I explore.... The small intestine using double-lumen enteroscopy].

PMID- 8650454
TI  - [Pharma-clinics. Drug of the month. Fluticasone propionate (Flixotide)].

PMID- 8650455
TI  - [Carvedilol in cardiac decompensation].

PMID- 8650456
TI  - Sleep characteristics in healthy children from birth to 6 years of age in the
      urban area of Rome.
AB  - The current survey is an attempt to evaluate age-specific sleep characteristics
      and to identify the presence of sleep problems in Italian normally developing
      preschool-aged children. A cross-sectional survey by parental interview on sleep
      behavior was carried out on 2,889 children (from birth to 6 years). Groups were
      formed based on age level. Results showed a developmental trend of some sleep
      characteristics, regarding mainly the length of sleep and rating of night
      wakings. Comparison with other studies showed that the children in this study had
      a later sleep onset time and slept less than children of the same age living in
      some other countries. These dissimilarities may be due to sociocultural and
      climate differences. Sleep problems (sleep latency longer than 30 minutes or
      disruptive night wakings) were found in 35% of children less than 2 years old, in
      23% of 2-3-year-olds and in 14% of 4-6-year-olds. Children with sleep problems
      slept significantly less (on average 30-40 minutes across all age levels,
      required parental presence at time of sleep onset and shared their parents' bed
      more frequently than those without sleeping problems.

PMID- 8650457
TI  - Kleine-Levin syndrome in a boy with Prader-Willi syndrome.
AB  - A 9 1/2-year-old Taiwanese boy with Prader-Willi syndrome had the following
      characteristics: difficulties with sucking, feeding and hypotonia during infancy,
      a dysmorphic face (triangular mouth, high arched palate, almond-shaped eyes and
      large head circumference with a relatively narrow bifrontal diameter), borderline
      intelligence, hypogonadism, hyperphagia, skin picking and truncal obesity. The
      boy experienced two hypersomnia episodes, at age 8 and 9 years, with both
      episodes lasting for 10 days. During the two episodes, he was found to have an
      exacerbated case of hyperphagia, pica, poor emotional control, stereotyped speech
      and agitated behavior upon awakening. After each episode, the boy had complete
      remission. Our findings show that the two episodes are compatible with Kleine
      Levin syndrome. The relationship between the two syndromes, the Prader-Willi
      syndrome and the Kleine-Levin syndrome, deserves further study.

PMID- 8650458
TI  - Computer classification of sleep in preterm and full-term neonates at similar
      postconceptional term ages.
AB  - A classification strategy of neonatal sleep is being developed by comparing
      visually scored minutes of 21 channels of electroencephalographic
      (EEG)/polygraphic recordings with the corresponding values for each physiological
      signal derived from either visual or computer analyses. Continuous 3-hour sleep
      studies on 54 preterm and full-term neonates at similar postconceptional term
      ages were acquired under environmentally controlled conditions using a
      computerized monitoring system. An on-line event marker program recorded
      behavioral observations. One of three EEG sleep states was assigned to each of
      8,995 minutes by traditional visual analysis criteria. EEG spectral values,
      spectral and nonspectral cardiorespiratory calculations and behaviorally observed
      movements, arousals and rapid eye movement counts were submitted for discriminant
      analysis. Based on the total minutes known for each of three states (i.e. active,
      quiet and awake), linear combinations of all specified digitized parameters were
      formed into an arithmetic algorithm by use of discriminant analysis, which served
      as the basis of a state assignment for each minute. Fifty percent of the data
      were arbitrarily used as the training set to derive the state classification
      model. The remaining fifty percent of the data were used as the cross-validation
      "test sample" to determine the accuracy of the classification when compared to
      the visually analyzed score for each corresponding minute. Thirteen out of 32
      physiological measures best predicted state of both preterm and full-term
      neonatal groups. For both groups, the correct classification for active sleep was
      90.3%, quiet sleep was 97.4%, awake was 97% and the overall accuracy was 93.3%.
      However, the order of significance for specific variables differed between these
      two neonatal groups. Differences in the order of variables that predict sleep
      states between preterm and full-term infants may reflect adaptation of brain
      function of the preterm infant to prematurity and/or prolonged extrauterine
      experience.

PMID- 8650460
TI  - Prolonged interval from body temperature nadir to sleep offset in patients with
      delayed sleep phase syndrome.
AB  - In order to clarify the relationship between sleep-wake and core body temperature
      rhythms in the delayed sleep phase syndrome (DSPS), we conducted simultaneous
      monitoring of these rhythms in seven patients with DSPS and nine healthy control
      subjects for 6-10 days during their conventional sleep-wake schedules. The sleep
      onset and offset times were determined visually from sleep logs, and the
      temperature data were fitted to 24-hour cosinor curves by the least squares
      method. The sleep onset and offset times and temperature nadir were delayed
      significantly in patients with DSPS compared with the control subjects (p = 0.01,
      0.003 and 0.02, respectively). We also found that sleep length and the
      temperature nadir to sleep offset interval were significantly longer in the DSPS
      than the control group (p = 0.03 and 0.02, respectively). The latter finding
      suggests that the inability of the patients with DSPS to normally phase-advance
      their circadian rhythm may be a consequence of masking of the advance portion of
      their phase-response curve by the last hours of their prolonged sleep episodes.

PMID- 8650459
TI  - Sleep stage scoring using the neural network model: comparison between visual and
      automatic analysis in normal subjects and patients.
AB  - In this paper, we compare and analyze the results from automatic analysis and
      visual scoring of nocturnal sleep recordings. The validation is based on a sleep
      recording set of 60 subjects (33 males and 27 females), consisting of three
      groups: 20 normal controls subjects, 20 depressed patients and 20 insomniac
      patients treated with a benzodiazepine. The inter-expert variability estimated
      from these 60 recordings (61,949 epochs) indicated an average agreement rate of
      87.5% between two experts on the basis of 30-second epochs. The automatic scoring
      system, compared in the same way with one expert, achieved an average agreement
      rate of 82.3%, without expert supervision. By adding expert supervision for
      ambiguous and unknown epochs, detected by computation of an uncertainty index and
      unknown rejection, the automatic/expert agreement grew from 82.3% to 90%, with
      supervision over only 20% of the night. Bearing in mind the composition and the
      size of the test sample, the automated sleep staging system achieved a
      satisfactory performance level and may be considered a useful alternative to
      visual sleep stage scoring for large-scale investigations of human sleep.

PMID- 8650461
TI  - Sleep-disordered breathing and its effects on sleep in infants.
AB  - Sleep apnea has been recorded in many infants, but little data exist concerning
      the amount and range of apnea in infants. We studied 49 infants referred to the
      sleep disorders unit. Single polysomnographic studies were performed on each
      infant. We examined the amount of apnea, presence and amount of upper airway
      obstruction and the sleeping pattern in each infant. Central apnea was common to
      all infants and varied in amount. Upper airway obstruction, recorded as mixed
      apnea, was found in 36 infants. Twenty of these infants had only occasional mixed
      apnea ( < 2 apneas/hour), whereas 16 infants displayed a higher amount of
      obstruction. All infants were separated into two groups according to amount of
      apnea and obstruction. Sixteen infants with obstruction plus 3 infants with a
      high amount of central apnea represented group I. The remaining 30 infants
      represented group II. Marked differences in the sleeping pattern were found when
      the groups of infants were separated. Infants from group I had significantly less
      rapid eye movement (REM) sleep than infants from group II. We conclude that sleep
      disordered breathing in infants is associated with disruptions in sleep.

PMID- 8650462
TI  - Influence of locus of control on mood state disturbance after short-term sleep
      deprivation.
AB  - Twenty-eight healthy university students were classified as having either an
      internal (n = 14) or external (n = 14) locus of control. Before and after 26-30
      hours of sleep deprivation, their mood state was evaluated using the Profile of
      Mood States questionnaire. There was a significant sleep status x locus of
      control interaction effect on mood state disturbance (p = 0.049). In the
      individuals with an external locus of control, there was an increase (p < 0.001)
      in total mood disturbance from (mean +/- standard deviation) 115 +/- 23 during
      baseline testing to 148 +/- 22 after sleep loss (effect size = 1.4). Sleep loss
      did not significantly affect total mood disturbance in the subjects with an
      internal locus of control (115 +/- 26 vs. 128 +/- 34). These results suggest that
      locus of control is a factor that influences the degree of mood state disturbance
      caused by short-term sleep deprivation.

PMID- 8650463
TI  - The impact of missile warfare on self-reported sleep quality. Part 1.
AB  - During the 1991 Gulf War, we investigated the effect of missile attacks through
      two telephone surveys of a large sample of an urban population that evaluated
      self-reported sleep quality, stress, fear, depressed mood, fatigue and power of
      concentration. We surveyed 1,045 people during the Gulf War itself, and we
      interviewed them again (excluding the chronic insomniacs) 30 days after the war.
      During the war, 51% of the subjects claimed to be suffering from disturbed sleep.
      Whereas 13% of the survey population had been chronic insomniacs before the war,
      38% developed insomnia during the war. The war provoked reported stress (67.5% of
      subjects), depressed mood (50.9%), difficulties in concentration (39.7%) and
      increased fatigue (25%). Four weeks after it ended, 19% of the previously normal
      subjects were still suffering from insomnia; 5% of the cases of insomnia were
      developed postbellum. Stress, depressed mood and impaired concentration were
      found to correlate significantly with subjectively evaluated insomnia. We
      concluded that modern missile warfare may induce long-lasting insomnia in one
      third of the population under threat. A small percentage may develop insomnia
      postbellum. The risk of developing long-lasting insomnia is higher in those who
      reported experiencing prolonged stress and depressed moods.

PMID- 8650464
TI  - Randomized, double-blind, placebo-controlled study of clonidine in restless legs
      syndrome.
AB  - Ten patients with idiopathic restless leg syndrome (RLS) were asked to rate their
      symptoms at baseline during 2 weeks of placebo and 2 weeks of clonidine treatment
      by using a four-point scale. On two consecutive nights each treatment period,
      polysomnography (PSG) and actigraphic studies were performed. Patients
      subjectively reported improvement in leg sensations (p = 0.02) and motor
      restlessness (p = 0.001) while receiving clonidine (mean = 0.05 mg/day). On PSG
      testing, sleep onset occurred faster with clonidine (12 minutes) compared with
      placebo (30 minutes) and baseline (47 minutes) (p = 0.006). Adverse findings
      associated with clonidine treatment included decreased percent REM sleep in the
      clonidine group (4%) compared with placebo (16%) and baseline (16%) (p = 0.001)
      and increased REM latency in the clonidine group (195 minutes) compared to the
      placebo (70 minutes) and baseline groups (89 minutes) (p = 0.028). There were no
      significant changes in total sleep time, stage 1 and 2 sleep, sleep efficiency,
      awakenings, arousals or periodic limb movements in sleep. There was a
      nonstatistical trend toward and increase in stage 3 and 4 sleep and a decrease in
      motor activity as measured by actigraphic recordings. Globally, seven out of 10
      patients felt clonidine was more effective than placebo. Four patients chose to
      continue clonidine after the study. Clonidine may be an effective treatment for
      RLS patients who don't have large numbers of sleep-disrupting periodic limb
      movements but have delayed sleep onset due to leg sensations and subsequent motor
      restlessness.

PMID- 8650465
TI  - Self report on sleep symptoms in older adults: correlates of daytime sleepiness
      and health.
AB  - Sleep problems in the healthy elderly were studied in 628 community-dwelling
      older adults. Self-report of daytime sleepiness in this group was evaluated. Self
      reported snoring was significantly associated with reports of daytime sleepiness
      (p < 0.001), and reported health showed significant associations with age group
      (p < 0.001), reports of breathing problems (p < 0.001), and reports of excessive
      daytime sleepiness (p < 0.01). The data strongly support the impact of sleep
      related factors on self-perceptions of health in community dwelling older adults.
      Even as a subjective self-report measure, snoring readily predicts self-reported
      problems with daytime sleepiness.

PMID- 8650466
TI  - Paradoxical sleep deprivation increases the content of glutamate and glutamine in
      rat cerebral cortex.
AB  - We investigated the influence of the sleep/waking cycle, the effects of
      paradoxical sleep deprivation (PSD) and of the vigilance-promoting drug modafinil
      on the amino acid contents of rat brain cortex. No significant nycthemeral
      variations in amino acid levels could be detected. PSD (12-24 hours), using the
      water tank method, significantly increased the levels of glutamate and glutamine.
      The increase was still observed after the sleep rebound period. gamma
      Aminobutyric acid (GABA) levels did not change significantly during the
      instrumental sleep deprivation but increased during the rebound period. Control
      experiments indicate that the increase in glutamate and glutamine levels is due
      to PSD rather than to the stress associated with the experimental procedure. The
      increase in glutamate content cannot arise only from transamination reactions,
      because the levels of other amino acids (such as aspartate) did not decrease.
      Modafinil treatment did not significantly modify the brain cortex content of any
      of the amino acids tested.

PMID- 8650468
TI  - Spontaneous food choice in narcolepsy.

PMID- 8650467
TI  - Classical conditioning during human NREM sleep and response transfer to
      wakefulness.
AB  - To assess learning abilities during human NREM sleep stages, five subjects
      underwent simple classical conditioning during stages 2-4 using heart rate (HR)
      as a measure. Results show (a) significant conditioning effect was observed
      during slow wave sleep (SWS; stage 3 + 4) but not during stage 2; (b) some
      evidence was obtained to support the view that conditioning effect during sleep
      transferred to wakefulness.

PMID- 8650469
TI  - Bibliography of recent literature in sleep research.

PMID- 8650470
TI  - Chagas' disease: The Brazilian experience.

PMID- 8650471
TI  - Chagas' heart disease. Introduction.

PMID- 8650473
TI  - Pathogenesis of chronic Chagas' myocarditis.
AB  - The pathogenesis of chronic Chagas' myocarditis is still not completely
      understood. Several theories have been advanced: 1) direct tissue destruction by
      Trypanosoma cruzi; 2) neurogenic theory; 3) anti-heart immune reactions; and 4)
      microvascular disease. We present herein a dynamic alternative hypothesis. We
      believe that the development of myocarditis is related to progressive and
      additive focal cellular necrosis, and associated reactive and reparative
      myocardial fibrosis and surrounding myocyte hypertrophy. These processes may be
      initiated and perpetuated by anti immune factors and alterations in the
      myocardial microcirculation. The destruction of the ganglion cells of the heart
      may be involved in the patho-clinical evolution of chronic Chagas' cardiopathy.
      This could imply future therapeutic strategies in the management of chronic
      Chagas' patients to enhance medical treatment and, hopefully, improve prognosis.

PMID- 8650472
TI  - Epidemiology of Chagas' heart disease.
AB  - Chagas' disease is a major public health problem in Latin America. About 16
      million persons are affected and 90 million others are exposed to the risk of
      being infected by the parasite. The knowledge of epidemiological aspects of the
      disease allowed to delineate the strategies for the control of the disease
      related with the vectorial transmission. However, these strategies have had no
      priority in all endemic countries. Rural-urban migration in most endemic areas
      carried infected individuals to urban centers increasing the problem of Chagas'
      disease by blood transfusion. In Brazil the control program has reached good
      results in the last years and in several states the vectorial transmission was
      controlled. More recently, hemotherapic practices are performed using screening
      procedures but this practice must be improved in order to eliminate the
      possibility of Chagas' disease transmission by another ways (congenital,
      accidental, oral, etc.). An adequate health care to the infected persons must be
      improved in order to diminish the social costs of the severe cardiopathy which
      has been responsible for the adults premature deaths.

PMID- 8650474
TI  - Autoimmunity in Chagas' heart disease.
AB  - The time scale dissociation between high parasitemia and tissue pathology, allied
      to the absence of parasites in the heart lesions of chronic Chagas' disease
      cardiopathy, casted doubt on the direct participation of Trypanosoma cruzi in
      tissue lesions. Moreover, the heart tissue lesions in chronic Chagas' disease
      cardiopathy are associated to an inflammatory mononuclear cell infiltrate,
      presumably the ultimate effectors of tissue damage. It has been hypothesized that
      the inflammatory cell infiltrate could mediate a delayed hypersensitivity process
      directed to the heart tissue components, an autoimmune response triggered by
      immunological cross-reactivity in the course of a protective immune response
      against some T. cruzi antigen homologous to heart proteins. However, little is
      known about the effector role of the T cells in the infiltrate, or about the
      nature of the antigen that lead to their accumulation in tissue. In this paper,
      we will review the published evidence on autoimmunity and immunological cross
      reactivity between T. cruzi and the mammalian host, along with data generated in
      our laboratory. The definition of the precise role played by autoimmunity in the
      pathogenesis of Chagas' disease cardiopathy may have important consequences both
      for immunoprophylaxis and for the therapeutic approach of chronic Chagas'
      disease.

PMID- 8650476
TI  - Functional alterations of the autonomic nervous system in Chagas' heart disease.
AB  - Several independent pathological studies in experimental models and in human
      beings showed conspicuous autonomic denervation in Chagas' disease. In spite of
      the inherently complex structural organization of the autonomic nervous system,
      the parasympathetic and sympathetic divisions are involved, as shown by many
      functional studies. Hence, Chagas' disease represents a unique model of
      impairment of the autonomic control of the heart, in absence of the nonspecific
      effects of cardiac failure. An improvement limitation of the studies thus far
      carried out is the lack of a better knowledge of the molecular biology
      characteristics of different strains of T. cruzi. This could explain some
      geographical discrepancies found in the clinical behaviour of Chagas' disease,
      and contribute to a better understanding of its pathophysiology.

PMID- 8650475
TI  - Laboratory diagnosis of Chagas' heart disease.
AB  - The laboratory diagnosis of Chagas' disease is a complex one. Factors relating to
      the host immune response and the antigenic variability of T. cruzi must be
      considered in the final interpretation of tests results. Parasitologic methods
      for detecting T. cruzi, immunologic methods for detecting T. cruzi antigens in
      different biological fluids and serologic tests for detection and quantification
      of different classes of immunoglobulins are well standardized and used in the
      diagnosis of the acute or chronic phase of the disease. Xenodiagnosis is the most
      common parasitologic test employed, although it detects only 50% of infections in
      the chronic phase. Indirect immunofluorescence for detecting IgG and IgM
      antibodies, hemagglutination and enzyme immunoassay are the serologic tests most
      frequently employed for diagnosis, to screen blood donors and for
      seroepidemiologic studies. An important caveat to be remembered is that serologic
      tests provide only a probable diagnosis, which depends on the prevalence of
      Chagas disease, as well as on the sensitivity and specificity of the test
      employed. The use of well defined specific antigens, obtained through recombinant
      methods or chromatography, opens an important field for the development of very
      specific tests, without significant loss of sensitivity.

PMID- 8650477
TI  - The apical ventricular lesion in Chagas' heart disease.
AB  - Apical lesions of the left ventricle, ranging from endocardial thickening to
      aneurysms, are commonly found in Chagas' heart disease. These abnormalities can
      be identified by ventriculography, two-dimensional echocardiography and
      radioisotopic studies. Generally, clinical manifestations are limited to
      arrhythmias and thromboembolic. The lesions are usually small and apparently do
      not play a role in ventricular dysfunction.

PMID- 8650478
TI  - Natural history of chronic Chagas' heart disease: prognosis factors.
AB  - Chronic Chagas' disease shows several progression modes. Usually, the different
      clinical syndromes manifest themselves together, however, isolated forms can
      occur. Cardiac arrhythmias, which are very frequent, are present in about 50% of
      patients. The cardiac damage manifests itself later, with the emergence of heart
      failure. Thromboembolism can occur in both pulmonary and systemic circulation.
      Pulmonary embolism is the most frequent, appearing in more advanced phases of
      heart disease. Sudden death is the fatal outcome of these patients. It
      predominates in males and generally occurs in a disease stage when patients have
      their highest productivity. The presence of serious ventricular arrhythmias,
      conduction disturbances in the electrocardiogram, and heart failure, provide an
      unfavorable prognosis.

PMID- 8650479
TI  - The undetermined form of Chagas' heart disease: concept and forensic
      implications.
AB  - The undetermined form of Chagas' disease is diagnosed in asymptomatic subjects
      with a positive blood test for Chagas' disease, normal resting electrocardiogram,
      chest X-ray, barium esophageal and large bowel radiological studies. Other
      investigation methods are not recommended for identification of other organs
      damage lesions in this phase of the disease. When other methods of investigation
      were employed, cardiac and digestive abnormalities of small magnitude were
      detected without prognostic implications. These findings do not warrant frequent
      examinations of patients with undetermined form of the disease except for the
      electrocardiogram or if the patients report other clinical manifestations. The
      benign course of the disease does not preclude ability to work and the subjects
      should be considered apt for work in any profession.

PMID- 8650480
TI  - Electrocardiography in Chagas' heart disease.
AB  - Conventional ECG still plays an important role in the overall knowledge of
      Chagas' cardiopathy, because of its importance in longitudinal and
      epidemiological studies, its diagnostic value, and its utility in prognostic
      evaluation. The authors discuss these aspects, as well as the use of eCG in the
      acute phase and the significance of a normal ECG in Chagas' disease. Correlations
      were made between ECG and Hemodynamic/angiographic variables among 1010 patients
      with positive laboratory tests for Chagas' disease: a) in the group with normal
      ECG there was no significant differences between symptomatic and non-symptomatic
      patients with regard to ejection fraction and angiographic abnormalities; b)
      slight abnormalities on the ECG corresponded to an intermediate level of severity
      of the disease, that is, between normal ECG and ECG with significant
      abnormalities C) fibrosis on the ECG was not predictive of akinesia in the
      related area on the angiography; d) combined ECG abnormalities generally
      correlated with greater myocardial compromises compared to isolated
      abnormalities; e) under multiple regression analysis the ECG abnormalities that
      independently correlated with depressed ejection fraction were: premature
      ventricular beats, ventricular tachycardia, left bundle branch block, atrial
      fibrillation, complete AV block, and anterior and inferior fibrosis. Male sex,
      cardiac insufficiency and cardiomegaly on the throat radiography were also
      significantly related.

PMID- 8650481
TI  - Ventricular function in Chagas' heart disease.
AB  - Invasive and noninvasive methods used to evaluate ventricular function in
      Chagas's disease are reviewed. The traditional indices of overall ventricular
      performance reflect the interaction of preload, contractility, afterload and
      heart rate. Therefore, they are unable to distinguish changes in contractility
      from modifications of loading conditions. The role of ventricular function as a
      predictor of mortality in chronic Chagas' heart disease is discussed. Ventricular
      function abnormalities in patients with indeterminate and digestive forms of
      Chagas' disease are especially emphasized. Finally, the evidence of early
      impairment of diastolic performance in digestive forms of Chagas' disease are
      especially emphasized. Finally, the evidence of early impairment of diastolic
      performance in patients with Chagas' disease is presented.

PMID- 8650482
TI  - Endomyocardial biopsy in Chagas' heart disease: pathogenetic contributions.
AB  - Endomyocardial biopsy procedure has been performed in many centers around the
      world, allowing a better treatment and follow-up of the patients with myocardial
      disease. In Chagas' disease, it has been performed in Sao Paulo Heart Institute
      since 1978 and has brought important contributions to the understanding of the
      disease and consequently of the patient's clinical stage. In the present work, we
      summarize the principal findings regarding the pathogenesis of Chagas' disease
      obtained mainly from the studies using endomyocardial biopsy specimens. Nowadays
      we do not have doubts that the inflammatory infiltrate aggressing myocardial
      fibers has fundamental role in the progression of the myocardial damage in
      Chagas' disease what culminates in chronic heart failure. The parasite seems to
      have active participation in the maintenance of such myocardial inflammation.

PMID- 8650483
TI  - Studies of the coronary circulation in Chagas' heart disease.
AB  - Pathogenesis of chronic Chagas' heart disease may include various disturbances in
      the coronary circulation, that could be responsible for the myocardial lesions
      seen in human hearts and in experimental models of the disease. In this paper we
      critically reviewed the anatomical and functional abnormalities described in
      chronic chagasic patients, pertaining to the so-called vascular pathogenetic
      theory of Chagas' disease. The epicardial coronary arteries are usually free of
      significant obstructive disease in nonselected groups of chagasic patients
      examined at autopsy or by coronary angiography. However, chagasic patients who
      were studied after an episode of acute myocardial infarction, show the same
      patterns of atherosclerotic coronary artery disease seen in the general
      nonchagasic population. Studies of chagasic patients with angiographically normal
      coronary arteries, by several scintigraphy methods, revealed myocardial perfusion
      abnormalities which may be caused by the microcirculatory derangements described
      in animals experimentally infected with the T. cruzi. Since hypoperfusion has
      been detected in regions with normal or mildly impaired wall motion, it is likely
      that the microvascular disturbances precede and may be causative mechanism for
      the subsequent myocardial damage. We speculate that hibernating ventricular areas
      may occur in chagasic patients, on the basis of the evidence gathered from these
      studies. Recent investigations of chronic patients with Chagas' disease and chest
      pain showed attenuation of the vasomotor responses to physiological and
      pharmacological stimuli, in the epicardial coronary arteries.

PMID- 8650484
TI  - Holter monitoring in Chagas' heart disease.
AB  - Electrocardiographic rhythm disturbance evaluation by Holter monitoring is
      increasingly becoming a useful methodologic tool for risk stratification as well
      as for therapeutic assessment in patients with Chagas' disease. Furthermore, late
      potential analyses, now being directly obtained from Holter recording has
      promising perspectives in enhancing identification of patients with high risk
      profiles for development of malignant ventricular arrhythmias. In addition,
      recently incorporated to Holter studies, heart rate variability analysis will
      certainly contribute to a better understanding of the characteristic autonomic
      nervous system disarray that commonly affects chagasic patients.

PMID- 8650485
TI  - Electrophysiologic study in chronic Chagas' heart disease.
AB  - Cardiac arrhythmias are common in chagasic patients. Electrophysiologic study is
      an invasive procedure for the investigation of sinus node function,
      atrioventricular node conduction and intraventricular (His-Purkinje) conduction
      and the mechanism of tachycardias. It is useful in elucidating syncope, dizziness
      and tachycardiac palpitations that remain unexplained by non-invasive diagnostic
      methods. It is fundamental in directing non-pharmacological therapy, especially
      in "sudden death" survivors. Chagasic patients may benefit from
      electrophysiologic study after a critical clinical evaluation.

PMID- 8650486
TI  - Signal-averaged electrocardiogram in chronic Chagas' heart disease.
AB  - The aim of the study was to register the prevalence of late potentials (LP) in
      patients with chronic Chagas' heart disease (CCD) and the relationship with
      sustained ventricular tachycardia (SVT). 192 patients (96 males), mean age 42.9
      years, with CCD were studied through a Signal Averaged ECG using time domain
      analysis. According to presence or absence of bundle branch block (BBB) and SVT,
      four groups of patients were created: Group I (n = 72): without SVT (VT-) and
      without BBB (BBB-): Group II (n = 27): with SVT (VT+) and BBB-; Group III (n =
      63): VT- and with BBB (BBB+); and Group IV (N = 30): VT+ and BBB+. The LP was
      admitted, with 40 Hz filter, in the groups without BBB using standard criteria of
      the method. In the group with BBB, the root-mean-square amplitude of the last 40
      ms (RMS) < = 14 microV was considered as an indicator of LP. RESULTS: In groups I
      and II, LP was present in 21 (78%) of the patients with SVT and in 22 (31%) of
      the patients with SVT (p < 0.001), with Sensitivity (S) 78%; Specificity (SP) 70%
      and Accuracy (Ac) 72%. LP was present in 30 (48%) of the patients without and 20
      (67%) of the patients with SVT, in groups III and IV. p = 0.066, with S = 66%; SP
      = 52%; and Ac = 57%. In the follow-up, there were 4 deaths unrelated to
      arrhythmic events, all of them did not have LP. Eight (29.6%) of the patients
      from group II and 4 (13%) from group IV presented recurrence of SVT and 91.6% of
      these patients had LP. CONCLUSIONS: LP occurred in 77.7% of patients with SVT and
      without BBB. In the groups with BBB, there was association of LP with SVT in
      66.6% of the cases. The recurrence of SVT was patient in 21% of the cases from
      which 91.6% had LP.

PMID- 8650487
TI  - Medical treatment of cardiac arrhythmias in Chagas' heart disease.
AB  - There are no controlled clinical trials evaluating drug therapy in patients with
      ventricular arrhythmias and chronic chagasic cardiomyopathy. Empirical treatment
      with disopyramide (400-1, 1,000mg/d), phenytoin (4-6mg/d), mexiletine 600
      1,200mg/d), propafenone (900mg/d), amiodarone (loading: 1,000mg/d, 10-14 days;
      maintenance 200-600mg/d), and sotalol (320mg/d) had efficacy and tolerance
      ranging from 18% to 90% with heterogeneous criteria for efficacy definition.
      Further studies with homogenous criteria are required to determine which is most
      appropriate drug therapy for patients with chronic chagasic cardiomyopathy and
      ventricular arrhythmias.

PMID- 8650488
TI  - Thromboembolism in chronic Chagas' heart disease.
AB  - Thromboembolic episodes are particularly important in chronic Chagas' heart
      disease. Systemic and pulmonary embolic phenomena are important complications of
      the disease. Prophylaxis of the thromboembolic phenomena with anticoagulant
      therapy should be considered in several clinical forms of the disease. Further
      studies will have to address the stratification risk issue.

PMID- 8650489
TI  - Ethiologic treatment of acute and chronic Chagas' Disease [corrected].
AB  - The uncertainties in the ethiological treatment of Chagas' Disease are
      consequence of the lack of entire knowledge of its pathogeny and the no existence
      of a healing criterium. There is a consensus that antiparasite drugs should be in
      the acute phase of the infection, regardless of the infection route, in new
      crisis, in patients under immunosuppression and in organs transplantation. There
      is still controversy regarding subacute, chronic or indetermined phase or cases
      with mild cardia/digestive forms, not included in the situations listed above
      neither in a research protocol. The treatment includes oral benzonidazol 5
      mg/kg/dat, bid or tid for 60 days. In 71 patients monitored in this fashion, the
      authors have found 60% of negative xenodiagnostic at the end of treatment It is
      still necessary, however, to continue to investigate and accomplishing more
      randomized trials to confirm the efficacy of such method, and also to try to
      obtain effective and less toxic agents. It is also fundamental to standardize a
      more reliable healing criterium.

PMID- 8650490
TI  - Heart transplants for patients with Chagas' heart disease.
AB  - The role of heart transplants for treating Chagas' heart disease is not quite
      clear. Immunosuppression could lead to resurgence of T. cruzi infection with
      acute or chronic damage to the allograft. There are few publications regarding
      this issue. Thus we reported the follow-up of 18-patients with Chagas' heart
      disease submitted to orthotopic heart transplants from 1985 to 1993 at The Heart
      Institute. The patients were in functional class IV or II, with sustained
      ventricular tachycardia episodes. The mean left ventricular ejection fraction was
      25 +/- 9% and the mean right ventricular ejection was 22 +/- 5% (MUGA).
      Immunosuppression was based on cyclosporin, azathioprine and corticosteroid. For
      specific post-transplant monitoring of T. cruzi infection, blood tests were
      performed (examination of blood or leukocyte concentrate, Giemsa-stained blood
      smears, blood culture, xenodiagnosis, mouse inoculation) and tissue biopsy (skin
      or myocardium). In addition, complement fixation hemagglutination and
      immunofluorescence assays were performed. T. cruzi parasitemias were detected in
      18 circumstances in 13 patients. Resurgence of Chagas' disease was diagnosed in
      11 circumstances in 5 patients. Fever, subcutaneous nodules and myocarditis
      predominated in these episodes. All episodes of parasitemia and Chagas' disease
      resurgence were successfully treated with benzonidazole. Al surviving patients
      had normal cardia function despite left ventricular function worsening during
      some myocarditis episodes. Neoplasias were important findings and 3 patients
      developed lymphoproliferative disease, 2 developed Karposi's sarcoma and 1
      patient developed skin cancer. The survival rates of 4 and 12 months were 83% and
      49% respectively. The survival of patients who underwent heart transplants from
      August 1991 to April 1993 was 100% at 4 months and 75% at 12 months. Heart
      transplants for Chagas' heart disease may be associated with episodes of
      parasitemia and a reoccurrence of episodes of Chaga's disease. The survival of
      heart transplanted patients has improved when associated with lower doses of
      cyclosporins and thus, fewer resurgences of the disease.

PMID- 8650491
TI  - Magnetic resonance imaging in Chagas' heart disease.
AB  - Many important aspects of Chagas' heart disease can be successfully assessed
      using magnetic resonance imaging of the heart. It is possible to obtain with
      great detail the anatomic characterization of the cardiac as well as important
      information of the functional or metabolic status of the heart. Magnetic
      resonance imaging after gadolinium infusion seems also a promising technique to
      obtain a better regional characterization of myocardial tissue, and may be
      important in the non-invasive diagnosis of active myocarditis in patients with
      Chagas' heart disease.

PMID- 8650492
TI  - [Temporomandibular joint luxation and Ehlers-Danlos disease. Apropos of a case].
AB  - First described by Tschernogobow in 1981, Ehlers-Danlos syndrome is usually
      observed in white males. Symptoms results from defective collagen synthesis.
      Diagnosis is based on clinical presentation. There are 9 different clinical
      groups. Maxillofacial manifestations are usually seen in type VIII Ehlers-Danlos
      syndrome. The clinical case presented here illustrates the problems involving the
      temporomandibular joints and focuses on an assessment of proposed therapeutic
      options.

PMID- 8650494
TI  - [Aneurysmal bone cyst of the mandible. Apropos of a case and review of the
      literature].
AB  - Aneurysmal bone cyst is a benign lesion, rarely found in the craniofacial region
      and exceptionally in the mandible. One previously unreported case originally in
      the mandible is presented with a review of the literature. The authors insist on
      pathological diagnostic and therapeutic characteristics.

PMID- 8650493
TI  - [False Merkel cell tumor of the gingival mucosa disclosed by small cell bronchial
      carcinoma].
AB  - Merkel cell tumours are exceptional and usually occur in exposed areas of the
      face or limbs. These tumours are related to small-cell bronchogenic cancer. The
      case reported here demonstrates the relationship between these two cancers since
      the diagnosis of Merkel cell tumour of the gingival mucosa, initially made in a
      patient with no other presenting signs other than the stomatological lesions, was
      corrected six weeks later when the buccal lesion was found to be a metastasis of
      small-cell bronchogenic cancer. This observation is in agreement with the
      retrospective study reported by the Institute of Stomatology of the Salpetriere
      hospital published in 1992 and presented at the XXIVth congress of the French
      Society of Cervicofacial Cancerology.

PMID- 8650495
TI  - [Class II dento-skeletal dysmorphism. Observations apropos of orthodontic
      surgical treatment].
AB  - The Classe II maxillofacial deformities are common, varied in their expression
      and most frequently have both dental and skeletal components. For this reason,
      combined orthodontic-surgical treatment is well suited to correction of problems
      from which the patient suffers. Several clinical deductions are presented which
      pertain to diagnosis and treatment of Class II vertical excess deformities.

PMID- 8650497
TI  - [Interposition of a full-thickness skin graft in the surgery of temporomandibular
      joint ankylosis. A study of 31 cases of which 20 had long-term follow-up].
AB  - Recurrence is the main problem in temporo-mandibular joint ankylosis treatment.
      Two therapy are used against this, physiotherapy and surgical joint
      interposition. Following ankylosis removal, many materials can be interposed but,
      for us, fullthickness skin graft using Popescu and Vasiliu technique seems to be
      the best and simplest one. This retrospective study of 31 cases, 20 with long
      term follow-up, shows that good results are obtained using this skin graft, with
      90% successful rate.

PMID- 8650496
TI  - [Tooth mobility disclosing an osteolytic process].
AB  - Excepting cases of trauma, dental mobility is often mistakenly neglected as a
      clinical sign. Dental mobility can in fact be the first sign of osteolytic
      processes or tumour development. A retrospective study noted that dental mobility
      may be the inaugural sign of osteolytic processes in the maxillary bone in up to
      as many as 40% of the cases. Pyorrhea+ is often misdiagnosed leading to
      unnecessary avulsion and delaying diagnosis of the osteolytic disease.

PMID- 8650499
TI  - [Lesions of the inferior alveolar nerve during extraction of the wisdom teeth.
      Consequences--prevention].
AB  - Neurological consequences of extractions of the third inferior molar can be
      severe. Progress in imaging techniques has made it possible to identify molars <<
      at risk >>. Extraction by wear without removal of the apex is proposed as a means
      of avoiding damage to the alveolar nerve. If no surgical prophylaxy is used the
      risk is major sequellae: painful anaesthesia of the area involved. There is no
      really effective treatment for such sequellae, creating persistent psychological
      problems throughout life.

PMID- 8650498
TI  - [The Bichat ball. The surgical value of oro-sinus communications].
AB  - Bichat's ball is a mass of adipose tissue used to fill communications between the
      buccal cavity and the sinus. The anatomy of the structure is presented. it has a
      body and 6 extensions. A surgical technique is proposed in comparison with
      previously described methods. At 6 weeks, there has been no recurrence of buccal
      sinus communication in a series of approximately 300 cases operated over a period
      of 15 years.

PMID- 8650500
TI  - [Removal through the coronal approach of the upper wisdom teeth. Apropos of a
      case of bilateral migration into the temporal fossa].
AB  - This report presents a case of double migration of third maxillary molar in
      temporal fossa and their removal by a coronal approach. A 15 years of old boy,
      was seen for major trismus. 2 months before, he underwent under general
      anaesthesy impacted third maxillary molar removal. The radiologic examination
      showed that superior third molar has been pushed and left into the temporal fossa
      in both sides. After computed tomography examination, teeth were removed by a
      coronal approach. This was the only approach in order to preserve facial nerve
      and to allow with good chances to remove the teeth. Intervention was successful.
      Postoperative course was uneventful. The buccal apperture was normalized three
      months after surgery.

PMID- 8650501
TI  - [A therapeutic approach using dental implants in an irradiated area. The
      experiences of the Rene Huguenin Center].
AB  - A therapeutic trial was conducted with six patients who were in remission after
      cancer therapy for at least two years. Twenty-four implants were performed in
      irradiated maxillary bone after local and general paraimplantation preparation
      using adjuvant hyperbaric oxygenotherapy. All implants integrated the bone within
      a minimal delay of nine months. All patients were fitted with a removable dental
      prosthesis which was anchored magnetically or with implant conjunction bars.
      Despite the limited number of implants and the short observation period, the
      results have been promising, in agreement with previous reports. These findings
      emphasize the importance of adjuvant hyperbaric oxygenotherapy and the need for
      good conditions in paraimplantation tissue. Although this technique demonstrates
      that dental implantation in irradiated tissue is possible, the risk of secondary
      failure has not been determined. In strictly selected cancer patients with
      reasonably healthy irradiated tissue, implantation can be proposed by a fully
      multidisciplinary team of specialists.

PMID- 8650502
TI  - International policies for rehabilitation of persons with disabilities.

PMID- 8650503
TI  - Restoration of gait by combined treadmill training and multichannel electrical
      stimulation in non-ambulatory hemiparetic patients.
AB  - Functional electrical stimulation and treadmill training with partial body weight
      support through suspension by a parachute harness were combined for gait
      restoration in 11 chronic non-ambulatory hemiparetic patients. Individually
      adjusted multichannel stimulation of the trunk and of upper and lower limb
      muscles, as well as a motor driven treadmill, induced functional gait within 3 to
      6 weeks. The improvement of gait ability was assessed by the Functional
      Ambulation Category test. Other motor functions were rated by the Rivermead Motor
      Score. The leg muscle strength, stride length, cadence, gait velocity and gait
      pattern were recorded. In seven of the patients, we did a single case research A
      B-A study that showed that this combined approach had advantages, in regard to
      gait restoration and walking velocity (p <0.05) as compared with our common
      physiotherapeutic programme.

PMID- 8650504
TI  - Gait abnormality is not the only motor disturbance in normal pressure
      hydrocephalus.
AB  - Thirteen different motor and balance functions were examined in 76 patients age
      65 +/- 13 (mean +/- SD) years with normal pressure hydrocephalus (NPH) before and
      3 months after a ventriculoperitoneal shunt operation. Preoperatively, the tests
      were performed before and after lumbar tap of 50 cc cerebrospinal fluid. The
      patients showed significant improvement in all thirteen functions at the 3-month
      examination. The improvement was approximately 25% in all the motor functions,
      except for balance, in which the improvement was even more striking. Different
      etiological subgroups of NPH patients, including the idiopathic form, exhibited
      the same degree of improvement. The improvement after the lumbar tap was
      significant in all functions except one-legged stance, and amounted to
      approximately 30% of the improvement seen after the shunt operation. Our results
      clearly show that the impairment in motor functions in NHP patients is general,
      involving many motor activities performed in daily life, and is not restricted
      solely to the gait.

PMID- 8650505
TI  - Description and validation of a test of motor function and activities in stroke
      patients. The Sodring Motor Evaluation of Stroke Patients.
AB  - A new method (The Sodring Motor Evaluation of Stroke Patients) has been developed
      for physiotherapists to evaluate motor function and activities in stroke
      patients. Its main characteristics are the assessment of motor activity without
      assisting the patient, and the use of a rating which reflects quantity as well as
      quality in motor performance. A hospitalised group of stroke patients (n = 93)
      was assessed three times after the acute event, by means of SMES. The data were
      analysed regarding construct validity as well as concurrent validity against
      another assessment method. Factor analyses showed a reasonably stable three
      factor pattern ("arm", "gross motor function", and "leg") which explained 84, 89
      and 90%, respectively, of the variance at the three study points, with Factor 1
      ("arm") as the dominant factor. The ordinality of the rating scale was assessed
      by means of linear regression analysis and found to be acceptable. The
      correlation coefficients were high between comparable parts of the new and the
      reference methods.

PMID- 8650506
TI  - Knee extensor and flexor strength in elderly women after recent hip fracture:
      assessment by the Cybex 6000 dynamometer of intra-rater inter-test reliability.
AB  - The reliability of knee extensor and flexor strength measurements was assessed in
      20 women (aged 68-88 years) who had experienced a hip fracture two to four weeks
      before but who were otherwise healthy. Using the Cybex 6000 isokinetic
      dynamometer, isokinetic knee extensor and flexor strength (peak torque, total
      work and power) at 30 and 120 degree/second and isometric knee extensor and
      flexor strength (peak torque) were measured by the same examiner in both legs,
      successively, on four separate days within one week. Compared with the non
      involved leg, the median reduction in peak extensor and flexor torque of the
      involved leg was 50% (p <0.001). With the protocol used, no significant change in
      muscle strength occurred during the test period Individual coefficients of
      variation (CVs) were calculated for each muscle strength variable. Depending on
      whether torque, work or power were measured, the median CVs of extensor and
      flexor strength measurements of the non-involved leg ranged from 5.6-14.6% and
      10.8-28.6%, respectively. The corresponding CVs for the involved leg were 10.9
      22.1% and 13.0-35.2%. Substantial variability between individual CVs were found
      for all strength variables. In conclusion, although muscle strength measurements
      may be applicable when comparing larger groups of hip fracture patients, the
      large CVs may be a limitation in monitoring individual patients. This finding
      should be taken into consideration when planning individual training programmes.

PMID- 8650507
TI  - Rehabilitation of hip fracture patients with Parkinson's Disease.
AB  - The incidence of hip fractures has increased over the past decades, and for
      patients with hip fractures, medical and social conditions have deteriorated
      during the same time. In this study the results of orthopaedic rehabilitation of
      patients with Parkinson's disease and a hip fracture are compared with those in
      all other hip fracture patients. A total of 74 patients with Parkinson's disease
      and hip fracture were compared with 1,361 patients without the disease. Prior to
      fracture, patients with Parkinson's disease were less likely to be living an
      independent life in their own homes. Postoperatively women with Parkinson's
      disease were hospitalized for a significantly longer period. Postoperative
      rehabilitation was significantly slower and less successful than among patients
      without the disease. Patients with Parkinson's disease comprise a subgroup of hip
      fracture patients who need more rehabilitation resources than can easily be
      provided at an ordinary orthopaedic ward. A team-work between an orthopaedic
      surgeon, a neurologist and a rehabilitation unit seems to be mandatory in order
      to achieve shorter hospitalization and earlier return to the pre-fracture
      environment.

PMID- 8650508
TI  - Functional balance tests in 76-year-olds in relation to performance, activities
      of daily living and platform tests.
AB  - Functional balance was studied in a sample of 98 women and 75 men from a
      population study. Tests used were one-legged stance and walking in a figure of
      eight. The results revealed that both static and dynamic functional balance were
      significantly correlated to isometric knee extensor strength, walking speed and
      stair-climbing capacity, while the association with activities of daily living
      (ADL) was modest in this sample of relatively healthy elderly persons. A sub
      sample of 17 women and 10 men also performed balance tests on a force plate.
      Velocity of the sway path with both open and closed eyes was significantly
      correlated to the functional balance tests. Mean sway in the anterior-posterior
      direction and area tested with closed eyes were significantly correlated to the
      functional static balance test. There were no significant associations between
      the platform variables and the results in the performance tests. This study
      demonstrated differences between the sexes in that males were able to stand for a
      longer time on one leg, while they swayed more than females on the platform.

PMID- 8650509
TI  - The effect of pain reduction on perceived tension and EMG-recorded trapezius
      muscle activity in workers with shoulder and neck pain.
AB  - The study was initiated to evaluate the effect of pain-reducing therapies on
      factors previously associated with work-related shoulder and neck pain, namely
      increased muscle activity in the upper trapezius and perceived general tension.
      Thirty-three women in three groups were assessed before and after an intervention
      period and by questionnaire 6 months later. The purpose of this study was
      primarily to investigate associations between upper trapezius muscle activity,
      perceived general tension and pain, and secondly, to compare effects of
      individually based physiotherapy and group exercise for workers with shoulder and
      neck myalgia. All three groups reported a significant alleviation of pain and
      perceived general tension, while the electromyographically (EMG) recorded upper
      trapezius muscle activity level remained unchanged or increased. Improvements
      were similar in all three treatment groups, but individual-based therapies were
      rated more beneficial on subjective measures. Significant correlation was found
      between pain and perceived general tension (r = 0.66, p <0.01), while there was
      no correlation between pain or perceived general tension and recorded muscle
      activity.

PMID- 8650510
TI  - Interrater reliability of the 7-level functional independence measure (FIM)

PMID- 8650511
TI  - [Ambulatory follow-up in oral anticoagulation: recommendations for clinical
      practice].
AB  - The aim of this investigation performed in 75 outpatients taking oral
      anticoagulant after an episode of pulmonary embolism was to specify the
      modalities of ambulatory monitoring during oral anticoagulation. All patients
      were followed up by their family doctor after hospital discharge. The principal
      results of this investigation were (1) the general difficulty of obtaining and
      maintaining anticoagulation stability in a recommended therapeutic range (INR 2
      3) for venous thromboembolic disease, (2) that in only 15% of personal
      anticoagulation notebooks were the laboratory results expressed in INR, (3) the
      lack of information given to the patients taking oral anticoagulant. Based on
      these results we started an education programme for nurses and physicians
      designed to promote the use of INR and to improve the quality of information
      given to anticoagulated patients. A new anticoagulation monitoring notebook
      should help medical staff and patients to increase the safety of anticoagulation.

PMID- 8650512
TI  - [Cerebral insult in heart surgery].
AB  - The aim of the study was to identify causes for perioperative stroke in cardiac
      surgery in order to reduce its occurrence. From 1989 to 1994, 3593 open heart
      operations were performed in adult patients. In 59 patients carotid
      endarterectomy for high grade stenosis was combined with the cardiac operation.
      There were a total of 68 (2%) focal strokes, 41 of which were considered minor
      and 14 major; 13 were lethal. The etiology of the 27 major and lethal events was
      most probably an embolus from the ascending aorta (6), from the ascending aorta
      or a cardiac valve (5), a thrombus in the left heart (6), air (1), cardiac arrest
      and resuscitation (4), cerebral hemorrhage (1), preoperatively unknown but high
      grade internal carotid stenosis (3), and a 50% stenosis of both internal carotid
      arteries preoperatively known but not operated on (1). There were 2 minor but no
      major neurologic complications in patients undergoing a combined carotid and
      cardiac procedure. A wide indication for preoperative neuroangiologic
      examination, echocardiography and careful intraoperative management may help to
      identify sources of possible emboli. Endarterectomy of high grade carotid
      stenosis is recommended simultaneously with the cardiac procedure.

PMID- 8650513
TI  - [Heparin-induced thrombopenia and thrombosis].
AB  - Heparin-induced thrombocytopenia (HIT) with thrombosis is a rare, but important
      complication of heparin therapy. We describe the case of a 53-year-old patient
      hospitalized with complicated pelvic fracture. Intravenous infusion of
      unfractionated heparin (15'000 IU/24 h) was given for thrombosis prevention.
      After 11 days' treatment the patient developed deep venous thrombosis of the left
      calf, complicated 2 days later by massive bilateral pulmonary embolism.
      Simultaneous with these thromboembolic events, thrombocytopenia, signs of
      activated coagulation, and antibodies to heparin occurred. In the context of this
      case the diagnostic and therapeutic possibilities of HIT, and in particular
      treatment with the heparinoid danaproid (Orgaran), are discussed.

PMID- 8650514
TI  - [Etiology and mechanism in cerebral infarction].
AB  - Cerebrovascular disease is the 3rd leading cause of death and an important cause
      of hospital admission and long-term disability in most industrialized
      populations. Many studies have shown that brain infarct is the most frequent form
      of cerebrovascular disease (83%). Brain infarct is a heterogeneous entity with
      several etiologies (mainly large-artery disease, small-artery disease, cardiac
      embolic disease). Different mechanisms are involved including arterial occlusion,
      thrombosis (atherosclerosis), embolism (from a cardiac or intraarterial source),
      and hemodynamic mechanisms (systemic hypoperfusion). Careful neurological
      assessment (cerebral computed tomogram, magnetic resonance imaging, Doppler
      ultrasound and angiography in selected cases) provides greater precision
      regarding these mechanisms and the choice of treatment.

PMID- 8650515
TI  - [Preoperative axillary ultrasound in breast carcinoma: value of the method in
      routine clinical practice].
AB  - AIM: To evaluate the significance of routinely performed preoperative axillary
      sonography in breast cancer patients. METHOD: 191 patients with surgical treated
      breast cancer were analysed retrospectively. 74 patients of these had an axillary
      sonography done by 5 different examiners. RESULTS: For detecting lymph node
      metastases sensitivity was 68.2% in all T-stages and 50% in T1-stages with a
      specificity of 100%. Classification of the axillary status (positive or negative
      for lymph node metastases) is possible in 90.5% for all T-stages and 94.9% for T1
      stages. Microscopic and small lymph node metastases are missed by ultrasound.
      Compared to axillary palpation, sonography is better. CONCLUSION: Preoperative
      axillary sonography is an useful diagnostic method even when done routinely. If
      further criteria are considered, axillary dissection could be avoided in some
      patients.

PMID- 8650516
TI  - [Evaluating the morphology of uncertain breast tumors using color coded Doppler
      ultrasound].
AB  - AIM: The relationship between tumour vessel density and tumour vitality in breast
      carcinoma has been well established in histopathological studies. Our objective
      was to find out if colour-coded sonography is helpful in the evaluation of
      suspicious breast masses. METHOD: 106 patients were studied; in all cases a
      biopsy was obtained. Peripheral and central blood vessels in a lesion were
      counted and peak systolic velocities (PSV) were measured as well as the resistive
      index (RI). The grade of vascularisation was scored on a scale from I-IV
      indicating an increasing vessel count and increasing PSV. RESULTS: 83% of the
      carcinoma (n = 61) and 45% of the benign lesions (n = 45) showed vascularity
      grade III or IV (hypervascularity). The mean PSV of all carcinomas was 0.23 m/s,
      in benign lesions 0.14 m/s (p < 0.005). Although G3 carcinomas showed higher
      vascularisation than G2 carcinomas, the difference was not statistically
      significant. T3 + 4 tumours had significantly higher PSV than T1 + 2 carcinomas
      (p < 0.01). In 12 of 23 cases with unclear morphology in the B-mode, the
      additional finding of hypervascularity led to the misinterpretation of a benign
      lesion as a carcinoma. CONCLUSION: Although increased vascularity correlated with
      degree of malignancy the finding of hypervascularity did not help to distinguish
      a benign from a malignant lesion in individual cases. Consequently, it did not
      help to reduce the biopsy rate. In benign lesions with hypervascularity and
      borderline morphology, the risk of a false positive diagnosis is high.

PMID- 8650517
TI  - [A review of epidemiologic studies on ultrasound during pregnancy].
AB  - This article reviews most of the more recent epidemiological studies on the
      effectiveness and possible risks of conventional sonography. With the help of
      such a review, case reports, very often cited out of context, can be better
      evaluated. Publications which have attempted to study the number of
      malformations, diagnosable by ultrasound, and to the effect of ultrasound on
      postnatal mortality and morbidity are scrutinized. Furthermore the question of
      possible late effects of ultrasound is addressed, such as effects on birth
      weight, neural development and cancer incidence. Routine sonography is of great
      value; no negative late effects on the child have been found. The effectiveness
      and risks of Doppler flow ultrasound have not been studied sufficiently well to
      allow a similar conclusion.

PMID- 8650518
TI  - [Morphometric findings of the healthy pediatric gallbladder in ultrasound].
AB  - AIM: Ultrasonographic determination of gallbladder wall thickness, volume and
      excretion in children. METHOD: In 76 children (1-16 years) we determined the
      volume of the fasting and stimulated gallbladder by the ellipsoid formula (length
      X width X depth X 0.523). We also measured the gallbladder wall thickness.
      Stimulation was performed with a standardised breakfast. RESULTS: We always
      measured the gallbladder wall thickness 3 mm or less and did not find a
      difference between fasting and stimulation. There was no correlation between
      gallbladder wall thickness and status of contraction. The healthy gallbladder
      should excrete at least 25% of the fasting volume within 1 hour. CONCLUSION:
      Ultrasound is a suitable method to determine the excretion of the gallbladder. In
      children standardised meals can be used as stimulus instead of commercial
      stimulating meals.

PMID- 8650519
TI  - [Diagnosis of a retroperitoneal BCG abscess in an infant. Case report and review
      of the literature].
AB  - We report on a Tunesian boy who was 1 year and 9 months of age and suffered from
      a large retroperitoneal Bacillus Calmette-Guerin (BCG) abscess. We specially
      emphasise the accurate diagnosis achieved by the interpretation of the
      sonographic results in association with the patient's anamnesis. The outcome of
      abdominal x-ray and contrast-enhanced CT is outlined. The diagnostic approach as
      well as the disease are described with reference to the literature.

PMID- 8650520
TI  - [Value of ultrasound in diagnosis of celiac disease].
AB  - AIM: To evaluate the potential benefits of sonographic assessment in the
      diagnostic work-up of children suspected of having coeliac disease. METHOD: 39
      infants with biopsy-proven coeliac disease were evaluated by sonographic
      assessment. Ten of them had presented with unusual clinical features such as
      acute abdomen and underwent sonography as the first diagnostic procedure.
      RESULTS: Various sonographic anomalies were observed: abdominal fluid in 76%,
      hyperperistalsis in 82%, pericardial effusion in 47% and unusual appearance of
      the small bowel wall in 94%. CONCLUSION: Although sonography cannot replace
      intestinal biopsy, awareness of the sonographic anomalies associated with coeliac
      disease in children can lead to a quicker diagnosis and prompt introduction of
      adequate therapy. It should be performed as a part of the diagnostic workup in
      infants who fail to thrive.

PMID- 8650521
TI  - [Prenatal diagnosis of Bourneville-Pringle disease (cerebral tuberous
      sclerosis)].
AB  - An infant presented with prenatal marked fetal cardiac arrhythmia, not related to
      labour, and had intracardiac tumours. The association of cardiac tumours with
      tuberous sclerosis (Bourneville-Pringle disease) is described, using ultrasonic,
      radiological and electrocardiographic data, and reviewing the literature.

PMID- 8650522
TI  - [Recommendations by the Urogynecology Working Group for sonography of the lower
      urinary tract within the scope of urogynecologic functional diagnosis].

PMID- 8650524
TI  - Antibiotics before surgery.
AB  - The antimicrobial era (along with greater surgical skill and precision) has
      brought us relative safety for procedures that previously were fraught with
      danger. Civil War amputation surgeries, for example, had an extraordinarily high
      incidence of infections and mortality. Staying aware of and avoiding the small,
      but real, risks associated with surgical antibiotic prophylaxis will help sustain
      the advances we enjoy today.

PMID- 8650523
TI  - [Ultrasound and mammography follow-up of findings after breast saving operation
      and adjuvant irradiation].
AB  - AIM: The aim of our controlled retrospective study was to assess the diagnostic
      value of sonography for detection and characterisation of changes compared to
      mammography and palpation. METHOD: In 80 patients sonographic and clinical follow
      up examinations were performed every 3 to 6 months, mammography examinations were
      performed every 6 to 12 months during the first 2 years after breast-preserving
      therapy (BPT) and irradiation. Extension, echogenicity, and configuration of
      lesions in sonography, and semiquantitiative description of diffuse or
      circumscribed changes in mammography were the basis of comparative follow-up
      observation. RESULTS: Postoperative seromas and haematomas, initially presenting
      echo-free or as hypoechoic lesions, showed an increase in echogenicity within 18
      months after irradiation. Fat necrosis occurred in 9.5% of patients, lymph cysts
      developed in 4%, granuloma in 3%, recurrence of neoplasma in 1.6%. The diffuse
      loss of transparency in mammography that was associated with radiation therapy,
      showed a peak 6-12 months after irradiation. CONCLUSION: Sonography and
      sonographic guided puncture are mandatory tools to characterise circumscribed
      unclear lesions after breast-conserving therapy and irradiation in specialised
      centers. We recommend a 6-month interval for combined sonography, palpation, and
      mammography within the first 2 years after BPT and irradiation, because shorter
      control intervals did not result in relevant diagnostic advantages.

PMID- 8650525
TI  - "Video lottery" and treatment for pathological gambling. A natural experiment in
      South Dakota.
AB  - Four agencies which offer specialized treatment for pathological gambling
      provided data on the number of inquiries about gambling treatment and the actual
      number of gamblers treated before, during, and after the shutdown of video
      lottery in the state of South Dakota. A marked decrease in the number of
      inquiries and number of gamblers treated was seen during the time the machines
      were turned off as compared to the time periods when video lottery gambling was
      available. The results suggest that the accessibility and availability of video
      lottery machines is an important factor in the number of people being adversely
      impacted by gambling.

PMID- 8650526
TI  - Quality--a moving and elusive target.

PMID- 8650527
TI  - State of South Dakota's child: 1995.
AB  - The total number of births in South Dakota declined again in 1994 to 10,504 with
      a .6% decrease in white babies and a 11% decrease in American Indian babies. The
      percent of low birth weight (LBW) newborns in South Dakota is lower than that
      observed nationally yet, increased in 1994 to 5.9%, the highest percent reported
      since 1974. These LBW newborns contributed to 79% of South Dakota's 1994 neonatal
      (less than 28 day mortality). Although there was a decrease in the total number
      of infant deaths in South Dakota, the infant mortality rate remained at 9.5
      compared to the US rate of 7.9. The neonatal mortality rate was also higher than
      the US rate (5.4 versus 5.0) as was the post neonatal rate (4.1 versus 2.9). The
      post neonatal mortality rate in 1994 for infants of color (8.1) was the lowest
      ever recorded. In recent years the state's perinatal mortality rate that combines
      the fetal and neonatal mortality rates has shown a decline, possibly reflecting
      advances in care available during pregnancy. Recognizing the importance of
      prenatal care to perinatal outcome, the prevention of alcohol-related birth
      defects is considered in this year's report. Several screening instruments are
      presented with a discussion of the complex inter and intrapersonal dynamics that
      must be considered when women with drinking problems are identified and helped
      during pregnancy.

PMID- 8650528
TI  - Tobacco council and research.

PMID- 8650529
TI  - Bioethical issues.

PMID- 8650530
TI  - Hippocampal cell death.

PMID- 8650531
TI  - Hippocampal cell death.

PMID- 8650532
TI  - Hippocampal cell death.

PMID- 8650533
TI  - NIH panel urges overhaul of the rating system for grants.

PMID- 8650534
TI  - Contraceptive technology. Panel wants to break R&D barrier.

PMID- 8650535
TI  - A shared strategy for virulence.

PMID- 8650536
TI  - Hyakutake produces another surprise.

PMID- 8650537
TI  - Combinatorial chemistry hits the drug market.

PMID- 8650538
TI  - The origin of programmed cell death.

PMID- 8650539
TI  - Infertility treatment: a nuclear restorer gene in maize.

PMID- 8650540
TI  - Detection of abundant ethane and methane, along with carbon monoxide and water,
      in comet C/1996 B2 Hyakutake: evidence for interstellar origin.
AB  - The saturated hydrocarbons ethane (C2H6) and methane (CH4) along with carbon
      monoxide (CO) and water (H2O) were detected in comet C/1996 B2 Hyakutake with the
      use of high-resolution infrared spectroscopy at the NASA Infrared Telescope
      Facility on Mauna Kea, Hawaii. The inferred production rates of molecular gases
      from the icy, cometary nucleus (in molecules per second) are 6.4 X 10(26) for
      C2H6, 1.2 X 10(27) for CH4, 9.8 X 10(27) for CO, and 1.7 X 10(29) for H2O. An
      abundance of C2H6 comparable to that of CH4 implies that ices in C/1996 B2
      Hyakutake did not originate in a thermochemically equilibrated region of the
      solar nebula. The abundances are consistent with a kinetically controlled
      production process, but production of C2H6 by gas-phase ion molecule reactions in
      the natal cloud core is energetically forbidden. The high C2H6/CH4 ratio is
      consistent with production of C2H6 in icy grain mantles in the natal cloud,
      either by photolysis of CH4-rich ice or by hydrogen-addition reactions to
      acetylene condensed from the gas phase.

PMID- 8650541
TI  - Crystal structure of the dual specificity protein phosphatase VHR.
AB  - Dual specificity protein phosphatases (DSPs) regulate mitogenic signal
      transduction and control the cell cycle. Here, the crystal structure of a human
      DSP, vaccinia H1-related phosphatase (or VHR), was determined at 2.1 angstrom
      resolution. A shallow active site pocket in VHR allows for the hydrolysis of
      phosphorylated serine, threonine, or tyrosine protein residues, whereas the
      deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate
      specificity to only phosphotyrosine. Positively charged crevices near the active
      site may explain the enzyme's preference for substrates with two phosphorylated
      residues. The VHR structure defines a conserved structural scaffold for both DSPs
      and PTPs. A "recognition region," connecting helix alpha1 to strand beta1, may
      determine differences in substrate specificity between VHR, the PTPs, and other
      DSPs.

PMID- 8650542
TI  - Dimerization of TFIID when not bound to DNA.
AB  - For unknown reasons, the eukaryotic transcription factor TFIID inefficiently
      recognizes promoters. Human TFIID was found to form highly specific homodimers
      that must dissociate before DNA binding. TFIID dimers formed through self
      association of the TATA-binding polypeptide (TBP) subunit and could be
      immunoprecipitated with antibodies to TAF(II)250, the core subunit of TFIID.
      Chemical cross-linking experiments in HeLa cells revealed the presence of TBP
      dimers in vivo. These findings suggest that dimerization through TBP is the
      physiological state of TFIID when not bound to DNA. Thus, the inefficiency of
      TFIID binding to a promoter may be partly attributable to the competitive effect
      of dimerization.

PMID- 8650543
TI  - The rf2 nuclear restorer gene of male-sterile T-cytoplasm maize.
AB  - The T cytoplasm of maize serves as a model for the nuclear restoration of
      cytoplasmic male sterility. The rf2 gene, one of two nuclear genes required for
      fertility restoration in male-sterile T-cytoplasm (cmsT) maize, was cloned. The
      protein predicted by the rf2 sequence is a putative aldehyde dehydrogenase, which
      suggests several mechanisms that might explain Rf2-mediated fertility restoration
      in cmsT maize. Aldehyde dehydrogenase may be involved in the detoxification of
      acetaldehyde produced by ethanolic fermentation during pollen development, may
      play a role in energy metabolism, or may interact with URF13, the mitochondrial
      protein associated with male sterility in cmsT maize.

PMID- 8650544
TI  - An orphan nuclear hormone receptor that lacks a DNA binding domain and
      heterodimerizes with other receptors.
AB  - SHP is an orphan member of the nuclear hormone receptor superfamily that contains
      the dimerization and ligand-binding domain found in other family members but
      lacks the conserved DNA binding domain. In the yeast two-hybrid system, SHP
      interacted with several conventional and orphan members of the receptor
      superfamily, including retinoid receptors, the thyroid hormone receptor, and the
      orphan receptor MB67. SHP also interacted directly with these receptors in vitro.
      In mammalian cells, SHP specifically inhibited transactivation by the superfamily
      members with which it interacted. These results suggest that SHP functions as a
      negative regulator of receptor-dependent signaling pathways.

PMID- 8650545
TI  - PKD2, a gene for polycystic kidney disease that encodes an integral membrane
      protein.
AB  - A second gene for autosomal dominant polycystic kidney disease was identified by
      positional cloning. Nonsense mutations in this gene (PKD2) segregated with the
      disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2
      gene product has six transmembrane spans with intracellular amino- and carboxyl
      termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis
      elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium)
      channels, and it contains a potential calcium-binding domain.

PMID- 8650546
TI  - Structural basis of ligand discrimination by two related RNA aptamers resolved by
      NMR spectroscopy.
AB  - In a previous study, an RNA aptamer for the specific recognition of arginine was
      evolved from a parent sequence that bound citrulline specifically. The two RNAs
      differ at only 3 positions out of 44. The solution structures of the two aptamers
      complexed to their cognate amino acids have now been determined by two
      dimensional nuclear magnetic resonance spectroscopy. Both aptamers contain two
      asymmetrical internal loops that are not well ordered in the free RNA but that
      fold into a compact structure upon ligand binding. Those nucleotides common to
      both RNAs include a conserved cluster of purine residues, three of which form an
      uneven plane containing a G:G pair, and two other residues nearly perpendicular
      to that surface. Two of the three variant nucleotides are stacked on the cluster
      of purines and form a triple contact to the amino acid side chain, whereas the
      edge of the third variant nucleotide is capping the binding pocket.

PMID- 8650547
TI  - Stress-induced phosphorylation and activation of the transcription factor CHOP
      (GADD153) by p38 MAP Kinase.
AB  - CHOP, a member of the C/EBP family of transcription factors, mediates effects of
      cellular stress on growth and differentiation. It accumulates under conditions of
      stress and undergoes inducible phosphorylation on two adjacent serine residues
      (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen
      activated protein kinase (MAP kinase). A specific inhibitor of p38 MAP kinase,
      SB203580, abolished the stress-inducible in vivo phosphorylation of CHOP.
      Phosphorylation of CHOP on these residues enhanced its ability to function as a
      transcriptional activator and was also required for the full inhibitory effect of
      CHOP on adipose cell differentiation. CHOP thus serves as a link between a
      specific stress-activated protein kinase, p38, and cellular growth and
      differentiation.

PMID- 8650548
TI  - G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's
      disease-associated mutants of APP.
AB  - Missense mutations in the 695-amino acid form of the amyloid precursor protein
      (APP695) cosegregate with disease phenotype in families with dominantly inherited
      Alzheimer's disease. These mutations convert valine at position 642 to
      isoleucine, phenylalanine, or glycine. Expression of these mutant proteins, but
      not of normal APP695, was shown to induce nucleosomal DNA fragmentation in
      neuronal cells. Induction of DNA fragmentation required the cytoplasmic domain of
      the mutants and appeared to be mediated by heterotrimeric guanosine triphosphate
      binding proteins (G proteins).

PMID- 8650549
TI  - Sterol esterification in yeast: a two-gene process.
AB  - Unesterified sterol modulates the function of eukaryotic membranes. In human
      cells, sterol is esterified to a storage form by acyl-coenzyme A (CoA):
      cholesterol acyl transferase (ACAT). Here, two genes are identified, ARE1 and
      ARE2, that encode ACAT-related enzymes in yeast. The yeast enzymes are 49 percent
      identical to each other and exhibit 23 percent identity to human ACAT. Deletion
      of ARE2 reduced sterol ester levels to approximately 25 percent of normal levels,
      whereas disruption of ARE1 did not affect sterol ester biosynthesis. Deletion of
      both genes resulted in a viable cell with undetectable esterified sterol.
      Measurements of [14C]acetate incorporation into saponified lipids indicated down
      regulation of sterol biosynthesis in the are1 are2 mutant cells. With the use of
      a consensus sequence to the yeast and human genes, an additional number of the
      ACAT gene family was identified in humans.

PMID- 8650550
TI  - Estimating the age of the common ancestor of men from the ZFY intron.

PMID- 8650551
TI  - Estimating the age of the common ancestor of men from the ZFY intron.

PMID- 8650552
TI  - Estimating the age of the common ancestor of men from the ZFY intron.

PMID- 8650553
TI  - Estimating the age of the common ancestor of men from the ZFY intron.

PMID- 8650554
TI  - Correlates of protective viruses damaging to HIV infection.

PMID- 8650556
TI  - Merit, quality, and the SBIR.

PMID- 8650555
TI  - Gene lineages and human evolution.

PMID- 8650557
TI  - Sexual warfare?

PMID- 8650558
TI  - Merit, quality, and the SBIR program.

PMID- 8650559
TI  - Merit, quality, and the SBIR.

PMID- 8650560
TI  - Merit, quality, and the SBIR program.

PMID- 8650561
TI  - Toxicology of a PFPE surfactant.

PMID- 8650562
TI  - Hot property: biologists who compute.

PMID- 8650563
TI  - Federal funding. Appropriators bullish on biomedicine.

PMID- 8650564
TI  - Salk Institute picks a new president.

PMID- 8650566
TI  - From genes to genome biology.

PMID- 8650565
TI  - Scientific misconduct. HHS is still looking for a definition.

PMID- 8650567
TI  - Genes seen turning imaginal fly eyes into reality.

PMID- 8650568
TI  - A second coreceptor for HIV in early stages of infection.

PMID- 8650569
TI  - Microbes hint at a mechanism behind punctuated evolution.

PMID- 8650570
TI  - Signaling inside neurons takes some new twists.

PMID- 8650571
TI  - Form follows function when plants harvest light.

PMID- 8650572
TI  - Receptor tails unlock developmental checkpoints for B lymphocytes.

PMID- 8650573
TI  - Remapping the brain.

PMID- 8650574
TI  - The complete 685-kilobase DNA sequence of the human beta T cell receptor locus.
AB  - The human beta T cell receptor (TCR) locus, comprising a complex family of genes,
      has been sequenced. The locus contains two types of coding elements--TCR elements
      (65 variable gene segments and two clusters of diversity, joining, and constant
      segments) and eight trypsinogen genes --that constitute 4.6 percent of the DNA.
      Genome-wide interspersed repeats and locus-specific repeats span 30 and 47
      percent, respectively, of the 685-kilobase sequence. A comparison of the germline
      variable elements with their approximately 300 complementary DNA counterparts
      reveals marked differential patterns of variable gene expression, the importance
      of exonuclease activity in generating TCR diversity, and the predominant tendency
      for only functional variable elements to be present in complementary DNA
      libraries.

PMID- 8650575
TI  - Patch-clamp detection of neurotransmitters in capillary electrophoresis.
AB  - Gamma-aminobutyrate acid, L-glutamate, and N-methyl-D-aspartate were separated by
      capillary electrophoresis and detected by the use of whole-cell and outside-out
      patch-clamp techniques on freshly dissociated rat olfactory interneurons. These
      neuroactive compounds could be identified from their electrophoretic migration
      times, unitary channel conductances, and power spectra that yielded corner
      frequencies and mean single-channel conductances characteristic for each of the
      different agonist-receptor interactions. This technique has the sensitivity to
      observe the opening of a single ion channel for agonists separated by capillary
      electrophoresis.

PMID- 8650576
TI  - Adenosine diphosphate as an intracellular regulator of insulin secretion.
AB  - Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels couple the
      cellular metabolic state to electrical activity and are a critical link between
      blood glucose concentration and pancreatic insulin secretion. A mutation in the
      second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an
      individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy
      generated KATP channels that could be opened by diazoxide but not in response to
      metabolic inhibition. The hamster SUR, containing the analogous mutation, had
      normal ATP sensitivity, but unlike wild-type channels, inhibition by ATP was not
      antagonized by adenosine diphosphate (ADP). Additional mutations in NBF2 resulted
      in the same phenotype, whereas an equivalent mutation in NBF1 showed normal
      sensitivity to MgADP. Thus, by binding to SUR NBF2 and antagonizing ATP
      inhibition of KATP++ channels, intracellular MgADP may regulate insulin
      secretion.

PMID- 8650577
TI  - Structural basis of light harvesting by carotenoids: peridinin-chlorophyll
      protein from Amphidinium carterae.
AB  - Peridinin-chlorophyll-protein, a water-soluble light-harvesting complex that has
      a blue-green absorbing carotenoid as its main pigment, is present in most
      photosynthetic dinoflagellates. Its high-resolution (2.0 angstrom) x-ray
      structure reveals a noncrystallographic trimer in which each polypeptide contains
      an unusual jellyroll fold of the alpha-helical amino- and carboxyl-terminal
      domains. These domains constitute a scaffold with pseudo-twofold symmetry
      surrounding a hydrophobic cavity filled by two lipid, eight peridinin, and two
      chlorophyll a molecules. The structural basis for efficient excitonic energy
      transfer from peridinin to chlorophyll is found in the clustering of peridinins
      around the chlorophylls at van der Waals distances.

PMID- 8650578
TI  - Neural substrates for the effects of rehabilitative training on motor recovery
      after ischemic infarct.
AB  - Substantial functional reorganization takes place in the motor cortex of adult
      primates after a focal ischemic infarct, as might occur in stroke. A subtotal
      lesion confined to a small portion of the representation of one hand was
      previously shown to result in a further loss of hand territory in the adjacent,
      undamaged cortex of adult squirrel monkeys. In the present study, retraining of
      skilled hand use after similar infarcts resulted in prevention of the loss of
      hand territory adjacent to the infarct. In some instances, the hand
      representations expanded into regions formerly occupied by representations of the
      elbow and shoulder. Functional reorganization in the undamaged motor cortex was
      accompanied by behavioral recovery of skilled hand function. These results
      suggest that, after local damage to the motor cortex, rehabilitative training can
      shape subsequent reorganization in the adjacent intact cortex, and that the
      undamaged motor cortex may play an important role in motor recovery.

PMID- 8650579
TI  - Stable expression of mosaic coats of variant surface glycoproteins in Trypanosoma
      brucei.
AB  - The paradigm of antigenic variation in parasites is the variant surface
      glycoprotein (VSG) of African trypanosomes. Only one VSG is expressed at any
      time, except for short periods during switching. The reasons for this pattern of
      expression and the consequences of expressing more than one VSG are unknown.
      Trypanosoma brucei was genetically manipulated to generate cell lines that
      expressed two VSGs simultaneously. These VSGs were produced in equal amounts and
      were homogeneously distributed on the trypanosome surface. The double-expressor
      cells had similar population doubling times and were as infective as wild-type
      cells. Thus, the simultaneous expression of two VSGs is not intrinsically
      harmful.

PMID- 8650581
TI  - Punctuated evolution caused by selection of rare beneficial mutations.
AB  - For more than two decades there has been intense debate over the hypothesis that
      most morphological evolution occurs during relatively brief episodes of rapid
      change that punctuate much longer periods of stasis. A clear and unambiguous case
      of punctuated evolution is presented for cell size in a population of Escherichia
      coli evolving for 3000 generations in a constant environment. The punctuation is
      caused by natural selection as rare, beneficial mutations sweep successively
      through the population. This experiment shows that the most elementary processes
      in population genetics can give rise to punctuated evolution dynamics.

PMID- 8650580
TI  - Binding of zinc finger protein ZPR1 to the epidermal growth factor receptor.
AB  - ZPR1 is a zinc finger protein that binds to the cytoplasmic tyrosine kinase
      domain of the epidermal growth factor receptor (EGFR). Deletion analysis
      demonstrated that this binding interaction is mediated by the zinc fingers of
      ZPR1 and subdomains X and XI of the EGFR tyrosine kinase. Treatment of mammalian
      cells with EGF caused decreased binding of ZPR1 to the EGFR and the accumulation
      of ZPR1 in the nucleus. The effect of EGF to regulate ZPR1 binding is dependent
      on tyrosine phosphorylation of the EGFR. ZPR1 therefore represents a prototype
      for a class of molecule that binds to the EGFR and is released from the receptor
      after activation.

PMID- 8650582
TI  - Aberrant B cell development and immune response in mice with a compromised BCR
      complex.
AB  - The immunoglobulin alpha (Ig-alpha)-Ig-beta heterodimer is the signaling
      component of the antigen receptor complex on B cells (BCR) and B cell progenitors
      (pre-BCR). A mouse mutant that lacks most of the Ig-alpha cytoplasmic tail
      exhibits only a small impairment in early B cell development but a severe block
      in the generation of the peripheral B cell pool, revealing a checkpoint in B cell
      maturation that ensures the expression of a functional BCR on mature B cells. B
      cells that do develop demonstrate a differential dependence on Ig-alpha signaling
      in antibody responses such that a signaling-competent Ig-alpha appears to be
      critical for the response to T-independent, but not T-dependent, antigens.

PMID- 8650583
TI  - Substitution of L-fucose by L-galactose in cell walls of Arabidopsis mur1.
AB  - An Arabidopsis thaliana mutant (mur1) has less than 2 percent of the normal
      amounts of L-fucose in the primary cell walls of aerial portions of the plant.
      The survival of mur1 plants challenged the hypothesis that fucose is a required
      component of biologically active oligosaccharides derived from cell wall
      xyloglucan. However, the replacement of L-fucose (that is, 6-deoxy-L-galactose)
      by L-galactose does not detectably alter the biological activity of the
      oligosaccharides derived from xyloglucan. Thus, essential structural and
      conformational features of xyloglucan and xyloglucan-derived oligosaccharides are
      retained when L-galactose replaces L-fucose.

PMID- 8650585
TI  - Antineutrophil cytoplasmic antibodies: major autoantigens, pathophysiology, and
      disease associations.
AB  - Antineutrophil cytoplasmic antibodies (ANCA) are important serological markers
      for the primary systemic vasculitides, including microscopic polyarteritis and
      necrotizing crescentic glomerulonephritis. Numerous reports have established the
      clinical utility of ANCA titer in monitoring disease activity, relapses, and
      response to treatment. ANCA, detected by indirect immunofluorescence (IIF) assays
      using patient's serum and ethanol-fixed human neutrophils, produce two common
      fluorescent staining patterns: cytoplasmic (C-ANCA), involving a 29-kD neutral
      serine protease termed proteinase 3 (PR3), and perinuclear (P-ANCA), the result
      mainly of myeloperoxidase (MPO), but occasionally by other components of the
      azurophilic granules including lysozyme, elastase, cathepsins, and lactoferrin.
      Some sera contain granulocyte-specific antinuclear antibodies (GS-ANA), which
      require formaldehyde fixation of neutrophils to cross link cytoplasmic antigens
      for distinguishing between ANCA and the GS-ANA by IIF. Positive IIF is confirmed
      by Western blot analysis or specific enzyme-linked immunosorbent assay for PR3,
      MPO, and other neutrophil granule antigens. The C-ANCA pattern is highly specific
      for Wegener's granulomatosis, a disease characterized by granulomatous
      inflammation, necrotizing and crescentic glomerulonephritis, and vasculitis; P
      ANCA is found in sera of individuals with vasculitis, glomerulonephritis, and
      several other diseases. ANCA are predominantly immunoglobulin (Ig)G isotype, but
      may be IgM and IgA. Various pathophysiologic mechanisms have been proposed
      involving ANCA-mediated neutrophil activation in a hypothetical model of
      vasculitic diseases: positive signals via the FcgammaRII (CD32) receptor after
      IgG-ANCA binding to membrane-associated PR3, relevant cytokines, production of
      adhesion molecules on both activated neutrophils and endothelial cells, and the
      release of neutrophil reactive oxygen species and degranulation causing
      endothelial cell damage. Interference of C-ANCA with PR3 proteolysis and PR3
      inhibition physiologically by the alpha1-proteinase inhibitor may have a
      pathogenic role. No convincing data have been reported for the existence of
      autoreactive T lymphocytes reactive to any degree with the neutrophil azurophilic
      enzymes. Studies of various drug- and infectious agent-related diseases and ANCA
      may contribute to understanding the mechanism(s) involved in some vasculitides.

PMID- 8650584
TI  - Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus.
AB  - Insulin-dependent diabetes mellitus (IDDM) is a multigenic autoimmune disease. An
      IDDM susceptibility gene was mapped to chromosome 2q34. This gene may act early
      in diabetogenesis, because "preclinical" individuals also showed linkage. Human
      leukocyte antigen (HLA)-disparate, but not HLA-identical, sibs showed linkage,
      which was even stronger in families with affected females. The genes encoding
      insulin-like growth factor-binding proteins 2 and 5 were mapped to a 4-megabase
      pair interval near this locus. These results indicate the existence of a gene
      that acts at an early stage in IDDM development, screening for which may identify
      a specific subset of at-risk individuals.

PMID- 8650586
TI  - Aortic dissection in giant-cell arteritis.
AB  - Twenty-three cases of aortic dissection in patients with giant-cell arteritis are
      reviewed and an additional case is reported. Forty-six percent presented
      catastrophically with aortic dissection and no prior history of giant cell
      arteritis. Eighty percent died within 2 weeks of the event; four patients had
      successful surgical grafts. There was diffuse involvement of the aorta with giant
      cells in 89%, but dissecting tears occurred primarily in the proximal aorta in
      85% of cases. The majority of cases with a preceding history of giant cell
      arteritis were on low doses of steroid or on no treatment at the time of
      dissection, and the median erythrocyte sedimentation rate of these patients was
      62 mm/h (range 21-98). Evidence of some form of hypertension, whether acute or
      chronic, mild or severe, was found in 77% of patients. Inadequate treatment of
      giant-cell arteritis and underlying hypertension (treated or untreated) are
      potential factors leading to aortic dissection in these patients.

PMID- 8650587
TI  - Cocaine-associated cerebral vasculitis.
AB  - Cocaine use is associated with a variety of serious neurological complications,
      including cerebral infarction, intracerebral and subarachnoid hemorrhage,
      transient ischemic attacks, migraines, and seizures. We report two cases of
      intracerebral hemorrhage with biopsy-proven cerebral vasculitis associated with
      the use of cocaine. The first case involved a 32-year-old man who presented with
      headache, left-sided hemiparesis, and severe hypertension and who was found to
      have a large right putaminal hemorrhage on cranial tomographic (CT) scan.
      Cerebral angiography did not show vasculitic changes, but brain tissue obtained
      during hematoma evacuation revealed a nonnecrotizing leukocytoclastic angiitis of
      the small vessels. The second case involved a 20-year-old man who presented with
      headache, agitation, and speech difficulty that progressed to disorientation and
      dysphasia. He had a large left temporoparietal hematoma seen on CT scan. Cerebral
      angiography was consistent with vasculitis, and brain tissue obtained during
      hematoma evacuation revealed a small vessel vasculitis. In both cases, thorough
      clinical and laboratory investigations found no evidence of systemic vasculitis
      or an etiologic agent other than cocaine. We also critically reviewed the
      previously reported cases of cocaine-associated cerebral vasculitis and the
      relevant medical literature to discuss the "cocaine-associated vasculitis
      syndrome" in the context of more established vasculitidies, including
      hypersensitivity vasculitis. In addition, we outline a diagnostic and therapeutic
      approach to patients with possible cocaine-associated vasculitis.

PMID- 8650588
TI  - Obstetric outcome in systemic lupus erythematosus.
AB  - A prospective study was performed to investigate the fetal and maternal outcome
      of 108 pregnancies in 90 lupus patients. The protocol was based on shared care of
      the patients by a rheumatologist and an obstetrician, with input from a
      hematologist, if necessary. Lupus flares were treated with low-dose prednisolone,
      azathioprine and hydroxychloroquine. The live birth rate was increased from 31 %
      in the patients' previous obstetric history to 82%. A high incidence of
      prematurity was observed (43%). Lupus patients with secondary antiphospholipid
      syndrome presented a higher risk for fetal loss (P = .006). Flares occurred in
      57% of the pregnancies, but most were mild (skin and joints). Flare during
      pregnancy did not increase the risk of fetal loss. We believe that careful
      monitoring and management of the lupus pregnancy has substantially improved the
      fetal outcome.

PMID- 8650589
TI  - Mortality in rheumatoid arthritis.
AB  - Patients with rheumatoid arthritis (RA) have a substantially reduced life
      expectancy. The standardized mortality ratio in different studies has ranged from
      1.13 to 2.98. This mainly applies to rheumatoid factor (RF)-positive cases,
      although there is a subgroup of RF-negative cases with an adverse long-term
      prognosis. Clinically based studies probably overestimate the true shortening of
      life span and population-based studies may underestimate it. Excess mortality
      from infection and from renal disease likely reflects the presence of severe
      disease, whereas most of the added mortality from gastrointestinal causes is
      treatment related. The reasons for the surplus of mortality from cardiovascular
      causes are not fully known. RF may have a direct role, and preillness factors
      such as smoking may predipose patients to RA and also render them susceptible to
      cardiovascular diseases. The excess mortality associated with RA is appreciably
      higher than is apparent from the cases in which RA is regarded as an underlying
      cause of death. The effect of treatment on mortality remains largely unknown.

PMID- 8650590
TI  - Clinical expression of rheumatoid arthritis in Chilean patients.
AB  - In populations such as Northern Europeans in which the HLA-DR4 subtypes DW14 and
      Dw4 show strong association with rheumatoid arthritis (RA), these alleles and the
      double allelic dose of the shared epitope are considered severity markers. The
      clinical expression of RA varies in different populations, which may be
      determined by variation in the prevalence of these markers. In the present study
      we analyzed the expression of RA in 112 consecutive Chilean patients and its
      relation to the prevalence of genetic factors, prompted by our previous
      observation that DR4 is weakly associated to RA in this population. Mean age was
      50 +/- 14 years; 90% were seropositive and 87% were female, with a disease
      duration of 10 +/- 8 years. Extra-articular manifestations were found in 38% of
      patients, rheumatoid nodules in 27%, vasculitis in 8%, and Sjogren's syndrome in
      29%. Functional capacity (ACR, 1991) I or II: 82%.15% of patients stopped
      working. Hand radiographs scored according to Steinbrocker in 89 patients: I,
      21%; II, 15%; III, 43%; IV, 21%. In this series, patients with less formal
      education seemed to have more benign arthritis. In 97 controls and in 65 (56%) RA
      patients the presence of DRB1 alleles corresponding to DR1 and DR4 serotypes, to
      DR4-Dw subtypes, and homozygocity, were determined by polymerase chain reaction
      followed by specific oligonucleotide hybridization. The shared epitope was
      present in 53% of RA patients and in 30% of controls (P = .0048, odds ratio [OR]
      = 2.64). A double allelic dose of the epitope was present in 15% of RA patients
      compared with 4% of controls (P = .026, OR = 4.23). In a subgroup of 31 erosive
      RA patients we did not find a significant association of disease severity with
      the shared epitope in a single or double allelic dose. None of the DR4 subtypes
      that associate with RA in other populations was found significantly more
      prevalent in our patients. The severity of RA in our study compared with
      published series was intermediate between British patients with severe RA and
      Greek patients with milder disease. This may be due to the high prevalence of
      Dwl3*0403 in our population.

PMID- 8650591
TI  - [The effect of contraception on fertility in the border region of Chiapas,
      Mexico].
AB  - OBJECTIVE: To estimate the effect of contraception on fertility in the border
      region of Chiapas, Mexico. MATERIALS AND METHODS: In 1994 an epidemiological
      cross-sectional study was carried out on a representative sample of 1,560 non
      indigenous women between ages 15 and 49 in the border region of Chiapas. The
      prevalence of contraception practices and the total fertility rates (TFR) were
      obtained and stratified by rural, intermediate and urban communities. TFR were
      compared between women who had never used contraceptives and those who had used
      them. RESULTS: The estimated TFR was 3.67 and varied from 4.14 in rural areas to
      3.36 in urban areas. There were no differences in the TFR (3.74 and 3.88) nor in
      the average live births (3.47 and 3.48) between women who had never used
      contraceptives and those who had used them. CONCLUSIONS: The major effect of
      contraception on fertility was observed in rural areas. Factors which influence
      the small impact of contraception on fertility include the late use of these
      methods and the early age of first union among users.

PMID- 8650592
TI  - [Territorial mobility in medical education in Mexico].
AB  - OBJECTIVE: This work aimed to determine the migration patterns of medical
      students within Mexico. MATERIALS AND METHODS: We obtained the places of origin
      of graduates and the states where they registered their medical degrees at the
      Ministry of Education General Registry of Professions (SEP), between 1970-1974,
      1980-1984 and 1985-1989. Data were organized as follows: Attracting foci, sending
      foci, transition foci, and important migrant flows. RESULTS: The concentration of
      medical human resource development, is reflected by the existence of a few
      attracting foci (D.F., Jalisco, Nuevo Leon, and to a less extent, Puebla and
      Michoacan). Also, we observed the persistence of traditional sending foci
      (Guanajuato, Chiapas, Colima, Campeche). However, some important changes occurred
      throughout the study period, namely, a decrease of the migratory mobility of
      university students. During 1970-1974, almost half of them (47%) obtained their
      degrees outside their place of origin; during 1980-1984 this figure decreased to
      34% and during 1985-1989, it decreased further to 30.6%. Second, the
      participation of D.F. as a main human resource development center diminished;
      from 59% to 40% during 1970-1974, it went down, to 30% in the following
      quinquennium, while it increased in Jalisco, Michoacan and Nuevo Leon.
      CONCLUSIONS: The establishment of medical schools in almost every Mexican state
      has had a central role in the migration patterns of medical students.
      Nevertheless, our results show that there are other reasons accounting for the
      persistence of the concentration of medical human resources development in main
      cities of the nation such as Guadalajara and Monterrey.

PMID- 8650593
TI  - Risk factors for hospitalization and death from diarrhea in a public pediatric
      hospital in Rio de Janeiro, Brazil.
AB  - OBJECTIVE: This study was carried out in a public pediatric hospital located in
      the city of Rio de Janeiro, Brazil, with the aim of identifying risk factors for
      hospitalization and/or death due to diarrhea in children. MATERIAL AND METHODS:
      The study included 406 children under three years of age who were seen or
      admitted for diarrhea from January 1987 to February 1988. The main variable of
      interest was the outcome of clinical evaluation and subsequent hospitalization,
      which was classified as follows: 1) outpatient treatment; 2) hospitalization and
      survival; and 3) death during hospitalization. The chi-square test was used to
      identify variables (p = < 0.05) that were significantly related to the treatment
      outcome. RESULTS: The group was composed by 60.6% males and 39.4% females. A
      proportion of 26.8% of children was under two months of age, 24.9% was 3-5 months
      old, 25.9% was 6-11 months old, and 22.4% was 12 months or older. The variables
      most significantly related to the risk of hospitalization from diarrhea were age,
      current nutritional status (weight-for-age percentile), and concomitant illness.
      Variables most significantly associated with risk of death from diarrhea were low
      birth weight and past hospitalization. CONCLUSIONS: Use of this study's results
      by health services could make a substantial contribution to reducing children's
      hospitalization and death due to diarrhea in the city of Rio de Janeiro.

PMID- 8650594
TI  - [Industrial pollution due to organic solvents as a cause of teratogenesis].
AB  - OBJECTIVE: To inform of a new teratogenic syndrome in human beings and its
      confirmation in rats. MATERIAL AND METHODS: The study comprised three phases: a
      field study; a case-control study; and a genetic epidemiology study, aiming at
      identifying the causes of the occurrence of congenital malformations and
      psychomotor retardation in the city of Matamoros, Tamaulipas. The second-phase
      clinical multidisciplinary study was carried out at a general hospital, to
      conduct a comprehensive evaluation of patients identified during the first phase
      and offer them the necessary treatment. The third-phase experimental study was
      done in rats in order to confirm the teratogenic effect of the agents detected in
      the first phase. RESULTS: A total of 44 patients had a peculiar phenotype and
      mental retardation of varying degrees, all children of ex-workers of the same
      factory who were in direct contact, without protection, with organic solvents
      (methyl cellosolve and ethylene glycol). In the clinical study a syndrome was
      delineated, previously unreported, consisting of a peculiar facies, mental
      retardation, and musculo-skeletal and sensorial abnormalities. In the
      experimental study it was demonstrated that both methyl cellosolve and ethylene
      glycol cause cranio-facial, musculo-skeletal and central nervous system
      abnormalities, which confirmed the teratogenic effect of these solvents.
      CONCLUSIONS: The results of this study establish the existence of a new
      teratogenic syndrome in humans, produced by methyl cellosolve and ethylene
      glycol, whose teratogenic capacity had not been reported previously.

PMID- 8650595
TI  - [Sample size for estimating attributable risk in cross-sectional studies].
AB  - The prevalence of a variety of risk factors and their strength of association
      with a disease can vary greatly among apparently similar communities. In small
      communities, risk estimates can also vary from year to year. An identification of
      important risk factors in each community is then needed, so that interventions
      can be specifically oriented towards the needs of each specific community. The
      attributable risk is the adequate measure of association for these purposes. The
      purpose of this paper is to determine the minimum sample size required to detect
      a given attributable risk in cross-sectional studies. A table was constructed,
      presenting the number of exposed subjects necessary to detect a given
      attributable risk for different combinations of prevalence of disease and
      prevalence of exposure to a given risk factor, with a power of 0.80 and alpha of
      0.05.

PMID- 8650596
TI  - [Coverage of Mexican articles and journals in the database Bibliomex Salud].
AB  - OBJECTIVE: To evaluate the coverage of Mexican journals and manuscripts of
      biomedical research in a Mexican data base (Bibliomex Salud) during its 10 years
      of existence (1985-1994). MATERIAL AND METHODS: All the manuscripts published by
      a single Mexican journal Revista de Investigacion Clinica (RIC) were searched for
      in Bibliomex: the absence of a RIC manuscript in Bibliomex was considered a
      failure. Also, the number and identity of the Mexican journals included in
      Bibliomex was also noted. From a total of 744 manuscripts 99 were excluded (22
      non-Mexican, 25 nonindexable, and 52 initially not indexed by Bibliomex). The
      remainder (645) were classified according to starting year of indexing: originals
      since the first year; letters to the editor since 1990; and editorials and
      authors' replies since 1993. RESULTS: Bibliomex started out with 21 Mexican
      journals and now has more than 50 (12 indexed during the 10 years, 27 for the
      last 5-9 years, and 16 for the last 1-4 years). Regarding manuscripts, Bibliomex
      had an 8% failure rate in originals (46/597) and letters (3/36), and 25% in
      editorials and authors' replies (3/12). CONCLUSIONS: a) The coverage of Bibliomex
      has improved in its second half of life in the number of both journals and
      manuscripts indexed; b) the retrieval of information could be improved by two
      changes in the procedures of Bibliomex; c) Bibliomex seems to be a database which
      could be used to analyze Mexican research production at several levels
      (institutional, regional, and national).

PMID- 8650597
TI  - [Molecular bases of papillomavirus and polyomavirus carcinogenesis].
AB  - Polyomavirus is able to induce tumors in its natural host as well as to transform
      cells in cultures. On the other hand, human papillomavirus has been involved in
      several types of neoplasias such as anogenital lesions. Little is known about the
      mechanisms through which these viruses induce both transformation and
      tumorigenesis. The present, work shows some characteristics of the mechanisms
      that papillomavirus and polyomavirus use to participate in tumorigenesis. It has
      also been noticed that the infection caused by polyomavirus resembles that
      performed by papillomaviruses (which belong to the same Papovaviridae family).
      Some similarities and differences between these viruses are considered.

PMID- 8650598
TI  - [Lactational amenorrhea as a method of family planning].
AB  - The contraceptive effects of breast-feeding still play an important role in child
      spacing in developing countries; however, its use as a method of family planning
      was untested until 1988, when an international group of researchers met in
      Bellagio and reached a consensus statement that reads "The maximum birth spacing
      effect of breast-feeding is achieved when mothers fully or nearly fully breast
      feed and remain amenorrheic (and no menstrual bleeding has occurred before the
      56th postpartum day). When these two conditions are present, breast-feeding
      provides more than 98% of protection in the first six months. That became the
      basis for a method of family planning called the lactational amenorrhea method
      (LAM). Which is a new introductory family planning method that simultaneously
      promotes child spacing and breast-feeding, with its optimal nutrition and disease
      preventive benefits for the infant. This method is based on the natural
      infertility caused by the hormonal suppression of ovulation.

PMID- 8650599
TI  - Blunt injury to the ascending aorta: three patterns of presentation.
AB  - BACKGROUND: Injury to the ascending aorta is a rare lesion that may present in
      various forms. A thorough analysis of this lesion is lacking in the literature.
      This study was undertaken to delineate the prevalence and modes of presentation
      of injuries to the ascending aorta after blunt trauma and to suggest guidelines
      for management. METHODS: A retrospective analysis of autopsies performed in our
      department of forensic medicine on blunt trauma victims from 1984 to 1993 and a
      literature review of autopsy series were undertaken to delineate the prevalence
      and relevant characteristics of this injury. A cash report from our institution
      and a review of the literature were used to provide information regarding
      clinical presentations of this injury and treatment approaches. RESULTS: Three
      modes of presentation were encountered. (1) Presentation at autopsy: The
      prevalence of injury to the ascending aorta after a traffic accident was 2% in
      our autopsy series. Among 13 patients with this injury 12 had other associated,
      potentially lethal lesions. A massive hemopericardium was present in two patients
      only. In autopsy series the incidence of injury to the ascending aorta in
      patients with an injury to the aorta ranged from 0% to 23%. (2) CLINICAL
      PRESENTATION: Twenty-one patients were treated surgically and reported in the
      literature. Fourteen presented with a pseudoaneurysm and seven with a chronic
      sinus of Valsalva fistula. One patient with a pseudoaneurysm presented with signs
      of cardiac tamponade and required immediate decompression; the others were
      hemodynamically stable. Seven patients had a cardiac lesion (valve tear in six
      and cardiac contusion in one), and three had an arch vessel lesion. Aorta repair
      was performed under cardiopulmonary bypass in every patient. (3) Incidental
      presentation: Seven patients with a traumatic tear of the aortic valve presented
      an incidental lesion of the ascending aorta. It was a subadventitial hematoma in
      three patients and an intimal and medial tear in four patients. Aortic tears were
      reinforced by direct suture. CONCLUSIONS: Injury to the ascending aorta after
      blunt trauma is rare but lethal mostly from associated injuries. Survivors may
      appear in stable condition and present mostly with pseudoaneurysms of the
      ascending aorta or sinus of Valsalva fistula. Associated lesions to the heart and
      arch vessels should be looked for. Repair of the ascending aorta injury is
      performed under cardiopulmonary bypass.

PMID- 8650600
TI  - Laparoscopic staging for gastric cancer.
AB  - BACKGROUND: Laparoscopy has become an increasingly important diagnostic tool for
      the staging of intraabdominal malignancies. Some investigators have suggested
      laparoscopy to be of questionable value in the preoperative staging of gastric
      cancer because many patients may require palliative surgery despite laparoscopic
      findings. However, in other studies laparoscopy was found to be a more accurate
      staging technique and useful in avoiding unnecessary laparotomy when compared
      with abdominal sonography, liver scintigraphy, or early generation computed
      tomography (CT). In recent years marked improvements have been made in CT
      technology, and laparoscopy has not been compared with current generation CT.
      Therefore we sought to determine the usefulness of laparoscopy for staging
      gastric adenocarcinoma in the era of current generation CT scanning. METHODS:
      Staging laparoscopy was performed in 71 patients with potentially resectable
      gastric cancer as determined by physical examination and current generation CT.
      The results of laparoscopy were evaluated in the context of negative or equivocal
      CT findings. RESULTS: Laparoscopic staging was successful in 69 patients (97%).
      Laparoscopy identified distant metastatic disease in 16 (23%) patients judged to
      be eligible for potentially curative resection by current generation CT scanning.
      Only one of these patients required laparotomy for palliation. Combined CT and
      laparoscopic staging resulted in a 93% resectability rate for patients operated
      on with curative intent. CONCLUSIONS: We advocate staging laparoscopy as an
      important staging procedure for all patients with potentially resectable gastric
      cancer. The additional cost of laparoscopy should be more than offset by the
      decreased morbidity and expense of hospitalization for those patients who avoid
      an unnecessary laparotomy.

PMID- 8650601
TI  - Ileal pouch-anal anastomosis as the first choice operation in patients with
      familial adenomatous polyposis: a ten-year experience.
AB  - BACKGROUND: The choice between ileal pouch-anal anastomosis (IPAA) and ileorectal
      anastomosis (IRA) in the treatment of patients with familial adenomatous
      polyposis remains controversial. The aims of this study were to assess our 10
      year experience with proctocolectomy, endoanal mucosectomy, construction of an
      ileal reservoir pouch, and IPAA in a series of 171 patients with familial
      adenomatous polyposis and to compare the functional results after IPAA with those
      after IRA. METHODS: Data from patients treated by IPAA at one institution were
      prospectively accumulated from October 1983 to October 1993. Medical records of
      171 consecutive patients were studied regarding morbidity and functional results.
      These functional results were compared with those of a series of 23 patients who
      underwent IRA at the same institution. RESULTS: One patient (0.6%) died after
      operation. Sixty-two patients (36%) had concomitant colorectal carcinoma, 36 of
      which tumors were invasive (15 stage A, 13 stage B, and 8 stage C). Forty-six
      patients (27%) had at least one postoperative complication, with 14 patients
      requiring reoperation (8%). Twenty-six patients (15%) had obstruction. Seven
      patients (4%) had pelvic sepsis, and one had transient impotence (0.6%). Only two
      patients (1%) had a typical episode of pouchitis. The mean follow-up was 29
      months (range, 3 to 100 months); 101 patients were monitored for more than 1
      year. Little difference was noted between bowel function after IRA and that after
      IPAA. The mean daytime stool frequency after IPAA was 4.2 with 26% of patients
      having an average of 1 bowel movement at nighttime, compared with a stool
      frequency of 3.0 and 13% of patients having night evacuation after IRA. Daytime
      continence was normal for 98% of patients after IPAA and for all the patients
      after IRA. Nighttime continence was normal in 96% and 98% of patients,
      respectively. CONCLUSIONS: Morbidity and functional results after IPAA for
      familial adenomatous polyposis do not differ from those reported after IRA. For
      this reason and because of the risk of rectal cancer after ileorectal
      anastomosis, IPAA with endoanal mucosectomy is our first choice in the treatment
      of patients with familial adenomatous polyposis.

PMID- 8650602
TI  - Persistent elevated serum levels of intact parathyroid hormone after operation
      for sporadic parathyroid adenoma: evidence of detrimental effects of severe
      parathyroid disease.
AB  - BACKGROUND: A significant number of patients with primary hyperparathyroidism
      (pHPT) who are surgically treated have increased serum levels of intact
      parathyroid hormone (PTH) during long-term follow-up despite normocalcemia. The
      cause and significance of this finding remain to be established. METHODS: A total
      of 82 patients operated on for sporadic parathyroid adenoma were investigated
      before and at 8 weeks and 1 year after operation with serum levels of intact PTH,
      bone mineral content, and biochemical variables known to reflect PTH activity.
      RESULTS: All patients had low or normal serum levels of calcium during follow-up.
      At 8 weeks after operation 20 (24%) patients had increased serum levels of PTH.
      These patients had severe parathyroid disease and low levels of 25(OH) vitamin D
      before operation. In contrast to patients with normal levels of PTH after
      operation, they did not have an elevated bone mineral content but had elevated
      levels of serum creatinin. At 1 year after operation 13 patients had elevated
      serum levels of PTH. Compared with patients with normal serum levels of PTH, they
      were older and had an increased frequency of cardiovascular disease and
      biochemical indications of compromised renal function. They did not have an
      elevated bone mineral content. CONCLUSIONS: Persistently increased serum levels
      of PTH indicate harmful effects of pHPT even after surgical cure, especially in
      elderly patients with severe disease before operation. The results in this
      investigation therefore favor early treatment of pHPT.

PMID- 8650603
TI  - Management of new hepatic nodules detected by intraoperative ultrasonography
      during hepatic resection for hepatocellular carcinoma.
AB  - BACKGROUND: During hepatic resection for hepatocellular carcinomas (HCCs) it is
      not uncommon that intraoperative ultrasonography detects "new nodules" that were
      not found by preoperative examinations. Because the operative procedure may have
      to be changed if the new nodule is another HCC lesion, differential diagnosis of
      such nodule is critical. This study examines ultrasonographic findings and
      clinical features of new nodules and discusses how to cope with such nodules in
      the operating room. METHODS: Fifty-one new nodules detected in 92 liver
      resections were analyzed. Intraoperative ultrasonography was performed by using
      5.0 or 7.5 MHz probes after mobilization of the liver. Histologic diagnosis of
      the new nodules was made by means of enucleation, resection with the primary
      lesions, thick-needle biopsy, or additional partial resection of the liver.
      RESULTS: New nodules were detected in 27 (29.3%) of 92 resected cases. Internal
      echoic pattern of the nodules were type I, hypoechoic (29 nodules); type II,
      hyperechoic (19); and type III, mosaic (3). Ten HCC nodules (17.9%) were
      included, and chance of being malignant for each type was 24.1%, 0%, and 100%,
      respectively. Of the seven patients with malignant new nodules, three underwent
      additional systematic resection and all were alive without recurrence 49, 13, and
      11 months after the operation. Others were treated by use of enucleation (two
      cases), intraoperative ethanol injection (one case), and intraarterial
      chemotherapy (one case). CONCLUSIONS: Although most of the new nodules lacked
      specific findings for HCC, hypoechoic nodules, 24.1% of which were HCCs, should
      not be overlooked. Histologic confirmation of the new nodules is necessary
      especially when the number of lesions detected before operation is multiple or
      the interval between lipiodol computed tomography and the operation is longer
      than 2 months. Once the diagnosis of HCC has been made for the new nodule,
      systematic additional resection to remove the new lesion is recommended.

PMID- 8650604
TI  - Functional perineal colostomy with pudendal nerve anastomosis following anorectal
      resection: an experimental study.
AB  - BACKGROUND: The aim was to reconstruct the functional anus by using a transposed
      skeletal muscle with pudendal nerve anastomosis (PNA) after anorectal resection.
      METHODS: Transposition of the biceps femoris muscle (BFM) with PNA around the
      perineal colostomy was performed in 22 dogs. In the control group (n = 11) the
      BFM with its own nerve was used. Evaluation was done at 3 to 5 months after the
      operation. RESULTS: A contraction with evoked potential on electrical stimulation
      of the pudendal nerve (22 of 22) and tonic electrical activity (10 of 10) were
      observed in the dogs with PNA but not in those without PNA. Increased electrical
      activity (6 of 6) and a reactive rise in the neoanal canal pressure (9 of 13)
      were seen just after the insertion of a microballoon in the dogs with PNA but not
      in those without PNA. The neoanal canal length was elongated, and the anorectal
      angle became acute on electrical stimulation in both groups. No difference was
      seen in the resting anal pressure between both groups. The pattern of actomyosin
      adenosine 5'-triphosphatase staining of the neosphincter with PNA converted from
      that of a BFM to that of the external anal sphincter. The defecatory status in
      the study group was better according to the evaluation of the feces on the cage
      floor. CONCLUSIONS: Acceptable neoanal function was achieved through the
      sphincter reconstruction with PNA.

PMID- 8650605
TI  - P-selectin mediates intestinal ischemic injury by enhancing complement
      deposition.
AB  - BACKGROUND: Ischemia and reperfusion injury of rodent intestine is complement
      mediated. P-selectin antagonism reduces local injury, yet neutrophil depletion
      does not. This study tests the thesis that the protective mechanism of P-selectin
      antagonists involves complement inhibition. METHODS: We subjected rats (n = 86)
      to 50 minutes of complete mesenteric ischemia and 4 hours of reperfusion.
      Treatment with a monoclonal antibody (PB1.3) against P-selectin reduced
      intestinal injury as judged by 125I-albumin permeability index (7.33 +/- 0.40)
      compared with saline solution treatment (11.4 +/- 0.49) (p < 0.05). RESULTS:
      However, intestinal neutrophil sequestration assessed by myeloperoxidase assay
      was unchanged. Immunohistochemistry revealed that mucosal C5b-9 was deposited in
      animals treated with saline solution and was absent in the sham group. PB1.3
      treatment reduced C5b-9 deposition in the intestinal mucosa compared with that in
      animals treated with saline solution (p < 0.05). Neutrophil-dependent remote lung
      injury assessed by 125I-albumin permeability and pulmonary myeloperoxidase assay
      were not significantly reduced by PB1.3. Treatment with a soluble form of P
      selectin ligand, sialyl Lewisx (sLex), reduced intestinal myeloperoxidase (0.065
      +/- 0.006) compared with saline solution treatment (0.136 +/- 0.02) (p < 0.05),
      but it did not reduce permeability. Remote lung permeability was reduced (4.52 +/
      0.65 x 10(-3)) by sLex compared with saline solution treatment (6.11 +/- 0.41 x
      10(-3)) (p < 0.05). CONCLUSIONS: Antagonizing the lectin domain of P-selectin and
      thereby neutrophil adhesion was without local benefit in this model. In contrast,
      PB1.3 exerted a novel antagonism of P-selectin and reduced complement deposition.

PMID- 8650606
TI  - Effects of granulocyte colony-stimulating factor in severe pancreatitis.
AB  - BACKGROUND: The effect of granulocyte colony-stimulating factor (G-CSF) on the
      rate of secondary infections in acute pancreatitis was evaluated in a canine
      model. Infectious complications are the major determinant of morbidity and
      mortality in severe pancreatitis. Bacterial translocation has been shown to be a
      cause of these secondary infections. The relative immunosuppression found with
      pancreatitis may promote translocation and the spread of bacteria to the
      pancreas. METHODS: Thirty-four mongrel dogs were studied. Pancreatitis was
      induced in 18 dogs; 9 were treated with 100 micrograms G-CSF/day and 9 were given
      only saline solution. Laparotomy alone was done in 16 dogs of which one half were
      given 100 micrograms G-CSF/day and one half were given saline solution. Daily
      blood counts and cultures were obtained. All dogs were killed on day 7, and the
      mesenteric lymph nodes, pancreas, liver, spleen, and peritoneal fluid were
      cultured and studied histologically. RESULTS: G-CSF caused a significant and
      sustained increase in mature granulocytes in dogs given pancreatitis. No
      difference was found in the rate of translocation to mesenteric lymph nodes in
      dogs given G-CSF (n = 4) versus dogs given saline solution (n = 6). However, a
      significant decrease occurred in the spread of bacteria to distant sites in dogs
      given G-CSF (1 versus 15, p < 0.05). CONCLUSIONS: Although G-CSF does not
      decrease the rate of translocation, it does decrease the rate of distant
      infection in severe acute pancreatitis.

PMID- 8650607
TI  - Regulation of the acute phase response genes alpha 1-acid glycoprotein and alpha
      1-antitrypsin correlates with sensitivity to thermal injury.
AB  - BACKGROUND: The response to thermal injury is a complex physiologic process
      requiring communication between sites of injury and distal target organs. The
      liver, one of these target organs, synthesizes a family of secretory proteins,
      the acute phase reactants (APRs), that carries out specific protective functions.
      This study investigates the response of positively regulated (alpha 1-acid
      glycoprotein and alpha 1-antitrypsin) and negatively regulated (albumin) APR
      genes to severe thermal injury in three rat strains with differing abilities to
      survive thermal stress. METHODS: Age and weight matched male Buffalo, Sprague
      Dawley, and Fischer 344, 12- to 16-week-old rats (275 to 325 gm) received a 40%
      total body surface area scald burn. Total RNA was isolated from livers at 0, 2,
      5, 12, 24, and 48 hours. Northern blot hybridization was performed with 32P
      labeled rat alpha 1-glycoprotein, rat albumin, and mouse alpha 1-antitrypsin
      cDNAs. Relative amounts of alpha 1-glycoprotein, alpha 1-antitrypsin, and albumin
      mRNAs were determined by means of densitometric analyses. RESULTS: All three
      strains elicit both a positive and negative acute phase (AP) response.
      Significant differences were observed in the degree and kinetics between strains.
      Those more sensitive to thermal injury exhibited a more intense positive AP
      response and possibly a delayed recovery. The AP response between these strains
      correlates with the variation in ability to survive severe trauma. CONCLUSIONS:
      The differences in the kinetics and intensity of induction of APR genes between
      Buffalo, Sprague-Dawley, and Fischer rat strains suggest that the least intense
      AP response and its timely recovery correlated with the ability to survive a
      severe thermal injury and that, conversely, the more intense and prolonged
      response correlated with sensitivity to severe thermal injury. We propose that
      this may be a basis for variation in survival to thermal injury.

PMID- 8650608
TI  - Effect of thermal injury on the expression of transcription factors that regulate
      acute phase response genes: the response of C/EBP alpha, C/EBP beta, and C/EBP
      delta to thermal injury.
AB  - BACKGROUND: Eukaryotic organisms possess natural defense mechanisms that protect
      against stress stimuli. One such mechanism is the activation of families of
      stress response genes (e.g., the acute phase response). Transcription of many of
      these genes is regulated by the leucine zipper or bZIP proteins (CCAAT
      binding/enhancer binding proteins [C/EBPs]). The aim of this study was to show
      that the C/EBP transcription factor genes respond to thermal injury. METHODS: Age
      and weight-matched male Buffalo, Sprague-Dawley, and Fischer 344 12- to 16-week
      old rats (275 to 325 gm) received a 40% total body surface area scald burn. Total
      RNA was isolated from livers at 0, 2, 5, 12, 24, and 48 hours. Northern blot
      hybridization was performed with 32P-labeled C/EBP alpha, C/EBP beta, and C/EBP
      delta cDNAs. Relative amounts of each mRNA were determined by densitometric
      analyses. For Western analyses liver nuclear and cytoplasmic protein extracts
      were prepared from burned and control rats. Nuclear protein extracts were
      resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, blotted
      onto a PVDF membrane, and detected by using an enhanced chemiluminescence
      detection kit. RESULTS: Expression of C/EBP genes is regulated in response to 40%
      total body surface area scald burn. A simultaneous decrease in C/EBP alpha and an
      increase in C/EBP beta and C/EBP delta mRNA levels occur in response to thermal
      injury. Western analyses detect changes in C/EBP alpha and C/EBP beta pool levels
      that suggest a differential regulation of these genes in response to thermal
      injury. CONCLUSIONS: The responses of C/EBP alpha, C/EBP beta, and C/EBP delta
      are similar in Buffalo, Sprague-Dawley, and Fischer rats. The induced level,
      however, of C/EBP beta mRNA was highest in the Sprague-Dawley strain and lowest
      in the Buffalo strain and correlates well with the mortality of these strains.
      Because C/EBP beta is associated with the transactivation of stress response
      genes, this may explain the intensity of the response in the susceptible strains.
      This agrees with our hypothesis that the higher degree of sensitivity of the
      Sprague-Dawley rat to stress relative to the Buffalo strain may be due to
      inherently higher levels of factors such as C/EBP whose functions are associated
      with activation of stress response genes.

PMID- 8650610
TI  - Sociologic factors are major determinants of prolonged hospital stay after
      abdominal aneurysm repair.
AB  - BACKGROUND: With increasing pressure to optimize the utilization of hospital
      resources, it is important to identify patients who may have prolonged hospital
      length of stay (LOS). The purpose of this report was to identify the preoperative
      variables that are predictive of prolonged postoperative hospital LOS for
      patients undergoing elective infrarenal abdominal aneurysm repair and to discuss
      strategies that might assist in minimizing LOS for these patients. METHODS: Three
      hundred sixty-five consecutive patients underwent elective infrarenal abdominal
      aneurysm repair between 1989 and 1994. The relationship between 13 preoperative
      variables and LOS was analyzed by using both univariate (Kaplan-Meier) and
      multivariate (Cox regression) statistical techniques. RESULTS: By using Cox
      regression a model was developed to estimate LOS (p < 0.001 for model). The
      independent predictors for prolonged LOS were (1) age older than 70 years and (2)
      absence of a spouse. CONCLUSIONS: Knowledge of the predictive factors that are
      associated with prolonged LOS should identify those patients who may require
      prompt and efficient discharge planning, early consultation with a home care
      nurse, or transfer to a convalescent facility. This approach may significantly
      improve the utilization of hospital resources.

PMID- 8650611
TI  - Hypothesis: compartmentalization of cytokines in intraabdominal infection.
AB  - BACKGROUND: Although the proximal role of systemic cytokines in the infectious
      inflammatory cascades is well recognized, the magnitude and meaning of its
      intraperitoneal levels in peritonitis have received little attention. We
      hypothesized that in peritonitis a significant and clinically relevant cytokine
      mediated inflammatory response is compartmentalized in the peritoneal cavity.
      METHODS: MEDLINE was used to search the literature for all articles dealing with
      experimental, primary, and secondary bacterial peritonitis and cytokines.
      RESULTS: Bacterial peritonitis is associated with an immense intraperitoneally
      compartmentalized cytokine response, with plasma levels of cytokines representing
      only the tip of the iceberg. Although certain amount of cytokines may be
      beneficial to the peritoneal defense mechanisms, higher levels correlate with
      adverse outcome. Thus it is plausible to look at acute peritonitis as initially a
      combined infective (microorganism) and inflammatory (cytokines) process. The
      clinical significance of the distinction between peritoneal inflammation and
      infection and the relevance of our findings to the stratification and treatment
      of peritonitis are discussed. CONCLUSIONS: Current surgical and antibiotic
      therapy for peritonitis is able to clear the peritoneal cavity of infective
      concentration of bacteria, but many patients continue to die of an uncontrolled
      activation of the inflammatory cascade. We suggest that one potential venue for
      therapeutic progress is the modulation of the compartmentalized peritoneal
      inflammatory response.

PMID- 8650609
TI  - Enhanced ketogenesis in the kidney during hepatic inflow occlusion with the
      administration of Ringer's acetate solution.
AB  - BACKGROUND: The blood levels of ketone bodies, which are synthesized principally
      in the liver, were maintained even during hepatic inflow occlusion if Ringer's
      acetate solution (AR) was administered, resulting in an improvement of hepatic
      energy level in the reperfusion phase, as reported in our previous experimental
      study. The current study was designed to prove that the kidneys are the organs
      that contribute to synthesize ketone bodies during hepatic inflow occlusion if AR
      is administered. METHODS: The arterial, central venous, renal venous, and renal
      tissue ketone body concentrations were determined in rabbits administered AR or
      Ringer's lactate solution (LR) at 20 minutes of hepatic ischemia and at 30
      minutes of reperfusion. The concentrations were also compared in rabbits under AR
      infusion with or without hepatic ischemia for 20 minutes. Statistical analyses
      were performed by means of ANOVA: RESULTS: With AR the renal venous ketone body
      concentration not only was higher than that with LR (p < 0.001) but also was
      higher than the arterial concentration (p = 0.05). The renal tissue ketone body
      concentration was higher than in those with LR (p < 0.001) and also than in those
      without occlusion (p < 0.001). CONCLUSIONS: Ketogenesis is enhanced in the kidney
      and may compensate for hepatic loss of ketogenic function during hepatic inflow
      occlusion under AR administration.

PMID- 8650612
TI  - Fibrinolysis in human peritoneum during operation.
AB  - BACKGROUND: A reduced local fibrinolysis seems to be an important mechanism in
      the formation of adhesions. Peritonitis may cause adhesions, and the aim of the
      present study was to determine peritoneal fibrinolytic capacity in inflamed and
      normal peritoneum. METHODS: Biopsy specimens from normal and inflamed human
      peritoneum were taken at the beginning and end of operation. After extraction
      plasminogen activator activity (PAA) was determined by using a chromogenic
      substrate assay in the presence or absence of inhibitory antibodies against
      tissue-type plasminogen activator (t-PA), urokinase or plasminogen activator
      inhibitor-1. RESULTS: t-PA exerted 95% of the PAA. PAA was significantly reduced
      (p < 0.01) during peritonitis (3.0 IU/micrograms protein; range, 0.3 to 4.2)
      compared with normal peritoneum (7.1 IU/micrograms protein; range, 0.6 to 18.1).
      A significant reduction (p < 0.05) in PAA occurred during operation both in
      normal peritoneum (3.8 IU/micrograms protein; range, 0.8 to 8.6) and in
      peritonitis (0.6 IU/micrograms protein; range, 0.16 to 2.1). Values are given as
      medians. CONCLUSIONS: The main PAA in human peritoneum was t-PA. The activity was
      decreasing during operation and reduced in peritonitis. This reduction in PAA
      might be a local response to inflammation.

PMID- 8650613
TI  - Practice guidelines in surgery.

PMID- 8650614
TI  - Hyperparathyroidism and pancreatitis during pregnancy.
AB  - Although the simultaneous occurrence of hyperparathyroidism and pancreatitis
      during pregnancy is rare, several points should be emphasized. Early recognition
      and treatment are essential. Pancreatitis should be kept in the differential
      diagnosis of unexplained nausea, vomiting, and abdominal pain during pregnancy.
      Hyperparathyroidism should always be included in the differential diagnosis of
      pancreatitis. Finally, the second trimester is the optimal period for surgical
      intervention.

PMID- 8650615
TI  - Preoperative angiography and embolization of the site of intermittent acute small
      bowel bleeding with a radiopaque microcoil: facilitated precise surgical excision
      of the source.

PMID- 8650616
TI  - Duodenocaval fistula complicating peptic ulcer disease: case report and review of
      the literature.

PMID- 8650617
TI  - Multivisceral injury after liquid caustic ingestion.

PMID- 8650618
TI  - [Diagnosis and treatment of amblyopia].
AB  - The word amblyopia means weak vision on a functional basis. The most important
      form is strabismic amblyopia. Its diagnosis is easy in cases of obvious
      unilateral strabismus; in cases with slight squint angles this may be difficult.
      The most important treatment is carefully controlled occlusion of the dominant
      eye.

PMID- 8650619
TI  - [Rapid eye fatigue--causes and therapy].
AB  - Tired eyes even after a short period of strain are well known as asthenopia. This
      term derives from a Greek expression meaning 'weak eye'. The following reasons
      are to be taken into account: uncorrected refractional errors such as hyperopia
      and astigmatism, accommodative and fusional defects and heterophoria, or
      combinations there of. With many cases of asthenopia the clinical symptomatology
      may resemble an organic eye disease or an affection of the brain [dry eye,
      Graves' disease, myasthenia, special form of essential blepharospasm, neurogenic
      latent eye muscle palsies, narcolepsy]. It is the aim of a precise patient's
      history to differentiate between functional and organic causes. By means of case
      reports and diagnostic tools, the development of symptomatology and the therapy
      are discussed.

PMID- 8650620
TI  - [Vision disorders in retrochiasmatic lesions of the visual pathways].
AB  - Anatomic elements of the retrochiasmatic pathway. Synopsis of homonymous pathway.
      Synopsis of homonymous hemianopia: unilateral forms [quadrant, total], bilateral
      forms [tunnel field, cerebral blindness], homonymous scotomas, horizontal
      hemianopsias, checkerboard hemianopsias, sparing of temporal crescent. Additional
      disorders: hemi-neglect, color agnosia, hemi-achromatopsia, alexia, abnormal
      optokinetic nystagmus, cog-wheel pursuit movement, hemianopic pupillary defect,
      statokinetic dissociation [Riddoch phenomenon], hallucinations, illusions, visual
      agnosia, prosopagnosia.

PMID- 8650622
TI  - [Assessment of vision disorders using color duplex ultrasonography].
AB  - Disturbed circulation is a common cause of visual impairment which time course
      and severity can vary. Prompt diagnosis and therapy are mandatory to restore
      visual function in cases of acute drop of vision. Color Doppler imaging is a
      noninvasive method to investigate blood-flow velocity. During the past years this
      method has been introduced into ophthalmology. For the first time it is possible
      to measure the blood-flow velocity in the ophthalmic artery, the central retinal
      artery and vein as well as the ciliary arteries to quantify the extent of
      impaired ocular circulation.

PMID- 8650621
TI  - [Vision disorders to vascular dysregulation].
AB  - As in the case in other organs, there are infarctions in the eye due to arterial
      sclerosis. Here, the classic risk factors apply. In addition to such infarctions,
      there are reversible perfusion disturbances caused by vascular dysregulation.
      These very frequently lead to slight, transient functional failures which are
      scarcely noticed by the patient. In more seldom cases, such dysregulation can
      contribute to the pathogenesis of various disease entities. Of these, the ocular
      vasospastic syndrome, migraine, glaucoma, apoplexy of the optic nerve, and vein
      thrombosis were examined.

PMID- 8650623
TI  - [Why are AIDS patients frequently visually impaired?].
AB  - Patients with HIV infection and, above all, patients with full-blown AIDS can get
      a variety of ocular diseases as well as some cerebral maladies which have an
      influence on ocular functions. First there are hematogenous opportunistic
      infections of the retina or the choroid. The cytomegalovirus [CMV] retinitis was
      found in nearly 20% of all AIDS patients. Without treatment this disease destroys
      the retina completely, and the involved eye becomes blind. This can be prevented
      by modern therapeutic strategies in most of the cases. Other infections affecting
      the retina are toxoplasmosis, systemic varizella zoster or herpes simplex virus
      infections, syphilis or, seldom, fungal or bacterial pathogens. The choroid
      mainly can be infested by mycobacteria, cryptococci and pneumocystis carinii.
      Early detection and treatment of all inflammations are necessary. The anterior
      eye can be affected by a sicca syndrome and various superficial infections but
      also noninfectious inflammation. The anterior uvea can be involved in various
      opportunistic infections of the posterior eye segment. An HIV-associated isolated
      anterior uveitis has been described in earlier stages of the HIV infection.
      Treatment of mycobacterial infections with rifabutin can cause an anterior
      uveitis as well. 1 to 2% of HIV-infected persons suffer from a zoster
      ophthalmicus with more severe keratitis than it occurs in immunocompetent
      persons. Last but not least, there are various cerebral affections which can
      cause visual disturbances. So the optic nerve can be involved in various forms of
      retinitic or meningoencephalitic processes, of ischemic mechanisms or elevated
      intracranial pressure. Neuroophthalmological symptoms also include homonymous
      hemianopsia caused by foci of cerebral toxoplasmosis, progressive multifocal
      leucencephalopathy or primary intracerebral malignant lymphoma situated in the
      central neuron of the afferent visual pathway. A variety of oculomotor
      abnormalities can be caused by a great variety of cerebral disease. Moreover,
      there are signs of neuroretinal dysfunction in computed perimetry and in color
      vision or contrast sensitivity testing. Some sight threatening diseases initially
      can be symptomless for the patient, though they should be treated immediately in
      order to keep the remaining visual damage small. Thus, regular ophthalmological
      investigations are necessary in patients with an advanced stage of the
      immunodeficiency, regardless whether they have ocular complaints or not.
      Moreover, the patients have to be advised to attend an ophthalmologist
      immediately, when they notice any kind of visual disturbances or ocular symptoms.

PMID- 8650624
TI  - [Vision disorders in inflammatory-rheumatic diseases].
AB  - The association of visual disturbances and rheumatic disease has been known for
      centuries. This review provides a synopsis of the ocular conditions that are
      associated with inflammatory rheumatic disease. The major ophthalmic
      manifestations of the rheumatic diseases include keratoconjunctivitis sicca,
      ulcerative keratitis, scleritis, uveitis, retinal vascular disease, and neuro
      ophthalmic lesions. Each of these ocular conditions is most characteristically
      associated with a few, but not all, of the rheumatic disorders. Scleritis, for
      example, is most often seen with rheumatoid arthritis or with vasculitis. Acute
      anterior uveitis is most often seen with the seronegative spondylarthropathies.
      Retinal vascular and neuro-ophthalmic lesions are seen with disorders having
      either a vaso-occlusive component, such as systemic lupus erythematosus, or with
      one of the vasculitides. Important considerations for a successful collaboration
      between ophthalmologists and physicians/rheumatologists are discussed.

PMID- 8650625
TI  - [Vision disorders and their causes].

PMID- 8650626
TI  - [Diabetes: can severe vision disorders be prevented?].
AB  - No matter how well known the causes of diabetic microangiopathy are, the growth
      factors responsible for the development of diabetic retinopathy are still not
      fully investigated; however, promising new concepts are presently in the
      experimental stage. Now known for decades, laser coagulation of the ocular fundus
      represents the only current method to stabilize a diabetic retinopathy or to
      treat an already existing diabetic macular edema. The results of almost all
      studies prove that besides an optimal management of metabolism timely begin of
      laser coagulation is of high priority. In addition to consistent therapy,
      continual follow-up of the patients is of importance, because recurrences can
      follow successful laser coagulation.

PMID- 8650627
TI  - [Severe hereditary retinal diseases in childhood].
AB  - In dependence on the various statistics, hereditary causes are identified in up
      to 50% of the visually handicapped and blind school children. Most common are
      retinal disorders, which account for 15 to 55%. The most important diseases are
      briefly reviewed: Leber's congenital amaurosis, rod monochromacy, blue cone
      monochromacy, congenital stationary night blindness (CSNB), X-linked retinitis
      pigmentosa, Usher syndromes, Bardet-Biedl syndrome, juvenile neuronal ceroid
      lipofuscinosis Spielmeyer-Vogt, the various forms of albinism, exsudative
      vitreoretinopathies including Norrie's disease, as well as Stargardt's macular
      dystrophy, vitelliform macular dystrophy, and hereditary retinoblastoma. In
      addition to the clinical symptoms, general genetic principles are stressed, such
      as mode of inheritance, heterogeneity, expressivity, penetrance, age at
      manifestation, X-chromosomal gene inactivation, and variability. They all have to
      be taken into account to correctly establish the diagnosis, to identify family
      members at risk, and to provide adequate genetic counselling. An overview of the
      actual molecular genetics of the various retinal disorders is also given.

PMID- 8650629
TI  - [Coverage by general practitioners--do we have the right distribution?].

PMID- 8650628
TI  - [Ribozymes--against virus diseases and cancer].

PMID- 8650630
TI  - [Femoral neck fractures].

PMID- 8650631
TI  - [Total hip arthroplasty after femoral neck fractures. Results from the national
      registry on joint prostheses].
AB  - From September 1987 to January 1994, data on 3,876 total hip arthroplasties
      performed because of previous hip fracture were collected in the Norwegian
      arthroplasty register. During the same period, 19,654 patients received total hip
      arthroplasties because of osteoarthrosis. The results of total hip arthroplasties
      after an earlier hip fracture were compared with prostheses in patients who were
      operated on because of primary osteoarthrosis. After five years the cumulative
      percentage failure was 4.1 in the fracture group and 3.7 in the arthrosis group
      (p = 0.19). After adjustment for differences in sex and age distribution in the
      Cox model, the fracture patients were shown to have 1.35 times higher risk of
      revision when compared with the osteoarthrosis patients (p = 0.008). The reasons
      for reoperation differed, however, in the two groups. More of the fracture
      patients than of the osteoarthrosis patients had to be reoperated because of
      dislocation or femoral shaft fracture, while fewer needed reoperation because the
      acetabular component had loosened.

PMID- 8650632
TI  - [Acute stroke. Patients treated in a stroke unit in Trondheim].
AB  - Treatment in a stroke unit raises the proportion of stroke patients who are able
      to live at home, improves functional outcome, reduces the need for institutional
      care, and brings down mortality. We have evaluated the data on the first 800
      patients treated in our stroke unit. Nine patients were incorrectly registered as
      acute stroke victims and were excluded from the analysis. Hence, 791 patients
      (429 men, 362 women; mean age 72.3 years range 35-101 years) fulfilled the
      criteria for acute stroke or TIA. In the group of 654 patients who had suffered
      an acute stroke, 85 patients (13%) had intracerebral haemorrhage, 439 (67.1%)
      nonembolic infarction, and 130 (19.9%) embolic infarction. The majority of the
      patients were discharged to home (55.4%), while 23.6% were discharged to a
      rehabilitation institution, and 6.1% were discharged to nursing homes. 48 (6.1%)
      of the patients died during the stay in hospital. The mean time spent in the
      stroke unit was 12.1 days.

PMID- 8650633
TI  - [High frequency ultrasonography of the gastrointestinal wall].
AB  - If an ultrasound probe comes close to the area of interest, high ultrasound
      frequencies can be applied. Endoscopic ultrasonography is performed by means of
      echoendoscopes or miniature probes using ultrasound frequencies between 7 and 30
      MHz. A high frequency ultrasound image of the normal gastrointestinal wall
      usually shows five layers corresponding closely to the histological layers of the
      wall. Corrections have to be made, however, for interface echoes between layers
      with different acoustic impedances. We describe studies performed with the aim of
      correlating ultrasound images of the normal and diseased gastrointestinal wall
      with the histology. Ultrasound images of the normal gastrointestinal wall and
      pathological changes like ischemia, ulcers, tumours and inflammation are
      presented.

PMID- 8650634
TI  - [Quick diagnosis of respiratory syncytial virus infection].
AB  - Respiratory syncytial virus (RSV) is a frequent cause of respiratory tract
      infections in children, and the infection spreads rapidly in hospitals. It is
      therefore important to diagnose the disease quickly. We have examined two quick
      tests for detecting RSV-antigen in nasopharyngeal aspirates: Directigen RSV
      (Becton Dickinson, MD, USA) and TestPack RSV (Abbott Laboratories, Chicago, IL,
      USA). Both tests are based on the enzyme immunoassay (EIA) principle. The results
      were compared with a method using direct immunofluorescence. When the
      immunofluorescence test was used as the standard, the sensitivities of Directigen
      and TestPack were 83 and 74%, and the specificities 84 and 100%, respectively.
      Both of the EIA-tests had a lower sensitivity than desired, and Directigen gave
      some uninterpretable results. The tests may be considered for use in small
      laboratories with limited facilities or as a supplement to other diagnostic
      methods.

PMID- 8650635
TI  - [Treatment with growth factors and cytokines in hematologic diseases].
AB  - The Norwegian Society of Haematology has worked out guidelines for the use of
      granulocyte-colony stimulating factor and granulocyte-monocyte colony stimulating
      factor and interferon alpha in clinical haematological practice. We recommend not
      using growth factors as a routine to prevent or to treat fever in patients with
      granulocytopenia induced by cytostatics, or patients with myelodysplastic
      syndromes. At present such treatment should be restricted to clinical trials. The
      same conclusion was reached in regard to use of erythropoietin in the case of
      myelodysplastic syndromes. Harvesting of stem cells from peripheral blood is a
      well documented indication for administration of growth factors. Interferon alpha
      as maintenance treatment for cases of multiple myeloma and low grade malignant
      lymphoma delays progression of the disease but does not improve chance of
      survival. There is no documentation of improved quality of life. Use of
      interferon alpha is not justified as a routine treatment for multiple myeloma. In
      chronic myelogenous leukemia, interferon alpha seems to be equal to or better
      than hydroxyurea, and may be considered for patients who cannot undergo
      allogeneic bone marrow transplantation.

PMID- 8650636
TI  - [ADP-based records in primary health care. Rationalization or reorganization?].
AB  - Computer-based patient record systems have become very common in the primary
      health service, but their effects have seldom been documented. Three surveys were
      carried out in the municipality of Sor-Varanger, in 1993, 1994 and 1995, to
      discover how such a system has affected the running of the municipal medical
      centres. The most significant changes were organisational. Certain tasks changed
      hands, others were dispensed with, and new ones were added. Information on
      patients became more readily available, and services to the public were improved.
      Many more patients received an answer to questions concerning information in the
      case record, and far fewer forms had to be filled in manually. Despite this,
      computerisation had seemingly led to little change in effectiveness, and the
      total load of work remained the same. The survey also showed that simple
      extensions to the system could produce marked improvements.

PMID- 8650637
TI  - [Physicians employed by municipalities--how big are the differences?].
AB  - The present paper discusses the geographical distribution of physicians employed
      in municipal primary care. In Norway, primary medical services are the
      responsibility of the local public authority (the municipality) and are financed
      primarily by the general taxation. The allocation of physicians is analysed using
      a municipal demand model. The model is a synthesis of consumers' demand and
      allocation of municipal funds. Analyses were performed on a panel data set of all
      Norwegian municipalities covering the period 1986-92. The results are
      encouraging, since they indicate that a decentralised system of primary medical
      services does seem to be fairly effective in securing the municipal population
      equity of access to the services. In particular, the municipalities seem to
      respond well to the health care needs of their population. Distribution of
      physicians depends to only a very small extent on the wealth of the municipality.

PMID- 8650638
TI  - [Statin therapy of individuals with high risk for coronary disease].
AB  - After the release of the results from the West of Scotland Prevention study
      (WOSCOPS) some questions have been raised with respect to validity of its finding
      on all cause mortality, which was reduced by 22% with pravastatin treatment (p =
      0.051) compared with placebo. Also, since WOSCOPS was a primary preventive study
      its results could affect a large proportion of Norwegian men. Thus, it can also
      be asked whether statin treatment should be preferred to standard, specific
      treatment for certain diseases, e.g. hypertension, if economic restrictions by
      the government make it necessary to make priorities. For example, expensive drugs
      are now given free to many diabetics and hypertensives, who should probably be
      treated with statins, almost regardless of their cholesterol level. The total
      social costs of medication could then exceed accepted budgets and could lead to
      restrictions. The author discusses the validity of the WOSCOPS findings on all
      cause mortality, and compares the results obtained in this study with those
      randomised trials and other statin trials. Finally, a comparison is made between
      results from two metaanalyses: one of randomised hypertension trials and one of
      all randomised statin trials. It is concluded that more favourable results are
      obtained from the latter. Caution should be shown, however, when interpreting
      such a comparison.

PMID- 8650639
TI  - [Can vitamin E prevent development of coronary heart disease?].

PMID- 8650641
TI  - [Should a physician always be a physician?].

PMID- 8650640
TI  - [Chronic fatigue syndrome and cognitive therapy].

PMID- 8650642
TI  - [The national agency of drug control approves of a "humbug" drug. Approval of
      natural drugs].

PMID- 8650643
TI  - [When does the occupational environment cause lung disease?].

PMID- 8650644
TI  - [Evolution, pregnancy and birth order].

PMID- 8650645
TI  - [An injection technique as an aid in the use of 20 ml needles].

PMID- 8650646
TI  - [Increased measures against smoking].

PMID- 8650647
TI  - [Interdisciplinary treatment of pain].

PMID- 8650648
TI  - [The Norwegian calendar for emergency services. An important initiative in cases
      of childhood emergencies].

PMID- 8650649
TI  - [Copyright of laboratories].

PMID- 8650651
TI  - [Problems with waiting lists].

PMID- 8650650
TI  - [The fight against "health criminality"].

PMID- 8650652
TI  - [Forensic psychiatry in Norway].

PMID- 8650653
TI  - [Multiple trauma and treatment of liver injuries. Some newer principles].

PMID- 8650655
TI  - [Cancer metastasis].
AB  - Despite increasing insight into the biology of tumour development, the number of
      cancer deaths has not been subsequently reduced. This may be because
      approximately half of the cancers have metastasized already at the time of
      initial diagnosis. It seems important therefore, to learn more about the complex
      metastatic process. This process includes several linked sequential steps, and
      depends on an intimate interaction between the metastatic cells and the
      environment. In this review, we discuss these steps with emphasis on recent
      studies of the various cellular interactions that take place. Understanding these
      factors should result in diagnostic improvements and more effective treatment of
      cancer metastasis.

PMID- 8650654
TI  - [Liver injuries].
AB  - We report on a series of 193 patients with traumatic liver injuries treated at
      our Trauma Centre I during the period 1983-94; i.e. about 13 patients per year.
      The centre has a catchment population of 850,000. Most of the patients were
      severely injured, with 3.2 injured organs per patient among the 151 patients with
      multiple injuries. The clinical diagnostic work was supplemented with peritoneal
      lavage, ultrasonography and computer tomography. 38 patients were not operated
      on, of whom 25 survived. Exploratory laparotomy with or without liver suturing
      was used in 125 patients and liver resection in 18 seriously injured patients,
      with more than 50% mortality. Perihepatic packing was used in 12 patients, all
      with other serious injuries and with a high rate of mortality from these
      injuries. Liver injuries can be divided into two groups. A few injured patients
      are admitted in severe shock, and may be treated with immediate thoracotomy and
      clamping of the aorta, followed by urgent laparotomy to control bleeding by means
      of packing. The rest of the abdomen is examined quickly and closed, to avoid well
      known complications of bleeding and multitransfusions, i.e. hypoxaemia, acidosis
      and hypothermia. Repeat laparotomy follows in 2-3 days, to remove the packing. A
      stable patient should be referred for computer tomography, and may be treated
      without operation, but must be followed closely clinically.

PMID- 8650656
TI  - [Disease-modifying drugs in rheumatoid arthritis. Duration of treatment and
      reasons for withdrawal].
AB  - Duration of treatment and the reasons for discontinuing medication were studied
      in 360 patients with rheumatoid arthritis who had received in all 710
      prescriptions for disease modifying antirheumatic drugs. The most frequently
      prescribed drugs were methotrexate, gold thiomalate, auranofin and
      sulphasalazine. Median duration of treatment ranged from 165 days (chlorambucil)
      to 341 days (methotrexate). The most common reason for discontinuing treatment
      with hydroxychloroquine was insufficient effect. The other drugs were most often
      discontinued because of adverse reactions. The probability of continued therapy
      with methotrexate after two years was 23% (Kaplan-Meier survival analysis), which
      is low compared with results from similar studies performed in other countries.
      This discrepancy may be due to differences both in local practices as regards
      monitoring of drug therapy and guidelines for conducting checks.

PMID- 8650657
TI  - [Tuberculous lymphadenitis caused by Mycobacterium bovis].
AB  - According to the literature, bovine tuberculosis in man has been an illness of
      minor importance in Norway, unlike in Sweden and Denmark. This situation cannot
      be explained, since in former days infected cattle were a problem in the
      southeastern part of the country in particular. No case of bovine tuberculosis in
      humans has been reported in Norway since 1940. Recently we have observed a 29
      year-old female immigrant from India with cervical lymph node tuberculosis caused
      by M. bovis. A second case is a 77-year-old Norwegian male. In the 1920s, at the
      age of ten, he was infected in Norway by drinking raw milk from tuberculous
      cattle. He developed tuberculosis of the mesenterial lymph nodes. Neither of
      these patients had tuberculosis in any other part of their body. Previous
      Norwegian reports, covering eight cases, are summarized.

PMID- 8650658
TI  - [Structural abnormalities of the hair shaft].
AB  - The diagnosis of structural abnormalities of the hair shaft is of clinical
      relevance, since such abnormalities may indicate underlying metabolic disorders,
      or may be associated with other diseases. Many of the abnormalities present
      themselves as alopecia and are due to greater fragility of the hair shaft. An
      outline of some of the most common hair shaft abnormalities is given, as shown by
      patients with trichorrhexis nodosa, pili torti, "uncombable hair" and pili torti
      et canaliculi.

PMID- 8650659
TI  - [Transjugular intrahepatic portasystemic shunt. A new therapeutic method in
      portal hypertension].
AB  - Over the last three years, 53 patients underwent transjugular portosystemic
      shunting (TIPS). 49 patients were treated successfully (92.5%). Procedure-related
      morbidity (intention to treat) was seen in 11 patients (20.8%): encephalopathy (n
      = 5), sepsis (n = 3), right heart failure (n = 2) and progressive liver failure
      (n = 1). 30-day mortality rate was 13.2% (7/53); five of these patients were in
      stage Child-Pugh C, one patient in stage B, and one patient had a known coronary
      heart disease. 30-day rebleeding rate was 6.1% (3/49), but all these patients
      could be retreated successfully by radiological methods (PTA, embolisation,
      thrombolysis). Angiographic follow-up (mean six months) of 35 patients detected
      30 (85.7%) haemodynamic relevant obstructions (stenosis of stent: n = 4, stenosis
      of hepatic vein: n = 15, stenosis of stent and hepatic vein: n = 5, occlusion of
      TIPS-shunt: n = 6). Secondary patency rate following percutaneous reintervention
      was 91.3%. All rebleedings in the follow-up (n = 7) were treated successfully by
      TIPS-revision. Five out of 12 patients (41.7%) with refractory ascites were
      treated successfully by TIPS (complete resolution of ascites after three months:
      n = 4, significant reduction of ascites: n = 1). We conclude that transjugular
      portosystemic shunt is an effective way of treating portal hypertension, but
      there is a need to develop methods to prevent the high incidence of shunt
      stenosis.

PMID- 8650660
TI  - [Digitalis in atrial fibrillation. Still relevant treatment or an old-fashioned
      therapy?].
AB  - The scientific validation of digitalis as the routine treatment for atrial
      fibrillation is far from satisfactory. Whereas digitalis reduces the ventricular
      rate at rest, patients may still experience a too rapid heart rate during
      exercise unless additional drugs are given to reduce atrio-ventricular
      conduction. Digitalis is often prescribed in paroxysmal atrial fibrillation
      despite lack of documentation of benefit from this treatment. Finally, digitalis
      may cause proarrhytmias, and a prothrombotic drug effect cannot be excluded.

PMID- 8650662
TI  - [Creutzfeldt-Jacob disease. A case report].
AB  - Creutzfeldt-Jacob disease is a rare, neurodegenerative disease caused by a prion
      protein. The patients are usually between 40 and 60 years old. Most of the
      patients die within one year after onset of the disease. A typical case is
      reported. It is pointed out that such a dramatic development can cause anxiety
      and a feeling of inadequacy for close relatives. To avoid adverse consequences,
      it is important that the family and the health personnel involved receive
      necessary and adequate information about the disease.

PMID- 8650661
TI  - [Cardiology education in Norway--does it keep up with the needs?].
AB  - Despite an increase in the number of education positions for cardiologists in
      Norway in the late 1980s, there is felt to be a marked lack of sub-specialists in
      cardiology in most types of hospitals. A working group under the Norwegian
      Society of Cardiology has used a questionnaire in 1993, membership data from the
      Norwegian Society of Cardiology in 1994, a telephone query to all hospitals in
      the country, and data from the Norwegian Medical Association in 1995 to examine
      this apparent lack of specialists and the potentials for educating them. We were
      able to confirm a current lack of approximately 60 cardiologists. In addition,
      the capacity for education has been reduced and will not compensate for the
      predicted retirement of specialists from approximately year 2000. The capacity
      for educating cardiologists must be increased.

PMID- 8650664
TI  - [Sick women and men with disability pensions. Some reflections].
AB  - According to population studies, chronic disease leading to a disability pension
      is common in the Norwegian population, and has increased during the last 15
      years. This trend is partly a consequence of the vast increase in the female work
      force during the last 20 years. Simultaneously, there has been a strong increase
      in health facilities and improvement in medical technology. Thus the increase in
      both morbidity and utilisation of the pension scheme seems paradoxical.
      Disability pensions function to secure people's purchasing power. The social
      benefit system in modern welfare states conforms with Keynesian economic
      principles, implying a redistribution of money from the well off on regular pay
      roll to members of the work force who are less adaptable due to disease and
      infirmity. However, there seems to be a substantial potential for further growth
      in the number of disabled persons receiving a pension, particularly among women.
      In many cases a pension serves as an alternative to unemployment benefit. From a
      welfare-state viewpoint such a development is politically and socially more
      acceptable.

PMID- 8650663
TI  - [Forensic psychiatry in Norway. A review of the period 1980-93].
AB  - 2,533 persons charged for serious criminal offences during the years 1980-93 were
      submitted for forensic psychiatric examination. The purpose of the examinations
      was to decide whether the person, because of his or her mental state at the time
      of the offence, was liable or not to prosecution. The three most common criminal
      offences were murder, arson resulting in potential murder and serious cases of
      sexual offence like paedophilia. There was a sharp increase in the number of
      forensically examined persons from 1980 to 1993. This reflects the increasing
      crime rates in Norway, particularly as regards sexual delinquency and violence. A
      majority of the clients had severe chronic drinking and/or drug problems. 27% of
      the females and 19% of the males were psychotic, mainly schizophrenic, at the
      time of the offence. 50-60% had serious personality disorders, mainly of
      antisocial and immature nature. All forensic reports are monitored by the
      Forensic Psychiatric Commission in order to secure the quality of forensic
      assessments. 85% of the reports were accepted. In a few cases the psychiatrists
      were asked to reconsider either parts of or the entire conclusion.

PMID- 8650665
TI  - [Educating future physicians for Ontario--eight roles of physicians].

PMID- 8650666
TI  - [Cancer as social category].

PMID- 8650667
TI  - Partial wave in human seminiferous tubules appears to be a random occurrence.
AB  - Serial cross sections were evaluated to determine the architectural arrangement
      of stages among men with varied spermatogenic efficiencies. Using autopsy
      specimens, glutaraldehyde-perfused testes from men with low or high daily sperm
      production per g parenchyma were compared. Lobes of testicular parenchyma were
      teased from connective tissue septa, further fixed in osmium, and embedded such
      that the straight portions of tubules could be sectioned perpendicularly.
      Unstained 22 microns serial sections were sectioned optically with Nomarski
      optics. Paired photomicrographs of each tubular cross section were taken under a
      40 x objective, and stages of the spermatogenic cycle were mapped by two
      observers using Clermont's criteria (Clermont, 1963). For comparison, numbers (1
      6) were assigned randomly to the stages, the stages were plotted in two
      dimensions (length and circumference of tubule) as if the tubule were cut down
      its length and laid flat, and geometric centers were plotted for each stage.
      Geometric centers consecutive and/or non-consecutive stages appeared to form an
      angle down the length of the tubule. When considering helical patterns along the
      tubule, men with neither low nor high spermatogenic efficiency had a complete
      wave composed of all six consecutive stages. The helical pattern of geometric
      centers indicated only 2-4 consecutive stages when the actual values of stages
      were used or when random numbers were substituted for actual numerical value of
      stages. The number of consecutive stages in tubules from these men was not
      different from consecutiveness found when stages were assigned random numbers.
      Given that no complete wave was found, regardless of spermatogenic efficiency,
      and that the degree of consecutiveness of stages down a helical pattern in human
      seminiferous tubules could be generated from random numbers, the arrangement of
      stages in human seminiferous tubules may simply be a random occurrence.

PMID- 8650668
TI  - Germ cell maturation and cellular associations in the seminiferous epithelial
      cycle of the chimpanzee.
AB  - Seminiferous tubule architecture, germ cell maturation steps and cellular
      associations (stages) of the spermatogenic cycle of the chimpanzee (Pan
      troglodytes) are resolved. Cross sections of seminiferous tubules usually exhibit
      2 to 4 stages, occasionally 1, and rarely 5; stages are not functionally
      sequential in structurally contiguous regions. The cellular maturation steps are:
      dark type A stem cell (Ad), pale type A (Ap), type B(B) spermatogonia; resting or
      preleptotene (P1), leptotene (L), zygotene (Z), pachytene (P), diplotene (Di)
      primary spermatocytes; meiotic divisions (M1, M2); secondary spermatocytes (2
      degrees S); six developmental stages of the spermatid (Sa, Sb1, Sb2, Sc, Sd1,
      Sd2) composing spermiogenesis. The germ cell maturation steps characteristic of
      the six cellular associations (stages I-VI) are: Ad, Ap, B, P, Sa, Sd1 (I); Ad,
      Ap, B, PI, P, Sa, Sd2 (II); Ad, Ap, B, PI, L, P, Sb1 (III); Ad, Ap, PI, L, P, Sb2
      (IV); Ad, Ap, L, Z, P, Di, Sc (V); Ad, Ap, B, Z, P, Di, 2 degrees S, Sc (VI).
      Surgical pressure trauma causes sloughing of some 2 degrees S spermatocytes and
      some Sa, Sb1, Sb2, Sd1, and Sd2 spermatids, resulting in missing generations, and
      disrupts Sertoli cell attachments, affecting germ cell development and
      associations. In structure and function, chimpanzee spermatogenesis appears most
      similar to the human.

PMID- 8650669
TI  - Tissue distribution and developmental expression of type XVI collagen in the
      mouse.
AB  - The expression of a recently identified collagen, alpha 1 (XVI), in adult mouse
      tissue and developing mouse embryo was examined by immunohistochemistry and in
      situ hybridization. A polyclonal antiserum was raised against a recombinant
      fusion protein, which contained a segment of 161 amino acids in the N-terminal
      noncollagenous domain of the human alpha 1 (XVI) collagen. Immunoprecipitation of
      metabolically labelled human or mouse fibroblast cell lysates with this antibody
      revealed a major, bacterial collagenase sensitive polypeptide of approximately
      210 kDa. The size agrees with the prediction from the full-length cDNA.
      Immunofluorescence examination of adult mouse tissues using the affinity purified
      antibody revealed a rather broad distribution of the protein. The heart, kidney,
      intestine, ovary, testis, eye, arterial walls and smooth muscles all exhibited
      significant levels of expression, while the skeletal muscle, lung and brain
      showed very restricted and low signals. During development, no significant
      expression of the mRNA or protein was observed in embryo of day 8 of gestation,
      but strong signals was detected in placental trophoblasts. Expression in embryos
      was detectable first after day 11 of gestation with weak positive signals
      appearing in the heart. In later stages of development, stronger RNA
      hybridizations were observed in a variety of tissues, particularly in atrial and
      ventricular walls of the developing heart, spinal root neural fibers and skin.
      These data demonstrate that type XVI collagen represents another collagenous
      component widely distributed in the extracellular matrix and may contribute to
      the structural integrity of various tissues.

PMID- 8650670
TI  - Ultrastructural and cytochemical analysis of sperm dimorphism in Drosophila
      subobscura.
AB  - In Drosophila subobscura the male produces two classes of motile spermatozoa that
      differ in total length and nucleus length. The significance of this within
      ejaculate polymegaly is obscure. We have carried out an ultrastructural and
      cytochemical analysis of both sperm morphs to understand their possible role at
      fertilization. Computer-aided analysis was used to clarify the complex three
      dimensional structure of the spermatozoa. Short and long spermatozoa have a
      similar architecture. The axoneme is of the classic insect type and, together
      with the major mitochondrial derivative, runs for almost the whole sperm length.
      The axoneme ends just below the sperm apex with a centriole adjacent to the
      acrosome. Minor differences between the two types of sperm are related to
      acrosome size, nucleus morphology and relationship between nucleus and minor
      mitochondrial derivative. Cytophotometry of Feulgen stained samples indicated
      that long and short spermatozoa contain a similar amount of DNA. Both short and
      long spermatozoa are transferred and stored in the female upon mating. As they
      have similar ultrastructural and cytochemical characteristics, both sperm are
      potentially functional in egg penetration and karyogamy.

PMID- 8650671
TI  - Langhans cells of human arterial intima: uniform by stellate appearance but
      different by nature.
AB  - The stellate cells in human arterial intima known as Langhans cells were
      investigated. Arterial specimens were obtained during carotid endarterectomy and
      aortic reconstruction and included atherosclerotic lesions as well as areas of
      the adjacent normal appearing arterial wall. Following immunohistochemical and
      electron microscopic analysis, most of the stellate cells were found to inhabit
      the elastic-hyperplastic layer of the intima in the normal arterial wall but in
      atherosclerotic lesions, stellate cells were distributed throughout all intimal
      layers. Immunohistochemical examination revealed that different types of intimal
      cells, including smooth muscle cells (HHF-35; smooth muscle alpha-actin +) and
      vascular dendritic cells (CD1a+, S-100+), exhibited a typical stellate appearance
      but the cell processes of macrophages (HAM56+, CD68+) were too short for
      macrophages to be considered as stellate. No other intimal cells formed processes
      which could be detected under immunohistochemical examination. In atherosclerotic
      lesions, some smooth muscle cells transforming to foam cells retained their
      stellate shape. Smooth muscle cells interacted with each other through gap
      junctions while other intimal cells including vascular dendritic cells contacted
      each other without forming any specialized structures. We conclude that Langhans
      cells comprise two histological types of intimal cells, namely, smooth muscle
      cells and vascular dendritic cells.

PMID- 8650672
TI  - Electron microscopic study of possible sites of ultrafiltration in Lumbricus
      terrestris (Annelida, Oligochaeta).
AB  - Electron microscopic investigations of blood vessels of Lumbricus terrestris (L.
      terrestris) were conducted to show sites of filtration such as podocytes or
      irregular fenestrations. The endothelia of the blood vessels consist of
      myoendothelial cells, chloragocytes and podocytes. The podocytes form large archs
      over a considerable area of the vessels. Numerous small pedicels are presented on
      the lumen side and the gaps between adjacent pedicels are bridged by slit
      membranes. The podocytes are restricted to the front part of the ventral vessel.
      They are regarded as the structural basis for ultrafiltration. Additionally to
      the filtration site between ventral vessel and coelomic cavity, a second putative
      filtration site was found in the front part of the body between intestinal blood
      sinus and coelomic cavity. The endothelium of the sinus is formed by
      myoendothelial cells, pedicels and chloragocytes with footlike processes. In such
      areas the basement membrane is the only continous layer between blood vessel and
      coelomic cavity. The basement membrane of the blood vessels of L. terrestris is a
      characteristic association of three layers of different composition and
      thickness. Possible filtration sites in form of podocytes and irregular
      fenestrations could be localized at the border between the blood compartment and
      the coelomic compartment. Presumably the primary urine is formed by
      ultrafiltration of blood.

PMID- 8650673
TI  - Annulate lamellae and lytic HAV infection in vitro.
AB  - The aim of this study was to examine the relationship between viral infection and
      annulate lamellae (AL) production by using quantitative and qualitative electron
      microscopy to document the size and numbers of AL in BS-C-1 cells infected with a
      lytic strain of hepatitis A virus (HAV). The progress of the HAV infection was
      found to occur in two phases. In phase 1, cell proliferation and cell death were
      roughly the same as that of the mock infected control, but there was an increase
      with time in the amount of hepatitis A antigen in the infected cells. In phase 2
      cell division was minimal and cell death became manifest. AL were detected in
      both infected and control cells. Quantitative analysis indicated that the average
      number of AL was greater in infected cells compared to that in control cells in
      phase 1; in infected cells there were greater numbers of AL in phase 1 than in
      phase 2; the average number of membraneous leaves/AL was greater in infected
      cells than in control cells. Quantitative analysis also indicated that AL were
      very rare, with only about three AL per entire control cell and eight AL per
      entire infected cell. The study clearly establishes that viral infection can
      stimulate AL production. The data suggest stimulation of AL production in the
      virus infected cells was linked to the synthesis of viral antigen.
      Ultrastructural observations indicated that AL could be derived from either the
      rough endoplasmic reticulum or the nuclear membrane.

PMID- 8650674
TI  - The effect of deamination and/or blocking arginine residues on the molecular
      assembly of acid-extracted rat tail tendon collagen.
AB  - We describe the effect of deamination of lysine and blocking of arginine residues
      on the assembly of collagen into native fibrils and SLS aggregates. Treatment of
      collagen solutions with one or both of these procedures does not prevent the
      formation of fibrils or SLS aggregates but reduces their ability to form
      assemblies with accurate longitudinal registration. These observations provide
      direct confirmation that hydrophobic interactions are important in collagen
      assembly. Unbanded fibrils were formed within the first 24 h at 4 degrees C from
      both acidic and neutralized deaminated and from neutralized control collagen
      solutions, transversely banded fibrils appearing later. This is compatible with
      the suggestion that initially, collagen fibrils are assembled by lyotropic liquid
      crystallization and with other observations which suggest that collagen molecules
      are initially free to move laterally within the fibril before being locked into
      place. Fibrils assembled from deaminated collagen solution show two variant
      longitudinal registration patterns which grade into one another. This suggests
      that, with a reduction in positively charged side chains, the thermodynamic
      energy minima responsible for longitudinal registration are less sharp compared
      with control collagen solutions. Reduction of positive charge by chemical
      modification helps to explain why the chemical modifications reduce swelling of
      collagen fibres. It also helps to explain why fibrils form spontaneously at 4
      degrees C in both arginine-blocked and deaminated collagen solutions. Thus
      chemical modifications of rat tail tendon provides new insight into the
      mechanisms in collagen assembly.

PMID- 8650675
TI  - Johnston's organ and central organ in Nezara viridula (L.) (Heteroptera,
      Pentatomidae).
AB  - The fine structure of Johnston's organ and central organ in Nezara viridula
      (Heteroptera, Pentatomidae) is described. Johnston's organ consists of 45
      scolopidia distributed around the periphery of the distal part of the third
      antennal segment (distal pedicellite). The scolopidia are anchored separately in
      invaginations of joint cuticle between the pedicel and flagellum. The scolopidia
      are amphinematic and each scolopidium comprises three sensory cells and three
      enveloping cells. The latter are a proximal scolopale cell with a typical
      labyrinth, an attachment cell filled with many microtubules, and a distal
      accessory cell also filled with microtubules. Axons of 17 scolopidia gather and
      join one antennal nerve; 28 scolopidia of the opposite side, extend axons into
      the other antennal nerve. The central organ consists of seven mononematic
      scolopidia, which comprise of one or two sensory cells. They anchor in the same
      joint as the scolopidia of Johnston's organ. The sensory cell bodies of the
      central organ are located close to the antennal nerves, more proximally than
      those of Johnston's organ. The axons of four scolopidia join one antennal nerve
      and those of the remaining three scolopidia join the other antennal nerve.
      Enveloping cells similar to those in Johnston's organ are present in the central
      organ.

PMID- 8650676
TI  - [Clinical case. Long-haired dachshund, male, 3 1/2 years].

PMID- 8650677
TI  - [Caruncle removal in cattle--subsequent treatment and use of a new cervix
      dilator].
AB  - Retention of the fetal membranes in bovines is frequently accompanied by necrosis
      of the caruncles. This is dependent on the kind of bacterial contamination and
      seems to be of regional variety. Necrosis of the caruncles requires extirpation
      which is the only treatment to save life, fertility and economic benefit of the
      animal. Following extirpation after-treatment over a period of eight to nine days
      essentially influences the success. Antibiotic therapy is not the main principle
      of treatment but to handle the atony of the uterus and its fatal consequences
      caused by the inflammatory contents. Since the cervix necessarily has to remain
      open for the period of treatment the use of a recently developed cervix dilatator
      (Ludwig Bertram GmbH, Hannover) is described and recommended.

PMID- 8650679
TI  - [Expert opinions about a case of injury which by a failure of a restraining
      device caused a life-threatening injury to a breeding stallion].
AB  - A stallion got fatal injuries by kicks of a maiden mare because a so called
      "panic hook" untied spontaneously. The use of such hooks to secure mares during
      mating should therefore not be recommended.

PMID- 8650678
TI  - [Acute pain in the horse and one possibility for its objective evaluation].
AB  - To judge acute processes of pain objectively the results are told of a
      determination of adrenaline and noradrenaline in the plasma of 30 horses
      suffering from pain. Besides a scheme basing on an awarding of points is
      developed to ascertain changes of physiological and ethological parameters caused
      by pain. These results in changes of behaviour are compared to results determined
      by laboratory experiments. Concerning pain of medium and high level a relation to
      the concentration of catecholamines is noticed. Therefore the total of certain
      clinical observations is suitable for graduating acute pain in horses.

PMID- 8650680
TI  - [Oximetry in veterinary anesthesia: the continuous determination of mixed venous
      oxygen saturation in dogs and horses].
AB  - The continuous fiberoptical measurement of the mixed venous partial oxygen
      saturation is described. It is an enrichment of the diagnostical possibilities in
      veterinary medicine. In the horse it is of great interest, because disturbances
      of the pulmonary gas exchange and the myocardial function are common in the
      anaesthetised horse, and reliable methods of assessing the cardiac output are
      rare. Using this monitoring technique in nearly 100 equine high risk patients
      facilitated insight into the complex changes of the pulmonary, cardiac and
      circulatory function in the anaesthetised horse. The registered data are the
      basis of the presented case reports. Values measured "behind the tissue" are
      influenced by the oxygen supply and the oxygen consumption within the periphery.
      Changes of the mixed venous oxygen status can be caused by a disturbance of the
      arterial oxygen status, by a insufficient performance of the cardiovascular
      system or by a change in metabolic activity. Being a multifactorial influenced
      parameter the mixed venous oxygen saturation can only be interpreted in
      connection with other parameters. The mixed venous oxygen status gives global
      information about the whole organism, but it is not able to inform about the
      oxygen supply of single organs. From our own personal experience it reflects an
      aggravation of the patient very early and reliable.

PMID- 8650681
TI  - [Significance of electroencephalography for the diagnosis of seizures in dogs].
AB  - The technique of the EEG recording is described and an overview of the
      interpretation of the EEG is given. Typical encephalographic elements and their
      clinical relevance are illustrated. The characteristic EEG changes for the
      different forms of seizures (extracerebral causes, symptomatic and idiopathic
      epilepsy) are shown and described.

PMID- 8650682
TI  - [Arthroscopic studies of the stifle of dogs].
AB  - Diagnosis by arthroscopy and arthrotomy of 36 dogs with stifle lesions (18 left,
      18 right) assessed by physical and radiological examination were compared. 48 of
      68 observations during arthrotomy had been diagnosed before by arthroscopy
      (accuracy 70.6%). Arthroscopical diagnosis of anterior cruciate ligament rupture
      (ACL) (n = 11), partial ACL (n = 11), avulsion of m. extensor digitorum longum (n
      = 2) and immune-mediated arthritis (n = 2) confirmed the diagnosis by arthrotomy
      in all patients. Arthroscopy failed to detect meniscal lesions in 50% (18 of 36).
      Nine of 20 normal medial and lateral meniscus, eight of 14 medial and one of two
      lateral meniscal lesions were detected by arthroscopy. Six meniscal tears (two
      transverse, two longitudinal, one bucket-handle type, one caudal horn) were not
      diagnosed. These results indicate that other known human portals have to be
      proven or new portals have to be evaluated.

PMID- 8650683
TI  - [Longterm ECG in the dog].
AB  - Holter monitoring was obtained from 44 clinically normal dogs and 68 dogs with
      heart disease or being suspicious for a cardiopathy. Several employments of the
      holter monitoring are shown by means of some examples. This method proved to be
      effective in the diagnosis of syncopes and the review of the therapy of
      arrhythmias. Limits and difficulties are discussed.

PMID- 8650684
TI  - [The treatment of pseudopregnancy in the bitch with prolactin inhibitors
      metergoline and bromocriptine].
AB  - In the present study, the prolactin inhibitor Metergoline was compared with
      Bromocriptine and tested against a placebo in 63 pseudogravid bitches.
      Bromocriptine has already been tested successfully in numerous investigations on
      the therapy of canine pseudogravidity, but--probably because of its high price
      and vomitus as a frequent side effect--it has not been really introduced as a
      therapeutical device in canine practice. It can be deduced from the results
      presented herein that prolactin is essential for maintaining the pseudogravidity,
      but keeping up the lactation process--especially galactopoiesis--can probably not
      be ascribed solely to prolactin. However, prolactin definitely plays an essential
      role in the hormonal scenario, the detailed regulating mechanisms of which are
      not known until today. Thus, no statistically convincing therapy outcome could be
      achieved by the prolactin inhibitors compared to the placebo group. A tendency
      towards earlier regression of the symptoms "mammogenesis", "behavioural change"
      and "galactorrhea" was however present in the treated animals. A striking
      difference was the much more lively behaviour of the bitches with 53% being more
      lively in the Metergoline group, 37% in the Bromocriptine and 10% in the placebo
      group. There were also clear differences in the compatibility of the drugs; in
      the Bromocriptine group, 30% of the animals vomited, in the Metergoline only
      6.3%. This however did not lead to termination of the therapy in any case. In two
      cases of the Metergoline group (6.3%), the medication was ended due to extreme
      restlessness.

PMID- 8650685
TI  - [Lip closure with buttons--a simple method for immobilization of
      temporomandibular joint injuries in the cat].
AB  - Injuries to the lower jaw in cats occur frequently in the area of the
      temporomandibular joint. In most of these cases, successful treatment
      necessitates a temporary surgical occlusion of the jaw. After a brief survey of
      various occlusion methods, a simple technique is opted for in which labial
      reverse sutures of non-absorbable material are threaded through buttons. This is
      the preferred method of treatment employed by the University of Munich Department
      of Animal Surgery. During the past ten years, 107 cats were treated using this
      method. It was possible to check the healing process via clinical and
      radiological examinations in 72 of these patients. In a further 21 cases,
      information was obtained through questioning the owners. The collected data
      revealed that the method described above, which originally had been intended to
      temporarily occlude the jaw in polytraumatized cats, has proven to be an
      effective final therapy in most cases. Of the total of 93 patients with a known
      case history, 81 cats (87%) showed no need for rigid fixation. Over all, 94% of
      treated patients were free of discomfort, while 68% of the fractures and
      luxations radiographically reevaluated had healed anatomically.

PMID- 8650686
TI  - [The use of bone morphogenetic proteins in delayed fracture healing,
      pseudoarthrosis and in ulna osteotomy carried out because of elbow joint
      diseases].
AB  - This study deals with the application of bone morphogenetic protein (BMP) as an
      osteoinductive factor in the treatment of fractures and elbow disease in the dog.
      Partially purified canine bone morphogenetic protein (cBMP) was used in the
      repair of a delayed union fracture and a pseudoarthrosis. The cBMP was applied in
      Biocoral and Tricalciumphosphate carriers using a subcortical grafting method.
      Two dogs suffering from incongruence and subluxation of the elbow joint were
      treated with a partially purified bone morphogenetic protein of moose bone origin
      placed in the gap produced by ulnar osteotomy.

PMID- 8650687
TI  - [Age dependency of laboratory values in dogs and cats. II. Electrolytes in
      serum].
AB  - Significant age dependent differences in dogs were found in sodium, potassium,
      calcium, chloride, and inorganic phosphorus, whereas in cats only potassium,
      chloride, and inorganic phosphorus were found to be age dependent. In both
      species special reference values must be established for different age groups.
      The higher reference values of potassium in young dogs and cats should be
      considered in cases of rehydration.

PMID- 8650688
TI  - [Doppler echocardiography of heart valve defects in the dog].
AB  - In the diagnosis of heart diseases the Doppler echocardiography makes it possible
      to distinguish physiological and pathological blood flow and thus to prove and
      judge valve defects in a noninvasive way. The color Doppler gives a survey about
      place and direction of the streams. The exact analysis and quantification of the
      stream speed results from the spectral Doppler. Valve stenosis is characterized
      by a flow acceleration on the level of the stenosis. The increased speed is used
      for estimation of the severity of the stenosis. Valve insufficiency is recognized
      by a reflux of blood to the ventricle or atrium, respectively. The extent of the
      insufficiency can be evaluated semiquantitatively.

PMID- 8650689
TI  - [Echocardiographic reference ranges of sedated cats].
AB  - The aim of this study was to get echocardiographic values of sedated healthy cats
      of the race European short hair for further reference. After the preliminary
      examinations checking on the state of health (anamnesis, general and special
      clinical examinations, ECG, X-ray of thorax and preparation of selected
      laboratory parameters), 74 sedated animals and additionally 33 cats without
      sedation were echocardiographically measured. For sedatives we used ketamine
      hydrochloride and xylazine in order to minimize defending movements of the
      animals and to reduce the heart rate, which facilitated the echocardiographical
      measurements. The covariance analysis of the measured values showed a
      statistically significant dependence on the weight. This did not hold for the two
      calculated values of the fractional shortening (FS) and the quotient of left
      atrium and aorta (LA/Ao), where the weight-dependence of each component was
      compensated by the calculation of the quotient. All stated weight-dependent
      reference values refer to an average bodyweight of 4.0 kg. A dependence on the
      age did not show in the covariance analysis. Due to the sedation, the diameter of
      the left atrium (LA) and the diameter of the left ventricular lumen in the
      diastole (LVDd) as well as the fractional shortening decreased significantly.

PMID- 8650690
TI  - [Vaccination against feline retrovirus infections].
AB  - Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV), both of
      veterinary importance, their antigenic and genetic variability as well as their
      pathogenicity are described. Disease following FeLV infection is interpreted as a
      consequence of genetic recombination, as a result of viral evolution in vivo. The
      principles and efficacy of vaccines are discussed.

PMID- 8650691
TI  - [Primary glaucoma in two German hunting terriers and a wire-haired fox terrier].
AB  - Primary glaucoma was diagnosed in a five- and a six-year-old female German
      Hunting Terrier and a four-year-old female Wirehaired Foxterrier. The five-year
      old Hunting Terrier had an absolute glaucoma in the right eye. The left eye
      showed a dysplastic pectinate ligament (DLP) and a narrow iridocorneal angle. The
      right eye was enucleated and the fellow eye fell sick five months later. Inspite
      of cyclocryotherapy glaucoma cannot be controlled without medication until now.
      In the six-year-old Hunting Terrier the iridocorneal angle could not be
      evaluated, because the right eye had an acute glaucoma and the left eye a chronic
      glaucoma with seclusio pupillae. A cyclocryotherapy was done on both eyes. Now
      the left eye is blind and vision is reduced in the right eye. Intraocular
      pressure values are within the normal range. The four-year-old Foxterrier had a
      chronic glaucoma in the right eye, because of DLP and a narrow iridocorneal
      angle. In the left eye the angle was narrow too, but rudimentary white trabecula
      with flow holes existed. This eye did not fall sick until now. In the right eye
      lowering of pressure could be obtained by medication only.

PMID- 8650692
TI  - Relative hepatotoxicity of 2-(substituted phenyl)thiazoles and substituted
      thiobenzamides in mice: evidence for the involvement of thiobenzamides as ring
      cleavage metabolites in the hepatotoxicity of 2-phenylthiazoles.
AB  - The hepatotoxicity of the 3 isomers of para-substituted thiobenzamides and the 3
      isomers of 2-(para-substituted phenyl)-4-methylthiazoles was evaluated in mice
      depleted of glutathione (GSH) by pretreatment with buthionine sulfoximine (BSO).
      In accordance with previous studies with the rat, p-methoxythiobenzamide was more
      toxic than thiobenzamide, and conversely p-chlorothiobenzamide was markedly less
      toxic as assessed by serum alanine aminotransferase (ALT) activity. The
      hepatotoxicity of 2-phenyl-4-methylthiazole was also altered by the addition of
      para-substituents to the phenyl ring in the same way as observed for
      thiobenzamide derivatives: the rank order of toxicity was 4-methylthiazoles
      having p-methoxyphenyl > phenyl >> p-chlorophenyl at the 2-position. This good
      correlation of the rank order of hepatotoxicity between series of 2-(para
      substituted phenyl)-4-methylthiazoles and para-substituted thiobenzamides
      supports the concept that thiobenzamides as ring cleavage metabolites play a role
      in the hepatotoxicity of 2-phenylthiazole derivatives.

PMID- 8650693
TI  - Dose-dependent reversal of digoxin-inhibited activity of an in vitro Na+K+ATPase
      model by digoxin-specific antibody.
AB  - We investigated the potency of digoxin-specific Fab fragments to reverse digoxin
      induced Na+K+ATPase inhibition in rat brain microsomes according to (a) the
      extent of initial inhibition of Na+K+ATPase and (b) the neutralizing dose of
      antibody. Mathematical analysis of the digoxin concentration-Na+K+ATPase
      inhibition curve supports the existence of 2 digoxin sensitive Na+K+ATPase
      isoforms. The IC50 was 1.3 x 10(-4) M and 2.5 x 10(-8) M for the low (alpha 1)
      and high (alpha 2) digoxin affinity isoenzyme, respectively. The reversal of
      digoxin-induced Na+K+ATPase inhibition was dependent on the digoxin-specific Fab
      concentration. The maximal effect was observed when the Fab:digoxin ratio was
      stoichiometrical and addition of an excess of antibodies did not result in a
      complete reversal of inhibition at the 4 digoxin concentrations studied. This
      simple and rapid in vitro model will be a useful tool to predict the efficacy of
      a new generation of antibodies.

PMID- 8650694
TI  - A methodology for solving physiologically based pharmacokinetic models without
      the use of simulation softwares.
AB  - The objective of the present study was to develop and validate a methodology for
      solving physiologically based pharmacokinetic (PBPK) models without the use of
      simulation software. The approach involves keying the parameter values and model
      equations into Microsoft Excel spreadsheets, and conducting simulations by
      solving the model equations according to Euler's method of numerical integration.
      This approach was applied to simulate the pharmacokinetics of styrene in rats
      exposed to 80 and 600 ppm for 6 h. The simulation results were plotted along with
      experimental data using the regular graphic features available in Excel, and
      validated by comparing them with simulation results obtained using a commercially
      available software (Advanced Continuous Simulation Language, ACSL). The
      simulations obtained with ACSL and Excel, in general, differed by <1%. The
      methodology developed in the present study should help informed individuals
      understand and solve PBPK models, without having to use "black-box' kind of
      computer programs and simulation softwares.

PMID- 8650695
TI  - Overlapping but unique DNA binding specificities of the Ah receptor and
      constitutive dioxin-responsive element binding proteins from human keratinocytes.
AB  - To understand the relationships between the protein architecture assembled on
      dioxin-responsive elements (DRE) and transcriptional regulation by dioxin in
      human keratinocytes, the nuclear DRE-binding proteins from human keratinocytes
      were identified and characterized. In addition to the aryl hydrocarbon receptor
      (AHR) complex inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), nuclear
      extracts from 3 human keratinocyte cell lines also contained one or more proteins
      that bound specifically to the DRE but whose levels were unaffected by TCDD or by
      anti-AHR antibody pretreatment. Alteration of a conserved T, within the core DRE
      sequence needed for transcriptional activation by the AHR complex, did not affect
      AHR binding but severely affected the ability of the constitutive proteins to
      bind. These data suggest that the nonidentical interplay of the AHR and
      constitutive DRE-binding proteins on the DRE is important in the regulation of
      genes whose expression is controlled by DRE.

PMID- 8650696
TI  - Change of the sex-dependent response to clofibrate in F344 rat liver during
      postnatal development.
AB  - Although it has been reported that male rats are more responsive than females to
      peroxisome proliferation induced by clofibrate, these sex differences have been
      confirmed in young adult rats. Using 4-, 8-, and 12-week-old F344 rats, postnatal
      change of the sex-dependent response to clofibrate was investigated. These
      animals were administered 200 mg/kg body wt./day clofibrate by gavage for 7 days.
      In 4-week-old rats clofibrate-dependent changes (hepatomegaly, induction of
      hepatic microsomal and peroxisomal enzymes, proliferation of smooth endoplasmic
      reticulum and peroxisomes of hepatocytes) were slight in both sexes. In 8- and 12
      week-old rats clofibrate-induced changes of males were moderate, whereas those of
      females were slight. These results suggest that the responsiveness of immature
      rat to clofibrate is weak and in males the susceptibility is gradually strong
      during postnatal development.

PMID- 8650697
TI  - Toxic effects of grass carp, snake and chicken bile juices in rats.
AB  - To evaluate the toxic effects of different animal bile juices, male Long-Evans
      rats were used and treated orally with different doses (0.03-0.6 ml) of grass
      carp, snake and chicken bile juices. After treating with one high dose (0.6 ml)
      for 6 and 24 h, the levels of glutamic oxaloacetic transaminase (GOT), glutamic
      pyruvic transaminase (GPT), alkaline phosphatase (ALP), blood urea nitrogen (BUN)
      and creatinine in the plasma of rats in the grass carp bile juice group became
      higher than those of the other two bile treated groups. After 3-days periodic
      treatment with 0.3 ml of each animal bile juice for 28 days, the levels of GOT,
      GPT, BUN and creatinine in the plasma of rats were significantly increased,
      especially the grass carp bile juice-treated rats. It appeared that the rats
      administered with snake and chicken bile juices for a much longer time were
      poisoned and had the same symptoms as those treated with grass carp bile juice.

PMID- 8650698
TI  - Intracellular high energy metabolite depletion and cell membrane injury with
      antioxidant enzymes during oxidant exposure in vitro.
AB  - We compared oxidant-induced intracellular adenine nucleotide catabolism and cell
      membrane injury in 4 different human cell types. Responses to oxidant exposure
      were correlated with endogenous antioxidant enzyme activities in these cells.
      Blood monocytes, amniotic fibroblasts, umbilical vein endothelial cells in
      primary culture, and transformed bronchial epithelial cells (BEAS 2B) were
      exposed to 0.1-5 mM hydrogen peroxide (H2O2) for 4 h. Some experiments were
      conducted in cells pretreated with 3-amino 1:2,4-triazole (ATZ) to inactivate
      catalase or with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to inactivate
      glutathione (GSH) reductase. Depletion of adenine nucleotides and accumulation of
      their catabolic products (hypoxanthine, xanthine and uric acid) occurred to
      varying extent, monocytes being the most resistant. There was a mutual
      relationship between catalase and GSH reductase activities and maintenance of
      cellular adenine nucleotide levels during H2O2 exposure. GSH reductase inhibition
      rendered BEAS 2B cells susceptible to lytic injury by H2O2, assessed by release
      of lactate dehydrogenase and intact nucleotides into the medium, there was no
      correlation between these markers of such injury and endogenous antioxidant
      enzymes. We conclude that adenine nucleotide depletion and nucleotide catabolite
      accumulation relate closely with the antioxidant enzyme activities, whereas the
      lack of a similar correlation between the enzyme levels and markers of lytic cell
      injury suggest that intracellular antioxidant enzymes do not protect cells from
      membrane damage due to extracellular oxidants.

PMID- 8650699
TI  - Homogeneous catalytic dehalodimerization of 17-iodo-delta 16 steroids.
AB  - 17-Iodo-delta 16 steroids undergo selective dimerization and carbonylative
      dimerization in the presence of palladium catalysts in dimethylformamide which
      result in 16-17'-coupled dienes and 17-carboxylic anhydrides, respectively.
      Moderate to good yields have been obtained for both types of dimers.

PMID- 8650700
TI  - Steroidal alkenylphosphonates via palladium-catalyzed coupling reactions.
AB  - The palladium-catalyzed coupling of various 17-iodo-delta 16 steroids (17-iodo
      androst-16-ene, 17-iodo-4-methyl-4-aza-androst-16-en-3-one, and 17-iodo-4-aza
      androst-16-en-3-one) with dialkyl phosphites (dimethyl phosphite, diethyl
      phosphite, and diisopropyl phosphite) was examined in detail. The only successful
      condition for homogeneous coupling involved carrying out the reaction in the
      absence of any solvents. A large excess of dialkyl phosphite was used, which
      means that the phosphite itself acted as a solvent. Eight new androst-16-ene
      derivatives with phosphonate groups at C-17 were synthesized and characterized.
      These steroids are of pharmacological interest as potential 5 alpha-reductase
      inhibitors. Under the same conditions, methylation of lactam NH was observed
      using dimethyl phosphite.

PMID- 8650701
TI  - 15 beta-hydroxysteroids (Part IV). Steroids of the human perinatal period: the
      synthesis of 3 alpha,15 beta,17 alpha-trihydroxy-5 alpha-pregnan-20-one and its
      A/B-ring configurational isomers.
AB  - In recent years several 15 beta-hydroxysteroids have emerged pathognomonic of
      adrenal disorders in human neonates of which 3 alpha,15 beta,17 alpha-trihydroxy
      5 beta-pregnan-20-one (2) was the first to be identified in the urine of newborn
      infants affected with congenital adrenal hyperplasia. In this investigation we
      report the synthesis of the three remaining 3 xi,5 xi-isomers, namely 3 alpha,15
      beta,17 alpha-trihydroxy-5 alpha-pregnan-20-one (3), 3 beta,15 beta,17 alpha
      trihydroxy-5 alpha-pregnan-20-one (7) and 3 beta,15 beta,17 alpha-trihydroxy-5
      beta-pregnan-20-one (8) for their definitive identification in pathological
      conditions in human neonates. 3 beta,15 beta-Diacetoxy-17 alpha-hydroxy-5-pregnen
      20-one (11), a product of chemical synthesis was converted to the isomeric 3 and
      7, while conversion of 15 beta,17 alpha-dihydroxy-4-pregnen-3,20-dione (4), a
      product of microbiological transformation, resulted in the preparation of 8. In
      brief, selective acetate hydrolysis of 11 gave 15 beta-acetoxy-3 beta,17 alpha
      dihydroxy-5-pregnen-20-one (12) which on catalytic hydrogenation gave 15 beta
      acetoxy-3 beta,17 alpha-dihydroxy-5 alpha-pregnan-20-one (13) a common
      intermediate for the synthesis of the 3 beta(and alpha),5 alpha-isomers.
      Hydrolysis of the 15 beta-acetate gave 7, whereas oxidation with pyridinium
      chlorochromate gave 15 beta-acetoxy-17 alpha-hydroxy-5 alpha-pregnan-3,20-dione
      (14) which on reduction with L-Selectride and hydrolysis of the 15 beta-acetate
      gave 3. Finally, hydrogenation of 4 gave 15 beta, 17 alpha-dihydroxy-5 beta
      pregnan-3,20-dione (10) which on reduction with L-Selectride gave 8.

PMID- 8650703
TI  - Improved synthesis of a protected 11-oxoestrone.
AB  - An improved synthesis of 11-oxoestrone-3-acetate-17-ethyleneketal is reported.
      Adjustments are proposed for the oxidation of estrone by 2,3-dichloro-5,6-dicyano
      1,4-benzoquinone into 9(11)-dehydroestrone. A complete hydroboration-oxidation of
      the resulting ketal, by means of borane-methylsulfide complex, gives the
      corresponding 11-hydroxy derivative. This latter compound is then acetylated for
      successful oxidation with pyridinium chlorochromate on alumina. The overall yield
      is 30%.

PMID- 8650702
TI  - A molecular modeling analysis of diethylstilbestrol conformations and their
      similarity to estradiol-17 beta.
AB  - Crystallographic and computer modeling studies throughout the last 25 years have
      shown the structure of diethylstilbestrol (DES) to exist in two symmetrical or
      one asymmetrical conformation. As a result of specific comparisons to estradiol
      17 beta (E2), the asymmetrical DES conformer has been suggested as the geometry
      possessing estrogenic activity. In the present study, a more complete set of DES
      conformations has been elucidated through the use of computer modeling. All
      previously defined DES geometries were found within this new set of ten
      structural forms. Differences between the molecular mechanics heat of formation
      energies of the ten conformers, as well as the transition energies separating
      them from each other, were found to be less than 1 kcal/mol. Additionally, a
      computer-based molecular alignment method was employed to quantitatively compare
      the steric and electrostatic molecular features of each DES conformer relative to
      E2. All ten DES structures were found to have shape relationships similar to E2.
      Thus, a model for the estrogen action of DES is presented whereby this stilbene
      can favorably interact with the estrogen receptor regardless of the conformation
      or orientation of the initial ligand-receptor association.

PMID- 8650704
TI  - Palladium-catalyzed homogeneous coupling reactions of steroids with
      organostannanes.
AB  - Direct and carbonylative coupling reactions of various steroid derivatives
      possessing iodo- and bromo-alkenyl moiety (17-iodo-androst-16-ene, 1, 17
      bromoandrost-2,16-diene, 2, 17-iodo-4-aza-4-methylandrost-16-en-3-one, 3, 17-iodo
      4-azaandrost-16-en-3-one, 4) with vinyltributylstannane and
      ethynyltributylstannane were carried out in the presence of various palladium
      catalysts. While carbonylation took place only with vinyltributylstannane, 17
      vinyl-, and 17-ethynyl-delta 16 steroids were produced via direct coupling with
      vinyltributylstannane and ethynyltributylstannane, respectively. Activities of
      some catalysts based on Pd(0) and Pd(II) precursors were compared, and Pd(PPh3)4
      was found to be superior to other complexes in most cases. In the coupling of 17
      iodoandrost-16-ene with organostannanes Pd2(dba)3 + 8 AsPh3 in situ catalyst was
      found to be even more effective.

PMID- 8650705
TI  - Corticosteroids in human blood: IX. Evidence for adrenal secretion of sulfate
      conjugated cortisol, 11 beta,17 alpha-dihydroxy-4-pregnene-3,20-dione-21-yl
      sulfate.
AB  - A method was developed for the estimation of levels of cortisol-21-sulfate (F
      KS), cortisone-21-sulfate (ES), and 20(alpha + beta)-reduced cortisol-21-sulfates
      in blood plasma. Levels of these conjugates were determined in peripheral vein
      plasma of 42 normal subjects, 21 men, and 21 women (age range 20-64 years) and in
      adrenal vein plasma of patients with various adrenocortical disorders, six
      patients with primary hyperaldosteronism, five patients with Cushing's syndrome,
      and in two obese patients, suspected to have Cushing's syndrome, but with
      inconclusive laboratory findings. Adrenal vein blood was obtained by
      percutaneous, trans-femoral adrenal vein catheterization. Levels of non
      conjugated (free) cortisol were determined in all plasma samples along with those
      of the sulfated steroids. F kappa S was found in all plasma samples, both in men
      and women. The variation in F kappa S levels paralleled that in the free cortisol
      levels, thus the ratio of F kappa/F kappa S was the same in the blood samples
      drawn at 8 AM as in those drawn at 4 PM or 5 PM (ranges: 17.5-36.3 in men, 23.6
      45.8 in women). The levels of F kappa S were relatively lower in women than in
      men (women 610-880 ng/100 mL at AM, 300-510 ng/100 mL at PM; men: 760-1,220
      ng/100 mL at AM, 380-760 ng/100 mL at PM). Plasma levels of total sulfate
      conjugated delta 4-3-keto-C-21 steroids (F kappa S + E kappa S + 20(alpha+beta)
      dihydrocortisol-21-sulfates) were 30-40% higher than those of the levels of
      cortisol-21-sulfate alone (separated by thin-layer chromatography). In the
      adrenal vein plasma, levels of delta 4-3-keto-C-21-steroid-21-yl sulfates were 20
      to 40 times higher than levels of these steroids in the peripheral blood. The
      bulk of the steroid sulfate measured in the adrenal vein plasma consisted of
      cortisol-21-sulfate. The ratio of F kappa/F kappa S in the adrenal vein plasma
      was markedly smaller than in the peripheral vein plasma; it was 6.9-12.3 in males
      and 4.9-6.7 in females, whereas in the peripheral vein of the same subjects it
      was 19.2-43.7 in males and 21.4-48.3 in females. Cortisol-21-sulfate isolated
      from adrenal vein plasma was identified by mass spectrometry. The data presented
      provide evidence for the secretion of this conjugate by the adrenal cortex. Its
      secretion appears to be markedly elevated in patients with Cushing's syndrome,
      both due to hyperplasia and due to adrenal adenoma, as compared with normal
      subjects and patients with primary aldosteronism, both males and females.
      However, the F kappa/F kappa S ratio was markedly lower in Cushing's patients due
      to adrenal adenoma than due to adrenal hyperplasia, this suggesting that ACTH is
      stimulating intra-adrenal hydrolysis of cortisol sulfate.

PMID- 8650706
TI  - The measurement of progesterone in serum by a non-competitive idiometric assay.
AB  - A novel non-competitive idiometric time-resolved fluoroimmunoassay for the
      determination of serum progesterone was developed, based on the use of two types
      of anti-idiotypic antibody that recognize different epitopes within the
      hypervariable region of the primary antiprogesterone antibody. The first anti
      idiotype, the betatype, competes with progesterone for an epitope of the primary
      antiprogesterone antibody at the binding site. The second anti-idiotype, the
      alphatype, binds to the antiprogesterone antibody in the presence of
      progesterone, but does not bind to the betatype antiprogesterone complex due to
      epitope proximity. In the present configuration, the biotinylated alphatype was
      captured onto anti-biotin IgG which was immobilized on microtiter wells. Reaction
      mixtures containing europium-labeled antiprogesterone antibody complexed
      sequentially with progesterone in standards or serum samples and with the
      betatype anti-idiotypic antibody were then reacted with the immobilized alphatype
      anti-idiotypic antibody. After 30 min of incubation, the fluorescence of europium
      is measured by time-resolved fluorescence and is proportional to the
      concentration of progesterone over the range 0-320 nmol/mL. The method
      demonstrates good sensitivity, precision, and comparability with a direct
      competitive radioimmunoassay. The idiometric assay for progesterone is suitable
      for dipstick technology and biosensors.

PMID- 8650707
TI  - 13C nuclear magnetic resonance study of 17 alpha-substituted estradiols.
AB  - We report the 13C NMR data for 20 compounds bearing a substituent (alkyl,
      alkenyl, alkynyl, alkylamide, spiro-gamma-lactone, phenyl, benzyl, naphthyl,
      etc.) at the 17 alpha-position of estradiol. The carbon assignments were done
      using 1D and 2D NMR experiments (distortionless enhancement by polarization
      transfer, homonuclear correlated spectroscopy, heteronuclear shift correlation,
      and heteronuclear shift correlation via long-range couplings). Only the chemical
      shifts of carbons 12-18, which surround the substitution site, were affected by
      the addition of a substituent. The magnitude of the effects (shielding or
      deshielding) was influenced by the 17 alpha-substituent. The individual effects
      at these carbons were sufficiently distinctive to identify specific centers and
      should be valuable for signal assignment of a variety of 17 alpha-derivatives of
      estradiol. In addition to carbon-skeleton assignment, we also report the carbon
      substituent assignments.

PMID- 8650708
TI  - Weekend and holiday increase in the onset of ischemic stroke in young women.
AB  - BACKGROUND AND PURPOSE: Chronobiological analyses of stroke onset may throw some
      light on the mechanisms that trigger stroke. Observations may generate new
      hypotheses for identifying significant causal relationships. METHODS: In the
      present study, both the circadian and the weekend and holiday versus workday
      times of the onset of ischemic cerebral infarction were determined for 723
      consecutive subjects, aged 16 to 60 years, who were admitted for hospital
      treatment in the acute phase without any selection. RESULTS: Among young adults
      (16 to 40 years) and women, more infarctions occurred during weekends and
      holidays than were expected. Young women in particular had an increased risk for
      brain infarction during weekends and holidays (odds ratio [OR], 2.14; 95%
      confidence interval [CI], 1.26 to 3.63). In a multivariate analysis, age of 16 to
      30 years (OR, 3.13; 95% CI, 1.57 to 6.50), female sex (OR 1.71; 95% CI, 1.12 to
      2.63), and recent drinking of alcohol (P < .01) were associated with the onset of
      brain infarction during weekends and holidays, whereas current cigarette smoking
      was associated with the onset of brain infarction during workdays (P < .001). A
      morning increase in the onset of brain infarction was observed among middle-aged
      people during both weekends/holidays and workdays. Among young adults, however,
      an evening increase was also seen during weekends/holidays and workdays.
      CONCLUSIONS: We found that young adults and women are frequently stricken by
      brain infarction during weekends and holidays and that the circadian distribution
      of the onset of brain infarction among young adults is different from that of
      middle-aged people. These observations suggest that there may be stroke
      triggering activities that are associated with lifestyle.

PMID- 8650709
TI  - Effect of malnutrition after acute stroke on clinical outcome.
AB  - BACKGROUND AND PURPOSE: Malnutrition has received little attention in acute
      stroke, although it represents a risk of decreased immunity and nosocomial
      infections. Our objectives were to determine the prevalence of malnutrition after
      1 week of hospitalization in acute stroke and to establish its relation to the
      stress response and neurological outcome. METHODS: The study included 104
      patients with an acute stroke of less than 24 hours' duration. Nutritional
      parameters (triceps skinfold thickness, midarm muscle circumference, serum
      albumin, and calorimetry) were evaluated at admission and after 1 week. Stress
      response (free urinary cortisol) was measured daily during the first week.
      Neurological deficit was evaluated by the Canadian Stroke Scale. Clinical outcome
      was estimated by the Barthel Index 1 month after the acute stroke. Patients
      received an oral standard diet or polymeric enteral nutrition when they had
      swallowing difficulties. RESULTS: Protein-energy malnutrition was observed in
      16.3% of patients at inclusion and in 26.4% after the first week, with a
      significant decrease in fat (P = .002) and visceral protein compartments (P =
      .049). Malnourished patients showed higher stress reaction and increased
      frequency of infections and bedsores in comparison with the appropriately
      nourished group. Multiple logistic regression analysis showed that malnutrition
      after 1 week (odds ratio, 3.5; 95% confidence interval, 1.2 to 10.2) and elevated
      free urinary cortisol (odds ratio, 3.3; confidence interval, 1.05 to 10.2)
      increased the risk of poor outcome (death or Barthel Index < or = 50 on the 30th
      day of follow-up) independently of age and nutritional status at admission.
      CONCLUSIONS: Our findings suggest that protein-energy malnutrition after acute
      stroke is a risk factor for poor outcome. Early appropriate enteral caloric
      feeding did not prevent malnutrition during the first week of hospitalization.

PMID- 8650710
TI  - Patterns of alcohol intake and risk of stroke in middle-aged British men.
AB  - BACKGROUND AND PURPOSE: The relationship between the pattern of alcohol intake
      and the risk of stroke is unclear, in particular the increased risk observed in
      abstainers and the possible protective effect of light to moderate drinking. For
      that reason, we examined in a large prospective study the role of alcohol
      consumption in the risk of a first major cerebrovascular event (stroke). METHODS:
      We prospectively studied 7735 middle-aged men drawn from general practices in 24
      British towns. With exclusion of those who had recall of physician diagnosis of
      ischemic heart disease or stroke, data were available for 7273 men all followed
      for 13.5 years, with 216 major stroke events (fatal and nonfatal). RESULTS:
      Compared with occasional drinkers, nondrinkers (lifelong abstainers plus ex
      drinkers) had an increased risk of stroke even after adjustment for age,
      lifestyle factors, and preexisting cardiovascular disease (relative risk [RR] =
      1.6; 95% CI, 1.0 to 2.7). All regular weekend drinkers (1 to 2, 3 to 6, and > 6
      drinks/d) and daily 1 to 2 and 3 to 6 drinkers showed no significant difference
      in adjusted risk of stroke compared with occasional drinkers. Heavy drinkers
      (daily > 6 drinks) showed significantly increased risk evident within the first 8
      years of follow-up only (RR = 1.9; 95% CI, 1.0 to 3.5); however, this finding was
      attenuated after additional adjustment for systolic blood pressure (RR = 1.5; 95%
      CI, 0.8 to 2.7). Information obtained 5 years after screening was used to
      separate lifelong abstainers and ex-drinkers. On subsequent 8.5 years of follow
      up, both groups showed similar increased risk (RR = 1.5) compared with occasional
      drinkers, but the risk in ex-drinkers was reduced after adjustment for lifestyle
      factors and cardiovascular disease status (RR = 1.2). Lifelong abstainers,
      however, showed an increase in risk after adjustment of 1.8 (95% CI, 0.7 to 4.6).
      CONCLUSIONS: Heavy drinking is associated with an increased risk of total stroke
      that is largely mediated through blood pressure. The apparent increased risk seen
      in lifelong abstainers but not in ex-drinkers or occasional drinkers is
      unexplained but is unlikely to be attributed to abstinence from alcohol. There is
      no convincing evidence that light or moderate drinking is beneficial for stroke
      risk compared with occasional drinking.

PMID- 8650711
TI  - Implementation of an acute stroke program decreases hospitalization costs and
      length of stay.
AB  - BACKGROUND AND PURPOSE: A large community hospital implemented an acute stroke
      program to respond to stroke patients in a consistent, systematic, and efficient
      manner. The primary objectives were to monitor the care delivered, improve the
      quality of care, and move the patients through their initial hospital stay in a
      timely manner. METHODS: Acute stroke standing orders were developed, with a
      critical path developed on the basis of these orders and an expected length of
      stay. A multidisciplinary team began the rehabilitation process early in the
      hospital stay, monitored patient progress and length of stay, and provided
      appropriate discharge placement. Retrospective chart reviews were performed over
      a 4-year period, and the data were collated on a yearly basis. RESULTS: Over a 4
      year period, 414 Medicare patients demonstrated a steady decline of initial
      hospital length of stay from 7.0 to 4.6 days. During this same period of time,
      there was a decline in total hospital charges from $14,076 to $10,740 per
      patient. This represented a total dollar savings in charges of $1,621,296
      (approximately $453,000 per year). The mortality rate for 1994 was 4.6%, with
      46.5% of survivors discharged to home, 16.9% to acute rehabilitation, and 32.6%
      to nursing homes. CONCLUSIONS: The implementation of a multidisciplinary acute
      stroke program decreased length of stay and hospitalization costs of Medicare
      patients.

PMID- 8650712
TI  - Plasma lipoprotein(a) is an independent factor associated with carotid wall
      thickening in severely but not moderately hypercholesterolemic patients.
AB  - BACKGROUND AND PURPOSE: To evaluate whether high levels of low-density
      lipoprotein cholesterol (LDL-C) may promote the atherogenic effect of
      lipoprotein(a) [Lp(a)], we investigated the association between elevated Lp(a)
      levels and thickening of intima plus media in the common carotid artery (CC-IMT)
      in patients with different degrees of hypercholesterolemia. METHODS: One hundred
      type II hypercholesterolemic patients and 25 normolipidemic subjects were
      selected for the study. Plasma lipid and lipoprotein levels were determined
      enzymatically; Lp(a) levels were determined by enzyme-linked immunosorbent assay.
      An Lp(a) concentration > 30 mg/dL was arbitrarily considered a risk factor. For
      each patient mean CC-IMT was determined by B-mode ultrasound; in 60 patients and
      in the 25 control subjects, the maximal IMT in the entire carotid tree was also
      determined. RESULTS: CC-IMT values were higher in hypercholesterolemic patients
      with plasma Lp(a) levels > 30 mg/dL than in those with lower levels (P < .01). CC
      IMT and maximal IMT directly and independently correlated with plasma levels of
      Lp(a) (r = .33 and r = .25, respectively; both P < .05). The effect of LDL-C
      concentrations on the relationship between IMT and Lp(a) was investigated by
      dividing the patients into quartiles of plasma LDL-C levels. After
      stratification, CC-IMT significantly correlated with plasma Lp(a) levels in the
      patients with severe hypercholesterolemia (LDL-C > 5.2 mmol/L) but not in
      patients in the lowest quartile, ie, those with moderate hypercholesterolemia. No
      correlation between CC-IMT and Lp(a) was found in normolipidemic control
      subjects. CONCLUSIONS: Elevated plasma levels of Lp(a) can be considered an
      additional independent factor associated with thickening of the common carotid
      arteries in patients with severe hypercholesterolemia but not in those with
      moderate hypercholesterolemia or in normocholesterolemic subjects.

PMID- 8650713
TI  - Familial cerebral aneurysms. A bias for women.
AB  - BACKGROUND AND PURPOSE: We evaluated the influence of gender on the formation and
      rupture of familial cerebral aneurysms. METHODS: We studied 30 patients with
      ruptured cerebral aneurysms from 14 consecutive families. These patients were
      compared with the patients with sporadic aneurysms reported by the first
      Cooperative Study. RESULTS: Eighty percent of familial aneurysms occurred in
      women versus 59% of sporadic aneurysms (P < .05, chi 2 test). This
      overrepresentation of women occurred at below the age of 50 years, where 78% of
      patients with familial aneurysms were women compared with 45% for sporadic
      aneurysms (P < .01, chi 2 test). Above this age, there was no statistical
      difference in incidence of familial aneurysms in men or women compared with
      sporadic aneurysms. In women with familial aneurysms, rupture occurred before the
      age of 50 years in 59%, compared with 31% for sporadic aneurysms (P < .01, chi 2
      test). In four of five families, aneurysms ruptured within 10 years of each other
      in sisters (mean, 6 years). Multiple aneurysms were equal in both groups (17%),
      but multiple familial aneurysms occurred mainly in women. There was no difference
      in the site of single cerebral aneurysms in either group, but familial aneurysms
      in females occurred at the same site in five of eight families (62%) and in 11 of
      17 mother-daughter or sister pairs (65%), compared with 20% for two randomly
      selected sporadic aneurysms (P < .01). CONCLUSIONS: There is an
      overrepresentation of women with ruptured familial aneurysms compared with those
      with sporadic aneurysms. Familial aneurysms rupture in females predominantly
      before the age of 50, in the same decade, and at the same site within families in
      the majority of cases. These observations support a possible genetic cause for
      cerebral aneurysms and a possible hormonal contribution to their rupture.

PMID- 8650714
TI  - Comparison of additive and multiplicative models of regional variation in the
      decline of stroke mortality in the United States.
AB  - BACKGROUND AND PURPOSE: Although previous studies have shown that geographic
      variation in the decline of stroke mortality rates may be an important
      contributor to the changing geographic distribution of stroke mortality in the
      United States, some concern has been raised that this phenomenon may be model
      dependent. This study examines the geographic variation in the decline of stroke
      mortality rates in the United States with the use of both additive and
      multiplicative models. METHODS: National Center for Health Statistics and Bureau
      of the Census data were used to assess regional-level temporal trends of
      underlying-cause stroke mortality rates in the United States for 1979 through
      1989. Both additive and multiplicative models were fit to the data. RESULTS:
      Underlying-cause stroke mortality rates have declined fairly steadily in all
      regions of the United States and for all race-sex groups, although there was
      significant regional variation in the rate of decline during the period 1979
      through 1989. The South, which initially had the highest rates, had the most
      rapid decline for all race-sex groups when either additive or multiplicative
      models were used. CONCLUSIONS: From 1979 through 1989 there was significant
      geographic variation in the rate of decline of stroke mortality rates, with the
      most rapid rates of decline in the South. As a result, there has been a decrease
      in interregional variation in stroke mortality rates.

PMID- 8650715
TI  - Neuroexcitatory amino acids and their relation to infarct size and neurological
      deficit in ischemic stroke.
AB  - BACKGROUND AND PURPOSE: The participation of excitatory amino acids (EAAs) in the
      pathogenesis of ischemic neuronal lesion has been experimentally demonstrated,
      but clinical experience is scarce. Our objective was to examine EAA levels during
      the acute phase of cerebral infarction in relation to infarct size and intensity
      of neurological deficit. METHODS: Using high-performance liquid chromatography,
      we determined the glutamate, aspartate, taurine, and glycine concentrations in
      the plasma and cerebrospinal fluid (CSF) of 128 patients with ischemic cerebral
      infarction confirmed by CT and 43 control subjects. Blood and CSF samples were
      obtained on admission within the first 24 hours from symptom onset. The severity
      of the neurological deficit was assessed with the Canadian Stroke Scale
      immediately after these tests and at 48 hours after inclusion in the study.
      Infarct volume was determined in a second CT performed between the 4th and 7th
      day after the patient's inclusion. RESULTS: The concentration of plasmatic
      glutamate was 121.39 +/- 80.89 mumol/L in the control group and 163.71 +/- 103.13
      mumol/L in the patient group (P = .015); in CSF it was 3.46 +/- 1.20 mumol/L in
      control subjects and 6.55 +/- 4.65 mumol/L in patients (P < .0001). The
      concentration of glycine in plasma was 158.02 +/- 32.15 mumol/L in control
      subjects and 189.37 +/- 74.04 mumol/L in patients (P = .007); in CSF it was 6.18
      +/- 2.28 mumol/L in control subjects and 11.23 +/- 6.96 mumol/L in patients (P <
      .0001). The concentrations of glutamate in plasma and in CSF were significantly
      higher in patients with large cerebral infarcts and in those with cortical
      infarcts. Levels of glutamate and glycine in plasma and CSF were significantly
      higher in patients with a higher degree of neurological deficit. CONCLUSIONS: Our
      results support the excitotoxic activity of glutamate and glycine in patients
      with cerebral infarction.

PMID- 8650716
TI  - Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke
      patients.
AB  - BACKGROUND AND PURPOSE: Abnormal endogenous fibrinolytic activity may be a risk
      factor for stroke. Since the possible variation of tissue-type plasminogen
      activator (TPA) antigen and plasminogen activator inhibitor-1 (PAI-1) antigen
      concentrations over time after stroke has been rarely studied, it was examined in
      plasma from stroke patients in the acute and convalescent phases of the disease
      and in a control group. METHODS: Plasma concentrations of TPA and PAI-1 were
      determined in 135 stroke patients and in 77 control subjects. All but 4 patients
      were examined within 7 days after stroke onset, and 32 patients and 18 control
      subjects were reexamined 2 to 4 years later. RESULTS: In the acute phase, stroke
      patients had significantly higher TPA (median, 10 micrograms/L) and PAI-1
      (median, 14 micrograms/L) antigen concentrations, compared with control subjects
      (median values, 6 micrograms/L [P = .0001] and 8 micrograms/L [P < .01],
      respectively); TPA levels were higher in both the cerebral infarction (n = 122)
      and cerebral hemorrhage (n = 12) subgroups, whereas PAI-1 levels were higher in
      the cerebral infarction subgroup only. Stepwise logistic regression analysis
      (with correction for age, sex, history of hypertension, diabetes mellitus, and
      heart disease) showed TPA antigen level to be an independent discriminator
      between the cerebral infarction subgroup and control subjects (P = .0001),
      whereas the corresponding difference for PAI-1 antigen levels just failed to
      reach significance (P = .05). TPA antigen levels were correlated with
      concentrations of serum cholesterol (Spearman's rho = 0.15; P < .05), serum
      triglyceride (rho = 0.33; P = .0001), and plasma homocysteine (rho = 0.19; P <
      .01). PAI-1 antigen levels were correlated with serum triglyceride levels only
      (rho = 0.41; P = .0001). At reexamination after 2 to 4 years, neither TPA nor PAI
      1 levels had changed significantly from the baseline values. CONCLUSIONS: In
      stroke patients, high TPA antigen concentrations may indicate an activation of
      the fibrinolytic system or may be due to a delayed clearance of TPA complexed
      with inhibitors. High PAI-1 antigen concentrations in patients with cerebral
      infarction represent increased fibrinolytic inhibition. The findings in this
      longitudinal study suggest that TPA and PAI-1 antigen concentrations both differ
      little between the acute and convalescent phases after stroke.

PMID- 8650717
TI  - Risk of intracranial arteriovenous malformation rupture due to venous drainage
      impairment. A theoretical analysis.
AB  - BACKGROUND AND PURPOSE: Increased resistance in the venous drainage of
      intracranial arteriovenous malformations (AVMs) may contribute to their increased
      risk of hemorrhage. Venous drainage impairment may result from naturally
      occurring stenoses/occlusions, or if draining veins (DVs) undergo occlusion
      before feeding arteries during surgical removal, or after surgery in the presence
      of "occlusive hyperemia." We employed a detailed biomathematical AVM model using
      electrical network analysis to investigate theoretically the hemodynamic
      consequences and the risk of AVM rupture due to venous drainage impairment.
      METHODS: The AVM model consisted of a noncompartmentalized nidus with 28 vessels
      (24 plexiform components and 4 fistulous components), 4 arterial feeders, and 2
      DVs. An expression for the risk of AVM nidus rupture was derived on the basis of
      functional distribution of the critical radii of component vessels. Risk was
      calculated from biomathematical simulations of volumetric flow rate with both DVs
      patent and for four stages of venous drainage obstruction: (1) 25%, (2) 50%, (3)
      75%, and (4) 100%. Each stage of occlusion was applied to each DV while the other
      DV was patent and then to the patent DV while the other DV was totally occluded.
      RESULTS: For flow through the AVM when both DVs were unobstructed, the baseline
      risk of AVM nidus rupture ranged from 4.4% to 91.2%. Theoretical rupture occurred
      in nidus components proximal to the DVs when the risk exceeded 100%, as was
      observed with the obstruction of DV1 and a patent DV2. The ranges for risk of
      rupture across the nidus for the four stages were (1) 4.7% to 90.5%, (2) 5.9% to
      86.9%, (3) 0% to 98.4%, and (4) 0% to 106.3%, respectively. Rupture was observed
      for an 86% occlusion of DV1 (ie, the DV fed by the intranidal fistula) and DV2
      patent, primarily because of the dramatic shift in the hemodynamic burden toward
      the weaker plexiform nidus vessels. CONCLUSIONS: On theoretical grounds, venous
      drainage impairment was predictive of AVM nidus rupture and was strongly
      dependent on AVM morphology (presence of intranidal fistulas and their spatial
      relation to DVs) and hemodynamics. Specifically, stenosis/occlusion of a high
      flow DV induces a rapid redistribution of blood into the weak plexiform vessels
      of the opposing region of the nidus, causing a hemodynamic overload and an
      increased risk of rupture. These findings should be carefully considered among
      all factors affecting the natural history of intracranial AVMs and the mechanisms
      implicated in their spontaneous rupture. They may also provide a theoretical
      rationale for some of the hemorrhagic complications that occur during and after
      surgical treatment.

PMID- 8650719
TI  - Assessment of regional cerebral blood volume in acute human stroke by use of
      single-slice dynamic susceptibility contrast-enhanced magnetic resonance imaging.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the clinical
      usefulness of dynamic susceptibility contrast-enhanced MRI (DSC-MRI) in acute
      cerebral ischemia. METHODS: During bolus injection of gadolinium
      diethylenetriamine pentaacetic acid, a series of rapid T2*-weighted images was
      recorded from one slice. Concentration-time curves and images of regional
      cerebral blood volume (rCBV) were calculated from this data set. DSC-MRI, MR
      angiography, conventional spin-echo MRI (SE-MRI), and CT were performed in 11
      patients within 6 hours after stroke onset and before thrombolytic or
      anticoagulant treatment was begun. A follow-up MRI examination was performed 24
      to 48 hours after stroke onset. RESULTS: In 7 of 11 patients (group 1) with
      territorial infarcts of the middle (n = 6) or posterior cerebral artery (n = 1),
      DSC-MRI showed reduced rCBV in the affected territory before conventional SE-MRI
      displayed ischemic lesions. DSC-MRI was helpful to differentiate severely
      ischemic tissue from peri-infarct parenchyma. Partial reperfusion (n = 3),
      unchanged reduction of rCBV (n = 2), and progressive reduction of rCBV (n = 2)
      were observed in the follow-up study. Normal DSC-MRI findings were present in 4
      of 11 patients (group 2) with lacunar infarcts. CONCLUSIONS: DSC-MRI accomplished
      the detection of the ischemic territory in the very early stage (< 6 hours)
      before SE-MRI delivered unequivocal results. DSC-MRI might be helpful to
      discriminate completely ischemic tissue from potentially salvageable ischemic
      parenchyma at risk and may play an important role in stroke therapy and
      evaluation.

PMID- 8650720
TI  - Performance of carotid ultrasound in evaluating candidates for carotid
      endarterectomy is optimized by an approach based on clinical outcome rather than
      accuracy.
AB  - BACKGROUND AND PURPOSE: The best method of selecting endarterectomy candidates
      for cerebral angiography is controversial. Carotid duplex ultrasound (CDUS) is
      widely used, but its performance varies across institutions. The clinical utility
      of CDUS could be improved with test criteria based on patient outcome rather than
      test accuracy. METHODS: In 155 carotid bifurcations studied by CDUS and cerebral
      angiography, the degree of angiographic stenosis was measured by a reader,
      blinded to CDUS, using the North American Symptomatic Carotid Endarterectomy
      Trial (NASCET) method. We calculated accuracy, sensitivity, and specificity for
      predicting > or = 70% angiographic carotid stenosis of different peak systolic
      frequencies (PSF) measured by CDUS and generated a receiver operator
      characteristic (ROC) curve. We used NASCET outcome data and published data on
      angiographic complications to define relative "costs" of false-positive and false
      negative CDUS, and we determined the point on the ROC curve representing the CDUS
      criterion with the highest clinical utility. We compared projected morbidity and
      mortality rates for 1000 hypothetical endarterectomy candidates resulting from
      the use of the most accurate CDUS criterion versus the CDUS criterion with the
      highest clinical utility by ROC analysis. RESULTS: While PSF > or = 8 kHz had the
      highest CDUS accuracy (93%), its projected stroke and death rate due to CDUS
      error was 10.4/1000. On the other hand, PSF > or = 7 kHz, defined by ROC analysis
      to have the highest clinical utility, had a lower morbidity and mortality rate of
      6.8/1000. CONCLUSIONS: The use of ROC analysis and available outcome data can
      improve the performance of CDUS in selecting endarterectomy candidates for
      cerebral angiography.

PMID- 8650718
TI  - Variability of magnetic resonance angiography and computed tomography angiography
      in grading middle cerebral artery stenosis.
AB  - BACKGROUND AND PURPOSE: Magnetic resonance angiography and computed tomography
      angiography are new, noninvasive methods to provide images of the cerebral
      vasculature. The reliability of magnetic resonance angiography and computed
      tomography angiography when used to grade middle cerebral artery stenosis remains
      to be established. We sought to study the interobserver and intraobserver
      variabilities of magnetic resonance angiography and computed tomography
      angiography in grading middle cerebral artery stenosis. METHODS: A total of 50
      middle cerebral arteries in 25 patients were studied with magnetic resonance
      angiography and computed tomography angiography. All patients had a history of
      ischemic stroke. The films were read independently by two observers on separate
      occasions. Films were shown again to the same observer 4 weeks after the first
      reading. The degree of middle cerebral artery stenosis was categorized into four
      grades: normal/mild, moderate, severe, and occluded. The interobserver and
      intraobserver variabilities were calculated by the kappa statistic method.
      RESULTS: Interobserver variability for grading middle cerebral artery stenosis
      was good (kappa = 0.78) for magnetic resonance angiography and moderate (kappa =
      0.51) for computed tomography angiography. There was perfect agreement between
      two observers in 86% of the vessels shown in magnetic resonance angiography and
      in 76% of the vessels shown in computed tomography angiography. Intraobserver
      variability for both imaging methods was good, with the kappa value in the range
      of 0.70 to 0.76. CONCLUSIONS: Our results suggest that according to our protocol,
      magnetic resonance angiography is more reliable than computed tomography
      angiography in grading middle cerebral artery stenosis.

PMID- 8650721
TI  - In vivo evaluation of antiplatelet agents in gerbil model of carotid artery
      thrombosis.
AB  - BACKGROUND AND PURPOSE: Antiplatelet agents are widely used for the prevention of
      ischemic stroke. However, their effects on thrombus formation have rarely been
      evaluated in experimental animals in vivo. We introduce methods for evaluating
      antithrombotic action in gerbils and the effects of several antiplatelet agents
      on thrombus formation. METHODS: In gerbils 8 to 10 weeks of age, we tightly
      compressed the unilateral common carotid artery for 2 minutes using the device
      prepared for this purpose to damage the endothelium. Thrombus formation in the
      damaged artery was observed directly through the microscope for 30 minutes. In
      six animals, the damaged artery was examined immediately after the experiments by
      electron microscopy. We studied the effects of antiplatelets by injecting the
      drugs intravenously 10 minutes before endothelial damage. RESULTS: In control
      studies, 70% to 90% of animals developed thrombi after arterial compression. The
      electron microscopic examination displayed endothelial damage in association with
      platelet thrombus at the damaged site. Administration of 2 mg/kg aspirin, 3 and
      10 mg/kg ticlopidine, and 0.3 and 1.0 mg/kg ibudilast, a novel prostacyclin
      accelerator, decreased the frequency of thrombus formation significantly, whereas
      20 mg/kg aspirin and 20 mg/kg dipyridamole failed to decrease thrombus formation.
      CONCLUSIONS: This model is considered useful for evaluating the antithrombotic
      effects of drugs because of its feasibility and high reproducibility. The present
      results support the view that a lower dose of aspirin may prevent cerebral
      vascular accidents as efficiently as a higher dose of aspirin.

PMID- 8650722
TI  - Electrophysiological transcortical diaschisis after cortical photothrombosis in
      rat brain.
AB  - BACKGROUND AND PURPOSE: The severity of functional deficits after a cortical
      infarction often does not correlate with lesion size. The stroke may affect
      pathways connecting to distant brain regions and therefore may also alter the
      function of remote parts of the cortex. Remote changes in electric activity,
      blood flow, and metabolism are called diaschisis. In the present study we
      addressed the question of whether in brain areas contralateral to a
      photochemically induced cortical infarction alteration of excitability can be
      observed as an indication of the effects of diaschisis. METHODS: We induced focal
      lesions in the sensory area at the border of the motor and occipital cortices by
      injecting the photosensitizing dye rose bengal and illuminating the skull
      stereotaxically. Seven days after induction of photothrombosis,
      electrophysiological recordings were obtained with standard methods from 400
      microns-thick neocortical coronal slices. As an indication of inhibition we used
      a paired-pulse stimulus protocol and calculated a ratio of the amplitudes of the
      second versus the first excitatory postsynaptic potential. RESULTS: In lesioned
      animals we found a significant increase of the ratio over a wide zone of the
      neocortex, both ipsilateral and contralateral, compared with unlesioned animals.
      CONCLUSIONS: Our results suggest that a neocortical infarction leads to
      hyperexcitability not only in its direct vicinity but also in the contralateral
      hemisphere. Such hyperexcitability may contribute to increased activation of
      contralateral brain areas and to functional reorganization after stroke.

PMID- 8650723
TI  - Depiction of infarct frequency distribution by computer-assisted image mapping in
      rat brains with middle cerebral artery occlusion. Comparison of photothrombotic
      and intraluminal suture models.
AB  - BACKGROUND AND PURPOSE: Histopathologic analysis of experimental brain damage has
      traditionally been performed by measuring areas of infarction and/or selective
      neuronal alterations on a section-by-section basis in individual animals. For
      series containing multiple replicate animals, quantitation of tissue injury is
      typically performed at similar coronal levels throughout an experimental group. A
      means of facilitating pictorial group comparisons of these histopathologic
      alterations between different series of replicate studies is highly desirable.
      METHODS: We introduce a newly designed approach to achieve this goal, based on a
      linear affine transformation that is used to map corresponding sections at the
      same anatomic level into a common template to yield a frequency distribution map
      depicting the aggregate data set. We have applied this approach to compare the
      histopathologic features of two models of middle cerebral artery (MCA) occlusion
      in rats: (1) photothrombotically induced permanent distal MCA occlusion in
      spontaneously hypertensive rats (SHR) and (2) temporary MCA occlusion by
      intraluminal suture in Wistar rats. RESULTS: The brains of SHR rats with
      permanent distal MCA occlusion showed a high frequency of infarction involving
      the dorsolateral and lateral portions of the ipsilateral neocortex, whereas
      Wistar rats with 90-minute MCA suture occlusion showed a zone of infarction
      largely concentrated in the dorsolateral portion of the ipsilateral caudoputamen.
      Infarct frequency distributions for the two animal groups were compared
      statistically at three corresponding anatomic levels by Fisher's exact test; the
      resulting statistical parametric maps are shown. CONCLUSIONS: With the use of
      frequency distribution maps, the pattern of trends within a group can be observed
      coronally or three-dimensionally. One can directly access data as to numbers of
      rats with infarction for any point on the map. Studies performed under different
      experimental conditions can also be compared with one another by means of the
      generated data sets.

PMID- 8650724
TI  - Confocal microscopic characterization of a lesion in a cerebral vessel of the
      stroke-prone spontaneously hypertensive rat.
AB  - BACKGROUND AND PURPOSE: Hypertension is a major risk factor for stroke and is
      associated with alterations in vascular structure and function. The aim of this
      study was to determine vascular function, wall morphology, and vascular smooth
      muscle cell (VSMC) arrangement in basilar arteries from stroke-prone
      spontaneously hypertensive rats (SHRSP) and normotensive control strain Wistar
      Kyoto rats (WKY). The effect of perindopril treatment on SHRSP structure and
      function was also assessed. METHODS: VSMC orientation was determined with laser
      scanning confocal microscopy and computer-assisted image processing in basilar
      arteries stained with 5(6)-carboxyfluorescein (wavelengths: excitation, 488;
      emission, 515) or propidium iodide (excitation, 529; emission, 550). Measurements
      of wall morphology and functional responses to serotonin and KCl were assessed
      with wire myography. RESULTS: In the WKY basilar arteries, VSMCs were uniformly
      oriented perpendicular to the longitudinal axis of the vessel, whereas in the
      SHRSP there were localized foci of VSMC geometric disorganization, with a
      significant deviation from 90 degrees. The SHRSP basilar arteries also showed
      structural remodeling and reduced contractile responses to serotonin and KCl.
      Perindopril treatment normalized blood pressure, prevented wall morphology
      alterations, and improved function but had no effect on VSMC disorganization.
      CONCLUSIONS: This is the first demonstration of lesions of VSMC geometric
      disorganization in a cerebral artery from a stroke-prone genetically hypertensive
      rat strain. These structural abnormalities are independent of blood pressure.
      Their functional sequel may play a role in the pathogenesis of stroke in this
      model.

PMID- 8650726
TI  - Spontaneous early improvement following ischemic stroke.

PMID- 8650725
TI  - Role of oxidants in ischemic brain damage.
AB  - BACKGROUND AND PURPOSE: Oxygen free radicals or oxidants have been proposed to be
      involved in acute central nervous system injury that is produced by cerebral
      ischemia and reperfusion. Because of the transient nature of oxygen radicals and
      the technical difficulties inherent in accurately measuring their levels in the
      brain, experimental strategies have been focused on the use of pharmacological
      agents and antioxidants to seek a correlation between the exogenously supplied
      specific radical scavengers (ie, superoxide dismutase and catalase) and the
      subsequent protection of cerebral tissues from ischemic injury. However, this
      strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain
      barrier permeability, etc) that may cloud the data interpretation. This mini
      review will focus on the oxidant mechanisms in cerebral ischemic brain injury by
      using transgenic and knockout mice as an alternative approach. METHODS:
      Transgenic and knockout mutants that either overexpress or are deficient in
      antioxidant enzyme/protein levels have been successfully produced. The
      availability of these genetically modified animals has made it possible to
      investigate the role of certain oxidants in ischemic brain cell damage in
      molecular fashion. RESULTS: It has been shown that an increased level of CuZn
      superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic
      mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in
      CuZn-superoxide dismutase or mitochondrial Mn-superoxide dismutase exacerbates
      ischemic brain damage. Target disruption of neuronal nitric oxide synthase in
      mice also provides neuronal protection against permanent and transient focal
      cerebral ischemia. CONCLUSIONS: I conclude that molecular genetic approaches in
      modifying antioxidant levels in the brain offer a unique tool for understanding
      the role of oxidants in ischemic brain damage.

PMID- 8650727
TI  - Concern about safety of carotid angioplasty.

PMID- 8650728
TI  - Influence of different techniques of breath holding on the measurement of
      cerebrovascular reserve in carotid artery disease.

PMID- 8650729
TI  - Visualization of cardiac emboli from mitral valve papillary fibroelastoma.

PMID- 8650730
TI  - Evaluation of the presence of premature atherosclerosis in adults with
      heterozygosity for cystathionine-beta-synthase deficiency.

PMID- 8650731
TI  - Susceptibility to rubella infection in females at high risk. Immune protection
      associated to population density.
AB  - Susceptibility to rubella in 428 Mexican females of childbearing age from four
      sanitary areas confined to a Mexican State (Queretaro) was determined. Members of
      the group were residents of urban and rural communities and selected by random
      sampling. Anti-viral antibodies were determined by inhibition of
      haemagglutination. Concentration was expressed as International Units of IgG anti
      rubella haemagglutinin (IU/ml). Antibody concentrations lower than 15.6 (IU/ml)
      were regarded as non-protective. The percentage of women immune-protected to
      rubella in the areas varied from 28.8 to 75.6 with an average of 61.9. The
      difference in percentages of immune-protected females within the areas was
      statistically significant (chi 2 = 48.26 and p < 0.001). Immune protection was
      associated to population density, with less protection in less populated areas.
      Our results differ from the reported values of a serosurvey performed in the same
      state one year before: immune protection 61.9% versus 79.96%, respectively.

PMID- 8650732
TI  - Quality assessment and quality control of radiographic units using simple tests.
      Experiences and results from Egypt.
AB  - To assess the image quality of radiographic units we developed a set of three
      relatively simple tests. With this set we investigated the performance of two
      small film x-ray units and seven dark rooms in chest disease clinics in Egypt. As
      a reference we performed the same tests at the Consultation Bureau for
      Tuberculosis and at the Radiology Department of the Medical Centre, Leeuwarden,
      The Netherlands. The tests revealed deficiencies during several phases of the
      production of radiographs at the chest disease clinics in Egypt, as well as at
      the Consultation Bureau for Tuberculosis, Leeuwarden, The Netherlands. The
      results of the tests were used to advise the radiology units tested on how to
      improve their quality. We believe, that this set of tests can be applied to any
      radiography unit to find ways for image quality improvement.

PMID- 8650733
TI  - Bacteriological profile and holding temperatures of ready-to-serve food items in
      an open market in Awassa, Ethiopia.
AB  - Various types of ready-to-serve food items purchased at the Awassa open market
      were evaluated for their bacteriological profile and holding temperatures. The
      food items included roasted offals, fish soup, cooked and sauced macaroni and
      spaghetti, and shiro sauce. Spaghetti and macaroni were held at ambient
      temperatures (20-30 degrees C) and had high aerobic mesophilic count (> 10(6)
      cfu/g) and Enterobacteriaceae count (> 10(5) cfu/g). They also yielded Shigella
      and Staphylococcus spp. Most of the other food items were held at higher
      temperatures (> 40 degrees C) and the aerobic mesophilic count in most cases was
      relatively lower (< 10(5) cfu/g). Several bacterial genera were isolated and
      Micrococcus and Bacillus spp. dominated the aerobic microflora. The unhygienic
      conditions of the food service environment, possibilities of cross contamination
      from utensils and keeping food items at ambient temperatures for several hours
      were considered to be critical points.

PMID- 8650734
TI  - Nutrition-related hair signs in Zairian preschool children and associations with
      anthropometry.
AB  - To assess prevalence of hair dyspigmentation, decurling, thinness and frailty, a
      random sample of more than 4,000 preschoolers, representative for a large area in
      Northern Zaire, was examined clinically and anthropometrically. Isolated
      dyspigmentation, isolated thinness and the combination of both were the most
      frequent signs (> 5%). Prevalence of hair signs did not differ according to sex
      or season. Peak prevalence was found between ages 6 and 18 months, suggesting a
      relationship with weaning. Most hair signs, studied separately or as
      combinations, increased gradually with lowering weight-for-age (WFA) or weight
      for-height but not with height-for-age. Isolated dyspigmentation, however, was
      unrelated to WFA or marasmus. All signs occurred also in children with 'normal'
      WFA (SD > -2). In these children, hair signs were associated with the presence of
      clinical muscle wasting.

PMID- 8650735
TI  - The use of quinine for treatment and control of malaria in The Netherlands.
AB  - The manufacturing of quinine in The Netherlands began shortly after 1820; large
      scale production started with the foundation of the Amsterdam Chinine Factory in
      1881. The quantity of sold quinine in the Province of North-Holland leads
      retrospectively to the conclusion that an epidemic of malaria had occurred around
      1880. At the start of a new epidemic in 1899, it was demonstrated that quinine
      killed the bloodforms of tertian malaria immediately. However, 50% of the
      patients experienced a relapse, particularly after interruption of treatment. The
      length--f the course did not change the chance of relapse. With the beginning of
      another epidemic in 1919, scientific work and education of the people started in
      an organized fashion and patients were urged to use quinine only at the
      prescription of physicians. Because of the inability to prevent relapses, an
      alternative to quinine was badly needed. In 1930 plasmochin became available,
      which proved to be useful in combination with quinine. It was not until 1934 that
      the asymptomatic carriers were recognized as a problem for control because their
      unobserved parasitic relapses were considered a major source of infection for
      mosquitoes. In 1939 it was proposed to apply autumnal quininization, which meant
      a scrupulous screening of the population. The early forties brought yet another
      major epidemic. Both quinine and Quiniplex were used until the fifties, when
      endemic malaria disappeared. The new schizonticidal drugs came too late to
      challenge the primate of quinine in the era of temperate zone Plasmodium vivax in
      The Netherlands.

PMID- 8650736
TI  - Schistosoma mansoni in the Nile Delta, Egypt. A large scale epidemiological study
      in Kafr El Sheikh Governorate.
AB  - This is an early descriptive report of the 'Epidemiology 123' project in Egypt
      which makes use of large probability sampling methods. These results focus on
      Schistosoma mansoni infection in the northern Nile Delta Governorate of Kafr El
      Sheikh. A probability sample of 18,777 persons, representing the rural population
      of the entire Governorate, was drawn. The sample was designed not to exclude
      villages based on location or presence of health care facilities and to include
      representation of the smaller ezbas or hamlets. The objective was to obtain
      detailed estimates on age and sex specific patterns of S. mansoni infection, and
      to provide a baseline for prospective studies. Stool specimens were examined by
      the Kato method. The estimated prevalence of S. monsoni infection in the rural
      population was 39.3% (SE +/- 3.3) in 44 villages and ezbas after weighing for the
      effects of the sample design. The estimated geometric mean egg count per gram
      stool (GMEC) was 72.9 (SE +/- 7.3). Prevalence and GMEC varied considerably by
      village and ezba, with ezbas having a significantly higher prevalence. Villages
      and ezba specific prevalence was strongly associated with GMEC (r2 = 0.61, p <
      0.001). The prevalence of S. mansoni infection increased by age to 55.4% (SE +/-
      3.2) at age 16, without significant change in the adult ages. There was no gender
      difference until age six, after which males were consistently higher until middle
      age, when the differences converged. The age and sex specific pattern of GMEC
      varied widely, however, when the GMEC data were collapsed into five year age
      groups, GMEC peaked at 81.5 (SE / + - 12.1) epg in the 10 to 14 year age group.
      These estimates provide the basis for evaluating control measures for reducing
      prevalence, intensity of infection, and transmission.

PMID- 8650738
TI  - Patterns of infection, incidence and reinfection with Schistosoma mansoni in Nile
      Delta Governorate: Kafr El Sheikh.
AB  - Two annual follow-up measures of incidence, reinfection after treatment and
      reversion rates were estimated in a large prospective study of Schistosoma
      mansoni located in the northern Nile Delta of Kafr El Sheikh. Rates were
      estimated in a cohort established from a probability sample of the entire rural
      area of Kafr El Sheikh. Infection was determined by the examination of two Kato
      stool slides. The weighted first and second annual overall incidence rates were
      20.4%, SE +/- 1.4 and 15.9%, SE +/- 1.4, respectively. Geometric mean egg counts
      in incident cases were 35.6 epg, SE +/- 1.2 and 31.0, SE +/- 1.6 in the first and
      second follow-ups. Incidence was strongly associated with first round prevalence
      (r2 = 0.34). Reinfection rates were higher: 33.4%, SE +/- 3.1 and 31.0%, SE +/-
      2.1. Reinfection was associated with incidence (r2 = 0.32). Reversion rates were
      highest in children 0 to 4 years old (61.2%, SE +/- 18.1 and 78.5%, SE +/- 7.0,
      respectively) and increased from the first to second follow-up: 37.2%, SE +/- 3.4
      and 47.0%, SE +/- 3.7, respectively. Patterns of these rates by village
      community, age and sex are also given over both follow-up examinations and
      comparison with limited data on rates of S. mansoni infection from previous
      studies, suggests a stable pattern of transmission over time in the Nile Delta.

PMID- 8650737
TI  - Impact of population-based selective chemotherapy on prevalence and intensity of
      Schistosoma mansoni infections in the Nile Delta: Kafr El Sheikh.
AB  - The impact of selective treatment with praziquantel (40 mg/kg) on Schistosoma
      mansoni prevalence and intensity of infection in two annual follow-up
      examinations was measured. The target population was the entire rural area of the
      northern Nile Delta Governorate, Kafr El Sheikh, from which a probability sample
      was drawn. The sample included 44 villages and hamlets (ezba). Baseline
      prevalence was determined by the examination of stool by two Kato slides and all
      infected persons treated and reexamined one year later. Those found infected in
      the second round were treated and examined again one year later. The prevalence
      and geometric mean egg count declined across all ages in each follow-up
      (prevalence: 39.3% (SE +/- 3.3), 28.4% (SE +/- 2.6), and 22.4% (SE +/- 2.3),
      respectively; and GMEC: 72.9 (SE +/- 7.3), 52.5 (SE +/- 4.5), and 41.9 (SE +/-
      2.4), respectively). Reduction in prevalence varied considerably by village and
      ezba and was strongly related to the proportion of the village or ezba population
      that was infected and treated (r2 = 0.29). This latter observation provides a
      rationale for the maximum application of chemotherapy in the endemic Nile Delta
      community.

PMID- 8650739
TI  - The evaluation of skin prick test in house dust mite allergy in Calcutta, India.
AB  - Immediate type allergy towards house dust and house dust mites was measured in
      188 dust-sensitive asthmatic patients in and around Calcutta by using the skin
      prick test. Of the 131 positive patients, 82% reacted to Dermatophagoides mites,
      80% to D. farinae, 46% to D. pteronyssinus, and 43% to both species of mites.
      Sixty-two per cent of the positive patients showed strong skin reaction to D.
      farinae as compared to 32% to D. pteronyssinus. Skin reaction (positive/strong)
      was highest in D. farinae as compared to other allergens tested in the present
      study. Skin test results were also analysed in relation to patients' age, sex and
      duration of disease.

PMID- 8650740
TI  - Tumor necrosis factor alpha interferon gamma and macrophage stimulating factor in
      relation to the Severity of Plasmodium falciparum malaria in the Brazilian
      Amazon.
AB  - We compared the tumor necrosis factor (TNF-alpha), interferon gamma (IFN-gamma)
      and granulocyte-macrophage colony stimulating factor (GM-CSF) serum levels in 87
      patients with malaria from the Brazilian Amazon. They included asymptomatic
      infected individuals and symptomatic patients with mild disease or severe malaria
      with or without cerebral involvement. As controls we examined individuals living
      in endemic areas without past history of malaria. The TNF-alpha serum levels were
      increased in patients with malaria and progressively decreased in those with
      severe disease 7 days after specific treatment. We found correlation between
      parasitaemia, TNF-alpha levels and severity of the disease. The correlation
      between high TNF-alpha levels and severe malaria was independent of cerebral
      involvement. The increase in both IFN-gamma and GM-CSF levels among malarious
      patients was not related to the degree of severity or mortality. IFN-gamma
      concentration, however, was associated with high parasitaemia at admission.

PMID- 8650741
TI  - Neonatal thyroid screening of a multi-racial population.
AB  - A retrospective study on the thyroid status of 832 infants, born in Panaga
      Hospital in Brunei, was conducted. Despite a high degree of ethnic variability,
      screening for congenital hypothyroidism (CHT) included a fixed T4 and a TSH
      reference interval, based on a population of Malay infants. We tested their
      reliability for this heterologous group of infants. New T4 and TSH intervals were
      determined for each ethnic group and compared, revealing false positive and false
      negative judgements made during the period of study. Caucasian infants showed
      significantly higher T4 and TSH serum levels than all other ethnic groups.
      Regarding T4, most false positive judgements were found among the Malay infants.
      False negative judgements were detected among the Caucasian female infants. A new
      reference scheme was recommended, consisting of reference values that are
      applicable in neonatal thyroid screening of all infants in Panaga Hospital,
      regardless of their ethnic origin.

PMID- 8650742
TI  - Changes in prevalence, intensity of infection and morbidity due to Schistosoma
      japonicum infection in a community following a single treatment with
      praziquantel.
AB  - A repeat survey for schistosomiasis japonica was carried out in Sisan community 1
      year after chemotherapy with praziquantel was stopped. Prevalence of infection
      had fallen from 43.7 to 10.2%, intensity (population geometric mean) had dropped
      from 6.3 to 0.6 eggs per gram of stool and morbidity decreased significantly.

PMID- 8650744
TI  - Reducing the cost of HIV-testing through use of the IgG antibody captured
      particle adherence test (GACPAT) in district hospitals.
AB  - Though the World Health Organization (WHO) has acted to reduce the price of anti
      HIV assays for developing countries, the cost of the large-scale testing to be
      done may still be prohibitive to the health budget of these countries. GACPAT, a
      modified commercial particle assay, is ten times cheaper than the WHO price of
      ELISAs. In this study GACPAT was introduced in three district hospital
      laboratories (DHL) in Tanzania, and the results compared with those on the same
      sera in a reference laboratory (RL). Sensitivity and specificity were 92.6% and
      98.7%, respectively at DHL. It is concluded that GACPAT is a valid, feasible and
      cheap alternative for ELISA anti-HIV-testing also at district hospital laboratory
      level.

PMID- 8650745
TI  - Features of centipede bites in Taiwan.
AB  - In order to define characteristics that would help differentiate a centipede bite
      from a viper bite, we designed a prospective study using the data collection
      system of a Poison Control Center. The clinical goal is to rapidly distinguish
      envenomations for which antitoxin may be indicated (viper) from those for which
      palliative care only is appropriate (centipede). During a year period, 31 cases,
      including two cases receiving double bites in each event, were reported.
      Centipede lengths were estimated to range from 3 to 20 cm. Ninety-two per cent of
      the bite marks were pointed in shape. A local reaction developed at the bitten
      site, but usually remaining localized to a 10 x 10 cm area of involvement. The
      length of the biting animal, the bite mark characteristics, the presence of
      haemorrhagic vesicles, the wound size and the progression of local reactions are
      useful in the rapid clinical differentiation between centipede bites and viper
      bites.

PMID- 8650743
TI  - Horizontal versus vertical transmission of human immunodeficiency virus type 1
      (HIV-1). Experience from southwestern Saudi Arabia.
AB  - Twenty-five confirmed cases of human immunodeficiency virus type 1 (HIV-1)
      infection due to blood transfusion have been documented at King Fahad Hospital
      (KFH) in Al-Baha, southwestern Saudi Arabia since 1986, but complete follow-up
      was only possible on 19 of these cases and their contacts. Seventeen cases were
      diagnosed as having acquired immunodeficiency syndrome (AIDS) or AIDS-related
      complex (ARC) after admission to the hospital due to the deterioration of their
      health status. Two cases were found to be anti-HIV-1 positive on routine
      screening for blood donation. This cluster of HIV-1 infected patients through
      blood transfusion allowed us to study the efficiency of sexual transmission of
      HIV-1 infection between spouses, the rate of perinatal transmission of HIV-1
      infection, and to see whether intrafamilial transmission is a possible route of
      spread of the virus. Firstly, the present results confirm our earlier observation
      that transmission of HIV-1 infection was more efficient from the infected husband
      to his wife(s) in contrast to the inefficient transmission of the infection from
      the infected wife to her husband. Secondly, by the age of 16 months, all nine
      newborns to HIV-1 infected mothers became HIV-1 infected. This highlights the
      importance of medical advice to those mothers regarding conception and/or breast
      feeding, particularly as breast-feeding up to 2 years is not an uncommon practice
      among Saudi women. Finally, none of the household contacts of the 19 cases was
      infected until now, indicating that intrafamilial spread of HIV-1 did not occur
      among the population studied.

PMID- 8650746
TI  - The diagnostic utility of serum ferritin. Estimation in patients with primary
      hepatocellular carcinoma.
AB  - Serum hepatitis B surface antigen (HBsAg) status and ferritin levels were
      measured in 3 groups of subjects: Group A (n = 14) with chronic non-neoplastic
      liver disease (CNLD), Group B (n = 14) with primary hepatocellular carcinoma
      (PHC) and Group C (n = 14) comprising healthy matched controls without liver
      disease. Serum ferritin values were lowest in Group C, intermediate in Group A
      and highest in the Group B patients (all p < 0.05). About 79% of the patients
      with PHC, 43% of those with CNLD and none (0%) of the healthy controls, had
      hyperferritinaemia (serum ferritin > 400 ng/ml). Hyperferritinaemia and HBsAg
      positivity coexisted in 15% and 73% of the patients with CNLD and PHC,
      respectively. Hyperferritinaemia and HBsAg were significantly positively related
      in the patients with PHC (chi 2 5.09, p < 0.05). The predictive indices of
      hyperferritinaemia in chronic liver disease appeared superior for PHC than for
      CNLD, and became somewhat enhanced with coexisting HBsAg positivity. These
      results suggest that serum ferritin could be useful as a tumour marker for PHC in
      patients with established chronic liver disease.

PMID- 8650747
TI  - Shellfish-borne illnesses. A Hong Kong perspective.
AB  - This article provides an overview of the spectrum of infectious and toxic
      illnesses that may occur following the consumption of contaminated shellfish in
      Hong Kong. These include hepatitis A, hepatitis E, infections due to vibrio
      species, paralytic shellfish poisoning, neurotoxic shellfish poisoning and heavy
      metal poisoning. Possible preventive measures are discussed.

PMID- 8650748
TI  - Primary cervical choriocarcinoma.
AB  - A case of primary cervical choriocarcinoma in a 40-year-old Indian woman is
      reported. Though malignant transformation of a cervical pregnancy is a
      possibility, we believe that a D & C performed three years ago could also be the
      source of trophoblasts implantation in the cervix followed by subsequent
      malignant transformation. Primary cervical choriocarcinoma should be considered a
      differential diagnosis in a woman of child-bearing age presenting with postcoital
      bleeding and having a negative cervical cytology. A timely beta hCG assay may
      confirm the diagnosis and prompt early treatment.

PMID- 8650749
TI  - Invasive strongyloidiasis.

PMID- 8650750
TI  - Problem of a specific serological test for the diagnosis of pulmonary and
      extrapulmonary tuberculosis.

PMID- 8650751
TI  - Malawi has the highest number of reported cases of AIDS.

PMID- 8650752
TI  - [Danger of infection by exposure to blood--risk for hospital personnel].

PMID- 8650753
TI  - [The meeting between patients and professionals who treat them].

PMID- 8650755
TI  - [The meeting between patients and professionals who treat them. Qualitative
      interview of patients with amyotrophic lateral sclerosis and their closest
      relatives].
AB  - The object of the present investigation was to know more about the experiences
      and the demands of patients with amyotrophic lateral sclerosis (ALS) and their
      closest relatives, and to relate these experiences and demands to the practice of
      the Danish health care system. Twelve patients and 11 relatives from two
      neurological wards were interviewed in the spring of 1993. The investigation
      shows that to patients and relatives the course of the illness and disease is a
      continuous one. Their experience of quality in treatment and care depends on
      whether the professional staff have knowledge of and see their own role in the
      entire course of the illness and disease. The conclusion of this investigation is
      that it is necessary to disseminate knowledge of amyotrophic lateral sclerosis
      and to strengthen a centralised professional competence in the treatment and
      support of patients with amyotrophic lateral sclerosis and their closest
      relatives.

PMID- 8650754
TI  - [Potentially hazardous exposure to blood among hospital personnel. A
      retrospective study of systematically registered exposure during the period 1990
      1994].
AB  - The purpose of this study was to investigate the self-reported incidence of
      needlesticks and other exposures to patients' blood or body fluids among
      employees at Glostrup County Hospital, Copenhagen. Furthermore the nature of and
      circumstances under which these exposures occurred were explored. Four hundred
      and thirty-two reports of exposure were received from 389 health care workers
      during a period of four years (1990-1994). Ninety-three percent of the exposures
      were percutaneous, 7% mucocutaneous. The incidence rates of exposure per full
      time employee per year were as follows: Midwives: 0.11; doctors: 0.093;
      laboratory - technicians: 0.084; registered nurses: 0.068; auxiliary nurses:
      0.025; porters: 0.024 and housekeeping staff: 0.016. Accidents related to
      disposal containers, where the health care worker is injured while disposing a
      needle or handling the disposal container, account for 10% of all percutaneous
      exposures. Improper placing of sharp instruments account for 7% and recapping is
      responsible for 6% of all percutaneous exposures. Mucocutaneous exposure was
      caused by unexpected splash during the procedure, in 86% of the cases the
      conjunctivae were contaminated. No occupationally acquired infections were
      observed. It is concluded that occupational exposure to blood and body fluids
      among health care workers is considerable. To reduce the frequency of blood
      exposure education of the health care workers and safer equipment are needed. A
      good strategy for preventing exposures must be based on careful registration of
      the accidents, which is obtained by encouraging reporting of the exposures among
      the health care workers. Data base registration would be desirable.

PMID- 8650756
TI  - [Pituitary function in hemochromatosis].
AB  - A review of the literature on pituitary function in haemochromatosis is
      presented. In morphological studies pituitary iron deposition, in particular in
      gonadotropic cells, has been demonstrated. In a number of case series,
      insufficiency of pituitary gonadotropic secretion with clinical hypogonadism was
      observed in 46% of the patients. Overt insufficiency of the other hormonal axes
      was infrequent. However, subclinical insufficiency of the growth hormone axis was
      present in 15%, of the lactotropic axis in 8%, of the thyroid axis in 4% and of
      the adrenocortical axis in 1.5% of the patients. Lactotropic, thyroid or
      adrenocortical insufficiency was usually associated with hypogonadism or growth
      hormone insufficiency. Investigation of pituitary function (in first line the
      gonadotropic and the somatotropic function) in patients with primary or secondary
      haemochromatosis is recommended on wide indications, in order to initiate
      relevant substitution therapy.

PMID- 8650757
TI  - [Patient assessment in ambulatory surgery. A questionnaire study].
AB  - In our department, from the beginning of December 1994 to the end of February
      1995, we operated upon a selected group of 199 patients, hospitalized as day
      surgery patients. Each patient was given a questionnaire to fill in after
      discharge. We asked them to evaluate day surgery from the consumer's point of
      view. We did not record any data which could identify the single patient. We
      received 158 questionnaires (79%) of which 151 were accepted. One hundred and
      seven patients (71%) found day surgery acceptable and a good alternative to
      conventional hospitalization, 82% preferred having the same doctor and primary
      nursing during the treatment. One hundred and sixteen patients were discharged as
      planned (77%). There were no serious complications. Provided that patients are
      carefully selected, we find day surgery a highly satisfactory method of
      management which is safe and efficient.

PMID- 8650758
TI  - [Preoperative scintigraphic localization of hyperfunctioning parathyroid glands].
AB  - Preoperative identification of hyperfunctioning parathyroid glands was performed
      by 99m-Tc-sestamibi scintigrams in 29 patients with hyperparathyroidism. Out of
      30 histopathologically proven diseased parathyroid glands 21 were identified by
      scintigraphy. The diagnostic specificity (PVpos) was 88%. All diseased glands
      weighing more than 1200 mg were identified by scintigraphy including four glands
      in the mediastinum. 99m-Tc-sestamibi scintigraphy can identify the larger
      hyperfunctioning parathyroid glands with high reliability. The method was of
      great value in situations with ectopic abnormal parathyroid glands.

PMID- 8650759
TI  - [Preoperative localization of parathyroid adenomas using Tc-99m-sestamibi].
AB  - Over an eight month period, ten patients with primary hyperparathyroidism were
      preoperatively scanned with Tc-99m-Sestamibi in order to locate adenomas. An
      adenoma was detected in nine patients, of which four were operated and good
      concordance was found between the scanning and the operative findings. Of the
      remaining six patients two were inoperable, two refused operation and two died of
      other causes.

PMID- 8650760
TI  - [Plasma cholinesterase and abnormal reaction to suxamethonium injection. 20-year
      experience with the Danish Cholinesterase Registry].
AB  - For more than 20 years, the Danish Cholinesterase Research Unit (DCRU) has
      collected information about patients showing an abnormal response to
      succinylcholine. The purpose of this study was to evaluate our clinical findings
      in patients referred because of prolonged response following succinylcholine.
      Also, we wanted to evaluate the results of our prospective controlled studies of
      the effect of succinylcholine in patients with normal and abnormal plasma
      cholinesterase genotypes. An explanation for the apparent abnormal response to
      succinylcholine was only found in roughly 60% of the 1247 patients referred to
      the Unit. In the remaining nearly 40% of the patients the reason for the abnormal
      response remained obscure, though our results indicate that the anaesthetic
      technique, including hyperventilation or central respiratory depression, was most
      likely to be the reason. The significance of the different genotypes, including
      two newly discovered genotypes (AK, AH), for the reaction to succinylcholine was
      evaluated and found to be comparable to previous findings. Our results indicate
      that it is a problem for many anaesthetists to correctly diagnose a prolonged
      response to succinylcholine. We therefore urge the anaesthetist to use a
      peripheral nerve stimulator when faced with a case of apparent abnormal response
      to succinylcholine.

PMID- 8650761
TI  - [Primary intestinal lymphangiectasis].
AB  - Primary intestinal lymphangiectasia (PIL), first described in 1961, is a rare
      disease of childhood. Oedema, hypoproteinaemia and diarrhoea are characteristic
      symptoms. Bioptic demonstration of dilated lymphatic capillary vessels in
      intestinal villi and increased intestinal protein loss are diagnostic. Two
      patients successfully treated with a low fat diet, containing medium chain
      triglycerides (MCT) are reported.

PMID- 8650762
TI  - [Third generation P-pills and deep venous thrombosis].

PMID- 8650763
TI  - [Questionable fish oils?].

PMID- 8650764
TI  - [Pain and sensation disorders after parotidectomy].

PMID- 8650765
TI  - [Epilepsy].

PMID- 8650767
TI  - [Status epilepticus].

PMID- 8650766
TI  - [Antiepileptic drug therapy--current aspects].

PMID- 8650768
TI  - [Drug therapy of children with epilepsy].

PMID- 8650770
TI  - [Surgical treatment of epilepsy].
AB  - Patients with drug resistant frequent partial seizures rarely remit despite
      intensive drug treatment. On the contrary, seizures provoke neuronal loss with
      early mental deterioration and increased mortality. An exact localization of a
      resectable epileptogenic focus can offer a curative treatment. Mesial temporal
      sclerosis and lesional cortical partial epilepsy may indicate surgical therapy,
      both offering freedom of seizures in 50-90% of the patients. Non-lesional
      cortical partial epilepsy is more problematic, as only 30-40% of the patients
      will be seizure-free. Volumetric MR investigations, T2 relaxation time
      measurement and magnetic resonance spectroscopy together with other non-invasive
      methods have reduced the need for invasive investigations. As the best results
      are often achieved in children with their greater brain plasticity, surgical
      therapy should also be considered in children below the age of 12. This will
      prevent development of their role as chronically ill patients with the known
      accompanying psychological handicaps.

PMID- 8650769
TI  - [Withdrawal of antiepileptic treatment].
AB  - A review is presented of factors influencing the prognosis for remaining free of
      seizures after withdrawal of anti-epileptic drugs. Adverse factors are found to
      be: a) being 16 years or older; b) having had many seizures after starting anti
      epileptic drug treatment; c) a history of myoclonic seizures; d) a history of
      generalised tonic-clonic seizures; e) polytherapy; and f) spike and wave
      paroxysms in the EEG. An EEG before withdrawal of antiepileptic drugs is only
      required in patients with primary generalised epilepsy. The social situation and
      individual wishes of the patient and relatives should be considered when
      withdrawal of anti-epileptic drugs is being planned. Continued treatment until
      the patient has remained seizure-free for five years will decrease the risk of
      relapse. In children, anti-epileptic drugs may be withdrawn after three years of
      treatment, if no adverse factors are present. Nothing definite is known
      concerning the withdrawal procedure. A stepwise, slow withdrawal with a duration
      of six months or more is recommended, as this reduces the risk of relapse.

PMID- 8650771
TI  - [Lamotrigine treatment of 92 patients with intractable epilepsy].
AB  - The efficacy of treatment with lamotrigine (LTG) was evaluated in 92 patients
      with refractory epileptic seizures (46 women and 46 men aged 14-80 years, median
      32 years). Seventy-one patients had partial epilepsy and 21 had primary
      generalized epilepsy. Patients were treated from zero to four (most frequently
      two) other antiepileptic drugs (AEDs). Maintenance dose of LTG was 50-800 mg
      daily (median 300 mg). Fifteen percent of the patients became seizure-free (13%
      of patients with partial epilepsy, 24% with primary generalized epilepsy). Thirty
      eight percent of patients experienced at least 50% reduction in seizure
      frequency. Twenty-six percent of patients had a significant increase in seizure
      frequency (the same percentage in the two groups). Adverse events were recorded
      in 61% of patients, but most symptoms disappeared after dose reduction in
      concomitant AEDs. LTG was discontinued in 22% of patients, either because of
      adverse events or lack of effect. We conclude, that LTG is effective in reducing
      seizure frequency in patients with therapyresistant primary generalized epilepsy
      or partial epilepsy. Toxicity appears to be limited.

PMID- 8650774
TI  - [Indication for radiological examination in acute ankle distorsion].
AB  - Inversion injuries of the ankle are a common cause of presentation to accident
      and emergency units. They impose a major load on radiological services. A
      prospective study was carried out to test the hypothesis that a thorough physical
      examination can eliminate the need for a large number of radiographs obtained in
      patients with acute ankle trauma. Two hundred and one patients were seen in the
      emergency department for acute ankle trauma. All patients were assessed
      clinically, then examined radiographically. Sensitivity and specificity of
      various clinical signs were calculated. Swelling, focal bony tenderness on the
      lateral malleollus, and decreased ability to bear weight were found to be the
      most important predictors, especially if present simultaneously. According to
      this material bimalleolar distance ratio cannot be used as predictor.

PMID- 8650773
TI  - [Danish primary school teachers' knowledge about epilepsy in children].
AB  - A questionnaire survey undertaken among 169 Danish primary school teachers
      revealed a comparatively good general understanding of epilepsy. Sixty-five
      percent had taught pupils with epilepsy and 78% had witnessed a child having a
      fit. Only 18% had attended courses on epilepsy, despite 63% stating a desire for
      training. Only 5% of the teachers judged their present knowledge on the subject
      as being sufficient. A considerable lack of confidence and knowledge on issues
      such as provoking factors, surveillance and management including medical
      treatment was found. The survey revealed a good understanding of restrictions
      that might be imposed on children with epilepsy. Only 18% of the teachers thought
      that children with epilepsy in general have learning problems. To achieve an
      optimal care for children with epilepsy a sufficient knowledge and confidence is
      necessary. It is recommended that education concerning epilepsy is introduced for
      teachers that have pupils with epilepsy in their classes. Such education might be
      provided by the local health services.

PMID- 8650772
TI  - [Treatment of childhood epilepsy with lamotrigine. An evaluation of efficacy in
      different types of epilepsy].
AB  - Fifty-two children with intractable epilepsy received lamotrigine as add-on
      therapy on a compassionate basis. The results were reviewed after three and six
      months of treatment in order to evaluate the efficacy in different epilepsy
      syndromes. Mental retardation was present in 60% of the children. Ictal EEG was
      obtained in 38 children. At three months the median monthly seizure frequency was
      reduced from 46 to 14 in the 37 children that still received lamotrigine (p <
      0.01). Seven children were seizure-free. Seizure reduction was most impressive in
      generalized epilepsy, since 63% of these had more than 50% seizure reduction
      compared to 18% in partial epilepsies (p < 0.05). This difference was unchanged
      after six months of treatment. Side effects were reported in 18 of the children.
      In 13 children the parents reported an improved wellbeing. Lamotrigine seems to
      be an efficient antiepileptic drug-especially in generalized epilepsy.

PMID- 8650775
TI  - [Arthritis and pustulosis palmoplantaris].
AB  - Pustulosis palmoplantaris (PPP) is a primary skin disease of unknown aetiology,
      clinically characterised by recurrent eruptions of sterile pustules on the palms
      and/or soles. About 15% of these patients have associating symptoms from the
      bones and joints, often localised to the anterior thorax wall where both
      osteolytic foci and arthritis can be seen. We present the case of a patient with
      the characteristic clinical picture of PPP and associating arthritis.

PMID- 8650776
TI  - [A new, very promising antiviral treatment of influenza].

PMID- 8650777
TI  - [Medical research and clinical practice].

PMID- 8650778
TI  - [Qualification--should letters by readers be peer-reviewed?].

PMID- 8650779
TI  - [Lamotrigine. A new possibility in the treament of epilepsy].

PMID- 8650780
TI  - [Ulcerative colitis--pouch or bag?].

PMID- 8650781
TI  - [Surgery for ulcerative colitis. Treatment with proctocolectomy, stapled ileum-J
      pouch, stapled pouch-anal anastomosis and temporary ileostomy].
AB  - Thirty-two patients with ulcerative colitis, median age 29 (range 14-49), were
      submitted to restorative proctocolectomy. Twenty-five patients had a three-stage
      procedure and seven had a two-stage procedure. A stapled J-pouch was formed, and
      a pouch-anal anastomosis was created by the double stapling technique. A
      temporary end ileostomy was closed through peristomal incision after three
      months. There were no pouch failures and no cases of pouch-anal anastomosis
      leakage. In one patient secondary mucosectomy and neo-anastomosis became
      necessary due to severe inflammation of remnant rectal mucosa. Five patients were
      operated for small bowel obstruction, and two had to have a dilatation of a
      slight stricture of the pouch-anal anastomosis. In two patients the final
      diagnosis was verified or probable Crohns disease, of whom one developed
      recurrence of a previous rectovaginal fistula. Twenty-seven patients have had the
      ileostomy closed for more than one month, 25 of these (93%) were fully continent
      three months after ileostomy closure and later on. After one year the patients
      had median five (range 3-9) bowel movements per day. It is concluded that
      restorative proctocolectomy with a stapled J-pouch-anal anastomosis and a
      temporary end ileostomy for ulcerative colitis carries few complications and
      provides a good functional result.

PMID- 8650782
TI  - [Results of ileoanal reservoir surgery].
AB  - We report our surgical, late complications and functional outcome of 157
      consecutive restorative proctocolectomies with an ileoanal J pouch at the
      Department of Surgery L, Arhus City Hospital. Nine patients had familial
      adenomatous polyposis, while 148 patients were operated for ulcerative colitis.
      All patients had a protecting ileostomy. There was no mortality. Surgical
      complications after J pouch: Six patients were reoperated, five due to intra
      abdominal bleeding, one for ileus. There was only one pelvic abscess, and it was
      drained percutaneously. There were no fistulae, no anastomotic leakage and no
      early pouch removal. Surgical complications after ileostomy closure: Eight
      patients were reoperated; two due to wound infections, five for ileus and one due
      to a wound rupture. Late Complications: Four pouches were removed, due to
      incontinence, difficult evacuation, chronic pouchitis or Crohn's disease. There
      were three late pouchovaginal fistulae more than one year after surgery. Five
      patients had surgery for ileus, one for an intra-abdominal abscess, one for a
      perianal fistula and eight for incisional hernia. Functional outcome: One year
      after pouch surgery more than 90% of patients were satisfied with the operation,
      2.2% had regretted and 3.6% were in doubt. The functional result was satisfactory
      in the majority of the patients, but 21.1% had one or more night evacuations and
      13.9% had variable degrees of incontinence.

PMID- 8650783
TI  - [Pleural empyema].
AB  - Despite of extensive use of antibiotics for respiratory tract infections pleural
      empyema is still seen as a complication to pneumonia (7-10 cases/100.000
      inhabitants pr. year). Pleural empyema as a complication to pulmonary surgery is
      reported in 2-3% of the patients even with use of antibiotic prophylaxis. Pleural
      empyema is most often a serious disease of long duration. The diagnosis is
      obtained with microbiological and histological examination of the pleural fluid.
      Mixed infection occurs in over half of the cases, most often including anaerobic
      bacteria, but most human pathogens have been reported as etiological agents.
      Treatment includes drainage of pus and administration of relevant antibiotics,
      systemically and pleurally. Drainage can be performed via thoracocentesis, by
      tubes, or by resection of a part of the rib. The optimal treatment strategy is so
      far unknown, since good prospective comparative clinical studies are lacking.

PMID- 8650784
TI  - [Changes in physical activity are not reflected in physical fitness of older
      teenagers. A 2-year follow-up study].
AB  - The study describes changes over two years in different physical fitness measures
      and the relationship between these changes and changes in physical activity.
      Maximal aerobic work capacity (watt(max)), functional strength, muscle endurance,
      agility and flexibility were measured in 259 randomly selected high school boys
      and girls 16.5 years of age and followed-up two years later, while they still
      attended school. Most physical fitness measures increased over time in boys, and
      in girls an increase was found in arm extensor strength and trunk extensor
      endurance, but watt(max) per kg body mass decreased. Changes in physical
      performance between 16 and 18 years of age seem to be very similar in different
      countries, despite differences in physical activity patterns and absolute level
      of performance. No change was found in time spent participating in physical
      activity or sports activity in either gender, but fewer girls participated in
      leisure-time sports at the second test (p < 0.001). Change in physical activity
      or sports activity did not relate to change in physical fitness level. The
      relationships between level of sports participation (competition, for health or
      none) and physical fitness measures at baseline and at the second test were weak
      or non-significant. Three explanations for the weak relationship between physical
      activity and fitness are suggested: a) part of the variability in fitness is
      explained by genetics, b) growth and hormonal changes, especially in boys,
      override the stimulus of training, and c) the physical fitness level in
      adolescents is so high that only physical activity at high relative intensity is
      supposed to have an effect on the fitness level.

PMID- 8650785
TI  - [Pattern of prescriptions for psychopharmaceuticals to first-admission
      schizophrenic patients in the county of Arhus].
AB  - Two cohorts of 61 and 70 schizophrenic patients first-admitted during the years
      1976-1978 and 1986-1988, respectively, were compared in order to find changes in
      the quantity of psychotropics prescribed in the same area in two periods
      separated by a 10-year interval. The standardized Anatomical Therapeutic Chemical
      Classification System-codes and the Defined Daily Doses were registered from the
      patients' case notes in the one year following the admission. The two cohorts
      were compared with respect to social conditions and presence of 37 syndromes from
      the Present State Examination 9th edition Syndrome Check List. We found a
      significant (5% level, Mann-Whitney) decline in the prescribed neuroleptics and a
      significant change from depot to non depot neuroleptics. The decline in
      prescribed neuroleptics was not correlated to an increase in the prescription of
      other psychotropics.

PMID- 8650786
TI  - [Ambulatory laparoscopic varicocelectomy. The first experiences].
AB  - Minimal invasive surgery has many benefits, and its application in different
      areas of surgery is still widening. This paper describes the results of treatment
      of varicoceles with laparoscopic technique on a day-in day-out basis. The
      operative time was acceptable and decreased with experience. The postoperative
      morbidity was low and time of convalescence short making the operation suitable
      for an out-patient regime, which again justifies the extra costs.

PMID- 8650787
TI  - [Spontaneous resolution of urodynamically proven sphincter lesion following
      surgery for prostatic hyperplasia].
AB  - Assuming that post-prostatectomy incontinence frequently resolves to various
      extents, forty patients from a background material of 105 consecutively referred
      patients with this complaint were reexamined three to 106 months (median 55
      months) after first examination. During the time interval between first
      examination and the revisit only four patients had some improvement of their
      incontinence. Eleven patients were evaluated urodynamically at both occasions
      showing no change in MUCP (maximal urethral closure pressure) or other urodynamic
      parameters. Consequently we could not confirm the dogma that sphincter lesion due
      to prostate surgery may gradually resolve. Our investigation indicates a poor
      continence prognosis in patients incontinent after transurethral or transvesical
      surgery of the prostate and that there therefore should be a more active
      treatment attitude. The patients should be offered an operation after evaluation
      of their incontinence, when a sphincter lesion is first diagnosed.

PMID- 8650788
TI  - [The impact of clean intermittent catheterization on bladder capacity and
      residual urine].
AB  - Clean intermittent catheterization (CIC) is a well-established method for
      treatment of bladder emptying failure. There have been many reports on the
      therapeutical benefits of CIC as well as on its complications. However, no
      reports have appeared on the impact of CIC on urodynamic parameters. We therefore
      investigated 18 women with urinary retention on the basis of a hypocontractile
      detrusor muscle and performed uroflowmetry and cystometry and recorded residual
      urine. The women were treated with CIC for an average of 26 months (1-62 months).
      At the time of investigation five had stopped because residual urine was reduced
      to below 50 ml. These patients were young and infrequent voiders. Two had stopped
      because of complications. In 11 patients there were still significant amounts of
      residual urine. When bladder capacity was measured cystometrically, there was a
      reduction in bladder capacity in ten patients but an increment in 8 cases.
      Patient compliance was high despite a high frequency of symptomatic urinary
      infections (16/18). On the basis of this study we suggest that CIC is efficient
      in normalizing mild cases of large bladders with emptying failure only.

PMID- 8650789
TI  - [Prolonged pseudodementia after treatment with tricyclic antidepressive agents
      and electroconvulsive therapy].
AB  - We present a case of a 62-year-old woman who developed severe and prolonged
      cognitive impairment after combined electro-convulsive therapy and tricyclic
      antidepressant drug therapy. The literature on the interaction between ECT and
      antidepressant drugs is sparse, and does not explain the severe cognitive
      impairment in our patient.

PMID- 8650790
TI  - United Kingdom Prospective Diabetes Study.

PMID- 8650791
TI  - [Vitamin C and disease].

PMID- 8650792
TI  - [Frozen shoulder].

PMID- 8650793
TI  - [The complicated tibial fracture].

PMID- 8650794
TI  - [Pediatric anesthesia].

PMID- 8650795
TI  - [Tibial pseudoarthrosis. Treatment using the Ilizarov technique].
AB  - In the period from the 1.1.1991 to the 31.5.1993 17 patients with a tibial
      pseudoarthrosis were treated by the Ilizarov method. The mean age was 35 years
      (13-88 years). Mean time from fracture to operation for pseudoarthrosis was 14.6
      months (3-39 months). There were two hypertrophic, 14 atrophic and one defect
      pseudoarthrosis. Six of the pseudoarthroses were infected. After stable external
      fixation the treatment was compression over the pseudoarthrosis in four cases and
      alternating distraction and compression in eight cases. In five cases the
      treatment was supplemented by bone transport for the defects between 15 and 50
      mm. Mean time of treatment with the external fixator was 5.2 months (2-11.5
      months). The overall treatment time was 9.8 months (3-19 months). At the follow
      up 14 pseudoarthroses were fully consolidated, one patient was still using an
      orthosis, and three patients were in need of reoperation with bone
      transplantation. During the period of fixation thirteen patients were
      hospitalized for short periods, and some of them several times. The treatments
      were for correction of the distraction, replacement of fixation of pintrack
      infection or treatment of pain. The Ilizarov method of treatment of
      pseudoarthrosis show a good stimulation of healing, but experience with the
      fixator system and aggressive treatment of various minor complications are
      essential for a successful outcome.

PMID- 8650796
TI  - [Postoperative pain relief in children].
AB  - Postoperative pain management in children has been subject to increasing interest
      during the last decade, but is still insufficient. A survey is presented
      concerning postoperative pain management in children. The value of monitoring the
      pain as well as the opioid side effects in children is stressed, and such methods
      are presented. Acute Pain Service is mentioned and the most important
      pharmacological aspects regarding non-steroidal anti-inflammatory drugs,
      paracetamol, opioids and local anaesthetics are discussed. The management of
      postoperative pain in neonates is reviewed separately. It is concluded that the
      present insufficient management of postoperative pain in children is not due to
      the lack of methods and techniques, but rather to lack of sufficient utilization
      and comprehension of the possibilities. Moreover, pain management in children
      should be individualised. It is also necessary to be more aware of side effects
      of the pharmacological treatment.

PMID- 8650797
TI  - [Congenital malformations of urinary tract and gastrointestinal canal. Incidence
      of diagnosed cases at 2 years of age compared with prenatal registration].
AB  - The aim of this study was to determine the incidence of diagnosed congenital
      malformations of the kidneys, urinary and gastrointestinal tracts at two years of
      age in an unselected population of 8952 children born in three Danish counties in
      1991. Further, to review how frequently these conditions were detected by
      obstetric ultrasound examination since no systematic screening for malformations
      was performed in 1991 in this area. Twenty-three children were found with
      congenital malformations of the kidneys or urinary tract which gives an incidence
      of 0.26%. Although 16 of the mothers had been examined with ultrasound during
      pregnancy, the malformation was only diagnosed or suspected in three of the 23
      children. Fourteen children had gastrointestinal malformations, eight were
      scanned prenatally and only one (diaphragmatic hernia) was diagnosed prenatally.
      Thus malformations in kidneys, urinary tract or gastrointestinal tract were
      rarely diagnosed prenatally by ultrasound although 70% of the mothers were
      scanned at least once during pregnancy.

PMID- 8650798
TI  - [Accidents caused by inflatable bouncers in 0-19 year-olds in Denmark in 1993].
AB  - The paper describes the epidemiology of accidents caused by inflatable bouncers.
      The estimated number of bouncers and bouncing castles in DK was 300-350 in 1993.
      The data were extracted from the Danish part of the EHLASS project ("the European
      Home and Leisure Accident Surveillance System). The project registers injuries in
      five Danish casualty wards, covering a total uptake area of 14.2% of the Danish
      population. In 1993, there were 91 injuries caused by inflatable bouncers, 37% of
      them in boys, and 63% in girls. Seventy-nine percent of the injuries were caused
      by falling, 19% by contact with an object or another person and 2% stress
      injuries. The type of injury were: bruises 42%, fractures 31%, distorsions 23%,
      and tendon/muscle strains 3%. The location of the fractures were: one in the
      spine, two in the clavicle, all other (25) were located in the limbs. Four
      patients had to be admitted for further observation or treatment. The average
      cost per injury was 839 dKr., or aprox 150 US$. It does not seem necessary to
      take special precautions or make restrictions in the use of this new playground
      article.

PMID- 8650799
TI  - [Spontaneous rectal hematoma].
AB  - Five cases of spontaneous rectus sheath haematomas observed during one year are
      reported. The female to male ratio was four to one. The age range was 26-75
      years. Precipitating factors were cough in three patients, physical exercise in
      one patient, and none in one patient. In three cases there were possible
      predisposing factors: anticoagulant therapy, Addison's disease with steroid
      treatment and abdominal scar. The localisations were three lower right quadrant,
      one lower left and one upper right. In three cases correct diagnoses were made
      based on clinical findings, confirmed by ultrasonography and treated
      conservatively. In two cases the diagnosis was not suspected clinically, and by
      ultrasonography the haematoma was overlooked in one case, and misinterpreted as
      an intraperitoneal tumour in the other; both cases underwent surgery. The
      incidence rate was estimated to 3.5 per 100,000 per year. The frequency was
      approximately 0.9% in patients admitted with "acute abdomen".

PMID- 8650800
TI  - [Mortality differences associated with moderate consumption of beer, wine and
      spirits].
AB  - In a prospective population study of 7,234 women and 6,051 men aged 30-79 years,
      information on beer, wine, spirits and tobacco consumption, and on education,
      income and body mass index were assessed in the period 1976-1978, and the
      population was followed until 1.1.1988 for mortality. With increasing intake, the
      wine-mortality risk function steadily decreased from a relative risk of 1.00 for
      those who never drank wine through 0.51 (95% confidence limits; 0.32-0.81) among
      those who drank three to five glasses per day. In contrast, neither beer nor
      spirits consumption was associated with reduced risk. For spirits consumption the
      relative risk of dying increased from 1.00 among those who never drank to 1.34
      (1.05-1.71) among those with an intake of 3-5 drinks per day. Wine drinking
      showed the same relation to risk of death from cardio- and cerebrovascular
      disease as to mortality from all causes.

PMID- 8650801
TI  - [Digoxin poisoning treated with Digibind].
AB  - A case of digoxin intoxication and hyperkalaemia causing cardiac arrest in a 63
      year-old female who had undergone cardiac surgery is presented. Symptomatic
      treatment was given. However, as the patient continued to be unstable we
      introduced digoxin Fab-antibody in the treatment. The patient changed her heart
      rhythm from atrioventricular conduction block to atrial fibrillation within a few
      minutes and recovered later on. The pharmacology and the indications for
      treatment with digoxin Fab-antibody fragments are discussed.

PMID- 8650802
TI  - [Enterobius vermicularis localized to the internal female genitalia].
AB  - Enterobius vermicularis is one of the most common helminthic infections in
      humans. It normally inhabits the large intestine and is of low pathogenecity. The
      ova are, however, occasionally found in ectopic sites in the peritoneal cavity,
      usually as asymptomatic granulomas, though in rare cases they may cause chronic
      lower abdominal pain. Two cases of ectopic enterobius vermicularis are presented
      in this paper.

PMID- 8650803
TI  - [Pediatric anesthesia in Denmark--a debate on the organization of pediatric
      anesthesia/surgery, intensive care and pain relief].

PMID- 8650804
TI  - [Cardiovascular diseases in Denmark in the year 2000--developmental trends].

PMID- 8650805
TI  - [Seborrheic dermatitis-- fungal infection or enzyme defect?].

PMID- 8650807
TI  - [Supinator syndrome, an underdiagnosed disease].

PMID- 8650806
TI  - [Melatonin--humbug or facts].

PMID- 8650808
TI  - [Supinator syndrome].

PMID- 8650810
TI  - [Oxygen inhalation therapy at home].

PMID- 8650811
TI  - [Can the import and spreading of multiresistant bacteria be prevented?].

PMID- 8650809
TI  - [A project on sedatives and psychopharmaceuticals in Fredericia. Reduction of the
      utilization of sedatives and psychopharmaceuticals by means of health education
      and training].

PMID- 8650812
TI  - [Early diagnosis of amiodarone-induced pulmonary toxicity: are repeated lung
      function tests of any value?].
AB  - Amiodarone therapy for certain life-threatening cardiac arrhythmias is associated
      with numerous side and adverse effects, of which pulmonary toxicity is one of the
      most serious adverse reactions. It appears to be generally accepted that
      amiodarone-induced pulmonary toxicity (APT) is associated with considerable
      morbidity and mortality. Based on the assumption that detection of APT in an
      asymptomatic phase would improve the prognosis for these patients, the value of
      monitoring for toxic effects with various paraclinical tests has been extensively
      studied. This article summarizes current knowledge of the pulmonary complications
      of amiodarone therapy with emphasis on the usefulness of pulmonary function tests
      in the detection of APT. Based on the findings in the published studies, it
      appears that changes in pulmonary function, including diffusion capacity, over
      time do not identify patients at risk for development of APT. It is suggested
      that it is worthwhile to obtain two or three measurements of pulmonary function,
      including diffusion capacity, within the first few months of therapy in order to
      establish the variation in the individual patient. When a stable maintenance dose
      has been reached, subsequent testing should be reserved for patients who develop
      new or progressive pulmonary symptoms or radiographic infiltrates.

PMID- 8650813
TI  - [AIDS--the leading cause of death among young adult men in Copenhagen and
      Frederiksberg].
AB  - The objective was to describe the extent to which HIV infection has become a
      major cause of death among young adults in Denmark. The design used was
      retrospective review of underlying causes of death recorded in the National
      Danish Register of Causes of Death on the basis of submitted death certificates.
      Analysis of mortality statistics revealed, that from 1980 to 1993 AIDS became the
      5th leading cause of death among men 25 to 49 years of age in Denmark after
      cancer, accidents, suicide and heart disease. AIDS among women had little impact
      on the vital statistics in the period. In the municipalities of the City of
      Copenhagen AIDS was the major cause of death among men already from 1990 and in
      1993 death from AIDS comprised 25% of all causes (n = 107, death rate =
      88/100,000). The rising rates of deaths attributed to AIDS among younger men show
      no sign of decreasing neither in the capital nor in the country as a whole.

PMID- 8650815
TI  - [The most recent part of the Danish Twin Registry. Establilshment and analysis of
      zygote specific twinning rates].
AB  - In order to be able to study the aetiology and pathogenesis of diseases with
      manifestation in childhood and youth a Danish register of young twins has been
      established. The compilation of the register is based on the Danish Civil
      Registration System, with the Danish Vital Statistics as source of validation.
      All twins were sent a one side questionnaire asking about diabetes, willingness
      to participate in other projects and pairwise similarity in the twins. Comprising
      20,888 twin pairs the register covers 74.4% of all twin pairs born 1953-67
      (incl.) and 97.4% of those born 1968-82 (incl.). The response rate of the
      questionnaire study was 92.3%. The responders represented 19 180 twin pairs.
      Ninety-six percent of the respondent twins declared their willingness to
      participate in additional studies. An analysis of trends in the twinning rates
      for the years 1968-82 showed that the rate in monozygotic twinning is increasing
      and the twinning rate of opposite-sexed twin pairs is decreasing, thus confirming
      earlier estimated trends in twinning rates. This register provides a valuable
      resource for future twin studies.

PMID- 8650814
TI  - [Clinical consequences of intranasal insulin therapy in insulin-dependent
      diabetes mellitus].
AB  - Metabolic control, hypoglycaemia frequency and nasal mucosal physiology were
      evaluated in 31 insulin-dependent diabetics treated with intranasal insulin at
      mealtimes for one month and with subcutaneous fast-acting insulin for another
      month in a randomized crossover trial. During both periods the patients were
      treated with intermediate-acting insulin at bedtime. Six of the patients were
      withdrawn from the study during intranasal insulin therapy due to metabolic
      dysregulation. Insulin concentrations increased more rapidly and decreased more
      quickly during intranasal as compared with subcutaneous insulin administration.
      Metabolic control, assessed by haemoglobin A1c concentrations, deteriorated after
      intranasal as compared with subcutaneous insulin therapy. The bioavailability of
      intranasally applied insulin was low, since intranasal insulin doses were
      approximately 20 times higher than subcutaneous doses. The frequency of
      hypoglycemia was similar during intranasal and subcutaneous insulin therapy, and
      nasal mucosal physiology was unaffected after intranasal insulin. We conclude
      that due to low bioavailability and to a high rate of therapeutic failure,
      intranasal insulin treatment is not a realistic alternative to subcutaneous
      insulin injections at the present time.

PMID- 8650817
TI  - [Use of fresh frozen plasma in patient treatment. Indications illustrated by a
      literature review and a study of practice at a university hospital].
AB  - We analyzed transfusion data on all patients transfused with fresh frozen plasma
      (FFP) during two periods of four weeks, before (phase one) and after (phase two)
      initiation of information and intervention. Information was based on the results
      of phase one and on information about appropriate use of FFP. The intervention
      consisted of introducing a new policy: Clinicians had to justify their
      prescription of FFP to the physician on duty in the blood bank. During phase one,
      the usage of FFP was 403 units, which decreased to 229 units during phase two
      (43% reduction). In both phases an unchanged proportion of FFP units (68%) were
      preceded by coagulation tests. In phase one, only 90 (22.3%) of the instances had
      documented coagulopathy by laboratory criteria, whereas in phase two the number
      was 77 (33.6%). A total of 186 (46.4%) FFP units in phase one were considered
      inappropriately transfused compared to a total of 89 (38.9%) units in phase two.
      Indications for transfusion were stated for 80 (19.9%) FFP units during phase one
      increasing to 114 (49.8%) units during phase two. Through information and
      intervention we were able to reduce the usage of FFP by 43%. The results reveal a
      need for quality assurance of the use of transfusions with FFP.

PMID- 8650816
TI  - [Determination of diurnal blood pressure variations in cirrhosis].
AB  - Cirrhotic patients have disturbed systemic haemodynamics with reduced arterial
      blood pressure, but this has not been investigated during daily activity and
      sleep. Systolic (SBP), diastolic (DBP), and man arterial blood pressure (MAP),
      and heart rate (HR) were measured by an automatic ambulatory device for
      monitoring blood pressure in 35 patients with cirrhosis and 35 healthy matched
      controls. During the day-time, SBP, DBP and MAP were significantly lower in the
      patients than in the controls (median 118 vs 127; 70 vs 78; 86 vs 94 mmHg, p <
      0.0001 to p < 0.05). The night-time blood pressures were almost similar in the
      two groups (108 vs 110; 65 vs 67; 78 vs 82 mmHg, NS). Conversely, HR was
      significantly higher in the patients both in the day-time (86 vs 72 min-1, p <
      0.0001) and night (80 vs 64 min-1, p < 0.0001). Consequently, the reduction in
      blood pressure and HR from day-time to night-time was significantly lower in the
      patients than in the controls (p < 0.0001 to p < 0.01). Multiple regression
      analysis revealed HR, serum albumin, serum sodium, and clotting factors 2, 7 and
      10 as significant independent predictors of SBP in cirrhosis. In conclusion,
      cirrhotic patients have elevated HR, but surprisingly normal arterial blood
      pressure during the night-time, and the circadian variation in blood pressure and
      HR is diminished probably due to an almost unaltered cardiac output during the 24
      hours. These results may reflect a major defect in the ability of optimal
      regulation of blood pressure in cirrhotic patients.

PMID- 8650818
TI  - [Spread of an imported multiresistant Staphylococcus aureus to other hospitals
      via secondary colonized patients].
AB  - A secondary spread of an imported methicillin-resistant Staphylococcus aureus
      strain (MRSA) to two other patients occurred within a Danish surgical ward in
      spite of isolation of a multitraumatized index-patient immediately after arrival
      from a hospital in the Mediterranean area. The two other colonized patients were
      later transferred to other hospitals in Denmark where it became apparent that
      they had developed serious infections with the MRSA strain. IN CONCLUSION: to
      prevent spread of imported MRSA within Danish hospitals, strict adherence to
      isolation procedures and a high level of general hygiene is essential not only
      when patients are transferred from hospitals situated in endemic areas of MRSA
      abroad, but also when admitted from Danish hospital wards where known cases of
      colonisation or infection with MRSA exist.

PMID- 8650819
TI  - [Aplasia cutis congenita in a premature infant].
AB  - A premature male dizygotic twin born at gestational age of 28 weeks with skin
      lesions located on hands, knees, pretibial regions and feet is presented. The
      patient differs from previously reported cases of aplasia cutis congenita (ACC)
      in that the cutaneous manifestations first appeared 10 days after birth. The twin
      brother was healthy. Based on the clinical manifestations the patient was
      regarded to have ACC (group 6).

PMID- 8650820
TI  - [Caffeine antagonizes the neuromuscular blockade of vecuronium].
AB  - It is known that theophylline antagonizes the neuromuscular blockade in animals
      and case reports, where the same phenomenon has been observed in man, are
      described. One patient is described where another methylxantine-caffeine-caused
      resistance to neuromuscular blockade by vecuronium, but successful blockade was
      achieved by pancuronium.

PMID- 8650821
TI  - [Sex and pregnancy].

PMID- 8650822
TI  - [Does the cardiologists' report on lipids forget primary prevention?].

PMID- 8650823
TI  - [Clinical use of sufentanil].

PMID- 8650824
TI  - The changing face of oesophageal cancer treatment in Northern Ireland.
AB  - In the late 1970's the options for treatment of oesophageal cancer were limited.
      When cure was thought possible, resection was performed by the Ivor Lewis or
      oesophagogastrectomy techniques. Mortality was high, local recurrence rates
      disappointing, and long-term survival poor. For those patients whose tumours
      could not be resected, palliative intubation required open operation with high
      morbidity, and gave poor quality of life. In 1994, selective screening is
      diagnosing cancers early, more extensive resections are possible with lower
      mortality, and fewer local recurrences. Adjuvant therapy is increasing the
      operability rates. Gradually the facade of poor prognosis is being etched away,
      so that more patients are being given better quality of life, and cure is a
      distinct possibility. Palliation can be achieved endoscopically by dilatation,
      intubation or laser ablation combined with local external beam radiation.
      Mortality for palliative procedures is now considerably reduced.

PMID- 8650825
TI  - Chemical lumbar sympathectomy in patients with severe lower limb ischaemia.
AB  - Over a 13 year period, 544 chemical lumbar sympathetic blocks with phenol in 489
      patients were performed by the author with the aid of X-ray image
      intensification. There was objective and subjective improvement in the signs and
      symptoms of limb ischaemia in 72%, judged by relief of rest pain, improvement in
      skin blood flow or healing of ischaemic ulcers. Of patients treated in the years
      1990-1993, 44% had suffered either death or major amputation within two years of
      their treatment. Three serious and probably avoidable complications are
      described.

PMID- 8650826
TI  - Complications associated with central venous catheters in a haematology unit.
AB  - The use of central venous catheters in patients suffering from haematological
      disorders has brought enormous benefits, but has been associated with an increase
      in septicaemia. We have reviewed septic and other complications in 43 patients
      who received one of three different forms of central venous catheters (type A
      Hickman, type B-Portacath, type C-Pasport) during 1991. All complications were
      reviewed up to 18 months following insertion. The total complication rate was 31%
      (0.97 per 100 catheter days), and the total sepsis complication rate was 18.8%
      (0.49 per 100 catheter days). Type A catheters had the greatest sepsis
      complication rate of 29.5% (0.84 per 100 catheter days), with type B 15% (0.39
      per 100 catheter days) and type C 9.9% (0.32 per 100 catheter days). Prophylactic
      antibiotics on the day of catheter insertion did not reduce the sepsis rate or
      prolong catheter survival.

PMID- 8650827
TI  - Myotonic dystrophy: relative sensitivity of symptoms signs and abnormal
      investigations.
AB  - Twenty-five symptoms, signs, and abnormal investigations were looked for in 20
      patients with clinically-definite myotonic dystrophy. Weakness of facial muscles,
      neck flexors, and arm external rotators was found in all patients (sensitivity =
      100%). Arm external rotation has not been reported as a frequently involved
      muscle in previous clinical studies on myotonic dystrophy. Careful examination of
      muscle strength may therefore predict which patients may or may not carry the
      abnormal gene for myotonic dystrophy.

PMID- 8650828
TI  - Changes in the pattern of deliberate self-poisoning presenting at Craigavon Area
      Hospital: 1976, 1986 and 1991.
AB  - Deliberate self-poisoning presenting at Craigavon Area Hospital in 1991 was
      examined and compared to the years 1976 and 1986. Self-poisoning has not declined
      over the 15 year period 1976-1991. The reduction in the use of benzodiazepines,
      and increase in paracetamol, previously reported, continues. Possible reasons for
      this are examined, in relation to local and national drug prescribing.

PMID- 8650829
TI  - Geriatric medicine: the anatomy of change.
AB  - We have studied workloads and patterns of care in geriatric medicine from 1982 to
      1993 in the Ulster Hospital. There was a 137% rise in admissions, a 16% reduction
      in domiciliary visits and a 31% increase in ward assessments. The continuing care
      waiting list fell to zero in 1993. The number of new outpatients rose by a factor
      of 8.6 between 1987 and 1993. Between 1990 and 1993 there was an increased
      admission rate from nursing homes and of patients suffering from respiratory
      system diseases. Mortality rates fell from 27.8% in 1982 to 19.3% in 1990 and to
      12.1% in 1993. Mean age and sex ratios remained unchanged over the years while
      the average length of stay halved from 43.3 to 22.6 days between 1990 and 1993.
      81% of admissions in 1993 were emergencies. Care of the elderly in hospital and
      the interface with general medicine are changing.

PMID- 8650831
TI  - The role of the general practitioner hospital in inpatient care.
AB  - The rationale of the general practitioner hospital continues to be questioned. A
      study of the services and case-mix of two of the four remaining general
      practitioner hospitals in Northern Ireland was undertaken to determine whether
      the nature and cost of inpatient care in these hospitals was comparable to the
      available alternatives. The case-notes of all non-maternity admissions (n = 509)
      were reviewed. The two hospitals provide acute medical care for a wide range of
      patients. The majority of patients appeared to require hospitalisation. It is
      likely that the beds at the two hospitals were mainly a substitute for district
      general hospital care. The general practitioner hospitals were estimated to be
      less costly than alternative forms of care, although it was doubtful whether they
      fulfilled all the structural criteria of quality generally regarded as important
      for hospitals of this type.

PMID- 8650830
TI  - Admission of nursing home patients to geriatric medical wards.
AB  - Comparison was made between patients admitted from a nursing home and all other
      patients admitted to a geriatric medical unit in 1990 and 1993. The number of
      nursing home patient admissions rose from 26 in 1990 to 106 in 1993. Nursing home
      patients were frailer both physically and mentally with a dementia rate of 78%
      (in those who survived, 1993) and a mortality rate of 19.8% (1993), compared with
      a dementia rate of 19% and a mortality rate of 11.3% in all other admissions in
      1993. Male patients admitted from a nursing home were more likely to die than
      females (33% versus 14.5%, 1993). Lengths of stay of nursing home patients were
      shorter, largely due to the availability of a 'safe environment' when discharged,
      but also related to shorter survival times. 61% of patient admissions from
      nursing homes in 1993 were considered 'unnecessary' and could have been avoided
      if specialist advice had been available before admission.

PMID- 8650832
TI  - 'Assessment and care management'--a hospital perspective.
AB  - Patients placed from hospital to nursing or residential homes or to home under
      the intensive domiciliary care scheme were compared before and after the
      introduction of 'assessment and care management' on the 1st April 1993. In
      geriatric medical wards there was a 69% increase in the average length of stay
      for patients assessed and care managed and a 52% increase in the length of stay
      for self-funding patients compared with patients placed before the introduction
      of assessment and care management. Care managed patients discharged on the
      intensive domiciliary care scheme had a 66% increase in their length of hospital
      stay compared with care managed patients placed in private nursing homes. In
      contrast, the length of stay for care managed patients in other hospital wards
      was half that for geriatric medical wards.

PMID- 8650834
TI  - Random recollections of World War II.

PMID- 8650835
TI  - The history of the Ulster Obstetrical and Gynaecological Society.

PMID- 8650833
TI  - The L-arginine/nitric oxide pathway--biological properties and therapeutic
      applications.

PMID- 8650836
TI  - Thomas Houston and the founding of clinical pathology at the Royal Victoria
      Hospital, Belfast.

PMID- 8650837
TI  - Parosteal lipoma.

PMID- 8650838
TI  - Ruptured silicone breast implant: a misleading chest X-ray.

PMID- 8650839
TI  - Adenocarcinoma of the distal duodenum: two cases managed by pylorus preserving
      pancreatico-duodenectomy and adjuvant chemotherapy.

PMID- 8650841
TI  - Hereditary coproporphyria.

PMID- 8650840
TI  - Hypercalcemia associated with a parathyroid cyst.

PMID- 8650842
TI  - [Hypospadias--results of correction].
AB  - Modern surgical treatment of hypospadias is reviewed. Early microsurgical
      correction of hypospadias is gaining ground in view of early presentation of the
      patient; this means minute tissue relations that require very precise
      reconstruction. The operative correction is described as an example of a complex
      treatment: psychosexual adjustment, endocrinological development and sexual
      function must all be taken into increasingly frequent account.

PMID- 8650843
TI  - [Cryptorchism--assessment from an andrologic viewpoint].
AB  - This report deals with the pathology, diagnosis and therapy of cryptorchidism
      from the andrological point of view. Hypothalamic-pituitary gonadal failure and a
      reduced transformation of gonocytes are the key factors in fertility disorders.
      The aim of all well-timed therapy must be to improve the fertility potential of
      the sexually mature male. At present, the determination through biopsy of the
      fertility index during orchiopexy offers the only possibility of prospective
      diagnosis in this respect. In the future, it will be necessary to have a
      standardized procedure in order to guarantee the long-term effect of correctly
      timed orchiopexy on fertility.

PMID- 8650844
TI  - [Interdisciplinary surgical therapy of renal tumors with intracardiac tumor
      thrombi].
AB  - A combination of increased perioperative morbidity, together with the technical
      difficulty of an R 0 (curative) resection, is responsible for the poor prognostic
      factors of supradiaphragmatically extending renal tumors. Six patients aged 53-70
      years with vena cava thrombosis extending into the right atrium or ventricle
      underwent en bloc resection of the primary tumor and tumor thrombus removal. If
      the atrial tumor mass was large or extended into the ventricle, resection was
      performed during cardiopulmonary arrest using a cardiopulmonary bypass method
      with the patient in deep hypothermia (< 18 degrees C). Alternatively if the
      cardiac tumor infiltration was minimal, resection was performed during an
      optionally short cardiopulmonary arrest period using a cardiopulmonary bypass
      method with the patient in hypothermia (23 degrees C). The operative procedure
      was determined by intracardiac tumor extension, tumor wall adhesions and tumor
      wall infiltrations, all of which were assessed intraoperatively by vena cava
      sonography. Six patients were strongly symptomatic preoperatively. Three
      developed sudden life-threatening cardiopulmonary insufficiency, possibly due to
      longer-lasting tricuspital valve prolapse with a consecutive right-to-left shunt
      through a newly reopened foramen ovale. One patient died 14 months
      postoperatively because of multiple metastases (hepatic, pulmonary and bone). One
      patient is still alive and has had a local recurrence for 2 months, which was
      diagnosed 65 months postoperatively. The remaining four patients are alive and
      well. They have been tumor-free for extended periods of time (29, 34, 62 and 84
      months, respectively).

PMID- 8650845
TI  - [Electrophysiologic diagnosis in erectile dysfunction].
AB  - So far, electrophysiological examinations have rarely been used in the diagnosis
      of erectile dysfunction (ED) mainly because the methods available only allow
      somatic neuron pathways to be examined whose relevance for the mainly
      autonomically controlled crection is evaluated differently. At present, impaired
      penile nerve supply as the possible cause of ED can only be evaluated through
      neurophysiological screening of the somatic and autonomic pathways of the pelvic
      floor, and not just by one simple method. Diagnosing ED should include testing of
      motoric efferences through electroneurography of the pudendal nerve and
      electromyography of the external anal sphincter and the urethral sphincter.
      Sensitive afference is tested with somatosensory evoked potentials of the
      pudendal nerve. New methods that are available for the examination of autonomic
      pathways are the penile sympathetic skin response and the EMG of the corpus
      cavernosum. Together with the other electrophysiological examinations, they allow
      neurogenic causes to be determined and differentiate not only between central and
      peripheric lesions, but also between acute and chronic changes. Prognosis can
      also be estimated. A crucial diagnostic deficit is the fact that it is still not
      possible to test the parasympathetic system directly.

PMID- 8650846
TI  - [Effect of HLA compatibility on the transplanted kidney in relation to recipient
      age].
AB  - Donor-recipient histocompatibility, as evaluated by the HLA matching results,
      plays an important role in the outcome of renal transplants, although much
      controversy surrounds the benefit of kidney allocation based on HLA typing. In
      this report HLA matching and survival data on 1,342 transplants performed at the
      University of California at San Francisco between 1984 and 1992 and treated
      uniformly by quadruple immunosuppression were analyzed in relation to the
      recipient's age. With respect to the influence of the increasing number of
      mismatches from 0 to 6, the analysis revealed decreasing 3-year graft survival
      rates as follows: 85.4%; 87.3%; 71.3%; 78.2%; 75.8%; 70.9% and 67.5%. Whereas the
      impact of cold ischemia time and histocompatibility was equally important during
      the 3-year postoperative period, the essential positive influence of good HLA
      matching on the long-term graft survival was demonstrated. The children aged
      between 5 and 18 years were identified as a high-risk group by the analysis, HLA
      A incompatibility being attributed to poor graft survival in this age group. With
      respect to the effect of HLA-A histoincompatibility, the data provide evidence
      that HLA-A matching results seem to play an important role in graft survival in
      children, whereas transplants well matched in terms of HLA-B did well in adult
      recipients. No age difference in the impact of HLA-DR could be detected. In
      conclusion, HLA matching is still essential. It seems that there are differences
      in the impact of HLA loci in relation to the recipient's age.

PMID- 8650847
TI  - [Can examination of spontaneous urine samples adequately replace 24-hour-urine
      samples for determining excretory rate of various lithogenic and inhibitory
      substances in metabolic evaluation of kidney calculi patients?].
AB  - The gold standard for metabolic evaluation of stone-forming patients is the 24-h
      urine specimen. Recently, some authors have suggested that for routine metabolic
      evaluation spot urine samples are as valuable as the 24-h urine specimen. The
      purpose of our study, was to determine the value of the spot urine sample in
      comparison with the 24-h urine specimens. Eighty-eight healthy volunteers on
      different diets were investigated (32 vegetarians, 12 body-builders without
      protein concentrates, 28 body-builders on protein concentrates, and 16 subjects
      on a regular European diet). Using 24-h specimens, excretion rates of oxalate,
      calcium, sodium and potassium were determined. The concentration ratio of these
      electrolytes to creatinine was calculated for spot urine samples. A highly
      significant correlation between the excretion rates and the results of the spot
      urine samples was found for all parameters. However, the correlations showed
      considerable variations. On the other hand, we were able to show that creatinine
      excretion is highly dependent on daily protein intake, body weight and glomerular
      filtration rate. This leads to a considerable inter- and intraindividual
      variation in creatinine excretion. This variation of the creatinine excretion is
      the major cause for the variation in the results of spot urine samples. It is
      concluded that spot urine samples are an inadequate substitute for the 24-h urine
      specimen and that the 24-h urine specimen is still the basis for metabolic
      evaluation in stone patients.

PMID- 8650848
TI  - [Therapy of hormone refractory prostate carcinoma with mitoxantrone. A clinical
      phase II study].
AB  - So far, no curative treatment is available for hormone-refractory prostate
      carcinoma. Therapy is thus focused on alleviating symptomatic tumor progression
      with the aim of improving quality of life. Therefore, anthracyclin-derived
      mitoxantrone was administered to 25 patients with hormone-refractory prostate
      carcinoma and symptomatic progressive disease. After a median treatment of 13
      weeks, a median of 4 cycles and a follow-up of 14 months, 48% of the patients
      (12/25) reported improvement in tumor-related pain; in 60% (15/25) there was
      improvement of the self-assessment symptom score and 32% of the patients (8/25)
      gained weight. Additionally, partial tumor response with regression of lymph-node
      metastases occurred in 3/25 patients (12%). In 10/25 patients the serum level of
      prostate-specific antigen (PSA) decreased as well as the alkaline phosphatase
      (AP) in 7/25 patients. Side effects subsequent to chemotherapy were leucopenia
      WHO grade III in 25% of the patients and thrombocytopenia WHO grade III in 3/25
      and grade V (treatment-related death) in 1/25 patients. Non-hematological
      toxicity occurred in 2 patients (cardiotoxicity n = 1, nephrotoxicity n = 1, WHO
      grade II each).

PMID- 8650850
TI  - [Traveling on the data highway--online information for urologists].
AB  - Global exchange of information is one of the major sources of scientific progress
      in medicine. Electronic media have recently supplemented the standard methods of
      scientific communication such as congresses, books and journals. Currently, 30
      million computers are part of the world-wide, exponentially growing network, the
      ""information superhighway''. Numerous resources offered by the network are
      becoming increasingly useful in clinical medicine. In Germany, three major
      networks are currently available: T-Online/Datex-J, Compuserve and Internet. The
      majority of information relevant to urologists can be found in the Internet. This
      information includes medical journals that can either partly or completely be
      read online, online library catalogs, scientific images (pathology and
      radiology), and databases on urologic oncology and basic research in urology.
      Even outside academic institutions access to the "information superhighway" is
      easily available. Currently, the "information superhighway" constitutes a new
      source of database-type information; in the near future, medical education,
      clinical consultation and worldwide cooperation in clinical studies will be new
      fields of scientific communication employing worldwide computer networks.

PMID- 8650849
TI  - [Positron emission tomography in diagnosis of renal cell carcinoma].
AB  - PET is a new method for staging malignant tumors; the metabolism is examined and
      not the morphology. In this study the staging of renal cell carcinoma (RCC) by
      PET was investigated. In 29 patients PET with fluorodeoxyglucose (FDG) was
      carried out preoperatively; the PET results were compared to the histology of the
      OR specimen. In 26 patients a RCC was found histologically, which was diagnosed
      correctly by PET in 20 patients; in 6 patients a false-negative PET result was
      obtained. An angiomyolipoma, a pericytoma and a pheochromocytoma showed a false
      positive PET result. For lymph-node staging positive nodes were found in 3
      patients which was correct; no false-negative result was obtained. In 25 patients
      the PET result was true-positive; once a false-positive finding occurred. In
      conclusion, PET offers the advantage that no allergy to FDG is known and a
      pacemaker or metal implants are not contraindications; in diagnosing RCC,
      according to our results there is no further advantage of FDG-PET in comparison
      to standard methods; for lymph-node staging the results are equivalent

PMID- 8650851
TI  - [Pathogenesis, diagnosis and therapy of testicular tumors].

PMID- 8650852
TI  - [What is new in pediatric urology?].

PMID- 8650853
TI  - [Pediatric ureteral ureteral outlet obstruction and obstructive megaureter:
      observation or operation?].
AB  - Stenosis of the ureteropelvic junction and obstructive megaureter are still a
      diagnostic and therapeutic problems. So far, there is no reliable prognostic
      factor to predict the outcome of a primary dilated upper urinary tract under the
      "wait and see" strategy and to decide which child must be operated upon and which
      should not. In practice, basic diagnostic evaluation with sonography, possibly
      i.v.-pyelography and voiding cystography is accompanied by quantifying isotope
      based procedures such as DMSA-uptake or diuretic renography. The Whitaker test
      has become less important. Based on the investigation by Koff et al., it seems to
      be possible to follow the "wait and see" procedure in more than 85% of the
      children without any loss of renal function of the dilated kidney.

PMID- 8650854
TI  - [Endoscopic treatment of vesicoureterorenal reflux in the child].
AB  - In the first part of this review reflux per se and its conventional surgical
      therapy are presented. Then the minimally invasive, endoscopic subureteral
      injection is discussed as an alternative treatment of reflux. Last, the
      advantages and disadvantages of the substances used are evaluated. In the second
      part our experience with endoscopic subureteral collagen injection is presented
      and the results are critically analysed.

PMID- 8650855
TI  - Urologic sequelae of childhood genitourinary trauma and abuse in men: principles
      of recognition with fifteen case illustrations.
AB  - Providing urologic care to men who have been traumatized during childhood may be
      especially challenging because of the extent, severity, and unusual character of
      their urogenital problems. Recognition of past trauma entails attentiveness to
      patients' background and behaviors. As illustrated through these 15 cases,
      patients who present with too many past surgeries, too many unremitting urologic
      complaints, too little sexual function and too few genital parts, sexual impulses
      that are too strong, sexualized conduct in clinical settings, and self
      destructive behaviors surrounding sexuality may have experienced trauma in the
      past. While empirical studies are necessary to demonstrate the ultimate utility
      of these categories, appreciation of these clinical indications improves the
      urologic care provided to traumatized men in four ways: by elucidating unusual
      and unusually recalcitrant urologic complaints, thereby clarifying clinical
      decisions; by allowing for appropriate use of psychiatric consultation; by
      promoting a better understanding of the sequelae of trauma in men; and by
      alleviating the discomfort naturally felt by urologists and their staff when
      caring for these difficult, multiproblem patients.

PMID- 8650856
TI  - Combined androgen blockade for the treatment of metastatic cancer of the
      prostate.

PMID- 8650857
TI  - Effectiveness of a urinary control insert in the management of stress urinary
      incontinence: early results of a multicenter study.
AB  - OBJECTIVES: The purpose of this study was to test the safety and effectiveness of
      a urethral insert for managing stress or mixed urinary incontinence. METHODS: We
      performed a prospective, multicenter study of 135 female patients who were
      treated for 4 months with the Reliance Urinary Control Insert. The effectiveness
      of the insert was measured objectively at the time of first use and after 4
      months' use by standardized pad weight studies. Insert effectiveness was also
      measured by reports of symptom improvement during patient interviews and on
      patient diaries. Urine microscopy and culture were obtained monthly; cystoscopy
      and urodynamics were conducted at study entry and at 4 months. RESULTS:
      Significant improvement in involuntary urine loss was observed. Objective
      measurement of urine loss revealed that 80% of the patients were completely dry,
      and 95% of the patients achieved greater than an 80% decrease in urine loss. In
      addition, patients' perceptions of acceptability, incontinence symptom
      improvement, ease of learning, comfort, and time to habituation also showed
      improvements. Untoward events reported during the study included hematuria,
      bacteriuria, and bladder irritation. These events did not require significant
      medical intervention and did not result in any long-term clinical sequelae.
      CONCLUSIONS: These preliminary results indicate that the Reliance Urinary Control
      Insert may be a safe, effective, and well-tolerated alternative to other
      available methods for the management of stress or mixed incontinence in women.
      Additional long-term follow-up will be required to substantiate this conclusion.

PMID- 8650858
TI  - The use of standard imaging techniques and their diagnostic value in the workup
      of renal colic in the setting of intractable flank pain.
AB  - OBJECTIVES: This study reviews the rate at which diagnostic imaging techniques
      are used in patients with intractable flank pain attributed to renal colic who
      are admitted to the hospital through the emergency room and determines the
      diagnostic values of plain film of the abdomen {kidney, ureter, bladder [KUB]}
      and of ultrasonography (US) of the urinary tract, using intravenous urography
      (IVU) as the gold standard for establishing the presence of a calculus. METHODS:
      We reviewed the medical records of 288 patients who were admitted to our medical
      center over a period of 5 consecutive years for intractable flank pain, the
      admission and working diagnosis in all cases being that of renal colic, and we
      retrieved all data pertaining to their diagnostic evaluation. RESULTS: A total of
      265 patients (92%) were subjected to KUB, 158 (55%) to IVU, and 135 (45%) to US
      of the renal-urinary tract. Two diagnostic imaging techniques were used in the
      same patient in the following combinations: KUB and IVU in 146 patients (51%),
      KUB and US in 110 (38%), and IVU and US in 60 (21%). Three imaging techniques
      (IVU, KUB, and US) were utilized in 54 patients (19%). The sensitivity and
      specificity of KUB alone were 95% and 65%, respectively, and the positive and
      negative predictive values were 82% and 88%. The sensitivity of US alone was 93%,
      its specificity 83%, the positive predictive value 93%, and the negative
      predictive value 83%. The sensitivity of combined KUB and US (requiring both
      tests to be positive for diagnosing the presence of a calculus) was 89%, the
      specificity 100%, the positive predictive value 100%, and the negative predictive
      value 81%. CONCLUSIONS: Our data indicate that combining US with KUB provides the
      best diagnostic algorithm that approaches the yield of IVU in excluding the
      presence of a calculus in the renal-urinary tract in patients who present with
      intractable flank pain.

PMID- 8650859
TI  - Patients with renal cysts associated with renal cell carcinoma and the clinical
      implications of cyst puncture: a study of 223 cases.
AB  - OBJECTIVES: To clarify the association between renal cysts and renal cell
      carcinoma (RCC), we analyzed patient demographics, types of cystic disease, and
      modes of cyst-tumor coexistence along with the results of cyst puncture. METHODS:
      A total of 507 hospitals provided information regarding clinical experiences with
      RCC and cyst puncture over a 2-year period. RESULTS: Renal cysts were identified
      by preoperative imaging in 223 (4%) of 5721 patients with RCC. Histologic
      examination revealed cystic RCC in 56 patients (25%) and RCC associated with
      cystic diseases in 167 (75%). Cystic disease included simple cysts in 72 patients
      (32%), acquired cystic disease of the kidney (ACDK) in 62 (28%), multilocular
      renal cysts in 20 (9%), polycystic kidney in 3 (1%), and unspecified or
      miscellaneous in 10. Cyst puncture performed in 47 (21%) of 223 patients
      demonstrated bloody fluid in 20 cases and nonbloody fluid in 27. Cytologic
      analysis of cystic fluid obtained from 37 patients revealed a malignancy in 5
      (14%), accounting for 25% of the bloody and 4.8% of nonbloody specimens. Cytology
      failed to detect RCC in ACDK and multilocular cysts but was positive in cases of
      cystic RCC and solitary cysts. Four of 5 cytology-positive cases comprised those
      of tumor in cyst and cyst within tumor. CONCLUSIONS: Simple cysts and ACDK
      accounted for 60% of the renal cysts associated with RCC. Cystic RCC was involved
      in 25% of cases. Positive cytology may be expected in select cases, including
      those with close cyst-tumor relationships and those involving bloody cyst fluid.
      However, negative cytology does not exclude RCC.

PMID- 8650860
TI  - Results of conservative treatment (transurethral resection plus adjuvant
      intravesical chemotherapy) in patients with primary T1, G3 transitional cell
      carcinoma of the bladder.
AB  - OBJECTIVES: To evaluate a selected population of 50 consecutive patients with
      primary T1, G3 bladder transitional cell carcinoma in the absence of carcinoma in
      situ (Tis) treated with a bladder-sparing approach. METHODS: Between January 1983
      and December 1992, all patients were treated by transurethral resection (TUR)
      plus adjuvant intravesical chemotherapy over 1 year. In most cases, doxorubicin,
      epirubicin, and mitomycin were used alone or in combination. RESULTS: At a mean
      follow-up period of 52 months (range, 18 to 126), 16 of 50 patients (32%) showed
      a recurrent superficial tumor. The recurrent lesion was of Stage T1 in 11 (22%)
      cases, but was a T1, G3 tumor only in 5 cases (10%). In 2 additional patients
      (4%) a Tis developed during the observation period after TUR. The mean interval
      between TUR and first recurrence was 14.6 months (range, 3 to 38). At a mean time
      of 17 months after the initial TUR, 3 patients (6%) underwent a radical
      cystectomy due to a progression in T category and 3 additional patients (6%)
      developed distant metastases at a mean time of 23 months after TUR. In brief, 84%
      of the patients are alive and tumor-free. Five patients (10%) died of bladder
      cancer with a mean follow-up of 52 months. CONCLUSIONS: If no concomitant Tis
      exist, a conservative approach is a legitimate option as an initial treatment of
      patients with primary T1, G3 bladder tumors.

PMID- 8650861
TI  - Combination transurethral resection, systemic chemotherapy, and pelvic
      radiotherapy for invasive (T2-T4) bladder cancer unsuitable for cystectomy: a
      phase I/II Southwestern Oncology Group study.
AB  - OBJECTIVES: Primarily to evaluate the toxicity and, secondarily, the tumor
      response and patient survival associated with a three-phase combined modality
      treatment plan for patients with invasive transitional cell carcinoma (TCC) of
      the bladder (T2-T4,NX-N2, MO) who are medically unsuitable for or who refuse
      cystectomy. METHODS: Eligible patients initially underwent extensive
      transurethral resection (TUR) of the primary tumor with the attempt to resect
      disease totally. Subsequently, they received systemic combination chemotherapy
      consisting of two cycles of methotrexate, cisplatin, and vinblastine (MCV),
      followed by cystoscopic re-evaluation of the bladder tumor. Patients then
      received 6480 cGy radiotherapy to the bladder with concurrent systemic cisplatin.
      Toxicity, primary tumor response, and overall survival were evaluated. RESULTS:
      Of 34 eligible patients, 27 patients completed the treatment series. Twenty-two
      received 80% to 100% of the prescribed doses of MCV and only 2 patients
      experienced grade 4 hematologic toxicities. The most common toxicities were
      gastrointestinal (23), hematologic (21), and renal (8). The complete response
      (CR) rate after all treatment phases was 56% (19 of 34), 10 patients achieving a
      complete tumor resection of visible tumor at the initial TUR of the bladder
      (TURB); 3, a CR after MCV; and 6, after radiotherapy and concomitant cisplatin.
      The median overall survival was 21 months with 6 of 34 (18%) alive at 57 months
      (range, 36 to 75). Complete resection of tumor by TURB was associated with
      prolonged overall survival. The bladder was the initial site of recurrence in 85%
      of patients who had achieved a CR status. CONCLUSIONS: This older age patient
      group tolerated this combined modality therapy with acceptable toxicities, but
      the overall survival rate was not improved compared with those reported with
      radiotherapy alone.

PMID- 8650862
TI  - Reproducibility of uroflow measurement: experience during a double-blind, placebo
      controlled study of doxazosin in benign prostatic hyperplasia.
AB  - OBJECTIVES: To evaluate the interindividual and intraindividual variation of
      uroflow measurements in men with benign prostatic hyperplasia (BPH). METHODS: A
      total of 147 men with clinical evidence of BPH underwent two uroflow measurements
      at each of two screening visits prior to recruitment into a placebo-controlled
      study of doxazosin in the treatment of BPH. The maximum and mean flow rates were
      determined on each occasion. Differences in the mean value of both parameters for
      the cohort were examined. The intraindividual variability was evaluated using
      intraclass correlation coefficients and differences in maximum uroflow at each
      visit were examined. RESULTS: Uroflow measurements for the cohort were
      reproducible and there was no clinically significant difference in maximum and
      mean flow rate on each occasion. However, the intraclass correlation coefficients
      for the mean and maximum flow rate varied between 0.70 and 0.82, indicating that
      intraindividual variation accounted for a substantial component of the total
      variation in uroflow observed among these patients. For many individuals, test
      retest differences were clinically relevant. CONCLUSIONS: For a group of
      patients, maximum and mean uroflow measurements are reproducible. However, for an
      individual, these parameters are subject to clinically significant variation and
      a single measurement may not be representative. This may be important when
      considering the need for therapeutic intervention.

PMID- 8650863
TI  - Transurethral microwave thermotherapy for management of benign prostatic
      hyperplasia: durability of response.
AB  - OBJECTIVES: The durability of clinical efficacy of transurethral microwave
      thermotherapy (TUMT) by Prostatron using a low-energy protocol (maximum power, 50
      W) was evaluated on an outpatient basis in patients with symptomatic benign
      prostatic hyperplasia (BPH). METHODS: One hundred eighteen patients were followed
      up for longer than 3 months (13.4 +/- 9.5 months; mean +/- SD). All evaluations
      were made at baseline and then 3, 6, 12, 24, and 36 months after therapy.
      RESULTS: International Prostate Symptom Score (IPSS) significantly decreased from
      18.2 to 10.6 at 6 months (P < 0.01), representing a mean improvement of 41% under
      the baseline. Peak flow rate increased from the baseline of 8.3 mL/s to 10.3 mL/s
      at 6 months (P < 0.01). The improvement in terms of mean values of both
      parameters was sustained up to 24 months. Six of 44 patients (14%) who were
      followed up for 31 months on average required transurethral resection of the
      prostate for recurring obstructive symptoms and 10 additional patients (23%) had
      to be treated with various drug regimens. When the clinical outcome was evaluated
      in terms of improvement from the baseline according to a response criteria,
      disease-free rates for IPSS (more than 25% improvement from the baseline) were
      76% at 12 months, 77% at 24 months, and 61% at 36 months. Disease-free rate for
      peak flow rate (more than 2.5 mL/s from the baseline) was sustained in 44% by 12
      months and in 48% by 24 months. The overall outcome of the treatment was assessed
      by adding scores based on both subjective and objective efficacy criteria. At 6
      months, 67% of the patients were responders, and 15 of 21 (71%) remained as
      responders at 24 months. Patients who had estimated prostate volume smaller than
      30 cc showed more marked improvement in peak flow rate (P < 0.02), and those with
      baseline IPSS of 20 or more showed greater reduction of IPSS (P < 0.05) at 24
      months compared with each counterpart. CONCLUSIONS: After TUMT with a low-energy
      protocol, satisfactory results were obtained and the improvement seems to last at
      least for 24 months. This low-energy protocol may be most beneficial in patients
      with relatively small size of the prostate.

PMID- 8650864
TI  - Variation in output power of laser prostatectomy fibers: a need for power
      measurements.
AB  - OBJECTIVES: The aim of this study was the assessment of the quality of side
      firing fibers that are being used for laser prostatectomy, either by a laser
      light transmission measurement or by visual inspection. METHODS: A power meter
      (Aquarius) was developed to measure the actual power transmitted through a side
      firing fiber and delivered to the prostatic tissue. The power measurements were
      performed under clinical conditions, that is, under water and at relatively high
      input power. Furthermore, a protocol was developed for visual inspection of the
      fibers. Eight types of side-firing fibers were measured before use. Before and
      after a procedure, three fiber types were measured: ProLase II (28 samples),
      UltraLine (23 samples), and UroLase (44 samples). All these fibers were used in
      standard treatment protocols. RESULTS: At 60 W the transmission of new fibers
      (not used) ranged between 49% and 83% when compared to a bare fiber. After use, a
      large variation was found in transmitted power between different samples of one
      device. A correlation with total transmitted power was not present. At higher
      power input, vapor bubbles are generated at the tip of the fibers. Depending on
      the fiber design, these bubbles have a major impact on the transmission. Only for
      the UroLase fiber was there a significant correlation between visual inspection
      and the transmission of used samples at 10, 20, and 40 W. CONCLUSIONS: The
      transmission strongly varies between fibers and between different samples of one
      fiber during clinical use. Moreover, the transmission does not correlate with
      visual inspection. A power measurement during a clinical treatment will
      contribute to a more controlled procedure and to a better comparison of clinical
      laser prostatectomy studies.

PMID- 8650866
TI  - Survival after high-dose intravenous infusion of irrigating fluids in the mouse.
AB  - OBJECTIVES: Fluid absorption is still a potentially fatal complication in
      patients undergoing transurethral resection of the prostate. We induced
      experimental overhydration in animals to find out which of three widely used
      irrigating fluids is most strongly associated with survival. METHODS: The
      survival and incidence of voiding was studied in 120 mice after an intravenous
      infusion of either 225, 250, 275, or 300 mL/kg of glycine 1.5%, mannitol 5%, or
      sorbitol 2% plus mannitol 1% over 60 minutes. RESULTS: Only 20% of the animals
      survived the glycine solution, whereas the overall survival rate after mannitol
      was 60%. The corresponding figure for sorbitol plus mannitol was 32%. Logistic
      regression analysis showed that survival was significantly more likely after
      infusion of mannitol 5% compared with the other irrigating fluids. The likelihood
      of survival was also higher in the animals in which the infusion induced diuresis
      and when the smaller volumes of irrigating fluid were given. CONCLUSIONS:
      Mannitol 5% offered the best chance of survival.

PMID- 8650865
TI  - Factors affecting size and configuration of electrovaporization lesions in the
      prostate.
AB  - OBJECTIVES: Transurethral electrovaporization of the prostate is a new, minimally
      invasive technique being used by urologists for surgical ablation of prostatic
      tissue. There are insufficient data concerning factors affecting the vaporization
      and coagulation lesions produced by this technique. The aim of this study was to
      determine the role of various parameters for adequate tissue evaporation.
      METHODS: This study compared bovine liver and human prostatic lesions made by the
      Vaportrode instrument with those produced by standard electrocautery loops,
      roller balls, and laser fibers. Additionally, two electrosurgical instruments
      with differing technical capabilities were compared for their ability to cause
      vaporization of tissue. RESULTS: Results revealed that the Vaportrode lesions
      were maximal with a new electrode when used with a Force 40S electrosurgical
      generator set at 300 W and a drag speed of 25 to 30 seconds per 10 mm of tissue.
      The lesions produced by this technique had a 74% greater coagulation volume
      compared to a standard cautery loop. The evaporation defect was comparable to a
      laser lesion produced in contact at 60 W. CONCLUSIONS: We conclude that
      electrovaporization under optimal conditions causes a vaporization lesion
      comparable to that produced by high power density laser prostatectomy.
      Additionally, the coagulation volume of a vaportrode lesion is considerably
      greater than that produced by standard electrocautery resection.

PMID- 8650867
TI  - Prostatic intraepithelial neoplasia does not appear to raise serum prostate
      specific antigen concentration.
AB  - OBJECTIVES: Conflicting findings have been reported regarding the relationship
      between prostatic intraepithelial neoplasia (PIN) and serum prostate-specific
      antigen (PSA) concentration. This study evaluates whether high-grade PIN
      significantly raises serum PSA concentration. METHODS: We evaluated 194 totally
      embedded whole-mounted radical prostatectomy specimens removed for clinically
      localized prostate cancer. No patient received preoperative therapy. In each
      specimen, the volume of high-grade PIN and carcinoma was calculated using the
      grid-counting method. Serum PSA concentration was determined prior to surgery.
      Cancer volume, gland weight, Gleason score, extraprostatic extension, and PIN
      volume were then compared according to serum PSA concentration and PSA density.
      RESULTS: Of the 194 patients, 170 (88%) had high-grade PIN-associated cancer and
      24 (12%) had PIN-free cancer within the specimen. PIN volume ranged from 0 to 8.1
      cc (mean, 1.3) and cancer volume ranged from 0 to 56.9 cc (mean, 9.1). In a
      subset of 93 patients with small cancers (less than 6.0 cc), PIN volume ranged
      from 0 to 6.1 (mean, 0.83) and did not correlate with serum PSA concentration or
      PSA density (P = 0.80 and P = 0.69, respectively). In the entire study group, PIN
      volume did not correlate with PSA density (P = 0.17), but did correlate with
      serum PSA concentration (P = 0.005). Using multiple regression analysis,
      adjusting for cancer volume, gland weight, Gleason score, and extraprostatic
      extension, log PIN volume did not contribute to log serum PSA concentration
      (regression coefficient -0.108; P = 0.51) or log PSA density (regression
      coefficient -0.104; P = 0.56) in small cancers (less than 6.0 cc). In the entire
      study group, log PIN volume did not contribute to log serum PSA concentration
      (regression coefficient -0.182; P = 0.05) or log PSA density (regression
      coefficient -0.202; P = 0.56). CONCLUSIONS: Our data indicate that high-grade PIN
      does not significantly contribute to serum PSA concentration. We suggest that
      patients with elevated serum PSA concentration found to have high-grade PIN on
      transrectal biopsy should not have their elevated serum PSA concentration
      attributed to high-grade PIN.

PMID- 8650868
TI  - Early detection of prostate cancer in men with prostatism and intermediate
      prostate-specific antigen levels.
AB  - OBJECTIVES: To determine the prevalence of prostate cancer and the diagnostic
      ability of prostate-specific antigen density (PSAD) in men with lower urinary
      tract symptoms and intermediate prostate-specific antigen (PSA) levels of 4 to 10
      ng/mL (Hybritech assay) and to assess the clinical significance of prostate
      cancers in men who subsequently underwent radical prostatectomy. METHODS: Six
      systematic transrectal ultrasonography (TRUS)-guided biopsies were performed in
      153 symptomatic men (mean age, 66 years) with PSA levels between 4 and 10 ng/mL,
      irrespective of digital rectal examination (DRE) findings. Prostate volume was
      also determined by TRUS and PSAD was calculated (serum PSA divided by volume of
      entire prostate). The rate of positive biopsies was compared with PSAD (more than
      0.2 versus less than 0.2), DRE (positive versus negative), and patient's age
      (more than 70 years versus 61 to 70 versus 60 or less). Eligible patients with
      cancer underwent radical prostatectomy, and specimens were analyzed with regard
      to clinical significance of tumors. RESULTS: The overall cancer detection rate
      was 29.4%. PSAD and DRE, but not age, were both statistically significant in
      differentiating negative from positive biopsies. Independent of DRE findings,
      mean PSAD was significantly lower in biopsy-negative cases (0.29 +/- 0.17 and
      0.25 +/- 0.16) than it was in positive cases (0.34 +/- 0.17 and 0.35 +/- 0.15).
      Half of the patients who underwent radical prostatectomy had pathologically
      nonorgan-confined disease (more than pT3), 34% had positive margins, and 47% had
      a Gleason score of 8 to 10. PSAD, DRE, and age could not predict outcome,
      probably owing to the small number of patients. However, the number of positive
      biopsies (1 or 2 versus 3 to 6) was able to predict pathologic stage.
      CONCLUSIONS: In men with lower urinary tract symptoms and intermediate PSA levels
      of 4 to 10 ng/mL, PSAD may be useful in the selection of patients for prostate
      biopsy. Carcinomas found using these criteria are of clinical importance.

PMID- 8650869
TI  - Do the results of systematic biopsies predict outcome in patients with T1-T2
      prostate cancer treated with radiation therapy alone?
AB  - OBJECTIVES: The present study examines whether findings from systematic biopsies
      add any prognostic information in men with clinical Stage T1-T2 prostate cancer
      treated with external beam radiation therapy alone. METHODS: Seventy-two men with
      clinical T1-T2 prostate cancer had ultrasound-guided quadrant or sextant prostate
      biopsies prior to treatment with external beam radiotherapy alone between January
      1, 1988 and December 31, 1993. The median follow-up is 23 months (range, 11 to
      65). Biochemical failure after irradiation was defined as a prostate-specific
      antigen (PSA) greater than 1.5 ng/mL (Hybritech assay) and rising. RESULTS: The
      biochemical relapse-free survival was 90% at 36 months. The percentage of
      biopsies involved by cancer was not predictive of biochemical relapse-free
      survival on univariate analysis. Patients with less than 50% positive biopsies
      had similar biochemical relapse-free survival at 36 months compared to patients
      with 50% or more positive biopsies (93% versus 89%; P = 0.80). After stratifying
      according to pretreatment PSA level, the percentage of positive biopsies was not
      prognostic. A multivariate analysis demonstrated that pretreatment PSA level was
      the only variable that predicted relapse-free survival (P = 0.01). CONCLUSIONS:
      At present, the results of ultrasound-guided quadrant or sextant biopsies do not
      add further prognostic information, beyond that provided by the pretreatment PSA
      level, in patients with T1-T2 prostate cancer treated with radiation therapy
      alone. Further follow-up will be required to confirm these results.

PMID- 8650870
TI  - Ability of serum prostate-specific antigen levels to predict normal bone scans in
      patients with newly diagnosed prostate cancer.
AB  - OBJECTIVES: To determine whether pretreatment serum prostate-specific antigen
      (PSA) levels in newly diagnosed prostate cancer patients can identify a group
      with a low probability of osseous metastasis and safely eliminate the need for a
      bone scan as a routine part of the staging evaluation. METHODS: We
      retrospectively reviewed 683 patients with prostate cancer between 1990 and 1993.
      Patients with prior therapy or serum PSA levels obtained longer than 3 months
      prior to bone scan were excluded. Bone scans were reviewed by two nuclear
      medicine physicians with a third deciding equivocal cases. RESULTS: Only 6% of
      490 evaluable patients had a positive bone scan on initial evaluation. Scans were
      positive in 0 of 290 (0%) with PSA levels below 10 micrograms/L, 4 of 88 (4.5%)
      with PSA levels between 10 and 20 micrograms/L, and 24 of 112 (21%) with PSA
      levels above 20 micrograms/L. Although the risk of a positive bone scan increased
      with increasing PSA levels, PSA is a poor positive predictor of positive bone
      scans. The risk of a positive bone scan was 8% (5 of 64 patients) when PSA was
      between 20 and 50 micrograms/L, and increased to 40% (19 of 48 patients) for PSA
      levels greater than 50 micrograms/L. In contrast, serum PSA levels below 10
      micrograms/L are strong negative predictors of positive bone scans, with no
      positive scans in 290 patients with PSA levels below 10 micrograms/L. Although
      the risk of a positive bone scan increased with increasing stage and grade, tumor
      stage and grade were poor negative predictors of positive bone scans. Up to 4% of
      patients with clinically confined or well-differentiated to moderately
      differentiated tumors had positive scans. Scans were positive in 12% of poorly
      differentiated tumors, but all these patients had PSA levels above 10
      micrograms/L. CONCLUSIONS: Our data support the elimination of routine bone
      scintigraphy in patients with newly diagnosed prostate cancer and PSA levels
      below 10 micrograms/L. Bone scans are indicated when PSA levels are above 10
      micrograms/L, or with T3 or poorly differentiated disease.

PMID- 8650871
TI  - Effect of flutamide and flutamide plus castration on prostate size in patients
      with previously untreated prostate cancer.
AB  - OBJECTIVES: Transrectal ultrasonography (TRUS) was used in previously untreated
      men with prostate cancer undergoing hormonal therapy to provide objective
      observations on the decrease in prostate size and to assess the usefulness of
      prostate size in estimating treatment response. METHODS: In this retrospective
      study, 31 patients with previously untreated prostate cancer (Stage T1c to D2)
      who received hormonal therapy (flutamide, n = 18; flutamide plus castration, n =
      13) were followed with serial estimations of prostate size by TRUS and by serum
      prostate-specific antigen (PSA). RESULTS: In both treatment groups, the major
      decreases in prostate size were noted within the first 6 months of therapy,
      whereas further follow-up examinations failed to show statistically significant
      changes. Prostate size decreased by 48% in men treated with flutamide, whereas
      those treated with flutamide plus castration showed a statistically significant
      greater decrease, mean of 56% (P < or = 0.01). Six patients (33%) in the
      flutamide group and 5 (38%) men in the total androgen deprivation group
      ultimately failed therapy as indicated by a rising PSA level. Only 55% (n = 6) of
      the patients who progressed showed an increase in prostate size. CONCLUSIONS:
      Total androgen deprivation in comparison to flutamide alone caused a larger
      reduction in prostate size. As a marker of hormonal failure, a rising PSA was
      more sensitive than an increase in prostate size.

PMID- 8650872
TI  - Acid phosphatase: defining a role in androgen-independent prostate cancer.
AB  - OBJECTIVES: In multivariable analysis, post-therapy change in prostate-specific
      antigen (PSA) was shown to be the most significant factor predictive of survival
      in patients with androgen-independent prostate cancer. To refine the model, we
      studied the patterns of change in acid phosphatase, alkaline phosphatase, and
      lactate dehydrogenase after treatment. METHODS: One hundred seven patients with
      androgen-independent prostate cancer treated on seven different protocols in
      Memorial Sloan-Kettering Cancer Center were evaluated. For tumor-specific (acid
      phosphatase and PSA) and nontumor-specific (alkaline phosphatase and lactate
      dehydrogenase) enzymes, a minimum 50% or 80% decrease from baseline documented on
      three separate occasions a minimum of 6 weeks apart was required to categorize a
      patient as having a decline. RESULTS: Nineteen patients (18%) had either a 50%
      decline in acid phosphatase or PSA, of whom 13 (68%) had a decline of both
      markers. Six (32%) patients showed discordance between the two parameters.
      Declines in PSA level typically preceded declines in acid phosphatase levels. The
      median survival of patients showing declines in both markers exceeded that of
      patients showing declines in PSA alone by 1 year. Although baseline measurements
      of alkaline phosphatase or lactate dehydrogenase did add additional prognostic
      information, post-therapy changes did not. CONCLUSIONS: Post-therapy declines in
      PSA and acid phosphatase represent reproducible endpoints for clinical trials in
      androgen-independent disease. The requirement of a repeated and parallel decline
      in both markers may improve the results observed by monitoring declines in PSA
      alone. Monitoring the two parameters may allow the development of models that can
      be used as surrogate endpoints for response and survival in a disease in which
      reproducible measurements of response are lacking.

PMID- 8650874
TI  - Genital Fournier's gangrene: experience with 38 patients.
AB  - OBJECTIVES: Fournier's gangrene (FG) is an extensive fulminant infection of the
      genitals, perineum, or the abdominal wall. We report our experience with the
      management of this difficult infectious disease. METHODS: Thirty-eight patients
      were admitted with the diagnosis of FG between May 1993 and May 1995. All
      patients were treated with broad-spectrum triple antimicrobial therapy, broad
      debridement, exhaustive cleaning, and application of unprocessed honey dressings.
      Patients then underwent split-thickness skin grafts or delayed closure as needed.
      RESULTS: Patient ages ranged between 33 and 86 years (mean, 54) with a mean
      hospital stay of 17 days (range, 1 to 45). Sixty-six percent of the patients were
      diabetic, 16% had previous orchiepididymitis, and 5% had scrotal and urethral
      trauma. All the patients underwent surgical debridement and application of
      unprocessed honey to the wound. Cystostomy was performed in 60% of the patients
      and 21% underwent orchiectomy of the affected side. Free skin grafts were applied
      to 6 patients (16%) and the remaining wounds, once clean, were approximated. One
      patient died as a result of severe metabolic acidosis and sepsis. CONCLUSIONS:
      The management of this infectious entity should be aggressive. Patients with FG
      need extensive debridement and cystostomy or colostomy when necessary. Broad
      spectrum triple antimicrobial regimen and aggressive debridement are mandatory.
      Topical application of unprocessed honey is beneficial to the healing process. A
      minority of patients require split-thickness skin grafts on denuded areas.

PMID- 8650873
TI  - Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic,
      and tumor tissue distribution.
AB  - OBJECTIVES: Heme oxygenase isozymes, HO-1 and HO-2, are members of the
      stress/heat shock (HSP) family of proteins, with the known function of cleaving
      the heme molecule to biliverdin, iron, and carbon monoxide. The aim of this study
      was to examine the pattern of tissue expression of HO-1 in the human prostate
      under different states of proliferation and differentiation and to investigate
      whether the pattern differs between these states. METHODS: Presently, we have
      determined the pattern of tissue expression of the stress-inducible isozyme, HO-1
      (HSP32), in human prostate under normal and pathologic conditions, by
      immunohistochemistry, using polyclonal antibodies, and have measured HO-1 and HO
      2 mRNA levels in normal prostate and benign prostatic hyperplasia (BPH) by
      Northern blotting. The activity of prostate to catalyze heme degradation was also
      assessed. RESULTS: In normal and BPH tissue, columnar epithelial cells of acini
      and ducts and cells in stroma displayed HO-1 immunoreactivity; in all cells,
      perinuclear staining was prominent. In BPH tissue, however, a more intense
      staining of the epithelial cells occurred, with notable staining of the basal
      cells. In undifferentiated malignant tumors, intense HO-1 staining was manifest
      in nearly all tumor cells, and also in the epithelial lining of blood vessels. HO
      1 in the prostate tissue was found catalytically active and oxidatively cleaved
      the heme molecule (Fe-protoporphyrin IX) to biliverdin. Northern blot analysis
      shows that two forms of HO are present in the human prostate. Compared with
      normal tissue, predominantly hyperplastic tissue demonstrates a pronounced
      increase in the approximately 1.8 kb mRNA that hybridizes to the rat HO-1 probe.
      The levels of two transcripts, approximately 1.3 and approximately 1.7 kb, that
      hybridize to the rat HO-2 probe are not increased in BPH tissue. CONCLUSIONS: The
      finding that HO-1 expression is increased in BPH and malignant prostate tissue is
      consistent with a role for this stress protein in the pathogenesis of BPH and
      prostate cancer; in the context of iron metabolism, an argument is made in
      support of this possibility.

PMID- 8650875
TI  - Renal Doppler ultrasound in children with normal upper urinary tracts: effect of
      fasting, hydration with normal saline, and furosemide administration.
AB  - OBJECTIVES: To study the age dependency of renal resistive index (RI) and to
      study the effect on the renal RI of fasting, intravenous infusion of normal
      saline, and administration of furosemide in children with normal upper urinary
      tracts. METHODS: The study included 28 nonobstructed renal units in 15 boys
      ranging in age from 3 to 11 years. Diuretic renography and Doppler
      ultrasonography were attempted in all children. Doppler ultrasonography was
      carried out under three different conditions: fasting state, 30 to 60 minutes
      after intravenous infusion of normal saline (15 mL/kg), and 10 minutes after
      administration of furosemide (1 mg/kg; maximum, 40 mg). RESULTS: There was an
      inverse correlation between age and RI of both renal units under the three
      conditions of Doppler studies. At fasting state mean RI was 0.70 +/- 0.04,
      whereas 15 of 28 renal units (54%) had an RI of 0.70 or higher. Intravenous
      infusion of normal saline significantly decreased the RI to 0.63 +/- 0.04 (P <
      0.000001). Injection of furosemide caused a further significant decrease of RI
      from 0.63 +/- 0.04 to 0.60 +/- 0.04 (P < 0.002). CONCLUSIONS: The renal RI in
      healthy children is age dependent. In the fasting state, 54% of nonobstructed
      renal units in children have an RI of 0.70 or higher. Intravenous infusion of
      normal saline and administration of furosemide can independently cause a
      significant decrease of the RI in nonobstructed renal units in children.

PMID- 8650876
TI  - Pediatric priapism associated with Mycoplasma pneumoniae.
AB  - OBJECTIVES: Priapism in the pediatric population is rare and most commonly occurs
      secondary to sickle cell disease or hematologic malignancy. We present a case of
      a 12-year-old boy with priapism who required aggressive surgical therapy for
      adequate detumescence. This patient had a recent viral upper respiratory
      infection and titers for Mycoplasma pneumoniae were indicative of infection. We
      propose that a hypercoagulable state was induced by the M. pneumoniae infection,
      which resulted in the priapism. METHODS: A 12-year-old boy with a recent upper
      respiratory illness presented to his pediatrician with priapism. After failing
      conservative management, the patient ultimately required a surgical shunt for
      detumescence. Serum was sent to detect antibodies against M. pneumoniae. RESULTS:
      The child failed to respond to corporeal irrigations and bilateral Winter shunts.
      He underwent an El-Ghorab procedure the following morning, which resulted in a
      flaccid penis. Serum M. pneumoniae antibodies were detected and indicated
      moderate infection. CONCLUSIONS: We propose that this 12-year-old boy had
      priapism secondary to infection with M. pneumoniae. M. pneumoniae infection can
      produce a hypercoagulable state, especially in selected areas of the circulation.
      This is the first reported case of priapism associated with M. pneumoniae.

PMID- 8650877
TI  - Use of proximal-based vaginal flap in stricture of the female urethra.
AB  - A proximal-based vaginal flap was used to repair a stenosis of the mid and distal
      urethra in a woman after a failure of urethral dilation and internal urethrotomy.
      A successful result was obtained with relief of the obstruction and preservation
      of the continence.

PMID- 8650878
TI  - Testicular trauma.

PMID- 8650879
TI  - Nephrolithiasis due to primary hyperparathyroidism and enteric hyperoxaluria: a
      case report.
AB  - Enteric hyperoxaluria and primary hyperparathyroidism have been associated with
      the development of nephrolithiasis. We report a case involving a patient who had
      hyperparathyroidism due to a parathyroid adenoma and enteric hyperoxaluria
      resulting from a small bowel bypass and who had severe stone-related
      complications. This combination of stone-generating factors has heretofore not
      been reported. The pathophysiology of these entities is discussed.

PMID- 8650880
TI  - Regression of large pelvic desmoid tumor by tamoxifen and sulindac.
AB  - A 54-year-old man was evaluated for symptoms of bladder outlet obstruction.
      Evaluation revealed a 10 by 9.8-cm tumor composed of bland, fibroblastic, poorly
      cellular material adjacent to the prostate. Administration of a course of
      antiestrogen (tamoxifen) and a nonsteroidal anti-inflammatory agent (sulindac)
      resulted in prompt relief of symptoms and a slow decrease in the size of the
      tumor as measured by computed tomography. After 54 months of therapy, the tumor
      was undetectable clinically and dramatically reduced in size as seen on computed
      tomography. Data on the natural history of desmoid tumors and the efficacy of
      various therapeutic strategies are reviewed.

PMID- 8650881
TI  - Artificially stimulated ejaculation in the brain dead patient: a case report.
AB  - Cutaneous vibratory stimulation and rectal probe electroejaculation are highly
      successful methods of obtaining semen in the anejaculate patient. We report a
      case in which spermatozoa were retrieved in a brain dead man by artificially
      stimulated ejaculation. The specimen was cryopreserved to be used at a later date
      in combination with assisted reproductive techniques.

PMID- 8650882
TI  - Bilateral giant abdominoscrotal hydroceles in childhood.
AB  - There is a paucity of cases in the literature describing the abdominoscrotal
      hydrocele (ASH). We report the diagnostic and therapeutic aspects of a rapidly
      expanding giant bilateral ASH in a 4-month-old boy.

PMID- 8650883
TI  - Epididymocutaneous fistula in a patient with the acquired immunodeficiency
      syndrome and Marfan's syndrome.
AB  - Epididymocutaneous fistula is a rare entity. A recent case in a patient with the
      acquired immunodeficiency syndrome and Marfan's syndrome led to this review. The
      patient's immunocompromised status as well as his past medical history
      necessitated special considerations in the diagnosis and management of his
      epididymocutaneous fistula.

PMID- 8650884
TI  - Rare metastases of signet ring cell carcinomas to the scrotum: report of two
      cases.
AB  - Metastases of signet ring cell carcinomas to the scrotum are rare. We present 2
      patients with this kind of tumor. In 1 patient, the scrotal pathologic
      examination helped to detect an adenocarcinoma of the appendix with a signet ring
      cell component, with an extent that had not been apparent clinically. The other
      patient was seen at an advanced stage of signet ring cell carcinoma of the
      sigmoid colon following surgical therapy and palliative chemotherapy. The route
      of metastases seems to be via seeding along the testicular cord and via lymphatic
      dissemination.

PMID- 8650885
TI  - Renal cryoablation in a canine model.
AB  - OBJECTIVES: To assess the potential safety and utility of cryoablation for
      treatment of selected renal tumors in a canine model. METHODS: Ultrasound and
      direct physical measurements (depth and width) of five cryolesions were compared.
      Cryolesions were examined histologically in 6 animals, which were killed at 4
      hours, 2 days, 1 week, 3 weeks, 6 weeks, and 12 weeks. Mortality/morbidity was
      assessed in 12 animals over a 1-month interval, where 6 animals received small
      (approximately 2 cm) cryolesions and 6 animals received large (one third to one
      half of kidney) cryolesions. Laparoscopic cryoablation was performed in 2
      animals. RESULTS: A statistically significant association of physical and
      ultrasound dimensions was observed (correlation coefficient R = 0.9295; P =
      0.0001). Histologic studies in animals killed up to 1 week after cryoablation
      revealed complete coagulative necrosis within the cryolesion. The boundary
      transition from normal to complete tissue necrosis occurred in 1 to 2 mm. Animals
      killed 3 weeks to 3 months after cryoablation revealed progressive organization
      with granulation tissue, chronic inflammation, hemosiderosis, fibrosis, and
      contraction of the cryolesion with parenchymal loss. Untreated renal tissue was
      histologically normal in all kidneys. No mortality or morbidity was detected in
      the 12 animals followed for 30 days regardless of the size of the cryolesion.
      Laparoscopic cryoablation was performed successfully in 2 animals without
      modification of standard laparoscopic methods. CONCLUSIONS: Sonographic,
      histologic, and laparoscopic data in a canine model suggest that cryoablation may
      be a safe, feasible, and useful method for treatment of selected renal neoplasms.

PMID- 8650887
TI  - Brief Male Sexual Function Inventory for urology.

PMID- 8650886
TI  - Preventive treatment of priapism in sickle cell disease with oral and self
      administered intracavernous injection of etilefrine.
AB  - OBJECTIVES: Priapism is a common and currently unsatisfactorily managed
      complication of sickle cell disease (SCD). In June 1994, 6 SCD patients received
      a new therapeutic regimen to prevent the occurrence and recurrence of priapism.
      METHODS: The patients (5 with SS and 1 with SC) were adults and had frequent
      episodes of stuttering priapism (SP), and two of them had had acute episodes (AP)
      lasting more than 3 hours. The treatment consists of preventive oral
      administration of the alpha-adrenergic agent etilefrine, and self-administered
      intracavernous injection (SICI) of the same agent to reverse episodes lasting
      more than 1 hour. RESULTS: Since the beginning of treatment, all patients were
      protected against AP, 4 patients had no recurrence with the oral treatment alone,
      2 had to use SICI, 1 occasionally and 1 constantly. There was no modification of
      sexual activity and no complications. Blood pressure was unaffected. CONCLUSIONS:
      This treatment is simple, cheap, and self-administered. It should be proposed to
      all patients with SCD in all geographic areas as part of an educational program
      for active prevention of this severe complication.

PMID- 8650888
TI  - Impact of prostate-specific antigen screening on prostate cancer.

PMID- 8650889
TI  - Methylene blue versus indigo carmine.

PMID- 8650890
TI  - Government responds to Agriculture Committee's report on medicines.

PMID- 8650891
TI  - Evaluation of flea control programmes for cats using fenthion and lufenuron.
AB  - Four groups of six cats were kept in carpeted pens similarly infected with
      Ctenocephalides felis. One group was left untreated, but the other groups were
      treated every 28th day with either an insecticide (fenthion at 30 mg); or an
      inhibitor of insect development (lufenuron at 133 or 266 mg) or with both. A
      sudden upsurge in the numbers of fleas occurred on the control cats after 50
      days. At this time, the three control strategies had reduced the counts by 91.3,
      72.5 and 98.6 per cent, respectively. Thereafter, welfare considerations demanded
      the limitation of the flea burden on the control cats, but conditions were shown
      to be favourable for flea development throughout the study. The mean numbers of
      fleas on the treated groups after six months were 1.2, 11.0 and 0.4 respectively.
      After this, in addition to the fleas acquired in the pen, the cats were each
      infected weekly with five fleas to mimic roaming animals introducing extraneous
      fleas into the home. This produced no obvious effect on the counts and the mean
      values three months later were 0.5, 11.0 and 0.2, respectively. None of the
      strategies eradicated the flea population but they all reduced the numbers
      considerably and worked equally well whether or not small numbers of new fleas
      were introduced into the system. Significantly lower flea counts were maintained
      in the early and later stages of the study by the strategies including the
      insecticide.

PMID- 8650892
TI  - Effect of pre-slaughter washing of lambs on the microbiological and visible
      contamination of the carcases.
AB  - Studies in four slaughterhouses with contrasting dressing systems showed that
      microbiological contamination with total aerobic bacteria and Escherichia coli
      was greater on carcases which had been washed before slaughter, irrespective of
      wool length, and was generally higher on carcases derived from woolly lambs than
      on those derived from shorn lambs. The effects of pre-slaughter washing on the
      forequarters compared with the hindquarters were not consistent, and this was
      attributed to differences between the dressing systems applied in the
      slaughterhouses. Over all trials the mean total aerobic count ranged from 3.45 to
      5.36 log10/cm2, and the mean counts of E coli ranged from 0.39 to 2.11 log10/cm2.
      There was less visible contamination on the carcases of washed lambs than on
      those of unwashed lambs. The differences in contamination with wool were largely
      dependent on the level of contamination of individual carcases, whereas the
      differences in contamination with faecal material and dirt or sand were largely
      dependent on the prevalence of affected carcases. The use of pre-slaughter
      washing to compensate in visual terms for poor pre-slaughter presentation results
      in a detrimental effect on microbiological loads on ovine carcases.

PMID- 8650893
TI  - A pathological study of a mycobacterial infection in a cat caused by a variant
      with cultural characteristics between Mycobacterium tuberculosis and M bovis.
AB  - A histological examination of a biopsy from a firm submandibular mass in a seven
      year-old domestic short-haired cat revealed a granulomatous lymphadenitis
      associated with the presence of small numbers of acid-fast bacilli. The cat was
      euthanased and subjected to a detailed post mortem examination which revealed
      extensive granulomatous inflammation in the right and left bronchial, para
      aortic, mesenteric and colic lymph nodes, with small or early lesions in the lung
      and Peyer's patches of the ileum. Mycobacteria were isolated from the
      submandibular, mesenteric and cervical lymph nodes. The bacilli reacted with a
      DNA probe specific for the tuberculosis complex, including Mycobacterium
      tuberculosis and M bovis, but had cultural characteristics intermediate between
      these two species. The pathological findings are compared with previous reports
      of mycobacterial infections in cats, and the public health implications are
      discussed.

PMID- 8650894
TI  - Obstructive pulmonary disease in 18 horses at summer pasture.
AB  - The clinical features of 18 cases of summer pasture associated obstructive
      pulmonary disease were reviewed. The horses had signs of obstructive pulmonary
      disease (expiratory dyspnoea, wheezing and crackling lung sounds and coughing)
      during the spring, summer or autumn while they were kept permanently at grass
      with no access to hay or straw, for at least two consecutive years. In nine cases
      there was a seasonal incidence with the disease occurring during April and May.
      Eleven of the horses were affected by bouts of severe dyspnoea. Eleven of the
      horses also suffered from chronic obstructive pulmonary disease and two were
      affected by idiopathic headshaking. Endoscopy revealed evidence of lower airway
      inflammation, and a cytological examination of tracheal aspirates and
      bronchoalveolar lavage fluid revealed a neutrophilia. Moving the horses into a
      stable controlled the clinical disease effectively in only two of the 16 cases.
      Oral clenbuterol was effective in only seven of 15 cases. Systemic dexamethasone
      or oral prednisolone, in combination with clenbuterol, was the most effective
      treatment.

PMID- 8650896
TI  - Attitudes to companion animals.

PMID- 8650895
TI  - Comparison of the persistent activity of ivermectin, abamectin, doramectin and
      moxidectin in cattle.

PMID- 8650897
TI  - Live animal exports.

PMID- 8650898
TI  - Live animal exports.

PMID- 8650899
TI  - Wildlife rehabilitation.

PMID- 8650900
TI  - Diazinon poisoning in pigeons.

PMID- 8650901
TI  - Iodine in feeds.

PMID- 8650902
TI  - Severe respiratory disease in dairy cows caused by infection with bovine
      respiratory syncytial virus.
AB  - Outbreaks of severe respiratory disease caused by bovine respiratory syncytial
      virus (BRSV) were recorded in dairy herds throughout Sweden in 1988 and
      subsequently. The virus was demonstrated in nasopharyngeal swab material from
      animals in the acute stage of the disease by culture, the polymerase chain
      reaction (PCR) and by immunofluorescence. Serological data from the herds
      investigated showed that the cows had seroconverted to BRSV rather than to bovine
      coronavirus, bovine viral diarrhoea virus or parainfluenza-3 virus. It was
      predominantly dairy herds in isolated areas that contracted a severe primary BRSV
      infection, often after the purchase of new animals. A nationwide survey for BRSV
      antibodies in bulk milk samples showed the highest prevalence, of 84 to 89 per
      cent, in the southernmost regions of Sweden and the lowest prevalence, of 41 to
      51 per cent, in the north of the country. The prevalence of BRSV was highest in
      areas with the highest populations of cattle.

PMID- 8650904
TI  - Identification of the virus of rabbit haemorrhagic disease in Tunisia.
AB  - During 1992 and 1993, outbreaks of an acute, highly fatal disease mainly
      affecting adult rabbits were observed in Tunisia. The clinical and pathological
      findings were consistent with rabbit haemorrhagic disease. A monoclonal antibody
      designated PG4G3 specific for surface determinants of the rabbit haemorrhagic
      disease virus was used to identify the aetiological agent by ELISA and by
      colloidal gold immunoelectron microscopy; a haemagglutination test and
      conventional immunoelectron microscopy were also used. The results confirmed the
      first recorded cases of the disease in Tunisia.

PMID- 8650903
TI  - Transient metabolic hyperammonaemia in young Irish wolfhounds.
AB  - Inherited portosystemic shunts occur in 2 to 3 per cent of Irish wolfhounds and
      are associated with high venous ammonia concentrations and signs of hepatic
      encephalopathy. Moreover, the vast majority of Irish wolfhound pups without signs
      of hepatic encephalopathy have moderate hyperammonaemia. The aim of this study
      was to investigate whether the increased ammonia levels in these clinically
      healthy dogs are caused by low-grade portosystemic shunting, and whether the
      hyperammonaemia persists in adulthood. The fasting venous ammonia concentration
      and the fraction of portal blood by-passing the liver, expressed as the shunt
      index (SI) were measured in 42 Irish wolfhound pups, and the dogs with high SI
      values were examined post mortem. The ammonia concentration was also measured in
      25 adult Irish wolfhounds in which it had been measured when they were seven to
      eight weeks old. Eleven of the 42 pups had a portosystemic shunt, as evidenced by
      a high SI (mean 0.82, range 0.12 to 1.00, normal range 0.01 to 0.05) and by post
      mortem examination. Their mean ammonia concentration was 249 mumol/litre (range
      121 to 350). The 31 pups with a normal SI (mean 0.025, range 0.00 to 0.05) had a
      mean ammonia concentration of 93 mumol/litre (range 51 to 125). In the 25 dogs in
      which the ammonia concentration was measured twice, the mean concentration at
      seven to eight weeks of age was 77 mumol/litre (range 47 to 115) and in the
      adults it was 17 mumol/litre (range 6 to 27) at a mean age of 3.1 years (range
      1.0 to 8.9). These results show that Irish wolfhounds with ammonia concentrations
      > 125 mumol/litre had a portosystemic shunt, whereas the hyperammonaemia in dogs
      with ammonia concentrations < 120 mumol/litre was transient and of metabolic
      origin.

PMID- 8650905
TI  - Pharmacokinetics of lignocaine in Icelandic horses after infiltration
      anaesthesia.
AB  - The pharmacokinetics of lignocaine was studied in four Icelandic horses after
      infiltration anaesthesia. A total of 240 mg of the drug was injected on either
      side of the left foreleg, over the medial and lateral branches of the palmar
      nerve. Blood samples were collected up to seven hours after injection and the
      concentrations of the drug in plasma were determined by gas chromatography/mass
      spectrometry. The results showed that lignocaine was rapidly absorbed. A mean
      maximum concentration of 232 ng/ml was observed after 20 minutes. In three of the
      horses the decline in the plasma concentration of the drug with time was best
      described by the sum of two exponential terms, but in one of the horses the
      decline was monoexponential. The mean half-life of the distribution phase (alpha)
      was 9.8 minutes and that of the elimination phase (beta) 48.4 minutes. In all the
      horses the plasma concentration was below the limit of detection (2 ng/ml) six
      hours after injection. Anaesthesia was tested in one horse and lasted for one
      hour.

PMID- 8650906
TI  - Isolation of bovine herpesvirus-2 (BHV-2) from a case of pseudo-lumpy skin
      disease in the United Kingdom.

PMID- 8650907
TI  - Use of a single anti-nucleocapsid monoclonal antibody to detect rabies antigen in
      formalin-fixed, paraffin-embedded tissues.

PMID- 8650908
TI  - Reviews of state veterinary services--a new disease?

PMID- 8650909
TI  - Dispensing medicines without first visiting the farm.

PMID- 8650910
TI  - Dispensing medicines without first visiting the farm.

PMID- 8650911
TI  - Feline parvovirus in pedigree kittens.

PMID- 8650912
TI  - Further isolation of Mokola virus in South Africa.

PMID- 8650913
TI  - Slow recovery from milk fever.

PMID- 8650914
TI  - Recent bruising in cattle at abattoirs.
AB  - In two surveys of a total of over 16,000 cattle carcases, animals from live
      auctions had more bruising and more meat rejected for bruising than animals from
      dealers and farms. The proportion of carcases with stick-markings was higher in
      market cattle (2.5 per cent) than in cattle from farms (0.9 per cent). The amount
      of bruising was much higher in animals which were stick-marked (35 per cent) than
      in the whole population surveyed (6.5 per cent). Young bulls had the lowest
      percentage of bruising and the least amount of meat rejected of all the
      categories of animals surveyed. There was less "important' bruising in animals
      travelling less than 50 miles from markets, but over 50 miles the amount of
      "important' bruising did not increase. However, the incidence of all bruising
      increased with the distance travelled and with the time the animal spent in the
      lairage. More than half the carcases surveyed (59 per cent) had some degree of
      bruising caused by preslaughter handling. The areas most frequently bruised were
      the butt and hip, loin, shoulder/foreleg and neck, hind leg and flank/brisket.
      The number of carcases with an ultimate pH (pHu) of over 5-8 and the average pHu
      of the muscle increased with the amount of carcase bruising.

PMID- 8650915
TI  - Clinical comparison of medetomidine with xylazine/l-methadone in dogs.
AB  - Seventy-two healthy dogs required sedation and analgesia for a variety of
      procedures causing discomfort or pain. They were treated either with the alpha 2
      agonist medetomidine at 40 micrograms/kg (15 intravenously and 17
      intramuscularly), or 80 micrograms/kg (15 intravenously and 15 intramuscularly)
      or with xylazine plus l-methadone (1.0 mg)(10 intravenously). The levels of
      sedation, analgesia and safety were compared clinically and by measurements of
      the effects on the electrocardiogram (ECG) and blood gases, body temperature,
      haematology and clinical chemistry. Sedation was achieved reliably with both
      medetomidine and xylazine plus l-methadone but its onset, depth and duration were
      influenced by the dose and route of administration. In the medetomidine-treated
      dogs, intravenous administration resulted in more rapid sedation and the effects
      of the higher dose were deeper and longer lasting. The small dogs receiving 40
      micrograms/kg may have been underdosed. The initial analgesic effects in response
      to a pin prick to the body surface were sufficient and similar for both drugs,
      except for the intramuscular dose of 40 micrograms/kg medetomidine. Analgesia for
      the clinical procedures was less reliable with medetomidine and was not always
      adequate even at the high dose, but xylazine plus l-methadone assured analgesia
      in almost every case. Medetomidine resulted in marked bradycardia, lasting as
      long as the sedation and the ECG revealed a sinus arrhythmia with sinoatrial and
      atrioventricular blocks grade I and II as a sign of interference with
      transduction. The bradycardia with xylazine plus l-methadone was less pronounced.
      A decrease in respiratory rate accompanying sedation had no influence on blood
      gases and blood acidity in the dogs treated with medetomidine but caused a
      respiratory acidosis with xylazine plus l-methadone. Body temperature decreased
      with all treatments for the duration of the period of sedation. Blood glucose
      concentration increased to a similar extent in all treatment groups, but all
      other haematological and clinicochemical variables remained unchanged. Treatment
      with the specific alpha 2 antagonist, atipamezole, reversed the sedation and
      cardiovascular and pulmonary effects due to medetomidine within minutes.

PMID- 8650916
TI  - Treatment of a coxofemoral luxation secondary to upward fixation of the patella
      in a Shetland pony.
AB  - A nine-year-old Shetland pony gelding, with a history of recurrent upward
      fixation of the patella, suddenly developed severe lameness in its right
      hindlimb. A luxation of the coxofemoral joint was diagnosed by a clinical and
      radiographic examination. The initial treatment of the luxation by closed
      reduction was not maintained, and the limb was placed in an Ehmer sling for four
      days after a second closed reduction. This allowed the femoral head to remain in
      the acetabulum, although a persistent subluxation remained, presumably owing to a
      rupture of the round ligament. The pony remained comfortable at pasture for over
      two years after the reduction, until osteoarthritis of the coxofemoral joint
      caused it to become severely lame and it had to be euthanased.

PMID- 8650917
TI  - Osteochondrosis in a pedigree Suffolk ram.

PMID- 8650918
TI  - Corneal orf in a lamb.

PMID- 8650919
TI  - Residual anti-Brucella abortus strain 19 antibodies detected in adult cattle by
      two indirect-ELISA tests.

PMID- 8650920
TI  - Wildlife rehabilitation.

PMID- 8650921
TI  - Ovine abortion caused by Yersinia pseudotuberculosis.

PMID- 8650922
TI  - Familial vasculopathy of German shepherd dogs.

PMID- 8650923
TI  - First isolation of avian paramyxovirus serotype 3 in Israel.

PMID- 8650924
TI  - [Food allergies and intolerance--epidemiologic studies].
AB  - The lack of standardized definitions and reliable test methods disclosed a wide
      field of often incorrect speculation on the incidence and importance of allergies
      and intolerance reactions to food and its ingredients. It was only recently that,
      based on guidelines in statements from national and international scientific
      societies, serious studies were initiated to determine the correct incidence and
      prevalence of these problems. First results clearly document that lay people and
      the press overestimate the role of food as causative agent for disease, which
      might result in unjustified dietary restrictions and exaggerate the problem,
      whereas the scientific community might have underestimated the dimensions. New
      developments in the field of antigen characterization and new guidelines for a
      correct test performance should soon enable unproven alternative methods which
      frequently hurt the person concerned more than they help, to be disposed of.

PMID- 8650925
TI  - [Risk of osteoporosis in women in 4 different occupational groups].
AB  - Primary osteoporosis is common, with significant sociomedical consequences. This
      paper studies the prevalence of risk factors and risk behavior for osteoporosis
      in women of four different occupational groups: housewives, blue collar workers,
      white collar workers/civil servants and farmers. We analyzed risk factors and
      risk behavior associated with osteoporosis in the scientific literature. The
      sample comprises 9,939 women. The data set is based on a health survey conducted
      in 79 selected rural communities of Styria (Austria) between 1989 and 1993.
      Sociodemographic data, lifestyle, health complaints, chronic conditions and
      utilization of preventive and treatment services were surveyed by means of
      standardized personal interviews. The results show that the women of the four
      occupational groups were subjected to very different stresses. White collar
      workers/civil servants had the lowest risk with regard to osteoporosis. Our
      results suggest that efficient intervention programs to prevent osteoporosis need
      to specifically focus on the different social life styles of women.

PMID- 8650926
TI  - [Pregnancy termination after prenatal diagnosis--data of the Styrian malformation
      register (1985-1992)].
AB  - 3098 embryos, fetuses or newborns with congenital anomalies were registered in
      the period from 1985 to 1992 by the Styrian Malformation Register (prevalence
      2.88%) the common screening tool for prenatal diagnosis is sonography. About 1/2
      of all pregnant women aged 35 or more took advantage of karyotyping offered to
      this group of patients. Altogether 4004 fetal karyotypes were performed, leading
      to 89 terminations of pregnancy. A total of 181 terminations of pregnancy
      following prenatal diagnosis of congenital anomalies were recorded by the Styrian
      Malformation Register. The annual rate of terminations of pregnancy did not
      change over the years (5.3-6.7%). About 2/3 of severe congenital anomalies were
      missed or diagnosed too late in pregnancy. A comparison of our data with those of
      EUROCAT, the central malformation register of Europe, showed that hydrocephalus
      was terminated significantly more frequently in the EUROCAT data, but the
      difference in other congenital anomalies was less marked. It follows that
      prenatal diagnosis in Austria and all over Europe is subject to equal social
      demands and medical standards. The study highlights, furthermore, the need for
      specialist doctors to receive standardized high-quality training in prenatal
      diagnosis in Austria.

PMID- 8650927
TI  - Evaluation of the pathogenesis of flatulence and abdominal cramps in patients
      with lactose malabsorption.
AB  - Aim of this study was to assess whether the interindividual differences in the
      development of flatulence and cramps in patients with lactose malabsorption are
      due to the quantity of malabsorbed lactose or gas accumulation, or if accelerated
      intestinal transit or increased perception of gas might play a role. Hydrogen
      breath tests were performed in 43 patients with lactose malabsorption after
      ingestion of 50 g lactose and, on a separate day, 25 g lactulose. The unabsorbed
      amount of lactose, small bowel transit time and colonic hydrogen accumulation
      were assessed in patients who did and did not develop flatulence and cramps after
      ingestion of lactose. The unabsorbed amount of lactose, small bowel transit time
      and volume and rate of colonic hydrogen accumulation were the same in patients
      who did or did not have symptoms after lactose. Patients with flatulence and
      cramps had a significantly longer time interval between the onset of the increase
      and peak breath hydrogen concentration (p < 0.05) and a significant correlation
      between the time of occurrence of peak symptoms and the time of peak breath
      hydrogen concentration (r = 0.75, p < 0.001). Our data suggest that subjective
      symptoms of lactose intolerance are not due to the amount of malabsorbed lactose
      or to the volume or rate of gas accumulation per se, but are related to increased
      perception of gas.

PMID- 8650929
TI  - [Gait analysis in patients with tumor endoprostheses of the HMRS type].

PMID- 8650928
TI  - [Enzyme therapy in treatment of mastopathy. A randomized double-blind clinical
      study].
AB  - In this randomized double-blind clinical study the efficacy of an enzyme
      preparation (Wobenzym) was compared with hormone therapy (Lynestrenol) in 29
      women with mastopathy. There was a significantly greater decrease in number of
      hardenings of the mammary gland after 2 months of enzyme therapy than Lynestrenol
      therapy: improvement in the former group was 100%, in the latter group 78.6%. No
      significant difference was observed regarding the numbers of lumps, or number and
      size of cysts, sensitivity to touch, feeling of tension, spontaneous pain, and
      pain on pressure. The efficacy of both medicines is valued as good. Wobenzym
      therapy was tolerated very well. No side effects appeared at all. Enzyme therapy
      is an alternative, low-risk therapy for the management of mastopathy, which does
      not interfere with the already upset hormonal balance of the patients.

PMID- 8650930
TI  - [Physiology and pathophysiology of the metabolism of lipoproteins].
AB  - PHYSIOLOGY: Lipoproteins (LP) are generally classified according to their
      density. Triglycerides are mainly transported in chylomicrons and very low
      density LP (VLDL), cholesterol is mainly transported in low density LP (LDL) and
      high density LP (HDL). The metabolism of LP is controlled by their
      apolipoproteins, by specific receptors, enzymes, and transfer proteins.
      Triglycerides and cholesterol from the diet are transported in chylomicrons. The
      triglycerides are rapidly hydrolyzed by LP-lipase to yield chylomicron remnants.
      The released free fatty acids are used either for storage in adipose tissue or
      for oxidation in other tissues. Dietary cholesterol is transported in the
      chylomicron remnants to the liver. Cholesterol and triglyceride are also
      synthesized in the liver and then secreted into the blood in the form of VLDL.
      VLDL triglycerides are metabolized by LP-lipase to intermediate density LP (IDL),
      which are either taken up by the liver or further catabolized to LDL. LDL are
      bound and taken up by specific receptors (LDL receptors) in the liver and many
      other tissues. By this pathway, cholesterol is transported from the liver to
      peripheral tissues. LDL can be modified by oxidation and then taken up by
      macrophages in the arterial intima resulting in the formation of foam cells, an
      important step in atherogenesis. HDL play an important role in reverse
      cholesterol transport (transport of cholesterol back to the liver, the only site
      of cholesterol excretion). PATHOPHYSIOLOGY: Various mutations in the LP-lipase
      gene or in the apo C-II gene result in LP-lipase deficiency. Homozygous carriers
      of the mutated gene show defective metabolism of chylomicrons and VLDL with
      extreme hypertriglyceridemia, eruptive xanthomas, hepatosplenomegaly and
      recurrent bouts of acute pancreatitis. Many mutations in the LDL receptor gene
      have been described as the primary cause of familial hypercholesterolemia due to
      LDL receptor deficiency. LDL receptor deficiency results in the accumulation of
      LDL in the plasma and deposition of LDL cholesterol in tendons and skin
      (xanthomas) and arteries (atheromas). In homozygotes, coronary heart disease
      begins in childhood. Familial defective apo B-100 is caused by a mutation in
      codon 3500 of the apo B gene. LDL with the mutated apo B is not recognized by the
      LDL receptor and LDL accumulates in the blood. Mutant forms of apo E (apo E-2 and
      others) are not bound to the LDL(B,E)-receptor resulting in accumulation of
      chylomicrons and VLDL remnants (beta-VLDL) and IDL. For the manifestation of type
      III hyperlipemia, additional genetic, hormonal or environmental factors are
      involved. Cholesterol deposition in macrophages of the arterial intima and skin
      gives rise to atherosclerosis of coronary and peripheral arteries and xanthomas.
      The pathogenesis of familial combined hyperlipemia, the most frequent form of
      primary hyperlipemias, is multifactorial and has not been clarified in detail.

PMID- 8650931
TI  - [Epidemiology of hyperlipidemia in Austria].
AB  - Hyperlipidemia is the most prevalent coronary risk factor in Austria. Several
      Austrian expert statements classified total cholesterol levels in adults below
      200 mg/dl (5.17 mmol/l) with "normal", levels from 200 to 250 mg/dl (5.17 to 6.47
      mmol/l) with "risk", and levels above 250 mg/dl (6.47 mmol/l) with "high risk".
      Based on different epidemiological studies we estimate that 25% of Austrians have
      "normal" and 75% elevated total cholesterol levels (50% "risk", respectively 25%
      "high risk"). Methodological factors prohibit general estimates for HDL
      cholesterol and triglycerides based on present data. In a randomized survey among
      25- to 64-year old adults in Western Austria, prevalence of low HDL-cholesterol
      levels below 35 mg/dl (0.91 mmol/l) was 4.0% in men, and 1.3% in women.
      Prevalence of triglyceride levels above 200 mg/dl (2.29 mmol/l) was 21.5% in men
      and 8.0% in women.

PMID- 8650932
TI  - [Classification of hyperlipoproteinemias and interpretation of laboratory
      parameters].
AB  - Hyperlipidemias are grouped according to their lipid levels in
      hypercholesterolemia, hypertriglyceridemias, and mixed hyperlipidemias. Among
      these, hypercholesterolemia has the strongest correlation to the risk for
      coronary heart disease. Based on the results from epidemiologic studies and
      intervention trials several expert panels have defined cholesterol values with
      low and high cardiovascular risk and cholesterol target levels for treatment. In
      the presence of hyperlipidemia additional parameters like LDL cholesterol, HDL
      cholesterol, and Lp(a) may be determined depending on the individual patient's
      risk profile. For classification of familial lipid disorders, analysis of
      relatives and the determination of special parameters may be necessary. These
      include apolipoproteins (concentration, isoforms, mutants), enzyme activities
      (lipases, LCAT), LDL receptor activity, oratypical lipoproteins.

PMID- 8650933
TI  - [Secondary disorders of lipid metabolism, metabolic syndrome and familial
      combined hyperlipidemia].
AB  - Secondary hyperlipoproteinemias are found in connection with other primary
      organic diseases. Typical examples are those seen with diabetes mellitus, liver
      and kidney diseases. In addition there are changes induced by hormonal
      dysfunctions such as hypothyroidism, by the use of oral contraceptives or in
      postmenopausal women. During pregnancy there is a physiological transient
      increase in lipoproteins. In addition to primary organic diseases there are a
      number of exogenous factors such as obesity, malnutrition and alcohol abuse
      causing hyperlipidemia. The relation between hypertension and hyperlipidemia
      described as familial dyslipidemic hypertension is less well known. Obesity,
      hypertension, dyslipidemia, hyperuricemia and impaired glucose tolerance are the
      basic conditions of the metabolic syndrome. Familial combined hyperlipidemia is a
      genetically determined, dyslipidemic syndrome with a high prevalence among
      patients with coronary artery disease and stroke. As there are some links between
      familial combined hyperlipidemia and secondary hyperlipoproteinemias, this
      disease entity is discussed together in this paper. Familial combined
      hyperlipidemia is metabolically, genetically and by this on a molecular level
      closely linked to familial dyslipidemic hypertension as well as the metabolic
      syndrome. The exact mechanism of this disease is currently unknown.

PMID- 8650934
TI  - [Hypertriglyceridemia].
AB  - The hypertriglyceridemias comprise a heterogenous group of lipoprotein disorders
      varying with respect to etiology, lipoprotein pattern, and its major clinical
      sequelae, i.e. pancreatitis and atherosclerosis. Therefore goals and modalities
      of treatment should be individualized to a large extent. Behavioral measures like
      diet, weight control, exercise, reduced alcohol consumption and smoking cessation
      form the cornerstone of medical management. Lipid lowering drugs should be
      considered when triglyceride levels exceed 1000 mg/dl to reduce the risk of
      pancreatitis and in patients at high risk for atherosclerosis, often
      characterized by a high total cholesterol/HDL ratio, to reduce cardiovascular
      endpoints.

PMID- 8650935
TI  - [Hypercholesterolemia ].
AB  - This review article describes the types, pathophysiology, differential diagnosis
      and therapy of hypercholesterolemia. Special attention has been directed towards
      familiar hypercholesterolemia and familiar apolipoprotein B 100 defect.
      Clinically, both forms present very similar and may cause severe coronary
      arteriosclerosis and death before the age of 40 years. In the homozygote form CHD
      even develops prior to adolescence. With a frequency of 1:500 these forms of
      hypercholesterolemia are among the most common genetic disorders worldwide. The
      poor prognosis and their monogenetic dominant character emphasize the need for an
      exact distinction from the poligenetic forms of hypercholesterolemia and moreover
      underscore the necessity to screen for affected members in the family of already
      diagnosed cases and call for more aggressive therapeutic interventions. By
      dietary measures and monotherapy only 25% of patients reach the recommended
      cholesterol values. HMG-CoA reductase inhibitors proved to be the most effective.
      The remainders have to be treated with combinations of up to 3 lipid-lowering
      drugs. Alternative treatment such as extracorporal cholesterol elimination may
      become necessary.

PMID- 8650936
TI  - [MED-PED: make early diagnosis--prevent early death].
AB  - The goal of MED-PED, a worldwide program including USA and many countries of
      Europe, Asia and Australia aims at diagnosing at the DNA level familial
      hypercholesterolemia (FH). There are currently 2 genetic defects under
      consideration: the LDL-R defect and familial Apo-B-100 defect (FDB). Whereas
      currently more than 160 mutations for the LDL-receptor defect are known, which
      can hamper the straight foreward characterization at the DNA level, FDB is caused
      by a single point mutation which may be easily characterized by routine methods.
      Austria participates since January 1st in MED-PED with subcenters in many
      different regions, which are listed in this article. We expect from the MED-PED
      program not only an optimation of health care in our country, with respect to
      preventive medicine, but also as studies from the US demonstrate, a positive cost
      effectiveness may be reached by this program. MED-PED in Austria is just at the
      beginning and in a rather preliminary stage, but we hope that after finding
      sponsors for covering the actual costs, this project will go on to a more
      advanced stage.

PMID- 8650937
TI  - [Hyperlipoproteinemias in childhood].
AB  - There is general agreement that hyperlipidemic states, in particular
      hypercholesterolemia, should be diagnosed during childhood, and treatment should
      start beyond the age of 2 years. The rationale for this procedure is the fact
      that increased cholesterol levels have been accepted to act as major risk factors
      for coronary vascular disease in adult populations, and therefore the
      significance of cholesterol must be inferred from less direct evidence. The
      diagnosis of hyperlipidemias is based on reference levels for the various age
      groups which are mainly transferred from studies in the USA. The classification
      of hyperlipidemias refers to a clinical and genetic concept; thus, familial
      hypercholesterolemia (incidence 1:500) is the most important disorder for the
      pediatric age group. Treatment of affected children should include dietary
      restrictions, in particular for saturated fats, but substitution of animal
      protein by soy protein has been shown to increase the cholesterol lowering
      effect. It is concluded that children from families with cardiovascular disease
      and/or hyperlipidemias should be referred to a special metabolic clinic for
      appropriate diagnosis and treatment. So far, a general screening for
      hyperlipidemias is not recommended in the neonatal period or during childhood.

PMID- 8650939
TI  - [Therapy of hyperlipidemia].
AB  - The identification of patients with monogenetic lipid disorders and a very high
      risk of premature coronary heart disease is the prerequisit for an intensive
      cholesterol lowering therapy with the goal to normalize serum cholesterol and
      prevent early coronary death which seems possible with the new potent drugs.

PMID- 8650938
TI  - [Lipoprotein(a)--atherogenic waste product of evolution?].
AB  - Lipoprotein(a) (Lp[a]) consists of a LDL-particle and an apolipoprotein(a) which
      is related to plasminogen. The physiological function of Lp(a) is largely
      unknown, but the clinical effects are well known: high plasma concentrations of
      Lp(a) correlate with a high risk for atherosclerosis independently from other
      risk factors. This was shown in several studies for coronary heart disease,
      stroke and peripheral atherosclerosis. Lp(a) has a special position within other
      risk factors because of the strict genetic control of the plasma concentrations
      by the apo(a) gene locus on chromosome 6q2.6-2.7. Studies which doubt this
      relationship have to be considered sceptically. Recent investigations with
      genetic markers confirm that Lp(a) is a risk factor for atherosclerotic vascular
      diseases.

PMID- 8650940
TI  - [Radical therapy of refractory hyperlipidemia: extracorporeal cholesterol
      elimination].
AB  - In Austria atherosclerosis related diseases are responsible for the death of more
      than 50% of the population. There is a linear relationship between lowering
      cholesterol and the mortality of coronary heart disease. Apart from diet and drug
      therapy for the treatment of hypercholesterolemia we nowadays have very potent
      extracorporeal cholesterol lowering therapies. In combination with HMG-CoA
      reductase inhibitors LDL-cholesterol can be lowered by 80% with these procedures.
      In particular homozygote familial hypercholesterolemia is an absolute indication
      for extracorporeal lipid lowering. Refractory heterozygote FH and secondary
      hypercholesterolemia in combination with other risk factors can also be
      controlled by extracorporeal cholesterol elimination. Since some of these
      extracorporeal therapies also improve the hemorheological situation they are also
      being used to treat peripheral vascular disease and cerebral atherosclerosis.

PMID- 8650941
TI  - [Wobenzyme and diuretic therapy in lymphedema after breast operation].
AB  - The authors of this clinical study report the results of a controlled clinical
      trial in randomized parallel groups (Wobenzym vs. diuretics) of 55 female
      patients suffering from brachial arm lymph edema subsequent to ablatio mammae.
      All patients received manual and machine lymph drainage as well as gymnastics as
      concomitant therapy. After 7 weeks of therapy the results of the volometric
      assessments of the arm, the circumference of the arm and the skinfold thickness
      showed significant improvements compared to diuretics. In addition, the patients
      receiving Wobenzym reported a significantly higher proportion of patients free of
      pain compared to the diuretics patients. Overall safety assessment results are
      satisfactory thus resulting in a superior benefit/risk relation of the Wobenzym
      group.

PMID- 8650942
TI  - Effect of mild dietary protein restriction on urinary protein excretion in
      patients with renal transplant fibrosis.
AB  - In recent studies, it has been demonstrated that strict dietary protein
      restriction has a beneficial effect on renal transplant patients who show chronic
      rejection, or transplant fibrosis respectively; however, the protein intake in
      those investigations usually has been below 0.6 g/kg day, and such a strong
      restriction may be associated with both a negative nitrogen balance, and low
      patient compliance. Our study was therefore undertaken to investigate whether the
      same beneficial effect could be attained with a more moderate dietary protein
      restriction in renal transplant recipients. In a randomized cross-over study, 14
      patients with biopsy-proven transplant fibrosis received a mildly protein
      restricted diet (0.7 g/kg/day), and a normal protein diet (1.2 g/kg/day)
      respectively during two 3-week periods. In the patients undergoing moderate
      protein restriction, a significant reduction in urinary albumin, and total
      protein excretion, as well as a decrease in albumin/creatinine ratio was observed
      at the end of the 3-week period when compared to the patients on normal protein
      diet (p < 0.05). The 51Cr-EDTA-clearance did not differ at the end of each of
      these dietary periods. In contrast to earlier studies with lower protein intake,
      the moderate protein restriction in our investigation was not associated with a
      decrease in serum proteins. In conclusion, a mildly restricted protein intake has
      also proved effective in significantly reducing the urinary protein excretion in
      patients with renal transplant fibrosis, yet, without causing decreasing
      serumprotein-concentrations, which are a sign for a negative nitrogen balance.

PMID- 8650943
TI  - [Patient rights alone are not enough, too many rights can also be harmful].
AB  - The nowadays running increased emphasis on patients rights can be seen positive
      as a way towards a "competent partner-patient". However, better health results to
      come out of it want mainly an important pre-condition, which we call "general
      renaissance of communication culture". This should work on the non-verbal, verbal
      and written level. We name the following examples on this way. -Schooling for
      communication, including the mechanism of "positivation", that we have introduced
      into basic psychotherapeutic schooling. -There are further levels of quality
      assurance, leading to quality amelioration via evaluation and motivation. The
      "Rasterzeugnis" (i.e. periodical doctors' certifications, which has become
      obligatory per legem now in Austria) is one of these instruments. -There are
      highly sensible territories like communication with the incurable as well as
      organ transplantations. -But also the seemingly so banal written doctor's report
      should be the subject of important ameliorations in the routine. Following a pure
      standpoint of the right with neglect of all said above, can be contra-productive.
      We give examples of the -patients' insight into medical documents as well as 
      simple juridical judgement of a patient's competence. Only by synopsis of right
      with communication, there can be reached an optimal result for the patient. This
      should run under the omnipresent principle of humanitas.

PMID- 8650945
TI  - [Statistics--lying, but correctly!].

PMID- 8650944
TI  - [The tragic testicular signal].

PMID- 8650946
TI  - WHO Expert Committee on Biological Standardization. Forty-fifth report.
AB  - This report presents the recommendations of a WHO Expert Committee commissioned
      to coordinate activities leading to the adoption of international requirements
      for the production and quality control of vaccines and other biologicals and the
      establishment of international biological reference materials. The report starts
      with a discussion of general issues brought to the Committee's attention and
      provides information on the status and development of reference materials for
      various antibiotics, antibodies, antigens, blood products, cytokines,
      endocrinological and related substances and toxins. The second part of the
      report, of particular relevance to manufacturers and national control
      authorities, contains guidelines on the regulation and licensing of biological
      products in countries with newly developing regulatory authorities, new
      requirements for hepatitis A vaccine (inactivated) and revised requirements for
      hepatitis B vaccine prepared from plasma.

PMID- 8650947
TI  - The physician-assisted suicide debate.

PMID- 8650948
TI  - Family practice residency training capacity in Wisconsin: current status and
      future projections.
AB  - BACKGROUND: High quality health care depends on superior training and outstanding
      residency opportunities for new physicians of all types, especially those
      entering family practice. But concern over the availability of adequate
      opportunity has caused the medical community concern across the country.
      Wisconsin is no different. To estimate future residency needs in the Badger
      State, we examined recent trends in specialty selection and information gathered
      from 1995 medical school graduates entering family practice residency training
      here and in other states. We surveyed all Wisconsin medical school graduates
      entering family practice training positions in July 1995, asking them to rank in
      state and out-of-state programs, as well as graduates' motivations for selecting
      those programs. RESULTS: Response rates to our surveys were exceptional. A full
      86% (n = 30) those entering residency in Wisconsin and 95% (n = 18) for those in
      out-of-state programs responded. One graduate who entered a Wisconsin program
      ranked an out-of-state program higher and one graduate who entered an out-of
      state program ranked a Wisconsin program higher than their ultimate residency
      sites. Not surprisingly, the variable most predictive of whether students pursued
      training in Wisconsin rather than out-of-state was the student's state of
      residency before entering medical school. CONCLUSIONS: The resulting trends show
      positive trends toward state-based family practice training, but may not be as
      optimistic as experts first predicted. If interest in family practice rises to
      goals set by the state's medical schools, more training positions will be needed,
      but not as many as proposed in medical school plans to the state Legislature.

PMID- 8650949
TI  - Graduates comment on issues related to the decline of Wisconsin family physicians
      providing maternity care.
AB  - Care for mother and child once were part and parcel of family medicine. But in an
      age of increased specialization, that touchstone of health care has changed in
      the way such care is delivered and administered. This study, based on survey
      responses from 235 University of Wisconsin (UW) graduates practicing in Wisconsin
      in 1991, examines issues related to the decline in maternity care provided by
      family physicians and factors that could reverse the trend.

PMID- 8650950
TI  - A curriculum in managed care for family medicine residents.

PMID- 8650951
TI  - Over-the-counter sales of cigarettes to children: results of compliance checks in
      Wisconsin, 1992-1995.

PMID- 8650952
TI  - WAPC position statement. Human immunodeficiency virus (HIV) education and testing
      in the perinatal period. Wisconsin Association for Perinatal Care.

PMID- 8650953
TI  - Combining sports medicine, rehabilitation and family clinical care makes physical
      and fiscal sense for UW clinics.

PMID- 8650955
TI  - ADA is changing the way physicians practice medicine.
AB  - Although 5 years old, the Americans with Disabilities Act of 1990 is still
      considered a relatively new law. Physicians' practices are influenced daily by
      the Act--from office hiring practices to treating disabled patients. This article
      is in response to several questions that have been raised concerning the scope of
      the Act as it applies to a physician's office when treating hearing impaired
      patients.

PMID- 8650954
TI  - Warfarin encouraged for stroke prevention in atrial fibrillation.

PMID- 8650956
TI  - Understanding where we are, where we want to be, and how to get there.

PMID- 8650958
TI  - [Osteoporosis and nutrition].
AB  - The high content of calcium-ions provides a solid bone structure with its high
      firmness. Therefore, the basic principle of the diet for a prevention and
      treatment of osteoporosis is to guarantee an optimal calcium uptake. It can be
      shown that especially in girls aged from 12-19 years as well as in elderly
      patients, the desired calcium supply is not reached. Important sources of calcium
      are all milk products but also soda. The calcium uptake is enhanced by vitamin D
      and sex hormones. Oxalic acid, phytate and a high intake of salt, which improves
      the elimination of calcium, are unfavorable. A high intake of animal proteins
      results in an increased elimination of calcium that a restriction of such
      proteins in the diet may be useful.

PMID- 8650957
TI  - [Nutrition in prevention of coronary heart disease].
AB  - Clinical as well as basic research in the field of atherogenesis indicates that
      the progression of this disease process can be slowed down or even reversed. It
      is well established that nutrition plays an important role in the prevention and
      treatment of the classical atherogenic risk factors such as obesity, diabetes
      mellitus and hyperlipidemia. In addition, some nutrients such as the
      polyunsaturated n-3-fatty-acids or antioxidative vitamins can intervene directly
      by influencing one or more steps of the atherogenetic and/or thrombogenetic
      process. A comprehensive understanding of the pathogenesis of this disease as
      well as of the mechanisms of nutrient action are essential to the planning of
      successful nutritional prevention strategies. Because most nutrients influence
      mainly the slow and long-standing development of the atherosclerotic lesion,
      their inclusion in primary nutritional prevention should be started at an early
      age. Few nutrients such as the n-3 fatty acids, which also reduce the
      thrombogenetic risk factors, have demonstrated some success in the secondary
      prevention of CHD. Given the complexity with which nutrients intervene in the
      atherosclerotic process and their interactions with each other, nutritional
      prevention strategies should be based on well-grounded dietary modifications
      rather than supplementation with individual nutrients.

PMID- 8650959
TI  - [Nutrition-related prevention studies in children and adolescents on a population
      level--concepts, methods, outcome].
AB  - Reports on 29 controlled intervention studies concerning the improvement of the
      diet of children and adolescents under preventive aspects mostly from the USA
      were found since 1970. Nearly all studies were done in schools, mostly with about
      500-2500 pupils aged 9-15 yrs. The design and methods of the interventions
      differed between the studies. In most cases, the interventions showed favourable
      results regarding physiological (serum cholesterol, blood pressure, BMI) as well
      as nutritional aspects (knowledge, food consumption).

PMID- 8650960
TI  - [Hypertension and nutrition].
AB  - Dietary treatment is especially suited for less severe increases in blood
      pressure (borderline hypertension or mild hypertension according to the
      respective classification). The most important measures in dietary treatment of
      hypertension are: salt restriction, lowering body weight in obesity, decreasing
      alcohol consumption. The following measures are less effective or have not been
      generally accepted to be effective: polyunsaturated fatty acids, increased
      potassium intake, increased magnesium intake, and increased fibre content of the
      food.

PMID- 8650961
TI  - [Internet--an introduction not only for the physician].
AB  - The Internet, a global computer network, is not only a fascinating new media
      limited to scientists and computer specialist but medical doctors in hospitals as
      well as private practitioners are increasingly finding interesting applications
      in their field. Access to data-bases of medical literature, forums dedicated to
      experts as well as the possibilities of instantaneous electronic data transfer
      open new possibilities for communication and ongoing education in their everyday
      work. A serious and yet playful interaction with this new technology offers the
      chance to prepare for future developments, perhaps to communicate with other
      physicians, colleagues and institutions using a yet to be founded "German Medical
      Network". This contribution is particularly suited for colleagues for whom the
      use of computers is not yet a daily routine.

PMID- 8650963
TI  - [Also HIV subtype E is not transmitted by kissing].

PMID- 8650962
TI  - [Diagnosis and therapy of hypothyroidism in adulthood].
AB  - In the majority of cases, the symptoms of hypothyroidism develop slowly and as a
      result, they often are not recognized or misjudged for a long time. The complete
      picture is a late diagnosis. Especially in older patients, the symptoms are quite
      frequently assigned to the aging process. The most important form is the primary
      hypothyroidism often caused by auto-immune thyroiditis. The presence of a
      hypothyroidism should be considered more often and a TSH examination should be
      run. Normal TSH levels exclude a primary hypothyroidism. Increased TSH levels in
      conjunction with lowered T4 levels prove the diagnosis. If a secondary form is
      suspected, complete pituitary diagnostics are mandatory. The substitution therapy
      is carried out with a medium dosage of levothyroxine, 2.0 micrograms/kg body
      weight per day. The appropriate dosage should be established slowly using small
      initial dosages. This is especially important in older patients and in those
      suffering from coronary disorders. For younger patients and those with a shorter
      history, a more immediate adjustment is possible. During gravidity, the hormone
      requirement increasing by 40% must be taken into consideration. The therapeutic
      effect is shown by the clinic as well as by the TSH level. Overdosage will lead
      to a reversible appearance of thyreoitoxicosis factitia and require re-adjustment
      of the dosage. A physiological dosage does not have negative consequences on the
      bone metabolism. Transitory corrections are possible although a continuous
      substitution is necessary most of the time. Regular checks must be made as the
      therapy may be discontinued in 40% of the cases. In case of subclinical
      hypothyroidism, an indication for treatment does not exist in all patients.
      However, treatment is indicated if there is a high risk for developing a
      permanent form of hypothyroidism or if additional findings exist possibly linked
      to subclinical hypothyroidism. This would make a hormone substitution necessary.
      In case of doubt, a probatory therapy can be initiated and discontinued after 6
      12 months when there is no therapeutic effect.

PMID- 8650964
TI  - [Prevention, standards and future developments in medical specialties-
      developments, deficits and outdated procedures in specialty fields. Working Group
      of Scientific Medical Specialty Societies, Dusseldorf].

PMID- 8650965
TI  - [The Ostringer (Prevention) Model. Results of family medicine supervised
      "community behavioral medicine"].
AB  - To evaluate the German intervention model of "Community-related Behavioural
      Medicine" in reducing cardiovascular risk during a major prevention study (phase
      I) and to investigate the efficiency of a long-term evaluation by establishing a
      Local Health Information System for which cooperating primary care physicians
      carry responsibility (phase II). In the intervention city of Bruchsal (GCP
      evaluation, phase I), the cardiovascular risk factors were reduced: smoking (
      9.4%), obesity (-17.1%), hypertension (-51.4%) and hypercholesteremia (-12.8%).
      In the general practices of Oestringen (LOHIS-evaluation, phase II), the
      prevalence of smoking, from 1992 to 1994 (-23.8%, p < 0.01) as well as
      hypertension (-22.2%), p < 0.01) continued to decrease; there was no further
      reduction of hypercholesteremia and over-weight.

PMID- 8650966
TI  - [Evidence based medicine, the Cochrane Collaboration and dealing with medical
      literature. Implications for medical education, graduate and continuing
      education].
AB  - The concept of evidence-based medicine yields to provide medical practice with
      actual scientific evidence, which raises from a comprehensive analysis of
      randomized controlled studies. The article reviews recent approaches, especially
      in the field of primary care (resp. family medicine) and points out the various
      outcomes of this concept within an analysis of the German system of medical
      instruction and continuing education. This approach, as all other components of
      medical education, shall prove its efficacy in further studies evaluating the
      impact on achievement in patient's care.

PMID- 8650967
TI  - [Current developments in prevention of coronary heart disease].
AB  - The Scandinavian Simvastatin Survival Study (4S-Studie) has provided proof beyond
      any doubt that reduction of plasma cholesterol decreases mortality. The enormous
      rise of morbidity and mortality from cardiovascular disease in both gender calls
      for preventative measures as an urgent task. With a reduction of cardiac events
      by 30-40% and of mortality in the same order of magnitude, cholesterol lowering
      and increase in HDL-cholesterol are most effective measures for the treatment of
      coronary artery disease. However, not treatment of late stages of the disease,
      but primary prevention to reduce the incidence of coronary artery disease in this
      country should be the principle aim. Thus, the international guidelines for the
      treatment of lipid disorders considering the individual patient's risk profile
      have been revised.

PMID- 8650968
TI  - Release of glucagon-like peptide 1 (GLP-1 [7-36 amide]), gastric inhibitory
      polypeptide (GIP) and insulin in response to oral glucose after upper and lower
      intestinal resections.
AB  - Glucagon-like peptide 1 (GLP-1[7-36 amide]) is an incretin hormone primarily
      synthesized in the lower gut (ileum, colon/rectum). Nevertheless, there is an
      early increment in plasma GLP-1 immediately after ingesting glucose or mixed
      meals, before nutrients have entered GLP-1 rich intestinal regions. The
      responsible signalling pathway between the upper and lower gut is not clear. It
      was the aim of this study to see, whether small intestinal resection or
      colonectomy changes GLP-1[7-36 amide] release after oral glucose. In eight
      healthy controls, in seven patients with inactive Crohn's disease (no surgery),
      in nine patients each after primarily jejunal or ileal small intestinal
      resections, and in six colonectomized patients not different in age (p = 0.10),
      body-mass-index (p = 0.24), waist-hip-ratio (p = 0.43), and HbA1c (p = 0.22),
      oral glucose tolerance tests (75 g) were performed in the fasting state. GLP-1[7
      36 amide], insulin C-peptide, GIP and glucagon (specific (RIAs) were measured
      over 240 min. STATISTICS: Repeated measures ANOVA, t-test (significance: p <
      0.05). A clear and early (peak: 15-30 min) GLP-1[7-36 amide] response was
      observed in all subjects, without any significant difference between gut-resected
      and control groups (p = 0.95). There were no significant differences in oral
      glucose tolerance (p = 0.21) or in the suppression of pancreatic glucagon (p =
      0.36). Colonectomized patients had a higher insulin (p = 0.011) and C-peptide (p
      = 0.0023) response in comparison to all other groups. GIP responses also were
      higher in the colonectomized patients (p = 0.0005). Inactive Crohn's disease and
      resections of the small intestine as well as proctocolectomy did not change
      overall GLP-1[7-36 amide] responses and especially not the early increment after
      oral glucose. This may indicate release of GLP-1[7-36 amide] after oral glucose
      from the small number of GLP-1[7-36 amide] producing L-cells in the upper gut
      rather than from the main source in the ileum, colon and rectum. Colonectomized
      patients are characterized by insulin hypersecretion, which in combination with
      their normal oral glucose tolerance possibly indicates a reduced insulin
      sensitivity in this patient group. GIP may play a role in mediating insulin
      hypersecretion in these patients.

PMID- 8650969
TI  - -Bile duct stenoses and leakage after cholecystectomy: endoscopic diagnosis,
      therapy and treatment outcome-.
AB  - Minimal invasive methods compete with surgical treatment in the therapy of
      complications after cholecystectomy. In this retrospective study we evaluate the
      efficacy of endoscopically placed biliary stents in 35 patients (25 female, ten
      male) with biliary strictures and/or leakage after cholecystectomy. 27 patients
      received a 10- or 11.5-French endoprosthesis, eight patients needed a
      percutaneous-transhepatic-cholangio-drainage (PTCD). Four patients (11.4%)
      underwent a surgical therapy. Endoscopic therapy was successfully completed in 23
      patients (65.7%), at which we noticed a superior result in patients with early
      incidenced stenosis/leakages after cholecstectomy. During a follow-up period of 1
      109 months (median 28 months) two recurrent strictures (5.7%) were observed. As a
      complication we have seen a prosthesis-dislocation after PTCD. None of the
      patients died of complications related to endoscopic therapy.

PMID- 8650970
TI  - Conservative management of foreign bodies in the gastrointestinal tract.
AB  - There are at present no clear guidelines whether foreign body ingestion in the
      gastrointestinal tract should be managed conservatively, endoscopically or
      surgically. Retrospectively we have, therefore, analyzed 78 foreign body
      ingestion's in 42 patients (age 15-72 years) admitted to the Emergency Department
      of the University Hospital in Vienna. Our intention was to assess the value of a
      conservative management, defined as daily follow-up visits until the foreign body
      spontaneously appeared in the feces and to find criteria when endoscopic or
      surgical management is required. Of 78 foreign bodies, 67 (86%) passed the
      gastrointestinal tract spontaneously without complications, 9 (11%) were removed
      endoscopically, and only 2 (3%) required surgery. There were no gastrointestinal
      perforations. Even foreign bodies with a maximal length of 13.5 cm appeared in
      the feces spontaneously within a few days. Our data suggests that more than 80%
      of adults with foreign body ingestion can be managed safely as outpatients by
      means of conservative treatment. Endoscopic or surgical removal is only indicated
      in very rare circumstances.

PMID- 8650972
TI  - -Severe hemobilia after percutaneous transhepatic biliary drainage. Successful
      treatment by arterial catheter embolization-.
AB  - We report on an 44-year-old man with Billroth-I-reoperation and transformation
      into Roux-Y-anastomosis, which was performed because of ulcer-relapse. The
      postoperative course was complicated by obstructive jaundice and cholangitis.
      Ultrasound and computed tomography could not clarify the cause. The subsequently
      performed percutaneous transhepatic cholangiography showed several small
      concrements in the biliary tract. For decompression of the dilated bile ducts
      percutaneous transhepatic biliary drainage was applied. Following that the
      patient developed recurrent episodes of hemobilia, which made the transfusion of
      altogether 17 units of blood necessary. Angiography clarified the bleeding source
      showing leakage of the right hepatic artery. By means of repeated selective
      transcatheter embolization definite hemostasis was achieved. Transcatheter
      embolotherapy is recommended as initial treatment to control serious iatrogenic
      hemobilia.

PMID- 8650971
TI  - -Cardiomyopathy as the cause of death in genetic hemochromatosis-.
AB  - Hemochromatosis is an autosomal-recessive disease which causes iron-overload of
      various organs including liver, pancreas and heart. This report analyzes the
      course of hemochromatosis in two patients (a 28-year-old man and a 57-year-old
      woman) in whom hemochromatosis was detected because of severe cardiomyopathy.
      Initial symptoms were edema, anasarca and dyspnea. Further examinations showed
      pleural effusion, decreased left-ventricular-function, skin pigmentation,
      diabetes mellitus and liver cirrhosis. Although phlebotomy treatment and iron
      chelation therapy with deferoxamine initially resulted in some improvement, both
      patients died from cardiomyopathy three months after diagnosis. The reports of
      these two cases underline that hemochromatosis-associated cardiomyopathy is often
      irreversible if severe congestive heart failure is present. In cardiac
      decompensation heart transplantation has to be considered as early as possible.

PMID- 8650973
TI  - -Therapy with ursodeoxycholic acid in primary biliary cirrhosis in pregnancy-.
AB  - Pregnancy is very uncommon in patients with primary biliary cirrhosis (PBC) and
      only few reports exist about pregnancy and PBC. However, no data are available on
      therapy and potential risks of treatment with ursodeoxycholic acid (UDCA) in PBC,
      especially in the first trimester of pregnancy. Furthermore, it is not known,
      whether UDCA is secreted into the breast milk during lactation. We report a 41
      year old patient with the diagnosis of PBC stage III, who had been treated with
      UDCA (750 mg/day) for three years. At the time of diagnosis of pregnancy (5th
      gestational week), UDCA was withdrawn. Within nine days, severe pruritus
      developed, alkaline phosphatase and gamma-glutamyltransferase increased. UDCA was
      administered again (750 mg/day). The pruritus disappeared completely within one
      week. Liver enzymes decreased to baseline values and remained stable throughout
      the remainder of the pregnancy. No drug-related side effects were observed.
      Caesarean section for placental insufficiency unrelated to PBC was performed at
      the 34th week of pregnancy. The newborn thrived normally during a follow-up
      period of six months. When the patient's breast milk was analyzed by high
      pressure liquid chromatography, cholic acid, deoxycholic acid and lithocholic
      acid, but not UDCA were detected in trace amounts. It is concluded that UDCA
      therapy in PBC may be continued in the early pregnancy and during the breast
      feeding period. UDCA may be effective for the prevention of cholestasis in PBC
      during pregnancy.

PMID- 8650974
TI  - Conservative treatment of acute hepatic failure.
AB  - Treatment of patients with acute liver failure has considerably improved in
      recent years. Effective treatment of these devastating situations requires early
      assessment of prognosis and early referral of these patients to specialized
      centers. The conservative management of extrahepatic complications in intensive
      care units appears to contribute to a better survival of patients whether or not
      they are subsequently submitted to a transplantation procedure. Specific
      hepatocyte-targeted treatment by prostaglandin E2 or similar drugs can be an
      option in the future. Dramatic progress has been made in the temporary
      substitution of liver function bridging the time period between liver failure and
      resumption of hepatocellular function due to liver regeneration. Presently,
      artificial liver assist devices as well as the extracorporeal perfusion of human
      or pig livers are evaluated in clinical trials. Initial results indicate that
      these measures allow to bridge the time until an appropriate donor liver is
      available. Permanent liver transplantation has been shown to save the lives of
      many patients suffering from acute liver failure. Selection of patients requiring
      urgent liver transplantation has been facilitated by the use of prognostic scores
      specifically adapted to the etiology of underlying liver disease. A temporary
      auxiliary liver transplantation can be a better treatment option preventing the
      patient from a life-long dependence upon medical surveillance and drug-induced
      immunosuppression.

PMID- 8650975
TI  - -Development of a mouse model for Helicobacter pylori infection in the human-
      progress toward vaccination against ulcer disease?-.

PMID- 8650976
TI  - -Comparison of lipiodol-assisted chemoembolization versus only conservative
      therapy in patients with nonresectable hepatocellular carcinomas-.

PMID- 8650977
TI  - -Stumbling blocks in weight reduction--new genetic and metabolic hindrances in
      weight reduction-.

PMID- 8650978
TI  - -Aneurysm of the pulmonary artery and pulmonary artery hypertension 22 years
      after Mustard reversal operation in transposition of great vessels-.
AB  - An increasing number of patients with transposition of great arteries reaches
      adult age after an atrial redirection operation. The well known late sequelae of
      the Mustard and Senning operations include supraventricular brady
      tachyarrhythmias, dilatation and failure of the systemic ventricle, severe
      tricuspid valve incompetence, obstruction of either the systemic or pulmonary
      venous return as well as left ventricular outflow tract obstruction, and baffle
      leaks. The case of a 26-year-old woman with a rarer postoperative course, namely
      severe aneurysmal dilatation of the pulmonary artery and pulmonary arterial
      hypertension 22 years after a Mustard operation is described. The pros and
      contras of the available therapeutic alternatives are discussed.

PMID- 8650979
TI  - -Congenital hypoplasia of the anterior tricuspid leaflet as a cause of high-grade
      tricuspid valve insufficiency in a 64-year-old patient-.
AB  - In a 64-year-old man a heart murmur was present since childhood and could be
      identified 8 years ago as isolated tricuspid regurgitation. Because of
      progressive dyspnea there was an indication for surgical treatment.
      Intraoperatively, we found a hypoplastic anterior leaflet, though the other two
      leaflets were preserved in totally good condition, without any evidence of
      endocarditis. Tricuspid valve replacement was performed as there was no chance of
      reconstruction. To our knowledge, this is the first description of a congenital
      hypoplastic anterior leaflet of the tricuspid valve.

PMID- 8650980
TI  - -Surgical occlusion of persistent ductus arteriosus in advanced age--determining
      indications based on 3 case reports-.
AB  - We present three cases of a surgical approach to close a patent ductus arteriosus
      in the elderly. In each case a transcatheter closure was not indicated for
      different reasons: Patient No. 1 had an extremely calcified aortic arch; Patient
      No. 2 was operated on under the erroneous diagnosis of an aortopulmonary window;
      Patient No. 3 concomitantly suffered a high-grade valvular aortic stenosis. The
      patent ductus arteriosus was closed transpulmonally via a median sternotomy under
      the conditions of extracorporal circulation in each of the three patients.
      Patient No. 3 additionally underwent an aortic valve replacement. We discuss the
      differential indications for a surgical closure of a patent ductus arteriosus in
      the elderly.

PMID- 8650981
TI  - -Value of activated blood coagulation time in monitoring anticoagulation during
      coronary angioplasty-.
AB  - Accurate heparin anticoagulation assessment is important to prevent complications
      (hemorrhage, thrombotic coronary occlusion) during and after coronary angioplasty
      (PTCA). Paired ACT-, aPTT- and prothrombin time (PT) measurements have not been
      studied after PTCA using a high dose heparin management. For that reason we
      analyzed in 150 consecutive patients (115 m., 35 f., 61 +/- 10 y.) immediately
      after PTCA and at the time of arterial sheath removal aPTT-(Neothromtin,
      Behring), PT- (Thromborel S, Behring) and ACT-(HR-ACT, HemoTec) values after
      application of 20,000 U of heparin (5,000 U intravenous, 15,000 U intracoronary)
      followed by a heparin-infusion (15,000-25,000 U/24 h). Immediately after PTCA in
      all patients a aPTT above the upper limit of >180 s was found. The average
      postprocedural ACT was 330 +/- 82 s. Only 9 patients showed an ACT below 200 s.
      All coronary reocclusions (n = 3) immediately after PTCA occurred in this group.
      Arterial sheaths were removed 13 +/- 3 h after PTCA. The incidence of minor
      peripheral bleeding complications at that time was 21% and was related to the
      anticoagulation level. Major bleeding complications requiring transfusion were
      noted in only one case. Our findings suggest that after high dose heparinization
      for PTCA the ACT test provides a reliable and broad range for the assessment of
      heparin anticoagulation. In contrast to the aPTT the ACT is ideally suited to
      determine the dosage of heparin infusion and the time of arterial sheath removal
      after PTCA. ACT measurements are superior to aPTT measurements in heparin
      anticoagulation assessment during and direct after PTCA.

PMID- 8650982
TI  - -Recanalization of chronic coronary artery occlusions: effect on clinical
      symptoms and left ventricular function-.
AB  - Angioplasty of chronically occluded coronary arteries is discussed
      controversially. This study was performed to investigate the potential benefit of
      recanalization procedures. Between 1/91 and 10/93 occlusion angioplasty was
      attempted in 408 patients. 322 persons were followed with repeat angiography
      performed in 177 patients. Quantitative analysis of left ventricular function was
      performed in 34 patients before and after successful occlusion angioplasty.
      Primary reopening rate was about 71% with highest success rate for occluded LAD
      (82%). Angiographic controls showed open arteries in 80 (45.2%) patients, 53
      (30.0%) had restenosis and 44 (24.8%) reocclusion. Anginal status was improved by
      one CCS-class or more in 197 patients (61%), mean exercise workload increased
      from 115.8 watts to 136.1 watts (p < 0.0001). Out of 34 patients, 25 (73.5%)
      showed improvement of regional ventricular function, mean ejection fraction
      increased from 56.9% to 64.1% (p < 0.001). Follow-up angiography revealed open
      arteries in 58% of patients if dissection was absent. When dissection type B, C
      or D NHLBI was present, only 32% of the vessels were open. CONCLUSION: In
      selected patients occlusion angioplasty is feasible with acceptable primary
      results. Anginal complaints and functional status were influenced positively,
      left ventricular function showed improvement indicating the presence of
      hibernating myocardium. In patients with suboptimal primary results (dissection)
      repeat angiography may be indicated.

PMID- 8650983
TI  - [Clinical experiences with pectoral defibrillator implantation].
AB  - The pectoral approach to implantation of cardioverter/defibrillators has the aim
      to further simplify the implantation of transvenous defibrillation systems. The
      PCD 7219 D/C is a device of the fourth generation which makes the pectoral
      implantation feasible due to a weight of 132 g, a size of 89 x 64 x 18 mm, a
      volume of 83 cm3 and a surface of 108 cm2. The use of the "active-can"-system
      (PCD 7219 C) requires the implantation of only one right ventricular lead. The
      PCD 7219 D/C was implanted in 75 patients with ventricular tachyarrhythmias, the
      follow-up period was 12 +/- 4 (1-24) months. Subpectoral implantation was
      feasible in 59 patients (79%), in 55 with a left pectoral, in 4 with a right
      pectoral approach due to previous left-sided operation or thrombosis of the left
      subclavian vein. Male sex (p < 0.005), body weight (p < 0.005) and body surface
      (p < 0.05) were predictors of pectoral implantation. In the 45 patients (60%)
      with a unipolar defibrillation system ("active can") the defibrillation threshold
      was significantly lower compared to those with a dual lead system (9.9 +/- 6.5,
      2.5-24 Joule vs. 19 +/- 4.5, 6-24 Joule p < 0.0001). In one patient with pectoral
      and in one patient with abdominal implantation a dislodgement of the right
      ventricular lead was diagnosed and an operative revision was indicated.
      CONCLUSION: The down-sized implantable cardioverter/defibrillator PCD 7219 D/C
      makes the pectoral implantation feasible in the majority of patients. The use of
      the "active-can"-system requires the implantation of only one right ventricular
      lead with significantly lower defibrillation thresholds.

PMID- 8650984
TI  - [Diurnal distribution of spontaneous ventricular tachyarrhythmias in patients
      with implanted cardioverter defibrillator].
AB  - The purpose of this study was to analyze temporal patterns of spontaneous
      ventricular tachyarrhythmias in patients (p) with implantable cardioverter
      defibrillator (ICD). By reading out the ICD-data logs 725 arrhythmic episodes (e)
      from 43 patients were investigated. After grouping the episodes into four defined
      time periods (period 1: midnight to 6 a.m., period 2: 6 a.m. to noon, period 3:
      noon to 6 p.m., period 4: 6 p.m. to midnight) according to the data stored by the
      device, the percentage of episodes per time period has been calculated for each
      patient who experienced at least 10 arrhythmic events (n = 22). A significant
      peak occurrence (mean 34%) could been demonstrated for the morning hours (period
      2). Analyzing patients individually, 4 subgroups could be identified: group 1
      with an episode peak in period 2 (9 p, 277 e, p < 0.01), group with an episode
      peak in period 3 (4 p, 83 e, p < 0.01), group 3 with a peak occurrence in period
      4 (3 p, 110 e, p < 0.01) and group 4 with an equal episode distribution over all
      four time periods (6 p, 187 e). Comparing sustained and nonsustained
      tachyarrhythmias, the nonsustained episodes were found to be distributed much
      more equally, meanwhile the circadian variation for fast (HR > or = 240/min) and
      slower (HR < 240/min) arrhythmias was identical. Regarding episodes of patients
      on beta-blocker or class III-antiarrhythmic therapy the same circadian variation
      has been found. There was no significant difference between the subgroups of
      patients with an episode peak in period 2 and the other patients concerning age,
      sex, cardiac disease, left ventricular ejection fraction, clinical arrhythmia,
      beta-blocker or class III-antiarrhythmics, number of recorded episodes or follow
      up time. Further studies are needed to determine a possible correlation between
      these findings and different circadian variations in individual psychovegetative
      activity.

PMID- 8650985
TI  - Re: Colour flow Doppler sonographic control of efficiency of a novel combination
      of pressure clamp and pressure dressing of femoral artery and vein after heart
      catheterization--Z Kardiol 84.436--442, 1995.

PMID- 8650986
TI  - -Myocardial protection by preconditioning. Experimental and clinical significance
      .
AB  - Short periods of ischemia render the myocardium more resistant to a subsequent
      prolonged coronary occlusion resulting in a reduction of infarct size. This
      cardioprotective mechanism has been called ischemic preconditioning. Acute
      myocardial ischemia results in a rapid decline of high energy phosphates. After
      short periods of ischemia the high energy phosphate levels are better preserved
      and the increase of lactate is slower during the prolonged subsequent ischemia in
      the preconditioned group compared to control. The duration of ischemia needed for
      induction of the protective effect is 2.5 min in dogs and 20 min in our swine
      model. In porcine myocardium the protection is lost about 1 h after induction and
      a renewal is not possible at that time, but is 24 h later. For rabbits or dogs,
      but not in pigs, a late protection 24 h after induction or preconditioning has
      been shown ("second window of protection"). Adenosine or adenosine A1 receptor
      agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and
      bradykinin B2 receptor agonists as well as opening of the K+ATP-channel
      substitute for ischemia in the induction of protection. Activation of protein
      kinase C results in protection in rats and rabbits, but not in dogs or pigs.
      Inhibition of protein kinase C translocation or kinase activity results in a loss
      of the protection induced by preceding ischemia. After blockade of the K+ATP
      channel the protection induced by adenosine A1 receptor activation is lost.
      Therefore opening of the K+ATP-channel is a prerequisite for induction of the
      protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has
      been shown to result in a loss of protection, therefore the Gi-protein seems to
      be involved in the evolution of protection. In humans during coronary angioplasty
      anginal pain and lactate production during a second balloon occlusion is
      diminished without any change in the regional myocardial perfusion. This
      adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1
      receptor. Intermittent cross-clamping before a longer occlusion during open-heart
      surgery results in a better preservation of high energy phosphates compared to
      controls without preceding short ischemia. These observations support the
      hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris
      preceding the myocardial infarction may have preconditioned the human heart
      against the subsequent myocardial infarction, but studies concerning the
      influence of angina pectoris on short-term outcome after thrombolysis are
      conflicting. In the future, ischemic preconditioning or preconditioning with
      drugs may prolong the duration of ischemia tolerated without necrosis and improve
      the prognosis of patients by reducing the infarct size.

PMID- 8650987
TI  - -Diagnostic shunt oximetry of atrial septal defect in adulthood-.
AB  - There are several circumstances in which data obtained at catheterization should
      alert the cardiologist to look for a shunt that had not been suspected
      previously. Aim of the study was to explore the most sensitive parameter which is
      easily practicable and which gives strong evidence for an atrial septal defect
      (ASD). Moreover, a simplified method for quantifying left-to-right shunts was
      analyzed. In 84 patients (58 with an atrial septal defect and 26 patients without
      shunt) a complete oxygen saturation status was determined. The oxymetrically
      determined relation between pulmonary bloodflow QP and systemic bloodflow QS was
      1.31 to 5.60 in patients with ASD and 0.75 to 1.19 in patients without shunt. The
      analysis of sensitivity and specificity was determined to define the marginal
      value which gives suspicion of an ASD. The best values for sensitivity and
      specificity was found for PA O2-SVC O2 = 7.4% (sens. = 98.3%, spec.= 96.2%), PA
      O2 -IVC O2 = 2.0% (sens./spec.= 100%), PA O2 - MV O2 = 5.0% (sens./spec.= 100%)
      and PA O2 = 78.4% (sens./spec. = 97.5%). The correlation between the modified
      ratio QP/QS and various differences in O2-saturation with the shunt size was
      examined. A high correlation was found for the modified QP/QS with SVC O2 instead
      of MV O2 (r = 0.98), PA O2-SVC O2 (r = 0.77) and PA O2 - MV O2 (r = 0.74) with
      QP/QS, respectively. CONCLUSION: The results demonstrate that an O2-saturation
      >78% in the pulmonary artery is highly suspicious for the diagnosis of an ASD.
      With the modified ratio QP/QS = (ART O2-SVC O2)/(PV O2-PA O2) a high sensitive
      and specific modus of quantifying shunts can be reached. Determination of oxygen
      saturation from the V. cava interior is therefore not useful.

PMID- 8650988
TI  - -Occlusion of atrial septal defect with a new occlusive device-.
AB  - An atrial septum defect was closed with an ASDOS (Babic) occluder in 13 patients
      aged from 22 to 67 years. The diameters of the ASD ranged from 12 to 36 mm, the
      left to right shunt from 35% to 70%. With one exception, the occluder could be
      implanted in all patients. Two patients with an oversized ASD (diameter 31 and 36
      mm respectively) had to be operated after 8 h and 2 weeks, respectively. In one
      patient, a small asymptomatic hemopericardium was detected after 24 h by routine
      echocardiogram and in another patient a single umbrella arm fracture was noticed
      by routine x-ray 4 months after the implantation. No further complications
      occurred. Follow-up is now 3 months to 1 year. With one exception, there was no
      residual shunt as measured by oximetry.

PMID- 8650989
TI  - [Modification of bone quality by extreme physical stress. Bone density
      measurements in high-performance athletes using dual-energy x-ray
      absorptiometry].
AB  - The treatment of osteoporosis is still controversial. Rehabilitation programs
      which stress strengthening exercises as well as impact loading activities
      increase the bone mass. On the other side activity level early in life has not
      been proven to correlate with increased bone mineral content later in life.
      Little is known on the influence of high performance sports on the bone density
      especially in athletes with high demands on weight bearing of the spine. In (n =
      40) internationally top ranked high performance athletes of different disciplines
      (n = 28 weight-lifters, n = 6 sports-boxers and n = 6 bicycle-racers) bone
      density measurements of the lumbar spine and the left hip were performed. The
      measurements were carried out by dual-photonabsorptiometry (DEXA; QDR 2000,
      Siemens) and evaluated by an interactive software-programme (Hologic Inc.). The
      results were compared to the measurements of 21 age-matched male control
      individuals. In the high performance weight lifters there was an increase of bone
      density compared to the control individuals of 23% in the Ward's triangle (p <
      0.01). The sports-boxers had an increase up to 17% (lumbar spine), 9% (hip) and
      7% (Wards' triangle). In the third athletes group (Tour de France-bikers) BMD was
      decreased 10% in the lumbar spine, 14% in the hip and 17% in the Wards' triangle.
      Our results show that training programs stressing axial loads of the skeletal
      system may lead to an increase of BMD in the spine and the hip of young
      individuals. Other authors findings, that the BMD of endurance athletes may
      decrease, is confirmed. Nevertheless the bikers BMD-loss of 10 to 17% was
      surprisingly high.

PMID- 8650990
TI  - [Wedge osteotomy of the tibial head using fractionated drilling. A complication
      reducing surgical modification].
AB  - Two techniques of closed wedge osteotomy of the proximal tibia in 132 cases using
      external fixation device were compared retrospectively for neurological
      complication rate. While in group 1 (n = 89) wedge osteotomy was performed
      conventionally using an oscillating saw, in group 2 (n = 43) osteotomy was done
      with consecutive drill holes of increasing diameter followed by osteoclasis.
      Neurological complications in group 1 were found postoperatively 15.7%
      (transient) and after 7 months follow-up time in 12.4% (persistent), in group 2
      14% transient and 4.7% persistent neurological deficits were registered. The
      lower complication rate in group 2 is due to the reduction of postoperative
      tibialis anterior syndrome (type B lesions). No differences for type C lesions
      (extension deficit of D1) were found. No complete peroneal palsy (type A)
      occurred in either group. The authors conclude that reduction of neurological
      complications in group 2 is related to the less extensive approach of the
      proposed technique.

PMID- 8650991
TI  - [Total femur replacement following multiple periprosthetic fractures between
      ipsilateral hip and knee replacement in chronic rheumatoid arthritis. Case report
      of 2 patients].
AB  - Periprosthetic femur fractures are one of the most severe complications in hip
      surgery. Osteoporosis as seen in patients with rheumatoid arthritis could favour
      such fractures, which are located mostly between the stems of the hip and knee
      prostheses. A traumatic event is not even required. The fracture rate increases
      with predisposing factors, such as preliminary changes of the prosthesis or
      osteoporosis. This paper reports two patients with rheumatoid arthritis (males,
      54 and 71 years old) with femur fractures after total hip and knee replacements.
      Both had a severe osteoporosis caused by a long-term steroid therapy.
      Consecutively, both patients showed refractures of the femur with loosening of
      the osteosynthetic material, so that a total femur replacement was required.
      However, both patients are able to walk. To reduce the risk of femur fractures
      between the tips of knee and hip prostheses it is advisable to use knee
      prostheses without a proximal intramedullary stem. In this way pressure stress is
      reduced.

PMID- 8650992
TI  - [Alloplastic replacement of the proximal femur--indications, results and
      experiences].
AB  - The aim of this follow-up study was to see if, by the application of a special
      endoprosthesis for the replacement of the proximal femur, a radical tumour
      resection could be achieved and/or the function of the lower limb could be
      preserved or restored respectively. Between 11/1986 and 12/1992 a proximal
      femoral endoprosthesis was implanted in 9 patients with metastases in the
      proximal femur. In 21 cases this special endoprosthesis was used in the revision
      of conventional cemented total hip arthroplasties with loosening of the implant
      and extreme bone loss at the proximal femur. Twenty-three patients were seen for
      a follow-up examination with an average follow-up period of 20 months. In all
      cases the walking ability was preserved or restored respectively. The majority
      (22/23) of the patients had complete or, nearly complete pain relief. In those
      patients with skeletal metastases, were no cases of local reoccurrence. The
      majority problem of this endoprosthesis was the increased risk of dislocation.
      There is a clear indication for such a special endoprosthesis in the treatment of
      primary and secondary bone tumours in the proximal femur. For revision of
      cemented total hip prostheses with loosening and bony defects a revision
      prosthesis with uncemented distal fixation should be used.

PMID- 8650993
TI  - [Stabilization of the proximal femur in hip joint replacement using M.E. Muller's
      acetabular roof socket].
AB  - Extreme changes of the hip joint often require individual technical supplements
      in addition to the endoprosthesis. But the base of success are procedures using a
      model of prosthesis and a technique that are matured. This is available e.g. with
      the old M. E. Muller curved stem hip joint prosthesis. In special cases of
      extreme changes or damage of the proximal femur we perform in artificial joint
      replacement of the hip or changing of prostheses a special kind of operative
      treatment. This is a combination of the Original-M. E. Muller curved stem
      endoprosthesis, long or short version of the femoral part, in addition fixated by
      bone-cement and M. E. Muller's special metal socket--primary indicated for
      stabilization of the acetabular roof. The indications for this method can be
      changes of proximal femur and hip-joint, especially dysplasias of pelvis or hip
      joint, extensive fractures especially in old patients, destructions in
      polyarthritis, dysplasia of pelvis and coxitis caused by juvenile chronic
      arthritis and long time therapy with corticosteroids, destructions, loosenings
      and fractures in changing operations of hip-endoprostheses. Until today we
      treated 15 different cases by this method--one case was operated 13 years ago-
      with good results, prooved by Merle d'Aubigne's score.

PMID- 8650994
TI  - [Improved radiological imaging of acetabular screw socket].
AB  - The improved radiological representation of the cementless acetabular screw
      socket at two levels is of fundamental importance for the postoperative
      determination of position as well as for the judgement of an aseptic loosening.
      To improve the radiological representation two special radiographic techniques in
      the anterior-posterior as well as in the axial view have been examined on a human
      preparation of pelvis and have been scrutinized on a great number of clinical
      patients. The a.-p. radiography with twenty degrees cranio-caudal prone view in
      the sagittal plane and the axial radiography with forty-five degrees caudo
      cranial prone view in the coronal plane shows the best and fewest overlayed
      representation of the screw-socket. The position of inclination and anteversion
      could have been directly determined out of these two radiographs. Malpositions of
      the screw-socket, especially with regard to the anteversion are easily
      identifiable due to the special axial radiographic technique. Overprojection of
      adjoining bone areas, which were possible should be considered at the judgment of
      the implant-bone-contact. Radiographic technical and positioning problems were
      not observed in patients. Out of these examinations the a.-p. radiography with
      twenty degrees cranio-caudal prone view in the sagittal plane and the axial
      radiography with forty-five degrees caudo-cranial prone view in the coronal plane
      could be recommended to the radiological diagnosis after implantations of hip
      prosthesis.

PMID- 8650996
TI  - [Technique and value of imaging methods in the assessment of the elbow joint].
AB  - Roentgenography is the standard diagnostic tool for study of skeletal injuries
      and diseases around the elbow. The basic x-ray examination of the elbow includes
      the two standard static positions (frontal and lateral). If necessary oblique
      views are required to evaluate the radial head and the coronoid process. Dynamic
      examination (flexion-extension, ulnar-radial deviation) is indicated when
      instabilities are suspected. Indication, technique and interpretation of these
      images should be of general knowledge in the common practice of the orthopaedic
      surgeon. For further evaluation in unclear conditions the patient should be
      referred to a specialized orthopaedic surgeon, who has not only to decide about
      the indication of further imaging techniques but also has to establish a concept
      for the different treatment options (e.g. arthroscopy, open surgery).

PMID- 8650995
TI  - [Late hip dislocation--treatment results of 1193 hips in attenuated abduction
      (Hanausek position)].
AB  - Results of 1193 dislocated and dysplastic hips in 695 children of a consistent
      treatment by skin traction and splinting in a mitigated abduction device
      (Hanausek position) are given with regard to the acetabular development and
      avascular head necroses. The acetabular development depends on the initial
      acetabular dysplasia and is overall satisfactory through final acetabular angles
      (Hilgenreiner) between 22 and 25 degrees even in highly dysplastic acetabula in
      late cases. The procedure is non-aggressive proven by low rate of femoral head
      necroses of 3.4%. Factors contributing to higher rates and degrees of iatrogenic
      damage to the femoral head are short time or no preceding longitudinal traction,
      low initial acetabular pathology and prolonged splinting.

PMID- 8650997
TI  - [Extracorporeal shockwave therapy of radiohumeral epicondylopathy-- an
      alternative treatment concept].
AB  - During the last 2 years 75 patients referred to our hospital for operation of a
      persistent tennis elbow were followed prospectively after receiving low-energetic
      extracorporal shock wave therapy. 3 times in weekly intervals all patients
      received 1000 impulses of the energy density 0.06 mJ/mm2. Follow-ups were
      performed at 3, 6, 12, 24 weeks. Statistical analysis showed significant
      improvement both of subjective and objective criteria. 41 patients became
      painfree. Only 7 patients decided to have an operation after the 24-weeks-follow
      up. Ambulatory shock wave therapy is a considerable alternative before surgical
      intervention in chronic tennis elbow.

PMID- 8650998
TI  - [Measurement of glenohumeral joint translation with a dynamic shoulder model].
AB  - Translation of the glenohumeral joint was measured with a dynamic shoulder model,
      during elevation of the arm in eight cadaveric specimens. Controlled hydrodynamic
      actuator forces were applied to the deltoid muscle and the rotator cuff through
      wire cables. Using a constant force ratio, the glenohumeral joint was elevated to
      90 degrees. The position of the arm in all spatial orientations was measured with
      an ultrasonic device. Reproducibility of glenohumeral joint motion was
      demonstrated on the basis of five cycles of glenohumeral joint elevation. The
      rotational center of the humeral head was used as the reference point for
      translation. Translation during elevation of the glenohumeral joint between 20
      degrees and 90 degrees averaged 9.0 mm +/- 5.2 mm superiorly and 4.4 mm +/- 1.3
      mm anteriorly. In vivo, this may be diminished by coordinated activity of the
      rotator cuff. The presence of significant glenohumeral joint translation
      underlines the importance of active, muscular guidance at the shoulder.
      Physiologic translation of total shoulder arthroplasty, in shoulder instability
      and in the impingement syndrome.

PMID- 8650999
TI  - [Patellar osteochondrosis dissecans--results of surgical therapy].
AB  - Osteochondritis dissecans of the patella is a rare condition. 15 patients who had
      been treated by surgery were evaluated retrospectively by clinical examination,
      standard radiographs of the patellofemoral joint and using the Lysholm-Score. The
      results of treatment were classified as good, sometimes excellent. The worst
      results were found in centrally located lesions or in chondromalacia changes
      occurred at the time of surgery.

PMID- 8651000
TI  - [Osteochondrosis dissecans of the humeral head].
AB  - Osteochondritis dissecans is most frequently seen at the knee, the elbow and the
      ankle joint. The localisation at the humeral head is very rare. There were 7
      cases like this reported up to now. We present two more patients with
      osteochondritis dissecans of the humeral head; a 26-year-old man and a 36-year
      old woman. For diagnosis and follow-up roentgenograms and MRI are used. MRI even
      helps to decide which operative strategy should be followed. Drilling of the
      sclerotic margin resulted in a satisfactory bony reintegration of the fragment in
      our male patient. The female patient refused an arthroscopy of her shoulder
      joint.

PMID- 8651001
TI  - [Role of transcranial magnetic stimulation in the diagnosis of cervical root
      compression and cervical myelopathy].
AB  - We were interested in the question, if transcranial magnetic stimulation of nerve
      structure can be used in the objective description of motor impairment in humans
      with cervical nerve root compression and myelopathies. We could demonstrate, that
      paresis is combined with an increase of the latency of the evoked muscle
      potentials. Applications of the method in Orthopaedics and Neurosurgery involve
      description of motor deficits in cervical compression radiculopathy and
      myelopathy. Although the value of the method for orthopaedic and neurosurgical
      purposes is not yet clear, our experiences indicate interesting diagnostic
      possibilities in cervical spine diagnostics.

PMID- 8651002
TI  - [Long-term treatment outcome in ventral and combined ventrodorsal spondylodesis
      in the surgical therapy of scoliosis].
AB  - We report on 48 patients with a mean postoperative follow-up of 7.7 years. 9
      patients underwent simple anterior derotation spondylodesis (VDS), 31 patients
      were additionally fused with posterior Harrington spondylodesis. In 7 of 8
      patients the Dwyer compression spondylodesis (DCS) was completed with the
      Harrington instrumentation. 2 of 3 scoliosis were idiopathic, the residual cases
      were mainly neuromuscular. The primary curve (preoperative mean: 69.9 degrees)
      was initially corrected by 62.8% and sustained a loss of correction of 7.6
      degrees resp. 10.9% during long-term follow-up. The long-term loss of correction
      was maximal after DCS showing 10.4 degrees (14.4%), on the average, and minimal
      after combined VDS and Harrington spondylodesis showing 6.9 degrees (9.3%). After
      simple VDS the long-term progression of the curve was 7.0 degrees (12.9%). In
      this group the initial correction was above-average high showing 76.4%. The main
      loss of correction occurred during the first 2 years after surgery. The long-term
      correction stability did not show significant differences between simple VDS and
      combined antero-posterior instrumentation. After anterior instrumentation of the
      primary curve the secondary cranial nerve spontaneously straightened up by 30%,
      on the average, and remained stable in the long-term. The anterior
      instrumentation of the spine lead to a mean loss of lordosis of 13.6 degrees
      which in the long-term additionally increased by 6.4 degrees due to the anterior
      epiphyseodesis effect. In 17 patients (42.5%) 24 fractures of the 3 mm-threaded
      VDS-compression rod occurred. In case of single rod fractures no higher loss of
      correction or differences in incidence of pain were observed in comparison to
      intact implants.

PMID- 8651003
TI  - [Long-term results in revision surgery following lumbar disk nucleotomy]].
AB  - In 6.26% of 846 patients with lumbar disc surgery a reoperation was necessary. A
      total of 93 patient had undergone a revision surgery inclusive a patient group
      with primary surgery performed elsewhere. 68 patient had 1 reoperation, 22
      patients 2, 2 patients 3, and one patient had even 4 revisions. Follow-up ranged
      between 19 and 42 years with an average of 31 years. 53 patients were clinically
      examined at a time of follow up and another 15 patients answered a questionnaire.
      An excellent result with no complaints and patients able to work could be
      achieved in only 16%. A good result with no radicular pain, but some minor back
      pain and some loss of sensibility and ability to work was found in 24%. In 40% of
      the patients the result was only fair with some radicular pain and limited
      capability for work. 20% of the patients had only a poor result with unchanged
      symptoms and continued therapy. Those patients were not able to work. Young and
      female patients had a better prognosis. Another positive predictor was a short
      period of preoperative pain. Negative predictors were multiple prior operation as
      well as scar tissue at time of revision. Also spondylodesis according to Cloward
      correlated also with a negative clinical outcome.

PMID- 8651005
TI  - [Prevention of cardiovascular diseases by hormone replacement in postmenopause].
AB  - Cardiovascular disease is the most important cause of death even among women.
      After menopause there is a steep increase in risk factors like LDL-cholesterol
      and lipoprotein (a) as well as the incidence of hypertension and diabetes
      mellitus. This is followed by a rise especially in coronary artery disease.
      Therefore women too have to be included in prevention programs for cardiovascular
      disease by normalizing risk factors. One means is hormone replacement therapy.
      Estrogens lower LDL-cholesterol by up to 20% and increase HDL-cholesterol up to
      30%. This effect remains even after addition of a suitable progestin. Numerous
      large scale studies indicate that every other cardiovascular death can be
      prohibited by the simple measure of hormone replacement therapy. Because of the
      high rate of cardiovascular disease low incidences of adverse events cannot
      prevent the marked decrease in total mortality.

PMID- 8651004
TI  - Hormone replacement therapy and vaginal bleeds. Theoretical aspects and clinical
      management.

PMID- 8651006
TI  - [Long-term observations of the extent and reversibility of bone demineralization
      after leuprorelin acetate depot therapy].
AB  - Therapy of endometriosis with a GnRH-agonist (Leuprorelin) demonstrated a good
      therapeutical efficiency. As a side effect it had a significant negative impact
      on trabecular bone mass (non significant on cortical bone) as measured by DXA.
      Rising levels of Osteocalcin indicated the stimulation of bone remodelling. Three
      years after the end of the therapy a long term follow up control was able to
      detect the complete recovery of the mean density values in the extremities with
      even higher values in some patients compared with the initial measurement. In the
      spine half of the patients reached or surpassed the initial values. Regarding the
      patients history the differences in the recovery were obviously due to a
      different lifestyle especially body exercise, and not due to a different reaction
      to the GnRH-agonist therapy. Without being able to predict the individual bone
      loss due to a GnRH agonist therapy the results of this study indicate that the
      transient oestrogen deficiency does not result in a relevant long term bone loss
      or an elevated risk of osteoporosis. On the other hand in case of known risk
      factors or of a prolonged or repeated GnRH-agonist therapy the individual bone
      density and the individual bone loss should be controlled by DXA. Those patients
      with a significant negative impact on their bone mass then can be treated
      directly.

PMID- 8651007
TI  - [Symptoms of ovarian failure after hysterectomy in premenopausal women. A
      retrospective study based on postoperative perception of 245 women].
AB  - A total of 437 patients who had undergone hysterectomy in the department of
      Obstetrics and Gynaecology, Heinrich Braun Clinic, Zwickau, between 1982 and 1992
      were asked about vegetative and psychological problems after the operation. All
      were under 42 years old and had at least one ovary left intact. In all, 245 women
      returned the questionnaires. After hysterectomy 26.1% reported ovarian failure
      and 36.7% did not observe typical menopausal symptoms. Symptoms were
      significantly more frequent in patients where ovary had been removed. It made no
      difference whether a vaginal or an abdominal incision had been made. Psychic
      problems were reported by 17.6% of the patients. Patients with ovarian failure
      had more negative symptoms. Postoperatively, 34 women received hormonal therapy,
      and 10 of them finished the therapy successfully. The rate of ovarian failure and
      psychic symptoms can be reduced by adequate information before and after
      hysterectomy. A decision to perform a hysterectomy should be made only if the
      operations is strictly indicated. Prophylactic oophorectomy should not be
      performed in patients under 50 years. Effective hormonal substitution is
      recommended for patients with menopausal symptoms.

PMID- 8651008
TI  - [Complications in HELLP syndrome due to peripartal hemostatic disorder].
AB  - 43 cases with severe preeclampsia with HELLP syndrome were observed out of 14890
      deliveries from 1980 to 1993 in the Department of Obstetrics and Gynecology,
      University of Mainz. In 17 cases there were grave complications (14 renal
      failure: 3 patients requiring dialysis; 6 bleedings: abdominal wall hematoma in 5
      patients after caesarean section, 1 rupture of the liver; 3 pulmonary
      complications; 9 cerebral complications: 7 eclamptic convulsions, 1 amaurosis
      caused by partial infarction of the posterior cerebral artery, 1 sinus venous
      thrombosis). The plasmatic blood-clotting factors were in the normal range,
      except for 2 cases. In 27 patients TAT and D-dimers were determined. In 17 of
      these 27 patients TAT and D-dimers increased up to extreme levels (TAT > 20
      micrograms/l and D-dimers > 1000 micrograms/l). In 12 of these 17 patients,
      complications occurred during in the course of the disease (70%). On the other
      hand, only 3 out of 12 patients (30%) with a low activation of blood coagulation
      (TAT > 10 and < 20 micrograms/l; D-dimers > 800 and < 1000 microgram(s)/l) had
      shown complications. It is suggested that the early determination of TAT and D
      dimers may help to avoid complications.

PMID- 8651009
TI  - [Sexual development of Czech girls before and after the "Velvet Revolution"].
AB  - Sexual development and behavior of 771 Czech girls 16 to 18 years old had been
      investigated by two sexuologists during the period of 1986 till 1994. A
      standardized interview of 78 items had been applied in a setting of a
      rehabilitation facility in Franzensbad. The majority of probands were there for
      rehabilitation after appendectomy. There were 389 examinees (158 apprentices and
      231 students) interviewed before "the velvet revolution" and 382 girls (159
      apprentices and 223 students) in the course of the years 1990 to 1994. A
      comparison of these two groups revealed a definite change in the psychosexual
      development of girls in the Czech society after the "Velvet Revolution".
      Particularly the motivation for the first coitus had changed. After November 1989
      it was noticed that the answer "obliged her partner" had significantly decreased
      and the answer "wished it for myself" has substantially increased. Also in the
      group of probands with multiple sexual partners (21.5% of the sample) their
      average number decreased unexpectedly after "the Velvet Revolution".

PMID- 8651010
TI  - [Type I allergy to latex after gynecologic examination].
AB  - A case of a 32 year-old woman with a allergic reaction of latex gloves is
      described. Due to the obviously increasing number of latex-related allergies,
      especially in atopic persons and patients with frequent latex exposure, the exact
      history is highly significant. If a latex-related allergy is suspected, all latex
      or rubber-containing materials have to be consequently avoided. The diagnosis of
      latex allergy should be verified by testing and Latex-RAST.

PMID- 8651011
TI  - [Intentional incision of the urinary bladder during complex gynecologic oncologic
      operations].
AB  - Extraperitoneal incision of the bladder is recommended for difficult gynecologic
      oncologic operations. Cystostomy facilitates dissection of the bladder and helps
      to prevent injury of the distal ureter. Six cases are reported (2 cervical
      carcinomas, 2 ovarian carcinomas, 1 vaginal carcinoma, 1 sarcoma) to illustrate
      the indication and technique of cystostomy.

PMID- 8651012
TI  - [Multiparity in Nicaragua].
AB  - The relation between birthweight and parity of the mother was examined in
      Nicaraguan patients from the capital Managua. 7431 births were taken into
      consideration from 1989-1991. 564 (= 7.6%) of these newborns were born to mothers
      with more than 5 deliveries. A positive correlation between the increasing number
      of the parity and the birthweight can be demonstrated in our patients until
      parity 10, however there are decreases in the birthweight of female newborns
      between parity 3 to 4 and 5 to 6 and in males between parity 6 to 7 and parity 8
      to 9. The average age of a Nicaraguan primipara is 20.7 years and increases by
      1.9-2.4 years until parity 5. From parity 6 to parity 15 it increases only by 0.7
      1.2 years.

PMID- 8651013
TI  - Should Burch colposuspension be replaced by fibrin glue colpofixation in women
      with urinary stress incontinence?
AB  - There are lots of articles recently concerning a very successful fibrin glue
      colpofixation used in treating stress urinary incontinence (SUI) instead of
      sutures according to Burch colposuspension [6, 5, 4]. Being in doubt about each
      modification of the original Burch surgery method, in spite of reported good
      results, I have decided to explain my own opinion concerning this problem.
      According to recent knowledge of the lower urinary tract anatomy, described by
      DeLancey and S. Raz [3, 11], supporting factors of the vesical neck as a part of
      the continence mechanism in women is more understandable.

PMID- 8651014
TI  - The cellular dermal infiltrate in experimental immediate type cutaneous
      hypersensitivity.
AB  - A previously developed guinea pig model for the study of the dermal inflammatory
      cell infiltrate of allergic, toxic, and irritant reactions was adapted to the
      study of the immediate intradermal reaction to ovalbumin. Comparison of
      qualitative and quantitative counts of infiltrating cells at three levels in the
      dermis showed that counting 20 subepidermal fields starting from the injection
      point of the allergen gave reliable figures. The reaction showed microscopically
      two phases. The first was of rapid onset and characterized by a high proportion
      of neutrophils, unlike the picture seen in the previously studied (allergic and
      toxic) reaction types. In the second phase, which can be termed "late phase"
      reaction, mononuclear cells and basophil granulocytes predominated. The late
      phase of the reaction bears similarities to the delayed allergic contact reaction
      at the same timepoint in that the response was rich in basophils. There were,
      however, other differences; e.g. eosinophils and neutrophils were more common.

PMID- 8651015
TI  - Frequency and activity of IgE-secreting peripheral blood B-cells in atopic
      eczema.
AB  - Increased immunoglobulin (Ig) E-levels are frequently found in the sera of
      patients with atopic eczema. To further understand the mechanisms underlying this
      increase of IgE, like enlarged number of IgE-producing cells, enhanced activity
      of IgE-producing cells or altered IgE metabolism, we analyzed the frequency and
      activity of IgE-producing B-lymphocytes within peripheral blood mononuclear cells
      of patients with atopic eczema. By use of a sensitive solid phase enzyme-linked
      immunospot assay (ELISPOT), IgE-secreting cells could be visualized within
      peripheral blood mononuclear cells of 14 individuals (12 patients with atopic
      eczema, one patient with impetigo contagiosa, one patient with allergic contact
      dermatitis) at a frequency of 10-1,120 IgE-secreting cells/10(5) B-lymphocytes.
      The number of IgE-secreting cells was markedly correlated with the corresponding
      serum IgE-level (r = 0.97). Secretory activity was also reflected by in vitro IgE
      production, which was assessed in parallel 7-day cultures and found to be related
      with actual serum IgE-levels. The enhanced serum IgE-levels in patients with
      atopic eczema seem to result primarily from an increased number of circulating
      IgE-secreting B-cells, which may also be found, however, in patients with
      elevated serum IgE-levels, showing different skin diseases.

PMID- 8651016
TI  - Pruritogenic effects of mitogen-stimulated peripheral blood mononuclear cells in
      atopic eczema.
AB  - The etiology of atopic pruritus is unclear and seems mostly histamine
      independent. In order to investigate non-mast cells as possible sources of
      pruritogenic agents, peripheral blood mononuclear cells from 12 atopic eczema
      patients and 12 controls were incubated in vitro for 24 h with phytohemagglutinin
      or concanavalin A (both at 10 micrograms/ml) or with medium alone, and each
      subject was tested with his own cell supernatants and lysates by prick testing
      and by application on tape-stripped skin. Histamine (0.1%) and substance P (500
      microM) were tested in comparison, and reactions were observed for up to 24 h.
      Cell supernatants were also analysed for their contents of several cytokines.
      Lymphocyte cell extracts or supernatants failed to cause symptoms in controls but
      induced whealing in 6 and itching in 3 patients on prick testing within 5 min,
      lasting for 30 min in 2 patients and persisting for 6 h in 1 patient. Histamine
      caused itching in all controls and in 7 patients within 5 min on prick testing,
      with decreasing reactivity at later times. Substance P yielded results with lower
      values. With all three types of test reagents, fewer subjects reacted on tape
      stripped skin. High levels of interleukins 2 and 6, low levels of interferon and
      no detectable levels of interleukin 4 and tumour necrosis factor were measured in
      stimulated cell supernatants and extracts, with even lower levels in subjects
      exhibiting skin reactivity. These findings thus provide evidence that as yet
      unidentified mononuclear cell products may be involved in whealing and itching
      associated with atopic eczema.

PMID- 8651017
TI  - Objective assessment of the skin of children affected by atopic dermatitis: a
      study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin.
AB  - In order to obtain objective data on skin functions in subjects with atopic
      dermatitis (AD), according to the different phases of the disease, we evaluated
      the skin of children with AD instrumentally and compared it to that of healthy
      subjects of the same age group. One hundred patients, aged 3 to 12, and 21
      healthy children were studied by means of measurements of pH, capacitance and
      transepidermal water loss (TEWL) at 8 different skin sites. At the moment of the
      investigation 55 children out of 100 presented skin lesions on at least one of
      the assessed skin areas, whereas 45 had been free from eczema for at least 1
      month. Considering all skin sites together, significant differences were found
      between mean values of pH, capacitance and TEWL of eczematous skin, both in
      respect to those referring to apparently healthy skin in the same patients and in
      respect to the skin of control subjects. Moreover, TEWL, pH and capacitance
      values referring to uninvolved skin of AD patients significantly differed from
      those of healthy subjects. Finally, when values referring to patients with skin
      lesions and to patients without lesions were separately considered, significant
      differences concerning the parameters of uninvolved skin were observed. These
      data show that, in subjects with AD, skin functions undergo fluctuations
      according to the phase of the disease and support the hypothesis that the
      presence of active eczema determines an impairment of the barrier of uninvolved
      skin, even at sites far from active lesions.

PMID- 8651018
TI  - Acetylcholine induces different cutaneous sensations in atopic and non-atopic
      subjects.
AB  - The mediators eliciting pruritus in atopic eczema are a matter of discussion,
      since several substances may be involved and histamine is unlikely to be the main
      agent. Hence, in this study we examined the cutaneous sensations and vascular
      reactions in 15 patients with atopic eczema and in 15 non-atopic subjects after
      i.c. injection of acetylcholine (Ach, 0,5 M, 20 microliter) or buffered saline,
      respectively. The sensory perceptions were rated by a visual analogue scale (VAS)
      as to quality and intensity, and the vascular reactions were monitored by laser
      Doppler flowmetry and evaluated planimetrically as to flare and wheal extension.
      The flares and wheals in both groups were similar; yet the cutaneous sensations
      significantly differed, since all patients with atopic eczema complained of
      "pure" itching after Ach-injection, whereas the controls reported a burning pain.
      The patients with atopic eczema started their ratings significantly earlier and
      rated significantly longer than the controls. Our results provide evidence that
      Ach may play an important role in the etiology of pruritus in atopic eczema
      patients.

PMID- 8651019
TI  - The dynamics of the response of normal skin to single and multiple epicutaneous
      leukotriene B4 applications analysed by three-colour flow cytometry.
AB  - Leukotriene B4 (LTB4) is a potent chemoattractant and a well-established
      stimulator of DNA-synthesis in keratinocytes. Previously, repeated applications
      of LTB4 have been reported to induce a topically defined tachyphylaxis with
      respect to the extravasation of polymorphonuclear neutrophils. The aim of the
      present study was to quantify epidermal proliferation (% basal keratinocytes in S
      and G2M phase), epidermal keratinization (% keratin 10-positive keratinocytes)
      and the appearance of "non-keratinocytes", including melanocytes, Langerhans'
      cells and infiltrate cells (% vimentin-positive cells) in order to further
      elucidate the effect of chronic exposition of normal skin to LTB4. Using three
      colour flow cytometry, we could reconfirm that the response to one single
      epicutaneous application of LTB4 was characterized by a marked increase of the
      percentage of basal keratinocytes in S- and G2M phase, and a marked increase of
      non-keratinocytes. Repeated applications of LTB4 induced a moderate increase of
      the percentage of cells in S- and G2M phase and a moderate increase of the
      percentage of keratin 10-positive keratinocytes. Remarkably, the percentage of
      non-keratinocytes had decreased following repeated applications of LTB4, compared
      to unchallenged normal skin. The present study suggests that chronic exposure of
      normal skin to LTB4 induces changes which differ markedly from the histological
      features of the chronic psoriatic lesion. Therefore, LTB4 is unlikely to be
      responsible for the perpetuation of the psoriatic plaque.

PMID- 8651020
TI  - Quantitative description of echographic images of morphea plaques as assessed by
      computerized image analysis on 20 MHz B-scan recordings.
AB  - In order to find image descriptors enabling the characterization of sclerotic
      skin of morphea plaques and their objective differentiation from normal skin, we
      studied 52 lesions in 35 patients affected by plaque type morphea. Echographic
      evaluations were carried out using a 20 MHz B-scanner, providing cross-sectional
      images of the skin. Images were processed by a program providing a numerical
      representation of the picture data, based on the following parameters, which were
      considered for 7 different amplitude intervals: 1) the extension of image areas
      marked by amplitude bands of interest, 2) the percentage of the image surface
      reflecting within a homogeneous amplitude band, 3) the number of objects
      composing the image, 4) the average object size, and 5) the "density" of the
      objects. For all parameters considered, marked differences between sclerotic skin
      and normal tissue were observable. When assessment is performed with amplitude
      bands covering the lower part of the scale, the image referring to sclerotic
      tissue appears relatively homogeneous with few, large objects within a thickened
      skin block, which occupy a more extended image surface in comparison to images of
      normal skin, characterized by spots, which are small and closely packed. On the
      contrary, binary images of morphea plaques transformed by intermediate to high
      amplitude intervals appear with fewer objects of approximately the same size or
      smaller, which are less compressed in respect to healthy skin images.

PMID- 8651021
TI  - Single cilia in human epidermis are susceptible to challenge.
AB  - Single cilia were found in melanocytes and basal keratinocytes in normal
      epidermis and in epidermis subjected to various types of exposure. Quantitative
      electron microscopy showed that about 31% of the melanocytes and 71% of the
      keratinocytes from normal skin possessed a ciliary apparatus, but there was a
      wide individual variation. A statistically significant decrease in the number of
      ciliated keratinocytes followed exposure to nickel, sodium lauryl sulphate, UVA
      and UVB irradiation. There was no statistically significant difference between
      controls and skin subjected to various exposures regarding the number of ciliated
      melanocytes. We have earlier reported that single cilia are frequently seen on
      epithelial cells capable of mitotic activity in human oral and vaginal epithelia.
      The present study showed that single cilia react to external exposures. The
      cilium might be a sensitive, easily damaged organelle, or the decrease in
      ciliated cells might reflect a change in normal mitotic activity as a result of
      exposure.

PMID- 8651022
TI  - The presence of body hair influences the measurement of skin hydration with the
      Corneometer.
AB  - Techniques for the assessment of skin hydration are often based on the electrical
      properties of the stratum corneum. A commonly used instrument for measurements of
      skin moisture is the corneometer, which detects changes in the dielectric
      constant of the material in contact with the probe. It has been suggested that
      different materials, for example cream residues and desquamating scales, may
      interfere with the Corneometer readings, but this question has not been settled
      conclusively in previous studies. In the present study the influence of body hair
      was examined. Significantly lower Corneometer values were obtained on the dorsal
      aspect of the forearm than on the volar aspect (p < 0.05), indicating that the
      former region was less hydrated than the latter. After shaving of the skin,
      however, there was no difference in the Corneometer readings between the two
      regions. Thus, the presence of hair needs to be considered when the hydration
      status of the skin is examined with the use of a Corneometer.

PMID- 8651023
TI  - Age-related regional variations of human skin blood flow response to histamine.
AB  - The process of ageing involves many changes in the skin. These changes are not
      necessarily uniform, so the pattern of regional variations may vary with ageing.
      The aim of the present study was to assess age-related regional variations in
      skin function, by measuring the cutaneous microvascular response to histamine.
      Histamine was topically applied to the back and forearm of a young and an aged
      group of volunteers (n = 28, 14 in each group), and the response was quantified
      utilizing laser Doppler flowmetry. The following parameters were calculated from
      the data and compared between the two groups: (i) peak response; (ii) the time
      required to reach the peak; (iii) the time required to decay to half the peak
      flow; and (iv) the area under the response time curve. For the young group, the
      magnitude of the maximum response, as well as the extent of the response as
      measured by the area under the response curve, were significantly greater on the
      back than on the forearm (p < 0.01 and p < 0.05, respectively). In contrast, for
      the aged group, the two sites did not significantly differ from each other. The
      time required to reach the peak was longer in the aged group over both sites, and
      so was the time required to decay to half the peak flow. These observations
      indicate regional anatomical or functional differences between old and young
      skin, which may provide insight into inherent differences influencing cutaneous
      manifestations of endogenous and exogenous diseases in various age groups.

PMID- 8651024
TI  - Functional changes in human stratum corneum induced by topical glycolic acid:
      comparison with all-trans retinoic acid.
AB  - The effects of topical glycolic acid and all-trans retinoic acid on stratum
      corneum barrier function and hydration of human skin were investigated in 6
      healthy volunteers utilizing non-invasive techniques. In addition, changes in
      stratum corneum turnover time induced by the substances were examined using the
      dansyl chloride fluorescence test. Twelve percent glycolic acid in water and 0.1%
      retinoic acid in ethanol, respectively, were applied for 60 min once daily, over
      a period of 2 weeks (5 consecutive days weekly) on dansyl chloride-labelled skin
      and on untreated skin. During a 10-day application period, both glycolic acid and
      retinoic acid similarly induced a significant increase in TEWL. However, after
      discontinuing treatment, TEWL in retinoic acid-exposed skin remained increased.
      Glycolic acid significantly reduced stratum corneum hydration from day 11 to day
      18 (p < 0.05), while retinoic acid induced skin dryness after 9 days of
      treatment, which persisted until day 18 (p < 0.005). Whereas glycolic acid
      rapidly induced an intense erythema implying a direct non-specific inflammatory
      response, the retinoic acid-exposed skin gradually developed erythema. Retinoic
      acid caused scaling to a greater extent than did glycolic acid, even after
      treatment cessation. Both glycolic acid and retinoic acid significantly decreased
      stratum corneum turnover time and stratum corneum turnover time50 (the time in
      days from labelling until approximately 50% of fluorescence disappeared),
      compared with the vehicle controls. However, glycolic acid shortened stratum
      corneum turnover time (12.8 +/- 0.9 days) as well as stratum corneum turnover
      time50 (7.3 +/- 0.7 d) significantly more than did retinoic acid (15.8 +/- 0.7 d
      and 9 +/- 0.8 d, respectively). While ethanol (vehicle of retinoic acid) slightly
      but significantly decreased stratum corneum turnover time (p < 0.05), water
      (vehicle of glycolic acid) did not. This study showed that both glycolic acid and
      retinoic acid induced certain functional changes in stratum corneum, mirroring
      their irritation potential. However, changes at retinoic acid-exposed sites
      appeared longer-lasting, implying a distinct mode of action. An increase in
      stratum corneum turnover induced by the substances may be, in part, linked with
      their irritation properties.

PMID- 8651025
TI  - Epidermal proliferation is not impaired in chronic venous ulcers.
AB  - In this study we have investigated epidermal growth and differentiation during
      wound healing in human skin. The studies were performed in excisional wounds in
      normal skin and in chronic venous ulcers. Tissues were analyzed by
      immunohistochemical staining for proliferation-associated nuclear antigens (PCNA
      and Ki-67 antigen) and cytokeratin 16. Healing of excisional wounds was studied
      from day 2 to 14. Recruitment of resting (G0) epidermal cells started within 2
      days after wounding; the number of cycling cells was maximal at day 4 and
      continued to be increased (compared to baseline levels in normal skin) after
      wound closure (7-14 days). Cytokeratin 16, a proliferation-associated keratin,
      was induced within 48 h and was expressed in the suprabasal keratinocytes of the
      wound edge. Cytokeratin 16 expression was maximal at day 4 and was still present
      in the neo-epidermis after restoration of epidermal continuity (7-14 days).
      Surprisingly, in chronic venous ulcers, cycling cells were present in the wound
      edges of all stages of the leg ulcers studied. Both the number and localization
      of cycling cells were similar to those in normal wound healing. Cytokeratin 16
      was strongly expressed in all these ulcers. Our in vivo data demonstrate that
      recruitment of G0-cells into the cell cycle is not impaired in venous ulcers,
      which suggests that epidermal proliferation is not a limiting factor in the
      healing process of chronic venous ulcers.

PMID- 8651026
TI  - The guinea pig maximization test--with a multiple dose design.
AB  - The guinea pig maximization test (GPMT) is usually performed with one moderately
      irritant induction dose of the allergen and gives a qualitative assessment-hazard
      identification-of the allergenicity of the chemical. We refined the GPMT by
      applying a multiple dose design and used 30 guinea pigs in a test divided into a
      control group and 5 test groups of 5 animals. Each group was treated with
      different induction concentrations of the allergens: formaldehyde, cinnamic
      aldehyde, propyl paraben, lidocaine, mercaptobenzothiazole or
      chlormethylisothiazolinone/methylisothiazolinone. The test results were analysed
      using a logistic multidose response model. The precision of the results depends
      only on the total number of animals, the dose design and the response pattern.
      The maximal sensitization rate for a chemical was determined, and the
      intracutaneous induction concentration that sensitized 50% of the animals (EC50)
      (or another percentage) was estimated. Further studies are needed to prove the
      validity of this idea. However, improvements in protocols for the GPMT are needed
      to reduce interlaboratory variability in results and to reduce the number of
      animals used for allergenicity tests.

PMID- 8651027
TI  - Anal and penile condylomas in HIV-negative and HIV-positive men: clinical,
      histological and virological characteristics correlated to therapeutic outcome.
AB  - Clinical, histological and HPV DNA hybridization findings were analyzed for 73
      homosexual and 38 heterosexual men attending for anal warts; therapy results were
      evaluated retrospectively for 76 of these patients. Concurrent anal and penile
      warts occurred most commonly in the heterosexual men (p < 0.001). While perianal
      warts were most common in heterosexuals (p < 0.05), intraanal warts were most
      common in homosexuals (p < 0.001). Altogether 23 homosexual men were HIV
      infected; 13 HIV-positive men followed regarding therapeutic outcome were
      immunologically relatively intact with mean CD4 counts of 524/mm3. Of 136 biopsy
      specimens 70% revealed benign hyperplasia, 27% AIN I, 2% AIN II and none AIN III.
      Of ISH positive samples 94% contained HPV 6/11 and 6% HPV 16/18/31/33. Anal warts
      were cured after an average of 2.5 (mean 1-10) therapy sessions in 64% of
      heterosexual, in 84% of HIV-negative homosexual and in 62% of HIV-positive
      homosexual men. The mean number of therapy sessions against anal warts was
      highest (p < 0.001) and the time for accomplishing cure for anal and penile warts
      was longest (p < 0.001) in the heterosexual study group.

PMID- 8651028
TI  - Acro-angiodermatitis: review of the literature and report of a case.
AB  - Acro-angiodermatitis is a very common disorder, with a close clinical, anatomical
      and morphological resemblance to Kaposi's sarcoma. Several types of this disorder
      can be found in different settings. However, these conditions are often
      misdiagnosed and therefore mistreated. A review of the literature and a
      classification of all types of acro-angiodermatitis are presented. We also
      describe a case of a patient with acro-angiodermatitis which completely regressed
      following a course of dapsone combined with leg elevation and elastic support
      stockings.

PMID- 8651029
TI  - Setleis' bitemporal "forceps marks" syndrome in a Japanese family.
AB  - Setleis' syndrome is an uncommon inherited condition characterized by bilateral
      "scarlike" depressions on the temples and a wide spectrum of associated facial
      abnormalities. We report on a typically affected Japanese boy, whose mother and
      grandfather show a much milder expression of this disorder, suggesting an
      apparent autosomal dominant inheritance.

PMID- 8651030
TI  - Psoriasis and hepatitis C virus.
AB  - We have analyzed 8 patients (6 men and 2 women, aged 52 to 70 years) with
      psoriasis associated with hepatitis C virus (HCV) infection among 79 psoriatic
      patients. Psoriasis preceded in 6 cases. One patient had generalized pustular
      psoriasis (GPP), and the others had psoriasis vulgaris (PV). The psoriasis area
      and severity index (PASI) score ranged from 2.7 to 32.4. Two of the patients were
      treated with interferon-gamma. Anti-HCV antibodies were detected in all cases by
      second generation enzyme-linked immunosorbent and recombinant immunoblot assay.
      HCV messenger RNA was demonstrated by reverse transcriptase polymerase chain
      reaction in the tissue sections of the lesions of 1 of the patients with PV and
      the patient with GPP, providing evidence for active viral replication in the skin
      lesion. HCV-related chronic active hepatitis might cause several immunological
      abnormalities. It is suggested that this infection might be one of the triggering
      factors of psoriasis.

PMID- 8651031
TI  - Pseudoallergen-free diet in the treatment of chronic urticaria. A prospective
      study.
AB  - In chronic urticaria, the possible pathogenetic role of pseudoallergic reactions
      to food has been repeatedly discussed, but stringent prospective studies
      regarding their clinical significance are not available. All patients with
      chronic urticaria and/or angioedema hospitalized at the department of dermatology
      during a period of 2 years were therefore included in a prospective study.
      Patients (n = 64) were screened for common causes of urticaria and then evaluated
      for possible benefits of a stringently controlled pseudoallergen-free diet.
      Double-blind, placebo-controlled oral provocation tests with food additives were
      performed on those patients benefitting from diet. In 73% of patients, symptoms
      ceased or were greatly reduced within 2 weeks on diet, although only 19% of them
      responded to individual pseudoallergens on provocation tests. Of the remaining
      patients, 11% responded to treatment of an associated inflammatory disease, and
      in 16%, no cause of the urticaria was ascertained. Follow-up at 6 months after
      hospitalization showed complete remission on diet in 46% and lasting improvement
      in all but one of the remaining patients on diet. An additive-free, stringently
      controlled diet thus provides a simple means of diagnosing and treating the
      majority of patients with chronic urticaria.

PMID- 8651032
TI  - Solar pruritus.
AB  - A case of solar pruritus is reported. Severe pruritus of the back, shoulders and
      upper lateral aspects of the arms, without any eruption, developed in a 28-year
      old outdoor worker during 4 to 6 weeks of intensive solar exposure. The pruritus
      was intense and described as a burning sensation deep in the skin. Only a few
      excoriations and slight xerosis were found. Solar pruritus or brachioradial
      pruritus is a condition primarily seen in Caucasian people living in the tropics
      or subtropics. Previously the disease has only been reported once outside these
      areas.

PMID- 8651034
TI  - The use of DAV (DTIC, ACNU and VCR) and natural interferon-beta combination
      therapy in malignant melanoma.

PMID- 8651033
TI  - Contact allergy to topical corticosteroids and systemic contact dermatitis from
      prednisolone with tolerance of triamcinolone.
AB  - We report the case of a 27-year-old female who had an allergic contact dermatitis
      to topical corticosteroids belonging to the corticosteroid groups A and D. Upon
      oral treatment with prednisolone a disseminated exanthema began within 24 h.
      Patch tests revealed sensitization to corticosteroids of group A, C and D,
      including prednisolone-21-acetate and betamethasone valerate, but not of group B
      corticosteroids such as triamcinolone. After intradermal testing of
      corticosteroids the exanthema flared again and the patient was treated with oral
      triamcinolone, with rapid improvement of her symptoms. A literature review
      revealed that exanthematous reactions after systemic treatment with
      corticosteroids have been rarely reported. Since corticosteroids are essential
      emergency drugs, a safe corticosteroid should be identified for such patients.
      Patch and intradermal tests may be used for that purpose.

PMID- 8651035
TI  - Steroid acne sparing an area of previous irradiation.

PMID- 8651036
TI  - No evidence of human papillomavirus infection in balanitis circumscripta
      plasmacellularis Zoon.

PMID- 8651038
TI  - Concordant urticaria pigmentosa in a couple of identical twins. A five-year
      follow-up.

PMID- 8651037
TI  - Langerhans' cell histiocytosis with proliferation of immature Langerhans' cells
      in the deep dermis.

PMID- 8651039
TI  - Factors influencing the development of glucose intolerance in Cushing syndrome.
AB  - BACKGROUND: Although the frequency of glucose intolerance in endogenous Cushing
      syndrome has been repeatedly evaluated, no attempt has been made so far at
      analyzing simple clinical factors in order to quantify their influence on the
      development of glucose intolerance. METHODS: The influence of 6 factors on the
      development of glucose intolerance (family history of diabetes, age and body mass
      index of patients, duration of hypercortisolism, its pathogenetic form, and the
      extent of its clinical manifestation) was evaluated by means of multiple
      regression in 74 patients with Cushing syndrome. RESULTS: The disappearance of a
      normal glucose tolerance in Cushing syndrome was a function of the time of
      duration of hypercortisolism.  The emergence of diabetes mellitus, but not of
      impaired glucose tolerance, was supported by ageing. Surprisingly, the family
      history failed to have any predictive value. CONCLUSIONS: The results suggest
      that diabetes mellitus in endogenous Cushing syndrome is a disorder genetically
      different from primary diabetes mellitus.

PMID- 8651040
TI  - Evaluation of the Cobas Core system for use in routine diagnosis of thyroid
      disorders.
AB  - The aim of this clinical study was to evaluate the TSH, FT4, FT3, T3, and T4
      assays designed for use on the Cobas Core Immunoassay Analyzer. Performance of
      these enzyme immunoassays (EIAs) was compared with well established and routinely
      used radioimmunoassays (RIA) or immunoradiometric assay (IRMA). In the first part
      of the study, the between-run and within-run data as well as the linearity of the
      Cobas Core assays was carried out, showing a very high precision; most
      coefficients of variation (CVs) were below 8%. In the second part of the study,
      serum samples from patients with different thyroid diseases were evaluated, and
      the results compared with those obtained by RIA or by IRMA. All results were
      highly comparable with the clinical aspects of all investigated thyroid
      disorders, and the data of TSH, FT4, T3 and T4 were completely in concordance
      with those assessed by RIA or IRMA methods; however, only the FT3 assays had a
      moderately correlation. In contrast to RIA methods, Cobas Core EIAs provided
      precise results in patients with thyroid hormone transport protein anomalies or
      T4/T3 autoantibodies; moreover, elevated serum concentrations of thyroxine
      binding globulin (TBG) did not affect measurement of total thyroid hormone
      concentrations.

PMID- 8651041
TI  - Vinorelbine and cisplatin in the treatment of advanced non-small cell lung
      cancer: results of a multicenter Czech study.
AB  - There is continuous discussion about the optimal treatment for patients with
      inoperable non small cell lung cancer. This is because chemotherapy can only
      improve the quality of life in a fraction of treated patients while prolonging
      survival by a couple of weeks at best. The new cytostatic drug "vinorelbine" has
      been tested in this indication during the last years. The drug has reached the
      response rate of 16 to 30% when used as monotherapy. The phase II studies proved
      the combination of vinorelbine with cisplatin to be the most efficient one and
      this combination was picked up for phase III clinical trials. The clinical trial
      with the aims to verify published data on treatment efficacy, to assess adverse
      effects of treatment and to evaluate appropriateness for routine application has
      been made in the Czech Republic. The treatment schedule was as follows: cisplatin
      (Platidiam Lachema) in a dose of 80 mg/m2 on day 1, vinorelbine (Navelbine Pierre
      Fabre) in a dose of 30 mg/m2 on days 1 and 8. The whole cycle was repeated on day
      22. The treatment was applied for 12 weeks. After that the efficacy of treatment
      was evaluated and only the patients with regression or stabilization of the
      disease continued the treatment. 44 (35%) partial remissions and 3 (2.3%)
      complete remissions were achieved in a group of 126 evaluable patients. The
      effect of treatment was evaluated as stable disease in 35 (27%) patients while
      the progression of disease occurred in 38 (30%) patients. The tolerance of
      treatment using effective antiemetic support (ondansetron or granisetron) was
      fairly good.

PMID- 8651042
TI  - [Treatment of hyperthyroidism with antithyroid drugs].
AB  - For the last 50 years the therapeutic possibilities in treating hyperthyroidism
      have comprised not only the reversible method of antithyroidal drugs but also the
      2 irreversible methods viz. surgery and application of radioiodine. Of late beta
      adrenergic blockers turned out to be an important adjuvant therapy enabling an
      early reduction in the hyper-sympathicomimetic condition of Graves's disease.
      Moreover, R-propranolol will in itself inhibit the peripheral conversion of T4 to
      T3. The selection of the method of choice is difficult to determine in the
      individual case requiring both endocrinologic knowledge and specific laboratory
      findings. Thanks to a striking reduction in the use of conventional antithyroid
      drugs it has also become possible to decrease the side effects markedly. In spite
      of far reaching investigations no reliable marker could be found in predicting
      long lasting remission following discontinuation of antithyroidal drugs. Not
      withstanding the enormous progress achieved in the pathogenesis and innummerable
      immunologic findings we are still lacking a causal therapy in treating Graves'
      disease.

PMID- 8651043
TI  - [Dilated cardiomyopathy--diagnosis and conservative therapy].
AB  - Diagnosis of dilated cardiomyopathy (IDC) is a diagnosis of exclusion. Physical
      examination of the patient, non-invasive tests and invasive tests have to be done
      to exclude secondary dilated cardiomyopathies. Treatment can be divided into
      baseline therapy, established treatment, e.g. ACE-inhibitors, digitalis and
      diuretics and optional treatment including betablocker, anticoagulation and an
      natural course of IDC for an individual patient is not clear although there are
      several prognostic parameters for this disease.

PMID- 8651044
TI  - [Obesity: physiology and possibilities for treatment].

PMID- 8651045
TI  - [Effect of dexfenfluramine on eating behavior and body weight of obese patients:
      results of a field study of Isomeride in Austrian general practice].
AB  - In a multicenter study by 243 practicing physicians in Austria 819 severely obese
      subjects of both sexes without overt disease were encouraged to keep a calorie
      restricted diet to reduce weight. After a run-in period of more than two weeks of
      dieting patients started taking 15 mg dexfenfluramine (Isomeride) twice daily for
      three month. While their weight was fairly stable during the run-in period
      progressive weight loss occurred during taking dexfenfluramine due to obvious
      changes in eating habits and appetite allowing to keep the reducing diet more
      strictly. Females lost 7.7 +/- 3.9 kg while obese men lost 9.32 +/- 4.6 kg.
      Laboratory tests obtained before starting dexfenfluramine and after 3 months at
      termination of medication showed blood glucose, cholesterol, LDL and
      triglycerides to decrease while HDL-cholesterol increased moderately.
      Dexfenfluramine was well tolerated by the majority of patients. Side effects such
      as fatigue, sedation, flatulence or diarrhea occurred in only 7.9% of the
      probands initially and dropped to 2.1% during the third month of the medication.
      It is concluded that Dexfenfluramine modifies eating habits and appetite thus
      making weight reducing diets easier acceptable and resulting in weight loss. It
      is suggested that Dexfenfluramine has a role in treatment regimes for morbid and
      refractory obesity.

PMID- 8651047
TI  - Which inhalation anaesthetic agent is best for pediatric use?

PMID- 8651046
TI  - Cardiovascular and autonomic effects of sevoflurane.
AB  - This review focuses on the effects of the newest volatile anesthetic,
      sevoflurane, on the cardiovascular system. In general, the cardiovascular effects
      of sevoflurane are quite similar to isoflurane but quite different from
      desflurane. Sevoflurane is not associated with increases in heart rate in adult
      patients and volunteers whereas higher MAC of isoflurane and desflurane and rapid
      increases in the inspired concentrations of these two agents have been associated
      with increased heart rates in unstimulated volunteers. Increasing concentrations
      of sevoflurane progressively decrease blood pressure and this decrease appears
      similar to isoflurane and desflurane. Sevoflurane is a less potent coronary
      vasodilator than isoflurane in rodents and it has not been associated with
      coronary steal in a dog model. Sevoflurane decreases myocardial contractility
      similar to equi-MAC concentrations of isoflurane and desflurane and does not
      potentiate epinephrine-induced cardiac arrhythmias. In several multi-center
      studies where patients with coronary artery disease or patients at high risk for
      coronary artery disease were randomized to receive either sevoflurane or
      isoflurane for cardiac or noncardiac surgery, the incidence of myocardial
      ischemia and infarction did not differ between treatment groups. Thus,
      sevoflurane has not been associated with untoward cardiovascular changes in
      volunteers and patients undergoing elective surgery and may have less potent
      effects on the vascular smooth muscle of select circulations.

PMID- 8651048
TI  - Adult clinical experience with sevoflurane and pharmaco-economic aspects.
AB  - This article has reviewed the physical-chemical properties and performance
      characteristics of sevoflurane. Both drugs provide a greater degree of control of
      anesthetic depth and a more rapid immediate recovery from anesthesia than is
      currently available with other inhaled agents because of their decreased
      solubility. Sevoflurane is currently in widespread clinical use in Japan and
      parts of Europe and the Americas. Compared to desflurane, sevoflurane has the
      additional advantage of being non-irritating to the airway; inhalation induction
      of anesthesia with sevoflurane is achieved rapidly and easily. The instability of
      sevoflurane with carbon dioxide absorbents and its in vivo biotransformation
      produce potentially toxic by-products. These by-products, including Compound A
      and fluoride have been extensively studied and although the possibility for
      iatrogenic sequella from sevoflurane exists, the likelihood of long-term toxicity
      appears quite low. Phase IV studies are indicated to determine the safety of
      administering sevoflurane: 1) to renally impaired patients, and 2) to any patient
      with fresh gas flows less than 2 liters per minute. Sevoflurane is otherwise very
      well tolerated and appears to offer the advantage of rapid and smooth induction
      and emergence from general anesthesia.

PMID- 8651049
TI  - Inhalational anaesthetics: an update.

PMID- 8651050
TI  - Metabolism and toxicity of the new anesthetic agents.
AB  - Human biotransformation of the newer anesthetics, desflurane and sevoflurane, has
      been characterized in vitro and in vivo. Major metabolites of desflurane are
      inorganic fluoride and trifluoroacyl chloride, which may bind to tissue proteins
      or form trifluoroacetic acid, which is excreted in urine. Major metabolites of
      sevoflurane are fluoride and hexafluoroisopropanolol (HFIP), which is rapidly
      glucuronidated and excreted as HFIP-glucuronide in urine. The rate of sevoflurane
      metabolism is approximately one-third that of methoxyflurane, and 1.5-2 times
      that of enflurane, while that of desflurane is minimal. The extent of metabolism
      of sevoflurane and desflurane is 2-5% and 0.02-0.2% of the dose taken up,
      respectively. Peak serum fluoride concentrations occur within one hour after
      sevoflurane anesthesia, are usually in the range of 20-40 microM, and decline
      rapidly. Fluoride concentrations have exceeded 50 microM in approximately 7% of
      sevoflurane patients. For sevoflurane, the plasma fluoride concentration-time
      profile most closely resembles that of enflurane. For desflurane, elevations of
      plasma metabolite concentrations can only be detected after prolonged anesthesia.
      Investigations to date suggest that the biotransformation of sevoflurane does not
      appear to result in clinically significant hepatotoxicity or nephrotoxicity. Only
      a single case of immune-mediated desflurane hepatotoxicity has been reported.

PMID- 8651051
TI  - [Effective mechanisms of laser photocoagulation for neovascularization in
      diabetic retinopathy].
AB  - Effective mechanisms of laser photocoagulation for neovascularization in diabetic
      retinopathy were investigated in regard to change in oxygen pressure in the
      retina and vitreous and cytokines related to ischemia. The mechanism of laser
      photocoagulation is suggested to be as follows. 1. Destruction of the outer
      retina, especially of photoreceptors that have high oxygen consumption decreases
      metabolic function of the outer retina and its oxygen consumption. 2. The
      destruction allows increase of oxygen diffusion from choroidal vessels to inner
      retina, which improves the metabolic function by equilibrating oxygen demand and
      supply in the inner retina. (3) Production and secretion of neovascular factors
      such as vascular endothelial growth factor (VEGF) is decreased by the improvement
      of hypoxia. 4. The neovascularization is decreased by the synergistic effect
      between the neovascular factors and suppressors such an VEGF, fibroblast growth
      factor (FGF), and transforming growth factor-beta (TGF-beta). The improvement of
      the retinal ischemia and the decrease of cytokines are implicated in the
      regression of neovascularization by the laser photocoagulation for diabetic
      retinopathy.

PMID- 8651052
TI  - [Glycosaminoglycans in subepithelial opacity after excimer laser keratectomy].
AB  - We evaluated histochemically the characteristics of glycosaminoglycans and
      proteoglycans in the corneal subepithelial opacity after excimer laser
      keratectomy on rabbit corneas. We also performed the same evaluations on the
      cornea after mechanical keratectomy. Twenty days after the operations, the area
      immediately subjacent to the epithelium showed strong staining with toluidine
      blue, alcian blue, and colloidal iron. However, after treatment with
      chondroitinase ABC or chondroitinase AC, alcian blue staining in this area
      decreased dramatically. Antilarge proteoglycan antibody also reacted strongly in
      this area. Histochemical and immunohistochemical examination of the cornea where
      mechanical keratectomy was done showed basically similar findings with the cornea
      of excimer laser keratectomy. These results suggest that large-molecula
      proteoglycans with chondroitine sulfate side chains become localized in the
      subepithelial area after two different kinds of keratectomies. We presume from
      histochemical and immunohistochemical observations that the subepithelial opacity
      observed after excimer laser keratectomy is not a special reaction to excimer
      laser but simply a corneal scar formed after stromal resection.

PMID- 8651053
TI  - [Vitrectomy in Coats' disease].
AB  - Four eyes of four patients with Coats' disease underwent vitrectomy because of
      exudative or tractional detachments involving the macula or premacular fibrosis.
      All cases had gelatinous vitreous and had no complete posterior vitreous
      detachment. The exudates decreased and the retina reattached after removing
      vitreous traction and coagulating abnormal vessels with endodiathermy and not
      removing subretinal fluid in 3 eyes with retinal detachment. In one eye with
      tractional detachment, retinal breaks were found beneath the proliferative
      membrane during the initial vitrectomy procedure. This eye needed multiple
      operations because of recurrent traction by the remaining peripheral vitreous.
      Exudation into the vitreous and vitreous traction may cause mutual progression in
      these eyes, and vitrectomy is an effective treatment, although there are
      difficulties in removing vitreous traction completely.

PMID- 8651054
TI  - [Multi-focal electroretinograms in normal subjects].
AB  - The multi-focal electroretinogram (multi-focal ERG), developed by Sutter (1992),
      is a method of recording the spatial distribution of focal ERG in a short time
      using multi-input stimulation. Using this technique, we can detect the spatial
      extent and severity of damage to the macula. In this study, we recorded multi
      focal ERGs from 20 eyes of 20 normal subjects and analyzed the topographical
      property of responses. In every subject, a negative wave followed by a positive
      wave could be recorded and we named them the N1-wave and the P1-wave,
      respectively. The amplitudes of the N1-wave and the P1-wave were the largest in
      the fovea and they became smaller with eccentricity. In P1-wave amplitude, the
      greatest inter-subject variability was observed at the fovea. The N1 and P1
      latencies were shorter in the upper retina than in the lower retina. The
      amplitude was larger in the upper retina than in the lower retina, which suggests
      functional superiority of the upper retina. There was no statistical difference
      of latency and amplitude between nasal and temporal retina. We found no
      statistical difference between the responses of the papillomacular bundle and
      those of the temporal retinal area. The mapping obtained by multi-focal ERG was
      useful as objective perimetry.

PMID- 8651055
TI  - [Comparison of free non-tryptophan fluorescent substances in water-soluble
      fraction of brunescent and non-brunescent human cataract].
AB  - We compared the concentrations of protein-unbound non-tryptophan fluorescent
      substances in the water-soluble fraction between non-brunescent (NBr) and
      brunescent (Br) human cataractous lens nuclei. Lens nuclei (NBr, 22 eyes: Br, 9
      eyes) from non-diabetic patients, obtained by extracapsular cataract extraction,
      were individually homogenized and centrifuged. The supernatants were subsequently
      ultra-dialyzed and assessed by high pressure liquid chromatography. 3
      Hydroxykynurenine-O-beta-glucoside (3-HKG) as well as an unidentified fluorescent
      substance was detected. While the concentrations of the former substance did not
      significantly differ between the NBr and the Br nuclei (NBr, 0.55 +/- 0.49
      mumol/g wet weight: Br, 0.90 +/- 0.64 mumol/g wet weight; p > 0.1), the
      concentration of the latter substance was significantly greater in the Br nuclei
      than in the NBr nuclei (NBr, 2.2 x 10(3) +/- 5.4 x 10(3) AU/g wet weight: Br, 1.4
      x 10(5) +/- 1.1 x 10(5) AU/g wet weight; AU: area unit, p < 0.01). An incubation
      of the dialysate with beta-glucosidase eliminated the peak corresponding to the
      latter substance. These results suggest that an unidentified protein-unbound
      fluorescent substance, which is presumably a beta-glucoside, in the lens nuclei
      is related to the coloration of human lens nuclei.

PMID- 8651056
TI  - [Complement regulatory proteins CR 1, MCP, DAF, and MACIF levels in patients with
      Behcet's disease].
AB  - We previously reported that serum complements in patients with Behcet's disease
      were extremely low just before the ocular attack. On the other hand, C3a and C5a
      levels, which have anaphylactic activity and chemotactic activity for
      polymorphonuclear leucocytes, were higher just before the ocular attack than at
      the time of the ocular attack, and there was negative correlation between C3a/C5a
      and CH50. In this report, we evaluated complement regulatory proteins. The
      results of low levels of C3b/C4b receptor (CR1) and membrane cofactor protein
      (MCP), and low tendency of decay accelerating factor (DAF) and membrane attack
      complex inhibition factor (MACIF) suggested that the function of complement
      regulatory proteins in patients with Behcet's disease decreases as a whole. But
      mean levels of both CH50 and ACH50 were significantly higher than in the
      controls. Although it is unclear which is the cause and which is the result, we
      suppose the function of complement production works excessively and these
      phenomena are caused by making up for the lack of complement regulatory proteins.

PMID- 8651057
TI  - [Optic neuritis and vitamin C].
AB  - Twenty five patients with optic neuritis (ON) of unknown etiology were treated
      with a high dosage of intravenous vitamin C. We measured blood levels of vitamin
      A, B1, B2, B6, B12, C, E, folate and zinc. All levels were compared with the
      normal values of our laboratory. The blood level of vitamin C (p < 0.001) was
      significantly less than the mean value of the normal. The blood levels of vitamin
      E, B6 (p < 0.01) and zinc (p < 0.001) also significantly decreased. Intravenous
      administration of vitamin C was given in those patients with decreased blood
      level of vitamin C. In order to compare the effect on vision by this treatment,
      the amplitude of recovery of vision, the time needed to attain the maximum
      vision, and the speed of visual recovery were analyzed. The results were compared
      with groups receiving other treatments. That is, Group A received intravenous
      administration of high dosage of vitamin C, Group B, intravenous pulse
      administration of corticosterone, Group C, oral administration of corticosterone,
      and Group D, oral administration of vitamin B12. Vision was significantly
      improved in all groups. There was no significant difference in improvement of
      visual acuity. Intravenous administration of vitamin C can be evaluated as the
      method of choice for the treatment of patients with ON. A possible mode of action
      by vitamin C on free radicals is discussed.

PMID- 8651059
TI  - [A histopathological study of corneal amyloidosis secondary to trichiasis].
AB  - We present a case of secondary corneal amyloidosis whose etiological mechanism
      was investigated by immunohistochemistry and electron microscopy. A 48-year-old
      woman had suffered from trichiasis in the right eye for 35 years, and developed
      secondary corneal amyloidosis, a phenomenon previously described but whose
      etiological mechanism has not been explained. Slitlamp examination of the cornea
      revealed a white excrescence with a diameter of 2 mm. The lesion was excised and
      examined by light and electron microscopy. Large deposits of an amorphous
      eosinophilic material were observed beneath the atrophic epithelium. Amyloid was
      detected in these deposits using Congo red stain, polarized light, and electron
      microscopy. Neither vascularization nor infiltration of inflammatory cells was
      observed. Immunohistochemical tests for protein AL, protein AA, prealbumin, beta
      2-microglobulin and cytokeratin in paraffin sections were all negative.
      Characteristic findings were observed in the border zone between the basal cells
      and the deposits. Numerous digitiform cell processes and membrane-bound globular
      fragments of basal cells were seen in the superficial region of the deposits. The
      cell membrane of some globules was interrupted and the contents appeared to have
      been discharged into the stroma. These findings suggest that basal cells of the
      corneal epithelium provide an amyloid precursor on the stroma.

PMID- 8651058
TI  - [The presence of IgE on limbal Langerhans cells in patients with
      atopicdermatitis].
AB  - Limbal conjunctival biopsies from 8 patients with atopic dermatitis and from 5
      age-matched healthy individuals undergoing cataract or retinal detachment surgery
      were analyzed by light microscopy and immunological techniques. They were immuno
      double labelled with anti-CD1a and anti-IgE or anti-CD23 (IgE receptor). In the
      specimens from atopic dermatitis 24 approximately 75% of positive anti-CD1a
      staining cells were double-stained by anti-IgE. Weak positive immuno-double
      stained cells with anti-CD23 were also observed, but less than with anti-IgE. The
      ratio of positive anti-IgE double-stained cells to positive anti-CD1a stained
      cells seemed to be parallel to serum IgE level, but not significant. The presence
      of IgE and CD23 (IgE receptor) on conjunctival Langerhans cells seems to have a
      positive effect on IgE-dependent antigen presentation.

PMID- 8651061
TI  - Cochlear implants and hearing aids.

PMID- 8651060
TI  - [An immunohistological study on a failed case of keratoepithelioplasty form
      alkali burn on the ocular surface].
AB  - We performed immunohistochemical study on a failed case of keratoepithelioplasty
      (KEP). A 33-year-old man underwent KEP with lammellar keratoplasty (LKP) for an
      alkali burn suffered 5 years previously. After several rejections, the cornea
      developed opacity. We performed surgery a second time with the same method, and
      investigated the removed keratoconjunctival tissue including the lenticule using
      enzyme labelled antibodies UCHL-1, MB-1, CD4, CD8, CD54 (ICAM-1), CD68, and HLA
      DR. Conjunctival tissue extended to the lamellar corneal graft over the
      lenticule. Either UCHL-1, CD4, or CD8 positive lymphocytes infiltrated the
      subconjunctival tissue dominantly, but they were blocked by the lenticule or
      Bowman's membrane of the graft cornea. In the stroma of the lamellar graft
      cornea, CD4 or CD8 positive, ICAM-1 or HLA-DR expression cells were detected. It
      was concluded that the lenticule and Bowman's membrane of the lamellar graft
      block infiltration of the immune cells.

PMID- 8651062
TI  - Cochlear implants benefit children.

PMID- 8651063
TI  - A hearing father, a deaf son.

PMID- 8651064
TI  - Robarts revisited 2.

PMID- 8651065
TI  - Validity of the WISC-III for deaf and hard of hearing persons.
AB  - The relationships of the WISC-III Performance scale with the WISC-R Performance
      scale and the WRAT-R subscales were investigated for a sample of 47 students who
      are deaf and hard of hearing. Over a three year time period, the relationships
      between the WISC-III and WISC-R Performance IQs was high, r(43) = +.93. As
      anticipated, the WISC-III and WISC-R Performance IQ. A Varimax rotation revealed
      the presence of two factors, Perceptual Organization and Processing Speed, which
      accounted for 76.5% of the variance in the WISC-III performance IQ. Of the six
      WISC-III Performance subtests, only Coding did not contribute to the Performance
      IQ. Students who communicated via Total Communication (M = 92.5) exhibited higher
      Performance IQ means than did students who communicated orally (M = 82.6). The
      WISC-III Performance IQ was moderately related to the WRAT-R subscales, having
      the strongest association with the Arithmetic subscale. Implications of these
      findings for practitioners are discussed.

PMID- 8651066
TI  - The concept of fractional number among deaf and hard of hearing students.
AB  - This study investigated deaf and hard-of-hearing students' understanding of the
      fractional number concept as measured by their ability to determine the order
      and/or equivalence of two fractional numbers presented in a pair. Analyses
      focused on the performance and strategies of 10-to-12 and 13-to-16 year old deaf
      and hard-of-hearing students (N = 21) and comparison groups of hearing students
      (N = 26). All students completed 18 fraction items requiring them to indicate
      which of two fractions presented in a pair was the larger value. On four items,
      students indicated their strategy. Results showed deaf and hard-of-hearing
      students in overall performance by fraction type and problem solving strategies.
      These students had a tendency to order fractions by the values of the counting
      numbers composing them.

PMID- 8651067
TI  - Stress in Greek mothers with deaf children. Effects of child characteristics,
      family resources and cognitive set.
AB  - In an effort to understand the impact of their children's deafness on Greek
      mothers, demographic, disability-related and stress characteristics were examined
      with 42 hearing mothers and their deaf children. The work was based on Hill's
      ABCX model and Bronfenbrenner's social ecology model, entailing a microsystem,
      mesosystem, ecosystem, and macrosystem. In addition to child history obtained
      from school records, Rotter's locus of control scale, Coopersmith's self-esteem
      inventory and the Clarke questionnaire on resources and stress were given to
      mothers. Onset of deafness before 18 months of age was associated with greater
      maternal stress. A tendency for mothers of younger children to report more stress
      was evident. The mothers mainly had an external locus of control, attributing
      events to outside agents beyond their control. Self-esteem proved the best
      predictor of stress, with a low-esteem associated with greater reported stress.
      The findings are discussed with reference to disability-related and cultural
      factors.

PMID- 8651068
TI  - Believability and importance as determinants of rumor among deaf college
      students.
AB  - In an attempt to develop a ?psychology of rumor? among the Deaf, equivalent in
      scope to what is already known about rumor among hearing populations, one of the
      main goals of this research was to address the roles of believability and
      importance in a sample of young adult college students. Believability and
      importance emerged as significant variables in rumor among Deaf college students.
      Importance of the rumor topic related to both extent of specific rumor knowledge
      and to extent of transmission rates of specific rumors. Subjects with more
      knowledge about a rumor viewed it as more important as did subjects who
      transmitted a rumor more frequently. Believability also was related to
      transmission rates. Subjects who transmitted a rumor more frequently also
      believed it more than did infrequent transmitters. Subjects who knew more about a
      rumor were also more anxious and more extroverted than their less knowledgeable
      counterparts. Frequent transmitters were also more anxious than infrequent
      transmitters. Multivariate analyses indicated that the best predictors of rumor
      knowledge were generalized anxiety, extroversion and gender. The best predictors
      of transmission rates were importance and generalized anxiety.

PMID- 8651069
TI  - Infants who are deaf or hard of hearing, with and without physical/cognitive
      disabilities.
AB  - This paper provides narrative summaries of the medical histories and interactive
      behaviors of five infants who are deaf or hard of hearing and have other
      disabilities (HI-MH). All were diagnosed before they were 9 months old, when
      mothers were interviewed and completed parenting stress questionnaires. Mothers
      and 12-month-old infants were videotaped in a free play situation. These dyads
      are compared with mothers adn (1) 10 infants with hearing deficits whose pre- or
      post-natal histories place them at-risk for other disabilities, but who have not
      been so diagnosed (HI-AR); (2) 8 infants not at-risk for other disabilities (HI
      NR) since their hearing deficits are hereditary or have no known cause; and (3)
      20 infants with no diagnosed disability of any kind (HG). Behaviors of the three
      groups of mothers whose babies are deaf or hard-of-hearing were rated below those
      of HG mothers although HI groups did not differ from each other. HI-MH infants
      and dyads ranked below those of the three other groups. Parenting stress scores
      did not differentiate among groups. However, scores for mothers of HI-MH infants
      were characterized either as extremely high (reflecting great stress) or
      extremely low (reflecting denial of stress) or extremely low (reflecting denial
      of stress). Discussion addresses implications for intervention.

PMID- 8651070
TI  - The deaf child and solving problems of arithmetic. The importance of
      comprehensive reading.
AB  - The present investigation is informed by two major considerations. First, the
      need for teachers to know more about the difficulties experienced by the deaf
      child when presented with written mathematical problems. Second, the idea of the
      relationship between linguistic competence in deaf subjects and their
      difficulties in the comprehension of verbal messages. In particular, the present
      article analyzes the influence of reading comprehension level on the solution of
      verbally expressed problems of arithmetic. The results indicate that reading
      comprehension level is clearly related to the problem-solving level of deaf
      subjects. In general, if the deaf are unable to understand the verbally presented
      problem, they will not be able to solve it correctly.

PMID- 8651071
TI  - Effects of unilateral hearing loss on teacher responses to the SIFTER. Screening
      Instrument for Targeting Educational Risk.
AB  - Eighteen school children with unilateral hearing loss were compared to their
      peers through administration of the Screening Instrument for Targeting
      Educational Risk (SIFTER) to their teachers. Results indicate that children with
      unilateral hearing loss are given SIFTER scores significantly lower than their
      peers in all five SIFTER areas of academics, attention, communication,
      participation, and behavior. Such results support previous findings regarding
      teachers' attitudes toward students with unilateral hearing loss and indicate a
      need for in-service education for the classroom teacher and special attention to
      the educational risks of such children.

PMID- 8651072
TI  - Social interaction. Assessment and intervention with regard to students who are
      deaf.
AB  - Personnel in school settings where deaf children are enrolled can play an
      important role in facilitating the acquisition of mature social skills. Social
      interaction assessment, curricula, and examples of goals and objectives are
      provided in this article as well as suggestions for facilitating social
      integration and developing a Circle of Friends. A tool that interpreters or other
      significant adults might utilize to empower hearing peers is also provided. It
      can be used for assessment purposes or as a model for appropriate comments.
      Finally, six commercially-available social skills curricula are described for use
      with students who are deaf.

PMID- 8651073
TI  - Evaluation of the mass balance model used by the Environmental Protection Agency
      for estimating inhalation exposure to new chemical substances.
AB  - The U.S. Environmental Protection Agency (EPA) is responsible for assessing the
      potential for unacceptable human health and environmental risks of new chemical
      substances prior to commercialization. Estimates of potential inhalation exposure
      to workers during manufacture, processing, and use of a new chemical substance
      are key elements of these assessments. However, the available information with
      which to assess the potential for exposure is often limited for new chemicals.
      One approach used by EPA to develop screening level estimates of inhalation
      exposure to vapors in the absence of data is the use of a mass balance model to
      predict the airborne concentration for various activities such as drumming and
      sampling. The mass balance model was evaluated by comparing the exposure
      estimates for specific operations with monitoring data reported in selected
      studies from the available literature. In general the estimated exposures based
      on the midpoint of the range of default input values were well within one order
      of magnitude of the measured exposures. Selection of more conservative (i.e.,
      protective) model input values overestimated exposures by one or more orders of
      magnitude. There are many simplifying assumptions inherent in the model and many
      variables that influence exposure that are not considered. Uncertainty analyses
      of the model demonstrated that values selected for the ventilation flow rate and
      generation rate greatly influence the estimate of exposure and should be
      carefully chosen. Additional research is recommended, and ultimately, model
      validation should be completed to further improve and refine the model.

PMID- 8651074
TI  - Estimating exposure intensity in an imperfectly mixed room.
AB  - The well-mixed room model is traditionally used to predict the concentration of
      contaminants in indoor environments. To account for imperfect air mixing, the
      room supply/exhaust air rate Q is frequently multiplied by a mixing factor m,
      where 0 < m < or = 1, and an effective ventilation rate QE = m . Q is used in
      place of Q in the well-mixed room equations. However, this procedure is
      inappropriate because a well-mixed room model, albeit with an adjusted
      ventilation rate, is still used to describe an imperfectly mixed room. To
      illustrate the errors that may result, a two-zone model is described in which a
      room is conceptually divided into an upper zone and lower zone, where the latter
      is the zone of occupancy. Air is supplied to and exhausted from the upper zone at
      rate Q, and air exchanges between the two zones at rate beta. The lower zone's
      true ventilation rate is termed its purging flow rate QL, where QL = [beta/(beta
      + Q)]Q. Expressions for the steady-state contaminant levels in the two zones and
      for decay from the steady-state levels are presented. In a two-zone room, if one
      ignores imperfect air mixing and attempts to estimate QE from a decay curve, QE
      will usually be greater than QL. Given that contaminant is emitted in the lower
      zone, subsequent use of QE rather than QL to predict steady-state exposure
      intensity in the room will cause an underestimation error. For a room with an
      upper- to lower-zone volume ratio of 2:3, the underestimation error can reach
      40%. If a room has a single or dominant point source of contaminant, it is
      recommended that the purging flow rate near the release point be determined,
      which permits a more accurate prediction of a worker's exposure intensity near
      the source. Alternative methods for determining the local purging flow rate are
      described. It is also shown that age-of-air analysis techniques do not provide
      information directly relevant to estimating exposure intensity.

PMID- 8651075
TI  - Noise exposure of truck drivers: a comparative study.
AB  - To investigate the extent of noise exposure to which truck drivers are subjected,
      a comparison was made of the noise levels in the cabs of two different brands of
      trucks. Both brands were manufactured with identical engines. The equivalent
      continuous A-weighted sound pressure levels, maximum sound pressure levels, and
      percentage noise dose were determined. This study sought to determine if truck
      drivers are exposed to excessive noise inside the cabs of these trucks.
      Furthermore, the most beneficial working environment in terms of the brand used
      was investigated. No significant differences regarding the individual noise
      exposure of the truck drivers were found (P > 0.05). Based on comparison of
      measured noise exposures to existing criteria, it was determined that the noise
      exposures of truck drivers are potentially hazardous to their hearing.

PMID- 8651076
TI  - House dust mite allergen.

PMID- 8651077
TI  - Mixture formula justified.

PMID- 8651079
TI  - A missing factor?

PMID- 8651078
TI  - Safety of workers with neurological disabilities.

PMID- 8651080
TI  - A question of calibration.

PMID- 8651081
TI  - Citation of drafts questioned.

PMID- 8651082
TI  - Exposures to power-frequency electric and magnetic fields at a Canadian
      electrical utility. Correction.

PMID- 8651083
TI  - Kudos for valuable article.

PMID- 8651084
TI  - Proficiency Analytical Testing Program report (March 1996).

PMID- 8651085
TI  - Reduction of reinfarction and angina with use of low-molecular-weight heparin
      therapy after streptokinase (and heparin) in acute myocardial infarction.
AB  - This study examined whether extending the anticoagulation effect of heparin by
      low-molecular-weight heparin (clexane) can prevent recurrent myocardial
      infarction (AMI) treated by streptokinase. On the fifth day after AMI and after
      heparin therapy cessation, 103 patients were randomly assigned to either
      treatment with low-molecular-weight heparin (40 mg subcutaneously per day for 25
      days, n=43) or control (no treatment, n=60). All patients were followed carefully
      for 6 months after the infarction date. A total of 32 patients (31%) sustained a
      cardiac event during the 6-month observation period. There were 12 patients (20%)
      with reinfarction in the control group versus 2 patients (4.6%) in the low
      molecular-weight heparin group during the first 30 days of the study (p=0.02).
      One additional patient sustained reinfarction at 3 months of followup in the
      control group, which yielded a total of 13 patients (21.6%) sustaining
      reinfarction in the control group versus 2 patients (4.6%) in the low-molecular
      weight heparin group during 6 months of followup (p=0.01). Angina pectoris after
      AMI was diagnosed in 13 control patients (21.6%) versus 4 low-molecular-weight
      heparin-treated patients (9.3%) (p=0.078) during the study period. No major
      bleeding events were reported in either low-molecular-weight heparin-treated or
      control patients. Among patients with recently diagnosed AMI treated by
      streptokinase, extending the anticoagulant effect of heparin for 25 days may
      prevent recurrent coronary events for at least one month.

PMID- 8651086
TI  - Left ventricular wall motion score as an early predictor of left ventricular
      dilation and mortality after first anterior infarction treated with thrombolysis.
      The CATS Investigators Group.
AB  - To recognize patients prone to subsequent left ventricular dilation after the
      acute phase of a myocardial infarction treated with thrombolysis, we studied 233
      patients with a first anterior infarction, treated with thrombolysis, with 2
      dimensional echocardiography within 12 hours after admission and 3 months later.
      A wall motion score index (WMSI) and left ventricular volumes were assessed, and
      enzymatic infarct size was expressed as cumulative alphahydroxybutyrate
      dehydrogenase determined in the first 72 hours after infarction. Patients who
      died (17 of 233, 7%) after a mean follow-up of 517 days had a significantly
      higher acute WMSI (2.1 +/- 0.3, mean +/- SD) than those who survived (1.9 +/-
      0.4)(p=0.006). With use of this cutoff value for 2 WMSI, ventricles with an acute
      WMSI < or = 2 (62%) showed no increase in end-diastolic volume index (EDVI) or
      end-systolic volume index (ESVI), whereas ventricles with an acute WMSI >2 (38%)
      showed a significant increase in ESVI (6.1 +/- 12.2 ml/m2) and in EDVI (10.3 +/-
      16.6 ml/m2) in the first 3 months. Using a cutoff value of 1,000 U/L for
      cumulative alphahydroxybutytrate dehydrogenase, only infarcts with a value of
      >1,000 U/L (52%) caused a significant increase in EDVI (10.8 +/- 14.3 ml/m2) and
      ESVI (6.5 +/- 10.0 ml/m2) in the first 3 months. Thus, acutely assessed WMSI of
      >2 can readily predict subsequent dilation in patients with a first anterior
      infarction treated with streptokinase and is a good predictor of mortality.
      Enzymatic infarct size also is a predictor of dilation, although not available
      until 3 days after infarction.

PMID- 8651087
TI  - Use of vital capacity for cardiac failure risk estimation in persons with
      coronary disease and left ventricular hypertrophy.
AB  - Cardiac failure is a common lethal outcome of coronary heart disease and left
      ventricular hypertrophy. The efficacy of forced vital capacity (FVC), measured
      biennially, in predicting the onset of cardiac failure was explored in 818
      Framingham Study subjects with those predisposing conditions, among 324 developed
      cardiac failure. Among the men and women who had coronary disease or left
      ventricular hypertrophy, those with FVCs in the lower quartile were at
      substantially increased risk of developing cardiac failure. For men, comparing
      the lowest quartile with men whose FVCs were in the highest quartile (<2.7 L vs
      >5.6 L), the risk ratio was 1.8; for women with FVCs <1.7 L, the risk was 2.3
      times those with FVCs of > or = 3.5L. The excess risk of cardiac failure imposed
      by a low FVC was similar in those with coronary disease and left ventricular
      hypertrophy. The simple FVC is an inexpensive and robust predictor of cardiac
      failure in persons predisposed by coronary disease or left ventricular
      hypertrophy. FVC determination should help identify candidates for cardiac
      failure needing echocardiographic examination for ventricular dysfunction.

PMID- 8651088
TI  - Effects of angiotensin-converting enzyme inhibitor alacepril in patients with
      stable effort angina during chronic isosorbide dinitrate treatment.
AB  - Nitrate tolerance has been reported to be reversed by certain types of
      angiotensin-converting enzyme (ACE) inhibitors. We examined whether alacepril, a
      new long-acting oral ACE inhibitor, has beneficial effects against exercise
      induced angina in patients with stable effort angina after substantial isosorbide
      dinitrate (ISDN) treatment. Thirteen men with stable effort angina were treated
      with oral ISDN (80 mg/d) for >3 weeks. After this period, efficacy of single oral
      administration of either alacepril (50 mg) or its placebo on exercise-induced
      angina and electrocardiographic changes was examined by treadmill exercise test
      in a double-blind crossover design. Alacepril significantly improved the exercise
      duration by 9.1% (p=0.03), the time to 1 mm ST-segment depression by 19%
      (p<0.01), and the maximal ST-segment depression by 33% (p=0.015) compared with
      placebo. Alacepril did not significantly alter the rate-pressure product, a
      marker of myocardial oxygen demand, during exercise test compared with placebo.
      Plasma renin activity was significantly increased (p<0.05) after administration
      of alacepril, indicating that alacepril significantly blocked ACE activity in our
      patients. In conclusion, a single oral administration of the ACE inhibitor
      alacepril (50mg) elicited beneficial effects against exercise-induced myocardial
      ischemia in patients with stable effort angina during chronic nitrate treatment.
      These effects may be mediated by increased coronary blood flow.

PMID- 8651089
TI  - Transesophageal assessment of coronary flow velocity reserve during "regular" and
      "high"-dose dipyridamole stress testing.
AB  - To assess the effect of regular and high-dose dipyridamole on coronary flow
      velocity in the left anterior descending artery (LAD), and to determine whether
      assessment of coronary flow velocity reserve (CFVR) is more sensitive for
      detection of ischemia than standard echocardiographic criteria, 47 patients were
      studied prospectively: 16 patients with stenosis of the LAD, 18 patients with
      angiographically normal LADs, and 13 patients with minimal disease. Patients
      underwent transesophageal echocardiographic study of wall motion and LAD flow
      velocity at baseline and at hyperemia, and for angina and electrocardiographic
      changes. The mean CFVR values after 0.56 mg/kg after 0.84 mg/kg of dipyridamole
      were similar: 2.52 +/- 0.87 versus 2.62 +/- 0.90. A CFVR <2.3 (normals mean -2
      SDs) was more sensitive (88% at both doses) for the detection of underlying
      coronary obstruction than was wall motion monitoring (44% and 75%, respectively).
      The combination of CFVR <2.3 and wall monitoring was more sensitive than index
      alone (94% at both 0.56 and 0.84 mg/kg). The rate-pressure product was not
      significantly different at the two doses of dipyridamole. When flow response is
      the end point of stress testing, as with transesophageal monitoring, the 0.56
      mg/kg dose of dipyrid mole is adequate, but when ischemia is the end point (as
      with wall motion monitoring by 2-dimensional echocardiography), the dose of 0.84
      mg/kg is more sensitive.

PMID- 8651090
TI  - Impact of the operating physician on costs of percutaneous transluminal coronary
      angioplasty.
AB  - The hospital charts and billing records of 250 consecutive admissions for
      percutaneous transluminal coronary angioplasty (PTCA) at a university hospital
      were reviewed. Clinical characteristics, performing physician, angiographic
      features of the dilated lesion, procedural outcome, length of stay, and total and
      departmental hospital costs were recorded for each patient. We identified several
      independent predictors of hospital cost, including the physician ($4,400 increase
      from highest- to lowest-cost physician, p=0.004), age ($790 increase per 10-year
      increase in age, p=0.002), urgency of the procedure ($4,100 increase for urgent
      vs elective, p < 0.001), and combined angiography and PTCA ($850 increase vs
      separate angiography, p=0.04). Independent predictors of catheterization
      laboratory cost included the physician ($1,280 increase from highest- to lowest
      cost physician, p=0.03), American College of Cardiology/American Heart
      Association lesion type B2 or C ($320 increase, p=0.03), and combined angiography
      and PTCA ($430 increase, p=0.003). Expensive operators used more catheterization
      laboratory resources than inexpensive operators; however, there are no
      significant differences in success rate or need for emergent bypass surgery
      between physicians. PTCA cost is determined by both patient characteristics and
      the performing physician. The increase in cost due to the physician was not
      explained by patient variables, lesions characteristics, success rate, or
      complications.

PMID- 8651091
TI  - Adjunctive intracoronary urokinase therapy during percutaneous transluminal
      coronary angioplasty.
AB  - Uncontrolled studies have suggested that intracoronary urokinase may be
      beneficial in patients undergoing percutaneous transluminal coronary angioplasty
      (PTCA). Therefore, 280 consecutive patients undergoing PTCA were prospectively
      randomized to receive a bolus injection of 12,500 U of heparin followed by a
      continuous intracoronary infusion via the guiding catheter of either 250 U
      heparin per minute or 250 U heparin plus 5,000 U urokinase per minute during the
      procedure. Procedural success rates (<50% final diameter stenosis by quantitative
      angiography and no major ischemic complications during in-hospital follow-up)
      were similar, with 87% in the heparin group (n=135) and 86% in the heparin plus
      urokinase group (n=127). Percent diameter stenosis after PTCA was 39 +/- 12% in
      the heparin group plus urokinase group (p=NS). There were no difference between
      groups with respect to PTCA-related acute vessels occlusion, angiographic
      evidence of intracoronary thrombus formation, creatine kinase increase after the
      procedure, Q-wave myocardial infarction, or emergency coronary artery bypass
      surgery. High-risk subgroup analysis revealed no beneficial effect of adjunctive
      intracoronary urokinase in patients with acute coronary insufficiency syndromes
      (n=86) or in stenoses with an irregular luminal contour (n=134). In addition,
      although risk stratification according to the criteria of the American College of
      Cardiology/American Heart Association Task Force classification proved to be very
      useful for the entire study population, no beneficial effect of intracoronary
      urokinase infusion was observed in any of the different risk groups. Thus,
      compared with heparin alone, adjunctive intracoronary urokinase therapy does not
      appear to have any beneficial effect upon procedural outcome or on type and
      frequency of acute complications during PTCA, even in subgroups of patients with
      high risk for thrombotic complications.

PMID- 8651092
TI  - Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major
      coronary events in middle-aged men.
AB  - Cardiovascular risk factors were analyzed in 4,849 male participants, aged 40 to
      65 years, in an 8-year follow-up of the Munster Heart Study (Prospective
      Cardiovascular Munster Study; PROCAM). One hundred eighty-one definite nonfatal
      myocardial infarctions, 49 fatal myocardial infarctions, and 28 sudden cardiac
      deaths were observed. Multiple logistic function analysis confirmed that age, low
      density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic
      blood pressure, cigarette smoking, diabetes mellitus, angina pectoris, and family
      history of myocardial infarction were important cardiovascular risk factors.
      Interestingly, this analysis revealed a significant and independent association
      between serum levels of triglycerides and the incidence of major coronary events.
      The relation between lipoprotein(a) [Lp(a)] levels and the occurrence of major
      coronary events was analyzed in a subgroup of 878 men. Thirty-three probands with
      major coronary events had significantly higher geometric mean levels of Lp(a)
      than 828 men who did not experience major coronary events (0.09 vs 0.05 g/L; p
      <0.011). Thus, in addition to established risk for factors, serum levels of
      triglycerides and Lp(a) are sensitive indicators of increased risk major coronary
      events.

PMID- 8651093
TI  - Natural history of isolated bundle branch block.
AB  - The purpose of this study was to determine the long-term outcome of patients with
      bundle branch block (BBB) who have no clinical evidence of cardiovascular
      disease. Among 110,000 participants in a screening program, 310 subjects with BBB
      without apparent of suspected heart disease were identified. Their outcome after
      a mean follow-up of 9.5 years was compared with that of 310 similarly screened
      age- and sex-matched controls. Among the screened population, isolated right BBB
      was more prevalent than isolated left BBB (0.18% vs 0.1%, respectively; p<0.001),
      and the prevalence of each abnormality increased with age (p<0.001). Total
      actuarial survival was no different for those with left BBB or right BBB and
      their respective controls. Cardiac mortality, however, was increased in the left
      BBB group when compared with their controls (p=0.01, log rank test). Left BBB,
      but not right BBB, was associated with an increased prevalence of cardiovascular
      disease at the follow-up (21% vs 11%; p=0.04). In the absence of clinically overt
      cardiac disease, the presence of left BBB or right BB is not associated with
      increased overall mortality. Isolated left BBB is associated with an increased
      risk of developing overt cardiovascular disease and increased cardiac mortality.

PMID- 8651094
TI  - Meta-analysis of morbidity and mortality in five exercise capacity trials
      evaluating ramipril in chronic congestive cardiac failure.
AB  - In 5 separate exercise capacity trials in similar patients with chronic
      congestive heart failure performed in Europe, the United States, and South
      Africa, 627 patients were randomized to ramipril and 428 to placebo. The dose of
      ramipril ranged from 1.25 to 20 mg/day. Follow-up was at 12 or 24 weeks. None of
      the trials were designed to assess efficacy with regard to clinical outcome. To
      assess in the combined experience whether there was an effect of ramipril on
      mortality, hospitalization, functional classification (New York Heart Association
      class), and exercise capacity, we pooled data from each trial and performed a
      mata-analysis. Of the patients randomized to ramipril and placebo, respectively,
      and based on intention to treat, 14 (2.2%) and 18 (3.8%) patients died (odds
      ratio 0.60, 95% confidence interval 0.28 to 1.29), and 59 (9.4%) and 67 (14.3%)
      patients died or were hospitalized (odds ratio 0.68, 95% confidence interval 0.46
      to 1.00). The New York Heart Association class improved in 29% and 25%
      respectively, whereas 8% and 15% deteriorated (p=0.04, based on intention to
      treat; death and hospitalization considered as deterioration). In ranked
      comparisons based on intention to treat and with imputation of exercise time as 0
      for patients who were unable to exercise because of death or who were
      hospitalized, exercise capacity was significantly improved by rampril. We
      concluded that rampiril is likely to have an effect on mortality, morbidity, and
      functional capacity in patients with chronic congestive heart failure similar to
      that of other angiotensin-converting enzyme inhibitors.

PMID- 8651095
TI  - Effects of aging on neuroendocrine activation in subjects and patients in the
      presence and absence of heart failure with left ventricular systolic dysfunction.
AB  - The neuroendocrine profile and echocardiographic features of 40 patients (81 +/-
      1 years, means +/- standard error) with heart failure and impaired left
      ventricular systolic function were compared with those of an age-matched group of
      healthy subjects, 20 younger patients with heart failure (aged 58 +/- 1 years)
      and 15 younger healthy subjects. Normal elderly subjects had a neuroendocrine
      profile similar to that of healthy younger subjects apart from elevated plasma
      norepinephrine (958 +/- 84 vs 302 +/- 118 pg/ml; p< 0.001) and atrial natriuretic
      peptide ( 40 +/- 6 vs 28 +/- 5 pg/ml; p<0.05). Despite a similar severity of
      heart failure, elderly patients had smaller ventricular dimensions (left
      ventricular internal dimension in diastole 51 +/- 2 vs 69 +/- 3 mm;p<0.0001 and
      greater impairment of ventricular compliance using Doppler indexes. Plasma
      norepinephrine was higher (1,191 +/- 80 vs 620 +/- 67 ppg/ml; p<0.01), and plasma
      atrial natriuretic peptide, plasma active renin, and angiotensin II were lower in
      elderly patients than in the younger patients with heart failure. As functional
      capacity declines with age, elderly patients may have less severe cardiac
      dysfunction for any given level of functional impairment, and this may account
      for most of the differences in neuroendocrine activity with age. Age appears to
      be an important determinant of plasma norepinephrine and may be a confounding
      factor in interpreting the prognostic significance of this hormone.

PMID- 8651096
TI  - Diagnosis of patent foramen ovale by transesophageal echocardiography and
      correlation with autopsy findings.
AB  - Transesophageal echocardiography (TEE) is accepted as the method of choice for
      the diagnosis of the patent foramen ovale (PFO). However, direct anatomic
      confirmation regarding the presence or absence of a PFO on transesophageal
      imaging has been obtained in only a limited number of patients. Consequently,
      this study was performed to assess the diagnostic accuracy of contrast and color
      Doppler TEE for detection of a PFO by comparing the results of TEE with autopsy.
      The study population comprised 35 consecutive patients (mean age 64 +/- 14 years)
      who underwent autopsy and prior TEE with examination of the atrial septum. For
      diagnosis of a PFO, the following criteria were used: (1) no defect in the
      continuity of the atrial septum on 2-dimensional imaging; (2) > or = 1 bright
      microbubble appearing in left the atrium within 3 heart cycles after
      opacification of the right atrium during contrast TEE; and (3) turbulent color
      jet within the atrial septum by color Doppler TEE. For estimating the PFO size,
      positive contrast studies were graded semiquantitatively (from 1 to 3), and the
      maximal color Doppler jet width was measured within the atrium septum at the area
      of maximal turbulence. At autopsy, a PFO was present in 9 of 35 patients (26%).
      All were correctly diagnosed by color Doppler TEE. The color Doppler jet width
      correlated well with the PFO diameter determined at autopsy (r=0.99, SEE=0.51 mm,
      p<0.0001). By contrast TEE, 8 of the 9 patients with autopsy-proven PFO were
      correctly identified. In 1 case with left heart disease and a long interatrial
      channel, a PFO was missed by contrast TEE but clearly demonstrated by color
      Doppler TEE. All patients with a PFO diameter >10 mm showed intense left atrial
      opacification of grade 3. With both methods, there were no false-positive
      results. Sensitivity and specificity for diagnosis of a PFO were 89% and 100%
      respectively, for contrast TEE, and both 100% for color Doppler TEE. Thus,
      contrast and color Doppler TEE are complementary and represent a highly sensitive
      and specific method for diagnosis of a PFO and for estimation of the PFO size.

PMID- 8651097
TI  - Immunohistochemical analysis of platelet-derived growth factor and basic
      fibroblast growth factor in cardiac biopsy and autopsy specimens of heart
      transplant patients.
AB  - The purposes of this study were to examine 250 heart biopsy specimens and 20
      autopsy specimens from heart transplant patients for the presence and
      localization of platelet-derived growth factor (PDGF)and basic fibroblast growth
      factor (bFGF) and to correlate these findings with the histologic features of
      rejection and the autopsy findings of graft coronary vasculopathy and global
      ischemia. Positive specimen staining was significantly more prevalent for PDGF
      (78% of specimens) than for bFGF (54% of specimens) (p< 0.001). PDGF was
      distributed more in an interstitial (53%) than a vascular (28%) pattern and was
      associated with macrophages, whereas bFGF was distributed more in a vascular
      (50%) than an interstitial (12%) pattern. The prevalence of PDGF (but not bFGF)
      staining was significantly greater in biopsy specimens with at least grade 2
      vascular rejection changes (81%) than in those without vascular rejection changes
      (58%) (p<0.001). In autopsy specimens, PDGF staining was present in the hearts of
      all 5 patients (100%) who died of graft failure from coronary vasculopathy and
      was present in all 11 hearts (100%) with global ischemic changes, but in only 4
      of 9 (44%) of the hearts without global ischemia (p<0.01). PDGF staining was
      absent in nontransplanted heart specimens, whereas bFGF staining in
      nontransplanted heart specimen was similar to that in transplanted hearts. We
      conclude that PDGF is increased in transplanted hearts, is distributed more in an
      interstitial pattern, and is associated with macrophages. Furthermore, PDGF
      staining is increased in transplanted hearts with evidence of vascular rejection,
      coronary vasculopathy, or global ischemia.

PMID- 8651098
TI  - Exercise echocardiography, angiography, and intracoronary ultrasound after
      cardiac transplantation.
AB  - Fifty-one consecutive patients underwent exercise echocardiography, angiography,
      and intracoronary ultrasound (ICUS) 2.5 years (range from 1 to 6) after cardiac
      transplantation. The average age of the donor was 29 years (range 13 to 50), and
      the average age of the recipient was 49 +/- 12 years. In total, 78 studies were
      performed, as 25 patients had >1 annual evaluation and 2 patients had 3
      consecutive annual evaluations. Of the 78 angiographic studies, 40 (26 patients)
      had evidence of coronary artery disease, defined as a focal stenosis (>20%, n=4)
      or luminal irregularities (n=36). However, by ICUS all 51 patients had intimal
      thickening at some point, with 34 patients possessing diffuse disease and 17
      focal intimal thickening only. Of the 25 serial studies, 12 progressed by at
      least 1 Stanford class. The sensitivity of angiography for determination of class
      III to IV intimal thickening was 64% and the specificity was 76%. On exercise
      echocardiography, 6 examinations revealed resting wall motions abnormalities,
      whereas 6 had inducible wall motion abnormalities with exercise. The sensitivity
      of exercise echocardiography to determine class III to IV intimal thickening was
      15%, and the specificity was 85%. In conclusion, exercise echocardiography is an
      insensitive method for predicting transplant-mediated coronary artery disease,
      whereas luminal irregularities on angiography may predict the presence of
      Stanford grade III to IV intimal thickening.

PMID- 8651099
TI  - A specific activity questionnaire to measure the functional capacity of cardiac
      patients.
AB  - Exercise testing is often performed in persons with cardiac disease to measure
      their functional capacity. Physical activity questionnaires assessing functional
      capacity have been used a low-cost and convenient alternative to exercise
      testing, but have not been well validated against measured oxygen consumption in
      a cardiac population. This study assesses the ability of a simple, 13-item
      activity questionnaire, known as the Specific Activity Questionnaire (SAQ), to
      measure functional capacity prospectively in a large sample of cardiac patients.
      Ninety-seven consecutive cardiac outpatients (85 men and 12 women aged 59 +/- 10
      years [mean +/- SD]) completed the SAQ before an elective symptom-limited
      treadmill test. Subjects returned within 10 days to repeat the treadmill test,
      following the same protocol, with the additional measurement of peak oxygen
      consumption, VO2 (ml x kg(-1)min(-1)), using open circuit spirometry. The SAQ
      score was significantly related to measured peak VO2(r=0.57, p<0.001). Stepwise
      multiple linear regression analysis found that the addition of patient age,
      height, and body weight to SAQ score improved the measurement of peak VO2,
      accounting for 51% of the sample variance (R=0.71, p<0.001). Peak VO2 was
      obtained from the following regression formula: [formula: see text]. Thus SAQ, a
      simple 13-item self-administered activity questionnaire, is able to provide a
      moderately good measure of functional capacity in cardiac patients and may be
      useful tool in studies of the cardiac population when formal exercise testing is
      impractical or uneconomical.

PMID- 8651100
TI  - Relation between blood pressure at rest and perception of angina pectoris during
      exercise testing.
AB  - We demonstrated that the prevalence of painful myocardial ischemia during
      exercise testing was 20% in patients with high blood pressure at rest (systolic
      blood pressure >140 mm Hg) and 36% in patients with normal blood pressure at
      rest(systolic blood pressure < or = 140 mm Hg). Thus, blood pressure at rest
      appears to be related to pain perception in cardiac patients.

PMID- 8651101
TI  - Stent jail: a minimum-security prison.
AB  - Small but significant side branches (particularly those with baseline ostial
      narrowing) may be further compromised by stent placement within parent vessel
      segments. Despite the theoretical risks associated with dilating branches in
      stent jail, the procedure was successfully completed in 84%, with minimal
      complications (mostly balloon rupture and local dissection) and no cases of
      balloon entrapment or deterioration of the final result achieved in the parent
      vessel.

PMID- 8651102
TI  - The Northridge earthquake as a trigger for acute myocardial infarction.
AB  - The Northridge earthquake was followed by a 35% increase in the number of
      admissions for myocardial infarction to coronary care units. Our observation
      suggest that onset of myocardial infarction is related to certain triggers, and
      stressful events may be one of them.

PMID- 8651103
TI  - Direct measurement of serum low-density lipoprotein cholesterol in patients with
      acute myocardial infarction on admission to the emergency room.
AB  - Measurement of low-density lipoprotein cholesterol during acute myocardial
      infarction in nonfasting patients on initial presentation to an emergency room by
      any of 3 methods (ultracentrifugation, immunoseparation, or the Friedewald
      estimate), identifies patients eligible for antilipemic interventions. Although
      slightly less sensitive, the conventional Friedewald estimate of low-density
      lipoprotein cholesterol levels provides clinicians good correlation with
      ultracentrifugation.

PMID- 8651104
TI  - Assessment of patients after coronary artery bypass grafting by dobutamine stress
      echocardiography.
AB  - Dobutamine stress echocardiography is an accurate method for the diagnosis and
      localization of vascular compromise in patients evaluated after coronary artery
      bypass graft surgery. The test provides useful data for selection of patients for
      whom coronary angiography may be indicated.

PMID- 8651105
TI  - Sum of ST-segment elevations on admission electrocardiograms in acute myocardial
      infarction predicts left ventricular dilation.
AB  - In summary, ST-segment elevations on the admission electrocardiogram not only
      diagnose acute myocardial infarction but also provide predictive information with
      respect to developing infarct size and left ventricular remodeling as well as
      survival.

PMID- 8651106
TI  - Coronary vasomotor function in a normotensive, nondiabetic referral population
      with normal coronary arteriograms.
AB  - In a referral normal cardiac population, endothelium-independent coronary
      relaxation is nearly always normal, but endothelium-dependent relaxation may be
      depressed in a significant proportion of patients. Further study of the natural
      history of referral subjects with endothelial dysfunction is necessary to assess
      the potential cardiovascular risk of this finding in a presumed low-risk
      population.

PMID- 8651108
TI  - Meta-analysis of the use of low-dose beta-adrenergic blocking therapy in
      idiopathic or ischemic dilated cardiomyopathy.
AB  - We concluded that low-dose beta-adrenergic blocking agents are beneficial in the
      treatment of patients with ischemic or idiopathic cardiomyopathy. Low-dose beta
      blockers appear to improve NYHA functional class and LVEF.

PMID- 8651107
TI  - Testosterone decreases lipoprotein(a) in men.
AB  - We administered testosterone, with or without the aromatase inhibitor
      testolactone, to determine the effects of testosterone and its aromatization to
      estradiol on Lp(a) levels in normal men. Average Lp (a) values decreased by 37%
      during testosterone alone and by 28% when testosterone and testolactone were
      combined, suggesting that testosterone reduces Lp(a) in men primarily by an
      androgenic effect and not by its conversion to estradiol.

PMID- 8651109
TI  - Energy expenditure and symptom severity in men with heart failure.
AB  - Our results demonstrate a graded increase in resting metabolic rate based on
      symptom severity as reflected in the New York Heart Association classification.
      This finding supports the hypothesis that clinical severity of illness
      corresponds to the magnitude of the increase in resting energy demands.

PMID- 8651111
TI  - Quantitative assessment of myocardial tissue velocities in normal children with
      Doppler tissue imaging.
AB  - Assessment of myocardial tissue velocities in children in feasible with DTI. We
      have described normal velocity values for left ventricular motion in children
      during systole and diastole, at the mitral annulus, and at the posterior wall.
      The pattern of mitral annular motion in diastole mimics that of mitral blood
      inflow, whereas the pattern of posterior wall motion differs and may provide for
      a new form of assessment of diastolic function. Further investigation of
      myocardial velocities in states of volume and pressure overload, as seen in
      various forms of congenital heart disease, is warranted.

PMID- 8651110
TI  - Regression of right ventricular hypokinesis after thrombolysis in acute pulmonary
      embolism.
AB  - We found a significant ABD-assisted right ventricular hypokinetic regression
      after thrombolytic therapy in acute pulmonary embolism but could not demonstrate
      a linear relation between improvement in early right ventricular function and
      angiography.

PMID- 8651112
TI  - Effects of high gravity on cardiac dimensions in trained air crew.
AB  - We conclude that there is no difference in LV wall thickness, dimensions, or
      functional parameters between air crew members who fly high + Gz aircraft and
      those who fly other types of aircraft. No differences were detected between high
      +Gz air crew personnel and others in development of structural and functional
      changes over the short-term course of a flying career.

PMID- 8651113
TI  - Radiofrequency catheter ablation of ventricular tachycardia from right ventricle
      late after myocardial infarction.
AB  - In summary, this case illustrates how complex VT circuits may be. If the findings
      of this case are substantiated with additional cases, mapping and radiofrequency
      energy application from right ventricle would have to be considered in VT with
      left bundle branch blocks QRS morphology, whenever ablation from the left
      ventricule is ineffective.

PMID- 8651114
TI  - Hypertrophic cardiomyopathy with left ventricular apical diverticulum.
AB  - In summary, 3 patients with HC and LV apical diverticula of various sizes are
      described. All 3 had morphologic evidence of severe midventricular obstruction,
      including 2 with documentation of greatly elevated LV systolic pressure and
      marked LV outflow pressure gradients.

PMID- 8651115
TI  - Value of programmed ventricular stimulation in predicting sudden death and
      sustained ventricular tachycardia in survivors of acute myocardial infarction.
AB  - To assess the prognostic value of the response to programmed ventricular
      stimulation in selected post-acute myocardial infarction (AMI) patients
      identified at risk of sudden death and spontaneous sustained ventricular
      tachycardia (VT) (arrhythmic events) by noninvasive, highly sensitive testing,
      286 consecutive patients were evaluated prospectively and followed for 12 months.
      One hundred three patients (group 1) with either left ventricular ejection
      fraction < or = 40% or ventricular late potentials or spontaneous complex
      ventricular arrhythmias were considered at risk of late arrhythmic events and
      eligible for programmed ventricular stimulation; the remaining 183 patients
      (group 2) were discharged without any further evaluation. Electrophysiologic
      study was performed 11 to 20 days after AMI utilizing up to 2 extrastimuli and
      rapid ventricular burst pacing. At the end of the follow-up period, 10 patients
      in group 1 and 2 in group 2 died of cardiac causes; in addition, 10 patients in
      group 1 and 1 in group 2 had arrhythmic events. Sustained monomorphic VT was the
      only inducible arrhythmia related either to cardiac death (p <0.0005) or to
      arrhythmic events (p <0.0001). It was induced in 11 patients (3 died suddenly,
      and 3 had spontaneous VT). Multivariate analysis showed that such arrhythmia was
      the strongest independent predictor of arrhythmic events (F = 9.76; p <0.0001).
      In the entire study population, it allowed identification of patients at risk,
      with a sensitivity, specificity, and positive predictive value of 55%, 99%, and
      67%, respectively. We conclude that programmed ventricular stimulation performed
      in selected post-AMI patients, utilizing a moderately aggressive stimulation
      protocol, is a specific but less sensitive procedure for predicting arrhythmic
      events; the induction of sustained monomorphic VT allows the accurate
      identification of patients who may profit by prophylactic antiarrhythmic therapy.

PMID- 8651116
TI  - Short- and long-term assessment of heart rate variability for risk stratification
      after acute myocardial infarction.
AB  - Depressed heart rate variability (HRV) has been shown to be a powerful and
      independent risk factor in patients following acute myocardial infarction (AMI).
      A detailed comparison of the predictive values between short- and long-term HRV
      has not been made. The predictive value of short-term HRV for 1-year total
      cardiac mortality was studied in 700 consecutive patients after AMI. All patients
      underwent 24-hour Holter monitoring before discharge from the hospital (5 to 8
      days after AMI) and were followed up for 1 year. Short-term HRV was computed as
      the standard deviation of all normal RR intervals (SDNN) from a 5-minute
      stationary period selected from 24-hour Holter electrocardiographic recordings.
      Long-term HRV was computed as an HRV index over the entire 24 hours. There was a
      significant but relatively poor correlation between SDNN and HRV index (r = 0.51,
      p <0.001). The positive predictive accuracy of SDNN for 1-year mortality (13% to
      18%) was lower than the HRV index (17% to 43%) over a range of sensitivity of 25%
      to 75%. Assessment of HRV index in > or = 35% of the patients preselected by the
      lowest SDNN was able to achieve predictive power similar to that of HRV index
      assessed in all the patients. These data suggest that lower predischarge short
      term HRV is associated with increased 1-year total cardiac mortality in patients
      after AMI. Analysis of long-term HRV for postinfarction risk stratification can
      safely be limited to patients preselected by depressed short-term HRV measures.

PMID- 8651117
TI  - Coronary stenting in patients undergoing percutaneous transluminal coronary
      angioplasty during acute myocardial infarction.
AB  - Although coronary stenting has been useful in the treatment of patients with
      suboptimal results, abrupt closure, and threatening occlusion after percutaneous
      transluminal coronary angioplasty (PTCA), its use in patients with acute
      myocardial infarction (AMI) is controversial because of the presence of
      intracoronary thrombus. In this study intracoronary stenting was used to treat
      suboptimal results and complications in 30 patients (35 lesions) undergoing PTCA
      during AMI. There were 28 men and 2 women, mean age 58 +/- 12 years. Thirteen
      patients (43%) had undergone rescue PTCA because of unsuccessful thrombolysis.
      Four patients had Killip's grade IV, 5 Killip's grade III, and 21 Killip's grade
      < or = 2 heart failure. Stents were placed in the 35 lesions because of
      suboptimal result (n = 19), early loss (n = 9), abrupt closure (n = 2), and
      coronary dissection with threatening occlusion (n = 5). All stents were deployed
      successfully. In-hospital complications included 1 in-hospital death (3.0%); no
      patient required emergency coronary artery bypass graft surgery. One patient
      (3.0%) developed abrupt closure and was successfully treated with PTCA and
      intracoronary thrombolysis. Vascular complications requiring blood transfusion
      developed in 3 of 30 patients (10%). At 11.8 months (range 4 to 24) follow-up,
      there were no deaths or myocardial infarction. One patient underwent coronary
      artery bypass grafting. The remaining patients were free of angina at follow-up.
      Thus, intracoronary stents can be used successfully to treat both suboptimal
      results and complications occurring in patients undergoing PTCA during AMI.

PMID- 8651118
TI  - Long-term results after successful percutaneous transluminal coronary angioplasty
      in patients over 75 years of age.
AB  - A prospective study comparing the long-term results of balloon angioplasty in
      patients over 75 years of age with those in a younger patient group is not
      available. A total of 192 consecutive patients aged > or = 75 years (group I) who
      underwent a balloon angioplasty were matched with 192 control patients aged 40 to
      65 years (group II). The groups were matched for gender, angina pectoris class,
      left ventricular function, 1-, 2-, and 3-vessel coronary artery disease, and
      previous myocardial infarction. The mean follow-up was 40.4 months (range 0 to
      110). Actuarial analysis (freedom from events) after 5 years yielded the
      following results for group I versus group II: free from death remained 77.1%
      versus 97.9% (p = 0.0001), from cardiac death 92.4% versus 97.9% (p = 0.049), and
      from angina pectoris 54.6% versus 75.1% (p = 0.03). The differences were not
      significant for those remaining free from myocardial infarction, repeat balloon
      angioplasty, or coronary artery bypass grafting. When elderly patients with
      complete revascularization (n = 127) were compared with a matched control group
      of 127 patients aged 40 to 65 years who underwent complete revascularization,
      there was only a significant difference in noncardiac death rates. We conclude
      that patients > 75 years of age have a significant higher cardiac and noncardiac
      death rate and a higher incidence of angina pectoris after successful balloon
      angioplasty. However, the incidence of reintervention and myocardial infarction
      is lower in the elderly. If complete revascularization is achieved in the
      elderly, then freedom from cardiac death and recurrence of angina pectoris would
      be comparable to that in younger patients.

PMID- 8651119
TI  - Sequential assessment of exercise tolerance in heart transplantation compared
      with coronary artery bypass surgery after phase II cardiac rehabilitation.
AB  - To investigate the improvement in exercise capacity of transplant patients after
      an early postoperative (phase II) cardiac rehabilitation program during the first
      year after surgery, we analyzed retrospectively exercise capacity within 3 months
      (at the completion of phase II rehabilitation) and 1 year after surgery in 17
      orthotopic heart transplantation patients (15 men and 2 women) and 17 age- and
      gender-matched coronary artery bypass graft (CABG) patients. All patients
      participated in a phase II cardiac rehabilitation exercise program followed by a
      home-based exercise program. At the completion of phase II cardiac
      rehabilitation, mean peak oxygen (VO2) adjusted for body weight in heart
      transplant patients was not significantly different from that in CABG patients
      (19.7 +/- 3.7 vs 21.9 +/- 4.1 ml/kg/min), and oxygen pulse at peak exercise did
      not differ between the 2 groups (11.5 +/- 2.5 vs 12.6 +/- 2.4 ml/beat). Between 3
      months and 1 year after surgery, CABG patients had a marked increase in exercise
      time, increase in heart rate from rest to peak exercise (heart rate reserve),
      peak VO2, and oxygen pulse. In contrast, heart transplant patients had a
      significant but only modest increase in peak VO2, and were much more limited in
      exercise capacity at 1 year than were CABG patients (21.3 +/- 3.9 vs 27.4 +/- 4.7
      ml/kg/min, p <0.0001). In our limited patient population, usual phase I
      rehabilitation with subsequent home-based exercise training was inadequate to
      improve the exercise capacity of heart transplant patients, and different
      rehabilitation protocols, such as long-term supervised exercise training,
      specific to this patient group may be indicated.

PMID- 8651120
TI  - Effect of 21 mg transdermal nicotine patches and smoking cessation on heart rate
      variability.
AB  - The effect of smoking cessation on cardiac autonomic tone, as reflected by
      indexes of heart rate variability (HRV), has not been reported. Current smokers
      (n = 54, mean +/- SD age 43 +/- 12 years) who desired to quit, and were smoking >
      or = 1 pack/day and had made > or = 1 prior attempt at quitting, had 24-hour
      electrocardiographic recordings. They then attended smoking cessation classes and
      used transdermal nicotine patches while abstaining from smoking. After 4 to 6
      weeks of using 21 mg patches, the 24-hour electrocardiogram was repeated (n =
      35). Four weeks after cessation of patch use, the 24-hour electrocardiogram was
      again recorded in subjects who continued to be abstinent (n = 25). Time and
      frequency domain measures of HRV based on normal R to R (NN) intervals were
      computed for all recordings. Smoking cessation significantly decreased heart
      rate, and increased all 24-hour time and frequency domain indexes of HRV. Part of
      this change occurred in the transition from smoking to the patch, and further
      changes occurred with cessation of patch use. For example, the standard deviation
      of average NN intervals was 114 +/- 28 ms at baseline, 121 +/- 41 ms with the
      patch, and 135 +/- 26 ms after quitting. At 4 weeks after cessation of all
      nicotine use, the average heart rate remained higher, and HRV remained lower than
      values reported for healthy, middle-aged adults.

PMID- 8651121
TI  - Unmasking the trifascicular left intraventricular conduction system by ablation
      of the right bundle branch.
AB  - Twenty-five patients underwent transcatheter right bundle ablation either for
      bundle branch reentrant tachycardias or inadvertent or deliberate right bundle
      ablation during atrioventricular junctional ablation for rate control.
      Electrophysiologic data and 12-lead electrocardiograms before and after right
      bundle ablation were available in all patients. Eleven of the patients had no
      significant intraventricular conduction abnormalities by surface
      electrocardiograms (group I), whereas 14 patients had underlying intraventricular
      conduction delays (group II). All group I patients had typical
      electrocardiographic changes of right bundle branch block after right bundle
      ablation, with minimal changes in initial or mean QRS axis. In group II, 5
      patients had an initial 40 ms QRS axis shift of > 45 degrees, in 7 patients the
      mean QRS axis changed significantly (leftward in 4 and rightward in 3), and a qR
      pattern in V1 was seen in 12 of 14 patients including 2 with structurally normal
      hearts. These changes, namely new Q waves, and rightward and leftward axis shifts
      are most likely the result of septal fascicular, left posterior fascicular, and
      left anterior fascicular delay/block, which were exposed by exclusive conduction
      via a diseased left bundle and its fascicles. The trifascicular nature of left
      intraventricular conduction is more apparent when diseased and unmasked by
      concomitant block in the right bundle branch.

PMID- 8651122
TI  - Sex- and age-related antihypertensive effects of amlodipine. The Amlodipine
      Cardiovascular Community Trial Study Group.
AB  - This community-based study assessed whether there were age, sex, or racial
      differences in response to amlodipine 5 to 10 mg once daily in patients with mild
      to moderate essential hypertension. This prospective, open-label trial had a 2
      week placebo period, a 4-week upward drug titration/efficacy period, and a 12
      week drug maintenance period. There were 1,084 evaluable patients (mean age 55.5
      years; 65% men and 35% women; 79% white and 21% black; 75% <65 and 25% > or = 65
      years old). At the end of the titration/efficacy phase, the mean +/- SD blood
      pressure (BP) decreased by -16.3 +/- 12.3/-12.5 +/- 5.9 mm Hg, (p < or = 0.0001).
      Amlodipine produced a goal BP response (sitting diastolic BP < or = 90 mm Hg, or
      a 10 mm Hg decrease) in 86.0% of patients overall. The BP response was greater in
      women (91.4%) than in men (83.0%, p < or = 0.001), and greater in those > or = 65
      years old (91.5%) than in those < 65 years old (84.1%, p < or = 0.01); however,
      it was similar between whites and blacks (86.0% vs 85.9%, respectively, p = NS).
      The sex difference in BP response could not be fully explained by differences in
      age, weight, dose (mg/kg), race, baseline BP, or compliance, and there were no
      differences among women based on use of hormone replacement therapy. Amlodipine
      was well tolerated; mild to moderate edema was the most common adverse effect.
      Thus, amlodipine was effective and safe as once-a-day monotherapy in the
      treatment of mild to moderate hypertension in a community-based population. Women
      had a greater BP response to amlodipine.

PMID- 8651123
TI  - Circulating concentrations of proinflammatory cytokines in mild or moderate heart
      failure secondary to ischemic or idiopathic dilated cardiomyopathy.
AB  - Proinflammatory cytokines are capable of modulating cardiovascular function by a
      variety of mechanisms. These cytokines are elevated in patients with severe heart
      failure, but changes in mild or moderate heart failure have not been reported.
      Therefore, simultaneous arterial and coronary sinus concentrations of interleukin
      1alpha, soluble interleukin-2 receptor, interleukin-6, and tumor necrosis factor
      alpha were measured in 78 patients with New York Heart Association functional
      class II to IV heart failure and compared with 17 healthy volunteers.
      Concentrations of interleukin-1alpha, soluble interleukin-2 receptor, and
      interleukin-6 were determined by a "sandwich" enzyme-linked immunosorbent assay
      and tumor necrosis factor-alpha by tissue culture technique. There were no
      statistical differences in interleukin-1alpha, soluble interleukin-2 receptor, or
      tumor necrosis factor-alpha concentrations in mild to moderate heart failure
      versus control subjects. Interleukin-6 was significantly elevated, 75 +/- 16
      versus 0.4 +/- 0.4pg/ml (p = 0.002). Cytokine concentrations did not differ by
      heart failure etiology. Paired arterial and coronary sinus concentrations were
      not significantly different. Soluble interleukin-2 receptor concentrations were
      significantly correlated with New York Heart Association functional class (r =
      0.59, p = 0.04) and negatively associated with exercise tolerance time (r = 
      0.59, p = 0.007). Thus, interleukin-6 is significantly elevated in mild or
      moderate heart failure.

PMID- 8651124
TI  - Comparison of transthoracic and transesophageal echocardiography with surgical
      findings in mitral regurgitation. The ESMIR Research Group.
AB  - This prospective study was conducted to ascertain whether echocardiographic
      evaluation could provide more insight into the genesis of mitral regurgitation
      (MR) before surgery. All patients underwent preoperative transthoracic and
      transesophageal echocardiography. Nine centers participated in the ESMIR
      (Echocardiographic Selection of patients for MItral valve Reconstruction) study
      and 350 patients were included. Compared with surgical findings, the percentage
      of functional abnormalities correctly predicted by both echo modalities was
      highest in patients with increased leaflet mobility (83% for transthoracic and
      86% transesophageal echocardiography). In contrast, in normal leaflet mobility,
      the prediction was better by transthoracic than by transesophageal
      echocardiography (75% vs 64%). In patients with restricted leaflet mobility, the
      predictive value of both techniques was similar. The diagnostic yield of anatomic
      abnormalities of both echo techniques was similar, except for chordal rupture; a
      sensitivity by transesophageal echocardiography of 79% and by transthoracic
      echocardiography of 57% (p < 0.001). In general, the sensitivity of each echo
      technique for detecting anatomic abnormalities was <70%, except for annular
      dilatation, leaflet thickening, and chordal rupture. At surgery, the prevailing
      functional condition was increased leaflet mobility (42%). The conclusion is that
      both echo techniques provide adequate information regarding the functional
      condition of the mitral valve apparatus, not withstanding limitations in
      assessing anatomic details. Transthoracic echocardiography appears to be
      sufficient for preoperative evaluation of MR.

PMID- 8651125
TI  - Collagen content in normal, pressure, and pressure-volume overloaded developing
      human hearts.
AB  - Increased myocardial collagen accompanies pressure overload of the adult left
      ventricle. This phenomenon is poorly understood in infants. This study compares
      the myocardial volume fraction of collagen in infants who did not have primary
      heart disease with infants with isolated pressure overload of the right ventricle
      (tetralogy of Fallot [ToF]), and with infants with combined volume and pressure
      overload (aortic valve atresia [AVA]). The distribution of collagen in the
      neonatal myocardium was also determined. We measured the volume fraction of
      collagen from right ventricular biopsy specimens of cadaver hearts in normal
      infants (1 to 9 months old; n = 7), infants with ToF (1 day to 9 months old; n =
      9), newborns with AVA (AVA-NB) (1 to 4 days old; n = 5), and older patients with
      AVA (AVA-I) (5 to 8 months old; n = 5). Myocardium from 3 patients undergoing
      repair of ToF (6 to 8 months old) was also analyzed. Specimens were stained with
      Masson's trichrome and myocardial volume fraction of collagen determined by point
      counting. Myocardial volume fraction of collagen was significantly higher (p =
      0.02) in AVA-I patients (8.0 +/- 3.5%) versus normal (3.3 +/- 2.7%), ToF (3.2 +/-
      1.8%), and AVA-NB (3.5 +/- 2.3%) patients. There was a tendency for increased
      collagen in the subendocardium, especially in AVA-I patients (p > 0.05). We
      conclude that patients with AVA-I have increased collagen relative to normal
      subjects, patients with ToF, and patients with AVA-NB, and that this increase is
      greatest in the subendocardium.

PMID- 8651126
TI  - Influence of obesity on the diagnostic value of electrocardiographic criteria for
      detecting left ventricular hypertrophy.
AB  - Easily applicable, clinically relevant electrocardiographic criteria are needed
      to screen large populations for left ventricular (LV) hypertrophy. The aim of
      this study was to evaluate, in a population of 380 hypertensive patients of both
      sexes, whether obesity modified the diagnostic performance of Sokolow-Lyon and
      Cornell voltage criteria by comparing them with echocardiographic evaluations
      using different indexation methods for LV mass presentation (body surface area
      and various powers of the height variable). For the population as a whole,
      Cornell voltage was better correlated to LV mass than was Sokolow-Lyon voltage (r
      = 0.48 and 0.36, respectively). The poorest performance of Sokolow-Lyon voltage
      was observed among obese patients (best r = 0.1 and 0.21 in obese women and men,
      respectively). Sensitivities were assessed at a 95% specificity level. In
      nonobese patients, using sex-adjusted voltage values (43 and 36 mm in men and
      women, respectively, for Sokolow-Lyon voltage, and 28 and 25 mm for Cornell
      voltage), the sensitivities of Cornell voltage and Sokolow-Lyon voltage were
      similar in men and women (near 22% and 36%, respectively), whatever the
      indexation method used for LV mass. In obese patients, Cornell voltage
      sensitivity was similar to that of nonobese patients, whereas Sokolow-Lyon
      voltage had a much poorer sensitivity (<10%). For simple LV hypertrophy detection
      criteria, Sokolow-Lyon voltage should be avoided in obese hypertensive patients
      and replaced by the Cornell voltage criteria, which are not influenced by the
      presence of obesity.

PMID- 8651127
TI  - Comparison of impedance cardiography with indirect Fick (CO2) method of measuring
      cardiac output in healthy children during exercise.
AB  - Electric bioimpedance has been used to measure cardiac output for decades.
      Improvements in modeling and microprocessor technology have spawned newer
      generations of such devices. This method would be especially useful in children,
      in whom the use of invasive methods is limited. We tested a device (ICG-M401, ASK
      Ltd.) in 30 healthy children at 2 levels of exercise (0.5 and 1.5 W/kg), and
      compared impedance measurements of cardiac output (QICG) with carbon dioxide
      (CO2) rebreathing measurements of cardiac output (QRB). The QICG-oxygen uptake
      (VO2) rel ation was expressed by QICG = 3.8 + 4.6 VO2; r(2) = 0.68. Mean +/- SD
      bias (QICG-QRB) was 0.14 +/- 1.05 L/min, not significantly different from zero
      (95% confidence interval -0.12 to +0.44 L/min). All QICG results were within +/-
      15% of the hypothetical mean value (Bland and Altman analysis). The largest
      deviation of QICG from QRB was +30%, found in 1 of 57 paired determinations.
      Eighty percent of QICG values were within +/- 20% of the QRB result. We conclude
      that impedance cardiography with the ICG-M401 provided realistic and reliable
      estimates of cardiac output in healthy children during exercise. This, along with
      its ease of operation and utility at rest and during exercise, make it both
      useful and attractive for clinic and research purposes.

PMID- 8651128
TI  - Comparison of technetium-99m sestamibi-gated tomographic perfusion imaging with
      echocardiography and electrocardiography for determination of left ventricular
      mass.
AB  - Left ventricular (LV) mass estimates obtained from post-stress gated single
      photon emission computed tomographic (SPECT) perfusion images were compared with
      2-dimensionally targeted M-mode echocardiograms and with resting
      electrocardiographic voltage in 32 patients with stress perfusion scans that were
      either normal or only mildly abnormal. Myocardial pixel volumes were obtained
      from SPECT transaxial slices at end-diastole, end-systole, and summed ("ungated")
      static reformatted SPECT images at 2 levels of background subtraction, 37.5% and
      35% of peak myocardial activity. The S-wave amplitude in lead V1 and the R-wave
      amplitude in V5 were summed for an electrocardiographic index of voltage.
      Echocardiographic LV mass was calculated using the modified Penn convention
      formula. SPECT myocardial mass estimates were significantly greater at diastole
      when compared with systolic or summed images. There was a moderated, although
      highly significant, correlation between echocardiographic and SPECT indexes of LV
      mass with the lower (35%) background threshold (r = 0.59, 0.60, and 0.53 for
      diastole, summed, and systole, each p < 0.001). The diastolic SPECT estimate of
      LV mass correlation with electrocardiographic voltage (r = 0.56) was superior to
      the correlation between echocardiography and electrocardiography (r = 0.30). With
      use of published criteria for the presence of LV hypertrophy on echocardiography,
      diastolic and systolic gated SPECT predicted echocardiographic results with 78%
      accuracy.

PMID- 8651129
TI  - Is coronary thrombolysis associated with side effects that significantly
      compromise clinical benefits?

PMID- 8651130
TI  - Serial measures of plasma homocyst(e)ine after acute myocardial infarction.
AB  - To determine whether plasma levels of homocyst(e)ine are affected by the acute
      phase response, we studied 10 subjects serially after acute myocardial
      infarction. Our data indicate that measurement of homocyst(e)ine in patients with
      myocardial infarction should ideally be deferred for 7 days if spuriously low
      levels are to be averted.

PMID- 8651131
TI  - Usefulness of three-dimensional reconstruction for interpretation and
      quantitative analysis of intracoronary ultrasound during stent deployment.
AB  - We examined 49 coronary stents in 33 patients after angiographically guided
      optimization of the deployment by intracoronary ultrasound, and compared the
      findings of a conventional 2-dimensional analysis approach with the results
      obtained from an automatic lumen recognition provided by a 3-dimensional
      reconstruction system. The automatic lumen analysis demonstrated that only 15
      stents (31%) fulfilled defined ultrasound criteria of adequate stent deployment,
      and that 5 of these cases were missed by the conventional approach, which
      systematically overestimated the dimensions of the minimal stent lumen.

PMID- 8651132
TI  - Effects of dispersive electrode position and surface area on electrical
      parameters and temperature during radiofrequency catheter ablation.
AB  - Positioning of the dispersive electrode has no significant effect during
      radiofrequency ablation. Doubling the surface are of the dispersive electrode
      results in a lower impedance, higher current delivery, and increased tip
      temperatures, particularly if the baseline impedance is >100 ohms. These findings
      may have important implications for optimizing radiofrequency energy delivery
      using currently available radiofrequency generators.

PMID- 8651133
TI  - Doppler-derived pulmonary arterial systolic pressure in patients with known
      systemic arterial pressures.
AB  - In the present study, we evaluated Doppler-derived systolic pulmonary artery
      pressure in 476 hypertensive patients. Clinical interpretation of systolic
      pulmonary arterial pressure should take into account age, body size, and systolic
      blood pressure values.

PMID- 8651134
TI  - Effect of isolated left atrial enlargement on mitral annular size and valve
      competence.
AB  - Effect of isolated left atrial enlargement on mitral annular size and valve
      competence was evaluated in 62 patients with normal left ventricular size and
      function and intrinsically normal mitral leaflets. Echocardiographic data showed
      that isolated left atrial enlargement could cause enlargement of the mitral
      annulus and cause mitral regurgitation.

PMID- 8651135
TI  - Decreased incidence of postoperative pericardial effusions after cardiac surgery
      for congenital heart disease.
AB  - There has been a striking decrease in the incidence of postoperative pericardial
      effusion to 13.6%. A higher incidence of postoperative pericardial effusion was
      found in the winter months.

PMID- 8651136
TI  - Comparison of hospital charges for closure of patent ductus arteriosus by surgery
      and by transcatheter coil occlusion.
AB  - Hospital charges for coil occlusion were significantly less than for surgical
      closure of patent ductus arteriosus, and were reduced over time as experience
      permitted refinement of the coil occlusion protocol. The expected hospital
      charges for closure by a coil occlusion strategy, including the charges for
      surgical closure in patients with failed coil occlusion, was less than the
      hospital charges for surgical closure strategy under any reasonable estimate of
      coil occlusion efficacy.

PMID- 8651137
TI  - Decrease in pacemaker incidence after orthotopic heart transplantation.
AB  - A decrease in sinus node dysfunction and pacemaker requirement after orthotopic
      heart transplantation was observed over a 6.5-year period, probably indicating
      the effect of a learning curve. Indirect evidence suggests a traumatic genesis of
      sinus node dysfunction after cardiac transplantation.

PMID- 8651138
TI  - Acute effects of dynamic cardiomyoplasty on ventricular geometry and left
      ventricular filling detected by transesophageal doppler echocardiography.
AB  - We investigated 7 patients with chronic congestive heart failure undergoing
      dynamic cardiomyoplasty with intraoperative transesophageal echocardiography.
      Biventricular wrapping acutely modified right or left ventricular geometry, but
      did not induce acute restriction to left ventricular filling.

PMID- 8651139
TI  - Pacemaker-induced superior vena cava syndrome with successful treatment by
      balloon venoplasty.
AB  - This is a case report of pacemaker-induced superior vena cava syndrome in which
      the patient was successfully treated with balloon venoplasty. Six-month follow-up
      demonstrates angiographic patency and resolution of symptoms.

PMID- 8651140
TI  - Psychoactive substance use in forensic psychiatry.
AB  - OBJECTIVE: The purpose of this article is to discuss the interface between
      judicial discipline and behavioral science in the context of substance-related
      disorders. METHOD: We review the epidemiology of psychoactive drug use and crime
      and discuss the courts' decisions on relevant landmark cases, particularly as
      they influence the practice of psychiatry. RESULTS: (1) The phenomenology of
      addiction and crime is of great epidemiological import. (2) Our legal system
      inclines toward the view that the use of alcohol or other substances involves an
      element of choice and therefore would not amount to a legal insanity defense if
      the substance abuser commits a crime while intoxicated. (3) A state can confine
      an addict or alcoholic for compulsory treatment if that individual presents a
      danger to self or others. (4) The law has found that alcoholism and drug abuse
      are both "willful misconduct" and a disabling condition; the former definition
      contains the end in view of punitive action. The latter is aimed toward treatment
      and rehabilitation. (5) The law gives the right to the employer to test a
      suspected employee for drug abuse. The addicted or alcoholic employee has the
      choice to either go for treatment or face job termination. (6) Our judicial
      system gives serious consideration to the welfare of a child whose parents are
      alcoholic or drug addicted. CONCLUSION: The two disciplines of psychiatry and law
      follow their own modes in resolving issues in alcoholism and other substance
      abuse. We need research and new approaches to build a bridge between the two.

PMID- 8651141
TI  - Reliability of paper-pencil assessment of drug use severity.
AB  - This research examines whether self-reported information about drug use severity
      can be obtained as reliably using a paper/pencil format as the traditional
      interviewer format. A sample of 67 patients seeking treatment for substance use
      disorders was recruited from a Veterans Administration Medical Center. Subjects
      self-reported information related to drug use severity using both paper/pencil
      and interview formats. The results of comparisons of the two approaches indicate
      that method of test administration does not affect the test-retest reliability
      for most questions tested. Test-retest reliability estimates for these relatively
      brief indicators of drug use severity generally ranged from good to excellent.
      Although assessing drug use severity using a paper/pencil format is certainly not
      appropriate for all individuals with substance use disorders, for many
      individuals and situations it may prove to be a cost-effective alternative to the
      interview format. Further research is required to determine if parallel
      paper/pencil versions of widely used interviews can be developed.

PMID- 8651142
TI  - Effects of ALANON attendance on family perception of inner-city indigents.
AB  - This study investigated the perception of family functioning of rehabilitating
      inner-city substance abusers and one of their family members. Subjects were 39
      residents of a treatment center and 39 family members. The design was compromised
      experimental, comparing the group who had family members in ALANON (n = 36) with
      a nonrandomized control group whose family members had no help (n = 42). Data
      were collected three times: at the beginning of the abuser's treatment, at the
      end, and one month after treatment. Subjects completed two family functioning
      instruments: Assessment of Strategies in Families (ASF) and Family APGAR.
      Repeated-measure MANOVAs yielded significant differences in all family scores
      between the ALANON and the control groups. An increase in the perception of
      family effectiveness was most pronounced between time 2 and time 3, after the
      substance abuse program was completed. Family members changed their perceptions
      more than the abusers and maintained their favorable family perception, even
      though five of the abusers had relapsed shortly after discharge. At 3 months
      after treatment, the relapse rate for addicts in the ALANON group (n = 15) was
      39% compared with 61% for addicts in the control group (n = 18). The difference
      was not of statistical significance due to the small group sizes, however.
      Evidence suggests the usefulness of ALANON in empowering families and assisting
      them in reevaluating the family system more positively.

PMID- 8651143
TI  - Patient factors related to early attrition from an outpatient cocaine research
      clinic.
AB  - The dropout rates among cocaine abusers in outpatient treatment programs have
      averaged 55%. We sought to find patient predictor variables associated with early
      attrition. Dropouts were more likely to be African-American or Hispanic-American,
      younger, with an earlier onset of substance abuse. Among minorities, those with
      more education were less likely to drop out. Patients who were less educated and
      smoked or injected cocaine were particularly prone to discontinue treatment
      prematurely. The implications of these findings, and promising interventions for
      reducing the dropout problem, are discussed.

PMID- 8651144
TI  - Correlates of crack abuse among drug-using incarcerated women: psychological
      trauma, social support, and coping behavior.
AB  - This investigation examines the relationship between psychological trauma and
      crack abuse among 158 women with a recent history of drug use who were
      incarcerated in a New York City jail facility. Interviewers obtained data on
      demographics, drug use, psychological trauma history, criminal history, social
      support, and coping behavior variables. Three-fourths of the total sample had
      used crack three or more times a week for a month in the past; a quarter had used
      other drugs, predominantly heroin, three or more times a week for a month in the
      past. Multiple logistic regression analysis was used to assess the association
      between adult psychological trauma variables (loss of custody of youngest child
      and lived in streets prior to arrest) and regular crack use in three sequential
      models. After adjusting for social support, coping behavior, demographics, and
      criminal history variables, women who had lost custody of their youngest child
      were 3.3 times more likely to be regular crack uses. Women who demonstrated more
      negative coping behavior and perceived themselves as having less emotional
      support were also more likely to be regular crack users. The association between
      childhood traumas (i.e., childhood sexual abuse, childhood physical abuse,
      parental alcohol abuse) and regular crack use was also assessed using multiple
      logistic regression; however, no significant associations were found between
      these childhood psychological traumas and regular crack use in both the
      unadjusted and adjusted models. Study findings underscore the importance of
      assessing environmental, interpersonal, and intrapersonal factors in tailoring
      treatment strategies for users of crack and other drugs.

PMID- 8651145
TI  - The consequences of drug use/abuse for vocational career: a longitudinal study of
      a male urban African-American sample.
AB  - This report is from a longitudinal study of a community sample of African
      American males (N = 197) on the relationship of the degree of earlier substance
      use/abuse up to average age 24, to vocational performance (employment and
      occupational level) 2 1/2 years later (at average age 26 1/2). The statistical
      analyses included numerous control variables developed from prospective data of
      the National Collaborative Perinatal Project, on the subjects and on their
      families from the subjects' birth to age 7, and from their school behavior and
      academic performance up to age 16, which may have influenced their vocational
      occupational behavior during early adulthood. It was found that greater earlier
      marijuana use and greater earlier alcohol use predicted, to a significant degree,
      poorer occupational performance.

PMID- 8651146
TI  - Victimization and PTSD in individuals with substance use disorders: gender and
      racial differences.
AB  - There is a paucity of studies concerning the prevalence of crime-related
      posttraumatic stress disorder (CR-PTSD) in individuals with substance use
      disorders, despite documentation of particularly high prevalence rates of sexual
      and physical assault in this population. A central objective of the present
      investigation was to assess victimization experiences and CR-PTSD among
      individuals receiving inpatient treatment for substance use disorders and
      evaluate gender and racial differences in assault characteristics CR-PTSD
      prevalence rates. A total of 95 inpatients (34 men and 61 women; 41 African
      Americans, 52 Caucasians, and 2 other minorities) were administered a structured
      interview to assess substance abuse/dependence, trauma, and PTSD. Approximately
      90% of the participants had a lifetime history of sexual and/or physical assault,
      and approximately 50% had CR-PTSD. With the exception of rape, no gender
      differences in assault or CR-PTSD prevalence rates were observed. Women were more
      likely than men to perceive their life as endangered during a rape. Men were
      younger than women when they experienced their first (or only) aggravated assault
      and were more likely to have been assaulted by a family member. No racial
      differences were detected for assault or PTSD, although African-American patients
      were significantly more likely to identify cocaine as their primary drug than
      Caucasian patients. Given the strikingly high rate of comorbid CR-PTSD among
      substance use disordered patients, exploration of the type and timing of
      interventions would be of clinical interest.

PMID- 8651147
TI  - Psychiatric comorbidity: prevalence in methadone maintenance treatment.
AB  - This study examines prevalence rates for DSM-III-R anxiety and affective
      disorders in three follow-up samples of opioid addicts who were treated with
      methadone maintenance. At least one anxiety disorder was diagnosed in 55% of the
      total sample. Affective disorders were found in 58%. At least one anxiety
      disorder coexisted with at least one affective disorder in 36% of the sample. The
      research demonstrates that opiate addiction in this sample is most often
      associated with other comorbid psychopathology. It suggests a need for thorough
      assessment for general psychopathology in opioid addicts entering addiction
      treatment, especially assessment for anxiety and affective disorders. It also
      suggests the need for treatment that focuses on diagnosed mental disorders in
      addition to drug counseling for the substance abuse disorder.

PMID- 8651148
TI  - Should the 1996 citation for Zollinger-Ellison syndrome read: "Acid-reducing
      surgery in, aggressive resection out"?

PMID- 8651149
TI  - Who should undergo testing for Helicobacter pylori?

PMID- 8651150
TI  - Choosing the best anti-Helicobacter pylori therapy: effect of antimicrobial
      resistance.
AB  - BACKGROUND: The development of effective therapies for the treatment of
      Helicobacter pylori infection has been a long and arduous process. There is
      considerable confusion about which is the best. METHODS: We review approaches to
      understanding the results of trials evaluating potentially new therapies and
      those comparing two or more potentially good regimens with particular emphasis on
      the role of antimicrobial resistance on the outcome of therapy. RESULTS:
      Antimicrobial resistance in vitro does not always correlate with poor results
      with multi-drug treatment regimes. Although it is not known if clinical
      resistance defined as failure of a therapy might be a better predictive of
      subsequent failure, overall effectiveness is influenced most strongly by the drug
      with the poorest cure rates in the presence of resistant microorganisms.
      Development of resistance is reduced in multiple drug therapies. Bismuth may be
      an especially useful antimicrobial in this regard because it is an effective
      topical therapy that markedly reduces the bacterial load. Resistance to
      antimicrobials can be thought of as a statistical event estimated as a proportion
      of the H.pylori population in the stomach (e.g., 1 in 10(8) bacteria).
      Elimination of most organisms with the first dose of bismuth might decrease
      likelihood of survival of resistant strains that were already present.
      CONCLUSION: Results of large clinical trials are needed to provide accurate
      estimation concerning the effectiveness of the different treatment regimes using
      different dosages, dosing intervals, and duration of therapy. For interpretation
      and comparison, clinical trials must report the overall effectiveness as well as
      effectiveness of the regimen separately for those with resistant and sensitive
      H.pylori.

PMID- 8651151
TI  - Clinical applications of esophageal manometry and pH monitoring.
AB  - In summary, GERD patients are usually well managed using a careful medical
      history, endoscopy, and empirical trials of antireflux medications. Extended
      esophageal pH monitoring is unnecessary in most patients but can be of
      considerable value in managing patients with typical or atypical symptoms who are
      refractory to standard therapy for GERD. Furthermore, the test can be useful in
      documenting abnormal reflux in an individual without esophagitis being evaluated
      for antireflux surgery. The test is done with compact, portable data loggers,
      miniature pH electrodes, and computerized data analysis. The pH electrode should
      be positioned 5 cm above the manometrically defined upper limit of the LES, and
      patients should undergo the test on an unrestricted diet. In terms of data
      analysis, the total percentage time of pH < 4 provides as much information as any
      other scheme of quantifying esophageal acid exposure, but symptom association is
      essential when evaluating atypical or sporadic symptoms. Enthusiasm for 24-h pH
      monitoring must, however, be tempered with an analysis of its proven clinical
      utility in patient management with its utility rightfully compared with that of
      an empirical trial of anti-reflux therapy. Ambulatory pH monitoring is probably
      most useful in examining patients without typical reflux symptoms or patients who
      have either partially or completely failed a trial of anti-reflux therapy. To
      date, there have not been any prospective, controlled clinical trials evaluating
      these uses. Suggested clinical indications for ambulatory pH monitoring are
      listed in Table 5 (53).

PMID- 8651152
TI  - Rheumatological complications of GI disorders.
AB  - The clinical features, pathogenesis, and management of the rheumatic
      manifestations of various GI disorders are reviewed. The major categories
      included are intestinal disorders (enterohepatic arthritides, inflammatory bowel
      disease, and several other less common conditions), hepatitis (acute and
      chronic), and pancreatic diseases (carcinoma and pancreatitis). Historical
      background is provided where appropriate, and several recent observations and
      associations are described and discussed.

PMID- 8651153
TI  - Laparotomy and proximal gastric vagotomy in Zollinger-Ellison syndrome: results
      of a 16-year prospective study.
AB  - OBJECTIVE: Pharmacological control of gastric acid hypersecretion in the
      Zollinger-Ellison syndrome has steadily improved, but medical treatment does not
      address the underlying tumor. The objective of this study was to evaluate the
      long-term effectiveness of a surgical approach to both tumor and acid
      hypersecretion in 22 patients with the Zollinger-Ellison syndrome. METHODS:
      Patients underwent laparotomy to resect tumors, combined with vagotomy to reduce
      acid secretion, followed by postoperative antisecretory therapy, if necessary.
      RESULTS: No surgical mortality or serious morbidity occurred. Tumor was found at
      laparotomy in nine patients (41%) and during long-term follow-up in an additional
      two patients (9%). Ten-year survival is 81%, with a long-term cure rate of at
      least 14%. Most patients (86%) have had long-term inhibition of acid secretion.
      Eight patients have discontinued regular use of acid-inhibiting medications.
      Patients requiring medication need less of it, and they have an improved acid
      inhibitory response to medication for up to 16 yr after surgery. CONCLUSION: Cure
      of the Zollinger-Ellison syndrome is possible in a minority of patients. Acid
      secretion can be safely reduced in almost all patients with laparotomy/vagotomy,
      usually allowing discontinuation, or reduced dose, of acid-inhibiting drugs. Long
      term survival and quality of life are generally excellent.

PMID- 8651154
TI  - Low point prevalence of peptic ulcer in normal individuals with Helicobacter
      pylori infection.
AB  - OBJECTIVE: A recent study from Italy reported a high prevalence of ulcer disease
      in asymptomatic Helicobacter pylori infection. Such results are at variance with
      previous endoscopy screening studies. Our study was performed to obtain data on
      ulcer prevalence in normal H. pylori-infected subjects in the United States.
      METHODS: One hundred and ninety healthy individuals of either gender, over the
      age of 18, were studied. After completion of a detailed questionnaire and a urea
      breath test for H. pylori status, endoscopy was performed. Ulcer was defined as a
      mucosal ulceration > 5 mm in diameter and with apparent depth. RESULTS: There
      were 108 (57%) women and 82 (43%) men. The mean (+/-SD) age was 38.9 (+/-10.7)
      yr, range 21-79 yr. Careful history obtained after enrollment revealed presence
      of dyspeptic symptoms in 35 subjects (18%); the remaining 155 individuals were
      completely symptom-free. Infection with H. pylori was present in 102 subjects
      (54%). The infection rate was highest in Hispanics (70%), followed by African
      Americans (58%), Caucasians (38%), and Asians (17%). The prevalence increased
      with age. Only two (1%) of 190 subjects, both with H.pylori infection, had peptic
      ulcer. In the H. pylori-infected group, the prevalence of peptic ulcer was 2%.
      CONCLUSION: In the United States, significant unrecognized and asymptomatic
      gastroduodenal disease is uncommon in H. pylori-infected individuals. These
      findings do not support the need for a mass screening program for H. pylori
      infection or for the use of antimicrobial treatment of asymptomatic subjects with
      this infection.

PMID- 8651155
TI  - The risk of withdrawing chronic anticoagulation because of acute GI bleeding.
AB  - OBJECTIVE: We sought evidence for thromboembolic sequelae after the transient
      withdrawal of chronic anti-coagulation because of acute GI bleeding. METHODS: Our
      Gastrointestinal Bleeding Team endoscopic database was reviewed over a 5-yr
      period to identify patients who underwent a transient withdrawal from chronic
      anticoagulation as a result of acute GI bleeding. Long term follow-up records
      were available for all study patients and were carefully scrutinized for any
      symptomatic thromboembolic events. RESULTS: Twenty-seven patients were included
      in the study, of which 17 (63%) were on chronic anticoagulation for prosthetic
      heart valves. Chronic anticoagulation was withheld for a median period of 3 days
      (range = 2-7 days) for patients with prosthetic heart valves and 7 days (range =
      2-15 days) for patients on chronic anticoagulation for other indications. Over a
      median follow-up period of 8 months (range = 1-54 months), one patient developed
      documented lower extremity thromboembolism. CONCLUSIONS: We conclude that
      symptomatic thromboembolism can occur after the transient withdrawal of chronic
      anticoagulation for acute GI bleeding but that it does not occur frequently.

PMID- 8651156
TI  - Efficacy and safety of combined meperidine and midazolam for EGD sedation
      compared with midazolam alone.
AB  - BACKGROUND/AIMS: Safety concerns have been raised about the use of the
      combination of an opioid and benzodiazepine for esophagogastroduodenoscopy (EGD)
      sedation, a common practice of American gastroenterologists. If we could show
      that patients in American practice settings satisfactorily tolerate EGD with
      midazolam alone, as is commonly done in Europe, it would provide impetus for
      American gastroenterologists to change practice habits. METHODS: We performed a
      randomized, double-blind trial to determine whether meperidine, used in addition
      to midazolam, improved patient tolerance to EGD compared with the use of
      midazolam alone in our academic practice setting. Safety parameters were also
      examined. One hundred twenty adult patients undergoing diagnostic EGD were
      randomized to receive either 50 mg of meperidine (group I) or 1 mg of midazolam
      (group II). Patients were then given additional midazolam in incremental doses at
      the discretion of the attending gastroenterologist to induce a state of conscious
      sedation. RESULTS: Including the study drug, patients in group I received an
      average of 1.8 mg less of midazolam compared with group II (mean total midazolam
      dose, 3.8 mg vs 5.6 mg; p = 0.037). Patients in group I showed improved tolerance
      for EGD compared with those in group II in terms of a physician rating of "poor"
      for the overall adequacy of sedation (7 vs 20%, p = 0.033), the need for
      supplemental narcotics or droperidol during the procedure (7 vs 20%, p = 0.033),
      the need for additional medication during intubation of the esophagus (12 vs 25%,
      p = 0.06), the need for a faculty member to accomplish esophageal intubation (7
      vs 20%, p = 0.051), the presence of retching, which interfered with the procedure
      (21 vs 39%, p = 0.046), and premature termination of the exam (0 vs 7%, p =
      0.055). No difference was seen in the degree of amnesia, in the willingness of
      patients to undergo another EGD in the future, or in cardiorespiratory
      parameters. CONCLUSIONS: In our academic practice setting, 50 mg of meperidine
      given i.v. at the start of the procedure improved the ability of our patients to
      tolerate EGD from the endoscopists' standpoint. We found no difference in
      cardiorespiratory parameters between the groups.

PMID- 8651157
TI  - Utility of parameters measured during pneumatic dilation as predictors of
      successful dilation.
AB  - OBJECTIVES: The ability to immediately predict the long term outcome of a
      pneumatic dilation in achalasia has not been well studied. This study
      prospectively compared immediate postpneumatic dilation parameters with long term
      efficacy to determine if any factors predicted a favorable long term outcome.
      METHODS: Twenty-nine previously undilated achalasia patients underwent graduated
      pneumatic dilation with Hurst-Tucker dilators (diameters 2.7, 3.3, 3.7, and 4.1
      cm). Dilations began with the smallest dilator followed by an observation period
      of at least 6 wk to determine clinical response. If no clinical improvement was
      noted, the next size dilator was used. Immediate postdilation parameters studies
      included: 1) severity of pain during dilation, 2) amount of blood on the dilator,
      3) insufflation pressures during dilation, 4) esophageal emptying of
      gastrograffin (30 ml), and 5) esophageal emptying of barium sulfate (90 ml).
      RESULTS: None of the postdilation parameters studied predicted which patients
      would have good long term results. Pain during dilation increased with increasing
      dilator size. CONCLUSIONS: The degree of pain associated with a pneumatic
      dilation, the amount of blood noted on the dilator, the difference in pressure
      required to inflate the dilator at the beginning versus the end of dilation, and
      the amount of esophageal emptying immediately postdilation did not predict long
      term outcome.

PMID- 8651158
TI  - Percutaneous endoscopic gastrojejunostomy with a tapered tip, nonweighted jejunal
      feeding tube: improved placement success.
AB  - OBJECTIVES: Gaining enteral access to the small bowel for patients unable to
      tolerate gastric feedings is a difficult challenge for today's endoscopist. A new
      over-the-guidewire method for placement of a percutaneous endoscopic
      gastrojejunostomy (PEG/J) is prospectively studied using a nonweighted, tapered
      tip, distal feed through jejunal tube (J-tube). METHODS: Twenty five hospitalized
      patients were referred to the nutrition service for enteral access. A Wilson-Cook
      24/12-French PEG/J system was placed and followed until removal or patient death.
      RESULTS: The PEG/J system was placed in 25/25 patients in an average of 26 min
      and 45 s. The tip of the J-tube was in the distal duodenum in 52% of patients and
      in the jejunum in 48% of patients. J-tube complications occurred in 20% of
      patients and included one incidence of clogging (4%) and four cases of
      inadvertent removal (16%). Average longevity of the J-tube was 63.9 days, with
      most patients converted to either oral or gastric feedings. CONCLUSION: The use
      of an nonweighted, tapered tip J-tube and the over-the-guidewire placement
      technique has resulted in a reliable method of accessing the small bowel for
      enteral nutrition.

PMID- 8651159
TI  - The interaction of pH, bile, and Helicobacter pylori may explain duodenal ulcer.
AB  - BACKGROUND: Inhibition of Helicobacter pylori growth by bile suggests that it
      should be difficult for H. pylori to colonize the duodenum and cause duodenal
      ulcer. To search for a common mechanism, we investigated the relationship between
      H. pylori strain (duodenal ulcer vs gastritis), type of bile acid conjugate, and
      inhibition of H. pylori growth. METHODS: H. pylori isolates from patients with
      duodenal ulcer and from volunteers with asymptomatic gastritis (six each) were
      grown in brain heart infusion broth medium containing mixtures of glycocholate,
      taurocholate, glycodeoxycholate, taurodeoxycholate, glycochenodeoxycholate, and
      taurochenodeoxycholate with and without lecithin. RESULTS: Synthetic human bile
      with or without lecithin inhibited H. pylori growth in a dose-dependent manner.
      There was no difference in inhibition between H. pylori gastritis and duodenal
      ulcer isolates. Glycine and mixed glycine and taurine-conjugated bile acids
      inhibited H. pylori more than taurine-conjugated bile acids (e.g., 51%, 67%, and
      80% compared to 21%, 39%, and 46% for 1, 2, and 4 mM mixed conjugates compared
      with taurine conjugates, p < 0.05, respectively. CONCLUSIONS: The ability of H.
      pylori to grow in the presence of taurine-conjugated bile acids and the
      precipitation of glycine but not taurine bile acid conjugates by acid may provide
      one missing link among inhibition of H. pylori by bile, acid secretion, ability
      of antisecretory therapy to accelerate ulcer healing, and the ability of H.
      pylori to colonize the duodenal bulb of ulcer patients, leading to duodenal
      ulcer. These data also explain the disparate results of previous investigations
      of the effect of bile reflux in the stomach on the presence of H. pylori.

PMID- 8651160
TI  - Do commercial serological kits for Helicobacter pylori infection differ in
      accuracy? A meta-analysis.
AB  - OBJECTIVES: To compare the accuracy of common commercial serological kits for
      Helicobacter pylori and to ascertain factors affecting accuracy. METHODS: A
      comprehensive MEDLINE and manual search strategy was used to identify all
      articles comparing two or more kits. Each article was critically appraised for
      sample characteristics, study design, and data handling. The data comparing
      accuracy of the kits was analyzed by standard statistical methods as well as
      summary receiver operator characteristic curves (sROCs). A sROC also was used to
      estimate overall test accuracy and to identify factors affecting the measurement
      of accuracy. RESULTS: The 21 studies identified were of varying quality, but our
      analyses suggested that different commercial kits did not have significantly
      different accuracy. Overall, at a sensitivity of 85%, specificity was estimated
      to be 79%. Test accuracy measured was significantly higher in studies with
      smaller proportions of infected patients. CONCLUSIONS: There is little evidence
      in the literature to suggest that any one of the common commercial serological
      kits is more accurate than any other. The overall accuracy of these kits may not
      be adequate for clinical decision-making in all patient groups.

PMID- 8651161
TI  - Detection of Helicobacter pylori infection by saliva IgG testing.
AB  - OBJECTIVES: Most currently available tests for the detection of Helicobacter
      pylori are invasive, time consuming, or impractical. We examined the test
      performance of a simple and rapidly administered salivary IgG assay kit in the
      diagnosis of Helicobacter pylori infection. METHODS: Patients referred to a
      tertiary care setting for upper gastrointestinal endoscopy were included in a
      prospective evaluation of the test performance of the Helisal Kit which uses an
      ELISA technique to determine IgG antibodies in saliva. The results of the
      salivary IgG assay were compared to those of the Helisal Serum Kit, and to
      gastric histology. Two by two contingency table analyses were performed, and 95%
      confidence intervals (CI) were determined. RESULTS: Upper gastrointestinal
      endoscopy was performed on 106 patients over a 3-month period. A statistically
      significant correlation was found between the blood and saliva IgG results (r =
      0.60, p = 0.0001). When compared to serum IgG, the salivary assay test
      performance was: sensitivity 84% (CI: 70-93%), specificity 81% (CI: 69-90%),
      positive predictive value 76% (CI: 61-87%), negative predictive value 88% (CI: 76
      95%), and diagnostic accuracy 88% (CI: 76-95%). Compared with gastric histology,
      the test performance of the salivary IgG assay decreased to: sensitivity 66% (CI:
      52-79%), specificity 74% (CI: 60-85%), positive predictive value 71% (CI: 57
      83%), negative predictive value 68% (CI: 55-80%), and diagnostic accuracy 70%
      (CI: 60-78%). More specifically, the salivary assay gave false-negative results
      in nine of 17 patients with duodenal ulcers. Results did not vary significantly
      when outcomes of the salivary and serum assays were combined. The incremental
      information obtained in the salivary test was greatest in the patient population
      exhibiting an intermediate pretest probability (30-70%) of being infected with
      Helicobacter. CONCLUSION: The salivary IgG results correlated significantly with
      the serum IgG titers but exhibited only modest test performance, compared with
      the results of gastric histology. This salivary test may be most useful in
      certain patient subpopulations or in specific clinical contexts.

PMID- 8651162
TI  - Interleukin-8 activity correlates with histological severity in Helicobacter
      pylori-associated antral gastritis.
AB  - OBJECTIVES: To examine the background histology, interleukin-8 (IL-8) secretion,
      and expression of IL-8 mRNA and protein, using the gastric antral mucosa infected
      with Helicobacter pylori. METHODS: The antral biopsies were obtained from an area
      of endoscopically intact mucosa in 147 patients whose endoscopic diagnoses were
      normal (n = 41), duodenal ulcer (n = 58), gastric ulcer (n = 21), or gastritis (n
      = 27). Levels of IL-8 secreted in the organ cultures of mucosal biopsies were
      measured by an ELISA assay, and the expression of IL-8 mRNA and protein was
      analyzed in fresh biopsy tissues with RT-PCR and immunofluorescent microscopy,
      respectively. RESULTS: Significantly greater levels of IL-8 were secreted in
      patients with H. pylori infection, and its elevation was more prominent in
      duodenal ulcer patients than in those with gastric ulcer or endoscopically
      defined gastritis. There was an association among H. pylori density, IL-8
      activity, and histological severity of activity and inflammation of gastritis in
      the Sydney system. Consistent with enhanced IL-8 activity in the organ cultures,
      IL-8 mRNA was detected in 16 of 23 fresh biopsy tissues studied in H. pylori
      positive patients. In contrast, IL-8 transcript was detected in only one of 12 H.
      pylori-negative cases. Immunofluorescent microscopy showed localization of IL-8
      protein in the gastric epithelial cells and lamina propria cells, primarily CD68+
      macrophages in specimens with H. pylori infection. CONCLUSIONS: This study
      indicates that a strong correlation exists between mucosal IL-8 activity and
      histological severity in H. pylori-associated antral gastritis. Further studies
      will be necessary to determine the mechanisms involved in elevated mucosal IL-8
      activity in H. pylori infection.

PMID- 8651163
TI  - Esophageal motility in patients with esophageal caustic injury.
AB  - OBJECTIVE: There are few studies of esophageal function subsequent to the
      ingestion of lye. We investigated the esophageal motility of patients who had
      ingested liquid sodium hydroxide. METHODS: Esophageal manometry was performed on
      21 patients who [1-53 yr before the manometric examination (median: 13 yr)] had
      drunk 10-30 g of sodium hydroxide diluted in water. The results were compared
      with those obtained for a control group of 22 healthy volunteers. RESULTS: The
      lower esophageal sphincter (LES) pressure of the caustic group (14.9 +/- 1.7 mm
      Hg, mean +/- SE) did not differ (p > 0.05) from that of the control group (17.4
      +/- 1.1 mm Hg). LES pressure in eight patients was below 10 mm Hg. The amplitude
      of contraction was lower (p < 0.01) in the caustic group than in the control
      group. In the proximal part of the esophageal body, the duration of contraction
      was longer (p < 0.01) in the caustic group (2.3 +/- 0.1 s) than in controls (1.8
      +/- 0.1 s). Nonperistaltic contraction was a finding in 14 patients, repetitive
      in five of them. The velocity of peristaltic contractions was higher (p < 0.05)
      in the caustic group (distal: 3.2 +/- 0.2 cm/s) than in the control group (2.2 +/
      0.2 cm/s). Although there was some impairment of esophageal motor function in
      71% of the patients, they were asymptomatic when we performed esophageal
      manometry. CONCLUSIONS: Esophageal motility impairment was present in most of the
      patients who ingested sodium hydroxide. Nonperistaltic contractions of low
      amplitude were found most frequently.

PMID- 8651164
TI  - Dual site ambulatory pH monitoring: a probe across the lower esophageal sphincter
      does not induce gastroesophageal reflux.
AB  - BACKGROUND: Twenty-four-hour ambulatory pH studies have traditionally been
      performed with placement of the pH electrodes proximal to the lower esophageal
      sphincter (LES). More recently, simultaneous gastric and esophageal pH monitoring
      studies have been performed to allow the simultaneous assessment and correlation
      of esophageal and gastric pH. OBJECTIVES: The purpose of this study was to
      determine if pH probe placement across the LES increases esophageal acid exposure
      either in asymptomatic, healthy volunteers or in symptomatic patients with a
      documented history of erosive esophagitis. METHODS: Ten healthy volunteers (five
      female, five male; mean age 27 yr) and 13 patients with endoscopically confirmed
      erosive esophagitis (seven female, six male; mean age 35 yr) were randomly
      assigned, in cross-over fashion, into two protocols. The first protocol required
      placement of a dual antimony pH electrode catheter (2.1-mm outside diameter)
      across the LES with pH electrodes positioned 5 cm above and 10 cm below the
      manometrically identified LES. The second protocol required catheter placement 5
      cm and 20 cm above the LES. Twenty-four-hour pH monitoring was performed on all
      subjects. Healthy volunteers were permitted an unrestricted diet and were studied
      in an out-patient setting. Symptomatic patients were assessed in an inpatient
      setting on a standardized diet with a refluxogenic dinner meal. RESULTS: The
      total number of reflux episodes, number of reflux episodes greater than 5 min,
      and the fraction of time that pH was less than 4 were evaluated over the total 24
      h time period in the upright and supine positions. Nonparametric paired tests
      including a Wilcoxon signed rank test and a Robust analysis were used for
      statistical assessment. There was no significant increase in gastroesophageal
      reflux observed with placement of the pH probe across the LES either in the
      asymptomatic healthy volunteers or in patients with documented erosive
      esophagitis. Neither upright nor supine esophageal acid exposures were modified
      by catheter placement. CONCLUSIONS: Our study results indicate that placement of
      a 2.1-mm diameter pH probe across the LES does not induce reflux in asymptomatic
      healthy volunteers or in patients with GERD. Dual site ambulatory pH monitoring
      with trans-sphincteric pH catheter placement is a valid diagnostic technique that
      can be applied clinically when required.

PMID- 8651165
TI  - A single intragastric pH electrode does not accurately measure intragastric
      acidity.
AB  - OBJECTIVES: Recent studies have raised concerns about the validity of using a
      single intragastric pH electrode to measure gastric acidity accurately and
      reproducibly. The aim of this study was to compare simultaneous intragastric pH
      measurements obtained from an indwelling glass pH electrode to those determined
      by aspirations from the gastric pool and from ex vivo measurement. METHODS:
      Twenty two normal volunteers were studied after fluoroscopically guided placement
      of a combined nasogastric tube-pH probe assembly. Simultaneous intragastric pH
      electrode and aspirate pH determinations were made basally for 120 min after
      administration of 15 ml of antacid (40 mEq buffering capacity) and for another
      120 min an hour postprandially after administration of a second 15-ml dose of
      antacid. Gastric acid concentration (pH) measurements were recorded every 15 min
      during the following study protocols: 1) fasting baseline (30 min); 2) fasting
      antacid (120 min); 3) test meal (60 min); and 4) postprandial antacid (120 min).
      RESULTS: Intragastric pH was consistently and significantly lower as measured by
      intragastric pH electrode than by aspiration. Baseline hydrogen ion concentration
      ([H+]) was 4.3 times higher by direct electrode measurement than by aspirate.
      Antacid-administered fasting decreased [H+] maximally at 15 min to 48% and 82% of
      baseline by electrode and aspiration, respectively. The minimal residual
      intragastric [H+] after fasting antacid was 12.4 times higher by electrode than
      by aspiration. Postprandial antacid maximally reduced [H+] by 46% at 15 min when
      recorded using an electrode compared with 60% at 30 min by aspiration.
      Correlation coefficients for intragastric electrode [H+] versus aspiration [H+]
      were 0.26 (p = 0.253), 0.61 (p < 0.001), 0.56 (p < 0.01), and 0.31 (p < 0.001),
      for baseline, fasting antacid, meal, and postprandial antacid, respectively.
      CONCLUSIONS: Quantitative evaluations of intragastric acidity (pH) using an
      intragastric pH electrode and aspiration of gastric juice may yield remarkably
      different results. Studies that rely on a single intragastric electrode to
      quantitate intragastric acidity may be highly inaccurate.

PMID- 8651166
TI  - Effect of Rennie Liquid versus Maalox Liquid on intragastric pH in a double
      blind, randomized, placebo-controlled, triple cross-over study in healthy
      volunteers.
AB  - OBJECTIVES: Despite years of successful use of calcium-containing antacids in
      acid-related disease, allegations of gastric rebound following their intake has
      brought these agents into disrepute. By assessing intragastric acidity over the
      24-h period, we evaluated whether antacids induce a clinically relevant acid
      rebound. METHODS: Twelve healthy volunteers were assigned to a double-blind,
      placebo-controlled, triple cross-over comparison of placebo, Maalox Liquid, and a
      calcium-containing antacid, Rennie Liquid. The two antacids had identical
      neutralizing capacity. Each drug was administered at standard doses q.i.d 1 h
      after the main meals (at 1000, 1400, and 1900 h) and at bedtime (2300 h).
      Intragastric acidity was monitored by continuous ambulatory 24-h pH-metry on 3
      separate days with a wash-out period of 1 wk. Special attention was given to the
      acidity of pre-determined postantacid time intervals during the day and night.
      RESULTS: Both antacids led to a significant increase of the median 24-h pH and
      the median pH of the first postantacid hour, compared with placebo. Neither
      Rennie Liquid nor Maalox Liquid led to a drop of intragastric pH during the
      putative acid rebound time (2nd and 3rd postantacid hr and at night). A marginal
      increase in serum calcium and gastrin concentration with Rennie Liquid, and
      magnesium concentration with Maalox Liquid, were observed. CONCLUSIONS: No
      gastric acid rebound was detected with the calcium carbonate-containing antacid,
      Rennie Liquid, or with Maalox Liquid at standard doses. An identical increase of
      intragastric pH was achieved with Rennie Liquid and Maalox Liquid during the
      first postantacid hour and the entire 24-h period.

PMID- 8651167
TI  - Comparison of barium radiology with esophageal pH monitoring in the diagnosis of
      gastroesophageal reflux disease.
AB  - OBJECTIVE: Barium radiology has recently been recommended as a screening
      procedure for gastroesophageal reflux disease. The aim of this study was to
      assess the accuracy of barium screening as a predictor of abnormal esophageal
      acid exposure on pH monitoring. PATIENTS AND METHODS: One hundred and twenty-five
      patients underwent both barium radiology and esophageal pH monitoring at the
      Thomas Jefferson Hospital, Philadelphia, from October 1989 through July 1991. The
      presence or absence of spontaneous reflux, reflux during the water-siphon test,
      and a hiatus hernia was recorded and assessed retrospectively. RESULTS: The
      proportion of patients with a positive pH test did not differ among those with
      spontaneous reflux (21/31, 68%) and those with no reflux, on barium study (61/94,
      65%). The proportion of patients with a positive pH test did not differ among
      those with a hiatus hernia (35/50, 70%) and those without (47/75, 63%). This was
      despite significantly higher median percent total times pH < 4 among those with
      spontaneous reflux or a hiatus hernia (p < 0.05). The additional application of a
      water-siphon test induced reflux in 91% of those tested. The sensitivities of
      spontaneous reflux and hiatus hernia were low (26% and 43%), and specificities
      were only modest (77% and 65%). The addition of the water-siphon test gave a
      sensitivity of 92%, but the specificity was zero. CONCLUSION: A significantly
      greater degree of abnormal esophageal acid exposure occurs in patients who have
      either a hiatus hernia or spontaneous reflux, demonstrated during fluoroscopy.
      However, the sensitivity and specificity of barium radiology for abnormal degrees
      of acid reflux are insufficient for it to be worthwhile as a screening procedure.

PMID- 8651168
TI  - Periampullary extraluminal duodenal diverticula and acute pancreatitis: an
      underestimated etiological association.
AB  - OBJECTIVES: The aim of this study was to investigate the etiological role of
      periampullary extraluminal duodenal diverticula (PEDD) in acute pancreatitis
      (AP). METHODS: The study included 433 consecutive patients who underwent
      successful ERCP during the period 1992-1994; PEDD were discovered in 58 cases
      (13.4%); patients without PEDD (n = 375) were considered the control group.
      Indication for ERCP and final diagnosis were recorded in each case. RESULTS: The
      age of patients with PEDD was significantly higher (p < 0.0001) than that of
      controls. The incidence of biliary lithiasis was 65.5% in PEDD and 40.8% in
      controls (p = 0.0001). A recent episode or acute phase of AP constituted the
      indication for ERCP in 62% of PEDD and 24.8% of controls (p < 0.0001); idiopathic
      AP was found more often (p = 0.04) in PEDD patients (13.7%) than in controls
      (1.8%). CONCLUSIONS: PEDD should be included in the list of possible etiological
      factors of AP. The presence of PEDD should be verified, mainly in elderly
      patients, before defining an AP episode as idiopathic.

PMID- 8651169
TI  - Ultrasound follow-up of patients at risk for hepatocellular carcinoma: results of
      a prospective study on 360 cases.
AB  - OBJECTIVES: We performed a prospective study with ultrasound (US) follow-up on a
      population at risk for hepatocellular carcinoma (HCC) to evaluate the
      possibilities of diagnosis of HCC at an early stage. METHODS: We studied 360
      patients; 254 of those patients had cirrhosis of the liver (of which 167 had HCV,
      28 had HBV, 53 were alcoholic, and six had autoimmune disease), and the remaining
      106 patients had chronic hepatitis. US scan was performed and alpha-fetoprotein
      was measured every 6 months. Mean duration of follow-up was 56 months (range 18
      72). We compared the results of HCC detection with those of 2170 patients with
      cirrhosis or chronic hepatitis observed with US in the same period, outside the
      follow-up protocol. RESULTS: In 24 of the follow-up patients, hepatic lesions
      were detected with US and proved to be HCC with fine needle biopsy, with a
      cumulative incidence of 6.6% and an annual incidence of 1.4%. The HCC was
      unifocal in 18 patients, always with diameter < or = 3 cm (small HCC). All but
      one of the 24 patients who developed HCC had liver cirrhosis, and the remaining
      patient had HBV-correlated chronic hepatitis. In the group of 2170 patients
      without serial follow-up, the percentage of detected unifocal tumors with
      diameters < or = 3 cm was only 15.5%, compared with 75% in the patients with
      serial follow-up. CONCLUSIONS: The US follow-up of a population at risk for HCC,
      consisting of patients with chronic liver diseases, made it possible to diagnose
      tumor < or = 3 cm in a high percentage of cases, with a statistically highly
      significant difference (chi 2, p = 0.000) compared with the patients not in the
      follow-up. Follow-up could increase the percentage of HCCs detected at a
      potentially curable stage. Cirrhosis is confirmed as being the main risk cause,
      regardless of etiology.

PMID- 8651170
TI  - The role of previous hepatitis B virus infection and heavy smoking in hepatitis C
      virus-related hepatocellular carcinoma.
AB  - OBJECTIVE: Worldwide epidemiological studies have demonstrated that hepatitis C
      virus (HCV) probably is a causative agent of hepatocellular carcinoma (HCC).
      However, there are no available reports that clearly identify the risk factors
      for the development of HCC in HCV-related chronic liver disease (CLD). The aim of
      the present study is to explore the risk factors for hepatocarcinogenesis in HCV
      related CLD. METHODS: We prospectively observed 412 patients with anti-HCV
      positive CLD but without co-infection of hepatitis B virus (232 patients with
      chronic hepatitis and 180 with liver cirrhosis) for between 0.5 and 15.8 yr
      (median: 4.9 yr). Risk factors for hepatocarcinogenesis were identified with a
      Cox proportional-hazard model. RESULTS: Sixty-three patients (15.3%) developed
      HCC during the observation period; the cumulative occurrence rates at the end of
      the 5th, 10th, and 15th yr was 3.7%, 12.1%, and 12.1%, respectively, for chronic
      hepatitis patients and 23.3%, 49.4%, and 90.7%, respectively, for 180 cirrhotic
      patients. The Cox proportional-hazard model showed that the risk of
      hepatocarcinogenesis increased almost 5-fold in cirrhotic patients (risk ratio,
      5.14; 95% confidence interval, 2.52-10.46, p = 0.0001), 2-fold in patients with
      positive antibodies against hepatitis B surface antigen and/or antibodies against
      hepatitis B core antigen (risk ratio, 2.14; 95% confidence interval, 1.13-4.07, p
      = 0.0201), and 2.5-fold in heavy smokers (risk ratio, 2.46; 95% confidence
      interval, 1.11-5.49, p = 0.0276). CONCLUSION: These epidemiological results
      indicate that previous infection with hepatitis B virus and heavy smoking (in
      addition to liver cirrhosis, a known risk factor) play important roles as risk
      factors for carcinogenesis in HCV-related CLD.

PMID- 8651171
TI  - Chronic hepatitis C in patients with sickle cell disease.
AB  - OBJECTIVE: To determine the prevalence of hepatitis C virus (HCV) antibody in
      patients with sickle cell disease and to analyze the nature of chronic liver
      disease in these patients. METHODS: A total of 99 patients attending a
      comprehensive sickle cell and thalassemia program at the Interfaith Medical
      Center, Brooklyn, NY, participated in the study. Eighty-five patients had sickle
      cell anemia (ss), eight had sickle C disease (sc), and six had sickle B
      thalassemia. History of blood transfusion, i.v. drug use, homosexuality, and
      alcohol abuse was obtained with a questionnaire and chart review. All patients
      were screened for HCV antibody by a first generation enzyme-linked immunosorbent
      assay. All positive results were confirmed with radioimmunoblot assay II (RIBA
      II). Patients were also checked for the presence of hepatitis B surface antigen.
      ALT levels were measured, and percutaneous liver biopsies were performed in
      patients positive for HCV antibody and greater than 1.5 times the normal ALT
      levels. RESULTS: Antibody to HCV was detected in 10/99 patients (10.10%). Seven
      of 30 patients (23.33%) who received more than 10 U of packed red blood cells
      were positive for HCV antibody. Only 3/38 (7.9%) patients with less than 10 U of
      packed red blood cells in the past were positive for HCV antibody. None of the
      patients who never received blood transfusion were positive for HCV antibody
      (0/31 or 0%). A total of seven liver biopsies were performed in patients positive
      for HCV antibody. Two out of seven specimens (28.57%) showed significant liver
      damage. One revealed cirrhosis, and the other showed chronic active hepatitis.
      The remainder of liver biopsies (5/7; 71.42%) showed only mild portal
      inflammation. CONCLUSIONS: The prevalence of HCV antibody is directly related to
      the number of blood transfusions in patients with sickle cell disease. Chronic
      HCV infection could be a major cause of cirrhosis of the liver in these patients.

PMID- 8651172
TI  - Chemical composition of gallbladder sludge in patients after marrow
      transplantation.
AB  - OBJECTIVES: Gallbladder sludge develops in approximately 70% of patients after
      bone marrow transplantation (BMT). Sludge often develops in these patients
      without known predisposing factors, such as fasting or narcotic use. In this
      study, we examined the chemical composition of sludge in BMT patients. METHODS:
      Gallbladder content samples from 15 patients were obtained at autopsy. Presence
      or absence of sludge was determined by examination of gallbladder contents.
      Sludge samples were examined with direct and polarizing microscopy and assayed
      for cholesterol, bilirubin, and calcium content and for the presence of a calcium
      binding protein. RESULTS: On microscopic examination, cholesterol monohydrate
      crystals were almost completely absent. Calcium bilirubinate crystals were
      present in large amounts in all samples. Calcium-ceftriaxone crystals were found
      in two patients who had received ceftriaxone. A large proportion of the sludge
      (84.6%) was found to be "unmeasurable residue." Of this part, 5-30% was accounted
      for by a calcium-binding protein. CONCLUSIONS: We conclude that gallbladder
      sludge in patients after marrow transplantation consists primarily of
      "unmeasurable residue," calcium bilirubinate, and a calcium-binding protein.
      Cholesterol crystals are almost absent. We conclude that formation of gallbladder
      sludge in these patients could serve as a model for studying the pathogenesis of
      pigment gallstones.

PMID- 8651173
TI  - Point mutations of the c-Ki-ras gene in carcinoma and atypical epithelium
      associated with congenital biliary dilation.
AB  - OBJECTIVES: Congenital biliary dilation (CBD) may be accompanied later by
      gallbladder carcinoma or bile duct carcinoma. These cancerous lesions are
      frequently associated with atypical epithelium that was suspected of being
      precancerous. To determine whether atypical epithelium may be precancerous, we
      examined the DNA sequence of the c-Ki-ras gene at codon 12 in nine cases of CBD
      concurrent with seven gallbladder carcinomas, one bile duct carcinoma, and one
      bile duct atypical epithelium. METHODS: Tumor specimens were surgically removed
      from nine patients with CBD at Nagoya University Hospital between 1979 and 1988.
      Tumor was isolated by microdissection, and DNA was amplified by a two-step
      polymerase chain reaction which then was directly sequenced. RESULTS: Four of
      seven gallbladder carcinomas and one bile duct carcinoma contained the c-Ki-ras
      point mutation at codon 12, and atypical epithelium associated with these
      carcinomas had the same mutation. One case of atypical bile duct epithelium also
      contained the mutation. CONCLUSIONS: These results indicate that the c-Ki-ras
      point mutation at codon 12 may be responsible for either cancer or atypical
      epithelia associated with CBD.

PMID- 8651174
TI  - Gastroesophageal reflux associated with cow's milk allergy in infants: which
      diagnostic examinations are useful?
AB  - Gastroesophageal reflux (GER) in infants can be secondary to food allergy. We
      have evaluated the frequency with which GER is associated with cow's milk protein
      allergy (CMPA) in infants < 1 yr old and tried to indicate the laboratory and
      instrumental examinations useful in diagnosing GER + CMPA. We studied 140 infants
      (60 M, 80 F), mean age 6.0 +/- 2.8 months. After 24-h esophageal pH-metry,
      esophageal endoscopy, and elimination diet, followed by a double-blind challenge,
      the patients were divided into four groups: primary GER, GER secondary to CMPA,
      CMPA without GER, and a control group with subjects suffering from neither GER
      nor CMPA. Thirty of 72 patients with GER were also suffering from CMPA. No
      differences were observed as regards age, sex, symptoms, and clinical or family
      history between patients with GER only and those with GER + CMPA. The
      immunological test most useful for GER + CMPA diagnosis was the IgG anti-beta
      lactoglobulin assay: positive in 27/30 subjects with GER + CMPA and in 4/42
      patients with GER only. We also observed a characteristic pattern of the pH
      monitoring tracing in 26/30 patients with GER + CMPA but in none of the 42
      patients with GER only. This consisted of a progressive, constant reduction in
      esophageal pH at the end of a feed, which continued up to the following feed,
      when pH rose steeply. We conclude that the evidence of this characteristic
      tracing and of a high IgG anti-beta-lactoglobulin value are specific and
      sensitive tests for GER + CMPA diagnosis.

PMID- 8651176
TI  - Bone remodeling indices and secondary hyperparathyroidism in celiac disease.
AB  - OBJECTIVES: To determine the prevalence of hypovitaminosis D and secondary
      hyperparathyroidism (SHPT) and to assess bone turnover by using markers of bone
      formation and resorption in celiac disease (CD). METHODS: Forty-three patients
      with CD were investigated: group 1, newly diagnosed celiacs (n = 19); group 2,
      treated celiacs responding histologically to a gluten-free diet (n = 16); group
      3, refractory celiacs, unresponsive to a gluten-free diet and immunosuppressive
      therapy (n = 8). Serum was drawn for intact parathyroid hormone (PTH), 25
      hydroxyvitamin D [25(OH)D], ionized calcium (Cai), total alkaline phosphatase
      (AP), and biochemical markers of bone formation: procollagen I carboxyterminal
      propeptide (PICP) and osteocalcin (Oc). Urinary indices of bone resorption,
      deoxypyridinoline (DPD), pyridinoline (PyD), and hydroxyproline (OHP), were
      measured in a 2-h fasting urine. In 22 patients, computerized tomographic scan
      for bone mineral density (BMD) was performed. RESULTS: The prevalence in groups
      1, 2, and 3, respectively, of hypovitaminosis D (< 50 nmol/L) was 58%, 25%, and
      88%, and the prevalence of SHPT (> 5.4 pmol/L) was 25%, 19%, and 25%. Bone
      resorption markers were significantly elevated in all groups, and bone formation
      indices were elevated in the newly diagnosed celiacs compared with a group of
      healthy adults. Low BMD (T-score greater than -1 SD unit) was found in 68% of
      patients assessed; 36% of patients had a T-score greater than -2.5 SD units.
      CONCLUSIONS: Hypovitaminosis D and SHPT are common in newly diagnosed and
      refractory celiacs but are less common in those who respond to a gluten-free
      diet. Newly diagnosed patients have a high bone turnover state with elevation of
      both bone formation and resorption indices. Those with refractory disease
      demonstrate a remodeling imbalance with high bone resorption.

PMID- 8651175
TI  - Determination of prothrombin activation fragments in young patients with
      inflammatory bowel disease.
AB  - OBJECTIVE: To assess coagulation cascade activation as a potential index of
      thromboembolic risk in inflammatory bowel disease (IBD). STUDY DESIGN: Fifty
      plasma samples were obtained during consecutive outpatient encounters with 29
      patients (male:female = 20:9) with either Crohn's disease (CD) (n = 23) or
      ulcerative colitis (UC) (n = 6). Disease activity for CD was determined using the
      Pediatric Crohn's Disease Activity Index (PCDAI) and for UC using signs/symptoms
      and mucosal histology. Patients were grouped as active, recently active (not
      currently active but had been active within the previous 2 months), or inactive.
      Prothrombin fragment 1.2 (F1.2) was determined by enzyme-linked immunosorbent
      assay on plasma samples. Lab parameters were compared using the Kruskal-Wallis
      test with pairwise comparisons made using Wilcoxian rank sum test. RESULTS: Forty
      three percent of samples taken during active phases of disease (13 of 30) had
      elevated prothrombin cleavage byproduct F1.2. Similarly, five of eight encounters
      (63%) with recently active IBD had elevated F1.2 values. In contrast, none of the
      patients with inactive disease exhibited F1.2 elevation. Median F1.2 levels in
      both the active (0.85 nM/L) and recently active (1.4 nM/L) patient groups were
      greater than that of the inactive group (0.6 nM/L; p < 0.05). CONCLUSIONS:
      Evidence of coagulation cascade activation in patients with active and recently
      active IBD suggests an increased risk of thrombogenesis during active disease
      that extends for a period of time after commencement of medications to induce
      remission in their disease process. It may be prudent to counsel patients to
      avoid risk factors associated with thrombotic phenomenon around the time of
      active IBD.

PMID- 8651177
TI  - Immune thrombocytopenic purpura in three patients with preexisting ulcerative
      colitis.
AB  - Ulcerative colitis (UC) is associated with extraintestinal diseases in numerous
      target tissues. Associated immune-mediated hematological diseases, however, are
      rarely described. We report three Caucasian adult patients with UC and immune
      thrombocytopenic purpura (ITP). Platelet-associated antibodies (IgG) were
      positive in two patients, and bone marrow examinations in two patients revealed
      normal to increased megakaryocyte numbers. ITP was treated with corticosteroids
      in all patients. Two patients eventually received intravenous immune gamma
      globulin, and one patient required surgical splenectomy. Of particular interest,
      UC preceded the onset of ITP in all patients (by from 1 to 19 yr). This suggests
      that ITP in these patients is causally associated with UC, possibly secondary to
      immunostimulation from lumenal antigens and altered immunoregulation.

PMID- 8651178
TI  - Angioimmunoblastic lymphadenopathy: an etiology for gastrointestinal lymphomatous
      polyposis.
AB  - We describe a case of angioimmunoblastic lymphadenopathy with multiple polyps of
      the gastrointestinal tract. The patient presented with fever, abdominal mass,
      ascites, diarrhea, generalized lymphadenopathy, anemia, and marked peripheral
      eosinophilia. She had multiple polyps in the colon, as well as in the stomach and
      duodenum. Histology of a colonic polyp showed involvement by angioimmunoblastic
      lymphadenopathy. The patient responded initially to combination chemotherapy,
      with total disappearance of polyps. However, she succumbed later to infections.
      Angioimmunoblastic lymphadenopathy, although rare, should be included as a cause
      of lymphomatous polyposis of the gastrointestinal tract.

PMID- 8651179
TI  - Multicentric primary adenocarcinomas of the midgut: the first case report.
AB  - Multicentric adenocarcinomas of the midgut have not been described; even multiple
      adenocarcinomas limited to the small intestine are extremely uncommon, with only
      14 cases reported in the literature. We report a case of multicentric synchronous
      involvement of the entire midgut with adenocarcinoma in a 52-yr-old Polish woman
      who had more than 30 lesions extending from duodenum to mid-transverse colon.
      There was no family history of cancer. Preoperative evaluation and intraoperative
      exploration were negative for primary malignancy of the lungs, breasts, ovaries,
      pancreas, and other parts of the gastrointestinal tract. Results of
      histopathological examination, immunohistochemical staining, and ras mutational
      analysis of the lesions uniformly support the diagnosis of multicentric poorly
      differentiated adenocarcinoma. The cause for this unusual presentation is
      unknown, although sporadic genetic alteration(s) of oncogene(s) might have been
      the precipitating event.

PMID- 8651181
TI  - Invasive candidiasis complicating spontaneous esophageal perforation (Boerhaave
      syndrome).
AB  - Spontaneous esophageal perforation is a rare condition that frequently results in
      infectious complications. Empirical broad-spectrum antibacterial therapy is
      therefore part of the standard management. We describe two patients suffering
      from spontaneous esophageal perforation who developed invasive candidiasis with
      hematogenous dissemination. One patient died of multiple organ failure due to
      Candida sepsis. Preexistent Candida colonization, incomplete mediastinal
      drainage, broad-spectrum antibacterial therapy, and prolonged intensive care
      therapy place patients with esophageal perforation at high risk for secondary
      fungal infection. Intense microbiological searching is mandatory, but the
      distinction between colonization and infection may be impossible. Empirical
      antifungal treatment with imidazole derivatives, particularly in patients with
      potential risk factors, should be considered.

PMID- 8651180
TI  - Giant gastric ulceration associated with antiphospholipid antibody syndrome.
AB  - The anticardiolipin or antiphospholipid antibody syndrome is characterized by an
      increased incidence of venous and arterial thromboses. This syndrome may occur in
      association with systemic lupus erythematosus or independently.
      Gastroenterological manifestations have included Budd-Chiari syndrome, hepatic
      infarction, esophageal necrosis with perforation, intestinal ischemia and
      infarction, pancreatitis, and colonic ulceration. We report a 39-yr-old man with
      antiphospholipid antibody syndrome complicated by adrenal insufficiency secondary
      to bilateral adrenal infarction who presented with severe epigastric pain.
      Endoscopic evaluation disclosed progressive gastric ulceration with necrosis in
      the distal body. Angiography revealed no vasculitis. Because of intractable pain
      despite intravenous anticoagulation and narcotic analgesia, the patient was taken
      to surgery, and an antrectomy with Billroth II gastrojejunostomy was performed.
      Histological examination revealed widespread vascular occlusive disease involving
      veins, small arteries, and arterioles present in all layers of the stomach and
      the perigastric fat consistent with the vasculopathy of the antiphospholipid
      antibody syndrome. Treatment with high intensity oral anticoagulation and
      corticosteroids resulted in clinical and endoscopic improvement. This case report
      extends the gastroenterological manifestations of the antiphospholipid antibody
      syndrome to include giant gastric ulceration and emphasizes the importance of
      anticoagulation in treatment.

PMID- 8651182
TI  - Pylephlebitis: a case report and review of outcome in the antibiotic era.
AB  - Pylephlebitis or septic thrombophlebitis of the portal vein, a precursor of
      hepatic abscesses, is an extremely rare and frequently fatal complication of
      diverticulitis. The following report describes a patient presenting with
      pylephlebitis and complicated diverticulitis. Diagnosis was confirmed by computed
      tomography. The patient had a favorable outcome with medical and surgical
      therapy, prompting us to evaluate historical treatment of pylephlebitis.

PMID- 8651183
TI  - Severe dysphagia, dysmotility, and unusual saccular dilation (diverticulum) of
      the esophagus following excision of an asymptomatic congenital cyst.
AB  - Iatrogenic dysmotility syndromes, particularly achalasia-like conditions,
      occasionally complicate esophageal and paraesophageal surgery. We describe a
      patient who developed a very unusual (and as far as we know unreported) syndrome
      characterized by severe dysphagia, esophageal dysmotility (segmental simultaneous
      contractions of the distal esophagus), and very large saccular outpouching
      (diverticulum) involving the right wall of the distal half of the esophagus as a
      consequence of excision of an asymptomatic congenital cyst. The cyst had been
      discovered as an incidental finding on a preemployment chest x-ray. Our patient's
      dysphagia did not improve with nonsurgical treatments that are usually successful
      for idiopathic and iatrogenic achalasia.

PMID- 8651184
TI  - Gastric tuberculosis presenting with massive hematemesis in association with
      acute myeloid leukemia.
AB  - This case report presents a patient with gastric tuberculosis, in remission from
      acute myeloid leukemia, who suffered a massive hematemesis, ultimately proving to
      be fatal. The literature of gastric tuberculosis is reviewed with particular
      reference to its clinical presentation and diagnosis.

PMID- 8651185
TI  - Oral sodium phosphate catharsis and acute renal failure.

PMID- 8651186
TI  - Thrombolysis for acute Budd-Chiari syndrome: case report and literature review.

PMID- 8651187
TI  - Delayed anoxic pseudolobular necrosis (terminal hepatic necrosis) after chemo
      lipiodolization for hepatocellular carcinoma.

PMID- 8651188
TI  - Acute pseudo-obstruction of the colon (Ogilvie's syndrome) resulting from
      combination tocolytic therapy.
AB  - We describe a case of colonic pseudo-obstruction occurring in a pregnant patient
      whose preterm labor was being treated with intravenous magnesium and nifedipine.
      Sequential colonoscopies were required to manage the recurrent colonic dilations
      prior to delivery of healthy twins. There was no recurrence after delivery and
      discontinuation of the tocolytics.

PMID- 8651189
TI  - Severe recurrent hepatic encephalopathy that responded to oral branched chain
      amino acids.
AB  - Hepatic encephalopathy is a neuropsychiatric syndrome occurring in patients with
      acute or chronic liver disease. Its pathogenesis remains unclear; however, it
      appears to be multifactorial. There are several conventional treatments for this
      condition, such as lactulose, neomycin, and protein restriction. There is
      significant controversy regarding the role of branched chain amino acids in the
      treatment of chronic hepatic encephalopathy. We describe a patient who had
      hepatic encephalopathy secondary to Budd-Chairi syndrome and a mesoatrial shunt
      that failed vigorous conventional therapy. She required multiple hospitalizations
      for severe recurrent encephalopathy. The patient was considered for a colonic
      exclusion procedure for the management of intractable encephalopathy. However,
      branched amino acid therapy was instituted as a last measure before the
      contemplated surgery, and the patient's encephalopathy responded in dramatic
      fashion, and she remained free from encephalopathy during a prolonged follow-up.

PMID- 8651190
TI  - Intraportal tumor thrombus of gallbladder carcinoma: detection with intravascular
      ultrasonography.

PMID- 8651192
TI  - Gastrointestinal problems in a child with dyskeratosis congenita.
AB  - We describe a pediatric patient with dyskeratosis congenita, whose symptoms
      included abdominal pain, vomiting, dysphagia, and hematochezia. Gastrointestinal
      symptom are prominent in this rare genetic disorder.

PMID- 8651191
TI  - Giant sigmoid diverticulum: report of two cases and endoscopic recognition.

PMID- 8651194
TI  - Specialized intestinal metaplasia in the cardia: not so special?

PMID- 8651193
TI  - Super turbo azathioprine: can Crohn's disease healing be accelerated?

PMID- 8651195
TI  - Hyperlipidemia and pancreatitis: the chicken or the egg?

PMID- 8651196
TI  - Esophagoprotection with NSAIDs: the way forward.

PMID- 8651197
TI  - Calcium metabolism and celiac disease.

PMID- 8651198
TI  - Should omeprazole be used for the treatment and prevention of duodenal ulcer as a
      monotherapeutic agent?

PMID- 8651199
TI  - Shome et al: The differential diagnosis for painless rectal bleeding.

PMID- 8651200
TI  - Re: Burning mouth syndrome.

PMID- 8651202
TI  - Alendronate-induced ulcerative esophagitis.

PMID- 8651201
TI  - Observer variation in histological assessment of Helicobacter pylori on gastric
      biopsies.

PMID- 8651203
TI  - Botulinum toxin in hypertensive lower esophageal sphincter.

PMID- 8651204
TI  - MIC-KEY skin-level gastrostomy: a short-term device?

PMID- 8651205
TI  - Gastric bezoar formation in a patient with scleroderma: endoscopic removal using
      the gallstone mechanical lithotripter.

PMID- 8651206
TI  - Autonomic neuropathy with gastropathy and elevated urinary 5-hydroxy indole
      acetic acid in insulin-dependent diabetes mellitus.

PMID- 8651207
TI  - Primary esophageal tuberculosis: a case report and 1996 update.

PMID- 8651208
TI  - Duodenal heterotopia of gastric mucosa.

PMID- 8651209
TI  - Permanent therapeutic embolization of cecal angiodysplasia.

PMID- 8651210
TI  - Spontaneous regression of hepatocellular carcinoma.

PMID- 8651211
TI  - Utility of endoscopic ultrasonography in rectal carcinoid tumors.

PMID- 8651212
TI  - Intestinal myiasis with Phaenicia cuprina.

PMID- 8651213
TI  - Risk for rebleeding of the duodenal bulbar ulcer is less than that of the gastric
      ulcer.

PMID- 8651214
TI  - Hepatic steatosis revealing celiac disease: a case complicated by transitory
      liver failure.

PMID- 8651215
TI  - CNS and gut responses to stress: which comes first?

PMID- 8651216
TI  - Variables associated with cognitive function in elderly California Seventh-day
      Adventists.
AB  - From a cohort of white, non-Hispanic California Seventh-day Adventists, 99
      subjects over age 75 years in 1991 were randomly selected. Dietary habits and
      educational status had been measured in 1976. Subjects completed the Mini-Mental
      State Examination (MMSE) in 1991, and at that time, they or caregivers also gave
      information on current medical problems and drug therapy. Those who ate more
      calories in 1976 had lower MMSE scores in 1991 (p = 0.03), an association
      strengthened by excluding those with previous stroke or Parkinson's disease by
      1991. This raises the possibility that higher consumption of calories in middle
      age may accelerate the decline in cognitive function seen with aging, as
      apparently occurs in some animals. Less-educated subjects had lower MMSE scores,
      especially among the very elderly. The statistical model predicts that the
      negative association between use of psychotropic drugs and MMSE score (p = 0.004)
      is particularly potent in those cognitively impaired for other reasons. If
      causal, this suggests that physicians should use these agents very cautiously in
      such subjects.

PMID- 8651217
TI  - Nursing home residence and risk of hip fracture.
AB  - This population-based case-control study was performed to determine whether the
      high incidence of hip fractures in people living in nursing homes is explained by
      the generally poor physical and mental health status of institutionalized older
      people. The study, which was conducted between 1990 and 1991, involved 209 hip
      fracture cases and 207 controls randomly selected from the same population in
      Sydney, Australia. Data on potential confounders were collected by using an
      interviewer-administered questionnaire. The age- and sex-adjusted odds ratio for
      the association between nursing home residence and risk of hip fracture was 2.4
      (95% confidence interval 1.4-4.3). However, after adjustment for multiple
      confounders, the odds ratio was 0.6 (95% confidence interval 0.2-1.6). It appears
      that living in a nursing home is not an independent risk factor for hip fracture.

PMID- 8651218
TI  - Reproductive factors and risk of endometrial cancer. The Iowa Women's Health
      Study.
AB  - Gravidity and parity have strong inverse relations with endometrial cancer
      occurrence. To determine whether gravidity masks an association with other
      reproductive factors, the authors analyzed data from a cohort study of 24,848
      postmenopausal Iowa women aged 55-69 years who were cancer free at baseline in
      1986 and who had not had a hysterectomy. During 5 years of follow-up, 167
      incident endometrial cancer cases were documented. As expected, the mean
      gravidity of cases was lower than that of noncases (2.6 vs. 3.5, p < 0.0001).
      Endometrial cancer occurrence was associated positively with early age at
      menarche, late age at natural menopause, and total length of ovulation span, but
      history of infertility and ages at first and last pregnancy were unrelated to
      risk after adjustment for gravidity. Two additional factors remained
      statistically significant independent of gravidity: a history of ever (vs. never)
      having had an induced abortion (relative risk = 2.5, 95% confidence interval 1.1
      5.7) and timing of spontaneous abortions (miscarriages). Results suggest that a
      miscarriage late in reproductive life, followed by lack of a subsequent full-term
      pregnancy, may be a marker for progesterone deficiency. If so, the findings
      support the "unopposed" estrogen hypothesis for the etiology of endometrial
      cancer.

PMID- 8651219
TI  - Determinants of hypertension in West Africa: contribution of anthropometric and
      dietary factors to urban-rural and socioeconomic gradients.
AB  - The determinants of hypertension in West Africa have not been well defined. The
      authors sampled 598 participants aged 45 years or more from a recent population
      based survey in southwest Nigeria (190 rural men and women, 205 urban poor men
      and women, and 203 retired railway workmen). The estimated mean age was 61 (10)
      years. Mean pressures were low relative to westernized societies: systolic blood
      pressure = 124 (24) mmHg, diastolic blood pressure = 72 (13) mmHg. Both men and
      women were remarkably lean: body mass index = 21.3 (3.6) and 23.0 (5.2) kg/m2,
      respectively. Hypertension prevalence increased across the gradient from rural
      farmers to urban poor to railway workers: 14, 25, and 29 percent, respectively,
      had a blood pressure of 140/90 mmHg or greater, and 3, 11, and 14 percent,
      respectively, had a blood pressure of 160/95 mmHg or greater (p for trend < 0.01
      for both cutpoints). On the basis of a 24-hour urine sample, daily electrolyte
      excretion was 110 (57) mEq of sodium and 46 (24) mEq of potassium. Mean
      sodium:potassium ratio was 2.6 (1.0) and was higher among the urban residents (p
      < 0.01) and correlated with systolic and diastolic pressures (r = 0.16-0.18, p <
      0.01). These findings provide quantitative estimates of the impact of known
      hypertension risk factors in West Africa and demonstrate the basis for increased
      prevalence with urbanization and associated economic and dietary change. These
      results also provide support for recommendations for prevention in West Africa
      and provide a benchmark against which to compare populations in the African
      diaspora.

PMID- 8651220
TI  - NHLBI Family Heart Study: objectives and design.
AB  - The NHLBI Family Heart Study is a multicenter, population-based study of genetic
      and nongenetic determinants of coronary heart disease (CHD), atherosclerosis, and
      cardiovascular risk factors. In phase I, 2,000 randomly selected participants and
      2,000 with family histories of CHD were identified among 14,592 middle-aged
      participants in epidemiologic studies. Medical histories from these individuals,
      their parents, and their siblings were used to calculate family risk scores that
      compared the number of reported and validated CHD events with the number expected
      based on the size, sex, and age of family members. A total of 657 families with
      the highest risk scores and early-onset CHD and 588 randomly sampled families had
      clinic examinations that included electrocardiograms, carotid artery ultrasound
      scans, spirometry, measurements of body size, blood pressure, lipids,
      lipoproteins, hemostatic factors, insulin, glucose, and routine chemistries.
      Additional biochemical and genetic studies are being performed on selected
      participants. Serum, plasma, lymphocytes, red cells, and DNA are stored for
      future studies, including genotyping of candidate genes and anonymous markers.
      Contributions of genes, shared and individual environments, and behaviors to
      variations in risk factors, preclinical atherosclerosis, and CHD will be
      estimated. Linkage studies, including the quantitative trait loci approach, are
      planned.

PMID- 8651221
TI  - Case-control study of periconceptional folic acid supplementation and oral
      clefts.
AB  - There is consistent evidence that the risk of neural tube defects is decreased by
      periconceptional supplementation with folic acid. A similar protective effect has
      been postulated for oral clefts. A case-control study was conducted in greater
      metropolitan Boston; Massachusetts; Philadelphia, Pennsylvania; and southeastern
      Ontario, Canada, from 1988 through 1991 to test the hypothesis that folic acid
      supplementation during the periconceptional period reduces the risk of oral
      clefts. Crude and multivariate-adjusted relative risks were calculated for all
      oral clefts (n = 303), cleft palate (n = 108), and cleft lip with or without
      cleft palate (n = 195). Controls (n = 1,167) were liveborn or stillborn infants
      less than age 6 months who had various congenital anomalies other than oral
      clefts, neural tube defects, or other "midline defects." Adjusted relative risks
      and 95 percent confidence intervals for daily folic acid supplementation during
      the periconceptional period were: oral clefts, 1.1 (95% confidence interval (CI)
      0.8-1.7), cleft palate, 0.9 (95% CI 0.5-1.6), and cleft lip with or without cleft
      palate, 1.3 (95% CI 0.8-2.1). These findings do not support a protective
      association between the periconceptional use of folic acid supplements and the
      risk of oral clefts.

PMID- 8651222
TI  - Prognostic indices for mortality of hospitalized children in central Africa.
AB  - A hospital-based follow-up study was conducted between 1986 and 1988 at Lwiro
      (South Kivu Province, Zaire). Of 1,129 children in the study, three of four were
      severely malnourished, and 17.4% died. This study analyzes the mortality in
      hospital; its objectives are to evaluate the prognostic power of edema and
      anthropometric and biologic indicators and to seek indices that perform better.
      Receiver operating characteristic curves were established for each parameter
      under study and for each index constructed. Areas under receiver operating
      characteristic curves were highest for biologic indicators, and simple indices,
      obtained by counting the number of risk factors present, performed best. In the
      absence of biologic parameters, the authors suggest classifying children as at
      risk of dying when they present with edema and/or with arm circumference of less
      than 115 mm. When biologic measurements are possible, in addition to edema and
      arm circumference, the authors suggest taking serum albumin and transthyretin
      into account. For serum albumin and transthyretin, mortality risk is defined in
      terms of values of less than 16 g/liter and 6.5 mg/dl, respectively. Children
      will be classified as at risk of dying when they present with at least two of the
      four risk factors. The resulting diagnostic test has a high sensitivity (91.2%)
      and positive and negative predictive values of 40.8% and 97.9%, respectively.

PMID- 8651224
TI  - Validated questionnaire for the identification of previous personal or familial
      venous thromboembolism.
AB  - The recognition of previous episodes of venous thromboembolism is of primary
      importance for the diagnosis of familial thrombophilia. Since there is no
      validated method to diagnose past venous thromboembolism for epidemiologic
      purposes, the authors administered a questionnaire to a group of subjects who had
      had venous thromboembolism in the past and to a group of normal controls. Both
      cases and controls were less than age 65 years and were identified by the
      discharge diagnosis International Classification of Diseases codes of records of
      the Vicenza general hospital, Italy, from 1975 to 1992. Cases were further
      validated by critical review of pertinent medical records. For each key question,
      the sensitivity and specificity were computed; questions were then aggregated
      into sets of maximal sensitivity and specificity. The best diagnostic efficiency
      (98.2%) was obtained by a set of questions about past symptoms and anticoagulant
      treatment; this set showed a very high specificity (99.4%), but a low sensitivity
      (37.1%). A higher sensitivity (71.3%) was obtained without loss of specificity
      (98.9%) by retaining as positive those subjects who gave a history of venous
      thromboembolism and anticoagulant treatment or those who had a history of venous
      thromboembolism and venous reflux at Doppler ultrasound scanning but had no
      treatment. The combined use of the questionnaire and Doppler scan is suggested
      for epidemiologic surveys in population.

PMID- 8651223
TI  - Effects of micronutrient intake on survival in human immunodeficiency virus type
      1 infection.
AB  - The authors examined the relation between dietary and supplemental micronutrient
      intake and subsequent mortality among 281 human immunodeficiency type 1 (HIV-1)
      infected participants at the Baltimore, Maryland/Washington, DC, site of the
      Multicenter Acquired Immunodeficiency Syndrome Cohort Study. Subjects completed a
      semiquantitative food frequency questionnaire at their baseline visit in 1984.
      Levels of daily micronutrient intake were examined in relation to subsequent
      mortality over the 8-year follow-up period by using multivariate Cox models,
      adjusting for age, symptoms, CD4+ count, energy intake, and treatment. The
      highest quartile of intake for each B-group vitamin was independently associated
      with improved survival: B1 (relative hazard (RH) = 0.60, 95% confidence interval
      (CI) 0.38-0.95), B2 (RH = 0.59, 95% CI 0.38-0.93), B6 (RH = 0.45, 95% CI 0.28
      0.73), and niacin (RH = 0.57, 95% CI 0.36-0.91). In a final model, the third
      quartile of beta-carotene intake (RH = 0.60, 95% CI 0.37-0.98) was associated
      with improved survival, while increasing intakes of zinc were associated with
      poorer survival. Intakes of B6 supplements at more than twice the recommended
      dietary allowance were associated with improved survival (RH = 0.60, 95% CI 0.39
      0.93), while intakes of B1 and B2 supplements at levels greater than five times
      the recommended dietary allowance were associated with improved survival (B1: RH
      = 0.61, 95% CI 0.38-0.98; B2:RH = 0.60, 95% CI 0.37-0.97). Any intake of zinc
      supplements, however, was associated with poorer survival (RH = 1.49, 95% CI 1.02
      2.18). These data support the performance of clinical trials to assess the
      effects of B-group vitamin supplements on HIV-1-related survival. Further studies
      are needed to determine the optimal level of zinc intake in HIV-1-infected
      individuals.

PMID- 8651225
TI  - Extension of the life table to repeating and changing events.
AB  - Estimation of cumulative and adjusted occurrence of life events and measures over
      time is often important in settings where study subjects have incomplete or
      different follow-up periods. Well-known methods to do this, such as the life
      table and age adjustment, exist for binary nonrecurrent events (i.e., death).
      However, a general approach to evaluate recurrent life events (e.g., repeated
      infections), life events with different durations (e.g., hospitalization days),
      costs, or changing life measures (e.g., body weight) is not available. This paper
      develops the "Life-Event Table," an analog of the life table that can analyze
      occurrence of diverse types of events and measures when the observation periods
      of subjects are incomplete and different. This method, based on a central limit
      theorem for incomplete multivariate data, obtains point estimates and variances
      for cumulative incidence, age-adjusted expectation, and other quantities. Simple
      hypotheses tests and comparisons are possible with this approach. Three
      applications are presented. The Life-Event Table may facilitate use of currently
      available robust multivariate analysis methods. Further research into other
      multivariate methods that take advantage of this Life-Event Table's specific
      covariance/variance structure may be warranted.

PMID- 8651226
TI  - Baldness and ischemic heart disease in a national sample of men.
AB  - A weak positive association between male pattern baldness and ischemic heart
      disease has been suggested previously. The authors examined this issue by using
      data from the Epidemiologic Follow-up Study of the First National Health and
      Nutrition Examination Survey. As part of the baseline medical examination between
      1971 and 1975, the presence and degree of male alopecia (none, minimal, moderate,
      and severe) were recorded for a subset of participants. Among 3,932 men aged 25
      76 years who had complete data, 378 deaths and 939 incident events from ischemic
      heart disease occurred during an average follow-up period of 14 years. Among
      2,019 men who were younger than age 55 years at baseline (61 deaths and 239
      incident events of ischemic heart disease), severe baldness was positively
      associated with ischemic heart disease mortality (rate ratio = 2.51, 95 percent
      confidence interval 1.01-6.24) and somewhat less associated with ischemic heart
      disease incidence (rate ratio = 1.72, 95 percent confidence interval 0.96-3.08).
      No dose-response relation with degree of baldness was seen. Although these
      findings are tempered by the absence of information concerning the type of
      baldness (frontal or vertex), they provide support for earlier studies that
      indicate male pattern baldness that occurs before age 55 years may be by some
      mechanism related to ischemic heart disease.

PMID- 8651227
TI  - Lowered risks of hypertension and cerebrovascular disease after vitamin/mineral
      supplementation: the Linxian Nutrition Intervention Trial.
AB  - A total of 3,318 men and women from a region in rural China were randomized to
      receive daily either a multiple vitamin/mineral supplement or a placebo. Deaths
      that occurred in the participants were ascertained and classified according to
      cause over the 6-year period from 1985 to 1991. At the end of supplementation,
      blood pressure readings were taken, and the prevalence of hypertension was
      determined. There was a slight reduction in overall mortality in the supplement
      group (relative risk (RR) = 0.93, 95 percent confidence interval (CI) 0.75-1.16),
      with the decreased relative risk most pronounced for cerebrovascular disease
      deaths (RR = 0.63, 95 percent CI 0.37-1.07). This benefit was greater for men (RR
      = 0.42, 95 percent CI 0.19-0.93) than for women (RR = 0.93, 95 percent CI 0.44
      1.98). Among the survivors, the presence of elevations in both systolic and
      diastolic blood pressures was less common in those who received the supplement
      (RR for men = 0.43, 95% CI 0.28-0.65; RR for women = 0.92, 95 percent CI 0.68
      1.24). This study indicates that supplementation with a multivitamin/mineral
      combination may have reduced mortality from cerebrovascular disease and the
      prevalence of hypertension in this rural population with a micronutrient-poor
      diet.

PMID- 8651228
TI  - Association of fibrinogen and coagulation factors VII and VIII with
      cardiovascular risk factors in the elderly: the Cardiovascular Health Study.
      Cardiovascular Health Study Investigators.
AB  - The cross-sectional correlates of three hemostatic factors--fibrinogen, factor
      VII, and factor VIII--were examined in the Cardiovascular Health Study, a
      population-based cohort study of 5,201 subjects over age 65 years. Subjects were
      recruited in 1989-1990 in Forsyth County, North Carolina; Sacramento County,
      California; Washington County, Maryland; and Pittsburgh, Pennsylvania. In
      multivariate linear regression models, cardiac risk factors significantly
      associated with fibrinogen were current smoking, race, lipids, and white blood
      count. In women, alcohol use, obesity, physical activity, and insulin level were
      also significant, while in men hypertension was correlated. The significant
      correlates of factor VII were lipids and white blood count in men and estrogen
      use, alcohol use, race, lipids, insulin level, white blood count, and obesity in
      women. The independent correlates of factor VIII were insulin, glucose, and race
      in both sexes; low density lipoprotein cholesterol, white blood count, and
      diuretic use in men; and alcohol use in women. In multivariate models, factors
      known to be modifiable risk factors for cardiovascular disease accounted for more
      of the population variance of these hemostatic factors in women than in men,
      especially for factor VII. The hemostatic factors may mediate some effects of
      risk factors on disease, and this should be considered in longitudinal studies.

PMID- 8651229
TI  - Heterogeneity of hip fracture: age, race, sex, and geographic patterns of femoral
      neck and trochanteric fractures among the US elderly.
AB  - To explore potential etiologic differences in the two major types of hip
      fracture, the authors computed the incidence rates of fractures of the femoral
      neck and trochanteric region of the proximal femur using a 5 percent sample of
      the US Medicare population aged 65-99 years. For the period they examined, July
      1, 1986, through June 30, 1990, the rates of both hip fracture types increased
      with age in all race and sex categories. The proportion of hip fractures that
      occurred in the trochanteric region rose steeply with age among white women, but
      not among black women, white men, or black men. Within the United States, a north
      to-south gradient in rates of both fracture types was observed among women, while
      no clear pattern was found for men. These findings raise the possibility of
      etiologic differences in the two fracture types, and the results provide further
      evidence of sex and racial differences in the risk of osteoporotic fractures.

PMID- 8651230
TI  - Aspirin use and cognitive function in the elderly.
AB  - Decline in cognitive function in the elderly is common and represents a major
      clinical and public health concern. Aspirin may reduce the decline in cognitive
      function by influencing multi-infarct dementia, but data are sparse. The East
      Boston Senior Health Project is a population-based cohort study that enrolled
      3,809 community-dwelling residents aged 65 years and older in 1982-1983 and
      followed them with home visits every 3 years until 1988-1989. Trained
      interviewers assessed cognitive function by using the Short Portable Mental
      Status Questionnaire and assessed medication use, including over-the-counter
      drugs. Response to the Short Portable Mental Status Questionnaire was scored as
      high, medium, or low, and decline was defined as transition to a lower category.
      Participants who used drugs containing aspirin in the 2 weeks prior to the
      interview were classified as aspirin users. Multiple logistic regression was used
      to obtain adjusted odds ratios and their 95% confidence intervals for decline of
      cognitive function. The estimating equation approach was used to adjust the
      standard errors for repeated measurements. Aspirin users had an odds ratio for
      cognitive decline of 0.97 (95% confidence interval 0.82-1.15). Low frequency of
      aspirin use (less than daily) was associated with an odds ratio of 0.87 (95%
      confidence interval 0.69-1.09). Although no substantial effect was observed, the
      data are also compatible with a modest benefit of aspirin, especially with
      intermittent use, on decline of cognitive function. Concern about small residual
      biases from self-selection or confounding suggests that randomized trials will be
      necessary to provide definitive data on this question.

PMID- 8651231
TI  - Alcohol use and prostate cancer risk in US blacks and whites.
AB  - Prostate cancer is the most common malignancy in US men (more than 165,000 cases
      per annum) and occurs substantially more frequently in blacks than in whites. The
      causes of this disease are, however, poorly understood. Alcohol consumption,
      which has been clearly related to malignancies of the upper aerodigestive tract,
      may also increase risk of cancer at other sites, including the prostate. The
      authors investigated alcohol use as a risk factor for prostate cancer among US
      blacks and whites. A population-based, case-control study was carried out among
      981 men (479 blacks and 502 whites) with pathologically confirmed prostate cancer
      diagnosed between August 1, 1986, and April 30, 1989, and 1,315 controls (594
      blacks and 721 whites) who resided in Atlanta, Georgia; Detroit, Michigan; and 10
      counties in New Jersey, geographic areas covered by three population-based cancer
      registries. In-person interviews elicited information on alcohol use and other
      factors possibly related to prostate cancer. Compared with never-users, risk for
      prostate cancer increased with amount of alcohol drunk (chi2 (trend), p < 0.001),
      with significantly elevated risks seen for those who had 22-56 drinks per week
      (odds ratio = 1.4; 95% confidence interval 1.0-1.8) and 57 or more drinks per
      week (odds ratio = 1.9; 95% confidence interval 1.3-2.7). The finding was
      consistent among blacks (chi2 (trend), p < 0.01) and whites (chi2 (trend), p <
      0.05), and among young and old subjects; it was not restricted to a specific type
      of alcoholic beverage. In this first large study among US blacks and whites,
      increased risk for prostate cancer was associated with increased alcohol use. The
      risk was similar for whites and blacks and could not be attributed to tobacco use
      or to a number of other potential confounders.

PMID- 8651232
TI  - Body size and breast cancer risk among women under age 45 years.
AB  - In a multicenter population-based case-control study that included 1,588 cases
      and 1,394 controls less than age 45 years, the authors examined the relation of
      adult body size and breast cancer risk among young women. Breast cancer patients
      and healthy controls were identified in Atlanta, Georgia; Seattle/Puget Sound,
      Washington; and central New Jersey. Cases were newly diagnosed with in situ or
      invasive breast cancer during the period of May 1, 1990, through December 31,
      1992. Anthropometric variables thought to reflect early environmental factors
      (e.g., height, sitting height, frame size), obesity, and body fat distribution
      were measured directly. Height, but not sitting height or frame size, was a
      breast cancer risk factor. Risk of the disease was increased 46 percent among
      women in the fourth quartile of height (> 167 cm) compared with women in the
      first quartile (< 159 cm). Body weight, but not body fat distribution, was
      related to breast cancer risk. Risk of the disease was 35 percent lower among
      women in the highest quartile of Quetelet index (> 28.8 kg/m2) compared with
      women in the lowest quartile (< 22.0 kg/m2). Risk of the disease was increased
      about 2.1-fold (95 percent confidence interval 1.2-3.8) among women who were thin
      and tall compared with women who were heavy and short. Thus, breast cancer risk
      was increased substantially among younger women with a linear body type.

PMID- 8651233
TI  - Ethylene glycol ethers and risks of spontaneous abortion and subfertility.
AB  - Potential reproductive effects from occupational exposures to ethylene glycol
      ethers (EGE) are of concern since these organic solvents have been used widely in
      industry, and their reproductive toxicity has been well documented in animal
      studies. For determination of whether occupational exposure to EGE was associated
      with increased risks of spontaneous abortion and subfertility (i.e., taking more
      than 1 year of unprotected intercourse to conceive), a retrospective cohort study
      was conducted among workers at two semiconductor manufacturing plants in the
      eastern United States in 1980-1989 as part of a larger evaluation of reproductive
      health. Reproductive and occupational histories were obtained from interviews of
      semiconductor manufacturing workers and spouses. Assessment of potential exposure
      to mixtures containing EGE (none, low, medium, and high) was based on reported
      processes and company records. There were 1,150 pregnancies to semiconductor
      manufacturers, 561 to female employees and 589 to wives of male employees. Among
      female manufacturers, potential exposure to mixtures containing EGE was
      associated with increased risks of spontaneous abortion (relative risk in the
      high exposure group = 2.8; 95% confidence interval (CI) 1.4-5.6) and subfertility
      (odds ratio in the high exposure group = 4.6; 95% CI 1.6-13.3). Both of these
      risks exhibited a dose-response relation with potential EGE exposure (p for trend
      = 0.02). Among spouses of male manufacturers potentially exposed to mixtures
      containing EGE, there was no increased risk of spontaneous abortion, but there
      was a nonsignificant increased risk of subfertility (odds ratio in the high
      exposure group = 1.7; 95% CI 0.7-4.3).

PMID- 8651234
TI  - Ethnic differences in immune responses to hepatitis B vaccine.
AB  - A national vaccination program against hepatitis B virus (HBV) to immunize every
      newborn was initiated in Taiwan in 1986. A serologic survey of 1,812 fully
      vaccinated children residing in four aboriginal villages and four adjacent
      nonaboriginal Han Chinese rural villages was conducted in 1993. Children in three
      of the four aboriginal villages had significantly lower titers of antibody
      against hepatitis B surface antigen (anti-HBs) than did children in the
      nonaboriginal villages. Evaluation of cold chain operation for vaccine storage
      and transport suggested that cold chain failure was not responsible for the fact
      that children residing in the more remote aboriginal villages had lower mean
      titers of anti-HBs. However, children whose parents were both aborigines had
      lower anti-HBs mean titer than did children whose parents were both ethnic Han
      Chinese. Children of mixed parental origins had intermediate mean titer of anti
      HBs. Serologic responses to Japanese encephalitis virus and diphtheria vaccines
      did not show such correlation with ethnic groups, indicating that the determinant
      for HBV hyporesponsiveness among the aboriginal children is distinct from that of
      other childhood vaccines. It was therefore concluded that host factors pertaining
      to ethnic origin might be responsible for the hyporesponsiveness to HBV vaccine
      in the aboriginal populations. This finding, if substantiated with further
      prospective studies, might provide possible means for more targeted trials to
      improve vaccine response and to reduce vaccine failure among these well-defined
      ethnic groups.

PMID- 8651235
TI  - Reliability of self-reported human immunodeficiency virus risk behaviors in a
      residential drug treatment population.
AB  - This study examined test-retest reliabilities of self-reported human
      immunodeficiency virus (HIV) sexual and drug injection behaviors among 246 prior
      drug users admitted to either of two residential drug treatment programs in
      Westborough, Massachusetts, and Providence, Rhode Island, between June 1990 and
      September 1992. Participants, selected by their date of admission, were
      administered admission and reliability questionnaires pertaining to HIV risk
      behaviors, the latter at approximately 2 weeks after admission. Estimated
      reliabilities (kappa coefficients) of the sexual behaviors ranged from 0.72 to
      0.91; those for the drug injection variables ranged from 0.63 to 0.98. These
      results were consistent across groups defined by sex and injection of drugs. The
      consistently good reliabilities are significant to the design of independent
      studies of drug treatment populations utilizing self-report measures of sexual
      and drug behaviors.

PMID- 8651236
TI  - Trends in human immunodeficiency virus seroprevalence among injection drug users
      entering drug treatment centers, United States, 1988-1993.
AB  - National unlinked sentinel surveillance data were used to describe trends in
      prevalent human immunodeficiency virus infection among injection drug users
      entering drug treatment programs in the United States from 1988 through 1993.
      During this 6-year period, unlinked testing was performed on 70,882 specimens
      from injection drug users at 60 sentinel sites. The annual change in
      seroprevalence was estimated for each site by odds ratios obtained from logistic
      regression models fit within site-specific age and race/ethnicity subgroups.
      Overall trends for age and race/ethnicity subgroups across sites were described
      by summary odds ratios calculated using the inverse variance method. A decrease
      was observed among younger (age less than 30 years) whites both in areas with
      high (10% or higher) and low (less than 10%) prevalence, although this decrease
      was significant only in high-prevalence areas (odds ratio = 0.90, 95% confidence
      interval 0.81-0.99). Seroprevalence also decreased among older whites in high
      prevalence areas, although this decrease was not significant (odds ratio = 0.95,
      95% confidence interval 0.89-1.00). Seroprevalence remained stable among all
      other age and race/ethnicity subgroups. Stable seroprevalence among the dynamic
      population of injection drug users entering treatment suggests continued
      transmission among these individuals in both high- and low-prevalence areas of
      the United States.

PMID- 8651237
TI  - Re: "Adult leukemia risk and personal appliance use: a preliminary study".

PMID- 8651238
TI  - Re: "Adult leukemia risk and personal appliance use: a preliminary study".

PMID- 8651239
TI  - The role of proteinuria in the progression of chronic renal failure.
AB  - The cause of the relentless progression of chronic renal failure of diverse
      origins remains unknown and is likely to be multifactorial. Numerous studies have
      now demonstrated a correlation between the degree of proteinuria and the rate
      progression of renal failure, which has led to the hypothesis that proteinuria
      may be an independent mediator of progression rather than simply being a marker
      of glomerular dysfunction. This article reviews the evidence underlying this
      hypothesis and the mechanisms by which particular proteins may cause renal
      pathology. The abnormal filtration of proteins across the glomerular basement
      membrane will bring them into contact with the mesangium and with the tubular
      cells. There is evidence to support a role of lipoproteins on mesangial cell
      function, which ultimately could contribute to glomerular sclerosis. The proximal
      tubular cells reabsorb proteins from the tubular fluid, which leaves them
      particularly vulnerable to any adverse effects proteins may have. It has been
      postulated that the sheer amount of protein to be metabolized by these cells may
      overwhelm the lysosomes and result in leakage of cytotoxic enzymes into the
      cells. In addition, the increased metabolism of proteins may result in production
      of ammonia, which can mediate inflammation through activation of complement.
      Specific proteins that have been shown to be cytotoxic are transferrin/iron, low
      density lipoprotein, and complement components, all of which appear in the urine
      in proteinuric states. Other specific proteins have been shown to stimulate
      production of cytokines, chemoattractants, and matrix proteins by tubular cells
      and thus may stimulate interstitial inflammation and scarring. The mechanisms by
      which the presence of proteins in the tubular fluid alters tubular cell biology
      is yet to be determined.

PMID- 8651240
TI  - The importance of renal impairment in the natural history of Bardet-Biedl
      syndrome.
AB  - Bardet-Biedl syndrome is a rare autosomal recessive disease characterized by
      dysphormic extremities, retinal dystrophy, obesity, hypogenitalism in males, and
      renal structural abnormalities. Because the clinical outcome of these patients is
      not well known, 21 families with Bardet-Biedl syndrome (BBS) were studied to
      determine the natural history of the disease. In a prospective cohort study, 38
      patients with the syndrome and 58 unaffected siblings were identified. Patients
      were studied in 1987 and again in 1993. Age of onset of blindness, hypertension,
      diabetes, renal impairment, and death was determined. The prevalence of obesity,
      gonadal dysfunction, and renal structural abnormalities was assessed. All but 5
      BBS patients (86%) were legally blind, 26% being blind by the age of 13 years and
      50% by 18 years. Eighty-eight percent were above the 90th percentile for height
      and weight. Twenty-five (66%) patients had hypertension, 25% of BBS patients by
      age 26 years, and 50% by age 34 years, whereas in the unaffected group, 25% had
      hypertension by age 49 years (P < 0.0001). Twelve (32%) BBS patients developed
      diabetes mellitus, compared with none of the unaffected group. Only 2 patients
      were insulin dependent. Twenty-five percent of BBS patients had diabetes by the
      age of 35 years. In 12 women of reproductive age, 1 (8%) had primary gonadal
      failure. In 10 men, 4 had primary testicular failure. Nine (25%) patients
      developed renal impairment, with 25% of the BBS group affected by the age of 48
      years. Imaging procedures of the kidney were performed in 25 patients with normal
      renal function. Whereas fetal lobulation and calyceal cysts/diverticula/clubbing
      were characteristic, occurring in 96% of patients, 20% (n = 5) had diffuse and 4%
      (n = 1) focal cortical loss. Eight patients with BBS died, 3 with end-stage renal
      failure and 3 with chronic renal failure. On life-table analysis, 25% of BBS
      patients had died by 44 years, whereas at that age 98% of unaffected siblings
      were still alive (P < 0.0001). Bardet-Biedl syndrome has an adverse prognosis,
      with early onset of blindness, obesity, hypertension, and diabetes mellitus.
      Renal impairment is frequent and an important cause of death. Survival is
      substantially reduced.

PMID- 8651241
TI  - Increased urinary NO2-/NO3- and cyclic guanosine monophosphate levels in patients
      with Bartter's syndrome: relationship to vascular reactivity.
AB  - Nitric oxide (NO) is a potent endogenous vasodilator and plays a pivotal role in
      the control of vascular tone by the formation of cyclic guanosine monophosphate
      (GMP). Patients affected by Bartter's syndrome have lower than normal vascular
      reactivity with normohypotension and decreased peripheral resistances in spite of
      biochemical and hormonal abnormalities typical of hypertension, and it is
      possible that increased production of NO may be involved in maintaining this
      reduced vascular response and vasodilatation. We have examined this possibility
      by studying NO2-/NO3- and cyclic GMP urinary excretions to assess NO production
      in vivo in seven patients affected by Bartter's syndrome compared with seven
      healthy controls. A group of five patients with hypokalemia other than Bartter
      syndrome (pseudo-Bartters) was also included in the study to evaluate the effect
      of hypokalemia on NO production. NO2-/NO3- urinary excretion (0.45 +/- 0.14 v
      0.25 +/- 0.04 micromol/micromol urinary creatinine [controls], P < 0.005, v 0.28
      +/- 0.05 [pseudo-Bartters], P < 0.01) and cyclic GMP urinary excretion (0.057 +/-
      0.028 v 0.022 +/- 0.01 micromol/micromol of urinary creatinine [controls], P <
      0.009, v 0.024 +/- 0.004 [pseudo-Bartters], P < 0.02) were increased in patients
      with Bartter's syndrome in comparison with controls and pseudo-Bartters, and a
      linear correlation between these two parameters was also present (P < 0.001). We
      conclude that in Bartter's syndrome the increased NO2-/NO3- and cyclic GMP
      urinary excretions point to an increased NO synthesis, which could account for
      the reduced vascular response of the disease, therefore adding its role in
      determining the vascular hyporeactivity of Bartter's syndrome.

PMID- 8651243
TI  - Pattern of glomerular disease in Saudi Arabia.
AB  - Clinical data and renal biopsy study of 186 adult patients found to have
      nephropathy and seen at the Security Forces Hospital, Riyadh, over a 5-year
      period (1989 to 1994) were reviewed. Primary glomerular disease accounted for
      more than three fourths of all patients (79%), and the most common histological
      lesion was focal segmental glomerulosclerosis (40.8%) associated with a high
      incidence of hypertension (86.7%), nephrotic syndrome (61.7%), hematuria (48.8%),
      and renal impairment (33.3%). Mesangioproliferative glomerulonephritis was the
      second most common lesion (21.1%), followed by membreous glomerulonephritis
      (13.6%), immunoglobulin A nephropathy (IgAN) (13.6%), membranoproliferative
      glomerulonephritis (9.5%), and minimal change disease (1.4%). Although not as
      common as in most other developed countries, IgAN is being increasingly
      recognized in Saudis. Lupus nephritis remained the commonest cause of secondary
      glomerulonephritis (48.5%), whereas amyloidosis was conspicuously absent. There
      is no evidence, at least in this series, that chronic infection such as hepatitis
      B virus infection has a major role in the development of glomerulonephritis.

PMID- 8651242
TI  - Increased nitric oxide formation in recurrent thrombotic microangiopathies: a
      possible mediator of microvascular injury.
AB  - The term thrombotic microangiopathy (TMA) has been used extensively to encompass
      hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, two syndromes
      of hemolytic anemia, and thrombocytopenia associated with renal or brain
      involvement or both. There is evidence that endothelial damage is a crucial
      feature in the sequence of events that precedes the development of microvascular
      lesions. More recent studies would suggest that endothelial dysfunction could be
      a consequence of neutrophil activation. Activated neutrophils generate superoxide
      anions (O2-) that, combining with endothelial-derived nitric oxide (NO), form the
      highly cytotoxic hydroxyl radical. Seven patients with recurrent forms of TMA and
      seven healthy volunteers were studied. Plasma concentrations of the NO
      metabolites, nitrites/nitrates, were elevated in the acute phase of TMA,
      indicating an increased NO synthesis in vivo. In addition, elevated serum
      concentrations of tumor necrosis factor, a potent inducer of endothelial NO
      synthase, were found in acute TMA. Serum from patients with acute TMA induced NO
      synthesis in cultured endothelial cells more than normal serum. Enhanced
      stimulatory activity was no longer found in the recovery phase. Release of O2- by
      neutrophils ex vivo was higher than normal in patients with acute TMA, but
      decreased in the recovery phase. Exactly the same trend was observed for plasma
      malondialdehyde and conjugated dienes, indicating that excessive oxygen radical
      formation in acute TMA is associated with increased lipid peroxidation. Thus, in
      recurrent forms of TMA, NO formation was increased as compared with controls.
      This was associated with signs of lipid peroxidation, likely the consequence of
      the interaction of NO with neutrophil-derived oxygen products.

PMID- 8651244
TI  - Low molecular weight proteinuria in human immunodeficiency virus-infected
      patients.
AB  - To determine whether human immunodeficiency virus (HIV) infection is associated
      with incipient tubular or glomerular defects, we determined the urinary excretion
      of four low molecular weight proteins (LMWP); beta2-microglobulin (U-beta2-m),
      cystatin C (U-cyst C), Clara cell protein (U-CC16), and retinol-binding protein
      (U-RBP), the markers of tubular dysfunction, the excretion of albumin (U-Alb), a
      marker of glomerular defect, and the excretion of N-acetyl-beta-D-glucosaminidase
      (U-NAG), a marker of structural damage of the proximal tubular epithelium. Their
      determinants have been assessed by stepwise regression analysis using as possible
      predictors age, sex, serum-beta2-m (S-beta2-m), CD4 lymphocyte count, or HIV
      infection stage and therapy. The study involved 76 HIV-infected patients without
      renal disease, 56 with S-beta2-m < 5 mg/L (Group B1), 20 with S-beta2-m > or = 5
      mg/L (Group B2), and 30 HIV-negative controls. Fourteen patients (18.4%) had no
      abnormal urinary protein loss, and 62 (81.6%) had elevated urinary excretion of
      at least one protein (Alb, LMWP, or NAG). A single urinary protein was abnormal
      in 21 patients (U-beta2-m, n = 9; U-RBP, n = 2; U-CC16, n = 4; and U-Alb, n = 6).
      At least two LMWP were abnormal without increased U-Alb in 23 patients (12 with
      increased and 11 with normal U-NAG). Ten patients had an increased urinary
      excretion of at least one LMWP together with U-Alb (5 with increased and 5 with
      normal U-NAG). An increased urinary excretion of all proteins was observed in the
      last 8 patients. The average urinary excretion of all proteins (except cyst C)
      was significantly higher in HIV than in the control group. As expected, U-beta2-m
      and the prevalence of abnormal U-beta2-m values were higher in the B2 than in the
      B1 group (P = 0.0001), whereas the average urinary excretion and the prevalence
      of elevated values of Alb, LMWP (except beta2-m) or NAG were the same in both HIV
      groups. By stepwise regression analysis, age emerged as a significant determinant
      of urinary excretion of beta2-m and CC16, whereas male sex was associated with
      increased U-CC16. S-beta2-m, CD4-lymphocyte count, or HIV infection stage emerged
      as significant determinants only for U-beta2-m as a consequence of a close
      correlation between S-beta2-m and either HIV infection stage (r = -0.52, P =
      0.0001), or CD4 count (r = -0.45, P = 0.0002). Over 80% of HIV-infected patients
      without overt renal disease have evidence of glomerular permeability defects or
      tubular dysfunction, whatever the stage of the disease. U-Alb, RBP, and CC16
      appear as the most sensitive and reliable early markers of these abnormalities.
      Their cause and prognostic value remain to be determined.

PMID- 8651245
TI  - The changing course of diabetic nephropathy: low-density lipoprotein cholesterol
      and blood pressure correlate with regression of proteinuria.
AB  - Diabetic nephropathy (DN) as manifested by persistent and clinically evident
      proteinuria, has long been considered an irreversible process that predicts a
      rapid decline in renal function. The observation of reversal of DN in several
      individuals enrolled in a prospective study of the natural course of diabetes
      complications challenged this view and led to the current investigation into the
      correlates of such regression of proteinuria. DN was defined as a median albumin
      excretion rate (AER) over 200 microg/min in two or three urine collections
      obtained at baseline, and again at 2 and 4 years of follow-up. Among 658
      individuals with childhood-onset insulin-dependent diabetes mellitus (IDDM), 146
      had DN at baseline. Nine subsequently died without renal failure, and 13 were
      lost to follow-up. Of the 124 subjects with at least survey follow-up data, 32
      (24%) developed renal failure, and 78 of the remaining 92 provided full
      quantitative data. AER decreased by > or = 10-fold into the microalbuminuric (20
      to 200 microg/min) or normal range (<20 microg/min) in 7 of these individuals and
      are called "regressors of proteinuria." Compared with the remaining 71 subjects,
      the strongest correlate of regression of proteinuria was an improvement in
      fasting plasma low-density lipoprotein cholesterol (LDL-C) in the 7 regressors (P
      < 0.008). Improved glycemic control was not a significant predictor of improved
      AER. Five of the 7 individuals with improved AER had a baseline median AER below
      500 microg/min. When the 7 regressors of proteinuria were combined with an
      additional 38 individuals who also experienced smaller decreases in median AER,
      such improvement was associated with a more favorable systolic (or diastolic)
      blood pressure (BP) change (P < 0.01), and a decrease in plasma LDL-C level (P =
      0.01). These data suggest that proteinuria in DN may substantially regress in
      approximately 6% and improve in at least 34% of individuals with IDDM over a 4
      year period, often in association with a decrease in plasma LDL-C concentration
      or stabilization or improvement in BP. Furthermore, the data suggest that the
      nonreversibility threshold for diabetic nephropathy may be higher (500 mg/min)
      than previously reported (200 microg/min).

PMID- 8651246
TI  - Blood pressure reduction after parathyroidectomy for secondary
      hyperparathyroidism: further evidence implicating calcium homeostasis in blood
      pressure regulation.
AB  - A link between plasma calcium, dietary cations, and blood pressure has been
      suspected for some time, with human, experimental animal, and epidemiological
      data adduced to support this hypothesis. We identified 21 patients receiving
      regular maintenance hemodialysis, but not receiving any regular antihypertensive
      treatment, who had undergone 22 surgical removals of the parathyroid glands in
      the period 1978 to 1992. These patients' records were then scrutinized. The group
      preparathyroidectomy mean systolic blood pressure (BP) was 142.6 +/- 19.4 mm Hg.
      After the operation, the mean systolic BP was 133.6 +/- 21.9 mm Hg (P = 0.004).
      Plasma calcium decreased from 2.72 +/- 0.18 mmol/L to 2.52 +/- 0.19 mmol/L (P <
      0.001). There was a correlation between the decreases in systolic blood pressure
      (SBP) (9.4%) and plasma calcium (7.3%); r = 0.60, P = 0.012. The decrease in SBP
      was not immediate, but delayed some months and complete by approximately 9 months
      after the operation. Furthermore, using ambulatory BP monitoring in a group of
      long-term hemodialysis patients, we found that parathyroidectomized patients had
      lower BP and pulse rates than those with intact parathyroid glands (SBP, 122.9 +/
      16.3 mm Hg v 102.9 +/- 9.9 mm Hg; pulse rates, 87.5 +/- 12.7 v 72.0 +/- 7.5
      beats/min, P < .001, nonparathyroidectomy v postparathyroidectomy, both
      comparisons). These data support a link between plasma calcium and BP in patients
      receiving maintenance hemodialysis.

PMID- 8651248
TI  - Enhanced glomerular retrieval for renal biopsies.
AB  - A substantial number of glomeruli were found to become dislodged from renal
      biopsy cores during the biopsy procedure. These "lost" glomeruli can be retrieved
      and immobilized on membrane substrates; the morphology of these membrane
      immobilized glomeruli is of diagnostic quality. Hence, this technique of
      glomerular retrieval offers an opportunity to maximize the number of glomeruli
      obtained at biopsy and also makes available additional material for diagnostic
      studies, physiology studies, and archiving.

PMID- 8651247
TI  - Lysosomal enzymuria in preeclampsia.
AB  - We hypothesize that the preeclamptic patient has proximal tubule epithelial
      injury, which leads to the release of lysosomal enzymes, and that the excretion
      of these enzymes might serve as a diagnostic or predictive marker in preeclamptic
      women. The study group consisted of 14 women with preeclampsia (10 severe and 4
      mild, as defined by The American College of Obstetricians and Gynecologists
      criteria) and 28 normotensive controls with singleton pregnancies at 27 to 41
      weeks. There were no significant differences between the two groups for
      gestational age, maternal age, or race. Maternal serum and urine specimens were
      prospectively obtained and analyzed for beta-glucuronidase, beta-hexosaminidase,
      alpha-galactosidase, beta-galactosidase, and alpha-mannosidase using fluorometric
      assays. Median serum and urine activities and fractional excretions of each of
      the five hydrolases were compared between the two study groups using the Mann
      Whitney two-sample rank test. The serum enzyme activities of beta-hexosaminidase
      (P = 0.002), alpha-galactosidase (P = 0.0001), and alpha-mannosidase (P = 0.02)
      were significantly lower in preeclamptic patients than in controls. The urine
      enzyme activities of beta-glucuronidase (P = 0.001), alpha-galactosidase (P =
      0.002), beta-galactosidase (P 0.0003), and alpha-mannosidase (P = 0.003) were
      significantly higher in the preeclamptic patients. The fractional enzyme
      excretions of all five lysosomal hydrolases were higher in preeclamptic patients
      than in controls with P < or = 0.0003 for each enzyme. Preeclampsia is associated
      with a significant decrease in serum activities of three of the five hydrolases
      studied, a significant increase in urine enzyme activities in four of the five
      hydrolases studied, and a significant increase in the fractional excretion of all
      five lysosomal hydrolases.

PMID- 8651249
TI  - Self-delivery of hemodialysis care: a therapy in itself.
AB  - Patient autonomy, sense of control, and well-being are thought to be enhanced by
      self-care hemodialysis as a therapy for end-stage renal disease. Dialysis in a
      satellite setting reduces travel time and can diminish therapy intrusiveness.
      Health-related quality of life (HRQOL), in terms of functional status and well
      being, was measured in a group of patients trained for self-care, and then
      measured again after these patients were transferred to a satellite unit.
      Comparison was made with an age- and comorbidity-matched cohort of full-care
      patients. Patients trained for self-care tended to score higher than the full
      care patients in the psychosocial domains of HRQOL, such as role function, social
      function, and emotional well-being, before and after transfer to the satellite
      unit. Physiological measurements did not differ significantly between groups at
      any time during the study, indicating that differences in HRQOL were not
      attributable to differences in metabolic stability. We conclude that patients
      trained for self-care hemodialysis experience better subjective quality of life
      than their full-care counterparts. This study highlights both the usefulness of
      measuring HRQOL as an outcome of hemodialysis therapy and the potential benefits
      of therapies such as self-care and satellite dialysis.

PMID- 8651250
TI  - Fibrinogen, coagulation factor VII, tissue plasminogen activator, plasminogen
      activator inhibitor-1, and lipid as cardiovascular risk factors in chronic
      hemodialysis and continuous ambulatory peritoneal dialysis patients.
AB  - Mortality rates associated with cardiovascular disease (CVD) are high in long
      term dialysis patients. Increased levels of plasma fibrinogen (FBG), coagulation
      factor VII (FVII), tissue plasminogen activator (t-PA), and plasminogen activator
      inhibitor-1 (PAI-1) as well as hyperlipidemia are regarded as important risk
      factors for CVD. To investigate whether there are differences in the risk of CVD
      between chronic hemodialysis (HD) and continuous ambulatory peritoneal dialysis
      (CAPD) patients, serum lipid levels and plasma FBG, FVII, t-PA, and PAI-1 levels
      were measured in 17 patients on HD and 17 patients on CAPD. FBG was measured by
      the thrombin time method, FVII activity (FVIIc) by the chromogenic prothrombin
      time method, and t-PA and PAI-1 activity by the chromogenic substrate assay. No
      difference was found in body mass index (BMI) between HD and CAPD patients. Total
      cholesterol (TC), TC/high-density lipoprotein (HDL)-C ratio, low-density
      lipoprotein (LDL)-C, and triglycerides (TG) were significantly increased, and HDL
      C was significantly decreased in CAPD patients compared with HD patients. FBG and
      FVIIc were significantly elevated in CAPD patients compared with controls or HD
      patients. T-PA activities were significantly higher in HD and CAPD patients than
      in controls. CAPD patients showed significantly higher PAI-1 activities than
      controls or HD patients. Significant positive correlations were found between FBG
      or FVIIc and TC, between FBG and LDL-C or TG, and between FVIIc and LDL-C in
      these patients. T-PA showed significant negative correlations with FBG, PAI-1,
      TC, LDL-C, and TG. There was a significant positive correlation between PAI-1 and
      TG and a significant negative correlation between PAI-1 and HDL-C. We conclude
      that CAPD patients may have a greater risk of CVD than do HD patients, and that
      coagulation and fibrinolytic activity are correlated with lipid disorders in
      these patients.

PMID- 8651252
TI  - Modification of disease progression in rats with inherited polycystic kidney
      disease.
AB  - The most common inherited form of human polycystic kidney disease (PKD),
      autosomal dominant PKD (ADPKD), is a leading cause of chronic renal failure, but
      has a variable clinical presentation, with end-stage renal disease occurring in
      only 25% to 75%. Several findings are consistent with the idea that factors in
      addition to the primary mutation can affect the progression of cystic change and
      chronic renal failure in PKD. Epithelial cell proliferation is a central element
      in the pathogenesis of renal cysts. We postulated that the superimposition of a
      growth-promoting stimulus might promote more intense proliferation of cystic
      epithelial cells in inherited cystic disease. To study this, we subjected
      Han:SPRD rats, with a form of ADPKD that resembles human ADPKD, from 4 until 10
      weeks of age to diets designed to promote tubule cell growth. The diets included
      supplemental NH4Cl (280 mmol/L in drinking water), limited dietary K+ (0.016% of
      diet; control diet was 1.1% K+), and increased dietary protein (50%; control diet
      was 23% protein). Treatments designed to promote cell growth caused more
      aggressive PKD in males and females, worsened azotemia in males, and resulted in
      azotemia in females (which normally develop PKD but not azotemia at the ages
      studied). NH4Cl, K+ restriction, and increased dietary protein each caused
      greater kidney enlargement in males (kidney weight/body weight ratios increased
      by 35%, 78%, and 105%, respectively) and worsened azotemia in males (serum urea
      nitrogen values increased by 63%, 514%, and 224%, respectively); in contrast,
      decreased dietary protein (4%) caused less severe PKD in males (kidney
      weight/body weight ratios decreased by 43%) and lessened azotemia in males (serum
      urea nitrogen values decreased by 49%). Similarly, NH4Cl and K+ restriction
      caused greater kidney enlargement in females (kidney weight/body weight ratios
      increased by 206% and 203%, respectively) and caused azotemia in females (serum
      urea nitrogen values increased by 177% and 430%, respectively). On the basis of
      these results, we conclude that growth-promoting stimuli can alter the expression
      of hereditary renal cystic disease. These findings demonstrate that the
      progression of hereditary renal cystic disease can be altered by factors in
      addition to the primary genetic defect.

PMID- 8651251
TI  - A cost-effectiveness analysis of OKT3 induction therapy in cadaveric kidney
      transplantation.
AB  - We evaluated the cost-effectiveness of a standard immunosuppressive regimen
      versus an OKT3 induction regimen in cadaveric kidney transplant recipients. Cost
      estimates were based on results from a five-center randomized trial comparing the
      safety and efficacy of OKT3 induction with a conventional triple-drug regimen and
      financial data from the National Cooperative Transplantation Study, the Medicare
      Provider and Analysis Review database, and other sources. Patients received OKT3
      (5 mg/day) by intravenous (IV) bolus injection for 10 to 14 consecutive days in
      conjunction with azathioprine, prednisone, and the delayed addition of
      cyclosporine (CsA) on day 11 (n = 105) or a conventional immunosuppressive
      regimen consisting of CsA, azathioprine, and prednisone (n = 102). The following
      measures were used to evaluate the two regimens: costs incurred between
      transplantation and graft failure; the effectiveness of the two regimens as
      defined by length of graft survival; and cost-effectiveness ratios through 5
      years of observed follow-up and modeled through the expected duration of graft
      survival. Results showed that OKT3 induction uniformly adds $8,219 to the cost of
      the transplant hospitalization. However, most of this cost is offset by a
      reduction in the cost of treating rejection episodes in the OKT3 group (P =
      0.002). A trend toward improved graft survival was detected in the OKT3 group (P
      = 0.158). Through 5 years of observed follow-up, costs per year of graft survival
      are $30,474 with OKT3 versus $32,687 with the conventional regimen. Modeled
      through the expected duration of graft survival, OKT3 induction costs $8,335 for
      each additional year of graft survival. Results are fairly insensitive to wide
      variations in baseline assumptions. We conclude that OKT3 induction improves the
      cost-effectiveness of kidney transplantation.

PMID- 8651253
TI  - Renal tubular acidosis and deafness: report of a large family.
AB  - The syndrome of distal renal tubular acidosis (dRTA) and sensorineural deafness
      has been reported in consanguineous families and is believed to be inherited in
      an autosomal recessive pattern. All affected patients also have nephrocalcinosis.
      We report here a family with 6 of 12 children affected with this syndrome. The
      parents are unaffected and are not blood related. This is the largest family
      described to date with distal renal tubular acidosis and sensorineural deafness.

PMID- 8651254
TI  - Development of nephrotic syndrome in a patient with acute myeloblastic leukemia
      after treatment with macrophage-colony-stimulating factor.
AB  - We describe a patient with acute myeloblastic leukemia (AML) who developed
      nephrotic syndrome after receiving several courses of chemotherapy, including
      macrophage-colony-stimulating factor (M-CSF). At the onset of nephrotic syndrome,
      the patient remained in a hematological remission. A renal biopsy showed diffuse
      mesangial proliferation with marked glomerular infiltration of macrophages and
      massive subendothelial and mesangial deposits. After the institution of the
      combined therapy with corticosteroid, anticoagulant, and dipyridamole, urinary
      protein excretion was attenuated to less than 1.0 g/day. It should be emphasized
      that the recurrence of nephrotic syndrome was observed after the following
      chemotherapy, including M-CSF, whereas the bone marrow still remained completely
      remitted. In contrast, after the last course of chemotherapy, which did not
      include M-CSF, urinary protein excretion was not enhanced. Of note is that the
      renal histology at autopsy showed a remarkable improvement of mesangial
      hypercellularity with concomitant reduction in the number of glomerular
      macrophages. These evolutional changes in both proteinuria and glomerular
      histology suggest a close linkage between the M-CSF treatment and macrophage
      related glomerular injury. The possibility can be raised that M-CSF accelerated
      the underlying renal disease in this case through enhancing macrophage
      accumulation into the glomerulus, leading to the development of nephrotic
      syndrome.

PMID- 8651255
TI  - Histological beta-2-microglobulin amyloidosis 10 years after a successful renal
      transplantation.
AB  - In a patient successfully transplanted 10 years earlier, we confirm that wrist
      and shoulder bone cysts, present at the time of transplantation, remain unchanged
      in size and number and demonstrate, for the first time, that they still contain
      beta-2-microglobulin (beta2m) amyloid. Regression of beta2m amyloid deposits in
      bone cysts disappears, if at all, very slowly.

PMID- 8651256
TI  - Selective renal transplantation in primary hyperoxaluria type 1.
AB  - Primary hyperoxaluria type I (PHI) is a cause of end-stage renal disease in young
      people. It is caused by deficient activity of hepatic peroxisomal
      alanine:glyoxylate aminotransferase (AGT), which results in hyperoxalemia and
      hyperoxaluria. The consequent urolithiasis and nephrocalcinosis result in renal
      impairment, with further reduction in oxalate excretion and eventual systemic
      oxalosis. Historically, renal transplantation has yielded very poor results in
      these patients because of recurrent oxalosis of the graft. Within the last 10
      years, combined hepatorenal transplantation has been successfully applied,
      simultaneously correcting the metabolic lesion in the liver and replacing the
      damaged kidneys. It has, however, become apparent that medical therapy with
      vigorous hydration, inhibitors of stone formation and pyridoxine (AGT co-factor),
      may be successful at delaying, and occasionally in preventing, urolithiasis in
      some hyperoxaluric patients, particularly those whose hyperoxaluria is reduced by
      pyridoxine. This, together with intensive perioperative management and modern
      surgical methods of stone management such as lithotripsy, laser or ultrasound
      stone fragmentation, and percutaneous nephrolithotomy, means that renal
      transplantation alone may be feasible in selected patients. We describe a patient
      with PHI with clinical and biochemical evidence of significant residual AGT
      activity who underwent a successful live-related renal transplantation with
      excellent renal function and no stone recurrence 1 year posttransplantation. The
      appropriate transplantation strategies for these complex patients are discussed
      and include isolated renal transplantation for those patients who are without
      significant systemic oxalosis and have evidence of residual AGT activity.

PMID- 8651257
TI  - Underlying defects in distal renal tubular acidosis: new understandings.

PMID- 8651258
TI  - Renal amyloidosis secondary to chronic rheumatic inflammatory disease.

PMID- 8651259
TI  - Demand for nephrologists.

PMID- 8651260
TI  - Over-the-counter analgesics and kidney disease.

PMID- 8651261
TI  - The impact of imprinting: Prader-Willi syndrome resulting from chromosome
      translocation, recombination, and nondisjunction.
AB  - Prader-Willi syndrome (PWS) is most often the result of a deletion of bands q11.2
      q13 of the paternally derived chromosome 15, but it also occurs either because of
      maternal uniparental disomy (UPD) of this region or, rarely, from a methylation
      imprinting defect. A significant number of cases are due to structural
      rearrangements of the pericentromeric region of chromosome 15. We report two
      cases of PWS with UPD in which there was a meiosis I nondisjunction error
      involving an altered chromosome 15 produced by both a translocation event between
      the heteromorphic satellite regions of chromosomes 14 and 15 and recombination.
      In both cases, high-resolution banding of the long arm was normal, and FISH of
      probes D15S11, SNRPN, D15S10, and GABRB3 indicated no loss of this material.
      Chromosome heteromorphism analysis showed that each patient had maternal
      heterodisomy of the chromosome 15 short arm, whereas PCR of microsatellites
      demonstrated allele-specific maternal isodisomy and heterodisomy of the long arm.
      SNRPN gene methylation analysis revealed only a maternal imprint in both
      patients. We suggest that the chromosome structural rearrangements, combined with
      recombination in these patients, disrupted normal segregation of an imprinted
      region, resulting in uniparental disomy and PWS.

PMID- 8651262
TI  - An ancient common origin of aboriginal Australians and New Guinea highlanders is
      supported by alpha-globin haplotype analysis.
AB  - The origins of aboriginal Australians and their relationship with New Guineans
      and neighboring Southeast Asians remains controversial. We have studied the alpha
      globin haplotype composition of an aboriginal tribe from central Australia, to
      address some of the ambiguities of previous studies. Australians have a haplotype
      repertoire that is shared with New Guinea highlanders, a fact that strongly
      supports a common origin of these two populations. Further, Australians and New
      Guinea highlanders have a different set of alpha haplotypes from Southeast Asians
      and a lower genetic diversity. This, coupled with the presence of many locally
      specific central Australian haplotypes, suggests that much of the original
      diversity was lost in a population bottleneck prior to or during the early
      colonization of Sahul and that subsequent recovery of diversity has been
      accompanied by the generation of new haplotypes. These conclusions contrast with
      some previous genetic studies suggesting links between Australians, coastal New
      Guineans, and present-day Southeast Asians. Much of this discrepancy appears to
      be due to more recent Southeast Asian admixture on the north coast of Australia.

PMID- 8651263
TI  - Mental status of females with an FMR1 gene full mutation.
AB  - The cloning of the FMR1 gene enables molecular diagnosis in patients and in
      carriers (male and female) of this X-linked mental retardation disorder. Unlike
      most X-linked disorders, a considerable proportion of the female carriers of a
      full mutation of the FMR1 gene is affected. In this study, the intelligence
      quotients (IQs) were ascertained by the Wechsler Adult Intelligence Scale in 33
      adult females with a full mutation, with 28 first-degree adult female relatives
      (mainly sisters) without a full mutation as controls. Seventy-one percent of the
      females with a full mutation had IQ scores below 85. In paired analysis, no
      significant correlation could be detected between the IQs of the females with a
      full mutation and those of their first-degree female relatives, reflecting a
      dominant effect of the FMR1 gene full mutation in the mental development of
      females. Considering females with a full mutation only, we observed a significant
      relation between the proportion of normal FMR1 alleles on the active X chromosome
      and IQ. We present a model to explain this relationship.

PMID- 8651264
TI  - Ascertainment bias in estimates of average heterozygosity.
AB  - Population geneticists work with a nonrandom sample of the human genome.
      Conventional practice ensures that unusually variable loci are most likely to be
      discovered and thus included in the sample of loci. Consequently, estimates of
      average heterozygosity are biased upward. In what follows we describe a model of
      this bias. When the mutation rate varies among loci, bias is increased. This
      effect is only moderate, however, so that a model of invariant mutation rates
      provides a reasonable approximation. Bias is pronounced when estimated
      heterozygosity is < approximately 35% Consequently, it probably affects estimates
      from classical polymorphisms as well as from restriction-site polymorphisms.
      Estimates from short-tandem-repeat polymorphisms have negligible bias, because of
      their high heterozygosity. Bias should vary not only among categories of
      polymorphism but also among populations. It should be largest in European
      populations, since these are the populations in which most polymorphisms were
      discovered. As this argument predicts, European estimates exceed those of Africa
      and Asia at systems with large bias. The magnitude of this European excess is
      consistent with the version of our model in which mutation rates vary across
      loci.

PMID- 8651265
TI  - Genetic segregation analyses of serum IgG2 levels.
AB  - Summary : The aim of this study was to determine whether there was evidence for a
      genetic component in the immune response as measured by IgG2 levels. The study
      was motivated by our studies of early-onset periodontitis (EOP), a group of
      disorders characterized by rapid destruction of the supporting tissues of the
      teeth in otherwise healthy individuals. EOP has two subforms, localized juvenile
      periodontitis (LJP) and a generalized form (G-EOP). IgG2 levels are elevated in
      LJP but not G-EOP individuals; and African-American IgG2 levels are higher than
      Caucasian levels regardless of EOP status. IgG2 levels were determined in 123 EOP
      families and in 508 unrelated non-EOP control individuals. Segregation analysis
      under the regressive model approach of Bonney was used to analyze IgG2 levels for
      evidence of major locus segregation. After adjusting for LJP status, race, sex,
      and age, the best fitting model was an autosomal codominant major locus model
      (accounting for approximately 62% of the variance in IgG2), plus residual
      parent/offspring and spousal correlations. Smoking and GM23 are also known to
      affect IgG2 levels. If additional adjustments are made for smoking and GM23, the
      best-fitting model is still a codominant major locus but with no significant
      residual correlations.

PMID- 8651266
TI  - Two-locus linkage analysis of cutaneous malignant melanoma/dysplastic nevi.
AB  - Previous linkage analyses of 19 cutaneous malignant melanoma/dysplastic nevi
      (CMM/DN) kindreds showed significant evidence of linkage and heterogeneity to
      both chromosomes 1p and 9p. Five kindreds also showed evidence of linkage (Z>0.7)
      to both regions. To further examine these findings, we conducted two-trait-locus,
      two-marker-locus linkage analysis. We examined one homogeneity and one
      heterogeneity single-locus model (SL-Hom and SL-Het), and two-locus (2L) models:
      an epistatic model (Ep), in which CMM was treated as a genuine 2L disease, and a
      heterogeneity model (Het), in which CMM could result from disease alleles at
      either locus. Both loci were modeled as autosomal dominant. The LOD scores for
      CMM alone were highest using the SL-Het model (Z = 8.48, theta = .0). There was
      much stronger evidence of linkage to chromosome 9p than to 1p for CMM alone; the
      LOD scores were approximately two times greater on 9p than on 1p. The change in
      LOD scores from an evaluation of CMM alone to CMM/DN suggested that a chromosome
      1p locus (or loci) contributed to both CMM and CMM/DN, whereas a 9p locus
      contributed more to CMM alone. For both 2L models, the LOD scores from 1p were
      greater for CMM/DN than for CMM alone (Ep: Z=4.63 vs. 3.83; Het: 4.94 vs. 3.80,
      respectively). In contrast, for 9p, the LOD scores were substantially lower with
      CMM/DN than with CMM alone (Ep: 4.64 vs. 7.06; Het: 5.38 vs. 7.99, respectively).
      After conditioning on linkage to the other locus, only the 9p locus consistently
      showed significant evidence for linkage to CMM alone. Thus, the application of 2L
      models may be useful to help unravel the complexities of familial melanoma.

PMID- 8651267
TI  - Assessing familial aggregation of age at onset, by using estimating equations,
      with application to breast cancer.
AB  - In genetic research of chronic diseases, age-at-onset outcomes within families
      are often correlated. The nature of correlation of age-at-onset outcomes is
      indicative of common genetic and/or shared environmental risk factors among
      family members. Understanding patterns of such correlation may shed light on the
      disease etiology and, hence, is an important step to take prior to further
      searching for the responsible genes via segregation and linkage studies. Age-at
      onset outcomes are different from those familiar quantitative or qualitative
      traits for which many statistical methods have been developed. In comparison with
      the quantitative traits, age-at-onset outcomes are often censored, i.e., instead
      of actual age-at-onset outcomes, only the current ages or ages at death are
      observed. They are also different from qualitative traits because of their
      continuity. Because of the complexity of correlated censored outcomes, few
      methods have yet been developed. A traditional approach is to impose a parametric
      joint distribution for the correlated age-at-onset outcomes, which has been
      criticized for requiring a stringent assumption about the entire distribution of
      age at onset. The purpose of this paper is to describe a method for assessing
      familial aggregation of correlated age-at-onset outcomes semiparametrically, by
      use of estimating equations. This method does not require any parametric
      assumption for modeling the age at onset. The estimates of parameters, including
      those quantifying the correlation within families, are consistent and have an
      asymptotic normal distribution that can be used to make inferences. To illustrate
      this new method, we analyzed two age-at-onset data sets that were obtained from
      studies conducted in the States of Washington and Hawaii, with the objective of
      quantifying the familial aggregations of age at onset of breast cancer.

PMID- 8651269
TI  - Diagnostic testing for Prader-Willi and Angleman syndromes: Report of the
      ASHG/ACMG Test and Technology Transfer Committee.

PMID- 8651268
TI  - The problem of ascertainment for linkage analysis.
AB  - It is generally believed that ascertainment corrections are unnecessary in
      linkage analysis, provided individuals are selected for study solely on the basis
      of trait phenotype and not on the basis of marker genotype. The theoretical
      rationale for this is that standard linkage analytic methods involve conditioning
      likelihoods on all the trait data, which may be viewed as an application of the
      ascertainment assumption-free (AAF) method of Ewens and Shute. In this paper, we
      show that when the observed pedigree structure depends on which relatives within
      a pedigree happen to have been the probands (proband-dependent, or PD, sampling)
      conditioning on all the trait data is not a valid application of the AAF method
      and will result in asymptotically biased estimates of genetic parameters (except
      under single ascertainment). Furthermore, this result holds even if the
      recombination fraction R is the only parameter of interest. Since the lod score
      is proportional to the likelihood of the marker data conditional on all the trait
      data, this means that when data are obtained under PD sampling the lod score will
      yield asymptotically biased estimates of R, and that so-called mod scores (i.e.,
      lod scores maximized over both R and parameters theta of the trait distribution)
      will yield asymptotically biased estimates of R and theta. Furthermore, the
      problem appears to be intractable, in the sense that it is not possible to
      formulate the correct likelihood conditional on observed pedigree structure. In
      this paper we do not investigate the numerical magnitude of the bias, which may
      be small in many situations. On the other hand, virtually all linkage data sets
      are collected under PD sampling. Thus, the existence of this bias will be the
      rule rather than the exception in the usual applications.

PMID- 8651271
TI  - Limits on fine mapping of complex traits.

PMID- 8651270
TI  - A gene for premature ovarian failure associated with eyelid malformation maps to
      chromosome 3q22-q23.

PMID- 8651272
TI  - Likelihood ratio tests for linkage and linkage disequilibrium: asymptotic
      distribution and power.

PMID- 8651273
TI  - The FRAXE Syndrome: is it time for routine screening?

PMID- 8651274
TI  - A study of FRAXE in mentally retarded individuals referred for fragile X syndrome
      (FRAXA) testing in the United Kingdom.
AB  - The folate-sensitive fragile site FRAXE is located in proximal Xq28 of the human
      X chromosome and lies approximately 600 kb distal to the fragile X syndrome
      (FRAXA) fragile site at Xq27.3. The cytogenetic expression of FRAXE is thought to
      be associated with mental handicap, but this is usually mild compared to that of
      the more common fragile X syndrome that is associated with the expression of the
      FRAXA fragile site. The exact incidence of FRAXE mental retardation is uncertain.
      We describe here the results of a U.K. survey designed to assess the frequency of
      FRAXE in a population of individuals referred for fragile X syndrome testing and
      found to be negative for expansion events at the FRAXA locus. No FRAXE expansion
      events were found in 362 cytogenetically negative males studied, and one
      expansion event was identified in a sample of 534 males for whom cytogenetic
      analyses were either unrecorded or not performed. Further FRAXE expansion events
      were detected in two related females known to be cytogenetically positive for a
      fragile site in Xq27.3-28. To gain insight into the FRAXE phenotype, the clinical
      details of the identified FRAXE male plus three other FRAXE individuals
      identified through previous referrals for fragile X syndrome testing are
      presented. For the population studied, we conclude that FRAXE mental retardation
      is a relatively rare but significant form of mental retardation for which genetic
      diagnosis would be appropriate.

PMID- 8651276
TI  - Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert
      syndrome.
AB  - Apert syndrome is a distinctive human malformation characterized by
      craniosynostosis and severe syndactyly of the hands and feet. It is caused by
      specific missense substitutions involving adjacent amino acids (Ser252Trp or
      Pro253Arg) in the linker between the second and third extracellular
      immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have
      developed a simple PCR assay for these mutations in genomic DNA, based on the
      creation of novel (SfiI) and (BstUI) restriction sites. Analysis of DNA from 70
      unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation
      and 25 had the Pro253Arg mutation. Phenotypic differences between these two
      groups of patients were investigated. Significant differences were found for
      severity of syndactyly and presence of cleft palate. The syndactyly was more
      severe with the Pro253Arg mutation, for both the hands and the feet. In contrast,
      cleft palate was significantly more common in the Ser252Trp patients. No
      convincing differences were found in the prevalence of other malformations
      associated with Apert syndrome. We conclude that, although the phenotype
      attributable to the two mutations is very similar, there are subtle differences.
      The opposite trends for severity of syndactyly and cleft palate in relation to
      the two mutations may relate to the varying patterns of temporal and tissue
      specific expression of different fibroblast growth factors, the ligands for
      FGFR2.

PMID- 8651275
TI  - Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine
      metabolism in man.
AB  - In two children with an accumulation of guanidinoacetate in brain and a
      deficiency of creatine in blood, a severe deficiency of guanidinoacetate
      methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT
      alleles were identified that carried a single base substitution within a 5'
      splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three
      of the transcripts encode truncated polypeptides that lack a residue known to be
      critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn
      error of creatine metabolism. It causes a severe developmental delay and
      extrapyramidal symptoms in early infancy and is treatable by oral substitution
      with creatine.

PMID- 8651277
TI  - Maternally inherited cardiomyopathy and hearing loss associated with a novel
      mutation in the mitochondrial tRNA(Lys) gene (G8363A).
AB  - A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two
      unrelated families, with a syndrome consisting of encephalomyopathy,
      sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from
      the probands showed mitochondrial proliferation and partial defects of complexes
      I, III, and IV of the electron-transport chain. The G8363A mutation was very
      abundant (>95%) in muscle samples from the probands and was less copious in blood
      from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis
      showed significantly higher levels of mutant genomes in cytochrome (c) oxidase
      negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was
      not found in >200 individuals, including normal controls and patients with other
      mitochondrial encephalomyopathies, thus fulfilling accepted criteria for
      pathogenicity.

PMID- 8651278
TI  - The spectrum of RB1 germ-line mutations in hereditary retinoblastoma.
AB  - We have searched for germ-line RB1 mutations in 119 patients with hereditary
      retinoblastoma. Previous investigations by Southern blot hybridization and PCR
      fragment-length analysis had revealed mutations in 48 patients. Here we report on
      the analysis of the remaining 71 patients. By applying heteroduplex analysis,
      nonisotopic SSCP, and direct sequencing, we detected germ-line mutations
      resulting in premature termination codons or disruption of splice signals in 51
      (72%) of the 71 patients. Four patients also showed rare sequence variants. No
      region of the RB1 gene was preferentially involved in single base substitutions.
      Recurrent transitions were observed at most of the 14 codons within the RB1. No
      mutation was observed in exons 25-27, although this region contains two CGA
      codons. This suggests that mutations within the 3'-terminal region of the RB1
      gene may not be oncogenic. When these data were combined with the results of our
      previous investigations, mutations were identified in a total of 99 (83%) of 119
      patients. The spectrum comprises 15% large deletions, 26% small length
      alterations, and 42 % base substitutions. No correlation between the location of
      frameshift or nonsense mutations and phenotypic features, including age at
      diagnosis, the number of tumor foci, and manifestation of nonocular tumors was
      observed.

PMID- 8651279
TI  - Mucopolysaccharidosis IVA: four new exonic mutations in patients with N
      acetylgalactosamine-6-sulfate sulfatase deficiency.
AB  - We report four new mutations in Japanese patients with mucopolysaccharidosis IVA
      (MPSIVA) who were heterozygous for a common double gene deletion. A nonsense
      mutation of CAG to TAG at codon 148 in exon 4 was identified, resulting in a
      change of Q to a stop codon and three missense mutations. V (GTC) to A (GCC) at
      codon 138 in exon 4, P (CCC) to S (TCC) at codon 151 in exon 5, and P (CCC) to L
      (CTC) at codon 151 in exon 5. Introduction of these mutations into the normal
      GALNS cDNA and transient expression in cultured fibroblasts resulted in a
      significant decrease in the enzyme activity. V138A and Q148X mutations result in
      changes of restriction site, which were analyzed by restriction-enzyme assay.
      P151S and P151L mutations that did not alter the restriction site were detected
      by direct sequencing or allele specific oligohybridization. Detection of the
      double gene deletion was initially done using Southern blots and was confirmed by
      PCR. Haplotypes were determined using seven polymorphisms to the GALNS locus in
      families with the double gene deletion. Haplotype analysis showed that the common
      double gene deletion occurred on a single haplotype, except for some variation in
      a VNTR-like polymorphism. This finding is consistent with a common founder for
      all individuals with this mutation.

PMID- 8651280
TI  - Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single
      deletion.
AB  - Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes
      mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract
      abnormalities, and neurological dysfunction. The association of clinical
      manifestations in tissues and organs unrelated functionally or embryologically
      suggested the possibility of a mitochondrial implication in the disease, which
      has been demonstrated in two sporadic cases. Nonetheless, familial studies
      suggested an autosomal recessive mode of transmission, and recent data
      demonstrated linkage with markers on the short arm of human chromosome 4. The
      patient reported here, as well as her parents and unaffected sister, carried a
      heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of
      mitochondrial genomes in lymphocytes from the patient and approximately 5% in the
      tissues studied from members of her family. The presence of the deletion in the
      patient in a proportion higher than in her unaffected parents suggests a putative
      defect in a nuclear gene that acts at the mitochondrial level.

PMID- 8651281
TI  - Molecular analysis of carnitine palmitoyltransferase II deficiency with
      hepatocardiomuscular expression.
AB  - Carnitine palmitoyltransferase (CPT) II deficiency, an inherited disorder of
      mitochondrial long-chain fatty-acid (LCFA) oxidation, results in two distinct
      clinical phenotypes, namely, an adult (muscular) form and an infantile
      (hepatocardiomuscular) form. The rationale of this phenotypic heterogeneity is
      poorly understood. The adult form of the disease is commonly ascribed to the Ser
      113-Leu substitution in CPT II. Only few data are available regarding the
      molecular basis of the infantile form of the disease. We report herein a
      homozygous A-2399-C transversion predicting a Tyr-628-Ser substitution in a CPT
      II-deficient infant. In vitro expression of mutant cDNA in COS-1 cells
      demonstrated the responsibility of this mutation for the disease. Metabolic
      consequences of the SER-113-Leu and Tyr-628-Ser substitutions were studied in
      fibroblasts. The Tyr-628-Ser substitution (infantile form) resulted in a 10% CPT
      II residual activity, markedly impairing LCFA oxidation, whereas the Ser-113-Leu
      substitution (adult form) resulted in a 20% CPT II residual activity, with out
      consequence on LCFA oxidation. These data show that CPT II activity has to be
      reduced below a critical threshold in order for LCFA oxidation in fibroblasts to
      be impaired. The hypothesis that this critical threshold differs among tissues
      could provide a basis to explain phenotypic heterogeneity of CPT II deficiency.

PMID- 8651282
TI  - Molecular characterization of mitochondrial trifunctional protein deficiency:
      formation of the enzyme complex is important for stabilization of both alpha- and
      beta-subunits.
AB  - Mitochondrial trifunctional protein (TP) is an enzyme complex with three
      activities: enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl
      CoA thiolase. Studies on defects in this enzyme in patients with TP deficiency
      suggest that there are two types of defect. Patients in group 1 have normal
      amount of cross-reacting material by immunoblot and lack only long-chain 3
      hydroxyacyl-CoA dehydrogenase activity. Patients in group 2 have a trace amount
      of cross-reacting material, with all three activities being low. We identified
      three patients in group 2, and analysis was made at the cDNA level. In patient 2,
      there was a heterozygous 71-bp deletion at position 110-180 in the alpha-subunit.
      In patients 1 and 3, there was an abnormal beta-subunit; patient 1 had an A-788
      to-G substitution, and patient 3 had G-182-to-A and G-740-to-A substitutions in
      each of separate alleles. This is the first demonstration of disease-causing
      mutations in the beta-subunit. cDNA-expression experiments in patients'
      fibroblasts, using a vaccinia virus system, and gel filtration analysis, using
      patients' fibroblasts, revealed that the existence of both normal alpha- and beta
      subunits, and possibly their association, are important for stabilizing TP and
      that A-788-to-G substitution on the beta-subunit in patient 1 seems to interfere
      with the association, the result being a rapid decomposition of TP.

PMID- 8651283
TI  - A GLRA1 null mutation in recessive hyperekplexia challenges the functional role
      of glycine receptors.
AB  - Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit
      gene (GLRA1) give rise to hereditary hyperekplexia. These mutations impair
      agonist affinities and change conductance states of expressed mutant channels,
      resulting in a partial loss of function. In a recessive case of hyperekplexia, we
      found a deletion of exons 1-6 of the GLRA1 gene. Born to consanguineous parents,
      the affected child is homozygous for this GLRA1(null) allele consistent with a
      complete loss of gene function. The child displayed exaggerated startle responses
      and pronounced head-retraction jerks reflecting a disinhibition of vestigial
      brain-stem reflexes. In contrast, proprio- and exteroceptive inhibition of muscle
      activity previously correlated to glycinergic mechanisms were not affected. This
      case demonstrates that, in contrast to the lethal effect of a null allele in the
      recessive mouse mutant oscillator (Glra1 spd-ot), the loss of the GlyR alpha 1
      subunit is effectively compensated in man.

PMID- 8651284
TI  - Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.
AB  - Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital
      anomalies/mental retardation syndrome caused by an interstitial deletion
      involving band p11.2 of chromosome 17. Toward the molecular definition of the
      interval defining this microdeletion syndrome, 62 unrelated SMS patients in
      conjunction with 70 available unaffected parents were molecularly analyzed with
      respect to the presence or absence of 14 loci in the proximal region of the short
      arm of chromosome 17. A multifaceted approach was used to determine deletion
      status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern
      analysis of somatic cell hybrids retaining the deleted chromosome 17 from
      selected patients, and (iii) genotype determination of patients for whom a
      parent(s) was available at four microsatellite marker loci and at four loci with
      associated RFLPs. The relative order of two novel anonymous markers and a new
      microsatellite marker was determined in 17p11.2. The results confirmed that the
      proximal deletion breakpoint in the majority of SMS patients is located between
      markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The
      common distal breakpoint was mapped between markers cCI17-638, which lies distal
      to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease
      type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and
      probes from this region can be used for diagnosis of the SMS deletion by FISH.
      Ten patients demonstrated molecularly distinct deletions; of these, two patients
      had smaller deletions and will enable the definition of the critical interval for
      SMS.

PMID- 8651286
TI  - Finding genes on the X chromosome by which homo may have become sapiens.

PMID- 8651285
TI  - Genetic control of X inactivation and processes leading to X-inactivation
      skewing.

PMID- 8651287
TI  - Heritability of X chromosome--inactivation phenotype in a large family.
AB  - One of the two X chromosomes in each somatic cell of normal human females becomes
      inactivated very early in embryonic development. Although the inactivation of an
      X chromosome in any particular somatic cell of the embryonic lineage is thought
      to be a stochastic and epigenetic event, a strong genetic influence on this
      process has been described in the mouse. We have attempted to uncover evidence
      for genetic control of X-chromosome inactivation in the human by examining X
      chromosome-inactivation patterns in 255 females from 36 three-generation
      pedigrees, to determine whether this quantitative character exhibits evidence of
      heritability. We have found one family in which all seven daughters of one male
      and the mother of this male have highly skewed patterns of X-chromosome
      inactivation, suggesting strongly that this quantitative character is controlled
      by one or more X-linked genes in some families.

PMID- 8651288
TI  - PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal
      signs, and macroorchidism maps to Xq28.
AB  - We report a three-generation family manifesting a previously undescribed X-linked
      mental retardation syndrome. Four of the six moderately retarded males have had
      episodes of manic-depressive psychosis. The phenotype also includes pyramidal
      signs, Parkinsonian features, and macroorchidism, but there are no characteristic
      dysmorphic facial features. Affected males do not show fragile sites at distal Xq
      on cytogenetic analysis, nor do they have expansions of the CGG repeats at the
      FRAXA, FRAXE, or FRAXF loci. Linkage analyses were undertaken, and a maximal LOD
      score of 3.311 at theta = .0 was observed with the microsatellite marker DXS1123
      in Xq28. A recombination was detected in one of the affected males with DXS1691
      (Xq28), which gives the proximal boundary of the localization. No distal
      recombination has been detected at any of the loci tested.

PMID- 8651289
TI  - Identification, expression, and biochemical characterization of N
      acetylgalactosamine-4-sulfatase mutations and relationship with clinical
      phenotype in MPS-VI patients.
AB  - Maroteaux-Lamy syndrome, or mucopolysaccharidosis type VI (MPS-VI), is a
      lysosomal storage disorder characterized by the defective degradation of dermatan
      sulfate due to the deficiency of N-acetylgalactosamine-4-sulfatase (4S). The
      clinical severity of MPS-VI ranges in a continuum from mildly affected to
      severely affected patients. Mutations in MPS-VI patient samples were identified
      by chemical cleavage and direct DNA sequencing of PCR products derived from
      patient cDNA. Five amino acid substitutions were identified (T92M, R95Q, Y210C,
      H393P, and L498P), individually introduced into the wild-type 4S cDNA by site
      directed in vitro mutagenesis, and transfected into Chinese hamster ovary cells.
      Three of the five mutations (R95Q, Y210C, and H393P) were observed in >1 of 25
      unrelated MPS-VI patients; however, the mutations were not found in 20 control
      individuals. The residual 4S activity and protein (biochemical phenotype) were
      determined for each mutant in order to confirm their identity as mutations and to
      dissect the contribution of each mutant allele to the overall clinical phenotype
      of the patient. For each patient, the combined biochemical phenotypes of the two
      4S mutant alleles demonstrated a good correspondence with the observed clinical
      phenotype (with the possible exception of a patient who was a compound
      heterozygote for T92M and L498P). This preliminary correspondence between
      genotype and the phenotype in MPS-VI may, with further refinement, contribute to
      the assessment of therapeutic approaches for MPS-VI patients.

PMID- 8651290
TI  - Mutational and protein analysis of patients and heterozygous women with X-linked
      adrenoleukodystrophy.
AB  - X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with
      impaired beta-oxidation of very-long-chain fatty acids (VLCFA), is due to
      mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter
      (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44
      French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and
      studied the effect of mutations on ALDP by immunocytofluorescence and western
      blotting of fibroblasts and/or white blood cells. Mutations were detected in 37
      of 44 kindreds and were distributed over the whole protein-coding region, with
      the exception of the C terminus encoded in exon 10. Except for two mutations
      (delAG1801 and P560L) observed four times each, nearly every ALD family has a
      different mutation. Twenty-four of 37 mutations were missense mutations leading
      to amino acid changes located in or close to putative transmembrane segments (TMS
      2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP
      binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP
      immunoreactivity in their fibroblasts and/or white blood cells. More than half of
      missense mutations studied (11 of 21) resulted in a complete lack of ALDP
      immunoreactivity, and six missense mutations resulted in decreased ALDP
      expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous
      carrier from ALD kindred with no ALDP showed a mixture of positive- and negative
      ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women
      have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be
      applicable in a majority of ALD kindred, to identify heterozygous women,
      particularly when the ALD gene mutation has not yet been identified.

PMID- 8651292
TI  - A mutation causing Alport syndrome with tardive hearing loss is common in the
      western United States.
AB  - Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome (AS), a
      nephritis characterized by progressive deterioration of the glomerular basement
      membrane and usually associated with progressive hearing loss. We have identified
      a novel mutation, L1649R, present in 9 of 121 independently ascertained families.
      Affected males shared the same haplotype of eight polymorphic markers tightly
      linked to COL4A5, indicating common ancestry. Genealogical studies place the
      birth of this ancestor >200 years ago. The L1649R mutation is a relatively common
      cause of Alport syndrome in the western United States, in part because of the
      rapid growth and migratory expansion of mid-nineteenth-century pioneer
      populations carrying the gene. L1649R affects a highly conserved residue in the
      NC1 domain, which is involved in key inter- and intramolecular interactions, but
      results in a relatively mild disease phenotype. Renal failure in an L1649R male
      typically occurs in the 4th or 5th decade and precedes the onset of significant
      hearing loss by approximately 10 years.

PMID- 8651291
TI  - Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in
      melanocytes from an individual with brown oculocutaneous albinism: a new subtype
      of albinism classified as "OCA3".
AB  - Most types of human oculocutaneous albinism (OCA) result from mutations in the
      gene for tyrosinase (OCA1) or the P protein (OCA2), although other types of OCA
      have been described but have not been mapped to specific loci. Melanocytes were
      cultured from an African-American with OCA, who exhibited the phenotype of Brown
      OCA, and his normal fraternal twin. Melanocytes cultured from the patient with
      OCA and the normal twin appeared brown versus black, respectively. Melanocytes
      from both the patient with OCA and the normal twin demonstrated equal amounts of
      NP-40-soluble melanin; however, melanocytes from the patient with OCA contained
      only 7% of the amount of insoluble melanin found from the normal twin. Tyrosinase
      related protein-1 (TRP-1) was not detected in the OCA melanocytes by use of
      various anti-TRP-1 probes. Furthermore, transcripts for TRP-1 were absent in
      cultured OCA melanocytes. The affected twin was homozygous for a single-bp
      deletion in exon 6, removing an A in codon 368 and leading to a premature stop at
      codon 384. Tyrosine hydroxylase activity of the OCA melanocytes was comparable to
      controls when assayed in cell lysates but was only 30% of controls when assayed
      in intact cells. We conclude that this mutation of the human TRP-1 gene affects
      its interaction with tyrosinase, resulting in dysregulation of tyrosinase
      activity, promotes the synthesis of brown versus black melanin, and is
      responsible for a third genetic type of OCA in humans, which we classify as
      "OCA3."

PMID- 8651293
TI  - Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer
      families: a genetic study of 15 185delAG-mutation kindreds.
AB  - We screened 163 women from breast-ovarian cancer-prone families, as well as 178
      individuals affected with breast and/or ovarian cancer but unselected for family
      history, for germ-line mutations in exon 2 of BRCA1, by SSCP analysis and direct
      sequencing. A total of 25 mutations were detected. Thirteen of 64 Jewish
      Ashkenazi women and 2 non-Jewish individuals were found to possess the 185delAG
      mutation. Haplotype data for all 15 individuals, with markers intragenic to
      BRCA1, suggest that the Jewish Ashkenazi individuals share a common ancestry that
      is distinct from the lineage shared by the other two women. These data provide
      the first evidence of two distinct lines of transmission for the 185delAG
      mutation, only one of which has its origins in the Jewish Ashkenazi population.
      Our screening also uncovered 10 affected individuals with an 11-bp deletion at
      nucleotide 188 of BRCA1 (188del11), 4 of whom are Ashkenazi Jews. This is only
      the third reported mutation detected within the Jewish Ashkenazi population and
      may represent the second most common alteration in BRCA1 found in Ashkenazi Jews
      in the United States. The observed overrepresentation of specific mutations
      within a subgroup of the general population may eventually contribute to the
      development of inexpensive and routine tests for BRCA1 mutations, as well as to
      the elucidation of other contributory factors (e.g., diet, environment, and
      chemical exposures) that may play a key role in cancer initiation and
      development. The implications of the mutational data, as well as the role that
      founder effect, demographic history, and penetrance play in the resulting
      observed phenomena, are discussed.

PMID- 8651294
TI  - Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin
      alpha2-chain in congenital muscular dystrophy with partial deficiency of the
      protein.
AB  - Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders
      of early onset. Approximately half of CMD patients present laminin alpha2-chain
      (merosin) deficiency in muscle biopsies, and the disease locus has been mapped to
      the region of the LAMA2 gene (6q22-23) in several families. Recently, two
      nonsense mutations in the laminin alpha2-chain gene were identified in CMD
      patients exhibiting complete deficiency of the laminin alpha2-chain in muscle
      biopsies. However, a subset of CMD patients with linkage to LAMA2 show only
      partial absence of the laminin alpha2-chain around muscle fibers, by
      immunocytochemical analysis. In the present study we have identified a homozygous
      missense mutation in the alpha2-chain gene of a consanguineous Turkish family
      with partial laminin alpha2-chain deficiency. The T-->C transition at position
      3035 in the cDNA sequence results in a Cys996-->Arg substitution. The mutation
      that affects one of the conserved cysteine-rich repeats in the short arm of the
      laminin alpha2-chain should result in normal synthesis of the chain and in
      formation and secretion of a heterotrimeric laminin molecule. Muscular
      dysfunction is possibly caused either by abnormal disulfide cross-links and
      folding of the laminin repeat, leading to the disturbance of an as yet unknown
      binding function of the laminin alpha2-chain and to shorter half-life of the
      muscle-specific laminin-2 and laminin-4 isoforms, or by increased proteolytic
      sensitivity, leading to truncation of the short arm.

PMID- 8651295
TI  - A novel mutation in the putative DNA helicase XH2 is responsible for male-to
      female sex reversal associated with an atypical form of the ATR-X syndrome.
AB  - We describe a pedigree presenting X-linked severe mental retardation associated
      with multiple congenital abnormalities and 46,XY gonadal dysgenesis, leading in
      one family member to female gender assignment. Female carriers are unaffected.
      The dysmorphic features are similar to those described in the alpha-thalassemia
      and mental retardation (ATR-X) syndrome, although there is no clinical evidence
      of alpha-thalassemia in this family. In addition, the family had other clinical
      features not previously observed in the ATR-X syndrome, including partial optic
      nerve atrophy and partial ocular albinism. Mutations in a putative DNA helicase,
      termed XH2, have been reported to give rise to the ATR-X syndrome. We screened
      the XH2 gene for mutations in affected members of the family and identified a 4
      bp deletion at an intron/exon boundary that removes an invariant 3' splice
      acceptor site. The mutation cosegregates with the syndrome. The genomic deletion
      causes missplicing of the pre-mRNA, which results in the loss of 8 bp of coding
      sequence, thereby generating a frameshift and a downstream premature stop codon.
      Our finding increases the range of clinical features associated with mutations in
      the XH2 gene.

PMID- 8651297
TI  - Mutations and phenotype in isolated glycerol kinase deficiency.
AB  - We demonstrate that isolated glycerol kinase (GK) deficiency in three families
      results from mutation of the Xp21 GK gene. GK mutations were detected in four
      patients with widely differing phenotypes. Patient 1 had a splice-site mutation
      causing premature termination. His general health was good despite absent GK
      activity, indicating that isolated GK deficiency can be silent. Patient 2 had GK
      deficiency and a severe phenotype involving psychomotor retardation and growth
      delay, bone dysplasia, and seizures, similar to the severe phenotype of one of
      the first described cases of GK deficiency. His younger brother, patient 3, also
      had GK deficiency, but so far his development has been normal. GK exon 17 was
      deleted in both brothers, implicating additional factors in causation of the
      severe phenotype of patient 2. Patient 4 had both GK deficiency with mental
      retardation and a GK missense mutation (D440V). Possible explanations for the
      phenotypic variation of these four patients include ascertainment bias; metabolic
      or environmental stress as a precipitating factor in revealing GK-related
      changes, as has previously been described in juvenile GK deficiency; and
      interactions with functional polymorphisms in other genes that alter the effect
      of GK deficiency on normal development.

PMID- 8651296
TI  - X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the
      COL4A5 gene.
AB  - The COL4A5 gene encodes the alpha5 (type IV) collagen chain and is defective in X
      linked Alport syndrome (AS). Here, we report the first systematic analysis of all
      51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have
      previously reported nine major rearrangements, as well as 18 small mutations
      identified in the same patient series by SSCP analysis of several exons. After
      systematic analysis of all 51 exons of COL4A5, we have now identified 30
      different mutations: 10 glycine substitutions in the triple helical domain of the
      protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense,
      and 5 splice-site mutations. These mutations were either unique or found in two
      unrelated families, thus excluding the presence of a common mutation in the
      coding part of the gene. Overall, mutations were detected in only 45% of
      individuals with a certain or likely diagnosis of X-linked AS. This finding
      suggests that mutations in noncoding segments of COL4A5 account for a high number
      of X-linked AS cases. An alternative hypothesis is the presence of locus
      heterogeneity, even within the X-linked form of the disease. A genotype/phenotype
      comparison enabled us to better substantiate a significant correlation between
      the degree of predicted disruption of the alpha5 chain and the severity of
      phenotype in affected male individuals. Our study has significant implications in
      the diagnosis and follow-up of AS patients.

PMID- 8651298
TI  - Somatic mosaicism of expanded CAG repeats in brains of patients with
      dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of
      mitotic instability.
AB  - Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant
      neurodegenerative disease caused by unstable expansion of a CAG repeat in the
      DRPLA gene. We performed detailed quantitative analysis of the size and the size
      distribution (range) of the expanded CAG repeats in various regions of the CNS of
      eight autopsied patients with DRPLA. Expanded alleles (AE) showed considerable
      variations in size, as well as in range, depending on the region of the CNS,
      whereas normal alleles did not show such variations, which indicates the
      occurrence of somatic mosaicism of AE in the CNS. The AE in the cerebellar cortex
      were consistently smaller by two to five repeat units than those in the
      cerebellar white matter. Moreover, the AE in the cerebral cortex were smaller by
      one to four repeat units than those in the cerebral white matter. These results
      suggest that the smaller AE in the cerebellar and cerebral cortices represent
      those of neuronal cells. The ranges of the AE in the cerebral cortex, cerebral
      white matter, and cerebellar white matter showed considerable variation ranging
      from 9 to 23 repeat units, whereas those in the cerebellar cortex showed little
      variance and were approximately 7 repeat units. The ranges of the AE in the
      cerebral cortex, cerebral white matter, and cerebellar white matter were much
      broader in patients with higher ages at death than they were in patients with
      lower ages at death, raising the possibility that the range of AE increases with
      time, as the result of mitotic instability of AE.

PMID- 8651299
TI  - Recombination hot spot in a 3.2-kb region of the Charcot-Marie-Tooth type 1A
      repeat sequences: new tools for molecular diagnosis of hereditary neuropathy with
      liability to pressure palsies and of Charcot-Marie-Tooth type 1A. French CMT
      Collaborative Research Group.
AB  - Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with
      liability to pressure palsies (HNPP) are autosomal dominant neuropathies,
      associated, respectively, with duplications and deletions of the same 1.5-Mb
      region on 17p11.2-p12. These two rearrangements are the reciprocal products of an
      unequal meiotic crossover between the two chromosome 17 homologues, caused by the
      misalignment of the CMT1A repeat sequences (CMT1A-REPs), the homologous sequences
      flanking the 1.5-Mb CMT1A/HNPP monomer unit. In order to map recombination
      breakpoints within the CMT1A-REPs, a 12.9-kb restriction map was constructed from
      cloned EcoRI fragments of the proximal and distal CMT1A-REPs. Only 3 of the 17
      tested restriction sites were present in the proximal CMT1A-REP but absent in the
      distal CMT1A-REP, indicating a high degree of homology between these sequences.
      The rearrangements were mapped in four regions of the CMT1A-REPs by analysis of
      76 CMT1A index cases and 38 HNPP patients, who where unrelated. A hot spot of
      crossover breakpoints, located in a 3.2-kb region, accounted for three-quarters
      of the rearrangements, detected after EcoRI/SacI digestion, by the presence of
      3.2-kb and 7.8-kb junction fragments in CMT1A and HNPP patients, respectively.
      These junction fragments, which can be detected on classical Southern blots,
      permit molecular diagnosis. Other rearrangements can also be detected by gene
      dosage on the same Southern blots.

PMID- 8651300
TI  - Molecular analysis of recombination in a family with Duchenne muscular dystrophy
      and a large pericentric X chromosome inversion.
AB  - It has been demonstrated in animal studies that, in animals heterozygous for
      pericentric chromosomal inversions, loop formation is greatly reduced during
      meiosis. This results in absence of recombination within the inverted segment,
      with recombination seen only outside the inversion. A recent study in yeast has
      shown that telomeres, rather than centromeres, lead in chromosome movement just
      prior to meiosis and may be involved in promoting recombination. We studied by
      cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in
      a three-generation family with a large pericentric X chromosome inversion,
      inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating
      with the inversion. On DNA analysis there was no evidence of meiotic
      recombination between the inverted and normal X chromosomes in the inverted
      segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No
      deletion or point mutation was found on analysis of the DMD gene. On the basis of
      the FISH results, we believe that the X inversion is the mutation responsible for
      DMD in this family. Our results indicate that (1) pericentric X chromosome
      inversions result in reduction of recombination between the normal and inverted X
      chromosomes; (2) meiotic X chromosome pairing in these individuals is likely
      initiated at the telomeres; and (3) in this family DMD is caused by the
      pericentric inversion.

PMID- 8651302
TI  - Progressive myoclonus epilepsy EPM1 locus maps to a 175-kb interval in distal
      21q.
AB  - The EPM1 locus responsible for progressive myoclonus epilepsy of Unverricht
      Lundborg type (MIM 254800) maps to a region in distal chromosome 21q where
      positional cloning has been hampered by the lack of physical and genetic mapping
      resolution. We here report the use of a recently constituted contig of cosmid,
      BAC, and P1 clones that allowed new polymorphic markers to be positioned. These
      were typed in 53 unrelated disease families from an isolated Finnish population
      in which a putative single ancestral EPM1 mutation has segregated for an
      estimated 100 generations. By thus exploiting historical recombinations in
      haplotype analysis, EPM1 could be assigned to the approximately 175-kb interval
      between the markers D21S2040 and D21S1259.

PMID- 8651301
TI  - Testing the feasibility of DNA typing for human identification by PCR and an
      oligonucleotide ligation assay.
AB  - The use of DNA typing in human genome analysis is increasing and finding
      widespread application in the area of forensic and paternity testing. In this
      report, we explore the feasibility of typing single nucleotide polymorphisms
      (SNPs) by using a semiautomated method for analyzing human DNA samples. In this
      approach, PCR is used to amplify segments of human DNA containing a common SNP.
      Allelic nucleotides in the amplified product are then typed by a colorimetric
      implementation of the oligonucleotide ligation assay (OLA). The results of the
      combined assay, PCR/OLA, are read directly by a spectrophotometer; the
      absorbances are compiled; and the genotypes are automatically determined. A panel
      of 20 markers has been developed for DNA typing and has been tested using a
      sample panel from the CEPH pedigrees (CEPH parents). The results of this typing,
      as well as the potential to apply this method to larger populations, are
      discussed.

PMID- 8651303
TI  - Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3.
AB  - Deafness is a heterogeneous trait affecting approximately 1/1,000 newborns.
      Genetic linkage studies have already implicated more than a dozen distinct loci
      causing deafness. We conducted a genome search for linkage in a large Palestinian
      family segregating an autosomal recessive form of nonsyndromic deafness. Our
      results indicate that in this family the defective gene, DFNB10, is located in a
      12-cM region near the telomere of chromosome 21. This genetic distance
      corresponds to <2.4 Mbp. Five marker loci typed from this region gave maximum LOD
      scores > or = to 3. Homozygosity of marker alleles was evident for only the most
      telomeric marker, D21S1259, suggesting that DFNB10 is closest to this locus. To
      our knowledge, this is the first evidence, at this location, for a gene that is
      involved in the development or maintenance of hearing. As candidate genes at
      these and other deafness loci are isolated and characterized, their roles in
      hearing will be revealed and may lead to development of mechanisms to prevent
      deafness.

PMID- 8651304
TI  - Deletion mapping of gliomas suggest the presence of two small regions for
      candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q.
AB  - The loss of genetic material on chromosome 10q is frequent in different tumors
      and particularly in malignant gliomas. We analyzed 90 of these tumors and found
      loss of heterozygosity (LOH) in >90% of the informative loci in glioblastoma
      multiforme (GBM). Initial studies restricted the common LOH region to 10q24-qter.
      Subsequently, the study of a pediatric GBM suggested D10S221 and D10S209,
      respectively, as centromeric and telomeric markers of a 4-cM LOH region. It is
      interesting to note that, in one subset of cells from this tumor, locus D10S209
      seems involved in the allelic imbalance of a larger region, with D10S214 as
      telomeric marker. This 17-cM region contains the D10S587-D10S216 interval of
      common deletion recently defined on another set of gliomas.

PMID- 8651305
TI  - Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE)
      gene, and study of their relationship to plasma ACE levels by two-QTL segregation
      linkage analysis.
AB  - Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically
      determined. A previous segregation-linkage analysis suggested the existence of a
      functional mutation located within or close to the ACE locus, in almost complete
      linkage desequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism
      and accounting for half the ACE variance. In order to identify the functional
      variant at the molecular level, we compared ACE gene sequences between four
      subjects selected for having contrasted ACE levels and I/D genotypes. We
      identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy
      nuclear families, in addition to the I/D polymorphism. These polymorphisms could
      be divided into two groups: five polymorphisms in the 5' region and three in the
      coding sequence and the 3' UTR. Within each group, polymorphisms were in nearly
      complete association, whereas polymorphisms from the two groups were in strong
      negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the
      5' group remained significantly associated with ACE levels, which suggests the
      existence of two quantitative trait loci (QTL) acting additively on ACE levels.
      Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two
      ACE markers were performed to test this hypothesis. The two QTLs and the two
      markers were assumed to be in complete LD. Results supported the existence of two
      ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents
      and offspring, respectively. One of these QTLs might be the I/D polymorphism
      itself or the newly characterized 4656(CT)2/3 polymorphism. The second QTL would
      have a frequency of approximately .20, which is incompatible with any of the yet
      identified polymorphisms. More extensive sequencing and extended analyses in
      larger samples and in other populations will be necessary to characterize
      definitely the functional variants.

PMID- 8651306
TI  - Affected-sib-pair analyses reveal support of prior evidence for a susceptibility
      locus for bipolar disorder, on 21q.
AB  - In 22 multiplex pedigrees screened for linkage to bipolar disorder, by use of 18
      markers on chromosome 21q, single-locus affected-sib-pair (ASP) analysis detected
      a high proportion (57%-62%) of alleles shared identical by descent (IBD), with P
      values of .049-.0008 on nine marker loci. Multilocus ASP analyses revealed locus
      trios in the distal region between D21S270 and D21S171, with excess allele
      sharing (nominal P values <.01) under two affection-status models, ASM I
      (bipolars and schizoaffectives) and ASM II (ASM I plus recurrent unipolars). In
      addition, under ASM I, the proximal interval spanned by D21S1436 and D21S65
      showed locus trios with excess allele sharing (nominal P values of .03-.0003).
      These findings support prior evidence that a susceptibility locus for bipolar
      disorder is on 21q.

PMID- 8651308
TI  - Beta-globin haplotype analysis suggests that a major source of Malagasy ancestry
      is derived from Bantu-speaking Negroids.
AB  - The origins of the inhabitants of Madagascar have not been fully resolved.
      Anthropological studies and preliminary genetic data point to two main sources of
      ancestry of the Malagasy, namely, Indonesian and African, with additional
      contributions from India and Arabia. The sickle-cell (beta s) mutation is found
      in populations of African and Indian origin. The frequency of the beta s-globin
      gene, derived from 1,425 Malagasy individuals, varies from 0 in some highland
      populations to .25 in some coastal populations. The beta s mutation is thought to
      have arisen at least five times, on the basis of the presence of five distinct
      beta s-associated haplotypes, each found in a separate geographic area. Twenty
      five of the 35 Malagasy beta s haplotypes were of the typical "Bantu" type, 1
      "Senegal" haplotype was found, and 2 rare or atypical haplotypes were observed;
      the remaining 7 haplotypes were consistent with the Bantu haplotype. The Bantu
      beta s mutation is thought to have been introduced into Madagascar by Bantu
      speaking immigrants (colonists or slaves) from central or east Africa. The
      Senegal beta s mutation may have been introduced to the island via Portuguese
      naval explorers. This study provides the first definitive biological evidence
      that a major component of Malagasy ancestry is derived from African populations,
      in particular, Bantu-speaking Negroids. beta A haplotypes are also consistent
      with the claim for a significant African contribution to Malagasy ancestry but
      are also suggestive of Asian/Oceanic and Caucasoid admixture within the Malagasy
      population.

PMID- 8651307
TI  - Toward localization of the Werner syndrome gene by linkage disequilibrium and
      ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1
      markers.
AB  - Werner syndrome (WS) is an autosomal recessive disorder characterized by
      premature onset of a number of age-related diseases. The gene for WS, WRN, has
      been mapped to the 8p 11.1-21.1 region with further localization through linkage
      disequilibrium mapping. Here we present the results of linkage disequilibrium and
      ancestral haplotype analyses of 35 markers to further refine the location of WRN.
      We identified an interval in this region in which 14 of 18 markers tested show
      significant evidence of linkage disequilibrium in at least one of the two
      populations tested. Analysis of extended and partial haplotypes covering 21 of
      the markers studied supports the existence of both obligate and probable
      ancestral recombinant events which localize WRN almost certainly to the interval
      between D8S2196 and D8S2186, and most likely to the narrower interval between
      D8S2168 and D8S2186. These haplotype analyses also suggest that there are
      multiple WRN mutations in each of the two populations under study. We also
      present a comparison of approaches to performing disequilibrium tests with
      multiallelic markers, and show that some commonly used approximations for such
      tests perform poorly in comparison to exact probability tests. Finally, we
      discuss some of the difficulties introduced by the high mutation rate at
      microsatellite markers which influence our ability to use ancestral haplotype
      analysis to localize disease genes.

PMID- 8651310
TI  - Descent graphs in pedigree analysis: applications to haplotyping, location
      scores, and marker-sharing statistics.
AB  - The introduction of stochastic methods in pedigree analysis has enabled
      geneticists to tackle computations intractable by standard deterministic methods.
      Until now these stochastic techniques have worked by running a Markov chain on
      the set of genetic descent states of a pedigree. Each descent state specifies the
      paths of gene flow in the pedigree and the founder alleles dropped down each
      path. The current paper follows up on a suggestion by Elizabeth Thompson that
      genetic descent graphs offer a more appropriate space for executing a Markov
      chain. A descent graph specifies the paths of gene flow but not the particular
      founder alleles traveling down the paths. This paper explores algorithms for
      implementing Thompson's suggestion for codominant markers in the context of
      automatic haplotyping, estimating location scores, and computing gene-clustering
      statistics for robust linkage analysis. Realistic numerical examples demonstrate
      the feasibility of the algorithms.

PMID- 8651309
TI  - The genetic relationship between the Finns and the Finnish Saami (Lapps):
      analysis of nuclear DNA and mtDNA.
AB  - The genetic relationships between two Finno-Ugric-speaking populations, the Finns
      and the Finnish Saami (Lapps), were studied by using PCR for six nuclear-DNA
      marker loci, mitochondrial restriction-site polymorphism, and sequence variation
      of a 360-bp segment of the mitochondrial control region. The allele frequencies
      of each of the nuclear-DNA marker loci and the frequencies of mtDNA restriction
      haplotypes were significantly different between the populations. The Saami showed
      exceptionally low variation in their mtDNA restriction sites. The 9-bp deletion
      common in East Asian populations was not observed, nor did the haplotype data fit
      into the haplogroup categorization of Torroni et al. The average number of
      nucleotide substitutions from the mtDNA haplotype data indicated that the Finnish
      Saami may be closer to the Finns than to the other reference populations, whereas
      nuclear DNA suggested that the Finns are more closely related to the European
      reference populations than to the Finnish Saami. The similarity of the Finns to
      the other Europeans was even more pronounced according to the sequence data. We
      were unable to distinguish between the Finns and either the Swiss or Sardinian
      reference populations, whereas the Finnish Saami clearly stood apart. The Finnish
      Saami are distinct from other Circumarctic populations, although two of the
      lineages found among the Saami showed closer relationship to the Circumarctic
      than to the European lineages. The sequence data indicated an exceptionally high
      divergence for the Saami mtDNA control lineages. The distribution of the pairwise
      nucleotide differences in the Saami suggested that this population has not
      experienced an expansion similar to what was indicated for the Finns and the
      reference populations.

PMID- 8651311
TI  - Conclusion of LOD-score analysis for family data generated under two-locus
      models.
AB  - The power to detect linkage by the LOD-score method is investigated here for
      diseases that depend on the effects of two genes. The classical strategy is,
      first, to detect a major-gene (MG) effect by segregation analysis and, second, to
      seek for linkage with genetic markers by the LOD-score method using the MG
      parameters. We already showed that segregation analysis can lead to evidence for
      a MG effect for many two-locus models, with the estimates of the MG parameters
      being very different from those of the two genes involved in the disease. We show
      here that use of these MG parameter estimates in the LOD-score analysis may lead
      to a failure to detect linkage for some two-locus models. For these models, use
      of the sib-pair method gives a non-negligible increase of power to detect
      linkage. The linkage-homogeneity test among subsamples differing for the familial
      disease distribution provides evidence of parameter misspecification, when the MG
      parameters are used. Moreover, for most of the models, use of the MG parameters
      in LOD-score analysis leads to a large bias in estimation of the recombination
      fraction and sometimes also to a rejection of linkage for the true recombination
      fraction. A final important point is that a strong evidence of an MG effect,
      obtained by segregation analysis, does not necessarily imply that linkage will be
      detected for at least one of the two genes, even with the true parameters and
      with a close informative marker.

PMID- 8651312
TI  - Parametric and nonparametric linkage analysis: a unified multipoint approach.
AB  - In complex disease studies, it is crucial to perform multipoint linkage analysis
      with many markers and to use robust nonparametric methods that take account of
      all pedigree information. Currently available methods fall short in both regards.
      In this paper, we describe how to extract complete multipoint inheritance
      information from general pedigrees of moderate size. This information is captured
      in the multipoint inheritance distribution, which provides a framework for a
      unified approach to both parametric and nonparametric methods of linkage
      analysis. Specifically, the approach includes the following: (1) Rapid exact
      computation of multipoint LOD scores involving dozens of highly polymorphic
      markers, even in the presence of loops and missing data. (2) Non-parametric
      linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show
      that NPL is robust to uncertainty about mode of inheritance, is much more
      powerful than commonly used nonparametric methods, and loses little power
      relative to parametric linkage analysis. NPL thus appears to be the method of
      choice for pedigree studies of complex traits. (3) Information-content mapping,
      which measures the fraction of the total inheritance information extracted by the
      available marker data and points out the regions in which typing additional
      markers is most useful. (4) Maximum-likelihood reconstruction of many-marker
      haplotypes, even in pedigrees with missing data. We have implemented NPL
      analysis, LOD-score computation, information-content mapping, and haplotype
      reconstruction in a new computer package, GENEHUNTER. The package allows
      efficient multipoint analysis of pedigree data to be performed rapidly in a
      single user-friendly environment.

PMID- 8651313
TI  - High male:female ratio of germ-line mutations: an alternative explanation for
      postulated gestational lethality in males in X-linked dominant disorders.
AB  - In this paper I suggest that a vastly higher rate of de novo mutations in males
      than in females would explain some, if not most, X-linked dominant disorders
      associated with a low incidence of affected males. It is the inclusion of the
      impact of a high ratio of male:female de novo germ-line mutations that makes this
      model new and unique. Specifically, it is concluded that, if an X-linked disorder
      results in a dominant phenotype with a significant reproductive disadvantage
      (genetic lethality), affected females will, in virtually all cases, arise from de
      novo germ-line mutations inherited from their fathers rather than from their
      mothers. Under this hypothesis, the absence of affected males is explained by the
      simple fact that sons do not inherit their X chromosome (normal or abnormal) from
      their fathers. Because females who are heterozygous for a dominant disorder will
      be clinically affected and will, in most cases, either be infertile or lack
      reproductive opportunities, the mutant gene will not be transmitted by them to
      the next generation (i.e., it will be a genetic lethal). This, not gestational
      lethality in males, may explain the absence of affected males in most, if not
      all, of the 13 known X-linked dominant diseases characterized by high ratios of
      affected female to male individuals. Evidence suggesting that this mechanism
      could explain the findings in the Rett syndrome is reviewed in detail.

PMID- 8651314
TI  - North and South Amerindians may have the same major founder Y chromosome
      haplotype.

PMID- 8651315
TI  - The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams
      syndrome deletion.

PMID- 8651316
TI  - Maple syrup urine disease: the E1beta gene of human branched-chain alpha-ketoacid
      dehydrogenase complex has 11 rather than 10 exons, and the 3' UTR in one of the
      two E1beta mRNAs arises from intronic sequences.

PMID- 8651317
TI  - Deletion mapping of 22q11 in CATCH22 syndrome: identification of a second
      critical region.

PMID- 8651318
TI  - Detection of linkage to affective disorders in the catalogued Amish pedigrees: a
      reply to Pauls et al.

PMID- 8651319
TI  - Barriers to forgoing nutrition and hydration in nursing homes.
AB  - In the two decades since the Karen Quinlan case first brought the issues that now
      go under the heading of the "right to die" to the attention of the courts and the
      public, a well-accepted legal consensus has developed about the law governing the
      forgoing of life-sustaining medical treatment. Law and clinical medical practice
      do not always run in tandem, however, and what law prescribes does not always
      occur in practice. One aspect of the legal consensus-that artificial nutrition
      and hydration is a medical treatment and thus may be withheld or withdrawn
      according to the same procedures and standards as other life-sustaining medical
      treatments-is probably less well accepted than the remainder. For reasons that I
      will explain, this is understandable. But what is puzzling is that this element
      of the consensus seems to be even less well accepted in nursing homes than in
      acute-care hospitals.

PMID- 8651320
TI  - Implications of negligent selection and retention of physicians in the age of
      ERISA.

PMID- 8651321
TI  - Home HIV testing and conflicts with state HIV testing regulations.

PMID- 8651323
TI  - Surfing the World Wide Web for AIDS information.

PMID- 8651322
TI  - Statutes aiding states' recovery of Medicaid costs from tobacco companies: a
      better strategy for redressing an identifiable harm?

PMID- 8651324
TI  - Med errors: caution with concentrations.

PMID- 8651325
TI  - More on metformin.

PMID- 8651326
TI  - More on metformin.

PMID- 8651327
TI  - Wrap for leg ulcers.

PMID- 8651328
TI  - Isolated despite negative sputum TB tests.

PMID- 8651329
TI  - Sounding the alarm.
AB  - Nurses need to continue broadcasting the dangers of shrinking RN-to- patient
      ratios. Here's some advice on how to do it convincingly.

PMID- 8651330
TI  - Planning for breakthrough cancer pain.

PMID- 8651332
TI  - Coordinating a successful discharge plan.
AB  - Whether you're working with a team or serving as liaison to a specially
      designated home care coordinator, your role is crucial in paving the way home for
      your patient. Here are the essential steps to take.

PMID- 8651331
TI  - Osteoporosis. It steals more than bone.
AB  - Research shows that osteoporotic fractures all too often cause an irreversible
      decline in the quality of life. To help these patients, here's what you need to
      know about primary and secondary prevention.

PMID- 8651333
TI  - Clinical snapshot: acute pancreatitis.

PMID- 8651334
TI  - Understanding intravascular ultrasound.
AB  - As research continues to demonstrate its value, this imaging process may soon
      replace coronary angiography in assessing atherosclerosis.

PMID- 8651335
TI  - 'My pain is God's will'.
AB  - Two colleagues, a clinical nurse specialist and a chaplain, explain how they've
      dealt with patients who feel obligated to suffer for religious reasons.

PMID- 8651336
TI  - 10 tips for success as a nurse manager.

PMID- 8651337
TI  - Emergency! Thoracic aortic dissection.
AB  - Back pain during labor is no surprise, which is why this very serious
      complication almost fooled this team.

PMID- 8651338
TI  - Enhancing support for the graduate nurse.
AB  - The authors describe how their new Clinical Entry Nurse Residency Program has
      helped beginning nurses advance along Benner's path toward expertise.

PMID- 8651339
TI  - Caught short-staffed.

PMID- 8651340
TI  - Alternatives to litigation: pros and cons.

PMID- 8651341
TI  - The scapegoating of managed care.

PMID- 8651342
TI  - Night interlude.

PMID- 8651343
TI  - Massive apoptosis detected by in situ DNA nick end labeling in neuroblastoma.
AB  - To seek evidence that tumor regression in neuroblastoma might result from massive
      apoptosis, we investigated tumor cell death in 39 neuroblastomas. Characteristic
      histologic features of apoptosis, condensed nuclear fragments and eosinophilic
      cytoplasm, were observed in all specimens. A ladder of DNA fragments induced by
      apoptosis was demonstrated by means of DNA agarose gel electrophoresis in 18 of
      the 19 tumors examined. In situ DNA nick end labeling (TUNEL) stained the nuclei
      with DNA fragmentation in 16 of 39 neuroblastomas. The TUNEL -positive cells were
      distributed in a scattered fashion in 10 tumors. In the remaining six tumors,
      they were densely located around nonviable areas of calcifications, where
      karyorrhectic or pyknotic cells were frequently observed. Five of six patients
      with such tumors were under 12 months of age, but there was no significant
      difference between the two groups in the patient age, origin of the primary
      lesion, or tumor stage. Biological features, including histology. DNA ploidy, and
      N-myc amplification, were not significantly different . Double fluorescent
      staining for bcl-2 oncoprotein and TUNEL showed that bcl-2 oncoprotein was
      expressed in the cytoplasm of tumor cells that were negative for TUNEL staining.
      This accumulated evidence suggests that massive apoptosis of tumor cells occurs
      in some neuroblastomas and may be related to tumor regression, whereas inhibition
      of apoptosis by bcl-2 oncoprotein expression might be associated with the
      tumorigenesis of neuroblastomas, as reported in our previous study.

PMID- 8651345
TI  - Cutaneous malignant melanotic neurocristic tumors arising in neurocristic
      hamartomas. A melanocytic tumor morphologically and biologically distinct from
      common melanoma.
AB  - Cutaneous neurocristic hamartomas (CNH) are pigmented lesions of neural crest
      origin that involve the skin and superficial soft tissue. They consist of a
      complex proliferation of nevomelanocytes, schwann cells, and pigmented dendritic
      and spindled cells. Malignancies can arise within the lesions, but few studies
      have dealt with this issue. We studied seven cases of CNH in which malignancy
      supervened. They included four congenital and three acquired lesions that
      involved the head and neck (five cases) or back (two cases) in patients aged from
      11 to 67 (mean, 32) years. Malignant tumors developed 15 to 67 (mean, 32) years
      after identification of the pigmented lesion in the congenital CNH and after 1 to
      6 (mean 3.5) years in the acquired CNH. The malignant tumors had a deep
      intradermal or subcutaneous origin and lacked a junctional component. Most were
      circumscribed, multinodular, melanin-containing tumors composed of bland, small,
      rounded to spindled cells, focally displaying a trabecular or nested growth
      pattern. Nuclear palisading and perivascular pseudorosettes were present in
      several tumors. In two examples, the neoplasm consisted predominantly of large
      pleomorphic epithelioid cells. Tumors contained immunoreactive S-100 protein (all
      of seven cases), a melanoma-associated antigen (HMB-45)( five of six cases,
      neuron-specific enolase (five of seven cases) and vimentin (six of six cases).
      The four patients with congenital lesions tended to have multiple recurrences and
      died of disease after 2 to 20 (mean, 9) years, three with metastases, one with
      direct invasion of the posterior fossa. The three patients with acquired lesions
      are alive after 1 to 5 years two with persistent disease. In contrast to common
      melanomas, these tumors have a propensity to recur as bulky nodules and to
      metastasize after many years or decades. Because these tumors exhibit melanocytic
      differentiation and arise in hamartomatous lesions composed of neural crest
      derivatives, we have designated them cutaneous malignant melanotic neurocristic
      tumors.

PMID- 8651344
TI  - Medullocytoma (lipidized medulloblastoma). A cerebellar neoplasm of adults with
      favorable prognosis.
AB  - This study describes three cases of neuroectodermal cerebellar neoplasms
      occurring in adults, characterized by a monomorphic population of round cells
      with scanty cytoplasm and focal areas of lipid accumulation. Astrocytic and
      neuronal differentiation was confirmed in these cells by glial fibrillary acidic
      protein and synaptophysin immunoreactivity. Electron microscopy performed in two
      cases showed neuritic processes, synapses, and dense-core granules. Patients
      included two men and one woman, and the age at diagnosis was 36, 37, and 57
      years, respectively. Two patients refused any postoperative treatment. One of
      these had two surgically removed recurrences after 10 and 11 years and died
      postoperatively from intracranial hemorrhage. The second had two recurrences
      after 10 and 15 years and is alive and in good health at the last follow-up. The
      third patient received postoperative radiotherapy and is alive and well after 2
      years. Review of the literature revealed seven cases of cerebellar neoplasms with
      histological features similar to those observed in our series. These lesions have
      been considered a variant of medulloblastomas. The age of patients ranged from 42
      to 77 years (mean age, 51 years); four were women, 3 men. Follow-up information
      available in two cases indicates a 5-year survival with surgery alone. These data
      indicate that these cerebellar neuroectodermal neoplasms have morphologically
      unique features and indolent biologic behavior that distinguish them from the
      highly aggressive medulloblastoma; the term medullocytoma for this form is
      suggested.

PMID- 8651346
TI  - Lipomatous hypertrophy of the atrial septum presenting as a right atrial mass.
AB  - Lipomatous hypertrophy of the atrial septum (LHAS) has been associated with
      cardiac arrhythmias and is defined as fatty infiltration > 2 cm thick in the
      atrial septum. The clinical and histologic features of surgically excised LHAS
      have not been previously studied. We studied 11 surgical resections of LHAS and
      compared them with 13 autopsy cases of LHAS and 24 control autopsy hearts. Of 11
      surgical patients, eight were women: patients' mean age was 63 years, and six
      were described as mildly to overtly obese. Symptoms included congestive heart
      failure, atrial fibrillation, supraventricular tachycardia, palpitations,
      syncope, and incidental mass found at surgery. Imagining studies typically
      revealed a right atrial mass with a mean size of 6 cm (range, 2.5-10 cm).
      Multivacuolated fat was more extensive in surgical (p = 0.005) and autopsy (p =
      0.009) cases of LHAS than in control hearts. Atypical, hypertrophied myocytes
      were presented in 72% of cases of LHAS compared with 8% of controls (p = 0.0003).
      In autopsy hearts, histologically abundant multivacuolated fat, heart weight, and
      body size were independently associated with increased atrial septal thickness.
      LHAS can be surgically excised, it has a distinctive histologic appearance marked
      by the presence of abundant multivacuolated fat and hypertrophied myocytes, and
      it is associated with increased body and cardiac mass.

PMID- 8651347
TI  - Poorly differentiated oxyphilic (Hurthle cell) carcinomas of the thyroid.
AB  - A series of 60 cases of oxyphilic (Hurthle cell) carcinomas (HCC) of the thyroid
      were reviewed to determine whether it is possible to correlate morphologic and
      clinical features as a means of assessing prognosis. Twenty cases showing
      predominant solid or trabecular patterns (as described in poorly differentiated
      carcinomas with a follicular pattern) were selected and the clinicopathological
      features were investigated. Based on cell size, two groups of solid or trabecular
      HCCs were identified: The first group (17 cases) was made up of typical large
      granular oxyphilic cells, and the second (three cases) had small oxyphilic cells.
      All tumors were reactive for thyroglobulin and for a mitochondrial antigen,
      selectively marking oxyphilic, mitochondrial-rich cells. Nuclear pleomorphism in
      individual cells was a common feature, but foci of anaplastic carcinoma were
      never found. Four cases overexpressed p53 protein and 10 expressed bcl-2 gene
      product. At follow-up, among the high-stage (pT3-pT4) tumors, seven patients had
      recurrences or metastases, six of whom were alive with disease or died of
      disease. In the control group of HCC with predominant follicular patterns, only
      one of 40 cases had a fatal outcome. The difference was statistically
      significant. Small-cell patterns and a p53 protein-positive/bcl-2 gene product
      negative phenotype were features of clinically aggressive HCC cases. We suggest
      that within the spectrum of oxyphilic (Hurthle cell) tumors, poorly
      differentiated HCC showing solid or trabecular patterns are a distinct group,
      based on both morphological and clinical features.

PMID- 8651348
TI  - Papillary carcinoma of the thyroid. Tall-cell variant with extensive lymphocyte
      infiltration.
AB  - Thirteen cases of tall-cell variant of papillary thyroid carcinoma (PTC) showing
      extensive lymphocyte and plasma cell infiltration within the fibrous stalks of
      the papillary architecture were compared with age-, sex-, and tumor size-matched
      cases of ordinary tall-cell variant without extensive lymphocyte infiltration and
      also with cases of PTC of the conventional type. All cases of the tall-cell
      variant of PTC with extensive lymphocyte infiltration exhibited the histologic
      features of chronic thyroiditis. Dissemination of tumor cells with the thyroid
      was significantly less frequent than in control cases, but there was no
      difference between the incidences of lymph node metastasis.
      Immunohistochemically, the lymphocytes infiltrating the carcinoma focus were
      mainly CD20+, CD45+, and CD45RO+ cells, that is, basically the same as those
      found in foci of chronic thyroiditis. No tumor recurrence was observed during the
      mean follow-up period of 3 years 8 months. The results of this study suggest that
      the tall-cell variant of PTC with extensive lymphocyte infiltration has less
      aggressive characteristics and a more favorable prognosis.

PMID- 8651349
TI  - Unclassified ovarian gonadal stromal tumors. A clinicopathologic study of 32
      cases.
AB  - Approximately 10% of gonadal stromal (sex cord-stromal) tumors of the ovary are
      difficult to classify. In most of these cases, the differential diagnosis is
      between granulosa and Sertoli-Leydig types. We studied 32 such neoplasms. The
      tumors were divided into two groups: Group 1 consisted of tumors with a
      predominance of a primitive spindle-cell stroma without specific differentiation,
      and group 2 consisted of tumors with a predominance of cords, trabecula, or
      tubules with features suggestive of or characteristics of both granulosa and
      Sertoli-Leydig cell differentiation in different areas. All tumors had overall
      features that did not permit definitive placement into granulosa or Sertoli
      Leydig categories. There were 18 group 1 tumors and 14 group 2 tumors. The mean
      patient age was 49 years. The International Federation of Gynecology and
      Obstetrics (FIGO) stage was known in 12 patients, all of whom were in stage I.
      Survival data were available for 17 patients, whose follow-up was a mean of 8
      years of until death. There were three deaths, one of which was of unrelated
      causes. the 5- and 10-year corrected actuarial survival rates were 92% and 74%.
      The number of patients was too small to make meaningful comparisons between the
      two groups. We concluded that the behavior of these unclassified tumors is
      similar to that of granulosa and Sertoli-Leydig tumors, with a favorable
      prognosis when confined to the ovaries.

PMID- 8651350
TI  - Primary epithelioid hemangioendothelioma of the brain.
AB  - Epithelioid hemangioendothelioma is an uncommon form of endothelial neoplasm, one
      of intermediate-grade malignancy and relatively favorable prognosis. Herein we
      report the third and fourth cases described in the central nervous system and
      compare their clinical and pathologic properties with those arising at systemic
      sites. Both patients presented with signs and symptoms of a mass lesion with
      seizures present in both cases. Imaging studies revealed well-demarcated mass
      lesions with surrounding edema. Gross total removal was accomplished surgically
      in both cases One case was partially cystic and nodular; the other was firm,
      focally gritty, and cartilaginous in appearance. Histologically they were
      identical to hemangioendotheliomas of other locales: multinodular neoplasms with
      regional variation in cellularity, cords and clusters of epithelioid cells with
      variable attempts at lumen formation, and spindled cells associated with a
      fibromyxoid matrix. Immunohistochemical stains confirmed the endothelial natures
      of the cells. These cases and those previously reported were treated with
      surgical excision. The few patients described have ranged in age from infants to
      older adults. Some patients have had residual neurologic defects, but no deaths
      due to tumor have been reported.

PMID- 8651351
TI  - Relationship of p53 gene alterations with tumor progression and recurrence in
      olfactory neuroblastoma.
AB  - Olfactory neuroblastoma (ONB) is a rare neuroectodermal tumor whose clinical
      course is not effectively predicted by initial stage or grade; p53 tumor
      suppressor gene alterations have not been determined concerning the ONB
      pathobiology and recurrence. We analyzed 18 formalin-fixed, paraffin-embedded ONB
      specimens (12 primary tumors and six recurrences or metastases) from 14 patients
      for p53 alterations using immunohistochemistry for p53 and WAF1 together with
      topographic genotyping (selection of minute tissue targets from unstained
      sections, PCR [polymerase chain reaction] amplification of exons 5-8 followed by
      direct DNA sequencing). Sequential material representing tumor recurrence or
      metastasis was available in four cases to compare genetic alterations over time
      in the same patient. None of the cases showed strong, diffuse p53 immunostaining.
      Focal weak to moderate intensity staining was evident in nine of 14 cases.
      Mutations in p53 were not detected in any of the cases, suggesting
      hyperexpression of p53 wild-type protein. Hyperexpression was further confirmed
      by correlation of WAF-1 and p53 immunopositivity. Importantly, in four cases with
      recurrence or metastasis, tumors manifested p53 wild-type hyperexpression. It
      appears that p53 point mutation does not play an important role in the initial
      development of ONB; however, p53 wild-type hyperexpression may occur in subsets
      of ONB likely to show local aggressive behavior and a tendency for recurrence.
      Wild-type p53 hyperexpression may be an important event in later stages of ONB
      growth and progression.

PMID- 8651352
TI  - Clear cell "sugar" tumor of the pancreas. A novel member of the family of lesions
      characterized by the presence of perivascular epithelioid cells.
AB  - We report at unique, previously unreported pancreatic tumor occurring in a 60
      year-old woman who was preoperative diagnosed on cytoaspiration as having clear
      cell carcinoma. The resected tumor consisted of a population of large epithelioid
      cells with clear or eosinophilic, granular cytoplasm, rich in glycogen, with
      nuclear pleomorphism and no mitotic activity. In spite of the epithelioid
      appearance, the tumor cells were negative for epithelial (CAM 5.2, KL1, AE1-AE3),
      endocrine (neuron-specific enolase [NSE], chromogranin A), and acinar (lipase,
      amylase) markers and positive for actin and melanogenesis-related marker HMB 45.
      Ultrastructurally, the neoplastic cells showed membrane-bound granules; no
      evidence of either epithelial or melanocytic differentiation was present. These
      morphophenotypic features have never been reported in a pancreatic tumor and
      overlap those of clear cell "sugar" tumor of the lung. The same morphophenotypic
      features are observed in a family of lesions characterized by the presence of the
      perivascular epithelioid cell that also includes lymphangiomyomatosis and
      angiomyolipoma. The present case may be considered a novel member of this family
      of lesions. We propose this new entity be named clear cell "sugar" tumor of the
      pancreas.

PMID- 8651353
TI  - Histologic progression of recurrent hepatitis C in liver transplant allografts.
AB  - The incidence and severity of recurrent hepatitis C virus (HCV) infection in
      liver transplant recipients vary widely, and the long-term sequelae of recurrent
      infection are not known. To better define the biology of recurrent HCV in liver
      transplant patients, we reviewed the histology of recurrent HCV in serial
      biopsies of 19 patients with pretransplant polymerase chain reaction (PCR)
      evidence of HCV infection. All posttransplant (post-TX) biopsies (n = 81) were
      reviewed, and RNA was extracted from at least one paraffin-embedded biopsy from
      each patient. RNA was analyzed for HCV by nested, reverse transcription-PCR (RT
      PCR) using primers for the 5' non-coding region of HCV as well as for albumin (as
      an internal control). All post-TX biopsies tested (12-1,677 days post-TX) were
      positive for HCV RNA by RT-PCR, while normal control biopsies were negative.
      Fifteen of 19 patients developed recurrent chronic hepatitis typical of HCV. Many
      of these patients showed a progression from early biopsies with acute lobular
      hepatitis to later biopsies with chronic hepatitis with portal lymphoid
      aggregates. An acute lobular hepatitis typified by sinusoidal lymphocytosis,
      acidophil bodies, and lobular disarray was seen an average of 135 days post-TX,
      with a range of 39-279 days. The time post-TX between this and earlier non
      hepatitis biopsies was significantly different (p < 0.0004, Student's t test).
      Chronic hepatitis with portal lymphoid aggregates was seen an average of 356 days
      post-TX, with a range of 89-1,365 days. The time post-TX was significantly longer
      than for acute lobular hepatitis (p < 0.03, Student's t test). Fifty-three
      percent of HCV TX patients progressed from acute lobular hepatitis to chronic
      hepatitis with lymphoid aggregates within 1 year of TX, and 79% showed these
      changes within 4 years. Six patients had progressive fibrosis; one die of liver
      failure and two became cirrhotic. Recurrent HCV appears to progress from an acute
      lobular hepatitis to chronic hepatitis with lymphoid aggregates in the majority
      of patients. Significant scarring occurred in 32% of patients and 16% developed
      end-stage liver disease from recurrent HCV. These later findings suggest that the
      long-term course of recurrent HCV in liver allografts may not be as indolent as
      first thought.

PMID- 8651354
TI  - Synchronous mucinous tumors of the appendix and the ovary associated with
      pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative
      analysis of c-Ki-ras mutations.
AB  - Mucinous tumors of the ovary are often associated with mucinous tumors of the
      appendix. It has not been clearly determined whether they are independent or
      metastatic neoplasms. A clinicopathologic study and a comparative analysis of c
      Ki-ras mutations were done in six cases of synchronous ovarian and appendiceal
      tumors. The clinicopathologic features (simultaneous presentation, bilaterality
      or right-sided predominance, similar histopathologic findings, presence of
      pseudomyxoma peritonei) suggested that they were primary appendiceal tumors
      metastatic to the ovaries. DNA was extracted from formalin-fixed, paraffin
      embedded tissue, and target sequences were amplified in vitro by the polymerase
      chain reaction. Mutations were detected by the presence of restriction fragment
      length polymorphism, artificially introduced by the use of mutant amplimers. The
      pattern of c-Ki-ras mutations was identical in the ovarian and appendiceal tumors
      of all patients. Four patients had a GGT --> GAT (Gly --> Asp) transition and one
      a GGT --> GTT (Gly --> Val) transversion, all detected in codon 12. No mutation
      was found in the sixth patient in either the ovarian or the appendiceal tumor.
      Because c-Ki-ras mutations are considered to represent an early event in
      tumorigenesis, our results support a clonal nature for both tumors and suggest
      that they are not independent tumors but rather originate one from another.

PMID- 8651355
TI  - Inflammatory pseudotumor of the liver. Evidence for follicular dendritic
      reticulum cell proliferation associated with clonal Epstein-Barr virus.
AB  - We describe an "inflammatory pseudotumor" of the liver that, which on detailed
      investigation, proved that the spindle-cell component of this lesion is derived
      from follicular dendritic reticulum cells (FDRC). This contention is supported by
      morphologic observations and by immunophenotype. The FDRC population contain
      Epstein-Barr virus (EBV). It is known that FDRC express the EBV receptor CD21. In
      this particular case, the FDRC contained clonal EBV genomes, EBV RNA (EBER)
      transcripts, and expressed EBV latent membrane protein (LMP1). DNA sequencing of
      PCR products showed three point mutations compared with the standard LMP1
      sequence of the EBV strain B95-8. The findings in this case corroborate those of
      other investigators concerning the possible role of EBV in the development of
      some inflammatory pseudotumors, including the recent production of functionally
      active EBV-transformed FDRC-like cell lines. This association could prove
      instructive in delineating the histogenesis of these tumors and further assist in
      making prognostic and therapeutic decisions.

PMID- 8651356
TI  - Primary cutaneous Hodgkin's disease with evolution to systemic disease.
      Association with the Epstein-Barr virus.
AB  - Hodgkin's disease rarely involves the skin and when it does is an indication of
      advanced stage disease. Primary cutaneous Hodgkin's disease is exceedingly rare,
      and only a few cases are reported. We describe a patient who developed multiple
      cutaneous lesions of Hodgkin's disease 2 years before manifesting nodal disease
      of mixed cellularity subtype. Reed-Sternberg cells in the skin as well as lymph
      nodes and bone marrow were positive for Epstein-Barr viral transcripts and
      expressed viral latent membrane protein. Epstein-Barr virus has not previously
      been demonstrated in primary cutaneous Hodgkin's disease, and its presence in
      lesions in all sites in this case supports a diagnosis of primary cutaneous
      disease with subsequent evolution into systemic disease.

PMID- 8651357
TI  - Pyothorax-associated lymphoma. An unusual case with biphenotypic character of T
      and B cells.
AB  - Pyothorax-associated lymphoma is known to develop in patients who received an
      artificial pneumothorax for pulmonary tuberculosis some 30 to 40 years
      previously. Such patients exhibit large, immunoblastic lymphoma cells and often
      have a B-cell phenotype. We present a patient with an artificial pneumothorax and
      such a late developing lymphoma but with the unique finding of aberrant T- and B
      cell phenotypes. Southern blot hybridization using immunoglobulin gene JH and T
      cell receptor beta chain receptors revealed germline configurations. Lymphomas
      developing in immunocompromised patients, such as those with acquired
      immunodeficiency syndrome, may show such unusual phenotypes. The unusual
      phenotypes found in this patient provide evidence that his pyothorax-associated
      lymphoma was related to an immunocompromised state.

PMID- 8651358
TI  - Bilateral primary ovarian squamous cell carcinoma associated with human papilloma
      virus infection and vulvar and cervical intraepithelial neoplasia. A case report
      with review of the literature.
AB  - Primary squamous cell carcinoma of the ovary is rare. Most cases represent
      malignant transformation of ovarian teratomas. Other cases are associated with
      preexisting Brenner tumor or ovarian endometriosis. We report a primary ovarian
      squamous cell carcinoma in a 40-year-old woman. The patient had recurrent high
      grade intraepithelial neoplasia of the vulva (VIN) and recurrent high-grade
      cervical intraepithelial neoplasia (CIN). Human papilloma virus (HPV) DNA 16/18
      was identified in an in situ and invasive carcinoma in the left ovary; CIN and
      VIN were identified with in situ hybridization with biotinylated DNA probes.
      Review of the literature revealed nine cases of primary ovarian squamous cell
      carcinoma not associated with a preexisting ovarian lesion. Three cases were not
      associated with CIN and occurred in women who ranged in age from 64 to 90 years
      and did not have carcinoma in situ component. Six cases were associated with CIN,
      had a carcinoma in situ, and occurred in younger women ranging from 33 to 54 of
      age. Our case belonged to the latter category. This report raises the possible
      causal relationship of HPV with primary ovarian squamous carcinoma in the group
      of middle-aged patients with CIN.

PMID- 8651359
TI  - The pathology of Omenn's syndrome.

PMID- 8651360
TI  - Peculiar electrolytic and hormonal abnormalities in acute renal failure due to
      leptospirosis.
AB  - Hypokalemia in leptospirosis acute renal failure (ARF) was studied in nine
      patients with severe leptospirosis ARF and five patients with moderate
      leptospirosis ARF and compared with five patients with severe acute tubular
      necrosis (ATN) and eight healthy individuals. Urinary volumes of both the severe
      and moderate leptospirosis groups were higher than those of the severe ATN group.
      Leptospirosis groups had serum potassium levels lower than those found in the
      healthy and severe ATN groups. Serum sodium levels were lower in the severe
      leptospirosis group than in the moderate leptospirosis, the severe ATN, and the
      healthy groups. There was a positive correlation between the fractional excretion
      of sodium and potassium in the severe leptospirosis group as well as between
      serum creatinine and potassium levels in the pooled leptospirosis groups. Urinary
      pH in the severe and moderate leptospirosis groups was lower than in the severe
      ATN group. Aldosterone levels were higher in the severe leptospirosis group than
      in the healthy individuals. Cortisol levels were higher in the leptospirosis
      groups than in the healthy subjects. These results strongly suggest that
      hypokalemia in leptospirosis ARF is due to renal potassium wasting potentialized
      by aldosterone and cortisol, requiring that special attention is given to
      potassium replacement as well as to volume repletion in the treatment of
      leptospirosis ARF.

PMID- 8651361
TI  - Dual host infections: enhanced infectivity of eastern equine encephalitis virus
      to Aedes mosquitoes mediated by Brugia microfilariae.
AB  - When mosquitoes feed on a vertebrate host that is infected concurrently with
      virus and microfilariae (mf), both pathogens are ingested. If mf penetrate the
      mosquito midgut, a small portion of the ingested virus may disseminate directly
      into the mosquito hemocoel. This phenomenon, termed microfilarial enhancement of
      arboviral transmission, has the potential to enhance the infectivity of
      arboviruses to mosquitoes. We investigated whether concurrent ingestion of Brugia
      mf and eastern equine encephalitis virus would enhance the infectivity and
      subsequent transmissibility of the virus by Aedes mosquitoes. Trials with Ae.
      triseriatus and B. pahangi mf indicated that microfilarial enhancement was dose
      dependent. Both a sufficient number of penetrating mf and a sufficient viremia
      were required for enhancement to occur. Furthermore, studies with B. malayi and
      three species of Aedes indicated that under comparable conditions of host viremia
      and microfilaremia, microfilarial enhancement occurred in some mosquito species
      (i.e., Ae. aegypti and Ae. taeniorhynchus) but not in others (Ae. triseriatus).
      We suggest that certain key parameters determine whether dual virus/mf host
      infections will enhance arboviral infectivity to mosquitoes. These include
      species differences in the capacity of mf to penetrate the mosquito midgut, the
      amount of virus passing into the hemocoel during mf penetration, and the innate
      susceptibility of mosquitoes to hemocoelomically introduced virus.

PMID- 8651362
TI  - Maternal Trypanosoma cruzi-specific antibodies and worsening of acute infection
      in mouse offspring.
AB  - The role of antibodies in the previously demonstrated harmful effect of
      Trypanosoma cruzi-infected mothers on progeny infection was studied by injecting
      either serum from chronically infected animals or purified T. cruzi-specific
      antibodies into uninfected mice during gestation and lactation periods. It was
      verified that injected antibodies were transferred to offspring. Pregnant or
      lactating animals exhibited lower circulating antibody levels than nonpregnant or
      pregnant but nonlactating mice, respectively, suggesting that such antibody
      transfer occurred in both fetuses and suckling offspring. When infected two
      months after birth, offspring of mice treated with chronic serum or purified
      antibodies displayed significantly higher parasitemia than offspring from mothers
      receiving control serum or immunoglobulins unrelated to T. cruzi. These results
      indicate that soluble factors contained in sera of infected mice, and
      particularly antibodies, when transferred from mothers to their young, are able
      to worsen T. cruzi acquired infection in the offspring.

PMID- 8651363
TI  - Rapid turnover of Plasmodium falciparum populations in asymptomatic individuals
      living in a high transmission area.
AB  - A polymerase chain reaction (PCR) typing technique, based on the amplification of
      polymorphic regions from the merozoite surface protein 1 (MSP-1) and MSP-2
      Plasmodium falciparum genes, was used to characterize parasites collected in a
      longitudinal study of asymptomatic carriers of malaria parasites living in two
      distinct epidemiologic situations. Blood samples were collected from children and
      adults living in the village of Dielmo, Senegal, when malaria transmission was 3
      6 infective bites/week/individual. For each individual, every sample collected at
      two-week intervals over a period of three months showed a specific PCR pattern.
      Changes involved both appearance and disappearance of specific alleles. Analysis
      of blood samples collected at a few-days interval showed that modifications of
      the PCR patterns occurred rapidly. Most alleles were detected over a period of 2
      3 weeks, but some alleles could be detected only for a few days. The frequent
      modifications of the PCR patterns indicate significant changes in allelic balance
      over time, and importantly, this was observed both in children and adults. These
      results strongly contrast with the stability of the parasite types harbored by
      asymptomatic individuals living in Pikine, Senegal during a period in which
      malaria transmission was interrupted, and therefore suggest that the rapid
      turnover observed in Dielmo may reflect the introduction of new parasite
      populations by mosquitoes.

PMID- 8651364
TI  - A simple computer-assisted method to identify schistosome cercariae.
AB  - Several methods have been suggested to identify schistosome cercariae. In the
      present work, a new method is proposed, based on the analysis of the distribution
      of sensory endings (sensillae) on the body of the cercariae, revealed by an
      impregnation with silver nitrate. We determined the mutual distances between the
      sensillae and calculated the mean values, standard deviations, coefficients of
      asymmetry, and of kurtosis of the distribution of these mutual distances. Applied
      to two species, Schistosoma mansoni from Brazil and S. intercalatum from
      Cameroon, these mutual distances had the same mean value and the same standard
      deviation but quite different coefficients of symmetry (0.34 +/- 0.11 versus 0.73
      +/- 0.08; P < 0.0001) and of kurtosis (-0.82 +/- 0.27 versus -0.58 +/- 0.31; P <
      0.0001). The latter two indices were therefore very effective for discriminating
      the two species. The present method can be applied to other species and to
      hybrids in the field.

PMID- 8651365
TI  - In vitro cultivation and development of Onchocerca volvulus and Onchocerca
      lienalis microfilariae.
AB  - Onchocerca volvulus and O. lienalis skin-derived microfilariae (mf) were cultured
      in vitro; parasite viability was assessed at intervals by measuring their ability
      to develop in Simulium ornatum. In the presence of monkey kidney feeder cells,
      both species retained full viability when cultured for up to 5 hr before
      intrathoracic injection into Simulium. In the absence of feeder cells and in
      contrast to O. lienalis, O. volvulus mf rapidly lost their viability. In further
      trials (including feeder cells), O. volvulus mf retained full viability for 14
      days, while O. lienalis mf retained full viability for a least 19 days but with a
      proportion able to develop to third-stage larvae (L3) after 70 days in culture.
      In experiments using this system to culture O. volvulus mf (ex utero) derived
      from adult female worms but with the addition of reduced glutathione and/or 20
      hydroxyecdysone, parasites were consistently more active over a 70-day period
      than those cultured without these additives. None of the mf cultured without
      additives were able to develop to L3 in Simulium when tested for up to 51 days in
      culture, while a proportion of mf incubated with reduced glutathione and/or 20
      hydroxyecdysone produced small but significant numbers of L3 after 28, 43, and 51
      days, representing the first time that uterine mf have been cultured to a form
      infective for the vector.

PMID- 8651366
TI  - Low-cost, low-maintenance rearing of maggots in hospitals, clinics, and schools.
AB  - With the recent resurgence in the interest and use of maggot therapy, blow fly
      rearing can be expected to increase. The rearing of these necrophagous flies is
      technically simple, but can be expensive, malodorous, and wasteful of space.
      Although there are numerous references to maggot rearing in the older literature,
      they do not adequately address these specific problems. Therefore, we describe
      several of the simple, low-cost, and unobtrusive strategies for rearing blow
      flies that have proven useful in our hospital-based insectary.

PMID- 8651367
TI  - Cryptic speciation in Lutzomyia (Nyssomyia) trapidoi (Fairchild & Hertig)
      (Diptera: Psychodidae) detected by multilocus enzyme electrophoresis.
AB  - Lutzomyia trapidoi is the major vector of cutaneous leishmaniasis in Ecuador. In
      the framework of an epidemiologic study, female Lu. trapidoi sand flies were
      captured on human bait in La Tablada and Paraiso Escondido. Some coloration
      heterogeneity among the specimens caught led us to look for the existence of
      cryptic species using multilocus enzyme electrophoresis. In 196 specimens
      studied, five of seven enzyme loci proved to be variable, making it possible to
      check for departures from panmixia both by Hardy-Weinberg statistics and linkage
      disequilibrium analysis. Two discrete groups were clearly distinguished, which
      could be differentiated by the diagnostic locus glycerophosphate dehydrogenase.
      The two groups occurred in sympatry within each locality. Genetic distances
      measured between these two groups were consistent with values usually found
      between distinct species. These results suggest the existence of a least two
      sibling species in Paraiso Escondido as well as La Tablada. The epidemiologic
      relevance of these results is discussed.

PMID- 8651368
TI  - Misidentification of a Philippine malaria vector revealed by allozyme and
      ribosomal DNA markers.
AB  - Morphologically identified Anopheles flavirostris (Diptera: Culicidae), the
      principal malaria vector in the Philippines, comprised two species in collections
      from the Bataan Province of Luzon based on allozyme and internal transcribed
      spacer 2 ribosomal DNA analysis. Seven percent of morphologically identified
      specimens were the closely related nonvector An. filipinae. Morphologic
      variability of An. filipinae may account for some of these misidentifications.
      Genetic identification tools promise to be useful not only for verifying the
      identification of morphologically defined taxa but also for detecting the
      presence of morphologically indistinguishable sibling species in the Philippines.

PMID- 8651370
TI  - Imported malaria in Montagnard refugees settling in North Carolina: implications
      for prevention and control.
AB  - In the winter of 1992, some 402 Southeast Asian refugees were resettled in North
      Carolina. They received very limited medical screening before immigration and
      many arrived in the United States with significant health problems, including
      several tropical infectious diseases. These refugees had lived for many years in
      remote areas along the Vietnam-Cambodia border, where there is intense
      transmission of malaria, including Plasmodium falciparum resistant to most
      antimalarial drugs available in the United States. Of 322 refugees screened after
      arrival in North Carolina, 187 (58%) were infected: 33% with P. falciparum, 23.5%
      with P. vivax, 23.5% with P. malariae, and 2.1% with P. ovale. Most infected
      persons were asymptomatic and infections with multiple species were common.
      Because of the documented high infection prevalence and the probable presence of
      many subpatent infections, all nonpregnant refugees were treated with
      halofantrine; those with P. vivax or P. ovale infections were given primaquine as
      well. This group accounted for the largest cluster of malaria cases reported in
      the United States in the last 50 years. Their rapid relocation, with minimal
      medical screening prior to arrival, resulted in a significant burden to the
      refugees and to the health-care system. Coordination between immigration
      agencies, the public health community, and medical workers in communities where
      the refugees are settled is critical for U.S.-based management of imported
      tropical diseases.

PMID- 8651369
TI  - Assessment of arthropod vectors of infectious diseases in areas of U.S. troop
      deployment in the Persian Gulf.
AB  - Beginning in August 1990, approximately 800,000 coalition troops were deployed to
      the Persian Gulf during Operations Desert Shield and Desert Storm. There was
      substantial concern about arthropod-borne diseases, particularly sand fly fever
      and cutaneous leishmaniasis, because of high morbidity rates in the Persian Gulf
      during World War II (WWII). In sharp contrast to WWII, there was no report of
      sand fly fever among coalition forces and only 31 cases of leishmaniasis among
      697,000 U.S. troops. To further evaluate the risk of arthropod-borne diseases, an
      entomologic survey was conducted in 12 areas of Kuwait and Saudi Arabia. A total
      of 1,556 arthropods was collected during four survey periods in 1992. The
      suspected vectors of cutaneous Leishmania major infection, sand fly fever, West
      Nile fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever were
      identified; however, there was no evidence of arboviruses or Leishmania among
      collected specimens nor from 51 trapped rodents. There are several possible
      reasons for the low risk of arthropod-borne infectious diseases among Desert
      Shield/Storm troops in an area where suspected vectors frequently were found: the
      use of insecticides and repellents, and the deployment of most ground troops to
      the open desert during the cooler, winter period--conditions least favorable for
      the transmission of arthropod-borne diseases.

PMID- 8651371
TI  - Thyroid function studies in normal pregnant Tanzanian women.
AB  - Iodine deficiency is well known as a cause of several disorders such as endemic
      goiter and cretinism, along with a wide spectrum of psychoneurologic development
      disorders including endemic mental deficiency, which are generally correlated
      with damage to the fetus. Since as much as 40% of the Tanzanian population is at
      risk for iodine deficiency disorders (IDD) because they live in iodine-deficient
      areas, and although the effects of iodine deficiency on human reproduction in
      Tanzania have not been objectively studied, it is estimated that there are
      approximately 600,000 cretins and cretinoids in the country as a result of IDD.
      As a baseline study for future research on iodine deficiency and its effects on
      human reproduction in Tanzania, we assayed serum thyroxine (T4), triiodothyronine
      (T3), thyrotropin (TSH), and free thyroxine (FT4) in 93 clinically euthyroid
      pregnant women and 34 nonpregnant women as controls. Pregnancy was accompanied by
      significantly increased levels of total T3 and T4, decreased FT4, and increased
      TSH concentration in serum. However, biochemical euthyroidism (assessed by FT4
      and basal TSH) was demonstrated in almost all (99%) of the pregnant subjects in
      conformity with most of the previous findings elsewhere. We conclude that
      pregnant Tanzanian women residing in areas without iodine deficiency experience
      changes in biochemical parameters of thyroid function similar to their
      counterparts in other places.

PMID- 8651372
TI  - Clinical studies of atovaquone, alone or in combination with other antimalarial
      drugs, for treatment of acute uncomplicated malaria in Thailand.
AB  - The therapy of Plasmodium falciparum malaria continues to be a problem in many
      parts of Southeast Asia because of multidrug resistance to nearly all existing
      antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad
      spectrum anti-protozoal activity. We recently evaluated the antimalarial activity
      of atovaquone in a series of dose-ranging studies in 317 patients with malaria at
      the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered
      alone. Using atovaquone alone resulted in satisfactory, initial clinical
      responses in all patients; the mean parasite and fever clearance times were 62
      and 53 hr, respectively. However, irrespective of the duration of therapy,
      overall cure rates were approximately 67%. In vitro sensitivity studies on
      parasites taken from patients prior to treatment and at the time of recrudescence
      showed a marked decrease in susceptibility to atovaquone in the recrudescent
      parasites. To improve cure rates, atovaquone was administered in combination with
      other drugs with antimalarial activity. Proguanil and tetracycline were chosen
      due to laboratory evidence of potentiation; doxycycline was selected because it
      has a longer half-life than tetracycline. Although pyrimethamine did not show
      laboratory evidence of potentiation with atovaquone, it was chosen as an
      alternative inhibitor of dihydrofolic acid reductase with a longer half-life than
      proguanil. The clinical studies with these drug combinations confirmed the
      laboratory results with marked improvement in cure rates for proguanil,
      tetracycline, and doxycycline; pyrimethamine showed only minimal improvement.
      Proguanil was subsequently selected as the preferred drug partner because of its
      long record of safety and the ability to use the drug in pregnant women and
      children. Of the 104 patients with falciparum malaria treated with atovaquone
      plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side
      effects. The combination of atovaquone and proguanil also was effective in
      eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most
      patients.

PMID- 8651373
TI  - In vitro antimalarial activity of vegetal extracts used in West African
      traditional medicine.
AB  - Among strategies for the development of new antimalarials, a study of plants
      traditionally used in Africa against malaria has been pursued. Extracts obtained
      from the plants Azadirachta indica, Cinnamonum camphora, Lippia multiflora,
      Vernonia colorata, Guiera senegalensis, Combretum micranthum, and Ximenia
      americana, commonly used in Cote d'Ivoire by native healers for the treatment of
      malaria, were tested on two strains of Plasmodium falciparum: FcB1-Colombia
      (chloroquine-resistant) and F32-Tanzania (chloroquine-sensitive). Extracts were
      obtained after infusion and decoction, both techniques being used by most native
      healers. The antimalarial activities of the extracts were tested first by
      parasite 3H-hypoxanthine incorporation and second by visual evaluation of the
      activities of plant extracts on thin blood smears, which also permitted the
      determination of parasitic stages and parasite alteration. Among the seven plants
      tested, some had an apparent inhibitory effect on P. falciparum growth in vitro,
      while other seemed to be less efficient.

PMID- 8651374
TI  - Antigen-specific immunosuppression in paracoccidioidomycosis.
AB  - To characterize the immune dysfunction associated with paracoccidioidomycosis, we
      studied the in vitro lymphocyte reactivity to phytohemagglutinin (PHA), pokeweed
      mitogen (PWM), a Candida albicans antigen (CMA), and a Paracoccidioides
      brasiliensis antigen (PbAg) in 32 patients with the acute and the chronic form of
      the disease before or during the initial phase of treatment and after clinical
      cure. We also studied, as controls, 30 healthy individuals, 15 of them immune to
      P. brasiliensis. Results showed a strong hyporesponsiveness to the PbAg while
      responses to mitogens and CMA were comparable with those of controls. Patients
      with the acute form of the disease (usually more severe) had more marked PbAg
      hyporesponsiveness than those with the chronic form. After patients' clinical
      cure, PbAg proliferative responses were similar to controls and greater than
      those seen before pretreatment. Changes in other parameters were also seen in the
      treated patients; skin test anergy to paracoccidioidin, high levels of anti-P.
      brasiliensis antibodies, leukocytosis, and eosinophilia. These changes were
      usually more intense in patients with the acute form of the disease. The post
      treatment CD4+, CD8+, and total lymphocyte counts were similar to those of
      controls. Correlation between these parameters and the lymphoproliferative
      responses to the various stimuli was only found with PbAg: PbAg responses
      correlated inversely with eosinophil and anti P. brasiliensis antibody levels.
      Overall, our results demonstrate an antigen-specific-cellular immunity defect,
      which is reversible with treatment and possibly related to a T helper cell-2
      pattern of immune response during active disease.

PMID- 8651376
TI  - Mycetomas in Mali: causative agents and geographic distribution.
AB  - Although Mali is situated in the African zone endemic for mycetomas, no report
      has been published on the characteristics of the disease in this country. We
      report a series of 54 cases observed in Bamako. The causative agents were
      Madurella mycetomatis in 20 patients, Leptosphaeria sp. in one patients,
      Actinomadura madurae in 12 patients, A. pelletieri in 15 patients, and
      Streptomyces somaliensis in three patients. In this series, the observed
      geographic distribution of the causative agents was in agreement with data on the
      causative agents and their geographic distribution in neighboring countries, and
      with those suggesting a relationship between the type of infectious agent and the
      annual rainfall.

PMID- 8651375
TI  - Polymerase chain reaction-based technique for the detection of Wuchereria
      bancrofti in human blood samples, hydrocele fluid, and mosquito vectors.
AB  - Oligonucleotide primers were designed to amplify a 490-basepair DNA fragment in
      the 5' end of the pWb 12 repeated DNA sequence in Wuchereria bancrofti for
      specific amplification of W. bancrofti DNA by the polymerase chain reaction
      (PCR). A single microfilaria in 100 microliter of blood or added to 1 ml of
      blood, a single third-stage larva in a pool of 20 uninfected mosquitoes, or 0.4
      pg of W. bancrofti genomic DNA added to 100 microliter of human blood or serum
      can be detected by this PCR method. The parasite DNA in human blood and hydrocele
      samples and in mosquitoes was isolated free of any PCR inhibitors using simple
      purification techniques. Detection of PCR products was carried out by agarose gel
      electrophoresis, followed by staining with ethidium bromide and visualization
      under ultraviolet illumination. The results indicate that the PCR method is
      species-specific, rapid, and more sensitive than that of DNA probes and routine
      microscopy.

PMID- 8651378
TI  - Reservoir competence of four chaparral-dwelling rodents for Borrelia burgdorferi
      in California.
AB  - Aspects of the reservoir competence of four rodents for the Lyme disease
      spirochete, Borrelia burgdorferi, were evaluated in California. Rodents were live
      trapped and ear-punch biopsies were cultured during each season. A second set of
      biopsies was cultured from representative individuals after 2-3 weeks of
      captivity and the results of culturing biopsies taken on both dates were compared
      with the results of feeding Ixodes pacificus larvae on hosts xenodiagnostically.
      The prevalence of infections did not differ significantly between dusky-footed
      woodrats (Neotoma fuscipes) and California kangaroo rats (Dipodomys californicus)
      nor among seasons. Combined results of the three tests showed that 85.7% of dusky
      footed woodrats (n = 21) and 78.6% of California kangaroo rats (n = 14) were
      infected with B. burgdorferi. In contrast, only 22.2% of brush mice (Peromyscus
      boylii) (n = 14) and 7.1% of pinyon mice (P. truei) (n = 9) were infected. The
      sensitivity of culturing ear-punch biopsies as an assay for borrelial infection
      was significantly greater when biopsies were taken after a short period of
      captivity (0.89) rather than on the day of capture (0.52). Tick xenodiagnosis, in
      which I. pacificus was used as the vector, revealed borrelial infections in 90.3%
      of infected rodents. Spirochetes were observed in 37.7% of 239, 45.2% of 155,
      60.0% of 10, and 7.1% of 14 cultures of nymphal I. pacificus fed as larvae on
      naturally infected woodrats, kangaroo rats, brush mice, and a pinyon mouse,
      respectively. The mean prevalence of infection in xenodiagnostic ticks varied
      significantly among host species with a greater proportion of ticks infected
      while feeding on woodrats and kangaroo rats than on mice. This study reconfirms
      previous reports that implicated woodrats and kangaroo rats as reservoirs of B.
      burgdorferi in California.

PMID- 8651379
TI  - Reservoir competence of the southeastern five-lined skink (Eumeces inexpectatus)
      and the green anole (Anolis carolinensis) for Borrelia burgdorferi.
AB  - The reservoir competence of two lizard species, the southeastern five-lined skink
      (Eumeces inexpectatus) and the green anole (Anolis carolinesis), for Borrelia
      burgdorferi was evaluated. Skinks and anoles were exposed by needle inoculation
      or tick bite to B. burgdorferi. Xenodiagnosis with larval Ixodes scapularis and
      culture of tissues were used to asses infection and the ability of infected
      lizards to infect attached ticks. Both lizard species were susceptible to B.
      burgdorferi by both routes of exposure. Xenodiagnostic ticks acquired spirochetes
      while feeding on both species. One tick that dropped from a skink on the ninth
      day after exposure was infected. The remainder of xenodiagnostic ticks that
      acquired spirochetes fed three weeks after exposure of the lizards to the
      spirochete. Lizards remained infectious to attached ticks for at least five
      weeks. Overall, more than 20% of xenodiagnostic larvae fed on southeastern five
      lined skinks acquired spirochetes. Individual skinks infected up to 34% of
      attached ticks. A smaller proportion of ticks feeding on green anoles became
      infected. Borrelia burgdorferi recovered from infected lizards retained their
      infectivity for mammalian hosts. The ability of the lizards to sustain a Borrelia
      infection and infect attached ticks suggests that they may play a role in the
      maintenance of spirochete transmission.

PMID- 8651377
TI  - The Nakalanga syndrome in Kabarole District, Western Uganda.
AB  - An acquired condition resulting in arrested growth was reported in the 1950s and
      1960s from along the Nile near Jinja in eastern Uganda. This became known as
      Nakalanga dwarfism, and an association with onchocerciasis was postulated. After
      control of onchocerciasis through larvaciding in this area some 30 years ago, no
      new cases have been noted. We now report this condition from western Uganda where
      its appearance seems to be a relatively recent event. Thirty-one persons with
      short stature, 15 years of age and older, were identified through household
      surveys in an area of Kabarole district with a high prevalence of onchocerciasis.
      Cases identified were matched with controls selected for age and sex from the
      nearest household. Cases of Nakalanga syndrome weighed significantly less and
      were shorter than controls. The Z scores for weight-for-age, weight-for-height,
      height-for-age, and body mass index were significantly less among cases. Other
      clinical features observed among cases included absence of secondary sexual
      characteristics, skeletal deformities, dental caries, and mental retardation. All
      cases and 22 (79%) controls had microfilariae of Onchocerca volvulus in skin
      snips. All community members interviewed were aware of the Nakalanga syndrome,
      and 93% believed it to be acquired sometime after birth. The possible association
      with onchocerciasis is discussed.

PMID- 8651380
TI  - A focus of endemic malaria in central Java.
AB  - This report describes one of the few remaining foci of endemic malaria on the
      island of Java, the Kokap subdistrict, near the Southcentral coast. Kokap was
      hypoendemic in June 1994 with prevalence of parasitemia at 0.98% (n = 10,606 of
      40,246 residents). Plasmodium vivax comprised 63% of infections and P. falciparum
      all others. The incidence of indigenous infection during 1993 was 48 cases/1,000
      person-years (p-yr), and it was relatively uniform among age groups (38 to
      53/1,000 p-yr). Nine deaths due to malaria had been recorded in the past three
      years (8.3 deaths per 100,000 p-yr); the case fatality rate was 0.17%.
      Subdistricts adjoining Kokap to the north, east, and south reported incidence
      rates of < 2 cases/1,000 p-yr. To the west, Purworejo District had a high case
      incidence (11 cases/1,000 p-yr) but other districts to the west did not (< 1.2
      cases/1,000 p-yr). The highest case incidence village area within Kokap (169
      cases/1,000 p-yr) bordered the district of Purworejo to the west. Endemic malaria
      in Kokap and Purworejo coincided with where steep hills and narrow valleys
      dominated the terrain.

PMID- 8651381
TI  - St. John and first aid for the weak leg.

PMID- 8651382
TI  - Resection of malignant primary liver tumors.
AB  - BACKGROUND: Malignant primary liver tumors are an uncommon and challenging
      surgical problem. In spite of multimodality therapies, surgical resection remains
      the mainstay of treatment and the most likely chance for cure. We reviewed the 13
      year resection experience of a single surgeon at our institution to evaluate the
      results. METHODS: A retrospective review from July 1982 to June 1995 was
      performed for patients presenting with a diagnosis of primary liver cancer. Those
      undergoing resection of their primary liver tumors form the basis of this report.
      RESULTS: One hundred eighty-four patients with a diagnosis of primary liver
      cancer were seen at our institution. Of these, 43 patients underwent 46
      resections of their cancers by a single surgeon. There were 22 females (51%) and
      21 males (49%). The average age was 61 years with a median age of 63 years
      (range, 19-85 years). Tumors resected included 27 hepatomas, 16 cholangiocellular
      carcinomas, 1 carcinoid tumor, 1 low grade mucinous cystadenocarcinoma, and 1
      cystadenocarcinoma. Resections were as follows: 9 right trisegmentectomies, 8
      right lobectomies, 1 left trisegmentectomy, 4 left lobectomies, 7 left lateral
      segmentectomies, and 17 partial lobectomies. Major complications occurred in 11
      patients (26%). There were 3 deaths, for a 30-day perioperative death rate of 7%.
      Of the 43 patients, 13 had follow-up of less than 12 months and 30 had follow-up
      for more than 1 year. The mean survival of the 30 patients who had their tumors
      resected and were followed up for more than 1 year was 27.2 months and the median
      survival was 21 months. The median survival of patients not undergoing resection
      was less than 6 months. The 1-, 2-, 3-, and 5-year survival rates were 57%, 52%,
      40%, and 33%, respectively. CONCLUSIONS: Primary liver cancer can be treated by
      resection with acceptable results. This remains the standard treatment of any
      liver cancer. Survival rates of patients after resection are much better than
      survival rates of patients who do not undergo surgery.

PMID- 8651383
TI  - Pelvic revascularization by direct hypogastric artery reconstruction.
AB  - BACKGROUND: While pelvic arterial insufficiency, either acute or chronic, results
      in stereotypic clinical findings which may readily be reversed by indirect
      techniques of revascularization, few reports document the indications for,
      techniques of, and results following direct pelvic revascularization by
      reconstruction of the hypogastric artery. METHODS: Retrospective review of 8
      patients with symptomatic pelvic arterial insufficiency undergoing direct
      hypogastric artery reconstruction during the period from 1984 to 1995. RESULTS:
      Eight patients underwent unilateral hypogastric artery reconstruction by bypass
      graft (3 patients) or endarterectomy and patch angioplasty (5 patients). One
      patient had immediate symptomatic relief of his symptoms, but was lost to follow
      up after 1 month. One patient manifested no symptomatic improvement despite a
      technically successful operation. The remaining 6 patients experienced
      significant symptomatic relief that has persisted during follow-up from 3 months
      to 11 years postoperatively. Among 4 men in whom erectile impotence comprised one
      of the indications for intervention, 3 reported sustained restoration of sexual
      function. CONCLUSION: In properly selected patients, direct pelvic
      revascularization by hypogastric artery reconstruction may predictably and
      durably relieve symptoms of pelvic arterial insufficiency.

PMID- 8651384
TI  - Effect of subcutaneous carbon dioxide insufflation on arterial pCO2.
AB  - PURPOSE: Subcutaneous emphysema following laparoscopy could result in
      postoperative respiratory acidosis from prolonged CO2 absorption. We studied the
      magnitude and duration of alterations in PaCO2 coincident with direct CO2
      insufflation into the subcutaneous fat of the anterior abdominal wall of 5
      anesthetized juvenile pigs. METHODS: First, each pig was insufflated with 6 L of
      CO2 to produce moderate emphysema over the trunk. Following return to baseline
      PaCO2, each pig was re-insufflated with 12 L of CO2 to produce severe emphysema
      over lower limbs, neck, head, and trunk. Measurements of arterial blood gases
      were performed every 5 or 10 min. Minute ventilation was held constant to
      represent the worst case scenario. RESULTS: From baseline PaCO2 of 41.8 +/- 2.3
      mm Hg, PaCO2 peaked at 68.3 +/- 8.6 (P < 0.02) and 92.9 +/- 10.7 (P < 0.01) mm Hg
      for the 6- and 12-L volumes, respectively, 20 to 25 minutes following
      insufflation. From baseline arterial pH of 7.40 +/- 0.02, respective nadirs of pH
      were 7.21 +/- 0.06 (P < 0.02) and 7.08 +/- 0.05 (P < 0.01). PaCO2 and arterial pH
      took approximately 100 minutes to return to baseline after insufflation with both
      6 and 12 L volumes. CONCLUSIONS: When minute ventilation is fixed, subcutaneous
      CO2 insufflation causes increased PaCO2 and decreased pH that may persist for a
      prolonged period of time. Therefore, patients with subcutaneous emphysema after
      laparoscopy should be observed in postanesthetic recovery until PaCO2 and pH
      approach baseline.

PMID- 8651385
TI  - Carbon dioxide pneumothorax in laparoscopic surgery.
AB  - BACKGROUND: We conducted this animal study to investigate the cardiopulmonary
      effects of carbon dioxide pneumothorax during laparoscopic surgery and determine
      what intervention, if any, is necessary for this phenomenon. METHODS: A swine
      animal model was used (n = 8). Animals were anesthetized and underwent peritoneal
      insufflation with carbon dioxide. A laceration was created in the left diaphragm.
      pO2, pCO2, oxygen saturation, peak inspiratory pressure (PIP), systolic blood
      pressure, and heart rate were measured and subjected to statistical analysis.
      RESULTS: Significant changes were noted in the pO2, O2 saturation, pCO2, and PIP
      upon creation of the pneumothorax. Trends were also noted in the heart rate and
      the systolic blood pressure. The physiologic changes could be corrected by
      noninvasive means and without terminating the procedure. CONCLUSIONS: Carbon
      dioxide pneumothorax produces reproducible cardiopulmonary changes in
      laparoscopic surgery. These changes are easily monitored and the resulting
      cardiopulmonary changes can be treated without invasive means.

PMID- 8651386
TI  - Community medical response to the Fairchild mass casualty event.
AB  - BACKGROUND: On June 20, 1994, a discharged serviceman with a psychiatric history
      opened fire with a MAC-90 assault rifle at Fairchild Air Force Base in Spokane,
      Washington. The attack killed 5 people and wounded 22. This report reviews the
      communication, triage, transport, injuries, and the community medical response to
      this mass casualty. METHODS: Data for the review were obtained from city-wide
      debriefing sessions, medical records, and evaluation forms from prehospital
      agencies. RESULTS: A total of 19 patients were triaged to four community
      hospitals, while 3 victims with comparatively minor injuries stayed at the Base
      hospital. All fatalities except a child in utero died at the scene. All victims
      surviving to hospital were discharged recovered from their injuries. Two patients
      were undertriaged, 1 of whom sustained a pelvic and buttock wound. CONCLUSIONS:
      Rapid triage was possible due to: (1) initial treatment by military medical
      personnel; (2) an established and practiced disaster plan; (3) the use of
      disaster packs and triage tags; (4) the immediate initiation of triage and
      transport; and (5) coordinated ground and air transport.

PMID- 8651387
TI  - The role of stereotactic biopsy in assessment of nonpalpable breast lesions.
AB  - BACKGROUND: When mammography identifies a lesion suspicious for cancer,
      stereotactic needle core biopsy (SCNB) and needle localization (NL) surgical
      biopsy are options for obtaining tissue. This study compared the results of these
      two biopsy methods in evaluating nonpalpable radiologically suspicious breast
      lesions. METHODS: Records of 292 women who underwent SCNB or surgical biopsy at
      two institutions were reviewed over 28 months. The women were separated into two
      groups, under 50 years of age and 50 years of age and older. RESULTS: A total of
      70 women over the age of 50 had stereotactic biopsy. One hundred and three had NL
      biopsies. The rate of positivity was 37% and 33% for stereotactic and NL biopsy
      respectively (P = 0.693). A total of 44 women under the age of 50 had
      stereotactic biopsy. Seventy had NL biopsies. The rate of positivity was 7% and
      21%, respectively, for stereotactic and NL (P = 0.082). NL surgical biopsy costs
      on average $2354.00. SCNB averages $949 including follow-up mammogram.
      CONCLUSION: SCNB is a cost-effective, accurate method of breast biopsy. This
      report retrospectively compares SCNB with surgical open biopsy aided by NL. The
      cost savings occurred primarily in surgeon's fees and anesthesia fees. We found
      no statistical difference in < 50- or > 50-year-old patients in the frequency of
      the diagnosis of breast cancer when comparing the two types of biopsies.

PMID- 8651388
TI  - Stereotactic breast biopsy is accurate, minimally invasive, and cost effective.
AB  - BACKGROUND: We reviewed our experience with stereotactic core needle breast
      biopsy (SCNBB) for accuracy, complication rate, and staging profile of
      malignancies diagnosed. METHODS: Since March 1993, 530 stereotactic biopsies were
      performed. Of these, 25 cases underwent stereotactic core needle biopsy with
      subsequent wire-guided biopsy. RESULTS: In 25 patients with stereotactic and open
      biopsy, there was an accuracy for SCNBB of 96%. The number of biopsies rose from
      100 to 250 biopsies annually, with an equivalent pre-test positive predictive
      value for mammography (17% to 19% historical versus 20% with SCNBB). The total
      number of de novo cancer diagnoses have increased from a mean of 57 to a mean of
      71 annually. The percentage of tumors in situ, stage I or stage II, has increased
      from 60% to 69%. CONCLUSIONS: Stereotactic core needle biopsy combines a high
      accuracy with a low complication rate. Its aggressive application for tissue
      diagnosis in suspicious nonpalpable mammographic lesions has increased the
      proportion of early (in situ and T1 or T2) tumors discovered, and increased the
      total number of breast cancers diagnosed.

PMID- 8651389
TI  - Laparoscopic Collis gastroplasty is the treatment of choice for the shortened
      esophagus.
AB  - BACKGROUND: The shortened esophagus has long been recognized as a potential
      complicating factor for reflux surgery or the repair of paraesophageal hernias.
      We discuss the incidence of shortened esophagus encountered in a prospective
      series of laparoscopic hiatal hernia repairs and present our current operative
      strategies for dealing with this problem, including a new technique for
      preforming a cut Collis gastroplasty for severe cases. METHODS: A prospectively
      gathered database on laparoscopic fundoplications (n = 213) and giant
      paraesophageal hernia repairs (n = 25) revealed 34 (14%) patients who had
      shortened esophagus as defined by the gastroesophageal (GE) junction being > 5 cm
      above the hiatus. Presentation preoperative diagnosis, operative times,
      techniques, and outcomes were evaluated. RESULTS: Three categories of dissection
      were determined from review of the operative data of these 34 patients. Category
      I (a normal esophagus easily brought into the abdominal cavity with minimal
      dissection) occurred in 30% of patients. Category II occurred in 50% of patients
      and was defined as shortened esophagus requiring extensive mediastinal dissection
      to allow the GE junction to be brought 2 cm below the diaphragm. Category III
      patients (20%) were unable, in spite of extensive dissection, to have their GE
      junction sufficiently reduced to permit fundoplication. Four of these patients
      had a simple cural closure and gastropexy. Three patients underwent an endoscopic
      Collis gastroplasty to lengthen the esophagus and allow a tension-free
      fundoplication. Patients who had a type I or type III dissection with Collis
      gastroplasty did uniformly well. Patients having type II dissections or no
      fundoplication had a higher rate of postoperative hernia recurrences and reflux
      disease. CONCLUSION: Approximately 14% of patients presenting for surgical
      treatment of gastroesophageal reflux disease or paraesophageal hernias
      demonstrate a shortened esophagus. While 30% of these patients are easily treated
      laparoscopically, 20% to 70% may benefit from an esophageal lengthening
      procedure. Proper utilization of the Collis gastroplasty should minimize the
      incidence of postoperative dysphagia, postoperative acid reflux, and hiatal
      hernia recurrence.

PMID- 8651390
TI  - Laparoscopic antireflux surgery.
AB  - BACKGROUND: The purpose of this paper is to review the experience of a community
      surgeon performing laparoscopic antireflux procedures (LAP). The experience has
      been difficult and at times unsettling, and underscores the need for advanced
      laparoscopic expertise not normally obtained performing laparoscopic
      cholecystectomies. METHODS: Sixty-one consecutive patients underwent attempted
      LAP. The preoperative evaluation is reviewed, and the length of operative times,
      conversion rates, complications, and patient satisfaction is discussed. RESULTS:
      Four patients were converted to an open procedure, and two more patients required
      later reoperation for dysphagia. While the operative times are shorter now, the
      technical difficulty in performing the procedure does not seem to be
      appreciatively decreasing. No deaths or esophageal perforations occurred;
      however, there were a large number of patients with varying degrees of troubling
      dysphagia that did not require reoperation but frequently required endoscopic
      gastroduodenoscopy (EGD) dilatation. No recurrence of reflux has been documented
      in the short 2-year follow-up period. CONCLUSIONS: LAP is still the most
      difficult procedure that I perform, and the learning curve is at least 60 cases.
      Patient satisfaction is quite good as only three have mild "heartburn." Dysphagia
      is a significant problem that has led to takedown of several short gastric
      vessels to obtain looser fundoplications around larger and larger bougies.
      Appropriate patient preoperative selection is paramount and the antireflux
      procedure should be tailored to the individual patient. Major complications have
      been reported elsewhere, but have not been seen in this review.

PMID- 8651391
TI  - Systematic use of gastric fundoplication in laparoscopic repair of paraesophageal
      hernias.
AB  - BACKGROUND: Early surgical treatment has been recommended in patients with
      paraesophageal hiatal hernias. Recently, the laparoscopic approach has emerged as
      an ideal way to perform the operation. But whether or not an antireflux procedure
      should be done remains controversial. PATIENTS AND METHODS: Four patients with
      type II and eleven with type III hiatal hernias were treated. Twelve of them
      manifested symptoms of reflux preoperatively. The operative technique consisted
      of resection of the sac, closure of the crura and gastric fundoplication,
      anchored to the diaphragm. RESULTS: All but two patients were completed
      laparoscopically. Mean operative time was 320 (+/-49 SD) minutes, and mean
      hospital stay was 3 (+/-1.2 SD) days. Early postoperative complications were
      subcutaneous emphysema (two patients) and atrial fibrillation (one patient). At
      one year all patients were asymptomatic without dysphagia, reflux, or recurrence
      of the hernia. CONCLUSION: The addition of fundoplication to paraesophageal
      hernia repair restores competency of the sphincter in patients with reflux
      associated to the hernia and prevents postoperative gastroesophageal reflux that
      results from the extensive dissection required. In addition, it provides an ideal
      means of fixing the stomach in the subdiaphragmatic position, decreasing the long
      term-risk of recurrence.

PMID- 8651392
TI  - Medium aperture meso-caval shunts reliably prevent recurrent variceal
      hemorrhages.
AB  - BACKGROUND: Objectives of partial medium aperture mesocaval shunts (MCS) include
      reduction of portal hypertension to prevent recurrent variceal hemorrhage,
      preservation of portal flow through liver while maintaining an intact porta
      hepatis to facilitate a future liver transplant (OLTx). PATIENTS AND METHODS:
      Fifteen patients were retrospectively analyzed to review the indications for the
      procedure, its short- and long-term complications as well as patency and
      functional status of the shunt. They were followed for a period of 21 months.
      RESULTS: The perioperative and long-term mortality rate was 0%. Rebleeding rate
      perioperatively and in follow-up was 0%. Early shunt nonfunction was 13% and post
      shunt encephalopathy (PSE) was 20%. The encephalopathy was grade I to II and
      controlled medically. Abdominal ultrasound and Doppler confirmed 13 patent shunts
      (2 patients did not agree to ultrasound) with preserved hepatopetal flow in 10.
      CONCLUSIONS: Medium aperture MCS utilizing ringed polytetrafluoroethylene (PTFE)
      grafts safely and reliably prevent recurrent variceal hemorrhage. Encephalopathy
      is infrequent and mild. This technique preserves the portal venous anatomy making
      a future OLTx technically easier.

PMID- 8651393
TI  - Do preoperative indicators predict the presence of common bile duct stones during
      laparoscopic cholecystectomy?
AB  - BACKGROUND: Criteria have been suggested to help decide if an intraoperative
      cholangiogram (IOC) should be performed during laparoscopic cholecystectomy (LC).
      They are a clinical history of passing a common bile duct (CBD) stone, elevated
      serum amylase, elevated liver function tests, or ultrasound findings suggesting a
      CBD stone. What is the sensitivity and specificity of the above criteria when the
      presence or absence of CBD stones is already known by IOC? What is the
      probability that these criteria will predict a CBD stone or be normal if a stone
      is absent, ie, the positive predictive value (PPV) and negative predictive value
      (NPV)? METHODS: We reviewed 420 cases of elective LC done between May 1990 and
      December 1992. In our teaching hospital, IOC is routine and acted as the
      reference standard for the presence of CBD stones. All 420 films were reviewed as
      well as the results of any preoperative endoscopic retrograde
      cholangiopancreatography (ERCP) (30 were done). The following preoperative
      indicators of CBD stones were recorded: any clinical history of CBD stones; an
      elevated amylase, SGOT, alkaline phosphatase, or bilirubin level; and ultrasound
      findings. The sensitivity, specificity, PPV, and NPV were calculated. RESULTS:
      CBD stones were found in 12% of these elective LC cases. The sensitivity,
      specificity, PPV, and NPV, respectively, for each preoperative indicator were: a
      history suggestive of CBD stones (36%, 94%, 45%, and 91%), serum biochemistries
      as a group (43%, 86%, 30% and 91%), and ultrasound findings of CBD stones (22%,
      92%, 28% and 89%). We compared any elevation versus > 2x from the normal range of
      the serum indicators and did not improve their accuracy. Combination of the
      indicators increased sensitivity and NPV but lowered specificity and PPV. The
      best predictor of CBD stones was the history (45%) and this was in a hospital
      with a CBD stone prevalence rate of 12%. CONCLUSION: There are no predictive
      tests that can sufficiently increase an observer's probability estimate of the
      presence or absence of CBD stones to allow for "selective" IOC decisions.

PMID- 8651394
TI  - The role of intra-operative duplex imaging in arterial reconstructions.
AB  - BACKGROUND: This study is a cost-benefit analysis of a less invasive method of
      intra-operative duplex imaging compared with the use of intra-operative angiogram
      (including C-arm fluoroscopy) in arterial reconstruction. METHODS: From September
      1994 to May 1995, 93 intra-operative duplex imaging studies were performed.
      Duplex scanning results were recorded for carotid endarterectomy (35), iliac
      balloon angioplasty and stent placement (12), and infra-inguinal bypass (46).
      Average cost and time were calculated for each type of study. RESULTS: Thirty
      four carotid endarterectomy patients (97%) had normal duplex findings. Three (9%)
      underwent intra-operative angiogram due to abnormal duplex findings and post
      operative neurological deficit. In iliac balloon angioplasty and stent placement
      cases (12), both intra-operative duplex and C-arm post-stent angiography yielded
      comparable results in both normal (11) and abnormal (1) studies. In infra
      inguinal bypass cases (46), 2 had abnormal duplex findings of the native vessels.
      Average time and cost required to perform intra-operative duplex studies is
      significantly less than that required for intra-operative angiogram or C-arm
      studies. CONCLUSION: Compared with traditional intra-operative angiography, the
      use of intra-operative duplex imaging is less expensive, less invasive, quicker,
      and equally accurate when used as an adjunct to access surgical results of
      arterial reconstructions.

PMID- 8651395
TI  - "Just in time" decision making for ICU care after carotid endarterectomy.
AB  - BACKGROUND: Many patients undergoing carotid endarterectomy (CE) do not require
      active intensive care unit (ICU) care (AIC). Until recently, all patients spent
      24 hours postoperatively in an ICU, but many of these patients were simply
      monitored and did not need unique ICU services. METHODS: To aid in developing a
      selective policy for ICU admission following CE, we reviewed preoperative risk
      factors, recovery room course, and total hospital stay of 126 patients for 2
      years when postoperative ICU admission was routine. Preoperative assessment
      included presence or absence of cardiac disease, hypertension, severe respiratory
      disease, diabetes, arrhythmia, renal failure, and a Goldman cardiac risk score.
      The operative, recovery room, and ward records were reviewed for conditions
      requiring AIC. Requirement for AIC was defined as need for infusion of
      vasoactive, bronchodilator, or antiarrhythmic medication beyond the recovery room
      period. In addition, treatment for coronary ischemia or MI, need for active
      diuresis, perioperative neurological event, or requirement for mechanical
      ventilation were indications for AIC. RESULTS: There were 132 CEs in 126
      patients; 37% required AIC as defined above. When patients who required AIC were
      compared with patients not requiring AIC, the only significant difference was the
      number of risk factors per patient. Goldman cardiac risk class I patients were at
      less risk for cardiac morbidity than the combined Class II and III patients.
      CONCLUSIONS: In an individual patient, preoperative risk assessment does not aid
      in predicting the need for AIC following CE. Selection of patients for ICU
      admission following CE can be accurately determined by a short period of recovery
      room observation.

PMID- 8651396
TI  - Aorto-iliac reconstruction without arteriography.
AB  - BACKGROUND: Duplex imaging has been shown to be as accurate as arteriography in
      detecting hemodynamically significant aorto-iliac stenosis or occlusions.
      METHODS: Review of the duplex scan and arteriogram reports for all primary aorto
      iliac reconstructions performed during an 18-month period was undertaken.
      Deviations from the preoperatively planned procedure were determined. The role of
      the duplex scan on procedure selection was assessed. RESULTS: Of the 54 patients
      identified, 13 had both duplex scan and arteriography (group I), 30 had only
      arteriography (group II), and 11 had only duplex scans (group III). Ten group I,
      15 group II, and 9 group III patients had an occluded aorta or iliac artery. Two
      patients (3 anastomosis) required placement of the distal anastomosis on the
      common femoral rather than the external iliac artery as planned preoperatively.
      Both had been arteriogrammed. No group III patient required deviation from the
      preoperative plan. CONCLUSION: Aorto-iliac reconstruction can be performed
      without arteriography when a totally occluded aorta or iliac artery is identified
      by duplex scanning.

PMID- 8651397
TI  - A prospective cost analysis of pancreatoduodenectomy.
AB  - BACKGROUND: In our cost-conscious health care system hospitals are finding that
      costs are as important as charges or reimbursements, especially as hospitals
      compete for managed care contracts. We have prospectively gathered cost data for
      more than 60 common operations performed at our institution over the last 3
      years. METHODS: Over a 25-month period, from January 1993 to February 1995, 30
      pancreaticoduodenectomy procedures were performed for which cost data were
      available. Cases were divided according to diagnosis (neoplastic or benign) and
      were evaluated for complications which prolonged length of stay (LOS). Costs were
      analyzed by an item-by-item prospective micro-cost analysis technique. Items were
      grouped into two areas: operating room (OR) costs and hospital (ward) costs. OR
      costs included disposable equipment, nondisposable equipment, OR room, OR staff,
      postanesthesia care, and anesthesia costs. Ward costs included hospital room,
      pharmacy, and radiology costs. RESULTS: OR costs for the 30 PD patients were
      similar and represented approximately 21% of total hospital costs. Of the 30
      patients, complications resulting in a prolonged LOS occurred in 10 (33%): intra
      abdominal abscess in 3 (2 with pancreatic leaks), superficial marginal ulceration
      in 2, delayed return of gastrointestinal function in 2 (1 with pulmonary edema)
      and 1 each of bile leak, urosepsis, and chylous ascites. No cost differences were
      observed when comparing neoplasm versus chronic pancreatitis for all parameters.
      When comparing patients who had complications versus those who did not, however,
      there was a statistically significant cost difference for both hospital ward or
      total costs. Regardless of whether a PD was performed for neoplastic or benign
      disease, postoperative complications increased hospital ward costs by 76% due to
      increased LOS. CONCLUSIONS: This cost analysis study is an example of the
      methodology that would allow surgeons to investigate any common surgical
      procedure by first identifying areas of increased costs. This quantitative
      knowledge focuses the clinician on areas to improve quality which will then lower
      costs.

PMID- 8651398
TI  - Patient selection and treatment modalities for chronic anal fissure.
AB  - BACKGROUND: Incontinence of feces or flatus is a serious complication of lateral
      internal sphincterotomy with a incidence of 0-35%. Multiple cofactors may
      predispose to fecal incontinence. METHODS: Review of 27 reported series of
      internal sphincterotomy and analysis of 34 consecutive cases of fecal
      incontinence seen by the author were carried out. Reports of the effect of
      topical nitroglycerin or botulinum toxin on the anal sphincter are discussed and
      supplemented by the author's experience. RESULTS: Reported postoperative
      incidence of incontinence to feces or flatus is remarkably variable (0-35%).
      Multiple factors (eg, multiparity, age, constipation, and previous surgery) were
      identified in each of the author's cases of incontinence. Pharmacologic
      sphincterotomy reliably relieves sphincter spasm and may promote healing.
      CONCLUSIONS: Reappraisal of current standard treatment of anal fissure is
      warranted. Many preexisting, possibly predisposing, factors should be considered
      when deciding on treatment. Pharmacological sphincterotomy requires further
      clinical study. New nonsurgical modalities should be included in the treatment
      algorithm.

PMID- 8651399
TI  - The role of whole organ pancreas transplantation in the treatment of type I
      diabetes.
AB  - BACKGROUND AND DEMOGRAPHICS: Clinical course was reviewed for 19 whole organ
      pancreas transplant recipients at UCLA between 11/14/93 and 5/31/95, 18 of which
      were simultaneous pancreas kidney transplants and 1 of which was an isolated
      pancreas after kidney transplant. The initial 4 pancreatic grafts were procured
      by classical warm dissection techniques while the remaining 15 were procured by
      rapid en bloc technique. Mean recipient age, duration of diabetes, and daily
      insulin requirements were 38 years, 25 years, and 45 units, respectively. Bladder
      drainage of exocrine secretions was used primarily in 18 cases and primary
      enteric drainage in one. RESULTS: All recipients manifested immediate dialysis
      and insulin independence. Actuarial patient and graft survival were 100% and 89%,
      respectively, at a mean follow-up of 396 days (range, 150-660 days). Mean maximal
      serum amylase on the first postoperative day was 366 U/dL. There were no
      instances of pancreatic graft vascular thrombosis. Three patients experienced
      pancreatic leaks (16%), 1 of which resulted in graft loss. Six month
      posttransplant Hgb A1c was within normal range and significantly lower than
      pretransplantation values (5.1 vs 10.7, P = 0.002). Mean length of initial
      hospitalization was 15 days, with 100% of patients requiring at least one read
      mission. Fifty-eight percent of patients experienced rejection episodes. Ninety
      one percent of patients responding to a quality of life survey reported
      improvement in general sense of well-being after transplantation. CONCLUSIONS: It
      is concluded that high rates of success may be possible with whole organ pancreas
      transplantation, even in new programs. Rapid en bloc dissection is a safe,
      expeditious method of pancreas procurement. Successful pancreatic transplantation
      is associated with freedom from exogenous insulin administration, normalization
      of glycated hemoglobin, and subjective improvement in quality of life. However,
      this modality is associated with higher rates of rejection and readmission, and
      longer duration of hospitalization when compared with isolated kidney
      transplantation.

PMID- 8651400
TI  - Synchronous non-small cell lung cancers.
AB  - INTRODUCTION: The few series of synchronous lung cancers have included small cell
      and carcinoid tumors. We wished to determine the prognosis for patients with
      synchronous non-small cell lung cancer (NSCLC). METHODS: A database of 3034 lung
      cancer patients was reviewed for synchronous NSCLC. Survival was determined by
      Kaplan-Meier method and compared by log-rank analysis. RESULTS: There were 27
      patients (0.8%). Fourteen were completely resected (CR) and had a 5-year survival
      rate of 45% The 5-year survival rate for patients whose highest stage tumor was
      stage I or II was 38%, versus 0% for patients whose highest tumor stage of III (P
      = 0.01). The 5-year survival rate for patients with two stage I tumors was 41%
      versus 0% for patients with 2 stage III tumors (P = 0.03). The 5-year survival
      rate for patients treated with wedge resections was similar to that for patients
      treated with lobectomies or pneumonectomy (L/P). CONCLUSIONS: We conclude that
      the prognosis for patients with synchronous NSCLC may not be dismal if both
      tumors are resectable and stage I or II. Wedge resections are an alternative for
      those who cannot tolerate L/P.

PMID- 8651401
TI  - The meaning of equivocal pancreatic cytology in patients thought to have
      pancreatic cancer.
AB  - INTRODUCTION: Fine needle aspirations (FNAs) and endoscopic retrograde
      cholangiopancreatography (ERCP)-guided brushings (BRUSH) are useful tools in the
      differentiation between malignant and benign disease of the pancreas. Once the
      decision to obtain a cytologic confirmation of one's clinical suspicion is made,
      the interpretation of the findings, especially an equivocal or negative cytology
      finding, can be unclear. This study seeks to evaluate the utility of cytologic
      studies in the evaluation of a patient with suspected pancreatic malignancy.
      METHODS: A retrospective review of 224 cytologic reports, including 174 FNAs and
      50 BRUSHs, from all pancreatic FNAs and BRUSHs performed between January 1989 and
      June 1995, was performed. Subsequent confirmation of the cytologic diagnosis was
      made either by histologic or strict clinical criteria. RESULTS: Forty-three
      percent of the cytologic reports were read as malignant, all others reported as
      suspicious, atypical, or negative. All cytology studies read as malignant and all
      FNAs reported as suspicious were histologically or clinically confirmed to be
      malignant. Of those reported as atypical or negative, 55% and 49% were confirmed
      to be malignant. Both FNA and BRUSH were 100% specific, 75% sensitive, and 80%
      accurate. CONCLUSIONS: We conclude that a cytological diagnosis of malignant or
      suspicious is reliable and useful for further therapy planning in the patient
      suspected to have a pancreatic malignancy. The reason for the cytologic tests was
      a strong clinical suspicion, therefore, a high incidence of cancer was found in
      the patients with atypical or negative readings. A diagnosis of atypical or
      negative is equivocal and requires further diagnostic maneuvers, frequently
      including surgery, to make the definitive diagnosis.

PMID- 8651402
TI  - Ventilatory management of pulmonary contusion patients.
AB  - BACKGROUND: The goal of this study was to evaluate two modes of mechanical
      ventilation in patients with pulmonary contusion: pressure-controlled ventilation
      (PCV) and volume-controlled ventilation (VCV). METHODS: One hundred and thirty
      five patients with pulmonary contusion, defined as an infiltrate on admission
      chest x-ray and hypoxemia, were treated over 45 months; 59 patients who required
      more than 48 hours of mechanical ventilation were initially managed with VCV.
      RESULTS: Twenty patients were converted from VCV to PCV when pulmonary function
      deteriorated. With PCV, peak inspiratory pressure decreased from 49 +/- 1 to 31
      +/- 1 cm H2O, the alveolar-arterial oxygen difference decreased from 491 +/- 36
      mm Hg to 300 +/- 36 mm Hg. These findings were significantly different (P < 0.05,
      by Student's paired t-test). Twenty patients managed with PCV had equivalent
      duration of mechanical ventilation and days in intensive care units to 39
      patients with less pulmonary dysfunction managed with VCV. None of the 10
      patients who died expired from pulmonary failure. CONCLUSIONS: PCV is an
      alternative mode to VCV in patients with poorly compliant lungs after pulmonary
      contusion.

PMID- 8651403
TI  - A clinical outcome and cost analysis of laparoscopic versus open appendectomy.
AB  - BACKGROUND: Benefits of laparoscopic appendectomy are controversial, and the
      results of recent clinical studies have contradictory conclusions. We performed a
      cost analysis comparing laparoscopic and open appendectomies to assess potential
      efficacy of the laparoscopic approach. METHODS: All patients operated on for
      suspected acute appendicitis at the University of Washington Medical Center
      (UWMC) from January 1, 1991 through January 1, 1995 were analyzed. Potential
      benefits of the laparoscopic approach were examined in five major categories:
      hospital length of stay, total hospital charges, operative time, operating room
      charges, and postoperative complications. Patients were stratified according to
      the presence or absence of perforation for outcome analysis. RESULTS: There were
      163 appendectomies performed in 82 men and 81 women. Twenty-seven (17%) patients
      had laparoscopic evaluation, of which 21 underwent attempted laparoscopic
      appendectomy. Among nonperforated patients, laparoscopic appendectomy did not
      reduce hospital stay compared with open appendectomy, but did lead to greater
      hospital charges ($7760 vs $5064; P < 0.001). Operating times were longer in the
      laparoscopic group (104 vs 74 minutes; P < 0.001) compared with open
      appendectomies. Operating room charges for laparoscopic appendectomies exceeded
      charges for the open approach ($4740 vs $1870; P < 0.001). Complication rates
      were similar (laparoscopic, 19% vs open, 16%; NS). The false diagnostic rate for
      women was four times greater than for men among patients undergoing open
      appendectomy (31% vs 8%; P < 0.01). Patients with perforation undergoing a
      midline incision had a longer hospital stay (9.5 vs 5.9; P < 0.02) than patients
      operated on through a right lower quadrant incision. CONCLUSIONS: In our
      analysis, laparoscopic appendectomy, while safe, was more expensive and was not
      associated with better clinical outcome compared with open appendectomy patients.

PMID- 8651404
TI  - A four-year experience with laparoscopy in the management of appendicitis.
AB  - BACKGROUND: The study was conducted to determine the influences of laparoscopy in
      the management and outcome of patients with appendicitis. METHODS: A
      retrospective analysis of 154 consecutive patients who were treated for suspected
      appendicitis. The pre-operative diagnosis included appendicitis, right lower
      quadrant pain of unknown etiology, and generalized peritonitis. RESULTS:
      Laparoscopy was used in 108 patients, including 70 laparoscopic appendectomies
      (LA) and 31 LAs converted to open appendectomy (OA). Forty-six patients had OA.
      The average operating time for LA was 74.3 minutes and 48.8 minutes with OA.
      Postoperative complications for LA (7%) included 1 trochar wound hemorrhage, 2
      wound infections, and 2 intra-abdominal sepsis; and for OA (9%) were 1 post
      operative intra-abdominal hemorrhage, 4 wound infections, 1 wound dehiscence, and
      1 intra-abdominal sepsis. Post-operative stay for LA averaged 2.5 days and for OA
      averaged 4.5 days (P = .0049). LA patients had a considerably faster return to
      work and/or normal activity than OA patients (P = .00065). CONCLUSIONS:
      Laparoscopy influenced the management of 29% of patients presenting with
      suspected appendicitis. LA resulted in shorter hospitalization and a more rapid
      return to work and/or normal activity than OA.

PMID- 8651405
TI  - Survival in carcinoma of the cervical esophagus.

PMID- 8651406
TI  - Laparoscopic repair of anterior abdominal wall herniation using composite mesh.

PMID- 8651407
TI  - Anamolous biliary anatomy.

PMID- 8651408
TI  - Short versus long tubes.

PMID- 8651410
TI  - [Shoulder dystocia--complications].
AB  - The author considers the causes for advent of shoulder dystocia and the
      complications from it for the mother and the foetus, making due conclusions. For
      the 6 years period (1985-1990) in the Clinic of Obstetrics & Gynaecology--St.
      Zagora, are occurred 18,466 deliveries commonly, at 45 of them it is founded
      shoulder dystocia. From the received results is clear, that, with the growth of
      the baby's weight increase the percentage of the shoulder dystocia and this
      difference become appreciable at weight of newborn babies over 4000-4500 g.

PMID- 8651409
TI  - [Risk factors for premature rupture of the amniotic sac and neonatal sepsis].
AB  - The aim of the study is to assess risk factors, who act directly or indirectly
      and mechanisms for PROM and neonatal sepsis. There has been examined 74 pregnant
      women and their newborn 38 infants was with proved neonatal sepsis. There has
      been established combination from factors for PROM (mechanical--88.4%, infectious
      -77.8%, and other factors--63.4%).

PMID- 8651411
TI  - [Ultrasonic screening of pregnant teenagers].
AB  - Ultrasonography was applied to investigate 218 pregnant girls aged 11 to 16 for a
      period of 6 years, 70 of whom were examined in the first trimester and 148--in
      the second and third trimester. The girls presented the following disturbances:
      bleeding, expected premature birth, complications of pregnancy such as
      preeclampsia-eclampsia, suspected pelvio-fetal disproportions. Standard biometry
      was applied using automatic recording of body weigh by the formula of Campel.
      Missed abortion was diagnosed in 10 patients in the first trimester and 12 were
      found with blighted ovum. Ultrasound screening and cardiotocography are the most
      reliable to examine the status of the fetus.

PMID- 8651412
TI  - [The evaluation of energy balance in pregnancy].
AB  - Energy balance assessment of 317 pregnant women in Sofia was conducted. Energy
      intake and energy expenditure during the first and the third trimester,
      gestational weight gain and prepregnancy body mass index have been studied. The
      regression analysis revealed a significant correlation between neonate body mass
      and energy expenditure level, but the decreased metabolic constants of physical
      activity, suggested an influence of increased basal metabolic rate, corresponding
      to the gestational body mass gain.

PMID- 8651413
TI  - [The possibilities for stimulating lactation].
AB  - The lactopoesis with Cerucal and by laser acupuncture is stimulated, concerning
      fifty-four women with an early milk insufficiency. An increase of the quantity of
      the secreted mother's milk and an increase of the serum level of prolactin have
      been ascertained. Both methods for stimulating the milk secretion have been
      recommended. The plan of medical treatment by Cerukal is suitable in an early
      milk insufficiency of hypoprolactinemic origin. Laser acupuncture is applied
      successfully in milk insufficiency owning to stagnant and inflammatory changes in
      the lacteal gland.

PMID- 8651414
TI  - [The role of chromosome anomalies in the origin of reproductive failures].
AB  - The results from chromosomal analysis of 185 couples, studied on the occasion of
      reproductive failures (RF), such as sterility, spontaneous abortions, stillbirths
      and malformed children are presented. Twenty nine couples (15.68%) with one of
      spouses--a carrier of a chromosomal anomaly (CA) are established. CA types
      include: aneuploidy--2, mosaic--5, Robertson's translocation--3, non-Robertson's
      translocation--7, and pericentric inversion--12. Recognition of genetic
      conditions is vital for accurate assessment of recurrence risks and in order in
      some instances, to provide specific prenatal diagnosis.

PMID- 8651416
TI  - [Defects of the anterior abdominal wall--their prenatal management].
AB  - The rate of the congenital malformations: gastroschisis and omphalocele, the
      prenatal management and the clinical issue were analyzed in a retrospective study
      during a period from January 1990 till October 1994 in the State Maternity
      Hospital "Maichin dom". The aim of the study was to establish the accuracy of the
      prenatal sonographic diagnosis of the defects of abdominal wall, the gestational
      age they were found out, and the perinatal issue of the affected newborn infants.
      The rate of the abdominal walls defects was 1:1525. They were diagnosed
      prenatally in 52% of the cases. The fatality rate among the alive-born infants
      with these malformations was 77%. The frequency of the associated anomalies with
      defects of the abdominal wall was 71%, which exceeds the mean frequency in Europe
      and presents one of the most important factors determining the high fatality
      rate.

PMID- 8651415
TI  - [Herpes simplex infection in newborn infants].
AB  - Six cases of proven herpes simplex infection in newborn babies are reported.
      Different clinical forms are observed: three babies with multisystem disease that
      attacked viscera and other three with central nervous system localisation. All
      six mothers have negative history for being carrier of herpes simplex virus. The
      babies are treated with Herpesbulin, Pandavir and Zovirax. One of them died with
      meningoencephalitis. The outcome at the age of three months after birth of the
      other 5 babies is: 2 babies are healthy, three developed late sequelae.

PMID- 8651417
TI  - [The sensitivity, specificity and prognostic values of peripheral secretions in
      the neonatal intensive unit].
AB  - We analyzed cultures (body surface and blood) from 125 infants-64 of them with
      proved neonatal bacterial sepsis. Isolates from cultures of material from the ear
      canal, nasopharynx, stomach, endotracheal tube were compared to those recovered
      from blood. The optimum sensitivity, specificity, and positive predictive values
      of surface cultures were 40%, 70.6% and 66.7% respectively. We conclude that
      surface cultures are of limited in predicting the etiology of sepsis in neonates.

PMID- 8651418
TI  - [A comparison between 11 clinico-laboratory indices for the early diagnosis of
      neonatal sepsis].
AB  - The authors have compared 11 laboratory tests for diagnosis f neonatal sepsis:
      WBC cont, neutr. count, band count (> 8%), immature/mature neutrophil ratio (I:M
      > 0.2), throm. count, C reactive protein, alpha 1-antitrypsin, alpha 2
      macroglobulin, IgM, GIC, C3 fraction of the complement. We determine higher
      sensitivity and specificity of CRP (80.1%; 80%), C3 fraction of the complement
      (82.4%; 86.5%) and I:M ratio (96.9%). We conclude that this tests are useful
      indicators of early diagnostic of neonatal infection.

PMID- 8651420
TI  - [A comparison of Clearview Chlamydia diagnostic tests and direct
      immunofluorescence (Chlamyset Antigen) in inflammatory gynecological diseases due
      to Chlamydia trachomatis].
AB  - The diagnostic performance of two direct antigen tests is compared, using
      parallel samples from 90 gynecologic patients. The latter were selected because
      of clinically suspicious symptoms for chlamydial infection. The incidence of
      infection in the study group was 33.3%. Compared to direct immunofluorescence
      Clearview Chlamydia had sensitivity of 80%, specificity of 100%, and the
      agreement between the two methods was 93.3%. Clearview Chlamydia may serve as a
      useful diagnostic test in case there is no available laboratory equipment and
      trained personal.

PMID- 8651419
TI  - [The sensitivity to the preparation cefotaxime of bacteria isolated from newborn
      infants].
AB  - Four hundred forty-four of S. aureus and 54 strains of E. coli were isolated from
      the neonates, born during the first six months of 1994 in the Maternity Hospital
      "Maichin dom". They were tested with the antibiotics--ampicilin, cephamandol and
      cefotaxime. Our results showed that 14.5% of the tested S. aureus were sensitive
      to ampicilin (e.g. broad-spectrum penicillins) and 85.5% resistant. Twenty
      percent of the strains E. coli were sensitive to ampicilin and 80% showed
      resistance. Fourty nine percent of the tested S. aureus were sensitive to
      cephamandol (a second generation cephalosporine) and 51% were resistant; 46.6% of
      the isolated strains E. coli were sensitive to cephamandol and 53.4% were
      resistant. Over 87% of the tested S. aureus were sensitive to cefotaxime, a third
      generation cephalosporine, and only 13% were resistant. From the tested strains
      E. coli 92.3% were sensitive to cefotaxime and 7.7% were resistant. The present
      study proved a high sensitivity of the isolated strains to cefotaxime. In
      addition this antibacterial drug showed good tolerance by the neonates when given
      in two doses per day and a lack of suppressive effect on the normal bacterial
      flora of the intestinal tract of the neonates.

PMID- 8651421
TI  - [The treatment of neglected cases of condylomata acuminata in pregnant women with
      the Nd:Yag laser].
AB  - The authors report for the therapeutical application of Nd:YAG Laser with wave
      length 106 nm--MEDILAS 4060N on a genital acute condyloma, caused by human
      papilloma virus at 19 pregnant women between 10-38 gestation week (g.w.). It is
      clinical studied a lot of exophytic formations on wide area included vulva,
      vagina, vaginal portion of uterine cervix (PVCU), perineum and anus. It is marked
      histological research of the biopsy material from the condyloma for excluding a
      malignant process, microbiological research of the attendant vaginal and cervical
      flux, as well as colposcopy of the cases with cervical localisation. It is done a
      destructive laser-therapy from 1 to 3 seances, depending on the condyloma, a
      size, count and localization with starting power between 20-30W with exposition
      time from 0.5 to 1 sec. and diameter of the focal ray--2mm. At the control
      studies it is found an epithelialization without cicatrices, absence of
      complications and recurrences during on year.

PMID- 8651422
TI  - [Malignant Mullerian mixed tumors of the female genitalia].
AB  - Morphological features and clinical data of 27 malignant mixed Mullerian tumors
      of uterus and ovaries are represented. These neoplastic entities have been
      systematized and controversial problems of terminology, nature and origin, as
      well as macroscopic and histopathological features have been discussed. Based on
      our own experience and on references to literature on this subject,
      clinicopathological correlation have been analyzed in order to point out reliable
      criteria for differential diagnosis, prognosis for therapeutic response and
      biological behavior of these tumors.

PMID- 8651423
TI  - [The outcome of delivery in the breech presentation at the Stara Zagora
      Obstetrics and Gynecology Clinic during 1990-1992].
AB  - The outcome from the deliveries in breech presentation deserves close attention,
      because they are although 4% only from the total number of deliveries, but they
      exert important influence on the frequency of the operative deliveries by
      caesarean section and the level of the perinatal mortality. In the modern
      literature, the breech presentation is recorded as the one of the main causes,
      which leads to considerable increase of the caesarean sections frequency.

PMID- 8651424
TI  - [The use of drugs in pregnant and nursing women with dermatologic diseases].

PMID- 8651425
TI  - [Current concepts in the diagnosis and treatment of pelvic inflammatory disease].

PMID- 8651426
TI  - [The prognostic factors in endometrial carcinoma (EC)].

PMID- 8651427
TI  - [The antenatal diagnosis of sacrococcygeal teratoma].
AB  - The teratomas are rarely met with the newborn and the sacrococcygeal teratomas
      are the most often among them. A private case is detailedly described, correctly
      diagnosed antenatally by the ultrasound method, the clinical session and the
      outcome of the pregnancy. In the discussion the theories of their origin are
      shown, the anomalies connected with them and the delivery. The opinions of other
      authors on this matter have been quoted.

PMID- 8651428
TI  - [The management of severe pelvioperitonitis of an inflammatory genital origin].
AB  - A description of clinical approach to heavy pelvioperitonitis from genital
      inflammatory origin. Author emphasizes that early and precise assessment of
      clinical and laboratory parameters as well as the adequate treatment are of great
      importance for saving patient's life.

PMID- 8651429
TI  - [Septic metrothrombophlebitis and acute kidney failure following a spontaneous
      abortion].
AB  - Author describes one case of septic metrothrombophlebitis and acute renal failure
      in pregnant woman as a result of spontaneous abortion. He discusses some clinical
      criteria of developing complications and proposes adequate therapeutic line of
      behaviour.

PMID- 8651430
TI  - [A case of mesenteric thrombosis occurring in a woman with a uterine myoma during
      her hospital stay].
AB  - The paper describes a case of a 40-year old woman who presented with complaints
      of crampy abdominal pain, weight loss, hypermenorrhea, anaemia, fever and
      peritoneal effusion which were attributed to a large solid pelvic tumour. During
      the preoperative investigations she had an attack of acute abdominal pain with
      bloody diarrhea assumed to be caused by gastrointestinal infection. The attack
      ceased quickly after intravenous infusions and antispasmodics were started.
      Several days later a second even stronger attack of abdominal pain with evidence
      of intestinal obstruction necessitated urgent laparotomy which revealed extensive
      necrosis of the small intestine with a coexistent large uterine myoma. A
      resection of the small intestine with a side-to-side anastomosis and hysterectomy
      with bilateral salpingo-oophorectomy were performed. The patient had an
      uncomplicated recovery gaining weight but still experienced mild discomfort after
      meals. The symptoms, the diagnostic difficulties as well as the therapeutic
      approaches in mesenteric ischaemia are discussed.

PMID- 8651431
TI  - [Combined neoplasms in the Mayer-RokLitansky-Kuster syndrome].
AB  - A case report of a 44-year-old patient is presented. There were combined
      neoplasms in Mayer-Rokitansky-Kuster syndrome and during the operation
      leiomyomas, originating from the uterine remnants and a Brenner tumor from the
      left ovary.

PMID- 8651432
TI  - [The cephalosporin sensitivity of microbial strains isolated from pregnant women
      and newborn infants].

PMID- 8651433
TI  - [A clinical study of the triphasic contraceptive Tri-Regol].

PMID- 8651434
TI  - [An efficacy and tolerance study of transdermal estrogen replacement therapy with
      the preparation Systen R50 (Cilag)].
AB  - Results from the first study, carried out in our country on the therapeutic
      effects of Systen [correction of System] R50 TTS in women with peri- and
      postmenopausal symptoms are reported. Eight women with postcastration syndrome
      and seven women older than 50 years, with an intact uterus and no vaginal
      symptoms are reported. Eight women with postcastration syndrome and seven women
      older than 50 years, with an intact uterus and no vaginal bleeding for at least 6
      months were treated. Progesterone was prescribed in the non-hysterectomised
      patients. In all women enrolled in the study the application of the preparation
      Systen [correction of System] R50 TTS led to a significant improvement of peri-
      and postmenopausal symptoms without serious side effects.

PMID- 8651435
TI  - [Comparative study of 4 combined hormonal contraceptive preparations with reduced
      hormonal levels].
AB  - The authors do clinic-laboratory investigation of the affect of four hormonal
      contraceptive preparations: Minisston, Gravistat 125, Rigevidon, Anteovin, on 179
      patients in reproductive age for the period of 895 menstrual cycles. The
      investigation is specified with respect of investigation of 10 clinic indexes,
      which are considered as side effects in the reception of hormonal contraception,
      as well as with respect to reconstruction of ovary function after reception
      breaking in first, second and third month. The received results demonstrate high
      effectiveness of the experimented preparations with respect to pregnancy
      prevention, good acceptance - the appearance of side effects is under the
      accidentally error limit, as well as good reproductive ability of ovaries after
      tablet reception breaking. Especially to Anteovin preparation the authors accept
      that it is with minimum side effects. They considered that this is due to
      increasing dose of gestagen during the second phase of the menstrual cycle, which
      appears stabilizing factor with respect to the good acceptance of the preparation
      without difference in age and fertile realization of the investigated patients.

PMID- 8651436
TI  - [The possibilities for treating vaginal candidiasis with a single dose of
      clotrimazole 500 mg].
AB  - The authors are describing their own clinical experience with the treatment of
      vaginal candidosis with the application of a single dose clotrimazole 500
      (Canesten 1) with only one vaginal globule. In 81% of the cases is obtained a
      perfect result with disappearing of the clinical symptoms (pruritus, bleeding,
      discomfort during excretion of urine) and negativisation of the microbiological
      results. In 9% the esteemed clinical result is not obtained. The authors are
      making the conclusion, that the treatment with a unique vaginal globule can be
      useful in light and acute cases of mycotic colpitis in non-pregnant as well as in
      pregnant women. A recommendation is given for follow-up of the pregnant patients
      in the last 3-4 weeks of the pregnancy, for a candidosis check-up and for
      prescription of an adequate treatment.

PMID- 8651437
TI  - [The large fetus--its obstetrical management and the results].
AB  - To find the maternal-fetal outcome 98 pregnancies with fetal weight over 4000 g
      have been observed. For the period 1993-1994 the rate of large fetus was 2.76%,
      0.84% of which were over 4500 g. The second period of delivery was prolonged in
      9.7% of all primigravidas. The registered shoulder dystocia and perineal
      lacerations of the mother were related to increasing birthweight. Difficult
      deliveries resulting in clavicle fracture or brachial plexus injuries and facial
      trauma. Fetal distress was observed in 7.14%. Congenital anomalies were not
      increased in the group of the large fetus. No maternal death was registered. The
      strict observation of the pregnant for latent diabetes mellitus and anticipation
      of the potential complications associated with delivery of a large infant may
      reduce maternal and neonatal morbidity rates and maintain low mortality rates.

PMID- 8651438
TI  - How much alcohol should I use in my experiments?

PMID- 8651439
TI  - Patterns of ethanol consumption in a continuous access situation: the effect of
      adding a sweetener to the ethanol solution.
AB  - The effect of the addition of sucrose to an ethanol solution upon daily intake
      patterns was examined in a continuous-access operant situation with Wistar rats.
      Rats were first initiated to self-administer orally a 10% ethanol (v/v) solution
      using the sucrose-substitution procedure in 30-min limited-access conditions.
      When then studied in a continuous-access operant situation (23 hr ethanol
      access), substantial increases in ethanol consumption were found when varying
      concentrations of sucrose were added to the ethanol solutions presented. This
      increased consumption was found to be a complex function of both an increase in
      the number of drinking occurrences each day and in the size of each drinking
      occurrence. When 2% sucrose was compared with 2% sucrose/10% ethanol, the
      consumption of the sweetened ethanol was greater than consumption of the
      sweetener alone, suggesting that the ethanol added to the ability of the solution
      to maintain behavior beyond that of the sucrose alone. This study supports the
      use of sweetened ethanol solutions for the study of ethanol drinking patterns,
      and as a model system for examining factors involved in the regulation of ethanol
      consumption.

PMID- 8651440
TI  - Failure to find postshock increases in ethanol preference.
AB  - Volpicelli at al. (Alcohol Clin Exp Res 14:913-916, 1990) found that rats given a
      choice between drinking 5% ethanol and water showed enhanced ethanol preference
      after daily sessions of shock, relative to No-Treatment controls. In our first
      experiment, rats were given a choice between 5% ethanol and isocaloric sucrose
      after daily sessions of shock. On shock days, rats received either 2 or 60 shocks
      over 1 hr. The 60-Shock group increased its ethanol preference from the baseline
      phase to the postshock phase, whereas the 2-Shock group decreased its ethanol
      preference from the baseline phase to the shock phase. However, the ethanol
      preferences of the two groups were not significantly different from each other
      during any phase. In four subsequent experiments, Shock, No-Shock, and No
      Treatment groups were given a choice between 5% ethanol and water. The
      experiments varied on: whether the treatments and measurements of consumption
      occurred in the light versus dark phase of the cycle, and whether there was one
      measurement per day or four. Baseline ethanol preference varied widely between
      experiments. In none of the experiments did shock differentially enhance ethanol
      preference. The findings of Volpiceli et al. were not replicated.

PMID- 8651441
TI  - Fetal ethanol exposure: hypothalamic-pituitary-adrenal and beta-endorphin
      responses to repeated stress.
AB  - Previous studies provide evidence that fetal ethanol exposure induces
      hypothalamic-pituitary-adrenal (HPA) and pituitary beta-endorphin (beta-EP)
      hyperresponsiveness to acute stressors. The present study demonstrates
      significant effects of in utero ethanol exposure on the parallel response
      patterns of the HPA axis and the pituitary beta-EP system to repeated exposures
      to a stressor, restraint stress, and indicates sex differences in response.
      Together, data from the two experiments indicate that, after repeated restraint
      exposures, fetal ethanol-exposed (E) males and females both show significantly
      increased plasma levels of adrenocorticotropin (ACTH), and E males also show
      significantly increased plasma levels of beta-endorphin-like immunoreactivity
      (beta-EPLIR), compared with their respective pair-fed and control counterparts.
      Marginal increases in the corticosterone response of E males and the beta-EPLIR
      response of E females, compared with their controls, were also observed. In
      addition, delayed or deficient habituation to restraint stress was observed in
      the beta-EPLIR response of E males and the ACTH response of E females. These data
      demonstrate that fetal E-exposed males and females both exhibit hormonal
      hyperresponsiveness and/or deficits in recovery after repeated exposures to
      restraint stress, but that the patterns of response may differ depending on the
      number and duration of restraint exposures, the time course measured, and whether
      the endpoint measured is corticosterone, ACTH, or beta-EPLIR. In addition, the
      finding that E and pair-fed animals both differed from their respective controls
      in certain developmental and hormonal measures suggests that prenatal nutritional
      factors may play a role in mediating some of the changes that are observed.

PMID- 8651443
TI  - Limited ethanol exposure selectively alters the proliferation of precursor cells
      in the cerebral cortex.
AB  - The present in vivo study tests the hypothesis that limited (4-day) exposure to
      ethanol differentially affects the proliferation of cortical precursors in the
      two cortical germinal zones [the ventricular zone (VZ) and the subventricular
      zone (SZ)] and their descendants in the mature brain. The offspring of pregnant
      rats fed a liquid diet containing 6.7% (v/v) ethanol when prosencephalic stem
      cells [gestation day (G) 6-69], VZ cells (G12-G15), and SZ cells were
      proliferating (G18- G21) throughout much of gestation (G6-G21). In addition, the
      offspring of rats pair-fed a liquid control diet or fed chow were examined. The
      pregnant dams were administered with bromodeoxyuridine (BrdU) on either G15 or
      G21. The ratio of the number of cells that incorporated BrdU to the total number
      (the labeling index) was determined 1-hr postinjection (i.e., on G15 or G21) or
      on postnatal day 60, Ethanol treatment between G6 and G21 reduced the ratio of
      cells labeled by an injection of BrdU on G15 in the fetus and in the adult, and
      increased the ratio of cells labeled on G21. Regardless of when the injection was
      placed, ethanol treatment between G6 and G9 had no effect upon the ratio of BrdU
      labeled cells in the fetus or mature cortex. Exposure from G12 to G15 decreased
      the number of VZ cells in the fetus and the number of immunolabeled cells in the
      adult cortex labeled by an injection on G15. This exposure had no effect on the
      incorporation by SZ cells. In contrast, ethanol exposure from G18 to G21
      increased the labeling indices for fetal SZ cells and for cells in the adult, but
      it had no effect on the ratio of labeled VZ cells. Although ethanol had no
      apparent effect on the proliferation of stem cells, it did alter the
      proliferation of cells in the VZ and SZ. These effects are time-dependent and
      underlie the ethanol-induced changes in the number of cells in the adult.

PMID- 8651442
TI  - Development and characterization of a binge drinking model in mice for evaluation
      of the immunological effects of ethanol.
AB  - This study describes the development and characterization of a binge drinking
      model in which a single dose of ethanol (EtOH) is administered by gavage to
      B6C3F1 mice. Blood EtOH levels were monitored over time after administration of
      EtOH at doses of 3.0-7.0 g/kg. Peak levels were in the range of 0.2-0.5%, and
      clearance was complete within 2-12 hr. Substantial increases in blood
      corticosterone levels were noted. Behavioral changes in EtOH-treated mice aged 8
      weeks ranged from no effect (3-4 g/kg) to severe ataxia (6-7 g/kg). In mice aged
      16 weeks, a dosage of 7 g/kg caused less of the righting reflex in some animals
      and severe ataxia in most of the others. Clinical chemistry results did not
      indicate biologically important changes in general physiological/homeostatic
      systems in EtOH-treated mice, but there were indications of minor liver damage at
      the 7 g/kg dosage. Thus, administration of EtOH to B6C3F1 mice by gavage produces
      behavioral changes, changes in blood EtOH levels, and probably glucocorticoid
      levels representative of at least some human binge drinkers. The model was used
      to evaluate the effects of binge drinking on antibody responses, and the results
      indicate the model will be useful for such studies.

PMID- 8651444
TI  - Effects of chronic alcohol consumption and aging on dopamine D2 receptors in
      Fischer 344 rats.
AB  - Aging and chronic alcohol consumption are each accompanied by significant changes
      in dopamine and dopamine receptors. This study extended previous work by
      investigating the combined effects of chronic alcoholism and aging on total
      dopamine D2 receptors in brain areas associated with the nigrostriatal and
      mesocorticolimbic systems. In addition, the effects of chronic alcohol
      consumption and aging on the high-affinity state of D2 receptors and their
      conversion to the low-affinity form is included. Quantitative autoradiography was
      used to assess [3H]spiperone-labeled D2 receptors in tissue sections from 5- to
      14- and 24-month Fischer 344 rats that were pair-fed a control or 6.6% (v/v)
      ethanol-containing liquid diet for 6 weeks. In addition, D2 receptors were
      determined in rats given the control liquid diet ad libitum. The results of these
      experiments demonstrated age-related changes in the nigrostriatal system. There
      was an age-related loss of total dopamine D2 receptors in the rostral and caudal
      striatum (approximately 25% decrease in Bmax). This decline in D2 receptors may
      be associated with changes in motor function. Despite the age-related decline in
      D2 receptors, there were no significant differences in the proportion of striatal
      receptors in the high-affinity form or in their conversion to the low-affinity
      state. Both aging and chronic alcohol consumption produced significant changes in
      the concentration of D2 receptors in brain areas associated with the
      mesocorticolimbic system. That is, the specific binding of [3H]spiperone was
      decreased in the frontal cortex of aged rats. In addition, chronic alcoholism was
      associated with a significant increase (approximately 20%) in the Bmax for D2
      receptors in the nucleus accumbens. Nonetheless, neither age nor chronic alcohol
      consumption altered the proportion of high-affinity D2 receptors in the nucleus
      accumbens or their conversion to the lower affinity state. The observed changes
      in D2 receptors in the frontal cortex and nucleus accumbens are of interest
      because of the involvement of the mesocorticolimbic dopamine areas in the
      rewarding properties of alcohol and other drugs of abuse. Although aging and
      chronic alcoholism both produced significant changes in dopamine D2 receptor
      concentrations, alcohol did not accentuate the age-related loss of D2 receptors.
      We cannot eliminate the possibility that a more prolonged exposure of higher
      ethanol dose may potentiate age-related changes in the dopaminergic system.

PMID- 8651445
TI  - Effect of chronic ethanol consumption on the activities of residual small bowel
      brush-border enzymes after proximal jejunum resection in the rat.
AB  - Ethanol consumption has a toxic effect on the epithelium of the small bowel, but
      enterocyte maturity is very difficult to measure under these circumstances.
      However, when ethanol intake is combined with enterectomy, enterocyte immaturity
      is greater, permitting an easier separation of these two effects. In a group of
      rats (13 male Wistar rats weighing approximately 220 g) fed a liquid diet
      containing 35% ethanol for 4 weeks after resection of the proximal jejunum, the
      residual small intestine brush border maltase, sucrase, and lactase activities
      were similar to those of a pair-fed control group (13 animals). However, alkaline
      phosphatase activity was decreased in the mucosa and in the enterocyte brush
      border, probably because of the lower activity of this enzyme in the jejunum
      ileum remnant of the alcoholic group.

PMID- 8651446
TI  - Alcohol modulates alveolar macrophage tumor necrosis factor-alpha, superoxide
      anion, and nitric oxide secretion in the rat.
AB  - We investigated the effect of alcohol (ethanol) on the ability of the alveolar
      macrophage to produce tumor necrosis factor-alpha (TNF-alpha), superoxide anion
      (O2-), and nitric oxide (NO)--three critical components of pulmonary host
      defense. Male rats were treated with alcohol either acutely (priming dose 175
      mg/100 g of body weight, followed by a 7-hr continuous intravenous infusion of 30
      mg/100 g of body weight/hr) or chronically (12-14 weeks of feeding ethanol in a
      liquid diet). Three hours before sacrifice, the rats received an intravenous
      injection of saline or lipopolysaccharide (LPS; Escherichia coli, 026:B6, 100
      micrograms/100 g of body weight). Alveolar macrophages (AMs) were then isolated
      by bronchoalveolar lavage and assessed for their in vitro capacity to produce TNF
      alpha, O2-, and NO spontaneously and in response to different stimuli. Acute
      alcohol administration suppressed in vitro LPS-stimulated AM TNF-alpha secretion
      by 52%. AMs from both pair-and alcohol-fed rats secreted TNF-alpha spontaneously
      in culture. However, the AMs from chronic alcohol-fed group secreted 42-53% less
      TNF-alpha spontaneously and in response to LPS, interferon-gamma (IFN-gamma) or
      IFN-gamma + LPS compared with the AMs from pair-fed group. Systemic LPS treatment
      inhibited in vitro LPS-stimulated AM TNF-alpha secretion (50%) only in the
      control rats. Acute alcohol administration enhanced significantly in vitro
      phorbol 12-myristate 13-acetate (PMA)- and opsonized zymosan (OPZ)-induced AM O2-
      secretion (4-and 1.8-fold, respectively). Systemic LPS treatment primed the AMs
      from control rats to secrete 83% more O2- in response to PMA but not OPZ;
      however, in the acute alcohol-treated group, it suppressed both PMA (54%)- and
      OPZ (66%)-induced AM O2- release (loss of priming effect of LPS). Chronic alcohol
      feeding suppressed PMA-induced AM O2- secretion (40%) without affecting the OPZ
      induced release. Although systemic LPS treatment had no significant effect on PMA
      or OPZ-induced AM O2- secretion in the pair-fed group, it enhanced the PMA
      stimulated AM O2- release (88%) in the alcohol-fed group. AMs recovered from
      control or acute alcohol-treated rats did not secrete NO spontaneously in vitro.
      However, AMs from both pair and chronic alcohol-fed rats secreted NO
      spontaneously with AMs from chronic alcohol-fed group secreting 34% less. Both
      acute and chronic alcohol treatment inhibited AM NO secretion in response to IFN
      gamma, LPS, and IFN-gamma + LPS significantly. Systemic LPS had no effect on AM
      NO production in response to different in vitro stimuli in any of the treatment
      groups. These data suggest that (1) both acute and chronic alcohol administration
      to rats inhibit AM TNF-alpha and NO secretion; (2) acute and chronic alcohol
      treatment have differential effects on AM O2- secretion; and (3) alcohol-induced
      alteration in AM TNF-alpha, O2-, and NO secretion may in part explain the
      increased susceptibility of alcohol-consuming individuals to pulmonary
      infections.

PMID- 8651447
TI  - Elevated rates of early discontinuation from pharmacotherapy trials in alcoholics
      and drug abusers.
AB  - The failure of subjects to complete clinical trials is a common problem with
      important implications for the interpretation of study results. Although a
      substantial literature exists on the high prevalence of premature termination
      from psychiatric and substance abuse treatment setting, there has been little
      attention paid to early discontinuation in clinical trials. There is evidence
      that the presence of substance abuse predicts higher rates of early
      discontinuation. This, combined with a recent increase in efforts to develop
      medications for treatment of substance use disorders, led us to conduct a
      literature review to determine whether pharmacotherapeutic trials for patients
      with these disorders have higher rates of premature discontinuation than
      comparable studies of patients with other psychiatric disorders. Of 267 articles
      that were initially identified, 83 met predetermined criteria for inclusion in
      the analysis. As hypothesized, after controlling for a number of potential
      contributing variables, treatment trials with substance abuse patients showed a
      significantly poorer retention rate than those of patients with other psychiatric
      diagnoses. The difference in retention rate was also evident when studies
      specific to alcohol dependence, the largest subgroup of substance use disorders,
      were evaluated separately. Although the retrospective nature of the study design
      limits the conclusions that can be drawn, the results suggest that, in
      pharmacotherapy trials with alcoholics or other substance abuse patients,
      particular attention should be paid to enhancing treatment retention.

PMID- 8651449
TI  - Effects of prenatal alcohol exposure and aging on auditory function in the rat:
      preliminary results.
AB  - This study investigated select aspects of peripheral and central auditory
      dysfunction, as well as the pathological effects of aging, In an animal model of
      fetal alcohol syndrome (FAS). Pregnant rats consumed liquid alcohol diets
      containing 0, 17.5, or 35% ethanol-derived calories, from gestation day 7 to
      parturition. A fourth group was untreated. Offspring of these mothers were tested
      for auditory and neurological function, using the auditory brainstem response at
      6, 12, and 18 months of age. Some animals in the alcohol-exposed groups showed a
      peripheral auditory disorder in the form of congenital sensorineural hearing
      loss. This was correlated with punctate lesions and malformed stereocilia on the
      auditory sensory receptor cells of the inner ear. Alcohol-exposed animals also
      showed a central auditory processing disorder characterized by prolonged
      transmission of neural potentials along the brainstem portion of the auditory
      pathway. Animals in the highest dose group also showed an augmentation in the age
      related deterioration of auditory acuity. Thus, increased peripheral and central
      auditory dysfunctions and pathological deterioration of auditory function in old
      age may be sequelae of FAS. Such morbidities have important implications for the
      long-term clinical assessment and management of FAS patients.

PMID- 8651448
TI  - Effects of chronic ethanol exposure on oral self-administration of ethanol or
      saccharin by Wistar rats.
AB  - The study of alcohol abuse traditionally has placed great emphasis on the
      development of tolerance and dependence as key factors. However, animal models of
      ethanol self-administration in dependent rats have been difficult to establish,
      caused in part by ethanol's aversive taste cues and subsequent aversive effects
      (i.e., "hangover" malaise) that prevent substantial ethanol consumption. In this
      study, this problem was addressed in animals trained to self-administer ethanol
      (10% w/v) in a sweetened-solution fading procedure before induction of dependence
      and repeated exposure to withdrawal. Once stable rates of responding for ethanol
      were achieved, a palatable liquid diet containing 8.7% (v/v) ethanol was
      introduced as the sole source of calories and fluid for one group of rats
      [ethanol diet (ED) group]. A second group of rats received a control diet with
      sucrose isocalorically substituted for ethanol (CD group). After 14-17 days of
      liquid diet exposure, the rats were withdrawn once a week for 4 weeks and 8 hr
      into each withdrawal session were allowed to self-administer ethanol or water for
      60 min. As compared with CD rats, ED rats showed significantly greater intake of
      ethanol, but not water. No significant differences were found when separate
      groups of ED/CD rats were allowed to self-administer an alternate reinforcer
      (0.0075% saccharin solution). Rats who consistently had blood alcohol levels
      (BALs) above 100 mg% at the time of withdrawal sustained high levels of ethanol
      self-administration throughout the four withdrawal sessions. In contrast, rats
      who had an average BAL at withdrawal below 100 mg% showed progressive decreases
      in ethanol self-administration during repeated withdrawal episodes. The results
      demonstrated that chronic exposure to ethanol and repeated periods of abstinence
      are accompanied by elevated rates of ethanol intake in certain animals, and the
      persistence of elevated self-administration behavior of individual rats is
      predicted by their BAL at the time of withdrawal.

PMID- 8651450
TI  - Ethanol at pharmacologically relevant concentrations inhibits contractility of
      isolated smooth muscle cells of cat esophagus.
AB  - Acute ethanol, in both man and cats, decreases contractility of both lower
      esophageal sphincter (LES) and smooth muscle portion of the lower esophageal (LE)
      body. Because these inhibitory effects were not abolished, in cats, by cervical
      vagotomy or intravenous tetrodotoxin, we surmised a direct inhibitory effect of
      ethanol on muscle cells. Accordingly, to test this possibility, we exposed
      isolated, esophageal smooth muscle cells (LES and LE) to ethanol (0-150 mM) for 0
      to 40 min, and then a contractile agent, carbachol, or its vehicle was added.
      Thirty seconds later, cells were fixed and cell shortening was measured as an
      index of contractility. In the absence of ethanol, carbachol dose-dependently
      induced shortening of muscle cells from both LE and LES. Ethanol significantly
      attenuated carbachol-induced maximal shortening of cells from both LE and LES.
      Potency for carbachol in LES (but not LE) was also decreased by ethanol. Isolated
      muscle cells remained viable after incubation with ethanol. Thus inhibition by
      ethanol: can occur directly on esophageal muscle; occurs at pharmacologically
      relevant ethanol concentrations; and is not simply caused by cytotoxicity of
      ethanol.

PMID- 8651451
TI  - Voluntary alcohol consumption in BXD recombinant inbred mice: relationship to
      alcohol metabolism.
AB  - Studies were initiated to characterize behaviorally and biochemically C57BL/6J
      and DBA/2J inbred mice, as well as BXD Recombinant Inbred (RI) strains derived
      from them. The C57BL/6J, DBA/2J, and 7 BXD RI strains were tested for voluntary
      alcohol consumption (VAC) by receiving 4 days of forced exposure to a 10% (w/v)
      solution of alcohol, followed by 3 weeks of free choice between water and 10%
      alcohol. Measures of VAC included the absolute intake of alcohol (g/kg), as well
      as alcohol preference. A wide range of VAC was displayed by the various BXD RI
      strains with a continuous (rather than bimodal) distribution, indicating that
      there is likely to be additive effects of several genes involved in regulating
      alcohol-related behaviors. Kinetic characteristics of aldehyde dehydrogenase and
      catalase in liver and brain of the C57BL/6J, DBA/2J, and BXD strains of mice were
      determined to test the hypothesis that the genetic regulation of the levels of
      alcohol-metabolizing enzymes mediate differences in VAC. Aldehyde dehydrogenase
      activity was determined spectrophotometrically by observing the change in
      absorption at 340 nm. Catalase activity was determined by measuring oxygen
      production with a Yellow Springs Biological Oxygen monitor and oxygen electrode.
      There was a strong negative relationship between VAC and brain catalase activity
      in the BXD RI and parental strains. These data suggest that RI strains are likely
      to be useful genetic models in the examination of quantitative trait loci
      controlling VAC and other responses to alcohol.

PMID- 8651452
TI  - Noradrenergic locus coeruleus neurons.

PMID- 8651454
TI  - From A to B to serendipity: the story of a monoamine oxidase knockout.

PMID- 8651453
TI  - To be or not to be: how ethanol can affect neuronal death during development.

PMID- 8651455
TI  - Evidence of alcohol-related efficiency deficits in an episodic learning task.
AB  - Using a component processes model, the current study examined the cognitive
      processes of alcoholic and community control subjects engaged in the acquisition
      of new context-bound (e.g., episodic) information. Of particular interest was
      whether alcoholics were inferior to controls in the efficiency with which
      information was acquired and whether there was a gender x group interaction in
      cognitive efficiency. Alcoholic (n = 16 females; n = 22 males) and community
      control (n = 21 females; n = 21 males) subjects participated in a serial learning
      task that consisted of three 12-item word lists. Standard administration
      protocols for serial learning tasks were used. On efficiency measures, there were
      significant differences between groups [F(1.75) = 8.51, p = 0.005] and sexes
      [F(1.75) = 4.05, p = 0.048]. There was also a group x sex interaction [F(1.75) =
      7.73, p = 0.007]. Duncan multiple-range comparisons revealed alcoholic females to
      be significantly inferior to control females, but equivalent to male controls and
      alcoholics. These data are consistent with other studies revealing the
      sensitivity of cognitive efficiency to alcohol-related effects and extend
      previous findings to tasks involving episodic learning tasks.

PMID- 8651456
TI  - Automatic activation of alcohol concepts in response to positive outcomes of
      alcohol use.
AB  - Seventy-one subjects with various levels of drinking experience completed a
      computerized semantic priming task. Prime phrases (describing positive outcomes
      of drinking alcohol or neutral phrases) were presented immediately before a
      target word (either alcohol-related or not). The results replicated earlier basic
      research examining the effects of semantically related primes on the processing
      of subsequent words. Furthermore, the results provided evidence that, for heavy
      drinking subjects, the presentation of phrases describing positive drinking
      outcomes significantly primed, or facilitated, responses to the alcohol-related
      words. These results are consistent with the view that for some individuals,
      thoughts about certain outcomes automatically prime, or make accessible, concepts
      related to alcohol use. An increase in the accessibility of these concepts has
      important implications for behavioral decisions about alcohol consumption.

PMID- 8651457
TI  - Harman and norharman in alcoholism: correlations with psychopathology and long
      term changes.
AB  - In the search for mechanisms specific for alcoholism, it has become evident that
      beta-carbolines (BCs; e.g., harman and norharman) are compounds that may act on
      brain reward systems, thereby mediating an increase in voluntary ethanol (ETOH)
      drinking in animals. This study was undertaken to analyze relationships between
      these compounds and clinical variables (e.g., family history, personality data,
      and affect) in alcoholics and to trace the time course of blood concentrations in
      subjects abstaining from alcohol for at least 6 months. Nonalcoholics were
      investigated during sober and ETOH-loading conditions (1 g ETOH/kg body weight).
      Levels of harman were elevated in the chronically intoxicated alcoholics and
      correlated with the scores on the self-rating depression (SDS) and the self
      rating anxiety (SAS) scales. The group of alcoholics with at least one alcoholic
      parent had higher levels than the group without such a history. Levels remained
      elevated for 6 months. Norharman levels were only slightly elevated on the day of
      admission. They were correlated to high harm avoidance and SDS scores. A family
      history of alcoholism and the severity of alcoholism as assessed by the number of
      ICD-10 criteria fulfilled were correlated with norharman levels. Long-term
      observation revealed elevated levels of norharman after 3 months of abstinence,
      but not after 6 months. The association of harman levels with anxiety and
      depression demonstrated in the present study suggests that alcoholics with high
      harman levels use alcoholic beverages as self-medication in an attempt to
      overcome possible anxiogenic/depressiogenic actions of harman. Norharman levels
      are less strongly associated with these mood states, but significantly correlated
      to harm avoidance tendencies. It has been suggested that the activity of the
      indolergic neurons is relatively high in individuals with a high harm avoidance
      score. Biosynthesis of norharman might be stimulated under these conditions
      (tryptamine serves as precursor).

PMID- 8651458
TI  - Abnormal development of the cerebellar vermis in children prenatally exposed to
      alcohol: size reduction in lobules I-V.
AB  - Abnormalities of the cerebellar vermis have been well documented in animal models
      of fetal alcohol syndrome. At this point, it is not known if the same brain
      region is affected in humans prenatally exposed to alcohol. In this study, the
      area of the cerebellar vermis was measured from brain magnetic resonance images
      of 9 children and young adults with prenatal alcohol exposure and 24 control
      subjects in the same age range. Six of the exposed children met standard criteria
      for fetal alcohol syndrome. The remaining three subjects had significant
      histories of prenatal exposure to alcohol, but did not have enough of the classic
      facial features for the diagnosis. For each subject with a suitable midsagittal
      section, three vermal areas were circumscribed: anterior vermis (vermal lobules I
      V), posterior vermis (vermal lobules VI and VII), and the remaining vermal area
      (including lobules VIII-X). Statistical analyses revealed that the anterior
      region of the vermis was significantly smaller in subjects with prenatal alcohol
      exposure, whereas the posterior region and the remaining vermal area did not
      differ between groups. Previous findings from an animal model of neonatal alcohol
      exposure have documented Purkinje cell loss in vermal lobules I-V and IX-X, with
      notable sparing in lobules VI-VII. Thus, the results of both studies indicate
      similar patterns of abnormal brain development in the anterior vermal region,
      with apparent sparing in the posterior vermal region. Our findings, for the first
      time, suggest that regionally specific Purkinje cell death may also occur in
      humans prenatally exposed to alcohol.

PMID- 8651459
TI  - Auditory event-related potentials in fetal alcohol syndrome and Down's syndrome
      children.
AB  - Abnormal or borderline electroencephalograms are commonly observed in cases of
      gross mental retardation. However, fewer studies have focused on the use of event
      related responses to aid in the differential diagnosis of developmental cognitive
      disorders. Fetal alcohol syndrome (FAS) and Down syndrome represent the most
      common known causes of mental retardation in the Western world. Although Down
      syndrome is easily diagnosed with a chromosome assay, FAS can be more difficult
      to diagnose since the diagnostic features are more subjectively based. The
      present study is the first to characterize auditory event-related potentials
      (ERPs) in children with FAS and contrast them to subjects with Down syndrome and
      controls. A passive auditory "oddball-plus-noise" paradigm was utilized to elicit
      ERPs. Parietal P300 latencies in response to the noise-burst stimuli for the FAS
      children were significantly longer, as were the P300s from all cortical sites in
      Down syndrome subjects in response to the both the infrequent tone and noise
      burst stimuli when compared with the controls. Frontal P300s in Down syndrome
      children were significantly larger in amplitude compared to the controls and FAS
      children in response to the infrequent tone. A discriminant function analysis
      also revealed that these children could be correctly classified as being either
      Down syndrome, FAS, or normal controls using measures of latency and amplitude of
      the P300. These data suggest that an evaluation of ERP characteristics may
      provide a better understanding of the differences between FAS and Down syndrome
      children, and prove to be an aid in the early identification of children with
      FAS. These results demonstrate neurophysiological differences between FAS and
      Down syndrome, and suggest that P300 amplitude and latency data collected from a
      passive ERP task may be helpful in the discrimination of developmental cognitive
      disorders.

PMID- 8651460
TI  - Cytochrome P4502E1 genotypes, alcoholism, and alcoholic cirrhosis in Han Chinese
      and Atayal Natives of Taiwan.
AB  - Genetic factors may play a role in the development of alcoholic liver disease
      (ALD). Cytochrome P4502E1 (CYP2E1) catalyzes the oxidation of ethanol, producing
      acetaldehyde and free radicals capable of reacting with and peroxidizing cell
      membranes. Polymorphisms have been identified in the 5-flanking region of the
      CYP2E1 gene that may alter the transcriptional activity. In our laboratory, no
      difference in c1 and c2 allele frequencies was observed between alcoholic
      patients with or without liver disease in Caucasian men, but there is reported
      data to the contrary for other populations. To determine if there is a
      differential susceptibility to ALD between ethnic groups that differ in the
      frequency of the c2 allele, we studied 30 Han Chinese with severe alcoholic liver
      disease. Allele frequencies of alcoholics with cirrhosis were compared with 46
      alcoholic and 100 nonalcoholic Han individuals without liver disease. To identify
      the type A (homozygous for c1), type B (heterozygous for c1 and c2) and type C
      (homozygous for c2) genotypes, DNA encompassing the polymorphisms was amplified
      by polymerase chain reaction, slot-blotted, and probed with allele-specific
      oligonucleotides, No significant differences in c2 allele frequencies were found:
      0.23 for alcoholics with severe liver disease, 0.20 for alcoholics without liver
      disease, and 0.26 for the normal population. There also was no difference in c2
      allele frequencies between alcoholic and nonalcoholic Atayal natives from Taiwan.
      Therefore, our results suggest that the allelic variations at the CYP2E1 gene
      locus also do not significantly affect the development of alcoholism or ALD in
      Han Chinese and Atayal natives of Taiwan.

PMID- 8651461
TI  - High diastolic blood pressure: common among women who are heavy drinkers.
AB  - The present study evaluates the relationship of different alcohol consumption
      levels to blood pressure among women. Blood pressure values were compared between
      four groups of women consuming different amounts of alcohol. Three groups were
      formed from the middle-aged female population participating in a health survey (n
      = 219): 15 consecutive alcohol abstainers, 136 consecutive moderate drinkers, and
      68 consecutive heavy drinkers. Also, 78 consecutive female alcoholics reporting
      for treatment were included, forming the fourth group. The prevalence of systolic
      blood pressure > or = 160 mm Hg did not increase in relation to alcohol
      consumption. In contrast, the percentage of women showing diastolic blood
      pressure > or = 90 mm Hg clearly increased (p = 0.004) from abstainers (7%) to
      moderate drinkers (18%), to heavy drinkers (32%), and to alcoholics (37%). The
      highest blood pressure values were found among heavy drinkers. Compared with
      abstainers, the mean difference in systolic blood pressure was -12 mm Hg, with a
      95% confidence interval from -2 to -23 mm Hg. For diastolic blood pressure, the
      difference was -6 mm Hg with a 95% confidence interval from 1 to -13 mm Hg. Among
      alcoholics, the blood pressure values had returned essentially to normal after 4
      days of abstinence. It is concluded that alcohol consumption increases both
      systolic and diastolic blood pressure values among women. However, only diastolic
      blood pressure values increase enough to be clinically significant. Moderately
      elevated diastolic blood pressure, combined with normal systolic blood pressure,
      might thus be a possible sign of alcohol abuse among women. Abstinence should be
      emphasized as an inexpensive and rapidly effective treatment for mild
      hypertension among female alcohol abusers.

PMID- 8651462
TI  - Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase
      2*2. I. A comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P
      4502E1 between alcoholics and nonalcoholics.
AB  - We examined the genotypes of the aldehyde dehydrogenase (ALDH)-2, alcohol
      dehydrogenase (ADH)-2, ADH3, and P-4502E1 loci of 53 alcoholics and 97
      nonalcoholics. All of the subjects fulfilled the DSM-III-R criteria for alcohol
      dependence. The control group consisted of 97 subjects who were either hospital
      staff or students. We also compared the frequencies of homozygous ALDH2*1/1 and
      heterozygous ALDH2*1/2 genotypes in alcoholics. Our study revealed differences in
      the allelic frequencies of the ALDH2, ADH2, and ADH3 loci between alcoholics and
      nonalcoholics. For alcoholics with both homozygous ALDH2*1/1 and heterozygous
      ALDH2*1/2 genotypes, it was found that ADH2 and ADH3 played important rates.
      Alcoholics with the heterozygous ALDH2*1/2 genotype showed a significantly higher
      frequency of ADH2*1/1 than ones with the homozygous ALDH2*1/1 genotype. We assume
      ADH2*1 plays an important role in the development of alcoholism in alcoholics
      with the heterozygous ALDH2*1/2 genotype.

PMID- 8651463
TI  - Carbohydrate-deficient transferrin evaluation in dry blood spots.
AB  - The aim of this study was to assess the performance of the isoelectric
      focusing/immunoblotting/laser densitometry (IEF/IB/LD) procedure to evaluate
      carbohydrate-deficient transferrin (CDT) derived from dry blood spots. Serum
      specimens obtained from insurance applicants were analyzed for CDT by IEF/IB/LD.
      Dry blood spots derived from 50 serum specimens were analyzed by IEF/IB/LD. A
      comparative analysis of these serum specimens and the paired dry blood spots by
      IEF/IB/LD shows a highly significant correlation of the CDT values (r = 0.94, p <
      0.0001). Stability studies indicate that, under proper storage conditions (2-3
      days at room temperature, 2 weeks at 4 degrees C, or frozen at or below -20
      degrees C indefinitely), dry blood spots can be used as a source of CDT for
      analysis by IEF/IB/LD, thus simplifying sampling, storage, and transportation of
      specimens to the testing site.

PMID- 8651464
TI  - Chronic alcoholics without Wernicke-Korsakoff syndrome or cirrhosis do not lose
      serotonergic neurons in the dorsal raphe nucleus.
AB  - Despite the considerable evidence that alcoholics have perturbation of
      serotonergic function, there is little pathological evidence for alcohol directly
      affecting the nervous system. The present study aims to assess neuronal loss that
      occurs as a consequence of alcohol neurotoxicity in the serotonergic dorsal raphe
      nucleus (DRN). To that end, the brains of eight alcoholics and eight age-matched
      control cases were carefully screened to eliminate serious liver disease, the
      sequela of thiamine deficiency, Wernicke-Korsakoff syndrome (WKS), and other
      pathological abnormalities. Brains were formalin-fixed for 2 weeks, cut, and then
      immunohistochemically stained using a monoclonal PH8 antibody specific for the
      rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. The
      morphology of the serotonin-synthesizing neurons and their average size was
      similar in all cases. However, there was a reduction in the staining intensity of
      the reaction product in the DRN serotonergic neurons of most alcoholics. Neuronal
      counts on spaced serial sections revealed that there were an estimated average
      total of 106,100 +/- 19,500 serotonergic neurons in the DRN of alcoholics and
      108,300 +/- 11,800 in the DRN of controls, indicating that in most alcoholics
      there is no reduction in the number of these neurons. Therefore, the effect of
      chronic alcohol consumption on the serotonergic system, in the absence of WKS or
      liver disease, seems to be functional rather than neuropathological.

PMID- 8651465
TI  - Indicators of genetic and environmental influence in alcohol-dependent
      individuals.
AB  - Although much is known about genetic and environmental influences in alcohol
      dependence at the population level, little is known about the relative
      contribution of such influences on individuals. As an initial step toward
      individual assessment, concordance for the Diagnostic Interview Schedule, version
      III alcohol symptoms was determined in a sample (n = 113) of male monozygotic
      (MZ) and dizygotic (DZ) twins. Items were assigned to a genetic or environmental
      scale on the basis of significant MZ/DZ differences in proband-wise concordance
      rates. Weights were assigned to items based on factor analyses. For the genetic
      scale, significant differences were found between MZ and DZ intraclass
      correlations. No significant differences were found between MZ and DZ
      correlations on the environmental scale. When scores on the environmental scale
      were controlled, genetic scale scores were correlated with earlier age of onset
      of alcohol problems and a shorter interval between first intoxication and onset
      of alcohol problems. When scores on the genetic scale were controlled,
      environmental scale scores were correlated with later age of onset of alcohol
      problems and a longer interval between first intoxication and onset of alcohol
      problems. These results suggest it is possible to assess relative influence of
      genetic and environmental factors in individual cases of alcohol dependence.

PMID- 8651466
TI  - Human immunodeficiency virus-type 1 infection in an inner-city alcohol treatment
      program.
AB  - The human immunodeficiency virus (HIV) infection rate was examined in a selected
      cohort of healthy clients of an inner-city alcohol treatment center from 1990
      through 1993. These subjects were also participating in a research protocol (n =
      258) designed to assess immunity and HIV risk behaviors in inner city alcohol
      dependent persons. Healthy alcohol-abusing heterosexual clients (165) had HIV
      testing conducted in an inner-city ambulatory alcohol treatment center between
      September 1990 and December 1993. Respondents were 93.9% African-American and
      3.6% Hispanic; 72.1% were male. Anonymous HIV-1 antibody testing was conducted
      retrospectively for an additional 80 subjects who participated in the research
      protocol during the same interval, but for whom HIV-1 antibody testing was not
      conducted clinically at the time. HIV infection rate among the clinic-tested
      subjects (n = 165) was 4.4% for individuals who were exclusively alcohol
      dependent, 1.4% for non-injecting drug use (IDU) mixed substance abusers, and
      46.8% for clients with a history of IDU. Rates did not differ among cohorts
      tested in different years. Among non-injecting drug users tested in the clinic,
      all infected respondents (n = 3) were women (p = 0.03). Among those tested
      anonymously (n = 80), however, infection rate for exclusively alcohol-dependent
      persons was 16.7%, non-IDU mixed abusers 11.1%, and injecting drug users 48.3%,
      with seropositive males as well as females in each group. HIV infection rates for
      the pooled samples (n = 245) were 8.7% for exclusively alcohol-dependent persons,
      5.1% for mixed abusers, and 54.5% for injecting drug users. Among non-injecting
      drug users, exclusively alcohol-dependent women had a significantly higher (p <
      0.01) infection rate (20.0%) than the remaining females and males. Infection
      rates among exclusively alcohol-dependent males, male and female polysubstance
      non-IDU abusers, and injecting drug users were comparable with that seen in an
      earlier screening in the same clinic in 1989, with apparently little diffusion of
      infection from the IDU population to other substance abusers. An exception seemed
      to be exclusively alcohol-dependent females, who show substantially elevated
      rates. Age, housing, and other social differences may help segregated substance
      abusing populations in the relatively small Newark metropolitan area, although
      not protecting exclusively alcohol-dependent females.

PMID- 8651468
TI  - Plasma and urine salsolinol in humans: effect of acute ethanol intake on the
      enantiomeric composition of salsolinol.
AB  - The tetrahydroisoquinoline (TIQ) salsolinol (SAL), a condensation product of
      dopamine and pyruvate or acetaldehyde, is one of the neuropharmacologically
      active alkaloids in mammals. Previous HPLC studies have shown that the R
      enantiomer of SAL is largely predominant, or is the only enantiomer in the urine
      of healthy subjects, whereas the S-enantiomer was found predominant in the urine
      of alcoholics. An enzymatic pathway for SAL formation that is influenced by
      chronic alcohol intake was proposed. However, our analyses showed that the SAL
      detectable in human urine and plasma is racemic, at least in healthy subjects. No
      change of the enantiomeric distribution was observed after an acute alcohol
      ingestion (1 g alcohol/kg body weight). Using a new method for the resolution of
      the SAL enantiomers and gas chromatography mass spectrometry analysis, the SAL
      enantiomers were quantified in the urine and plasma of 24 subjects before and
      after the intake of alcohol. Special dietary conditions were observed to avoid
      interferences by the SAL of the foodstuff. Although the distribution of SAL
      enantiomers was not changed after alcohol intake, the total urinary SAL output
      and the plasma concentration of SAL were significantly influenced in different
      ways. Only five subjects showed a significant increase both in plasma SAL
      concentration and in the total urinary SAL output, whereas 19 subjects showed
      decreased or unchanged SAL levels after alcohol administration. Data also show
      that only the subjects with low baseline levels (mean of 0.148 ng SAL/ml plasma)
      tend to increase SAL levels after ethanol ingestion, which may imply some genetic
      basis for the response.

PMID- 8651467
TI  - Alcohol reactions in subjects of European descent: effects on alcohol use and on
      physical and psychomotor responses to alcohol.
AB  - Self-reports of reactions to small amounts of alcohol, obtained between 1990 and
      1992, were compared with reports of alcohol use, obtained in 1990-1992 and also
      in 1979-1981, in twin subjects of European descent. Data on subjective,
      physiological, psychomotor, and metabolic responses to a test dose of alcohol,
      taken in 1979-1981, were also available. Alcohol reactions were more common in
      women than in men, and were associated with less alcohol use, both at the time
      that information about reactions was obtained and as recorded on average 12 years
      previously, in both sexes. Physiological and psychomotor responses to alcohol
      were similar across the reaction groups, except that deterioration in standing
      steadiness was greater in those who subsequently reported adverse reactions to
      alcohol. Contrary to expectation, skin temperature changes after alcohol were
      less in the subjects who reported always reacting to alcohol than in the other
      groups. Subjective reports of intoxication were greatest in subjects who
      subsequently reported alcohol reactions. The pattern of twin pair concordance for
      reactions suggests low heritability, so alcohol reactions in subjects of European
      descent are not caused by a single gene of high penetrance of the type found in
      the Asian alcohol flush reaction.

PMID- 8651469
TI  - A simple auditory oddball task in young adult males at high risk for alcoholism.
AB  - The reduction in the amplitude of the auditory P300 in young adult males at high
      risk for alcoholism has not been as consistently replicated as has been the
      reduction in the visual P300 amplitude in the same group. The easier nature of
      the auditory task was thought to be responsible for the inconsistency. We
      examined the auditory P300 amplitude in a group that has not yet been studied,
      young adult sons of alcoholics (mean age = 24.9 years, n = 48), and compared them
      with age and sex-matched controls (mean age = 27.8 years, n = 23). We found the
      auditory P300 amplitude to be reduced in the high-risk group and this reduction
      to be the greatest over the posterior centroparietal and occipital areas when
      individual leads were examined. We further analyzed the data using current source
      density, a mathematical transformation that circumvents some of the errors
      inherent in measuring scalp-evoked potentials, and found reduced current source
      density in the high-risk group in the posterior central and parietal areas. Thus,
      we found that a simple auditory oddball task was effective in eliciting P300
      differences in groups at high and low risk for alcoholism. The clinical
      significance of the P300 is discussed, as well as the relevance of task
      difficulty in eliciting auditory P300 differences in young males at high risk for
      alcoholism.

PMID- 8651470
TI  - Voice of the victims.
AB  - Over the past 10 years, I have been privileged to conduct educational forums for
      audiences containing many recovering alcoholics or otherwise chemically dependent
      persons. In these forums about the addictive diseases, their treatment, and
      research possibilities, significant interaction with the audience members occurs.
      During these interactions, certain anecdotal phenomena seem to predominate. The
      repetitive nature of these reports suggests the need for systematic
      investigation. As  with editorial comments in major medical journals, observed
      phenomena and unanswered questions from the victims can be valuable in the
      generation of testable hypotheses. Perhaps the ideas presented herein will be
      useful in the development of future research on alcohol abuse and alcohol
      dependence.

PMID- 8651471
TI  - In utero exposure to ethanol alters mRNA for insulin-like growth factors and
      insulin-like growth factor-binding proteins in placenta and lung of fetal rats.
AB  - Insulin-like growth factors I and II (IGF-I and IGF-II) play a role in regulating
      fetal growth and development. Their actions in target tissues are modulated in
      part by binding to IGF binding proteins 1 and 2 (IGFBP-1 and IGFBP-2). In this
      study, we examined the effect of fetal exposure to alcohol IGF-I and on IGF-II
      and IGFBP-1 and IGFBP-2 mRNA in placenta and fetal lung tissue. Timed-pregnant
      Sprague-Dawley dams were fed a diet consisting of 35% ethanol-derived calories
      [alcohol-fed (AF)], an Isocaloric diet with sucrose substituted for alcohol (pair
      fed; PF), or ad libitum rat chow (CF). Alcohol feeding began on gestational age
      (G) 14. At G20, dams were killed, and we examined placenta and fetal lung for the
      steady-state levels of mRNA for IGF-1 and IGF-II and for IGFBP-1 and IGFBP-2. In
      all dams, body weight increased throughout gestation, and there were no
      differences between the three groups. At G20, the mean weight for the fetuses
      from the AF group was lower (p < 0.001) than the fetuses from the CF and PF
      groups. Steady-state mRNA levels were detected in fetal lung and in placentas by
      Northern-blot hybridization analysis and semiquantitated by slot-blot
      hybridization analysis. Multiple transcripts for IGF-I and IGF-II, 1.8 kb species
      for IG-FBP-1 and 1.6 kb species for IGFBP-2 were detected from total RNA isolated
      from the fetal lung and placenta, Slot-blot hydridization analysis of fetal lung
      RNA showed that IGF-I mRNA was significantly increased (p < 0.001) in AF males
      and females by 4.0 +/- 0.28-fold and by 3.25 +/- 0.2-fold, respectively. IGF-II
      transcript levels were not affected. IGFBP-1 and IGFBP-2 were increased in AF
      males, whereas only IGFBP-2 was increased in AF females. In the placenta, there
      was a significant increase in IGFBP-1 and IGFBP-2 transcripts [(p < 0.001) 1.75
      +/- 0.5-fold and 3 +/- 0.53-fold increase, respectively]. No differences between
      the groups in serum levels of IGFBP-1 or -2 were detected when measured by
      Western-blot analysis. The increased gene expression for IGFBPs within fetal lung
      and placenta may decrease bioavailability of locally synthesized, IGFs that may
      contribute to the fetal growth retardation observed in this model system.

PMID- 8651472
TI  - Speed of onset of action of Tilarin.
AB  - Two studies have been carried out specifically to examine the speed of onset of
      action of intranasal nedocromil sodium 1% (Tilarin) for the relief of symptoms
      due to ragweed allergic rhinitis. One, a multicentre placebo-controlled
      comparative study using a QID regimen, 1 spray per nostril, was designed to
      assess the speed of onset of action of nedocromil sodium during the first week of
      treatment in patients with rhinitis symptoms, and to evaluate the efficacy and
      safety of nedocromil sodium during 6 weeks of treatment (1). A 1-week baseline,
      the start of which was timed to coincide with the start of the ragweed season,
      was followed by 6 weeks double-blind trial treatment; only patients (n = 166) who
      were symptomatic at the end of baseline were included in the double-blind phase.
      Non-parametric analyses of all variables including a summary score (stuffy nose,
      runny nose, itchy nose and sneezing) showed that the onset of action of
      nedocromil sodium occurred on the first day of treatment. Further, patients using
      nedocromil sodium had less symptoms during the 10 days of peak pollen, at which
      time physician assessment showed reduced mucosal oedema and nasal discharge, and
      both patient and clinician opinions favoured nedocromil sodium. No significant
      adverse events were reported during this 6-week study. In the second study (2),
      104 patients were randomly allocated to receive either nedocromil sodium or
      placebo, QID. They then spent 10 hours per day for 2 consecutive days in Iowa
      City Park during the peak of the ragweed season. Only patients showing
      significant symptoms of seasonal allergic rhinitis (SAR) during 3 hourly baseline
      assessments were included. Over the 2-day period, symptom scores for stuffy nose,
      runny nose, itchy nose and sneezing, and global symptom summary scores, were
      recorded at 19 hourly time points. At home in the evening, patients recorded
      symptom scores for the post-exposure period. In comparison with placebo,
      nedocromil sodium significantly improved rhinitis symptoms within 2 hours, and
      this reduction in SAR symptoms was maintained throughout the 2-day exposure
      period. Post exposure symptom summary scores were also significantly lower in
      patients treated with nedocromil sodium than in those patients treated with
      placebo. Overall, very few adverse events were reported, none of them serious. In
      conclusion, nedocromil sodium 1% nasal spray acts rapidly, within 2 hours on the
      first day of treatment, to reduce ongoing symptoms of SAR. Relief of rhinitis
      symptoms is maintained throughout the peak pollen period with nedocromil sodium
      QID, which appears to be a safe and well tolerated treatment for ragweed SAR.

PMID- 8651473
TI  - Tilarin in combination with astemizole.
AB  - This multicentre double-blind, placebo controlled study had a practical
      objective, based on the expectation that many patients with seasonal allergic
      rhinitis will be prescribed oral antihistamine monotherapy by their primary care
      physician, whereas allergy specialists are more likely to prescribe combination
      therapy including antiinflammatories. The specific question was, "Will the
      addition of nedocromil sodium 1% nasal spray to astemizole tablets improve
      control of symptoms of seasonal allergic rhinitis induced by ragweed pollen, as
      compared to astemizole therapy alone?'. Following a one-week baseline, planned to
      coincide with the start of the local ragweed pollen season, patients (aged 12-64)
      were randomly assigned to four weeks' double-blind test treatment with either
      nedocromil sodium 1% nasal spray four times daily (QID) + astemizole (n = 146) or
      placebo nasal spray + astemizole (n = 148) or double-dummy (nasal spray +
      capsules) placebo (n = 71). Patient diary cards were kept throughout the five
      weeks, and clinic visits were made before and after baseline and after one and
      four weeks' treatment. During the 10-day peak pollen period, the diary card
      rhinitis symptom summary score (0-4 severity scale) was significantly reduced in
      patients receiving either astemizole alone (p < 0.001) or the combination therapy
      (p < 0.001) as compared with placebo. Direct comparison of the active treatments
      further showed that symptoms were significantly less severe (p < 0.01) with the
      combined therapy than with astemizole alone, and this despite significantly
      greater reliance on permitted rescue medications (p < 0.05 for pseudoephedrine
      usage) in the astemizole group. Clinical assessments of rhinitis made during the
      peak pollen visit, after the first week of test treatment, were also
      significantly (p < 0.05 - p < 0.01) in favour of combined therapy with nedocromil
      sodium 1% nasal spray + astemizole rather than astemizole alone, and at the same
      time this preference was confirmed by physician (p = 0.011) and patient (p =
      0.003) opinions of symptom control. In conclusion, this antiinflammatory +
      antihistamine treatment proved superior to antihistamine alone for effective
      management of allergic rhinitis. The combined therapy worked quickly and was well
      tolerated, with no serious adverse events or untoward effects on blood or urine
      variables.

PMID- 8651474
TI  - A clinical overview of Tilarin.
AB  - Tilarin is a nasal spray containing 1% nedocromil sodium, a non-toxic
      pyranoquinoline dicarboxylate compound with potent antiallergic antiinflammatory
      properties. As a first-line topical treatment for seasonal allergic rhinitis
      (SAR) the pharmacokinetics of nedocromil sodium nasal formulation are such that
      it rivals sodium cromoglycate for safety. Less than 8% of the total dose of
      nedocromil sodium is systemically absorbed from the nasal mucosa, and this is
      reversibly bound to plasma proteins and is cleared rapidly from the circulation.
      Nedocromil sodium is eliminated unmetabolised in the urine and faeces, with an
      elimination half-life of 5.3 +/- 0.9 minutes. No significant adverse effects have
      been reported following intranasal administration of 1% nedocromil sodium four
      times daily, to a total of 964 patients with allergic rhinitis during clinical
      trials. Laboratory studies have shown that nedocromil sodium has a more wide
      ranging pharmacological antiinflammatory profile than sodium cromoglycate and
      this is manifest in its clinical efficacy in allergic asthma and
      rhinoconjunctivitis. Analysis of pooled data from a series of double-blind,
      placebo-controlled group comparative studies in SAR patients demonstrated that,
      despite a significantly lower use of rescue antihistamines than with placebo
      treatment (31% reduction; p = 0.005), four times daily dosage with nedocromil
      sodium 1% nasal spray significantly reduced daily symptoms of rhinitis (p <
      0.001) and was considered effective by the majority of patients (p < 0.001).
      Specific examples of the therapeutic efficacy of nedocromil sodium compared with
      placebo in patients with grass or ragweed pollen SAR can be found in the
      literature. One ragweed study (1) included four times daily sodium cromoglycate
      4% nasal spray as an active comparator and showed a consistent, if non
      significant, trend in favour of nedocromil sodium 1%, which was the more
      effective drug in comparison to placebo. An Italian paediatric study (2) compared
      nedocromil sodium 1% nasal spray with placebo in 149 children of whom 72% were
      under twelve years of age. After one week, the clinicians observed a significant
      reduction (p = 0.03) in sneezing with nedocromil sodium and after four weeks,
      patient (p < 0.01) and clinican (p < 0.001) opinions favoured the active
      treatment. Overall, the clinical profile of topical nedocromil sodium in SAR
      demonstrates fast relief of existing symptoms, sustained efficacy with four times
      daily use during peak pollen challenge, and a reduced need for concomitant
      symptomatic therapies. Nedocromil sodium 1% nasal spray is well tolerated, with
      minimal side-effects, and is acceptable to a wide age-range of patients.

PMID- 8651475
TI  - Seasonal allergic rhinitis--a review of current therapy.
AB  - Epidemiological studies in many countries strongly suggest an increase in the
      prevalence of seasonal allergic rhinitis, particularly in urban communities. The
      mechanisms of allergic rhinitis have been the subject of much research,
      elucidating symptomatology and improving the focus of therapeutic strategies.
      Ideally, avoidance of the offending allergen may be undertaken but is often
      incompatible with normal activity. Thus, active therapy is usually required,
      selected from a range of pharmacologic agents. Choice is determined by the
      severity of the symptoms, the age and individual circumstances of the patients,
      and may vary considerably from country to country. The menu will primarily
      include rapid onset, oral non-sedating H1 antihistamines, topical nasal steroids
      and topical sodium cromoglycate to the nose, eyes or both. These medications may
      be given alone or in combination, usually under the direction of the primary care
      physician, and should be commenced in advance of exposure to the seasonal
      allergen. If this proves ineffective, specialist referral should be made for
      further management.

PMID- 8651476
TI  - Clinical implications of the pharmacological profile of Tilarin.
AB  - The pharmacological activity of nedocromil sodium is extensive and the compound
      should affect a variety of inflammatory processes by preventing activation of the
      involved cells or blocking release of their mediators. Some in vitro actions of
      nedocromil sodium are particularly relevant to the mechanisms of allergic
      rhinitis, and the response of the nasal epithelium to pollutants such as ozone.
      The effects of nedocromil sodium on mucosal mast cells, eosinophils, sensory
      nerves and nasal epithelial cells can each be linked to its potential clinical
      effectiveness by our own biopsy studies from patients with active allergic
      rhinitis. Nedocromil sodium has been shown to modulate production of a number of
      powerful cytokines, such as GM-CSF and TNF alpha, which are produced by the human
      nasal epithelium, as well as by involved inflammatory cells and lymphocytes, and
      which orchestrate the inflammatory response to allergen or to pollutant
      provocation. So, in addition to inhibiting activated mast cells and eosinophils,
      nedocromil sodium acts on the nasal epithelium itself to prevent further
      accumulation of these cells and thus to break the inflammatory chain of events.
      On this evidence of its preclinical activity, nedocromil sodium promises to
      become a very useful topical treatment for allergic rhinitis.

PMID- 8651477
TI  - Off-line coupling of capillary electrophoresis and matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry.
AB  - An automated fraction collection interface is used in conjunction with matrix
      assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry to
      analyze material isolated by capillary electrophoresis (CE). CE fractions are
      deposited directly on the MALDI probes so that individual peaks from the
      electropherogram are associated with a single sample spot on the probe. MALDI
      matrices with high acid concentrations afford enhanced tolerance of
      electrophoresis buffers. The utility of this hybrid instrument is demonstrated by
      separation and mass analysis of a tryptic digest of cytochrome c and synthetic
      mixtures of four proteins. Mass assignments corresponding to the protonated
      molecular ions are in good agreement with those predicted from molecular
      structure. Miniaturization of the interface affords enhanced sensitivity, with
      good-quality spectra from separations of as little as 25 fmol of protein.

PMID- 8651478
TI  - On-line fluorescence lifetime determinations in capillary electrophoresis.
AB  - A near-infrared time-correlated single-photon counting instrument was developed
      for on-line fluorescence lifetime determinations of components separated by
      capillary electrophoresis (CE). The lifetimes of the migrating components were
      determined using maximum likelihood estimators, which are computationally easy to
      perform and yield values with high precision and favorable accuracies in the
      limit of low photocounts within the decay profile. The laser source used in the
      present system was a passively mode-locked Ti-sapphire laser with a single-photon
      avalanche diode serving as the fast detector. The instrument response function of
      this system was determined to be 165 ps (fwhm). Electrophorectic separation of
      two near-IR dyes, DTTCI (cationic) and IR-125 (anionic), in a 95:5 methanol/water
      running buffer (pH = 9.5) produced electrophoretic peak widths at the base of
      approximately 1 -9 s, which set the integration time for collection of the decay
      profiles. At a loading level of 1.42 zmol for IR-125 and 49 zmol for DTTCI,
      lifetime values  were determined to be 482 +/- 14 ps for IR-125 and 943 +/- 23 ps
      for DTTCI, which agreed favorably with the lifetimes determined for these dyes
      using static measurements at high concentrations. To minimize background
      resulting from scattered photons in ultradilute conditions, which introduces bias
      into the lifetime determination, the calculation was initiated at a fixed time
      delay with respect to the excitation pulse. To demonstrate the feasibility of
      making lifetime determinations in capillary gel electrophoresis, where the gel
      can produce high scattering backgrounds, the lifetimes of C-terminated fragments
      produced from the M13mp 18 template and labeled at the 5' end of a universal M13
      sequencing primer with a near-IR fluorescent tag were determined. The collection
      of lifetimes for 30 different peaks in the electropherogram yielded a mean value
      of 581 ps and a standard deviation of +/- 9 ps.

PMID- 8651479
TI  - A perfluorosulfonated ionomer end-column electrical decoupler for capillary
      electrophoresis/electrochemical detection.
AB  - An end-column electrical decoupler contructed with perfluorosulfonated ionomer
      (Nafion) is described. This decoupler was fabricated at the cathodic end of the
      separation capillary by casting liquid Nafion ion exchange powder over a copper
      plated tungsten wire. The internal diameter of the flow channel was controlled by
      adjusting the thickness of the copper plating. This design overcomes problems of
      conventional end-column detection such as low sensitivity due to low collection
      efficiency of analytes at the detection electrode, difficulty in precise
      placement of the detection electrode, and the need to use small-bore capillaries
      (<-25 micron). The loss of cationic analytes observed with long-cast Nafion on
      column decouplers was significantly reduced. The high current shunting capability
      of the long Nafion decoupler was maintained in this configuration. Elimination of
      the detection capillary required for on-column electrical decouplers provided
      higher separation efficiency by maintaining plug-type flow throughout the system.
      Four model catecholamines were well separated within 5 min with separation
      efficiency of up to 230 000 plates and migration time reproducibilities of <0.6%
      RSD.  With the optimized experimental conditions, detection limits of 3 nM for
      the catecholamines were achieved in a Ringer's solution matrix (to model a
      microdialysis sample).

PMID- 8651480
TI  - Method to assay the concentrations of phenolic constituents of biological
      interest in wines.
AB  - We describe a reversed-phase HPLC method that uses gradient elution and diode
      array detection to quantitate eight biologically active phenolic constitutions of
      wine: the cis and trans isomers of resveratrol and their glucosides, catechin,
      epicatechin, quercetin, and rutin. ODS Hypersil served as the stationary phase;
      the gradient was formed by acetic acid, methanol and water. Each analysis
      required an equilibration period of ten minutes and a run time of fourty minutes
      for completion. Satisfactory peak resolution was achieved following direct
      injection of a 20-muL sample, and validation was accomplished by on-line spectral
      comparisons with known standards. Excellent linearity was obtained for all
      constituents, and the detection limits ranged from 30 mug/L (trans-resveratrol)
      to 1.5 mg/L (catechin). Recoveries approximated 100% range (95.2-105.5%), and the
      method provided good precision, with coefficients of variation between 1.17 and
      3.38%. All of the phenolics measured were reasonably stable in opened wines
      protected against sunlight for up to 1 week at room temperature or 4 degrees C,
      but most showed losses of 10-40% when stored for 6 weeks at either temperature.

PMID- 8651481
TI  - A novel method of immobilizing antibodies on a quartz crystal microbalance using
      plasma-polymerized films for immunosensors.
AB  - A novel method of immobilizing antibodies on quartz crystals for use in
      immunosensors was developed using an ethylenediamine plasma-polymerized film
      matrix. The films formed on the quartz crystals are extremely thin and
      homogeneous, and they incorporate amino groups. Sensors produced using this
      method are more reproducible from sample to sample and exhibit lower noise and
      higher sensitivity than sensors made using conventional immobilization methods,
      e.g., via polyethylenimine and (gamma-aminopropyl)trimethoxysilane. This is, to
      our knowledge, the first reported application of plasma-polymerized films to
      quartz crystal microbalance immunosensors. Results on orientation-controlled
      immobilization of anti-bodies, reusability and calibration tests are also
      presented.

PMID- 8651482
TI  - Ammonium ion minisensors form self-assembled bilayer lipid membranes using
      gramicidin as an ionophore. Modulation of ammonium selectivity by platelet
      activating factor.
AB  - The present paper reports the electrochemical investigation of ion transport
      through self-assembled bilayer lipid membranes on a metal support and represents
      a technology suitable for development of an ammonium ion minisensor. Gramicidin D
      was used as a channel-forming ionophore for selective conduction of ammonium ion
      through lipid bilayers composed of egg phosphatidylycholine. The ammonium ion
      sensor exhibited good mechanical stability and longevity (routinely over 48 h)
      and constant sensitivity and response to a given concentration of ammonium ion in
      solution. The use of stabilized metal-supported BLMs has allowed the
      electrochemical investigation of the reversibility of response to ammonium ions
      and of ionophore binding to lipid membranes. The effects of pH and some possible
      interferents were examined. Semisynthetic platelet-activating factor (PAF; 1-O
      alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, AGEPC) was found to enhance
      transport of ammonium ions by gramicidin and to reduce potassium interference,
      whereas the non-acetylated derivative of AGEPC did not exert any alterations in
      transport ammonium ions. The present microfabricated ammonium sensor based on
      thin lipid film technology provides advantages of extremely fast response times
      (to millisecond speeds) to alterations of ammonium ion concentration (0.02-5 mmol
      L-1), high selectivity to ammonium ions in the presence of volatile amines, and
      the capability of analyzing small volumes of samples. A detection limit of
      ammonium ions of approximately 1 x 10(-6) M was attained using BLMs modified with
      PAF. Furthermore, a device can now simply and reliably be fabricated at low cost
      and therefore can be used as a disposable sensor.

PMID- 8651483
TI  - Multiphoton-excited fluorescence of fluorogen-labeled neurotransmitters.
AB  - Fluorescence detection of fluorogen-labeled neurotransmitters is demonstrated
      using 100 fs pulses from a titanium-sapphire mode-locked laser to achieve
      molecular excitation by simultaneous absorption of two and three photons of near
      IR radiation. Two-photon excitation spectra are determined for the naphthalene
      2,3 dicarboxaldehyde derivative of glycine and the fluorescamine derivative of
      leucine enkephalin, with the peak excitation cross section (o2) approximately
      equal to 1 x 10(-50) cm4 s/photon for both species. Three-photon-excitation
      fluorescence is demonstrated for o-phthaldialdehyde-labeled glutamate using
      excitation wavelengths between 965 and 1012 nm. The three-photon excitation cross
      section (o3) remains nearly constant in this wavelength range, with an absolute
      value of approximately 10(-84)-10(-85) cm6 s2/photon 2. Rapid cycling of analytes
      through the fluorescent excited state and detection that is free from background
      caused by Rayleigh and Raman scatter combine to make multiphoton-excited
      fluorescence a highly sensitive approach for detecting trace amounts of
      neurotransmitters. Measurements of two-photon-excited fluorescence of
      fluorescamine-labeled bradykinin and analysis of multiphoton-excited background
      reveal the potential of this method to detect fewer than 1000 neurotransmitter
      molecules.

PMID- 8651484
TI  - A practical ion trap mass spectrometer for the analysis of peptides by matrix
      assisted laser desorption/ionization.
AB  - The present paper describes the performance of a newly configured matrix-assisted
      laser desorption/ionization quadrupole ion trap mass spectrometer (MALDI-ITMS),
      designed for biological applications that require the determination of the
      primary structures of proteins, e.g., the rapid identification of proteins and
      the elucidation of posttranslational modifications. The strategy used for solving
      problems of this type involves enzymatic digestion of the protein, followed by
      MALDI ion trap mass spectrometric analysis of the components of the resulting
      complex mixture of peptide ions. The new instrument is demonstrated to be a
      highly practical tool for analyzing proteins. In particular, mixtures containing
      as many as 30 peptide components can be rapidly and sensitively analyzed without
      prior chromatographic separation of the components. Informative tandem mass
      spectra can be obtained from the peptide components with m/z values up to 3500. A
      single subpicomole sample loading of a complex peptide mixture is more than
      sufficient for a complete set of experiments that includes both low- and high
      resolution molecular mass determinations as well as a complete MS/MS study of the
      various components present in the sample. Extensive use is made of improved
      methods for trapping, isolating, fragmenting, and detecting ions in the ITMS
      (details are to be provided in two future papers).

PMID- 8651485
TI  - A dual vacuum chamber fourier transform mass spectrometer with rapidly
      interchangeable LSIMS, MALDI, and ESI sources: initial results with LSIMS and
      MALDI.
AB  - A design is presented involving two separate vacuum chambers to provide nearly
      simultaneous capabilities of liquid secondary ion mass spectrometry (LSIMS),
      matrix-assisted laser desorption/ionization (MALDI), and electrospray ionization
      (ESI) in an external source Fourier transform mass spectrometer. The instrument
      consists of two vacuum chambers, one with five stages of differential pumping for
      a combined LSIMS/MALDI source. The chamber dedicated to ESI was formerly a three
      stage chamber with LSIMS and electron ionization. Two additional stages were
      added with the ESI source. LSIMS and MALDI have similar vacuum requirements and
      were moved to a newly built chamber with two stages of pumping. We present our
      first results obtained on the new vacuum chamber. Data presented for the MALDI
      source show that, with only two stages of pumping, and with shorter radio
      frequency-only quadrupole rods for ion injection, spectra comparable to those
      obtained on the formerly three-stage instrument can be obtained. Characterization
      of the MALDI source and data on linear, cyclic, and branched oligosaccharides are
      given. Finally, the design of the secon chamber is proposed as a low-cost
      prototype for an external source FTMS instrument.

PMID- 8651486
TI  - Characterization of SDS--PAGE-separated proteins by matrix-assisted laser
      desorption/ionization mass spectrometry.
AB  - A new strategy to characterize SDS--PAGE-separated proteins with MALDI MS is
      described. The proteins, electroblotted onto nitrocellulose after SDS--PAGE
      separation and stained with reversible Ponceau S dye, are readily recovered by
      dissolving the membrane in matrix solutions prepared with acetone. The resulting
      mixtures are amenable to direct MALDI MS analysis, which provides a rapid and
      accurate means of measuring the molecular weights of SDS--PAGE-separated proteins
      and of peptides that result from CNBr digestion of proteins on the nitrocellulose
      membrane. Compared with the traditional elution method, this procedure provides
      more efficient detection of proteins and peptides, especially the higher
      molecular weight proteins from the membrane. As little as 3.5 pmol of lysozyme
      and 15 pmol of bovine albumin loaded onto a gel can be detected using this
      method. The detection sensitivity is higher than or comparable to that of the
      traditional Coomassie Brilliant Blue staining procedure.

PMID- 8651487
TI  - Applications of delayed extraction matrix-assisted laser desorption ionization
      time-of-flight mass spectrometry to oligonucleotide analysis.
AB  - A delayed ion extraction technique is shown to dramatically improve mass
      resolution and the overall quality of matrix-assisted laser desorption ionization
      (MALDI) mass spectra of oligonucleotides. Isotope limited mass resolution was
      obtained on samples up to 10-kDa molecular mass in linear mode, and as high as
      7500 mass resolution (defined at half peak height) was observed in reflector
      mode. This performance is as good as that achieved to date for peptides and
      proteins. Applications included the detection of oxidized byproducts of
      phosphorothioate DNA and separation of components differing only by 15 Da at 9.5
      kDa molecular mass. In addition to single components, complex mixtures could also
      be analyzed at greatly improved performance over conventional MALDI. An example
      is shown for sequence verification of an oligonucleotide of 31 bases in length by
      analyzing the failure products. Mass accuracy was adequate to verify sequences of
      oligodeoxyribonucleotides up to 9500-Da molecular mass. Fast fragmentation taking
      place between the ionizing pulse and the extraction pulse is demonstrated to be a
      sequencing tool for small oligonucleotides. By proper selection of matrix
      material, wavelength, and irradiance, fast fragmentation can be promoted
      efficiently. Fragment ions tend to form from cleavage of phosphodiester bonds, as
      previously observed in infrared MALDI.

PMID- 8651488
TI  - Near-infrared detection of flow injection analysis by acoustooptic tunable filter
      based spectrophotometry.
AB  - The instrumentation development of a near-infrared (near-IR) spectrophotometer
      based on an acoustooptic tunable filter (AOTF) and its application as a detector
      for flow injection analysis (FIA) are reported. In addition to being compact and
      all solid state, this AOTF-based instrument is very sensitive, has high
      resolution, and can be rapidly scanned. The latter advantage make it uniquely
      suited as a detector for FIA, in that it can rapidly record the whole near-IR
      absorption spectrum of a mixture passing through the FIA flow cell. Subsequent
      treatment of the recorded spectra with multivariate calibration methods makes it
      possible to use the FIA, for the first time, for such applications as the
      simultaneous determination of trace amounts of water and benzene in ethanol.
      Because all organic compounds absorb light in the near-infrared region, this AOTF
      based near-IR detector can serve as a universal detector for FIA; as a
      consequence, applications of the FIA techniques can be expanded to other areas
      which are not possible otherwise.

PMID- 8651489
TI  - Near-infrared spectroscopic measurement of physiological glucose levels in
      variable matrices of protein and triglycerides.
AB  - Selective calibration models are generated for glucose over the 1-20 nM
      concentration range by use of partial least-squares regression analysis of near
      infrared spectra from 5000 to 4000 cm-1. Two spectral data sets are used to
      simulate triglyceride and protein variations in clinical samples. Triacetin is
      used in one data set to simulate variations in triglyceride levels, and bovine
      serum albumin (BSA) is used in the second data set to simulate variations in
      blood protein levels. Although these matrix components possess strong absorption
      bands that overlap and overshadow the absorption bands of glucose, successful
      calibration models can be generated with no evidence of prediction bias caused by
      the different levels of the matrix components. Furthermore, the benefits of using
      digital Fourier filtering as a preprocessing step are evaluated in terms of
      calibration performance. The resulting calibration models provide standard errors
      of prediction of 0.5 and 0.2 mM in triacetin and BSA matrices, respectively.
      Accurate glucose predictions are demonstrated from spectra that correspond to
      protein concentrations not present in the calibration data set. Lastly, digital
      Fourier filtering alone is shown to have only limited ability to isolate glucose
      signals from those of BSA and triacetin due to similarities in the widths of the
      absorption bands of the three species.

PMID- 8651490
TI  - Cell-to-cell scanning in capillary electrophoresis.
AB  - A widespread limitation in using cell-based biosensors for repetitive chemical
      analysis is loss of agonist-induced response caused by receptor desensitization.
      We overcome this problem by scanning an array of immobilized cells underneath a
      capillary electrophoresis column outlet. In this way, electrophoretically
      fractionated components that exit the separation capillary are always directed
      onto cells previously unexposed to receptor agonists. To demonstrate this concept
      of response recovery using a scanning format, we have chosen the bradykinin B2
      receptor system in the NG108-15 cell line, which is known to undergo
      desensitization. Whereas four subsequent injections of 250 microM bradykinin
      separated by 120 s are found to reduce the NG108-15 cell response markedly,
      scanning to new cells can fully restore the response during the separation.
      Furthermore, by pretesting individual NG108-15 cells for an agonist response and
      then later scanning back to the same cell, we achieved a 100% success rate in
      detecting bradykinin in subsequent electrophoretic separations.

PMID- 8651491
TI  - Comparison of an intercalating dye and an intercalant-enzyme conjugate for DNA
      detection in a microtiter-based assay.
AB  - Two methods have been developed for the detection of DNA immobilized on the
      surface of microtiter wells. An intercalating dye, 3,6-diaminoacridine, is used
      in stain and rinse solutions, so that measured absorbance values (450 nm) reflect
      the sum of DNA-bound and free dye. With diaminoacridine, signal increases of
      0.056 +/- 0.010 were achieved on immobilizing double-stranded calf thymus DNA. An
      intercalant-enzyme conjugate, consisting of an average of four daunomycin
      moieties covalently bound to each glucose oxidase, was shown to provide a 10-fold
      signal enhancement (optimum 0.25 microM, with rinsing and peroxidase-o
      dianisidine detection) compared to diaminoacridine, due to catalytic
      amplification; signals of 0.50 +/- 0.05 were obtained. This conjugate possesses
      56% of the activity of native glucose oxidase and was prepared using water
      soluble carbodiimide and N-hydroxysuccinimide reagents. Single-stranded DNA was
      immobilized onto avidin-coated polystyrene plates and commercially available
      (Covalink) plates possessing secondary amine groups. Following hybridization with
      complementary DNA, detection was performed with the daunomycin-glucose oxidase
      conjugate. Both immobilization methods showed optimum DNA concentrations of 0.10
      microgram/mL, and maximum signal intensities were obtained when > 0.5
      microgram/mL complementary DNA was present in the hybridization solution. Some
      nonspecific binding of the intercalant-enzyme conjugate was suggested by results
      obtained with avidin-coated polystyrene plates, but not with Covalink plates.

PMID- 8651492
TI  - Reversed-phase liquid chromatography coupled on-line to receptor affinity
      detection based on the human estrogen receptor.
AB  - On-line coupling of reversed-phase liquid chromatography to a biochemical
      detection system based on receptor-ligand interactions is described. The receptor
      affinity detection is performed using a postcolumn reaction detection system with
      open-tubular reaction coils. In the first step, a solution containing the steroid
      binding domain of the human estrogen receptor is added to the LC effluent via a
      mixing union, and the mixture is allowed to react. In the second step, a
      fluorescent estrogenic ligand, coumestrol, is added to saturate the remaining
      free binding sites of the estrogen receptor. Both heterogeneous and homogeneous
      detection systems have been developed. In the former case, free and receptor
      bound coumestrol were separated prior to detection by means of a short column
      containing a restricted-access reversed-phase support. Since free and receptor
      bound coumestrol differ significantly in fluorescence intensity, the system can
      also be operated in the homogeneous mode without requiring a separation step.
      Using 5 nmol/L of human estrogen receptor, a detection limit of 5 nmol/L was
      obtained for compounds possessing a high affinity for the estrogen receptor, such
      as 17 beta-estradiol and diethylstilbestrol. Detection limits for weaker ligands
      amount to 20 nmol/L. Non-estrogenic steroids such as methyltestosterone or
      progesterone are not detected at all. The selectivity of the present method is
      demonstrated for the analysis of urine samples.

PMID- 8651493
TI  - Affinity countercurrent chromatography using a ligand in the stationary phase.
AB  - In countercurrent chromatography (CCC), an addition of a ligand to the liquid
      stationary phase remarkably improved both retention time and peak resolution of
      the analytes: various amino acid derivatives were separated by N-dodecanoyl-L
      proline-3,5-dimethylanilide, while polar catecholamines and dipeptides were
      separated by bis-(2-ethylhexyl)phosphoric acid. By selecting an appropriate
      ligand and dissolving it in the liquid stationary phase, the present CCC
      technique can perform a variety of separations comparable to chiral
      chromatography, ion chromatography, and affinity chromatography. Leakage of the
      ligand from the column can be entirely eliminated by introducing a small volume
      of a ligand-free stationary phase at the end of the column as an absorbent. The
      method further facilitates application of pH-zone-refining CCC and can increase
      the sample loading capacity over 10 times for a given column.

PMID- 8651494
TI  - Preparation and evaluation of slurry-packed liquid chromatography microcolumns
      with inner diameters from 12 to 33 microns.
AB  - Fused silica capillary liquid chromatography columns with inner diameters between
      12 and 33 microns were slurry packed with 5 microns octadecylsilane-modified
      silica particles. Column efficiencies and van Deemter coefficients were compared.
      A linear decrease of the A term as column diameter was decreased was the most
      significant contributor to a lower overall plate height at the optimum velocity.

PMID- 8651495
TI  - Chiral separation mechanisms in protein-based HPLC columns. 2. Kinetic studies of
      (R)- and (S)-warfarin binding to immobilized human serum albumin.
AB  - This work used plate height measurements to investigate the kinetics of (R)- and
      (S)-warfarin binding to an immobilized HSA column. The dissociation rate
      constants for (R)- and (S)-warfarin on this column increased from 0.06 to 1.9 s-1
      and from 0.06 to 0.36 s-1 between 4 and 45 degrees C. The corresponding
      association rate constants increased from 2.4 x 10(4) to 3.2 x 10(5) M-1 s-1 for
      (R)-warfarin and from 4.4 x 10(4) to 7.2 x 10(4) M-1 s-1 for (S)-warfarin over
      the same temperature range. From the dissociation data, it was found that an
      increase in temperature led to a large decrease in the plate height due to
      stationary phase mass transfer for both enantiomers. Further studies indicated
      that (R)- and (S)-warfarin had similar activation energies for their binding to
      HSA. For (R)-warfarin, most of this energy requirement was due to the change in
      enthalpy of the system, while for (S)-warfarin, it was mainly due to the change
      in entropy. All of these results agree with an earlier model, in which (R)- and
      (S)-warfarin were proposed to interact with regions on the interior and exterior
      of HSA, respectively. In addition, these results offer a number of useful
      insights into the mechanisms of protein-based chiral separations.

PMID- 8651496
TI  - Dynamic delay and maximal dynamic error in continuous biosensors.
AB  - When biosensors are operated continuously, a dynamic delay and a dynamic error
      relate the sensor signal to the changing analyte concentration. The dynamic delay
      is the temporal displacement of the signal, or the lag, and is specified solely
      by properties of the biosensor and external mass transfer. The dynamic error is
      the difference between the actual concentration and the simultaneous reported
      concentration and is the product of the dynamic delay and the instantaneous rate
      of concentration change. In real-time operation of sensors, a maximal dynamic
      error based on the maximal expected rate of concentration change must be employed
      to estimate the worst-case error because the actual instantaneous rate is not
      independently known. Values of dynamic delay and maximal dynamic error that are
      acceptable in particular monitoring situations can be used in the design of
      acceptable continuous biosensors. This analysis suggests experimental
      alternatives to the standard response time approach for sensor characterization
      that are particularly advantageous for continuously operated biosensors. The
      concepts are applied here to in vitro operation of a continuous glucose sensor.

PMID- 8651497
TI  - Three-dimensional motional stabilization in the trapping field of an open-ended
      trapped-ion cell: application to the remeasurement experiment in Fourier
      transform ion cyclotron resonance mass spectrometry.
AB  - Three-dimensional motional stabilization of radial trajectories of low-mass
      organic ions in an open cell using only a dc trapping field is applied to the FT
      ICR remeasurement experiment. More than 300 remeasurement cycles are observed
      with 99.59% remeasurement efficiency for benzene (m/z 78) using a high-pressure
      helium buffer gas. The enhancement in remeasurement efficiency is due to
      collisional stabilization of the guiding center of ion motion by dynamic motional
      averaging in the axial position-dependent radial electric field. Such dc-induced
      radial stabilization is in contrast to the stability produced by application of
      radio frequency fields characteristic of quadrupolar axialization or rf-only mode
      operation. The same effect is produced because ions experience a radial
      "pseudopotential" during axial oscillation as in time-varying fields. Trajectory
      simulations for ions oscillating in an open cell trapping well above a z
      amplitude critical threshold energy of 0.60 eV (in a potential well of 0.84 V)
      indicate that radially stabilized trapping motion is achieved because the outward
      directed radial electric field existing near the cell center line is compensated
      by an opposing inward-directed radial electric field at extended z-amplitude.
      Sufficient axial kinetic energy permits ion penetration into the inward-directed
      radial electric field regions, enabling > 50% residence time of each trapping
      oscillation period in regions inducing radial stability, thereby inhibiting
      magnetron radius growth. A high-pressure, low-mass buffer gas such as helium
      provides the requisite increase in the axial amplitude of the ion cloud, similar
      to the mechanism observed for axial excitation of low-mass ions observed in
      collision-induced dissociation. The result is radial stability at high pressure,
      even after multiple remeasurement cycles. An optimized excitation radius of 12.5%
      of the cell radius yields maximum remeasurement efficiency with a 500 ms
      relaxation delay between excitation events. Summed signal intensity decreases
      with increased trap potential due to the greater radial electric field and
      reduced axial expansion of the ion cloud and also decreases with buffer gas mass
      in response to greater radial scattering.

PMID- 8651498
TI  - Application of sulfated cyclodextrins to chiral separations by capillary zone
      electrophoresis.
AB  - Mixtures of randomly substituted sulfated cyclodextrins (degree of substitution,
      approximately 7-10) were successfully used as chiral additives for the
      enantioseparation of 56 compounds of pharmaceutical interest, including
      anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines,
      antihypertensives, antimalarials, relaxants, and bronchodilators. The separations
      were accomplished at pH 3.8, with the anode at the detector end of the column.
      Under these conditions, in which electroosmotic flow is directed toward the
      injection end of the column and the electrophoretic mobility of the negatively
      charged cyclodextrin is toward the detector, none of the analytes reached the
      detector in the absence of the sulfated cyclodextrin. Most (40) of the
      successfully resolved enantiomers contained basic functionality and a stereogenic
      carbon. However, the versatility of this sulfated cyclodextrin additive was also
      demonstrated by the fact that three atropisomers, 1,1'-binaphthyl-2,2'-diyl
      hydrogen phosphate, 1.1'-binaphthyl-2,2'-diol, and Troger's base, and several
      neutral analytes were also successfully enantioresolved under these conditions.
      The separation mechanism seems to involve inclusion complexation.

PMID- 8651500
TI  - Analytical properties and sensor size effects of a micrometer-sized optical fiber
      glucose biosensor.
AB  - A micrometer-sized fiber-optic fluorescence biosensor for glucose has been
      fabricated. The sensor is 100 times smaller than existing glucose optodes. It is
      based on the enzymatic reaction of glucose oxidase that catalyzes the oxidation
      of glucose to gluconic acid and hydrogen peroxide while consuming oxygen.
      Tris(1,10-phenanthroline)ruthenium chloride, an oxygen indicator, is used as a
      transducer. The ruthenium complex and glucose oxidase are incorporated into
      acrylamide polymer that is attached covalently to a silanized optical fiber tip
      surface by photocontrolled polymerization. A study of the dependence of the
      fluorescence intensity on sensor size shows that, under normal operating
      conditions, the signal decreases with the sensor diameter rather than its volume.
      Also, the response of micrometer-sized sensors is improved by about 20% compared
      to that of larger fiber-optic glucose sensors. Due to its small size and the lack
      of membrane support, the response time of the sensor is only 2 s. An absolute
      detection limit of around 1 x 10(-15) mol is achieved. The new glucose sensor is
      at least 25 times faster and its absolute sensitivity 5-6 orders of magnitude
      higher than that of current glucose optodes.

PMID- 8651499
TI  - A sulfated cyclodextrin chiral stationary phase for high-performance liquid
      chromatography.
AB  - A new sulfated beta-cyclodextrin (degree of substitution approximately 13
      14/cyclodextrin) bonded chiral stationary phase (CSP) for high-performance liquid
      chromatography is introduced. The novel CSP was used to resolve a number of
      enantiomeric pairs, including antihistamines, antidepressants and
      phenylhydantoins, using HPLC under a variety of mobile phase conditions. Among
      the 33 analytes successfully enantioresolved, all but six had some amine
      functionality. Generally, the best separations were obtained for analytes in
      which the stereogenic center was either incorporated in a ring system or
      positioned between two aromatic rings. Retention seemed to arise from either
      inclusion complexation or electrostatic interactions. Ionic strength and pH were
      found to influence chiral recognition.

PMID- 8651501
TI  - Fluorescent fiber-optic calcium sensor for physiological measurements.
AB  - A new optical sensor based on covalent immobilization of a newly synthesized
      calcium-selective, long-wavelength, fluorescent indicator has been constructed,
      with a response dynamic range optimal for physiological measurements.
      Immobilization occurs via photoinitiated copolymerization of the indicator with
      acrylamide on the distal end of a silanized 125 micrograms diameter multimode
      optical fiber. The working lifetime of this sensor is limited only by
      photobleaching of the indicator. Due to the inherent hydrophilic nature of the
      acrylamide polymer, the response time of this new sensor is governed by simple
      aqueous diffusion of the ionic calcium. This results in sensor response times
      fast enough to monitor some concentration fluctuations at physiological rates.
      The ability to monitor calcium concentration fluctuations in a high background
      level of magnesium is also demonstrated with a calculated selectivity of 10(
      4.5).

PMID- 8651502
TI  - Detection and identification of benzo[a]pyrene diol epoxide adducts to DNA
      utilizing capillary electrophoresis-electrospray mass spectrometry.
AB  - Capillary zone electrophoresis (CZE) coupled with negative ion electrospray mass
      spectrometry (ES-MS) is used for the detection and identification of adducts
      formed from the reaction of DNA with (+/-)-anti-7,8,9,10-tetrahydrobenzo[a]pyrene
      7,8-diol 9,10-epoxide (BPDE),an active metabolite of benzo[a]pyrene (BaP).
      Results presented in this paper demonstrate low nanogram detection limits ( < 10
      ng or < 15 pmol) for normal scan spectra and collision-induced dissociation
      spectra of the main nucleotide adduct formed from this reaction. (BPDE reacts
      predominantly with the exocyclic amino group of guanine.) Exploitation of
      selective reaction monitoring (SRM) produces detection limits in the low picogram
      range ( < 85 pg or < 130 fmol). The application of sample stacking significantly
      increases the concentration detection limit (to approximately 10(-8) M).
      Nucleotide adducts are negatively charged at most pHs and are therefore ideally
      suited to the stacking process used in this research. These techniques have been
      applied to the analysis of the adducts formed from the in vitro reaction of BPDE
      with DNA. In addition it is shown that CZE-ES-MS, combined with solid-phase
      sample cleanup, can detect adducts at levels of four adducts in 10(7) unmodified
      bases or less.

PMID- 8651503
TI  - Effect of surface-attached heparin on the response of potassium-selective
      electrodes.
AB  - Heparin (or hydrolyzed heparin) was covalently attached on the surface of
      derivatized cellulose triacetate membranes, which were subsequently impregnated
      with the potassium-selective ionophore valinomycin. The resulting ion-selective
      electrodes presented near-Nernstian response to potassium and had selectivity
      coefficients of the same order of magnitude as those of conventional poly-(vinyl
      chloride)-based electrodes. It was found that the heparin layer does not alter
      significantly the response characteristics of the electrodes. The biological
      activity of the immobilized heparin (or hydrolyzed heparin) was measured in terms
      of its inactivation of blood coagulation factor Xa. It was found that the
      covalently anchored hydrolyzed heparin was not biologically active, but the
      immobilized heparin was able to inactivate factor Xa. Therefore, by covalently
      attaching heparin on the surface of ion-selective electrodes, electrodes with
      improved blood compatibility characteristics may be prepared.

PMID- 8651504
TI  - Neuronal circuitry of the lower urinary tract; central and peripheral neuronal
      control of the micturition cycle.
AB  - A new presentation technique is introduce to describe the neuronal circuitry
      involved in the control of the uropoetic system and its control mechanisms during
      the micturition cycle. This method is based on the preparation of flow charts and
      is applied to the discussion of four qualitative models which are derived from
      the literature. Opinions concerning the reflex arcs and supraspinal connections
      said to be involved in micturition and continence are different and sometimes
      contradictory. Little is known about supraspinal (inter)connections and their
      function in micturition control is still fragmentary. The control mechanisms
      which terminate voiding are not totally clear. Moreover, the role of the pelvic
      floor musculature in the control of the lower urinary tract is probably
      underestimated. The flow charts presented in this paper contribute to the future
      design of a single complete qualitative model representing the general central
      and peripheral nervous connections and control mechanisms. Such a model would
      provide an approach for future research in neuromodulation and neurostimulation
      of the uropoetic system and a reduced version could be used for quantitative
      modelling, e.g. in neural network simulations.

PMID- 8651505
TI  - Differential expression of N-CAM, vimentin and MAP1B during initial pathfinding
      of olfactory receptor neurons in the mouse embryo.
AB  - Olfactory receptor neurons extend their primary axons from the nasal epithelium
      to the olfactory bulb primordium via the frontonasal mesenchyme. In the present
      study, expression of neuronal markers (vimentin and MAP1B) and N-CAM was
      immunohistochemically investigated in the development of the olfactory system in
      mouse embryos. Expression of vimentin and MAP1B was first observed at early day
      10 of gestation (D10) in the posterosuperior region of the medial nasal
      epithelium, while N-CAM was initially detected in the mesenchyme adjacent to the
      vimentin- and MAP1B-positive nasal epithelium. As development proceeded, the
      localization of neuronal marker-positive cells was mostly included in the N-CAM
      positive region. In addition, we adopted in situ labelling with vital dye (DiI)
      to directly determine the localization of the olfactory nerve and N-CAM on the
      same sections. We demonstrated that most extending axons were located in the N
      CAM positive region. These results suggest that the expression of N-CAM plays a
      crucial role in the initial pathfinding of the olfactory nerve.

PMID- 8651506
TI  - Pax-1 in the development of the cervico-occipital transitional zone.
AB  - The Pax-1 gene has been found to play an important role in the development of the
      vertebral column. The cervico-occipital transitional zone is a specialized region
      of the vertebral column, and malformations of this region have frequently been
      described in humans. The exact embryonic border between head and trunk is a
      matter of controversy. In order to determine a possible role of Pax-1 in the
      development of the cervico-occipital transitional zone we studied the expression
      of this gene in a series of quail embryos and murine fetuses with in situ
      hybridization and immunohistochemistry. Pax-1 is expressed in all somites of the
      embryo, including the first five occipital ones. During embryonic days 3-5 the
      gene is down-regulated in the caudal direction within the first five somites,
      whereas more caudally Pax-1 is strongly expressed in the cells of the
      perinotochordal tube. In 5-day-old quail embryos, the cartilaginous anlage of the
      basioccipital bone has developed and ther is no more expression of Pax-1 in this
      region. The fusion of the dens axis with the body of the axis also coincides with
      switching off of the Pax-1 gene. More caudally, the gene is continuously
      expressed in the intervertebral discs of murine embryos and therefore seems to be
      important for the process of resegmentation. Quail embryos do not possess
      permanent intervertebral discs. ?Hyper-? or ?hyposegmentation? defects may be
      explained by an over- or under-expression of Pax-1 during development. We also
      reinvestigated the border between the head and trunk in chick embryos by
      performing homotopical grafting experiments of the 5th somite between chick and
      quail embryos.

PMID- 8651507
TI  - An investigation of a possible direct projection from the medial nucleus of the
      cerebellum to the paraventricular nucleus of the hypothalamus in the rat: a study
      using retrograde WGA-HRP and Fluoro-Gold tracing techniques.
AB  - Retrograde transport of lectin-conjugated horseradish peroxidase and Fluoro-Gold
      was used in an attempt to obtain data to confirm the existence, predicted from
      physiological studies, of a direct, monosynaptic projection from the medial
      nucleus of the cerebellum (MN) to the paraventricular nucleus of the hypothalamus
      (PVH) in the rat. Injections of these two tracers that included the PVH and
      surrounding diencephalic structures, or that in the case of Fluoro-Gold were
      localized to the PVH, resulted in retrograde neuronal labeling in widely
      separated nuclei known to project to the areas included in the injection sites.
      Thus, effective uptake and transport of both tracers occurred under the
      experimental conditions employed in this study. However, injections confined to
      the PVH and regions of the hypothalamus adjacent to it, or to the PVH alone,
      produced no retrograde neuronal labeling in the medial nucleus, indicating that
      the MN does not project directly to the PVH. Alternative explanations for the
      findings from physiological experiments were sought. The possibility that
      electrical stimulation of fibers of passage through the region of the MN might
      produce a monosynaptic response in the contralateral PVH was discarded, because
      retrogradely labeled neurons in nuclei such as the locus ceruleus and lateral
      parabrachial nucleus were distributed mainly ipsilateral to hypothalamic
      injection sites. However, tracer injections into the MN produced retrograde
      labeling of neurons in the same region of the lateral paragigantocellular nucleus
      (LPGi) in which labeled cells were found following tracers injections into the
      PVH. Axon collaterals of individual neurons in the LPGi might, therefore, project
      both to the MN and to the PVH. The possibility that such a circuit could, in the
      absence of a direct MN to PVH projection, provide the basis to explain the
      physiological findings is discussed.

PMID- 8651508
TI  - Distribution of NADPH-diaphorase activity in the embryonic chicken gut.
AB  - The appearance and distribution of NADPH-diaphorase activity in neuronal cells
      and fibres in different regions of the embryonic chicken gut was studied
      histochemically using whole mount preparations and cryostat sections. NADPH
      diaphorase activity was detected in neuronal cell bodies as early as embryonic
      day 5.5 (E5.5 - the earliest age examined), mainly in the foregut, although some
      positive cells were also seen in the hindgut at this stage. NADPH-diaphorase
      positive fibres were first detected in the developing nerve tracts which connect
      the ganglia at E5.5. The complexity of the network was maximal in the
      proventriculus-gizzard junction. By E9.5, NADPH-diaphorase-positive fibres were
      found in the circular muscle layer. NADPH-diaphorase-positive submucosal neurons
      were first detected at E11.5. The density of innervation was maximal at E15.5 and
      declined later development. The expression of neuronal NADPH-diaphorase activity
      progressed in a craniocaudal direction and followed a developmental pattern
      similar to that previously described for several neuropeptides in the avian gut.

PMID- 8651509
TI  - Transient local presence of nerve fibers at onset of secondary ossification in
      the rat knee joint.
AB  - In view of recent evidence that nerves may be involved in bone formation, the
      present study examines the local occurrence of axons at the onset of secondary
      ossification center formation in the knee region of developing rats. Radiographic
      and histological examination showed that secondary ossification center formation
      commenced at day 10. At day 15 the epiphyseal ossification had reached a
      relatively mature state. As seen by light microscopy, cartilage canals first
      appeared at day 5, reaching the epiphyseal center by day 9. Axons exhibiting a
      neurofilament-like immunoreactivity emerged from the perichondrial plexa into the
      cartilage canals. Many calcitonin gene-related peptide (CGRP)-immunoreactive
      axons were found in the canals, as well as in the perichondrium. Axons with
      tyrosine hydroxylase-like immunoreactivity were not found in the canals, but such
      fibers occurred in relation to blood vessels at other sites. The canal-related
      axons disappeared between days 13 and 15, and the canals themselves did not
      persist beyond bone formation. As seen in the electron microscope, an individual
      canal contained 3-10 unmyelinated Schwann cell-enclosed axons with diameters of
      0.1-2.0 microM. These observations show that putative sensory unmyelinated axons
      with CGRP-and SP-like immunoreactivity are transiently present during initiation
      of bone formation in developing epiphyses. Whether there is a causal relation
      between transient innervation and osteogenesis remains to be determined.

PMID- 8651510
TI  - Activity of acetylcholinesterase and unspecific cholinesterase during
      differentiation of somites in mouse embryos.
AB  - During the development of somites in mouse embryos, widespread activity of
      unspecific cholinesterase (BuChE) was demonstrated after prolonged incubation.
      Independent of their position, all somite cells and their derivatives (dermatome,
      myotome and sclerotome) exhibited enzyme activity in the perinuclear space and in
      the endoplasmic reticulum. The plasmalemma did not show any enzyme activity.
      Differentiation of the sclerotome into vertebrae was accompanied by a reduction
      of BuChE. However, a low enzyme reaction was still present in the first typical
      differentiated chondroblasts. Notochordal cells were detectable by their high
      BuChE content. This was also found in cells already showed severe degeneration.
      In addition to BuChE, acetylcholinesterase (AChE) was first visible of day 9 of
      embryonic development in newly formed myotubes of the myotomes. Some hypotheses
      on the functional significance of of embryonic BuChE are discussed in the light
      of these results.

PMID- 8651511
TI  - The morphology of valves and valve-like structures in the canine and feline
      thoracic duct.
AB  - The microanatomy and ultrastructure of the feline and canine thoracic duct and
      afferent lymphatics were studied by scanning and transmission electron
      microscopy. We found that the lymphatic vessels were always terminated by ostial
      valves of two shapes, crescent- and navicular-like, in a ratio of 4:1. Specific
      regulatory structures along the free edges of the valves, including marginal
      thickenings and buttresses, are described. The tissue and cellular organization
      of the valve endothelium showed distinct peculiarities, particularly in the
      orientation and shape of the cells and their microrelief. We found that valvular
      endothelial cells, especially ?tip cells?, which are situated in unfavourable
      lymphodynamic conditions, were characterized by an increased volume density of
      intermediate (probably vimentin-based) filaments, suggesting an accommodative
      mechanism involving such filaments.

PMID- 8651512
TI  - Development of Reichert's membrane in the early mouse embryo.
AB  - Although the composition of Reichert's membrane, a thick multilayered basement
      membrane between the parietal endoderm cells and the trophoblast cells of
      rodents, has often been investigated, the site of its production remains a
      subject of controversial discussion. In particular, the role of the trophoblast
      cells is unclear. In the present work we examined the initial development of
      Reichert's membrane in the early mouse embryo, using glutaraldehyde fixation with
      tannic acid. In the early blastocyst the occurrence of a tannic-acid-positive
      layer located at the inner surface of the mural trophoblast indicated the onset
      of basement membrane formation by the trophoblast cells. In the peri-implantation
      phase, this basement membrane extended into lateral areas of the inner cell mass
      separating the newly differentiated ectoderm and endoderm cells from each other.
      In these lateral regions, where the recently formed primitive endoderm cells had
      been attached to the monolayered basement membrane of the mural trophoblast
      cells, followed by an apposition of basement membrane material, probably
      synthesized by primitive endoderm cells, along this primary membrane.

PMID- 8651513
TI  - Critical period in muscle spindle regeneration in grafts of developing rat
      muscles.
AB  - Extensor digitorum longus (EDL) muscles from rats at various intervals after
      birth were grafted into EDL muscles of adult recipients. Three to twelve months
      after the operation, host muscles containing the grafts were removed and examined
      for the presence of muscle spindles in the graft. The aim of the study was to
      establish when muscle spindles become capable of regeneration during development.
      Regenerated muscles grafted during the first week after birth were virtually
      spindleless. Grafts of muscles transplanted 10 and 15 days postnatally contained
      only 5-8 muscle spindles on average. In contrast, the regenerated grafts
      originating from muscles of 24- and 28-day-old rats were spindle-rich as in
      mature muscle grafts; the number of spindles in the transplanted EDL muscles
      (25.0 +/- 2.3; mean +/- SE) attained values comparable to free standard
      autografts of these muscles in adult animals. Thus, the critical period after
      grafting, which also involves the loss of a vascular supply, is considerably
      longer than the critical period for muscle-spindle survival after nerve injury.
      Fifteen days after birth, when muscle spindles still survive denervation, only a
      few regenerated spindles were present in the individual muscle regenerates. We
      assume that the low resistance of immature spindle capsules to ischaemia accounts
      for their massive degeneration and abortive spindle regeneration in grafts from
      10- to 15-day-old rats.

PMID- 8651514
TI  - Risk factors for infectious complications after abdominal surgery for malignant
      disease.
AB  - BACKGROUND: The emergence of nosocomial infection as a serious complication after
      intraabdominal operations for cancer prompted us to identify major independent
      risk factors associated with postoperative infection. METHODS: Risk factors were
      studied in single and multivariate analyses. Variables considered were remote
      infection, antimicrobial prophylaxis, preoperative stay, chemotherapy,
      radiotherapy, weight loss, elective versus emergency operation, wound class,
      duration of operation, drains, sex, age, and physical status. RESULTS: During 24
      months, 236 patients were entered in the study. The overall postoperative
      infection rate was 45.7%; the surgical site infection rate was 22.4%.
      Multivariate analysis identified three independent variables: duration of
      operation longer than 5 hours (odds ratio 6.41, 95% confidence interval 3.28 to
      12.54), presence of remote infection at operation (odds ratio 3.76, 95%
      confidence interval 1.76 to 8.03), and preoperative stay longer than 22 days
      (odds ratio 2.03, 95% confidence interval 1.04 to 3.95). The relative risk of
      infection increased from 3.0 when one risk factor was present to 7.3 when all
      three risk factors were present. CONCLUSIONS: The predictive power of our final
      multivariate risk index clearly groups these patients according to differing risk
      for postoperative infection. This classification contributes substantially to the
      effectiveness of infection control strategies to prevent the occurrence of
      postoperative infection in the high-risk population of patients with cancer.

PMID- 8651515
TI  - Nosocomial mumps: report of an outbreak and its control.
AB  - BACKGROUND: Mumps is a relatively uncommon disease in the United States, and
      nosocomial transmission of mumps is rare. METHODS: When a recently arrived
      Mexican immigrant became ill with mumps in a pediatric hospital in the United
      States, control measures and careful secondary case surveillance were instituted.
      Outbreak control included isolation of the patient with symptoms, seclusion of
      patients potentially incubating mumps virus, and immunization of susceptible
      patients and health care workers. RESULTS: A 3-year-old patient showed symptoms
      of mumps 18 days after onset of illness in the index patient. Two employees, a
      physical therapist and a nurse, became ill with mumps 20 and 28 days after the
      onset of illness in the index patient. No other hospital or community cases of
      mumps were identified. CONCLUSIONS: Outbreak control measures were incompletely
      successful in stopping the spread of mumps. Preadmission immunization of all
      patients and mumps-specific screening and vaccination of hospital employees might
      be indicated in such a situation, but such measures are neither easy nor
      inexpensive.

PMID- 8651516
TI  - Mycobacterium gordonae in fiberoptic bronchoscopes.
AB  - BACKGROUND: Failure of high-level disinfection of bronchoscopes has caused
      several outbreaks of nosocomial infection or pseudoinfection involving
      mycobacteria. METHODS: Inocula (10(5) colony-forming units/ml and 10(8) colony
      forming units/ml) of a clinical Mycobacterium gordonae isolate were used to
      contaminate bronchoscopes. Glutaraldehyde, iodophor, and peracetic acid
      disinfectants were evaluated in manual and automated disinfection procedures
      after 10- to 20-minute exposures at 20 degrees and > or = 25 degrees C. RESULTS:
      Four of five manual disinfectant procedures failed to eliminate experimental M.
      gordonae infection after 10-minute exposure at 20 degrees C. All five manual
      procedures tested at 20 degrees C were effective after 20-minute exposure to the
      five disinfectants (two 2% alkaline glutaraldehyde preparations, 3.2% alkaline
      glutaraldehyde, 75 ppm iodophor, and 0.5% glutaraldehyde-0.03% phenolic). Three
      of four manual (one 2% glutaraldehyde, 3.2% glutaraldehyde, and 0.5%
      glutaraldehyde-0.03% phenolic) and three automated (one 2% glutaraldehyde, 0.5%
      glutaraldehyde-0.03% phenolic, and 0.2% peracetic acid) disinfectant procedures
      eliminated contamination after a 10- to 12-minute exposure at > or = 25 degrees
      C. Effective total cycle times for the three automated procedures ranged from 20
      to 45 minutes. CONCLUSIONS: Previously Environmental Protection Agency-approved
      tuberculocidal agents may be ineffective against M. gordonae when used according
      to label claims under normal clinical conditions. A minimum 20-minute exposure
      time at 20 degrees C is necessary for manual disinfection methods. Higher
      temperatures may improve disinfectant efficacy. Newer automatic disinfection
      machines may be as effective as traditional manual methods and also may reduce
      hazards to employees.

PMID- 8651517
TI  - Guideline for isolation precautions in hospitals. Part I. Evolution of isolation
      practices, Hospital Infection Control Practices Advisory Committee.

PMID- 8651518
TI  - Guideline for isolation precautions in hospitals. Part II. Recommendations for
      isolation precautions in hospitals. Hospital Infection Control Practices Advisory
      Committee.

PMID- 8651519
TI  - Departmental role and scope in infection control: use of a template that meets
      Joint Commission requirements.
AB  - Since its inception in 1990, departmental role and scope in the infection control
      program have developed into the five important aspects currently defined by the
      Joint Commission. Each health care worker needs to understand his or her role in
      infection prevention and control, integrate it into daily activities, and
      articulate this role to others. This strategy for complying with Joint Commission
      standards meets customer needs and can easily be adapted for use in other medical
      centers. The process of defining departmental roles in the infection control
      program will continue to evolve with increased awareness of customer needs and
      emphasis on continuous quality improvement.

PMID- 8651520
TI  - Positive tuberculin skin test reactions among house staff at a public hospital in
      the era of resurgent tuberculosis.
AB  - BACKGROUND: The number and significance of tuberculin skin test reactions were
      compared with self-reported baseline values among house staff working in a public
      hospital. High-risk medical specialties, locations, and infection control
      practices were examined. METHODS: House staff interviews, tuberculin skin test
      applications, review of employee health service records, and environmental
      monitoring of high-risk areas were performed. RESULTS: Among house staff self
      reported as having negative tuberculin skin test status, 46.2% (95% CI 27.0% to
      65.4%) of internal medicine house staff, compared with 4.8% (95% CI 4.3% to
      13.9%) of house staff from other areas (p < 0.005), had positive results on a
      repeat tuberculin skin testing before graduation. These differences were not
      entirely explained by the use of surgical masks, year of training, or previous
      vaccination with bacille Calmette-Guerin. Most skin test reactions (69%) occurred
      among house staff who had not been vaccinated with bacille Calmette-Guerin.
      Increased skin reactivity probably represented excess conversions from
      unprotected exposure. Tuberculosis transmission was facilitated by delays in
      diagnosis, inadequate isolation facilities, and suboptimal ventilation. House
      staff did not comply with recommended tuberculosis surveillance because of time
      constraints, fear, and misunderstandings about tuberculin skin test
      interpretations in light of previous bacille Calmette-Guerin vaccination.
      CONCLUSIONS: House staff in high-exposure settings with suboptimal environmental
      controls are at increased risk for tuberculosis infection. Participation in
      surveillance programs can be increased by enlisting the participation and
      advocacy of respected medical colleagues, screening house staff differentially
      according to exposure and job classifications, and more accurately interpreting
      subsequent test results from baseline two-step testing.

PMID- 8651521
TI  - Surgical aspects of MEN I syndrome.
AB  - Multiple endocrine neoplasia (MEN) Type I syndrome is a rare tumor of unknown
      etiology with a prevalence of 0.02 to 0.2 per 1000. Some of the tumors associated
      with MEN I include pituitary adenomas, parathyroid adenomas, hyperplastic tissue,
      and pancreatic B and non-B islet cell tumors. The clinical presentation is
      usually secondary to the specific hyperfunction characteristic of the different
      endocrine glands. Hyperparathyroidism and hypercalcemia precede all other
      manifestations in the majority of cases. Surgery plays a major role in
      management, and the condition should be considered when a tumor is diagnosed
      along the endocrine axis of glands, especially in hyperparathyroid patients.

PMID- 8651522
TI  - Conservative management strategy for pancreatitis-associated mesenteric venous
      thrombosis.
AB  - Mesenteric venous thrombosis is a rare, but potentially lethal, complication of
      pancreatitis. Although management is usually directed toward the underlying
      pancreatitis, there is no standard defined for treatment of the associated
      mesenteric venous thrombosis. Anticoagulant therapy was chosen as treatment for
      the case presented in this report, but other management methods for this entity
      have been described in the literature. Based on our experience and review of the
      literature, a management strategy for patients with pancreatitis-associated
      mesenteric venous thrombosis has been developed.

PMID- 8651523
TI  - Fludarabine phosphate: A DNA synthesis inhibitor with potent immunosuppressive
      activity and minimal clinical toxicity.
AB  - Fludarabine phosphate selectively eliminates normal and malignant mononuclear
      cells in large animals and man through the inhibition of DNA synthesis. The drug
      depletes mononuclear cells from culture within 24 hours of initial exposure, CD4
      and CD8 T cells being more sensitive than either CD20 B cells or CD34 bone marrow
      precursors. Mitogenic activation of lymphocytes enhances cellular elimination
      from culture. Fludarabine inhibits PHA-induced T-cell proliferation by >90 per
      cent and mixed lymphocyte reactions (allogeneic and xenogeneic) by >95 per cent.
      Fludarabine exerts its cytolytic effects through the induction of endonuclease
      independent apoptosis. A 5-day course of fludarabine (50 mg/m2 intravenously once
      daily) induces both T- and B-cell lymphopenia in Cynomolgus monkeys and Papio
      baboons. Transient neutropenia was the only side-effect seen in experimental
      animals. Pretreatment of Cynomolgus monkeys with this regimen of fludarabine
      causes a prolongation of ABO-compatible skin allograft survival from 8 days
      (control) to 16 days (drug treated group). Secondary allotransplantation into
      presensitized recipients showed a similar prolongation of graft survival with
      fludarabine pretreatment (8 days vs 5 days control). Fludarabine promises to be a
      potent immunosuppressive agent with low clinical toxicity.

PMID- 8651524
TI  - The use of omentum in mesh repair of ventral hernias.
AB  - In mesh repairs of abdominal wall defects, contact of the prosthesis with the
      abdominal viscera must be prevented. The omentum may be used to complete tension
      free repair of these defects when dissection of the peritoneum is difficult or
      when there is insufficient peritoneum or posterior rectus sheath to close the
      peritoneal cavity.

PMID- 8651525
TI  - Urgent endoscopic retrograde pancreatography the stable trauma patient.
AB  - Major ductal injury is a determinant of outcome after blunt pancreatic trauma.
      The retroperitoneal location makes physical examination and diagnostic peritoneal
      lavage unreliable, and computed tomography does not demonstrate ductal integrity.
      Urgent endoscopic retrograde pancreatography clearly delineates ductal anatomy,
      facilitating management of this potentially devastating injury.

PMID- 8651526
TI  - Temporal arteritis: diagnostic and therapeutic considerations.
AB  - BACKGROUND: Giant cell arteritis of surgical significance includes two clinical
      entities, temporal arteritis and Takayasu's arteritis, and they are
      pathologically indistinguishable from one another. This study summarizes our
      experience in 21 cases of temporal arteritis during a recent 5-year period.
      Patient Population and Results: This study includes patients who were discharged
      with a clinical diagnosis of temporal arteritis. There were 12 women and 9 men,
      with a mean age of 69 years. Six patients were admitted with an initial diagnosis
      of polymyalgia rheumatica, nine with severe headache and/or nonspecific symptoms,
      three with ischemic symptoms of the limbs, one with a cerebrovascular accident,
      one with syncope, and one with osteomyelitis of the limb. The sedimentation rate
      ranged from 26 to 110, with a mean of 41. Eight patients had a preoperative
      duplex ultrasound of their temporal arteries; six of these had a peak systolic
      velocity of 2 > or = 200 cm/s, and five had a positive temporal artery biopsy.
      Nineteen patients had temporal artery biopsies, 15 were positive for giant cell
      arteritis, and the diagnosis was not conclusive in 4. All patients were treated
      with prednisone with a satisfactory outcome, except for two who had ischemic
      symptoms of the upper extremity requiring a carotid-axillary artery bypass in one
      and a carotid-brachial artery bypass in the other. Both patients had satisfactory
      outcomes after surgery. CONCLUSIONS: The primary treatment of temporal arteritis
      is medical, and surgery should be reserved for severe specific disabling symptoms
      that have failed medical therapy. Duplex ultrasound might be helpful in
      predicting the side and location for temporal artery biopsy.

PMID- 8651527
TI  - Is routine drainage of pelvic anastomosis necessary?
AB  - The routine use of drains for pelvic anastomosis is controversial. This study was
      undertaken to determine whether drainage alters leak rate, aids in diagnosing a
      leak, and/or prevents the need for laparotomy when a leak occurs. Records of 156
      consecutive patients who underwent elective resection and pelvic anastomosis for
      cancer from 1986 to 1994 were retrospectively reviewed. The patients were
      stratified into two parent groups, I and II. One hundred and eleven Group I
      patients who routinely had Jackson-Pratt 10-mm drains inserted were subdivided
      into subgroup I-A (n = 24) with proximal intraoperative diversion and subgroup I
      B (n = 87), without diversion. Forty-five Group II patients routinely did not
      have drains inserted. They were also subdivided, into II-A (n = 3) and II-B (n =
      42), i.e., with and without simultaneous diversion, respectively. The overall
      leak rate was 5.1 per cent (8/156). Subgroups I-A and II-A had leak rates of 8.33
      per cent (2/24) and 0 per cent (0/3), respectively. The leak rates were 4.6 per
      cent (4/87) in subgroup I-B and 4.8 per cent (2/42) in subgroup II-B, with no
      significant difference (P > 0.05). Also, no significant difference was noted when
      the overall leak rate for diverted cases was compared with nondiverted ones. Of
      the four leaks in I-B, three occurred after the drains were removed; two of these
      required laparotomy, drainage, and diversion. The fourth occurred with the drain
      in place, but failed to demonstrate feces or pus in the drainage fluid or prevent
      the need for laparotomy. The presence of a drain did not affect the leak rate (P
      > 0.10). Drain contents did not aid in diagnosing anastomotic dehiscence. Routine
      prophylactic use of Jackson-Pratt drains seems unjustified because leaks either
      occurred after the drains were removed or failed to prevent the need for
      laparotomy.

PMID- 8651528
TI  - Breast cancer evaluation and follow-up: a survey of The Ohio Chapter of The
      American College of Surgeons.
AB  - Preoperative evaluation and postoperative follow-up of breast cancer patients
      vary considerably. Recent literature suggests that routine surveillance studies
      for breast cancer patients can be reduced without compromising the outcome. The
      Ohio State Chapter of The American College of Surgeons Committee on Cancer
      sponsored a survey of its general surgeon fellows to determine their practice
      philosophies regarding these issues. The questions centered around breast cancer
      screening, evaluation and treatment, and follow-up. The fellows were also
      questioned as to their opinions regarding practice parameters and whether the
      State Chapter should take a role in this area. Of the 764 surveys sent out, 34.2%
      were appropriate for evaluation. For breast cancer screening, 96.1% believe
      yearly mammography is important. Newly diagnosed breast cancer patients are
      generally evaluated with history and physical exam, chest X-ray, complete blood
      cell count, and liver function tests. Bone scans are used by 38.6% of surgeons.
      Most patients with positive lymph nodes see a medical oncologist. About half of
      primary breast cancer treatment (44.7%) is by breast preservation. Essentially
      all surgeons follow their patients after treatment for breast cancer
      surveillance. Essentially all surgeons feel that physical exam and mammograms are
      important for post-treatment follow-up. Complete blood cell count, liver function
      studies, and chest X-rays are used less commonly but still by more than half of
      the surgeons. 44.4% of the surgeons have found difficulty with third-party payers
      covering the costs of surveillance studies. 87.7% of surgeons surveyed felt the
      State Chapter should become involved in establishing clinical guidelines or
      practice parameters.

PMID- 8651529
TI  - Penetrating ureteral injuries: the impact of associated injuries on management.
AB  - The ideal management for penetrating ureteral trauma is primary repair, but the
      effect of other abdominal injuries might preclude this. We attempted to determine
      what factors could be used to predict a poor outcome of a ureteral anastomosis,
      so that the initial management can be modified appropriately. The case notes of
      41 patients treated for penetrating ureteral trauma were studied retrospectively.
      Any factors that could influence postoperative complications and outcome were
      statistically analyzed in order to determine which could be used pre- or
      intraoperatively to indicate a poor prognosis for the ureteral anastomosis. The
      presence of shock on admission (P = 0.013), intraoperative bleeding (P = 0.006),
      colonic injury and specifically injury requiring colectomy (P = 0.006) were
      associated with a high complication and mortality rate. Patients presenting with
      penetrating ureteral trauma who are severely shocked and have complicated
      intraoperative hemostasis and patients who require colectomy should not have a
      primary ureteral anastomosis, but rather initial ureteral exteriorization or even
      nephrectomy.

PMID- 8651530
TI  - Exercise-induced compartment syndrome: case report.
AB  - Exercise-induced rhabdomyolysis is a frequent event occurring after severe forms
      of exercise. This is usually a short-lived, uncomplicated phenomenon that is
      seldom of any clinical significance. The rare progression of this muscle injury
      to compartment syndrome is, however, a limb- and life-threatening condition that
      typically presents in the anterior compartment of the lower leg. A case is
      reported of a young man who participated in physical activity well beyond his
      normal level of exertion and subsequently developed bilateral lower extremity
      compartment syndrome requiring surgical decompression. To our knowledge, this is
      the only description of this complication occurring in a multicompartment,
      bilateral distribution. The combination of the rarity and morbidity of this
      condition, as well as the multitude of very common benign injuries that present
      in the same manner as the problem discussed, make this insult especially
      dangerous.

PMID- 8651533
TI  - Ophthalmic thermal injuries.
AB  - Reflex lid closure often protects the eyes during facial burns. Although corneal
      burns are uncommon, other ophthalmic injuries occur more frequently. Ophthalmic
      burns are usually associated with marked facial damage and possible inhalation
      injury. Failure to recognize and appropriately treat ophthalmic burns can lead to
      catastrophic sequelae. We performed a 2-year survey of all facial burns in our
      burn unit. Forty-four patients with thermal facial burns were identified. Sixteen
      patients had ophthalmic injuries. Corneal injury was detected in 13 per cent
      (2/16). Intubation was required in 43.75 per cent (7/16) of patients with
      ophthalmic injuries. Mortality was 25 per cent (4/16). We conclude that patients
      with facial burns severe enough to cause ophthalmic injuries may be associated
      with other lethal injuries, and a high index of suspicion should be maintained
      until all lethal injuries are ruled out. All ophthalmic injuries should be
      evaluated by an ophthalmologist.

PMID- 8651532
TI  - Characteristics of Xanthomonas infections in critically ill surgical patients.
AB  - The aim of our study was to describe the characteristics of Xanthomonas
      infections in a population of critically ill surgical patients. The clinical
      records and microbiological data on 93 patients in a surgical intensive care unit
      (SICU) developing Xanthomonas infections were reviewed. Xanthomonas was isolated
      in 125 sites in the 93 patients. Their average age was 48 years (range, 14-94).
      Mortality occurred in 25 patients (26.9%) versus 10.3 per cent of SICU patients
      in general (P < 0.05). Patients were in the SICU for an average of 11.9 days
      before developing a positive Xanthomonas culture, and 87 per cent (81/93) of
      patients developed an infection at some other site before isolation of
      Xanthomonas. Trimethoprim sulfamethoxazole was the only drug to which the
      isolates were commonly sensitive (123/125 = 98.4%). We conclude that Xanthomonas
      1) is associated with increased mortality; 2) is resistant to many of the drugs
      that usually cover Gram-negative infections; and 3) commonly complicates a
      prolonged intensive care stay, thus serving as a marker for severity of illness.

PMID- 8651531
TI  - Candida arteritis: are GI endoscopic procedures a source of vascular infections?
AB  - A 53-year-old woman, 11 years after a renal transplant on chronic
      immunosuppression, presented with a sudden onset of a painless left groin mass.
      Ultrasound revealed a 3 cm common femoral artery pseudoaneurysm and a 3 cm
      saccular aneurysm of the infrarenal aorta. Operative repair was excision and
      patch angioplasty of the aortic aneurysm with internal iliac artery and
      interposition grafting of the femoral artery aneurysm with saphenous vein.
      Postoperatively, Candida albicans was identified in the aortic and common femoral
      arterial cultures. Candida infections often occur in patients with impaired
      cellular immunity due to seeding from urinary tract infections, vascular
      catheters, or manipulation of the gastrointestinal tract. Our patient, without
      any prior history of a fungal infection, had undergone a colonoscopy 3 weeks
      earlier. Without any other possible source being identified, the proposed
      mechanism for fungal entry into the vascular system was via the gastrointestinal
      tract, with seeding from the portal venous system. The exact medical and surgical
      management of these patients remains undefined, and a transplant vascular
      registry is really needed. However, immunocompromised solid organ transplant
      recipients undergoing gastrointestinal endoscopic procedures may be at a greater
      risk for the development of subsequent septicemia. Further reports are really
      needed to confirm the possible need in these patients for both periprocedural
      antibiotic and antifungal prophylactic coverage.

PMID- 8651534
TI  - Medical-legal pitfalls for the breast surgeon: incomplete mammographic
      localization of suspicious lesions and the correlation between palpable and
      mammographic abnormalities.
AB  - In approximately 5 per cent of mammographically detected lesions, the
      mammographic abnormality is present in only one view, either craniocaudal or
      mediolateral. In such a scenario, the physician has been left with the option of
      closely following the lesion, hoping it will eventually become apparent in two
      views, or guessing the approximate location of the lesion for subsequent open
      biopsy. However, with today's advances in technology, CT scan and its production
      of a three-dimensional image can compensate for mammography's two-dimensional
      limitation. With diminished need for identification on two mammographic views,
      localization in these instances falls more within the realm of possibility. This
      paper highlights Moffitt Cancer Center's experience with CT-directed breast
      biopsy as an alternative to close follow-up or blind-biopsy. In addition, because
      palpable breast abnormalities may not be the same as mammographic abnormalities,
      the report details the accuracy of CT-directed biopsy in allowing the surgeon to
      perform precise open biopsy, thus avoiding medical-legal exposure.

PMID- 8651535
TI  - Evaluation of intrapleural analgesia in the management of blunt traumatic chest
      wall pain: a clinical trial.
AB  - Intrapleural analgesia (IPA) has been successfully used for the relief of chest
      wall pain. Previous studies investigating its use have yielded conflicting
      results and have often suffered from design defects. The theoretical lower
      incidence of respiratory and circulatory depression with IPA suggests significant
      advantages over epidural analgesia. Patients who had documented blunt chest wall
      trauma were entered into a prospective, randomized, double-blinded, crossover,
      placebo-controlled study within 16 hours of their injury. Patients who were
      intubated or had significant trauma outside of the chest wall were not entered.
      Intrapleural catheters were placed using a standardized technique. Each patient
      received either a placebo solution of normal saline or a combination of
      bupivacaine/lidocaine in a blinded, crossover fashion for two 24-hour periods.
      Data were obtained on the use of supplementary narcotics, transcutaneous pCO(2')
      pulse oximetry, pulmonary function tests, and both patient and nursing
      evaluations of pain based on a numeric analogue scale. A series of 16 patients
      from a Level I trauma center were identified over a 2-year period. The ratio of
      male to female was approximately 2:1, with an age range of 35-80 years. There
      were no complications related to catheter placement or anesthetic toxicity. Mean
      values for patient and nursing pain ratings revealed opposite trends. We found no
      significant difference in the mean values for supplemental narcotic use, pCO(2')
      p0(2') forced vital capacity, or forced expiratory volume between the placebo and
      the test solution. Although previous studies have suggested that IPA may be
      beneficial in the management of chest wall pain, this was not confirmed in our
      study for blunt chest injuries. The addition of IPA to the more traditional use
      of opioid analgesics was not more effective for management of blunt chest wall
      pain. Despite our small patient population (n = 16), the crossover design should
      have allowed clinically significant differences to become evident (alpha value =
      0.95). A review of the literature and a historical basis for the evolution in the
      management of this type of pain is included.

PMID- 8651537
TI  - Effect of epidural analgesia on postoperative ileus after ileal pouch-anal
      anastomosis.
AB  - Epidural analgesia has been reported to enhance gastrointestinal motility and
      shorten postoperative ileus. Postoperative ileus can be influenced by many
      factors, including the operative procedure. Our aim was to evaluate the effect of
      supplemental epidural anesthesia and postoperative analgesia on ileus after ileal
      pouch-anal anastomosis (IPAA). This was a retrospective review of 50 consecutive
      nonrandomized patients undergoing IPAA over a 10 year period by a single surgeon.
      27 patients received general anesthesia and parenteral analgesia. 23 patients
      received supplemental epidural anesthesia and analgesia. The two groups were
      comparable with respect to age, sex, diagnosis, and American Society of
      Anaesthesiology status. Operative time, blood loss, and transfusion requirements
      were also similar, but massive (>1,000 mL) blood loss was more frequent in the
      general group (37% vs 13%, P < .05). Twelve (44%) patients in the general group
      and seven (30%) in the epidural group had complications (NS). Mean duration of
      nasogastric suction, tube reinsertion, and interval to taking liquid and regular
      diets was similar in the two groups. Mean pain scores for the first 24 hours were
      significantly lower in the epidural group (1.9 +/- 1.0 vs 2.5 +/- 0.6, P < 0.05).
      Supplemental epidural anesthesia and analgesia does not shorten clinical
      postoperative ileus after a complex colorectal procedure (IPAA).

PMID- 8651536
TI  - Repletion of high energy phosphates in the postischemic neonatal heart.
AB  - Milrinone improves function in failing adult hearts, but it has not been examined
      in the immature myocardium. The purpose of this study was to characterize the
      effects of milrinone, a phosphodiesterase inhibitor, on immature hearts, and
      compare these to dobutamine, a commonly used catecholamine inotrope. One hundred
      isolated working neonatal rabbit hearts were used. Hearts were made ischemic (37
      degrees C) for 1 hour and reperfused for 0, 10, 40, or 70 minutes. In separate
      groups, infusion of milrinone (1.0 microg/mL) or dobutamine (0.1 microg/mL) was
      begun after reperfusion for 10 or 40 minutes. High energy phosphates, total
      nondiffusable nucleotides, cyclic adenosine monophosphate (cAMP), and the percent
      recovery of cardiac output were determined. Cardiac output returned to normal,
      and adenosine triphosphate (ATP) and total nondiffusable nucleotide levels did
      not decline when dobutamine or milrinone were begun after 10 minutes of
      reperfusion. In hearts receiving inotropes after 40 minutes of reperfusion, when
      high energy phosphates were low, ATP increased, and total nondiffusable
      nucleotide repletion was observed. Cardiac output did not improve when inotropes
      were begun after 40 minutes. cAMP was higher in milrinone hearts compared to
      dobutamine, but there was no simple relation between cAMP and ventricular
      function. Inotropes may increase purine salvage pathway activity. Deriving
      maximum benefit from inotropes may depend on beginning infusions early, before
      the appearance of irreversible changes.

PMID- 8651538
TI  - The impact of implementation of neuromuscular blockade monitoring standards in a
      surgical intensive care unit.
AB  - The purpose was to determine whether implementation of standards for peripheral
      nerve monitoring could decrease the incidence of neuromuscular dysfunction
      related to the administration of paralytic agents. Over a 2-year period,
      consecutive patients admitted to a surgical intensive care unit who received
      continuously-infused or >6 daily doses of neuromuscular blocking agents were
      subjected to train-of-four (TOF) monitoring of the adductor pollicis. Therapy was
      titrated to the maintenance of one to two twitches at all times. The incidence of
      prolonged (>12 h) paralysis after drug discontinuation was documented in these
      patients and compared to that in patients treated in the previous 12 months. The
      presence of electrolyte abnormalities, organ dysfunction, and concomitant
      medications was also recorded. Chi-square analysis with Yates correction was
      employed. Before implementation of routine TOF monitoring, there were five
      instances of paralytic-associated neuromuscular dysfunction (5/43). After
      implementation of the TOF protocol, no instances of paralytic-associated
      neuromuscular dysfunction occurred (0/90), despite the same incidence of risk
      factors (100%) (P < 0.05). A protocol for neuromuscular blockade monitoring is
      efficacious in preventing paralytic-associated neuromuscular dysfunction. This
      can be a cost-effective measure, minimizing the prolonged mechanical ventilation
      and intensive rehabilitation required secondary to unmonitored use of
      neuromuscular blocking agents.

PMID- 8651540
TI  - Uncommon valor is a common virtue.

PMID- 8651539
TI  - Is complete laparoscopic colectomy superior to laparoscopic assisted colectomy?
AB  - Much debate has centered around what constitutes a true laparoscopic colon
      resection. Purists argue that intracorporeal division of the mesentery and
      anastomosis confer a benefit over a "laparoscopic assisted" procedure. The aim of
      this study was to further examine this issue. Data were prospectively collected
      on 102 consecutive laparoscopic colon resections. Five procedures were converted
      to open cases and were excluded from analysis. Procedures were divided into two
      groups. Group 1 (n = 34) consisted of complete laparoscopic procedures (no
      abdominal incision was made): abdominoperineal resection (3), Hartmann's reversal
      (3), end colostomy (7), low anterior resection (5), proctectomy (1), sigmoid
      colectomy (15). Group 2 (n = 63) consisted of laparoscopic "assisted" procedures
      (i.e., an incision was made to facilitate anastomosis, division of the mesentery,
      and/or specimen retrieval): Ileocolic resection (6), restorative proctocolectomy
      (26), right colectomy (19), subtotal colectomy/end ileostomy (5), subtotal
      colectomy/ileorectal anastomosis (7). Length of hospitalization and duration of
      postoperative ileus were compared. A subset analysis of right colectomy
      (intracorporeal mobilization and extracorporeal division of the mesentery and
      anastomosis) versus sigmoid colectomy (intracorporeal mobilization, division of
      the mesentery and anastomosis) was also performed. There were no statistically
      significant differences in length of hospital stay (Group 1, 7.47 +/- 2.75 days;
      Group 2, 7.78 +/- 5.55 days) or duration of postoperative ileus (Group 1, 3.24 +/
      1.56 days; Group 2, 3.68 +/- 1.58 days). Similarly, in the sigmoid colectomy
      versus right colectomy subset analysis, there were no statistically significant
      differences in length of hospital stay (sigmoid colectomy, 7.92 +/- 2.90 days;
      right colectomy, 6.40 +/- 1.50 days) or duration of postoperative ileus (sigmoid
      colectomy, 3.36 +/- 1.39 days; right colectomy, 3.18 +/- 1.07 days). Our data
      demonstrate that intracorporeal division of the mesentery and anastomosis confer
      no advantage over the laparoscopic assisted procedures. Data were prospectively
      collected on 102 consecutive laparoscopic colon resections. There were no
      statistically significant differences in length of hospital stay or duration of
      postoperative ileus regardless of whether intracorporeal or extracorporeal
      mesenteric division and anastomosis were undertaken. These data demonstrate that
      a completely laparoscopic procedure does not appear to offer any advantage as
      compared to a laparoscopic assisted one.

PMID- 8651541
TI  - Dr. Werner Forssman's self-experimentation.

PMID- 8651542
TI  - Re: Laparoscopic L5-S1 diskectomy: a cost-effective, minimally invasive general
      surgery-neurosurgery team alternative to laminectomy.

PMID- 8651543
TI  - Re: Central venous catheterization via persistent left superior vena cava.

PMID- 8651544
TI  - Axillary node metastases in relation to size and location of breast cancers:
      analysis of 147 patients.
AB  - This prospective study of 147 patients undergoing axillary lymphadenectomy for
      treatment of breast cancer over a 3 1/2-year period relates frequency and number
      of involved lymph nodes to the size and location of the tumor within the breast.
      A total of 35.3 per cent of patients in the entire series had axillary
      metastases. Of 29 patients with cancers 0-10 mm, five had axillary metastases
      (17.2%). All five cancers were located at the upper outer quadrant (UOQ) of the
      breast. Thirteen of 58 patients with cancers 11-20 mm had positive nodes. Eight
      of the 13 cancers were at the UOQ. Only one of 13 patients with cancer at the
      lower inner quadrant had nodal metastases. A total of 25.8 per cent of cancers 0
      20 mm located at the upper half of the breast were associated with positive
      nodes, in contrast with 11.1 per cent of those located in the center and 7.1 per
      cent of those located in the lower half of the breast; likewise, 28 per cent of
      cancers 0-20 mm located at the lateral aspect of the breast had axillary nodes
      involved, and 11.5 per cent when cancer was located in the median half. Using
      such an analysis, 25 per cent of all lymphadenectomies could have been omitted,
      as could 37.9 per cent of those performed for T1 cancers (0-20 mm) without
      compromising systemic adjuvant therapy.

PMID- 8651545
TI  - Hepatic and vena cava resection using cardiopulmonary bypass with hypothermic
      circulatory arrest.
AB  - When large hepatic or retroperitoneal tumors encroach upon hepatic veins or vena
      cava and make conventional resection hazardous, the most commonly used method of
      hepatic resection or vena cava reconstruction includes hepatic vascular
      exclusion, at times with venovenous bypass or aortic occlusion. These techniques
      result in warm liver ischemia, and may be accompanied by significant systemic
      hypotension, despite aggressive central venous preloading. Hepatic lobe (two
      patients) and retroperitoneal sarcoma (one patient) resections were done in a
      cold, bloodless field without significant complications. Standard cardiopulmonary
      bypass techniques with heparin and cardioplegia were used. Systemic circulatory
      arrest was done at 15 degrees C with isolated retrograde perfusion of the brain
      through the jugular veins. Hepatic vein and vena cava reconstructions were
      performed with arrest times of between 30 and 78 minutes. Blood loss was gradual
      and easily controlled, occurring during the rewarming phase when clot formation
      was inhibited by cold and heparin.

PMID- 8651546
TI  - Penetrating chest trauma: should indications for emergency room thoracotomy be
      limited?
AB  - A total of 160 patients underwent emergency room thoracotomy (ERT) from January
      1988 to June 1995. There were 142 male and 18 female patients with ages ranging
      from 15 months to 72 years old with a mean age of 31 years. Blunt trauma was the
      mechanism of injury in 11 patients; none of them survived, and they were excluded
      from further analysis. A total of 149 patients sustained penetrating trauma, 111
      patients gunshot wounds, and 38 patients stab wounds. A total of four patients
      survived to discharge for an overall survival rate of 2.7 per cent. All four were
      victims of a stab wound and were neurologically intact at the time of discharge.
      Special interest was placed in classifying patients according to their
      physiologic status both at the scene and on arrival to the emergency department.
      Class I, patients with no signs of life; Class II, Agonal--patients in
      electromechanical dissociation/pulseless electrical activity with no palpable
      pulse or blood pressure; Class III, Profound Shock--patients with blood pressure
      less than 60 mm Hg; and Class IV, Mild Shock--patients with blood pressure
      between 60 and 90 mm Hg. 122 patients (89%) fitted the criteria for Scene Classes
      I and II. None of these patients improved or responded to prehospital
      resuscitation to be moved up to Emergency Department Classes III or IV, and all
      of them died. Of the four survivors, three were in Scene Class III and one was in
      Scene Class IV. This study confirms a previous report that, overall, ERT has a
      very low survival rate. ERT should be abandoned in patients sustaining blunt
      trauma, and should probably be limited to patients sustaining penetrating chest
      injuries who fall into the physiologic Classes III or IV at the scene.

PMID- 8651547
TI  - The single-stapled ileo pouch anal anastomosis: a reasonable compromise.
AB  - Minimal anal sphincter disruption and preservation of the transitional epithelium
      during ileal pouch anal anastomosis (IPAA) are believed to play important roles
      in improving functional outcome. As a result, many surgeons have abandoned the
      traditional mucosectomy in favor of a double-stapled technique. The natural
      history of the retained colonic epithelium that occurs with this approach is
      uncertain. The authors have employed a technique of single circular-stapled IPAA,
      which accomplishes both of the described goals, while insuring that all the
      colonic mucus is removed during mucosectomy. We present a series of patients (n =
      39) undergoing IPAA with transanal mucosectomy and a circular stapled
      anastomosis. The series consists of 16 males and 23 females with a mean age of
      33.4 +/- 1.7 years. Twenty-nine patients had temporary ileostomies (2 not closed
      yet), and 10 did not. Pelvic sepsis occurred in two patients. However, three (9%)
      patients developed anastomotic sinus tracts that delayed ileostomy closure. With
      a follow-up of 24.0 +/- 3.2 months, the mean number of bowel movements are: day
      6.4 +/- 0.4; night 1.1 +/- 0.2. Continence has been good or excellent in 97 per
      cent of patients during the day and 86 per cent at night. Therefore, this series
      indicates that good to excellent functional results following IPAA in the vast
      majority of patients can be accomplished with a transanal mucosectomy and a
      single stapled IPAA anastomotic technique. These results are comparable with
      those obtained with the double stapling technique without risk of retained rectal
      mucosa. Therefore, this technique provides good functional results because of
      minimal anal sphincter stretching, while at the same time insuring removal of all
      abnormal colonic epithelium.

PMID- 8651548
TI  - Parathyroid hormone-related protein expression in the human colon:
      immunohistochemical evaluation.
AB  - Parathyroid hormone-related protein (PTHrP) has been shown to be the primary
      factor responsible for humoral hypercalcemia of malignancy. In addition to its
      hypercalcemic action, PTHrP has been implicated as an autocrine modulator of
      growth and differentiation, as well as an early response gene in some tissues.
      Several different types of tumors have been evaluated for the presence of PTHrP
      immunoreactivity. In the present study, we evaluated the expression of PTHrP by
      immunohistochemical staining in tissue samples from normal colorectal mucosa,
      polyps, and colorectal carcinoma removed from the same patients (n = 10 each). We
      have used a commercially available monoclonal antibody directed against epitopes
      between amino acids [53-64] which share no homology to parathyroid hormone (PTH).
      In normal colon, 94.3 per cent of the tissue samples were negative for PTHrP
      immunoreactivity. In polyps of the colon, only 22.6 per cent of the cells showed
      positive immunostaining, whereas 91.5 per cent of the samples from colon cancer
      stained positive for PTHrP. In the case of polyps, the intensity of staining was
      1-3+; however, all of the samples from adenocarcinoma stained with 4+ intensity.
      In the positive samples, the immunoreactivity was present throughout the
      cytoplasm of the glandular epithelium. Omission of primary antibody, as well as
      substitution of the primary antibody by a negative control monoclonal antibody or
      non-immune rabbit serum, resulted in a negative reaction. All analyses were
      performed in duplicate, and the data have been presented as mean +/- SEM.
      Differences in normal polyps, carcinoma of the colon, and PTHrP expression were
      tested for statistical significance by student's t test. Our results show the
      expression of PTHrP is enhanced in colon cancer tissue as compared to normal
      colorectal mucosa and polyps. In addition, the expression appears to be greater
      in polyp than in normal colon. The role of PTHrP in the pathogenesis of colon
      cancer deserves further study.

PMID- 8651549
TI  - Patterns of recurrence for advanced colon cancer modified by whole abdominal
      radiation and chemotherapy.
AB  - Abdominal failure for colonic carcinoma patients following curative resection has
      been high in patients with advanced disease stage, particularly when increased
      numbers of lymph nodes are involved. Surgeons desire curative treatment for their
      patients, but they interpret local and regional lymph node recurrence as a
      failure of surgical resection. The effect of current adjuvant treatment protocols
      on modifying patterns of relapse, particularly in the abdomen, has not been well
      studied and is of interest to surgeons. We analyzed reported patterns of failure
      of patients with Stage C2 colon cancer from two colon cancer adjuvant treatment
      studies; 5-FU plus levamisole (SWOG 8591) and 5-FU, whole-abdominal radiation,
      and tumor boost. The total number of recurrences in SWOG 8591 at all sites was
      reduced. The percent of lung relapses was reduced from 34 per cent to 20 per cent
      in the treatment group, but the percentage of local relapse increased from 20 per
      cent in the observation group to 27 per cent in the 5-FU plus levamisole group.
      Similarly, the number of first relapses was fewer at a local site in the 5-FU
      plus levamisole group, but the percent of relapses at the local site was not
      reduced (18 vs. 22%). Advanced C2 patients who received regional treatment on 5FU
      and whole-abdominal radiation produced the lowest percent of local relapse (12%),
      suggesting a benefit for regional treatment. Further study of patterns of relapse
      after resection and adjuvant treatment in high risk C2 patients may lead to
      further progress in control of advanced, curative colon carcinoma.

PMID- 8651550
TI  - A novel 5-lipoxygenase inhibitor prevents gallstone formation in a lithogenic
      prairie dog model.
AB  - Gallstone formation is dependent on biliary cholesterol supersaturation, the
      pronucleating effects of gallbladder mucin, and inflammation. We evaluated the
      effect of aspirin (ASA) and a 5-Lipoxygenase inhibitor (FLAPI) on cholesterol
      precipitation and leukotriene levels in an animal model of cholesterol gallstone
      formation. Male prairie dogs were divided into four dietary groups: normal chow
      controls, 1.2 per cent cholesterol (XOL), 1.2 per cent cholesterol plus ASA (XOL
      + ASA, 100 mg/kg/d), and cholesterol plus FLAPI (XOL + FLAPI, 100 mg/kg/12h). At
      3 weeks the subjects were anesthetized, cholecystectomy performed, and the common
      duct cannulated for bile sampling. Cholesterol precipitation, lithogenic indices,
      and leukotriene content were analyzed. The group XOL + FLAPI did not form
      cholesterol crystals, whereas the group XOL + ASA did (P < 0.05, Fisher's exact
      test). All cholesterol-fed groups had significantly increased lithogenic indices
      when compared to controls. The XOL + FLAPI group showed a significant and
      paradoxical increase in LTB4 compared to the other groups (P < 0.05, ANOVA,
      Fisher's PLSD). This study has shown a significant decrease in the rate of
      cholesterol stone formation through the use of a novel leukotriene inhibitor at
      high doses, despite a high cholesterol diet.

PMID- 8651551
TI  - Colonic ischemia: the Achilles heel of ruptured aortic aneurysm repair.
AB  - Colonic ischemia is an often fatal complication of abdominal aortic aneurysm
      (AAA) repair. In elective AAA repair, patency of the inferior mesenteric artery
      (IMA) has been shown to be an important contributing factor. The purpose of this
      study was to determine which clinical and operative factors are important in the
      development of colonic ischemia in ruptured AAA repair. A retrospective review of
      all patients treated for ruptured AAA over a 7-year period was performed. Of 101
      patients who were treated for ruptured AAA, 71 (70 per cent) survived for longer
      than 24 hours postoperatively, and these patients are the basis for this study.
      Colonic ischemia, primarily left sided, was a common perioperative complication
      (n = 24; 35 per cent) requiring colectomy in 11 patients (44 per cent). It
      carried a 44 per cent mortality compared to 20 per cent in patients without this
      complication (P = 0.07). Colonic ischemia occurred more frequently in patients
      with preoperative shock (P = 0.01) and a greater intraoperative blood loss (P =
      0.003), but showed no correlation with patient age, co-morbid medical conditions,
      laboratory values, time to operation, or treatment of the IMA. Most patients with
      postoperative bowel ischemia were found to have chronic IMA occlusion, including
      8 of the 11 patients requiring colectomy. Revascularization would not be feasible
      in this group. Revascularization of patent IMAs had little effect on outcome. Of
      the 17 patent IMAs, 9 were reimplanted and 5 (55 per cent) developed bowel
      ischemia, two of which required colectomy. Eight were ligated and 3 (38 per cent)
      developed bowel ischemia, one requiring colectomy. The presence of preoperative
      shock is the most important factor predicting the development of colonic ischemia
      following ruptured AAA. The incidence of ischemia is not altered by the presence
      of a patent IMA or with attempts at IMA revascularization. Colonic ischemia
      remains a significant source of morbidity and mortality in these patients.

PMID- 8651552
TI  - Prospective comparison of dual-phase technetium-99m-sestamibi scintigraphy and
      high resolution ultrasonography in the evaluation of abnormal parathyroid glands.
AB  - Technetium-99m-sestamibi (MIBI) is a new radionuclide for imaging parathyroid
      tissue. The purpose of this study was to evaluate parathyroid localization using
      single radiotracer, dual-phase MIBI scintigraphy and to compare the results to
      ultrasonography. Twenty-one patients with hyperparathyroidism underwent dual
      phase scintigraphy using 25 mCi MIBI and high resolution ultrasonography before
      parathyroidectomy. Scan results were correlated with size, weight, location, and
      histopathology of excised parathyroid glands, thyroid abnormalities, and cost.
      Seventeen patients were female, five had secondary or tertiary
      hyperparathyroidism, and three had a previous parathyroid exploration. Twenty
      patients (95%) were cured, 14 with a single and 1 with a double adenoma, and 5 of
      6 patients with generalized hyperplasia. There were no false positive MIBI scans
      and one false positive ultrasound study, despite associated thyroid nodules in 29
      per cent of patients. The sensitivity of MIBI and ultrasound in the
      identification of adenomas was 87 per cent versus 57 per cent (P = 0.046), and
      the rate of detection of hyperplastic glands was 44 per cent versus 24 per cent
      (P = 0.19), respectively. There was no correlation between scan results and size,
      weight, or location of adenomatous glands. The cost of dual-phase MIBI was
      comparable to that of ultrasound. Dual-phase MIBI is more sensitive than
      ultrasound in the localization of adenomas and is the preferable modality for
      preoperative parathyroid localization. Neither MIBI nor ultrasound is effective
      in localization of hyperplastic glands, underscoring the importance of routine
      bilateral neck exploration.

PMID- 8651553
TI  - Effects of interleukin-6 and its neutralizing antibodies on peritoneal adhesion
      formation and wound healing.
AB  - This study investigates the effects of preoperative IV administration of IL-6 and
      anti IL-6 on peritoneal adhesion formation and wound healing. Thirty-six male
      Sprague-Dawley rats (350-400 mg) were divided into three groups: control (group
      1); IL-6 (group 2); and anti IL-6 (group 3). Under sterile conditions, all rats
      underwent a midline laparotomy. Ten cm2 of cecal serosa was abraded, the cecum
      further irritated with 0.1 ml of 70 per cent alcohol, and the incision closed in
      layers. At 3 weeks, peritoneal adhesions were graded using a score of 0 (none) to
      3 (extensive, dense). Skin samples from incisional sites were examined
      tensiometrically (true stress and true strain), biochemically (collagen content),
      and histologically. Adhesion formation score was significantly increased in IL-6
      group (2.78 +/- 0.44, Mean +/- SD) and decreased in anti IL-6 group (1.40 +/-
      0.52) compared to control (2.00 +/- 0.50). (P < 0.03 by Kruskal Wallis test).
      There was no significant difference in true stress, true strain, and collagen
      content between the two treatment groups and controls at the 0.05 level by ANOVA.
      Histological analysis showed higher number of inflammatory cells and fibroblasts
      in IL-6 treated groups. We conclude that IL-6 plays a major role in peritoneal
      adhesion formation. Selective immunosuppression, using IL-6 neutralizing
      antibodies preoperatively, leads to a reduction of such adhesion formation
      without a significant effect on wound healing.

PMID- 8651554
TI  - Squamous cell carcinoma of the esophagus.
AB  - The role of surgery as primary treatment for patients with squamous cell
      carcinoma of the esophagus (SCCE) has been challenged by an improved response
      rate for radiotherapy that is made possible by adding radiosensitizing
      chemotherapy. The purpose of our study was to review our institution's treatment
      results for SCCE and to compare results of radiation versus surgery as primary
      treatment of early stage disease. A retrospective chart review was done on 241
      patients who were treated with SCCE at Kansas University Medical Center and
      affiliated hospitals between 1970 and 1990. Patients were divided into five
      groups based on treatment received: (A) No Treatment; (B) Surgery Only; (C)
      Surgery plus Adjuvant Chemoradiotherapy; (D) Radiation Therapy Only; and (E)
      Chemoradiotherapy. Surgical treatment groups B and C had the best overall
      survival of all groups. To reduce any bias due to stage differences in groups,
      survival of groups was assessed only for early stage disease patients (Stage I,
      IIa, IIb). For Stage I and II patients receiving surgery as primary treatment
      (groups B and C), 29 per cent had a survival at 5 years compared to patients
      receiving primary radiation treatment (groups D and E) who had a combined
      survival of only four per cent. Although attempting comparison of risk groups is
      always a problem in nonrandomized studies, it is significant that only one 5-year
      survivor was in the nonresection radiation treatment groups D and E. Surgical
      resection for SCCE had the best survival in our study, especially in patients
      with early stage disease.

PMID- 8651555
TI  - Endoscopic Nd:YAG laser therapy for villous adenomas of the colon and rectum.
AB  - We reviewed 34 villous tumors of the colon and rectum treated endoscopically with
      neodymium:YAG laser therapy from 1983 to the present. Twenty-three tumors were
      benign, and 11 contained carcinoma in situ. Invasive carcinomas were excluded.
      Treatment locations included cecum (6), descending colon (1), sigmoid colon (2),
      and rectum (25). Fourteen males and 20 females with a mean age of 70 years (31
      93) completed an average of 3.3 total treatments per patient under no sedation
      (9), intravenous demerol (24), or general anesthesia (1). Treated tumors ranged
      between 2-12 cm in greatest dimension, and one fourth were 50 to 100 per cent
      circumferential. Four patients presented with recurrent tumors subsequent to
      transanal excisions, done elsewhere. Five patients suffered complications of mild
      stricture (2), self-limited bleeding (2), and one pinhole colovaginal fistula.
      There was one incomplete treatment and one recurrence in the cecum that was
      carcinoma in situ at resection. There were no missed cancers during follow up
      that ranged from 1-120 months (average 32 months). The average total cost for the
      entire treatment per patient was $3627. Endoscopic neodymium:YAG laser therapy of
      villous tumors of the colon and rectum is a safe and effective outpatient
      procedure. The complication rate is lower than most reported series of
      operatively treated patients, and sphincter dysfunction, incontinence, or fecal
      fistula is avoided. With close follow up and repeated biopsy, invasive carcinoma
      can be ruled out. We believe this is the procedure of choice for management of
      these tumors.

PMID- 8651556
TI  - Surgical palliation for ductal adenocarcinoma of the pancreas.
AB  - The short and long term outcomes of operative palliation for unresected ductal
      adenocarcinoma were evaluated in a critical review of 319 patients from 1972
      1990. A total of 154 of 243 operated patients had palliative procedures,
      including biliary drainage in 86 per cent and combined biliary drainage and
      gastrojejunostomy in 53 per cent. Overall mortality rate was 13 per cent; one
      half of the patients had some complication during their remaining lifetime.
      Biliary enteric anastomoses provided clinical relief of jaundice in 78 per cent
      of patients at hospital discharge; jaundice recurred in 16.7 per cent. The
      overall outcomes of choledochojejunostomy, cholecystojejunostomy, and
      choledochoduodenostomy were similar and superior to biliary intubation.
      Choledochojejunostomy was associated with a trend toward longer survival.
      Gastrojejunostomy did not affect overall results. However, upper gastrointestinal
      hemorrhage was more frequent when gastrojejunostomy was added to biliary bypass.
      Late duodenal obstruction developed in 6 per cent of patients initially treated
      by biliary drainage alone. Mean survival was 8.1 months; one-year survival was
      18.2 per cent. Operative palliation for ductal cancer of the pancreas has
      important morbidity and mortality. Biliary enteric anastomoses provide lifelong
      relief of jaundice for most patients. Selective, rather than routine,
      gastrojejunostomy is recommended.

PMID- 8651557
TI  - Elective conventional colectomy in the era of laparoscopic surgery.
AB  - Laparoscopic surgery, since its introduction into the general surgery, has
      reduced hospital stay. Can lessons learned from laparoscopic surgery about
      aggressive postoperative care be applied to elective conventional colectomy?
      Between August 1994 and February 1995, a prospective study was conducted on 24
      consecutive patients undergoing elective conventional colectomy with primary
      anastomosis. A comparison of 30 consecutive patients in the 7 months immediately
      before this study were used as a historical control group. Both groups were
      comparable in age, indications for operation, type of operation, and operative
      time. The protocol consisted of an outpatient bowel prep, hospital admission on
      day of surgery, and intravenous metoclopramide starting before the operation and
      continued every 6 hours with diet started at 24 hours. Patients were discharged
      on regular diet after a bowel movement and were continued on oral metoclopramide
      for a total of 7 days. Hospital stay was reduced from 8 days (range 4-19 days) to
      4 days (range 2-7 days) on the protocol P < 0.001). Hospital charges were also
      reduced by 20 per cent (from $18,450 to $14,586) (P = 0.066). Complication rate
      and postoperative emergency room visits as a measure of quality of care did not
      differ between the two groups. By implementing this protocol, hospital costs and
      length of stay for elective conventional colectomy were reduced without
      compromising patient care.

PMID- 8651558
TI  - Prospective comparison of gastric emptying after laparoscopic-aided colectomy
      versus open colectomy.
AB  - Laparoscopic colectomy has been associated with a shorter postoperative ileus
      when compared to open colectomy, although the mechanism is unclear. This study is
      designed to evaluate gastric emptying following open colectomies (OC) versus
      laparoscopic-aided colectomies (LAC) using serial serum acetaminophen levels
      (ACE), which correlate with gastric emptying. The study groups were limited to
      patients undergoing either right or left colectomy who received general
      anesthetic. Patients with diabetes mellitus or other colon resections were
      excluded. Postoperative analgesia was provided with intramuscular ketorolac and
      opioids for breakthrough pain. Patients received 500 mg ACE at 24 and 48 hours
      postoperatively, and ACE levels were measured 5, 10, 20, 30, 45, 60, 90, and 120
      minutes following ingestion. The OC and LAC groups were matched in terms of
      operation performed. There were multiple carcinomas in the OC group, and none in
      the LAC group. Normal control values were also obtained for ACE absorption
      curves. Of all the time intervals tested at both 24 and 48 hours, there was only
      a single time interval (30 minutes at the 48-hour testing interval) in which
      there was a significant difference between the OC and LAC groups. In both the OC
      and LAC groups, there were multiple time intervals when the ACE levels were
      significantly different when compared to controls. The results indicate no
      significant difference in gastric emptying as measured by acetaminophen
      absorption in postoperative colectomy patients. Therefore, although laparoscopic
      patients have a clinically shorter postoperative ileus, the mechanism for this
      reduction appears unrelated to gastric emptying.

PMID- 8651559
TI  - Acute cholecystitis treated urgently by nonselective laparoscopic
      cholecystectomy.
AB  - Beginning in 1990, all patients encountered by the author requiring
      cholecystectomy were attempted by laparoscopy. This study reports the results of
      83 patients with acute cholecystitis who were urgently treated, nonselectively,
      by laparoscopic cholecystectomy. Acute cholecystitis was diagnosed clinically by
      the presence of right upper quadrant peritoneal pain, gallbladder phlegmon and
      fever, and/or increased white blood cell count. In addition, a confirming
      pathology report and/or elevated white blood cell count was present in all 83
      patients. Age ranged from 18 to 82 years with an average of 39.4 years. Fifteen
      patients were male and 68 female. Insufflation was obtained in all patients
      without a complication. Discharge occurred by postoperative Day one for 24
      patients, Day two for 66 and by Day three for 75 patients (range 19-300 hours).
      No patient had common duct stones. Most patients had stones impacted in the
      cystic duct, including one patient who had Mirizzi's syndrome. Operative time
      ranged from 28 to 300 minutes, with an average of 106.3 minutes. No conversion to
      open cholecystectomy was required. Complications included bile spillage in five
      patients, stone spillage in ten, and ileus in three patients. One patient with
      Mirizzi's syndrome required a postoperative radiological procedure for removal of
      a cystic duct stone remnant that was not completely removed at the time of
      operation. The high complication rate initially associated with laparoscopic
      cholecystectomy probably resulted from violating cardinal principles of surgery,
      not from the inappropriateness of laparoscopy. In conclusion, it is recommended
      that urgent laparoscopy is an appropriate initial approach for patients with
      acute cholecystitis.

PMID- 8651560
TI  - The clinical spectrum of Clostridium difficile colitis in immunocompromised
      patients.
AB  - Clostridium difficile colitis is a nosocomial infection that continues to cause
      significant hospital morbidity despite adequate treatment. This morbidity may be
      especially costly in the immunocompromised patient who now makes up a greater
      percentage of hospitalized patients. The purpose of this study was to evaluate if
      patients in immunocompromised states are at risk for relapse of Clostridium
      difficile colitis, and to determine the efficacy of metronidazole in these
      patients. A retrospective chart review was conducted of patients with Clostridium
      difficile colitis over a 1-year period between 1990 and 1991. From this study
      group, 114 patients were identified who had both positive Clostridium difficile
      toxin assays of fecal specimens and documented in-house clinical infection. There
      were 67 immunocompromised patients (59%) in the study group. Oral vancomycin was
      given alone in 41 (36%) patients, metronidazole was used in 36 (32%) patients,
      and a combination was given in 15 (13%) patients. Twenty-two (19%) patients
      received no antibiotic therapy and had their preceding antibiotics terminated.
      Twelve (10.5%) patients had documented relapses, and all had an
      immunocompromising condition. There was no statistically significant difference
      in relapse rates between the vancomycin and metronidazole-treated patients. We
      conclude that metronidazole, with its significantly lower cost, should be used as
      first-line therapy in immunocompromised patients.

PMID- 8651561
TI  - The role of flow cytometric DNA analysis in determining prognosis of resectable
      ductal adenocarcinoma of the pancreas.
AB  - Carcinoma of the pancreas is a leading cause of cancer mortality in the United
      States. Improvement in prediction of survival is needed. Flow cytometric analysis
      as a prognostic tool has produced conflicting results. We retrospectively
      analyzed the clinicopathologic features, operative factors, and outcome of 39
      curative resections for ductal adenocarcinoma of the head of the pancreas
      performed at Indiana University Medical Center between 1989 and 1994. The group
      was composed of 20 females and 19 males. Procedures performed were Whipple
      without vagotomy (n = 5), Whipple with vagotomy (n = 19), pylorus-preserving
      Whipple (n = 12) and total pancreatectomy (n = 3). Thirty-two tumors were
      suitable for DNA analysis. Of the 32 patients with flow cytometric data, 33 per
      cent (3/9) of living patients and 39 per cent (9/23) of deceased patients had
      aneuploid tumors (P = 0.999). The average S-phase for living patients was 8.3 per
      cent +/- 3.8 per cent, and 16.1 per cent +/- 13.6 per cent for deceased patients
      (P = 0.115). In the multivariate analysis, only lymphatic invasion (P = 0.015)
      and alkaline phosphatase level (P = 0.024) predicted poor survival. Our data show
      no correlation between flow cytometric DNA ploidy, S-phase analysis, and
      prognosis in patients undergoing curative resection for ductal adenocarcinoma of
      the pancreatic head.

PMID- 8651562
TI  - Re: abdominal wall endometrioma in a laparoscopic trocar tract: a case report.

PMID- 8651563
TI  - Steroid hormones, receptors, and antagonists.
AB  - In the thirty-odd years since the first demonstration of estrogen-binding
      components in reproductive tissues, much has been learned about the molecular
      details of steroid hormone action. Facts still to be elucidated include the
      precise mechanism by which interaction with the steroid disrupts the native
      receptor complex to generate an active transcription factor, just how this
      activated receptor enhances expression of target genes, and the role of
      phosphorylation in these events. The concept of receptor-medicated steroid
      hormone action has provided useful methods for predicting the risk of metastatic
      recurrence of breast cancers and the response of disseminated disease to
      endocrine therapy. Application of immunochemical techniques for receptor assay
      and elucidation of the role of mutant receptors in hormone resistance promise to
      increase the utility of these diagnostic procedures. A better understanding of
      the molecular details of steroid hormone antagonism should be helpful in the
      search for new and more effective agents for the endocrine control of breast
      cancers.

PMID- 8651564
TI  - New 17 beta-hydroxysteroid dehydrogenases. Molecular and cell biology of the type
      IV porcine and human enzymes.

PMID- 8651565
TI  - Molecular biology of steroid sulfotransferases.

PMID- 8651566
TI  - Protein tyrosine phosphorylation and estradiol action.

PMID- 8651567
TI  - Insulin receptors in breast cancer.

PMID- 8651568
TI  - Estrogen biosynthesis in adipose. Significance in breast cancer development.

PMID- 8651569
TI  - Insulin-like growth factor-I (IGF-I) receptors in breast cancer.

PMID- 8651570
TI  - Prognostic significance of receptors for epidermal growth factor, estrogen, and
      progesterone in ovarian cancer.

PMID- 8651572
TI  - Immunomodulatory mechanisms mediated by sex hormones in rheumatoid arthritis.

PMID- 8651571
TI  - Luteinizing hormone-releasing hormone (LHRH) receptors in the neuroendocrine
      immune network. Biochemical bases and implications for reproductive
      physiopathology.
AB  - It seems apparent that the brain-pituitary-reproductive axis and the brain-thymus
      lymphoid axis are linked by an array of internal mechanisms of communication that
      use similar signals (neurotransmitters, peptides, growth factors, hormones)
      acting on similar recognition targets. Moreover, such communication networks form
      the basis and control of each step and every level of reproductive physiology.
      This work has focused on the LHRH system, a primary central and peripheral clock
      of both neuroendocrine and immune functions. From the initiation of a sexually
      organized response, the detection of sexual odors, and the induction of mating
      behavior, extrahypothalamic and hypothalamic LHRH orchestrates the neuroendocrine
      modulation of gonadotropin secretion, while its expression within the ovary
      directly controls specific events such as follicular atresia. The presence of
      LHRH receptors in oocytes clearly anticipates a potential action of the
      decapeptide during the process of fertilization and/or implantation. Within the
      thymus and other peripheral immune organs, LHRH plays a unique role of
      immunomodulator, contributing to the sex-dependent changes in immune
      responsiveness during the estrous-menstrual cycle as well as pregnancy. The
      reciprocity of the neuroendocrine-immune signaling systems is further supported
      by the ability of sex steroids to modulate thymus-dependent immune functions via
      direct effects on specific target genes involved in the development of sex
      dimorphism and sex-dimorphic immune responses, including the downregulation of
      immune response observed during pregnancy. Such cyclic changes in immune
      responsiveness could have a physiological implication, such as the decrease or
      suppression in cell-mediated immunity observed in the postovulatory phase of the
      cycle and in pregnancy, respectively, and might play a role during the
      implantation process and the establishment of pregnancy. In this context, the
      ability of corticosterone to directly inhibit both GR transcript levels as well
      as a cell-mediated immune response within the thymus, and the modulation of such
      an inhibitory effect by the sex steroid hormone milieu, may offer an explanation
      and a molecular mechanism whereby stress may be deleterious for reproduction,
      also via immunomodulation. On the other hand, hormonally mediated alterations in
      immunity might also have a pathological implication in sexually related immune
      diseases. For example, in mouse and humans, lupus erythematosus is more prevalent
      in females and estrogen accelerates the disease process, while menstruation is
      known to exacerbate idiopathic thrombocytopenia purpura. Sex steroid hormone
      milieu might also have a role in controlling the stress response through
      immunomodulation. Within the placenta, an intricate network of signaling systems
      controls a delicate interplay between the neuroendocrine hormones, growth
      factors, and cytokines that are susceptible to play a major local role in the
      processes of implantation and the establishment and completion of pregnancy. The
      neuroendocrine and immunomodulatory role of LHRH continues well after parturition
      because the presence of LHRH-like material within the mammary gland and milk
      participates in the physiological modulation of hypophyseal, gonadal, and immune
      functions of the pups. Such a significant role played by the hypothalamic peptide
      in the modulation of immune responsiveness would indicate LHRH as the signal
      conveying information to both neuroendocrine and immune cells, with the role of
      informing and then transducing the messages into appropriate biological
      responses.(ABSTRACT TRUNCATED)

PMID- 8651573
TI  - The cell cycle and regulation of cancer cell growth.
AB  - There are two points (brake-points) through which the cell must pass before it
      can enter cell division. Progress through each brake-point requires the presence
      of an active cyclin-dependent kinase (Cdk). There are specific cyclins to
      activate the Cdk's at different parts of the cell cycle. Activation of the cyclin
      Cdk complex is tightly regulated by the phosphorylation state of the Cdk.
      Exogenous growth stimulators (hormones, growth factors, and cytokines) all work
      through an intracellular kinase cascade that drives the production and activation
      of early nuclear proteins that, in turn, induce transcription of the genes for
      cyclins, Cdk's, and other cell cycle regulators. Retinoblastoma protein regulates
      cell division by inactivating specific growth-promoting proteins. Therefore,
      mutation of the Rb gene can lead to uncontrolled cell division and thus promotion
      of transformed cells. p53 protein will prevent replication of cells with damaged
      DNA. Hence, transformed cells can only readily progress to tumors if the p53 gene
      is mutated in a manner that inactivates the protein product. Members of the bcl-2
      family act, in homodimers and heterodimers, to shunt cells either into cell
      division or into apoptosis. Understanding the mechanisms by which the balance of
      cell cycle: apoptosis can be manipulated will lead to new ways of controlling
      abnormal cellular growth. Most aspects of cellular function reflect changes in
      phosphorylation of critical serine, threonine, and tyrosine residues on the
      relevant regulatory proteins. The kinases the phosphatases involved are
      themselves under tight control.

PMID- 8651574
TI  - Regulation and role of TGF beta production in breast cancer.
AB  - The influence of antiestrogens on the secretion of transforming growth factor
      beta (TGF beta) proteins that have an autoinhibitory potential for human cancer
      cells was studied in the estrogen-responsive human breast cancer cell line, MCF
      7: Antiestrogens induce the secretion of TGF beta-1 via a nontranscriptional
      pathway; TGF beta-1 itself induces TGF beta-2 by a direct transcriptional
      mechanism; and TGF beta-2 is a marker of antiestrogen action. This hypothesis was
      confirmed in a clinical study with 18 patients with advanced metastatic breast
      cancer. TGF beta-2 plasma levels were measured before and after 4 weeks of
      treatment with tamoxifen. In the majority of patients who responded to the
      treatment, increasing TGF beta-2 concentrations were seen under therapy. Patients
      who did not respond did not show changes in the TGF beta-2 plasma level after 4
      weeks of treatment. These results suggest that the sequential analysis of TGF
      beta-1 in plasma before and under treatment with tamoxifen allows the early
      identification of patients with antiestrogen resistance.

PMID- 8651575
TI  - Immunohistochemical analysis of steroid 5 alpha-reductase type 1 in human scalp
      and prostate.

PMID- 8651577
TI  - Prognostic value of a novel interferon-inducible 90K tumor antigen.

PMID- 8651576
TI  - Oncogenes, estradiol biotransformation, and mammary carcinogenesis.

PMID- 8651578
TI  - Sensitivity of breast and ovarian cancer cells for interferons (IFNs) and
      retinoids.

PMID- 8651579
TI  - Estrogen receptor mRNA variants. Do they have a physiological role?

PMID- 8651580
TI  - Estrogen content and metabolism in human breast tumor tissues and cells.

PMID- 8651581
TI  - Pure antiestrogens. The most important advance in the endocrine therapy of breast
      cancer since 1896.

PMID- 8651582
TI  - Hormonal control of growth factor receptor expression.
AB  - In this report, we have discussed a series of results obtained in our laboratory
      that, together with data by other authors, demonstrate that the expression of the
      erbB-2 tyrosine kinase receptor oncogene in breast cancer cells is regulated by
      multiple factors and hormones, which modulate their growth and differentiation.
      In particular, we have shown that estrogens specifically inhibit erbB-2
      expression by transcriptional repression, which is exerted through a sequence
      within the erbB-2 gene promoter. Estrogens control mammary cell growth directly,
      by inducing early gene expression, and indirectly, by increasing autocrine growth
      factor production or decreasing growth inhibitors. The data presented here
      suggest that mammary cells respond to estrogen also by modifying the receptor
      array on their surface, thus setting their own sensitivity to the different
      autocrine and paracrine factors. As a first consequence, the modulation of erbB-2
      expression level by antiestrogen may represent a point to consider when selecting
      breast cancer patients for hormonal therapy, in those (few) cases where estrogen
      receptor positivity accompanies erbB-2 amplification. On the other hand,
      antiestrogen-induced upregulation of erbB-2 may improve tumor targeting of drugs
      designed to interact or interfere with erbB-2, such as humanized antibodies,
      immunotoxins, or engineered ligands. These possibilities should be tested in
      appropriate model systems in the future.

PMID- 8651583
TI  - Adrenal androgen action in breast cancer.

PMID- 8651584
TI  - Sex steroid binding protein is a negative modulator of estrogen-induced breast
      cancer cell growth.

PMID- 8651585
TI  - In vitro models for the effects of sex hormones on neurons.
AB  - The results of these two in vitro models share some striking similarities. In
      both, estrogen was able to induce or promote the formation of either dendrites
      themselves in hippocampal neurons or dendritic specializations in PC12 neurites,
      and these specializations were then able to induce interneural interactions. In
      both models, androgen was able to promote the development of axons that branched
      frequently, while not directly fostering interneuronal contact. These findings
      recapitulate in part some of the effects of estrogen and androgen on neurons in
      vivo and suggest the inherent ability of cells of neural crest origin to respond
      to these hormones with specific neural morphogenetic programs designed to alter
      interneuronal communication. In these ways, it seems likely that both sex
      hormones are acting as neural growth factors in cells that express the
      appropriate receptor, leading to stereotyped changes in neural growth and pattern
      formation. Through the examination of such subcellular mechanisms, we hope to
      further understand the effects of sex hormones on brain development and the
      ontogeny of behavioral, cognitive, and reproductive differences between the
      sexes.

PMID- 8651586
TI  - Biological staging of incipient, in situ, and invasive breast carcinomas.

PMID- 8651587
TI  - Objective quantitative grading. A study of breast ductal hyperplasias and ductal
      carcinomas in situ.

PMID- 8651588
TI  - Regulation and inhibition of steroid sulfatase activity in breast cancer.

PMID- 8651589
TI  - Oncogene products and other diagnostic markers in human breast cancer patients.
      Treatment effects and their significance.

PMID- 8651590
TI  - The impact of surgery on breast cancer.

PMID- 8651591
TI  - Effects of primary chemotherapy on biological parameters of locally advanced
      breast cancer.

PMID- 8651592
TI  - Hormonal intervention in breast cancer. Past, present, and future.

PMID- 8651593
TI  - Potential role of 11 beta-hydroxysteroid dehydrogenase in human trophoblast
      endometrial interactions.

PMID- 8651594
TI  - Indirect growth inhibition of the MDA-MB-231 hormone-independent breast cancer
      cell line by dihydrotestosterone.

PMID- 8651595
TI  - NDF/heregulins stimulate expression of the erbB-2 tyrosine kinase growth factor
      receptor gene in human breast cancer cells.

PMID- 8651597
TI  - MCF-7 cell progesterone receptor (PGR) is additionally modulated by sex steroid
      binding protein (SBP) and its membrane receptor (SBP-R) through cAMP and PKA.

PMID- 8651596
TI  - Detection of MAGE-1, -2, and -3 messenger RNA in tissue samples derived from lung
      and mammary tumors.

PMID- 8651598
TI  - Biological heterogeneity of breast carcinoma in situ.

PMID- 8651599
TI  - Loss of retinoblastoma gene (RB1) is associated with deletions at the 17p13.3
      chromosome and S-phase index in human breast cancer.

PMID- 8651600
TI  - Breast cancer incidence in Palermo city (Italy).

PMID- 8651601
TI  - DNA ploidy, cell kinetics, and epidermal growth factor receptor and HER2/neu
      oncoprotein expression in primary operable breast cancer.

PMID- 8651602
TI  - Prevalence of depressive mood disorders in breast cancer patients of southern
      Italy.

PMID- 8651603
TI  - Liver function assessment by MEGX. Application to oncology.

PMID- 8651604
TI  - Recent postmenopause, but not ER status, identifies a subset of primary breast
      cancer patients with a higher risk of relapse.

PMID- 8651605
TI  - Cytoskeletal and cytocontractile protein composition of stromal tissue in normal,
      hyperplastic, and neoplastic human prostate. An immunocytochemical study with
      monoclonal antibodies.
AB  - Monoclonal antibodies specific for protein markers of smooth muscle and nonmuscle
      cell differentiation were applied to cryosections of normal, hyperplastic, and
      neoplastic human prostate specimens in order to determine whether differences in
      the distribution of target antigens could be detected among the various tissues.
      Immunofluorescence assays showed that vimentin, desmin, smooth-muscle-type alpha
      actin, and both smooth muscle and nonmuscle myosin heavy chains do not change
      their patterns of labeling in the stromas of normal, BPH, and carcinomatous
      prostates. By contrast, cytokeratin 18, a differentiation marker of simple
      epithelia, and to a lesser extent cytokeratin 8, was consistently found in
      stromal tissue of the "transition zone", but only scarcely in the stroma of the
      "peripheral zone" from normal prostate, and was completely unexpressed in benign
      hyperplasia. Prostatic carcinoma from the "peripheral zone" expressed this
      cytoskeletal component only in trace amounts. Moreover, in prostate showing
      coexistence of hyperplasia and neoplasia (in the "peripheral zone"), the stroma
      of BPH closely resembled the stroma surrounding the carcinoma; that is, it was
      completely unreactive with the anti-cytokeratin 18 antibody. Expression of
      cytokeratins in extraepithelial tissues has been previously correlated with the
      achievement of a proliferative state, notably in embryogenesis, in tissue
      regeneration, and in various pathological forms of proliferation and growth,
      including some tumors of mesenchymal origin. Our results indicate the following:
      (1) cells in the stromal tissue of normal prostate are of smooth muscle type and
      are heterogeneous as concerns cytokeratin distribution; (2) we show, for the
      first time, the existence of a marker that is differentially distributed in the
      "transition" versus "peripheral" zone; (3) the expression of cytokeratins in the
      stroma is lost with the development of hyperplasia and only partially recovers
      with neoplasia; (4) the pattern of stromal tissue, concerning cytokeratin 18
      expression, does not change with different BPH locations ("transition" versus
      "peripheral" zone); and (5) contrary to expectations, cytokeratin 18 expression
      disappears in conditions presumably involving stromal cell proliferation.

PMID- 8651606
TI  - Normal development and carcinogenesis of the prostate. A unifying hypothesis.

PMID- 8651607
TI  - NM23 in Ovarian Cancer. Correlation with clinicopathological and biochemical
      parameters.

PMID- 8651608
TI  - Growth factors released from astroglial cells in primary culture participate in
      the cross talk between luteinizing hormone-releasing hormone (LHRH) neurons and
      astrocytes. Effects on LHRH neuronal proliferation and secretion.

PMID- 8651609
TI  - Chemosensitizing effect of tamoxifen and ICI 182,780 on parental and adriamycin
      resistant MCF-7 human breast cancer cells.

PMID- 8651610
TI  - Biological parameters in breast cancer.

PMID- 8651611
TI  - Effects of taxol on TNF-alpha and IL-6 production by human peripheral blood
      cells.

PMID- 8651612
TI  - Timing of surgery during menstrual cycle and prognosis in operable breast cancer.

PMID- 8651613
TI  - Primary cultures of human synovial macrophages metabolize androgens.

PMID- 8651614
TI  - Presence and distribution of growth factors in breast cyst fluid.

PMID- 8651615
TI  - Apoptosis susceptibility of human carcinoma and leukemia cell lines to taxol.
      Relationship with cell cycle and drug concentration.

PMID- 8651616
TI  - Relationships between proliferative activity and oncogene expression in human
      breast cancer.

PMID- 8651617
TI  - Oral contraceptive use and breast cancer risk in areas with different incidence.
      A case-control study among young women.

PMID- 8651618
TI  - Apoptosis in prostate cancer. Molecular basis to study hormone refractory
      mechanisms.

PMID- 8651619
TI  - Multiple estrogen function in human prostate cancer cells.

PMID- 8651620
TI  - Radical surgery for clinically confined prostate cancer.

PMID- 8651621
TI  - Control of transcription by steroid hormones.

PMID- 8651622
TI  - Inhalation accidents reported to the SWORD surveillance project 1990-1993.
AB  - Inhalation accidents are the fifth most common cause of illness reported by
      occupational and chest physicians to the SWORD surveillance scheme, with an
      estimated total of 1180 cases in the 5-year period 1989-1994. Questionnaires were
      sent to all physicians still participating, to record the circumstances of each
      inhalation accident they had reported between January 1990 and July 1993,
      covering case management and any resultant effects on health or employment; 93%
      of physicians returned the forms completed with adequate data on 85% of cases.
      From the information provided, 30% of the accidents resulted from lack of
      effective respiratory protection or other contraventions of safety regulations,
      19% from leaks or spills and 13% from equipment failure. Resultant symptoms were
      described in 92% of cases: of these 48% were respiratory, 12% non-respiratory or
      toxic and 39% a combination of the two. The symptoms persisted often with absence
      from work for 1 month or more, in 26% of cases, including 9% with asthma or
      reactive airways dysfunction syndrome (RADS), 11% other respiratory diseases, 3%
      non-respiratory conditions and 3% unspecified. It was evident that cases reported
      by chest physicians were more seriously ill than those from occupational
      physicians, but of those with persistent symptoms the proportion with asthma or
      RADS was fairly similar in the two groups (24 and 37%, respectively). Agents
      associated with asthma or RADS were mainly respiratory irritants and those
      associated with non-respiratory conditions were organic chemicals or combustion
      products. Published by Elsevier Science Ltd.

PMID- 8651623
TI  - Re-examination of cadmium in urine data reported in 1979 relating to some men in
      1968 and after.

PMID- 8651624
TI  - Inflammatory myopathy causing pharyngeal dysphagia: a new entity.
AB  - Seven patients presented to our swallowing center with solid food dysphagia. The
      age range at presentation was 69 to 90 years. All patients had normal findings on
      neurologic evaluation, and in those patients undergoing electromyography and
      nerve conduction studies, results of all such tests were also normal. Pooling of
      saliva in the pharyngeal recesses was noted on fiberoptic laryngoscopy in most
      cases. The swallowing videofluoroscopy findings were strikingly similar. All
      patients had a prominent cricopharyngeus muscle, and some had a prominence in a
      more proximal portion of the inferior constrictor muscle. All patients had
      decreased epiglottic tilt and moderate or severe residue in the pharyngeal
      recesses. Three patients underwent pharyngoesophageal sphincter myotomy. Biopsies
      of the omohyoid and cricopharyngeus muscles showed inflammatory myopathy with no
      evidence of inclusion bodies. This is a distinct clinical entity defined by
      isolated pharyngeal dysphagia in elderly patients with a unique videofluoroscopic
      appearance and pharyngeal myopathy.

PMID- 8651625
TI  - Laryngotracheal manifestations of rhinoscleroma.
AB  - Rhinoscleroma is a rare, chronic granulomatous disease of infective causation. It
      usually begins in the nose and may progress to involve the larynx and trachea and
      cause dysphonia, stridor, and airway obstruction. Early rhinoscleroma is usually
      successfully treated with oral tetracycline, yet laryngotracheal disease may
      require operative intervention. The disease is rare in the United States, but
      with an increase in immigration from endemic areas, otolaryngologists should be
      familiar with the management of this rare disease. Current literature contains
      only a few reports describing the manifestations of this disease, mostly in the
      form of case studies. This study is a retrospective review of our institutional
      experience with the management of 22 patients with rhinoscleroma, 13 of whom had
      laryngotracheal involvement. The focus of this report is on the clinical
      manifestations of laryngotracheal scleroma. All of the patients were treated with
      long-term antibiotics. Nine patients underwent endoscopy with or without dilation
      and laser excision. Three patients required emergency tracheostomy, all of whom
      were ultimately decannulated without any sequelae. A rational approach to
      management of this unusual disease is provided.

PMID- 8651627
TI  - Fragmented, distorted cricoid cartilage: an acquired abnormality.
AB  - This paper reports the identification of the fragmented, distorted cricoid
      cartilage. The laryngeal findings in four patients with this acquired abnormality
      are presented. The postmortem whole organ serial section of their larynges is
      described and illustrated with horizontal sections from the Laryngeal Development
      Laboratory in Chicago. The histopathologic sequence, pathogenesis, and clinical
      relevance are elucidated.

PMID- 8651626
TI  - Vocal fold submucosal infusion technique in phonomicrosurgery.
AB  - Phonomicrosurgery is optimized by maximally preserving the vocal fold's layered
      microstructure (laminae propriae). The technique of submucosal infusion of saline
      and epinephrine into the superficial lamina propria (SLP) was examined to
      delineate how, when, and why it was helpful toward this surgical goal. A
      retrospective review revealed that the submucosal infusion technique was used to
      enhance the surgery in 75 of 152 vocal fold procedures that were performed over
      the last 2 years. The vocal fold epithelium was noted to be adherent to the vocal
      ligament in 29 of the 75 cases: 19 from previous surgical scarring, 4 from
      cancer, 3 from sulcus vocalis, 2 from chronic hemorrhage, and 1 from
      radiotherapy. The submucosal infusion technique was most helpful when the vocal
      fold epithelium required resection and/or when extensive dissection in the SLP
      was necessary. The infusion enhanced the surgery by vasoconstriction of the
      microvasculature in the SLP, which improved visualization during cold-instrument
      tangential dissection. Improved visualization facilitated maximal preservation of
      the SLP, which is necessary for optimal pliability of the overlying epithelium.
      The infusion also improved the placement of incisions at the perimeter of benign,
      premalignant, and malignant lesions, and thereby helped preserve epithelium
      uninvolved by the disorder.

PMID- 8651628
TI  - Reconstruction of the rabbit trachea with vascularized auricular perichondrium.
AB  - Success in laryngotracheal reconstruction has been limited, in part, by the lack
      of an ideal grafting material. Perichondrium is thin, pliable, and highly
      vascularized and has the ability to generate new cartilage providing rigid
      support. These qualities make vascularized perichondrium potentially the ideal
      grafting material for circumferential airway stenosis. A pedicled vascularized
      flap of auricular perichondrium was used in a rabbit model (n = 39) to
      reconstruct a near-circumferential tracheal defect without a tracheostomy. A
      stent was used to support the reconstructed airway for 6 weeks, after which time
      it was removed by direct laryngoscopy. Animals were observed for an additional 6
      weeks prior to sacrifice. Qualitative and quantitative histologic analysis of
      neochondrogenesis is reported. Vascularized perichondrium and periosteum show
      promise as potential grafts for reconstruction of circumferential tracheal
      defects.

PMID- 8651629
TI  - Laryngotracheal reconstruction using a Vitallium alloy miniplate.
AB  - When stenosis of the larynx and trachea involves loss to anterior support, this
      is usually corrected by an autograft of costochondral cartilage or of hyoid bone
      anchored with suture material. This paper describes an alternative technique
      employing a Vitallium alloy miniplate placed anterior to the airway as a means
      for providing support. This is placed over a fascial or auricular cartilage
      graft. Together, they provide a smooth scaffold for mucosal migration. Thirteen
      patients were treated at Indiana University Medical Center between 1991 and 1993
      by means of this technique. Ten of the 13 patients (77%) achieved an adequate
      airway to allow decannulation. There have been no significant complications
      related to the use of the miniplate, and specifically, there have been no
      instances of infection or extrusion. It has been unnecessary to remove any of the
      miniplates. The Vitallium alloy miniplate offers unique advantages in
      laryngotracheal reconstruction in that it not only accurately approximates
      tissues, but it also provides external support to the airway.

PMID- 8651630
TI  - Adherence of nontypeable Haemophilus influenzae to respiratory epithelium of
      otitis-prone and normal children.
AB  - Three hundred six children were enrolled at birth in a prospective study of
      otitis media and followed up for 2 years. Adherence of nontypeable Haemophilus
      influenzae to buccal epithelial cells was compared between otitis-prone children
      and age- and sex-matched normal controls at birth, 1 year, and 2 years. The mean
      +/- SD/median percent adherence was similar for the two groups at birth (1.6 +/-
      2.3/1.0 versus 1.2 +/- 1.4/1.0; NS) and at 2 years (1.6 +/- 1.7/1.5 versus 2.1 +/
      2.1/1.5; NS). At 1 year of age the adherence rate for the otitis-prone group
      (2.4 +/- 2.6/1.0) was statistically greater than that for the control group (1.0
      +/- 1.3/0.0; p < .02). Because this difference is probably clinically
      insignificant, other explanations must be sought for the increased colonization
      rates of nontypeable H influenzae observed in otitis-prone children.

PMID- 8651631
TI  - Bell's palsy treatment with acyclovir and prednisone compared with prednisone
      alone: a double-blind, randomized, controlled trial.
AB  - In a double-blind study, we compared the final outcome of 99 Bell's palsy
      patients treated with either acyclovir-prednisone (53 patients) or placebo
      prednisone (46 patients). For patients receiving acyclovir, the dosage was 2,000
      mg (400 mg 5 times daily) for 10 days. Electrical tests included
      electroneurography and the maximal stimulation test. Univariate comparisons of
      outcome and electrical tests between the two groups were made with chi 2
      analysis, Fisher's exact test, and t-tests. The outcome in acyclovir-prednisone
      treated patients was superior to that in placebo-prednisone-treated patients.
      Treatment with acyclovir-prednisone was statistically more effective in returning
      volitional muscle motion (recovery profile of 10; p = .02) and in preventing
      partial nerve degeneration (p = .05) than placebo-prednisone treatment. The t
      tests indicated that the recovery profile and index means were significantly
      better for the acyclovir-treated group (recovery profile t = 1.99, p = .051;
      recovery index t = 2.10, p = .040). We conclude that acyclovir-prednisone is
      superior to prednisone alone in treating Bell's palsy patients and suggest that
      herpes simplex is the probable cause of Bell's palsy.

PMID- 8651632
TI  - Hearing results following modified radical versus canal-up mastoidectomy.
AB  - Modified radical mastoidectomy (MRM) provides relatively safe surgical access for
      the removal of chronic middle ear and mastoid disease and gives reproducible
      results. However, it had been suggested that hearing may not be as good as that
      after "intact canal wall mastoidectomy" (ICWM). This paper reviews 153 tertiary
      referrals suffering from extensive disease who underwent MRM and compares their
      hearing results with those obtained by other authors using ICWM and MRM and a
      variety of reconstructive techniques. In this study there were no dead ears and
      no significant changes in bone conduction despite prolonged drilling and
      extensive disease. Hearing results after MRM were found to be better after
      primary surgery than after revision and better in the presence of an intact
      stapes. No rigid prostheses were used at first-stage surgery. There were no
      significant differences found between hearing results obtained by MRM in this
      series and other published results of canal wall down mastoidectomy and ICWM,
      irrespective of the use of ossicular replacement prostheses.

PMID- 8651633
TI  - Postintubation arytenoid subluxation.
AB  - Arytenoid subluxation (AS), ie, malpositioning of the arytenoid cartilage with
      abnormal but existent contact between the joint surfaces, is an uncommon entity,
      and fewer than 70 cases have been reported, 26 of which were in a recently
      published series. Usually, AS is the result of upper airway instrumentation, and
      only a few cases were reported to occur with external trauma to the neck. Some
      predisposing factors and possible mechanisms have been suggested, but the reason
      for its occurrence remains obscure. Hoarseness and, to a lesser degree,
      dysphagia, odynophagia, cough, and sore throat may be indicative of AS. Diagnosis
      is established by the clinical course, laryngoscopy, and computed tomography.
      Electromyography and strobovideolaryngoscopy are additional diagnostic measures
      described. We report 7 cases of postintubation AS of long standing. Three of
      these patients had prior unilateral vocal cord paralysis, formerly undescribed as
      a possible contributing factor for AS. The pertinent literature is reviewed and
      treatment options are discussed.

PMID- 8651634
TI  - Carcinoma of the anterior commissure of the larynx: II. Proposal of a new staging
      system.
AB  - On the basis of embryology and clinical experience, we have defined here an
      anterior commissure (AC) subsite of the human larynx and have addressed the issue
      as to whether the degree of involvement of this subsite is related to the outcome
      of glottic cancer, in terms of local control within 5 years of therapy.
      Retrospective analysis of 534 patients included 1) classification of patients
      according to the TNM, 2) actuarial evaluation of the outcome, 3) reclassification
      of patients according to the involvement of the AC subsite, and 4) reevaluation
      of the outcome according to this latter classification. The results showed that
      the outcome was not well correlated with TNM classification, whereas patients
      with progressively heavier involvement of the AC subsite had a progressively
      worse outcome. On the basis of these data, we suggest that TNM classification of
      cancer involving the AC be implemented by and AC classification, in order to
      better forecast the prognosis and design specific conservative surgery.

PMID- 8651635
TI  - Healing of tympanic membrane after myringotomy during Streptococcus pneumoniae
      otitis media. An otomicroscopic and histologic study in the rat.
AB  - The purpose of our study was to elucidate the course of healing of the tympanic
      membrane (TM) when myringotomy was performed during acute otitis media. The early
      and long-lasting structural changes of the TM were studied in an animal model.
      Rats were inoculated with Streptococcus pneumoniae (PnC) type 3 in the bulla.
      When the infection was manifest, myringotomy was performed. On days 4 and 12, and
      3 and 6 months after myringotomy, the TM status was checked by otomicroscopy and
      TMs were prepared for light and electron microscopy. Comparison was made with PnC
      infected TMs that were not perforated, as well as myringotomized noninfected TMs.
      The infection resolved more slowly in myringotomized ears compared to PnC
      infected ears that were left untouched. After 6 months, the pars tensa of the
      myringotomized infected ears was thickened and showed a disorganized collagen
      structure, compared with myringotomized noninfected ears, in which TMs were
      normalized. The PnC-infected TMs without myringotomy were completely normalized
      after 2 months. We conclude that a combination of bacterial infection and
      myringotomy causes long-lasting changes in TM structure. This impaired structure
      of the connective tissue could be of importance in chronic middle ear disease as
      a presumptive site for retraction and perforation of the TM.

PMID- 8651636
TI  - Radiologic findings in a carcinoma-associated laryngocele.

PMID- 8651637
TI  - Mucosal adenoid squamous cell carcinoma of the head and neck.
AB  - Adenoid squamous cell carcinoma is an uncommon variant of squamous cell
      carcinoma. The lesion is histologically distinctive and it is usually localized
      on the skin of the head and neck region; it only rarely involves the mucosal
      sites. The differential diagnoses include adenosquamous carcinoma, adenoid cystic
      carcinoma, mucoepidermoid carcinoma, basaloid squamous cell carcinoma, and
      metastatic adenocarcinoma. Surgery is the treatment of choice. The biologic
      behavior of this neoplasm is more aggressive when it involves mucosal areas, and
      the prognosis seems worse than that of conventional squamous cell carcinoma.

PMID- 8651638
TI  - Understanding Alzheimer's disease: expect more genes and other things.

PMID- 8651639
TI  - Polymerase chain reaction in situ hybridization--opening Pandora's box?

PMID- 8651640
TI  - Opportunities and challenges in academic neurology: report of the Long Range
      Planning Committee of the American Neurological Association.
AB  - By most measures, academic neurology is thriving as never before, yet convening
      forces are changing the face of academic neurology. This report focuses on
      changes that academic neurology and the American Neurological Association could
      undertake to seize new opportunities and resist damaging potential changes. These
      proposals can be categorized in the following four major goals: (1) enhance the
      quality of a smaller neurology workforce and augment the recruitment of gifted
      young neuroscientists into neurology; (2) foster new diversity in neurological
      investigation, including clinical research in neurology; (3) document the
      benefits and relative costs of neurological care, in general, and of academic
      neurology, in particular; and (4) foster the role of neurologists as teachers to
      medical caregivers at all levels, including medical students, nonneurological
      house staff, and primary practitioners.

PMID- 8651641
TI  - Alzheimer's disease and apolipoprotein E-4 allele in an Amish population.
AB  - Alzheimer's Disease (AD) is a complex genetic disorder with four loci already
      identified. Mutations in three of these, the amyloid precursor protein,
      presenilin I, and presenilin II, cause early-onset AD. The apolipoprotein E
      (APOE) gene contributes primarily to late-onset AD. The APOE-4 allele acts in a
      dose-related fashion to increase risk and decrease the age-of-onset distribution
      in AD. We examined the effect of APOE on AD in a previously unstudied Amish
      population that has a lower prevalence of dementia compared with other
      populations. We sampled a large inbred family with 6 late-onset AD members. We
      also genotyped 53 individuals from the general Amish population as controls for
      the APOE allele frequency estimates. The frequency of the APOE-4 allele in the
      Amish controls was 0.037 +/- 0.02. This differed significantly compared with
      three independent sets of non-Amish white controls (p < 2 x 10(-4), p < 6 x 10(
      5), and p < 2 x 10(-6)). In addition, all Amish AD-affected individuals had APOE
      3/3 genotypes; no APOE X/4 or 4/4 individuals were observed. We suggest that the
      lower frequency of dementia in the Amish may be partially explained by the
      decreased frequency of the APOE-4 allele in this population, and that the inbred
      nature of this pedigree, with its strong clustering of cases contrasted against
      the lower frequency of dementia, indicates that additional genetic factors
      influence late-onset AD.

PMID- 8651642
TI  - Localization of HIV-1 in human brain using polymerase chain reaction/in situ
      hybridization and immunocytochemistry.
AB  - Human immunodeficiency virus type 1 (HIV-1) infects the brains of a majority of
      patients with the acquired immunodeficiency syndrome (AIDS), and has been linked
      to the development of a progressive dementia termed "HIV-associated dementia."
      This disorder results in severe cognitive, behavioral, and motor deficits.
      Despite this neurological dysfunction, HIV-1 infection of brain cells does not
      occur significantly in neurons, astrocytes, or oligodendrocytes, but is
      restricted to brain macrophages and microglia. To identify possible low-level or
      latent infection of other brain cells, we combined the techniques of the
      polymerase chain reaction with in situ hybridization for the detection of HIV
      DNA, and used immunocytochemistry to identify the HIV-expressing cells. In the 21
      adult brains studied (15 AIDS and 6 seronegative control brains), we found that
      polymerase chain reaction/in situ hybridization was both sensitive and specific
      for identifying HIV-infected cells. In all brains, the majority of infected cells
      were macrophages and microglia. In several brains, however, a substantial
      minority of cells harboring HIV DNA were identified as astrocytes. Neurons,
      oligodendrocytes, and endothelial cells were not infected with HIV, even in cases
      with HIV-associated dementia. These findings confirm previous data regarding the
      importance of macrophage/microglial infection, and essentially exclude neuronal
      infection in pathogenetic models of HIV-associated neurological disease. These
      data also demonstrate that latent or low-level infection of astrocytes occurs in
      AIDS, a finding that may be of importance in understanding HIV neuropathogenesis.

PMID- 8651643
TI  - A beta-subunit mutation in the acetylcholine receptor channel gate causes severe
      slow-channel syndrome.
AB  - Point mutations in the genes encoding the acetylcholine receptor (AChR) subunits
      have been recognized in some patients with slow-channel congenital myasthenic
      syndromes (CMS). Clinical, electrophysiological, and pathological differences
      between these patients may be due to the distinct effects of individual
      mutations. We report that a spontaneous mutation of the beta subunit that
      interrupts the leucine ring of the AChR channel gate causes an eightfold increase
      in channel open time and a severe CMS characterized by severe endplate myopathy
      and extensive remodeling of the postsynaptic membrane. The pronounced
      abnormalities in neuromuscular synaptic architecture and function, muscle fiber
      damage and weakness, resulting from a single point mutation are a dramatic
      example of a mutation having a dominant gain of function and of hereditary
      excitotoxicity.

PMID- 8651644
TI  - Gender differences in autoimmune demyelination in the mouse: implications for
      multiple sclerosis.
AB  - Gender-related differences in experimental allergic encephalomyelitis (EAE) were
      examined in the SJL mouse with the purpose of characterizing an animal model
      ideal for the study of gender-related differences in multiple sclerosis (MS). For
      the model to allow for study of the induction and the effector phase of disease,
      the adoptive EAE model was characterized. First, the SJL strain was shown to be
      nonresponsive with regard to the development of antisyngeneic HY-specific
      responses in females, thereby permitting intergender adoptive transfers of T
      lymphocytes during EAE induction. Then, when myelin basic protein (MBP)-specific
      T cells derived from females were adoptively transferred into female and male
      recipients, female recipients demonstrated a more rapid onset of disease (p =
      0.01), greater maximal acute-phase clinical scores (p < 0.0001) and greater mean
      clinical scores (p < 0.0001) compared with male recipients. When MBP-specific T
      cells derived from males were adoptively transferred, female recipients again
      tended to be more severely affected. Histopathologic analysis revealed
      quantitative differences between genders that paralleled clinical expression.
      These results document a clear gender-related difference in adoptive EAE in the
      SJL, with clinical and histopathologic disease greater in females compared with
      males. This model will be a useful tool for addressing autoimmune mechanisms
      underlying gender-related differences in MS.

PMID- 8651645
TI  - The neuropathology of chromosome 17-linked dementia.
AB  - We recently described a family with chromosome 17-linked dementia, characterized
      clinically by disinhibition-dementia-parkinsonism-amyotrophy complex. We report
      now the neuropathology of 6 affected family members. This included
      semiquantitative scoring of neuronal loss, gliosis, and spongiosis and
      immunocytochemical and ultrastructural characterization of neuronal and glial
      inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and
      spongiosis of limbic neocortical areas and frontal, temporal, and occipital
      association areas. Similar changes were present in subcortical nuclei, most
      severe in the substantia nigra, but also involved the ventral striatum and
      amygdala. The hippocampus was spared except for degeneration of the afferent
      perforant tract, secondary to entorhinal nerve cell loss. Argyrophilic neuronal
      inclusions, with a characteristic immunocytochemical profile, were found in
      brainstem nuclei, hypothalamus and basal ganglia. Ultrastructurally, in 3
      patients these inclusions showed hitherto undescribed abnormally assembled
      filaments. Glial cytoplasmic inclusions were widespread in white matter
      structures. Immunocytochemistry failed to demonstrate the protease-resistant
      prion protein. The pathology appears to be unique, involving various cortical and
      subcortical structures, and is consistent with the clinical findings of Kluver
      Bucy-like syndrome, parkinsonism, and frontal lobe dementia. For this entity we
      suggest the term "chromosome 17-linked dementia."

PMID- 8651646
TI  - Evidence for anticipation and association of deletion size with severity in
      facioscapulohumeral muscular dystrophy. The FSH-DY Group.
AB  - Facioscapulohumeral muscular dystrophy (FSHD) is characterized by marked inter-
      and intrafamilial heterogeneity in its clinical expression. The contribution of
      genetic factors to this variability is not well characterized. We examined the
      relationship of phenotype to genotype in a clinically and genetically well
      defined FSHD population. Quantitative isometric myometry (QMT) scores, normalized
      for age, gender, and height, were used to quantify disease severity. We found a
      significant (r = 0.92, p < 0.004) correlation between disease severity and the
      size of the 4q35-associated deletion. In addition, when relative disease severity
      of parent-offspring pairs was compared, the offspring were found to be
      significantly more severely affected (p = 0.011). This generational effect
      suggests the presence of anticipation in FSHD and raises the possibility of an
      underlying dynamic mutation.

PMID- 8651647
TI  - Abnormalities of smooth eye and head movement control in Parkinson's disease.
AB  - The control of horizontal head and eye movements was examined in 13 nondemented
      patients with Parkinson's disease (PD) of mild to moderate severity. During
      pursuit of single-frequency sine waves, smooth component eye velocity was lower
      in the PD group at frequencies of 1.2 Hz and above; but the differences in
      overall eye displacement were even greater, indicating an impaired ability to
      generate catch-up saccades at high frequencies. A corresponding deficit in
      saccadic performance was observed during a high-frequency saccadic tracking task
      where predictive saccades of reduced gain and variable timing were generated.
      During pursuit of pseudo-random target motion with varying degrees of
      predictability, small differences in smooth component eye velocity were observed,
      but prediction was otherwise well preserved in the patient group. Vestibulo
      ocular reflex (VOR) suppression was also normal during head-free pursuit. No
      major improvement in smooth pursuit gain could be attributed to drug treatment,
      based on a comparison of patient results before and after administration of
      levodopa.

PMID- 8651648
TI  - MELAS- and Kearns-Sayre-type co-mutation [corrected] with myopathy and autoimmune
      polyendocrinopathy.
AB  - A 35-year-old woman with features of Kearns-Sayre syndrome consisting of
      progressive ptosis, ophthalmoparesis, mitochondrial myopathy, and pigmentary
      retinopathy also had autoimmune polyglandular syndrome type 11 (Addison's
      disease, autoimmune insulin-dependent diabetes mellitus, Hashimoto's thyroiditis,
      and primary ovarian failure). There was no history of similarly affected
      relatives. Analysis of muscle mitochondrial DNA (mtDNA) revealed a 2,532-bp
      deletion of the type seen in Kearns-Sayre syndrome as well as a heteroplasmic
      A3243G mutation in the tRNA-Leu(UUR) gene of the type seen in mitochondrial
      myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). The
      patient's blood and her mother's blood harbored the A3243G mutation but not the
      deletion, and the maternal grandmother's blood had neither mutation. In muscle,
      the species of mtDNA harboring the deletion was exclusively associated with the
      species harboring the A3243G mutation, suggesting that the point mutation
      predisposed to the large-scale deletion. The mtDNA species with both mutations
      accounted for 88% of total muscle mtDNA. Other and as yet unrecognized point
      mutations in mtDNA might also be associated with, and possible causally related
      to, large-scale mtDNA deletions.

PMID- 8651649
TI  - Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.
AB  - We sequenced the prion protein gene and studied the biochemical characteristics
      and the intracerebral distribution of protease-resistant prion protein with
      Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob
      disease. We identified four groups of subjects defined by the genotype at codon
      129 of the prion protein gene, the site of a common methionine/valine
      polymorphism, and two types of protease-resistant prion proteins that differed in
      size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct
      clinicopathological features that corresponded to previously described variants.
      The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the
      Heidenhain variant were linked to methionine homozygosity at codon 129 and to
      "type 1" protease-resistant prion protein. The atypical and rarer variants such
      as that with dementia of long duration, the ataxic variant, and the variant with
      kuru plaques were linked to different genotypes at codon 129 and shared the "type
      2" protease-resistant prion protein. Our data indicate that the sporadic form of
      Creutzfeldt-Jakob disease comprises a limited number of variants. The
      methionine/valine polymorphism at codon 129 of the prion protein gene and two
      types of protease-resistant prion proteins are the major determinants of these
      variants. These findings suggest the existence of prion strains in humans and
      provide the molecular basis for a novel classification of sporadic Creutzfeldt
      Jakob disease.

PMID- 8651650
TI  - The syndrome of posterior choroidal artery territory infarction.
AB  - Posterior choroidal artery (PChA) territory infarcts remain the least well-known
      type of thalamic infarcts. Our study of 10 personal cases, selected from 2,925
      stroke patients admitted consecutively to a community-based primary care center,
      and 10 published cases of unilateral PChA territory infarct suggests that they
      can often be differentiated clinically from other thalamic infarcts. Patients
      with PChA territory infarct associated with superficial posterior cerebral artery
      territory infarct or with another infarct were excluded. Damage was
      characteristically limited to the lateral geniculate body, pulvinar, posterior
      thalamus, hippocampus, and parahippocampal gyros, without involvement of the
      upper midbrain and the anterior nucleus of thalamus. In lateral PChA territory
      infarct, the most common clinical manifestations included homonymous
      quadrantanopsia, with or without hemisensory loss and neuropsychological
      dysfunction (transcortical aphasia, memory disturbances). A homonymous horizontal
      sectoranopsia is exceptional but particularly suggestive of the involvement of
      the lateral geniculate body in this territory. Media] PChA territory infarct was
      less frequent. Its neurologic picture was dominated by eye movement disorders not
      particularly suggestive of thalamic involvement. Late disability was usually
      absent or slight, being related to pain and delayed abnormal movements. The most
      common stroke etiology was presumed small-vessel occlusive disease.

PMID- 8651651
TI  - Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study
      of 56 patients.
AB  - Inclusion body myositis, a chronic inflammatory disorder, is the most common
      cause of myopathy in adults over the age of 50. Diagnosis is based on clinical
      features and distinctive morphological findings by both light and electron
      microscopy. The causes of inclusion body myositis are still unknown.
      Ultrastructural mitochondrial changes and ragged-red fibers are common in
      patients with sporadic inclusion body myositis, and multiple [correction of
      mutiple] mitochondrial DNA (mtDNA) deletions have been reported in 3 such
      patients, suggesting that mtDNA mutations may have a pathogenetic role. We
      studied 56 patients with sporadic inclusion body myositis, using a combination of
      clinical, morphological, biochemical, and molecular genetic analyses to determine
      the frequency and the distribution of mtDNA deletions. Using the polymerase chain
      reaction, we found multiple mtDNA deletions in 73% of patients, compared to 40%
      of normal age-matched control subjects and 47% of disease control subjects. The
      presence of deletions correlated with morphological evidence of ragged-red,
      cytochrome c oxidase-negative fibers, and with defects of complexes I and IV of
      the electron transport chain. Although aging may account for a proportion of
      mtDNA deletions in patients with sporadic inclusion body myositis and control
      subjects, mtDNA alterations may be accelerated in sporadic inclusion body
      myositis.

PMID- 8651652
TI  - Analysis of chromosome 5q13 genes in amyotrophic lateral sclerosis: homozygous
      NAIP deletion in a sporadic case.
AB  - Although defects in the gene encoding the enzyme cytosolic copper/zinc superoxide
      dismutase (SOD1) have been reported in 20% of familial amyotrophic lateral
      sclerosis (ALS) patients, the etiology of the remaining familial cases and the
      more common sporadic form of the disease remains unknown. Recently, deletions of
      the neuronal apoptosis inhibitory protein gene NAIP, of the survival motor neuron
      gene SMN, and of a further cDNA fragment, XS2G3, have been reported in childhood
      onset proximal spinal muscular atrophy (SMA), another disorder with pathology
      restricted to the motor system. We have therefore investigated the possibility of
      alterations in SMN and NAIP in 154 patients with ALS (135 sporadic cases, 17
      familial cases). None of these patients revealed mutations in SMN by single
      strand conformation polymorphism analysis. A single patient revealed a partial
      deletion of NAIP, with a homozygous absence of NAIP exon 5. While it is possible
      that this individual is one of the rare carriers of SMA who show NAIP deletions,
      a further explanation is that the NAIP deletion is in some way contributing to
      the ALS phenotype in this individual.

PMID- 8651653
TI  - Lack of association of trinucleotide repeat polymorphisms in very-low-density
      lipoprotein receptor gene with Alzheimer's disease.
AB  - Inheritance of the apolipoprotein E epsilon 4 allele is a risk factor for
      Alzheimer's disease (AD). A recent report studying Japanese patients suggested
      that a polymorphism of a trinucleotide repeat in the 5' untranslated region of an
      apolipoprotein E receptor, the very-low-density lipoprotein receptor, is
      genetically associated with AD, with overrepresentation of the allele containing
      five copies of the repeat. We determined the allele frequencies of the very-low
      density lipoprotein receptor in 3 white populations totaling 469 individuals. In
      contrast to the previous report, we found no differences in allele frequencies
      between case patients and control subjects. The discrepancy could be due to
      differences in Japanese and white populations. Nonetheless, these data weaken the
      likelihood that this polymorphism in the very-low-density lipoprotein receptor
      gene is strongly associated with AD.

PMID- 8651654
TI  - DR2/DQw1 inheritance and haplotype sharing in affected siblings from multiple
      sclerosis families.
AB  - Although the human leukocyte antigen DR2/DQw1 allele has been associated with
      multiple sclerosis, studies of DR2/DQw1 inheritance in multiple sclerosis
      multiplex families have yielded conflicting results. We examined this question in
      "high-incidence" families, defined as families with more than 50% of siblings
      affected. DR2/DQw1 allele frequencies were significantly increased, particularly
      in mothers and affected siblings (p < 0.0001). The transmission of DR2/DQw1 from
      both parents was more frequent in affected offspring (p = 0.005). While evidence
      for segregation of disease with a particular parental allele was lacking in most
      families, the frequency of haplotype sharing was higher in affected sib pairs (p
      < 0.01).

PMID- 8651655
TI  - Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on
      chromosome 7q.
AB  - Cerebral cavernous angiomas are collections of closely clustered vessels without
      intervening normal brain parenchyma, with microscopic evidence of hemorrhage,
      frequently multiple; they are best visualized with magnetic resonance imaging.
      Familial cerebral cavernous angioma occurs as an autosomal dominant disorder,
      although carriers of the gene are often asymptomatic. Recently, a gene
      responsible for familial cerebral cavernous angioma in a large Hispanic kindred
      was mapped to human chromosome 7q11-22, representing a large segment of DNA
      containing approximately 33 cM (about 33 million base pairs). This distance did
      not allow more restricted isolation of the region containing the familial
      cerebral cavernous angioma gene. In this report, we present a large white kindred
      with familial cerebral cavernous angioma and confirm the mapping to 7q11-22,
      including the genetic markers D7S558/D7S1789 and D7S804. Recombination between
      several markers in the region suggests that the candidate region is distal to
      D7S804. Combining our results with those previously published, we suggest that
      the gene is likely to reside within a 15-cM region bounded by markers D7S660 and
      D7S558/D7S1789. These results should assist the further refinement of the
      candidate region for familial cerebral cavernous angioma and facilitate the
      search for the gene.

PMID- 8651656
TI  - Difficulties in distinguishing sporadic from familial amyotrophic lateral
      sclerosis.
AB  - Mutations of the copper/zinc superoxide dismutase (SOD-1) gene are present in
      around 20% of patients with a family history of amyotrophic lateral sclerosis.
      The finding of these mutations in patients with sporadic amyotrophic lateral
      sclerosis is rare. We describe a family with amyotrophic lateral sclerosis
      associated with the SOD-1 mutation Asp 101 Asn. This mutation was previously
      described as occurring in a patient with sporadic disease. We discuss the
      difficulties in defining truly sporadic amyotrophic lateral sclerosis, and the
      consequent implications on the neurogenetic advice given to other family members.

PMID- 8651657
TI  - Ultrastructural PMP22 expression in inherited demyelinating neuropathies.
AB  - Charcot-Marie-Tooth type 1A (CMT-1A) disease results from a duplication of the
      PMP22 gene on chromosome 17p11.2. A deletion of the same region causes hereditary
      neuropathy with liability to pressure palsies (HNPP). We examined the expression
      of PMP22 in sural nerve biopsies from 2 unrelated patients with CMT-1A, 2
      unrelated patients with HNPP, and control patients. The ultrastructural
      immunocytochemical quantitative analysis of cases of CMT-1A and HNPP showed,
      respectively, an elevated and reduced expression of PMP22 level compared with
      controls.

PMID- 8651658
TI  - Cost-effectiveness analysis: what is it and how will it influence neurology.
AB  - Cost-effectiveness analysis (CEA) refers to a set of research methods that
      consider the resources consumed by a medical technology in decisions about how
      best to use the technology. This analytic method is an evolving, controversial,
      and often misunderstood field in health services research. The basic set of
      principles underlying CEA is deceptively simple, but sufficient methodological
      challenges and controversies exist that have, thus far, limited its use in the
      development of health policy and in bedside decision making. Nonetheless,
      neurologists like other specialty groups may feel concerned that the results from
      such analyses may prove unfavorable to their specialty and the patients they
      serve. This article reviews the fundamental notions surrounding CEA, provides
      examples from the literature with particular relevance to the neurological
      community, and highlights critical issues for neurologists regarding the future
      of CEA.

PMID- 8651659
TI  - mtDNA contributes to neural loss in aging.

PMID- 8651660
TI  - Sudden death from hypoventilation during epileptic seizures.

PMID- 8651661
TI  - Stereotaxic posteroventral pallidotomy in idiopathic Parkinson's disease.

PMID- 8651662
TI  - Evaluation of cisplatin neuroprotection by NT-3.

PMID- 8651663
TI  - Human immunodeficiency virus in brain and correlation with dementia.

PMID- 8651664
TI  - Don't be a victim of surgical smoke.

PMID- 8651665
TI  - A western OR delegation to the People's Republic of China.
AB  - Nursing in the People's Republic of China (PRC) is beginning to revitalize after
      decades of the repression and obliteration of nursing education programs under
      the rule of Mao Tse-tung. A delegation of American, Australian, and Canadian
      perioperative nurses traveled to the PRC for a series of professional exchanges
      with Chinese OR nurse colleagues. The exchange was an affirmation of the common
      commitment to caring that all nurses share.

PMID- 8651666
TI  - Transcultural perioperative nursing in Berlin.
AB  - Political events and military base closures in the early 1990s caused the US Army
      Hospital, Berlin, to extend care to include British military forces and to
      contract the services of civilian German surgeons and nurses. This article
      describes transcultural perioperative nursing in Berlin from 1991 to 1994. It
      also compares the differences between American, British, and German military and
      civilian expectations of OR nurses, anesthesia care providers, and surgeons and
      explores nursing education, licensing, practice issues, and socialized medicine
      in a transcultural environment.

PMID- 8651667
TI  - Promoting perioperative nursing through international cooperation.
AB  - Adequate development of human resources is a challenge facing all societies and
      nations, especially those in transition from one development stage to another.
      Through international cooperation programs, perioperative nurses can share and
      exchange knowledge, experience, and expertise. They also can expand their
      clinical horizons, fostering collegiality and friendships and further advancing
      nursing professionalism internationally. In Israel, we developed and implemented
      a special, short-term course for perioperative nurses from developing countries.
      Planners and participants found this course to be an outstanding experience.

PMID- 8651668
TI  - Video-assisted thoracoscopic releases of scoliotic anterior spines.
AB  - Anterior thoracic discectomy procedures with endplate ablations and posterior
      spinal fusions are advocated for patients with severe scoliosis. These surgical
      procedures traditionally are accomplished through extensive open thoracotomy
      incisions. At Children's Hospital Medical Center, Cincinnati, surgical team
      members have used a minimally invasive procedure, video-assisted thoracoscopic
      surgery (VATS), to release the anterior spines of patients with scoliosis. This
      surgical technique has many benefits, including reduced blood loss, decreased
      postoperative pain, and improved postoperative pulmonary function. Perioperative
      nurses play key roles in the team approach to patient care through provision of
      preoperative education programs for patients and family members, organization of
      OR equipment, anticipation of possible intraoperative complications, and
      postoperative patient care planning. The implementation of a VATS program within
      an institution requires a significant financial investment and a long-term
      commitment to the ongoing education of OR personnel.

PMID- 8651669
TI  - You can be in Jeopardy.
AB  - Clinical nurse educators are challenged continually to develop interesting and
      meaningful education sessions for staff members. At the Mayo Medical Center,
      Rochester, Minn, clinical nurse educators in the surgical services department
      created an education session based on the television game show Jeopardy. Staff
      members found they could remember information presented during the education
      session more easily because of the game show format.

PMID- 8651670
TI  - A perioperative elective for college credit.
AB  - The authors developed a collaborative perioperative elective course between the
      Veterans Affairs Medical Center, Louisville, and Indiana University Southeast,
      New Albany. The course is for students studying for bachelor of science degrees
      in nursing and is offered as a four-hour elective. The course allows nursing
      students to participate more in surgical procedures; learn the proper use, care,
      and cleaning of surgical instruments; and learn nursing theory. Students' and
      staff members' responses have been favorable.

PMID- 8651672
TI  - Application of prediction levels to OR scheduling.
AB  - Many perioperative managers record operating room times (ORTs) and use average
      ORTs to facilitate scheduling of elective surgical procedures. A second
      statistic, the upper 95% prediction level (ie, 95% chance the next ORT will be
      less than the upper prediction level) can be calculated from previous ORTs and
      used in scheduling elective procedures. The author used eight elective surgical
      procedures to test a distribution-free method for calculating ORT upper
      prediction levels. Upper prediction levels can provide perioperative managers
      better knowledge than average ORTs to facilitate decision making during the
      scheduling of elective surgical procedures. This method can be used to find upper
      prediction levels for any desired measure of procedure duration (eg, surgeon,
      scheduled procedure-specific times).

PMID- 8651671
TI  - Effect of continuously warmed i.v. fluids on intraoperative hypothermia.
AB  - The investigators examined the effect of infusing continuously warmed (ie, 37.0
      degrees C [98.6 degrees F]) i.v. fluids in two groups of middle-aged female
      patients undergoing laparoscopic cholecystectomy procedures. They hypothesized
      that increasing i.v. fluid temperature during surgery would decrease patients'
      risk for hypothermia. One group of patients received prewarmed i.v. fluids that
      cooled to room temperature during surgery. The second group received i.v. fluids
      that were warmed continuously by a fluid warmer during the surgical procedures.
      Analyses of covariance, with the first intraoperative temperature measurement
      treated as the covariate, revealed nonsignificant results at the P < .05 level.
      The results suggest that administering continuously warmed i.v. fluids
      intraoperatively has no significant effect on maintaining patients' body
      temperatures during short laparoscopic surgical procedures.

PMID- 8651673
TI  - Becoming knowledgeable in the legislative process can help nurses shape their own
      future.

PMID- 8651674
TI  - Quality circles as problem-solving tools in perioperative settings.

PMID- 8651675
TI  - Perioperative nursing certification and recertification issues.

PMID- 8651676
TI  - Cost v cost-effective.

PMID- 8651677
TI  - Inadvertent hypothermia in elderly surgical patients.

PMID- 8651678
TI  - Environmental laws and the perioperative setting.

PMID- 8651680
TI  - Recommended practices for traffic patterns in the perioperative practice setting.
      Association of Operating Room Nurses.

PMID- 8651679
TI  - Recommended practices for use and selection of barrier materials for surgical
      gowns and drapes. Association of Operating Room Nurses.

PMID- 8651681
TI  - The construction of a stable starch-fermenting yeast strain using genetic
      engineering and rare-mating.
AB  - To develop a yeast strain that is able to produce ethanol directly from starch,
      alpha-amylase cDNA (originated from mouse salivary glands) was introduced into
      the hyploid Saccharomyces diastiticus cells secreting glucoamylase by using a
      linearized integrating vector. The integrating vector contains a LEU2 gene and
      the inside of the LEU2 gene was cut by KpnI to make the linearized vector. One of
      the transformants exhibited 100% mitotic stability after 100 generations of cell
      multiplication. To improve its ethanol-fermentability, the haploid transformant
      was rare-mated with a polyploid industrial strain having no amylase activity. The
      resulting hybrid RH51 produced 7.5 (w/v) ethanol directly from 20% (w/v) soluble
      starch and its mitotic stability was 100% at the end of fermentation.

PMID- 8651682
TI  - The effect of alternative carbohydrates on the growth and antibody production of
      a murine hybridoma.
AB  - A murine hybridoma (CC9C10) was adapted to grow in media containing alternative
      carbohydrates to glucose. Cell yields relative to the glucose-based culture
      decreased in order of the following supplements: glucose = maltose > galactose >
      fructose = sorbitol = xylitol, although significant yields (> 50% of glucose
      control) were observed in all cultures. In the absence of glucose, glutamine
      consumption rates were enhanced significantly. Antibody production was directly
      related to the viable cell concentration in each culture and was independent of
      the phase of culture. A high specific antibody productivity (qMab) was observed
      in the cultures containing the polyols, sorbitol, or xylitol, even though the
      cell yields and growth rates were lower than the glucose-based control. The
      measured qMab in the xylitol culture was 5.6 x that of the glucose culture and
      the volumetric yield of MAb was 29% higher.

PMID- 8651683
TI  - Inactivation of cysteine proteases.
AB  - The cysteine proteases papain and cathepsin B are inactivated by a Michael
      acceptor, a peptidyl-beta-chloro-alpha, beta-unsaturated ester (N-Ac-L-Phe-NHCH2
      CCl=CH-COOMe). Inactivation occurred concomitant with chloride release which was
      stoichiometric with the amount of enzyme. This result is consistent with
      nucleophilic attack of the active site cysteine on the beta-carbon of the
      inhibitor, followed by expulsion of chloride ion. Inactivation by this class of
      compounds requires the carbon skeleton about the double bond to be in the trans
      configuration. The cis isomer was a competitive inhibitor. The difference in the
      mode of inhibition between the isomers is probably due to non-productive binding
      of the cis isomer due to bulky chlorine substituent in the beta-position.

PMID- 8651685
TI  - Mechanism of rabbit muscle enolase: identification of the rate-limiting steps and
      the site of Li+ inhibition.
AB  - Steady-state and non-steady-state techniques have been used to identify the rate
      limiting steps for beta beta enolase (rabbit muscle enolase), at pH 7.1, with
      Mn2+ as the required cation. A minimum mechanism for enolase includes eight
      steps, [see text] where S is phosphoglycerate, P is phosphoenolpyruvate (PEP), I
      is the carbanion intermediate, M is Me2+ and EM is the holoenolase (i.e., the
      first Me2+ is bound). Asterisks represent a different conformation of the
      quaternary complexes. At pH 7.1, the primary kinetic isotope effect = 1, and
      kappa(cat) decreases as solvent viscosity increases. The changes in protein
      fluorescence that occur upon substrate binding and product release [EMSM <->
      (EMSM)* and (EMPM)* <-> EMPM] were followed by stopped-flow fluorimetry; the
      viscosity dependence of the observed rates was also determined. The data support
      the following mechanism. Product formation is fast and precedes the slow steps of
      the reaction, consistent with the observation of a pre-steady-state burst of PEP.
      The rate-limiting steps are kappa(+6) the conformational change associated with
      product release, and kappa(+8) the dissociation of PEP. Li+ inhibits the activity
      of enolase by increasing kappa(+6) and kappa(-3), thus decreasing the steady
      state concentration of (EMSM)*.

PMID- 8651684
TI  - Effect of superoxide dismutase mimics on radical adduct formation during the
      reaction between peroxynitrite and thiols--an ESR-spin trapping study.
AB  - We have reexamined the formation and reactions of radicals formed from
      peroxynitrite (ONOO-)-mediated oxidation of glutathione (GSH), L-cysteine (Cys),
      N-acetyl-D,L-penicillamine (NAP), and sodium bisulfite (NaHSO3). Sulfur-centered
      and superoxide union radicals were trapped using 5,5-dimethyl-1-pyrroline-N-oxide
      (DMPO) and the radical adducts were analyzed by electron spin resonance (ESR)
      spectroscopy. The following sulfur-centered radicals were detected: glutathionyl
      radical (GS') from GSH, L-cysteinyl radical ('Scys) from L-cysteine, N-acetyl-D,L
      penicillamine thiyl radical ('SNAP) from NAP, and sulfite anion radical (SO3-.)
      from NaHSO3. Additionally the formation of the hydroxyl radical adduct of DMPO
      (DMPO/'OH) was observed. DMPO/'OH formation was totally inhibited by low
      molecular-weight superoxide dismutase (SOD) mimics. This suggests that DMPO/'OH
      was formed from the decay of the superoxide radical adduct of DMPO. In the
      presence of SOD mimics, the DMPO-sulfur-centered adducts were more persistent,
      suggesting that O2-. is partially responsible for the instability of DMPO-thiyl
      adducts. Sulfur-centered radicals formed during oxidation of thiols and sulfite
      by peroxynitrite react with ammonium formate to form the carbon dioxide anion
      radical (CO2-.). We conclude that sulfur-centered radicals produced from the
      oxidation of thiols and sulfite by peroxynitrite arise from a hydroxyl-radical
      independent mechanism. Biological implications of peroxynitrite-mediated
      oxidation of thiols as well as the use of SOD mimics in biological spin-trapping
      are discussed.

PMID- 8651686
TI  - Mechanical changes after histamine activation of intact single vascular smooth
      muscle cells.
AB  - Although several different models have been proposed to explain force maintenance
      in vascular smooth muscle, the molecular mechanism responsible for this phase of
      contraction has yet to be elucidated. To investigate the molecular mechanism for
      force maintenance, force and stiffness were measured during (1 microM histamine)
      activation of single intact arterial smooth muscle cells. After histamine
      stimulation, the rise in quadrature stiffness preceded force (P < 0.05) and
      reached a steady state plateau before force (P < 0.05). These data suggest that
      the number of cycling cross-bridges increases during force activation and then
      remains constant during force maintenance. In-phase stiffness, on the other hand,
      continued to increase in amplitude after force had reached a steady state. The
      increase in the in-phase stiffness during force maintenance suggests that during
      force maintenance either a population of cross-bridges in an attached nonforce
      producing state develop or noncross-bridge force bearing structures are formed.

PMID- 8651687
TI  - Induction of lithostathine/reg mRNA expression by serum from rats with acute
      pancreatitis and cytokines in pancreatic acinar AR-42J cells.
AB  - During the acute phase of pancreatitis, expression of most pancreatic enzymes
      decreases, whereas mRNAs of pancreatitis associated protein and lithostathine/reg
      increase dramatically. In the present study we have investigated the effect of
      serum from rats with acute pancreatitis (SAP) and cytokines on the
      lithostathine/reg mRNA expression in AR-42J cells. Lithostathine/reg mRNA was
      strongly induced by SAP in a dose-dependent manner. Induction was abolished by
      preheating the SAP or by treating the cells with cycloheximide. Treatment with
      interleukins (IL) IL-1 or IL-6 or dexamethasone alone was ineffective.
      Combination of IL-1 with IL-6 was also ineffective. Combination of IL-6 with
      dexamethasone resulted in strong induction of the lithostathine/reg gene, but the
      further addition of IL-1 to the mixture reduced induction. Treatment with tumor
      necrosis factor-alpha (TNFalpha) or interferon-gamma (IFNgamma) induced
      lithostathine/reg mRNA expression. Combination of dexamethasone with TNFalpha or
      IFNgamma showed an inhibitory effect on lithostathine/reg mRNA expression. These
      findings suggest that expression of the lithostathine/reg mRNA during acute
      pancreatitis could be mediated by specific combinations of cytokines and/or
      glucocorticoids.

PMID- 8651688
TI  - Isolation and characterization of membrane vesicles of Saccharomyces cerevisiae
      harboring the high-affinity phosphate transporter.
AB  - Membrane vesicles with an inside-out orientation were isolated from the plasma
      membrane of Saccharomyces cerevisiae by an improved aqueous two-phase
      partitioning technique. The activity of the orthovanadate-sensitive H+-pumping
      ATPase, the plasma membrane marker, was highly enriched by the partitioning
      technique. The obtained results suggest that the membrane vesicles produced were
      predominantly oriented inside-out. The isolated plasma membrane vesicles
      displayed cross-reactions with antibodies raised against synthetic peptide
      corresponding to the N-terminal (residues 1-10) and the C-terminal (residues 578
      597) regions of the plasma membrane phosphate transporter encoded by the PHO84
      gene and the H+-pumping ATPase of S. cerevisiae. The purified membrane vesicles
      catalyzed a derepressible inhibitor-sensitive phosphate uptake at levels
      comparable with the situation in intact cells of S. cerevisiae indicating that
      transport of phosphate across the membrane is both functional and bidirectional.
      The PHO84 transporter harbored in isolated plasma membranes could moreover be
      enriched in a high state of purity by immunoaffinity chromatography using
      immobilized anti-PHO84 antibodies.

PMID- 8651690
TI  - Similarities and differences between the properties of native and recombinant
      Na+/K+-ATPases.
AB  - Progress of mutagenesis studies on the relation of the structure of Na+/K+-ATPase
      to its reaction mechanism has been impeded by the paucity of information on the
      properties of small amounts of impure recombinant enzyme obtained in the
      currently available expression systems, and the uncertainty of whether expression
      in a new environment alters the various catalytic activities of this membrane
      enzyme. Hence, our aim was to make a detailed comparison of the properties of the
      extensively studied canine kidney Na+/K+-ATPase with those of its alpha1,beta1
      subunits expressed in the baculovirus-infected Sf-9 cells. The active fraction of
      the recombinant enzyme, containing 10-20% of the expressed a subunits, was found
      to have normal molar activity, all the partial reactions, and the ability to
      catalyze ATP-dependent Na+/K+ exchange after reconstitution into proteoliposomes.
      Comparison of steady-state kinetics of the hydrolytic activities of recombinant
      and native enzymes showed that (a) ATP and Na+ plots of Na+-ATPase were the same
      in the two preparations; (b) apparent K+ affinity of K+-phosphatase of
      recombinant enzyme was lower than that of kidney enzyme; and (c) for Na+/K+-
      ATPase activity, apparent K+ affinity of recombinant enzyme was lower, and its
      apparent Na+ and ATP affinities were higher than those of kidney enzyme. The two
      enzymes had similar ADP- and K+-sensitive phosphointermediates, identical
      affinities for ouabain, and similar ligand sensitivities of dissociation rates of
      ouabain-enzyme complexes. Evidently, the recombinant enzyme has reduced affinity
      at cytoplasmic K+ sites, but no changes at multiple Na+, ATP, and ouabain binding
      sites. Likely causes of this selective change include altered glycosylation state
      of beta and interactions among active and inactive recombinant enzymes. The
      present results provide the necessary database for the appropriate use of an
      expression system in structure-function studies on canine alpha1,beta1 isoform of
      Na+/K+-ATPase, and indicate the need for similar studies on recombinant Na+/K+
      ATPases obtained in other expression systems.

PMID- 8651689
TI  - Identification and characterization of cytochrome P4501A1 amino acid residues
      interacting with a radiolabeled photoaffinity diazido-benzphetamine analogue.
AB  - The photolabile benzphetamine analogue N-(p-azidobenzyl)-N-methyl-p
      azidophenetylamine (N3-BP-N3) and its tritiated derivative were synthesized and
      used as photoaffinity ligands for P4501A1 substrate binding. The enzymatic
      activity of P4501A1 toward ethoxycoumarin was competitively inhibited by N3-BP
      N3. After irradiation with UV light a radioactive photolysis product remained
      bound to P4501A1. After large scale labeling in the absence and in the presence
      of alpha-naphthoflavone, P-450 was digested with 1-p-tosyl-amino-2-phenylethyl
      chloromethyl ketone-treated trypsin and the resultant peptide fragments were
      separated with HPLC on a reverse-phase column. Six peptides with increased levels
      of incorporated radioactivity were detected and from a competition experiment in
      the presence of the inhibitor, four of them could be tentatively assigned as
      involved in substrate interaction. Amino acid sequences were determined and
      compared with the primary P-4501A1 sequence. N3-BP-N3 can bind amino acid
      residues through both ends of the molecule and, therefore, crosslinked peptides
      could be identified. Alignment of the primary structure of cytochrome P4501A1
      with that of cytochrome P450102 revealed that two of the isolated crosslinked
      peptides can be placed in the vicinity of heme (in the L helix region and beta10
      beta11 sheet region of cytochrome P450102) and could be involved in substrate
      binding. The other two peptides were located on the surface of the protein with
      the label bound specifically to Lys residues that were predicted to be involved
      in reductase-P450 interaction.

PMID- 8651692
TI  - Reversible unfolding of Escherichia coli alkaline phosphatase: active site can be
      reconstituted by a number of pathways.
AB  - Acid-induced and guanidine hydrochloride (GdnCl)-induced reversible unfolding of
      Escherichia coli alkaline phosphatase (AP) was characterized under equilibrium
      conditions. The protein was exposed to extreme conditions of pH 2.0 or 6 M GdnCl
      and was subsequently returned to normal conditions. Associated changes in the
      protein structure was probed by various spectroscopic methods. The changes in the
      functional properties were monitored by measuring enzymatic activity, capacity to
      renature spontaneously upon removal of the denaturant, and renaturation in
      presence of various site-specific and nonspecific effector molecules, in the
      absence and presence of beta-mercaptoethanol. Analysis of the fluorescence and CD
      spectra showed that the unfolding of the organized structures was much more
      extensive in 6 M GdnCl than at pH 2.0. Intrachain S-S bonds in each unfolded
      state were accessible to reduction by beta-mercaptoethanol. The effectors Zn2+
      and ATP induced renaturation of active site only under reducing conditions,
      whereas Triton X-100 or alpha-crystallin needed the presence of some organized
      structure. The reconstituted protein from each denatured state without or with an
      effector showed different CD spectra. It is concluded that the active site domain
      of AP could be reconstituted independently of other structural domains in
      different pathways.

PMID- 8651691
TI  - Characterization and immunohistochemical localization of the glycoconjugates of
      the rabbit bladder mucosa.
AB  - An impairment of the mucosal glycoconjugates could be an important factor in the
      development of bladder disorders such as interstitial cystitis. However, very
      little definitive biochemical information is available on the glycoco-jugate
      components of the mammalian bladder mucosa. In this-study, the mucosa from
      metabolically radiolabeled rabbit bladder was separated, delipidated, and
      digested with protease, and the released glycosaminoglycans and glycopeptides
      were fractionated. About 80 and 36% of the nondialyzable tritium and 35S
      activities, respectively, was associated with the sialoglycopeptide fractions.
      The balance of the total tritium activity in the protease digest was in
      glycosaminoglycans identified as hyaluronan, chondroitin sulfates, and heparan
      sulfate. Immunohistochemical examination using anti-heparan sulfate antibodies,
      including one against mouse syndecan-1, indicated the presence of heparan sulfate
      proteoglycan in the epithelium. In contrast, there was no significant staining of
      the bladder epithelium with anti-chondroitin-4- and 6-sulfate antibodies or
      hyaluronan-binding protein. The lamina propria and muscle layers showed strong
      staining with anti-chondroitin-4-sulfate antibody and hyaluronan-binding protein
      and weak staining with anti-chondroitin-6-sulfate antibody. The insignificant
      levels of glycosaminoglycans in the glycocalyx of bladder mucosa epithelium
      suggest that glycosaminoglycans may be less important than other glycoconjugates
      in maintaining normal epithelial function and in bladder disorders such as
      interstitial cystitis.

PMID- 8651693
TI  - Association of the type I regulatory subunit of cAMP-dependent protein kinase
      with cardiac myocyte sarcolemma.
AB  - Cardiac sarcolemmal vesicles purified from bovine and porcine left ventricles
      contained approximately 45 pmol of cAMP-dependent protein kinase (PKA) regulatory
      (R) subunit per milligram membrane protein based on [3H]cAMP-binding activity.
      Less than 26% of this activity was complexed with the catalytic subunit forming
      the type H holoenzyme of PKA. The remainder was contributed by the free type I R
      subunit (RI). Purification of sarcolemma with buffers containing 0.15 M NaCl
      instead of 0.75 M NaCl did not affect the ratio of RI to RII, nor did it increase
      the total amount of membrane-associated cAMP-binding or kinase activity. Canine,
      rabbit, and rat heart sarcolemma also contained RI, but in highly varying
      proportions compared with RII as determined by 8-N3-[32P]cAMP photoaffinity
      labeling. Analysis of sarcolemmal vesicles from isolated porcine ventricular
      myocytes demonstrated that this cell type was the source of the membrane
      associated RI. The results indicate that sarcolemmal RI must be considered as a
      factor that could influence the varied responses of the heart to agents that
      elevate intracellular cAMP.

PMID- 8651694
TI  - Cosolvent-induced adsorption and desorption of serum proteins on an amphiphilic
      mercaptomethylene pyridine-derivatized agarose gel.
AB  - We studied the effects of the following cosolvents on the adsorption and
      desorption of serum proteins from an amphiphilic mercaptomethylene pyridine
      derivatized agarose gel: glucose, sucrose, polyethylene glycol (PEG), 2-methyl
      2,4-pentanediol (MFD), sorbitol, pentaerythritol, glycerol, and Na2SO4. The water
      structuring salt 0.4 M Na2SO4 was the most potent promoter of protein adsorption,
      followed by 5 M sorbitol and, to a lesser extent, 0.2 M PEG 1000 and 2.25 M MPD.
      The other cosolvents (4 M glucose, 1.5 M sucrose, 0.3 M pentaerythritol, and 7.6
      M glycerol) were unable to promote protein adsorption to the gel. Attempts to
      modulate the salt-promotion effect of Na2SO4 with different cosolvents
      demonstrated the occurrence of synergistic effects for pentaerythritol, sorbitol,
      and glucose and antagonistic effects for the other cosolvents. Sorbitol and
      glycerol were found to be the most interesting co-solvents studied, as the first
      promoted protein adsorption, whereas the other disrupted protein interaction. As
      a consequence of these novel findings we propose sorbitol and glycerol, both well
      known protein stabilizers, as possible alternatives to water-structuring salts
      during the adsorption phase and to deleterious organic solvents during the
      desorption phase on amphiphilic gels.

PMID- 8651695
TI  - Isolation and characterization of two distinct growth hormone cDNAs from the
      goldfish, Carassius auratus.
AB  - As a first step toward the development of a ribonuclease protection assay for
      studying the regulation of growth hormone (GH) gene expression in pituitary cells
      of the goldfish, Carassius auratus, we report the isolation of two cDNA clones
      encoding goldfish GH from a cDNA library prepared from pituitary poly(A)+ RNA.
      The complete nucleotide sequences of these two GH cDNA clones have been
      determined and both of them were predicted to encode a polypeptide of 210 amino
      acids (aa) including a putative signal peptide of 22 aa. One of the GH cDNAs
      encodes a polypeptide (gfGHI) with five cysteine residues (similar to other carp
      Ms), whereas another encodes a polypeptide (gfGHII) with four cysteine residues
      (similar to most teleostean GHs). Because these two GH cDNAs have distinct
      nucleotide sequences at their coding and 3' untranslated regions, they are likely
      to be encoded by two different genes.

PMID- 8651696
TI  - Nitric oxide inhibits peroxynitrite-induced production of hydroxyeicosatetraenoic
      acids and F2-isoprostanes in phosphatidylcholine liposomes.
AB  - Lipid peroxidation is a component of various pathologies associated with nitric
      oxide (NO). It has been suggested that in vivo production of peroxynitrite (ONOO
      ) is responsible for the detrimental effects of pathologies associated with NO.
      To investigate the role of NO and ONOO- in the formation of specific lipid
      peroxidation products, liposomes of phosphatidylcholine were incubated at 37
      degrees C for 1 h with various NO sources [NO, diethylamine NONOate (DEA/NO)] or
      ONOO-sources [3-morpholinosydnonimine-HCl (Sin-1), ONOO-]. Gas chromatography
      mass spectrometry was used to quantify the formation of hydroperoxy- and
      hydroxyeicosatetraenoic acids (HETEs) and F2-isoprostanes. Peroxynitrite (0.5 mm)
      caused significant oxidation of phosphatidylcholine liposomes as measured by the
      increased formation of HETEs and F2-isoprostanes. NO, either added directly to
      the liposomes as a bolus or delivered by slow diffusion or via the donor compound
      DEA/NO, caused no lipid peroxidation itself and significantly inhibited both iron
      and ONOO--induced lipid peroxidation. Sin-l (1 mM), which releases both NO and
      superoxide, resulted in minor increases in peroxidation and did not inhibit iron
      induced HETE formation. We conclude that peroxynitrite but not nitric oxide can
      directly cause lipid peroxidation and that NO can act as an antioxidant by
      terminating lipid radical chain propagation reactions.

PMID- 8651697
TI  - The omega-hydroxlyation of lauric acid: oxidation of 12-hydroxlauric acid to
      dodecanedioic acid by a purified recombinant fusion protein containing P450 4A1
      and NADPH-P450 reductase.
AB  - The recombinant fusion protein rF450[mRat4Al/mRatOR]L1, containing the heme
      domain of P450 4A1 and the flavin domains of NADPH-P450 reductase, when incubated
      with dilaurylphosphatidylcholine (DLPC), Chaps, cytochrome b5, and a 20-fold
      excess of purified NADPH-P450 reductase, catalyzes the omega- oxidation of lauric
      acid at a rate of about 300 nmol/min/nmol P450. This is the first report of a
      mammalian P450 enzyme with such a high turnover number. The resultant 12
      hydroxydodecanoic acid [12-hydroxylauric acid (12-OH LA)] is further oxidized by
      the P450 oxygenase reaction to dodecanedioic acid (decane-1,10-dicarboxylic acid)
      via 12,12-dihydroxydodecanoic acid. Spectral binding studies show that 12-OH LA
      inhibits the binding of lauric acid to the active site of P450 with a Ki of about
      1.9 microM. The construction and expression of recombinant P450 4A1 containing a
      six-member polyhistidine domain at the carboxy-terminus of the protein is
      described. Reconstitution experiments with this purified recombinant P450 4A1,
      DLPC, Chaps, b5, and purified NADPH-P450 reductase show results similar to those
      obtained with the purified fusion protein, albeit at lower turnover rates. The
      requirement for normal-phase HPLC in resolving the metabolites formed during
      lauric acid metabolism is demonstrated.

PMID- 8651698
TI  - Oxidation-reduction and transient kinetic studies of spinach ferredoxin-dependent
      glutamate synthase.
AB  - Spinach leaf ferredoxin-dependent glutamate synthase has been shown to contain
      one FMN but no FAD. The oxidation-reduction midpoint potentials of the FMN and
      the other prosthetic group, a [3Fe-4S]1+,0 cluster, have both been estimated to
      be -225 mV by cyclic voltammetry. Confirmation of the isopotential nature of the
      two prosthetic groups of the enzyme has been obtained using deazariboflavin
      phototitrations. Flash photolysis measurements have allowed determination of the
      second-order rate constants for reduction of both of the prosthetic groups of the
      enzyme by the 5-deazariboflavin semiquinone radical.

PMID- 8651699
TI  - Selenium-containing compounds protect DNA from single-strand breaks caused by
      peroxynitrite.
AB  - Peroxynitrite (ONOO-/ONOOH) is a powerful oxidant that can induce mutations and
      cause single-strand breaks in plasmid supercoiled DNA. The selenium-containing
      compound ebselen rapidly reacts with peroxynitrite. Therefore, ebselen [2-phenyl
      1,2-benzisoselenazol-3(2H)-one] and other selenium-containing molecules,
      selenomethionine and selenocystine, were studied as agents protecting DNA from
      single-strand breaks induced by peroxynitrite. Selenomethionine and selenocystine
      protected DNA from single-strand breaks more effectively than their sulfur
      analogs, methionine and cystine, and they also were more effective than
      glutathione or the hydroxyl radical scavenger mannitol. These results suggest
      that selenium-containing compounds can protect DNA from damage caused by
      peroxynitrite.

PMID- 8651700
TI  - Mechanism of simultaneous iodination and coupling catalyzed by thyroid
      peroxidase.
AB  - Thyroid peroxidase (TPO) simultaneously catalyzes two very different types of
      reaction in the thyroid gland- iodination and coupling. The present study
      addresses the mechanism of this simultaneous dual activity. Compound I, the two
      electron oxidation product of TPO, exists in two different forms--an oxoferryl
      porphyrin pi-cation radical and an oxoferryl protein radical. It has been
      proposed that iodination is mediated by the porphyrin pi-cation radical form of
      TPO compound I, while coupling is mediated by the protein radical form. However,
      results obtained in the present study favor the view that both iodination and
      coupling are mediated by the porphyrin pi-cation radical form of compound I. In
      the first part of the study, we compared coupling and iodination activities of
      two peroxidases with very similar crystal structures--cytochrome c peroxidase
      (CcP) and lignin peroxidase (LiP). Although these two peroxidases have very
      similar three-dimensional structures, CcP forms a compound I only of the protein
      radical type, whereas compound I of LiP exists only as a porphyrin pi-cation
      radical. Comparison of the catalytic activities of the two enzymes showed that
      diiodotyrosine (DIT)-stimulated coupling activity of LiP was significantly
      greater than that of CcP. Moreover, lignin peroxidase displayed very significant
      iodinating activity at acid pHs, whereas iodination with CcP was negligible at
      all pHs tested. Our findings with these two structurally similar peroxidases
      suggested that TPO-catalyzed iodination and coupling could both be mediated by
      the porphyrin pi-cation radical form of compound I. More direct evidence in
      support of this view was obtained in the second part of this study, employing TPO
      and lactoperoxidase (LPO) model systems in which iodination and coupling occurred
      simultaneously. Heme spectral analysis was used to correlate formation of the
      protein radical form of compound I with the kinetics of the iodination and
      coupling reactions. Formation of the compound I protein radical was not observed
      until the iodination and coupling reactions had almost been completed. In
      separate experiments it was shown that the spontaneous conversion of the
      porphyrin pi-cation radical form of TPO or LPO compound I to the protein radical
      form was markedly inhibited by a low concentration of iodide, especially in the
      presence of an iodide acceptor. These studies provide compelling evidence that
      both iodination and coupling are mediated by the porphyrin pi-cation radical form
      of compound I. This was further substantiated by the finding that coupling was
      inhibited in the presence of excess iodide, an observation readily explained by
      competition between iodide and DIT residues in thyroglobulin for oxidation by the
      porphyrin pi-cation radical.

PMID- 8651701
TI  - Detection and characterization of the electron paramagnetic resonance-silent
      glutathionyl-5,5-dimethyl-1-pyrroline N-oxide adduct derived from redox cycling
      of phenoxyl radicals in model systems and HL-60 cells.
AB  - The antioxidant function of glutathione includes enzymatic reduction of hydrogen
      peroxide by glutathione peroxidase and nonenzymatic reduction of organic radicals
      and reactive oxygen species. The glutathionyl S-centered radical, formed by the
      nonenzymatic reduction process, is a marker of oxidative reactions proceeding by
      radical mechanisms. Spin-adducts of glutathionyl radicals with the spin trap
      DMPO, 5,5-dimethyl-1-pyrroline N-oxide, are not sufficiently stable and can be
      detected only under steady-state conditions. We developed a novel HPLC method for
      the detection of an EPR-silent DMPO adduct of glutathionyl radicals in model
      systems and in cells. We synthesized a sufficient quantity of the adduct for
      characterization by UV spectrophotometry, ionspray mass spectrometry, and 1H NMR
      spectroscopy. The UV absorption lambda max of the adduct, 258 nm, was indicative
      of a 2-(S-alkylthiyl)pyrroline N-oxide chromophore. The molecular mass of the
      adduct was 418 amu. No signal for the C2 proton of the DMPO-derived portion of
      the adduct was evident in its 1H NMR spectrum. The results were consistent with
      the structure 2-(S-glutathionyl)-5,5-dimethyl-1-pyrroline N-oxide (GS-DMPO
      nitrone). We showed that this adduct accumulated in the course of peroxidase
      dependent redox cycling of phenol in the presence of glutathione and DMPO as well
      as in HL-60 cells exposed to a phenol/H2O2/DMPO reaction mixture. The EPR-silent
      GS-DMPO nitrone was readily assayed by HPLC under conditions incompatible with
      the detection of the GS-DMPO nitroxide by EPR. This is to our knowledge the first
      direct experimental evidence for the redox cycling of phenol in this bone marrow
      derived cell line. The method may prove useful in the study of radical-driven
      oxidations of glutathione in various pathophysiological processes associated with
      radical mechanisms.

PMID- 8651702
TI  - Biosynthesis of cyclic diterpene hydrocarbons in rice cell suspensions:
      conversion of 9,10-syn-labda-8(17),13-dienyl diphosphate to 9beta-pimara-7,15
      diene and stemar-13-ene.
AB  - The biosynthesis of diterpene hydrocarbons with enzyme extracts from rice cell
      suspension cultures was investigated to verify proposed pathways and
      intermediates in the production of the momilactone and oryzalexin phytoalexins.
      Diterpene synthase activity in cells treated with chitin to elicit the
      phytoalexin response was compared with the activity in untreated cells using the
      acyclic substrates [1-3H](E,E,E)- and [1-3H] (E,Z,E)-geranylgeranyl diphosphates
      (GGPPs 4-OPP and 11-OPP) as well as the bicyclic substrates [15-3H]ent-copalyl
      and [15-3H] syn-copalyl diphosphates (CPPs, 5-OPP, and 6-OPP). ent-kaurene (7),
      ent-sanda, racopimaradiene (8), 9 beta H-pimara-7,15-diene (9), and stemar-13-ene
      (10) were identified as major products by comparisons with authentic standards.
      Marked increases in diterpene synthase activities were observed with enzyme from
      chitin-treated cells: (E,E,E)-GGPP (approximately 100 fold), ent-CPP
      (approximately 3 fold), and syn-CPP (approximately 60 fold). The very low
      conversions of (E,Z,E)-GGPP to hydrocarbon products excludes its role in the
      biosynthesis of 9,10-syn-diterpenes in rice cells. ent-Kaurene was the major
      diterpene formed from ent-CPP with enzyme from unelicited cells. In contrast the
      enzyme from chitin-treated cells converted ent-CPP to a mixture of ent-kaurene,
      ent-sandaracopimaradiene, and a third unidentified diterpene. With syn-CPP as
      substrate the induced syntheses afforded a mixture of 9 beta-pimaradiene,
      stemarene, and a third, unidentified syn-diterpene. Overall the results are
      consistent with the hypothesis that rice cells respond to treatment with chitin
      fragments by producing new diterpene synthases not present in the untreated
      cells. These induced cyclases initiate phytoalexin biosynthesis by diverting
      (E,E,E)-GGPP into new cyclization modes that produce ent-sandaracopimaradiene,
      stemarene, and 9 beta-pimaradiene, the presumed precursors to oryzalexins A-F,
      oryzalexin S, and momilactones A-C, respectively. The intermediate role of 9,10
      syn-CPP in syn diterpene biosynthesis is verified.

PMID- 8651703
TI  - Construction of a human cytochrome P450 1A1: rat NADPH-cytochrome P450 reductase
      fusion protein cDNA and expression in Escherichia coli, purification, and
      catalytic properties of the enzyme in bacterial cells and after purification.
AB  - A plasmid (pCW) was modified to code for a fusion protein consisting of the
      complete sequence of human cytochrome P450 (P450) 1A1 (with only the second amino
      acid changed) in the N-terminal portion connected by a Ser-Thr linker to the
      portion of rat NADPH-P450 reductase beginning at amino acid 57. This plasmid was
      used to express the fusion protein in Escherichia coli DH5alpha cells and the
      protein was purified from detergent-solubilized bacterial membranes using DEAE
      and 2',5'-ADP agarose chromatography. The purified fusion protein catalyzed
      benzo[a]pyrene 3-hydroxylation, 7-ethoxyresorufin O-deethylation, and
      zoxazolamine 6-hydroxylation. Catalytic activity was not increased in the
      presence of added NADPH-P450 reductase, cytochrome b5, or phospholipid. The
      fusion protein could also transfer electrons to cytochromes c and b5 but not P450
      lA2. The same oxidation products of benzo[a]pyrene were formed with the purified
      fusion protein and the fusion protein functioning in bacterial cells. The
      catalytic activity of the human P450 1A1 fusion protein toward several substrates
      is markedly less than that of a similar fusion protein constructed with rat P450
      1A1, in line with the reported differences in catalytic activities of the rat and
      human P450 1A1 enzymes. The purified fusion protein also oxidized (+)- and (-)
      benzo[a]pyrene 7,8-dihydrodiols and eight aryl and heterocyclic amines to
      genotoxic products, in the absence of added NADPH-P450 reductase. The
      demonstration of catalytic activities of the human fusion protein within
      bacterial cells suggests the prospect of utilizing such cellular systems for
      production of human P450 metabolites.

PMID- 8651704
TI  - A novel marsupial protein expressed by the mammary gland only during the early
      lactation and related to the Kunitz proteinase inhibitors.
AB  - A novel whey protein has been found in marsupial milk, the early lactation
      protein (ELP). The whey of Trichosurus vulpecula, the Australian common brush
      tailed possum, contains two forms of ELP, estimated by protein electrophoresis at
      8 and 16 kDa. The 16-kDa form contains approximately 60% N- linked carbohydrate.
      The ELP cDNA was obtained by the screening of an early lactation cDNA library
      with an early lactation total cDNA probe and random selection of strongly
      positive clones. The full-length cDNA sequence of 306 bp codes for an 82 amino
      acid residue mature protein and a 20-residue secretory signal peptide. The mature
      protein has a calculated molecular weight of 9325.4 and a pI of 8.1. Protein and
      RNA analysis show that the expression of the ELP is restricted only to the early
      lactation phase. The ELP has amino acid sequence homologies with the Kunitz
      proteinase inhibitor family and the whey acidic proteins.

PMID- 8651705
TI  - Differential expression of the two duplicated insecticyanin genes, ins-a and ins
      b, in the black mutant of Manduca sexta.
AB  - The black (bl) mutant larvae of Manduca sexta produces no detectable juvenile
      hormone (JH) during the molt to the 5th instar. To investigate the JH control of
      expression of the two insecticyanin genes, ins-a and ins-b, developmental changes
      of the two mRNAs were examined in this mutant. In the epidermis of the freshly
      ecdysed larvae, the two mRNAs were hardly detectable. Twelve hours after ecdysis,
      the two mRNAs appeared in low levels and were then gradually increased with ins-a
      mRNA rising to a plateau from Day 1 to Day 2 morning and ins-b mRNA in Day 2.
      During these early developmental stages, the epidermal level of the two mRNAs in
      the bl mutant was substantially lower than that observed in the wild-type larvae.
      On Day 3 of the 5th instar when the larval epidermis becomes pupally committed,
      the two mRNAs in both bl mutant and wild-type larvae show a similar differential
      expression pattern. In the fat body, the level of both ins-a and ins-b mRNAs was
      higher than that found in the wild-type larvae. Exogenous JH almost restores the
      level of the two mRNAs in both epidermis and fat body of the Day 0 5th-instar bl
      mutant larvae to that observed in wild-type animals of the same stage. These
      results suggest that JH may enhance expression of the two insecticyanin genes in
      the epidermis but partially repress their expression in the fat body during early
      development of the wild-type 5th-instar larvae.

PMID- 8651706
TI  - Human p53 expressed in baculovirus-infected Sf9 cells displays a two-dimensional
      isoform pattern identical to wild-type p53 from human cells.
AB  - Baculovirus expression of human p53 protein, a nuclear cell cycle regulator, was
      examined in Sf9 cells and compared to native p53 synthesized in primary human
      cells. Maximum expression of the recombinant p53 protein occurred 48 h
      postinfection. De novo synthesis of the protein was evident for only 2 days
      postinfection; however, in pulse-chase studies, 30% of the synthesized protein
      remained stable up to 5 days. Seventy-seven percent of immunoprecipitated, [35S]
      methionine-labeled, recombinant p53 protein resided in the cytoplasm of Sf9
      cells, while 15% localized to the nucleus and 8% was released extracellularly.
      Separation of modified p53 protein, by charge and molecular weight, was
      accomplished by two-dimensional PAGE, and the electrophoretic pattern of the
      recombinant protein was identical to the wild-type protein from primary human
      mammary epithelial cells, indicating that the posttranslational modifications of
      the recombinant protein in this system are similar to those in primary human
      cells. Eleven isoforms focused between pI 5.75 and pI 6.5. The recombinant p53
      isoforms were phosphorylated by 32P-labeling. Phosphatase digestion of
      immunoprecipitated p53 effectively removed phosphorous groups from the
      recombinant protein, reducing the number of isoforms from 11 to 2, demonstrating
      that phosphorylation is the major posttranslational event in the recombinant
      protein.

PMID- 8651707
TI  - Identification and partial characterization of cytosolic progesterone-binding
      sites in the filamentous fungus Rhizopus nigricans.
AB  - Progesterone and some other steroids have been shown to induce a steroid 11alpha
      hydroxylating enzyme system requiring cytochrome P450 in the filamentous fungus
      Rhizopus nigricans. In the present work, we attempted to find out whether the
      mycelial cytosol contained progesterone-binding sites (PBS) which could function
      as receptors for P450-inducing steroids and might, therefore, be included in the
      induction process. Two types of constitutive PBS, PBS-I and PBS-II, were
      identified in the cytosol pretreated with dextran-coated charcoal which removed
      the endogenous ligand. The protein nature of these binding activities was
      indicated by their susceptibility to trypsin and proteinase K digestion, heat
      denaturation, and their resistance to DNase. Progesterone binding was rapid, the
      maximal level being reached after 45 min of incubation at 22 degrees C. At this
      temperature, dissociation of progesterone from PBS-I proceeded with a t1/2 of 17
      min and that from PBS-II with a t1/2 of 133 min. The apparent Kd of PBS-I
      determined by Scatchard analysis was 2.1-7.0 x 10(-9)M, and Bmax 36-218 fmol/mg
      protein. Bmax for PBS-II was >400 fmol/mg protein, whereas the value of Kd could
      not be determined accurately due to the sigmoidal nature of the association
      kinetics. The biological role of PBS-I in transcriptional regulation is suggested
      by the observation that this receptor-like protein contains a functional DNA
      binding domain. A specific function of PBS-I in the induction of 11alpha
      hydroxylase seems to be, however, questionable because of poor correlation
      between the affinity and the inducing capability of corresponding steroids.

PMID- 8651708
TI  - Biochemical characterization of the human liver cytochrome P450 arachidonic acid
      epoxygenase pathway.
AB  - Human liver microsomal fractions metabolized arachidonic acid in the presence of
      NADPH yielding epoxyeicosatrienoic acids and their hydration products,
      dihydroxyeicosatrienoic acids, as the principal reaction products. Inhibition
      studies using polyclonal antibodies prepared against recombinant CYP2C8, an
      abundant human liver cytochrome P450 epoxygenase, demonstrated 85-90% inhibition
      of arachidonic acid epoxide formation. Both epoxyeicosatrienoic acids and
      dihydroxyeicosatrienoic acids were detected in large amounts in human liver using
      gas chromatography/mass spectrometry. Chiral analysis of the endogenous liver
      epoxides demonstrated a preference for the 14(R),15(S)-, 11(R),12(S)-, and
      8(S),9(R)-epoxyeicosatrienoic acid enantiomers. Importantly, the chirality of
      liver epoxyeicosatrienoic acids matched that previously reported for recombinant
      CYP2C8 (Zeldin et al. (1995) Arch. Biochem. Biophys. 322, 76-86). Incubations of
      both human liver cytosolic and microsomal fractions with synthetic
      epoxyeicosatrienoic acids revealed a 10-fold higher rate of
      dihydroxyeicosatrienoic acid formation with cytosolic relative to microsomal
      fractions. Recombinant human liver cytosolic epoxide hydrolase rapidly and
      regioselectively hydrated epoxyeicosatrienoic acids. We conclude, based on these
      data, that CYP2C8 is one of the primary, constitutive hepatic arachidonic acid
      epoxygenases responsible for formation of epoxyeicosatrienoic acids and that
      cytosolic epoxide hydrolase is the principal liver enzyme which forms the
      dihydroxyeicosatrienoic acids. We speculate that these biologically active
      eicosanoids may be important in maintaining homeostasis in the liver.

PMID- 8651709
TI  - Topogenesis of a microsomal cytochrome P450 and induction of endoplasmic
      reticulum membrane proliferation in Saccharomyces cerevisiae.
AB  - Cytochrome P450 52A3 (P450Cm1) is one of the membrane proteins known to trigger
      by its high-level expression a marked proliferation of the endoplasmic reticulum,
      (ER). To gain insight into the relationship between the expression of a membrane
      protein and the induction of ER proliferation we have characterized the membrane
      topology of P450Cm1 and identified the structural determinants required for ER
      targeting, formation of correct membrane orientation, and ER retention. We show
      that all these features are interrelated and determined by sequence elements
      within the NH2-terminal region of P450Cm1. Using several approaches--a protease
      protection assay followed by probing with peptide-specific antibodies,
      immunolabeling of the intact membrane-bound P450 protein, and expression of
      fusion proteins in Saccharomyces cerevisiae--membrane topology was defined as
      follows: residues 2-16 are located in the ER lumen, only the first hydrophobic
      segment (residues 17-34) spans the membrane, a second hydrophobic segment (48-66)
      is exposed at the cytoplasmic side, and the remaining part (67-523) forms a large
      cytosolic domain. Fused to a cytosolic reporter protein, the first 44-amino-acid
      sequence of P450Cm1 was sufficient to mediate ER targeting, wild-type membrane
      orientation, and retention in the ER. Similar to wild-type P450Cm1, various
      fusion proteins were able to induce distinctly organized structures of
      proliferated ER provided that they were either permanently retained in the ER or
      accumulated in this compartment due to a delay in further transportation. Thus,
      we conclude that membrane insertion of the first hydrophobic segment is
      sufficient to deliver a signal for increased membrane formation.

PMID- 8651710
TI  - Herpetic trigeminal trophic syndrome. Treatment with acyclovir and sublesional
      triamcinolone.

PMID- 8651711
TI  - Perirectal hematoma presenting as purpura.

PMID- 8651712
TI  - Long-term safety of cyclosporine in the treatment of psoriasis.
AB  - BACKGROUND AND DESIGN: Cyclosporine has proved to be highly effective in the
      treatment of psoriasis. However, cyclosporine is potentially toxic. Side effects
      include renal toxic effects, hypertension, and an increased risk of malignant
      neoplasm. The toxicity of cyclosporine is dose-related, yet the safe duration of
      treatment is undefined. We studied the hospital records of all patients with
      psoriasis treated with cyclosporine at Saint Louis Hospital, Paris, France,
      between January 1, 1987, and December 31, 1993. In total, 122 patients treated
      for 3 to 76 months were evaluated. RESULTS: The percentage of patients who
      discontinued treatment because of side effects rose from a mean +/- SD of 14% +/-
      2.4% at 12 months to 41% +/- 6.7% at 48 months. An increase in serum creatinine
      levels to more than 30% above the baseline value occurred in 53 patients after a
      median treatment time of 23 months. Hypertension developed in 29 patients after a
      median treatment time of 53 months. Three initial patient characteristics--age
      older than 50 years (P = .04), initial diastolic pressure higher than 75 mm Hg (P
      = 0.5), and serum creatinine levels more than 100 mumol/L (1.1 mg/dL) (P = .02,
      log rank test)--predicted discontinuation of cyclosporine because of side
      effects. CONCLUSIONS: The risk of cyclosporine-induced toxic effects increases
      with age of the patient and with preexisting hypertension or high serum
      creatinine levels. The data suggest that the incidence of side effects increases
      with time. Thus, cyclosporine is not an acceptable long-term monotherapy for
      psoriasis.

PMID- 8651713
TI  - Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of
      photodamaged skin. A double-blind vehicle-controlled clinical trial.
AB  - OBJECTIVE: To evaluate the efficacy and tolerability of 2 widely used topical
      alpha-hydroxy acids at low concentrations, 8% glycolic acid and 8% lactic (L
      isoform) acid creams, in the treatment of photodamaged skin. DESIGN: A single
      center, 22-week, double-blind, vehicle-controlled, randomized clinical trial
      assessed the overall severity of photodamage on the faces and forearms of
      volunteers, based on 7 individual clinical components of cutaneous photodamage.
      SETTING: The study was performed in an outpatient clinical research unit at the
      Massachusetts General Hospital, Boston. PATIENTS: Seventy-four women, aged 40 to
      70 years, with moderately severe photodamaged facial skin were enrolled in the
      study. One subject withdrew from the study early because of skin irritation, and
      6 subjects withdrew from the study for personal reasons. INTERVENTIONS: Glycolic
      acid, L-lactic acid, or vehicle creams were applied twice daily to the face and
      outer aspect of the forearms. MAIN OUTCOME MEASURES: Improvement in alpha-hydroxy
      acid-treated photodamaged skin as determined by patient self-assessments and
      physician evaluations of efficacy and irritancy. RESULTS: The percentage of
      patients using either 8% glycolic acid or 8% L-lactic acid creams on the face
      achieving at least 1 grade of improvement (using a scale from 0 through 9) in
      overall severity of photodamage was significantly greater than with the vehicle
      cream (76% glycolic acid, 71% lactic acid, and 40% vehicle; P < .05). On the
      forearms, after 22 weeks, treatment with glycolic acid cream was superior to the
      vehicle in improving the overall severity of photodamage and sallowness (P <
      .05). L-Lactic acid cream was significantly superior to the vehicle in reducing
      the overall severity of photodamage (P < .05), mottled hyperpigmentation (P <
      .05), sallowness (P < .05), and roughness on the forearms (P < .05) at week 22.
      CONCLUSIONS: Topical 8% glycolic acid and 8% L-lactic acid creams are modestly
      useful in ameliorating some of the signs of chronic cutaneous photodamage. These
      agents are well tolerated and available without prescription.

PMID- 8651714
TI  - Linkage of an American pedigree with palmoplantar keratoderma and malignancy
      (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and
      proposed updated classification of the keratodermas.
AB  - OBJECTIVES: To determine linkage in a pedigree with palmoplantar keratoderma
      (PPK) associated with squamous cell carcinoma of the esophagus. DESIGN: A large
      American pedigree was studied and the clinical phenotype was described. Linkage
      analysis was performed using genomic DNA from key individuals. SETTING: A
      community-based family study. PATIENTS: The family pedigree was expanded from a
      single index case. MAIN OUTCOME MEASURES: To demonstrate linkage and the relative
      risk of squamous cell carcinoma of the esophagus in this pedigree. RESULTS: Focal
      PPK was inherited as an autosomal dominant with variable expression, but signs
      were not limited to the palmoplantar epidermis. The generalized nature of this
      pattern of PPK was highlighted by the perifollicular papules and oral
      hyperkeratosis. Affected individuals (125 individuals) in 7 generations were
      identified, with 17 affected individuals having associated cancer. Seven of the 8
      squamous cell carcinomas of the esophagus occurred in smokers. Other tumors were
      seen in nonsmokers, but these were not significantly increased. The combined male
      female expected incidence of squamous cell carcinoma of the mouth and esophagus
      was 0.21; observed, 8 (relative risk of 38; P < .001). Linkage to the tylosis and
      esophageal cancer gene locus on 17q24 was demonstrated with a maximum 2-point lod
      score of 8.20 at zero recombination fraction for the DNA marker D17S1603.
      CONCLUSION: The distinctive clinical phenotype in this family suggests a new
      classification for PPKs, in particular a reappraisal of the phenotype as a focal
      PPK. A very similar phenotype is found in patients with keratin K16 gene
      mutations.

PMID- 8651715
TI  - The use of high-frequency ultrasound as a method of assessing the severity of a
      plaque of psoriasis.
AB  - BACKGROUND AND DESIGN: Ultrasound imaging, while initially developed to visualize
      internal organs, is now being applied to image the skin. In this preliminary
      study, we used a high-frequency, 40-MHz ultrasound imaging system to provide high
      resolution images in psoriasis and examined the relationship between clinical and
      ultrasound ratings in plaque-type psoriasis. The ultrasound image of a psoriatic
      plaque demonstrates a superficial echogenic band (band A), followed by a
      nonchogenic band (band B), and a deeper echogenic band (band C). RESULTS: In
      psoriatic plaques (N = 145), the severity of the psoriasis as assessed according
      to the degree of scaling, erythema, and thickness (SET score) correlated best
      with the width of band B (P < .001, r = 0.86) and less well with the width of
      bands A (P < .001, r = 0.59) and C (P < .001, r = 0.44). For the treated
      psoriatic plaques (n = 64), for which paired readings were available before and
      after therapy, changes in the SET scores correlated best with the change in the
      width of band B (P < .001, r = 0.96) and less well with the change in the width
      of bands A (P < .001, r = 0.61) and C (P < .001, r = 0.45). Ultrasound analyses
      and clinical evaluation were performed by independent raters. CONCLUSIONS: The
      data suggest that high-frequency ultrasound imaging may prove to be a noninvasive
      technique that can be used as an adjunct to the clinical evaluation of the
      lesional severity of psoriatic plaques.

PMID- 8651716
TI  - Chronic radiodermatitis following cardiac catheterization.
AB  - BACKGROUND: Fluoroscopy and cineradiography used during coronary angiography
      expose patients to some of the highest doses of ionizing radiation in diagnostic
      radiology. The possibility of radiation-induced damage has been discussed by
      several authors in the past. However, to the best of our knowledge, chronic
      radiation dermatitis caused by exposure to x-rays during cardiac catheterization
      has not been described. OBSERVATIONS: We describe 4 patients in whom chronic
      radiodermatitis developed following multiple cardiac catheterizations and
      coronary angioplasties. The cumulative radiation doses to which these patients
      were exposed were retrospectively calculated to be a mean of 24.6 Gy per patient,
      with a range of 11.4 to 34.9 Gy. CONCLUSIONS: Chronic radiodermatitis is a threat
      in patients undergoing multiple cardiac catheterizations and angioplasties. In
      susceptible patients, radiation doses as small as 11.4 Gy, which can sometimes be
      emitted during 1 or 2 procedures, are potentially harmful. Awareness and
      protective measures against this long-term side effect of cardiac catheterization
      should be encouraged.

PMID- 8651717
TI  - Spontaneous atrophic patches in extremely premature infants. Anetoderma of
      prematurity.
AB  - BACKGROUND: Anetoderma, characterized clinically by macular depressions or
      outpouchings of skin, is associated with loss of dermal elastic tissue as noted
      on histopathologic findings. We report on 9 extremely premature infants who
      developed patches of anetoderma during their course in the neonatal intensive
      care unit. OBSERVATIONS: All 9 patients were born between the ages of 24 and 29
      weeks of gestation and had numerous complications associated with prematurity.
      Eight of the 9 infants were noted to have developed anetoderma on the trunk and
      proximal extremities while in the neonatal intensive care unit. The locations of
      the lesions on the skin were not explained by previous trauma, although many
      areas corresponded with placement of monitoring leads or with adhesive for a
      monitoring device. Reduction or absence of elastic tissue supported the diagnosis
      of anetoderma in 4 of 5 biopsy specimens. CONCLUSION: We report a previously
      unrecognized type of anetoderma associated with extreme prematurity. The exact
      cause is uncertain, although reactions to cutaneous monitoring leads or adhesives
      is suspected.

PMID- 8651718
TI  - Cimetidine therapy for recalcitrant warts in adults.
AB  - BACKGROUND: Common warts, or verrucae vulgaris, occur most often in children.
      However, many adults are plagued by this ubiquitous viral infection. Various
      modalities have been used to treat warts, but none is uniformly effective or
      directly antiviral. A recent study showed cimetidine to be effective in the
      treatment of multiple warts in children. Anecdotal reports have suggested that
      the administration of high doses of cimetidine, through various proposed
      immunomodulating mechanisms, can improve recalcitrant warts in adults. There have
      been no data published to date supporting these claims. OBSERVATIONS: An open
      label study was conducted to determine the safety and efficacy of high-dose
      cimetidine in 20 adult patients with recalcitrant warts. Of the 18 patients who
      completed the study, 16 patients (84%) had either dramatic clinical improvement
      or complete resolution of their wart lesions after 3 months of cimetidine therapy
      without any adverse effects. No patient demonstrated disease progression while
      receiving the medication and complete responders remained free of lesions at 1
      year follow-up. CONCLUSIONS: This study further confirms that high-dose
      cimetidine therapy appears to be beneficial and safe in the treatment of
      recalcitrant warts in adults. Further placebo-controlled studies are needed to
      determine its true efficacy.

PMID- 8651719
TI  - Pilotropic cutaneous T-cell lymphoma without mucinosis. A variant of mycosis
      fungoides? French Study Group of Cutaneous Lymphomas.
AB  - BACKGROUND: In the course of mycosis fungoides, pilofollicular manifestations
      without mucinosis (papules, keratoses, comedones, or epidermal cysts) are rare
      (15 cases reported). Therefore, histological and clinical diagnoses may be
      difficult. The clinical course and histopathological and immunohistochemical
      findings in 9 patients are described. OBSERVATIONS: Pilofollicular lesions were
      present at the onset (n = 3), before (n = 3), or during a relapse of mycosis
      fungoides (n = 3). Comedones and epidermal cysts were most frequent (n = 5). They
      disappeared with lymphoma therapy (n = 4), therapy with isotretinoin (n = 3), or
      spontaneously (n = 1), or they persisted (n = 1). Clues to the histopathological
      diagnosis consisted of pilotropism of the infiltrate with minor alteration of the
      hair follicle walls. The infiltrate was monomorphous and composed of sezariform
      CD4+ lymphocytes. Pilotropic or peripilofollicular infiltrates, or the absence of
      infiltrate, were detected in consecutive biopsy specimens obtained from the same
      patient. The keratinocyte expression of intercellular adhesion molecule type 1
      was observed in the hair follicle bulb in front of the pilotropic infiltrate but
      not in the epidermis. No staining was observed in biopsy specimens of 6 of 7
      patients with follicular mucinosis, of folliculitis lesions, or of normal hair
      follicles. CONCLUSIONS: Our findings indicate the role of adhesion molecules in
      pilotropism leading to mechanical obstruction of the follicle by tumoral cells
      followed by hyperkeratosis and cyst formation. It remains to be determined if the
      expression of intercellular adhesion molecule type 1 is the cause or the
      consequence of pilotropism. By becoming more aware of it, this variant of mycosis
      fungoides is probably not so rare.

PMID- 8651720
TI  - Long-term use of cyclosporine in dermatology.

PMID- 8651722
TI  - Ruling out the diagnosis.

PMID- 8651721
TI  - Radiation injury to skin following fluoroscopically guided procedures.

PMID- 8651723
TI  - Slowly enlarging, erythematous macule in a child. Tufted angioma.

PMID- 8651724
TI  - Vascular papules on the dorsum of the hands. Multinucleate cell angiohistiocytoma
      (MCAH).

PMID- 8651725
TI  - Multiple painful blue nodules. Multiple glomus tumors (glomangiomas).

PMID- 8651726
TI  - Unilateral keratotic vascular lesion on the leg. Verrucous hemangioma.

PMID- 8651727
TI  - Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome
      are clinically different disorders.

PMID- 8651728
TI  - Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous
      leukemia.

PMID- 8651729
TI  - Osteoporosis and long-term etretinate therapy.

PMID- 8651730
TI  - Osteoporosis and long-term etretinate therapy.

PMID- 8651731
TI  - Hair growth therapy(ies) for androgenetic alopecia.

PMID- 8651732
TI  - Unilateral solar purpura as a manifestation of asymmetrical photodamage in taxi
      drivers.

PMID- 8651733
TI  - Erythrasma owing to an unusual pathogen.

PMID- 8651734
TI  - How great is the risk of further psoriasis following a single episode of acute
      guttate psoriasis?

PMID- 8651735
TI  - Extensive fixed drug eruption induced by oxazepam.

PMID- 8651736
TI  - Seed corn. Impact of managed care on medical education and research.

PMID- 8651738
TI  - Parathyroid autotransplantation during thyroidectomy. Results of long-term follow
      up.
AB  - SUMMARY BACKGROUND DATA: Permanent hypoparathyroidism is a recognized
      complication of thyroidectomy. Operative strategies to prevent this complication
      include preservation of parathyroid glands in situ and autotransplantation of
      parathyroid glands resected or devascularized during thyroidectomy. METHODS: An
      analysis of 194 patients having thyroidectomy and simultaneous parathyroid
      autotransplantation at Barnes Hospital from 1990 to 1994 was performed. Data were
      collected regarding patient demographics, indication for thyroidectomy, operative
      procedure, pathologic diagnoses, and postoperative course, including biochemical
      assessment of parathyroid autograft function. RESULTS: Of 194 patients having
      either total, subtotal, or completion thyroidectomy, 104 (54%) experienced a
      [Ca(+2)]nadir less than or equal to 8.0 mg/dL and had symptoms and signs of
      hypocalcemia. Parathyroid autotransplantation was successful in 103 (99%) of
      these 104 cases and resulted in a 1.0% incidence of hypoparathyroidism in this
      series. CONCLUSIONS: Although preservation of parathyroid glands in situ is
      desirable, routine parathyroid autotransplantation during thyroidectomy virtually
      eliminates postoperative hypoparathyroidism. Normal parathyroid glands resected
      or devascularized during thyroidectomy for well-differentiated thyroid carcinoma
      or benign disease should be transplanted in the sternocleidomastoid muscle.
      Patients with Multiple Endocrine Neoplasia type 2A should have parathyroid glands
      resected at the time of thyroidectomy for medullary thyroid carcinoma and
      transplanted in the nondominant forearm. Postoperative management in most
      patients after thyroidectomy and parathyroid autotransplantation involves
      temporary calcium and vitamin D replacement and close biochemical evaluation.
      This precautionary measure of parathyroid autotransplantation markedly reduces
      the incidence of permanent postoperative hypoparathyroidism.

PMID- 8651737
TI  - Fetal and neoplastic expression of the neurotensin gene in the human colon.
AB  - OBJECTIVE: The authors identified various colon cancers that express the gene for
      the gut peptide neurotensin (NT/N). In addition, the authors sought to delineate
      the temporal pattern of NT/N gene expression in the human fetal colon. SUMMARY
      BACKGROUND DATA: Expression of NT/N is localized to the mucosa of the adult small
      bowel but also has been identified in the fetal colon, which resembles the small
      bowel until the end of the second trimester. Ectopic NT/N expression has been
      shown in certain types of colon cancer, suggesting a reversion to a fetal
      phenotype. METHODS: Sensitive ribonuclease protection assays were used to
      determine NT/N expression in colon cancers and adjacent normal mucosa as well as
      colon cancers established as tumor xenografts and fetal colon samples. RESULTS:
      NT/N gene expression was shown in 4 of 12 (25%) human colon cancer xenografts and
      in 11 of 40 (28%) freshly resected colon adenocarcinomas; NT/N gene expression
      was not expressed in any of the samples of normal colonic mucosa adjacent to the
      tumors. The NT/N gene was expressed maximally in the fetal colon between 16 and
      18 weeks' gestation; NT/N expression was decreased between 19 and 22 weeks and
      was not apparent in either the 24-week fetal colon or the adult samples.
      CONCLUSIONS: The NT/N gene expression is expressed transiently in the fetal colon
      during a development stage that is characterized by morphologic similarity to the
      small bowel. In addition, NT/N is reexpressed in approximately one fourth of the
      human colon cancers, indicating that neoplastic transformation leads to reversion
      to a fetal phenotype in certain types of colon cancer. The NT/N gene will provide
      a useful model to further define the complex differentiation pathways in the
      normal gut as well as the process of fetal "dedifferentiation" in certain types
      of colon cancer.

PMID- 8651740
TI  - A statewide, population-based time-series analysis of the outcome of ruptured
      abdominal aortic aneurysm.
AB  - OBJECTIVES: The purpose of this study was to perform the first statewide,
      population-based, time-series analysis of the frequency of ruptured abdominal
      aortic aneurysm (RAAA), to determine the outcomes of RAAA, and to assess the
      association of patient, physician, and hospital factors with survival after RAAA.
      The hypotheses of the study were as follows: 1) the rate of RAAA would increase
      over time and 2) patient, surgeon, and hospital factors would be associated with
      survival. BACKGROUND: Ruptured abdominal aortic aneurysm is a life-threatening
      emergency that presents the surgeon with a technically demanding challenge that
      must be met and surmounted in a short time if the patient is to survive. METHODS:
      Data were obtained from the following four separate data sources: 1) the North
      Carolina Hospital Discharge database, 2) the North Carolina American Hospital
      Association database, 3) the North Carolina State Medical Examiner's database,
      and 4) the Area Resource File. All patients with the diagnosis of an abdominal
      aortic aneurysm (AAA) were selected for initial assessment. Patients were grouped
      into those with and those without rupture of the abdominal aneurysm. RESULTS:
      During the 6 years of the study, 14,138 patients were admitted with a diagnosis
      of AAA. Of these, 1480 (10%) had an RAAA. The yearly number of patients with
      elective AAAs increased 33% from 1889 in 1988 to 2518 in 1993. The yearly number
      of RAAAs increased 27% from 203 to 258. The mortality rate for AAA was 5%, as
      compared with 54% in RAAA patients. The patient's age was found to be the most
      powerful predictor of survival. Univariate logistic regression analyses
      demonstrated an association of the surgeon's experience with RAAA and patient
      survival after RAAA. Analysis of the survival rates of board-certified and
      nonboard-certified surgeons demonstrated that patients with RAAAs who were
      treated by board-certified surgeons had significantly better survival. When the
      survival was compared in small (less than 100 beds) and large (more than 100
      beds) hospitals, survival was significantly better in the larger hospitals.
      CONCLUSIONS: Ruptured abdominal aortic aneurysm remains a highly lethal lesion,
      even in the best of hands. Despite the many improvements in the care of seriously
      ill patients, there was no significant improvement in the survival of RAAA during
      this study. This suggests that early diagnosis is the best hope of survival in
      these patients. The study demonstrated that survival after RAAA was related most
      strongly to patient age at the time of the RAAA. The physician's and the
      hospital's experience with RAAA, the physician's background as measured by board
      certification, and the type of hospital at which the operation was performed
      (small vs. large) also may be associated with survival. These findings may have
      important implications for the regionalization of care and the education and
      credentialling of physicians. Given the lack of recent progress of improving the
      outcome of RAAA, aggressive efforts to treat patients before rupture are
      appropriate.

PMID- 8651739
TI  - Infant survival after cesarean section for trauma.
AB  - HYPOTHESIS: Emergency cesarean sections in trauma patients are not justified and
      should be abandoned. SETTING AND DESIGN: A multi-institutional, retrospective
      cohort study was conducted of level 1 trauma centers. METHODS: Trauma admissions
      from nine level 1 trauma centers from January 1986 through December 1994 were
      reviewed. Pregnant women who underwent emergency cesarean sections were
      identified. Demographic and clinical data were obtained on all patients
      undergoing a cesarean section. Fetal distress was defined by bradycardia,
      deceleration, or lack of fetal heart tones (FHTs). Maternal distress was defined
      by shock (systolic blood pressure < 90) or acute decompensation. Statistical
      analyses were performed. RESULTS: Of the 114,952 consecutive trauma admissions,
      more than 441 pregnant women required 32 emergency cesarean sections. All were
      performed for fetal distress, maternal distress, or both. Overall, 15 (45%) of
      the fetuses and 23 (72%) of the mothers survived. Of 33 fetuses delivered, 13 had
      no FHTs and none survived. Twenty infants (potential survivors) had FHTs and an
      estimated gestational age (EGA) of greater than or equal to 26 weeks, and 75%
      survived. Infant survival was independent of maternal distress or maternal Injury
      Severity Score. The five infant deaths in the group of potential survivors
      resulted from delayed recognition of fetal distress, and 60% of these deaths were
      in mothers with mild to moderate injuries (Injury Severity Score < 16).
      CONCLUSIONS: In pregnant trauma patients, infant viability is defined by the
      presence of FHTs, estimated gestational age greater than or equal to 26 weeks. In
      viable infants, survival after emergency cesarean section is acceptable (75%).
      Infant survival is independent of maternal distress or Injury Severity Score.
      Sixty percent of infant deaths resulted from delay in recognition of fetal
      distress and cesarean section. These were potentially preventable. Given the
      definition of fetal viability, our initial hypothesis is invalid.

PMID- 8651741
TI  - Management of adenocarcinoma of the body and tail of the pancreas.
AB  - OBJECTIVE: The authors examined the resectability, operative morbidity mortality,
      and survival of patients with pancreatic adenocarcinoma of the body and tail
      compared with lesions in the head. SUMMARY BACKGROUND DATA: Adenocarcinoma of the
      body and tail of the pancreas is characteristically thought of as a disease that
      presents late and rarely is operable or resectable. METHODS: In an 11-year
      period, 1981 patients were admitted and entered into a prospective database at
      Memorial Sloan-Kettering Cancer Center with a diagnosis of peripancreatic cancer,
      1363 of whom had adenocarcinoma of the pancreas, 75% with lesions in the head and
      25% with lesions in the body and tail. RESULTS: Of 271 patients resected, 237
      (23%) had lesions in the head and 34 (10%) had body and tail lesions.
      Perioperative mortality was 4% for patients with pancreatic lesions in the head
      and 0% for patients with pancreatic lesions in the body and tail. Five-year
      actuarial survival for body and tail lesions was projected at 14% for 5 years.
      Actual survival was 19%, with three patients alive for more than 5 years.
      CONCLUSIONS: Adenocarcinoma of the body and tail of the pancreas, although less
      likely to be resectable at presentation than lesions in the pancreatic head, have
      similar postresection survival.

PMID- 8651743
TI  - Lung volume reduction surgery. Case selection, operative technique, and clinical
      results.
AB  - OBJECTIVE: A clinical study was undertaken to define optimal preoperative
      strategies and intraoperative techniques that would result in the least morbidity
      and maximum physiologic improvements in patients with end-stage emphysema
      selected for lung volume reduction surgery. BACKGROUND: Lung volume reduction
      surgery recently has been advocated as an alternative or a bridge to lung
      transplantation for patients with end-stage chronic obstructive pulmonary
      disease. The risks, benefits, and long-term results have not been clarified.
      METHODS: Twenty-six patients underwent lung volume reduction surgery with a 3
      month follow-up on 17 patients. Preoperative and postoperative changes in
      pulmonary function parameters, quality of life, and oxygen requirement were
      analyzed. The value of preoperative localization of diseased lung segments and
      how this affects intraoperative resection is addressed. RESULTS: Forty-nine
      percent improvement in FEV1 (forced expiratory volume in 1 second) and 23%
      improvement in FVC (forced vital capacity) were seen after lung volume reduction
      surgery. Supplemental oxygen requirement was decreased and 79% of patients
      reported a much better quality of life. Mortality was 3.8% and air leak morbidity
      was 18%. CONCLUSIONS: Lung volume reduction surgery can predictably improve
      objective and subjective pulmonary function in selected patients with end-stage
      emphysema with low morbidity and mortality. Careful patient selection, accurate
      preoperative localization of diseased target areas, skilled anesthetic technique,
      meticulous operative approach, and intense postoperative support are essential to
      achieve favorable results.

PMID- 8651742
TI  - Blunt carotid injury. Importance of early diagnosis and anticoagulant therapy.
AB  - OBJECTIVE: The incidence, associated injury pattern, diagnostic factors, risk for
      adverse outcome, and efficacy of anticoagulant therapy in the setting of blunt
      and carotid injury (BCI) were evaluated. SUMMARY BACKGROUND DATA: Blunt carotid
      injury is considered uncommon. The authors believe that it is underdiagnosed.
      Outcome is thought to be compromised by diagnostic delay. If delay in diagnosis
      is important, it is implied that therapy is effective. Although anticoagulation
      is the most frequently used therapy, efficacy has not been proven. METHODS:
      Patients with BCI were identified from the registry of a level I trauma center
      during an 11-year period (ending September 1995). Neurologic examinations and
      outcomes, brain computed tomography (CT) results, angiographic findings, risk
      factors, and heparin therapy were evaluated. RESULTS: Sixty-seven patients with
      87 BCIs were treated. Thirty-four percent were diagnosed by incompatible
      neurologic and CT findings, 43% by new onset of neurologic deficits, and 23% by
      physical examination (neck injury, Horner's syndrome). There were 54 intimal
      dissections, 11 pseudoaneurysms, 17 thromboses, 4 carotid cavernous fistulas, and
      1 transected internal carotid artery. Thirty-nine patients had follow-up
      angiograms. Mortality rate was 31%. Of 46 survivors, 63% had good neurologic
      outcomes, 17% moderate, and 20% bad. Logistic regression analysis demonstrated
      heparin therapy to be associated independently with survival (p < 0.02) and
      improvement in neurologic outcome (p < 0.01). CONCLUSIONS: Blunt carotid injury
      is more common than appreciated, seen in 0.67% of patients admitted after motor
      vehicle accidents. Therapy with heparin is highly efficacious, significantly
      reducing neurologic morbidity and mortality. Heparin therapy, when instituted
      before onset of symptoms, ameliorates neurologic deterioration. Liberal
      screening, leading to earlier diagnosis, would improve outcome.

PMID- 8651745
TI  - Ventricular outflow tract reconstructions with cryopreserved cardiac valve
      homografts. A single surgeon's 10-year experience.
AB  - OBJECTIVE: From January 1, 1985 through December 31, 1994, one surgeon implanted
      cryopreserved valved homografts into 149 patients--65 since December 1988. This
      latter series (II) was accomplished in a single hospital, facilitating patient
      follow-up with biannual echocardiograms. Analysis of these 65 patients is the
      primary focus of this report; the indications and early surgical results for the
      two parts of the series (I and II) are compared to assess the evolution of a
      single surgeon's use of homografts in a mixed pediatric and adult practice.
      METHODS: Fifty-one variables for each patient (series II) were entered into a
      computerized database and analyzed (multivariate and univariate) using SPSS 6.1
      software (Statistical Products and Service Solutions, Chicago, IL). Cox
      proportional hazard model was used to identify the independent contribution of
      each variable for patient mortality and homograft failure. Cumulative survival
      estimates were made using Kaplan-Meier analysis. Homograft failure was defined as
      requirement for replacement or death. In series I, there were 41 left ventricular
      outflow tract (LVOT) reconstructions (31 adult) and 43 right ventricular outflow
      tract (RVOT) reconstructions (42 pediatric). In series II, there were 55 RVOT
      reconstructions (52 pediatric) and 10 LVOT reconstructions (7 adult). RESULTS:
      There were no technical surgical failures. Total surgical mortality rate was 6%
      (5/84) in series I (3 LVOT, 2 RVOT) and 15% (10/65) in series II (2 LVOT, 8 RVOT)
      (I vs. II NS; p = 0.11, two-tailed Fisher exact test). By the Cox analysis, only
      age < 2 years (p < 0.03) and cross-clamp time > 120 minutes (p < 0.05) were
      significant predictors for death. Age-based survival curves were compared in a
      sequential bivariate analyses (log rank test) and age < 2 years again was a
      significant predictor of decreased patient survival (p < 0.006). Actuarial
      freedom from patient death or reoperation for homograft failure was 82% +/- 7% at
      1000 days and 77% +/- 10% at 2000 days. Three patients required re-replacement
      for homograft failure (5.4%); one of these patients died. The only significant
      predictor of homograft failure was postoperative endocarditis (p < 0.05).
      Homograft performance was evaluated by an extensive echocardiography protocol: in
      surviving patients and homografts, three valved conduits were judged to have
      severely impaired performance (stenosis or regurgitation), awaiting surgical
      replacement for a putative total homograft-related structural failures rate of
      11% at 5 1/2 years. CONCLUSIONS: Comparisons of series I and II shows, in one
      surgeon's practice, an evolution away from use of cryopreserved homografts for
      LVOT reconstructions except when needed for destructive bacterial endocarditis or
      complex congenital anatomy. Homograft efficacy and durability were similar in
      RVOT and LVOT positions, with 78.5% of patients surviving at 5 1/2 years; in
      surviving patients, 89% of homografts have continued to function well. Homografts
      are not immune to prosthetic bacterial endocarditis, and its occurrence is
      associated with accelerated deterioration. Cryopreserved homograft valves are an
      imperfect but satisfactory biological material for specific ventricular outflow
      reconstructions.

PMID- 8651744
TI  - Is clamp and sew still viable for thoracic aortic resection?
AB  - OBJECTIVE: The authors reviewed the morbidity and mortality of surgical resection
      of the descending thoracic and thoracoabdominal aorta using the clamp-and-sew
      technique. BACKGROUND: Paraplegia remains a devastating complication after
      thoracoabdominal aortic resection, despite many strategies for spinal cord
      protection. Because of its simplicity, clamp and sew has been the preferred
      technique at the University of Virginia for the thoracoabdominal aortic resection
      when proximal control is possible. METHODS: Between 1987 and 1994, the authors
      reviewed 91 consecutive patients who underwent thoracic aortic resection using
      clamp-and-sew techniques without any additional adjuncts for spinal cord
      protection. RESULTS: The average age of patients was 60.8 years; 57.1% were male.
      No intraoperative deaths occurred. In-hospital mortality was 13% (12/91), with an
      overall incidence of postoperative spinal cord injury manifested as paraparesis
      or paraplegia of 9.9% (9/91). Eighty-nine percent (81/91) of all repairs were
      completed with aortic clamp times of 40 minutes or less, and nearly six out of
      ten were completed in 30 minutes or less (53/91). Cross-clamp times were not
      significantly different between those patients who sustained neurologic injury
      and those who had no deficits. CONCLUSIONS: The authors conclude that clamp and
      sew is still a viable technique for thoracoabdominal aortic resection. Nearly all
      resections can be completed within 40 minutes of aortic occlusion. However, the
      "safe" duration of thoracic aortic occlusion remains unknown, and spinal cord
      injury can occur even with short clamp times. Reproducible, safe, and technically
      simple means of spinal cord protection must be developed.

PMID- 8651746
TI  - Combined aortic and renal artery surgery. A contemporary experience.
AB  - PURPOSE: This retrospective study examines results with simultaneous aortic and
      renal artery repair in 133 consecutive hypertensive patients. These results are
      compared with consecutive patient groups undergoing aortic reconstruction alone
      (269 patients) or renal artery reconstruction alone (182 patients). METHODS: From
      January 1987 through July 1995, 61 women and 72 men (mean age, 62.5 years)
      underwent combined repair of renal artery and aortic disease (abdominal aortic
      aneurysm [AAA]: 47 patients; occlusive disease: 86 patients; both: 12 patients).
      All patients were hypertensive (mean blood pressure: 194/103 mmHg; mean
      medications: 2.4). Evidenced by serum creatinine levels > or = 2.0 mg/dL, 46
      patients (35%) had significant renal dysfunction (mean serum creatinine level:
      3.78 mg/dL; range 2.0-10.6 mg/dL, including 7 dialysis-dependent patients).
      Aortic replacements (29% tube grafts; 71% bifurcated grafts) were combined with
      unilateral renal artery repair in 47% of patients; 53% had bilateral repair.
      Preoperative clinical features and perioperative mortality were compared with
      those groups having isolated aortic and renal repairs. RESULTS: There were seven
      perioperative deaths (5.3%) after combined repair, which differed significantly
      from isolated aortic repair (mortality: 0.74%; p = 0.005), but did not reach
      statistical significance when compared with the isolated renal artery group
      (mortality: 1.65%; p = 0.145). Risk analysis did not reveal a significant
      association between preoperative clinical features and mortality in either the
      combined repair group or the groups undergoing renal repair alone or aortic
      repair alone. Among survivors in the combined group, a favorable hypertension
      response was observed in 63%. This differed significantly from the group
      receiving renal repair alone (90% cured/improved; p < 0.001). Based on a 20%
      decrease in serum creatinine levels, excretory renal function was improved in 33%
      of patients with combined repair, including four of the seven patients removed
      from hemodialysis. There were eight late deaths in the combined group.
      CONCLUSIONS: Our experience suggest that contemporary perioperative mortality for
      combined aortic and renal repair has improved compared with earlier reports;
      however, perioperative mortality for simultaneous reconstruction remains greater
      than repair of aortic disease alone. Moreover, a lower rate of favorable
      hypertension response was observed after combined correction compared with renal
      artery repair alone. These differences suggest that aortic and renal artery
      repair should only be combined for clinical indications rather than for
      prophylactic repair of clinically silent disease.

PMID- 8651747
TI  - Endovascular grafting of abdominal aortic aneurysms. A preliminary study.
AB  - OBJECTIVE: The authors report the experience of a single investigational center
      involving two Phase I and a Phase II clinical trials approved by the Food and
      Drug Administration (FDA) for the transfemoral implantation of woven Dacron
      grafts for abdominal aortic aneurysms. SUMMARY BACKGROUND DATA: In 1993,
      EndoVascular Technologies, Inc. ([EVT]; Menlo Park, CA), began an FDA-approved
      clinical trial of repair of abdominal aortic aneurysms by transfemoral placement
      of a tube endograft. Subsequently, a bifurcated endograft trial was started. This
      the first single institution report using the EVT endograft for both tube and
      bifurcated aortic replacement. METHODS: Seventeen patients were enrolled in two
      Phase I and one Phase II clinical trials. The Phase I tube graft trial and the
      Phase I bifurcated graft trial were nonrandomized studies. The Phase II tube
      graft trial consisted of a randomized prospective control trial of open
      endoaneurysmorrhaphy versus transfemoral placement of an endograft. RESULTS:
      Seventeen patients were enrolled in the trial. The graft was placed successfully
      in all but one patient. Five patients randomized to open procedure and one
      declined to participate. Eleven patients with endografts are available for follow
      up. One graft has been explanted for attachment system migration. One patient is
      a late failure because of persistent filling of the aneurysm sac. CONCLUSION:
      Transfemoral placement of an endovascular graft is a viable and effective
      treatment of abdominal aortic aneurysms in the short term. Use of a bifurcated
      endograft will open the procedure to more patients. The ideal attachment system
      and graft material await long-term implantation follow-up.

PMID- 8651748
TI  - Survival benefits of heart and lung transplantation.
AB  - OBJECTIVE: Heart and lung transplantation has gained acceptance as therapy for
      end-stage cardiac and pulmonary failure. The early and intermediate survival
      benefits of one center's 10-year experience with 177 patients undergoing thoracic
      transplantation were examined. SUMMARY BACKGROUND DATA: As experience in cardiac
      and pulmonary transplantation has increased, improvements in patient selection,
      organ preservation, preoperative support, and perioperative care have
      significantly reduced the early threats to patient survival. Graft dysfunction
      due to chronic rejection appears to be the main risk for longer-term survival,
      and data compiled by the United Network for Organ Sharing (UNOS) indicate a 70% 5
      year survival for heart transplants and a 50% 5-year survival for lung transplant
      recipients. METHODS: The medical records of 120 heart recipients, 52 lung
      transplant recipients, and 5 heart-lung recipients were reviewed. Cumulative
      survival estimates were made using Kaplan-Meier analysis. The etiologies of
      operative and long-term mortality in each transplant population were identified.
      A comparison of long-term survival after heart transplantation versus coronary
      revascularization in a group of patients with ischemic cardiomyopathy was
      performed. RESULTS: Operative mortality in both the cardiac and pulmonary
      transplant recipients was 8%. From 1990 to 1995, 70 consecutive adult cardiac
      transplant procedures were performed without an operative mortality. Three of
      five patients survived heart-lung transplantation. The extended actuarial
      survival rate at 5 years was 80% for the cardiac transplant recipients. The 2
      year actuarial survival rate for the lung transplant recipients was 88%. Graft
      dysfunction was the most common cause of operative mortality in the heart
      transplant group whereas infection was responsible for most of the operative
      mortality after lung transplantation. CONCLUSIONS: Cardiac and pulmonary
      transplantation can be applied to morbidly ill patients with excellent operative
      and intermediate-term survival.

PMID- 8651749
TI  - The rationale for esophagectomy as the optimal therapy for Barrett's esophagus
      with high-grade dysplasia.
AB  - OBJECTIVE: The authors determined the incidence of invasive adenocarcinoma after
      esophagectomy in patients endoscopically diagnosed as having Barrett's esophagus
      with high-grade dysplasia. SUMMARY BACKGROUND DATA: Barrett's esophagus is a well
      recognized premalignant condition. There is controversy with regard to the
      optimal treatment of high-grade dysplasia in Barrett's esophagus. Recognizing the
      morbidity and mortality associated with esophagectomy, some recommend a selective
      approach, reserving esophagectomy only for evidence of invasive cancer identified
      through endoscopic surveillance. Other advocate esophagectomy for all suitable
      operative candidates. METHODS: The authors reviewed their experience between 1985
      and 1995 with 11 patients with high-grade dysplasia arising in Barrett's
      esophagus diagnosed by endoscopic biopsy and treated by esophagectomy. RESULTS:
      All patients were white men ranging in age from 47 to 70 years. Ten patients
      underwent esophagectomy by the Ivor Lewis technique; one had a transhiatal
      resection. Eight patients (73%) had invasive adenocarcinoma identified after
      esophagectomy; two (18%) had positive lymph nodes; one required a prolonged
      hospital stay for an anastomotic leak; two (18%) temporarily suffered delayed
      gastric emptying. The authors' review identified 85 additional patients
      previously reported during the same period. Including the current series, 39
      patients (41%) had invasive adenocarcinoma identified in the resected specimen. A
      preponderance of early, potentially curable carcinomas are characteristically
      found in these patients. CONCLUSION: A high incidence of endoscopically
      undetected invasive carcinoma strongly supports esophagectomy as the preferred
      approach for suitable operative candidates with high-grade dysplasia in Barrett's
      esophagus.

PMID- 8651750
TI  - Caloric restriction increases the expression of heat shock protein in the gut.
AB  - OBJECTIVE: The authors determined whether caloric restriction (CR) either acutely
      or chronically, alters heat shock protein 70 (hsp70) gene expression in the gut.
      SUMMARY BACKGROUND DATA: Caloric restriction prolongs the life span and delays
      age-related disease (e.g., cancer) in mammals; the mechanisms responsible for
      these effects are not known. Heat shock proteins are a group of stress-responsive
      genes of which the most prominent member is hsp70. METHODS: In the first
      experiment, adult (4-month-old) rats (n = 3/group) were killed after a 48-hour
      fast or 6 and 24 hours after refeeding. In addition, three rats (controls) were
      killed without fasting or refeeding. The stomach was removed and RNA was
      extracted for hsp70 gene expression. In the second experiment, aged (22- to 26
      month-old) rats were fed ad libitum (AL) or a CR diet (60% caloric intake of AL
      diet). Rats were killed, the stomach and duodenum were removed, and RNA was
      extracted for determination of hsp70 gene expression. RESULTS: In the first
      experiment, hsp70 mRNA levels were increased approximately threefold in the
      stomach of rats fasted for 48 hours; levels decreased to control values by 6 and
      24 hours after refeeding. In the second experiment, hsp70 mRNA levels were
      increased significantly in both the stomach and duodenum of aged CR rats compared
      with AL controls. CONCLUSIONS: The authors have demonstrated that hsp70 mRNA
      levels are increased in the proximal gut of young and old rats, either acutely
      (with fasting) or with CR. Increased expression of the cytoprotective hsp70 gene
      in the gut may provide a possible cellular mechanism for the beneficial effects
      noted with CR.

PMID- 8651751
TI  - Pyogenic hepatic abscess. Changing trends over 42 years.
AB  - OBJECTIVE: The authors document changes in the etiology, diagnosis, bacteriology,
      treatment, and outcome of patients with pyogenic hepatic abscesses over the past
      4 decades. SUMMARY BACKGROUND DATA: Pyogenic hepatic abscess is a highly lethal
      problem. Over the past 2 decades, new roentgenographic methods, such as
      ultrasound, computed tomographic scanning, direct cholangiography, guided
      aspiration, and percutaneous drainage, have altered both the diagnosis and
      treatment of these patients. A more aggressive approach to the management of
      hepatobiliary and pancreatic neoplasms also has resulted in an increased
      incidence of this problem METHODS: The records of 233 patients with pyogenic
      liver abscesses managed over a 42-year period were reviewed. Patients treated
      from 1952 to 1972 (n = 80) were compared with those seen from 1973 to 1993 (n =
      153). RESULTS: From 1973 to 1993, the incidence increased from 13 to 20 per
      100,000 hospital admissions (p < 0.01. Patients managed from 1973 to 1993 were
      more likely (p < 0.01) to have an underlying malignancy (52% vs. 28%) with most
      of these (81%) being a hepatobiliary or pancreatic cancer. The 1973 to 1993
      patients were more likely (p < 0.05) to be infected with streptococcal (53% vs.
      30%) or Pseudomonas (30% vs. 9%) species or to have mixed bacterial and fungal
      26% vs. 1%) infections. The recent patients also were more likely (p < 0.05) to
      be managed by percutaneous abscess drainage (45% vs. 0%). Despite having more
      underlying problems, overall mortality decreased significantly (p < 0.01) from
      65% (in 1952 to 1972 period) to 31% (in 1973 to 1993 period). The reduction was
      greatest for patients with multiple abscesses (88% vs. 44%; p < 0.05) with either
      a malignant or a benign biliary etiology (90% vs. 38%; p < 0.05). Mortality was
      increased (p < 0.02) in patients with mixed bacterial and fungal abscesses (50%).
      From 1973 to 1993, mortality was lower (p = 0.19) with open surgical as opposed
      to percutaneous abscess drainage (14% vs. 26%). CONCLUSIONS: Significant changes
      have occurred in the etiology, diagnosis, bacteriology, treatment, and outcome
      patients with pyogenic hepatic abscesses over the past 4 decades. However,
      mortality remains high, and proper management continues to be a challenge.
      Appropriate systemic antibiotics and fungal agents as well as adequate surgical,
      percutaneous, or biliary drainage are required for the best results.

PMID- 8651754
TI  - I have seen the future and it is on the internet.

PMID- 8651752
TI  - Glucocorticoid-dependent induction of interleukin-6 receptor expression in human
      hepatocytes facilitates interleukin-6 stimulation of amino acid transport.
AB  - OBJECTIVE: The authors studied the effects of interleukin-6 (IL-6) and tumor
      necrosis factor-alpha (TNF-alpha) on glutamine and alanine transport in isolated
      human hepatocytes. They also evaluated the role of dexamethasone in modulating
      this response and its effects on the expression of the plasma membrane high
      affinity IL-6 receptor. SUMMARY BACKGROUND DATA: Animal studies indicate that
      cytokines are important mediators of the increased hepatic amino acid uptake that
      occurs during cancer and sepsis, but studies in human tissues are lacking. The
      control of transport by cytokines and cytokine receptor expression in the liver
      may provide a mechanism by which hepatocytes can modulate amino acid availability
      during catabolic disease states. METHODS: Human hepatocytes were isolated from
      wedge biopsy specimens and plated in 24-well trays. Interleukin-6 and TNF-alpha,
      in combination with the synthetic glucocorticoid dexamethasone, were added to
      hepatocytes in culture, and the transport of radiolabeled glutamine and alanine
      was measured. Fluorescent-activated cell sorter (FACS) analysis was used to study
      the effects of dexamethasone on IL-6 receptor number in the well-differentiated
      human hepatoma HepG2. RESULTS: Both IL-6 and TNF-alpha exerted a small
      stimulatory effect on alanine and glutamine transport. Dexamethasone alone did
      not alter transport rates, but pretreatment of cells augmented the effects of
      both cytokines on carrier-mediated amino acid uptake. Dexamethasone pretreatment
      and a combination of IL-6 and TNF-alpha resulted in a greater than twofold
      increase in transport activity. Fluorescent-activated cell sorter analysis
      demonstrated that dexamethasone induced a threefold increase in the expression of
      high-affinity IL-6 receptors. CONCLUSIONS: Interleukin-6 and TNF-alpha work
      coordinately with glucocorticoids to stimulate amino acid uptake in human
      hepatocytes. Dexamethasone exerts a permissive effect on cytokine-mediated
      increases in transport by increasing IL-6 receptor expression on the cell
      surface. It is likely that this upregulation of IL-6 receptors "primes" human
      liver cells for subsequent stimulation by cytokines. The resulting increase in
      hepatic amino acid transport provides the liver with substrate to support key
      metabolic pathways during catabolic states.

PMID- 8651755
TI  - The Internet and the thoracic surgeon: a "virtual" future.

PMID- 8651756
TI  - SIRS--the systemic inflammatory response syndrome after cardiac operations.

PMID- 8651753
TI  - Intestinal cell cycle regulations. Interactions of cyclin D1, Cdk4, and p21Cip1.
AB  - OBJECTIVE: The p21Cip1 protein is a potent stoichiometric inhibitor of cyclin
      dependent kinase activity, and p21Cip1 mRNA expression is localized to the
      nonproliferative compartment of the intestinal villus, suggesting an in vivo
      growth-inhibitory role in the gut. The authors determined whether nontransformed
      rat intestinal epithelial cells (IECs) underwent reversible cell cycle arrest by
      contact inhibition, and determined whether increases in the relative amount of
      p21 associated with cyclin D/Cdk4 protein complexes were associated with cell
      growth arrest. METHODS: Density arrest was achieved by prolonged culture IEC-6 in
      confluent conditions (5 or more days). Release from density arrest was achieved
      by detaching the cells from the culture plate and reseeding them at a 1:4 ratio.
      The DNA synthesis was estimated by [3H]-thymidine incorporation and expressed as
      mean plus or minus standard error of the mean (n = 4). Cyclin D1, Cdk4, and p21
      mRNA and protein levels were determined by standard Northern and Western blot
      analyses, respectively. Cyclin D1, Cdk4, and p21 protein complex formation was
      analyzed by immunoprecipitating the complexes from cell lysates with an antibody
      to one of the constituents, followed by SDS polyacrylamide gel electrophoresis
      (SDS-PAGE) and Western blot analysis of the precipitated complexes using
      antibodies to the other proteins. The kinase activity of the immunoprecipitated
      Cdk4 was determined using recombinant Rb as substrate. RESULTS: The IEC-6[3H]
      thymidine incorporation was decreased 7.5-fold from day 1 confluence to day 7 of
      confluence. Twenty-four hours after release from density arrest, there was a 43
      fold increase in [3H]-thymidine incorporation. Cyclin D1 and Cdk4 mRNA levels
      remained relatively constant during contact inhibition, whereas immunoblotting
      showed that the levels of cyclin D1 and Cdk4 proteins decreased by 70.9% and
      68.7%, respectively, comparing day 3 with day 9 during density arrest. The levels
      of cyclin D1 increased 5.8-fold and Cdk4 increased by 4.4-fold by 24 hours after
      reseeding the day 9 density-arrested cultures, coincident with the increase in
      DNA synthesis. The amount of p21 associated with the cyclin D1 and Cdk4 complex
      in the density-arrested cells was 170% of that observed in the reseeded,
      proliferating cells. More important, the p21::Cdk4 ratio was 6.4-fold higher in
      the density-arrested (quiescent) cells as compared with rapidly proliferating
      cells by 24 hours after release from growth arrest. Recovery of Cdk4-dependent
      kinase activity occurred by 4 hours after release from growth arrest, coincident
      with decreased binding of p21 to the complex. CONCLUSIONS: Intestinal epithelial
      cells in culture can undergo density-dependent growth arrest. This process
      involves downregulation of cyclin D1 and Cdk4 at the level of protein expression,
      whereas the mRNA levels remain relatively unchanged. Further, during contact
      inhibition, there is more p21 associated with cyclin D1/Cdk4, which further
      contributes to the inhibition of the kinase complex. The authors also have shown
      that the process of contact inhibition is reversible, which may explain partly
      the ability of the intestinal epithelium to increase proliferative activity in
      response to injury.

PMID- 8651757
TI  - Isolated lung perfusion with tumor necrosis factor for pulmonary metastases.
AB  - BACKGROUND: A phase I trial was initiated to define the feasibility and safety of
      single-lung isolation perfusion with tumor necrosis factor-alpha, interferon
      gamma, and moderate hyperthermia for patients with unresectable pulmonary
      metastases. METHODS: Twenty patients with lung metastases (Ewing's, 2; sarcoma,
      8; melanoma, 6; other, 4) were considered for single-lung isolation perfusion
      with 0.3 to 6.0 mg of tumor necrosis factor-alpha and 0.2 mg interferon-gamma
      delivered through an oxygenated pump circuit. Sixteen perfusions were performed
      in 15 patients (bilateral in 1). Metastases were completely resected (no single
      lung isolation perfusion) in 3 patients, 1 patient had extrapulmonary disease,
      and one single-lung isolation perfusion was aborted for mechanical reasons.
      RESULTS: There were no significant changes in systemic arterial blood pressure or
      cardiac output during perfusion. Systolic pulmonary artery pressure increased
      with isolation, but returned to pre-single-lung isolation perfusion levels after
      clamp release. The maximum systemic tumor necrosis factor-alpha level was 8
      ng/mL, whereas pump-circuit levels ranged from 200 to 10,976 ng/mL. There were no
      deaths, and the mean hospitalization period was 9 days (range, 5 to 34 days). A
      short-term (6 to 9 month) unilateral decrease in perfused nodules was noted in 3
      patients (melanoma in 1, adenoid cystic carcinoma in 1, renal cell carcinoma in
      1). CONCLUSIONS: Future studies using a combination of biologic modifiers,
      chemotherapy, and hyperthermia should be pursued to define active cytotoxic
      agents that will preserve underlying pulmonary function.

PMID- 8651758
TI  - Chest wall constriction after too extensive and too early operations for pectus
      excavatum.
AB  - BACKGROUND AND METHODS: Since 1990 we have evaluated 12 children and teenagers in
      whom severe cardiorespiratory symptoms have developed due to failure of chest
      wall growth after very extensive pectus excavatum operations (removal of five or
      more ribs) at very early ages (< 4 years). RESULTS: Apparently these extensive
      procedures have removed or prevented growth center activity, which resulted in
      restriction of chest wall growth with marked limitation of ventilatory function.
      The forced vital capacity ranged from 30% to 50% of predicted and the forced
      expiratory volume in 1 second from 30% to 60%. All patients are symptomatic with
      mild exercise and cannot compete in running games. Our protocol for critical
      evaluation includes exercise pulmonary function studies and axial computed
      tomographic reconstruction. CONCLUSIONS: This report is an alert to recognize
      such patients and also to recommend delay in operative repair in small children
      until at least 6 to 8 years of age. The younger the patient the more limited the
      chest wall resection for pectus excavatum should be. Five of these patients have
      had a chest cavity expansion operation with encouraging early results.

PMID- 8651759
TI  - VATS debridement versus thoracotomy in the treatment of loculated postpneumonia
      empyema.
AB  - BACKGROUND: There are approximately 60,000 new cases of postpneumonic empyema
      every day in the United States. Usually the fibrinopurulent stage of this
      complication has been treated by either tube thoracostomy or thoracotomy and
      debridement. According to the literature, thoracoscopic treatment has not been
      used often for this disease. METHODS: Sixty-four cases of postpneumonic
      fibrinopurulent empyema were operated on at our institution: 33 cases (group I)
      by means of a formal thoracotomy and 31 cases (group II) by thoracoscopy. In the
      thoracoscopic subset the data were collected prospectively since 1992. These
      results were compared with those of a historical series treated by thoracotomy
      between 1985 and 1991. Both populations were similar in terms of age (mean, 49
      years), number of cases (33/31), sex (2.1 male/female), and comorbid status.
      RESULTS: Mean preoperative length of the medical management (11.5 versus 17 days)
      (p = 0.03) and chest tube removal (4.3 versus 6.1 days) were shorter in group II
      than in group I (p = 0.02). Morbidity and mortality were identical: one death and
      five complications in each group. Mean operative time was similar in both groups,
      and hospital stay was shorter in the video-assisted thoracic surgery group (6.8
      versus 11.2 days) (p = not significant). Three patients from group II needed
      utilitary thoracotomies for debridement completeness (10% conversion rate).
      CONCLUSIONS: We conclude that video-assisted thoracic surgical treatment has the
      same rate of success as open thoracotomy but offers substantial advantages over
      thoracotomy in terms of resolution of the disease, hospital stay, and cosmesis. A
      prospective and randomized study is needed to confirm the findings of this
      nonrandomized initial experience.

PMID- 8651760
TI  - Critical importance of the first 10 minutes of lung graft reperfusion after
      hypothermic storage.
AB  - BACKGROUND: We have shown previously that lung graft function can be improved by
      achieving reperfusion with stepwise increments of perfusion pressure over 60
      minutes. This study aimed to establish whether similar benefit could be achieved
      with a shorter, simpler protocol and different storage conditions. METHODS: Rat
      lungs were flushed with University of Wisconsin or modified Euro-Collins solution
      and reperfused for 1 hour with blood from a support animal. Grafts were
      reperfused immediately or after storage at 4 degrees C for 24 hours (University
      of Wisconsin solution) or 6 hours (Euro-Collins solution). Stored-graft
      reperfusion was initiated with a 0-, 5-, or 10-minute period during which
      reperfusion pressure was reduced by 50%. RESULTS: Stored grafts receiving 0 to 5
      minutes of initial low-pressure reperfusion performed poorly, with reduced
      oxygenation and blood flow and elevated pulmonary artery pressure, airway
      pressure, and wet/dry weight ratio. In contrast, 10 minutes of initial 50%
      pressure reperfusion yielded function comparable with that in controls with both
      storage conditions. CONCLUSIONS: An initial 10-minute period of 50%-pressure
      reperfusion improves the function of stored rat lung grafts, whereas 5 minutes is
      insufficient.

PMID- 8651761
TI  - Bronchogenic cysts of the lung.
AB  - BACKGROUND: The clinical presentation of lung bronchogenic cysts (BC) is
      variable, from respiratory distress at birth to late appearance of symptoms.
      METHODS: This study of BC was based on a retrospective review of 41 cases: 21
      infants and children and 20 adults, aged 1 day to 68 years. The diagnosis was
      antenatal in 4 cases. Three infants required mechanical ventilation, and 2 had
      their cyst drained before resection. Twenty infants and children and 17 adults
      underwent operations. RESULTS: Compression was the most important complication in
      infants and children. Cough, infection, and hemoptysis occurred later in life;
      80% of the total population was symptomatic. Seven cysts were infected. There
      were no deaths after resection, and there was no recurrence of symptoms during
      the follow-up period (13 months to 21 years). CONCLUSIONS: Bronchogenic cysts
      originate from the foregut. Differentiation from other acquired or congenital
      lesions can be difficult. It is uncertain what proportion of BC remain
      asymptomatic. More than half of patients are diagnosed after the age of 15 years,
      and complications may appear late. Clinical findings and plain chest radiograms
      are often sufficient for diagnosis. Lobectomy is the standard treatment, whereas
      drainage is a temporary, palliative, and risky procedure in cases of life
      threatening compression. We conclude that a symptomatic BC is an indication for
      resection and that the long-term prognosis of an asymptomatic BC is
      unpredictable. Thus, there is a role for preventive operations.

PMID- 8651762
TI  - Immediate and long-term results after surgical treatment of primary spontaneous
      pneumothorax by VATS.
AB  - BACKGROUND: Video-assisted thoracic surgery has recently evolved as a viable
      alternative to thoracotomy for spontaneous pneumothorax. METHODS: A series of 163
      patients with primary spontaneous pneumothorax were treated by video-assisted
      thoracic surgery. Seventy patients were treated for a recurrent episode, 64
      patients for a persistent primary spontaneous pneumothorax, 24 patients for a
      contralateral episode, and 5 patients for a bilateral primary spontaneous
      pneumothorax. Stapling of bullae with an Endo-GIA stapler (Auto-Suture,
      Elencourt, France) was performed in 90% of the cases and parietal pleural
      abrasion was performed in each case. RESULTS: One revisional lateral limited
      thoracotomy was required for bleeding. Six patients had a prolonged air leak; 2
      of them were reoperated on by lateral limited thoracotomy. Two patients have had
      an incomplete reexpansion of the lung and required a reoperation. The duration of
      hospitalization was 6.9 +/- 3 days. With a mean follow-up of 24.5 months, three
      recurrences requiring a reoperation occurred; 3 other patients had a partial
      recurrence and healed by rest without drainage. The mean time to return to the
      occupational activity of the patients was 42 +/- 34 days. These results were
      compared with those of a previous series of 87 patients operated on by lateral
      limited thoracotomy. CONCLUSIONS: With the development of surgical technique and
      video equipment, video-assisted thoracic surgery will probably become the
      treatment of choice of primary spontaneous pneumothorax.

PMID- 8651763
TI  - Pneumothorax and wound dehiscence related to collagenase deregulation: treatment
      with diphenylhydantoin.
AB  - BACKGROUND: Wound dehiscence is an uncommon complication of operation, usually
      related to a recognized risk factor. A clinical dilemma arises when dehiscence
      has no identifiable cause or treatment. METHODS: We describe the case of a
      previously healthy 45-year-old man in whom recurrent spontaneous pneumothoraces
      developed followed by multiple dehiscences of thoracotomy, diaphragmatic, and
      abdominal wounds. Analysis over several years of laboratory investigation of
      cultured tissue from test incisions was initially unsuccessful. The patient was
      supported symptomatically until a remarkable laboratory finding enabled us to
      develop an effective treatment plan. RESULTS: Cultured patient fibroblasts were
      ultimately found to express abnormally elevated levels of collagenase, which
      could be inhibited by diphenylhydantoin (phenytoin) in vitro. Treatment of the
      patient with a course of diphenylhydantoin allowed adequate healing of test
      incisions and subsequent definitive surgical treatment with successful wound
      healing. CONCLUSIONS: This report of the rigorous application of the scientific
      method to the investigation and treatment of an enigmatic case of wound
      dehiscence might serve as a guide to surgeons faced with similar healing
      problems.

PMID- 8651764
TI  - Effect of L-arginine on metabolic recovery of the ischemic myocardium.
AB  - BACKGROUND: The release of nitric oxide is decreased after myocardial ischemia
      and reperfusion. Whereas the precursor L-arginine can stimulate the release of
      nitric oxide, its effect on metabolic recovery after myocardial ischemia is
      unknown. METHODS: To study the effect of L-arginine on metabolic recovery after
      myocardial ischemia, cardioplegia infusion, and reperfusion, 33 dogs were placed
      on cardiopulmonary bypass and subjected to a sequence of 30 minutes of
      normothermic global ischemia, 30 minutes of warm blood cardioplegic arrest, and
      30 minutes of reperfusion. A pH probe was inserted in the anterior wall of the
      left ventricle, and tissue pH was measured throughout the experiment. Coronary
      blood flow in the left anterior descending coronary artery and the circumflex
      coronary artery was measured. Blood samples from the coronary sinus were taken to
      measure blood pH and levels of lactate, creatine kinase, and troponin T. RESULTS:
      In the control group of 9 dogs, tissue pH averaged 6.4 +/- 0.1, 6.5 +/- 0.1, and
      6.8 +/- 0.1 after the end of global ischemia, cardioplegia, and reperfusion,
      respectively. Tissue pH averaged 6.4 +/- 0.1, 6.6 +/- 0.1, and 6.9 +/- 0.1,
      respectively, in the experimental group of 9 animals with 2 mmol/L of L-arginine
      added to the cardioplegic solution. Tissue pH averaged 6.2 +/- 0.1, 6.7 +/- 0.1,
      7.1 +/- 0.1, respectively, in the third group of 9 animals that received an
      additional infusion of L-arginine (10 mg.kg-1.min-1) during reperfusion. Tissue
      pH recovered faster in groups with L-arginine (p = 0.00001). A hyperemic response
      of coronary blood flow was shown at reperfusion in animals in the control group
      only. In 6 dogs, L-NAME (N-nitroarginine methyl ester), an inhibitor of nitric
      oxide synthesis, was injected and resulted in a slower pH recovery on reperfusion
      compared with that of animals that received L-arginine. CONCLUSIONS: The addition
      of L-arginine to the cardioplegic solution and the systemic circulation during
      reperfusion resulted in a significant increase in coronary blood flow during
      cardioplegia infusion and in a faster recovery of myocardial tissue pH, possibly
      by increasing coronary blood flow through the release of nitric oxide.

PMID- 8651765
TI  - Left anterior descending coronary artery grafting via left anterior small
      thoracotomy without cardiopulmonary bypass.
AB  - BACKGROUND: We explored the possibility of anastomosing the left anterior
      internal mammary artery (LIMA) to the left anterior descending artery in a
      beating heart via a left anterior small thoracotomy. METHODS: This procedure was
      performed in 155 of 162 scheduled patients; in 7 (4.3%) the left anterior
      descending artery was not suitable or was too small. The chest was opened in the
      fourth intercostal space (mean wound length, 10.5 cm) and the LIMA was harvested
      for about 4 cm. The left anterior descending artery was occluded by means of two
      4/0 Prolene (Ethicon, Somerville, NJ) sutures, and the proximal suture was
      snared. The anastomosis was performed with two 8/0 Prolene sutures while the
      heart was beating. Early postoperatively all patients underwent repeat
      angiography or a Doppler flow assessment of the LIMA or both. RESULTS: The LIMA
      was connected directly to the left anterior descending artery in 144 patients and
      with interposition of an inferior epigastric artery in 11. In 2 patients the
      diagonal branch was also grafted using an inferior epigastric artery from the
      LIMA. One patient (0.6%) died 38 days after the operation due to multiorgan
      failure. Nine patients (5.8%) had failure requiring a redo operation: 7 (4.5%)
      early and 2 (1.3%) late. One additional patient had a late percutaneous
      transluminal coronary angioplasty for anastomotic stenosis. At a mean 5.6 months
      of follow-up, 143 patients (92.2%) were alive, asymptomatic with or without
      medical treatment, and without cardiac events. CONCLUSIONS: Left internal mammary
      artery-to-left anterior descending artery anastomosis performed on a beating
      heart via a left anterior small thoracotomy is a safe procedure. In selected
      patients the operation has good early and midterm results.

PMID- 8651766
TI  - Characterization and surgical ablation of atrial flutter after the classic Fontan
      repair.
AB  - BACKGROUND: Atrial flutter (AFL) is a frequent postoperative complication of the
      classic Fontan operation, which uses an atriopulmonary connection. We
      hypothesized that the suture lines alone, in the absence of any hemodynamic
      alterations, provide the necessary electrophysiologic substrates for AFL. The
      objectives of this study were to determine if the Fontan suture lines alone are
      sufficient to permit sustained AFL in an acute canine model and to characterize
      any resulting reentrant circuits to surgically ablate the AFL. METHODS: After
      cardiopulmonary bypass, adult dogs (n = 18) underwent a simulated classic Fontan
      operation. This included a longitudinal right atriotomy and an incision from the
      base of the right atrial appendage toward the dome of the left atrium,
      representing the atriopulmonary connection. In 6 of 18 dogs, an atrial septal
      defect was created at the level of the fossa ovalis. Unipolar 253-point biatrial
      endocardial mapping electrodes were placed via bilateral ventriculotomies.
      Induction of AFL was attempted by atrial burst pacing. If AFL could not be
      induced, isoproterenol was administered and pacing repeated. Activation sequence
      maps of the pathways of atrial reentry were generated. In 8 dogs with inducible
      AFL, an incision was made from the atriotomy to the atriopulmonary connection and
      burst pacing repeated. RESULTS: Sustained AFL could not be induced after bypass
      alone in any case. After the simulated Fontan operation, sustained AFL was
      reproducibly induced in all 18 dogs, 6 of which required isoproterenol. The mean
      cycle length of all cases was 177 +/- 20 ms. During AFL, atrial activation
      sequence maps demonstrated lines of conduction block created by both the
      atriotomy and the atriopulmonary connection. The isthmus of tissue between these
      two lines of block was essential for propagation of the reentrant wavefront.
      Interruption of this isthmus with an incision successfully terminated AFL in 8 of
      8 dogs. CONCLUSIONS: In an acute canine model, the Fontan suture lines alone, in
      the absence of atrial hypertension or stretch, permit the induction of AFL. An
      essential electrophysiologic substrate is an isthmus of myocardium between the
      atriotomy and the atriopulmonary connection. Interruption of conduction through
      this isthmus terminates the AFL in this model and suggests a technique for
      ablation of AFL in patients who have undergone a classic Fontan operation.

PMID- 8651768
TI  - Safety of remote aortic valve replacement after prior coronary artery bypass
      grafting.
AB  - BACKGROUND: A previous coronary artery bypass grafting (CABG) procedure may
      complicate subsequent aortic valve replacement (AVR). However, the operative
      risks and long-term outcome of patients who undergo these two procedures remain
      poorly defined. METHODS: The medical records of all patients undergoing AVR
      between February 1986 and September 1995 were reviewed retrospectively. The
      patients selected for analysis had previously undergone CABG. RESULTS: We
      performed AVR in 23 consecutive patients who had previously undergone CABG (mean
      number of grafts, 2.8). The AVR was performed an average of 7.6 years after CABG
      (range, 2 to 17 years). There were 20 men and 3 women, with a mean age of 69
      years (range, 56 to 85 years). Twenty patients were operated upon for aortic
      stenosis (mean gradient 54 mm Hg, mean valve area 0.7 cm2), and 3 patients
      underwent operation for aortic regurgitation. The average aortic valve gradient
      at the initial revascularization operation was 8 mm Hg (range, 0 to 29 mm Hg).
      There was no correlation between the aortic valve gradient at the initial
      revascularization and the interval between CABG and AVR. At the second operation,
      AVR was performed alone in 11 patients, combined with repeat CABG in 11 patients
      (mean number of grafts, 1.4), and with mitral valve replacement in 1 patient. A
      mechanical prosthesis was selected in 14 patients, and a bioprosthesis was used
      in 9 patients. There were no perioperative deaths. There were five late deaths at
      an average follow-up of 44 months. The 5-year actuarial survival was 71%.
      CONCLUSIONS: Previous CABG poses added technical challenges at the time of
      reoperation for AVR. The operation can be performed safely, with the expectation
      of satisfactory long-term survival.

PMID- 8651767
TI  - Myocardial protection with pinacidil cardioplegia in the blood-perfused heart.
AB  - BACKGROUND: Adenosine triphosphate-sensitive potassium-channel openers are potent
      vasodilators that have been found to be cardioprotective during myocardial
      ischemia. The potassium-channel opener pinacidil was investigated to determine
      its efficacy as a cardioplegic agent. METHODS: A blood-perfused, parabiotic,
      isolated rabbit heart Langendorff preparation was used. Fifty-six hearts
      underwent 30 minutes of global normothermic ischemia after a 50-mL infusion of
      cardioplegia, followed by 60 minutes of reperfusion. The cardioplegia consisted
      of Krebs-Henseleit solution with either vehicle alone (control), 20 mmol KCl, or
      pinacidil (10, 50, 100, 150, or 200 mumol/L). The developed pressure was measured
      at baseline and after reperfusion. Coronary blood flow was measured with an in
      line ultrasonic probe. RESULTS: Pinacidil (50 mumol/L), as opposed to potassium
      cardioplegia, provided significantly better postischemic percentage recovery of
      developed pressure compared with controls (68.3% +/- 4.0% versus 44.6% +/- 5.5%;
      p < 0.05). The time until electrical arrest was significantly shorter in the
      hyperkalemic group than in all other groups. Linear end-diastolic pressure-volume
      relationships revealed an increase in slope after ischemia in all groups.
      Coronary flow after 5 minutes of reperfusion was significantly higher in both the
      50-mumol/L and 100-mumol/L pinacidil groups compared with traditional
      hyperkalemic arrest, and this returned to baseline after 15 minutes. CONCLUSIONS:
      The potassium channel opener pinacidil provided dose-dependent myocardial
      protection during global ischemia in the blood-perfused rabbit heart model.
      Potassium-channel openers are a promising class of drugs that may provide an
      alternative to traditional hyperkalemic cardioplegia.

PMID- 8651769
TI  - Management of asymptomatic mild aortic stenosis during coronary artery
      operations.
AB  - BACKGROUND: Management of asymptomatic mild aortic stenosis at the time of
      coronary artery bypass grafting (CABG) remains controversial. We have
      retrospectively analyzed a cohort of patients requiring aortic valve replacement
      (AVR) subsequent to CABG and compared their operative morbidity and mortality
      with that of a group receiving CABG and AVR simultaneously at the first
      operation. METHODS: Analysis is drawn from 28 patients who required AVR 8 +/- 4
      years subsequent to CABG (group A) and 175 patients receiving AVR along with CABG
      at the primary operation (group B). Groups were similar with respect to age, sex,
      risk factors for cardiac disease, extent of coronary artery disease, left
      ventricular function, New York Heart Association class, aortic valve area, number
      of grafts, and size of prosthesis inserted. RESULTS: Patients having AVR
      subsequent to CABG had a significantly prolonged aortic cross-clamp time and
      global myocardial ischemic time and incurred a twofold increase in operative
      mortality. The actuarial survival at 10 years was not significantly different
      between cohorts. In the 28 patients in group A, the aortic valve area during the
      period between operations decreased 0.05 mm2/y. CONCLUSIONS: The operative
      mortality and morbidity of a second operation for AVR is high, but there is no
      significant difference in survival at 10 years. In at least a portion of patients
      having mild aortic stenosis at the time of CABG there will be progression of the
      stenosis necessitating reoperation at a later date.

PMID- 8651770
TI  - Nitric oxide production affects cerebral perfusion and metabolism after deep
      hypothermic circulatory arrest.
AB  - BACKGROUND: Use of deep hypothermic circulatory arrest (DHCA) in infant cardiac
      surgery is associated with reduced cerebral perfusion and metabolism during the
      recovery period. We investigated the impairment of nitric oxide production as a
      possible cause. METHODS: A group of 1-week-old piglets underwent normothermic
      cardiopulmonary bypass (group A); three other groups (B, C, and D; n = 6 per
      group) underwent 60 minutes of DHCA at 18 degrees C and 60 minutes of rewarming.
      The animals were then treated as follows: Groups A and B received L-omega-nitro
      arginine-methyl-ester (L-NAME, 50 mg.kg-1); group C, saline solution; and group
      D, L-arginine (600 mg.kg-1). RESULTS: In group A, global cerebral blood flow
      decreased to 37.3% +/- 4.2% of baseline after L-NAME administration (p < 0.005).
      In group B, global cerebral blood flow decreased to 44.6% +/- 4.4% of baseline
      after DHCA and 28.9% +/- 3.4% after L-NAME administration (p < 0.001). Following
      L-arginine treatment after DHCA (group D), global cerebral blood flow increased
      from 43.8% +/- 3.0% of baseline to 61.6% +/- 9.1% (p < 0.05); cerebral oxygen
      metabolism increased from 1.93 +/- 0.16 mL.min-1.100 g-1 after DHCA to 2.42 +/-
      0.25 mL.min-1.100 g-1 (p < 0.05). CONCLUSIONS: Tonal production of nitric oxide
      is impaired in the brain after DHCA and is partly responsible for the circulatory
      and metabolic changes observed. Stimulation of nitric oxide production (L
      arginine) significantly improved recovery of cerebral blood flow and cerebral
      oxygen metabolism after DHCA.

PMID- 8651771
TI  - Right internal thoracic artery through the transverse sinus in myocardial
      revascularization.
AB  - BACKGROUND: This study presents the late patency rate of the right internal
      thoracic artery (ITA) used in situ through the pericardium transverse sinus to
      the circumflex artery and its branches. METHODS: From April 1983 to December
      1994, 2,642 patients were submitted to myocardial revascularization; 201 of them
      had bilateral ITAs. The right ITA through the transverse sinus was grafted to
      obtuse marginal artery in 170 patients (84.5%) and the left ITA was grafted to
      the anterior descending artery in 188 patients (93.5%). Angiographic studies were
      performed in 80 patients, 44 patients in the immediate postoperative period and
      36 patients in the late follow-up (mean, 51.6 months). RESULTS: The right ITA was
      patent in 75 patients (93.7%) and the left ITA was patent in 77 (96.2%). At the
      late postoperative period, the right ITA was patent in 33 patients (91.6%) and
      the left ITA was patent in 34 (94.4%). CONCLUSIONS: The right ITA placed through
      the pericardium transverse sinus has a good long-term patency rate, similar to
      that observed with the left ITA and superior to that of saphenous vein grafts for
      myocardial revascularization.

PMID- 8651772
TI  - Systemic inflammatory response syndrome after cardiac operations.
AB  - BACKGROUND: A systemic inflammatory response after open heart operation may be
      responsible for hyperdynamic circulatory instability and organ dysfunction. To
      what extent mediator release is involved needs to be clarified. METHODS: Ten
      patients with postoperative hyperdynamic circulatory dysregulation (group I)
      requiring application of alpha-constrictors and 10 patients with routine cardiac
      procedures and stable postoperative hemodynamic indices (group II) were analyzed
      for mediator release and metabolic and hemodynamic changes until the third
      postoperative day. RESULTS: Group I patients showed a significantly increased
      cardiac index and decreased systemic vascular resistance after bypass (cardiac
      index, group I: 5.2 +/- 1.2 L.min-1.m-2, group II: 2.5 +/- 1.6 L.min-1.m-2;
      systemic vascular resistance, group I: 495 +/- 204 dyne.s. cm-5, group II: 1,356
      +/- 466 dyne.s.cm-5) and at 3 hours (cardiac index, group I: 4.4 +/- 0.8 L.min
      1.m-2, group II: 2.9 +/- 0.6 L.min-1.m-2; systemic vascular resistance, group I:
      567 +/- 211 dyne.s.cm-5, group II: 1,053 +/- 273 dyne.s.cm-5). Significantly
      higher serum levels of interleukin-6 were assessed in group I (postbypass, group
      I: 6,812 +/- 9,293 pg/mL, group II: 295 +/- 303 pg/mL; 3 hours, group I: 3,474 +/
      5,594 pg/mL, group II: 286 +/- 296 pg/mL). Concentrations of elastase, tumor
      necrosis factor, soluble tumor necrosis factor receptor, and interleukin-8 were
      elevated in group I (not significant). Early postoperative levels of soluble E
      selectin and soluble intercellular adhesion molecule were also higher in group I
      (not significant). Continuously increased levels of endotoxin could be detected
      in only 3 of 10 patients in group I. Severe lactic acidosis (> or = 5 mmol/L)
      occurred in group I only. CONCLUSIONS: Postoperative hyperdynamic instability
      after open heart operations appears to be associated with a certain pattern of
      mediator release. In particular, interleukin-6 appears to be involved in
      circulatory dysregulation and metabolic derangement.

PMID- 8651773
TI  - Combined left-sided recurrent laryngeal and phrenic nerve palsy after coronary
      artery operation.
AB  - BACKGROUND: Ice/saline slush used along with cold cardioplegia for heart arrest
      in cardiac operations can cause hypothermic damage to certain structures, an
      important one being the left phrenic nerve, damage of which results in raised
      left hemidiaphragm and delayed recovery of the patient. In coronary artery bypass
      grafting, opening of the pleura and collection of the ice/saline slush in the
      pleural cavity increases the incidence of injury. METHODS: Three of our
      nonconsecutive patients underwent coronary artery bypass grafting with cold
      cardioplegia and open pleura, with collection of ice/saline slush in the pleural
      cavity for a sufficiently long time. RESULTS: Simultaneous involvement of left
      recurrent laryngeal nerve along with left phrenic nerve was found in all patients
      without any concurrent topical injury around the larynx. the recurrent laryngeal
      nerve took 8 to 10 months to recover. CONCLUSIONS: The left recurrent nerve as it
      arches around aorta lies in the thorax very close to the parietal pleura and may
      be prone to hypothermic injury by ice/slush collecting in the pleural cavity
      during cardiac operations. Judicious use of ice/saline slush had helped in
      eliminating the problem to some extent.

PMID- 8651776
TI  - Cardiac transplantation after mechanical circulatory support: a Canadian
      perspective.
AB  - BACKGROUND: To assess the relative efficacy of cardiac transplantation after
      mechanical circulatory support with a variety of support systems, we analyzed our
      consecutive series of patients who had and did not have mechanical support before
      transplantation. METHODS: A review of 209 patients undergoing cardiac
      transplantation from 1984 to May 1995 was performed. Group 1 consisted of 110
      patients who were maintained on oral medications while awaiting transplantation,
      and group 2 consisted of 60 patients who required intravenous inotropic support.
      Group 3 included 39 patients who had transplantation after mechanical circulatory
      support for cardiogenic shock. The indication for device implantation was acute
      onset of cardiogenic shock in 38 patients and deterioration while awaiting
      transplantation in 1 patient. The support systems were an intraaortic balloon
      pump in 13 (subgroup 3A), a ventricular assist device in 7 (subgroup 3B), and a
      total artificial heart in 19 patients (subgroup 3C). RESULTS: After
      transplantation, infection was more common in group 3 (56%) than in group 1 (28%)
      or group 2 (32%) (p = 0.005). Survival to discharge was lower for group 3 (71.7%)
      than for group 1 (90.9%) or 2 (88.3%) (p = 0.009). For mechanically supported
      patients, survival to discharge was 84.6% in subgroup 3A, 71.4% in subgroup 3B,
      and 63.1% in subgroup 3C (p = not significant). CONCLUSIONS: Transplantation
      after mechanical support offers acceptable results in this group of patients for
      whom the only alternative is certain death. Patient selection and perioperative
      management remain the challenge to improving these results.

PMID- 8651775
TI  - Heart transplantation for chronic Chagas' heart disease.
AB  - BACKGROUND: Chagas' disease has been considered a contraindication to heart
      transplantation as Trypanosoma cruzi infection could recur after
      immunosuppression. METHODS: We report the follow-up of 22 patients who underwent
      orthotopic heart transplantation for treatment of end-stage chronic Chagas' heart
      disease, divided in two groups. Group 1 consisted of 9 patients operated on from
      September 1985 to June 1991, and group 2 patients underwent transplantation from
      July 1991 to June 1995. After our early experience with group 1, we attempted to
      use a lower cyclosporine dosage in group 2. RESULTS: Total actuarial survival at
      24 months was 60%, and it was better for group 2 (33% for group 1, 80% for group
      2, p = 0.008). Parasitemia occurred similarly in both groups, but Chagas' disease
      reactivation was seen in 5 group 1 patients and in 1 group 2 member (p < 0.002).
      Neoplasia developed in 5 group 1 patients and 1 group 2 patient, and contributed
      to death in 3 of them. CONCLUSIONS: These data demonstrate satisfactory outcome
      of cardiac transplantation in patients with end-stage Chagas' heart disease in
      the second phase of our experience. Further progress is necessary to improve the
      results and evaluate its proper role in the management of this disease.

PMID- 8651774
TI  - Perioperative complications in combined aortic valve replacement and
      extraanatomic ascending-descending bypass.
AB  - BACKGROUND: In adult patients, the combination of severe aortic valve stenosis
      and coarctation is rare. Surgical options comprise either a two-stage approach
      with valve replacement and subsequent repair of the coarctation or a one-stage
      repair involving valve replacement and insertion of an extraanatomic bypass graft
      from the ascending to the descending aorta. METHODS: We report the cases of 2
      adult patients with this combined lesion who underwent simultaneous aortic valve
      replacement and transpericardial bypass of the coarctation. RESULTS: Weaning from
      extracorporeal circulation and restoration of spontaneous circulation required
      resuscitative measures. By increasing mean arterial perfusion pressure using
      norepinephrine, the observed hemodynamic instability could be controlled
      effectively. CONCLUSIONS: Changes in the hemodynamics of the thoracic vascular
      bed resulting in coronary malperfusion are discussed to be the major cause of
      heart failure and life-threatening ventricular arrhythmias seen in our patients
      after aortic valve replacement and insertion of an ascending-descending aorta
      bypass graft. Awareness of the complications described is considered important
      for successful management of these high-risk patients.

PMID- 8651778
TI  - Aortic valve replacement in elderly patients: influence of concomitant coronary
      grafting on late survival.
AB  - BACKGROUND: Aortic valve replacement (AVR) has been an accepted therapy for
      elderly patients (> 70 years) with aortic valve disease. This study was designed
      to investigate the determinants of survival after the implantation of aortic
      valve prostheses, with emphasis on the effect of concomitant coronary artery
      bypass grafting on survival. METHODS: From November 1964 to July 1994,963 elderly
      patients underwent isolated AVR. Long-term survival was investigated in 877
      patients (70 to 94 years) who survived operation, with 92% follow-up completeness
      (mean +/- standard deviation, 4.5 +/- 3.9 years; maximum, 20.1 years; total,
      3,920.2 patient-years), by univariate and multivariate analyses. RESULTS:
      Actuarial survival was 38.1% +/- 2.8% at 10 years, 17.8% +/- 3.0% at 15 years,
      and 9.0% +/- 3.1% at 20 years. Eight variables (age, sex, body surface area [less
      or greater than 1.7 m2], period of operation, type of prosthesis, size of
      prosthesis, re-replacement, and concomitant coronary artery bypass grafting) were
      investigated with regard to long-term survival by the Kaplan-Meier method. Age,
      sex, and body surface area were significant. Multivariate analysis revealed that
      older age (p = 0.0005) and male sex (p = 0.0001) were independent variables that
      determined long-term survival. CONCLUSIONS: Elderly patients may have
      satisfactory long-term results after AVR. Age and sex are independent
      determinants. Other factors (such as concomitant coronary artery bypass grafting
      and type of prosthesis) did not independently influence long-term survival.
      Coronary revascularization in elderly patients with coronary disease undergoing
      AVR may lead to a long-term survival similar to that in patients without coronary
      disease undergoing AVR.

PMID- 8651777
TI  - Preoperative prediction of postoperative morbidity in coronary artery bypass
      grafting.
AB  - BACKGROUND: The risk factors of patients selected for coronary artery bypass
      grafting have increased in recent years because of the aging population.
      Prediction of postoperative complications is essential for optimal use of the
      available resources. The aim of this study was to develop a scoring method for
      prediction of postoperative morbidity of individual patients undergoing bypass
      grafting. METHODS: Data from 386 consecutive patients who underwent coronary
      artery bypass grafting in a single center were retrospectively collected. The
      relationship between the preoperative risk factors and the postoperative
      morbidity was analyzed by the Bayesian approach. Three risk indices (15-factor
      and seven-factor computed and seven-factor manual models) were developed for the
      prediction of morbidity. The criterion for morbidity was a prolonged hospital
      stay postoperatively (> 12 days) because of adverse events. RESULTS: The best
      predictive preoperative factors for increased morbidity were emergency operation,
      diabetes, rhythm other than sinus rhythm on the electrocardiogram or recent
      myocardial infarction, low ejection fraction (< 0.49), age greater than 70 years,
      decreased renal function, chronic pulmonary disease, cerebrovascular disease, and
      obesity. The sensitivity of the scoring methods ranged from 51% to 72% and the
      specificity, from 77% to 86%. CONCLUSIONS: The results show that individual
      patients can be stratified according to postoperative risk for complications on
      the basis of preoperative information that is available for most patients.

PMID- 8651779
TI  - Early mortality after surgical repair of postinfarction ventricular septal
      rupture: importance of rupture location.
AB  - BACKGROUND: The aim of this study was to identify factors influencing early
      outcome after surgical treatment of postinfarction ventricular septal rupture. We
      investigated the influence of proximal or distal rupture location. METHODS:
      Between 1980 and 1992 109 patients were treated surgically for ventricular septal
      rupture using a standardized technique. A division in time periods was made. The
      rupture was categorized according to its anterior or posterior site and proximal
      or distal location. RESULTS: The 30-day mortality rate was 27.5%. Multivariate
      logistic regression analysis identified preoperative shock (p = 0.0007) and right
      atrial oxygen saturation less than 60% (p = 0.021) as predictors for early death;
      the risk for early death declined over the time periods from 50% to 12.8% (p =
      0.0007). Proximal ventricular septal rupture location (p = 0.0092) and interval
      between infarction and ventricular septal rupture less then 1 day (p = 0.034)
      were risk factors for the occurrence of preoperative shock. CONCLUSIONS: Proximal
      ventricular septal rupture location was the main determinant of preoperative
      cardiogenic shock, which in turn was the strongest predictor of early mortality.
      Over the time periods a decrease in early mortality was reached.

PMID- 8651780
TI  - Autologous tissue cardiac valve for aortic valve replacement: technical aspects
      and early results.
AB  - BACKGROUND: The known complications of heterograft bioprostheses and homograft
      valves have renewed the interest in the use of autologous material. A new
      technique to construct a tissue prosthesis for aortic valve replacement using the
      patient's pericardium harvested at the time of operation was developed. The
      glutaraldehyde-tanned pericardium is mounted on a stent requiring no suturing.
      Intraoperative testing assures adequate valve function. METHODS: The autologous
      tissue cardiac valve was implanted in 50 patients in the aortic position between
      March 1994 and May 1995. Echocardiograms were performed in all patients before
      hospital discharge, at 3 months (41 patients), and at the end of first
      postoperative year (12 patients). The mean age was 69.8 +/- 5 years (range, 58 to
      82 years). Eighty-four percent of patients presented with aortic stenosis and 16%
      had a combined lesion. Additional cardiac procedures were performed in 21
      patients. RESULTS: Aortic cross-clamp time was 72 +/- 19 minutes, and bypass time
      was 97 +/- 28 minutes. There were three in-hospital deaths, and 2 patients died
      within the first postoperative year. Predischarge echocardiography demonstrated
      excellent hemodynamics, with a mean gradient of 20 +/- 8 mm Hg and no or trivial
      aortic insufficiency in 45 patients. One patient had moderate aortic
      insufficiency. At first follow-up 36 patients (90%) were in New York Heart
      Association class I and 4 patients were in class II. Echocardiography showed no
      evidence of valve failure or degeneration (mean gradient, 17 +/- 5mm Hg; aortic
      insufficiency = grade 0 [trivial] in 35 patients, grade II in 3 patients, and
      grade III in 1 patient). Similarly, no degeneration or valve failure with
      increasing aortic insufficiency was seen in the patients studied at the end of
      the first postoperative year. CONCLUSIONS: These results demonstrate that an
      autologous tissue cardiac valve can be manufactured in the operating room without
      significant additional operating time. Intraoperative testing minimizes the risk
      of primary failure with aortic insufficiency. Short-term results are encouraging
      with good hemodynamic performance of the valve and no signs of degeneration.
      However, long-term durability needs to be demonstrated.

PMID- 8651781
TI  - Is potassium channel opening an effective form of preconditioning before
      cardioplegia?
AB  - BACKGROUND: Opening of adenosine triphosphate-sensitive potassium channels might
      be one of the mechanisms by which preconditioning preserves the myocardium
      against ischemic damage. The present study was therefore designed to compare the
      protective efficacy of ischemic preconditioning with that of pharmacologic
      preconditioning involving the use of a potassium channel opener in a surgically
      relevant model of cold cardioplegic arrest. METHODS: Thirty isolated isovolumic
      rat hearts were subjected to 2 hours of potassium arrest at an average myocardial
      temperature of 23 degrees C, followed by 1 hour of reperfusion. Three groups (n =
      10 per group) were studied: (1) control (no prearrest intervention); (2) ischemic
      preconditioning, achieved with 5 minutes of noflow ischemia followed by 5 minutes
      of reperfusion before arrest; and (3) pharmacologic preconditioning, achieved
      with a 5-minute infusion of the potassium channel opener nicorandil (10 mumol/L)
      followed by 5 minutes of drug-free perfusion before arrest. Standard functional
      indices were measured at multiple times during reperfusion, at the end of which
      pressure-volume curves were constructed and compared with those obtained at
      baseline. RESULTS: Both ischemically and pharmacologically preconditioned hearts
      recovered systolic and diastolic function to a significantly greater extent than
      the controls. There was no difference in the recovery patterns between the forms
      of preconditioning. However, analysis of the postischemic pressure-volume curves
      demonstrated that nicorandil-preconditioned hearts incurred the smallest losses
      of compliance throughout the ischemia-reperfusion sequence. CONCLUSIONS: The
      protective effects of a standard ischemic preconditioning challenge on functional
      recovery after an episode of moderately hypothermic cardioplegic arrest can be
      duplicated by pharmacologic opening of adenosine triphosphate-sensitive potassium
      channels. This finding may be of clinical relevance because of the availability
      of potassium channel openers, such as nicorandil, for human use.

PMID- 8651782
TI  - Indication and technique of total correction of tetralogy of Fallot in 228
      patients.
AB  - BACKGROUND: Several factors, such as old age, high hemoglobin level, pulmonary
      artery hypoplasia, and diminutive left ventricle, have been identified as high
      risk factors for operative mortality. This group of patients includes all these
      factors. METHODS: Between September 1987 and March 1995, I performed total
      correction of tetralogy of Fallot on 228 unselected consecutive patients at Fu
      Wai Hospital in Beijing. There were 140 male and 88 female patients. RESULTS:
      Only 2 patients died of nonsurgical causes postoperatively. The mortality was
      0.9%. The remaining patients recovered uneventfully. The late mortality was 1.8%
      (4/228). CONCLUSIONS: The results suggested that hypoplastic pulmonary artery and
      left ventricle were not an absolute contraindication of total correction of
      tetralogy of Fallot. High hematocrit and old age were also not high risk factors
      causing death. The key factor was to correct the pathology completely and manage
      the complications properly.

PMID- 8651783
TI  - Pulmonary vasoconstriction due to impaired nitric oxide production after
      cardiopulmonary bypass.
AB  - BACKGROUND: Pulmonary hypertension is a serious complication after
      cardiopulmonary bypass (CPB). This study tests the hypothesis that CPB provokes
      oxidant-mediated pulmonary endothelial dysfunction, leading to reduced nitric
      oxide (NO) production and pulmonary vasoconstriction. METHODS: Twelve piglets
      underwent 2 hours of CPB. In 6 of them, CPB prime was supplemented with N
      mercaptopropionylglycine and catalase, whereas the others were not treated. Left
      and right ventricular function were evaluated from end-systolic elastance and
      Starling analysis. Pulmonary vascular resistance and transpulmonary NO production
      (measuring NO2-, NO3-) were determined to assess pulmonary endothelial function.
      RESULTS: Cardiopulmonary bypass caused a significant increase in pulmonary
      vascular resistance (83 +/- 12 to 212 +/- 30 dynes.cm-5.s kg-1, p < 0.05),
      associated with a reduction of NO production (8.8 +/- 1.4 to 2.5 +/- 0.5
      mumol/min, p < 0.05) and depressed right ventricular function (56 +/- 12% of
      control), whereas N-mercaptopropionylglycine and catalase added to the CPB
      allowed a substantial improvement of these deleterious effects of CPB.
      CONCLUSIONS: Cardiopulmonary bypass impairs pulmonary NO production, resulting in
      pulmonary vasoconstriction and right ventricular dysfunction, which can be
      reduced by antioxidants. These findings imply the validity of NO inhalation
      therapy for postoperative pulmonary hypertension as a supplementation of
      endogenous endothelium-derived relaxing factor.

PMID- 8651785
TI  - Mid-term results of pulmonary thromboendarterectomy for chronic thromboembolic
      pulmonary hypertension.
AB  - BACKGROUND: In patients with chronic thromboembolic pulmonary hypertension, acute
      and striking decreases of pulmonary artery pressures and vascular resistance can
      be achieved by pulmonary thromboendarterectomy. In this study, the long-term
      effects of pulmonary thromboendarterectomy on hemodynamic indices and right
      ventricular function were investigated. METHODS: Sixty-five patients (31 women
      and 34 men; mean age, 47 +/- 17 years; range, 19 to 69 years; New York Heart
      Association [NYHA] functional class II, n = 3; class III, n = 38; class IV, n =
      24) were reassessed 13 to 48 months (mean, 27 months) after pulmonary
      thromboendarterectomy. Measurements are reported as mean +/- standard deviation.
      RESULTS: All patients reported a significant improvement of symptoms: 46 patients
      were in NYHA functional class I, 16 patients in class II, and 3 patients in class
      III. Mean pulmonary vascular resistance was significantly reduced compared with
      preoperative and postoperative values (preoperative: 1,015 +/- 454 dynes.s.cm-5;
      postoperative: 322 +/- 154 dynes.s.cm-5; follow-up: 198 +/- 72 dynes.s.cm-5; p <
      0.001 versus preoperative; p < 0.025 versus postoperative). Concomitantly,
      cardiac index was significantly increased compared with preoperative values
      (preoperative: 2.0 +/- 0.7 L.min-1.m-2; follow-up: 2.9 +/- 0.5 L.min-1.m-2; p <
      0.001). Significant reductions of right ventricular dimensions and recovery of
      right ventricular function could be demonstrated radiologically and
      echocardiographically. In 3 patients (preoperative NYHA class IV, NYHA class III
      at follow-up) with proven coagulation abnormalities, pulmonary vascular
      resistance was moderately increased at follow-up compared with postoperative
      measurements. CONCLUSIONS: In patients with chronic thromboembolic pulmonary
      hypertension, a persistent decrease of pulmonary vascular resistance and
      improvement of right ventricular function and NYHA functional status can be
      achieved by pulmonary thromboendarterectomy.

PMID- 8651784
TI  - Video-assisted mitral valve operations.
AB  - BACKGROUND: Video-assisted endoscopy has been applied frequently in the
      management of a variety of surgical diseases. However, it has rarely been applied
      in mitral valve surgery. METHODS: We report 2 patients who received emergency
      operations for thrombosis of a mitral prosthesis (patient 1, a 68-year-old man)
      and acute mitral regurgitation due to rupture of anterior chordae (patient 2, a
      75-year-old woman). They both had severe congestive heart failure. Cardiogenic
      shock was noted in patient 2. The mitral valve was approached through a right
      anterior minithoracotomy with the aid of an endoscope by means of projected
      images on the video monitor under femorofemoral cardiopulmonary bypass. The aorta
      was not cross-clamped, and the myocardium was protected by continuous coronary
      perfusion with hypothermic fibrillatory arrest. The left atrium was entered
      posterior to the interatrial groove. Thrombectomy and mitral valve repair were
      performed successfully. RESULTS: The duration of extracorporeal circulation was
      204 and 147 minutes, respectively. Both patients recovered from the operation
      rapidly with uneventful postoperative courses. CONCLUSIONS: Our preliminary
      results suggest that video-assisted endoscopic cardiac surgery is technically
      feasible and could be performed in the milieu of open heart surgery.

PMID- 8651786
TI  - Comparison of clinical outcomes of coronary artery bypass grafting and
      percutaneous transluminal coronary angioplasty in renal dialysis patients.
AB  - BACKGROUND: The leading cause of death in chronic renal dialysis patients is
      cardiovascular disease. As the number of dialysis patients increases, we are
      encountering more patients with severe ischemic heart disease requiring coronary
      intervention. METHODS: A retrospective analysis was performed of the short- and
      long-term clinical results in 23 coronary artery bypass grafting patients and 20
      coronary angioplasty patients undergoing chronic renal dialysis. RESULTS: Among
      coronary bypass grafting patients, there were no hospital deaths. The graft
      patency rate was 100% for arterial grafts. There were four late deaths and four
      cardiac events. In coronary angioplasty patients, the lesion success rate was
      76%. There were no hospital deaths and three major complications. The restenosis
      rate was 70%. There were two late deaths and 14 cardiac events. The 5-year
      cardiac event-free rate was 70% in coronary bypass grafting patients,
      significantly better than 18% in coronary angioplasty patients (p < 0.001).
      CONCLUSIONS: Coronary artery bypass grafting in chronic renal dialysis patients
      can be accomplished with a better short- and long-term outcome than coronary
      angioplasty, through an intensive perioperative dialysis program and extensive
      use of arterial grafts.

PMID- 8651787
TI  - Clinical improvement after revision in Fontan patients.
AB  - BACKGROUND: Arrhythmias, decreased exercise tolerance, or malabsorption will
      develop in a significant number of Fontan patients. Fontan revision consisting of
      creation of lateral atrial tunnel, reconnection of the Glenn shunt when present,
      or both appears to improve these patients. METHODS: Over a 34-month period, 9
      patients underwent Fontan revision. The mean age was 11 +/- 5 years and the mean
      interval from Fontan operation to revision was 3 +/- 2 years. The reason for
      revision included marked impairment in exercise capacity, inability to go to
      school consistently, and chronic fatigue in 6 patients, 3 of whom also had
      serious atrial arrhythmias. Five of the 6 patients had a classic Glenn shunt. The
      mean right atrial pressure was greater than the pressure of the Glenn shunt (20
      +/- 1.6 versus 17 +/- 0.8 mm Hg). Three of the 6 patients also showed a
      significant gradient between the right or left pulmonary artery wedge and
      ventricular end-diastolic pressure, indicating pulmonary vein obstruction from
      the bulging atrial septum or partitioning patch (13 +/- 3 versus 6.8 +/- 1 mm
      Hg). The remaining 3 patients had revision because of malabsorption (1),
      hepatomegaly and obstructed right pulmonary veins from bulging atrial septum (1),
      and tricuspid insufficiency (1). Fontan revision was accomplished with creation
      of a lateral atrial tunnel and Glenn reconnection in 6 patients, Glenn
      reconnection in 2, and creation of a lateral atrial tunnel in 1. Four patients
      had additional procedures. RESULTS: One patient died of Pseudomonas pneumonia.
      Early extubation, chest tube removal, and postoperative hospital discharge were
      accomplished in 8 patients (mean = 1.4 +/- 1, 2.8 +/- 1, and 8 +/- 3 days,
      respectively). One patient died 8 months postoperatively of brain damage after
      ventricular fibrillation from attempted cardioversion for atrial flutter. The
      remaining patients had marked improvement in exercise capacity with ability to
      consistently go to school, improvement in duration and tolerance to arrhythmias
      on less medication, and resolution of malabsorption up to 37 months
      postoperatively (mean, 20 +/- 12 months). CONCLUSIONS: We conclude that creation
      of lateral atrial tunnel with excision of a bulging atrial septum or atrial
      partitioning patch that causes pulmonary venous obstruction, reconnection of the
      Glenn shunt, which allows better distribution of flow based on the pulmonary
      vascular bed and resistance of each lung, or a combination of these procedures
      will improve Fontan patients.

PMID- 8651788
TI  - Aortico-left ventricular tunnel in fetuses and infants.
AB  - BACKGROUND: Aortico-left ventricular tunnel is a rare congenital abnormal
      communication between the aorta and the left ventricle presenting in early
      childhood as aortic regurgitation and cardiac failure. This condition has rarely
      been reported in fetuses. Operation is the only treatment, and postoperative
      aortic incompetence could be related to the age or the type of repair. METHODS:
      We conducted a retrospective, two-institution review, from 1983 to 1995, of
      aortico-left ventricular tunnel diagnosed in utero and before 6 months of age.
      RESULTS: Three cases of aortico-left ventricular tunnel were diagnosed in utero
      by Doppler echocardiography between 22 and 24 weeks' gestation. Prenatal aortico
      left ventricular tunnel was associated with severe left ventricular dysfunction,
      aortic valve anomalies, and fetal hydrops. One death occurred in utero and one
      immediately after birth, and in 1 case pregnancy was interrupted. In these 3
      cases the diagnosis was confirmed by autopsy. Three neonates and 2 infants had
      the diagnosis of aortico-left ventricular tunnel made after birth and underwent
      successful surgical repair. At short and midterm follow-up all patients are alive
      and aortic valve regurgitation is absent or trivial. CONCLUSIONS: This series
      shows that aortico-left ventricular tunnel covers an anatomic spectrum of
      lesions. Cases diagnosed in utero by Doppler echocardiography are characterized
      by severe ventricular dysfunction, associated aortic valve lesions, and poor
      outcome. Postnatal cases represent the more favorable end of the spectrum, with
      no associated lesions, and can be repaired without mortality and with good
      functional results.

PMID- 8651789
TI  - Autologous monocusp pulmonary valve: preliminary results.
AB  - BACKGROUND: There is growing recognition that postoperative pulmonary
      regurgitation may result in early or late progressive right heart failure.
      METHOD: A technique for fashioning an autologous monocusp pulmonary valve from
      the wall of the pulmonary artery was developed. The monocusp valve was fashioned
      from the anterior wall of the main pulmonary artery, and the remaining defect was
      filled with autologous pericardium. The procedure was performed in 8 dogs and 5
      children. RESULTS: Early follow-up and serial echocardiographic assessment in
      both dogs and children proved the functionality of this monocusp pulmonary valve.
      All valves were pliable and demonstrated mild to moderate pulmonary stenosis and
      insufficiency. CONCLUSIONS: Construction of the autologous monocusp pulmonary
      valve is a feasible technique, and the valve performs efficiently. The acute
      performance in the canine model was excellent, and preliminary midterm results in
      the clinical study are reasonable. It is logical to assume that the monocusp,
      being an integral part of the arterial wall, will retain its viability and share
      in the subsequent growth of the pulmonary artery. Should follow-up studies
      demonstrate its long-term competence, this autologous valve may provide a good
      solution for various forms of pulmonary regurgitation and be useful in pulmonary
      autograft replacement of the aortic valve.

PMID- 8651790
TI  - Repair of postinfarction ventricular septal defect on a beating heart.
AB  - Two elderly patients with postinfarction ventricular septal defect underwent
      repair by endocardial patch with infarct exclusion on a beating heart under
      normothermic cardiopulmonary bypass with ultra-short-acting beta-blocker
      infusion. Their hemodynamic states soon recovered, and postoperative angiographic
      studies showed improvement of cardiac function and no residual shunt. Ultra-short
      acting beta-blocker has the potential to facilitate safe repair of postinfarction
      ventricular septal defect on a beating heart, and this operative approach can be
      beneficial for myocardial protection.

PMID- 8651792
TI  - Left thoracotomy for distal tracheal repair.
AB  - When consulted emergently by another surgeon in the operating room, we
      accomplished repair of a major laceration of the posterior wall of the distal
      trachea with associated avulsion of the left upper-lobe bronchus via the existing
      left thoracotomy exposure in a 7-year-old girl. Mobilization of the descending
      aorta anteriorly provided adequate exposure of the tracheal injury.

PMID- 8651791
TI  - Mesenteric ischemia after a cardiac operation: conservative treatment with local
      vasodilation.
AB  - Acute mesenteric ischemia is a rare and often fatal event after cardiopulmonary
      bypass. We describe a diagnostic and therapeutic algorithm and present a patient
      with nonocclusive intestinal ischemia who had a successful conservative
      treatment.

PMID- 8651793
TI  - Usefulness of ultrasonography in operation for pulmonary arteriovenous fistula.
AB  - A 54-year-old woman presented with nonhereditary, bilateral pulmonary
      arteriovenous fistulas. One of them was small (10 x 10 mm) and embedded in the
      parenchyma; it was neither visible nor palpable from the pleural surface. We
      therefore used intraoperative ultrasonography and succeeded in detecting and
      enucleating the small fistula with minimal resection of the normal lung tissue.

PMID- 8651794
TI  - Resection of multiple pulmonary metastases from a recurrent intracranial
      meningioma.
AB  - Surgical resection of multiple pulmonary metastases from a recurrent intracranial
      meningioma in a 53-year-old woman is presented. The primary tumor was diagnosed
      in 1984 and partially excised in early 1985. The tumor recurred and was re
      excised in 1989 and 1992. A fourth intracranial recurrence was noted in 1993,
      accompanied by multiple bilateral pulmonary metastases. The metastases were
      excised using staged thoracotomies in July and September 1994. The patient is
      surviving with cranial tumor residual.

PMID- 8651795
TI  - Successful complete tracheal resection in a three-month-old infant.
AB  - We report an infant with severe long-segment tracheal stenosis in whom the
      posterior trachea was formed by complete cartilage rings and the anterior trachea
      was almost totally formed by a solid cartilage plate. The child was successfully
      treated initially by complete resection of the trachea and primary end-to-end
      repair and subsequently with tracheal homograft transplantation for secondary
      stenosis.

PMID- 8651796
TI  - Cystic adenomatoid malformation involving an entire lung in a 22-year-old woman.
AB  - Congenital cystic adenomatoid malformation is an uncommon cause of respiratory
      distress in infants and is a rare entity in adults. Presentation in older
      patients is that of recurrent pulmonary infections. Usually a single lobe is
      involved. This report describes congenital cystic adenomatoid malformation
      involving the entire right lung in a 22-year-old woman presenting with
      gastrointestinal bleeding due to cavernous transformation of the portal and
      splenic veins.

PMID- 8651797
TI  - Annuloplasty for severe mitral regurgitation due to dilated cardiomyopathy.
AB  - We present a 74-year-old woman who underwent corrective annuloplasty for severe
      mitral regurgitation due to dilated cardiomyopathy. Postoperatively, congestive
      heart failure improved, with her New York Heart Association status changing from
      IV to II, although her cardiac functional improvement was minimal. Severe mitral
      regurgitation may be the indication for annuloplasty in symptomatic patients with
      dilated cardiomyopathy when cardiac transplantation is not indicated.

PMID- 8651798
TI  - Mitral valve replacement in the transplanted heart.
AB  - Because of the scarcity of donor hearts, conventional operations on heart
      allografts are now being performed in lieu of retransplantation. Our experience
      with mitral valve replacement in the orthotopically transplanted heart is
      presented, supporting the utility of conventional operations when indicated.

PMID- 8651799
TI  - Bench repair of donor mitral valve before heart transplantation.
AB  - Bench repair of the donor mitral valve was performed before orthotopic heart
      transplantation in a 57-year-old status I recepient. Mitral regurgitation in the
      structurally normal mitral valve was due to annular dilatation at the attachment
      of the posterior leaflet and was corrected with posterior annuloplasty. The
      patient is clinically well 18 months after transplantation.

PMID- 8651801
TI  - Video-assisted thoracoscopic resection of pulmonary sequestration in an infant.
AB  - Pulmonary sequestration is a congenital anomaly of lung parenchyma that can be
      definitively treated only with surgical resection. We report a case of an
      intralobar sequestration of the right lower pulmonary lobe in an infant
      successfully treated with video-thoracoscopic surgical removal of the involved
      lobe at 6 months of age.

PMID- 8651800
TI  - Surgical treatment of right ventricular myxoma in infancy.
AB  - Myxomas are the most common of all primary cardiac tumors in adults. They are
      extremely rare in infancy. We report on a 5-month-old infant who was admitted in
      a state of cardiogenic shock. Echocardiography showed a right ventricular myxoma
      completely occluding the right ventricular outflow tract. prompt surgical removal
      of the tumor resulted in a excellent outcome.

PMID- 8651802
TI  - Ventricular septal aneurysm after atrioventricular septal repair with
      pericardium.
AB  - A 2-month-old infant underwent a two-patch repair of a type C atrioventricular
      septal defect using autologous pericardium. Several months later a large,
      symptomatic aneurysm of the ventricular septal patch developed, requiring
      resection. The use of untreated autologous pericardium for large, congenital
      ventricular septal defects is unpredictable and should be avoided.

PMID- 8651803
TI  - Leiomyosarcoma of the pulmonary veins with extension to the left atrium.
AB  - A leiomyosarcoma of the right pulmonary vein in a 43-year-old woman extended to
      the right atrial wall and compromised the posterior mitral leaflet. Successful
      surgical treatment was accomplished with a right pneumonectomy, partial resection
      of the left atrial wall, and mitral valve replacement under cardiopulmonary
      bypass. Six months later a mediastinal recurrence with extension to the left
      hemithorax was treated with resection and postoperative radiotherapy.

PMID- 8651805
TI  - Successful salvage of aortoesophageal fistula caused by a fish bone.
AB  - We report saving the life of a 66-year-old woman with an aortoesophageal fistula
      caused by a fish bone. In this case, a hemostastic clip, which was applied to the
      lesion during emergency endoscopy, facilitated the subsequent diagnosis of this
      fistula by diagnostic imaging. Compressive hemostasis was effective in
      controlling preoperative bleeding.

PMID- 8651804
TI  - Mitral valve reconstruction in sickle cell disease.
AB  - As survival improves in patients with sickle cell anemia, the prospects of
      performing cardiac surgical procedures on older patients with this genetic defect
      increase. We describe the successful management of a 52-year-old patient with
      sickle cell disease (homozygous for hemoglobin S) and a history of multiple
      sickle crisis undergoing cardiopulmonary bypass for mitral valve repair.
      Preoperative partial exchange transfusion followed by total exchange transfusion
      at the time of operation was performed to reduce the level of hemoglobin S to
      5.4% during bypass. Other management strategies included high-flow normothermic
      bypass with aortic crossclamping, topical hypothermia, and cold crystalloid
      cardioplegia.

PMID- 8651806
TI  - Paraganglioma of the interatrial septum.
AB  - The case of a patient undergoing successful resection of an interatrial septal
      paraganglioma is presented. The diagnosis of an interatrial mass was established
      preoperatively by echocardiography, ultrafast cine computed tomographic scan, and
      cardiac catheterization. The tumor was excised in total, and the interatrial
      septum and the roof of the left atrium were reconstructed using a bovine
      pericardial patch.

PMID- 8651807
TI  - Maximal utilization of the left internal mammary artery for coronary bypass
      grafting.
AB  - A technique is described for using the internal mammary artery to bypass the left
      anterior descending coronary artery and another adjacent coronary artery even
      when the alignment of the two vessels is not favorable for a conventional
      sequential graft. The distal end of the mammary artery is amputated and used to
      construct a Y graft to the anterior descending artery and to the secondary target
      vessel.

PMID- 8651808
TI  - Simple, cost-efficient valve suture organizer.
AB  - A simple, efficient, disposable valve suture organizer is described. It is easy
      to construct and helps in the smooth conduct of a valve replacement procedure.

PMID- 8651809
TI  - Cannulation of neonates for venovenous extracorporeal life support.
AB  - Venovenous access via a double-lumen cannula in the right internal jugular vein
      is the extracorporeal life support mode of choice for neonates with respiratory
      failure. We report a simplified method of cannulation. The advantages of this
      "semi-Seldinger" method include the ability to cannulate without ligating the
      internal jugular vein, and to adjust the position of the cannula and decannulate
      without re-exploring the wound.

PMID- 8651810
TI  - Coronary reoperation via small laparotomy using right gastroepiploic artery
      without CPB.
AB  - The elective use of the right gastroepiploic artery as an in situ graft has been
      well established in coronary surgery. We propose a surgical technique for
      patients undergoing coronary reoperations with a patent mammary graft to the left
      anterior descending artery. The gastroepiploic artery is used through a small
      laparotomy when only the right coronary artery or the posterior descending artery
      needs revascularization. The described technique allows avoidance of both
      resternotomy and cardiopulmonary bypass.

PMID- 8651811
TI  - Inhaled nitric oxide: therapeutic applications in cardiothoracic surgery.
AB  - Hypoxemia and increased pulmonary vascular resistance can greatly complicate the
      management of cardiothoracic surgical patients. These complications are commonly
      found in the setting of thoracic organ transplantation, adult and pediatric
      cardiac surgical procedures, and general thoracic surgical procedures. Inhaled
      nitric oxide is a new therapy that promises to be extremely valuable to the
      cardiothoracic surgeon. It has been shown to improve oxygenation in the setting
      of acute lung injury and to selectively lower pulmonary vascular resistance,
      without producing unwanted systemic vasodilation. The purpose of this review is
      to discuss the biochemistry, toxicity, experimental studies, and therapeutic
      applications of inhaled nitric oxide administration in cardiothoracic surgical
      patients.

PMID- 8651812
TI  - Cardiopulmonary bypass during pregnancy.
AB  - Despite the incidence of heart disease during pregnancy falling to 1.5% over the
      last 25 years, when a cardiac operation is required the risk is obviously greater
      as two lives are at risk. The risk to the mother is now similar to that for
      nonpregnant female patients (3% overall) but the fetal mortality remains high
      (19%). Cardiac operation is ill advised except in extreme emergencies during the
      first two trimesters as the incidence of teratogenesis is high. During the third
      trimester, with improvements in the outcome for premature infants with modern
      neonatal intensive care, delivery of the child immediately before commencing
      cardiopulmonary bypass is a safe option. If this is inappropriate, high-flow,
      high-pressure, normothermic bypass for as brief a period as possible should be
      used. However, although it has theoretic advantages, the benefit of pulsatile
      perfusion is unproven. The fetal response to cardiopulmonary bypass is
      bradycardia thought to be due to hypoperfusion secondary to uterine contractions,
      and this dysrhythmia is reversible by increasing the perfusion rate. Fetal heart
      rate monitoring is therefore essential to allow these manipulations. The response
      of the fetoplacental unit is more complex, comprising two elements: an early
      vasoactive response is due to prostaglandin synthesis, whereas a more profound
      late acidosis appears to be related to a fetal stress response. Whether these
      responses can be modified by changes in our approach to cardiopulmonary bypass in
      pregnant women remains to be proven. Finally, uterine contractions occur in
      response to bypass, possibly due to a dilutional effect from the stabilizing
      influence of progesterone. Various techniques to modify this include the
      administration of progesterone, beta2-agonists, and intravenous alcohol, all with
      some effect. Uterine monitoring is essential to allow early control of these
      contractions as they are associated with significant fetal loss.

PMID- 8651813
TI  - As originally published in 1988: Results of total correction of tetralogy of
      Fallot performed in adults. Updated in 1996.

PMID- 8651814
TI  - Amiodarone for ventricular tachycardia after coronary artery bypass grafting.

PMID- 8651815
TI  - Myocardial revascularization.

PMID- 8651817
TI  - Pleural slide technique for covering the left bronchial stump.

PMID- 8651818
TI  - Is the current system of staging lung cancer the best it can be?

PMID- 8651816
TI  - Diagnosis of congenital bronchoesophageal fistula during anesthesia.

PMID- 8651819
TI  - En bloc resection of lung cancer invading the spine.

PMID- 8651820
TI  - Anomalous coronary artery in tetralogy.

PMID- 8651821
TI  - Outcome versus volume in coronary-bypass operations.

PMID- 8651822
TI  - [Operation of systems for purification of sewage and surface waters based on
      sorption-oxidative technology].
AB  - A universal scheme for the treatment of water containing different concentrations
      of organic compounds is described. The treatment is based on the principle of the
      water saturation with an active oxidant followed by aerobic purification in units
      with microflora fixed on active carbon. Active chlorine forming during the
      electrochemical treatment provides the water disinfection and plays the role of a
      source of the formation of monatomic and molecular oxygen during the
      dechlorination.

PMID- 8651823
TI  - [Preparation and antiviral properties of Bacillus intermedius ribonuclease
      modified by chloranhydride of adamantanecarboxylic acid].
AB  - Bacillus intermedius ribonuclease modified by the residue of adamantane
      carboxylic acid was prepared. When the cells of chick embryo fibroblasts infected
      by the fowl plague virus were exposed to the modified ribonuclease, the antiviral
      activity proved to be higher by comparison to that of the native enzyme. The
      chemotherapeutic index of the RNAse after the modification increased 4 times.

PMID- 8651824
TI  - [Ribosomal RNA degradation in gram-negative and gram-positive bacteria under the
      action of minimal bactericidal doses of chlorhexidine and heating].
AB  - The mechanism of the minimal bactericidal action of chlorhexidine, an antiseptic,
      and heating was studied. The bactericidal doses (BD99) of the above factors were
      determined with respect to the representatives of 5 families: Enterobacteriaceae,
      Pseudomonas, Vibrio, Bacillus and Bifidobacterium. Their effect on the ribosomes
      in the cells of the exponentially growing cultures was estimated. It was shown
      that these factors induced selective damage of the 30S subunits in the gram
      negative bacteria at the account of a specific degradation rRNA in them while in
      the gram-positive bacteria there was observed no rRNA degradation under such
      conditions. Differences in the mechanisms of the ribosome damage in the cells of
      the gram-negative bacteria of the various families were detected. Since the above
      factors at the levels used had no effect on the bacterial ribosomes in vitro, it
      was suggested that the primary link in the damages was the cell membrane while
      the ribosome degradation was secondary, though biologically the process leading
      to the bacteria death was of great importance.

PMID- 8651825
TI  - [Features of oral cavity microflora in congenital cleft lip and palate].
AB  - Cheilloschisis and uranoschisis are the most important congenital defects in
      children. This pathology increases the incidence of purulent inflammatory
      affections due to Staphylococcus spp., Streptococcus spp., Pseudomonas aeruginosa
      and Escherichia coli. The isolates were found to have multiple drug resistance
      determined by R plasmids of different incompatibility groups. The molecular
      weights of the plasmids were: 3.0, 8.0 and 9.0 MD in Staphylococcus spp., 90.0
      and 110.0 MD in P. aeruginosa and P. putida, 33.0, 38.0, 49.0 and 53.0 MD in E.
      coli. 87.0 per cent of the Staphylococcus strains, 78.9 per cent of the
      Streptococcus strains, 83.3 per cent of the E. coli strains, 74.0 per cent of the
      P. aeruginosa strains and 66.6 per cent of the Acinetobacter stains were shown to
      be sensitive to the commercial pyophage product used in the study.

PMID- 8651826
TI  - [One hundred years after Pasteur].

PMID- 8651828
TI  - [Sensitivity of bacteria of the genus Proteus to antibiotics].
AB  - Antibiotic susceptibility of 481 cultures of the bacteria belonging to the genus
      Proteus isolated within 1990-1994 from children with enterocolitis was studied.
      The study included 10 antibiotics. The efficacy of the antibiotic therapy in 388
      children with the above disease was estimated. It was shown that the Proteus
      isolates were most frequently susceptible to kanamycin, gentamicin and
      carbenicillin. When used clinically in the treatment of children with Proteus
      enterocolitis, the antibiotics proved to be the most efficient agents.

PMID- 8651827
TI  - [Cefpiramide (Tamicin) in the treatment of purulent complications of abdominal
      surgery].
AB  - Fifty patients with purulent infection of the abdominal cavity were treated with
      cefpiramide (Lek, Slovania). The analysis of the results showed that the clinical
      effect was favourable in 92 percent of the patients. The bacteriological efficacy
      amounted to 65.2 percent. The index of the isolates susceptibility was high (72
      percent at the average). The concentration of cefpiramide in the bile from the
      bile common duct was low (23 micrograms/ml) as a result of its partial or
      complete obstruction. The adverse reaction (diarrhea) was stated in 1 patient.

PMID- 8651829
TI  - [Experimental and clinical study of antibiotics administered intravitreally in
      endophthalmitis].
AB  - The concentrations of gentamicin and cefotaxime (claforan) in the humor of the
      anterior chamber and vitreous body of the eye were estimated in the study on the
      pharmacokinetics of the antibiotics in rabbits. The antibiotics were administered
      intravitreally in single doses. It was shown that the residence time of the
      antibiotics in the therapeutic concentrations in the eye cavity was 48 hours.
      Cefotaxime proved to be the most efficient agent in the prevention and treatment
      of postoperative endophthalmitis.

PMID- 8651830
TI  - [Clinical pharmacokinetics of fluorazole].
AB  - The ftorazole pharmacokinetics was studied in 14 patients after the oral
      administration of 40 and 80 mg as a single dose. The ftorazole concentrations in
      the serum specimens sampled within 8 hours were determined by GLC with an
      electron-capture detector. A pronounced variability was inherent in the
      individual concentration-time profiles: the mean values of the serum peak
      concentrations (Cmax) following the 40 and 80 mg dosing were 30-119 and 55-195
      ng/ml respectively. Nonetheless, a dose-proportional increasing of the areas
      under the concentration-time curve (AUC) was observed. The mean values (SD) of
      the AUC related to the dose, absorption lag-time, time for reaching Cmax, the
      Cmax/AUC ratio as an index of the absorption rate, the elimination half-life and
      mean residence time were 6.64 (2.98) (ng.h/ml), 0.31 (0.17) h, 1.17 (0.55) h,
      0.26 (0.05) h-1, 2.40 (0.70) h and 3.06 (0.28) h respectively. The data obtained
      are indicative of the ftorazole pharmacokinetics linearity in humans.

PMID- 8651831
TI  - [Contemporary macrolides--characterization of the action, importance in the
      treatment of bacterial infections].

PMID- 8651832
TI  - Exercise decreases the risk of development of diabetes mellitus, So...

PMID- 8651833
TI  - Informed consent. From bodily invasion to the seemingly mundane.

PMID- 8651834
TI  - Beta-blockers in hypertensive and coronary heart disease.
AB  - Beta-Blockers are widely used in cardiovascular medicine. In patients with
      hypertension, beta-blockers show beneficial effects on clinical end points of
      stroke and coronary heart disease prevention and mortality. beta-blockers also
      are well established in improving exercise tolerance and decreasing the number
      and duration of anginal attacks in patients with angina pectoris. Based on
      evidence showing reduced mortality and morbidity, beta-blockers are the
      cornerstone of therapy after acute myocardial infarction. Unfortunately,
      presumption of poor tolerance has left these drugs underutilized in this clinical
      setting, despite data that indicate a wide range of tolerability. The use of beta
      blockers in patients with congestive heart failure results in beneficial
      hemodynamic effects and symptomatic improvement. Among factors that should be
      considered when selecting a beta-blocker for an individual patient are
      demonstrated efficacy of the drug in a specific indication, tolerability, product
      formulation and duration of action, and the presence or absence of specific
      properties such as cardioselectivity.

PMID- 8651835
TI  - Beyond low-density lipoprotein cholesterol. A perspective on low high-density
      lipoprotein disorders and Lp(a) lipoprotein excess.
AB  - Evidence supports the involvement of 2 common dyslipidemias---low high-density
      lipoprotein disorders and Lp(a) lipoprotein excess--in coronary heart disease.
      Until clinical trials determine whether specific therapeutic interventions can
      prevent the occurrence and recurrence of coronary heart disease in patients with
      these dyslipidemias, the implementation of cholesterol-lowering guidelines can
      provide a reasonable way to manage low high-density lipoprotein disorders and to
      identify specific categories of patients who may be at particularly high risk for
      premature coronary heart disease. Empiric treatment guidelines are suggested for
      low high-density lipoprotein disorders and Lp(a) lipoprotein excess in order to
      foster further discussion and validation by clinical trial data.

PMID- 8651836
TI  - See one, do one, teach one? House staff experience discussing do-not-resuscitate
      orders.
AB  - BACKGROUND: Medical residents commonly discuss resuscitation decisions with
      hospitalized patients. Previous studies suggest that the quality of these
      discussions is poor. OBJECTIVE: To learn about residents' experience with do-not
      resuscitate (DNR) discussions and their attitudes toward them. METHODS: Medical
      house officers on the wards of three teaching hospitals were eligible to
      participate. A subset had previously audiotaped actual DNR discussions as part of
      a study that described the quality of discussions. In a self-administered
      questionnaire, house officers rated their performance conducting a recent DNR
      discussion, stated their attitudes, and described their experience learning to
      talk to patients about these issues. RESULTS: One hundred one (88%) of 115
      residents responded to the survey. Eighty-six (90%) of 96 stated they had done a
      good job with the discussion and 78 (77%) of 101 reported feeling comfortable
      discussing the topic with patients. Ninety-four (94%) of 100 residents said they
      discuss code status with all seriously ill patients and while on the medical
      wards they conduct a median of one DNR discussion per week. On average, they had
      observed four discussions conducted by more senior clinicians. One third of the
      residents had never been observed talking to patients about DNR decisions and 71%
      had been observed two or fewer times. CONCLUSIONS: These findings help explain
      the observations about the quality of DNR discussions. House staff "see" and "do"
      these discussions, but are not taught through observation and feedback. We
      recommend that communication about end-of-life treatment decisions be treated as
      a medical skill to be taught with the same rigor as other clinical procedures.

PMID- 8651837
TI  - Estrogen replacement therapy. A survey of older women's attitudes.
AB  - OBJECTIVES: To understand the low prevalence of estrogen use among older women.
      To examine the reasons for the use and nonuse of estrogen replacement therapy.
      SUBJECTS AND METHODS: Nonblack women (n = 7667), aged 65 years or older, who
      participated in the Multicenter Study of Osteoporotic Fractures completed an
      estrogen questionnaire. RESULTS: Of the subjects, 1335 (17.4%) were currently
      using oral estrogens, 2084 (27.2%) were past users, and 4248 (55.4%) had never
      used oral estrogen therapy. The self-reported primary reasons for current users
      to have initiated therapy included hysterectomy (43.5%), menopausal symptoms
      (39.3%), prescribed by a physician (38.7%), or prevention or treatment of
      osteoporosis (33.6%). Of the 2084 former estrogen users (27.2%), the main reasons
      for starting therapy included prescribed by a physician (44.7%), menopausal
      symptoms (49.2%), and hysterectomy (28.5%). Approximately 30% of past estrogen
      users reported the primary reason for discontinuing therapy as "feeling that they
      didn't need it," whereas 16.4% reported undesirable side effects with bleeding as
      the most common (45.0%). The main reason women never started estrogen therapy
      (55.4%) was they feared that the medication was harmful (38.1%) or they felt they
      did not need it (29.5%). CONCLUSIONS: We conclude that older women in the United
      States remain skeptical about long-term estrogen use despite its potential for
      protection against 2 major chronic diseases, osteoporosis and cardiovascular
      disease. Greater understanding about the barriers to estrogen replacement therapy
      and improved knowledge of its risks and benefits may reduce the skepticism
      surrounding estrogen replacement therapy among older women.

PMID- 8651838
TI  - Three-year follow-up of participants in a commercial weight loss program. Can you
      keep it off?
AB  - BACKGROUND: One third of Americans are obese, according to the 1988-1991 National
      Health and Nutrition Endpoint Survey III survey. Obesity increases the risk of
      death and a variety of chronic diseases. Numerous commercial weight loss programs
      demonstrate short-term success. OBJECTIVE: To assess maintenance of weight loss
      achieved during dieting. METHODS: We surveyed 192 participants in the Sandoz
      Nutrition (Sandoz Pharmaceuticals, Minneapolis, Minn) diet program approximately
      3 years after participation. Initial date were supplied by the diet clinics and
      follow-up data, including weight at various points after the program,
      participation in other weight loss programs, and lifestyle variables, such as
      exercise, smoking, and television watching, were collected by a mailed
      questionnaire. RESULTS: On average, the group lost 22 kg during the diet program.
      After the follow-up period, the mean weight (mean, 102.6 kg) was only modestly
      less than the group's original weight at the start of the diet (mean, 105.9 kg).
      Twelve percent of the subjects maintained 75% of their weight loss after leaving
      the diet program, 57% maintained at least 5% of the loss, and 40% gained back
      more than they had lost during the diet. The frequency of exercise after the diet
      program was the strongest predictor of weight loss maintenance, while television
      viewing predicted a gain in weight. CONCLUSION: Given the apparent lack of
      substantial, long-term success at weight reduction, perhaps greater emphasis
      should be placed on prevention of obesity.

PMID- 8651839
TI  - Moderately intense physical activities and high levels of cardiorespiratory
      fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged
      men.
AB  - BACKGROUND: Physical activity has been advocated as an important factor in the
      primary prevention of non-insulin-dependent diabetes mellitus (NIDDM), but
      information concerning the specific intensities and durations that are protective
      has been unavailable. OBJECTIVE: To examine prospectively the association between
      self-reported levels of the intensity and duration of physical activities, and
      cardiorespiratory fitness (assessed by respiratory gas exchange) and incident
      cases of NIDDM (assessed by the oral glucose tolerance test) in a population
      based sample of 897 middle-aged Finnish men. RESULTS: After adjustment for age,
      baseline glucose values, body mass index, serum triglyceride levels, parental
      history of diabetes, and alcohol consumption, moderately intense physical
      activities (> or = 5.5 metabolic units) that were undertaken for at least a 40
      minute duration per week were associated with a reduced risk of NIDDM (odds
      ration [OR], 0.44; 95% confidence interval [CI], 0.22-0.88). Activities with less
      than an intensity of 5.5 metabolic units, regardless of their duration, were not
      protective. Cardiorespiratory fitness levels greater than 31.0 mL of oxygen per
      kilogram per minute were protective against NIDDM (OR, 0.26; 95% CI, 0.08-0.82).
      A subgroup of men at high risk of NIDDM, because they were overweight and were
      hypertensive and had a positive parental history of NIDDM, who engaged in
      moderately intense physical activities above the 40-min/wk duration reduced their
      risk of NIDDM by 64% compared with men who did not participate in such
      activities. CONCLUSIONS: After adjustment for age, baseline glucose levels, and
      known risk factors, physical activities with an intensity of 5.5 metabolic units
      or greater and a duration of 40 minutes or greater per week protected against the
      development of NIDDM. These protective effects were even more pronounced in a
      subgroup of men who were at high risk for the development of the disease.

PMID- 8651840
TI  - Usefulness of childhood low-density lipoprotein cholesterol level in predicting
      adult dyslipidemia and other cardiovascular risks. The Bogalusa Heart Study.
AB  - OBJECTIVE: To examine the usefulness of childhood low-density lipoprotein
      cholesterol (LDL-C) measurement for predicting future dyslipidemia and other
      cardiovascular risk in adulthood. METHODS: A longitudinal cohort over 15 years
      was identified from a community study of the natural course of arteriosclerosis:
      1169 individuals (34% black), aged 5 to 14 years, were included at initial study.
      RESULTS: Levels of lipoprotein variables in childhood were associated with levels
      in adulthood, more strongly for total cholesterol (r = .4-.6) and LDL-C (r = .4
      .6) than for high-density lipoprotein cholesterol (r = .2-.4) and triglycerides
      (r = .1-.4). In a stepwise multiple regression, the childhood level was most
      predictive of the adulthood level, followed by change in body mass index (weight
      in kilograms/height in meters squared) from childhood to adulthood, with
      explained variability (R2) of .29, .30, .27, and .19 for total cholesterol, LDL
      C, high-density lipoprotein cholesterol, and triglycerides, respectively.
      Adulthood dyslipidemia, as defined by the National Cholesterol Education Program
      criterion, was best predicted by childhood LDL-C level among other lipoprotein
      variables. Compared with subjects with acceptable childhood risk (LDL-C level, <
      2.84 mmol/L [< 110 md/dL]), those (6%) with high childhood risk (LDL-C level, >
      or = 3.36 mmol/L [> or = 130 mg/dL]) not only had a higher prevalence of
      dyslipidemic total cholesterol level (24%, 8.3-fold), LDL-C level (28%, 5.4
      fold), triglyceride level (7%, sevenfold) and lower HDL-C level (14%, 2.1-fold),
      but also had a significantly higher (P < .05) prevalence of obesity (43%, 1.6
      fold) and hypertension (19%, 2.4-fold). In addition, if the childhood LDL-C
      elevation (> 90th percentile) was persistent, the prevalence of adult
      dyslipidemia would be markedly increased (P < .001). CONCLUSIONS: Adverse levels
      of LDL-C in childhood persist over time, progress to adult dyslipidemia, and
      relate to obesity and hypertension as well. National Cholesterol Education
      Program guidelines to classify cardiovascular risk on the basis of LDL-C level
      are helpful in targeting individuals at risk early in life.

PMID- 8651841
TI  - Leisure-time physical activity among older adults. United States, 1990.
AB  - OBJECTIVE: To investigate the prevalence and selected correlates of leisure-time
      physical activity in a nationally representative sample of persons aged 65 years
      or older. METHODS: Data from 2783 older male and 5018 older female respondents to
      the 1990 National Health Interview Survey were used. Regular physical activity
      was defined as participation in leisure-time physical activities 3 times or more
      per week for 30 minutes or more during the previous 2 weeks. Odds ratios (ORs)
      were estimated from multivariate logistic regression analysis. RESULTS:
      Prevalence of regular physical activity was 37% among older men and 24% among
      older women. Correlates of regular physical activity included the perception of
      excellent to good health (men: OR, 1.5; 95% confidence interval [CI], 1.1-1.9;
      women: OR, 1.6; 95% CI, 1.3-1.9), correct exercise knowledge (men: OR, 2.4; 95%
      CI, 1.9-3.1; women: OR, 2.7; 95% CI, 2.2-3.4), no activity limitations (men: OR,
      1.3; 95% CI, 1.0-1.6; women: OR, 1.7; 95% CI, 1.4-2.0) and not perceiving "a lot"
      of stress during the previous 2 weeks (men: OR, 1.7; 95% CI, 1.2-2.4; women: OR,
      1.3; 95% CI, 1.0-1.6). Among those who had been told at least twice that they had
      high blood pressure, physician's advice to exercise was associated with regular
      physical activity (men: OR, 1.6; 95% CI, 1.2-2.3; women: OR, 1.5; 95% CI, 1.2
      1.9). The 2 major activities among active older adults were walking (men, 69%;
      women, 75%) and gardening (men, 45%; women, 35%). CONCLUSIONS: Prevalence of
      regular physical activity is low among older Americans. Identifying the
      correlates of physical activity will help to formulate strategies to increase
      physical activity in this age group.

PMID- 8651842
TI  - Risk of acute liver injury associated with the combination of amoxicillin and
      clavulanic acid.
AB  - BACKGROUND: Amoxicillin-clavulanic acid combination-associated hepatitis and
      jaundice was first identified in 1988. Numerous case reports and case series have
      been published since then, but there is no precise estimate of this risk.
      METHODS: A retrospective cohort study in the United Kingdom to estimate the risk
      of acute liver injury associated with the combination of amoxicillin and
      clavulanic acid and compare it with the one of amoxicillin alone. Data were
      derived from a cohort of 93,433 users of the combination drug amoxicillin
      clavulanic acid and 360,333 users of amoxicillin alone who were aged between 10
      and 79 years and who were followed up from 1991 through 1992. After reviewing the
      information on subjects with suspected liver injury that was recorded on computer
      files, the clinical records of 177 patients from the attending general
      practitioners were requested. RESULTS: They were 35 cases of idiopathic acute
      liver injury. None was fatal. There were 14 cases of acute liver injury among
      users of amoxicillin alone. The type of liver injury was hepatocellular in half
      the cases. There were 21 cases of acute liver injury among users of amoxicillin
      and clavulanic acid together. The type of liver injury was cholestatic in three
      quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of
      developing acute liver injury associated with the combination of amoxicillin and
      clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (.02-0.5) per 10
      000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver
      injury for amoxicillin and clavulanic acid together compared with amoxicillin
      alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients
      presenting with jaundice. Among users of amoxicillin and clavulanic acid
      together, the risk of developing acute liver injury was more than 3 times greater
      after a course of 2 or more consecutive prescriptions than after a single course
      of therapy. The risk also increased with age among users of amoxicillin and
      clavulanic acid together. The combination of advancing age and repeated
      prescriptions resulted in a risk of developing acute liver injury greater than 1
      per 1000 users of amoxicillin and clavulanic acid together.

PMID- 8651844
TI  - Mortality risks associated with specific clinical manifestations of systemic
      lupus erythematosus.
AB  - BACKGROUND: Mortality in patients with systemic lupus erythematosus (SLE) is
      often related to disease in particular organ systems. We examined the risks of
      mortality associated with 8 clinical manifestations of SLE and determined whether
      these risks differed among patients with different sociodemographic
      characteristics. METHODS: Using life table analysis, we determined the
      associations of hemolytic anemia, leukopenia, thrombocytopenia, arthritis,
      serositis, nephritis, psychosis, and seizures with both all-cause mortality and
      SLE-related mortality in a cohort of 408 patients. RESULTS: Over a median
      duration of follow-up of 11 years, 144 patients died; 78 deaths (54%) were SLE
      related. In univariate analyses, the presence of hemolytic anemia, serositis,
      nephritis, psychosis, and seizures was associated with greater all-cause
      mortality, while the presence of arthritis was protective. In multivariate
      analyses that controlled for patient demographic characteristics, nephritis
      (relative risk, 2.34) and seizures (relative risk, 1.77) were associated with
      poorer overall survival. Nephritis and seizures, along with thrombocytopenia,
      were also associated with greater SLE-related mortality, while leukopenia was
      protective. The risk of death in association with these clinical manifestations
      did not differ among patient age, sex, race, or socioeconomic subgroups.
      CONCLUSIONS: The presence of nephritis and seizures each increased the risk of
      death in patients with SLE approximately 2-fold. Thrombocytopenia also increased
      the risk of SLE-related mortality, while leukopenia was protective.

PMID- 8651845
TI  - Cost-effectiveness of cancer screening in end-stage renal disease.
AB  - BACKGROUND: Limited evidence suggests that persons with end-stage renal disease
      (ESRD) may be at increased risk for malignancy. The appropriateness of screening
      procedures in this population has not been evaluated. OBJECTIVE: To determine the
      relative cost-effectiveness of hypothetical cancer screening programs in the
      population with ESRD compared with the general population. METHODS: We performed
      a cost-effectiveness analysis, employing the declining exponential approximation
      of life expectancy. Assumptions were put forth to bias the model in favor of
      cancer screening. Secondary comparisons were made between cancer screening and
      other interventions targeted to patients with ESRD. RESULTS: The costs per unit
      of survival benefit conferred by cancer screening were 1.6 to 19.3 times greater
      among patients with ESRD than in the general population, depending on age, sex,
      and race, and assumptions outlined herein. For persons with ESRD, the net gain in
      life expectancy from a typical cancer screening program was calculated to be 5
      days or less. Similar survival gains could be obtained via a reduction of 0.02%
      or less in the baseline ESRD-related mortality rate. CONCLUSIONS: These analyses
      suggest that routine cancer screening in the population with ESRD is a relatively
      inefficient allocation of financial resources. Direction of funds toward
      improving the quality of dialysis could attain such an objective at substantially
      lower cost. Furthermore, these findings highlight the importance of competing
      risks as a consideration in the evaluation of screening strategies and other
      interventions targeted to patients with ESRD and to other populations with
      chronic diseases associated with reduced survival.

PMID- 8651843
TI  - The impact of informed consent on patient interest in prostate-specific antigen
      screening.
AB  - BACKGROUND: Because of the many uncertainties surrounding screening for prostate
      cancer, authorities recommend that patients be involved in the screening
      decision. OBJECTIVE: To determine the impact of informed consent on patient
      interest in undergoing prostate-specific antigen (PSA) screening. METHODS: Men 50
      years or older with no prior PSA testing and no history of prostate cancer
      presenting to 1 of 4 university-affiliated primary care practices were eligible
      for enrollment. Patients were randomized to receive either a scripted
      informational intervention simulating an informed consent presentation
      (intervention group, n = 103) or a single sentence about the PSA (control group,
      n = 102). The main outcome measure was patient interest in undergoing PSA
      screening measured on a 5-point Likert scale. RESULTS: Patients who received the
      informational intervention were significantly less interested in undergoing PSA
      screening than controls (mean difference in interest, 0.8 on 5-point scale, P <
      .001). Informed patients were much less likely to indicate high interest in
      screening (odds ratio, 0.34; 95% confidence interval, 0.19-0.60; P < .001). In a
      multivariate model, family history of prostate cancer was associated with
      increased interest and advancing age with decreased interest in PSA screening,
      but the informational intervention remained the strongest predictor of interest.
      CONCLUSIONS: Among primary care patients of predominantly lower socioeconomic
      status, those who received informed consent were significantly less interested in
      PSA screening than those who did not. For physicians who offer the PSA as a
      screening test, this finding highlights the importance of apprising patients of
      the associated benefits, burdens, and uncertainties and allowing them to
      participate in the screening decision.

PMID- 8651846
TI  - DRE-PSA data revisited: PSA sampling should precede DREs.

PMID- 8651847
TI  - The public's preference for bedside rationing.

PMID- 8651848
TI  - Whatever happened to access to health care?

PMID- 8651849
TI  - Bladder carcinoma surgical pathology report adequacy.

PMID- 8651850
TI  - Intraosseous malignant peripheral nerve sheath tumor.

PMID- 8651851
TI  - Rescreening in gynecologic cytology. Rescreening of 8096 previous cases for
      current low-grade and indeterminate-grade squamous intraepithelial lesion
      diagnoses--a College of American Pathologists Q-Probes study of 323 laboratories.
AB  - OBJECTIVE: To quantitate, characterize, and analyze errors identified in the
      rescreening of previous gynecologic cytology specimens with original diagnoses of
      within normal limits or benign cellular changes for current cases diagnosed as
      low-grade squamous intraepithelial lesion or squamous intraepithelial lesion of
      indeterminate grade. DESIGN AND SETTING: College of American Pathologists Q
      Probes laboratory quality improvement study in 323 laboratories. MAIN OUTCOME
      MEASURE: False-negative rate in cases rescreened as a result of a current
      cytologic diagnosis of low-grade squamous intraepithelial lesion or squamous
      intraepithelial lesion of indeterminate grade. RESULTS: A total of 8096 smears
      performed within the 5 years preceding the current examination were rescreened.
      Of the rescreened cases, 284 (3.5%) were reclassified as a squamous
      intraepithelial lesion or carcinoma, 474 (5.9%) as atypical squamous cells of
      uncertain significance, 7 (0.09%) as atypical glandular cells of uncertain
      significance or glandular intraepithelial lesion, and 39 (0.5%) as
      unsatisfactory. Ninety-three percent (261/280) of all false-negative cases were
      identified in cases from the previous 3 years. CONCLUSION: Rescreening archival
      cytology cases previously diagnosed as within normal limits or benign cellular
      changes for current cases diagnosed as low-grade squamous intraepithelial lesion
      or squamous intraepithelial lesion of indeterminate grade will identify screening
      and diagnostic errors. This may be a useful quality improvement monitor in many
      laboratories.

PMID- 8651852
TI  - Cervical biopsy-cytology correlation. A College of American Pathologists Q-Probes
      study of 22 439 correlations in 348 laboratories.
AB  - OBJECTIVE: To study the diagnostic correlation between cervical cytology
      specimens and corresponding surgical biopsies. DESIGN AND SETTING: College of
      American Pathologists Q-Probes laboratory quality improvement study in 348
      laboratories. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive
      predictive value of cervicovaginal cytology diagnosis. RESULTS: Statistical
      analysis of 22 439 paired cervicovaginal cytology--cervical biopsy specimens
      reveals a sensitivity of 89.4%, specificity of 64.8%, and predictive value of a
      positive cytology of 88.9%. The majority of discrepancies were attributed to
      cytology or biopsy sampling errors. Routinely providing the patient's recent
      cervical cytology report to the surgical pathologist at the time the biopsy was
      examined resulted in improved sensitivity. Correlations for cytology specimens
      obtained at the time of biopsy revealed lower sensitivity and higher specificity
      than for those obtained at a time prior to the biopsy. CONCLUSIONS: We have
      defined current statistical expectations for cervical cytology-biopsy
      correlation, reasons for noncorrelation, and have provided recommendations for
      quality improvement.

PMID- 8651853
TI  - Mesial temporal sclerosis. A clinicopathologic study of 27 patients, including 5
      with coexistent cortical dysplasia.
AB  - OBJECTIVE: Mesial temporal sclerosis (MTS) is a fairly well-recognized cause of
      intractable epilepsy. Its coexistence with cortical dysplasia is less commonly
      described. Herein, we describe the clinical and pathologic features of MTS,
      including cases in which cortical dysplasia was also identified. DESIGN:
      Retrospective surgical series of 27 patients. SETTING: Tertiary referral center
      with a high volume of epilepsy surgery. PATIENTS: Patients with medically
      intractable epilepsy who underwent hippocampal resections and in whom an
      unequivocal histologic diagnosis of MTS could be made. RESULTS: The patients
      studied included 18 males and 9 females ranging in age from 15 to 48 years (mean
      32 years). Mesial temporal sclerosis was characterized by severe neuronal loss
      accompanied by gliosis occurring in the CA1/prosubiculum (27 patients, 100%),
      focally in the dentate gyrus (12 patients, 44%), and in the CA4 region (11
      patients, 41%). Five patients (24%) had coexistent cortical dysplasia with
      increased molecular layer neurons (five patients), gyral fusion (two patients),
      diffuse architectural disorganization of the cortex (one patient), and clusters
      of atypical neurons and glial cells within the cortex (one patient). Twenty-five
      (93%) of the 27 patients had white matter neuronal heterotopia. Follow-up data
      were available for each patient (mean 23 months). Twenty-two of the patients are
      free of seizures postoperatively, including all five with coexistent cortical
      dysplasia; the five remaining patients have fewer seizures. There appeared to be
      no difference clinically between patients with MTS and no dysplasia and those
      with coexistent cortical dysplasia. CONCLUSION: We conclude that (1) MTS most
      severely involves the CA1/prosubiculum and CA4 regions of the hippocampus (the
      dentate gyrus may also be focally severely involved); (2) MTS and cortical
      dysplasia do occasionally exist; and (3) surgical outcome for MTS appears to be
      independent of coexistent cortical dysplasia.

PMID- 8651854
TI  - Calcium oxalate crystals in human pathology. Molecular analysis with the laser
      Raman microprobe.
AB  - OBJECTIVE: Calcium oxalate crystals in pathologic specimens were examined by the
      laser Raman microprobe, a nondestructive spectroscopic technique. Although
      research focused on the identification of calcium oxalate deposits in tissue
      sections, kidney stones were also studied to determine the in situ structural
      specificity of the technique. DESIGN: Paraffin-embedded tissue specimens were cut
      into sections of 2 to 6 microns. The unstained sections were placed on metal
      (aluminum)-plated slides and excited with the 514.5-nm line of an argon-ion
      laser, which was focused to a 1-micron spot size using a high-resolution optical
      microscope. MAIN OUTCOME MEASURE: The laser Raman microprobe technique generates
      spectra that differentiate the monohydrate (CaC2O4.H2O, whewellite) and the
      dihydrate (CaC2O4.2H2O, weddellite) forms of calcium oxalate inclusions in tissue
      sections. RESULTS: Characteristic spectra were generated and provided unequivocal
      evidence for the identification of the dihydrate oxalate form of calcium oxalate
      crystals in cases of oxalosis of the myocardium and for the monohydrate oxalate
      structure in a case of oxalosis of the pituitary. Finally, the combined
      occurrence of both oxalate structures was confirmed in kidney stone specimens.
      CONCLUSION: The results obtained in this investigation demonstrate the efficacy
      of the laser Raman microprobe as a useful adjunct in diagnostic pathology.

PMID- 8651855
TI  - Postradiation malignant triton tumor. A case report and review of the literature.
AB  - OBJECTIVE: To report the third case of postradiation malignant triton tumor and
      to review the literature on malignant triton tumor with regard to features of
      possible prognostic significance. DATA SOURCES: Published articles were retrieved
      through MEDLINE, and additional articles were obtained through searches of the
      bibliographies. STUDY SELECTION: Cases were selected on the basis of histologic,
      immunohistochemical, and ultrastructural studies of malignancies showing both
      neurogenic and myogenic differentiation. Only those cases with survival data were
      selected for analysis. DATA EXTRACTION: The relationship between survival time
      and the possible prognostic variables of sex, presence or absence of von
      Recklinghausen's disease, age, and tumor location were evaluated by Cox
      regression analysis. RESULTS: Kaplan-Meier analysis showed a 5-year specific
      survival of 26%. Tumor location showed a statistically significant association
      with survival time (P = .01). CONCLUSIONS: This study suggests that malignant
      triton tumors occurring in the upper extremities, lower extremities, and head and
      neck have a better prognosis than tumors located in the retroperitoneum, buttock,
      or trunk. It is not clear if this variation is due to a difference in tumor
      grade, tumor stage, or resectability, or if it is a consequence of therapy.

PMID- 8651856
TI  - Inflammatory pseudotumor (plasma cell granuloma) of the heart. Report of two
      cases and literature review.
AB  - We report pathologic findings in two patients with inflammatory pseudotumor of
      the heart. The first patient was a 15-year-old-boy who died suddenly and
      unexpectedly of myocardial ischemia caused by an angiocentric inflammatory
      pseudotumor affecting all of the major coronary arteries and some of their
      branches. Inflammatory pseudotumor was also centered around some intrasplenic
      arteries. The second patient was a 5-month-old girl who had subtotal resection of
      a mass in the right atrial free wall. Her inflammatory pseudotumor was confined
      to the myocardium and showed no angiocentricity. The patient is doing well 22
      months after surgery. Inflammatory pseudotumor is a benign inflammatory response
      evoked by an unknown agent(s). In both patients, the inflammatory cells comprised
      a mixture of B and T lymphocytes. Among B cells, a mixture of kappa and lambda
      plasma cells was evident. A moderate number of tissue macrophages was also
      observed. The process is usually self-limited but may cause death if vital
      structures are involved.

PMID- 8651857
TI  - Primary cardiac lymphoma. No evidence for an etiologic association with Epstein
      Barr virus.
AB  - OBJECTIVES: To report two cases of primary cardiac lymphoma, a rare extranodal
      lymphoma with an unknown pathogenesis, and to compare them to secondary B-cell
      cardiac lymphoma. DESIGN: Clinicopathologic features are described, using
      histologic and immunophenotypic examinations. The Epstein-Barr virus genome is
      detected by in situ hybridization. PATIENTS: Of 80 autopsied cases of malignant
      lymphoma identified at Nagoya (Japan) University Hospital, two patients with
      primary cardiac lymphoma and five patients with secondary cardiac B-cell lymphoma
      were selected. RESULTS: None of the seven selected cases showed immunodeficiency,
      autoimmune disorders, or chronic inflammatory processes. Primary cardiac
      lymphomas had B-cell phenotypes with mu and lambda chain monoclonality.
      Immunostaining for Epstein-Barr virus (latent membrane protein-1) and Epstein
      Barr virus-encoded RNA-1 in situ hybridization did not demonstrate an association
      of these lymphoma with Epstein-Barr virus infection. The majority of secondary
      cardiac B-cell lymphomas were extranodal lymphomas and extranodal or serosal
      involvement was more prominent than nodal involvement. CONCLUSION: These findings
      suggest that primary cardiac lymphoma, unlike pyothorax-associated pleural
      lymphoma, appears to have no association with chronic inflammation or Epstein
      Barr virus infection.

PMID- 8651858
TI  - Immunoreactivity to neurohormonal polypeptide in colorectal carcinomas and tumor
      neighboring mucosa, and its significance.
AB  - OBJECTIVE: To clarify whether advanced colorectal carcinomas possess an
      amphocrine nature and produce both pancreatic and gut neurohormonal polypeptide
      and epithelial mucin in comparison with surrounding colorectal mucosa. DESIGN:
      Retrospective analysis of paraffin-embedded specimens from 100 cases of
      colorectal carcinoma (39 colonic and 61 rectal) and surrounding mucosa, with
      histochemical and immunohistochemical studies. RESULTS: The immunoreactivity of
      the carcinomas and surrounding mucosa by the labeled streptavidin-biotin complex
      method for polyclonal rabbit antibody against human vasoactive intestinal
      polypeptide, pancreatic polypeptide, and somatostatin was 61%, 59%, and 82%
      respectively; that of mucosa neighboring immunoreactive tumors was 87%, 85%, and
      90%; and that of mucosa neighboring nonimmunoreactive tumors was 67%, 63% and
      61%. Double staining for different types of neurohormonal polypeptide revealed
      that most carcinoma cells had a multiendocrine nature, and a number of
      neurohormonal polypeptide--positive and epithelial mucin-positive carcinoma cells
      (amphocrine cells) were found in almost every histological type of carcinoma by
      double staining for immunoreactivity and periodic acid-Schiff reaction or
      mucicarmin. CONCLUSION: Colorectal carcinomas exhibit not only multiendocrine
      characteristics, producing various types of neurohormonal polypeptide, but also
      amphocrine characteristics of different grades, and most tumor-neighboring crypt
      cells possess those characteristics, too. We concluded that these characteristics
      of colorectal carcinomas may be related to their origin as multipotential
      endodermal stem cells.

PMID- 8651859
TI  - Clinicopathologic study of tetraploid hydropic villous tissues.
AB  - BACKGROUND: Because there are differences in the origin, morphology, and natural
      history of hydropic placental villous tissues, it is important to identify and
      document rare specimens that deviate from the diploid complete mole (CM),
      triploid partial mole (PM), or diploid hydropic abortion (HA). DESIGN: We
      clinicopathologically investigated 35 cytometric specimens of formalin-fixed,
      paraffin-embedded, tetraploid hydropic villous tissue. RESULTS: Of 35 cases, 25
      were CMs, 10 were hydropic abortions, and none were partial moles. Assuming that
      the degree of molar change roughly correlates with the proportion of paternal
      chromosomes present, all chromosomes might be paternally derived in our 25
      tetraploid CMs. Ten hydropic abortions, including two that were karyotypically
      either 92,XXYY or 90,XXYY,-13,14, were presumably due to two sets of chromosomes
      each from paternal and maternal origin. Of 14 tetraploid CMs for which follow-up
      data were available, two developed an invasive lesion and one developed
      choriocarcinoma with a diploid DNA content. However, as we reported previously,
      tetraploidy in CMs is not considered to be an independent predictor of persistent
      disease. CONCLUSION: These results indicate that patients with tetraploid CM
      require the same close follow-up given to diploid CM patients.

PMID- 8651861
TI  - Blastic transformation of mantle cell lymphoma.
AB  - In contrast to chronic lymphocytic lymphoma and low-grade follicular lymphomas,
      mantle cell lymphoma, formerly known as intermediate lymphocytic lymphoma, rarely
      transforms histologically into large cell lymphoma. Because of its rarity, little
      information is available on the prognostic or therapeutic implications of
      histologic transformation of mantle cell lymphoma to a "blastic" form. Here we
      report a case of a 68-year-old man whose mantle cell lymphoma transformed into a
      high-grade lymphoma with blastic cytology, which was associated with an extremely
      rapid clinical course. Flow cytometric analysis revealed the immunophenotype of
      the original lymphoma, which had typical mantle cell morphology, and the
      subsequent bone marrow aspirate was virtually identical, as was the
      immunophenotype of the small cells versus the blastic cells in the subsequent
      specimen. The rapid clinical course in the patient reported here is similar to
      that of other rare cases reported and suggests that mantle cell lymphoma in
      blastic transformation appears to be a very aggressive lymphoma with a clinical
      course similar to that of other low-grade lymphomas in histologic transformation.

PMID- 8651860
TI  - Primary angiitis of the central nervous system associated with Hodgkin's disease.
AB  - An unusual case of primary angiitis of the central nervous system associated with
      Hodgkin's disease in a 55-year-old-man is reported. After a 10-month history of
      acute transverse myelitis, the patient was diagnosed as having nodular sclerosing
      type Hodgkin's disease involving the retroperitoneal lymph nodes. The patient
      died of a brainstem hemorrhage 1 week after a 15-day course of chemotherapy.
      Primary angiitis was documented on autopsy examination. To our knowledge, only
      nine similar cases have been reported in the literature, and none of them was
      associated with a sole initial spinal cord presentation. Owing to the rarity of
      this disease entity, a high index of suspicion and awareness of the association
      between primary angiitis and Hodgkin's disease are essential for early diagnosis.

PMID- 8651862
TI  - Basal cell carcinoma with collagenous crystalloids.
AB  - We describe here a unique feature seen in a case of conventional basal cell
      carcinoma of the skin. In the central portion of the tumor, clusters of
      collagenous crystalloids composed of radially arranged needle-shaped fibers were
      found. Such distinct extracellular matrix deposits may occur in rare cases of
      pleomorphic adenomas and myoepitheliomas of salivary glands, but to the best of
      our knowledge, they have never before been described in basal cell carcinoma of
      the skin.

PMID- 8651863
TI  - An unusual myxoid leiomyosarcoma of the heart.
AB  - We report a case of myxoid leiomyosarcoma originating from the interventricular
      septum in the outflow tract of the right ventricle. Although the gross features
      suggested a benign myxoma, histologic examination demonstrated features of a
      smooth muscle tumor, which was characterized by low mitotic index and a bland
      degree of atypia with few cells immunoreactive for cell cycle-associated Ki-67
      antigen. The tumor relapsed twice, and the patient (a 61-year-old woman) died 18
      months after the first diagnosis. This case demonstrates that myxoid
      leiomyomatous proliferations of the heart must be considered potentially
      malignant, even when the gross features and degree of cellular atypia seem to
      suggest otherwise.

PMID- 8651864
TI  - Meningioangiomatosis and oligodendroglioma in a 15-year-old boy.
AB  - A case of meningioangiomatosis occurring in a 15-year-old boy is reported. The
      patient did not show signs of neurofibromatosis on physical examination, and his
      medical history included only one previous episode of loss of consciousness,
      which was accompanied by a self-limited focal seizure. The lesion was associated
      with an oligodendroglioma and was incidentally discovered during the macroscopic
      sampling of the neurosurgical specimen. The literature relating to this uncommon
      entity is reviewed and discussed. To the best of our knowledge, the concurrence
      of meningioangiomatosis and oligodendroglioma has not been documented previously.

PMID- 8651865
TI  - Specimen collection and storage for diagnostic molecular pathology investigation.
AB  - The success of the newest discipline in the diagnostic clinical pathology
      laboratory, molecular pathology, is dependent on proper collection and storage of
      both the original and processed (nucleic acid) specimen. This issue will grow in
      importance as test volumes increase in the diagnostic molecular pathology
      laboratory. This review is a distillation of a literature review by the Patient
      Preparation and Specimen Handling Committee of the College of American
      Pathologists. It describes specific collection, storage, and anticoagulant or
      preservative requirements based on the diagnostic molecular technique and/or
      specimen type used for analysis. This review serves as a guide for clinical
      laboratories interested in appropriate collection and storage of specimens to be
      used in nucleic acid-based analysis.

PMID- 8651866
TI  - Mitochondrial disorders. Methods and specimen selection for diagnostic molecular
      pathology.
AB  - Mitochondrial DNA is a circular double-stranded macromolecule. Each strand
      contains 16 569 base pairs. Mutations in mitochondrial DNA, including base
      substitutions in tRNA or rRNA genes, deletions, duplications, or base
      substitutions in genes for protein subunits, lead to specific diseases. The ratio
      of mutated to normal mitochondrial DNA may vary from tissue to tissue
      (heteroplasmy) in mitochondrial DNA diseases. Therefore, the source of the
      specimen is important in the evaluation of mitochondrial DNA mutations. Detection
      method selection is also critical. For example, single-strand conformation
      polymorphism is not as specific for tRNA mutations as is gene sequencing or
      amplification of a specific gene by polymerase chain reaction. Care in both
      specimen collection and analytic method are important in the successful
      evaluation of patients with a potential mitochondrial DNA disease.

PMID- 8651867
TI  - DNA on a chip.

PMID- 8651868
TI  - Are patients with Parkinson's disease more likely to have periventricular
      hyperintensities develop?

PMID- 8651870
TI  - Neurocysticercosis.

PMID- 8651869
TI  - Multiple system atrophy.

PMID- 8651871
TI  - Ischemic stroke in young adults.

PMID- 8651872
TI  - Apolipoprotein E epsilon4/4 in a neuropathologically normal very elderly
      individual.

PMID- 8651873
TI  - Medical education.

PMID- 8651874
TI  - Amyotrophic lateral sclerosis, heterogeneous susceptibility, trauma, and
      epidemiology.
AB  - Epidemiological studies relating antecedent trauma and amyotrophic lateral
      sclerosis (ALS) demonstrate a contradiction: positive (but poorly structured)
      retrospective case-control studies and negative (but uninterpretably small)
      prospective cohort studies. In this report, the equations for the case-control
      odds ratio and cohort relative risk in populations with heterogeneous
      susceptibility to ALS are analyzed. The case-control odds ratio and cohort
      relative risk converge as the proportion of ALS-nonsusceptible individuals in a
      population increases and the rate of ALS in nonsusceptible individuals decreases.
      Cohort studies of antecedent trauma and ALS have no significant advantage over
      case-control studies in populations in which most individuals are relatively
      nonsusceptible to ALS. Accordingly, the relationship between antecedent trauma
      and ALS can be addressed by carefully defined case-control studies.

PMID- 8651875
TI  - Unilateral focal preponderance of interictal epileptiform discharges as a
      predictor of seizure origin.
AB  - OBJECTIVE: To test the hypothesis that seizure origin may be predicted from scalp
      recorded electroencephalographic interictal epileptiform patterns that occur
      exclusively or preponderantly over a single focal region. PATIENTS AND METHODS:
      Fifty-nine of 98 patients (>=16 years old) with intractable epilepsy who
      underwent sphenoidal/scalp electroencephalographic video monitoring were
      identified as having interictal epileptiform discharges preponderantly (>=75% of
      all discharges) or exclusively over a single unilateral region (basal-temporal,
      midposterior temporal, frontopolar, superior frontal, central). Ictal recordings
      in 48 patients could be interpreted as demonstrating focal origins, and the ictal
      findings were compared with the interictal findings. Eleven patients had
      uninterpretable ictal recordings or no seizures during monitoring and were not
      further considered. RESULTS: All seizures arose from the expected region in 39 of
      the 48 patients (Fisher's exact test, P<.001). Interictal discharges occurred
      exclusively over a single region in 23 of the 48 patients, and all seizures arose
      from the expected region in 22 of the 23 patients (P<.001). Seventeen patients
      among this group of 23 had exclusively unilateral basal-temporal discharges, and
      all seizures arose from the expected side, with the exception of one seizure that
      arose from the opposite side in one patient, with her other seizure arising from
      the expected side (P<.001). All seizures arose from the expected region in three
      patients who exhibited all interictal discharges arising from a single superior
      frontal region, in two patients with discharges only over a single midposterior
      temporal region, and in one patient with exclusively unilateral frontopolar
      discharges. CONCLUSIONS: Interictal discharges that demonstrate a consistent
      unilateral focal preponderance over a single region, regardless of location,
      generally predict seizure origin. If the discharges are exclusive to a single
      region, there is a greater than 95% probability that all recorded seizures will
      originate from the expected region.

PMID- 8651876
TI  - Cerebrovascular complications of neurocysticercosis. Clinical and neuroimaging
      spectrum.
AB  - OBJECTIVE: To describe the clinical and neuroimaging spectrum of cerebral
      Cysticercus arteritis to clarify the mechanisms of a stroke that is associated
      with neurocysticercosis. DESIGN: Case series. SETTING: Tertiary care center.
      PATIENTS: Sixty-five patients with strokes that were associated with
      neurocysticercosis. Based on the extension of cysticercosis, the study group was
      divided into patients with focal or diffuse cysticercal disease. Patients with
      focal affection were subdivided into those with small- and large-vessel angiitis.
      MEASURES: For each group. stroke syndromes, mode of onset, associated neurologic
      syndromes, neuroimaging features of cysticercosis and cerebral infarcts,
      angiographic and cerebrospinal fluid findings, and outcome were analyzed.
      RESULTS: Thirty-five patients had focal cysticercosis (13 with small-and 22 with
      large-vessel angiitis), and 30 had diffuse disease with either small-or large
      vessel involvement. A high frequency of subarachnoidal cysts was found,
      neighboring the ischemic area. Patients with focal cysticercosis has a vascular
      onset in 80% compared with 20% in those with diffuse cysticercosis (P<.001).
      Distinctive findings in diffuse cysticercosis were hydrocephalus (80%), multiple
      cerebral infarcts (64%), and mental disorders (43%) (P<.001). There was a close
      parallelism between the type of cysticercosis and the degree of cerebrospinal
      fluid inflammatory changes, reflecting in the outcome. Death or incapacitating
      sequelae were associated with diffuse cysticercosis, and total recovery was
      common in patients with focal disease and small-vessel angiitis, whereas
      intermediate morbimortality occurred with focal cysticercosis and large-vessel
      vasculitis. CONCLUSION: Based on the distribution of cysticercal disease and the
      severity of concomitant chronic arachnoiditis, it is possible to identify a wide
      spectrum of cerebrovascular involvement caused by neurocysticercosis.

PMID- 8651877
TI  - Striatopallidal and thalamic dystonia. A magnetic resonance imaging
      anatomoclinical study.
AB  - OBJECTIVE: To determine which brain structures are involved in symptomatic
      unilateral dystonia caused by localized cerebral infarction. DESIGN: Three
      dimensional T1-weighted magnetic resonance imaging sequence and stereotactic
      analysis were used to analyze the topography of the lesions. Stereotactic
      localization of thalamic lesions was conducted according to the atlas of Hassler
      with a Voxtool software (Advantage Windows Workstation, General Electric,
      Milwaukee, Wis) workstation system. PATIENTS: Eight patients with hemidystonia,
      segmental dystonia, or focal dystonia were selected from among 51 consecutive
      patients (between January 1988 and May 1993) with symptomatic unilateral
      dystonia. RESULTS: Patients had dystonic spasms (n=4) or myoclonic dystonia
      (n=4). Lesions associated with dystonic spasms were located in the
      striatopallidal complex, and those with myoclonic dystonia were in the thalamus
      contralateral to the dystonia. Lesions of the striatopallidal complex involved
      the putamen posterior to the anterior commissure in all patients and extended
      variably into the dorsolateral part of the caudate nucleus, the posterior limb of
      the internal capsule, or the lateral segment of the globus pallidus. These
      lesions were centered in the "sensorimotor" part of the striatopallidal complex,
      with a trend toward a somatotopical distribution. Lesions of the thalamus were
      located in the ventral intermediate and ventral caudal nuclei, while the ventral
      oral anterior and posterior nuclei (which receive pallidal efferents) were
      largely spared. CONCLUSIONS: These results suggest that striatopallidal and
      thalamic dystonia may have different pathophysiologic bases.

PMID- 8651878
TI  - Neuropsychological alterations in patients with computed tomography-detected
      basal ganglia calcification.
AB  - OBJECTIVE: To investigate the cognitive and mental status of patients with basal
      ganglia calcification on a computed tomographic scan. DESIGN: Eighteen ambulatory
      patients with basal ganglia calcification and without other radiological findings
      who were identified from the computed tomography records of a general hospital in
      a 2-year period and 16 control subjects who were matched for age, education, sex,
      and premorbid IQ estimation consented to participate. All subjects underwent a
      neurological evaluation, a comprehensive neuropsychological battery, and tests
      with psychiatric rating scales. RESULTS: Significant differences for the control
      group were found in tests that evaluated motor speed and executive, visuospatial,
      and some memory functions. Four patients (22%) met criteria for organic mood
      disorder (minor depression, three patients; bipolar depression, one patient)
      according to the Diagnostic and Statistical Manual of Mental Disorders, Revised
      Third Edition, whereas six other patients (33%) met diagnostic criteria for
      obsessive-compulsive disorder. CONCLUSIONS: These results indicate that patients
      with basal ganglia calcifications frequently have a subcortical pattern of
      neuropsychological dysfunction and behavioral changes that are known to be
      associated with alterations of the frontal-limbic-basal ganglia circuits. The
      pattern of neuropsychological impairment is consistent with basal ganglia damage.
      However, poor performance in other neuropsychological tests suggest additional
      involvement of other connected networks.

PMID- 8651879
TI  - Postictal psychiatric events during prolonged video-electroencephalographic
      monitoring studies.
AB  - BACKGROUND: Postictal psychiatric events presenting as postictal psychotic events
      and postictal nonpsychotic events are known to occur following seizure clusters.
      Accordingly, patients undergoing prolonged video-electroencephalographic (EEG)
      monitoring studies may be at increased risk of experiencing postictal psychiatric
      event, as they often have flurries of seizures during these studies. OBJECTIVES:
      To determine the annual incidence and clinical characteristics of postictal
      psychotic events and postictal nonpsychotic events in video-EEG monitoring
      studies in patients with partial seizure disorders and to identify potential
      pathogenic factors. RESULTS: Thirteen patients met the criteria for a postictal
      psychiatric event during the 18-month study period, 10 presenting as postictal
      psychotic events and three as postictal nonpsychotic events. The annual incidence
      of postictal psychiatric events at our monitoring unit for 1988 was 7.8%, 6.4%
      presenting as postictal psychotic events and 1.4% as postictal nonpsychotic
      events. Seven patients had their first-ever postictal psychiatric event during
      the monitoring study. In 12 of the 13 patients, the postictal psychiatric events
      mimicked well-defined psychiatric entities of shorter duration (mean, 66.5
      hours); they appeared 12 to 72 hours after the last seizure and remitted
      spontaneously or with the use of low-dose psychotropic medication. No significant
      differences in EEG, neuroradiologic, psychiatric, medical, or psychosocial data
      were found between the patients with postictal psychiatric events and a group of
      13 age-matched control patients. Follow-up data of comparable duration were
      available in nine patients with postictal psychiatric events and nine controls.
      Psychiatric events were reported more frequently by patients with postictal
      psychiatric events than by control patients (P=.03). In three patients, postictal
      psychiatric events converted to interictal events. CONCLUSION: These findings
      suggest that monitoring studies increase the risk for postictal psychiatric
      events, which neurologists need to be familiar with, as they represent important
      morbidity associated with these studies.

PMID- 8651880
TI  - Stroke subtypes and hypertension. Primary hemorrhage vs infarction, large- vs
      small-artery disease.
AB  - BACKGROUND: Hypertension is the major risk factor for stroke associated with
      small-artery disease and large-artery disease, but the factors behind the
      development of a particular stroke subtype in individual patients are not known.
      METHODS: We determined risk factors potentially predictive of stroke subtype in
      822 of 2760 patients consecutively admitted to a primary care stroke center with
      (1) first-ever stroke, (2) hypertension (blood pressure >160/90 mm Hg at least
      twice before the stroke), and (3) no cardioembolic source. We used logistic
      regression analysis to delineate factors associated with ischemic (brain infarct)
      vs hemorrhagic (primary hemorrhage) stroke and with large- vs small-artery
      disease. A scoring system was elaborated on the basis of the estimated regression
      coefficients. Observed proportions and calculated risks were determined. RESULTS:
      Age greater than 67 years, cigarette smoking, hypercholesterolemia, and a family
      history of stroke or ischemic heart disease were independent predictors of
      ischemic vs hemorrhagic stroke. In women, diabetes mellitus was an additional
      risk factor for ischemic vs hemorrhagic stroke. Only one of 144 patients with
      primary hemorrhage had an ipsilateral carotid stenosis. In men with brain
      infarct, cigarette smoking, cardiac ischemia, and a family history of stroke or
      ischemic heart disease were significantly and independently associated with large
      vs small-artery disease. In women with brain infarct, smoking was the only
      predictive factor for large- vs small-artery disease. CONCLUSION: In patients
      with stroke and hypertension, associated risk factors influence the subtype of
      stroke (hemorrhage vs brain ischemia, large- vs small-artery disease).

PMID- 8651881
TI  - Cerebral venous sinus surgery for epilepsy 60 years ago.
AB  - The recent singular advances in the past 20 years in the medical and surgical
      treatment for epilepsy stand in marked contrast to the limited therapeutic
      methods available earlier in this century. George W. Swift, MD, one of the
      earliest neurosurgeons in Seattle, Wash, interpreted the anatomic and physiologic
      data of his time and concluded that impaired cerebral venous blood flow was
      responsible for recurrent seizures. Accordingly, he advocated and practiced
      decompression of the transverse sinuses. Although his operation was not practiced
      by his peers, a review of this procedure provides a past perspective of earlier
      advances and therapies for epilepsy.

PMID- 8651882
TI  - Glucose retention on the surfaces of primary teeth in 3- and 4-yr-old children.
AB  - Glucose retention was determined in 38 kindergarten children ages 3-4 yr. The
      children rinsed their mouths with 10 ml of a 0.5 mol/l glucose solution for 15 s
      and then spat out. Three minutes after they put the solution in their mouths, a
      small paper-point was used to collect samples of saliva from the labial and
      buccal surfaces of the maxillary and mandibular primary teeth. The concentration
      of glucose in the small amount of saliva collected was measured with an
      immobilized enzyme system. Glucose retention was highest on the maxillary central
      primary incisor, second highest on the maxillary first primary molar and third
      highest on the maxillary lateral primary incisor. An intermediate value was seen
      on the maxillary and mandibular second primary molars, the mandibular first
      primary molar and the maxillary primary canine. A lower value was observed on the
      mandibular primary canine and the lowest on the mandibular incisors. It was
      concluded that there were site differences in glucose retention on primary teeth
      of 3- and 4-yr-old children.

PMID- 8651883
TI  - Comparison of the effects of growth hormone, insulin-like growth factor-I and
      fetal calf serum on mouse molar odontogenesis in vitro.
AB  - The effects of growth hormone, its mediator insulin-like growth factor-I (IGF-I),
      and fetal calf serum on odontogenesis were compared to those of serum-free
      medium. Explanted, 16-day, fetal mouse first molar tooth germs in early bell
      stage were grown on semisolid, serum-free medium supplemented with ascorbic and
      retinoic acids. Recombinant human growth hormone at 50 or 100 ng/ml, IGF-I at 100
      or 200 ng/ml, or fatal calf serum at 20% concentration were added to the media.
      Volumetric changes in serial sections of six tooth germs per treatment over 3
      days of treatment (4, 5, 6 days in vitro) were compared by digitized morphometry.
      Mitotic indices were also compared and the cell densities of the dental papillae
      recorded. Qualitative ratings of differentiation were ascribed to each tooth germ
      by light microscopy. Differences in volume, mitotic activity and cell densities
      were found. The growth hormone-treated tooth germs were not larger than the serum
      free ones but had increased mitotic indices and higher cell densities in the
      dental papillae. IGF-I-treated tooth germs had larger volumes than with all other
      treatments, e.g. germs treated with 200 ng/ml of IGF-I, after 6 days in culture,
      were significantly larger than with all other treatments (p<0.01-<0.001). Whilst
      IGF-I-treated germs displayed the greatest extent of differentiation, growth
      hormone-treated germs also showed advanced differentiation compared to those on
      serum-free medium. These results suggest that growth hormone and IGF-I are
      involved in odontogenesis of murine teeth in vitro by affecting mitotic activity,
      tissue volume and cell differentiation. In conjunction with previous
      immunohistochemical studies that show expression of growth hormone receptor and
      IGF-I in developing teeth, these results provide evidence that both growth
      hormones and its mediator play a part in odontogenesis.

PMID- 8651884
TI  - Fine structure of tooth germs during the formation of enameloid matrix in Tilapia
      nilotica, a teleost fish.
AB  - Tooth germs were examined by light and transmission electron microscopy. Collagen
      fibrils were relatively dispersed and thin at the early and middle stages of
      formation of the enameloid matrix, when the enameloid layer was thin. At the late
      stage, the fibrils became thicker, reaching nearly 30 nm dia, and formed the
      interwoven thick bundles that are characteristic of teleost cap enameloid.
      Abundant flocculent and/or fine, network-like material, probably representing
      glycosaminoglycans or proteoglycans, was located between the collagen fibrils.
      Tall, columnar, inner dental epithelial cells contained abundant rough
      endoplasmic reticulum and many mitochondria, and a well-developed Golgi apparatus
      was seen around the nuclei at the late stage. Elongated vesicles enclosing fine,
      filamentous material that resembled procollagen granules, and large granules
      containing fibril-like structures that were 150 nm in thickness and had periodic
      cross-banding at 32-nm intervals, were usually observed near the Golgi apparatus.
      The contents of the large granules were well stained with phosphotungstic acid,
      which suggests that inner dental epithelial cells synthesize collagen fibrils. At
      this time, odontoblasts also contained abundant rough endoplasmic reticulum and
      mitochondria, a well-developed Golgi, several kinds of granule including those
      that probably contained procollagen, and many microtubules. It is proposed that
      odontoblasts are involved in the formation of a considerable portion of the
      enameloid matrix, including collagen fibrils.

PMID- 8651885
TI  - Haemodynamic and immunohistochemical studies of rat incisor pulp after
      denervation and subsequent re-innervation.
AB  - The effects of injury to the inferior alveolar nerve on the distribution of
      neuropeptides and neurogenic blood-flow reactions were studied in rat mandibular
      dental pulp. In normal incisor pulps, calcitonin gene-related peptide (CGRP)-like
      immunoreactivity was common, while substance P- and neurokinin (NKA)-positive
      nerve fibres were much less abundant. There were no signs of vasoactive
      intestinal peptide-like, neuropeptide Y-like or 5-hydroxytryptamine-like
      immunoreactivity. In normal pulps, electrical stimulation (100 microA, 5 ms, 15
      Hz for 30 s) of the tooth crown resulted in transient vasoconstriction followed
      by vasodilation, which was enhanced after alpha-adrenoceptor blockade. At 3 days
      4 weeks after unilateral nerve section there were no signs of CGRP-, substance P-
      and NKA-immunoreactivity, and there was no vasodilation in response to tooth
      stimulation. The vasoconstrictor response was also absent during this period but
      at 4 weeks postoperatively a weak response was obtained and after 7 weeks the
      vasoconstrictor response had regained normal amplitude. At 7 weeks
      postoperatively, a large number of CGRP-positive fibres had reappeared and at 11
      weeks the pattern of CGRP-immunoreactivity was normal. However, substance P- and
      NKA-immunoreactivity were not found at 7 or 11 weeks after surgery. Vasodilator
      responses appeared at 7 weeks, and showed normal amplitude at 11 weeks after the
      creation of the nerve lesion. The results show that during nerve regeneration,
      sympathetic vasoconstriction was regained earlier than neurogenic vasodilation in
      rat incisor teeth. The reappearance of neurogenic vasodilation after nerve injury
      was temporarily associated with the presence of CGRP-immunoreactivity in
      regenerating trigeminal afferent nerves.

PMID- 8651886
TI  - Phosphotyrosyl protein phosphatase-like activity of a clonal osteoblastic cell
      line (MC3T3-E1 cell).
AB  - The homogenate of MC3T3-E1 cells hydrolysed phosphotyrosine, but not
      phosphoserine or phosphothreonine at acidic pH. It dephosphorylated lysozyme and
      Raytide (a gastrin analogue peptide) phosphorylated by tyrosine kinase, but
      showed little activity toward histones phosphorylated by cyclic AMP-dependent
      protein kinase. Dephosphorylation of phosphorylated lysozyme and Raytide were
      inhibited by zinc and vanadate, but were insensitive to okadaic acid. These data
      suggest that the osteoblastic cell line MC3T3-E1 has a phosphotyrosyl protein
      phosphatase-like activity that may participate in cellular regulation involving
      protein tyrosine phosphorylation.

PMID- 8651887
TI  - Spatial and temporal distribution of sonic hedgehog mRNA in the embryonic mouse
      mandible by reverse transcription/polymerase chain reaction and in situ
      hybridization analysis.
AB  - Hedgehog genes have recently been implicated in the control of pattern formation
      in many developing organ system. Vertebrate homologues of the Drosophila hedgehog
      have been identified in mouse and rate embryos. The temporal regulation of sonic
      hedgehog (mouse homologue) has previously been studied by Northern analysis of
      whole embryos with varying results. Sonic hedgehog transcript expression in the
      mouse mandibular process was now characterized using polymerase chain reaction
      (PCR) an in situ hybridization techniques. PCR analysis revealed transcripts at
      gestational days 10 and 11, before the formation of the dental lamina, but not at
      days 12-14, after tooth buds have formed. Transcripts were localized to,
      primarily, the epithelium in the presumptive incisor region of the mandibular
      midline at gestational day 10. No mRNA was detected by in situ hybridization
      techniques in the presumptive molar regions of odontogenic epithelium. Sonic
      hedgehog expression may be involved in the regulation of pattern formation
      through establishment of an incisor-molar axis of polarity.

PMID- 8651888
TI  - Molecular characterization of plasminogen activators in human gingival crevicular
      fluid.
AB  - Plasminogen activators (PAs), a family of serine proteases, and their inhibitors
      (PAIs) are important in fibrinolysis, wound healing and tissue remodelling.
      Previous studies revealed differences in the localization of PA activity between
      healthy and diseased gingival tissues, suggesting that PAs and PAIs could play a
      part in periodontal homeostasis and disease. PAs and PAIs are synthesized by most
      of the cells types making up the periodontium and can be identified in gingival
      crevicular fluid (GCF). These studies sought to characterize the molecular
      species of PAs and their inhibitors in GCF collected from clinically healthy
      sites. PA enzymatic activity in GCF samples demonstrated by fibrin zymography
      revealed the presence of only tissue-type PA (tPA) activity. No urokinase-type PA
      (uPA) enzymatic activity was detected. tPA enzymatic activity appeared
      predominantly as an uncomplexed 70-kDa species, although some samples contained
      enzyme-inhibitor complexes. Quantitation of total tPA by enzyme immunoassay
      showed a mean concentration of 1.6 ng/microl. Analysis of GCF samples for uPA by
      immunoblotting and enzyme immunoassay disclosed the presence of small amounts of
      uPA (0.2 ng/microl), which were present predominantly in activator-inhibitor
      complexes. Immunoblotting showed specific PAI-2 immunoreactivity bands in high
      molecular-weight complexes and low molecular-weight degradation products, but
      less than nanogram amounts of free PAI-2 molecules. Enzyme immunoassay revealed
      that PAI-2 was present in an at least a seven times greater amount than PAI-1.
      These observations support the hypothesis that PA-generated proteolysis and its
      regulation by endogenous inhibitors has a role in the diverse biochemical
      mechanisms underlying periodontal physiology and pathology including host
      microbial interaction, polymorphonuclear leucocyte infiltration, turnover and
      migration of epithelial cells, connective tissue degradation and remodelling,
      fibrinolysis and wound healing.

PMID- 8651889
TI  - Bone morphogenetic protein-2 and -4 expression during murine orofacial
      development.
AB  - In the developing orofacial region, epithelial-mesenchymal interactions induce a
      differentiation cascade leading to bone and cartilage formation. Although the
      nature of this interaction is unknown, bone morphogenetic proteins (BMP)-2 and -4
      have been suggested as putative signalling molecules. Using 35S-labelled cDNA
      probes, the expression patterns of BMP-2 and -4 mRNA were examined in murine
      perioral tissues preceding, during and following the time of the epithelial
      mesenchymal interaction leading to mandibular formation. At embryonic age (e) 9.5
      days, a restricted pattern of BMP-4 mRNA was expressed in the epithelium of the
      developing facial processes. This decreased rapidly, with little or no signal on
      E10.5 or E11.5. By E13.5, BMP-4 signal was restricted to the dental lamina,
      follicle and papilla. BMP-2 expression was not prominent in the developing face
      until E13.5. At this stage, signal was widespread throughout mesenchyme of neural
      crest, but not somatic origin. Different domains of expression were present in
      the developing epithelium: for example, there was strong signal in the floor of
      the mouth and the ventral tongue, in contrast to that of the dorsum of the tongue
      and primary palate, which were negative. These results support the role of BMP-2
      and -4 as regulators of orofacial development and demonstrates different fields
      of BMP-2 expression in developing oral mucosal epithelium.

PMID- 8651890
TI  - Gene expression of markers associated with proliferation and differentiation in
      human keratinocytes cultured from epidermis and from buccal mucosa.
AB  - Normal keratinocytes from epidermis and from buccal mucosa underwent dissimilar
      stages of differentiation in the same culture medium and responded differently to
      changes in the composition of the medium. Manifestations of these variations were
      examined in terms of the expression at the mRNA level (as measured by reverse
      transcriptase-polymerase chain reaction) of three regulatory genes (cdc2, c-myc,
      and p53) and five that encode structural proteins (keratins K5, K10 and K13,
      involucrin, and filaggrin), in three growth-medium formulations. The culture
      conditions enhanced or retarded maturation; the observed alterations in gene
      expression correlated with these changes. Except for the proliferation genes, the
      non-keratinizing buccal mucosa generally responded more weakly than the
      orthokeratotic epidermis to culture-medium supplementation favouring
      differentiation. Gene expression in cultured keratinocytes reflected their
      ability to differentiate in vivo; genes were expressed even when the
      corresponding protein was not seen in vitro. Although keratin K10 is not
      prevalent in the buccal mucosa nor keratin K13 in the epidermis, the genes for
      both were found to be expressed in both tissues.

PMID- 8651892
TI  - Response characteristics of periodontal mechanoreceptors to mechanical
      stimulation of canine and incisor teeth in the cat.
AB  - The alveolar bone that overlies the labial aspect of the root of the right lower
      canine tooth was pared down until paper thin. Thirty-five periodontal
      mechanosensitive (PM) units sensitive to stimulation of the canine and incisor
      and to punctate stimulation through the thinned bone of the periodontal ligament
      of the canine were recorded from the inferior alveolar nerve rostral to the
      masseter muscle. The units showed a sustained and directionally selective
      response to pressure applied to the teeth. The optimal directions of stimulation
      for each tooth in the receptive field were parallel and oriented linguolabially.
      When the canine was stimulated mechanically in the optimal stimulus direction,
      the interspike intervals of the responses were relatively regular in most PM
      units (91%). The conditioning and test stimuli were applied to the adjacent
      canine and third incisor. The conditioning stimulus (0.10 N) was given to one of
      these teeth in the optimal stimulus direction. The test stimulus (0.02 N or 0.05
      N) was applied to the adjacent tooth in the opposite direction in order to
      examine the effect of mechanical spreading of the conditioning stimulus on the
      adjacent tooth. In most PM units, the spike discharges evoked by the conditioning
      stimulus given to the incisor were stopped by the test stimulus given to the
      canine. When the given stimuli were reversed, the firings evoked by the
      conditioning stimulus were slightly depressed by the test stimulus. After
      removing the spot-like PM receptor site(s) in the paper-thin area of bone, all
      units but one did not respond to stimulation. These results provide evidence that
      neurones with multiple-tooth receptive fields and regular spike-interval
      responses recorded from the inferior alveolar nerve come from the mechanical
      spreading effect of the stimulation of one tooth on an adjacent tooth through the
      trans-septal fibre system and that neurones with irregular-interval responses are
      due to the ramification of PM fibres peripherally.

PMID- 8651891
TI  - A methodical study of shape changes in human oral cells perturbed by a simulated
      orthodontic strain in vitro.
AB  - Cells are known to alter their shape as a response to physical and chemical
      changes. Mechanical loads applied to teeth produced cellular perturbations
      resulting in orthodontic movement. An in vitro model was developed to simulate
      the in vivo strain of orthodontic movement. Calibrated forces were applied to
      human periodontal ligament cells and buccal mucosal fibroblasts (controls). A
      biaxial strain-producing device was used to stretch vital cells growth on
      flexible polytetrafluorethylene membranes. In addition, a new cell adhesive, Cell
      Tak, was employed to examine the effect of an adhesive substrate on the cellular
      response to two known loads. The shape changes of unstrained (control) and
      strained cells were evaluated by time-lapse telemicroscopy, and plots of time
      dependent alterations in area and shape were recorded. The fusiform cells became
      more rounded over a given time of up to 1400 s. The responses appeared to be
      independent of cell type, the strain employed, and the presence of cell adhesive.
      Scanning electron microscopy demonstrated, irrespective of cell type, that the
      surface of stressed cells produced a striking number of microvilli as compared
      with the relatively smooth-surfaced controls.

PMID- 8651893
TI  - Effect of low levels of fluoride on calcium uptake by demineralized human enamel.
AB  - The effect of fluoride (ca. 0.1 parts/10(6)) on calcium uptake by enamel was
      examined under alternating remineralizing and demineralizing conditions. The
      remineralizing solutions contained either 0, 0.058, 0.104, or 0.138 parts/10(6)
      fluoride (ex NaF), while the demineralizing solutions contained no added
      fluoride. During the demineralization periods, calcium loss was similar for all
      groups. However, during the remineralizing periods, all levels of added fluoride
      were found to promote calcium uptake. Calcium levels taken up by the artificial
      lesions were sound to increase with increasing fluoride concentration in
      solution, and were independent of surface area of exposed enamel. In the absence
      of fluoride, even under conditions that are considered to be remineralizing,
      further demineralization took place.

PMID- 8651894
TI  - [The importance of tropical animal hygiene for indigenous animal production].
AB  - Tropical animal hygiene firstly supports the improvement of animal production in
      tropical countries. Examples show the different disease complexes and the
      possible ways of transmission. The possibility of an importation of ?tropical
      flues? means an important danger for our indigenous animal production. Therefore
      it is necessary to improve both the hygienic situation in the tropics as well as
      the knowledge on these diseases here, to protect our own animals.

PMID- 8651895
TI  - [The organization of veterinary services in African animal husbandry systems:
      chances for the exchange of interdisciplinary learning processes].
AB  - The structure of the veterinary services to date hinders--together with massive
      intervention in the land tenure systems and the animal keepers' rights in arid
      and semi-arid areas--the future organization of productive animal-keeping systems
      adapted to the ecological conditions. The consensus of the findings of research
      in the social as well as in the natural sciences, is that state (agrarian)
      policies and international development cooperation have led to centralism and
      authoritarian administrations which formalize formerly informal, locally specific
      rules for securing the health of the animals and the maintenance of grazing and
      water resources. As a result, the animal-keeping groups have lost their rights,
      social conflicts arose and the environment suffered. Thus, decentralization,
      subsidarity and--above all--comprehensive participation on the part of the animal
      keepers are regarded as the guidelines for the future organization of state
      and/or private services for maintaining the health of the animals. Thereby, the
      planning at the various administrative levels is faced by great challenges in
      view of the progressing differentiation in the animal-keeping systems (e.g. peri
      urban systems; urban absentee herd owners; marginalized, subsistence-oriented
      households).

PMID- 8651896
TI  - [Promotion of Moroccan national agricultural research in the area of sheep
      production--a project of German development cooperation].
AB  - With a population size of 14 mio. animals the sheep herders of Morocco produce 25
      30% of the national red meat production. Moroccan sheep production is
      characterized by a low productivity of the females. With a support of the
      national research in the sector of sheep production, reasons for that, and
      possibilities of improvement should be found. The German development agency
      (Deutsche Gesellschaft fur Technische Zusammenarbeit) promotes this fact with 2
      scientific advisers. They will implement a problem and client-oriented research
      formation and advice in management and methodology activities of the project.
      Already in the stage of setting research priorities and formulate research
      subjects the later user of the research results (extension service, breeders) are
      actively involved. A stronger triangle relation Research-Extension-Breeder is the
      objective. Examples of the project work are given.

PMID- 8651897
TI  - [The fertility of the water buffalo (Bubalus bubalus)].
AB  - In the present study the conception- and calving-frequencies of Nili-Ravi milk
      buffaloes were calculated over a year's period in the Punjab region of Pakistan.
      The results show prominent fluctuations throughout the year with a minimum
      calving-frequency of 1.6% in March and a minimum conception-frequency of 1.8% in
      May and maximum calving frequencies of 15.2% in November. This distribution
      occurs in association with unsuitable and suitable climatic conditions
      respectively, and also in association with the feeding situation which is better
      in autumn than in spring (Nothelle, 1992). Thibault and Levasseur (1974) believe
      that there is an inborn seasonal nature of sexual activity for nearly all
      mammals. This principle surely applies to the milk buffaloes, although it is
      confirmed that the buffalo cow is a poly-oestrous animal with a regular sexual
      cycle all over the year. Through breeding-, feeding-, animal husbandry- and
      management practice it is possible to compensate the fluctuations of conception-
      and calving frequencies over the whole year.

PMID- 8651898
TI  - [Preliminary studies of the immunization of shrimp (Penaeus monodon) against
      vibrio infections].
AB  - There is a great demand for an applicable vaccine against bacterial infections of
      prawns, especially Vibriosis. The results of the tests that had been carried out
      can be evaluated as promising and indicate that the vaccination of prawns against
      bacterial diseases is possible. Nevertheless it is still necessary to increase
      the scale of research on this subject, above all, the basics of the immuno-system
      of prawns. Adult prawns should be vaccinated to check if they are able to pass
      their immuno-protection to their progeny. If that is the case only a few breeding
      animals have to be vaccinated, instead of all the larvae. Actually the
      prophylactic application of antibiotics is the only method to prevent infections
      with Vibriosis. 100-150 mg of Oxytetracycline per kg of prawns are fed during one
      production period and these antibiotics are also used in humans. Assuming that
      the average amount of harvested prawns per production unit is 8-10 metric
      tons/pond (1 ha). 800-1500 g of antibiotics are used. Since different pathogenic
      strains have developed resistance to Oxytetracycline, also other kinds of
      antibiotics (for example oxolinic acid) are given today. Antibiotics are often
      fed until harvesting, however, there are laws which prohibit use to antibiotics
      during the last thirty days before harvesting, to prevent residues in the prawn
      body. A vaccine against bacterial diseases could decrease the production costs
      and reduce the amount of the applied antibiotics.

PMID- 8651899
TI  - [Detection of Clostridium perfringens toxins on cell cultures].
AB  - An important prerequisite for the possible application of cell culture systems as
      an in vitro method for the potency test of C. perfringens vaccines is the
      detection of cytotoxic effects of non-neutralized toxins on cell cultures. For
      this purpose eight cell lines were investigated in terms of the sensitivity to
      toxins using microscopy and the MTT assay. The results suggest that the MDCK cell
      line is a sensitive and specific detection system for epsilon-toxin. The VERO
      cell line is a suitable indicator for the detection of beta-toxin. Another task
      was the selection of a sensitive method for the analysis of cytotoxic effects of
      the toxins used. The neutral red and the tetrazolium-(MTT)-assays were compared
      for three cell lines (MDCK, FBTR, MA 104). The MTT assay was proved to be the
      optimal test system under our conditions.

PMID- 8651900
TI  - [Protective effect in mice of the live rabies vaccine produced using the
      Gottingen bioreactor].
AB  - For the control of urban rabies in developing countries, the SAD-virusstrain was
      used in the Gottingen two-step Bioreactorsystem as a model-virus for oral vaccine
      production. The quality of the antigen had been tested by challenge. In the
      Bioreactorsystem, controlled by computer, a high standard of cell quality and
      cell density up to 6 x 10(6) cells/ml had been maintained. The high cell quality
      is correlated to high proliferation of rabies virus. Virus titres up to 10(8.5)
      pfu/ml were reached. The protectivity of the antigen had been tested by
      challenge. In comparison to a commercial vaccine with a PD50 of 10(-1.92) the SAD
      Antigen of the Gottingen Bioreactorsystem reached a PD50 of 10(-1.63) by a
      challenge doses of 70-75 MLD50.

PMID- 8651901
TI  - Mitochondrial targeting of glutathione reductase requires a leader sequence.
AB  - Glutathione reductase (GR), which catalyzes the conversion of glutathione
      disulfide to glutathione, is encoded in nuclear DNA, but is active in cytoplasm
      and mitochondria. However, analyses of known protein and DNA sequences for human
      GR have not revealed a potential mitochondrial targeting signal (MTS). We
      generated two 5'-truncated GR clones, which resulted in omission of the N
      terminal 5 or 10 amino acids, to disable a potential targeting signal, and
      generated two GR clones containing synthetic MTS cDNAs. Transfection of Chinese
      hamster ovary cells with the full length human GR cDNA or with the 5'-truncated
      clones increased cytosolic GR activities 6- to 14-fold, but increased
      mitochondrial activities less than 2-fold. In contrast, transfection with either
      of the GR clones containing MTS cDNAs increased GR activities in mitochondria
      more than 24-fold. We conclude that the existing protein and DNA sequences for
      human GR do not contain a MTS and that such a signal is needed for effective
      mitochondrial targeting.

PMID- 8651902
TI  - Functional maintenance of hepatocytes on collagen gel cultured with simple serum
      free medium containing sodium selenite.
AB  - We found that simple serum-free medium containing sodium selenite (Se) is
      effective for long-term maintenance of functional hepatocytes cultured on a
      pepsin-digested collagen gel (DC-gel). The concentration of Se was important for
      maintenance of hepatocytes, and its optimal concentration was 10(-7)
      approximately 10(-6)M. The effect of Se was specific, as other metals did not
      have the same effect. The effect was equal to that of fetal bovine serum for
      maintenance of functional hepatocytes. Using this medium, we could obtained a
      high level of hepatocellular function including the production of albumin and
      transferrin, and activity of p450 throughout a long-term culture. Matrigel was
      almost equal to DC-gel for albumin secretion, but less effective for transferrin
      secretion, and P450 activity in long-term cultures. The growth of cells on DC-gel
      or matrigel was not observed, and cell morphology of a round-shaped form was
      similar on both substrata. These results indicate that serum-free medium
      containing Se in a DC-gel culture system provides a simple method for long-term
      culture of hepatocytes.

PMID- 8651903
TI  - Stage-specific elevated expression of the genes for hepatocyte growth factor,
      keratinocyte growth factor, and their receptors during the morphogenesis and
      differentiation of rat stomach mucosa.
AB  - Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are two
      factors considered to be involved in the morphogenesis of several organs. To
      understand the role of HGF and KGF in the stomach development, we analyzed
      changes in the levels of expression of the genes for the two growth factors and
      their receptors in the fetal rat stomach by competitive RT-PCR. Resembling our
      previous results for HGF, the expression of the genes for KGF and its receptor
      was observed in the mesenchyme and epithelium of 16.5 day fetal stomach,
      respectively, indicating the possibility that KGF mediates the epithelial
      mesenchymal interaction in the early stage of stomach development. The
      developmental profile of the expression of the genes for the two growth factors
      and their receptors were different, indicating a difference in their roles; the
      genes for HGF and c-met, the receptor for HGF, are expressed mainly during the
      morphogenetic period, while the genes for KGF and its receptor mainly after the
      morphogenetic period. Thus, it is probable that HGF controls the proliferation of
      epithelial cells during the morphogenetic process. The expression of the genes
      for KGF and its receptor is not correlated with epithelial proliferation during
      morphogenesis, but it does appear to be linked with epithelial differentiation.
      These results, together with the absence of significant mitogenic effect of KGF
      on the epithelial cells of the fetal rat glandular stomach in vitro, suggest a
      role for KGF as a differentiation factor. In addition, the expression profile of
      the genes for KGF and its receptor towards the end of fetal period appears to be
      closely correlated with that of mesenchymal cell proliferation, suggesting
      another role for the growth factor that is not regulated by the epithelial
      mesenchymal interaction.

PMID- 8651904
TI  - Detection of hepatitis C virus RNA from the heart of patients with hypertrophic
      cardiomyopathy.
AB  - We investigated hepatitis C virus (HCV) infection in 35 patients with
      hypertrophic cardiomyopathy and 40 patients with ischemic heart disease who were
      consecutively admitted to our hospital. Frequency of positive anti-HCV antibody
      was significantly higher in patients with hypertrophic cardiomyopathy (6 of 35
      patients, 17.1%) than that in patients with ischemic heart disease (1 of 40
      patients, 2.5%, p = 0.036). In three of these six patients with hypertrophic
      cardiomyopathy, HCV RNA was detected in myocardial tissue. In two of these three
      patients, HCV RNA was detected from biopsy and autopsy specimens of the
      ventricles, but not in the serum, suggesting that HCV may replicate in myocardial
      tissue and may be relevant to ventricular hypertrophy. Thus, HCV infection may
      play a role in the development of hypertrophic cardiomyopathy.

PMID- 8651905
TI  - Enhanced glomerular profilin gene and protein expression in experimental
      mesangial proliferative glomerulonephritis.
AB  - Profilin is a cytoplasmic protein that binds to actin monomer and regulates actin
      polymerization. In a number of experimental and human glomerular diseases, the
      mesangial cell expresses alpha-smooth muscle actin and undergoes a phenotypic
      change to myofibroblast. We used a rat model of mesangial proliferative nephritis
      induced with antibody to the Thy 1 antigen present on mesangial cells to
      investigate whether profilin is upregulated. We amplified and sequenced rat
      profilin cDNA by the reverse-transcribed-polymerase chain reaction (RT-PCR). The
      nucleotide and amino acid sequences were highly conserved across the mammalian
      profilins. We raised affinity purified antibody to rat profilin in rabbits
      immunized with a synthetic profilin peptide (EFTMDLRTKS). At 7 days after disease
      induction, enhanced expression in both profilin mRNA and protein was demonstrated
      in the isolated glomeruli by RT-PCR and Western blot analysis. These results
      suggest that profilin may be involved in the pathogenesis of glomerulonephritis
      by reorganizing actin cytoskeleton.

PMID- 8651906
TI  - Nitric oxide down-regulates endocytosis in rat liver endothelial cells.
AB  - Hepatic sinusoidal endothelial cells (SEC) were challenged with inducers,
      blockers or donor of nitric oxide (NO) production in vitro to test the effect of
      this reactive nitrogen agent on endocytosis in SEC. NO was measured as its stable
      form nitrite (NO2-) in culture media and trace amounts of radioiodinated ligands
      were tested for endocytosis and binding after 6 and 24 h of incubation. Among
      several proinflammatory reagents tested, IL-1 beta induced most strongly NO
      synthesis after 24 h in culture. Although endocytosis was significantly enhanced
      in SEC that had been exposed to IL-1 beta for 6 h, prolonged exposure (24 h) to
      this proinflammatory cytokine, which triggered increased production of NO by the
      cells, yielded a decreased endocytic activity. The presence of aminoguanidine, an
      inhibitor of NO synthase, gave significant up-regulation of endocytosis compared
      with control cells. To fully verify the role of NO as an endocytosis modulator,
      SEC were preincubated with sodium nitroprusside, an exogenous NO donor. Again,
      increased concentration of NO2- in the medium was associated with decreased
      endocytosis of SEC. Binding studies at 4 degrees C revealed that the down
      regulation of endocytosis in SEC after increased exposure to NO was due to a
      decreased number or affinity of receptors on the cell surface.

PMID- 8651907
TI  - Effect of O-glycosylated mucin on invasion and metastasis of HM7 human colon
      cancer cells.
AB  - Mucinous colorectal cancers have a poorer prognosis than colorectal cancers which
      produce a low amount of mucin, but the exact mechanism is not well understood.
      The present study was undertaken to elucidate the possible mechanisms of invasion
      and metastasis of colon cancer cells producing high levels of mucin using mucin
      glycosylation inhibitor, benzyl-alpha-N-acetylgalactosamine. The binding activity
      of treated HM7 cells to endothelial leukocyte adhesion molecule (ELAM-1) was
      significantly decreased and fixed cell binding of MoAb SNH-3 and 19-9 (specific
      for sialyl Le(x) and sialyl Le(a), respectively) was also significantly
      decreased. Metalloproteinase activity in conditioned medium and invasion of
      matrigel-coated porous filters by treated HM7 cells were decreased. However,
      there was no difference between control and treated HM7 cells in terms of matrix
      protein binding. These results suggest that O-glycosylated mucin is important in
      the invasive and metastatic properties of HM7 human colon cancer cells.

PMID- 8651908
TI  - Advanced glycation endproducts-receptor interactions stimulate the growth of
      human pancreatic cancer cells through the induction of platelet-derived growth
      factor-B.
AB  - The molecular basis for the clinical association between diabetes mellitus and
      pancreatic cancer was investigated, using Mia PaCa-2 human pancreatic cancer
      cells in culture. Advanced glycation endproducts (AGE) prepared with bovine serum
      albumin and glucose were found to stimulate Mia PaCa-2 cell synthesis of DNA in a
      dose-dependent manner and also to significantly increase the number of viable
      cells. Evidence that platelet-derived growth factor-B (PDGF-B) mediates this
      growth promotion was obtained; AGE upregulated the level of PDGF-B mRNA, and
      antibodies against PDGF-BB completely neutralized the AGE-induced DNA synthesis.
      Antisense oligodeoxyribonucleotides complementary to mRNA encoding a receptor for
      AGE were found to reverse both the PDGF-B upregulation and the AGE-induced DNA
      synthesis. These results thus indicate that AGE ligand-receptor interactions
      could play an active part in the progression of pancreatic cancer through the
      induction of autocrine PDGF-B.

PMID- 8651909
TI  - White adipose tissue nitric oxide synthase: a potential source for NO production.
AB  - Nitric oxide synthase (NOS) activity was detected in soluble and membranous
      fractions of adipose tissue homogenates of control rats. After LPS-treatment,
      this activity was (i) markedly increased (about 10-fold) in both fractions, (ii)
      unaltered after dexamethasone pretreatment, (iii) partly calcium-calmodulin
      sensitive, and (iv) almost entirely accounted by the NOS activity found in
      isolated adipocytes. In adipose tissue homogenates from control rats, Western
      blot analysis demonstrated the presence of the endothelial (eNOS) isoform in the
      membranous fraction of control rats and of the inducible (iNOS) isoform in the
      soluble and membranous fractions. After LPS treatment, the amount of
      immunoreactive iNOS protein was dramatically increased, suggesting that adipose
      tissue is an important site of NO production during the endotoxic shock.

PMID- 8651910
TI  - Constitutive activation of the thyrotropin receptor by mutating CYS-636 in the
      sixth transmembrane segment.
AB  - The rat thyrotropin receptor (TSHR) has 7 Cys residues in its transmembrane (TM)
      segments. We investigated the roles of these Cys residues by individually
      mutating each to Ser, transfecting the mutant DNA into Cos-7 cells and measuring
      TSH binding and cAMP/phosphoinositide (PIP2) responses to TSH and Graves' IgGs.
      Mutation of Cys-636 in the 6th TM helix to Ser markedly increased cAMP level
      without stimulation. Constitutive activation by this mutation contributes to a
      more complete map for activating TSHR mutation. Mutation of other Cys residues
      partially impaired responses but no mutants showed complete loss of receptor
      function, indicating that these residues have no major contribution to the
      overall 3-D structure of the TSHR.

PMID- 8651911
TI  - Genomic structure of the human bradykinin B1 receptor gene and preliminary
      characterization of its regulatory regions.
AB  - We report on the isolation of the human BK B1 receptor gene from a human lung
      fibroblast genomic library. The gene is present as a single copy, spans more than
      10 kilobases and includes three exons interrupted by two introns. The relative
      position of the exons was mapped using RNase protection assay, and genomic DNA
      and cDNA sequence matches. Exon and intron-exon boundaries, and 5', 3' flanking
      regions were sequenced. While the 5' untranslated region is distributed on all
      three exons, the coding region is located entirely on the third exon. The exon
      intron junction sequences are highly conserved. Primer extension analysis mapped
      the transcriptional initiation site 21 base pairs downstream of a TATA sequence.
      Two Aluc sequences and two distinct functional promoters were found in the human
      BK B1 receptor gene.

PMID- 8651912
TI  - Hepatocyte growth factor expressed by a retrovirus-producing cell line enhances
      retroviral transduction of primary hepatocytes: implications for in vivo gene
      transfer.
AB  - Hepatocyte Growth Factor (HGF) is the more potent mitogen of mature hepatocytes.
      We have examined the effect of human HGF expression by a recombinant retroviral
      cell line (MFG-LacZ) on retroviral transduction of primary mouse and human
      hepatocytes. The HGF in the supernatant of MFG-LacZ cell line was correctly
      processed and biologically active. Transduction of mouse and human hepatocytes
      with the supernatant of transfected cells was increased 5-fold, as determined by
      beta-galactosidase activity. The production of HGF was stable and did not
      interfere with the viral titers of the producer cells. This study provides
      evidence that expression of HGF within a retrovirus-producer cell line increases
      the transduction rate of primary hepatocytes. Since the number of corrected cells
      is a limiting step for phenotypic correction of liver deficiencies, our approach
      should improve hepatic gene therapy efficiency. Furthermore this cell line should
      be useful for in vivo liver gene therapy.

PMID- 8651913
TI  - A methyltransferase for synthesis of the flavanone phytoalexin sakuranetin in
      rice leaves.
AB  - Rice (Oryza sativa L.) leaves irradiated with short wave UV light accumulated the
      major rice phytoalexin, flavanone sakuranetin. The extracts from these leaves
      catalyzed the methylation of the hydroxyl group at position 7 of naringenin to
      yield sakuranetin, with S-adenosyl-L-methionine as the methyl donor. Activity of
      the naringenin 7-O-methyltransferase was not found in healthy rice leaves but
      increased upon irradiation with UV light in parallel with increase in
      sakuranetin. The autoradiogram of the enzymatic product on 2D-TLC was found to be
      sakuranetin. The enzyme did not methylate sakuranetin, but methylated other
      flavanones, but not isoflavanones.

PMID- 8651914
TI  - POU transcription factors differentially regulate the D1A dopamine receptor gene
      in cultured cells.
AB  - Transcription is regulated by complex interactions between cis-elements and
      transcription factors. In this study, we found that members of the POU
      transcription factor family differentially regulate a cis-element of the human
      D1A dopamine receptor gene. The differences in transactivating abilities among
      POU factors are derived neither from their different binding affinities to the
      responsive element nor from their interaction with other types of transcription
      factors, suggesting the participation of coactivators. We also observed that POU
      family members, when expressed simultaneously, act competitively on this
      regulatory element. Our findings demonstrate that members of the same
      transcription factor family result in different outcomes in cultured cells. These
      observations suggest a novel model for in vivo gene regulation by different
      members of a transcription factor family through a single cis-element.

PMID- 8651915
TI  - Humanized prion protein knock-in by Cre-induced site-specific recombination in
      the mouse.
AB  - To establish humanized mice with a knock-in (gene replacement) technique, we
      constructed a targeting vector which consists of the human prion protein and the
      loxP sequences. The introduced human prion protein with the loxP system in the
      embryonic stem cells was transmitted through the mouse germ line. Transient
      expression of Cre recombinase in the fertilized eggs resulted in the prion
      protein humanized mice. The Cre-loxP-mediated gene replacement is a simple and
      efficient method which is generally applicable to make humanized animal models.

PMID- 8651916
TI  - Enhancement of helicase activity and increase of eIF-4E phosphorylation in
      ornithine decarboxylase-overproducing cells.
AB  - In mouse FM3A ornithine decarboxylase (ODC) overproducing cells (EXOD-1), the
      amount of ODC protein was approximately 100-fold that of normal cells. Since it
      is well known that the translational efficiency of ODC mRNA is very low and that
      eIF-4E is a limiting factor for the mRNA recognition and the scanning of 40 S
      ribosomal subunits, we measured the amount and phosphorylation of eIF-4E in EXOD
      1 cells. An increase in the phosphorylation of eIF-4E, its association with p220
      protein, and an enhancement of RNA helicase activity were observed in the cells.
      These results support the hypothesis that phosphorylation of eIF-4E enhances RNA
      helicase activity through eIF-4F (4A, 4E, and p220) complex formation.

PMID- 8651917
TI  - Involvement of protein kinase C in hypoxia-induced desensitization of the beta
      adrenergic system in human endothelial cells.
AB  - In order to better understand the mechanisms whereby oxygen deficiency promotes
      blunting of the endothelial beta-adrenergic receptor (beta-AR) system we examined
      the effects of hypoxia on beta-AR, adenylate cyclase (AC) activity and
      phosphoinositide turnover in cultures of human pulmonary artery and umbilical
      vein endothelial cells. 1 hr of hypobaric hypoxia (290 mm Hg) increased basal
      levels of inositol mono-, bis-, and tris-phosphate to those following histamine
      stimulation under normoxia. Basal and isoproterenol-stimulated AC activities were
      lowered after 1 hr of hypoxia. beta-AR density was decreased after 2-3 hrs of
      hypoxia and after treatment of EC with histamine, platelet activating factor or
      phorbol myristate acetate (PMA). In protein-kinase C (PK-C)-downregulated EC,
      neither hypoxia nor PMA influenced beta-AR density or AC activity. Hypoxia
      induced desensitization of beta-AR signal transduction in EC may involve hypoxia
      stimulated phosphoinositide turnover and subsequent PK-C activation.

PMID- 8651918
TI  - In vivo effect of prednisolone on release of leukotriene B4 from neutrophils from
      asthmatic patients.
AB  - We examined the release of leukotriene B4 from calcium ionophore A23187
      stimulated neutrophils from asthmatic patients treated with or without
      intravenous prednisolone during an asthmatic attack. The mean level of LTB4 in
      the supernatant of stimulated neutrophils from patients treated with intravenous
      prednisolone was significantly lower than that in the supernatant of stimulated
      neutrophils from those without prednisolone treatment. Preincubation with
      prednisolone caused a dose-dependent inhibition of LTB4 release from calcium
      ionophore A23187-stimulated neutrophils. These findings suggest that intravenous
      prednisolone inhibits the release of LTB4 from neutrophils in vivo.

PMID- 8651919
TI  - Studies on cooperative binding of an extended distamycin A analogue in the minor
      groove of DNA by NMR spectroscopy.
AB  - An analogue of the DNA minor groove binding antibiotic distamycin A, P4+, was
      found to bind in a 2:1 cooperative manner into the narrow groove of
      oligodeoxybibonucleotide d(CGTATATACG)2 by 1D-NMR titration. The resulting 2:1
      ligand-DNA complex was characterized by 2D NMR experiments including NOESY, COSY,
      and TOCSY. Two molecules are oriented side by side opposite to each other; each
      has the N terminus to C terminus direction parallel to the 5' to 3' direction of
      its adjacent DNA strand. This study corroborates our previous CD and ethidium
      fluorometry results and provides new support for the generality of the
      antiparallel side by side binding motif first observed with distamycin A.

PMID- 8651920
TI  - The effect of hepatitis B virus X gene expression on response to growth
      inhibition by transforming growth factor-beta 1.
AB  - Hepatitis B virus X protein (HBx protein), which seems to be involved in
      hepatocarcinogenesis, was studied for its effect on cell growth regulation. We
      examined the response to growth inhibition of transforming growth factor beta 1
      (TGF-beta 1) in HBx gene-introduced cells. HBx gene in pRc/CMV was transfected to
      mink lung epithelial cells (Mv1Lu cells) and a stable transformant was obtained.
      The inhibition rates of [3H] thymidine incorporation by addition of TGF-beta 1
      (0.08 ng/ml) to parent cells and pRc/CMV-transfected cells were 34% and 26%,
      respectively. However, the inhibition rates in the HBx gene-transfected cells
      were 3-8%. The amount of TGF-beta type II receptor on the surface of HBx gene
      transfected cells was about half of that on the parent or pRc/CMV-transfected
      cells. Our results indicated that expression of HBx gene reduces the response to
      growth inhibition by TGF-beta 1.

PMID- 8651921
TI  - Cloning and sequencing of the gene for Na+/H+ antiporter of Vibrio
      parahaemolyticus.
AB  - A gene encoding an Na+/H+ antiporter was cloned from vibrio parahaemolyticus into
      the plasmid pBR322 and expressed in Escherichia coli cells. The gene enabled
      mutant E. coli cells to grow in the presence of 0.2 M NaCl (or 10 mM LiCl). These
      cells were originally unable to grow under such conditions because of the lack of
      major Na+(Li+)/H+ antiporters. We detected Na+/H+ antiporter activity due to the
      gene in membrane vesicles. The gene was sequenced and the deduced amino acid
      sequence was found to be 72% identical to the NhaB Na+/H+ antiporter of E. coli.

PMID- 8651922
TI  - Nitric oxide inhibits ATP-dependent Ca2+ uptake into platelet membrane vesicles.
AB  - The reduction by nitric oxide donors of Ca2+ mobilization in stimulated platelets
      lead us to investigate the direct effect of authentic NO on ATP-dependent Ca2+
      uptake into platelet membrane vesicles. The effects of NO were compared to those
      of thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone, two specific
      inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPases. All three compounds
      modulated the initial rate of ATP-dependent Ca2+ uptake. NO effects on the
      initial rate of active Ca2+ uptake were biphasic, with an inhibition above 10
      nmol/L and a stimulation below this concentration. These effects could not be
      attributed to cGMP, its usual effector molecule, or to nitrite ions, its
      metabolic product. NO inhibitory effects were decreased after a five min
      incubation, indicating that they were due to a short-lived compound and
      reversible. These results suggest that NO is functionally coupled to SERCA pumps
      of the dense tubular system through a cGMP-independent mechanism.

PMID- 8651923
TI  - Spontaneous calcium-independent nitric oxide synthase activity in porcine ciliary
      processes.
AB  - In the cornea, iris, retina, and ciliary processes of porcine eyes the nitric
      oxide synthase (NOS) activity was assayed by measuring the transformation of L-[U
      14C]-arginine into L-[U-14C]-citrulline: (1) in the absence or presence of the
      calcium-chelator, ethylene glycol tetra acetic acid (EGTA), and (2) in the
      presence of EGTA and the false precursor of L-arginine, NG-nitro-L-arginine
      methyl ester (L-NAME). In the retina and the iris a high calcium-dependent NOS
      activity was present, while in the cornea the activity was relatively low. In
      these three tissues no significant calcium-independent NOS activity was detected.
      In contrast, a marked calcium-independent NOS activity, but no calcium-dependent
      NOS activity, was found in the ciliary processes. The presence of a spontaneous
      calcium-independent NOS activity in the ciliary processes suggests that nitric
      oxide (NO) production is highly regulated in this tissue.

PMID- 8651924
TI  - Peroxisome proliferators activate cytochrome P450 genes in an alkane-assimilating
      yeast, Candida maltosa.
AB  - Candida maltosa can assimilate n-alkane as a sole carbon source and cytochromes
      P450ALK (P450ALK) are critical for the first oxidation step. Four major P450ALKs
      that are encoded by genes ALK1, ALK2, ALK3 and ALK5 are induced by n-alkane and
      repressed by glucose at the transcriptional level. In the present work, we found
      that all these four genes but ALK5 are transcriptionally activated in response to
      a peroxisome proliferator, clofibrate. This is the first report on the peroxisome
      proliferator responsive gene expression in lower eucaryotes.

PMID- 8651925
TI  - Combined detection of CD44 isoforms by exon-specific RT-PCR and
      immunohistochemistry in primary human brain tumors and brain metastases.
AB  - Expression of CD44 has been implicated in tumor growth and metastasis. Here we
      demonstrate CD44 expression in primary human brain tumors (n = 44) and brain
      metastases (n = 7) by RT-PCR and immunohistochemistry. Standard CD44 was found to
      be expressed by the majority of primary brain tumors and brain metastases. For
      the first time to our knowledge, CD44 expression is demonstrated for acoustic
      neurinomas and pituitary adenomas. Exon-specific analysis by RT-PCR and indirect
      immunofluorescence revealed expression of alternatively spliced CD44 isoforms in
      the group of brain metastases only. However, in one glioblastoma multiforme,
      expression of CD44v5 and CD44v6 was found immunohistochemically. This tumor took
      an unusual clinical course giving rise to multiple intrahepatic and lymph node
      metastases. Quantitatively different expression of standard CD44 in gliomas
      versus meningiomas is reported (p < 0.01).

PMID- 8651926
TI  - The polyether bistratene A activates protein kinase C-delta and induces growth
      arrest in HL60 cells.
AB  - Bistratene A (BisA) induced growth arrest in G2/M in HL60 cells. In addition,
      BisA-treated cells (50 nM for 48 h) became adherent and expressed the adhesion
      molecule CD11c, but did not express the monocyte enzyme alpha-napthyl acetate
      esterase or phagocytose complement coated yeasts. BisA activated protein kinase C
      (PKC)-delta and induced translocation of PKC-delta to the nucleus. This suggests
      that activation of PKC-delta can induce growth arrest and cell adhesion, but is
      insufficient to mediate full differentiation of HL60 cells. BisA has potential as
      a new probe for determining the function of PKC isoenzymes, specifically PKC
      delta.

PMID- 8651927
TI  - Activation of calcium sparks by angiotensin II in vascular myocytes.
AB  - Contraction in smooth muscle is triggered by an increase in cytoplasmic free
      calcium ([Ca2+]i) which depends on both Ca2+ influx through L-type Ca2+ channels
      and Ca2+ release from the sarcoplasmic reticulum (SR). Two mechanisms have been
      shown to be involved in SR Ca2+ release, one is stimulated by Ca2+ and involved
      ryanodine-sensitive Ca2+-release channels; the other is stimulated by an increase
      in inositol 1,4,5-trisphosphate (InsP3) generation induced by various mediators
      and involved InsP3-sensitive Ca2+ release channels. Here, we examined the effects
      of angiotensin II on [Ca2+]i in single rat portal vein myocytes using both the
      whole cell patch-clamp method and a laser scanning confocal microscope.
      Elementary Ca2+ release events (Ca2+ sparks) were obtained spontaneously or in
      response to L-type Ca2+ channel current activation, and resulted from activation
      of ryanodine-sensitive Ca2+-release channels in the SR. We show that angiotensin
      AT1 receptors stimulate Ca2+ sparks through activation of L-type Ca2+ channels
      without involving InsP3-induced Ca2+ release. This novel transduction pathway may
      be a common mechanism for vasoconstrictors which do not stimulate generation of
      chemical second messengers.

PMID- 8651928
TI  - Molecular cloning of human hyaluronan synthase.
AB  - We report here the cDNA sequence of human hyaluronan synthase. The cDNA clone was
      isolated from a human fetal brain cDNA library by screening with a DNA probe
      generated from the coding sequence of murine hyaluronan synthase. It contains a
      2107 bp cDNA insert which is composed of a 1629 bp open reading frame and a short
      segment of the 3'-untranslated region. Comparative analysis of the predicted
      coding region with the murine hyaluronan synthase sequence indicates 84.4% and
      96.0% identity in nucleotide sequence and amino acid sequences, respectively.
      Northern analysis indicated that the gene was ubiquitously expressed in various
      human tissues.

PMID- 8651929
TI  - Cloning of the human homologue of the TGF beta-stimulated clone 22 gene.
AB  - We have isolated the human homologue if the TGF beta-stimulated clone 22 gene
      from a human embryo cDNA library. This gene maps to the q14 region of chromosome
      13. Its deduced amino acid sequence is almost 99% identical to that of mouse or
      rat proteins and includes a putative leucine zipper motif. An abundant major
      transcript of 1.8 kb and in some instances an additional 5 kb transcript were
      detected by Northern blotting of several human tissues. The TSC-22 protein has
      been shown to be well conserved across evolution as evidenced by the existence of
      a Drosophila homologue. These observations prompt discussion on the strong
      conservation of TSC-22 during evolution but also on its general function as a
      primary response gene expressed either when stimulated by several different
      factors during early human development, or in the adult in response to inducing
      differentiation signals.

PMID- 8651930
TI  - Folding-dependent in vitro protein splicing of the Saccharomyces cerevisiae VMA1
      protozyme.
AB  - VMA1 translational product undergoes excision of a 50-kDa intervening segment
      (VDE: VMA1-derived endonuclease) and religation of the flanking regions to create
      a 69-kDa catalytic subunit of vacuolar membrane H+-ATPase. VDEs conjugated with
      polypeptides at both N- and C-terminal ends were expressed in Escherichia coli
      and examined for their ability to catalyze self-splicing. Processed VDE was found
      in soluble pools, while unspliced precursors accumulated in insoluble pools,
      forming inclusion bodies. We demonstrate in vitro protein splicing by refolding
      of the denatured precursor molecules. The processing reaction efficiently occurs
      with the purified precursor peptide. VDE bracketed by only 6 proximal and 4
      distal amino acids is autocatalytically processed.

PMID- 8651931
TI  - Reduced cell surface expression of a mutated dipeptidyl peptidase IV (DPP
      IV/CD26) correlates with the generation of a beta strand in its C-terminal
      domain.
AB  - Dipeptidyl peptidase IV (DPP IV/CD26) belongs to a non-classical subfamily of
      serine-proteases. Sequence comparisons have identified Asp599, Ser624, Asp657,
      Asp702, and His734 as highly conserved residues of mouse DPP IV. We previously
      reported the identification of Ser624, Asp702 and His734 as the catalytic triad
      of mouse DPP IV (David, F., Bernard, A. M., Pierres, M., and Marguet, D. (1993) J
      Biol. Chem. 268, 17247-17252). Using site-directed mutagenesis, we have shown
      here that substitution of Asp599 for Ala (D599A) specifically decreases the cell
      surface expression of DPP IV in stably transfected mouse fibroblasts. The D599A
      mutant remained as a high mannose immature glycoprotein and was rapidly degraded.
      This retention/degradation process correlates with the generation of a beta
      strand in the C-terminal region of DPP IV as shown by three dimensional computer
      modeling. Our results suggest that conserved residue Asp599 is important for the
      proper folding, glycosylation and transport of mouse DPP IV.

PMID- 8651932
TI  - The expression of and insulin binding to cellular thyroid hormone binding
      protein, but not insulin degrading enzyme, is increased during 3T3-L1 adipocytes
      differentiation.
AB  - Specific insulin binding to several proteins (cytosolic insulin binding proteins;
      CIBPs) in the isolated cytoplasm of numerous cell types has been demonstrated.
      CIBPs include insulin degrading enzyme (IDE), CIBP p55 (identified as cellular
      thyroid hormone binding protein (CTHBP), which is also known as protein disulfide
      isomerase, or glutathione insulin transhydrogenase). To assess the possible role
      of CIBP p55/CTHBP in insulin action, we compared 125I-insulin binding to CIBP in
      cytosol isolated from 3T3-L1 cells at various time points during differentiation
      of the adipocytes. Insulin did not bind to CTHBP in fibroblasts, but the labeling
      was markedly increased during adipocyte differentiation. In contrast, insulin
      binding to IDE did not change during differentiation. Protein expression level of
      CTHBP in the cytosol fraction increased gradually during the differentiation of
      adipocytes, whereas that of IDE did not change throughout the period. These data
      indicate that CTHBP, but not IDE, was up-regulated during differentiation of the
      adipocytes, suggesting that CIBP p55/CTHBP may play a role in regulating some
      insulin action, especially the counter regulation between insulin and other
      hormones during adipocyte differentiation.

PMID- 8651933
TI  - Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse
      colonic mucosa.
AB  - The peroxisome proliferator-activated receptor (PPAR), a member of the steroid
      nuclear receptor superfamily, has been shown to be activated by various compounds
      such as fibrates, thiazolidinediones, prostaglandins, and fatty acids. Here we
      demonstrate expression of PPAR in mouse colonic and small intestinal mucosa by
      Western blot analysis and immunohistochemistry, indicating a higher expression
      level in the differentiated colonic epithelial cells facing the intestinal lumen.
      Quantification of PPAR mRNA by ribonuclease protection assay revealed relatively
      high expression of PPAR gamma and Nuc1 in the colon as compared to the small
      intestine. In contrast, PPAR alpha expression was higher in the small intestine
      as compared to the colon. These results demonstrate the presence of PPAR in the
      intestinal mucosa; however, the physiological roles of the various isoforms in
      the intestine remain to be established.

PMID- 8651934
TI  - Characterization of the Duffy gene promoter: evidence for tissue-specific
      abolishment of expression in Fy(a-b-) of black individuals.
AB  - We have previously identified a novel first exon of Duffy gene and two inverse
      GATA motifs in the 600 bp 5' flanking region. The proximal GATA is positioned
      downstream from the start position of endothelium and upstream from that of
      erythroid. One base substitution (-365T --> C) was found in the proximal GATA
      motif from three black Fy(a-b-) individuals, and was regarded as a common
      polymorphic mutation in black Fy(a-b-) individuals. The upstream sequence of the
      novel first exon was inserted in the upstream of chloramphenicol
      acetyltransferase (CAT) gene and transfected in human erythroleukemia cell line
      (HEL) and human microvascular endothelial cells (HMvEC). The black type mutation
      abolished the CAT transcription in HEL cells but not in HMvEC. Deletion
      mutagenesis study revealed that the proximal GATA motif represent the erythroid
      regulatory core region for Duffy gene. Gel shift assay showed that the proximal
      GATA motif is the target sequence of GATA-1. These studies indicate that the
      black type mutation abolishes Duffy gene expression in erythroid but not in
      postcapillary venule endothelium, which is compatible with the Northern blot and
      immunohistochemical observation in black Fy(a-b-) individuals.

PMID- 8651935
TI  - Physiological inhibitors of protein kinase C.
AB  - Increasing numbers of proteins that have the capacity of interacting with protein
      kinase C isozymes in vitro and inhibiting their enzymatic activity in a
      noncompetitive manner have been purified. While these proteins can be
      hypothesized to be part of a tight regulatory system for protein kinase C
      enzymatic activity, critical examinations of the roles of these proteins in the
      context of whole cells have not yet been performed. Interesting new data suggest
      that some of the classes of protein kinase C inhibitors may have a much broader
      role of interacting with multiple types of kinases and proto-oncogene products.
      cDNAs encoding a number of these inhibitor proteins have been isolated, which
      will allow the design and implementation of experiments on their cell biology and
      help address their function outside of the context of their operational
      definitions.

PMID- 8651936
TI  - Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic
      inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II
      catalytic cycle.
AB  - The complex catalytic cycle of topoisomerase II is the target of important
      antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin,
      inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled
      cell kill is susceptible to pharmacological regulation by drugs interfering with
      other steps in the enzyme's catalytic cycle (i.e. so-called catalytic
      inhibitors). From in vitro studies, is appears that there are 2 distinct sites in
      the cycle at which a complete antagonism of the toxicity of topoisomerase II
      poisons can be obtained. The first is the inhibition of the enzyme's binding to
      its DNA substrate as seen with intercalating drugs such as chloroquine and
      aclarubicin; a second, more specific, interaction is elicited by
      bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II
      in the form of a closed bracelet surrounding the DNA at the postreligation step.
      To investigate these in vitro findings in the more complex whole cell system, we
      studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from
      human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine
      ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent
      decrease in the extractable levels of both the alpha and the beta isoforms of
      topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of
      extractable enzyme from cells. Further, when using the terpenoid clerocidin,
      which differs from conventional topoisomerase II poisons by forming a salt-and
      heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on
      formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which
      interferes early in the topoisomerase II catalytic cycle, was able to antagonize
      DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4
      different steps in the topoisomerase II cycle that can be uncoupled in the cell
      by different drug types: etoposide and clerocidin cause reversible and
      irreversible inhibition of DNA resealing, respectively, and DNA intercalating
      agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its
      DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy
      dependent inappropriate binding of topoisomerase II to DNA after the resealing
      step. This knowledge may enable the design of rational combinations of
      topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of
      anticancer therapy.

PMID- 8651937
TI  - A novel vitamin D analog with two double bonds in its side chain. A potent
      inducer of osteoblastic cell differentiation.
AB  - EB 1089 (1 alpha,25-dihydroxy-22,24-diene-24,26,27-trihomovitamin D3) is a novel,
      synthetic analog of calcitriol, characterized by two extra double bonds in its
      side chain. It is less potent than calcitriol in its calcemic action, but is an
      order of magnitude more potent in its antiproliferative action. The aim of this
      study was to determine the ability of EB 1089 to induce the well-known biological
      effects of calcitriol in MG-63 human osteosarcoma cells (i.e. by inhibiting cell
      proliferation and by induction of differentiation). Both calcitriol and EB 1089
      significantly decreased cell growth after 2 days in culture. At 5 days, however,
      Eb 1089 was more potent than the natural hormone in inhibiting the proliferation
      of MG-63 cells. Potent effects of EB 1089 on cell differentiation were also seen
      in the stimulation of alkaline phosphatase activity, cellular vitamin D receptor
      mRNA levels, and medium osteocalcin synthesis. EB 1089 was clearly more effective
      than calcitriol in stimulating alkaline phosphatase activity and osteocalcin
      synthesis. In gel shift assays, the binding of vitamin D receptor to the
      composite AP-1 plus vitamin-D responsive promoter region of the human osteocalcin
      gene after EB 1089 treatment was stronger and longer-lasting than after
      calcitriol treatment.

PMID- 8651938
TI  - Effect of metformin on SGLT1, GLUT2, and GLUT5 hexose transporter gene expression
      in small intestine from rats.
AB  - The effect of the antihyperglycaemic agent metformin was studied on gene
      expression of the energy-dependent sodium-hexose cotransporter (SGLT1) and the
      facilitative hexose transporters GLUT2 and GLUT5 in rat intestine. Metformin
      treatment (125 mg/kg body wt. twice daily for a period of 3 days) significantly
      increased SGLT1 gene expression in duodenum and jejunum. GLUT5 gene expression
      was increased by metformin treatment only in the jejunum. Gene expression of
      GLUT2 in the intestine was not significantly affected by metformin treatment.
      This increase in transporter gene expression offers the potential for increases
      in hexose uptake at the brush border membrane, and may compensate for other
      effects of the drug that have been suggested to decrease glucose uptake by SGLT1,
      as well as for metformin stimulation of glucose utilization by the intestinal
      mucosa.

PMID- 8651940
TI  - Griseofulvin: a novel interaction with bovine brain tubulin.
AB  - Griseofulvin is an anti-fungal drug whose mechanism of action is directed against
      microtubules. Although it inhibits the assembly of mammalian brain tubulin, its
      binding to tubulin has not been directly measured successfully. We have examined
      the interaction of griseofulvin with tubulin fluorometrically by measuring the
      quenching of tubulin tryptophan fluorescence by griseofulvin. From Scatchard
      analysis, we found that griseofulvin bound to tubulin at one class of binding
      site with an affinity constant of 1.2 +/- 0.19 x 10(4) M(-1), and the binding was
      largely reversible. Griseofulvin caused a major change in the conformation of
      tubulin in that it increased the sulfhydryl titer of tubulin approximately 2
      fold. The drug affected both the alpha and beta subunits of tubulin equally.
      Interestingly, griseofulvin did not increase the sulfhydryl titer of the tubulin
      colchicine complex although the binding site of griseofulvin was distinctly
      different from that of colchicine. The change of conformation of tubulin upon
      interaction with griseofulvin did not affect the exposure of hydrophobic areas on
      tubulin as shown by binding of bis-5,5'-[8(N-phenyl)aminonapthalene-1-sulfonic
      acid] (BisANS). Even in combination with colchicine, griseofulvin had very little
      effect on BisANS binding to tubulin. Thus, griseofulvin appears to interact with
      tubulin in a manner that is very different from that of many other tubulin
      ligands.

PMID- 8651939
TI  - Effects of P2-purinoceptor antagonists on degradation of adenine nucleotides by
      ecto-nucleotidases in folliculated oocytes of Xenopus laevis.
AB  - The aim of the present study was to examine the effects of a number of P2
      purinoceptor antagonists on degradation of adenine nucleotides by Xenopus laevis
      oocyte ecto-nucleotidase. Folliculated oocytes readily metabolize all three
      naturally-occurring nucleotides, the order of preferential substrates being ATP
      >ADP > AMP. The degradation of ATP and ADP was decreased significantly in the
      presence of several P2X- and P2Y-purinoceptor antagonists, including suramin,
      PPADS, Cibacron blue, Coomassie Brilliant blue, Evans blue, Trypan blue, Congo
      red, and PIT (each compound was used at 100 microM). All these compounds
      inhibited the degradation of ATP by up to 60%, whereas the hydrolysis of ADP was
      inhibited by Congo red and PIT by 75-80%. In addition, DIDS (100 microM) and TNP
      ATP (100 microM) selectively inhibited the breakdown of ATP, and sodium azide (10
      mM) selectively inhibited the breakdown of ADP. The enzymatic breakdown of either
      ATP or ADP was unaffected by 8-pSPT (100 microM), an antagonist of P1
      purinoceptors, or by oxidized ATP (100 microM), an antagonist of P2Z
      purinoceptors. The degradation of AMP was prevented completely by PIT (100
      microM) and ingibited significantly by Congo red (100 microM). In conclusion, the
      present study shows that most of currently available antagonists of P2
      purinoceptors inhibit the enzymatic breakdown of extracellular ATP and ADP. The
      inhibitory effect on ecto-nucleotidase activity should be taken into account when
      these antagonists are used in pharmacological experiments.

PMID- 8651941
TI  - Regulation of phosphorylation of deoxycytidine and 2',2'-difluorodeoxycytidine
      (gemcitabine); effects of cytidine 5'-triphosphate and uridine 5'-triphosphate in
      relation to chemosensitivity for 2',2'-difluorodeoxycytidine.
AB  - Deoxycytidine kinase(dCK) and deoxycytidine deaminase (dCDA) are two key enzymes
      in the activation and inactivation, respectively, of deoxycytidine and its
      antiviral and anticancer analogues. One purpose of this study was to determine
      whether or not the deoxycytidine-converting activity of both enzymes would
      correlate with growth inhibition by 2',2'-difluorodeoxycytidine (dFdC), a
      deoxycytidine analogue with established antitumour activity in solid tumours.
      Another aim of this work was to determine the effects of normal nucleotides on
      dCK. dCK and dCDA activities were measured with both deoxycytidine and dFdC as
      substrates in 5 solid tumour cell lines, but no correlation with cellular
      sensitivity to dFdC was found with either substrate. The normal dCK activities
      with deoxycytidine as substrate varied between 0.8 and 13 nmol/hr/10(6) cells.
      The activities determined with dFdC as substrate were remarkably similar in all 5
      cell lines (1.1-1.6 nmol/hr/10(6) cells). dCDA activities varied considerably
      with both substrates (20-30 fold). Because dFdC markedly affected intracellular
      concentrations of cytidine 5'-triphosphate (CTP) and uridine 5'-triphosphate
      (UTP), we studied their effect on deoxycytidine-and dFdC-phosphorylating
      activities in 3 cell lines (i.e., A2780, WiDr and C26-10) with similar dCK
      activity but major differences in dFdC sensitivity, 1 mM CTP inhibited
      deoxycytidine phosphorylation (at 230 muM) by 20-30% in A2780 and C26-10 cells,
      but increased that of WiDr cells by approximately 70%. CTP did not++ affect dFdC
      phosphorylation (at 230 muM) in A2780 cells, but did increase it by 40% in WiDr
      cells. At 1 and 10 muM of deoxycytidine the effects of CTP on dCK activity in
      A2780, C26-10 and WiDr cells were less pronounced. 1mM UTP enhanced deoxycytidine
      phosphorylation at 230 muM in WiDr cells by approximately 40%, whereas dFdC
      phosphorylation was increased 40% by UTP in C26-10 cells but decreased by 70-80%
      in WiDr cells. UTP caused a more pronounced increase in dCK activity at 1 and 10
      muM deoxycytidine in C26-10 cells, but provoked a higher inhibition in A2780 and
      WiDr Cells at 10 muM. Because of these complex results, dCK kinetics were studied
      in greater detail. Biphasic kinetics for deoxycytidine were observed in all 3
      cell lines, with Km values of 23.2 and 0.4 muM for A2780 cells, 15.9 and 1.5 muM
      for C26-10 cells, and 27.2 and 0.9 muM for WiDr cells. In all 3 cell lines,
      adenosine 5'-triphosphate (ATP) was the optimal phosphate donor, as compared to
      CTP and UTP. In conclusion, the efficiency of dCK (Vmax/Km ratio) seems to
      correlate with accumulation of dFdCTP, the active metabolite of dFdC, and with
      cellular sensitivity. UTP and CTP, which are seriously affected in cells exposed
      to dFdC, display varying effects in these solid tumour cell lines. Both
      activation and inhibition have been observed; the physiologically low CTP pools
      and the relatively minor effect on dCK in A2780 cells seem to favour dFdC
      phosphorylation in these cells, which are the most sensitive.

PMID- 8651942
TI  - Reactivity of lipophilic diSchiff-Base coordinated copper in rat hepatocytes.
AB  - The membrane permeability and intracellular fate of ([N,N'-bis(2 pyridyl-phenyl
      methylene)-1,4-butanediamine](N,N ',N",N"')-copper(II))-diperchlorate
      (CuPuPhePy), a copper-diSchiff-base complex of superoxide dismutase(SOD)-mimetic
      activity surviving biochelation, were examined using rat hepatocytes.
      Lipophilicity was quantified by determining the octanol/water partition
      coefficients (K(p)) employing PBS as the aqueous phase. K(p)(octanol/water) was
      close to 1 (0.7 +/- 0.31) for Cu-PuPhePy. The complex associates with
      phosphatidylcholine liposomes, as deduced from ultracentrifugation and gel
      filtration experiments. The ability of the complex to permeate cellular membranes
      was proven by correlating copper release and viability of rat hepatocytes
      preincubated with CuPuPhePy and treated with digitonin and diethylmaleate (DEM),
      respectively. The toxicity and reactivity of CuPuPhePy (LD (50) approximately 10
      muM for rat hepatocytes under the given conditions) were higher than those of
      CuSO (4)(LD(50) approximately 16 mu M) and CuZn-SOD (no toxicity in the tested
      range of concentration). Unlike CuSO(4) and CuZn-SOD, the toxicity and reactivity
      of the diSchiff-base complex were increased (LD(50) approximately 5 muM) when the
      concentration of intracellular glutathione was reduced to 16% of the initial
      content, by preincubating the cells with DEM. The toxicity of Cu-PuPhePy
      paralleled lipid peroxidation. This phenomenon was strongly enhanced when Cu
      PuPhePy and cumene hydroperoxide (CumOOH) were simultaneously allowed to react
      with rat hepatocytes. This effect was intensified following preincubation with
      DEM. A decline in Cu(II)-EPR signals was indicative of the reduction of CuPuPhePy
      by GSH and liver extract, respectively. The concomitant formation of the Cu(I)
      GSH complex during this reduction was monitored by the formation of luminescent
      Cu(I)-thiolate chromophores.

PMID- 8651943
TI  - Growth arrest and non-apoptotic cell death associated with the suppression of c
      myc expression in MCF-7 breast tumor cells following acute exposure to
      doxorubicin.
AB  - In the MCF-7 human breast [correction of beast] adenocarcinoma cell line, acute
      exposure to 1 muM doxorubicin inhibited cell proliferation by approximately 75%.
      Analysis of cell cycle distribution indicated that within 24 hr, the G(2)/M
      fraction increased more than 3-fold and the S-phase population declined by >50%.
      In addition to growth arrest, there was an approximately 40% reduction in the
      viable cell population after 72 hr. Gel electrophoretic resolution of low
      molecular weight DNA immediately after exposure of cells to doxorubicin failed to
      demonstrate "laddered" oligonucleosomal profiles associated with apoptosis. The
      absence of intracellular DNA fragments or release of fragmented DNA into the
      incubation medium was confirmed by spectrofluorophotometry over a 72 hr interval
      following exposure of cells to 1 muM doxorubicin. In addition, there was no
      evidence of the morphological features associated with apoptosis during this
      period. Acute exposure to 1 muM doxorubicin also produced a transient increase in
      c-myc message expression (within the first hour) followed by a decline to 70% of
      control levels within 2-4 hr. The reduction in c-myc mRNA levels was
      concentration dependent and corresponded closely with growth arrest (as well as
      with inhibition of DNA synthesis). These findings (as well as similar reports
      demonstrating a correspondence between reduced c-myc expression and growth
      inhibition by VM-26 and m-AMSA in MCF-7 cells) suggest that the down-regulation
      of c-myc expression may reflect perturbations in regulatory processes
      contributing to growth arrest in MCF-7 cells exposed to topoisomerase II
      inhibitors.

PMID- 8651944
TI  - Inhibition of Epstein-Barr virus replication by a novel L-nucleoside, 2'-fluoro-5
      methyl-beta-L-arabinofuranosyluracil.
AB  - A novel L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L
      FMAU), was found to be a potent and selective inhibitor of Epstein-Barr virus
      (EBV) replication. The decrease in the amount of viral production was
      concentration dependent with a 90% inhibitory concentration of approximately 5
      muM. Upon removal of the drug from treated cells, virus production resumed in 21
      days. Metabolism studies indicated that L-FMAU could be converted to its mono-,di
      and triphosphate metabolites in both EBV producing and non-producing cells than
      in EBV non-producing cells. The mechanism of selectivity of L-FMAU against EBV
      producing cells. However, the amount of L-FMAU nucleotides formed was three times
      larger in EBV producing cells than in EBV non-producing cells. The mechanism of
      selectivity of L-FMAU against EBV does not appear to be due solely to the
      preferential phosphorylation of L-FMAU in EBV producing cells. The triphosphate
      of L-FMAU could not be utilized as a substrate by EBV DNA polymerase or the human
      DNA polymerases alpha, beta, gamma, or delta. Therefore, the incorporation of L
      FMAU residues into viral DNA may not be the mechanism of antiviral activity. This
      compound appears to have a mechanism of action different from that of any other
      antiherpes virus nucleoside analogs. In addition, L-FMAU has very low
      cytotoxicity with 50% inhibition of cell growth occurring at a concentration of
      1mM. Given the potent inhibitory activity of this compound against EBV and its
      inability to be incorporated into cellular DNA, L-FMAU analogs should be explored
      as a new class of anti-EBV agents.

PMID- 8651945
TI  - Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4)
      inhibitors with either inhibition of PDE4 catalytic activity or competition for
      [3H]rolipram binding.
AB  - Phosphodiesterase 4 (PDE4) inhibitors are novel anti-inflammatory compounds.
      Unfortunately, the archetypal PDE4 inhibitor rolipram produces central nervous
      system and gastrointestinal side-effects. To exploit these agents, we need to
      identify PDE4 inhibitors that retain the anti-inflammatory activity with a
      reduced potential to elicit unwanted side-effects. PDE4 possesses both cyclic AMP
      catalytic activity that is inhibitable by rolipram and a high affinity binding
      site for rolipram. The function of this high affinity rolipram binding site is
      unclear; however, certain pharmacological effects of PDE4 inhibitors are
      associated with competition for this site. Since PDE4 inhibitors suppress both
      monocyte and neutrophil activation, the present experiments were carried out to
      establish a correlation between suppression of monocyte activation [tumor
      necrosis factor alpha (TNF alpha) formation] or suppression of neutrophil
      activation (degranulation) with inhibition of either PDE4 catalytic activity or
      [3H] rolipram binding. Suppression of TNF alpha formation demonstrated a strong
      correlation with inhibition of PDE4 catalytic activity (r=0.87; P<0.01;
      Spearman's Rho = 0.79, P<0.05), whereas there was no correlation with inhibition
      of [3H]rolipram binding(r=0.21, P>0.5; Spearman's Rho=0.16, P>0.5). Suppression
      of neutrophil degranulation was not associated with inhibition of PDE4 catalytic
      activity (r=0.25, P>0.4; Spearman's Rho=0.33, P>0.2), but was associated with
      inhibition of [3H]rolipram binding (r=0.68, P<0.05; Spearman's Rho=0.6, P=0.06).
      These results indicate that anti-inflammatory effects of PDE4 inhibitors can be
      associated with either inhibition of PDE4 catalytic activity or high affinity
      rolipram binding.

PMID- 8651946
TI  - Biphasic effect of ATP on neutrophil functions mediated by P2U and adenosine A2A
      receptors.
AB  - In agreement with previous findings, the oxidative burst induced by fMet-Leu-Phe
      (fMLP) in polymorphonuclear neutrophils was enhanced by adenosine triphosphate
      (ATP) and uridine 5'-triphosphate (UTP), although these nucleotides were inactive
      as agonists per se. However, the enhancement by ATP was rapidly reversed to an
      inhibition by prolonged incubation. Adenosine diphosphate (ADP) was always
      inhibitory. Inhibition mediated by ATP coincided with its conversion into ADP,
      adenosine monophosphate (AMP), and adenosine. In addition, the inhibitory effects
      of ATP and ADP on the oxidative burst were virtually abolished by 9-chloro-2-(2
      furanyl)-5,6-dihydro-[1,2,4]-triazolo[1,5] quinazolin-5-imine
      monomethanesulfonate (CGS 15943), a nonselective adenosine receptor antagonist,
      whereas the priming effect of ATP was antagonized by adenosine. Both ATP and UTP
      showed a similar potency in activating elastase release, intracellular inositol
      (1,4,5)-triphosphate (IP3) formation and an increase in cytosolic calcium.
      Neither ATP nor UTP affected the initial rise in cytosolic calcium induced by
      fMLP, but did enhance the secondary calcium increase. When added simultaneously
      with fMLP, ADP and adenosine abolished this second calcium peak without
      influencing the first. These results indicate that purine and pyrimidine
      nucleotides acting on P2U-like receptors, which are coupled to the IP3 pathway,
      can increase calcium, release elastase, and enhance the oxidative burst induced
      by chemo-kines. Adenosine formed by hydrolysis from ATP and ADP, by contrast,
      reduces the oxidative bursts and the influx of extracellular calcium induced by
      fMLP.

PMID- 8651947
TI  - Delta-9-tetrahydrocannabinol: an inhibitor of STAT1 alpha protein tyrosine
      phosphorylation.
AB  - Tyrosine-phosphorylated signal transducer and activator of transcription 1 alpha
      (STAT1 alpha) is a 91-kDa protein responsible for interferon-gamma (IFN-gamma)
      dependent transcription. The present study demonstrates that activation by IFN
      gamma of murine macrophages resulted in tyrosine phosphorylation of STAT1 alpha
      identified by immunoprecipitation. The tyrosine phosphorylation of STAT1 alpha
      was found highly sensitive to treatment by delta-9 tetrahydrocannabinol (THC), a
      major marijuana component. Subsequently, the isoform formation of p91 due to
      tyrosine phosphorylation was reduced in THC-treated macrophages. Although
      inhibition by THC of the tyrosine phosphorylation of STAT1 alpha induced by IFN
      gamma was in a THC concentration-related manner, the tyrosine phosphorylation of
      other proteins induced by lipopolysaccharide/IFN-gamma treatment of macrophages
      appeared insensitive to THC treatment. Our data suggest that blockade by THC of
      tyrosine phosphorylation of STAT1 alpha may be an important mechanism involved in
      the broad immunosuppressive effects of THC.

PMID- 8651948
TI  - Identification of efflux systems for large anions and anionic conjugates as the
      mediators of methotrexate efflux in L1210 Cells.
AB  - Two ATP-dependent efflux systems for methotrexate have been identified in inside
      out vesicles from an L1210 mouse cell variant with a defective influx carrier for
      methotrexate. Transport at 40 muM [3H]methotrexate was separated by inhibitors
      into two components comprising 62 and 38% of total transport activity. The
      predominant route was inhibited by low concentrations of indoprofen (Ki=2.5 muM,
      4-biphenylacetic acid (Ki=5.3 muM), and flurbiprofen (Ki=5.2 muM, whereas the
      second component showed a high sensitivity to the glutathione conjugates of
      bromosulfophthalein (Ki=0.08 muM), ethacrynic acid (Ki=0.52 muM, and 1-chloro-2,4
      dinitrobenzene (Ki=0.77 muM). Bilirubin ditaurate was a potent inhibitor of both
      transport components (Ki=1.5 and 0.17 muM, respectively). Separation of transport
      activities without interference from the other route was achieved by adding an
      excess (100 muM) of either the glutathione conjugate of ethacrynic acid or
      biphenylacetic acid. Double-reciprocal plots of transport at various substrate
      concentrations gave Km values of 170 and 250 muM for methotrexate transport via
      the anion-sensitive and conjugate-sensitive routes, respectively. A comparison of
      inhibitor specificities indicated that the anion-sensitive transport activity in
      vesicles represents efflux system II for methotrexate in intact cells and is the
      same system identified previously in vesicles as an anion/anion conjugate pump.
      The conjugate-sensitive activity corresponds to efflux system I for methotrexate
      in intact cells and is the same system identified in vesicles as the high
      affinity glutathione conjugate pump.

PMID- 8651949
TI  - The isomers of thioctic acid alter C-deoxyglucose incorporation in rat basal
      ganglia.
AB  - Nigral cell death in Parkinson's disease is associated with decreased reduced
      glutathione (GSH) levels, impaired complex I activity and inhibition of alpha
      ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid
      exerts antioxidant activity through a thiol-disulphide redox couple and is an
      essential cofactor for alpha-KGDH. However, it is not known whether or not
      thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's
      disease. As a global measure of altered cerebral function, the effect of R- and S
      thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in
      rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9%
      saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was
      assessed. Following acute administration, R- but not S-thioctic acid caused an
      overall increase in 14C-2DG incorporation that was significant in both substantia
      nigra zona compacta and zona reticulata. R-thioctic acid also increased the
      incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red
      nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic
      nucleus, but increased it in the red nucleus. Following repeated administration,
      R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta
      or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now
      decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that
      thioctic acid does enter the brain can alter neuronal activity in areas of the
      basal ganglia intimately associated with the motor deficits exhibited in
      Parkinson's disease.

PMID- 8651950
TI  - Modulation effects of cyclosporine on etoposide pharmacokinetics and CNS
      distribution in the rat utilizing microdialysis.
AB  - In the present study, we evaluated the pharmacokinetics of the chemotherapeutic
      agent etoposide (ET) under steady-state conditions and examined its extent of
      distribution into the CNS of conscious animals. An i.v. infusion of 15 mg/kg/hr
      was administered to nine rats. Each of the nine rats also received the potent
      multidrug resistance (MDR) modulator cyclosporine (CSA). Upon the addition of
      CSA, the i.v. treated animals demonstrated a 53% decrease in ET clearance. This
      decrease resulted in a greater than 2-fold increase in the steady-state
      concentrations of ET> The corrected brain-blood ratio (BBR (corr)) was 0.36 +/-
      0.18 prior to CSA treatment, and although CNS concentrations increased upon the
      addition of CSA, there was no increase in the BBR(corr) (0.24 +/- 0.10). The
      present study demonstrates that the increase of ET in the CNS following CSA is a
      result of a decrease in ET systemic clearance and not an inhibition of ET efflux
      from the CNS.

PMID- 8651952
TI  - [Denatured state of lysozyme in dimethyl sulfoxide].
AB  - An influence of DMSO on lysozyme structure in solution was studied by
      fluorescence and optical rotary dispersion methods. Change in the protein
      structure was shown to proceed at DMSO concentration in water greater than 60%
      and result in an increase of the protein helicity. However, this structural state
      of lysozyme is similar to that of the unstructured peptides obtained by its
      complete proteolysis and is characterized by parameters of accessibility to
      solvent and mobility of their intrinsic chromophores. The data obtained evidenced
      that long range interactions have a little influence on the maintenance of the
      residual secondary structure of lysozyme in the presence of DMSO.

PMID- 8651951
TI  - [Recombinant proteins containing oxytocin oligomeric sequences].
AB  - Expression plasmids were constructed with genes encoding the ILOX3, ILOX6, and
      ILOX9 recombinant proteins, which contain the C-terminal fragments of trimer,
      hexamer, or nonamer of oxytocinoyl-Lys. Upon expression in E. coli, all three
      genes yielded inclusion bodies containing protein products of similar length and
      heterogeneous in the C-terminal region. It is likely that in the case of the
      ilox3 gene, the obtained protein mixture includes the full-length product of
      translation with the C-terminal lysine. In the case of the ilox6 and ilox9 genes,
      the protein products are formed as the result of a site-specific proteolysis in
      the regions between the second and the fourth oxytocin units.

PMID- 8651953
TI  - [Plasma-desorption mass spectrometry of natural compounds. 1. Basic properties of
      the method and its use for analyzing proteins and peptides].
AB  - Applications of plasma desorption mass spectrometry (PD MS) to the analysis of
      natural substances are reviewed with the special emphasis on its use in peptide
      and protein chemistry (Part I). PD MS of nucleotides, carbohydrates, lipids, and
      pigments will be reviewed in Part II (see the following issue of this journal).
      The review covers the literature from 1982 to 1994.

PMID- 8651954
TI  - [Prospects for use of hapten-heterologous conjugates in immunoassay of thyroid
      hormones].
AB  - The effect of hapten heterology on the characteristics of indirect ELISA methods
      for determination of thyroxine and triiodothyronine using monoclonal antibodies
      was studied. The use of the heterologous triiodothyronine-bovine serum albumin
      conjugate in immunoassays for thyroxine improved the sensitivity of these assays
      twofold and reduced the cross-reactivity with triiodothyronine from 1 to 0.5% as
      compared to the homologous variant. By contrast, the heterology in the
      immunoassays for triiodothyronine appeared inadequate. It was shown that the
      specificity and sensitivity of hapten immunoassays can be modulated by altering
      the chemical structure of the hapten-label conjugate, which is most evident in
      experiments with monoclonal antibodies.

PMID- 8651955
TI  - [Selective amplification of evolutionally conserved expressed sequences].
AB  - An efficacious method of cloning the sequences common for two cDNAs was proposed.
      The method was used for constructing a library of expressed sequences
      evolutionarily conserved for human and hamster.

PMID- 8651956
TI  - [Structure of an oligonucleotide of bleomycin A5 from 13C-NMR data].
AB  - The localization of the covalent bond in the conjugates of bleomycin A5 and
      oligonucleotides was established by 13C NMR using the bleomycin derivative of
      uridine-5'-phosphate synthesized as a model compound. The phosphate group of the
      nucleotide was shown to form a phosphamide bond with the primary amino group of
      the spermidine moiety of bleomycin A5. The formation of the P-N bond causes the
      downfield shift of the signals of the neighboring carbon atoms of the spermidine
      fragment by 1.8 and 4.2 ppm and the splitting of the signal of the C-2 atom of
      the spermidine fragment with J 6.8 Hz due to vicinal spin-spin coupling with the
      phosphorous atom.

PMID- 8651957
TI  - [Gangliosides with 8-O-methyl-N-glycolylneuraminic acid and N-acetylgalactosamine
      from the star fish Asterias rathbuni].
AB  - The structure of gangliosides isolated from the liver of starfish Asterias
      rathbuni was established by chemical methods, mass spectrometry, and enzymic
      hydrolysis with a neuraminidase. The major ganglioside was found to be a
      disialoganglioside with two 8-O-methyl-N-glycolylneuraminic acid residues bound
      with an N-acetylgalactosamine residue: 8-O-Me-NeuGc alpha 2-3 (8-O-Me-NeuGc alpha
      2-6)GalNAc beta 1-3Gal beta 1-4Glc beta 1-1 Cer. Its lipid part contains
      unsubstituted higher fatty acids (mainly palmitic and stearic) and sphingosines
      (for the most part C20 and C22). The minor ganglioside fraction consists of two
      monosialogangliosides the carbohydrate chains of which differed only in the
      position of the terminal 8-O-methyl-N-glycolylneuraminic acid residue in the N
      acetylgalactosamine moiety: 8-O-Me-NeuGc alpha 2-3GalNAc beta 1-3Gal beta 1-4Glc
      beta 1-1 Cer and 8-O-Me-NeuGc alpha 2-6GalNAc beta 1-3Gal beta 1-4Glc beta 1-1
      Cer. The higher fatty acid composition of the minor gangliosides was determined
      too.

PMID- 8651958
TI  - [Primary structure of delta-latroinsectotoxin from venom of the Latrodectus
      mactans tredecimguttatus spider].
AB  - The structural gene of delta-latroinsectotoxin was cloned and its nucleotide
      sequence was determined. The gene contains an open reading frame of 3642 bp. The
      deduced amino acid sequence is homologous to the sequences of latrotoxins studied
      earlier.

PMID- 8651959
TI  - [Mechanism of action of the plant hormone jasmonate. 1. Jasomonate-interacting
      proteins that regulate transcription of the p. pinII potato gene].
AB  - A fragment containing the regulatory region of the p. pinII gene was isolated
      from potato DNA by polymerase chain reaction. Interactions of this DNA region
      with jasmonate determines the transcriptional activation. The isolated DNA
      fragment was cloned into the pTE2pb plasmid, which was used for preparing an
      affinity sorbent. Using this sorbent, four proteins were isolated from the total
      protein capable of desorption at physiological concentration of jasmonate. These
      proteins are likely to be subunits of two transcription repressors, whereas
      jasmonate serves as an inducer. Three sequences of the regulatory regions (boxes
      G, I, and III) are binding sites for repressors; similar sequences were found in
      various plant genes activated by jasmonate.

PMID- 8651960
TI  - [Bsp153AI and BspM39I--new isoschizomers of PvuII restriction enzyme].
AB  - New restriction endonucleases, Bsp153AI and BspM39I, were isolated from Bacillus
      species strains 153A and M39, respectively. The enzymes recognize and cleave the
      nucleotide sequence [sequence: see text] and are true isoschizomers of
      restriction endonuclease PvuII.

PMID- 8651961
TI  - [Increase in the effectiveness of site-specific cleavage of target DNA by
      tetranucleotide bleomycin derivatives using oligonucleotide-effectors].
AB  - The efficiency of site-specific interaction of target DNA with bleomycin
      derivatives of short nucleotides can be significantly increased using flanking
      effector oligonucleotides. The cleavage of a 20-mer single-stranded target DNA by
      a tetranucleotide containing a bleomycin A5 residue at the 5'-end was studied in
      the presence of effector oligonucleotides bearing phenazine residues at the 5'-
      and 3'-ends. In the presence of two effectors, the extent of the target DNA
      modification at 37 degrees C increased from 20 to 70%. Site-specific cleavage
      occurs, by up to 90%, at a single site of the target DNA. The melting temperature
      of the complementary complex formed by the bleomycin A5-modified tetranucleotide
      and target DNA in the presence of two effectors was 45 degrees C, whereas in the
      absence of the effectors, below 7 degrees C.

PMID- 8651962
TI  - [New activators for phosphoramidate synthesis of oligonucleotides].

PMID- 8651963
TI  - Slow progression of joint damage in early rheumatoid arthritis treated with
      cyclosporin A.
AB  - OBJECTIVE: To evaluate the ability of low-dose cyclosporin A (CsA) to control
      radiologic disease progression, and to assess the clinical efficacy and
      tolerability of CsA, compared with conventional disease-modifying antirheumatic
      drugs (DMARDs), in patients with early active rheumatoid arthritis (RA). METHODS:
      In this long-term, multicenter, prospective, open, blinded end point, randomized
      trial, 361 consenting patients with early (<4 years since diagnosis) active RA
      were enrolled. Of the eligible patients, 167 were treated with CsA at 3
      mg/kg/day, and 173 with DMARDs. The decision to use conventional antirheumatic
      drugs as controls was based on the fact that joint erosion could be expected to
      occur after 1 year regardless of the type of DMARD being used. The possibility of
      switching therapies in both groups was intended to keep the largest possible
      number of patients in the study. RESULTS: Blinded evaluation of hand and foot
      radiographs after 12 months of treatment showed that CsA led to a significant (P
      < 0.001) delay in the mean +/- SD progression in the eroded joint count (1.3 +/-
      3.1 versus 2.4 +/- 3.0 for the control group) and in the joint damage score (3.6
      +/- 8.9 versus 6.9 +/- 9.1 for the control group), both measured by the Larsen
      Dale method. When only the patients without erosion at baseline were considered
      (37 in the CsA-treated group and 54 in the control group), erosion appeared in
      only 10.8% of the CsA-treated patients, but in 51.8% of the controls (P =
      0.00005). Low-dose CsA was as effective as traditional DMARDs in controlling
      clinical symptoms. Maintenance on the initially prescribed treatment regimen
      ("survival on treatment") was also better at 12 months with CsA than with DMARDs
      (89.2% versus 77.5%; P = 0.002). The tolerability of CsA was acceptable.
      CONCLUSION: These 12-month results suggest that low-dose CsA decreases the rate
      of further joint damage in previously involved joints as well as the rate of new
      joint involvement in previously uninvolved joints, in patients with early RA.

PMID- 8651964
TI  - Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who
      are receiving combined therapy with methotrexate and azathioprine.
AB  - OBJECTIVE: To assess the frequency and clinical features of an acute febrile
      toxic reaction (AFTR) in patients with refractory rheumatoid arthritis (RA)
      receiving combined therapy with methotrexate (MTX) and azathioprine (AZA).
      METHODS: A cohort of 43 RA patients being treated with MTX/AZA combination
      therapy were studied. In all of them, RA had been refractory to single-therapy
      disease-modifying antirheumatic drugs. We analyzed the frequency and clinical
      features of AFTR, which consisted mainly of the development of fever,
      leukocytosis, and cutaneous leukocytoclastic vasculitis when AZA was added to the
      MTX regimen. RESULTS: Four of the 43 patients (9.3%) who had been receiving long
      term, well-tolerated treatment with MTX (mean +/- SD 375.5 +/- 159.5 days, range
      227-561 days) developed AFTR shortly (mean +/- SD 25.7 +/- 13.6 days, range 17-46
      days) after the addition of AZA to the regimen. The AFTR resolved rapidly (3 +/-
      1.4 days) after discontinuation of AZA and MTX. In 2 cases, rechallenge with AZA
      and MTX was linked to a new flare of AFTR. CONCLUSION: The knowledge of this side
      effect is particularly important because it mimics a severe infectious
      complication related to immunosuppressive therapy, and because rechallenge can
      produce severe toxicity. Most of the new combined therapies for RA do not seem to
      be more toxic than single-drug treatment. Nevertheless, clinicians should be
      aware of a possible increase in side effects due to drug interactions or some
      other unidentified mechanism.

PMID- 8651966
TI  - Failure of low-dose intravenous immunoglobulin therapy to suppress disease
      activity in patients with treatment-refractory rheumatoid arthritis.
AB  - OBJECTIVE: Treatment with high-dose (400 mg/kg/day) intravenous immunoglobulin
      (IVIg) shows benefit in many autoimmune diseases but is very expensive. Low-dose
      IVIg has also been shown to be effective in inhibiting adjuvant arthritis in the
      rat. This pilot, randomized, double-blind, placebo-controlled trial was conducted
      to assess the use of low-dose IVIg in patients with treatment-refractory
      rheumatoid arthritis (RA). METHODS: Twenty patients with active RA were
      recruited. Ten patients received IVIg and 10 received albumin. Study subjects
      were given 6 courses of either IVIg (5 mg/kg) or albumin (5 mg/kg), once every 3
      weeks. Baseline medications were continued and not changed throughout the study.
      RESULTS: There were no complications. Five patients dropped out before the 18
      week followup visit. No significant differences between treatment groups were
      noted during the 18-week trial in terms of global activity indices (patient or
      physician assessment), joint swelling, joint pain or tenderness, erythrocyte
      sedimentation rate, C-reactive protein level, or rheumatoid factor. The protocol
      was terminated prematurely because of reported contamination of IVIg by hepatitis
      C virus. None of the patients showed evidence of hepatitis C infection by
      serologic analysis or by polymerase chain reaction. CONCLUSION: Low-dose IVIg, as
      administered in this trial, does not show a therapeutic effect in patients with
      refractory RA.

PMID- 8651965
TI  - N-[4-hydroxyphenyl] retinamide in rheumatoid arthritis: a pilot study.
AB  - OBJECTIVE: To evaluate the efficacy and tolerability of N-[4 hydroxyphenyl]
      retinamide (4-HPR), a synthetic retinoid, in the treatment of rheumatoid
      arthritis (RA). METHODS: An uncontrolled, open clinical trial with synovial
      biopsy pre- and postmedication to evaluate the clinical effects of 4-HPR as well
      as its effects on metalloproteinase gene expression. RESULTS: Twelve patients
      with severe, longstanding RA were enrolled in this study. Six patients withdrew
      before study completion, 2 because of drug toxicity, 2 because of a flare of RA,
      and 2 because of intercurrent medical problems. No patient met predetermined
      Paulus criteria treatment response, and there was no improvement in the
      laboratory parameters, except for a modest decrease in C-reactive protein. No
      decrease in messenger RNA for the metalloproteinases collagenase and stromelysin
      was seen in the 2 patients in whom paired synovial biopsies were obtained.
      CONCLUSION: No beneficial clinical effect was observed with the retinoid 4-HPR in
      the treatment of severe, longstanding RA at the 300 mg/day dosage studied. The
      use of higher dosages is precluded by the observed toxicities. The effect of this
      drug in patients with early or mild disease was not studied. Although this
      particular retinoid was not effective in this pilot study, the use of other
      retinoids in RA should still be considered.

PMID- 8651967
TI  - Renal vascular damage in systemic sclerosis patients without clinical evidence of
      nephropathy.
AB  - OBJECTIVE: To evaluate the use of color-flow Doppler ultrasonography, a direct,
      noninvasive technique, for measurement of kidney blood flow in patients with
      systemic sclerosis (SSc). METHODS: Twenty-five normal volunteers and 25 SSc
      patients (median disease duration 8 years, range 2-21 years) were studied. All
      were free of clinical symptoms of renal damage. The resistance index (RI) was
      determined on main, interlobar, and cortical vessels. RESULTS: In SSc patients,
      the RI was significantly increased at every sampling site examined (P < 0.001).
      RI values were strongly correlated with disease duration (main artery r = 0.56, P
      < 0.04; interlobar artery r = 0.63, P < 0.02; cortical artery r = 0.75, P <
      0.002). Regression analysis showed no relationship between RI and creatinine
      clearance values. CONCLUSION: Color-flow Doppler ultrasonography is a sensitive
      and noninvasive technique for evaluating vascular damage of the kidney in
      patients with SSc.

PMID- 8651968
TI  - Depressive symptoms associated with scleroderma.
AB  - OBJECTIVE: To examine the prevalence and correlates of depressive symptoms among
      patients with systemic sclerosis (SSc; scleroderma). METHOD: Fifty-four
      outpatients with scleroderma were administered the Beck Depression Inventory, the
      Neuroticism-Extraversion-Openness Personality Inventory, the Health Assessment
      Questionnaire, and the Psychosocial Adjustment to Illness Scale. In addition,
      patients underwent a comprehensive clinical assessment, and pulmonary function
      tests were obtained. RESULTS: Nearly half of the patients had mild depressive
      symptoms, and an additional 17% had symptoms in the moderate-to-severe range.
      Younger patients, those with digital ulceration, and those with more self-rate
      functional impairment had more depressive symptoms, but there were few other
      relationships between depressive symptoms and either demographic or physician
      rated medical variables. In contrast, there were highly significant relationships
      between depression and aspects of personality, psychosocial adjustment to
      illness, and social support. CONCLUSION: Depressive symptoms in patients with SSc
      are more strongly related to personality, self-rated disability, and adequacy of
      emotional support than to objective medical indices of illness severity.
      Depression in scleroderma is a debilitating comorbid condition that should be
      recognized and treated in its own right.

PMID- 8651969
TI  - Childhood-onset scleroderma: is it different from adult-onset disease.
AB  - OBJECTIVE: To distinguish childhood-onset scleroderma from adult-onset disease.
      METHODS: The clinical and serologic features of 58 patients with childhood-onset
      scleroderma (11 patients with diffuse cutaneous systemic sclerosis [SSc], 16 with
      linear SSc, 14 with linear morphea, and 17 with morphea) were examined in the
      largest cohort of such patients studied to date. These parameters were compared
      with data obtained from patients with adult-onset disease. RESULTS: Childhood
      onset scleroderma resembled adult-onset disease with regard to the heterogeneity
      of clinical expression and subsets of disease, but it also differed from adult
      onset disease in a number of clinical and laboratory parameters. The predominant
      childhood-onset disease presentation was the localized form of the disease, with
      limited and diffuse SSc being less notable. There was a significant association
      of trauma with childhood-onset scleroderma (P < 0.0001), which was not noted in
      adult-onset disease. Furthermore, in contrast to adult disease, patients with
      childhood-onset disease had normal levels of parameters of vascular activation
      (von Willebrand factor, angiotensin-converting enzyme, E-selectin, and endothelin
      1), T cell activation (soluble interleukin-2 receptors), and collagen synthesis
      (carboxy-terminal type I and amino-terminal type III), a notable lack of
      anticentromere antibodies, and abnormal coagulation indices. CONCLUSION: A number
      of features distinguish childhood-onset scleroderma from adult-onset disease.

PMID- 8651970
TI  - Malignancy in systemic lupus erythematosus.
AB  - OBJECTIVE: To estimate the risk of cancer in patients with systemic lupus
      erythematosus (SLE). METHODS: Patients with SLE (n = 724) have been followed
      prospectively, for 24 years, at the University of Toronto Lupus Clinic. The
      diagnosis of cancer was confirmed by histologic or autopsy reports. Standardized
      rates of cancer and standardized incidence rates (SIR) (ratio of observed-to
      expected cancers) were used to estimate the risk for cancers. RESULTS: Twenty
      four cancers were identified in 23 SLE patients (3.2%) during 7,233 patient-years
      of followup. Compared with the Ontario population, the overall estimated risk for
      all cancers was not increased in the lupus cohort (SIR 1.08, 95% confidence
      interval 0.70-1.62). A 4.1-fold increased risk for hematologic cancers was
      observed, due mainly to an increased risk of non-Hodgkin's lymphoma. The risk for
      cancer was significantly lower in the SLE cohort compared with patients with
      rheumatoid arthritis (RA) and systemic sclerosis (SSc). CONCLUSION: SLE is
      associated with a lower risk of all cancers compared with RA and SSc, but an
      increased risk for non-Hodgkin's lymphoma compared with the general population.

PMID- 8651971
TI  - Utility of anti-Sm, anti-RNP, anti-Ro/SS-A, and anti-La/SS-B (extractable nuclear
      antigens) detected by enzyme-linked immunosorbent assay for the diagnosis of
      systemic lupus erythematosus.
AB  - OBJECTIVE: To determine the utility of anti-extractable nuclear antigen (anti
      ENA) antibodies detected by enzyme-linked immunosorbent assay as a predictor for
      the diagnosis of systemic lupus erythematosus (SLE). METHODS: Among 2,185 serum
      samples sent for testing for antinuclear antibodies (ANA) by indirect
      immunofluorescence, 259 consecutive patients with positive ANA were identified.
      Medical charts of these patients were reviewed to assess the clinical diagnosis,
      with the reviewer having no knowledge of the anti-ENA result. Clinical data were
      abstracted for all patients, and diagnoses established using American College of
      Rheumatology criteria. The utility of ENA antibodies in the diagnosis of SLE was
      determined by univariate and multivariate analysis among all patients who were
      positive for ANA, patients who were positive for ANA and for anti-double-stranded
      DNA (anti-dsDNA), and patients who were positive for ANA and negative for anti
      dsDNA. Clinical differences between SLE patients with and those without anti-ENA
      antibodies were assessed. RESULTS: Anti-ENA antibodies, especially anti-Ro/SS-A,
      showed strong predictive diagnostic value among ANA+/anti-dsDNA- patients, but
      were of no utility among ANA+/anti-dsDNA+ patients. The only clinical
      manifestations that were more common among anti-ENA+ SLE patients were pleuritis
      and the use of hydroxychloroquine. CONCLUSION: The presence of anti-ENA
      antibodies, especially anti-Ro/SS-A, is a useful predictor for the diagnosis of
      SLE, primarily among patients attending a referral rheumatology center who are
      positive for ANA and negative for anti-dsDNA. No major clinical differences were
      noted among ANA+ SLE patients with versus those without ENA.

PMID- 8651972
TI  - Pyoderma gangrenosum in association with undifferentiated seronegative
      spondylarthropathy.
AB  - The cases of 2 women with pyoderma gangrenosum (PG) and undifferentiated
      seronegative spondylarthropathy (SpA) are described. These 2 cases, together with
      the recently reported case of PG and B27-positive psoriatic spondylarthropathy,
      suggest that PG may also occur in association with forms of seronegative SpA that
      are different from primary ankylosing spondylitis (AS) and AS associated with
      inflammatory bowel disease.

PMID- 8651973
TI  - Monoclonal cryo-antifibrinogenemia.
AB  - We report on a 54-year-old female patient with arthritis and a severe cold
      induced leukocytoclastic vasculitis of the skin caused by a rare form of
      cryofibrinogenemia ("type II" cryofibrinogen). Affinity chromatography of
      cryoprecipitates from the patient's plasma revealed reversible
      cryoprecipitability of complexes composed of fibrinogen and a monoclonal
      antifibrinogen antibody (IgG3 kappa). Conventional serum and plasma
      electrophoresis did not detect the paraprotein. Control of symptoms was achieved
      by long-term plasmapheresis.

PMID- 8651974
TI  - Treatment of systemic sclerosis with topical tretinoin: report of two cases.

PMID- 8651975
TI  - More on vasodilatation, joint swelling, and nitric oxide.

PMID- 8651976
TI  - Fibroblast adhesion to articular cartilage.

PMID- 8651977
TI  - Giant cell arteritis and amyloidosis: comment on the article by Salvarani et al.

PMID- 8651979
TI  - Lack of radiographic evidence of tracheostenosis: comment on the clinical image
      from Kraus and Valencia.

PMID- 8651978
TI  - Polymyositis, lung fibrosis, and cranial neuropathy in a patient with hepatitis C
      virus infection.

PMID- 8651980
TI  - The American College of Rheumatology as a "professional" society: an oxymoron?

PMID- 8651981
TI  - A remembrance of Fred, the lowland gorilla.

PMID- 8651982
TI  - Nephritogenic autoantibodies in lupus: current concepts and continuing
      controversies.
AB  - In summary, we suggest that the following statements regarding lupus nephritis
      are best supported by the existing data. 1) Lupus nephritis is an immunologically
      complex disorder. Autoantibodies directed against multiple epitopes on chromatin,
      including but not limited to dsDNA, may contribute to nephritis. 2) The presence
      of charged residues within autoantibody heavy chain CDR regions, particularly
      CDR3, may be essential to the property of nephritogenicity. 3)
      Chromatin/antichromatin immune complexes (formed either in the circulation or in
      situ in the GBM) are likely the proximal cause of lupus nephritis. Cross-reactive
      autoantibodies or antibodies reacting directly to glomerular antigens are less
      likely to play a major pathogenic role. 4) The induction of lupus nephritis may
      relate to the propensity of chromatin or its components to bind to the GBM by
      virtue of the interactions of histones with type IV collagen and heparan-sulfated
      glycosaminoglycans. Nonetheless, as indicated above, there are numerous issues
      that remain to be addressed and clarified with respect to lupus nephritis.
      Insight into these issues is not only of theoretical interest, but may lead to
      new approaches to diagnostic testing and more specific therapies to replace
      currently use nonspecific immunosuppressive drugs, which have substantial
      toxicities.

PMID- 8651983
TI  - Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their
      unaffected siblings.
AB  - OBJECTIVE: To analyze whether patients with rheumatoid arthritis (RA) have an
      intrinsic defect in T cell proliferation and survival, possibly contributing to
      the infiltration of the synovial membrane with CD4+ T cells. METHODS: Fifteen
      patients with seropositive RA, 11 patients with psoriatic arthritis, 20 normal
      controls, and 9 affected and 13 unaffected siblings from 7 multiplex families
      with RA were analyzed for clonal proliferation. To investigate this clonal T cell
      proliferation, CD4+ T cells were purified from peripheral blood and synovial
      fluid by magnetic bead separation. T cell receptor (TCR) beta-chain sequences
      were amplified by reverse transcriptase-polymerase chain reaction, using TCR BV
      and BJ gene segment-specific primer sets. Clonally expanded T cell specificities
      were identified by size fractionation and sequencing of the amplified product.
      RESULTS: All RA patients carried clonally expanded CD4+ T cells in the peripheral
      blood compartment. Such expanded CD4+ T cell clonotypes were only infrequently
      observed both in normal individuals (P < 0.0001) and in patients with psoriatic
      arthritis (P = 0.004). Lymphoproliferation of selected CD4+ T cells was shared by
      affected and unaffected siblings from RA multiplex families (P = 0.005 and P =
      0.0003, respectively, compared with normal controls). Expanded clonotypes
      persisted for several years and contributed to the T cell infiltrate in the
      joint. Clonal T cell proliferation involved a diverse spectrum of TCR molecules.
      CONCLUSION: RA patients have an abnormality in the homeostasis of CD4+ T cells,
      characterized by the emergence of clonally proliferating populations. The
      presence of clonal outgrowth of selected CD4+ T cells specificities in unaffected
      siblings of RA patients suggests that oligoclonality of CD4+ T cells is inherited
      and is a risk factor for, rather than a result of, synovial inflammation.

PMID- 8651984
TI  - Expression and functional expansion of fibroblast growth factor receptor T cells
      in rheumatoid synovium and peripheral blood of patients with rheumatoid
      arthritis.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory disorder of the
      diarthroidial joints, characterized by fibroblast proliferation, angiogenesis,
      and perivascular CD4+ T cell infiltration. The present study examined the
      interactions between fibroblast growth factor-1 (FGF-1) and T cells. METHODS:
      Synovial tissues from patients with RA or noninflammatory arthritis were examined
      for the expression of FGF-1 and its receptor, FGFR-1, by immunohistology and
      reverse transcriptase-polymerase chain reaction. Functional assays were used to
      detect enrichment of FGF-1-responsive peripheral CD4+ T cells in RA. RESULTS: FGF
      1 is abundantly expressed by rheumatoid synovium. Enhanced expression of its
      receptor, FGFR-1, was found in perivascular CD4+ T cells. In addition, T cells
      that are activated by FGF-1 are increased in the peripheral blood of patients
      with RA, as compared with other inflammatory conditions. CONCLUSION: The
      increased frequency of peripheral T cells that respond to FGF-1 in RA is
      consistent with expansion of FGFR-1-expressing T cells in the rheumatoid
      synovium.

PMID- 8651985
TI  - Inhibition of synoviocyte collagenase gene expression by adenosine receptor
      stimulation.
AB  - OBJECTIVE: To characterize the regulation of matrix metalloproteinases (MMPs) by
      adenosine. METHODS: Cultured fibroblast-like synoviocytes (FLS) were stimulated
      with interleukin-1 (IL-1) in the presence or absence of adenosine receptor
      agonists. Immunoreactive MMPs were measured using specific enzyme-linked
      immunosorbent assays, and gene expression was assessed by Northern blot analysis.
      RESULTS: The nonselective adenosine receptor agonist 5'-N
      ethylcarboxamidoadenosine (NECA) decreased collagenase production by IL-1
      stimulated synoviocytes from 196 +/- 28 ng/ml (mean +/- SEM) to 66 +/- 9 ng/ml (P
      < 0.001). There was minimal effect on stromelysin production (decrease from 107
      +/- 16 ng/ml to 97 +/- 15 ng/ml). Selective adenosine receptor agonists
      implicated the A2b adenosine receptor in this activity, and reverse transcriptase
      polymerase chain reaction studies confirmed that FLS express this receptor.
      Northern blot analysis demonstrated that the mechanism of action was pre
      translational since NECA decreased collagenase, but not stromelysin or tissue
      inhibitor of metalloproteinases 1 (TIMP-1), messenger RNA levels. Cyclic AMP
      levels were increased by NECA, and a direct adenylate cyclase activator
      (forskolin) also suppressed collagenase gene expression. These data suggest that
      cAMP mediates the inhibitory effect of NECA on collagenase production.
      CONCLUSION: Stimulation of the A2b receptor on FLS decreases collagenase gene
      expression, with little or no effect on stromelysin and TIMP-1. The combination
      of antiinflammatory and MMP-regulating properties of adenosine or adenosine
      regulating agents suggest that treatment based on this approach might be useful
      in rheumatoid arthritis.

PMID- 8651986
TI  - Synergy between T cell receptor beta gene polymorphism and HLA-DR4 in
      susceptibility to rheumatoid arthritis.
AB  - OBJECTIVE: To investigate the etiologic significance of germline polymorphisms in
      the T cell receptor beta variable region 6S7 (TCRBV6S7) gene segment and adjacent
      loci in susceptibility to rheumatoid arthritis (RA). METHODS: Ten TCRB allelic
      polymorphisms were analyzed from 3 groups of white women: 112 with RA, 72 with
      systemic lupus erythematosus, and 70 healthy controls. All participants were also
      HLA typed. RESULTS: HLA-DR4+ RA patients showed significantly increased
      frequencies of TCRBV6S7*1, 13S5P*1 (an allelic variant of BV13S5 promoter), and
      12S4*2, compared with healthy controls. The combination of DR4 with either
      BV6S7*1, 13S5P*1, or 12S4*2 conferred greater risk for RA than HLA-DR4 alone.
      Pairwise analyses showed a high degree of linkage disequilibrium (P = 10(-5)-10(
      8)) between these 3 TCRBV loci that span 47 kilobases (kb). CONCLUSION: Our data
      suggest that a TCR gene segment in or linked to this 47-kb region may be involved
      in genetic susceptibility to RA through an interaction with HLA-DR4.

PMID- 8651987
TI  - Clinical correlations with HLA type in Japanese patients with connective tissue
      disease and anti-U1 small nuclear RNP antibodies.
AB  - OBJECTIVE: To elucidate the roles of HLA genes in the clinical presentation of
      patients with connective tissue disease and serum anti-U1 small nuclear RNP
      antibody. METHODS: HLA class I antigens and HLA class II alleles were determined
      in 43 Japanese patients with anti-U1 RNP antibody alone, by microcytotoxicity
      testing and DNA typing, respectively. Prospectively recorded clinical and
      laboratory features were analyzed in relation to HLA class I and class II types.
      RESULTS: DQB1*0303 was associated with lupus-related symptoms including fever,
      malar rash, oral ulcers, hypocomplementemia, and high-titer anti-double-stranded
      DNA antibody. Other HLA-clinical associations included DR2 with pleuritis, DR4
      with hand swelling, and DRB1*0405 with arthritis. CONCLUSION: These HLA-clinical
      associations explain, in part, the heterogeneous clinical presentation in
      patients with anti-U1 RNP antibody.

PMID- 8651988
TI  - A comparative study of HLA genes in HLA-B27 positive ankylosing spondylitis and
      HLA-B27 positive peripheral reactive arthritis.
AB  - OBJECTIVE: To determine whether HLA-B27 positive patients with ankylosing
      spondylitis (AS) and reactive arthritis (ReA) share additional HLA factors that
      confer disease susceptibility. METHODS: HLA class I antigens were typed
      serologically, and class II antigens molecularly, in samples taken from 33
      patients with AS, 30 patients with ReA, and 55 healthy HLA-B27 positive controls.
      RESULTS: There was no major difference between the HLA alleles in AS and ReA
      patients, but deviations were observed when compared with healthy controls,
      especially between the antigens that were probably encoded by genes in the non
      B27 chromosome. CONCLUSION: These results suggest that both HLA class I and class
      II genes may influence the pathogenesis of HLA-B27 positive ReA, whereas class I
      antigens seem to be the major additional genetic factors in HLA-B27 positive AS.

PMID- 8651989
TI  - Molecular detection of bacterial DNA in venereal-associated arthritis.
AB  - OBJECTIVE: To evaluate the utility of polymerase chain reaction (PCR)
      amplification in detecting DNA from venereal-associated microorganisms in the
      synovial fluid of patients with inflammatory arthritis. METHODS: Oligonucleotide
      primers were developed for nested PCR based on Chlamydia, Ureaplasma, and
      Neisseria DNA sequences. PCR products were detected by gel electrophoresis and
      dot-blot hybridization. Primers specific for the target bacterial DNA were used
      to search for bacterial DNA in 61 synovial fluid specimens from patients with
      inflammatory arthritis, including several clinically associated with venereal
      infection. RESULTS: Five of the 61 synovial fluid specimens were positive for
      Neisseria gonorrhoeae DNA. Four of the 5 patients had clinical diagnoses of
      gonococcal arthritis; the other patient had an unexplained monarthritis. One
      specimen from a patient with a clinical diagnosis of gonococcal arthritis was
      negative for N gonorrhoeae. Three of the 61 specimens were positive for Chlamydia
      DNA. Two were derived from patients with clinical diagnoses of reactive arthritis
      or Reiter's syndrome, and 1 was from a patient with unexplained monarthritis. One
      of the 61 specimens was positive from Ureaplasma DNA; this sample was from a
      patient with a clinical diagnosis of Reiter's syndrome. In an additional patient
      with Reiter's syndrome, Ureaplasma DNA was also found in prostate biopsy tissue
      and a urine sample obtained after prostate massage (synovial fluid not
      available). CONCLUSION: These data support the classification of these 3 venereal
      associated arthritides as infectious processes, and suggest that PCR for
      bacterial DNA is a useful method for detecting infectious agents in synovial
      fluid.

PMID- 8651991
TI  - Normal expression of type 1 insulin-like growth factor receptor by human
      osteoarthritic chondrocytes with increased expression and synthesis of insulin
      like growth factor binding proteins.
AB  - OBJECTIVE: Our previous research demonstrated that, in contrast to normal
      chondrocytes, human osteoarthritic (OA) chondrocytes were hyporesponsive to
      stimulation by insulin-like growth factor 1 (IGF-1). The aim of the present
      investigation was to examine whether this finding was due to an alteration in the
      level of IGF receptors (IGFRs) and/or IGF binding proteins (IGFBP). METHODS: A
      quantitative reverse transcriptase polymerase chain reaction technique (RT-PCR)
      was used to measure the type 1 IGFR messenger RNA (mRNA) level, and Northern
      blotting was used to measure type 2 IGFR and IGFBP mRNA levels. Western
      immunoblotting was used to identify and measure IGFBP levels. RESULTS: There were
      similar levels of type 1 IGFR mRNA in normal and OA chondrocytes. The level of
      type 2 IGFR mRNA, in which an increased amount of which can interfere with the
      biologic effects of IGF-1, was lower in OA chondrocytes compared with normal
      chondrocytes. Articular chondrocytes produced IGFBP-2, IGFBP-3, and IGFBP-4, and
      OA chondrocytes secreted and expressed higher amounts than did normal
      chondrocytes. There was also an increased level of IGFBP-3 in the OA chondrocyte
      lysates. IGFBPs 1, 5, and 6 were not detectable. CONCLUSION: OA chondrocytes
      synthesize and express a larger amount of 3 IGFBPs. This observation, along with
      a lack of detectable change in type 1 IGFR mRNA level, suggests that the
      hyporesponsiveness of OA chondrocytes to IGF-1 might implicate the involvement of
      IGFBPs in this pathologic process.

PMID- 8651990
TI  - In situ hybridization analysis of synovial and systemic cytokine messenger RNA
      expression in superantigen-mediated Staphylococcus aureus arthritis.
AB  - OBJECTIVE: To investigate patterns of synovial and systemic cytokine messenger
      RNA (mRNA) expression in mice with superantigen-mediated Staphylococcus aureus
      arthritis. METHODS: Mice were inoculated intravenously with 1 x 10(7) colony
      forming units of toxic shock syndrome toxin-1-producing S aureus LS-1. Synovial
      tissues and spleens were obtained at varying time intervals after bacterial
      inoculation, and examined for mRNA expression of interleukin-1beta (IL-1beta), IL
      4, IL-10, IL-12, tumor necrosis factor alpha (TNFalpha), TNFbeta, interferon
      gamma (IFN-gamma), transforming growth factor beta, and perforin, by an in situ
      hybridization technique. RESULTS: In situ hybridization revealed early synovial
      up-regulation of TNFalpha and IL-1 beta mRNA expression. Peak frequencies of
      these proinflammatory cytokines were observed at the second and third week of the
      infection. Expression of T cell-derived cytokine mRNAs was detected later, and in
      a relatively low frequency. Notably, induction and peak numbers of Th2 cytokine
      (IL-4 and IL-10) mRNA expression preceded Th1 cytokine (IFNgamma and TNFbeta)
      mRNAs. In comparison with synovial tissues, peak spleen cytokine mRNA expression
      of IL-1beta, TNFalpha, TNFbeta, IL-12, and IFNgamma occurred earlier, but
      displayed a clearly lower magnitude of expression. CONCLUSION: These findings
      demonstrate synovial and systemic up-regulation of cytokine mRNA expression
      during S aureus arthritis, indicating that both monocyte/macrophage and T cell
      derived products are involved in the pathogenesis of this disease.

PMID- 8651992
TI  - Why health care costs more in the US: comparing health care expenditures between
      systemic lupus erythematosus patients in Stanford and Montreal.
AB  - OBJECTIVE: Recent studies to identify the causes of higher health care
      expenditure in the US versus Canada have relied on population-based measures of
      health care utilization and have restricted their analysis to one sector, such as
      physician or hospital expenditures. We present a detailed comparative analysis of
      the direct costs (health services utilized) of treating systemic lupus
      erythematosus (SLE) patients in Stanford, CA and Montreal, Quebec. METHODS: Using
      the self-report Stanford Health Assessment Questionnaire, we assessed 6-month
      direct costs incurred by 174 American and 164 Canadian SLE patients. We explored
      3 potential reasons for the differential expenditure. These were 1) higher prices
      for health care inputs, 2) more severe disease in the patient case mix, and 3)
      greater resource utilization. RESULTS: The direct health care costs for the
      American SLE patients exceeded those for the Canadian patients by almost 2-fold
      ($10,530 versus $5,271, expressed in 1991 US dollars). The higher direct costs
      were explained by the higher price of health services in the US and the more
      severe disease mix. In fact, for all health resources categories studies,
      Canadians utilized at least as many services as their American counterparts.
      Canadians had longer hospital stays, made more emergency room visits, and used
      more medications. CONCLUSION: Despite significantly greater per capita health
      care expenditure in the US, our data show that Canadian SLE patients actually
      receive more medical services.

PMID- 8651993
TI  - Risk of osteoarthritis associated with long-term weight-bearing sports: a
      radiologic survey of the hips and knees in female ex-athletes and population
      controls.
AB  - OBJECTIVE: To estimate the risk of osteoarthritis (OA) of the hip and knee due to
      long-term weight-bearing sports activity in ex-elite athletes and the general
      population. METHODS: A retrospective cohort study was conducted of 81 female ex
      elite athletes (67 middle- and long-distance runners, and 14 tennis players),
      currently ages 40-65, recruited from original playing records, and 977 age
      matched female controls, taken from the age-sex register of the offices of a
      group general practice in Chingford, Northeast London, England. The definition of
      OA included radiologic changes (joint space narrowing and osteophytosis) in the
      hip joints, patellofemoral (PF) joints, and tibiofemoral (TF) joints. RESULTS:
      Compared with controls of similar age, the ex-athletes had greater rates of
      radiologic OA at all sites. This association increased further after adjustment
      for height and weight differences, and was strongest for the presence of
      osteophytes at the TF joints (odds ratio [OR] 3.57, 95% confidence interval [95%
      CI] 1.89-6.71), at the PF joints (OR 3.50, 95% CI 1.80-6.81), narrowing at the PF
      joints (OR 2.97, 95% CI 1.15-7.67), femoral osteophytes (OR 2.52, 95% CI 1.01
      6.26), and hip joint narrowing (OR 1.60, 95% CI 0.73-3.48), and was weakest for
      narrowing at the TF joints (OR 1.17, 95% CI 0.71-1.94). No clear risk factors
      were seen within the ex-athlete groups, although the tennis players tended to
      have more osteophytes at the TF joints and hip, but the runners had more PF joint
      disease. Within the control group, a small subgroup of 22 women who reported long
      term vigorous weight-bearing exercise had risks of OA similar to those of the ex
      athletes. Ex-athletes had similar rates of symptom reporting but higher pain
      thresholds than controls, as measured by calibrated dolorimeter. CONCLUSION:
      Weight-bearing sports activity in women is associated with a 2-3-fold increased
      risk of radiologic OA (particularly the presence of osteophytes) of the knees and
      hips. The risk was similar in ex-elite athletes and in a subgroup from the
      general population who reported long-term sports activity, suggesting that
      duration rather than frequency of training is important.

PMID- 8651995
TI  - [An update on primary Gougerot-Sjogren's syndrome in 1995].

PMID- 8651994
TI  - Outcome in patients with early rheumatoid arthritis treated according to the
      "sawtooth" strategy.
AB  - OBJECTIVE: To investigate the outcome of early rheumatoid arthritis (RA) when
      treated according to the "sawtooth" strategy, and to compare the results with the
      findings of other studies. METHODS: In this prospective study, 142 patients with
      early RA were treated actively with slow-acting antirheumatic drugs (SAARDs) for
      an average of 6.2 years, and were closely monitored clinically. Several outcome
      measures were applied, and the results were compared with findings in previously
      described cohorts. RESULTS: The mean cumulative number of SAARDs used during the
      study was 3.3. Treatment changes were made because of inefficacy more often than
      because of adverse events. The percentage of patients whose disease entered
      remission increased with time to 32% (45 of 142). Only 24% of the patients (34 of
      142) had deterioration to Steinbrocker functional class III or IV. The "sawtooth"
      treatment strategy seemed to improve the outcome of the patients with early RA.
      CONCLUSION: In the majority of patients with early RA, "sawtooth" therapy remains
      beneficial for at least 6 years. However, in one-fourth of the patients, the
      disease fails to respond to this drug treatment strategy.

PMID- 8651996
TI  - [What about histopathologic classifications of childhood rhabdomyosarcoma?].

PMID- 8651997
TI  - [Stromal tumors of the digestive tract. Prognostic evaluation of a series of 36
      cases].
AB  - Clinical outcome of gut's stromal tumors is difficult to predict by morphological
      data. The prognostic significance of a set of morphological criterias and
      immunostaining for proliferating cell nuclear antigen (PCNA) was studied. Thirty
      six tumours were classified benign (group A) or malignant (group B) according to
      ten year follow-up. Patient's sex and age, site of origin, tumour size, mitotic
      count and cytonuclear atypia were considered. Growth kinetic was studied by
      immunohistochemical analysis of PCNA (PC 10, DakoR). In univariate analysis,
      mitotic count, PCNA index, tumor size and cytonuclear atypia were associated with
      patient outcome. However, in multivariate analysis, only mitotic count and tumour
      size were independent prognosis factors. Thus, mitotic count remains the best
      prognostic indicator for these tumours since a cut off value of 2 mitosis/high
      power field allows an accurate prognosis in 33/36 tumors.

PMID- 8651998
TI  - [Diabetic mastopathy with epithelioid fibroblasts :differential diagnosis from an
      infiltrating lobular carcinoma of the breast. Report of two cases].
AB  - Two cases of diabetic mastopathy are reported. The patients presented with a
      rapidly increasing mammary mass. The pathologic findings of diabetic mastopathy
      usually consist of a lymphocytic lobulitis, a dense stromal fibrosis and
      prominent epithelioid fibroblasts. In our two cases, the latter findings were
      initially misinterpreted as malignant cells of an invasive lobular carcinoma.
      These lesions were first described in longstanding insulin dependent diabetics
      but recent reports showed that they could also occur in patients with other auto
      immune disorders (systemic lupus erythematous, hypothyroidism). Diabetic
      mastopathy may reoccur locally and the treatment remains to be determined.

PMID- 8651999
TI  - [Rare tumors of the prostate or seminal vesicles. Report of a case of
      leiomyosarcoma].
AB  - An unusual case of leiomyosarcoma of the prostate presented as a recurrent pelvic
      cystic mass. Prostatic sarcoma are rare in adults with a poor prognosis. It is
      often difficult to determine a definite origin. The authors reviewed the
      differential diagnosis with pseudosarcoma, inflammatory fibrosarcoma and others
      rare tumors of the prostate and the seminal vesicle.

PMID- 8652000
TI  - [Extra-pulmonary pneumocystosis in the course of AIDS. Report of a case].
AB  - We report a case of splenic pneumocystosis in a human immunodeficiency virus
      positive individual treated prophylactically with aerosolized pentamidine.
      Despite this infection with Pneumocystis carinii, the bronchoalveolar lavage
      revealed no microorganisms. The use of aerosolized pentamidine as prophylaxis for
      Pneumocystis carinii is not protective against extrapulmonary pneumocystosis
      because of inadequate systemic distribution of the drug.

PMID- 8652001
TI  - [Encrusted pyelo-ureteritis and cystitis by Corynebacterium D2 in a renal
      transplant].

PMID- 8652002
TI  - [Alveolar sarcoma. Report of a case].
AB  - Alveolar soft part sarcoma occurs mostly in the deep soft tissues. An unusual
      case of primary pulmonary alveolar soft part sarcoma is reported. A 39-year-old
      woman presented with thoracic pain revealing the tumor. The left lower lobe was
      surgically resected. The microscopic features of this tumor, including
      characteristic alveolar pattern and the PAS-positive crystals were typical of
      alveolar soft part sarcoma. Immunohistochemically, granular cytoplasmic
      reactivities were observed with antibodies against vimentin, myoglobin,
      methionine-enkephalin, S100 protein and neuron-specific-enolase. Electron
      microscopic study demonstrated numerous crystallized structures in the tumor cell
      cytoplasm. This is the third case of pulmonary alveolar soft part sarcoma, one
      arising from the pulmonary vein. The histogenesis of alveolar soft part sarcoma
      is still debated. Our case does not allow distinction between myogenic or neural
      origin of this tumor.

PMID- 8652003
TI  - [Bifocal lesion of striated muscle (hamartoma or focal myositis) in the course of
      Proteus syndrome].
AB  - We report a case of bifocal recurrent lesion developed in muscles of the left
      thigh in a 5 year-old-girl with Proteus syndrome (rare congenital hamartomatous
      disorder). We discuss the diagnosis of focal myositis versus hamartoma. The
      clinical and morphological features favour the second hypothesis.

PMID- 8652004
TI  - [Complaints in pathology].

PMID- 8652005
TI  - [A rare etiology of celiac trunk aneurysm].

PMID- 8652007
TI  - [Effect of microwave pretreatment on the detection of Epstein-Barr virus EBER
      RNA's using in situ hybridization].
AB  - We have tested the influence of microwave pretreatment of tissue sections on in
      situ hybridization applied to the detection of Epstein-Barr virus-encoded small
      RNAs (EBER). To this end, different protocols have been tested on slides of 4
      lymph node lymphomas: microwave pretreatment, proteinase K pretreatment,
      microwave followed by proteinase K and no pretreatment. To compare the
      sensitivity of each technique, several dilutions of oligoprobes were used.
      Hybrids have been detected by immunohistochemistry. The analysis of the nuclear
      stainings obtained shows an enhancement of the sensitivity in protocols using
      microwaves.

PMID- 8652006
TI  - [Mesocolon mass in an adolescent].

PMID- 8652008
TI  - [Use of a greater dilution of the silver nitrate solution to reveal the nucleolar
      organizer regions (AgNOR)].

PMID- 8652009
TI  - [Gougerot-Sjogren syndrome in 1996].

PMID- 8652010
TI  - Immunohistochemical expression of tumor necrosis factor alpha in neonatal
      leukomalacia.
AB  - The expression of tumor necrosis factor alpha (TNF alpha) was examined in infants
      with leukomalacia by means of immunohistochemical methods with an antihuman TNF
      alpha monoclonal antibody. We studied 23 patients with neonatal leukomalacia,
      classified as having "focal," "widespread," or "diffuse" disease according to the
      distribution of the lesions, and 18 age-matched controls. TNF alpha
      immunoreactivity was positive in 19 of the 23 (83%) patients with leukomalacia,
      and in 7 of the 18 (39%) controls. TNF alpha was expressed mainly in glial cells
      in the deep white matter in both groups, and was most abundant around the
      necrotic foci in the focal group. TNF alpha immunoreactivity appeared earlier in
      patients with leukomalacia than in controls, being first detected at 25 and 29
      weeks gestation, respectively. Immunofluorescence double-labeling revealed the
      TNF alpha -immunoreactive cells were Ricinus communis agglutinin-1 (RCA-1)
      positive microglial cells. Thus, our study revealed increasing expression of TNF
      alpha in the normally developing brain during the late fetal period, and
      overproduction of TNF alpha by microglial cells associated with the pathogenesis
      of neonatal leukomalacia.

PMID- 8652011
TI  - Developmental changes in the noradrenergic innervations of spinal motoneurons in
      neonatal rats.
AB  - Developmental changes in the noradrenergic innervations of spinal motoneurons in
      both the cervical and lumbar cords were studied in neonatal rats. The labeling of
      motoneurons was done using choleratoxin B subunit as a retrograde neurotracer.
      The noradrenergic fibers were detected by immunohistochemistry for tyrosine
      hydroxylase. At postnatal day 1, tyrosine hydroxylase immunoreactive fibers were
      evident in the entire ventral horn, including the triceps brachii motoneuron
      pools at the cervical level. In contrast, they were observed only in that portion
      of the ventral horn medial to the quadriceps femoris motoneuron pools at the
      lumbar level. Subsequently, tyrosine hydroxylase immunoreactive fibers increased
      at both levels, and they were distributed in most of the gray matter at postnatal
      day 14. At this age, the distribution pattern of tyrosine hydroxylase
      immunoreactive fibers in the lumbar level was almost identical to that of the
      cervical level. The number of closely apposed tyrosine hydroxylase immunoreactive
      varicosities on motoneurons (close appositions) increased continuously from
      postnatal day 1 to 14 at both the cervical and lumbar levels. At postnatal day 1,
      triceps brachii motoneurons had more close appositions than quadriceps femoris
      motoneurons in number and, after postnatal day 7, there was no difference in the
      number of close appositions between triceps brachii motoneurons and quadriceps
      femoris motoneurons. Based on these results, we discuss the significance of
      monoaminergic influences on the postnatal development of spinal motoneurons and
      of motor behavior with a rostrocaudal gradient.

PMID- 8652012
TI  - "Pseudo-BECRS": intracranial focal lesions suggestive of a primary partial
      epilepsy syndrome.
AB  - Benign epilepsy of childhood with rolandic spikes (BECRS) is an electroclinical
      entity that is the most common primary partial epilepsy syndrome of childhood.
      Typically presenting between the ages of 3 and 13 years, it is characterized by a
      well-recognized seizure pattern arising in a normal child with EEG findings
      restricted to rolandic/centrotemporal regions. Seizure control is usually easily
      achieved and prognosis is believed to be uniformly good. Some authors have
      suggested that individuals fitting the electroclinical parameters of this entity
      need not undergo neuroimaging due to the benign evolution of this disorder. Five
      patients presenting over a 13-year period with peribuccal seizures, normal
      neurologic examinations, and EEG data initially suggestive of BECRS found to have
      focal lesions on neuroimaging are summarized. Independent bilateral
      centrotemporal epileptiform abnormalities were seen in 3 patients. Imaging
      studies (CT, MRI, or both) documented a mass lesion in all in variable locations.
      Histologic examination documented a low-grade astrocytoma in 3 patients and a
      cavernous angioma in another. The fifth patient refused treatment or biopsy.
      Careful retrospective review of the clinical features of these patients reveals
      variable atypical features in each. Therefore, despite an electroclinical
      phenotype initially suggestive of the BECRS presentation, the presence of
      atypical clinical features raises the possibility of an underlying structural
      lesion and thus a negative neuroimaging study may in some patients be essential
      to the definitive accurate diagnosis of BECRS.

PMID- 8652013
TI  - Discontinuation of phenobarbital in children: effects on neurocognitive behavior.
AB  - Neurocognitive performances were evaluated in 9 children with different types of
      epilepsy prior to and at least 6 months after discontinuation of phenobarbital.
      The patients treated with phenobarbital monotherapy were seizure free for at
      least 2 years, without electro-encephalographic anomalies for at least 1 year.
      Results indicated that phenobarbital at low therapeutic doses causes attentional
      and memory deficits, reversible after therapy discontinuation. Further research
      utilizing the same design is needed on larger samples in order to confirm our
      results.

PMID- 8652014
TI  - Ontogenetic development of the locomotor response to levodopa in the rat.
AB  - Administration of exogenous levedopa triggers locomotion in young rats prior to
      the onset of quadripedal movement. The same substance decreases locomotion in
      adult animals. The ontogenetic development of the response to levodopa was
      investigated in rats. Intraperitoneal injection of levodopa (150 micrograms/kg
      body weight) caused characteristic "crawling" or "swimming-like" locomotion
      patterns in 5- to 6-day-old animals. Noradrenergic mechanisms may be involved in
      this behavior. In 18- to 20-day-old rats, levodopa caused excessive locomotor
      activity, including running, jumping, and wall climbing. This effect can be
      attributed to the activation of postsynaptic dopaminergic receptors that are
      already present during the early stages of life. At 25-30 days of age, levodopa
      induced motor activity was decreased in comparison with that of the 18- to 20-day
      old rats, possibly due to changing patterns of D1/D2-dopamine receptor subtype
      interactions. In contrast to observations in younger rats, the same dose of
      levodopa suppressed motor activity in 60- to 75-day-old rats. The presence of
      functional dopamine autoreceptors at this age may account for the change.

PMID- 8652015
TI  - The parachute reactions in normal and late walkers.
AB  - To study the relationship of the parachute responses to the age of independent
      walking, three groups of infants were prospectively examined: a normal sitting,
      normal walking group; a late sitting, normal walking group; and a late sitting,
      late walking group. All other spheres of the neurodevelopmental examination were
      normal. It was found that when the parachute responses appeared by age 10 months
      in the late sitting infants, most of them would achieve independent walking by 15
      months. A delay in the parachute reaction in these infants predicted a delay in
      walking.

PMID- 8652016
TI  - Autonomic dysfunction in newly diagnosed insulin-dependent diabetes mellitus
      children.
AB  - In order to evaluate the presence of electrophysiologic signs of autonomic
      dysfunction (AD) in newly diagnosed diabetic children, cardiovascular reflex
      tests were performed in 55 (30 female, 25 male) newly diagnosed insulin-dependent
      diabetes mellitus (IDDM) patients aged 10.3-20.7 years (mean +/- S.D.: 15.2 +/-
      5.6). Ten (18.2%) diabetic children had cardiovascular AD, defined as abnormal
      results in 2 of 5 tests. Autonomic function tests were assessed at entry and
      after 12, 24, and 36 months of the study. All diabetic children received human
      insulin and followed an intensive insulin treatment (3 or 4 injections per day),
      associated with a teaching program of self-management of the disease. In the 3
      years of follow-up, all children improved the quality of metabolic control
      (glycosylated hemoglobin, HbA1c: 10.3 +/- 1.1% versus 7.7 +/- 0.9; P < .01) and
      manifested no significant difference between baseline and follow-up values of
      autonomic function tests which remained unchanged in spite of this improvement.
      Cardiovascular autonomic dysfunction can be present in newly diagnosed IDDM
      children and it seems to be stable in children who follow an intensive insulin
      injection therapy.

PMID- 8652017
TI  - A common mutation site in the beta-galactosidase gene originates in Puerto Rico.
AB  - Several mutation sites have been found in the beta-galactosidase gene of patients
      with GM1 gangliosidosis. In a previous report we found a common point mutation
      site in American patients with GM1 gangliosidosis resulting in a 208Arg --> Cys
      amino acid substitution. From the patients' family history, we suggested that
      this mutation may have come to South and North America via Puerto Rico. Four new
      patients with infantile GM1 gangliosidosis have been analyzed with allele
      specific hybridization. Two siblings from Puerto Rico of Spanish ancestry are
      homozygous for this mutation. Another patient also from Puerto Rico is
      heterozygous for this allele, and another black patient does not have this
      mutation. These results support our initial hypothesis that this mutation has
      probably arisen in Puerto Rico.

PMID- 8652018
TI  - MERRF syndrome with overwhelming lactic acidosis.
AB  - Myoclonic epilepsy with ragged-red fiber syndrome has been associated with a
      mitochondrial DNA base substitution at nucleotide 8344 in the mitochondrial
      tRNA(Lys) gene. In several reported series, adult patients with these mutations
      have mild to moderate symptoms that progress slowly over many years. We describe
      a girl with MERRF syndrome who had an unusually rapid and severe clinical course,
      with onset of symptoms at age 7 years and death by age 14 years of overwhelming
      lactic acidosis. Postmortem tissue biopsy revealed variable but generally high
      percentages of mutant mitochondrial genomes in multiple organ systems. Twenty-one
      other members of her family were tested for the mutation and had varying
      percentages in leukocytes.

PMID- 8652019
TI  - Ptosis associated with sinusitis.
AB  - An adolescent male developed eye pain and a drooping lid. Imaging revealed
      adjacent pansinusitis and a swollen levator palpebrae and superior rectus muscle.
      Compression of a branch of the oculomotor nerve is the postulated cause because
      vertical eye movements were normal.

PMID- 8652020
TI  - Availability of frequency-selective fat-saturation pulse (Fat-Sat) MRI in
      childhood optic neuritis.
AB  - A 2-year-old boy with acute optic neuritis, confirmed by gadolinium-DTPA
      enhancement of the optic nerve using frequency-selective fat-saturation pulse
      magnetic resonance imaging (Fat-Sat MRI), is reported. Because it is difficult in
      very young children to sufficiently evaluate visual acuity, visual field, and
      retroocular pain on eye movement, and visual evoked potential during wakefulness,
      Fat-Sat MRI will be useful for revealing optic nerve inflammation and for
      monitoring treatment.

PMID- 8652021
TI  - Nonprogressive congenital unilateral ventriculomegaly.
AB  - Congenital unilateral ventriculomegaly is a rare condition, usually caused by
      obstruction of the foramen of Monro. In the past, this condition required
      surgical intervention. We present a female newborn with nonprogressive unilateral
      ventriculomegaly which was initially detected by prenatal sonography. No surgical
      intervention was performed, and during the 9 months of follow-up, she had normal
      head growth and reached appropriate developmental milestones.

PMID- 8652022
TI  - Leigh disease with deficiency of lipoamide dehydrogenase: treatment failure with
      dichloroacetate.
AB  - A 6-month-old female infant with hypotonia and keto and lactic acidosis was
      diagnosed with lipoamide dehydrogenase (E3) deficiency. This enzyme is a
      component of the pyruvate, alpha-ketoglutarate, and branched chain alpha-ketoacid
      dehydrogenase complexes. At the time of diagnosis her plasma contained elevated
      branched chain amino acids, alanine, alloisoleucine, ketones, pyruvate, and
      lactate, and her urine contained elevated branched chain ketoacids and lactate.
      By neuroimaging she was found to have Leigh subacute necrotizing
      encephalomyelopathy. Modest branched-chain amino acid restriction led to the
      disappearance of alloisoleucine and normalization of her branched chain amino
      acid values, while institution of a high fat diet precipitated hypoglycemia and
      acidosis. A trial of lipoic acid led to a transient modest improvement in her
      lactic acidemia. Use of dichloroacetate to activate the pyruvate dehydrogenase
      complex led to a significant decline in lactate levels, but this was also
      transient. The patient had significant growth failure despite a high
      carbohydrate, high calorie diet, yet remained clinically well until 28 months of
      age when she developed acute acidosis and brainstem dysfunction and died.

PMID- 8652023
TI  - Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy.
AB  - The goals of this study were to describe the clinical course of skeletal,
      cardiac, and gastrointestinal muscle manifestations and trends in age at
      diagnosis and survival of Duchenne muscular dystrophy (DMD) patients. A
      retrospective cohort of 33 male patients with DMD, born between 1953 and 1983 and
      followed at the Mayo Clinic during their second decade of life, was studied. The
      mean age at DMD diagnosis was 4.6 years. Skeletal muscle weakness present in all
      patients at diagnosis progressed to wheelchair dependency in 32 patients (97%) by
      the age of 13 years (median age 10 years). Cardiac muscle failure developed in 5
      patients (15%) (median age 21.5 years). Smooth muscle manifestations related to
      the digestive and urinary tracts occurred in 7 (21%) and 2 (6%) patients (median
      age 15 years), respectively. The gastrointestinal dilatations were primary in 2
      patients or secondary to surgery or acute respiratory illness in 5 patients. By
      the end of the study period, 17 deaths had occurred (median age 17 years). Over
      time, there was a decrease in the time to DMD diagnosis (P = .05) but no
      significant change in survival (P = .44). Cardiac and smooth muscle
      manifestations occur late in the course of DMD. Clinical gastrointestinal
      symptoms related to smooth muscle function most often were secondary to surgery
      or a respiratory illness. In recent years, the diagnosis of DMD has been made at
      a younger age, but survival has not changed.

PMID- 8652024
TI  - Intravenous gamma-globulin treatment in a patient with subacute sclerosing
      panencephalitis.
AB  - A 10-year-old boy with subacute sclerosing panencephalitis was treated with
      intravenous gamma-globulin and inosiplex and followed for 18 months. Clinical
      improvement, demonstrated by decreasing scores on the Neurologic Disability
      Index, was observed. There were no side effects. We recommend intravenous immune
      globulin as an alternative therapy in the treatment of subacute sclerosing
      panencephalitis.

PMID- 8652025
TI  - Brain dysplasia associated with Larsen-like syndrome.
AB  - We present an autopsy case of Larsen-like syndrome with unusually severe
      neurologic complications. The patient, a 3-year-old girl, manifested severe
      psychomotor retardation, tetraplegia, and intractable partial seizures as well as
      multiple joint dislocations with other skeletal deformities, minor external
      anomalies, and laryngotracheomalacia. Neuropathological examination of the brain
      revealed (1) cortical dysgenesis in the bilateral perisylvian region; (2)
      protrusions of the brain parenchyma into the subarachnoid space, (3) abnormal
      arrangement of olivary neurons, (4) dilation of the lateral ventricles with
      subventricular gliosis and multiple glial nodules, (5) hypoplasia of the cerebral
      white matter with subcortical astrocytosis, and (6) necrotic change in Sommer
      sector of the hippocampus. There were no microscopic abnormalities in the
      mesenchymal tissue of the brain (i.e., vascular walls and the meninges). Cortical
      dysgenesis in the perisylvian region was characterized by a zonal heterotopia of
      pyramidal and granule neurons in the molecular layer, which clinically may be
      closely related to intractable partial seizures in the orofacial area. Findings
      1, 2, and 3 may represent a disturbance of neuroblast migration, speculated to
      have occurred during the latest stage of migration (around 20-25 weeks
      gestation). There are few published reports describing the combination of Larsen
      like syndrome and brain dysplasia. Correlation of brain dysplasia with congenital
      skeletal abnormalities is unclear in our patient. We speculate that systemic
      hypoxic-ischemic insults during the second half of gestation and/or some genetic
      factors might be possible causes of brain dysplasia.

PMID- 8652026
TI  - [A comparison of the morphology of mammalian and bird ear ossicles and
      reflections on the asymmetrical form of the human stapes arch].
AB  - BACKGROUND: The human middle ear presents some anatomical detail which can not be
      explained exclusively by sound transmission (joints, muscles). These details can
      be interpreted as an adaptation to environmental atmospheric pressure loads. In
      order to further investigate the influence of these non-acoustic loads on the
      geometry of the middle ear structures, the ossicles of animals from different
      environments were examined. METHODS: In the first half of our century, the
      zoologist C. F. Werner collected the ossicles of 175 species, mostly mammals and
      birds. This collection was now cataloged and analysed with light and x-ray
      microscopy. RESULTS AND DISCUSSION: The diversity in size and design of the
      ossicles seems to be influenced not only by the acoustic environment of the
      animal--the ossicles of mammals living in the desert are relatively large,
      reflecting the better sensitivity of their middle ear for the far traveling low
      frequencies--but especially the bony structure of the ossicles can be related to
      the static loads of the environment of the animal. Ossicles of aquatic mammals
      are more solid and denser than in terrestrial forms. The bony structure aligns to
      the static load. This structural principle forms the basis of the skeleton and
      muscles and can also be found in the human stapes: the asymmetry of the stapedial
      arch can be explained as adaptation of the bony structure to the pull of the
      stapedius muscle. CONCLUSIONS: The anatomical structure of the ossicles of human
      and animal origin is not only influenced by its function as sound transmitter,
      but it is also shaped by nonacoustic forces and static loads of the environment.

PMID- 8652028
TI  - [Reaction times at auditory threshold: a comparison of normal hearing probands
      and patients with hearing damage].
AB  - BACKGROUND: The purpose of the study was to examine the latencies between tonal
      stimuli and response of normal ears at the threshold compared with ears with a
      frequency-specific threshold above 70 dB. PATIENTS AND METHODS: Reaction times to
      tonal stimuli of 122 adults with normal hearing and adults with hearing loss were
      compared at the threshold of hearing to reaction times beyond the threshold. The
      study group of tested patients was divided into four groups corresponding to the
      frequency-specific hearing loss on the basis of previous audiometric
      investigations. RESULTS: The results reveal that response latencies in ears with
      normal hearing asymptomatically approach the auditory threshold. In contrast, we
      failed to measure a significant prolongation of reaction times in presence of
      extensive hearing loss (above 70 dB) even at the minimum level of auditory
      perception. In the presence of extensive hearing loss (above 70 dB), we detected
      a significantly lower rise of threshold response latencies at normal audiometric
      frequencies than in normal ears. CONCLUSION: The reaction time results are
      evaluated, and the possible role of the outer hair cells are discussed.

PMID- 8652027
TI  - [Clinical application of distortion products of otoacoustic emissions in
      presbycusis].
AB  - BACKGROUND: DPOAE are still undergoing evaluation for clinical use. The aim of
      the present study is to assess DPOAE in a clinical setting in order to examine
      the response of 15 normally hearing adults and to compare the results with those
      of 15 people with presbycusic ears of known sensorineural high-frequency hearing
      loss. METHODS: For realizing DPOAE input-output (I/O) functions, the two primary
      stimuli were presented at intensities of the same level ranging from 20 to 71 dB
      SPL. The geometric mean of primaries represented auditory frequencies varying
      between 1.0 and 8.0 kHz. RESULTS: We found two clearly separated portions in I/O
      functions of normally hearing ears. The first portion, in response to primary
      intensities of 60 dB SPL and below, showed saturation behavior. If primary
      intensities exceeded 60 dB SPL, I/O functions became more linear. In presbycusic
      ears, the loss of a saturation portion in response to stimulus levels below 60 dB
      SPL shows two particularities: Firstly, the linearity in I/O functions, as a
      response to geometric mean value of primaries with elevated audiometric threshold
      (above 1.5 kHz), could be explained by lesions in the active properties of the
      outer hair cells, revealing the cochlear nature of presbycusis. Secondly, the
      additional loss of a saturation portion in frequencies with normally pure-tone
      audiometric threshold (up to and including 1.5 kHz) could be interpreted as a
      result of onset of injury in the active micromechanics of the cochlea--just
      before its clinical manifestation. CONCLUSIONS: DPOAE growth functions may reveal
      discrete pathological alterations both in the active cochlear signal processing
      and in the passive mechanisms of the presbycusic cochlea prior to their detection
      by clinical audiometric tests.

PMID- 8652029
TI  - [Molecular analysis of the heterogeneity of hereditary monosymptomatic
      sensorineural hearing loss].
AB  - BACKGROUND: Genetic characterization of hereditary hearing impairment has
      progressed considerably with the mapping of nine chromosomal loci for
      monosymptomatic autosomal-inherited hearing loss over the last three years.
      METHODS: Following thorough clinical evaluation, linkage analysis using
      microsatellite markers was performed in two large families from Westphalia/West
      Germany. RESULTS: For all the dominant (DFNA1--4) and three autosomal-recessive
      loci (DFNB1--3) described to date, linkage was finally excluded. CONCLUSIONS: A
      high degree of genetic heterogeneity must be assumed. Identification of
      individual genes for monosymptomatic sensorineural hearing loss by linkage
      analysis in large pedigrees may help in molecular differentiation of hearing.

PMID- 8652030
TI  - [Effect of various electrode configurations and voluntary, reproducible artifacts
      in computer-assisted analysis of nystagmus].
AB  - BACKGROUND: There is no detailed information in the current literature about the
      best position for the electrodes with regard to electronystagmography. The
      computer nystagmograph registers potential changes resulting from electrodes on
      the forearm as nystagmus (pseudonystagmus). This phenomenon led us to investigate
      more closely the effect of various electrode arrangements and artifacts on the
      result of computer nystagmography. METHODS: The following four electrode
      arrangements were investigated on 20 human subjects: distance between the
      horizontal electrode and the lateral canthus (1 cm versus 2 cm), diagonal
      arrangement of the lateral electrodes, and changes to the lower vertical
      electrode. Recorded parameters included calibration potential, rotary nystagmus,
      post-rotary nystagmus, and optokinetic nystagmus. After determining the basic
      activity with closed eyes, the influence of five human artifacts on the computer
      nystagmography was investigated, namely blinking, contractions of the masticatory
      muscles, swallowing, facial expression, and squinting. RESULTS: The arrangement
      in which the horizontal electrodes were placed 1 cm away from the lateral canthus
      showed the greatest calibration potential and the smallest degree of human
      influence with regard to frequency and amplitude of the pseudonystagmus since a
      larger potential does not have to be amplified as much as a smaller one to
      achieve the same needle deflection. For this reason, the artifacts experience a
      smaller degree of amplification. CONCLUSIONS: We think the following arrangement
      of the electrodes guarantees the best signal reproduction: a distance between
      horizontal electrodes and the lateral canthus of 1 cm. The medial electrode is
      centered between the eyes on the bridge of the nose. The upper vertical electrode
      is placed above the left eyebrow in the line with the middle of the pupil. The
      lower vertical electrode is also in line with the middle of the pupil, 1 cm below
      the lower eyelid. The result is a clear recording of a physiological nystagmus,
      e.g. on rotation. In the absence of nystagmus, the analysis program is too
      unreliable and produces a multiplicity of pseudonystagmi. To avoid this we have
      to improve the recognition of nystagmus in the analysis program.

PMID- 8652031
TI  - [Pathophysiology of post-traumatic anosmia].
AB  - BACKGROUND: Head injury is one of the most common causes of olfactory
      disturbances. The incidence of posttraumatic anosmia depending from the severity
      of the injury lies between 5% and over 80%. METHODS: Clinical assessments were
      performed in 26 cases with posttraumatic anosmia using subjective olfactometric
      tests. Additionally, morphological studies were performed in 26 other patients,
      who died between 36 hours and six weeks after head injuries. RESULTS: Frontal
      basal injuries as well as minor occipital blows are capable of causing complete
      olfactory loss. About one-third of all patients were not aware of their
      chemosensory deficits, especially when associated neurological deficits occurred.
      Moreover, the studies show that: 1: The vulnerability of the fila olfactoria
      varies extremely and depends on unknown, highly individual parameters. 2: Trauma
      can induce local hemorrhage within the olfactory tracts and bulbs without any
      other intracranial lesions. 3: An intracerebral contusion is often misunderstood
      as the direct substrate of a posttraumatic anosmia. However, in a number of cases
      it is merely the sign of a strong injuring force, potentially capable of injuring
      the fila or the olfactory bulbus. CONCLUSIONS: The findings indicate that the
      pathophysiology and biomechanics of posttraumatic anosmia should be the subject
      of critical discussion.

PMID- 8652032
TI  - [Experiences with transverse resections and vertical incisions in treatment of
      tracheal stenoses and tracheal injuries].
AB  - BACKGROUND: The treatment of stenoses and traumatic lesions in subglottic and
      tracheal areas often requires long term follow-up. This study was undertaken to
      evaluate the efficiency of tracheal resections and vertical dissections with
      respect to the length and the quality of the treatment. PATIENTS: Thirty-one
      adult patients underwent tracheal resections. This group includes one patient
      with an esophagotracheal fistula which was closed after segmental resection. Two
      cases of traumatic tracheal lesions in the lower third of the trachea in children
      are also presented. RESULTS: Long-term intubation was the reason of stenosis in
      93.5% of the patients. The tracheal stenosis was successfully resected in 87% of
      the patients without any complications. The healing process was not related to
      age and sex. The prognosis was influenced negatively by the type and frequency of
      previous treatments. We detected paresis of the recurrent nerve postoperatively
      in two patients. CONCLUSIONS: 1. Our experience has shown that tracheal resection
      is the optimal treatment of stenosis. 2. The transtracheal access in childhood is
      very suitable for the closure of tracheal lesions located in the lower third of
      the trachea.

PMID- 8652033
TI  - [Therapy of cystic lymphangioma in childhood. Report of 4 cases with
      manifestations in the area of the head-neck].
AB  - BACKGROUND: Lymphangiomas are localized in the head and neck area in about 75% of
      cases. About 75% of these cases are children less than one year old. Treating
      lymphangiomas with installation therapy to obliterate the cysts has been
      discussed, but surgery remains the treatment of choice. PATIENTS: Two
      lymphangiomas in newborns required resection due to the size of the lesions. The
      surgery involved monitoring of the facial and hypoglossal nerves. A third child
      had a large lesion with infiltration into the supraglottic space and the tongue
      requiring a tracheotomy. In a four-and-one-half-year-old child, a parapharyngeal
      lymphangioma caused stridor and had to be incised before it could be completely
      excised through an intraoral and extraoral approach. RESULTS: Lymphangiomas can
      be excised safely even in newborns. CONCLUSIONS: The use of neurologic monitoring
      is recommended for surgery of lymphangiomas in children since these lesions
      conceal neurovascular structures making them difficult to identify.

PMID- 8652034
TI  - [Distant metastasis of renal cell carcinomas to the head-neck area].
AB  - BACKGROUND: Metastases of hypernephroma to the head and neck, especially to the
      larynx, are rare occurrences. PATIENTS: We report on two cases with solitary
      spread in the head and neck. A 73-year-old woman who underwent nephrectomy
      because of a hypernephroma six years ago had a manifestation in the right false
      vocal cord, which was resected by laser surgery. The specimen of the strumectomy
      in the other patient revealed a metastasis of an asymptomatic hypernephroma to
      the thyroid gland and finally led to correct diagnosis of the primary tumor.
      RESULTS: The female patient refused any further treatment and died of cachexia
      with tumor dissemination four months later. The other patient is still living
      with a local recurrence after palliative irradiation and administration of
      interleukin-2 and alpha-interferon. CONCLUSIONS: In absence of other tumor
      manifestations, choosing an adequate therapy can be difficult because of the long
      survival rates in some patients even after hematogenous spread and the
      unpredictable behavior of this malignancy.

PMID- 8652035
TI  - [Free microsurgical superior musculocutaneous trapezius flap of the swine: an
      ideal training model for microvascular reconstructions and in vitro model for
      experimental microsurgery].
AB  - BACKGROUND: Until now there have been no published studies on musculocutaneous
      porcine free flaps with an uncompromised vascular pedicle, easy surgical access
      and anatomic orientation allowing unlimited postoperative movement, as German
      animal research regulations require. RESULTS: The authors present the porcine
      musculocutaneous superior trapezius flap. It is supplied by the transverse neck
      artery, a branch of the thyrocervical trunk of the subclavian artery as in human
      anatomy. CONCLUSION: The advantages of this flap are its easy surgical access,
      its uncompromised vascular anatomy, and the easy closure of the donor area. The
      authors demonstrated the uncompromised vascular anatomy in 40 pigs with body
      weights ranging between 24 and 68 kg. The pigs were able to move normally
      following surgery.

PMID- 8652036
TI  - [Perforation of the ear drum. On the history of paracentesis and grommet
      insertion].
AB  - As early as 1649, Jean Riolan the Younger pierced an ear drum, after which the
      patient's hearing improved. This occurred as a result of an accidental ear drum
      injury while cleaning an ear canal with an ear-spoon. In 17th and 18th centuries,
      several pioneers in medicine (Thomas Willis, Antonio Mario Valsalva, William
      Cheselden) conducted experiments in an effort to ascertain the function of the
      ear drum in hearing. At the end of the 18th century, ear drum perforation, like
      perforation of a cataract, was indiscriminately performed by itinerent quacks and
      "physicians" in England, France, and Germany. Ear drum perforation was performed
      in many places even for the healing of deaf and dumb. Astlee Cooper reported
      about success with ear drum perforation in 1800 and listed strict indications. He
      recommended the operation only in the presence of obturation of the Eustachian
      tube. Because of the negative results of indiscriminate ear drum perforation, the
      operation soon acquired a bad reputation and was not performed for decades. It
      was only Herrmann Schwartze who reintroduced paracentesis into the daily practice
      of otorhinolaryngology. He was director of the royal ENT clinic in Halle and
      published a trailblazing treatise on the indications, value, and success of this
      operation. Since physicians had soon realized that spontaneous healing tendencies
      of the ear drum quickly lead to closure of an artificial perforation, many
      physicians tried different techniques to obtain a permanent opening. Gruber
      resected half of the ear drum--unsuccessfully. Others put foreign bodies into the
      ear drum apertures, such as catgut, whalebone rods, and lead wires. In his
      textbook of 1845, Martell Frank first described a grommet made of gold foil.
      Politzer experimented with a hard rubber ring but later abandoned his attempts
      because of lack of success. Voltolini manufactured an open hollow ring of gold
      foil or aluminium, which had to be fixed at the handle of the malleur. Armstrong
      described a "new" therapy for chronic secretory otitis media consisting of
      inserting a vinyl tube into the ear drum. While he was not the inventor of the
      grommet, he was the first to reintroduce grommets in the middle of the 20th
      century. Theromoparacentesis was performed as early as 1867 by Voltolini, who
      performed this operation using a galvanic cautery device. After more than 100
      years, the Japanese physician Saito reintroduced thermoparacentesis into the
      therapy of tube ventilation disorders. Paracentesis, grommet insertion, and
      thermoparacentesis are among the most successful treatments currently available
      to the ENT specialist when used properly. They are treatments with a long
      history.

PMID- 8652037
TI  - [Treatment after and patient education before tonsillectomy].

PMID- 8652038
TI  - [Comparison of the effectiveness of orally administered clorazepate dipotassium
      and nordiazepam on preoperative anxiety].
AB  - Clorazepate dipotassium (Tranxilium) is one of the benzodiazepines which is
      widely used for oral premedication. After oral administration it is
      decarboxylated to its active metabolite nordiazepam (desmethyldiazepam).
      Nordiazepam is also commercially available in the form of drops (Tranxilium N).
      The aim of the present study was to compare the effect of these drugs on
      preoperative anxiety. One hundred and eight patients scheduled for orthopaedic
      surgery (ASA I-II) were studied. Medication was administered at 10 p.m. the
      evening before surgery (E) and at 7 a.m. on the morning of surgery (M). There
      were four groups: 1) E no medication; M clorazepate dipotassium; 2) E no
      medication; M nordiazepam; 3) E clorazepate dipotassium; M clorazepate
      dipotassium, 4) E clorazepate dipotassium; M nordiazepam. Dosages were:
      clorazepate dipotassium: body weight < 55 kg: 10 mg; body weight > 55 kg: 20 mg;
      nordiazepam: 1 gtt/kg; 5 mg = 24 gtt). Anxiety was measured by using the self
      evaluating Erlangen anxiety scales, which measure both background and situational
      anxiety. Background anxiety (EAS-H) was evaluated during the evening before
      surgery; situational anxiety (EAS-S) was evaluated at the same time and also on
      the day of surgery before premedication and immediately before surgery. Pulse
      rate was measured each time the test was administered. There were no differences
      between the groups in sex, age, weight or the intervals between premedication and
      anaesthesia induction (p > 0.05). There were no statistically significant
      differences between the groups with respect to background anxiety. Situational
      anxiety did not significantly increase or decrease at any of the testing times,
      nor were there any differences between the groups (p > 0.05). Heart rate did not
      vary between the groups or with time (p > 0.05). In this group of patients
      undergoing elective orthopaedic procedures, clorazepate prevented a rise in
      anxiety in the immediate preoperative period. Since clorazepate is rapidly
      metabolized to nordiazepam when administered orally it might be predicted that
      the two drugs have similar properties. This hypothesis is confirmed by the
      results of the present study. We conclude that orally administered clorazepate
      dipotassium and nordiazepam have a similar effect on preoperative anxiety.

PMID- 8652039
TI  - [Value of acupuncture in treatment of migraine].
AB  - Approximately 12% of the population suffers from migraine. This sudden, usually
      unbearable headache can last for up to 72 hours and can be accompanied by
      vegetative symptoms. Prophylactic treatment is recommended if more than three
      attacks of headache occur monthly. For prophylactic therapy, beta-blockers or the
      calcium antagonist flunarizine are mostly used. Serotonin blockers, which have
      undesirable side-effects, and dihydroergotamine, which can only be used for a
      short time as well as non-steroidal antirheumatics and antidepressants and
      relaxation exercises are used more rarely. The literature reports on the
      successful treatment of migraine with acupuncture. Although none of the studies
      made to date fulfil the necessary quality criteria, there is no doubt about the
      efficacy of acupuncture in the treatment of migraine. Acupuncture therapy only
      makes sense if it reduces the patient's discomfort and the taking of drugs.

PMID- 8652040
TI  - [Transfusion incidence and indications for homologous blood sparing measures in
      single stage breast carcinoma operations].
AB  - Under a ruling by the Bundesgerichtshof from December 17, 1991 (AZ VI ZR 40/91),
      the surgeon is obliged to inform a patient about the risks of a possible blood
      transfusion if the transfusion frequency is 5% or more. Between January 1989 and
      December 1994, 273 patients with primary breast cancer at the stages pT1-3, N1-2,
      M0 underwent one-time modified radical mastectomy (n = 164) or a breast
      conserving operation (n = 109) in our hospital. The number of blood transfusions,
      pre- and postoperative haemoglobin, age, tumour size, lymph node involvement,
      kind and duration of the operation and the postoperative course were analysed. In
      all, 44 of the 273 patients (16.1%) received an homologous blood transfusion
      perioperatively. The annual transfusion rates were 39.4% (1989), 44.8% (1990),
      12.2% (1991), 16.6% (1992) and 3.1% (1993), falling to 2.2% in 1994. The mean pre
      and postoperative haemoglobin concentrations did not differ significantly (p >
      0.05) over the years: 13.4 +/- 1.0 g/dl and 12.0 +/- 1.1 g/dl in 1989 and 13.7 +/
      1.2 g/dl and 11.8 +/- 1.2 g/dl in 1994. Patients who received transfusions had
      preoperative anaemia (p < 0.021), bigger tumours (p < 0.0005) and mastectomy
      operations significantly more frequently than patients not given transfusions.
      There were no correlations between transfusions and age, lymph node involvement
      and kind and duration of operation. We conclude that, cognizant of a transfusion
      frequency of 2.2% in our hospital in one-time breast cancer operations, only
      patients with anaemia or large tumours require blood transfusions, for which
      autologous blood donations or normovolaemic haemodilution are the choices. The
      patients' attention is to be drawn to these. In cases of normal preoperative
      haemoglobin and small tumours, the physician should inform the patient that
      experience has shown that in all probability a blood transfusion will not be
      necessary and so a preoperative autologous blood donation or normovolaemic
      haemodilution can be dispensed with.

PMID- 8652042
TI  - [Nitric oxide in therapy of pulmonary hypertension after correction of congenital
      single atrium].
AB  - We report on a 19-month-old boy with congenital single atrium. Cardiac
      catheterization preceding the surgical repair revealed an elevated pulmonary
      artery pressure of 60/15 mmHg (mean pressure 40 mmHg). Pulmonary flow was 8.4
      l/min.m2 and systemic flow was 5.5 l/min.m2. Pulmonary arteriolar resistance was
      elevated to 4.2 U.m2 with 64% left-right shunt and 25% right-left shunt. Arterial
      O2-saturation varied around 90%. After surgical repair (insertion of a Goretex
      patch), the patient required mechanical ventilation with 100% oxygen for adequate
      oxygenation. Cardiac catheterization was repeated on the first postoperative day.
      No residual shunts were found. The pulmonary artery pressure was 66/40 mmHg (mean
      pressure 50 mmHg), systemic arterial pressure was 85/62 mmHg (mean pressure 68
      mmHg). Cardiac index was 2.8 l/min.m2, pulmonary vascular resistance was 12 U.m2.
      After administration of prostacyclin a significant decrease of pulmonary artery
      pressure was observed, but without changing the ratio between pulmonary and
      systemic pressure. The AaDO2 varied between 400 and 580 mmHg and the oxygenation
      index (PaO2/FiO2) was less than 1.0. In this situation, an attempt with inhaled
      nitric oxide (NO) was performed. After adding 20 ppm NO to the inspired gas, the
      AaDO2 decreased significantly from 580 to 270 mmHg and the oxygenation-index (OI)
      rose from 0.9 to 1.5. The inspired fraction of oxygen could be reduced quickly to
      60%. During the next days, the concentration of NO was reduced stepwise to 1 ppm.
      Finally, the AaDO2 was within the normal range (25-65 mmHg) and the OI rose to a
      level about 4.0. The FiO2 could be reduced to 30% and nitric oxide therapy could
      be stopped and the child could be extubated.

PMID- 8652041
TI  - [The "narcotization statistics" of Ernst Julius Gurlt of 1895--an early
      contribution to quality control in anesthesia].
AB  - The fifth compilation of anaesthetization statistics "Zur
      Narkotisirungsstatistik", presented by the surgeon Ernst Julius Gurlt in 1895
      summarizes the answers to a questionnaire of the German Surgical Society given by
      78 mainly large German surgical hospital departments. It comprises 55,395
      anaesthetic procedures, most of them (34,412) performed under chloroform,
      although this substance was still associated with many more fatal complications
      than ether. At the same time, unpleasant non-fatal complications in connection
      with the application of ether are also pointed out. Details concerning
      premedication, the role of the anaesthetist, postoperative care, documentation
      and especially complications and how to prevent and deal with them are taken from
      38 reprinted reports. Gurlt's activities initiated more than 100 years ago are to
      be seen as pioneer work in the field of anaesthesiological quality assessment.

PMID- 8652043
TI  - The contrasting roles of CD4+ T cells in intracellular infections in humans:
      leishmaniasis as an example.

PMID- 8652044
TI  - Interplay of T cells and cytokines in the context of enzymatically modified
      extracellular matrix.

PMID- 8652045
TI  - Jenner Institute--a shot in the arm for UK immunology research.

PMID- 8652046
TI  - Protective immunity against HIV infection: has nature done the experiment for us?

PMID- 8652048
TI  - Nobel lab subject of radiation probe.

PMID- 8652047
TI  - Antigen receptor 'capacity' and the sensitivity of self-tolerance.

PMID- 8652049
TI  - Soluble HIV-suppressive factor.

PMID- 8652050
TI  - Expanding the role of Peyer's patches in B-cell ontogeny.

PMID- 8652051
TI  - Preventing abnormalities in signal transduction of T cells in cancer: the promise
      of cytokine gene therapy.

PMID- 8652052
TI  - Syk deficiency--a knockout for B-cell development.

PMID- 8652053
TI  - Psoriasis: a T-cell-mediated disease?

PMID- 8652054
TI  - Molecular mimicry: CLIP, MHC Class II supermotifs and MAIDS.

PMID- 8652055
TI  - Ceramide, AIDS and long-term survivors.

PMID- 8652056
TI  - The pathogenetic role of HLA-B27.

PMID- 8652057
TI  - Transplantation of pancreas and islets of Langerhans: a review of progress.

PMID- 8652058
TI  - Immunotherapy in rheumatic disease: an idea whose time has come--or gone?

PMID- 8652059
TI  - Detailed behavioral analysis of water maze acquisition under systemic NMDA or
      muscarinic antagonism: nonspatial pretraining eliminates spatial learning
      deficits.
AB  - A detailed behavioral analysis of water-maze acquisition showed that the N-methyl
      D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine
      caused sensorimotor disturbances in behaviors required for maze performances and
      that these correlated with acquisition impairments in both hidden and visible
      platform versions of the maze in male rats. Behavioral disturbances included
      thigmotaxic swimming, swimming over and deflecting off the platform, abnormal
      swim behavior, and hyperactivity. Rats familiar with the behavioral strategies
      involved in the task performed normally under NPC17742 or scopolamine. The
      results indicated that drug-induced sensorimotor disturbances contributed to poor
      acquisition scores in naive rats. NMDA or muscarinic activity may contribute to
      but do not appear to be essential for spatial learning in the water maze.

PMID- 8652060
TI  - HemiParkinson analogue rats display active support in good limbs versus passive
      support in bad limbs on a skilled reaching task of variable height.
AB  - Rats with unilateral dopamine (DA) depletion (hemiParkinson analogue rats) are
      impaired in using the contralateral (bad) limbs for skilled movements and for
      postural adjustments and compensate by using their good limbs in novel ways. The
      present study consisted of a reaching task in which compensatory adjustments
      using the good limbs would not be affective, thus forcing the rats to use their
      bad limbs. The DA-depleted rats failed to use their bad hindlimb to extend their
      reach at high reaching heights and failed to lower their body with their bad
      forelimb to reach at low reaching heights. It is suggested that extensive DA
      depletion may result in the loss of the ability to apply forces with the affected
      limbs.

PMID- 8652061
TI  - Impaired motor learning performance in cerebellar En-2 mutant mice.
AB  - Mice homozygous for a null mutation in their En-2 gene exhibit cerebellar
      neuroanatomical alterations including absence and misplacements of specific
      fissures and size reduction. The present study investigated cerebellar function
      by comparing the behavior of age-matched homozygous and heterozygous En-2 mutant
      and wild-type mice. Motor function of the mutants was found normal in several
      situations. Habituation to novelty in the open field was not significantly
      different in mutants. However, in a motor learning paradigm, the rotating rod,
      the performance of homozygous mutant mice improved significantly less than that
      of the heterozygous mice which were also significantly impaired compared to wild
      type mice. Unlike other cerebellar mutants in which severe motor or sensory
      defects are obvious, the En-2 mouse model offers a unique tool to study the role
      of cerebellum in complex behavioral phenomena, including motor learning, without
      confounding effects.

PMID- 8652062
TI  - Neural unit activity in the trigeminal complex with interpositus or red nucleus
      inactivation during classical eyeblink conditioning.
AB  - During classical conditioning, many neurons in the trigeminal complex of rabbits
      exhibit activity that is related to the conditioned stimulus (tone), the
      unconditioned stimulus (airpuff), or to the conditioned response (eyeblink). For
      these reasons the trigeminal complex has been hypothesized to be a brainstem
      locus for the neuronal plasticity associated with conditioning. In this
      experiment, the learning-related activity (unit activity associated with the
      conditioned response) in the trigeminal is abolished when either the red nucleus
      or interpositus nucleus of the cerebellum is temporarily inactivated by cooling,
      but the stimulus-evoked activity is unaffected by cooling. This study and
      previous results support the suggestion that the learning-related activity seen
      in the trigeminal is driven by the interpositus by way of the red nucleus.

PMID- 8652063
TI  - The effects of olfactory and somatosensory desensitization on Fos-like
      immunoreactivity in the brains of pup-exposed postpartum rats.
AB  - Fos-like immunoreactivity (fos-lir) was examined in sites within the "maternal
      circuit" in postpartum female rats that received various sensory desensitizations
      and were exposed to pups for 1 or 2 hr. Neither olfactory bulbectomy nor
      thelectomy (nipple removal) significantly reduced the fos-lir in the anterior
      medial preoptic area (MPOA), although reductions following bulbectomy in medial
      amygdala did occur. Peripherally induced hyposmia by ZnSo4 reduced fos-lir in the
      olfactory structures (olfactory bulbs, piriform cortex, and olfactory tubercle),
      in medial and cortical nuclei of the amygdala, but not in anterior MPOA.
      Application of the topical anesthetic Emla to the ventrum only reduced fos-lir in
      the somatosensory cortex. Combined olfactory and ventral desensitizations
      produced marginal reductions in posterior MPOA. It is suggested that the MPOA is
      primarily involved as part of the effector system in the expression of the
      behavior. In contrast, the amygdala is involved in processing sensory cues
      received from pups during dam-litter interactions.

PMID- 8652064
TI  - Classical conditioning in the fetal rat: reinforcing properties of dynorphin A (1
      13).
AB  - This study examined the reinforcing properties of dynorphin A (1-13) in a single
      trial classical conditioning paradigm in the E20 rat fetus. Injection of
      dynorphin into the cisterna magna increased fetal motor activity and reduced
      facial wiping in a test of perioral cutaneous responsiveness. Dynorphin was
      effective as an unconditioned stimulus (US) in a classical conditioning paradigm
      using an artificial nipple conditioned stimulus (CS) and dynorphin A (1-13) US.
      The association between CS and US was dependent on activity in the kappa opioid
      system. Re-exposure to the artificial nipple CS after a single pairing of the
      nipple with dynorphin resulted in conditioned activation of the kappa opioid
      system. Dynorphin A (1-13) functions as a reinforcer for classical conditioning
      in the rat fetus after intracisternal or intrahemispheric injection, with the
      conditioned response depending on route of administration and site of injection.

PMID- 8652065
TI  - Interoceptive sensory signals produced by 24-hr food deprivation, pharmacological
      glucoprivation, and lipoprivation.
AB  - The energy antimetabolites 2-deoxy-D-glucose (2-DG) and Na-2-mercaptoacetate (MA)
      both reliably augment food intake in rats. The present research was designed to
      assess if they also give rise to interoceptive cues like 24-hr food deprivation.
      Rats were first trained to discriminate a mild shock based on interoceptive cues
      arising from 1- and 24-hr food deprivation. They were then tested for generalized
      control of conditioned responding to interoceptive cues produced by 2-DG, MA, and
      saline. Results suggest that 2-DG (350 mg/kg) produces interoceptive sensory cues
      like those following 24-hr food deprivation. Further, no evidence was found to
      suggest that MA, either alone or in combination with 2-DG (100 mg/kg), produces
      interoceptive cues like 2-DG or 24-hr food deprivation.

PMID- 8652067
TI  - Area postrema mediates the formation of rapid, conditioned palatability shifts in
      lithium-treated rats.
AB  - The rapid acquisition and subsequent retention of lithium-induced conditioned
      changes in taste reactivity responses to sucrose were examined in rats with the
      area postrema (AP) either ablated or intact. On 2 conditioning days, a series of
      brief intraoral sucrose infusions was paired with the effects of LiCl or NaCl
      injections. Repeated associations of the sucrose taste with the effects of
      lithium significantly reduced ingestive responses and increased aversive
      responses only in the AP-intact group. AP-ablated rats treated with LiCl and rats
      injected with NaCl displayed an ingestive pattern of responses. Only the AP
      intact rats, previously injected with LiCl, subsequently displayed evidence of a
      conditioned taste aversion. We conclude that toxin activation of the AP is
      required to produce the conditioned shift in taste reactivity responses and
      subsequent expression of a taste aversion in rats treated with lithium.

PMID- 8652066
TI  - Separate neural substrates mediate the motivating and discriminative properties
      of morphine.
AB  - A previous study (T. V. Jaeger & D. van der Kooy, 1993) has implicated a visceral
      and taste region (parabrachial nucleus), but not mesolimbic dopamine terminal
      fields (nucleus accumbens), as a substrate for opiate discriminative effects. The
      authors now show that (a) morphine's discriminative effects in the parabrachial
      nucleus (PBN) require the activation of opiate receptors; (b) in rats trained to
      discriminate morphine from saline, infusions of morphine into the ventral
      tegmental area (VTA) do not generalize to the systemic training condition; (c)
      infusions of morphine into the PBN, but not the VTA, serve as a stimulus for the
      acquisition of discrimination learning; and (d) morphine applied to the VTA, but
      not the PBN, is motivating. The data show that the motivating and discriminative
      effects of morphine are processed separately by the brain. Further,
      discriminative drug effects are neither necessary nor sufficient for opiate
      motivational effects.

PMID- 8652068
TI  - Training to criterion in eyeblink classical conditioning in Alzheimer's disease,
      Down's syndrome with Alzheimer's disease, and healthy elderly.
AB  - The cholinergic antagonist scopolamine delays acquisition of eyeblink classical
      conditioning (EBCC) in rabbits and humans, but scopolamine-treated organisms
      eventually acquire conditioned responses (CRs). Patients with probable
      Alzheimer's disease (AD) and older adults with Down's syndrome (DS/AD) have
      disrupted cholinergic systems and perform EBCC very poorly. It was hypothesized
      that patients with probable AD and DS/AD, like scopolamine-injected organisms,
      would acquire CRs if given sufficient training. Twelve probable AD patients, 12
      DS/AD patients, and 6 healthy elderly control individuals participated in 5 daily
      90-trial sessions of EBCC. Fifty-eight percent of the probable AD, 92% of the
      DS/AD, and 100% of the control participants achieved learning criterion. Probable
      AD, DS/AD, and control participants had statistically significant increases in
      the percentage of CRs produced over 5 EBCC sessions. The neural substrate for
      EBCC was not eliminated in probable AD or DS/AD patients, although the learning
      mechanism was disrupted.

PMID- 8652069
TI  - Frontal brain asymmetry predicts affective style in men.
AB  - Recent research suggests that a significant relationship between frontal brain
      asymmetry (FBA) and affective style can be documented in women with 1-measurement
      occasion. The purpose of this study was to determine whether this finding is
      generalizable to men. Resting electroencephalogram (EEG) activity was recorded
      from male adults during 5 60-s baselines on 1 measurement occasion. Mean alpha
      power asymmetry was extracted in midfrontal and lateral-frontal sites. For the
      lateral-frontal site, but not the midfrontal site, there was a significant
      relationship between relative left anterior activation and positive affective
      style. These results suggest that lateral FBA is a robust and state-independent
      measure of affective style in men.

PMID- 8652070
TI  - Anterior rhinal cortex and amygdala: dissociation of their contributions to
      memory and food preference in rhesus monkeys.
AB  - Rhesus monkeys were trained on 2 versions of delayed nonmatching-to-sample, one
      with multiple pairs of objects and the other with a single pair, to evaluate
      their ability to remember objects. They then received either bilateral aspiration
      lesions of the anterior rhinal cortex or bilateral excitotoxic lesions of the
      amygdala, or were retained as unoperated controls. On re-presentation of the
      multiple-pair task, monkeys with anterior rhinal cortex lesions failed to show
      the improvement observed in both other groups in remembering the objects over
      delay intervals ranging from 10 to 60 s. Also, monkeys with anterior rhinal
      cortex lesions were impaired relative to the controls in relearning the single
      pair version of the task. Conversely, on a formal test of food preference,
      monkeys with amygdala lesions showed abnormal patterns of food choice, whereas
      monkeys with anterior rhinal cortex lesions did not. Visual memory impairments
      formerly attributed to amygdala damage are probably due to the rhinal cortex
      damage associated with aspiration lesions of the amygdala.

PMID- 8652071
TI  - Hyperexcitability: exaggerated fear-potentiated startle produced by partial
      amygdala kindling.
AB  - The present study asked whether partial amygdala kindling would affect the
      expression of conditioned fear-potentiated startle. Rats were conditioned to be
      fearful of a light. They were then stimulated bilaterally in the amygdala or
      hippocampus on 2 consecutive days (partial kindling). Rats were tested 24 hr
      later for fear-potentiated startle. Amygdala-kindled rats had exaggerated fear
      potentiated startle compared to sham-kindled rats. Hippocampus-kindled rats also
      displayed fear-potentiated startle, but no greater than that of sham-kindled
      rats. Partial amygdala kindling induced c-fos messenger RNA (mRNA) expression, a
      marker for neuronal activation, throughout the limbic and neocortices. In
      contrast, partial hippocampus kindling induced c-fos mRNA in the hippocampus
      only. The data suggest that kindled-induced hyperexcitability of the amygdala and
      limbic cortices produced exaggerated conditioned fear-potentiated startle.

PMID- 8652072
TI  - Amygdala stimulation enhances the rat eyeblink reflex through a short-latency
      mechanism.
AB  - Amygdala stimulation was shown to enhance the trisynaptic (fast, R1) component of
      the electromyogram recorded in the rat orbicularis oculi (oo) muscle, which is
      responsible for the active force generating eyelid closure. The eyeblink was
      elicited via direct electrical stimulation of the supraorbital branch of the
      trigeminal nerve. Possible mechanisms responsible for the effect of amygdala
      stimulation on the eyeblink reflex were evaluated by measuring the amount of R1
      enhancement as a function of the interstimulus interval (ISI) between the onset
      of amygdala and trigeminal nerve stimulation. Amygdala stimulation produced
      significant R1 enhancement at ISIs that imply short-latency excitation of the
      eyeblink circuit by way of a fast-acting neurotransmitter.

PMID- 8652073
TI  - Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and
      nucleus accumbens on the reaction to novelty: implication for limbic-striatal
      interactions.
AB  - The effects of bilateral excitotoxic lesions of 3 major sources of afferents to
      the ventral striatum (nucleus accumbens) were compared on an open field test of
      food neophobia allowing the choice between familiar and novel food. Whereas
      lesions of the basolateral amygdala and ventral subiculum had qualitatively
      similar effects to reduce food neophobia (although not affecting the latency to
      eat), amygdala lesions increased and the ventral subiculum decreased locomotor
      activity. In contrast, damage to the ventromedial prelimbic prefrontal cortex
      only affected initial food choice and latency measures. By comparison,
      excitotoxic lesions of the nucleus accumbens itself and intra-accumbens infusion
      of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 increased activity and
      attenuated food neophobia. Results are discussed in terms of the role of limbic
      and prefrontal neuronal networks converging in the nucleus accumbens to control
      different aspects of the behavioral response to novelty.

PMID- 8652074
TI  - Functional significance of the early component of the human blink reflex.
AB  - The relationship between the size of the first electromyographic (EMG) component
      of the cutaneous blink reflex (R1) and onset of eyelid closure in human adults
      was determined in 4 experiments in which R1 size was varied by different means:
      change in stimulus intensity, paired stimulation, and warning. Two-phase lid
      movements were frequently seen, with an early small movement followed by a large
      rapid movement. All experiments showed that larger R1s were associated with
      shorter latencies of both movements. This covariation was general across
      participants and was independent of shifts in the excitability of the blink
      reflex pathways indexed by R1 latency, R2 latency, and R2 area (R2 is the more
      prolonged, later EMG component). The results indicate that R1 acts first to evoke
      an early lid movement and second to facilitate eyelid closure by the later R2
      burst. Identification of this second behavioral function for R1 aids the
      interpretation of other findings and encourages its use as a model system.

PMID- 8652075
TI  - Effects of lesions of the associative parietal cortex on the acquisition and use
      of spatial memory in egocentric and allocentric navigation tasks in the rat.
AB  - It has been hypothesized that the rat associative parietal cortex (APC) is
      involved in the association between visuospatial and locomotion-generated
      (kinesthetic) information. To study the kinesthetic component, APC-lesioned and
      control rats were trained in total darkness to reach a submerged platform in the
      Morris water maze. In the egocentric task, the relative position of the starting
      point and the platform was constant all over training. Parietal rats have been
      found impaired in acquisition and to a less extent in retention of this task. In
      the allocentric task, rats were then trained in the standard version of the
      navigation task. A mild deficit was observed in acquisition of this task because
      the APC-lesioned rats displayed longer escape latencies but control-like search
      patterns. These results suggest that the APC is involved in the coding of
      kinesthetic information that plays an important role in place navigation.

PMID- 8652076
TI  - Detailed behavioral analysis of water maze acquisition under APV or CNQX:
      contribution of sensorimotor disturbances to drug-induced acquisition deficits.
AB  - N-methyl-D-aspartate (NMDA) receptor antagonists disrupt acquisition of the water
      maze and cause sensorimotor disturbances. In a detailed behavioral analysis in
      male rats, it was found that the NMDA antagonist DL-2-aminophosphonovaleric acid
      (APV) caused sensorimotor disturbances in behaviors required for maze performance
      and that these correlated with acquisition impairments in both hidden and visible
      platform versions of the maze. Behavioral disturbances included thigmotaxic
      swimming, swimming over and deflecting off the platform, abnormal swim behavior,
      and hyperactivity. Rats familiar with the behavioral strategies involved in the
      task performed normally under APV. The results are consistent with the known role
      of NMDA receptors in sensorimotor mechanisms and suggest that drug-induced
      sensorimotor disturbances contributed to poor acquisition scores in naive rats.
      NMDA may contribute to but does not appear to be essential for spatial learning
      in the water maze.

PMID- 8652077
TI  - Safety implications of transferring the oral contraceptive from prescription-only
      to over-the-counter status.
AB  - The idea of making oral contraceptives available without prescription has a long
      history, and has been recently revived in the US and the UK. High dose oral
      contraceptives have generally been replaced by low dose formulations and,
      subsequently, most cardiovascular risks have been reduced and a protection
      against ovarian and uterine cancers has been consistently demonstrated. Oral
      contraceptive compliance, however, continues to be a problem, but there is no
      reason to assume that wise practice would be any more or less if oral
      contraceptives were available over-the-counter (OTC). Some countries have
      introduced alternatives to prescription-only oral contraceptives, whereby nurses,
      midwives, social workers and/or pharmacists are incorporated into the
      distribution process. This article concludes that the balance of risks and
      benefits is in favour of OTC access for oral contraceptives.

PMID- 8652078
TI  - A reappraisal of quinolone tolerability. The experience of their musculoskeletal
      adverse effects.
AB  - The experience of the rheumatological adverse effects of fluoroquinolones should
      be helpful for both toxicologists and epidemiologists. In the case of
      fluoroquinolone-related arthropathy, the paediatric clinical experience seems to
      support the possible use of newer derivatives like ciprofloxacin in children who
      really need it. This therapeutic attitude is still contradictory to the labelling
      of fluoroquinolones. Inversely, there has been an important time-lag between the
      first reports of fluoroquinolone-related tendinopathies and the official
      recognition of this unusual toxic phenomenon. This delay, along with the
      widespread use of fluoroquinolones, makes it difficult to return to more
      reasonable prescribing guidelines for these very useful and effective anti
      microbial compounds. The reasons why potentially serious adverse effects of
      fluoroquinolones were not anticipated before their commercialisation may be
      related to the lack of adequate in vitro and in vivo models, and the
      unexpectedness of the events. When it occurs, fluoroquinolone-induced arthropathy
      is most frequently benign, and heals without sequelae. The prognosis is not so
      favourable in the case of fluoroquinolone-related tendinopathy, which carries an
      important risk of immediate or secondary tendon rupture. Increasingly,
      fluoroquinolones are being prescribed for benign infections of the urinary or
      bronchopulmonary tracts. Sometimes, they are even used for antimicrobial
      prophylaxis before surgical or endoscopic procedures. We believe that for any
      prescription, the risk/benefit ratio of the fluoroquinolones should be carefully
      considered, since better tolerated, less expensive drugs can usually be
      prescribed. Clear information dedicated both to physicians and patients regarding
      the cautions for use and possible adverse effects of fluoroquinolones would help
      reduce the risk and severity of adverse reactions. This is especially important
      for phototoxicity, tendinopathy and cardiovascular adverse effects. As underlined
      by Ball and Tillotson in this issue, the future clinical use of the
      fluoroquinolones will be determined by the balance between the antibacterial
      efficacy and adverse effects of these agents. The adverse reactions affecting the
      musculoskeletal system provide a good example of this dilemma. Given the absence
      of an adequate model of tendinopathy and the poor predictivity of animal
      manifestations in arthropathy and cartilage lesions in humans, careful monitoring
      of patients during phase II and III trials and, more importantly, long term
      pharmacovigilance during the postmarketing period, are still strongly warranted.

PMID- 8652079
TI  - Tolerability of fluoroquinolone antibiotics. Past, present and future.
AB  - New fluoroquinolones have been in clinical use for 10 years and have an excellent
      record of safety and tolerance. The main elements of their adverse reaction
      profile were predictable from human experience with precursor naphthyridines and
      quinolones, and from toxicological studies in animals. Thus gastrointestinal
      reactions (1 to 5%), skin disturbances (less than 2.5%) and central nervous
      system (CNS) effects (usually around 1 to 2%) were anticipated. Individual group
      members exhibit particular properties in relation to their chemical structures,
      for example the phototoxicity associated with 8-halogenation of the nucleus and
      found to be a particular problem with lomefloxacin and sparfloxacin. Other
      members, for example ofloxacin, are linked to a higher than usual incidence of
      CNS reactions and psychological disturbance. However, despite increasing usage,
      none of the present group have been implicated in joint damage in children, which
      had been a major concern following reports of this effect in juvenile animals in
      chronic toxicity studies. Furthermore, intravenous formulations appear to have no
      associated increase in toxicity. Crystalluria with associated renal damage,
      originally thought likely to limit intravenous dosage, has not proved to be a
      problem in humans. Clinically significant interactions may occur but, as with
      those involving various NSAIDs and potentially leading to convulsions, they have
      been defined and are thus avoidable. Postmarketing surveillance studies and
      prescription event monitoring have largely confirmed the limited adverse reaction
      profile defined during clinical trials. However, some unexpected reactions have
      appeared after launch, most notably the episodes of haemolysis, renal failure and
      hypoglycaemia which led to the withdrawal of temafloxacin. These effects have not
      been observed with other fluoroquinolones. However, severe tendinitis appears to
      be a group effect, albeit rare, and anaphylactoid reactions have been reported
      with several of the fluoroquinolone group, often in AIDS patients. The new
      fluoroquinolones are essentially a well tolerated group of antibacterials, the
      benefits of which clearly outweigh their disadvantages in a wide range of
      indications. Clinical efficacy has been a larger determinant of which members
      have succeeded in the marketplace than potential toxicity. However, the lesser
      potential for adverse effects of some of the class, e.g. norfloxacin, ofloxacin
      and ciprofloxacin, has undoubtedly led to their more widespread use. For others,
      e.g. enoxacin, limited clinical utility and a perception of increased toxicity
      have resulted in sidelining. There remains the potential for development of safer
      and yet more active fluoroquinolones via chemical manipulation both of the
      nucleus and the side chain substituents.

PMID- 8652080
TI  - beta-blockers. Drug interactions of clinical significance.
AB  - The clinician prescribing beta-blockers for his or her patients is faced with an
      often difficult situation. There are many beta-blockers, each with its own
      pharmacological profile. Patients are often taking multiple medications, thus
      increasing the risk of both anticipated and unexpected drug interactions. Reports
      of drug interactions are frequently anecdotal. The prescriber may not be aware of
      the patient's other medications or lifestyle habits. Pharmacokinetic and
      pharmacodynamic drug interactions involving beta-blockers are documented in the
      literature, but these studies often examine small numbers of patients. For these
      reasons, it is difficult for the practitioner to distill guidelines for the
      administration of beta-blockers in conjunction with other medication. In general,
      beta-blockers are well tolerated, and symptomatic drug interactions are
      relatively infrequent. It is incumbent upon the clinical practitioner to have
      knowledge of his or her patient's drug profile and to be aware of the various
      drug interactions as well as each patient's unique pathophysiological profile
      when prescribing any medication, including beta-blockers. beta-Blockers may
      interact with a large number of commonly prescribed drugs, including
      antihypertensive and antianginal drugs, inotropic agents, anti-arrhythmics,
      NSAIDs, psychotropic drugs, anti-ulcer medications, anaesthetics, HMG-CoA
      reductase inhibitors, warfarin, oral hypoglycaemics and rifampicin (rifampin).

PMID- 8652083
TI  - Campomelic dysplasia associated with mandibular clefting.
AB  - Campomelic dysplasia (CD), is a lethal dwarfism of the newborn, characterised by
      rhizomelic dwarfism, bowed femora and tibiae, associated with other skeletal and
      extraskeletal defects. It is suggested that there are long-limbed and short
      limbed varieties. Various clinical and radiological anomalies have been described
      in both types of CD. Here, we describe for the first time a cleft in the
      mandibula in a patient with campomelic dysplasia.

PMID- 8652082
TI  - Presymptomatic diagnosis of familial adenomatous polyposis using intragenic
      polymorphisms and CA repeats flanking the APC gene.
AB  - To assess the value of DNA markers for the diagnosis of familial adenomatous
      polyposis (FAP) in South Africa, two highly informative CA-repeat polymorphisms
      (LNS CA-repeat in D5S346 and YN5.64c CA-repeat in D5S82) flanking the adenomatous
      polyposis coli (APC) gene, and three intragenic restriction fragment length
      polymorphisms (RFLPs) (exon 11/RsaI, exon 15.11/MspI, 3'UTR/SspI), were used for
      haplotype analysis in 13 South African families with the disease. The combination
      of these polymorphic markers proved to be highly informative and allowed an
      accurate diagnosis of FAP in 34/35 of the at-risk individuals analysed. Indirect
      molecular screening can therefore provide a comprehensive pre-clinical diagnostic
      test for FAP in South Africa. No predominant haplotype was found to be associated
      with FAP within the South African population. This suggests the absence of
      founder-type mutations in affected families and therefore marker studies remain
      important for the pre-clinical diagnosis of FAP in South Africa.

PMID- 8652084
TI  - A Croatian case of the Schinzel-Giedion syndrome.
AB  - The Schinzel-Giedion syndrome is an infrequently described malformation syndrome,
      mainly characterized by a profound mental deficiency, a typical face including a
      midface hypoplasia, urogenital abnormalities, and minor radiographic features.
      Death prior to two year of age is the rule. A boy with typical features of the
      syndrome is described. He died at the age of 21 months. This is the first case of
      this syndrome reported from Croatia. The recurrence in only one of the 20
      families, does not firmly sustain an autosomal recessive pattern of inheritance,
      although this still remains possible.

PMID- 8652085
TI  - Costello syndrome: report of an 8-month-old marasmic boy.
AB  - An 8-month-old boy having multiple congenital anomalies (MCA) and mental
      retardation (MR) as part of the Costello syndrome is described. This observation
      emphasizes once more the severe and early-onset postnatal growth failure as the
      first, major clinical sign of this MCA/MR syndrome.

PMID- 8652086
TI  - Marden-Walker phenotype: a diagnostic dilemma.
AB  - Two cases are presented with a phenotype mostly resembling the condition named
      Marden-Walker syndrome. Main features of this condition are blepharophimosis,
      micrognatia, congenital joint contractures, mental retardation, growth
      retardation and decreased muscular mass. Follow-up data of patients with this
      condition are scarce and most patients reported so far were infants or young
      children. We report two patients meeting many of the criteria proposed for
      diagnosing this particular phenotype. One case was diagnosed in adolescence and
      the other as an adult. Initially described as a syndrome, this condition is more
      likely to be a phenotypic expression of various heterogeneous diseases.

PMID- 8652087
TI  - Temperament in Williams syndrome.
AB  - In this study we evaluated the temperament characteristics of a group of 13
      subjects with Williams-Beuren syndrome (WBS) and compared the results to the
      findings in a control group of 13 individuals with the same degree of mental
      retardation of different etiology. On the different subscales of the Dutch
      adaptation of the Parent Temperament Questionnaire no statistically significant
      differences between the WBS and the control group were noted. An easier
      temperament was noted in the control group, and we also found greater intensity,
      less persistence and lower treshold in WBS subjects. The present findings
      indicate that the "specific" behavioural phenotype in WBS patients is apparently
      more related to mental retardation itself than to the underlying genetic defect.
      Further studies on a large group of WBS patients and mentally retarded control
      group are needed to confirm these findings.

PMID- 8652088
TI  - Mental retardation, hypotrichosis and syndactyly: a new entity?
AB  - We have studied a boy with a particular clinical picture of mental retardation,
      hypotrichosis, early eruption of teeth, and syndactyly of hands. One sister, who
      died at four month of age, probably was also affected. This clinical association
      may represent an undescribed condition. Autosomal recessive inheritance is
      suggested.

PMID- 8652089
TI  - A distinct phenotype associated with partial trisomy 10q due to proximal direct
      duplication 10q11 --> q223?
AB  - We describe a 15-months-old female child with proximal 10q trisomy due to direct
      duplication 10q11 --> q223. Reviewing the literature a further delineation of the
      clinical phenotype of this rare chromosomal abnormality is proposed. The main
      clinical features associated with 10q11-q22 duplication are: mild to moderate
      mental retardation, microcephaly, postnatal growth retardation, ocular
      malformations, heart defects, abnormalities of the extremities and typical facies
      with thin, bowed upper lip, upturned nasal tip, high palate, small chin and
      everted ears.

PMID- 8652081
TI  - Clinical toxicity of cytokines used as haemopoietic growth factors.
AB  - A number of cytokines are used as haemopoietic growth factors and this review
      focuses on toxicities associated with granulocyte-macrophage colony-stimulating
      factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)
      1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF
      and G-CSF, currently approved for clinical use, are generally well tolerated by
      the majority of patients during short term administration. Constitutional
      symptoms and bone pain are the most frequently reported adverse effects, but they
      are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and
      exacerbation of autoimmune thyroiditis or autoimmune haematological disorders
      have sometimes been described. Severe cardiovascular complications include the
      possibility for arterial thromboses and the vascular leak syndrome, which is more
      specifically observed with GM-CSF. Reports of several cases and small series of
      patients have suggested that growth factors might increase the pulmonary toxicity
      of chemotherapy, a possibility that remains debated and requires further
      attention. Generalised or local cutaneous reactions are frequently noted with GM
      CSF. Leukocytoclastic vasculitis was observed with both growth factors, while
      neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of
      psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G
      CSF. The hepatotoxic potential of the growth factors is not clearly established,
      but the occurrence of coagulation abnormalities has recently been reported. Renal
      and biological disturbances are usually transient. Long term treatment with GM
      CSF and G-CSF also seems to be well tolerated, but the possible occurrence of
      several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration
      of underlying disease, require further investigation in patients receiving
      prolonged treatment, as in myelodysplasia. Finally, antibodies against growth
      factors have been reported only with GM-CSF. Other cytokines are still under
      investigation. Flu-like and constitutional symptoms, sometimes dose-limiting,
      have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally
      associated with such adverse effects. More specific adverse events, also
      frequently considered as dose-limiting toxicities, include hypotension with IL-1,
      severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal
      lesions with IL-4. Severe capillary leak syndrome has been reported only with IL
      4. M-CSF toxicity is minimal and limited to reversible but sometimes dose
      limiting thrombocytopenia and ophthalmological symptoms with the recombinant
      product. Again, the safety of long term administration of these cytokines has not
      yet been determined, and IL-3-induced disease progression in myelodysplastic
      patients has been suggested.

PMID- 8652091
TI  - Inverted nipples in Robinow syndrome.
AB  - We report a female newborn with typical clinical and radiological signs and
      symptoms of Robinow syndrome. We noted inverted nipples, which became only
      clearly evident after the age of 6 months, as a "new" associated clinical symptom
      in this syndrome.

PMID- 8652090
TI  - Follow-up of a patient with partial trisomy 9p and partial monosomy 8p;
      description of physical and psychosocial development.
AB  - A patient is described with partial trisomy 9p and partial monosomy 8p due to a
      maternal translocation (t(8;9)(p23;p13)). The clinical phenotype is compatible
      with the partial trisomy 9p syndrome. This is a clinically recognizable syndrome
      with mental retardation as a constant feature. Little is known about the outcome
      and level of functioning of patients with this condition. We present the follow
      up of a patient with partial trisomy 9p who has been regularly examined from
      birth until age 10 years.

PMID- 8652093
TI  - Neuroblastoma in patients with constitutional chromosomal changes.

PMID- 8652092
TI  - Cerebro-costo-mandibular syndrome: a follow-up study with 6 patients.

PMID- 8652094
TI  - Bilateral aplasia of the mandibular ramus and condyle in Klinefelter syndrome.

PMID- 8652095
TI  - Implications of prenatal diagnosis of sickle cell disease.
AB  - Prenatal diagnosis (PND) of sickle cell disease (SCD) has been feasible since
      about 15 years. The number of PND performed for SCD has constantly increased
      during these years, but its availability raises difficult ethical questions for
      parents and counsellors. Concerning at-risk parents, only 50% (data in the
      literature) to 70% (personal data) ask for PND. Our study shows that mainly
      cultural reasons, then religious ones, educational level and the number of
      children in the family weigh on the parents' decision to request this diagnosis.
      The counsellors' position is difficult since clinical severity of the disease is
      highly variable, there is no early prognostic factor, and the median life
      expectancy of patients in industrialized countries exceeds 40 years. We need to
      define a counselling which would consider the image of the illness in the
      populations involved, in order to help parents understand the implications of the
      choice they are asked to make.

PMID- 8652096
TI  - Effects of cation interactions on sugar anion conformation in complexes of
      lactobionate and gluconate with calcium, sodium or potassium.
AB  - In the investigated compounds, the tetrahydrated calcium chloride salt of
      lactobionic acid (Ca2+.-Cl(-).C12H21O12(-).4H2O), potassium lactobionate (K+.
      C12H21O12-), sodium lactobionate monohydrate (Na+.-C12H21O12-.H2O) and calcium
      galactonate hydrate (Ca2+.2C6H11O7(-).5H2O), the cations and hydrogen-bonding
      systems have a strong influence on the geometries and conformations of the
      carbohydrate anions.

PMID- 8652097
TI  - Redetermination of octahydrochrysene.
AB  - The central rings of 1,2,3,4,7,8,9,10-octahydrochrysene, C18H20, are essentially
      planar, with the r.m.s. deviation of the atoms defining the plane from the best
      fit plane being 0.013 (2) A. The outer rings are found to be substantially non
      planar, contrary to the conclusion of an earlier study based on photographic data
      [Ferrier & Iball (1958). Acta Cryst. 11, 325-329]. The C-C single-bond distances
      in the outer rings are quite uniform, with the range of observed values varying
      by only 0.017 (6) A. There are no notably close intermolecular approaches.

PMID- 8652098
TI  - A pyrazoline derivative of eunicin acetate.
AB  - The present crystal structure determination established spiro
      [?3a,4,5,6,7,8,11,12,13,14,15,15a-dodecahydro-6,10,14-trimet hyl-2-oxo-5, 15
      epoxy-3H-cyclotetradeca-[b]furan?-3,3'-1'-pyrazoline]-6-yl acetate, C23H34N2O5,
      as a pyrazoline derivative of eunicin acetate. The spiro substitution of the
      pyrazoline ring causes elongation of the bonds within the lactone ring and also
      shortening of the carbonyl bond. The cembranolide skeleton is slightly more bent
      than that observed in the parent eunicin molecule.

PMID- 8652099
TI  - A new analogue of nifurtimox.
AB  - 1-?[(5-Nitro-2-furyl)methylene]amino?-1,2,4-triazole, C7H5N5O3, is a new analogue
      of nifurtimox with activity against Tripanosoma cruzi. In the crystal structure,
      the molecule lies on a mirror plane and has an E-sZ conformation along the N = C
      C moiety. The molecules are linked through C-H...O and C-H...N interactions.

PMID- 8652100
TI  - Chiral alpha -hydroxy acids: racemic 2-hydroxy-2,3,3-trimethylbutanoic acid and 2
      hydroxy-2-trimethylsilylpropanoic acid.
AB  - Both C7H14O3 and C6H14O3Si crystallize as racemates from acetone solution, the
      former incorporating water of crystallization (C7H14O3.0.5H2O). The crystal
      structures display extensive intermolecular hydrogen bonding involving the
      hydroxy and carboxylic acid groups to give polymeric networks.

PMID- 8652101
TI  - Hippuryl-L-histidyl-L-leucine, a substrate for angiotensin converting enzyme.
AB  - The tripeptide crystallizes as a zwitterion with a protonated histidyl ring and
      the C-terminus ionized and with five water molecules of hydration
      (C21H27N5O5(.5)H2O). The tripeptide adopts an all trans extended conformation
      with the histidine and phenyl rings parallel to one another. The C-terminus coils
      into a helical conformation. An intramolecular hydrogen bond between the C
      terminus and the N delta atom of the histidine ring stabilizes the helical
      conformation. The principal torsion angles are phi 1 = -67.7 (8), psi 1 = 140.8
      (5), omega 1 = 171.0 (6), phi 2 = -156.5 (5), psi 2 = 162.7 (5), omega 2 = 175.0
      (5), phi 3 = -96.4 (6), psi T1 = 14.5 (8) and psi T2 = -164.6 (6) degrees [IUPAC
      IUB Commission on Biochemical Nomenclature (1970). J. Mol. Biol. 52, 1-17]. The
      tripeptides are linked in infinite chains through a short intermolecular hydrogen
      bond between the C-terminal carboxylate group and the protonated histidy1 N
      epsilone atom.

PMID- 8652102
TI  - Surface modification of polymers: chemical, biological and surface analytical
      challenges.
AB  - Surface modification methods can optimise the biocompatibility or the specificity
      of biointeraction of a biosensor or medical device. With only the surface
      modified, the manufacture and implantation protocol remain unchanged. This review
      article summarises some of the chemical, surface analytical and biological
      challenges associated with surface modification of biosensors and biomedical
      devices.

PMID- 8652103
TI  - Engineered fusion molecules at chelator lipid interfaces imaged by reflection
      interference contrast microscopy (RICM).
AB  - In molecular biology, biotechnology, and protein-engineering, the expression of
      histidine fusion proteins is a very powerful technique for the identification and
      one-step purification based on the interaction of the histidine stretch with
      immobilized metal complexes. By synthesis of a novel class of chelator lipids,
      this technique was combined with the concept of self-assembly leading to
      interfaces for immobilization and orientation of histidine-tagged biomolecules
      (Schmitt et al., 1994). Here, the chelator lipid layers were transferred onto
      solid substrate by vesicle fusion and Langmuir-Blodgett-techniques. Specific
      binding of a peptide containing an oligohistidine sequence to these
      functionalized interfaces was demonstrated by reflection interference contrast
      microscopy (RICM). Due to the phase separation behaviour of lipid mixtures, the
      chelator lipid interface could be further structured in two dimensions. Binding
      and organization of histidine-tagged molecules at these two-dimensional
      recognition arrays was imaged by RICM with a layer thickness resolution of 0.2
      nm, and 0.5 microm laterally. Specific docking can be triggered by adding nickel
      ions and disrupted by EDTA. This concept opens up possibilities for reversible
      immobilization, enrichment and organization of histidine fusion proteins at
      interfaces and their application in biosensing.

PMID- 8652104
TI  - Photo-patterning of sensor surfaces with biomolecular structures:
      characterisation using AFM and fluorescence microscopy.
AB  - The miniaturisation of biosensors has resulted in the need to develop techniques
      for the high resolution patterning of different biological molecules onto
      surfaces. In this paper, we describe a procedure for the selective deposition of
      antibodies using biological self-assembly with photo-activation of a bound
      ligand, and we will detail methods which may subsequently be used to characterise
      the resultant biomolecular constructs.

PMID- 8652105
TI  - A laser assisted deposition technique suitable for the fabrication of biosensors
      and molecular electronic devices.
AB  - The recently developed technique of laser induced plasma deposition is used to
      obtain layers of different protein molecules on a substrate. The biological
      activity of the deposits is checked and micropatterning of active antibodies is
      achieved.

PMID- 8652106
TI  - Interface analysis in biosensor design.
AB  - In a survey, the analytical tools to characterise and optimise properties and
      stabilities of interfaces in thin film biosensors are discussed. After an
      introduction to microscopic and spectroscopic techniques and different
      transducers, case studies are presented. They concern bioaffinity sensors with
      particular emphasis on biomimetic recognition structures, catalytic sensors,
      transmembrane sensors, cell sensors, and the ambitious goal of addressing
      individual biomolecular function units.

PMID- 8652107
TI  - Optical probes and transducers.
AB  - Biosensors are by definition a combination of a biological receptor compound and
      a physical or physicochemical transducer. Therefore, the transducing structure is
      a critical part of every biosensor. In the development of new and improved
      biosensing layers the importance of the transducing structure is not restricted
      to the substrate to which biological structures have to be coupled. A field of
      even greater importance is the use of transducers as probes providing information
      on the structure and function of biosensing layers, and their relation to a
      transducer surface. The aim of this paper is to give an overview on optical
      transducer principles and optical (surface) analytical techniques relevant as
      part of biosensing structures as well as probes in the development and
      optimisation of biosensing layers. Categories discussed are basic optical
      effects, materials involved, surface chemistry, the principal and technological
      limits of spatial resolution, and sensitivity. The intimate relation between the
      spatial resolution of a probe, the resulting size of interaction areas, and the
      feasibility of array structures is pointed out. Two interferometric methods are
      presented in principle, and their application to biosensing and some results are
      discussed in detail. The necessity to characterise receptor layers to get
      detailed information about the interaction process is pointed out. The close
      relationship between optimal characterisation of layers by selection of adequate
      probe technologies and improvement of probe performance, and the development of
      new biosensing layers is discussed. Finally, an outlook is given for future
      aspects of improved spatial resolution and multianalyte detection.

PMID- 8652108
TI  - The use of differential measurements with a glucose biosensor for interference
      compensation during glucose determinations by flow injection analysis.
AB  - A novel detection system for the determination of glucose in the presence of
      clinically important interferents, based on the use of dual sensors and flow
      injection analysis (FIA), is described. The normalisation methodology involves
      measurement of the interference signal at a reference sensor; this signal can
      then be subtracted from the glucose sensor signal (post-run) to give a corrected
      measurement of the glucose concentration. The detection system consists of a thin
      layer with dual glassy carbon working electrodes. One electrode was surface
      modified to act as a glucose biosensor by immobilisation of glucose oxidase (GOx)
      (from Aspergillus niger) with 1% glutaraldehyde and bovine serum albumin. The
      second electrode (glucose oxidase omitted) was utilised to measure the
      interference signal responding only to electroactive species present in the
      injected sample. A computer controlled multichannel potentiostat was used for
      potential application and current monitoring duties. The sensor responses were
      saved in ASCII format to facilitate post-run analysis in Microsoft Excel. Cyclic
      voltammetry (CV) was utilised to investigate the manner in which the interference
      signal contributed to the total signal obtained at the biosensor in the presence
      of glucose. The kinetics parameters Imax and the apparent Michaelis-Menten
      constant, K'm, were calculated for the sensor operating under flow-injection
      conditions.

PMID- 8652109
TI  - Biosensors and bioelectronics special issue on "Artificial Biosensing Interfaces
      (ABI)" Workshop No. 2: "Surface characterization and optical sensing methods in
      biosensors".

PMID- 8652110
TI  - Functionalisation of Si/SiO2 and glass surfaces with ultrathin dextran films and
      deposition of lipid bilayers.
AB  - Dextran with molecular weight of 500 kDalton was covalently coupled to glass and
      Si/SiO2-surfaces by epoxy functionalisation or by photo reactive
      functionalisation of the solid surface. With the described methods we can control
      the deposited mass density between 0.3 and 4.8 ng/m2 corresponding to mean film
      thicknesses of a dry dextran film between 2 A and 30 A. We studied the structural
      properties (thickness, density) of ultrathin dextran layers coupled to silicon
      wafers of glass surfaces in humid atmosphere and under water by ellipsometry and
      reflection interference contrast microscopy (RICM) and developed a new method to
      measure the interfacial forces in ultrathin films. We demonstrate, that these
      hydrophilic polymer films from soft cushions which can be reversibly swollen both
      under water and in humidified air. In water the films swell up to thicknesses of
      about 600 to 800 A as measured by reflection interference contrast microscopy
      (RICM) and ellipsometry. The interaction of the polymer films with Si/SiO2
      surfaces in contact with humidified air was studied by ellipsometry. We measured
      the thickness of the polymer layers as a function of the relative humidity of the
      atmosphere surrounding the sample in a hydration chamber. Depending on the
      humidity of the surrounding air and induced by the hydration the film thickness
      changes by about a factor of 10. Coupling of N-hydroxysuccinimide to dextran
      enables the functionalisation of the dextran cushions with a broad range of
      different specific binding molecules for various detection tasks. The possibility
      of soft hydrated dextran films as a cushion for the deposition of self healing
      lipid bilayers is shown.

PMID- 8652111
TI  - Surface modification for direct immunoprobes.
AB  - The modification of glass-type surfaces by several hydrophilic polymers of
      different molecular masses and functional properties [chitosan, dextran,
      poly(oxyethylene), poly(ethyleneimine) and poply(acrylamide)] with respect to the
      application for direct immunoprobes was investigated. Activation of the surface
      was carried out by silanisation and the polymers were coupled to the surface via
      amide bonds. The carboxyl derivative of a hapten was attached to the functional
      groups of the polymers by carbodiimide-activated coupling. As a reference system,
      the ligand was directly coupled to the silanised surface. Non-specific protein
      adsorption, specific binding of antibodies and regeneration were monitored by
      evaluation of reflectance spectra obtained by white light interference at a thin
      silica layer (RifS). All polymer modified layers showed improved properties
      compared to those with direct attachment of the hapten. The non-specific
      adsorption was reduced to 5-50%. Binding of a specific antibody was significantly
      increased by the polymer modification: Mass transport limited binding of the
      specific antibody in low concentrations (30 nM) up to a surface coverage value of
      2 ng/mm2 and a maximum surface coverage in the range of a monolayer of IgG (5-6
      ng/mm2) was observed for most of the polymers. The surface coverage found for IgG
      bound specifically to the dextran-modified surface exceeded a protein monolayer.

PMID- 8652112
TI  - Label-free observation of DNA-hybridisation and endonuclease activity on a wave
      guide surface using a grating coupler.
AB  - Hybridisation of nucleic acid oligomers to an immobilised target has been
      observed in real time using evanescent field technology. A biotinylated 24-mer
      with random sequence including the EcoRI recognition site was immobilised via
      streptavidin onto a grating coupler wave guide surface. Hybridisation of 22-mer,
      15-mer and 8-mer was observed. Activity of restriction endonuclease EcoRI was
      visualised by measurement of the loss of bound DNA after incubation.

PMID- 8652113
TI  - Review: optimizing inducer and culture conditions for expression of foreign
      proteins under the control of the lac promoter.
AB  - This review examines factors which influence the expression of foreign proteins
      in Escherichia coli under the transcriptional control of the lac and tac
      promoters, and discusses conditions for maximizing the production of a foreign
      protein using this system. Specifically, the influence of IPTG (isopropyl-beta-D
      thiogalactoside) concentration, temperature, composition of the growth medium,
      the point in the growth curve at which cells are induced with either IPTG or
      lactose, and the duration of the induction phase are discussed.

PMID- 8652114
TI  - Purification and characterization of recombinant Streptomyces clavuligerus
      isopenicillin N synthase produced in Escherichia coli.
AB  - Recombinant isopenicillin N synthase from Streptomyces clavuligerus was produced
      in the form of inactive inclusion bodies in Escherichia coli. These inclusion
      bodies were solubilized by treatment with 5 M urea under reducing conditions.
      Optimization of refolding conditions to recover active isopenicillin N synthase
      indicated that a dialysis procedure carried out at a protein concentration of
      about 1.0 mg ml(-1) gave maximal recovery of active isopenicillin N synthase.
      Solubilized isopenicillin N synthase of more than 95% purity was obtained by
      passing this material through a DEAE-Trisacryl ion exchange column. Expression
      studies conducted at different temperatures indicated that isopenicillin N
      synthase was produced predominantly in a soluble, active form when expression was
      conducted at 20 degrees C, and accounted for about 20% of the total soluble
      protein. This high-level production facilitated the purification of soluble
      isopenicillin N synthase to near homogeneity in four steps. Characterization of
      the purified soluble and solubilized isopenicillin N synthase revealed that they
      are very similar.

PMID- 8652115
TI  - Initial oxidative and subsequent conjugative metabolites produced during the
      metabolism of phenanthrene by fungi.
AB  - Three filamentous fungi were examined for the ability to biotransform
      phenanthrene to oxidative (phase I) and conjugative (phase II) metabolites.
      Phenanthrene metabolites were purified by high-performance liquid chromatography
      (HPLC) and identified by UV/visible absorption, mass, and 1H NMR spectra.
      Aspergillus niger ATCC 6275, Syncephalastrum racemosum UT-70, and Cunninghamella
      elegans ATCC 9245 initially transformed [9-(14)C]phenanthrene to produce
      metabolites at the 9,10-, 1,2-, and 3,4-positions. Subsequently, sulfate
      conjugates of phase I metabolites were formed by A. niger, S. racemosum, and C.
      elegans. Minor glucuronide conjugates of 9-phenanthrol and phenanthrene trans-9,
      10-dihydrodiol were formed by S. racemosum and A. niger, respectively. In
      addition, C. elegans produced the glucose conjugates 1-phenanthryl beta-D
      glucopyranoside and 2-hydroxy-1-phenanthryl beta-D-glucopyranoside, a novel
      metabolite. [9-(14)C]Phenanthrene metabolites were not detected in organic
      extracts from biotransformation experiments with the yeasts, Candida lipolytica
      37-1, Candida tropicalis ATCC 32113, and Candida maltosa R-42.

PMID- 8652116
TI  - A method for the selective isolation of Myxococcus directly from soil.
AB  - A new method is described for the selective isolation of species of Myxococcus
      directly from soil by dilution plating. The method involves suppression of
      competing microorganisms with antibiotics combined with air drying and wet heat
      treatment of soils. Fungi were eliminated by supplementing the plating medium
      with cycloheximide and nystatin. Non-sporulating bacteria were controlled by air
      drying soils and then heating aqueous soil dilutions for 10 min at 56 degrees C.
      The predominant sporulating bacteria in soil, Streptomyces and Bacillus, were
      suppressed by adding either tiacumicin B, ristocetin or vancomycin to the medium.
      Swarming of Myxococcus colonies was controlled with a casein digest-yeast extract
      plating medium (CY-C10 agar). Ultrasound treatment of soil suspensions gave the
      highest number of Myxococcus colonies in the soils studied, but these cultures
      could be recovered without ultrasound. Strains of Myxococcus fulvus, M. xanthus,
      M. coralloides, M. stipitatus and M. virescens were isolated from soil using this
      technique. Soils examined yielded one or two Myxococcus species per sample.

PMID- 8652117
TI  - Continuous ethanol production by Zymomonas mobilis and Saccharomyces cerevisiae
      in biofilm reactors.
AB  - Continuous ethanol fermentations were performed in duplicate for 60 days with
      Zymomonas mobilis ATCC 331821 or Saccharomyces cerevisiae ATCC 24859 in packed
      bed reactors with polypropylene or plastic composite-supports. The plastic
      composite-supports used contained polypropylene (75%) with ground soybean-hulls
      (20%) and zein (5%) for Z. mobilis, or with ground soybean-hulls (20%) and
      soybean flour (5%) for S. cerevisiae. Maximum ethanol productivities of 536 g L-1
      h-1 (39% yield) and 499 g L-1 h-1 (37% yield) were obtained with Z. mobilis on
      polypropylene and plastic composite-supports of soybean hull-zein, respectively.
      For Z. mobilis, an optimal yield of 50% was observed at a 1.92 h-1 dilution rate
      for soybean hull-zein plastic composite-supports with a productivity of 96 g L-1
      h-1, whereas with polypropylene-supports the yield was 32% and the productivity
      was 60 g L-1 h-1. With a S. cerevisiae fermentation, the ethanol production was
      less, with a maximum productivity of 76 g L-1 h-1 on the plastic composite
      support at a 2.88 h-1 dilution rate with a 45% yield. Polypropylene-support
      bioreactors were discontinued due to reactor plugging by the cell mass
      accumulation. Support shape (3-mm chips) was responsible for bioreactor plugging
      due to extensive biofilm development on the plastic composite-supports. With
      suspension-culture continuous fermentations in continuously-stirred benchtop
      fermentors, maximum productivities of 5 g L-1 h-1 were obtained with a yield of
      24 and 26% with S. cerevisiae and Z. mobilis, respectively. Cell washout in
      suspension-culture continuous fermentations was observed at a 1.0 h-1 dilution
      rate. Therefore, for continuous ethanol fermentations, biofilm reactors out
      performed suspension-culture reactors, with 15 to 100-fold higher productivities
      (g L-1 h-1) and with higher percentage yields for S. cerevisiae and Z. mobilis,
      respectively. Further research is needed with these novel supports to evaluate
      different support shapes and medium compositions that will permit medium flow,
      stimulate biofilm formation, reduce fermentation costs, and produce maximum
      yields and productivities.

PMID- 8652118
TI  - Reductive microbial dechlorination of indigenous polychlorinated biphenyls in
      soil using a sediment-free inoculum.
AB  - In laboratory experiments, unagitated soil slurry bioreactors inoculated with
      micro-organisms extracted from polychlorinated biphenyl-contaminated (PCBs)
      sediments from the Hudson River were used to anaerobically dechlorinate PCBs. The
      onset of dechlorination activity was accelerated by the addition of certain
      organic acids (pyruvate and maleate) and single congeners (2,3,6
      trichlorobiphenyl). Dechlorination was observed under several working conditions
      after 19 weeks of incubation with PCB-contaminated soil and nutrient solution.
      Best results showed a drop in average chlorine content from 4.3 to 3.6 chlorines
      per biphenyl due to a loss of m-chlorines. Soil used for these experiments was
      obtained from a PCB-contaminated (weathered Aroclor 1248) site at an electric
      power substation. Dechlorination was observed with no sediment particles or other
      matrix being added.

PMID- 8652119
TI  - Spatial variations in growth rate within Klebsiella pneumoniae colonies and
      biofilm.
AB  - The use of acridine orange to visualize and quantify spatial variations in growth
      rate within Klebsiella pneumoniae colonies and biofilm was investigated.
      Bacterial colonies supported on polycarbonate filter membranes were grown on R2A
      agar plates. Some colonies were sampled for cell enumeration, while others were
      cryoembedded, sectioned, and stained with the fluorescent nucleic acid stain
      acridine orange. Spatial patterns of fluorescent color and intensity with depth
      in the colony were quantified using confocal microscopy and image analysis of
      stained cross sections. Colonies sampled in the midexponential phase were thin
      (20 microns), had high average specific growth rates (> 1 h-1), and had all the
      cells stained bright orange. Colonies sampled after more than 24 h of growth were
      thick (> 200 microns) and were growing slowly (mu < 0.15 h-1). These older
      colonies were characterized by distinct bands of orange at the colony edges and a
      dark green center. Stained biofilm cross sections displayed a similar orange band
      at the biofilm-bulk fluid interface and a green interior. Colony-average specific
      growth rates, determined by calculating the local slope of the cell accumulation
      versus time data, were correlated with colony-average fluorescence intensities.
      There was no correlation between average specific growth rate and orange or green
      intensity individually, but growth rate did correlate with the orange:green
      intensity ratio (r2 = 0.57). The resulting regression was used to predict
      specific growth rate profiles within colonies. These profiles indicated that
      bacteria were growing rapidly near the air and agar interfaces and more slowly in
      the center of the colonies when thicker than about 30 microns. The dimension of
      the orange bands ranged from 10 to 30 microns, which may indicate the thickness
      of growing regions. The inherent variability associated with this technique
      suggests that it is best applied in single species systems and that the results
      should be regarded as qualitative in nature.

PMID- 8652120
TI  - High-level expression and efficient recovery of ubiquitin fusion proteins from
      Escherichia coli.
AB  - The transition in growth and induction of bacterial cultures expressing
      recombinant proteins from the laboratory bench to the pilot scale for production
      has been performed successfully for several ubiquitin fusion-expressing clones.
      Increased protein turnover and decreased metabolic efficiency of Escherichia coli
      at high cell densities are often responsible for failures in fermenter cultures.
      Current data indicate that (1) yields in shaker flask cultures are directly
      scalable to a 10 L fermenter, (2) higher cell densities actually augment the
      specific yield of ubiquitin fusion proteins, (3) an in vivo heat shock during
      fermentation increases the ubiquitin fusion yield, which provides an initial
      separation step in the fermenter, and (4) the ubiquitin fusion expression clone
      makes at least 3-fold more total protein, including host proteins, than the
      parent strain of E. coli. A series of three fermentations was performed, using
      the model strain, with varied temperature shift protocols. These fermentations
      showed that a maximal heat shock of 12 degrees C (from 30 to 42 degrees C),
      initiated simultaneously with induction, gave a maximal specific yield (over 90%
      of the total soluble protein by densitometry, 709 mg/L by protein assay), in
      which the recoverable ubiquitin fusion product comprised 16% of the wet weight of
      the cell paste. These results illustrate the enormous potential of ubiquitin
      fusion technology for the economical production of peptides, even in a 10 L
      fermenter.

PMID- 8652121
TI  - Hybridoma and CHO cell partitioning in aqueous two-phase systems.
AB  - The partitioning of mouse/mouse hybridoma cell line BIF6A7, mouse/rat hybridoma
      PFU-83, and CHO DUKX B11-derived cell line BIC-2 in aqueous two-phase systems
      (ATPSs) of poly(ethylene glycol) (PEG) and dextran was studied. The partitioning
      of BIF6A7 was investigated systematically by using a statistical experimental
      design. The aims were to identify the key factors governing cell partitioning and
      to select ATPSs with suitable cell partitioning for extractive bioconversions
      with animal cells. The influence of five factors, i.e., the poly(ethylene glycol)
      molecular weight (PEG MW), dextran molecular weight (Dx MW), tie-line length
      (TLL), pH, and the ratio of potassium phosphate to potassium chloride, defined as
      the fraction KPi/(KPi + KCl), on BIF6A7 cell partitioning was characterized by
      using a full factorial experimental design. The cell partitioning ranged from
      complete partitioning into the interface to an almost complete partitioning to
      the lower phase. In all cases less than 1% of the cells partitioned to the top
      phase. The potassium phosphate fraction had the largest effect on cell
      partitioning. Low potassium phosphate fractions increased the proportion of cells
      in the lower phase. To a lesser extent the other factors also played a role in
      the cell partitioning. The best partitioning for the BIF6A7 cell line was
      obtained in ATPSs with PEG MW = 35,000, Dx MW = 40,000, TLL = 0.10 g/g, pH 7.4,
      and KPi/(KPi + KCl) = 0.1, where 93% of the cells were present in the lower
      phase. The previously reported partitioning of BIF6A7 cells in ATPS culture
      medium, corresponded well with the current findings. The partitioning of
      mouse/rat hybridoma cell line PFU-83 and CHO cell line BIC-2 was studied in an
      ATPS culture medium with PEG 35,000, dextran 40,000, TLL = 0.12 g/g, and
      hybridoma culture medium. Both cell lines partitioned almost completely into the
      lower phase. Moreover, the PFU-83 cell line was able to grow in the ATPS
      hybridoma culture medium. This ATPS hybridoma culture medium therefore seems to
      be suitable for extractive bioconversions with a wide range of hybridoma cell
      lines, provided that their product can be partitioned into the upper PEG-rich
      phase.

PMID- 8652122
TI  - Characterization of the stress response of a bioluminescent biological sensor in
      batch and continuous cultures.
AB  - The effects of temperature, growth stage, and inducer (ethanol) concentration on
      the kinetics and magnitude of the stress response were investigated by using an
      Escherichia coli strain with the grpE heat shock promoter fused to the Vibrio
      fischeri lux genes. When stressed, the cells responded by changing the level of
      specific light emission, which was measured both on- and off-line. These
      measurements were used to characterize and optimize the sensitivity of the
      construct by determining the conditions at which the culture exhibited maximum
      specific bioluminescence and minimum response time to ethanol induction in batch
      cultivation. The results of the batch study were then applied to continuous
      cultivation, and the effect of dilution rate was determined. These results are of
      considerable interest in the development of an on-line biological sensor system
      for the detection and toxicity assessment of chemical pollutants.

PMID- 8652123
TI  - A miniature bioreactor for sensing toxicity using recombinant bioluminescent
      Escherichia coli cells.
AB  - A miniature bioreactor was fabricated as a contactor between biosensing cells and
      toxic materials. This miniature bioreactor (58 mL working volume) showed
      performance similar to that of a conventional bioreactor, as well as the
      advantages of easy installation, facile operation, and small medium requirements
      during long-term continuous operation. A performance evaluation measured the
      response to ethanol in continuous operation by using a recombinant bioluminescent
      Escherichia coli strain. Continuous cultures were repeatedly induced by the
      ethanol challenge. Steady-state cell concentrations (OD) were found to be
      decreased, the induced specific bioluminescence (SBL) peak value was found to be
      increased, and the peak response time, which is the time constant of this
      continuous monitoring system, was found to be decreased with increasing dilution
      rate. Finally on- and off-line bioluminescence monitoring was shown to be
      reliable, suggesting that this system is suitable for applications such as
      monitoring the influent and effluent streams of waste water biotreatment plants.

PMID- 8652124
TI  - Confocal laser scanning microscopy examination of cell distribution in
      macroporous microcarriers.
AB  - Macroporous microcarriers are often used to cultivate animal cells. The pores in
      the interior of the beads provide surface and space for cell growth. It is not
      clear how anchorage-dependent and suspension cells populated these microcarriers
      during cultivation. Confocal laser scanning microscopy was employed to perform
      time lapse observation of the cells in the interior. The structure of the bead
      was stained with fluorescein isothiocyanate for visualization, while the cells
      were stained with dialkyl indocarbocyanines for tracking over time. It was
      observed that mouse fibroblastic cells CRE BaG2 did not move extensively after
      initial attachment. Some cell divisions were observed during the course of the
      experiments, and essentially all cells remained viable throughout. Few hybridoma
      cells were deposited into the pores in the interior of the microcarriers. The
      results suggest that the occupancy of the internal volume by cells after
      prolonged cultivation is largely due to the growth of cells that are deposited in
      the interior as opposed to the migration of cells from the external surface into
      the interior. This method of observing cell behavior in a three-dimensional
      structure may find applications in other three-dimensional cell culture systems.
      The animation of time lapse sections is available on the worldwide web at http:/
      www.cems.umn.edu/ approximately wshu_grp/acre/microcarrier.html.

PMID- 8652125
TI  - Optimization of poly(ethylene glycol) precipitation of hepatitis A virus used to
      prepare VAQTA, a highly purified inactivated vaccine.
AB  - Poly(ethylene glycol) precipitation has been successfully used to concentrate and
      purify hepatitis A virus from crude lysate preparations for production of VAQTA,
      a highly purified, formalin-inactivated hepatitis A vaccine. Initial results
      showed that nucleic acids present in the starting material were problematic for
      the performance of the poly(ethylene glycol) precipitation step. Extensive
      experiments were carried out to identify processing conditions suitable for
      vaccine manufacture which would enhance product yield and improve purity. Results
      of these studies indicated that the earlier practice of concentrating crude virus
      containing lysate using semipermeable membranes led to aggregation of high
      molecular weight nucleic acids. This aggregated material coprecipitated with the
      virus during the subsequent poly(ethylene glycol) precipitation step; variable
      amounts of nucleic acids led to inconsistent virus recovery and product purity.
      Nuclease treatment of the crude lysate preparations decreased the molecular size
      of the nucleic acids and significantly reduced their coprecipitation with the
      virus. Further experiments demonstrated that optimal placement of the nuclease
      treatment was at the lysate stage followed by a capture step using anion exchange
      chromatography. These steps combined with optimization of the virus
      concentration, ionic strength, and pH of the poly(ethylene glycol) precipitation
      led to effective and selective concentration of the virus which significantly
      enhanced process reproducibility and control.

PMID- 8652126
TI  - alpha-Ketoglutarate assay based on fluorescence quenching by NADH.
AB  - A new assay procedure for the measurement of ketoglutarate concentrations is
      described which is based on substrate-induced quenching (SIQ) of a fluorophore.
      The method makes use of the photoreaction between a fluorophore (thionine) and
      NADH. The latter is consumed during an enzymatic reaction between ketoglutarate
      and L-glutamic dehydrogenase. The conversion yield of cofactor from its reduced
      form to oxidized forms represented as an overall change in the population of the
      excited state population of the fluorophore thionine. An empirical relation is
      described that correlates initial substrate concentration to the observed yield
      of the cofactor conversion via a fluorescence recovery constant,Kt. The analysis
      of data obtained over a range of 0-500 microM results in a constant of 2748 M-1.
      The applicability of the proposed method is demonstrated by performing the assay
      for alpha-ketoglutarate in human urine. The ketoglutarate SIQ assay was not
      affected by the background interference that is inherent to this complex matrix.

PMID- 8652127
TI  - Regulation of protein synthesis in eukaryotic cells by the guanine nucleotide
      exchange factor and chain initiation factor 2.
AB  - In eukaryotes, the guanine nucleotide exchange factor (eIF-2B) is a key protein
      in the control of polypeptide chain initiation. It catalyzes the exchange of
      chain initiation factor (eIF)-2-bound GDP for GTP and facilitates the formation
      of a ternary complex (eIF-2.GTP.Met-tRNAf). The activity of eIF-2B is inhibited
      indirectly by phosphorylation of the smallest subunit of eIF-2 which sequesters
      eIF-2B into an inactive eIF-2(alpha P).eIF-2B complex. On the other hand, eIF-2B
      activity may be regulated directly by covalent modification of its largest
      subunit with different kinases, such as casein kinase (CK)-I, CK-II and glycogen
      synthase kinase (GSK)-3. After stimulation of mammalian cells by insulin or
      growth factors, the allosteric activation of eIF-2B activity by sugar phosphates
      and inositol phosphates may also provide an important parameter in the regulation
      of protein synthesis.

PMID- 8652128
TI  - Identification of novel mRNAs in immature seeds of Arabidopsis thaliana.
AB  - Although most of the major discernible morphogenetic events in plants occur after
      germination, the overall architectural pattern of the mature plant is established
      during early events of embryogenesis. So far, few genes that are expressed
      specifically during embryogenesis have been identified. This is due primarily to
      technical difficulties associated with the mass ratios of the embryo and the
      surrounding maternal tissue and to the lack of molecular and cellular markers to
      direct screening efforts. We have developed a series of molecular approaches to
      study the early events of embryogenesis. These include 'virtual subtraction' of a
      cDNA library with high specific-activity cDNA probes generated from both seed and
      non-seed tissue, PCR amplification of gene family members from an immature seed
      cDNA library using primers specific to conserved domains, differential display
      analysis of mRNA populations and high throughput expressed sequence tag (EST)
      analysis. These techniques have led to the identification and isolation of
      several novel seed-specific cDNAs.

PMID- 8652130
TI  - Geranylgeraniol restores cell proliferation to lovastatin treated C6 glial cells.
AB  - Since we have previously shown that farnesol (F-OH) and geranylgeraniol (GG-OH)
      can be utilized for protein isoprenylation, the ability of the free allylic
      isoprenols to overcome the lovastatin-induced block on rat C6 glial cell
      proliferation has been investigated. Lovastatin an inhibitor of 3-hydroxy-3
      methylglutaryl coenzyme A reductase, the rate-limiting enzyme in mevalonate
      biosynthesis, inhibited the rate of cell growth in a concentration dependent
      manner. The addition of mevalonate and GG-OH to lovastatin treated cells was
      shown to overcome the drug induced inhibition of cell proliferation. This result
      indicates that geranylgeraniol is capable of providing the mevalonic acid-derived
      products necessary to support cell growth. These results suggest that isoprenols
      are converted to an "activated' form, possibly the corresponding allylic
      pyrophosphate intermediate by reactions that remain to be characterized, prior to
      being utilized for sterol biosynthesis and protein isoprenylation.

PMID- 8652129
TI  - Are flavonoids synthesized by a multi-enzyme complex?
AB  - An enormous variety of metabolic processes are characterized by enzyme complexes,
      which are likely to play important roles in directing the efficient operation and
      specificity of cellular metabolism. In many cases membranes or cytoskeletal
      elements provide scaffolding for these highly ordered assemblies of enzymes.
      Biochemical and immunocytochemical studies indicate that the flavonoid
      biosynthetic pathway of higher plants involves a complex of sequentially-acting
      enzymes localized at the cytoplasmic face of the endoplasmic reticulum. This
      paper describes preliminary efforts to define the organization of this putative
      flavonoid biosynthetic complex and elucidate its role in controlling the
      synthesis of different flavonoid end-products in the model plant, Arabidopsis
      thaliana.

PMID- 8652131
TI  - A comparative analysis of plant mitochondrial small subunit ribosomal RNA
      sequences.
AB  - The small subunit of the ribosomal RNA has long been used as a tool in
      determining phylogenetic relationships. This project explored a region of the
      mitochondrial small subunit ribosomal RNA (MSrRNA) that is found only in the
      plant mitochondrial genome referred to as Variable Region 7 (V7). The V7 region
      of cauliflower and radish, both members of the Brassicaceae family, was amplified
      with the polymerase chain reaction, cloned into the expression vector PBSSK +,
      and sequenced. There was only a 0.3% sequences difference between the cauliflower
      and radish V7 region, thus suggesting that there will not be sequence variation
      in this region within a plant species. Cauliflower and radish V7 sequence was
      compared with the 6 other sequences of plant MSrRNA V7 region available: wheat,
      corn, oats, evening primrose, soybean and lupine. Based on percent difference
      between the V7 region sequences, a phylogenetic tree was constructed that
      supports the placement of these 8 species in Cronquist's morphologically based
      phylogenetic tree of flowering plants.

PMID- 8652132
TI  - Radioreceptor characterization of cardiovascular nucleoside transporters.
AB  - The nucleoside transport system (NTS), an integral part of the adenosine
      inactivation mechanism, is physiologically significant in adenosine-mediated
      autoregulation of cardiovascular function. Radioreceptor approaches have been
      employed in the characterization of nucleoside transporters as potential targets
      in the therapy of cardiovascular diseases. Unanswered questions that are being
      addressed relate to their pharmacological regulation and their involvement in the
      pathogenesis of disease states. A brief overview of the characterization of
      nucleoside transporters in the cardiovascular system is presented and discussed
      in terms of their relevance to cardiovascular function.

PMID- 8652133
TI  - Regulation of the cellulolytic activity of Eubacterium cellulosolvens 5494: a
      review.
AB  - Eubacterium cellulosolvens 5494 is a cellulolytic gram positive bacterium
      isolated from the rumen. Substrate specific regulation has not been previously
      demonstrated in any members of this genera. However, we have recently found that
      E. cellulosolvens regulates some of its membrane proteins. Growth on different
      substrates, including cellulose and cellobiose, gave different SDS-PAGE profiles
      of proteins from the membrane fraction. Using scanning electron microscopy, we
      also found that growth of E. cellulosolvens on cellulose induces an
      ultrastructural complex that is not present when grown on any other substrate.
      Further study revealed that this ultrastructure was subsequently lost when an
      alternative substrate was made available to cellulose growing cells. We also
      found that cellulose, cellobiose, and maltose utilization are inhibited in the
      presence of a glucose analog, indicating glucose is the preferred substrate.

PMID- 8652134
TI  - Introduction of relaxin properties into other hormones of insulin-like structure.
AB  - Sequence comparison of natural relaxins and the investigation of the structure
      function relationship of chemically synthesized relaxin analogs have been used to
      identify two arginine residues on the surface of the main helix of the B chain as
      hormone-receptor interaction site. This site is sensitive to structural changes,
      in particular the conformation of the A chain loop. Introducing the active site
      of relaxin into noncrossreacting structural analogs such as insulin and bombyxin
      required a four amino acid exchange. Both hybrid hormones bound to the anti
      porcine relaxin antibody R6 with high affinity, and the insulin analog, with an
      additional C-terminal truncation of the B chain, crossreacted with rat relaxin
      receptors.

PMID- 8652135
TI  - Genetic engineering of Minnesota superfish.
AB  - There is a chronic need to develop growth-enhanced fish for aquaculture. To meet
      this need we have developed techniques for genetically engineering fish to grow
      larger and faster. We found that the major difficulty in genetically engineering
      fish is the extremely high rate of mosaicism due to the late integration of
      transgenes into the genome. This delay also reduces the chances of passage of the
      transgene through the germ line. Consequently, we have engineered new vectors and
      mechanisms for accelerating the rate of integration of exogenous DNA into fish
      chromosomes.

PMID- 8652136
TI  - Circularizing ribozymes and decoy-competitors by autocatalytic splicing in vitro
      and in vivo.
AB  - An Anabaena group I intron was circularly permuted at loop 5, loop 6 and loop 8,
      and tested for self-splicing activity. Precursor RNAs from these constructs
      spliced efficiently and produced circular exons in vitro. Using group I permuted
      intron-exon sequences, circular forms of the HDV ribozyme, the RNA component of
      RNaseP from B. subtilis, the HIV TAR and a short HIV Rev-binding element were
      generated and tested for activity and stability. The activity of circular
      ribozymes is comparable to the linear counterparts with similar core sequences.
      Circular forms of the TAR and Rev-binding element showed specific binding to Tfr
      38 and Rev(35-50) peptide, respectively. To explore the potential for using this
      methodology to express circular RNA in vivo, circular forms of the HDV ribozyme
      and RNaseP RNA were produced in E. coli. Analysis of total RNA indicated that the
      precursor RNA spliced efficiently and accurately to produce circular ribozymes.
      The activity of in vivo expressed circular ribozymes could be demonstrated
      indicating that they fold into active conformation. These results suggest that
      self-splicing group I PIE sequences could prove useful for expressing small
      stable circular ribozyme/decoy-competitor or antisense RNAs in cells.

PMID- 8652137
TI  - The yeast, Saccharomyces cerevisiae, as a model system for the study of human
      genetic disease.
AB  - Many human genes associated with disease have close homologs in yeast. Based on
      this homology, many human proteins have been studied using yeast expression
      systems. This paper will review research done in our laboratory using a yeast
      expression system to study the human protein galactose-1-phosphate
      uridylyltransferase, associated with galactosemia, as well as highlighting some
      of the advantages of this model system.

PMID- 8652138
TI  - Acid phosphatase and proteinase activities of selected crotalid venoms.

PMID- 8652139
TI  - Biological mechanisms of HIV sexual transmission.

PMID- 8652140
TI  - HIV-1 RNA in blood and pathogenesis of HIV infection.

PMID- 8652141
TI  - Budesonide or prednisolone in active Crohn's disease.

PMID- 8652142
TI  - Passive smoking and lung cancer.
AB  - Evidence that environmental tobacco smoke may be a risk factor for lung cancer
      among individuals who themselves have never smoked tobacco products has been the
      subject of expert review over the last decade by several United States and
      international agencies. The most recent comprehensive review, published in 1993
      by the United States Environmental Protection Agency, concluded that
      environmental tobacco smoke is a Group A (known human) carcinogen. This report,
      coming in the midst of rapid social and political change in attitudes towards
      public policy implications for protecting human health, has been the subject of
      considerable discussion. Issues involved in these discussions, as well as more
      recently published studies on the topic, are reviewed with respect to current
      thinking about the risk of lung cancer in passive smokers, particularly women,
      who are lifetime never-smokers.

PMID- 8652144
TI  - Management of menopausal symptoms in breast cancer patients.

PMID- 8652143
TI  - Pathogenesis, clinical picture and treatment of von Willebrand's disease.
AB  - Von Willebrand's disease is probably the most common congenital bleeding
      disorder, with a prevalence close to 1% in some epidemiological studies. The
      disease is caused by a quantitative deficiency or a qualitative defect of the von
      Willebrand factor, which is a multimeric glycoprotein consisting of subunits of
      2050 amino acids. The size of multimers ranges from approximately 500 kDa to 20
      MDa. Each subunit consist of repeated domain structures. Several functional
      domains have been identified which can bind such structures as platelet receptors
      glycoprotein Ib or IIb/IIIA, heparin, collagen or factor VIII. The von Willebrand
      factor has two main functions in haemostasis, to promote normal platelet adhesion
      and to be a carrier protein for factor VIII. Von Willebrand's disease is divided
      into three major types and several subtypes depending on the quantity and quality
      of the von Willebrand factor in plasma and platelets. A new classification has
      recently been proposed. Typical symptoms are mucosal bleeding, easy bruising and
      increased bleeding tendency in connection with tooth extractions and other
      invasive procedures. Severe cases may have joint bleeding and other haemophilia
      like bleeding. Desmopressin is the treatment of choice in mild cases, whereas
      more severe cases need treatment with factor VIII concentrates.

PMID- 8652145
TI  - Acute neuroradiology: methods, indications and timing.
AB  - The rapid development of radiological examination methods, technical innovations
      and creative and critical radiological research have dramatically changed the
      diagnostic approach with new indications and changed timing in the examination of
      patients with acute neurological lesions. The role of CT as the primary
      radiological examination method in these patients is well established, and is
      routinely used before the start of suitable treatment to detect or exclude
      intracranial haemorrhage, either traumatic or nontraumatic, or to detect other
      causes of acute onset of neurological disease, such as intracerebral tumours or
      subdural haematoma. The role of MRI still needs further confirmation. The
      sensitivity of MRI is superior to that of CT, especially in examination of the
      spinal cord. The main drawbacks of MRI are the problems in monitoring acutely ill
      patients, the unfamiliarity with the method, and capacity problems. Today, MRI is
      mainly used as a complement to CT, with the exception of spine injuries where MRI
      is the method of first choice. Also, the role of digital subtraction angiography
      is changing from diagnostic examinations towards endovascular therapeutic
      procedures. An experienced neuroradiologist has the key position in choosing and
      performing the most suitable examination method for each specific indication.

PMID- 8652146
TI  - Apolipoprotein E, synaptic plasticity and Alzheimer's disease.
AB  - Apolipoprotein E (apoE) has been studied extensively with regard to its role in
      plasma lipoprotein lipid transport. A role for apoE in the transport of membrane
      cholesterol and phospholipid in the central and peripheral nervous system has
      also been studied. Entorhinal cortex-lesioned rats have been used extensively to
      examine the molecular mechanisms associated with deafferentation and
      reinnervation in the CNS; studies of the role of apoE in this process using this
      animal model are described. In all human populations examined, three common apoE
      isoforms, apoE2, apoE3 and apoE4, result from multiple alleles epsilon 2, epsilon
      3 and epsilon 4 at a single apoE genetic locus. These isoforms impart well
      characterized functional differences in plasma lipoprotein transport, which are
      reviewed herein. Also discussed are less well-studied possible apoE-isoform
      specific differences in central nervous system function. These are currently of
      critical importance due to numerous recent studies showing an association of
      epsilon 4 with increased risk for Alzheimer's disease. Diverse hypotheses as to
      the molecular basis for this association, as well as the supporting experimental
      evidence, are reviewed.

PMID- 8652147
TI  - Abnormal immune system and hypertension: where are we?
AB  - In reviewing the available evidence, the involvement of an immunological
      mechanism behind hypertension has been proposed. However, whether altered
      immunological function is a primary factor in the pathogenesis of hypertension or
      secondary to tissue damage of vascular beds induced by hypertension is still
      poorly defined. A major difficulty has been the relative paucity of information
      about the nature of specific immune targets which initiate and perpetuate
      abnormal immune responses in hypertension. This article will discuss the status
      of understanding of the involvement of immunological factors in both clinical and
      experimental hypertension.

PMID- 8652148
TI  - Regulation of oestrogen action: role of 17 beta-hydroxysteroid dehydrogenases.
AB  - The target cell responses to steroid hormones, such as oestrogens, are dependent
      on the expression of their receptors. Apart from receptor concentration, another
      key regulatory factor in steroid hormone action is the intracellular hormone
      concentration, which is affected by three main variables: the concentration of
      the steroid in plasma, local production and local conversion into metabolites.
      During the reproductive years the main source of oestrogens is the ovarian
      follicle, but in postmenopausal women most of the oestrogens are formed in
      peripheral tissues. The present overview deals with the formation of active
      oestrogens in steroidogenic tissues and in oestrogen target tissues, and the main
      focus is on 17 beta-hydroxysteroid dehydrogenases, which catalyse the
      interconversion between oestradiol and oestrone. It is evident that different 17
      beta-hydroxysteroid dehydrogenase isoenzymes are responsible for the
      oxidation/reduction of oestradiol or oestrone in oestrogen target cells. Because
      these enzymes are involved in the biosynthesis and metabolism of oestrogens, they
      have an important physiological significance for the growth of oestrogen
      dependent tissues and, hence, the growth and progression of hormone-dependent
      tumours.

PMID- 8652149
TI  - Asymptomatic atherosclerosis in HIV-positive patients: A case-control ultrasound
      study.
AB  - Atherosclerosis has been reported in some HIV-positive subjects without any known
      risk factor. The purpose of the present study was to investigate cervical
      arteries, abdominal aorta and femoral arteries by B-mode ultrasonography and
      doppler in 30 HIV-positive subjects matched to 18 controls for sex, age, tobacco
      consumption and arterial hypertension. Although no haemodynamically or clinically
      relevant lesions were found, plaques occurred more often in patients than in
      controls (11 patients, 36.7% vs. 2, 11.1%; P = 0.05). Compared to the HIV
      positive patients without plaques, those with plaques had a tendency to have
      decreased lower HDL cholesterol, higher tobacco consumption and lower CD4-cell
      count (77 +/- 85/mm3 vs. 220 +/- 202/mm3). The patients with plaques (but not
      those without plaques) had lower HDL cholesterol than controls (P = 0.03).
      Asymptomatic atherosclerosis seems to be more frequent in HIV-positive patients
      and is associated to lower HDL cholesterol.

PMID- 8652151
TI  - Three-dimensional course of the vestibular aqueduct.
AB  - Three-dimensional (3-D) reconstruction methods were employed to study the anatomy
      of the vestibular aqueducts (VAs) in ten postmortem temporal bone specimens
      obtained from ten individuals aged 4 months to 70 years at death. After
      reconstruction, the ten 3-D images of VAs were superimposed on one another and
      differences evaluated. The VA showed postnatal growth and variations in size and
      shape. However, the variations in angle at which the VA bends near the isthmus
      were not correlated with age. Furthermore, study of the superimposed images
      revealed that the 3-D course of the VA was essentially the same in individuals of
      all ages, despite its wide variability in size and shape. These results indicate
      that the basic course of the VA is determined before early infancy although the
      VA grows thereafter, suggesting that VA anomalies such as "large vestibular
      aqueduct syndrome" (in which the VA takes an abnormally straight and wide course)
      may be established prenatally.

PMID- 8652150
TI  - Current concepts in the diagnosis and treatment of sudden sensorineural hearing
      loss.
AB  - Sudden hearing loss (SHL) has been a controversial topic in the literature for
      the past several decades. Although much theoretical work has been done regarding
      its diagnosis and treatment, no useful practical guidelines exist for application
      to current patient management. Many authors have discussed the various treatment
      protocols available to treat this entity, but only a handful of dated, clinical
      studies supporting these treatments are available. More recent studies applying
      treatment protocols including vasodilators, plasma expanders, anti-coagulants,
      and carbogen inhalations have shown no improvement over the rate of spontaneous
      recovery without therapy. Except in cases of therapy directed toward known
      predisposing factors, there is insufficient evidence in the literature to support
      medical treatment for SHL, although steroid therapy appears to be useful in
      selected patients. Our own review of 14 patients with SHL is presented. A
      standard diagnostic and therapeutic approach based on a comprehensive review of
      the literature is described that can be applied to most patients presenting with
      SHL.

PMID- 8652152
TI  - The Blom-Singer tracheostoma valve as a valuable addition in the rehabilitation
      of the laryngectomized patient.
AB  - Prosthesis-assisted tracheo-esophageal speech has proven its value in post
      laryngectomy voice rehabilitation, although manual occlusion of the tracheostoma
      during speech is necessary. In contrast a tracheostoma valve enables hands-free
      speech. We have now had experience with 30 patients using the Blom-Singer
      tracheostoma valve for more than 6 months and have found that most patients
      prefer prosthesis-assisted speech with the tracheostoma valve. Measurement of
      several speech parameters with digital and valve occlusion of the tracheostoma
      did not show any significant differences between the two speaking conditions.
      Problems included maintenance of an airtight seal, outward forcing of the valve
      diaphragm during forced expiration and subjective increased airflow resistance.

PMID- 8652153
TI  - Verrucous squamous cell carcinoma of the larynx: diagnostic and therapeutic
      considerations.
AB  - The clinical findings, histopathology, management and outcome of 31 patients with
      verrucous squamous cell carcinoma of the larynx (VSCC) are discussed. Laryngeal
      VSCC is a rare, highly differentiated variant of SCC and has specific
      morphological features and clinical behavior. A close liaison between the
      laryngologist and pathologist is needed to formulate a correct diagnosis, because
      this tumor appears to be malignant clinically and histologically benign. A low
      power magnification of multiple large specimens, including the deep margins of
      the lesion, is required in order to differentiate VSCC from keratosis, verruca
      vulgaris or SCC with verrucous appearance, and to detect underlying microscopic
      foci of invasive SCC within or adjacent to a verrucous carcinoma. Long-lasting
      hoarseness was the most common symptom as the glottic region was the most common
      site of VSCC. Presumed clinically positive N1 lymph nodes were observed in the
      necks of 7 patients, but none had metastatic disease on histopathological study.
      Surgery alone was the most effective form of treatment, as it allowed a good
      outcome of all treated patients. Surgery plus radiotherapy was associated with an
      early recurrence and a poor outcome in 2 of 7 patients treated. The generally
      "benign" behavior of VSCC allows for conservative surgery, with complete
      endoscopic resection using the carbon dioxide laser representing a more
      conservative surgical approach. Neck dissection is not indicated due to the non
      metastatic behavior of this tumor.

PMID- 8652154
TI  - Time-dependent alterations of 3-fucosyl-N-acetyl-lactosamine (CD15) expression in
      the endolymphatic sac of adult guinea pigs after glycerol administration.
AB  - The present study examined the effect of glycerol administration on 3-fucosyl-N
      acetyl-lactosamine (CD15) epitope expression in the endolymphatic sac (ES) of the
      guinea pig's inner ear. Adult guinea pigs were injected intravenously with
      glycerol (2 g/kg body wt.). CD15 expression was studied at 80 min up to 5 h after
      treatment. In untreated animals single cells and cell groups in the ES expressing
      CD15 epitope intra- and intercellularly were identified by immunohistochemistry
      to be mainly in the epithelial layer of the rugosal and distal part of the sac.
      Glycerol administration modulated the expression of CD15 epitope. In the
      epithelial layer, expression decreased and was nearly depleted after 3 h. After 4
      h of glycerol administration, CD15 expression reappeared and reached the
      comparable level of controls. The numbers of CD15-positive cells in the lumen of
      the ES increased steadily and arrived at their the highest levels in 2-h
      specimens. The localization of CD15-epitope expression and its modulation after
      glycerol administration within the ES implies that this molecule may play a role
      in re-establishing the sac's normal function. In addition, we speculate that CD15
      may be associated with processes of an immune response in the inner ear.

PMID- 8652156
TI  - Morphological variability of smooth muscle cells in human nasal swell bodies.
AB  - The complex functional behavior of nasal swell bodies is still not completely
      understood. In the present study the histology of the vessels involved in the
      swelling mechanism is examined and the ultrastructural appearances described of
      the different types of smooth muscle cells located in the vascular wall of swell
      bodies in the human inferior turbinate. Even though the majority of smooth muscle
      cells of the nasal swell bodies showed a normal, elongated appearance comparable
      to other smooth muscle cells elsewhere in the body, a variety of cells with
      atypical shapes could be detected that have not been described previously in
      vessels of the nasal mucosa. The diameters of the smooth muscle cells in general
      were strikingly variable. The individual smooth muscle cells were surrounded by a
      basal lamina that was occasionally disrupted or doubled. Myoblasts were separated
      by a connective tissue space containing collagen fibrils, mature elastin fibers
      and bundles of microfibrils. The latter two types of fibers and fibrils occurred
      mainly in the outer parts of the muscular coat. The endowment of cytoplasmic
      components was similar in all smooth muscle cells of the vascular wall in the
      swell bodies. These findings indicate that the specific feature of smooth
      musculature presumably resides in the unusual morphological variability of the
      single cells present, as well as in the striking heterogeneity of the arrangement
      of bundles of these cells in the vascular wall.

PMID- 8652155
TI  - Distribution of immunocompetent cells in various areas in the normal laryngeal
      mucosa of the rat.
AB  - The larynx can be divided into a supraglottic, a glottic and a subglottic area,
      each serving different functions. In many cases of laryngitis the site of
      infection is located in one area, leaving other areas unaffected. It seems
      reasonable to speculate that the underlying cause of the heterogeneous infection
      pattern in the larynx is the different processing of infectious agents.
      Therefore, the number and distribution of granulocytes, macrophages, dendritic
      cells, natural killer cells and T and B lymphocytes in the normal laryngeal
      mucosa of young rats were studied. The results show that, with the exception of
      granulocytes, all subpopulations were present in different numbers. Many
      macrophages and dendritic cells but only a few natural killer cells and T and B
      lymphocytes were located in the mucosa. Dendritic cells, natural killer cells and
      T and B lymphocytes were rarely present in the vocal fold area, whereas in the
      subglottic area they were present in high numbers. Thus, differences in the
      composition of immunocompetent cell populations between laryngeal areas were
      detectable.

PMID- 8652157
TI  - Role of interleukin 6 in epithelial hyperproliferation and bone resorption in
      middle ear cholesteatomas.
AB  - Locally produced pro-inflammatory cytokines are considered to play an important
      role in the initiation and/or maintenance of inflammatory diseases. In
      cholesteatomatous lesions there are increased levels of some cytokines and
      inflammatory mediators like interleukin 1, tumor necrosis factor and colony
      stimulating factor, etc. Interleukin 6 (IL-6) can be produced by different cells
      present in cholesteatoma (e.g. keratinocytes, lymphocytes, fibroblasts and
      macrophages). Until now, no data have been available on the role of IL-6 in
      cholesteatoma. In this study we used immunohistochemistry to investigate the
      presence and distribution of IL-6 in tissue samples from cholesteatoma patients.
      Levels of the cytokine were quantified in tissue extracts using an enzyme-linked
      immunosorbent assay. Finally, the presence of biologically active IL-6 was
      analyzed in the murine cell line 7TD1. Human skin samples obtained from the
      external ear canal were used as controls. Using the anti-IL-6 antibody in an
      alkaline phosphatase anti alkaline phosphatase technique, a moderate diffuse
      staining of the whole epidermis was observed in sections of normal skin. In
      cryostat sections of cholesteatoma samples, a stronger staining of the whole
      epithelium was observed. Many of the cells infiltrating the cholesteatoma stroma
      also showed positive immunostainings. The concentration of IL-6 in relation to
      the total protein concentration in cholesteatoma (119.33 +/- 30) were higher than
      in human skin (9.16 +/- 13). While IL-6 activity was not detected in skin
      samples, two of the ten cholesteatoma samples studied showed a stimulatory effect
      when incubated with the cell line 7TD1. The overexpression of IL-6 in middle ear
      cholesteatoma suggests a participation of this cytokine in some of the clinical
      features seen: epithelial hyperproliferation and bone resorption. The absence of
      biological activity in the majority of the cholesteatoma samples points to the
      presence of natural inhibitors for IL-6.

PMID- 8652158
TI  - A follow-up study of long-term results after cochlear implantation in children
      and adolescents.
AB  - The time course of speech development in children after cochlear implantation may
      extend over many years, thus making long-term studies necessary to evaluate any
      outcome. We report our long-term results after cochlear implantation in children
      and adolescents. Mean follow-up was 28 months, ranging from 1 to 5 years. After
      at least 1 year of experience all children were found to benefit from their
      cochlear implants. The majority of children scored above chance in speech
      identification tasks requiring closed set word and sentence understanding). At
      the 4-year interval, all children tested including prelingually deaf children had
      developed open set sentence understanding. The most relevant factor accounting
      for differences in the results was the duration of implant use in all groups.
      Even beyond 3 years the results continued to improve. Peri- or postlingually
      deafened children tended to have favorable results. For prelingually deaf
      children, duration of deafness and age at implantation were correlated negatively
      with the results.

PMID- 8652159
TI  - Limitations in the use of distortion product otoacoustic emissions in objective
      audiometry as the result of fine structure.
AB  - There is strong evidence for a link between intact cochlear function and
      otoacoustic emissions (OAE). However, all attempts to find a close correlation
      between auditory thresholds and amplitudes of distortion product otoacoustic
      emissions (DPOAE) have failed. As an explanation for these findings, we have
      studied DPOAE fine structure and its dependence on increasing primary sound
      levels. Errors due to different calibrations of equipment for measuring DPOAE and
      auditory thresholds were also investigated. DPOAE were measured in 16 subjects
      using a frequency range of 500-1000 Hz. Frequencies were changed in 12.5 Hz steps
      at primary levels of 55, 60, 65 and 70 dB SPL. DPOAE amplitudes were found to
      vary by up to 20 dB for a frequency step of 50 Hz. Some fine structures showed
      narrow dips that shifted in frequency and diminished in amplitude with increasing
      primary levels. These findings demonstrated that sampling DPOAE amplitudes at
      widely spaced frequencies gave incomplete information about true course. DPOAE
      growth functions measured close to a dip in the DPOAE fine structure were
      rendered useless by interference with either the frequency shift or amplitude
      variations of the dip at different primary levels.

PMID- 8652161
TI  - Brainstem ischemic damage following occlusion of the blood vessels in the rat's
      posterior cerebral circulation.
AB  - Progression of ischemic damage was investigated immunohistochemically in neural
      dendrites using microtubule-associated protein 2 (MAP2) as a dendritic marker in
      the rat's brainstem. Neuronal soma and dendrites were clearly stained by this
      protein but some structures such as axonal bundles, glia and endothelial cells
      were not visualized. When the anterior inferior cerebellar artery (AICA) was
      occluded unilaterally for 30 min, a wide ischemic lesion was detected in the
      occluded side of the brainstem and was observed as a loss of reaction to MAP2.
      After ischemia for 2 h, loss of reaction in the perikarya and dendrites was seen
      to expand to the ipsilateral (occluded side) cochlear nucleus. When the basilar
      artery was blocked, ischemic damage in the vestibular nucleus was more intense
      than that in the cochlear nucleus. In all specimens studied, differences in
      anatomical blood supply demonstrated selective tissue vulnerability for ischemic
      damage.

PMID- 8652160
TI  - Transpalatine excision of a cavernous hemangioma of the infratemporal fossa.
AB  - Hemangiomas of the head and neck region can represent a therapeutic challenge
      depending on their size, location and symptoms. We report a case of a 40-year-old
      woman who presented with a 2-cm encapsulated cavernous hemangioma in the
      infratemporal fossa (ITF). Extensive workup included CT, MRI and angiography. A
      transoral/transpalatine approach avoiding osteotomy was used for surgical
      excision. After an unremarkable postoperative course the patient has remained
      disease-free after a 2-year follow-up period. We suggest this surgical approach
      as an alternative in carefully selected cases of circumscribed small, benign
      lesions of the ITF.

PMID- 8652162
TI  - Choristoma of the middle ear.
AB  - Choristoma is a mass of tissue histologically normal for an organ or part of the
      body other than the site at which it is located. A rare case of ectopic salivary
      gland choristoma in the middle ear is described in a 4-year-old boy whose only
      symptom was a 50 dB conductive hearing loss in the presence of a normal tympanic
      membrane.

PMID- 8652163
TI  - Metastatic hypopharyngeal carcinoma to the temporal bone.
AB  - Two cases of temporal bone metastasis by hypopharyngeal carcinomas are reported.
      One patient was a 43-year-old Japanese male who developed palsy of left
      oculomotor, trochlear, trigeminal, abducens and facial nerves. Carcinoma
      infiltrated the petrous portion of the left temporal bone. Tumor had destroyed a
      part of the facial canal and invading tumor cells were in contact with the
      perineurium. The other patient was a 59-year-old male who had no obvious facial
      nerve or otologic symptoms during the clinical course of his disease. Postmortem
      findings showed that carcinoma had invaded the right temporal bone and had
      produced extensive destruction of the facial canal. Degenerative findings were
      evident in the nerve. In the cases presented here, tumor resulted either from
      metastatic lymph nodes or had invaded through the suture of the temporal and
      sphenoid bones around the foramen lacerum to the middle cranial fossa and then
      infiltrated the temporal bone.

PMID- 8652164
TI  - Preliminary results of photodynamic therapy for recurrent nasopharyngeal
      carcinoma.
AB  - Photodynamic therapy (PDT) is a promising new modality in the treatment of
      cancer. In Hong Kong where nasopharyngeal carcinoma (NPC) is endemic,
      radiotherapy has been the primary treatment of choice. For recurrent disease
      after radiotherapy, there is no effective treatment. This latter report
      summarizes our initial experience in using PDT for these patients. Twelve
      patients (three females and nine males) with ages ranging from 33 to 65 years
      were treated with an infusion of hematoporphyrin derivative (5 mg/kg) 48-72 h
      before exposure to 200 J/cm2 light (wavelength, 630 nm) delivered from a gold
      vapor laser. All 12 patients showed a dramatic response as judged by computed
      tomography or magnetic resonance imaging at 6 months post-PDT. Of the eight
      patients in whom cure was aimed for, three remained disease-free at 9-12 months
      after a single treatment. Three of the remaining four patients achieved useful
      palliation. Skin hypersensitivity occurred in two patients and was the only
      significant complication encountered. This experience indicates that PDT can be
      an encouraging palliative or definitive management for recurrent superficial NPC.

PMID- 8652165
TI  - Proceedings of the 10th SAMBA (Society for Ambulatory Anesthesia) annual meeting.
      Indian Wells, California, April 27-30, 1995.

PMID- 8652166
TI  - Remifentanil: a new opioid.
AB  - Remifentanil appears to have pharmacodynamic properties similar to other potent
      mu opioid agonists. It does, however, have unique pharmacokinetic properties,
      with a rapid onset and rapid offset of effect, irrespective of the duration of
      its administration. With this property, remifentanil appears to be a very
      titratable opioid that will make it suitable for administration for either very
      brief periods, in which analgesia is required, or over prolonged periods, without
      the concern for prolonged recovery.

PMID- 8652168
TI  - Global fees for managed care in ambulatory surgery.
AB  - Managed care, especially health maintenance organizations (HMOs), has expanded
      rapidly in the United States, with nearly 52,300,000 enrollees. HMOs seek to
      provide health services in an efficient setting at the most reasonable price. To
      facilitate this objective, HMOs are shifting the financial risk from payors to
      the providers. Historically, ambulatory surgery was viewed as a significant cost
      savings compared with inpatient surgery, eliminating or reducing costly nursing
      care, boarding charges, medications, and therapies. As the incidence of
      ambulatory surgery utilization increased from approximately 20% of all surgery
      performed in the United States in 1982, to nearly 60% in 1993, consuming larger
      quantities of scarce health dollars, the emphasis shifted to reducing the charges
      for ambulatory surgery. Initial efforts to contain costs involved utilization
      management and discounted fee-for-service reimbursement methodologies. When this
      proved ineffective, a fixed fee per procedure was employed. Recently, full-risk
      capitation reimbursement has been applied to transfer financial risk and
      incentive to the provider to mitigate increasing health care costs. Surplus
      capacity and the consolidation of many covered lives or enrollees with fewer
      institutional payors (e.g., Blue Cross Blue Shield or Prudential) has made this
      transformation possible. The combination of these events has provided the HMOs
      with great leverage. The payors have more choices of providers than ever before,
      and they seek a safe ambulatory surgery environment at a low charge. In some
      areas of the country, facility and professional fees are being bundled to
      differentiate their product and attract more volume. Subcapitation of anesthesia
      services is being implemented or discussed in regions with very high HMO market
      penetration. This paper reviews the concept of bundling of services involving
      anesthesia in ambulatory surgery. It also seeks to provide a process that will
      assist anesthesiologists to achieve appropriate capitation reimbursement rates
      from HMOs.

PMID- 8652167
TI  - Inhalational anesthetics: desflurane and sevoflurane.
AB  - This article reviews the physico-chemical properties and performance
      characteristics of the two new potent inhaled anesthetics, desflurane and
      sevoflurane. Both drugs provide a greater degree of control of anesthetic depth
      and a more rapid immediate recovery from anesthesia than is currently available
      with other inhaled agents because of their decreased solubility. Desflurane is
      currently in widespread clinical use in the United States and parts of Europe.
      Compared with sevoflurane, it has the additional advantage of being extremely
      resistant to degradation and biotransformation. However, its pungent odor and
      tendency to irritate the respiratory tract make it unsuitable for inhalational
      inductions, and it has been linked to CO production in CO2 absorbents. The
      sympathetic nervous system activation that occurs with desflurane limits its use
      in patients with cardiac disease. Otherwise, its hemodynamic and physiologic
      effects are similar to those seen with isoflurane. Studies of the economics of
      using desflurane are mixed, although it may offer the advantage of shorter
      postoperative recovery time. Sevoflurane is currently in widespread clinical use
      in Japan and parts of South America. The FDA Advisory Panel has recently
      recommended approval of sevoflurane in the United States, and we can expect the
      drug to be clinically available in the United States in the second quarter of
      1995. Compared with desflurane, sevoflurane has the additional advantage of being
      nonirritating to the airway; inhalational induction of anesthesia with
      sevoflurane is achieved rapidly and easily. The instability of sevoflurane with
      CO2 absorbents and its in vivo biotransformation produce potentially toxic
      byproducts. These byproducts, including Compound A and fluoride, have been
      extensively studied, and although the possibility for iatrogenic sequelae from
      sevoflurane exists, the likelihood of long-term toxicity appears quite low. Phase
      IV studies are indicated to determine the safety of administering sevoflurane (1)
      to renally impaired patients and (2) to any patient with fresh gas flows less
      than 2 L/min. Sevoflurane is otherwise very well tolerated and appears to offer
      the advantage of rapid and smooth induction and emergence from general
      anesthesia.

PMID- 8652169
TI  - Creating greater efficiency in ambulatory surgery.
AB  - Ambulatory surgery emerged as a new modality in health care 25 years ago, and it
      has continued to grow substantially since that time. Several thousand facilities
      and programs have been established, developed, and expanded, while hundreds of
      millions of dollars were expended and committed to react to industry demands.
      Ambulatory surgery growth between 1970 and 1980 (Figure 1) was primarily fueled
      by patient, physician, and cost considerations. Surgical facilities and programs
      were initially faced with establishing credibility and legitimacy by
      demonstrating safety and quality in the outpatient setting. Thus began the
      competition for the ambulatory surgery patient in the United States. Ambulatory
      surgery became synonymous with efficiency in that there was a reduction in
      overnight stays, lowering the cost for the ambulatory surgery patient and
      providing hospital beds for those who required them. In addition, ambulatory
      surgery centers' fees were initially considerably less than hospital ambulatory
      surgery fees. Between 1980 and 1990 (Figure 2), the principal influences in
      ambulatory surgery expanded from surgeons and patients to include insurance
      companies and government reimbursement programs, including Medicare and Medicaid.
      A substantial growth in technology occurred, the investment community discovered
      ambulatory surgery, and an increase in reimbursement was a result of those
      marketplace dynamics. From 1990 (Figure 3) to the present, principal influences
      expanded from surgeons, patients, insurance, and government, to include managed
      care, creative alliances, affiliations, and employers. The health care industry
      is now dominated by cost control, competition, exclusionary contracts, changing
      referral patterns, fragmentation, self-referral legislation, continuing
      governmental regulations, consumerism, accountability and measurability, over
      capacity, capital limitations, and technological advances. Health care clinicians
      and analysts comfortably project that, by the year 2000, 75% of all surgery will
      be performed on an ambulatory basis./4+ key/(ABSTRACT TRUNCATED AT 400 WORDS)

PMID- 8652171
TI  - Pediatric ambulatory anesthesia: NPO--before or after surgery?

PMID- 8652170
TI  - A hospital administrator's view of the operating room.
AB  - The need for greater efficiency in OR management will become apparent as
      hospitals are forced to respond to a myriad of pressures imposed by the external
      environment. The most effective strategy in dealing with this challenge will be
      realized by adopting a "systems" approach to OR functions as opposed to the more
      traditional methodology that emphasizes a review of individual problematic
      components. One issue that challenges many ORs is "throughput": the backlog of
      patients in ORs that occurs because the recovery room is filled to capacity. The
      traditional approach is to focus on the recovery room's inefficiency and to
      expend energy on improving recovery room function. A "systems" approach would
      examine all factors that affect recovery room function and analyze the
      interdependencies that exist between the recovery room and other hospital service
      functions. These might include the way cases in the OR are scheduled, as well as
      issues that involve patient transfer from the recovery room to intensive,
      intermediate, and routine floor care. By establishing a dialogue with parties
      outside of the traditional OR community, the opportunity to solve problems that
      affect the OR but that are outside of its direct sphere of control, presents
      itself. This approach will require the acquisition of new skills by those
      responsible for OR management in addition to promulgating a change in the culture
      that dominates many ORs today. An insular approach that reinforces the concept of
      the OR as a microcosm unto itself is an outmoded one. The hospital community at
      large will benefit from the expert skills possessed by those proficient in
      efficient OR management, while enabling the OR to fulfill its mission in the
      challenging times ahead.

PMID- 8652172
TI  - Pediatric ambulatory anesthesia: role of parents.
AB  - Preschool children depend on their parents for support and guidance in dealing
      with new or stressful situations. When requested, the parents should be allowed
      to support their children during ambulatory surgical procedures, especially
      during the induction of anesthesia. With proper understanding on our part, and
      with proper preparation and counseling, the parents can become our allies and
      help to smooth the experience for the child, for the staff, and for themselves.
      Future efforts should be directed at studying the effects of different methods of
      preoperative preparation and counselling on the parents' attitude and cooperation
      during induction.

PMID- 8652173
TI  - Pediatric postanesthesia recovery care.
AB  - The PACU is a dynamic environment where children undergo significant physiologic
      changes. Their safe care is dependent on the concerted, prospective efforts of
      the medical and nursing staff. This can best be done when the staff is well
      trained in the care of children and the unit is sufficiently equipped. Attention
      and leadership from anesthesiologists can ensure ongoing quality care for
      children.

PMID- 8652174
TI  - Practical cost-effective choices: ambulatory general anesthesia.
AB  - To determine cost-effectiveness, we need to determine the value obtained for the
      price paid. Several points emerge. We need to identify specific recovery goals as
      our benefits, looking at early, intermediate, and late phases of recovery.
      Benefits such as effects on nausea may be specific to the procedure, duration,
      and site of practice. Time savings in the OR or recovery areas do not generate
      cost savings unless utilization actually increases or staffing actually
      decreases. Recovery care protocols that mandate a specific duration of stay in
      the PACU can negate any intraoperative or postoperative benefit differences
      generated by an anesthetic agent. Most of all, it is difficult to assign a dollar
      value to a very important benefit: patient satisfaction. Each of us, in our
      practices, must identify cost-effective choices for ambulatory anesthesia.
      Determining prices is simple. This we can and should do. Determining value,
      however, is more complicated and it is in this direction our work must lie.

PMID- 8652175
TI  - Practical, cost-effective regional anesthesia for ambulatory surgery.

PMID- 8652176
TI  - Spinal anesthesia for outpatients: appropriate agents and techniques.
AB  - With attention to appropriate selection of drugs, techniques, and needles, spinal
      anesthesia offers significant advantages in the outpatient setting. The
      combination of rapid onset, high reliability, and technical ease, along with the
      lower incidence of postoperative nausea and vomiting, allows for rapid turnover
      and discharge. The incidence of headache should not be a limiting factor if
      appropriate small, rounded bevel needles are used, and the technique is used
      primarily in the population aged over 40 years.

PMID- 8652177
TI  - Recovery advantages of regional anesthesia compared with general anesthesia:
      adult patients.
AB  - The data support but do not conclusively prove, that RA results in a superior
      recovery compared with GA. However, several questions need to be answered. Even
      though the patient may leave the hospital or surgicenter sooner after RA, how
      does the patient treat pain at home once the block has "worn off"? Since short
      acting sedatives and opioids are so commonly used with RA, to what extent is
      recovery due to them and to what extent is recovery due to the RA alone? Many of
      the studies examining beneficial effects of RA have been poorly conducted,
      combining RA with GA and producing inconclusive results. Anesthetic techniques
      need to be carefully compared to determine whether they are equal in quality,
      efficiency, and cost. Finally, to determine whether RA is cost-effective, future
      studies involving ambulatory patients with a focus on outcome and well-being need
      to be conducted.

PMID- 8652178
TI  - Cytokine signaling in mesothelial cells: receptor expression closes the autocrine
      loop.

PMID- 8652179
TI  - Interleukin 6 is an autocrine growth factor for normal human pleural mesothelial
      cells.
AB  - Interleukin 6 (IL-6) is a multifunctional inflammatory cytokine whose abnormal
      production has been implicated in a variety of diseases. Our previous study
      demonstrated that exudative pleural effusions contain a large amount of IL-6, and
      the levels of IL-6 in pleural effusion have diagnostic and pathophysiologic
      values. Although IL-6 is produced by a variety of cells, the origin of IL-6 in
      pleural effusion has not been determined clearly. We hypothesized that pleural
      mesothelial cells (PMCs) are an important source of IL-6 in pleural diseases. In
      this study, we tried to demonstrate whether PMCs could produce IL-6 and to
      characterize the modulation of its production. PMCs were established from
      patients with nonmalignant pleural effusion. Immunoreactive IL-6 could be
      detected in cultured supernatants of all PMCs from five patients, and all IL-6
      detected in the supernatants were biologically active. IL-6 production was
      augmented by the addition of interleukin 1 alpha (IL-1 alpha) in a dose-dependent
      manner and suppressed by dexamethasone. Expression of IL-6 mRNA was spontaneously
      observed and was increased by IL-1 alpha. PMCs also expressed mRNA for IL-6
      receptors gp80 and gpl30. Spontaneous cell growth and DNA synthesis of PMCs were
      inhibited by the addition of a neutralizing anti-IL-6 monoclonal antibody and
      were promoted by the addition of IL-6 to the culture. These results suggest that
      IL-6 is an autocrine growth factor for PMCs.

PMID- 8652180
TI  - Inhibition of ozone-induced nitric oxide synthase expression in the lung by
      endotoxin.
AB  - Inhalation of the pulmonary irritant ozone is associated with an accumulation of
      macrophages in the lung. These cells, along with type II epithelial cells, are
      activated to release increased quantities of hydrogen peroxide and nitric oxide,
      two reactive mediators that have been implicated in tissue injury. In the present
      studies we determined whether pretreatment of rats with bacterially derived
      endotoxin, which modulates oxidant levels in tissues, could abrogate the effects
      of ozone on lung injury and nitric oxide production. Acute exposure of rats to
      ozone (2 parts per million, 3 h) resulted in nitric oxide production in the lung
      as measured by electron paramagnetic resonance spin trapping. This was correlated
      with expression of inducible nitric oxide synthase (iNOS) mRNA in the lung as
      determined by in situ hybridization. Particularly high levels of iNOS were
      evident in alveolar macrophages and type II cells. Alveolar macrophages isolated
      from ozone-treated rats also expressed increased iNOS mRNA and protein as
      measured by Northern and Western blotting, respectively, and produced more nitric
      oxide compared with cells from air-exposed animals. Treatment of rats with
      endotoxin (5 mg/kg, intravenously), 30 min prior to ozone, was found to abrogate
      ozone-induced increases in iNOS mRNA and protein expression, as well as nitric
      oxide production by alveolar macrophages. This was associated with a reduction in
      ozone-induced tissue injury as determined by levels of lung lavage fluid protein.
      Ozone inhalation also resulted in a reduction in intracellular glutathione in
      alveolar macrophages, an effect that was blocked by endotoxin administration.
      Taken together, these data provide evidence that the protective effects of
      endotoxin against ozone-induced injury are mediated, at least in part, by
      alterations in levels of lung oxidants and antioxidants.

PMID- 8652182
TI  - p172: An alveolar type II and Clara cell specific protein with late developmental
      expression and upregulation by hyperoxic lung injury.
AB  - The epithelium of the alveolus and distal airway meets unique requirements,
      functioning as a gas exchange membrane and barrier to alveolar flooding by
      vascular contents as well as to bloodstream contamination by airborne toxins and
      pathogens. Gene products specifically expressed by this epithelium, notably the
      surfactant apoproteins, have had important clinical application. No cell surface
      antigen specific for alveolar type II and Clara cells has been described. We
      report the biochemical characterization, tissue and developmental expression, and
      upregulation by injury of a 172 kD protein recognized by a monoclonal antibody,
      3F9, synthesized in response to immunization with freshly isolated rat alveolar
      type II cells. p172 is expressed in a polarized fashion by the apical surface of
      rat alveolar type II and Clara cells. An immunohistochemical survey of various
      rat tissues and organs reveals lung specificity. p172 is first detectable in rare
      epithelial cells at 19 days of gestation, a time when the fully differentiated
      alveolar type II cell is identified by the first detection of lamellar bodies.
      There is a dramatic increase in p172 expression just prior to birth. Hyperoxic
      lung injury results in increased expression of p172. The upregulation of p172 by
      hyperoxia and its cell-specific expression suggests an important adaptive
      function.

PMID- 8652181
TI  - Developmental regulation of angiotensin converting enzyme and angiotensin type 1
      receptor in the rat pulmonary circulation.
AB  - Factors that influence the development of the normal pulmonary vasculature are
      poorly understood. Since increased local production of angiotensin II (AII) by
      angiotensin converting enzyme (ACE) has been implicated in the medial hypertrophy
      of systemic and pulmonary hypertension, we questioned whether ACE and angiotensin
      receptor expression may influence the muscularization of the normal pulmonary
      vasculature during development. The approach employed measurement of lung ACE
      activity, assessment of local ACE expression by immunohistochemistry, and
      angiotensin type 1 receptor (AT1) expression by in situ hybridization in rat
      lungs ranging from 15 days of intrauterine life (term = 21 d) to adulthood. The
      temporal and spatial pattern of ACE expression was compared with that of the
      endothelial marker, von Willebrand factor (vWF), and the smooth muscle cell
      markers, alpha smooth muscle actin and smooth muscle myosin. ACE activity was
      first detected in lung homogenates on day 17 of gestation (1 +/- 0.2 mU/mg) and
      increased progressively to term (27.7 +/- 3.2 mU/mg). However, the greatest
      increase in lung ACE activity to adult levels (379 +/- 25.2 mU/mg) occurred
      between 2 and 4 wk of postnatal life. Immunohistochemistry demonstrated vWF
      expression by vascular endothelium throughout the lung as early as day 15 of
      gestation. In contrast, ACE expression was observed in the endothelium of only
      hilar pulmonary arteries on day 15 of gestation, and thereafter was noted to be
      expressed in endothelial cells of progressively more distal arteries, such that
      by term, endothelial cells of all muscularized arteries expressed ACE. Alveolar
      capillary ACE expression was not detected until day 20 of gestation, and
      increased dramatically after birth. Smooth muscle actin expression in lung
      arteries closely paralleled the expression of endothelial ACE. AT1 receptor mRNA
      was first expressed in the peripheral lung on day 17 of gestation by non
      epithelial undifferentiated mesenchyme. In contrast, AT1 mRNA signal was much
      reduced in differentiated smooth muscle. We speculate that ACE expression in the
      fetal lung circulation may influence the muscularization of fetal pulmonary
      arteries by the interaction of locally produced angiotensin II with the AT1
      receptor.

PMID- 8652183
TI  - TNF alpha gene and protein expression in alveolar macrophages in acute and
      chronic hyperoxia-induced lung injury.
AB  - Alveolar-capillary membrane remodeling, including microvessel wall thickening and
      interstitial fibrosis, is a well-known sequela of cell proliferation in the
      hyperoxia-injured lung. The array of growth molecules released locally that
      potentially mediate this response, and their cell(s) of origin, are currently
      being defined. To elucidate the role of tumor necrosis factor alpha (TNF alpha),
      an effector molecule of cell injury and proliferation, and the role of the
      alveolar macrophage (AM) as its source during the acute (1 to 24 h) and chronic
      stages (3 to 28 days) of hyperoxia-induced injury, we have analyzed gene and
      protein expression in cells recovered from rat lung by bronchoalveolar lavage. In
      the hyperoxic lung, cell number was similar to that in normal lung (1 x 10(6))
      except on day 7, when it was higher (5 x 10(6)). Virtually all cells recovered
      from the normal and hyperoxic lung were AMs, with the exception that on days 3
      and 7 of hyperoxia these cells represented 69% and 55% of the population,
      respectively, and polymorphonuclear leukocytes and lymphocytes the remainder.
      Probe specificity was confirmed by detection of TNF alpha RNA (1.6 kb) from lung
      cells recovered after lipopolysaccharide (LPS) treatment (positive control) and
      from the hyperoxic lung (at day 3), with an extremely low level of constitutive
      expression detected in cells from normal lung. In cytospin preparations, TNF
      alpha mRNA transcripts were detected in few AMs recovered from normal lung and in
      most AMs after LPS treatment. In the hyperoxic lung, a signal was detected at 3
      h, when approximately 25% of the population was positive. The number of
      hybridizing cells then increased, being highest on day 7 (day 1 approximately
      30%, day 3 approximately 58%, day 7 approximately 90%, day 28 approximately 65%).
      No expression of TNF alpha protein was detected in AMs from normal lung; positive
      cells were detected in the hyperoxic lung from day 1 and thereafter. We conclude
      from upregulation of the TNF alpha gene in a significant number of cells, and
      from the increase in the number expressing biologically active protein, that AMs
      are an important source of this molecule both in the acute and chronic stages of
      hyperoxic lung injury. It is anticipated that an increased understanding of the
      cellular sources of mediators effecting vascular and alveolar wall remodeling in
      vivo will contribute to the development of strategies to inhibit the response.

PMID- 8652184
TI  - Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung
      injury.
AB  - Using hyperoxia as a model of oxidant-induced lung injury in the rat, we explored
      the regulation of heme oxygenase-1 (HO-1) expression in vivo and in vitro. We
      demonstrate marked increase of HO-1 messenger ribonucleic acid (mRNA) levels in
      rat lungs after hyperoxia. Increased HO-1 mRNA expression correlated with
      increased HO-1 protein and enzyme activity. Immunohistochemical studies of the
      rat lung after hyperoxia showed increased HO-1 expression in a variety of cell
      types, including the bronchoalveolar epithelium and interstitial and inflammatory
      cells. We then examined the regulation of HO-1 expression in vitro after
      hyperoxia and observed increased HO-1 gene expression in various cultured cells
      including epithelial cells, fibroblasts, macrophages, and smooth muscle cells.
      Increased HO-1 mRNA expression correlated with increased HO-1 protein in vitro,
      and resulted from increased gene transcription and not from increased mRNA
      stability. We show that transcriptional activation of the HO-1 gene by hyperoxia
      requires cooperation between the HO-1 promoter and an enhancer fragment located 4
      kb upstream from its transcription site. Increased HO-1 gene transcription was
      associated with increased activator protein-1 (AP-1) binding activity and
      supershift of the AP-1 complex by antibodies to c-Fos and c-Jun after hyperoxia.
      Taken together, our data suggest that AP-1 activation may represent one mechanism
      mediating hyperoxia-induced HO-1 gene transcription.

PMID- 8652185
TI  - Expression and localization of tropoelastin mRNA in the developing bovine
      pulmonary artery is dependent on vascular cell phenotype.
AB  - During vascular development, the expression of tropoelastin (TE) messenger
      ribonucleic acid (mRNA) has been shown to be time dependent and to form complex
      patterns along the longitudinal and radial arterial axes. The factors
      contributing to these patterns of TE expression are not known, but it has been
      suggested that they reflect phenotypic changes in developing smooth muscle cells
      (SMC). In order to examine a possible correlation between the developmental state
      of the SMC and TE expression during lung vascular development, we localized and
      assessed relative TE mRNA expression in the developing bovine main pulmonary
      artery (PA), and correlated the observed patterns of TE expression to changes in
      SMC phenotype as determined by the expression of various developmentally related
      SMC proteins. Further, because TE expression can be modulated by physical forces
      such as pressure, fetal PA TE expression was evaluated with regard to changes in
      fetal arterial pressure. We found that expression of TE mRNA exhibited a biphasic
      pattern during fetal development. In early gestation, expression was noted
      throughout the entire PA wall; at midgestation, expression was markedly decreased
      in the outer wall but maintained in the inner vascular media; at late gestation,
      reexpression was observed throughout the entire PA wall, albeit in a
      heterogeneous pattern. Immunohistochemical studies showed that the decrease in
      SMC TE expression during midgestation coincided with the acquisition of SMC
      specific proteins such as smooth muscle myosin heavy chains and desmin. The
      reexpression of TE late in gestation occurred in these "differentiated" SMC and
      was temporally associated with a large increase in arterial pressure shown to
      occur in late gestation. In addition, we identified an SMC population defined by
      its immunoreactivity to the muscle-specific cytoskeletal protein meta-vinculin
      that did not express TE mRNA either during fetal PA development or postnatally
      when PA hypertension was induced. We conclude that both the developmental state
      of the SMC and hemodynamic forces correlate with the pattern of PA TE mRNA
      expression during pulmonary vascular development. Further, a subpopulation of SMC
      defined by meta-vinculin expression exists in the fetal and neonatal bovine
      vascular wall and does not express detectable levels of TE mRNA regardless of
      vascular pressure.

PMID- 8652186
TI  - T1 alpha protein is developmentally regulated and expressed by alveolar type I
      cells, choroid plexus, and ciliary epithelia of adult rats.
AB  - T1 alpha is the first marker gene known to be expressed in the adult lung solely
      by the alveolar type I epithelial cell. Previous studies showed that T1 alpha
      transcripts are abundant in early rat embryos where they are found in the nervous
      system and in the foregut and certain of its derivatives including the primitive
      lung. By mid- to late gestation T1 alpha messenger RNA (mRNA) expression is lost
      from neural tissues but appears to increase in the lung throughout fetal life. To
      determine whether the T1 alpha transcripts are translated into protein,
      especially in early embryos which sometimes express transcripts that are
      translationally silent, we performed immunohistochemistry on embryos and fetal
      tissues and analyzed certain tissues by western blotting using a monoclonal
      antibody against T1 alpha protein. T1 alpha protein is present at all sites that
      have previously been shown to express the mRNA and at similar developmental
      stages. As estimated from western blots, T1 alpha protein abundance peaks at
      about fetal day 16 in the brain and decreases thereafter to a relative level in
      the adult that is lower than that of the neural tube of the day 13 embryo.
      Relative protein abundance in the lung is very low, although detectable, on
      embryonic day 13 but increases slowly until fetal day 20 when there is a dramatic
      increase. At the time of birth, restriction to the type I cell is not complete
      and therefore must occur during postnatal lung development. Immunostaining
      reveals additional sites of expression in fetal and adult rats that had not been
      clearly visualized in previous in situ hybridization studies. T1 alpha is present
      in mesonephric tubules and apparently in primitive germ cells but is not
      detectable in specific cells in the adult kidney, ovary, or testis. However,
      cells of the choroid plexus of the central nervous system and the ciliary
      epithelium of the eye express T1 alpha in both fetuses and adults. The well-known
      functions of these epithelia are to elaborate cerebrospinal fluid and aqueous
      humor respectively by processes of active ion transport and water fluxes,
      probably through the aquaporin 1 (channel-forming integral membrane protein
      [CHIP] 28). We speculate therefore that T1 alpha protein may modulate or
      participate in these types of cellular functions in the lung.

PMID- 8652187
TI  - Maintenance of differentiated murine Clara cells in microdissected airway
      cultures.
AB  - Nonciliated bronchiolar epithelial (Clara) cells, as both the primary target for
      metabolically activated pulmonary cytotoxicants and the progenitor during repair
      after bronchiolar injury, are critical for distal airway epithelial function and
      regeneration. The role of Clara cells in normal lung function is poorly
      understood partly because their abundance, sensitivity to cytotoxicants, and
      expression of differentiation markers vary by airway level and species. This
      study defines a strategy for maintenance in vitro of differentiated Clara cells
      within their local microenvironment. Lungs from adult mice were infalted with 1%
      agarose and distal airways were isolated by microdissection. Explants were
      cultured for 7 days in serum-free medium. Preservation of Clara cell morphology
      after 7 days in culture (DIC) was demonstrated using light and electron
      microscopy. Ciliated cells were also present. Cytochrome P450 monooxygenase
      activity, as measured by naphthalene epoxidation, was decreased 50% between 0 and
      7 DIC, but the apparent stereoselectivity of metabolism was unchanged at 7 days.
      Marker proteins for differentiated Clara cells (secretory protein, CYP2F2 and
      CYP2B4) were detectable immunochemically throughout time in culture. Glutathione
      S-transferase activity and levels of reduced glutathione were unchanged over 7
      DIC. We conclude that differentiated Clara cells can be maintained in cultures of
      explants from defined airway regions. Bronchiolar epithelial cells in this system
      are viable, synthesize and secrete secretory protein, metabolize xenobiotics via
      the cytochrome P450 system, have a stable phase II enzyme system, and maintain
      glutathione pools.

PMID- 8652188
TI  - Transcriptional regulation of human pulmonary surfactant proteins SP-B and SP-C
      by glucocorticoids.
AB  - Expression of the pulmonary surfactant-associated proteins SP-B and SP-C is under
      both developmental and hormonal regulation. We used human fetal lung to
      investigate developmental changes and the mechanism of glucocorticoid stimulation
      of SP-B and SP-C gene expression. There were similar approximately 3-fold
      increases in SP-B cytoplasmic mRNA content and transcription rate comparing lung
      samples of 24 wk versus 16 wk gestation. During 5 days of lung explant culture
      without hormones, the transcription rate increased for SP-B and decreased for SP
      C, paralleling changes in mRNA content. Treatment with 100 nM dexamethasone
      maximally increased transcription of the SP-B gene (approximately 3-fold) and SP
      C gene (approximately 11-fold) after 2 and 8 h, respectively, similar to changes
      in mRNA content. In dose-response studies, the maximal increase in transcription
      rate occurred at approximately 10 nM dexamethasone for SP-B and at > or = 100 nM
      for SP-C. Induction of SP-B mRNA content and transcription rate were not affected
      by prior cycloheximide exposure, whereas induction of SP-C mRNA was decreased by
      as little as 1 h exposure to inhibitor. We conclude that glucocorticoids, acting
      directly in type II cells, regulate the SP-B and SP-C genes primarily at the
      level of transcription. Induction of SP-C, but not SP-B, requires ongoing protein
      synthesis which likely reflects involvement of a labile transcription factor. The
      difference in glucocorticoid sensitivity may indicate that the two surfactant
      protein genes contain glucocorticoid response elements with different affinities
      for receptor.

PMID- 8652189
TI  - Surfactant protein A accumulating in the alveoli of patients with pulmonary
      alveolar proteinosis: oligomeric structure and interaction with lipids.
AB  - Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease of unknown
      etiology in which the alveoli and terminal bronchioles of the lung fill with
      large amounts of surfactant-rich lipoproteinaceous materials. Its major
      pathologic manifestations are a small number of normal tubular myelin structures
      and an unusual abundance of multilamellated structures. Since surfactant protein
      A (SP-A) plays an important role in surfactant phospholipid homeostasis, we
      investigated the structural features of SP-A oligomers (alveolar proteinosis
      protein, APP) accumulating in the alveoli of individuals with PAP, and examined
      the abilities of APP to interact with lipids. Analysis of APP by Bio Gel A15m
      column chromatography revealed that it was composed of two protein peaks, one of
      which (APP-I) eluted at the position near that of blue dextran whereas the other
      (APP-II) eluted far behind blue dextran but ahead of thyroglobulin. These
      populations of APP showed almost identical amino acid compositions. Electron
      microscopic observations of APP molecules using the rotary shadow technique
      revealed that APP-II was observed as hexameric particles, presumably consisting
      mainly of octadecamers whose diameter was approximately 30 nm. The population
      seen for APP-II was similar to that seen for SP-A from healthy individuals. In
      contrast, APP-I was observed as multimerized larger aggregates whose diameter
      appeared to be about 70 to 90 nm. Both APP-I and APP-II retained the abilities to
      bind dipalmitoylphosphatidylcholine (DPPC). They also induced phospholipid
      vesicle aggregation in a concentration-dependent manner. The maximal turbidity
      for light scattering induced by APP-I and APP-II was almost equivalent when
      analyzed as a function of molar concentration. In vitro reconstitution
      experiments with porcine surfactant protein B (SP-B) and phospholipids revealed
      that the multilamellated membranes in structures formed from APP-I consisted of
      several layers of doubled unit membranes. APP-I failed to form tubular myelin
      structures. In contrast, APP-II formed well-formed lattice structures seen in
      tubular myelin. From these data we conclude that there exists an abnormal
      multimerized form of SP-A oligomer in the alveoli of patients with PAP, and that
      this unusual subpopulation of SP-A oligomer exhibits abnormal function on
      phospholipid membrane organization.

PMID- 8652191
TI  - Cyclosporin A attenuates genetic airway hyperresponsiveness in mice but not
      through inhibition of CD4+ or CD8+ T cells.
AB  - We examined the influence of T lymphocytes on genetically determined airway
      hyperresponsiveness to acetylcholine (ACh) in mice. A/J and C3H/HeJ mice were
      treated with the T-cell suppressant cyclosporin A [(CsA) 25 to 100 mg/kg,
      intraperitoneally (i.p.), for 5 to 10 days], whereas control animals received the
      vehicle or remained untreated. CsA treatment induced a dose-dependent suppression
      of mitogen-stimulated spleen cell proliferation which was equivalent between the
      two strains. A/J control animals demonstrated approximately 8-fold greater ACh
      stimulated airway responsiveness, assessed by the time-integrated peak
      inspiratory pressure (APTI) compared with C3H/HeJ control mice. ACh-induced APTI
      was attenuated by CsA in a dose- and time-dependent manner in the A/J strain; no
      significant changes occurred in the C3H/HeJ strain. To determine whether
      lymphocyte subtypes mediated this response, we depleted T-cell subsets with
      either rat anti-mouse CD4+ (L3T4) monoclonal antibody (GK1.5, 500 micrograms,
      i.p.) or anti-CD8+ monoclonal antibody (J1.2, 500 micrograms; or YTS169.4, 150
      micrograms, i.p.) and assessed airway responsiveness. No significant change in
      airway responsiveness was detected in either strain after CD4+ or CD8+ T-cell
      depletion. Thus, although CsA administration attenuated spleen cell activation
      and was associated with a marked attenuation of airway responsiveness in mice
      with genetically hyperresponsive airways, CD4+ and CD8+ T cells do not appear to
      mediate this response.

PMID- 8652190
TI  - Histamine inhibits tumor necrosis factor alpha release by mast cells through H2
      and H3 receptors.
AB  - Histamine was one of the first inflammatory mediators thought to be important in
      the pathophysiology of asthma, but it is not now thought to be a mediator with
      primary importance in airway constriction. However, histamine has several effects
      that may be relevant. One of these effects, its immunoregulatory role, has been
      largely ignored in asthma. Thus, because mast cells (MC) are an important source
      of histamine and cytokines, the modulation by histamine of the release of one
      cytokine, tumor necrosis factor alpha (TNF alpha), was investigated. Rat
      peritoneal MC (PMC) were pretreated with different concentrations of histamine
      (10(-14) to 10(-4) M) for 2 h before being tested for their TNF alpha-dependent
      cytotoxicity. A concentration-dependent inhibition of cytotoxicity was observed
      from 21% at 10(-12) M to 38% at 10(-4) M, reaching a plateau at 10(-8) M. At
      least 1 h pretreatment with histamine or its presence throughout the cytotoxic
      assay was required for the inhibitory effect of histamine. This inhibition was
      abrogated by indomethacin or anti-PGE2, suggesting that PGE2 may be an important
      mediator in the inhibition of TNF alpha by histamine. To investigate the type of
      histamine receptor implicated in this effect, PMC were treated for 20 min with H1
      (clemastine and diphenhydramine), H2 (ranitidine and cimetidine), or H3
      (thioperamide) receptor antagonists before the addition of histamine. H2 or H3
      antagonists abrogated the inhibitory effect of histamine on PMC TNF alpha
      dependent cytotoxicity. Furthermore, blockage of H2 receptors with ranitidine
      increased the release of TNF alpha from PMC stimulated with antigen, suggesting
      that histamine released by MC within 10 min of antigen stimulation downregulates
      the subsequent release of TNF alpha from the same MC population. These results
      suggest that histamine may act as an autocrine regulator of cytokine release by
      MC and thus modulate inflammatory responses in allergic asthma.

PMID- 8652192
TI  - [Benign neonatal convulsions. Review of 23 cases].
AB  - Benign neonatal convulsions, though rare, are seen with increasing frequency and
      are characterized by seizures during the neonatal period with favorable
      prognosis. Two distinct entities can be identified, based on whether the syndrome
      is familial or non-familial, with epilepsy developing in 14% of patients with the
      familial form. We report a retrospective study of 23 patients, 13 with benign
      familial neonatal seizures and 10 with benign idiopathic neonatal seizures. All
      except one had normal neurologic development. We observed central temporal
      (rolandic) EEG foci in the follow-up of a few patients in both groups, with no
      clinical manifestations. We consider the possibility that these entities may
      share common genetic factors with benign rolandic epilepsy.

PMID- 8652193
TI  - [Diagnosis and treatment of drug-resistant epilepsy].
AB  - Important progress has been made in the treatment of drug-resistant epilepsy in
      recent years as the result of the introduction of new antiepileptic drugs and
      surgical procedures. Drug resistance can be the result of a variety of factors:
      incorrect diagnosis, lack of compliance with treatment, inappropriate
      antiepileptic therapy, as well as drug resistance per se. Appropriate drug
      therapy for epileptic syndromes, or symptomatic treatment of the type of seizure,
      are in general the most effective treatments for the patients whose conditions
      remain uncontrolled. Dose should be the highest tolerated by the patients without
      side effects, regardless of plasma levels reached. New antiepileptic drugs are
      indicated as alternatives for complementary therapy in drug-resistant patients,
      though their use is still experimental. Surgery is not the last option, but
      rather constitutes yet another valid alternative. In certain cases of temporal
      mesial syndrome, for example, early surgery may be indicated.

PMID- 8652194
TI  - [Parry-Romberg syndrome].

PMID- 8652195
TI  - [Movement disorders and AIDS].
AB  - We describe the clinical characteristics, causes and response to treatment in 6
      patients with AIDS who presented with abnormal movement disorders between January
      1987 and July 1993 in our hospital, 3 with hemiballismus-hemichorea, 1 with
      athetosis, 1 myoclonia and 1 with "rubric" tremor. Brain imaging showed lesions
      in the corpus striatum in all the patients. Suspected diagnoses were cerebral
      toxoplasmosis in 4, cerebral lymphoma in 1 and progressive multifocal
      leukoencephalopathy in 1. The toxoplasmosis patients showed improvement (2 cases)
      or disappearance (2 cases) of movements with antiparasitic therapy. Treatment
      provided no benefit to the patients with leukoencephalopathy and lymphoma.
      Hemiballismus-hemichorea was the most common movement disorder in AIDS patients.
      The underlying cause is usually lesions in the basal ganglia arising from
      toxoplasmosis. If the lesions are so caused, movements may improve with
      antiparasitic therapy.

PMID- 8652196
TI  - The spectrum of cluster headaches: a case report.
AB  - Cluster headache and chronic paroxysmal hemicrania are two syndromes which,
      although sharing many characteristics, are coded separately under the
      International Headache Classification system. I report a patient who, over a 15
      year period presented at sometime or other, many features of these two syndromes.
      Rather than continuously reclassifying the patient's diagnosis according to the
      characteristics of individual attacks, I propose that such patients be
      categorized as having a "cluster spectrum disorder", at least until biological
      markers point to the contrary.

PMID- 8652197
TI  - [Hemiballismus heralding thrombosis of the basilar artery].
AB  - We present a patient with top-of-the-basilar syndrome that was preceded by
      hemiballismus and progressed to coma and tetraplegia. Magnetic resonance imaging
      showed extensive infarction in the basilar artery territory. Cerebral angiography
      confirmed basilar artery obstruction. The patient died in spite of
      anticoagulation therapy.

PMID- 8652198
TI  - [Non-giant cell temporal arteritis as a manifestation of Churg-Strauss syndrome.
      Presentation of a case and review of literature].
AB  - Most cases of temporal arteritis are of the giant cell variety, with cases
      involving other histologic patterns occurring rarely. There are only 4
      descriptions in the literature of non giant cell temporal arteritis as a
      manifestation of Churg-Strauss syndrome. We report the case of a 74-year-old man
      with a history of bronchial asthma who presented with systemic symptoms and right
      temporal cephalea with diplopia, diffuse muscle pain and transient skin lesions
      on the extremities. The right temporal artery was enlarged and painful but
      pulsatile. Tests showed a high erythrocyte sedimentation rate and leukocytosis
      with relative and absolute eosinophilia. Biopsy of the temporal artery revealed
      polymorphic inflammatory infiltration throughout the vas, with numerous
      eosinophils and non giant cells, confirming a diagnosis of Churg-Strauss syndrome
      with extension to the temporal artery. Temporal arteritis should be considered a
      syndrome with variable substrate pathology; the possibility that it is a rare
      manifestation of systemic necrotizing vasculitis should not be ruled out.

PMID- 8652199
TI  - [Neurological complication and gold therapy].

PMID- 8652200
TI  - [Metastasis of the pineal gland].

PMID- 8652201
TI  - [First report of spastic dysphonia].

PMID- 8652202
TI  - Adult-onset neuroblastoma with intraspinal (dumbbell) extension.

PMID- 8652203
TI  - The use of high doses of adrenaline in paediatric cardiac resuscitation.
AB  - Adrenaline has been used in cardiac resuscitation for many years, yet until
      recently its mechanism of action and optimal dosage remained poorly investigated
      or understood. Recent guidelines suggest the use of higher doses of adrenaline at
      an early stage in paediatric resuscitation. This paper examines the use of
      adrenaline in paediatric resuscitation and studies the arguments in favour of
      using higher doses than previously accepted.

PMID- 8652204
TI  - Mutations, malformations and mortality.
AB  - Although DNA replication is a very accurate process, a small number of new
      mutations are generated at every cell division. The generation of a new mutation
      during the formation of an ovum or sperm cell can cause an early miscarriage or
      birth defect. The generation of new mutations during embryogenesis can cause a
      variety of localized birth defects. The molecular delineation of these errors in
      somatic and gonadal cells has clarified the basis of some birth defects, and has
      both refined and complicated genetic counselling for a number of paediatric
      conditions. The processes responsible for these new mutations are present in all
      cells. For this reason new mutations accumulate in all cells throughout life and
      contribute to the ageing process. Thus the molecular events that cause many
      miscarriages and birth defects are the same as those that ultimately lead to
      death.

PMID- 8652205
TI  - Oral rehydration solutions in gastroenteritis before and after admission to
      hospital.

PMID- 8652206
TI  - Pre-admission management of acute gastroenteritis.
AB  - OBJECTIVE: Acute gastroenteritis contributes to significant morbidity and need
      for hospital admission. The current literature suggests outpatient management is
      often inappropriate. This study examines the pre-admission management of children
      admitted with acute gastroenteritis to a major children's hospital. METHODOLOGY:
      Information was obtained from parental questionnaires and the medical notes for
      164 children. RESULTS: Parents were poorly informed regarding appropriate home
      management. Over 70% sought professional advice prior to admission, usually from
      their general practitioner. Although 58% received advice on fluid therapy, an
      oral rehydration solution was recommended for only 32%, and only 9% actually used
      one before admission. Advice regarding fluid requirements was usually inadequate.
      Inappropriate medications were prescribed for 22% of children, including
      antibiotics (15.4%), antidiarrhoeals (1.2%) and anti-emetics (5.5%). Hospitalized
      children were generally well nourished with minimal dehydration and electrolyte
      disturbance. CONCLUSIONS: Oral rehydration therapy is utilized rarely and
      medications are over-utilized in home management of gastroenteritis. Education of
      parents, general practitioners and hospital doctors is essential to optimize
      outpatient management. The impact of optimal outpatient management on hospital
      admission rates and morbidity requires formal assessment.

PMID- 8652207
TI  - Primary omental torsion in children.
AB  - OBJECTIVE: A retrospective review was conducted to establish the prevalence and
      clinical features of omental torsion or infarction as a cause of acute abdominal
      pain in childhood. METHODOLOGY: The case records were analysed for all patients
      admitted with primary omental pathology to the Department of General Surgery,
      Royal Children's Hospital, Melbourne, between January 1975 and July 1994.
      RESULTS: From 1975 to 1994 (20 years) 13 children were admitted to our General
      Surgical Department with primary omental disease. There were nine males and four
      females under 16 years of age. The presenting complaint was abdominal pain with
      vomiting or diarrhoea. Four children had major medical conditions. Pre-operative
      diagnosis in all cases was acute appendicitis. Appendicectomy and omentectomy
      were performed without complication in all cases. Histology of the omentum
      demonstrated torsion, infarction or haemorrhage. CONCLUSIONS: All children
      presented with features of acute appendicitis, a majority were male, and two out
      of the 13 patients were obese. The absence of any children under 4 years was
      consistent with the relative paucity of omental fat in younger children. We found
      no clear mechanism for primary omental torsion, although rotation around the
      right epiploic artery was observed.

PMID- 8652208
TI  - Predictive value of the Griffiths assessment in extremely low birthweight
      infants.
AB  - OBJECTIVE: To assess the relationship between the Griffiths Mental Development
      Scales at 1 and 3 years and the Stanford-Binet Intelligence Scale (S-B) and Beery
      Test of Visual-Motor Integration (VMI) at 5 years in extremely low birthweight
      (ELBW) children. METHODOLOGY: Prospective study of 45 ELBW infants, without
      severe neurosensory impairment, cared for in a single Level III neonatal
      intensive care unit. RESULTS: At 5 years, 36 (80%) children were of average
      intelligence, 8 (18%) had borderline intelligence and one was mentally retarded.
      The Griffiths general quotient (GQ) at 1 year had a weak correlation with the 5
      year IQ (corr. coeff. = 0.47), with only 17% of children with a GQ < -1 s.d. at 1
      year receiving an IQ < -1 s.d. at 5 years. In contrast, the Griffiths GQ at 3
      years correlated strongly with 5 year IQ (corr. coeff. = 0.78). Among those
      children with a 3 year GQ < -1 s.d., 67% had a 5 year IQ < -1 s.d. and all had a
      5 year 1Q < 89. The 3 year hearing and speech subscale correlated strongly with
      the 5 year S-B verbal comprehension factor (corr. coeff. = 0.753) and the 3 year
      combined eye/hand co-ordination/performance quotient had a moderate correlation
      with the S-B non-verbal reasoning factor (corr. coeff. = 0.597) and with the
      Beery VMI (corr. coeff. = 0.49). CONCLUSIONS: The 3 year Griffiths GQ is a good
      predictor of 5 year S-B IQ in ELBW children and can be used to identify children
      who may benefit from intervention prior to school entry.

PMID- 8652209
TI  - Neonatal neutropenia and thrombocytopenia following maternal hypertension.
AB  - OBJECTIVE: To assess the relationship between the subtypes of hypertension in
      pregnancy and subsequent neonatal haematology. METHODOLOGY: Retrospective review
      of the haematology of newborns of hypertensive mothers at a tertiary neonatal
      unit. RESULTS: Over a 2 year period, 249 infants had full blood examinations.
      Nineteen (7.6%) were neutropenic and 35 (14.1%) thrombocytopenic, including 11
      (4.4%) who were both neutropenic and thrombocytopenic. Neutropenia occurred only
      in infants whose mothers had severe pre-eclampsia and eclampsia or pre-eclampsia
      with pre-existing hypertension, whereas thrombocytopenia complicated all maternal
      hypertension subtypes. Two (10%) of the neutropenic infants developed nosocomial
      infection while seven (20%) of the thrombocytopenic infants bled. Thirteen (68%)
      of the neutropenic infants compared with 15 (43%) of the thrombocytopenic infants
      developed their haematological abnormality within 24 h of birth. All but two
      infants developed the haematological abnormality by the 5th day of life.
      CONCLUSION: Although haematological abnormalities in infants born to hypertensive
      mothers are uncommon, serious neonatal complications can occur and therefore
      early haematological screening of these infants is recommended.

PMID- 8652210
TI  - Rollerblading injuries in young people.
AB  - OBJECTIVE: To study injuries in young people associated with the use of
      rollerblades, draw comparisons with skateboarding and rollerskating injuries, and
      suggest strategies for injury prevention. METHODOLOGY: Injuries associated with
      the use of rollerblades, skateboards and rollerskates in young people aged < or =
      14 years recorded on the Victorian Injury Surveillance System database since its
      inception in 1989 were examined to identify secular trends. All injuries
      associated with these pastimes recorded on the database by three sentinel
      hospitals during a 1 year period were examined in detail. Medical notes were
      perused to verify features of the event and obtain further information. A semi
      structured telephone interview of a sample of 10-14 year old rollerbladers, the
      most commonly injured age-group, was carried out to obtain more specific
      information. RESULTS: There has been a marked increase in the absolute numbers of
      injuries associated with the use of rollerblades since 1989. In 1992, they were
      most common in the 10-14 year age group, which sustained 59% of all injuries; 47%
      of injuries were fractures of the forearm and wrist. Of a sample of 33 of those
      injured in the 10-14 year age group, 10 (30%) had been using rollerblades for the
      first time. There is some evidence to suggest a concomitant fall in skateboarding
      injuries. CONCLUSIONS: Injury surveillance data collected in Melbourne suggest an
      increasingly important contribution by rollerblading to the pattern of injury
      seen in young people. Preventive strategies require further evaluation but could
      include learning basic techniques in a controlled setting, separation from road
      traffic and the wearing of helmets and wrist, elbow and knee guards.

PMID- 8652211
TI  - Does the amniotic fluid protein absorption contribute significantly to the fetal
      weight?
AB  - OBJECTIVE: This study was carried out to evaluate the significance of amniotic
      fluid protein ingestion and absorption on fetal growth. METHODOLOGY: Neonates
      with small bowel atresia during a 30 year period were studied retrospectively.
      RESULTS: There were 56 patients enlisted, 17 with duodenal atresia, 18 with
      jejunal atresia and 21 with ileal atresia. The percentage of mothers with
      polyhydramnios and the percentage of premature babies decreases as the intestinal
      atresia becomes more distal. The mean gestational age and the mean birthweight
      increase as the intestinal atresia becomes more distal. On the other hand, the
      percentage of the neonates with birthweight below the 50th and the 10th
      percentiles do not differ significantly as the intestinal atresia becomes more
      distal. CONCLUSIONS: It appears that the variation of birthweights in babies with
      different levels of small bowel atresia may be due to the difference in gestation
      caused by polyhydramnios. The effect of amniotic fluid protein absorption on
      fetal bodyweight could not be demonstrated clinically in this study.

PMID- 8652212
TI  - New perspectives on inflammation in atopic dermatitis.
AB  - Recent information implicates the stimulation of T cells by Staphylococcus aureus
      antigens and exotoxins as a likely factor in provoking the inflammatory response
      in atopic dermatitis. S. aureus secrets exotoxins called superantigens, which
      stimulate a large proportion of T cells. In addition, protein A, a component of
      the cell wall of S. aureus, is a potent B cell mitogen. This understanding
      provides a rationale for attempting to reduce the staphylococcal skin
      colonization of patients with severe atopic dermatitis and correlates with the
      clinical observation in a number of situations of marked improvement in atopic
      dermatitis following antibiotic treatment.

PMID- 8652213
TI  - Health care and its costs for children with perinatally acquired HIV infection.
AB  - OBJECTIVE: To describe survival patterns, use of health services and related
      costs for Australian children with perinatally acquired human immunodeficiency
      virus (HIV) infection. METHODOLOGY: A retrospective cross-sectional survey was
      made of 20 children with HIV infection (91% of those diagnosed) and 13 children
      with maternal antibodies who subsequently seroreverted, treated at 10 medical
      centres. Details of disease progression and use of health services were obtained
      from hospital medical records. Monthly costs for three phases of infection were
      estimated by linking service usage rates with estimates of the unit cost of each
      service. The average lifetime cost was estimated by combining monthly costs and
      phase duration estimates from the literature. RESULTS: Patterns of disease
      progression were similar to those reported internationally, with a median
      survival of 8 years. Use of health services increased with severity of illness.
      Mean monthly costs were $120 per month (1992 Australian dollars) for children
      with maternal antibodies who subsequently seroreverted, $320 per month for
      children with HIV infection but no acquired immunodeficiency syndrome (AIDS)
      defining illness, and $1830 per month for children with AIDS. The present value
      of total lifetime cost for a child with HIV infection was $48174, 46% of which
      was for treatment of AIDS. DISCUSSION: The mean lifetime cost for a perinatally
      infected child was just over half that for a man with HIV in Australia. Health
      service usage and costs were lower for Australian than American children with
      HIV.

PMID- 8652214
TI  - Inhaled hypertonic saline increases sputum expectoration in cystic fibrosis.
AB  - OBJECTIVE: To determine whether inhalation of hypertonic saline (HS) increases
      sputum expectoration in patients with cystic fibrosis (CF). METHODOLOGY: Ten
      adolescents with CF, who were receiving inpatient treatment for a pulmonary
      exacerbation, were enrolled in a controlled cross-over clinical trial. After
      inhalation of beta adrenergic drug to prevent possible broncho-constriction, each
      patient inhaled for 10 min either 0.9% isotonic saline (IS) or 6% HS prior to
      routine physiotherapy. The following day the patient received the alternative
      solution. Seven patients undertook a second block after 1-5 days. Outcome
      measures included weight of sputum, a visual analogue score to assess the
      subjective feeling of a cleared chest after physiotherapy, and spirometry.
      RESULTS: Sputum expectoration (median; Q1,Q3) from the beginning of the
      inhalation of HS or IS to the final spirometry measure 60 min post-physiotherapy
      was significantly greater after HS than IS [17.2g (11.7, 34.8) vs 11.3g (6.5,
      16.1): P = 0.006]. A clinical score of the patient's own judgement of a cleared
      chest was significantly better after HS than IS. Spirometry results did not
      change following either of the two inhalations. CONCLUSIONS: These data show that
      the inhalation of 6% HS prior to physiotherapy can increase sputum expectoration
      in patients with CF and suggest that HS might be an effective, safe and cheap
      adjunct to regular physiotherapy in patients with CF.

PMID- 8652215
TI  - Reducing the anxiety of children undergoing surgery: parental presence during
      anaesthetic induction.
AB  - OBJECTIVE: The primary aim was to determine whether child anxiety could be
      reduced by the presence of a parent during anaesthetic induction. Secondary aims
      involved clarification of the effect of the timing of parental separation, the
      use of premedication, the seriousness of the surgical procedure, and the flow-on
      effect of parental anxiety on the level of child anxiety. METHODOLOGY: Subjects
      were obtained by approaching all parents of children aged from 1 to 8 years
      admitted for day surgery to a private hospital in Adelaide, South Australia
      during a 3 month period. Data pertaining to 74 children, representing a response
      rate of 80.4%, were obtained. Parents were instructed to rate the anxiety of
      their child for the period immediately prior to separation, and to then rate
      their own anxiety for the same period of time. RESULTS: Children accompanied
      during induction were less anxious than those who were not accompanied. Contrary
      to the belief that child anxiety might be reduced by allowing separation in the
      theatre holding bay area, it was demonstrated that child anxiety was higher in
      this group than when separation occurred in the ward. No relationship between
      premedication or operation severity and either child or parental anxiety was
      observed. However, parental anxiety was noted to be a significant predictor of
      child anxiety. Suggestions for a more detailed examination of the relationship
      between child and parental anxiety in future research were outlined. CONCLUSIONS:
      It was concluded that there are benefits in allowing parents to be present during
      anaesthetic induction. However, the potential negative effect of parental anxiety
      must be acknowledged before parents are allowed to accompany their child as a
      matter of course.

PMID- 8652216
TI  - Stress and work relationships in the neonatal intensive care unit: are they worse
      than in the wards?
AB  - OBJECTIVE: To compare working conditions, sources of stress and professional
      relationships between a group of nurses working in neonatal intensive care units
      (ICU) and those working in general paediatric teaching hospital wards.
      METHODOLOGY: Surveys were sent to 96 nurses working in general paediatric wards
      in three Sydney paediatric teaching hospital centres and to 291 nurses working in
      six major neonatal ICU in Sydney. The survey asked about work environment,
      patient care, decision-making, sources of stress and professional relationships.
      Thirty-one questions were identical in each survey. The survey also included the
      General Health Questionnaire (GHQ) as a measure of emotional health. RESULTS: The
      response rate was ward nurses 86% and neonatal intensive care nurses 66%. Of the
      31 identical statements, nine were significantly different between the two
      groups. Neonatal nurses were more likely to feel that their ward work areas were
      overcrowded and poorly laid out with little patient-free space. They had more
      concerns about inadequate staffing and conflict between nurses and doctors. The
      general ward nurses were more likely to feel that adequate priority was given to
      patient pain relief and that they had more influence in such decisions but
      experienced more stress in keeping up to date and were more likely to feel that
      communication problems between doctors and nurses were a major source of
      conflict. Forty per cent of general ward nurses and 32% of neonatal nurses had
      GHQ scores indicating possible psychological impairment, a significantly higher
      proportion than would be expected in the population. CONCLUSIONS: Paediatric
      nurses perceive a variety of stresses in their work, with problems in
      communication between doctors and nurses being a prominent perception. The high
      GHQ scores may be a reflection of some of those problems. Attention to problems
      of under-staffing, better work environment and improved communication may help
      resolve some of these issues and may have implications for improving patient
      care.

PMID- 8652217
TI  - Accelerated schedule of hepatitis B vaccination in high-risk youth.
AB  - OBJECTIVE: To perform a feasibility and immunogenicity study of an accelerated
      schedule of hepatitis B immunization for high-risk youth. METHODOLOGY: High-risk
      adolescents attending a youth health centre and nearby youth refuges were
      immunized with Engerix-B recombinant vaccine, 20 micrograms intramuscularly, at
      0, 2 and 6 weeks. Serology was performed prior to immunization and 3 months after
      the third dose. RESULTS: Forty-two subjects (27 female) aged 13-20 years entered
      the study. Two (4.8%), already hepatitis B virus (HBV) seropositive, were
      excluded. Thirty-six of 40 subjects had one or more risk factors for HBV.
      Participants were often elusive, needing multiple attempts to establish contact.
      Twenty (50%) of the 40 completed three immunizations and all 14 studied developed
      anti-hepatitis B surface titres of > 100 mlU/mL (geometric mean titre 630 mlU/mL,
      95% confidence intervals 309-1290). CONCLUSIONS: High-risk youth can be immunized
      against hepatitis B successfully using an accelerated schedule, but compliance is
      difficult.

PMID- 8652218
TI  - "On the spot' vaccination: does it work?
AB  - OBJECTIVE: To trial and evaluate a system of "on the spot' vaccination for
      children up to the age of 15 years in the Early Childhood Centres of the Central
      Sydney Area Health Service, at the Royal Alexandra Hospital for Children and in a
      number of general practices in the area. METHODOLOGY: A brief questionnaire was
      used to collect data from parents and health care professionals about the child's
      vaccination status and vaccines given "on the spot'. RESULTS: Over an 8 week
      period in August-September 1993, 5162 questionnaires were completed; 71% of
      children were up to date with their vaccination. If Haemophilus influenzae type b
      vaccine, which had been introduced only 2 months before commencement of the
      study, was excluded, 84% of the children were up to date. A total of 441 children
      were given 663 vaccinations "on the spot'. Very few children were too ill to be
      vaccinated (6%). However, only 30% of those who needed vaccination "on the spot'
      actually received it (441 of 1480), and only 41% (24 of 58) of a subset of those
      who were not vaccinated were known to have complied 1 month later. Children
      attending Early Childhood Centres were younger than children attending general
      practices or the hospital. CONCLUSIONS: A high proportion of children who
      attended for routine or acute health care had vaccinations overdue (30%). If this
      scheme could be continued and expanded it would have an important impact on
      vaccination coverage, and hence on the incidence of vaccine-preventable diseases.

PMID- 8652219
TI  - Aortic aneurysm complicating bacterial endocarditis in childhood.
AB  - Bacterial endocarditis is an uncommon diagnosis in childhood with significant
      morbidity and mortality. Aortic aneurysm as a complication is well described in
      adults but there are few reports in the paediatric literature. Two children with
      bacterial endocarditis are described, whose illnesses were complicated by aortic
      aneurysm formation requiring surgical intervention.

PMID- 8652220
TI  - Microvascular complications of insulin-dependent diabetes: risk factors,
      screening and intervention.
AB  - The ability to detect subclinical signs of the microvascular complications of
      diabetes during adolescence and our increased understanding of risk factors for
      their development provide an opportunity to prevent irreversible organ damage.
      Glycaemic control makes a major contribution to the risk and progression of
      microvascular complications. However, the unique psychological and physiological
      changes of childhood and adolescence present a considerable challenge for those
      attempting to reduce the burden of adult microvascular disease.

PMID- 8652221
TI  - An unusual congenital dorsal midline thoracic mass.
AB  - OBJECTIVE: To describe the presentation and investigation of an unusual form of
      congenital dorsal midline thoracic mass. RESULTS: An infant born by emergency
      Caesarean section at 34 weeks gestation was found to have a large dorsal midline
      thoracic mass. The infant had normal neurological function in all limbs.
      Radiological investigation showed no abnormality in the vertebrae.
      Ultrasonographic investigation suggested the mass to consist of subcutaneous
      oedema. The mass resolved completely within the first 2 weeks. CONCLUSIONS: The
      lesion observed in this infant represents a very unusual location for a benign
      condition caused by cervical pressure on the presenting fetal part. The use of
      ultrasonography enabled rapid exclusion of the more common, potentially serious,
      causes of a congenital midline dorsal thoracic mass.

PMID- 8652223
TI  - Bottle feeding not even second-best choice.

PMID- 8652222
TI  - Increased serum creatinine associated with severe primary hypothyroidism.
AB  - A case of myxoedema due to Hashimoto's thyroiditis associated with a significant
      increase in serum creatinine is reported. Thyroid hormone replacement therapy
      resulted in normalization of the serum biochemistry within 1 month.

PMID- 8652224
TI  - Child sexual abuse.

PMID- 8652225
TI  - Newborn screening for congenital adrenal hyperplasia: testing to commence in New
      South Wales.

PMID- 8652226
TI  - Misleading Haemophilus influenzae type B antigenuria following immunization.

PMID- 8652227
TI  - Positive McDonald's sign.

PMID- 8652228
TI  - Barriers to hepatitis B immunization in infancy.

PMID- 8652229
TI  - Effects of hospitalization on behaviour.

PMID- 8652230
TI  - Towards a cure in indolent lymphoproliferative diseases?

PMID- 8652231
TI  - Mutations in the Wilms' tumour gene, WT1. What do they mean?

PMID- 8652232
TI  - Non-Hodgkin's lymphomas--current status of therapy and future perspectives.
AB  - Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of disorders which can
      either be classified according to their biology, represented by corresponding
      counterparts of normal lymphocyte development as in the Kiel classification, or
      according to their clinical course, used in the Working Formulation. The recently
      proposed Revised European-American Lymphoma (R.E.A.L.) classification may unify
      both aspects and facilitate the comparability of international studies. Besides
      histology, the extent of disease still comprises the major determinant of
      therapy. In high-grade lymphomas combination chemotherapy with cyclophosphamide,
      hydroxydaunorubin, vincristine and prednisone (CHOP) represents the treatment of
      first choice, and may be restricted to 3-4 cycles in patients with limited stages
      of the disease when followed by involved field radiotherapy. In more extended,
      bulky stage II to IV disease, treatment must be extended to six courses of CHOP
      and, potentially, additional irradiation. Even in advanced states of the disease,
      long-term remission and potential cure are achieved in 30-50% of cases. In low
      grade lymphomas, most patients present with advanced stages III and IV for which
      chemotherapy can be applied with palliative intention only. Hence, a watch-and
      wait approach still seems appropriate outside clinical investigations until the
      disease requires a therapeutic intervention. This consists preferentially of
      chemotherapy of moderate intensity such as cyclophosphamide, vincristine and
      prednisone (COP) or prednimustine and mitoxantrone (PmM). In responding patients,
      maintenance therapy with interferon-alpha is currently being explored and may
      result in prolongation of disease-free and, possibly also, overall survival. In
      both high- and low-grade lymphomas, intensification of therapy by myeloablative
      chemotherapy or combined chemoradiotherapy followed by autologous bone marrow
      transplantation (ABMT) or peripheral stem cell transplantation provides a
      promising and potentially curative prospective. In addition, new cytostatic
      agents such as the purine analogues--fludarabine, chlorodeoxyadenosine and
      deoxycoformycin--enlarge the therapeutic spectrum. More experimental approaches
      consist of the application of immunotoxins or radioisotypes, coupled to
      monoclonal antibodies directed against lymphoma-specific antigens. Overall, the
      substantial advances that have been achieved in the understanding of the biology
      and pathogenesis of malignant lymphomas, as well as the current achievements of
      therapy and the new promising perspectives, justify the hope that curative
      therapy can soon be offered to an increasing proportion of patients with NHL.

PMID- 8652233
TI  - Key issues in the treatment of chronic lymphocytic leukaemia (CLL)
AB  - The outcome of the treatment of chronic lymphocytic leukaemia (CLL) has improved
      little over the past 30 years. The recent introduction of purine analogues,
      particularly fludarabine, may change this situation. These agents are highly
      effective and generally well tolerated. They raise the possibility of improved
      disease-free survival and allow appropriate patients to be considered for bone
      marrow transplantation (BMT). Randomised clinical trials are needed to establish
      the roles of purine analogues and other novel agents in improving the survival of
      CLL patients. These trials should use consistent diagnostic and assessment
      criteria to allow for the clinical heterogeneity of CLL.

PMID- 8652234
TI  - 3rd biannual meeting: "Trends in invasive fungal infection".

PMID- 8652235
TI  - A single-blind, randomised, vehicle-controlled dose-finding study of recombinant
      human granulocyte colony-stimulating factor (lenograstim) in patients undergoing
      chemotherapy for solid cancers and lymphoma.
AB  - This study evaluated the effect of glycosylated recombinant human granulocyte
      colony-stimulating factor (rHuG-CSF; lenograstim) on neutrophil granulocyte
      counts and on cells of other haematopoietic lineages in 66 patients with solid
      cancer or lymphoma who received myelosuppressive chemotherapy. Beginning 1 day
      after completion of chemotherapy, patients received lenograstim (at dosages of
      0.5, 2, 5 or 10 micrograms/kg) or vehicle subcutaneously once daily for 14
      consecutive days. Compared with vehicle, lenograstim significantly accelerated
      neutrophil recovery after chemotherapy in a dose-dependent manner. Mean
      neutrophil counts recovered to > 1.0 x 10(9) cells/l by day 13 in the vehicle
      group compared with days 11, 10, 8 and 7 in the 0.5, 2, 5 and 10 micrograms/kg
      lenograstim groups, respectively. Doses of 0.5 and 2 micrograms/kg of lenograstim
      had a significant effect on the duration of neutropenia (< 1.0 x 10(9) cells/l),
      the area under the absolute neutrophil count (ANC) curve and the time to ANC
      nadir. The dose of 5 micrograms/kg additionally decreased the total area of
      neutropenia and gave the narrowest range of values for all neutrophil parameters,
      while the 10 micrograms/kg dose brought no added benefit. A dose-response effect
      of lenograstim on time to neutrophil recovery was observed both for patients who
      received chemotherapy on a single day (n = 35) and for those who received
      chemotherapy over several days (n = 29). Based on these findings, a dose of 5
      micrograms/kg/day was chosen for further trials.

PMID- 8652236
TI  - Recombinant human granulocyte-macrophage colony-stimulating factor after combined
      chemotherapy in high-grade non-Hodgkin's lymphoma--a randomised pilot study.
AB  - High-grade non-Hodgkin's lymphomas (NHL) can potentially be cured with
      combination chemotherapy, although the optimum schedules still have to be
      defined. Clinical trials with intensive chemotherapy are predominantly limited by
      myelosuppression. Here, haematopoetic growth factors open up the possibility of
      reducing chemotherapy-associated toxicities. In this randomised pilot study, we
      investigated the effects of a recombinant human granulocyte-macrophage colony
      stimulating factor (rhGM-CSF) following combined chemotherapy with vincristine,
      doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE). A total of 35
      patients with high-grade NHLs were randomised to receive either rhGM-CSF or
      placebo during the first two chemotherapy cycles and rhGM-CSF for all following
      cycles. rhGM-CSF was administered at a dosage of 5 micrograms/kg for 10 days or
      until neutrophils were > 1/nl following chemotherapy. The analyses revealed a
      significant reduction of neutropenia and duration of neutropenia in the rhGM-CSF
      group. Adverse events were rare and generally mild apart from one anaphylactoid
      reaction. No effects of rhGM-CSF were observed concerning the platelet nadir or
      duration of thrombocytopenia. The benefit of rhGM-CSF for response induction and
      survival via rhGM-CSF-supported dose intensification remains to be determined.

PMID- 8652237
TI  - Randomised phase II study of epirubicin-vindesine versus mitoxantrone-vindesine
      in metastatic breast cancer.
AB  - The purpose of this study was to compare the activity and toxicity of epirubicin
      vindesine (EV) with mitoxantrone-vindesine (MV) in patients with metastatic
      breast cancer. A total of 295 patients was randomly allocated to treatment with
      vindesine 3 mg/m2 combined with either epirubicin 40 mg/m2 or mitoxantrone 10
      mg/m2. All drugs were given by intravenous push, treatment cycles were repeated
      at 3-4 week intervals. 255 patients were available for response, and 283 for
      toxicity. EV and MV yielded similar objective response rates (34 and 26%,
      respectively), response durations, times to progression and survival. Median time
      to remission was 1.8 and 3.1 months (P = 0.006) with EV and MV, respectively. In
      patients with visceral metastases, response rate was higher with EV than MV (40
      versus 23%; P = 0.03). Patients receiving MV had less nausea/vomiting (P = 0.007)
      and alopecia (P = < 0.001) of WHO grade > or = 2. Bone marrow, cardiac and other
      toxicities were mild with both treatments. The observed differences in activity
      and toxicity between the two regimens appear to have clinical relevance. EV
      proved to be more active in visceral disease and to be able to induce remissions
      more rapidly. Accordingly, patients with visceral metastases or severe tumour
      related symptoms may benefit from epirubicin-based treatment. Subjective
      toxicities, i.e. nausea/vomiting and alopecia, were less frequent and severe with
      MV. Thus, MV may prove useful in patients with more indolent disease and appears
      to warrant phase III evaluation in such patients.

PMID- 8652239
TI  - Cyclical tumour variations in premenopausal women with early breast cancer.
AB  - The hormonal milieu at the time of tumour excision may have a significant impact
      on survival in premenopausal patients with breast cancer, with those undergoing
      surgery between days 3 and 12 of the menstrual cycle having a worse prognosis. To
      investigate possible mechanisms which might explain this finding, histological
      features of tumours from 363 patients included in two studies from Guy's Hospital
      have been reviewed. Axillary nodal involvement occurred in 71/115 (62%) of
      patients whose primary tumour was excised between days 3 and 12 of the cycle,
      compared with 116/248 (47%) of patients undergoing surgery at other phases of the
      cycle (chi 2 = 7.04, P < 0.01). Vascular invasion was observed in 54/115 (47%) of
      primary tumours removed between days 3 and 12 and 82/248 (33%) of tumours removed
      at other times (chi 2 = 6.47, P < 0.02). Multivariate analysis of factors
      influencing survival indicated that both axillary nodal status and phase of the
      cycle were highly significant independent predictors of prognosis.

PMID- 8652238
TI  - Economic analyses of toxicity secondary to anthracycline-based breast cancer
      chemotherapy.
AB  - Doxorubicin (D) is one of the most active agents in the treatment of breast
      cancer but can be associated with cardiotoxicity (CT) and febrile neutropenia
      (FN). Epirubicin, a stereoisomer of doxorubicin, is reported to have similar
      efficacy but reduced toxicity. A retrospective chart audit was performed to
      estimate the incidence, average length of hospitalisation and resource
      consumption for the management of CT and FN in 200 patients breast cancer
      patients receiving equidoses of doxorubicin or epirubicin. Overall, there were
      three more episodes of CT in the doxorubicin group than in epirubicin patients
      (five versus two) at a cost of Canadian dollars C$4268/episode. With regard to
      FN, there were 11 more episodes in the doxorubicin arm (25 versus 14) at a cost
      of C$5419/episode. The results of the study support the substitution of equidose
      epirubicin for doxorubicin in women undergoing treatment for malignancies of the
      breast. Such a policy may result in reduced toxicity-related management costs.

PMID- 8652241
TI  - Safe selection criteria for breast conservation without radical excision in
      primary operable invasive breast cancer.
AB  - In a previous series from this unit of 263 women with primary operable breast
      cancer treated by macroscopic lumpectomy and breast irradiation, local recurrence
      was high. An audit at a median follow up of 36 months showed 56 (21%) ipsilateral
      breast recurrences. Eighteen of these recurrences were aggressive and
      uncontrolled. Multivariate analysis shows patient age, lymphovascular invasion,
      tumour size and nodal status to be predictive of local recurrence (Locker AP, et
      al., Br J Surgery 1989, 76, 890-894). New selection criteria for breast
      conservation were defined based on these data and also on securing an adequate
      clear margin of excision. In a subsequent prospective series of 275 women
      fulfilling these criteria, 6 women (2.2%) developed ipsilateral breast recurrence
      at the same median follow up of 36 months. In none was this uncontrolled and
      aggressive. Breast conservation, without radical excision, is safe as long as the
      selection criteria described are followed.

PMID- 8652240
TI  - c-erbB-2 expression and benefit from adjuvant chemotherapy and radiotherapy of
      breast cancer.
AB  - Frozen tissue from primary tumours of 152 premenopausal breast cancer patients,
      who participated in a trial comparing radiotherapy with adjuvant chemotherapy
      (cyclophosphamide, methotrexate, 5-fluorouracil, CMF), was analysed for c-erbB-2
      protein expression, measured by flow cytometry. The relative risk of distant
      recurrence or death in the chemotherapy group as compared with the radiotherapy
      group was 3.0 (95% confidence interval (CI) 1.1-7.8) for patients whose tumours
      showed high c-erbB-2 levels and 0.87 (95% CI 0.43-1.7) for those with tumours
      with low levels of c-erbB-2 protein. Patients with highly proliferative tumours
      that did not overexpress c-erbB-2 benefited most, in terms of survival, from CMF.
      In addition, we found an increased risk of locoregional recurrence for tumours
      overexpressing c-erbB-2 when radiotherapy was replaced by chemotherapy.

PMID- 8652242
TI  - A phase I/II evaluation of metoclopramide as a radiosensitiser in patients with
      inoperable squamous cell carcinoma of the lung.
AB  - The feasibility of administering metoclopramide (MCA) as a radiosensitizer has
      been evaluated in 23 patients with a pathological or cytological diagnosis of a
      squamous cell carcinoma of the lung, clinically evaluated as inoperable. All
      patients received 40-60 Gy radiotherapy fractionated into 1.8 Gy fractions 5
      times per week (Monday-Friday). Two MCA treatment regimens were used: (i) MCA at
      2 mg/kg administered by intravenous-infusion 1-2 h prior to radiotherapy 3 times
      per week (Monday, Wednesday, Friday); and (ii) MCA at 1 mg/kg administered by
      intravenous infusion 1-2 h prior to radiotherapy 5 times per week (Monday
      Friday). 11 of the 23 patients treated with radiotherapy and MCA had none to mild
      pneumonitis or fibrosis and another 8 of the 23 had moderate levels. No patient
      had their therapy interrupted due to radiation-related side-effects. The MCA
      related side-effects were as expected, i.e. 78% of the patients experienced
      sedation/tiredness and 48% expressed restlessness/anxiety symptoms. Both the
      total dose and serum levels of MCA were significantly associated to the MCA side
      effect profile. Tumour response, duration of tumour response and survival were
      significantly positively correlated to the total and weekly doses of MCA
      administered to the patients during their radiotherapy treatment. These
      favourable phase II data have justified the initiation of a phase II/III
      randomised multicentred trial being carried out in Europe to evaluate MCA as a
      radiosensitiser.

PMID- 8652243
TI  - Effects of intrapleural mitoxantrone and mepacrine on malignant pleural effusion-
      a randomised study.
AB  - 30 patients with malignant pleuritis were randomised to be treated, either with
      intrapleural instillation of mepacrine chloride or with mitoxantrone. The
      patients were evaluated with chest X-ray and a symptom questionnaire during a
      follow-up period of 12 weeks. Mitoxantrone levels in the pleural space and plasma
      were measured at different time points in some of the patients. High
      concentrations of mitoxantrone were found in the pleural fluid while the plasma
      concentrations were low, giving a plasma/intracavity ratio generally of less than
      1:60. The chest X-rays showed excellent results for both treatment modalities.
      However, the patients treated with mepacrine chloride experienced greater
      discomfort with fever and pain, and those treated with mitoxantrone reported
      significantly less dyspnoea and less asthenia after 4 weeks. We conclude that
      both treatments are equally effective in preventing the recurrence of malignant
      effusion. However, mitoxantrone seems to have further advantages when it comes to
      improving the quality of life.

PMID- 8652244
TI  - Squamous oesophageal cancer can be downstaged using protracted venous infusion of
      5-fluorouracil with epirubicin and cisplatin (ECF).
AB  - 21 patients with squamous oesophageal carcinoma were treated with a new regimen
      designed in our unit and effective in treating gastric adenocarcinoma, consisting
      of continuous venous infusion of 5-fluorouracil for up to 24 weeks (200
      mg/m2/day) with epirubicin (50 mg/m2) and cisplatin (60 mg/m2) every 3 weeks. 12
      patients (57%) had an objective response. The median relapse free period was 7
      months, median survival from start of chemotherapy 8.4 months, and median
      survival from diagnosis, 14 months. Symptomatic improvements were reported by
      10/11 patients with pain (91%), 8/9 with anorexia (89%), 8/10 with reflux (80%)
      and 10/14 with dysphagia (71%). Grade 3 or 4 toxicity was reported by 11
      patients: 5 had haematological toxicity, 3 vomiting, 2 infection and 1 diarrhoea.
      One patient developed peripheral neuropathy, 1 renal impairment and another
      peripheral vascular disease. Following chemotherapy, surgery was attempted in 5
      patients. One remains well 3 years on, 2 had macroscopic clearance of tumour but
      died of postoperative complications. In 2, disease was irresectable. This regimen
      of moderate toxicity is effective at improving symptoms in the majority of
      patients. In some patients, tumours are briefly downstaged so that inoperable
      tumours may become operable.

PMID- 8652245
TI  - Efficacy of oral tegafur modulation by uracil and leucovorin in advanced
      colorectal cancer. A phase II study.
AB  - A phase II study was performed to assess the efficacy and toxicity of UFT
      (tegafur-uracil in the molar ratio 1:4) modulated with leucovorin (LV) in
      previously untreated patients with advanced colorectal carcinoma (CRC). 79
      patients with measurable advanced colorectal cancer (CRC) and no prior
      chemotherapy were included. 75 patients were evaluable for toxicity and response.
      The regimen consisted of LV 500 mg/m2 administered intravenously on day 1,
      followed by oral UFT 390 mg/m2 on days 1-14. Patients received oral LV 15 mg
      every 12 h on days 2-14. Treatment was repeated every 28 days for a minimum of
      four courses per patient. Three hundred and ninety-eight cycles of chemotherapy
      were delivered (median five per patient). 7 patients (9%) had a complete
      response, and 22 a partial response for an overall response rate of 39%. Mild
      gastrointestinal toxicity was dose limiting: grade 3-4 diarrhoea appeared in 9%
      of patients. Other grade 3-4 toxicities were nausea/vomiting and mucositis in 4%
      of patients, gastric pain and leucopenia in 3%. Oral UFT modulated by oral LV is
      active in advanced CRC and can be administered on an outpatient basis with no
      significant toxicity requiring hospitalisation. Given its excellent tolerance
      profile and low toxicity, the regimen should be thoroughly studied and compared
      with 5-fluorouracil modulated by LV.

PMID- 8652246
TI  - p53 immunoreactive stain and early colorectal adenocarcinomas.
AB  - 565 cases of early colorectal adenocarcinomas were used in this study to examine
      mechanisms of carcinogenesis. Specimens were paraffin embedded and histological
      sections were stained with haematoxylin-eosin and p53. Macroscopically, early
      colorectal adenocarcinomas could be classified into two types: protruding and
      depressed. The former were composed of branching glands, while the latter were
      composed of straight glands which opened to the surface. The p53 positive ratio
      was similar for protruding tumours but was higher in depressed submucosal
      invasive adenocarcinomas than in depressed intramucosal adenocarcinomas. These
      results raise the possibility of at least two pathways for colorectal
      carcinogenesis, adenoma-carcinoma lesions and de novo carcinoma lesions.

PMID- 8652247
TI  - Carboplatin and ifosfamide and selective consolidation in advanced seminoma.
AB  - This prospective phase II study assesses the clinical efficacy and complications
      of a treatment regimen comprising combination chemotherapy with carboplatin and
      ifosfamide and selective consolidation in advanced seminoma. Of 43 patients who
      entered the study, between May 1989 and May 1992, 42 were evaluable. 30 achieved
      a complete remission (71%; 95% confidence interval, 56-84%) after chemotherapy
      alone. 10 achieved a complete remission (24%; 95% confidence interval, 13-39%)
      after chemotherapy plus consolidation. 38 of the 42 patients (91%; 95% confidence
      interval, 83-98%) remained in remission after a median follow-up period of 35
      months (20-56 months). No patient experienced nephrotoxic, neurotoxic, or
      ototoxic effects, or haemorrhagic cystitis. Ten per cent of the patients had
      leucopenic fever requiring hospitalisation. Twenty-four per cent required
      platelet transfusions, and 26% required transfusions of packed red blood cells.
      For patients with seminoma, treatment with carboplatin and ifosfamide and
      selective consolidation is safe and effective.

PMID- 8652248
TI  - Secondary Raynaud's phenomenon and other late vascular complications following
      chemotherapy for testicular cancer.
AB  - 182 patients treated with cisplatin-based chemotherapy for testicular cancer at
      Hannover University Medical School who were in complete remission (CR) for more
      than 1 year after therapy were randomly selected for the evaluation of late
      vascular toxicity. 90 patients with a mean age of 28 years (19-53) and a median
      follow-up of 57.9 months (15-159) participated in this examination. Patients were
      examined clinically and digital photoelectric pulse plethysmography (PP) and
      Doppler-flow of the digital arteries after cold exposure were performed. Thirty
      seven per cent of patients developed symptoms of Raynaud's phenomenon (RP) after
      chemotherapy, which were transient in 7%. PP proved to be highly diagnostic for
      RP with a sensitivity of 95% and a specificity of 100%. As significant risk
      factors for the development of RP, the cumulative dose of bleomycin (P < 0.05)
      and the use of bleomycin in combination with vinblastine (PVB-regimen) instead of
      etoposide (PEB-regimen) (P < 0.01) were found. A trend for an increased frequency
      of RP was observed in patients who received bleomycin as a bolus instead of
      continuous infusion. No significant correlation was seen with the cumulative or
      single doses of cisplatin, etoposide or vinblastine, serum magnesium levels
      during or after chemotherapy or a history of smoking. RP was not associated with
      the occurrence of neuro- or ototoxicity. All 7 patients with hypertensive blood
      pressure before chemotherapy developed RP. Furthermore, the median
      postchemotherapy diastolic blood pressure had increased by 8 mmHg compared to
      prechemotherapy values, leading to significant hypertension in 8 patients (> 20
      mmHg increase). 2 patients developed major vascular events with myocardial
      infarctions at 4 years and 5 years after chemotherapy, respectively. No cerebral
      infarction was registered. In summary, RP is the main late vascular toxicity
      affecting one third of patients after curative chemotherapy for testicular
      cancer. However, the incidence of RP following PEB-therapy in contrast to PVB
      therapy appears to be lower. Major vascular events seem to be rare. The
      prospective evaluation of late toxicity should be part of current chemotherapy
      treatment for testicular cancer, and long-term follow-up of surviving patients is
      recommended.

PMID- 8652249
TI  - Alpha-fetoprotein-concanavalin A binding as a marker to discriminate between germ
      cell tumours and liver diseases.
AB  - In order to differentiate whether slight alpha-fetoprotein (AFP) increases
      observed in any patient are due to germ cell tumours (GCT) or to liver diseases
      (including hepatotoxicity of chemotherapy), we measured the binding ratio of the
      AFP to concanavalin A (ConA). A total of 218 serum samples were studied: 102
      samples from 72 GCT patients and 116 from patients with liver diseases.
      Considering a cut-off value to be a ConA binding ratio of 15%, we distinguished
      AFP produced by GCT (> 15%) from AFP produced by tumoral and non-tumoral liver
      diseases (< or = 15%) with a sensitivity of 98% and specificity of 100%. The
      difference between mean ConA binding ratios was statistically significant (P <
      0.0001). We did not distinguish AFP produced by tumoral and non-tumoral liver
      diseases. ConA binding ratio may be a sensitive index to distinguish whether an
      increase of AFP concentration as low as 15 U/ml in a GCT patient during the
      follow-up is produced by the tumour or by liver dysfunction (including
      hepatotoxicity of chemotherapy).

PMID- 8652250
TI  - p53 overexpression as a prognostic factor for advanced stage bladder cancer.
AB  - Overexpression of the TP53 gene protein detected by immunohistochemistry appears
      to identify those patients with superficial bladder cancer at risk of the
      development of muscle invasive or metastatic disease. However, the role of p53
      overexpression in patients with advanced or metastatic bladder cancer is not yet
      well established. In the present study, 44 specimens from 44 patients with
      advanced stage bladder tumours (T2-T4) undergoing radical cystectomy were
      investigated for different biological and clinical characteristics as possible
      prognostic factors: sex, age, depth of tumour infiltration, T-stage, histological
      grade, lymph node status, application of adjuvant systemic chemotherapy (MVAC),
      proliferative activity (staining for proliferating cell nuclear antigen (PCNA) by
      monoclonal antibody (PC10) as well as overexpression of the p53 oncoprotein
      (monoclonal antibody pAb 1801)). After a median follow-up of 22 months, 16 of the
      23 patients (70%) with more than 40% of tumour cells stained positively for p53
      (Group B) died from tumour progression compared with 7 of the 21 patients (33%)
      with less than 40% of tumour cells positive for p53. During univariate analysis,
      p53 overexpression (P = 0.008), staining for PCNA (> or = 80% of cells positive)
      (P = 0.01) and tumour stage (P = 0.01) were significant prognostic factors for
      survival, among which p53 overexpression (P = 0.023) as well as T-stage (P =
      0.012) remained independent significant predictors during multivariate analysis.
      Prospective studies are needed to confirm the independent prognostic potential of
      p53 overexpression in patients with advanced bladder cancer. The availability of
      more refined prognostic factors should assist decision making regarding the value
      of more aggressive treatment options, such as adjuvant or neoadjuvant
      chemotherapy, for prognostically defined subgroups of patients.

PMID- 8652251
TI  - An I.T.M.O. group study on second-line treatment in advanced epithelial ovarian
      cancer: an attempt to identify clinical and biological factors determining
      prognosis.
AB  - The aim of the present study was to determine the activity of a combined regimen
      of mitoxantrone (DHAD) and ifosfamide (IFO) and identify clinical and biological
      factors with prognostic importance for the second-line treatment of ovarian
      cancer. The following factors were investigated for their prognostic importance:
      age, disease sites, platinum responsiveness, histological grade, the presence of
      clinically/radiologically detectable versus not detectable disease, residual
      disease volume after first surgery, p53 protein, c-erbB-2 oncoprotein and laminin
      receptor. 72 patients entered the trial. DHAD and IFO therapy led to a 15%
      response rate among the 47 cases with clinically/radiologically detectable
      disease (1 complete and 6 partial responses), with a median response duration of
      4 months. The response rate was significantly different according to platinum
      responsiveness (4% objective responses in platinum-resistant versus 27% in
      platinum-sensitive disease). The time to treatment failure (TTF) and overall
      survival (OS) were affected by the presence of clinically detectable disease at
      study entry (median TTF 4 months in the presence of clinically/radiologically
      detectable disease versus 9 months if the disease was not similarly detectable, P
      = 0.02; median OS 10 months versus 21 months, P = 0.01). Initially overexpressed
      in only a few tumours, the c-erbB-2 oncoprotein became overexpressed in 36% of
      platinum-resistant tumours; this modulation did not occur in platinum-sensitive
      tumours. Furthermore, laminin receptor was expressed in 77% of platinum-sensitive
      versus 39% of platinum-resistant patients. There were no differences in p53
      protein expression according to drug responsiveness.

PMID- 8652252
TI  - Prognostic factors in chordoma: role of postoperative radiotherapy.
AB  - We have investigated prognostic factors for survival in a series of 26 patients
      with chordoma treated in Lyon, France, between 1979 and 1993. In this series, the
      median progression-free (PFS) and overall survival (OS) were 10 and 90 months,
      respectively. In univariate analysis, PFS, but not OS, was found significantly
      longer in males as compared to females (median: 19 versus 7 months, P = 0.05);
      and patients under 60 years of age had a longer PFS (median: 18 versus 6 months;
      P = 0.06) and OS (median: 108 versus 47+, P = 0.05) than older patients. A
      favourable prognostic subgroup including male patients under 60 years and a poor
      prognostic group including female patients and male over 60 years were thus
      defined (median PFS: 36 versus 6 months, P = 0.001; median OS: 108 versus 55+, P
      = 0.15). Primary treatment combining surgery and postoperative radiotherapy was
      associated with a longer PFS than surgery only (median: 36 versus 7 months, P =
      0.002) in the whole series and in both prognostic subgroups.

PMID- 8652253
TI  - The EORTC core quality of life questionnaire (QLQ-C30): validity and reliability
      when analysed with patients treated with palliative radiotherapy.
AB  - The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to
      measure cancer patients' physical, psychological and social functions. The
      questionnaire is composed of multi-item scales and single items. 247 patients
      completed the EORTC QLQ-C30 before palliative radiotherapy and 181 after
      palliative radiotherapy. The questionnaire was well accepted with a high
      completion rate in the present patient population consisting of advanced cancer
      patients with short life expectancy. In addition, the questionnaire was found to
      be useful to detect the effect of palliative radiotherapy over time. The scale
      reliability was excellent for all scales except the role functioning scale.
      Excellent criterion validity was found for the emotional functioning scale where
      it was correlated with GHQ-20. Performance of the questionnaire was improved
      after the second evaluation as compared with the first. The present study shows
      that the EORTC QLQ-C30 is found to be practical and valid in measuring quality of
      life in patients with advanced disease.

PMID- 8652254
TI  - The influence of audiotapes on patient participation in the cancer consultation.
AB  - This study examined the effect of providing patients with an audiotape of a
      previous consultation on their level of participation during a subsequent
      consultation. 117 newly referred medical oncology patients randomised to receive
      a tape (n = 63) or not (n = 54) had two linked consultations which were both
      audiotaped. A content analysis revealed no significant differences between tape
      and control group in the mean number of questions asked during the second
      consultation. However, significantly more tape group patients (77%) asked for
      clarification of at least one piece of information compared to the control group
      (57%) (P = 0.04). A larger number of control group patients (61%) made at least
      one request for facts already provided in their first consultation compared to
      tape group patients (39%) (P = 0.05). Audiotapes appear to facilitate patients'
      requests for the clarification of previously given information and permit the re
      absorption of complex information given when patients may have been too
      distressed for it to be assimilated.

PMID- 8652255
TI  - Splicing of exon 5 in the WT1 gene is disrupted in Wilms' tumour.
AB  - Using a reverse transcriptase polymerase chain reaction to examine alternate
      splicing at site I (exon 5) and site II (exon 9) in the Wilms' tumour suppressor
      gene, WT1, we found that in seven of the 10 Wilms' tumours examined, splicing at
      site I was disrupted. This is predicted to result in isoform imbalance in Wilms'
      tumours, with an increase in isoforms in which the 17 amino acids encoded by exon
      5 are missing. These observations could not be explained by mutations or
      rearrangements in flanking introns. Disrupted alternate splicing of exon 5 may
      play a role in the aetiology of Wilms' tumour.

PMID- 8652256
TI  - Siblings of childhood cancer survivors: how does this "forgotten" group of
      children adjust after cessation of successful cancer treatment?
AB  - Siblings of childhood cancer patients are labelled the "forgotten children"
      because they experience significant psychosocial distress and are isolated from
      support systems inside and outside the family. This study investigates the late
      consequences of the cancer experience for siblings. 60 siblings of cancer
      survivors were compared with control subjects on measures of psychosocial
      adjustment. No differences were found between siblings of cancer survivors and
      controls on emotional and behavioural problems and competence, suggesting that
      siblings adjust well to the period after cessation of treatment. The effect of
      demographic, family and disease-related characteristics on the siblings'
      psychosocial adjustment was limited. Whereas during treatment many psychosocial
      problems for siblings have been reported, this does not result in a heightened
      risk of psychological disturbance for siblings as a late effect. The implications
      for patient care are discussed.

PMID- 8652257
TI  - Ewing's sarcoma of the ribs. A report from the cooperative Ewing's sarcoma study.
AB  - 31 patients with primary Ewing's sarcoma of the ribs were treated according to
      the protocols of CESS 81, CESS 86P and CESS 86. The results of treatment were
      reviewed and analysed. 24 patients presented with localised disease and 7 with
      regional disease. 20 of 24 localised cases and 6 of 7 regional cases underwent
      tumour resection. All but 2 localised cases received irradiation. The cumulative
      relapse-free survival (RFS) rate of 31 patients was 61% at 12.8 years. Patients
      with poor prognosis had tumour of the upper ribs (P = 0.0338), the posterior
      component of the ribs (P = 0.0597), or regional disease (P = 0.0001). Tumour
      size, existence of pleural effusion, type of the surgical margin and response to
      chemotherapy were not significant prognostic factors. Most of the localised cases
      could be controlled by combined treatment, but in regional cases prognosis
      remained poor.

PMID- 8652258
TI  - Medullary carcinoma of the breast. Prevalence and prognostic importance of
      classical risk factors in breast cancer.
AB  - In an earlier study of 235 breast cancers with medullary features, we concluded
      from a multivariate Cox regression analysis that only four histopathological
      features contained significantly positive prognostic information. In the present
      study, continuing our work on the same population base, we used these
      histological characteristics (predominantly syncytial growth pattern, no tubular
      component, diffuse stromal infiltration with mononuclear cells and sparse
      necrosis (< 25%), as diagnostic criteria for medullary carcinoma of the breast
      (MC). We found a significantly better prognosis for patients with MC than those
      with non-medullary carcinoma (NMC) or infiltrating ductal carcinoma (IDC). All
      tumours in the MC group were grade II or III (96% grade III). A significantly
      different distribution of general risk factors such as lymph node status,
      invasion, steroid receptor status, and menopausal status, was found between the
      group of MC and the control group of IDC grades II + III. Further, general risk
      factors, which are found to be of major prognostic importance in IDC, had little
      prognostic impact in MC. We found MC to be biologically unique, and patients with
      MC have a better than average prognosis compared to that of IDC. We propose a new
      histological definition of MC, but stress that prospective studies have to be
      performed.

PMID- 8652259
TI  - Clinico-pathological features and survival of lung cancer patients in Paris,
      France.
AB  - We studied the clinico-pathological features of 750 lung cancers identified in
      Paris, France, during 1988. An internal comparison was performed between
      adenocarcinomas and other subtypes. Survival of 502 patients was studied. 85% of
      patients were males; 93% were smokers or ex-smokers. Squamous cell carcinomas,
      adenocarcinomas, small cell carcinomas and large cell cancers accounted for 51,
      22, 15 and 12% of all cases, respectively. Differences were found for the
      distribution of histological subtyping according to sex (P = 0.001) and smoking
      status (P = 0.0001) with a greater proportion of adenocarcinomas for women and
      non-smokers. Median overall survival was less than one year. In multiple
      regression analysis, small cell lung cancer patients appeared to have a worse
      prognosis than other histological subtypes. This study describes patients who
      were treated in community practice and might be more representative of the real
      clinico-pathological profile of this disease in France.

PMID- 8652260
TI  - A new allogeneic model for metastatic melanoma.
AB  - Metastatic melanoma cells, clonally derived from an affected lymph node of an
      ultraviolet-irradiated laboratory opossum, were allografted subcutaneously into
      suckling young, juveniles and adults to determine their tumorigenicity and
      metastatic potential. All injected 1- and 3-week-old suckling young survived well
      beyond weaning at 8 weeks. One died 12 weeks after injection from the effects of
      rampant metastatic involvement, while the rest were killed 13 to 26 weeks after
      injection. At necropsy, most animals showed extensive primary tumour growth, many
      showed metastasis to nodes and/or lungs, and in some there was dissemination to
      distant sites including liver and spleen. Animals injected as juveniles or adults
      rejected the allografts. Injection of allogeneic malignant melanoma cells during
      early postnatal development facilitates successful, long-term allografting and
      metastasis without concomitant immunosuppressive agents. Developmental lack of
      self-recognition (immunological immaturity) or induced tolerance may be
      responsible. This unique model system will be useful for further metastasis
      studies and may be valuable for investigations of novel antineoplastic therapies.

PMID- 8652261
TI  - Tumour purine nucleotides and cell proliferation in response to exercise in rats.
AB  - Voluntary physical exercise can delay the onset of anorexia and cachexia in
      tumour-bearing rats. A substrate deviation in the host which has been
      hypothesised as tumour burden is reduced despite an increase in food intake.
      Therefore, we determined the levels of purine nucleotides, the energy charge and
      the cell division rate in tumours from exercising animals in the postexercise
      period. Tumour content of purine nucleotides was analysed by HPLC. Tumour cell
      kinetics was studied by flow cytometry after incorporation of bromodeoxyuridine
      (BrdU) into DNA. Exercising animals demonstrated a 34.4% reduction in tumour
      volume (P < 0.05) but a 1.31-fold increase in energy charge in tumour tissue (P <
      0.05). Labelling index (LI), DNA synthesis time (Ts) and potential doubling time
      (Tpot) were not significantly altered. These results suggest that the influence
      on tumour growth is closely related to the exercise period.

PMID- 8652262
TI  - The influence of BIBW22BS, a dipyridamole derivative, on the antiproliferative
      effects of 5-fluorouracil, methotrexate and gemcitabine in vitro and in human
      tumour xenografts.
AB  - Dipyridamole is known as a potent inhibitor of facilitated diffusion-mediated
      nucleoside transport as well as a modulator of 'classical' multidrug resistance.
      BIBW22BS, a derivative of dipyridamole, has been found to be 20- to 100-fold more
      potent in the reversal of multidrug resistance when compared to the parent
      compound. In parallel, we studied the efficacy of BIBW22BS in the modulation of
      the antiproliferative effects of 5-fluorouracil, methotrexate and gemcitabine in
      human cancer cell lines. BIBW22BS, at non-toxic concentrations up to 1.0 microM,
      increased the antiproliferative effects of 5-fluorouracil 2- to 6-fold in seven
      of the eight colon cancer cell lines tested in a dose-dependent manner. The
      addition of 1.0 microM BIBW22BS to methotrexate resulted in a slight increase in
      the antiproliferative effects, but inhibited the activity of gemcitabine 30- to
      100-fold in various cancer cell lines. In vitro, no notable difference was found
      between BIBW22BS and dipyridamole in their capacity to modulate the activity of
      the antimetabolites studied. BIBW22BS did not affect the growth inhibition
      induced by 5-fluorouracil or gemcitabine in human tumour xenografts grown
      subcutaneously in nude mice. We confirmed the higher potency of BIBW22BS when
      compared to dipyridamole in the reversal of drug resistance in the Pgp-positive
      COLO 320 cell line.

PMID- 8652263
TI  - Determination of radiation-induced damage in lymphocytes using the micronucleus
      and microgel electrophoresis 'Comet' assays.
AB  - DNA damage assays may be useful as rapid predictors of normal tissue
      radiosensitivity in clinical samples. We measured in vitro radiation-induced (2
      Gy) damage to lymphocytes from cancer patients and normal healthy donors using
      both the micronucleus and microgel electrophoresis (Comet) assays simultaneously.
      For damage assessment, there was a good correlation (P < 0.001) between the mean
      comet lengths and the fraction of cells with comets. There was no correlation
      with initial damage, determined as the proportion of cells within a sample that
      formed comets, in comparison with the mean frequency of micronuclei per
      binucleate cell. However, there appeared to be an association between the
      determination of repair proficiency in the Comet assay and the mean frequency of
      micronuclei per binucleate cell in lymphocytes from cancer patients.

PMID- 8652264
TI  - The influence of the local environment on tissue architecture of colorectal
      carcinoma (CRC) cell aggregates and its consequence for tumour attack by
      lymphocytes in vitro and in vivo.
AB  - We analysed colorectal carcinoma (CRC) specimens, tumour cell spheroids and
      artificial tumours (ArTs) for tissue architecture, carcinoembryonic antigen (CEA)
      expression and lymphocyte infiltration. Two distinct organisation forms of well
      differentiated CRC cells were found in vivo and in vitro. Tumour cells having
      contact with the tumour stroma in primary tumours, and tumour cells growing
      within a stroma-like structure in vitro (ArTs) were arranged as pseudoglands. In
      contrast, tumour cells grown as spheroids or tumour cells having lost contact
      with the tumour stroma in primary tumours, and most probably in the circulation,
      showed an inversion of the architecture of these pseudoglands, presenting their
      apical cell membrane to the environment. These different tumour cell formations
      affect lymphocytes attacking the tumour, which need contact with specific
      cellular membranes of polarised tumour cells, depending on the tumour
      architecture. Recently, we demonstrated that the CEA expression of CRC cells
      correlated with their resistance against LAK-cell lysis. Since CEA is mainly
      expressed on the apical membrane of the tumour cells, independent of the tissue
      architecture, the change from the pseudoglandular to the spheroid-like formation
      may represent an escape mechanism for malignant cells.

PMID- 8652265
TI  - Infrequent occurrence of microsatellite instability in sporadic and familial
      breast cancer.
AB  - Microsatellite instability was analysed in 93 primary breast tumours at 13
      chromosomal loci frequently altered in breast cancer. RER (replication errors)
      were observed at a low (5%) frequency in sporadic, familial and hereditary breast
      tumours, as well as in breast tumours from patients with multiple primary
      cancers. Our study suggests that the RER+ phenotype is rare in breast tumours,
      and that breast cancer is not included in the hereditary non-polyposis colon
      cancer (HNPCC) syndrome. Moreover, the RER+ tumours revealed an atypical pattern
      of microsatellite alteration as compared with those usually seen in HNPCC
      tumours. In agreement with the findings in HNPCC tumours, all RER+ breast tumours
      were diploid, although having a similar frequency of allelic imbalance as RER-
      tumours. Thus, mismatch repair deficiency is rare in breast cancer, is most
      likely caused by somatic mutations, and possibly in a set of DNA repair genes
      different from that involved in the HNPCC syndrome.

PMID- 8652266
TI  - Schedule-dependent therapeutic efficacy of the combination of gemcitabine and
      cisplatin in head and neck cancer xenografts.
AB  - Gemcitabine and cisplatin are both drugs with proven clinical activity in various
      tumour types, have no overlapping toxic side-effects and are different with
      respect to cellular metabolism. We, therefore, performed an in vivo study to
      determine the efficacy of the combination of these two drugs using two human head
      and neck squamous cell carcinoma xenograft lines, subcutaneously growing in
      athymic nude mice. 100 mg/kg gemcitabine was given intraperitoneally on days 0,
      3, 6 and 9 and 4 mg/kg cisplatin intravenously on days 0 and 6. In one tumour
      line, the combination treatment resulted in better effects than those observed
      when the drugs were administered individually. In the other cell line, addition
      of cisplatin did not increase the moderate effect of gemcitabine. Experiments
      with single dose injections of both drugs showed adverse effects when the
      interval was extended to 24 h. These data are of potential interest for clinical
      application, and suggest that the drugs should be administered either
      simultaneously or with a short time interval in which cisplatin should precede
      gemcitabine.

PMID- 8652267
TI  - Schedule-dependent interaction between paclitaxel and doxorubicin in human cancer
      cell lines in vitro.
AB  - The schedule-dependent interaction of paclitaxel and doxorubicin was evaluated in
      four human cancer cell lines. The cells were exposed simultaneously or
      sequentially to the two agents for 24 h, and were then incubated in drug-free
      medium for 4 and 3 days, respectively. The cell growth inhibitions were
      determined by the MTT assay. The cytotoxic interactions at the IC80 level were
      evaluated by the isobologram method of Steel and Peckham. In non-small cell lung
      cancer A549, breast cancer MCF7 and colon cancer WiDr cells, antagonistic effects
      were observed for the paclitaxel and doxorubicin combination on simultaneous
      exposure to the two agents and on sequential exposure to doxorubicin followed by
      paclitaxel, while additive effects were observed for the combination on
      sequential exposure to paclitaxel followed by doxorubicin. In ovarian cancer PA1
      cells, additive effects were observed for all schedules. These findings suggest
      that sequential administration of paclitaxel followed by doxorubicin may be the
      most suitable sequence, while the simultaneous administration of the two agents
      and the sequential administration of doxorubicin followed by paclitaxel may
      result in less tumour cell kill than anticipated. Further preclinical and
      clinical studies are required to elucidate the relationship between paclitaxel
      and doxorubicin with regard to both antitumour activity and toxicity.

PMID- 8652268
TI  - Can alpha-tocopherol and beta-carotene supplementation reduce adverse radiation
      effects on salivary glands?
AB  - In this study, we evaluated whether supplementation with antioxidant vitamins can
      reduce the adverse effects of irradiation on the salivary glands in the rat. Four
      groups of adult Sprague-Dawley rats were given a basic diet providing 0.6 mg
      alpha-tocopherol and no beta-carotene per day. In two groups the basic diet was
      supplemented with 3.4 mg alpha-tocopherol and 6 mg beta-carotene per day from 14
      days before irradiation until 12 days after completed irradiation. One group of
      rats given basic diet and one group given supplemented diet were irradiated with
      7 Gy daily for five consecutive days. Isoproterenol and pilocarpine-stimulated
      whole saliva was collected from all rats 2, 4 and 26 weeks after irradiation.
      Vitamin-supplemented irradiated rats had higher secretion rates on all three
      occasions compared with those of irradiated rats given basic diet. The changes in
      saliva composition seen in irradiated rats were less accentuated in vitamin
      supplemented, irradiated rats. The proportions of acinar cells were significantly
      decreased both in parotid and submandibular glands 26 weeks after irradiation.
      Supplementation with alpha-tocopherol and beta-carotene did not alter the
      morphology of the glands.

PMID- 8652269
TI  - The dithiane Ro 44-5912 enhances vinblastine sensitivity of drug resistant and
      parental KB lines in vivo.
AB  - The multidrug resistance modifying activity of a dithiane analogue of tiapamil,
      Ro 44-5912, was examined in vivo. Results of acute toxicity studies in mice
      indicated that lethal toxicity occurred with doses greater than 1 mmol/kg of body
      weight. In a preliminary pharmacokinetic investigation, Ro 44-5912 appeared to
      have a longer half-life in mice than did its (R) enantiomer Ro 44-5911 (3.15 +/-
      0.02 h versus 2.15 +/- 0.14 h) as measured by total radiolabel in plasma. In non
      tumour bearing mice, Ro 44-5912 enhanced the toxicity of vinblastine in a manner
      that was dependent on the dose of both drugs. Vinblastine did not have a
      significant effect on tumour growth when given to nude mice bearing the parental
      cell line KB-3-1 at a dose of 1.5 mg/kg once per week for 3 weeks. Combination
      treatment with Ro 44-5912 markedly enhanced the antitumour activity of
      vinblastine. Similar results were seen when KB-3-1 tumours were treated with the
      combination of vinblastine plus cyclosporin A. Another tiapamil analogue, Ro 11
      2933, had no enhancing activity with this tumour when used at an equitoxic
      combination dose. Ro 44-5912 also significantly enhanced vinblastine activity
      with P-glycoprotein-expressing KB-8-5 tumours. In three independent experiments,
      Ro 44-5912 enhanced the growth inhibiting activity of vinblastine by a mean of
      approximately 40%. Neither Ro-11-2933 nor cyclosporin A, at the maximal tolerated
      doses in combination with vinblastine, led to significant inhibition of KB-8-5
      tumour growth compared to treatment with the two vehicles alone. These results
      show that Ro 44-5912 is an active modulator of drug resistance in vivo.

PMID- 8652270
TI  - Expression of the bacterial nitroreductase enzyme in mammalian cells renders them
      selectively sensitive to killing by the prodrug CB1954.
AB  - A recombinant retrovirus encoding E. coli nitroreductase (NTR) was used to infect
      mammalian cells. NIH3T3 cells expressing NTR were killed by the prodrug CB1954,
      which NTR converts to a bifunctional alkylating agent. Admixed, unmodified NIH3T3
      cells could also be killed. In contrast to the Herpes simplex virus (HSV)
      thymidine kinase (TK)/ganciclovir(GCV) enzyme/prodrug system, NTR/CB1954 cell
      killing was effective in non-cycling cells. Co-operative killing was observed
      when cells expressing both NTR and TK were treated with a combination of CB1954
      and GCV. NTR expression in human melanoma, ovarian carcinoma or mesothelioma
      cells also rendered them sensitive to CB1954 killing. These data suggest that
      delivery of the NTR gene to human tumours, followed by treatment with CB1954, may
      provide a novel tumour gene therapy approach.

PMID- 8652271
TI  - Recombinant human stem cell factor does exert minor stimulation of growth in
      small cell lung cancer and melanoma cell lines.
AB  - We have previously reported on the stimulation of clonal growth of a glioblastoma
      cell line by rhSCF (Berdel et al., Cancer Res 1992, 52, 3498-3502). Within an
      extensive screening programme of haematopoietic growth factor activity on
      malignant cells, the effects of rhSCF were further tested on the growth of 29
      different human cell lines derived from a wide range of solid tumours, among them
      six lung cancers and five melanomas. RhSCF (0, 1, 10, 100 ng/ml) was tested in a
      human tumour cloning assay (HTCA) which reliably detects growth modulation of
      tumour cells by cytokines. Additionally, a tritiated thymidine uptake test was
      used. Growth of 27 of the 29 cell lines tested was not affected by rhSCF.
      However, growth of the small cell lung cancer (SCLC) cell line HTB 120 was
      slightly stimulated (1.5 fold that of controls), and that of the melanoma cell
      line MeWo was stimulated up to 1.3-fold. This activity was eliminated dose
      dependently by the tyrosine kinase inhibitor, genistein. We further analysed the
      cell lines for expression of the proto-oncogene C-KIT and its ligand SCF. All
      melanoma and lung cancer cell lines expressed SCF as assessed at the mRNA level.
      Northern blotting also revealed clear C-KIT mRNA expression in three melanoma
      (HAS, MeWo, SK-MEL-28), one NSCLC (HTB 53), and four SCLC cell lines (HTB 119,
      HTB 120, HTB 171, HTB 175). Furthermore, C-KIT protein expression was detected by
      flow cytometric analysis on the cell surface of MeWo, HTB 119 and HTB 120 cells.
      Our data indicate that SCF can be operative in growth modulation of non
      haematopoietic malignant cells, especially SCLC and melanoma. However, our
      extensive screening of SCF/tumour cell interaction shows that this interaction is
      rare and makes potential hazards, such as tumour stimulation upon clinical use of
      rhSCF in conjunction with chemotherapy in cancer patients, unlikely for the
      majority of other tumour histologies.

PMID- 8652272
TI  - Interleukin-2 and interleukin-4 display potent antitumour activity on rat
      medullary thyroid carcinoma cells.
AB  - Currently, surgical resection is the only treatment used for human medullary
      thyroid carcinoma (MTC). However, as metastases are commonly observed, we
      investigated the potential of adjuvant therapy with interleukin-2 (IL-2) and
      interleukin-4 (IL-4) in a rat model. The interleukins were delivered by means of
      xenogeneic tumour cells engineered to secrete IL-2 and IL-4. We found that when a
      mixture of MTC cells and IL-2 or IL-4 secreting cells were implanted in rats, the
      growth of the resulting tumours was inhibited as a function of the number of
      interleukin-secreting cells in the inoculum. Moreover, association of the two
      interleukins exerted a synergistic antitumour effect. These experimental results,
      showing thyroid C cell tumour rejection, are of major interest, as they show the
      potential therapeutic application for these two interleukins, which could be
      used, in particular, as postsurgical adjuvants.

PMID- 8652273
TI  - Splice variants of the cell surface glycoprotein CD44 associated with metastatic
      tumour cells are expressed in normal tissues of humans and cynomolgus monkeys.
AB  - Certain isoforms of the CD44 glycoprotein family play an essential role in the
      metastatic spread of tumour cells. Protein expression of such CD44 isoforms has
      also been observed in a variety of human malignancies. In this study, we compared
      the expression of exon v5- and v6-containing CD44 isoforms in normal human and
      cynomolgus monkey (Macacca fasciculata) tissues. Cloning and sequencing of
      cynomolgus CD44 exons v5 and v6 revealed a homology of 97% and 95%, respectively,
      between man and monkey. Two monoclonal antibodies (MAbs) directed against an
      epitope encoded by human exon v5 (VFF8) and an epitope encoded by exon v6 (VFF18)
      were used to determine expression of CD44 isoforms in man and monkey.
      Immunohistochemical screening of a representative profile of normal human and
      cynomolgus tissues revealed that expression of exon v5- and v6-containing CD44
      isoforms was almost identical in the two species. Exon v6 staining was observed
      only in a subset of epithelial tissues, whereas v5 staining was additionally
      detected on certain non-epithelial tissues. These data suggest that cynomolgus
      monkey could serve as a system to test the usefulness of antivariant CD44 MAbs
      with regard to antibody-based tumour therapy.

PMID- 8652274
TI  - Molecular genetic analysis of the von Hippel-Lindau disease (VHL) tumour
      suppressor gene in gonadal tumours.
AB  - Chromosome 3p allele loss is frequent in ovarian and testicular tumours. The von
      Hippel-Lindau (VHL) disease tumour suppressor gene maps to chromosome 3p25.
      Gonadal tumours may occur in patients with VHL disease, so somatic VHL gene
      mutations might be involved in the pathogenesis of sporadic gonadal tumours. To
      investigate this hypothesis, we screened 60 gonadal tumours (36 ovarian and 24
      testicular) for VHL gene mutations and chromosome 3p allele loss. Although 38%
      (10/26) of informative ovarian and 54% (7/13) of testicular tumours demonstrated
      3p allele loss, no somatic VHL gene mutations were detected in the 60 gonadal
      tumours analysed. This suggested that chromosome 3p tumour suppressor gene(s)
      other than VHL are involved in gonadal tumorigenesis.

PMID- 8652275
TI  - Development of immunogenic colorectal cancer cell lines for vaccination:
      expression of CD80 (B7.1) is not sufficient to restore impaired primary T cell
      activation in vitro.
AB  - The capacity of colorectal carcinoma and melanoma cell lines to induce primary
      versus effector T lymphocyte activation in vitro was investigated. Established
      epithelial tumour cell lines derived from colorectal carcinoma and melanoma did
      not activate a primary proliferative response of resting T lymphocytes in
      allogeneic mixed lymphocyte tumour cell cultures (MLTCs). In contrast, the same
      tumour cells were effectively lysed by preactivated cytolytic T cell clones. This
      demonstrates that tumour cells are impaired in inducing a primary immune response
      but are susceptible to effector immune responses. Attempts at improving primary T
      cell activation revealed that exogenous cytokines, including interferon-gamma
      (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2),
      were not effective. Expression of CD80 (B7.1), by transfecting a CD80 cDNA into
      the melanoma cell line SkMel63, improved T cell proliferation considerably. In
      contrast, CD80 expression in two colorectal carcinoma cell lines (SW480, SW707)
      did not result in T cell activation. This was not due to lack of class II MHC
      expression on SW480 since coexpression of a HLA-DR3 alloantigen and CD80 had no
      effect. Our data suggest that de novo CD80 expression is not, in general,
      sufficient to improve primary T cell activation by human tumour cells.

PMID- 8652276
TI  - Sequential chemoimmunotherapy for advanced non-small cell lung cancer using
      cisplatin, etoposide, thymosin-alpha 1 and interferon-alpha 2a.
AB  - A phase II study was performed to evaluate the clinical and immunological effects
      of a regimen of cisplatin (DDP) and etoposide (VP-16) combined with thymosin
      alpha 1 (TA1) and low-dose interferon-alpha 2a (IFN) in the treatment of patients
      with advanced non-small cell lung cancer (NSCLC). Chemoimmunotherapy cycles were
      repeated every 3 weeks. There were 24 responses (two complete, 22 partial) among
      56 assessable patients. Median survival was 12.6 months. Overall, treatment was
      well tolerated. Natural killer cell activity and lymphocyte subtypes were
      depressed by chemotherapy, but this effect was less prominent in patients
      receiving TA1 and IFN in comparison with a concomitant group of patients treated
      with DDP and VP-16 only. The combination of DDP and VP-16 and TA1 and IFN is
      effective in advanced NSCLC with acceptable toxicity. However, the results of
      this study need to be confirmed in a randomised trial.

PMID- 8652277
TI  - Vinorelbine and epirubicin in metastatic breast cancer. A dose finding study.
AB  - The aim of the study was to define the maximum tolerated dose (MTD) of
      vinorelbine given as one or two weekly doses in combination with epirubicin 60
      mg/m2 every third week. The MTD was defined as the dose resulting in a WHO grade
      III or IV leucopenia exceeding 50% of patients. Patients were treated in groups
      of 10 at escalating doses of vinorelbine. The number of patients at the final
      dose level was expanded to 20. The dose of epirubicin was kept constant at 60
      mg/m2 every third week. At dose level 1, 15 mg/m2 vinorelbine was given on day 1
      at level 2, 20 mg/m2 was given on day 1 and at level 3, 20 mg/m2 was given on
      days 1 and 8. The MTD was reached at dose level 3. WHO haematological toxicity
      grade IV occurred in 0, 10 and 45% and grade III at 60, 30 and 30% of patients at
      dose levels 1, 2 and 3, respectively. Despite the common occurrence of grade IV
      haematological toxicity, only two serious infections were noted. Non
      haematological toxicity of vinorelbine included neurotoxicity, manifesting as
      muscle weakness, constipation and paresthesias in the majority of patients.
      Neurotoxicity was usually mild and did not require treatment discontinuation.
      Phlebitis at the injection site was troublesome in many patients. Alopecia and
      nausea, probably due to epirubicin, occurred in most patients. The response rates
      were 22% (95% CI (confidence interval) 3-60%), 40% (12-74%) and 60% (36-81%) at
      levels 1, 2 and 3, respectively (non-significant).

PMID- 8652278
TI  - Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide
      phosphate (BMY-40481).
AB  - Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and
      pharmacokinetic study has been performed over the dose range 25-110 mg/m2/day for
      5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110
      mg/m2/day for 5 days every 3 weeks and the dose-limiting toxicity was
      neutropenia. Other toxicities were mild, with the exception of 2 patients who
      displayed significant hypersensitivity reactions. The etoposide
      phosphate:etoposide area under the plasma concentration versus time curve (AUC)
      ratio was < 1% and the pharmacokinetic parameters for etoposide were within
      previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide
      AUC and baseline white blood cell count were significant determinants of
      leucopenia (model r2 = 0.51).

PMID- 8652279
TI  - Portable pumps in cancer chemotherapy: how to deal with marked fluctuations in 5
      fluorouracil blood concentrations.

PMID- 8652280
TI  - Intermittent hormone therapy in prostate and breast cancers.

PMID- 8652281
TI  - Granulocyte-macrophage colony-stimulating factor therapy in patients with
      chemotherapy-induced aplasia and Clostridium difficile enterocolitis.

PMID- 8652282
TI  - Short-term versus continuous infusion: no influence on ifosfamide side-chain
      metabolism.

PMID- 8652283
TI  - A case of radiation myelopathy after 2 x 8.5 Gy for inoperable non-small cell
      lung cancer.

PMID- 8652284
TI  - Trofosfamide is effective in refractory non-Hodgkin's lymphoma.

PMID- 8652285
TI  - High-dose therapy followed by autologous bone marrow transplantation in
      previously untreated high grade non-Hodgkin's lymphoma: 10-year long-term
      results.

PMID- 8652286
TI  - Routine bone scan and serum alkaline phosphatase for staging in patients with
      renal cell carcinoma is not cost-effective.

PMID- 8652287
TI  - Thyroid cancer: different outcomes to chemotherapy according to tumour histology.

PMID- 8652288
TI  - Phase II study of intensive CEV (carboplatin, epirubicin and VP-16) plus G-CSF
      (granulocyte-colony stimulating factor) in extensive small cell lung cancer.

PMID- 8652289
TI  - Oral chemotherapy with doxifluridine and folinic acid in biliary tract cancer.

PMID- 8652290
TI  - Long-term survival in a patient with Rosai-Dorfman disease treated with
      interferon-alpha.

PMID- 8652293
TI  - Dental prescribing.

PMID- 8652292
TI  - Mike Grace talks to Penny Vasey.

PMID- 8652291
TI  - Anaphylactic reaction after a first filgrastim (granulocyte-colony stimulating
      factor) injection.

PMID- 8652294
TI  - Self-funded training courses in orthodontics.

PMID- 8652295
TI  - Shelf life.

PMID- 8652296
TI  - The mysterious Florida AIDS mystery.

PMID- 8652297
TI  - Localising maxillary canines.

PMID- 8652298
TI  - Private practice.

PMID- 8652300
TI  - Tuberculosis: a re-emerging problem for health care workers.
AB  - The current upward trend in the incidence of tuberculosis, particularly in the
      USA, and the problems of treating multiply drug resistant strains of
      Mycobacterium tuberculosis have caused a resurgence of interest in this
      infection. This review describes the microbiology, routes of transmission and
      epidemiology of Mycobacterium tuberculosis infections. The emergence and problems
      of treating multiply drug resistant strains are outlined. The significant
      potential for occupationally acquired infection among health care workers is
      discussed, together with a summary of the available infection control measures
      currently being examined. The true level of occupational risk to dental personnel
      remains uncertain.

PMID- 8652302
TI  - Practical marketing for dentistry. 1. What is marketing?
AB  - Do you really understand what 'marketing' means? Are you suspicious about the
      motives of those practising marketing? Is it ethical to promote dental and health
      services? Are we trying to make out that we offer more than we actually do? Is
      this a scheme dreamed up as a front for inferior services? The aim of this series
      is to demonstrate that marketing theory and concepts do have an ever increasing
      importance in today's dental practices. The series will explore different aspects
      of marketing thought and relate them to the practice environment, by use of
      practical examples and a case study.

PMID- 8652301
TI  - Mandibular tori, migraine and temporomandibular disorders.
AB  - In this study the presence of mandibular tori was related to conditions
      associated with parafunctional activity. Parafunction in the form of tooth
      clenching or grinding has been associated with temporomandibular disorders (TMD)
      and recently migraine. Patients attending a facial pain clinic in Belfast were
      assessed for the presence of tori and results compared to age and gender matched
      controls. The findings were that mandibular tori were present significantly more
      commonly in both migraineurs and TMD patients. The results support an association
      with parafunction in the aetiology of mandibular tori and suggest that tori are a
      useful marker of past or present parafunction in some patients.

PMID- 8652299
TI  - A survey of the methods of disinfection of dental impressions used in dental
      hospitals in the United Kingdom.
AB  - The potential for cross-infection from microbial contaminated dental impressions
      has long been recognised. This study set out to investigate impression
      decontamination procedures currently used in UK dental hospitals (1995) and to
      see how these may have changed since a previous survey, carried out in 1988. A
      variety of disinfection solutions and regimes were highlighted both within and
      between dental hospitals. Several of the disinfecting solutions currently being
      used have not been specifically tested for efficacy with impression materials.
      The laboratories were asked to highlight any adverse reactions. Five laboratories
      reported that some alginates resulted in casts with poor surface properties when
      immersed in hypochlorite (0.1 and 1%), sodium dichloroisocyanurate, and 2%
      glutaraldehyde solutions. This paper highlights that there is no universally
      recognised impression disinfection/sterilisation protocol. It is recommended that
      all impressions should at least undergo a disinfecting procedure by immersion in
      1% sodium hypochlorite for a minimum of 10 minutes.

PMID- 8652303
TI  - Centenary year of scientific papers in the British Dental Journal.
AB  - This part of the centenary series covers Sir Wilfred Fish's paper on the
      pathology and treatment of periodontal diseases. Newell Johnson comments on this
      important British contribution to the developing science of periodontology
      earlier this century. Newell is a particularly apt commentator because he is now
      Head of the RCS Department of Dental Sciences, which was founded by Fish in 1936.

PMID- 8652304
TI  - Drink, drugs and dentistry--are you at risk?
AB  - My long love affair with alcohol started at seventeen, when I had my first
      serious drink. I never saw it as a problem, it was just a way of dealing with all
      my other ones.

PMID- 8652305
TI  - Diagnostic radiology in Denmark. Persons and organizations.

PMID- 8652306
TI  - Development of radiology in Finland.

PMID- 8652307
TI  - The introduction of medical radiology into Iceland. Early pioneering and later
      developments.

PMID- 8652309
TI  - Swedish radiology as reflected in Acta Radiologica 1921-96.

PMID- 8652308
TI  - Medical radiology in Norway.

PMID- 8652310
TI  - History of panoramic radiography.
AB  - The first attempts to image the whole jaw were made with intraoral radiation
      sources at the beginning of this century. The narrow-beam principle was described
      in 1922. Experimental work and development of equipment in the 1950s resulted in
      commercially available machines in the early 1960s. The panoramic technique
      originated from the need to image the jaws, but it was also applied to other
      anatomic regions, before CT became available. Panoramic radiography is an
      essential element in oral radiology today.

PMID- 8652311
TI  - Low-field MR imaging--development in Finland.
AB  - The development project for application of MR imaging to diagnosis of internal
      hemorrhages was initiated by the Instrumentarium Corporation in 1978. The goal
      was to develop a diagnostic tool for emergency clinics. Due to the rapid
      development of imaging technology, the goal was changed to a cost-effective MR
      unit. During the past 16 years, several generations of low-field units have been
      introduced. Consequently, a vast amount of clinical and technical knowledge about
      low-field MR has been gained. The interest in low-field units is rapidly
      increasing. A part of this may be explained by the pressure to reduce the cost of
      health care. There are some features which make the low-field approach clinically
      interesting. These include the feasibility of open magnet configurations, and the
      availability of unique contrast parameters such as magnetization transfer and
      T1p. One important aspect is the inherent safety of a low-field MR unit. This
      article reviews the methods and devices introduced through the development of low
      field technology in Finland.

PMID- 8652313
TI  - Radiation physics in Acta Radiologica.

PMID- 8652312
TI  - The history of Swedish neuroradiology.

PMID- 8652314
TI  - The 11th World Congress of Anaesthesiology.

PMID- 8652315
TI  - Rocuronium: the newest aminosteroid neuromuscular blocking drug.

PMID- 8652316
TI  - Dose requirements, efficacy and side effects of morphine and pethidine delivered
      by patient-controlled analgesia after gynaecological surgery.
AB  - We have compared the dose requirements and side effects of morphine with those of
      pethidine when administered by patient-controlled analgesia in 40 patients (ASA I
      II, 20-65 yr) after elective total abdominal hysterectomy. Patients were
      allocated randomly, in a double-blind manner, to receive either morphine (bolus
      dose 2 mg, lockout time 10 min) or pethidine (bolus dose 20 mg, lockout time 10
      min) for postoperative pain relief. Mean 24-h morphine and pethidine consumption
      was 70 (SEM 6.2) mg and 660 (67.8) mg, respectively (ratio 1:9.4). There were no
      significant differences in postoperative sedation, nausea, pain relief and
      patient satisfaction (VAS 0-100 mm), and requirements for antiemetics. Four
      patients receiving pethidine were withdrawn because of postoperative confusion
      and one receiving morphine because of intractable nausea and vomiting. The 95%
      confidence interval for this difference between the groups for VAS scores of
      sedation, nausea and pain were approximately 30 mm.

PMID- 8652317
TI  - Postoperative analgesia by continuous extradural infusion of ropivacaine after
      upper abdominal surgery.
AB  - Ropivacaine is a new local anaesthetic with advantages that suggest an important
      role in the provision of postoperative analgesia. The main aim of this study was
      to investigate the dose-response relationship of extradural infusion of
      ropivacaine. We studied 36 ASA I-III patients undergoing upper abdominal surgery
      during general anaesthesia and extradural block (catheter insertion at T6-9)
      using 0.5% ropivacaine in a randomized, double-blind study. After surgery nine
      patients each received an extradural infusion of either ropivacaine 0.1%, 0.2%,
      0.3% or saline at a rate of 10 ml h-1 for 21 h. All patients had access to i.v.
      morphine via a PCA device. The ropivacaine groups consumed significantly less
      morphine over the 21-h infusion period than the saline group (medians: saline 75
      mg; 0.1% ropivacaine 32 mg; 0.2% ropivacaine 39 mg; 0.3% ropivacaine 13 mg) (P <
      0.05). Pain (VAS scores) at rest was significantly lower in all ropivacaine
      groups than in the saline group after 4 h of infusion (medians: saline 45 mm;
      0.1% ropivacaine 15 mm; 0.2% ropivacaine 12 mm; 0.3% ropivacaine 0 mm). Pain on
      coughing was significantly less in all ropivacaine groups than in the saline
      group after 4 h infusion (medians: saline 67 mm; 0.1% ropivacaine 44 mm; 0.2%
      ropivacaine 33 mm; 0.3% ropivacaine 0 mm) and for 0.2% and 0.3% ropivacaine at
      later times. Motor block was negligible throughout the infusion. Patient
      satisfaction was higher in the 0.2% and 0.3% ropivacaine groups than in the two
      other groups.

PMID- 8652318
TI  - Is there implicit memory after propofol sedation?
AB  - Recent evidence indicates that implicit memory may be preserved during general
      anaesthesia. We tested for the presence of explicit and implicit memory in
      patients undergoing surgical procedures with local or regional anaesthesia and
      sedation with propofol. Initial i.v. boluses of propofol 0.5 mg kg-1 and fentanyl
      1 microgram kg-1 were administered, followed by an infusion of propofol 50
      micrograms kg-1 min-1. Administration of one or more doses of propofol 30 mg i.v.
      during operation was controlled either by the patient or the anaesthetist. At the
      start of the last skin stitch, patients were presented with a list of 15 stimulus
      words and the most frequently associated response. The infusion was then
      discontinued. After 1 h in the recovery area, all patients were tested for free
      recall, free association, cued recall and recognition on the list presented
      during surgery (critical list) and a matched list not presented (neutral list).
      Data of all patients without free recall (explicit memory) were analysed with
      repeated-measures analysis of variance. Of 36 patients, five demonstrated free
      recall. For the remaining 31 patients, cued recall and recognition showed no
      evidence of explicit memory. However, the free association tests demonstrated
      significant priming. The mean number of critical free associations was 6.6 (SEM
      0.4) compared with 5.5 (0.4) neutral free association (P < 0.05). In the absence
      of explicit memory, implicit memory persists after intraoperative sedation with
      propofol.

PMID- 8652319
TI  - Activation of the electrocorticogram by propofol during surgery for epilepsy.
AB  - Propofol is used widely during general anaesthesia but there has been concern
      that it may be implicated in provoking seizure activity. We have investigated the
      effects of low-dose propofol on the electrocorticogram of anaesthetized patients
      undergoing surgery for medically intractable epilepsy. During continuous
      peroperative recording of the electrocorticogram, propofol was administered in 25
      mg increments until burst suppression occurred. Activation of the
      electrocorticogram occurred in 17 of 20 patients. There was an increase in mean
      spike frequency in 16, extension of spike distribution in 15 and polyphasia in 13
      patients. The mean dose of propofol required to cause burst suppression was 88.2
      (range 25-175) mg. We conclude that at low doses, propofol caused activation of
      the electrocorticogram in epileptic patients but at higher doses burst
      suppression was induced.

PMID- 8652320
TI  - Periodic cardiovascular and ventilatory activity during midazolam sedation.
AB  - We have examined the effects of sedation with midazolam 0.1 mg kg-1 and reversal
      with flumazenil 0.5 mg on beat-to-beat heart rate (HR) variability (HRV),
      systolic arterial pressure (SAP), finger photoplethysmograph amplitude (PLA) and
      impedence pneumography in eight volunteers. With the onset of sedation there was
      a small decrease in SAP and increase in HR (ns). Spectral analysis of the HR time
      series showed reductions in the proportion of power in the high (> 0.15 Hz)
      frequency "ventilatory" band consistent with midazolam causing vagolysis. During
      sedation, low frequency (< 0.05 Hz) oscillations of PLA, HR, SAP and ventilation
      were observed. These were thought to be secondary to activity of coupled
      cardiorespiratory neurones within the brain stem and the ventilatory periodicity
      appeared similar to that observed during the early stages of sleep. The
      diminished high frequency and increased low frequency oscillations induced by
      midazolam sedation were reversed by administration of flumazenil.

PMID- 8652321
TI  - Anatomical configuration of the spinal column in the supine position. III.
      Comparison of adolescent and adult volunteers.
AB  - To clarify the anatomical configuration of the spinal column in the adolescent in
      the supine position, we have studied 10 adolescent (13-17 yr) and 10 adult (26-38
      yr) volunteers using magnetic resonance imaging. T1-weighted sagittal midline
      magnetic resonance images of the spinal column were obtained with subjects in the
      supine position. The maximum angles of decline of the lumbar spinal canal did not
      differ between the adolescent (mean 13.6 (SD 3.3) degrees) and adult (12.4 (3.8)
      degrees) groups. The maximum angles of incline of the upper thoracic spinal canal
      were smaller in the adolescent group (15.9 (4.7) degrees) than in the adult group
      (26.4 (5.8) degrees). The median highest point of the lumbar spinal canal was
      located at L4 (range L3-4 to L4-5) in both groups. The lowest points of the
      thoracic spinal canal in the adolescent and adult groups were located at T8-9 (T7
      to T9) and T8 (T6-7 to T9), respectively. This study showed that thoracic
      kyphotic curvature in adolescents was reduced significantly in the supine
      position compared with that in adults. This minimized thoracic kyphosis may
      explain, in part, the enhanced cephalad spread of subarachnoid hyperbaric
      anaesthetic solutions in adolescents.

PMID- 8652322
TI  - Convective warming combined with vasodilator therapy accelerates core rewarming
      after coronary artery bypass surgery.
AB  - In a prospective, randomized, controlled study, we have investigated the effect
      of forced air warming on the rate of change of nasopharyngeal and rectal
      temperatures in 20 patients after coronary artery bypass grafting. All patients
      had nasopharyngeal temperatures less than 36 degrees C on arrival in the
      intensive care unit and received an infusion of glyceryl trinitrate 15 mg h-1,
      but none received inotropes. Ten patients were warmed under an aluminized plastic
      "space" blanket (control group) and 10 were warmed under a "Bair Hugger" blanket
      connected to its power unit on "high" setting (Bair Hugger group). The rates of
      increase in nasopharyngeal temperature were 0.4 and 0.95 degrees C h-1,
      respectively, in the control and Bair Hugger groups (P < 0.01) during the first 2
      h after operation. Over the same period of time, rectal temperatures increased at
      a rate of 0.25 and 0.75 degrees C h-1 in the control and Bair Hugger groups,
      respectively (P < 0.01).

PMID- 8652323
TI  - Single-dose i.v. granisetron in the prevention of postoperative nausea and
      vomiting.
AB  - In this randomized, double-blind, parallel group, placebo-controlled, dose
      ranging study, we have compared three doses (0.1 mg, 1.0 mg and 3.0 mg) of the 5
      HT3 receptor antagonist, granisetron (Kytril), as prophylactic therapy for the
      prevention of postoperative nausea and vomiting. The aims were to determine the
      optimal dose of granisetron and to evaluate its safety profile. We studied 527
      adult patients, undergoing elective open abdominal surgery or vaginal
      hysterectomy during general anaesthesia. Antiemetic prophylaxis with a single
      dose of granisetron 1.0 mg or 3.0 mg resulted in a significant reduction (P <
      0.001 compared with placebo) in the numbers of patients experiencing
      postoperative vomiting, or nausea, or who achieved total control during the
      postoperative periods 0-6 h and 0-24 h. The two higher doses of granisetron (1.0
      mg and 3.0 mg) provided effective prophylaxis against vomiting, with 78% and 77%
      of patients, respectively, being free from vomiting in the first 6 h after
      surgery, and 63% and 62% in the first 24 h. This compares with 50% and 34% at 0-6
      h and 0-24 h, respectively, in the placebo group. Granisetron was well tolerated
      and the optimum dose was 1.0 mg.

PMID- 8652324
TI  - Rheological properties of commonly used plasma substitutes during preoperative
      normovolaemic acute haemodilution.
AB  - Preoperative normovolaemic acute haemodilution (PNAH) is used to reduce major
      blood loss during elective surgery. Considerable attention has been paid to
      colloid osmotic pressure, index of diffusibility and intravascular half-life of
      the currently available substitutes, but there is little information on their
      rheological properties from in vivo studies. Forty patients undergoing elective
      aortic reconstruction were given 4% human albumin (HA), 3.5% dextran 40 (Dxt 40),
      6% dextran 60 (Dxt 60), 6% hydroxyethylstarch 200 (HES) or modified fluid gelatin
      (Gel) during PNAH to produce a packed cell volume (PCV) of approximately 30%.
      Mean volumes of more than 1000 ml were infused. Blood samples were obtained
      before infusion, immediately after, and 1.5 h after the end of haemodilution. The
      following variables were measured: PCV, plasma viscosity, whole blood viscosity
      at measured and corrected PCV (0.45), and erythrocyte aggregation. Haemodynamic
      and metabolic variables were determined at the same time. The five substitutes
      had very different effects on red blood cell aggregation and low shear rate
      viscosity at corrected PCV. Red blood cell aggregation was reduced in the
      presence of HA, Dxt 40, but was increased moderately to markedly in the presence
      of the other substitutes in the following order: HES < Dxt 60 < Gel. The
      influence of the rheological conditions on tissue oxygenation was assessed by
      measuring the concentration of lactic acid; this was unchanged after PNAH with HA
      or Dxt 40, but was increased in the presence of HES, Dxt 60 or Gel.

PMID- 8652325
TI  - Rocuronium pretreatment reduces suxamethonium-induced myalgia: comparison with
      vecuronium.
AB  - We have studied, in 150 patients undergoing elective oral surgery, the
      effectiveness and sequelae of pretreatment with rocuronium for reducing myalgia
      after suxamethonium. Patients were allocated randomly to one of three groups:
      anaesthesia was induced with propofol and fentanyl, and group V received
      vecuronium 1 mg, group R rocuronium 6 mg and group P placebo pretreatment.
      Suxamethonium 1.5 mg kg-1 was given 60 s after the pretreatment agent. All
      patients received ketorolac 10 mg i.v. and morphine 10 mg i.m. for analgesia. The
      incidence of postoperative myalgia on day 1 after rocuronium (20%) was
      significantly less than after vecuronium (42%) (P < 0.05) or placebo (70%) (P <
      0.01). By day 4 the incidence of myalgia was 28.6% in the rocuronium group, 46.3%
      in the vecuronium group and 95% in the placebo group. Intubating conditions were
      not affected adversely by any pretreatment regimen.

PMID- 8652326
TI  - Carbon dioxide output in laparoscopic cholecystectomy.
AB  - In pneumoperitoneum, carbon dioxide eliminated in expired gas (carbon dioxide
      output) contains both metabolic and absorbed carbon dioxide from the peritoneal
      cavity. When elimination of carbon dioxide is much higher than carbon dioxide
      output, storage of tissue carbon dioxide and arterial carbon dioxide
      concentrations change. Finally, the rate of carbon dioxide eliminated in expired
      gas is not a match for the real rate of metabolic production and absorbed carbon
      dioxide from the peritoneal cavity. During and after insufflation of carbon
      dioxide, changes in carbon dioxide output were elucidated under constant arterial
      carbon dioxide pressure (PaCO2), the same as the preinduction level. We studied
      patients undergoing elective laparoscopic cholecystectomy. Carbon dioxide output,
      oxygen uptake, respiratory exchange ratio (RER), expired minute ventilation (VE),
      deadspace to tidal volume ratio (VD/VT ratio) and arterial to end-tidal carbon
      dioxide partial pressure difference (PaCO2-PE'CO2) were determined before
      induction, and during anaesthesia, pneumoperitoneum and recovery. By controlling
      ventilatory frequency (f) every 1 min, PaCO2 was adjusted to concentrations
      before induction. Constant monitoring of end-tidal carbon dioxide partial
      pressure (PE'CO2) and intermittent measurement of (PaCO2-PE'CO2) (15-min
      intervals) were conducted to predict PaCO2). Carbon dioxide output and oxygen
      uptake decreased significantly from mean values of 83.5 (SEM 5.2), 101.6 (5.1) to
      68.5 (4.2), 81.1 (4.6) ml min-1 m-2 (ATPS, P < 0.05) with sevoflurane
      anaesthesia, and RER did not change. During carbon dioxide pneumoperitoneum
      (intra-abdominal pressure 8 mm Hg), carbon dioxide output increased by 49% (102.4
      (5.0) ml min-1 m-2) (P < 0.05) while oxygen uptake remained stable and RER
      increased from 0.84 (0.02) to 1.16 (0.03) (P < 0.05). It was necessary to
      increase VE during pneumoperitoneum by 1.54 times that during anaesthesia to
      maintain individual PaCO2 values constant. After removal of carbon dioxide from
      the abdominal cavity, the regression equation of excess carbon dioxide output/BSA
      best fitted a two-compartment model. The time constants of the rapid and slow
      compartments were 8.2 and 990 min, respectively. Excess carbon dioxide output/BSA
      was still 5.5 ml min-1 m-2, 30 min after pneumoperitoneum.

PMID- 8652327
TI  - Effect of propofol and thiopentone on free radical mediated oxidative stress of
      the erythrocyte.
AB  - Propofol has free radical scavenging properties similar to those of recognized
      phenol-based antioxidants. We have examined these properties in an in vitro model
      of radical-induced cellular injury, comparing its activity with that of
      thiopentone (which has also been shown to have radical scavenging activity).
      Haemolysis of human erythrocytes was induced using the azo compound 2,2'-azo
      bis(2-amidinopropane) dihydrochloride (ABAP). This was achieved by incubating a
      10% suspension of erythrocytes with ABAP 100 mmol litre-1 at 37 degrees C. For
      propofol, at concentrations of 12.5, 25 and 50 mumol litre-1, the times to
      achieve 50% haemolysis were mean 126 (SEM 7) min (95% confidence interval 108-144
      min), 150 (8) (129-170) min and 182 (12) (160-180) min, respectively (Intralipid
      control 107 (7) (90-125) min, ANOVA P < 0.0001). For thiopentone, at
      concentrations of 62.5, 125 and 250 mumol litre-1, the values were 117 (2) (112
      121) min, 126 (3) (119-133) min and 138 (2) (132-144) min, respectively (saline
      control 109 (2) (104-113) min, ANOVA P < 0.0001). Spectroscopic analysis in the
      visible and ultraviolet spectra demonstrated a steady increase in the proportion
      of methaemoglobin during haemolysis, with the highest concentrations in the
      propofol-containing flasks. The formation of methaemoglobin was preceded by the
      generation of ferrylhaemoglobin (a Fe4+ haemoglobin species). Further experiments
      examining oxidation of purified methaemoglobin to ferrylhaemoglobin by hydrogen
      peroxide suggested that propofol, but not Intralipid or thiopentone, reduced
      ferrylhaemoglobin back to the met- state, and thereby explained the higher
      concentrations of methaemoglobin in the propofol-containing erythrocyte
      suspensions. We conclude that propofol is a more potent free radical scavenger in
      this model of oxidant stress than thiopentone, and that reduction of high
      oxidation states of haemoglobin may contribute to such activity.

PMID- 8652328
TI  - Antinociceptive actions of intrathecal xylazine: interactions with spinal cord
      opioid pathways.
AB  - We have studied rats with chronically implanted subarachnoid catheters. Xylazine,
      an alpha 2 adrenoceptor agonist, was injected intrathecally and nociceptive
      thresholds measured at two skin sites: the tail and the neck. Intrathecal
      xylazine (dose range 24.3-389 nmol) produced increases in electrical thresholds
      for nociception in the tail without any change in the neck; this observation
      suggested that the antinociceptive action of this drug was confined to the caudal
      part of the spinal cord responsible for tail innervation. The magnitude of this
      effect was dose-dependent. Tail flick latency also increased in these rats and
      the antinociceptive effects were antagonized in a dose-dependent manner by the
      selective alpha 2 adrenoceptor antagonist idazoxan (dose range 6.7-540 nmol).
      Intrathecal idazoxan also suppressed the increase in tail flick latency caused by
      the mu opioid agonist fentanyl (0.74 nmol) given intrathecally. This effect was
      also dose-dependent. The idazoxan dose-response curve for this suppression of
      fentanyl antinociception assessed with tail flick latency was the same as that
      for suppression of xylazine. In contrast, the antinociceptive effects of
      intrathecal xylazine were not affected by concurrent administration of opioid or
      GABAA antagonists. We conclude that intrathecal xylazine produced spinally
      mediated antinociceptive effects by combination with spinal cord alpha 2
      adrenoceptors and that neither opioid nor GABA-containing propriospinal neurones
      were involved in the mediation of this effect. However, alpha 2 adrenoceptors in
      the spinal cord appear to be involved with antinociception produced by
      intrathecal fentanyl.

PMID- 8652329
TI  - Postoperative sleep disturbances: mechanisms and clinical implications.

PMID- 8652330
TI  - Effect of apparatus on functional residual capacity.
AB  - As the route of breathing and use of airway apparatus such as mask, mouthpiece
      and noseclip can alter breathing pattern, this study has used the helium dilution
      method to estimate the effects of mouthpiece and mask breathing on functional
      residual capacity (FRC) in the supine position, and the change in FRC that occurs
      between the sitting and supine positions while breathing by mouthpiece. In 13
      normal subjects, breathing by mouthpiece, FRC was smaller, by a median of 1.07
      litre (interquartile values 0.73-1.43 litre) in the supine compared with the
      sitting position (P < 0.01), but residual volume (RV) did not change
      significantly. FRC measured in the supine position was significantly greater when
      breathing by mask than by mouthpiece (0.25, 0.04-0.38 litre) and RV was greater
      by similar amounts (0.20, -0.02 to 0.49 litre). This difference may result from
      increased inspiratory activity while breathing via the mask.

PMID- 8652331
TI  - Measurement technique and variation in intramucosal pH.
AB  - We have calculated gastric intramucosal pH (pHi) from Trip catheter saline
      tonometered samples in two patients undergoing ventilation using four different
      sampling techniques, each repeated five times. pHi was calculated from
      measurement of PCO2 in tonometered saline (TCO2). TCO2 was measured immediately,
      and then at 6-min intervals for 30 min. Variation in measurement was greatest for
      capped syringes stored at room temperature, and least when stored uncapped on
      ice. TCO2 always decreased significantly within 12 min. The mean difference in
      pHi (all sampling techniques) over 30 min was 0.1005 pH units. The results
      indicate that the calculated pHi was subject to variation as a result of both the
      method of sample storage and delay in measurement. An error of +/- 0.1 pH units
      may have clinically important implications if pHi is used to monitor either
      severity of illness or efficiency of resuscitation.

PMID- 8652332
TI  - Magnesium sulphate enhances residual neuromuscular block induced by vecuronium.
AB  - Magnesium sulphate (MgSO4) is currently used for haemodynamic control during
      anaesthesia and the early postoperative period. We have investigated the effect
      of this treatment on residual neuromuscular block after administration of
      vecuronium. Twenty adult patients were allocated randomly to one of two groups to
      receive MgSO4 60 mg kg-1 either at recovery from vecuronium block to a train-of
      four (TOF) ratio of 0.7, or 1 h after recovery to a TOF ratio of 0.7.
      Neuromuscular transmission was monitored using electromyography and TOF
      stimulation. MgSO4 caused rapid and profound recurarization in all 20 patients.
      MgSO4 decreased the amount of acetylcholine released at the motor nerve terminal
      and thus may lead to recurarization in patients previously exposed to
      neuromuscular blocking agents.

PMID- 8652334
TI  - Unilateral convulsion after induction of anaesthesia with propofol.
AB  - We report a case in which a 42-yr-old man suffered a unilateral convulsion
      immediately after i.v. injection of propofol, and was discovered subsequently to
      have an old contralateral cerebral infarct. This complication and the current
      information on the relationship between propofol and abnormal neurological
      activity are discussed.

PMID- 8652333
TI  - Comparison of the effect of two dose schedules of oral omeprazole with oral
      ranitidine on gastric aspirate pH and volume in patients undergoing elective
      surgery.
AB  - We have compared gastric aspirate pH and volume at induction of anaesthesia in
      222 patients who had received either omeprazole or ranitidine before elective
      operations. Omeprazole was given orally either as 40 mg on the evening before and
      40 mg on the morning of surgery or as 80 mg on the morning of surgery. Ranitidine
      150 mg was given orally on the evening before surgery and 2 h before anaesthesia.
      Treatment success was defined as aspirate pH > or = 2.5 and volume < 25 ml at
      induction of anaesthesia. Treatment was successful in 84% (95% confidence
      interval (CI) 73-91%) of patients in the omeprazole 40 + 40 mg group, 84% (95% CI
      73-91%) in the ranitidine group and 73% (95% CI 61-83%) in the omeprazole 80 mg
      group. There were no statistically significant differences between the groups.
      Twelve patients in the omeprazole 80 mg group had gastric pH < 2.5 and four had
      volume > 25 ml. Only three patients had a gastric pH < 2.5 in the omeprazole 40 +
      40 mg group and none had volume > 25 ml, which compared well with the ranitidine
      group. Omeprazole, given as 40 mg in the evening and 40 mg on the morning of
      operation, has a potential role for use in patients at risk for aspiration during
      general anaesthesia.

PMID- 8652335
TI  - Airway management for patients with a tracheal bronchus.
AB  - A tracheal bronchus is an aberrant, accessory or ectopic bronchus arising almost
      invariably from the right lateral wall of the trachea, causing hypoxaemia,
      atelectasis, or both, during anaesthesia. We describe two patients with a
      tracheal bronchus found before anaesthesia. One tracheal bronchus was found by
      tracheobronchoscopy and the other by chest x-ray. Because of recognition of the
      anomaly before operation, anaesthesia was uneventful in each patient.

PMID- 8652337
TI  - Ulnar and common peroneal nerve block revisited.

PMID- 8652336
TI  - Psychological characteristics and patient-controlled analgesia.

PMID- 8652338
TI  - Nebulized lignocaine before gaseous induction with desflurane.

PMID- 8652339
TI  - Factors governing onset of neuromuscular block.

PMID- 8652340
TI  - Effects of propofol and isoflurane on right ventricular function.

PMID- 8652341
TI  - Automated RNA probe assay for the identification of Listeria monocytogenes.
AB  - Recent epidemics of human listeriosis have shown the importance of Listeria
      monocytogenes as a food-borne risk. We have developed an automated identification
      assay for L. monocytogenes using the specificity of the 16S rDNA probe described
      by Wang et al. (1991). Bacterial cultures were lysed quickly by a chemical step
      releasing the target nucleic acids. Extracts were loaded into the VIDAS automate
      (bioMerieux) which performed a non-radio-active hybridisation reaction for 2 h.
      This assay recognised specifically 68 out of 69 L. monocytogenes isolates from
      clinical and food origins, including serovars 4b and 1/2, without cross
      hybridising to other Listeria species (103 strains) or other bacterial species
      (15 strains). The sensitivity of the assay was 10(7) bacteria. This automated
      technology is faster than conventional biochemical identification.

PMID- 8652342
TI  - Rapid detection and enumeration of Salmonella in chicken carcass rinses using
      filtration, enrichment and colony blot immunoassay.
AB  - A strategy was developed for 24-h detection and enumeration of Salmonella spp. on
      processed chicken carcasses. Carcasses were rinsed with saline and the rinses
      spiked with known numbers of serogroup B, C, D or E Salmonella. The total rinse
      volume was passed through two filter units of decreasing pore size. These removed
      most of the extraneous material while permitting rapid passage of more than 77%
      of the Salmonella. At least 100 ml of the filtrate was passed through a third
      filter unit containing a nitrocellulose capture membrane. Captured bacteria were
      selectively enriched by incubating the nitrocellulose membrane on filter pads
      soaked in Rappaport-Vassiliadis broth and then on pads soaked in brilliant green
      broth containing sulfadiazine and novobiocin. A colony blot immunoassay using two
      anti-Salmonella monoclonal antibodies was used to identify and enumerate the
      captured Salmonella. As few as five Salmonella colony forming units per carcass
      rinse could be detected. An evaluation of this system with 24 field samples
      indicated that the specificity was comparable to and the sensitivity higher than
      that of standard culture procedures.

PMID- 8652343
TI  - Multilocus enzyme electrophoresis typing of New Zealand Listeria monocytogenes
      isolates.
AB  - Eighty-five strains of Listeria Monocytogenes, comprising 74 strains isolated
      from the environment, humans, animals and foods in New Zealand; 10 strains from
      similar sources in Denmark, and one reference strain, were studied using
      multilocus enzyme electrophoresis (MEE). Fifty-five electrophoretic types (ETs)
      were identified among the 85 strains, most (71%) of which were represented by
      only one isolate. The 74 New Zealand isolates produced 45 ETs, most (67%) of
      which were represented by only one isolate. There was no link between the source
      of the isolates and ET, as most ETs contained only one isolate. One cluster of
      ETs, designated cluster 45, contained only environmental isolates. Of the five
      ETs that contained isolates from more than one source, four contained isolates
      that were obtained from clinical specimens and foods indicating a possible link
      between isolates from these two sources. The population of New Zealand isolates
      of L. monocytogenes studied appears to be genetically diverse when compared with
      the diversity found in similar studies in other countries.

PMID- 8652345
TI  - Differentiation of Saccharomyces cerevisiae strains isolated from fermenting
      musts according to their karyotype patterns.
AB  - Pulsed field electrophoresis is a suitable technique for differentiation of
      Saccharomyces cerevisiae strains. In this work, karyotype analysis was used to
      study the ecology of the wild S. Cerevisiae flora in musts in fermentation in the
      A.C. (Appellation Controlee) area of Valdepenas (Spain). In order to do this, 392
      colonies isolated from different vats in different cellars, where dry yeast was
      never used to make wines, were submitted to the Countour Homogeneous Electric
      Field (CHEF) technique. Each of the resulting CHEF profiles was subjected to
      Cluster Analysis and four main karyotypes were found in this viticultural area.

PMID- 8652344
TI  - Sapal: a traditional fermented taro [Colocasia esculenta (L.) Schott] corm and
      coconut cream mixture from Papua New Guinea.
AB  - Sapal is a traditional fermented food made by mixing cooked, grated taro
      [Colocasia esculenta (L.) Schott] corm with coconut cream and allowing it to
      ferment at ambient temperature. The fermentation was primarily due to
      heterofermentative lactic acid bacteria, which reached 10(10) cfu/ml. Seven out
      of 10 isolated bacterial strains were identified as Leuconostoc mesenteroides or
      Leuc. paramesenteroides. The initial microbial flora was derived from the coconut
      cream. Yeasts grew on the surface of the sapal in the later stages of the
      fermentation. Overnight storage of the grated taro corm resulted in the glucose
      concentration increasing from 1.1 to about 5 g/l. During the fermentation the
      glucose concentration decreased to undetectable levels. The pH value fell from an
      initial value of 6.1 to 4.1 after 24 h.

PMID- 8652346
TI  - Survival and growth of Aeromonas hydrophila on modified atmosphere packaged
      normal and high pH lamb.
AB  - The growth of A. hydrophila on normal pH (5.5-5.8) and high pH ( > 6.0) lamb
      stored under modified atmospheres was examined. Lamb pieces and mince, inoculated
      with A. hydrophila were packaged in air, vacuum pack, 80% O2/20% CO2, 50% CO2/50%
      N2, or 100% CO2 and stored at 5 or 0 degrees C for up to 42 days. Samples were
      examined for the survival and/or growth of A. hydrophila by enrichment in
      alkaline peptone water and/or direct plating on starch ampicillin agar. The pH of
      each sample was estimated. On lamb pieces and mince of normal pH, A. hydrophila
      numbers decreased during storage at 5 and 0 degrees C under all the packaging
      conditions. The organism was not detected after 21 days storage. In contrast, A.
      hydrophila numbers were maintained or increased on high pH lamb under most
      storage regimes. Storage at 5 degrees C allowed significant increases in A.
      hydrophila numbers on high pH lamb under all the atmospheres, except 100% CO2. In
      lamb held at 5 degrees C under 100% CO2 for up to 42 days, A. hydrophila was
      recovered from most samples, although cell numbers decreased during storage.
      After storage at 0 degrees C, A. hydrophila was recovered from high pH packs
      stored under all atmospheres. Significant increases in cell numbers were only
      observed in minced lamb of high pH stored under air or vacuum. The pH values of
      lamb pieces and mince held at 5 or 0 degrees C under any of the packaging
      atmospheres did not change in a uniform manner during storage.

PMID- 8652347
TI  - The occurrence and growth of yeasts in Camembert and blue-veined cheeses.
AB  - Yeast populations greater than 10(6) cfu/g were found in approximately 54% and
      36%, respectively in surface samples of retail Camembert (85 samples) and Blue
      veined (45 samples) cheeses. The most predominant species isolated were
      Debaryomyces hansenii, Candida catenulata, C. lipolytica, C. kefyr, C.
      intermedia, Saccharomyces cerevisiae, Cryptococcus albidus and Kluyveromyces
      marxianus. The salt concentration of the surface samples of the cheeses varied
      between 2.5-5.5% (w/w) (Camembert) and 7.5-8.3 (Blue-veined), depending upon
      brand, and influenced the yeast ecology, especially the presence of S.
      cerevisiae. Yeasts grew to populations of 10(6)-10(8) cfu/g when cheeses were
      stored at either 25 degrees C or 10 degrees C. These populations decreased on
      continued storage at 25 degrees C, but such decreases were not so evident on
      storage at 10 degrees C. The properties of yeasts influencing their occurrence
      and growth in cheese were: fermentation/assimilation of lactose; production of
      extracellular lipolytic and proteolytic enzymes, utilisation of lactic and citric
      acids; and growth at 10 degrees C.

PMID- 8652349
TI  - Incidence of histamine-forming bacteria and histamine content in scombroid fish
      species from retail markets in the Barcelona area.
AB  - Incidence and diversity of histidine decarboxylating bacteria were determined in
      samples of tunafish, bonito and mackerel purchased at different retail markets.
      Histamine-forming bacteria occurred in a low proportion and always accounted for
      less than 0.1% of the total bacterial load in the fish samples studied.
      Similarly, histamine content in fish samples also was low ( < 25 ppm) and all of
      them met current histamine standards established by the European Union. Histamine
      was found in 83.3% of the tested tunafish samples with an average of 8.9 ppm. In
      contrast, none of mackerel samples and only 2 out of 12 of bonito showed
      detectable amounts of histamine. Morganella morganii and Klebsiella oxytoca were
      the most active histamine formers under experimental conditions, and produced on
      average 2765 and 1415 ppm of histamine, respectively, after incubation at 37
      degrees C for 18 h. Some new histamine formers, such as Plesiomonas shigelloides,
      Enterobacter intermedium, Serratia marcescens, Serratia plymuthica and Serratia
      fonticola, have been identified. Especially Plesiomonas shigelloides would have
      an important role within histidine decarboxylating bacteria because it was the
      sole histamine former isolated that has frequently been associated with the
      marine aquatic environment. However, only 8-340 ppm of histamine was formed by
      these strains in laboratory trials.

PMID- 8652350
TI  - Expanded programme on immunization. Progress towards poliomyelitis eradication,
      WHO south-east Asia region, 1988-1994.

PMID- 8652351
TI  - Arbovirus surveillance.

PMID- 8652348
TI  - Effect on pH heating medium on the thermal resistance of Bacillus
      stearothermophilus spores.
AB  - The influence of the pH of heating medium on heat resistance of Bacillus
      stearothermophilus spores (ATCC 7953, 12980, 15951 and 15952) were studied. The
      pH values tested were: 4.0, 5.0, 6.0 and 7.0 at temperatures of 115, 120, 125,
      130 and 135 degrees C. It was found that at low treatment temperatures (115
      degrees C) D-values decreased between 7- and 10-fold with 7953, 12980 and 15951
      strains and about 23-fold with 15952 strain when pH dropped from 7.0 to 4.0. At
      highest treatment temperatures (135 degrees C) D-values obtained with pH 6.0 and
      7.0 did not show any significant statistical differences (p > 0.05). z-Values
      appeared to be higher when the medium was acidified, ranging from 7.58 to 8.20
      and 9.43 10.0 for spores suspended in McIlvaine buffer pH 7.0 and pH 4.0,
      respectively, although the difference was not statistically significant. Heat
      resistance of strain ATCC 7953 at 120, 128, and 135 degrees C in asparagus puree
      and tomato puree at pH 5.0 under continuous monitoring of pH was also determined.
      D-values obtained in asparagus puree were similar to those obtained in buffer at
      the same pH, whereas those observed in tomato puree were found to be lower.

PMID- 8652352
TI  - Expanded programme on immunization. Statement on poliomyelitis eradication.

PMID- 8652353
TI  - WHO policy statement on polio vaccines.

PMID- 8652354
TI  - Influenza.

PMID- 8652355
TI  - Metamemorial functioning of children with moderate learning difficulties.
AB  - This study investigates whether children with moderate learning difficulties
      (MLDs) have a knowledge of which mnemonic strategies are available and applicable
      across a range of hypothetical memory tasks. The study compared the strategic
      awareness of 20 MLD and 20 typical children. Recall tasks were varied to include
      both discrete, abstract or context free items (described as 'non-authentic') and
      meaningful items (described as 'authentic'). The results suggest that, when
      required to make strategic judgments relating to the recall of non-authentic
      items, MLD children are significantly less efficient than their typical peers.
      Under these task conditions, the modal strategy mentioned was of the
      'look/think/say' variety. By way of contrast, when required to make strategic
      judgments relating to the recall of authentic items the MLD children demonstrated
      mnemonic awareness that was equal to that of their typical peers. The
      implications of this for the design of strategy training programmes are
      discussed, with particular reference to the need to utilise the mnemonic
      awareness already at the disposal of MLD children.

PMID- 8652356
TI  - Season of birth and gender effects in children attending moderate learning
      difficulty schools.
AB  - This paper examines the effects of season of birth and gender on academic
      achievement and cognitive abilities in children attending moderate learning
      difficulty schools. Given the high preponderance of both boys and children born
      in summer attending special schools it is important to consider how well these
      children perform in relation to their peers. A multivariate analysis reveals that
      both boys and summer born children perform better on tests of intelligence,
      mathematical ability, and reading comprehension. Summer born children also
      perform better on a test of communication skills. Discriminant functions analysis
      reveals that for both gender and season of birth IQ is the major predictor
      variable followed by reading comprehension, mathematical ability and
      communication skill. For gender, IQ discriminates more successfully than the
      other variables, whereas with season of birth the relative sizes of the effects
      are more comparable. The results of the analysis are discussed in terms of the
      implications for the identification of children for placement in moderate
      learning difficulty schools.

PMID- 8652358
TI  - British Connective Tissue Society meeting, London. Abstracts.

PMID- 8652357
TI  - Perceptions of mathematics ability versus actual mathematics performance:
      Canadian and Hong Kong Chinese children.
AB  - This study compared levels of mathematics achievement between Canadian and Hong
      Kong Chinese children and explored the relations between perceptions of
      children's competence and mathematics achievement. The Canadian sample was made
      up of 125 4th-grade children who were randomly selected from five schools in
      Calgary. A comparative sample of 128 children was drawn from five Chinese
      speaking schools in Hong Kong. Parents, teachers and children rated children's
      competence and a mathematics achievement test was given to the children. Hong
      Kong Chinese children outperformed their Canadian peers in the mathematics test.
      However, ratings of children's scholastic/mathematical abilities by Canadian
      respondents were significantly higher than those by Hong Kong Chinese informants.
      The Harter Self-Perception Profile Scale revealed that the aspects of themselves
      considered most important for sense of general self-worth were for Canadian
      children: physical appearance and social acceptance, for Hong Kong children:
      behavioural conduct and scholastic competence. Discussion centres on the
      contributions that expectations and evaluations of competence and self-worth make
      to the large difference in the mean levels of mathematics achievement between
      children in the two cultures.

PMID- 8652359
TI  - Lung injury: cell-specific bioactivation/deactivation of circulating
      pneumotoxins.
AB  - Many of the blood-borne xenobiotics which result in injury to the lung are not
      inherently pneumotoxic but cause damage within the target cells following
      metabolic activation. This injury is usually restricted to those cells capable of
      bioactivation and thus, in addition to its clinical significance, it provides a
      valuable indicator of the normal metabolic activity within the numerous cell
      types present in lung. Not surprisingly, injury does not simply reflect the
      presence or absence of a particular enzyme but rather the balance between
      mechanisms for activation and deactivation. A change in the balance between
      different enzymes may also determine whether activation results in injury or
      tumorigenesis (Foster et al. 1992). Changes in particular types of cells cannot
      be determined by analysing whole lung homogenates. Isolation of particular cell
      types can provide valuable information but this approach does not address the
      differences between adjacent cells of the same type (Forkert & Moussa 1989;
      Dinsdale et al. 1992). Further progress may require the correlation of the injury
      with the status of individual cells; the quantitation of histochemical and
      immunocytochemical data is notoriously labour intensive but this approach may
      well be inescapable.

PMID- 8652360
TI  - Prevention of reovirus type 2-induced diabetes-like syndrome in DBA/1 suckling
      mice by treatment with antibodies against intercellular adhesion molecule-1 and
      lymphocyte function-associated antigen-1.
AB  - Reovirus type 2-induced diabetes-like syndrome in suckling mice is considered to
      be an animal model for human insulin-dependent diabetes mellitus. We have
      previously demonstrated that immunopathologic pancreatic islet cell damage might
      be relevant to reovirus type 2 infection. In this study the involvement of
      adhesion molecules in the development of reovirus type 2-induced diabetes-like
      syndrome was examined. In infected mice infiltration of mononuclear cells mixed
      with polymorphonuclear leucocytes in and around pancreatic islets (insulitis) was
      observed in association with abnormal glucose tolerance. The treatment with
      monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1) and
      lymphocyte function-associated antigen-1 (LFA-1) prevented the development of
      insulitis with abnormal glucose tolerance in a dose dependent manner. These
      results suggest that ICAM-1 and LFA-1 molecules may, at least in part,
      participate in islet cell damage, resulting in reovirus type 2-induced diabetes
      like syndrome. The role of ICAM-1 and LFA-1 molecules on the development of
      insulitis is discussed.

PMID- 8652361
TI  - Effects of cigarette smoke and asbestos on airway, vascular and mesothelial cell
      proliferation.
AB  - In order to determine whether exposure to both cigarette smoke and asbestos leads
      to enhanced cell proliferation, and whether pleura cell proliferation reflects
      the presence of fibres at or near the pleura, rats were exposed to air (control),
      daily cigarette smoke, a single intratracheal instillation of amosite asbestos,
      or a combination of smoke and asbestos. Dividing cells were labelled with
      bromodeoxyuridine (BrdU) and animals were sacrificed at 1, 2, 7 or 14 days. Both
      cigarette smoke and asbestos produced increases in the labelling index of small
      airway wall, epithelial cells and pulmonary artery cells. In the small airways
      there was a brief marked positive synergistic interaction between these two
      agents, but synergism was not seen in the vessels. Cigarette smoke did not
      increase the labelling of mesothelial or submesothelial cells, whereas asbestos
      caused a persisting increase in mesothelial cell labelling. There was no
      correlation between the number of BrdU labelled mesothelial or submesothelial
      cells and the number of fibres touching the pleura, or located within 180 microns
      of the pleura. We conclude that the combination of cigarette smoke and asbestos
      exposure produces a complex set of interactions and has the potential to markedly
      increase cell proliferation in the parenchyma, an effect that may be important in
      both fibrogenesis and carcinogenesis. In contrast to the diminishing effects over
      time of a single dose of asbestos on cell proliferation in the small airways and
      vessels, the same dose of asbestos leads to sustained mesothelial cell
      proliferation. However, the latter process does not correlate with local
      accumulation of asbestos fibres.

PMID- 8652362
TI  - In vivo and in vitro study of the primary and secondary antibody response to a
      bacterial antigen in aged mice.
AB  - One of the most important manifestations of aging in both humans and laboratory
      animals is a gradual decline in immune effectiveness. However, it is not clear as
      to how general is this decline. We here report that aged BALB/c mice showed no
      decline in the magnitude of the in vivo primary antibody response to
      phosphorylcholine (PC), an immunodominant epitope of the Streptococcus pneumoniae
      R36a (Pn). Often it appeared that aged mice responded better than young syngeneic
      mice. In contrast, the secondary antibody response had a different profile, with
      aged mice showing a marked decrease in PC-specific antibody. Further in vitro
      studies were conducted in order to determine the cause of the decline of the
      secondary antibody response in aging. We noted that B cells from young and aged
      donors, either primed or twice immunized with the antigen, when cultured without
      T cells and in the presence of antigen did not display any significant difference
      in their antibody response to PC. However, L3T4 cells from aged BALB/c mice,
      previously immunized twice with Pn, failed to augment the in vitro B cell
      response as compared to L3T4 cells from young mice. Moreover, we found that Lyt 2
      cells from young and aged mice had no regulatory effects on the anti-PC response
      in vitro. Further in vivo experiments demonstrated that alteration of the
      idiotypic network may not be related to a decline in the secondary antibody
      response since two injections of the antigen are unable to elicit an anti
      idiotypic antibody response in either young or aged mice. These data demonstrate
      that the decline of the anti-PC response after a secondary challenge with Pn is
      linked to defects in the T cell compartment.

PMID- 8652364
TI  - Distribution of viral RNA in the spinal cord of DBA/2 mice developing biphasic
      paralysis following infection with the D variant of encephalomyocarditis virus
      (EMC-D).
AB  - DBA/2 mice infected with the D variant of encephalomyocarditis virus (EMC-D)
      (10(1) PFU/head) developed biphasic hind limb paralysis. As a first step in
      clarifying its pathogenesis, we examined the distribution of viral RNA in the
      spinal cord using in situ hybridization. At 3 days post inoculation (DPI), in the
      spinal cord of mice showing slight paralysis, viral RNA was observed in capillary
      endothelial cells and a few adjacent glia cells in the funiculus lateralis from
      thoracic to lumbar enlargement. At 7 DPI, in the spinal cord of mice showing
      apparent paralysis, viral RNA was observed in a larger number of glia cells in
      the demyelinated lesion associated with infiltration of macrophages in the
      funiculus lateralis and in a small number of degenerated neurons in the cornu
      ventrale. In the funiculus lateralis, viral RNA could not be observed after 28
      DPI. On the other hand, viral RNA was observed in degenerated neurons in the
      cornu ventrale of mice showing the second phase paralysis at 42 DPI. Many CD4+T
      cells infiltrated around these degenerated neurons. These results suggest that:
      (1) the viral entry zone was the capillary endothelial cells in the funiculus
      lateralis; (2) first phase paralysis was due to demyelination caused by EMC-D and
      associated with macrophage infiltration; (3) second phase paralysis was due to
      degeneration of motor neurons bearing viral RNA associated with infiltration by
      CD4+T cells.

PMID- 8652365
TI  - Sir James Paget and his contributions to pathology.
AB  - Sir James Paget's Lectures on Surgical Pathology, published in 1853, was based on
      Lectures given at the Royal College of Surgeons of England in the previous six
      years. It makes use of the pathological material collected by John Hunter in the
      late eighteenth century which was housed in the College. It expands the
      principles of pathophysiology enunciated by Hunter using microscopic
      observations. The first half of the book covers mainly inflammation and repair;
      the second is involved in a description of tumours with particular emphasis on
      the difference between benign and malignant growths. This book indicates a
      concept of pathology before the realization of the role of infectious organisms.
      However, there is some inkling of the contagious nature of syphilis and variola
      following on Hunter's work. The concept, current at that time, that tuberculosis
      was related to cancer is expressed. This work acts as a bridge between the
      pathology of John Hunter and that of the present time.

PMID- 8652363
TI  - Immunotoxic effects of exposure of rats to xenobiotics via maternal lactation.
      Part I 2,3,7,8-tetrachlorodibenzo-p-dioxin.
AB  - Exposure of lactating female Leeds rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD) resulted in a reduction in the body, spleen and liver weights of their
      male offspring at 130 days of age. None of the total administered doses (0.2, 1.0
      or 5.0 micrograms/kg b.wt over 18 days) induced thymic atrophy in the offspring
      of either sex as adults. Most of the growth inhibition occurred during the
      suckling period and the effect was near maximal following maternal exposure to
      the lowest dose of TCDD. After this dose, at post-natal day 130 the body weights
      of the female offspring remained depressed, while those of the males had
      recovered to untreated control values. Maternal exposure to TCDD affected the
      immunocompetence of the adult offspring: in vitro T cell dependent and T cell
      independent responses and mitogen induced in vitro production of interleukin 1
      (IL-1) and interleukin 2 (IL-2) were suppressed at post-natal day 130. The total
      dose of TCDD that has to be administered to dams over an 18-day nursing period in
      order to reduce the humoral responses of their offspring as adults by 50% of the
      maximum was estimated to be in the range 0.3-1.0 micrograms/kg b.wt to the
      antigens SRBC, DNP-Ficoll or TNP-LPS and 3.5-3.9 micrograms/kg b.wt. to the
      antigen LPS.

PMID- 8652366
TI  - Bisphosphonates in multiple myeloma: current status; future perspectives.

PMID- 8652367
TI  - Characterization of TGF-beta 1-binding proteins in human bone marrow stromal
      cells.
AB  - The proliferation and differentiation of haemopoietic progenitor cells is
      dependent on their close relation with bone marrow stromal cells, which
      constitute a source of cytokines as well as expressing receptors for both the
      cytokines and progenitor cell adhesion molecules necessary for regulated
      haemopoiesis. We have generated human bone marrow stromal cell cultures and
      analysed the TGF-beta 1 receptor components expressed by these cells. [125I]TGF
      beta 1-affinity labelling experiments showed the involvement of type I and II
      receptors in the binding of TGF-beta 1, as demonstrated by specific
      immunoprecipitation of [125I]TGF-beta 1-receptor complexes. In addition, large
      TGF-beta 1-labelled complexes displaying an electrophoretic mobility similar to
      betaglycan were also observed in these experiments. Endoglin, another component
      of the TGF-beta receptor system, was detected by flow cytometry on the surface of
      cultured marrow stromal cells, and in the human bone marrow stromal cell line Str
      5, and was immunoprecipitated from surface-iodinated cells. Endoglin on the
      stromal cells was able to bind TGF-beta 1, as demonstrated by specific
      immunoprecipitation of [125I]TGF-beta 1-endoglin complexes using anti-endoglin
      antibodies. The results presented provide evidence that bone marrow stromal cells
      are fully capable of responding to TGF-beta 1. Given the important role of TGF
      beta as a regulator of the synthesis of cytokines and cytokine receptors, as well
      as cell adhesion molecules, these data indicate that the binding of TGF-beta 1 by
      stromal cells might represent an important step in the regulation of the
      proliferation and differentiation of haemopoietic progenitor cells.

PMID- 8652368
TI  - Growth factor induction of cytosolic protein tyrosine kinase activity in human
      haemopoietic progenitor cells isolated by flow cytometry.
AB  - We employed a highly sensitive method to assay protein tyrosine kinase activity
      in extracts of subpopulations of CD34+ bone marrow progenitor cells isolated by
      fluorescence activated cell sorting in an attempt to better define how growth
      factor induction of enzymatic activity relates to progenitor cell maturation.
      FACS analysis confirmed that, under the conditions employed, essentially all of
      the CD34+ cells in adult human marrow that lacked the CD38 antigen were devoid of
      the myeloid maturation marker CD33 as well as the lineage antigens: CD10, 13, 14,
      15, 16, 19, 71 and glycophorin A. A variable portion (50-90%) of these CD34+,
      CD38- progenitor cells expressed HLA-DR. CD34+, CD38- cells that did not express
      HLA-DR were found to lack detectable levels of either membrane or cytosolic
      tyrosine kinase activity. HLA-DR+ progenitor cells that lacked CD38 possessed
      elevated levels of cytosolic tyrosine kinase activity but only low levels of
      plasma membrane activity. In contrast, CD34+ cells that expressed CD38 (and HLA
      DR) possessed high levels of membrane-associated tyrosine kinase activity. A
      cocktail of haemopoietic growth factors that included IL-3, IL-6 and stem cell
      factor effectively induced tyrosine kinase activity in CD34+, CD38-, HLA-DR-
      progenitor cells. Growth factor induction of tyrosine kinase activity in these
      cells was not inhibited by actinomycin D or cyclohexamide. Most of the tyrosine
      kinase activity induced by these growth factors was recovered from the cytosolic
      fraction of disrupted cells. Thus, induction of cytosolic tyrosine kinase
      activity is an early event in the response of uncommitted haemopoietic cells to
      haemopoietic growth factors. Subsequent activation of membrane tyrosine kinases
      may initiate key transduction processes as these cells begin to differentiate.

PMID- 8652369
TI  - Analysis of granulocyte colony stimulating factor receptor isoforms,
      polymorphisms and mutations in normal haemopoietic cells and acute myeloid
      leukaemia blasts.
AB  - Deletion mutants of the intracytoplasmic domain of the granulocyte colony
      stimulating factor receptor (G-CSFR) have shown that it contains a membrane
      proximal region which must be conserved to allow the receptor to transduce a
      mitotic signal, and a C-terminal region necessary for transduction of cell
      differentiation. Changes in the intracytoplasmic domain may result in the
      uncoupling of these two processes, as in acute leukaemia, and such alterations
      could occur either as isoforms or mutations. We have studied the transmembrane
      domain and intracytoplasmic tail of the G-CSFR in RNA from blood or bone marrow
      of 11 haematologically normal controls and 40 patients with acute myeloid
      leukaemia (AML). Two novel transcripts of the receptor were identified, both were
      minor components and are unlikely to be of major physiological significance. We
      could find no evidence for altered levels of expression of these transcripts in
      the AML patients. In addition, only one point mutation was detected in the 40
      patients screened by RT-PCR-SSCP, a C-->A substitution at nucleotide 2088 which
      changes a threonine to asparagine in the transmembrane domain and is probably a
      polymorphism. These results suggest that abnormalities in the G-CSFR are uncommon
      in AML.

PMID- 8652370
TI  - Interleukin-6 inhibits the chemotaxis of human malignant plasma cell lines.
AB  - The chemotaxis of human malignant plasma cells is promoted by two extracellular
      matrix proteins (ECMs): fibronectin (FN) and laminin (LN). We examined the effect
      of the supernatant from a bone marrow stroma cell line, KM-101, on the chemotaxis
      of human malignant plasma cell lines to assess the chemotaxis-regulatory roles of
      the bone marrow microenvironment. Five human malignant plasma cell lines, FR4ds,
      OPM-1ds, U266/B1, RPMI-8226 and ARH-77 showed different profiles of the
      expression of beta 1 integrins of FN and LN receptors. FR4ds, OPM-1ds and U266/B1
      cells showed chemotaxis promoted by FN (ChFN) and LN (ChLN). ARH-77 cells showed
      ChFN but not ChLN. RPMI-8226 cells did not show either ChFN or ChLN. The
      supernatant from KM-101 cells inhibited the chemotaxis of each of these cell
      lines regardless of whether the chemotaxis was promoted by FN or LN. Among the
      cytokines produced by KM-101 cells, it was postulated that IL-6 mediated this
      inhibitory effect because anti-IL-6 monoclonal antibody (MoAb) and anti-IL-6
      receptor MoAb significantly reversed the inhibition. Recombinant IL-6 (rIL-6)
      also exhibited a similar inhibitory effect. Because anti-gp130 MoAb significantly
      reversed the chemotaxis inhibitory effect of rIL-6, the inhibitory signal is
      probably transduced via the signal transducing receptor component, gp130. The
      chemotaxis-regulatory effect is another previously unrecognized function of this
      pleiotropic cytokine, IL-6. High levels of IL-6 in the bone marrow
      microenvironment of patients with multiple myeloma appears to be favourable for
      the localization of myeloma cells there.

PMID- 8652371
TI  - Nuclear translocation of protein kinase C-alpha and -zeta isoforms in HL-60 cells
      induced to differentiate along the granulocytic lineage by all-trans retinoic
      acid.
AB  - We investigated whether members of the protein kinase C (PKC) family of enzymes
      were involved in the nuclear events underlying granulocytic differentiation
      induced by 10(-6) M all-trans retinoic acid (ATRA) in HL-60 cells. PKC activity
      was analysed by using a serine substituted specific peptide which enabled the
      evaluation of the whole catalytic activity of both Ca2+ -dependent and Ca2+ 
      independent PKC isoforms. In parallel, the subcellular distribution of various
      PKC isoforms was evaluated by Western blot, immunoprecipitation and in situ
      immunocytochemistry analyses. The level of PKC catalytic activity in the nuclei
      of HL-60 cells significantly (P < 0.01) and progressively increased from 1 h of
      ATRA treatment onwards. Consistently, PKC-alpha and -zeta showed a striking and
      selective accumulation inside the nucleus upon treatment with ATRA. On the other
      hand, PKC-beta I and -beta II, the only two other isoforms present at nuclear
      level, did not show any significant modification upon ATRA treatment. The
      remaining PKC isoforms were not detectable inside the nucleus and showed only
      modest and non-significant variations, also in whole cell homogenates, upon ATRA
      treatment, except PKC-delta which showed a progressive down-regulation. Our data
      suggest that a selective nuclear translocation of PKC-alpha and -zeta might be
      involved in the process of granulocytic differentiation induced by ATRA in HL-60
      cells.

PMID- 8652372
TI  - Effect of the protein tyrosine kinase inhibitor genistein on normal and leukaemic
      haemopoietic progenitor cells.
AB  - Receptor and nonreceptor protein tyrosine kinases (PTKs) play a key role in the
      control of normal and neoplastic cell growth. The availability of PTK inhibitors
      prompted us to evaluate the effects of genistein, a natural inhibitor of PTKs, on
      in vitro colony formation by normal multilineage colony-forming units (CFU-Mix),
      erythroid bursts (BFU-E), granulocyte-macrophage colony-forming units (CFU-GM),
      long-term culture-initiating cells (LTC-IC) and acute myelogenous leukaemia
      colony-forming units (CFU-AML). Continuous exposure of normal marrow and blood
      mononuclear non-adherent cells, blood CD34+CD45RA- cells, and leukaemic blasts to
      increasing doses of genistein (1-100 microM) resulted in a statistically
      significant (P < or = 0.05) dose-dependent suppression of CFU-Mix, BFU-E, CFU-GM
      and CFU-AML growth. Regression analysis showed that growth inhibition was
      linearly related to genistein concentration. Genistein dose causing 50%
      inhibition (ID50) of CFU-AML was significantly lower compared to CFU-GM ID50 for
      marrow (19 v 32 microM, P < or = 0.017), unseparated blood (19 v 44 microM, P <
      or = 0.028) or CD34+CD45RA- blood (19 v 36, P < or = 0.04). Preincubation of
      leukaemic blasts with genistein (200 microM) for 1-2h confirmed that CFU-AML were
      significantly more sensitive than normal marrow and blood CFU-GM to genistein.
      Preincubation conditions which maximally suppressed leukaemic and normal colony
      growth spared a substantial percentage of marrow (29 +/- 4%) and blood (40 +/-
      3%) LTC-IC. In conclusion, our data demonstrate that: (a) genistein strongly
      inhibits the growth of normal and leukaemic haemopoietic progenitors; (b) growth
      inhibition is dose- and time-dependent; (c) leukaemic progenitors are more
      sensitive than normal progenitors to genistein-induced growth inhibition; (d)
      genistein exerts a direct toxic effect on haemopoietic cells while sparing a
      substantial proportion of LTC-IC. The potent CFU-AML growth inhibition associated
      with the relative resistance of normal LTC-IC strongly supports the use of
      genistein for marrow purging.

PMID- 8652373
TI  - The effect of granulocyte colony-stimulating factor (G-CSF) on the degranulation
      of secondary granule proteins from human neutrophils in vivo may be indirect.
AB  - Granulocyte colony-stimulating factor (G-CSF) was administered at a dose of 7.5
      or 10 micrograms/kg s.c. once daily for 6d (days 1-6) to two groups consisting of
      eight and six healthy volunteers. The administration of G-CSF resulted in a rapid
      decrease in neutrophil counts and serum levels of the secondary granule protein,
      human neutrophil lipocalin (HNL) after 30 min, followed by a recovery and gradual
      increase within 180 min. The number of circulating neutrophils and plasma and
      serum levels of neutrophil secondary granule proteins were dramatically elevated
      on day 2 (1 d after the administration of G-CSF) and stayed so until day 7. The
      plasma levels of HNL and lactoferrin (LF) showed a biphasic pattern with peaks at
      day 2 and days 5-7, and remained highly elevated at day 12. The serum levels of
      HNL and LF increased rapidly (about 8-fold and 6-fold, respectively) on day 2 and
      stayed elevated until day 7, subsequently returning to baseline levels. At day 5,
      neutrophil release induced in vitro by f-MLP was significantly enhanced. The
      cellular contents of HNL and LF were reduced to about 50% of levels before G-CSF
      administration at day 5. The release of lactoferrin and HNL, but not of
      myeloperoxidase (MPO), was slightly enhanced after preincubation of isolated
      normal neutrophils with G-CSF in vitro, but no obvious release of these proteins
      was observed with G-CSF alone. The administration of G-CSF resulted in a dramatic
      increase in the alkaline phosphatase (AP) activity in the plasma membrane, with
      maximal activity occurring at day 5. Furthermore, during administration of G-CSF,
      TNF-alpha in plasma increased about 25-fold. TNF-alpha started to rise at day 2
      and peaked at day 6. After discontinuation of G-CSF the levels of TNF-alpha
      gradually decreased. The elevated levels of TNF-alpha (tumour necrosis factor
      alpha) were temporally correlated to the other signs of neutrophil activation. GM
      CSF and IL-8, however, were not detected in plasma. Our data suggest that G-CSF
      affects the neutrophils not only directly but also indirectly by the induction of
      the production of other cytokines such as TNF-alpha.

PMID- 8652374
TI  - CD30 ligand is expressed on resting normal and malignant human B lymphocytes.
AB  - CD30, a member of the tumour necrosis receptor superfamily, is physiologically
      expressed on a subpopulation of T helper cells in normal individuals but is also
      expressed on several malignant and virally transformed cells. Its ligand (CD30L)
      is a pleiotropic cellular transmembrane protein that can induce cell death in
      several CD30+ cell lines. CD30L expression has been reported on activated human
      peripheral blood T lymphocytes and macrophages but not on B cells. Here we show
      that the CD30L is expressed on resting normal and on malignant B cells in
      addition to both CD4+ and CD8+ subsets of activated T cells, making it the second
      tumour necrosis family member, in addition to the CD27 ligand, that can be
      expressed on both T and B cells. These findings raise the possibility that the
      CD30L has a role in B-cell/T-cell communication and that B and T cells are likely
      to be involved in the growth regulation of CD30+ tumours.

PMID- 8652375
TI  - Successful treatment of virus-associated haemophagocytic syndrome in adults by
      cyclosporin A supported by granulocyte colony-stimulating factor.
AB  - Two young adult patients with typical virus-associated haemophagocytic syndrome
      (VAHS) were treated with cyclosporin A and granulocyte colony-stimulating factor
      (G-CSF). Clinical symptoms such as high fever and malaise disappeared rapidly
      with concurrent haematological improvement in both patients. The serum levels of
      interleukin-6 (IL-6), soluble IL-2 receptor, tumour necrosis factor and
      macrophage-CSF were all elevated before treatment but that of G-CSF was not. The
      dramatic effect of cyclosporin A observed implies that it efficiently and rapidly
      suppresses the cytokine storm caused by dysregulated T cells in VAHS. In
      addition, G-CSF may promote haematological recovery without syndrome regression.
      We believe that the combination of cyclosporin A and G-CSF may be effective, at
      least in selected patients with VAHS. Further studies are required to confirm its
      role as first-line therapy for adult patients with VAHS.

PMID- 8652376
TI  - Composition of the intra-erythroblastic precipitates in thalassaemia and
      congenital dyserythropoietic anaemia (CDA): identification of a new type of CDA
      with intra-erythroblastic precipitates not reacting with monoclonal antibodies to
      alpha- and beta-globin chains.
AB  - Ultrathin sections of bone marrow cells from two patients with homozygous beta
      thalassaemia, two patients with haemoglobin H (HbH) disease, a patient with
      congenital dyserythropoietic anaemia (CDA) type III and two patients with severe
      congenital dyserythropoietic anaemia of an unusual type were reacted with mouse
      monoclonal antibodies against various globin chains and the reaction visualized
      using a gold-labelled goat antibody against mouse IgG. The multiple rounded intra
      erythroblastic inclusions found in homozygous beta-thalassaemia reacted with the
      monoclonal antibody against alpha-globin chains but not beta-globin chains, thus
      confirming that they consisted of precipitated alpha-globin chains. The branching
      intra-erythroblastic inclusions found in HbH disease and CDA type III reacted
      with the monoclonal antibody against beta-globin chains but not alpha-globin
      chains, indicating that they consisted of precipitated beta-globin chains. The
      two patients with severe CDA had been transfusion-dependent since infancy, had a
      normal alpha:beta globin chain synthesis ratio or parents with normal red cell
      indices, displayed prominent dysplastic changes in their erythroblasts, and had
      intra-erythroblastic inclusions resembling those seen in homozygous beta
      thalassaemia. However, unlike those in beta-thalassaemia, the inclusions in these
      two patients did not react with the monoclonal antibody against either alpha- or
      beta-globin chains. The inclusions reacted with antibody against zeta-globin
      chains, but detailed studies in one of the patients indicated that the antigen
      involved was not zeta-globin. These patients have features not reported in the
      condition known as dominantly inherited inclusion body beta-thalassaemia and
      appear to suffer from a novel type of CDA in which the intra-erythroblastic
      inclusions may consist of some non-globin protein or structurally-abnormal alpha
      globin chains.

PMID- 8652377
TI  - Aplastic anaemia and paroxysmal nocturnal haemoglobinuria: a study of the GPI
      anchored proteins on human platelets.
AB  - Twenty-six consecutive patients with acquired aplastic anaemia (AA) and nine
      patients with de novo paroxysmal nocturnal haemoglobinuria (PNH) were included in
      this study. In these 35 patients a GPI-anchored molecule defect at the platelet
      surface was investigated by flow-cytometry. Platelets from eight out of the nine
      patients with de novo PNH were found to be deficient for the GPI-anchored
      molecule CD55, CD58 and CD59. We also detected a GPI-anchored molecule defect on
      monocytes, granulocytes, and erythrocytes in all patients with de novo PNH. Among
      the 26 AA patients, a GPI defect was detected on platelets in five patients.
      Interestingly, these five patients were also found to have a GPI-anchored
      molecule defect on erythrocytes, whereas in 10 patients the GPI-anchored molecule
      defect was only detected on monocyte and polymorphonuclear (PMN) cells.

PMID- 8652378
TI  - Identification and characterization of an inherited mutation of PIG-A in a
      patient with paroxysmal nocturnal haemoglobinuria.
AB  - Analysis of the X-linked gene PIG-A from haemopoietic cells of a female PNH
      patient showed a homozygous C-55-T substitution that caused replacement of
      arginine with tryptophan at codon 19. Aval restriction analysis of PIG-A cDNA
      demonstrated that the patient was homozygous for this mutation, whereas her
      mother was heterozygous and her father was hemizygous. Flow cytometry, however,
      showed normal expression of glycosyl phosphatidylinositol anchored proteins on
      blood cells of the patient's mother and father. Therefore the C-55-T mutation is
      an inherited sequence variant that does not account for the PNH phenotype of this
      patient.

PMID- 8652379
TI  - Cytogenetic clonality analysis: typical patterns in myelodysplastic syndrome and
      acute myeloid leukaemia.
AB  - The cell morphology and karyotype of bone marrow samples from 24 patients with
      myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) were studied
      simultaneously with a combined technique of May-Grunwald-Giemsa (MGG) staining
      and fluorescence in situ hybridization (FISH) with chromosome-specific DNA
      probes. This enabled us to investigate cell lineage involvement in three
      malignant conditions: MDS (n = 12), leukaemia-transformed MDS (LT-MDS) (n = 5)
      and de novo AML (n = 7). In MDS we found blasts and often significant proportions
      of mature granulocytic and erythroid cells to be cytogenetically abnormal.
      Percentages of granulocytic and erythroid cells with cytogenetic aberrations were
      generally less than those of blasts. These data support the involvement of a
      transformed pluripotent stem cell that has retained maturation abilities. In two
      patients with chronic myelomonocytic leukaemia (CMMoL) the clonal involvement of
      monocytes was predominant. Results in the five patients with LT-MDS were similar
      to those in MDS. In the bone marrow of five of the seven de novo AML patients the
      cytogenetic abnormalities were restricted to the blasts and did not include the
      more mature granulocytic or erythroid populations. In the other two patients with
      AML, both with a t(8;21) and a loss of the Y chromosome, high percentages of
      mature neutrophils were cytogenetically abnormal. These patterns of clonal
      lineage involvement in MDS, LT-MDS, t(8;21) AML and AML appear typical and may be
      of clinical use, for example, for distinguishing LT-MDS from de novo AML in newly
      presenting patients.

PMID- 8652380
TI  - Myelodysplastic syndrome with karyotype abnormality is associated with elevated F
      cell production.
AB  - A sensitive F-cell assay has been used to examine the production of fetal
      haemoglobin (Hb F) in a group of 77 adult patients with myelodysplastic syndrome
      (MDS), and a control group composed of 100 normal blood donors. Although the mean
      F-cell percentage in the MDS group (6.0%) is not statistically different from
      that in the normal blood donors (3.1%), a higher proportion of myelodysplastic
      patients have elevated F-cell values and the magnitude of the increases is
      greater than that observed in blood donors. In order to investigate the
      association further, the karyotypes of the MDS patients have been examined. 13/21
      (61.9%) of the MDS patients with karyotypic abnormalities have F-cell values >
      5%, compared to only 6/56 (10.9%) of the MDS patients with a normal karyotype and
      11/100 (11%) of the blood donors. The observed difference in the distributions of
      F cells between the two subgroups of patients with MDS is highly significant (P <
      0.0001).

PMID- 8652381
TI  - Alloreactive CD4+ T lymphocytes can exert cytotoxicity to chronic myeloid
      leukaemia cells processing and presenting exogenous antigen.
AB  - Existing evidence supports that CD4+ T lymphocytes play a role in the graft
      versus-leukaemia (GVL) reaction after allogeneic bone marrow transplantation
      (BMT) for chronic myeloid leukaemia (CML), not only as initiators of the immune
      response but also as effectors of GVL. In BMT between HLA-identical pairs this
      CD4-mediated GVL would require CML cells to process and present antigens through
      MHC class II molecules. To investigate whether CML cells are capable of
      processing and presenting antigens, and suitable targets for CD4+ T-cell-mediated
      cytotoxicity, we generated HLA-DR1-restricted CD4+ cytotoxic T-cell clones that
      specifically recognized tuberculous purified protein derivative (PPD). We have
      shown that CML cells and B lymphoblastoid cell line (B-LCL) cells but not PHA
      blasts from patients with CML processed exogenous antigen, PPD, and induced
      proliferative and cytotoxic CD4+ T-cell responses. Antigen presentation was
      blocked by antibodies to HLA-DR but not to MHC class I and by treatment with
      chloroquine and brefeldin. This indicates that CML cells use a classic MHC class
      II antigen processing pathway to present PPD antigens to CD4+ T cells.
      Cytotoxicity to CML was shown by antibody blocking studies to be mediated mainly
      through fas antigen. These findings indicate that donor CD4+ T cells alone are
      sufficient to mediate GVL effects following allogeneic BMT for CML.

PMID- 8652383
TI  - Molecular alterations of IL-6R, lck and c-myc genes in transforming monoclonal
      gammopathies of undetermined significance.
AB  - We studied the molecular alterations of IL-6R, lck and c-myc genes in the tumour
      cells of 50 patients with multiple myeloma (MM) and 20 patients with monoclonal
      gammopathies of undetermined significance (MGUS). Southern blot analysis revealed
      a 5.3 kb IL-6R amplified band by digestion with EcoRI and HindIII in three MGUS
      patients, but no IL-6R gene alteration was found in MM patients. BamHI digestion
      revealed a 6.2 kb rearranged band of the lck gene in two MGUS patients with IL-6R
      amplification. In one MGUS patient we detected a rearrangement upstream of the
      lck coding region. Myc rearrangement was observed in three MM and two MGUS
      patients who showed coexistent lck rearrangement and IL-6R amplification. These
      molecular alterations were detected in the MGUS patients with an IgA monoclonal
      component, who showed a rapid progression into aggressive MM. Myc rearrangement
      seems to be associated with a small group of a clinically aggressive MM at
      diagnosis, secreting IgA or k light chains. Multiple rearrangements and/or
      molecular alterations are likely to occur at the time of MGUS-IgA transformation
      into aggressive MM and myc rearrangement may promote a positive pressure for
      transformation and progression. MM tumourigenesis remains a heterogenous
      multistep process involving the deregulation of many genes and gene products.

PMID- 8652382
TI  - CD34 selections from myeloma peripheral blood cell autografts contain residual
      tumour cells due to impurity, not to CD34+ myeloma cells.
AB  - Malignant cells in haemopoietic autografts can contribute to post-transplant
      relapse. Engraftment of myeloma patients with CD34+ peripheral blood progenitors
      selected from total autografts reduces the number of tumour cells infused by 2.7
      4.5 logs. Residual tumour cells detected in CD34+ selected cells may be due to
      selection impurity or the existence of malignant CD34+ progenitors. In three
      patients we evaluated the CD34 purity and tumour load of total autografts, CD34+
      progenitors selected with immunomagnetic beads and highly purified CD34+
      progenitors obtained in two rounds of selection (combining magnetic with flow
      cytometry activated cell sorting) to determine the cause of residual tumour cells
      in CD34 selections. Using allele-specific oligonucleotides (ASO) complementary to
      the unique Ig heavy chain sequence (CDRIII region) of the malignant clone, semi
      quantitative ASO-PCR was capable of detecting one malignant cell in 10(4)-10(5)
      normal white blood cells. Selection of CD34+ cells from bone marrow (BM) with
      approximately 20% malignant plasma cells resulted in a 1.4 log reduction of
      tumour burden. Using two-colour flow-cytometry we observed CD34-, BB4+ malignant
      plasma cells contaminating this CD34 selection. Prior to sorting, peripheral
      blood cell autografts (PBCA) contained approximately 0.1% malignant cells.
      Selection of > 99% pure CD34+ cells using immunomagnetic beads (Dynal) resulted
      in an approximate 2 log reduction of malignant cells, but residual tumour cells
      were still detectable. ASO-PCR detected no malignant cells in > 99.9% pure CD34+
      peripheral blood progenitors obtained with two rounds of selection (combining
      magnetic with flow cytometry activated cell sorting). We conclude that CD34+
      malignant cells are not detectable in myeloma PBCA and that residual tumour cells
      in CD34 selections are due to contaminating CD34-negative cells.

PMID- 8652384
TI  - P16INK4A gene homozygous deletions in human acute leukaemias with alterations of
      chromosome 9.
AB  - Acute leukaemias are characterized by nonrandom chromosomal aberrations which are
      often strictly related to the inactivation of tumour suppressor genes (TSGs).
      Alterations at the short arm of chromosome 9 have been reported in a remarkable
      percentage of acute lymphoblastic leukaemias (ALL) and have been suggested to
      cause the loss of activity of the putative TSG, p16INK4A (MTS1/CDKN2) gene. In
      order to evaluate the correlation between this gene inactivation and visible
      cytogenetic abnormalities, we have investigated p16INK4A homozygous gene
      deletions in 10 paediatric acute leukaemias of different cell lineages which
      demonstrated karyotype aberrations involving chromosome 9. Moreover, the
      dimension of the genetic alteration was evaluated by studying the loss of
      heterozygosity of two highly polymorphic markers of chromosome 9p, namely alpha
      interferon (IFNA) and D9S104, and the deletion of 5'-methylthioadenosine
      phosphorylase (MTAPase) gene. Finally, the deletion of a gene belonging to
      p16INK4A family, the p18 gene, was analysed in these acute leukaemias. Our
      results demonstrated that: (1) the biallelic loss of p16INK4A gene is strictly
      related to a specific immunophenotype, namely ALL of T-cell lineage; (ii) no
      significant correlation exists between alterations at chromosome 9p level and the
      homozygous deletions of p16INK4A gene; and (iii) p18 gene was not deleted in the
      examined cases. These findings suggest a possible correlation between the T
      lymphocyte phenotype and the expression of p16INK4A gene. Moreover, the absence
      of MTAPase activity seems to be a valuable marker of p16INK4A gene inactivation,
      thus indicating that the deleted chromosomal area on 9p21 very frequently
      involves the MTAPase gene.

PMID- 8652385
TI  - A comparison of busulphan versus total body irradiation combined with
      cyclophosphamide as conditioning for autograft or allograft bone marrow
      transplantation in patients with acute leukaemia. Acute Leukaemia Working Party
      of the European Group for Blood and Marrow Transplantation (EBMT).
AB  - We retrospectively compared the outcome in patients in the EBMT database
      transplanted for acute leukaemia from January 1987 to January 1994 who received
      busulphan and cyclophosphamide (BU/CY) as a pretransplant regimen versus those
      who received cyclophosphamide and total-body irradiation (CY/TBI). The patients
      were matched for type of transplant (autologous bone marrow transplantation
      (ABMT) versus allogeneic (BMT)), diagnosis (acute lymphoblastic leukaemia (ALL)
      or acute myeloid leukaemia (AML)), status (early (first complete remission, CR-1)
      versus intermediate (second or later remission, first relapse)), age, FAB
      classification for AML, prevention of graft-versus-host disease and year of
      transplantation. In ABMT recipients (matched paired 530 x 2) with ALL CR-1, AML
      CR-1 and AML intermediate disease, transplant-related mortalities (TRM) relapse
      incidence (RI) and leukaemia-free survival (LFS) did not differ significantly in
      patients treated with BU/CY or CY/TBI. However, in ABMT recipients with ALL
      intermediate disease, the probability of relapse was 82 +/- 5% (+/- 95%
      confidence interval) in the BU/CY group compared to 62 +/- 6% in the CY/TBI group
      (P = 0.002) and the 2-year leukaemia-free survival 14 +/- 4% and 34 +/- 6%,
      respectively (P = 0.002). In BMT recipients of bone marrow from HLA-identical
      siblings (matched paired 391 x 2), the TRM, RI and LFS did not differ
      significantly between the two treatments in all groups. In particular, the 2-year
      LFS in patients with AML CR-1 was 64 +/- 3% in those treated with BU/CY (n = 237)
      compared to 66 +/- 3% in those given CY/TBI (n = 237). In all groups the findings
      were confirmed in a multivariate analysis of prognostic factors. Veno-occlusive
      disease (VOD) of the liver (P < 0.05) and haemorrhagic cystitis (P < 0.001) was
      more common in the BU/CY group compared to the CY/TBI group for ABMT and BMT
      patients. In conclusion, BU/CY and CY/TBI as pretransplant regimens gave similar
      results in all situations, except ABMT for ALL intermediate stages with more than
      2 years from diagnosis to transplantation, where a lower RI and a higher LFS were
      associated with CY/TBI.

PMID- 8652386
TI  - Tretinoin induces bone marrow collagenous fibrosis in acute promyelocytic
      leukaemia: new adverse, but reversible effect.
AB  - In 11/13 acute promyelocytic leukaemia (APL) cases treated with tretinoin (RA) we
      observed RA-induced inaspirable collagenous fibrosis of the bone marrow. To study
      the mechanism of RA on collagen production, we cultured a human bone marrow
      derived stromal cell line and an osteoblastic cell line with RA in vitro. 10(-7)
      and 10(-6)M of RA stimulated collagen production. Clinical and experimental
      observation may be important to understand this adverse effect of RA as it is
      useful in cancer chemoprevention as well as treatment for APL. This adverse
      effect is spontaneously reversible after stopping RA or following chemotherapy.

PMID- 8652387
TI  - The detection of rhodamine 123 efflux at low levels of drug resistance.
AB  - Although many cell models of multidrug resistance (MDR) have been developed, most
      have been high-resistance models which generate up to 100-fold increases in drug
      resistance. However, the drug concentrations required to achieve these levels of
      resistance are much higher than those found in vivo. In this paper we describe
      the development of a cell model that reflects the resistance levels that are
      likely to be found clinically. We then investigated the methods used to detect
      MDR1 expression at these low levels of drug resistance. We demonstrated that the
      immunological and PCR-based methods are unable to detect increased MDR1
      expression in cells with a < 5.2- and 6.5-fold increase in vinblastine
      resistance, respectively, in our drug-resistant sublines. The rhodamine 123 (Rh
      123) efflux assay was able to discriminate the vinblastine-sensitive parent cells
      from all the vinblastine-resistant sublines, including cells with a 1.7-fold
      increase in resistance. However, this assay is non-specific to the MDR1 gene and
      may detect the activity of other drug efflux proteins such as the MDR-associated
      protein (MRP). Our results show that the Rh 123 efflux assay is able to detect
      the activity of drug efflux proteins such as the P-glycoprotein, MRP or other
      efflux systems at the low levels of drug resistance that are likely to be
      attained in vivo.

PMID- 8652388
TI  - Molecular diagnosis of t(11;14) in mantle cell lymphoma using two-colour
      interphase fluorescence in situ hybridization.
AB  - t(11;14) is observed in up to 70% of mantle cell lymphoma (MCL) cases and is
      therefore an important diagnostic element. In routine practice, detection of
      t(11;14) by conventional cytogenetic techniques is hindered by the low yield and
      quality of tumour metaphases. Molecular techniques (Southern blot, PCR) are
      unable to detect a large number of 11q13 breakpoints due to scattering over
      distances up to 1 Mb. Using 23 MCL patients with karyotypically determined
      t(11;14) and eight negative controls, we have devised a two-colour interphase
      FISH assay for detection of the 14q + chromosome. We chose an 11q13 probe
      telomeric to the major 11q13 translocation cluster sites and an IGH probe
      centromeric of the 14q32 breakpoints. This method detected the translocation in
      all 23 t(11;14) positive patients, with an overall average of 60% nuclei showing
      colocalized signals. Widespread application of this technique will constitute an
      important diagnostic aid in clinical management of MCL patients. Since FISH is a
      convenient method for retrospective analysis of large numbers of patient
      specimens, this method should contribute to an accurate estimation of t(11;14)
      frequency in MCL and other chronic B-cell malignancies and consequently to their
      better nosological characterization.

PMID- 8652389
TI  - An aggressive subtype of B-CLL is characterized by strong CD44 expression and
      lack of CD11c.
AB  - In a retrospective study based on 107 B-CLL patients, the expression of the
      adhesion molecules CD44, CD11a, CD11b, CD11c, CD18, CD25 and CD54 was analysed in
      bone marrow cryostat sections by immunohistochemistry. CD44 expression clearly
      identified two subgroups of B-CLL patients with different clinical course. In
      particular, CD44-positive patients presented with advanced disease, more often
      displayed a diffuse pattern of bone marrow infiltration, and had a worse
      prognosis. 33/61 patients positive for CD44 died within the observation period
      compared to 7/46 patients negative for CD44 (P = 0.0012). Multivariate analysis
      emphasized the independent prognostic value of CD44 expression for overall
      survival (P = 0.022). In contrast, patients positive for CD11c showed a longer
      survival, with 9/40 patients dying within the observation period compared to
      31/67 negative for CD11c (P = 0.0013). Patients lacking CD11c were in advanced
      Rai and Binet stage. Multivariate analysis confirmed CD11c as a relevant
      independent prognostic marker (P = 0.033). Moreover, CD11c was able to separate
      patients with significantly different prognosis in the subgroup of CD44-positive
      cases. 4/18 patients positive for CD44 and CD11c died before median survival time
      was reached. Patients positive for CD44 but negative for CD11c had an adverse
      prognosis: 29/43 patients died, median survival time was 33.4 months. Our results
      indicate that CD44 positivity and CD11c negativity are associated with more
      advanced disease and worse prognosis in B-CLL and suggest CD44-positive/CD11c
      negative cases represent a more aggressive form of the disease.

PMID- 8652390
TI  - p53 tumour suppressor gene and RAS oncogenes: molecular analysis in the chronic
      and leukaemic phases of essential thrombocythaemia.
AB  - A panel of 51 cases of essential thrombocythaemia (ET), in chronic or leukaemic
      phase, was investigated for p53 gene and RAS oncogenes mutations by PCR-SSCP
      direct sequencing. No RAS oncogenes mutations were detected, but p53 mutations
      were identified in three cases: 1/27 cases (approximately 4%) in chronic phase
      not undergoing chemotherapy, 1/19 cases (approximately 5%) in chronic phase
      undergoing chemotherapy, and 1/5 cases (20%) which had progressed to leukaemia.
      Our results suggest that: (1) p53 gene mutations occur sporadically in the
      chronic phase of ET, independent of chemotherapy, and may contribute to the
      progression to the leukaemic phase in a limited number of ET patients; (2) the
      RAS genes family does not seem to be involved in the pathogenesis of ET, unlike
      other bcr/abl negative chronic myeloproliferative diseases (CMPDs).

PMID- 8652391
TI  - Matched and mismatched unrelated donor bone marrow transplantation for juvenile
      chronic myeloid leukaemia.
AB  - Juvenile chronic myeloid leukaemia (JCML) is a rare haematological condition of
      childhood curable only by bone marrow transplantation (BMT). We report our
      experience using matched and mismatched unrelated donor BMT for JCML in five
      patients. Although the procedure is hazardous in terms of toxicity and relapse,
      two patients are alive and disease-free 28 and 49 months post BMT.

PMID- 8652392
TI  - Isochromosome 12p in two cases of acute myeloid leukaemia without evidence of
      germ cell tumour.
AB  - An isochromosome 12p [i(12p)], typical of germ cell tumours (GCT), has, to date,
      been observed in 10 cases of acute myeloid leukaemia (AML) or myelodysplastic
      syndrome, nine of which had concurrent or preceding GCT. We report two i(12p)
      positive AML cases without clinical evidence of GCT. One patient with AML-M1 had
      two i(12p) as the only cytogenetic anomalies. In the other case of AML-M3 with
      t(15;17)(q22;q11-12) at diagnosis, the i(12p) was clearly a secondary
      rearrangement since it first appeared at relapse and always accompanied the
      t(15;17). Our results suggest that i(12p) does not always indicate neoplastic
      disease of germ cell origin.

PMID- 8652393
TI  - Establishment of cell lines derived from chronic lymphocytic leukaemic cells by
      transfection with myc and ras.
AB  - Seventy-one samples from 37 cases of chronic lymphocytic leukaemia (CLL) were
      transfected with human c-myc and/or N-ras. In only three cases did the CLL cells
      further transform and four cell lines were established following transfection
      with myc plus ras. Surface marker profiles and immunoglobulin gene rearrangement
      studies confirm that all cell lines have arisen from the original CLL cells. The
      cell lines are EBNA positive but negative for EBV latent membrane protein (LMP).
      Karyotyping of the cell lines is as follows: SA4, 46,XY; SA4-2, 45,XY, 20; RK4,
      48,XY,+ 5,+ 12; EHC4, 47,XY, t(14;18)(q32;q21), + 12. Although the majority of
      CLL cells appear resistant to transformation in vitro with myc and ras with the
      methods used, it does occur in a small percentage (about 8%). There appeared to
      be no correlation between the ability to transform in vitro and clinical
      behaviour.

PMID- 8652394
TI  - Acquired von Willebrand factor deficiency during high-dose infusion of
      recombinant factor VIII.
AB  - Constant infusion of factor VIII (FVIII) into patients with haemophilia A after
      major surgery has been recommended as optimal treatment to avoid peaks and
      valleys in the circulating levels of FVIII and to allow the use of much lower
      doses of FVIII than are historically required. One of our young patients with
      severe (< 0.01 U/ml FVIII) haemophilia suffered a subdural haematoma for which he
      received treatment with 815190 recombinant FVIII (rFVIII) units over a period of
      52d. 2 weeks after admission, because of low FVIII levels and the presence of
      FVIII inhibitors, the infusion rate was increased to > 100 U/kg/h for 14d. During
      this time the FVIII level fluctuated between 0.6 and 4.2 U/ml. For some period it
      was not possible to detect ristocetin co-factor activity in this patient's plasma
      and the von Willebrand factor (VWF) level and VWF multimer pattern resembled
      those of a patient with von Willebrand's disease. Subsequently, when the rFVIII
      dose was increased 2-fold, this was not reflected by the plasma level of FVIII
      although antibodies were not detected. The data suggest that the prolonged
      infusion of very high levels of rFVIII which is deficient in von Willebrand
      factor can result in depletion of VWF from existing stores, producing a
      laboratory picture which is consistent with the diagnosis of von Willebrand's
      disease. Further, in the absence of complexing with VWF, FVIII appears to be
      cleared from the circulation at an increased rate. This is expensive and
      potentially compromising. Therefore, when administering very high doses of FVIII
      concentrates devoid of VWF for prolonged periods of time, ristocetin cofactor and
      VWF levels should be monitored.

PMID- 8652395
TI  - High incidence of anti-FVIII antibodies against non-coagulant epitopes in
      haemophilia A patients: a possible role for the half-life of transfused FVIII.
AB  - The occurrence of antibodies (Abs) capable of inhibiting factor VIII (FVIII)
      coagulant activity is a severe complication in haemophilia A, leading to the
      inhibition of transfused FVIII activity. It is not known whether, or to what
      extent, post-transfusion antibodies may also arise against non-coagulant
      epitopes. Therefore we set up a system capable, in theory, to detect all the
      FVIII-induced antibodies by use of an enzyme-linked immunoassorbent assay (ELISA)
      based on coating human recombinant FVIII onto polystyrene microtitre plates.
      Serum samples from 23 patients affected by haemophilia A of different gravity (22
      referred to our Centre and one to the Bari Centre) were analysed. Although only
      one patient was positive at Bethesda assay, the presence of antibodies in ELISA
      was detected in 39% of patients in variable degrees; transfusion with FVIII was
      found to induce a raise in antibody titre, arguing in favour of the specificity
      of the phenomenon. The clinical relevance of these non-inhibitory antibodies was
      evaluated in three patients; although half-life did not show any change in the
      patients without or with low amount of antibodies, FVIII clearance was found
      enhanced in the patient displaying high titre antibodies. We propose detection of
      anti-FVIII antibodies by ELISA when routinely assessing haemophilia A patients.

PMID- 8652396
TI  - Activated protein C resistance: a comparison between two clotting assays and
      their relationship to the presence of the factor V Leiden mutation.
AB  - Resistance to the anticoagulant effect of activated protein C (APC resistance), a
      frequent abnormality in patients with a history of venous thrombosis, is known to
      be due, in the large majority of cases, to the presence of an abnormal factor V:
      the factor V Leiden. It is reasonable to surmise that screening for this
      abnormality should be performed with a clotting method for APC resistance, before
      submitting the patients with abnormal results to DNA analysis. The present study
      was performed on 216 individuals enrolled at the Bologna centre, of which 189
      were unrelated patients with a history of juvenile venous thromboembolism and 27
      were relatives with or without thrombosis. APC resistance was first measured in
      Bologna by a standard commercial method and then, in Leiden, by an in-house
      method: DNA analysis was performed in those cases in which at least one of the
      clotting methods was abnormal. The data obtained confirm the good performance and
      the optimal positive predictive value for the Leiden mutation (100%) of the
      Leiden in-house clotting method. Performance of the commercial method was less
      satisfactory but markedly improved by expressing the data in relation to the
      values simultaneously obtained with a normal plasma pool. Even with optimal data
      expression, however, the positive predictive value of the commercial method,
      versus DNA analysis, did not exceed 88%. It is concluded that further
      standardization of the commercial method here evaluated is necessary before it
      can be widely adopted for the screening of APC resistance and prediction of the
      presence of factor V Leiden.

PMID- 8652397
TI  - Characterization of an acquired IgG inhibitor of coagulation factor XIII in a
      patient with systemic lupus erythematosus.
AB  - An acquired IgG inhibitor to factor XIII was identified in a 30-year-old
      Vietnamese woman with systemic lupus erythematosus. The IgG fraction was isolated
      from plasma by chromatography on an agarose gel column and by protein G
      adsorption. The anti-factor XIII activity, identified within the IgG fraction,
      inhibited factor XIII from both normal plasma (a2b2) and platelets (a2). A normal
      level of the b subunit was measured by immunoelectrophoresis of the patient's
      plasma, but the a subunit was not detected. These results suggested the presence
      of an IgG immunoglobulin which recognized the a subunit and interfered with its
      activity.

PMID- 8652398
TI  - Circulating thrombopoietin level in chronic immune thrombocytopenic purpura.
AB  - The circulating thrombopoietin (TPO) level in 43 patients with chronic immune
      thrombocytopenic purpura (ITP) was examined by an ELISA system. The TPO level
      (mean +/- SD) in ITP patients was mildly elevated (1.86 +/- 1.17 fmol/ml)
      compared to that in normal subjects (0.76 +/- 0.21), and was within the normal
      range in 30% of ITP patients. In contrast, the TPO level in patients with
      aplastic anaemia was very high, 12.35 +/- 6.42 fmol/ml. There was no correlation
      between TPO level and platelet count in ITP patients. Splenectomy was performed
      in two ITP patients, after which platelet counts increased to normal levels and
      TPO levels showed a transient increase. These data suggest that reactive TPO
      production against thrombocytopenia in ITP is small when compared to that in
      aplastic anaemia. Relative endogenous TPO deficiency may play some role in the
      pathophysiology of thrombocytopenia in ITP patients.

PMID- 8652399
TI  - Transfusion-related acute lung injury due to HLA-A2-specific antibodies in
      recipient and NB1-specific antibodies in donor blood.
AB  - Transfusion-related acute lung injury (TRALI) is a hazardous but little-known
      complication of blood transfusion, characterized by non-cardiogenic lung oedema
      after blood transfusion. Leucoagglutinating antibodies in the donor plasma are
      considered to play a central role in the pathogenesis of TRALI but no recommended
      procedure currently exists for their detection, and most of them have not yet
      been well characterized. Serum samples of two patients who have developed TRALI
      within 30 min of blood transfusion and the sera of the involved blood donors were
      investigated for leucocyte antibodies by granulocyte immunofluorescence,
      granulocyte agglutination and lymphocytotoxicity assays using typed test cells.
      Suspected specificities of the detected antibodies were confirmed by a
      luminoimmunoblot assay and the antigen capture assay MAIGA. One case was
      associated with granulocyte agglutinating anti-HLA-A2 antibodies in the
      recipient's (i.e. patient's) own blood and the other with donor-related non
      agglutinating antibodies directed against the granulocyte-specific antigen NB1.
      Leucocyte incompatibility between donor and recipient was shown in both cases by
      crossmatching and typing of the incompatible cells for the appropriate antigen.
      The results show that TRALI is associated not only with donor- but also with
      recipient-related leucocyte antibodies. In addition to leucoagglutinating
      antibodies, non-agglutinating granulocyte-specific antibodies can be also
      involved. For immunodiagnosis, sera from both must be investigated by a
      combination of granulocyte and lymphocyte (HLA) antibody screening tests and
      leucocyte incompatibility verified by crossmatching.

PMID- 8652400
TI  - Detection of human parvovirus B19 DNA in plasma pools and blood products derived
      from these pools: implications for efficiency and consistency of removal of B19
      DNA during manufacture.
AB  - The polymerase chain reaction (PCR) assay was used to detect human parvovirus B19
      DNA in 38 blood products and start plasma pools from five different
      manufacturers. The products examined were albumin, factor VIII, intravenous
      (i.v.) and intramuscular (i.m) immunoglobulin batches. The majority of pools from
      all the manufacturers had detectable B19 DNA (64/75:85%; ranging from 60% to 100%
      for individual manufacturers). B19 DNA was found in 3/12 albumin samples, in 7/7
      factor VIII samples, 3/15 IVIG samples and 3/4 IMIG samples. The levels of B19
      DNA in pools varied from 10(2) to 10(9) genome equivalents/ml, whereas the levels
      in products varied from 10(2) to 10(6) genome equivalents/ml, but there was no
      clear relationship between the levels of B19 DNA in start pools and final
      products. The levels of B19 DNA varied between different batches of the same
      product from a single manufacturer, possibly due to small variations in the
      processing parameters. In addition, there was some indication from the study of
      IVIG samples that treatment at low pH may result in removal of PCR-detectable B19
      DNA.

PMID- 8652402
TI  - Kell typing by allele-specific PCR (ASP).
AB  - The Kell blood group system is important in transfusion medicine, and the Kell
      antigen (K1) is probably second in importance to Rh D as an immunogen in
      alloimmunized pregnancies which cause haemolytic disease of the newborn. The K/k
      (K1/K2) blood group polymorphism has been recently defined. A point mutation
      changes Thr193 (k) to Met193 (K) in the Kell glycoprotein. The mutation which
      creates K destroys a consensus N-glycan addition site. We describe a simple PCR
      test for K blood group typing. The test is based on the use of an allele-specific
      K-primer. We have shown the test to give results in complete concordance with
      serologically defined Kell blood group status using 65 genomic DNA samples
      derived from both amniocytes and peripheral blood lymphocytes. The test is
      suitable for the prenatal determination of Kell type.

PMID- 8652401
TI  - The genetic basis of a new partial D antigen: DDBT.
AB  - The Rh system, the most polymorphic system on red cells, is genetically
      controlled by two different but highly homologous genes on chromosome 1. The RHCE
      gene encodes different RhCcEe polypeptides and the RHD gene encodes D antigens.
      It is well established that in D negative individuals the RHD gene is either
      absent or grossly deleted. The D antigen comprises at least nine serologically
      defined D epitopes. The D antigen can be divided into different partial D
      categories, reflecting a different pattern of specific D epitopes. In this study
      a newly defined partial D antigen, DDBT, was studied. D epitope mapping revealed
      the presence of D epitopes 6/7 and 8 and the absence of the other D epitopes. The
      molecular basis of this phenotype was studied by Southern blotting, by RHD typing
      using the polymerase chain reaction (RHD-PCR) and by sequence analysis of Rh
      transcripts. The DBT phenotype appeared to be encoded by a hybrid RHD gene, in
      which exons 5, 6 and 7 (and possibly the identical exon 8) were replaced by the
      corresponding exons of the RHCE gene. From this study it may be concluded that D
      epitopes 1, 2, 3, 4, 5 and 9 are dependent on the presence of RHD exons 5, 6, and
      7.

PMID- 8652403
TI  - Splenic lymphoma with villous lymphocytes: clinical presentation, biology and
      prognostic factors in a series of 100 patients. Groupe Francais d'Hematologie
      Cellulaire (GFHC).
AB  - The diagnosis of splenic lymphoma with villous lymphocytes (SLVL) was assessed by
      a panel of cytologists in a series of 100 patients. Clinical and biological
      characteristics were analysed in relation to prognosis. SLVL is a chronic B-cell
      lymphoproliferative disorder characterized by splenomegaly and the presence, in
      peripheral blood, of lymphocytes with "villous' projections. The cytological
      diagnosis can be difficult in patients without an absolute lymphocytosis which
      was observed in 24% of cases. B-cells expressed CD19+, CD20+, CD22+, CD24+ and
      DBA44+, whereas the expression of CD5, CD10 and CD25 was usually negative. SLVL
      is a disease of the elderly with a relatively benign clinical course. In the
      present series the 5-year overall survival was 78%. Deaths in 15 patients were
      related to disease progression or treatment (nine cases). Patients with a
      leucocyte count > 30 x 10(9)/1 or lymphocyte count < 4 x 10(9)/1 or initially
      treated with chemotherapy had significantly (P < 0.001) lower overall survival
      than other patients. From these findings, treatment abstention should be
      considered in patients with favourable prognostic factors; on the other hand, the
      efficacy of conventional chemotherapy remains to be evaluated in patients with
      unfavourable prognostic factors.

PMID- 8652404
TI  - RhG-CSF-mobilized peripheral blood haemopoietic progenitors reside in G0/G1 phase
      of cell cycle independently of the expression of myeloid antigens.

PMID- 8652405
TI  - Pulsed high-dose dexamethasone in the treatment of refractory immune
      thrombocytopenia.

PMID- 8652406
TI  - Transfusion-associated graft-versus-host disease (TA-GVHD) in fludarabine-treated
      patients: is it time to irradiate blood component?

PMID- 8652407
TI  - mex-1 and the general partitioning of cell fate in the early C. elegans embryo.
AB  - It is thought that at least some of the initial specification of the five somatic
      founder cells of the C. elegans embryo occurs cell-autonomously through the
      segregation of factors during cell divisions. It has been suggested that in
      embryos from mothers homozygous for mutations in the maternal-effect gene mex-1,
      four blastomeres of the 8-cell embryo adopt the fate of the MS blastomere. It was
      proposed that mex-1 functions to localise or regulate factors that determine the
      fate of this blastomere. Here, a detailed cell lineage analysis of 9 mex-1
      mutants reveals that the fates of all somatic founder cells are affected by
      mutations in this gene. We propose that mex-1, like the par genes, is involved in
      establishing the initial polarity of the embryo.

PMID- 8652408
TI  - The Xenopus laevis homeobox gene Xgbx-2 is an early marker of anteroposterior
      patterning in the ectoderm.
AB  - In a search for homeobox genes expressed during early Xenopus development, we
      have isolated a gene which appears to be the Xenopus cognate of the mouse Gbx-2
      gene. Expression of Xgbx-2 is first detectable by in situ hybridization at the
      midgastrula stage when it is predominantly expressed in the dorsolateral
      ectoderm, with a gap in expression at the dorsal midline. By the end of
      gastrulation and during neurulation, Xgbx-2 is expressed dorsolaterally in the
      neural ectoderm and laterally and ventrally in the epidermis with sharp anterior
      expression borders in both tissues. The anteriormost expression in the neural
      ectoderm persists throughout the early stages of development, and was mapped to
      the region of rhombomere 1, with an anterior expression border in the region of
      the midbrain-hindbrain boundary. Thus Xgbx-2 is expressed anterior to the Hox
      genes. Xgbx-2 expression is induced by retinoic acid (RA) in animal caps, and RA
      treatment of whole embryos expands and enhances Xgbx-2 expression in the
      ectoderm. We suggest a role for Xgbx-2 in establishing the midbrain-hindbrain
      boundary, which appears to separate early neurectodermal regions expressing genes
      that are positively and negatively regulated by RA.

PMID- 8652409
TI  - Cloning and expression studies of cDNA for a novel Xenopus cadherin (XmN
      cadherin), expressed maternally and later neural-specifically in embryogenesis.
AB  - From a Xenopus tailbud cDNA library, we obtained the cDNA for a novel cadherin
      which was named as XmN-cadherin (Xenopus maternally expressed neural cadherin).
      The cDNA consisted of 3690 bp and encoded 922 amino acid residues. XmN-cadherin
      preserved five extracellular cadherin motifs, a single transmembrane domain, and
      a cytoplasmic domain, and was closely related by its sequence to R- and N
      cadherin. In the adult frog, XmN-cadherin mRNA was detected strongly in ovary,
      testis, brain, eye, and kidney, and weakly in stomach, and intestine. In the egg,
      the mRNA occurred as a maternal mRNA at a relatively high level, and its level
      became very low by the neurula stage, then increased steadily thereafter.
      Dissection experiments with 8-cell stage and neurula stage embryos revealed that
      the maternally inherited mRNA was relatively uniformly distributed within the
      embryo. By a sharp contrast, whole mount in situ hybridization revealed that the
      zygotically expressed mRNA occurred almost exclusively in neural tissues such as
      brain, the anterior part of spinal cord, and the optic and otic vesicles. Thus,
      XmN-cadherin appears to have at least triple functions; it probably contributes
      in early embryos to cell-type non-specific cell adhesion, but in post-neurula
      embryos may be responsible for the development and/or maintenance of anterior
      neural tissues, and may be used in adult frog for the development and/or
      maintenance of neural, endodermal and reproductive organs.

PMID- 8652410
TI  - Developmental expression and differential regulation by retinoic acid of Xenopus
      COUP-TF-A and COUP-TF-B.
AB  - COUP-TFs (Chicken Ovalbumin Upstream Promoter Transcription Factors) have been
      proposed to be negative regulators of retinoid receptor-mediated transcriptional
      activation. In a previous paper we reported the cloning of a Xenopus (x) COUP-TF
      (Matharu, P.J. and Sweeney, G.E. (1992) Biochim. Biophys. Acta 1129, 331-334).
      Here we describe the cloning of a second xCOUP-TF. Amino acid sequence comparison
      between these two Xenopus COUP-TFs revealed a high level of similarity. Extensive
      amino acid sequence conservation was found among all Drosophila, Xenopus,
      zebrafish and mammalian COUP-TF genes examined. Phylogenetic tree analyses
      indicate that the vertebrate COUP-TFs fall into three classes. The two Xenopus
      COUP-TF genes show similar temporal expression patterns: both are expressed from
      the end of gastrulation. In situ hybridization studies reveal complex expression
      patterns in the developing central nervous system (CNS), besides expression in
      the eye and in some mesodermal tissues. Retinoic acid (RA) treatment enhances
      xCOUP-TF-A expression in neurula stage embryos, whereas the expression of xCOUP
      TF-B is inhibited during the same developmental period. The strictly conserved
      amino acid sequences and the strong similarities between the expression patterns
      of the two different xCOUP-TFs on the one hand, and other vertebrate COUP-TF
      homologues on the other, make it likely that COUP-TFs have a conserved role in
      patterning the nervous system.

PMID- 8652411
TI  - The restricted expression pattern of the POU factor Oct-6 during early
      development of the mouse nervous system.
AB  - Oct-6 is a POU transcription factor that is thought to play a role in the
      differentiation of cells of neuroectodermal origin. To investigate whether the
      Oct-6 protein could play a role in the establishment of neuroectoderm in vivo we
      studied the expression of the Oct-6 protein during early mouse development.
      Expression is first observed in the primitive ectoderm of the egg cylinder stage
      embryo. In gastrulating embryos, Oct-6 protein is found in the extra-embryonic
      ectoderm of the chorion and the anterior ectoderm of the embryo proper. As
      development proceeds, Oct-6 expression becomes more restricted to the anterior
      medial part of the embryo until Oct-6 positive cells are observed only in the
      neural groove of the headfold stage embryo. In the late headfold stage embryo,
      Oct-6 expression is detected in the neuroepithelium of the entire brain and later
      is restricted to a more ventral and anterior position. As the anterior neuropore
      closes, Oct-6 protein is detected in a segment-like pattern in the mid-and
      forebrain. Thus, the expression pattern of the Oct-6 gene agrees with a role for
      the Oct-6 protein in the establishment and regional specification of the
      neuroectoderm in vivo. The two waves of widespread induction of the Oct-6 gene,
      one in the primitive ectoderm and another in the primitive brain, both followed
      by a progressive restriction in the expression patterns suggest a mechanism for
      the regulation of the gene.

PMID- 8652412
TI  - Specific localization of zebrafish hsp90 alpha mRNA to myoD-expressing cells
      suggests a role for hsp90 alpha during normal muscle development.
AB  - Members of the eukaryotic hsp90 family function as important molecular chaperones
      in the assembly, folding and activation of a select group of cellular signalling
      molecules and transcription factors. Several of the molecules with which hsp90
      interacts, such as the bHLH transcription factor myoD, are known to be important
      regulators of developmental events in vertebrates. However, little information is
      available in support of any specific role for hsp90 in developing embryos in
      vivo. In this study, we provide the first in vivo evidence that the hsp90 alpha
      gene may play a role in the process of myogenesis. We show that constitutive
      hsp90 alpha mRNA in zebrafish embryos is restricted primarily to a subset of
      cells within the somites and pectoral fin buds which also express myoD.
      Furthermore, expression of the hsp90 alpha gene is down-regulated along with myoD
      in differentiated muscles of the trunk at a time when levels of mRNA encoding the
      muscle structural protein alpha-tropomyosin remain high. No hsp90 alpha mRNA is
      detectable within the CNS at control temperatures. In contrast, heat shock
      induced expression of the hsp90 alpha gene occurs throughout the embryo at all
      stages of development examined. The expression patterns strongly suggest that the
      hsp90 alpha gene plays a specific role in the normal process of myogenesis in
      addition to providing protection to all cells of the embryo during periods of
      environmental stress.

PMID- 8652413
TI  - Female germ cells of Drosophila require zygotic ovo and otu product for survival
      in larvae and pupae respectively.
AB  - Mutations in the genes ovo or otu can cause abnormal proliferation of XX germ
      cells, which leads to so-called ovarian tumors, or they can lead to the
      elimination of XX germ cells, such that adult females possess empty ovaries.
      Males carrying ovo or otu mutations are unaffected. To find out when this sexual
      dimorphism affects germ cells, we analyzed the requirement of embryos and larvae
      for zygotic ovo and otu products. We found that ovo is required for the survival
      of XX germ cells during larval stages, while XX germ cells lacking otu survive
      until metamorphosis. Furthermore, we found no sex-transformed mutant larval germ
      cells and no evidence for an early sex-specific vital process acting in germ
      cells of the embryo, contrary to what had been suggested earlier.

PMID- 8652414
TI  - Expression of a novel member of estrogen response element-binding nuclear
      receptors is restricted to the early stages of chorion formation during mouse
      embryogenesis.
AB  - Members of the nuclear hormone receptor gene family of transcription factors have
      been shown to be expressed in characteristic patterns during mouse organogenesis
      and postnatal development. Using an RT-PCR based screening assay, we have
      identified nuclear receptors expressed in embryonal carcinoma stem cells. One of
      the cDNAs characterized, mERR-2, was found to be expressed exclusively during a
      narrow developmental window in trophoblast progenitor cells between days 6.5 and
      7.5 post coitum (p.c.). From 8.5 days p.c. and onwards, the mERR-2 gene activity
      evaded detection as analysed by in situ hybridization. We also show that the mERR
      2 gene product and the estrogen receptor share a common target DNA-sequence
      recognition specificity unique among members of the gene family. Furthermore,
      efficient homodimerization and DNA-binding of the orphan receptor mERR-2 was
      found to be dependent on interaction with the heat shock protein 90, a molecular
      chaperone hitherto recognized to interact only with the steroid hormone receptor
      subgroup of nuclear receptors. Based on our results we suggest that the mouse
      orphan receptor mERR-2 has the potential to regulate overlapping gene networks
      with the estrogen receptor and may participate in signal transduction pathways
      during a short developmental period coinciding with the formation of the chorion.

PMID- 8652416
TI  - QRI, a retina-specific gene, encodes an extracellular matrix protein exclusively
      expressed during neural retina differentiation.
AB  - Neural retina development results from growth arrest of neuroectodermal
      precursors and differentiation of postmitotic cells. The QRI gene is specifically
      expressed in Muller retinal glial cells. Its expression coincides with the stage
      of withdrawal from the cell cycle and establishment of differentiation and is
      repressed upon induction of retinal cell proliferation by the v-src gene product.
      In this report, we show that the QR1 gene encodes several glycosylated proteins
      that are secreted and can either associate with the extracellular matrix or
      remain diffusible in the medium. By using pulse-chase experiments, the 100-103
      kDa forms seem to appear first and are specifically incorporated into the
      extracellular matrix, whereas the 108 and 60 kDa polypeptides appear later and
      are detected as soluble forms in the culture medium. We also report that
      expression of the QR1 gene is developmentally regulated in the chicken. Its mRNA
      is first detectable at embryonic day 10, reaches a maximal level at embryonic day
      15 and is no longer detected at embryonic day 18. Immunolocalization of the QR1
      protein in chicken retina sections during development shows that expression of
      the protein parallels the differentiation pattern of post-miotic cells (in
      particular Muller cells and rods), corresponding to the two differentiation
      gradients in the retina: from the ganglion cell layer to the inner nuclear layer
      and outer nuclear layer, and from the optic nerve to the iris. At embryonic day
      10, expression of the QR1 protein(s) is restricted to the optic nerve region and
      the inner nuclear layer, colocalizing with Muller cell bodies. As development
      proceeds, QR1 protein localization spreads towards the iris and towards the outer
      nuclear layer, following Muller cell elongations towards the photoreceptors.
      Between embryonic days 16 and 18, the QR1 protein is no longer detectable in the
      optic nerve region and is concentrated around the basal segment of the
      photoreceptors in the peripheral retina. Our results suggest a role for the QR1
      gene product in the process of growth arrest and establishment of photoreceptor
      differentiation.

PMID- 8652415
TI  - Active complex formation of type I and type II activin and TGF beta receptors in
      vivo as studied by overexpression in zebrafish embryos.
AB  - We have investigated the involvement of activin receptors and TGF beta type I
      receptor in zebrafish development. Overexpression of either full-length or a
      truncated form of mouse ActR-IIA interferes with the development. Different
      splice variants of mouse ActR-IIB have distinct effects; ActR-IIB4 induces
      abnormal embryos, whereas ActR-IIB2 does not. Activin and TGF beta type I
      receptors can induce axis duplications. Co-expression of ActR-IA or ActR-IB with
      the type II activin receptors results in a synergistic increase of the frequency
      of axis duplication. Moreover, ActR-IIB2 is synergistic with ActR-IA and ActR-IB,
      demonstrating that ActR-IIB2 can interact with the zebrafish ligand.
      Overexpression of TGF beta R-I with ActR-IIA or ActR IIB4 results in a
      synergistic increase in frequency of abnormal embryos, whereas in combination
      with ActR-IIB2 no such increase occurs.

PMID- 8652417
TI  - Modelling human memory: connectionism and convolution.
AB  - The mathematical operation of convolution is used as an associative mechanism by
      several recent influential models of human memory. Convolution can be used to
      associate two vectors (representing items to be remembered) into a memory trace
      vector in one operation. An approximation to either of the input vectors can then
      be retrieved, using the other vector as a probe. Recent convolution-based memory
      models have accounted for a wide range of data. Connectionist models may have
      greater potential for providing developmental accounts, but the architectures
      that have been most widely used to account for developmental phenomena cannot
      perform one-trial learning and this has limited their use as models of human
      memory. We show that a connectionist-like architecture can learn, using a
      gradient-descent algorithm, to perform single-trial learning in a similar manner
      to convolution. The solution that the network finds leads to less variable
      retrieval than does convolution. Furthermore, the network can learn to carry out
      the convolution operation itself. This provides a link between connectionist and
      convolution approaches, and a basis for models with many of the attractions of
      both connectionist and convolution approaches.

PMID- 8652418
TI  - A survey of theory and methods of invariant item ordering.
AB  - In many testing situations, ordering the items by difficulty is helpful in
      analysing the testing data; examples include intelligence testing, analysis of
      differential item functioning, person-fit analysis, and exploring hypotheses
      about the order in which cognitive operations are acquired by children. In each
      situation, interpretation and analysis are made easier if the items are ordered
      by difficulty in the same way for every individual taking the test, i.e. the item
      response functions do not cross. This is an invariant item ordering. In this
      paper we review a class of non-parametric unidimensional item response models in
      which the ordinal properties of items (and persons) can be studied, and survey
      both old and new methods for the investigation of invariant item ordering in
      empirical data sets. Our model formulation derives in particular from the work of
      Holland & Rosenbaum (1986), Junker (1993) and Mokken (1971). We survey methods
      based on the work of Mokken (1971), Rosenbaum (1987a, b), and Sijtsma & Meijer
      (1992), and we also discuss some new proposals for checking invariant item
      ordering. When violations are detected, these methods allow a rough assessment of
      where on the latent scale the item response functions cross. We also study
      similarities and differences between these various methods and provide guidelines
      for their use. Finally, the methods are illustrated with data from a
      developmental psychology experiment in which the ability to draw inferences about
      transitive relations is explored.

PMID- 8652419
TI  - Estimating minimum allele frequencies for DNA profile frequency estimates for PCR
      based loci.
AB  - In order that there can be confidence that DNA profile frequency estimates will
      not place undue bias against a defendant, 2 methods are described for estimating
      minimum allele frequency bounds for PCR-based loci. One approach estimates
      minimum allele frequencies for VNTR and STR loci using sample size and the
      observed heterozygosity at a locus, while the second approach, appropriate for
      loci typed with allele-specific oligonucleotide probes, is based only on sample
      size. The use of a minimum allele frequency enables compensation for sparse
      sampling of infrequent alleles in population databases.

PMID- 8652420
TI  - DNA typing of cellular material on perforating bullets.
AB  - DNA typing of cellular debris from perforating bullets was investigated following
      shooting experiments. A total of 14 perforating gunshots were fired into 9
      calves. PCR typing of tissue fragments was done using bovine-specific primers
      flanking a 247 bp segment within the bovine lactoglobulin gene. Positive
      amplification results were obtained for all 9 hollow point (HP) and all 5 full
      metal jacket (FMJ) bullets. In contrast to HP bullets the smooth surfaces of the
      FMJ bullets did not have visible biological material, which resulted in weaker
      bands in the DNA analysis compared to HP bullets. Tissue seemed to accumulate at
      the base of the projectiles. Due to the lack of a suitable marker in bovines,
      only a species identification was carried out on the DNA from tissue on the
      bullets. The small amount of DNA extract (up to 5%) required for specification is
      promising for the successful application of a set of short tandem repeat (STR)
      systems for individualization in humans. By individualizing tissue on perforating
      bullets, the bullet and the victim it passed through can be linked. This can
      assist the investigation of gunshot deaths, especially when several persons are
      involved in a gun fight.

PMID- 8652421
TI  - Structural variation in the alleles of a short tandem repeat system at the human
      alpha fibrinogen locus.
AB  - This paper reports the sequences of 22 alleles identified at the HumFGA (human
      alpha fibrinogen) short tandem repeat locus in the British Caucasian and Afro
      Caribbean populations. Alleles at the lower end of the observed size range were
      found to increase in size by 4-bp increments with the repeat unit following the
      pattern TC(TCTT)n. However, 5 alleles were identified that differed in size by 2
      bp from the 4 bp increment as a result of the deletion of a TC dinucleotide, or
      the addition of a TT dinucleotide, immediately prior to the 1st repeat unit.
      Alleles at the upper end of the observed size range were found to have a more
      complex repeat unit structure and also exhibited duplication of both 5' and 3'
      flanking sequences. A nomenclature for the designation of HumFGA alleles is
      proposed on the basis of this sequence data.

PMID- 8652422
TI  - Evaluation of MHS-5 in detecting seminal fluid in vaginal swabs.
AB  - Vaginal swabs taken in 211 cases of alleged sexual assault were examined for
      seminal vesicle-specific antigen (SVSA) using an MHS-5-ELISA (SEMA kit). The
      results were compared with those obtained by sperm detection by means of light
      microscopy and the acid phosphatase reaction (ACP), using Phosphatesmo-KM papers.
      Especially in fresher samples (duration of storage between 10 days and 2 1/2
      months), a high degree of correlation was observed between the results of light
      microscopic and MHS-5 methods. Several cases with positive MHS-5 showed
      concurrent positive ACP reactions, even though no spermatozoa had been seen
      microscopically. The results are displayed in the light of time elapsed between
      the alleged assault and examination of the swabs. The longest time span after the
      alleged assault in which MHS-5 yielded a positive result was 47 h; in this case
      spermatozoa were also seen microscopically. SVSA is not totally stable in vaginal
      swabs stored over long (9 months to 5 1/2 years) periods of time. Furthermore,
      results in eight penile swabs are reported. MHS-5 is a useful tool for medico
      forensic semen detection in vaginal swabs, probably even in cases of azoospermic
      or aspermia.

PMID- 8652423
TI  - Trichloroethanol is not a metabolite of alpha chloralose.
AB  - Head space capillary gas chromatography was used to detect alpha chloralose and
      its potent metabolite, trichloroethanol in clinical and forensic cases. Although
      alpha chloralose was identified in blood and urine in all cases, trichloroethanol
      was never detected. In a fatal case the alpha chloralose concentration in blood
      was 151.3 mg/l. It was concluded that trichloroethanol is not a metabolite of
      alpha chloralose.

PMID- 8652424
TI  - Techniques in facial identification: computer-aided facial reconstruction using a
      laser scanner and video superimposition.
AB  - A facial image was reconstructed from the skull, part of a complete skeleton
      found in woodland, of a male person who hanged himself from a tree. In addition,
      video superimposition was carried out with antemortem photographs of a person
      suspected of being the victim, and a good match was obtained. In a further case,
      a cheaper video-transparency superimposition was carried out, with identity later
      being confirmed on the basis of dental records. The techniques and the problems
      encountered are discussed. According to our experience, 3D computer
      reconstruction and video superimposition have a useful role in the process of
      identification, particularly in the early stages of an investigation and when
      other more definitive methods may not be available.

PMID- 8652425
TI  - Radiological findings in gunshot wounds caused by hunting ammunition. An
      experimental study.
AB  - Experimental gunshots were made with hunting ammunition using a dummy model made
      of skin and foam rubber as the target. After penetration of intermediate targets
      of wood by the bullets, the characteristics of the wounds changed and their
      dimensions increased. The morphology of the wounds presented a very varied
      spectrum. When the gunshots had initially passed through wood 50 mm thick,
      radiographs of the skin showed a quantity of metallic residues between 10 microns
      and 1 mm. The metallic particles were wiped off the surface of the projectile by
      the target itself, whereby the best "wipe-off effect" was achieved with skin. The
      experimental findings suggest that the formation of the fine metallic residues is
      analogous to the development of the bullet wipe formed by lead bullets. Larger
      fragments flew into the target independently of the bullet and depending on the
      distance between the intermediate and final targets. A case example is
      documented.

PMID- 8652426
TI  - Identification of vegetable species in gastric contents using HPLC.
AB  - Identification of 16 vegetables, focusing on the influence of digestion in the
      stomach, was carried out on the basis of the types of flavonoids detected on
      chromatograms using HPLC. Among the 12 vegetables for which flavonoids were
      detected, the chromatographic patterns of the flavonoids in digested vegetables
      were the same as those of the corresponding raw vegetables, making it possible to
      identify the species of vegetables even after digestion. In our analysis, 5 mg of
      a freeze-dried sample was found be an adequate quantity to enable the detection
      of flavonoids. Brief practical cases are also described.

PMID- 8652427
TI  - Immunohistochemical identification of syncytiotrophoblastic cells and
      megakaryocytes in pulmonary vessels in a fatal case of amniotic fluid embolism.
AB  - The histological diagnosis of amniotic fluid embolism (AFE) is based on finding
      amniotic fluid components in the pulmonary microvasculature. In addition to the
      distinctive constituents of AFE, placental and decidual tissue fragments as well
      as isolated trophoblastic cells and megakaryocytes are potentially detectable
      within pulmonary vessels. The identification of single syncytiotrophoblastic
      cells (STC), and their differentiation from circulating megakaryocytes (MK)
      within the lumen of small and medium-sized pulmonary vessels is difficult by
      classical morphological methods. In a fatal case of AFE, we have successfully
      detected the simultaneous presence of STC and MK in the pulmonary
      microvasculature by means of a panel of specific monoclonal (CD61-GpIIIa, beta
      hCG) and polyclonal (FVIII-vW, hPL) antibodies. The immunohistochemical analysis
      for identification of STC and MK should provide more precise data on their
      incidence and distribution in physiological and pathological conditions as well
      providing new insights into their physiopathological implications and their
      correlation with AFE and other gynaecological complications.

PMID- 8652428
TI  - Fibromuscular dysplasia of coronary arteries as a rare cause of death.
AB  - A case of fibromuscular dysplasia of the coronary arteries in a 15-year-old boy
      is reported. After a quarrel involving no violence the boy suddenly suffered from
      ventricular fibrillation, collapsed and was initially successfully defibrillated.
      After 37 days of deep unconsciousness the boy died of bronchopneumonia. The cause
      of the ventricular fibrillation was clarified only after histological
      investigations. Fibromuscular dysplasia of the coronary arteries with narrowing
      was found, which has very occasionally been described in the literature. However,
      its localization in the A-V node artery, as described here, only seems to have
      been observed once.

PMID- 8652429
TI  - Suicide by sharp instruments: a case of harakiri.
AB  - A case of suicide by harakiri is described. The position of the subject, the
      absence of the shirt and the abdominal L-shape cut agreed well with the formal
      procedure of harakiri. The characteristics of the stab wounds present on the
      right-hand side of the neck confirmed the assumption of self-infliction and
      excluded, from a legal point of view, murder by consent.

PMID- 8652430
TI  - Sudden unexpected death in childhood due to eosinophilic myocarditis.
AB  - A 12-year-old boy with no previous serious medical history experienced abdominal
      discomfort and chest pains for 5 days and suddenly died. The autopsy revealed
      diffuse and extensive infiltration of eosinophils into the myocardium, with
      poorly formed granulomas and few fibrotic changes. The necrotic changes was so
      extensive that Charcot-Leyden crystals formed. The other visceral organs had no
      specific pathologic changes except for mild lymphocytic infiltration with an
      increase in goblet cells in the bronchial areas and eosinocytosis in the blood
      vessels. An initial viral infection seemed to have caused subsequent eosinophil
      activation due to an allergic condition. Eosinophilic myocarditis is a rare cause
      of sudden death in apparently healthy children. Cardiac toxicity of eosinophils
      is, however, well established and dominates the ultimate prognosis of patients
      with complicated eosinophilia.

PMID- 8652431
TI  - Analysis of STR-PCR products with high-resolution denaturing PAGE.
AB  - The Pharmacia Multiphor II horizontal electrophoresis chamber is a widespread
      tool for analysis of PCR products in forensic casework. Up to date, however,
      there is no protocol for successfully running high-resolution denaturing PAGE
      (poly-acrylamide gel electrophoresis) on a horizontal electrophoresis chamber. We
      modified the electrophoresis conditions to make this possible.

PMID- 8652432
TI  - F13B and CD4 allele frequencies in an Austrian population sample.
AB  - Allele frequencies of the two short tandem repeat (STR) systems F13B and CD4 were
      determined in an Austrian population sample by PCR analysis. A total of 6 alleles
      for F13B and 8 alleles for CD4 could be observed in a population of 216 (F13B)
      and 198 (CD4) unrelated individuals. No significant deviations from Hardy
      Weinberg equilibrium were observed.

PMID- 8652433
TI  - Paternity evaluation in cases lacking a mother and nondetectable alleles.

PMID- 8652434
TI  - Primary peritonitis in previously healthy children--clinical and bacteriological
      features.
AB  - A prospective study of cases of primary peritonitis in children at the Korle-Bu
      Teaching Hospital, Accra, was undertaken to find diagnostic clinical and
      aetiological features of the disease. Seventeen children, 15 females and two
      males, diagnosed as primary peritonitis underwent laparotomy with peritoneal
      toiletting. Peritoneal exudate and high vaginal swabs (HVS) were taken under
      anaesthesia for bacteriological analysis. Patients were followed up for one
      month. Thirteen patients (70%) were aged between 6 to 10 years. Presentation was
      early (65% presented in less than 48hrs of onset of symptoms). The commonest
      presenting feature were fever (100%) and abdominal pain (100%) in the absence of
      headache (100%). All had classical signs of diffuse peritonitis. There was
      leucocytosis in 15 cases (88%). No bacterial growth was obtained in 50% of cases
      cultured. Pneumococcus was the commonest organism isolated (33.3%). Of the 7HVS
      taken, 4 did not yield any bacterial growth and 2 grew escherichia coli but no
      pneumococcus. There was no correlation between the bacteriological findings of
      the peritoneal exudate and the HVS. Post-operative complications were few,
      insignificant and there was no mortality recorded. Sixty five percent (11/17) of
      cases could be predicted from the clinical symptoms and signs. The results of
      this study do not support any aetiological theory of causation.

PMID- 8652435
TI  - Salivary gland neoplasms in Lagos, Nigeria.
AB  - This 14 year retrospective clinico-statistical analysis of 237 salivary gland
      neoplasms in Lagos, Nigeria, was undertaken with a view to providing further
      insights into the presentation of this disease in Africans. These neoplasms
      constituted 10.0% of all head and neck neoplasms, and were most frequently
      situated at the parotid gland (32.1%), the palate (24.9%) and the submandibular
      gland (19.4%). While parotid squamous cell carcinoma affected more males (41.2%)
      than females (4.7%) (P = 0.03); parotid mucoepidermoid carcinoma affected more
      females (53.3%) than males (11.8%) (P = 0.0149). Furthermore, labial salivary
      gland tumours affected more females (6.8%) than males (1.7%) (P = 0.05). At
      presentation, patients with palatal tumours were relatively more advanced in age
      (Peak = 6th decade) than those with parotid and submandibular tumours (Peak = 3rd
      decade). Males presenting with pleomorphic adenoma were relatively younger than
      their female counterparts. This is especially true of palatal pleomorphic
      adenoma. The recurrence rate for benign tumours was 4.8%. Majority of patients
      with malignant tumours (83.9%) had significant local extension, regional or
      distant metastasis at presentation. In twenty-nine percent of these patients with
      cancer, the disease was controlled for 1-5 years of follow-ups. However, a
      quarter of these patients with cancer defaulted the planned treatment regime
      because they could not afford the cost of treatment or they opted for traditional
      medical care.

PMID- 8652436
TI  - Controversies in community based education.
AB  - An attempt has been made to discuss in broad terms the subject of Community based
      Education. The approach adopted has been to critically examine five major
      controversial issues from opposing standpoints. Drawing from the literature and
      personal experience some light was shed on the worrying questions of each issue.
      Working conclusions upon which individuals can further ponder were reached. It is
      hoped that this presentation will refreshen the knowledge of some, answer many of
      the objective questions of a number of faculty staff (traditional and innovative)
      and stimulate the interest of those not yet exposed to Community Based Education.

PMID- 8652437
TI  - Salmonella typhi infection in Schistosoma mansoni infected mice.
AB  - Aspects of the biology of Salmonella typhi in concurrent infection with
      Schistosoma mansoni in mice was studied. 0.2ml of 1 x 10(6) per S. tyhi was
      inoculated intraperitoneally into mice harbouring different developmental stages
      of S. mansoni. The rate of bacterial growth, the distribution and duration of the
      bacterial infection in mice and in Schistosome, as well as the drug
      (Chloramphenicol) response of the bacteria were studied. S. typhi was cultured
      more frequently in schistosome-infected mice than in mice that were not infected
      with schistosme (P < 0.05). The bacterial growth rate was more rapid in mice
      infected with older schistosomes. Similarly the bacteria persisted much longer in
      mice infected with adult S. mansoni (8 weeks old) than those infected with
      younger (2 and 4 weeks old) schistosomes. The results of treatment of S. typhi
      infected mice previously infected with schistosomes of different ages made us to
      conclude that adult schistosomes (8 weeks old) are more relevant in the modified
      response to treatment of patients with S. typhi infection with concurrent
      Schistosoma mansoni infection.

PMID- 8652438
TI  - Psychiatric disorder among adolescents attending a psychiatric out-patient clinic
      in Accra, Ghana: a seven year review study (1987-1994).
AB  - The records of four hundred and fifty four (454) adolescent comprising of two
      hundred and thirty nine (239) female and two hundred and fifteen (215) male who
      had attended a psychiatric out-patient clinic in Accra over a seven year period
      were reviewed. Only 269 patients had psychiatric illness while 185 (40.7%) had
      purely physical illness with no associated psychiatric illness. Of the 269
      (59.3%) with psychiatric illness, there were 88 (32.7%) with functional psychoses
      consisting mainly of depression, 47 (17.5%), and psychoneurotic disorders 63,
      (23.4%); with personality disorders, 55 (20.4%) and with organic psychosis, 27,
      (10%) while 36, (13.4%) had psychiatric disorders. The aetiology of these
      disorders could be deduced from the profound biological events that occur during
      adolescence and the rapid period for personality growth and its associated
      emotional turmoil. It was suggested that due to the large numbers who attended
      the psychiatric out-patient clinic with non identifiable psychiatric illness,
      residency in general practice and internal medicine should include a posting in
      Psychiatry and that the national health care should pay a greater attention to
      mental health.

PMID- 8652439
TI  - The development and state of health and safety in the workplace in west Africa:
      perspectives from Nigeria.
AB  - Occupational health practice originated in Europe following the systematic work
      of Bernadino Ramazzini in Italy at the turn of the 17th century. It grew mostly
      under the notion of Industrial health, concentrating on the chemical, mechanical
      and social conditions of labourers as well as the work of the arts and trades,
      until the work of Charles Turner Thackrah in Britain broadened its understanding
      to include the professions and certain civic ways of living. In West Africa, as
      in most of the developing world, occupational health and safety practice came to
      us mostly as side products of the colonial company health work, in their attempt
      to fulfil the requirements of their national health laws to their citizens here.
      The first organised effort to boost occupational health and practice for the
      Africans among the Africans, and involving mainly Africans, came in the 1960s
      with the first African Conference on Occupational health in Africa in Lagos in
      1968. This process has gone on now, albeit rather slowly, until the citing of a
      Chair of Occupational health at the University of Ibadan by the Society of
      Occupational Health Physicians of Nigeria in the 1992/93 academic year. The
      health and safety in industries in Nigeria have however not been in anyway
      adequate from studies in that area, especially among the indigenous small and
      medium sized companies. This paper reviews these developments and proposes some
      suggestions on how to improve on the speed and accuracy of these developments,
      specifically in Nigeria; and by extrapolation, for the West Africa sub-region as
      well.

PMID- 8652440
TI  - The value of ultrasonic abdominal circumference in the prediction of gestational
      age.
AB  - The reliability of assessment of gestational age by ultrasonic fetal abdominal
      circumference in late pregnancy was evaluated in 204 Scottish women. The results
      showed that the method was very accurate, reliable and compared favourably with
      the data from other communities. The relationship between the target (gestational
      age) and the independent (abdominal circumference) variables as verified by a
      simple regression equation was a linear one. This method could therefore be very
      useful within the limit of two standard deviations of the mean in the prediction
      of gestational age and in the monitoring of fetal growth in late pregnancy.

PMID- 8652441
TI  - Profile of protein energy malnutrition amongst children under four years in urban
      areas of Rivers State.
AB  - The incidence of protein-energy malnutrition (PEM) in Rivers State children aged
      0-4 years has been studied. The incidence rate for a period of 30 months
      investigated gave a range of 3.97 to 4.81% of the total number of patients
      examined while the point prevalence gave a range of 0.13 to 0.99% of the total
      urban population of children aged 0-4 years. PEM was found to occur at a very low
      rate in Rivers State and persisted throughout the period investigated. PEM
      occurred in both males and females. The mean difference between the two sexes was
      not significant (p > 0.05) suggesting a non-sex dependent PEM within this age
      range.

PMID- 8652442
TI  - Prostatic tumours in Benin City, Nigeria.
AB  - Prostatic tumours accounted for 10.2% of all surgical specimens from male
      patients received in the Department of Anatomic Pathology of the University of
      Benin Teaching Hospital, Nigeria between 1973 and 1990. Nodular prostatic
      hyperplasia accounted for 83% of the cases and the peak age incidence was in the
      sixth decade of life. Prostatic cancer occurred in the remaining 17% of the cases
      and the peak age incidence for occurrence was in the seventh decade of life. The
      commonest malignant neoplasms encountered were adenocarcinomas, out of which 64%
      were-well 27% moderately-and 9% poorly-differentiated. Sixty-one adenocarcinomas
      were classified as cases of incidental carcinoma of the prostate. Rare
      histological variants of prostatic cancer encountered in the present study
      included a case each of mucinous carcinoma, transitional cell carcinoma and
      rhabdomyosarcoma.

PMID- 8652444
TI  - Antepartum haemorrhage: the influence of first trimester uterine bleeding.
AB  - The influence of first trimester uterine bleeding on the incidence of antepartum
      haemorrhage was evaluated in 374 patients. The incidence of abruptio placentae
      and placenta previa were 1.0% and 2.0% respectively in these patients. In the
      control group of patients who did not experience first trimester uterine
      bleeding, the incidence was 0.4% for abruptio placentae and 1.0% for placenta
      previa. The study indicates that first trimester threatened abortion is
      associated with about 21/2 fold risk of abruptio placenta and placenta previa
      than in the general obstetric population. The possible reasons for these
      incidences are discussed.

PMID- 8652443
TI  - Sexual behaviour and condom acceptance among Nigerian drivers.
AB  - A survey of 180 randomly selected drivers was carried out in June 1994 in Ilorin,
      Nigeria in order to gain information about high-risk sexual behaviours, to
      ascertain condom use and to identify obstacles to condom acceptance so as to
      facilitate the design of an intervention to prevent Sexually Transmitted
      Diseases/Acquired Immuno-deficiency Disease in this target population. Data was
      collected through face-to-face interview. Three-quarters of the respondents were
      married. Multiplicity of sexual partners including casual and commercial
      contacts, was common. Half of the respondents engaged in high-risk sexual
      behaviour and a high proportion of them (60 percent) reported unwillingness to
      use the condom. This was mainly due to general dislike and lack of knowledge of
      the method. Risk perception was poor. These findings support the need for male
      reproductive health services especially for this sub-population.

PMID- 8652445
TI  - Acute pancreatitis: current concepts and practice.

PMID- 8652446
TI  - [Recent problems on the endocrine and chemotherapy].
AB  - The endometrial carcinoma, as well as the breast cancers and some kinds of
      ovarian cancers, was considered to a hormone dependent carcinoma. Even if we
      tried to do the endocrine therapy using such as medroxy progesterone acetate
      (MPA), we could expect only 30% of anti-tumor effects on the endometrial
      carcinoma. Endocrine therapy was thought to have a different action mechanisms
      from the other anti-cancer drugs. Whereas cisplatin (CDDP) has strongly an
      effectiveness for ovarian cancers, but the drug resistance of cancer cells for
      CDDP was causing a serious problem. This paper will be discussed about the
      problems of the endocrine and chemotherapy from the point of view of cell cycle
      analysis. Additionally, we would like to describe about the new anticancer drug
      such as Taxol.

PMID- 8652447
TI  - Establishment of a melanoma cell line with metastatic characteristics.
AB  - We report here the establishment and characterization of a human melanoma cell
      line derived from the ascitic fluid of a patient with metastatic malignant
      melanoma with peritonitis carcinomatosa. This cell line was easily transplanted
      into nude mice. Flow cytometry and immunocytochemical analyses demonstrated that
      the cells expressed melanotransferrin and S-100 protein. Expression of cell
      adhesion and HLA molecules on the cells was also investigated. The results
      indicate that the cell line possesses some metastatic characteristics.

PMID- 8652448
TI  - [Significance of PUVA therapy for adult T-cell leukemia/lymphoma--PUVA therapy
      can induce apoptosis in leukemic cells].
AB  - PUVA therapy is known to be effective for treating cutaneous T-cell lymphoma
      (CTCL). Considering that adult T-cell leukemia/lymphoma (ATL) represents a T
      lymphocytic proliferative disorder similar to CTCL, it is likely that PUVA
      therapy is effective for treating ATL. We applied PUVA therapy to a 53 year old
      man with acute (i.e. crisis)-type ATL associated with generalized erythematous
      papules, and succeeded in achieving a complete remission (CR). To elucidate the
      mechanism of PUVA therapy in this case, we compared ultrastructures of leukemic
      cells obtained before and after PUVA therapy by electron microscopy, and found
      that PUVA therapy caused apoptosis in leukemic cells in the peripheral blood. In
      this paper, the antitumor mechanism of PUVA is discussed, and its efficacy is
      emphasized.

PMID- 8652449
TI  - [The study of the biological activation induced by the lymphocyte transfusion-
      the induction of the bio-reproducing protein (BRP)].
AB  - A small amount of allo-lymphocytes were transfused to tumor bearing hosts to
      introduce tumor antigen. We found the lymphocyte transfusion significantly
      effective for the treatment of cancer, of animals and of human as well. We also
      found that by using a small amount of anti-cancer agents together, this treatment
      was effective for peritonitis/pleuritis carcinomatosa. Furthermore, we took the
      ascites and/or the pleural fluid from those peritonitis/pleuritis carcinomatosa
      patients at their remission stage, and fractionate the fraction V by the alcohol
      fractionation method from the supernatant of the fluid, and transfuse it back to
      the patient for the purpose of improving hypoproteinemia, and we found the
      fraction effective for the cure of the cancer. We designated this fraction the
      bio-reproducing protein (BRP). The clinical test treatments using the BRP were
      performed for terminal stage cancer of digestive system, respiratory system,
      mammary, and others with the efficacy of 76 percent. The detail analysis of the
      characteristics and the working mechanism of the BRP is in progress.

PMID- 8652450
TI  - [Flow cytometric analysis of cell cycle for the action mechanism of
      antineoplastic agents].
AB  - Cell kinetics of cancers have been described in books, texts and other reports,
      but the correlation with action mechanism of antineoplastic agents has rarely
      been mentioned in the literature. The action mechanism of the antineoplastic
      agents such as interferon, ACNU and cisplatin was analyzed with use of propidium
      iodide and BrdU double staining by flow cytometer. Interferon showed S phase
      accumulation, ACNU and cisplatin blocked the stage of G(2)M phase. Flow cytometry
      was useful for the analysis of cell kinetics.

PMID- 8652451
TI  - [Cell cycle analysis of temperature sensitive mutants for cell growth].
AB  - Cells proliferate through the cell cycle consisting of G1, S, G2 and M. Even in
      the case of animal cells, the temperature sensitive mutants for the cell growth
      are an important method to analyse the cell cycle.

PMID- 8652452
TI  - [The effectiveness of interferon-beta against glioma cells and its augmentation
      of growth inhibitory effect by transfection of its gene].
AB  - The mortality and morbidity of patients with malignant glioma is not
      satisfactory, although the survival time is prolonged by several adjuvant
      therapies. In order to increase the survival time, various studies have been
      undertaken. In the present article, at first we discuss the effectiveness of the
      single and/or combined therapy of interferon-beta. Although a synergistic effects
      with radiation is noted in nitrosoureas and interferon-beta, and it is the most
      effective treatment for malignant glioma at present, it is still necessary to
      continue to search for an effective strategy to prolong survival of the patients.
      To improve the interferon-beta cytokine therapy, we have studied liposome
      mediated transfection of cytokine genes to control glioma cells. For this
      purpose, human beta-interferon gene entrapped in liposome was transfected into
      glioma cells and the growth inhibitory effect was observed. Successful secretion
      of interferon-beta and remarkable suppression effect to the glioma cells was
      demonstrated and this effect was enhanced by conjugating with monoclonal antibody
      G-22 on the surface of liposome. These results suggest that interferon-beta gene
      transfection by the use of liposome coupled with monoclonal antibody might become
      a useful technique for gene therapy of malignant glioma.

PMID- 8652453
TI  - [Glial tumor cell proliferation and immune response in the brain].
AB  - The mechanism of glial tumor cell proliferation and the immune response to glioma
      cells in the brain were examined both in vitro and in vivo experimental systems,
      using mouse malignant glioma cell line, 203-glioma. A fura-2 fluorescence image
      showed marked rise in the intracellular calcium ion concentration in mechanically
      stimulated single cells. The increased calcium spread to adjacent cells, probably
      due to some stimulating factor released from cells. Dye microinjection revealed
      no gap junction between cells. Antagonists of voltage-dependent calcium channels
      did not act on the calcium response. These suggest that calcium signaling in the
      glioma cells may be mediated via a membrane receptor but not through a gap
      junction. Depletion of extracellular calcium ion and addition of intracellular
      calcium blocker demonstrated that calcium signaling in stimulated cells may be
      related to both an influx of extracellular calcium and a redistribution of
      intracellular calcium from internal stores, whereas calcium transmission to
      adjacent cells may involve calcium influx alone. The splenic cytotoxic T
      lymphocyte (CTL) activity in intracerebral tumor-bearing hosts increased with a
      peak 2 weeks after tumor cell inoculation, but rapidly decreased concurrently
      with increased intracranial pressure. The major histocompatibility complex, MHC,
      class I antigen expression on tumor cells grafted intracerebrally was found to
      enhance markedly, resulting in an increase in susceptibility to CTL. It was
      suggested that there may be a positive correlation between the cell surface MHC
      class I antigen expression and sensitivity to CTL in glioma cells.

PMID- 8652454
TI  - Subperiosteal abscess of the orbit: computed tomography and the clinical course.
AB  - In an earlier study, a trial of i.v. antibiotics, with surgical drainage reserved
      for failure to respond, was recommended for children aged < 9 years with medial
      subperiosteal abscesses (SPAs) of modest size and without compromised vision.
      Careful monitoring is mandatory in these cases, and comparison of serial computed
      tomography (CT) scans frequently guides therapy. The present study examines how
      the CT findings actually relate to the clinical course of SPA. Initial and
      subsequent CT scans in 37 cases were analyzed with respect to the subperiosteal
      material encountered at surgery and the response to treatment. The subperiosteal
      material could not be predicted from the size or relative radiodensity of the
      collections in CT scans. Initial scans were not predictive of the clinical
      course. Serial scans showed enlargement of abscesses during the first few days of
      i.v. antibiotic therapy, regardless of the ultimate response to treatment. It is
      concluded that expansion of an SPA in serial CT scans during the first few days
      of treatment should not be equated to failure of the infection to respond to
      antibiotics alone. In interpreting serial scans, the time-dependent
      pharmacokinetics of antibiotic therapy should be considered.

PMID- 8652456
TI  - Results of dacryoscintigraphy in massage of the congenitally blocked nasolacrimal
      duct.
AB  - Between November 1990 and November 1993, 580 children with lacrimal outflow
      obstruction were examined at the Children's Hospital of Philadelphia. After
      excluding patients previously treated for nasolacrimal duct obstruction, we
      obtained a prospectively selected series of 20 children for this study. These
      patients underwent dacryoscintigraphy before and immediately after lacrimal sac
      massage to investigate the effect of external compression on fluid movement
      within the lacrimal outflow system. In 12 patients, tracer did not enter the
      lacrimal outflow system on the side(s) of obstruction. The absence of
      radiopharmaceutical correlated with clinical obstruction. In eight patients,
      tracer was noted to enter the lacrimal sac. After massage of the lacrimal sac, we
      observed progression of the tracer in five of the eight subjects. In these eight
      subjects, the pre- and postmassage tear column measurements showed a relative
      increase of 34.3%. Massage of eight clinically normal ducts showed a relative
      increase of 2.4% (p = 0.06). We conclude that progression of the tear column
      after lacrimal massage can be demonstrated on dacryoscintigraphy.

PMID- 8652455
TI  - Prevention and management of complications associated with the hydroxyapatite
      implant.
AB  - The hydroxyapatite orbital implant offers many advantages compared to
      conventional implants; however, its use is not entirely free of complications.
      The objectives of this study are to review the complications encountered with the
      hydroxyapatite orbital implant, suggest mechanisms contributing to the
      development of these complications, and emphasize aspects of surgical technique
      that will minimize the risk of the most frequent complication, implant exposure.
      Preoperative, operative, and postoperative records of 154 patients receiving
      primary and secondary hydroxyapatite implants were studied retrospectively. Three
      clinical types of exposure defects were observed; dehiscences along the
      horizontal suture line, defects over holes in the hydroxyapatite, and a defect
      adjacent to the site of radiation plaque therapy. Most small exposures healed
      spontaneously. Medium and large defects were associated with anteriorly
      malpositioned implants, most often required surgical intervention, and were
      successfully managed with one or a combination of techniques including flaps,
      mucous membrane grafts, or repositioning of the implant more posteriorly. Placing
      the hydroxyapatite implant as far posteriorly as possible and advancing the
      extraocular muscles 3-5 mm from the apex of the implant will prevent most
      exposures. Unlike other types of implants, the hydroxyapatite implant does not
      migrate or extrude, and when exposed, usually does not require removal.

PMID- 8652457
TI  - Management of paralytic lagophthalmos with a modified gold-weight implantation
      technique.
AB  - A modified gold-weight implantation technique was used to treat paralytic
      lagophthalmos in 15 patients. Three patients had suffered extrusions of
      previously placed gold-weight implants, two had other complications necessitating
      reoperation, and 10 had no previous surgery. The surgical modifications were
      intended to reduce the incidence of implant extrusion, postoperative ptosis, and
      implant visibility beneath the skin. The important changes in the surgical
      technique included (a) advancing the levator aponeurosis over the implant and (b)
      adjusting the final eyelid height intraoperatively with levator myotomies. Follow
      up ranged from 6 to 11 months. None of the patients in this study had
      postoperative problems associated with ptosis, implant extrusion, or implant
      visibility. Mild, prolonged, postoperative edema was noted in several patients.
      This resolved spontaneously. Mild eyelid retraction and lagophthalmos were seen
      postoperatively in two patients. This was caused by a failure to perform marginal
      myotomies at the time of the initial surgeries.

PMID- 8652459
TI  - The significance of positive margins (known and unknown) at the conclusion of
      Mohs surgery in the orbital region.
AB  - The Mohs fresh tissue technique has provided a high rate of cure in cases of
      malignant tumors in the orbital region. However, in some patients, tumor may
      persist after Mohs surgery if margins are falsely negative or if the Mohs surgeon
      elects to terminate the procedure with known positive margins. We report six
      patients who had residual tumor present in the periorbital region after Mohs
      surgery. These patients have a serious prognosis associated with subsequent
      morbidity. Accurate communication between the Mohs surgeon and subsequent
      treating surgeons, combined with aggressive tumor management, may help to
      minimize morbidity and improve mortality.

PMID- 8652460
TI  - Mucinous eccrine carcinoma of the eyelid.
AB  - A 78-year-old woman with recurrent chalazia of the upper eyelid was found to have
      mucinous eccrine carcinoma. This rare pathologic entity, with low metastatic
      potential, nevertheless has a significant recurrence rate. This case underscores
      the importance of considering this tumor in recalcitrant eyelid lesions and
      highlights the pathology of this tumor. A summary of previous cases is also
      presented.

PMID- 8652461
TI  - The bubble test: an atraumatic method for canalicular laceration repair.
AB  - Canalicular lacerations need to be correctly identified before surgical repair.
      Methods to find the medial cut end are numerous. With the use of direct sight or
      the bubble test or both, the identification and repair of the medial cut end of
      the lacerated canaliculus should be achievable in the majority of cases.

PMID- 8652458
TI  - Complications of tarsoconjunctival grafts.
AB  - The authors reviewed 44 tarsoconjunctival grafts performed from 1983 to 1993 to
      determine the nature and severity of complications related to these grafts.
      Follow-up ranged from 3 weeks to 10 years, with a mean of 23 months. The
      complications were categorized as none, minor, or major. A complication was
      deemed major if it required a second surgical procedure for treatment. Eleven
      percent (5/44) of patients had major complications, including marked upper lid
      retraction after upper lid reconstruction (1), wound dehiscence (2), cicatricial
      ectropion (1), and excessive lower lid laxity (1). Seventy-three percent (32/44)
      of patients had minor complications. Minor complications included trichiasis (5),
      notching of the donor and/or recipient lid margin (9), mild lid retraction (3),
      contour deformity (2), granuloma (2), prolonged edema or erythema (4),
      symblepharon (1), mild ectropion (2), punctate keratitis (1), minimal ptosis (1),
      and epiphora (1). Sixteen percent (7/44) had no complications. Despite the
      frequent minor complications and the occasional major complications, the use of
      free tarsoconjunctival grafts remains a valuable procedure in the surgeon's
      armamentarium for reconstruction of major eyelid defects. Knowledge and early
      recognition of the possible complications may result in better patient care.

PMID- 8652462
TI  - Iatrogenic canalicular foreign body.
AB  - An 81-year-old woman was seen with a suture granuloma 7 years after medial
      canthal tendon tightening. One end of the suture extended through the inferior
      punctum. Excision of the granuloma and suture without retightening the canthal
      tendon resulted in relief of the purulent discharge and foreign-body sensation
      and no recurrence of epiphora.

PMID- 8652463
TI  - Diplopia after surgical repair of orbital floor fractures.
AB  - Blowout fractures of the orbit are common sequelae to blunt facial trauma. Many
      aspects of this injury have been studied, in particular, the timing of and
      indications for surgical intervention. Although diplopia is often an indication
      for surgery and is presented to patients as a potential postoperative
      complication, the incidence of diplopia after surgical repair of orbital blowout
      fractures has not been well studied. We retrospectively studied 54 patients who
      underwent repair of an orbital blowout fracture. A minimum of 6 months follow-up
      was available for all patients included in the study. A total of 47 of 54 (86%)
      patients had clinically significant diplopia preoperatively, and 20 of 54 (37%)
      remained diplopic. A total of 17 of 54 (31%) fractures involved the medial wall
      and orbital floor, and 13 of these 17 patients (86%) had postoperative diplopia.
      Patients with combined orbital floor and medial wall fractures appear to be at
      higher risk for clinically significant diplopia postoperatively than those with
      fractures of the orbital floor only. The explanation for this observation may be
      related to a greater difficulty in restoring the preoperative contour of orbits
      with combined fractures.

PMID- 8652464
TI  - Natural versus surgical menopause: implications for the pathogenesis of
      osteoporosis.

PMID- 8652465
TI  - Intrapartum fetal cerebral near infrared spectroscopy: apparent change in
      oxygenation demonstrated in a non viable fetus.

PMID- 8652466
TI  - Fertility in women with unicornuate uterus.

PMID- 8652467
TI  - Exposure to pentachlorophenol as a possible cause of miscarriages.

PMID- 8652468
TI  - Parvovirus associated fetal hydrops: reversal of pregnancy induced proteinuric
      hypertension by in utero fetal transfusion.

PMID- 8652470
TI  - Successful pregnancy after treatment of stage III bilateral ovarian dysgerminoma.

PMID- 8652469
TI  - Prenatal diagnosis of extra-amniotic pregnancy.

PMID- 8652471
TI  - Maternal health in the developing world: how can the RCOG contribute?

PMID- 8652472
TI  - 27th British Congress of Obstetrics and Gynaecology.

PMID- 8652473
TI  - Reproductive health in developing countries: a new initiative.

PMID- 8652474
TI  - Dilatation and curettage in patients with cervical polyps: a retrospective
      analysis.

PMID- 8652475
TI  - Dilatation and currettage in patients with cervical polyps: a retrospective
      analysis.

PMID- 8652476
TI  - First trimester fetal nuchal translucency: problems with screening the general
      population 1 & 2.

PMID- 8652477
TI  - Fetal fibronectin detection for prediction of preterm birth in low risk women.

PMID- 8652478
TI  - Outpatient vulval biopsy--a note of caution.

PMID- 8652479
TI  - Length of hospital stay after vaginal hysterectomy.

PMID- 8652480
TI  - The use of a tissue expander as a vaginal stent in vaginal reconstruction.

PMID- 8652481
TI  - Why do we still circumcise male babies?

PMID- 8652482
TI  - The persistence of newborn circumcision: an American perspective.

PMID- 8652483
TI  - Postmenopausal oestrogens and arteries.
AB  - Postmenopausal oestrogen use is associated with a significant reduction in
      cardiovascular morbidity and mortality. The fact that a large scale controlled
      trial has not been conducted is a valid criticism, but the epidemiological data
      are compelling and there is evidence of biologically plausible mechanisms which
      may mediate this effect. Postmenopausal HRT also abolishes climacteric symptoms
      and conserves bone. For the postmenopausal woman who has had a hysterectomy,
      unless there are compelling reasons to the contrary, we believe that unopposed
      oestrogen therapy should be offered routinely. Women who still have a uterus (and
      these form the majority of potential HRT users) require oestrogens with cyclical
      progestogens. Whether such opposed therapy results in any reduction in
      cardiovascular protection needs to be addressed urgently. Meanwhile, it could be
      argued that these women should also be offered HRT routinely. Indeed, a recent
      consensus conference (Lobo & Speroff 1994) concluded that because of the
      magnitude of cardiovascular disease as a cause of morbidity and mortality, the
      beneficial role of estrogen in the primary prevention of cardiovascular disease
      in most women outweighs its potential risk. At the present time, there are
      insufficient data to indicate whether there are any groups of women for whom the
      risks may be too great to prescribe some form of estrogen therapy. As life
      expectancy increases in developed countries, such reductions in the leading cause
      of mortality are likely to benefit not only the individual woman, but the society
      in which she lives.

PMID- 8652484
TI  - Pregnancy in sickle cell disease in the UK: results of a multicentre survey of
      the effect of prophylactic blood transfusion on maternal and fetal outcome.
AB  - OBJECTIVE: To determine the outcome of pregnancies complicated by sickle cell
      disease in the UK during 1991-1993 and the effect of prophylactic blood
      transfusion programmes on maternal and fetal outcome. DESIGN: A multicentre
      study. SUBJECTS: Eighty-one pregnancies complicated by sickle cell disease and
      100 pregnancies from women of black African descent without haemoglobinopathies
      to act as a comparative group. Pregnancies complicated by sickle cell disease
      were divided by the type of haemoglobinopathy and also by transfusion regimen.
      MAIN OUTCOME MEASURES: Antenatal and postnatal complications of sickle cell
      disease, proteinuric hypertension, preterm delivery, emergency delivery by
      caesarean section, fetal distress, birthweight, perinatal and maternal mortality.
      RESULTS: There were two maternal deaths in the 81 pregnancies and the perinatal
      mortality rate was 60/1000. Antenatal sickling complications occurred in 46.2% of
      pregnancies and postnatal sickling complications occurred in 7.7% of pregnancies.
      Pregnancies complicated by sickle cell disease were significantly more likely to
      be associated with anaemia, preterm delivery, proteinuric hypertension,
      birthweight below the 10th centile and caesarean section as an emergency
      procedure than the comparative group. Severe sickling complications occurred more
      commonly in the third trimester and there was some evidence that a prophylactic
      transfusion programme reduced the risk of this. Prophylactic transfusion did not
      improve obstetric outcome when compared with those pregnancies that were
      untransfused. CONCLUSIONS: Sickle cell disease remains a severe complicating
      factor to pregnancy and perinatal mortality and maternal mortality rates in the
      UK have increased since last reported. A policy of exchange transfusing all women
      with homozygous sickle cell disease (HbSS) from 28 weeks gestation is recommended
      to reduce the risk of maternal complications in the third trimester and
      puerperium. There remains a role for earlier prophylactic blood transfusion
      programmes in women with poor obstetric and haematological histories.

PMID- 8652485
TI  - Communication following a stillbirth or neonatal death: room for improvement.
AB  - OBJECTIVE: To assess the extent of knowledge which mothers had about a previous
      stillbirth or neonatal death, their satisfaction with the information and advice
      given them, and their degree of anxiety during a subsequent pregnancy. DESIGN:
      Personal interview. SETTING: Antenatal clinic of a British military hospital in
      Germany. SUBJECTS: Forty-eight caucasian, pregnant women, 28 of whom had had a
      previous stillbirth (Group A) and 20 a neonatal death (Group B). RESULTS: Over
      half (25/48) the women had a poor or confused knowledge of the events surrounding
      the death, only 29% were satisfied with the information they had received, and
      nearly 40% became pregnant within six months of the death despite medical advice
      against conceiving soon after such an event. The mothers of stillborn babies were
      significantly less likely to know the birthweight than the mothers of babies who
      died after birth (60% vs 95%), and 40% had not given the baby a name. Over a
      third of the mothers were admitted to hospital because of anxiety about the
      current pregnancy. CONCLUSIONS: Dissatisfaction with the quality of information
      given by hospital staff, rapid conception despite medical advice to the contrary,
      and anxiety in a subsequent pregnancy were common after a previous stillbirth or
      neonatal death. A poor or confused knowledge about the baby's death was more
      likely if the death had been intrauterine and unexplained, or associated with
      maceration, a lethal abnormality, an emergency delivery resulting in stillbirth,
      or a preventable cause.

PMID- 8652486
TI  - Screening for fetal trisomies by maternal age and fetal nuchal translucency
      thickness at 10 to 14 weeks of gestation.
AB  - OBJECTIVE: To evaluate screening for chromosomal defects by a combination of
      fetal nuchal translucency thickness and maternal age. DESIGN: A prospective
      multicentre screening study where fetal nuchal translucency thickness was
      measured at 10 to 14 weeks of gestation. SUBJECTS: 20,804 women with singleton
      pregnancies screened at 10 to 14 weeks of gestation from 1 September 1992 to 28
      October 1994. MAIN OUTCOME MEASURES: Trisomy 21 and other chromosomal defects
      identified by increased nuchal translucency thickness and by a combination of
      nuchal translucency thickness and maternal age. RESULTS: In normal fetuses nuchal
      translucency thickness increased significantly with crown-rump length. The nuchal
      translucency was above the 95th centile in 77% (66 of 86) of fetuses with trisomy
      21 and in 78% (61 of 78) of those with other chromosomal defects. On the basis of
      the distribution of nuchal translucency measurements in normal fetuses and those
      with trisomy 21, a new method of screening is proposed which involves assessment
      of individual risk based on the combination of fetal nuchal translucency, crown
      rump length and maternal age. The minimum risk was 1/100 in 4.9% of the normal
      pregnancies, in 80% of those with trisomy 21 and in 77% of those with other
      chromosomal defects. CONCLUSION: Screening for fetal trisomy 21 can be carried
      out effectively during the first trimester of pregnancy.

PMID- 8652487
TI  - The value of fetal arterial, cardiac and venous flows in predicting pH and blood
      gases measured in umbilical blood at cordocentesis in growth retarded fetuses.
AB  - OBJECTIVE: To assess the value of Doppler indices, calculated from fetal arterial
      peripheral vessels, cardiac outflow tracts and venous vessels, in the
      identification of acidaemia, hypercapnia and hypoxaemia as determined by pH and
      gas analysis of fetal blood obtained by cordocentesis in growth retarded fetuses.
      DESIGN: Doppler measurements were taken from umbilical artery, thoracic
      descending aorta, renal artery, middle cerebral artery, cardiac outflow tracts,
      inferior vena cava and ductus venosus immediately before cordocentesis. Logistic
      regression and receiver-operator characteristic curve analysis were performed to
      examine the relation between Doppler indices and acid-base status. SETTING:
      Tertiary centre for fetal medicine. SUBJECTS: Forty-eight growth retarded fetuses
      fulfilling these criteria for inclusion: 1. absence of chromosomal and structural
      anomalies; 2. an abdominal circumference or ultrasonographic estimated fetal
      weight less than the 5th centile; 3. presence of abnormal velocity waveforms in
      umbilical artery; and 4. postnatal confirmation of a birthweight below the 5th
      centile and absence of structural anomalies. RESULTS: The percentage of reverse
      flow in inferior vena cava was a more closely related variable for acidaemia (chi
      2 = 29.69; P < or = 0.001) and hypercapnia (chi 2 = 12.86; P < or = 0.001) than
      the other Doppler indices. Hypoxaemia was better predicted by the pulsatility
      index from middle cerebral artery (chi 2 = 15.31; P < or = 0.001). CONCLUSION:
      The analysis of velocity waveforms from inferior vena cava and middle cerebral
      artery can be used to predict acid-base status in growth retarded fetuses
      secondary to placental insufficiency. This may lead to a more accurate antepartum
      monitoring of such fetuses.

PMID- 8652488
TI  - Labour and delivery of 'normal' primiparous women: analysis of routinely
      collected data.
AB  - OBJECTIVE: To ascertain whether there is variation in obstetric practice within a
      defined subgroup of primiparous women. DESIGN: Analysis of routinely collected
      data. SUBJECTS: Ten thousand two hundred and ninety-five primiparous deliveries
      defined as 'normal' in Scotland during 1990 and 44,820 primiparous deliveries
      defined as 'normal' in England between April 1990 and April 1991. RESULTS: Little
      variation was found in the distribution of mothers' ages and gestational ages at
      delivery, and babies' birthweights. In both England and Scotland there was
      considerable variation between regions in instrumental delivery rates and
      caesarean section rates. There were many deficiencies in the quality of the data
      provided by the English Maternity Hospital Episode System. CONCLUSIONS: There is
      regional variation in instrumental delivery rates and caesarean section rates in
      England and Scotland. The poor quality of data for England makes interpretation
      of the cause of variation difficult because the extent to which variation may
      reflect deficiencies in the data, rather than differences in practice, is
      unknown. Improvements need to be made in Maternity Hospital Episode system data,
      increasing both coverage and data quality. Nevertheless, similar variations in
      instrumental delivery and caesarean section rates may be associated with
      differences in population characteristics not measured in these data sets of
      differences in obstetric practice.

PMID- 8652489
TI  - Infertility and the seeking of infertility treatment in a representative
      population.
AB  - OBJECTIVE: To investigate lifetime prevalence of infertility, the seeking of
      infertility treatment and outcomes of treatment. DESIGN: Cross-sectional postal
      questionnaire study. SETTING: County of Copenhagen, Denmark. SUBJECTS: Three
      thousand, seven hundred and forty-three women, 15 to 44 years old, selected at
      random were asked about infertility, their seeking of infertility treatment,
      diagnoses provided by their doctors and subsequent parenthood. Response rate was
      78%, n = 2865. A random sample of non-responders was interviewed by telephone.
      MAIN OUTCOME MEASURES: Fertility status, seeking of infertility treatment,
      subsequent deliveries and adoptions. RESULTS: Of the women who had attempted to
      have a child, 26.2% had experienced infertility; 4.1% of the women aged 25 to 44
      years were currently primarily infertile and 8.6% had involuntarily not delivered
      a first child; 47.4% of the infertile women had sought infertility treatment.
      Significant predictors for seeking infertility treatment were school education >
      9 years and not having delivered a child. Of the infertile women 54.9%
      subsequently had a child. Only 30% of these reported that the successful delivery
      was treatment-related. CONCLUSIONS: The health care system should see to it that
      infertile couples from lower social classes are offered information on the
      possibility of infertility treatment. High quality infertility treatment has to
      include both the "supply" of taking care of the infertile couple's psychosocial
      strain and the goal of ensuring successful pregnancies.

PMID- 8652490
TI  - The effect of topical oestradiol on skin collagen of postmenopausal women.
AB  - OBJECTIVE: To examine the effect of topical oestradiol on skin collagen and
      elastin. SUBJECTS: Twelve postmenopausal women, aged 52 to 76 years.
      INTERVENTIONS: Topical oestradiol treatment on the skin of lower abdomen and the
      vehicle only on the contralateral site; once a day for three months. MAIN OUTCOME
      MEASURES: The content of skin hydroxyproline; the levels of the carboxyterminal
      propeptide of human type I procollagen (PICP) and of the aminoterminal propeptide
      of human type III procollagen (PIIINP). The number and the quality of collagen
      and elastic microfibrils. RESULTS: The amount of hydroxyproline in the skin
      significantly (P = 0.012) increased from 11.8 to 16.3 micrograms (38%) during
      oestradiol treatment. After treatment, the PICP level in the blister fluid was
      significantly (P = 0.024) higher on the treated site than on the control site.
      Also the level of PIIINP increased, but the change was not statistically
      significant. Electron microscopy showed morphologic improvement of elastic and
      collagen fibres, while the number of oxytalan and elaunin fibres was unchanged in
      light microscopy. CONCLUSIONS: Topical oestradiol treatment increases the amount
      of skin collagen. The increase in the level of PICP and PIIINP in skin blister
      fluid indicates that oestradiol treatment stimulates collagen synthesis.
      Furthermore, our results show that topical ostradiol treatment has a greater
      influence on the amount than on the quality of skin collagen. On the contrary, in
      elastic tissue the oestradiol treatment will only result in morphologic
      improvement.

PMID- 8652492
TI  - The development and validation of an orthodontic expert system.
AB  - An expert system for providing advice on the selection and treatment of cases
      suitable for treatment by means of removable appliances has been developed. Its
      assessment by peer review is described.

PMID- 8652491
TI  - Pre-operative morphological and colour Doppler features of borderline ovarian
      tumours.
AB  - OBJECTIVE: To evaluate pre-operatively the sonographic morphology and colour
      Doppler findings of borderline ovarian tumours and to compare these findings to
      those of benign and malignant tumours. METHODS: Pre-operative transvaginal and
      colour Doppler ultrasound examinations were performed on 150 women with adnexal
      tumours. Pulsatility index, resistance index, peak systolic velocity, site,
      number and confluence of vessels were recorded. RESULTS: Fifty-six women had
      malignant ovarian tumours, 74 had benign and 20 had borderline tumours. No
      biological, morphological or demographic parameters were specifically predictive
      of borderline tumours. Intratumoral vessels with a pulsatility index of below 1.0
      were observed in 19 of the 20 borderline tumours; a morphological score suggested
      malignancy in 15 women whereas the CA125 exceeded 30 u/ml in 10 cases. Confluence
      of blood vessels was observed only in three cases. A model including intracystic
      complexity (either vegetations or septa), pulsatility index of less than 1.0,
      absence of confluence of vessels, CA125 of less than 150 u/L, in a woman under 60
      years of age allowed borderline tumours to be detected with 85% sensitivity, 92%
      specificity and 91% accuracy. CONCLUSION: Borderline tumours have haemodynamics
      resembling those of malignant tumours but the distribution of vessels is often
      similar to that observed in benign tumours; this observation should be considered
      when proposing multiparameter scoring systems including colour Doppler ultrasound
      to identify malignancies of the ovary. Colour Doppler findings may be of
      assistance in the follow up of women after conservative surgery for ovarian
      malignancies.

PMID- 8652493
TI  - A national survey of orthodontic facebow injuries in the UK and Eire.
AB  - There have been several reports of soft tissue injuries from orthodontic facebows
      in the dental and medical literature, but the magnitude of the problem in the UK
      and Eire has never been previously investigated. In order to obtain information,
      questionnaires were distributed to 1682 Dental practitioners providing
      orthodontic treatment in the UK and Eire. A total of 1117 (66 per cent) replied.
      Of these 859 (77 per cent) reported using Kloehn type facebows. Thirty-one
      practitioners (3.6 per cent) gave details of 33 injuries from Kloehn type
      facebows. The results of this questionnaire are compared and discussed with
      previous reports in the dental and medical literature. The relative effectiveness
      of extra-oral traction safety products is discussed.

PMID- 8652494
TI  - Individualized catenary curves: their relationship to arch form and perimeter.
AB  - Study casts of the lower arches of 35 children in whom arch alignment was
      considered acceptable, were examined using a reflex microscope. Arch perimeter
      was calculated mathematically from a method which required measurement of the
      mesio-distal widths of the teeth only. This was described as the 'overlap'
      method. Arch perimeter was also calculated using individualized catenary curves
      for each subject. Two calculations were made, recording arch width either at the
      distal contact points of the first permanent molars or between their mesio-buccal
      cusps. Arch perimeter measured from the length of the catenary curves was
      consistently shorter than that calculated by the overlap method. The variation
      ranged from 0.02 to 4.58 mm. The catenary constructed using the distal molar
      contacts gave a better representation of the actual arch form: the mean
      discrepancy was 2.36 mm, compared with 2.86 mm with the second method where arch
      width was measured between mesio-buccal cusps. Both techniques for calculation of
      arch perimeter were highly reproducible. The catenary curve only approximated
      arch form well when the arch was relatively narrow across the inter canine
      region. For square arches this method was unsatisfactory. It is suggested that
      alternative techniques would be more reliable and the overlap method described
      here is considered satisfactory.

PMID- 8652495
TI  - Class II/Division 2 malocclusion: a method of planning and treatment.
AB  - This paper presents a method of cephalometric treatment planning for Class II
      division 2 malocclusions. The method combines improvement in dental and facial
      aesthetics, with reduction in overbite and inter-incisor angle. An individual
      case is illustrated; examples of the appliances commonly used being shown in the
      treatment of an adolescent patient.

PMID- 8652496
TI  - The effects of cross-infection control procedures on the tensile and flexural
      properties of superelastic nickel-titanium wires.
AB  - The development of superelastic nickel-titanium archwires has simplified the
      alignment phase of orthodontic treatment by permitting the use of highly
      flexible, resilient archwires and avoiding the need for complex loops. The
      majority of these archwires appear undistorted when removed from the mouth after
      use. This feature, coupled with the disadvantage of relatively high cost has led
      to sterilization and recycling of these wires by some clinicians. This study was
      designed to examine the effects of currently used infection control procedures on
      the mechanical properties of superelastic nickel-titanium alloy (SENTA)
      archwires. One-hundred-and-forty lengths of a SENTA wire were subjected to
      various sterilization and disinfection procedures. These included cold
      disinfection in 2 per cent glutaraldehyde solution for 3- and 24-hour cycles, and
      steam autoclaving. Single and double cycles were used. The properties
      investigated were the 0.1 per cent yield strength, the ultimate tensile strength,
      and the flexural rigidity. No statistically significant differences were found
      between the groups or against an untreated control.

PMID- 8652497
TI  - A scanning electron microscopic study of early enamel caries formed in vivo
      beneath orthodontic bands.
AB  - A clinical trial was conducted to investigate the development of caries lesions
      associated with fixed orthodontic appliance therapy. To introduce a cariogenic
      challenge on sound buccal enamel surfaces in vivo, specially designed orthodontic
      bands were attached to premolars scheduled for extraction for orthodontic
      reasons. The bands were modified by having two metal wires (0.8 mm in diameter)
      welded to the inner surface of the band to produce a space for plaque
      accumulation similar to that occurring under loose orthodontic bands. The bands
      were cemented with a zinc phosphate cement (Tenet) and left in situ for 4 weeks.
      Of 22 premolar teeth banded in eight different patients, eight showed definite
      white spot lesions, eight showed definite faint enamel opacities, and six showed
      no discernible lesions. Examination of definite white spot lesions by scanning
      electron microscopy revealed characteristic patterns of initial tissue
      destruction. Focal holes and an accentuation of the perikymata were observed
      affecting the enamel surface zone, an area previously considered to remain
      relatively intact during the development of a caries lesion. The superficial
      nature of the caries lesions observed and the rapidity of their formation is
      significant in the clinical management of decalcified areas forming beneath
      orthodontic bands.

PMID- 8652498
TI  - Lesions of the mandibular condyle in juvenile chronic arthritis.
AB  - A total of 371 serial dental panoramic radiographs from 71 children with juvenile
      chronic arthritis (JCA) were examined to determine the presence and extent of
      radiographically detectable condylar abnormalities. The series included 12
      children with so called 'bird face' deformity and 55 in whom facial growth was
      judged to be normal. By the age of 15 years, 27 patients (38 per cent), showed
      lesions of the TMJ, of which 14 (55 per cent) were bilateral. Of those cases with
      unilateral destruction, the left condyle was affected nine times more frequently
      than the right. All of the children with 'bird face' deformity had condylar
      abnormality, but these facial characteristics should not be considered
      pathognomonic of juvenile chronic arthritis. Moderate to severe condylar
      abnormality was detectable in 10.9 per cent of children with normal facial
      growth, and where condylar destruction is present it can often be established as
      early as 8 years. Systemic corticosteroids appear to have little or no effect on
      the condyle or mandibular growth.

PMID- 8652499
TI  - The Consultant Orthodontists Group 1994 survey of the use of the Index of
      Orthodontic Treatment Need (IOTN).
AB  - A questionnaire, relating to the use and acceptance of occlusal indices and in
      particular the Index of Orthodontic Treatment Need (IOTN), was sent to all UK
      hospital consultants in the orthodontics. Of the respondents 74.6 per cent
      routinely recorded the Dental Health Component of IOTN for their new patient
      referrals. The reasons for the increased acceptance of the IOTN amongst hospital
      orthodontic consultants are evaluated and some of the difficulties in usage,
      reported by respondents, are discussed.

PMID- 8652500
TI  - The re-establishment of molar occlusion following orthognathic surgery.
AB  - The effect on distal molar occlusion following mandibular orthognathic surgery is
      highlighted. Two cases are presented in which at the completion of
      orthodontic/surgical treatment a stable molar occlusion was re-established by
      adjunctive restorative treatment. The clinical problem highlighted, illustrates
      the importance of restorative support for patients with residual post-orthodontic
      and post-surgical occlusal problems.

PMID- 8652501
TI  - Direct bonding to typodont teeth.
AB  - Three methods of bonding orthodontic brackets to acrylic teeth were investigated
      for use with a typodont. One-hundred-and-twenty Dentaurum 0.018 x 0.025 inch
      standard Edgewise brackets were bonded to Crylopax cross-linked acrylic teeth
      using three cements: Concise composite, Concise with acrylic primer, and GAC
      acrylic cement on a previously roughened tooth surface. Half the specimens in
      each group was immersed in a thermostatically controlled water bath for 15 min on
      20 occasions over a 5-day period, to simulate the conditions of a typodont, prior
      to measuring tensile bond strength on an Instron machine. Under dry conditions
      Concise composite was significantly stronger than either Concise with acrylic
      primer or GAC cold cure acrylic resin. Under wet conditions, however, the mean
      bond strength of the acrylic resin increased significantly compared to the other
      cements. The bond strength of both Concise and Concise composite with primer
      deteriorated following water immersion. It is suggested that when setting up
      typodont teeth with brackets bonded with GAC acrylic resin, immersion of the
      bonded teeth in hot water prior to positioning of the teeth in the typodont may
      greatly reduce the risk of subsequent bracket loss.

PMID- 8652502
TI  - "A question too far".

PMID- 8652503
TI  - Current software for teaching orthodontics.

PMID- 8652504
TI  - Orthodontics in the third dimension. A report of the Spring Meeting of the
      British Orthodontic Society, Heythrop Park, Oxfordshire, Saturday, May 6th 1995.

PMID- 8652505
TI  - "Starting from scratch".
AB  - The process of establishing a new orthodontic service in any area requires a
      combination of patience and perseverance. It is a prolonged project littered with
      frustrating experiences, many of which we encountered. We endeavour to outline
      the pros and cons of such an undertaking and describe our experiences in
      implementing a marketing strategy prior to the practice opening. This was
      specifically geared to running a practice in a 'mixed' NHS/Private environment.

PMID- 8652506
TI  - Influence of the carbohydrate moiety on the stability of glycoproteins.
AB  - To study the role of oligosaccharides on the properties of glycoproteins, five
      glycoproteins (yeast external invertase, bovine serum fetuin, glucoamylase from
      Aspergillus niger, and chicken egg white ovotransferrin and avidin) of previously
      established glycan patterns were purified to homogeneity and deglycosylated with
      endo- and exo-glycosidases in native conditions. Thermal stability and
      conformational changes were measured by high-resolution differential scanning
      microcalorimetry and circular dicroism spectroscopy before and after they were
      deglycosylated. It was found that deglycosylation decreases protein thermal
      stability, as judged by the decrease in denaturation temperature and denaturation
      enthalpy, while it does not affect substantially the conformation as indicated by
      the CD spectra in the far UV range. The destabilization effect of deglycosylation
      seems to depend on the carbohydrate content, i.e., the maximum effect was
      observed for the most heavily glycosylated protein, irrespective of the types (N
      linked or O-linked) or patterns (mono- or multi-branched) of the covalently
      attached carbohydrate chains. In addition, studies of the reversibility to heat
      denaturation revealed that deglycosylated proteins have a poorer thermal
      reversibility in calorimetric scans than their native counterparts and tend to
      aggregate during thermal inactivation at acidic pH. These results suggest that
      carbohydrate moieties, in addition to the apparent stabilizing effect, may
      prevent the unfolded or partially folded protein molecules from aggregation. Our
      results support the hypothesis that the general function of protein glycosylation
      is to aid in folding of the nascent polypeptide chain and in stabilization of the
      conformation of the mature glycoprotein.

PMID- 8652507
TI  - Murine DNA cytosine-C5 methyltransferase: pre-steady- and steady-state kinetic
      analysis with regulatory DNA sequences.
AB  - We present the first description of KmDNA, KdDNA, Kcat, and Kmethylation for a
      mammalian DNA methyltransferase. Homogeneous, 190 000 MTDNA (cytosine-5-)
      methyltransferase isolated from mouse erythroleukemia cells has turnover
      constants of 0.15-0.59 h-1 with single-stranded and unmethylated double-stranded
      oligonucleotides containing a single CpG dinucleotide. These substrates were
      designed to mimic DNA transcriptional cis elements previously reported to have
      cytosine C-5-methylated regulation. The rate-limiting step for these substrates
      is the methylation step itself. In contrast, hemimethylated double-stranded
      substrates show burst kinetics, consistent with a rapid methylation event (3 h-1)
      followed by a slower step which determines steady-state Kcat. Hemimethylated and
      unmethylated double-stranded DNA shows similar binding affinities; these results
      reveal the molecular basis for the enzyme's preference for hemimethylated DNA to
      be the methyl transfer step. Substrates with multiple recognition sites do not
      show burst kinetics and have turnover rate constants of 6 h-1. Catalytic turnover
      for the mammalian enzyme is thus approximately 10-fold slower than that for the
      related bacterial enzymes. Our combined results show quantitatively that one
      enzyme is certainly capable of both maintenance and de novo methylation and that
      maintenance of the genomic methylation pattern is preferred over the de novo
      establishment of new patterns. Direct comparison of the mammalian enzyme with the
      bacterial DNA cytosine-C5 methyltransferase, M.SssI, indicates dramatic
      differences in preferences for single-stranded, double-stranded, and
      hemimethylated double-stranded substrates. Moreover, the specificity hierarchy
      shown for the M.SssI is derived from very different changes in K(m) and catalysis
      than those observed for the mammalian DCMTase. These results demonstrate that the
      M.SssI, and perhaps other DNA cytosine methyltransferases from bacteria, is
      functionally dissimilar to the mammalian enzyme.

PMID- 8652508
TI  - Major groove (S)-alpha-(N6-adenyl)styrene oxide adducts in an
      oligodeoxynucleotide containing the human N-ras codon 61 sequence: conformations
      of the S(61,2) and S(61,3) sequence isomers from 1H NMR.
AB  - The (S)-alpha-(N6-adenyl)styrene oxide adducts at positions X6 in d(CGGACXAGAAG).
      d(CTTCTTGTCCG) and X7 in d(CGGACAXGAAG).d(CTTCTTGTCCG), incorporating codons 60,
      61 (underlined), and 62 of the human n-ras protooncogene, were examined by 1H
      NMR. These were the S(61,2) and S(61,3) adducts. Chemical shift perturbations
      were in the 3'-direction from the sites of adduction; upfield changes associated
      with the styrene aromatic ring current were noted for S-SOA6 H2 and H1', T16 N3H,
      H6, and CH3 resonances in the S(61,2) oligomer. In the S(61,3) oligomer, S-SOA7
      H1', T16 H1', C15 N4Ha, and H5 shifted upfield. The styrene aromatic rings
      flipped rapidly on the NMR time scale; under these conditions the ortho and meta
      aromatic protons were equivalent. A sequence effect, in which the S(61,2) adduct
      equilibrated between two conformers, while the S(61,3) adduct exhibited only a
      single conformation, was observed. Potential energy minimization of the S(61,2)
      adduct major conformation yielded a structure in which the styrene ring was
      oriented in the 3'-direction and interacted primarily with the complementary
      strand. For the S(61,3) adduct, 291 restraints were obtained from NOE data at
      three mixing times using relaxation matrix analysis. The emergent structures
      refined to an average rms difference of 1.3 A, determined by pairwise analysis.
      These were compared to NOE intensity data; the calculated sixth root residual
      index was 9.2 x 10-2 at 250 ms. In the refined structure, the styrene ring was
      also oriented in the 3'-direction and interacted with the complementary strand.
      The minor conformation of the S(61,2) adduct was not identified. These results
      contrasted with the diastereomeric R(61,2) and R(61,3) adducts, which underwent
      slow ring flips on the NMR time scale and for which small sequence effects
      involving the minimum energy conformation of the styrene ring were observed.

PMID- 8652509
TI  - Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as
      crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active
      site.
AB  - The cyclooxygenase activity of the membrane protein prostaglandin H2 synthase
      isoform 1 (PGHS-1) is the target of the nonsteroidal antiinflammatory drugs
      (NSAIDs). The X-ray crystal structures of PGHS-1 in complex with the NSAIDs
      flurbiprofen and bromoaspirin have been determined previously [Picot, D., et al.
      (1994) Nature 367, 243-249; Loll, P. J., et al. (1995) Nat. Struct. Biol. 2, 637
      643]. We report here the preparation and characterization of novel potent
      iodinated analogs of the NSAIDs indomethacin and suprofen, as well as the refined
      X-ray crystal structures of their complexes with PGHS-1. The PGHS-iodosuprofen
      complex structure has been refined at 3.5 A to an R-value of 0.189 and shows the
      suprofen analog to share a common mode of binding with flurbiprofen. The PGHS
      iodoindomethacin complex structure has been refined at 4.5 A to an R-value of
      0.254. The low resolution of the iodoindomethacin complex structure precludes
      detailed modeling of drug-enzyme interactions, but the electron-dense iodine atom
      of the inhibitor has been unambiguously located, allowing for the placement and
      approximate orientation of the inhibitor in the enzyme's active site. We have
      modeled two equally likely binding modes for iodoindomethacin, corresponding to
      the two principal conformers of the inhibitor. Like flurbiprofen, iodosuprofen
      and iodoindomethacin bind at the end of the long channel which leads into the
      enzyme active site. Binding at this site presumably blocks access of substrate to
      Tyr-385, a residue essential for catalysis. No evidence is seen for significant
      protein conformational differences between the iodoindomethacin and iodosuprofen
      of flurbiprofen complex structures.

PMID- 8652510
TI  - Ternary complex crystal structures of glycogen phosphorylase with the transition
      state analogue nojirimycin tetrazole and phosphate in the T and R states.
AB  - Catalysis by glycogen phosphorylase involves a mechanism in which binding of one
      substrate tightens the binding of the other substrate to produce a productive
      ternary enzyme-substrate complex. In this work the molecular basis for this
      synergism is probed in crystallographic studies on ternary complexes in which the
      glucosyl component is substituted by the putative transition state analogue
      nojirimycin tetrazole, a compound which has been established previously as a
      transition state analogue inhibitor for a number of glycosidases. Kinetic studies
      with glycogen phosphorylase showed that nojirimycin tetrazole is a competitive
      inhibitor with respect to glucose 1-phosphate and uncompetitive with respect to
      phosphate. Ki values for the phosphorylase-AMP-glycogen complex and the
      phosphorylase-AMP-glycogen-phosphate complexes are 700 microM and 53 microM,
      respectively, indicating that by itself norjirimycin tetrazole has poor affinity
      for glycogen phosphorylase but that phosphate substantially improves the binding
      of norjirimycin tetrazole. X-ray crystallographic binding studies to 2.4 A
      resolution with T state phosphorylase b crystals showed that nojirimycin
      tetrazole binds at the catalytic site and promotes the binding of phosphate
      through direct interactions. Phosphate binding is accompanied by conformational
      changes that bring a crucial arginine (Arg569) into the catalytic site. The
      positions of the phosphate oxygens were definitively established in X-ray
      crystallographic binding experiments at 100 K to 1.7 A resolution using
      synchrotron radiation. X-ray crystallographic binding studies at 2.5 A resolution
      with R state glycogen phosphorylase crystals showed that the protein atoms and
      water molecules in contact with the nojirimycin tetrazole and the phosphate are
      similar to those in the T state. In both T and R states the phosphate ion is
      within hydrogen-bonding distance of the cofactor pyridoxal 5'-phosphate group and
      in ionic contact with the N-1 atom of the tetrazole ring. The results are
      consistent with previous time-resolved structural studies on complexes with
      heptenitol and phosphate. The structural and kinetic results suggest that
      nojirimycin tetrazole in combination with phosphate exhibits properties
      consistent with a transition state analogue and demonstrate how one promotes the
      binding of the other.

PMID- 8652511
TI  - Crystal structure implies that cyclophilin predominantly catalyzes the trans to
      cis isomerization.
AB  - The crystal structure of human recombinant cyclophilin A complexed with a
      substrate of succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (AAPF) has been determined
      and refined to an R-factor of 0.189 at 2.4 A resolution. The structure revealed
      only the cis form of the substrate bound to cyclophilin A in a stoichiometry of
      1:1. This binding ratio is different from the structure of cyclophilin A
      complexed with the tetrapeptide N-acetyl-Ala-Ala-Pro-Ala-amidomethylcourmarin.
      Model docking revealed that the trans form of AAPF does not fit into the active
      site. The observation that only the trans cis form of AAPF binds to cyclophilin A
      implies that cyclophilin A predominantly catalyzes the trans to cis isomerization
      of a peptidylprolyl amide bond. On the basis of the structure, it is proposed
      that Arg55 hydrogen-bonds to the nitrogen to deconjugate the resonance of the
      prolyl amide bond and thus facilitates the cis-trans rotation.

PMID- 8652512
TI  - Mechanistic implication of crystal structures of the cyclophilin-dipeptide
      complexes.
AB  - The structures of cyclophilin A complexed with dipeptides of Ser-Pro, His-Pro,
      and Gly-Pro have been determined and refined at high resolution. Comparison of
      these structures revealed that the dipeptide complexes have the same molecular
      conformation and the same binding of the dipeptides. The side chains of the N
      terminal amino acid of the above dipeptides do not strongly interact with
      cyclophilin, implying their minor contribution to the cis-trans isomerization and
      thus accounting for the broad catalytic specificity of the enzyme. The binding of
      the dipeptides is similar to that of the common substrate succinyl-Ala-Ala-Pro
      Phe-p-nitroanilide in terms of the N-terminal hydrogen bonding and the
      hydrophobic interaction of the proline side chain. However, substantial
      difference between these structures are observed in (1) hydrogen bonding between
      the carboxyl terminus of the peptides and Arg55 and between Arg55 and Gln63, (2)
      the side chain conformation of Arg55, and (3) water binding at the active site.
      These differences imply either that dipeptides are not substrates but competitive
      inhibitors of peptidyl-prolyl cis-trans isomerases or that dipeptides are subject
      to different catalytic mechanisms from tetrapeptides.

PMID- 8652513
TI  - Arazoformyl dipeptide substrates for thermolysin. Confirmation of a reverse
      protonation catalytic mechanism.
AB  - Cleavage by thermolysin of N-(4-methoxyphenylazoformyl)-L-leucyl-L-leucine plus
      some congeneric peptides provides a highly sensitive new kinetic assay for
      proteolytic activity. The pH dependence of Michaelis-Menten parameters Kcat and
      Km establishes kinetically a reverse protonation catalytic mechanism for this
      metalloprotease [Mock, W.L., & Aksamawati, M. (1994) Biochem. J. 302, 57-68]. An
      acidified water molecule (pKa of 5, seen in Km) becomes displaced by substrate
      carboxamide from the hypercationic Zn2+ of the enzyme, yielding potent Lewis acid
      activation of the peptide linkage for subsequent hydrolysis. Conversion to
      product is induced by the side chain of enzymic residue His 231 (pKa of 8, seen
      in Kcat), which provides general base catalysis for addition of H2O to the zinc
      activated scissile carboxamide of the bound substrate. A previously described
      "superactivation" through chemical modification of the enzyme with
      acetylphenylalanyl-N-hydroxysuccinimide is nonexistent in the case of the new
      substrates, which indicates that their binding to thermolysin is largely
      productive, unlike normal peptides. Correct assignment of kinetically observed
      pKa values to active site residues, along with recognition of a predominantly
      nonproductive binding mode for ordinary substrates and thermolysin, forces
      reinterpretation of previous mechanistic formulations for the enzyme.

PMID- 8652514
TI  - Evidence of a low-barrier hydrogen bond in the tryptophan synthase catalytic
      mechanism.
AB  - In the absence of other substrates, L-Ser reacts rapidly with the tryptophan
      synthase alpha 2 beta 2 bienzyme from Salmonella typhimurium at pH 7.8 and 25
      degrees C to give an equilibrating mixture of species dominated by comparable
      amounts of the L-Ser external aldimine Schiff base, E(Aex1), and the alpha
      aminoacrylate Schiff base, E(A-A). The D-isomer of Ser is unreactive toward alpha
      2 beta 2, and therefore, D,L-Ser can be used in place of L-Ser for investigations
      of catalytic mechanism. Due to the equilibrium isotope effect, when alpha-2H-D,L
      Ser is substituted for alpha-1H-D,L-Ser, the position of equilibrium is shifted
      in favor of E(Aex1). On a much slower time scale, the 2H sample undergoes the
      exchange of enzyme bound 2H for the 1H of solvent water and is converted to a
      distribution of E(Aex1) and E(A-A) identical to that obtained with the 1H sample.
      This slow exchange indicates that the proton abstracted from the alpha-carbon of
      E(Aex1) is sequestered within a solvent-excluded site in E(A-A). Analysis of the
      UV/vis spectra gave an isotope effect on the equilibrium distribution of E(Aex1)
      and E(A-A) of KH/KD = 1.80 +/- 0.18. This large equilibrium isotope effect is the
      consequence of an unusual isotope fractionation factor of 0.62 for the residue
      which functions as the base to deprotonate and protonate the alpha-carbon proton
      in E(Aex1). A fractionation factor of 0.62 qualifies as evidence for the
      involvement of a low-barrier H-bond (LBHB) in this equilibration. Since this
      effect arises from abstraction of the alpha-proton from E(Aex1), the LBHB must be
      associated with the E(A-A) species. In contrast to weak H-bonds with energies of
      3-12 kcal/mol, LBHBs are proposed to exhibit energies in the 12-24 kcal/mol range
      [Frey, P.A., Whitt, S.A., & Tobin, J. B. (1994) Science 264, 1927-1930]. Possible
      roles for this LBHB both in the chemical mechanism and in the stabilization of
      the closed conformation of E(A-A) are discussed.

PMID- 8652516
TI  - Interactions of aristololactam beta-D-glucoside with right-handed and left-handed
      forms of synthetic deoxyribonucleic acid: spectroscopic and thermodynamic study.
AB  - The interaction of aristololactam beta-D-glucoside (ADG) with different
      polymorphic structures of poly(dG-me5dC).poly(dG-me5dC), poly(dG-dC).poly(dG-dC),
      and poly(dI-dC). poly(dI-dC) has been studied by spectrophotometric,
      spectrofluorimetric, circular dichroism, UV melting profiles, and thermodynamic
      analysis. The binding of ADG to B-form duplexes is characterized by the typical
      bathochromic and hypochromic effects in the absorption spectrum, quenching of
      steady-state fluorescence intensity, a decrease in fluorescence quantum yield of
      ADG, an increase in fluorescence polarization anisotropy, an increase of thermal
      transition temperature, and perturbation in circular dichroic spectrum. Scatchard
      analysis indicates that ADG binds to the right-handed form of each polymer in a
      noncooperative manner. Comparative binding parameters determined from absorbance
      titration by Scatchard analysis, employing the excluded site model, indicate a
      stronger binding of ADG to the B-form of poly(dG-me5-dC). poly(dG-me5dC) than to
      the B-form of poly(dG-dC).poly(dG-dC) or poly(dI-dC). poly(dI-dC). Thermodynamic
      parameters (delta G degree, delta H degree, and delta S degree) obtained by van't
      Hoff analysis of the data show that the process of binding to all B-form duplexes
      is exothermic and enthalpy driven as characterized by a favorable negative
      enthalpy change (delta H degree). The binding is opposed by a negative entropy
      change (delta S degree) contribution. Conformational changes indicate that the
      alkaloid converts the left-handed form of poly(dG-dC). poly(dG-dC), and its
      methylated analogue and high salt form of poly(dI-dC). poly(dI-dC) to a bound
      right-handed form, while it inhibits both the rate and extent of the B to Z
      transition. These studies reveal that ADG binds strongly to B-form polymers while
      it does not bind to polymers of Z-form.

PMID- 8652515
TI  - DNA cleavage is not required for the binding of quinolone drugs to the DNA gyrase
      DNA complex.
AB  - The primary target for the quinolone group of antibacterial agents is DNA gyrase.
      One model for the interaction of quinolone drugs with gyrase and DNA suggests
      that the drugs bind to the single-stranded regions revealed following DNA
      cleavage by the enzyme. We have tested this hypothesis by using mutants which
      have the active-site tyrosine in the gyrase A subunit altered to phenylalanine or
      serine. We have found that proteins bearing these mutations are still able to
      bind drug, suggesting that DNA cleavage is not a prerequisite for drug binding.
      We have also found that the blocking of transcription by RNA polymerase in vitro
      by the gyrase-quinolone complex on DNA does not occur when the active-site
      tyrosine is mutated to serine; i.e., polymerase blocking requires DNA cleavage.

PMID- 8652518
TI  - Dimorphism of hepatitis B virus capsids is strongly influenced by the C-terminus
      of the capsid protein.
AB  - Hepatitis B virus (HBV) is an enveloped virus with an icosahedral capsid. Its
      homodimeric capsid protein ("core antigen") assembles into particles of two
      sizes, one with T = 3 icosahedral symmetry (90 dimers) and the other with T = 4
      symmetry (120 dimers). We have investigated this assembly process in vitro, using
      a variety of purified, bacterially expressed, capsid proteins. All of our
      constructs lacked the predominantly basic C-terminal 34 amino acids of the full
      length capsid protein (183 amino acids) and were further truncated to terminate
      at specific points between residues 138 and 149. While the smallest construct
      (138 residues) did not assemble into capsids, those terminating at residue 140,
      and beyond, assembled into mixtures of T = 3 and T = 4 particles. The two kinds
      of capsids could be separated on sucrose gradients and did not interconvert upon
      protracted storage. The proportion of T = 3 capsids, assayed by sucrose gradient
      fractionation, analytical ultracentrifugation, and cryoelectron microscopy, was
      found to increase systematically with larger deletions from the C-terminus. The
      variant terminating at residue 149 formed approximately 5% of T = 3 capsids,
      while the 140-residue protein produced approximately 85% of this isomorph. For
      the 147-residue capsid protein, the structures of both capsids were determined to
      17 A resolution by three-dimensional reconstruction of cryoelectron micrographs.
      In these density maps, the boundaries of the constituent dimers can be clearly
      seen and the quaternary structures of the two capsids compared. The arrangement
      of dimers around their icosahedral five-fold axes is almost identical, whereas
      the quasi-six-fold arrangements of dimers are distinctly different.

PMID- 8652517
TI  - Changing the transition state for protein (Un) folding.
AB  - (Un)folding transition states of Saccharomyces cerevisiae iso-1-ferri- and
      ferrocytochromes c were studied using equilibrium and kinetic denaturation
      experiments. The wild-type protein and the global suppressor variant, N52I
      (isoleucine replaces asparagine 52), were examined. Denaturation was induced by
      guanidinium chloride (GdmCI) and monitored by circular dichroism (CD)
      spectropolarimetry without stopped-flow devices. Soret CD spectra indicate that
      thermal and GdmCl denatured states are different, and heat is the more effective
      denaturant. Equilibrium data show that the high stability of ferrocytochrome c
      can be rationalized as a requirement to bury the oxidation-induced positive
      charge and remain folded under physiological conditions. Kinetic data are
      monoexponential and permit characterization of the rate-limiting transition state
      for unfolding as a function of [GdmCl]. For the oxidized wild-type protein, the
      transition state solvent accessibility is nearly the same as that of the
      denatured state. Three perturbations, reducing the wild-type protein, reducing
      the N52I variant, and substituting position 52 in the oxidized protein, change
      the free energy and solvent accessibility of the transition state. In contrast,
      substituting position 52 in the reduced protein apparently does not change the
      transition state solvent accessibility, allowing more detailed characterization.
      In the reduced proteins' transition states at 4.3 M GdmCl, the position 52 side
      chain is in a denatured environment, even though transition state solvent
      accessibility is only one-third that of the denatured state (relative to the
      native state).

PMID- 8652519
TI  - Unusual effects of an engineered disulfide on global and local protein stability.
AB  - The global and local stabilities of a eukaryotic ferricytochrome c variant with
      an engineered disulfide are examined. The disulfide connects position 20, which
      is usually a valine, to position 102, which is usually a threonine. The cross
      linked variant is approximately 1.2 kcal mol-1 less stable than the wild-type
      protein at 298 K, pH 4.6, in H2O and D2O. Circular dichroism studies show that
      the decreased stability results from structure-induced stabilization of the
      denatured state [Betz, S. F., & Pielak, G. J. (1992) Biochemistry 31, 12337
      12344]. Here, we use proton chemical shift, paramagnetic shift, and amide proton
      exchange data to obtain atomic level structural and energetic information.
      Chemical and paramagnetic shift data indicate only minor native state structural
      changes. Local stability is obtained from amide proton-deuterium exchange data,
      using model peptide intrinsic exchange rates. As expected, the exchange data
      indicate that cross-link incorporation decreases the majority of local
      stabilities. Near the cross-link, however, local stability seems to increase
      despite the overall global stability decrease. Furthermore, local stability
      changes for hydrophobic core residues seem to be greater than the global
      stability change. We interpret these observations as cross-link-induced changes
      in exchange competent states and relate them to changes in the denatured state.

PMID- 8652520
TI  - NMR solution structure of a synthetic troponin C heterodimeric domain.
AB  - The C-terminal domain from the muscle protein troponin C (TnC) comprises two
      helix-loop-helix calcium-binding sites (residues 90-162). The assembly of these
      two sites is governed by calcium binding enabling a synthetic C-terminal domain
      to be preferentially and stoichiometrically assembled from two synthetic peptides
      (residues 93-126, SCIII, and 129-162, SCIV) in the presence of calcium only. It
      is therefore of great interest to know how closely the structure of this
      heterodimeric domain is to the intact protein domain. Analysis of such a
      structure has important implications in protein engineering and in understanding
      the stability of calcium-binding proteins in terms of biological function. The
      solution structure of this heterodimeric protein was determined by 1H NMR
      spectroscopy using 802 NOE derived distance restraints and 23 phi and 22 chi
      angle restraints. Distance geometry-simulated annealing calculations yielded a
      family of 42 converged structures (rmsd 0.86 +/- 0.17 A) showing an arrangement
      of four alpha-helices similar in fold to the C-terminal of troponin C. The dimer
      interface has several important interactions between helix pairs E/H and F/G
      responsible for the association of the two peptides. However, neither the peptide
      complex nor the solution NMR structure of TnC pack as tightly as that observed in
      the TnC X-ray structure. The interhelical distance between the F/G helix is about
      1.4 A greater in solution than in the crystal. A comparison of the exposed
      surface area of the hydrophobic residues in the SCIII/SCIV heterodimer revealed
      that residues 1104, Y112, and 1121 are more exposed than in the previously
      determined solution structure of the SCIII homodimer. These residues are
      important for the interaction with the inhibitory region of TnI and provide
      evidence for their involvement in the regulation of muscle contraction.

PMID- 8652521
TI  - Tetracycline analogs affecting binding to Tn10-Encoded Tet repressor trigger the
      same mechanism of induction.
AB  - We examined the influence of substituents in tetracycline (tc) analogs modified
      at positions 2 and 4-9 and anhydrotetracycline (atc) on induction of the Tn10
      encoded Tet repressor (TetR) by a quantitative in vitro induction assay. The
      equilibrium association constants of the modified tc to TetR were independently
      determined to distinguish effects on binding from those on induction. We found a
      correlation between the binding affinity and induction of TetR for most tc
      analogs. While a substitution at position 5 revealed only minor effects, changes
      at position 6 increased binding and induction efficiencies up to 20-fold. A
      chlorine at position 7 or 8 enhanced binding and induction about 4- and 9-fold,
      respectively. Substituents at position 9 decreased binding up to 5-fold.
      Epimerization of the dimethylamino function at position 4 in 4-epi-tc resulted in
      about 300-fold-reduced binding and 80-fold-reduced induction. Substitution of
      this grouping by hydrogen in 4-de(dimethylamino)-tc resulted in no binding and no
      induction. The respective atc analog failed to induce as well, although binding
      was still observed. The dimethylamino function may, thus, play a role in
      triggering the conformational change of TetR necessary for induction.
      Substitution of the 2-carboxamido by a nitrilo function did not influence binding
      and induction efficiencies. Atc showed about 30-fold increased binding and
      induction, being the most effective inducer tested in this study. The equilibrium
      association constants of most TetR-[Mg-tc]+ and TetR-([Mg-tc]+)2 analog complexes
      with tet operator are decreased about 10(2)- and 10(8)-fold, respectively, as
      compared to those of free TetR. This suggests that these tc analogs share the
      same molecular mechanism of TetR induction.

PMID- 8652522
TI  - Identity of prokaryotic and eukaryotic tRNA(Asp) for aminoacylation by aspartyl
      tRNA synthetase from Thermus thermophilus.
AB  - The aspartate identity of tRNA for AspRS from Thermus thermophilus has been
      investigated by kinetic analysis of the aspartylation reaction of different tRNA
      molecules and their variants as well as of tRNAPhe variants with transplanted
      aspartate identity elements. It is shown that G10, G34, U35, C36, C38, and G73
      determine recognition and aspartylation of yeast and T.thermophilus tRNA(Asp) by
      the thermophilic AspRS. This set of nucleotides specifies also tRNA aspartylation
      in the homologous yeast and Escherichia coli systems. Structural considerations
      indicate that the major aspartate identity elements interact with amino acids
      conserved in all AspRSs. It follows that the structural features of tRNA and
      synthetase specifying aspartylation are mainly conserved in various structural
      contexts and in organisms adapted to different life conditions. Mutations of tRNA
      identity elements provoke drastic losses of charging in the heterologous system
      involving yeast tRNA(Asp) and T. thermophilus AspRS. In the homologous systems,
      the mutational effects are less pronounced. However, effects in E. coli and T.
      thermophilus exceed those in yeast which are particularly moderate, indicating
      variations in the individual contributions of identity elements for aspartylation
      in prokaryotes and eukaryotes. Analysis of multiple tRNA mutants reveals
      cooperativity between the cluster of determinants of the anticodon loop and the
      additional determinants G10 and G73 for efficient aspartylation in the
      thermophilic system, suggesting that conformational changes trigger formation of
      the functional tRNA/synthetase complex.

PMID- 8652523
TI  - Simultaneous binding and bending of promoter DNA by the TATA binding protein:
      real time kinetic measurements.
AB  - The binding and bending of tetramethylrhodamine-5'-(GGGCTATAAAAGGG) duplex-3'
      fluorescein by native Saccharomyces cerevisiae TATA binding protein (TBP) have
      been investigated using fluorescence resonance energy transfer. Probability
      distributions derived from fluorescein emission lifetime measurements show a
      decrease in the mean 3'-fluorescein-5'- rhodamine distance from 56.5 to 46.8 A
      upon binding of the oligomer to TBP, consistent with the DNA bend observed by X
      ray crystallography. The kinetics, monitored in real time using stopped flow
      fluorimetry, demonstrate simultaneous binding and bending of a TATA box by TBP
      with a single second-order rate constant of (2.4 +/- 0.3) x 10(6) M-1 s-1 at 30
      degrees C.

PMID- 8652524
TI  - Fatty acid transfer in taurodeoxycholate mixed micelles.
AB  - Dietary triacylglycerol is acted upon by lipolytic enzymes in the stomach and the
      proximal small intestine, releasing fatty acids and monoacylglycerol as the
      ultimate products. These digestive products are solubilized by bile released from
      the gall bladder, resulting in the formation of two product phases-vesicles and
      micelles-depending upon the concentration of bile in the small intestine.
      Absorption of lipid is thought to occur from these two phases. We have previously
      examined the rate and mechanism of long-chain fatty acid transfer between
      unilamellar vesicles [Kleinfeld, A. M., & Storch, J. (1993) Biochemistry 32, 2053
      2061]. In order to begin to assess the relative contributions of micellar vs
      vesicular phases in the absorption of dietary lipid, a simple model system was
      designed to investigate the transfer of fatty acid and monoacylglycerol between
      micelles. A fluorescence self-quenching assay was used to monitor the transfer of
      fluorescent anthroyloxy-labeled lipids from donor micelles to acceptor micelles.
      The mechanism of fatty acid transfer was found to be a combination of diffusional
      and collisional processes, with the latter dominating at high micelle
      concentrations. The rate of diffusional transfer of fatty acid and
      monoacylglycerol analogues was approximately 30-fold greater from micelles than
      vesicles. Intermicellar and intervesicular rates of transfer were 3-fold greater
      for fatty acids as compared with monoacylglycerol. The results suggest that
      uptake of the products of intestinal lipase hydrolysis is more efficient from
      micellar than vesicular phases. Nevertheless, fatty acid and monoacylglycerol
      transfer from unilamellar vesicles could account, in part, for the relatively
      efficient uptake of dietary lipid observed in conditions of intestinal bile salt
      insufficiency.

PMID- 8652525
TI  - Substrate behavior of plasminogen activator inhibitor-1 is not associated with a
      lack of insertion of the reactive site loop.
AB  - Plasminogen activator inhibitor-1 (PAI-1) is a unique member of the serpin
      superfamily. In the present study, we have evaluated the effect of substitution,
      with a proline, at positions P5, P7, P14, P15, or P16, on the conformational
      flexibility and functional properties of PAI-1. These mutants (PAI-1-P5, IIe-
      >Pro at P5; PAI-1-P7, Ala-->Pro at P7; PAI-1-P14, Thr-->Pro at P14; PAI-1-P15,
      Gly-->Pro at P15; PAI-1-P16, Ser-->Pro at P16) were purified and fully
      characterized. WtPAI-1 had a specific activity of 68 +/- 10% (mean +/- SD, n = 6)
      whereas PAI-1-P5, PAI-1-P7, and PAI-1-P16 had specific activities of 34 +/- 9.3%,
      42 +/- 10%, and 36 +/- 11%, respectively. PAI-1-P14 and PAI-1-P15 did not exhibit
      significant inhibitory activity. Conformational analysis revealed that wtPAI-1
      preparations contained 12 +/- 2.0% substrate, whereas PAI-1-P5, PAI-1-P7, and PAI
      1-P16 were characterized with a significantly (p < 0.001) increased substrate
      behavior (i.e., 43 +/- 6.1%, 42 +/- 1.5% and 22 +/- 1.7%, respectively). The
      inactive variants PAI-1-P14 and PAI-1-P15 behaved exclusively as substrates
      toward various serine proteinases. Heat denaturation studies revealed that
      cleavage of any noninhibitory substrate form of PAI-1 resulted in an insertion of
      the NH2-terminal side of the reactive site loop. Incubation with plasmin showed
      the presence of a unique plasmin cleavage site (Lys191-Ser192) exclusively
      present in all latent forms studied. We conclude that (a) the entire P5 to P16
      region in PAI-1 plays an important role in the functional and conformational
      properties of PAI-1; (b) the substrate behavior of serpins is not associated with
      a lack of insertion of the reactive site loop; (c) the identification of a
      plasmin cleavage site in latent PAI-1 may provide new insights in the mechanisms
      for the inactivation of storage pools of PAI-1.

PMID- 8652526
TI  - Soluble phospholipids enhance factor Xa-catalyzed prothrombin activation in
      solution.
AB  - Acidic phospholipids play an important but incompletely understood role in
      prothrombin activation. Here we report the effect of short-chain
      phosphatidylserine (dicaproylphosphatidylserine, C6PS) and the corresponding
      phosphatidylglycerol (C6PG) and phosphatidylcholine (C6PC) derivatives on the
      rate of prothrombin activation by factor Xa. The critical micellar concentrations
      of these short-chained phospholipids have been determined under a variety of
      conditions that we used for kinetic and structural studies. Under conditions for
      which these lipids exist in a soluble form, the results demonstrate that: (i) the
      rate of human prothrombin activation by human factor Xa was enhanced in a calcium
      dependent fashion up to 60-fold by addition of C6PS, roughly 20% of the optimal
      enhancement seen with bovine
      phosphatidylserine/palmitoyloleoylphosphatidylcholine (25/75 PS/POPC) membranes;
      (ii) C6PS inhibited the rate of hydrolysis of synthetic factor Xa substrate (S
      2765), an effect that was mimicked, but at much lower lipid concentrations, by
      PS/POPC membranes; (iii) there was no enhancement of prothrombin activation and
      much less inhibition of hydrolysis of S-2765 by factor Xa in the presence of C6PG
      or C6PC; and (iv) the thermal denaturation of prothrombin was altered in a
      calcium-independent but dose-dependent fashion by either C6PS or C6PG. These
      results have been interpreted in terms of the existence of (a) specific PS
      binding site(s) on factor Xa (Kd approximately 73 microM) that regulate(s) the
      activity of this serine protease. Our results do not rule out the possibility
      that the rate of prothrombin activation is also influenced by a weaker, calcium
      independent, and less specific acidic lipid binding site on prothrombin, the
      occupancy of which results in conformational changes in this protein. The results
      clearly suggest that PS binding regulates the rate of prothrombin activation.

PMID- 8652527
TI  - A study of subunit interface residues of fructose-1,6-bisphosphatase by site
      directed mutagenesis: effects on AMP and Mg2+ affinities.
AB  - The structural transformation of fructose-1,6-bisphosphatase upon binding of the
      allosteric regulator AMP dramatically changes the interactions across the C1-C4
      (C2-C3) subunit interface of the enzyme. Asn9, Met18, and Ser87 residues were
      modified by site-directed mutagenesis to probe the function of the interface
      residues in porcine liver fructose-1,6-bisphosphatase. The wild-type and mutant
      forms of the enzyme were purified to homogeneity and characterized by initial
      rate kinetics and circular dichroism (CD) spectrometry. No discernible
      alterations in structure were observed among the wild-type and Asn9Asp, Met18Ile,
      Met18Arg, and Ser87Ala mutant forms of the enzyme as measured by CD spectrometry.
      Kinetic analyses revealed 1.6- and 1.8-fold increases in kcat with Met18Arg and
      Asn9Asp, respectively. The K(m) for fructose 1,6-bisphosphate increased about 2
      approximately 4-fold relative to that of the wild-type enzyme in the four
      mutants. A 50-fold lower Ka value for Mg2+ compared with that of the wild-type
      enzyme was obtained for Met18Ile with no alteration of the Ki for AMP. However,
      the replacement of Met18 with Arg caused a dramatic decrease in AMP affinity (20
      000-fold) without a change in Mg2+ affinity. Increases of 6- and 2-fold in the Ki
      values for AMP were found with Asn9Asp and Ser87Ala, respectively. There was no
      difference in the cooperativity for AMP inhibition between the wild-type and the
      mutant forms of fructose-1,6-bisphosphatase. This study demonstrates that the
      mutation of residues in the C1-C4 (C2-C3) interface of fructose-1,6
      bisphosphatase can significantly affect the affinity for Mg2+, which is
      presumably bound 30 A away. Moreover the mutations alternatively reduce AMP and
      Mg2+ affinities, and this finding may be associated with the destabilization of
      the corresponding allosteric states of the enzyme. The kinetics and structural
      modeling studies of the interface residues provide new insights into the
      conformational equilibrium of fructose-1,6-bisphosphatase.

PMID- 8652528
TI  - The role of G protein methylation in the function of a geranylgeranylated beta
      gamma isoform.
AB  - The gamma subunit of heterotrimeric G proteins is isoprenylated and methylated on
      its carboxyl terminal cysteine residue. While retinal transducin is farnesylated,
      all other gamma subunits are modified by geranylgeranylation. An immobilized form
      of pig liver esterase (iPLE) is able to hydrolyze the methyl ester of a
      geranylgeranylated beta gamma isoform (beta 1 gamma 2). Since methylation is the
      only reversible reaction in the isoprenylation pathway, it could be a site of
      regulation of G protein activity. With both the methylated and demethylated beta
      1 gamma 2 now available, the role of methylation for a geranylgeranylated
      heterotrimeric G protein may be addressed. Here, it is reported that methylation
      has no effect on the ability of beta gamma to interact with an alpha subunit, as
      probed by ADP-ribosylation studies with pertussis toxin, and has a small effect
      (less than 2-fold) on the ability of geranylgeranylated beta gamma to activate
      phosphatidylinositol-specific phospholipase C (PIPLC) and phosphoinositide 3
      kinase (PI3K). In binding studies, demethylation only slightly decreased the
      ability of beta 1 gamma 2 to adhere to azolectin vesicles. Therefore, methylation
      of heterotrimeric G proteins appears to have only a minor effect in signal
      transduction processes which can be correlated to a decrease in hydrophobicity of
      the beta gamma subunit.

PMID- 8652529
TI  - Dual inhibitory effect of gangliosides on phospholipase C-promoted fusion of
      lipidic vesicles.
AB  - The effect of a variety of gangliosides has been tested on the phospholipase C
      induced fusion of large unilamellar vesicles. Bilayer composition was
      phosphatidylcholine:phosphatidylethanolamine: cholesterol (2:1:1 mole ratio) plus
      the appropriate amounts of glycosphingolipids. Enzyme phosphohydrolase activity,
      vesicle aggregation, mixing of bilayer lipids and mixing of liposomal aqueous
      contents were separately assayed. Small amounts ( < 1 mol %) of gangliosides in
      the lipid bilayer produce a significant inhibition of the above processes. The
      inhibitory effect of gangliosides increases with the size of the oligosaccharide
      chain in the polar head group. Inhibition depends in a nonlinear manner on the
      ganglioside proportion, and is complete at approximately 5 mol %. Inhibition is
      not due to ganglioside-dependent changes in vesicle curvature or size.
      Ganglioside inhibition of vesicle fusion is due to two different effects:
      inhibition of phospholipase C activity and stabilization of the lipid lamellar
      phase. Enzyme inhibition leads to a parallel decrease of vesicle aggregation and
      lipid mixing rates. Mixing of aqueous contents, though, is depressed beyond the
      enzyme inhibition levels. This is explained in terms of the fusion pore requiring
      a local destabilization of the lipid bilayer, the lamellar structure being
      stabilized by gangliosides. 31P-NMR and DSC experiments confirm the inhibitory
      effect of gangliosides in various lamellar-to-nonlamellar transitions.

PMID- 8652531
TI  - Conformation and dynamics of [3-13C]Ala- labeled bacteriorhodopsin and
      bacterioopsin, induced by interaction with retinal and its analogs, as studied by
      13C nuclear magnetic resonance.
AB  - 13C nuclear magnetic resonance (NMR) spectra of [3-13C]Ala-labeled
      bacteriorhodopsin (bR), bacterioopsin (bO), and regenerated bR with retinal or bO
      complex with retinal analogs were recorded in order to gain insights into how the
      conformation and dynamics of apoprotein (bO) vary with or without retinal or its
      analogs. First, we assigned the 13C NMR peak resonating at 16.3 ppm to Ala 53 of
      both bR and bO, which appears to contact the side chain of Lys 216 at the site of
      the Schiff base in the former, utilizing the 13C NMR peaks of A53V and A53G
      proteins in comparison with those of wild-type bR and bO. Characteristic spectral
      differences between the apoprotein and bR were observed upon removal of the
      retinal: the changes of the peak intensities at 16.4, 15.9, and 16.9 ppm are
      notable. We found that the loops (17.4 ppm) and transmembrane alpha II helical
      region (15.9 ppm) acquired motional freedom with a correlation time of 10(-5)s
      when the retinal was removed, as detected by proton spin-lattice relaxation times
      in the rotating frame. A 13C NMR spectrum very similar to that of native bR was
      recorded when bR was regenerated by addition of retinal to bO. On the other hand,
      the addition of the retinal analogs retinol or beta-ionone, which are bound in
      the retinal binding site but are incapable of forming a Schiff base to the
      apoprotein, caused distinct spectral changes different from those of bR, as
      manifested from the displacements of 13C chemical shifts. These spectral changes
      must be ascribed to significant conformational changes of apoprotein at various
      locations in the protein, including the site of Ala 53 induced by modified
      interaction between the apoprotein and chromophore.

PMID- 8652530
TI  - Structure of the bradykinin B2 receptors' amino terminus.
AB  - The peptide hormone bradykinin exerts important biological functions by binding
      to and activating bradykinin B2 receptors. B2 receptors belong to the seven
      transmembrane domain (7TM) receptor family. Cloning of the cDNA sequences for the
      rat, human, and mouse bradykinin B2 receptor revealed several in-frame AUG
      triplets as potential initiation sites for translation. Due to "Kozak-like"
      consensus nucleotides, the AUG codon closest to transmembrane domain 1 was
      assumed the preferred initiation site for translation, but the real amino
      terminus of the B2 receptor protein was unknown. The amino terminus of several
      7TM receptors has been shown to be essentially involved in receptor activation
      and/or ligand binding. Therefore we determined the amino terminus of the human
      and of the rat B2 receptor using domain-specific antipeptide antibodies, amino
      acid sequence analysis, and in vitro transcription/translation. We report that
      the human and rat B2 receptor protein start with the methionine which is
      translated from the first in-frame AUG. This start site extends the known amino
      terminus of the human and rat B2 receptors by 27 or 30 amino acid residues,
      respectively. Antibodies raised against a peptide of the initial 27 amino acids
      of the human B2 receptor stained B2 receptors on intact cells. This finding
      excludes the existence of a signal sequence for this receptor.

PMID- 8652532
TI  - The flavoprotein domain of P450BM-3: expression, purification, and properties of
      the flavin adenine dinucleotide- and flavin mononucleotide-binding subdomains.
AB  - P450BM-3 is a self-sufficient fatty acid monooxygenase that can be expressed in
      Escherichia coli as either the holoenzyme or as the individual hemo- and
      flavoprotein domains. The flavoprotein domain (BMR) of P450BM-3 is soluble and
      contains an equimolar ratio of flavin adenine dinucleotide (FAD) and flavin
      mononucleotide (FMN) and is functionally analogous to microsomal nicotinamide
      adenine dinucleotide phosphate (NADPH)-P450 reductases. These reductases have
      been proposed to have evolved through a fusion of genes encoding simple flavin
      containing electron-transport proteins [Porter, T. D. (1991) Trends Biochem. Sci.
      16, 154-158]. The gene encoding BMR has been divided into the coding regions for
      the FAD/NADPH- and FMN-binding domains. These proteins were overexpressed in E.
      coli and both domains were found to contain not less than 0.9 +/- 0.05 mol of FAD
      or FMN/mol of protein. Compared to BMR, the electron-accepting properties of the
      recombinant flavin domains were mainly conserved. Titration of the FMN domain
      with sodium dithionite resulted in the conversion of the protein to the fully
      reduced FMNH2 form without accumulation of intermediate semiquinone forms;
      however, a similar titration of the FAD domain gave clear evidence for the
      presence of a neutral, blue flavin semiquinone during the reduction. Titrations
      of the reduced forms of the domains with artificial electron acceptors indicated
      that the electron-transferring properties of both the FAD- and FMN domains were
      also conserved. The rate constants of reoxidation of the fully reduced FAD and
      FMN domains by molecular oxygen at 20 degrees C were found to be 2.5 and 0.1 min
      1, respectively. The cytochrome c reductase activity of BMR could be fully
      reconstituted with the individual domains. The data presented support the
      hypothesis that BMR has a discrete multidomain structure.

PMID- 8652533
TI  - Characterization of the mutant visual pigment responsible for congenital night
      blindness: a biochemical and Fourier-transform infrared spectroscopy study.
AB  - A mutation in the gene for the rod photoreceptor molecule rhodopsin causes
      congenital night blindness. The mutation results in a replacement of Gly90 by an
      aspartic acid residue. Two molecular mechanisms have been proposed to explain the
      physiology of affected rod cells. One involves constitutive activity of the G90D
      mutant opsin [Rao, V. R., Cohen, G. B., & Oprian, D. D. (1994) Nature 367, 639
      642]. A second involves increased photoreceptor noise caused by thermal
      isomerization of the G90D pigment chromophore [Sieving, P. A., Richards, J. E.,
      Naarendorp F., Bingham, E. L., Scott, K., & Alpern, M. (1995) Proc. Natl. Acad.
      Sci. U.S.A. 92, 880-884]. Based on existing models of rhodopsin and in vitro
      biochemical studies of site-directed mutants, it appears likely that Gly90 is in
      the immediate proximity of the Schiff base chromophore linkage. We have studied
      in detail the mutant pigments G90D and G90D/E113A using biochemical and Fourier
      transform infrared (FTIR) spectroscopic methods. The photoproduct of mutant
      pigment G90D, which absorbs maximally at 468 nm and contains a protonated Schiff
      base linkage, can activate transducin. However, the active photoproduct decays
      rapidly to opsin and free all-trans-retinal. FTIR studies of mutant G90D show
      that the dark state of the pigment has several structural features of
      metarhodopsin II, the active form of rhodopsin. These include a protonated
      carboxylic acid group at position Glu113 and increased hydrogen-bond strength of
      Asp83. Additional results, which relate to the structure of the active G90D
      photoproduct, are also reported. Taken together, these results may be relevant to
      understanding the molecular mechanism of congenital night blindness caused by the
      G90D mutation in human rhodopsin.

PMID- 8652534
TI  - Comparison of the "Rieske" [2Fe-2S] center in the bc1 complex and in bacterial
      dioxygenases by circular dichroism spectroscopy and cyclic voltammetry.
AB  - Two different types of "Rieske" [2Fe-2S] clusters have been observed in proteins,
      one in the bc complexes of the respiratory chain and the other in bacterial
      dioxygenases. We have compared the circular dichroic (CD) spectra and redox
      properties of the water soluble fragment of the Rieske center of the bovine heart
      mitochondrial bc1 complex (ISF) and of the ferredoxin from benzene dioxygenase in
      Pseudomonas putida ML2 (FDBED). Spinach ferredoxin was also measured for
      comparison. The redox potential of both proteins could be determined in solution
      by cyclic voltammetry (CV) and by CD-monitored spectroelectrochemistry using a
      specially constructed optically transparent thin layer (OTTLE) cell. Whereas the
      redox potential of the ISF (+312 +/- 5 mV at pH 7.0) depended both on the pH
      above pH 7 and on the ionic strength, the redox potential of the FDBED (-155 +/-
      5 mV at pH 7.0) was observed to be independent of pH and ionic strength. The ISF
      showed a marked dependence of its redox potential on temperature, while the FDBED
      showed no temperature dependence. The entropy of the redox reaction delta S
      degrees rc was calculated as -88 +/- 11 J K-1 mol-1 for the bc1 Rieske center and
      approximately 0 J K-1 mol-1 for the FdBED. The CD spectra of Rieske type clusters
      are significantly different from those of plant type [2Fe-2S] ferredoxins. A
      strong negative CD band is present at 20 000 cm-1 (500 nm) in all reduced Rieske
      clusters. The possible assignment of this band is discussed as arising from the
      highest energy magnetically allowed d --> d transition (dz2 --> dxz) of the FeII
      site. If so, this band is highly indicative of the distortion of the ligand field
      of the FeII site.

PMID- 8652535
TI  - Intestinal fatty acid-binding protein: the structure and stability of a helix
      less variant.
AB  - The structure of Escherichia coli-derived rat intestinal fatty acid-binding
      protein (I-FABP) exhibits a beta-clam topology comprised of two five-stranded
      antiparallel beta-sheets surrounding a large solvent-filled cavity into which the
      ligand binds. It also contains two alpha-helices that span residues E15-A32 and
      join beta-strands A and B. This helical domain is conserved in all proteins of
      this family for which structures have been determined. In order to assess the
      structural and functional role of the helical domain, we engineered a variant of
      I-FABP by deleting residues 15-31 and inserting a Ser-Gly linker after residue
      14. Circular dichroism measurements indicated that this I-FABP variant, termed
      delta 17-SG, has a high beta-sheet content similar to that of the wild-type
      protein. Two-dimensional NMR spectra of delta 17-SG revealed patterns similar to
      those observed for wild-type I-FABP, except for the selective absence of
      resonances and through-space interactions assigned to the helical domain. The
      delta 17-SG variant was less stable to denaturant than wild-type I-FABP, but the
      folding-unfolding transition was highly cooperative and reversible. Taking into
      account the lower stability, the refolding kinetics of delta 17-SG were
      essentially identical to those of wild-type. We conclude that delta 17-SG is a
      helix-less, essentially all-beta-sheet variant of I-FABP and that the helical
      domain is not a required element of the beta-clam topology of I-FABP. In
      addition, the helical domain does not appear to serve as a nucleation site for
      the refolding process. As shown in the accompanying paper [Cistola, D. P., Kim,
      K., Rogl, H., & Frieden, C. (1996) Biochemistry 35, 7559-7565], the helices may
      function to regulate the kinetics and energetics of ligand binding.

PMID- 8652536
TI  - Fatty acid interactions with a helix-less variant of intestinal fatty acid
      binding protein.
AB  - Intestinal fatty acid-binding protein (I-FABP) binds a single molecule of long
      chain fatty acid in an enclosed cavity surrounded by two antiparallel beta
      sheets. The structure also contains two short alpha-helices which form a cap over
      one end of the binding cavity adjacent to the methyl terminus of the fatty acid.
      In this study, we employed a helix-less variant of I-FABP known as delta 17-SG
      [Kim, K., Cistola, D.P.,& Frieden, C. (1996) Biochemistry 35, 7553-7558] to
      investigate the role of the helical region in maintaining the integrity of the
      binding cavity and mediating the acquisition of ligand. Fluorescence and NMR
      experiments were used to characterize the energetic, structural, and kinetic
      properties of fatty acid binding to this variant, and the results were compared
      and contrasted with those of wild-type I-FABP and a single-site mutant, R106T.
      Remarkably, oleate bound to delta 17-SG with a dissociation constant of 4.5
      microM, a value comparable to that for R106T and approximately 20-100-fold higher
      than that for wild-type I-FABP. Heteronuclear two-dimensional NMR spectra for [2
      13C]palmitate complexed with delta 17-SG revealed a pattern nearly identical to
      that observed for the wild-type protein, but distinct from that for R106T. In
      addition, the ionization behavior of bound [1-13C]palmitate and the nearest
      neighbor patterns for [2-13C]palmitate derived from 13C-filtered NOESY
      experiments were very similar for delta 17-SG and the wild-type protein. These
      results implied that the fatty acid-protein interactions characteristic of the
      carboxyl end of the fatty acid binding cavity in the wild-type protein were
      essentially intact in the helix-less variant. In contrast, 13C-filtered NOESY
      spectra of [16-13C]palmitate bound to delta 17-SG indicated that the fatty acid
      protein interactions at the methyl end of the binding cavity were disrupted. As
      determined by stopped-flow fluorescence, the observed ligand association rates
      for both delta 17-SG and wild-type I-FABP increased with increasing oleate
      concentration, but only the wild-type protein exhibited a limiting value of 1000
      s-1. This rate-limiting process was interpreted as a conformational change
      involving the helical region that allows the ligand access to the internal
      cavity. Simulation and fitting of the kinetic results yielded ligand association
      rates for delta 17-SG and wild-type I-FABP that were comparable. However, the
      dissociation rate for wild-type protein was 16-fold lower than that for delta 17
      SG. We conclude that the alpha-helices of I_FABP are not required to maintain the
      integrity of the fatty acid binding cavity but may serve to regulate the affinity
      of fatty acid binding by selectively altering the dissociation rate constant. In
      this manner, conformational changes involving the alpha-helical domain may help
      control the transfer of fatty acids within the cell.

PMID- 8652537
TI  - Substrate specificity of IphP, a cyanobacterial dual-specificity protein
      phosphatase with MAP kinase phosphatase activity.
AB  - The substrate specificity of the cyanobacterial dual-specificity protein
      phosphatase, IphP, was explored using a variety of potential substrates. The
      enzyme displayed phosphomonoesterase activity toward a broad range of peptide,
      protein, and low molecular weight organophosphate compounds. It displayed little
      or no hydrolase activity toward phosphodiesters, phosphoramides, carboxyl esters,
      or sulfoesters. However, it did display measurable pyrophosphatase activity,
      especially toward ADP and ATP. Among the low molecular weight phosphomonoesters,
      the presence of an aromatic ring either as part of the leaving group alcohol or
      immediately adjacent thereto, as in 5'-AMP, was a strong positive determinant for
      hydrolysis. Among peptide and protein substrates, a rough, but imperfect,
      correlation between charge character and hydrolysis was noted in which proteins
      and phosphorylation sites of an acidic nature seemed favored. Heparin affected
      IphP activity in a substrate-dependent manner. Toward small organophosphates,
      heparin had no significant effect, but it was inhibitory toward most protein and
      peptide substrates. However, toward phosphoseryl casein and MAP kinase, it
      enhanced activity as much as 10-fold. This enhancement was attributed to the
      ability of heparin to bind to these substrate proteins, as well as IphP, and
      recruit them to the same microenvironment.

PMID- 8652538
TI  - Unfolding and refolding of Coprinus cinereus peroxidase at high pH, in urea, and
      at high temperature. Effect of organic and ionic additives on these processes.
AB  - The unfolding and refolding rates of the heme-and Ca2+ -containing Coprinus
      cinereus peroxidase (CIP) have been measured at pH 12.1, in 4 M urea, and at 61.2
      degrees C. The change in peroxidase activity paralleled the change in the Soret
      band absorbance of the heme group. The unfolding rate constant (ku), was
      determined independently in thermolysin digestion and EDTA experiments at 59.4
      degrees C. Both gave ku values of 1.5 ms-1, and also showed that the presence of
      4 mM EDTA made CIP unfolding practically irreversible. Unfolding and refolding
      rates could therefore be determined under identical conditions of denaturation
      having either EDTA or Ca2+ in excess. The refolding rates at high pH and in 4 M
      urea were measured by adding Ca2+ to the unfolded CIP, whereas refolding at 61.2
      degrees C was evaluated by comparing the unfolding carried out under reversible
      (excess of Ca2+) and irreversible conditions (excess EDTA). The activation
      energies for the unfolding at 61.2 degrees C are approximately delta G++(u) 100,
      T delta S++(u) 200, and delta H++(u) 300 kJ/mol. Five different additives,
      glycerol, EtOH, Na2SO4, guanidinium chloride (GdmCl), and NaCl, all at 100 mM,
      were used as probes to evaluate the mechanism of base, urea, and heat on
      unfolding and refolding. Salts destabilized CIP at high pH, primarily by
      enhancing the unfolding rate but also by decreasing the refolding rate. Glycerol
      had the reverse effects and thus stabilized CIP at high pH. The unfolding rate in
      urea was only slightly affected by the additives, with the exception of GdmCl
      which enhanced the unfolding rate. The refolding rate was decreased in urea by
      EtOH and GdmCl, in contrast to glycerol and Na2SO4 which increased the refolding
      rate. At high temperature the unfolding was affected only slightly by the
      additives, except for GdmCl, and to a lesser extent NaCl, which enhanced the
      unfolding rate. The refolding rates were greatly decreased by Na2SO4, EtOH, and
      GdmCl, whereas glycerol and Nacl enhanced the process. It appears that 100 mM
      NaCl functions as a catalyst for the temperature-induced process, enhancing both
      the unfolding and refolding rates. The results indicate that the mechanisms of
      CIP unfolding and refolding are similar in urea and at high temperature but
      different at high pH.

PMID- 8652539
TI  - Human placental tissue expresses a novel 22.7 kDa apolipoprotein A-I-like
      protein.
AB  - Since apolipoprotein A-I (apo A-I) and HDL stimulate the expression of the
      placental hormone human placental lactogen (hPL), experiments were performed to
      determine whether the human placenta synthesizes apo A-I. Western blot analysis
      of a partially purified extract of human term placenta with an antiserum to human
      apo A-I yielded an immunoreactive band with an apparent mass of approximately
      23.5 kDa, which is smaller than human plasma apo A-I (28 kDa). HPLC
      chromatography of the partially purified placental extract on a preparative
      reverse-phase C-18 column yielded two fractions that reacted to the apo A-I
      antiserum. The mass of both fractions by mass spectral analysis was 22 721
      daltons, and N-terminal amino acid sequences were identical to the first four
      amino acids of apo A-I (Asp, Glu, Pro, Pro). The apo A-I-like protein was not a
      proteolytic product of apo A-I since Northern analysis of placental RNA with a
      641 bp apo A-I cDNA fragment encoding most of the 5' region of the apo A-I mRNA
      detected a single band of 850 nt, which is smaller than the size of apo A-I mRNA
      (1100 nt). Placental mRNA, however, did not hybridize with a 3' apo A-I
      riboprobe, indicating that the 3' region of the apo A-I-like mRNA is different
      from that of apo A-I mRNA. Differences in the mRNAs were confirmed by S1 nuclease
      analysis of placental RNA with a cDNA probe that included the 3' end of the apo A
      I cDNA and by RT-PCR analysis with a series of oligonucleotide primers that span
      the entire cDNA for apo A-I. Since there is only a single apo A-I gene in the
      human genome, these findings strongly suggest that human placental tissue
      expresses a novel 22.7 kDa apo A-I-like protein (ALP) that results from
      alternative splicing of the apo A-I primary transcript.

PMID- 8652540
TI  - Distortion of the active site of chymotrypsin complexed with a serpin.
AB  - There is no complete understanding of how serine protease inhibitors of the
      serpin family inhibit their target enzymes. Structural and biochemical studies
      have suggested that serpins utilize a mechanism that is distinct from the
      standard mechanism of inhibition proposed for most small protein protease
      inhibitors. Proton nuclear magnetic resonance spectroscopy was used in the
      present study to demonstrate a fundamental difference in the atomic environment
      of the catalytic triad of enzyme in complex with serpins when compared to
      uncomplexed enzyme and enzyme in complex with standard mechanism inhibitors. This
      work demonstrates that the active site of chymotrypsin is distorted when
      complexed to a serpin and makes tenable a mechanism of inhibition in which the
      serpin induces a conformational change in the enzyme that dramatically reduces or
      completely abrogates the catalytic activity of the protease.

PMID- 8652541
TI  - Membrane potential regulates sea urchin sperm adenylylcyclase.
AB  - Adenylylcyclase (AC) from sea urchin sperm does not appear to be regulated by G
      proteins [Hildebrandt, J. D., Tash, J. S., Kirchick, H. J., Lipschunits, L.,
      Secra, R. D., & Birmbaumer, L. (1985) Endocrinology 116, 1357-1366]. During sperm
      activation and the acrosome reaction, membrane potential changes and cAMP
      increases. Here we explore if membrane potential can modulate the sperm AC.
      Hyperpolarization of Lytechinus pictus sea urchin sperm either with valinomycin
      in artificial sea water (ASW) without K+ or with dilution in ASW without Na+
      increased the [c-AMP] (2.2- and 5.8-fold, respectively). This increase also
      occurred in the absence of extracellular Ca2+ (1.9- and 3.1-fold, respectively)
      and was enhanced by 100 microM IBMX, a phosphodiesterase inhibitor. It has been
      suggested that sea urchin sperm AC is stimulated by increases in intracellular
      Ca2+ and intracellular pH. In ASW without Na+ and Ca2+ (0Na0CaASW), sea urchin
      sperm intracellular pH decreases, and intracellular Ca2+ cannot increase.
      Therefore, these observations taken together indicate that AC in these cells in
      modulated by membrane potential. Dilution of Strogylocentrotus purpuratus sperm
      in 0Na0CaASW hyperpolarized them and increased their cAMP levels (1.3-fold). This
      stimulation was enhanced by IBMX (1.6-fold). Addition of the egg peptide speract
      under this condition further hyperpolarized S. purpuratus sperm and
      synergistically increased [cAMP] above 0Na0CaASW. This stimulation became larger
      in the presence of IBMX (from 1.6- to 5.2-fold). Since speract cannot elevate
      intracellular pH or [Ca2+] in 0Na0CaASW, the increase in [cAMP] it causes must be
      due to sperm hyperpolarization.

PMID- 8652543
TI  - Oxidation of phenols, anilines, and benzenethiols by fungal laccases: correlation
      between activity and redox potentials as well as halide inhibition.
AB  - A comparative study has been performed with several fungal laccases for the
      oxidation of a series of phenols, anilines, and benzenethiols and for the
      inhibition by halides. The observed K(m) and kcat were correlated to the
      structure of substrate. The change in log (kcat/K(m)) was found to be
      proportional to the one-electron redox potential difference between laccase's
      type 1 copper site and substrate. This correlation indicated that the first
      electron transfer from substrate to laccase was governed by the "outersphere"
      mechanism. Compared to the electronic factor, the steric effect of small o
      substituents (such as methyl and methoxy groups) was found to be unimportant. The
      depth of the laccase's type 1 copper site was estimated as approximately 10 A by
      comparing the steric effect among five 2-methoxyphenols whose 4-substituents
      ranged from 0.1 to 14 kDa in mass. The observed inhibition potency order of F- >
      Cl- > Br- was attributed to limited accessibility of laccase's type 2/type 3
      trinuclear copper cluster site. Although the enzymes studied have homologous
      primary sequences and predicted similar backbone structures, the difference
      exhibited by each enzyme (in interacting with individual substrate or inhibitor)
      suggested the structural variation in their functional domains.

PMID- 8652542
TI  - Identification of an active acidic residue in the catalytic site of beta
      hexosaminidase.
AB  - Human beta-hexosaminidases A and B (EC 3.2.1.52) are dimeric lysosomal
      glycosidases composed of evolutionarily related alpha and/or beta subunits. Both
      isozymes hydrolyze terminal beta-linked GalNAc or GlcNAc residues from numerous
      artificial and natural substrates; however, in vivo GM2 ganglioside is a
      substrate for only the heterodimeric A isozyme. Thus, mutations in either gene
      encoding its alpha or beta subunits can result in GM2 ganglioside storage and Tay
      Sachs or Sandhoff disease, respectively. All glycosyl hydrolases ae believed to
      have one or more acidic residues in their catalytic site. We demonstrate that
      incubation of hexosaminidase with a chemical modifier specific for carboxyl side
      chains produces a time-dependent loss of activity, and that this effect can be
      blocked by the inclusion of a strong competitive inhibitor in the reaction mix.
      We hypothesized that the catalytic acid residue(s) should be located in a region
      of overall homology and be invariant within the aligned deduced primary sequences
      of the human alpha and beta subunits, as well as hexosaminidases from other
      species, including bacteria. Such a region is encoded by exons 5-6 of the HEXA
      and HEXB genes. This region includes beta Arg211 (invariant in 15 sequences),
      which we have previously shown to be an active residue. This region also contains
      two invariant and one conserved acidic residues. A fourth acidic residue, Asp
      alpha 258, beta 290, in exon 7 was also investigated because of its association
      with the B1 variant of Tay-Sachs disease. Conservative substitutions were made at
      each candidate residue by in vitro mutagenesis of a beta cDNA, followed by
      cellular expression. Of these, only the beta Asp196Asn substitution decreased the
      kcat (350-910-fold) without any noticeable effect on the K(m). Mutagenesis of
      either beta Asp240 or beta Asp290 to Asn decreased kcat by 10- or 1.4-fold but
      also raised the K(m) of the enzyme 11- of 3-fold, respectively. The above results
      strongly suggest that beta Asp196 is a catalytic acid residue in beta
      hexosaminidase.

PMID- 8652544
TI  - UDP-galactose 4-epimerase: NAD+ content and a charge-transfer band associated
      with the substrate-induced conformational transition.
AB  - UDP-galactose 4-epimerase from Escherichia coli contains tightly bound NAD+,
      which participates in catalyzing the interconversion of UDP-galactose and UDP
      glucose through its redox properties. The purified enzyme is a dimer of identical
      subunits that consists of a mixture of catalytically active subunits designated
      E.NAD+ and inactive, abortive complexes designated E.NADH.uridine nucleotide, in
      which the uridine nucleotide may be UDP-glucose, UDP-galactose, or UDP [Vanhooke,
      J. L., & Frey, P. A. (1994) J. Biol. Chem. 269, 31496-31404]. The abortive
      complexes are transformed into active E.NAD+ by denaturation of the purified
      enzyme at 4 degrees C in 6 M guanidine hydrochloride buffered at pH 7.0 in the
      presence of 0.126 mM NAD+ for 3 h, followed by dilution of guanidine
      hydrochloride to 0.18 M and of NAD+ to 0.076 mM for 2 h. The renatured enzyme is
      fully active and contains negligible amounts of NADH and uridine nucleotides. The
      extinction coefficent of the epimerase at 280 nm is 1.81 +/- 0.15 mL mg-1 cm-1
      (epsilon 280 = 137 +/- 11 mM-1 cm-1), as determined by quantitative amino acid
      analysis and spectrophotometric measurements. This value allows the value of the
      extinction coefficient for the reduced enzyme (E.NADH)to be calculated as epsilon
      344 = 5.7 mM-1 cm-1. On the basis of the new value of epsilon 280, analytical
      measurements of the nAD+ content of epimerase show that there are two molecules
      of NAD+ per dimer, which confirms conclusions from X-ray crystallography and
      revises the earlier bioanalytical determinations. The ultraviolet/visible
      absorption spectrum of E.NAD+ from denaturation-renaturation experiments reveals
      the presence of a broad absorption band extending from 300 nm to beyond 360 nm
      that cannot be attributed to NADH and appears to be a charge-transfer band. This
      band is partially bleached by UMP and almost totally abolished by UDP, indicating
      that the interactions leading to the charge-transfer band are altered by the
      uridine nucleotide-induced conformational change in this enzyme. This
      conformational change is associated with control of the chemical reactivity of
      NAD+ in the reaction mechanism.

PMID- 8652545
TI  - Parsing the free energy of anthracycline antibiotic binding to DNA.
AB  - The DNA binding free energy of eight anthracycline antibiotics was determined as
      a function of NaCl concentration. Compounds were chosen for study that differed
      from the parent compounds, doxorubicin or daunorubicin, at a single chemical
      substituent. Determination of the salt concentration dependence of the binding
      constant allowed us to dissect the DNA binding free energy of each compound into
      its component nonelectrostatic and polyelectrolyte contributions. Comparison of
      the nonelectrostatic free energy contribution allowed us to evaluate the net
      energetic contribution of specific functional groups to DNA binding. These
      quantitative data revealed a surprisingly large and favorable energetic
      contribution (2 kcal (mol-1)) of the groove-binding daunosamine moiety and a
      substantial energetic penalty for alteration of its stereochemistry. The
      energetic cost of removal of hydroxyl groups at the C-9 and C-14 positions (which
      structural studies indicate may participate in hydrogen-bonding interactions with
      the DNA) was approximately 1 kcal mol(-1). Replacement of the 3'-amino group with
      a hydroxyl group led to a loss of 0.7 kcal mol(-1) in binding free energy, above
      and beyond the energetic penalty resulting from the removal of its positive
      charge from the antibiotic. The results and analysis presented here provide a
      rigorous and detailed description of structure-DNA affinity relationships among
      anthracycline antibiotics. The results are of general interest in understanding
      how total ligand binding free energies are partitioned among substituents and
      will be useful in the formulation of rules for the rational design of novel DNA
      binding agents.

PMID- 8652546
TI  - Erythromycin biosynthesis: kinetic studies on a fully active modular polyketide
      synthase using natural and unnatural substrates.
AB  - 6-Deoxyerythronolide B synthase (DEBS) is a modular polyketide synthase (PKS)
      that catalyzes the biosynthesis of the parent macrolide of erythromycin. On the
      basis of a recently developed cell-free assay (Pieper et al., 1995a) we report
      the results of steady-state kinetic studies on a modular PKS. A truncated form of
      DEBS (DEBS 1+TE), in which DEBS 1 is fused to the thioesterase domain from the C
      terminal end of DEBS 3, was used for most of these studies. The overall k(cat)
      for (2S,3S,4S,5R)-2,4-dimethyl-3,5-dihydroxy-n-heptanoic acid delta-lactone (C9
      lactone) synthesis is 3.4 min(-1), indicating that the enzyme is at least as
      active in vitro as in vivo. The apparent K(m) for (2S)-methylmalonyl-CoA
      consumption by DEBS 1+TE is 24 microM. The catalytic activity of DEBS 1+TE is
      strongly dependent on the phosphate concentration in the reaction buffer in the
      range 0-250 mM, suggesting that hydrophobic interactions may be crucial to the
      assembly of DEBS monomers into a functional complex. Although DEBS 1+TE can
      convert acetyl-, propionyl-, or butyryl-CoA into the corresponding C8-, C9-, and
      C10-lactones (Pieper et al., 1995b), it has a 32-fold preference for a propionate
      primer over an acetate primer and a 7.5-fold preference for a propionate primer
      over a butyrate primer. In the absence of any added primer unit, synthesis can be
      primed via decarboxylation of methylmalonyl-CoA; under these conditions the
      overall k(cat) for polyketide synthesis remains unchanged. Decarboxylation of
      methylmalonyl-CoA is negligible in the presence of saturating concentrations of
      propionyl-CoA but competes with the priming of the enzyme by acetyl-CoA or
      butyryl-CoA. The k(cat) for 6-deoxyerythronolide B synthesis by the complete DEBS
      is 0.5 min(-1). Under these assay conditions, the C9-lactone is also produced as
      an abortive chain elongation product with a k(cat) of 0.23 min(-1), presumably
      due to inefficient assembly of the multimeric protein complex involving DEBS 1,
      2, and 3. Together, these results provide the first comprehensive kinetic
      insights into a fully active modular PKS.

PMID- 8652547
TI  - Glycerol decreases the volume and compressibility of protein interior.
AB  - The addition of hydrogen-bonded cosolvents to aqueous solutions of proteins is
      known to modify both thermodynamic and dynamic properties of the proteins in a
      variety of ways. Previous studies suggest that glycerol reduces the free volume
      and compressibility of proteins. However, there is no directly measured evidence
      for that. We have measured the apparent specific volume (V) and adiabatic
      compressibility (K) of a number of proteins, sugars, and amino acids in water and
      in 30% glycerol at pH 7.4 and 30 degrees C. The values of V and K in water and
      their changes induced by glycerol were extrapolated to the limit of infinite
      solute size. The main results were the following: (a) glycerol decreases V and K
      of proteins, but increases it for amino acids; (b) the V and K values of the
      protein interior in water were found to be 0.784 +/- 0.026 mL/g and (12.8 +/-
      2.5) x 10(-6) mL/g x atm, where the glycerol reduces these values by 8 and 32%,
      respectively; (c) the coefficient of adiabatic compressibility of the structural
      component of proteins affected by the glycerol is estimated to be (50 +/- 10) x
      10(-6) atm(-1), which is comparable to that of water. We propose that the
      glycerol induces a release of the so-called "lubricant" water, which maintains
      conformational flexibility by keeping apart neighboring segments of the
      polypeptide chain. This is expected to lead to the collapsing of the voids
      containing the water as well as to increase intramolecular bonding, which
      explains the observed effect.

PMID- 8652548
TI  - Recombinant Phabs reactive with 7,8-dihydro-8-oxoguanine, a major oxidative DNA
      lesion.
AB  - Antibody Fabs that bind to DNA damages provide useful models for understanding
      DNA damage-specific protein interactions. BSA and RSA conjugates of the
      nucleoside and nucleotide derivatives of the oxidative DNA lesions, 7,8-dihydro-8
      oxoguanine (8-oxoG) and 7,8-dihydro-8-oxoadenine (8-oxoA), were used to immunize
      mice. RNA from the responders was isolated and used to repertoire clone and phage
      display Fabs that bind to these haptens. Direct binding and competitive enzyme
      linked immunosorbent assay (ELISA) demonstrated that phage Fabs (Phabs) specific
      for 8-oxopurine-BSA conjugates and 8-oxoguanine were produced although the Phabs
      did not react with 8-oxopurines in DNA. Amino acid sequence comparisons among
      clones having different binding properties suggested that a relatively small
      portion of the binding surfaces defined by the complementarity determining
      regions (CDR) accounted for hapten binding specificity, whereas other regions
      appeared to stabilize hapten binding by interacting with protein or DNA epitopes.
      Chain shuffling between 8-oxopurine-BSA binding Fabs and a DNA binding Fab showed
      that the heavy chain of the DNA binder conferred DNA binding capacity to the
      light chain of only one of the 8-oxopurine-BSA binders. Homology modeling of the
      8-oxoG-specific clone g37 showed significant similarities to two previously
      isolated monoclonal antibodies specific for single-stranded nucleic acids. In the
      8-oxoG Fab, which did not bind to DNA, the presumptive DNA binding canyon was
      blocked by heavy chain residues in the CDR2 region and appeared to lack part of
      the canyon wall due to the different placement of the light chain framework
      region.

PMID- 8652550
TI  - X-ray crystal structure of human acidic fibroblast growth factor.
AB  - Fibroblast growth factors (FGFs) are mitogenic and chemotactic agents for a wide
      variety of cell types and play a primary role in the regulation of angiogenesis.
      Angiogenesis is involved in a variety of critical physiological events including
      organogenesis, wound healing, ischemic collateral circulation, and solid tumor
      growth. High-resolution structural information is key to understanding the
      mechanism of action of these growth factors. We report here the X-ray crystal
      structure of human acidic FGF (aFGF), with data extending to 2.0 angstroms
      resolution. The crystal contains four independent molecules in the asymmetric
      unit. Each molecule contains a single bound sulfate ion, in similar
      juxtapositions. The bound sulfate is stabilized through hydrogen-bond
      interactions with residues Asn 18, Lys 113, and Lys 118 and defines a potential
      heparin binding site. The hydrogen bond with the N delta 2 moiety of Asn 18
      appears to be the most conserved interaction, being similar to those observed for
      sulfate ion bound to human basic FGF (bFGF) and similar but not identical to
      interactions observed for bovine aFGF with heparin analogs. Of the added solvent
      groups, five ordered water molecules are conserved in each of the four
      independent structures of human aFGF. These water molecules, located at buried
      positions, provide hydrogen bonding partnerships with several buried polar groups
      in the core of the protein. A central interior cavity exists in each of the four
      structures, with sizes ranging from approximately 20 to 50 angstroms3. The cavity
      sizes appear to be significantly smaller than that observed in the related
      protein interleukin-1 beta. The region comprising the high affinity FGF receptor
      binding site is structurally very similar to the corresponding region from human
      bFGF, whereas the low affinity site is structurally quite different. The results
      provide a structural basis for the role of the low affinity binding site in FGF
      receptor discrimination.

PMID- 8652549
TI  - Modulation of a salt link does not affect binding of phosphate to its specific
      active transport receptor.
AB  - Electrostatic interactions are among the key forces determining the structure and
      function of proteins. These are exemplified in the liganded form of the receptor,
      a phosphate binding protein from Escherichia coli. The phosphate, completely
      dehydrated and buried in the receptor, is bound by 12 hydrogen bonds as well as a
      salt link with Arg 135. We have modulated the ionic attraction while preserving
      the hydrogen bonds by mutating Asp 137, also salt linked to Arg 135, to Asn, Gly
      or Thr. High-resolution crystallographic analysis revealed that Gly and Thr (but
      not Asn) mutant proteins have incorporated a more electronegative Cl- in place of
      the Asp carboxylate. That no dramatic effect on phosphate affinity was produced
      by these ionic perturbations indicates a major role for hydrogen bonds and other
      local dipoles in the binding and charge stabilization of ionic ligands.

PMID- 8652551
TI  - Solution structure of the DNA-binding domain of a human papillomavirus E2
      protein: evidence for flexible DNA-binding regions.
AB  - The three-dimensional structure of the DNA-binding domain of the E2 protein from
      human papillomavirus-31 was determined by using multidimensional heteronuclear
      nuclear magnetic resonance (NMR) spectroscopy. A total of 1429 NMR-derived
      distance and dihedral angle restraints were obtained for each of the 83-residue
      subunits of this symmetric dimer. The average root mean square deviations of 20
      structures calculated using a distance geometry-simulated annealing protocol are
      0.59 and 0.90 angstroms for the backbone and all heavy atoms, respectively, for
      residues 2-83. The structure of the human virus protein free in solution consists
      of an eight-stranded beta-barrel and two pairs of alpha-helices. Although the
      overall fold of the protein is similar to the crystal structure of the bovine
      papillomavirus-1 E2 protein when complexed to DNA, several small but interesting
      differences were observed between these two structures at the subunit interface.
      In addition, a beta-hairpin that contacts DNA in the crystal structure of the
      protein-DNA complex is disordered in the NMR structures, and steady-state 1H-15N
      heteronuclear NOE measurements indicate that this region is highly mobile in the
      absence of DNA. The recognition helix also appears to be flexible, as evidenced
      by fast amide exchange rates. This phenomenon has also been observed for a number
      of other DNA-binding proteins and may constitute a common theme in protein/DNA
      recognition.

PMID- 8652552
TI  - Modifying the specificity and activity of the Enterobacter cloacae P99 beta
      lactamase by mutagenesis within an M13 phage vector.
AB  - A library of Enterobacter cloacae P99 beta-lactamase mutants was produced to
      investigate the importance of residues 286-290 for substrate binding and
      catalysis and to characterize mutants with altered specificities and activities
      for various 3'-substituted cephalosporins. This region of the enzyme is a
      component of the active site that has not been implicated as participating in the
      catalytic mechanism but, based on molecular modeling, should contact the 3'
      substituents of cephalosporins. Random mutagenesis was carried out within an M13
      phage vector by hybridization mutagenesis, and the phage library could be highly
      enriched for active beta-lactamase genes by incubation of infected bacteria with
      beta-lactam antibiotics. The mutants were characterized by Michaelis-Menten
      kinetic analyses with several cephalosporin substrates and spanned a 25-fold
      range of k(cat), 24-fold range of K(m), and 6-fold range of k(cat)/K(m) values.
      All five amino acid positions were found to be permissive to substitution, but
      the active mutant proteins carried substitutions that likely maintained the
      structure of the region. Serine 287 was the least permissive to change, requiring
      small, uncharged residues for retention of catalytic activity. The variation of
      Michaelis-Menten kinetic parameters observed in these enzymes was shown to be
      significant in the context of in vitro cytotoxicity assays with the cephalosporin
      doxorubicin prodrug C-Dox and is suitable for experiments to probe the
      relationship between enzyme kinetics and efficacy in enzyme-prodrug approaches to
      targeted therapy.

PMID- 8652553
TI  - Interaction of pyridoxal 5'-phosphate with tryptophan-139 at the subunit
      interface of dimeric D-amino acid transaminase.
AB  - The crystal structure of dimeric bacterial D-amino acid transaminase shows that
      the indole rings of the two Trp-139 side chains face each other in the subunit
      interface about 10 angstroms from the coenzyme, pyridoxal 5'-phosphate. To
      determine whether it has a role in the catalytic efficiency of the enzyme or
      interacts with the coenzyme, Trp-139 has been substituted by several different
      types of amino acids, and the properties of these recombinant mutant enzymes have
      been compared to the wild-type enzyme. In the native wild-type holoenzyme, the
      fluorescence of one of the three Trp residues per monomer is almost completely
      quenched, probably due to its interaction with PLP since in the native wild-type
      apoenzyme devoid of PLP, tryptophan fluorescence is not quenched. Upon
      reconstitution of this apoenzyme with PLP, the tryptophan fluorescence is
      quenched to about the same extent as it is in the native wild-type enzyme. The
      site of fluorescence quenching is Trp-139 since the W139F mutant in which Trp-139
      is replaced by Phe has about the same amount of fluorescence as the wild-type
      enzyme. The circular dichroism spectra of the holo and the apo forms of both the
      wild-type and the W139F enzymes in the far-ultraviolet show about the same degree
      of ellipticity, consistent with the absence of extensive global changes in
      protein structure. Furthermore, comparison of the circular dichroism spectrum of
      the W139F enzyme at 280 nm with the corresponding spectral region of the wild
      type enzyme suggests a restricted microenvironment for Trp-139 in the latter
      enzyme. The functional importance of Trp-139 is also demonstrated by the finding
      that its replacement by Phe, His, Pro, or Ala gives mutant enzymes that are
      optimally active at temperatures below that of the wild-type enzyme and undergo
      the E-PLP --> E-PMP transition as a function of D-Ala concentration with reduced
      efficiency. The results suggest that a fully functional dimeric interface with
      the two juxtaposed indole rings of Trp-139 is important for optimal catalytic
      function and maximum thermostability of the enzyme and, furthermore, that there
      might be energy transfer between Trp-139 and coenzyme PLP.

PMID- 8652554
TI  - A general method of analysis of ligand binding to competing macromolecules using
      the spectroscopic signal originating from a reference macromolecule. Application
      to Escherichia coli replicative helicase DnaB protein nucleic acid interactions.
AB  - Quantitative and accurate analyses of protein-nucleic acid interactions in
      solution are greatly facilitated if the formation of the complex is accompanied
      by a large change of the spectroscopic signal (e.g., fluorescence) originating
      from the protein or nucleic acid. However, there are many instances when protein
      nucleic acid interactions do not induce adequate changes in spectroscopic
      properties of the interacting macromolecules. We describe the theoretical and
      experimental aspects of a general method to analyze such protein-nucleic acid
      interactions. The method is based on quantitative titrations of a reference
      nucleic acid with the protein in the presence of a competing nucleic acid whose
      interaction parameters with the protein are to be determined. The Macromolecule
      Competition Titration (MCT) method allows for the determination of the absolute
      average binding density and the free protein ligand concentration over a large
      binding density range, unavailable by other methods, and construction of a model
      independent true binding isotherm. Moreover, the determination of the absolute
      binding density of the ligand on nonfluorescent nucleic acid is independent of a
      priori knowledge of the binding characteristics of the protein to the reference
      fluorescent nucleic acid. Although the MCT method is applicable to any type of
      physicochemical signal that can be used to monitor the binding, we discuss the
      details of the method as it applies to the analysis monitored by a change in the
      nucleic acid fluorescence intensity and anisotropy upon binding a ligand.
      Moreover, the interaction parameters for a given nucleic acid can be determined
      by using as a reference the long polymer nucleic acid as well as short oligomers.
      In particular, the analysis is greatly simplified if the short fluorescent
      nucleic acid fragment, spanning the exact site-size of the complex and binding
      with only a 1:1 stoichiometry to the protein, is used as a reference
      macromolecule. We have illustrated the MCT method by applying it to the binding
      of the Escherichia coli DnaB helicase to unmodified, nonfluorescent single
      stranded nucleic acids where the interactions are not accompanied by any adequate
      spectroscopic signal changes. In order to analyze simultaneous binding of a
      ligand to different competing nucleic acid lattices, we introduced the combined
      application of the McGhee-von Hippel theory and the Epstein combinatorial
      approach for the binding of a large ligand to a linear, homogeneous nucleic acid
      lattice. Our approach allows one to perform a direct fit of the entire
      experimental isotherm for the protein binding to two competing nucleic acid
      lattices without resorting to complex numerical calculations.

PMID- 8652555
TI  - Binding of Escherichia coli primary replicative helicase DnaB protein to single
      stranded DNA. Long-range allosteric conformational changes within the protein
      hexamer.
AB  - Quantitative analyses of the interactions of the Escherichia coli primary
      replicative helicase DnaB protein with single-stranded DNA have been performed
      using the thermodynamically rigorous fluorescence titration technique. This
      approach allowed us to obtain absolute stoichiometries of the formed complexes
      and interaction parameters, without any assumptions about the relationship
      between the observed signal change and the degree of binding. The analysis of the
      DnaB helicase interactions with nonfluorescent, unmodified nucleic acids has been
      performed, using a novel spectroscopic Macromolecular Competition Titration (MCT)
      method developed in the accompanying paper [Jezewska, M. J., & Bujalowski, W.
      (1996) Biochemistry 35, 2117-2128]. In the presence of the ATP nonhydrolyzable
      analog AMP-PNP, the DnaB helicase binds polymer DNA with a site-size of 20 +/- 3
      nucleotides per protein hexamer. This site-size is independent of the type of
      nucleic acid base as well as the salt concentration and type of salt. Direct
      thermodynamic studies of the polynucleotide and oligomer binding to the DnaB
      hexamer, as well as the competition studies, show that independently of the type
      of nucleic acid base, as well as salt concentration and type of salt in solution,
      the helicase has only a single, strong binding site for DNA. Only this site is
      used when the protein interacts with polymer DNA. Moreover, UV photo-cross
      linking experiments with oligonucleotides of different lengths, dT(pT)19,
      dT(pT)55, and dT(pT)69, suggest that primarily a single subunit of the DnaB
      helicase hexamer is in contact with the DNA. In interactions with polymer nucleic
      acids, the DnaB protein shows preferential intrinsic affinity for poly(dA),
      characterized in our standard conditions (pH 8.1, 10 degrees C, 100 mM NaCl, 5 mM
      MgCl2) by the intrinsic binding constant K = 6 +/- 2 x 10(6) M-1. These
      affinities are comparable to the affinities of the single-strand binding proteins
      in the corresponding solution conditions and strongly suggest that the helicase
      is capable of binding DNA without additional facilitating factors. Both the
      intrinsic affinity and the cooperativity are salt dependent. The formation of the
      DnaB-DNA complex is accompanied by the net release of approximately 2 ions, while
      another net release of approximately 2 ions accompanies the cooperative
      interactions. The data indicate an anion effect on the studied interactions and
      suggests that the released ions most probably originate from both the protein and
      the nucleic acid. The presence of a single, strong binding site on the hexamer,
      built of six chemically identical subunits, the very low site-size of the large
      helicase-DNA complex, and the involvement of a single subunit in contact with the
      nucleic acid indicate the presence of long-range allosteric interactions in the
      DnaB helicase which encompass the entire DnaB hexamer. Our sedimentation velocity
      measurements of the DnaB protein-(AMP-PNP)-5'-fluorescein-(dT)20 ternary complex
      show that the sedimentation coefficient of the complex is S20,W = 12.3 +/- 0.3,
      compared with S20,W = 10.5 +/- 0.3 of the free enzyme, indicating large changes
      in the hydrodynamic properties of the enzyme in the complex. These results
      provide direct evidence that the DnaB hexamer undergoes dramatic conformational
      changes which include all six subunits of the enzyme in the ternary complex.
      Moreover, sedimentation velocity studies of the ternary complex provide direct
      evidence that the hexamer is the species which binds ss nucleic acid. The
      significance of these results for a mechanistic model of the functioning of the
      DnaB helicase in DNA replication is discussed.

PMID- 8652556
TI  - Efficient extraction and partial purification of the polyribosome-associated stem
      loop binding protein bound to the 3' end of histone mRNA.
AB  - Replication-dependent histone mRNAs end in a highly conserved stem-loop sequence
      rather than a polyA sequence. A 45-kDa stem-loop binding protein (SLBP), which
      specifically binds the stem-loop of histone mRNA, is present in both
      polyribosomes and nuclei. An identical 45-kDa protein, as determined by partial
      protease digestion, is cross-linked to a 30 nt RNA containing the 3' stem-loop
      from both nuclei and polyribosomes. The SLBP can also be detected by a
      Northwestern blot procedure using the 30 nt RNA as a probe. As judged from the
      Northwestern assay, more than 90% of the SLBP in the cell is found in the
      polyribosomes with the remaining SLBP localized to the nucleus. Only 5-10% of the
      SLBP could be extracted from the polyribosomes with salt. Treatment of the
      polyribosomes with micrococcal nuclease prior to salt extraction solubilized 5-10
      times more SLBP as an RNA-protein complex. The SLBP could be subsequently
      partially purified from this complex.

PMID- 8652557
TI  - Interactions involving the human RNA polymerase II transcription/nucleotide
      excision repair complex TFIIH, the nucleotide excision repair protein XPG, and
      Cockayne syndrome group B (CSB) protein.
AB  - The human basal transcription factor TFIIH plays a central role in two distinct
      processes. TFIIH is an obligatory component of the RNA polymerase II (RNAP II)
      transcription initiation complex. Additionally, it is believed to be the core
      structure around which some if not all the components of the nucleotide excision
      repair (NER) machinery assemble to constitute a nucleotide excision repairosome.
      At least two of the subunits of TFIIH (XPB and XPD proteins) are implicated in
      the disease xeroderma pigmentosum (XP). We have exploited the availability of the
      cloned XPB, XPD, p62, p44, and p34 genes (all of which encode polypeptide
      subunits of TFIIH) to examine interactions between in vitro-translated
      polypeptides by co-immunoprecipitation. Additionally we have examined
      interactions between TFIIH components, the human NER protein XPG, and the CSB
      protein which is implicated in Cockayne syndrome (CS). Our analyses demonstrate
      that the XPB, XPD, p44, and p62 proteins interact with each other. XPG protein
      interacts with multiple subunits of TFIIH and with CSB protein.

PMID- 8652558
TI  - Role of methionine 184 of human immunodeficiency virus type-1 reverse
      transcriptase in the polymerase function and fidelity of DNA synthesis.
AB  - Methionine 184 of HIV-1 RT is a constituent of the catalytically crucial and
      highly conserved YXDD motif in the reverse transcriptase class of enzymes. We
      investigated the role of this residue by substituting it with Ala and Val by site
      directed mutagenesis followed by extensive characterization of the two mutant
      enzymes. The kinetic parameters governing DNA synthesis directed by RNA and DNA
      templates indicated that both M184A and M184V mutants are catalytically as
      efficient as the wild type enzyme. Photoaffinity labeling of both the mutant and
      the wild type enzyme exhibited an identical affinity for RNA-DNA and DNA-DNA
      template primers. We further demonstrate that M-->V substitution at 184 position
      significantly increases the fidelity of DNA synthesis while M-->A substitution
      results in a highly error-prone enzyme without having compromised its efficiency
      of DNA synthesis. The M184V mutant exhibited a 25-45-fold increase in mismatch
      selectivity (ratio of k(cat)/K(m) of correct versus incorrect nucleotides) as
      compared to the WT enzyme. This pattern of error-prone synthesis is also
      confirmed by examining the abilities of the enzyme-(template-primer) covalent
      complexes to incorporate correct versus incorrect nucleotide onto the immobilized
      template-primer. The nature of error-prone synthesis by the M184A mutant shows an
      increase in both the mismatch synthesis and extension of the mismatched primer
      termini. Using a three-dimensional molecular model of the ternary complex of HIV
      1 RT, template-primer, and dNTP, we observe that the strategic location of M184
      may allow it to interact with the sugar moiety of either the primer nucleotide or
      the dNTP substrate.

PMID- 8652559
TI  - Photoreactivity of platinum(II) in cisplatin-modified DNA affords specific cross
      links to HMG domain proteins.
AB  - Cisplatin-modified DNA forms specific complexes with proteins that contain the
      DNA binding motif known as the high-mobility group (HMG) domain. As a tool for
      investigating the role of these proteins in mediating the cytotoxic effects of
      cisplatin, a set of cisplatin analogs was prepared in which one of the ammine
      ligands was replaced with a photoreactive tethered aryl azide ligand. The ability
      of DNA modified by these platinum complexes to photo-cross-link to HMG1 was
      investigated. During this study, it was discovered that DNA modified with
      cisplatin itself can undergo photoinduced cross-linking to HMG1 when irradiated
      with 300 nm light. The covalent complexes resulting from this latter cross
      linking reaction are completely reversed by the addition of sodium cyanide and
      can be degraded by proteinase K. These results confirm the presence of a protein
      DNA cross-link and demonstrate that the platinum atom itself forms the point of
      attachment. By contrast, DNA modified with transdiamminedichloroplatinum(II),
      [Pt(dien)Cl]Cl, or [Pt(NH3)3Cl]Cl does not cross-link to HMG1 upon irradiation.
      The photochemistry was exploited to cross-link a 15-base pair oligonucleotide
      containing a single, site-specific cis-[Pt(NH3)2{d(GpG)-N7(1),-N7(2)}]
      intrastrand adduct to domain B of HMG1. Following proteolytic digestion of the
      resulting covalent complex, the site of attachment to the protein was determined
      by Edman degradation of the resulting peptide-DNA complex to be a single residue
      on HMG domain B, Lys-6. The data further suggest that this amino acid binds to
      platinum at a site made available by photolabilization of a purine ligand. These
      results afford the first structural information about the interaction of HMG
      domain proteins with cisplatin-modified DNA.

PMID- 8652560
TI  - Slow rate of phosphodiester bond formation accounts for the strong bias that Taq
      DNA polymerase shows against 2',3'-dideoxynucleotide terminators.
AB  - Taq and T7 DNA polymerases have become basic molecular biology "tools" for DNA
      sequence analysis. However, Taq, unlike T7 DNA polymerase, is strongly biased
      against the incorporation of 2',3'-dideoxynucleotide triphosphates (ddNTPs)
      indicating very different substrate selectivities. Equilibrium binding and rate
      constants were measured for 2',3'-ddNTPs as well as for several other 3'
      substituted terminators and compared to 2'-deoxynucleotide substrates (dNTPs). In
      steady-state experiments, Taq Pol I was strongly biased in favor of dATP1 over
      ddATP incorporation by about 700 to 1, in contrast to T7 DNA polymerase which
      showed a preference of only about 4 to 1. Manganese reduced but did not eliminate
      selectivity against 2',3'-ddNTPs. Transient kinetic traces indicated different
      rate-limiting steps for substrate and terminator incorporation. Further
      mechanistic studies showed that the binding constants for substrates and
      terminators were equivalent. However, the rate constants for phosphodiester bond
      formation for 2',3'-ddNTPs were 200-3000-fold lower than for dNTPs. Alternative
      terminators showed only slight improvements. The data were consistent with a
      model in which both substrates and terminators undergo ground-state binding
      followed by formation of a tight-binding Enz.DNA.Nucleotide complex. Immediately
      after complex formation, substrates undergo a rapid nucleoside phosphoryl
      transfer reaction. However, the reaction rates for terminators were slower
      presumably due to misalignment of reactive groups in the active site. Thus, the
      strong bias that Taq DNA polymerase shows against terminators is due to a very
      slow "chemistry" step. Such a strong bias has several kinetic consequences for
      DNA sequence patterns. These consequences are discussed in the text.

PMID- 8652561
TI  - Contribution of facilitated diffusion and processive catalysis to enzyme
      efficiency: implications for the EcoRI restriction-modification system.
AB  - The contribution of nonspecific DNA to enzyme efficiency (k(cat)/K(m)) is
      described for a sequence-specific DNA-modifying enzyme. Our investigation focuses
      on the EcoRI DNA methyltransferase which transfers a methyl group from the
      cofactor S-adenosylmethionine to the second adenine in the double-stranded DNA
      sequence GAATTC. k(cat)/K(m) increases 4-fold as DNA length increases from 14 to
      429 base pairs and increases 2-fold as the distance from the site to the nearest
      end is increased from 29 to 378 base pairs. No changes in k(cat)/K(m) result from
      further increases in either case. A facilitated diffusion mechanism is proposed
      in which the methyltransferase scans an average of <400 base pairs prior to
      dissociation from a DNA molecule. The methyltransferase was found to methylate
      two sites on a single DNA molecule in a distributive rather than a processive
      manner, suggesting that the enzyme dissociates from the DNA prior to release of
      the reaction product S-adenosylhomocysteine. A direct competition experiment with
      the EcoRI endonuclease shows the methyltransferase to be slightly more efficient
      at specific site location and catalysis. A rationale for the role of facilitated
      diffusion in this type II restriction-modification system is proposed.

PMID- 8652562
TI  - Facilitated diffusion of the EcoRI DNA methyltransferase is described by a novel
      mechanism.
AB  - The contribution of nonspecific DNA to binding parameters (K(d), k(off), and
      k(on)) was determined for the EcoRI DNA methyltransferase under noncatalytic
      conditions. An increase in DNA size from 14 to 775 base pairs causes a 20-fold
      decrease in K(d), while k(off) remains constant over the same range. The
      calculated k(on) increases with longer substrates, consistent with a facilitated
      diffusion mechanism. However, the combined results deviate from the model
      developed to describe facilitated diffusion [Berg, O. G., Winter, R. B., & von
      Hippel, P. H. (1981) Biochemistry 20, 6929-6948]. Our results were successfully
      simulated using numerical integration of a kinetic scheme invoking protein
      dissociation via the ends of DNA. Consistent with this scheme, the
      methyltransferase dissociates more slowly from a circularized DNA molecule than
      from the identical linearized form. The simulation strategy correctly models our
      data with the methyltransferase and should be generally useful for routine
      modeling of facilitated diffusion involving protein-DNA systems.

PMID- 8652563
TI  - Cooperative interactions of nucleotide ligands are linked to oligomerization and
      DNA binding in bacteriophage T7 gene 4 helicases.
AB  - The equilibrium nucleotide binding and oligomerization of bacteriophage T7 gene 4
      helicases have been investigated using thymidine 5'-triphosphate (dTTP),
      deoxythymidine 5'-(beta, gamma-methylenetriphosphate)(dTMP-PCP), thymidine 5'
      diphosphate (dTDP), adenosine 5'-triphosphate (ATP), and adenosine 5'-O-(3
      thiotriphosphate) (ATP gamma S). In the presence of nucleotide ligands, T7
      helicases self-assemble into hexamers with six potential nucleotide binding sites
      that are nonequivalent both in the absence and in the presence of single-stranded
      DNA. All nucleotides tested bind with high affinity to three sites (K(d) = 5 x
      10(-6) M, dTTP; 6 x 10(-7) M, dTMP-PCP; 4 x 10(-6) M, dTDP; 3 x 10(-5) M, ATP; 2
      x 10(-6) M, ATP gamma S), while binding to the remaining sites is undetectable.
      Interestingly, nucleotide binding to the high-affinity sites exhibits positive
      cooperativity which is sensitive to protein concentration. This effect is a
      result of ligand binding-linked oligomerization wherein helicase oligomer
      equilibrium changes as a function of both nucleotide and protein concentration. A
      study of DNA binding shows that 1-2 NTPs bound per hexamer are sufficient for
      stoichiometric interaction between the helicase and DNA. Thus, the ring-shaped
      helicase hexamers assemble around DNA with one, two, or three NTPs bound to each
      hexamer. This study also examines the preferred use of dTTP for T7 helicase
      catalyzed DNA unwinding by comparison with ATP, the more commonly used nucleotide
      ligand. ATP binds to the helicase with 6-fold weaker affinity than dTTP and
      promotes hexamerization as well as DNA binding. Nevertheless, DNA unwinding with
      ATP is at least 100-fold slower than with dTTP. Thus, the difference in ATP and
      dTTP utilization probably lies in a highly specific step in the coupling of NTP
      hydrolysis to DNA unwinding.

PMID- 8652564
TI  - Arginine-binding RNAs resembling TAR identified by in vitro selection.
AB  - Specific binding of the human immunodeficiency virus Tat protein to its RNA site
      (TAR) is mediated largely by a single arginine residue located within a basic
      region of the protein. Many essential features of the interaction can be mimicked
      by the free amino acid arginine, and an NMR model has been proposed in which the
      arginine guanidinium group binds to a guanine base in the major groove and to two
      phosphates adjacent to a bulge, with the RNA structure stabilized by a base
      triple between a U in the bulge and an adjacent A:U base pair. To compare the TAR
      structure to other arginine-binding RNAs, we performed in vitro selection
      experiments and identified RNAs with arginine-binding affinities similar to TAR.
      About 40% of the selected RNAs contained the same motif found in TAR: two stems
      separated by a bulge of at least two nucleotides, a U at the 5' position of the
      bulge, and G:C and A:U base pairs above the bulge. In many cases, the upper stems
      contained only the G:C and A:U pairs, located next to small loops. Chemical
      modification experiments demonstrated that these "TAR-like" RNAs bound arginine
      in a manner similar to TAR, and in some cases identified nucleotides outside the
      binding site that contributed to binding. To explore how small loops might help
      stabilize the structures of adjacent arginine-binding sites, we measured arginine
      binding affinities of TAR-like RNAs having all possible three-nucleotide loops.
      An RNA with a UAG loop bound with highest affinity, and chemical modification and
      RNase mapping experiments suggested that the RNA changes conformation upon
      arginine binding, converting a large unstructured loop into a bulge conformation
      related to that of TAR. The results suggest that the arginine-binding site in TAR
      is structurally versatile and demonstrate how binding can be modulated by the
      surrounding RNA context.

PMID- 8652565
TI  - Anatomy of highly expressing chromosomal sites targeted by retroviral vectors.
AB  - The eukaryotic genome contains chromosomal loci with a high transcription
      promoting potential. For their identification in cultured cells, transfer of a
      reporter gene has to be performed by a technique that grants the integration of
      individual copies. We have applied retroviral vectors in conjunction with inverse
      polymerase chain reaction techniques to reconstruct a number of these sites for a
      further characterization. Remarkably, all examples conform to the same design in
      that the process of retroviral infection selected a scaffold- or matrix-attached
      region (S/MAR) that was flanked by DNA with high bending potential. The S/MARs
      are of an unusual type in that they show a high incidence of certain dinucleotide
      repeats and the potential to act as topological sinks. The anatomy of retroviral
      integration sites reveals principles that can be exploited for the development of
      predictable transgenic systems on the basis of expression and targeting vectors.

PMID- 8652566
TI  - Structure of the polyadenylation regulatory element of the human U1A pre-mRNA 3'
      untranslated region and interaction with the U1A protein.
AB  - The N-terminal RNP domain of U1A binds two different RNA substrates with high
      affinity and specificity: stem-loop II of the U1 snRNA and a complex secondary
      structure in the 3'-untranslated region (3'-UTR) of the U1A pre-mRNA. Both RNAs
      contain a single-stranded sequence which is the main site of interaction with the
      protein, but in completely different structural contexts. Here we describe the
      solution structure of the free 3'-UTR RNA molecule and the NMR characterization
      of its complex with the U1A protein N-terminal domain. The structure of the free
      RNA indicates that the stems are nearly canonical A-form helices and that the
      single-stranded region contains local stacking interactions in the context of a
      generally flexible structure. Upon protein binding, the internal loop region
      folds into an ordered structure containing significant changes in the local
      stacking interactions. These results demonstrate the role of RNA structure and
      folding in specific RNA-protein recognition.

PMID- 8652568
TI  - Folding and membrane insertion of the trimeric beta-barrel protein OmpF.
AB  - We have studied folding and membrane insertion of the porin OmpF and compared it
      to OmpA. Both are beta-barrel membrane proteins from the outer membrane of
      Escherichia coli, OmpF forming trimers and OmpA monomers. Each of them can be
      unfolded in solubilized form in a water/urea mixture. Refolding is initiated by
      dilution into a dispersion of lipid vesicles or lipid/detergent vesicles,
      whereupon OmpF and OmpA refold and insert into the membranes. Folding and
      insertion of the monomers proceed in a similar way for the two proteins, but
      native OmpF appears more slowly and with a lower yield than native OmpA because
      of trimerization of OmpF. The dependence of the yield of refolding, membrane
      insertion, and trimerization on pH, lipid concentration, and the presence of
      detergent was investigated. Trimerization of OmpF is shown to take place at or in
      the membrane and a membrane-inserted dimer is detected as an intermediate of this
      process.

PMID- 8652567
TI  - Kinetic mechanism of DNA binding and DNA-induced dimerization of the Escherichia
      coli Rep helicase.
AB  - The monomeric Escherichia coli Rep protein undergoes a DNA-induced dimerization
      upon binding either single-stranded (ss) or duplex DNA with the dimer being the
      active form of the Rep helicase. Using stopped-flow fluorescence, we have
      determined a minimal kinetic mechanism for this reaction in which Rep monomer (P)
      binds to ss oligodeoxynucleotides (dN(pN)15) (S) by a two-step mechanism to form
      PS*, which can then dimerize with P to form P2S as indicated: [reaction in text].
      This minimal mechanism is supported by four independent studies in which the
      kinetics were monitored by changes in fluorescence intensity of three different
      probes: the intrinsic Rep tryptophan fluorescence, the fluorescence of d(T5(2
      AP)T4(2-AP)T5), containing the fluorescent base, 2-aminopurine (2-AP), and
      dT(pT)15 labeled at its 3'-end with fluorescein (3'-F-dT(pT)15). Simultaneous
      (global) analysis of the time courses of d(T5(2-AP)T4(2-AP)T5) (100 nM) binding
      to a range of Rep monomer concentrations (25-400 nM) yields the following rate
      constants: k1 = (3.3 +/- 0.5) x 10(7) M-1 s-1; k-1 = 1.4 +/- 0.4 s-1; k2 = 2.7 +/
      0.9 s-1; k-2 = 0.21 +/- 0.06 s-1; k3 = (4.5 +/- 0.3) x 10(5) M-1 s-1; k-3 =
      0.0027 +/- 0.0008 s-1 [20 mM Tris-HCl, pH 7.5, 6 mM NaCl, 5 mM MgCl2, 5 mM 2
      mercaptoethanol, and 10% (v/v) glycerol, 4.0 degrees C]. This mechanism provides
      direct evidence that Rep monomers can bind ss DNA and that ss DNA binding induces
      a conformational change in the Rep monomer that is probably required for Rep
      dimerization. This conformational change is likely to be large and global since
      it is detected by all three fluorescence probes. The apparent bimolecular rate
      constant for Rep monomer binding to 3'-F-dT(pT)15 [k1(app) = (6.0 +/- 0.7) x
      10(7) M-1 s-1] is slightly larger than measured with d(T5(2-AP)T4(2-AP)T5)
      binding. The apparent rate constant for dissociation of d(T5(2-AP)T4(2-AP)T5) (S)
      from the half-ligated Rep dimer, P2S, increases with increasing concentration of
      a nonfluorescent competitor ss DNA (d(T5-AT4AT5)) (C), indicating transient
      formation of a doubly ligated P2SC intermediate. However, the apparent
      bimolecular rate constant for binding of C to P2S is extremely slow (> or = 250 M
      1 s-1), suggesting the occurrence of a multistep process before dissociation of
      ss DNA. In the absence of competitor DNA, dissociation of ss DNA from P2S occurs
      only after slow dissociation of the Rep dimer to form PS* + P. The implications
      of these results for Rep-catalyzed DNA unwinding are discussed.

PMID- 8652569
TI  - Ligand-induced conformational change of lipoprotein(a).
AB  - Lipoprotein(a) undergoes a dramatic, reversible conformational change on binding
      6-amino-hexanoic acid (6-AHA), as measured by a decrease in the sedimentation
      rate, the magnitude of which is directly proportional to apo(a) mass. A similar
      reversible transition from a compact to an extended form has been shown to occur
      in plasminogen on occupation of a weak lysine binding site. The magnitude of the
      change in Lp(a) with large apo(a) is about 2.5 times that seen for plasminogen,
      however. Regardless of apo(a) size, binding analysis indicated that 1.4-4
      molecules of 6-AHA bound per Lp(a) particle; the midpoint of the conformational
      change occurs at 6-AHA concentrations of 100-200 mM. Since rhesus Lp(a), which
      lacks both kringle V and the strong lysine binding site on kringle IV 10, also
      undergoes a similar conformational change, the phenomenon may be attributable to
      weak sites, possibly located in K-IV 5-8. Compact Lp(a), i.e., native Lp(a), had
      a frictional ratio (f/f0) of 1.2 that was independent of apo(a) mass, implying
      constant shape and hydration. For Lp(a) in saturating 6-AHA, f/f0 ranged from 1.5
      to over 2.1 for the largest apo(a) with 32 K-IV, indicating a linear relationship
      between hydrodynamic volume and number of kringles, as expected for an extended
      conformation. However, only the variable portion of apo(a) represented by the K
      IV 2 domains, participates in the conformational change; the invariant K-IV 3-9
      domains remain close to the surface. These results suggest that apo(a) is
      maintained in a compact state through interactions between weak lysine binding
      sites and multiple lysines on apoB and/or apo(a), and that these interactions can
      be disrupted by 6-AHA, a lysine analog.

PMID- 8652570
TI  - Kinetic and spectroscopic characterization of fluorescent ribose-modified ATP
      analogs upon interaction with skeletal muscle myosin subfragment 1.
AB  - The interaction of fluorescent ATP analog 2'(3')-O-[N-[2-[3-(5
      fluoresceinyl)thioureido]-ethyl]carbamoyl]adenosine 5'-triphosphate (FEDA-ATP)
      with rabbit skeletal myosin subfragment 1 (S1) and acto-S1 was studied. This and
      related ATP analogs are potentially useful for determination of the ATPase
      activity of single myosin filaments using fluorescence microscopy [Sowerby et al.
      (1993) J. Mol. Biol. 234, 114-123]. However, it is necessary that such analogs
      mimic ATP in their kinetics of turnover. The apparent second-order association
      rate constants for FEDA-ATP binding to S1 and for FEDA-ATP-induced dissociation
      of acto-S1 are about 4 times slower than those for ATP. As with ATP, the
      hydrolysis step is fast, so that the M.FEDA-ADP.P(i) complex is the major steady
      state intermediate. The turnover rate is the same for the 2' and 3' FEDA-ATP
      derivatives and similar to that of ATP itself. The dissociation rate constant for
      FEDA-ADP from S1 is identical to that for ADP. Actin-activated turnover is
      comparable for both FEDA-ATP and ATP. The corresponding rhodamine and
      sulfoindocyanine, Cy3.18 (Cy3), derivatives also appear to be reasonable analogs.
      FEDA-ATP binding leads to a 25-40% reduction in fluorescein fluorescence.
      Spectral properties of the bound nucleotide were explored by trapping FEDA-ADP as
      its aluminum fluoride complex. The fluorescence quenching is a consequence of a
      reduction in both absorbance and excited-state lifetime, but there is little
      change in spectral shape.

PMID- 8652571
TI  - Salt effects on the amide hydrogen exchange of bovine pancreatic trypsin
      inhibitor.
AB  - Peptide hydrogen exchange is measured in bovine pancreatic trypsin inhibitor
      (BPTI) by 2D NMR in KCl solutions varying between 0.02 and 0.43 M. The effects of
      salt are analyzed for 16 assigned peptide groups located near the protein-solvent
      interface in the crystal structure. Salt effects are obtained for exchange by H+
      and OH- catalysis, at pH 2.3 and 5.3, respectively. Semilogarithmic plots of rate
      constants vs the square root of the ionic strengths are virtually linear. The
      salt effects, taken as the slopes of these plots, vary both in size and sign for
      each catalytic process, reflecting the variation of local electrostatic field at
      the exchanging site. The effects are correlated with electrostatic potentials
      calculated by the finite differences method, taking into account both ionic and
      dipolar charges in the static structure. This suggests that the transition
      complexes between the catalyst and the protein are formed with the protein
      structure very similar to the crystal structure.

PMID- 8652572
TI  - Unusual trigonal-planar copper configuration revealed in the atomic structure of
      yeast copper-zinc superoxide dismutase.
AB  - The three-dimensional structure of yeast copper-zinc superoxide dismutase
      (CuZnSOD) has been determined in a new crystal form in space group R32 and
      refined against X-ray diffraction data using difference Fourier and restrained
      crystallographic refinement techniques. The unexpected result is that the copper
      ion has moved approximately 1 angstrom from its position in previously reported
      CuZnSOD models, the copper-imidazolate bridge is broken, and a roughly trigonal
      planar ligand geometry characteristic of Cu(I) rather than Cu(II) is revealed.
      Final R values for the two nearly identical room temperature structures are 18.6%
      for all 19 149 reflections in the 10.0-1.7 angstrom resolution range and 18. 2%
      for 17 682 reflections (F > 2 sigma) in the 10.0-1.73 angstrom resolution range.
      A third structure has been determined using X-ray data collected at -180 degrees
      C. The final R value for this structure is 19.0% (R(free) = 22.9%) for all 24 356
      reflections in the 10.0-1.55 angstrom resolution range. Virtually no change in
      the positions of the ligands to the zinc center is observed in these models. The
      origin of the broken bridge and altered Cu-ligand geometry is discussed.

PMID- 8652573
TI  - Human interleukin 4 receptor complex: neutralization effect of two monoclonal
      antibodies.
AB  - The interaction of human interleukin 4 with the extracellular domain of its
      receptor alpha-subunit (shuIL-4R alpha) was characterized in studies utilizing
      chemical cross-linking, size exclusion chromatography, and Western blot analysis.
      A 1:1 stoichiometric complex could be demonstrated over a wide range (0.04-2.7)
      of ligand-receptor concentration ratios. It could also be cross-linked with
      bifunctional reagents containing a minimum chain length of eight methylene
      residues or the equivalent (11.4 angstroms). Using surface plasmon resonance,
      (SPR) technology, we established the high-affinity of human interleukin 4 (huIL
      4) to shuIL-4R alpha which was immobilized on a BIAcore sensor chip (K(d) = 46
      pM). The mechanisms of action of neutralizing monoclonal antibodies (Mab) 25D2
      and 35F2 [Abrams et al. (1991) U.S. Patent 5,041,381; Ramanathan et al. (1990) in
      Advances in Gene Technology: The Molecular Biology of Immune Diseases and the
      Immune Response (Streilein, J. W., et al., Eds.) p 163, IRL Press, Oxford;
      DeKruyff et al. (1989) J. Exp. Med. 170, 1477-1493] were subsequently evaluated
      on the basis of their interaction with huIL-4 in the presence of shuIL-4R alpha.
      SPR studies showed that Mab 25D2 binds to huIL-4 and reduces its affinity for
      shuIL-4R alpha by 54-fold. Formation of a ternary complex between Mab 25D2 and
      the huIL-4/shuIL-4R alpha complex was demonstrated in size exclusion
      chromatography experiments. In contrast, Mab 35F2 which also binds huIL-4 failed
      to form a stable ternary complex with huIL-4 and shuIL-4 alpha during size
      exclusion chromatography. SPR studies supported this finding and showed that the
      interactions of Mab 35F2 and shuIL-4R alpha to huIL-4 are mutually exclusive.
      These data are consistent with results of previous epitope mapping studies
      showing that Mabs 25D2 and 35F2 bind to huIL-4 at two different sites [Ramanathan
      et al. (1993) Biochemistry 32, 3549-3556]. Together, the results suggest that Mab
      25D2 binds to a domain in huIL-4 including helix D and exerts its inhibitory
      effect through a dual action. It decreases the affinity of huIL-4 for huIL-4R
      alpha and potentially blocks interaction with a secondary receptor subunit such
      as the IL-2R gamma [Reusch et al. (1994) Eur. J. Biochem. 222, 491-499]. Mab 35F2
      operates through a direct and simpler mechanism, binding to helix C and
      inhibiting huIL-4 activity by sterically excluding all interaction with huIL-4R
      alpha.

PMID- 8652574
TI  - Characterization of the covalent binding of thiostrepton to a thiostrepton
      induced protein from Streptomyces lividans.
AB  - Thiostrepton is a highly modified multicyclic peptide antibiotic synthesized by
      diverse bacteria. Although best known as an inhibitor of protein synthesis,
      thiostrepton is also a potent activator of gene expression in Streptomyces
      lividans. In these studies, we characterize the nature of the interaction between
      thiostrepton and two proteins that it induces, TipAL and TipAS. In the absence of
      added cofactors, thiostrepton formed a complex with either TipAL or TipAS in
      aqueous solution. The TipA-thiostrepton complex was not dissociated by
      denaturants such as SDS, urea, or disulfide reducing agents. The mass of the
      TipAS-thiostrepton complex as determined by both sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry (MS) was
      equivalent to the sum of TipAS and thiostrepton. Thiostrepton also reacted
      spontaneously with free cysteine (but not with other amino acids tested) to
      generate stable compounds having masses equivalent to thiostrepton plus 3 to 4
      cysteines. Blocking experiments indicated that complex formation required
      dehydroalanine residues on thiostrepton and cysteine residues on TipAS. When the
      TipAS-thiostrepton complex was digested with trypsin and analyzed by MS, the
      thiostrepton adduct was found bound only to the unique cysteine-containing TipAS
      peptide fragment. Amino acid analysis confirmed that the TipAS-thiostrepton
      complex contained lanthionine, the product of a reaction between dehydroalanine
      and cysteine. Together, these data document a covalent attachment of thiostrepton
      to TipA proteins mediated by bond formation between dehydroalanine of
      thiostrepton and cysteine of TipAS. Implications regarding the function of TipAS
      as a thiostrepton (electrophile)-sequestering protein and thiostrepton-mediated
      activation of TipAL as a model of irreversible transcriptional activation are
      discussed.

PMID- 8652575
TI  - Strategy for recombinant multichain protein synthesis: fibrinogen B beta-chain
      variants as thrombin substrates.
AB  - Thrombotic disease has been found in patients with congenital dysfibrinogens that
      have abnormalities in the amino terminal domain of the fibrinogen B beta-chain.
      Surprisingly, these fibrinogens are poor substrates for thrombin. In order to
      examine the molecular basis for this impaired thrombin-fibrinogen interaction, we
      synthesized three fibrinogens with single amino acid substitutions in this
      domain: B beta A68T, B beta P70S, and B beta L72S. B beta-chain expression
      vectors were altered by PCR-directed mutagenesis of the B beta cDNA. The altered
      vectors were transfected into a Chinese hamster ovary (CHO) cell line that was
      constructed as a first step in recombinant fibrinogen synthesis, this CHO line
      synthesizes fibrinogen A alpha- and gamma-chains. More than 86% of the stably
      selected clones expressed significant levels of fibrinogen, confirming that a two
      step strategy permitted efficient synthesis of variant fibrinogens. In large
      scale cultures variant fibrinogen accumulation in serum-free medium fluctuated
      between 1 and 15 micrograms/mL. Normal and variant recombinant fibrinogens were
      compared to plasma fibrinogens by following the time course of thrombin-catalyzed
      release of fibrinopeptides. Only the variant B beta A68T, a change identified in
      a congenital dysfibrinogen, showed significantly impaired kinetics. The rate of
      fibrinopeptide A release was decreased 27-fold, and the rate of fibrinopeptide B
      release was decreased 45-fold relative to normal fibrinogen. Fibrinopeptide
      release was not significantly altered by the substitutions B beta P70S or B beta
      L72S. These results suggest that B beta residue Ala68 has a novel and critical
      role in the interaction between thrombin and fibrinogen.

PMID- 8652576
TI  - In vitro selection of RNA specifically cleaved by bacteriophage T4 RegB
      endonuclease.
AB  - T4 RegB endonuclease specifically cleaves at -GGAG- sites in several early T4
      messages, rendering them nonfunctional. Not all -GGAG- sites are processed
      equally by RegB; those found at the Shine-Dalgarno sequences and in
      intercistronic regions are processed with higher efficiency than the -GGAG- sites
      located in coding regions. The low activity of RegB observed in vitro is enhanced
      by 1-2 orders of magnitude by the Escherichia coli ribosomal protein S1. We have
      used SELEX (systematic evolution of ligands by exponential enrichment) on a
      combinatorial RNA library to obtain molecules that are specifically cleaved by T4
      RegB endonuclease in the presence of S1. The sequences obtained contain the
      required -GGAG- tetranucleotide and were unusually enriched in adenosine and
      cytosine nucleotides. No consensus structure or sequence motif other than -GGAG-
      was conserved among the selected molecules. The majority of the RNAs are entirely
      dependent on S1 for RegB-catalyzed cleavage; however, a few RNAs are found to be
      S1 independent but are cleaved by RegB with much lower rates.

PMID- 8652577
TI  - Recombinant gene expression and 1H NMR characteristics of the kringle (2 + 3)
      supermodule: spectroscopic/functional individuality of plasminogen kringle
      domains.
AB  - The plasminogen kringle 2 (K2HPg) and kringle 3 (K3HPg) modules occur in tandem
      within the polypeptide segment that affords the heavy chain of plasmin. The K2HPg
      and K3HPg are unique among the plasminogen kringle domains in that they also are
      linked to each other via the Cys169-Cys297 (Cys4 of K2HPg to Cys43 of K3HPg,
      kringle numbering convention) disulfide bridge, thus generating a K2HPg-K3HPg
      "supermodule". The kringle (2 + 3) sequence of human plasminogen (r
      EE[K2HPgK3HPg]DS) was expressed in Escherichia coli, using an expression vector
      containing the phage T5 promoter/operator N250PSN250P29 and the codons for an N
      terminal hexahistidine tag to ensure the isolation of the recombinant protein by
      affinity chromatography on Ni(2+)-nitrilotriacetic acid/agarose under denaturing
      and reducing conditions. Kringle (2 + 3) was refolded in the presence of
      glutathione redox buffer. By taking advantage of the lysine affinity of kringle
      2, the protein was purified by affinity chromatography on lysine-Bio-Gel.
      Recombinant kringle (2 + 3) was identified by amino acid composition, N-terminal
      sequence and mass determination. The 1H NMR spectrum shows that the intact r
      K2HPgK3HPg is properly folded. By reference to spectra of the individual
      kringles, r-K2HPg and r-K3HPg, resonances of the K2HPg and K3HPg components in
      the spectrum of the intact r-K2HPgK3HPg can be readily distinguished. The
      strictly conserved Leu46 residue (kringle residue number convention) yields delta
      methyl signals that are characteristic for K2HPg and K3HPg, exhibiting chemical
      shifts of -0.87 and -0.94 ppm, respectively, which are distinct from those of
      K1HPg, K4HPg, and K5HPg, (-1.04 to -1.05 ppm). Thus, the high-field Leu46 signals
      from K2HPg and K3HPg are well resolved from those of other kringles and can be
      identified unambiguously in spectra of the K1HPgK2HPgK3HPg elastolytic fragment
      of plasminogen as well as in spectra of Glu-plasminogen. Overall, r-K2HPgK3HPg
      exhibits broader resonance line widths than does the K1HPg component, consistent
      with a lesser mobility of the K2HPgK3HPg segment within the K1HPgK2HPgK3HPg
      fragment, a reflection of the extra structural constraint imposed by the
      disulfide bridge linking K2HPg to K3HPg. The ligand 6-aminohexanoic acid (6-AHA),
      which is known to interact with r-K2HPg but not with r-K3HPg, selectively
      perturbs K2 aromatic signals in the intact r-K2HPgK3HPg spectrum while leaving K3
      resonances largely unaffected. Association constant (K(a)) values for 6-AHA
      determined from 1H NMR ligand titration experiments yield K(a) approximately 2.2
      +/- 0.3 mM(-1) for the intact r-K2HPgK3HPg, comparable to K(a) approximately 2.3
      +/- 0.2 mM(-1) determined for the isolated r-K2HPg, which demonstrates that the
      interactions of 6-AHA with the K2HPg ligand-binding site are not significantly
      affected by the neighboring K3HPg domain within the intact r-K2HPgK3HPg
      supermodule.

PMID- 8652578
TI  - Kinetics and motility of the Eg5 microtubule motor.
AB  - We have investigated the kinetic properties of the slow plus end directed
      microtubule (MT) motor Eg5. The recombinantly expressed fusion protein E437GST,
      containing residues 12-437 of Eg5 fused to the N-terminus of glutathione S
      transferase (GST), is dimeric and motile, translocating MTs at an average speed
      of 0.063 (+/-0.01) micrometers(-1). The kinetics of ATP turnover by E437GST were
      investigated using the fluorescent ATP analogue methylanthraniloyl-ATP (mantATP).
      In the absence of MTs, mantADP release from E437GST is slow (0.006 s(-1) in 50 mM
      NaCl) and rate-limiting. MTs accelerate this kinetic step approximately 850-fold
      to a maximal rate of 4.94 s(-1). Under these conditions, the steady-state rate of
      mantATP turnover was 1.92 s(-1), indicating that MT-activated mantADP release
      accounts for at least 40% of the total cycle time of the motor and is probably
      rate-limiting. This step is around 10-fold slower in Eg5 than in kinesin,
      consistent with it limiting the rate of physical stepping in both Eg5 and
      kinesin. The dissociation constants of the motor in the presence of various
      nucleotides were determined using MT pelleting assays. ADP stabilizes the weakest
      bound state of the motor, while ATP, ATP gamma S, AMPPNP, and apyrase all induce
      a shift toward tighter binding states. Overall, the data indicate that Eg5
      displays strong kinetic homologies with the two other well-characterized MT
      motors, kinesin and non claret disjunctional, suggesting that all kinesin
      superfamily motors may share the same basic mechanochemistry.

PMID- 8652579
TI  - Comparison of the conformation, hydrophobicity, and model membrane interactions
      of diphtheria toxin to those of formaldehyde-treated toxin (diphtheria toxoid):
      formaldehyde stabilization of the native conformation inhibits changes that allow
      membrane insertion.
AB  - Toxoids are inactivated protein toxins that are used in vaccines. The behavior of
      diphtheria toxin reacted with formaldehyde (diphtheria toxoid) was compared to
      that of diphtheria toxin in order to understand the nature of the changes that
      occur in toxoids upon protein reaction with formaldehyde. Despite the
      intramolecular cross-links in the toxoid, the conformations of the toxoid and the
      toxin were very similar in both the native and low pH-induced membrane
      penetrating states as judged by fluorescence and hydrophobicity properties.
      However, the toxoid underwent thermal-, low-pH-, and guanidinium chloride-induced
      conformational changes only at more extreme conditions than needed to induce such
      changes in the toxin. This implies that formaldehyde modification stabilizes the
      native conformation relative to several conformations that involve different
      degrees of unfolding. The stabilization to conformational changes induced by low
      pH is particularly interesting because low pH induces partial unfolding of the
      toxin to a molten globule-like state. It was found that the toxoid only gained
      the ability to interact with model membrane vesicles at a lower pH than the
      toxin. Because low-pH-induced unfolding and membrane interaction are critical
      steps in the entry of diphtheria toxin into cells, the resistance of the toxoid
      to these changes may be linked to its lack of toxicity. The implications of these
      results for the construction of toxoids are discussed.

PMID- 8652580
TI  - The active-site histidine-10 of enterococcal NADH peroxidase is not essential for
      catalytic activity.
AB  - In order to test the proposal [Stehle, T., Claiborne, A., & Schulz, G. E. (1993)
      Eur. J. Biochem. 211, 221-226] that the active-site His10 of NADH peroxidase
      functions as an essential acid-base catalyst, we have analyzed mutants in which
      this residue has been replaced by Gln or Ala. The k(cat) values for both H10Q and
      H10A peroxidases, and the pH profile for k(cat) with H10Q, are very similar to
      those observed with wild-type peroxidase. Both mutants, however, exhibit
      K(m)(H2O2) values much higher (50-70-fold) than that for wild-type enzyme, and
      stopped-flow analysis of the H2O2 reactivity of two-electron reduced H10Q
      demonstrates that this difference is due to a 150-fold decrease in the second
      order rate constant for this reaction with the mutant. Stopped-flow analyses also
      confirm that reduction of the enzyme by NADH is essentially unaffected by His10
      replacement and remains largely rate-limiting in turnover; the formation of an
      E.NADH intermediate in the conversion of E-->EH2 is confirmed by diode-array
      spectral analyses with H10A. Both H10Q and H10A mutants, in their oxidized E(FAD,
      Cys42-sulfenic acid) forms, exhibit enhanced long-wavelength absorbance bands
      (lambda(max) = 650 nm and 550 nm, respectively), which most likely reflect
      perturbations in a charge-transfer interaction between the Cys42-sulfenic acid
      and FAD. Combined with the 50-fold increase in the second-order rate constant for
      H2O2 inactivation (via Cys42-sulfenic acid oxidation) of the H10Q mutant, these
      observations support the proposal that His10 functions in part to stabilize the
      unusual Cys42-sulfenic acid redox center within the active-site environment.

PMID- 8652581
TI  - Solution X-ray scattering data show structural differences between yeast and
      vertebrate calmodulin: implications for structure/function.
AB  - We present here the first evidence, obtained by the use of solution X-ray
      scattering, of the solution structure of yeast calmodulin, a poor activator of
      vertebrate enzymes. The radius of gyration of yeast calmodulin decreased from
      21.1 to 19.9 angstroms when excess Ca2+ ions were added. The profiles of the pair
      distribution function suggested that yeast calmodulin without Ca2+ has a dumbbell
      like shape which changes toward a rather asymmetric globular shape, from its
      dumbbell shape, by the binding of Ca2+. In the presence of a calmodulin binding
      peptide such as MLCK-22 (a synthetic peptide corresponding to residues 577-598 of
      skeletal myosin light chain kinase), the radius of gyration of yeast calmodulin
      decreased by 1.6 angstroms, and the molecular shape of it estimated from the
      profile of the pair-distribution function was globular but less compact than that
      of vertebrate calmodulin. These results for the structure of yeast calmodulin
      complexed with Ca2+ and with Ca(2+)-peptides are quite different from those of
      vertebrate calmodulin. Thus, the functional differences between yeast and
      vertebrate calmodulin which we reported previously [Matsuura, I., et al. (1993)
      J. Biol. Chem. 268, 13267-13273] have been interpreted on the basis of the
      structural differences between them. Moreover, the structural studies on chimeric
      proteins of chicken and yeast calmodulin suggest that Ca2+ binding at site IV is
      essential to form the full active dumbbell structure, which is characteristic of
      vertebrate-type calmodulin.

PMID- 8652582
TI  - Kinetic and X-ray structural studies of a mutant Escherichia coli alkaline
      phosphatase (His-412-->Gln) at one of the zinc binding sites.
AB  - Site-specific mutagenesis has been used to replace His-412 with glutamine in
      Escherichia coli alkaline phosphatase. In the wild-type enzyme His-412 is a
      direct ligand to one of the catalytically important zinc atoms (Zn1) in the
      active site. The mutant enzyme (H412Q) exhibited about the same k(cat), but a 50
      fold increase in K(m) compared to the corresponding kinetic parameters for the
      wild-type enzyme. Furthermore, the H412Q enzyme had a lower zinc content than the
      wild-type enzyme. In contrast to the wild-type enzyme, Tris was less effective in
      the transferase reaction and dramatically inhibited the hydrolysis reaction of
      the H412Q enzyme. The addition of zinc to the mutant enzyme increased the k(cat)
      value above that of the wild-type enzyme, partially restored the weak substrate
      and phosphate binding, and also alleviated the inhibition by Tris. The structure
      of the H412Q enzyme was also determined by X-ray crystallography. The overall
      structure of the H412Q enzyme was very similar to that of the wild-type enzyme;
      the only alpha-carbon displacements over 1 angstrom were observed near the
      mutation site. In the H412Q structure no phosphate was bound in the active site
      of the enzyme; however, two water molecules were observed where phosphate
      normally binds in the wild-type enzyme. Close examination of the active site of
      the H412Q structure revealed structural changes in Ser-102 as well as at the
      mutation site. For example, the carbonyl oxygen of the side chain of Gln-412
      rotated away from the position of His-412 in the wild-type structure, although
      too far away (3.2 angstroms) to coordinate to Zn1. Studies on the H412Q enzyme,
      and a comparison of the H412Q and H412N structures, suggest that the structure
      and electostatics of the imidazole ring of histidine are critical for its
      function as a zinc ligand in alkaline phosphatase.

PMID- 8652583
TI  - Resonance Raman spectroscopic identification of a histidine ligand of b595 and
      the nature of the ligation of chlorin d in the fully reduced Escherichia coli
      cytochrome bd oxidase.
AB  - Cytochrome bd oxidase is a bacterial terminal oxidase that contains three
      cofactors: a low-spin heme (b558), a high-spin heme (b595), and a chlorin d. The
      center of dioxygen reduction has been proposed to be a binuclear b595/d site,
      whereas b558 is mainly involved in transferring electrons from ubiquinol to the
      oxidase. Information on the nature of the axial ligands of the three heme centers
      has come from site-directed mutagenesis and spectroscopy, which have implicated a
      His/Met coordination for b558 (Spinner, F., Cheesman, M. R., Thomson, A. J.,
      Kaysser, T., Gennis, R. B., Peng, Q., & Peterson, J. (1995) Biochem. J. 308, 641
      644; Kaysser, T. M., Ghaim, J. B., Georgiou, C., & Gennis, R. B. (1995)
      Biochemistry 34, 13491-13501), but the ligands to b595 and d are not known with
      certainty. In this work, the three heme chromophores of the fully reduced
      cytochrome bd oxidase are studied individually by selective enhancement of their
      resonance Raman (rR) spectra at particular excitation wavelengths. The rR
      spectrum obtained with 413.1-nm excitation is dominated by the bands of the 5cHS
      b595(2+) cofactor. Excitation close to 560 nm yields a rR spectrum dominated by
      the 6cLS b558(2+) heme. Wavelengths between these values enhance contributions
      from both b595(2+) and b558(2+) chromophores. The rR bands of the ferrous chlorin
      become the major features with red laser excitation (595-650 nm). The rR data
      indicate that d2+ is a 5cHS system whose axial ligand is either a weakly
      coordinating protein donor or a water molecule. In the low-frequency region of
      the 441.6-nm spectrum, we assign a rR band at 225 cm-1 to the (b595)Fe(II)-N(His)
      stretching vibration, based on its 1.2-cm(-1) upshift in the 54Fe-labeled enzyme.
      This observation provides the first physical evidence that the proximal ligand of
      b595 is a histidine. Site-directed mutagenesis had suggested that His 19 is
      associated with either b595 or d (Fang, H., Lin, R. -J., & Gennis, R. B. (1989)
      J. Biol. Chem. 264, 8026-8032). On the basis of the present study, we propose
      that the proximal ligand of b595 is His 19. We have also studied the reaction of
      cyanide with the fully reduced cytochrome bd oxidase. In approximately 700-fold
      excess cyanide (approximately 35 mM), the 629-nm UV/vis band of d2+ is blue
      shifted to 625 nm and diminished in intensity. However, the rR spectra at each of
      three different gamma(0) (413.1, 514.5, and 647.1 nm) are identical with or
      without cyanide, thus indicating that both b595 and d remain as 5cHS species in
      the presence of CN-. This observation leads to the proposal that a native ligand
      of ferrous chlorin d is replaced by CN- to form the 5cHS d2+ cyano adduct. These
      findings corroborate our companion study of the "as-isolated" enzyme in which we
      proposed a 5cHS d3+ cyano adduct (Sun, J., Osborne, J. P., Kahlow, M. A.,
      Kaysser, T. M., Hill, J. J., Gennis, R. B., & Loehr, T. M. (1995) Biochemistry
      34, 12144-12151). To further characterize the unusual and unexpected nature of
      these proposed high-spin cyanide adducts, we have obtained EPR spectral evidence
      that binding of cyanide to fully oxidized cytochrome bd oxidase perturbs a spin
      state equilibrium in the chlorin d3+ to yield entirely the high-spin form of the
      cofactor.

PMID- 8652584
TI  - The structure-function relationship and reduction potentials of high oxidation
      states of myoglobin and peroxidase.
AB  - In these studies, we substitute electron-withdrawing (diacetyl) or -donating
      (diethyl) groups at the 2- and 4-positions of the heme in sperm whale Mb and HRP,
      and examine the structural and biochemical consequences. X-ray absorption
      spectroscopy shows that increased electron density at the heme results in an
      increased iron-pyrrole nitrogen average distance in both HRP and Mb, while
      decreased electron density results in shorter average distances. In HRP, the
      proximal ligand is constrained by a H-bonding network, and axial effects are
      manifested entirely at the distal site. Conversely, in Mb, where the proximal
      ligand is less constrained, axial effects are seen at the proximal side. In HRP,
      electron density at the heme iron depends linearly on pK3, a measure of the
      basicity of the porphyrin pyrrole nitrogens [Yamada, H., Makino, R., & Yamazaki,
      I. (1975) Arch. Biochem. Biophys. 169, 344-353]. Using diethyl substitution (pK3
      = 5.8) and diacetyl substitution (pK3 = 3.3) in HRP and Mb, we measured the one
      electron reduction potentials (E(O)') of HRP compounds I and II and ferryl Mb.
      Compound I showed a decreased E(O)' with increasing electron density at the heme
      (pK3), similar to E(O)' of ferric HRP. E(O)' of HRP compound II and ferryl Mb
      showed an opposite dependence. This behavior of E(O)', while initially
      surprising, can be explained by the apparent net positive charge on the iron
      porphyrin in each oxidation state of the hemoproteins.

PMID- 8652585
TI  - Mg coordination by amino acid side chains is not required for assembly and
      function of the special pair in bacterial photosynthetic reaction centers.
AB  - A conserved histidine serves as the axial ligand to the Mg of
      bacteriochlorophylls in the photosynthetic reaction center (RC) and many other
      photosynthetic systems. The histidine axial ligands to each and both
      bacteriochlorophylls of the special-pair primary electron donor of the
      Rhodobacter sphaeroides RC have been replaced with glycine to create a cavity. In
      each case, RCs assemble and a normal special-pair comprised of Mg-containing
      bacteriochlorophylls is formed, as judged by many different spectroscopic and
      functional probes (e.g., absorption and Stark spectra, *P decay kinetics, P+Q(A)-
      recombination rate, and the redox potential of P). In contrast with heme
      proteins, where this strategy has been exploited to introduce exogenous organic
      ligands that can greatly affect the functional properties of the protein
      [DePillis, G. D., Decatur, S. M., Barrick, D., & Boxer, S. G. (1994) J. Am. Chem.
      Soc. 116, 6981-6982], addition of exogenous imidazole, pyridine, and ethanethiol
      has no measurable effect on the functional properties of the special pair in
      these cavity mutants. FT-Raman spectroscopy is used to provide more detailed
      information on local interactions around the special pair. Data in the core-size
      marker mode and carbonyl stretching region suggest that an adventitious ligand
      replaces histidine as the axial ligand to bacteriochlorophylls in the cavity
      mutants. We speculate that this ligand is water. Furthermore, the position of the
      core-size marker mode changes when the cavity mutant RCs are incubated with
      exogenous ligands such as imidazole, pyridine, or ethanethiol, suggesting that
      the axial ligand to the special pair BChls can be exchanged in the cavity
      mutants. Interestingly the temperature dependence of P+Q(A)- recombination
      kinetics is very similar in the cavity mutants and WT, suggesting that the axial
      ligands to the special pair are not significant contributors to the solvent
      reorganization energy for this reaction. These results lead to the surprising
      conclusion that the nature of the axial ligand to the special pair has little
      influence on the properties of the macrocycle, and that axial coordination from
      the protein by histidine is not required for bacteriochlorophyll binding or for
      efficient electron transfer in the RC.

PMID- 8652586
TI  - Environment of copper in Pseudomonas aeruginosa azurin probed by binding of
      exogenous ligands to Met121X (X = Gly, Ala, Val, Leu, or Asp) mutants.
AB  - The binding of small exogenous ligands to mutants of the blue copper protein
      azurin from Pseudomonas aeruginosa, altered in the axial position, Met121X (X =
      Gly, Ala, Val, Leu, or Asp), has been studied with optical and electron
      paramagnetic resonance (EPR) spectroscopy. The results show that small molecules
      can enter the pocket left by the side chain of Met121. For azide, the
      dissociation constants are Leu > Val > Ala, reflecting the increasing space
      available. The Gly and Asp mutants bind azide less strongly than the Ala mutant,
      due to competition with water (Gly) and the polar side chain (Asp). Similar
      trends are found for thiocyanate. Cyanide binds equally well to the Ala and Val
      mutants. A number of other small potential ligands were tried. Alcohols do not
      affect room-temperature optical spectra, but at low temperatures, the EPR
      spectrum is stellacyanin-like, indicative of a weak axial interaction. Ligands
      binding with a carboxyl group or nitrogen (e.g. acetate or azide) convert the
      metal center to a form intermediate between regular types 1 and 2, presumably by
      pulling the copper ion out of the trigonal plane formed by Cys(S) and two His(N).
      Cyanide interacts strongly as shown by the hyperfine coupling to the 13C nucleus.
      With increasing strength of the axial interaction, the two major bands in the
      visible region (600 and 400-500 nm) shift in parallel to higher energy, and at
      the same time, the strength of the latter transition increases at the expense of
      the former. This demonstrates that these transitions have a common origin, namely
      S-to-Cu charge transfer transition.

PMID- 8652587
TI  - 15N and 1H NMR spectroscopy of the catalytic histidine in chloromethyl ketone
      inhibited complexes of serine proteases.
AB  - The hemiketal hydroxyl groups in chloromethyl ketone (cmk) complexes of trypsin
      and chymotrypsin have been reported to ionize to the oxyanion with pK(a) values 2
      4 pK(a) units below expectations for such a functional group on the basis of the
      behavior of the hemiketal carbon atom in 13C NMR spectra [Finucane, M. D., &
      Malthouse, J. P. G. (1992) Biochem. J. 286, 889-900]. The low pK(a) indicates the
      enzymes selectively stabilize the oxyanion form of the bound inhibitor, and
      therefore that cmk complexes may be good models of enzyme-mediated transition
      state stabilization. However, the 13C NMR studies could not rule out His57 as the
      titrating group. Here we report the behavior of the ring 15N atoms of His57 in
      the Ala-Ala-Pro-Val-cmk complex of alpha-lytic protease. Both N(delta 1) and
      N(epsilon 2) of His57 respond to an ionization with a pK(a) of approximately 7.5,
      but His57 itself does not titrate as N(epsilon 2) remains alkylated and N(delta
      1) remains bonded to a proton over the entire pH range. The species titrating
      with a pK(a) of approximately 7.5 must therefore be the hemiketal hydroxyl. The
      results also show that the 1H NMR signal from the proton in the Asp-His hydrogen
      bond behaves in a characteristic manner in cmk complexes and can be used
      diagnostically to confirm that His57 does not titrate and to measure the pK(a) of
      the hemiketal hydroxyl in cmk-protease complexes without resorting to 15N
      labeling. We have used the behavior of this signal to directly confirm that His57
      does not titrate in the trypsin and chymotrypsin complexes that were the subjects
      of the original 13C NMR studies.

PMID- 8652588
TI  - Kinetic model for the regulation by substrate of intramolecular electron transfer
      in trimethylamine dehydrogenase.
AB  - The reaction of trimethylamine dehydrogenase (TMADH) with trimethylamine has been
      studied by rapid-scanning stopped-flow spectroscopy and steady-state kinetics.
      The covalently bound 6-S-cysteinylflavin mononucleotide (FMN) cofactor is
      initially reduced by substrate and exhibits a limiting first order rate constant
      of 230 s(-1) at pH 7.5 and 30 degrees C. One electron is then transferred
      intramolecularly from the reduced FMNH2 to the oxidized [4Fe-4S]2+ center. This
      reaction is biphasic, and the extent of the reaction which corresponds to the
      faster and slower rates is dependent upon the concentration of trimethylamine.
      The limiting first order rate constants are 160 and 4 s(-1). At low substrate
      concentrations, the faster rate is dominant, and at high substrate
      concentrations, the slower rate is dominant. These results are used to develop a
      model for the reductive half-reaction of TMADH in which two molecules of
      substrate bind to TMADH. One binds at the active site of oxidized TMADH and is
      converted to products. A second molecule binds but is not converted to products
      and influences the rate of intramolecular electron transfer. Analysis of the
      transient kinetic data yielded apparent dissociation constants for trimethylamine
      of 36 and 148 mu M, respectively, for binding to the catalytic and noncatalytic
      sites. Steady-state kinetic studies indicated substrate inhibition which was best
      described by a model in which binding of a second molecule of trimethylamine
      causes a 10-fold reduction in k(cat) from 11 to 1.1 s(-1). This suggests that, at
      high substrate concentrations, the rate of the intramolecular electron transfer
      reaction has become sufficiently slow to be at least partially rate-limiting for
      the steady-state reaction. These kinetic data are interpreted in the context of
      the known crystal structure of TMADH. The mechanistic implications regarding long
      range electron transfer and possible physiologic significance of these findings
      are discussed.

PMID- 8652589
TI  - A synthetic module for the metH gene permits facile mutagenesis of the cobalamin
      binding region of Escherichia coli methionine synthase: initial characterization
      of seven mutant proteins.
AB  - Cobalamin-dependent methionine synthase from Escherichia coli is a monomeric 136
      kDa protein composed of multiple functional regions. The X-ray structure of the
      cobalamin-binding region of methionine synthase reveals that the cofactor is
      sandwiched between an alpha-helical domain that contacts the upper face of the
      cobalamin and an alpha/beta (Rossmann) domain that interacts with the lower face.
      An unexpected conformational change accompanies binding of the methylcobalamin
      cofactor. The dimethylbenzimidazole ligand to the lower axial position of the
      cobalt in the free cofactor is displaced by histidine 759 from the Rossmann
      domain [Drennan, C. L., Huang, S., Drummond, J. T., Matthews, R. G., & Ludwig, M.
      L. (1994) Science 266, 1669]. In order to facilitate studies of the roles of
      amino acid residues in the cobalamin-binding region of methionine synthase, we
      have constructed a synthetic module corresponding to nucleotides (nt) 1741-2668
      in the metH gene and incorporated it into the wild-type metH gene. This module
      contains unique restriction sites at approximately 80 base pair intervals and was
      synthesized by overlap extension of 22 synthetic oligonucleotides ranging in
      length from 70 to 105 nt and subsequent amplification using two sets of primers.
      Expression of methionine synthase from a plasmid containing the modified gene was
      shown to be unaffected by the introduction of the synthetic module. E. coli does
      not synthesize cobalamin, and overexpression of MetH holoenzyme requires
      accelerated cobalamin transport. Growth conditions are described that enable the
      production of holoenzyme rather than apoenzyme. We describe the construction and
      initial characterization of seven mutants. Four mutations (His759Gly, Asp757Glu,
      Asp757Asn, and Ser810Ala) alter residues in the hydrogen-bonded network His-Asp
      Ser that connects the histidine ligand of the cobalt to solvent. Three mutations
      (Phe708Ala, Phe714Ala, and Leu715Ala) alter residues in the cap region that
      covers the upper face of the cobalamin. The His759Gly mutation has profound
      effects, essentially abolishing steady-state activity, while the Asp757, Ser810,
      Phe708, and Leu715 mutations lead to decreases in activity. These mutations asses
      the importance of individual residues in modulating cobalamin reactivity.

PMID- 8652590
TI  - Mutations in the B12-binding region of methionine synthase: how the protein
      controls methylcobalamin reactivity.
AB  - Vitamin B12-dependent methionine synthase catalyzes the transfer of a methyl
      group from methyltetrahydrofolate to homocysteine via the enzyme-bound cofactor
      methylcobalamin. To carry out this reaction, the enzyme must alternately
      stabilize six-coordinate methylcobalamin and four-coordinate cob(I)alamin
      oxidation states. The lower axial ligand to the cobalt in free methylcobalamin is
      the dimethylbenzimidazole nucleotide substituent of the corrin ring; when
      methylcobalamin binds to methionine synthase, the ligand is replaced by histidine
      759, which in turn is linked by hydrogen bonds to aspartate 757 and thence to
      serine 810. We have proposed that these residues control the reactivity of the
      enzyme-bound cofactor both by increasing the coordination strength of the
      imidazole ligand and by allowing stabilization of cob(I)alamin via protonation of
      the His-Asp-Ser triad. In this paper we report results of mutation studies
      focusing on these catalytic residues. We have used visible absorbance
      spectroscopy and electron paramagnetic resonance spectroscopy to probe the
      coordination state of the cofactor and have used stopped-flow kinetic
      measurements to explore the reactivity of each mutant. We show that mutation of
      histidine 759 blocks turnover, while mutations of aspartate 757 or serine 810
      decrease the reactivity of the methylcobalamin cofactor. In contrast, we show
      that mutations of these same residues increase the rate of AdoMet-dependent
      reactivation of cob(II)alamin enzyme. We propose that the reaction with AdoMet
      proceeds via a different transition state than the reactions with homocysteine
      and methyltetrahydrofolate. These results provide a glimpse at how a protein can
      control the reactivity of methylcobalamin.

PMID- 8652591
TI  - A conformational change in the methyltransferase from Clostridium thermoaceticum
      facilitates the methyl transfer from (6S)-methyltetrahydrofolate to the
      corrinoid/iron-sulfur protein in the Acetyl-CoA pathway.
AB  - The methyltetrahydrofolate:corrinoid/iron-sulfur protein methyltransferase (MeTr)
      from Clostridium thermoaceticum catalyzes the methylation of a corrinoid/iron
      sulfur protein (C/Fe-SP) by the N5 methyl group of (6S)-methyltetrahydrofolate
      (CH3-H4folate). This is an important reaction in the reductive acetyl-CoA
      pathway. The forward and reverse reactions of MeTr have a pH dependence that
      appears to reflect protonation of a group on the protein [Zhao, S., Roberts, D.
      L., & Ragsdale, S. W. (1995) Biochemistry 34, 15075-15083]. In the work reported
      here, fluorescence and rapid reaction kinetics were used to demonstrate that this
      protonation elicits a rate-limiting conformational change. As the pH was lowered,
      the emission maximum for intrinsic tryptophan fluorescence underwent a red shift
      (pK(a) = 5.4) and the emission intensity increased (pK(a) = 5.1). The extrinsic
      fluorescence probe, 4,4'-bis-1-phenylamino-8-napthalenesulfonate (bis-ANS) was
      used to report on the conformational change. The bis-ANS fluorescence was
      strongly enhanced upon binding MeTr. As the pH was decreased, the fluorescence
      was further enhanced and the emission maximum underwent a 14 nm blue shift (pK(a)
      = 5.0). By stopped-flow fluorescence studies, it was shown that these
      fluorescence changes occur at rates similar to the k(cat) for the MeTr reaction
      and thus reflect catalytically competent events. The combined results indicate
      that CH3-H4folate binds to a hydrophobic region in MeTr that includes a
      tryptophan residue(s). MeTr undergoes a pH-dependent conformational change that
      exposes this region to solvent and facilitates substrate binding.

PMID- 8652592
TI  - Regulation of HIV-1 protease activity through cysteine modification.
AB  - The homodimeric protease of the human immunodeficiency virus 1 contains two
      cysteine residues per monomer which are highly conserved among viral isolates.
      However, these cysteine residues are not essential for catalytic activity which
      raises the question of why they are conserved. We have found previously that
      these cysteine residues are unusually susceptible to oxidation by metal ions, and
      this results in inhibition of protease activity. Recombinant protease mutants
      (C67A, C95A, and the double mutant C67A,C95A) were prepared to assess the
      possible role of these cysteines in redox regulation of the enzyme. Mixed
      disulfides were formed between the cysteine residues of the enzymes and low
      molecular weight thiols. Enzyme activity was lost when a mixed disulfide was
      formed between 5,5'-dithiobis(2-nitrobenzoic acid) and cysteine 95, while the
      same mixed disulfide at cysteine 67 reduced activity by 50%. This effect was
      reversible as normal activity could be restored when the enzyme was treated with
      dithiothreitol. The cysteines could also be modified with the common cellular
      thiol glutathione. Modification with glutathione was verified by mass
      spectrometry of the protein peaks obtained from HPLC separation. Glutathiolation
      of cysteine 95 abolished activity whereas modification at cysteine 67 increased
      the k(cat) by more than 2-fold with no effect on K(m). In addition,
      glutathiolation at cysteine 67 markedly stabilized the enzyme activity presumably
      by reducing autoproteolysis. These results demonstrate one possible mechanism for
      regulation of the HIV-1 protease through cysteine modification and identify
      additional targets for affecting protease activity other than the active site.

PMID- 8652593
TI  - Lipopolysaccharide of the Helicobacter pylori type strain NCTC 11637 (ATCC
      43504): structure of the O antigen chain and core oligosaccharide regions.
AB  - Smooth- and rough-form lipopolysaccharides from phenol-water extraction of cells
      from Helicobacter pylori type strain NCTC 11637 were isolated as the water
      soluble component of high-M(r) and water-insoluble low-M(r) gel. Structural
      investigations were performed on the intact water-soluble smooth-form
      lipopolysaccharide, various oligosaccharides formed as chemical and enzymic
      degradation products, and three oligosaccharide fractions liberated by acetic
      acid hydrolysis from the water-insoluble rough-form lipopolysaccharide. A
      structure is proposed for the complete polysaccharide component of the smooth
      form lipopolysaccharide comprising the O antigen chain, an intervening region,
      and the inner core oligosaccharide on the basis of 1H and 13C NMR experiments,
      fast atom bombardment/mass spectrometry, and methylation linkage analysis of
      permethylated oligo- and polysaccharide derivatives. The most striking feature of
      the O antigen region in the lipopolysaccharide is the presence of extended chains
      with fucosylated and nonfucosylated N-acetyllactosamine (LacNAc) units that mimic
      human cell surface glycoconjugates in normal human granulocytes. The chains are
      terminated by di- or trimeric Lewis(x) (Le(x)) determinants, which are also found
      in tumor-associated carbohydrate antigens in many adenocarcinomas.

PMID- 8652594
TI  - Lipopolysaccharides of Helicobacter pylori strains P466 and MO19: structures of
      the O antigen and core oligosaccharide regions.
AB  - Lipopolysaccharides (LPS) from phenol-water extraction of dyspeptic (P466) and
      asymptomatic (MO19) strains of Helicobacter pylori were each isolated as water
      soluble material of high relative molecular mass (high M(r)) and as water
      insoluble gels of low M(r). Chemical and spectroscopic analyses of the soluble
      LPS and oligosaccharides liberated from the water-insoluble gels led to proposed
      structures for chains comprising the O antigen, intervening, and core regions. As
      in the LPS from the type strain NCTC 11637 [Aspinall, G. O., et al. (1996)
      Biochemistry 35, 2489-2497], the O antigen region of the P466 LPS is
      characterized by the presence of extended chains with fucosylated and
      nonfucosylated N-acetyllactosamine units, the former carrying alpha-L
      fucopyranose units at O-3 of beta-D-GlcNAc residues. This structure differs from
      that of the type strain in termination of the O chain by a Lewis(y) (Le(y))
      antigenic determinant [alpha-L-Fuc(1-->2)beta-D-Gal(1-->4)[alpha-L-Fuc(1-
      >3)]beta-D-GlcNAc] but also has internal Lewis(x) (Le(x)) units. The inner core
      region of the P466 LPS is indistinguishable from that in the type strain. In
      contrast, the O antigen region of the LPS from strain MO19 consists of a single
      Le(y) epitope linked via a 3-linked beta-D-Gal to an intervening region on the
      basis of a sequence of 3-linked D-glycero-alpha-D-manno-heptose residues which is
      in turn linked to an inner core identical to that in the type strain and the P466
      strain. Results in this and the preceding paper show that LPS from the three H.
      pylori strains display molecular mimicry of human cell surface glycoconjugates
      but may vary in the expression of Le(x) or Le(y) determinants, the degree of O
      antigen chain extension, or in the presence of an additional region between the
      inner core and the O antigen.

PMID- 8652595
TI  - Sequence of a Na+/glucose symporter gene and its flanking regions of Vibrio
      parahaemolyticus.
AB  - The nucleotide sequence of an approximately 6 kbp segment of chromosomal DNA of
      Vibrio parahaemolyticus was determined. The nucleotide sequence revealed four
      open reading frames (ORFs) in this region. Hydropathy profiles of the deduced
      amino acid sequence of the ORFs indicate that ORF1 encodes a hydrophobic
      polypeptide with typical characteristics of a membrane transport protein. All
      other ORFs encode hydrophilic polypeptides. ORF1 showed significant amino acid
      sequence similarity to proteins of the SGLT (Na+/glucose symporter) family, and
      the amino acid sequence of ORF4 showed very high similarity to several bacterial
      transcriptional repressor proteins (GalR-LacI family). We observed elevated
      glucose transport activity in cells harboring a plasmid carrying the DNA region
      corresponding to ORF1, and the glucose transport was greatly stimulated by Na+.
      Thus, we believe that ORF1 encodes a Na+/glucose symporter.

PMID- 8652596
TI  - Phospholipid asymmetry in red blood cells and spectrin-free vesicles during
      prolonged storage.
AB  - Erythrocytes and spectrin-free DMPC-induced vesicles released from the cells were
      incubated for 3 weeks at 6 degrees C under conditions of metabolic ATP-depletion.
      Phosphatidylserine (PS) asymmetry was monitored during this period by use of the
      prothrombinase assay. Prothrombinase activities measured at the beginning of the
      incubation period indicated that approximately 0.06% of PS was located at the
      outer layer of the red cell membrane, whereas in DMPC-induced vesicles
      approximately 1.5% the PS was exposed on the outside. After completion of the
      incubation period PS exposure on the outside of red cells and vesicles was
      increased by no more than 5-fold. On the other hand, with vesicles prepared with
      a significantly increased (4-fold) ATP-content to sustain translocase activity,
      the incubation process resulted in a surprisingly high (20-fold) increase of PS
      exposure. With vanadate, an inhibitor of the aminophospholipid translocase,
      included in the incubation medium, the redistribution of PS was even more
      pronounced. These observations indicate that PS asymmetry in spectrin-free
      vesicles can not be directly correlated to either ATP content or translocase
      activity and suggest that besides the aminophospholipid translocase and the
      membrane skeleton, other mechanisms must be involved in maintaining phospholipid
      asymmetry.

PMID- 8652597
TI  - 20S human proteasomes bind with a specific orientation to lipid monolayers in
      vitro.
AB  - 20S Proteasomes are non-lysosomal, high molecular weight proteinases implicated
      in the degradation of misfolded proteins and several short-lived regulatory
      proteins. They have a well established role, as the core of the 26S proteasome
      complex, in the ubiquitin-dependent proteolytic pathway and in antigen
      processing. While correctly folded proteins are not degraded by the 20S
      proteasome, unfolding, for example by oxidation, may render them degradable. The
      20S proteasome is a 700-kDa cylindrical particle, composed of 14 subunits of
      molecular masses 20-35 kDa. There is evidence that 20S proteasomes are in close
      proximity to or associate with the endoplasmic reticulum and nuclear and plasma
      membranes in vivo. To better understand the lipid association of 20S proteasomes
      in vitro, we used a lipid monolayer system as a simple model system for
      biological membranes. The structure and orientation of the monolayer lipid bound
      20S proteasomes has been determined by electron microscopy. 20S proteasomes
      associated in an "end-on' configuration specifically on PI lipid monolayers
      forming large arrays, with their channels opposite the lipid headgroups. On ER
      and Golgi lipid films 20S proteasomes were oriented in the same way as on the PI
      lipid film but were monodisperse. Protein molecules were randomly oriented in the
      presence of PA, PG, PS, PC and mitochondrial lipid monolayers. We show that 20S
      proteasomes bind to phospholipids in vitro in a preferred orientation which
      places the proteasome channel perpendicular to the membrane.

PMID- 8652599
TI  - Subcellular distribution of "intersecting' beta-N-acetylglucosaminyltransferase
      in Dictyostelium discoideum. A likely marker for the Golgi apparatus.
AB  - Glycoprotein processing in Dictyostelium discoideum is characterized by enzyme
      catalyzed steps not reported in other organisms. One of these is the formation of
      a beta 1 --> 4 linkage between GlcNAc and the mannose linked to the core mannose
      in the alpha 1 --> 6 position of N-glycosides. A simple and sensitive assay for
      this GlcNAc transferase activity, using a tri-mannose acceptor and a low
      concentration of UDP-GlcNAc, was developed. Homogenates of the organism were
      subjected to sub-cellular fractionation by centrifugation in discontinuous
      sucrose gradients. The specific activity was enriched 4-5-fold in a crude
      membrane fraction. The transferase was purified 10-12-fold in a membrane fraction
      that bands on top of 1.1 M sucrose. This fraction was also enriched in
      nucleotidyldiphosphatase. The enriched fraction was deficient in glucose-6
      phosphatase, an endoplasmic reticulum marker. Approx. 80% of the transferase
      activity was latent, and unavailable to protease. Purified membranes were either
      subjected to phase separation in Triton X-114, or sodium carbonate extraction or
      sonication. In each case, the transferase behaved as an intrinsic membrane
      protein. Several secreted and lysosomal proteins are modified by the enzyme.
      These data support the idea that the GlcNAc transferase is present as an integral
      Golgi membrane protein and that at least the catalytic center of the transferase
      is on the lumenal side of the vesicles.

PMID- 8652598
TI  - Phosphate deprivation induces overexpression of two proteins related to the rat
      renal phosphate cotransporter NaPi-2.
AB  - Polyclonal antibodies were raised in rabbits against the C-terminal portion of
      the rat renal brush-border membrane sodium/phosphate cotransporter NaPi-2.
      Antibody specificity and molecular sizes of proteins related to NaPi-2 were
      assayed by Western blot analysis. Proteins of 40 and 70-75 kDa (p40 and p70) were
      immunodetected in rat and mouse brush-border membranes and proteins of 72 and 82
      kDa were detected in rabbit. The absence or presence of beta-EtSH in the samples
      before electrophoresis greatly influenced the immunodetection profile of the rat
      proteins. Since the 40 kDa protein (p40) can only be detected under reducing
      conditions, it probably originates from reduction of disulfide bonds in p70.
      Tryptic cleavage of p40 and p70 revealed identical protein fragments showing the
      close structural identity of those proteins. Both proteins were more abundant in
      the outer cortex portion of the rat kidney than in the juxtamedullary portion.
      Furthermore, rats fed a low-phosphate diet for 24 h showed a 20- and 14-fold
      increase in the amount of p40 and p70, respectively, compared to control rats,
      showing that the adaptation to P(i) deprivation by increasing renal phosphate
      reabsorption is not only the result of overproduction of p70, as previously
      shown, but is also due to the novel p40 which most probably derives from p70.

PMID- 8652600
TI  - The interaction of alpha-tocopherol with phosphatidylserine vesicles and calcium.
AB  - The interaction of alpha-tocopherol with dimyristoylphosphatidylserine (DMPS) has
      been studied in the presence and in the absence of Ca2+ by using differential
      scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and
      45Ca2+-binding. In the absence of Ca2+, DSC showed that alpha-tocopherol
      decreases the temperature of the lamellar gel to lamellar liquid crystalline
      phase transition as well as it decreases delta H of this transition. Two
      different peaks were detected at 10 mol% of alpha-tocopherol and probably one of
      the peaks correspond to pure or nearly pure DMPS and the other to DMPS
      incorporating most of the alpha-tocopherol. The phase transition was totally
      abolished at 30 mol% of alpha-tocopherol. In the presence of Ca2+ this L(beta) to
      L(alpha) phase transition of DMPS was even more perturbed by alpha-tocopherol, so
      that it was totally abolished by only 7 mol% of alpha-tocopherol, at Ca2+
      concentrations which were clearly non-saturating, like those giving DMPS/Ca2+
      molar ratio of 4:1 and 10:1. Furthermore, the transition of the DMPS/Ca2+ complex
      observed at 91.6 degrees C was perturbed by the presence of alpha-tocopherol,
      indicating a change in the structure of the crystalline complex. The FT-IR
      analysis of the effect of alpha-tocopherol on DPMS phase transition confirmed the
      decrease in the phase transition temperature of the phospholipid, and also that
      alpha-tocopherol increases the number of gauche isomers in the gel state but has
      no effect in the liquid crystalline state. The binding of 45Ca2+ was also
      affected by the presence of alpha-tocopherol, so that the number of binding sites
      was decreased, and this may be interesting for situations in which
      phosphatidylserine and Ca2+ are simultaneously implicated in biological
      functions, such as membrane fusion and enzyme activation.

PMID- 8652601
TI  - Influence of dose on liposome clearance: critical role of blood proteins.
AB  - It is well established that the circulation half-life of liposomes increases with
      increasing dose. This effect is commonly attributed to "saturation' of the fixed
      and free macrophages of the reticuloendothelial system resulting in reduced
      clearance rates. However, it is also known that the clearance rate of liposomes
      is dependent on the amount of associated blood protein, leading to the
      possibility that dose-dependent increases in circulation lifetimes could be due
      to decreases in the amount of blood protein associated per liposome. In order to
      test this hypothesis, the protein binding and clearance properties of large
      unilamellar liposomes composed of distearoylphosphatidylcholine/cholesterol and
      egg phosphatidylcholine/dioleoylphosphatidic acid/cholesterol were examined in
      mice. Liposomes were injected over a dose range of 10 to 1000 mg lipid/kg body
      weight, and the circulation lifetime and liver and spleen accumulation monitored.
      As expected, longer circulation half-lives were observed at higher doses for both
      liposome compositions. However, it was also found that at higher liposome doses,
      significantly less protein was bound per liposome. The results indicate that
      there is a limited pool of blood proteins that is able to interact with liposomes
      of a given composition. At higher lipid doses these blood proteins are
      distributed over more liposomes resulting in lower protein binding values and
      longer circulation lifetimes.

PMID- 8652602
TI  - Insulin stimulates the Na+,K(+)-ATPase and the Na+/K+/Cl- cotransporter of human
      fibroblasts.
AB  - Insulin regulation of K+ (Rb+) transport was investigated in cultured human
      fibroblasts using a non-radioactive method which allows the simultaneous
      determination of the intracellular concentration of other monovalent cations.
      Insulin stimulated Rb+ influx through the Na+,K(+)-ATPase and the Na+/K(+)/Cl-
      cotransporter in human fibroblasts. Insulin stimulation was very rapid and
      maximal effect was observed within 10 min. Insulin stimulation of Rb+ uptake via
      the Na+,K(+)-ATPase and the Na+/K(+)/Cl- cotransporter was dose-dependent, with
      half-maximal stimulation at 2-3 nM of hormone. Insulin increased the V(max) of
      both transporters involved, affecting only minimally their Km. In other cells,
      insulin stimulates the Na+,K(+)-pump by increasing Na+ availability through the
      Na+/H+ exchanger. In human fibroblasts, insulin stimulation of Na+,K(+)-ATPase
      occurred in the presence of ethyl-isopropyl amiloride, an inhibitor of the Na+/H+
      exchanger, and without sustained changes in intracellular[Na+]. By contrast,
      insulin action on Na+,K(+)-ATPase was impaired by the protein kinase inhibitors
      staurosporine and genistein. These results indicate that, in human fibroblasts,
      insulin stimulates both the Na+,K(+)-ATPase and the Na+/K+/Cl- cotransporter,
      that stimulation of the Na+,K(+)-ATPase occurs in the absence of changes in
      intracellular [Na+], and that protein kinase activity is essential for this
      insulin action.

PMID- 8652603
TI  - Mechanism of hemolysis of human erythrocytes exposed to monosodium urate
      monohydrate crystals. Preliminary characterization of membrane pores.
AB  - Microcrystals of monosodium urate monohydrate (MSUM) have the ability to cause
      rapid hemolysis of erythrocytes. The nature of the initial MSUM crystal
      erythrocyte membrane binding interaction was investigated over a range of
      different ionic strength media. There was negligible binding of MSUM to
      erythrocyte ghost membranes in low ionic strength media such as isotonic mannitol
      but binding was dramatically increased in isotonic NaCl/mannitol solutions or
      isotonic mannitol containing 1 mM Ca2+. Hemolysis induced by MSUM crystals was
      preceded by the leakage of K+ from the cells suggesting a colloid-osmotic
      mechanism of hemolysis. The inclusion of large (oligosaccharide) molecules in the
      extracellular media or the modulation of the extracellular solution tonicity
      inhibited both the rate and extent of hemolysis supporting the concept of MSUM
      induced pores followed by colloid osmotic hemolysis.

PMID- 8652604
TI  - Forces on biological cells due to applied alternating (AC) electric fields. II.
      Electro-rotation.
AB  - Measurements are presented of angular velocities of rotation of mammalian cells
      of K562 (human) and SP2 (mouse) in external alternating electric fields over a
      frequency range of 0.5 kHz to 12 MHz. Electro-rotation of the cells was observed
      for the case of "two cells in contact' using two parallel, cylindrical
      electrodes; only one cell was located on the electrode. A theoretical analysis is
      also presented which shows that the cell rotation arises from a torque produced
      by the interaction between the primary electric dipole moment induced in the
      spinning cell and the secondary electric fields, generated by the primary dipole
      induced in the adjacent cell. These secondary fields are out of phase with the
      applied electric field. The results show that (a) only the cell not located on
      the electrode rotates, (b) maximal electro-rotation occurs at two different
      excitation field frequency domains for the frequency range employed here, (c) the
      spin speed of the rotating cell at each frequency domain is much less than the
      excitation frequency, (d) the rotation direction of the cell depends on the angle
      (theta) between the external electric field and the line joining the centres of
      the two cells and (e) for a given angle theta, the rotation direction is the same
      for both excitation frequency domains. The experimental measurements allowed us
      to estimate the conductivities of the cytoplasms and membrane capacitances of the
      cells of K562 and SP2. The conductivities of the cytoplasms of the cells of K562
      and SP2 were estimated to be 0.2 and 0.3 Sm-(1), respectively, whereas the
      membrane capacitances of these cells were found to be 2.7 +/- 0.8 and 9.8 +/- 0.6
      mFm-(2), respectively.

PMID- 8652606
TI  - Effect of biocide concentration on electrorotation spectra of yeast cells.
AB  - The effect of the biocide Cosmocil (polyhexanide) at different concentrations on
      the electrorotation spectra of yeast cells is investigated over the frequency
      range from 1 kHz to 10 MHz. The dielectric properties of the yeast, before and
      after biocide treatment, were deduced from the electrorotation spectra using two
      shell ellipsoid modelling methods that have been well tested for other
      heterogeneous biological systems. The results show a gradual increase in the
      cytoplasmic membrane conductivity with increasing biocide concentration, rather
      than an "all-or-nothing' breakdown of the membrane. The technique gives a
      quantitative analysis of the toxic damage by chemicals to cells and can be
      exploited in the development of new pharmacological agents.

PMID- 8652605
TI  - Interaction of phospholipid liposomes with plasma membrane isolated from alveolar
      type II cells: effect of pulmonary surfactant protein A.
AB  - Pulmonary surfactant protein A (SP-A) augments the uptake of phospholipid
      liposomes containing dipalmitoylphosphatidylcholine (DPPC) by alveolar type II
      cells. The SP-A-mediated uptake process of lipids by type II cells have not been
      well understood. In the present study we investigated the SP-A-mediated
      interaction of phospholipids with plasma membrane isolated from alveolar type II
      cells. SP-A increased the amount of liposomes containing radiolabeled DPPC
      associated with type II cell plasma membrane by 4-fold compared to the control
      without SP-A when analyzed by sucrose density gradient centrifugation. This
      effect is dependent upon the SP-A concentration. The enhancement was inhibited by
      anti-SP-A antibody and EGTA. When type II cell plasma membrane and liposomes
      containing [14C]DPPC and [3H]triolein were coincubated with or without SP-A,
      analysis on sucrose density gradients revealed that the profiles of [14C]DPPC and
      [3H]triolein in each fraction were almost identical with or without SP-A,
      indicating that SP-A mediates the binding of liposomes to plasma membrane but not
      transfer of DPPC. SP-A increased the association of liposomes containing DPPC
      with the membrane by 2-fold more than that containing 1-palmitoyl-2-linoleoyl
      phosphatidylcholine (PLPC). SP-A induced aggregation of phospholipid liposomes
      containing PLPC as well as those containing DPPC, but the final turbidity of DPPC
      liposomes aggregated by SP-A was only by 15% greater than that of PLPC liposomes.
      The amount of DPPC liposomes associated with the plasma membrane derived from
      type II cells was 2-fold greater than that from liver. We speculate that the SP-A
      mediated interaction of lipids with type II cell plasma membrane may contribute,
      in part, to the lipid uptake process by type II cells.

PMID- 8652607
TI  - Interaction of ethylazinphos with the physical organization of model and native
      membranes.
AB  - The interaction of ethylazinphos with the physical organization of model and
      native membranes was investigated by means of fluorescence polarization of 1,6
      diphenyl-1,3,5-hexatriene (DPH) and of its propionic acid derivative (DPH-PA).
      Ethylazinphos shifts the phase transition midpoint to lower temperature values
      and broadens the phase transition profile of bilayers reconstituted with
      dimyristoyl-, dipalmitoyl- and distearoylphosphatidylcholines (DMPC, DPPC, DSPC),
      as detected by DPH and DPH-PA. Additionally, both probes detect significant
      effects of ethylazinphos in the fluid phase of the above lipid bilayers. The
      insecticide perturbations are more pronounced in bilayers of short-chain lipids,
      e.g., DMPC, in correlation with the higher partition in these membranes. On the
      other hand, the insecticide increases to some extent the ordering promoted by
      cholesterol in the fluid phase of DMPC, but high cholesterol concentrations (> or
      = 30 mol%) almost prevent insecticide interaction, as revealed by DPH and DPH-PA.
      In agreement with the results in models of synthetic lipids, the increase of
      intrinsic cholesterol in fluid native membranes depresses the partition values of
      ethylazinphos and consequently its effects.

PMID- 8652608
TI  - The effect of free radicals on the conductance induced by alamethicin in planar
      lipid membranes: activation and inactivation.
AB  - Exposure to ionizing radiation of planar lipid membranes doped with alamethicin
      gives rise to an increase and to a subsequent decrease of the membrane
      conductance. Both effects are due to the presence of radiation-induced free
      radicals of water radiolysis as was shown by addition of various radical
      scavengers. The increase of the conductance was found to be a consequence of free
      radical-initiated lipid peroxidation favouring the formation of active ion
      channels. The decrease of the conductance observed at larger radiation doses is
      due to an inactivation of alamethicin monomers. The characteristic D37 dose of
      inactivation was found to be about two orders of magnitude larger than in the
      case of gramicidin A. The comparatively high sensitivity of the latter is due to
      the presence of its four tryptophan residues. Inactivation of trichorzianine
      AIIIc, an analogue of alamethicin with a C-terminal tryptophanol residue, occurs
      at radiation doses two orders of magnitude lower than observed with alamethicin.

PMID- 8652609
TI  - Functional expression of the cystic fibrosis transmembrane conductance regulator
      in yeast.
AB  - Recombinant human cystic fibrosis transmembrane conductance regulator (CFTR) has
      been produced in a Saccharomyces cerevisiae expression system used previously to
      produce transport ATPases with high yields. The arrangement of the bases in the
      region immediately upstream from the ATG start codon of the CFTR is extremely
      important for high expression levels. The maximal CFTR expression level is about
      5-10% of that in Sf9 insect cells as judged by comparison of immunoblots. Upon
      sucrose gradient centrifugation, the majority of the CFTR is found in a light
      vesicle fraction separated from the yeast plasma membrane in a heavier fraction.
      It thus appears that most of expressed CFTR is not directed to the plasma
      membrane in this system. CFTR expressed in yeast has the same mobility (ca. 140
      kDa) as recombinant CFTR produced in Sf9 cells in a high resolution SDS-PAGE gel
      before and after N-glycosidase F treatment, suggesting that it is not
      glycosylated. The channel function of the expressed CFTR was measured by an
      isotope flux assay in isolated yeast membrane vesicles and single channel
      recording following reconstitution into planar lipid bilayers. In the isotope
      flux assay, protein kinase A (PKA) increased the rate of 125I- uptake by about
      30% in membrane vesicles containing the CFTR, but not in control membranes. The
      single channel recordings showed that a PKA-activated small conductance anion
      channel (8 pS) with a linear I-V relationship was present in the CFTR membranes,
      but not in control membranes. These results show that the human CFTR has been
      expressed in functional form in yeast. With the reasonably high yield and the
      ability to grow massive quantities of yeast at low cost, this CFTR expression
      system may provide a valuable new source of starting material for purification of
      large quantities of the CFTR for biochemical studies.

PMID- 8652610
TI  - Structural organisation and lipid composition of the epicuticular accessory layer
      of infective larvae of Trichinella spiralis.
AB  - The epicuticle of infective larvae of Trichinella spiralis represents the
      interface between this intracellular nematode parasite and the cytosol of
      mammalian skeletal muscle. The macromolecular structures that make up the
      epicuticle were studied by freeze-fracture electron microscopy and compositional
      analysis. Three fracture planes were observed: one with a typical plasma membrane
      type bilayer organisation which was overlaid by two extended layers of lipid in
      an inverted cylindrical configuration. This overall structure remained unchanged
      in response to variations in temperature between 20 degrees C and 45 degrees C.
      The lipid cylinders were on average 6.8 nm in diameter, with randomly-associated
      particles that were not dissociated by high-salt treatment, indicative of
      hydrophobically associated proteins. The majority of the lipids were non-polar,
      consisting of cholesterol, cholesterol esters, mono- and tri-glycerides, and free
      fatty acids. Three major classes of phospholipids were identified:
      phosphatidylethanolamine, phosphatidylglycerol and phosphatidylcholine. Total
      lipid extracts did not adopt an inverted cylindrical or micellar configuration on
      isolation, but formed flat sheets of lamellae as did the purified polar and non
      polar fractions of the lipids. Isolated lipids did not undergo thermally-induced
      polymorphism between 20 degrees C and 60 degrees C and there was no pH dependency
      of the structures adopted. The fatty acid saturation levels of the phospholipids
      were compatible with the observation that they did not form polymorphic
      structures on isolation. We suggest that this unusual configuration is probably
      stabilised by the associated (glyco)proteins and may be required for selective
      permeation of nutrients from the host cell cytosol and/or for maintaining the
      high curvature of the parasite within the cell.

PMID- 8652611
TI  - Deciphering neuronal secretion: tools of the trade.

PMID- 8652612
TI  - The secretory pathway: mechanisms of protein sorting and transport.

PMID- 8652613
TI  - Phospholipid vesicles and other cholesterol carriers in bile.

PMID- 8652614
TI  - Synthesis and interactions with thymidylate synthase of 2,4-dithio analogues of
      dUMP and 5-fluoro-dUMP.
AB  - The 2,4-dithio analogues of 2'-deoxyuridine and 2'-deoxy-5-fluorouridine have
      been synthesized by thiation of the previously described 2-thio analogues, and
      then phosphorylated enzymatically or chemically to yield 2,4-dithio-dUMP and 2,4
      dithio-5-fluoro-dUMP. In striking contrast to the 2-thio and 4-thio analogues of
      dUMP, which are good substrates of thymidylate synthase, 2,4-dithio-dUMP is not a
      substrate. But, surprisingly, it is a competitive inhibitor, relative to dUMP, of
      the purified enzymes from both parental and FdUrd-resistant L1210 cells, with
      K(i) values of 32 microM and 55 microM, respectively. Although 2,4-dithio-5
      fluoro-dUMP behaved as a typical slow-binding inhibitor of the enzyme, its K(i)
      value was 10(3)-10(4)-fold higher than those for the corresponding 2-thio and 4
      thio congeners. Similarly, 2,4-dithio-FdUrd was a much weaker inhibitor of tumour
      cell growth (IC50 approximately 10(-5)M) than FdUrd (IC50 approximately 10(-9)M),
      2-thio-FdUrd(IC50 approximately 10(-7)M) or 4-thio-FdUrd (IC50 approximately
      5x10(-8)M), while with 2,4-dithio-dUrd no influence on cell growth could be
      observed. Theoretical considerations, based on calculated aromaticities of the
      uracil and thiouracil rings, suggest that lack of substrate activity of 2,4
      dithio-dUMP may result from increased pyrimidine ring aromaticity of the latter,
      leading to resistance of C(6) to nucleophilic attack by the enzyme active center
      cysteine.

PMID- 8652615
TI  - Archaeal elongation factor 1 beta is a dimer. Primary structure, molecular and
      biochemical properties.
AB  - The elongation factor 1 beta (EF-1 beta), that in eukarya and archaea promotes
      the replacement of GDP by GTP on the elongation factor 1 alpha x GDP complex, was
      purified to homogeneity from the thermoacidophilic archaeon Sulfolobus
      solfataricus (SsEF-1 beta). Its primary structure was established by sequenced
      Edman degradation of the entire protein or its proteolytic peptides. The
      molecular weight of SsEF-1 beta was estimated as about 10000 or 20000 under
      denaturing or native conditions respectively; this finding suggests that the
      native protein exists as a dimer. The peptide chain of SsEF-1 beta is much
      shorter than that of its eukaryotic analogues and homology is found only at their
      C-terminal region; no homology exists between SsEF-1 beta and eubacterial EF-Ts.
      At 50 degrees C, at a concentration of SsEF-1 beta 5-fold higher than that of
      SsEF-1 alpha x [3H]GDP the rate of the exchange of [3H]GDP for GTP becomes about
      160-fold faster. An analysis of the values of the energetic parameters indicates
      that in the presence of SsEF-1 beta the GDP/GTP exchange is entropically
      favoured. At 100 degrees C the half-life of SsEF-1 beta is about 4 h.

PMID- 8652616
TI  - Isolation and characterization of domain I of ovoinhibitor.
AB  - Domain I of ovoinhibitor was isolated by subjecting the protein to specific
      chemical cleavage by cyanogen bromide followed by repeated gel filtration. The
      first domain of ovoinhibitor was found to be homogeneous by the criteria of gel
      chromatography, SDS-PAGE and PAGE. Mr values by gel filtration (10900) and SDS
      PAGE (8300) were slightly higher than that computed from amino-acid sequence.
      This discrepancy has been attributed to the glycoprotein nature of domain I as it
      was found to contain 10% neutral carbohydrate and 2% sialic acid. Fluorescence
      spectral properties showed the presence of tryptophan in domain I. The amino-acid
      composition of domain I isolated in this study was in very good agreement with
      that computed from amino-acid sequence. Gel filtration behaviour of the first
      domain was consistent with a Stokes radius of 1.6 nm and a frictional ratio of
      1.2 suggesting asymmetry and/or excessive hydration. Domain I was found to be a
      potent inhibitor of bovine trypsin but was virtually devoid of activity against
      chymotrypsin, elastase and proteinase K. The equilibrium association constant for
      domain I-trypsin complex was computed to be 6.6x10(8)M-1.

PMID- 8652617
TI  - Identification of cysteine and lysine residues present at the active site of beef
      liver glutamate dehydrogenase by o-phthalaldehyde.
AB  - Beef liver glutamate dehydrogenase (GDH) is inactivated by the bifunctional
      reagent, o-phthalaldehyde. The initial rate of inactivation follows pseudo first
      order kinetics. The reaction of the enzyme with o-phthalaldehyde results in
      isoindole derivative formation which is characterized by typical fluorescence
      emission and excitation maximum at 410 nm and 337 nm, respectively. The
      inactivation of GDH by o-phthalaldehyde is partially prevented by alpha
      ketoglutaric acid, whereas NADH does not provide any protection. This clearly
      indicates that cysteine and lysine residues are located near the alpha
      ketoglutaric acid binding center. The dissociation constant of 2.2 mM was
      obtained for enzyme-alpha-ketoglutaric acid complex. Stoichiometry of o
      phthalaldehyde binding with glutamate dehydrogenase showed that the formation of
      approximately one isoindole derivative per subunit of glutamate dehydrogenase is
      accompanied by complete loss of activity.

PMID- 8652618
TI  - NMR study of the active site of shark met-cyano myoglobins.
AB  - The myoglobins from the sharks Galeorhinus japonicus and Musterus japonicus
      possess a distal Gln-E7 instead of the usually found His-E7. The met-cyano form
      of these shark myoglobins has been studied by 1H- and 15N-NMR in order to gain
      insight into the functional properties of the Gln-E7. The analysis of
      paramagnetic relaxation has provided the assignment of the resonance arising from
      one of the Gln-E7 N epsilon H labile protons, whilst the rate of its chemical
      exchange has been analyzed in detail by using a saturation transfer method. The
      hydrogen-bonding interaction between this proton and Fe-bound-CN(-) has been
      clearly manifested in the hyperfine shift of the Gln-E7 N epsilon H proton
      resonance as well as its chemical exchange behavior. The resonances of the Gln-E7
      side-chain non-labile protons have been partly assigned on a basis of both scalar
      and dipolar connectivities. The analysis of the dipolar connectivities among the
      side-chain protons and the iron-proton distances determined from their
      paramagnetic relaxation rate has revealed that the side chain adopts a
      conformation with its carbonyl oxygen oriented away from the heme. Although (1)H
      NMR spectra of these two myoglobins are essentially similar, a relatively large
      difference in the shift of Gln-E7 N(epsilon)H proton and Fe-bound C15 N-
      resonances between the two has been observed which is attributed to a
      differential hydrogen-bonding interaction between these proteins. The present
      study demonstrates the sensitivity of NMR parameters to the hydrogen-bonding
      interaction between coordinated ligand and a distal amino-acid side chain in
      paramagnetic hemoproteins.

PMID- 8652619
TI  - Picosecond geminate recombination of CO to the complexes calmodulin*heme-CO and
      calmodulin*heme-CO*melittin.
AB  - Picosecond CO recombination kinetics have been measured after photodissociation
      of the artificial complexes calmodulin*heme-CO and calmodulin*heme-CO*melittin.
      These systems show an enhancement of the geminate fraction of kinetics relative
      to unbound heme-CO, due in part to fast geminate kinetics (tau=50ps for the
      initial phase), as well as a decrease in the rate of migration of CO away from
      the binding site. This indicates that calmodulin provides a complete pocket
      around the heme group. Rather than competing with the hemes for binding to
      calmodulin, the melittin seems to act as a cap to further enclose the hemes;
      melittin increases the affinity of calmodulin for heme-CO, but only weakly
      affects the CO recombination kinetics.

PMID- 8652620
TI  - Substrates containing phosphorylated residues adjacent to proline decrease the
      cleavage by proline-specific peptidases.
AB  - Thirteen dipeptide rho-nitroanilides of the common structure H-Xaa-Pro-4-NA (Xaa
      = serine, threonine and tyrosine) and seven tripeptide rho-nitroanilides of the
      common structure H-Gly-Xaa-Pro-4-NA (Xaa = serine or threonine) were prepared and
      analyzed as substrates of the proline-specific peptidases dipeptidyl peptidase IV
      and prolyl endopeptidase, respectively. The side chains of the hydroxy amino
      acids were synthetically modified by various acyl-, benzyl- and phosphate
      residues. The presence of aliphatic or aromatic residues attached to the side
      chain of the P2-hydroxy amino acids resulted in no significant change of the
      specificity constants of the enzyme-catalyzed substrate hydrolysis. In some
      cases, however, substrate inhibition was observed. In contrast, the reactivity of
      dipeptidyl peptidase IV and prolyl endopeptidase decreases more than two orders
      of magnitude towards the phosphorylated di- and tripeptide substrates compared to
      the hydrolysis of unmodified substrates. The kinetic data obtained with the model
      compounds suggest that side-chain modification of proline-containing peptide
      substrates may influence their resistance towards the hydrolytic activity of
      proline-specific hydrolases. Additionally, the results support that structural
      changes of the substrate during enzyme-hydrolysis may be involved in the
      mechanism of action of proline-specific serine peptidases. From this result we
      speculate that posttranslational phosphorylation of peptide sequences found in
      protein kinase recognition motifs such as -Xaa-Ser/Thr-Pro-Yaa- and -Xaa-Pro
      Ser/Thr-Yaa- may serve as structural determinants that modulate their proteolytic
      stability.

PMID- 8652622
TI  - Small-angle X-ray scattering studies on cellobiose dehydrogenase from
      Phanerochaete chrysosporium.
AB  - Limited proteolysis of cellobiose dehydrogenase (CDH) from the white rot fungus
      Phanerochaete chrysosporium by papain cleaves the enzyme into two fragments
      containing flavin (FAD) and heme, respectively. Small-angle X-ray scattering
      (SAXS) was employed to investigate size and shape of intact CDH and of its
      fragments in solution. The largest dimension of CDH amounts to about 18 nm,
      whereas the corresponding quantity of each of the two fragments is only around 9
      nm. CDH as well as its fragments appear to be of prolate shape, the cross-section
      of the FAD fragment (diameter 4.3 to 5.1 nm) being considerably larger than that
      of the heme fragment (diameter 3.3 nm). These findings suggest a collinear
      arrangement of the two domains in the CDH particle. Simulations based on the
      method of finite elements corroborate this structure model and furthermore
      suggest the existence of a possibly flexible linker between the two domains.

PMID- 8652623
TI  - Hydroperoxidase activity of lipoxygenase: a kinetic study of isoproterenol
      oxidation.
AB  - The hydroperoxidase activity of soybean lipoxygenase, a non-heme protein,
      oxidized isoproterenol using H2O2 at pH 6.0. This oxidation was enzymatic, since
      neither heat-denaturated enzyme or iron ions in the presence of H2O2 produced an
      increase in absorbance. The initial rate was not linear and showed a
      characteristic lag period whose length depended on the enzyme and substrate
      concentration. The lag was decreased if the enzyme and isoproterenol
      concentration were increased, whereas it increased if the H2O2 concentration was
      increased. Lipoxygenase showed the typical low specificity for electron donor
      characteristic of this hydroperoxidase activity (26 mM), but a high affinity for
      H2O2 (94 microM), although with substrate inhibition (ksi = 3.6 mM). The chemical
      intermediates produced during the oxidation of isoproterenol were characterized
      in order to determine the origin of the lag period. A plausible kinetic mechanism
      is proposed to explain the observed lag period and inhibition by high
      concentrations of H2O2.

PMID- 8652621
TI  - Physical and kinetic effects on induction of various linker regions in beta
      galactosidase/galactose dehydrogenase fusion enzymes.
AB  - To examine the role of the connecting region in the artificial bifunctional
      enzyme beta-galactosidase/galactose dehydrogenase, linkers of different length
      were inserted between the catalytic units. The specific activity of the galactose
      dehydrogenase part of the complex was increased when longer linkers (9 and 13
      amino acids) were used as connectors. These bifunctional enzymes were
      predominantly found to comprise hexamers, however, complexes of higher molecular
      weight were also formed. The sequential reaction was carried out more efficiently
      when hybrid enzymes with the longer linkers were used as demonstrated both in
      vitro by using purified protein preparations as well as in vivo by determining
      the growth rates of recombinant E. coli cells on a minimal medium containing
      lactose.

PMID- 8652624
TI  - Proton NMR study of peptides from myelin basic protein: evidence for Lys74-His77
      interaction revealed from histidine line broadening.
AB  - Residues 69-84 of guinea pig myelin basic protein contain the encephalitogenic
      determinant for the Lewis rat. Insertion of histidine and glycine at positions 77
      and 78 in bovine MBP greatly reduces the encephalitogenicity of the protein.
      Synthetic peptides analogous to this region of MBP containing glycine and
      histidine are encephalitogenic if they lack the N-terminal half, residues 69-74.
      However, if they contain both histidine plus the N-terminal half,
      encephalitogenicity is abolished, suggesting that an interaction of histidine
      with an amino acid in the N-terminal half changes the conformation or the
      properties of the peptide. This was investigated by measuring the 1H-NMR spectra
      of synthetic peptides analogous to this region of MBP, both containing histidine
      but with and without the N-terminal half. The major difference in the spectra of
      the two peptides was the pH dependence of line broadening of the histidine
      resonances. The histidine C2H and C4H resonances were broadened at intermediate
      pH values in both peptides. However, sharpening of the lines at high pH showed a
      different pH dependence in the two peptides. For the longer peptide containing
      the N-terminal half, the lines did not sharpen until the pH was increased above
      10.2, coinciding with the pKa of Lys-74. Acetylation of this peptide caused the
      pH at which the lines began to sharpen to drop to 8.8. In the shorter peptide,
      lacking the N-terminal half and Lys-74, the lines also sharpened at pH 8.8. The
      greater broadening which persisted up above pH 10 for the longer peptide suggests
      slow exchange between two different conformations or environments of the
      histidine. One of these could be a conformation in which the deprotonated
      histidine hydrogen bonds with Lys-74. The Lys side-chain resonances indicated a
      decrease in rotational freedom above the pKa of histidine, consistent with this
      conclusion. Although this putative interaction between His and Lys-74 did not
      appear to have a significant effect on the overall conformation of the peptide,
      it could result in a reduction in encephalitogenicity by altering the properties
      of the peptide. This could affect processing and presentation of this determinant
      by antigen presenting cells.

PMID- 8652625
TI  - Evidence that human milk isolated cyclophilin B corresponds to a truncated form.
AB  - Cyclophilin B (CyPB) is a member of the cyclophilin family (cyclosporin A-binding
      proteins) with specific N- and C-terminal extensions. In contrast to cyclophilin
      A, CyPB owns a signal sequence leading to its translocation in the endoplasmic
      reticulum. CyPB was reported to be present in human blood and milk, suggesting it
      is secreted. For this purpose, CyPB was purified to homogeneity from human milk
      and compared to recombinant CyPB expressed in E. coli. Ion spray mass
      spectrometry revealed that CyPB secreted in human milk exhibits a lower molecular
      mass than the one expected. Identification of phenylalanine as the C-terminus
      amino-acid residue of human milk CyPB indicates that the difference in molecular
      mass may be explained by the absence of the five C-terminal amino-acid residues
      AIAKE. These results suggest that in the sequence VEKPFAIAKE known to be
      responsible for retention of CyPB in the endoplasmic reticulum, the sequence
      AIAKE is more particularly necessary. Our findings raise the possibility that the
      CyPB may be processed to promote its release. As recombinant CyPB was shown to
      bind specifically to Jurkat cells, a lymphoblastic T-cell line, we then wanted to
      investigate the binding of human milk CyPB to these cells. Despite lacking the
      five C-terminal amino-acid residues, human milk CyPB is able to inhibit the
      binding of recombinant CyPB to Jurkat T cells.

PMID- 8652626
TI  - Hydroxylation of quinaldic acid: quinaldic acid 4-monooxygenase from Alcaligenes
      sp. F-2 versus quinaldic acid 4-oxidoreductases.
AB  - The N-heterocycles quinaldic acid (quinoline 2-carboxylic acid), kynurenic acid
      (4-hydroxyquinoline 2-carboxylic acid), 2-oxo-1,2-dihydroquinoline, and xanthine
      are utilized by Alcaligenes sp. F-2 as sole source of carbon and energy. Although
      quinoline did not serve as growth substrate, 8-hydroxy-2-oxo-1,2-dihydroquinoline
      and 8-hydroxycoumarin, metabolites of the 'coumarin pathway' of quinoline
      catabolism, were isolated from the culture fluid during growth on 2-oxo-1,2
      dihydroquinoline. Contrary to Serratia marcescens 2CC-1 and Pseudomonas sp. AK-2
      (Sauter et al. (1993) Biol. Chem. Hoppe-Seyler 374, 1037-1046), which possess
      different molybdenum-containing hydroxylases catalysing the 4-hydroxylation of
      quinaldic acid to kynurenic acid with incorporation of oxygen derived from water
      and concomitant reduction of an electron acceptor, Alcaligenes sp. F-2 contains
      an inducible quinaldic acid 4-monooxygenase that catalyses the very same
      conversion in the presence of O2 and NADH. The activity of the monooxygenase was
      enhanced 1.5-fold by Fe2+ ions. The extremely thermolabile enzyme (apparent
      molecular mass: 155 kDa) exclusively accepted quinaldic acid as substrate. The
      'pseudosubstrates' menadione, 8-hydroxyquinoline, and 8-hydroxy-2-oxo-1,2
      dihydroquinoline effected consumption of NADH and oxygen without being
      hydroxylated. Quinaldic acid 4-monooxygenase was inhibited by sulfhydryl
      modifying and chelating agents, and by various divalent metal ions, whereas
      reducing agents did not affect enzymatic activity.

PMID- 8652627
TI  - Regulation of the redox order of four hemes by pH in cytochrome c3 from D.
      vulgaris Miyazaki F.
AB  - The assignment of 1H-NMR signals of the heme methyl and propionate groups of
      cytochrome c3 of D. vulgaris Miyazaki F was performed. The heme assignment was
      revised for hemes 2 and 3 (sequential heme numbering). Namely, heme 4 is mainly
      reduced at first with hemes 1, 2 and 3 following it in this order. The p2H
      titration of heme methyl signals in four macroscopic oxidation states was
      performed in the p2H range of 5.2 to 9.0. While the heme methyl resonances in the
      fully oxidized state showed just small changes with p2H, most resonances in the
      intermediate oxidation states revealed clear p2H dependence. In particular, the
      methyl resonances of heme 1 shifted significantly in the acidic region. Then, the
      chemical shifts of beta-CH2 (next to the carboxyl group) of all propionate groups
      in the fully oxidized state were observed at various p2H in the range of 4.5 to
      9.0. Only the propionate group at C-13 (IUPAC-IUB nomenclature) of heme 1 showed
      a clear change in this p2H range, its titration curve being similar to those of
      the methyl resonances of heme 1 in the intermediate oxidation states. pKa of the
      propionate group was 5.95 +/- 0.05. Analysis of the microscopic formal redox
      potentials was carried out for the observations at p2H 5.2, 7.1 and 9.0. The
      redox potentials of heme 1 showed the most remarkable p2H dependence, resulting
      in the change of the order of the redox potentials of four hemes. A significant
      change was also found in the interacting potential between hemes 1 and 2. In the
      light of the p2H-titration experiments, the propionate at C-13 of heme 1 was
      identified as the most plausible ionizable group responsible for the p2H
      dependence of microscopic redox potentials of heme 1 in the acidic region.

PMID- 8652628
TI  - Cytoplasmic and peroxisomal catalases of the guinea pig liver: evidence for two
      distinct proteins.
AB  - Catalase, a peroxisomal marker enzyme in the liver of most mammals, is found by
      immuno-electron microscopy in guinea pig (GP) hepatocytes not only in
      peroxisomes, but also in the cytoplasm (Beier et al. (1988) Eur. J. Cell Biol.
      46, 129-135). We have been able to distinguish in GP liver homogenates between
      the cytosolic catalase and that part of the enzyme activity which is due to
      leakage of the enzyme from peroxisomes by adding 4% polyethylene glycol to the
      homogenization medium. This approach revealed that approximately 40% of the total
      catalase activity and almost all of alpha-hydroxy-acid oxidases are peroxisomal,
      while 60% of catalase is of genuine cytosolic origin. The cytosolic and
      peroxisomal catalases of guinea pig were purified to homogeneity and were
      analyzed by SDS-PAGE and isoelectric focussing. The cytosolic catalase exhibited
      a slightly higher Mr (approximately 1000) and a less acidic pI than the
      peroxisomal enzyme. Limited proteolysis and amino-acid analysis revealed also
      slight differences between the two molecular forms of catalase. Total RNA was
      isolated from guinea pig liver and translated in vitro by using a rabbit
      reticulocyte lysate system. Immunoprecipitation with an antibody against guinea
      pig catalase followed by high-resolution polyacrylamide gel electrophoresis
      revealed two polypeptide bands differing slightly in Mr. These observations
      suggest strongly, that cytoplasmic and peroxisomal catalases in guinea pig liver
      are two closely related but distinct proteins.

PMID- 8652629
TI  - Comparison of stored and secreted rat pancreatic digestive enzymes by mass
      spectrometry: alpha-amylase.
AB  - As part of a continuing effort to better understand the mechanisms of protein
      secretion, we compared the mass of pancreatic digestive enzymes, in resting and
      stimulated states, both in secretion and in the zymogen granule to determine
      whether their secretion is accompanied by chemical modification. Mass spectra
      were obtained applying the electrospray method on samples separated by reverse
      phase HPLC. We report here our results for alpha-amylase (1,4-alpha-D-glucan
      glucanohydrolase EC 3.2.1.1). The data illustrate structural differences between
      states and compartments for this enzyme. Multiple isozymes were identified from
      the mass spectra, varying roughly from 52 to 60 kDa. On the basis of mass
      comparisons, not all of the products seen in the zymogen granule were found in
      secretion, nor were all secreted isoforms in the granule. Stimulation of protein
      secretion with a cholinergic agonist, led to time-dependent changes in the number
      and masses of isoforms in secretion, leaving only one of five resolvable forms in
      the granule. Only one form, 55.5 kDa, was found in all samples, granule and
      secretion. In addition to these differences, microheterogeneities of 400 Da or
      less were observed. The data suggest the differential or non-parallel release of
      different amylase forms and their chemical modification during the secretion
      process. As such, release appears to involve a third, intermediate compartment,
      between zymogen granule to ductal space, such as the cytoplasm, in which chemical
      modification takes place.

PMID- 8652630
TI  - NMR and stopped-flow studies of metal ion binding to alpha-lactalbumins.
AB  - 1H-NMR spectroscopy and stopped-flow techniques have been used to investigate the
      binding of a host of metal ions to alpha-lactalbumins from bovine, goat, and
      human sources. We have identified two 1H-NMR markers diagnostic of metal ion
      binding to the high-affinity Ca2+-binding site of bovine alpha-lactalbumin,
      namely the signals corresponding to the delta-CH3 groups of Met-90, and a
      leucine, tentatively assigned to Leu-96. A number of metal ions other than Ca2+
      bind to this site in either slow (La3+, Lu3+, Y3+, Sr2+, Sc3+) or fast (Cd2+,
      Ba2+, Pb2+) exchange. From competition experiments using this approach, we have
      determined an affinity series for metal ion binding at this site, in which
      lanthanides and Y3+ bind the strongest (Y3+>La3+, Lu3+>Ca2+>Sr2+>Cd2+, Pb2+,
      Ba2+>Sc3+). Several metal ions do not alter the 1H spectrum of bovine alpha
      lactalbumin, retaining the protein in an 'apo-like' state. Evidence is given to
      support the notion that the paramagnetic divalent metal ions Co2+ and Cu2+ bind
      to a second distinct site, termed the 'zinc site', and that His-68 is involved in
      metal ion coordination. Finally, stopped-flow techniques using the indicator
      Xylenol orange were employed to obtain lanthanide off-rates for bovine, human,
      and goat alpha-lactalbumins (bovine and goat alpha-LA: k(off)(s-1) approximately
      0.2 to 0.01 from La3+ to Lu3+; human alpha-LA: k(off)(s-1) approximately 0.02 to
      0.001 from La3+ to Lu3+). In each case, we found that k(off) values decreased by
      an order of magnitude across the series, meaning that the dissociation constants
      for these metal ions are relatively constant. Data for the bovine and goat
      proteins are virtually identical, while the off-rates for human alpha-lactalbumin
      are appreciably slower. In addition, these rates are much slower than the Ca2+
      off-rate for the bovine protein (k(off)(s-1) approximately 2 to 5), determined
      using the fluorescent indicator, BAPTA.

PMID- 8652631
TI  - Characterization of single chain urokinase-type plasminogen activator with a
      novel amino-acid substitution in the kringle structure.
AB  - ECV304 is a cell line established by a spontaneous transformation of endothelial
      cells of a human umbilical vein. It was shown that ECV304 secretes single chain
      urokinase-type plasminogen activator (scu-PA). A subclone, ECV304 clone 15, was
      obtained by acclimatization of parental clone to serum-free medium followed by
      limiting dilution. The clone was found to produce approximately five times as
      much scu-PA (approximately 20 IU/10(6) cells per day) as the parental clone after
      a 40 days' culture. Though the biochemical characteristics of the purified scu-PA
      were indistinguishable from those of the native scu-PA, it had a lower affinity
      for fibrin clots under the employed conditions. Molecular cloning of a cDNA
      encoding the scu-PA has identified a novel substitution from C to T in the
      nucleotide sequence encoding the kringle structure. The substitution resulted in
      an alteration from Pro (CCG) to Leu (CTG) at amino-acid position 121, which may
      be directly or indirectly involved in the decrease in the apparent affinity.

PMID- 8652632
TI  - Purification and properties of human urinary beta-D-mannosidase.
AB  - Two forms of the lysosomal enzyme beta-mannosidase were identified and purified
      from human urine. The purification strategy employed allowed sufficient
      quantities of both forms to be obtained for subunit analysis and for further
      characterizations. The two beta-mannosidases were identified as beta-mannosidase
      B and A, in order of their elution from an ion-exchange column. In all samples
      examined, the A form was predominant, and the B/A ratio was consistently 0.14.
      The two forms displayed the same optimum pH (i.e., 4.3) and both were retained by
      a Concanavalin-A Sepharose column, but showed different isoelectric points,
      molecular masses and subunit compositions. Native- and sodium dodecyl sulfate
      polyacrylamide gel electrophoresis analyses of pure beta-mannosidases B and A
      suggest that active protein B (160 kDa) consists of three subunits, one 75 kDa
      and two 49 kDa subunits. Protein A is smaller and appears to be composed of three
      subunits of 75 kDa, 49 kDa and 37 kDa. Two forms of beta-mannosidase, exhibiting
      a chromatographic behaviour comparable to the urinary forms, were also detected
      in human kidney. Nevertheless, in this tissue their relative distribution was
      different, the B/A ratio being 19.

PMID- 8652633
TI  - Synthesis, characterization and properties of sialylated catalase.
AB  - Colominic acid (CA), an alpha-(2-->8) N-acetylneuraminic acid (sialic acid)
      polymer (average molecular weight of 10 kDa) was activated by periodate oxidation
      of carbon 7 at the non-reducing end of the saccharide. The oxidized CA was then
      coupled to catalase by reductive amination in the presence of sodium
      cyanoborohydride. The extent of sialylation of catalase, estimated by ammonium
      sulfate precipitation as 3.8+/-0.4 (mean+/-S.D.) moles of CA per mole of
      catalase, did not improve significantly when depolymerized CA was used in the
      coupling reaction. At the end of the coupling reaction, sialylated catalase
      exhibited a two-fold (70%) retention of initial activity compared to enzyme
      controls (29-35%) subjected to the same conditions. Formation of sialylated
      catalase was confirmed by ammonium sulfate or trichloroacetic acid precipitation,
      molecular sieve chromatography and SDS-PAGE electrophoresis. Enzyme kinetics
      studies revealed an increase in the apparent Km of the enzyme from 70.0 (native)
      to 122.9 mmol l-1 H2O2 (sialylated catalase) indicating a reduction of enzyme
      affinity for the substrate (hydrogen peroxide) on sialylation. Compared to native
      enzyme, sialylated catalase was much more stable in the presence of specific
      proteinases, completely resisting degradation by chymotrypsin and losing only
      some of its activity in the presence of trypsin. The increased stability
      conferred to catalase by sialylation agrees with similar observations on enzymes
      modified by other hydrophilic molecules (e.g., monomethoxypoly(ethyleneglycol))
      and suggests that steric stabilization with the biodegradable polysialic acid may
      prove an alternative means to render therapeutic proteins more effective in vivo.

PMID- 8652634
TI  - 1H-NMR studies on association of mRNA cap-analogues with tryptophan-containing
      peptides.
AB  - 1H-NMR spectroscopy was applied to a study of the mode of interaction, in aqueous
      medium in the pH range 5.2-8.5 and at low and high temperatures, between several
      mono- and dinucleotide analogues of the mRNA cap m7GpppG and a selected
      tripeptide Trp-Leu-Glu, and a tetrapeptide Trp-Glu-Asp-Glu, the sequence of which
      corresponds to one of the suspected binding sites in the mRNA cap-binding protein
      (CBP). A program, GEOSHIFT, was developed, based on ring-current anisotropy
      theory, for analysis of experimentally observed changes in chemical shifts
      accompanying interactions between aromatic heterocyclic rings. This permitted
      quantitative evaluation of stacking interactions between the m7G cap and the
      tryptophan indole ring, and the relative orientations of the planes of the two
      rings, spaced about 3.2 angstroms apart. The structures of the stacked complexes
      were determined. In particular, stacking between m(2,2,7)3G (which has no free
      amino group for hydrogen bonding) and the indole ring is weaker and quite
      different from that between m7G and m(2,7)2G and indole. With the dinucleotide
      cap-analogues, only the m7G component stacks with the indole ring, without
      disruption of intramolecular stacking. In contrast to numerous earlier reports,
      the calculated stacking interactions are quantitatively in accord with the values
      derived from fluorescence measurements. It also has been shown that the
      positively charged (cationic) form of m7G stacks much more efficiently with the
      indole ring than the zwitterionic form resulting from dissociation of the guanine
      ring N1H (pKa approximately 7.3).

PMID- 8652635
TI  - Alterations in the physiochemical characteristics of low and high density
      lipoproteins after lipolysis with phospholipase A2. A spin-label study.
AB  - Human low and high density lipoproteins (LDL and HDL, respectively) were treated
      with porcine pancreatic phospholipase A2 (PLA2) in the presence of albumin
      resulting in hydrolysis of 40-84% of the lipoproteins phospholipids. The
      resulting PLA2-treated LDL and HDL and concurrent control lipoproteins incubated
      without PLA2 were reisolated by ultracentrifugation and labelled with 5-doxyl-
      and 16-doxyl-stearic acid, and with a spin-labelled analogue of maleimide.
      Analysis of ESR spectra showed that phospholipid hydrolysis both of LDL and HDL
      resulted in an increase in order, micro-viscosity and polarity of lipid regions
      in the surface monolayer of the particles. In the temperature range from 3
      degrees C to 50-60 degrees C, Arrhenius plots of a spectral parameter of LDL and
      HDL labelled with 5-doxyl-stearate exhibited alterations which suggest an
      increase in free cholesterol content near the surface of the lipoproteins after
      PLA2-treatment. ESR spectra of the maleimide analogue bound covalently to the
      protein moiety of the lipoproteins have demonstrated that, following phospholipid
      hydrolysis, the conformation of the apoproteins became more condensed, with more
      masked domains. The possible implications of the revealed alterations for
      enhanced delivery of LDL and HDL cholesterol to cells after phospholipolysis of
      the lipoproteins are discussed.

PMID- 8652637
TI  - Distribution of myristoyl-CoA:protein N-myristoyl transferase activity in rabbit
      intestine.
AB  - Myristoyl-CoA:protein N-myristoyl transferase (NMT) attaches the fatty acid,
      myristate, to the amino-terminal glycine residue of various proteins involved in
      cellular regulation and/or signal transduction. We report differences in the
      activity and properties of NMT in New Zealand rabbit small intestine, ascending
      colon and descending colon. The mucosa of the small intestine, ascending colon
      and descending colon was assayed for NMT activity using peptides of known
      myristoylated proteins (pp60src and catalytic subunit of cAMP dependent protein
      kinase). Total NMT activity per gram tissue was 5-fold higher in the small
      intestine and 1.5-fold higher in the ascending colon than in the descending
      colon. Smooth muscle from the colon also contained low levels of NMT activity.
      NMT activity was 2- to 3-fold higher in the particulate fraction than in the
      cytosolic fraction of the mucosa in the descending colon. The apparent molecular
      mass of NMT in the intestine mucosa was 78 kDa.

PMID- 8652636
TI  - Bumetanide is not transported by the Ntcp or by the oatp: evidence for a third
      organic anion transporter in rat liver cells.
AB  - The loop diuretic bumetanide which inhibits hepatic bile acid uptake
      competitively according to its transport kinetics has been proposed to serve as a
      substrate of a multispecific bile acid transport system in liver parenchymal
      cells. However, when the in vitro transcripts of two cloned hepatic bile acid
      uptake carriers, the Ntcp (Na+/taurocholate cotransporting polypeptide) and the
      oatp (organic anion transporting polypeptide), was expressed for three days in
      Xenopus laevis oocytes [3H]bumetanide uptake was not increased although bile acid
      uptake was stimulated. The data presented show that bumetanide is taken up by a
      third organic anion transport system which is different from the cloned bile acid
      transporters.

PMID- 8652638
TI  - Changes in phosphatidylcholine liposomes caused by a mixture of Triton X-100 and
      sodium dodecyl sulfate.
AB  - The mechanisms governing the interaction of equimolecular mixtures of Triton X
      100 (Tx-100) and sodium dodecyl sulfate (SDS) with phosphatidylcholine liposomes
      were investigated. Permeability alterations were determined as a change in 5(6)
      carboxyfluorescein released from the interior of vesicles and bilayer
      solubilization as a decrease in the static light-scattered by liposome
      suspensions. At subsolubilizing level, a maximum bilayer/water partitioning of
      surfactant mixture was reached at 30% CF release, which correlated with the
      increased presence of SDS in the bilayers. However, transition stages between 70%
      CF release and 100% light-scattering corresponded to the increased presence of Tx
      100 in these structures. These findings may be correlated with the reduced
      deleterious effects caused by this mixture in different tissues versus pure SDS,
      given that the presence of Tx-100 may modulate the level of SDS partitioning in
      the human stratum corneum. At subsolubilizing level, the mixture showed higher
      affinity with bilayers than those reported for single components, whereas at
      solubilizing level this affinity was slightly lower and higher than those
      reported for Tx-100 and SDS respectively. A direct relationship was established
      in the initial interaction steps between the growth of vesicles, the leakage of
      entrapped CF and the effective molar ratio of surfactant to phospholipid in
      bilayers (Re). This dependence was also detected during solubilization, where the
      decrease in the vesicle size and in the scattered light of the system depended on
      the Re parameter and hence on the bilayer composition. The fact that the free
      surfactant concentration at subsolubilizing and solubilizing levels showed
      respectively lower and similar values than the critical micelle concentration
      (c.m.c.) of the surfactant mixture indicates that permeability alterations and
      solubilization were determined respectively by the action of surfactant monomer
      and by the formation of mixed micelles. This finding supports the generally
      admitted assumption, for single surfactants, that the concentration of free
      surfactant must reach the c.m.c. for solubilization to occur and highlights the
      influence of the negative synergism of this surfactant mixture on the free
      surfactant concentration needed to saturate or solubilize liposomes.

PMID- 8652639
TI  - Increased expression of scavenger receptor type I gene in human peripheral blood
      from hyperlipidemic patients determined by quantitative additive RT-PCR.
AB  - The scavenger receptors type I and II are mediators for the binding and uptake of
      chemically modified lipoproteins and are restricted to cells of monocyte origin.
      These receptors are highly expressed during the process of monocyte to macrophage
      differentiation. Quantitative mRNA levels of scavenger receptors from peripheral
      blood mononuclear cells have been analyzed in 29 hyperlipidemic patients and 15
      healthy controls. Macrophage scavenger receptor isoforms transcripts were studied
      in circulating peripheral blood mononuclear cells with a modified RT-PCR method
      based on the use of a non-modified internal standard and a mathematical logistic
      adjustment of the standard curve. This method makes it feasible to study the
      variation in the expression of the scavenger receptors gene in peripheral blood
      during different physiopathological conditions. We studied the expression of the
      scavenger receptors gene in different blood cell lines and was present in only
      those of monocytic origin. The results have shown evidence that levels of
      scavenger receptor type I transcripts were proportional to apoB/cholesterol
      levels whereas type II receptors did not show any transcriptional variability.
      These findings suggest that the cholesterol level exerts a selective up
      regulation of the scavenger receptor type I which is detectable by the induced
      increment of circulating monocytes in the blood of hyperlipidemic patients.

PMID- 8652641
TI  - Pre-beta HDL: structure and metabolism.

PMID- 8652640
TI  - Metabolism of arachidonic acid by canine polymorphonuclear leukocytes synthesis
      of lipoxygenase and omega-oxidized metabolites.
AB  - Both polymorphonuclear (PMN) leukocytes and metabolites of arachidonic acid,
      especially lipoxygenase products, have been reported to contribute to myocardial
      damage after coronary artery occlusion and reperfusion. While canine models of
      myocardial ischemia were used in many of these studies, very little is known
      about arachidonic acid metabolism by canine PMNs. Moreover, it is unclear whether
      arachidonic acid metabolites released by canine PMNs affect vascular tone.
      Therefore, we characterized arachidonic acid metabolism by canine PMNs and
      determined the effect of these metabolites on vascular tone of isolated canine
      coronary arteries. Suspensions of canine PMNs were incubated with
      [14C]arachidonic acid and the calcium ionophore A23187. The incubation media was
      extracted, and the metabolites resolved by HPLC. 20-Hydroxy-leukotriene B4
      (LTB4), 12,20-dihydroxyeicosatetraenoic acid (diHETE), LTB4, 12
      hydroxyheptadeclatrienoic acid (HHT), and 12-(S)-hydroxyeicosatetraenoic acid
      (HETE) were isolated, and their structures confirmed by gas chromatography/mass
      spectrometry. There was also evidence for the formation of 20-HETE, thromboxane
      B2 (TXB2), 5-HETE, and several isomers of LTB4. None of the arachidonic acid
      metabolites that were isolated from incubates of canine PMNs augmented vascular
      tone, but material migrating with 12,20-diHETE relaxed canine coronary arteries.
      Authentic 12(S),20-diHETE also produced a concentration-related relaxation of
      canine coronary artery. 12(R), 20-diHETE was inactive. 20-HETE inhibited A23187
      induced PMN aggregation. Thus, arachidonic acid is metabolized in canine PMNs
      through the cyclooxygenase, lipoxygenases and cytochrome P-450 pathways. Whether
      these metabolites contribute to myocardial injury remains to be determined.

PMID- 8652643
TI  - Surfactant protein B metabolism in newborn rabbits.
AB  - Surfactant protein B (SP-B) is critical to the biophysical function of
      surfactant. To characterize its metabolism in vivo in the newborn, we
      administered [35S]methionine and [3H]palmitate to newborn rabbits
      intravascularly. Three groups of 4 rabbits per group were killed at each of 4
      time points followed by isolation of SP-B from alveolar wash and lamellar bodies.
      The labeling kinetics for alveolar wash associated SP-B and saturated
      phosphatidylcholine (Sat PC) had similar patterns. To characterize SP-B clearance
      from the airspace, rabbit SP-B was iodinated, mixed with
      [14C]dipalmitoylphosphatidylcholine and given by intratracheal injection.
      Alveolar washes and lamellar bodies were recovered from 4 animals at each of 7
      time points. Both SP-B and Sat PC were cleared slowly from the total lung (half
      life values approximately 25 h). However, SP-B was cleared more rapidly from the
      airspaces than was Sat PC. The ratio of [125I]SP-B to [14C]Sat PC in lamellar
      bodies increased 2-fold by 8 h. These results support the concept of linked
      secretion and clearance pathways for SP-B and Sat PC, although small differences
      in reuptake were detected.

PMID- 8652642
TI  - Long-term effect of tetradecylthioacetic acid: a study on plasma lipid profile
      and fatty acid composition and oxidation in different rat organs.
AB  - Administration of tetradecylthioacetic acid (a 3-thia fatty acid) increases
      mitochondrial and peroxisomal beta-oxidative capacity and carnitine
      palmitoyltransferase activity, but reduces free fatty acid and triacylglycerol
      levels in plasma compared to palmitic acid-treated rats and controls. The
      decrease in plasma triacylglycerol was accompanied by a reduction (56%) in VLDL
      triacylglycerol. Prolonged supplementation of tetradecylthioacetic acid caused a
      significant increase in lipogenic enzyme activities (ATP-citrate lyase and acetyl
      CoA carboxylase) and diacylglycerol acyltansferase, but did not affect
      phosphatidate phosphohydrolase. Plasma cholesterol, LDL- and HDL-cholesterol
      levels were reduced. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity
      was, however, stimulated in 3-thia fatty acid-treated rats compared to controls.
      In addition. the mRNAs of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and LDL
      receptor were increased. Tetradecylthioacetic acid administration affected the
      fatty acid composition in plasma and liver by increasing the amount of monoenes,
      especially 18:1(n-9), mostly at the expense of omega-3 fatty acids. Compared to
      liver a large amount of tetradecylthioacetic acid accumulated in the heart, and
      this accumulation was accompanied by an increase in omega-3 fatty acids,
      particularly 22:6(n-3) and a decrease in omega-6 fatty acids, mainly 20:4(n-6).
      The results show that the hypolipidemic effect of tetradecylthioacetic acid is
      sustained after prolonged administration and may, at least in part, be due to
      increased fatty acid oxidation and upregulated LDL-receptor gene expression. The
      increase in lipogenic enzyme activities as well as increased 3-hydroxy-3
      methylglutaryl-coenzyme A reductase activity, may be compensatory mechanisms to
      maintain cellular integrity. Decreased level of 20:4(n-6) combined with increased
      omega-3/omega-6 ratio in cardiac tissue after tetradecylthioacetic acid treatment
      may have influence on membrane dynamics and function.

PMID- 8652644
TI  - Identification of 14-hydroxy-4,14-retro-retinol as an in vivo metabolite of
      vitamin A.
AB  - Retinol (vitamin A alcohol) undergoes extensive metabolism in vertebrates. We
      report here (i) the identification of a yet undescribed in vivo metabolite of
      retinol as 14-hydroxy-4,14-retro-retinol in pregnant mice, rats and rabbits
      following dosing with vitamin A, and (ii) the preferential accumulation of 14
      hydroxy-4,14-retro-retinol in maternal and embryonic tissues, rather than in
      material plasma.

PMID- 8652645
TI  - Thermoalkalophilic lipase of Bacillus thermocatenulatus. I. molecular cloning,
      nucleotide sequence, purification and some properties.
AB  - An expression library was generated by partial Sau3A digestion of genomic DNA
      from the thermophile Bacillus thermocatenulatus and cloning of DNA fragments in
      pUC18 in Escherichia coli DH5alpha. Screening for lipase activity identified a
      4.5 kb insert in pUC18 which directed the production of lipase in E. coli
      DH5alpha. A subclone with a 2.2 kb insert was sequenced. The lipase gene codes
      for a mature lipase of 388 amino acid residues, corresponding to a molecular
      weight of 43 kDa. As in other Bacillus lipases, an Ala replaces the first Gly in
      the conserved pentapeptide Gly-X-Ser-X-Gly found in most lipases. The region
      upstream of the lipase gene contains a Bacillus promoter which directs the
      expression of lipase in E. coli DH5alpha. The expressed lipase was isolated and
      purified 312-fold to homogeneity. N-terminal sequencing of the purified lipase
      revealed a correct cleavage of the preprotein in E. coli DH5alpha. Maximum
      activity was found at pH 8.0-9.0 with tributyrin and olive oil as substrates and
      at 60-70 degrees C with p-NPP and olive oil as substrates. The lipase showed high
      stability at pH 9.0-11.0 and towards various detergents and organic solvents.

PMID- 8652646
TI  - Disparate effects of oxidation on plasma acyltransferase activities: inhibition
      of cholesterol esterification but stimulation of transesterification of oxidized
      phospholipids.
AB  - Oxidation of lipoproteins results in the formation of several polar phospholipids
      with pro-inflammatory and pro-atherogenic properties. To examine the possible
      role of lecithin/cholesterol acyltransferase (LCAT) in the metabolism of these
      oxidized phospholipids, we oxidized whole plasma with either Cu(2+) or a free
      radical generator, and determined the various activities of LCAT. Oxidation
      caused a reduction in plasma phosphatidylcholine (PC), an increase in a short
      chain polar PC (SCP-PC), and an inhibition of the transfer of long-chain acyl
      groups to cholesterol (LCAT activity) or to lyso PC (lysolecithin acyltransferase
      (LAT) I activity). However, the transfer of short-chain acyl groups from SCP-PC
      to lyso PCLAT II activity) was stimulated several fold, in direct correlation
      with the degree of oxidation. LAT II activity was not stimulated by oxidation in
      LCAT-deficient plasma, showing that it is carried out by LCAT. Oxidized normal
      plasma exhibited low LCAT activity even in the presence of exogenous
      proteoliposome substrate, indicating that the depletion of substrate PC was not
      responsible for the loss of activity. Oxidation of isolated LDL or HDL abolished
      their ability to support LCAT and LAT I activities of exogenous enzyme, but
      promoted the LAT II activity. Purified LCAT lost its LCAT and LAT I functions,
      but not its LAT II function, when oxidized in vitro. These results show that
      while oxidation of plasma causes a loss of LCAT's ability to transfer long-chain
      acyl groups, its ability to transfer short-chain acyl groups, from SCP-PC is
      retained, and even stimulated, suggesting that LCAT may have a physiological role
      in the metabolism of oxidized PC in plasma.

PMID- 8652647
TI  - Differential effects of glycero- and sphingo-phospholipolysis on human high
      density lipoprotein fluidity.
AB  - This study investigates the effect of enzymatic modifications of the HDL(3)
      surface lipid composition on their physical properties. Human HDL(3) (d: 1.125
      1.21 g/ml) was treated either by an exogenous phospholipase A(2) from Crotalus
      adamanteus or by a sphingomyelinase from Staphylococcus aureus in the presence of
      albumin for various periods of time in order to obtain several degrees of
      hydrolysis. Glycerophospholipid hydrolysis ranged from 13 to 81% and
      sphingomyelinase action led to a 31-92% sphingophospholipid degradation. Physical
      properties of the surface of HDL(3) were examined by two spectroscopic methods:
      fluorescence polarisation and electron spin resonance. Glycerophospholipolysis
      treatment of HDL(3) enhanced the fluorescence anisotropy values (6-18%) and both
      relaxation correlation time (30-100%) and degree of order. All these results
      indicated a more rigid environment, a decreased mobility and an increased order
      of the surface lipids. Conversely, treatment of the HDL(3) with
      sphingophospholipase induced a progressive fluidization: fluorescence
      polarisation and degree of order decreasing down to 10% and relaxation
      correlation time down to 35% compared to native HDL(3). Taken together, all these
      observations suggest the relative importance of the two major phospholipids to
      modulate the fluidity and order of the surface of HDL(3) and could account for
      several recent physiological observations.

PMID- 8652648
TI  - The selective uptake of the cholesteryl esters of low density lipoproteins
      parallels the activity of protein kinase C.
AB  - The analysis of the association of (125)I-LDL and [(3)H]cholesteryl ethers (CEt)
      LDL with HepG2 cells revealed a selective uptake of cholesteryl esters (CE) of
      the LDL, as in the order of three-fold more CE were associated with the cells
      than LDL-proteins for an incubation of 4 h. To determine if a trans-signalling
      pathway is involved in this selective uptake, HepG2 cells were pre-treated for 2
      h with either a Protein Kinase A activator [8-(4-chlorophenylthioadenosine 3'-5'
      cyclic monophosphate (CPT-cAMP)] or a Protein Kinase C activator [phorbol 12
      myristate 13-acetate (PMA)]. We found that CPT-cAMP had a minimal effect, while
      PMA was able to significantly increase the selective uptake of the CE of LDL.
      Indeed, upon a 2 h pre-incubation of HepG2 cells with PMA at a concentration of
      160 microM, an increase of more than 3-fold in CE selective uptake was registered
      and was shown to occur by the lipoprotein binding sites (LBS) of HepG2 cells.
      Also, an incubation of the cells with 100 nM calphostin C, an inhibitor of
      protein kinase C, decreased the selective uptake by 41%. The effect of PMA is not
      abolished by either cycloheximide or actinomycin D. However, cycloheximide was
      shown to potentiate the effect of PMA on the LBS activity, suggesting that a
      protein which synthesis is affected by cycloheximide is involved in maintaining
      the LBS activity low. Our results show that the HepG2 cell activity of CE
      selective uptake parallels the activity of Protein Kinase C and suggest that the
      LBS could be a G-protein linked receptor.

PMID- 8652649
TI  - Effects of isomeric cis and trans eighteen carbon monounsaturated fatty acids on
      porcine platelet function.
AB  - The effects of different positional cis and trans isomers (9, 11, 12 and 13) of
      C(18) monoenoic fatty acids on the response of porcine platelets to collagen and
      thrombin stimulation were determined. Cis isomers inhibited aggregation in
      response to 2 microgram/ml or 5 microgram/ml collagen and 0.1 U/ml of thrombin
      with almost equal effectiveness, with the exception of the 9- and 11-isomers
      which gave reduced inhibition of aggregation with thrombin and collagen
      stimulation respectively. All cis isomers inhibited TXA(2) formation (determined
      as TXB(2)) elicited by collagen with almost equal effectiveness. Trans isomers
      were less effective than cis in inhibiting collagen induced aggregation
      particularly at the higher collagen concentrations. Inhibition of TXB(2)
      formation was less marked with trans isomers but a clear dissociation between the
      extent of inhibition of aggregation and TXB(2) formation was evident. Cis isomers
      also inhibited aggregation in response to 0.1 U/ml thrombin whereas trans isomers
      augmented aggregation but still reduced TXB(2) formation. Isomers did not elicit
      their effects through incorporation into platelet membrane phospholipids.
      Aggregation studies were carried out using the impedance method which is more
      sensitive than the optical method hitherto described, particularly for lipid
      studies.

PMID- 8652650
TI  - Incorporation of 12(S)-hydroxyeicosatetraenoic acid into the phosphatidylcholine
      signaling pathway.
AB  - The incorporation of 12-lipoxygenase metabolites into phospholipids (PLs) could
      modify second messengers such as diacylglycerols (DAG) and phosphatidic acids.
      Incubation of [(14)C]12(S)-HETE (1 microM) with bovine pulmonary artery
      endothelial cells (BPAEC), resulted in its incorporation in PLs with
      concentration-dependent kinetics. After a 4 h incubation, the proportion of
      radioactive phosphatidylcholine (PC), phosphatidylethanolamine (PE),
      phosphatidylserine (PS) + phosphatidylinositol (PI) isolated by TLC, was 77.9%,
      16.4% and 5.7%, respectively. In PC, [(14)C]12(S)-HETE was incorporated at the
      position 2 of the glycerol. Three major peaks of radioactive PC were isolated on
      RP-HPLC which were hydrolysed by phospholipase C (PLC). The resulting
      diacylglycerols were derivatized and identified by GC/MS as 1-oleyl-, 1-stearoyl-
      and 1-palmitoyl-2-[12-HETE] PC. BPAEC were incubated with [(14)C]12(S)-HETE (1
      microM) before stimulation with bradykinin (1 microM). (A) 1-acyl-2-[12-HETE]
      diacylglycerols were isolated, derivatized and analysed by MS. We identified a
      major ion with m/z = 926 that corresponds to the molecular ion of authentic 1
      stearoyl-2-12(S)-HETE DAG, and 2 other ions with m/z = 924 and 898 that
      correspond to the molecular ions of 1-oleyl- and 1-palmitoyl-2-12(S)-HETE DAG,
      respectively. (B) Radioactive PA was isolated and hydrolysed by alkaline
      phosphatase. The MS of resulting diacylglycerols identified 1-stearoyl-, 1-oleyl
      , and 1-palmitoyl-2-12(S)-HETE phosphatidic acids. The quantities of 12-HETE PA
      and the 3 major 12-HETE diacylglycerols were shown to increase following
      bradykinin stimulation. Thus, the incorporation of 12(S)-HETE into PLs results in
      the production of altered phosphatidic acids and diacylglycerols. The time-course
      of increases in 1-acyl-2-(12-HETE) phosphatidic acids and 1-acyl-2-(12-HETE)
      diacylglycerols showed maximal concentrations 1 and 2 min after bradykinin
      stimulation, respectively, followed by the decrease of both compounds.
      Propranolol, an inhibitor of PA phosphohydrolase, totally abolished the
      bradykinin-induced increase in 12-HETE DAG while increasing the magnitude and
      duration of 12-HETE PA release. The inhibiting effect of propranolol on
      bradykinin-induced increase of 12-HETE DAG demonstrates that 12-HETE PA is the
      principal precursor for 12-HETE DAG. This affords a novel method for confirming
      the major role of phospholipase D in PC metabolic pathways triggered during cell
      signaling.

PMID- 8652651
TI  - Hydrolysis and esterification of acylglycerols and analogs in aqueous medium
      catalyzed by microbial lipases.
AB  - The stereoselectivity of microbial lipases from Chromobacterium viscosum (CVL)
      and Rhizopus arrhizus (RAL) towards monoacylglycerols (rac-1(3)-oleoylglycerol
      and 2-oleoylglycerol), diacylglycerols (1,3-dioleoylglycerol and rac-1,2(2,3)
      dioleoylglycerol) and 2-O-ether analogs (rac-1(3)-oleoyl-2-O-hexadecylglycerol
      and rac-1(3)-octanoyl-2-O-hexadecylglycerol) was determined. The results of the
      hydrolysis of 2-O-ether analogs confirmed the importance of the substituent at C
      2 of acylglycerols in the stereoselective recognition by microbial lipases and
      also showed that acylation of mono- and diradylglycerols with oleic acid overlaps
      the hydrolysis reaction in aqueous medium. With the short-chain, water-soluble
      octanoic acid no significant esterification occurred. Using rac-1,2(2,3)
      dioleoylglycerol as a substrate for the hydrolysis with RAL and CVL, the
      appearance of 1,3-dioleoylglycerol and of 1(3)-monooleoylglycerol was
      demonstrated. The possibility of chemical vs. enzyme-catalyzed isomerization of
      1,2-dioleoylglycerol and of 2-oleoylglycerol is discussed.

PMID- 8652653
TI  - Recent advances in the biosynthesis of plant fatty acids.

PMID- 8652652
TI  - Characterization of 5'AMP-activated protein kinase activity in the heart and its
      role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia.
AB  - Despite the high expression of 5'AMP activated protein kinase (AMPK) in heart,
      the activity and function of this enzyme in heart muscle has not been
      characterized. We demonstrate that rat hearts have a high AMPK activity,
      comparable to that found in liver, which could be stimulated up to 3-fold by
      5'AMP. Cardiac AMPK is also under phosphorylation control, since in vitro
      incubation of cardiac AMPK with protein phosphatase 2A completely abolished
      activity, while incubation with ATP/Mg(2+) resulted in over a 2-fold increase in
      activity. To investigate the function of AMPK in heart muscle, isolated working
      rat hearts were subjected to 30 min of global no-flow ischemia, followed by 60
      min of aerobic reperfusion. AMPK activity was increased in heart at the end of
      reperfusion compared to aerobic controls (379 +/- 53 (n=5) vs. 139 +/- 19 (n=5)
      pmol x min(-1) x mg protein(-1), P<0.05, respectively). Treatment of AMPK in
      vitro with protein phosphatase 2A reversed this activation. Since AMPK can
      phosphorylate and inactivate acetyl-CoA carboxylase (ACC) in other tissues, and
      heart ACC has an important role in regulating fatty acid oxidation, we measured
      ACC activity in hearts reperfused post-ischemia. ACC activity was decreased at
      the end of reperfusion compared to aerobic controls (3.64 +/- 0.36 (n=9) vs.
      10.93 +/- 0.60 (n=11) nmol x min(-1) x mg protein(-1), respectively, P<0.05). A
      significant negative correlation (r= -0.78) was observed between AMPK activity
      and ACC activity measured in aerobic and reperfused ischemic hearts. Low ACC
      activity could be reversed if ACC was extracted from hearts in the absence of
      phosphatase inhibitors, suggesting that phosphorylation of ACC decreased enzyme
      activity. This suggests that following ischemia AMPK is phosphorylated and
      activated (possibly by an AMPK kinase). AMPK then phosphorylates and inactivates
      ACC. The resultant decrease in malonyl-CoA levels could explain the acceleration
      of fatty acid oxidation that is observed during reperfusion of ischemic hearts.

PMID- 8652654
TI  - Activation of acyl-coenzyme A:cholesterol acyltransferase activity by cholesterol
      is not due to altered mRNA levels in HepG2 cells.
AB  - Many studies have shown that sterols can stimulate acyl-coenzyme A:cholesterol
      acyltransferase (ACAT) activity in cells. To elucidate this mechanism, effects of
      sterol-mediated induction on both the enzyme activity of ACAT and its mRNA levels
      were studied in human hepatoblastoma cell line, HepG2 cells. When HepG2 cells
      were loaded with cholesterol and 25-hydroxycholesterol, both the whole-cell ACAT
      activity and the microsomal ACAT activity were increased by 85.1% and 41.3%. In
      contrast, cholesterol depletion of HepG2 cells with compactin, a 3-hydroxy-3
      methylglutaryl coenzyme A reductase inhibitor, resulted in a decrease in both the
      whole-cell and the microsomal ACAT activity by 46.4% and 58.3%. Under identical
      conditions, RT-PCR and Northern blotting analyses revealed that neither
      cholesterol loading nor cholesterol depletion of HepG2 cells altered the amounts
      of ACAT mRNA. Moreover, these treatments had no effect on the enzymatic ACAT
      activity determined by the reconstituted assay in which HepG2 cell homogenate had
      been supplemented in vitro with a saturating level of exogenous cholesterol.
      These results indicate that cholesterol-induced up-regulation of ACAT activity in
      HepG2 cells does not occur at the level of transcription, but rather at a
      posttranscriptional level.

PMID- 8652655
TI  - Phospholipase A(2) activity in non-glycated and glycated low density
      lipoproteins.
AB  - The oxidation of low density lipoprotein (LDL) is believed to be an important
      risk factor for atherosclerosis. We have previously reported that glycation of
      LDL enhances LDL oxidation. Incubation of LDL in the presence of 200 mM glucose
      resulted in the enhanced formation of phosphatidylcholine hydroperoxide (PC-OOH)
      and cholesteryl ester hydroperoxide (CE-OOH). Fe(3+)-ADP accelerated the
      formation of hydroperoxides. The concentration of PC-OOH was much smaller than
      that of CE-OOH. In addition, we found a PC-OOH decomposing activity in LDL by
      following linoleic acid hydroperoxide (18:2-OOH) formation from 1-stearoyl-2-[13'
      (S)-hydroperoxy-9', 11'-octadecadienoyl]-sn-glycero-3-phosphocholine (SLPC-OOH).
      Hydrolysis was similar between LDL and glycated LDL. Pretreatment by para
      bromophenacylbromide, histidine modifier and phospholipase A(2) inhibitor,
      retarded the formation of 18:2-OOH only by 30%. The addition of equimolar
      platelet activating factor (PAF) reduced hydrolysis by 50%, indicating PAF
      acetylhydrolase may be responsible for the hydrolysis of PC-OOH.

PMID- 8652656
TI  - Alterations in surfactant neutral lipid composition during the development of
      bleomycin-induced pulmonary fibrosis.
AB  - The purpose of this investigation was to correlate changes in the neutral lipids
      of pulmonary surfactant with previously observed changes in surfactant
      phospholipids and lung compliance in the rat model of bleomycin-induced pulmonary
      fibrosis. Bronchoalveolar lavage fluid (BAL) obtained at 0, 1, 3, 7, 14, 30 and
      120 days after transtracheal instillation of bleomycin was used as a source of
      surfactant lipids. The mean concentration of neutral lipids in normal BAL was 439
      nmol/lung and was composed of 55% cholesterol (CHO), 27% cholesterol ester (CE)
      and 19% free fatty acids (FFA). CHO was elevated at 1 day, reaching a maximum 4
      fold increase in concentration at 14 days before subsiding to normal at 120 days.
      In contrast to CHO, CE and FFA were significantly reduced at 1 day after
      bleomycin with FFA below detectable levels. However, both these species were
      twice normal levels at 3-30 days before returning to normal at 120 days. The
      fatty acid composition of CE did not change; however, unsaturated fatty acids
      were significantly increased in FFA between 3 and 120 days. The data indicate
      that there are significant alterations in the neutral lipid composition of
      pulmonary surfactant at various stages of bleomycin induced lung injury. The
      significance of these changes are not fully understood; however, the possibility
      exists that an abnormal surfactant results which in turn affects lung function.

PMID- 8652657
TI  - Phase transitions of rat stratum corneum lipids by an electron paramagnetic
      resonance study and relationship of phase states to drug penetration.
AB  - In order to relate barrier function to stratum corneum structure and the thermal
      transitions of corneum lipids, samples from hairless rat skin were investigated
      by using ESR and drug penetration techniques. The phase transition of stratum
      corneum lipids was estimated using a deeper probe (16-doxyl-stearic acid)
      inserted in the lipid bilayers and measuring the rotational correlation time,
      tau(c). Results of ESR study showed that stratum corneum lipids underwent thermal
      transitions at 39.3 +/- 1.6 degrees C and 63.6 +/- 2.6 degrees C roughly similar
      to the data obtained by differential scanning calorimetry measurements.
      Cholesterol oxidase treatment decreased the fluidity of the lipids at lower
      temperatures. The treatment of stratum corneum with laurocapram (1%) and
      isopropyl myristate (IPM, 2%) little changed both phase transition temperatures,
      although the treatment highly increased the molecular motion of the lipids. The
      flux (J(s)) of lipophilic drugs (beta-estradiol, indomethacin and betahistine)
      through the skin was enhanced with increasing temperatures, with an increase in
      the diffusion constant within skin and a decrease in the lag time. There was a
      good relationship between log J(s) or log permeability coefficient (K(p)) and
      1/tau(c) in the temperature range of 45 to 64 degrees C. The calculated
      activation energy (delta E) for diffusion of these drugs across skin was 17-40
      kcal/mol. Judging from our data, stratum corneum lipids of rat probably exist as
      the gel, crystalline state below 39 degrees C, the mesomorphic state between 39
      and 64 degrees C and the fluid, liquid-crystalline state at temperatures of 64
      degrees C or above. These results are in line with the permeability of these
      lipophilic drugs through the intercellular lipids disordered is highly increased.

PMID- 8652658
TI  - A gene, han1A, encoding an archaeal histone-like protein from the Thermococcus
      species AN1: homology with eukaryal histone consensus sequences and the
      implications for delineation of the histone fold.
AB  - The han1A gene, encoding a subunit of the histone-like protein HAN1 from the
      Thermococcus species AN1, has been cloned and sequenced. Sequence analysis of the
      translation product of the gene demonstrates homology with other archaeal histone
      like proteins of the 'HMf family' and eukaryal consensus sequences, particularly
      H4. The region of highest homology between the AN1 histone subunit, termed the
      HAN1A1 subunit, and the H4 consensus is suggested, by the 3-dimensional structure
      of the histone octamer, to interact with the minor groove of DNA. The results
      presented add further weight to the notion that the 'archaeal histones' and the
      eukaryal histones are indeed related and that the approximate 65 amino acid
      residue length of the archaeal histones represents the archaeal equivalent of the
      histone fold structural building block common to all eukaryal histones.

PMID- 8652659
TI  - Transcriptional regulation of the human NAD(P)H:quinone oxidoreductase (NQO1)
      gene by monofunctional inducers.
AB  - The upstream region of the human NAD(P)H:quinone oxidoreductase (NQO1) gene
      contains a functional antioxidant responsive element (ARE) and an overlapping 12
      O-tetradecanoyl-phorbol-13-acetate responsive element (TRE), with the sequence
      TGACTCAGCA. We show that the ARE (TGACNNNGCA) is required for induction by redox
      cycling phenolics (p-benzoquinone, catechol and hydroquinone), which are
      monofunctional inducers and induce NQO1 without the requirement for activation by
      cytochrome P-450. The TRE (TGACTCA) is involved only in basal expression. A
      plasmid containing overlapping ARE-TRE (TGACTCAGCA) sequences (-587 to -379) from
      the NAD(P)H:quinone oxidoreductase gene was transiently transfected into Hep G2
      cells. In the absence of inducers, basal expression was 4-fold higher than in F9
      cells (which lack AP-1 activity). Using subcloned oligonucleotides containing the
      ARE-TRE sequence (-473 to -440), the ARE sequence alone (TCA changed to GAC) and
      the TRE sequence alone (GC changed to TA), the basal level of expression was in
      the order: TRE > TRE-ARE > ARE in Hep G2 cells. Using F9 cells, basal expression
      was detected using the combination ARE-TRE sequence or the ARE, but not the TRE
      alone, p-Benzoquinone, catechol and hydroquinone, but not resorcinol, induced
      gene expression in both Hep G2 and F9 cells via the ARE-TRE and ARE sequences,
      but the TRE sequence did not contribute to this induction. We therefore conclude
      that induction of human NAD(P)H:quinone oxidoreductase by monofunctional inducers
      is via the ARE and not the TRE, and that the induction is mediated by proteins
      other than Fos and Jun.

PMID- 8652660
TI  - Construction and partial characterization of an L-amino acid oxidase-free
      Synechococcus PCC 7942 mutant and localization of the L-amino acid oxidase in the
      corresponding wild type.
AB  - The gene (aoxA) coding for an L-amino acid oxidase (L-AOX) with high specificity
      for basic L-amino acids (L-arginine being the best substrate) in the
      cyanobacterium Synechococcus PCC 6301 has previously been identified, sequenced
      and analysed (Bockholt, R., Masepohl, M., Kruft, V., Wittmann-Liebold, B. and
      Pistorius, E.K. (1995) Biochim. Biophys. Acta 1264, 289-293). Here we report on
      the inactivation of the aoxA gene in the closely related Synechococcus PCC 7942
      by interrupting the gene with a kanamycin resistance cassette from Tn5. The
      mutant called D6 has no detectable L-AOX activity and no detectable L-AOX
      protein. Characterization of the mutant showed that in contrast to Synechococcus
      PCC 7942 wild-type (WT) cells the mutant cells can not grow on L-arginine as sole
      N-source, suggesting that the L-AOX is essential for growth on L-arginine. Mutant
      cells can grow on nitrate or ammonium as N-source under photoautotropic
      conditions with a growth rate of about 75% of the WT rate. Under these conditions
      the photosynthetic O2 evolving activity is reduced by about the same amount, and
      the pigment content, especially the phycobiliprotein content, is much lower than
      in WT cells, indicating that the mutant suffers from some type of deficiency.
      Immunocytochemical investigations and extraction of the soluble proteins from
      periplasma after plasmolysing the cell wall gave evidence that the L-AOX is
      predominantly located in the periplasma with only a small amount being
      intracellularly located. A model of the possible function of the L-AOX in
      Synechococcus PCC 6301/7942 will be given.

PMID- 8652661
TI  - Identification of a third thioredoxin gene from Corynebacterium nephridii.
AB  - We identified and sequenced a gene encoding a third thioredoxin (C3) from
      Corynebacterium nephridii. The determined nucleotide sequence encodes a
      thioredoxin of 145 amino acid residues, which is larger than most thioredoxins
      found in microbial cells and contains 6 cysteine residues. C. nephridii
      thioredoxin C3 is able to serve as a subunit of T7 DNA polymerase. C. nephridii
      is the first nonphotosynthetic procaryotic organism known to carry three
      different thioredoxins.

PMID- 8652662
TI  - Molecular cloning of the forkhead transcription factor HNF-3 alpha from a human
      pulmonary adenocarcinoma cell line.
AB  - We have cloned the human homologue of HNF-3 alpha from the pulmonary
      adenocarcinoma cell line NCI-H441. Full-length HNF-3 alpha which was found to be
      2872 bp encoded a protein of 473 amino acids. The human protein is highly related
      to the rat and mouse homologues and the forkhead DNA binding domain is highly
      conserved between all species yet identified. Northern blotting with a variety of
      human-derived cell lines identified a single 3 kb mRNA species. RNA levels are >
      10-fold higher in the H441 cells than in any of the others.

PMID- 8652663
TI  - Molecular cloning of an intronless gene for the hamster centromere antigen CENP
      B.
AB  - Centromere protein B (CENP-B) is a DNA-binding protein present at both active and
      inactive centromeres. It was first localized at the kinetochore region by human
      autoimmune sera from CREST patients. Using a previously identified human cDNA we
      have isolated a genomic clone containing the complete hamster CENP-b intronless
      coding sequence. At the nucleotide level it was found to possess a high degree of
      homology with the human and mouse CENP-B genes, being 75% and 90% respectively.
      This codes for 606 amino acid residues, which represent seven more than the human
      and mouse centromeric proteins. Hamster CENP-B protein analysis revealed at the N
      terminal region a 133 amino acid fragment of 100% homology to the DNA binding
      motif identified previously for the human autoantigen. Expression of hamster CENP
      B during the cell cycle was analyzed by using a specific antiCENP-B serum
      generated against the C-terminal conserved region. These data indicate that CENP
      B is highly conserved and it represents a universal component of the centromere
      structure and function in mammals.

PMID- 8652664
TI  - Long tandemly repeated repetitive (LTRR) sequences in the filamentous
      cyanobacterium Anabaena sp. PCC 7120.
AB  - Nucleotide sequence analysis of the DNA region carrying transposon Tn5-1087b from
      the Anabaena 7120 nitrogen fixation-deficient mutant YC16 revealed the presence
      of a novel repeated DNA element in cyanobacteria designated long tandemly
      repeated repetitive (LTRR) sequence. The LTRR element is 37 bp long and contains
      an inverted repeat sequence. 17 copies of the LTRR element, 13 of which were
      completely identical, were identified within a 1.3 kb DNA fragment, which was
      flanked by two divergently transcribed genes homologous to bacteriophage T4 'gene
      15' and Rhizobium meliloti exoD, respectively. LTRR-like sequences occur in
      several DNA regions in Anabaena 7120 and in other cyanobacteria. Furthermore, the
      presence of an LTRR-like DNA region in mitochondrial plasmids of Vicia faba
      indicates strong conservation of such structures during evolution.

PMID- 8652665
TI  - Cloning of a cDNA encoding a human homologue of CDC47, a member of the MCM
      family.
AB  - A complementary DNA (cDNA) clone encoding a 719-amino acid (aa) protein was
      isolated, which has a 49% aa identity with budding yeast CDC47, a member of the
      MCM family. Antiserum raised against a C-terminal polypeptide bacterially
      produced from the cDNA clone detected a cellular protein about 80 kDa, which
      coincides with the size of the in vitro transcription/translation product of the
      cDNA. These results indicate that the cDNA covers the entire coding region of a
      human homologue of CDC47.

PMID- 8652666
TI  - Identification of a thyroid-specific and cAMP-responsive enhancer in the upstream
      sequences of the human thyroglobulin promoter.
AB  - Functional analysis of remote 5'-flanking sequences from the human thyroglobulin
      gene in primary cultured dog thyrocytes led to the identification of a partly
      cAMP-responsive enhancer, located between -3.6 to -2.2 kb from the
      transcriptional start site. Deletion analysis of the 1.4 kb-long region localised
      the enhancer activity in a 0.5 kb-long fragment (located between -3.2 and -2.7 kb
      relative to transcription start), which could be divided into two functional sub
      fragments of 0.2 and 0.3 kb. A potential binding site for the CREB/ATF
      transcription factors was found in the 0.3 kb element. The complete enhancer
      region had no detectable activity when assayed in Hela cells, suggesting that it
      constituted a thyroid-specific regulatory element. Accordingly, footprinting
      experiments revealed the presence of several binding sites for Thyroid
      Transcription Factor-1 (TTF-1) in both the 0.2 and 0.3 kb elements.

PMID- 8652667
TI  - Mechanism and evolution of RNA editing in kinetoplastida.

PMID- 8652668
TI  - Complex interactions with direct repeats of a mitogen-responsive VL30 enhancer.
AB  - The RVL-3 VL30 enhancer is an LTR-derived triple direct repeat of 35 base pairs
      that mediates gene induction in response to several different intracellular
      signaling pathways. Using mobility shift assays, methylation interference and
      DNase I footprinting, we have investigated the physical interactions between the
      RVL-3 enhancer and components of nuclear extracts from Rat-1 cells. Each enhancer
      repeat unit contains a single binding site. Our studies suggest that binding to
      the double or triple repeat enhancer is cooperative, involving simultaneous
      occupation of two sites, with a preference for adjacent sites. Binding
      cooperativity would have implications for the mechanism of gene activation
      directed from the native VL30 enhancer.

PMID- 8652669
TI  - Nucleotide and aminoacyl-tRNA specificity of the mammalian mitochondrial
      elongation factor EF-Tu.Ts complex.
AB  - The bovine mitochondrial elongation factor Tu.Ts complex (EF-Tu.Tsmt) promotes
      the binding of aminoacyl-tRNA to ribosomes. In the presence of GTP, this complex
      functions catalytically. Both dGTP and ddGTP can replace GTP although about 4
      fold higher concentrations are required. ATP, CTP and UTP are not active. ITP can
      replace GTP when used at 10- to 20-fold higher concentrations. The catalytic use
      of EF-Tu.Tsmt is inhibited by GDP but not by GMP. XDP also inhibits although
      about 20-fold higher concentrations are required. EF-Tu.Tsmt will promote the
      binding of Phe-tRNA to either Escherichia coli or mitochondrial ribosomes. Unlike
      E. coli EF-Tu, EF-Tu.Tsmt will promote the binding of AcPhe-tRNA to ribosomes
      about 25% as efficiently as Phe-tRNA. EF-Tu.Tsmt is active in catalyzing the
      binding of E. coli Met-tRNAmmet to ribosomes. EF-Tu.Tsmt has about 30% as much
      activity with E. coli Met-tRNAimet but has essentially no activity with E. coli
      fMet-tRNAimet. Neither yeast Met-tRNAimet nor fMet-tRNAimet is recognized by
      bovine EF-Tu.Tsmt.

PMID- 8652670
TI  - Expression of the gene for cytochrome P-450 17 alpha-hydroxylase/C17-20 lyase
      (CYP17) in porcine Leydig cells: identification of a DNA sequence that mediates
      cAMP response.
AB  - Regulation of CYP17 gene expression in porcine Leydig cells was investigated in
      primary culture. We previously reported the sequence of the 5' upstream and much
      of the pig gene. (Zhang et al. (1992) Biochim. Biophys. Acta. 1131, 345-348).
      DNase I footprinting assays identified a region between -193 and -174 that was
      bound by nuclear proteins. Examination of the DNA sequence in this region
      revealed putative Sp1 and AP-2 binding sites, but gel retardation assays using an
      oligonucleotide from -198 to -168 as a probe revealed two specific DNA-protein
      complexes that were not Sp1 or AP-2. The oligonucleotide was cloned into a
      reporter gene containing a minimal porcine CYP17 promoter and the resultant
      construct was transiently transfected into porcine Leydig cells. This chimeric
      construct had both basal and cAMP-induced transcriptional activities.
      Southwestern blot identified a prominent binding of a nuclear protein around 68
      kDa and a weaker binding of a nuclear protein around 110 kDa. Sequences between 
      250/+1 are highly homologous to those sequences from human, bovine and rodent
      CYP17 gene, but the -193/-174 region has no homology to those genes. Other
      regions of the porcine CYP17 were also important for the basal and cAMP-mediated
      regulation. Luciferase expression vectors were prepared with 5' flanking DNA from
      the porcine CYP17 gene and were expressed in primary culture of porcine Leydig
      cells. The region between -587/-325 was important for basal transcription, and a
      region of DNA between -325 and -140 was important for cAMP regulation.

PMID- 8652671
TI  - Identification of two prolactin cDNA sequences from a goldfish pituitary cDNA
      library.
AB  - We have identified two different cDNA clones encoding for goldfish prolactin
      (gfPRL) from a pituitary cDNA library. The coding regions of these clones are
      predicted to encode for an identical amino acid (aa) sequence with four silent
      mutations. The 3'-untranslated regions (UTRs) of these clones show only 72%
      nucleotide (nt) sequence identity. The two genes each encoding gfPRL might have
      derived from recent gene duplication before the divergence of goldfish from other
      Cypriniforms. Genomic Southern blot analysis of goldfish DNA also demonstrated
      that there is a small family of two genes for prolactin in the genome of
      goldfish.

PMID- 8652672
TI  - Modification of the alternative splicing process of testosterone-repressed
      prostate message-2 (TRPM-2) gene by protein synthesis inhibitors and heat shock
      treatment.
AB  - During the course of the study to examine the effect of cycloheximide on
      apoptosis-related genes, the variant rat testosterone-repressed prostate message
      2 (TRPM-2) mRNA deficient of the exon 5 was found. The putative protein encoded
      by the variant TRPM-2 mRNA is only constituted from the N-terminal one-third
      portion of the ordinary TRPM-2 protein. The expression of the variant form was
      increased dramatically by cycloheximide treatment, while that of the ordinary
      form was not affected very much. The similar phenomenon was also observed by the
      use of other types of protein synthesis inhibitors, anisomycin and emetine. The
      enhancement of expression of the variant was observed in the rat treated with
      heat shock as well. The variant form was presumably generated by the exon skip
      mechanism. Systematic analyses of cycloheximide effect on the alternative
      splicing at various splicing junctions were performed. However, cycloheximide did
      not exhibit any remarkable effects on other types of alternative splicing,
      including exon skip in beta A4-amyloid protein precursor (APP) gene, alternative
      donor selection in Fas antigen gene and alternative acceptor selection in
      catechol O-methyltransferase (COMT) gene. These results indicated that the
      induction of exon skip by both protein synthesis inhibition and heat shock
      treatment occurs in a limited number of genes, if not only in TRPM-2.

PMID- 8652673
TI  - Developmental regulation of expression of rabbit C-reactive protein and serum
      amyloid A genes.
AB  - Serum amyloid A (SAA) and C-reactive protein (CRP) are acute phase plasma
      proteins which increases 100- to 1000-fold after inflammatory stimuli. In this
      study pregnant rabbits were given lipopolysaccharide (LPS) or subjected to
      laparotomy with fetal injections of LPS at different stages of gestation. Newborn
      rabbits were given LPS or saline. SAA and CRP mRNA were studied using Northern
      blot analyses and scanning densitometry. In vitro transcribed RNAs were used as
      standards for quantitative mRNA analyses. A gradual increase in LPS-induced SAA
      and CRP mRNA levels was observed during development, but only SAA mRNA induction
      was seen at gestational day 19. Fetal SAA and CRP mRNA induction was not seen
      after maternal LPS stimulation. The constitutive level of SAA and CRP mRNA was
      significantly lower in fetal rabbits than in adults. The control level of SAA
      mRNA in one-day-old rabbits was higher than the normal adult level, while the
      neonatal CRP mRNA level was lower. SAA2 seemed to be the major acute phase
      reactant in both fetal, neonatal and adult rabbits, while relatively more SAA3
      was found during early developmental stages. The study demonstrated that CRP and
      three SAA genes are differentially regulated during development.

PMID- 8652675
TI  - Where does Hippocrates fit into managed care?

PMID- 8652674
TI  - Pax 8 expression in primary cultured dog thyrocyte is increased by cyclic AMP.
AB  - Pax 8 proteins are paired domain-containing transcription factors expressed in
      thyroid, kidney, ovary, placenta and developing brain. Thyroglobulin (Tg) and
      thyroperoxidase (TPO) genes, which are specifically expressed in thyroid
      follicular cells, both harbor a Pax 8 binding site in their proximal promoter
      region. The transcription of these genes is, as is the expression of most of the
      other differentiated functions of the thyrocyte, positively regulated by
      thyrotropin (TSH) via a cyclic-AMP (cAMP)-dependent mechanism. However, no
      typical cAMP-responsive element has been detected in the promoter region of Tg
      and TPO genes. We therefore investigated whether Pax 8 activity itself could be
      regulated by cAMP, which would support a role for these factors in the cAMP
      dependent expression of differentiation in thyroid cells. In this paper we show
      that the expression of Pax 8 mRNA and proteins are increased by treatment of the
      thyrocyte with forskolin. This suggests that Pax 8 could indeed participate in
      the mediation of the transcriptional activation of thyroid specific genes by
      cAMP. We also show that Pax 8 are nuclear phosphoproteins, although neither their
      phosphorylation, nor their nuclear translocation seem to be highly regulated by
      cAMP. During the course of this study, a new splicing variant of dog Pax 8,
      termed Pax 8g, has been isolated.

PMID- 8652676
TI  - Eastern European public health: opportunity and challenge.
AB  - Allied health professionals in the United States have a unique opportunity to
      help people living in countries of the former Eastern Bloc. The United States
      government has shown its willingness to help by including Czechoslovakia in the
      1990 SEED (Support for East European Democracies) Act which gives financial
      support and favored treatment. The National Institutes of Health have allocated
      three million dollars a year for the past three years for projects in Eastern
      Europe. However, money and laws alone will not solve the ongoing problems in
      Eastern Europe. It will require people who appreciate what they have and care
      enough to make a difference in the world community. By educating, facilitating,
      and temporarily executing change, a health care tragedy can be turned around. It
      is an inherent violation of our oaths and ethical contracts if we turn our backs
      when so very little time and effort can make so great a difference.

PMID- 8652677
TI  - Worker's compensation.

PMID- 8652678
TI  - A new licensure examination for medical doctors.

PMID- 8652679
TI  - Appreciating MSV's founders. Reflections on 19th century enigmas.

PMID- 8652680
TI  - Richmond's physician mayors.

PMID- 8652681
TI  - Jefferson's vision of medical education and his quest for a professor of
      medicine.

PMID- 8652682
TI  - Herbert Milton Nash, MD. Warrior, surgeon and Christian gentleman.

PMID- 8652683
TI  - Winder Hospital. Richmond 1863.

PMID- 8652684
TI  - Portrait of a private hospital, 1895.

PMID- 8652685
TI  - Wade Hampton Frost, MD. A wider view of the world.

PMID- 8652686
TI  - Remembering the good old days of MSV.

PMID- 8652687
TI  - Sexual, vertical and household transmission of hepatitis C.
AB  - Hepatitis C infection is one of the most common forms of chronic liver disease.
      This increasingly recognized infection often presents in asymptomatic or mildly
      symptomatic individuals who are otherwise functional. Although sexual, vertical
      (mother to infant) and household routes of transmission are of perhaps minor
      concern in an epidemiologic sense, these potential problems are of considerable
      concern to most patients. Appropriate counseling in this setting depends on fully
      informing these patients of the low but possible risk of transmission through
      these routes. In this article, we have reviewed the current literature regarding
      these sources of hepatitis C infection.

PMID- 8652688
TI  - Factors precluding patients' discharge to the community. A geropsychiatric
      hospital survey.
AB  - Study subjects were the 206 inpatients at a 210-bed university-affiliated, state
      operated geropsychiatric hospital in July 1993. Staff psychiatrists, using the
      behavioral component of the Agitation Behavior Mapping Instrument (ABMI) and a
      nonbehavioral component added by the authors, determined reasons why their
      patients could not return to the community at the time of the study. Aggression,
      nonbehavioral problems, and inability to care for self accounted for three
      quarters of the primary reasons precluding immediate community placement. Of
      these three reasons, aggressive behavior was both the most common and the most
      correctable factor keeping subjects in the hospital. Aggressive behavior occurred
      most commonly among psychotic patients, intermediate among demented patients and
      least commonly among patients with mood disorders. The authors suggest the need
      to better define those aggressive behaviors and to develop effective treatments
      that can be transported with patients as they return to the community.

PMID- 8652690
TI  - Physician practice mergers. Part II: The antitrust implications of a merger.

PMID- 8652689
TI  - Waardenburg syndrome and gastric stasis in adults.

PMID- 8652691
TI  - Socio-economic and demographic characteristics and HIV-1 infection among female
      commercial sex workers in Thailand.
AB  - To identify socio-economic and demographic factors related to prevalent HIV-1
      infection among female commercial sex workers (CSW) in Thailand oral interviews
      and blood samples were taken from 800 female commercial sex workers in northern
      and southern Thailand during a cross-sectional survey in 1992. The overall HIV-1
      prevalence rate was 22% and showed a statistically significant decrease from 36%
      when the age at start of commercial sex work was between 12 and 15 years old to
      11% when the age at start was 21 years or over. Working in direct service,
      working in the north, not being Thai, lower education, having no children and
      having a debt to the employer were all related to an elevated risk for HIV-1
      infection in univariate analysis. In multivariate analysis younger age at start
      of commercial sex work, working in direct service, working in the north and
      having a debt to the employer were independently associated with prevalent HIV-1
      infection. Prevention activities are urgently needed to prevent younger girls
      from entering sexual service business and to protect them from HIV 1 infection
      once they start working in the commercial sex service.

PMID- 8652692
TI  - Sexual risk behaviour reduction associated with voluntary HIV counselling and
      testing in HIV infected patients in Thailand.
AB  - Sexual risk behaviour, measured by anonymously self-reported sexual activity,
      number of sexual partners, and condom use rates, was studied in age- and gender
      matched HIV-1 positive consecutive patients from the Thai Red Cross Immune Clinic
      (IC) (study group, questioned after voluntary HIV counselling and testing) and
      the Thai Red Cross Anonymous Clinic (AC) (control group, questioned before
      voluntary HIV counselling and testing) in Bangkok, Thailand in 1993/94. More than
      80% of study patients reported having decreased their sexual activity and their
      number of sexual partners since receipt of the positive HIV test result. Compared
      to control patients, study patients reported more often abstaining from sex (42%
      vs 14%), and more often using condoms during all their last three incidences of
      sexual intercourse (44% vs 14%). These findings give evidence for the value of
      voluntary HIV counselling and testing in contributing to the reduction of HIV
      transmission in Asia.

PMID- 8652694
TI  - Two HIV/AIDS community support teams: patient characteristics, problems at
      referral and during the last 6 weeks of life.
AB  - Following the debate over the role and funding of specialist HIV/AIDS services
      there has been a call for more information about the needs of people with
      advanced HIV/AIDS and the processes and outcomes of care. This study describes
      the characteristics and problems of patients referred to two HIV/AIDS community
      teams in central London: Home Support Team (HST) and Community Care Team (CCT).
      Data was collected prospectively for consecutive referrals. A validated outcome
      measure of palliative care assessed 17 items (e.g. symptoms and anxieties), each
      rated 0 (best = no problem) to 4 (worst = severe problems). In total 234 patients
      (HST 116, CCT 118) were referred. Of these 215 died in care (HST 109, CCT 106).
      Most (232) were male (197 homosexual), mean age 37.8 years and 199 had AIDS at
      referral. Main sources of referral to HST were hospital ward rounds or nurses
      (51%); and to CCT genito-urinary medicine clinic staff (59%). Patients were
      referred to CCT much later in the course of their disease and spent a
      significantly shorter time in care (median time: HST 42 weeks, CCT 9.5 weeks).
      Symptom control, family anxiety and patient anxiety were identified as severe
      problems for 11%-58% of patients in the care of both teams. During the last 6
      weeks of life HST patients' ratings for symptom control and family anxiety became
      more severe compared with CCT, where patients' ratings for four items improved.
      These findings suggest that staff referring patients may need further training in
      the recognition and management of the needs of patients and their carers and
      families. The similarity of problems between these patients and those reported
      for cancer patients suggests that the transfer of principles of good practice
      between services caring for these patient groups would be beneficial.

PMID- 8652693
TI  - AIDS awareness among a cohort of young Thai men: exposure to information, level
      of knowledge, and perception of risk.
AB  - Structured interviews and focus group discussions were conducted among 834 young
      Thai men drafted into military service by random lottery in northern Thailand.
      Level of AIDS risk, exposure to AIDS information, level of knowledge about AIDS,
      and perception of risk for acquiring HIV and AIDS were assessed at baseline and
      six months after induction into the Army in 1991. General fear of AIDS was high,
      yet personal perception of risk for acquiring HIV was low, even for those at
      enhanced behavioural risk of infection with HIV. Multivariate PATH analysis shows
      that exposure to information about AIDS significantly reduced risk taking from
      baseline to follow-up, but only by first affecting personal risk perception.
      Focus group discussions revealed that risk perception for acquiring AIDS was low
      due to never knowing a person with AIDS, because prostitutes had health
      certificates for STD, and since many believed that AIDS could be cured or
      prevented with folk medicines. Implications and recommendations for intervention
      programmes are discussed.

PMID- 8652695
TI  - Psychological distress among gay men supporting a lover or partner with AIDS: a
      pilot study.
AB  - To date, there has been little research to examine how much psychological
      distress is caused to people providing care and support to a lover or partner
      with AIDS. This study aimed to determine the level of psychological distress
      experienced by a sample of gay men providing care and support to a lover or
      partner with AIDS. It was conducted as a cross-sectional questionnaire survey. A
      control group was not enlisted, thus the study was descriptive in nature. The
      experimental hypothesis proposed that providing care and support would result in
      a high level of psychological distress. Thirty-eight gay men, some of whom
      themselves were infected with HIV, who were the primary carer of a lover or
      partner with an AIDS diagnosis were assessed using a self-report questionnaire.
      The 28-item General Health Questionnaire was used as a measure of global
      psychological distress. In addition, Martin's (1988) Traumatic Stress Response
      Scale was used as a measure of psychological distress arising specifically from
      AIDS. The sample reported high levels of global and AIDS-specific psychological
      distress. The levels of distress reported were of such a degree to indicate that
      the majority of the sample were probably suffering from significant psychiatric
      problems. The results strongly suggest that providing care and support to a lover
      or partner with AIDS may have an adverse affect on the carer's own psychological
      health: however, because of the design of the study it is impossible to state
      this conclusively.

PMID- 8652697
TI  - Heterosexually acquired HIV infection in female blood donors: case series between
      1985-1990.
AB  - The case histories aimed to describe the risk behaviours of a series of seven
      Australian women who acquired the human immunodeficiency virus (HIV) through
      heterosexual contact. Between 1985 and 1990 eight HIV antibody positive female
      donors were identified through routine HIV antibody screening at the NSW Red
      Cross Blood Transfusion Service. These donors were recalled and interviewed to
      assess risk factors for HIV and establish how and/or why the declaration form and
      the interview process prior to donation did not identify a risk factor. The most
      likely risk factor in seven cases was then assessed by the Blood Bank to be
      heterosexual transmission. Histories for three cases were based on the standard
      risk assessment interview at the Blood Bank and four case histories were based on
      additional interviews conducted independently from the Blood Bank with informed
      consent.

PMID- 8652696
TI  - Gay men's accounts of unsafe sex.
AB  - This paper provides a qualitative analysis of the explanations given by a sample
      of 78 gay men in England of the most recent occasion on which they engaged in
      anal intercourse without a condom. Explanations are analysed and interpreted from
      the sociological perspective of 'accounts': that is, they are not viewed as exact
      descriptions of the 'real' motives for behaviour but are seen as a powerful
      resource that can illuminate the knowledge, assumptions and values that inform
      behaviour. Four distinct types of accounts were identified from the men's
      descriptions of the circumstances and motivations surrounding their most recent
      unsafe sexual encounter. These related to: (i) their emotional needs and drives;
      (ii) the calculus of risk; (iii) issues of trust; and (iv) lapses of control.
      Each of these types of account is described and the implications of the typology
      are considered, both for our understanding of the meanings, considerations and
      constraints surrounding high-risk sexual behaviour and for developing more
      relevant health education interventions.

PMID- 8652698
TI  - The vaginal use of herbs/substances: an HIV transmission facilitatory factor?
AB  - Heterosexual intercourse accounts for 80% of HIV transmission in sub-Saharan
      Africa. Factors facilitating cross-infection may include sexual practices such as
      the vaginal use of herbs/substances to dry, contract and heat the vagina for
      enhancement of sexual pleasure. The behavioural-analytic study investigated the
      use of different types of herbs/substances used by 75 HIV positive and 76
      negative sexually active females and the perceived effects of these agents.
      Individual in-depth interviews were conducted. 99% of all subjects admitted using
      herbs/substances mainly to contract (94%), dry (58%) and heat (28%) the vagina.
      There was no significant difference in the pattern of use of herbs and reasons
      given for using the agents by HIV positive and negative women. 69% of HIV
      negative and 80% of positive subjects had used a mean of 4 difference types of
      herbs and/or substances during the last 5 years. 39% negative and 25% positive
      subjects had experienced intra-vaginal pain and lower abdominal pains during and
      after sexual intercourse, laceration of the vagina and excessive vaginal
      secretions after using herbs. These effects were attributed to Wankie (herb or
      substance) in 70% of the complaints. 14 HIV positive subjects compared with 7 in
      the negative group had used Wankie. The role of Wankie and similar substances in
      transmitting HIV cross-infection requires further investigations. From the point
      of view of AIDS prevention, expectations of a dry and contracted vagina in sexual
      intercourse may reduce acceptability and use of female and male condoms.

PMID- 8652700
TI  - Vertical transmission of HIV--a rediscussion of testing.
AB  - It is worthwhile reconsidering the debate on mandatory or voluntary testing for
      HIV antibody among women of childbearing age, in the light of recent virological
      and therapeutic discoveries that have altered the parameters of the issue. The
      therapeutic possibilities of reducing the risk of transmission for women
      confirmed as seropositive are an incontestable benefit for anyone who is aware of
      her serological status; the fact of being able to detect real infection at birth
      could mean that causing unnecessary distress to the antibody positive but
      uninfected newborn infant is avoided. Medical professionals now have convincing
      arguments to persuade women at risk to accept the test when it is offered. But,
      in any case, the voluntary nature of the decision for testing must be respected.

PMID- 8652699
TI  - Determinants of HIV risk among men who have homosexual sex and inject drugs.
AB  - Men with histories of both homosexual contact and injecting drug use (IDU) are at
      increased risk of HIV infection over men who have only one such risk. Despite
      this, their special needs and circumstances have been neglected by AIDS
      prevention programmes. A survey of a wide spectrum of homosexual male IDUs was
      carried out in Melbourne and Sydney in 1993 to inform the development of specific
      policy and programmes for HIV prevention in these subcultures. Of 169 men, self
      reported HIV prevalence was 27%. Decreasing compliance with safe sex guidelines
      (as measured by numbers of casual partners, participation in anal intercourse and
      use of condoms) was associated with HIV seropositivity, increased age, and
      increased participation in sex work; having a regular male partner was not
      protective against unsafe sexual behaviour, no matter the length of the
      relationship. A substantial proportion (15%) reported inconsistent condom use
      during anal sex with more than two partners in the preceding month: they were
      slightly more likely to be engaging in sex work, less 'stable' and more likely to
      be HIV infected. Sexual risk was not strongly associated with unsafe injecting,
      which was in general safe. Men who both have homosexual sex and inject drugs are
      groups at high risk of HIV, more from unsafe sex than from shared injecting
      equipment; men who believed themselves to be HIV infected were continuing to have
      sex in such a way that would allow transmission. These are clearly groups in need
      of priority targeted interventions.

PMID- 8652701
TI  - Developing AIDS care in Zimbabwe: a case for residential community centres?
AB  - New support services are needed as the AIDS epidemic escalates. Home care has
      been the cornerstone of new developments in Zimbabwe and the southern African
      region, essentially resource-strapped countries. However, while home care has
      many benefits, levels of coverage are often low and many patients at some phase
      of their disease need more than their home can provide, even with access to
      support services. Hospital admission is often not a viable option and the need
      may arise for some form of respite or hospice community centre to provide
      residential care. This option is debated and potential benefits and pitfalls are
      explored.

PMID- 8652702
TI  - WHO global AIDS statistics. AIDS cases reported to the World Health Organization
      as at 7 July 1995.

PMID- 8652703
TI  - Oral ganciclovir: a new option for patients with CMV retinitis.
AB  - Cytomegalovirus retinitis is a major cause of morbidity in patients with AIDS.
      The conventional treatment approach has involved insertion of a central venous
      catheter and intravenous administration of ganciclovir and/or foscarnet. This has
      been associated with systemic toxicity, line-related sepsis, and implications for
      patient quality-of-life. An oral formulation of ganciclovir has now been licensed
      for use as maintenance therapy in CMV retinitis. Multicentred trials comparing
      oral and intravenous ganciclovir have suggested that although the efficacy may be
      marginally reduced with the oral formulation, the associated toxicity is
      significantly lower. With careful and informed decision-making by both clinician
      and patient, the opportunity exists to enhance the quality of life in this
      patient group.

PMID- 8652704
TI  - Vulval intraepithelial neoplasia.

PMID- 8652705
TI  - Uses and limitations of gonococcal serotyping.

PMID- 8652706
TI  - Tests for infection with Chlamydia trachomatis.

PMID- 8652707
TI  - The radiological manifestations of the acquired immune deficiency syndrome--Part
      1.

PMID- 8652708
TI  - Case-control study of sexually transmitted diseases as cofactors for HIV-1
      transmission.
AB  - The aim of the study was to investigate the association between infection with
      HIV-1 infection and a history of other sexually transmitted diseases (STD). We
      were able to match 1295 HIV-1 infected patients who attended St Mary's Hospital
      between 1985 and 1991 with 1273 seronegative controls on gender, sexual
      orientation, injecting drug use and age at time of test. The cases were 3 times
      more likely to have a history of ever having had another STD than the controls:
      multivariate conditional logistic regression showed that, after controlling for
      sexual behaviour, for known sexual contact with an HIV infected individual or
      AIDS patient or with a resident from a high HIV prevalence area, area of
      residence and for year of test, a history of gonorrhoea, syphilis, hepatitis B,
      genital herpes or genital warts were all significantly associated with HIV-1
      seropositive status. These findings reinforce the need for HIV containment
      strategies to be promoted in conjunction with containment programmes for others
      STDs.

PMID- 8652709
TI  - Judging a book by its cover: gay men's use of perceptible characteristics to
      infer antibody status.
AB  - This study investigated gay men's use of perceptible characteristics to infer
      antibody status. Participants (n = 66) read brief descriptions of men they did
      not know and estimated the likelihood that they were HIV-infected. Each
      description highlighted one of 6 characteristics: physical attractiveness,
      intelligence/education level, healthy appearance and lifestyle, personality, a
      combination of the preceding, and wealth. Three versions of each sketch were
      used; they depicted the man in positive, neutral, and negative terms
      respectively. There were significant differences in the ratings for the 3
      versions in the case of every characteristic except wealth. In general, the
      negative version elicited higher ratings (corresponding to a greater likelihood
      that the man was HIV-positive) than either the positive or neutral versions; in
      the case of physical attractiveness, the positive version elicited higher ratings
      than the neutral version. Results are discussed in relation to earlier findings
      regarding gay men's inferences during sexual encounters, of antibody status from
      perceptible characteristic; to possible differences between AIDS-related thinking
      during sexual encounters and in the cold light of day; and to educational
      techniques that might be used to counter inferences of this type.

PMID- 8652710
TI  - Sexually transmissible agent and African Kaposi's sarcoma.
AB  - Kaposi's sarcoma (KS) has a higher incidence in some parts of Africa than
      anywhere else in the world. Recent studies in western homosexual men with AIDS-KS
      suggest that KS may be caused by a putative sexually transmissible agent. Our
      analytical review of studies on KS in Africa before and during the AIDS era
      reveals a disparate epidemiological picture. Its occurrence in sexually
      inexperienced children; overwhelming male preponderance in an almost exclusively
      heterosexual population; rarity of concordant couples in areas of very high
      incidence; sequestration of high incidence to Eastern and Central Africa; and
      regional variations in incidence even in high-incidence countries are all
      difficult to reconcile with a conventional sexually transmissible aetiology.
      There is a need for prospective studies specifically designed to test the
      hypothesis in Africa. Also, we recommend that studies pursuing the aetiology of
      KS in western countries be linked with studies in high incidence areas in Africa.

PMID- 8652711
TI  - AIDS defining conditions in Africans resident in the United Kingdom.
AB  - A retrospective study of 55 HIV-1 seropositive African patients living in the UK,
      seen between January 1986 and November 1993, showed a total of 26 (47%) patients
      with AIDS. Thirty-one (56%) had symptomatic HIV disease at the time of
      presentation of whom 19 (34.5%) had an AIDS defining condition. Tuberculosis was
      the most common AIDS defining illness, accounting for 27% of all initial AIDS
      diagnoses, followed by by Pneumocystis carinii pneumonia and oesophageal
      candidiasis in 19% each and chronic mucocutaneous genital herpes in 15%. The mean
      CD4 count at the time of the first AIDS defining event was 91 x 10/mm3 (range 4
      320 x 10/mm3). The profile of AIDS defining illnesses was different to published
      data of homosexual men and injecting drug users in the UK. This has practical
      implications when considering differential diagnoses and screening as well as
      prophylaxis for opportunistic infections in this group of patients.

PMID- 8652712
TI  - Increasing trend of HIV seropositivity in a sexually transmitted diseases centre
      and epidemiology of HIV seropositive individuals.
AB  - 11,539 STD clinic attenders and 20,897 antenatal clinic (ANC) attenders at a New
      Delhi hospital were screened for HIV antibodies by ELISA over a 3-year period.
      Results were confirmed by Western Blot. A low HIV seropositivity rate (1 per
      1000) with an increasing trend in 1993 (4 per 1000) was observed in the STD
      attenders as against 0.1 per 1000 in the normal control populations. Most of the
      STD attenders including all the HIV seropositives had heterosexual contact with
      female sex workers. Both the HIV seropositive ANC attenders acquired the
      infection through blood transfusion. Thirteen of 23 HIV positive STD attenders
      had genital lesions, 5 having ulcerative and 8 having nonulcerative STD. Their
      clinical presentation did not differ from the HIV negative cases but the
      therapeutic response in 4 was altered. None had signs of symptoms of ARC/AIDS.
      Two out of 6 spouses and a 2-year-old child of HIV seropositive patients were
      seropositive. Increasing HIV seropositivity observed in this study reflects the
      changing situation in the country and highlights the importance of improvement of
      surveillance, early diagnosis and combined approaches to the management and
      control of STDs and HIV.

PMID- 8652713
TI  - The effects of peer education on STD and AIDS knowledge among prisoners in
      Mozambique.
AB  - The study was designed to evaluate the impact of education on AIDS knowledge
      among prison inmates in Maputo, Mozambique. A 6-month follow-up study was carried
      out in 1993 among 300 prisoners. A knowledge, attitudes, and practices
      questionnaire regarding AIDS and STD was administered to each subject as part of
      the intake medical examination and after an educational intervention provided by
      30 prisoner 'activists'. A large proportion of prisoners had high risk behaviours
      (65% had 2 or more sexual partners per month and 39% had a history of STD) and
      low AIDS knowledge at incarceration. Statistically significant increases in
      knowledge occurred after the intervention. Prisoners with less formal education
      had a poorer performance on the initial questionnaire (43% vs 69% P < 0.00001)
      and had a greater improvement after the intervention (41% vs 24%, P < 0.00001).
      The results demonstrate that educational interventions involving peer health
      educators contribute positively to the acquisition of knowledge among prisoners.

PMID- 8652715
TI  - Undernotification of tuberculosis in patients with AIDS.
AB  - The purpose of this study was to establish the extent of undernotification of
      tuberculosis in AIDS patients resident in 2 inner London local authorities. For
      residents of the 2 authorities, statutory notifications of tuberculosis between
      1986 and 1992 were compared, using soundex codes of surnames, sex and year of
      birth, with AIDS cases reported to the Public Health Laboratory Service (PHLS)
      AIDS Centre during the same period where TB had been recorded on the AIDS report
      form. In 36 of 613 AIDS cases reported as residents of the 2 authorities
      tuberculosis was recorded on the AIDS report form. Matching revealed that only 2
      (6%) of these cases had been notified to the local authority. These results
      highlight the need to resolve the dilemma between concerns about patient
      confidentiality and the statutory requirement to notify tuberculosis so that
      clinical management of contacts can be undertaken and the true impact of HIV
      infection on the incidence of tuberculosis in the UK can be elucidated.

PMID- 8652714
TI  - Autoimplantation technique in the treatment of anogenital warts: a clinico
      immunological study.
AB  - An autoimplantation technique was adopted in the treatment of 50 cases of
      anogenital warts and was compared with the conventionally used podophyllin
      regimen in a matched group of 50 patients. They were assessed with 15 untreated
      subjects in a control group for the rate of clinical cure after 6 weeks,
      recurrence after 1 year follow up and for humoral and cell mediated immune
      responses before and after treatment. In the podophyllin group, 70% of patients
      were cured after 6 weeks while in autoimplantation, only 44% of patients were
      cured, and none in the control group had natural remission of warts without any
      treatment. After 1 year all the cured cases (100%) that completed follow up had
      recurrence of warts with podophyllin treatment, while none had recurrence of
      lesions in the autoimplantation group. Results of the humoral and cell mediated
      immune (CMI) response studies revealed that autoimplantation technique
      significantly augmented both humoral and CMI responses while there was not
      significant change in the immune status after podophyllin treatment (P > 0.001).

PMID- 8652716
TI  - Coinfection with chlamydia and gonorrhoea among pregnant women and bacterial
      vaginosis.
AB  - The role of sexual transmission of microorganisms in bacterial vaginosis (BV) is
      controversial. If sexual intercourse were a risk factor for BV, then we would
      expect that women with BV would also be coinfected with other sexually
      transmitted diseases (STD). We investigated the prevalence of STD among pregnant
      women a low socio-economic status with bacterial vaginosis in Indonesia. Among
      these women, 23.3% had at least one STD (chlamydia, gonorrhoea, syphilis or
      trichomoniasis). Chlamydial infection was the most prevalent (19.5%), followed by
      trichomoniasis (3.8%), gonorrhoea (3.2%) and syphilis (0.4%). Compared to the
      rates of STD observed in a previous study of all pregnant women (with or without
      BV) in Indonesia, pregnant women with BV have more than a 2-fold increase in
      chlamydia (19.5% vs 8.2%) and a 6-fold increase in gonorrhoea (3.2% vs 0.5%).
      Because detection of BV by Gram stain is easy to perform and economical,
      detection of BV has potential as a prescreening marker for chlamydia and
      gonorrhoea among asymptomatic pregnant women of low socio-economic status in
      Indonesia. Further work is needed to evaluate the usefulness of BV as a
      prescreening marker for chlamydia and gonorrhoea.

PMID- 8652718
TI  - Syphilis makes a comeback.

PMID- 8652717
TI  - Contraceptive use and HIV infection in Kenyan family planning clinic attenders.
AB  - This pilot study aimed to determine the feasibility of a larger study of
      contraception and risk of HIV infection in women. We also measured risk factors
      for and occurrence of HIV infection in the participants. A cohort of 1537
      seronegative women attending a family planning clinic in Nairobi, Kenya was
      enrolled and followed for up to 12 months per woman. HIV testing was done
      quarterly. A nested case-control analysis was done with seroconverting women
      (cases) and 3 matched controls per case, who had detailed interviews and received
      physical examinations and STD tests. The prevalence of HIV at enrollment was
      6.1%; seropositive women were excluded from further analysis. The 12-month life
      table cumulative incidence of HIV was 2.1 per 100 women (95% confidence interval
      [CI] 1.1-3.2). In the nested case-control analysis (17 cases and 51 controls),
      the crude odds ratio of HIV infection comparing oral contraceptive (OC) users
      with other women was 3.5 (95%) CI 0.8-21.5), which persisted after control for
      single confounders at a time. The putative association between OC use sand HIV
      infection is critical to public health policy, yet no study has been conducted
      specifically to measure it, yielding weak and conflicting evidence. We intend to
      conduct a larger study with a similar design as the current pilot study, which
      confirmed the feasibility of a more definitive project.

PMID- 8652719
TI  - Azithromycin in sexually transmitted diseases.

PMID- 8652721
TI  - Azithromycin in the management of opportunistic infections.

PMID- 8652720
TI  - Treatment of syphilis with azithromycin.
AB  - The efficacy of oral azithromycin (500 mg daily for 10 days or 500 mg on
      alternate days for 11 days) in 100 patients with seropositive syphilis was
      studied. Clinical manifestations regressed more rapidly in azithromycin-treated
      patients compared with patients who received erythromycin or penicillin, and
      there was also a more rapid reduction in serum antibody levels. In 90.3% of
      patients, the complete resolution of classic serological tests was observed
      within 4 months of completion of the azithromycin treatment. The immobilization
      (TPI) test and absorbed fluorescent treponema antibody tests became negative 12
      months after treatment in 40% of patients. After 4 years of follow-up, no
      symptoms of neurosyphilis or syphilitic changes of visceral organs were observed.

PMID- 8652722
TI  - The potential role of azithromycin in the treatment of prophylaxis of
      toxoplasmosis.
AB  - Infection with Toxoplasma gondii is the most common parasitic infection worldwide
      with an estimated prevalence of 1-2 billion people. The risk of developing severe
      toxoplasmosis is higher for immunocompromised individuals and fetuses of mothers
      who have acquired a primo-infection. The current therapy of choice for
      toxoplasmosis is the synergistic combination of pyrimethamine and sulphadiazine.
      This therapy is highly effective but its use is complicated in immuno-compromised
      individuals due to adverse secondary effects. In addition, since pyrimethamine is
      potentially teratogenic, its use is not recommended during early pregnancy.
      Clindamycin, a lincosaminide, in combination with pyrimethamine has been shown to
      be an acceptable therapeutic alternative in patients who are unable to tolerate
      pyrimethamine plus sulphadiazine. In the search for new, effective compounds with
      less adverse or toxic effects, recent efforts have focused on the new macrolides
      and the azalides. Here, the results of the investigations and, in particular, the
      theoretical considerations for the potential use of azithromycin in the therapy
      of toxoplasmosis in immunocompromised individuals are reviewed.

PMID- 8652723
TI  - Azithromycin in gonorrhoea.
AB  - The clinical applications of azithromycin in gonorrhoea, often complicated by
      simultaneously acquired infection with Chlamydia trachomatis, are reviewed in
      this paper. Clinical trails from major centres in Europe are compared with a
      large, more recent US study. At the present time, azithromycin is recommended
      throughout the world as a useful antibiotic in treatment of gonorrhoea. It has
      several advantages in that it can be given as single-dose therapy, it can be
      given where the causative pathogen of urethritis/cervicitis is uncertain, and it
      is often, therefore, most useful in acute therapy where there is no immediate
      microbiological back-up. All these considerations are reviewed in detail.

PMID- 8652724
TI  - Treatment and prophylaxis of Mycobacterium avium complex.
AB  - The most common pathogens involved in disseminated bacterial infection in people
      with acquired immunodeficiency syndrome (AIDS) are organisms of the Mycobacterium
      avium-intracellulare complex (MAC). Azithromycin and clarithromycin, a new
      azalide and macrolide, respectively, are among the most potent monotherapies for
      MAC bacteraemia, Although many bloodstream isolates demonstrate increased minimum
      inhibitory concentrations after 4 months of treatment. Current recommended
      prophylaxis, based on the results of two randomized, double-blind, prospective
      studies, is rifabutin 300 mg daily for people with AIDS with < 100 CD4
      lymphocytes/mm3. In the beige mouse model, we have shown that both azithromycin
      and clarithromycin prevent MAC bacteraemia following repetitive oral challenge.
      Clinical trails are now underway to confirm these effects in man; comparative
      treatments include placebo, rifabutin and an azalide/macrolide plus rifabutin.
      While combinations might be more effective and reduce the emergence of
      resistance, the spectre of cytochrome P-450 drug interactions necessitates
      careful study before combination prophylactic approaches are accepted. Such
      interactions are associated with rifabutin and some macrolides, although
      azithromycin may be less problematic in this respect as it appears to have little
      potential to interact with other antimicrobial agents.

PMID- 8652725
TI  - Human cryptosporidiosis.
AB  - Cryptosporidium parvum is a protozoan which can cause severe debilitating disease
      in immunocompromised individuals. Animal models have shown that cellular immunity
      is the most important factor against the development of the disease. Individuals
      with a humoral immune deficiency are also at risk. In HIV-infected patients there
      is a clear relationship between disease severity and CD4 cell counts. Insight
      into the pathogenesis and development of new agents is hampered by the lack of an
      in vitro culture system. Prevention is of the utmost importance due to the
      difficulties of therapy and the severity of clinical disease which can develop.
      Oocysts are highly resistant to commonly used disinfectants. In HIV-infected
      patients with cryptosporidiosis, antiretroviral therapy should be instituted or
      modified. Moreover, non-specific therapy with antidiarrhoeal agents should also
      be instituted. If no effect is seen, therapy with paromomycin 500 mg 4 times
      daily for 2-3 weeks should be initiated, followed by maintenance therapy with 500
      mg twice daily to prevent relapse.

PMID- 8652726
TI  - Azithromycin in the prophylaxis of opportunistic infections in AIDS.
AB  - Prevention of opportunistic infections contributes to improved quality of life
      and survival in individuals with acquired immunodeficiency syndrome (AIDS).
      Agents which are more effective and convenient, less costly, and better tolerated
      are needed for multiple organism primary prophylaxis. Azithromycin, azalide with
      high and prolonged intracellular levels, promise to provide to protection against
      Mycobacterium avium complex (MAC) disease in those with advanced AIDS when given
      weekly. A large trail comparing rifabutin (300 mg daily), a currently approved
      primary prophylactic agent for MAC, with azithromycin (1200 mg weekly) has been
      completed and is under analysis. If weekly azithromycin provides equivalent or
      better protection from disseminated MAC, the cost effectiveness and convenience
      of MAC prophylaxis may be improved.

PMID- 8652727
TI  - Azithromycin in the management of Chlamydia trachomatis infections.
AB  - The unique pharmacological profile of the azalide macrolide azithromycin, coupled
      with its in vitro activity against both Chlamydia trachomatis and the
      ureaplasmas, suggested that genital infections caused by these bacteria could be
      successfully treated with a single dose of the antibiotic. This has now been
      confirmed in worldwide clinical studies. A single oral dose of azithromycin 1 g
      eradicates C. trachomatis in almost 100% of cases of non-gonococcal urethritis
      and cervicitis. Unfortunately, there are no specific clinical signs for genital
      chlamydial infection. It is therefore necessary to use therapy effective against
      known and unknown pathogens for treating lower genital tract infection. Clinical
      cure rates for both chlamydial and non-chlamydial, non-gonococcal infections
      compare favourably with standard 7-day doxycycline therapy, being in excess of
      85%. Side effects are few (< 20%) and essentially minor.

PMID- 8652728
TI  - Treatment of chancroid with azithromycin.
AB  - A randomized, comparative study undertaken in Nairobi, Kenya and a non
      comparative evaluation undertaken in Carletonville, South Africa have both shown
      that a single oral dose of azithromycin 1 g is effective in the treatment of the
      genital ulcer disease (GUD), chancroid, with cure rates of 89% and 92% recorded
      respectively. While treatment failure was associated with human immunodeficiency
      virus seropositivity and lack of circumcision in Kenya, no such association could
      be found in the South African study. In both series, azithromycin treatment
      resulted in cure of both Haemophilus ducreyi culture-positive and culture
      negative cases of GUD, including two cases subsequently diagnosed as
      lymphogranuloma venereum. A combination of single-dose azithromycin with single
      dose benzathine penicillin may provide effective 'single-visit' syndromic
      treatment for GUD in many developing countries.

PMID- 8652729
TI  - Endogenous beta-galactosidase activity in the larval, pupal, and adult stages of
      the fruit fly, Drosophila melanogaster, indicates need for caution in lacZ fusion
      gene studies.
AB  - Beta-galactosidase activity is known to exist in Drosophila melanogaster, but a
      detailed analysis of the tissue-specific patterns of activity has not previously
      been reported. Such an analysis is of particular interest because Drosophila is
      commonly used for making transformants that carry fusion genes in which the E.
      coli beta-galactosidase gene, lacZ, is used as a reporter gene. When these
      transformants are analyzed for beta-galactosidase activity by using chromogen X
      gal staining, the method does not distinguish true fusion-gene activity from
      endogenous beta-galactosidase activity or from the beta-galactosidase activity of
      bacterial contaminants. Therefore, detailed maps of endogenous beta-galactosidase
      activity in this organism would help to prevent errors in data interpretation and
      would indicate which stages were most appropriate for experiments with the lacZ
      transformants. We have constructed such maps by applying X-gal staining methods
      to serial frozen sections and whole mounts of larval, prepupal, pupal, and adult
      stages of D. melanogaster reared under axenic conditions. Results showed
      endogenous beta-galactosidase activity in a variety of organs including the
      larval intestine, spiracles, lymph glands, cellular epidermis, and eye-antenna
      imaginal discs; the pupal cellular epidermis, lymph glands, imaginal tissues, fat
      body, and spiracle; and the adult pericardial cells, thoracic nephrocytes,
      ventriculus, and reproductive system. The good correlation between staining and
      metamorphic remodeling and phagocytic activity indicates that endogenous beta
      galactosidase is physiologically interesting.

PMID- 8652730
TI  - Vertical transmission of chemoautotrophic symbionts in the bivalve Solemya velum
      (Bivalvia: Protobranchia).
AB  - Adults of the bivalve species Solemya velum live in symbiosis with
      chemoautotrophic bacteria in specialized gill bacteriocytes. The bacteria play an
      essential nutritional role in the mature association, fixing CO2 via the Calvin
      cycle with energy obtained through the oxidation of reduced sulfur compounds. To
      understand how the continuity of this partnership is maintained between host
      generations, we investigated the mode of symbiont transfer in S. velum. A
      diagnostic assay using the polymerase chain reaction and primers specific for the
      S. velum symbiont ribulose-1,5-bisphosphate carboxylase (RubisCO) gene
      consistently detected bacterial sequence in female gonad tissue, suggesting the
      presence of symbiont cells in host ovaries and a vertical mode of symbiont
      transmission from mother to offspring. Furthermore, intracellular bacteria were
      present in the developing gills of juveniles that had not yet hatched from the
      gelatinous capsule in which larval development occurs (11 days after
      fertilization). By 64 days postfertilization, the typical adult gill
      ultrastructure of alternating bacteriocytes and symbiont-free-intercalary cells
      was apparent. Knowledge about the mode of symbiont transfer in S. velum allows
      further study into the dynamics of host-symbiont interactions in chemoautotrophic
      associations.

PMID- 8652731
TI  - Visual pigment types and quantum-catch ratios: implications from three marine
      teleosts.
AB  - Experimental data on photoreceptor cells and visual pigments are the basis for
      model calculations performed to assess photoreceptor quantum catches under
      disparate irradiance conditions. Three unrelated species of fish--black sea bass
      (Centropristis striata), sea raven (Hemitripterus americanus), and adult winter
      flounder (Pseudopleuronectes americanus)--are considered. In each case, receptor
      type quantum catches are compared for various water types and depths. By
      associating the habit and habitat of an organism with the physical properties of
      its photoreceptors, quantum-catch ratios are found as possible criteria in the
      selection of pigment peaks (lambda max). In addition to integrated ("total")
      quantum catches by the receptor types, rates of quantum catches are determined as
      a function of wavelength. The latter functions are replotted as pairwise
      difference spectra. These, in turn, are used to assess the ability of receptor
      types to participate in wavelength discrimination.

PMID- 8652732
TI  - Expression sites of two byssal protein genes of Mytilus galloprovincialis.
AB  - Mussels form byssal threads that can attach tenaciously to wet and irregular
      surfaces. The byssus consists of a fibrous collagenous core, and at least two
      types of polyphenolic proteins surround it. One of these proteins, designated
      Mgfp-1, coats the collagenous core; the other, designated Mgfp-2, is the major
      component of the terminal adhesive plaque of byssal threads. Both proteins
      contain 3,4-dihydroxyphenylalanine (DOPA) in their primary sequences. In this
      study, the sites of expression of the genes encoding the polyphenolic proteins
      were investigated in Mytilus galloprovincialis. By northern blot analysis, we
      found that the expression of both genes is foot-specific. Northern blot analysis
      of RNA isolated from the distal end and the remaining proximal portion of the
      foot indicated that the Mgfp-2 gene is expressed primarily in the distal part,
      whereas Mgfp-1 expression occurs in both parts. In situ hybridization indicated
      that the Mgfp-1 gene transcript is localized in the accessory gland along the
      ventral groove of the foot, and the Mgfp-2 gene transcript is localized in the
      phenol gland near the foot apex. Thus, it was shown that tissues expressing Mgfp
      1 and Mgfp-2 are located around the ventral groove in an arrangement appropriate
      for byssus formation.

PMID- 8652733
TI  - We still invoke friction and Occam's razor to explain catch in the spines of
      Eucidaris tribuloides.

PMID- 8652734
TI  - The National Association of Marine Laboratories: a connected web for studying
      long-term changes in U.S. coastal and marine waters.
AB  - Long-term time-series measurements provide data that test specific hypotheses or
      suggest new avenues of study. Such studies are widely acknowledged as important
      for differentiating the influence of human activities from natural background
      variability. Several long-term research or monitoring programs are active in
      coastal and marine environments around the world and serve as models for
      development of new studies. The spatial array of U.S. coastal laboratories is
      suitable for resolving latitudinal trends and for many types of comparative
      studies. However, establishing a network of coastal laboratories focused on long
      term monitoring and research problems presents special challenges in setting
      research priorities at appropriate scales, in data management, and in
      coordination of the scientific effort. The National Association of Marine
      Laboratories (NAML) is uniquely positioned to promote long-term studies among
      networks of its member institutions. The NAML can play an effective role in
      publicizing the importance of long-term studies, in providing access to expertise
      in this type of research, and in promoting its continuance for periods longer
      than the length of individual scientific careers.

PMID- 8652736
TI  - [The risk factors for hepatitis D viral infection in southern Italy].
AB  - The aims of this study were to evaluate the prevalence of hepatitis delta virus
      (HDV) infection and risk factors associated to it. Three hundred sixty-one HBsAg
      chronic carriers from southern Italy were studied and 13.8% of them resulted anti
      delta positive. 80% of these subjects were less than 50 years old. When anti
      delta positive subjects were compared with anti-delta negative ones, a lower
      number of healthy HDV carriers and a higher frequency of cirrhotics were noted
      among anti-delta positive. Of lower than 50 years, imprisonment, sexual contacts
      with drug abusers and male homosexuality were risk factors of HDV infection. No
      association was found with sex, household contacts with HBV or HDV carriers,
      number of family members and transfusion of blood products. These data confirm
      the high prevalence of HDV infection in southern Italy.

PMID- 8652735
TI  - [The current status of the perendoscopic treatment of biliary lithiasis].
AB  - The role of therapeutic biliary endoscopy, for management of bile duct stones,
      continues to be defined. Actually the endoscopic management should be considered
      the procedure of choice for treatment of retained or recurrent stones of the main
      bile duct, gallstone pancreatitis an acute cholangitis. It's role in the era of
      laparoscopic cholecystectomy is evolving. Actually new techniques and accessories
      continue to be developed for treatment of bile duct stones. The problem of the
      difficult bile duct stones has essentially been solved by the development of a
      variety of lithotripsy techniques. This work focuses on new developments in the
      therapeutic biliary endoscopy for treatment of main bile duct stones.

PMID- 8652737
TI  - [The metabolic role of glutamine].
AB  - Glutamine is a non essential amino acid. Nevertheless it has to be considered a
      "conditionally essential" amino acid for several metabolic reactions in which it
      is involved. Glutamine is the most abundant amino acid in human plasma and
      muscle. Because glutamine is highly unsteady, it was never used for enteral and
      parenteral nutrition in the past. It appears to be a unique amino acid for
      rapidly proliferating cells serving as a preferred fuel compared to glucose. It
      seems to be essential for cellular replication such as a "nitrogen carrier"
      between the tissues. A deficiency state of glutamine causes morphology and
      functional changing and negative nitrogen metabolism. The need for glutamine is
      particularly high when metabolism is increased as in the critically ill (surgical
      stress, sepsis, inflammatory states, fasten, burns) especially in the tissues
      with a rapid cell turn-over. In these conditions the body requirements of
      glutamine appear to exceed the individual's muscle deposits (muscle is the most
      important place of synthesis and storage), causing an increased synthesis with a
      high energy waste and loss of muscle mass. Glutamine is essential for bowel
      mucosa trophism and its deficiency in all the catabolic states allows bacterial
      translocation. In these cases feeding is not sufficient to restore basal
      conditions. At present enteral or parenteral glutamine supplementations are of
      high interest for the feeding of critically ill patients.

PMID- 8652738
TI  - [Group treatment programs for obese subjects].
AB  - Weight gain substantially modifies the exterior appearance and the body of obese
      subjects assumes a shape which does not conform to esthetic concepts and socially
      accepted body image, thus exposing the subject to a series of difficulties. In
      this study the a. illustrate the importance of group treatment in this context,
      and also review the most recent literature on this subject.

PMID- 8652739
TI  - [The role of ERCP in the diagnosis and therapy of Mirizzi's syndrome. Apropos a
      clinical case].
AB  - Mirizzi syndrome is a rare variant of obstructive jaundice due to compression of
      the hepatic duct caused by a stone inserted in the cystic duct or in the Hartmann
      recess and it is referred with a prevalence of 0.05-1% of patients with
      cholelithiasis. These percentages are, nevertheless, unreliable because only an
      accurate preoperative cholangiography allow to detect a Mirizzi syndrome and so,
      very often, the real cause of the jaundice remains unacknowledged. Early
      diagnosis of the syndrome is particularly important because it suggests an
      accurate and prudential surgical approach considering the frequent fibrotic
      adherences caused by chronic inflammation. In this paper the authors present a
      clinical case quickly and successfully cured operative endoscopy, followed by
      traditional surgery. The authors believe that the study of obstructive jaundices
      must include an ERCP either for the diagnosis or because operative endoscopy
      could ameliorate clinical feature and hepatic performance in order to allow a
      safer surgical operation.

PMID- 8652741
TI  - [Preoperative eating behavior and weight loss after gastric banding for obesity].
AB  - The relationships between the cognitive restraint and the tendency to
      disinhibition prior to gastric banding for obesity, as assessed by the Three
      Factor Eating Questionnaire, and the weight loss at one year following the
      operation were investigated. The amount of overall weight loss was correlated
      positively to the disinhibition and negatively to the cognitive restraint score.
      When the food consumption overtakes the proximal gastric pouch capacity, the
      patient feels a strong aversive stimulus, thus stopping eating. Therefore, more
      is the patient's tendency to lose the control on food intake more is the
      postoperative weight loss. On the contrary, the high restraint patient only
      seldom feels such an aversive stimulus, and only seldom stops eating, thus the
      weight loss is smaller. Except for the overeating due to the disinhibition, the
      aversive stimulus arising from the gastric restriction cannot influence by itself
      any other aspect of eating behavior.

PMID- 8652740
TI  - [Gastric carcinoid. A clinical case and review of the literature].
AB  - INTRODUCTION: Endoscopic examination of the gastrointestinal tract is very
      useful, because it allows a rapid diagnosis and, in some cases, a therapeutical
      effect. CLINICAL CASE: The authors have seen a woman, 72 years old, with
      epigastric pain, dryness of the mouth, diarrhoea and meteorism. She had an old
      simple gastritis (of two years standing) and her therapy, since the time of the
      diagnosis, is omeprazole (20 mg/die). The patient was submitted to gastroscopic
      examination that revealed two spot lesions and a polypous lesion on which was
      made a biopsy. The patient was submitted also to the following examination: 1)
      urinary dosage of 5 HIAA; 2) urinary dosage of 5 OHT; 3) Computed tomography of
      the abdomen; 4) Heart echography; 5) Endoscopy of the colon; 6) Endoscopy of the
      bronchus. DISCUSSION: Carcinoid tumors are usually small and rare lesions and
      they are in the following sites: A) between mouth and the second part of
      duodenum; B) between the second part of the duodenum and the transverse segment
      of the colon; C) between the latter and the anus. CLINICAL PICTURE: Patients are
      usually 50-60 years old, with other neoplasm. The picture is marked by flushing,
      diarrhoea, abdominal cramp and disease of the right heart valve. DIAGNOSIS:
      Diagnosis is based on urinary dosage of 5-HIAA (n.v. > 10 mg/24 h.) that is
      higher than the normal value. Computed tomography and echography are useful.
      THERAPY: The small neoplasm are treated by local surgical resection, while the
      biggest tumors have been treated by pharmacological therapy with useless results.

PMID- 8652742
TI  - Optimal control problems arising in cell-cycle-specific cancer chemotherapy.
AB  - We explore mathematical properties of models of cancer chemotherapy including
      cell-cycle dependence. Using the mathematical methods of control theory, we
      demonstrate two assertions of interest for the biomedical community: 1 Periodic
      chemotherapy protocols are close to the optimum for a wide class of models and
      have additional favourable properties. 2 Two possible approaches, (a) to minimize
      the final count of malignant cells and the cumulative effect of the drug on
      normal cells, or (b) to maximize the final count of normal cells and the
      cumulative effect of the drug on malignant cells, lead to similar principles of
      optimization. From the mathematical viewpoint, the paper provides a catalogue of
      simplest mathematical models of cell-cycle dependent chemotherapy. They can be
      classified based on the number of compartments and types of drug action modelled.
      In all these models the optimal controls are complicated by the singular and
      periodic trajectories and multiple solutions. However, efficient numerical
      methods have been developed. In simpler cases, it is also possible to provide an
      exhaustive classification of solutions. We also discuss developments in
      estimation of cell cycle parameters and cell-cycle dependent drug action.

PMID- 8652743
TI  - Direct comparison of bromodeoxyuridine and Ki-67 labelling indices in human
      tumours.
AB  - Direct comparison of bromodeoxyuridine (BrdUrd) and Ki-67 labelling indices was
      achieved by selecting similar areas from serial sections of human tumours.
      Fifteen patients were selected who had been administered BrdUrd in vivo and both
      proliferation markers were assessed by immunohistochemistry. The data show a good
      correlation between both BrdUrd LI and MIB-1 LI and Tpot (calculated using the
      flow cytometry derived duration of S phase) and MIB-1 LI. The contribution of
      BrdUrd LI to growth fraction varied as a function of proliferation
      characteristics. In tumours with a high LI, the number of DNA synthesizing cells
      represented half the growth fraction, whilst in tumours with lower LI's ( < 10%)
      the ratio of DNA precursor labelled cells as a function of growth fraction fell
      to between 10% and 20%. Tpot showed a linear correlation with MIB-1/BrdUrd ratio
      with a slope approaching unity. It was apparent that both intra- and interpatient
      variation in proliferation index was greater for BrdUrd labelling than for MIB-1
      expression.

PMID- 8652744
TI  - Pleomorphic adenoma and adenoid-cystic carcinoma of salivary glands:
      immunohistochemical assessment of proliferative activity in comparison with flow
      cytometric study.
AB  - In this study, 32 pleomorphic adenomas (PAs) and seven adenoid cystic carcinomas
      (ACCs) were analysed for the evaluation of proliferating cell nuclear antigen
      (PCNA) indices and flow cytometric variables. Our aim was to assess any possible
      relationship between these parameters and the clinico-pathological variables and
      to clarify their histogenesis and reasons for their biological differences. The
      tumours were divided into three groups, mainly epithelial (E), myxoid (M) and
      chondroid (C); PCNA labelling index (LI) and weighted mean index (WI) and the
      WI/LI ratio were analysed in the predominant components; a single PCNA index,
      weighted by the percentage of each component, was also calculated. Only WI/LI was
      found to be significantly different in the three components, while PCNA single
      index did not show either significant differences by sex, age, site and size, or
      any correlation with the S phase fraction. A significant difference was found
      between PAs and ACCs by site (P < 0.01) and DNA ploidy (P < 0.05); furthermore,
      all PCNA indices (single index) were significantly lower in PAs than in ACCs.

PMID- 8652745
TI  - Isolation and culture of hamster ectoplacental cone trophoblasts: an in vitro
      study on the cell types and their growth pattern.
AB  - The method of isolation of trophoblast cell types from ectoplacental cone of
      hamster embryo of day 8 post coitum (plug day as day 1) and examination of their
      growth pattern in vitro is presented in this study. Based on their size, three
      types of trophoblast cells were identified. (1) the smaller cells having clear
      cytoplasm formed the major portion (70% to 80%) of the total cell population (2)
      moderately bigger cells having mono or binucleated appearance and containing
      minute granules in the nuclear region formed 5% to 10% and (3) extra large and
      multinucleated cells shared 10% to 20% of the total cell number. While the
      smaller and slightly bigger cells showed moderate growth the larger ones had
      extensive growth and were seen to acquire different shapes on extending the
      duration of culture, such as fusiform, dumb-bell, polygonal, rectangular or
      flowery. The extremities of the cytoplasmic growth of these cells were seen to be
      thickened at one end giving the impression of a pad-like structure. The
      significance of these adaptations are not known at present.

PMID- 8652746
TI  - Special issue: Psychophysiology of workload.

PMID- 8652747
TI  - Psychophysiology and adaptive automation.
AB  - Adaptive automation is an approach to automation design where tasks are
      dynamically allocated between the human operator and computer systems.
      Psychophysiology has two complementary roles in research on adaptive automation:
      first, to provide information about the effects of different forms of automation
      thus promoting the development of effective adaptive logic; and second,
      psychophysiology may yield information about the operator that can be integrated
      with performance measurement and operator modelling to aid in the regulation of
      automation. This review discusses the basic tenets of adaptive automation and the
      role of psychophysiological measures in the study of adaptive automation.
      Empirical results from studies of flight simulation are presented.
      Psychophysiological measures may prove especially useful in the prevention of
      performance deterioration in underload conditions that may accompany automation.
      Individual differences and the potential for learned responses require research
      to understand their influence on adaptive algorithms. Adaptive automation
      represents a unique domain for the application of psychophysiology in the work
      environment.

PMID- 8652748
TI  - Work-physiological synchronization as a determinant of performance in repetitive
      computer work.
AB  - The present study tested the hypothesis that performance would improve when the
      work rhythm of a highly repetitive task was synchronous with a worker's internal
      physiological rhythms. Experienced office workers (n = 20) used video display
      terminals (VDTs) to perform a repetitive, self-paced data-entry task in a
      simulated office environment over a 2-day period. Each work day consisted of six
      40-min work periods. Work rhythm changes were induced by varying input data field
      lengths (3-13 characters) across eleven of the twelve work periods. The degree of
      synchronization between the work and breathing rhythms, and also between the work
      rhythm and variations in the interbeat interval, was scored using cross-spectral
      analysis. Synchronization scores were then used to predict keying performance
      using multiple regression analysis. The degree of synchronization between the
      work and breathing rhythms was not predictive of performance. However, increased
      synchronization between the work and cardiac rhythms was predictive of (a)
      increased keystroke output, (b) lower error rate and (c) lower correction rate.
      The results suggest that performance in repetitive VDT work might improve if the
      task is designed to promote work-physiological synchronization.

PMID- 8652749
TI  - Psychophysiological assessment of human reliability in a simulated complex
      system.
AB  - Stress-strain processes affect human reliability in operators in control of
      highly automated systems. Job demand and decision latitude play an important role
      in the modification of these processes. Objective methods of task analysis
      involving the study of 50 operators controlling an electroenergy network were
      used to define three "typical' tasks. The present study was carried out at
      simulated computer work places with the same equipment and the same relations of
      information transfer as in the work settings. During the 3-h activity HR, BP and
      motor activity were recorded with an ambulatory monitoring system. The operators
      answered questions concerning subjective strain, emotion, motivation, perceived
      control, and success by means of a pocket computer. The study revealed marked
      increases in strain with increasing job demand and increased decision latitude.
      The results partly contradict Karasek's (1979) model. The operator in a dyadic
      team having decision authority showed significantly higher systolic blood
      pressure, heart rate, and self-reported strain compared to the co-operator. Human
      reliability cannot be increased by means of increasing decision latitude in order
      to enrich the job. It is suggested that human reliability can be improved by
      spreading decision authority over the whole team. Further psychophysiological
      investigations will be necessary, testing not only Karasek's but also alternative
      assumptions for the design of complex systems in order to reduce strain and
      boredom induced decrements in human reliability.

PMID- 8652750
TI  - Psychophysiological stress effects from the combination of night-shift work and
      noise.
AB  - The influence of night-shift work and noise on arousal and stress reactions have,
      to date, been investigated separately. The aim of this study was to compare their
      psychophysiological effects in combination. Twenty-four male student subjects
      continuously performed ten hours of visual display tasks per 24 h under highly
      controlled conditions for either five consecutive day or night shifts, followed
      by two days of rest. Each group worked in conditions of simulated traffic noise,
      at either 80 or 50 dB(A). Urinary catecholamines, electrodermal activity, heart
      rate, and ratings of mood and physical symptoms were recorded continuously or at
      specified intervals. Catecholamine excretion rates, autonomic reactions, reaction
      times, and ratings of subjective alertness showed changes typical for night-shift
      work. No main effects of noise were found, but significant interactions between
      the two experimental factors reflected differential actions of noise dependent on
      the type of shift. The results favor a multiple-arousal concept. Night-shift work
      primarily influences general arousal, while noise affects both general and goal
      directed arousal, dependent on the presentation during day or night shift.

PMID- 8652751
TI  - Physiological indices of workload in a simulated flight task.
AB  - The sensitivity of physiological measures to evaluate workload was investigated
      in a simulated flight task. Heart rate, blood pressure (from beat to beat),
      respiration and eye blinks were recorded in 14 subjects while they performed a
      complex task in a flight simulator. Workload was manipulated by introducing an
      additional task and by varying the task difficulty of segments of the flight
      scenarios. Heart rate and blood pressure were both affected by the different
      levels of task difficulty. Heart-rate variability was found to be confounded by
      respiration. Slow respiratory activity contributed considerably to heart rate
      variability, especially after periods of high workload (for example, after
      landing). The gain between blood-pressure and heart-rate variability (modulus)
      was sensitive to mental effort and was not influences by respiration. Eye blinks,
      in particular the duration, were specifically affected by the visual demands of
      the task and not by the workload in general. When subjects had to process visual
      information, the number and duration of blinks decreased.

PMID- 8652752
TI  - Electrooculographic and performance indices of fatigue during simulated flight.
AB  - The investigation evaluated specific components of eye and eyelid movement as
      predictors of performance decrements resulting from pilot fatigue. Ten partially
      sleep deprived pilots flew a GAT-1 moving-base flight simulator on a 4.5-h
      sortie. The scored flight portion consisted of eight legs, each leg made up of
      two segments, a flight maneuvers task (FMT) and a straight and level flying task
      (SLT). Error scores were calculated across altitude, airspeed, heading, and
      vertical velocity. An electrooculogram provided measures of blink rate (BR),
      blink duration, long closure rate (LCR), blink amplitude (BA), saccade velocity,
      saccade rate, and peak saccade velocity. Subjective fatigue, workload and
      sleepiness were estimated using the USAFSAM seven-point forced-choice scales, the
      Stanford Sleepiness Scale, and the USAFSAM Sleep Survey Form. Error scores
      increased significantly during the first seven legs of the sortie and decreased
      slightly for the last leg. Subjective reports of fatigue increased significantly
      over time and were positively correlated with increased error. For the combined
      data set and for FMTs alone, BA was the best predictor of changes in error with
      decreased amplitude corresponding to increased error. BR and LCR were the second
      and third best predictors, respectively. For SLTs alone, LCR and BA were the
      first and second best predictors of increased error, respectively. The
      investigation demonstrated that measurable flying performance decrements do occur
      due to changes in fatigue and that one can measure physiological correlates of
      those performance decrements.

PMID- 8652753
TI  - Psychophysiological responses to changes in workload during simulated air traffic
      control.
AB  - In this investigation, eight Air Force air traffic controllers (ATCs) performed
      three scenarios on TRACON (Terminal Radar Approach Control), a computer-based air
      traffic control (ATC) simulation. Two scenarios were used each with three levels
      of difficulty. One scenario varied traffic volume by manipulating the number of
      aircraft to be handled and the second scenario varied traffic complexity by
      manipulating arriving to departing flight ratios, pilot skill and mixture of
      aircraft types. A third scenario, overload, required subjects to handle a larger
      number of aircraft in a limited amount of time. The effects of the manipulations
      on controller workload were assessed using performance, subjective (TLX), and
      physiological (EEG, eye blink, heart rate, respiration, saccade) measures.
      Significant main effects of difficulty level were found for TRACON performance,
      TLX, eye blink, respiration and EEG measures. Only the EEG was associated with
      main effects for the type of traffic. The results provide support for the
      differential sensitivity of a variety of workload measures in complex tasks,
      underscore the importance of traffic complexity in ATC workload, and support the
      utility of TRACON as a tool for studies of ATC workload.

PMID- 8652754
TI  - Occupational stress and strain of female students: results of physiological,
      behavioral, and psychological monitoring.
AB  - This study of 50 female students (mean age 23) investigated the level of acute
      and chronic subjective stress, objective strain of everyday university life, and
      behavior (time budget during a normal day). Physiological parameters, behavioral
      activities, and psychological parameters were assessed simultaneously both while
      at the university and at home using a special ambulatory monitoring device
      capable of storing 23-h records. Comparison between typical study (seminar,
      lecture) and leisure activities (resting, conversation, etc.) revealed lower
      heart rate variability during university-related activities, indicative of
      increased mental load. Physical activity was higher during leisure activities,
      but heart rate was even higher during study time. Students rated leisure
      activities to be more enjoyable but less exciting or arousing than studies. Two
      factorial MANOVAs with the factors "stay' (at the university, at home) and
      "chronically stressed by studies', a rating made one week before the monitoring
      (stressed versus non-stressed students), showed significantly higher heart rates
      for the chronically stressed students, particularly while at the university as
      opposed to at home. These students also showed decreased heart rate variability
      as compared to the non-stressed students, indicating greater mental workload. No
      differences between the groups were found in socioeconomic variables and
      personality traits (neuroticism, extraversion, achievement motivation). The
      results are discussed in the context of the stress concept.

PMID- 8652755
TI  - Intra-individual patterns of hormonal and affective adaptation to work demands:
      an n = 2 study of junior doctors.
AB  - This paper examines the detailed pattern of hormonal and affective response to
      natural variations in work demands, in relation to a taxonomy of adaptive
      response based on Frankenhaeuser's (1986) psychobiological analysis of coping
      modes and Hockey's (1993) regulatory control model. Two junior doctors were
      monitored every day over a 7-week period of work on a cardio-thoracic surgery
      ward. Measurements were made for each morning and afternoon work period of self
      rated workload, effort and affective state, and the level of urinary
      catecholamines and cortisol. The de-trended data were analysed separately for the
      two individuals, using multivariate methods. Following reduction of work
      variables by principal components analysis, canonical correlation analyses were
      carried out for each individual. These revealed differences in the patterns of
      adaptation to two distinctive work contexts (enabling and demanding work) across
      the two doctors, as identified through loadings on two significant pairs of
      canonical variates. As expected, enabling work (high medical demands, with high
      personal resources) was associated with active coping in both subjects (low
      fatigue, high effort/adrenaline and low cortisol). However, demanding work (high
      general demands) was associated with marked differences between them in the
      pattern of loadings. One subject showed the strain pattern normally associated
      with effortful engagement in difficult tasks (high anxiety and fatigue, high
      effort/adrenaline), though without the anticipated reduction in cortisol. The
      response pattern of the other individual was indicative of passive coping (high
      anxiety and cortisol, with no effort/adrenaline component). The findings are
      interpreted in terms of the role of personal coping styles on the adaptive
      response to work demands. The use of canonical correlation methods with intra
      individual data sets, although relatively unusual, appears to provide potentially
      valuable evidence on the nature of individual differences in the process of
      psychobiological response to stress underlying work-health relationships.

PMID- 8652756
TI  - Effects of work demands on immunoglobulin A and cortisol in air traffic
      controllers.
AB  - The professional activity of air traffic controllers (ATC) is often considered to
      be rather stressful. Certain characteristics of this job are likely to produce
      stress; for example an ATC can not predict when a situation becomes critical and
      he is not able to regulate the workload. In order to assess psychophysiological
      stress reactions in this working situation, saliva samples were taken from 158
      male air traffic controllers before and after each of two working sessions. In
      contrast to the expected immunosuppressive effects, the working sessions caused a
      marked increase in the concentration and secretion rate of salivary
      immunoglobulin A (sIgA), as well as in the concentration of salivary cortisol.
      The increase in sIgA, however, was not correlated with the salivary cortisol
      response or with the amount of actual or perceived workload, whereas the cortisol
      response was correlated with both workload measures. It is suggested that
      positive emotional engagement is responsible for the observed sIgA increase and
      that measuring this physiological response may be a valuable tool for
      differentiating between positive and negative stress effects or between
      successful and unsuccessful adaptation or coping with situational demands.

PMID- 8652757
TI  - Concentrations of sodium, potassium and cortisol in saliva, and self-reported
      chronic work stress factors.
AB  - One hundred and fifteen electronics factory employees completed questionnaires
      relevant to work stress, and gave unstimulated saliva samples. As previously
      found, Perceived Coping Incapacity correlated very significantly with self
      reported emotional upset and psychosomatic complaints. Salivary [Na+] correlated
      significantly with Perceived Coping Incapacity (rho = -0.30, p < 0.01), and also
      with emotional upset (rho = -0.19, p < 0.05). Raised [K+] tended to be associated
      with reduced fatigue (rho = -0.21, p < 0.05) and lower self-medication (rho = 
      0.21, p < 0.05) together with a greater perceived personal work responsibility
      (rho = 0.19, p < 0.05)-all consistent with the perception of work demands as
      positive challenges rather than stressors. Self-reported fatigue and emotional
      upset at work gave higher correlations with [K+] and [Na+] than either did on its
      own. Salivary [cortisol] was uncorrelated with self-reported work stress indices,
      and with [K+] and [Na+].

PMID- 8652758
TI  - Working with new technologies: hormone excretion as an indicator for sustained
      arousal. A pilot study.
AB  - Effects of working with new technologies (visual display units) on hormone levels
      were investigated in a pilot study. The relationship between subjective strain
      and hormone levels was also assessed. Twenty subjects participated in the study
      reported here, which is a part of a comprehensive longitudinal study, in which
      279 employees participated. Measurements were taken two months before the new
      technology was installed (baseline: work with conventional technology), during
      the implementation phase of the new technology, and at a 12-month interval.
      Fourteen complete data sets were analysed. The introduction of new technologies
      was accompanied by enhanced levels of catecholamines (epinephrine and
      norepinephrine). Levels also remained high one year after the implementation.
      Similar values were found on work days and rest days. Cortisol changes were less
      evident; excretion tended to increase after the implementation had been
      completed. The relationship was weak between hormone levels and subjective strain
      measurements. The results indicate that working with new technologies was
      accompanied by enhanced physiological arousal of the employee. Reactivity was
      related more to a particular occupational setting than to scales of subjective
      assessment.

PMID- 8652759
TI  - [Indications for primary or initial use of hyperbaric oxygenation].

PMID- 8652760
TI  - [Indications for hyperbaric oxygenation in chronic diseases].

PMID- 8652761
TI  - [Expanding indications for hyperbaric oxygenation--current development and status
      of clinical evaluation].

PMID- 8652762
TI  - [Technical prerequisites, required personnel and practical implementation of
      hyperbaric oxygenation].

PMID- 8652764
TI  - [Comments on the position of Sibrowski et al. on the comment by v. Bormann et
      al.: autologous blood is safer than donated blood--fact or fiction?].

PMID- 8652763
TI  - [Priority conflict concerning the discovery of lumbar anesthesia between August
      Bier and August Hildebrandt].
AB  - The history of anaesthesiology like that of other medical branches has not been
      free of quarrels concerning priority. International disputes between the surgeon
      August Bier from Kiel and his former colleague August Hildebrandt concerning the
      question of who was the actual inventor of spinal anesthesia have almost fallen
      into oblivion. While Hildebrandt and numerous other colleagues frequently stated
      that the New York neurologist James Leonhardt Corning was the inventor of spinal
      anesthesia, Bier insisted on having described and developed this method first and
      without any knowledge of Corning's experiments. Corning's use of the term "spinal
      anesthesia" in his publications probably caused the error that he was the first
      to describe and apply this new widespread technique. Only recently, American
      scientists emphasized the fact that this is not true. There will, unfortunately,
      not be an answer to the Question why Hildebrandt started this quarrel about
      priority. His reason might have been hurt feelings as he had not been mentioned
      as co-author in Bier's epoch-making survey.

PMID- 8652765
TI  - [150 years ether narcosis (1846-1996)].

PMID- 8652767
TI  - [Lasting and ephemeral trends in medicine and naturopathy].

PMID- 8652766
TI  - [Adrenergic beta receptors in anesthesia and intensive care medicine].
AB  - beta-Adrenoceptors (beta-AR) are divided into a beta 1-, a beta 1-, and a
      recently cloned beta 3-subtype. beta-AR belong to the group of 7-transmembrane
      spanners which are coupled via GS-proteins to the enzyme adenylyl cyclase.
      Instead of being static entities, beta-AR undergo dynamic regulation upon
      repeated or prolonged exposure to agonists (down-regulation) or antagonists (up
      regulation). After exposure to agonists, an early desensitisation caused by
      phosphorylation of amino acid residues can be distinguished from receptor
      sequestration. Finally, the internalised receptor is digested by proteolytic
      enzymes. The present article describes the basic patterns of molecular biology of
      beta-AR, signal transduction, and receptor desensitisation. In the human heart,
      beta-AR are the most important receptor system to provide positive inotropic and
      chronotropic effects. The alterations of the beta-adrenergic system in cardiac
      insufficiency, after heart transplantation, and after extracorporeal circulation,
      as well as changes induced by surgery and single anaesthetic agents, are
      reviewed.

PMID- 8652768
TI  - [Mechanical autotransfusion also in transurethral resection of prostatic adenoma?
      Studies of preserved washed erythrocyte concentrates before possible
      retransfusion].
AB  - AIM: Does cell-saving during transurethral resection of prostatic adenoma (TURP)
      provide autologous washed erythrocyte concentrates (AWECs) of the same
      haematological and bacteriological quality as that of established indications of
      a cell-saving device? Should the cell-saving device be used routinely in TURP?
      METHODS: 37 patients underwent TURP with written, informed consent. All patients
      had antibiotic therapy prior to surgery. Shed blood was processed by a cell
      saving device. AWECs specimens were analysed for red blood count, electrolytes,
      LDH, extracellular haemoglobin, osmotic fragility, blood culture and bacterial
      concentration. In addition, data of urine cultures, adenoma cultures and adenoma
      histology were analysed. AWEcs were not retransfused. RESULTS: Haematological
      quality was shown to be comparable to that of established applications of a cell
      saving device. However, 82% of the AWECs were contaminated with bacteria.
      Concentrations were as high as > 10(6) bacteria/ml. Isolated bacteria ranged from
      e. coli and pseudomonas to staphylococci, streptococci and candidae. Bacteria
      found in the urine cultures of patients with urinary tract infections could also
      be isolated in their AWECs. 16% of the patients had prostatic cancer not know
      preoperatively. Mass of resected adenoma and volume of AWEC did not correlate.
      CONCLUSIONS: In despite of good haematological quality we considered the rate of
      82% bacterial and 16% tumour cell contamination of the AWECs unacceptable and,
      contrary to some literature data, we no longer use a cell-saving device in TURP.

PMID- 8652769
TI  - [Changes in various metabolic parameters following bloodletting].
AB  - OBJECTIVE: We investigated hypovolaemia induced by bloodletting, accompanied by
      statistically significant, but clinically irrelevant increase of heart rate
      together with unchanged blood pressure, with regard to hepatic glucose production
      as well as alanine and glycerol turnover rates. METHODS: Healthy male volunteers
      (n = 18) were bled 15 ml/kg body weight over 20 min and remained hypovolaemic for
      60 minutes. Heart rate was recorded by ECG and blood pressure by an oscillometric
      device. Before and after bloodletting hepatic glucose production as well as
      alanine and glycerol turnover rates were determined using the stable isotopes 6.6
      D2-glucose, 15N-alanine and D5-glycerol as tracers. Simultaneously, the blood
      concentrations of adrenaline, noradrenaline, free fatty acids and glycerol were
      measured. RESULTS: Bleeding did not change the mean arterial blood pressure, but
      increased the heart rate significantly from 61 +/- 9 to 70 +/- 13 1/ min.
      Noradrenaline levels increased significantly from 1.16 +/- 0.41 to 2.15 +/- 0.69
      nmol/l. Hepatic glucose production (HGP) as well as alanine (AlaTO) and glycerol
      turnover (GlyTO) decreased significantly during hypovolaemia. HGP fell from 2.72
      +/- 0.29 to 2.56 +/- 0.28 mg/kg/min, AlaTO from 0.71 +/- 0.27 to 0.53 +/- 0.25
      mg/kg/min and GlyTO from 4.9 +/- 2.1 to 3.8 +/- 1.4 mumol/kg/min, respectively.
      The blood levels of adrenaline, free fatty acids and glycerol did not change
      during the study. DISCUSSION: In respect of clinical signs, the cardiovascular
      status of the volunteers was stable after bleeding. In contrast, the decrease of
      HGP as well as the drop in alanine and glycerol turnover rates might be
      interpreted as a sign of an altered functional status of single organs, induced
      by changes of regional perfusion.

PMID- 8652770
TI  - [Quality management in autologous blood donation].
AB  - In many anaesthesia departments, the autologous transfusions concept is an
      integral part of the perioperative measures catalogue. All patients benefit from
      this procedure, especially those who face an operation during which much blood
      will be lost. If a patient donates his/her own blood for their operation, there
      should not be any increase in risk to this patient. By employing contemporary
      quality management practices, including computer technology, the quality of the
      execution and management of the components as well as the quality of the patient
      care can be evaluated according to the quality of the structure, process and
      results. By this assessment the efficiency of the procedure can be confirmed and
      the advantages of using this technique, when utilised by an anaesthesiologist
      experienced in transfusion, can be underlined. An overview of the pre-existing
      and expected perioperative risk is of special advantage to the anaesthesiologist
      to make a realistic and effective decision regarding the possibility of safely
      processing the autologous blood donation concept.

PMID- 8652771
TI  - [Hyperbaric oxygen therapy--principles and indications].

PMID- 8652772
TI  - [Hyperbaric oxygenation: therapy with oxygen using hyperbaric pressure].

PMID- 8652773
TI  - Characterization of hydrogels using nuclear magnetic resonance spectroscopy.
AB  - Literature relevant to characterization of hydrogels and cross-linked polymer
      networks using nuclear magnetic resonance (NMR) spectroscopy has been extensively
      reviewed. After a brief introduction to the fundamentals of NMR spectroscopy, a
      variety of NMR techniques are considered, including 13C NMR of swollen polymer
      networks, end-group studies by 13C NMR with labelled initiators, spin-spin and
      spin-lattice relaxational studies to distinguish species based upon mobility, and
      characterization of specific interactions using the nuclear Overhauser effect.
      Finally, a brief treatment of the characterization of polymer structural
      quantities such as composition, tacticity and sequence distribution by NMR
      spectroscopic studies is presented. Although our discussion is representative
      rather than exhaustive, we are confident that this review will demonstrate the
      utility of NMR spectroscopy for characterization of hydrogel networks which have
      applications as biomaterials.

PMID- 8652774
TI  - Hepatocyte culture on carbohydrate-modified star polyethylene oxide hydrogels.
AB  - We describe the synthesis and in vitro biological characterization of a new class
      of carbohydrate-modified hydrogels based on radiation-cross-linked star
      polyethylene oxide (PEO). Hydrogels were synthesized from either of two types of
      PEO star molecules in order to vary the terminal hydroxyl content of the gels
      while keeping other gel properties such as molecular weight between cross-links
      and water content constant. The resulting gels were covalently modified with
      monosaccharide ligands and the behaviour of primary rat hepatocytes on the
      modified gels was evaluated under culture conditions. Hepatocytes exhibited a
      sugar-specific adhesion to the modified gels, adhering to gels bearing galactose
      but not glucose. Cell spreading was observed on both types of galactose-modified
      PEO star gels; moreover, the gels supported long-term (6 d) culture and
      differentiated function of primary hepatocytes. Further, on comparing the cell
      spreading behaviour observed on the PEO star gels with that reported previously
      for galactose-modified polyacrylamide, we find that our gels elicit spreading at
      ligand concentrations lower by an order of magnitude. A simple mechanistic
      analysis indicates that this enhanced ability of PEO star gels to support
      spreading of primary hepatocytes on low concentrations of immobilized galactose
      derives from freedom of the immobilized ligands to come within sufficiently close
      proximity to mimic a high-affinity branched oligosaccharide.

PMID- 8652775
TI  - Calcification of pericardial tissue pretreated with different amino acids.
AB  - Since the development of cardiac prostheses, numerous chemical treatments have
      been assayed to prevent the process of their mineralization. The effect of
      chemical treatment with amino acids is assessed in a subcutaneous implantation
      model in rats. Pericardial tissue from young calves was treated with L-lysine, L
      glutamine, L-arginine or L-glutamic acid, each at a concentration of 0.5 M,
      following treatment with 0.625% glutaraldehyde. Then, the tissue was implanted
      into young rats for periods of 21 and 60 d, after which the calcium accumulated
      was quantified by atomic absorption spectroscopy. Values similar to or higher
      than those found in control samples indicated a lack of effectiveness of these
      treatments. Only in the 21-d implantation samples treated with L-lysine and L
      arginine was less calcium accumulated than in the control tissue. After 60 d of
      implantation, all groups showed high levels of calcium deposition. The values
      obtained after 60 d of subcutaneous implantation were 87.5 +/- 52.4 mg Ca2+ per g
      dry weight of tissue for L-lysine, 108.7 +/- 43.5 mg Ca2+ per g dry weight of
      tissue for L-glutamine, 130.4 +/- 22.4 mg Ca2+ per g dry weight of tissue for L
      glutamic acid, 119.3 +/- 27.6 mg Ca2+ per g dry weight of tissue for L-arginine
      and 100.0 +/- 38.3 mg Ca2+ per g dry weight of tissue for the control group.
      Treatment with amino acids does not appear to prevent the calcification of
      cardiac bioprostheses or of collagen-based biomaterials when assayed in a model
      of subcutaneous implantation.

PMID- 8652776
TI  - Structural studies on bovine bioprosthetic tissues and their in vivo
      calcification: prevention via drug delivery.
AB  - Cardiovascular calcification, the formation of calcium phosphate deposits in
      cardiovascular tissue, is a common end-stage phenomenon affecting a wide variety
      of bioprostheses. To study the process of calcification in tissue prosthetics,
      glutaraldehyde-treated bovine pericardium, dura mater and fascialata were
      implanted subcutaneously in rats and retrieved 21 days later and thereby
      morphological findings were correlated with biochemically determined levels of
      calcium. Transmission electron microscopy showed that calcification primarily
      involved the surface of collagen fibrils and the interfibrillar spaces. The
      deposition of calcium was higher with dura and fascia prostheses compared to
      pericardium. However, the release of Fe3+ ions from chitosan matrix had
      substantially inhibited the deposits of calcium in all implanted tissues. It
      seems that the structural and anatomical features of the tissue is one of the
      important factors for tissue-associated calcification. It is also confirmed that
      glutaraldehyde-preserved pericardium is the most suitable material for the
      development of cardiac prosthesis, with an appropriate drug combination therapy
      for prevention of pathological calcification.

PMID- 8652777
TI  - Artificial cornea: surface modification of silicone rubber membrane by graft
      polymerization of pHEMA via glow discharge.
AB  - A method for producing various surfaces of silicone rubber membrane (SR) was
      developed in this study by grafting various amounts of poly(2-hydroxy ethyl
      methacrylate) (pHEMA) onto SR by plasma-induced grafted polymerization (PIP) as a
      homobifunctional membrane. The elemental composition and different carbon
      bindings on the surface of SR were examined by electron spectroscopy for chemical
      analysis with the amount of O1s/C1s being approximately 0.7 at 1 min, 60 W, 200
      mTorr of Ar-plasma treatment. The peroxide group introduced on SR was measured
      via 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the amount of 6.85 x 10(-8) mol cm-2
      reached optimum value at 1 min of Ar-plasma treatment. After Ar-plasma treated
      SR, the peroxide group (33D peak) was introduced on the surface of SR by negative
      spectra of secondary ion mass spectroscopy analysis, whereas ester groups (72D
      peak) were observed for pHEMA-grafted SR. For the in vitro test, the influence of
      various surfaces of SR on attachment and growth of rabbit corneal epithelial
      cells (CEC) was studied by cell culture assay. These results indicated that 56
      150 micrograms cm-2 of pHEMA grafted onto SR were suitable values for attachment
      and growth of CEC. On the contrary, the large grafted amounts (500-1650
      micrograms cm-2) of pHEMA on SR were insufficient for attachment and growth of
      CEC. For the in vivo test, the migration of CEC from host cornea to implant was
      investigated by slit lamp microscopy. The experimental results indicated that SRs
      grafted with pHEMA were completely covered with CEC 3 weeks after implantation of
      the membranes into the host cornea. These results provide a valuable reference
      for developing an artificial cornea.

PMID- 8652778
TI  - Relationships between chemical characteristics and anticomplementary activity of
      fucans.
AB  - We have shown previously that a low-molecular-weight fucan extracted from the
      brown seaweed Ascophylum nodosum strongly inhibited human complement activation
      in vitro and its mechanism of action was largely elucidated. We further
      investigated the influence of molecular weight and chemical composition of fucan
      on its anticomplementary activity. The capacity of 12 fragments of fucan (ranging
      from a molecular weight of 4100 to 214,000) to prevent complement-mediated
      haemolysis of sheep erythrocytes (classical pathway) and of rabbit erythrocytes
      (alternative pathway) increased with increasing molecular weight, and reached a
      plateau for 40,000 and 13,500, respectively. The most potent fucan fractions were
      40-fold more active than heparin in inhibiting the classical pathway. They were,
      however, as active as heparin in inhibiting the alternative pathway. In addition,
      we have developed a haemolytic test based on the CH50 protocol, which allows
      discrimination between activators and inhibitors of complement proteins. Although
      the mannose content within the different fucan fragments did not vary, the
      galactose and glucuronic acid contents increased with increasing activity,
      suggesting that these residues should be essential for full anticomplementary
      activity. Meanwhile, sulphate groups appeared to be necessary, but were clearly
      not a sufficient requirement for anticomplementary activity of fucans. Taken
      together, these data illustrate the prospects for the use of fucans as potential
      anti-inflammatory agents.

PMID- 8652779
TI  - Bone response to surface-modified titanium implants: studies on the early tissue
      response to machined and electropolished implants with different oxide
      thicknesses.
AB  - The bone formation around titanium implants with varied surface properties is
      investigated. Machined and electropolished samples with and without thick,
      anodically formed surface oxides were prepared, surface characterized and
      inserted in the cortical bone of rabbits (1, 3 and 6 weeks). Scanning electron
      microscopy, scanning Auger electron spectroscopy and atomic force microscopy
      revealed marked differences in oxide thickness, surface topography and roughness,
      but no significant differences in surface chemical composition, between the
      different groups of implants. Light microscopic morphology and morphometry showed
      that all implants were in contact with bone and had a large proportion of bone
      within the threads at 6 weeks. The smooth, electropolished implants, irrespective
      of anodic oxidation, were surrounded by less bone than the machined implants
      after 1 week. After 6 weeks the bone volume as well as the bone-implant contact
      were lower for the merely electropolished implants than for the other three
      groups. Our study shows that a high degree of bone contact and bone formation are
      achieved with titanium implants which are modified with respect to oxide
      thickness and surface topography. However, the result with the smooth
      (electropolished) implants indicates that a reduction of surface roughness, in
      the initial phase, decreases the rate of bone formation in rabbit cortical bone.

PMID- 8652780
TI  - Mineral evolution of bone.
AB  - A study on the evolution with age of the mineral composition of bones was
      performed on samples belonging to human and other common mammalian species
      (cattle, sheep, dog). The study was carried out on the ashes obtained by
      calcination of the bone samples (1 h at 900 degrees C). The calcined powders were
      carefully examined by X-ray diffraction, from which precise quantitative
      evaluation (also confirmed by chemical analysis) of the crystalline phases
      present was derived. These data were analysed as a function of the introduced
      fractional age phi, a new relative scale that allows even largely different
      lifespan species to be compared. An overall linear increase in (Ca + Mg)/P ratio
      with log phi was found and the other considerations on molecular constitution
      (especially as regards Mg2+ substituting for Ca2+ in very young subjects) of the
      various phases detected were formulated and relative implications evaluated. The
      results appear promising for an improvement of knowledge in the field of
      biomedical experimentation and clinical implantology.

PMID- 8652781
TI  - Effect of manufacturing tolerances on the micromotion at the Morse taper
      interface in modular hip implants using the finite element technique.
AB  - This study reports on the examination of the effect of manufacturing tolerances
      on the micromotion at the Morse taper interface in modular hip implants. The
      finite element technique was used as a tool of analysis. Special emphasis was
      placed on the consideration of the transient dynamic conditions under which a
      prosthesis works inside the human body. In order to simulate approximately the
      repetitive forces acting on a hip implant during the human walking cycle, a time
      variant sinusoidal load was applied on the head of the taper. The locking of the
      Morse taper joint by the surgeon in the operating room at the time of
      implantation was simulated by specifying an axial displacement to the female
      taper component as an initial condition.

PMID- 8652782
TI  - Pre-conditioning and dual constant composition dissolution kinetics of pulsed
      laser deposited hydroxyapatite thin films on silicon substrates.
AB  - The kinetics of dissolution of pulsed laser deposited crystalline and amorphous
      thin films of hydroxyapatite on silicon substrates were measured at 37 degrees C
      and a pH value of 6.5 using the dual constant composition method. Solutions in
      which the pulsed laser deposited films were pre-conditioned (0.15 M NaCl)
      remained undersaturated or slightly supersaturated with respect to hydroxyapatite
      after equilibrium was reached, indicating only a very small coating release and
      the absence of re-precipitation on the surfaces. The amorphous films released
      more calcium and phosphate during pre-conditioning than the more crystalline
      films. Dual constant composition dissolution rates decreased as film
      crystallinity increased. The film with the lowest dissolution rate (approximately
      one sixth that of a crystalline film deposited using a hydroxyapatite powder
      target) was fabricated using a human tooth as the laser target. During pre
      conditioning of plasma-sprayed coatings, more calcium and phosphate were released
      than for pulsed laser deposited films, and dual constant composition dissolution
      rates were much higher.

PMID- 8652783
TI  - Structural changes of thermally sprayed hydroxyapatite investigated by Rietveld
      analysis.
AB  - Hydroxyapatite (HA) coatings were prepared by three thermal spraying methods:
      flame spraying, high velocity oxygen fuel spraying and plasma spraying. The HA
      was then examined by Rietveld analysis using the General Structure Analysis
      Software package (GSAS) and the results compared with those for the precursor
      powder. A comparison between HA before and after spraying showed that all three
      spraying methods caused a distortion in the unit cell in the form of a unit cell
      a-axis length decrease and a c-axis increase. Overall unit cell volumes showed a
      difference between the three thermal methods, with flame spraying and high
      velocity oxygen fuel methods giving a unit cell volume increase and the air
      plasma spraying method showing a decrease, compared to the starting powders. The
      two different starting powders used each showed a high oxygen occupancy for the
      hydroxyl oxygen. When thermally sprayed, both powders gave a reduction in
      occupancy, which suggested carbonate substitution for the OH group, but this was
      subsequently removed when thermally processed. The spraying also formed
      oxyapatite, indicated both by spectral analysis showing a reduction in the
      hydroxyl peak and by the hydroxyl oxygen occupancy falling to a level below 0.5.
      Major differences between the three spraying methods could be seen in the
      distortion index calculations. The thermal spraying techniques gave an increase
      in the distortion index, but it was significantly higher for the plasma-sprayed
      coating.

PMID- 8652784
TI  - [Analytic design and clinical application of an intelligent control system for
      pharmacotherapy with insulin--2].
AB  - To determine whether insulin dosage recommendations provided by a computer system
      are as effective as those given by human experts, we developed an intelligent
      control system and prospectively studied its use in 42 type-1 diabetics attending
      a diabetes education center. Control algorithms were based on blood glucose self
      monitoring and included parameter estimations to determine glucose metabolism.
      The algorithms were implemented in a vest pocket-sized system. Over a period of
      32 days, 21 patients used the computer to determine the necessary dose of
      insulin, while a second group of 21 patients followed the recommendations of the
      diabetes specialists. Baseline HbA1 levels (9.8 +/- 1.6 vs 9.9 +/- 1.6%) were
      identical in the two groups. The mean serum glucose over the last two weeks of
      the study was lower in the computer group (151.3 +/- 25.2 vs 165.7 +/- 36.0
      mg/dl; p < 0.01) although the rates of hypoglycaemic episodes were equal (1.7 vs
      2.3%). Metabolic control, measured by the day-to-day standard deviation of the
      serum glucose (46.8 +/- 14.4 vs 50.4 +/- 16.2 mg/dl; p < 0.01), was more stable
      in the computer group. We conclude that metabolic control and safety were
      comparable in the two groups, and suggest that such an intelligent control system
      may be of benefit for use at home, when the help of doctors or diabetes educators
      is not available.

PMID- 8652785
TI  - [Breath alcohol analyzers with electrochemical sensory--accuracy of measurements
      in lung model ventilation].
AB  - Absorption of irrigating fluid by blood vessels during endoscopic urological
      surgery may result in cardiac insufficiency, impairment of electrolyte metabolism
      and neurological disorders. For detection and quantification of the volume
      absorbed, ethanol is added to the irrigating fluid. The resulting blood alcohol
      concentration can be obtained by measuring the alcohol concentration in the
      expired air. For artificially ventilated patients receiving a general anesthetic,
      electrochemical sensors that remain uneffected by volatile anaesthetics are used.
      In the present study, the measuring accuracy of three different alcohol analyzers
      using electrochemical sensors was tested against an infrared reference sensor
      during simulated ventilation in a lung model, and the optimal trigger time point
      for sampling determined. All three devices tested show the same degree of
      accuracy as the reference. For manual endexpiratory triggering devices with short
      sampling times are best suitable. Portable devices powered by rechargeable
      batteries and usable with both spontaneously breathing and ventilated patients
      are recommended for clinical application.

PMID- 8652786
TI  - [Development of a measuring set-up for determination of light distribution of
      scattered light applicators for interstitial laser treatment].
AB  - In the medical setting, scattering dome applicators are used in various
      therapeutic and diagnostic procedures, e.g. laser-induced interstitial
      thermotherapy. The present study reports on the development of an automatic
      measuring system for determining the light distribution along the active end of
      scattering dome applicators. Using a stepper motor, the applicator is gradually
      moved into an integrating sphere, in which the light intensity is measured with a
      photodetector. It was shown the light distribution is determined mainly by the
      conditions under which the laser beam is coupled to the transmission fiber. The
      results made it possible to optimize the production of applicators, and showed
      that the set-up was suitable for quality control use.

PMID- 8652787
TI  - [Ultrasound imaging of osteosynthesis materials in traumatology--an experimental
      study].
AB  - The aim of the present study was to establish the typical ultrasound (US)
      patterns of metal implants used for internal fracture fixation, and consequently
      to use US for the identification and localisation of such implants. We
      investigated both the visualization of the implants in term of size and shape,
      material (titanium, steel, biodegradable screws) and surface structures, and
      possible changes in the echo pattern in relationship to surrounding structures
      (muscles, body fluid), proximity to bone, and changes in the angle of insonation.
      For this purpose ultrasonography was performed on artificial and isolated cadaver
      bones in a water bath, as well as on cadaver limbs following prior implantation
      of screws, plates, K-wires and cerclage wires. We found that, from a certain size
      upwards, metal implants can be easily localised on the basis of typical artefacts
      (resonance artefact, comet-tail artefact). US is thus most suitable for
      localisation of metal implants. The spatial and anatomical relationship to bony
      structures, joints, tendons, muscles and blood vessels can be determined with a
      high degree of accuracy.

PMID- 8652788
TI  - [Dynamic in vivo measurements of local pressure of compression stockings with a
      microprobe].
AB  - Conservative treatment of chronic venous incompetence is based on compression
      therapy, Carried out correctly, compression therapy improves the venous return
      from the legs, and also relieves cutaneous congestion. These positive
      haemodynamic effects are, however, only obtained when the pressure exerted by the
      compression stocking remains within the desired therapeutic range, not only at
      rest, i.e. while the patient is seated or reclining, but also during exertion
      while the patient is standing or walking, furthermore, the pressure exerted must
      decrease continuously from the tips of the toes to the trunk. Using the dynamic
      pressure monitoring system described here, the pressure exerted by the
      compression stocking can be measured continuously between the stocking and the
      skin at any desired site. The main component of the new microprocessor-based
      system is a microtip probe for measuring piezoresistance. The probe has an
      integrated signal filter and is connected to peripheral equipment which records
      the measured data. The technical design of the system makes it possible
      accurately to record dynamic measurements of the pressure exerted by compression
      materials in vivo. This measuring system represents a major step forward in
      understanding the dynamics of compression during locomotion in vivo, and towards
      optimizing modern compression therapy.

PMID- 8652789
TI  - Isomerization of the Xaa-Pro peptide bond induced by ionic interactions of
      arginine.
AB  - Inclusion of Arg or Pro residues in proteins and peptides has been proved to play
      an essential role in biochemical functions through ionic interactions,
      conformational transitions, and formation of turns as well. In this study we
      present the conformational properties of the Ac-Arg-Ala-Pro (1), Ac-Arg-Ala-Pro
      NH2 (2), Ac-Arg-Pro-Asp-NH2 (3), and Ac-Arg-Pro-Asp (4) tripeptides, using 1H-nmr
      spectroscopy and molecular dynamics. These peptides were modeled with the aim of
      studying the role of the Arg-guanidinium to carboxylate ionic interactions on the
      Xaa-Pro peptide bond isomerization. It was found with 1 and 4 that arginine
      preferentially interacts with the C-terminal carboxylate group, even though the
      beta-carboxylate is also accessible. This tendency of the Arg moiety was found to
      induce the cis disposition of the Ala-Pro peptide bond in 1. It was also
      confirmed that the Arg...Asp side chain-side chain ionic interaction in 3 plays a
      key role in backbone folding and structural stabilization through a type I beta
      turn. The nmr pattern for 3 showed a remarkable similarity with that for various
      Arg-Tyr-Asp containing peptides, a sequence that is crucial for the adhesion
      properties of the Leishmania gp63 glycoprotein.

PMID- 8652790
TI  - Unusual conformational preferences of beta-alanine containing cyclic peptides.
      VII.
AB  - In the present paper we describe the synthesis, purification, and single crystal
      x-ray analysis of the cyclic pentapeptide cyclo-(Pro-Phe-Phe-beta-Ala-beta-Ala).
      This compound crystallizes in the orthorhombic space group P2I2I2I from methanol
      and adopts in the solid state an unusual conformation characterized by a cis beta
      Ala5-Pro1 peptide bond and by an intramolecular hydrogen bond stabilizing a C11
      and a C12-ring structure. The C11 structure contains the Phe3 and the beta-Ala4
      at the corner position of the turn; it is the first observation of a type II beta
      turn enlargement due to the insertion of an extra methylene group of the beta
      alanine residue. The rest of the molecule participates in a newly characterized
      C12-ring structure, which incorporates a beta-Ala residue at position i of the
      turn.

PMID- 8652792
TI  - Discovering protein secondary structures: classification and description of
      isolated alpha-turns.
AB  - Irregular protein secondary structures are believed to be important structural
      domains involved in molecular recognition processes between proteins, in
      interactions between peptide substrates and receptors, and in protein folding. In
      these respects tight turns are being studied in detail. They also represent
      template structures for the design of new molecules such as drugs, pesticides, or
      antigens. Isolated alpha-turns, not participating in alpha-helical structures,
      have received little attention due to the overwhelming presence of other types of
      tight turns in peptide and protein structures. The growing number of protein X
      ray structures allowed us to undertake a systematic search into the Protein Data
      Bank of this uncharacterized protein secondary structure. A classification of
      isolated alpha-turns into different types, based on conformational similarity, is
      reported here. A preliminary analysis on the occurrence of some particular amino
      acids in certain positions of the turned structure is also presented.

PMID- 8652791
TI  - Solvent-mediated conformational transition in beta-alanine containing cyclic
      peptides. VIII.
AB  - In the present paper we describe the solution nmr structural analysis and
      restrained molecular dynamic simulation of the cyclic pentapeptide cyclo-(Pro-Phe
      Phe-beta-Ala-beta-Ala). The conformational analysis carried out in CD3CN and
      dimethylsulfoxide (DMSO) solutions by nmr spectroscopy was based on interproton
      distances derived from rotating frame nuclear Overhauser effect spectroscopy
      spectra and homonuclear coupling constants. A restrained molecular dynamic
      simulation in vacuo was also performed to build refined molecular models. The
      molecule is present in both solvent systems as two slowly interconverting
      conformers, characterized by a cis-trans isomerism around the beta-Ala5-Pro1
      peptide bond. In CD3CN solution, the conformer with a ci5 peptide bond is quite
      similar to that observed in the solid state, while the conformer containing all
      trans peptide bonds is characterized by an intramolecular hydrogen bond
      stabilizing a C10- and a C13-ring structure. In DMSO solution, the trans isomer
      is partly similar to that observed in CD3CN solution while the cis isomer is
      different from that observed in the solid state. The effect of the solvent in
      stabilizing different conformations was also investigated in DMSO-CD3CN solvent
      mixtures.

PMID- 8652793
TI  - A search for the ideal type I beta-turn.
AB  - In 1968 C. Venkatachalam (Biopolymers, Vol. 6, pp. 1425-1436) predicted the ideal
      forms of beta-turns (type I, type II, etc.) based entirely on theoretical
      calculations. Subsequently, over a thousand x-ray structures of different
      globular proteins have been analyzed, with results suggesting that the most
      important form among the hairpin conformers is the type I beta-turn. For the
      latter type of hairpin conformation, the original computations had predicted phi
      i+I = -60 degrees, psi i+1 = -30 degrees, phi i+2 = -90 degrees, and psi i +2 = 0
      degrees as backbone torsion angle values, and these have been used from that time
      as reference values for the identification of the type I beta-turn. However, it
      has never been clarified whether these "ideal" backbone torsion angle values
      exist in real structures, or whether these torsion angles are only "theoretical
      values." Using the most recent release of the Protein Data Bank (1994), a survey
      has been made to assign amino acid pairs that approach the ideal form of the type
      I beta-turn. The analysis resulted in four sequences where the deviation from
      ideal values for any main-chain torsion angles was less than 2 degrees. In order
      to determine whether such a backbone fold is possible only in proteins owing to
      fortuitous cooperation of different folding effects, or whether it occurs even in
      short peptides, various attempts have been made to design the optimal amino acid
      sequence. Such a peptide model compound adopting precisely the predicted torsion
      angle values [phi i+1 = -60 degrees, psi i +1 = -30 degrees, phi i +2 = -90
      degrees, and psi i+2 = 0 degrees] could provide valuable information. The solid
      state conformation of cyclo[(delta)Ava-Gly-Pro-Thr(OtBu)-Gly] reported herein,
      incorporating the -Pro-Thr- subunit, yields values suggesting that the "ideal"
      type I beta-turn is even possible for a peptide where there are no major
      environmental effects present.

PMID- 8652794
TI  - Oxidative folding of omega-conotoxin MVIIC: effects of temperature and salt.
AB  - Oxidative folding of omega-conotoxin MVIIC, a highly basic 26-amino acid peptide
      with three disulfide bonds, predominantly gave two products with mismatched
      disulfide bonds in 0.1M NH4OAc buffer (pH 7.7) at 21 degrees C both in the
      presence and absence of redox reagents such as reduced and oxidized glutathione.
      A low reaction temperature (5 degrees C) and a high salt concentration in buffer
      such as 2M (NH4)2SO4 were necessary to obtain the correctly folded biologically
      active product. The folding reaction was found to proceed via a two-stage pathway
      of (I) the formation and (II) the rearrangement of the mismatched disulfide
      bonds. Both the reaction temperature and the salt strongly affected the
      equilibrium between mismatched and correctly formed disulfide bonds in the second
      stage. Such an effect of salts on the rearrangement reaction could be explained
      by anion binding at a low concentration and the salting out effect at a high
      concentration by analyzing the rank order of their effectiveness. The anion
      binding effect was also confirmed by examining the folding of the tetra
      acetylated peptide at the Lys side chains. CD study suggested that the yield of
      the biologically active product was correlated with its conformational change as
      functions of temperature and salt concentration.

PMID- 8652795
TI  - 1H-NMR structural analysis of ethidium bromide complexation with self
      complementary deoxytetranucleotides 5'-d(ApCpGpT), 5'-d(ApGpCpT), and 5'
      d(TpGpCpA) in aqueous solution.
AB  - Complexation of the trypanocidal drug, ethidium bromide (EB), and the self
      complementary deoxytetraribonucleoside triphosphates, 5'-d(ApCpGpT), 5'
      d(ApGpCpT), and 5'-d(TpGpCpA), in aqueous salt solution has been investigated
      using one-dimensional and two-dimensional 500/600 MHz 1H-nmr spectroscopy. Six
      hundred megahertz two-dimensional homonuclear 1H-nmr spectroscopy (nuclear
      Overhauser effect spectroscopy) was used for a qualitative determination of the
      structures of EB binding with the deoxytetranucleotides. Concentration
      dependencies of proton chemical shifts of the molecules have been measured at
      constant temperatures (T = 303 or 308 K). Different successive schemes of complex
      formation between the dye molecule and the tetranucleotides have been examined by
      taking into account various molecular associations in solution, viz., 1:1, 1:2,
      2:1 and 2:2 complexes. Equilibrium reaction constants and the limiting proton
      chemical shifts in the complexes have been determined. The relative contributions
      of different types of complexes in the equilibrium mixture have been determined
      and special features of the dynamic equilibrium have been revealed by analysis of
      chemical shifts as a function of both the dye and tetranucleotide concentrations.
      The present analysis leads to the conclusion that EB binds preferentially to the
      pyrimidine-purine sites of the tetranculeotide duplexes. The results show that
      the energy of EB binding depends on the base content in the pyrimidine-purine
      sites of the tetramers and on the nucleotide residuals flanking the preferential
      site. The most favorable structures of the 1:2 and 2:2 complexes of the dye with
      the tetranucleotides have been constructed using calculated values of induced
      chemical shifts of EB protons in conjunction with intermolecular nuclear
      Overhauser effects. The structures of the EB: tetranucleotide complexes depend on
      tetramer base sequence and are characterized by differences in helix parameters.

PMID- 8652796
TI  - Characterization of the bioactive form of linear peptide antagonists at the omega
      opioid receptor.
AB  - The stereochemical requirements for omega-opioid receptor binding of a series of
      linear peptide antagonists with a novel conformationally restricted Phe analogue
      (Tic) as a second residue were examined by using a variety of computational
      chemistry methods. The omega-opioid receptor analogues with significant affinity,
      Tyr-Tic-NH2(TI-NH2), Tyr-Tic-Phe-OH(TIP), Tyr-Tic-Phe-NH2(TIP-NH2), Tyr-Tic-Phe
      Phe-OH(TIPP), Tyr-Tic-Phe-Phe-NH2)(TIPP-NH2), and the low affinity omega-opioid
      peptides Tyr-Pro-Phe-Pro-NH2(morphiceptin) and Tyr-Phe-Phe-Phe-NH2 (TPPP-NH2),
      were included in this study. The conformational profiles of these peptides were
      obtained by consecutive cycles of high and low temperature molecular dynamic
      stimulations, coupled to molecular mechanical energy minimization carried out
      until no new conformational minima were obtained. Comparing the results for TPPP
      NH2 and TIPP-NH2, the presence of the conformationally restricted Tic residue did
      not greatly reduce the number of unique low energy conformations, but did allow
      low energy conformers involving cis bonds between the first two residues. The
      conformational libraries of these peptides were examined for their ability to
      satisfy the three key ligand components for receptor recognition already
      identified by previous studies of high affinity cyclic (Tyr1-D-Pen2-Gly3-Phe4-D
      Pen5) enkephalin (DPDPE) type agonists: a protonated amine group, an aromatic
      ring, and a lipophilic moiety in a specific geometric arrangement. Two types of
      conformations common to the five high omega-opioid affinity L-Tic analogues were
      found that satisfied these requirements, one with a cis and the other with a
      trans peptide bond between the Tyr1 and Tic2 residues. Moreover, both the Tic2
      and Phe3 residues could mimic the hydrophobic interactions with the receptor of
      the Phe4 moiety in the cyclic DPDPE type agonists, consistent with the
      appreciable affinity of both di- and tripeptides. The low omega-opioid receptor
      affinity of morphiceptin can be understood as the result of conformational
      preferences that prevent the fulfillment of this pharmacophore for recognition.

PMID- 8652797
TI  - RNA loop structure prediction via bond scaling and relaxation.
AB  - We have developed a method for predicting the structure of small RNA loops that
      can be used to augment already existing RNA modeling techniques. The method
      requires no input constraints on loop configuration other than end-to-end
      distance. Initial loop structures are generated by randomizing the torsion
      angles, beginning at one end of the polynucleotide chain and correlating each
      successive angle with the previous. The bond lengths of these structures are then
      scaled to fit within the known end constraints and the equilibrium bond lengths
      of the potential energy function are scaled accordingly. Through a series of
      rescaling and minimization steps the structures are allowed to relax to lower
      energy configurations with standard bond lengths and reduced van der Waals
      clashes. This algorithm has been tested on the variable loops of yeast tRNA-Asp
      and yeast tRNA-Phe, as well as the sarcin-ricin tetraloop and the anticodon loop
      of yeast tRNA-Phe. The results indicate good correlation between potential energy
      and the loop structure predictions that are closest to the variable loop crystal
      structures, but poorer correlation for the more isolated stem loops. The number
      of stacking interactions has proven to be a good objective measure of the best
      loop predictions. Selecting on the basis of energy and stacking, we obtain two
      structures with 0.65 and 0.75 A all-atom rms deviations (RMSD) from the crystal
      structure for the tRNA-Asp variable loop. The best structure prediction for the
      tRNA-Phe variable loop has an all-atom RMSD of 2.2 A and a backbone RMSD of 1.6
      A, with a single base responsible for most of the deviation. For the sarcin-ricin
      loop from 28S ribosomal RNA, the predicted structure's all-atom RMSD from the nmr
      structure is 1.0 A. We obtain a 1.8 A RMSD structure for the tRNA-Phe anticodon
      loop.

PMID- 8652798
TI  - Peptides and peptoids--a quantum chemical structure comparison.
AB  - Peptoids represent a very interesting structure alternative to peptides. Based on
      ab initio MO theory employing the 6-31G* and 3-21G basis sets and considering
      correlation energy, a systematic structure comparison between the basic structure
      units of peptoids and peptides is performed. The calculations show three minimum
      conformations denoted as C7 beta, alpha D, and alpha that do not correspond to
      conformers on the peptide potential energy hypersurface. The possibility of cis
      peptide bonds in the peptoids was examined. The solvent influence on the
      structure was estimated by means of various quantum chemical continuum models.

PMID- 8652799
TI  - The impact of estimation method and population adjustment on Canadian life table
      estimates.
AB  - Abridged life tables centred on 1991 were produced from the 1991 Canadian census,
      net census undercoverage estimates, and death data from 1990 to 1992. The
      sensitivity of life table values to differing methods of estimation and
      population estimates was investigated. The results from four methods by Greville,
      Chiang, and Keyfitz were compared, and population estimates, both adjusted and
      unadjusted for net census undercoverage, were used to test the effects of method
      and type of population estimates on life table values. The results indicate that
      the method used to derive the estimates had much less influence on the life table
      values than did the choice of population estimate. The change in life expectancy
      at birth due to the method of calculation chosen was at most 15 days, whereas the
      change due to the population estimate chosen was about 73 days. Since there are
      age, sex and provincial variations in net undercoverage rates, life expectancies
      differed accordingly.

PMID- 8652801
TI  - Older residents of health care institutions.

PMID- 8652800
TI  - Life expectancy of Canadians.

PMID- 8652802
TI  - Transition homes.

PMID- 8652803
TI  - The elimination of disease: a mixed blessing.
AB  - The increase in life expectancy that would result from the elimination of certain
      diseases and the resulting change in hospital utilization vary, depending on the
      disease. In some cases, life expectancy would rise and total days spent in
      hospital would decline, while in others, the gain in life expectancy would be
      accompanied by an increase in hospital days. For instance, if mental health
      disorders were eliminated, the increase in life expectancy at age 45 would be
      minimal: from 34.9 to 35.3 years, but time spent in hospital would decline from
      168 to 151 days. By contrast, if diseases of the circulatory system were
      eliminated, life expectancy at age 45 would rise from 34.9 to 41.6 years, but
      time spent in hospital would also rise: from 168 to 209 days. Elimination of not
      only mental illnesses but also injuries and poisoning and diseases of the nervous
      system has the potential of both increasing life expectancy and reducing hospital
      use.

PMID- 8652804
TI  - Flow cytometry: a clinical test of platelet function.

PMID- 8652805
TI  - Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) in primary effusion
      lymphoma: ultrastructural demonstration of herpesvirus in lymphoma cells.
AB  - Recent molecular evidence suggests an association with a new herpesvirus,
      Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), and primary effusion
      lymphomas (PELs). PELs have a characteristic morphology, phenotype, and clinical
      presentation, with malignant effusions in the absence of a contiguous solid tumor
      mass. We have established a cell line (KS-1) from a KSHV-positive human
      immunodeficiency virus (HIV)-negative patient with pleural cavity-based lymphoma
      that was passaged into triple-immunodeficient BNX mice. In contrast to cell lines
      from body cavity-based lymphomas derived from HIV-positive individuals that
      contain both KSHV and Epstein Barr viral genome, these cells contain only KSHV,
      allowing for uncontaminated virologic studies. Ultrastructural examination
      identified malignant cells with features of late differentiating B cells
      (immunoblasts). Cells with viral cytopathic effect contained typical 110-nm
      intranuclear herpesvirus nucleocapsids and complete cytoplasmic virions,
      confirming the association of PEL with KSHV.

PMID- 8652806
TI  - Preferential hematopoiesis by paroxysmal nocturnal hemoglobinuria clone engrafted
      in SCID mice.
AB  - In paroxysmal nocturnal hemoglobinuria (PNH), little is known about the molecular
      events leading to the clinical manifestations except for the hemolysis. To unfold
      the complex pathophysiology, it is necessary to elucidate the nature of the PNH
      clone. PNH exhibits an acquired stem cell disorder, a clonal expansion of
      affected cells, concomitant depression of normal hematopoiesis in bone marrow
      (BM), and, although infrequently, the development of leukemia. The PNH clone is
      thus expected to exhibit some neoplastic features. We report here that CD34+
      hematopoietic progenitor cells of PNH-BM yielded blood cells of three lineages
      with PNH phenotype alone when transplanted into sublethally irradiated severe
      combined immunedeficient mice. The hematopoiesis persisted for more than 10
      months and did not always need human cytokines. In contrast, the hematopoiesis by
      control grafts obtained from healthy volunteers required an intense cytokine
      treatment. This in vivo model defines the preferential hematopoiesis of
      pluripotent PNH progenitor cells, indicating the intrinsic growth abnormality of
      PNH clone.

PMID- 8652807
TI  - Inactivation of multiple tumor-suppressor genes involved in negative regulation
      of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in
      primary lymphoid malignancies.
AB  - It is now evident that the cell cycle machinery has a variety of elements
      negatively regulating cell cycle progression. However, among these negative
      regulators in cell cycle control, only 4 have been shown to be consistently
      involved in the development of human cancers as tumor suppressors: Rb
      (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin
      dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are
      functional interrelations among these negative regulators in the cell cycle
      machinery, it is particularly interesting to investigate the multiplicity of
      inactivations of these tumor suppressors in human cancers, including
      leukemias/lymphomas. To address this point, we examined inactivations of these
      four genes in primary lymphoid malignancies by Southern blot and polymerase chain
      reaction-single-strand conformation polymorphism analyses. We also analyzed Rb
      protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were
      homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively.
      Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens,
      respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all
      four tumor suppressors had one or more abnormalities of these four tumor
      suppressor genes, indicating that dysregulation of cell cycle control is
      important for tumor development. Statistical analysis of interrelations among
      impairments of these four genes indicated that inactivations of the individual
      tumor-suppressor genes might occur almost independently. In some patients,
      disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A,
      p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53
      inactivations; and 1 case with Rb and p53 inactivations. It is suggested that
      disruptions of multiple tumor suppressors in a tumor cell confer an additional
      growth advantage on the tumor.

PMID- 8652808
TI  - Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus
      infected persons: differential in vitro preventive effect of cytokines and
      protease antagonists.
AB  - Human immunodeficiency syndrome (HIV) infection leads to a progressive loss of T
      cell-mediated immunity associated with T-cell apoptosis. We report here that CD4+
      and CD8+ T cells from HIV-1-infected persons are sensitive to Fas (CD95/APO-1)
      mediated death induced either by an agonistic anti-Fas antibody or by the
      physiologic soluble Fas ligand, although showing no sensitivity to tumor necrosis
      factor alpha-induced death. CD4+ and CD8+ T-cell apoptosis induced by Fas
      ligation was enhanced by inhibitors of protein synthesis and was prevented either
      by a soluble Fas receptor decoy or an antagonistic anti-Fas antibody. Fas
      mediated apoptosis could also be prevented in a CD4+ or CD8+ T-cell-type manner
      (1) by several protease antagonists, suggesting the involvement of the
      interleukin-1beta (IL-1beta)-converting enzyme (ICE)-related cysteine protease in
      CD4+ T-cell death and of both a CPP32-related cysteine protease and a calpain
      protease in CD8+ T-cell death; and (2) by three cytokines, IL-2, IL-12, and IL
      10, that exerted their effects through a mechanism that required de novo protein
      synthesis. Finally, T-cell receptor (TCR)-induced apoptosis of CD4+ T cells from
      HIV-infected persons involved a Fas-mediated death process, whereas TCR
      stimulation of CD8+ T cells led to a different Fas-independent death process.
      These findings suggest that Fas-mediated T-cell death is involved in acquired
      immunodeficiency syndrome (AIDS) pathogenesis and that modulation of Fas-mediated
      signaling may represent a target for new therapeutic strategies aimed at the
      prevention of CD4+ T-cell death in AIDS.

PMID- 8652809
TI  - An autosomal dominant, qualitative platelet disorder associated with multimerin
      deficiency, abnormalities in platelet factor V, thrombospondin, von Willebrand
      factor, and fibrinogen and an epinephrine aggregation defect.
AB  - Multimerin is a massive soluble, multimeric protein found in platelets and
      endothelial cells. Recent studies identified multimerin as a specific coagulation
      factor V binding protein, complexed with platelet, but not plasma, factor V.
      These findings led us to investigate individuals with inherited factor V
      deficiencies for possible multimerin abnormalities. Platelet proteins were
      evaluated using immunoassays, sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis, immunoblotting, immunoprecipitation, and direct binding studies.
      Patients with factor V Quebec, a disorder with abnormal platelet factor V, had a
      quantitative deficiency in multimerin (n = 11 tested; mean, 12.5%; range, 5% to
      27% of the normal pool; normal range, 45% to 214%) with a normal multimer
      pattern. Quantitative and qualitative abnormalities were detected in their
      platelet factor V. An unrelated patient who was deficient in platelet and plasma
      factor V had normal platelet multimerin. The levels of platelet beta
      thromboglobulin, von Willebrand factor, thrombospondin, and fibrinogen antigen
      were normal in the factor V Quebec patients. However, proteins with abnormal
      mobility were detected in their platelet lysate and releasate, and their platelet
      thrombospondin, von Willebrand factor, and fibrinogen showed evidence of
      proteolytic degradation. Platelet counts of the factor V Quebec patients ranged
      from mildly thrombocytopenic to low normal (mean, 159 x 10(9)/L; range, 104 to
      198 x 10(9)/L). In addition, their platelets failed to aggregate in response to 6
      to 10 micromol/L epinephrine despite normal numbers of platelet alpha 2
      adrenergic receptors. These data indicate that patients with factor V Quebec have
      an inherited bleeding disorder distinct from other platelet disorders and
      associated with multiple abnormalities, including multimerin deficiency, abnormal
      platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen, and an
      epinephrine aggregation defect.

PMID- 8652810
TI  - Timed-sequential induction therapy improves postremission outcome in acute
      myeloid leukemia: a report from the Children's Cancer Group.
AB  - Timed sequencing of cycles of induction chemotherapy in acute myeloid leukemia
      (AML) has been proposed as a way to achieve maximal leukemic cell kill through
      recruitment and synchronization of residual neoplastic cells. Furthermore,
      whether intensive induction therapy should be continued in the presence of
      profound myelosuppression is an important question. The Children's Cancer Group
      (CCG) conducted a prospective randomized trial in which 589 patients with AML
      were randomized at diagnosis to one of two induction approaches involving a 4-day
      cycle of five active chemotherapeutic agents, with the second cycle administered
      either 10 days after the first cycle, despite low or dropping blood counts
      (intensive timing), or 14 days or later from the beginning of the first cycle,
      depending on bone marrow status (standard timing). All patients achieving
      remission received a total of four cycles of induction therapy. They were then
      allocated to allogeneic bone marrow transplantation (BMT) if a compatible family
      donor was present or randomized to aggressive nonmyeloablative therapy or to
      myeloablative therapy with purged autologous BMT rescue. The three postremission
      arms remain coded. Induction success and median days to complete induction were
      similar for the 295 patients randomized to the intensive timing arm (75%, 99
      days) compared with the 294 patients randomized to the standard timing arm (70%,
      105 days; P = .18 for remission). However, a marked improvement in outcome was
      demonstrated in patients randomized to the intensive timing arm, with an
      actuarial event-free survival at 3 years of 42% +/- 7% (95% confidence interval
      [CI]) versus 27% +/- 6% for patients on the standard timing arm (P = .0005).
      Disease-free survival results at 3 years from the end of induction were superior
      for patients receiving intensively timed induction therapy (N = 211), 55% +/- 9%
      versus 37% +/- 9% for standard timing patients (N = 195, P = .0002), with a
      median follow-up from achieving remission of 28 months. Superior results were
      documented for patients receiving intensive timing irrespective of the
      postremission therapy to which they were allocated. Intensively timed induction
      therapy for patients with AML markedly improves event-free survival, even for
      patients undergoing myeloablative therapy with BMT rescue. Without controlling
      for the type of induction therapy received, results of various BMT studies in AML
      comparing different preparative regimens will be difficult to interpret.

PMID- 8652811
TI  - National Cancer Institute-sponsored Working Group guidelines for chronic
      lymphocytic leukemia: revised guidelines for diagnosis and treatment.

PMID- 8652812
TI  - The effect of thrombopoietin on the proliferation and differentiation of murine
      hematopoietic stem cells.
AB  - In this study, we explored whether thrombopoietin (Tpo) has a direct in vitro
      effect on the proliferation and differentiation of long-term repopulating
      hematopoietic stem cells (LTR-HSC). We previously reported a cell separation
      method that uses the fluorescence-activated cell sorter selection of low Hoescht
      33342/low Rhodamine 123 (low Ho/low Rh) fluorescence cell fractions that are
      highly enriched for LTR-HSC and can reconstitute lethally irradiated recipients
      with fewer than 20 cells. Low Ho/low Rh cells clone with high proliferative
      potential in vitro in the presence of stem cell factor (SCF) + interleukin-3 (IL
      3) + IL-6 (90% to 100% HPP-CFC). Tpo alone did not induce proliferation of these
      low Ho/low Rh cells. However, in combination with SCF or IL-3, Tpo had several
      synergistic effects on cell proliferation. When Tpo was added to single growth
      factors (either SCF or IL-3 or the combination of both), the time required for
      the first cell division of low Ho/low Rh cells was significantly shortened and
      their cloning efficiency increased substantially. Moreover, the subsequent clonal
      expansion at the early time points of culture was significantly augmented by Tpo.
      Low Ho/low Rh cells, when assayed in agar directly after sorting, did not form
      megakaryocyte colonies in any growth condition tested. Several days of culture in
      the presence of multiple cytokines were required to obtain colony-forming units
      megakaryocyte (CFU-Mk). In contrast, more differentiated, low Ho/high Rh cells,
      previously shown to contain short-term repopulating hematopoietic stem cells (STR
      HSC), were able to form megakaryocyte colonies in agar when cultured in Tpo alone
      directly after sorting. These data establish that Tpo acts directly on primitive
      hematopoietic stem cells selected using the Ho/Rh method, but this effect is
      dependent on the presence of pluripotent cytokines. These cells subsequently
      differentiate into CFU-Mk, which are capable of responding to Tpo alone. Together
      with the results of previous reports of its effects on erythroid progenitors,
      these results suggest that the effects of Tpo on hematopoiesis are greater than
      initially anticipated.

PMID- 8652813
TI  - Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in
      mice.
AB  - PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase
      in megakaryocytes and platelets. At the same time that platelet numbers are
      increased, the mean platelet volume (MPV) and platelet distribution width (PDW)
      can be either decreased, normal, or increased depending on the dose and time
      after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and
      PDW, MGDF at an intermediate dose causes an initial increase followed by a
      decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in
      MPV and PDW followed by a gradual normalization of these platelet indices. In
      addition to the expected thrombocytosis after 7 to 10 days of daily injection of
      high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell
      numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic
      hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and
      deposition of a fine network of reticulin fibers. Splenomegaly, an increase in
      splenic megakaryocytes, and extramedullary hematopoiesis accompany the
      hematologic changes in the peripheral blood and marrow to complete a spectrum of
      pathologic features similar to those reported in patients with myelofibrosis and
      megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology
      including the increase in marrow reticulin is completely and rapidly reversible
      upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic
      proliferation of megakaryocytes does not cause irreversible tissue injury.
      Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced
      thrombocytopenia at a low-dose that does not cause the hematopathology associated
      with myelofibrosis.

PMID- 8652814
TI  - Ability of flt3 ligand to stimulate the in vitro growth of primitive murine
      hematopoietic progenitors is potently and directly inhibited by transforming
      growth factor-beta and tumor necrosis factor-alpha.
AB  - The recently cloned flt3 ligand (FL) stimulates the growth of primitive
      hematopoietic progenitor cells through synergistic interactions with multiple
      other cytokines. The present study is the first demonstrating cytokines capable
      of inhibiting FL-stimulated hematopoietic cell growth. Tumor necrosis factor
      alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta l) potently
      inhibited the clonal growth of murine Lin-Sca-l+ bone marrow progenitors
      stimulated by FL alone or in combination with granulocyte colony-stimulating
      factor (G-CSF), stem cell factor (SCF), interleukin (IL)-3, IL-6, IL-11, or IL
      12. TGF-beta 1 inhibited more than 96% of the myeloid colony formation in
      response to these cytokine combinations, whereas TNF-alpha reduced the number of
      colonies by 58% to 96% depending on the cytokine by which FL was combined. In
      addition, both TNF-alpha and TGF-beta 1 inhibited more than 90% of B220+ cell
      production from B220- bone marrow cells stimulated by FL + IL-7. The effects of
      TNF-alpha and TGF-beta 1 appeared to be due to a direct effect and on the early
      progenitors because the inhibition was observed at the single cell level, and
      because delayed addition of the two inhibitors for only 48 hours dramatically
      reduced their inhibitory effects. A neutralizing anti-TGF-beta antibody showed
      the presence of endogenous TGF-beta in the cultures and potently enhanced the
      ability of FL to stimulate progenitor cell growth in the absence of other
      cytokines. Agonistic antibodies specifically activating the p75 TNF receptors
      were more efficient than wild type murine TNF-alpha in signaling growth
      inhibition of Lin-Sca-l+ progenitor cells, whereas the p55 agonist had less
      effect than murine TNF-alpha. Finally, TGF-beta increased the number of FL + IL
      11-stimulated Lin-Sca-1+ cells in the G1 phase of the cell cycle with 76%,
      whereas TNF-alpha only had a marginal effect on cell cycle distribution. Thus,
      TGF-beta, TNF-alpha, and p75 TNF receptor agonists are potent direct inhibitors
      of FL-stimulated progenitor cell growth in vitro.

PMID- 8652815
TI  - Morphogenesis of the bone marrow: fractal structures and diffusion-limited
      growth.
AB  - Bone marrow (BM) provides a particular spatial organization that allows
      interaction between its various components. Characterization of the spatial
      patterns in the BM and understanding the mechanisms that give rise to them may
      play a role in better understanding of the BM pathologic processes. Morphometric
      analyses were performed in BM biopsy samples from 30 patients (16 men and 14
      women) with an average age of 46 years, ranging from 17 to 77 years. The biopsies
      were obtained during the course of patient care to rule out BM involvement in a
      variety of hematologic disorders before or after therapy. Three different, but
      structurally interrelated, parameters were measured: (A) cellular area, (B)
      nuclear area, and (C) cell numbers. All three methods, in all cases, showed that
      the spatial structure of the BM is fractal. The average values of the fractal
      dimensions (Df) were 1.7 +/- 0.08, 1.64 +/- 0.1, and 1.69 +/- 0.04 for categories
      A, B, and C, respectively. The overall value of Df for the cellularity in the
      range of 40% to 60% was about 1.67 +/- 0.09. Fractal dimensions of 1.6 to 1.7
      represent configurations that correspond to two-dimensional diffusion limited
      aggregation structures, suggesting that the structural configuration of
      hematopoietic cells is dependent on the diffusion of regulatory cytokines in the
      BM.

PMID- 8652816
TI  - Gene transfer into human bone marrow hematopoietic cells mediated by adenovirus
      vectors.
AB  - Human bone marrow mononuclear cells (BMMNCs) and enriched CD34 positive (CD34+)
      cells were transduced with adenovirus vectors encoding Escherichia coli beta
      galactosidase gene. Tranductions were carried out by 24-hour coincubation with
      adenovirus vectors at different multiplicities of infections (moi). Efficacy of
      gene transfer into BM cells and expression of the gene product (ie, beta
      galactosidase) were studied using X-Gal histochemical staining and flow
      cytometric analysis. X-Gal staining demonstrated that the percentage of positive
      cells at mois of 5 to 500 was 3.4% to 34.5% for BMMNCs and 6.0% to 20.0% for
      enriched CD34+ cells. Similar results (1.5% to 35.7% for BMMNCs and 5.4% to 24.2%
      for enriched CD34+ cells) were obtained with flow cytometric analysis using
      fluorescein di-beta-D-galactopyranoside (FDG). Multicolor flow cytometry
      analysis, which included FDG, demonstrated that BM progenitors (CD34+ or
      CD34+CD38-), T cells (CD2+), B cells (CD19+), natural killer cells (CD56+),
      granulocytes, and monocytes all expressed the adenovirus transgene. To ascertain
      the effects of adenovirus vectors on normal BM progenitors, the numbers of colony
      forming unit-granulocyte/macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU
      E), and high-proliferative potential-colony-forming cells (HPP-CFC) after 24-hour
      coincubation with adenovirus vectors were determined. When BMMNCs or enriched
      CD34+ cells were incubated with adenovirus vectors at mois of 5 and 50, no
      significant differences in the numbers of CFU-GM, BFU-E, and HPP-CFC were
      observed compared with the uninfected control cells. However, the numbers of CFU
      GM were significantly (P < .01) decreased when BMMNCs or enriched CD34+ cells
      were incubated with adenovirus vectors at a moi of 500, compared with the
      uninfected control cells. The adenovirus infected cells, purified by cell sorting
      for FDG expression, were capable of growing in culture and gave rise to various
      colonies (ie, CFU-GM, BFU-E, and HPP-CFC). These data indicate that recombinant
      adenovirus vectors can be used to transfer genes to human BM hematopoietic cells
      with expression of the exogenous gene at a high transduction efficiency.

PMID- 8652817
TI  - Continuous activation and deactivation of integrin CD11b/CD18 during de novo
      expression enables rolling neutrophils to immobilize on platelets.
AB  - In an in vitro flow model, unstimulated neutrophils rolled steadily over a
      surface coated with platelets, until superfusion of the chemotactic peptide
      formyl-methionyl-leucyl-phenylalanine (fMLP) caused a dose-dependent (10(-11) to
      10(-7) mol/L) transition from rolling to stationary attachment in seconds,
      followed more slowly by neutrophil shape change and spreading on the surface,
      However, at low concentrations of Ca2+ and Mg2+ (0.1 mmol/L and 0.05 mmol/L,
      respectively, rather than physiologic 1 mmol/L and 0.5 mmol/L), neutrophils first
      halted but then started to roll again and to detach from the surface over 5 to 10
      minutes. At the low cation concentration, stopping was largely inhibited by
      antibodies to the neutrophil integrins CD18 or CD11b, but not CD11a. When
      neutrophils were pretreated with antibodies to CD11b or CD18 in 1 mmol/L Ca2+ 0.5
      mmol/L Mg2+, stopping was not prevented but delayed. However, if antibodies were
      also included with the superfused fMLP, stopping was inhibited, and detachment
      followed. This indicates that CD11b/CD18 was newly expressed during shape change
      and mediated the second phase of neutrophil immobilization and spreading in a
      cation-dependent manner. Prestimulated neutrophils also bound to platelets and
      spread, but immobilization was blocked if they were perfused with antibody to
      CD18 or CD11b or with low Ca2+ and Mg2+. Examining the cation-dependence further,
      it was evident that the presence of Mg2+ was essential for integrin-mediated
      adhesion and that the Mg2+ concentration determined whether immobilization could
      be maintained or was transient. Continuous superfusion of fMLP was also essential
      for maintenance of stable adhesion and spreading. Thus, activation of
      constitutive CD11b/CD18 rapidly and reversibly converted rolling to stationary
      attachment, whereas maintenance of adhesion and neutrophil spreading required
      continual expression of additional CD11b/CD18 that was only functional at
      physiologic Mg2+. Continual activation and deactivation of CD11b/CD18 during de
      novo expression could mediate immobilization and onward migration of neutrophils
      in vivo, and activated platelets appear capable of supporting this process as
      well as endothelial cells.

PMID- 8652818
TI  - The proinflammatory cytokine response to coagulation and endotoxin in whole
      blood.
AB  - Acute inflammatory illnesses, including the sepsis syndrome, often include a
      component of coagulation. A human whole blood culture system was developed so
      that the relationship between coagulation activation and cytokine responses in
      the presence or absence of lipopolysaccharide (LPS) could be evaluated. In the
      absence of LPS stimulation, coagulation activation resulted in a novel pattern of
      cytokine production. During a 4-hour culture of coagulating blood, significant
      production of interleukin-8 (IL-8; >2,000 pg/mL) was observed, whereas other
      proinflammatory cytokines including IL-1 beta, IL-6, or tumor necrosis factor a
      were undetectable or less than 35 pg/mL. The cytokine profile was distinct from
      that of fully anticoagulated, LPS-stimulated blood, which showed levels of all
      the indicated proinflammatory cytokines > or = 2,000 pg/mL over the same time
      period. Over 24 to 48 hours, the coagulation-induced cytokine response was
      characterized by marked and sustained IL-8 production, limited IL-6 generation
      (with kinetics delayed relative to IL-8), and minimal or undetectable tumor
      necrosis factor alpha levels. The magnitude of the whole blood IL-8 response
      correlated with the level of coagulation activation as determined by measurement
      of thrombin-antithrombin III complex formation. The combined stimuli of
      coagulation activation and LPS challenge induced a synergistic enhancement of IL
      8 production but not of IL-6. Coagulation-induced cytokine production and the
      synergistic production of IL-8 by coagulation and LPS could be attenuated by
      hirudin or tissue factor pathway inhibitor (TFPI). Studies to elucidate
      mechanisms implicated (1) the TFPI third Kunitz and carboxy-terminus as important
      structural components for TFPI regulation of coagulation activation and (2)
      thrombin as a candidate mediator of the mononuclear cell cytokine response to
      coagulation activation. In summary, a unique aspect of the crosstalk between the
      coagulation and cytokine cascades in whole blood is shown with the identification
      of IL-8 as a key proinflammatory participant.

PMID- 8652819
TI  - Differential mechanisms targeting type 1 plasminogen activator inhibitor and
      vitronectin into the storage granules of a human megakaryocytic cell line.
AB  - Type 1 plasminogen activator inhibitor (PAI-1) and its cofactor vitronectin (Vn)
      are stored within the alpha-granules of platelets. The two possible sources for
      their biosynthetic origin are endogenous synthesis in megakaryocytes or
      endocytosis from plasma. Using ultrastructural and confocal laser scanning
      microscopic (CLSM) image analysis, we observed that treatment of Dami cells, a
      human megakaryocytic cell line, with phorbol myristate acetate (PMA) induces the
      accumulation of PAI-1 and Vn in intracellular storage vacuoles that contain other
      alpha-granule proteins such as von Willebrand factor. To examine evidence for
      biosynthesis of PAI-1 and Vn by Dami cells, we immunoprecipitated PAI-1 and Vn
      from the conditioned media of cells biosynthetically radiolabeled with 35S
      methionine in the presence or absence of PMA. In contrast to Hep G2 cells, which
      synthesize both PAI-1 and Vn, only 35S-PAI-1 was recovered from PMA-treated Dami
      cells. Reverse transcription-PCR analysis of RNA extracted from resting and PMA
      treated Dami cells confirmed that PAI-1 mRNA expression was detectable at low
      levels in resting cells and induced by PMA treatment. In contrast, Vn mRNA was
      not detected. We examined binding and internalization (endocytosis) of PAI-1 and
      Vn by Dami cells using biotinylated analogs (b-PAI-1 and b-Vn). Flow cytometry
      analysis indicated that the binding of b-Vn to Dami cells was dose-dependent,
      saturable, and specific for multimeric forms of Vn. Cells were incubated at 4
      degrees C or 37 degrees C and endocytosis of b-Vn was shown by probing
      electrophoretically fractionated cell lysates with 125I-labeled streptavidin.
      Only cells incubated at 37 degrees C internalized b-Vn. CLSM image analysis
      confirmed that the b-Vn was internalized and that it colocalized with PAI-1 in
      storage granules. The binding of b-Vn to cells was inhibited by the presence of
      PAI-1, and there was no evidence of specific b-PAI-1 binding or uptake to resting
      or PMA-treated cells. These data suggest that accumulation of PAI-1 in Dami cell
      storage granules is due to endogenous synthesis and that the accumulation of Vn
      is due to endocytosis of serum-derived Vn.

PMID- 8652820
TI  - Regulation of human heme oxygenase-1 gene expression under thermal stress.
AB  - Heme oxygenase-1 is an essential enzyme in heme catabolism, and its human gene
      promoter contains a putative heat shock element (HHO-HSE). This study was
      designed to analyze the regulation of human heme oxygenase-1 gene expression
      under thermal stress. The amounts of heme oxygenase-1 protein were not increased
      by heat shock (incubation at 42 degrees C) in human alveolar macrophages and in a
      human erythroblastic cell line, YN-1-0-A, whereas heat shock protein 70 (HSP70)
      was noticeably induced. However, heat shock factor does bind in vitro to HHO-HSE
      and the synthetic HHO-HSE by itself is sufficient to confer the increase in the
      transient expression of a reporter gene upon heat shock. The deletion of the
      sequence, located downstream from HHO-HSE, resulted in the activation of a
      reporter gene by heat shock. These results suggest that HHO-HSE is potentially
      functional but is repressed in vivo. Interestingly, heat shock abolished the
      remarkable increase in the levels of heme oxygenase-1 mRNA in YN-1-0-A cells
      treated with hemin or cadmium, in which HSP70 mRNA was noticeably induced.
      Furthermore, transient expression assays showed that heat shock inhibits the
      cadmium-mediated activation of the heme oxygenase-1 promoter, whereas the HSP70
      gene promoter was activated upon heat shock. Such regulation of heme oxygenase-1
      under thermal stress may be of physiologic significance in erythroid cells.

PMID- 8652821
TI  - A Thr359Met mutation in factor VII of a patient with a hereditary deficiency
      causes defective secretion of the molecule.
AB  - We elucidated the genetic basis responsible for factor VII deficiency in an
      Italian woman with a severe bleeding diathesis. In the allele inherited from the
      patient's father, we identified a G to A mutation at nucleotide 6070 at the 5'
      splice site of intron 4 and a G to A substitution at nucleotide 10976 resulting
      in the Arg353Gln polymorphism. The maternal allele demonstrated a C to T
      substitution at nucleotide 10994 resulting in Thr359Met. The mutation at
      nucleotide 6070 alters an invariant GT dinucleotide and disrupts normal mRNA
      processing. To investigate the mechanism by which Thr359Met reduces factor VIl
      levels, we expressed wild type factor VII cDNA (FVIIwt) and a mutant factor VII
      cDNA containing the base substitution resulting in Met359 (FVII359M) in Chinese
      hamster ovary cells (CHO). In cells transfected with the mutant factor VII cDNA,
      FVII359M accumulated intracellularly, and no factor VII was detected in the media
      after 3 hours of chase. The carbohydrate side chains associated with FVII359M
      were sensitive to Endo H digestion, which indicates that the protein is retained
      in the endoplasmic reticulum. Analysis of cell lysates also showed that FVII359M
      was associated with the 78 kD protein corresponding to GRP78/BiP. We conclude
      that a Thr359Met mutation in factor VII results in a severe secretion defect that
      probably results from abnormal folding of the molecule.

PMID- 8652822
TI  - Delivery of human factor IX in mice by encapsulated recombinant myoblasts: a
      novel approach towards allogeneic gene therapy of hemophilia B.
AB  - A potentially cost-effective strategy for gene therapy of hemophilia B is to
      create universal factor IX-secreting cell lines suitable for implantation into
      different patients. To avoid graft rejection, the implanted cells are enclosed in
      alginate-polylysine-alginate microcapsules that are permeable to factor IX
      diffusion, but impermeable to the hosts' immune mediators. This nonautologous
      approach was assessed by implanting encapsulated mouse myoblasts secreting human
      factor IX into allogeneic mice. Human factor IX was detected in the mouse plasma
      for up to 14 days maximally at approximately 4 ng/mL. Antibodies to human factor
      IX were detected after 3 weeks at escalating levels, which were sustained
      throughout the entire experiment (213 days). The antibodies accelerated the
      clearance of human factor IX from the circulation of the implanted mice and
      inhibited the detection of human factor IX in the mice plasma in vitro. The
      encapsulated myoblasts retrieved periodically from the implanted mice up to 213
      days postimplantation were viable and continued to secrete human factor IX ex
      vivo at undiminished rates, hence suggesting continued factor IX gene expression
      in vivo. Thus, this allogeneic gene therapy strategy represents a potentially
      feasible alternative to autologous approaches for the treatment of hemophilia B.

PMID- 8652823
TI  - Predominant HLA-class II bound self-peptides of a hematopoietic progenitor cell
      line are derived from intracellular proteins.
AB  - Human myeloid progenitor cells temporarily express HLA class II molecules during
      the differentiation pathway to granulocytes and macrophages. The significance of
      major histocompatibility complex (MHC) class II molecules at this stage of
      development is unknown. As a first stop of inquiry into their function, we have
      characterized the profile of major self-peptides bound to the HLA-DR molecules
      expressed by KG-1 cells, a line that shares many of the phenotypic
      characteristics of colony-forming unit-granulocyte-macrophage progenitors.
      Searches of protein data bases showed that all matching peptides bound to the HLA
      DR molecules of KG-1 cells corresponded to intracellular, rather than exogenous
      or transmembrane, precursor proteins. Because the absence of a conventional self
      peptide repertoire could be related to altered trafficking of class II molecules,
      the biosynthesis of HLA-DR and the invariant chain proteins was determined. The
      MHC class II associated invariant chain protein is synthesized normally in KG-1
      cells, but processed fragments of invariant chain, class II-associated invariant
      chain peptides (CLIPs), occupy the antigen-binding groove of KG-1 class II
      molecules at a much lower frequency compared with that of mature antigen
      presenting cells. Low CLIP occupancy of HLA-DR is a characteristic shared by KG-1
      cells, normal CD34+ progenitor cells, and HLA-DR+ breast carcinoma cells. The
      unusual profile of MHC class II bound peptides and the low level of CLIP bound to
      HLA-DR suggest that the antigen-processing pathway of KG-1 is different from that
      characterized in professional antigen-presenting cells and that exogenous antigen
      processing may be a developmentally acquired characteristic in the myeloid
      lineage.

PMID- 8652824
TI  - Ecto-sialyltransferase of human B lymphocytes reconstitutes differentiation
      markers in the presence of exogenous CMP-N-acetyl neuraminic acid.
AB  - The existence of an ecto-sialyltransferase (ecto-ST) on B lymphocytes with
      increasing activity at late maturation stages is shown using a novel flow
      cytometric enzyme assay. This ecto-ST is effective in reconstituting different
      surface glycoconjugates on desialylated B cells in the presence of exogenous CMP
      NeuAc. We found that this ecto-ST is distinct in its activity from soluble ST
      released into the culture supernatant. Surface sialylation was independent of the
      amount of ST secreted into the culture supernatant and followed different
      kinetics than sialylation of exogenous substrate by soluble ST. Four human B-cell
      lines representing different maturation stages were analyzed for secreted and
      ecto-ST activity. The myeloma cell line U266 and the lymphoblastoid cell line JOK
      1 showed higher activity of both ST forms than the acute lymphoblastic leukemia B
      cell line Nalm-6. ST activity in culture supernatants of U266, JOK-1, and Nalm-6
      cells consisted predominantly of the alpha 2,6 ST type with specificity for N
      linked oligosaccharides. As an exception, the myeloma cell line IM-9, deficient
      of alpha 2,6 ST activity, secreted only small amounts of ST and showed low
      activity of ecto-ST. Sialylation of surface-expressed glycoconjugates by ecto-ST
      was measured by incubating B-cell lines in the presence of fluorescent CMP-sialic
      acid. Surface structures labeled with fluorescent sialic acid under this
      condition were visualized by confocal laser scanning microscopy and fluorescent
      label was quantitatively assessed by flow cytometric analysis on live cells.
      Incubation of cells in acidified culture medium, to release possibly receptor
      bound ST, did not alter the intensity of cell surface sialylation. Inhibition of
      internalization and membrane traffic by various approaches (reduced incubation
      temperature and chloroquine or brefeldin A treatment) did not block surface
      sialylation. Together, these observations point to cell surface sialylation in B
      lymphocytes mediated by a cell surface-expressed ecto-ST distinct from the
      secreted ST form. On desialylated JOK-1 cells, ecto-ST in the presence of
      exogenous CMP-NeuAc was able to resialylate the B-cell surface sialoglycans CDw75
      and HB-6 and major surface glycoproteins of B cells, such as HLA class I and II
      antigens, transferrin receptor, and surface IgM. In contrast, cell surface
      glycans of coincubated desialylated erythrocytes were not sialylated by the B
      cell ecto-ST. Ecto-alpha 2,6 ST of B cells may be involved in the sialylation of
      distinct differentiation glycan antigens.

PMID- 8652825
TI  - Target cell-induced apoptosis of interleukin-2-activated human natural killer
      cells: roles of cell surface molecules and intracellular events.
AB  - We previously reported that natural killer (NK)-sensitive target cells, K562,
      kill interleukin-2-stimulated (lymphokine-activated killer [LAK]) but not
      unstimulated NK cells. We have now investigated the molecular basis of this
      phenomenon. Soluble monoclonal antibody (MoAb) to CD18 inhibited 75% of K562
      induced DNA fragmentation and membrane disruption, whereas blocking MoAb to Fas
      partially inhibited only the DNA fragmentation. MoAbs to CD2, CD11a, CD11b, B7,
      or CD16 had limited or no effect on K562-induced death of LAK cells. Receptor
      ligation with either immobilized MoAb to CD18 or Fas induced membrane disruption
      and DNA degradation in LAK cells independently of K562, and MoAb to CD18, CD11a,
      or CD11b enhanced DNA fragmentation induced by anti-Fas. Fas-L-transfected Raji
      cells also killed LAK cells, but only if Fas-L expression was amplified. K562
      cells rapidly triggered protein phosphorylation in LAK cells, and the tyrosine
      kinase inhibitor, Herbimycin A, inhibited DNA fragmentation and membrane
      disruption. Protease inhibitors strongly suppressed K562-mediated DNA
      fragmentation of LAK cells, but not membrane disruption. In conclusion, (1) K562
      induced death of LAK cells involves primarily CD18, although other molecules,
      such as Fas, may also be involved; (2) K562-mediated apoptosis of LAK cells
      requires tyrosine phosphorylation and protease activity; (3) engagement of Fas by
      immobilized MoAb or Fas-L on target cells can also kill LAK cells; and (4) Fas
      immobilized MoAb synergizes with coimmobilized MoAb to CD11a, CD11b, or CD18 for
      LAK cell killing. Activation-induced death of NK cells may represent a mechanism
      for NK cell regulation.

PMID- 8652826
TI  - Involvement of nitric oxide in target-cell lysis and DNA fragmentation induced by
      murine natural killer cells.
AB  - Although it has been recognized for sometime that target cells destroyed by
      natural killer (NK) cells die largely by apoptosis, the underlying mechanisms are
      not fully understood. The aim of the present study was to examine the role of
      nitric oxide (NO) in mediating murine NK-cell-induced killing of YAC-1 lymphoma
      cells. NK calls induced extensive release of 125I-DNA and 51Cr from YAC-1 cells.
      The target killing ability of NK cells was associated with an increased
      production of NO as measured by concentrations of nitrite in the culture medium.
      That YAC-1 killing resulted, in part, from the production of NO was confirmed by
      the significant protection of cell lysis in L-arginine-depleted medium and by
      approximately 30 % attenuation of cell lysis and DNA fragmentation by an
      inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME) in a culture
      medium containing 1 mmol/L L-arginine. Fluorescence microscopic examination of
      YAC-1 cells showed the presence of changes in nuclear morphology characteristic
      for apoptosis. The percentage of apoptotic cells was markedly decreased by L
      NAME. Further evidence for apoptosis is provided by the specific pattern of
      internucleosomal DNA fragmentation both in the absence and presence of L-NAME.
      During target-cell killing, an increased oxidation of intracellularly trapped
      dichlorofluorescein was observed in cells labeled with an antimouse NK-cell
      monoclonal antibody, as measured by flow cytometry. These increases were
      effectively prevented by L-NAME, but not W-13, an inhibitor of calmodulin. The
      ability of NO to induce cell lysis and DNA fragmentation in YAC-1 cells was
      further demonstrated by exposing tumor cells to chemically generated NO. Taken
      together, these observations suggest a role for NO as one of the mediators of NK
      cell-mediated DNA fragmentation and cell lysis.

PMID- 8652827
TI  - Release of interleukin-12 in experimental Escherichia coli septic shock in
      baboons: relation to plasma levels of interleukin-10 and interferon-gamma.
AB  - Interleukin (IL)-12 is thought to be a key factor for the induction of interferon
      gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We
      report here on the release of the nonfunctional subunit of IL-12, p40, as well as
      biologically active heterodimeric IL-12, p70, after administration of a lethal (n
      = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably,
      on lethal challenge, peak levels of p40 were observed at 3 hours that were about
      twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL
      v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a
      lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL
      and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E
      coli, respectively. Circulating p70 antigen correlated with IL-12 biologic
      activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions,
      lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels
      of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL
      1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in
      the lethal group may have resulted in part from the enhanced production of IL-10,
      a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3
      hours postchallenge inversely correlated with peak levels of IL-12, in particular
      p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were
      solely induced by IL-12, lethally challenged baboons generated threefold more IFN
      gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover,
      higher levels of IFN-gamma were associated with lower p40/p70 ratios, suggesting
      that, in agreement with observations in vitro, IFN-gamma may have preferentially
      upregulated the release of p70 over p40. These data show that IL-12 is released
      in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN
      gamma are involved in the regulation of this release. Furthermore, this study
      indicates that the systemic release of IL-12 might be essential, but is not
      likely sufficient, to promote lethal production of IFN-gamma in sepsis.

PMID- 8652828
TI  - Vasoactive intestinal peptide and pituitary adenylate cyclase-activating
      polypeptides (PACAP27) and PACAP38) protect CD4+CD8+ thymocytes from
      glucocorticoid-induced apoptosis.
AB  - In the present study, the effects of vasoactive intestinal peptide (VIP) and the
      pituitary adenylate cyclase-activating polypeptides, PACAP27 and PACAP38, in a
      concentration range from 10(-13) to 10(-6) mol/L were studied in vitro on the
      spontaneous and dexamethasone (DEX)-induced apoptosis in rat thymocytes. The
      results show that VIP and both PACAPs inhibit significantly and in a similar way
      the DNA fragmentation characteristic of glucocorticoid-induced apoptosis and
      increase the cell survival of thymocytes, with a maximal effect observed at 10(
      8) to 10(-9) mol/L. This study showed the ability of the VIP-receptor (VIP-R)
      antagonist [N-Ac-Tyr1,D-Phe2]-GRF(1-29) amide to partially reverse the inhibitory
      effect of VIP and both PACAPs on DEX-induced apoptosis, providing evidence for a
      specific VIP1-R-mediated response and supporting the involvement of a single
      receptor for the three neuropeptides. Phenotypic analysis showed that VIP,
      PACAP27, and PACAP38 protect predominantly CD4+CD8+ thymocytes from
      glucocorticoid-induced apoptosis. These findings suggest that these neuropeptides
      could be involved in intrathymic T-cell maturation.

PMID- 8652829
TI  - Demonstration of functional CD40 in B-lineage acute lymphoblastic leukemia cells
      in response to T-cell CD40 ligand.
AB  - Because activated T cells were previously shown to induce proliferation of human
      normal B-cell precursors (BCP) via the CD40 pathway, we investigated the effects
      of T cells on leukemic blasts isolated from patients with B-lineage acute
      lymphoblastic leukemia (BCP-ALL). An anti-CD3 activated human CD4+ T-cell clone
      was found to induce significant call proliferation in four of nine BCP-ALL
      samples analyzed. In one of these cases, the T-cell effect was clearly dependent
      on interaction between CD40 and its ligand. Accordingly, a more thorough analysis
      was performed on this particular leukemia (case 461, adult early pre-B-ALL,
      mBCR+, Philadelphia+, i(9q)+). Thus, autologous CD4+ T cells isolated from the
      patient were also able to induce CD40-dependent proliferation of the leukemic
      blasts. Analysis of the phenotype after coculture showed that, among the CD19+
      cells, a proportion gradually lost expression of CD10 and CD34, whereas some
      cells acquired CD23. In addition, and in contrast with normal BCP, activated T
      cells promoted maturation of a subset of the case 461 leukemic cells into surface
      IgM+ cells. The leukemic origin of the cycling and the maturing cells was
      assessed by the presence of i(9q), a chromosomal abnormality associated with this
      leukemia and evidenced by fluorescence in situ hybridization. Taken together,
      these results show that leukemic BCP can be activated via CD40 but that not all
      cases display detectable stimulation in response to T cells despite their
      expression of CD40. In addition, the present data suggest that CD4+ T cells could
      potentially play a role in the physiology of BCP-ALL.

PMID- 8652830
TI  - Monoclonal Lym-1 antibody-dependent lysis of B-lymphoblastoid tumor targets by
      human complement and cytokinine-exposed mononuclear and neutrophilic
      polymorphonuclear leukocytes.
AB  - Lym-1 is a murine IgG2a monoclonal antibody that recognizes a polymorphic variant
      of HLA-DR antigens on malignant B cells, with minimal cross-reactivity with
      normal tissues. Because it can be safely administered in vivo, a detailed
      knowledge of its ability to recruit and trigger the antitumor immune effector
      systems is required to optimize potential serotherapeutic approaches in B
      lymphoma patients. By using Raji cells as a model of B-lymphoma targets, we found
      that Lym-1 activates complement-mediated lysis efficiently. Moreover, Lym-1 was
      capable of triggering the antibody-dependent cellular cytolysis (ADCC) by
      peripheral blood mononuclear cells (MNCs). On the contrary, it failed to trigger
      neutrophilic polymorphonuclear leukocyte (PMN)-mediated ADCC activity. In an
      attempt to enhance Lym-1 ADCC by MNCs and PMNs, nine biologic response modifiers
      were tested. MNC-mediated Lym-1 ADCC was significantly stimulated by interleukin
      2 (IL-2) and unaffected by other mediators, including gamma-interferon (gamma
      IFN), tumor necrosis factor a (TNFalpha), and granulocyte-macrophage colony
      stimulating factor (GM-CSF). On the other hand, PMN-mediated Lym-1 ADCC was
      induced or significantly augmented by various cytokines, such as GM-CSF,
      TNFalpha, and gamma-IFN, and chemotaxins, such as formyl peptides (FMLP),
      complement fragment C5a, and IL-8. Both MNC- and PMN-mediated ADCC was unaffected
      by granulocyte colony-stimulating factor (G- CSF) and insulin-like growth factor
      1 (IGF-1). Finally, only GM-CSF and TNFalpha augmented the number of PMNs
      actually engaged in the binding of Raji target cells. The findings presented
      here, in particular those showing stimulatory activity of biologic response
      modifiers, may inspire new attempts for developing Lym-1 antibody-based
      approaches to the therapy of B lymphomas.

PMID- 8652831
TI  - Single human T cells stimulated in the absence of feeder cells transcribe
      interleukin-2 and undergo long-term clonal growth in response to defined
      monoclonal antibodies and cytokine stimulation.
AB  - The two-signal model of T-cell activation postulates that T lymphocytes require
      at least two distinct signals for activation. This model has been established
      with bulk cultures of T cells in which T-cell-T-cell interaction can occur,
      possibly delivering further unrecognized costimulatory signals. The signal
      requirements of single T cells for the induction of clonal cell growth or the
      transcription of cytokines would best be studied in a cell cloning system in the
      absence of feeder cells; however, such an experimental system has not been
      reported so far. In this study, we report the long-term cloning of human resting
      peripheral blood CD4+CD45RO- T cells under feeder cell-free conditions in
      response to CD3 and CD28 stimulation in the presence of exogenous interleukin-2
      (IL-2). Cloning efficiency ranged from 40% to 60% depending on the presence of
      additional cytokines IL-1 and IL-6. Single-call polymerase chain reaction showed
      that transcription of IL-2 occurred in cells stimulated through CD3 plus CD28
      alone. T cells grown in response to CD3 plus CD28 plus IL-2 stimulation produced
      both IL-4 and interferon-gamma (IFN-gamma) on restimulation (Th0 cells) and could
      be functionally differentiated into Th1- or Th2-type cells by the addition of IFN
      gamma or IL-4, respectively, during cell cloning. These data show on the single
      cell level a two-signal model of T- cell activation for the transcription of IL
      2. In addition, these experiments show that IFN-gamma and IL-4 exert their T-cell
      differentiating effects directly on the T cell without any further need for
      antigen-presenting cells. Together, our experiments show the feasability of a
      defined long-term clonal cell culture system to study the growth and
      differentiation of human T lymphocytes.

PMID- 8652832
TI  - Antiphosphatidylserine antibodies in human immunodeficiency virus-1 patients with
      evidence of T-cell apoptosis and mediate antibody-dependent cellular
      cytotoxicity.
AB  - Serum reactivities to a panel of phospholipid antigens, including cardiolipin
      (CL), phosphatidylserine (PS), sphingomyelin, phosphatidylcholine, and
      phosphatidylethanolamine, were measured by enzyme-linked immunosorbent assay in
      196 human immunodeficiency virus-l+ (HIV-1+) patients with CDC II to IVC clinical
      disease. Significant levels of IgG to CL, PS, or both were observed in 23
      patients lacking evidence of thrombophilic events or any peculiar clinical
      feature of HIV-1 infection. Fluorescence-activated cell sorting analyses showed
      that in vitro apoptosis of T cells was increased in patients with high serum anti
      PS IgG, whereas the overexpression of Fas/Apo-1 marker was detected in all
      patients regardless of their antiphospholipid reactivities. Macrophages from
      patients with significant titers of anti-PS IgG antibodies were not activated by
      the presence of apoptotic CEM lymphoblasts or by purified anti-PS IgG from the
      same patients. By contrast, these antibodies greatly improved the effector
      functions of autologous macrophages in antibody-dependent cellular cytotoxicity
      (ADCC) assays using 51Cr-labeled CEM cells, whereas polyspecific IgG were unable
      to induce an equivalent cytotoxicity in all instances. An increasing effect on
      ADCC was also observed in tests using macrophages from healthy controls to CEM
      coated with anti-PS IgG. These results support a potential correlation of anti-PS
      specificity with T-cell apoptosis in HIV-1 infection. Because PS is exteriorized
      by apoptotic lymphocytes, its persistence may stimulate antibodies which
      cooperate with macrophages in the clearance of dead cells by an enhanced ADCC
      mechanism. This interpretation could explain the absence of thrombophilia in HIV
      1+ patients with serum elevations of antiphospholipid reactivities.

PMID- 8652833
TI  - CD34+CD38dim cells in the human thymus can differentiate into T, natural killer,
      and dendritic cells but are distinct from pluripotent stem cells.
AB  - Recently we reported that the human thymus contains a minute population of
      CD34+CD38dim cells that do not express the T-cell lineage markers CD2 and CD5.
      The phenotype of this population resembled that of CD34+CD38dim cells present in
      fetal liver, umbilical cord blood, and bone marrow known to be highly enriched
      for pluripotent hematopoietic stem cells. In this report we tested the hypothesis
      that the CD34+CD38dim thymocytes constitute the most primitive hematopoietic
      cells in the thymus using a combination of phenotypic and functional analyses. It
      was found that in contrast to CD34+CD38dim cells from fetal liver and bone
      marrow, CD34+CD38dim cells from the thymus express high levels of CD45RA and are
      negative for Thy-1. These data indicate that the CD34+CD38dim thymocytes are
      distinct from pluripotent stem cells. CD34+CD38dim thymocytes differentiate into
      T cells when cocultured with mouse fetal thymic organs. In addition, individual
      cells in this population can differentiate either to natural killer cells in the
      presence of stem cell factor (SCF), interleukin-7 (IL-7), and IL-2 or to
      dendritic cells in the presence of SCF, granulocyte-macrophage colony-stimulating
      factor, and tumor necrosis factor alpha(TNFalpha), indicating that CD34+CD38dim
      thymocytes contain multi-potential hematopoietic progenitors. To establish which
      CD34+ fetal liver subpopulation contains the cells that migrate to the thymus, we
      investigated the T-cell-developing potential of CD34+CD38dim and CD34+CD38+ fetal
      liver cells and found that the capacity of CD34+ fetal liver cells to
      differentiate into T cells is restricted to those cells that are CD38dim.
      Collectively, these findings indicate that cells from the CD34+CD38dim fetal
      liver cell population migrate to the thymus before upregulating CD38 and
      committing to the T-cell lineage.

PMID- 8652834
TI  - True histiocytic lymphoma following therapy for lymphoblastic neoplasms.
AB  - True histiocytic lymphomas (THLs) are rare tumors in which the malignant cells
      show morphologic and immunophenotypic evidence of histiocytic differentiation. We
      describe THLs that arose after therapy for one case of T-lineage lymphoblastic
      lymphoma (LyL) and two cases of acute lymphoblastic leukemia (ALL) (both CD10+,
      one pre-B phenotype). The lymphoblastic neoplasms were not unusual in any way,
      and responded well to standard therapy. The THLs arose 10 to 20 months after
      complete remission was achieved for the lymphoblastic neoplasms, at which time
      there was still no clinical or pathologic evidence of the lymphoblastic
      neoplasms. All three THLs exhibited clinical and morphologic features of
      malignancy. Neoplastic cells in the THLs had abundant eosinophilic vacuolated
      cytoplasm and pleomorphic nuclei, and expressed histiocytic antigens in the
      absence of lymphocyte-specific lineage markers. Because THLs are rare neoplasms,
      their occurrence after otherwise successful therapy for lymphoblastic neoplasms
      in these three cases may constitute a distinct clinicopathologic entity.

PMID- 8652835
TI  - p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and
      acute lymphoblastic leukemias.
AB  - One hundred and forty-three patients with p210 BCR-ABL-positive leukemia were
      studied for coexpression of p190 BCR-ABL mRNA. p190 mRNA was detected in 14 of 16
      (88%) patients with chronic-phase chronic myeloid leukemia (CML) at diagnosis, in
      10 of 10 (100%) CML patients in blast crisis, in 75 of 107 (70%) CML patients
      receiving interferon-alpha (IFN-alpha), and 10 of 10 (100%) patients with p210
      BCR-ABL-positive acute lymphoblastic leukemia (ALL). Neither p210 nor p190 BCR
      ABL transcripts were detected in normal healthy adults (n = 20). The numbers of
      p190 transcripts determined by competitive PCR in patients with CML were low
      compared with the numbers of p210 transcripts. The median numbers of p210 and
      p190 transcripts per unit volume of cDNA in positive samples were 1.0 x 10(5)
      (range, 15 to 1.4 x 10(6)) and 10 (range, 10 to 2.9 x 10(3)), respectively. The
      numbers of p190 and p210 transcripts were significantly correlated in individual
      samples (r = .65, P < .001). The median number of p210 BCR-ABL transcripts was
      significantly lower in samples negative for p190 BCR-ABL transcripts than in
      samples in which p190 BCR-ABL transcripts were identified (3.1 x 10(3)[n = 73] v
      1.0 x 10(5)[n = 115]; P < .0001). The median ratio of p190 to p210 BCR-ABL mRNA
      was not significantly different between chronic phase CML (1.9 x 10(-4)) and CML
      in blast crisis (1.7 x 10(-4)). The median ratio in p210 ALL was also low (1.9 x
      10(-3)) but significantly higher than that of CML. We conclude that pl90 BCR-ABL
      transcripts are frequently present at a low level in p210 BCR-ABL-positive
      leukemias. p190 mRNA may arise through alternative or missplicing and its
      presence is probably of no pathogenetic significance.

PMID- 8652836
TI  - Linkage of a familial platelet disorder with a propensity to develop myeloid
      malignancies to human chromosome 21q22.1-22.2.
AB  - Linkage analysis was performed on a large pedigree with an autosomal dominant
      platelet disorder and a striking propensity in affected family members to develop
      hematologic malignancy, predominantly acute myelogenous leukemia. We report the
      linkage of the autosomal dominant platelet disorder to markers on chromosome
      21q22. Four genetic markers completely cosegregate with the trait and yield
      maximum logarithm of difference scores ranging from 4.9 to 10.5 (theta = .001).
      Two flanking markers, D21S1265 and D21S167, define a critical region for the
      disease locus of 15.2 centimorgan. Further analysis of this locus may identify a
      gene product that affects platelet production and function and contributes to the
      molecular evolution of hematologic malignancy.

PMID- 8652837
TI  - Id2 expression increases with differentiation of human myeloid cells.
AB  - Id proteins are helix-loop-helix (HLH) transcriptional factors that lack the
      basic DNA binding domain. The Id proteins have been reported generally to
      function as inhibitors of cell differentiation, and their gene expression is
      often downregulated during cell differentiation. We examined the expression of
      human Id mRNAs by Northern hybridization in 11 human myeloid cell lines, several
      myeloid cell lines induced to differentiate, fresh myeloid leukemia samples, and
      normal human myeloid cells. Id2 mRNA was expressed in myelomonoblastic and
      monoblastic leukemic cells (PLB-985, THP-1, and U-937) but was weakly expressed
      in myeloblastic leukemic cells (KG-1 and HL-60). Id2 mRNA levels markedly
      increased with induction of differentiation of myeloid blasts (HL-60, PLB-985,
      THP-1, and U-937) toward either granulocytes or macrophages. Examination of fresh
      acute myeloid leukemic samples from 22 individuals also showed prominent Id2 mRNA
      expression in those samples having more differentiated blasts. Using the French
      American-British classification, only 2 of 8 M0/M1 samples expressed Id2 mRNA;
      however, 10 of 13 M2/M3/M4 samples expressed it. In normal human myeloid cells,
      Id2 mRNA was expressed in cultured macrophages from bone marrow and in mature
      granulocytes and monocytes from peripheral blood. The half-life of Id2 mRNA was
      short (1 hour), and its expression was inducible by cessation of protein
      synthesis. Id3 mRNA was moderately expressed in monoblastic cell lines (THP-1 and
      U-937), and levels decreased with their differentiation. Almost no Id3 expression
      was detectable in either other myeloid leukemia lines, fresh leukemic samples, or
      normal human myeloid cells by Northern analyses. Id1 mRNA was not detected by
      polymerase chain reaction in either leukemic or normal myeloid cells except in
      K562 myeloid/erythroid cells. These results showed that Id2 mRNA was
      constitutively expressed in more mature myeloid blast cells and level markedly
      increased with terminal myeloid differentiation, suggesting that Id2 protein may
      inhibit an HLH transcriptional complex that normally represses myeloid
      differentiation.

PMID- 8652838
TI  - Macrophages can recognize and kill tumor cells bearing the membrane isoform of
      macrophage colony-stimulating factor.
AB  - NBXFO hybridoma cells produced both the membrane and secreted isoforms of
      macrophage colony-stimulating factor (M-CSF). Murine bone marrow cells stimulated
      by the secreted form of M-CSF (sM-CSF) became Mac1+, Mac2+, Mac3+, and F4/80+
      macrophages that inhibited the growth of NBXFO cells, but not L1210 or P815 tumor
      cells. In cytotoxicity studies, M-CSF activated macrophages and freshly isolated
      macrophages killed NBXFO cells in the presence of polymyxin B, eliminating the
      possibility that contaminating lipopolysaccharide (LPS) was responsible for the
      delivery of the cytotoxic signal. Retroviral-mediated transfection of T9 glioma
      cells with the gene for the membrane isoform of M-CSF (mM-CSF), but not for the
      secreted isoform of M-CSF, transferred the ability of macrophages to kill these
      transfected T9 cells in a mM-CSF dose-dependent manner. Macrophage-mediated
      killing of the mM-CSF transfected clone was blocked by using a 100-fold excess of
      recombinant M-CSF. Catalase, superoxide dismutase, and the nitric oxide
      inhibitor, N-omega-nitro-arginine methyl ester (NAME), did not effect macrophage
      cytotoxicity against the mM-CSF transfectant T9 clones. T9 parental cells when
      cultured in the presence of an equal number of the mM-CSF transfectant cells were
      not killed, indicating specific target cell cytotoxicity by the macrophages.
      Electron microscopy showed that macrophages were capable of phagocytosizing mM
      CSF bearing T9 tumor cells and NBXFO hybridoma cells; this suggested a possible
      mechanism of this cytotoxicity. This study indicates that mM-CSF provides the
      necessary binding and triggering molecules through which macrophages can initiate
      direct tumor cell cytotoxicity.

PMID- 8652839
TI  - Analysis of clonal rearrangements of the Ig heavy chain locus in acute leukemia.
AB  - Clonal rearrangements of the Ig heavy chain (IGH) locus occur in nearly all cases
      of B-cell precursor acute leukemia (BCP-ALL). Some of these rearrangements may be
      detected by polymerase chain reaction (PCR) using VH gene framework III (FRIII)
      and JH consensus primers. However, about 20% of BCP-ALLs fail to amplify with
      this technique. To determine the causes of these PCR failures and to investigate
      any possible association with specific subgroups of disease, we analyzed 72 acute
      leukemias of defined immunophenotype and cytogenetics, comparing FRIII with VH
      family leader-specific PCR methods and Southern blotting. Of 37 BCP-ALL cases, 6
      (16.2%) failed totally to amplify with FRIII and JH primers. None of these cases
      amplified with VH leader primers. Additionally, all cases retained germline VH6
      genes and 5 of 11 rearranged alleles amplified with a consensus DH primer,
      indicating that these rearrangements represented biallelic DH-JH recombinations.
      Among the 6 FRIII and VH leader PCR-negative BCP-ALL cases, there was no common
      immunophenotype or consistent cytogenetic abnormality, although all showed
      structural chromosomal abnormalities and 3 of 5 successfully karyotyped had
      abnormalities of chromosome 12p. 13 cases with t(9;22)(q34;q11) Philadelphia
      chromosome-positive [Ph+]) and IGH rearrangements (9 BCP-ALL and 4 biphenotypic
      cases) were also analyzed. Of 23 rearranged IGH alleles, 19 (82%) were positive
      by FRIII PCR, and all 4 remaining alleles were amplified by VH leader primers.
      Use of the leader primers in these Ph+ cases also detected 3 additional clonal
      rearrangements that were not anticipated from Southern blotting; such unexpected
      bands were not observed in 21 other Ph- cases. The additional bands represented
      "new" and unrelated VH rearrangements rather than VH-VH replacement events. We
      conclude that biallelic DHJH rearrangements occur in a subgroup of BCP-ALL; in
      these cases, the activation of the full VHDHJH recombination mechanism had not
      occurred. Therefore, these cases of BCP-ALL were arrested at an early stage of B
      cell differentiation. In contrast, all Ph+ BCP-ALLs and biphenotypic acute
      leukemias, which may represent the transformation of multipotent hemopoietic stem
      cells, had undergone VHDHJH recombination. Of 9 Ph+ BCP-ALL cases, 3 also showed
      ongoing VHDHJH rearrangement, reflecting the persistent expression of the VHDHJH
      recombinase. Finally, sequence analysis of 33 rearranged VHDHJH genes showed that
      only 3 including 2 Ph+ BCP-ALL maintained an intact open-reading frame. Loss of
      the open-reading frame occurred not only because of out-of-frame VHDH and DHJH
      joining, but also because of VH gene mutation and deletion. These data show that
      most BCP-ALLs may represent the neoplastic transformation of BCPs destined to die
      in the bone marrow.

PMID- 8652841
TI  - BCL-6 expression during B-cell activation.
AB  - Translocations involving the BCL-6 gene are common in the diffuse large cell
      subtype of non-Hodgkin's lymphoma. Invariably, the BCL-6 coding region is intact,
      but its 5' untranslated region is replaced with sequences from the translocation
      partner. The present study shows that BCL-6 expression is regulated in
      lymphocytes during mitogenic stimulation. Resting B and T lymphocytes contain
      high levels of BCL-6 mRNA. Stimulation of mouse B cells with anti-IgM or IgD
      antibodies, bacterial lipopolysaccharide, phorbol 12-myristate 13-acetate plus
      ionomycin, or CD40 ligand led to a five-fold to 35-fold decrease in BCL-6 mRNA
      levels. Similar downregulation of BCL-6 mRNA was seen in human B cells stimulated
      with Staphylococcus aureus plus interleukin-2 or anti-IgM antibodies and in human
      T lymphocytes stimulated with phytohemagglutinin. BCL-6 mRNA levels began to
      decrease 8 to 16 hours after stimulation, before cells entered S phase. Although
      polyclonal activation of B cells in vitro invariably decreased BCL-6 MRNA
      expression, activated B cells from human germinal centers expressed BCL-6 mRNA at
      levels comparable to the levels in resting B cells. Despite these similar mRNA
      levels, BCL-6 protein expression was threefold to 34-fold higher in germinal
      center B cells than in resting B cells, suggesting that BCL-6 protein levels are
      controlled by translational or posttranslational mechanisms. These observations
      suggest that the germinal center reaction provides unique activation signals to B
      cells that allow for continued, high-level BCL-6 expression.

PMID- 8652840
TI  - Relationship between minimal residual disease and outcome in adult acute
      lymphoblastic leukemia.
AB  - In children with acute lymphoblastic leukemia (ALL), the level of minimal
      residual disease (MRD) at the end of induction strongly predicts outcome,
      presumably because it measures both drug sensitivity and the number of leukemic
      cells requiring elimination. Children with high levels (> 10(-3) leukemic cells
      per marrow cell) nearly always relapse, whereas those with low levels (<2 x 10(
      5)) seldom do. However, the importance of MRD in adult ALL is unclear. We studied
      27 patients aged 14 to 74 who were treated with a standard protocol and who
      attained morphological remission. MRD in the marrow at first remission was
      quantified by using the polymerase chain reaction (PCR), with the rearranged
      immunoglobulin heavy chain gene as a molecular marker. Levels of MRD varied from
      3 x 10(-1) to <7 x 10(-7). The probability of long-term relapse-free survival was
      significantly related to the level of MRD and only one of nine patients with MRD
      >10(-3) did not relapse. For patients who did relapse, there was an inverse
      relationship between MRD level and the length of remission. Overall, MRD in
      adults in whom a translocation had not been identified was significantly higher
      than in comparably-treated children, suggesting that ALL in adults is more drug
      resistant than in children.

PMID- 8652842
TI  - DNA copy number changes in diffuse large B-cell lymphoma--comparative genomic
      hybridization study.
AB  - We studied DNA copy number changes in diffuse large B-cell lymphoma using
      comparative genomic hybridization analysis on 20 primary tumors and on 12
      recurrent tumors excised after chemotherapy or radiotherapy. Twenty-nine (91%) of
      the cases showed abnormal copy number karyotypes. Chromosomal regions at X (41%),
      1q (38%), 7 (31%), 3 (24%), 6p (21%), 11 (21%), 12 (21%), and 18 (21%) were most
      frequently gained, and the most common losses involved 6q (38%), X (21%), 1p
      (14%), and 8p (10%). High-level amplifications were observed at 6p23-ter, 10p12
      14, 17p1l.2, 18q21-ter, and Xq22-ter, all but 18q appearing only in the recurrent
      tumors. Gains (median, 2; range, 0 to 10) were more frequent than losses (median,
      1; range, 0 to 7; P = .0004). The median number of aberrations found in the
      recurrent tumors (6.5) was greater than that in the primary tumors (2; P = .01).
      The copy number changes found in the recurrent tumors were more random than those
      found in the primary tumors, which were mainly located in the most frequently
      affected regions. Our findings are in line with those observed using conventional
      cytogenetic analysis, but especially novel high-level amplifications were
      detected. Southern blot analysis showed BCL2 amplification, but not translocation
      t(14;18)(q32;q21), in cases in which a gain at 18q was detected by comparative
      genomic hybridization, which strongly suggests that, in addition to
      translocation, gene amplification is another mechanism for the overexpression of
      the BCL2 protein.

PMID- 8652843
TI  - Expression of Epstein-Barr virus-gene products in Burkitt's lymphoma in Northeast
      Brazil.
AB  - The Epstein-Barr Virus (EBV) is consistently found in tumor cells of Burkitt's
      lymphoma (BL) endemic in central Africa and malaria is considered a pathogenic
      cofactor. In contrast, fewer than 20% of BL cases occurring in Western countries
      are EBV-associated. We have investigated 54 BL cases from Bahia, a tropical
      region of Northeast Brazil, for expression of EBV gene products by in situ
      hybridization and immunohistology and performed typing of the EBV by polymerase
      chain reaction. Ten pediatric BL cases from Germany served as controls. New cases
      of malaria were not observed in the period and area of our study. Small nuclear
      EBV encoded transcripts, EBER, were found in tumor cells of 47 of 54 Brazilian
      cases (87%) but in only 2 of 10 German cases (20%). Type I latency of the EBV
      infection with absence of EBV-encoded proteins LMP1 and EBNA2 was found in 45 of
      47 of the EBER-positive Brazilian cases. In two cases, occasional LMP1-containing
      tumor cells were found in the neighborhood of small Schistosoma mansoni
      granulomas and scars. BHLF1 transcripts associated with lytic EBV infection could
      be detected in few cells in 3 of the 40 EBER-positive Brazilian cases
      investigated. EBV type A was found in the majority of Brazilian BL cases (20 of
      30 A-type, 7 of 30 B-type, and 3 of 30 not amplifiable). Our results indicate
      that the association of Bahian BL with EBV, but not the regional prevalence of
      malaria, is similar to endemic African BL. In two cases, type II latency was
      found in association with schistosomiasis, suggesting a role of this parasitosis
      in the induction of an EBV expression pattern that is unusual for BL. Because
      chronic schistosomiasis is associated with elevated Th2 cytokine expression
      resulting in reduced cell-mediated cytotoxicity, it seems possible that altered
      local immunity is responsible for this peculiar phenotype.

PMID- 8652844
TI  - Activation of MAP kinase-activated protein kinase 2 in human neutrophils after
      phorbol ester or fMLP peptide stimulation.
AB  - In response to extracellular stimulation, one of the earliest events in human
      neutrophils is protein phosphorylation, which mediates signal transduction and
      leads to the regulation of cellular functions. Mitogen-activated protein (MAP)
      kinases are rapidly activated by a variety of mitogens, cytokines, and stresses.
      The activated MAP kinases in turn regulate their substrate molecules by
      phosphorylation. MAP kinase-activated protein (MAPKAP) kinase 2, a Ser/Thr
      kinase, has been shown to be phosphorylated by p38 MAP kinase both in vivo and in
      vitro. Phosphorylation of the Thr-334 site of MAPKAP kinase 2 results in a
      conformational change with subsequent activation of the enzyme. To better define
      the role of MAPKAP kinase 2 in the activation of human neutrophils, its enzymatic
      activity was measured after stimulation by either a phorbol ester (phorbol
      myristate acetate [PMA]), a potent protein kinase C activator, or the tripeptide
      fMLP, which is a chemotactic factor. The in vitro kinase assays indicate that
      both PMA and fMLP stimulated a transient increase in the enzymatic activity of
      cellular MAPKAP kinase 2. The induced kinase activation was concentration
      dependent and reached a maximum at 5 minutes for PMA and 1 minute for fMLP. To
      identify potential substrate molecules for MAPKAP kinase 2, a highly active
      kinase mutant was generated by mutating the MAP kinase phosphorylation site in
      the C-terminal region. The replacement of threonine 334 with alanine resulted in
      a marked augmentation of catalytic activity. Analysis of in vitro protein
      phosphorylation in the presence of the active kinase indicates that a 60-kD
      cytosolic protein (p60) was markedly phosphorylated and served as the major
      substrate for MAPKAP kinase 2 in human neutrophils. Based on the MAPKAP kinase 2
      phosphorylation site of Hsp27, a competitive inhibitory peptide was synthesized.
      This competitive inhibitory peptide specifically inhibited MAPKAP kinase 2
      enzymatic activity, as well as the in vitro and in vivo kinase-induced p60
      phosphorylation. To assess the contribution of MAPKAP kinase 2 in neutrophil
      function, the oxidative burst response after manipulation of endogenous kinase
      activity was measured. Intracellular delivery of the competitive inhibitory
      peptide into human neutrophils reduced both PMA- and fMLP-stimulated superoxide
      anion production. Thus, the results strongly suggest that MAPKAP kinase 2 is
      involved in the activation of human neutrophils.

PMID- 8652845
TI  - Selectins mediate eosinophil recruitment in vivo: a comparison with their role in
      neutrophil influx.
AB  - The role of selectins in mediating eosinophil recruitment in vivo was assessed in
      a model of lipopolysaccharide (LPS)-induced mouse pleurisy. LPS administration
      resulted in significant eosinophil influx at 24 hours, whereas neutrophil
      recruitment to the cavity peaked at 4 hours and persisted for 24 hours. The anti
      L-selectin monoclonal antibody (MoAb) MEL-14 effectively inhibited (by 97%)
      eosinophil influx at 24 hours and also inhibited neutrophil recruitment at both
      times (75% to 95%). Eosinophil recruitment was partially reduced (54%) by the
      anti-P-selectin MoAb 5H1 but, in contrast, was unaffected by the anti-E-selectin
      MoAb 10E6. Neutrophil influx at 4 or 24 hours was not affected by the anti-P- or
      anti-E-selectin MoAbs. However, coadministration of anti-P-selectin and anti-E
      selectin was very effective at inhibiting eosinophil influx at 24 hours (86%) and
      neutrophil influx at 4 (93%) and 24 hours (92%). These results show that all
      three selectins play a role in LPS-induced eosinophil and neutrophil recruitment
      in vivo, although P- and E-selectin show a degree of functional redundancy. The
      demonstration that P-selectin mediates eosinophil but not neutrophil influx
      suggests that suppressing the function of this adhesion molecule may be
      beneficial in blocking eosinophil accumulation in pleural inflammation.

PMID- 8652846
TI  - A single dose of granulocyte-macrophage colony-stimulating factor induces
      systemic interleukin-8 release and neutrophil activation in healthy volunteers.
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony
      stimulating factor (G-CSF) are frequently used in the clinical management of
      neutropenia. These cytokines not only enhance the proliferation of myeloid
      precursor cells but also influence the function of mature leukocytes. In a
      previous study, we found that the in vivo effects of G-CSF on neutrophils
      differed from those in vitro. In the present study, we investigated the effects
      of a single dose of recombinant GM-CSF (7.5 microg/kg, subcutaneously) on
      neutrophils, eosinophils, and monocytes in healthy volunteers. We analyzed
      leukocyte kinetics, phenotypical changes, neutrophil degranulation, and systemic
      cytokine production. After GM-CSF injection, phenotypical changes included
      upregulation of CD11b on all three cell types and a decreased expression of L
      selectin and Fc(gamma)RIII on neutrophils. Neutrophil degranulation was evident
      from the increased plasma concentrations of lactoferrin and elastase. GM-CSF
      induced the release of interleukin-8 (IL-8), but not of IL-6 or tumor necrosis
      factor alpha. In comparison to the results from our previous study with G-CSF in
      healthy volunteers, GM-CSF induced a stronger activation of mature neutrophils
      but had a much less pronounced effect on the production and maturation of
      neutrophil precursors. These data may help to guide the choice between the two
      cytokines in different clinical situations.

PMID- 8652847
TI  - The stability of human beta-globin mRNA is dependent on structural determinants
      positioned within its 3' untranslated region.
AB  - Controls that act at both transcriptional and posttranscriptional levels assure
      that globin genes are highly expressed in developing erythroid cells. The
      extraordinary stabilities of alpha- and beta-globin mRNAs permit globin proteins
      to accumulate to substantial levels in these cells, even in the face of
      physiologic transcriptional silencing. Structural features that determine alpha
      globin mRNA stability have recently been identified within its 3'UTR; in
      contrast, the structural features that determine beta-globin mRNA stability
      remain obscure. The current study begins to define the structural basis for beta
      globin mRNA stability. Two tandem antitermination mutations are introduced into
      the wild-type human beta-globin gene that permit ribosomes to read into the 3'UTR
      of the encoded beta-globin mRNA. The readthrough beta-globin mRNA is destabilized
      in cultured erythroid cells, indicating that, as in human alpha-globin mRNA, an
      unperturbed 3'UTR is crucial to maintaining mRNA stability. Additional
      experiments show that the beta-globin and alpha-globin mRNA 3'UTRs provide
      equivalent levels of stability to a linked beta-globin mRNA coding region,
      suggesting a parallel in their functions. However, destabilization of the
      antiterminated beta-globin mRNA is independent of active translation into the
      3'UTR, whereas translation into the alpha-globin mRNA 3'UTR destabilizes a linked
      beta-globin coding region in a translationally dependent manner. This indicates
      that the alpha- and beta-globin 3'UTRs may stabilize linked mRNAs through
      distinct mechanisms. Finally, it is shown that neither of the two mutations that,
      in combination, destabilize the beta-globin mRNA have any effect on beta-globin
      mRNA stability when present singly, suggesting potential redundancy of
      stabilizing elements. In sum, the current study shows that a functionally intact
      beta-globin mRNA 3'UTR is crucial to maintaining beta-globin mRNA stability and
      provides a level of stability that is functionally equivalent to, although
      potentially mechanistically distinct from, the previously characterized alpha
      globin mRNA 3'UTR stability element.

PMID- 8652848
TI  - Differential use of protein 4.1 translation initiation sites during
      erythropoiesis: implications for a mutation-induced stage-specific deficiency of
      protein 4.1 during erythroid development.
AB  - Expression of multiple protein 4.1 isoforms in erythroid progenitors and in a
      variety of nonerythroid tissues results from alternative pre-mRNA splicing. In
      4.1 pre-mRNA, several translation initiation sites are present; synthesis of
      isoforms larger than 80 kD occurs when an upstream 5' AUG is spliced in, whereas
      the 80-kD mature erythroid isoform is produced when the upstream AUG is spliced
      out and translation is initiated at the downstream AUG. During erythropoiesis,
      this splicing switch is developmentally regulated. We studied this developmental
      switch in hereditary elliptocytosis 4.1Alg, in which a DNA rearrangement
      involving the exon containing the downstream AUG results in loss of coding
      capacity for the 80-kD 4.1, leading to mature red blood cells deficient in 4.1
      with decreased membrane mechanical stability. Analysis of erythroblast RNA by
      reverse transcriptase-polymerase chain reaction showed that, although it retained
      the upstream AUG, its coding region was approximately 2.2 kb, compared with
      approximately 2.5 kb of normal 4.1 mRNA, because of the deletion of exons,
      including the one that codes for the downstream AUG. Immunofluorescent microscopy
      and Western blot analysis documented protein 4.1 expression in HE 4.1Alg
      erythroblasts. These studies emphasize the crucial role of differentiation
      regulated RNA splicing because, within the same erythroid tissue, the HE 4.1Alg
      phenotype did not appear until after the differentiation-associated splicing
      event.

PMID- 8652849
TI  - The use of monoclonal antibodies and flow cytometry in the diagnosis of
      paroxysmal nocturnal hemoglobinuria.
AB  - We have characterized the erythrocytes, granulocytes, and platelets of 54
      patients with paroxysmal nocturnal hemoglobinuria (PNH) with antibodies to
      glycosylphosphatidylinositol-anchored proteins (anti-CD55, anti-CD59, and anti
      CD16) and flow cytometry to establish the usefulness of this technique in the
      diagnosis of this disorder. All patients demonstrated either completely (PNH III)
      or partially (PNH II) deficient red cells and granulocytes. Anti-CD59 best
      demonstrated PNH II red cells, which were present in 50% of the patients. The
      proportion of abnormal granulocytes was usually greater than the proportion of
      abnormal red cells; 37% of the patients had >80% abnormal granulocytes. Anti-CD55
      did not delineate the erythrocyte populations as well as did anti-CD59. Either
      anti-CD55 or anti-CD59 could be used equally well to analyze granulocytes; anti
      CD16 did not demonstrate cells of partial deficiency. Platelets could not be used
      for detailed analysis as the normal and abnormal populations were not well
      distinguished. Flow cytometry of erythrocytes using anti-CD59 or of granulocytes
      using either anti-CD55 or anti-CD59 provides the most accurate technique for the
      diagnosis of paroxysmal nocturnal hemoglobinuria; it is clearly more specific,
      more quantitative, and more sensitive than the tests for PNH that depend upon
      hemolysis by complement (the acidified serum lysis [Ham] test, the sucrose lysis
      test, and the complement lysis sensitivity [CLS] test).

PMID- 8652850
TI  - Human herpesvirus 6: infection and disease following autologous and allogeneic
      bone marrow transplantation.
AB  - Human herpesvirus 6 activity (HHV-6) was studied in 15 allogeneic and 11
      autologous marrow transplantation patients. After transplantation, HHV-6 was
      isolated from the peripheral blood mononuclear cells of 12 of 26 patients (6
      allogeneic and 6 autologous). All isolates were variant B. Eleven of 26 and 12 of
      19 patients showed salivary shedding of HHV-6 DNA before and after
      transplantation, respectively. The antibody titer increased in 7 of 26 patients.
      Thus, 23 of 26 patients showed evidence of active HHV-6 infection either by virus
      isolation, salivary shedding, or increases in antibody titers. The fraction of
      saliva specimens positive in 19 patients was negatively associated with their
      antibody titers (P= .005). The proportion of cultures positive increased after
      transplantation (P = .007). Sinusitis was associated with HHV-6 isolation in
      autologous recipients (P= .002). In allogeneic patients, active human
      cytomegalovirus infection was associated with HHV-6 isolation (P = .04). No
      association was observed between HHV-6 infection and GVHD, pneumonia, delay in
      engraftment, or marrow suppression. Of the 120 clinical events analyzed in 26
      patients, HHV-6 was defined as a probable cause of 16 events in 9 patients based
      on the propinquity of HHV-6 activity and the clinical event plus the absence of
      other identified causes of the event.

PMID- 8652851
TI  - Treatment of donor mice with an alpha beta T-cell receptor monoclonal antibody
      induces prolonged T-cell nonresponsiveness and effectively prevents lethal graft
      versus-host disease in murine recipients of major histocompatibility complex
      (MHC)-matched and MHC-mismatched donor marrow grafts.
AB  - The purpose of this study was to determine whether the administration of high
      doses of an anti-T-cell receptor (TCR) monoclonal antibody (H57-597) to donor
      animals could induce a state of T-cell nonresponsiveness and prevent the
      development of graft-versus-host disease (GVHD) in murine recipients of major
      histocompatibility complex (MHC)-matched (B10.BR[H-2k] --> AKR/J[H-2k]) and
      mismatched (B10.BR[H-2k] --> DBA/2[H-2d]) marrow grafts. Transplantation of H57
      597-treated B10.BR T cells into irradiated AKR or DBA mice resulted in protection
      from GVHD, which was otherwise lethal in transplanted recipients receiving
      untreated T cells. The administration of H57-597-treated T cells did not
      compromise alloengraftment in either strain combination and was found to
      accelerate donor T-cell reconstitution in recipients of MHC-matched marrow
      grafts. Optimal protection for GVHD was dependent on the duration of antibody
      exposure in donor mice. T cells from donor exposed to antibody for only 1 day
      caused lethal GVHD, whereas exposure for at least 4 days was necessary to
      abrogate graft-versus-host reactivity. The ability of antibody treatment to
      protect against the development of GVHD could not be ascribed to the antibody
      induced production of Th2 cytokines, the induction of a T- or non-T-suppressor
      cell population, or the preferential depletion of CD4+ T cells by H57-597. Donor
      T cells exposed to H57-597 antibody were detectable in recipients for up to 5
      weeks after transplantation, indicating that these cells were not eliminated in
      the host immediately after bone marrow transplantation and contributed to
      enhanced donor T-cell reconstitution. Moreover, in B10.BR --> DBA chimeras that
      did not have any clinical evidence of GVHD, potentially MIs-reactive donor
      derived Vbeta6+ T cells were present in the spleens of recipients at comparable
      numbers to normal mice but appeared functionally nonresponsive in vivo. These
      data strongly suggested that protection from GVHD was due to the fact that
      antibody treatment resulted in a state of prolonged T-cell anergy that persisted
      despite the presence of potential costimulatory signals in the recipient. This
      observation is of potential clinical significance in that it shows that the
      prevention of GVHD can be accomplished without posttransplantation
      immunosuppression or the need for in vitro or in vivo T-cell depletion.

PMID- 8652852
TI  - Individual stem cell quality in leukapheresis products is related to the number
      of mobilized stem cells.
AB  - Peripheral blood stem cells (PBSC) are used for stem cell support in patients
      after intensive chemotherapy and generally permit faster hematopoietic recovery
      than bone marrow. The development of different protocols for chemotherapy
      conditioning, mobilization, and ex vivo manipulation of PBSC may potentially lead
      to loss of primitive hematopoietic stem cells or reduction of their quality. To
      characterize the frequency of different stem cell subsets and their quality per
      mobilized PBSC, we have studied 47 leukapheresis products (LPs) of 21 cancer
      patients using stroma-dependent long-term culture (LTC) and limiting dilution
      type cobblestone area forming cell (CAFC) assays. A large variation in CAFC week
      type frequencies between the LPs was observed. The frequencies of CAFC week 2 as
      a tentative indicator of progenitor cells and transiently repopulating
      hematopoietic stem cells ranged from 0.89 to 205 per 10(5) mobilized nucleated
      cells and the frequencies of more primitive CAFC week 6 varied between 0.37 and
      48. The average total colony-forming cell (CFC) production per CAFC at week 6
      varied between 1.2 and 730, as determined in parallel LTC. In contrast to LPs,
      bone marrow samples generated 4.2 to 48 CFC per CAFC at week 6. Notably, a poor
      stem cell quality was consistently found in LPs that contained less than 5,000
      CAFC week 6 per kilogram of body weight. Frequency analyses of CFCs, CAFC
      subtypes, and immunophenotypic subsets showed a good level of mutual correlation,
      suggesting identical mobilization kinetics of different stem cell subsets. The
      premobilization chemotherapy intensity was directly correlated with both
      decreasing frequency and quality of the CAFC week 6 in LPs. The frequency of
      CFCs, immunophenotypic subsets, and CAFC subsets transplanted and the transplant
      quality as determined in LTC assays was related to the neutrophil and platelet
      recovery time after PBSC transplantation. Although the number of progenitor cells
      transplanted and the in vitro transplant quality showed the best correlation with
      early hematopoietic recovery, the data did not permit determination of which stem
      cell subsets are predominantly responsible for early posttransplantation
      recovery. As a result, frequency and quality analysis of stem cell subsets may be
      a useful tool to monitor and calibrate the efficacy of novel mobilization
      regimens and ex vivo manipulation of PBSC.

PMID- 8652853
TI  - Radioimmunotherapy: promising treatment of aggressive adult T-cell leukemia?

PMID- 8652854
TI  - Primary hepatosplenic lymphoma: association with hepatitis C virus infection.

PMID- 8652855
TI  - Differences in the chromosomal profile of AML-M0 versus AML-M1: response.

PMID- 8652856
TI  - Thrombopoietin and its alternatively spliced form are expressed in human amygdala
      and hippocampus.

PMID- 8652857
TI  - Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: a comparative
      analysis of the Italian and German chronic myeloid leukemia trials with
      interferon-alpha.
AB  - In 1994, the Italian and the German Chronic myeloid leukemia (CML) trials
      comparing interferon-alpha (IFN-alpha) with conventional chemotherapy were
      published. The survival advantage in favor of IFN-alpha compared with hydroxyurea
      (HU; 72 v 52 months) was significant in the Italian (P < .002), but not in the
      German trial (66 v 56 months, P < .44). We set up a collaborative study to
      identify the reasons for the different outcomes. There are major differences in
      the trial protocols concerning admission criteria, treatment strategy, and
      definitions. The German patients were older and more seriously sick. Fifty-two of
      the 327 patients in the German IFN and HU arms did not fulfil Italian admission
      criteria, and 41 of the 322 Italian patients did not fulfil German admission
      criteria. Using mutually uniform admission criteria, the median survival times of
      the IFN patients are 76 (Italian) and 72 (German) months (P = .56). The Italian
      group administered IFN combined with HU as needed, whereas the German group
      strictly used IFN as monotherapy with rerandomization to busulfan (BU) or HU
      after IFN resistance or intolerability. The differences seen between the Italian
      and the German trial results can be accounted for by objective differences in
      study design, especially the admission criteria, treatment strategy, and bias due
      to intention to treat analysis. The detailed analysis of the data suggests that
      the combination of IFN with HU as needed is more effective than either agent
      alone.

PMID- 8652858
TI  - Probability calculations for a matched donor in the extended family.

PMID- 8652859
TI  - Xerocytosis with concomitant intrauterine ascites: first description and
      therapeutic approach.

PMID- 8652860
TI  - A newly discovered frameshift at codons 120-121 (+A) of the beta gene is not
      associated with a dominant form of beta-thalassemia.

PMID- 8652861
TI  - bcl-2, Epstein-Barr virus-latent membrane protein, EBNA-1, and EBNA-2 staining in
      posttransplantation lymphoproliferative disorders.

PMID- 8652862
TI  - Using naturally produced speech to elicit the mismatch negativity.
AB  - The mismatch negativity (MMN) was recorded from 10 young adults with normal
      hearing using naturally produced speech contrasts. Consonant-place and vowel
      height contrasts were examined in consonant-vowel (CV) syllables by pairing
      either the consonant /t/ or /p/ with the vowel /I/ or /E/. Vowel-height was also
      examined as a pseudovowel; one cycle of the vowel segment of a CV was extracted
      and replicated over 200 msec. A total of five contrasts were examined: vowel
      height following /p/, vowel-height following /t/, consonant-place preceding /E/,
      consonant-place preceding /I/, and pseudovowels. Significant MMN responses were
      elicited from all five contrasts, albeit with different amplitudes, latencies,
      and waveform morphology. The pseudovowel elicited the most well-defined MMN with
      the greatest amplitude and was found to be significantly different from the other
      four contrasts. Naturally produced speech stimuli appear to be viable stimuli for
      eliciting the MMN.

PMID- 8652863
TI  - Development of a hearing performance standard for law enforcement officers.
AB  - A hearing performance standard for new police officer candidates in the State of
      Michigan was developed by a task force consisting of the authors and four members
      of the Michigan Law Enforcement Officers Training Council. Ratings of the
      importance of hearing sensitivity and speech intelligibility in performing each
      of 135 specific job tasks formed the basis for pass-fail criteria. The standard,
      described in this report, includes specifications for unaided and aided hearing
      performance, types of hearing assessment measures, hearing measurement
      procedures, and the appropriate examining professional. The authors believe that
      the standard provides an appropriate accommodation to hearing-impaired law
      enforcement officer candidates with respect to The Americans with Disabilities
      Act.

PMID- 8652864
TI  - Comparison of acoustic immittance measures obtained with different commercial
      instruments.
AB  - Three acoustic admittance measurements (tympanometric peak pressure, peak
      compensated static acoustic admittance, and tympanometric width) were compared
      across seven commercially available acoustic immittance systems. Forty-nine adult
      subjects (45 females and 4 males), 16 to 50 years of age (mean = 27.7 years),
      with normal middle ear function participated in this investigation. Small but
      statistically significant differences were observed for each of the tympanometric
      variables for several of the instruments evaluated. In most instances, the
      differences were small enough that the same normative data could be applied
      across the instrumentation employed in this study; however, there were two
      measurement conditions, peak compensated static acoustic admittance and
      tympanometric width, where, for selected instruments, the range in values
      differed by an amount great enough to warrant consideration in clinical decision
      making.

PMID- 8652865
TI  - Evaluation of a maximum likelihood procedure for measuring pure-tone thresholds
      under computer control.
AB  - An adaptive, maximum likelihood (ML) procedure was assessed as an automated tool
      for estimating audiometric pure-tone thresholds in the clinic under computer
      control. Pure-tone air-conduction thresholds were measured from 101 workmen who
      received annual hearing rechecks as part of their employee hearing conservation
      program. A pure-tone threshold was measured bilaterally for each of the standard
      audiometric frequencies in a 15-trial block to yield 60 percent correct detection
      with the ML procedure. The workmen were tested on a modified "yes-no" task. On a
      trial, the signal was presented in a visually cued 200-msec observation interval.
      Each workman then had 1000 msec to make a "yes" response. If the workman did not
      respond during the 1000-msec response period, then the computer assumed a "no"
      response. After either the "yes" or "no" response, the computer adjusted the
      signal level for the next trial. The thresholds measured by ML procedure compared
      favorably with thresholds measured from the same listeners by conventional (CONV)
      audiometry. The efficiency of the ML procedure was also compared in terms of the
      time necessary for an experienced audiologist to instruct the listener and
      perform CONV audiometry. CONV audiometry (3-4 minutes per listener) required
      about half of the time needed for the ML procedure (6-7 minutes per listener).
      The relatively longer time associated with measuring an audiogram with the ML
      procedure was due primarily to more trials being used to estimate threshold.

PMID- 8652866
TI  - An in-situ calibration procedure for click stimuli.
AB  - The use of insert earphones for delivering acoustic signals to subjects and
      patients has grown in popularity in auditory research and clinical audiology. In
      conjunction with transducer characteristics, the insertion of an earphone into
      the ear canal modifies ear canal acoustics and results in an acoustic signal in
      the ear canal unlike the original signal delivered to the earphone. The modified
      ear canal signal will differ within and between individuals depending on the
      depth of earphone insertion and ear canal geometry. We describe a new procedure
      for correcting earphone and ear canal acoustics. When applied to the calibration
      of click stimuli, the resultant ear canal signal in each individual is an impulse
      with a spectrum almost identical to the rectangular pulse delivered to the
      transducer.

PMID- 8652868
TI  - Noise control/hearing conservation.

PMID- 8652867
TI  - Real-ear sound pressure level.

PMID- 8652870
TI  - Within-subject comparison of speech perception benefits for congenitally deaf
      adolescents with an electrotactile speech processor and a cochlear implant.
AB  - This study assessed speech perception benefits for three congenitally deaf
      adolescents who used an electrotactile speech processor (Tickle Talker(TM)) and
      subsequently went on to use a Nucleus Minisystem 22 cochlear implant. Both
      devices provided significant and comparable benefits for all children in the
      device plus lipreading condition. All children benefited from the additional
      information provided by either the Tickle Talker(TM) or the cochlear implant, and
      were able to perceive speech information with these devices that was not
      available through either aided residual hearing or lipreading. None of the three
      children were able to understand open-set words or sentences using either hearing
      aids alone or Tickle Talker(TM) alone, without the aid of lipreading. Two of the
      children showed significant open-set speech perception benefits while using their
      cochlear implant alone.

PMID- 8652869
TI  - Hearing loss and congenital symptomatic cytomegalovirus infection: a case report
      of multidisciplinary longitudinal assessment and intervention.
AB  - More than 6000 children born annually in this country have hearing loss resulting
      from congenital cytomegalovirus (CMV) infection, the leading nonhereditary
      congenital cause of hearing loss in children. This exemplary congenital
      symptomatic CMV case focuses on the results of longitudinal audiologic,
      educational, medical, psychological, and visual evaluations and intervention.
      Decreased ocular motor control and visual acuity were observed as was bilateral
      deterioration of hearing from 3 days though 9 years of age. Treatment with
      dexamethasone and histamine resulted in almost complete reversal of the most
      recent progression of hearing loss in the left ear.

PMID- 8652871
TI  - Large vestibular aqueduct syndrome: a tutorial and three case studies.
AB  - The large vestibular aqueduct (LVA) syndrome is a congenital malformation that
      predisposes the patient ultimately to a loss of hearing and possible continuing
      vestibular disorder. If the LVA patient is diagnosed, it typically is not until
      later life, when he/she exhibits profound sensorineural hearing loss. To better
      understand this disorder and to bring it to the attention of audiologists, we
      provide a brief tutorial of LVA and present three case studies that illustrate
      the syndrome.

PMID- 8652872
TI  - Effects of exam procedures on transient evoked otoacoustic emissions (TEOAEs) in
      neonates.
AB  - Debris in the ear canal and ear canal collapse in newborns have been shown to
      interfere with recording transient evoked otoacoustic emissions (TEOAEs). The
      purpose of this study was to prospectively evaluate the effects of two simple ear
      canal cleaning procedures on the TEOAE responses of normal newborns. Three
      hundred and sixteen ears were studied with an initial TEOAE followed randomly by
      either an otoscopic exam and refit procedure or a probe refit procedure. At the
      time of each procedure, any superficial debris attached to the otoscope or probe
      were removed before the second TEOAE was repeated with identical procedures. The
      study sample consisted of two equal groups of ears (otoscopic exam and refit).
      Each group initially had equal proportions of ears with no emission, a weak
      emission, or a robust emission. In the otoscopic group, 12 of 51 (24%) weak
      emissions converted to robust emissions, 10 of 53 (19%) no emissions converted to
      robust emissions, and 15 of 53 (28%) no emissions improved to weak emissions. In
      the refit group, 20 of 50 (40%) weak emissions converted to robust emissions, 13
      of 57 (23%) no emissions converted to weak emissions, and 9 of 57 (16%) no
      emissions improved to weak emissions. Both the otoscopic viewing procedure and
      the refit procedure were effective in improving the TEOAE response.

PMID- 8652873
TI  - Effects of age, signal level, and signal rate on the auditory middle latency
      response.
AB  - The effects of age, signal rate, and signal level on the maturing auditory middle
      latency response (AMLR) were evaluated in 50 normal-hearing subjects ranging in
      age from 2 days to 35 years. Ipsilateral and contralateral AMLR waveforms were
      recorded in newborns (n = 10), children (n = 10), preteens (n = 10), teens (n =
      10), and adults (n = 10). The AMLR Pa waveform was obtained in 70 to 100 percent
      of all subjects. The variables of age, signal level, and site of recording
      significantly affected Pa peak amplitude and absolute latency. However, stimulus
      rate did not significantly affect the response.

PMID- 8652874
TI  - Selecting different amplification for different listening conditions.
AB  - Ten subjects with diverse hearing impairment trialled a multiple-memory hearing
      aid in everyday life and in a paired-comparison laboratory test. Five subjects
      evaluated systematic variations of the compression characteristic in two bands,
      around an individually fitted response, using the Resound PHS-ED instrument.
      Another five subjects evaluated systematic variations of the frequency response
      characteristic, around an individually fitted NAL response, using the Widex
      Quattro B hearing device. In all, five subjects showed benefit from multiple
      amplification schemes. Both variations in compression and frequency response
      characteristics were used for different background noises and/or response
      criteria. There were some similarities across subjects in the choice of
      amplification schemes in the paired-comparison test. However, data were not
      sufficient to derive a relationship between preferred amplification schemes and
      listening conditions. For a number of audiometric and disability-related
      parameters, no differences were found between those who selected multiple
      amplification schemes and those who did not.

PMID- 8652875
TI  - Molecular mass measurement of polymerase chain reaction products amplified from
      human blood DNA by electrospray ionization mass spectrometry.
AB  - We report here on the first analysis of polymerase chain reaction (PCR) products
      amplified from a small amount of human blood DNA by electrospray ionization mass
      spectrometry (ESI-MS). Adenomatous polyposis coli (APC) gene fragment of about 50
      base pairs (bp) with a relative molecular mass (M(r)) of approximately 15,000 u
      was amplified from human blood DNA by PCR. The accurate molecular mass of the PCR
      products was determined with an accuracy of approximately 0.005% by ESI-MS. The
      amount of DNA used was only 100 ng (approximately 50 zmol; the theoretically
      required amount of blood is therefore less than 1 microliter for PCR). The ESI-MS
      measurement of the PCR products proved to be a new accurate, sensitive and fast
      tool for gene diagnosis.

PMID- 8652876
TI  - Ebrotidine and its metabolites studied by mass spectrometry with electrospray
      ionization. Comparison of tandem and in-source fragmentation...
AB  - Electrospray ionization was used for the analysis of ebrotidine and its potential
      metabolites. Since standard electrospray gave only the quasi-molecular ions for
      most of the compounds, two collision-induced dissociation (CID) experiments were
      carried out in order to obtain structural information: tandem mass spectrometry
      (MS/MS) and in-source fragmentation by increasing the cone voltage (CVF, cone
      voltage fragmentation). CVF produced more fragmentation than MS/MS, and the
      intensities of the fragments formed were also greater. Unlike Ms/MS spectra, CVF
      spectra gave ions which showed retention of the bromine isotope pattern, adducts
      with acetate and dehydration. The general fragmentation pathways observed for
      ebrotidine and its derivatives were basically the same for the CVF and MS/MS
      experiments. Most of the fragments were formed by the breaking of bonds to
      heteroatomics. In order to analyse biological samples containing ebrotidine and
      its biotransformation products, an HPLC/MS separation procedure with simultaneous
      UV detection was developed, allowing the identification of ebrotidine and its
      metabolites in human urine.

PMID- 8652877
TI  - Molecular weight determination of megadalton DNA electrospray ions using charge
      detection time-of-flight mass spectrometry.
AB  - We present results obtained with a novel mass spectrometer capable of determining
      the mass of multiply charged electrospray ions generated from samples of
      macromolecules in the megadalton (MDa) size range. The instrument utilizes a
      sensitive amplifier which can detect the charge on a single ion as it passes
      through a tube detector. A velocity measurement of an ion with known
      electrostatic energy provides the ion's mass-to-charge ratio. Simultaneous
      detection of the ion charge permits a mass assignment to be made for each ion.
      Electrospray ions of DNA and polymer molecules with masses greater than 1 x 10(6)
      Da and charge numbers (z) in excess of 425 e(-) are readily detected in this mass
      spectrometer. The weights of small particles were also measured. The on-axis
      single-ion detection configuration provides a duty cycle of nearly 100% and
      extends the practical application of electrospray mass spectrometry to the
      analysis of very large molecules with relatively inexpensive instrumentation.

PMID- 8652878
TI  - Direct database searching with MALDI-PSD spectra of peptides.
AB  - The analysis of matrix-assisted laser desorption ionization post-source decay
      (MALDI-PSD) mass spectra of peptides by using the cross-correlation method for
      database searching is illustrated. MALDI-PSD mass spectra are shown to contain
      sufficient fragmentation information to uniquely identify the correct amino acid
      sequence from large protein databases (approximately 160,000 entries). A search
      employing the MALDI-PSD mass spectrum of a phosphorylated peptide that correctly
      identifies the amino acid sequence and the site of phosphorylation is also
      illustrated.

PMID- 8652879
TI  - Comparison of fragmentation modes for the structural determination of complex
      oligosaccharides ionized by matrix-assisted laser desorption/ionization mass
      spectrometry.
AB  - Fragment ions from underivatized N-linked oligosaccharides ionized by matrix
      assisted laser desorption/ionization mass spectrometry were obtained by
      spontaneous fragmentation on a magnetic sector mass spectrometer, by post-source
      decay (PSD) on a reflectron time-of-flight (TOF) instrument and by collision
      induced dissociation on a magnetic sector instrument fitted with an orthagonal
      TOF analyser. Spontaneous fragmentation on the magnetic sector instrument
      produced ions mainly by glycosidic cleavage together with two abundant ions
      formed by cross-ring cleavage of the reducing-terminal residue. The PSD spectra
      were similar, the majority of ions being formed by glycosidic cleavage. Internal
      fragment ions were abundant. High-energy collision-induced dissociation spectra
      recorded with the orthagonal-TOF analyser, differed considerably from the other
      types of spectra, particularly in the appearance of major fragment ions produced
      by cross-ring cleavages of most of the constituent monosaccharide residues. These
      ions allowed much sequence and branching information to be obtained from the
      oligosaccharide.

PMID- 8652880
TI  - Analysis of linear oligogalacturonic acids by negative-ion electrospray
      ionization mass spectrometry.
AB  - Linear oligogalacturonic acids (1,4-linked alpha-D-galacturonic acid oligomers),
      obtained by partial acid hydrolysis of orange polygalacturonides, were studied by
      negative-ion electrospray ionization mass spectrometry, without prior sample
      derivatization. After preparative separation using high-resolution anion-exchange
      chromatography, some fractions enriched in uronic acids were desalted,
      transferred into a methanol+water solution adjusted to pH 10, and directly
      submitted to electrospray ionization mass spectrometry in the negative-ion
      recording mode. Clear molecular mass assignments of the oligomers, covering a
      degree of polymerization between 4 and 7, were obtained.

PMID- 8652881
TI  - Characterization of a recombinant antihaemophilia-A factor (factor VIII-delta II)
      by matrix-assisted laser desorption/ionization mass spectrometry.
AB  - Factor VIII-delta II is a genetically engineered deletion variant of factor VIII,
      expressed by recombinant Chinese hamster ovary cells. This 1436-residues-long
      protein has a molecular mass, calculated from its sequence, of 164,954 Da and
      exhibits seven potential glycosylation sites. The glycoprotein, secreted as a
      single polypeptide chain, can be cleaved after Arg740 to generate a heavy-light
      chain complex of 90-80 kDa as revealed by sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis (SDS-PAGE) analysis. Due to its high mass range and excellent
      sensitivity, matrix-assisted laser desorption/ionization-mass spectrometry (MALDI
      MS) has been chosen to play a key role in the precise determination of the
      molecular masses of recombinant factor VIII and the localization of the post
      translational modifications within the protein. Native factor VIII-delta II
      displays a molecular mass of 178 kDa. The masses measured by MALDI for the heavy
      and light chains are respectively 89,900 Da and 87,100 Da. These mass values,
      found reproducible from batch to batch, are used to characterize factor VIII
      delta II during the course of preclinical studies. The difference from the
      theoretical molecular molecular masses and the observation of broad molecular
      peaks suggest that recombinant FVIII-delta II has been effectively glycosylated
      by the host cell on both heavy and light chains. Similarly to plasma-derived
      factor VIII, the recombinant protein is proteolyzed by thrombin to generate the
      A1/A2/A3-C1-C2 trimer that is the active form of factor VIII in the coagulation
      pathway. MALDI-MS analysis of activated factor VIII-delta II suggested the
      presence of N-linked oligosaccharides in the proteolyzed light chain (A3-C1-C2 of
      77,750 Da) and in the A1 domain (46,400 Da) of the heavy chain. By contrast, the
      similarity between the experimental and theoretical masses of the A2 domain
      indicated that its single potential glycosylation site has not been utilized.

PMID- 8652882
TI  - Thickness measurement of hydrated and dehydrated cryosections by EELS.
AB  - Electron energy-loss spectroscopy (EELS) provides a useful method for determining
      the thickness of frozen-hydrated and dehydrated cryosections in terms of the
      inelastic mean free path. Cryosection thickness is an important parameter because
      plural inelastic scattering limits the sensitivity of elemental microanalysis
      based on core-loss EELS, and because overlapping structures can affect
      interpretation of microanalytical data as well as the quality of electron images.
      The purpose of this work was to establish the minimum practical thickness for
      cutting cryosections and to explain the measured values for hydrated and
      dehydrated specimens. Hydrated sections were typically found to be between 1.5
      2.5 times thicker than expected from the nominal microtome setting; this
      difference can be largely explained by compression during cutting. Comparison of
      micrographs from hydrated and dehydrated cryosections of rapidly-frozen,
      vitrified liver revealed a lateral shrinkage of approximately 20% on drying. The
      measured compression and shrinkage factors are consistent with dark-field
      scanning transmission electron microscopy (STEM) mass measurements on freeze
      dried sections. Freeze-dried cryosections, cut to a nominal thickness of 90 nm
      and supported on thin Formvar/carbon films, had a relative thickness t/lambda i
      in the range of 0.5 for cytoplasm to 0.9 for mitochondria when analyzed at 100
      keV beam energy. Mass loss of approximately 30% occurring at high electron dose
      enabled useful core-loss spectra to be recorded even from high-mass compartments
      such as mitochondria without excessive plural scattering.

PMID- 8652883
TI  - Freeze-substitution as a preparative technique for immunoelectronmicroscopy:
      evaluation by atomic force microscopy.
AB  - Cryofixation followed by freeze substitution in osmium tetroxide was evaluated as
      a method for preparing biological specimens for immunoelectronmicroscopy. Samples
      were rapidly frozen by impact onto a sapphire block cooled with liquid nitrogen,
      substituted at -80 degrees C in acetone containing osmium tetroxide, and embedded
      in epoxy resin. With this protocol, excellent ultrastructure can be combined with
      localization of antigens that otherwise would be inactivated by the osmium, but
      labeling may need to be enhanced by chemically etching the sections prior to
      staining. The effects of etching on various structures in the sections were
      investigated by examining the sections with atomic force microscopy, an approach
      that yields three-dimensional views of the surface of the section. A considerable
      part of the section was removed or collapsed by the etching, and these effects
      occurred differentially in several components of the tissue and with different
      etching protocols. Nevertheless, the results suggest that the partial removal of
      the plastic by etching of freeze-substituted tissue can be explored as a method
      for exposing fine biological structures for observation with atomic force
      microscopy.

PMID- 8652884
TI  - Slow-speed freezing of chemically unfixed biological tissues and long-term
      storage of frozen samples for cryoscanning electron microscopy.
AB  - We describe a procedure in which plant tissue as well as a yeast culture on agar
      are frozen with slow cooling rates for observation of surface structures in a
      cryoscanning electron microscope. A system is also presented for long-term
      storage of frozen specimens under liquid nitrogen, in which the material is
      maintained for direct observation. Some small tools are described, which are
      essential for making preparations using slow-speed freezing and for the storage
      of prepared samples. Three examples of preparations with different complications
      are given: the "sculptures" on the surface of a leaf of Allium schoenoprasum, an
      early stage of flower development of Allium cernuum, and a part of an agar-grown
      colony of Arxula adeninivorans. In our experience, it is possible to store fully
      hydrated samples under the described conditions for more than a year without
      damaging the fine structures.

PMID- 8652885
TI  - Soot morphology: an application of image analysis in high-resolution transmission
      electron microscopy.
AB  - Interest in the fine structure of soots and carbon blacks is motivated by a
      variety of possible applications. The structure provides information on the
      origins of the particles and on their adsorptive and reactive properties. This
      paper describes a method for quantification of the structure of soots and carbon
      blacks based on direct electron microscopic observation followed by image
      analysis of these materials. High-resolution transmission electron microscopy
      (HRTEM) provides a very detailed observation of particle structure. The
      differences in soot structure, because of its complexity, may not be easily
      quantifiable with the human eye; therefore, high-level computer software has been
      used to manipulate HRTEM images. This technique involves the application of fast
      Fourier transforms (FFT) to single particles and the measurement of
      characteristic parameters such as interplanar spacings and crystallite sizes from
      these particles. The methodology and application of this characterization
      technique are presented here. Results are shown for different samples obtained
      from soot and carbon black particles selected to illustrate the capabilities of
      the methodology. Quantitative information can be obtained on structural
      characteristics, e.g., interplanar spacing, circularity, orientation, elongation,
      and length distribution of lattice fringes, as well as on the fractional coverage
      of the extracted pattern.

PMID- 8652886
TI  - Energy-filtered high-resolution electron microscopy and composition-sensitive
      imaging.
AB  - Energy-filtered electron imaging is one of the future directions of high
      resolution electron microscopy (HREM). In this paper, characteristics and
      applications of energy-selected HREM are illustrated. Image contrast can be
      dramatically improved with the use of an energy filter. High-resolution chemical
      sensitive imaging using ionization edge loss electrons is demonstrated in studies
      on Ni/Ti and A1/Ti multilayer thin films. It has been shown that the spatial
      resolution of energy-selected ionization edge electron images is dominated by the
      signal-to-noise ratio. Experimental parameters which may be selected to improve
      the signal-to-noise ratio are discussed. It is pointed out that since the width
      of the energy-selecting window is small, the energy-filtered ionization edge
      electron image is sensitive to the specimen composition, but the calculation of
      the specimen composition based on the energy-filtered images relies on the
      integrated ionization cross-sections which are largely determined by the solid
      state effects. Therefore, the energy-filtered ionization image should be referred
      as composition-sensitive image rather than compositional image.

PMID- 8652887
TI  - Image segmentation and bright contrast spot localization of the high resolution
      atomic image.
AB  - Some basic quantitative analysis techniques of digitized high resolution atomic
      image are developed in this paper. We describe how to divide the atomic image
      into small independent areas with special structure information by the valley
      mesh segmentation method. The procedure is with regard to the bright contrast
      spot segmentation of atomic images. We suggest several ways for bright contrast
      spot localization in images. Calculation routines for peak detection and weighted
      local position average methods for this purpose are given.

PMID- 8652888
TI  - Conjunctiva.

PMID- 8652889
TI  - Ultrastructure of the human cornea.

PMID- 8652890
TI  - Morphology of the aqueous outflow pathway.

PMID- 8652891
TI  - Expanding the donor pool: use of marginal donors for solid organ transplantation.
AB  - Organ transplantation has become a viable treatment for an increasing number of
      patients suffering from irreversible organ failure. In response to the steeply
      rising demand for transplantation, both the number of transplant centers and the
      number of patients on waiting lists have grown rapidly. Because organ donation
      has not kept pace with demand, each year a greater number of patients die while
      awaiting donor organs. (About 9% of all patients on the list in 1993 but not
      transplanted died. Death rates were highest, 19% and 16% respectively, for
      patients awaiting hearts and livers.) Among the factors contributing to the organ
      shortage are cultural and psychological barriers to donation and missed
      opportunities to request donation. An accompanying diminution in traumatic deaths
      of potential young donors has made older and other marginal, or higher-risk,
      donors the focus of studies on expansion of the donor pool. The studies reviewed
      herein evaluated donor risk factors such as age, disease (including infection),
      obesity, cold ischemia time, suboptimal organ function, and nontraumatic causes
      of death. Overall, broadened criteria for acceptable donor kidneys, hearts, and
      livers appear to lessen graft survival rates somewhat compared with rates for
      ideal donor organs. Nonetheless, use of higher-risk organs allows lifesaving
      transplants that could not otherwise be performed and results in acceptable
      prognoses for survival. Further research is needed to identify better tests for
      evaluating donor organs, provide longer-term follow-up of recipients of higher
      risk organs, and develop alternative means to fill the donor-organ shortfall.

PMID- 8652892
TI  - Role of granulocyte colony stimulating factor (G-CSF) in reversing neutropenia in
      renal allograft recipients.
AB  - Neutropenia in solid organ transplant recipients may be caused by
      immunosuppressive therapy, antimicrobial therapy, as well as bacterial and viral
      infections. Filgrastim, a human granulocyte colony stimulating factor (G-CSF) is
      used for the reversal of neutropenia. Although its influence is principally
      restricted to neutrophil progenitors, the safety of G-CSF in terms of
      percipitating or aggravating allograft rejection and its efficacy in reversing
      neutropenia in kidney and combined kidney and pancreas transplant patients has
      not been studied or reported. In this study we retrospectively analyzed the use
      of G-CSF between March 1992 and May 1994 at the University of Cincinnati Medical
      Center, in patients who received either a kidney or a combined kidney and
      pancreas transplant. A total of 25 patients developed 35 episodes of neutropenia
      and received an average of 2.9 doses of G-CSF per episode. The mean WBC nadir was
      2.6 x 10(3)/cu mm with an average peak WBC count of 15.5 x 10(3)/cu mm following
      treatment (p = < 0.00001). The average number of days to peak WBC after
      initiation of treatment was 4.6 days. The mean pre-treatment serum creatinine
      level was 2.3 mg/dl and the peak serum creatinine in the week following treatment
      remained the same. We conclude that G-CSF is an effective treatment in reversing
      neutropenia in renal transplant recipients and does not precipitate or aggravate
      allograft rejection.

PMID- 8652893
TI  - Mediators of fibrinolysis in orthotopic liver transplantation.
AB  - Activation of fibrinolysis remains a clinical problem in orthotopic liver
      transplantation. We have measured tissue plasminogen activator (t-PA), plasmin
      and alpha-2-anti-plasmin (alpha 2AP) activities in plasma from 10 patients
      undergoing elective transplantation. t-PA activity increased during the anhepatic
      phase and immediately after graft reperfusion (p > 0.001). This increase could
      not be attributed to t-PA released by the donor liver. Overall transfusion
      requirements did not relate with either t-PA or alpha 2AP activities
      individually, but were strongly correlated with the ratio t-PA/ alpha 2AP (p >
      0.02). These results suggest that routine prophylactic use of antifibrinolytic
      agents may be beneficial.

PMID- 8652894
TI  - Transient suppression of pancreatic endocrine function in patients following
      brain death.
AB  - To investigate pancreatic endocrine function in brain-dead patients, an
      intravenous glucose tolerance test (i.v. GTT) was performed in 8 brain-dead
      subjects maintained using the combined administration of vasopressin (ADH) and
      catecholamines during the first 3 days following the onset of brain death. Ten
      healthy adults served as control subjects. Although plasma glucose concentrations
      markedly increased and exceeded 300 mg/dl in most subjects just after the onset
      of brain death, they decreased to less than 200 mg/dl in most subjects after 24
      h. The early insulin release also was significantly lower in brain dead subjects
      compared to controls (p < 0.01). The late insulin release was not decreased
      compared to controls but rather increased, which was accompanied by decreased
      glucose disappearance rate. The early insulin release recovered rapidly during
      the first 3 days following brain death without significant changes in the plasma
      hormone concentrations such as epinephrine, human growth hormone, thyroid
      stimulating hormone, triiodothyronine, thyroxine, cortisol, and glucagon. The
      early insulin release and the plasma glucose concentration just before i.v. GTT
      was negatively correlated (R = -0.55, p < 0.05). We suggest awaiting recovery
      from hyperglycemia and early insulin release provides a reasonable approach to
      transplantation of the pancreas.

PMID- 8652895
TI  - Cimetidine or ranitidine in renal transplant patients receiving cyclosporine.
AB  - While H2-receptor antagonists are commonly used in renal transplant patients to
      prevent peptic ulcer disease, they have been associated with immunostimulation,
      interference with cyclosporine (CsA) metabolism, and inhibition of tubular
      secretion of creatinine. In renal transplant patients, cimetidine in high doses
      has been shown to cause a sustained rise in serum creatinine (SCr) and to reduce
      creatinine clearance (CrCl) with no change in inulin clearance. In this short
      term prospective study, we evaluated the effects of single daily doses of
      cimetidine or ranitidine on renal function, and CsA serum concentration. Fourteen
      renal transplant patients with stable renal function were assigned to receive
      either cimetidine 400 mg daily or ranitidine 150 mg daily for 7 days. In patients
      who received cimetidine, a slight rise in SCr was observed at days 2 and 5 which
      was not statistically significant, but no significant change in CsA trough level
      was noted. No changes in SCr or CsA level were noted in the patients who received
      ranitidine. No changes in GFR were observed in either cimetidine- or ranitidine
      treated patients. We conclude that, in our short-term study, cimetidine or
      ranitidine in the doses used in this study did not affect the GFR or CsA level,
      or SCr.

PMID- 8652896
TI  - Proteinuria in recipients of liver transplants.
AB  - We investigated the incidence and significance of proteinuria in recipients of
      liver transplants. The overall incidence of proteinuria was 59.72%. The peak
      incidence of proteinuria was at 3 months and at the end of 1 yr posttransplant.
      Proteinuria was higher in those patients who developed posttransplant diabetes
      mellitus, and those who developed both posttransplant diabetes and posttransplant
      hyperlipidemia. Patients who received higher total dosage of steroids and CsA had
      significantly greater proteinuria. Patients who had a Cr Cl greater than 50
      ml/min had greater proteinuria posttransplant for the first 6 months, but the
      trend was reversed later. We did not find any association of proteinuria with
      age, weight, rejection episodes, or with the etiology of liver failure.
      Hypertension was a common occurrence in our patients, and therefore its
      significance in the causation of proteinuria could not be defined.

PMID- 8652897
TI  - Serial monitoring of soluble interleukin-2 receptor as a rapid marker of
      cytomegalovirus infection and response to antiviral therapy.
AB  - Serial sIL-2R serum levels were evaluated as an indicator of cytomegalovirus
      infection and response to antiviral therapy. All cases of post-transplant CMV
      infection or disease were studied over a 2.5-year period with serial sIL-2R serum
      levels monitored daily post-transplant until discharge, during each inpatient
      admission and with each outpatient laboratory analysis. Mean sIL-2 levels +/-
      S.E.M. rose from a baseline level of 3662 +/- 321 U/ml to 11657 +/- 3311 U/ml at
      the time of diagnosis. Serum sIL-2R concentrations were significantly elevated
      from baseline as early as 14 days prior to diagnosis of CMV. Mean peak sIL-2R
      levels occurred an average of 4 days after the initiation of ganciclovir therapy
      and remained significantly elevated for an average of 20 days of treatment. Serum
      sIL-2R levels in patients with resolved CMV returned to within 20% of baseline
      after 20 days of therapy. These data support the idea that serial monitoring of
      sIL-2R serum levels may be useful adjunctively in the diagnosis of CMV as well as
      determining the response to and duration of antiviral therapy.

PMID- 8652898
TI  - Increased incidence of renal allograft thrombosis after continuous ambulatory
      peritoneal dialysis.
AB  - Allograft thrombosis occurred in 44 cases (4.8%) among 915 consecutive cadaveric
      renal transplantations performed in a single center over a 13-year period.
      Multiple logistic regression analysis of risk factors revealed that continuous
      ambulatory peritoneal dialysis (CAPD) was the only independent variable
      associated with renal allograft thrombosis. When CAPD was used for prior renal
      replacement therapy graft thrombosis occurred in 7.3% (22/303), whereas
      hemodialysis was associated with 3.6% (22/612) of graft thromboses (p < 0.02). No
      differences in transplant characteristics, including hemodynamics, hematological
      parameters, immunosuppressive therapy, graft anatomy and preservation, were
      observed between the cases with graft thrombosis and a matched control group (n =
      88). CAPD treatment appears to be a risk factor in the development of renal
      allograft thrombosis that requires further perioperative coagulation studies in
      order to design an effective prophylaxis.

PMID- 8652899
TI  - Cyclosporine bioavailability: dosing implications and impact on clinical outcomes
      in select transplantation subpopulations.
AB  - Reports in the literature indicate that clinical outcomes in select patient
      subpopulations have been inferior to those in the general transplantation
      population. Of potential interest in this regard is the finding that lower
      cyclosporine bioavailability correlates with a higher incidence of acute
      rejection and graft loss. To gain insights into these issues, we examined data
      from renal transplant recipients at our own centers and in one large data base.
      Our experience revealed that cyclosporine bioavailability was markedly lower in
      patients who developed acute or chronic rejection than in those with stable graft
      function. An analysis by demographic or clinical factors showed that cyclosporine
      bioavailability was lower in diabetics and black patients. In one study,
      diabetics required much higher daily doses of cyclosporine to achieve outcomes
      comparable to those in non-diabetics; even then, diabetics attained lower
      cyclosporine blood levels. Other work found that long-term graft survival rates
      were poorer in blacks, even though cyclosporine dosages and blood levels were
      comparable to those in whites. A case-controlled study from the pregnancy
      registry found that cyclosporine dosages were consistently higher in pregnant
      patients who maintained good graft function than in those who experienced graft
      dysfunction. These results suggest that the subpopulations examined should
      receive immunosuppression with higher cyclosporine dosages than those used in the
      general transplantation population. These subpopulations may also benefit from a
      cyclosporine formulation that provides better absorption, resulting in more
      consistent and predictable cyclosporine bioavailability.

PMID- 8652900
TI  - Effect of HLA-DR3 gene expression on cadaveric renal allograft survival in
      blacks.
AB  - The effect of HLA-DR3 gene expression was studied in black cadaveric renal
      allograft recipients of organs from the same donor race. From January 1984 to
      June 1992, 70 patients received cadaveric renal allografts at the Medical
      University of Southern Africa (MEDUNSA). The average age and F:M ratio was 30
      years and 1: 1.2 respectively. HLA-A, B and DR matching was zero to one in 80%.
      Actuarial graft survival at yearly intervals in 22 HLA-DR3 gene expressors was
      62, 55, 38, 30 and 24% as compared to 82, 78, 70, 64 and 58% in 48 non-HLA DR3
      gene expressors (Breslow p = 0.01 and Mantel-Cox p = 0.05). There was no
      statistical differences in creatinine values associated with HLA-DR3 gene
      expression during the 1st year after transplantation. Renal allografts were lost
      from rejection in 9 out of 16 HLA-DR3 gene expressors as compared to 19 out of 29
      non-HLA DR3 gene expressors (Fisher's exact test p = 0.8). HLA-DR3 gene
      expression is a risk factor for earlier graft loss in black South Africans.

PMID- 8652901
TI  - Ketanserin: a new perspective in posttransplant erythrocytosis?
AB  - We have recently shown that ketanserin, an antagonist of peripheral serotonin 5
      HT2 receptors lowers blood erythropoietin (Epo) levels in some chronic
      hemodialysis patients. Based on this finding, a preliminary study was undertaken
      to investigate the effect of a 3-week oral ketanserin administration on serum Epo
      concentration and relevant hematological parameters in 4 renal allograft
      recipients with posttransplant erythrocytosis (PTE). We found a marked decrease
      in Epo concentrations following ketanserin administration, from 48% to 76% of the
      abnormally elevated pretreatment values with subsequent increases at 3 weeks
      after discontinuation of the drug in all patients studied. In 3 of them a
      corresponding decrease or no rise in the erythrocyte count were noted. During the
      6-week study period, the need for monthly phlebotomies was eliminated in these
      patients. It is hypothesized that ketanserin diminishes erythropoietin synthesis
      and may become a new drug in the treatment of posttransplant erythrocytosis.

PMID- 8652902
TI  - Urethritis/dysuria after simultaneous pancreas-kidney transplantation.
AB  - We evaluated the role of conservative treatment for urethritis and its
      complications after simultaneous pancreas-kidney (SPK) transplant. Twenty-six
      type I diabetic recipients with end-stage renal disease underwent SPK transplants
      with bladder exocrine drainage. Urethritis/ dysuria occurred in 4/26 (16%) of the
      patients. All cases resolved with conservative treatment that included Foley
      catheter and/or suprapubic cystostomy. Despite the frequency of this urological
      complication, none of the patients needed diversion of the exocrine drainage from
      the bladder to the intestine.

PMID- 8652903
TI  - Gingival overgrowth in renal transplant patients administered cyclosporin A in
      mixture or in capsule form. A longitudinal study.
AB  - Cyclosporin A (CsA)-induced gingival overgrowth was longitudinally studied in 45
      adult renal transplant patients randomly assigned to be administered CsA orally
      in mixture or in capsule form. After 1 year of CsA therapy, 37% of the mixture
      and 43% of the capsule patients exhibited gingival overgrowth. In mixture
      patients gingival overgrowth was present, already after 1 month of CsA therapy
      and, after 12 months, mixture patients exhibited an increased number of sites
      with gingival overgrowth in the regions of the upper front and lower molars
      compared to capsule patients. In addition, the relative increase in gingival
      width of the interdental papillae of the maxillary central incisors and the
      mandibular first molars, measured buccolingually on stone casts, was also higher
      in mixture patients than in capsule patients. In a stepwise multiple logistic
      regression analysis, the use of nifedipine and the total CsA dose administered
      during the first 6 posttransplant months were the predictors associated with
      gingival overgrowth. The study suggests that concomitant administration of
      nifedipine in renal transplant patients should be avoided and a change from the
      mixture form of CsA to the capsule form should be considered in order to minimize
      the development of CsA-induced gingival overgrowth.

PMID- 8652904
TI  - [Gene transfer and radiotherapy].
AB  - Recent studies have shown that experimental tumors could be treated more
      efficiently with ionizing radiation if genetic material was transfered into tumor
      cells. Several approaches have been reported, and among them, the first one
      consisted of increasing the apoptotic response to radiation by modulating genes
      involved in the regulation of the apoptotic pathway. Indeed the modulation of p53
      and bcl-2 gene expression has recently been used successfully in several
      experimental models to increase the apoptotic death after radiation. A second
      approach consisted of taking advantage of the conditional expression of some
      genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio
      inducible promoter which can be combined to a gene, able to enhance or decrease
      the biological effect of radiation. The irradiation of such a transgene under the
      control of a radio-inducible promoter can lead to a second biological effect,
      concomitant to the irradiation, as reported for the TNF alpha under the control
      of the EGR (early growth response) promoter. A third approach consisted of
      enhancing the effect of radiation induced tumor cell death by the expression of a
      suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus
      thymidine kinase gene). These preliminary results obtained in experimental models
      appear to be very promising and might improve the efficacy and specificity of
      radiation therapy in a not too distant future.

PMID- 8652906
TI  - [Involvement of sulfated proteoglycans in the control of proliferation of MCF-7
      breast cancer cells].
AB  - The MCF-7 breast cancer cells exhibit remarkable growth enhancement in response
      to basic fibroblast growth factor (FGF-2) stimulation in a dose dependent manner.
      To investigate the involvement of proteoglycans on control of FGF-2 induced
      proliferation, polysaccharide chains were degraded by specific enzymes. Our
      results showed that MCF-7 cells were unsensitive to FGF-2 after enzymatic
      degradation of heparin sulfate proteoglycans (HSPG) by heparinase. After
      metabolic inhibition of sulphation by sodium chloride, radiolabelled
      proteoglycans were purified and quantified by ion exchange chromatography. Sodium
      chlorate treatment reduced by 70% sulfation of proteoglycans. This decrease of
      sulphation totally inhibited FGF-2-mediated proliferation. The sulphated
      glycosaminoglycans which were critical in FGF-2-induced proliferation were
      strictly HSPG, as an addition of heparin in cell culture medium can restore FGF-2
      mitogenic activity. In contrast, other glycosaminoglycans (chondroitin
      sulfate/hyaluronic acid) did not show any effect. These results provide clear
      evidence for the critical role of HSPG in FGF-2-induced proliferation on MCF-7
      breast cancer cells.

PMID- 8652905
TI  - [Mental confusion syndromes in oncology].
AB  - Delirium is a complication related with the treatment and the evolution of cancer
      diseases. This disorder occurs more often among patients who are under treatment
      (chemo or radiotherapy) and among those who are terminally ill. Estimates of
      prevalence of delirium range from 4% to 40%. Delirium must be detected and
      treated as soon as possible because it is often associated with a poor prognosis
      of the cancer disease and with the development of an important distress of
      patients and their relatives. Delirium may have several underlying causes.
      Management of delirium has to be symptomatic and etiological, including support
      of the family. Education of the caregivers, for a better detection, treatment and
      control of these disorders, should be more systematic in order to improve the
      quality of the care given to patients with cancer. The present work reviews
      literature concerning these different aspects.

PMID- 8652907
TI  - [Modification of the response to paclitaxel of human differentiated colon cancer
      line after long-term treatment at very low dose].
AB  - Taxoids (paclitaxel, Taxol and docetaxel, Taxotere), drugs which stabilize
      microtubules, demonstrate marked activity against ovarian, brain and lung cancer.
      We investigated, on the human colon adenocarcinoma HT29-D4 cell line, firstly the
      effects of taxoids in function of the differentiation state and secondly the
      effects of a low dose of paclitaxel on the differentiation process. The cellular
      parameters studied were microtubular network, cell cycle and cell tubulin
      content. Undifferentiated cells treated with paclitaxel or docetaxel (10-100 nM)
      classically induced bundles in interphasic cells and pseudoasters in mitotic
      cells, arrest in cell cycle in G2M and increase in tubulin content. Inversely, no
      modification was observed in differentiated cells after similar taxoid treatment.
      Long-term low-dose pretreatment of differentiated cells restitutes some
      sensitivity to taxoids since these cells become responsive to further taxoid
      treatment, as reflected by modifications of the microtubule network.

PMID- 8652908
TI  - [Prognostic factors of survival in infiltrating urothelial bladder carcinoma. A
      retrospective study of 158 patients treated by radical cystectomy].
AB  - The clinical files of 158 patients who were treated by radical cystectomy for
      infiltrating bladder carcinoma were retrospectively reviewed to define prognostic
      factors. PATIENTS AND METHODS.--All patients had a radical cystectomy with
      bilateral pelvic lymph node dissection for an infiltrating operable bladder
      urothelial tumor. Each tumor was classified according the pTNM staging system and
      were analysed for the presence of vascular invasion, carcinoma in situ and tumor
      grade. Twenty-three patients (14.5%) had an irradiation. Sixty-seven patients
      (42%) received chemotherapy (neoadjuvant in 31, adjuvant in 30, both in 6).
      RESULTS.--The median overall survival of the whole group was 19 months. The 5
      years disease free survival (DFS) and overall survival (OS) were 44% and 31%,
      respectively. In the univariate analysis, the factors with significant prognostic
      value were: pT stage and the tumor size for OS, age and lymph node involvement
      for DFS, presence of carcinoma in situ (CIS) and tumor size for local recurrence
      free survival (LRFS) and sex and lymph node involvement for metastatic free
      survival (MFS). The following variables attained significant prognostic value in
      the multivariate analysis: pT stage and an interaction between lymph node
      involvement and vascular invasion for OS, pT stage and presence of CIS for LRFS,
      pT stage for MFS. CONCLUSION.--The pT stage, lymph node involvement and vascular
      invasion are the most important prognostic factors of survival in infiltrating
      bladder cancer.

PMID- 8652909
TI  - [Efficacy of ondansetron in acute and delayed cisplatin-induced nausea and
      vomiting].
AB  - Nausea and vomiting have always been associated with anti-cancer agents in
      patients' minds because these effects were the main ones to occur during
      chemotherapy. Since 1990, a novel class of antiemetic agents has been available:
      the 5-HT3 serotonin receptors antagonists. Several randomised, international
      phase III studies have been carried out with ondansetron, the first compound of
      this therapeutic agent class. Today, the combination of ondansetron with
      corticosteroids appears to be one of the most efficient antiemetic treatment for
      high-dose cisplatin acute induced emesis and can be therefore considered as a
      reference treatment for acute cisplatin-induced emesis, cisplatin being the most
      emetogenic cytotoxic drug. A complete control (0 emetic episode) reached at the
      first course allows the maintenance of the efficacy over repeated courses for the
      majority of patients. In delayed emesis (24 hours after the start of
      chemotherapy), it is believed that the serotonin is not the only neuromediator
      involved in the mechanism.

PMID- 8652910
TI  - [Hypercalcemia a sign of medullar transformation of low grade malignant lymphoma.
      Apropos of a case].
AB  - The authors report a case of transformation of a low grade non-Hodgkin's lymphoma
      (LGL) to an agressive lymphoma in a 55 year-old woman who was treated by
      fludarabine phosphate. The only sign of transformation was the supervention of an
      hypercalcemia. This complication is rare in the evolution of the LGL and the
      mechanism is original.

PMID- 8652912
TI  - Transoesophageal echocardiography in congenital heart disease.
AB  - The development of paediatric transoesophageal ultrasound imaging represents an
      important advance in the diagnosis and management of the patient with congenital
      heart disease. Although primary diagnostic transoesophageal studies are seldom
      indicated in infants and unoperated children, they have an important role in the
      older child, especially where there has been prior cardiac surgery. Diagnostic
      studies are most appropriate for abnormalities of venous return, the atria,
      atrioventricular valves and the left ventricular outflow tract. Two other
      important areas in which transoesophageal imaging is playing an increasing role
      in the management of the paediatric patient is in monitoring of surgical repair.

PMID- 8652911
TI  - [Use of vinorelbine in non-small cell bronchial cancer: current aspects and
      perspectives].

PMID- 8652913
TI  - Role of intraoperative transesophageal echocardiography during repair of
      congenital cardiac defects.
AB  - Intraoperative epicardial echocardiography has been available for several years,
      and has been demonstrated to be very useful in intraoperative echocardiography.
      With the availability of small pediatric transesophageal (TEE) probes, it has
      become possible to perform intraoperative TEE in infants and children of all
      sizes. With advantages of serial assessment of anatomy, function and flow, and
      lack of interference in the operative field, TEE has become routine in many
      surgical centers. Our experience supports its routine use in nearly all patients
      undergoing repair of congenital heart disease. We generally use pediatric probes
      in patients less than 15 kg and adult size probes for those over 15 kg.
      Examinations are performed before and after bypass for use in surgical planning,
      anesthetic and hemodynamic management, and in evaluation of repairs. In 44 of 667
      (6.6%) cases, TEE findings prompted a return to bypass for further surgery or
      revision of surgery. In 75% of these patients, the problem identified by TEE was
      relieved, and patients had a good outcome. The benefit obtained by avoiding later
      reoperation in these patients has also proved cost-effective, supporting the use
      of TEE on a routine basis. Complications have been few (24/667, 3.5%), without
      long-term sequelae. They include failure to insert the TEE probe (1.2%), airway
      obstruction (0.9%), vascular compression (0.7%), tracheal extubation (0.6%) and
      gastric incision (0.1%); several of these complications are now considered
      avoidable. Intraoperative TEE offers major advantages in intraoperative
      assessment and management of patients undergoing repair of congenital heart
      disease.

PMID- 8652914
TI  - Assessment of congenital heart defects by dynamic three-dimensional
      echocardiography: methods of data acquisition and clinical potential.
AB  - To evaluate the use of three-dimensional (3D) echocardiography in the diagnosis
      of congenital heart defects, we studied 238 patients aged 3 days to 19 years
      (mean 4.3 years) with normal hearts (n=13) or a variety of congenital heart
      defects (n=225). Three different modalities of data acquisition suitable for 3D
      reconstruction were applied. For parallel scanning, the transducer is held in a 6
      cm long scan frame and then moved over the thorax, or in the subcostal position,
      by a stepper motor using 0.5-mm steps with acquisition of perpendicular parallel
      images of the heart. For rotational scanning, the transducer is rotated at
      sectors of 2 degrees over a span of 180 degrees. For fan-like scanning, the
      transducer is moved in an arc 45 degrees each way from its vertical axis.
      Movement of the transducer is computer-controlled and performed with
      electrocardiographic and respiratory gating. Between 80 and 120 slices of the
      heart are thus obtained, which form the 3D dataset. This dataset can then be
      ?sectioned? in any desired plane, thus permitting generation of views simulating
      intraoperative perspectives. Ventricular septal defects and atrioventricular
      valves can be displayed as viewed via the atrium. Muscular ventricular septal
      defects can be viewed as seen through a ventriculotomy. Obstruction in the left
      ventricular outflow tract can be viewed as via an aortotomy, and so on. We
      concluded that this new imaging modality has a vast potential and may facilitate
      planning of intracardiac surgery.

PMID- 8652915
TI  - Colour Doppler myocardial imaging: potential applications in acquired and
      congenital heart disease.
AB  - Doppler myocardial imaging (DMI) is a new ultrasound technique which has been
      developed to allow colour Doppler imaging of cardiac structures as opposed to
      blood pool imaging. This is achieved by changing the velocity, filtering and
      threshold parameters of the standard colour Doppler algorithms. DMI parameters
      which can be measured are regional tissue velocity, acceleration and reflected
      Doppler energy. In addition, concomitant changes in the pulsed Doppler algorithms
      allow interrogation of instantaneous peak velocities during the cardiac cycle in
      the myocardial region in which the sample volume is placed. In both adult
      acquired heart disease and congenital heart disease, these new ultrasound
      parameters may provide new information on myocardial contractile function,
      diastolic function, myocardial perfusion and myocardial structure. The relative
      lack of image quality by chest wall attenuation inherent in the Doppler technique
      means that the methodology is potentially superior to standard grey-scale two
      dimensional imaging in boundary detection and may prove to be of value in
      providing a robust boundary detection algorithm for use in volume calculations
      and in three-dimensional reconstruction of ventricular function.

PMID- 8652916
TI  - MR flow quantification with cardiovascular applications: a short overview.
AB  - We present a short overview of the potential of magnetic resonance imaging (MRI)
      for quantification of flow in the cardiovascular system. The most widespread
      method for creation of MRI flow information utilized flow-sensitizing magnetic
      field gradients. Objects that move in the varying magnetic field introduced by
      such gradients change their precession frequency and therefore obtain a velocity
      dependent offset phase angle. The exact phase behaviour for different types of
      gradients and motion patterns can be calculated and a very simple linear
      relationship is predicted by theory as well as confirmed in experiments between
      constant velocity and phase angle. Phase-sensitive flow MRI (velocity mapping) is
      frequently performed as a two-dimensional gradient-echo technique with flow
      sensitivity (flow encoding) in the through-plane direction, but other encoding
      directions are possible. Parameters that can be determined from a velocity map
      are linear velocity in each voxel, vessel area and flow rate. In the case of a
      stenotic vessel, the trans-stenotic pressure gradient can also be estimated. The
      velocity mapping method has been extensively used for cardiac flow studies in
      adult patient groups, e.g. for indirect measurements of coronary artery flow and
      for the study of aortic valve diseases. In children, the method has recently been
      used to determine shunt volumes in congenital heart disease. We conclude that
      flow investigation with MRI may in the future present a good alternative for the
      clinical evaluation of cardiovascular disorders.

PMID- 8652917
TI  - Non-invasive imaging techniques in pediatric cardiology: impact on clinical
      decision-making.
AB  - To plan the treatment of congenital heart malformations, a detailed knowledge of
      anatomy and hemodynamics is essential. This has previously been obtained by heart
      catheterization and angiocardiography. During the past 20 years, several non
      invasive techniques, such as echocardiography with Doppler, magnetic resonance
      imaging and isotope techniques have evolved. They have profoundly changed the way
      we practise pediatric cardiology. For the initial investigation of a patient with
      suspected heart disease, echocardiography is the routine method. For the less
      experienced, tele-transmission to a pediatric cardiology center can be used to
      complement to investigation. In the preoperative investigation, echocardiography
      with Doppler plays an important role. In some situations, such as aortic lesions
      or complex cardiac malformations, magnetic resonance imaging is useful. Isotope
      methods have been used mainly for quantification of the degree of left-to-right
      shunts. During a 5-year period, 695 infants and children were operated on for a
      heart malformation: 40% were operated on without previous heart catheterization.
      For patients needing surgery before 1 month of age, 58% could be operated on
      based on non-invasive data alone.

PMID- 8652918
TI  - MR imaging and heart function in patients pre- and post-Fontan surgery.
AB  - MR imaging allows functional evaluation of the ventricles of the entire heart
      because it evaluates cardiac anatomy three-dimensionally. Such evaluation is
      independent of chamber size and shape, and virtually independent of mathematical
      assumptions. Applying standard measurements of volume and function in children
      who have undergone multi-staged Fontan operations, we have shown diminished
      ventricular volumes and mass, and decreased cardiac indices, in post-Fontan
      procedure. These variations may be predictive of ultimate outcome in these
      complex patients.

PMID- 8652919
TI  - Three-dimensional reconstruction of MR images in congenital heart disease.
AB  - Commercially available software is now available for reconstructing three
      dimensional (3D) tomographic slices. We have used these 3-D images for 8 years to
      enhance anatomic diagnosis and functional evaluation pre- and postoperatively in
      children with congenital cardiac and great vessel diseases. The advantages of 3-D
      imaging are reduced examination time, improved display of complex intracardiac
      relationships, better understanding of relationships between great vessels and
      adjacent major airways, and facilitated demonstration of cardiovascular anatomy
      for those unfamiliar with tomographic images.

PMID- 8652920
TI  - Postoperative pulmonary vascular supply in congenital heart disease evaluated
      with MR imaging at 0.3 T.
AB  - The aim of this study was to investigate the usefulness of static spin-echo MR
      imaging at low field strength in evaluating postoperative pulmonary arterial
      supply. Twenty-seven patients operated on for complex congenital heart disease
      underwent cardiac MR imaging: 27 stenoses in 20 patients and 4 aneurysms were
      present in the material. Five of the overlooked stenoses were located in the
      ventricular outflow tract or in the valvular region. All four aneurysms were well
      depicted. The final diagnosis were based on two-dimensional echocardiography,
      Doppler and invasive studies. MR correctly evaluated the pulmonary arterial
      supply in 21 patients. In two cases the evaluation was incomplete and in the
      remaining four patients MR failed to show the stenoses. MR imaging at 0.3 T is an
      effective non-invasive tool for postoperative evaluation of pulmonary arteries.

PMID- 8652921
TI  - A postoperative follow-up study of infantile coarctation of the aorta.
AB  - Follow-up investigations were performed in 16 patients operated on for
      coarctation during infancy. The follow-up period ranged from 4.5 to 11 years
      (median 5.5 years). Four different surgical techniques were used: resection with
      end-to-end anastomosis (REE) (4 patients), subclavian flap aortoplasty (SFA) (10
      patients), patch aortoplasty (1 patient) and resection and SFA (1 patient). One
      patient developed recoarctation (6%). She had been operated on by REE at 7 days
      of age. The other three patients operated on by REE had equal pulses in the arms
      and legs; none had hypertension and all had normal arm/leg pressure gradients at
      rest. Seven (58%) of the 12 patients operated on by SFA or aortoplasty had weak
      radial pulses in the left arm but no limitation of left arm function. The left a
      rm showed a normal bone age but was smaller and shorter than the right arm in 9
      (81%) of the patients. None of the patients operated on by SFA had hypertension
      and the arm/leg gradient at rest was normal.

PMID- 8652922
TI  - Evolution of echocardiography in neonatal diagnosis.
AB  - In the late 1960's, Edler and Lundstrom introduced ?ultrasoundcardiography? for
      the evaluation of congenital heart disease. Initial evaluations using A- and M
      mode echocardiography produced non-invasive diagnosis of many defects, including
      specific complex malformations such as hypoplastic left heart, Ebstein's
      malformation, endocardial cushion defect and transposition, all with single
      crystal techniques. Normal values for dimensions related to patient size and
      indices of function developed at that time remain as components of contemporary
      examinations. Two-dimensional imaging technology has evolved from 20 channels on
      Bom's linear array to 128-channel systems currently providing detailed imaging of
      structures as small as neonatal coronary arteries. The contribution of Doppler
      techniques for qualitative evaluation of blood flow characteristics has been
      greatly augmented by both the quantitative Doppler methods for accurate
      assessment of pressure gradients and pulmonary pressure, and by the development
      of color Doppler display of intracardiac and intravascular flow. These
      contributions have come from centers worldwide, with many initial and ongoing
      contributions from Lund. The evolution of instruments, and of application, now
      provides neonatal echocardiographic delineation of anatomic detail, function and
      hemodynamics of sufficient clarity and accuracy to replace the need for invasive
      study, or alternative technologies, in most cases.

PMID- 8652923
TI  - Pulmonary hypertension in connective tissue disease.

PMID- 8652924
TI  - Induction therapy with all-trans retinoic acid for acute promyelocytic leukemia:
      a clinical study of 10 cases, including a fatal [correction of fetal] case with
      thromboembolism.
AB  - Ten patients with acute promyelocytic leukemia (APL) were treated with all-trans
      retinoic acid (ATRA). Eight of 10 patients achieved complete remission (CR), and
      among the 8 newly diagnosed cases, 7 achieved CR. Five of 8 CR cases remained in
      CR after 8 to 30 months. Except for hypotension and a large gastric ulcer
      resulting from hyperhistaminemia, the adverse effects of ATRA were generally
      mild. Severe thrombotic tendency occurred in a patient treated with ATRA combined
      with tranexamic acid. Intensive chemotherapy consisting of daunorubicin (DNR) and
      other agents was scheduled for the patients who achieved CR with ATRA.

PMID- 8652925
TI  - Intraocular hemorrhage developing during interferon therapy.
AB  - A 43-year-old man with chronic active hepatitis C was treated with interferon
      beta (IFN-beta) at a dosage of 6 x 10(6) IU/day for a planned 6-week period.
      Ocular hyperemia, ophthalmalgia, and increased intraocular pressure in the right
      eye developed 20 days after the start of treatment. Intraocular pressure remained
      high, even after discontinuation of IFN therapy, laser therapy, and iridectomy.
      Two days later, the right eye was removed because perforation had occurred. The
      ocular symptoms that developed in this case were thought to have been caused and
      exacerbated by IFN administration.

PMID- 8652926
TI  - Sarcoidosis after interferon therapy for chronic active hepatitis C.
AB  - Sarcoidosis is characterized by multisystemic granulomatous lesions of unknown
      etiology. A 62-year-old woman developed sarcoidosis after treatment with alpha-2a
      interferon (IFN) for 24 weeks (total dose: 522 million units) for chronic
      hepatitis C. She developed complete atrioventricular block and multiple
      noncaseating granulomatous lesions in the lung. IFN therapy, which may disturb
      cellular immune activation in some patients, may have contributed to the onset
      and progression of sarcoidosis.

PMID- 8652928
TI  - Immune network and autoimmunity.
AB  - The concept of autoimmunity is regarded as the inability of the immune system to
      distinguish between self and non-self. This oversimplification of the concept is
      far from explaining the complex and perplexing mechanisms that are postulated to
      lead to its development. The transition from autoimmune state, in which no
      corresponding clinical manifestation exist, to an autoimmune disease, is further
      complicated by the evidence of multiple factors that participate in the evolution
      of the disease state. This article is written in a stepwise manner, initially
      reviewing the basic elements of the immune system, which are essential to
      understanding the fundamental processes underlying the occurrence of
      autoimmunity. Subsequently, a description of the factors involved in the
      etiopathogenesis and the presumed triggering events leading to the emergence of
      autoimmune diseases are described, with special emphasis on the important role of
      the idiotypic network, either in the maintenance of the normal immune response,
      or in the breakdown of self-tolerance eventuating in the autoimmune disease.

PMID- 8652927
TI  - Total obliteration of colonic lumen by localized giant inflammatory polyposis in
      ulcerative colitis: report of a Japanese case.
AB  - Although inflammatory polyposis of the colon is a recognized local complication
      of ulcerative colitis, giant inflammatory polyposis that totally obliterates the
      colonic lumen is uncommon, and most of the patients have been from Western
      countries. We report a Japanese man who had localized giant inflammatory
      polyposis that obstructed the retrograde flow of barium in a double-contrast
      barium enema study at the splenic flexure in ulcerative colitis. After resection
      by total proctocolectomy and ileostomy, pathological examination of the specimen
      confirmed localized giant inflammatory polyposis in the descending colon and
      spelnic flexure without malignancy.

PMID- 8652929
TI  - Pancreaticopleural fistula visualized by computed tomographic scan combined with
      endoscopic retrograde pancreatography.
AB  - We report a case with left pleural effusion caused by a pancreaticopleural
      fistula, which was formed between a small pseudocyst in the pancreatic body and
      the posterior mediastinal side of left costophrenic recess. The patient, a 66
      year-old male with an alcohol drinking habit, had cough and chest pain but no
      symptoms or signs suggestive of abdominal pathology. In this case, computed
      tomographic scan performed immediately after endoscopic retrograde
      pancreatography was very useful not only in demonstrating the presence of the
      pancreatic internal fistula but in clarifying its anatomical relation to the
      surrounding organs.

PMID- 8652930
TI  - Interventricular septal dissection in a patient with an old myocardial
      infarction.
AB  - We observed an unusual case of interventricular septal wall dissection in a
      patient with a prior myocardial infarction. Echocardiography, magnetic resonance
      imaging, and left ventriculography revealed separation of the right-side and left
      side walls of the interventricular septum with an accessory chamber between the
      two walls. Morphologic findings were consistent with interventricular septal
      dissection.

PMID- 8652931
TI  - Rhabdomyolysis complicating polymicrobial sepsis in a patient with acute
      leukemia.
AB  - Rhabdomyolysis with myoglobinuria is an uncommon complication of sepsis, whether
      monomicrobial or polymicrobial, even in its severe form. We describe a middle
      aged woman with acute leukemia who developed rhabdomyolysis and myoglobinuria
      during the fatal course of chemotherapy-induced sepsis due to Bacteroides
      thetaiotaomicron and Enterococcus faecalis, followed by multiple organ
      dysfunction syndrome. In addition, autopsy revealed disseminated infections with
      Aspergillus and Candida. None of these organisms has been reported to be involved
      in the pathogenesis of rhabdomyolysis. Therefore, the etiology of the
      rhabdomyolysis in this case was probably multifactorial, with polymicrobial
      septic processes being possibly important contributing factors.

PMID- 8652932
TI  - Systemic lupus erythematosus with pulmonary hypertension.
AB  - A 50-year-old Japanese female with a long history of Raynaud's phenomenon
      presented with progressive dyspnea due to pulmonary hypertension. The diagnosis
      of systemic lupus erythematosus was confirmed by proteinuria, lymphocytopenia,
      bilateral pleurisy, and a seizure of convulsion which was consistent with
      neurological manifestations of systemic lupus erythematosus, whereas the
      antinuclear antibody showed a low titer. Despite improvement in the activity of
      systemic lupus erythematosus, steroid treatment did not alter the progression of
      pulmonary hypertension, which increased in severity, eventually resulting in her
      death. We believe pulmonary hypertension to be an unusual but critical
      complication of systemic lupus erythematosus.

PMID- 8652933
TI  - Abnormalities of pupils.

PMID- 8652934
TI  - Sleep and internal medicine.

PMID- 8652935
TI  - Orthostatic hypotension and postprandial hypotension.

PMID- 8652937
TI  - Micturitional disturbance.

PMID- 8652936
TI  - Diseases affecting sudomotor function.

PMID- 8652938
TI  - The disturbance of defecation.

PMID- 8652939
TI  - Heart failure and the renin-angiotensin system.

PMID- 8652940
TI  - Roles of neurohumoral factors in the progression of heart failure.

PMID- 8652941
TI  - Role of cytokines in the syndrome of heart failure.

PMID- 8652942
TI  - Positive inotropic agents: a double-edged sword for chronic heart failure.

PMID- 8652943
TI  - Evaluation of angiotensin-converting enzyme inhibitor in congestive heart
      failure.

PMID- 8652944
TI  - Comprehensive therapy for congestive heart failure: a novel approach
      incorporating thermal vasodilation.

PMID- 8652945
TI  - Autologous bone marrow transplantation.

PMID- 8652946
TI  - Bone marrow transplantation and graft-versus-host reaction.

PMID- 8652947
TI  - Peripheral blood stem cell transplantation.

PMID- 8652948
TI  - Analysis of 55 transplantations from unrelated volunteer donors facilitated by
      Tokai Marrow Donor Bank.
AB  - In October, 1989, the Tokai Marrow Donor Bank (TMDB) was established through the
      cooperation of patients' families, the branches of blood centers of Japanese Red
      Cross and the hematologists' group in Tokai Area (Aichi, Shizuoka, Gifu and Mie
      Prefectures) in Japan to facilitate the procurement of suitable marrow from
      unrelated volunteer donors for patients lacking related donors. The number of
      human leukocyte antigen (HLA)-A, B typed donors totaled 3,083 and the number of
      patients registered for donor search totaled 1,415 by June 1992, when the
      activities of TMDB were transferred to the newly created Japan Marrow Donor
      Program (JMDP), and 55 transplanations from unrelated donors facilitated by TMDD
      were performed.

PMID- 8652949
TI  - Early re-feeding in the management of acute diarrhoea in infants of 0-1 year of
      age.
AB  - We compared early versus late re-feeding in the management of acute diarrhoea in
      the first year of life. In the study group (73 groups) breast feeding was resumed
      or early re-feeding was performed in non-breast-fed infants, so that the feeding
      regimen used prior to the onset of the disease was reached within 2-3 days. In
      the control group (49 patients) late re-feeding was performed so that the infants
      returned to their original feeding pattern after 4-6 days. there were no
      significant differences between the two groups in the number of stools and stool
      output per day, or in the duration of the disease. No weight gain or loss during
      the diet was noted more frequently in the late re-feeding group (67.2% versus
      2.3.4%). This study confirms the favourable effect on body weight of early re
      feeding in the management of acute diarrhoea.

PMID- 8652950
TI  - A prospective, double-blind, placebo-controlled trial of i.v. immunoglobulin and
      trimethoprim-sulfamethoxazole in children with recurrent respiratory tract
      infections.
AB  - In a prospective, double-blind, placebo-controlled study of iv immunoglobulin
      (IVIG) and trimethoprim-sulfamethoxazole (TMS), 130 children less than 8 years of
      age were referred for recurrent bacterial respiratory tract infections, as judged
      by the referring physician. Of the 130 children referred, only 24 continued to
      have bacterial respiratory infections over a 4-month observation period. They
      were randomized and 23/24 treated for 4 months during the winter-spring season.
      The 7 children given placebo for both IVG adn TMS continued to have bacterial
      respiratory infections, while 14 of 16 children given active therapy with either
      IVIG or TMS became infection-free (p=0.002). No relation to IgG subclass level or
      between the two modalities of treatment was found. We concluded that most
      infection-prone children suffer from viral infections and are given antibiotics
      unnecessarily. Of the small group of children that have documented, repeated
      bacterial infections, prophylactic therapy with either IVIG or TMS can
      substantially diminish the number of infections.

PMID- 8652951
TI  - Nutritional status in active juvenile chronic arthritis not treated with
      steroids.
AB  - Nutritional status and nutrient intake were assessed in 17 children with active
      juvenile chronic arthritis (JCA) who never received steroids and in 17 controls
      matched for age and sex. Five patients had systemic, seven polyarticular and five
      oligoarticular JCA. Values significantly below those of the controls were found
      in systemic patients for height (p<0.05), upper arm circumference (p<0.05) and
      arm muscle area (p<0.01), and in polyarticular subjects for arm muscle area
      (p<0.01). All patients had unremarkable anthropometric fat measurements. All
      anthropometric measurements were normal in oligoarticular patients. Twelve JCA
      patients had reduced serum iron (Fe), 6 reduced serum zinc (SZn), 14 reduced
      intra-erythrocytic zinc (EZn) and 2 reduced serum copper (SCu). SZn was inversely
      correlated with erythrocyte sedimentation rate (ESR) (p=0.023). EZn was inversely
      related to lymphocyte count (p=0.022). SCu was related to ESR (p=0.037) and to
      lymphocyte count (p=0.016). No significant difference in nutrient intake was
      found between patients and controls. Active JCA was associated with reduced
      muscular mass, Fe, SZn, EZn. These alterations did not depend on reduced nutrient
      intake.

PMID- 8652952
TI  - Combined treatment with enuresis alarm and desmopressin for nocturnal enuresis.
AB  - Seventy-one children with nocturnal enuresis were enrolled in a controlled trial.
      The children were allocated to two matched groups. Children in both groups used
      an enuresis alarm until the end of treatment. Children in the first group were
      treated with 40 micrograms of intranasal desmopressin (Desmospray) for up to 6
      weeks at the start of treatment with the alarm. During the observation period
      treatment there were 2.3 dry nights per week in both groups. At the end of
      treatment there was a significant difference in the mean number of dry nights per
      week between the two groups (6.3 in the alarm and desmopressin group and 4.8 in
      the alarm group) and also in the number of children becoming reliably dry. The
      combination of desmopressin and alarm was particularly helpful for children with
      severe wetting and those with family and behavioural problems.

PMID- 8652953
TI  - Swedish population reference standards for height, weight and body mass index
      attained at 6 to 16 years (girls) or 19 years (boys).
AB  - Swedish population reference standards for height, weight and body mass index
      (BMI) attained at 6 to 16 years (girls) or 19 years (boys) are presented. Data
      were obtained from two independent nationwide samples of Swedish children; one
      (740 children) born in 1955, the other (2907 children) born in 1967. The weights
      of the children born in 1955 were adjusted to equal those born in 1967; heights
      did not differ. These reference standards refer therefore to Swedish children
      born at around 1970. The observations were fitted by the power transformation, or
      L, M, S method of Cole and Green. Weights and BMIs were thus normalized and valid
      SD scores for individuals obtained. Centile charts are given for clinical use.
      The means of the present, nationwide standards were 1-2 cm and 1-2 kg greater
      than those of the Solna-based standards currently in use.

PMID- 8652954
TI  - Breast feeding and seasonal determinants of child growth in weight in east
      Bhutan.
AB  - In a prospective study of 113 children in rural Bhutan, morbidity, nutritional
      status and feeding practices were recorded monthly over a period of 32 months.
      This information was related to seasonal variations in rainfall. Diarrhoea had a
      negative impact on growth, as measured in monthly intervals, during the second
      and third years of life, reducing daily weight gain by 4.4 +/- 2.0 g (p<0.0001).
      this impact was largest during the monsoon season. For respiratory tract
      infections the value was 2.6 +/- 1.7 g (p<0.01). Growth in weight was lowest
      during the monsoon period (p<0.0001). Continued breast feeding was associated
      with an odds ration for diarrhoea of 0.51 (95% CI 0.34-0.78), and for respiratory
      tract infections of 0.63 (95% CI 0.40, 0.99). Growth in weight was less reduced
      during the monsoon season for children who were breast fed (2.5 +/- 1.7 g/day)
      than for those not breast fed (7.5 +/- 3.5 g/day) (p<0.01). We conclude that
      breast feeding is of particular importance throughout the warm and rainy season.

PMID- 8652955
TI  - Non-epidemiological Kala-azar cases in Turkey.

PMID- 8652956
TI  - A longitudinal study of iron status in healthy Danish infants: effects of early
      iron status, growth velocity and dietary factors.
AB  - In a cohort of term infants (n=91), followed from birth to 12 months, iron intake
      was examined by 24-h food records, and iron status by blood samples (haemoglobin
      (Hb)), mean corpuscular volume (MCV), serum values for iron, ferritin and
      transferrin, and erythrocyte protoporphyrin) at 2, 6 and 9 months. At 9 months of
      age, 5% had anaemia (Hb<105 g/l), but none had developed iron deficiency
      according to strict definitions used in this study (serum ferritin < 13
      micrograms/l and transferrin saturation < 10%). Infants with high serum ferritin,
      serum transferrin and erythrocyte protoporphyrin values at one blood sampling
      also had high values at the following sample (tracking, r=0.45-0.80), suggesting
      that iron stores at delivery are an important determinant of iron stores during
      late infancy. Factors related to changes in serum ferritin were investigated by
      multiple linear regression. From 2 to 6 months, serum ferritin was negatively
      associated with knee-heel growth velocity (p=0.006) and positively with intake of
      infant formula (p=0.04). From 6 to 9 months it was negatively associated with
      intake of bread (p=0.001), and there was a trend for a positive association with
      intake of meat (p=0.07) and fish (p=0.08) and for a negative association with
      intake of cow's milk (p=0.07). In conclusion, those with a high growth velocity
      and a dietary pattern with a high intake of bread and a low intake of meat and
      fish had lower ferritin values and thereby an increased risk of depleting their
      iron stores later during infancy.

PMID- 8652957
TI  - Young child feeding in a rural area in the Red River delta, Vietnam.
AB  - Infant and young child feeding practices were investigated in a sample survey
      (1132 mothers) in a rural area in northern Vietnam. Pre-lacteal feeding was
      almost universal. Mean duration of breast feeding was 17 months, but foods other
      than breast milk were introduced early. Only 50% of infants between 3 and 5
      months of age were predominantly breast fed. The educational level of the mother
      was strongly associated with breast feeding duration, with illiterate mothers
      breast feeding the longest. Christian mothers breast fed for longer than non
      Christians. Very few were using feeding bottles at the time of the study,
      although formulas and bottles have recently been appearing on the local market.
      The breast feeding pattern described together with the rapidly changing social
      and economic situation in Vietnam could mean a risk of rapid decline in breast
      feeding.

PMID- 8652958
TI  - Tracking of serum lipids and dietary energy, fat and calcium intake from 1 to 15
      years.
AB  - We describe the results of tracking serum lipids, and dietary intake of energy,
      fat and calcium in a cohort of 106 children in the Adelaide Nutrition Study who
      were followed to 15 years of age together with an additional 123 children
      recruited from 11 years of age. Measures of energy, fat and calcium intakes were
      obtained from analyses of 4-day weighed records. The pattern and level of
      tracking were similar for males and females. The tracking coefficient for total
      cholesterol was 0.28-0.49 between 1 and 15 years of age, 0.3-0.64 between 2-8 and
      15 years of age adn 0.71-0.78 between 13 and 15 years of age. The pattern was
      similar for low density lipoprotein cholesterol, but lower for high density
      lipoprotein cholesterol. For mean daily energy, fat and calcium intake, tracking
      coefficients were low below 4 years of age, but from then on were 0.46-0.64 for
      energy intake, 0.38-0.51 for fat (g) and 0.51-0.62 for calcium (mg).

PMID- 8652959
TI  - Respiratory water loss in relation to gestational age in infants on their first
      day after birth.
AB  - Respiratory water loss, oxygen consumption and carbon dioxide production were
      measured in 32 infants on their first day after birth. Gestational age was
      between 27 and 41 weeks. All infants were studied in incubators with 50% ambient
      relative humidity and an ambient temperature that allowed the infant to maintain
      a normal and stable body temperature. During the measurements the infants were
      usually asleep. Respiratory water loss was found to be highest in the most
      preterm infants and lower in more mature infants. Respiratory water loss per
      breath (mg/kg) was almost the same at all gestational ages and the higher
      respiratory water loss found in the most preterm as compared with the more mature
      infants is thus and increased with increasing gestational age. Thus, in full-term
      infants respiratory water loss and transepidermal water loss are of approximately
      equal magnitude at an ambient humidity of 50%, while respiratory water loss
      constitutes a smaller proportion than transepidermal water loss in very preterm
      infants. Respiratory water loss increases with the rate of breathing.

PMID- 8652960
TI  - Plasma lecithin: cholesterol acyltransferase and plasma lipolytic activity in
      preterm infants given total parenteral nutrition with 10% or 20% Intralipid.
AB  - The effect of 10% or 20% Intralipid on lipid clearing enzymes, plasma lipids and
      apoproteins was investigated during the first 5 days after birth in 37 premature
      infants maintained on total parenteral nutrition; 21 infants received 20% and 16
      received 10% Intralipid, respectively. Lipid was infused over a 20-h period at
      rates of 1, 2 and 3 g/kg/day on consecutive days. Plasma lecithin: cholesterol
      acyltransferase (LCAT) activity was low and increased significantly (p<0.05) only
      during infusions of 3 g/kg/day in both groups of infants. Plasma lipolytic
      activity was generally not affected by the regimen or preparation (10% or 20%) of
      Intralipid infused, except for higher (p<0.05) levels at 3 g/kg/day of 20%
      compared with prelipid infusion. Plasma triglyceride concentrations wer similar
      after 10% or 20% Intralipid, whereas plasma total cholesterol was significantly
      higher during infusion of 2 and 3 g/kg/day of 10% compared with 20% Intralipid.
      The efficient clearing of 20% Intralipid might be related to the lower lecithin:
      triglyceride ration which is compatible with the low LCAT activity of premature
      infants.

PMID- 8652961
TI  - Subaponeurotic haemorrhage in the 1990s: a 3-year surveillance.
AB  - A 3-year survey of subaponeurotic haemorrhage (January 1991 to December 1993) in
      a tertiary referral centre in Hong Kong revealed that the incidence of this life
      threatening condition was 6.4 per 1000 ventouse-associated deliveries, which is
      60-fold more common than with other modes of childbirth. We highlight a lesser
      known phenomenon of marked male predominance (male to female ration 8:1). Three
      of 18 (17%) infants with subaponeurotic haemorrhage died. Severe subaponeurotic
      haemorrhage with a decrease in venous haematocrit >25% of the baseline value at
      birth and requiring urgent blood transfusion in the first 12 h, in association
      with significant birth asphyxia with arterial cord blood pH <7.20 and 1-min Apgar
      score < or = 3 were the most important risk factors for death. A worrying feature
      was the silent presentation of occult subaponeurotic haemorrhage in two of the
      fatal cases. Frequent monitoring of haematocrit, early and rapid restoration of
      blood volume and prompt commencement of cardiac inotropes are the keys to the
      management of this condition, which should be suspected in all ill newborn
      infants subjected to the ventouse applicator.

PMID- 8652962
TI  - Rett syndrome in Estonia: prevalence of the classical phenotype.

PMID- 8652963
TI  - Stomach ache and headache among the siblings of children with acute lymphoblastic
      leukaemia.

PMID- 8652964
TI  - Primary idiopathic hypomagnesemia in two female siblings.
AB  - Two female siblings with primary idiopathic hypomagnesemia, born to
      consanguineous parents, are described. Both presented at 6 weeks of age, with
      convulsions and persistent hypocalcemia (calcium 1.5 adn 1.6 mmol/l; normal range
      (NR) 2.2-2.6 mmol/l), which could not be controlled with anticonvulsants and/or
      calcium gluconate. On further investigation they were also found to have
      hypomagnesemia (magnesium 0.17 mmol/l and 0.22 mmol/l; NR 0.65-1.05 mmol/l).
      Convulsions and the low serum calcium and magnesium levels were first managed by
      im and then by oral administration of magnesium supplements. A burst in
      circulating parathyroid hormone levels to well above the physiological range was
      observed at the start of therapy. Serum magnesium values of the mother and father
      were just below the normal range, with normal serum calcium. This type of
      infantile primary hypomagnesemia appears to be a hereditary disease with
      autosomal recessive characteristics, although a partially penetrant X-linked or
      autosomal dominant trait cannot be excluded.

PMID- 8652965
TI  - Bronchopleural fistula: successful selective bronchial occlusion with a Fogarty's
      catheter in a preterm infant.
AB  - A preterm infant (26 weeks' gestation) mechanically ventilated for respiratory
      distress syndrome developed severe interstitial emphysema of the right lung with
      a bronchopleural fistula, pneumothorax and mediastinal shift. Selective occlusion
      of the right main bronchus with a Fogarty's catheter produced rapid improvement
      in the clinical condition and radiological features. Occlusion of the main
      bronchus in a newborn with a bronchopleural fistula and pulmonary interstitial
      emphysema is an easily performed manoeuvre that can be life-saving.

PMID- 8652966
TI  - Recurrent reversible rhabdomyolysis associated with hyperthermia and status
      epilepticus.
AB  - A 6-year-old boy developed rhabdomyolysis following hyperthermia and status
      epilepticus with a diagnosis of severe myoclonic epilepsy of infancy. At 2 and 3
      years of age, he had similar episodes. Each time he recovered completely in 3-4
      weeks with conservative management, in spite of renal insufficiency and marked
      liver dysfunction. Several cases of recurrent myoglobinuria after intense
      exercise of generalized tonic-clonic convulsions were reported to have genetic
      errors of carbohydrate or lipid metabolism of muscle. In our patient, however,
      the activity of these enzymes was found to be normal. This indicates that status
      epilepticus may cause recurrent rhabdomyolysis in subjects with normal glycolytic
      and lipolytic enzyme activity.

PMID- 8652967
TI  - Recurrent chest pain as the presenting manifestation of spinal meningioma.
AB  - We report the case of a 9-year-old boy with a spinal cord meningioma whose only
      manifestations were recurrent episodes of chest pain lasting for 2 years. This
      case shows that spinal cord meningioma should be considered among the possible
      causative factors of chronic chest pain in childhood.

PMID- 8652968
TI  - Rosen von Rosenstein. His textbook and the award.

PMID- 8652969
TI  - Rett syndrome: clinical peculiarities and biological mysteries.
AB  - Rett syndrome, a peculiar neurodevelopmental deficiency affecting females, which
      starts in early childhood, is reviewed based on a Swedish series of 170 females,
      2-52 years of age (to December 1994). To date, the well recognized classical
      phenotype was found in 75% of cases. Atypical variant forms, mainly more mildly
      affected mentally retarded girls and adolescent women, were still in a minority,
      but constitute, with increasing experience, an expanding cohort. The biology and
      genetics of the condition seem puzzling. Traditional neurodegenerative pathology
      has been excluded. An age-limited neurodevelopmental, as yet unknown, brain
      growth deficiency, is at present indicated. The syndrome is most probably
      genetically determined, but the mode of transmission is not convincingly
      compatible with any known pattern.

PMID- 8652970
TI  - Munchausen syndrome by proxy: a review.

PMID- 8652971
TI  - Imaging in congenital heart disease.

PMID- 8652972
TI  - Early re-feeding in the management of acute diarrhoea.

PMID- 8652973
TI  - CO2 rebreathing: a possible contributory factor to some cases of sudden infant
      death?
AB  - Physical and geometrical conditions influencing carbon dioxide (CO2) accumulation
      near the face of a sleeping infant positioned deep in a cot or pram (open cot
      shaft) or underneath bedding (closed cot shaft) were investigated. By means of
      mathematical and data-based simulation, and an experimental rebreathing model,
      both hypothetical (dry, exhaled air +20 degrees C) and more physiological
      conditions (heated, humidified exhaled air, room temperature +20 degrees C; with
      and without pooling of cold air within the shaft) were tested. With exhaled air
      at +20 degrees C, the CO2 concentration increased to about 10% within 5 min. The
      increase was faster the smaller the volume, and the smaller the opening of the
      cot shaft. When expiratory air was heated, the CO2 concentration increased with
      the same speed as when the shaft was closed, but to only 0.1-0.3% when the shaft
      was open. Pooling of cold air in the shaft increased CO2 accumulation 70-200
      times the concentration in air (to <5.5%) when the shaft was open. Turbulence of
      the air outside the open shaft reduced the increase in CO2 concentration. The
      experiments imply that CO2 may accumulate around an infant's head when placed
      deep in a cot or pram with the bedding and walls creating a narrow, vertical,
      shaft-like tunnel to the surrounding air. Although the CO2 concentration may
      theoretically attain dangerous levels in such circumstances, a rapid equilibrium
      between the air within and outside the cot usually occurs due to convection of
      the expiratory air and turbulence from drafts, the infant's body movements and
      breathing. Such factors will largely eliminated any significant rebreathing with
      the exception of the extreme situation when expired air is contained within a
      closed space.

PMID- 8652975
TI  - [Recurrent vitreoretinal membranes in intravitreal silicon oil tamponade.
      Morphologic and immunohistochemical studies].
AB  - During intraocular silicon oil tamponade, recurrent vitreoretinal membranes can
      become clinically relevant and may need surgical excision. We investigated 40 PVR
      and 10 diabetic membranes which had formed during intraocular tamponade with
      highly purified silicone oil (5000 cs). The membranes were investigated by light
      and electron microscopy with respect to silicone oil-specific alterations. The
      participating cells were differentiated immunohistochemically. Mechanisms of
      intercellular growth regulation were analyzed by the use of antibodies against
      cell adhesion molecules and growth factor receptors (PDGFr-B). Most of the
      membranes showed typical signs of the underlying disease process. However, seven
      PVR and four diabetic membranes had specific interstitial and intracellular
      vacuoles which were considered to be silicone oil droplets. The phagocytosing
      cells were macrophages, partially embedded within vitreous residues. T
      lymphocytes can be drawn to the area of macrophage activity by the expression of
      ICAM-1 and LFA-1. The residual parts of the membranes are typical vitreoretinal
      membranes. The receptors for PDGF, fibronectin and laminin were negative, but the
      receptors for collagen and vitronectin were positive within these membranes. The
      silicone oil-specific macrophage reaction might be supported by emulsified
      silicone oil droplets, which might get phagocytosed at a certain size. The
      secondary inflammatory reactions can further enhance silicone oil emulsification
      and start a vicious circle. Nevertheless, the underlying disease process seems to
      be much more important in stimulating recurrent membrane formation than silicone
      oil-specific cell reactions.

PMID- 8652974
TI  - Hyperimmune cow colostrum reduces diarrhoea due to rotavirus: a double-blind,
      controlled clinical trial.
AB  - The therapeutic efficacy of hyperimmune bovine colostrum (HBC) from cows
      immunized with four serotypes of human rotavirus was evaluated in a double-blind,
      randomized trial in 75 boys, aged 6-24 months, infected with rotavirus diarrhoea.
      The treatment group received 100 ml of HBC three times a day for 3 consecutive
      days, while the controls received the same amount of bovine colostrum from
      significantly shorter duration of diarrhoea than the controls (median 56 versus
      72 h (p<0.001); confidence interval of median difference (CI) 8-32 h). Total
      stool output (g/kg) between admission and cessation of diarrhoea was reduced by
      29% in the HBC-treated group compared with controls (median 205 versus 290 g
      (p=0.04); CI = 1-154 g). In 50% of the children in the study group, diarrhoea
      stopped by 48 h, whereas 100% of the controls were still suffering from
      diarrhoea. No untoward effects were noted in either group. Colostrum from cows
      immunized with rotavirus antigen is clinically effective in reducing the duration
      and severity of childhood diarrhoea due to rotavirus.

PMID- 8652976
TI  - [Contamination of intraocular fluid in pars plana vitrectomy].
AB  - Endophthalmitis after pars plana vitrectomy is rare, with an incidence of 0.05
      0.14%. The aim of this study was to evaluate the microbiological situation during
      pars plana vitrectomy and to ascertain what organisms and how many enter the eye
      during the operation. PATIENTS AND METHODS: Twenty-five consecutive subjects
      undergoing primary pars plana vitrectomy were included in the study. Patients
      were excluded if they had evidence of local or systemic infections or had
      undergone antibiotic therapy within 3 weeks before surgery. A standard three-port
      pars plana vitrectomy was performed on each patient. Preoperative smears of the
      conjunctiva and intraoperative aspirates of the vitreous were taken immediately
      after sclerotomy, and aspirates of the intraocular fluid at the conclusion of
      operation. RESULTS: We obtained preoperative smears from the conjunctival sac of
      all patients, and found that 19 patients (76%) had positive cultures, with
      coagulase-negative staphylococci as the most commonly isolated organisms, (n =
      14; 56%). Vitreous--aspirated immediately after sclerotomy--was sterile in 68% (n
      = 17). In 32% (n = 8) contamination occurred, the microorganisms isolated being
      coagulase-negative staphylococci (20%) and Staphylococcus aureus (12%). Five of
      the samples (20%) of intraocular fluid from the vitreous cavity--aspirated before
      wound closure--were contaminated, coagulase-negative staphylococci (8%) and
      Staphylococcus aureus (12%) again being found in culture. In no case did
      postoperative endophthalmitis develop. CONCLUSIONS: This study demonstrates that
      bacteria enter the eye during pars plana vitrectomy and that there is a change in
      the contaminating bacterial species during operation. Even if bacteria remain in
      the eye after pars plana vitrectomy, postoperative endopthalamitis does not
      necessarily develop.

PMID- 8652977
TI  - [Intraocular silicone oil tamponade. A clinico-pathologic study of 36 enucleated
      eyes].
AB  - BACKGROUND: Previous histological studies have shown that intraocular silicone
      oil induces irreversible changes in ocular tissues, especially the retina. The
      purpose of this study was to analyze, in a larger group of enucleated eyes,
      changes in intraocular tissue after silicone oil injection, dependent on
      intraocular pressure, how long the oil was in the eye, and the viscosity of
      intraocular silicone oil. PATIENTS AND METHODS: We did histological examinations
      on 36 enucleated globes with intraocular silicone oil after vitreoretinal surgery
      and compared them with 68 enucleated globes treated with buckle and encircling
      band using immunohistochemistry (n = 5) and electron microscopy (n = 7). For
      statistical evaluation we used the chi(2) test and analysis of variance. RESULTS:
      After silicone oil injection we observed a more pronounced reduction in corneal
      endothelial cells (58%), more frequent closed chamber angle (86%), atrophy of the
      ciliary body (80%) (P < 0.05), proliferative vitreoretinopathy (89%), and
      glaucomatous atrophy of the optic nerve (56%) (P < 0.01). The retinae showed
      independent of the use of silicone oil a loss of inner and outer segments of
      photoreceptors and of ganglion cells and thinning and rareficaton of all other
      retinal layers. Globes with silicone oil revealed vacuoles both free and
      incorporated by macrophages in all layers of the retina. Similar vacuoles were
      seen in the optic nerve, choroid, retinal pigment epithelium, ciliary body, iris,
      chamber angle and the corneal endothelium. Silicone oil vacuoles were seen in the
      retina and optic nerve by 1 month after surgery in two eyes with high intraocular
      pressure (42 mmHg). Six of eight eyes with normal intraocular pressure levels
      showed retinal vacuoles, 3 of them after 2 months. Vacuoles in the optic nerve
      were found in eight of nine eyes with intraocular instillation of 1000 mPa
      silicone oil. There was no clinicohistopathological correlation between the
      presence of vacuoles in the retina or optic nerve and the duration and viscosity
      of intraocular silicone oil. CONCLUSIONS: This study suggests that vacuoles in
      eyes with silicone oil instillation can be found in the retina after 4 weeks. The
      period of intraocular silicone oil should be limited to 3-6 months.

PMID- 8652978
TI  - [Complications of preventive cryoretinopexy in retinal foramina and degeneration
      in 1,000 eyes].
AB  - INTRODUCTION: Prophylactic treatment of full-thickness retinal breaks is widely
      accepted. The side effects and benefits of prophylactic treatment, however, have
      to be considered critically. The complication rates of prophylactic procedures
      must be compared. The aim of our study was to find out the complication rate of
      cryopexy in prophylactic retinal surgery. PATIENTS: Retrospectively we analyzed
      1000 eyes of 746 patients who were prophylactically treated by cryopexy for
      different reasons. We included eyes with round holes, horse shoe tears and
      peripheral degenerations. Follow-up time ranged from 6 months to 7 years (average
      30 months). RESULTS: Further surgical treatment was necessary in 3.4% of the
      patients (1.8% had a second cryopexy, 0.1% needed laser coagulation, and in 1.5%
      a subsequent scleral buckling procedure was necessary. In 17.6% of these cases
      (0.6% of all cases) the retinal detachment occurred in the periphery of the
      primary cryopexy after more than 1 year. In all our patients we did not find
      postoperative macular pucker or cystoid macular edema. CONCLUSIONS: The
      complication rate of cryopexy performed for the treatment of retinal holes and
      degeneration is low. This method has to be regarded as a therapeutic tool in the
      prophylactic treatment of (dangerous) retinal areas.

PMID- 8652979
TI  - [Retinal detachment despite preventive coagulation].
AB  - From 1974 to 1989 a total of 3447 cases of retinal detachments were treated
      surgically in three departments of ophthalmology in Hamburg. It was found that
      245 (7.2%) of these eyes had previously been subjected to prophylactic
      coagulation because of lattice degeneration, tears, and retinoschisis. Retinal
      detachment followed the coagulation in 45% within 1 year in 45% of cases within
      10 years in a further 45%, and after 11 years or longer in a further 5%. (In 5%
      the time of coagulation was unknown). The retinal defects responsible for
      detachment were within or at the border of the coagulation scars in 66% of cases.
      In this group the time interval between the coagulation and the occurrence of
      retinal detachment was half that in the eyes in which defects developed in the
      untreated retina. The obvious faults of the prophylactic coagulation are
      discussed.

PMID- 8652980
TI  - [Selective percutaneous transluminal thrombolytic therapy with rt-PA in central
      retinal artery occlusion].
AB  - In central retinal arterial occlusion systemic fibrinolytic therapy can involve a
      variety of serious complications. The local application of a fibrinolytic agent
      close to the embolus by means of a femoral catheter should reduce the rate of
      complications. We therefore present the results of a preliminary study of nine
      consecutive patients treated with rt-PA via transcutaneous femoral catheter.
      PATIENTS: From October 1993 to January 1994, nine patients ranging in age from 50
      to 83 years who had central retinal occlusion were treated with rt-PA. The
      latency from the onset of the symptoms to the beginning of the therapy was 10-37
      h. A catheter was placed via the femoral artery, the tip being located either at
      the common carotid artery or at the internal carotid artery or at the internal
      carotid artery. A continuous infusion containing 10 micrograms (ACTILYSE (rt-PA)
      was given over 2 h. Thereafter, each patient received 7000 IU heparin sulfate 4
      times daily for 3 days and 1200 micrograms pentoxifylline i.v. daily for 10 days.
      On discharge, permanent therapy with salicylic acid (100 micrograms) was
      prescribed. The patients have been followed up for up to 18 months so far.
      RESULTS: In five of eight patients an improvement of central visual acuity was
      observed. It changed from perception of hand movement only to 12/20 in three
      patients. In two of these patients visual acuity had continued to improve after 6
      9 months, to 16/20 and 20/20. In one patient visual acuity fell to 6/20 because
      of progression of ischemic ophthalmopathy. In our patients visual acuity could
      still be improved even 27 h after arterial occlusion. CONCLUSION: A low incidence
      of complications and the good effect on thrombolysis support the local rt-PA
      therapy. Good interdisciplinary cooperation is required. Patients must be
      referred for this therapy as early as possible.

PMID- 8652981
TI  - [Long-term outcome of radiotherapy of choroid hemangioma].
AB  - The usual therapeutic approach to circumscribed choroidal hemangiomas of the
      posterior pole consists of scatter photocoagulation of the tumor surface. This
      may often require repetitive treatment or additional invasive measures prior to
      coagulation due to massive exudative detachment of the retina. In this study,
      external beam irradiation with high-energy photons (total absorbed dose: 20 Gy)
      was applied to 36 symptomatic patients. The indication for treatment was
      exudative retinal detachment including or threatening the fovea. The mean
      duration of follow-up was 4.5 years (4 months to 24 years, median 4 years). In 23
      cases (63.8%) complete resolution of the subretinal fluid could be achieved; 13
      cases (36.2%) showed residual serous detachment at some distance from the fovea.
      The visual acuity improved by two or more lines in 14 cases (38.9%), remained
      stable in 14 cases and decreased in only 8 cases (22.2%). The functional success
      was dependent on the interval between onset of first subjective symptoms and
      treatment. External beam irradiation is a successful form of treatment for
      choroidal hemangiomas.

PMID- 8652982
TI  - [Retinal angiomatosis. Long-term follow-up].
AB  - Meyer-Schwickerath reported his first results with light coagulation in 1959.
      This report on the results of treatment in this disease is based on more than 34
      years experience at the university eye hospital in Essen. Important prognostic
      factors are the number of retinal hemangiomas and secondary retinal lesions, such
      as exudative retinal detachment, lipid deposits, vitreous hemorrhages, preretinal
      membranes and traction retinal detachment. PATIENTS: Treatment was performed in
      156 patients, with 220 involved eyes. The median follow-up was 8.9 years and the
      average age before treatment, 27.5 years. RESULTS: A positive family history was
      found in 36.5% and extraocular hemangiomas in 24% of all cases. There were 64
      patients with bilateral hemangiomas. In 64.5% of cases the tumor was destroyed
      without further recurrences. Xenon light coagulation was the only treatment
      applied in 70%. The other patients received combined procedures with light
      coagulation, cryocoagulation, Ru 106 plaque and proton beam. Salvage of 90% of
      all treated eyes was achieved. CONCLUSION: Treatment at an early stage of the
      disease, before any secondary retinal damage has developed, seems to be crucial
      for satisfactory results. Light coagulation is extremely effective at this stage.
      However, the treatment options for advanced cases have also become better
      recently.

PMID- 8652984
TI  - [Indications and prognosis of cataract surgery in patients with retinitis
      pigmentosa].
AB  - BACKGROUND: Retinitis pigmentosa (RP) is associated with the development of
      posterior subcapsular cataract (PSC). Due to their retinal pathology, RP patients
      need optimal contrast conditions to attain good visual acuity. Lens opacities
      like PSC, therefore, decrease central visual acuity in RP patients earlier and
      more markedly than in patients without retinal problems. PATIENTS AND METHODS: We
      examined 39 patients aged 52.2 +/- 15.4 years who had underwent 61 cataract
      operations with intraocular lens implantation 1-4 years previously. Patients with
      autosomal dominant (n = 7), autosomal recessive (n = 1), X chromosomal recessive
      (n = 2), and simplex RP (n = 21), as well as eight patients with Usher's syndrome
      (RP and sensoneurinal deafness), were evaluated. RESULTS: Visual acuity (VA) of
      all patients increased from 0.17 +/- 0.13 preoperatively to 0.33 +/- 0.22
      postoperatively. The mean age of the patients at the onset of RP was 28.8 +/-
      19.6 years. The average time between subjective onset of RP and cataract
      operation was 20 years. Patients with early manifestation of RP, before the age
      of 20 years, had significantly lower postoperative VA (P = 0.0005) than patients
      with late manifestation. A short duration of RP, less than 20 years, was
      associated with significantly better postoperative VA (P = 0.016). The surgical
      trauma of the cataract operation did not influence the course of RP. Visual field
      testing did not show statistically significant differences between preoperative
      and postoperative (1-4 years) results. The development of clinically significant
      posterior capsule opacification was observed in 70.7% of all RP patients.
      CONCLUSIONS: Patients with RP and cataract should be operated early to provide,
      for as long as possible, an optimal optical image to compensate and support the
      inferior retinal function. Early onset of RP symptoms and longer duration of the
      disease have an negative impact on postoperative visual outcome in cataract
      surgery.

PMID- 8652983
TI  - [Late vision loss after focal hemorrhagic chorioretinopathy].
AB  - Prospective clinical studies about photocoagulation of extrafoveolar choroidal
      neovascularizations in focal hemorrhagic chorioretinopathy (CR) have demonstrated
      that the risk of visual loss years after successful treatment is related to the
      development of retinal pigment epithelium (RPE) atrophy around the laser scar.
      The reason for this event was thought to be late damage of RPE cells due to the
      laser treatment. However, because RPE atrophy can also be seen in untreated
      patients, a prospective study was started to test this pathogenetic hypothesis
      and to analyze the pathogenetic factors and prognostic importance of RPE atrophy
      in focal hemorrhagic CR. Eighty-eight patients (52 women, 36 men, 15-45 years
      old; mean follow-up 62 months; 26 patients treated by photocoagulation) with
      focal hemorrhagic CR were reexamined. Fifty-two patients (15 treated by
      photocoagulation and 37 untreated) showed clinically visible RPE atrophy. In
      these 52 patients the initial and final visual acuity, the amount of initial
      subretinal fluid (34.6% < 500 microns, 50% 500-750 microns, 15.4% > 750 microns)
      and the amount RPE atrophy (23.2% < 500 microns, 53.6% 500-750 microns, 23.2% >
      750 microns) were analyzed. The development of RPE atrophy was dependent on the
      time of follow-up (36 patients without RPE atrophy, mean follow-up 29 months; 52
      patients with RPE atrophy, mean 84 months, P < 0.001). Of the 52 patients with
      RPE atrophy, 15 were treated by photocoagulation. The distribution of RPE atrophy
      was similar to what was found in the 37 untreated patients (P = 0.4). With
      pronounced RPE atrophy, a decrease in final visual acuity was seen (RPE atrophy <
      500 microns, mean visual acuity 0.5; 500-750 microns mean visual acuity 0.3; >
      750 microns, mean visual acuity 0.1; P = 0.005). Increased RPE atrophy was also
      associated with a higher incidence of visual loss (p = 0.009). The amount of RPE
      atrophy was not dependent on the time of follow-up (P = 0.3), but only correlated
      with the initial amount of subretinal fluid (atrophy < 500 microns: subretinal
      fluid < 500 microns 15.4%, 500-750 microns 7.7%, > 750 microns 0%; atrophy 500
      750 microns: subretinal fluid < 500 microns 19.2%, 500-750 microns 32.7%, < 750
      microns 1.9%; atrophy > 750 microns: subretinal fluid < 500 microns 0%, 500-750
      microns 9.6%, > 750 microns 13.5%; P < 0.0001). Because RPE atrophy in focal
      hemorrhagic CR was seen in patients both with and without photocoagulation
      therapy, laser treatment cannot be the causative factor. With increased follow-up
      the risk of the development of RPE atrophy increases in all patients. The
      resulting amount of RPE atrophy was only dependent on the initial amount of
      subretinal fluid. If the fovea is included in the exudative detachment, there is
      a higher risk of long-term visual loss.

PMID- 8652985
TI  - [Calculated birth date as critical temporal marker for cryocoagulation of
      retinopathy of prematurity].
AB  - The time course of retinopathy of prematurity (ROP) is investigated for all
      preterm babies who underwent initial ocular therapy (cryocoagulation, encircling
      band or vitrectomy; 1983-1992; 156 eyes, 82 children; mean gestational age 28.1
      weeks; mean birth weight: 864 g). Group I (ROP3+ in 5 adjacent or 8 accumulated
      clock hours): 63 eyes, 34 babies. The conceptional age at the time of cryo was
      37.4 +/- 2.1 weeks. The disease progressed to cryo threshold before the presumed
      date of birth in 81% of cases. Group 2 (ROP4 and 5): 51 eyes, 27 babies. The
      gestational age at the time of first observation of ROP4 was 41.7 +/- 3.5 weeks.
      At least 39% of the detached cases arrived at stage 4 before the presumed date of
      birth. Group 3 (ROP3+ in less than 5 clock hours): Cryo-application in this grade
      of ROP is not generally accepted. We treated 42 eyes of 21 babies. Conceptional
      age at cryo therapy was 39.2 +/- 3.4 weeks. CONCLUSIONS: The time window for
      efficient ablative cryotherapy of ROP is clearly before the presumed date of
      birth. Eyes requiring therapy are at high risk for retinal detachment (ROP4) to
      be already present at 40 weeks conceptional age and later. Exceptions are ROP3+
      cases of minor lateral extension.

PMID- 8652986
TI  - [Diode laser coagulation of stage 3+ retinopathy of prematurity].
AB  - BACKGROUND: Laser photocoagulation in retinopathy of prematurity (ROP) appears to
      have fewer adverse effects and to be at least as effective as cryotherapy.
      METHODS: To evaluate the efficacy and safety of diode laser photocoagulation we
      examined 50 eyes affected by stage 3+ ROP in 30 very low birth weight infants
      (gestational age 24-29 weeks, mean +/- SD 26.5 +/- 1.4 weeks; birth weight 480
      1400 g, 898 +/- 208 g) in a prospective (uncontrolled) clinical study.
      Photocoagulation treatment was performed using a diode laser (810 nm) with a
      laser indirect ophthalmoscope delivery system. Follow-up ranged from 3 to 23
      months (10.5 +/- 6.4 months). RESULTS: In 46 (92%) of the 50 eyes ROP regressed
      after a single laser treatment and the outcome was a flat, attached retina. Two
      eyes (4%) had a second laser session and one other eye (2%) had additional
      retinal detachment surgery, resulting in the regression of ROP and a flat,
      attached retina. Thus, the success rate was 98% (49 out of 50 eyes). In 1 (2%) of
      the 50 eyes treatment failed and ROP progressed to stage 5, although additional
      retinal detachment surgery was performed. No adverse side effects of diode laser
      treatment were noted, except for a small amount of retinal/preretinal bleeding in
      the ridge in 8 eyes (16%) and slight postoperative anterior chamber bleeding in 1
      eye (2%) with dense tunica vasculosa lentis. There were neither lenticular
      opacities nor cataract formation. CONCLUSION: Diode laser photo coagulation using
      the laser indirect ophthalmoscope for stage 3+ ROP was easy to administer. Laser
      treatment had only minor side effects and was at least as effective as
      cryotherapy.

PMID- 8652987
TI  - [Congenital toxoplasmosis retinochoroiditis after primary infection of the mother
      in pregnancy].
AB  - An infection with Toxoplasma gondii during pregnancy means that the unborn baby
      may be infected as well. In addition to the risk that the baby may be born dead,
      central chorioretinitis could also occur. Pregnant women with primary infection
      were treated with spiramycin or a combination of pyrimethamine and sulfadiacine.
      A total of 153 children (1 month-1 year) were examined twice with particular
      attention to the macula region. Only two cases showed central retinochoroiditis.
      In one case the treatment was insufficient, and in the other the time between the
      serological examinations was too long. None of the other children showed any
      central pathological changes within the follow-up period. Screening methods, the
      appropriate treatment and the results are presented.

PMID- 8652988
TI  - [Microsurgical endonasal decompression in traumatic and neoplastic optic nerve
      compression].
AB  - The therapy of traumatic optic neuropathy remains controversial. Some authors
      recommend observation and others, the use of megadose corticosteroids or surgical
      decompression of the optic nerve. Improvements in visual acuity from no light
      perception (NLP) preoperatively to close to normal visual acuities have been
      reported after transethmoidal decompression and systemic steroids. The transnasal
      microscopic approach offers safe and effective access to the optic canal.
      MATERIALS AND METHODS: Retrospectively 15 patients (13 men/2 women) ranging in
      age from 17 to 67 years, who were surgically decompressed in the Ear-Nose-Throat
      Department between 1989 and 1994, were analyzed. Thirteen patients had
      experienced sudden visual loss after trauma; in 2 patients a tumor was diagnosed.
      After an initial ophthalmologic examination and CT scans, the patients underwent
      transnasal decompression of the optic canal for at least 180 degrees. In the
      postoperative period, visual acuity, pupillary reaction, visual field and optic
      nerve morphology were monitored. RESULTS: The overall visual results were poor.
      In 8 patients with no light perception (NLP) preoperatively, no improvement in
      visual acuity was found. Minor improvements were seen with an initial vision of
      20/200 or less. Dramatic improvements were found in both patients with rapidly
      progressive neoplastic optic nerve compression. No intra- or postoperative
      complications were seen. CONCLUSION: In our study we were unable to reproduce the
      good visual results of some series. If there is NLP preoperatively, surgical
      intervention does not seem to be promising. However, in patients with incurable
      tumors transnasal decompression of the optic canal offers a minimally invasive
      palliative measure to preserve and restore vision.

PMID- 8652989
TI  - [Ultrasound biomicroscopy imaging of accommodative configuration changes in the
      presbyopic ciliary body].
AB  - Direct observation of the position of the ciliary body was possible only in cases
      of gross anatomic, and probably also functional, abnormalities. Utilizing the 50
      MHz ultrasound biomicroscope, we investigated the profile changes of the ciliary
      body in ten eyes of ten patients, ranging in age from 54 to 86 years while they
      were ocusing on a target at a distance and afterwards on an object up close.
      After electronic image processing of ten single video pictures from each
      accommodative status, a summarized picture for every accommodative status was
      obtained. In seven of ten cases, during accommodation a remarkable shift of the
      ciliary body was observed anterior to the iris and in the direction of the lens
      equatore, while the iridociliary body contact zone became wider in five of the
      ten eyes. Ultrasound biomicroscopy allows visualization of the dynamics of the
      accommodative process. As the human ciliary body does not lose its contractility
      in the senium, the loss of accommodation in presbyopia is mainly caused by age
      related changes of the lens and capsula.

PMID- 8652990
TI  - [Rutheim 106 applicator for irradiation of carcinoma in situ of the cornea and
      conjunctiva].

PMID- 8652991
TI  - [Scleritis and episcleritis. Diagnosis and therapy].

PMID- 8652992
TI  - [Abdominal ultrasound as a screening method].
AB  - Abdominal ultrasound is increasingly used as part of the initial patient
      evaluation, without a specific indication. However, such an indiscriminate use of
      abdominal ultrasound is still controversial. The review of available literature
      on the value of abdominal ultrasound in clinical screening suggests the following
      conclusions: 1) The primary screening examination of asymptomatic persons leads
      to clinically relevant findings in less than 0.5% of cases. However,
      approximately 50% of the persons examined have abnormal findings without clinical
      relevance. This high frequency of abnormal findings may cause high costs due to
      unnecessary follow-up examinations. 2) A sonographic screening of asymptomatic
      persons may, however, be useful for specific indications in preselected
      individuals. This has been demonstrated for the detection of abdominal aortic
      aneurysm in the age group over 65 years. 3) Routine abdominal ultrasound in
      patients with a known internal disease appears to be useful even in the absence
      of a specific indication. This 'secondary screening' yields unexpected findings
      which turn out to be relevant for therapeutic decisions or for the final
      diagnosis in 6-25% of the cases. Routine abdominal ultrasound of all patients
      with internal disease may thus be a valuable extension of the initial patient
      evaluation.

PMID- 8652993
TI  - Hydrocolonic sonography: a novel screening method for the detection of colon
      disease?
AB  - Hydrocolonic sonography is an easy and harmless technique for the evaluation of
      the colon wall. In our study, 106 patients were examined by means of hydrocolonic
      sonography and colonoscopy. The results were compared. Polyps larger than 7 mm
      were detected, whereas smaller polyps were often missed. Colon cancers were found
      in 5 patients, and it was possible to stage them. In moderately to severely
      active forms of inflammatory bowel disease this technique was able to make a
      differentiation between ulcerative colitis and Crohn's disease. In elderly and
      very young patients it may well be the primary screening method for evaluating
      the bowel.

PMID- 8652994
TI  - Characteristics of thyroid ultrasound pictures in children with nodular thyroid
      changes effected by radionuclides.
AB  - 97 children with thyroid nodules found through screening programs in regions of
      White Russia (Belarus) affected by fallout from the Chernobyl disaster underwent
      thyroid ultrasound examination by one team at a central reference hospital. 46 of
      these children were operated on. 31 of these had thyroid carcinoma (30 papillary
      carcinoma, 1 follicular carcinoma), 9 adenoma, 3 nodular goitre, 2 thyroiditis
      and one colloid goitre. Sex distribution was equal in the carcinoma group while
      in all other groups females prevailed. In younger age groups (3-6 and 7-10 years)
      carcinomas were found more often than adenomas and cysts. A carcinoma was present
      most likely if there were a single nodule with a volume of more than 1.5 cm3,
      inhomogeneous echo structure, unclear, hypoechogenic margins, and enlarged
      regional lymph nodes.

PMID- 8652995
TI  - [HIV infections in Germany].

PMID- 8652996
TI  - [Endoscopy of the upper gastrointestinal tract in HIV disease].
AB  - Gastrointestinal (GI) symptoms are part of the most frequent complaints in HIV
      disease. A methodical effort is required to identify treatable syndromes.
      Progressive immunodeficiency is associated with increased prevalence of
      opportunistic or non-opportunistic infections and neoplasms. Dysphagia and
      odynophagia, in the majority due to candida esophagitis, are best evaluated by
      endoscopy. In the presence of diarrhea, upper GI endoscopy is indicated if
      evaluations of stool and endoscopy of the lower GI tract are negative and may
      uncover proximal small-bowel infection by Cryptosporidium, Microsporidium or
      Mycobacterium avium. HIV-associated neoplasias (Kaposi's sarcoma, non-Hodgkin
      lymphomas), not rarely affecting the upper GI tract and sometimes leading to
      obstruction or bleeding, are reliably diagnosed only by endoscopy. Since visible
      lesions mostly are nonspecific and normal-appearing mucosa may harbor pathogens,
      biopsies for pathology and cultures are crucial for correct diagnosis in GI
      diseases of HIV-infected patients.

PMID- 8652997
TI  - [HIV infection and the lower gastrointestinal tract--characteristics of
      endoscopic diagnosis].
AB  - In the course of HIV infection intestinal complaints, particularly diarrhoea, are
      frequent. As a result of the HIV-induced immunosuppression infections with
      unusual viral, mycobacterial and protozoan pathogens occur. In addition usually
      self-limiting intestinal infections become frequently persistent in HIV-positive
      patients with advanced cellular immunodeficiency. Intestinal manifestation of HIV
      associated neoplasm is not rare. In combination with microbiological examination
      of stool specimen endoscopy of the lower gastrointestinal tract is a valuable
      diagnostic method, especially for the diagnosis of viral infections and neoplasm.

PMID- 8652998
TI  - [HIV infection: findings in liver and bile ducts].
AB  - Gastrointestinal diseases in HIV-infected patients mainly affect the bowel, the
      oesophagus, and the liver. Most of the hepatic diseases are due to opportunistic
      infections and associated to AIDS. In the advanced AIDS disease Mycobacterium
      avium intracellulare is the most frequent bacterial infections agent.
      Mycobacterium tuberculosis is often diagnosed in less immunocompromised patients.
      Viral hepatitis (A, B, C, D) is more often diagnosed in HIV-infected patients
      than in non-infected controls. Non-Hodgkin's lymphoma of the liver is a
      relatively frequent tumour in HIV-infected patients. Kaposi's sarcoma may also
      affect the liver. Infections with the cytomegalovirus or cryptococci mainly
      affect the biliary system causing acalculous cholecystitis or secondary
      sclerosing cholangitis. In addition to clinical and laboratory diagnostics
      sonographic and computer tomographic examinations are important. The diagnostic
      power of sonographic and computer tomographic examinations can be increased by
      guided biopsies. Biliary diseases can be diagnosed by retrograde endoscopic
      diagnostic investigations (ERC, ERCP). This overview resumes the most important
      diagnostic and differential diagnostic data in HIV-associated liver and biliary
      tract diseases.

PMID- 8652999
TI  - [Ultrasound findings in HIV patients].
AB  - A wide range of abnormal findings can be seen at abdominal ultrasonography in
      patients with HIV infection. The most frequent findings, hepatomegaly,
      splenomegaly, and enlarged lymph nodes, are nonspecific, however. Increased
      echogenicity or focal lesions of parenchymal organs, dilated bile ducts,
      nephromegaly, gut wall thickening or abscesses are uncommon findings. If there is
      clinical suspicion for a treatable disease, abnormalities seen on ultrasound
      examination of HIV-infected patients need to be confirmed by guided biopsy.

PMID- 8653000
TI  - [Ultrasound skin findings in HIV infection by imaging with 7.5 MHz linear
      transducers].
AB  - Sonography is an important tool in aiding the diagnosis of tumor-like and cystic
      findings in the skin and soft tissues. This is also true in patients with HIV
      infection and AIDS. While sonography of the skin often is performed with 20-MHz
      transducers, also lower-frequency devices which are more readily available
      contribute substantially to dermatologic diagnoses. The domain of skin sonography
      are tumors; in the special context of AIDS, Kaposi's sarcoma and lymphomas are of
      major interest. The characteristic appearance of Kaposi's tumors is a spindle
      shaped outline with low echogenicity and relative homogenicity. The tumor volume
      is easily established using measurements in two directions. Shrinkage of the
      volume after therapy, e.g. chemotherapy, may be documented in a more objective
      manner as compared to subjective rating of nodularity. Several characteristic
      images of Kaposi's sarcoma, lymphoma, lymph nodes, lipoma, and cysts are
      demonstrated in the paper.

PMID- 8653001
TI  - [AIDS: infections of the retina and choroid].
AB  - Various viral, bacterial, parasitic and fungal agents have been found to cause
      infections of retina and choroidea in HIV-infected patients. Usually these
      infections are opportunistic infections caused by the profound immunodeficiency,
      which is a result of the decay of lymphocytes by HIV. Before the HIV epidemic
      only rare cases of cytomegalovirus (CMV) retinitis were known in the literature.
      Now CMV retinitis has become the most common infection of the eye in AIDS
      patients. Ocular toxoplasmosis in HIV-infected patients can have a severe
      clinical appearance without treatment. Spontaneous recovery, as it usually occurs
      in otherwise healthy patients, does not take place in HIV-infected patients, so
      that a lifelong maintenance therapy is mandatory. Pneumocystis carinii
      chorioiditis was unknown before the HIV epidemic. In 1987 Pneumocystis carinii
      were found in the choroidea and two years later the clinical appearance could be
      described. Infections of choroidea and retina associated with AIDS may not be
      seen as isolated diseases. Commonly other organs are infected by the same or
      another organism. In case of AIDS-associated eye infections other organs should
      be checked for opportunistic disease. Diagnosis can be difficult. Because most of
      all intraocular infections associated with AIDS are CMV retinitis, an effective
      therapy can be initiated in most cases and in the follow-up a diagnosis can
      finally be made. Serological testing may be inconclusive because of occasional
      false-negative findings. Treatment often only suppresses the infections and so
      ongoing maintenance therapy may be necessary, as in the cases of CMV retinitis
      and Toxoplasma retinochorioiditis. A variety of different diseases, which can be
      treated by a multitude of different substances with a lot of adverse effects and
      contraindications, can complicate the therapeutic modalities used for the
      management of each individual disorder. Additionally HIV-infected patients suffer
      from at least two or three different diseases and must be treated lifelong with
      plenty of substances, which often are given with higher doses than usual. Only by
      cooperation of HIV-experienced doctors of different specialities in hospitals and
      offices the complex subject of HIV infection can be managed.

PMID- 8653002
TI  - [Differential radiologic diagnosis of HIV-associated lung diseases].
AB  - In 1993 in Germany an estimated number of 50,000-70,000 individuals were infected
      with the human immunodeficiency virus (HIV), WHO estimations ranged up to 14
      million HIV-positive individuals including 1 million children. AIDS-related
      diseases frequently occur in the lung. 65% of all AIDS-defining illnesses begin
      with life-threatening pulmonary infections. Most frequently HIV-positive patients
      present with Pneumocystis carinii pneumonia, followed by atypical
      mycobacteriosis, bacterial infections, Kaposi's sarcoma and non-Hodgkin lymphoma.
      The purpose of this article is to identify pulmonary HIV-associated diseases by
      focusing on radiological patterns and correlating them with clinical findings.

PMID- 8653003
TI  - Imaging methods as a diagnostic tool in neuro-AIDS. A review.
AB  - Since 1983, central nervous system (CNS) involvement in acquired immune
      deficiency syndrome (AIDS) is well recognized. Imaging methods are important in
      diagnosing AIDS-related primary and secondary CNS processes as HIV-1-associated
      encephalopathy, cerebral toxoplasmosis, primary CNS lymphoma, cytomegalovirus
      (CMV) encephalitis, progressive multifocal leukoencephalopathy (PML), and
      infectious spinal cord granulomas. This paper presents a review of typical AIDS
      related CNS findings as seen in morphological radiologic techniques, i.e. cranial
      computed tomography (CCT) or magnetic resonance imaging (MRI). Furthermore, the
      paper discusses the value of CCT, MRI and functional (positron emission computed
      tomography = PET, single-photon emission computed tomography = SPECT, and
      magnetic resonance spectroscopy) as well as morphometric imaging methods in
      evaluating subclinical HIV-1-related cerebral deficits and predicting their
      clinical course.

PMID- 8653004
TI  - [Doppler and color Doppler ultrasound diagnosis in differentiation of focal liver
      lesions].
AB  - The frequent detection of benign liver lesions during ultrasound routine
      examination and a possible curative therapy of early detected malignant tumors
      require a reliable method of differentiation. Conventional gray-scale ultrasound,
      according to this problem, has been extended by the Duplex technique and color
      Doppler ultrasound. Measurement of blood flow velocity by Doppler in the center
      and at the periphery of liver lesions is not reliable enough to distinguish
      between benign and malignant lesions. Color Doppler ultrasound possesses some
      reliable criteria for differentiation. A central spot could be detected in 2 out
      of 12 hemangiomas, a giant spot in 1 out of 3 giant cavernous hemangiomas. The
      halo sign without detectable blood flow is considered to be specific for
      malignancy. We found this sign in 26 out of 81 malignant liver lesions and only
      in one benign lesion (sensitivity 32%, specificity 97%). The vascularization of
      focal liver lesions is excellently demonstrated with color Doppler ultrasound.
      This is very helpful for the diagnosis (e.g. "chaotic blood vessel architecture'
      in malignant tumors) and for the therapy of focal liver lesions (e.g. follow-up
      examinations after chemotherapy or chemoembolization). Therefore, application of
      Duplex and color Doppler ultrasound is highly recommended as a noninvasive
      diagnostic method of first choice for unknown liver lesions.

PMID- 8653005
TI  - [Pancreaticoscopy: experiences, possibilities and limits].
AB  - Cholangioscopy in the mother-baby technique is well accepted and widespread these
      days. On the other hand, the peroral pancreaticoscopy (POPS) is still in the
      initial phase of development. In cases of doubtful stenoses, duct
      discontinuation, and radiolucent shadows during an endoscopic retrograde
      cholangiopancreatography (ERCP) the POPS can be carried out as a clarifying
      examination. Two variations of babyscopes are currently available. The ultra-thin
      endoscope allows only limited results due to the lack of tip control and
      irrigation. On the other hand, devices with an outer diameter of 3.2 mm and
      larger provide for a sufficient assessment of the duct mucosa. Biopsies can be
      taken through the working channel, and the probes for intracorporeal shock wave
      lithotripsy (ISWL) can be placed under visual control. We performed POPS on 9
      patients with an average age of 60 years using a tip-controlled endoscope. In 8
      of these cases a diagnostic or therapeutic advantage was gained. A 29-year old
      patient with alcohol-induced chronic pancreatitis and an occluding duct stone
      underwent electrohydraulic lithotrips (EHL). A 60-year-old patient with
      pancreatic duct stones underwent laser-induced shock wave lithotripsy (LISL) in 2
      sessions. Afterwards remaining parts of the calculi were extracted. The
      importance of this method in diagnosis and therapy of pancreatic diseases remains
      to be established, as evaluation studies of any great extent are still to be
      done.

PMID- 8653006
TI  - Power Doppler--a new tool for transcranial duplex assessment of intracranial
      vasculature.
AB  - The present study was undertaken to assess the clinical use of power Doppler (PD)
      as a new tool for transcranial vessel imaging. Power Doppler displays the
      integrated power of the Doppler signal instead of the Doppler frequency shift
      used in the conventional color flow Doppler (CFD) technique. Twenty-one patients
      were evaluated who had intracranial malformations or arterial stenoses [4 middle
      cerebral artery (MCA) stenoses, 2 intracranial carotid stenoses, 7 arteriovenous
      malformations (AVM), 5 intracranial carotid aneurysms, 3 Moya-Moya syndromes].
      The PD results were compared with those obtained from CFD and digital subtraction
      angiography (DSA). Power Doppler was able to visualize 3 of 4 MCA stenoses with
      greater morphological detail than CFD, whereas PD and CFD were equally effective
      in diagnosing carotid stenoses. All AVMs were visualized using PD as well as CFD,
      but again PD revealed more morphological details, in a manner similar to DSA.
      Power Doppler was also superior to CFD in imaging intracerebral aneurysms and
      pathological collateralization associated with Moya-Moya syndromes. It is evident
      from these data that PD permits reliable and detailed transcranial imaging and
      therefore is a superior method for visualizing intracerebral vascular
      malformations and arterial stenoses.

PMID- 8653007
TI  - [Imaging methods in intensive care].
AB  - Imaging procedures are important for diagnosis and surveillance of patients in
      intensive care units. Radiologic examination, ultrasound and echocardiography are
      of paramount importance because they can be done bedside. Portable chest x-ray
      examination is the procedure of choice for documentation of tubes, lines and
      devices, estimation of cardiopulmonary function, demonstration of pulmonary
      edema, ARDS pneumonia, atelectasis and pneumothorax Plainfilm radiologic imaging
      of the abdomen is indicated when perforation ileus or acute intestinal
      pseudoobstruction is suspected Echocardiography can give information about
      ventricular function, pericardial effusion, cardiac valves, functional importance
      and complications of myocardial infarction, and hemodynamic changes of pulmonary
      embolism. Transesophageal echocardiography (TEE) is the method of choice when
      endocarditis, aortic dissection or cardiac thromboembolism is considered.
      Ultrasound can show many pathologic changes important for the management of
      intensive care patients concerning liver, gallbladder, bile duct, pancreas,
      kidney, spleen, pleural space and vessels. Other imaging procedures such as CT,
      methods of nuclear medicine, MRT, angiography etc. are done outside the intensive
      care unit and therefore need a more restricted indication.

PMID- 8653008
TI  - [Theoretical principles and technical realization of high resolution nuclear
      magnetic resonance tomography with the example of a dedicated coil system].
AB  - The theory of high-resolution magnetic resonance imaging (MRI) and the physical
      properties of a dedicated coil system with its clinical application are reviewed.
      To evaluate the spatial resolution of the system, a phantom sample was depicted
      by a transverse T1-weighted sequence (time of repetition 500 ms, time of echo 25
      ms, 256 x 256 matrix, 3 acquisitions, field of view 25 mm2). Relative signal
      intensity decrease was less using the 5-cm coil, as signal intensity field
      distribution depends on coil diameter. The phantom appeared as an attainable
      resolution of 100-microns pixel width using the 2.5-cm coil. For the 5-cm coil
      the pixel width was 200 microns, not accomplishing clear resolution of the
      phantom. Coil head choice depends on the anatomic depth of the target organ. Work
      up of the skin and musculoskeletal lesions is the main indication for high
      resolution MRI using surface coils.

PMID- 8653009
TI  - [Reversible esophageal dysfunction as a side effect of levodopa].
AB  - We are reporting the case of a 94-year-old male patient with a 10-year history of
      Parkinson's disease, who was admitted to our hospital with acute obstruction of
      esophageal passage. Esophageal obstruction was refractory to endoscopic
      intervention. However, discontinuation of the pre-existing levodopa medication
      led to its resolution within hours. While dysphagia is commonly encountered in
      patients with Parkinson's disease, the observed succession of drug
      discontinuation and resolution of obstruction in this case suggests an as yet
      rarely described side effect of levodopa. This potential side effect should be
      included in the differential diagnosis of dysphagia in Parkinson's disease,
      especially in the case of older patients, who may exhibit an increased rate of
      intestinal absorption of levodopa.

PMID- 8653010
TI  - Interventional radiology in the treatment of blunt liver trauma: case report with
      review of literature.
AB  - Hepatic trauma remains one of the most serious problems in abdominal injury.
      Whenever possible a non-resectional approach is clearly preferred. Refinements of
      interventional radiology as an adjunct to surgery in blunt liver trauma may play
      an increasingly vital role in reducing mortality. The literature is reviewed with
      reference to the diagnostic procedure and the treatment strategy in blunt liver
      trauma.

PMID- 8653011
TI  - [Isovolemic hemodilution for avoiding homologous blood transfusions:
      effectiveness in large gynecologic interventions].
AB  - OBJECTIVE: The practicability and efficiency of a standardized, preoperative
      isovolemic hemodilution was investigated during major gynecological operations
      (Wertheim's operation, etc.). DESIGN: Prospective clinical trial with a
      historical control group. SETTING: Operating room of a gynecological university
      hospital. PATIENTS AND INTERVENTIONS: Under general anesthesia hemodilution to a
      hemoglobin concentration of 9 g/dl was performed in 48 patients (mean age: 53
      years). Shed blood volume amounted to 900 +/- 210 ml. Transfusion of autologous
      or homologous blood was provided when Hb concentration decreased beyond 7 g/dl
      intraoperatively. RESULTS: Compared to a control group of 57 patients without
      hemodilution the total number of PRBC units transfused was significantly reduced.
      Moreover, in 65% of all patients the transfusion of homologous blood could
      completely be avoided perioperatively (control group: 21% of patients). Adverse
      effects did not occur. CONCLUSIONS: The data reflect that acute isovolemic
      hemodilution before major gynecological operations represents a safe, easy to
      handle and effective procedure to avoid transfusion of homologous blood up to a
      total blood loss of 1,300-1,400 ml.

PMID- 8653012
TI  - [Effect of administration of blood products on the course of tetanus antibody
      concentration in immuno-incompetent patients].
AB  - OBJECTIVE: Collecting of data for immunoprophylaxis of tetanus in immunodeficient
      patients via administration of blood products. DESIGN: Prospective single case
      studies. SETTING: Clinical therapy in a department of hematology with continuous
      determination of tetanus antibody concentrations in patients' sera and
      administered blood products with an enzyme immunoassay. PATIENTS: 3 patients with
      acute myeloid leukemia (FAB classifications M1, M3, M4). INTERVENTIONS: Regular
      administration of blood products due to clinical therapy. RESULTS: After
      administration of about 4,000 IU tetanus antitoxin i.v., serum concentration is
      increasing by 1 IU/ml. Half life in serum amounts to 7 days. Protection lasts
      therefore up to 6 weeks. CONCLUSIONS: Immunodeficient patients may receive a
      medium-term effective protection against tetanus after selection of suitable
      blood products. This method is interesting also for prophylaxis of postoperative
      tetanus in immunocompetent patients.

PMID- 8653013
TI  - Can blood group O red cells of donor origin acquire weak group A reactivity
      through serum A transferase of the recipient after bone marrow transplantation?
AB  - BACKGROUND: Blood group A substance was detected on red cells of a patient who
      received a bone marrow transplant from a blood group O donor 3.5 years ago.
      MATERIALS AND METHODS: Peripheral blood was investigated by conventional
      serological techniques, fluorescence in situ hybridisation, and polymerase chain
      reaction. RESULTS: All peripheral blood cells are of donor origin. Anti-A and not
      anti-A, B of blood group O individuals can be absorbed to the group O red cells
      of the patient. CONCLUSION: We suppose that the patient's residual serum A
      transferase attaches the appropriate sugar to substance H on the red cell
      membrane to form substance A.

PMID- 8653014
TI  - Intensification of donor interviewing procedures: a feasibility study.
AB  - OBJECTIVE: To determine the feasibility and acceptability for the blood donor of
      an intensified blood donor interviewing procedure on high-risk factors for
      infectious diseases. To answer the question whether an intensified blood donor
      interviewing procedure would lead to an unacceptable loss of blood donors.
      DESIGN: Feasibility study. SETTING: Red Cross Bloodbank Rotterdam. DONORS: Study
      group of 240 first-time donors. INTERVENTIONS: Intensified donor interviewing
      techniques by direct questioning and workload assessment. RESULTS: Intensified
      interviewing was welcomed by 88-91% of first-time donors and rejected by 2-5%. On
      the question whether the intensified interviewing procedure should be the
      standard approach of the blood bank the answer was positive in 76-82% of first
      time donors and negative in 11-14%. No blood donors indicated that this would be
      a reason to withdraw from blood donation. The workload for the blood bank
      physician increased by approximately 30%. CONCLUSION: The approach of intensified
      donor interviewing techniques in first-time donors is acceptable both to the
      donors and the blood bank workload.

PMID- 8653015
TI  - [The revised PEDINFUS computer program for total and added parenteral nutrition
      in children].
AB  - The computer program PEDINFUS, first described in 1991, has been fundamentally
      revised and further developed. The area of application has been considerably
      widened as additive parenteral nutrition has been included and the group of
      newborn and preterm infants has been taken into account. Consequently, the
      program can be used for children of all age groups. In addition, the program has
      a graphical user interface and can be used on several hardware platforms. The
      flexibility of the program has also been increased to a considerable degree. Now
      the nutrient amounts per kilogram per day, the limits of the laboratory values,
      the combination of enteral food and infusion solutions, and the already drawn-up
      infusion plans can be changed at liberty. Considerably more matters of clinical
      interest accompanying parenteral nutrition have been integrated in the program.
      Further plausibility controls have also been introduced to achieve greater
      certainty in the calculation of the infusion solutions. In consequence, the
      preconditions for ensuring and controlling the quality of infusion therapy
      regimens can be established on an improved level.

PMID- 8653016
TI  - [Importance of introduction of PCR in blood banks].

PMID- 8653017
TI  - [Microbial safety of blood products].
AB  - OBJECTIVE: Septicemia caused by contaminated stored blood is a rare event, and
      the actual incidence is hard to determine due to a considerable variation of the
      different study protocols. This review is intended to give an overview of the
      pertinent literature considering causes, frequencies and kind of agents in
      contaminated blood products. SOURCES: English and German literature as well as
      own data. SELECTION CRITERIA: Original and review articles relevant to the topic.
      FINDINGS: The rate of septic episodes after transfusion of contaminated blood
      donations is approximately 0.3% (0.003-5%) of all blood transfusions.
      Contaminations of red cell preparations are predominantly caused by gram-negative
      bacteria, most often psychrophiles (Pseudomonas sp. Yersinia enterocolitica,
      Serratia). In platelet concentrates the prevailing bacterial organisms are
      represented by staphylococcal species. Bacterial contamination of blood and blood
      products may be generated in the process of blood collection and preparation of
      blood components. Materials and machinery used for blood processing may well
      serve as sources of contaminations. A considerable proportion of all
      contaminations must be attributed to transient, asymptomatic bacteremia of the
      donor. An additional predonation questionnaire addressing clinical symptoms
      associated with various pathological conditions (abdominal pain, tick-bites,
      malaria) has proven unpractical and may lead to a rejection rate of donors as
      high as 11%. CONCLUSIONS: In-process bacteriological surveillance, stringent
      control of technical and hygienic conditions, and the use of leukocyte filters
      can reduce the risk of bacteria transmission. In case of transfusion reactions
      due to suspected bacterial contamination, blood samples of the patient as well as
      of the transfused blood product and the transfusion equipment used must be secure
      for microbiological examination.

PMID- 8653018
TI  - [Thrombocyte collection with the A3p program using the blood cell separator
      Haemonetics MCS 3p].

PMID- 8653019
TI  - The clinical application of two newly developed lipid emulsions (Solipid 20% S&E)
      in critically ill patients.
AB  - OBJECTIVE: The clinical compatibility of two newly developed lipid emulsions
      based on soy oil (20%) emulsified with egg lecithin (12 g/l) or soy lecithin (15
      g/l) (Solipid 20% E&S) has been compared. DESIGN: Double-blind prospective
      randomized study. SETTING: Intensive care unit of a university hospital.
      PATIENTS: 20 patients (16 men, 4 women, age 20-59 years) were entered into the
      study. INTERVENTIONS: One g of lipids/kg body weight per day was administered on
      day 1 and subsequently 2 g/kg/day on days 2-5. Blood was drawn once a day,
      lipids, lipoproteins, apoproteins and other routine clinical chemistry parameters
      were determined. RESULTS: No significant increase of total triglycerides could be
      observed. Total cholesterol, low-density lipoprotein cholesterol, high-density
      lipoprotein cholesterol, apolipoproteins A I and B usually remained below the
      reference ranges. Electrolytes, uric acid and glucose, blood cells, parameters of
      liver and kidney function, coagulation and protein metabolism did not show
      relevant changes; only the activity of gamma-GT in both groups--independent of
      the sort of lecithin--increased significantly. CONCLUSION: The results indicate
      adequate elimination of both tested lipid emulsions from the plasma at usual
      clinical conditions. Therefore Solipid 20% S&E can be used in critically ill
      patients.

PMID- 8653020
TI  - Capitated practices. Do they work.

PMID- 8653021
TI  - What we want. Part 4: Case reports and committee reports.

PMID- 8653022
TI  - Occupational and environmental health. Preparing residents to treat related
      illnesses.

PMID- 8653023
TI  - Tracking programs waste of time.

PMID- 8653024
TI  - Safety of medications in lactation cessation.

PMID- 8653025
TI  - Value of certification.

PMID- 8653026
TI  - Accepting spinal manipulation as an effective treatment.

PMID- 8653027
TI  - Sex vs gender.

PMID- 8653028
TI  - What exacerbates asthma?

PMID- 8653029
TI  - Hair care during pregnancy.

PMID- 8653030
TI  - Dermacase. Keratoderma climactericum.

PMID- 8653031
TI  - Needs for CME in geriatrics. Part 2: Physician priorities and perceptions of
      community representatives.
AB  - OBJECTIVE: To explore physicians' responses to the needs for education in
      geriatrics identified by a community needs survey. DESIGN: Interviews conducted
      during a cross-sectional survey. SETTING: Private family practices in Calgary.
      PARTICIPANTS: Randomly selected family physicians in Calgary who had previously
      recruited patients for a community needs survey. Thirty of 60 volunteer
      physicians randomly selected for phase 1 of the study were interviewed. One
      physician recruited patients for phase 1 but declined to be interviewed. MAIN
      OUTCOME MEASURES: Demographic variables, practice characteristics, and opinions
      on urgency of potential topics for continuing medical education. RESULTS:
      Physicians agreed with community informants that they need more education about
      medication for the elderly, medical management, and mental health issues.
      Physicians did not perceive pressing needs for education in communication skills
      with patients, in compassion, or in health promotion for patients. Physicians
      identified many barriers to meeting needs identified by the community. Among the
      most notable obstacles were inadequate time, inadequate remuneration, and lack of
      accessible community resources. CONCLUSIONS: Continuing medical education should
      help physicians recognize the community's needs and design programs that will
      address them.

PMID- 8653032
TI  - Chronic unhappiness. Investigating the phenomenon in family practice.
AB  - PURPOSE: To investigate the experience of chronic unhappiness as it presents in
      family practice. DESIGN: A descriptive, qualitative study of both patients and
      physicians using an existential phenomenologic approach. SETTING: Two village
      general practices in South Africa. PARTICIPANTS: Four patients who were
      difficult, "heartsink" patients, who gave their doctors an overwhelming feeling
      of exasperation and defeat. METHOD: We investigated the clinical records
      thoroughly and explored patients' relationships with others. Through
      interpretation and reflection, we tried to discover what role the doctor could
      play with these patients. FINDINGS: Chronic unhappiness was found to be not only
      a condition of life for the patients but also for the doctor. It was an important
      factor in the relationship they shared. Unhappiness was revealed in part by
      frequent visits by the patients, a constellation of negative feelings in the
      doctor, and difficult patient-doctor relationships. CONCLUSION: Chronic
      unhappiness is not "treatable" in the normal curative or therapeutic sense. This
      does not prevent our quest to diagnose and cure, but enlarges our horizons to
      recognizing and accepting our own human reactions to patients and understanding
      how we can meet their needs.

PMID- 8653033
TI  - Staphylococcus aureus and sore nipples.
AB  - OBJECTIVE: To correlate clinical symptoms and signs of sore nipples with the
      presence of Staphylococcus aureus and to determine the probability of mothers
      having S aureus-infected nipples when these local symptoms and signs are found.
      DESIGN: Two cohorts of consecutive patients were enrolled regardless of
      presenting complaint. A questionnaire was administered to determine the presence
      and severity of sore nipples. Objective findings on breast examination were
      documented. A nipple swab was taken for culture and sensitivity. SETTING:
      Breastfeeding clinic serving patients referred by family physicians,
      pediatricians, and community health nurses. PATIENTS: A sample of 227
      breastfeeding mothers was collected in two cohorts. MAIN OUTCOME MEASURES:
      Answers to questions about sore nipples, objective findings from physical
      examination, and results from nipple swabs. RESULTS: Most subjects (51%) had sore
      nipples, and 45% of subjects had objective findings on examination; 23% of
      subjects had a positive nipple swab culture; 15% grew S aureus on culture. The
      risk of having S aureus colonization was 4.8 times greater if nipple pain was
      moderate or severe rather than mild. A break in nipple integument associated with
      cracks, fissures, ulcers, or pus gave a 35% chance of having S aureus
      colonization, five times greater than when the integument was intact.
      CONCLUSIONS: The study showed that mothers with infants younger than 1 month who
      complained of moderate to severe nipple pain and who had cracks, fissures,
      ulcers, or exudates had a 64% chance of having positive skin cultures and a 54%
      chance of having S aureus colonization.

PMID- 8653035
TI  - Treating alcoholism through a narrative approach. Case study and rationale.
AB  - A case study illustrates the narrative or story-telling approach to treating
      alcoholism. We discuss the rationale for this method and describe how it could be
      useful in family practice for treating people with alcohol problems.

PMID- 8653036
TI  - Alcohol risk assessment and intervention for family physicians. Project of the
      College of Family Physicians of Canada.
AB  - At-risk and problem drinkers (excluding those with severe dependency) are
      estimated to be 20% of the Canadian population. With minimal training family
      physicians can effectively manage patients with alcohol problems. The Alcohol
      Risk Assessment and Intervention Project of the College of Family Physicians of
      Canada has developed materials and training for family physicians to use in
      helping their patients reduce the risks of alcohol-related harm.

PMID- 8653034
TI  - Identifying and managing problem drinkers.
AB  - Problem drinking is far more common than severe alcohol dependence and is
      associated with considerable morbidity and health care costs. Whereas patients
      with alcohol dependence respond best to intensive treatment, one or more brief
      sessions of physician advice and counseling reduces alcohol consumption among
      problem drinkers. The two most useful tools to identify problem drinkers are the
      CAGE and the drinking problem question.

PMID- 8653037
TI  - External cephalic version. Does it have a role in modern obstetric practice?
AB  - External cephalic version (ECV) for breech presentation at term substantially
      reduces the incidence of breech birth and cesarean section. Appropriate
      counseling and surveillance is important to ensure an acceptably low complication
      rate and reduce potential for litigation. Even a high success rate for ECV only
      minimally reduces the overall cesarean section rate.

PMID- 8653038
TI  - [Hypertension. A new way to approach an old problem].
AB  - High blood pressure is frequently seen in family practice. In response to recent
      surveys and clinical trials, the Canadian Hypertension Society has changed its
      recommendations on the management of HBP. This article reviews family physicians'
      approach to HBP according to the recent report of the Canadian Hypertension
      Society Consensus Conference.

PMID- 8653039
TI  - Early detection of prostate cancer. Role of prostate-specific antigen.
AB  - Pressure to request prostate-specific antigen (PSA) tests for early detection of
      prostate cancer in middle-aged and older men is increasing. However, current
      scientific data suggest that such testing does more harm than good. Most
      professional groups do not advise routine screening for prostate cancer. This
      paper reviews the current status of PSA testing.

PMID- 8653040
TI  - Phrenology.

PMID- 8653041
TI  - Time for a new societal norm for sexuality.

PMID- 8653042
TI  - Impending flu pandemic.

PMID- 8653043
TI  - [Microecology of non spore-forming anaerobes in health and in disease].
AB  - The authors studied the species-specific and quantitative composition of the
      large intestinal microbiocenosis on exposures to various factors of endo- and
      exogenous etiologies: the presence of a pathological process and its specific
      features, dietary trace element composition, unfavorable environmental (chemical)
      factors, as well as the impact of coexistence in the same family and the factors
      of family variability (the individual genotype of the macro-organism). The
      microenvironment of non spore-forming anaerobes that colonize the large bowel was
      found to be influenced by a number of various factors, both exo- and endogenous.
      The magnitude of these changes is associated with the intensity and specificity
      of an influencing factor.

PMID- 8653044
TI  - [Role of non spore-forming anaerobes in the formation of microbial landscape of
      the large intestine in patients with inflammatory processes at different sites].
AB  - Clinical microbiological techniques were used to study 300 patients with
      clinically verified urinary infections and chronic intestinal diseases. It was
      ascertained that examining the large intestinal content in average statistical
      groups of patients with inflammatory processes at various sites cannot
      objectively characterize the presence or absence of clinical manifestations of
      gastrointestinal diseases. The pathogenetic factors that predispose to the
      development of intestinal diseases are lower phagocytic activity, decreased
      complement and deficiency of B lymphocytes and IgA. The concentrations of IgM,
      IgG, secretory IgA and protein, as well as those of B. bifidum in the large
      intestinal content may serve as an additional diagnostic criterion for evaluating
      the mucosa of the ecological niche.

PMID- 8653045
TI  - [Results of clinical and laboratory studies of anaerobic non-clostridial
      infection in a surgical clinic].

PMID- 8653046
TI  - [Obligate anaerobic microbes in obstetric and gynecologic diseases].
AB  - The paper reviews recent-years' papers and the data of their own investigations
      on a role of obligate anaerobic microbes in obstetric and gynecological
      abnormality. The fact that secondary pelvic inflammatory processes caused chiefly
      by non spore-forming anaerobes is ascertained. There is evidence that obligate
      anaerobic bacteria are involved in the abnormality directly unassociated with the
      development of an inflammatory process: preterm labor, premature discharge of
      amniotic fluid, intranatal fetal hypoxia, respiratory distress syndrome and
      hyaline membrane disease of the premature newborn. Among vaginal infections the
      key role is played by bacterial vaginosis which is, from the pathophysiological
      point of view, now a severe derangement of the vaginal environment system with
      greatly prevalent obligate anaerobic bacteria and without lactoflora.
      Complications associated with this abnormality are noted.

PMID- 8653048
TI  - [Anaerobic infection in abdominal surgery].
AB  - The etiological pattern of non-clostridial anaerobic infection, its natural
      history and drug therapy in patients with its various types were studied and
      analyzed at the Surgery Research Center, Russian Academy of Medical Sciences.
      Peritonitis and cholangitis were examined in detail. Multimodality treatment of
      patients with acute peritonitis caused by a combination of aerobic and anaerobic
      pathogens by using hyperbaric oxygenation and therapy with directly acting
      antibiotics was found to enhance its efficiency, decrease therapy duration,
      prevent inflammation progression, and reduce mortality rates from 25.64 to 8.8%.
      The application to the techniques of preliminary decompression and the developed
      regimens of antibacterial therapy and hyperbaric oxygenation in the multimodality
      treatment for suppurative cholangitis noticeably yielded better therapeutical
      results, reduced mortality rates from 5.7 to 0% and these patients' hospital
      stay.

PMID- 8653047
TI  - [Infections caused by non spore-forming anaerobic bacteria].
AB  - Pyo-inflammatory diseases continue to be one of the topical problems of modern
      medicine. Their etiological agents are opportunistic microorganisms among which
      non spore-forming anaerobes are prevalent in the normal microscopic flora. They
      cause a pathological process when the body's immunity is decreased. The authors
      consider the biological features of this group of bacteria, epidemiological and
      pathogenetic aspects, the problems of laboratory and clinical diagnosis of non
      clostridial anaerobic infection and outline immediate steps to be taken to solve
      the problems.

PMID- 8653049
TI  - [Progress and perspectives in the study of non-clostridial anaerobic infection of
      female genitalia].
AB  - The paper summarizes the results from 15-year studies of non-clostridial
      anaerobic infection in obstetrics and gynecology. The authors show that strict
      non-spore-bearing anaerobic microbes are prevalent in the etiological pattern of
      pyoinflammatory diseases of the female genitals, present the basic pathogenetic
      features of the development and clinical signs of anaerobic infections. The
      present-day principles of diagnosis and treatment of these diseases are given.
      Prospects are shown for further studies of non-clostridial anaerobic infection in
      obstetric and gynecological care.

PMID- 8653050
TI  - [Several aspects of non-clostridial anaerobic infection in cancer patients].
AB  - The specific features of the development and natural history of nonclostridial
      anaerobic infection (NACI) were studied in 125 cancer patients with various site
      tumors. It was shown that after surgery for malignant abdominal and genital
      tumors, NCAI might develop in the late postoperative period despite antibacterial
      antianaerobic prevention and even long-term antianaerobic therapy. NCAI treated
      with antianaerobic therapy was found to run long with aggravations and remissions
      in patients undergone surgery and drug therapy for genital cancer. Radiation
      therapy is a risk factor for NCAI in patients with malignant genital neoplasms.
      The risk factors for NCAI in skin cancer patients are tumor ulceration, second
      infection, and resolution. The most severe problem is likely anaerobic bacteremia
      in cancer patients. Anaerobic bacteremia appears to be more common than we
      thought and this issue requires further in-depth study.

PMID- 8653051
TI  - [Study of pathogenetic mechanisms of intoxication in patients with anaerobic non
      clostridial infection].
AB  - Pyoinflammatory diseases continue to be one of the most topical problem of modern
      medicine. Anaerobic non-clostridial infection is essential in the etiological
      pattern of pyoinflammatory diseases. Its specific feature is early developed
      severe intoxication. The authors have developed laboratory criteria for
      evaluating the degree of intoxication in patients with anaerobic non-clostridial
      infection, which are based on chromatographic determination of the concentrations
      of specific metabolic products, such as volatile fatty acids and toxic
      metabolites of the phenol group, in the patients' peripheral blood, which allows
      the detected disorders to be promptly corrected. The metabolic products of non
      spore-forming anaerobes, such as volatile fatty acids, are important pathogenetic
      factors since they inhibit the dynamic activity of platelets and the phagocytic
      activity of leukocytes in blood.

PMID- 8653053
TI  - [Diagnosis and treatment of suppurative complication of anaerobe etiology in
      trauma and orthopedic patients].

PMID- 8653052
TI  - [Microbiology and immunology of suppurative surgical infection caused by non
      spore-forming anaerobes].
AB  - Examinations of 230 patients with local pyogenic infection and those of 117
      patients with sepsis revealed that asporogenic anaerobes on pure culture were
      isolated in 17.8% with local pyosis and in 10.2% of patients with sepsis.
      Anaerobes along with aerobic microbes were found 15.6% of patients with local
      infection and in 10.2% of patients with sepsis. The involvement of obligate
      anaerobes in the development of pyogenic infection was displayed by the lower
      phagocytic activity of neutrophils, the impaired differentiation of lymphocytes,
      the great increased peripheral blood levels of O-cells, and diminished serum
      complementary, lysozyme, and overall bactericidal activities and IgM levels.

PMID- 8653054
TI  - [Microbiological diagnosis and antibacterial therapy of non spore-forming
      anaerobic infections in emergencies].
AB  - A total of 240 patients with soft tissue and wound suppurations, peritonitis, and
      suspected sepsis were examined. Anaerobic isolates were more frequently obtained
      in 20-75% of patients infections associated with facultative microbes. The use of
      non-culture media (bacterioscopy and gas-liquid chromatography) increased the
      detection rate of anaerobic infection up to 82% as compared with bacteriological
      diagnosis (63%). The findings and the data of monitoring of suppuration agents
      for several years allowed the authors to work out effective combined treatment
      regimes for early mixed aerobic and anaerobic infections in 80-100% of patients.

PMID- 8653055
TI  - [Chromatographic mass spectrometry detection of microorganisms in anaerobic
      infectious processes].
AB  - The selective ion assay (mass-fragmentography) was used to detect some species of
      microbes in the human biological fluids (urea, pus discharge, pleural fluid, and
      sperm). This technique is highly sensitive and selective and prompt-to-use.
      Examinations of the chemical composition of pure microbial cultures determined
      structural marker substances from a number of fatty acids, hydroxy acids, and
      aldehydes of the cellular membrane and lipopolysaccharides. The assay can detect
      microorganisms typical of infectious processes within hours if the bacteria
      amount to more than 10,000 cells in the culture sample.

PMID- 8653056
TI  - [Rational approach to correction of intestinal microflora].
AB  - This paper reviews the present notions of the mechanisms of probiotics' action
      and analyzes selective approaches to correcting the intestinal microflora, such
      as the use of antibiotic-resistant and highly-adhesive probiotics, treatment with
      autostrains of lactobacilli and bifidobacteria, and the application of fermented
      milk probiotics. Methods for optimization of the intestinal microflora in the
      newborns by using the maternal strains of bifidobacteria and the drug Zlemik that
      contains highly-adhesive lactobacilli are discussed. It is shown that parameters
      of immunotropic activity and involvement in the bacteriocin-mediated interactions
      may be used to design new probiotics. In future, the application of gene
      engineering methods will aid in designing a new generation of probiotics with
      predicted biological properties.

PMID- 8653057
TI  - [Validity of epidemiological classification: study of asymptomatic properties of
      a discriminant criterion].

PMID- 8653058
TI  - [Role of anaerobic non spore-forming bacteria in maintaining human health].
AB  - The paper gives brief information on the fact that anaerobic non spore-forming
      bacteria take an active part in the metabolism of various substances and
      imbalance in their microscopic flora may be a trigger in the development of many
      human diseases. In the past 2 decades, Russia has been using various
      pharmaceuticals based on bifidobacteria, lactobacilli and their complexes,
      increasing colonization resistance, normalizing the pool of cholesterol, oxalic
      acid, free histamine, and making the liver function normally. Special emphasis is
      laid on the design of functional nutrition products by means of the above
      bacteria. It is emphasized that the industrial development of functional
      nutrition will determine human health in the twenty-first century.

PMID- 8653059
TI  - Effect of hyperbaric oxygenation on bone in HEBP-induced rachitic rats.
AB  - The effect of hyperbaric oxygenation (HBO) treatment on rachitic change was
      studied using 4-wk-old, 1-hydroxyethylidene-1, 1-bisphosphonic acid disodium
      (HEBP-EHDP)-induced rachitic rats. After treatment, the dry weight, ash weight,
      Ca and P content, and bone mineral density of the hind leg bones were measured in
      each rat. These parameters were significantly increased in the rats that were
      treated with HBO after HEBP administration compared with those parameters in the
      rats that received HEBP alone. However, there was no significant differences
      between the rats treated simultaneously with HEBP and HBO and those that were
      treated with HEBP alone. These results were consistent with radiologic and
      histologic findings. Marked calcification in the center of the growth plate was
      revealed in the rats treated with HBO after HEBP administration. We suggest that
      intermittent high-pressure pure oxygen has a beneficial effect on osteogenesis in
      rachitic bone but does not prevent rachitic change.

PMID- 8653061
TI  - Reduction of decompression illness risk in pigs by use of non-linear ascent
      profiles.
AB  - An established swine model of neurologic decompression illness (DCI) was adapted
      to investigate the influence of no-stop ascent profile shape on DCI risk after
      deep air and heliox dives. Pigs underwent a simulated air dive in a dry chamber
      to 200 fsw (613 kPa) for 24 min bottom time. They were then decompressed at
      either a linear rate of 20 fsw/min (61 kPa/min) or on a non-linear, fast
      deep/slow-shallow profile. Both decompressions lasted 10 min. In the linear
      group, there were 11/20 cases of neurologic DCI, including 1 death and 8 severe
      cases, compared to 5/20 cases (1 severe) in the fast/slow group. Thirteen out of
      20 from the linear group, vs. 6/20 of the non-linear group, had moderate or
      severe skin DCI affecting > 20% skin surface area. A similar study, but of
      paired, randomized, investigator-blind, and sequential design was performed with
      pigs breathing 80/20% heliox: Pigs were compressed to 250 fsw (766 kPa) for 8 min
      50 s, then decompressed at either a linear 30 fsw/min (92 kPa/min), or on a
      fast/slow profile. Neurologic DCI occurred more frequently (P = 0.024) in the
      linear group (16/20; 1 death and 11 severe) than in the fast/slow group (8/20; 3
      severe). Moderate or severe skin DCI affected 16/20 of the linear group compared
      to 3/20 of the fast/slow group (P = 0.0002). The study findings suggest that
      substantial reductions in DCI risk may be obtainable by manipulating the ascent
      profile after deep no-stop diving. This finding has potential application in both
      military and civil diving operations.

PMID- 8653062
TI  - Pressure antagonism of nitrous oxide depression of intracellular calcium in a
      neuroblastoma cell line.
AB  - While the ability of increased pressure to reverse anaesthesia has been well
      documented, the cellular or molecular mechanism(s) responsible for their mutual
      antagonism have remained elusive. Previous work in our laboratory, using diverse
      cell types, has indicated several processes requiring Ca2+ are affected in
      opposite directions by hydrostatic pressure [as represented by helium (He)],
      narcotic gases, and some anesthetics. Here we report on the effects of elevated
      pressures of He, and of 1 atm abs of the anesthetic gas nitrous oxide (N2O), when
      present alone and in combination, on calcium mobilization in the human
      neuroblastoma cell line SK-N-SH. Cytosolic-free Ca2+ ([Ca2+]i) was monitored by
      fluorescence spectrophotometry in cell suspensions loaded with the intracellular
      Ca2+ indicator fura-2. N2O reversibly depressed the carbachol-stimulated increase
      in [Ca2+]i (P < 0.01). The application of both 18 and 35 atm abs He attenuated
      this N2O-induced depression of carbachol-stimulated increase in [Ca2+]i. These
      findings support the hypothesis that pressure/anesthetic antagonism may be due in
      part to effects on neuronal [Ca2+]i and its regulation.

PMID- 8653060
TI  - Breathing a mixture of inert gases: disproportionate diffusion into decompression
      bubbles.
AB  - To study the consequences of diving with gas mixtures, we simulated growth of
      decompression bubbles using an equation system that accounts for major
      determinants of bubble behavior. When breathing a mixture, bubbles are smaller
      than expected from linear interpolation between bubbles with either of the
      unmixed component gases because of disproportionate diffusion effects: a) When
      few bubbles form, the inert gas that permeates fastest becomes over-represented,
      relative to the breathing gas, inside bubbles during growth; this slows further
      entrance of the fast gas and enhances entrance of the slower gas. b) With N2-He
      mixtures and few bubbles, the over-represented gas is He in aqueous tissue, but
      is N2 in lipid tissue. c) When many bubbles form, the over-represented gas is the
      one with higher tissue solubility. Our simulations indicate that the smallest
      bubbles always occur with breathing of one of the component gases, but which gas
      that is depends on whether the tissue is lipid or aqueous and whether few or many
      bubbles form.

PMID- 8653063
TI  - Complement system response to decompression.
AB  - A role for the activated complement system in the pathogenesis of decompression
      sickness has recently been suggested. In this study we aimed at evaluating the
      response of the complement system to decompression in 24 human volunteers. A
      significant reduction was observed in the levels of iC3, which is a
      conformationally changed form of the third complement component (C3), and C3A
      after decompression (P < 0.001). The levels of total C3 did not change during the
      experiment. A relatively mild decompression has thus led to a distinct change in
      the complement activation profile in human volunteers.

PMID- 8653064
TI  - Effect of 12 atmospheres helium-oxygen on the response of mice to convulsant
      drugs.
AB  - The mechanism by which 12 atm abs of a helium-oxygen gas mixture (heliox)
      antagonizes behavioral effects of ethanol is unknown. Although the threshold for
      pressure-reversal of general anesthesia and expression of the high pressure
      neurologic syndrome (HPNS) is well above 12 atm abs in mice, the ethanol
      antagonism by 12 atm abs heliox could result from similar underlying excitatory
      effects. To investigate this possibility, the behavior of water-injected control
      mice and the latency to convulsions in drug-injected mice were determined in 1
      atm abs air and 12 atm abs heliox. Four convulsant drugs were tested: picrotoxin
      (2 mg/kg), dl-allylglycine (300 mg/kg), isoniazid (300 mg/kg), and l-methionine
      dl-sulfoximine (170 mg/kg). Responses were videotaped to observe behavior and to
      measure latency to the onset of myoclonus and clonus. Results indicated no
      observable excitatory effects of 12 atm abs in control mice. The latency to
      myoclonus was significantly reduced by pressure in allylglycine-treated mice but
      not in mice treated with the other convulsants. Latency to clonus was not
      significantly altered by pressure, relative to latency at 1 atm abs heliox, for
      any drug tested. In conclusion, the present findings indicate that exposure to 12
      atm abs heliox is not proconvulsant and, thus, the findings do not support the
      hypothesis that 12 atm abs heliox antagonizes ethanol indirectly via an increase
      in central nervous system excitability.

PMID- 8653065
TI  - Chemical safety of U.S. Navy Fleet soda lime.
AB  - Contamination was suspected of U.S. Navy Fleet soda lime (High Performance
      Sodasorb) when an ammonia-like odor was reported during its use in August 1992.
      This material contained indicator dye and was used for carbon dioxide absorption
      during diving. This incident had a major impact on the U.S Navy diving program
      when the Navy temporarily banned use of Sodasorb and authorized Sofnolime as an
      interim replacement. The Naval Medical Research Institute was assigned to
      investigate. Testing involved sampling from the headspace (gas space) inside
      closed buckets and from an apparatus simulating conditions during operational
      diving. Volatile organic compounds were analyzed by gas chromatography and mass
      spectrometry; ammonia and amines were measured by infrared spectroscopy.
      Significant amounts of ammonia (up to 30 ppm), ethyl and diethyl amines (up to
      several ppm), and various aliphatic hydrocarbons (up to 60 ppm) were detected
      during testing of both Sodasorb and Sofnolime. Contaminants were slowly removed
      by gas flow and did not return. The source(s) of the ammonia and amines are
      unknown, although they may result from the breakdown of the indicator dye.
      Hydrocarbon contamination seems to result from the materials of which the bucket
      is constructed. Unfortunately, evaluation of potential hazards associated with
      this contamination is difficult, due in part to the large number of variables of
      operational use and the absence of appropriate exposure limits. Based on these
      findings, the U.S. Navy has begun to phase in, for all diving, non-indicating
      soda lime that will be required to meet defined contaminant limits.

PMID- 8653066
TI  - Bone composition and metabolism after hyperbaric oxygenation in rats with 1
      hydroxyethylidene-1,1-bisphosphonate-induced rickets.
AB  - We examined bone composition and metabolism after hyperbaric oxygenation (HBO) in
      Wistar rats with 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP)-induced rickets.
      Twenty rats at 4 wk of age were divided into four groups of five rats each. The
      HEBP + HBO group received high dose (50 mg.kg-1.day-1) HEBP injections
      subcutaneously for 7 days and were then exposed to HBO for 7 days. The HEBP group
      received only high dose HEBP injection for the first 7 days. Control group A
      received neither HEBP nor HBO. Control group B received no HEBP injection and was
      exposed to HBO only for the second 7 days. Both bone mineral and hydroxyproline
      contents significantly increased in rats in the HEBP + HBO group as compared with
      the HEBP group. Alkaline phosphatase activity of bone, which is a marker of
      osteoblastic activity and bone formation, was high in the HEBP + HBO and HEBP
      groups compared with control groups A and B, although there was no difference
      between the former two groups. On the other hand, tartrate-resistant acid
      phosphatase activity, which is a marker of bone resorption, was lower in the HEBP
      + HBO group than in the HEBP group. These findings suggest that HBO suppresses
      bone resorption in high osteoblastic activity after the cessation of HEBP
      administration, and this phenomenon increases total bone mass.

PMID- 8653067
TI  - An evaluation of the Sharpened Romberg's Test in diving medicine.

PMID- 8653068
TI  - Comments on "Does hyperbaric oxygen have a cancer-causing or -promoting effect?".

PMID- 8653069
TI  - Comments on Maine urchin divers.

PMID- 8653070
TI  - Reciprocal protective effects of all-trans retinol and alpha-tocopherol during
      lipid peroxidation in retinal membranes.
AB  - Interactions between vitamin A and vitamin E in suppressing lipid peroxidation
      were observed in bovine retinal membrane preparations submitted to peroxidative
      injury by the water soluble azo initiator 2,2'-azobis(2-amidino-propane)
      hydrochloride (AAPH). Incorporation of 0.75 nmol mg prot(-1) all-trans retinol,
      an amount comparable with that of the endogenous alpha-tocopherol, significantly
      elongated the induction time preceding the release of TBA-reactive lipid
      peroxidation products, and reduced the consumption rate of the endogenous alpha
      tocopherol. On the other hand, all-trans retinol was not able to induce any delay
      to the onset of lipid peroxidation when incorporated in membranes deprived of
      endogenous alpha-tocopherol by exposure to UV light, although TBARS produced
      within 60 min decreased slightly. Consumption of all-trans retinol during
      peroxidation was more rapid when all-trans retinol was incorporated in membranes
      deprived of alpha-tocopherol than in native membranes. These data suggest that
      reciprocal protective effects between vitamin A and vitamin E may strongly
      contribute to the defence of membranes against oxidative stress.

PMID- 8653071
TI  - Thiamine pyrophosphate as an effector of 2-oxoglutarate dehydrogenase complex
      from European bison heart.
AB  - The purified 2-oxoglutarate dehydrogenase complex (OGDC) from the European bison
      heart was near saturated with endogenous bound thiamine pyrophosphate (TPP).
      Exogenous TPP added to the full OGDC reaction medium decreased S0.5 for 2
      oxoglutarate approximately 2.6-fold without any notable change in the maximum
      reaction rate. The TPP effect was observed in the presence of 1 mM ADP which
      alone is a strong positive allosteric effector of OGDC. At an unsaturating 2
      oxoglutarate concentration the A50 value for TPP was approximately 0.05 mM. The
      ADP-like action of exogenous TPP was also found in the 2-oxoglutarate
      dehydrogenase (E1) reaction, determined in the presence of 2,6
      dichlorophenoloindophenol as an electron acceptor.

PMID- 8653072
TI  - Organization and nucleotide sequence of a gene cluster comprising the translation
      elongation factor 1 alpha, ribosomal protein S10 and tRNA(Ala) from Halobacterium
      halobium.
AB  - Lambda EMBL clone containing a gene cluster coding for the translation elongation
      factor 1alpha, ribosomal protein S10 and tRNA(ala) was identified in a genomic
      library for the halophilic archaebacterium Halobacterium halobium using a PCR
      probe amplified by two oligonucleotide primers for conserved amino acid sequences
      of the elongation factor 1 alpha family. The gene coding for elongation factor EF
      2 was also found 4.3kb upstream from the 5'end of the elongation factor 1 alpha
      by hybridization analysis using a DNA fragment specific for EF-2 from
      Halobacterium halobium [1]. Halobacterial and eukaryotic elongation factor 1
      alpha homologues are very similar in sequence and in length and appear to be more
      closely related to each other than to the eubacterial protein.

PMID- 8653073
TI  - Does prediction of epitopes from the primary structure of a protein represent the
      epitope in the native structure? A study using cobrotoxin.
AB  - In contrast to observations made with S. aureus V8 protease-digest hydrolysates,
      the antigenic structures of reduced and S-carboxymethylated (RCM)-cobrotixin were
      notably affected following hydrolysis of RCM-cobrotoxin with chymotrypsin. The
      peptide separated from the V8 protease-digest hydrolysates with a sequence at
      positions 22-38 of cobrotoxin exhibited a nearly equal reactivity toward the anti
      RCM-cobrotoxin antibodies as RCM-cobrotoxin. Chymotryptic cleavage on this
      segment caused a precipitous drop in the antigenicity of RCM-cobrotoxin.
      Alternatively, the N-terminal and C-terminal regions of RCM-cobrotoxin
      encompassed other antigenic determinants which exhibited low reactivities toward
      anti-RCM-cobrotoxin antibodies. The epitope structures of RCM-cobrotoxin are in
      line with those predicted from the hydrophobicity profile of cobrotoxin, but the
      notably immunoreactive region in the C-terminal region of native toxin molecule
      (Ref. 1) cannot be predicted from analysis of its primary structure. Moreover,
      RCM-cobrotoxin had a superior reactivity toward anti-RCM-cobrotoxin antibodies
      than cobrotoxin did. These results indicate that the epitope structures in RCM
      cobrotoxin and cobrotoxin are different.

PMID- 8653075
TI  - Age-related differences in synaptosomal membrane fluidity.
AB  - Fluidity of the lipid bilayer near the surface of the membranes and in the core
      of the lipid bilayer of synaptosomal membranes isolated from the cortex,
      hippocampus, striatum, hypothalamus, midbrain, pons-medulla oblongata and
      cerebellum of mice at 1, 2, 4, 12, and 18 months of age was examined using
      electron spin resonance spectrometry. Using the spin labels, 5- and 16-DS-stearic
      acid, the order parameter for 5-DS was found to be increased in all brain areas
      with aging and a much greater increase was found in the hippocampus and
      cerebellum at 18 months of age. The results demonstrated that there was a
      different pattern of the increase of the parameter between 15-DS and 16-DS in
      synaptosomal membranes of different brain regions with aging.

PMID- 8653074
TI  - Inhibition of PDGF-induced phosphoinositide-turnover by glucopiericidin A.
AB  - In the search for a substance which would specifically block a particular step in
      the signal transduction cascade, we identified glucopiericidin A produced by
      Streptomyces sp. as an inhibitor of phosphoinositide (PI)-turnover in
      phospholipase-Cgamma1 (PLC-gamma1) overexpressing NIH 3T3 fibroblasts (NIH
      3T3gamma1). Glucopiericidin A inhibited the formation of inositol phosphate (IPt)
      in platelet-derived growth factor (PDGF)-stimulated NIH 3T3gamma1 cells with an
      IC50 of 5.0 microM. In vitro enzyme assay showed the compound had no inhibitory
      effect on PLC-gamma1 even at 100 microM concentration. Glucopiericidin A reduced
      PDGF-induced tyrosine phosphorylations of proteins, including PDGF receptor and
      PLC-gamma1, in the cells. In contrast, glucopiericidin A showed only a slight
      inhibitory effect on epidermal growth factor (EGF)-induced IPt production and
      protein tyrosine phosphorylations in A431 cells. These results suggest that
      glucopiericidin A inhibits PDGF-induced activation of PLC-gamma1 by reducing the
      tyrosine kinase activity of the PDGF receptor and it more potently inhibits PI
      turnover induced by PDGF than by EGF.

PMID- 8653076
TI  - The reducing ability of iron chelates by NADH-cytochrome B5 reductase or
      cytochrome B5 responsible for NADH-supported lipid peroxidation.
AB  - We studied iron reduction, NADH oxidation, and lipid peroxidation in the presence
      of iron chelates with a chelator, such as nitrilotriacetate, ADP, citrate, and
      pyrophosphate, in NADH-supported reconstituted system. The results showed the
      selectivity of NADH-cytochrome b5 reductase or cytochrome b5 towards iron
      chelates and the subsequent ability of this system to promote peroxidation. The
      lipid peroxidation was partially inhibited by superoxide dismutase. In the
      presence of any iron chelate, hydrogen peroxide was produced in the systems
      including the reductase, and the production was accompanied with an increase in
      NADH oxidation.

PMID- 8653077
TI  - The in vivo effect of hyaluronan associated protein-collagen complex on wound
      repair.
AB  - Fetal skin wounds heal without scarring, however the underlying mechanisms remain
      unknown. Immunohistochemical staining and biochemical studies indicate the
      deposition of a collagen repair matrix that is highly organized. We have
      previously described a unique hyaluronan associated protein-collagen complex (HA
      PC) profile present during the period of scarless healing in the sheep fetus. In
      this study, we examined the biologic activity of this HA-PC in an in vivo model
      of adult rat wound repair. A total of 84 incisional and 84 excisional wounds were
      examined by histology, TGF-beta immunocytochemistry and computer planimetry
      (excisional wounds only). Planimetry of the excisional wounds demonstrated the
      mean wound area remaining at day 1 was 88.7% for the control and 63.6% for the
      treated (p<0.01). At day 2, mean wound area was 81.5% for the control and 63.6%
      for the treated (p<0.01). At day 4, mean wound area was 56.6% for the control and
      41.9% for the treated (p<0.01). At day 7, mean wound area was 26.9% for the
      control and 16.8% for the treated (p<0.01). At day 14, mean wound area was 7.9%
      for the control and 3.4% for the treated (p<0.05). Collagen organization was
      judged to be greater in the treated compared to control wounds, with a mean
      organization score of 2.3 vs. 1.9 (p=0.0596; Wilcoxon Signed Rank Sum Test).
      There were significantly more neutrophils at the wound margin of the treated
      compared to control wounds, 4.0 vs. 2.7 (p=0.038; Paired Two Tailed Student's t
      Test). There was no difference in the number of microphages at the wound margin
      of the treated compared to control wounds, 6.15 vs. 6.0 (p>0.05). TGFbeta1 and
      beta2 staining was decreased whereas TGFbeta3 staining was increased in the HA-PC
      treated wounds. These results suggest that compared to control wounds HA-PC
      treated wounds heal more quickly, with more organized collagen, more neutrophils
      at the wound margin and increased TGFbeta3 expression. Furthermore, these data
      suggest that the manipulation of scarring in adult wounds is possible by the
      addition of proteins present in fetal skin.

PMID- 8653078
TI  - Differences in regulation of alpha 1(I) collagen promoter in vascular smooth
      muscle cells in transfection studies and transgenic mice.
AB  - It has previously been shown that the expression of a transgene containing 3.5 kb
      of alpha 1(l) collagen (COL1A1) promoter sequence fused to the chloramphenicol
      acetyl transferase (CAT) reporter gene (ColCAT3.6) paralleled the expression of
      the endogenous type I collagen gene in bone, tendon and skin whereas the
      expression in aorta was extremely low. In contrast, the same promoter construct
      showed comparable activity in a variety of transiently transfected smooth muscle
      and fibroblastic cells. In order to compare the activity of the transiently
      transfected and the ?endogenous? transgene from a transgenic animal, in this
      study, vascular smooth muscle cells (VSMC) were isolated from ColCAT3.6
      transgenic animals and used in a transfection assay. The endogenous transgene
      remained inactive in primary cultures of transgenic VSMC while transiently
      transfected ColCAT3.6 cells had comparable activity to NIH3T3 fibroblasts,
      primary rat tendon fibroblasts or primary rat VSMC. The immortalized cell line
      SM3T3, derived from the aorta of ColCAT3.6 transgenic mice did not express
      endogenous transgene but dis express stably transfected ColCAT3.6 to levels
      similar to NIH3T3 fibroblasts or osteoblastic ROS17/2.8 cells. This result
      stresses the influence of transgene history, possibly its passage through the
      germline, in regulation of tissue specific expression.

PMID- 8653079
TI  - Application of anti-E1 monoclonal antibodies to the study of the pyruvate
      dehydrogenase complex.
AB  - It has been shown that monoclonal antibody (mAb) F7F10 raised against pyruvate
      dehydrogenase component (E1) of pigeon breast muscle pyruvate dehydrogenase
      complex (PDC) has no influence on the E1 activity, measured in the system with
      artificial oxidants. However it inhibited the full NAD+ and coenzyme A dependent
      activity of PDC. The competition of the F7F10 antibody with the E2 component of
      PDC for the binding with E1 was revealed by immunoenzymatic and kinetic analysis.
      It is suggested that F7F10 mAb interacts with an antigenic determinant, located
      in the immediate vicinity of or overlapping with the E1 region, responsible for
      the interaction with the E2 component of PDC.

PMID- 8653080
TI  - Cytokines and programmed cell death in burkitt lymphoma cells.
AB  - Tumour necrosis Factor (TNF), Interleukin 1alpha and beta (IL-alpha and IL-beta),
      Interleukin 7 (IL-7) and Stem Cell Factor (SCF) are cytokines synthesized by
      immune system cells under stimulation of various agents. Apoptosis, or programmed
      cell death, is a process that appears in response to specific stimuli, apparently
      following an intrinsic program. In this work we examined, in RA-1 human
      lymphoblastoid B cell line, the effect induced by different cytokines in cell
      proliferation and in programmed cell death. After 48 hours of treatment is
      present an antiproliferative affects, detected by 3H-thymidine incorporation and
      morphological changes related to apoptotic process.

PMID- 8653081
TI  - Mutations in DNA polymerase beta mRNA of stilbene estrogen-induced kidney tumors
      in Syrian hamster.
AB  - We report here the alteration(s) in the expression of the DNA repair gene, DNA
      polymerase beta, in kidney tumors induced by stilbene estrogen
      (diethylstilbestrol, DES). RT-PCR, slot blotting, and Northern blotting
      experiments revealed that expression of DNA polymerase beta (DNA pol beta) was
      several fold lower in stilbene-estrogen-induced kidney tumors than in age-matched
      controls. Several mutations were identified in DNA pol beta mRNA from DES-induced
      kidney tumors, but not in age-matched control kidney. The mutations in DNA pol
      beta mainly occurred in the catalytic domain of pol beta, and not in the DNA
      binding domain. All the mutations produced a stop codon at nucleotide 199
      indicating that a protein of aberrant size may be synthesized. These data suggest
      that mutation of DNA pol beta coupled with attenuation in expression might
      compromise the DNA repair system. This in turn may allow a greater error rate
      during DNA repair and the accumulation of lesions in the genome.

PMID- 8653082
TI  - Antigenic determinants of Streptococcus pyogenes ribosomes.
AB  - An attempt has been made to identify the ribosomal proteins responsible for the
      production of antibodies upon immunization of monkeys with 70S ribosomes of
      Streptococcus pyogenes group A 29 M type. Identification was carried out by
      immunoblotting after isolation and separation of the proteins of 70S, 50S and 30S
      ribosomal particles on one- and two-dimensional gel electrophoresis. Three major
      proteins of S. pyogenes 70S ribosomes with clearly expressed antigenic properties
      were identified by Western blotting. One of these proteins belonged to the 50S
      subunit and the other two--to the 30S ribosomal subunit. We assume that these
      proteins represent those of group A streptococci. As a result the antibodies are
      produced first of all against these antigenic proteins in contrast to the others
      evolutionary conservative ribosomal proteins.

PMID- 8653083
TI  - Oxidant stress causes alteration in the attachment of mononuclear cells to
      collagen.
AB  - The effect of oxidant stress on the attachment of blood mononuclear cells to
      collagen was investigated. Study of the kinetics of attachment of mononuclear
      cells pretreated with 0.2% H2O2 for 10' showed significantly lower attachment to
      collagen I substrata when compared to untreated controls. Reduced glutathione at
      2.5mM concentration partially reversed the H2O2 induced alteration in attachment.
      Pretreatment with H2O2 caused a reduction in the number of free thiol groups both
      at the cell surface and intracellular sites. Changes in cell surface free thiol
      groups could be reversed by reduced glutathione. These results point to the
      importance of a stable redox status in the cellular environment for normal
      interaction of mononuclear cells with extracellular matrix components.

PMID- 8653084
TI  - Evidence suggesting a role for phospholipase C isozyme, PLC-delta 1 in
      corticomedullary osmotic gradients in rat kidneys.
AB  - We determined the distributional patterns of phospholipase C isozymes within the
      rat kidneys. PLC-beta1 was localized in the inner medulla at the highest degree
      followed by the inner stripe of the outer medulla, the cortex and the outer
      stripe of the outer medulla. PLC-gamma1 was distributed homogeneously along the
      corticomedullary axis. PLC-delta1 showed gradual increase from the cortex to the
      inner medulla. Tissue osmotic gradients were measured using 4 slices, resulting
      in gradual increase from the cortex to the inner medulla. The pattern of PLC
      delta1 appeared very similar to the osmotic gradient in the kidney. The results
      suggest that the distinct patterns of the PLC isozymes may be associated with
      different signal transduction pathways along the corticomedullary axis and PLC
      delta1 may play a role in the osmoregulation of the medullary region.

PMID- 8653085
TI  - Evidence for the regulation of small intestinal Na+/glucose cotransporter by
      insulin.
AB  - The small intestinal sodium dependent absorption of D-glucose has been known to
      be increased by diabetes mellitus. Furthermore, we previously showed that the
      enhanced activity of Na+/glucose cotransporter (SGLT1) was restored by the
      treatment with insulin. The present study was designed to investigate the
      mechanism by which diabetes mellitus and insulin regulated the activity of the
      small intestinal SGLT1. The acute diabetes at 2 weeks after the injection of
      streptozotocin increased the expression of SGLT1 protein in rat small intestinal
      brush border membrane vesicles without changing the mRNA level for SGLT1. In
      addition, we showed that the increased content of SGLT1 protein was restored by
      the subcutaneous treatment with insulin. In contrast, there was no change of the
      mRNA level for SGLT1 in diabetic and insulin-treated diabetic rats. These results
      suggest that rat intestinal SGLT1 activity is under the translational or
      posttranslational controls by insulin.

PMID- 8653086
TI  - Rat monoamine oxidase B expressed in Escherichia coli has a covalently-bound FAD.
AB  - Rat liver monoamine oxidase B (MAO B) was expressed in E. coli as catalytically
      active form, though inclusion bodies of the enzyme were also formed as a major
      protein in the cell. The active form of the recombinant MAO B exhibited similar
      properties as rat liver enzyme and localized in membrane of the bacteria.
      Covalent attachment of FAD to polypeptide chain of the recombinant enzyme was
      revealed by a labeling experiment with [3H]-pargyline, an irreversible mechanism
      based inhibitor, indicating that the covalent linkage of FAD to the apoprotein
      was formed even in the prokaryotic cell. This observation suggests autocatalytic
      formation of the linkage in MAO B.

PMID- 8653088
TI  - Telomeres of higher primates.
AB  - The telomeres of gorilla, chimpanzee and human peripheral blood cells have been
      examined by hybridization to an oligonucleotide probe, (TTAGGG)4, following
      conventional and pulsed-field electrophoresis procedures. The MspI site present
      near the chromosome terminus undergoes methylation in gorilla, chimpanzee and
      human genome as shown by the HpaII digestion. Minor (TTAGGG)4-hybridizing
      sequences have been also detected in the chimpanzee HindIII and MspI digests.

PMID- 8653087
TI  - Effects of synthesized elastin peptides on human leukocytes.
AB  - It is well demonstrated that various peptides derived from elastin are
      biologically active. The hexapeptide (Val-Gly-Val-Ala-Pro-Gly; VI) as well as
      elastin peptides were demonstrated to be chemotactic for fibroblasts, while kappa
      elastin had marked biological effects on human PMNLs. The aim of our present work
      was to synthesize various elastin peptides and compare their action to that of
      kappa-elastin and this hexapeptide. The results indicate that the hexapeptide
      (Val-Gly-Val-Ala-Pro-Gly) and the two other synthesized hexapeptides (Pro-Gly-Val
      Gly-Val-Ala; III and Val-Gly-Val-Gly-Val-Ala; IV) had very similar and specific
      effects on intracellular free calcium metabolism, on superoxide anion production
      and elastase release. The other peptides had no effects on these parameters,
      except a tripeptide (Val-Gly-Val; V) on superoxide anion production. Moreover,
      the effect of the hexapeptides (III and VI) could be abolished by Pertussis toxin
      preincubation. All peptides had very similar stimulating effects on H2O2
      production and myeloperoxidase release. We conclude that most probably the
      peptide size and conformation, as well as peptide composition play a role in the
      biological effects of these peptides, through specific receptors on PMNLs
      surface.

PMID- 8653089
TI  - Comparison of the metabolism of alcohols by rat hepatic and pulmonary alcohol
      dehydrogenase.
AB  - The metabolism of 1-butanol, 1-pentanol and 1-propanol by rat hepatic and
      pulmonary cytosolic preparations was measured with regard to ADH activity as
      influenced by pH and substrate concentration. Compared to lung, hepatic ADH
      activity showed little pH dependence with apparent Vmax values similar for the 3
      alcohols. Apparent Km values were also similar and were lower than previously
      reported for ethanol. In contrast to the liver, little ADH activity was observed
      in pulmonary preparations at pH 7.2 or 9.0 with any alcohol. Pulmonary apparent
      Km values were considerably higher than those in the liver. Thus the optimum
      conditions for pulmonary ADH activity require an alkaline pH and high substrate
      concentrations.

PMID- 8653090
TI  - Stimulation of erythrocyte membrane Mg(2+)-ATPase activity by glutathione S
      conjugates.
AB  - Pig erythrocyte membrane Mg2+-ATPase activity was stimulated by various
      glutathione S-conjugates. For alkyl S-conjugates, the Km for the stimulation was
      lower, the more hydrophobic was the conjugate. 2,4-Dinitrophenyl-S-(N
      acetyl)cysteine also stimulated the Mg2+-ATPase activity, suggesting a low
      specificity of the ?glutathione S-conjugate pump?. The Km values for the
      stimulation by 2,4-dinitrophenyl conjugates were lower than predictable on the
      basis of hydrophobicity which indicates a high affinity of the transporter for
      these conjugates.

PMID- 8653092
TI  - Over-expression, purification and phosphorylation of the Bacillus subtilis CheA
      protein.
AB  - The CheA (Bacillus subtilis) protein was over-expressed in a CheA minus E. Coli
      strain. Cells induced for the over-expression of CheA were lysed by passage
      through a French press device. The French press lysate was partially purified by
      ammonium sulfate precipitation and the resulting lysate was loaded onto a
      cibacron blue column and eluted with a NaCl gradient. CheA was finally purified
      by separation with a G-150 column. The purity and identity of CheA was verified
      by SDS-PAGE, CnBr digestion and amino acid analysis. Purified material
      autophosphorylated at the expected molecular weight of CheA.

PMID- 8653091
TI  - Study of second messenger levels and of sugar catabolism enzyme activities in
      transformed cells resistant to ionizing radiations.
AB  - We measured the level of second messengers, the activity of carbohydrate
      metabolism enzymes, and the resistance to ionizing radiations in normal 32D
      hematopoietic cells, in v-erbB transformants and in spontaneous transformants. v
      erbB and spontaneous transformants were resistant to radiations as compared with
      their normal counterpart. The second messenger diacylglycerol was elevated in
      radioresistant clones. Only v-erbB transformants showed increase of the
      activities of enolase and glucose-6-phosphate dehydrogenase. v-erbB-transformed
      NIH/3T3 cells, selected as control, showed identical correlation between
      radioresistance, increase of diacylglycerol, and of enolase and glucose-6
      phosphate dehydrogenase activity. These results indicate that increase of
      diacylglycerol is correlated with resistance to the killing effect of ionizing
      radiations and could be proposed as a marker of radioresponse.

PMID- 8653094
TI  - Conceptual automaticity in recognition memory: levels-of-processing effects on
      familiarity.
AB  - Recognition memory can reflect both conscious recollection and automatically
      generated feelings of familiarity. Previous research has suggested that
      perceptual factors mediate familiarity. Three experiments show that familiarity
      can also arise from prior conceptual (meaning-based) processing. Each experiment
      manipulated level of processing (LoP) and tested recognition memory using two
      response-signal delays (500 and 1500 ms). In Experiment 1, a modality effect was
      found for fast, but not slow, responses, thus supporting dual-process theories;
      the LoP effect was reliable at both points in time. In Experiment 2, recollection
      was set in opposition to familiarity by telling subjects to accept only test
      items from a to-be-remembered list which followed the incidental (LoP) study
      list; fast responses were associated with significantly more "false-alarms" to
      words encoded semantically than those encoded nonsemantically. Experiment 3 used
      the process dissociation procedure (Jacoby, 1991) to obtain quantitative
      estimates of recollection and familiarity. Both estimates were elevated by prior
      conceptual processing. Moreover, estimates of recollection, but not familiarity,
      were affected by response-signal delay, suggesting functional independence
      between the two processes. Relations to implicit memory are discussed.

PMID- 8653093
TI  - Isolation of cDNAs and tissue specific expression of ovine glucose transporters.
AB  - The facilitative glucose transporters are a family of proteins responsible for
      the transmembrane transport of glucose and other hexose sugars (1,2). In mammals,
      the seven glucose transporter isoforms display a characteristic tissue
      distribution reflecting the physiological requirement and metabolism of glucose.
      This report describes the isolation and sequencing of the full length ovine GLUT
      3 cDNA and the tissue distribution of ovine GLUT-1 and GLUT-3 mRNA. The ovine
      GLUT-3 cDNA is 3854 base pairs and the coding nucleotides show 82% and 79%
      homology with the human and mouse GLUT-3 sequences respectively. In addition, a
      reverse transcriptase-polymerase chain reaction strategy is described for the
      rapid isolation of mammalian cDNA subclones for GLUT-1, GLUT-2 and GLUT-4. This
      method has been used to isolate the corresponding ovine subclones.

PMID- 8653095
TI  - Visual specificity effects on word stem completion: beyond transfer appropriate
      processing?
AB  - An important, but poorly understood, aspect of memory retrieval concerns the
      conditions under which priming is influenced by perceptual changes in the form of
      target items. According to transfer appropriate processing perspectives,
      perceptual specificity effects on priming require a study task that focuses
      attention on the perceptual, rather than semantic, features of the items. Other
      research suggests that perceptual specificity effects are enhanced by conditions
      yielding high levels of explicit memory. The present experiments manipulated
      encoding tasks and other variables known to influence explicit memory (repetition
      and retention interval) in order to gain insight into the determinants of
      perceptual specificity effects on visual word-stem completion. In Experiment 1 we
      found that perceptual specificity (letter case) effects on stem completion
      priming depend on perceptual encoding when subjects' awareness of the study-test
      relationship is limited. In Experiments 2-4 we found that perceptual specificity
      effects can be obtained after semantic encoding--especially when the study-test
      retention interval is short. Perceptual specificity effects after short retention
      intervals were independent of encoding task, and may reflect a form of
      involuntary explicit memory.

PMID- 8653096
TI  - The effect of imagery on explicit and implicit tests of memory in young and old
      people: a double dissociation.
AB  - The use of imagery as an elaborative study task was examined to determine its
      effects on implicit and explicit tests of memory in both young and old adults.
      Both the implicit and explicit tests were word-stem completion tests, identical
      except for their instructional content. Results showed that imaging the referent
      of a visually-presented word during the initial study period significantly
      improved the performance of the young adults on the explicit test of memory, but
      reduced their performance on the implicit test. The test results of the elderly
      subjects showed a similar trend in that explicit test performance was
      significantly improved following an imagery study task whereas implicit test
      performance was reduced following this same task. These results did not, however,
      reach the level of significance, observed for young adults. The results are
      discussed within the framework of a processing account of implicit/explicit
      dissociations.

PMID- 8653097
TI  - Functional mapping of human memory using PET: comparisons of conceptual and
      perceptual tasks.
AB  - An experiment is reported in which regional cerebral blood flow (rCBF) as
      measured using positron emission tomography (PET) as participants performed
      conceptual and perceptual memory tasks. Blood flow during two conceptual tests of
      semantic cued recall and semantic association was compared to a control condition
      in which participants made semantic associations to nonstudied words.
      Analogously, rCBF during two perceptual tasks of word fragment cued recall and
      word fragment completion was compared to a word fragment nonstudied control
      condition. A direct comparison of conceptual and perceptual tasks showed that
      conceptual tasks activated medial and lateral left hemisphere in frontal and
      temporal regions as well as the lateral aspect of bilateral inferior parietal
      lobule. Perceptual tasks, in contrast, produced relatively greater activation in
      right frontal and temporal cortex as well as bilateral activation in more
      posterior regions. Comparisons of the memory tasks with their control conditions
      revealed memory-specific deactivations in left medial and superior temporal
      cortex as well as left frontal cortex for both conceptual tasks. In contrast,
      memory-specific deactivations for both perceptual fragment completion tests were
      localized in posterior regions including occipital cortex. Results from this and
      other functional imaging experiments provide evidence that conceptual and
      perceptual memory processes are subserved, at least in part, by different
      neurological structures in the human brain.

PMID- 8653098
TI  - Exact and conceptual repetition dissociate conceptual memory tests: problems for
      transfer appropriate processing theory.
AB  - Three experiments examined whether a conceptual implicit memory test
      (specifically, category instance generation) would exhibit repetition effects
      similar to those found in free recall. The transfer appropriate processing
      account of dissociations among memory tests led us to predict that the tests
      would show parallel effects; this prediction was based upon the theory's
      assumption that conceptual tests will behave similarly as a function of various
      independent variables. In Experiment 1, conceptual repetition (i.e., following a
      target word [e.g., puzzles] with an associate [e.g., jigsaw]) did not enhance
      priming on the instance generation test relative to the condition of simply
      presenting the target word once, although this manipulation did affect free
      recall. In Experiment 2, conceptual repetition was achieved by following a
      picture with its corresponding word (or vice versa). In this case, there was an
      effect of conceptual repetition on free recall but no reliable effect on category
      instance generation or category cued recall. In addition, we obtained a picture
      superiority effect in free recall but not in category instance generation. In the
      third experiment, when the same study sequence was used as in Experiment 1, but
      with instructions that encouraged relational processing, priming on the category
      instance generation task was enhanced by conceptual repetition. Results
      demonstrate that conceptual memory tests can be dissociated and present problems
      for Roediger's (1990) transfer appropriate processing account of dissociations
      between explicit and implicit tests.

PMID- 8653099
TI  - Integration of orthographic, conceptual, and episodic information on implicit and
      explicit tests.
AB  - An experiment was conducted to determine how orthographic and conceptual
      information are integrated during incidental and intentional retrieval. Subjects
      studied word lists with either a shallow (counting vowels) or deep (rating
      pleasantness) processing task, then received either an implicit or explicit word
      fragment completion (WFC) test. At test, word fragments contained 0, 1, 2, or 4
      letters, and were accompanied by 0, 1, 2, or 3 semantically related words. On
      both the implicit and explicit tests, performance improved with increases in the
      numbers of letters and words. When semantic cues were presented with the word
      fragments, the implicit test became more conceptually drive. Still, conceptual
      processing had a larger effect in intentional than in incidental retrieval. The
      Fuzzy Logical Model of Perception (FLMP) provided a good description of how
      orthographic, semantic, and episodic information were combined during retrieval.

PMID- 8653100
TI  - The elusive cramp.

PMID- 8653101
TI  - Effect of caffeine ingestion on perception of effort and subsequent work
      production.
AB  - The purpose of this investigation was to determine the effect of caffeine
      ingestion on work output at various levels of perceived exertion during 30 min of
      isokinetic variable-resistance cycling exercise. Ten subjects completed six
      trials 1 hr after consuming either 6 mg.kg-1 caffeine (3 trials) or a placebo (3
      trials). During each trial the subjects cycled at what they perceived to be a
      rating of 9 on the Borg rating of perceived exertion scale for the first 10 min,
      a rating of 12 for the next 10 min, and a rating of 15 for the final 10 min.
      Total work performed during the caffeine trials averaged 277.8 +/- 26.1 kJ,
      whereas the mean total work during the placebo trials was 246.7 +/- 21.5 kJ (p <
      .05). However, there were no significant differences between the conditions in
      respiratory exchange ratio. These data suggest that caffeine may play an
      ergogenic role in exercise performance by altering both neural perception of
      effort and substrate availability.

PMID- 8653102
TI  - Treatment of athletic amenorrhea with a diet and training intervention program.
AB  - The purpose of this study was to determine the effect of a 15-week diet and
      exercise intervention program on energy balance, hormonal profiles, body
      composition, and menstrual function of an amenorrheic endurance athlete. The
      intervention program reduced training 1 day/week and included the use of a sport
      nutrition beverage providing 360 kcal/day. Three eumenorrheic athletes served as
      a comparison group and were monitored over the same 15-week period. The
      amenorrheic athlete experienced a transition from negative to positive energy
      balance, increased body fat from 8.2 to 14.4%, increased fasting luteinizing
      hormone (LH) from 3.9 to 7.3 mIU/ml, and decreased fasting cortisol from 41.2 to
      33.2 micrograms/dl. The eumenorrheic subjects showed a 0.4% reduction in body
      fat, a decrease in follicular phase levels of LH from 7.9 to 6.5 mIU/ml, and no
      change in cortisol. These results suggest that nonpharmacological treatment can
      contribute to reestablishing normal hormonal profiles and menstrual cyclicity in
      amenorrheic athletes.

PMID- 8653103
TI  - Nutrient intake and psychological and physiological assessment in eumenorrheic
      and amenorrheic female athletes: a preliminary study.
AB  - The present study showed that amenorrheic athletes (AAs) scored higher on the
      Eating Attitudes Test (EAT) (p < .05) than eumenorrheic athletes (EAs),
      indicating more aberrant eating patterns in the first group. Scores on the EAT
      were inversely correlated with fat intake (p < .05), simple carbohydrate intake
      (p < .01), and percentage saturation of iron (p < .05) and were positively
      correlated with total iron binding capacity (p < .01) for the total sample.
      Physiological assessment of athletes revealed that there were no significant
      differences between groups in serum lipoproteins, with both EAs and AAs having
      serum lipid profiles indicative of low cardiovascular risk. Furthermore, low
      density lipoprotein cholesterol was the only lipoprotein significantly and
      positively correlated with serum estradiol levels for the entire sample (p =
      .01). The present study was in agreement with previous work showing that scores
      of the EAT represent a primary difference between EAs and AAs; the present study
      was somewhat different than previous work in that serum lipoproteins were not
      significantly related to menstrual status.

PMID- 8653104
TI  - Effects of diet and diet-plus-exercise programs on resting metabolic rate: a meta
      analysis.
AB  - Studies examining the effects of diet (D) and diet-plus-exercise (DE) programs on
      resting metabolic rate (RMR) report equivocal results. The purpose of this study
      was to use meta-analysis to determine if exercise prevents the decrease in RMR
      observed with dieting. Results from the 22 studies included in this analysis
      revealed that the majority of studies used female subjects ages 31-45 years, who
      were fed a relatively low-fat, high-carbohydrate diet of less than 5,023 kJ.day
      1. The predominant prescribed exercise was aerobic in nature, 31-60 min in
      duration, performed 4-5 days per week, and of moderate intensity (51-70% of
      VO2max). Contrary to what is reported in narrative reviews, RMR decreased
      significantly with both D and DE programs, and the drop with D was significantly
      greater than that with DE. In conclusion, the addition of exercise to dietary
      restriction appears to prevent some of the decrease in RMR observed in
      premenopausal women.

PMID- 8653105
TI  - Heat cramps during tennis: a case report.
AB  - A 17-year-old, nationally ranked, male tennis player (AH) had been experiencing
      heat cramps during tennis match play. His medical history and previous physical
      exams were unremarkable, and his in-office blood chemistry profiles were normal.
      On-court evaluation and an analysis of a 3-day dietary record revealed that AH's
      sweat rate was extensive (2.5 L.hr-1) and that his potential daily on-court sweat
      sodium losses (89.8 mmol.hr of play-1) could readily exceed his average daily
      intake of sodium (87.0-174.0 mmol.day-1). The combined effects of excessive and
      repeated fluid and sodium losses likely predisposed AH to heat cramps during
      play. AH was ultimately able to eliminate heat cramps during competition and
      training by increasing his daily dietary intake of sodium.

PMID- 8653106
TI  - The bioZone nutrition system: a dietary panacea?

PMID- 8653107
TI  - Separate digits tests: a brief history, a literature review, and a reexamination
      of the factor structure of the Test of Memory and Learning (TOMAL).
AB  - Following a brief history of Digit Span, a review of 27 articles, selected from
      76, addresses the question of whether to scale Digits Forward and Backward
      separately. The review begins with studies involving Digits Forward, followed in
      turn by studies of Digits Backward and of both subtests. Finally, the loadings of
      four TOMAL subtests, Digits Forward and Backward and Letters Forward and
      Backward, undergo examination in the context of two, three, and four factor
      promax solutions, with corresponding varimax solutions provided for comparison.
      The analysis leads to several conclusions. Though Digits Forward and Backward
      show similarities, they load differently in the three and four factor solutions;
      Digits Backward also displays a spatial element, and perhaps a transformative
      element, not apparent in Digits Forward. Moreover, the differences between the
      two measures have important neurologic and diagnostic implications.

PMID- 8653108
TI  - The California Verbal Learning Test: psychometric characteristics and clinical
      application.
AB  - The California Verbal Learning Test (CVLT) is a popular clinical and research
      test that claims to measure key constructs in cognitive psychology such as
      repetition learning, serial position effects, semantic organization, intrusions,
      and proactive interference. The psychometric characteristics of the CVLT are
      reviewed and related to the test's clinical utility. The utility of the CVLT is
      shown to be limited by its poor standardization and inflated norms. Further, the
      validity is limited because the CVLT uses multiple trials whereas the constructs
      it purports to measure are based on single-trial paradigms. The review proposes
      modifications to the CVLT and guidelines for its clinical use. It concludes that
      if the limitations of the CVLT are recognized, it can still make a useful
      contribution to the clinical assessment of verbal learning and memory.

PMID- 8653110
TI  - mCCG methylation in angiosperms.
AB  - Two different methods were used to investigate the abundance of cytosine
      methylation at the outer (5') position in 5'-CCG-3' trinucleotides in angiosperm
      genomes. Mspl is unable to cut its target site if the outer cytosine is
      methylated (5'-mCCGG-3'). Using Mspl restriction analysis, it was shown that 5'
      mCCG-3' is present in all angiosperm genomes examined, and that the amount of
      cytosine methylation at this site varies between species. Subsequently, direct
      measurements were made of the amount of methylation at both cytosines in a subset
      of 5'-CCG-3' trinucleotides in the Arabidopsis thaliana genome. Based upon these
      analyses, it was estimated that approximately 20-30% of 5'-CCG-3' trinucleotides
      in A. thaliana are methylated at the outer cytosine. Approximately 20% of the 5'
      CCG-3' trinucleotides contain 5-methyl-cytosine at the inner cytosine position,
      which corresponds to a previous determination of 5'-mCG-3' methylation in A.
      thaliana. The implications of 5'-mCCG-3' methylation are discussed.

PMID- 8653109
TI  - Issues associated with repeated neuropsychological assessments.
AB  - Distinguishing practice effects from other factors in repeated neuropsychological
      assessments are discussed in the context of research studies and
      clinical/forensic assessments. Potential methodological procedures for reducing
      the impact of practice effects in research settings are outlined. In contrast,
      the potential clinical utility and interpretation of practice effects in clinical
      assessments and forensic evaluations are highlighted.

PMID- 8653111
TI  - Differential activation of the primary auxin response genes, PS-IAA4/5 and PS
      IAA6, during early plant development.
AB  - The plant growth hormone auxin typified by indoleacetic acid (IAA)
      transcriptionally activates early genes in pea, PS-IAA4/5 and PS-IAA6, that are
      members of a multigene family encoding short-lived nuclear proteins. To gain
      first insight into the biological role of PS-IAA4/5 and PS-IAA6, promoter-beta
      glucuronidase (GUS) gene fusions were constructed and their expression during
      early development of transgenic tobacco seedlings was examined. The comparative
      analysis reveals spatial and temporal expression patterns of both genes that
      correlate with cells, tissues, and developmental processes known to be affected
      by auxin. GUS activity in seedlings of both transgenic lines is located in the
      root meristem, sites of lateral root initiation and in hypocotyls undergoing
      rapid elongation. In addition, mutually exclusive cell-specific expression is
      evident. For instance, PS-IAA4/5-GUS but not PS-IAA6-GUS is expressed in root
      vascular tissue and in guard cells, whereas only PS-IAA6-GUS activity is
      detectable in glandular trichomes and redistributes to the elongating side of the
      hypocotyl upon gravitropic stimulation. Expression of PS-IAA4/5 and PS-IAA6 in
      elongating, dividing, and differentiating cell types indicates multiple functions
      during development. The common and yet distinct activity patterns of both genes
      suggest a combinatorial code of spatio-temporal co-expression of the various PS
      IAA4/5-like gene family members in plant development that may mediate cell
      specific responses to auxin.

PMID- 8653112
TI  - A novel, soluble form of phytoene desaturase from Narcissus pseudonarcissus
      chromoplasts is Hsp70-complexed and competent for flavinylation, membrane
      association and enzymatic activation.
AB  - A cDNA coding for the carotenoid biosynthetic enzyme phytoene desaturase from
      Narcissus pseudonarcissus was cloned and the corresponding protein expressed in
      insect cells using the baculovirus system. Polyclonal antibodies raised against
      the recombinant protein allowed the detection of soluble and tightly membrane
      bound populations of phytoene desaturase in the chromoplasts isolated from
      petals. The soluble form is enzymatically inactive and a constituent of a larger
      Hsp 70-containing protein complex in the stroma, whereas the membrane-bound form
      is functional. In vitro, the soluble form is able to associate on to/into protein
      free liposomal membranes made from chromoplast lipids, thereby gaining activity
      by binding added flavine adenine dinucleotide (FAD). Once bound to membranes,
      activated phytoene desaturase works independently of any added FAD, employing
      membrane-bound electron acceptors. FAD, however, exerts no positive effect on the
      membrane-association process. Its role is confined to enzymatic activation.
      Although carotenoid accumulation is strongly induced during flower development,
      only very low concentrations of phytoene desaturase transcripts are detectable,
      while the corresponding protein accumulates in low, but measurable amounts,
      appearing in soluble and membrane-bound states. Post-transcriptional mechanisms
      contribute significantly to carotenoid accumulation, as do factors determining
      the enzymatic activity of phytoene desaturase, for example by influencing the
      redox-state of membrane-bound electron acceptors.

PMID- 8653113
TI  - Characterization of anther-expressed genes encoding a major class of
      extracellular oleosin-like proteins in the pollen coat of Brassicaceae.
AB  - A large, heterogeneous, highly expressed gene family encoding oleosin-like
      proteins is described in the Brassicaceae. Seven related cDNA sequences were
      isolated from Brassica napus anther mRNA using RACE-PCR and compared with other
      recently described anther-specific oleosin-like genes from B. napus. The
      expression patterns of four representative members of this diverse gene family
      were analyzed by Northern blotting and in situ hybridization. In all cases, the
      genes were expressed specifically in the tapetum of 3-5 mm B. napus buds, which
      contained microspores at the late-vacuolate and bicellular stages of development.
      The predicted protein products are ordered into subclasses, each of which has a
      characteristic C-terminal domain, containing different amino acid motifs or
      repeated residues. Tryphine (pollen coat) fractions from mature B. napus pollen
      were found to be particularly enriched in polypeptides of apparent molecular
      weights 32-38 kDa, plus numerous less abundant polypeptides of less than 15 kDa.
      The N-terminal 15-20 residues of three of these polypeptides (12, 32 and 38 kDa)
      were found by microsequencing to be identical to parts of the predicted amino
      acid sequences of three of the tapetal-expressed oleosin-like genes. This
      indicates the possibility of post-translational modification of these proteins
      resulting in a cleavage of the primary translation products in order to generate
      the mature tryphine polypeptides. These data imply that a large and diverse group
      of oleosin-like proteins is synthesized in the tapetum of B. napus anthers and
      that following tapetal degradation, these proteins, possibly in modified form,
      then relocate to the developing microspores where they eventually constitute some
      of the major components of the extracellular tryphine of mature pollen grains.
      These proteins share a conserved 70 amino acid residue hydrophobic domain and are
      related structurally to the seed-specific intracellular oleosins, although their
      biological function may be different.

PMID- 8653114
TI  - Phloem-specific expression of a plant homeobox gene during secondary phases of
      vascular development.
AB  - This paper reports the isolation and characterization of a homeobox gene (VAHOX1)
      from Lycopersicon esculentum encoding a homeodomain protein that contains a
      leucine zipper motif. The bipartite homeodomain-leucine zipper (HD-Zip) motif has
      only been found in homeobox genes from dicotyledonous plants, indicating that
      this type of transcription factor regulates particular developmental processes in
      these plant species. Here, the genomic organization, sequence comparison and
      expression analysis of VAHOX1 are described. Transcriptional fusion of the 5'
      promoter region of VAHOX1 with the reporter GUS gene (VAHOX1-GUS) and expression
      analysis of this construct in transgenic plants indicates that VAHOX1 is
      specifically expressed in the phloem during phases of secondary growth. Unlike
      other plant homeobox genes, VAHOX1 does not appear to be expressed in meristems,
      and the function of VAHOX1 is considered a likely candidate molecule that may
      participate in the regulation of the identity and/or activity of phloem tissues
      during secondary phases of vascular development.

PMID- 8653115
TI  - CLA1, a novel gene required for chloroplast development, is highly conserved in
      evolution.
AB  - An albino mutant designated cla1-1 (for "cloroplastos alterados', or "altered
      chloroplasts') has been isolated from a T-DNA-generated library of Arabidopsis
      thaliana. In cla1-1 plants, chloroplast development is arrested at an early
      stage. cla1-1 plants behave like wild-type in their capacity to etiolate and
      produce anthocyanins indicating that the light signal transduction pathway seems
      to be unaffected. Genetic and molecular analyses show that the disruption of a
      single gene, CLA1, by the T-DNA insertion is responsible for the mutant
      phenotype. RNA expression patterns indicate that CLA1 is positively regulated by
      light and that it has different effects on the steady-state RNA levels of some
      nuclear- and chloroplast-encoded photosynthetic genes. Although the specific
      function of the CLA1 gene is still unknown, it encodes a novel protein conserved
      in evolution between photosynthetic bacteria and plants which is essential for
      chloroplast development in Arabidopsis.

PMID- 8653116
TI  - Reduction of the cytosolic fructose-1,6-bisphosphatase in transgenic potato
      plants limits photosynthetic sucrose biosynthesis with no impact on plant growth
      and tuber yield.
AB  - Sucrose produced in source leaves is the predominant carbon source for developing
      sink tissues in most higher plants. Consequently the rate of sucrose synthesis is
      likely to be important for sink development and final crop yield. Two sucrose
      biosynthetic enzymes are believed to possess regulatory properties with respect
      to the rate of sucrose synthesis: (i) cytosolic FBPase and (ii) sucrose phosphate
      synthase. To study the impact of reduced photosynthetic sucrose biosynthesis on
      plant growth and crop yield a cDNA clone encoding cytosolic FBPase was isolated
      from a potato leaf cDNA library and used for antisense experiments in transgenic
      potato plants. The cDNA clone cy-F1, containing an open reading frame of 1020 bp
      highly homologous (85%) to other known sequences of plant cytosolic FBPases, was
      cloned in reversed orientation between the 35S CaMV promoter and the octopine
      synthase polyadenylation signal. Out of 75 independent transformants five
      transgenic lines having 9 to 55% of the wild-type FBPase activity were chosen for
      further analysis. A 45% reduction of the cytosolic FBPase activity did not cause
      any measurable change in metabolite concentrations, growth behaviour or
      photosynthetic parameters of the transgenic plants. Inhibition of cytosolic
      FBPase activity below 20% of the wild-type activity led to an accumulation of 3
      PGA, triose-phosphates and fructose-1,6-biphosphate in source leaves. This
      resulted in a reduced light-saturated rate of assimilation measured via gas
      exchange and a decreased photosynthetic rate under conditions of the leaf disc
      electrode with saturating light and CO2. Measuring photosynthetic carbon fluxes
      by labelling leaf discs with 14CO2 revealed a 53-65% reduction of sucrose
      synthesis whereas starch synthesis decreased only by 18-24%. The flux into the
      anionic and cationic fraction was not altered. Despite these changes steady-state
      sucrose concentrations were not effected in source leaves from transgenic plants.
      Starch accumulated by more than a factor of 3 compared with wild-type leaves and
      was degraded during the night. This provides strong evidence for the hypothesis
      that hexoses and/or hexosephosphates are exported out of the chloroplasts,
      thereby circumventing the limitation of sucrose biosynthesis caused by the
      inhibition of cytosolic FBPase in the dark. Accordingly, plant growth and potato
      tuber yield remained unaltered. From these data it can be concluded that a
      reduced photosynthetic sucrose biosynthetic capacity can be efficiently
      compensated without any reduction in crop yield under greenhouse or growth
      chamber conditions by changing carbon export strategy. Whether the same holds
      true for field conditions remains to be elucidated.

PMID- 8653117
TI  - Transgenic tobacco plants expressing the Arabidopsis thaliana nitrilase II
      enzyme.
AB  - Nitrilase (E.C. 3.5.5.1) cloned from Arabidopsis thaliana converts indole-3
      acetonitrile to the plant growth hormone, indole-3-acetic acid in vitro. To probe
      the capacity of ths enzyme under physiological conditions in vivo, the cDNA
      PM255, encoding nitrilase II, was stably integrated into the genome of Nicotiana
      tabacum by direct protoplast transformation under the control of the CaMV-35S
      promotor. The regenerated plants appeared phenotypically normal. Nitrilase II was
      expressed, based on the occurrence of its mRNA and polypeptide. The enzyme was
      catalytically active, when extracted from leaf tissue of transgenic plants
      (specific activity: 25 fkat mg(-1) protein with indole-3-acetonitrile as
      substrate). This level of activity was lower than that found in A. thaliana, and
      this was deemed essential for the in vivo analysis. Leaf tissue from the
      transgenic plants converted 1-[13C]-indole-3-acetonitrile to 1-[13C]-indole-3
      acetic acid in vivo as determined by HPLC/GC-MS analysis. Untransformed tobacco
      was unable to catalyze this reaction. When transgenic seeds were grown on medium
      in the absence of indole-3-acetonitrile, germination and seedling growth appeared
      normal. In the presence of micromolar levels of exogenous indole-3-acetonitrile,
      a strong auxin-overproducing phenotype developed resulting in increased lateral
      root formation (at 10 microM indole-3-acetonitrile). Collectively, these data
      prove the ability of nitrilase II to convert low micromolar levels of indole-3
      acetonitrile to indole-3-acetic acid in vivo, even when expressed at
      subphysiological levels thereby conferring a high-auxin phenotype upon transgenic
      plants. Thus, the Al thaliana nitrilase activity, which exceeds that of the
      transgenic plants, would be sufficient to meet the requirements for auxin
      biosynthesis in vivo.

PMID- 8653118
TI  - Pollination induces mRNA poly(A) tail-shortening and cell deterioration in flower
      transmitting tissue.
AB  - Pollination induces many physiological responses in the flower, including
      deterioration and death in specific pistil cell types. It is shown here that
      within the style of tobacco, pollination-induced cell deterioration was
      restricted to the transmitting tissue while the surrounding cortical tissue was
      not affected. It was distinct from general senescence since exogenously applying
      the senescence-inducing hormone ethylene, or its precursor aminocyclopropane-1
      carboxylic acid (ACC), to the flower or the pistil induced overall deterioration
      in the entire flower. Furthermore, both pollen tube growth and ethylene action
      were needed for the entire spectrum of cellular changes associated with this
      pollination-induced transmitting tissue deterioration process. It is also shown
      that pollination-induced mRNA poly(A) tail-shortening for at least three major
      classes of transmitting tissue-specific mRNAs. As is commonly observed for
      poly(A) tail-shortened mRNAs, the levels of two of these three mRNA classes
      decline after pollination. On the other hand, the third class of mRNAs,
      transmitting tissue-specific (TTS) mRNAs, was maintained at a very high level
      subsequent to pollination, even after substantial poly(A)-tail shortening. TTS
      mRNAs encode a pollen tube growth-promoting and -attracting protein needed for
      optimal in vivo pollen tube growth. The specific preservation of TTS mRNAs in the
      deteriorating transmitting tissue cells suggests that these cells can distinguish
      molecules needed in the pollinated styles from those that are dispensable, and
      protect them from degradation. It is suggested that the pollination-induced mRNA
      poly(A) tail-shortening and cell death are programmed processes suited to the
      post-pollination transmitting tissue environment. Results showing that ACC is a
      candidate signal molecule for the pollination-induced mRNA-shortening which is
      accentuated by ethylene and mediated via a protein phosphorylation-dependent
      signal transduction pathway are also presented.

PMID- 8653119
TI  - Salt regulation of transcript levels for the c subunit of a leaf vacuolar H(+)
      ATPase in the halophyte Mesembryanthemum crystallinum.
AB  - The halophyte Mesembryanthemum crystallinum is an inducible crassulacean acid
      metabolism (CAM) plant native to seasonally arid coastal environments that has
      been widely used to study plant responses to environmental stress. On exposure of
      plants to salt, the activities of both the tonoplast (vacuolar) H(+)-ATPase (V
      ATPase) and Na+/H+ antiporter increase in leaf cells, thereby energizing vacuolar
      salt accumulation. To investigate the molecular basis of this response, a cDNA
      (Vmac1) encoding the H(+)-conducting c subunit (16.6 kDa) of an M. crystallinum V
      ATPase has been cloned. Northern analysis of RNA from leaves of plants treated
      with NaCl or with isoosmotic mannitol solutions demonstrated (i) that NaCl
      increased steady-state transcript levels for the V-ATPase c subunit, and (ii)
      that this effect was caused by the ionic rather than the osmotic component of
      salt stress. Southern analysis of genomic DNA suggested the probable existence of
      more than one gene for this subunit of the V-ATPase in M. crystallinum.
      Expression studies using the 3'-untranslated region of the Vmac1 cDNa as a probe
      showed that the corresponding salt-inducible transcript was preferentially
      expressed in leaves. Induction by salt was also observed in juvenile plants in
      addition to adult ones. These findings, as well as the inability of mannitol to
      upregulate mRNA levels for this gene, clearly differentiate between the induction
      of transcript for the V-ATPase c subunit and for genes involved in the CAM
      pathway in M. crystallinum. Further, the plant growth regulator abscisic acid
      (ABA) was able to mimic the effect of salt on transcript levels for the V-ATPase
      c subunit, suggesting the possible involvement of ABA in a distinct signal
      transduction pathway linked to vacuolar salt accumulation in this highly salt
      tolerant species.

PMID- 8653120
TI  - Visualization of differential gene expression using a novel method of RNA
      fingerprinting based on AFLP: analysis of gene expression during potato tuber
      development.
AB  - Using a highly synchronous in vitro tuberization system, in combination with an
      amplified restriction fragment polymorphism (AFLP)-derived technique for RNA
      fingerprinting (cDNA-AFLP), transcriptional changes at and around the time point
      of potato tuberization have been analyzed. The targeted expression analysis of a
      specific transcript coding for the major potato storage protein, patatin and a
      second transcript, coding for ADP-glucose pyrophosphorylase, a key gene in the
      starch biosynthetic pathway is described. This paper confirms that kinetics of
      expression revealed by cDNA-AFLP analysis are comparable to those found in
      Northern analysis. Furthermore, this paper reports the isolation and analysis of
      two tuber-specific transcript-derived fragments (TDFs) coding for the
      lipoxygenase enzyme, which are differentially induced around the time point of
      tuber formation. Analysis of the two lox TDFs demonstrates that it is possible to
      dissect the expression modalities of individual transcripts, not independently
      detectable by Northern analysis. Finally, it is shown that using cDNA-AFLP, rapid
      and simple verification of band identity may be achieved. The results indicate
      that cDNA-AFLP is a broadly applicable technology for identifying developmentally
      regulated genes.

PMID- 8653122
TI  - Finance. Giving 'til it helps.

PMID- 8653121
TI  - Detailed description of four YAC contigs representing 17 Mb of chromosome 4 of
      Arabidopsis thaliana ecotype Columbia.
AB  - The detailed arrangement of 563 YAC clones comprising four contigs covering
      approximately 17 Mbp of chromosome 4 is presented. YAC clones were positioned
      relative to each other and to markers by taking into account marker and end
      fragment hybridization data and the sizes of all YAC clones. This analysis made
      it possible to estimate physical distances between the majority of chromosome 4
      markers. It also identified a relatively large number of YAC clones containing
      chimaeric inserts. The YAC contig map of the Columbia ecotype presents an
      important resource for map-based cloning experiments, rapid mapping of DNA
      sequences and large-scale genomic sequencing programs.

PMID- 8653123
TI  - Purchasing ... seventh annual Health Capital Survey.

PMID- 8653124
TI  - Continuum of care. Dying with dignity.

PMID- 8653125
TI  - Managed care ... doctors, nurses and consumers are loudly complaining about the
      system's shortfalls.

PMID- 8653126
TI  - Liability. Taking risk to heart.

PMID- 8653127
TI  - Public health ... American children are living in fear.

PMID- 8653128
TI  - True values. While ethical decisionmaking and managed care aren't mutually
      exclusive, executives are struggling to find a common denominator.
AB  - Whether they're fulfilling a mission or just trying to avoid bad publicity,
      health care executives are facing a tough new world of deal- and decisionmaking
      based on managed care and the often murky area of ethics. Some are trying to
      solve the dilemma by developing a set of ethical guidelines from which to work.
      "It's an exercise in self-understanding," says one health care ethicist who's
      helping to write such guidelines. Ultimately, he says, it comes down to one
      question: "What are we really about?"

PMID- 8653129
TI  - What ethicists talk about when they talk about managed care.
AB  - Defining the values at stake as we move into managed care is an awesome--yet
      necessary--endeavor. To help sort things out, the Society for Health and Human
      Values brought together health care ethicists and medical humanists to discuss
      how human values are being incorporated into health care reform. Here's an
      excerpt from that conversation.

PMID- 8653130
TI  - Easier said than done.

PMID- 8653131
TI  - Provider networks. Mullikin proves it's ready for risk.

PMID- 8653132
TI  - HospitalPulse ... February 1996.

PMID- 8653133
TI  - Chronic care. The military's assault on AIDS.

PMID- 8653134
TI  - Quality patrol. Technology and treatments on trial.

PMID- 8653135
TI  - Politics & policy. The Great Lakes debate.

PMID- 8653136
TI  - Banking on diversity.

PMID- 8653137
TI  - Medicare/Medicaid ... big business for doctors.

PMID- 8653138
TI  - Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and
      diabetes.
AB  - beta 3-Adrenoceptor (beta 3-AR) agonists were first identified more than twelve
      years ago and were found to be remarkably effective in animal models of obesity
      and Type II (non-insulin dependent) diabetes. Those that have been taken forward
      to clinical studies have not, however, proved so effective in humans: they have
      either been of limited efficacy, or their activities have been accompanied by
      significant side-effects. Reasons for the failure of some beta 3-AR agonists in
      humans have included a poor pharmacokinetic profile and, possibly, a failure of
      prodrugs to be metabolised to selective beta 3-AR agonists. A more fundamental
      problem, however, is that the human and rat beta 3-AR differ pharmacologically,
      and those compounds that have been evaluated in humans have much lower efficacy
      at the human than the rat receptor. This problem may be compounded by there being
      a low number of beta 3-AR relative to beta 1-AR and beta 2-AR in those tissues
      that mediated thermogenesis in humans, so that low efficacy compounds tend to
      exhibit mainly beta 1-AR or beta 2-AR-, rather than beta 3-AR-mediated effects,
      despite their having selective affinity for human beta 3-AR. Nevertheless,
      studies using CGP 12177, which is an agonist at beta 3-AR but an antagonist at
      beta 1-AR and beta 2-AR, demonstrate that functional beta 3-AR are present in
      human adipose tissue. Moreover, the association of a polymorphism in the human
      beta 3-AR with obesity and diabetes demonstrates that this receptor is relevant
      to these diseases in humans. Thus the true potential of beta 3-AR agonists in
      humans can only be evaluated when a compound with good selectivity and efficacy
      at the human beta 3-AR, coupled with a long duration of action in vivo, has been
      identified.

PMID- 8653139
TI  - Gastric emptying of solids in morbid obesity.
AB  - OBJECTIVE: To evaluate the effect of weight loss induced by dietetic treatment,
      with or without an intragastric balloon, on gastric emptying of obese subjects.
      SUBJECTS: 20 morbidly obese subjects (21-54 years, 45.3-58.0 kg/m2) and 20
      healthy controls (21-56 years, 20.3-24.8 kg/m2). DESIGN: Parallel study of a 4
      month, low calorie dietetic treatment with or without a 500 ml intragastric
      balloon. RESULTS: In basal conditions, obese subjects had accelerated gastric
      emptying as compared to healthy controls. At the end of the dietetic treatment
      period, a significant decrease of body weight was obtained. Patients also showed
      a slowing of gastric emptying. Both the weight loss and the slowing of gastric
      emptying occurred irrespective of the presence or absence of the intragastric
      balloon. CONCLUSION: The present findings are compatible with the hypothesis that
      gastric emptying, food intake and body weight are integrated parameters in
      subjects with morbid obesity.

PMID- 8653140
TI  - Moderate alcohol consumption and its relation to visceral fat and plasma
      androgens in healthy women.
AB  - OBJECTIVE: To study the inter-relationships between daily alcohol intake, fat
      distribution and plasma androgens in order to verify whether daily alcohol intake
      correlates with abdominal body fat and, if so, to what extent such a relation is
      mediated by plasma androgens. SUBJECTS: A random sample of 87 clinically healthy
      women (aged 38 y) with a light-moderate alcohol consumption and without clinical
      evidence suggestive of any endocrine disorder. MEASUREMENTS: Anthropometric and
      computed tomography (CT scans made at the level of L4-L5 in a subgroup of 18
      women) measurements of body fatness and adipose tissue distribution, main
      behavioural factors, including daily alcohol intake and plasma androgens (i.e.
      total and free testosterone levels). RESULTS: After adjustment for BMI, cigarette
      smoking and physical activity, significant differences were found in waist
      circumference and waist-hip ratio as well as in plasma androgens with increasing
      daily alcohol intake. Waist-thigh ratio tended to parallel waist-hip ratio, but
      did not achieve statistical significance. In simple linear regression analysis,
      abdominal visceral fat area, derived from CT, correlated positively with both
      plasma free testosterone and alcohol intake. While the above reported difference
      in body fat distribution totally disappeared after controlling also for free
      testosterone level, the differences in plasma androgens with increasing alcohol
      intake remained essentially unchanged when allowance was made also for waist-hip
      ratio. In multiple linear regression analysis, daily alcohol intake appeared to
      be positively and independently correlated to both plasma total and free
      testosterone levels. Neither BMI nor waist-hip ratio nor fasting insulin made any
      significant contribution to the prediction of plasma androgens after daily
      alcohol intake had been taken into account. CONCLUSIONS: The results of this
      study show that moderate alcohol consumption correlates with abdominal
      distribution of body fat, likely due to enlarged visceral fat area, and increased
      plasma androgenicity (i.e. higher total and free testosterone levels) in adult
      healthy women. These data also suggest that the relation between alcohol intake
      and fat distribution may be, at least in part, mediated by plasma androgens.

PMID- 8653141
TI  - Reproductive history in relation to relative weight and fat distribution.
AB  - OBJECTIVE: To investigate the relationship between reproductive history and body
      composition. DESIGN: Prospective population study in Sweden. SUBJECTS: 1462
      randomly selected women representing five separate age cohorts (38, 46, 50, 54
      and 60 at the 1968-1969 baseline examination) have been followed longitudinally.
      MEASUREMENTS: Relative weight, fat distribution, and fat cellularity were related
      to menarche, parity, lactation, menopause and oestrogen medication. RESULTS: Age
      of menarche did not show any association with subsequent fat distribution, nor
      did length of lactation time. On the other hand parity was positively associated
      to total as well as central obesity, and lactation time was positively associated
      to abdominal fat cell diameter. Premenopausal women showed higher mean body
      weight and hip circumference than postmenopausal women of the same age. Change
      from pre- to postmenopausal status was associated with increase of waist
      circumference as well as reduction of hip circumference, resulting in an
      increased waist-hip ratio (WHR). Oestrogen replacement suggested some
      postponement of this increase. CONCLUSION: Parity and menopause are the
      reproductive factors most associated with gradual changes in body fat
      distribution. Oestrogen medication seems to play an additional role in
      diminishing waist circumference increase and could thus contribute to decreased
      cardiovascular morbidity in women.

PMID- 8653142
TI  - Evaluation of the microdialysis ethanol technique for monitoring of subcutaneous
      adipose tissue blood flow in humans.
AB  - OBJECTIVE: To investigate the feasibility of the microdialysis ethanol perfusion
      technique for monitoring nutritive blood flow in subcutaneous adipose tissue.
      RESEARCH DESIGN AND METHODS: Microdialysis probes were inserted percutaneously
      into the subcutaneous adipose tissue in 15 non-obese women, and were perfused
      with 50 mmol/l of ethanol. The experiments were carried out during basal
      conditions and in conjunction with local vasodilation induced by external
      heating. The ethanol exchange ratio (ethanol concentration in the outgoing tissue
      dialysate vs ethanol concentration in the ingoing perfusate) was determined. A
      comparison was made with the 133Xe clearance technique to assess the adipose
      tissue blood flow. RESULTS: At rest, the ethanol exchange ratio in the individual
      subjects was inversely correlated to the adipose tissue blood flow, as measured
      with 133Xe wash-out (r = -0.78-0.82, p < 0.05-0.01). When the subcutaneous
      temperature was increased in a stepwise fashion by external heating, adipose
      tissue blood flow, as determined with 133Xe clearance, was increased by about 50%
      and 100%, respectively, above resting values (F = 26.7, p < 0.0001). At the same
      time, the ethanol exchange ratio was progressively and significantly (F = 24.6, p
      < 0.0001) reduced. In the individual subjects there was a close negative
      correlation (r = -0.90-0.94) between the ethanol exchange ratios and the
      corresponding adipose tissue blood flow values, as measured by 133Xe clearance,
      in response to local vasodilation. CONCLUSION: The microdialysis ethanol
      perfusion technique provides a valid indicator of small changes within the
      physiological range in adipose tissue blood flow.

PMID- 8653143
TI  - Effectiveness of an abdominal obesity reduction programme in men: the GutBuster
      "waist loss' programme.
AB  - OBJECTIVE: To examine the long term (1-2 year), as well as immediate
      effectiveness of a "waist loss' programme for men. DESIGN: Two preliminary
      studies are reported; one following a small group of 42 men over two years after
      a 6 week "GutBuster' course, the second following men for 1 year after having
      completed the initial 6 week programme (n = 83), or the initial course plus an
      additional six fortnightly "advanced' course (n = 37). MEASUREMENTS: Waist, hip
      and weight measures were reported for the 2 year group; waist and hip only in
      study 2. Dietary fat, exercise and alcohol intake were also recorded in study 2
      through the use of questionnaires. The goal for the initial course was a 1% waist
      loss per week. RESULTS: All groups achieved an average waist loss > 1%/week
      during the initial programme. Waist sizes reported in study 1 were significantly
      less after 2 years (t = 8.28, p < 0.001) averaging a 6% loss in the group. This
      equated with an average weight loss of 5.5 kg. A repeated measures ANOVA also
      showed a significant main effect (F = 85.35; p < 0.0001) for waist losses and an
      interaction effect (F = 16.53; p < 0.0001) between initial and advanced groups
      after 1 year in study 2. Average waist losses were 4% and 10% respectively. There
      were also significant changes in dietary fat intake, exercise and alcohol
      consumption. CONCLUSION: Reductions in waist size in men appear to be more
      feasible than weight losses in women. "Waist loss' may also be a more valid
      measure of fat loss in men that body mass measures.

PMID- 8653144
TI  - Adrenalectomy reverses pre-existing obesity in adult genetically obese (ob/ob)
      mice.
AB  - OBJECTIVE: To determine if adrenalectomy would reverse the pre-existing gross
      obesity, characteristic of adult genetically obese (ob/ob) mice. DESIGN: Adult
      (12 week old) female ob/ob mice were adrenalectomized and fed a stock diet for 6
      or 14 weeks. They were housed at 23-25 degrees C or 33 degrees C. Food intake and
      total body energy were determined. RESULTS: Adrenalectomy abolished the
      hyperphagia characteristic of ob/ob mice. Adrenalectomized ob/ob mice consumed 8
      17% less food than intact lean mice. Adrenalectomized ob/ob mice housed at 23-25
      degrees C lost 55% of their pre-existing body energy within 6 weeks after surgery
      and 75% of their body energy within 14 weeks after surgery. At 14 weeks after
      surgery, body weights and body energy content of the adrenalectomized ob/ob mice
      were comparable with values for intact lean mice. Intact ob/ob mice pair-fed to
      adrenalectomized ob/ob mice lost only half as much body energy as the
      adrenalectomized ob/ob mice did, indicating that adrenalectomy not only
      diminished food intake in ob/ob mice but also increased their energy expenditure
      per unit food consumed. Adrenalectomized ob/ob mice housed at 33 degrees C lost
      only half as much body energy in 6 weeks as did mice housed at 23-25 degrees C.
      CONCLUSION: Adrenalectomy reverses the gross obesity characteristic of adult
      ob/ob mice by abolishing their hyperphagia and increasing their energy
      expenditure per unit food consumed.

PMID- 8653145
TI  - Energy expenditure, television viewing and obesity.
AB  - OBJECTIVE: To measure energy expenditure (EE) of television viewing, sitting, and
      resting and duration of self-selected television viewing in obese and non-obese
      men and women. DESIGN: Cross-over randomized study consisting of two separate 24
      h stays in a whole-room indirect calorimeter. SUBJECTS: 123 obese and non-obese
      healthy men and women (age: 38 +/- 9, BMI: 29.4 +/- 7.9) MEASUREMENTS: Rates of
      energy expenditure during resting (RMR), sitting (EEsit) and television viewing
      (EEtv) using indirect calorimetry technique on two separate 24-h stays in a whole
      room indirect calorimeter. Physical activities and work of body movements during
      these periods using a large force platform system located inside the calorimeter.
      RESULTS: Rates of EE for television viewing, adjusted for differences in body
      composition were 18% higher than resting metabolic rate (RMR), but similar to
      rates of other sedentary activities. There were no significant differences
      between obese and non-obese subjects in metabolic rates during resting,
      television viewing, and other sedentary activities. Average time of self-selected
      television viewing was significantly greater in obese than in non-obese subjects
      and also in women than in men. CONCLUSION: EE rate for television viewing in
      adults is higher than RMR and similar to other sedentary activities. Obese adults
      choose television viewing as a form of leisure activity more often than non-obese
      individuals and as a result they could significantly reduce other forms of
      physical activities and total daily EE.

PMID- 8653146
TI  - Association between cardiac pathology and fat tissue distribution in an autopsy
      series of men without premortem evidence of cardiovascular disease.
AB  - OBJECTIVE: To determine the relationship between cardiovascular status and body
      fat tissue distribution in men without any premortem clinical evidence of
      cardiovascular disease. SUBJECTS: 30 forensic autopsy cases which consisted of
      sudden deaths resulting from accidental causes, suicides or homicides or from
      unexpected natural causes. METHODS: Body height and weight, the circumferences of
      the waist and hip and the thicknesses of the subscapular and abdominal
      subcutaneous fat were measured, and Body Mass Index (BMI) and Waist-to-Hip ratio
      (WHR) were calculated. Perirenal, omental and mesenterial fat deposits were
      weighed and supraclavicular-pericarotid and perirenal-periadrenal fat was excised
      and serial samples analyzed for brown adipose tissue (BAT) by computerized image
      analysis. The heart weight was indexed for height. The degree of coronary
      narrowing was determined in each artery, and myocardial collagen volume fraction
      and myocyte cross-sectional area were measured. RESULTS: There were significantly
      positive correlations between age and the degree of coronary arteriosclerosis and
      heart weight/height. After adjusting for age, BMI and waist circumference had a
      significant positive correlation with all the cardiac parameters. The degree of
      coronary narrowing and heart weight/height were related to tertiles of BMI and
      waist circumstance. The age-adjusted correlations between the subscapular fat
      thickness and cardiac parameters were significant and positive, and perirenal fat
      weight also had a significantly positive association with all the cardiac
      parameters. BAT decreased with age and when adjusted for age, the cervical BAT
      percentage had a significant negative correlation with waist circumference and
      WHR, and a significant negative correlation was also found between cervical BAT
      and the degree of coronary arteriosclerosis and between perirenal BAT and heart
      weight/height. CONCLUSIONS: The results suggest that body fatness is associated
      with coronary and myocardial pathology in men without any clinical evidence of
      cardiovascular disease. An abdominal accumulation of fat seems to be connected
      with both the severity of coronary lesions and myocardial hypertrophy in men, in
      whom there is also a connection between abdominal obesity and a relative scarcity
      of BAT. Future investigations will require more detailed analyses of the extent
      and ultrastructural of coronary artery lesions in order to obtain more specific
      information on the relationship of body fat distribution to the early
      asymptomatic phase of coronary disease in younger individuals.

PMID- 8653147
TI  - Metabolic fuel utilisation in obese women before and after weight loss.
AB  - OBJECTIVE: To test the hypothesis that weight rebound following slimming diets
      may be caused by an adaptive alteration in fuel utilisation involving a
      suppression of fat oxidation thus favouring fat storage in adipose tissue.
      DESIGN: Repeat measurements before and after two 14 d cycles of controlled weight
      loss using a very low energy diet (1.9MJ/d). SUBJECTS: Eight moderately obese
      women (body weight: 85.6 +/- 10.1 kg, BMI: 31 +/- 2 kg/m2, age: 42.6 +/- 10.1
      years). MEASUREMENTS: Energy expenditure and substrate balances using 24-h whole
      body indirect calorimetry and naturally labelled 13C-glucose. RESULTS: Aggregate
      weight loss was 5.1 +/- 0.8 kg. Twenty-four hour energy expenditure declined by
      12% (8359 +/- 282 to 7366 +/- 191 kJ/d, p < 0.001). Net fat utilisation was not
      significantly depressed (4009 +/- 366) to 3613 +/- 191 kJ/d, NS), and the
      proportion of energy derived from fat was unchanged at 48.0% before weight loss
      and 49.0% after weight loss. CONCLUSION: The well-recognised phenomenon of
      reduced energy expenditure is unlikely to be a major cause of weight regain. The
      results do not support the theory that altered fuel selection in post-obese
      subjects may be the cause of difficulty in maintaining weight loss.

PMID- 8653148
TI  - The prevalence of obesity and its changes over time in middle-aged and elderly
      men and women in Jerusalem.
AB  - OBJECTIVE: To study the prevalence and correlates of overweight and obesity in
      Jerusalem, and changes over a 15-17 year period. DESIGN: Two cross-sectional
      surveys in 1970 and in 1986, among residents aged 50 years and more in a defined
      neighbourhood. SUBJECTS: The study samples comprised 1267 individuals in 1970 and
      1858 in 1986. RESULTS: In 1986, 33% of women and 16% of men were obese (BMI > or
      = 30.0 kg/m2). There was a decreasing trend in the prevalence of obesity with age
      among women, and in men there was no overall trend but the lowest prevalence was
      in the 75-84 age-group. Significant relationships with education and region of
      birth were observed in women only. Prevalence was lowest in the more educated and
      in women born in Europe and America. Subjects' self-appraisal and their report of
      physicians' diagnosis of health disorders, revealed a significantly higher
      prevalence of ill-health among obese people. In 1986 the mean body mass index and
      the prevalence of obesity were higher than in 1970, in both sexes and in almost
      all age groups. The prevalence rate of obesity (standardized by sex and age) was
      21% in 1970 and 25% in 1986, the difference was statistically significant (p =
      0.008). The age standardized prevalence rate in each sex was also higher in 1986
      although statistically significant only in men (p = 0.037). CONCLUSION: A
      community study in Jerusalem revealed a high prevalence of overweight and obesity
      in 1986 in this middle-aged and elderly population; and a higher mean body mass
      index and an increased prevalence of obesity were found in 1986 than in 1970, in
      both sexes. The increased prevalence of obesity among men could not be explained
      by changes in the age, education and ethnic composition of the population. Among
      women, the possibility cannot be excluded that part of the increase in obesity
      was attributable to changes in the distribution of the population by region of
      birth.

PMID- 8653149
TI  - Body fat distribution in South Asian women and children.
AB  - OBJECTIVE: To compare levels of abdominal fatness in South Asian and European
      mothers and children. SUBJECTS: 49 mothers and children from South Asian
      backgrounds and 63 mothers and children from European backgrounds who took part
      in a study on family health behaviours. MEASUREMENTS: Anthropometric measures and
      abdominal fatness indices, including WHR and conicity. RESULTS: Asian mothers
      were shorter, and lighter than European mothers, but had a higher WHR and a
      higher conicity. Among children, boys had a higher WHR and conicity than girls
      but there were no ethnic differences in fat distribution. CONCLUSION: Different
      patterns of fat distribution were observed in South Asian and European women,
      with South Asian women having a relatively large waist circumference, relative
      either to hip circumference (WHR) or to overall size (conicity). Sex differences
      in fat distribution, but not ethnic differences, were observed in the children.
      This suggests that the adult patterns of fat distribution may not be established
      at this stage.

PMID- 8653150
TI  - The problem with weighing: effects on mood, self-esteem and body image.
AB  - OBJECTIVE: To examine the effect of weighing and comparison with social norms on
      self-esteem, mood and body dissatisfaction. DESIGN: An experimental design was
      used. SUBJECTS: Seventy-four normal weight individuals took part in the study.
      PROCEDURE: Subjects completed a set of measures before and after being weighed
      and sequentially allocated to either the under, average or over weight conditions
      according to a fictional height-weight chart. RESULTS: The results showed that
      subjects allocated to the overweight group showed an increase in depression and a
      decrease in self esteem following the manipulation, compared to subjects in the
      average weight group who reported improvements in these measures and the
      underweight group who similarly showed decreased depression, but showed some
      deterioration of their self-esteem. CONCLUSION: Weighing and comparison with
      height weight charts of weight norms is used both to detect and treat overweight
      and obesity. The results from this study indicate that this procedure may not be
      as benign as believed and may contribute to the negative psychological state of
      the individual.

PMID- 8653151
TI  - The Bcl I polymorphism of the human uncoupling protein (ucp) gene is due to a
      point mutation in the 5'-flanking region.
AB  - The polymorphic Bcl I site in the human ucp gene associated to percentage fat
      gain over time in the Quebec Family Study cohort (Oppert et al. Int J Obesity
      1994; 18: 526-531) has been positioned to the 5'-flanking region. This
      polymorphism results from a unique A/G mutation. Oligonucleotides used to amplify
      the polymorphic region, and allowing future studies of any cohort of patients,
      are described.

PMID- 8653152
TI  - The effect of withdrawal and re-introduction of dexfenfluramine in the treatment
      of obesity.
AB  - In this study 25 patients, who had completed the INDEX trial (Guy-Grand et al.
      Lancet 1989; 2: 1142-1145) were reexamined 2 months after withdrawal of the study
      medication. The patients then in an open trial received dexfenfluramine (dF) for
      6 months. The observed weight gain after withdrawal of study medication was
      higher in patients treated beforehand with dF (2.6 +/- 1.2 kg) than in patients
      who had received placebo (0.8 +/- 1.0 kg). In the open dF trial rate of weight
      loss was lower than it had initially been in the patients receiving dF from the
      outset of the INDEX trial (13.1 +/- 4.6 kg within 6 months). In the previous dF
      treated patients weight loss after re-introduction of dF was 3.7 +/- 2.7 kg. The
      previous placebo-treated patients, now receiving dF for the first time, lost 4.8
      +/- 1.1 kg. Thus, after withdrawal of dF, patients experience weight gain, but
      after re-introduction of dF, renewed weight loss is achieved. However, the rate
      of weight loss declines with time.

PMID- 8653153
TI  - High prevalence of overweight in a children population living in Naples (Italy).
AB  - OBJECTIVE: The present study estimates the prevalence of obesity among ten-year
      old children living in Southern Italy and compares it with the prevalence of
      obesity among children living in other western countries. METHODS: 110 children
      attending the 4th grade of a randomly selected primary school in Naples were
      studies in the 1992. Eighty-eight per cent of the total school population was
      examined: 52 girls, 58 boys: mean age = 9.6 years (SEM = +/- 0.10). Each child
      underwent medical examination and anthropometric assessment. The percentile
      values for Body Mass Index (BMI = weight/height 2) and triceps skinfolds
      thickness (mm) were calculated and compared to that of children of the same age
      and sex living in other countries, chosen from comparable studies available in
      the literature. RESULTS: Percentile values for triceps skinfolds thickness in
      Neapolitan children are similar to those reported in the other populations
      considered for comparison, however BMI values were different. Children in Naples
      have the highest BMI values at the 50th, 75th, 90th and 95th percentile. The
      prevalence of obesity among Neapolitan children was estimated using as a cut-off,
      the BMI value at the 90th percentile of each population considered for the
      comparison and calculating the rate ratio with 95% confidence interval (95% CI).
      The prevalence of obesity in Naples among girls, was 5.2 times (3.8-6.6 95% CI)
      as high as in France, 3.3 times (2.2-4.4) as high as in Holland, 1.7 times (0.9
      2.5) as high as in USA, 2.5 times (1.7-3.4) as high as in Milan (Northern Italy);
      among boys it was 4.3 times (3.0-5.6) as high as in France, 4.0 times (2.7-5.2)
      as high as in Holland, 2.1 times (1.2-3.0) as high as in the USA, 2.5 times (1.7
      3.4) as high as in Milan.

PMID- 8653154
TI  - Effects of weight loss on single meal eating behaviour in obese subjects.
AB  - In 22 obese patients the eating pattern during a single meal as evaluated by the
      universal eating monitor VIKTOR was assessed after one year of treatment,
      initially with VLCD (Nutrilett) followed by combined long term diet, exercise and
      behavioural modification, underscoring the importance of appropriate meal habits.
      A mean weight loss from 117 to 101 kg was achieved. Before treatment a
      decelerated eating curve was found; after treatment this curve changed
      significantly towards a flatter and more linear shape.

PMID- 8653155
TI  - Fucosylated glycoconjugates of the human spermatozoon. Comparison of the domains
      of these glycoconjugates with the alpha-fucosyl binding sites, and with
      lactosaminic glycoconjugates and beta-D-galactosyl binding site domains.
AB  - Fucosylated glycoconjugates play an important role in fertilization as the
      recognition signal of the zona pellucida. In this work, using "critical"
      concentrations of either, FITC Lotus tetragonolobus lectin or FITC alpha-L
      fucosyl-BSA neoglycoprotein as molecular probes, population densities of
      fucosylated glycoconjugates and of their "complementary" molecules (carrying
      fucosyl receptors), were found all over the sperm surface with higher population
      densities in post acrosomal sheath, neck and midpiece. These results were
      compared with previously reported data on the population densities of
      lactosaminic compounds and their "complementary" molecules, obtained on same
      samples of spermatozoa. Statistical data demonstrate that fucosylated
      glycoconjugates share the same domains with biantennary N-acetyllactosaminic
      oligosaccharides carrying outer galactose and bisected N-acetylglucosamine
      residues. These domains highly differ with those of the lactosaminic
      glycoproteins carrying tri and tetraantennary N-acetyllactosaminic
      oligosaccharides. These studies also show that the domains of fucosylated
      glycoconjugates and their "complementary" molecules (carrying fucosyl receptors)
      locate in different zones of the spermatozoon than those of the compounds
      carrying beta-galactosyl receptors. Besides, the results suggest structural
      differences between fucosylated glycoconjugates of the acrosome, equatorial zone
      and post acrosomal sheath. This may be relevant to the different biological
      behavior of these compounds and zones, in fertilization.

PMID- 8653156
TI  - Isolation and biochemical characterization of the plasma membrane of
      Tritrichomonas foetus.
AB  - A fraction containing plasma membrane-enriched vesicles has been prepared from
      Tritrichomonas foetus. Cells were ruptured using a Potter type homogenizer, under
      well controlled conditions, and membranes were isolated by differential
      centrifugation and in discontinuous sucrose gradient. This fraction was enriched
      8 and 10-fold in the plasma membrane marker enzymes 5'-nucleotidase and (Na+ +
      K+)-dependent, ouabain-sensitive ATPase, respectively. Determination of Glucose-6
      phosphatase and NADPH cytochrome c reductase activities in this fraction,
      indicates a minimal contamination with endoplasmic reticulum membranes. Analysis
      by Sodium Dodecyl Sulfate-Polyacrylamide (SDS-PAGE) gradient gel showed that the
      plasma membrane fraction contains several proteins with major bands corresponding
      to apparent molecular weights of 48, 45, 39, 37, 32, 30, 27, 23, 20, 19, 17, and
      15 kDa.

PMID- 8653157
TI  - Presence and release of immunoreactive atrial natriuretic peptide (ANP) in Bufo
      arenarum spermatozoa after HCG treatment.
AB  - Atrial natriuretic peptide (ANP)-like immunoreactivity has been demonstrated in
      mature spermatozoa of Bufo arenarum. However, after spermiation induced by
      Gonadotropin Releasing Hormone (GnRH), no ANP immunoreactivity was detected in
      testicular spermatozoa. Recently, the presence of GnRH and GnRH receptors in
      amphibian testes has been demonstrated. To clarify if the loss of ANP-like
      immunoreactivity in spermatozoa is a direct effect of GnRH or pituitary
      gonadotropins, a study on Bufo arenarum adult males, has been performed. The in
      vivo treatment with Human Chorionic Gonadotropin (HCG) induced spermiation and
      loss of ANP-like immunoreactivity. The in vitro treatment with HCG showed the
      same results. However, in vitro GnRH treatment failed to cause spermiation and
      loss of ANP-like immunoreactivity. The present results indicate that ANP from
      mature spermatozoa is regulated via gonadotropic hormones and may be involved in
      the spermiation process.

PMID- 8653158
TI  - Unilateral enucleation induces an increase of 160 kd neurofilament in lateral
      geniculate nuclei synapses.
AB  - Ultrastructural synaptic changes of retinal origin in the pars dorsalis lateral
      geniculate nuclei (dLGN) after enucleation have been studied in this laboratory,
      showing a filamentous hypertrophy with maximal expression at 4-6 days post-lesion
      in monkeys (Pecci Saavedra et al., 1970, 1971). The aim of this work was to
      elucidate the nature of the newly formed filament in dLGN in post-enucleated
      rats. Male Wistar rats were fixed with 4% paraformaldehyde plus 0.25%
      glutaraldehyde in 0.1M phosphate buffer, through the abdominal aorta after 3, 5,
      and 7 days postenucleation. Sections obtained were incubated with antibodies to
      the phosphorylated portion of the 160 Kd neurofilaments (1:3000) and anti-GFAP
      (1:25000). There was an increase in 160 Kd neurofilament staining in axons and
      degenerating nerve endings in dLGN, as well as a typical astroglial immunostained
      reaction. Our results show that the newly formed neurofilaments after
      deafferentation are of the 160 Kd type, commonly present in normal axons.

PMID- 8653159
TI  - Vitelline envelope formation during oogenesis in Bufo arenarum.
AB  - The formation of vitelline envelope (VE) during the oogenesis of Bufo arenarum
      (Amphibia Anura) is described. At the stage of early vitellogenesis, the first
      structures appear: the number of oocyte microvilli increases, and many cross
      sections of them are observed between the follicle cells and the oocyte. A
      filamentous material is observed inside the follicle cells and between the
      follicle cells and the oocyte. Multivesicular bodies are also found in the
      follicle cells, and in the perivitelline space. The micrographs also suggest the
      participation of the oocyte in the process of VE formation: large vesicles are
      present in the cortex of the oocyte, filled with an amorphous material of low and
      uniform electron density. Some of them are in the process of releasing their
      content to the perivitelline space. Many vesicles (probably resulting from
      microvilli fragmentation) are also observed in the perivitelline space. During
      late vitellogenesis the VE is a continuous structure between the layer of
      follicle cells and the oocyte. The filamentous material is aggregated in bundles,
      forming a net, and the spherical components are now either included in the
      orifices of the net, or free near the oocyte's surface. At the end of oogenesis,
      when the VE is completely formed, it is difficult to distinguish its components
      independently. Immunolocalization with antibodies against VE, show a positive
      reaction in follicle cells and oocytes in previtellogenic and full grown ovarian
      follicles. This analysis suggests that both the oocyte and the follicle cells are
      directly involved in the synthesis and secretion of the components of the
      vitelline envelope in Bufo arenarum.

PMID- 8653160
TI  - Role of endogenous polyamines in the proliferation of normal hematopoietic
      progenitor cells: high-proliferative potential colony-forming cells (HPP-CFC),
      and low-proliferative potential colony-forming cells (LPP-CFC). Studies "in
      vitro".
AB  - This study concerns the role of endogenous polyamines in the proliferation of
      normal hematopoietic progenitor cells: high-proliferative potential colony
      forming cells (HPP-CFC), and low-proliferative potential colony-forming cells
      (LPP-CFC) in CFW/ep mouse bone marrow cells in the agar culture system. DL-a
      difluoromethylornithine (DFMO) was used as a selective and irreversible inhibitor
      of ornithine decarboxylase which is the first limiting step in polyamine
      biosynthesis. The polyamines have been implicated in cell proliferation and
      differentiation. The results showed that DFMO significantly inhibited the
      formation of LPP-CFC colonies and completely inhibited the growth of the HPP-CFC
      colonies. Addition of exogenous putrescine at the concentration of 10(-7) M
      reverses the suppressive action of DFMO in both progenitor cells. At this
      concentration putrescine alone had no affect on the number or the size of the
      colonies. It was then concluded that endogenous polyamines appear to be essential
      for HPP-CFC proliferation and an important requirement for LPP-CFC proliferation.

PMID- 8653161
TI  - Effects of interpleural bupivacaine on pleural chest tube removal pain: a
      randomized controlled trial.
AB  - BACKGROUND: Moderate to severe pain associated with the removal of pleural chest
      tubes is poorly controlled with opioids. New methods are needed to manage the
      pain associated with this procedure. OBJECTIVES: To compare the effects of
      interpleural injections of 0.25% bupivacaine without epinephrine to those of
      normal saline on chest tube removal pain in cardiothoracic surgery patients.
      METHODS: A randomized, double-blind, placebo-controlled trial was used, with a
      repeated measures design. Pain intensity and distress were measured before,
      immediately after, and 1 hour after chest tube removal. Pain sensations and
      affect were evaluated immediately after chest tube removal. The experimental
      group (n = 21) received bupivacaine and the control group (n = 20) received
      normal saline. RESULTS: In both groups pain intensity and distress scores were
      significantly higher at the time of chest tube removal than immediately before or
      1 hour after. No significant differences in pain intensity, distress, sensation,
      or affect scores were found between the two treatment groups. The 13 patients who
      received intramuscular ketorolac an average of 3.5 hours before the procedure,
      independent of the study design, had significantly lower pain intensity scores at
      the time of chest tube removal than the 26 who did not. CONCLUSIONS: These data
      demonstrate that chest tube removal pain is of moderate to severe intensity and
      that pleural chest tube injections of bupivacaine were not effective in
      decreasing chest tube removal pain. However, the decrease in pain associated with
      the administration of ketorolac warrants future study.

PMID- 8653162
TI  - Acute gastrointestinal complications after cardiac surgery.
AB  - Gastrointestinal problems, with an incidence of about 1%, may complicate the
      postoperative period after cardiovascular surgery, increasing morbidity, length
      of stay, and mortality. Several risk factors for the development of these
      complications, including preexisting conditions; advancing age; surgical
      procedure, especially valve, combined bypass/valve, emergency, reoperative, and
      aortic dissection repair; iatrogenic conditions; stress; ischemia; and postpump
      complications, have been identified in multiple research studies. Ischemia is the
      most significant of these risk factors after cardiovascular surgery. Mechanisms
      that have been implicated include longer cardiopulmonary bypass and aortic cross
      clamp times and hypoperfusion states, especially if inotropic or intra-aortic
      balloon pump support is required. These risk factors have been linked to upper
      and lower gastrointestinal bleeding, paralytic ileus, intestinal ischemia, acute
      diverticulitis, acute cholecystitis, hepatic dysfunction, hyperamylasemia, and
      acute pancreatitis. Gastrointestinal bleeding accounts for almost half of all
      complications, followed by hepatic dysfunction, intestinal ischemia, and acute
      cholecystitis. Identification of these gastrointestinal complications may be
      difficult because manifestations may be masked by postoperative analgesia or not
      reported by patients because they are sedated or require prolonged mechanical
      ventilation. Furthermore, clinical manifestations may be nonspecific and not
      follow the "classic" clinical picture. Therefore, astute assessment skills are
      needed to recognize these problems in high-risk patients early in their clinical
      course. Such early recognition will prompt aggressive medical and/or surgical
      management and therefore improve patient outcomes for the cardiovascular surgical
      population.

PMID- 8653163
TI  - Effect of lateral position on arterial and venous blood gases in postoperative
      cardiac surgery patients.
AB  - BACKGROUND: Investigators have suggested that lateral position may have
      clinically significant effects on oxygenation in cardiac surgery patients.
      Presence of lung disease and type of cardiac surgery may be important
      considerations. OBJECTIVES: To determine the effect of position (left, right,
      supine) on blood gases in patients who have had coronary artery bypass or cardiac
      valvular surgery and to compare the effect of position on blood gases in cardiac
      surgery patients having preoperatively diagnosed lung disease with those having
      no lung disease. METHODS: A repeated measures design was used to study 120
      mechanically ventilated, postoperative cardiac surgery patients. Subjects were
      randomly assigned a sequence of three positions (supine, and 45; right and left
      lateral) after cardiac surgery. Heart rate, respiratory rate, and arterial blood
      gas values were collected in each position. Venous blood gas values were
      collected from a subset of 40 subjects. RESULTS: A statistically significant
      effect of position on PaO2 was found in the group as a whole. The mean PaO2 in
      the left lateral position was lower than the value in the right or supine
      positions. No significant effects for position and pH, PaCO2, or bicarbonate were
      detected. No significant effects were found for type of surgery or the presence
      of absence of preoperative lung disease. A significant effect of position on
      venous pH was detected. No significant position effects were found for PvO2,
      PvCO2, bicarbonate, or venous saturation. No significant position effects were
      found for the calculated arterial-venous oxygen difference. CONCLUSIONS: The
      results of this study support those of previous research, which reported lower
      PaO2 in postoperative coronary artery bypass graft patients in the left lateral
      position. Mean differences in PaO2 were small, suggesting that the known benefits
      of lateral positioning in the early postoperative period outweigh the potential
      risks.

PMID- 8653164
TI  - Factors associated with cognitive recovery after cardiopulmonary resuscitation.
AB  - BACKGROUND: A range of neuro-cognitive sequelae, from mild intellectual
      impairments to brain death, have been reported in survivors of aborted sudden
      cardiac death. PURPOSE: To determine to what extent, if any, factors associated
      with cardiopulmonary resuscitation, left ventricular function, and mood state are
      related to outcomes in five cognitive areas, namely orientation, attention,
      memory, reasoning, and motor performance. METHODS: Repeated measures were used to
      assess cognitive outcomes in 45 sudden cardiac arrest survivors over the 6 months
      following cardiopulmonary resuscitation. A battery of neuro-psychological tests
      was used to assess cognitive outcomes and psychological status over time. The
      relationship of the cardiopulmonary resuscitation, left ventricular function, and
      psychological variables to cognitive outcomes were assessed at each data point.
      The independent variables included time to cardiopulmonary resuscitation, time to
      defibrillation, duration of cardiopulmonary resuscitation, time to awakening,
      ejection fraction, New York Heart Association Class I to IV, tension, anger, and
      depression. RESULTS: During hospitalization 38 of the 45 survivors (84%) had mild
      to severe deficits in one or more cognitive areas; 19 of 38 survivors (50%)
      continued to be impaired in one or more cognitive areas at 6 months. Of these,
      all had mild to severe deficits in at least one aspect of memory, with delayed
      recall the most frequent impairment. Time to awakening accounted for a unique
      portion of the variance in orientation and memory outcomes over time. The left
      ventricular function variables accounted for a significant portion of the
      variance in motor speed. CONCLUSIONS: Our results suggest that half of the long
      term survivors of aborted sudden cardiac death are cognitively intact 6 months
      after resuscitation but that 25% have moderate to severe impairment in memory,
      which could hamper and/or preclude the resumption of prearrest roles.

PMID- 8653166
TI  - Knowing the score: using predictive scoring systems in clinical practice.
AB  - Outcome scores have been promoted as adjuncts to clinical decision making,
      especially when further care is thought to be futile. The Pediatric Risk of
      Mortality score is used to calculate the risk of mortality for patients admitted
      to pediatric intensive care units. In this article the Pediatric Risk of
      Mortality score in evaluated for its ability to contribute to individual patient
      care decisions in the context of clinical practice. Through analysis several
      features of the Pediatric Risk of Mortality score were identified that require
      discretion if the score is to be used in decisions involving individual patients.
      These features include variability and bias introduced in data collection and
      data presentation. Also, outcome scores do not allow for the incorporation of
      patient and family values into the decision process. Outcome scores can provide
      some adjunctive information to clinicians, but they should be used with caution
      when making patient care decisions. Use of Pediatric Risk of Mortality scores in
      clinical practice must be tempered with a knowledge of the limitations of the
      scores, individual patient variability, the conditions under which the scores
      have been validated and collected and, most importantly, an awareness that
      outcome scores do not take into account the caregiver and patient values that are
      inherent in any treatment decision.

PMID- 8653165
TI  - The influence of illness severity and family resources on maternal uncertainty
      during critical pediatric hospitalization.
AB  - BACKGROUND: Psychological management of parents during a child's critical illness
      is a challenge to intensive care nurses because of the uncertainty that
      accompanies hospitalization. OBJECTIVE: To explore the relationship among illness
      severity, family resources, and maternal uncertainty during the initial stage of
      a child's hospitalization in a pediatric intensive care unit for a life
      threatening illness. METHODS: A convenience sample of 40 mothers rated
      perceptions of uncertainty (using Mishel's Uncertainty of Illness Scale: Parent
      Child Form), family cohesion (using Olson's Family Adaptability and Cohesion
      Evaluation Scale), and social support (using Norbeck's Social Support
      Questionnaire). Illness severity was estimated with the Pediatric Risk of
      Mortality Scale. RESULTS: ? Results showed a positive association between illness
      severity and maternal uncertainty and a negative association between family
      cohesion and maternal uncertainty. Severity of illness contributed less to
      maternal uncertainty than did family cohesion. CONCLUSIONS: Family relationship
      are important factors to consider when clinicians estimated the effect on parents
      of their child's critical illness, particularly when uncertainty over their
      child's outcome may lead to parental stress that can interfere with coping and
      child management. (American Journal of Critical Care.)

PMID- 8653167
TI  - A rapid recovery program for cardiac surgery patients.
AB  - Despite a strong national commitment to excellence in healthcare, the available
      resources are limited. Cardiac surgery consumes more healthcare resources than
      any other single treatment. It is imperative that healthcare professionals
      evaluate the traditional methods used to deliver quality care. Rapid recovery
      programs have been implemented in response to this challenge. The purpose of this
      article is to discuss development, implementation, and outcome evaluation of a
      rapid recovery program for cardiac surgery patients in a single health center. A
      multidisciplinary team examined care before, during, and after surgery, as well
      as after discharge. The team also evaluated standards of care and CARE Pathways.
      Changes in protocols were made to prevent the predictable complications of
      cardiac surgery. A decrease in intubation time, respiratory infections, wound
      infections, laboratory procedures, length of stay, and costs has been
      demonstrated. In a follow-up patient and family survey, high satisfaction with
      nursing care, patient and family education, and length of hospitalization has
      been voiced. Anticipated goals have been exceeded and improvements in standards
      continue to be made.

PMID- 8653168
TI  - Thrombolysis of primary angioplasty? An ongoing controversy in the management of
      acute myocardial infarction.

PMID- 8653169
TI  - Outcomes, endpoints, and expectations.

PMID- 8653170
TI  - Are nurses still practicing coronary precautions? A national survey of nursing
      care of acute myocardial infarction patients.
AB  - BACKGROUND: Coronary precautions were common when coronary care units were
      instituted in the 1960s. However, research has failed to provide evidence of the
      validity of most of these restrictions. Only the avoidance of the Valsalva
      maneuver is clearly indicated as a universal precaution in patients who have
      experienced acute myocardial infarction. OBJECTIVES: To determine if nurses
      continue to restrict iced and hot fluids, caffeine, rectal temperature
      measurement, and vigorous back rubs, and to feed and mandate bedrest for acute
      myocardial infarction patients. METHODS: Survey techniques were used to describe
      practice patterns of nurses working in hospitals across the United States. Two
      sampling methods were used to access a random sample. The survey was mailed to
      members of the American Association of Critical-Care Nurses and nonmembers
      working in a hospital accredited by the American Hospital Association and with an
      intensive care unit. RESULTS: Of the 2549 mailed surveys, 882 were returned with
      usable data (34.8% response rate). Iced (28.1%) and hot (8.7%) fluids continued
      to be restricted by nurses. Most (85.6%) restricted stimulant beverages such as
      coffee. Rectal temperature measurement was avoided by 55.7%, and only 73.3%
      taught avoidance of the Valsalva maneuver. In terms of rest, 15.6% reported
      avoiding vigorous back rubs, 8.4% still fed patients, and 33.8% offered bedpans
      to pain-free patients on the first day after admission. A complete bedbath was
      offered by 19.8% of nurses to stable, pain-free patients even a day after
      admission. CONCLUSIONS: The data supporting liberalization of coronary
      precautions have not been adequately disseminated.

PMID- 8653171
TI  - Syndrome X: a discussion of angina and normal coronary arteries.
AB  - Syndrome X was diagnosed in a female patient who presented with typical angina
      and a non-Q wave myocardial infarction, yet demonstrated normal coronary
      arteries. Syndrome X has been described as an impairment in normal endothelial
      function of the coronary microvasculature, resulting in inappropriate
      vasoconstriction and inadequate coronary flow reserve. In this article we review
      pathophysiology, diagnosis, treatment, and prognosis in a single case.

PMID- 8653172
TI  - Cryptosporidiosis in England and Wales.

PMID- 8653173
TI  - AIDS and HIV-1 infection worldwide.

PMID- 8653175
TI  - Traumatic vocal fold avulsion injury in a newborn.
AB  - A full-term newborn developed respiratory compromise in the immediate
      postparturition period requiring urgent intubation. Evaluation of post-extubation
      stridor later the same day revealed an avulsion injury extending from the left
      vocal fold into the lateral glottic musculature. Primary repair was accomplished
      with anatomic realignment of the torn vocal fold and muscle. Endotracheal
      intubation was utilized for stenting and the patient was extubated following 3
      days of paralysis with sedation. Follow-up examination revealed a reparative
      granuloma, which was lasered. Eight-week follow-up examination revealed normal
      vocal fold architecture. At 18 months the patient continues to have a normal
      voice and normal laryngeal development.

PMID- 8653174
TI  - Vocalization and breathing during the first year of life.
AB  - Vocalization and breathing were studied in 40 healthy infants, including five
      boys and five girls each at ages 5 weeks, 2.5 months, 6.5 months, and 12 months.
      Breathing was monitored through the use of a variable inductance plethysmograph
      that enabled estimates of the volume changes of the rib cage, abdomen, and lung,
      as well as estimates of selected temporal features of the breathing cycle. Four
      vocalization types were studied intensively. These included cries, whimpers,
      grunts, and syllable utterances. Breathing behavior was highly variable across
      the four vocalization types, demonstrating the degrees of freedom of performance
      available to the infant to accomplish the aeromechanical drive required. Such
      behavior was influenced by body length, body position, and age, but not by
      vocalization type and sex. The protocol established is a useful tool for
      observing the natural course of the emergence of vocalization and breathing
      during the first year of life.

PMID- 8653176
TI  - Neural control of vocalization: respiratory and emotional influences.
AB  - Previous research has shown that a region of the midbrain, the periaqueductal
      gray matter (PAG), is critical for vocalization. In this review, we describe the
      results of previous investigations in which we sought to find out how PAG neurons
      integrate the activity and precise timing of respiratory, laryngeal, and oral
      muscle activity for natural-sounding vocalization using the technique of
      excitatory amino acid microinjections in cats. In these studies, all surgical
      procedures were carried out under deep anaesthesia. In the precollicular
      decerebrate cat two general types of vocalization, classified as voiced and
      unvoiced, could be evoked by exciting neurons in the lateral part of the
      intermediate part of the PAG. The patterns of evoked electromyographic activity
      were strikingly similar to previously reported patterns of human muscle activity.
      Coordinated patterns of activity were evoked with just-threshold excitation
      leading to the conclusion that patterned muscle activity corresponding to the
      major categories of voiced and voiceless sound production are represented in the
      PAG. In a parallel series of human and animal experiments, we also determined
      that the speech and vocalization respiratory patterns are integrated and
      coordinated with afferent signals related to lung volume. These data have led to
      the proposal of a new hypothesis for the neural control of vocalization: that the
      PAG is a crucial brain site for mammalian voice production, not only in the
      production of emotional or involuntary sounds, but also as a generator of
      specific respiratory and laryngeal motor patterns essential for human speech and
      song.

PMID- 8653177
TI  - Respiratory function during speaking and singing in professional country singers.
AB  - Respiratory function during speaking and singing was investigated in six male
      professional country singers. Function was studied using magnetometers to
      transduce anteroposterior diameter changes of the rib cage and abdomen while
      subjects performed various respiratory maneuvers, speaking activities, and
      singing activities. Results indicated that respiratory behavior during speaking
      was generally the same as that of other normal subjects. Respiratory behavior
      during singing resembled that of speaking. Discussion includes comparison of
      respiratory performance of present singers with untrained singers and classically
      trained singers. Implications are offered regarding how the results might be
      applied to the prevention of voice disorders by education and training of country
      singers.

PMID- 8653178
TI  - Velocity distributions in glottal models.
AB  - Velocity distributions within three models of the human larynx, namely, a rigid
      plexiglas model, an excised canine larynx, and a computational model are
      investigated with experimental and theoretical analyses. A plexiglas wind tunnel
      with interchangeable glottal constrictions was used as a two-dimensional steady
      flow model to measure velocity and pressure for various glottal shapes. A canine
      excised larynx was used as a prototype pulsatile flow model to study pressure and
      velocity variations during phonation. Results of the plexiglas modelling
      indicated a parabolic laminar velocity profiles upstream of the glottal
      constriction and turbulent and asymmetric velocity profile downstream of the
      glottal constriction. The time-averaged velocities of the excised larynx had
      similarities with the plexiglas model results, and instabilities and asymmetries
      were also demonstrated by the computational method.

PMID- 8653179
TI  - Differences in voice quality between men and women: use of the long-term average
      spectrum (LTAS).
AB  - The goal of this study was to determine if there are acoustical differences
      between male and female voices, and if there are, where exactly do these
      differences lie. Extended speech samples were used. The recorded readings of a
      text by 31 women and by 24 men were analyzed by means of the Long-Term Spectrum
      (LTAS), extracting the amplitude values (in decibels) at intervals of 160 Hz over
      a range of 8 KHz. The results showed a significant difference between genders, as
      well as an interaction of gender and frequency level. The female voice showed
      greater levels of aspiration noise, located in the spectral regions corresponding
      to the third formant, which causes the female voice to have a more "breathy"
      quality than the male voice. The lower spectral tilt in the women's voices is
      another consequence of this presence of greater aspiration noise.

PMID- 8653180
TI  - A physiological and acoustic study on voiced bilabial fricative/beta:/as a vocal
      exercise.
AB  - The voiced bilabial fricative/beta:/has been used as a vocal exercise. The
      present study investigated the effects of the exercise on voice production and
      voice source. This study compared vowel phonation on the syllable /a:p/ with the
      production of the exercise and vowel phonation before and immediately after the
      exercise. The methods were (a) dual-channel electroglottography, from which the
      vertical laryngeal position was derived, (b) electromyography using surface
      electrodes, and (c) inverse filtering of the acoustic signal to obtain an
      estimate of the voice source. In the production of /beta:/ as compared with vowel
      phonation in most of the cases, the vertical laryngeal position seemed to be
      higher, the muscular activity of the larynx lower, and the slope of the voice
      source spectrum steeper. In vowel phonation after the exercise, the muscular
      activity seemed to be lower in most cases, although the voice source remained
      unchanged. This seems to indicate improved vocal economy.

PMID- 8653181
TI  - External laryngeal frame function in voice production revisited: a review.
AB  - Research indicates significant contribution of extrinsic laryngeal mechanisms to
      voice production. This article reviews the major theories of the role of the
      external laryngeal factors in voice production and relevant experimental data.
      The review suggests that partly neglected external factors and possibly even
      misinterpretation of some of the recently documented individual variation in
      physiological data may have unnecessarily complicated the issues pertaining to
      the interplay between the physiological mechanisms of the larynx. The
      implications of contemporary findings and documentation in the modeling of the
      extrinsic factors are discussed and a synthesis of empirical data into two simple
      models of the extrinsic forces of pitch control is presented. Also suggested by
      the review, a basic principle, probably underlying the laryngeal control of
      phonation, is put forward.

PMID- 8653182
TI  - Episodic paroxysmal laryngospasm: voice and pulmonary function assessment and
      management.
AB  - Episodic paroxysmal laryngospasm (EPL) is a sign of laryngeal dysfunction, often
      without a specific organic etiology, which can masquerade as asthma, vocal fold
      paralysis, or a functional voice disorder. The intermittent respiratory distress
      of EPL may precipitate an apparent upper airway obstructive emergency, resulting
      in unnecessary endotracheal intubation, cardiopulmonary resuscitation, or
      tracheostomy. During 27 months, seven women and three men, age 30-76 years, were
      assessed by a high diagnostic index of suspicion, an intensive history including
      psychosocial factors, physical examination of the airways, provocative asthma
      testing, and swallowing studies. Videolaryngoscopy, stroboscopy, and pulmonary
      flow-volume loop testing were definitive. The classic appearance was paradoxic
      inspiratory adduction of the anterior vocal folds with a posterior diamond-shaped
      glottic gap. During an attack of stridor or wheezing, attenuation of the
      inspiratory flow rate as depicted by the flow-volume loop suggested partial
      extrathoracic upper airway obstruction. Swallowing evaluation by
      videolaryngoscopy and videosophagography may uncover gastroesophageal reflux
      disease. Hallmarks of management include patient and family education by
      observation of laryngoscopic videos, a specific speech therapy program,
      psychotherapy, and medical treatment of associated disorders. Electromyography
      may become a valuable future adjunct. Unlike laryngeal dystonia, patients with
      EPL do not benefit from botulinum toxin type A.

PMID- 8653183
TI  - Relative fees and the utilization of physicians' services in Canada.
AB  - STUDY QUESTION: The study objective is to estimate the relationship between
      changes in the relative fee physicians receive for a procedure and the
      utilization of the procedure. DATA SOURCES/STUDY SETTING: The study uses claims
      based, procedure-specific, quarterly, aggregate utilization data for physicians
      in three specialties and four provinces in Canada for the period 1977-1989. STUDY
      DESIGN: The unit of analysis is an individual procedure. Multi-variate regression
      methods for cross-sectional/times-series data are applied to estimate the
      utilization-fee relationship while controlling for supply- and demand-side
      determinants of utilization. PRINCIPAL FINDINGS: There is no evidence of a
      strong, uniform utilization response among the 11 procedures analyzed. The
      results include a mixture of significant and non-significant fee coefficients,
      and among the significant coefficients, a mixture of signs is observed. The
      results are consistent with utility-maximizing behaviour by physicians rather
      than with profit-maximizing behaviour. CONCLUSIONS: The fact that the direction
      and degree of the utilization effect associated with changing fees is procedure
      specific has direct implications for our ability to develop effective policies to
      modify physician behaviour that are based primarily on financial incentives,
      particularly those based on manipulating fees. The study also highlights the
      limitations of analyses based on aggregate data and suggests methodological
      approaches that have potential to overcome some of these limitations to fill gaps
      in our current knowledge.

PMID- 8653184
TI  - Willingness to pay for antenatal carrier screening for cystic fibrosis.
AB  - We report on a study of women's willingness to pay (WTP) for a cystic fibrosis
      carrier test by one or other method of service delivery (disclosure or non
      disclosure). The results demonstrate that there was no statistically significant
      difference in WTP for the methods of testing. Those women who received a negative
      test result were followed up and asked their WTP for such a result. Values
      obtained at this stage were 16 per cent higher than those obtained pretest
      result. Use of prompts, rather than simply asking women to state their WTP, had a
      statistically significant effect on post-test result values. The opportunity to
      terminate the pregnancy, if a test proved positive, was important, but was not
      the only consideration. This demonstrates the importance to women of other
      benefits of screening.

PMID- 8653185
TI  - Explaining the utilisation of dental care. Experiences from the Finnish dental
      market.
AB  - In this paper a model based on the theory of demand for health and of supplier
      inducement is developed to explain the utilisation of dental care. Of special
      interest are the effects of money price and various forms of inducement. It is
      also explored how the results are affected if different model specifications and
      estimation techniques are applied and what is the most appropriate one, when
      utilisation is measured by dental expenditure. The data come from a sample of
      1779 employees, whose dental expenditure is refunded from 0 to 99.75%. Other
      things being equal, the methodological choices make a clear difference in
      parameter estimates. Only a log-linear two-part model and two-part tobit with
      selectivity were suitable for explaining expenditure and produced quite similar
      results. Money price elasticity was small, but significant (-0.069). General and
      personal inducement appear to have a considerable effect on utilisation, but did
      not have any systematic connection with dentist/population ratio.

PMID- 8653186
TI  - Investigating hospital efficiency in the new NHS: the role of the translog cost
      function.
AB  - The reforms to the United Kingdom's National Health Service (NHS) of recent years
      have greatly increased the role of economic incentives in the hospital sector.
      Hospitals now have to compete for the business of GP and health authority
      purchasers and are assumed to have an incentive to minimise costs. This makes the
      analysis of cost functions much more relevant than has previously been the case.
      The objective of this paper is to assess the potential usefulness of the translog
      cost function applied in the NHS internal market. Three main issues are
      identified that limit the role of this type of cost function in the internal
      market: the adequacy of the econometric model (including data quality); the
      assumptions underlying the model, and; the interpretation of economies of scale,
      marginal costs and economies of scope that can be derived from such a cost
      function. It is concluded that at present the application of translog cost
      function analysis in the NHS is of limited usefulness, but that it does indicate
      areas for further methodological research.

PMID- 8653187
TI  - Provision of health care services in Austria. A time series approach.
AB  - The presented article describes the investigation of three main variables of the
      health care system in Austria by applying time series analysis. The quantities
      under consideration are the stock of physicians working in the ambulatory sector,
      the number of medical services provided and the related costs. The article
      discusses non-stationarity and unit root tests and presents an outlook for the
      considered variables. One conclusion to be drawn from the presented analysis is
      the presence of a stochastic element in the analyzed variables.

PMID- 8653188
TI  - Problems of using modelling in the economic evaluation of health care.

PMID- 8653189
TI  - Indirect cost in economic evaluation: the opportunity cost of unpaid inputs.
AB  - Unpaid time represents a potentially significant input into the health production
      function. The paper sets out the basis for valuation of time inputs consistent
      with the notion of opportunity cost. Such analysis requires consideration of
      whether time displaced in the production of health involves lost work or lost
      leisure. Furthermore, because valuation of opportunity cost requires the
      consistent treatment of costs and benefits, the study also considers the
      valuation of outputs. The basis for valuing the shadow price of work time is
      examined by firstly assuming perfect competition. The analysis then considers the
      presence of monopoly and monopsony in product markets and income and sales taxes.
      The basis for valuing the shadow price of leisure ("leisure' being all uses of
      time except paid employment) is restricted to an examination of methods
      previously used to value unpaid housework. The two methods examined are the
      replacement cost and the opportunity cost method. As the methods are not
      equivalent, the circumstances where each is appropriate vary depending on whether
      the output lost in producing health is replaced. Although not set out as the
      primary focus of the paper, the issues surrounding the valuation of outputs
      generated by non-market and quasi-market activity are examined. In particular,
      where activities such as informal care result in indirect utility to the carers
      (and patients) themselves, it is likely the full market wage provides a lower
      bound estimate of the value of marginal benefit. Finally the paper provides a
      practical approach to examining opportunity cost of unpaid inputs consistent with
      the concepts set out in preceding sections.

PMID- 8653190
TI  - Transaction costs, externalities and information technology in health care.
AB  - This paper discusses some of the economic issues which underpin the rationale for
      investment in information and communications technologies (ICTs). Information
      imperfections lead to significant transaction costs (search, negotiating and
      monitoring) which in turn confer a negative externality on parties involved in
      exchange. This divergence in private and social costs leads to a degree of
      resource misallocation (efficiency loss) which, uncorrected, results in a sub
      optimal outcome. Traditional solutions to this problem are to rely upon direct
      government action to reduce the costs of transacting between market agents, or to
      employ tax/subsidy measures and other legislative action to achieve the desired
      market outcome. Three key policy questions are raised in the context of the NHS
      purchaser/provider relationship. Firstly, what is the optimum level of
      transaction costs; secondly, can ICTs assist in lowering the level of transaction
      costs to the optimum level; thirdly, who should bear the investment cost in
      reducing the level of transaction costs? The issue of property rights in
      different information systems is discussed and raises interesting policy
      questions about how much investment should be undertaken centrally rather than
      devolved to a more local level. In some ways this economic framework offers a
      post hoc justification of why different ICT systems have been introduced at
      various levels of the NHS. Essentially this reduces to the problem of
      externalities: providing good information confers a positive externality: not
      providing relevant, timely and accurate information confers a negative
      externality, by increasing further the level of transaction costs. The crucial
      role which ICT systems can play lies in attempting to reduce the level of
      transaction costs and driving the market towards what Dahlman has described as
      the transaction-cost-constrained equilibrium.

PMID- 8653191
TI  - Cost recovery and improved drug availability in Niger--implications for total
      patient treatment costs.
AB  - Using quasi-experimental design methods, this study investigated, for a cost
      recovery intervention in Niger, how the total costs of an episode of treatment
      for an acute illness for a typical patient changed when user fees were imposed
      but accompanied by an improved drug supply. Episode costs included both cash and
      opportunity costs. With few exceptions, the comparisons of both the unadjusted
      and adjusted patient episode costs showed that patient total episode costs in the
      intervention sites increased relative to the control site. The infusion of
      resources in Say and Boboye meant that now patients had essential medicines to
      buy, in comparison to Illela where stocks of essential medicines continued to
      deteriorate. Trends in episode costs within each intervention district
      demonstrated that to some extent cost recovery accompanied by an improved drug
      supply did not significantly change the total cost of an episode of treatment. In
      Say, this was true for malaria cases, females and the poor. However, in Boboye,
      reductions in copayments were offset by a mandatory tax payment paid by both
      users and non-users.

PMID- 8653192
TI  - Choice of health insurance by families of the mentally ill.
AB  - This paper investigates whether choice of health insurance is influenced by the
      perceived mental and physical health of family members among a sample of policy
      holders with private health insurance. A multinomial probit model of the choice
      among major medical coverage only, traditional full coverage, and coverage
      through a health maintenance organization is estimated. Results indicate that the
      presence of at least one family member who rates his or her general health as
      poor does not affect the policy-holder's choice of health insurance. However, the
      presence of at least one family member considered at risk of mental illness does
      in some instances affect the policy-holder's choice of health insurance: We
      observe significant effects for policy-holders who are female, black, have some
      college education, work for a large firm, and live in an urban area. These
      findings suggest that adverse selection may arise when individuals are able to
      choose between health insurance policies with different degrees of coverage for
      mental health care and that such effects are far more pronounced for those people
      who consider themselves at risk for mental illness than physical illness.

PMID- 8653194
TI  - UV detection of triazine herbicides and their hydroxylated and dealkylated
      degradation products in well water.
AB  - The aim of this work was to develop a simple method to confirm the presence of
      hydroxytriazine products (hydroxyatrazine, hydroxysimazine,
      hydroxyethylterbutyltriazine and hydroxydiaminotriazine) in water and to apply it
      to well water samples. The hydroxytriazines were concentrated on a Sep-Pak C18
      cartridge. Analysis was performed by HPLC using an RP8-DB column with phosphate
      buffer (pH 4.7)-acetonitrile (72:28, v/v) as the mobile phase and photodiode
      array detection at 233 nm. Hydroxyatrazine, hydroxysimazine and
      hydroxyethylterbutyltriazine were detected at ppb levels in samples from two
      shallow wells under a very sandy soil citrus orchard taken at three different
      times in a 1-year period.

PMID- 8653193
TI  - The impact of alcohol consumption and marijuana use on high school graduation.
AB  - In this study we use data from the National Longitudinal Survey of Youth (NLSY)
      to estimate the relationship between high school graduation, and alcohol and
      marijuana use among high school students. We also estimate the demand
      determinants for each of these substances. Our results show that there are
      significant adverse effects of alcohol and marijuana use on high school
      graduation. In particular, increases in the incidence of frequent drinking,
      liquor and wine consumption, and frequent marijuana use, significantly reduce the
      probability of high school graduation. Our results also show that beer taxes,
      liquor prices and marijuana decriminalization have a significant impact on the
      demand for these substances. These findings have important policy implications. A
      ten percent increase in beer taxes, reduces alcohol consumption among high school
      students, which in turn raises the probability of high school graduation by about
      three percent. A 1 percent increase in liquor prices raises the probability of
      high school graduation by over 1 percent. Raising the minimum drinking age for
      liquor also reduces liquor and wine consumption, and thus, improves the
      probability of high school graduation. Although the relationship between
      marijuana decriminalization and marijuana use is not significant,
      decriminalization is found to reduce the probability of becoming a frequent
      drinker. This result suggests that marijuana use and frequent drinking are
      substitute activities. Illicit substance abuse reduces the rate of high school
      completion, reduces expected future earnings and creates potential health
      problems. Thus, high-school-based preventive programs which discourage alcohol
      consumption and marijuana use are highly recommended, in order to alleviate these
      problems.

PMID- 8653195
TI  - Rapid and sensitive determination of zidovudine and zidovudine glucuronide in
      human plasma by ion-pair high-performance liquid chromatography.
AB  - A rapid, simple and sensitive method is described for the simultaneous
      determination in human plasma of the well known antiviral agent zidovudine (AZT)
      and its main metabolite, zidovudine-5'-O-glucuronide (G-AZT), using a solid-phase
      extraction method for sample preparation and a rapid ion-pair HPLC separation
      method with diode-array ultraviolet detection. The method overcomes the problems
      experienced in other procedures because of the large difference in polarity of
      the two compounds and the pH-sensitive retention of G-AZT by using n-octylamine
      to increase the retention of the glucuronide and improve the overall
      chromatographic behaviour. AZT and G-AZT are eluted at 3.6 and 5 min,
      respectively, with 7-ethyltheophylline used as internal standard eluting at 4.2
      min. Caffeine, a good marker for the elution of related compounds present in
      plasma, appears well before, at 2.6 min. Quantification limits were established
      at 0.025 and 0.050 micrograms/ml for AZT and G-AZT, respectively. The improvement
      in method reproducibility due to the late elution of G-AZT could be observed even
      at the quantification limit at which an inter-assay relative standard deviation
      of only 6.4% was found after 3 months of routine use of the method.

PMID- 8653196
TI  - Postcolumn excitation of aflatoxins using cyclodextrins in liquid chromatography
      for food analysis.
AB  - Measurement of fluorescence increase was used for the comparative quantification
      of the effect that several cyclodextrins (alpha-, beta-, heptakis-2,6-beta
      omicron-dimethyl- and gamma-) produce on the fluorescent response of aflatoxins
      B1 and G1. This constitutes a new chromatographic method with stability of the
      mobile phase, and shows general improvements in the chromatographic conditions
      with respect to other methods (especially those using an iodine reservoir as a
      postcolumn reactor). A C18-type column was used, with methanol-water (60:40, v/v)
      as the mobile phase. The excitation phase of the natural fluorescence of
      aflatoxins, a 10(-2) M solution of each cyclodextrin, was introduced postcolumn.
      The determination of the elution order aflatoxin G2 > G1 > B2 > B1 was performed
      for each phase in less than 15 min. As expected using an aqueous-alcoholic
      medium, an increase in the fluorescence response of aflatoxins with an
      unsaturated furanic ring was found to occur with all the cyclodextrins studied,
      except gamma-cyclodextrin. The observed increase was larger for heptakis-2,6-beta
      omicron-dimethyl- than for beta-cyclodextrin (to our knowledge, the only
      cyclodextrin previously described in the literature to serve for the
      determination of aflatoxins). The difference is of the order of 70.1-fold in the
      case of aflatoxin G1 and 45.2-fold in the case of aflatoxin B1. The detection
      limit in the mobile phase used was determined (for aflatoxin B1) for beta
      cyclodextrin and 2,6-beta-omicron-dimethylcyclodextrin (signal-to-noise ratio
      1:3) to be 4 and 9 mg 1(-1), respectively.

PMID- 8653197
TI  - Isocratic high-performance liquid chromatographic determination of tryptophan in
      infant formulas.
AB  - The application to infant formulas of a method for tryptophan determination by
      isocratic HPLC with UV detection at 254 nm, after derivatization with phenyl
      isothiocyanate, was studied. Protein was hydrolysed by barium hydroxide at 120
      degrees C for 8 h, followed by derivatization with phenyl isothiocyanate, HPLC
      and UV detection at 254 nm. The optimum chromatographic conditions (pH, ionic
      strength of elution solvent and eluent ratio) were established. The analytical
      parameters (linearity, precision, accuracy of derivatization and limits of
      detection and quantification) were determined. The values obtained demonstrated
      that the method is useful for determining the tryptophan content of infant
      formulas. The tryptophan contents in six different types of infant formulas were
      0.535-0.848 g per 100 g of protein.

PMID- 8653198
TI  - Separation of B-3 monodesamidoinsulin from human insulin by high-performance
      liquid chromatography under alkaline conditions.
AB  - The separation of human insulin (HI) and related compounds such as A-21
      monodesamido HI (A-21DHI) and B-3 monodesamido HI (B-3DHI) was investigated using
      reversed-phase HPLC and capillary zone electrophoresis (CZE). In the case of HPLC
      under the usual acidic conditions, whereas A-21DHI was separately eluted, B-3DHI
      was included in the HI peak. Then it was found that by applying a novel ODS
      column resistant to alkaline conditions, a good separation of B-3DHI from HI
      could be achieved using an alkaline eluent, and two peaks corresponding to B-3DHI
      were eluted in front of the HI peak.

PMID- 8653199
TI  - Determination of imidacloprid in vegetables by high-performance liquid
      chromatography with diode-array detection.
AB  - An HPLC method is described for the determination of imidacloprid residues in
      vegetables at levels ranging from 0.01 to 0.60 mg/kg. The selection of the
      extraction and clean-up procedure is discussed. Spectral data obtained with diode
      array detection allow the identification of imidacloprid residues. Thermospray
      mass spectrometric studies were carried out in combination with HPLC. The mean
      recoveries and standard deviations were 95% and 4.7%, respectively, in the
      various crops tested. Registration of the analytical results for a control sample
      in quality control charts demonstrated the performance of the method. Data for
      incurred residues of imidacloprid in vegetable samples routinely applying the
      proposed method are also presented.

PMID- 8653200
TI  - Element- and isotope-specific detection for high-performance liquid
      chromatography using chemical reaction interface mass spectrometry.
AB  - We have developed a combination of high-performance liquid chromatography (HPLC)
      and the chemical reaction interface mass spectrometry (CRIMS) method by using a
      Vestec Universal Interface (UI). This interface provides the extremely high
      degree of solvent removal that the CRIMS process requires. In doing so, we have
      produced an HPLC detector with the ability to carry out the element- and isotope
      selective analyses with detection that is inherently: linear, structure
      independent, sensitive, selective, comprehensive and flexible. The
      characteristics of the instrumentation and its performance are described.

PMID- 8653201
TI  - Isolation of calcium-binding proteins on selective adsorbents. Application to
      purification of bovine calmodulin.
AB  - We report the fractionation of calcium-binding proteins using immobilized metal
      ion affinity chromatography (IMAC) with hard metal ions. Various hard metal ions
      (Mn2+, La3+, Nd3+, Eu(3 were immobilized on cross-linked agarose substituted with
      Tris(carboxymethyl)ethylenediamine (TED) and used as an adsorbent. After
      systematic studies, europium was selected for further work on the fractionation
      of calcium-binding proteins. It was found that the presence of Ca2+ in the sample
      and the solvent strongly promoted the adsorption and selectivity. Selective
      elution was accomplished in stepwise mode by the addition of calcium chelators
      such as malonate, citrate and phosphate. Calmodulin of high purity was isolated
      from a crude extract. Similar behavior of other calcium-binding proteins
      indicates that the reported chromatographic procedure can be generally applied to
      such proteins.

PMID- 8653202
TI  - Isolation of 4'-bromo-4,5,6,7-tetrachlorofluorescein from a synthetic mixture by
      pH-zone-refining counter-current chromatography with continuous pH monitoring.
AB  - A synthetic mixture containing mainly 4'-bromo-4,5,6,7-tetrachlorofluorescein
      (4'BrTCF, ca. 25% by high-performance liquid chromatography) was prepared by
      direct bromination of tetrachlorofluorescein in ethanol. The 4'BrTCF was isolated
      and purified by pH-zone-refining counter-current chromatography (CCC), using two
      different two-phase solvent systems: diethyl ether-acetonitrile-water (4:1:5,v/v)
      and ter.-butyl methyl ether-water (1:1,v/v). For each system, the upper organic
      phase was acidified and used as the stationary phase and the lower aqueous phase
      was made basic and used as the mobile phase. pH-Zone-refining CCC of two 5-g
      batches of the crude mixture yielded 1.65 g of 4'BrTCF that was ca. 95% pure by
      HPLC. For these separations, a commercial counter-current chromatograph was
      fitted with a pH electrode in a flow cell to record the pH of the effluent "on
      line,' thereby replacing the tedious and time-consuming manual measurement of the
      pH of each fraction. Additionally, UV spectra of the effluent were continuously
      monitored and stored by using a computerized scanning UV-Vis detector equipped
      with an adjustable short-pathlength flow cell.

PMID- 8653203
TI  - Improved rapid method for the isolation, purification and identification of
      collagen glycosides.
AB  - An updated method for obtaining purified glucosylgalactosyl hydroxylysine (Glc
      Gal-Hyl) is presented. Marine sponge is subjected to alkaline hydrolysis followed
      by ion-exchange chromatography and gel filtration. Identification is confirmed by
      consecutive mild acid hydrolysis of the extract to produce galactosyl
      hydroxylysine (Gal-Hyl) and hydroxylysine (Hyl). High-performance liquid
      chromatography (HPCL) with a sodium acetate-acetonitrile buffer and dabsyl
      chloride as the derivatizing agent demonstrated the purity of the extract and its
      hydrolyzates. Glc-Gal-Hyl is not commercially available but this easy and
      efficient method can provide large amounts of it for collagen metabolism studies.

PMID- 8653204
TI  - High-performance liquid chromatographic separation of carminic acid, alpha- and
      beta-bixin, and alpha- and beta-norbixin, and the determination of carminic acid
      in foods.
AB  - During a study of natural food colours, a simple and reliable high-performance
      liquid chromatography system was developed for use with cochineal and annato. An
      isocratic mobile phase, consisting of methanol and 6% aqueous acetic acid,
      resolved bixin and norbixin, while a gradient system was used to separate
      carminic acid and the annato compounds. The carminic acid contents of cochineal
      extract, carmine and carmine hydrosoluble were determined using an isocratic
      mobile phase (40:60, v/v). The detection limit for carminic acid in the various
      products was approximately 100 ng/g. Carminic acid was determined quantitatively
      in fruit beverages, yogurt and candies. It was demonstrated that, because of
      decomposition, carminic acid was not suitable for use in candies when
      manufacturing temperatures above 100 degrees C were required. Most membrane
      filters are not suitable for use with cochineal solutions, but a cellulose
      membrane filter did not adsorb carminic acid and was used successfully to remove
      impurities from water-based cochineal products and food extracts containing
      carminic acid.

PMID- 8653205
TI  - Using administratively collected hospital discharge data for AIDS surveillance.
AB  - The objectives of this study were twofold: to improve methods of identifying
      possible and acquired immunodeficiency syndrome (AIDS)-related hospital
      discharges in administrative databases and to measure AIDS-reporting completeness
      in Massachusetts both overall and by subgroup. We used fiscal year 1988 discharge
      data from the Massachusetts Rate Setting Commission (RSC) and data from the
      Massachusetts AIDS Reporting System (ARS). We identified 3362 discharges of adult
      patients (> 12 years old) from the RSC file that had diagnosis codes which are
      human immunodeficiency virus (HIV)-specific (042.x, 043.x, 044.x, or 795.8) or
      pertain to AIDS-defining "manifestations." Medical records of 650 patients
      apparently not reported to the ARS were reviewed. THe best set of codes overall
      consisted of either (a) the 042.x code or (b) the 043.x, 044.x, or 795.8 code
      plus selected manifestation codes (sensitivity, 93%; specificity, 86%; predictive
      value positive, 71%). Of the 927 AIDS cases identified from the 3362 discharges,
      only 36 had not been reported. AIDS cases among women (odds ratio (OR) = 2.9; 95%
      confidence interval (CI): 1.33 to 6.33), intravenous drug users (OR = 4.2; 95%
      CI: 2.20 to 8.02), and persons residing outside the Boston metropolitan area (OR
      = 2.3; 95% CI: 1.18 to 4.57) were more likely to be unreported than those among
      comparison groups.

PMID- 8653206
TI  - The relationship between maternal education and mental retardation in 10-year-old
      children.
AB  - We conducted a case-control study of mental retardation (MR) in which case
      children (aged 10 years) were identified from existing records at multiple
      sources, primarily the public school systems. Control children were drawn from a
      roster of public school students not receiving special education services. We
      found that maternal educational level at the time of delivery was strongly and
      inversely related to a form of MR not accompanied by other serious neurologic
      conditions. For this isolated form of MR, maternal educational level was by far
      the most important predictor from among seven sociodemographic variables
      examined. There was a significant race-education interaction that indicated a
      steeper gradient in risk among white mothers than among black mothers. Relative
      to children of white mothers with 12 years of education, all children of black
      mothers, except those whose mothers had 16 or more years of education, were at
      increased risk. The results may be useful as a guide for selecting high-risk
      groups as candidates for early childhood intervention programs.

PMID- 8653207
TI  - Childhood cancer and parental use of alcohol and tobacco.
AB  - Reported consumptions of alcohol and tobacco for the parents of 1641 children who
      died with cancer in England and Wales during the period 1977 to 1981 were
      compared with similar information for the parents of 1641 control subjects.
      Consumption of alcohol by fathers was not associated with an increased risk of
      childhood cancer (relative risk (RR)) = 1.05; 95% confidence interval (CI): 0.86
      to 1.28), but for daily consumption of cigarettes was not shown to be associated
      with an increased risk and consumption of alcohol was associated with a
      relatively low cancer risk (RR = 0.82; 95% CI: 0.70 to 0.96). Relations between
      maternal consumption of cigarettes and birth weights suggested that the smoking
      data were equally reliable for case patients and control subjects.

PMID- 8653208
TI  - The effects of race, household income, and parental education on nutrient intakes
      of 9- and 10-year-old girls. NHLBI Growth and Health Study.
AB  - Nutrient intakes of 2149 black and white, 9- and 10-year-old girls varied by
      race, household income, and parental education. Of the three variables, higher
      education was most consistently associated with more desirable levels of nutrient
      intakes, that is, lower percentage of dietary fat and higher levels of vitamin C,
      calcium, and potassium. Higher income was related to higher intakes of vitamin C,
      but lower intakes of calcium and iron. Higher income was associated with lower
      percentage of dietary fat. After adjustment for income and education, race was
      associated with intakes of calcium, vitamin C, and to a lesser extent,
      percentages of kilocalories from total fat and polyunsaturated fat, and
      potassium. Black girls had a significantly lower intake of calcium (720 versus
      889 mg) and a higher intake of vitamin C (91 versus 83 mg). Proportions of the
      cohort with inadequate or excessive intakes of micronutrients and macronutrients
      were also estimated. A high proportion of girls exceeded the recommended intake
      level of 30% of kilocalories from total fat (90% of black girls; 84% of white
      girls) and 10% of kilocalories from saturated fat (92 and 93%, respectively). Low
      intakes of calcium (40% of black girls and and 20% og white girls) and zinc (36
      and 38%, respectively) commonly were found for girls of both names.

PMID- 8653209
TI  - Reproducibility and validity of a food-frequency questionnaire designed for use
      in girls age 7 to 12 years.
AB  - This study focused on a food-frequency questionnaire (FFQ) designed to measure
      nutrient intake in girls aged 7 to 12 years, inclusive. The instrument's
      reproducibility and validity were assessed using food records (FRs) as gold
      standards of measurement. Log-transformed nutrient intake estimates were compared
      from two FFQs and between FFQs and FRs. Intraclass correlation coefficients
      measuring the reproducibility of the FFQ ranged from 0.11 (starch) to 0.69
      (fiber). Intraclass correlation coefficients measuring agreement between FFQ and
      14l-day FR data varied between 0.15 (starch) and 0.68 (vitamin B2) for the first,
      and between 0.06 (starch) and 0.95 (vitamin B1) for the second FFQ. FFQs were in
      the best agreement with FRs for the following nutrients: fiber, vitamin B1,
      vitamin B2, vitamin C, and beta-carotene. Joint classifications revealed that
      overall, 36% of subjects were similarly categorized by FFQ and FR, and 70% of
      those in the lowest or highest FR quartiles were were found in the lowest or
      highest FR quartiles were found in the lowest or highest two FFQ quartiles,
      respectively.

PMID- 8653210
TI  - Food-frequency questionnaire validation among Mexican-Americans: Starr County,
      Texas.
AB  - A food-frequency questionnaire (FFQ) for low-income Mexican-Americans in Starr
      County, Texas, was developed as part of an epidemiologic study of gallbladder
      disease during 1985 and 1986. The FFQ was developed from 7-day food records
      collected from the first sample. In the validity study, using the second sample,
      correlations between nutrients calculated from 3-day food records and the FFQ
      were 0.77, 0.76, and 0.61 for energy, total fat, and saturated fat, respectively.
      In the reliability study, using the third sample, for the 1-month interval
      between baseline and a repeat FFQ measurement correlations ranged from 0.90 for
      energy to 0.85 for total fat and for the 2-month interval they were 0.84 for
      energy and 0.70 for total fat. The high correlations are largely explained by the
      lack of diversity in the diets of Starr County individuals which facilitated the
      high agreement between the FFQ and the food records for estimates of energy,
      fats, and cholesterol.

PMID- 8653211
TI  - Inaccuracy of self-reported weights and heights among American Indian
      adolescents.
AB  - To determine the accuracy of self-reported weights and heights and of relative
      weight status in a sample of American Indian adolescents, a survey was conducted
      in middle and high schools on or near three Indian reservations-Navajo, Choctaw,
      and Blackfeet. Self-reported weights and heights were compared with measured
      weights and heights. Participants were 12 through 19 years old. (N = 806, 47.4%
      male). Overall, both boys and girls underreported weight (mean difference = self
      reported - measured mean values)(-3.4 +/- 13.1 and -4.6 +/- 13.0 lb,
      respectively) and overreported height (0.6 +/- 2.1 and 0.2 +/- 2.6 in,
      respectively) However, underweight boys and girls overreported weight (normal: 
      1.6 +/- 7.9 and -1.4 +/- 6.3; overweight: -7.5 +/- 17.9 and -11.6 +/- 19.0 lb,
      respectively). Although correlations between measured and reported weight,
      height, and body mass index (BMI) were high, the sensitivity of relative weight
      categories based on BMI using self-reported weight and height compared with
      measured weight and height was poor: 66.7% for underweight (BMI < 15th
      percentile, based on a national reference population), 88.9% for normal weight,
      and 73.6% for overweight (> 85th percentile). These results call into question
      the accuracy of self-reported weight and height measurements among American
      Indian youth and are similar to findings among non-American Indian adolescents.
      Therefore, their use in prevalence studies should be avoided, and they should be
      used cautiously in other types of epidemiologic studies.

PMID- 8653212
TI  - An investigation into the disparity between Australian aboriginal and Caucasian
      perinatal mortality rates.
AB  - The babies of Australian Aboriginal mothers have higher overall perinatal
      mortality rates than the babies of Caucasian mothers. They are also more likely
      to be preterm and of low birth weight. This study used Poisson regression models
      to adjust the perinatal mortality rates for differences in the gestational age
      and birth weight distributions of Aborigines and Caucasians. The intriguing
      finding was that full-term Aboriginal neonates (the group at lowest absolute
      risk) fare particularly poorly in comparison with Caucasian (adjusted relative
      risk: 2.9; 95% confidence interval; 1.5 to 5.5). Possible explanations for this
      phenomenon are explored.

PMID- 8653213
TI  - Hodgkin's disease and Vietnam service.
AB  - Earlier studies that showed an association between exposure to phenoxy herbicides
      and the risk of malignant lymphomas have sparked concerns among Vietnam veterans
      over Agent Orange exposure. The Department of Veterans Affairs (VA) undertook a
      hospital-based case-control study to examine the association between military
      service in Vietnam and several histologic types of malignant lymphomas. This is a
      report of 283 Vietnam-era veteran patients who were treated in one of 172 VA
      hospitals from 1969 to 1985 with a diagnosis of Hodgkin's Disease (HD). Four
      hundred and four Vietnam-era veteran patients with diagnosis other than malignant
      lymphoma served as a comparison group. Military service in Vietnam was not
      associated with any significant increase in the risk of HD (adjusted odds ratio =
      1.28; 95% confidence interval = 0.94, 1.76). Surrogate measures of potential
      Agent Orange exposure such as service in a specific military branch, in a certain
      region within Vietnam, in a combat role, or extended Vietnam service time were
      not associated with any significant increased risk of HD.

PMID- 8653214
TI  - Military service in Vietnam and the risk of death from trauma and selected
      cancers.
AB  - The postservice mortality of a cohort of 10,716 US Marine veterans who served in
      Vietnam was compared with that of 9,346 Marine veterans who did not serve in
      Vietnam. There was a significant excess of death for Vietnam Marines from all
      causes and all external causes. After adjustments for age and rank in military,
      overall mortality continued to be statistically significant, with a relative risk
      of 1.15 (95% confidence interval (CI) = 1.02 to 1.29) for Vietnam Marines
      compared to non-Vietnam Marines. All external causes was also significant, with a
      relative risk of 1.21 (95% CI = 1.00 to 1.47). The excess overall mortality was
      mainly due to excess deaths from external causes. The risks for several site
      specific cancers were elevated but not statistically significant. Periodic follow
      up of this Marine cohort should continue to determine whether there are
      statistically significant differences in the mortality patterns of Marine Vietnam
      and non-Vietnam veterans, especially for cancers.

PMID- 8653215
TI  - Food-frequency questionnaires. How far have we come and where are we going?

PMID- 8653216
TI  - Epidemiologic research on Vietnam veterans. Difficulties and lessons learned.

PMID- 8653217
TI  - Allergic and immunologic pediatric disorders of the eye.
AB  - Numerous allergic and immunologic disorders occur in the eyes and frequently
      present to nonophthalmologists. This article presents a review of ocular
      immunology, as well as the specific ocular and systemic disorders that are
      frequently seen. Also included is a discussion of some of the more common ocular
      disorders in the differential diagnosis of conjunctival inflammation. The
      treatment of these disorders is presented.

PMID- 8653219
TI  - Correlation between the clinical classification of bronchial asthma severity and
      the methacholine test in children.
AB  - The purpose of this study was to validate the Methacholine Bronchial Challenge
      Test in its different degrees and to compare them with the different clinical
      classifications of bronchial asthma. Fifty-four child asthmatic patients over 6
      years of age from the Respiratory Outpatient Clinic at La Union Hospital (Chile)
      were submitted to the clinical classification of bronchial asthma and later to
      the Methacholine Bronchial Challenge Test, which classified the children as
      mildly, moderately or severely hyperreactive to the test. In mildly asthmatic
      children, the Methacholine Test showed both a high sensitivity (100%) and
      specificity (92.3%). In moderately asthmatic children, the sensitivity decreased
      to 84.5%, whilst the specificity was maintained (92.3%). In severely asthmatic
      children, however, the sensitivity decreased to 53.5%, whilst the specificity
      increased 97.2%. The latter could be explained as a consequence of the previous
      exposure of this group of children to either inhaled or oral corticoids.
      According to our experience, the Methacholine Test is not only useful for the
      diagnosis of bronchial hyperreactivity in dubious cases, but also for
      contributing together with the clinical findings to the adequate classification
      of these patients.

PMID- 8653220
TI  - Immunotherapy with a standardized Dermatophagoides pteronyssinus glutaraldehyde
      modified extract against an unmodified extract: a comparative study of efficacy,
      tolerance and in vivo and in vitro modification of parameters.
AB  - We comparatively studied clinical efficacy, tolerance and modifications of
      different in vivo and in vitro parameters induced by two biologically
      standardized Dermatophagoides pteronyssinus extracts (HEP units), one
      glutaraldehyde-modified, in patients with allergic rhinitis and/or bronchial
      asthma after a year of treatment. A decrease in drug consumption was observed in
      both treatment groups (p < 0.0001). Of all the in vivo parameters studied
      (cutaneous, conjunctival and bronchial reactivity to the allergen), a decrease in
      specific bronchial reactivity was only observed in the group treated with the
      modified extract (p < 0.05). The modifications in total IgE, specific IgE and
      specific total IgG levels are superimposable on those described in previous
      papers on immunotherapy. However, IgG4 levels remained stable with respect to
      time. Tolerance was good and very similar for both treatments; both types of
      extracts are equally efficacious and safe.

PMID- 8653218
TI  - Lepidoglyphus destructor acarus in the urban house environment.
AB  - To assess the presence of Lepidoglyphus destructor in the household environment
      of sensitized children living in an urban environment, samples of house dust were
      collected at the homes where two groups of patients were living, as well as in
      two bakeries in the city of Valencia, which were taken as a reference. Patients
      were divided into two groups. Group A included atopic children suffering from
      rhinitis and/or asthma, who were sensitized to L. destructor, as proven by prick
      test and specific IgE (CAP). Group B included children with the same features as
      those included in Group A, who were sensitized to Dermatophagoides pteronyssinus,
      with prick and CAP tests showing no significant sensitization to L. destructor.
      The samples of dust were analyzed, and the amounts of Der p I, Der f I, Der II
      and Lep d I per gram of dust were assessed through a solid-phase ELISA with
      monoclonal antibodies. In Group A, all patients but two showed a sensitization to
      D. pteronyssinus by prick test and serum IgE. At the homes of the patients from
      both groups, significant levels of Dermatophagoides were found. In Group A, only
      three houses showed levels of L. destructor which were comparable to those found
      in bakeries. Lep d I was not found in the houses of Group B patients. This means
      that a sensitization to L. destructor, as assessed with full extracts, is not
      always an indicator of its presence at the patient's house environment; it may
      rather refer to cross-reactivity to Dermatophagoides. Thus, availability of the
      main antigen Lep d I seems necessary to increase the specificity of the
      allergologic study.

PMID- 8653221
TI  - Nasal mucociliary clearance in perennial rhinitis.
AB  - Mucociliary clearance is one of the homeostatic systems of the respiratory
      mucosa. Alterations in mucociliary clearance have been extensively studied in
      asthma, but less frequently in allergic rhinitis. In rhinitis, conflicting
      results have arisen: while some authors reported no change, others noticed a
      reduction in nasal mucociliary clearance. The aim of this study was to compare
      the nasal mucociliary clearance in allergic and non-allergic patients with
      perennial rhinitis and a healthy control group. One hundred and three patients
      and 14 healthy control subjects were studied. Nasal mucociliary clearance was
      assayed with the saccharin test modified with a food dye to add a visual
      parameter. Patients were divided into allergic and non-allergic rhinitis
      according to the presence of three of the following factors: total serum IgE
      above 180 KIU/L, positive skin prick tests to a battery of standardized allergens
      relevant to Uruguay, family and personal history of atopic diseases, and blood
      eosinophilia above 450 cells/mm3. The aspect of the nasal mucosa was not
      considered for categorizing the patients. Fifty-seven patients (29 males, mean
      age: 22.2 years) with allergic perennial rhinitis and 46 patients (15 males, mean
      age: 24.8 years) with non-allergic perennial rhinitis were compared with 14
      controls (6 males, mean age: 35 years). A significant difference in nasal
      mucociliary clearance was observed between the three groups, with a mean of 8.8
      minutes for the controls, 10.27 minutes for allergic rhinitis and 11.73 minutes
      for non-allergic patients. We suggest that the differences we observed were due
      to changes in the rheology of nasal mucus as a consequence of the underlying
      inflammatory process in rhinitis.

PMID- 8653222
TI  - Application of a fluorochrome-lysostaphin assay to the detection of phagocytic
      and bactericidal disturbances in human neutrophils and monocytes.
AB  - The evaluation of phagocytic and microbicidal activities of the blood neutrophils
      has been recognized as one of the important tools for investigating phagocytic
      dysfunctions in patients with recurrent infections. In the present study, these
      activities were examined in neutrophils and monocytes from healthy adults and
      patients affected by primary phagocytic dysfunctions by using a modified
      fluorochromic microbicidal assay, discriminating simultaneously the extracellular
      adherence, ingestion and intracellular killing of Staphylococcus aureus Cowan I.
      The assay employs acridine orange staining, as described in Bellinati-Pires et
      al. (1989) (AO assay), but was modified by the addition of an alternative
      leukocyte treatment with 0.5 U/ml of lysostaphin (LS) for 5 min at 37 degrees C,
      after phagocytosis (AO-LS assay). The LS treatment was standardized to eliminate
      staphylococci adhered to the outer surface of the phagocytes without affecting
      the determination of intracellular live or dead bacteria, as demonstrated in
      normal neutrophils and monocytes. Our purpose in this study was to compare AO and
      AO-LS assays in order to evaluate the effect of LS on the determination of
      actually ingested staphylococci and to provide a means for improving the
      fluorochromic assay for detecting phagocytic defects, as well as bactericidal
      disturbances. By using the AO-LS assay, decreased ingestion of staphylococci by
      neutrophils in Chediak-Higashi Syndrome (CHS) was demonstrated. However,
      increased staphylococci adherence, as well as ingestion, was observed in
      neutrophils or monocytes from chronic granulomatous disease (CGD) patients,
      comparing AO and AO-LS assays. Bactericidal defect, which is a common feature in
      CHS and CGD, was detected in neutrophils or monocytes in both assays. We
      emphasize that such alterations were deduced by comparing the patients' results
      with those obtained from their respective normal controls and with the normal
      range of values previously established for 160 healthy adults. No alteration was
      observed in hyper IgE syndrome phagocytes. Despite the possible penetration of LS
      into the leukocytes, as stated in other studies, we concluded that a short period
      of phagocyte incubation with this enzyme increased the sensitivity of the
      fluorochromic assay to detect phagocytic defect without affecting the
      determination of the bactericidal activity. Moreover, comparations between AO and
      AO-LS assays may be important in the study of the initial pathways of
      staphylococci phagocyte interaction, including adherence by non-phagocytic
      receptors.

PMID- 8653223
TI  - Is mast cell activation during asthmatic reaction reflected in the circulation?
AB  - Allergic asthmatic patients were challenged with specific allergen that resulted
      in early asthmatic reaction (EAR). Serum tryptase concentration (STC) and
      neutrophil chemotactic activity (NCA) were measured before and during EAR. A
      significant increase in neutrophil chemotactic activity was noticed in the 60th
      min, without an accompanying increase in serum tryptase concentration. The rise
      in neutrophil chemotactic activity in our study confirms previous observations in
      this field. However, because of the numerous cellular sources for neutrophil
      chemotactic activity, it does not seem to be a gold standard for measurement of
      mast cell activation. Undetectable levels of serum tryptase concentration during
      EAR in our study do not exclude the role of the mast cell in its pathogenesis. To
      our knowledge, only massive mast cell degranulation is reflected in the
      circulation as an increased tryptase concentration. In the case of upper
      respiratory allergic reactions, mast cell degranulation definitely takes place,
      but does not result in evident changes in serum tryptase concentration. We
      conclude that mast cell activation during allergen-induced EAR is poorly
      represented in the circulation.

PMID- 8653224
TI  - The value of the lymphocyte proliferation test with phytohemagglutinin in the
      immune evaluation of Brazilian HIV-infected patients.
AB  - We evaluated phytohemagglutinin (PHA) lymphocyte proliferation and delayed-type
      hypersensitivity tests in 130 Brazilian HIV-infected patients with the objective
      of assessing the value of these tests in staging HIV infection. Patients were
      divided into three groups according to their CD4+ cell counts (cells/mm3): < 200
      (n = 28); 200 to 499 (n = 50); and > or = 500 (n = 52). An additional 114
      individuals, who had come to the same institution for elective surgeries, were
      enrolled as controls. Results showed a significant decrease in PHA responses when
      CD4+ cell counts fell below 500 cells/mm3. This decrease was, however,
      indistinguishable from that of patients with < 200 cells/mm3. In contrast, skin
      test anergy to common antigenic preparations was only evident in the group of
      patients with less than 200 CD4+ cells/mm3. Decreases in PHA responses and in
      CD4+ cell counts were significantly correlated. Since the introduction of
      antiretroviral therapy is recommended when CD4+ cell counts are below 500
      cells/mm3, the PHA proliferation test, in our conditions, could be useful as an
      additional parameter to initiate antiretroviral therapy. Further prospective
      studies are needed to establish the value of this test in HIV-infected patients.

PMID- 8653225
TI  - Impaired response to HBcAg in a hepatitis B virus carrier.
AB  - Hepatitis B virus (HBV) carriers usually produce antibody to HB core antigen
      (anti-HBc). We present the case of an HBV carrier who has lacked anti-HBc for a 2
      year observation period. Antibody titers against several common viruses (herpes
      simplex virus-1, varizella-zoster virus and Epstein-Barr virus) were detected in
      his serum. His lymphocytes proliferated in vitro in response to
      phytohemagglutinin and concanavalin A. In contrast to other naturally immune or
      chronic HBV carriers, anti-HBc was not produced by his peripheral mononuclear
      cells (PBMC) in culture supernatant of pokeweed mitogen-induced anti-HBc
      production system. These results suggested that he was in a state of impaired
      specific antibody response to HB core antigen (HBcAg).

PMID- 8653226
TI  - Comparative performance for immediate hypersensitivity skin testing using two
      skin prick test devices.
AB  - Fifty-five patients were skin-tested by Multi-Test (M) and needle prick test
      (NPT) to compare the reproducibility of the methods. We used 6 allergenic
      extracts: Dermatophagoides pteronyssinus, Dermatophagoides farinae, dog
      epithelium, cat pelt, American cockroach and mixed molds. A glycerosaline and a
      positive control (histamine 1 mg/ml) were performed in both methods.
      Statistically significant differences in histamine and Dermatophagoides farinae
      wheal reactions between the two methods (M > NPT) were found, with no differences
      with the other allergenic extracts. We concluded that the two methods are similar
      with respect to determining the immediate hypersensitivity, but the Multi-Test is
      better accepted by children.

PMID- 8653227
TI  - Quantitative three-dimensional confocal imaging of the cornea in situ and in
      vivo: system design and calibration.
AB  - A new depth encoding system (DES) is presented, which makes it possible to
      calculate, display, and record the z-axis position continuously during in vivo
      imaging using tandem scanning confocal microscopy (TSCM). In order to verify the
      accuracy of the DES for calculating the position of the focal plane in the cornea
      both in vitro and in vivo, we compared TSCM measurements of corneal thickness to
      measurements made using an ultrasonic pachymeter (UP, a standard clinical
      instrument) in both enucleated rabbit, cat, and human eyes (n = 15), and in both
      human patients (n = 7). Very close agreement was found between the UP and TSCM
      measurements in enucleated eyes; the mean percent difference was 0.50 +/- 2.58%
      (mean +/- SD, not significant). A significant correlation (R = 0.995, n = 15, p <
      0.01) was found between UP and TSCM measurements. These results verify that the
      theoretical equation for calculating focal depth provided by the TSCM
      manufacturer is accurate for corneal imaging. Similarly, close agreement was
      found between the in vivo UP and TSCM measurements; the mean percent differences
      was 1.67 +/- 1.38% (not significant), confirming that z-axis drift can be
      minimized with proper applanation of the objective. These results confirm the
      accuracy of the DES for imaging of the cornea both ex vivo and in vivo. This
      system should be of great utility for applications where quantitation of the
      three-dimensional location of cellular structures is needed.

PMID- 8653228
TI  - Advantages of backscatter electron imaging scanning electron microscopy for
      intracellular localization of cardiac analytes by gold conjugated antibody.
AB  - Myoglobin and myosin light chain 1 (MLC1) are intracellular human cardiac marker
      proteins which are released as a consequence of ischemia. Human cardiomyocytes
      were isolated from fresh biopsies and also maintained for several passages in
      cell culture. The cardiomyocytes were fixed in 100% methanol at -20 degrees C,
      and labeled. The immunolocalization of intracellular antigen by fluorescence
      conjugated imaging was compared with scanning electron microscopy (SEM)
      backscatter electron (BSE) imaging of gold conjugated antibody. Ultra-violet
      light microscopy showed the intracellular distribution of both proteins to be
      mainly in the nuclear envelope, the cytoplasm immediately surrounding the nucleus
      and along portions of the cell membrane. To confirm this observed distribution of
      myoglobin and MLC1, labeling was repeated with antimyoglobin and anti-MLC1
      monoclonal antibodies conjugated to colloidal gold particles. The advantage of
      colloidal gold labeling is that the intracellular antigen-antibody complexes may
      be more precisely located because of the significant improvement in resolution
      provided by BSE imaging in the SEM. BSE imaging confirmed the presence and
      subsarcolemma localization of myoglobin in cardiomyocytes directly isolated from
      fresh biopsies. The distribution of colloidal gold-conjugated antibodies did not
      coincide with the intracellular distribution of the two proteins in the
      cardiomyocytes grown in cell culture as indicated by immunofluorescence. A
      relatively random, intracellular gold particle distribution was confirmed by x
      ray microanalysis. BSE imaging resulted in consistent auto-backscatter labeling
      patterns very similar to the labeling patterns obtained with immunofluorescent
      labeling. X-ray microanalysis confirmed that these auto-backscatter labeling
      patterns were formed by concentrations of intracellular phosphate. Sodium dodecyl
      sulfate-poly-acrylamide gel electrophoresis (SDS-PAGE) and subsequent Western
      blotting indicated that myoglobin and MLC1 were no longer present in detectable
      quantities in these cells after several passages. Polymerase chain reaction (PCR)
      amplification of mRNA for human myoglobin and cardiac MLC1 confirmed the absence
      of their transcripts. Electrophoretic analysis of proteins in cardiomyocytes
      grown in cell culture confirmed an increasing presence of alkaline phosphatase.
      Staining of this enzyme with 5-bromo-4-chloro-3-indolyl phosphate and nitroblue
      tetrazolium showed that alkaline phosphatase was distributed in the same
      intracellular pattern as the fluorescence conjugated anti-body and the
      phosphatase auto-backscatter. These results indicate that high-resolution
      backscatter SEM imaging may be used as necessary control to confirm fluorescence
      light microscope intracellular labeling of antigens.

PMID- 8653229
TI  - Suicide rate following attendance at an accident and emergency department with
      deliberate self harm.
AB  - OBJECTIVE: To determine the risk of suicide in patients attending an accident and
      emergency (A&E) department with deliberate self harm. METHODS: Information was
      obtained on suicides and open verdicts from the coroner's office and cross
      checked with computerised records in the A&E department. RESULTS: There was a
      trend to suicide among younger socially isolated males and older females.
      CONCLUSIONS: There is a significant association between suicide and a previous
      attendance at A&E with deliberate self harm. Appropriate assessment of these
      patients is an efficient way of managing self harm.

PMID- 8653230
TI  - Is fasting necessary before prilocaine Bier's block?
AB  - OBJECTIVE: To determine whether fasting is necessary before intravenous regional
      anaesthesia (Bier's block). METHODS: A questionnaire study was carried out to
      assess accident and emergency (A&E) departments' policies and opinions in
      relation to Bier's block anaesthesia. Questionnaires were sent to 282 A&E
      consultants, of whom 216 replied (77% response rate). RESULTS: About 5000 Bier's
      block procedures are carried out each year in the United Kingdom. Intravenous
      regional anaesthesia appears safe. Over one third of units did not fast their
      patients. The complication rate was similar in fasted and unfasted groups.
      CONCLUSIONS: Starvation of the patient before intravenous regional anaesthesia is
      not necessary and should be abandoned.

PMID- 8653231
TI  - "Fast tracking" patients with a proximal femoral fracture.
AB  - OBJECTIVE: To assess the management of elderly patients presenting to the
      accident and emergency (A&E) department with a proximal femoral fracture.
      METHODS: A retrospective audit carried out on 30 patients with proximal femoral
      fracture showed an unacceptably long waiting time in the A&E department. A new
      "fast track" system for managing these patients, involving the use of a flow
      chart for expediting admission, was devised. A prospective study of 100 patients
      > 60 years of age with proximal femoral fracture admitted by fast track system
      was then carried out. RESULTS: Implementation of the fast track system resulted
      in earlier admission to the ward (median time to admission 2.5 h v 4.5 h in the
      retrospective audit, P < 0.001). Eighteen patients were not admitted by fast
      track during the study period, in some cases because of inconclusive diagnosis or
      because there was no identifiable orthopaedic bed; mean admission time for this
      group was 4 h 8 min. CONCLUSIONS: The fast track system was of benefit to all
      involved, including the patient, A&E staff, ward staff, and orthopaedic
      personnel.

PMID- 8653232
TI  - The value of accident and emergency based physiotherapy services.
AB  - OBJECTIVE: To investigate whether accident and emergency (A&E) department based
      physiotherapy has any advantages over its traditional counterpart in providing
      treatment for soft tissue injuries. METHODS: Two A&E departments were compared:
      hospital A had a traditional physiotherapy service, while hospital B had A&E
      based physiotherapy. Groups of adult patients from these two hospitals were
      compared over a one month period. Data on injuries, number of physiotherapy
      treatment sessions, and outcome were recorded. RESULTS: There were 27 referrals
      for physiotherapy in hospital A during the study period (1.17% of attendances)
      and 111 referrals in hospital B (4.03%) (P < 0.001). The waiting time for
      physiotherapy was significantly less at hospital B (3 v 7 d, P < 0.001) despite a
      far greater number of patients referred. Non-referral at the hospital with the
      traditional service was due to a perceived long waiting time by the referring
      doctors. Patients with longer waiting times were found to be less likely to
      attend their first appointment, and this was therefore more common in the
      hospital with the traditional service (39.5% v 9.8%). CONCLUSIONS: An A&E based
      physiotherapy service results in a greater referral rate and a shortened time
      between referral and first treatment. Further research is needed to evaluate and
      compare long terms outcomes following treatment by both types of physiotherapy
      service.

PMID- 8653233
TI  - Patients' knowledge about their drug allergies.
AB  - OBJECTIVE: To investigate the nature and accuracy of information carried by
      patients about their drug allergies. SUBJECTS: 2500 new adult patients. SETTING:
      Accident and emergency department of a tertiary referral centre. METHODS:
      Patients were questioned about drug allergies. Where they claimed allergies,
      general practitioners were contacted for corroboration. RESULTS: 242 patients
      (9.7%) claimed 276 allergies; 32 different drugs were implicated. Penicillin was
      implicated most often (151 patients); 38 patients could not remember what they
      were allergic to; 21 described severe reactions, but four could not remember the
      drugs involved. Only seven patients carried evidence of their allergies. General
      practitioners were contacted about 240 of the drug allergies; only 114 were
      confirmed as described. CONCLUSIONS: Many patients who believe themselves to have
      drug allergies are poorly informed about them. Emergency prescribing for these
      patients may risk anaphylaxis. The future acceptance of "Smart cards"would reduce
      this risk. In the meantime, patients with drug allergies should be strongly
      encouraged to carry evidence of their allergies.

PMID- 8653234
TI  - An accident and emergency based child accident surveillance system: is it
      possible?
AB  - OBJECTIVE: To evaluate the possibility of setting up a database on childhood
      accidents within an accident and emergency (A&E) department. DESIGN: A proforma
      detailing epidemiological details about the child and details of the injury was
      designed and tested for accuracy. It was completed in parallel with the existing
      case documentation. A retrospective sample was analysed after completion of the
      study to determine times when data collection was poorest. SETTING: Regional
      paediatric hospital (total catchment population c. 500,000). RESULTS: Of 13,958
      patients in whom full information was available, 65% had all the information
      available on the forms. Areas of discrepancy in the remainder included (1)
      transposition of date and time of injury with date and time of attendance (73%),
      (2) wrong coding (11%), (3) illegible digits (6%), (4) inaccurate data entry to
      computer (6%). Form completion was worst between 1800 hours and midnight.
      CONCLUSIONS: Data collection is feasible in the A&E department and is a necessary
      step in effective child accident prevention. It should be done using real time
      entry onto computer systems. Additional audit staff must be employed to ensure
      data collection is as complete as possible as close to the time of the initial
      attendance as possible. Regular analysis of the findings is essential.

PMID- 8653236
TI  - Do the national performance tables really indicate the performance of accident
      and emergency departments?
AB  - OBJECTIVE: To determine the current practice of nurse triage in accident and
      emergency departments in England, and to examine the relation between triage
      systems and performance in the Department of Health comparative performance
      guide. DESIGN: A postal questionnaire was sent to all consultants in accident and
      emergency medicine in England. RESULTS: 151 responses were analysed, representing
      72% of the departments seeing at least 15,000 new patients annually. Triage
      systems vary widely throughout departments, ranging between advanced triage,
      partial triage, and "eyeballing". There is no standardisation of the process or
      duration of triage. There appears to be no standard method of measuring the time
      to immediate assessment. There is no correlation between the quality of initial
      assessment and performance in the tables. CONCLUSION: The national performance
      figures do not correlate with the quality of the initial assessment; comparisons
      based on these figures are therefore misleading. More effective performance
      indicators are available, which would provide a truer indication of the quality
      of accident and emergency services.

PMID- 8653237
TI  - Rules for collection of clinical data: the eight Rs.
AB  - Many reports in medical journals give advice on statistical analysis of data
      collected in clinical studies. The terms used are statistical, and clinicians
      often ponder how their data stand up to these analyses. Eight simple, easy to
      remember words are suggested that will help clinicians both to interpret their
      own data and to assess the accuracy of presented or published data.

PMID- 8653235
TI  - Topical anaesthesia for children's lacerations: an acceptable approach?
AB  - OBJECTIVE: To compare the anaesthetic properties of conventional intradermal 1%
      plain lignocaine with a topical gel preparation of adrenaline (1:2000) and
      cocaine (4.7%) for use in treatment of children's lacerations. METHODS: Children
      aged 3-16 years with lacerations (not of the digits or mucous membranes) were
      consecutively assigned to receive either adrenaline and cocaine (AC) or
      lignocaine. Pain scores, as perceived by patients, parents, and staff, were
      measured conventionally using Wong Baker faces and visual analogue scales on
      administration of the local anaesthetic and on suturing the wound in the AC group
      (n = 56) and the lignocaine group (n = 51). RESULTS: Mean and median pain scores
      on administration of the anaesthetic in the AC group were significantly lower
      than in the lignocaine group as perceived by patient (P < 0.001), parent (P <
      0.001), and staff (P < 0.001). There was no significant difference in mean and
      median pain scores between the two groups on suturing the wounds, as perceived by
      patient, parent and staff. There was a significantly higher number of "failed"
      anaesthetics (pain scores 8-10) in the lignocaine group (P < 0.01). On direct
      questioning the overall procedure was considered acceptable by 84.5% of parents
      in the AC group compared with 61% of parents in the lignocaine group (P < 0.01).
      There were no significant complications in either group. CONCLUSIONS: Topical AC
      should be considered the local anaesthetic of first choice for suturing
      appropriate children's lacerations.

PMID- 8653238
TI  - A survey of teaching and the use of clinical guidelines in accident and emergency
      departments.
AB  - OBJECTIVE: To investigate organised teaching in accident and emergency (A&E)
      departments in England and Wales. METHODS: A survey was carried out by postal
      questionnaire. Directed to senior house officers (SHOs), the questionnaire
      examined the nature and extent of departmental teaching, and measured the
      availability, suitability, and actual use made of guidelines. Of 231
      questionnaires sent, 164 were returned (response rate 71%). RESULTS: The results
      show that most SHOs attended A&E induction courses at the beginning of their
      attachments, although the scope of these coursed varied widely. Most SHOs also
      received regular teaching, although the programmes were generally of less than 3
      h in duration. The majority of respondents were well supported with written
      documentation in a variety of formats. However, a significant minority (29%) of
      SHOs requested more detailed clinical guidance, and these tended to be the
      respondents who received the most departmental teaching. CONCLUSIONS: More time
      could be allocated to structured teaching than at present, and greater use made
      of complementary educational methods such as practical skill teaching, case
      presentation, clinical audit, and involvement in journal clubs. More extensive
      departmental teaching should also be supported by making available more detailed
      and comprehensive clinical guidelines.

PMID- 8653239
TI  - The swimmer's nose clip in epistaxis.

PMID- 8653240
TI  - Near hanging presenting to an accident and emergency department.
AB  - Victims of near hanging are being increasingly seen in accident and emergency
      (A&E) department. This paper reports on seven cases of near hanging seen over
      four years in a district general hospital. The mechanism of injury is ligature
      strangulation rather than cervical spinal cord injury. All cases of near hanging
      should be actively and vigorously resuscitated, as initial presenting features
      bear a poor correlation to eventual outcome.

PMID- 8653241
TI  - Munchausen syndrome presenting as major trauma.
AB  - The case is described of a man who feigned being struck by a vehicle, leading to
      an unnecessary major trauma response by the ambulance service and hospital.
      Suspicion that the patient suffered from Munchausen syndrome was confirmed by
      later investigation. Accident and emergency staff should file details of such
      patients on the department computer records system, where available, so that
      staff are alerted automatically to their presence, and share this information
      with neighbouring hospitals. All such patients should be treated according to
      ATLS guidelines until injury is ruled out, as for any other patient.

PMID- 8653242
TI  - Hair thread tourniquet syndrome.
AB  - Tourniquet of hair and thread fibres may become tightly wrapped around a child's
      digit. The resultant ischaemia may lead to tissue necrosis and autoamputation.
      Experience with two patients is reported. The need for prompt recognition and
      complete removal of all fibres is stressed. The possibility of non-accidental
      injury should be born in mind.

PMID- 8653243
TI  - Weever fish stings: a report of two cases presenting to an accident and emergency
      department.
AB  - Two patients are described who suffered weever fish stings and presented to an
      accident and emergency department. The characteristic symptoms and treatment are
      described.

PMID- 8653244
TI  - Lumps, bumps and soft tissue sarcomas.
AB  - A case of soft tissue sarcoma in a young person is described. Accident and
      emergency workers should be aware of this highly malignant group of tumours.
      Lumps in young people should not necessarily be assumed to be benign without a
      definite histological diagnosis.

PMID- 8653245
TI  - Health care resource groups in accident and emergency medicine.

PMID- 8653246
TI  - Advanced life support courses.

PMID- 8653247
TI  - Benefits of immediate printing of blood test results within an A&E department.

PMID- 8653248
TI  - Anaphylactic shock.

PMID- 8653249
TI  - Chest drain insertion.

PMID- 8653250
TI  - Paracetamol overdose.

PMID- 8653251
TI  - The patient's charter.

PMID- 8653252
TI  - Detection of aluminium ring pulls.

PMID- 8653253
TI  - Finding and removing small foreign bodies: a new technique for A&E.

PMID- 8653254
TI  - Advances in the early diagnosis and management of acute myocardial infarction.
AB  - The effective early diagnosis of acute myocardial infarction still rests
      primarily on the clinical history and the electrocardiogram. ST segment elevation
      is specific though sometimes short lived and less than ideally sensitive; but
      with bundle branch block it defines a population that benefits importantly from
      thrombolysis. Novel electrode configurations can further enhance diagnosis but
      have not become popular. Biochemical markers are rarely of help in the first four
      hours and cardiac scanning is impractical for routine care. Computerised
      diagnostic systems show promise in prototype but are not widely available. Early
      management involves reestablishing coronary flow by thrombolytic and
      antithrombotic agents and reducing myocardial oxygen requirement by analgesics
      and beta blockers. Nitrates and magnesium have limited roles. Immediate access to
      defibrillation and advanced life support is mandatory. Diagnosis and management
      can only begin after help has been sought. Public alertness to the symptoms of
      myocardial infarction and a coordinated response by health care personnel are
      fundamental to successful care.

PMID- 8653255
TI  - Computerised tomography and acute traumatic head injury: time for change?
AB  - The aim was to reconsider the "Guidelines for initial management of head injury
      in adults"--particularly with respect to the indications for computerised
      tomographic (CT) scanning--suggested by "a group of neurosurgeons" over a decade
      ago and still followed in some accident and emergency (A&E) departments. These
      recommendations are placed in the context of more recent research and the
      increased number of A&E departments with on-site rapid access to a CT scanner but
      without a resident neurosurgical facility. A case can be made for an updated
      policy with more liberal indications for CT scanning of acutely head injured
      adults in peripheral A&E departments. However, calculating the cost-efficiency of
      more frequent use of what is now a common but relatively expensive resource would
      remain a challenge.

PMID- 8653256
TI  - Should accident and emergency nurses request radiographs? Results of a
      multicentre evaluation.
AB  - OBJECTIVE: To evaluate whether waiting time in accident and emergency (A&E)
      departments is shortened when experienced nurses request peripheral limb
      radiographs before a patient is assessed by a doctor. DESIGN: Simultaneous
      prospective trial in four A&E departments in the United Kingdom with doctors and
      nurses requesting radiographs; 2000 patients were randomly allocated to either a
      "Nurse First" or "Doctor First" category. SUBJECTS: Patients older than 5 years
      presenting with recent peripheral limb injuries. MAIN OUTCOME MEASURES: Timing of
      the various stages of a patient's passage through the A&E department comparing
      the orthodox route with a group of patients in whom an experienced A&E nurse had
      the option of requesting a radiograph before a medical assessment. RESULTS: There
      was a significant reduction in the time spent in A&E when no radiograph was
      requested (P << 0.001). The mean time saved in the "Doctor First" (DF) group was
      51 min, and in the "Nurse First" (NF) group 36 min. For those who were sent for
      an x ray 14 min was saved by getting the patient to see the nurse first. However,
      because the overall referral rate for x rays was greater in the NF group, (78% of
      patients compared with 74% of the DF group, a significant 4% increase (P = 0.05)
      this potential benefit was largely lost. Overall the average waiting time in the
      DF group of 92.5 min (95% confidence interval: 89.2 to 96.1 min) was reduced to
      88.5 min (95% CI:85.2 to 91.8 min) in the NF group, a non-significant saving of 4
      min. There was no overall difference between the proportion of relevant
      abnormalities reported by the radiologists for the DF or NF groups (G2 = 0.739,
      1df, P = 0.30); however, there was a significant association between the number
      of relevant abnormalities reported by the radiologists and the different
      hospitals (G2 = 9.7626, 3df, P = 0.02). Hospital C had the highest abnormality
      rate reported by the radiologists in both the DF (45%) and the NF (51%) groups.
      The most time saved in A&E was in the DF category when comparing those who did
      not have an x ray [58 (CI 54-63) min] with those who did [109 (CI 104-114) min],
      a saving of 51 min. The corresponding time saved in the NF category between those
      who did not have an x ray [59 (CI 53-65) min] and those who did [95 (CI 91-99)
      min] was 36 min. CONCLUSIONS: 14 min can be saved by getting the patient to see
      the nurse first; however, because nurses in three out of four hospitals requested
      more radiological examinations than doctors, overall only 4 min waiting time was
      saved when peripheral limb radiographs were requested by nurses. The findings are
      somewhat against expectations but do identify that specific training and constant
      monitoring is essential if nurses are to request peripheral limb radiographs, as
      reflected in hospital C results.

PMID- 8653257
TI  - Interhospital transfer of the critically ill trauma patient: the potential role
      of a specialist transport team in a trauma system.
AB  - A specialist transfer team based in the regional intensive therapy unit (ITU) at
      the Western Infirmary, Glasgow, acts as a central interhospital retrieval team
      for Glasgow and the west of Scotland. The establishment of trauma systems has
      been proposed. This paper describes the activities of the specialist transfer
      team to illustrate the potential role of a central retrieval team within such a
      system.

PMID- 8653259
TI  - Decision making in resuscitation from out of hospital cardiac arrest.
AB  - OBJECTIVE: To determine which factors are perceived by senior house officers
      (SHOs), consultants, and medical registrars in accident and emergency (A&E)
      medicine as being important in decision making. METHODS: 132 SHOs in A&E
      medicine, of 172 attending an induction course at the start of their job (77%),
      completed a questionnaire relating to 20 factors of possible importance in
      decision making; 73 completed the questionnaire at six weeks and 55 at six
      months. Ten medical registrars and 31 consultants in A&E medicine also completed
      the questionnaire. RESULTS: The SHOs were able to recognise bystander
      cardiopulmonary resuscitation and early advanced I support, as well as the
      presence of ventricular fibrillation, as important prognostic factors. There was
      considerable variation in all three groups in their opinions on the importance of
      the other factors considered. There was no obvious change in SHO responses over
      the period of training. CONCLUSIONS: Lack of guidelines may result in more
      patients receiving resuscitation than are salvageable, as doctors maintain a low
      threshold for continuing resuscitation to avoid missing potential survivors. A
      decision making algorithm is recommended.

PMID- 8653258
TI  - Effect of a preprinted form on the management of acute asthma in an accident and
      emergency department.
AB  - OBJECTIVE: To assess the effect of a preprinted form on the documentation of
      clinical data and compliance with the national guidelines for the management of
      asthma. METHODS: Prospective audit six months before and after introduction of
      the form. RESULTS: Use of the form improved the documentation of past asthma
      history (69% v 93%, P < 0.001), current treatment (81% v 95%, P < 0.01),
      predicted peak flow (23% v 75%, P < 0.001), per cent predicted peak flow (1% v
      62%, P < 0.001), and respiratory rate (81% v 95%, P = 0.007). Compliance with the
      British recommendations for treatment improved with use of the form (50% v 89%, P
      < 0.001) The prescription of steroids on discharge did not improve significantly
      (26% v 44%, P > 0.05). CONCLUSIONS: The preprinted form resulted in enhanced
      documentation of data and conformity with current guidelines for the management
      of asthma.

PMID- 8653260
TI  - [Recommendations for the treatment of asthmatic crisis].

PMID- 8653261
TI  - [Recommendations for education of patients with asthma].

PMID- 8653262
TI  - [Recommendations for the use of inhaled drugs].

PMID- 8653263
TI  - Molecular analysis of the structure of the maize B-chromosome.
AB  - The overall composition of the maize B is similar to that of the standard
      chromosome complement (A-chromosomes). This has been demonstrated by the use of
      several methods including: (a) genomic in situ hybridization (GISH), (b) analysis
      of highly repetitive sequences by the comparison of restriction digests of 0B and
      +B DNA and (c) the characterization of middle-repetitive cloned sequences. By the
      use of the technique of random amplification of polymorphic DNA-polymerase chain
      reaction, we have identified a B-specific repetitive sequence family. Sequence
      analysis of the B-specific clone reveals a relationship to the PREM-1 family of
      maize retroelements, which are preferentially transcribed in pollen. These
      results suggest an internal origin of the B-chromosome from within the maize
      genome, but demonstrate also that specific sequences can evolve by rapid
      processes of genomic turnover. Models for the origin of the maize B are discussed
      in the context of the present data.

PMID- 8653264
TI  - Preparation of tomato meiotic pachytene and mitotic metaphase chromosomes
      suitable for fluorescence in situ hybridization (FISH).
AB  - Fluorescence in situ hybridization (FISH) is an increasingly powerful tool with a
      variety of applications in both basic and applied research. With excellent
      genetic, cytogenetic and molecular maps available, the tomato genome provides a
      good model to benefit from the full potential of FISH. Tomato chromosomes at
      mitotic metaphase are small and not particularly suitable for high-resolution
      FISH. In contrast, chromosomes at meiotic pachytene are about 15 times longer,
      and easier to identify by their differences in chromosome arm lengths and
      chromomere pattern. We have developed a technique for preparing chromosomal
      spreads of young pollen mother cells at mid-prophase I which is suitable for
      FISH. In a first series of experiments, the hybridization patterns of three
      classes of repetitive DNA sequences were studied in single and multicolour FISH.

PMID- 8653265
TI  - Chromosome complement, C-banding, Ag-NOR and replication banding in the zebrafish
      Danio rerio.
AB  - The chromosome complement of Danio rerio was investigated by Giemsa staining and
      C-banding, Ag-NORs and replication banding. The diploid number of this species is
      2n = 50 and the arm number (NF) = 100. Constitutive heterochromatin was located
      at the centromeric position of all chromosome pairs. Nucleolus organizer regions
      appeared in the terminal position of the long arms of chromosomes 1, 2 and 8.
      Replication banding pattern allowed the identification of each chromosome pair.

PMID- 8653266
TI  - Mapping of 22 Notl linking clones on human chromosome 3 by polymerase chain
      reaction and somatic cell hybrid panels.
AB  - Twenty-two human chromosome 3 derived and partially sequenced Notl linking clones
      were mapped using two somatic cell hybrid panels. Somatic cell hybrid mapping was
      performed by Southern hybridization and/or by polymerase chain reaction (PCR),
      using 300-500 bp CpG-rich sequences surrounding Notl sites. Thus, 22 new Notl
      site-tagged (sequence tagged sites) STSs were created, distributed over the
      entire human chromosome 3. The majority of these linking clones tag known or
      unknown expressed sequences (genes). Together with other physical and genetic
      mapping methods, localization of Notl linking clones facilitates the construction
      of a long-range physical map and, at the same time, a transcriptional map of
      human chromosome 3.

PMID- 8653268
TI  - Achiasmate segregation of X and B univalents in males of the grasshopper
      Eyprepocnemis plorans is independent of previous association.
AB  - B chromosomes proved to be more frequent in males than females of the grasshopper
      Eyprepocnemis plorans collected from the population in Jete (Granada, Spain) in
      1992. The meiotic behaviour of the X and B univalents was analysed in a high
      number of 1B males collected from this population in 1991 and 1992, and in males
      from another population (Salobrena, Granada, Spain) for comparison. These two
      chromosomes showed a significant tendency to migrate to opposite poles in the
      Jete population, during the 2 years analysed, but separated randomly in the
      Salobrena population. Thus, sex differences in the B frequency in Jete seemed to
      be due to the non-random X-B segregation during male meiosis. The analysis of
      association patterns between the two univalents over several stages of the first
      meiotic division indicated a heterochromatic affinity rather than association by
      chiasmata because most X-B associations had resolved by metaphase I. The X and B
      chromosomes share two different DNA sequences, so that some associations during
      prophase I undoubtedly involve homologous DNA sequences. The frequency with which
      X and B migrated to opposite poles at anaphase I in Jete, however, did not show
      any significant dependence on previous association at zygotene, diplotene or
      metaphase I.

PMID- 8653267
TI  - Comparative fluorescence in situ hybridization mapping of primate chromosomes
      with Alu polymerase chain reaction generated probes from human/rodent somatic
      cell hybrids.
AB  - We have used Alu polymerase chain reaction generated probes from rearranged
      human/rodent somatic cell hybrids for fluorescence in situ hybridization and
      comparative mapping of some intrachromosomal changes in the karyotypes of great
      apes (Pan troglodytes, P. paniscus, Gorilla gorilla, Pongo pygmaeus), a gibbon
      (Hylobates lar), and an Old World monkey (Macaca fuscata). Probes containing
      chromosomes 2 and 18 fragments confirmed inversions already suggested by the
      banding pattern of great ape homologues. However, a chromosome 3 fragment showed
      complex rearrangements in the gibbon and macaque karyotype which were previously
      not well defined from banding. 'Subchromosomal painting' will allow the
      identification of intrachromosomal changes on the basis of DNA homology and
      provides a powerful method to study karyological and genomic evolution.

PMID- 8653269
TI  - The chromosomal distribution and organization of sheep satellite I and II
      centromeric DNA using characterized sheep-hamster somatic cell hybrids.
AB  - A panel of sheep-hamster somatic cell hybrids containing single sheep chromosomes
      was used to study the chromosomal distribution and organization of two families
      of sheep centromeric satellite DNA. This study shows that the centromeres of the
      sheep metacentric chromosomes 1, 2 and 3 differ in their organization and
      relative quantities of sheep satellite I DNA. The results, when correlated with
      the proposed formation of these metacentric chromosomes by ancient Robertsonian
      translocations, suggest a loss or replacement of satellite I centromeric DNA from
      the centromeres of these sheep chromosomes. Using Southern blot analysis and
      fluorescence in situ hybridization, this study shows that the recent centric
      fusion chromosome t2 (rob 9;10) contains little satellite II DNA. Together these
      results suggest the possibility of substantial reorganization of sheep
      centromeric DNA families after Robertsonian translocations.

PMID- 8653270
TI  - The distribution of topoisomerase II on mammalian chromosomes.
AB  - The distribution of topoisomerase II (Topo II) has been studied using
      immunofluorescence on cytocentrifuged preparations of mammalian chromosomes.
      Immunolabelling of Topo II is affected by choice of fixative, by barriers to
      accessibility and by the lability of the enzyme. Chromosomes still embedded in
      cytoplasm remain unlabelled, while in contrast Topo II can easily be lost from
      some sites in chromosomes free of cytoplasm. The definitive distribution of Topo
      II consists of a line along the centre of each chromatid, corresponding to the
      chromosome core or scaffold, and quantities of Topo II elsewhere in the
      chromosomes which vary during the course of mitosis. A strong reaction for Topo
      II can be seen throughout prophase chromosomes, consistent with a role in
      condensation and/or segregation of the chromosome arms at this stage. At
      metaphase, Topo II is restricted to the centromeric regions, the only parts of
      the chromosomes that still have to be separated at this stage, while in anaphase,
      after segregation has occurred, this centromeric concentration of Topo II is
      lost. The distribution and quantity of Topo II in mammalian chromosomes is thus
      wholly consistent with the known functions of this enzyme in chromosome
      condensation and segregation.

PMID- 8653271
TI  - Patterns of DNase I sensitivity in the chromosomes of the grasshopper Chorthippus
      parallelus (Orthoptera).
AB  - We have analysed the patterns of DNase I/nick translation in the chromosomes of
      the grasshopper Chorthippus parallelus erythropus. Sites of preferential DNase I
      nicking were concentrated at the distal chromosome regions, thus showing the non
      uniform DNase I sensitivity of different chromosome domains. Among centromeric C
      bands, the heterochromatin of metacentric and acrocentric chromosomes differed
      with respect to their DNase I resistance.

PMID- 8653272
TI  - Analysis using dual-colour fluorescence in situ hybridization of meiotic
      chromosome segregation in male mice heterozygous for a reciprocal translocation.
AB  - Meiotic chromosome behaviour was investigated in male mice heterozygous for the
      translocation T(7;16)67H. At metaphase I, chain-of-four quadrivalents were
      present in approximately 80% of the spermatocytes; the bulk of remaining cells
      contained a ring quadrivalent, with only a few having either a trivalent plus
      univalent configuration or two bivalents. A low rate of non-disjunction,
      approximately 5%, was found through analysis of C-banded metaphase II
      spermatocytes. Using fluorescence in situ hybridization with differentially
      labelled whole chromosome paints, a wide array of segregation products were
      observed at metaphase II, depending on whether they arose from alternate,
      adjacent I, adjacent II orientation at metaphase I or were uninformative for
      alternative/adjacent I because of the presence of a chiasma in an interstitial
      pairing segment. Some 62% of the cells fell into this latter category, with only
      small proportions clearly arising through alternate (1.8%) or adjacent I (0.7%)
      orientations. Approximately 30% of the cells contained the products of adjacent
      II orientation. Consideration of the data suggested that most of these cells
      arose from metaphase I cells that contained a chain quadrivalent. Ring
      quadrivalents appeared predominantly to orientate in an alternate/adjacent I
      manner.

PMID- 8653273
TI  - Chiasma localization, heterochromatin and synaptonemal complexes in the
      grasshopper Pyrgomorpha conica.
AB  - Surface-spread synaptonemal complexes and chiasma distributions in spermatocytes
      with different C-banding patterns and chiasma distributions in oocytes were
      analyzed in the grasshopper Pyrgomorpha conica. Male meiosis was characterized by
      a proximal/distal chiasma localization and complete pairing of homologous
      chromosomes at pachytene. However, there were indications of a relationship
      between the frequency and location of pairing initiation sites and chiasma
      distribution. The presence of a proximal supernumerary segment in a medium-sized
      chromosome does not increase the mean cell chiasma frequency of carrier
      individuals compared with those lacking it but may modify chiasma distribution in
      at least some carrier bivalents. This effect could be related to heterosynapsis
      in the region near the segment. Mean cell chiasma frequency was significantly
      lower in females than in males. Females also showed altered chiasma distributions
      compared with males, with fewer proximal chiasmata and more interstitial and
      distal chiasmata.

PMID- 8653274
TI  - G-banding and chromosome condensation in the ant, Tapinoma nigerrimum.
AB  - Well-defined G-bands were obtained on metaphase chromosomes from Tapinoma
      nigerrimum using trypsin and warm 2 x SSC in sequence. The G-banded pattern
      allowed the identification of all chromosomes. Evidence for asynchronous
      condensation of the chromosomes of this species is provided. Different banding
      patterns were obtained when metaphase chromosomes were stained with DA/DAPI alone
      and with DA/DAPI after a standard G-banding procedure. The G-banding phenomenon
      is discussed using the result obtained.

PMID- 8653275
TI  - [Systemic enzyme therapy].
AB  - The paper summarizes the hitherto knowledge concerning the absorption of
      perorally administered enzymes in the digestive tract. After the transport
      through the intestinal wall the enzymes are protected against immunity
      recognition and they reach the affected regions via blood and lymphatic routes. A
      survey of enzymes taken into consideration and the essence of their action are
      presented. In the final part, the fields are summed up in which systemic
      enzymotherapy proves useful.

PMID- 8653276
TI  - [Interactions of surfactants with model and biological membranes. XXII.
      Spectrophotometric determination of partition coefficient of heptacaine, a local
      anesthetic, between the phospholipid liposome and water phase].
AB  - The partition coefficient of the local anaesthetic heptacaine (monohydrochloride
      of [2-(heptaloxy)phenyl]-2-(1-piperidinyl)ethyl ester of carbamic acid) between
      unilamellar liposomes prepared from chromatographically pure egg yolk
      phosphatidylcholine and the aqueous phase (NaCl solution, ionic strength I =
      0,1,pH 4,5, temperature t = 20 degrees C) was determined using UV-VIS
      spectrophotometry. The contribution to the anaesthetic spectra due to light
      scattering on liposomes was eliminated numerically using the scattering function.
      This procedure gave more precise results than the subtraction of liposomes
      spectra. The values of the partition coefficient defined with the use of molar
      concentrations, weight concentrations and molar fractions estimated at a
      wavelength of lambda = 292 nm were Kp = 1116 +/- 49, Kp(m) = 1098 +/- 48 and
      Kp(x) = 47575 +/- 2089, respectively.

PMID- 8653277
TI  - [Antineoplastic effects of natural substances].
AB  - The present paper surveys natural substances with antitumour activity,
      particularly primary metabolites--polysaccharides, lectins and lipids tested in
      vitro or on laboratory animals. The presented data cover the period of 1990-1995.

PMID- 8653278
TI  - Pyridinium cross-links as urinary markers of bone metastases in patients with
      prostate cancer.
AB  - OBJECTIVES: To determine whether the urinary excretion of urinary pyridinoline
      (Py) and deoxypyridinoline (dPy) serve as markers to evaluate the activity of
      bone metastases and the response to endocrine therapy, by determining the
      relationship between the excretion of these compounds and the activity of bone
      metastases in patients with prostate cancer. PATIENTS AND METHODS: Urine
      specimens were obtained from 15 patients with benign prostatic hypertrophy (BPH),
      17 with carcinoma clinically confined to the prostate and 26 with prostate cancer
      and bone metastases. Among the patients with prostate cancer and bone metastases,
      15 were new or reactivated cases and the 11 others were well controlled by
      hormonal therapy. Urinary Py and dPy were analysed using high-pressure liquid
      chromatography. RESULTS: Patient with new or reactivated prostate cancer with
      bone metastases had a higher urinary excretion of Py and dPy than did the
      patients with BPH, patients with prostate cancer and no bone metastases and
      patients with prostate cancer and bone metastases well controlled with hormonal
      therapy. Urinary levels of these compounds correlated with the extent of bone
      metastases in new and reactivated cases. Initial high levels of these cross
      linked compounds in patients with multiple bone metastases fell as the prostate
      cancer was controlled by hormonal therapy. CONCLUSION: Urinary excretion of Py
      and Dpy appears to be a useful marker for evaluating the activity of bone
      metastases and their response to hormonal treatment in prostate cancer.

PMID- 8653279
TI  - Immunohistochemical evaluation of proliferating cell nuclear antigen, prostate
      specific antigen and alpha 1-antichymotrypsin in human prostate cancer.
AB  - OBJECTIVE: To determine the relationship between growth fractions defined by
      proliferating cell nuclear antigen (PCNA), prostate-specific antigen (PSA) and
      alpha 1-antichymotrypsin (ACT) staining in prostate cancer. MATERIALS AND
      METHODS: A total of 96 lesions, including 71 from prostate cancers and 25 from
      benign prostatic hyperplasia (BPH) were evaluated in microscopic sections of the
      prostatic tissues from 34 patients with prostate cancer. Immunohistochemical
      staining was performed with an avidin-biotin system using monoclonal anti-PCNA
      antibodies, polyclonal anti-PSA and anti-ACT antibodies. RESULTS: There was a
      significant difference in the mean PCNA labelling index between tissue from
      prostate cancer (4.2 +/- 7.1) and BPH (0.5 +/- 1.1) (P = 0.002). The mean
      labelling index of PCNA tended to increase with increasing Gleason score. The
      proportion of cells positive for PSA was significantly higher in tissue from BPH
      than from prostate cancer (P = 0.005). While the proportion of cells
      immunostaining for ACT was significantly higher in tissue from BPH compared to
      that from prostate cancer (P = 0.02), there was no significant difference in the
      proportion of ACT-positive cells among prostate cancers of differing Gleason
      score. The mean labelling index of PCNA decreased significantly with the increase
      in the proportion of PSA-positive cells (P = 0.013). There was a significant
      relationship between the proportion of ACT- and PSA-positive cells (P = 0.001).
      CONCLUSION: These results indicate a reciprocal relationship between cell growth
      and tumour differentiation in prostate cancer. Although the significance of ACT
      deserves further study, there was evidence for the complexing of PSA with ACT
      from the immunohistochemical studies.

PMID- 8653280
TI  - Evaluation of mucinous metaplasia of the prostate gland by mucin histochemistry.
AB  - OBJECTIVE: To evaluate the presence of mucinous metaplasia in normal and benign
      hyperplastic prostates, using stains for neutral and acidic mucins. PATIENTS,
      MATERIALS AND METHODS: Normal prostate glands were removed during the post-mortem
      examination of 11 consecutive subjects (median age 45 years, range 17-79) who had
      died accidentally. Specimens were also obtained from 10 patients (median age
      70.2, range 61-82) undergoing suprapubic prostatectomy for prostatic hyperplasia.
      The specimens were examined histologically; sections were stained using the
      periodic acid-Schiff (PAS) method for neutral mucins and the alcian blue (AB)
      method at pH 2.5 for acidic mucins. The positive sections were also immunostained
      for high molecular weight cytokeratin (KER), and prostate-specific antigen (PSA)
      using the strept-avidin-biotin (SAB) method. RESULTS: Mucinous metaplasia was
      found in six of the normal prostates and in three of the hyperplastic glands.
      Usually, the cells were tall columnar, containing both AB- and PAS-positive
      material. The cells were negative both for PSA and KER. Mucinous metaplasia
      affected all ages, including a 17-year-old, and mostly involved the inferior
      periurethral area. CONCLUSION: Benign mucinous metaplasia was more frequent than
      previously appreciated, involved all ages, was mainly periurethral and did not
      correlate with the usual distribution of adenocarcinoma of the prostate.

PMID- 8653281
TI  - Changes in sexual function after radiotherapy treatment of prostate cancer.
AB  - OBJECTIVE: To assess sexual function before and after definitive irradiation for
      the treatment of cancer of the prostate. PATIENTS AND METHODS: The study
      comprised 67 patients (mean age 68 years) treated in five radiotherapy
      departments and assessed with repeated questionnaires about their libido,
      arousal, frequency and quality of intercourse, and sexual satisfaction.
      Interviews were obtained before radiotherapy and at the end of the first year
      after treatment. Sixty-three patients were married and 50 had a sexually
      effective partner. Forty-six patients presented with another pathology or medical
      treatment capable of inducing sexual dysfunction. Before radiotherapy, 40
      patients were sexually active, with good to acceptable intercourse. RESULTS:
      Between 10 and 24 months after the end of radiotherapy, no disease progression
      was observed and prostate-specific antigen levels remained high in only two
      patients. Sexual function was preserved in 67% of patients but only 50% observed
      no change. The functional prognosis seemed to be related to the initial frequency
      and quality of intercourse; more than three times per month, the prognosis
      remained good, under three per month, it was poor. The patient's age was a
      predictive factor for the frequency of intercourse. CONCLUSION: Several causes of
      impairment of sexual function may be associated and can change over a long time.
      A longer survey should be conducted to analyse the organic response to radiation.

PMID- 8653282
TI  - Post-surgical recurrent varicocele: efficacy of internal spermatic venography and
      steel-coil embolization.
AB  - OBJECTIVE: To delineate the venographic anatomy of the varicoceles which recur
      following conventional inguinal varicocele ligation and to determine the
      therapeutic efficacy of steel-coil embolization as assessed by improvements in
      seminal parameters and paternity. PATIENTS AND METHODS: Thirty-nine patients with
      post-surgical recurrent varicoceles underwent bilateral internal spermatic
      venography approached through the right femoral vein. The collateral venous
      channels were identified and occluded using appropriate sizes of steel coils.
      RESULTS: The procedure was technically successful in 33 patients (85%). Analysis
      of the 33 venograms showed a unilateral left-sided recurrent varicocele in 28
      patients (85%) and bilateral recurrent varicoceles in five patients (15%). The
      mid and lower parallel collateral channels were observed in 27 patients (82%).
      The recurrences were treated easily with stainless steel-coil embolization. Five
      patients were lost to follow-up. Of the remaining 28 patients the sperm count and
      motility became normal in 16 (57%); only the motility improved in three patients
      (10%) while in nine patients (33%) there were no changes in either of the seminal
      parameters. Five patients achieved paternity. CONCLUSIONS: Internal spermatic
      venography allowed a precise anatomical definition of the recurrent varicocele
      and the use of steel-coil embolization provided satisfactory improvements in
      sperm quality and paternity.

PMID- 8653283
TI  - Financial analysis of antegrade scrotal sclerotherapy for men with varicoceles.
AB  - OBJECTIVE: To calculate and compare the costs of the treatment of varicocele by
      antegrade scrotal sclerotherapy with other modalities. PATIENTS AND METHODS: A
      total of 2305 operations using antegrade scrotal sclerotherapy to treat
      varicocele in childhood and adolescence were analysed for cost factors and
      compared with different surgical treatment methods for varicocele. RESULTS:
      Calculation of the pre-, intra- and post-operative costs showed that antegrade
      scrotal sclerotherapy was the most economically effective of all forms of
      surgical management for varicocele. CONCLUSIONS: Because antegrade scrotal
      sclerotherapy is a cost-effective treatment for varicocele, the indications for
      treatment may be widened to include more men with potential infertility, and thus
      avoid the need for expensive methods of artificial fertilization.

PMID- 8653284
TI  - An intra-operative seminal and prostate emission test as a control for nerve
      sparing procedures in primary and secondary retroperitoneal lymphadenectomy.
AB  - OBJECTIVE: To determine the value of an intra-operative electrostimulatory test
      of post-ganglionic nerves for the preservation of ejaculation in primary and
      secondary retroperitoneal lymph-node dissection (RLND). PATIENTS AND METHODS:
      Between 1991 and 1994, 21 patients with non-seminomatous testicular cancer of
      clinical stage A and 15 patients with bulky or clinical stage C disease underwent
      primary or secondary RLND, respectively. During surgery, post-ganglionic nerves
      were electrostimulated at 30 Hz and up to 20 V, for 3-10 s. Emissions were
      recorded simultaneously by suprapubic ultrasonography of the seminal vesicals and
      bladder neck (in 36 patients) and by endoscopy of the posterior urethra (in 11
      patients). RESULTS: A positive intra-operative emission test in 15 pathological
      stage A (with bilateral nerve-sparing) and six pathological stage B (with
      contralateral nerve-sparing) patients predicted the post-operative preservation
      of antegrade ejaculation. In the group undergoing secondary RLND, the test
      allowed the identification and sparing of the emission-related nerves in four of
      15 patients with a residual mass consisting of necrosis/fibrosis, and preserved
      antegrade ejaculation after surgery. CONCLUSIONS: A positive result in the
      seminal emission test predicted the preservation of antegrade ejaculation after
      surgery. The test is not necessary in patients with clinical stage A disease, but
      improves the chances of reducing morbidity. If the residual mass consists of
      necrosis or fibrosis, then electrostimulation during secondary RLND can help to
      identify important nerve structures when their origin is unknown initially.
      However, attempts to retain nerve function must not jeopardize the patient's
      survival. The test can be an option for clinical stage B disease with initial
      bilateral RLND, to identify and preserve emission-relevant nerves while the
      retroperitoneal space is removed radically. The test may also give additional
      information about the physiology of emission.

PMID- 8653285
TI  - Significance of placental alkaline phosphatase (PLAP) in the monitoring of
      patients with seminoma.
AB  - OBJECTIVE: To investigate the significance of placental alkaline phosphatase
      (PLAP) as a tumour marker for seminoma. PATIENTS AND METHODS: A total of 673
      serum samples from 116 patients with testicular germ cell tumours (78 seminomas
      and 38 non-seminomas) were analysed for several markers including PLAP, total
      alkaline phosphatase (AL-P), alpha fetoprotein (AFP), beta human chorionic
      gonadotrophin (HCG-B), and lactic dehydrogenase (LDH). RESULTS: Serum PLAP was
      increased initially in about 50% of patients with seminoma, and the mean
      magnitude of elevation was about five times the normal value. There was no
      significant correlation between PLAP and LDH or between PLAP and HCG-B.
      Therefore, a combination of these three markers was of value, and resulted in a
      positive identification rate of 82% of patients with seminoma. False-positive
      results for PLAP appeared in 1.6% of 673 samples investigated. CONCLUSION: The
      monitoring of serum PLAP might be of value, as fluctuations in this marker
      provide information about disease status and prognosis.

PMID- 8653286
TI  - Paratesticular sarcomas revisited: a review of cases in the British Testicular
      Tumour Panel and Registry.
AB  - OBJECTIVE: To assess differences in the histopathological diagnoses of a series
      of paratesticular sarcomas following changes in the morphological classification
      of these tumours and the availability of investigations to define their
      immunophenotype, and to consider the impact of these changes on clinical
      management. MATERIALS AND METHODS: Thirty-six soft tissue tumours of the
      paratesticular region, originally submitted to the British Testicular Tumour
      Panel and Registry between 1958 and 1967 were re-examined histologically using
      modern diagnostic criteria, including immunohistochemical features. Where
      possible, follow-up was brought up to date. RESULTS: Thirteen (35%) of the
      diagnoses made in 1967 were changed; of these, seven changes were attributable to
      the results of immunohistochemical tests and one involved the identification of
      an entity not recognized in 1967 (spindle cell rhabdomyosarcoma). CONCLUSION: The
      changes in diagnoses of major clinical relevance involved three neoplasms (8%) in
      which the recent opinion was rhabdomyosarcoma, a tumour for which successful
      treatment protocols are currently available.

PMID- 8653287
TI  - A computerized ureteric stent retrieval system.

PMID- 8653288
TI  - Fibre-optic cystoscope-guided insertion of J-J ureteric stent.

PMID- 8653289
TI  - Intramuscular tenoxicam to treat acute renal colic.
AB  - OBJECTIVE: To study the possible therapeutic effects on acute renal colic of a
      single 20 mg intramuscular dose of tenoxicam. PATIENTS AND METHODS: The study
      comprised 30 patients (22 men and eight women, mean age 32 years, range 17-60)
      who presented with acute renal colic and were diagnosed by intravenous urography,
      a general urine examination and ultrasonography. Each patient was treated with 20
      mg of tenoxicam given intramuscularly. The severity of pain was assessed on a
      verbal six-point scale. RESULTS: Twenty-four patients markedly improved within 1
      h of receiving tenoxicam (P < 0.001). No side-effects were reported and the drug
      was tolerated well by all the patients. CONCLUSION: Tenoxicam can be used
      successfully to treat acute renal colic.

PMID- 8653290
TI  - Using the 'pusher first' technique to facilitate insertion of J-J stent
      guidewire.

PMID- 8653291
TI  - Digitally-guided prostatic biopsies--the Sheffield biopsy guide.

PMID- 8653292
TI  - A simple technique for the intra-operative placement of a suprapubic catheter.

PMID- 8653293
TI  - Psoas abscess secondary to metastases from transitional cell carcinoma of the
      bladder.

PMID- 8653294
TI  - Ovarian-type papillary serous cystadenocarcinoma of the testis.

PMID- 8653295
TI  - Clinico-pathological findings simulating prostatic malignancy following
      sclerotherapy: a diagnostic pitfall.

PMID- 8653296
TI  - A case of renal parenchymal malacoplakia with bilateral pulmonary lesions.

PMID- 8653297
TI  - Seminal vesicle metastasis--an overlooked occurrence of testicular tumours?

PMID- 8653298
TI  - Laparoscopic ureterolysis for retrocaval ureter.

PMID- 8653299
TI  - Severe urological complication of leech bite in the tropics.

PMID- 8653300
TI  - High-flow priapism due to bilateral arteriosinusoidal fistulae.

PMID- 8653301
TI  - Transrectal ultrasound appearances of schistosomal prostato-seminovesiculitis.

PMID- 8653302
TI  - Colonic metaplasia of the bladder in a young man.

PMID- 8653303
TI  - Reagent strip testing for significant bacteriuria in a urodynamic clinic.

PMID- 8653304
TI  - Urodynamic study of laser ablation of the prostate.

PMID- 8653306
TI  - Kropp-onlay procedure: a simplification of the technique of urethral lengthening.

PMID- 8653307
TI  - A simple method for checking J-J stent position.

PMID- 8653305
TI  - Management of ureteric calculi during pregnancy by ureteroscopy and laser
      lithotripsy.
AB  - OBJECTIVE: To evaluate the efficacy and safety of ureteric stone treatment by
      ureteroscopy and laser lithotripsy during pregnancy. PATIENTS AND METHODS: Four
      pregnant women (mean age 29.5 years, range 27-35) with five episodes of ureteric
      stones were treated by ureteroscopy and laser lithotripsy when the fetus was at
      26-35 weeks of gestation. The stones (between 5 and 16 mm in diameter) were
      located in the proximal (one) or distal ureter (four). RESULTS: All five stones
      were removed successfully by ureteroscopy and laser lithotripsy. The operating
      time varied between 15 and 70 min. In two of the five cases, topical anaesthesia
      was adequate and in no case was fluoroscopy necessary. No complications occurred
      that could be related to the procedure. CONCLUSIONS: Ureteroscopy and laser
      lithotripsy seem, in experienced hands, to be a safe and reliable method in the
      treatment of ureteric calculi during pregnancy. Most cases can be treated without
      using fluoroscopy and in some cases the operation can be performed under local
      anaesthesia.

PMID- 8653308
TI  - Successful management of pelvic arteriovenous malformation by repeated
      particulate intra-arterial embolization.

PMID- 8653309
TI  - Burch colposuspension facilitated by means of the Ferguson speculum.

PMID- 8653310
TI  - Synchronous presentation of different testicular tumours.

PMID- 8653311
TI  - Obstetric and gynaecological ureteric injuries: treatment and results.
AB  - OBJECTIVE: To compare endourological techniques and open surgery in the treatment
      of ureteric injuries following obstetric and gynaecological surgery. PATIENTS AND
      METHODS: From January 1982 to February 1994, 63 women (mean age 51 years, range
      22-70) were treated for 72 ureteric lesions consequent upon obstetric or
      gynaecological surgery. In nine patients, 10 ureteric lesions were detected intra
      operatively and repaired immediately. In the remaining 54 patients, the 62
      ureteric injuries were diagnosed and treated after a delay; 29 patients with 37
      ureteric injuries underwent repair by open surgery while 25 patients with a
      unilateral ureteric lesion underwent elective primary endourological treatment.
      RESULTS: The results of repair were not related to the type of treatment; the
      cure rate was 87, 88 and 90% for delayed open surgical, endourological and
      immediate intra-operative repair, respectively. The site (vesico-ureteric
      junction, uterine artery or infundibulopelvic ligament) and the type (fistula or
      stenosis) of ureteric lesion had no influence on the results, regardless of the
      type of treatment. The results of ureteric repair were related to the surgery
      that caused the lesion; 88% of the poor results occurred in the patients who
      underwent radical hysterectomy alone or combined with radiotherapy and
      approximately half of the irradiated patients required major surgery. CONCLUSION:
      When the patients are correctly selected, endourological treatment plays an
      equally important role in the treatment of gynaecologically-related ureteric
      injuries when compared to open surgery. Special attention should be paid to the
      treatment of lesions caused by radical hysterectomy alone or associated with
      radiotherapy, as these may lead to poor results.

PMID- 8653312
TI  - Adrenalectomy--still a must in radical renal surgery?
AB  - OBJECTIVE: To investigate the incidence of adrenal involvement and survival in
      patients with renal cell carcinoma. PATIENTS AND METHODS: A retrospective,
      multicentre trial was initiated by the Austrian Association of Urologic Oncology
      (AUO); between January 1980 and December 1984, 225 patients were eligible for the
      study. All patients had unilateral renal tumours and nephrectomies were performed
      either with (group A, 109 patients) or without (group B, 116 patients)
      adrenalectomy. The two groups were matched for sex, age, laterality and nodal
      status. The mean follow-up time was 78 months. RESULTS: The location of the
      intrarenal tumour had no significant effect on adrenal involvement. By univariate
      and multivariate analysis (Cox's proportional hazards model) significant
      differences in outcome were found only for pT stages. The mean survival times of
      patients in group A were 122.9 months in those with stage pT1/2, 76.6 months with
      stage pT3 and 75.3 months with stage pT4. In group B, survival times were 109
      months in those with stage pT1/2 (not significant) and 111 months in stage pT3 (P
      = 0.0076). Eight patients had adrenal involvement and died from their tumours
      after a median of 15.3 months (range 4-63). The slightly longer survival of
      patients in group B with stage T1/2 tumours and the significantly better survival
      of patients with stage T3 disease may be attributable to statistical bias, but
      there was no benefit from adrenalectomy. CONCLUSION: The effect of adrenalectomy
      on the prognosis was at best comparable to that of lymphadenectomy and no
      curative effect was demonstrated. The removal of a healthy adrenal may be
      detrimental and cause subsequent problems in those patients requiring hormone
      replacement.

PMID- 8653313
TI  - Technical editing.

PMID- 8653314
TI  - Impaired production of interferon-alpha in whole-blood cultures from patients
      with renal cell carcinoma.
AB  - OBJECTIVE: To determine the immune status of patients with renal cell carcinoma
      (RCC) by estimating the production of interferon-alpha (IFN-alpha) in whole-blood
      cultures from these patients and from healthy subjects. PATIENTS, SUBJECTS AND
      METHODS: Peripheral blood (2 mL) was collected from 30 untreated patients (23 men
      and seven women, mean age 59 years, range 35-78) with RCC and 30 healthy subjects
      (23 men and seven women, mean age 62 years). The patients with RCC comprised 17
      with low-stage (stage I, II) and 13 patients with high-stage (stage III, IV) RCC.
      Sendai virus was added to the samples and incubated at 37 degrees C for 20 h, the
      supernatants collected and the activity of IFN-alpha determined by a conventional
      cytopathic-effect inhibition assay performed in microtitre plates with FL cells
      and challenged with vesicular stomatitis virus. RESULTS: The production of IFN
      alpha was suppressed significantly in patients with high-stage RCC compared with
      that in the control subjects (P < 0.05), but there was no significant difference
      when compared to patients with low-stage RCC. CONCLUSION: This study demonstrated
      that the immune status of patients with high-stage RCC was impaired significantly
      and exogenous IFN-alpha therapy might be beneficial clinically for this group.

PMID- 8653315
TI  - Clinical significance of routine pre-cystectomy bone scans in patients with
      muscle-invasive bladder cancer.
AB  - OBJECTIVE: To evaluate the clinical significance of bone scans taken routinely
      before total cystectomy in patients with bladder cancer of clinical stage > or =
      T2. PATIENTS AND METHODS: Of 227 consecutive patients with stage > or = T2
      bladder cancer diagnosed between 1980 and 1990 but with no clinical suspicion of
      bone metastases, 91 had a pre-cystectomy bone scan performed at the Norwegian
      Radium Hospital. The medical records of these patients were reviewed to examine
      the subsequent development of distant metastases and survival. RESULTS: Of the 91
      patients, 37 (41%) developed skeletal bone metastases after cystectomy, unrelated
      to the clinical T category. In 35 patients, the pre-cystectomy bone scan showed
      pathological uptake of isotope which was interpreted by the specialist in nuclear
      medicine as suspicious of (13 patients) or probably caused by (22 patients)
      skeletal metastases. In either circumstance, the clinician decided that total
      cystectomy was precluded, particularly as most of the changes could be explained
      radiologically as being degenerative. In the individual patient, there was no
      clinically useful correlation between the findings on the pre-cystectomy bone
      scan and the clinical course of disease, nor if serum alkaline phosphatase (SAP)
      level was included as an additional predictive factor. However, although not
      statistically significant, the follow-up of all patients revealed an association
      between the degree of change on the pre-cystectomy bone scan and the subsequent
      development of skeletal metastases and cancer-corrected survival. CONCLUSION:
      Unless further investigations, particularly magnetic resonance imaging (MRI), can
      be performed, the findings of a routine pre-operative bone scan are usually
      unable to identify patients with bladder cancer of stage > or = T2 who will not
      be cured by total cystectomy. An increased level of SAP did not improve the
      predictive accuracy of a pre-cystectomy bone scan. However, the results indicate
      that future clinical research should be directed at combining the findings of
      bone scans and MRI in the search for micrometastases.

PMID- 8653316
TI  - Intragranular activation of bladder mast cells and their association with nerve
      processes in interstitial cystitis.
AB  - OBJECTIVE: To investigate the presence of progesterone receptors and the extent
      and type of degranulation exhibited by the increased numbers of mast cells (MCs)
      found in interstitial cystitis (IC), a painful bladder disorder which occurs
      almost exclusively in women, worsens perimenstrually and is characterized by
      increased numbers of oestradiol receptor (OR)-positive MCs. PATIENTS AND METHODS:
      The state of MC degranulation was analysed blindly using electron microscopy of
      bladder biopsies from 26 patients with IC and six control patients which included
      five women with incontinence, with none of the established characteristics of IC,
      and one man with transitional carcinoma of the bladder. Emphasis was placed on
      preserving the secretory granule ultrastructure. The presence of progesterone
      receptors (PRs) in five patients with IC and three controls was investigated
      using commercially available antibodies against PRs. RESULTS: Over 85% of bladder
      MCs expressed high affinity PRs, but the number of PR-positive MCs in patients
      with IC did not differ significantly from that of controls despite the overall
      increase in MCs seen in IC. MCs were activated to various degrees and were often
      near to neuronal processes. The secretory granule content of MCs from patients
      with IC was in different stages of dissolution, ranging from heterogeneous loss
      of electron density to the appearance of crystalline substructure and target
      forms containing only remnants of the original material. Typical degranulation by
      compound exocytosis was not observed. MCs from control patients contained
      secretory granules with mostly intact, electron-dense granules. CONCLUSION: These
      findings indicate that the symptoms of IC may depend on an imbalance of the
      relative number of oestrogen receptors (ORs) to PRs on bladder MCs resulting in a
      'progesterone deficient' state. This possibility is strengthened by demonstration
      that oestradiol augments the secretion of MC histamine in response to the
      neuropeptide substance P, which is pro-inflammatory, nociceptive and
      overexpressed in bladders with IC. Intragranular activation of bladder MCs is a
      characteristic pathological finding in patients with IC. The lack of extensive
      degranulation, typically seen in anaphylaxis, may indicate a unique mode of
      stimulation and/or differential release of mediators.

PMID- 8653317
TI  - Biological characteristics of inverted papilloma of the urinary bladder.
AB  - OBJECTIVES: To elucidate the biological characteristics of inverted papilloma
      (IP) of the bladder. MATERIALS AND METHODS: The immunoreactivity of p53, nuclear
      DNA content (assessed by ploidy and 2c deviation index [2cDI]) and the expression
      of proliferating cell nuclear antigen (PCNA) in 17 IPs were evaluated using a
      computer-assisted image analyser and compared with those in 12 superficial
      transitional cell carcinomas (TCCs), 29 invasive TCCs and one inverted papillary
      TCC of the bladder. RESULTS: Positive staining for p53 and PCNA and intense
      staining with Feulgen were observed predominantly in the basal layer of the
      bladder mucosa. All IPs and most superficial TCCs were diploid, while most
      invasive TCCs were aneuploid. Although the 2cDI and the immunoreactivities for
      PCNA and p53 were significantly lower in IPs than in invasive TCCs, there was no
      significant difference in these three variables between IPs and superficial TCCs.
      However, some IPs were more immunoreactive for p53 than were the superficial
      TCCs. CONCLUSIONS: The distribution of cells with p53 and PCNA immunoreactivity,
      and with intense Feulgen staining, indicated that IP of the bladder might have
      high proliferative activity and that those IPs with a high immunoreactivity for
      p53 may be susceptible to malignant transformation.

PMID- 8653318
TI  - Farmers at risk for prostate cancer.
AB  - OBJECTIVE: To summarize the literature on the risk of prostate cancer among
      farmers and farm workers, to evaluate the magnitude of the risk and to determine
      the presence of risk factors peculiar to agricultural work. METHODS: Recent
      literature was searched and reviewed, selecting only case-control studies in
      which both positive and negative odds ratios were presented for several
      occupations, while only cohort studies and death-certificate studies were
      selected which presented risk estimates for several cancer sites, elevated as
      well as decreased. RESULTS: In most of the studies reviewed, a slight excess risk
      of prostate cancer incidence or mortality was observed among farmers. It is as
      yet unclear whether this excess risk is caused by particular occupational
      exposures or by risk factors in their personal lifestyle (e.g. dietary habits).
      Evidence was found for a relationship between the use of pesticides and of other
      agricultural chemicals and the risk of prostate cancer. CONCLUSION: Farmers
      probably have a slightly elevated risk of contracting prostate cancer. However,
      the actual risk factors are still a matter of conjecture.

PMID- 8653319
TI  - Urinary concentration of human chorionic gonadotrophin and its fragments as a
      prognostic marker in bladder cancer.
AB  - OBJECTIVE: To examine the prognostic significance of elevated urinary beta human
      chorionic gonadotrophin (beta-hCG) in patients with bladder cancer. PATIENTS AND
      METHODS: Total beta-hCG was measured in the urine of 142 patients referred for
      cystoscopic examination. Patients were followed for a minimum of 17 months and
      grouped according to stage of disease. Because the water output by individual
      patients varied, urinary creatinine levels were measured as an indicator of the
      concentration of the urine sample. Patient outcomes were correlated with urinary
      total beta-hCG levels both corrected and uncorrected for creatinine
      concentration. After correcting for urinary creatinine levels, 40 patients were
      excluded because the sample was too dilute (undetectable beta-hCG and a
      creatinine level of < 4 mmol/L). A further four patients were excluded as they
      had concurrent malignancies not in the bladder and one patient was lost to follow
      up. RESULTS: None of the 52 patients with benign conditions, nine of the 27 with
      Ta-T1, and nine of the 25 with T2-T4 bladder disease had urinary total beta-hCG
      levels > 3.74 IU/mmol/L creatinine. There was no significant association between
      urinary total beta-hCG concentrations and the rates of recurrence or progression
      for Ta-T1 disease at 17 months of follow-up. For patients with T2-T4 disease
      there was a significant association with widespread metastasis (P < 0.01) and
      mortality (P < 0.01) at 17 months of follow-up. These associations persisted when
      urinary total beta-hCG levels were not corrected for urinary creatinine
      concentration (metastasis, P < 0.01; mortality, P = 0.07; Kaplan-Meier survival
      time analysis, uncorrected for creatinine P = 0.027, corrected for creatinine P <
      0.001). This association could not be accounted for by differences in age,
      histopathology or treatment. CONCLUSION: Although sample concentration was a
      serious confounding factor, after correcting for dilution using the creatinine
      content, the elevated urinary levels of total beta-hCG indicated those T2-T4
      lesions which were likely to metastasize and those patients likely to die early.
      If this test is to be used clinically, concentrated samples, i.e. early-morning
      urine, and a more sensitive beta-hCG assay are required. Nevertheless, for T2-T4
      bladder tumours, an elevated pre-treatment level of urinary beta-hCG is a marker
      of poor prognosis and may prove useful in deciding appropriate therapy.

PMID- 8653320
TI  - A retrospective study of the investigation and management of muscle-invasive
      bladder cancer in the South West Region.
AB  - OBJECTIVE: To evaluate the present management of muscle-invasive bladder cancer
      in the South West Region and to assess the workload resulting from the
      rationalization of treatment in specific centres. METHODS: A retrospective survey
      was undertaken in all the hospitals in the South West Region, to assess the
      management of all patients presenting with muscle-invasive bladder cancer in the
      years 1989 and 1993. Data were collected from histopathology records and hospital
      in-patients' notes. The optimum standard of assessment and treatment were defined
      by a panel of specialists in urological tumours. The management of patients was
      compared against these defined standards. RESULTS: A total of 186 and 199
      patients in 1989 and 1993, respectively, were evaluated. When comparing their
      assessment against the defined standard, only 69% of patients in 1989 and 58% in
      1993 had an intravenous urogram, with 7% and 4%, respectively, having no upper
      tract imaging (the remainder undergoing ultrasonography). Evidence from an
      examination under anaesthetic (EUA) was found for 80% of patients in 1989 and 84%
      of patients in 1993. Only 23% of patients in 1989 and 36% in 1993 were staged by
      either computed tomography or magnetic resonance imaging. In both 1989 and 1993,
      54% of patients had definitive treatment, 31% had an endoscopic follow-up only
      and 15% had no treatment; there were no differences in age or co-morbidity among
      these groups. The median time elapsed between referral and diagnosis was 59 days
      (1989) and 52 days (1993), and the median delay to definitive treatment was 114
      and 96 days, respectively. CONCLUSION: There was insufficient upper tract
      imaging, poor clinical staging in the EUA and too few investigations for staging.
      The low rate of definitive treatment may be a consequence of the delays in
      management, allowing the tumour to progress, and suggesting the need for a more
      rapid assessment of haematuria.

PMID- 8653321
TI  - Combined cytotoxic effects of tamoxifen and chemotherapeutic agents on bladder
      cancer cells: a potential use in intravesical chemotherapy.
AB  - OBJECTIVE: To evaluate whether tamoxifen enhances the cytotoxicity of
      chemotherapeutic agents on bladder cancer cells, and the possible mechanism(s) of
      action. MATERIALS AND METHODS: The in vitro inhibition of cell growth was
      examined in a model simulating intravesical chemotherapy using two bladder cancer
      cell lines (TSGH-8301, HTB9) and three commonly used intravesical cytotoxic
      agents (doxorubicin, mitomycin C, and thiotepa) in the presence or absence of
      tamoxifen or verapamil as modulators. The expression of the multi-drug resistance
      related gene mdr-1 was evaluated by reverse-transcription polymerase chain
      reaction and Southern blotting (RT-PCR-SB) to determine its transcript level, by
      flow cytometric analysis of the P-glycoprotein (P-gp) product level with C-219
      monoclonal antibody and by the rhodamine-123 retention and efflux assay for P-gp
      activity. Transforming growth factor beta-1 (TGF beta-1) levels in tamoxifen
      conditioned culture medium were determined with enzyme-linked immunosorbant assay
      (ELISA). RESULTS: Tamoxifen at concentrations > or = 30 microM significantly
      enhanced the cytotoxicity of the three chemotherapeutic agents to both cell
      lines, as shown by a marked reduction in the drug concentration which inhibited
      growth by 50% (IC50). The enhancement of cytotoxicity was significantly dependent
      on the concentration of tamoxifen. However, tamoxifen alone caused significant
      toxic effects to TSGH-8301 at > or = 40 microM and to HTB9 at > or = 30 microM.
      Median-effect analysis showed additive or less-than-additive combination effects
      between tamoxifen and chemotherapeutic agents and only a minimal synergism in a
      narrow range of maximal cytotoxicity (fraction affected > 0.9). Thus, the
      reduction of IC50s by tamoxifen was mostly because it was cytotoxic to the
      bladder cancer cells used. No enhancement of cytotoxicity was observed in
      verapamil-modulated cells. Transcripts of mdr-1 could not be detected by RT-PCR
      SB, nor was P-gp detected by flow cytometric analysis in the two cell lines.
      Furthermore, no active P-gp function was detected by the rhodamine-123 retention
      and efflux study, indicating that the primary chemoresistance mechanisms of the
      two cell lines were not mediated by mdr-1, nor could tamoxifen or verapamil act
      through modulation of the mdr-1 pathway in the two cell lines. Tamoxifen at 3 and
      10 microM down-regulated the secretion of TGF beta-1 from TSGH-8301 in a
      concentration-dependent manner, in contrast to the findings that tamoxifen was
      cytotoxic to the bladder cancer cells used and that tamoxifen up-regulated TGF
      beta-1 in a breast cancer model, suggesting that there may be a different
      mechanism of response to TGF beta-1 in these bladder cancer cells. CONCLUSION:
      Tamoxifen enhanced the cytotoxicity of chemotherapeutic agents largely through
      its toxic effects on the bladder cancer cells. The mode of action of tamoxifen
      was not through the regulation of TGF beta-1 or the function of mdr-1. Although
      cytotoxic levels of tamoxifen (> 50 microM) can be achieved easily in the
      intravesical model, further study is necessary before tamoxifen can be used
      clinically in intravesical chemotherapy.

PMID- 8653322
TI  - Long-term follow-up results with the Stamey operation for stress incontinence of
      urine.
AB  - OBJECTIVE: To assess the results of the Stamey operation for genuine stress
      incontinence in those patients with over 10 years of follow-up. PATIENTS AND
      METHODS: Of 46 patients who had undergone a Stamey procedure and had a follow-up
      of over 10 years, 30 were willing to attend for a clinical review and pad
      testing. RESULTS: Of the 30 patients assessed, 20 were initially cured, a further
      eight were significantly improved and two were no better. At 10 years, the number
      totally dry had fallen to 10, but a further 15 were still symptomatically
      improved. Only three that had shown some initial benefit were subjectively no
      better than before the operation. CONCLUSION: There appears to be a continuous
      decline in the cure rate with time from the Stamey procedure. However, most
      patients maintain some lasting benefit.

PMID- 8653323
TI  - Critical temperature for in vivo cryoablation of human prostate cancer in a
      xenograft model.
AB  - OBJECTIVES: To assess the in vivo sensitivity of human prostate cancer cells
      (PC3) to cryoablation and thus define the minimum temperature needed to prevent
      the recurrence of cancer after percutaneous transperineal radical prostatic
      cryoablation. MATERIALS AND METHODS: Twenty-five male nu/nu mice were inoculated
      by a subcutaneous injection with 5 x 10(5) PC3 cells. After 3 weeks the tumours
      (mean area 60.4 mm2, SEM 5.7) were frozen using a 3 mm cryotherapy probe (LCS
      3000 Cryotech UK) to temperatures ranging from 0 degrees to -40 degrees C.
      RESULTS: No tumours recurred in seven mice which had tumours frozen to < -15
      degrees C. There were eight recurrences in 15 mice which had tumours frozen to
      between 0 degree and -15 degrees C, and all were confirmed histologically.
      CONCLUSIONS: The minimum temperature required to prevent recurrence of tumours
      from human prostate cancer cells was < -15 degrees C in this in vivo mouse model.

PMID- 8653324
TI  - The role of cystoscopy before radical prostatectomy.
AB  - OBJECTIVE: To determine the role of pre-operative cystoscopy in men undergoing
      radical prostatectomy for clinically localized adenocarcinoma of the prostate.
      PATIENTS AND METHODS: One hundred men undergoing radical prostatectomy for
      clinically localized adenocarcinoma of the prostate were evaluated for coexisting
      bladder pathology from a retrospective review of their charts and records.
      RESULTS: Four of 100 men undergoing radical prostatectomy for clinically
      localized prostate cancer were found to have synchronous bladder tumours. Two of
      these had superficial low-grade transitional cell carcinoma (TCC), one had a
      poorly differentiated invasive TCC and the last was found to have an inverted
      papilloma during radical retropubic prostatectomy. The patient with invasive
      disease died before the initiation of definitive therapy. The other three men are
      free of disease 2 years after diagnosis and treatment. CONCLUSION: Because of the
      low cost and minimal morbidity of pre-operative flexible cystoscopy, we recommend
      that this procedure be performed on the operating table before prostatectomy. In
      patients with gross or microscopic haematuria, a significant history of smoking,
      a prior history of urothelial malignancy or symptoms of bladder outlet
      obstruction, cystoscopy would be best performed before surgery in an out-patient
      setting.

PMID- 8653325
TI  - Estramustine-binding protein to dihydrotestosterone ratio in human prostatic
      carcinoma: a new marker for predicting disease progression.
AB  - OBJECTIVE: To elucidate the clinical significance of estramustine-binding protein
      (EMBP) in human prostatic carcinoma (PC) as an indicator for predicting disease
      progression. PATIENTS AND METHODS: EMBP concentrations in prostate tissue samples
      taken from 35 patients with benign prostatic hyperplasia (BPH), 33 patients with
      prostatic carcinoma (PC) taken before treatment, and from nine patients with
      hormone-refractory PC (hr-PC) were measured by radioimmunoassay using an antibody
      raised against rat EMBP. The dihydrotestosterone (DHT), prostatic acid
      phosphatase (PAP), prostate-specific antigen (PSA) and zinc levels in the tissue
      were also measured. RESULTS: The EMBP concentration in well differentiated PC (W
      PC) samples was no higher than in samples of BPH tissue, whereas concentrations
      in moderately differentiated PC (M-PC) and poorly differentiated PC (P-PC) were
      significantly higher (P < 0.01 and P < 0.005, respectively); the highest levels
      were those in tissue from hr-PC (P < 0.001). Levels of PAP, PSA and zinc were
      significantly lower in tissue from PC than from BPH, while the differences in
      levels between W-PC, M-PC and P-PC were not significant. The EMBP to DHT ratio in
      the tissue increased significantly from W-PC through M-PC to P-PC and was
      greatest in hr-PC tissue. Conversely, the PAP:DHT, PSA:DHT and zinc:DHT ratios
      did not correlate with the progress of histological grade. In addition, the pre
      treatment EMBP:DHT and zinc:DHT ratios in 14 patients who developed hr-PC within
      3 years after the administration of estramustine phosphate were significantly
      higher when compared with the remaining 19 patients (P < 0.001 and P = 0.0184,
      respectively), whereas the PAP:DHT and PSA:DHT ratios showed no significant
      difference between the groups. Moreover, patients with a high EMBP:DHT ratio (>
      or = 82) had a low progression-free probability compared to those with a lower
      ratio. CONCLUSION: The androgen-dependent property of EMBP tends to decline with
      the transformation of prostatic tissue into biologically more malignant disease.
      The tissue EMBP:DHT ratio before treatment may be a good indicator of the
      individual malignant potential of PCs.

PMID- 8653326
TI  - Intestinal obstruction in patients with advanced malignant disease.

PMID- 8653327
TI  - Ultrasonographically guided excisional biopsy of non-palpable breast lesions.

PMID- 8653328
TI  - 'Soup ladle' autotransfusion.

PMID- 8653329
TI  - Midgut volvulus in children.

PMID- 8653330
TI  - Pattern of recurrence after oesophageal resection for cancer: clinical
      implications.
AB  - Patterns of disease recurrence were reviewed in 108 patients who had curative
      resection for squamous cell cancer of the thoracic oesophagus. At a median follow
      up of 20 months, 56 patients (52 per cent) had recurrence. Most presented within
      2 years. Extrathoracic recurrence was found in 41 per cent of patients and
      intrathoracic recurrence in 25 per cent. Systemic organ metastases (26 per cent)
      were as frequent as intrathoracic recurrences. Twelve patients (11 per cent)
      developed cervical lymph node (CLN) recurrence; their mean time to recurrence was
      12.6 months, compared with 13.1 months for recurrence at locations other than the
      neck (P = 0.8). Median survival was 23 and 13 months respectively (P = 0.27).
      Preoperative chemotherapy lowered the recurrence rate from 60 per cent to 30 per
      cent, (P = 0.01) but did not affect survival. The addition of cervical
      lymphadenectomy would benefit few patients and must be counterbalanced with
      increased morbidity and cost. The frequency of systemic organ metastases calls
      for further investigation of the possible benefits of chemotherapy.

PMID- 8653331
TI  - Randomized trial of fibrin tissue glue for low output enterocutaneous fistula.

PMID- 8653333
TI  - Prolonged peripheral parenteral nutrition with an ultrafine cannula and low
      osmolality feed.
AB  - Peripheral parenteral nutrition is an attractive alternative to centrally
      delivered parenteral nutrition because it obviates the need for central venous
      cannulation and its attendant complications. Some 45 consecutive patients were
      fed peripherally using a 22-G polyurethane catheter and a fat-based, low
      osmolality feed. Of these patients, 36 were fed for a median of 8.5 (range 3-31)
      days without peripheral vein thrombophlebitis (PVT). Seven patients developed PVT
      after a median of 6 (range 5-7) days. The cumulative daily risk of PVT was 0.016
      episodes per day. These results suggest that prolonged (more than 7 days) problem
      free peripheral parenteral nutrition is possible.

PMID- 8653332
TI  - Management of intestinal obstruction after gastrectomy for carcinoma.

PMID- 8653334
TI  - Hepatectomy with an ultrasonic dissector for hepatocellular carcinoma.
AB  - This study compared the results of hepatectomy for hepatocellular carcinoma (HCC)
      using an ultrasonic dissector with those of a combination of the crushing clamp
      and finger fracture techniques. The crushing clamp and finger fracture method was
      used from 1989 to 1992 in 96 patients (group 1) and the ultrasonic dissector from
      1993 to 1994 in 69 patients (group 2). Data from these two sets of patients were
      collected prospectively. The groups were comparable in terms of preoperative
      liver function, tumour size and stage, and the incidence of cirrhosis. Major
      hepatectomy was performed in 69 patients (72 per cent) of group 1 and in 52 (75
      per cent) of those in group 2. Use of the ultrasonic dissector resulted in lower
      mean (s.e.m.) blood loss (group 1 3.4(0.4) litres versus group 2 2.4(0.2) litres,
      P = 0.02), lower mean (s.e.m.) blood transfusion requirement (2.2(0.2) versus
      1.2(0.2) litres, P = 0.001) and more patients not requiring blood transfusion (8
      per cent of group 1 versus 32 per cent of group 2, P = 0.0001). Postoperative
      complications occurred in 45 patients (47 per cent) of group 1 and 19 (28 per
      cent) of those in group 2 (P = 0.012). There were no deaths in group 2 whereas
      the hospital mortality rate in group 1 was 16 of 96 (17 per cent) (P = 0.0004). A
      wider tumour-free resection margin (mean(s.e.m.) 1.2(0.1) versus 0.9(0.1) cm, P <
      0.05) and lower serum bilirubin level throughout the postoperative period were
      also observed in group 2 patients. The ultrasonic dissector is better than the
      crushing clamp and finger fracture technique in hepatectomy for HCC.

PMID- 8653336
TI  - Effect of a low-fat, low-protein, high-carbohydrate diet on gallstone formation
      in the hamster.

PMID- 8653335
TI  - Effects and limitations of prolonged intermittent ischaemia for hepatic resection
      of the cirrhotic liver.
AB  - Intermittent clamping of the hepatic pedicle during hepatectomy may reduce
      operative bleeding, but its limitations and long-term effects on the cirrhotic
      liver are unknown. Eighty-three patients with cirrhosis undergoing hepatectomy
      with repeated clamping for 15 min and declamping for 5 min were divided into
      three groups based on total clamping duration: group 1 less than 40 min (39
      patients); group 2 40-80 min (28); group 3 more than 80 min (16). Larger tumours
      were associated with longer ischaemia times (P = 0.002), longer operating times,
      greater operative blood loss and increased blood transfusion requirements (P <
      0.001), and resulted in higher postoperative levels of serum transaminases and
      lactic dehydrogenase (P < 0.001). Operative morbidity and mortality rates, and
      the late hepatic failure rate, were not affected. The longest total ischaemia
      time was 204 min but the uppermost time limit for hepatic ischaemia remains to be
      determined.

PMID- 8653337
TI  - Repeat hepatectomy for recurrent hepatocellular carcinoma.
AB  - This study evaluated the results of repeat hepatectomy for recurrent
      hepatocellular carcinoma (HCC) and delineated the limitations of such a treatment
      strategy. Of 290 patients who had radical hepatic resection, 167 had intrahepatic
      tumour recurrence. Fifty patients underwent a second hepatectomy. Third and
      fourth hepatectomies were carried out on six and two patients respectively. There
      were 36 men and 14 women. Age ranged from 32 to 77 years (mean 59.1 years). Liver
      cirrhosis was present in 38 and chronic hepatitis in 12 patients. Operative death
      occurred in four patients (8 per cent) after a second and in one of six after a
      third hepatectomy, compared with 4.5 per cent after first hepatectomy. The five
      postoperative deaths were attributed to either Child grade B or C liver disease,
      or severe intraoperative bleeding. The 5-year survival rate was better in these
      50 patients (41 per cent) than in 117 patients who were treated otherwise (7 per
      cent). The present study indicates that repeat hepatectomy may be useful for
      recurrent HCC. It is indicated principally for patients with a solitary tumour
      and Child grade A liver disease.

PMID- 8653338
TI  - Budd-Chiari syndrome.

PMID- 8653339
TI  - Efficacy of tumoricidal agents in vitro and in vivo.

PMID- 8653340
TI  - Introduction of laparoscopic cholecystectomy in a large teaching hospital:
      independent audit of first 3 years.

PMID- 8653341
TI  - Port site metastases after laparoscopic colorectal surgery for cure of
      malignancy.

PMID- 8653342
TI  - Mobility after lower-limb amputation.

PMID- 8653343
TI  - Splenic abscess.

PMID- 8653344
TI  - Technique for closure of port sites under laparoscopic visual control.

PMID- 8653345
TI  - Exfoliative cytology in the diagnosis of breast disease.

PMID- 8653346
TI  - Influence of screening on the incidence of ruptured abdominal aortic aneurysm: 5
      year results of a randomized controlled study.

PMID- 8653347
TI  - Clinical outcome and restenosis following percutaneous transluminal angioplasty
      for ischaemic rest pain or ulceration. Percutaneous transluminal angioplasty for
      lower-limb critical ischaemia.

PMID- 8653349
TI  - The Wilcoxon-Mann-Whitney test condemned.

PMID- 8653348
TI  - Risk-adjusted analysis of surgeon performance: a 1-year study.

PMID- 8653350
TI  - New concepts in the pathophysiology of oxygen metabolism during sepsis.

PMID- 8653351
TI  - Treatment of non-disseminated cancer of the lower rectum.
AB  - Apart from the occasional tumour which is suitable for local excision, most low
      rectal cancers are best treated by anterior resection with complete removal of
      the rectum; the construction of a coloanal reservoir should allow routine
      sphincter saving. This surgery may be carried out independently of adjuvant
      radiotherapy which, if given, should be administered before operation.

PMID- 8653352
TI  - Phlegmasia caerulea dolens and venous gangrene.
AB  - Phlegmasia caerulea dolens and venous gangrene are rare conditions that tend to
      occur in association with malignancy. They are characterized by total or near
      total occlusion of the venous drainage of the limb, including the microvascular
      collaterals. Associated mortality and morbidity rates are high, especially when
      progression to venous gangrene has occurred. Treatment options are limited;
      elevation and anticoagulation are recommended as first-line management.
      Experience with thrombolysis has been disappointing although intra-arterial
      administration of thrombolytic agents may improve results. Thrombectomy cannot be
      advocated routinely. Little advance in management, or in life and limb salvage,
      has been made in the past 30 years.

PMID- 8653353
TI  - Growth enhancement of implanted human colorectal cancer cells by the addition of
      fibroblasts in vivo.
AB  - The effect of fibroblasts on the growth of HT29 human colorectal cancer cells was
      used to study stromal modulation of tumour growth dynamics. Fibroblasts were
      isolated from rat livers, 1, 2.5 and 4 days after two-thirds partial hepatectomy
      and from normal livers. Cells harvested 2.5 and 4 days after hepatectomy ('fast'
      fibroblasts) had a significantly faster growth rate in vitro than those harvested
      on day 1 or those from normal livers (P < 0.02). The fibroblasts were inoculated
      with HT29 colorectal cancer cells into nude mice. Controls received cancer cells
      with or without a fibroblast cell line (C3H10T 1/2). At 3 weeks both tumour take
      and growth (size) were significantly greater in the group inoculated with cancer
      cells and 'fast' fibroblasts than in the other groups (tumour take 100 versus 42
      75 per cent, P < 0.03; median tumour size 3.5 versus 0.3-0.4 g, P < 0.02). In
      conclusion, tumour growth is enhanced by fibroblasts, especially by those derived
      from actively regenerating liver. It is suggested that the stimulation is not
      only mechanical but may also involve a humoral mechanism.

PMID- 8653355
TI  - Rectal prolapse.

PMID- 8653354
TI  - Prospective study of hand-sutured anastomosis after colorectal resection.
AB  - A total of 370 patients underwent colorectal resection: 320 had a primary single
      layer seromucosal anastomosis without a protective colostomy, 22 had Hartmann's
      procedure and 28 abdominoperineal resection. There were 260 elective procedures
      and 110 patients had peritonitis and/or bowel obstruction at the time of surgery.
      Overall the mortality rate was 2.7 per cent, the morbidity rate was 18.3 per cent
      and clinical anastomotic leak rate 3.4 per cent. After elective operation, the
      leak rate for intraperitoneal anastomosis was 0.6 per cent and for low
      extraperitoneal anastomosis 7 per cent. The mortality rate was 1.2 per cent and
      morbidity rate 11.9 per cent. Patients with peritonitis had a significant
      increase in morbidity rate (46 per cent) in comparison with those having elective
      surgery (chi 2 = 31.5, 1 d.f., P < 0.0001). Patients who had bowel obstruction
      and no bowel preparation had a significantly higher morbidity rate of 26 per cent
      and mortality rate of 7 per cent, compared with those having an elective
      procedure (chi 2 = 11.2, 1 d.f., P < 0.001; chi 2 = 8.7, 1 d.f., P < 0.005
      respectively). Patients having palliative surgery had the highest mortality rate
      (19 per cent), compared with those operated on with curative intent (1.5 per
      cent) (chi 2 = 28.7, 1 d.f., P < 0.0001). Cost-saving hand-sutured anastomosis is
      effective and, in experienced hands, technically feasible after all kinds of
      colorectal resection and should remain the standard in colorectal surgery.

PMID- 8653356
TI  - Total pelvic exenteration for locally advanced colorectal carcinoma.
AB  - Twenty-six patients who underwent total pelvic exenteration for locally advanced
      colorectal cancer were studied retrospectively. The operative mortality rate was
      8 per cent (two deaths). In patients with stage II primary disease the recurrence
      rate after curative surgery was three of seven, although the mean survival time
      was 58 months and the 5-year survival rate 71 per cent. Patients with stage III
      primary disease had a shorter mean survival time regardless of supposed
      curability (curative 14 months versus non-curative 9 months). Patients with stage
      IV disease had a mean survival time of 5 months. In patients who underwent
      curative surgery for recurrent disease the mean survival time was 33 months and 5
      year survival rate 25 per cent, although in those receiving non-curative surgery
      the survival time was significantly shorter at 10 months (P < 0.05). Total pelvic
      exenteration is warranted for patients with stage II locally advanced colorectal
      carcinoma and is an option for those with recurrent carcinoma when performed with
      curvative intent.

PMID- 8653357
TI  - Cell proliferation kinetics are abnormal in transitional mucosa adjacent to
      colorectal carcinoma.
AB  - The transitional mucosa adjacent to colorectal carcinoma shows characteristic
      morphological and histochemical abnormalities that may be indicative of
      premalignant changes. Sixteen colorectal carcinomas were studied to analyse the
      proliferative activity and its distribution pattern in tissue samples from
      transitional mucosa located within 2 cm of the cancer and from uninvolved mucosa
      10 cm from the cancer. Proliferative activity was assessed using a monoclonal
      antibody to proliferating cell nuclear antigen (PCNA). The total labelling index
      (percentage of labelled cells in a column) of transitional mucosa was not
      significantly different from that of uninvolved mucosa and normal control mucosa
      but it was significantly higher in cancer tissue (P < 0.001). An upward shift of
      the compartment of proliferating epithelial cells towards the bowel lumen was
      seen in transitional mucosa. The labelling index of the middle compartment
      (compartment 3) of the crypt in transitional mucosa was significantly higher than
      that in uninvolved mucosa and control mucosa (P < 0.001). Unstable cytokinetic
      change may already have started in apparently normal transitional mucosa.
      Assessment of cell proliferation kinetics by PCNA immunostaining may be useful in
      screening for heightened risk of the development of colorectal cancer.

PMID- 8653358
TI  - Randomized trial of fibrin glue to seal mechanical oesophagojejunal anastomosis.

PMID- 8653359
TI  - Multicentre study of surgical complications of colonoscopy.
AB  - A total of 196 records of colonoscopic surgical complications were reviewed
      during a 12-year period. Perforation (183 patients) and haemorrhage (11) were the
      two main complications. Diagnosis of perforation was delayed in 58 per cent of
      patients. The sigmoid colon was the site of perforation in 72 per cent with
      evidence of peritoneal contamination in 59 per cent. Postoperative mortality rate
      of perforation was 12 per cent and was significantly related to a past history of
      medical disease and size of perforation. Postoperative morbidity rate was 43 per
      cent. There were two deaths after colostomy closure. The overall mortality rate
      of colonoscopic perforation requiring an emergency surgical procedure reached 14
      per cent. Haemorrhage always occurred after endoscopic polypectomy; the
      postoperative course was uneventful in these patients.

PMID- 8653360
TI  - Failure of the unopened colostomy to protect high-risk rectal anastomoses.

PMID- 8653361
TI  - Long-term outcome following curative surgery for malignant large bowel
      obstruction.
AB  - This study determined whether the long-term outcome of patients with obstructing
      colorectal cancer could be related to conventional pathological prognostic
      variables or to other clinical, operative or histological features. Ninety-eight
      patients with bowel obstruction who had undergone potentially curative surgery
      and survived the postoperative period were studied. Features related to poor long
      term outcome after a median follow-up of 5 years included bowel perforation at
      initial operation (P = 0.007), advanced tumour stage (P < 0.001), poor tumour
      differentiation (P = 0.02), mucin production by tumour (P = 0.004) and the
      presence of vascular (P = 0.08) and neural (P = 0.004) invasion. Outcome was not
      significantly related to the seniority of the operating surgeon (P = 0.52), even
      when this was adjusted for potentially confounding variables (adjusted hazard
      rate ratio for trainee surgeons 1.4 (95 per cent confidence interval 0.9-2.4), P
      = 0.16). Conventional prognostic features may help to identify the majority of
      patients with obstructed colorectal cancer at high risk of tumour recurrence and
      death.

PMID- 8653362
TI  - Wandering spleen: a rare emergency condition.

PMID- 8653363
TI  - Sphincter function after transanal endoscopic microsurgical excision of rectal
      tumours.

PMID- 8653364
TI  - Anorectal angle enhances faecal continence.
AB  - This study was performed with an in vitro model to assess the relative importance
      of sphincter pressure and anorectal angulation in maintaining faecal continence.
      Water and semisolid material were infused separately into porcine intestine
      compressed by an inflatable cuff until leakage was observed. Angulation of the
      bowel with respect to the cuff was 180 degrees and then 90 degrees. With water,
      holdback pressure was independent of angulation. In contrast, when semisolid
      material was used, angling the bowel to 90 degrees increased holdback pressure by
      at least 100 per cent. Measurements taken in solid tubes demonstrated that both a
      restriction in the tube and an unconstricted 90 degrees bend produced a
      resistance to flow of the semisolid material which was dependent on flow rate.
      These data suggest that liquid is retained in the rectum by occlusion pressure
      alone, whereas the retention of semisolid material is enhanced by angulation.

PMID- 8653365
TI  - Total anorectal reconstruction results in complete anorectal sensory loss.
AB  - Six patients underwent objective measurement of anorectal sensory function
      following abdominoperineal excision of the rectum and total anorectal
      reconstruction. No patient perceived neorectal distension as a desire to
      defaecate or as a feeling of flatus. Anal mucosal sensation was preserved in two
      patients in whom some anal mucosa was retained. These sensory deficiencies may
      result in faecal retention and incontinence in patients undergoing reconstructive
      surgery. The loss of rectal sensation suggests that the prime sensors of rectal
      filling may lie within the rectum itself.

PMID- 8653366
TI  - Malignant ascites.
AB  - Investigation and treatment of malignant ascites are often in the hands of the
      general surgeon and can be difficult. This article considers the aetiology and
      pathophysiology of malignant ascites and explores the best form of management.
      Established treatment modalities and new therapeutic options are reviewed and a
      new management regimen based on a knowledge of the tumour of origin is proposed,
      which aims to balance potential benefit against morbidity.

PMID- 8653367
TI  - Anastomotic leakage and functional outcome after anterior resection of the
      rectum.
AB  - Nineteen patients with symptomatic anastomotic leakage after anterior resection
      were compared with 19 without leakage. The two groups were closely matched
      according to age, sex, height of anastomosis and follow-up. No patient had any
      sign of anastomotic stricture or neoplastic recurrence at the time of the study.
      After a median of 30 (range 12-87) months there was no difference in sphincter
      function as measured by manometry. 'Neorectal' volume at distension pressures of
      40 and 50 cmH2O and compliance at sensation of filling, urge to defaecate and
      maximum tolerated volume were significantly reduced in patients with leakage.
      This reduction in neorectal reservoir function was reflected in impaired
      anorectal function, measured by a combination of: (1) frequency of bowel
      movements; (2) degree of urgency; (3) incontinence score; and (4) degree of
      impaired evacuation. Long-term functional outcome may be impaired by anastomotic
      leakage.

PMID- 8653369
TI  - New technique for subcuticular suture in lengthy wounds.

PMID- 8653368
TI  - Ischaemic nature of anal fissure.
AB  - Microvascular perfusion of the anoderm was assessed by laser Doppler flowmetry in
      27 patients with anal fissure. Anal pressure was recorded simultaneously. Both
      measurements were repeated 6 weeks after lateral internal sphincterotomy and
      compared with those obtained from 27 controls. Means(s.d.) maximum anal resting
      pressure was significantly higher in those with a fissure than in controls
      (121.07(24.48) versus 68.78(16.97) mmHg, P < 0.001). Anodermal blood flow at the
      fissure site was significantly lower than at the posterior commissure of the
      controls (0.46(0.20) versus 0.76(0.28) V, P < 0.001). The fissure healed in 24
      patients within 6 weeks of sphincterotomy. In these patients a significant
      pressure decrease was noted (35 per cent) which was accompanied by a consistent
      rise in blood flow (65 per cent) at the original fissure site. The increased
      internal sphincter tone in patients with a fissure reduces anodermal blood flow
      at the posterior midline. Reduction of anal pressure by sphincterotomy improves
      anodermal blood flow at the posterior midline, resulting in fissure healing.
      These findings provide evidence for the ischaemic nature of anal fissure.

PMID- 8653370
TI  - Thoracic and thoracoabdominal aortic aneurysm and dissection: an investigation
      based on autopsy.
AB  - The city of Malmo (population approximately 230,000) has a fairly stable urban
      population and a high autopsy rate (83 per cent of all deaths). Autopsy records
      for the period from 1958 to 1985 were scrutinized and three groups of patients
      were defined: those with asymptomatic thoracic aortic aneurysm (TAA), those with
      rupture of the thoracic aorta, and those with dissection. The findings were used
      to calculate prevalence and incidence according to age and sex. Asymptomatic TAA
      was found in 205 patients (109 men). There was a predominance of men in higher
      age groups and about 5 per cent of the lesions were thoracoabdominal. Rupture of
      the thoracic aorta was the cause of death in 63 patients; no age difference
      between the sexes was observed. Death as a result of dissection occurred in 216
      patients, women dying on average 7 years later than men. The incidence of rupture
      was 0.9 per 100,000 for men and 1.0 per 100,000 for women; the incidence of
      dissection was 3.2 per 100,000 for both sexes. Prevalence and incidence of fatal
      complications of TAA are low; this may influence decisions about where these
      patients should be treated.

PMID- 8653371
TI  - Role of cimetidine in the prevention of intimal hyperplasia in rat carotid
      artery.
AB  - In vitro studies have revealed that histamine increases smooth muscle cell
      proliferation and migration, an effect abolished by the H2 antagonist cimetidine.
      This study examined the effect of cimetidine on intimal hyperplasia in vivo.
      Thirty male Wistar rats underwent endothelial denudation of the left carotid
      artery; 15 received cimetidine 350 mg per kg per day for four weeks and 15
      received vehicle only. Four weeks after injury the left carotid arteries were
      perfusion fixed and harvested. Morphometric analysis revealed that there was no
      significant difference between the intima:media ratio of rats treated with
      cimetidine (median (interquartile range (i.q.r.)) 1.69 (0.59)) and those treated
      with vehicle (median (i.q.r.) 1.59 (0.59), P = 0.28). Similarly, the percentage
      luminal reduction was not significantly different between the groups (median
      (i.q.r.) 54.7 (19.9) per cent and 45.8 (13.4) per cent respectively, P = 0.30).
      It is concluded that treatment with cimetidine does not reduce the formation of
      intimal hyperplasia in rat carotid arteries de-endothelialized with a balloon
      catheter.

PMID- 8653373
TI  - Real and apparent mortality from congenital diaphragmatic hernia.
AB  - Some 50 cases of congenital diaphragmatic hernia (CDH) born in the authors'
      regional referral area over the 14 years from 1980 to 1993 were reviewed,
      contrasting 7 years when management included preoperative ventilatory
      stabilization with the preceding 7 when urgent surgery was performed. Six
      children experienced no respiratory distress and suffered no mortality. For
      infants with respiratory distress in the first 6 h of life, ventilatory
      stabilization improved survival rates of those who reached the surgical centre
      from 45 per cent between 1980 and 1986 to 59 per cent between 1987 and 1993. A
      larger proportion of the total number of patients, however, continued to die
      without reaching the surgical centre. The improvement in survival rate based on
      the true incidence of CDH was from 28 per cent in the first period to 38 per cent
      in the second. The apparent poor survival rate of patients born in central
      obstetric units compared with those born in peripheral units (37 versus 75 per
      cent) can be attributed to patient selection; a larger number of children born in
      central units were transferred for surgery (70 versus 57 per cent). There is no
      evidence that paediatricians have altered their referral practice to include
      prolonged ventilation outside the surgical unit since delayed surgery was
      advocated. Assessment of the impact of altering the management of CDH cannot be
      made without knowing the number of patients who die before transfer to a neonatal
      surgical unit. Any serious attempt to reduce the mortality rate of CDH must be
      directed to neonates who are not presently referred to the surgical service.

PMID- 8653372
TI  - Importance of human immunodeficiency virus-associated lymphadenopathy and
      tuberculous lymphadenitis in patients undergoing lymph node biopsy in Zambia.
AB  - The relative importance of human immunodeficiency virus (HIV)-associated
      lymphadenopathy amongst patients presenting for lymph node biopsy in Central
      Africa is unknown. HIV-1 serology and histology of patients undergoing
      superficial lymph node biopsy during 1989-1990 in Lusaka, Zambia, were examined
      in a prospective cohort study of HIV serology and by retrospective review of
      laboratory records. Of 727 lymph nodes biopsied in Lusaka in 1989-1990, 380 (52
      per cent) showed tuberculous lymphadenitis, 160 (22 per cent) histology
      suggestive of primary HIV lymphadenopathy and 66 (9 per cent) nodal Kaposi's
      disease. HIV serology was tested in 280 adults and was positive in 91 per cent
      (255 patients), including 89 per cent (153 of 171) of those with tuberculous
      lymphadenitis, 98 per cent (63 of 64) of those with histology suspicious of
      primary HIV lymphadenopathy and all (24 of 24) with nodal Kaposi's disease. Other
      HIV-associated lymphadenopathy included nodal lymphomas and lymphoepithelial
      cysts. HIV serology was tested in 22 children and was positive in eight,
      including four of 14 with tuberculous lymphadenitis. It is concluded that HIV
      associated lymphadenopathy, especially tuberculous lymphadenitis, is very common
      amongst patients presenting for lymph node biopsy in Central Africa.

PMID- 8653374
TI  - Management options in vertebral artery injuries.
AB  - The treatment of 22 patients with vertebral artery injuries was reviewed. Only
      four patients required an emergency operation. Most of the injuries (13 of 22)
      were successfully managed by observation. Five patients were managed by
      angiographic embolization which was successful in three. In three patients with
      an aneurysm and arteriovenous fistula, proximal embolization of the vascular
      lesion was not adequate and a suboccipital craniectomy was required for distal
      ligation. Most vertebral artery injuries can safely be managed without an
      operation, or by angiographic embolization. Surgical intervention should be
      reserved for patients with severe bleeding or where embolization has failed.

PMID- 8653375
TI  - Open diagnostic peritoneal lavage.

PMID- 8653376
TI  - Diaphragmatic herniation after penetrating trauma.
AB  - A study was made of 45 patients with diaphragmatic herniation after penetrating
      trauma. In 29 the diagnosis was established during the first admission (early
      presentation) and in 16 during a subsequent admission (delayed presentation). The
      mortality rate in the early presentation group was 3 per cent compared with 25
      per cent in the delayed presentation group. The presence of gangrenous or
      perforated abdominal viscus in the chest cavity was the single most common and
      severe aggravating factor. The need for diagnosis of diaphragmatic herniation
      during the initial admission is emphasized. As isolated diaphragmatic injuries
      provide few helpful clinical features to aid diagnosis, appropriate
      investigations and good follow-up are of paramount importance in preventing late
      herniation of intra-abdominal viscera through a penetrating diaphragmatic injury.

PMID- 8653377
TI  - Audit of outcome of major surgery in the elderly.
AB  - The clinical outcome of 152 patients aged 65 years or over who were referred to
      the author's institute between August 1990 and August 1991 with certain specified
      gastrointestinal malignancies and acute, life-threatening abdominal conditions,
      were audited concurrently. Two groups were considered: patients aged 65-79 years
      and those over 80 years. The mortality rate within 30 days of surgery was 14 per
      cent in both age groups, although significantly fewer patients aged over 80 years
      (35 of 54) were considered suitable for surgery than in the 65-79 years age group
      (84 of 98) (0.01 > P > 0.001). Morbidity after operation and cost of treatment
      were not significantly different between the two groups. Two years after surgery
      40 per cent of the patients aged over 80 years and 58 per cent of those aged 65
      79 years were alive. Quality of life in these survivors was good with 85 per cent
      of those aged over 80 years living at home and 72 per cent fit enough to
      undertake light work.

PMID- 8653378
TI  - Cell kinetics in vivo of human breast cancer.
AB  - Rates of cell proliferation within tumours may provide prognostic information and
      help in the rational administration of chemotherapy and radiotherapy. In vivo
      labelling with 5-bromo-2'-deoxyuridine (BrdU) was used in 89 women with breast
      cancer to determine the labelling index for BrdU (BLI), the length of S phase
      (TS) and the potential doubling time of the tumour (Tpot). Kinetic data were
      obtained in 84 patients. The median BLI was 3.2 per cent, TS 12 h, and Tpot 12.5
      days. There was no systematic difference in the labelling index determined by
      flow cytometry and by manual counting on sections. Labelling indices were
      significantly higher in aneuploid tumours, and in tumours not expressing
      oestrogen receptors, but were not correlated with tumour size, nodal status, or
      expression of c-erbB2. In vivo measurement of tumour cell kinetics can be made
      rapidly and reliably in the majority of human breast cancers, and may have a role
      to play in planning therapy.

PMID- 8653379
TI  - Organochlorine compounds in blubber, liver and brain in neonatal grey seal pups.
AB  - The present study focuses on the distribution and accumulation of persistent
      organochlorine compounds in different tissues and organs of grey seal
      (Halichoerus grypus) pups. Thus, levels of drins (aldrin, dieldrin, endrin),
      chlordanes (heptachlor, heptachlorepoxide, oxychlordane, transnonachlor), DDTs
      (p,p'-DDE, o,p'-DDD, p,p'-DDD, o,p'-DDT, p,p'-DDT) and 22 PCB congeners were
      determined in samples of brain, fat, and liver of 0-10 days old grey seal pups
      from the species' main breeding site in Norway. Whereas 10 different compounds
      were detected in the blubber, 8 compounds were detected in the liver. The
      concentrations of the two major classes of OCs (PCBs and DDTs) in liver were both
      about 75% of that in blubber. In cerebral tissue, only two PCB congeners were
      detected, and sigma PCB was only about 1% of that measured in the blubber. The
      distribution pattern of PCB-congeners in liver and brain differed significantly
      from that in blood and blubber tissue, indicating that the physico-chemical
      properties of the individual congeners and the lipid composition of the tissue
      are decisive for the tissue-specific pattern of congener distribution. A
      significant increase of the sigma DDT/sigma PCB-ratio as a function of blubber
      thickness indicates that DDT compounds are more readily accumulated in older
      pups.

PMID- 8653380
TI  - Temporal induction pattern of hepatic cytochrome P450 1A in thermally acclimated
      dab (Limanda limanda) treated with 3,3',4,4'-tetrachlorobiphenyl (CB77).
AB  - Mature male dab (Limanda limanda) acclimated at 10 degrees and 16 degrees C were
      orally administered a single dose of 0.5 mg/kg 3,3',4,4'-tetrachlorobiphenyl
      (CB77). At both temperatures, levels of cytochrome P450 1A (CYP1A) protein and 7
      ethoxyresorufin O-deethylase (EROD) activity showed a two to six fold induction
      40 days after CB77 treatment compared to control groups. Maximum responses of
      both EROD activity and CYP1A protein for the warm-acclimated fish were observed
      at 5 days after treatment. For the cold-acclimated fish a slow, progressive
      elevation for both EROD activity and CYP1A protein was observed and maximum
      responses were measured 40 days after treatment. Absolute EROD activity and CYP1A
      protein levels of fish from both temperatures were equally high at 40 days after
      treatment. Since in the control groups EROD activity and CYP1A protein levels
      were higher in the cold-acclimated fish, the magnitude of induction was higher in
      the warm acclimated ones. The highest concentrations of CB77 in muscle of fish
      from both temperatures were found at 5 and 10 days after treatment. The liver
      somatic index (LSI) showed 1.5 fold significantly higher values for the fish
      acclimated at 10 degrees C.

PMID- 8653381
TI  - Evaluation of toxicity and sex-related variation of PCB levels in Mediterranean
      striped dolphins affected by an epizootic.
AB  - Individual PCB congener concentrations, including non-ortho chloro substituted,
      were determined in 30 striped dolphins (Stenella coeruleoalba) affected by the
      1990-92 Mediterranean epizootic to investigate their toxic potential. PCB
      congener concentrations in these dolphins were among the highest ever found in
      comparable studies on marine mammals. Concentrations in males and females were
      significantly different because of pollutant transfer to offspring by females.
      Thus, PCB concentrations and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic
      equivalents (TEQ) in males were approximately double those in females. Non-ortho,
      mono-ortho and di-ortho coplanar congeners accounted for approximately one third
      of the overall toxicity assessed through toxic equivalent factors (TEFs), as
      defined by Ahlborg et al. (1994). Di-ortho congener 170 and non-ortho congener
      126 were the major contributors to TEQ (33% and 30% respectively).

PMID- 8653382
TI  - Pilot study on the contamination of drinking water by organotin compounds from
      PVC materials.
AB  - Raw and treated water samples and tap water samples from four to six houses
      located on distribution lines where PVC pipe/tubing had been recently installed
      were collected in five Canadian municipalities for the analysis of organotin
      compounds. After derivatisation with sodium tetraethylborate the ethylated
      organotin compounds were extracted with hexane and analysed by gas chromatography
      microwave induced plasma atomic emission spectrometry using a wavelength (326.234
      nm) specific for tin. Organotin compounds, mainly methyltin and dimethyltin at
      concentrations ranging respectively from 0.5 to 257 ng Sn/L and from 0.5 to 6.5
      ng Sn/L, were detected in samples from ten of the twenty-two houses. No organotin
      compounds were detected in raw water or treated water leaving the treatment
      plant, indicating that the organotin compounds were leaching into the water from
      some component of the distribution system.

PMID- 8653383
TI  - A survey of PCB congeners in U.K. cows' milk.
AB  - Samples of unpasteurised bulked milk, taken directly from ten herds of dairy
      cattle on rural and urban farms in the north west of England on five separate
      sampling occasions, were analysed for a range of PCB congeners. Sigma PCB
      concentrations (sum of 37 congeners) ranged from 3.4-16.4 ng/g milk fat with a
      mean sigma PCB concentration of 8.4 ng/g milk fat. The dominating congeners were
      118, 153, 138 and 180, which contributed 15%, 20%, 17% and 9% of the sigma PCB
      load respectively. The chlorine pattern of the congeners which made moderate or
      major contributions to the sigma PCB concentration were typically substituted at
      both para positions (4,4'), while the PCB congeners not detected in the milk had
      at least one ring that was not 4-substituted. These results indicate the 4,4'
      substitution pattern as being the key to PCB persistence in cows. It is estimated
      that consumption of typical daily intakes of milk with the PCB concentrations
      measured in this study would contribute 11% of the average daily sigma PCB intake
      for individuals in the UK. This contribution would increase to 30% when exposure
      through the consumption of dairy products prepared from such milk (e.g. cheese,
      butter) is taken into account. It is estimated that the inclusion of the TEF
      assigned PCBs would typically increase the TEQ rating of cows' milk by
      approximately 40% over that attributed to PCDD/Fs alone.

PMID- 8653384
TI  - Structure-toxicity relationships for phenols to Tetrahymena pyriformis.
AB  - Quantitative structure-activity relationships are developed for the toxicity of
      166 varied phenol derivatives to the ciliate Tetrahymena pyriformis. A variety of
      physico-chemical descriptors were calculated but no significant relationship
      could be obtained for all 166 compounds. When certain chemical groups were
      omitted from the correlation however, notably the carboxyl-, amino-, nitro,
      nitroso and acetamide- substituted phenols, an excellent correlation was obtained
      between toxicity and two parameters. These two parameters (log P and energy of
      the lowest unoccupied molecular orbital) are explained mechanistically in that
      they model transport and electrophilicity. The resultant QSAR gave accurate
      prediction of the toxicity of alkyl, halogenated, alkoxy and aldehyde substituted
      phenols.

PMID- 8653385
TI  - The presence of glass beads or Triton X-100 in the medium enhances the aerobic
      dechlorination of Aroclor 1221 in Pseudomonas sp. CPE1 culture.
AB  - The culture pure Pseudomonas sp. CPE1 strain capable of metabolizing low
      chlorinated biphenyls in the presence of biphenyl was found to be able to grow on
      Aroclor 1221 in the absence of an additional carbon source. The presence of glass
      beads (diameter = 3 mm, 30% w/v) or Triton X-100 (0.066% v/v) in the culture
      medium significantly enhanced the aerobic dechlorination of the polychlorinated
      biphenyls present in Aroclor 1221 in batch cultures of CPE1 strain. This result
      has been ascribed to an increase of Aroclor 1221 bioavailability in the cultures
      containing glass beads or Triton X-100, probably deriving from a greater
      interface area PCB-water, i.e. the surface area on which the polychlorobiphenyl
      degradation seems to take place.

PMID- 8653386
TI  - Aroclor 1221 aerobic dechlorination by a bacterial co-culture: role of
      chlorobenzoic acid degrading bacteria in the process.
AB  - A bacterial co-culture, ECO3, constituted by a polychlorobiphenyl degrading
      bacterium, Pseudomonas sp. strain CPE1, and two chlorobenzoic acid degrading
      bacteria, could grow on Aroclor 1221 (75 mg/L) as the sole carbon source without
      accumulating chlorinated aromatic metabolites in the medium; 44.5% of the Aroclor
      1221 organic chlorine was detected as chloride ion in the medium after 115 h of
      incubation in batch condition. When glass beads (diameter = 3 mm, 30% w/v) or
      Triton X-100 (0.066% v/v) were added to ECO3 cultures, average dechlorination
      percentages were 80% and 89.5%, respectively, after the same incubation time.
      These percentages were significantly higher than those previously observed with
      the only polychlorobiphenyl degrading member of ECO3, CPE1 strain, in the same
      culture conditions. This result can be ascribed to the capability of the ECO3
      chlorobenzoic acid degrading bacteria of completely mineralizing the chlorinated
      benzoic acids produced during the Aroclor 1221 degradation. The depletion of
      these intermediates seems to prevent toxic or inhibitory effects on the bacteria
      thus permitting a larger Aroclor 1221 metabolization.

PMID- 8653387
TI  - Biodegradability of fluorinated surfactants under aerobic and anaerobic
      conditions.
AB  - The "ready biodegradability" of three fluorinated surfactants was determined
      under aerobic and anaerobic conditions. Surfactant 1, a solution of a fluorinated
      surfactant in water, was easily degradable under both aerobic and anaerobic
      conditions during the incubation periods of 28 and 60 days, respectively.
      Surfactant 2, a nonionic fluorinated surfactant, was degraded under aerobic
      conditions in a range of 35-77% during 28 days depending on the source of
      activated sludge. Aerobic degradation was inhibited by the nitrification
      inhibitor dicyandiamide indicating that ammonium oxidizing bacteria may play a
      role in degradation of surfactant 2. Under anaerobic conditions surfactant 2 was
      not degraded. Surfactant 3, an anionic fluorinated surfactant, was degraded
      neither under aerobic nor under anaerobic conditions. Under anaerobic conditions,
      surfactant 3 inhibited the methane production rate of sludge from a digester. The
      EC50, i.e. the concentration of surfactant 3 that inhibited 50% of
      methanogenesis, was determined at 160 mg/l.

PMID- 8653388
TI  - An exploration of right-hemisphere contributions to the pragmatic impairments of
      autism.
AB  - This study examined the potential contribution of the right hemisphere to the
      communicative impairments of autism. Pragmatic language measures sensitive to
      right-hemisphere damage were administered to nonretarded adults with autism and
      to controls matched on age and intellectual ability. The experimental battery
      included measures of humor, inference, and indirect request comprehension.
      Autistic subjects performed significantly less well than controls on all
      measures, replicating results of an earlier investigation by Rumsey and Hanahan
      (Journal of Clinical and Experimental Neuropsychology, 12, 81, 1990). The
      performance of the autistic group on the three tasks was also similar to that of
      right-hemisphere stroke patients reported previously (Molloy, Brownell, &
      Gardner, in Y. Joanette and H. M. Brownell (Eds.), Discourse ability and brain
      damage: Theoretical and empirical perspectives, New York: Springer-Verlag,
      1990,pp. 113-130). Generalizability of these results and implications for the
      neuropathology of autism are discussed.

PMID- 8653389
TI  - Silent speech activates prefrontal cortical regions asymmetrically, as well as
      speech-related areas in the dominant hemisphere.
AB  - Regional cerebral blood flow (rCBF) was measured simultaneously over the right
      and left hemispheres by 2 x 32 detectors in 30 healthy volunteers with a two
      dimensional iv xenon-133 technique, during (1) rest and during (2) audible and
      (3) silent counting (101, 102,...). Mean hemisphere CBF increased significantly
      in both hemispheres during the activations. Audible speech activated rolandic and
      temporoparietal regions mainly on the right side. This pattern covers auditory
      and para-auditory as well as motor (tongue/larynx) regions. Most likely those
      regions are involved in auditory feedback and voice control. Silent speech
      (internal speech) gave a clearly different activation pattern involving (1) left
      sided regions related to speech perception and speech motor control (including
      the SMA) and (2) a right dorsolateral prefrontal area that may be related to
      attention mechanisms. The silent speech pattern appears to demonstrate aspects of
      internal (cognitive) feedback activity in which prefrontal cortical regions are
      activated significantly. Audible and silent counting may represent two
      principally different types of cerebral feedback systems, one for overt sensory
      motor activity and one for a pure internal cognitive feed-back.

PMID- 8653390
TI  - Localization of syntactic comprehension by positron emission tomography.
AB  - Positron Emission Tomography (PET) was used to determine regional cerebral blood
      flow (rCBF) when eight normal right-handed males read and made acceptability
      judgments about sentences. rCBF was greater in Broca's area (particularly in the
      pars opercularis) when subjects judged the semantic plausibility of syntactically
      more complex sentences as compared to syntactically less complex sentences. rCBF
      was greater in left perisylvian language areas when subjects had to decide
      whether sentences were semantically plausible than when subjects had to decide
      whether syntactically identical sentences contained a nonsense word. The results
      of this experiment suggest that overall sentence processing occurs in regions of
      the left perisylvian association cortex. The results also provide evidence that
      one particular aspect of sentence processing (the process that corresponds to the
      greater difficulty of comprehending center-embedded than right-branching relative
      clause sentences) is centered in the pars opercularis of Broca's area. This
      process is likely to be related to the greater memory load associated with
      processing center-embedded sentences.

PMID- 8653391
TI  - Atypical hemispheric specialization in intellectual deficiency.
AB  - In order to determine the relation between hemispheric specialization for
      language and intellectual deficiency, two groups of lower-IQ subjects were
      compared to normal-IQ controls on word-dichotic listening tasks. Two conditions
      in which stimuli differed by their level of phonological complexity were used.
      Normal controls showed the expected right-ear advantage in both conditions.
      Moreover, they showed a greater magnitude of ear difference on the condition
      requiring higher-order phonological processing. In the mentally deficient group,
      almost half the subjects exhibited a left-ear advantage and they showed no
      difference between the two conditions in terms of the magnitude of ear
      difference. These results point to the presence of atypical hemispheric
      specialization in mentally deficient subjects.

PMID- 8653392
TI  - A grammatical specific language impairment in children: an autosomal dominant
      inheritance?
AB  - The aim of this study is to provide further characterization of a subgroup of so
      called "Grammatical specific language-impaired (SLI)" children. The Grammatical
      SLI children have a persistent and disproportionate impairment in grammatical
      comprehension and expression of language. Previous research has indicated that
      their language impairment may be characterized by a domain-specific and modular
      language deficit. This study provides an initial investigation as to whether
      there is a genetic basis underlying their disorder as has been found for other
      forms of SLI and for SLI in general. The incidence of familial aggregation of
      language impairment was investigated in 12 Grammatical SLI children (aged 9:3 to
      12:10). A familial language impairment (LI) history was classified as positive if
      one or more of the probands' relatives had a history of a speech/language or
      reading/writing problem which required speech therapy or any other form of
      remedial help. Case history information provided an initial indication that the
      Grammatical SLI children had a significantly higher incidence of a positive
      familial LI history than could be expected by chance. A questionnaire provided
      evidence of a positive LI history in the first-degree relatives of the SLI
      probands and 49 normally developing control probands. The SLI probands had a
      clearly and significantly higher incidence of a positive familial LI history than
      the control probands (77.8 vs. 28.5%, respectively). The results are consistent
      with a genetic basis underlying Grammatical SLI. The pattern of impairment in the
      SLI probands' relatives is consistent with an autosomal dominant genetic
      inheritance. In contrast to the control probands, the SLI probands' impaired
      relatives did not show a male gender bias. Thus, the gene does not appear to be
      sex-linked. The data indicate that further research is warranted to investigate
      the nature of the LI in the relatives of the Grammatical SLI probands and the
      genetic characteristics of this subgroup. The implications for the biological,
      domain-specific, and modular bases to language are discussed.

PMID- 8653393
TI  - Tonal coarticulation in Thai after unilateral brain damage.
AB  - The magnitude and temporal extent of anticipatory and perseverative tonal
      coarticulation was investigated in Thai-speaking normal and brain-damaged adults.
      A total of 47 speakers (10 young normal, 10 old normal, 13 nonaphasic right-brain
      damaged patients, 14 left-brain-damaged aphasic patients, 9 fluent, 5 nonfluent)
      produced all 25 possible sequences of two tones from the five lexical tones of
      Thai embedded in a carrier sentence. F0 contours were analyzed in terms of height
      and slope at 10% intervals throughout the duration of the two syllables. Acoustic
      analysis revealed that anticipatory and perseverative tonal coarticulation of
      tones was markedly reduced in left fluent aphasics, totally absent in left
      nonfluent aphasics, but reasonably intact in right hemisphere patients. Findings
      are interpreted to highlight the nature of speech disturbances in nonfluent and
      fluent aphasia, hemispheric specialization for tone, and tonal coarticulation in
      Thai.

PMID- 8653394
TI  - Category and attribute knowledge deterioration in Alzheimer's disease.
AB  - A prevalent theory regarding the deterioration of semantic memory in Alzheimer's
      disease is that it is a bottom-up process. If this is true, performance on tests
      of attribute knowledge should decline more rapidly than performance on tests of
      categorical knowledge as dementia severity increases. In the present study, a
      convincing pattern of findings to either support or reject the theory failed to
      emerge. This raised questions regarding the ability to separate attribute and
      categorical knowledge, and whether one can be tested without influence of the
      other. Questions also were raised regarding the additional cognitive processes
      needed to complete tasks of semantic memory.

PMID- 8653395
TI  - Lexical and nonlexical spelling deficits in dementia of the Alzheimer type.
AB  - Written spelling was assessed in 16 subjects with dementia of the Alzheimer type
      (DAT) using an information processing approach. The results were compared to the
      performance in a group of healthy elderly subjects. The Alzheimer subjects scored
      significantly lower in word spelling and nonword spelling ability than the
      controls (F(1, 7) = 187, p < .0001), and both the lexical and the nonlexical
      spelling strategies were affected. The results did not support the hypothesis
      that nonlexical ability is preserved in DAT. In the DAT group, spelling
      correlated significantly (p < 0.01) with the severity of dementia, but spelling
      performance was not associated with the age of onset of dementia or family
      history of dementia.

PMID- 8653396
TI  - Inhibitor of protein synthesis phase-shifts the circadian oscillator and inhibits
      the light induced-phase shift of the melatonin rhythm in pigeon pineal cells.
AB  - Our recent study showed that dissociated pigeon pineal cells expressed a
      circadian oscillation of melatonin release which entrained to light-dark cycle
      and persisted under constant darkness in vitro, suggesting that pigeon pineal
      cells contain the circadian oscillator and photoreceptors. Six-hour pulses of
      anisomycin, an inhibitor of protein synthesis that acts at hte 80S ribosomal
      subunit, induced steady state and phase depended phase shifts of the circadian
      oscillation of melatonin release. The phase advances and delays were produced at
      CT 7.9 h and between CT 18.6 h and CT 4.5 h, respectively. The magnitudes of
      phase shifts were dose dependent and correlated with the magnitudes of inhibition
      of protein synthesis determined at CT 4.5 h. Furthermore, anisomycin blocked the
      light-induced phase advance. Two dimensional electrophoresis revealed that
      synthesis of two proteins with Mr of 17,600 and less than 5000 are stimulated by
      a 3-h light pulse at CT 18.6 h which corresponds to the light-induced phase
      advance region. These results suggest that 80S ribosomal protein synthesis is
      involved in normal or light-entrainment functions of the circadian oscillator in
      pigeon pineal cells.

PMID- 8653397
TI  - Phospholipase A2-induced neurotoxicity in vitro and in vivo in rats.
AB  - The present study evaluated the neurotoxic potential of phospholipase A2 (PLA2)
      in in vitro (primary neuronal cultures) and in vivo (EEG and behavior) rat models
      of CNS excitability. In vitro, PLA2 (0.0038-5.8 nM) or melittin (a potent
      activator of endogenous PLA2; 100-5000 nM), were highly neurotoxic, causing
      approximately 500 units/ml LDH release. The neurotoxic EC50s for PLA2 and
      melittin were 1.8 (1.4-2.3) and 848 (501-1280) nM, respectively. Neurotoxic
      concentrations of PLA2 stimulated neuronal release of [3H]AA. Preliminary in
      vitro experiments evaluating changes in neuronal calcium flux indicated that PLA2
      caused transient, and melittin sustained, increases in [Ca2+]i. In vivo, PLA2
      (0.5-5 micrograms i.c.v.) or melittin (2.5-20 micrograms i.c.v.) produced
      nonconvulsive EEG seizures, which generalized to status epilepticus. While the
      onset of seizure development was markedly delayed for PLA2 (1.5-4.5 h), the
      seizure inducing effects of melittin were evident within 3.5 +/- 0.2 min and more
      severe. Both PLA2 and melittin were lethal, exhibiting LD50s of 0.62 micrograms
      and 8.4 micrograms, respectively. Pretreatment with (+)-MK801 (5 micrograms,
      i.c.v.) significantly attenuated melittin, but not PLA2, in vivo neurotoxicity.
      PLA2 induced neuropathology in surviving rats revealed extensive cortical and
      subcortical injury to forebrain neurons and fibre pathways. Collectively, these
      results demonstrate the potent neurotoxic potential of PLA2, the delayed clinical
      nature of its in vivo neurotoxicity and the applicability of these model systems
      to future studies on mechanisms of PLA2 neurotoxicity and the development of
      potential PLA2 antagonists.

PMID- 8653398
TI  - Expression of estrogen receptor in the facial nucleus is suppressed by estradiol,
      but not by testosterone, indicating a lack of requirement for aromatization.
AB  - The transient expression of estrogen receptor (ER) in the ventromedial subnucleus
      of the facial nucleus was previously detected in the newborn rat, and the
      expression of ER molecules was down-regulated by daily injections of estradiol.
      Here we examined possible involvement of aromatization in this process. ER
      molecules were measured by immunohistochemistry and in situ hybridization
      histochemistry after daily injections of testosterone propionate (TP; 100
      micrograms/0.02 ml) and estradiol benzoate (EB; 10 micrograms/0.02 ml) in the
      male pups castrated within 24 h of birth. Daily injections of TP for 5
      consecutive days did not suppress ER and ER mRNA in the facial nucleus, while
      they were both suppressed by daily injections of EB. Moreover, aromatase
      immunoreactivity was not detected in the facial nucleus of both castrated, TP
      injected and intact control males at 6 days of age. The present findings
      therefore suggest that ER molecules expressed transiently in the facial nucleus
      are not directly involved in masculine sexual differentiation of the brain in
      newborn rat.

PMID- 8653399
TI  - 1,2,5-Thiadiazole derivatives of arecoline stimulate M1 receptors coupled to
      phosphoinositide turnover.
AB  - A series of alkoxy-1,2,5-thiadiazole derivatives of arecoline was synthesized in
      an effort to develop M1 muscarinic agonists. The 3-butenyloxy, 2-butynyloxy,
      cyclopropylmethyloxy, and hexyloxy derivatives stimulated phosphoinositide
      turnover through muscarinic receptors in the rat hippocampus. The dose-response
      curves of 2-butynyloxy, cyclopropylmethyloxy and hexyloxy compound together was
      the same as the response of each separately. Pirenzepine was somewhat more potent
      than AF-DX 116 for inhibiting the responses produced by low concentrations of
      thiadiazole derivatives. The data suggest that the cyclopropylmethyloxy-TZTP
      derivative is functionally a selective M1 agonist. Molecular mechanics
      calculations indicate that the anti form of the 1,2,5-thiadiazole derivatives of
      arecoline may be active at M1 receptors.

PMID- 8653400
TI  - Post-transcriptional regulation of gene expression in hippocampal neurons by
      glutamate receptor activation.
AB  - Previous work from this laboratory has documented that glutamate receptor
      activation and extracellular calcium entry into hippocampal neurons caused a long
      lasting down-regulation of ligatin mRNA and protein. Here, we investigated
      whether glutamate reduced ligatin mRNA levels by decreasing the transcriptional
      activity of the gene and/or by regulating post-transcriptional RNA processing
      steps including mRNA stability. Using nuclear run-on assays, it was demonstrated
      that transcriptional activity of the ligatin gene was not significantly decreased
      after glutamate receptor activation. Further, Northern analysis of RNA from
      neurons maintained in the presence of the transcription inhibitor, alpha
      amanitin, showed that glutamate shortened the half life of the ligatin message
      from 10 h to 58 min. This post-transcriptional destabilization of ligatin mRNA
      was mimicked by NMDA, dependent on Ca2+, blocked by MK801, and not affected by
      AMPA and kainic acid, indicating that message stability was governed by changes
      in intracellular calcium. Moreover, using in situ hybridization and confocal
      microscopy, we showed that glutamate and NMDA decreased ligatin message within
      dendritic and somal regions without increasing nuclear levels. These findings
      demonstrated that glutamate receptor activation altered neuronal gene expression
      posttranscriptionally by destabilizing mRNA. Our data suggest that post
      transcriptional regulation of gene expression may be part of the normal receptor
      mediated regulatory program of plasticity and provides the first description of a
      glutamate receptor-modulated, calcium-dependent mechanism which rapidly
      destabilizes mRNA in neurons.

PMID- 8653401
TI  - Synaptic interactions of substance P immunoreactive nerve terminals in the baro-
      and chemoreceptor reflexes of the cat.
AB  - The neurochemical anatomy and synaptic interactions of morphologically identified
      chemoreceptor or baroreceptor afferents in the nucleus of the solitary tract
      (NTS) are poorly understood. A substantial body of physiological and light
      microscopic evidence suggests that substance P (SP) may be a neurotransmitter
      contained in first order sensory chemo- or baroreceptor afferents, however
      ultrastructural support of this hypothesis is lacking. In the present report we
      have traced the central projections of the carotid sinus nerve (CSN) in the cat
      by utilizing the transganglionic transport of horseradish peroxidase. Medullary
      tissues including the commissural NTS (cNTS) were processed for the histochemical
      visualization of transganglionically labeled CSN afferents and for the
      immunocytochemical detection of SP by dual labeling light and electron
      microscopic methods. At the light microscopic level, dense bilateral labeling
      with TMB was found in the tractus solitarius (TS) and cNTS, caudal to the obex.
      Rostral to the obex, significant ipsilateral TMB labeling was detected in the
      dorsal, dorso-lateral, and medial subnuclei of the NTS, as well as in the TS.
      Significant staining of SP immunoreactive processes was detected in most
      subnuclei of the NTS. The cNTS was examined by electron microscopy. Either HRP or
      SP were readily identified in single labeled unmyelinated axons, myelinated
      axons, and nerve terminals in the cNTS. SP immunoreactivity was also identified
      in unmyelinated axons, myelinated axons, and nerve terminals in the cNTS which
      were simultaneously identified as CSN primary afferents. These ultrastructural
      data support the hypothesis that SP immunoreactive first order neurons are
      involved in the origination of the chemo- and baroreceptor reflexes. Axo-axonic
      synapses were observed between CSN primary afferent terminals and: (a) unlabeled
      nerve terminals; (b) other CSN primary afferent terminals; and (c) terminals
      containing SP. Axo-axonic synapses were also observed between CSN primary
      afferents which contained SP, and other SP terminals. These observations may
      mediate the morphological bases for multiple forms of presynaptic inhibition in
      the cNTS, including those involved in cardiorespiratory integration. In
      conclusion, our results indicate that SP immunoreactive nerve terminals may be
      important in both the origination and the modulation of the chemo- and/or
      baroreceptor reflexes.

PMID- 8653402
TI  - Moderate elevation of extracellular potassium transiently inhibits regeneration
      of sensory axons in cultured adult sciatic nerves.
AB  - The adult frog dorsal root ganglia (DRG) together with the sciatic nerve (ScN)
      has previously been shown to survive in organ culture for several days. If a
      local test crush is made at the beginning of culturing, there is an initial delay
      of about 3 days before the sensory axons start to grow into the distal nerve
      stump at a rate of about 0.6-0.9 mm/day. The present results showed that axonal
      growth was unaffected in preparations maintained for 8 days in medium containing
      10 mM K+ (5 mM is the physiological level). In contrast, the outgrowth was
      markedly reduced by 15 mM K+ and still more by 20 and 25 mM K+. The growth
      inhibition was partially counteracted by nifedipine, a Ca(2+)-channel antagonist.
      Other experiments clearly showed that high K+ exerted its effects during the
      early phase of the regeneration and lacked effects at later stages. The
      possibility that Ca(2+)-binding proteins, e.g. calbindin, which showed
      immunohistochemical reactivity in different structures, contribute to the growth
      adaptation to high K+ will be considered. The generality of the findings was
      supported by inhibition of axonal outgrowth of adult mouse sciatic sensory axons
      by high K+.

PMID- 8653404
TI  - Pretreatment with antisense oligodeoxynucleotides directed against the NMDA-R1
      receptor enhances survival and behavioral recovery following traumatic brain
      injury in rats.
AB  - Treatment with N-methyl-D-aspartate (NMDA) receptor antagonists limits tissue
      damage following CNS ischemia or trauma, supporting the hypothesis that NMDA
      receptors participate in the pathophysiology of such injuries. An alternative
      approach for evaluating this hypothesis is to examine the effects of selective
      inhibition of NMDA receptor synthesis, using antisense oligodeoxynucleotides. In
      the present studies, the effects of antisense oligodeoxynucleotides directed at
      NMDA-R1 receptor subunit, administered intracerebroventricularly (i.c.v.) prior
      to injury, were evaluated in a well-defined traumatic brain injury model in rats.
      Outcome measures included survival, motor recovery, and histological changes.
      Administration of antisense oligodeoxynucleotides (15 nmol/ml twice daily x 2
      days) did not alter physiological variables or motor function prior to trauma.
      However, such treatment significantly decreased mortality and improved behavioral
      recovery at 2 weeks after trauma as compared to animals treated with the
      corresponding sense oligodeoxynucleotides. Although cell counts in hippocampus
      did not differ between treatment groups, astrocyte activation as reflected by
      glial fibrillary astrocytic protein (GFAP) immunocytochemistry was significantly
      reduced in antisense treated animals. These findings provide additional evidence
      that NMDA receptors contribute to secondary injury after brain trauma and may
      suggest an alternative treatment approach.

PMID- 8653403
TI  - Cerebral cell volume regulation during hypernatremia in developing rats.
AB  - Cell volume regulation is a vital biological function in all species. Maintenance
      of cerebral cell size in the face of osmotic stress is especially important
      because the brain is contained in the non-complaint skull. The developmental
      aspects of this adaptive process are not known. Therefore, we evaluated cerebral
      cell volume regulation during hypernatremia in pre-weaning and adult rats.
      Hypernatremia was induced by injections of 1 M NaCl for 48 h. Brain water,
      electrolyte, and organic osmolyte contents were measured in hypernatremia and
      sham injected littermate control rats at the following ages: 12, 18 and 20 days
      and adults. In normonatremic rats, there was a steady decline in brain water
      content during development that was paralleled by a gradual fall in the cerebral
      levels of Na+, K+, and all organic osmolytes. The change in brain water content
      correlated most closely with the decrease in cerebral taurine content. In the
      face of equivalent elevations in serum Na+ concentration, there was comparable
      brain cell shrinkage and similar increases in total cerebral electrolyte and
      organic osmolyte content in rats at all 4 ages studied. Taurine was the
      predominant organic osmolyte prior to weaning, constituting 16-49% of the
      increment in nonperturbing solute content in hypernatremic animals between 12-20
      days of age; in contrast, taurine contributed only 10% to the cerebral organic
      osmolyte pool in adult rats. We conclude that the capacity of brain cells to
      accumulate inorganic electrolytes and organic osmolytes during adaptation to
      hypernatremia is adequately expressed in developing rats, aged 12 days or older.
      Moreover, we speculate that the immature animal behaves as if it has an elevated
      'set point' to protect the higher brain water content that is present earlier in
      development.

PMID- 8653405
TI  - Male Fischer 344 and Lewis rats display differences in locomotor reactivity, but
      not in anxiety-related behaviours: relationship with the hippocampal serotonergic
      system.
AB  - Recent studies have shown that arthritis-susceptible Lewis female rats display a
      marked hypoactivity of the hypothalamo-pituitary-adrenal (HPA) axis and decreased
      concentrations of hippocampal serotonin receptors (5-HT1A), when compared with
      arthritis-resistant Fischer 344 female rats. Although previous studies have
      suggested that these inter-strain differences may extend to several behaviours,
      the hypothesis that Fischer 344 and Lewis differ in their anxiety and locomotor
      scores when placed in novel environments has been only scarcely tested. The
      present study has thus analysed the behaviours of male Fischer 344 and Lewis rats
      placed successively in activity cages, in an open field (low and high aversive
      conditions), and in two animal models of anxiety (the elevated plus-maze, the
      black/white box). Moreover, because the present study was conducted with male
      rats, we have also checked whether the HPA axis- and 5-HT1A receptor-related
      differences previously described between female Fischer 344 and Lewis rats
      extended to males. Under basal conditions: (i) activity of the HPA axis; and (ii)
      hippocampal 5-HT1A receptor binding and activity of tryptophan hydroxylase (the
      rate-limiting enzyme in 5-HT biosynthesis) were decreased in Lewis rats, compared
      with Fischer 344 rats. In addition, the response of the HPA axis to a mild stress
      (10 min in a novel environment) was lower in Lewis rats than in Fischer 344. When
      placed in activity cages, Lewis rats displayed a lower locomotor activity,
      compared with Fischer 344 rats. In the open-field, Lewis rats cross a lower
      number of inner squares and groomed less than Fischer 344 rats. In the elevated
      plus-maze and in the black/white box, Fischer 344 and Lewis rats exhibited
      similar 'anxious' profiles as none of the rats visited the open arms (elevated
      plus-maze) and the white compartment (black/white box). This study, which extends
      earlier neurochemical and neuroendocrine findings in females, suggests that both
      strains display high levels of anxiety but markedly differ in their locomotor
      activities. Whether the latter strain difference is due to alterations in the HPA
      axis and/or the central serotonergic systems is an issue that remains to be
      explored.

PMID- 8653406
TI  - Light transmittance as an index of cell volume in hippocampal slices: optical
      differences of interfaced and submerged positions.
AB  - Light transmittance (T) in the CA1 region of hippocampal slices was measured
      during exposure to media of various osmolarities to determine the utility of
      optical measurements as an index of changes in cell volume. In slices positioned
      at the gas-liquid interface, hypo-osmotic medium consistently produced a decrease
      in T and hyperosmotic medium produced an increase in T. The magnitude of deltaT
      was graded as a function of the strength of osmotic change. All changes in T were
      reversible upon return to isosmotic medium. In contrast, osmotically induced
      changes in T in submerged slices were consistently opposite in direction to those
      observed in slices at the interface. The magnitude and direction of deltaT could
      be altered by systematic variation of the level of the bathing medium within the
      same chamber, indicating that both extrinsic optical properties of various
      interfaces, such as refraction and reflection, and intrinsic optical properties
      of the tissue contribute to the observed T. Spectral measurements eliminated the
      possibility that osmotically induced deltaT was the result of changes in light
      absorbance by intrinsic chromophores such as cytochromes or hemoglobin. The
      results show that measurements of deltaT can be a useful index of changes in cell
      volume in brain slices, provided that the level of the bath remains constant.

PMID- 8653407
TI  - Relationship between analgesia and extracellular morphine in brain and spinal
      cord in awake rats.
AB  - Extracellular concentrations of morphine from the dorsal spinal cord, the
      periaqueductal gray (PAG) including the dorsal raphe, and the lateral
      hypothalamus were measured by microdialysis in awake rats after intraperitoneal
      (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrations
      in all areas showed similar time courses: morphine was detected in the first
      dialysate sample (13-15 min) and maximal concentrations were reached at 45 min
      after injection. When in vivo recoveries of morphine from the spinal cord and
      brain areas were taken into account, no significant differences between morphine
      concentrations in the various areas were found. The relationship between
      extracellular morphine concentrations and morphine-induced analgesic behavior was
      investigated by simultaneously measuring morphine in the dialysate and its
      analgesic effect in the paw-withdrawal and tail-flick tests. In all areas
      sampled, the extracellular concentrations of morphine at different times after
      i.p. injection, significantly correlated with the magnitude of behavioral
      analgesia assessed by either test. The highest correlation was obtained between
      extracellular concentrations of morphine in the spinal cord and PAG and
      behavioral analgesia assessed in the paw-withdrawal test. Our data indicate that,
      after systemic injection, morphine is evenly distributed throughout the spinal
      cord and brain including potential anatomical sites of morphine's analgesic
      action. We estimate that the minimal extracellular morphine concentration in
      spinal cord that is required to produced a significant increase in nociceptive
      threshold is approximately 100 pg/25 microl, which corresponds to a tissue
      concentration of about 100 mg/g of morphine.

PMID- 8653408
TI  - Expression of c-fos and c-jun in rat retina following protracted illumination.
AB  - Illumination produces degeneration of outer photoreceptor segments, a phenomenon
      that may be reversed after a period of darkness. Neuronal expression of the
      immediate early genes (IEGs) c-fos and c-jun, both recognized as proto-oncogenes,
      has been reported after stimulation of different regions in the central nervous
      system (CNS). We performed a sequential study on Fos and Jun immunoreactivity to
      investigate the role of IEGs following 8 days of continuous illumination in 30-35
      day-old Wistar rats. Retinas were fixed by perfusion in 4% paraformaldehyde,
      after a period of illumination followed by 0, 2, 7, 10 and 20 days in total
      darkness. Cryostat sections were immunocytochemically stained using antibodies to
      Fos and Jun. Fos and Jun immunoreactivities were detected in all photoreceptors
      evaluated, peaking in nuclei of rats kept in total darkness for 2 days, and
      becoming negative as from 7 days. Increases in c-fos and c-jun products during
      the darkness period may play a role in triggering molecular events participating
      in plastic changes in photoreceptors and/or in the protection for oxidative
      damage cause by free radicals induced by light irradiation.

PMID- 8653409
TI  - A stereological study of substantia nigra in young and old rhesus monkeys.
AB  - The number of pigmented and non-pigmented neurons in the substantia nigra (SN) of
      10 old and six young female Macaca mulatta monkeys and in three old alpha male
      monkeys were estimated using new stereological cell counting methods. No
      systematic right-left differences were noted, nor were old animals different from
      young ones with respect to SN volume (68.9 mm3 vs. 62.8 mm3) or absolute number
      of nerve cells (320,000 vs. 312,000). However, the total number of pigmented
      neurons was about eight times higher in old animals compared with young ones
      (166,000 vs. 21,400) while the total number of non-pigmented SN neurons was less
      than half in old animals compared with young ones (139,000 vs. 285,000). These
      differences create difficulties in generalizing experimental results from the
      rhesus animal model to man. It seems unlikely that a simple correlation can be
      made between pigmented and tyrosine hydroxylase (TH) positive neurons in SN in
      monkeys. Instead of estimating the total number of pigmented and non-pigmented
      cells, only SN neurons positive for TH using immunohistochemical techniques might
      be used an indicator of the total number of dopaminergic neurons in SN in
      monkeys.

PMID- 8653410
TI  - Limbic seizures originating in the olfactory bulb: an electro-behavioral and
      glucose metabolism study.
AB  - We studied seizures which were induced by a microinjection of kainic acid (KA)
      into the unilateral olfactory bulb (OB) in the rats. The first epileptiform
      discharge appeared in the OB, was then propagated to the amygdala and the
      hippocampus unilaterally, and finally propagated to the unilateral sensori-motor
      cortex. Consistent graded behavioral changes, almost identical to those of the
      amygdaloid and hippocampal seizures, occurred during the development of the
      seizures, and three stages were classified: stage 1 was staring, stage 2
      consisted of masticatory movement and stage 3 demonstrated rearing and rearing
      and falling. Local cerebral glucose utilization (LCGU) measured with the [14C]2
      deoxyglucose method revealed a graded propagation of seizure activities at each
      stage in the unilateral structures. At stage 1, the increased activities
      propagated from the OB localized in the anterior olfactory nucleus; at stage 2,
      the endopiriform nucleus, the nucleus accumbens, the entorhinal cortex, the
      ventral globus pallidus and the globus pallidus were all activated; at stage 3,
      the thalamic nuclei (mediodorsal, ventrolateral, ventromedial and centromedian
      nuclei), the substantia nigra pars reticulata, the entopeduncular nucleus and the
      sensorimotor cortex were also activated. The globus pallidus, which receives
      afferent fibers from the nucleus accumbens, was the first structure that was
      activated metabolically among the extralimbic structures. No metabolic activation
      occurred in the amygdala and the hippocampus in spite of the early propagation of
      epileptiform discharges to these structures on EEG. These results suggest that OB
      seizures involve the limbic structures, while the amygdala and the hippocampus
      have a little contribution to OB seizures. In addition, the nucleus accumbens
      plays an important role as a functional interface between the limbic and the
      motor system in OB seizures.

PMID- 8653411
TI  - Sexual activity increases dopamine transmission in the nucleus accumbens and
      striatum of female rats.
AB  - In vivo microdialysis was used to monitor extracellular concentrations of
      dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and
      homovanillic acid (HVA) in the nucleus accumbens and dorsal striatum of sexually
      active female rats during tests of locomotor activity, exposure to a novel
      chamber, exposure to sex odors, the presentation of a sexually active male rat,
      and copulation. DA increased slightly but significantly in the nucleus accumbens
      when a sexually active male was placed behind a wire-mesh screen, and further
      during copulation. DA also increased significantly in the dorsal striatum during
      copulation; however, the magnitude of this effect was significantly lower than
      that observed in the nucleus accumbens. The metabolites DOPAC and HVA generally
      followed DA with a delay, and increased significantly during copulation in both
      regions. In contrast, forced locomotion on a rotating drum, exposure to a novel
      testing chamber, and exposure to sex odors did not increase DA significantly in
      either region, although forced locomotion increased DOPAC significantly in both
      regions, and HVA significantly in the nucleus accumbens. The magnitude of DA
      release in the nucleus accumbens was significantly greater during copulation than
      running, whereas no significant difference was detected for striatal DA release
      between these two behavioral conditions. These results indicate that novelty or
      locomotor activity alone do not account for the increase in DA observed in the
      nucleus accumbens of female rats during copulation, and suggest that DA
      transmission in the nucleus accumbens is associated with anticipatory and
      consummatory aspects of sexual activity, as it is in male rats. In the dorsal
      striatum, however, DA release during copulation may reflect an increase in
      locomotor activity associated with active pacing of the male.

PMID- 8653412
TI  - Alpha 2-adrenoceptor agonist, dexmedetomidine, protects against kainic acid
      induced convulsions and neuronal damage.
AB  - Kainic acid (KA)-induced convulsions are accompanied by histopathological changes
      that are most prominent in the temporal lobe structures. In the present study, we
      investigated whether a selective alpha2-adrenoceptor agonist, dexmedetomidine
      could attenuate KA-induced epileptic convulsions and subsequent neuronal damage
      in the rat hippocampus. Rats were pretreated 30 min before KA injection (9 mg/kg,
      i.p.) with dexmedetomidine (3 micrograms/kg, s.c.). The behavior of animals was
      observed for at least 3 h. Dexmedetomidine suppressed the development (p <
      0.001), generalization (p < 0.05) and severity (p < 0.01) of convulsions. In
      addition, histological analysis revealed that dexmedetomidine-treated animals
      without convulsions or with only partial convulsions had no neuronal damage in
      the principal cell layers of the hippocampus. A selective alpha2-antagonist,
      atipamezole (1 mg/kg, s.c.) potentiated KA-induced convulsions and increased the
      mortality in status epilepticus. In conclusion, the present study demonstrated
      that dexmedetomidine, in addition to possessing anticonvulsant properties, has a
      neuroprotective effect in the KA model of status epilepticus.

PMID- 8653414
TI  - Ketamine antagonizes hypoxia-induced dopamine release in rat striatum.
AB  - The purpose of this study is to investigate the hypothesis that ketamine, a non
      competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, attenuates
      hypoxia-induced striatal dopamine release in vivo. High-speed chronoamperometric
      recording techniques, using Nafion-coated carbon fiber electrodes, were used to
      evaluate extracellular dopamine (DA) concentration in the striatum. KCl and DA
      were locally applied directly to the striatum of urethane-anesthetized Sprague
      Dawley rats, in order to measure release and clearance, respectively, of DA.
      These anesthetized animals were paralyzed with D-tubocurarine and connected to a
      respirator to allow controlled respiration. Systemic concentrations of oxygen and
      carbon dioxide were altered by changing the partial pressure of O2, CO2, N2 of
      inspired air and the rate of the respirator. Our data indicate that lowering the
      respiratory rate from 90 to 20 times/min for 5 min, in room air, caused a
      decrease in blood O2 while increasing the CO2 concentration. These changes in
      blood gas concentration were reversible and reproducible. We also found that
      lowering the respiratory rates potentiated K(+)-induced DA release but not DA
      clearance in the striatum. In an attempt to induce hypercapnia, the room air was
      replaced with high CO2-containing air (15% CO2 + 20% O2 + 65% N2), and this
      change resulted in increased blood CO2 levels without lowering O2 concentration.
      The hypercapnia did not alter K(+)-induced DA release in the striatum. Next, we
      attempted to simulate anoxic hypoxia in the absence of hypercapnia. Respiration
      with pure N2 for 30 s resulted in lowering blood O2 without increasing CO2
      levels. Both basal and K(+)-evoked DA releases were increased during N2-induced
      anoxic hypoxia. These data suggested that transient hypoxia facilitates DA
      release in the striatum. It has been suggested that NMDA is involved in many
      hypoxia-mediated responses. We also found that systemic application of ketamine,
      which itself did not affect blood O2 or CO2 levels, antagonized hypoxia-induced
      electrochemical responses. These data suggest that the increase in DA release in
      vivo during short-term hypoxia may probably be mediated through NMDA receptors.

PMID- 8653415
TI  - Non-NMDA glutamatergic excitatory transmission in the descending limb of the
      spinobulbospinal micturition reflex pathway of the rat.
AB  - I.v. administration of GYKI-52466, a non-competitive AMPA/kainate glutamatergic
      receptor antagonist, inhibited bladder contractions elicited by electrical
      stimulation in the pontine micturition center (PMC) in urethane-anesthetized
      rats. The mean threshold dose of GYKI-52466 was 2 mg/kg i.v. (range = 1-4 mg/kg).
      Maximum inhibition (mean = 57.7 +/- 8.2%, range = 24-83.3% of control) occurred
      at a dose of 8 mg/kg. CNQX, a competitive AMPA/kainate glutamatergic receptor
      antagonist, did not significantly alter the evoked contractions. These results
      indicate that AMPA/kainate receptors are involved in bulbospinal excitatory
      pathway from the PMC to the parasympathetic nucleus in the lumbosacral spinal
      cord in the rat.

PMID- 8653413
TI  - Characterization of progesterone-3-[125I-BSA] binding sites in the medial
      preoptic area and anterior hypothalamus.
AB  - In this study we utilized radiolabeled progesterone (P) conjugated to bovine
      serum albumin (BSA) at position 3 (P-3-[125I-BSA]) to examine steroid receptors
      in membrane fractions from the medial preoptic area-anterior hypothalamus (MPOA
      AH) of ovariectomized (OVXed) rats. In the MPOA-AH binding of P-3-[125I-BSA] was
      linear across a tissue concentration range of 0.005 to 0.02 mg protein/0.1 ml of
      membrane suspension. Kinetic experiments revealed an association t(1/2) of 51.4
      min and a dissociation t(1/2) of 122.5 min for P-3-[125I-BSA] at 0 degrees C.
      Analysis of data from competition binding experiments using P-3-BSA revealed high
      and low-affinity binding sites in the MPOA-AH. Involvement of MPOA-AH binding
      sites with a G-protein was suggested by a reduction of P-3-[125I-BSA] binding in
      the presence of the non-hydrolyzable GTP analog GTPgammaS but not ATPgammaS. In
      addition, if homogenates from the MPOA-AH were preincubated with 10(-5) M of the
      G-protein antagonist cholera toxin for 30 min at 37 degrees C, competition
      binding data indicated only high-affinity binding sites. Once daily injections of
      OVXed rats with 4 mg P for 12 days significantly increased the density of P-3
      [125I-BSA] binding sites in the MPOA-AH. This treatment did not affect P-3-[125I
      BSA] binding in the dorsal tectum, medial basal hypothalamus, ventral tegmental
      area or the thymus.

PMID- 8653416
TI  - Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D
      COSY 1H-NMR study.
AB  - The effects of modafinil, a vigilance-enhancing drug, on brain metabolism were
      investigated directly in situ by the 2D COSY 1H-NMR spectroscopy in anesthetized
      rats. Modafinil (600 mg/kg, i.p.) induced significant increases in both aspartate
      (72% +/- 15%) and glutamate-glutamine pool (28% +/- 8%) simultaneously with
      increases in inositol (51% +/- 19%) and creatine-phosphocreatine pool (47% +/-
      14%) in comparison with control values (P < 0.05; n = 5). These results suggest
      that the awakening properties of modafinil could be mediated by metabolic
      activation.

PMID- 8653417
TI  - Blocking actions of BIDN, a bicyclic dinitrile convulsant compound, on wild-type
      and dieldrin-resistant GABA receptor homo-oligomers of Drosophila melanogaster
      expressed in Xenopus oocytes.
AB  - The receptor antagonist actions are described for a novel bicyclic dinitrile
      compound (BIDN, 3,3-bis-(trifluoromethyl)-bicyclo [2.2.1] heptane-2,2
      dicarbonitrile) on a Drosophila melanogaster homo-oligomeric GABA receptor
      expressed in Xenopus oocytes. BIDN blocked the wild-type form of the receptor in
      a neither purely competitive, nor purely non-competitive manner, being dependent
      on the GABA concentration yet insurmountable, and block was independent of the
      membrane potential. BIDN was found to be less effective against a mutant (A(302) 
      -> S) form of the receptor resistant to dieldrin and picrotoxinin. This cross
      resistance of dieldrin-resistant receptors to BIDN is of interest in the light of
      recent findings that BIDN binding to insect membranes is displaced competitively
      by dieldrin, but not by picrotoxinin.

PMID- 8653418
TI  - Increased light intensity prevents the age related loss of vasopressin-expressing
      neurons in the rat suprachiasmatic nucleus.
AB  - We investigated whether increased light input can counteract the age-related
      decrease in vasopressin- (AVP) and vasoactive intestinal polypeptide (VIP)
      expressing neurons of the suprachiasmatic nucleus (SCN) by determining the
      numbers of these neurons in rats of different ages, housed under low or high
      intensities of light. The significant age-related decrease for AVP was prevented
      in old animals after high light housing. For VIP, no effects were found.

PMID- 8653419
TI  - Immunocytochemical localization of the heparin-binding growth-associated molecule
      (HB-GAM) in the developing and adult rat cerebellar cortex.
AB  - The heparin-binding, growth-associated molecule (HB-GAM) is a developmentally
      regulated protein that belongs to a new family of heparin-binding molecules, not
      related to the fibroblast growth factors (FGFs), with putative functions during
      cell growth and differentiation. In order to further study the functional role of
      HB-GAM we have used a polyclonal antiserum, raised against the purified protein
      to localize HB-GAM in the developing and adult rat cerebellar cortex. During
      postnatal development HB-GAM-like immunoreactivity (IR) was found to be present
      in all layers of the cerebellar cortex. IR was mainly associated with processes
      or extracellular structures but not with cell bodies. Throughout all the stages
      examined the molecular layer was clearly labeled, whereas staining in the
      internal granular layer was diffuse. IR in the external granular layer on
      postnatal day 1 and 8 was found to be associated with radially oriented fibres
      connecting the internal granular layer with the pial surface of the cerebellum.
      The intensity of this staining seemed to increase from day 1 to 8. Staining of
      corresponding areas with an antiserum against the glial fibrillary acidic protein
      (GFAP) suggested that the HB-GAM antiserum in the developing cerebellar cortex
      labels Bergmann glia fibres of Golgi epithelial cells. Because of the diffuse
      staining of the molecular layer in the adult rat it was not possible to
      distinguish whether radial fibres in the adult contained any HB-GAM IR. Golgi
      epithelial cells are considered as crucial for the migration of granular cells
      during the differentiation of the cerebellar cortex. We therefore speculate that
      the association of HB-GAM-like IR may be of functional relevance. The fact that
      molecules, such as tenascin, known to be involved in morphogenetic events show a
      similar spatiotemporal distribution pattern further underscores this hypothesis.
      HB-GAM, which possesses a classical signal sequence, might be release in the
      extracellular space and could mediate adhesion phenomena by binding to heparin
      like molecules associated with the neuronal membrane. Therefore, it will be
      important to investigate whether specific antibodies against HB-GAM are able to
      interfere with normal cerebellar development in vitro and in vivo.

PMID- 8653420
TI  - Properties of otolith-related vestibular nuclear neurons in response to
      bidirectional off-vertical axis rotation of the rat.
AB  - In decerebrate rats, the responses of tilt-sensitive neurons in the lateral and
      descending vestibular nuclei were studied during constant velocity 10 degrees off
      vertical axis rotations (OVAR) in the clockwise (VW) and counterclockwise (CCW)
      directions. Seventy three otolith-related units showed a sinusoidal position
      dependent discharge modulation to OVAR of both directions; 20 of these showed
      clipped firing rates in parts of a 360 degree OVAR cycle. With increase in the
      velocity of rotation (1.75-15 degrees/s), one group of units (n = 36) showed a
      stable ratio of bidirectional response sensitivity and symmetric response
      magnitudes to CW and CCW rotations. These units showed gain tuning ratios similar
      to those of narrowly spatiotemporal-tuned neurons. The other group of OVAR
      responsive units (n = 13) exhibited velocity-variable and asymmetric
      bidirectional response sensitivities. Their gain tuning ratios were similar to
      those of broadly spatiotemporal-tuned neurons. For units with velocity-stable and
      symmetric bidirectional response sensitivity as well as gain tuning ratio of the
      narrowly spatiotemporal-tuned neurons, their response gains remained stable with
      velocity. Some showed stable response phase lead or lag with velocity increase
      while others showed progressive shifts from response lead of 13 degrees to
      response lag of -25 degrees. The best response orientations of these units with
      velocity-stable and symmetric bidirectional response sensitivity were found to
      point in all directions on the place of rotation. The functional significance of
      these tilt- and OVAR-sensitive central otolith neurons is discussed.

PMID- 8653421
TI  - Nucleus tractus solitarius efferent terminals synapse on neurons in the caudal
      ventrolateral medulla that project to the rostral ventrolateral medulla.
AB  - The caudal ventrolateral medulla (CVL) contains neurons that are vasodepressor
      and are a critical component of the baroreceptor reflex pathway. While
      electrophysiological studies suggest that CVL neurons are intercalated in the
      baroreceptor pathway between the nucleus tractus solitarius (NTS) and the rostral
      ventrolateral medulla (RVL), there is no direct evidence for this projection.
      Therefore, we identified CVL neurons that project to RVL by retrogradely
      labelling them with wheat germ agglutinin-apo-horseradish peroxidase conjugated
      to colloidal gold (WAHG) injected into the RVL. Retrogradely labelled neurons
      were seen in previously identified vasodepressor areas of the rostral CVL that
      are critical for the baroreceptor reflex. Double labelling for WAHG and tyrosine
      hydroxylase (TH) immunocytochemistry indicated that CVL neurons that project to
      the RVL (CVL --> RVL neurons) are distinct from the noradrenergic neurons of the
      A1 cell group. To establish the presence of a direct projection from the NTS to
      CVL --> RVL neurons, the retrograde tracer WAHG was pressure injected into the
      RVL and the anterograde tracer biocytin was iontophoresed into the NTS of
      anesthetized rats. After 4-6 h, anesthetized rats were perfused transcardially
      with 3.75% acrolein in 2% paraformaldehyde and sections through the CVL were
      processed for both markers. By light microscopy, numerous biocytin-labelled
      varicose processes overlapped neurons containing WAHG in the CVL. By electron
      microscopy, biocytin was found in myelinated and unmyelinated axons and in axon
      terminals (0.9 + 0.02 microns) that contained primarily small clear vesicles.
      These terminals formed predominantly asymmetric synapses on large (1.5-6.0
      microns in diameter) dendrites within the CVL. Some of the post-synaptic
      perikarya and large dendrites contained WAHG associated with lysosomes and
      multivesicular bodies, indicating that they belong to neurons which project to
      the RVL. We conclude that CVL --> RVL neurons are (a) distinct from A1
      noradrenergic cells; (b) receive direct synaptic contacts from NTS efferent
      terminals; (c) are potently and monosynaptically excited (asymmetric synapses) by
      NTS efferent terminals. These data support the hypothesis that CVL neurons are
      intercalated between the NTS and the RVL in the baroreceptor reflex pathway.

PMID- 8653422
TI  - Tolerance to ketamine-induced blockade of cortical spreading depression transfers
      to MK-801 but not to AP5 in rats.
AB  - Tolerance to ketamine (KET) induced blockade of cortical spreading depression
      (CSD) was investigated in 31 rats anesthetized with pentobarbital. CSD was
      elicited by injection of 1 microl of 5% KCl into cortex at 15 min intervals and
      monitored by recording the accompanying slow potential waves. After control
      recording, five injections of KET (50 mg/kg) were applied at 75 min intervals.
      The first KET injection elicited CSD blockade lasting for 30-45 min at the near
      and for 60-75 min at the far electrode. The CSD blocking effect of subsequent
      injections gradually declined and was not recognizable after the fifth KET
      injection. MK-801 (2.5 mg/kg) injected to rats with fully developed KET tolerance
      30 min after the last KET dose, failed to block CSD. Without KET pretreatment the
      same dosage of MK-801 induced CSD blockade lasting more than 1 h. KET tolerance
      did not prevent local CSD blockade in a cortical area superfused with 10(-3)
      mol/l AP5. It is concluded that repeated applications of KET may induce some
      conformational changes at binding site(s) in the N-methyl-D-aspartate (NMDA)
      controlled channels shared by both KET and MK-801.

PMID- 8653423
TI  - Selective destruction of midbrain raphe nuclei by 5,7-DHT: is brain 5-HT involved
      in alcohol drinking in Sprague-Dawley rats?
AB  - Since serotonin (5-HT) reportedly is involved in aberrant drinking of ethyl
      alcohol, the present study examined a possible role of the concentration of 5-HT
      in systems originating in the dorsal raphe nucleus (DRN), median raphe nucleus
      (MRN) or both nuclei. The preference for alcohol offered in concentrations
      increased over 10 days from 3% to 30% was determined for each Sprague-Dawley rat.
      After the rats were anesthetized with sodium pentobarbital, either 10 microg 5,7
      DHT or artificial cerebrospinal fluid (CSF) was micro-injected stereotaxically
      into the DRN, MRN or both nuclei. After 10 days, a second alcohol preference test
      was offered to the animals. Then the rats were decapitated, each brain removed,
      and the block of tissue containing injection sites was saved for histological
      analysis. The remaining portion was dissected into separate regions for analysis
      by HPLC of 5-HT, 5-hydroxyindoleacetic-acid (5-HIAA), norepinephrine (NE),
      dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid
      (HVA). The 5,7-DHT lesion of the DRN depleted the levels of 5-HT and 5-HIAA by 50
      55% in the midbrain and pons and by 70-80% in the frontal cortex, whereas, the
      5,7-DHT lesion of MRN reduced 5-HT in all regions except the corpus striatum. The
      depletion of 5-HT was lower in MRN-lesioned than in DRN-lesioned rats in the
      frontal cortex and nucleus accumbens. The combined lesion of both DRN and MRN
      produced a massive decline of >90% of 5-HT and 5-HIAA in all structures except
      the pons where 5-HT was reduced by 70%. Whereas the level of NE was reduced
      mainly in the frontal cortex, the levels of DA and its metabolites were
      essentially unaffected by the 5,7-DHT lesions. Although single or combined
      lesions of the DRN and MRN failed to alter the intake of alcohol of the rats, the
      combined serotonergic lesions increased significantly the ingestion of water but
      not food. Correlational analyses in the sham groups showed a negative association
      between the intake of alcohol and cortical dopamine and possible hippocampal 5-HT
      and NE as well as between the ingestion of food and of 5-HT in the frontal
      cortex. Taken together, these observations in the Sprague-Dawley rat suggest that
      lower levels of these monoamines in certain regions of the brain may play a role
      in the maintenance of the basal intake of alcohol but not in the drinking after
      the injection of 5,7-DHT. Explanations of our findings include: (1) a
      compensatory neurochemical change in pre- or postsynaptic 5-HT receptors
      subsequent to the dysfunction of serotonergic neurons in the forebrain; (2) a
      unique characteristic of the Sprague-Dawley strain of rat; and (3) residual
      quanta of 5-HT which sustains the pattern of alcohol drinking.

PMID- 8653424
TI  - Cation and anion unitary ion channel currents in cultured bovine microglia.
AB  - The use of excised patches has led to the identification and characterization of
      two channels not previously reported in microglia. A calcium-dependent K+ channel
      K(Ca) was activated in inside-out patches obtained from cultured bovine microglia
      and had a unitary conductance of 240 pS with symmetrical 140 mM K+ across
      patches. Mean open times of K(Ca) were exponentially dependent on patch potential
      and were increased with patch depolarization. Channel open probability (Popen)
      was increased with patch depolarization with either 5 mM or 140 mM internal K+
      and was attributable to potential dependent enhancement of both opening frequency
      and mean open time. Whole cell currents showed the presence of a slowly
      activating K+ conductance, blocked by external TEA (at 2 mM) and likely the
      macroscopic correlate of the unitary K(Ca); half-maximal activation of the
      current occurred at +25 mV. An anion channel (unitary conductance of 325 pS with
      symmetrical Cl- across patches) was activated in inside-out patches with
      depolarizing and hyperpolarizing potential steps from 0 mV. Channel activation
      was not dependent on internal Ca2+. The anion currents inactivated during
      maintained potential steps with the time constant for inactivation faster with
      increased patch depolarization. The properties of the K(Ca) and anion channels in
      microglia membrane may have relevance to cell function in response to neuronal
      damage in the CNS.

PMID- 8653425
TI  - Cardiovascular neurons in cat caudal ventrolateral medulla: location and
      characterization of GABAergic input.
AB  - The purposes of the present study were to: (1) characterize the GABAergic input
      to vasodepressor neurons in the caudal ventrolateral medulla of the cat, and (2)
      define more precisely the anatomical localization of these neurons in this
      species. This was done by microinjecting GABA receptor antagonists and agonists,
      and a negative allosteric modulator of the GABA receptor, namely, ethyl-beta
      carboline-3-carboxylate, into the caudal ventrolateral medulla of alpha
      chloralose-anesthetized animals while monitoring arterial blood pressure and
      heart rate. Localization studies where performed relating injection sites in the
      caudal ventrolateral medulla where cardiovascular responses were elicited, to
      neurons exhibiting immunoreactivity to tyrosine hydroxylase (TH) and phenethyl-N
      methyl-transferase (PNMT). Microinjection of 1 and 10 ng of bicuculline into the
      caudal ventrolateral medulla produced decreases in mean blood pressure and heart
      rate of -34 +/- 6.4 and -49 +/- 9.2 mmHg, and -22 +/- 4.3 and -35 +/- 8.2
      beats/min, respectively. Hypotension and bradycardia were also observed with
      picrotoxin microinjection (120 ng). Microinjection of muscimol (100-200 ng) and
      GABA (12 microgram) had no effect on mean blood pressure and heart rate.
      Microinjection of ethyl-beta-carboline-3-carboxylate also decreased mean blood
      pressure (-39 +/- 7.0 mmHg). The location of the micropipette tip after
      bicuculline microinjection in relation to TH and PNMT immunoreactive cells was as
      follows: (1) TH-immunoreactive cells of the A1 cell group were visible in the
      same relative location as the micropipette tip, and (2) no PNMT-positive cells
      were noted at the sites where bicuculline elicited hypotension. These results
      indicate that there is a tonic GABAergic input to neurons in the caudal
      ventrolateral medulla. The location of these neurons overlaps with the A1 cells.

PMID- 8653426
TI  - Chronic antioxidant treatment improves the cognitive performance of aged rats.
AB  - Free radicals and oxidative damage have been implicated in brain aging and
      several neurodegenerative diseases. The purpose of the present study was to
      determine whether antioxidants could alleviate age-associated cognitive and motor
      changes. Aged 24-month-old male Sprague-Dawley rats were treated for 4-5 months
      with daily i.p. injections of spin-trapping compound phenyl-alpha-tert
      butylnitrone (PBN; 32 mg/kg) and alpha-tocopherol (200 mg/kg) or with vehicles.
      Antioxidant-treated animals also received ascorbate in their drinking water. In
      Morris water maze testing after two months, antioxidant-treated rats exhibited
      significantly greater memory retention than vehicle-treated rats in water maze
      testing. Subsequent tests for passive avoidance behavior and motor activity/skill
      revealed no effect of antioxidant treatment. In a separate group of aged 33-month
      old rats that received the same combination of antioxidants for only 14 days,
      antioxidant treatment did not affect basal levels of brain lipid peroxidation (as
      indexed by TBAR formation) compared to controls. The results of this study
      provide initial evidence that chronic antioxidant treatment can improve cognitive
      function during aging, thus supporting the 'free radical hypothesis of aging'
      related to brain function.

PMID- 8653427
TI  - Fine localization of low and high calcium dependent ATPase activities in the rat
      sciatic nerve.
AB  - We tried to demonstrate the electron microscopic histochemical localization of
      membrane Ca(2+)-ATPase activity in glutaraldehyde-fixed rat sciatic nerves.
      Although conventional glutaraldehyde fixatives containing impurities interfered
      with the reactivity of Ca(2+)-ATPase, this activity was successfully preserved in
      the tissues fixed with pure glutaraldehyde as well as in those fixed with
      paraformaldehyde. In unmyelinated nerve fibers, an ATPase activity depending on
      10 mM CaCl2 was detected on the whole external surface of Schwann cell plasma
      membranes. In myelinated fibers, this activity was localized on the surface of
      Schwann cell outer loops at the paranodal region of Ranvier nodes and on the
      axonal membrane at the nodal region. Another activity depending on 0.1 mM CaCl2
      was demonstrated on the axolemma of unmyelinated fibers. These results indicated
      that there may be two types of Ca(2+)-ATPase activities showing high and low
      affinity to calcium ions localized in peripheral nerve systems in a different
      manner between myelinated and unmyelinated fibers.

PMID- 8653428
TI  - Hyperechogenic fetal bowel.

PMID- 8653429
TI  - Fetal growth velocity: kinetic, clinical, and biological aspects.
AB  - With the aim of determining fetal growth kinetics, prenatal data were analysed
      which had been longitudinally collected in the framework of a perinatal growth
      survey. The sample comprised 238 singleton normal pregnancies, selected in Genoa
      and Turin (between 1987 and 1990), and repeatedly assessed by ultrasound scans
      (five to nine per pregnancy). Five morphometric traits were considered: BPD
      (biparietal diameter), OFD (occipitofrontal diameter), HC (head circumference),
      FDL (femur diaphysis length) and AC (abdomen circumference). Growth rate seemed
      to increase in the early part of the second trimester, and decrease subsequently:
      velocity peaks were steeper and earlier for head diameters and circumference
      (about 18 weeks) than for femur length (20 weeks) and abdomen circumference (22
      weeks). Velocity standards were traced using a longitudinal two-stage linear
      model: this ensures unbiased description of the shape of the growth curve, even
      when growth kinetics are asynchronous, and efficient estimation of the outer
      centiles--the most useful for diagnostic purposes.

PMID- 8653430
TI  - Neonatal otoacoustic emission screening and the identification of deafness.
AB  - Using transient evoked otoacoustic emissions (TEOAEs), a two stage screen with
      the testing of failures by auditory brainstem response (ABR), has been
      implemented in Whipps Cross Hospital in East London. From January 1992 to 1995,
      11,606 infants received an initial TEOAE test. Once initial difficulties were
      resolved, coverage of district residents remained stable at 91.5%. Long term
      follow up of the cohort is being undertaken. Of those receiving an initial test,
      13% failed in both ears. Only 1.75% of the cohort failed both stages of the TEOAE
      screen bilaterally. These infants were tested by ABR. The yield of infants with a
      bilateral permanent hearing loss of moderate or worse degree was 2/1000. The
      overall cost of implementing the programme was not prohibitive and the cost per
      hearing impaired child detected was little more than the widely accepted notional
      cost of identifying such children through targeted at risk screens. The screen
      was clearly sensitive. The priority for such universal TEOAE programmes, however,
      is to increase specificity without losing this sensitivity.

PMID- 8653431
TI  - Haemodynamic features at presentation in persistent pulmonary hypertension of the
      newborn and outcome.
AB  - Thirty four newborns presenting with persistent hypoxaemia in the first three
      days of life underwent detailed haemodynamic assessment using Doppler
      echocardiography, including measurements of pulmonary arterial pressure (PAP),
      left ventricular (LV) function, and left ventricular output (LVO). Results were
      compared with values from 51 healthy babies, and those of survivors were compared
      with non-survivors. Four of the 34 babies were excluded from this analysis
      because one was found to have transposed great arteries, one had a large left-to
      right shunt with no evidence of persistent pulmonary hypertension, and two had
      diffuse skeletal myopathy. Tricuspid regurgitation was present in 70%, permitting
      systolic PAP estimation. The pulmonary:systemic arterial pressure ratio range was
      0.7:1 to 1.83:1 (mean 1.02:1). A patent duct was present in 83%, and flow
      patterns indicated PAP approaching, or above, systemic pressure in all. Systolic
      time interval ratio TPV/RVET (time to peak velocity at the pulmonary valve/right
      ventricular ejection time) was mostly (65%) in the normal range, and did not
      correlate with other PAP measurements. LV function was below the 10th centile in
      only 11%, but values for LVO lay below the 10th centile in 41%, and for left
      ventricular stroke volume index (LSVI) in 66%. Results of 18 survivors were
      compared with 10 non-survivors (excluding two premature babies who died early
      with pulmonary interstitial emphysema). There were no significant differences for
      any parameter of PAP or LV function, but LVO and LSVI were significantly lower in
      non-survivors: LVO survivors (mean (SD)), 205 (57), non-survivors 138 (63)
      ml/kg/minute (P < 0.01); LSVI survivors, 1.29 (0.51), non-survivors 0.86 (0.31)
      ml/kg (P < 0.05). All four babies with LVO < 100 ml/kg/minute died, and 6/7
      babies with LSVI < 1 ml/kg died. Detailed echocardiographic evaluation shows that
      the haemodynamic features of persistent pulmonary hypertension are diverse and
      that clinical diagnosis can be incorrect. Low LV output and stroke volume,
      usually with normal LV function, were the only Doppler echocardiographic
      parameters to predict subsequent death. This correlation with outcome requires
      further prospective evaluation.

PMID- 8653432
TI  - Posthypoxic cooling of neonatal rats provides protection against brain injury.
AB  - AIM: To determine whether moderate hypothermia, applied after a hypoxic-ischaemic
      insult in neonatal rats, reduces cerebral damage. METHOD: Unilateral hypoxic
      ischaemic brain damage was induced in 7 day old rats by left carotid ligation,
      followed by 120 minutes of normothermic exposure to 8% O2, followed by random
      selection to three hours of hypothermia (rectal temperature, mean (SD), 32.5
      (0.4) degrees C) or normothermia (38.3 (0.4) degrees C). One hundred and one
      animals were used for brain temperature or blood chemistry studies and 24 for
      survival studies (7 days) with neuropathology, including cell counting as outcome
      measures. RESULTS: Thirty sections from each brain were histologically examined
      with respect to distribution and pattern of damage and given a score from 0 to 4.
      Animals treated with hypothermia had significantly less damage than normothermic
      animals (score 0.5 (0.3) vs 1.8 (0.5)). CONCLUSIONS: Posthypoxic hypothermia
      reduces brain damage in awake, unrestrained 7 day old rats.

PMID- 8653434
TI  - Antenatal diagnosis of cystic hygroma or nuchal pad--report of 92 cases with
      follow up of survivors.
AB  - Information on the outcome of pregnancy was collected on 92 fetuses with cystic
      hygroma or nuchal pad, identified prenatally. Forty three (47% of the total) were
      associated with abnormal karyotype. Twenty five (27%) had normal karyotype but an
      additional abnormality was identified on ultrasound scan. There were 10 liveborn
      babies in this group of whom seven had significant problems postnatally. In
      twenty four (26%) cases the cystic hygroma or nuchal pad was an isolated finding.
      Seventeen (89% of those in which the pregnancy was electively continued) were
      liveborn and reported to be normal. Those with a normal karyotype, no other
      anomaly identified on antenatal scan, and smaller non-septate lesions have a good
      prognosis.

PMID- 8653433
TI  - Failure of early postnatal dexamethasone to prevent chronic lung disease in
      infants with respiratory distress syndrome.
AB  - OBJECTIVE: To study the effect of early postnatal dexamethasone (days 1-3) on the
      incidence and severity of chronic lung disease in preterm infants with
      respiratory distress syndrome. METHODS: A multicentre, randomised, placebo
      controlled, blinded study was carried out in 18 neonatal intensive care units in
      Israel. The primary outcome measure was survival to discharge without requirement
      for supplemental oxygen therapy beyond 28 days of life. The secondary outcome
      measures were requirement for mechanical ventilation at 3 and 7 days, duration of
      ventilation or oxygen therapy, need for subsequent steroids for established
      chronic lung disease and incidence of major morbidities. RESULTS: The study
      consisted of 248 infants (dexamethasone n = 132; placebo n = 116). No differences
      were found in the outcome variables except for a reduction in requirement for
      mechanical ventilation at age 3 days in treated infants (dexamethasone 44%,
      placebo 67%; P = 0.001). Gastrointestinal haemorrhage, hypertension, and
      hyperglycaemia were more common in treated infants, but no life threatening
      complications, such as gastrointestinal perforation, were encountered.
      CONCLUSIONS: These data do no support the routine use of early postnatal
      steroids, but may justify further study in a selected, high risk group of
      infants.

PMID- 8653435
TI  - Meningococcal antibody titres in infants of women immunised with meningococcal
      polysaccharide vaccine during pregnancy.
AB  - Seventy five Gambian women were immunised with a single dose of a group A+group C
      meningococcal polysaccharide vaccine during the last trimester of pregnancy. IgG
      antibody titres were measured in mothers and in their infants by an enzyme-linked
      immunosorbent assay (ELISA). All women had a good response to vaccination and
      maternal antibodies were high at the time of delivery (23.2 micrograms/ml for
      group A antibodies and 14.3 micrograms/ml for group C antibodies). However, only
      a proportion of this antibody crossed the placenta; cord blood:maternal antibody
      ratios were 30% for group A antibody and 44% for group C antibody, respectively.
      Considerable variability in cord blood:maternal blood ratios was seen between
      individuals. This could not be related to age, parity, or ethnic group. Mean
      group A and group C cord blood:maternal blood ratios were lower in women with
      serological evidence of syphilis than in seronegative women, and diminished
      transfer of group A antibody was noted in women with active malarial infection of
      the placenta. Antibody titres declined rapidly in infants and by the age of 3-4
      months these had reached control values. Maternal immunisation may give infants
      some protection against group A and group C meningococcal disease but only during
      the first few months of life.

PMID- 8653436
TI  - Plasma lactate as a predictor of early childhood neurodevelopmental outcome of
      neonates with severe hypoxaemia requiring extracorporeal membrane oxygenation.
AB  - Although plasma lactate concentration has been widely used as an indicator of
      tissue hypoxia, no clinical study has been conducted to relate these values to
      the neurological outcome of sick neonates. Seventeen consecutively cared for and
      surviving neonates with severe hypoxaemia requiring extracorporeal membrane
      oxygenation (ECMO) were evaluated at a mean age of 19.6 months. The serial plasma
      lactate concentrations were significantly correlated with the scores of the
      Bayley Scales of Infant Development. Admission and peak plasma lactate of < or =
      15 mmol/l predicted favourable outcome (MDI and PDI > 70 and no disability):
      sensitivity 100%, specificity 88%, positive predictive value 90%, and negative
      predictive value 100%. Plasma lactate values could help predict
      neurodevelopmental outcome in these sick neonates.

PMID- 8653438
TI  - Use of Wigglesworth pathophysiological classification for perinatal mortality in
      Malaysia.
AB  - A one year prospective study of perinatal deaths was conducted to test the
      feasibility of using the Wigglesworth pathophysiological classification in the
      Malaysian health service. Four regions with high perinatal mortality rates were
      selected. Deaths were actively identified. Nursing staff were trained to use the
      classification and every death was reviewed by a clinician. A total of 26,198
      births and 482 perinatal deaths were reported. The perinatal mortality rate was
      18.4. Only 14 (2.9%) deaths had their Wigglesworth category reclassified. Most
      deaths were in the normally formed macerated stillbirths (34.4%), asphyxial
      conditions (26.8%), and immaturity (20.1%) subgroups. The results were compared
      with data from other countries that used this classification. This study has
      shown that the Wigglesworth pathophysiological classification can be applied to
      perinatal deaths in the existing Malaysian health service.

PMID- 8653437
TI  - Inflammatory bronchopulmonary response of preterm infants with microbial
      colonisation of the airways at birth.
AB  - The inflammatory indicators in the tracheobronchial aspirate (TA) of 81
      ventilated preterm infants with microbial colonisation of the airways and in non
      colonised neonates were analysed on the first day of life. TA was assessed for
      chemotactic activity, neutrophil cell count, and concentrations of leukotriene
      B4, C5a, interleukin-1, interleukin-8, elastase-alpha 1-proteinase inhibitor,
      free elastase and albumin. Concentrations of mediators were related to
      concentrations of the secretory component of IgA. The infants' gestational age
      was mean (SD) 27.9 (2.0) weeks, birthweight 945 (179) g. In 12 infants (15%)
      microbial colonisation of the airways was present (Ureaplasma urealyticum n = 7;
      bacteria n = 5). Compared with non-colonised neonates (n = 69), chemotactic
      activity, neutrophil count, and concentrations of interleukin-1, leukotriene B4
      and elastase-alpha 1-proteinase inhibitor were significantly higher in the
      colonised group. The difference was most pronounced for IL-1 concentrations, both
      with and without correction for secretory component. There was also a trend
      towards increased concentrations of interleukin-8 in the latter group. There were
      no differences for concentrations of C5a and albumin in the TA of both groups. It
      is concluded that airway colonisation with U urealyticum or bacteria at birth is
      associated with a clinically relevant bronchopulmonary inflammatory response.
      Increased concentrations of interleukin-1 in TA on the first day of life may be a
      marker of perinatal colonisation of the airways.

PMID- 8653439
TI  - Effect of fortifying breast milk on gastric emptying.
AB  - A study was performed to determine if the addition of a fortifier to expressed
      breast milk (EBM) affected gastric emptying in low birthweight infants. Using
      ultrasonography, the gastric emptying of EBM alone was compared with that
      containing a fortifier, in a blind, crossover study. Twenty two low birthweight
      infants were studied: median (range) gestation 31.5 weeks (28-37); birthweight
      1495 g (1000-2480 g). The gastric antral cross-sectional area (ACSA) was measured
      by ultrasonography before each feed and then sequentially after its completion
      until the ACSA returned to its pre-feed value. The half emptying time was
      calculated as the time taken for the ACSA to decrease to half the maximum
      increment. The mean difference (standard error) between half emptying times for
      EBM alone and for EBM with added fortifier was not significant: 1.48 (4.9)
      minutes. These data show that fortifying breast milk does not affect gastric
      emptying and suggests that the practice is unlikely to affect feed tolerance in
      low birthweight infants.

PMID- 8653440
TI  - Cerebral blood flow in the newborn infant.
AB  - Studies of CBF have provided some insight into cerebrovascular physiology and
      pharmacology. However, the precise relation between CBF and cerebral damage
      remains elusive, and there is no definition of a threshold CBF below which
      ischaemic brain damage always occurs. Measurement of CBF thus does not currently
      provide a secure guide in the clinical management of sick infants. Further work,
      particularly using techniques like magnetic resonance imaging and NIRS, which
      provide data in addition to CBF measurements, may yet disclose strategies which
      manipulate CBF to reduce cerebral ischaemia. While cerebral injury remains a
      substantial problem in neonatal intensive care, such research is urgently needed.

PMID- 8653442
TI  - Dr Edward Jenner (1749-1823) of Berkeley, and vaccination against smallpox.

PMID- 8653443
TI  - Indirect estimates of pulmonary artery pressure.

PMID- 8653441
TI  - Use of evoked potentials in preterm neonates.
AB  - This paper has reviewed the techniques used for recording evoked potentials in
      the premature infant and the early developmental changes. The maturational
      changes in the evoked potentials, including morphological changes, and the very
      rapid latency changes within the first months of life, provide an invaluable
      means for assessing and monitoring development within the central nervous system.
      The maturational changes are such that normative values are requisite, and the
      norms must take into account both the infant's gestational age at birth as well
      as the postnatal age. These norms can then be used to aid in the assessment of
      gestational age, and whether there has or has not been normal maturational
      development, either in utero or during the postnatal preterm period. Evoked
      potentials are of increasing value clinically in preterm neonates, primarily
      because of the difficulty in obtaining reliable neurological evaluation of these
      infants. Median nerve SEPs may provide reliable information in preterm infants at
      risk of PVL, and when recorded in the second week of life, predict cerebral
      palsy. PTN SEPs seem to be even more reliable indicators of outcome, but the
      difficulty in obtaining them in preterm infants needs to be taken into
      consideration. Further study is needed in some areas, such as in apnoeic preterm
      babies clearly to establish the role that evoked potentials (in this case BAEPs)
      may have in understanding both the aetiology and the clinical course of this
      dysfunction. In other conditions, such as delayed intrauterine growth, that may
      lead to neurological sequelae, evoked potentials can provide objective CNS
      assessment. Evoked potentials may also prove useful in the monitoring of
      treatment modalities for preterm infants. The evoked potentials are a valuable
      adjunct in the assessment of preterm neonates and, as their value is recognised,
      we expect their use to increase.

PMID- 8653445
TI  - Neonatal pulmonary arteriovenous malformation.

PMID- 8653444
TI  - CRIB and performance indicators for neonatal intensive care units (NICUs)

PMID- 8653446
TI  - Information management of a medical school educational program: a state-of-the
      art application.
AB  - Quality in the design and management of a medical school education program
      depends on the ability to access and analyze relevant information in a timely
      fashion. The components of medical-education information system should support
      learning and instruction as well as the administrative and research
      responsibilities of the program. A system capable of meeting these needs requires
      core, operational, and strategic components. This article discusses a conceptual
      schema of the medical school environment and reports the results of 3 1/2 years'
      experience developing core, operational, and strategic components as the
      University of Pittsburgh School of Medicine. The value of a simple conceptual
      schema as a design and development instrument was confirmed. Limitations of the
      system are discussed along with potential solutions.

PMID- 8653447
TI  - Strategies for integrating computer-based activities into your educational
      environment: a practical guide.
AB  - Strategies for implementing instructional technology are based on recent
      experiences at the University of Michigan Medical Center. The issues covered
      include 1) addressing facilities, hardware, and staffing needs, 2) determining
      learners' skill requirements and appropriate training activities, and 3)
      selecting and customizing educational software. Many examples are provided, and
      nine key points for success are emphasized.

PMID- 8653448
TI  - The visible human male: a technical report.
AB  - The National Library of Medicine's Visible Human Male data set consists of
      digital magnetic resonance (MR), computed tomography (CT), and anatomic images
      derived from a single male cadaver. The data set is 15 gigabytes in size and is
      available from the National Library of Medicine under a no-cost license
      agreement. The history of the Visible Human Male cadaver and the methods and
      technology to produce the data set are described.

PMID- 8653449
TI  - Artificial neural networks can distinguish novice and expert strategies during
      complex problem solving.
AB  - OBJECTIVE: To determine whether expert problem-solving strategies can be
      identified within a large number of student performances of complex medical
      diagnostic simulations. METHODS: Self-organizing artificial neural networks were
      trained to categorize the performances of infectious disease subspecialists on
      six computer-based clinical diagnostic simulation that used the sequence of
      diagnostic tests requested as the input data. Six hundred seventy-six student
      solutions to these problems were presented to these trained neural networks to
      determine which, if any, of the student solutions represented those of the
      experts. RESULTS: For each simulation, the expert performances clustered around
      one dominant output neurode, indicating that there were common problem-specific
      features associated with the experts' problem-solving performances. When the
      performances of students who also made correct problem diagnoses were tested on
      these expert-trained neural networks, 17% were classified as representing expert
      strategies, indicating that expert performance was a somewhat rare and
      inconsistent occurrence among the students. CONCLUSIONS: The ability to identify
      a small number of expert-like strategies within a large body of student
      performances may provide an opportunity to study the dynamics of complex learning
      at both individual and population levels as well as the emergence of medical
      diagnostic expertise.

PMID- 8653450
TI  - Privacy, confidentiality, and electronic medical records.
AB  - The enhanced availability of health information in an electronic format is
      strategic for industry-wide efforts to improve the quality and reduce the cost of
      health care, yet it brings a concomitant concern of greater risk for loss of
      privacy among health care participants. The authors review the conflicting goals
      of accessibility and security for electronic medical records and discuss
      nontechnical and technical aspects that constitute a reasonable security
      solution. It is argued that with guiding policy and current technology, an
      electronic medical record may offer better security than a traditional paper
      record.

PMID- 8653451
TI  - Development of a replicated database of DHCP data for evaluation of drug use.
AB  - This case report describes development and testing of a method to extract
      clinical information stored in the Veterans Affairs (VA) Decentralized Hospital
      Computer System (DHCP) for the purpose of analyzing data about groups of
      patients. The authors used a microcomputer-based, structured query language (SQL)
      compatible, relational database system to replicate a subset of the Nashville VA
      Hospital's DHCP patient database. This replicated database contained the complete
      current Nashville DHCP prescription, provider, patient, and drug data sets, and a
      subset of the laboratory data. A pilot project employed this replicated database
      to answer questions that might arise in drug-use evaluation, such as
      identification of cases of polypharmacy, suboptimal drug regimens, and inadequate
      laboratory monitoring of drug therapy. These database queries included as
      candidates for review all prescriptions for all outpatients. The queries
      demonstrated that specific drug-use events could be identified for any time
      interval represented in the replicated database.

PMID- 8653452
TI  - Retrieval feedback in MEDLINE.
AB  - OBJECTIVE: To investigate a new approach for query expansion based on retrieval
      feedback. The first objective in this study was to examine alternative query
      expansion methods within the same retrieval-feedback framework. The three
      alternatives proposed are: expansion on the MeSH query field alone, expansion on
      the free-text field alone, and expansion on both the MeSH and the free-text
      fields. The second objective was to gain further understanding of retrieval
      feedback by examining possible dependencies on relevant documents during the
      feedback cycle. DESIGN: Comparative study of retrieval effectiveness using the
      original unexpanded and the alternative expanded user queries on a MEDLINE test
      collection of 75 queries and 2,334 MEDLINE citations. MEASUREMENTS: Retrieval
      effectivenesses of the original unexpanded and the alternative expanded queries
      were compared using 11-point-average precision scores (11-AvgP). These are
      averages of precision scores obtained at 11 standard recall points. RESULTS: All
      three expansion strategies significantly improved the original queries in terms
      of retrieval effectiveness. Expansion on MeSH alone was equivalent to expansion
      on both MeSH and the free-text fields. Expansion on the free-text field alone
      improved the queries significantly less than did the other two strategies. The
      second part of the study indicated that retrieval-feedback-based expansion yields
      significant performance improvements independent of the availability of relevant
      documents for feedback information. CONCLUSIONS: Retrieval feedback offers a
      robust procedure for query expansion that is most effective for MEDLINE when
      applied to the MeSH field.

PMID- 8653454
TI  - Education and informatics: it's time to join forces.

PMID- 8653453
TI  - The PEN-Ivory project: exploring user-interface design for the selection of items
      from large controlled vocabularies of medicine.
AB  - OBJECTIVE: To explore different user-interface designs for structured progress
      note entry, with a long-term goal of developing design guidelines for user
      interfaces where users select items from large medical vocabularies. DESIGN: The
      authors created eight different prototypes of a pen-based progress-note-writing
      system called PEN-Ivory. Each prototype allows physicians to write patient
      progress notes using simple pen-based gestures such as circle, line-out, and
      scratch-out. The result of an interaction with PEN-Ivory is a progress note in
      English prose. The eight prototypes were designed in a principled way, so that
      they differ from one another in just one of three different user-interface
      characteristics. MEASUREMENTS: Five of the eight prototypes were tested by
      measuring the time it took 15 users, each using a distinct prototype, to document
      three patient cases consisting of a total of 63 medical findings. RESULTS: The
      prototype that allowed the fastest data entry had the following three user
      interface characteristics: it used a paging rather than a scrolling form, it used
      a fixed palette of modifiers rather than a dynamic "pop-up" palette, and it made
      available all findings from the controlled vocabulary at once rather than
      displaying only a subset of findings generated by analyzing the patient's problem
      list. CONCLUSION: Even simple design changes to a user interface can make
      dramatic differences in user performance. The authors discuss possible influences
      on performance, such as positional constancy, user uncertainty and system
      anticipation, that may contribute significantly to the effectiveness of systems
      that display menus of items from large controlled vocabularies of medicine.

PMID- 8653455
TI  - Is the jaw bone connected to the hip bone?

PMID- 8653456
TI  - Impacted third molar and mandibular angle fractures.

PMID- 8653457
TI  - Hyperbaric oxygen therapy.

PMID- 8653458
TI  - Development of the bulletin board for oral pathology.

PMID- 8653459
TI  - Epidemiologic review of pediatric and adult maxillofacial infections in
      hospitalized patients.
AB  - OBJECTIVE: Previous studies documented that location of infection (upper face
      versus lower face) was a useful tool in managing pediatric facial infections.
      This study's two objectives were (1) to determine if location of infection was a
      useful parameter for managing adults with maxillofacial infections, and (2) to
      compare and contrast the epidemiologic patterns of maxillofacial infections in
      adults and children. STUDY DESIGN: We used a retrospective cohort study design to
      review the medical records of adults (age > or = 18) and children (age < or = 14)
      admitted for treatment of facial infections. Study variables were grouped into
      the following sets: demographic, clinical, laboratory, treatment, and outcome
      data. Bivariate data analyses were used to measure associations between study
      variables. RESULTS: The study sample was composed of 339 adults and 143 pediatric
      patients. For adult patients, upper and lower face infections could be
      differentiated on the basis of age, admission white blood cell count, cause of
      infection, microbiologic variability, treatment, and duration of outpatient
      treatment. Adults and children with facial infections differed as to duration of
      preadmission symptoms, presence of constitutional symptoms, admission
      temperature, location of infection, source of infection, culture results,
      treatment, duration of treatment, and complications. CONCLUSIONS: Location of
      infection may not be a clinically useful parameter in managing adults with facial
      infection. Important differences exist between adults and children with facial
      infection. The management of pediatric facial infections should reflect these
      differences.

PMID- 8653460
TI  - Vital staining with iodine solution in delineating the border of oral dysplastic
      lesions.
AB  - OBJECTIVE: The borders of dysplastic lesions of the oral mucosa are often vaguely
      delineated. The purpose of this study was to determine if vital staining with an
      iodine solution can precisely delineate the boundary of superficial spread of
      dysplastic or malignant epithelium. STUDY DESIGN: Thirty-seven biopsies were
      obtained from 18 patients with possible malignant lesions of the oral mucosa.
      Deviations between the clinical boundary obtained with vital staining and the
      histopathologic boundary determined in hemotoxylin-eosin-and lectin-stained
      sections were measured with light microscopy. RESULT: The clinical boundaries
      defined with the vital staining agreed well with the pathologic border lines and
      were in error by less than 3 mm. CONCLUSION: This result suggests that vital
      staining with an iodine solution has great potential in determining the extent
      and precise borders of the dysplastic epithelium. A 5-mm border of normal tissue
      peripheral to the iodine-positive area would be adequate for the complete removal
      of the dysplastic epithelium.

PMID- 8653461
TI  - Ten-year longitudinal study of periodontal attachment loss in healthy adults.
AB  - Despite much research, it is still difficult to make generalizations concerning
      aging and periodontal diseases. This study examined 95 healthy men and women
      (aged 29 to 76 years at initial visit) from the oral physiology component of the
      Baltimore Longitudinal Study of Aging over a 10-year period. Periodontal
      measurements were taken at two visits, and recession, pocket depth, and level of
      attachment determined. The change of level of attachment and attachment loss was
      assessed as a longitudinal measure of disease progression. Overall there were
      only slight changes in periodontal measurements over the 10-year period.
      Attachment loss was age-dependent and was due primarily to increased recession
      not to changes in pocket depth. Periodontal disease destruction (as measured by
      attachment loss) occurred over time but was not related to the age or gender of a
      person. These results from healthy persons suggest that periodontal diseases are
      not a natural consequence of the aging process, and that advanced age is not an
      accurate predictor of attachment loss.

PMID- 8653463
TI  - Changes in dentists' infection control practices, knowledge, and attitudes about
      HIV over a 2-year period.
AB  - OBJECTIVE: To investigate changes in the infection control practices, attitudes,
      and knowledge of dentists as they relate to HIV/AIDS: STUDY DESIGN: A comparison
      of responses to surveys conducted in 1992 (n = 258) and 1994 (n = 262) with the
      use of univariate/multivariate analyses and McNemar's test for paired data.
      RESULTS: The response rate were > 70%. There were significant increases in
      reports of continuing education related to HIV/AIDS, heat sterilization of
      handpieces, use of masks, and knowledge of risk of HIV infection after a
      needlestick injury. Significantly fewer respondents reported concerns about staff
      fears about HIV/AIDS: Reports of willingness to treat patients with HIV increased
      from 68% to 77%. The best predictors of willingness to treat changed from
      primarily infection control variables to lack of concern with respect to risk or
      loss of patients when treating persons with HIV. CONCLUSIONS: Increased use of
      infection control procedures and knowledge may be partly attributable to the
      introduction of mandatory continuing education in 1993.

PMID- 8653462
TI  - Prophylaxis of candidiasis in patients with leukemia and bone marrow transplants.
AB  - OBJECTIVES: The increased risk for systemic fungal infection and the potential
      fatal consequences of disseminated candidiasis in bone marrow transplant patients
      has prompted study of prophylaxis and early treatment of candida colonization and
      infection. STUDY DESIGN: Patients with leukemia who received fluconazole
      prophylaxis were compared with a concurrent group of patients not given
      prophylaxis for fungal organisms. RESULTS: A trend to reduction of oropharyngeal
      colonization by Candida albicans was seen (p = 0.07) although no significant
      differences in systemic candidiasis were seen. In patients with documented
      systemic candidiasis, oral colonization was present and systemic infection was
      identified after the development of ulcerative oral mucositis. CONCLUSIONS: Our
      results support the potential of fluconazole to reduce oropharyngeal colonization
      by Candida albicans, however, we did not show prophylaxis of oral candidiasis or
      systemic candidiasis. These findings and reports of fluconazole-resistant
      candidal species and a rising number of cases of infection as a result of Candida
      krusei indicate the need for further studies of prophylaxis of candidal infection
      in patients who are anticipated to develop profound neutropenia.

PMID- 8653464
TI  - Review of oral histoplasmosis in Malaysians.
AB  - We reviewed biopsy records for 37 cases of oral histoplasmosis for patient
      characteristics, clinical features, and histopathologic findings. These
      represented cases diagnosed in the Division of Stomatology, Institute for Medical
      Research, Kuala Lumpur between July 1967 and October 1994. All were male patients
      who ranged in age from 11 to 79 years (mean age, 56.7 years). There were 40.6%
      Malays, 37.8% Chinese, 18.9% Indians, and 2.7% other races. Five patients with
      mouth lesions as the initial presenting lesions were proven to be cases of
      disseminated histoplasmosis. In the remaining cases apart from the biopsy-proven
      oral histoplasmosis lesions, the extent of the disease elsewhere was unknown. The
      majority of these lesions involved the gingiva, tongue, and palate in decreasing
      order of frequency. The most frequent presenting symptom was oral mucosal
      ulceration. Squamous cell carcinoma and tuberculosis were the two most common
      clinical differential diagnoses. Our present findings compare favorably with
      published reports from other regions.

PMID- 8653465
TI  - Lymphoma in Sjogren's syndrome. From histopathology to molecular pathology.
AB  - A number of autoimmune diseases predispose to the development of neoplasia. A
      particularly well-recognized association is the development of lymphoma in
      Sjogren's syndrome. Although this risk has been estimated to be 44 times that of
      the general population, few reliable prognostic indexes exist for individual
      patients. Recent advances in molecular biology have improved our understanding of
      Sjogren's syndrome and permitted better characterization of the generalized
      lymphoproliferation associated with the condition. This article reviews the
      histopathology of the major and minor salivary gland lesions of Sjogren's
      syndrome and discusses advances in molecular biology that have permitted more
      accurate prediction of lymphoma development in this group of patients.

PMID- 8653466
TI  - Mandibular lymphomas with sclerosis.
AB  - Two cases of non-Hodgkin's lymphoma that show a sarcomatoid pattern within the
      jaw are described. Their primary origin in bone was demonstrated by radiologic
      studies. In one case, diagnosis was delayed because the clinical picture
      suggested inflammatory periodontal disease. In both cases, the histologic picture
      was similar to that of a sarcomatoid neoplasm with intense stromal sclerosis;
      hemimandibulectomy was performed in one case. The tumor contained cells with
      large, irregular, sometimes lobulated nuclei and high mitotic activity, and
      perforated mandibular bone with infiltration into adjacent soft tissues. The
      lymphoid nature of these neoplasms was demonstrated by immunohistochemical and
      ultrastructural study.

PMID- 8653467
TI  - Unicentric angiofollicular hyperplasia (Castleman's disease) of the parotid: a
      case report.
AB  - Angiofollicular lymph node hyperplasia, or Castleman's disease, is a condition of
      uncertain cause usually presenting with mediastinal lymphadenopathy. Occasionally
      other lymph node groups may be involved with or without associated systemic
      manifestations. A case of Castleman's disease involving parotid lymph nodes is
      reported in a 16-year-old female patient who presented with a painless swelling
      that initially was noticed at the age of 3 years. Diagnosis was established by
      histopathologic examination of the respected specimen. Histologic and clinical
      features of Castleman's disease are also discussed.

PMID- 8653468
TI  - Diffuse sclerosing osteomyelitis and florid osseous dysplasia.
AB  - The literature on diffuse sclerosing osteomyelitis of the mandible has included
      at least two groups of lesions: (1) those from which bacterial infectious agents
      are rarely isolated (chronic-tendoperiostitis); and (2) those from which bacteria
      are readily isolated (true diffuse sclerosing osteomyelitis). The latter should
      be distinguished from secondarily infected florid osseous dysplasia. In this
      article the features of 16 patients with sclerotic jawbone lesions associated
      with symptoms of infection are analyzed. Eleven patients showed a large area of
      sclerosis of the mandible that was not restricted to the alveolar process and was
      surrounding an infectious focus. The histologic pattern revealed a deposition of
      reactive bone. These lesions are considered to represent true diffuse sclerosing
      osteomyelitis. The remaining five patients showed sclerotic lesions restricted to
      the alveolar process in one or more quadrants of the jaws. Apart from
      inflammation and reactive changes, histologic pattern revealed a fibroblastic
      stroma with bone and cementum-like structures that are formed by metaplasia.
      These lesions are considered to represent secondarily infected florid osseous
      dysplasia.

PMID- 8653469
TI  - Magnetic resonance imaging used to assess patients with trigeminal neuralgia.
AB  - To assess the value of magnetic resonance imaging in the evaluation of trigeminal
      neuralgia, 51 patients were studied by magnetic resonance imaging after a
      trigeminal protocol. Clinical and magnetic resonance imaging results were
      correlated. Seventeen (33%) nonvascular abnormalities and 27 (53%) vascular
      contacts or compressions of the trigeminal nerve were demonstrated. Of the
      patients younger than of 29 and 39 years of age, 100% and 45%, respectively, had
      a tumor or multiple sclerosis compared with 20% and 18% of those older than 40
      and 60 years of age, respectively. One third of the patients with pain in more
      than one branch of the trigeminal nerve had tumors. On the basis of this study,
      magnetic resonance imaging may be useful in discovering underlying pathoses
      associated with trigeminal neuralgia if patients have failed to respond to an
      initial conservative treatment. The patients most likely to exhibit significant
      magnetic imaging resonance findings are young and with pain in more than one
      trigeminal branch.

PMID- 8653470
TI  - Impact of lossy image compression on accuracy of caries detection in digital
      images taken with a storage phosphor system.
AB  - Image compression may reduce storage needs whether in the lossless (reversible)
      or lossy (irreversible) form. The aims of the study were to evaluate (1) storage
      needs, (2) subjective image quality, and (3) accuracy of caries detection in
      digital radiographs compressed to various levels by a lossy compression method.
      The material consisted of 116 extracted human premolars and molars. The teeth
      were mounted three in a line and radiographed by the Digora system (Sorodex
      Medical Systems, Helsinki, Finland). The images were exported in tagged image
      file format and compressed with the Lempel-Ziv-Welch reversible and the Joint
      Photographic Experts Group irreversible compression algorithm on four levels. The
      total of 580 images were assessed by five observers on a 5-rank confidence scale
      for caries diagnosis. The observers subjectively judged image quality on an 11
      point rank scale. With the reversible compression, images could be compressed to
      less than 50% of the original storage needs whereas the four irreversible
      compression factors compressed to 20%, 8%, 5%, and 3%, respectively. For occlusal
      surfaces, when receiver operating characteristic curve areas were increasingly
      smaller and the compression rate was higher. The difference between the original
      and the most compressed images was 14% (p = 0.1). The median quality score was
      above middle on the 11-point rank scale for all except the most compressed images
      (median score = 1). In conclusion, for caries diagnosis, compression ratio rates
      of 1:12 can be justified before accuracy and image quality is significantly
      affected.

PMID- 8653471
TI  - Osteopathia striata, short stature, cataracts, and microdontia: a new syndrome? A
      case report.
AB  - A case of osteopathia striata, childhood cataracts, short stature, elbow
      deformity, and microdontia with rhizomicry in a white male is reported. The
      report includes a detailed analysis of dental changes. The relationship of this
      syndrome to other similar conditions including osteopathia striata with cranial
      base sclerosis and Rothmund-Thomson syndrome are discussed.

PMID- 8653472
TI  - Radiographic features of the mandible in neurofibromatosis: a report of 10 cases
      and review of the literature.
AB  - The radiographs of 10 cases with a diagnosis of neurofibromatosis involving the
      mandible were evaluated by two reviewers to document common radiographic
      characteristics. The most common findings included increase in bone density,
      enlarged mandibular foramen, lateral bowing of the mandibular ramus, increase in
      dimensions of the coronoid notch, and a decrease in the mandibular angle. The six
      cases for which computed tomography scans were available, enlargement of the
      mandibular foramen and concavity of the medial surface of the ramus were seen. In
      five of these cases, there was no associated tumor mass adjacent to the
      concavity; instead a soft tissue mass with density of fat was found. This
      supports the theory that neurofibromatosis may have manifestations of a
      mesodermal dysplasia.

PMID- 8653473
TI  - Effects of tomographic motion, slice thickness, and object thickness on film
      density.
AB  - The experiment used the computer-aided CommCat model IS 2000 tomographic machine
      (Imaging Sciences International, Roebling, N.J.). The objective of the experiment
      was to study the influence of tomographic tube motion, tomographic slice
      thickness, and object thickness on film density. The experiment was conducted by
      x-radiating an aluminum step-wedge placed along the x-axis. Exposures were made
      for different tube motions and for different slice thicknesses. In linear
      horizontal and linear vertical motions, an increased slice thickness decreased
      film density. Slice thickness had a stronger effect on film density when the
      object to be x-radiated was thinner. In circular, elliptical, spiral, and
      hypocycloidal motions, changes in slice thickness had no noticeable effect on
      film density because the manufacturer had programmed the machine to produce
      approximately similar exposure times by increasing the x-ray tube velocity
      thickness had a greater effect on film density for circular, elliptical, spiral,
      and hypocycloidal tube motions than for linear horizontal and linear vertical
      tube motions. Clinical observation showed that except for the linear vertical
      motion (motion that was oriented in the same direction as that of the tube
      travel) all other motions produced a zone of diffusion along the edges of the
      steps of the step-wedge. An increase in slice thickness had an effect on film
      density. Slice thickness had a noticeable effect on film density in linear but
      not in multidirectional tomography. Object thickness had a greater effect on film
      density in multidirectional than in linear tomography.

PMID- 8653474
TI  - Fewer health professionals and schools needed, says Pew Commission.

PMID- 8653475
TI  - New nucleoside analogue, lamivudine, released for HIV therapy.

PMID- 8653476
TI  - Doxorubicin liposome formulation gains marketing approval.

PMID- 8653477
TI  - New data refine role of adjuvant tamoxifen in early breast cancer.

PMID- 8653478
TI  - Hypertension and diabetes outcomes unaffected by payment structure of health
      systems.

PMID- 8653479
TI  - Projecting future drug expenditures--1996.
AB  - The use of information on inflation, pharmacoeconomics, generic competition, new
      drug entities, site-specific drug-use patterns, legislation, and the changing
      health care environment in the projection of drug expenditures is discussed. Drug
      price inflation has declined from 6.9% in 1991 to 2.1% for part of 1995. Much of
      the decline is attributable to deep discounts given by manufacturers to managed
      care institutions. Some marketing specialists are predicting that drug
      manufacturers will begin to scale back discounts. Pharmaceutical industry
      analysts project that overall price increase for pharmaceuticals in the next 12
      24 months will average 2.8% (range, 0-6%). Pharmacists need to be able to
      understand and critically evaluate pharmacoeconomic research, particularly
      studies conducted by the pharmaceutical industry. Savings due to increases in
      generic product selection may be offset to some degree by extensions of patent
      expiration dates under the General Agreement on Tariffs and Trade (GATT). Drug
      budget projections should include a complete review of new drugs and
      biotechnology agents pending FDA approval, drugs pending approval for new
      indications, and common unlabeled uses of expensive existing agents. Various
      methods are available for tracking drug-use patterns in specific practice
      settings. When resources are limited, pharmacy managers may elect to target only
      high-cost drugs; a proactive approach, such as projecting costs and developing
      guidelines for costly agents before their market release and before consideration
      by the pharmacy and therapeutics committee, is advantageous. Relevant legislative
      activities in 1995 included reform proposals for Medicare, Medicaid, and FDA; the
      Federal Acquisition Streamlining Act; and GATT. Disease management and other
      approaches to pharmacy benefits have increased opportunities for cooperative
      arrangements between drug companies and health care providers that may have major
      effects on drug marketing and pricing. Combining information on inflation,
      pharmacoeconomics, generics, new drugs, practice-site drug-use patterns, federal
      legislation, and the changing health care environment is necessary for accurate
      projections of drug expenditures.

PMID- 8653480
TI  - Antisense strategies and therapeutic applications.
AB  - The concepts underlying the antisense approach to disease therapy are discussed,
      and potential applications are examined. Antisense therapeutic agents bind to DNA
      or RNA sequences, blocking the synthesis of cellular proteins with unparalleled
      specificity. Transcription and translation are the two processes with which the
      agents interfere. There are three major classes of antisense agents: antisense
      sequences, commonly called antisense oligonucleotides; antigene sequences; and
      ribozymes. Antisense sequences are derivatives of nucleic acids that hybridize
      cytosolic messenger RNA (mRNA) sense strands through hydrogen bonding to
      complementary nucleic acid bases. Antigene sequences hybridize double-stranded
      DNA in the nucleus, forming triple helixes. Ribozymes, rather than inhibiting
      protein synthesis simply by binding to a single targeted mRNA, combine enzymatic
      processes with the specificity of antisense base pairing, creating a molecule
      that can incapacitate multiple targeted mRNAs. Antisense therapeutic agents are
      being investigated in vitro and in vivo for use in treating human
      immunodeficiency virus infection, hepatitis B virus infection, herpes simplex
      virus infection, papillomavirus infection, cancer, restenosis, rheumatoid
      arthritis, and allergic disorders. Although many results are preliminary, some
      are promising and have led to clinical trials. A major goal in developing methods
      of delivering antisense agents is to reduce their susceptibility to nucleases
      while retaining their ability to bind to targeted sites. Modification of the
      phosphodiester linkages in oligonucleotides can lend the sequences enzymatic
      stability without affecting their binding capacities. Carrier systems designed to
      protect the antisense structure and improve passage through the cell membrane
      include liposomes, water-soluble polymers, and nanoparticles. The
      pharmacokinetics of antisense agents are under investigation. Antisense
      therapeutic agents have the potential to become an integral part of medicinal
      regimens.

PMID- 8653481
TI  - Home care reimbursement for intravenous ganciclovir therapy.
AB  - Variability in reimbursement for home i.v. ganciclovir therapy among three types
      of payers was investigated. A survey was developed to estimate reimbursement for
      drug and medical supplies and nursing services associated with preparing i.v.
      ganciclovir and administering it to persons with cytomegalovirus (CMV)-associated
      retinitis in the home care setting. The questionnaire was mailed to 45 home
      health care agencies and 11 nursing agencies. Of the 56 surveys mailed, 26 (46%)
      were returned and considered usable. Of the 26 respondents, 22 were home health
      care companies, 4 were nursing agencies, 22 served patients covered by managed
      care or state assistance that reimbursed on a per diem basis, and 9 did not
      provide care to fee-for-service patients. The mean total daily reimbursement rate
      (for ganciclovir, supplies, and nursing services) from managed care per diem
      plans was $137.69 per patient, compared with $129.18 from fee-for-service plans
      and $72.68 from state assistance per diem plans. The dissimilarity may have been
      due to geographic variations in reimbursement and different mechanisms of
      reimbursement. Providers of home i.v. ganciclovir therapy for persons with CMV
      retinitis received the highest mean total daily reimbursement from managed care
      per diem plans, followed by fee-for-service plans and state assistance per diem
      plans.

PMID- 8653482
TI  - Relational database for drug-use review of Tennessee Medicaid claims.
AB  - The development of a relational database from Tennessee Medicaid files for the
      purpose of retrospective drug-use review (DUR) and application of the database
      for DUR of angiotensin-converting-enzyme inhibitors (ACEIs) are described.
      Computer queries were designed to create profiles of physicians' or pharmacies'
      experiences from claims data and other Medicaid data. Outlying patients (patients
      for whom at least one DUR criterion was unmet) were grouped according to their
      physicians or pharmacies. Thresholds for defining outlying physicians and
      pharmacies (i.e., those with more than a specified number of outlying patients)
      were based on the provider population instead of the patient population as a
      whole; aggregating patient outliers by provider allowed trends of inappropriate
      practices to be detected. As the threshold for outlying providers rose, the
      number of such providers fell, as did the number of outlying patients with whom
      they were associated. Stratification of the outliers by provider for specific
      drug-drug interactions and drug-disease complications afforded the option to set
      individual thresholds for outlying providers based on individual subsets; for
      example, for ACEIs, a threshold of greater than five patient outliers could be
      set for the criterion of no concurrent potassium supplements and a threshold of
      greater than three, for the criterion of no unmonitored concurrent lithium
      therapy. Tennessee patients formerly covered by Medicaid are now enrolled in
      managed care plans, and the flexibility of the database has allowed it to be
      modified accordingly. The relational database allows flexibility in the analysis
      of certain patterns of drug use. Such a database may be useful to other Medicaid
      programs that are converting to managed care models.

PMID- 8653483
TI  - Compatibility and activity of enoxaparin sodium in 0.9% sodium chloride injection
      for 48 hours.
AB  - The stability of enoxaparin sodium in 0.9% sodium chloride injection in polyvinyl
      chloride (PVC) containers was studied. Triplicate solutions of 120 mg (1.2 mL) of
      enoxaparin (as the sodium salt) and 98.8 mL of 0.9% sodium chloride injection
      were prepared in 250-mL PVC containers and stored at room temperature (20-22
      degrees C). Samples were taken immediately after preparation and at 0.25, 0.5,
      0.75, 1, 4, 12, 16, 24, and 48 hours. Inspections for color change and
      precipitation were performed with a clarity inspection station and a magnifying
      glass. Samples of the three admixtures were evaluated in duplicate for
      pharmacologic activity by an automated coagulation heparin assay. Throughout the
      48-hour study period, the enoxaparin admixtures were free of color change,
      evolution of gas, and precipitates. The pharmacologic activity of enoxaparin in
      the PVC containers remained > 94% of the initial measured activity for 48 hours.
      Enoxaparin 1.2 mg/mL (as the sodium salt) in 0.9% sodium chloride injection in
      PVC containers was stable for up to 48 hours at 20-22 degrees C.

PMID- 8653484
TI  - Stability of bupivacaine hydrochloride and hydromorphone hydrochloride during
      simulated epidural coadministration.
AB  - Bupivacaine hydrochloride 625 and 1250 micrograms/mL and hydromorphone
      hydrochloride 20 and 100 micrograms/mL in 0.9% sodium chloride injection were
      stable and compatible for up to 72 hours under fluorescent light when stored in
      polyvinyl chloride containers at 24 degrees C.

PMID- 8653485
TI  - Estimating the rate of adverse drug reactions with capture-recapture analysis.
AB  - The capture-recapture technique used to estimate the number of ADRs at UICMC may
      offer institutions and health systems a way to better identify and address the
      occurrence of ADRs.

PMID- 8653486
TI  - Incompatibility of amiodarone hydrochloride and evacuated glass bottles.

PMID- 8653487
TI  - Suspected vein irritation from i.v. pentamidine isethionate.

PMID- 8653488
TI  - Improved detection of drug-related problems in intensive care unit patients.

PMID- 8653489
TI  - Stability of dopamine hydrochloride and of dobutamine hydrochloride in plastic
      syringes and administration sets.

PMID- 8653490
TI  - Long-term bone mass evaluation of mandible and lumbar spine in a group of women
      receiving hormone replacement therapy.
AB  - The overall aim of this study was to examine the relationship between bone mass
      of the jaw and the axial skeleton. Sixty-nine subjects (age at entry: 32-64), who
      underwent hormone replacement therapy during the study period, participated. Bone
      mass of the lumbar spine was determined using dual photon absorptiometry. The jaw
      bone of the posterior region of the mandible was evaluated by means of
      standardized long-cone radiography using individual bite-blocks. A densitometric
      wedge in the film holder provided a reference to quantify bone mass. From both
      measurements, it appeared that the bone mass of the mandible and the lumbar spine
      showed a moderate relationship. The present results also confirmed that estrogen
      replacement therapy had a positive effect on the bone mass of the mandible and
      the lumbar spine. Different estrogen regimens resulted in different increases in
      bone mass during the observation period, which was on average 5 yr.

PMID- 8653491
TI  - Excavation of caries lesions induces transient decrease of total salivary
      immunoglobulin A concentration.
AB  - Salivary immunoglobulin A (IgA) secreted by salivary glands is the predominant
      humoral factor of the local immune system in the oral cavity. Epidemiological
      studies emphasize the importance of salivary IgA in the protection from
      infections and caries. This study investigated how excavation of caries lesions
      affects total salivary IgA concentration. Fifteen patients were assigned to two
      sessions: the first session consisted of the excavation of a caries lesion.
      Thirty min before, during, directly after, and 30 min after the excavation,
      patients were asked for saliva samples. One wk later, a control session was
      performed on the same patients at the same time of the day, consisting of a
      dental inspection without any drilling. Marked, transient decreases were observed
      in concentration and secretion rate of total salivary immunoglobulin A during and
      immediately after caries excavation. Thirty min after caries excavation,
      immunoglobulin A concentrations returned to baseline. No differences were found
      between sessions with regard to saliva flow and cortisol concentration. It was
      concluded that transient decreases of total salivary immunoglobulin A
      concentrations are induced by excavation of caries lesions.

PMID- 8653492
TI  - Alcian blue. Now you see it, now you don't.
AB  - A brief outline of the history and chemistry of the copper pthalocyanin-based
      Alcian blue dyes highlights the adverse effects of commercial secrecy and
      entrepreneurial dishonesty on the use of these valuable histochemical and
      biochemical reagents in the biological sciences. The acquisition of detailed and
      validated chemical structures required the avoidable expenditure of much time
      that otherwise would have been spent on new research. The combination of this
      chemical knowledge with experiments on isolated polyanions, using critical
      electrolyte concentration (CEC) techniques, established a molecular recognition
      paradigm of Alcian blue usage in histochemistry. New reagents (Cuprolinic and
      Cupromeronic blues) were synthesised to investigate and support the hypothesis
      that Alcian blue did not intercalate with DNA. They were made with the important
      additional aim of using them in electron microscopy of polynucleotides (in the
      case of Cuprolinic blue) and non-nucleotide polyanions, such as sulphated
      proteoglycans in extracellular matrices (in the case of Cupromeronic blue). The
      cationic groups of Alcian blue are easily removed in very mild conditions,
      producing insoluble blue pigment in situ (ingrain dying). This reaction underlies
      its unique capability to stain in repeated cycles, thus greatly amplifying
      sensitivity of detection of substrates present in very small amounts in tissues
      and on electrophoretic strips etc.

PMID- 8653493
TI  - Oral mucosal desquamation caused by two toothpaste detergents in an experimental
      model.
AB  - Sodium lauryl sulfate (SLS), the most widely used detergent in toothpastes, has
      been reported to cause adverse effects on oral soft tissues. This double-blind
      cross-over study describes the oral mucosal effects of SLS-containing toothpastes
      and pastes containing a zwitterionic detergent, cocoamidopropyl-betaine (CAPB) in
      an experimental model in 28 healthy females. Seven toothpastes, differing only in
      detergent concentration and/or type, were used: SLS (0.5, 1.0, 1.5%), CAPB (0.64,
      1.27, 1.90%) and a placebo. Each participant applied 1 cm of assigned test
      toothpaste via a cap splint to the teeth and the mucosa of the upper jaw. The
      splints were used twice daily for 2 min during a period of 4 d, after which the
      participants were examined for oral desquamation. No other oral hygiene was
      allowed during the test periods. Ten days brushing with a detergent-free
      toothpaste was performed between each test period. Forty-five desquamative
      reactions were observed in 21 of 27 subjects (one was excluded) during the trial.
      Forty-two reactions were recorded during the SLS periods and the remaining three
      during the CAPB periods. The detergent-free toothpaste did not result in oral
      desquamation. SLS in toothpastes significantly increased the incidence of
      desquamation of the oral mucosa compared with toothpastes containing the
      detergent CAPB. The model used is not directly relevant to normal toothbrushing
      with toothpaste, but indicates that sensitive patients may contract mucosal
      irritation through SLS in toothpastes. Less toxic detergents, e.g. CAPB, are
      desirable in oral hygiene products.

PMID- 8653494
TI  - Effect of phenytoin on interleukin-1 beta production in human gingival
      fibroblasts challenged to tumor necrosis factor alpha in vitro.
AB  - Effects and interaction of tumor necrosis factor alpha (TNF alpha) and the
      antiepileptic drug phenytoin (PHT) on interleukin-1 beta (IL-1 beta) production
      as well as on prostaglandin E2 (PGE2) formation were studied in gingival
      fibroblasts in vitro. TNF alpha, in contrast to PHT, dose-dependently stimulated
      the production of cell-associated IL-1 beta. The stimulatory effect of TNF alpha
      on IL-1 beta production was accompanied by enhanced PGE2 formation. When PHT and
      TNF alpha were added simultaneously, the drug potentiated the stimulatory effect
      of TNF alpha on both IL-1 beta production and PGE2 formation. The major PHT
      metabolite, p-HPPH, did not affect IL-1 beta production, either alone or in
      combination with TNF alpha. The production of IL-1 beta induced by TNF alpha and
      the combination of TNF alpha and PHT was further enhanced in the presence of the
      prostaglandin endoperoxide (PGH) synthase inhibitors, indomethacin and
      flurbiprofen. The PHT-mediated enhancement of TNF alpha-induced IL-1 beta
      production and PGE2 formation in gingival fibroblasts may be an important link in
      the pathogenesis of gingival overgrowth induced by PHT.

PMID- 8653495
TI  - The human vomeronasal organ: prenatal developmental stages and distribution of
      luteinizing hormone-releasing hormone.
AB  - The purpose of this study was to describe in 49 normal human prenatal specimens,
      15-156 mm crown-rump length (CRL), the histomorphological development of the
      bilateral vomeronasal organ localized in the mucosa of the nasal septum. In
      addition, immunohistochemical localization of luteinizing hormone-releasing
      hormone (LHRH) was undertaken. The material was classified into five
      developmental stages (NAS I/V), based on the morphology of the nasal cavity. The
      vomeronasal organ was visible in stages NAS II, III and IV, corresponding to 21
      102 mm CRL. Positive immunohistochemical reaction for LHRH neurons was pronounced
      in the vomeronasal organ in NAS II and III, corresponding approximately to fetal
      ages 8-12 gestational weeks (21-51 mm CRL). The study demonstrates in normal
      human prenatal material that LHRH can be recorded in the bilateral vomeronasal
      organs during approximately 4 weeks of intrauterine life.

PMID- 8653497
TI  - Detection by physico-chemical techniques of an amphiphilic surface component on
      Streptococcus mitis strains involved in non-electrostatic binding to surfaces.
AB  - Indications for the presence of an amphiphilic molecule in Streptococcus mitis
      strains cultured on TY-agar were obtained from infrared absorption spectra,
      especially from the shape of the CH2/CH3 absorption bands around 2900 cm-1, which
      were absent when strains were grown on blood agar. It was the aim of this study
      to determine for S. mitis strains grown on different growth media whether the
      amphiphile is located intracellularly or on the cell surface by measuring zeta
      potentials, elemental surface compositions and adhesion to hexadecane of
      differently grown cells. There was no significant effect of the presence of the
      amphiphile on the zeta potentials of the S. mitis strains, but adhesion to
      hexadecane was increased by the presence of the amphiphile when the pH of the
      suspension was such that electrostatic interactions between the organisms and the
      hexadecane could be neglected. Furthermore, lower N/C surface concentration
      ratios were found for organisms possessing the amphiphilic molecule.
      Consequently, it was concluded that the amphiphilic molecule is located on the
      cell surface, and that it is involved in the non-electrostatic binding of S.
      mitis cells to surfaces.

PMID- 8653496
TI  - Characterization of new periodontal and endodontic isolates of spirochetes.
AB  - Gas chromatographic analysis of cellular fatty acids (CFA), biochemical
      reactions, electrophoresis of soluble cellular proteins, as well as
      immunodiffusion were used to discriminate between 16 fresh spirochete isolates
      from periodontal and endodontic infections. CFA patterns were compared by the
      Hewlett Packard MIDI library to all available reference strains, and results of
      the biochemical tests were compared to VPI's records for treponemal strains. The
      electrophoretograms of soluble proteins of the fresh isolates were compared to
      those of previously well described strains of Treponema denticola, T.
      pectinovorum, T. vincentii, T. socranskii subsp. socranskii, T. socranskii subsp.
      paredis, T. socranskii subsp. buccale, and T. socranskii 04. Immunodiffusion was
      carried out by using adsorbed polyclonal rabbit antibodies to representative
      strains of the species mentioned. These methods separated most clinical strains
      from approved species strains, suggesting that new species had been isolated.

PMID- 8653499
TI  - Four-year evaluation of the effect of 10% polyacrylic acid or water rinsing
      pretreatment on retention of glass polyalkenoate cement.
AB  - To optimize the bonding of glass polyalkenoate (ionomer) cement to dentin,
      different conditioning methods have been suggested. The effect of two easily
      applied conditioning methods, a 10-15 seconds cleaning with a 10% polyacrylic
      acid or rinsing with copious amounts of water, was compared in class V
      abrasion/erosion lesions. The cervical lesions were restored, without any form of
      mechanical cavity preparation, with an anhydrous glass ionomer cement. During a 4
      yr period, 137 restorations were evaluated every 6 months. Cumulative loss rates
      after 4 yr were 15.6% for the polyacrylic acid group and 21.9% for the water
      rinsing group. The difference was not significant. No secondary caries was
      registered.

PMID- 8653498
TI  - Mercury vapor release from dental amalgam in patients with symptoms allegedly
      caused by amalgam fillings.
AB  - The aim of this study was to determine whether a group of patients with symptoms,
      self-related to their amalgam restorations, experienced an exposure to mercury
      vapor from their amalgam restorations that reached the range at which subtle
      symptoms have been reported in the literature. Furthermore, the aim was to
      determine whether the mercury exposure for these patients was significantly
      higher than for controls with no reported health complaints. The symptom group
      consisted of 10 consecutively selected patients from a larger group, referred by
      their physicians for investigation into any correlation between subjective
      symptoms and amalgam restorations. The control group consisted of 8 persons with
      no reported health complaints. The intra-oral release of mercury vapor was
      measured between 7:45 a.m. and 9:00 p.m. at intervals of 30-45 min, following a
      standardized schedule. The mercury levels in plasma, erythrocytes, and urine were
      also determined. The calculated daily uptake of inhaled mercury vapor, released
      from the amalgam restorations, was less than 5% of the daily uptake calculated at
      the lower concentration range given by the WHO (1991), at which subtle symptoms
      have been found in particularly sensitive individuals. The symptom group had
      neither a higher estimated daily uptake of inhaled mercury vapor, nor a higher
      mercury concentration in blood and urine than in the control group. The study
      provides no scientific support for the belief that the symptoms of the patients
      examined originated from an enhanced mercury release from their amalgam
      restorations.

PMID- 8653500
TI  - Proceedings of the Aegean Cornea and Refractive Surgery Congress II. Rhodes,
      Greece, September 29-October 8, 1995.

PMID- 8653501
TI  - Results of photorefractive keratectomy for myopia with the technolas keracor 116
      excimer laser.
AB  - BACKGROUND: The refractive results of first consecutive 157 myopic eyes
      undergoing photorefractive keratectomy with the Technolas Keracor 116 excimer
      laser are presented with a 6-month follow up. METHODS: Preoperative refractive
      errors (spherical equivalent) ranged between -1.75 diopters (D) and -20.00 D
      (mean: -7.19 +/- 3.73). A single ablation zone ranging from 4.5 mm to 6 mm was
      used. In all eyes except for those with myopia over -15 D, emmetropia was a goal.
      Postoperatively patients used fluoromethalone drops for 1 month. RESULTS: Treated
      eyes were divided into four groups based on preoperative myopia. Group 1
      contained 15 eyes with myopia less than -3 D (93% were within +/- 1 D
      postoperatively). In Group 2 there were 53 eyes with preoperative myopia between 
      3.25 D and -6.00 D (64.1% were within +/- 1 D postoperatively). Group 3 consisted
      of 53 eyes with preoperative myopia between -6.25 D and -10.00 D (41.5% were
      within +/- D postoperatively). Group 4 contained 36 eyes with myopia over -10.00
      D (13.8% were within +/- 1 D of attempted correction and 11.1% were within +/- 1
      D postoperatively). CONCLUSIONS: Our study suggests that excimer laser
      photorefractive keratectomy using a 4.5 to 6.0 mm ablation zone effectively
      reduces myopia; however, predictability decreases as the attempted correction
      increases.

PMID- 8653502
TI  - Early results of photorefractive keratectomy for myopic astigmatism.
AB  - BACKGROUND: The Technolas Keracor 116 excimer laser has been used to correct
      myopic astigmatism. The purpose of this study was to evaluate the early results
      in our patients. METHODS: The Technolas Keracor 116 excimer utilizes a scanning
      beam to correct myopic astigmatism. Following the correction of the astigmatic
      error, spherical myopic component is then treated. Twenty-eight eyes with myopic
      astigmatism were treated utilizing a 4 x 12 mm ablation zone for astigmatism and
      4.5 mm to 6.6 mm transition zone for the spherical component at the same session.
      The mean preoperative spherical equivalent refraction was -4.87 +/- 3.48 diopters
      (D) (range: -1.00 to -14.25) and the mean preoperative astigmatic error was -2.53
      +/- 1.49 D (range: -1.00 to -6.00 D) All eyes received dexamethasone eye drops
      for 3 months. RESULTS: At 6 months, the mean spherical equivalent refraction was
      +0.23 D (range +1.38 to -1.50 D), the mean postoperative refractive cylinder was 
      0.16 +/- 0.99 D (range: +1.50 to -2.00 D) and 78% of the eyes had a refraction
      within +/- 1 D. Fifty-five percent achieved 20/40 or better uncorrected visual
      acuity. In three cases there was one line loss and in two cases there was two
      line loss in best corrected spectacle visual acuity. CONCLUSIONS: Early results
      from this study suggest that excimer laser photorefractive keratectomy
      effectively reduces myopic astigmatism. The treatment of astigmatism offers a new
      challenge for excimer laser corneal surgery. Lasers utilize different methods to
      control the beam that reshapes the cornea.

PMID- 8653503
TI  - Photorefractive keratectomy with a transition zone for myopia from -7 to -14
      diopters.
AB  - PURPOSE: To study transition zone excimer laser photorefractive keratectomy (PRK)
      in moderate and high myopia defined as a spherical equivalent of -7.00 diopters
      (D) or more. The follow-up period was 18 months. METHODS: Forty eyes of 40
      patients with myopia of 7.00 to -13.50 D (mean +/- SD, -921 +/- 1.98) underwent
      transition zone (5.0 to 7.0 mm transition zone) PRK using the Aesculap Meditec
      Mel 60 excimer laser. The mean attempted correction was 8.3 +/- 1.64 D (range: 
      6.50 to -12.00 D). RESULTS: At 18 months, 83% achieved an unaided visual acuity
      of 20/50 or better and HOW 12% 20/25 or better. Eighty-eight percent were within
      +/-2 D of emmetropia. the mean spherical equivalent was -1.1 D (+3.00 to -9.00
      D). CONCLUSIONS: Transition zone PRK is useful in moderate to high myopia.
      Regression, as well as overcorrection are issues for further investigation.

PMID- 8653504
TI  - Stability and complications of photorefractive keratectomy over 2.5 years.

PMID- 8653505
TI  - Disability glare after excimer laser photorefractive keratectomy for myopia.
AB  - BACKGROUND: A change of corneal topography and haze after excimer laser
      photorefractive keratectomy (PRK) can reduce contrast sensitivity and cause
      glare. Both glare and contrast sensitivity can be examined in a reproducible
      manner with one instrument. METHODS: We have used the Berkeley Glare Test to
      examine 46 eyes of 32 patients before and 1, 3, 6, 9, and 12 months after excimer
      laser PRK for moderate to high myopia. Multiple regression analysis was used for
      statistical analysis. RESULTS: High contrast visual acuity showed a statistically
      significant deterioration during the first 6 months after PRK (p = 0.01); 1 year
      after treatment visual acuity returned to almost pretreatment levels (p = 0.2).
      High- and low contrast visual acuity under glare deteriorated significantly 3
      months after PRK and had only risen slightly 1 year later (p < or = 0.0065). A
      similar development could be observed for the low contrast visual acuity without
      glare. CONCLUSION: Although high contrast visual acuity recovers by 1 year after
      PRK, low contrast visual acuity and glare deteriorate significantly and do not
      recover, even after 1 year.

PMID- 8653506
TI  - Centration of excimer laser photorefractive keratectomy and changes in
      astigmatism.
AB  - One of the most important factors that influence the success of PRK might be
      corneal centration during treatment. We evaluated our centration rate in 49 eyes
      by using computer-assisted corneal topography. Only single zone treated eyes were
      chosen for the analysis and 91.5% of the eyes were centered within a 1 mm
      treatment zone while 51% were within 0.5 mm. At the end of the follow-up time of
      10.4 months, these centration zones were found to have no influence on the
      attempted spherical refractive outcome, whereas increasing decentration induced
      an increase in postoperative astigmatism.

PMID- 8653507
TI  - Double zone PRK for high myopia.
AB  - INTRODUCTION: Although excimer laser PRK is our operation of choice for treating
      myopia, the correction of myopia exceeding -8.00 dpt is still a challenge as this
      procedure requires a deeper keratectomy. Therefore a double zone treatment may be
      beneficial to reduce ablation depth. METHODS: Twenty-one eyes with myopia between
      -8.00 dpt and -14.00 dpt were included in this study. Twelve eyes were treated
      60% of myopia by 5 mm zone and the remaining 40% in a 4 mm zone in the same
      session (Group 1). RESULTS: Nine eyes achieved 60% of the desired correction
      treated with a 4 mm zone whereas 40% correction was achieved in a 5 mm zone
      (Group 2). No significant difference in postoperative healing, pain, hyperopic
      shift, myopic regression and haze was observed at the end of the mean follow-up
      time (10.4 months) but photophobic complaints were less in Group 2. Best
      corrected visual acuity did not decrease significantly. CONCLUSIONS: Double zone
      treatment seems to be an interesting method for treating moderate to high myopia.

PMID- 8653508
TI  - Comparison of photorefractive keratectomy for myopia using 5 mm and 6 mm diameter
      ablation zones.
AB  - BACKGROUND: We compared the 5 mm and 6 mm ablation zones of the Summit Omnimed in
      the treatment of myopia in 2 eyes of the same patient. METHOD: One hundred and
      twenty-four consecutive patients with myopia less than 6 diopters (D) has one eye
      treated with a 5 mm ablation zone and the other eye with a 6 mm ablation zone.
      Minimum follow up was 6 months. RESULTS: Follow-up was achieved in 101 patients
      of the total 124. In the 5 mm group 79% achieved 20/30 uncorrected visual acuity
      while 68% of the 6 mm group achieved 20/30 acuity. Ninety-seven percent of all
      eyes in both groups achieved 20/40. Some of the disparity between the 20/30
      acuity in the two groups is that initial corrections with the 6 mm zones were
      conservative. Corneal haze was less in the 6 mm group; subjectively they had
      better night vision. CONCLUSIONS: Both lasers with the different ablation zones
      gave reasonably predictable correction of myopia of up to -6 D. Overcorrection
      and corneal haze were less in the 6 mm group and night vision was subjectively
      better.

PMID- 8653509
TI  - Keratometric readings after photorefractive keratectomy are unreliable for
      calculating IOL power.

PMID- 8653510
TI  - A computer model for predicting image quality after photorefractive keratectomy.
AB  - BACKGROUND: Accurately predicting visual performance remains a concern in
      refractive surgery. The effects of the eye's optics on retinal image quality were
      investigated using computer ray tracing to model the human eye after
      photorefractive keratectomy (PRK). METHODS: Ray-tracing analysis was used with an
      anatomically realistic model of the human eye including aspheric surfaces and
      crystalline lens gradient index distributions. The contribution of corneal
      curvature to refractive error was investigated using data of axial length,
      corneal power, anterior chamber depth, and lens power from 318 eyes from the
      literature. The computer interface was specifically designed for use with PRK and
      provides graphical plots of the remodeled eye, ray paths and retinal image
      formation. RESULTS: Modeling the optical contribution of corneal curvature
      resulted in an improvement in predicted refractive state of the eye as a function
      of axial length expressed as the R2 value of the regression analysis from 0.88 to
      0.96. Subsequently, analyses were conducted for single and multizone treatment
      areas of differing diameter and with varying pupil size. Retinal image quality
      following PRK for the human cornea was found to be affected by not only the
      corneal parameters of anterior curvature and thickness, but also by axial length,
      pupil size, and anterior chamber depth. CONCLUSIONS: The inclusion of multiple
      interdependent optical parameters showed differences from conventional methods in
      predicting refractive outcome following PRK and revealed factors affecting image
      quality may account for some imperfections in visual performance based on simpler
      optical modeling.

PMID- 8653511
TI  - Intrastromal photorefractive keratectomy for myopia by Nd:YLF picosecond laser.
AB  - BACKGROUND: An intrastromal photorefractive keratectomy (ISPRK) by Nd:YLF
      Picoseconds Laser has been performed on 17 eyes with corrected visual acuity of
      20/200 or worse. The purpose of this study was to study the safety and
      effectiveness of ISPRK using different laser parameters. METHODS: The Neodymiun
      Yttrium Lithium Fluoride laser system (Nd:YLF) was used to perform the myopic
      treatment. We studied the effect of pattern depth, the numbers of patterns, the
      thickness of a single spiral pattern, the distance between two patterns along Z
      axis, the pattern curvature perpendicular to the Z axis, the energy, the spatial
      density, and the repetition frequency of the laser pulse. RESULTS: The laser
      treatment was completed in 12 patients. In the first group at 180 days
      postoperatively we did not find corneal opacities, anterior chamber or lens
      opacities. Pupil diameter and reactivity, endothelial cell density, and IOP were
      normal. Pachymetry showed an average reduction of the central corneal thickness
      of 99 microns (+/- 14.7 SD). Topography showed an average reduction of the
      corneal dioptric power of 2 D (+/- 0.4 SD). In the second group at 120 days
      postoperatively findings were similar. Pachymetry showed an average reduction of
      the central corneal thickness of 118.5 mu (+/- 12.5 SD). Topography showed an
      average reduction of the corneal dioptric power of 2.4D (+/- 0.9 SD).
      CONCLUSIONS: It is possible to change the corneal power by reducing the corneal
      thickness with the Nd:YLF laser but the predictability of the result is unknown.
      Because Bowman's layer is intact, there is no scarring or haze.

PMID- 8653512
TI  - Excimer laser phototherapeutic keratectomy for corneal opacities and recurrent
      erosion.
AB  - BACKGROUND: Phototherapeutic keratectomy (PTK) has been used to treat superficial
      corneal opacities, as well as the recurrent corneal erosion syndrome. METHODS: We
      performed PTK 6 eyes of 6 patients to treat corneal opacities, and in one eye of
      another patient to treat recurrent corneal erosion syndrome. Opacities were
      caused by a healed corneal ulcer, herpetic keratitis, band keratopathy, corneal
      burn, corneal dystrophy, and an excised pterygium. The follow-up period ranged
      from 2 to 6 months. RESULTS: Corneal clarity improved to variable degrees in all
      eyes with corneal opacities. There was no recurrence in the Recurrent Corneal
      Erosion Syndrome. A hyperopic shift was observed in 2 eyes. CONCLUSIONS: PTK
      appears to be an effective alternative to penetrating keratoplasty in patients
      with selected anterior stromal opacities can treat the Recurrent Corneal Erosion
      Syndrome.

PMID- 8653513
TI  - Successful phototherapeutic keratectomy for recurrent erosions in bullous
      keratopathy.
AB  - BACKGROUND: The treatment of patients with recurrent erosions due to bullous
      keratopathy is disappointing in cases when penetrating keratoplasty cannot be
      performed. A trial has been made to prevent recurrent erosions through the
      smoothing of the cornea with the excimer laser. METHODS: Excimer laser
      phototherapeutic keratectomy (PTK) was performed after removal of the epithelium.
      RESULTS: Sixteen patients (17 eyes) with recurrent erosions due to bullous
      keratopathy were treated. The mean follow-up period was 17.2 months (range: 3 to
      32 months). All patients responded well to the treatment; their pain subsided
      after a few weeks. In four cases, a second treatment was necessary because areas
      with loose epithelium remained, which resulted in recurrent erosions. No
      complications have been seen so far. CONCLUSION: Excimer laser PTK is an
      effective, easy to perform treatment of bullous keratopathy.

PMID- 8653514
TI  - Phototherapeutic keratectomy in macular corneal dystrophy with recurrent
      erosions.

PMID- 8653515
TI  - Incision depth vs. incision number in the rupture strength of pig eyes following
      radial keratotomy.
AB  - The effects of incision depth and the number of incisions on globe rupture were
      studied in porcine enucleated eye model. In one group, radial keratotomy was
      performed using a diamond blade set at 100%, 75%, and 50% of corneal thickness.
      In another set of eyes, 16, 8, and 4 incisions were made with the diamond knife
      set at 100% of corneal thickness. The eyes were then subjected to blunt trauma.
      The mean energy of globe rupture for incisions at 100%, 75%, and 50% of corneal
      thickness was 3.0, 4.2, and 4.6 joules respectively. In contrast, mean energy of
      globe rupture for 16, 8, and 4 incisions at 100% corneal thickness was 2.8, 2.9,
      and 3.0 joules, respectively. This study suggests that incision depth in radial
      keratotomy reduces the strength of the cornea more than incision number.

PMID- 8653516
TI  - Arcuate transverse keratotomy with a mechanical arcutome based on
      videokeratography.
AB  - Corneal topographic hardware was used to develop software analysis for
      configuration and localization of relaxing astigmatic arcuate incisions. The
      software is based on the assessment of the results of corneal topographic
      measurements, performed by the EyeSys Corneal Analysis System. Data assessment
      includes: A) plotting the dioptric power curves along the circular zones that may
      be considered appropriate for the placement of arcuate cuts; B) determination of
      the astigmatic axes position in each selected arc; and C) finding the position of
      points with the mean dioptric power value between the neighboring astigmatic axes
      which determine the proposed placement of the arcuate incisions. The new
      instrument developed for arcuate astigmatic keratotomy includes the algorithm for
      incision(s) disposition, the software, and the arcutome.

PMID- 8653517
TI  - Effect of incision direction on refractive outcome after radial keratotomy.
AB  - PURPOSE: Radial keratotomy incisions can be made centripetally or centrifugally.
      The benefits and effects of both techniques have been disputed since American
      surgeons began performing RK in the late 1970s. We examined the RK databases of a
      single surgeon to determine if incision direction was associated with refractive
      outcome. METHODS: Stepwise regression was employed to select the important
      predictors of refraction change in the population. In addition to incision
      direction, variables eligible for entry into the model were optic clear zone
      diameter, incision number, patient age, corneal curvature and planned incision
      depth. RESULTS: All variables except for planned incision depth and corneal power
      entered the model. CONCLUSIONS: The results were consistent with previous
      investigations that found incision number, optic clear zone diameter and patient
      age important predictors of outcome. We also found incision direction to be a
      significant predictive variable with centripetal incisions decreasing myopia 0.6
      diopters more than centrifugal incisions.

PMID- 8653518
TI  - A new scleral suction trephine for retrieval of corneoscleral donor tissue.
AB  - BACKGROUND: Removal of donor corneo-scleral shell from a cadaver, leaving the
      remainder of the eye in place, has become a popular technique. Manual removal can
      result in excessive trauma to the corneal endothelium or an uneven scleral rim.
      METHODS: We describe a new technique for corneal retrieval using a sceral suction
      trephine. RESULTS: The scleral suction trephine was cut evenly in our eyebank
      study. There was no additional trauma to the endothelium and the scleral rim was
      regular. CONCLUSION: Suction trephination of the sclera in retrieval of corneal
      donor tissue appears to be safe and effective.

PMID- 8653519
TI  - Penetrating keratoplasty and transsclerally suture-fixated intraocular lenses.
AB  - BACKGROUND: One of the options the surgeon has, in the absence of lens capsule in
      an eye to be rendered pseudophakic, is a transsclerally sutured posterior chamber
      intraocular lens. This procedure can be combined with penetrating keratoplasty,
      in aphakic or pseudophakic covered edema. METHODS: We studied retrospectively the
      results of the first 10 cases of bullous keratopathy in which we performed
      penetrating keratoplasty combined with transsclerally suture fixated intraocular
      lenses. RESULTS: Nine grafts remained transparent and 1 became opaque due to
      graft rejection with a mean follow up of 26.4 months. Postoperative visual acuity
      was improved in 7 eyes, remained the same in 2 and became worse in 1 (graft
      rejection) The poor postoperative visual acuity in 2 eyes was attributed to
      cystoid macular edema. All sutured intraocular lenses remained in situ; there was
      no apparent degradation of the Prolene suture. Two eyes developed postoperative
      medically controlled glaucoma. CONCLUSIONS: Intraocular lens scleral fixation
      with sutures, combined with penetrating keratoplasty, seems to be a good
      procedure for visual rehabilitation for aphakic or pseudophakic bullous
      keratopathy.

PMID- 8653520
TI  - Corneal topography, arcuate keratotomy, and compression sutures for astigmatism
      after penetrating keratoplasty.
AB  - BACKGROUND: Twenty (20) patients with post-penetrating keratoplasty (PKP) (21
      eyes) and excessive corneal astigmatism were studied using corneal topography to
      determine placement of arcuate incisions and compression sutures for astigmatism
      reduction. METHODS: Keratoplasty wounds and compression sutures were placed
      asymmetrically based on corneal topography only. Incisions were at the donor-host
      junction at a depth of 500 microns. RESULTS: A 56% reduction in corneal
      astigmatism was accomplished with an average cylinder reduction of 5.3 D.
      Keratometry readings were reduced in 18 of 20 (90%) of eyes and refractive
      cylinder was reduced in 15 of 20 (75%) of eyes. Corrected visual acuity improved
      in 15 of 20 (75%) declined in 15%, and did not change in 10%. CONCLUSION: Visual
      acuity can be improved by manipulating the astigmatism after penetrating
      keratoplasty using corneal topography maps to determine placement of arcuate
      incisions and compression sutures.

PMID- 8653521
TI  - Corneal topography for intraocular lens power calculations.
AB  - BACKGROUND: In patients undergoing cataract extraction with PC IOL insertion, pre
      op and post-op corneal power measurement is necessary to calculate induced
      astigmatism. In cases with irregular corneal astigmatism, measurements with
      traditional keratometry is inaccurate. We report the use of video keratography in
      three cases that required keratometry readings in order to calculate IOL power.
      These cases were characterized by irregular or incomplete keratometer mires, so
      quantitative descriptors derived from computer-assisted corneal topography (TMS
      1) were used instead. CONCLUSION: The standard keratometer is useless in cases in
      which the mires appear irregular or incomplete. In such cases, computer-assisted
      corneal topography can be used successfully. Recently, a new corneal topography
      index has been developed, the average corneal power, which is a measure of the
      average corneal power within the entrance pupil. We are currently evaluating the
      use of average corneal power to assist in the calculation of IOL powers.

PMID- 8653522
TI  - Night vision testing in unoperated eyes.
AB  - BACKGROUND: We previously described a simple test which evaluates image
      degradation in post-excimer laser (PRK) patients under scotopic conditions. After
      refractive surgery, corneal haze, ablation zone decentration, ablation
      zone/pupillary diameter disparity, and under-correction each result in a
      characteristic pattern on the Night Vision Recording Chart. METHODS: Using the
      same method, further studies evaluated night vision image degradation in 118 un
      operated emmetropic, myopic, hyperopic, and astigmatic eyes and in 26 contact
      lens wearers. RESULTS: Scotopic image degradation increases with myopic
      refractive error, image displacement increases with astigmatism, and contact lens
      wearers have more image degradation that with spectacle correction. CONCLUSION:
      Our Night Vision Recording Chart offers a simple, reproducible method to
      characterize image degradation under scotopic conditions.

PMID- 8653523
TI  - Histological evaluation of phthalocyanine mediated photodynamic occlusion of
      corneal neovascularization enhanced by hyperbaric oxygenation.
AB  - PURPOSE: We evaluated the effective irradiation parameters for photodynamic
      thrombosis of experimental corneal neovascularization enhanced by simultaneous
      hyperbaric oxygenation. METHODS: Neovascularization was provoked in both eyes of
      each of 35 albino rabbit corneas using the intracorneal suture technique. The
      lasered animals were divided in 3 groups. Group 1 (10 rabbits) was treated under
      hyperbaric conditions (28 atm for 25 min.); group 2 (5 rabbits) was treated
      breathing pure oxygen delivered by a face mask; group 3 (10 rabbits) was treated
      breathing room air. The fourth group (10 rabbits) was used for control. Animals
      were anaesthetized, and irradiation of new corneal vessels was carried out 30
      minutes after the injection of 5 mg/kg chloroaluminum sulfonated phthalocyanine.
      A 670 nm diode laser with a power 4 mW and a spot diameter 350 mm was used.
      Exposure times necessary for vascular occlusion were registered. Histological
      examination was carried out at the end of the follow-up time. RESULTS: Exposure
      times were significantly lower in groups 1 and 2 as compared to group 3 (1.75 +/-
      0.15 min., 3.1 +/- 0.4 min., and 4.75 +/- 0.15 min. respectively). Total light
      dose averaged 490 J/cm,2 870 J/cm,2 and 1330 J/cm,2 respectively. Histological
      examination revealed thrombus formation in the targeted vessels of all three
      investigated groups. CONCLUSION: Combination of PDT with hyperbaric oxygenation
      results in an acceleration of the photodynamic process and provides for a
      possibility of significant reduction of photodynamic dose.

PMID- 8653524
TI  - Laser in situ keratomileusis (LASIK) for myopia from -7 to -18 diopters.
AB  - BACKGROUND: Laser in situ keratomileusis (LASIK) combines a lamellar corneal flap
      with an excimer laser ablation in the stromal bed to correct a wide range of
      myopia. We reviewed 43 eyes treated with LASIK to correct -7.00 to -18.50
      diopters (D). METHOD: The data from 43 consecutive eyes of 30 patients aged 24 to
      46 years were analyzed. Surgery was performed under topical anesthesia using the
      Chiron Automated Corneal Shaper and Keracor 116 Excimer laser with the multizone
      mode and our modified nomogram. Manifest and cycloplegic refraction, uncorrected
      visual acuity, spectacle corrected visual acuity, videokeratography, endothelial
      cell count, slit-lamp microscopy, fundus examination, and applanation tonometry
      were recorded preoperatively and at 1 week and 1, 3, and 6 months,
      postoperatively. RESULTS: We divided the eyes into two groups. The lower myopia
      group had a mean preoperative spherical equivalent refraction of -9.30 +/- 1.31 D
      (range: -7.00 D to -12.00 D) and mean postoperative refraction of -0.80 +/- 0.79
      (range: -0.25 D to -3.50 D). The mean spectacle corrected visual acuity
      preoperatively was 0.74 +/- 0.20 and postoperatively was 0.74 +/- 0.18. The
      higher myopia group had a mean preoperative spherical equivalent refraction of 
      14.86 +/- 1.87 D (range: -12.25 D to -18.50 D) and a mean postoperative
      refraction of -1.80 +/- 1.29 D (range -1.00 D to -5.25 D). The mean spectacle
      corrected visual acuity preoperatively was 0.50 +/- 0.19 and postoperatively was
      0.51 +/- 0.18. No overcorrections occurred in either group. One eye of the higher
      group lost one line of spectacle corrected visual acuity. No eye had visually
      significant corneal haze. The mean change in spherical equivalent refraction
      between preoperatively and 6 months postoperatively was 8.50 D for the lower
      myopia group and 13.06 D for the higher myopia group, in the myopic direction.
      Visual rehabilitation was rapid after surgery. CONCLUSIONS: In this study, LASIK
      resulted in insignificant corneal scarring, stable refractive correction over six
      months, no irregular astigmatism, and excellent visual acuity. Predictability was
      more accurate up to -12.00 D of intended correction.

PMID- 8653525
TI  - Comparison of three videokeratoscopes in measurement of toric test surfaces.
AB  - PURPOSE: We compared the accuracy of the Computed Anatomy TMS-1 (1.41), the
      EyeSys Laboratories Corneal Analysis System (2.1), and the Visioptic EH-270 (3.0)
      videokeratoscopes in measuring toric surfaces. These non-rotationally symmetric
      aspheric surfaces served as models of corneal astigmatism. METHODS: Precision
      diamond-turned toric surfaces modeling 0.00 diopter (D) to 7.00 D of astigmatism
      were fabricated. A three-dimensional contact profiler was developed to calibrate
      the aspheric surfaces. Videokeratoscopic data taken at "best focus" were compared
      to the theoretical shape to quantify device measurement errors. RESULTS: The
      Computed Anatomy system measurement accuracy shows no statistically significant
      correlation between measurement error and surface toricity (r2 < 0.13).
      Measurement error increased linearly with surface astigmatism for the EyeSys
      Laboratories system (0.12 D rms error per D of astigmatism, r2 > 0.96, p < 0.001
      and the Visioptic system (0.03 D error per D of astigmatism, r2 = 0.88, p <
      0.001). CONCLUSIONS: This study found systematic performance differences among
      the three machines. Under ideal alignment conditions, the Computed Anatomy TMS-1
      is more accurate at detecting astigmatism. The EyeSys Laboratories Corneal
      Analysis System apparently underestimates the amount of surface astigmatism
      because of excessive data smoothing. The Visioptic EH-270 errors are primarily in
      the central zones and may be due to ring localization errors.

PMID- 8653526
TI  - Tracker-assisted photorefractive keratectomy for myopia of -1 to -6 diopters.
AB  - BACKGROUND: The Autonomous Technologies T-PRK (Tracker-assisted Photorefractive
      Keratectomy) excimer laser system uses a small beam scanner that allows
      flexibility in the ablation pattern that is applied to the cornea and
      incorporates a sophisticated LADARVision eye tracker that is capable of following
      saccadic movements. This paper describes the first clinical results on sighted
      eyes for the correction of low myopia. METHODS: Forty-two normal sighted eyes of
      42 patients were treated for spherical myopia between -1.00 diopters (D) and 
      6.00 D with 6 mm ablations. Visual acuity, refractive error, contrast sensitivity
      (with and without glare), corneal haze, endothelial cell density, and patient
      satisfaction were measured. RESULTS: Mean manifest refraction was -0.39 D +/-
      0.68 D at 1 month with regression to -0.94 D at 3 months and -1.05 D at 6 months.
      At 6 months, 5 (20%) eyes were +/- 0.50 D and 14 (56%) eyes were +/- 1.00 D.
      Consistent with this undercorrection and regression, uncorrected visual acuity
      (UCVA) of 20/20 and 20/40 or better was achieved by 10 (40%) and 34 (85%) eyes at
      3 months and 16 (40%) and 17 (68%) eyes at 6 months. None of the eyes lost 2 or
      more lines of spectacle corrected visual acuity. Corneal haze was graded as 1/2
      trace or less in 89% to 100% of eyes at all intervals. There was no loss of
      endothelial cells (mean +/- SD cell density centrally: preop 3115 +/- 322 and 6
      months 3220 +/- 333) and contrast sensitivity recovered to baseline levels at 3
      months. CONCLUSIONS: The Autonomous Technologies T-PRK excimer laser system is
      safe and effective for the reduction or correction of myopia from -1.00 D or 
      6.00 D. The refractive results may be improved by adjusting the calibration to
      reduce the undercorrection and by instituting use of topical corticosteroids on
      an individual basis for those who regress.

PMID- 8653527
TI  - Mathematical simulation of retinal image contrast after photorefractive
      keratectomy with a diaphragm mask.
AB  - BACKGROUND: Photorefractive keratectomy (PRK) using a dilating diaphragm mask
      engraves a delicate three-dimensional staircase pattern into a formerly smooth
      corneal surface. The created steps are later smoothed by tear film and wound
      healing processes. The present study investigates, in a mathematical simulation,
      the effects that such staircase patterns and their smoothing may have on retinal
      image contrast. METHODS: All simulations are based on the Gullstrand eye model
      and calculate retinal image contrast from point spread function (PSF) analysis of
      Gullstrand eyes treated by simulated PRK under various conditions. RESULTS: The
      simulations indicate that PRK can reduce retinal contrast markedly. The most
      critical factor for such a reduction is the step height of the ablation pattern.
      With step heights below 0.4 microns, loss of contrast due to the created
      staircase pattern is always moderate and should be restored during early wound
      healing. Complete wound healing may smooth out larger step heights.
      Micromovements during PRK also can lead to partial loss of retinal image
      contrast. CONCLUSIONS: Simulation of retinal contrast after PRK shows that step
      heights below 0.4 microns seem to be acceptable. A minimization of the
      micromovements during PRK can offset some of the reduction of retinal contrast.

PMID- 8653528
TI  - Long-term weight cycling in female Wistar rats: effects on metabolism.
AB  - Weight cycling (WC) induced by ad-lib and restricted high fat (HF) feeding has
      been shown to reduce final body weight but not body fat percent in female Wistar
      rats. We examined the metabolic consequences of this type of WC. Five groups of
      female Wistar rats were fed a HF diet and the sixth group was fed a low fat diet
      to serve as a control group. Of the five HF groups, four groups were weight
      cycled by ad-lib and restricted feeding of the HF diet. One of these groups
      weight cycled three times (HFCYC group) while the remaining three groups weight
      cycled once only, corresponding to the first, second and the third cycle of the
      HFCYC group. HF feeding induced hyperinsulinemia, hypertriglyceridemia, insulin
      resistance and elevated adipose tissue lipoprotein lipase (AT-LPL) activity
      levels as compared to rats fed the low fat (LF) control diet. WC further
      increased blood insulin concentrations and insulin resistance in rats with three
      cycles of WC. However, blood pressure was not affected by HF feeding or WC. The
      magnitude of increase of AT-LPL was reduced in weight cycled, HF fed obese rats
      after 15 weeks refeeding. We concluded that even though WC did not enhance weight
      gain nor impair weight loss, it did facilitate the development of insulin
      resistance and may predispose animals to diabetes.

PMID- 8653529
TI  - Cross-validation of fat-free mass estimated from body density against
      bioelectrical resistance: effects of obesity and gender.
AB  - The major purpose of this study was to examine whether estimates of body
      composition from bioelectrical resistance were systematically biased by obesity
      and/or gender (using hydrodensitometry as a comparison method). We compared fat
      free mass (FFM) by bioelectrical resistance (BR) using 5 equations (Lukaski,
      Kushner, Rising, Khaled, and Segal) to FFM by hydrodensitometry (HD) in 20 lean
      men, 30 lean women, 33 obese men and 22 obese women. None of the BR equations was
      successfully cross-validated against FFM by HD in all 4 sub-groups. The Lukaski
      equation significantly underestimated FFM in all 4 groups by 2.7 to 4.7 kg; the
      Kushner equation significantly underestimated FFM by 2.0 to 2.9 kg except in
      obese women; the Rising equation significantly overestimated FFM in obese women
      (5.3 kg) and men (2.9 kg); the Khaled equation successfully predicted FFM in all
      groups except obese men; and the Segal equation successfully predicted FFM in all
      groups except lean men. In some groups, a portion of the discrepancy could be
      explained by bias originating from body fat. Analysis of our data by forward
      regression analysis demonstrated that height2/resistance, body weight, gender and
      suprailiac skinfold thickness provide the most accurate estimates of FFM (R2 =
      0.92; SEE = 3.58 kg) that are free of bias originating from gender and body fat.
      We conclude that the estimation of fat-free mass by BR is significantly
      influenced by gender and obesity. An alternative equation is proposed for
      estimating fat-free mass based on measurement of height2/resistance, body weight,
      gender and suprailiac skinfold thickness.

PMID- 8653530
TI  - Fiber intake of normal weight, moderately obese and severely obese subjects.
AB  - The lack of dietary fiber may be a contributing factor in obesity. This study
      examined the fiber intake of three weight groups: normal (20.0 < or = BMI < or =
      27.0), moderately obese (27.1 < or = BMI < or = 39.9) and severely obese (BMI >
      or = 40.0). Each group contained 50 subjects. Detailed 3-day food records were
      used to gather the nutritional data. Fiber intake in the normal weight group was
      18.8 +/- 9.3 grams, the moderately obese consumed 13.3 +/- 5.8 grams of fiber and
      the severely obese 13.7 +/- 5.7 grams. Total fiber intake in grams was found to
      be significantly higher in the lean group (p < 0.05) and was positively
      associated with sex and education level with men and more highly educated
      individuals consuming more fiber. Using regression analysis total fiber in grams
      and fiber in g/1000 kcalories was inversely associated with BMI after adjusting
      for sex, age, education level and income (p < 0.01). A high fiber diet may help
      to promote a negative energy balance by causing early satiety secondary to
      gastric distention. Dietitians and physicians need to emphasize the importance of
      a high fiber diet to their obese patients.

PMID- 8653532
TI  - Absence of linkage between human obesity and the mouse agouti homologous region
      (20q11.2) or other markers spanning chromosome 20q.
AB  - Mutant alleles of the agouti gene cause obesity in the mouse and the homologous
      gene in humans has been mapped to chromosome 20q11.2. An allelic variant of the
      agouti gene could account for obesity in humans and we tested this hypothesis by
      genotyping 210 sibling pairs from 45 families segregating an obesity phenotype.
      Using sibling pair linear regression analysis, evidence for linkage between
      obesity and markers flanking the agouti locus and other markers spanning
      chromosome 20q was assessed. We found no correlation between identity-by-descent
      at these markers and obesity differences within pairs. In the mouse, obesity
      caused by mutations of the agouti gene develops later in life, so a subset of
      families with adult-onset obesity were also tested for linkage, with negative
      results. Although it is not possible to exclude alleles of the agouti gene as a
      contributor to obesity in humans, the absence of positive linkage in this study
      suggests that either the agouti gene has small effects or the allele frequency is
      low.

PMID- 8653531
TI  - Sertraline and relapse prevention training following treatment by very-low
      calorie diet: a controlled clinical trial.
AB  - This study examined the combination of sertraline, a selective serotonin reuptake
      inhibitor, and relapse prevention training in the maintenance of weight loss
      following treatment by a very-low-calorie diet. A total of 53 women who had lost
      a mean (+/- SD) of 22.9 +/- 7.1 kg from a pretreatment weight of 103.1 +/- 17.8
      kg were randomly assigned to a 54-week weight maintenance program that was
      combined with either: 1) 200 mg/d of sertraline; or 2) placebo. During the first
      6 weeks, sertraline subjects lost significantly more weight and reported
      significantly greater reductions in hunger and preoccupation with food than did
      subjects on placebo. After this time, however, women in both conditions regained
      weight steadily. The 13 sertraline subjects who completed the 54-week study
      regained 17.7 +/- 10.6 kg of their original 26.3 +/- 7.6 kg loss, equal to a
      regain of 70.9 +/- 41.7%. The 17 placebo completers regained 11.8 +/- 9.0 kg of
      their 23.4 +/- 7.8 kg loss, equal to a 46.5 +/- 34.6% regain. End-of-treatment
      differences between groups in weight change were not statistically significant.
      Nor were there significant differences between the two conditions at any time in
      changes in fat-free mass, resting metabolic rate or dysphoria, all of which
      tended to increase with weight regain. The results are discussed in relation to
      findings from other long-term studies that combined diet and medication.

PMID- 8653533
TI  - Relation of the white blood cell count to obesity and insulin resistance: effect
      of race and gender.
AB  - Recent reports suggest that the white blood cell (WBC) count is related to plasma
      insulin concentrations and insulin resistance in healthy individuals. The present
      study examines whether these relations are independent of obesity and the pattern
      of body fat distribution and tests whether race and gender affect these
      relations. WBC counts, insulin responses to a 75 gram oral glucose tolerance test
      (OGTT) and glucose disposal during a two-step hyperinsulinemic euglycemic clamp
      were measured in 300 men and women (149 Pima Indians, 100 whites, and 51 blacks)
      with a wide range of obesity. WBC counts were lower in blacks than Pima Indians
      or whites and tended to be higher in women than men. The subgroups were
      comparable in age and body weight, but percent body fat and plasma insulin
      concentrations were higher and glucose disposal during the glucose clamp was
      lower in Pima Indians than in blacks or whites. In the group as a whole, the WBC
      count correlated with obesity (body mass index and percent body fat), the waist
      to thigh ratio (an index of the pattern of body fat distribution), and plasma
      insulin concentrations and was negatively related to age and glucose disposal
      during the clamp. In multiple regression analyses, only age, race and obesity
      were significantly associated with the WBC count. When the analyses were
      restricted to Pima men, in whom correlations between the WBC count and the
      metabolic variables appeared the strongest, the WBC count remained significantly
      associated with plasma insulin concentrations, but not glucose disposal, after
      controlling for age and obesity. The results of this study indicate that age,
      race, and obesity are significantly associated with the WBC count in healthy
      individuals. Plasma insulin concentrations, but not insulin resistance per se,
      may also be weakly associated with the WBC count, but this may be population
      specific.

PMID- 8653535
TI  - Weight regain following sustained weight reduction is predicted by relative
      insulin sensitivity.
AB  - Ten moderately obese women (body mass index 34.9 +/- 1.1 kg/m2, mean +/- SEM),
      had previously been through a 3-month weight loss program followed by 3 months of
      weight maintenance at the reduced weight. A euglycemic clamp for determination of
      insulin sensitivity was performed on each subject prior to weight loss, and
      another at the end of the weight maintenance phase. The mean weight loss for the
      group was 11.4 +/- 2.2 kg. The women were then seen for follow-up weights 12
      months and 18 months after the conclusion of the weight maintenance period. All
      of the women except one had regained their weight by the time of the 12-month
      visit. It was found that the amount of weight regained both at 12 months and 18
      months was correlated with the change in insulin sensitivity which occurred from
      the baseline study to after weight loss/maintenance. The data indicate that
      increased insulin sensitivity following sustained weight loss in obese women
      predicts weight regain.

PMID- 8653534
TI  - Lipase inhibition and hormonal status, body composition and gastrointestinal
      processing of a liquid high-fat mixed meal in moderately obese subjects.
AB  - The effect of Orlistat, a lipase inhibitor used in the treatment of obesity was
      studied on gastrointestinal transit time, on body composition and on hormones
      known to be influenced by the degree of hydrolysis of nutritional triglycerides
      or by reduced nutrient intake and absorption. After a placebo run-in period 14
      patients were randomized to a 12-week treatment period on Orlistat 360 mg per day
      (mean body weight 93.1 +/- 9.8 kg) or placebo (mean body weight 90.7 +/- 10.5
      kg). At randomization and after 12 weeks body weight, body composition, thyroid
      hormones, catecholamines, insulin-like growth factor I (IGF-I) and IGF-binding
      protein 3 were measured. During 4 hours after consumption of a liquid fat-rich
      mixed meal containing study medication, 15 g lactulose and 25 g xylose, blood
      levels of glucose, insulin, c-peptide, glucagon, triglycerides, free fatty acids,
      cholecystokinin, pancreatic polypeptide and xylose and expiration air levels of
      hydrogen were measured. Weight loss was 4.2 +/- 3.5 kg in the Orlistat group
      versus 3.0 +/- 1.9 kg in the placebo group. Fat mass decreased to an equal
      degree, whereas lean body mass remained stable. No differences were found for
      thyroid hormones, catecholamines, IGF-I and IGFBP-3 levels. By comparing the
      areas under the curve (AUC) and the peak levels at randomization (acute effects)
      of insulin and c-peptide a tendency was found to be increased in the Orlistat
      group, whereas those of xylose were increased significantly, suggesting faster
      gastric emptying after Orlistat. No differences were found in the other
      parameters. By comparing the changes in responses (longer term effects) no
      significant differences were found. In conclusion, the presence in the gut of
      undigested and unabsorbed fat does not seem to have a relevant influence on
      hormonal status and body composition in a small group of moderately obese
      patients.

PMID- 8653536
TI  - A commentary on weighing the options: criteria for evaluating weight-management
      programs.

PMID- 8653537
TI  - Weighing the options: criteria for evaluating weight-management programs. The
      Committee to Develop Criteria for Evaluating the Outcomes of Approaches to
      Prevent and Treat Obesity.
AB  - The United States is experiencing an epidemic of obesity among both adults and
      children. Approximately 35 percent of women and 31 percent of men age 20 and
      older are considered obese, as are about one-quarter of children and adolescents.
      While government health goals for the year 2000 call for no more than 20 percent
      of adults and 15 percent of adolescents to be obese, the prevalence of this often
      disabling disease is increasing rather than decreasing. Obesity, of course, is
      not increasing because people are consciously trying to gain weight. In fact,
      tens of millions of people in this country are dieting at any one time; they and
      many others are struggling to manage their weight to improve their appearance,
      feel better, and be healthier. Many programs and services exist to help
      individuals achieve weight control. But the limited studies paint a grim picture:
      those who complete weight-loss programs lose approximately 10 percent of their
      body weight, only to regain two-thirds of it back within 1 year and almost all of
      it back within 5 years. These figures point to the fact that obesity is one of
      the most pervasive public health problems in this country, a complex,
      multifactorial disease of appetite regulation and energy metabolism involving
      genetics, physiology, biochemistry, and the neurosciences, as well as
      environmental, psychosocial, and cultural factors. Unfortunately, the lay public
      and health-care providers, as well as insurance companies, often view it simply
      as a problem of willful misconduct--eating too much and exercising too little.
      Obesity is a remarkable disease in terms of the effort required by an individual
      for its management and the extent of discrimination its victims suffer. While
      people often wish to lose weight for the sake of their appearance, public health
      concerns about obesity relate to this disease's link to numerous chronic diseases
      that can lead to premature illness and death. The scientific evidence summarized
      in Chapter 2 suggests strongly that obese individuals who lose even relatively
      small amounts of weight are likely to decrease their blood pressure (and thereby
      the risk of hypertension), reduce abnormally high levels of blood glucose
      (associated with diabetes), bring blood concentrations of cholesterol and
      triglycerides (associated with cardiovascular disease) down to more desirable
      levels, reduce sleep apnea, decrease their risk of osteoarthritis of the weight
      bearing joints and depression, and increase self-esteem. In many cases, the obese
      person who loses weight finds that an accompanying comorbidity is improved, its
      progression is slowed, or the symptoms disappear. Healthy weights are generally
      associated with a body mass index (BMI; a measure of whether weight is
      appropriate for height, measured in kg/m2) of 19-25 in those 19-34 years of age
      and 21-27 in those 35 years of age and older. Beyond these ranges, health risks
      increase as BMI increases. Health risks also increase with excess
      abdominal/visceral fat (as estimated by a waist-hip ratio [WHR] > 1.0 for males
      and > 0.8 for females), high blood pressure (> 140/90), dyslipidemias (total
      cholesterol and triglyceride concentrations of > 200 and > 225 mg/dl,
      respectively), non-insulin-dependent diabetes mellitus, and a family history of
      premature death due to cardiovascular disease (e.g., parent, grandparent,
      sibling, uncle, or aunt dying before age 50). Weight loss usually improves the
      management of obesity-related comorbidities or decreases the risks of their
      development. The high prevalence of obesity in the United States together with
      its link to numerous chronic diseases leads to the conclusion that this disease
      is responsible for a substantial proportion of total health-care costs. We
      estimate that today's health-care costs of obesity exceed $70 billion per
      year.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID- 8653538
TI  - The tide shifts again: the ebb and flow of history.

PMID- 8653539
TI  - Obesity and leanness. 1940.

PMID- 8653540
TI  - Mechanism of increase in basal lipolysis of enlarged adipocytes in obese animals.
AB  - Sonication of rat fat cells caused an increase in lipolysis in the absence of
      lipolytic hormones (basal lipolysis) and loss of epinephrine responsiveness.
      Sonication of endogenous lipid droplets from fat cells also induced an increase
      in lipolysis in the presence of HSL. Addition of phosphatidylcholine to the
      sonicated lipid droplets reduced the hydrolysis of triglyceride by HSL. These
      results suggest that the active HSL is already present in the fat cell even in
      the absence of lipolytic hormone, and phosphatidylcholine on the surface of
      endogenous lipid droplets causes inhibition toward lipolytic action of HSL. The
      decrease in the surface phosphatidylcholine concentration in endogenous lipid
      droplets was proved to cause the increase in basal lipolysis. It is demonstrated
      that basal lipolysis was elevated in the enlarged fat cells of obese rats by
      reduction of surface phosphatidylcholine concentration of the endogenous lipid
      droplets.

PMID- 8653541
TI  - Integrative Regulation of Energy Metabolism: From Brain to Periphery. Proceedings
      of the Yufuin Symposium. Oita, Japan, November 26-29, 1994.

PMID- 8653542
TI  - Altered functions of ion channels in diabetic beta cells.
AB  - Selective impairment of glucose-induced insulin secretion and hyper
      responsiveness to arginine are known features of GK rats, a genetic model of
      NIDDM. We focus on the ionic mechanism underlying these phenomena using patch
      clamp techniques. Pancreatic islets were isolated from male GK rats and age
      matched control Wistar rats and were subjected to dispersion and culture. Single
      channel recordings of KATP channels were performed using either on-cell mode or
      inside-out patch mode. Ca2+ channel currents were recorded under conventional
      whole-cell mode. In GK beta cells, ATP sensitivity of KATP channels itself was
      not altered, although glucose-induced closure of KATP channels was severely
      impaired. Among substrates for fuel metabolism, only dehydroxyacetone (DHA)
      reproduced this anomaly. On the other hand, current densities of L-type Ca2+
      channels were increased in GK beta cells. Since DHA is a known substrate for
      glycerol phosphate shuttle, current data suggest that major metabolic deficit of
      GK beta cells resides in this shuttle. On the other hand, increased L-type Ca2+
      channel activities might be an ionic basis for augmented insulin response to
      nonglucose depolarizing stimuli in GK beta cells.

PMID- 8653543
TI  - The antiobesity effect of dehydroepiandrosterone in castrated or noncastrated
      obese Zucker male rats.
AB  - Although antiobesity effect of dehydroepiandrosterone (DHEA) has been reported in
      rats, it remains unclear whether the effect is brought about by itself or
      mediated by sex steroids converted from DHEA in gonads. In the present study, to
      clarify this point, the effect of DHEA on growth in obese Zucker male rats was
      reevaluated under two conditions: with or without castration. Castration did not
      affect the pattern of growth curve of obese Zucker male rats. Three-months
      treatment of castrated Zucker rats with 0.3% DHEA in the diet resulted in
      dramatic decrease of body weight gain in comparison to DHEA-untreated and
      castrated rats. The degree of antiobesity effect of DHEA in castrated rats was
      almost same as that observed in non-castrated rats. These results suggest that
      DHEA exerted its antiobesity effect by itself rather than through conversion to
      testosterone in testis.

PMID- 8653544
TI  - Visceral fat accumulation and cardiovascular disease.
AB  - Classification of Obesity. It has been noted that the incidence of metabolic
      complications among equally obese subjects differs depending on their physique
      (11) and there has been more scientific assessment in recent years that
      complications such as diabetes mellitus or hyperlipidemia are related to adipose
      tissue distribution (5). In 1983, we reported a method for adipose tissue
      analysis using computed tomography (CT), which enables the analysis of adipose
      tissue in the body cavity, e.g., abdominal cavity or thoracic cavity, as well as
      subcutaneous fat (10). Using this method, we found that the patients with
      accumulation of fat in the abdominal cavity have a higher incidence of
      complication (1). Based on this finding, we proposed a classification into
      visceral fat obesity by visceral fat area (V)/subcutaneous fat area (S) ratios
      obtained from CT cross sectional pictures of the umbilical region. We divided
      obese subjects at a V/S ratio of 0.4, classifying those with a ratio of 0.4 or
      more as a visceral fat obesity group and those with V/S ratio of below 0.4 as a
      subcutaneous fat obesity group. Disorders of glucose and lipid metabolism were
      more marked in the visceral fat obesity than subcutaneous fat obesity even when
      sex and age were matched. We also demonstrated that visceral fat obesity is more
      frequently accompanied by circulatory disorders such as left ventricular
      enlargement (8) and hypertension than subcutaneous fat obesity (2).

PMID- 8653545
TI  - The association among fat distribution, physical fitness, and the risk factors of
      cardiovascular disease in obese women.
AB  - The purpose of this study was to see whether fat distribution and physical
      fitness are independent risk factors of cardiovascular diseases in obese women.
      Seventy-four obese women aged 19 to 65 years participated in this study. The data
      were collected on plasma lipid profiles, plasma glucose and insulin during an
      oral glucose tolerance test, blood pressure, fat distribution determined by the
      waist to hip ratio (WHR), total body fat determined by the hydrostatic weighing
      method and a direct measurement of blood lactate threshold. Significant
      correlations were found between WHR and plasma cholesterol (TC), plasma LDL
      cholesterol (LDL-c) and LDL-c to the plasma HDL cholesterol ratio (LDL-c/HDL-c),
      independent of age, percent body fat, and VO2 per lean body mass at blood lactate
      threshold (LT). On the other hand, LT was significantly related to the area under
      the curve of insulin during OGTT (insulin area) and DBP, independent of age,
      percent body fat, and WHR. In conclusion, both fat distribution and physical
      fitness are considered to be independently related to some important risk factors
      in obese women after adjustment for percent body fat.

PMID- 8653546
TI  - Hypothalamic monoamines and insulin in relation to feeding in the genetically
      obese Zucker rat as revealed by microdialysis.
AB  - Dynamic changes in VMH and PVN monoamines and immunoreactive insulin (IRI) were
      investigated by microdialysis in freely-moving genetically obese Zucker rats in
      order to relate possible disturbances to the impaired regulation of food intake
      of this model. Serotonin (5-HT), 5-HIAA and dopamine (DA) increased at the
      beginning of spontaneous meals while DOPAC decreased. Although similar in normal
      and obese rats, these changes were much more dramatic in the latter, as if more
      "signal" for satiety were necessary at the VMH-PVN level. Glucoprivic feeding or
      satiety are induced in normal rats by intravenous infusions of insulin or
      insulin+glucose respectively. The Zucker rat is resistant to these treatments.
      The monoaminergic changes brought about by these infusions were similar in obese
      and normal rats (decreases in 5-HT and DA and increases in 5-HIAA and DOPAC), but
      the occurrence of meals, in the obese, showed a superim-position of monoaminergic
      changes resembling those related to spontaneous feeding. The monoaminergic
      effects of insulin must therefore be dissociated from its effects on feeding.
      Hypothalamic insulin itself might be the brain signal. At the beginning of meals
      presented for the first time, VMH-PVN IRI increased earlier and with a smaller
      magnitude in the obese. When the rats were accustomed to scheduled meals, a
      similar anticipatory increase in IRI was found in both obese and lean rats. This
      suggests that brain insulin is more than a satiety signal. In addition, in
      response to an i.v. insulin infusion, IRI increased twice as much in obese rats
      despite lower basal levels. Whatever the origin of hypothalamic insulin, the
      larger response of the obese Zucker rat, known to be insulin resistant, may
      reflect the inefficiency of the peptide in reducing feeding and body weight in
      this pathological model.

PMID- 8653547
TI  - Effects of auricular acupuncture stimulation on nonobese, healthy volunteer
      subjects.
AB  - Effects of auricular acupuncture stimulation on nonobese healthy volunteers were
      investigated. Subjects (n = 35) averaged 34.5 years old, and BMI was 25.3 kg/m2.
      Small (0.15 x 2.0 mm) auricular needles were applied intracutaneously into the
      bilateral cavum conchae that was identified by having less than 100 k omega
      resistance. Body weight was measured four times a day and charted by the subjects
      themselves. Results showed that, in the period 11-2, in which only body weight
      was measured, without auricular acupuncture stimulations, 57.1% of the subjects
      reduced their body weight. This indicates that charting body weight themselves
      might be useful to maintain their weight. In the auricular acupuncture treated
      period, 19 (70.4%) out of 27 decreased (p < 0.01), 5 (18.5%) was increased, and 3
      (11.1%) had no change in body weight. In conclusion, the results suggest that
      success in maintaining weight reduction can be attributed to graphic illustration
      of one's weight pattern. Bilateral auricular acupuncture stimulation can also
      reduce body weight of healthy non-obese subjects. This is consistent with the
      suggestion that it might be effective in the treatment of obese patients.

PMID- 8653548
TI  - The effect of infused nutrients and absorbed foods on daily food intake in rats.
AB  - Studies with crossed intestines rats show that daily food intake is controlled by
      internal signals that arise at the level of the small intestines or from the
      absorption of food into the bloodstream and its subsequent metabolism. The gut
      can produce endogenous signals such as neural messages responding to the presence
      of nutrients in the wall of the small intestine or in the portal vein leading to
      the liver. GI hormones can be released from various regions of the small
      intestine and may partially inhibit food intake. When nutrients bypass the gut
      and are infused indirectly into the bloodstream, they produce a partial 50% to
      80% compensation for the number of calories infused. Clearly, nutrients play a
      major role in the control of daily intake. Infusion of these nutrients into
      specific vascular sites suggest that they do not act directly on the brain or the
      liver to reduce daily intake. Cross-circulation studies suggest that the
      combination of hormones and nutrients do not affect intake during a single meal.
      It is possible that nutrients act directly on the gut to inhibit stomach emptying
      or on the storage tissues, such as muscle or fat, to control daily food intake.

PMID- 8653549
TI  - Recognition and neural plasticity responding to deficient nutrient intake scanned
      by a functional MRI in the brain of rats with L-lysine deficiency.
AB  - Each L-amino acid (AA) in plasma and brain remains unchanged while normal diet is
      available. Once L-lysine (Lys) deficient diet was offered to rats, Lys in plasma
      and brain declined, and anorexia occurred. When solutions of AAs were offered,
      they selected the Lys solution, and their food intake and growth normalized. The
      single neuron activity in the lateral hypothalamic area of these rats suggested
      that neural plasticity occurred, specifically responding to Lys, both by
      iontophoretic application and during ingestion of AA. The recognition site for
      deficient nutrient intake in the brain of rats with Lys deficiency was identified
      by non-invasive magnetic resonance imaging (MRI 4.7 tesla, 40 cm bore in
      diameter) developed to monitor changes in cerebral blood flow and oxygenation in
      rat brain. Wistar strain young male rats fed with Lys deficient diet for 4 days,
      were adapted to be settled in the center of the bore. When they received a Lys
      injection intraperitoneally (0.2 M, 10 mL/kg), a signal intensity decrease in the
      medial and lateral hypothalamus appeared 30 minutes later in T2 weighted images,
      reflecting increased oxygenation which lasted for 30 minutes, and then gradually
      recovered. These changes never occurred in any other areas of the brain of rats
      with Lys deficiency, i.e., the thalamus, the cortex, the hippocampus, etc. There
      were no changes in the signal intensity with control injection of saline. In
      addition, oxygen consumption in the brain of rats without Lys deficiency was not
      altered by intraperitoneal Lys injection. The present results suggest that in
      essential AA deficiency, the medial and lateral hypothalamus may play important
      roles in recognition responses to particular deficient nutrients in order to
      maintain homeostasis.

PMID- 8653550
TI  - Apolipoprotein A-IV: a circulating satiety signal produced by the small
      intestine.
AB  - How fat feeding, especially lipoproteins and apolipoproteins, may affect food
      intake is unclear. Apolipoprotein A-IV (apo A-IV) is a protein associated with
      chylomicrons, and its synthesis by the small intestine is markedly stimulated
      following ingestion of fat. We explored the anorectic effect of chylous lymph on
      feeding behavior. Intestinal lymph samples collected during lipid infusion
      intraduodenally when administered intravenously markedly suppressed food intake
      in fasting rats. To determine if the suppressor was lipid or apo A-IV, fasting
      rats were infused intravenously with a 2% Intralipid emulsion, but it did not
      suppress food intake. These data suggest that the factor in chylous lymph that
      suppresses food intake is probably apo A-IV. To test this, apo A-IV in chylous
      lymph was removed by immunoprecipitation, and the chylous lymph with apo A-IV
      removed lost its anorectic effect. Next, we infused purified apo A-IV
      intravenously in fasted rat, and it inhibited food intake in a dose-dependent
      manner. We therefore conclude that increased apo A-IV in chylous lymph is a
      factor involved in anorexia after fat feeding. Infusion of 0.5 microgram of apo A
      IV into the third ventricle failed to suppress food intake. Higher doses (1
      microgram or higher) of apo A-IV infused into the third ventricle inhibited food
      intake in a dose-dependent manner. To further test the hypothesis that apo A-IV
      is an important factor controlling food intake, we administered goat anti-rat apo
      A-IV serum into the third ventricle of rats that were allowed food and water ad
      libitum. In all rats tested, this treatment resulted in enhanced food intake. In
      conclusion, we propose that apo A-IV may act centrally to control food intake.

PMID- 8653551
TI  - Actions of acidic fibroblast growth factor fragments on food intake in rats.
AB  - Acidic fibroblast growth factor (aFGF) has suppressive effects on food intake. In
      the present study, the effect of aFGF fragments on food intake were investigated
      in rats. Infusion of a carboxyl-terminal fragment of aFGF, aFGF-(114-140), did
      not affect food intake, whereas an amino-terminal fragment of aFGF, aFGF-(1-15),
      was significantly inhibitory. Other amino-terminal fragments, aFGF-(1-20), aFGF
      (1-29) and aFGF-(9-29), did not affect food intake. However, [Ala16]aFGF-(1-29)
      and [Ser16]aFGF-(1-29) in which the cysteine residue at position 16 was replaced
      with alanine and serine, respectively, had significant suppressive effects on
      food intake. Infusion of a functional antagonist for FGF receptor, anti-FGFR-1
      antibody, into the lateral hypothalamus (LHA) significantly increased food
      intake. The results suggest that: the amino-terminal portion of aFGF is active in
      food intake suppression; the replacement of cysteine residue by alanine or serine
      is important in some amino-terminal aFGF fragments; and the LHA is involved in
      feeding suppression actions by aFGF and some fragments.

PMID- 8653552
TI  - Hypothalamic neuronal histamine modulates adaptive behavior and thermogenesis in
      response to endogenous pyrogen.
AB  - Homeostatic involvement of hypothalamic neuronal histamine in adaptive behavior
      and thermogenesis was investigated when interleukin-1 beta (IL-1 beta), one of
      the endogenous pyrogens, was infused peripherally in rats. IL-1 beta decreased
      food and water intake and elevated body temperature. Depletion of neuronal
      histamine in the hypothalamus induced by alpha-fluoromethylhistidine, a suicide
      inhibitor of the histamine synthesizing enzyme histidine decarboxylase (HDC),
      attenuated the suppressive effect of IL-1 beta on food intake, facilitated the
      inhibitory effect on water intake, and enhanced its thermogenic effect.
      Simultaneously IL-1 beta increased activity of HDC and histamine-N
      methyltransferase (HMT), a neuronal histamine catabolizing enzyme. Pretreatment
      with indomethacin completely blocked those increases in turnover of neuronal
      histamine induced by IL-1 beta. Hypothalamic prostaglandin E2 (PGE2) activated by
      peripheral IL-1 beta, but not peripheral PGE2, increased both activities of HDC
      and HMT. Ginsenoside Rg1, a major component of panax ginseng, modulated the
      suppressive effects of IL-1 beta on ingestive behavior, resulting in a lowering
      of body temperature. The findings suggest that the effects of IL-1 beta on
      ingestive behavior and thermogenesis may be modulated by dynamics of hypothalamic
      neuronal histamine through activation of hypothalamic PGE2 which is elevated by
      peripheral IL-1 beta.

PMID- 8653554
TI  - Energy homeostasis, autonomic activity and obesity.
AB  - Obesity is often accompanied by alterations in both sympathetic and
      parasympathetic autonomic functions. The present paper summarizes the results of
      a number of studies designed to investigate autonomic functioning in normal,
      genetically, and experimentally obese rats. Particular emphasis is given to
      autonomic functioning and dysfunctioning in relation to the processes that are
      involved in the regulation of peripheral energy substrate homeostasis. It is
      concluded that alterations in autonomic regulation in obesity are determined by
      causal factors such as overeating, genetic make-up, age and/or the duration of
      obesity.

PMID- 8653553
TI  - Low ambient temperature and neuroendocrine response to hypoglycemia in men.
AB  - Nutritional factors, such as an excess or a deficiency of glucose, play an
      important role in neuroendocrine regulations. Hormonal and metabolic responses to
      hypoglycemia were examined in healthy non-obese volunteers under conditions of
      low ambient temperature. Hypoglycemia was induced by intravenous injection of
      insulin in two randomized trials performed at room temperature and at 4 degrees
      C. At room temperature, the typical neuroendocrine response to hypoglycemia was
      established. The increases of ACTH, beta-endorphin, growth hormone and cortisol
      in response to insulin hypoglycemia failed to be modified by low ambient
      temperature. Acute cold exposure significantly reduced epinephrine and totally
      inhibited prolactin response to insulin-induced hypoglycemia. In spite of
      significant changes in epinephrine response to hypoglycemia at low ambient
      temperature, no striking differences in plasma glucose levels compared to those
      measured at room temperature were observed. However, under conditions of low
      temperature the reestablishment of normoglycemia was delayed. No changes in free
      fatty acids were found under our experimental conditions. The presented data show
      that low ambient temperature exerts selective effects on some neuroendocrine and
      metabolic parameters.

PMID- 8653555
TI  - 2-Deoxy-D-glucose but not 2-mercaptoacetate increases Fos-like immunoreactivity
      in adrenal medulla and sympathetic preganglionic neurons.
AB  - 2-Deoxy-D-glucose (2DG) and 2-mercaptoacetate (MA) are drugs that competitively
      inhibit metabolism of glucose and fatty acids, respectively. Both 2DG and MA
      stimulate food intake. In addition, 2DG-induced glucoprivation is a known
      stimulus for adrenomedullary secretion. However, very little is known about the
      effects of MA on the sympathoadrenal system. In the present study, we examined
      effects of 2DG and MA on the activity of preganglionic neurons and the adrenal
      medulla, as indicated by expression of Fos-like immunoreactivity (Fos-li). 2DG,
      MA, or saline was administered using a stress-attenuated paradigm incorporating
      remote drug infusion. Expression of Fos-like immunoreactivity (Fos-li) was
      subsequently examined in the adrenal medulla and in preganglionic sympathetic
      neurons throughout the intermediolateral column (IML) of the thoracic and lumbar
      spinal cord. We found that 2DG increased Fos-li in the adrenal medulla and in the
      IML primarily at spinal cord segments T7-T10, where adrenomedullary preganglionic
      neurons reside. In contrast, MA did not induce Fos-li either in the adrenal
      medulla or in sympathetic preganglionic neurons at any cord level. Results
      support the hypothesis that decreased fatty acid oxidation is not a stimulus for
      adrenal medullary secretion and provide evidence for a highly selective
      stimulation of adrenal medullary preganglionic neurons by 2DG.

PMID- 8653556
TI  - Glucose-responsive neurons in the brainstem.
AB  - AREA POSTREMA: The influence on feeding behavior caused by ablation of the area
      postrema (AP) in rodents indicates the participation of this structure in the
      control of ingestion. Two types of glucose responsive neurons were identified in
      the AP: one is characterized by increasing the discharge rate in response to
      glucose (glucoreceptor type) and the other by decreasing the discharge rates in
      response to glucose (glucose sensitive type). These glucose responsive neurons
      may participate in glycemic homeostasis. NUCLEUS OF SOLITARY TRACT: The glucose
      responsive neurons exist within the caudal portion of nucleus of the solitary
      tract (NTS), a relay station in visceral afferents. Two types similar to the AP
      were also recognized. It is confirmed that hepatic glucose sensitive afferents
      terminate on some of the glucose sensitive neurons. This convergence may serve as
      a fail-safe mechanism. In addition, the NTS involving complex neural networks of
      excitatory and inhibitory interneurons may be concerned with integration of
      glycemic information. DORSAL MOTOR NUCLEUS OF VAGUS: Some neurons within the
      dorsal motor nucleus of the vagus (DMV) were identified as the glucose responsive
      ones. Both types were also recognized. It is confirmed by antidromic activation
      that these glucose responsive DMV neurons send their axons toward the gastric or
      coeliac branch that innervates either the stomach, intestine or pancreas. Some of
      the DMV neurons may subserve an enteroceptor function by themselves. They may
      also play a role in the brainstem neural control of glycemic homeostasis as the
      fail-safe mechanism.

PMID- 8653557
TI  - An electrophysiological study on amino acid sensors in the hepato-portal system
      in the rat.
AB  - The existence of amino acid sensors sensitive to arginine, alanine, leucine and
      glycine in the hepato-portal region was previously reported based on recording of
      the afferent signals from the hepatic branch of the vagus nerve. The present
      study was carried out to investigate the effects of fifteen different amino acids
      on the activity of the vagal hepatic afferents. Intraportal administration (10
      mM, 0.1 mL) of alanine, arginine, histidine, leucine, lysine, serine, tryptophane
      and valine increased vagal afferent discharge rate, and that of cysteine,
      glycine, isoleucine, methionine, phenylalanine, proline and threonine suppressed
      it. The results indicate the existence of two groups of amino acids sensors which
      exhibit excitatory or inhibitory effect on the afferent activity of the hepatic
      branch of the vagus nerve. The change in afferent activity to the hypothalamus
      may affect reflex regulation of the visceral functions and thereby influence
      appetite.

PMID- 8653558
TI  - Effects of selective vagotomy on circadian rhythms of plasma glucose, insulin and
      food intake in control and ventromedial hypothalamic (VMH) lesioned rats.
AB  - Effects of hepatic and celiac vagotomy on circadian rhythms of plasma glucose,
      insulin, and food intake were examined in sham-operated (control) and
      ventromedial hypothalamic (VMH) lesioned rats. Rats were acclimated to the
      condition with a 12-hour light-dark cycle for 1 week before surgery. One week
      after VMH lesions, control and VMH lesioned rats were divided into three groups:
      sham vagotomy, hepatic vagotomy, and celiac vagotomy. Three days after vagotomy,
      food intake was measured at 6-hour intervals. Seven days after vagotomy, plasma
      glucose and insulin were measured at the midpoint of each feeding period. In
      control rats, hepatic vagotomy destroyed circadian rhythms of plasma glucose and
      insulin probably due to removal of afferent function. In VMH lesioned rats,
      celiac vagotomy destroyed circadian rhythm of food intake due to the reduction of
      plasma insulin by removal of efferent function without affecting the loss of
      circadian rhythms of plasma glucose and insulin.

PMID- 8653559
TI  - Immunohistochemical localization of glucose transporters (GLUT1 and GLUT3) in the
      rat hypothalamus.
AB  - Immunohistochemical localization of the glucose transporters was studied in the
      rat hypothalamus by using a specific rabbit antiserum raised against either the
      isoform 1 (GLUT1) or the isoform 3 (GLUT3). Immunoreactive staining for GLUT1 was
      found in glia cells and capillaries, whereas positive staining for GLUT3 occurred
      mainly in neurons and partly in ependymal cells. Double immunostaining indicated
      that a small population of GLUT1-positive cells were reactive for glial
      fibrillary acidic protein, a marker for astrocytes. Another doubly stained
      section showed that GLUT1-positive glia cells were never stained with an OX42
      antibody, a marker for microglia cells. Neurons staining positively for GLUT3,
      often large in cell size, were confined mainly in the lateral hypothalamic area
      and partly in the dorsomedial and periventricular hypothalamic nuclei. Possible
      significance of these two glucose transporters in the hypothalamus is briefly
      discussed.

PMID- 8653560
TI  - New infrared spectroscopic technique as a tool to reveal roles of unsaturated
      fatty acids in diseases and synaptic functions.
AB  - Newly developed Fourier-transform infrared spectroscopic analysis (FTIR)
      techniques were applied to diagnosis of adulthood disease and to reveal the role
      of unsaturated fatty acids in neuronal function. A new FTIR technique was
      developed to monitor the change of lipid content in the human oral mucosa
      noninvasibly. By this technique the infrared spectrum of oral mucosa was found to
      change in good relation to that of triglyceride level in blood of adult
      volunteers. This indicates that the new infrared technique may be useful for
      future diagnoses of hyperlipidemia or triglyceridemia noninvasively. It was found
      that the deficiency of n-3 polyunsaturated fatty acids in brain membranes
      decreased the bright-ness-discrimination learning performance in rats, and a
      change of membrane surface structures was detected nondestructively by FTIR after
      the learning task in comparison with the structure of membrane surfaces before
      the learning. The evidence obtained from this technique suggested that a change
      of sialic acid binding form in the brain membranes occurred after the learning
      task in rats fed n-3 rich diet but not in rats fed n-3 deficient diet. This was
      further confirmed by a chemical analysis of sialidase-sensitive sialic acid
      contents in the membrane. These evidences show that the newly developed infrared
      spectroscopic techniques are useful not only for the noninvasive diagnoses for
      human adulthood diseases but also for the nondestructive analysis of biomembrane.

PMID- 8653561
TI  - Time-dependent rundown of GABA response in mammalian cns neuron during
      experimental anoxia.
AB  - Gamma-Aminobirtyric acid (GABA) is one of the major neurotransmitters in the
      mammalian central nervous system (CNS). The activation of post-synaptic GABAA
      receptor-chloride channel complex is thought to underlie inhibitory postsynaptic
      potentials ubiquitously in various CNS regions. GABAA receptors are modulated by
      convulsant, hypnotic-anticonvulsant, anxiolytic and anxiogenic agents and
      endogenous agents such as nurosteroids and intracellular calcium, ATP, and cyclic
      AMP. The function of GABAA receptor in CNS neuron is also affected by some
      pathophysiological processes, e.g., anoxia. For example, it is currently believed
      that delayed neuronal death after brain ischemia results from excessive cell
      excitability and/or loss of inhibition. In the present study, we investigated how
      the GABA-gated chloride current is affected by anoxic conditions. All experiments
      were carried out on neurons freshly dissociated from rat CNS by the use of both
      conventional and nystatin perforated patch recording configurations. The GABA
      response showed a considerable rundown with time in anoxic condition. The rundown
      was prevented by adding either ouabain or SPAI-I (Na+-K+ ATPase inhibitor-I),
      suggesting that the experimental anoxia reduced GABA response by decreasing
      intracellular ATP synthesis. This result was also confirmed by finding that the
      direct decrease of intracellular ATP concentration using a conventional whole
      cell patch recording mode inhibited the GABA-gated chloride response in mammalian
      CNS neurons.

PMID- 8653562
TI  - Chronically administered 3-nitropropionic acid produces selective lesions in the
      striatum and reduces muscle tonus.
AB  - Systemically administered 3-nitropropionic acid (3- NPA), irreversible inhibitor
      of succinate dehydrogenase, produced characteristic bilateral lesions in the
      striatum (STR) in the rat. Inside the lesion, neutrophils invaded and strong
      immunoreaction for IgG as well as complement factor C3b/C4b receptor (C3b/C4br)
      were observed. The core of the lesion lost the immunoreaction for glial
      fibrillary acidic protein (GFAP) while the marginal area had abundant GFAP
      labeled astrocytes around the vessels. Intoxicated rats often became somnolent
      and were awkward in cooperative movement on a pole climbing test, but they had a
      quite good memory retention in a passive avoidance learning. Muscle tonus in some
      of the intoxicated rats became hypotonic with low voltage electromyogram (EMG)
      activity, especially in lower limbs. In summary, 3-NPA intoxicated rats had
      selective bilateral lesions in the STR and exhibited disturbances in a
      cooperative movement owing to the impairment in muscle tonus, thus it would be a
      useful animal model to deduce the central pathogenesis of Huntington's disease.

PMID- 8653564
TI  - Cardiovascular-related peptides influence hypothalamic neurons involved in
      control of body water homeostasis.
AB  - The cardiovascular-related peptides, atrial natriuretic peptide (ANP), brain
      natriuretic peptide (BNP) and endothelin (ET) were originally isolated from the
      atrium, brain and endothelial cells, respectively. ANP and BNP have hypotensive,
      natriuretic, diuretic and vasodilator effects. ET has strong vasoconstrictor
      effects. Centrally applied ANP and BNP attenuate pressure and drinking responses
      and vasopressin secretion induced by angiotensin II. Similar application of ET
      increases blood pressure in vivo and vasopressin secretion in vitro. To clarify
      direct effects of these peptides on neurons in the regions involved in body water
      homeostasis, extracellular recordings were made from neurons in the supraoptic
      nucleus (SON) and regions of anteroventral third ventricle (AV3V) of rat
      hypothalamic slice preparations. ANP and BNP inhibited AV3V neurons, suggesting
      direct actions of the peptides on drinking. In the SON, these peptides inhibited
      selectively putative vasopressin neurons but not putative oxytocin neurons,
      suggesting direct actions of the peptides on vasopressin secretion. We
      demonstrated that the inhibitory response by ANP and BNP is mediated through a
      second messenger cGMP system but not cAMP. Contrary to natriuretic peptides, ET
      excited AV3V neurons but inhibited SON neurons. Roles of ANP, BNP and ET on the
      central regulatory systems of body water homeostasis, acting as neurotransmitters
      or neuromodulators, will be discussed.

PMID- 8653563
TI  - The effect of protoporphyrinogen oxidase inhibitors on microsomal and
      mitochondrial cytochromes.
AB  - Neurological dysfunction is a characteristic feature of acute porphyrias,
      unexplained until now. One of the possible explanations is a deficiency of heme
      in the central nervous system, caused by a block in porphyrin biosynthesis. To
      test this possibility, the content of brain mitochondrial cytochrome a3 was
      determined after intracerebroventricular administration of the protoporphyrinogen
      oxidase-inhibiting herbicide fomesafen. It was established in in vitro
      experiments that fomesafen is a potent inhibitor of brain mitochondrial
      protoporphyrinogen oxidase (PROTOOX). Addition of 10(-6) M fomesafen to
      incubation mixture decreased PROTOOX from 1.02 nmol/mg/h (controls) to 0.42
      nmol/mg/h. 10(-5)M of fomesafen decreased this activity to 0.27 nmol/mg/h. In in
      vivo experiments, 5 microleters of fomesafen solution containing 0.2 M
      fomesafen/l was administered to male rats by intracerebroventricular injection.
      The content of brain mitochondrial cytochrome a3 was determined 72 hours later. A
      slight decrease of the a3 content was observed (control rats 0.25 nmol/mg
      protein, treated rats 0.22 nmol/mg). Brain cytochrome P450 activities were below
      detection limits in both control and treated groups. In a separate experiment,
      male ICR mice were fed 1000 ppm of the protoporphyrinogen oxidaseinhibiting
      herbicide oxadiazon in the diet for 10 days. Liver microsomal cytochrome P450
      content was decreased and liver porphyrins increased. An increase of porphyrin
      content was also observed in the testes of oxadiazon-fed mice, but testicular
      cytochrome a3 content was unchanged. The results indicate that, contrary to liver
      microsomal cytochromes P450, the mitochondrial cytochromes are not susceptible to
      changes in heme biosynthesis.

PMID- 8653565
TI  - Histaminergic control of mucosal repair in the small intestine.
AB  - The aim of the present paper was to summarize histamine-mediated repair of rat
      intestinal mucosa. To evaluate intestinal repair, we examined lipid transport (an
      index of intestinal mucosal function) after 15 minutes occlusion of the superior
      mesenteric artery. Rats were pretreated with alpha-fluoromethylhistidine (a
      suicide inhibitor of histidine decarboxylase, a synthesizing enzyme of
      histamine), H1-receptor antagonist (chlorpheniramine maleate), H2-antagonist
      (cimetidine), or H3-antagonist (thioperamide) before ischemia-reperfusion (I/R).
      Lipid transport to rat mesenteric lymph decreased significantly 24 hours after
      I/R in all groups tested compared to sham-treated rats. Lipid transport was
      restored 48 hours after I/R in the vehicle-pretreated control group. Lipid
      transport was not restored to the control level 48 hours after I/R in rats
      pretreated with H1-antagonist and a suicide inhibitor of histidine decarboxylase.
      In contrast, intestinal function was restored to the control level 48 hours after
      I/R in rats pretreated with H2- and H3-antagonists. These results support our
      previous findings that newly formed histamine after I/R plays an important role
      in mucosal recovery through H1-receptors.

PMID- 8653567
TI  - Optimization of hemodynamic energy expenditure in the arterial system.
AB  - Experimental evaluations and comparisons of the passive and active biomechanical
      properties of isolated blood vessels from different species (dog, pig, calf,
      human), as well as the nature of different arterial pressure oscillations, reveal
      that: 1) Characteristic impedance of middle-size and large arteries changes with
      intraluminal mean pressure usually resulting in a U-shaped function with a
      minimum value around the normal physiological 100 mmHg pressure; 2) Similarly,
      pressure dependent adrenergic diameter responses (active strain) of different
      large arteries also exhibit parabolic shape with an extreme (maximum) value at 50
      100 mmHg intraluminal pressure, suggesting that biomechanical characteristics of
      the vessel wall may define an optimum for hemodynamic operations; 3) Changes in
      the arterial smooth muscle tone shift the characteristic impedance curve along
      the pressure axis and alter the slopes of the parabola; 4) There are significant
      interactions between the fast 1st-order (pulsatile) and the slow 3rd-order
      arterial pressure wave components. These and some other characteristics of the
      circulatory system suggest the existence of an "extremal" forced oscillation
      blood pressure control mechanism in the body, optimizing the afterload of heart
      and the blood perfusion of systemic microvessels by minimizing the pulsatile
      energy expenditure at the physiological mean pressure operation level. A
      versatile mathematical model of this hypothetical mechanism was developed by us
      on an IBM PC using Pascal and 8086 Assembly languages. Simulation experiments
      show that such a physiological adaptive system could control arterial pressure
      effectively. The computer model is available on a PC disc.

PMID- 8653566
TI  - The function of 5-HT3 receptors on colonic transit in rats.
AB  - The function of serotonin (5-HT)3 receptors on colonic transit was investigated
      in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg,
      s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.),
      corticotropin releasing factor (CRF; 1 microgram intracerebroventricular
      administration) and restraint stress (for 45 minutes). A potent and selective 5
      HT3 receptor antagonist, azasetron (+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro
      4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride ;
      0.01-10 mg/kg, p.o. inhibited the 5-HT-, CRF- and stress-accelerated colonic
      transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron
      (1 mg/kg, p.o) also inhibited the stress-accelerated colonic transit, but
      azasetron was more effective than these two drugs. Atropine methylbromide (0.1
      mg/kg, s.c.) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated
      colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.),
      SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300
      mg/kg, p.o.), did not. Azasetron (10 micrograms) administered
      intracerebroventricularly did not inhibit the stress-induced acceleration. These
      results suggest that endogenous 5-HT which is released through stress accelerates
      the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism.
      It is considered that azasetron inhibits colonic transit particularly under
      stress conditions through the blockade of the peripheral 5-HT3 receptors.
      Azasetron may improve bowel function in stress-related colonic dysfunction like
      irritable bowel syndrome.

PMID- 8653568
TI  - [Small-caliber polyurethane arterial prosthesis: clinical and angiomorphological
      follow-up of 20 patients in a prospective study].
AB  - The five year patency rate for femoropopliteal vein bypass grafts is around 70%
      according to the literature. Patency rates for synthetic grafts (eg PTFE, Dacron)
      range between 43 and 57%. If a vein is not available there is a new polyurethane
      6 mm artery substitute on the market, that has shown in vitro promising physical
      characteristics and good long term results after implantation in dogs. In a
      prospective, randomized trial the results of the new polyurethane graft (PUR)
      were compared with those of a Dacron graft of the same diameter. Included in the
      study were 20 patients with lower limb ischemia stage Fontaine II B, III and IV,
      10 in each group. Patency rates, handling of the graft and complications were
      analysed. During the one year follow up 7 PUR grafts had to be changed due to
      recurrent bypass occlusion within the first 3 months. At the end of the year
      there were only one PUR-bypass but 8 Dacron grafts open. 5 PUR grafts were
      examined histologically and no morphological reason for the occlusion, especially
      no myointimal hyperplasia, was found. A special regard was brought to the
      arterial run-off in both groups. It was confirmed to be comparable with only
      slightly better data for the PUR group. The exact reasons for the astonishing bad
      results of the PUR graft for femoropopliteal above knee bypass cannot be
      explained in our study. Due to the unexpected high occlusion rate the study was
      stopped earlier then planned.

PMID- 8653569
TI  - [Should heart surgery and thromboendarterectomy of the carotid artery be done
      simultaneously?].
AB  - The management of patients with coexisting severe carotid and coronary artery
      disease continues to be controversial. To evaluate the actual risks we have
      reviewed our experience of 92 patients that underwent simultaneous cardiac
      surgery and carotid thrombendarterectomy (TEA) over a 10 year period. The mean
      age was 65 +/- 7 year (41-80), 75% were men. There were 11 REDO cardiac
      procedures. There were 15 symptomatic and 77 asymptomatic carotid artery
      stenosis, including 21 with bilateral carotid disease. Mean preop.LVEF was 57.4%
      (15-80%). Carotid TEA was performed under hypothermia (26 degrees C), preferably
      with beating heart after an equilibration period of 10 min. The overall mortality
      was 5.4% (5 patients). 4 of the deaths were reoperative cardiac surgery. Non
      fatal myocardial infarction occurred in 1 patient. Postop. neurological
      complications were diagnosed in 7 patients (8%), 3 transient and 4 permanent
      neurological deficits occurred. 33 patients had no post-operative complications
      at all and 25 patients had as only complication, transient arrhythmia. Follow-up
      revealed a 5-year survival rate of 83% and a cardiac event-free survival of 70%,
      without neurological events. We therefore conclude that simultaneous carotid TEA
      and cardiac surgery can be performed using controlled hypothermic cardiopulmonary
      bypass (26 degrees C), in experienced hands, with an acceptable mortality (5.4%)
      and low morbidity. Carotid TEA combined with two or more cardiac procedures has
      the highest mortality and morbidity and should be avoided.

PMID- 8653570
TI  - [Asymptomatic endocarditis? Are consequent histological studies useful in valve
      surgery?].
AB  - After aortic valve replacement for endocarditis, follow-up treatment with
      antibiotics is imperative. However, the question of how reliable preoperative and
      intraoperative diagnosis of endocarditis is in cases involving aortic defects is
      unclear. Of the 187 patients who underwent aortic valve replacement with or
      without coronary bypass surgery between June 1992 and June 1994, 150 exhibited no
      indications of endocarditis during preoperative and intraoperative examinations.
      In 17 cases (Group A) histological findings indicated acute florid endocarditis
      in 7 patients and chronic lymphocytic endocarditis in 10. Contrarily,
      histological examinations of 133 patients (Group B) revealed myxoid and/or
      sclerotic valve degeneration. WBC and LDH activity, examined one day
      preoperatively and on the first and second days postoperatively, exhibited no
      significant differences between the two groups, with the exception of LDH
      activity on the first postoperative day (Group A: 490 +/- 114, Group B: 403 +/-
      132, p = 0.04). Of the clinically asymptomatic patients requiring aortic valve
      replacement, 11.3% exhibited acute florid endocarditis upon histologic
      examinations. This subgroup cannot be identified based upon routine preoperative
      or postoperative laboratory tests or intraoperative observation. Histological
      examination of the aortic valve is useful for identifying the high percentage of
      otherwise nonidentifiable endocarditis. Further study will be required to
      determine therapeutic recommendations based upon such diagnosis.

PMID- 8653572
TI  - [32 years of Senning's correction for transposition of the great vessels].
AB  - Between 1962 and 1994 342 patients with transposition of the great arteries (TGA)
      were treated by atrial correction. Since 1992 the atrial switch operation is the
      treatment of choice for TGA. We reviewed our 32 year experience. Average age of
      the patients at operation was 69 months (7 days--8.5 years). 177/342 (52%)
      patients had a complex TGA: 74 patients with ventricular septal defect (VSD), 49
      patients with pulmonary stenosis (PS) and 54 with both (VSD and PS). The 30 day
      mortality was for the whole series 15.7%. In the last 4 years 7.5%. The actuarial
      survival rate for all patients was 88% after 10 years and 82% after 20 years. For
      simple TGA 91% after 10 years and 83% after 20 years, for complex TGA 84% and
      81%. The most important cause of death during our longterm observation were heart
      failure (19 patients) and sudden death (7 patients). Average follow-up for the
      whole group was 13.4 years. Most of the survivors are functionally symptom free
      (66% NYHA I) or they have slight symptoms (29% NYHA II). Only 5% were NYHA III or
      IV. Arterial switch operation has replaced the atrial correction for TGA.
      Nevertheless the longterm results after atrial correction remains encouraging.
      The main threat to the patients is the failure of the systemic ventricle.

PMID- 8653571
TI  - [Analysis of early and late results of surgically treated Wolff-Parkinson-White
      syndrome].
AB  - The results of surgical procedures for termination of Wolff-Parkinson-White (WPW)
      Syndrom were assessed in 59 patients undergoing operation between January, 1980
      and December, 1993. All cases of WPW were refractory to medical treatment and 14
      of 58 patients had one or several syncopes, and 4 of them had to be reanimated.
      The surgical treatment of these patients was a dissection of an accessory
      atrioventricular pathway. 15 patients required additional heart operation. A
      total of 60 accessory pathways were diagnosed preoperatively, 64 were located
      intraoperatively. The reoperation rate was 3% (2 patients) due to persistent WPW.
      Incidence of total AV block after the operation was 7% (4 patients). In the late
      postoperative stage, 12 patients developed supraventricular tachycardias, but
      none of these cases required a surgical treatment. The actuarial survival rate
      after 10 years was 100% and after 14 years 96%. We conclude that surgical
      dissection of accessory pathways offers a good alternative in cases of
      unsuccessful catheter ablative procedure or in cases of additional heart
      operation.

PMID- 8653573
TI  - [Thrombosis-resistant heparin-coated diffusion membrane oxygenators: an
      experimental study].
AB  - In the present study the thromboresistance of heparin-coated diffusion membrane
      oxygenators (Jostra, M 30) combined with heparin-coated venous reservoirs, tubing
      sets and arterial filters was investigated in six bovine experiments (70 +/- 5
      kg). The perfusion with reduced systemic heparin dose (100 IE/kg) body weight)
      was performed with activated clotting time over 180 seconds. The perfusion began
      with a blood flow of 31/min and was maintained during six hours. Clotting studies
      including blood platelet count, activated clotting time, fibrinogen (factor I),
      antithrombin III and fibrinopeptid A were performed before the operation and ten
      minutes, two hours and five and six hours after beginning of bypass. The venous
      and arterial saturation remained stable during the whole investigation. After ten
      minutes activated clotting time dropped from 619 +/- 114s to 203 +/- 15s after
      six hours (p < 0.05). The antithrombin III level changed significantly from 109
      +/- 11% to 95 +/- 16%. Factor 1 and fibrinopeptid A changes were not significant:
      from 1.6 +/- 0.3 g/1 to 1.5 +/- 0.3 g/1, and 3.0 +/- 1.4 ng/mL to 3.5 +/- 1.2
      ng/mL, accordingly. There were no mechanical defects and especially no plasma
      leakage. Slight sediments were found only in areas of stagnant blood flow. The
      investigated bypass circuit with reduced systemic heparinization seems therefore
      particularly appropriate for long-term perfusions.

PMID- 8653574
TI  - [Self-expanding endoluminal vascular prosthesis: experimental basis and in-vivo
      evaluation].
AB  - The present study investigates the physical properties and the in vivo
      application of in vivo of a self-expandable stent (Wallstent) with an
      incorporated sealant of microporous polyurethane. Measurements of diameter and
      length as a function axial load featured the data for the calculation for radial
      pressure. Porosity control was assessed in comparison to non gelatin-sealed
      knitted Dacron. 11 stents on a 11.5F catheter were inserted in the aorta of three
      minipigs and evaluated by pressure measurement and angiography. The coverage of
      the stent causes an increase of 0.05-0.1 bar of radial pressure. The graph
      received by calculations demonstrates the corresponding pressure for every given
      diameter of the stents. Porosity is similar to the Dacron graft. The patency-rate
      is 100%. Characteristics of this covered stents meet requirements of an
      endovascular prostheses. Exclusion of fistulas and small aneurysms seems to be
      possible.

PMID- 8653575
TI  - Hypoxic stress alone does not modulate endothelial surface expression of bovine E
      selectin and intercellular adhesion molecule-1 (ICAM-1).
AB  - Hypoxemia is a common event in many vascular diseases, especially vascular
      ischemia. Since endothelial cells of blood vessels are exposed to conditions
      within the vascular space and leucocytes play a key role in ischemia/reperfusion
      injury, we hypothesized that endothelial exposure to hypoxia may regulate
      expression of surface proteins important in leucocyte-endothelial interactions,
      such as E-selectin and intercellular adhesion molecule (ICAM-1). In this study,
      we used isolated bovine aortic endothelial monolayers to examine endothelial
      surface alterations of E-selectin and ICAM-1 induced by tumor necrosis factor
      alpha (TNF-alpha), lipopolysaccharide (LPS) and hypoxia using a whole cell enzyme
      linked immunosorbent assay (ELISA). Bovine endothelial exposure to TNF-alpha (50
      ng/mL) induced a time dependent increase (range 0-24h) in specific E-selection
      surface expression. Endothelial exposure to hypoxia alone (pO2 approximately 3
      mmHg, range 0-24 h), however, failed to elicit endothelial E-selectin expression.
      Endothelial exposure to LPS brought about a dose- and time-dependent (range 0.5
      ng/mL and 2-8 h) increase in specific ICAM-1 surface expression (max. 3.5 +/-
      0.15-fold increase over no cytokine control at 10 ng/mL, 4 h). Hypoxia (pO2
      approximately 3 mmHg, 8h), however, did not induce ICAM-1 surface expression over
      normoxia levels. IN CONCLUSION: i) bovine endothelial E-selectin and ICAM-1
      surface expression are regulated molecules, ii) hypoxia, per se, does not
      regulate surface expression of either E-selectin or ICAM-1. These results suggest
      that hypoxic endothelia may require additional external signals for generation of
      adaptive inflammatory responses.

PMID- 8653576
TI  - [Thoracic surgery for non-small cell lung cancer. Cost-benefit of its management
      in specialized intermediate care].
AB  - In 1989, we reorganized acute and rehabilitation cares for patients operated for
      non small cell lung cancer (NSCLC) in order to decrease costs by setting up a
      specialised intermediate care unit (SICU). This report deals with the
      postoperative complications and the total cost of these cares (SICU, acute and
      rehabilitation cares) as well as their cost/benefit. From 1990 to 1994, we
      performed 95 thoracotomies, 7 exploratory and 88 with lung resection (24
      pneumonectomies, 8 bilobectomies, 48 lobectomies and 8 segmentectomies or wedge
      resections). The postoperative staging was I in 52, II in 17, III a in 15, S III
      b in 2, IV in 2. Patients 30-days postoperative mortality was 2/95 (2.1%). We had
      in 11 patients respiratory complications (12%; 3 bronchopleural fistulas, 3
      pneumonias, 3 pneumothorax > 7 days, 1 empyema, 1 chronic hypoxemia), in 15
      patients cardiac arrhythmias which were easily controlled by medication and in 2
      general complications (1 hemiplegia, 1 transitory stupor state). The total
      duration of hospital stay, including SICU, acute and rehabilitative cares, was 32
      +/- 10 (3-70) days with a mean total cost of 14,722 Sfr. per case. In conclusion,
      surgery for NSCLC can be safely performed in intermediate cares without intensive
      care unit at low costs and with a low morbidity and mortality provided they are
      staffed by a specialised and well trained team.

PMID- 8653577
TI  - [Improvement of venous diameter in bypass surgery: initial applications of
      ultraflexible biocompound grafts in patients].
AB  - The use of varicose-ectatically altered veins in bypass surgery is unsatisfactory
      due to unfavorable flow dynamics and high closure rates. To date surgical repair
      possibilities to improve the flow profile of autologous vein bypasses have been
      limited. Using the patient's own veins to produce a biocompound graft, i.e. an
      ultraflexible hybrid prosthesis, is a simple method by which the surgeon can
      influence the profile and wall pressure of the bypass. The authors hope thus to
      improve the patency rate. When forming a biocompound graft, a vein is
      intraoperatively sheathed inside a fine ultraflexible metal mesh and the two
      joined with fibrin glue. The mesh hose is pulled over the entire length of the
      vein with the aid of an application set. Biocompound grafts were used as aorto
      coronary bypasses in 9 patients (5 women, 4 men) in whom the possibility of using
      alternative bypasses did not exist. In 2 patients with femoro-popliteal bypass
      procedure the autologous varicose-ectatically altered vein was used as a
      biocompound-graft. Aorto-coronary bypasses: at the time of discharge from the
      hospital all biocompound bypasses were patent. No perioperative myocardial
      infarctions were observed. No wound infections occurred. Femoro-popliteal
      bypasses: at time of discharge from the hospital all biocompound bypasses were
      patent. The results prove the simplicity and reliability of this method in
      difficult surgical cases. The biocompound graft offers the surgeon the
      possibility of using varicose-ectatic veins if alternative bypasses are not
      available.

PMID- 8653578
TI  - Purification and characterisation of L-DOPA decarboxylase from pharate pupae of
      Ceratitis capitata. A comparison with the enzyme purified from the white
      prepupae.
AB  - In this paper we describe the purification of L-DOPA decarboxylase (DDC) to
      homogeneity from the developmental stage just before the eclosion (pharate pupae)
      of Ceratitis capitata. The enzyme was found to have a mol wt of approximately
      100,000 and to be composed of two identical subunits (50,000 mol wt each).
      Polyclonal antibodies raised against the isolated enzyme reacted with the 50,000
      dalton subunit and precipitated enzyme activity. Furthermore, properties of the
      enzyme isolated from the pharate pupa stage, were compared with those of DDC
      purified from the white prepupa stage with respect to substrate specificity,
      response to polyclonal antibodies, behaviour towards different cations and
      dependence of enzyme activity on the concentration of pyridoxal phosphate.

PMID- 8653579
TI  - Phospholipid composition of erythrocyte membranes and plasma of mammalian blood
      including Australian marsupials; quantitative 31P NMR analysis using detergent.
AB  - The phospholipid classes of erythrocyte membranes and plasma from several
      domestic animals and marsupials were quantified by 31P NMR using detergents.
      Washed erythrocyte samples were thoroughly haemolysed by tip-sonication and
      dissolved in sodium cholate; plasma samples were dissolved in Triton X-100. The
      species studied were: common wombat (Vombatus ursinus), black-striped wallaby
      (Macropus dorsalis), bandicoot (Isoodon macrocarpus), Eastern grey kangaroo
      (Macropus giganteus), Tammar wallaby (Macropus eugenii), sheep (Ovis aries), goat
      (Capra hircus), cattle (Bos taurus), horse (Equus caballus), dog (Canus
      familiaris) and rabbit (Orytolagus caniculus). There were considerable species
      variations in the relative abundance of erythrocyte and plasma phospholipid
      classes. The variations may be attributed to the habitats and diets of the
      animals as well as to their phylogenetic differences.

PMID- 8653580
TI  - Juvenile hormone metabolism in the ovary, gut, head and carcass after blood
      feeding in the southern house mosquito, Culex quinquefasciatus.
AB  - The regulation of JH epoxide hydrolase, JH esterase and 1-naphthyl acetate (NA)
      esterase activity was studied in ovary, gut, head and carcass after blood feeding
      in Culex quinquefasciatus. The combined tissues had the greatest JH epoxide
      hydrolase and JH esterase activity from 24-36 hr after a blood meal. JH epoxide
      hydrolase activity per female was 2.1-, 1.8- and 1.1-times greater than the JH
      esterase activity at 24, 36 and 48 hr after blood feeding, respectively. JH
      epoxide hydrolase activity per until protein was also the major route of primary
      JH metabolism at most time points examined, and peak JH epoxide hydrolase
      activity per unit protein in the gut, head and carcass was approximately 2-5
      times the highest JH esterase activity per unit protein in corresponding tissues
      and 4-times the peak JH esterase activity in the ovary. The differential
      expression of JH epoxide hydrolase versus JH esterase in specific tissues and
      between tissues suggested that regulation of JH metabolism is tissue specific.
      Two isoelectric forms of JH esterase were found. The juvenoid, (RS)-methoprene,
      interfered with the regulation of JH esterase activity, but failed to change the
      activity levels of JH epoxide hydrolase and 1-NA esterase.

PMID- 8653581
TI  - The evolution of fibrillar collagens: a sea-pen collagen shares common features
      with vertebrate type V collagen.
AB  - The extracellular matrix of marine primitive invertebrates (sponges, polyps and
      jellyfishes) contains collagen fibrils with narrow diameters. From various data,
      it has been hypothesized that these primitive collagens could represent ancestral
      forms of the vertebrate minor collagens, i.e., types V or XI. Recently we have
      isolated a primitive collagen from the soft tissues of the sea-pen Veretillum
      cynomorium. This report examines whether the sea-pen collagen shares some
      features with vertebrate type V collagen. Rotary shadowed images of acid-soluble
      collagen molecules extracted from beta-APN treated animals, positive staining of
      segment-long-spacing crystallites precipitated from pepsinized collagen, Western
      blots of the pepsinized alpha1 and alpha2 chains with antibodies to vertebrate
      types I, III and V collagens, and in situ gold immunolabeling of ECM collagen
      fibrils were examined. Our results showed that the tissue form of the sea-pen
      collagen is a 340-nm threadlike molecule, which is close to the vertebrate type V
      collagen with its voluminous terminal globular domain, the distribution of most
      of its polar amino-acid residues, and its antigenic properties.

PMID- 8653582
TI  - Expression and induction of an immunochemically related class of glutathione S
      transferases in Daphnia magna.
AB  - The cytosolic glutathione S-transferases (GSTs) are dimeric enzymes that are
      responsible for the conjugation of glutathione to an electrophilic center of a
      variety of lipophilic compounds. The purpose of the present study was to
      characterize the GSTs of Daphnia magna with respect to enzyme multiplicity,
      molecular weight, isoelectric points, and immunochemical distinction and to
      determine the inducibility of these enzymes by the prototypical mammalian GST
      inducer, phenobarbital. GSTs were purified from crude cystosols prepared from
      daphnids by glutathione-sepharose affinity chromatography. SDS-polyacrylamide gel
      electrophoresis of the affinity purified GSTs revealed the presence of multiple
      subunits with molecular weights ranging from 26.9 to 30.2 kDa. Preparative
      electrofocusing separated GST activity into three major fractions having
      approximate isoelectric points of 4.5, 4.8 and 5.6. All of the catalytically
      active fractions contained a single protein band of the same molecular weight
      (30.2 kDa) during SDS-PAGE. A monoclonal antibody, prepared against the affinity
      purified GST proteins, recognized three distinct proteins separated during
      analytical-scale isoelectric focusing (pI 4.6, 4.7 and 4.8). These proteins may
      represent a class of GSTs distinct from the GST having a pI of 5.6. Treatment of
      daphnids with phenobarbital elevated both GST catalytic activity and
      immunodetectable protein. These results demonstrate that multiple
      immunochemically related proteins of the same molecular weight but varying
      isoelectric points are responsible for most of the GST catalytic activity with
      the substrate 1-chloro-2,4-dinitrobenzene.

PMID- 8653583
TI  - Nucleotide sequence of transferrin cDNAs and tissue-specific of the transferrin
      gene in Atlantic cod (Gadus morhua).
AB  - Atlantic cod (Gadus morhua) transferrin cDNAs were isolated from a liver cDNA
      library using a cod transferrin-derived polymerase chain reaction product as a
      hybridization probe. The composite nucleotide sequence of two overlapping clones
      was 2223 bp in length excluding the poly(A) sequence and was equivalent to 87% of
      the 3' end of the Atlantic salmon transferrin cDNA sequence. Comparison of the
      deduced amino acid sequence of cod, salmon, Xenopus and several mammalian
      transferrins revealed that the two fish sequences are more similar with respect
      to their amino acid sequence and the position of additions/deletions than to
      other vertebrate transferrins. Conservation of the iron-binding domains and
      cysteine residues involved in disulphide bridges indicates that all transferrins
      share similar tertiary structure and support the hypothesis that extant
      vertebrate transferrin genes were derived from a gene duplication before the
      divergence of fish, frogs and mammals. Cod transferrin mRNA was detected in both
      brain and liver RNA and to a much lesser extent in RNA isolated from kidney and
      heart in contrast to salmon and several other vertebrates in which the
      transferrin gene is not expressed in brain.

PMID- 8653584
TI  - Tissue distribution and characterization of a 30-kDa cysteine proteinase
      inhibitor from bovine skeletal muscle.
AB  - Gel chromatography on a Sephadex G100 column of a crude extract obtained from
      bovine diaphragma muscle separated four fractions (F-I, F-II, F-III and F-IV) in
      the range of 12-70 kDa that were active against either papain, trypsin or both.
      From the F-III fraction, a cysteine proteinase inhibitor was purified by two
      successive anionic exchange chromatographies on Q-Sepharose and Mono Q columns.
      The pooled active fraction had a Mw of approximately 30 kDa, and
      isoelectrofocusing revealed one band with a pI of 6.7. The papain-inhibiting
      activity was unaffected by dithiothreital or 2-mercaptoethanol treatment, and
      only one band was obtained after SDS-poly acrylamide gel electrophoresis under
      both reducing and non-reducing conditions. These results suggest that the 30-kDa
      muscle cysteine proteinase inhibitor did not contain disulphide bonds essential
      for activity and the protein was a monomer. This proteinase inhibitor is stable
      between 40 and 80 degrees C and pH 5-12. Furthermore, the 30-kDa inhibitor is
      stable to papain proteolysis. The tissue distribution of this inhibitor was
      investigated using double immunodiffusion and Western blot techniques that
      provided evidence for its presence in bovine heart, spleen, liver and lung and
      its absence in bovine plasma.

PMID- 8653585
TI  - Programmed cell death in the anuran tadpole tail requires expression of a cell
      surface glycoprotein.
AB  - Programmed cell death is generally perceived as a suicide process involving
      activation of an internal death program thought to be common to all cells. We
      have previously presented evidence supporting the view that, at least in the
      tadpole tail, programmed cell death may involve assassination by cytotoxic cells
      such as resident macrophages. In this report, we show that regression of tadpole
      tail slices in culture is blocked by tunicamycin and brefeldin A, demonstrating
      that the intracellular protein trafficking machinery must be intact. Regression
      is also blocked by concanavalin A and fucose, suggesting a requirement for a cell
      surface glycoprotein. These observations are consistent with our hypothesis that
      programmed cell death requires expression of specific markers on the surfaces of
      cells destined to die, identifying the cells bearing those markers as targets for
      destruction.

PMID- 8653587
TI  - Molecular cloning of an ecdysone receptor (B1 isoform) homologue from the
      silkworm, Bombyx mori, and its mRNA expression during wing disc development.
AB  - We reported the isolation and sequence of a clone encoding a putative ecdysone
      receptor B1 isoform of the silkworm, Bombyx mori. The predicted open reading
      frame encoded 543 amino acids, with 51%, 95% and 71% identities with the
      Drosophila melanogaster ecdysone receptor B1 isoform in the N terminal A/B
      region, DNA binding domain (C region) and ligand binding domain (E region),
      respectively. A single 6.2 kb message for the EcR gene was abundant in wing discs
      and fat bodies at the onset of metamorphosis. At the same stage, however, no or a
      tiny amount of mRNA was shown in posterior or middle silk glands, respectively.
      During the final instar, the mRNA expression in wing discs was maximal on the day
      of wandering. These data suggest the transcription of the Bombyx EcR gene is
      regulated in tissue-specific and stage-specific manner during metamorphosis.

PMID- 8653586
TI  - Structural and functional comparison of toxins from the venom of the scorpions
      Centruroides infamatus infamatus, Centruroides limpidus limpidus and Centruroides
      noxius.
AB  - Two novel toxins containing 66 amino acid residues each were isolated from the
      venom of the scorpions Centruroides infamatus infamatus and Centruroides limpidus
      limpidus, respectively. Their full amino acid sequences were determined.
      Comparison of primary structures showed that they share 97% similarity among
      themselves and 83% to that of toxin 2 from Centruroides noxius. The three toxins
      studied compete with each other for the same binding sites on membranes prepared
      from rat brain synaptosomes, suggesting that they are all beta-scorpion toxins.
      Toxin action was assayed into the microI-2 rat skeletal muscle Na+ channel
      heterologously expressed into Xenopus oocytes. All three toxins block this Na+
      channel in a similar fashion, without affecting inactivation, and showed IC50
      values in the micromolar concentration range.

PMID- 8653588
TI  - Sensitivity to platelet aggregation appears related to the lipoprotein profile
      and atherosclerosis risk in humans and across species.
AB  - Platelet aggregation sensitivity was assessed in nine species of animals,
      including humans, with disparate susceptibility to atherosclerosis and a wide
      range in their LDL/HDL profiles. Platelet aggregation sensitivity between species
      varied almost 20-fold. The most sensitive platelets were found in humans and
      rabbits, followed by squirrel and rhesus monkeys with the most resistant
      platelets in cats, hamsters, rats, cebus monkeys, and gerbils. Species platelet
      aggregation sensitivity correlated well with relative susceptibility to
      atherosclerosis. The relationship between LDL/HDL ratio and platelet aggregation
      was significant, both across species (r = 0.76, without cebus) and within species
      (r = 0.50 for humans).

PMID- 8653589
TI  - Urinary and plasma purine derivatives in fed and fasted llamas (Lama glama and L.
      guanacoe).
AB  - The changes in urinary and plasma purine derivatives in response to fasting and
      level of feeding in llamas were examines. In one experiment, four llamas were
      gradually deprived of feed within 3 days and then fasted for 6 days. Daily
      urinary excretion of purine derivatives decreased with feed intake and leveled on
      the last 3 days of fasting at 177 +/- 26 mumol/kg W0.75. Allantoin and uric acid
      comprised 71% and 15% of total purine derivatives, respectively, in both fed and
      fasted states, but hypoxanthine plus xanthine increased from 9% to 36%. Plasma
      concentration of allantoin declined with feed intake reduction, but those of uric
      acid (217 mumol/l) and hypoxanthine plus xanthine (27 mumol/l) remained
      relatively unchanged. Concentration of uric acid was higher than that of
      allantoin, probably due to a high reabsorption of uric acid in renal tubules,
      which was measured as over 90%. In a second experiment, the four llamas were fed
      at 860 and 1740 g dry matter/d in a crossover design. Urinary total purine
      derivatives excretion responded to feed intake (10.4 vs 14.4 mmol/d), although
      the observed differences did not reach significance. Compared with some ruminant
      species, it appears that the llama resembles sheep regarding the magnitude of
      urinary purine derivatives excretion but is unique in maintaining a high
      concentration of uric acid in plasma, which could be part of the llama's
      adaptation to their environment.

PMID- 8653590
TI  - Computer-aided comparison of the inhibition of arginase and nitric oxide synthase
      in macrophages by amino acids not related to arginine.
AB  - Macrophages contain arginase and an inducible nitric oxide (NO) synthase that use
      the same substrate, L-arginine, to produce nitric oxide and urea, respectively.
      Arginase was inhibited by various amino acids not related to L-arginine. These
      compounds were bound to the substrate binding site of the enzyme as supported by
      kinetic studies. Five binding sites were defined in this area by computer-aided
      analysis, and three complementary sites in a compound were sufficient to give an
      inhibitory character. NO synthase could not be inhibited by these compounds, but
      certain derivatives (e.g., putrescine or L-valinol) caused a marked and probably
      allosteric inhibition. The possible biological importance of these inhibitions in
      the tumoricid function of macrophages is discussed.

PMID- 8653591
TI  - Two types of parenchymal cells in the lung fluke Paragonimus ohirai (Digenea:
      Troglotrematidae) characterized by the cytochemistry of their mitochondria.
AB  - Morphology and respiratory function were studied in situ and in the isolated
      mitochondria of Paragonimus ohirai. Two types of parenchymal cells (i.e., Pc1 and
      Pc2 cells), whose mitochondria differ in terms of morphology and staining for
      cytochrome c oxidase activity, were found in fluke tissues. Enzymatic and
      spectrophotometric analyses of the isolated mitochondria showed that fluke
      mitochondria possess both aerobic and anaerobic respiratory chains. These results
      suggest that there are two mitochondrial populations in fluke parenchymal cells,
      one possessing an aerobic respiratory chain and the other an anaerobic
      respiratory chain.

PMID- 8653592
TI  - Low blood protein heterozygosity in zoo-bred hamadryas baboons.
AB  - An electrophoretic study of erythrocyte allozymes and serum proteins representing
      32 genetic loci in 32 hamadryas baboons (Papio H.hamadryas) from Cologne and
      Frankfurt zoos revealed biallelic polymorphism in phosphoglucomutase (PGM),
      mannose phosphate isomerase (MPI) and transferrin (Tf). Polymorphism amounted to
      P = 0.097 over 31 loci and observed heterozygosity to H(o) = 0.011, indicating
      significant reduction from the respective gene diversity parameters encountered
      in free-living hamadryas baboons. Polygynous mating reduced numbers of
      heterozygotes at the Tf and the PGM-II loci significantly below Hardy-Weinberg
      expectations. This results support the importance of active genetic management in
      programmes for captive breeding and species conservation.

PMID- 8653593
TI  - Accumulation of gossypol enantiomers in ovine tissues.
AB  - Tissue residue levels of gossypol enantiomers in cottonseed-fed and lethally
      intoxicated lambs were determined by the high-performance liquid chromatography
      ultraviolet detection method. Gossypol was derivatized with (+)-2-amino-1
      propanol and separated with a reversed-phase C18 column and the elution of
      analytes was monitored at 254 nm. The highest residue level was found in the
      liver tissue (318-416 ng total gossypol/mg dry tissue), and the residue of (-)
      gossypol was higher than (+)-gossypol in the heart, muscle and spleen. The
      detection limit was 2 ng, and the detector response of gossypol-amine adducts was
      linear between 2 and 100 ng enantiomers.

PMID- 8653594
TI  - Lipoprotein lipase and glucose-6-phosphate dehydrogenase activities in bovine and
      ovine adipose tissue incubated for 7 days: effects of insulin and/or
      dexamethasone.
AB  - The in vitro regulation of lipoprotein lipase (LPL) and glucose-6-phosphate
      dehydrogenase (G6PDH) activity in bovine and ovine adipose tissue was
      investigated. Adult non-lactating non-pregnant cows (n = 5) or ewes (n = 5) were
      given limited amounts of feed for 8 or 10 days and then overfed for 10 (ewes) or
      21 (cows) days. Perirenal adipose tissue explants were incubated for 2, 4 or 7
      days. Regardless of the experimental conditions, the activity of LPL and G6PDH
      after 2 days of incubation was lower than in fresh tissue. Insulin significantly
      increased LPL activity in bovine but not in ovine adipose tissue, and it had no
      effect on G6PDH activity in the two species. Dexamethasone addition to the
      insulin-supplemented medium significantly increased LPL activity in ovine adipose
      tissue, whereas it was decreased in bovine adipose tissue on days 4 and 7.
      Moreover, dexamethasone addition to the insulin-supplemented medium did not
      change G6PDH activity in the two species on day 2, whereas it was increased in
      bovine and ovine adipose tissue on days 4 and 7. Therefore, the effects of
      insulin and/or dexamethasone on LDL and G6PDH differed with ruminant species and
      incubation time.

PMID- 8653595
TI  - Activation of renal renin by a protein plasma fraction: a novel enzymatic
      mechanism.
AB  - A 3-fold increase in active renin was found after a kidney cortex extract was
      incubated with plasma from either normal or nephrectomized rats (0.34 +/- 0.04 to
      1.34 +/- 0.08 and 1.60 +/- 0.06 micrograms Angiotensin I/mg tissue/hr,
      respectively). A plasma protein that activates renal renin was purified 900-fold.
      Purification of the protein was achieved by a combination of ammonium sulfate
      fractionation, molecular filtration on Sephacryl S-200 HR and ion-exchange
      chromatography on Mono Q HR 5/5 associated to an fast performance liquid
      chromatography (FPLC) system. The protein shows a molecular weight of
      approximately 54,000 Da. Renin activation was not inhibited by serine protease
      inhibitors, such as phenylmethyl sulfonylfluoride, aprotinin, soybean trypsin
      inhibitor and N-tosyl-L-phenylalanine chloromethyl ketone or by the cystein
      protease inhibitors N-ethylmaleimide and leupeptin. By using enzyme inhibitors,
      it was found that the activation process is not mediated by kallikrein, plasmin,
      tonin, cathepsin B or trypsin-like enzymes. From these results, we conclude that
      there is in circulating plasma a previously unidentified enzyme capable of
      activating inactive kidney renin. However, the possibility that this protein acts
      by activating the renin-substrate reaction cannot be dismissed.

PMID- 8653596
TI  - [Effectiveness of clonazepam in depressive disorders].
AB  - Clonazepam was administered to 55 patients with depressive disorder (DSM-III-R)
      in average minimal and maximal doses of 2.40 and 6.54 mg/day for 21-28 days.
      Complete remission was achieved in 60% patients (Serejskij AB, drop of global
      HAMD and FKD score by more than 50%), in particular in case of concurrent
      anxiety. A marked antidepressive effectiveness of clonazepam was suggested also
      by a drop of the total HAMD and FKD score already after the first week of
      treatment. All items of the HAMD and FKD scale were significantly positively
      influenced with the exception of agitation, somatic anxiety, insight,
      paranoidity, obsession respectively hypochondriasis and paranoidity. No
      correlation was found between the effect of clonazepam and sex, the patients'
      age, duration of the depressive disorder, period of the index episode and
      severity of depression. As to undesirable effects, the authors recorded fatigue
      and sleepiness (40%) and hypotension (20% of the patients), in particular at the
      onset of treatment and after larger daily doses. In 3/10 bipolar patients a
      switch to hypomania was observed.

PMID- 8653597
TI  - [Psychodynamics of aggression in neurotic structures].
AB  - The authors describe the psychodynamics of aggressive attitude and behaviour in
      schizoid, depressive, obsessive and hysterical neurotic personality structures
      (personality disorders) as well as in different psychosomatic syndromes. Outline
      of development of views regarding aggressiveness in deep psychology and important
      conclusions of ethological research. Implications for therapeutic practice and
      the solution of relationships between the therapist and patient in the
      therapeutic team.

PMID- 8653598
TI  - [Pharmacotherapy in resistance depression].
AB  - This article reviews pharmacological approaches used to overcome treatment
      resistance in patients with serious unipolar depressive disorders. Resistant
      depression is defined as depression the symptoms of which persist despite
      adequate treatment. Main causes of unsuccessful treatment are incorrect
      diagnosis, inadequate duration of treatment or inadequate dosage. Other reasons
      for resistance are also discussed in the article. There are three basic
      strategies in treatment of resistance: optimization of treatment, substitution
      replacement of the current treatment with a different one, combination-concurrent
      use of several treatments to enhance the effect. Treatment recommendations
      related to these strategies are discussed.

PMID- 8653599
TI  - [Plasma levels of clozapine].
AB  - At the beginning some rules and conclusions concerning neuroleptic blood levels
      are mentioned. Clozapine blood levels are discussed in a more detailed way. A
      survey of the most important studies about the relation between therapeutic
      effect and blood levels of clozapine is given. Finally, the author presents his
      own experience with blood levels of clozapine in patients on maintenance
      treatment with the aim to find the lowest effective dose.

PMID- 8653600
TI  - [Psychological therapy in children affected by the war in Bosnia].

PMID- 8653601
TI  - [Instructions of Empress Maria Teresa proscribing child homicide].

PMID- 8653603
TI  - [The Spanish course of the American Academy of Neurology].

PMID- 8653602
TI  - [Abstracts in medical journals in Spanish].

PMID- 8653604
TI  - [Interobserver variability in the evaluation of functional systems and Kurzke
      expanded disability status scale in a multiple sclerosis patient].
AB  - Changes in the progression of disability is still the main variable measured in
      clinical trials involving patients with multiple sclerosis (EM). The amplified
      scale of the state of disability (EEDA) of Kurtzke continues to be the most
      widely used scale. One of the most important limitations of the EEDA is
      interobserver variability. The object of our study was to find the interobserver
      variability between members of our EM unit in patients with EEDA between 0 and
      3.5 when applying functional systems (SF) and EEDA. Seven patients with recurrent
      remittent EM (EEDA 0-3.5), participating in a multicentric trial with natural
      beta-interferon, were assessed monthly for 12 months by two of four neurologists.
      The SF were assessed and the EEDA applied separately and without knowing the
      former. 80 paired examinations were made. Complete concordance of SF was only
      seen when a variation of 2 points was allowed, while it was very high for a
      variation of 0 and 1 points. Complete concordance for EEDA was seen in 36.6% of
      the cases and only in 11% was there discordance of 1 or 1.5 points. The average
      variability of EDSS was 0.39. There was greater variability when the two scores
      were at different levels of incapacity.

PMID- 8653606
TI  - [Validation of Allen's scale for the diagnosis of stroke].
AB  - INTRODUCTION: The importance of cerebrovascular pathology demands the most exact
      and complete diagnosis possible, by general physical and neurological examination
      and complementary techniques including computerized tomography (CT). Without CT,
      diagnosis may be delayed, for which reason such authors as Allen have put forward
      scales which by means of diagnostic scoring distinguish between stroke types.
      AIM: To validate the Allen scale as opposed to CT scan in a series of patients
      suffering from haemorrhagic and ischaemic stroke. MATERIALS AND METHOD: Sixty-two
      consecutive hospitalized patients suffering from stroke were studied, who all
      underwent CT scan within fifteen days of admission. RESULTS: The group consisted
      of 62 patients, 33 males (53%) and 29 females (47%) having an average of 70.2 +/-
      11.2 years. The most frequent type of stroke was ischaemic (63%) as opposed to
      haemorrhagic (37%). Globally for all strokes we obtained the following results:
      Sensitivity (S) = 61%, Specificity (Sp) = 40%, positive predictive value ( + PV)
      = 84% and negative predictive value (-PV) = 17%. For ischaemic stroke the results
      were as follows: S = 76%, Sp = 66%; +PV = 67% and -PV = 76%. Finally for
      haemorrhagic stroke the results were S = 43%; Sp = 100%; +PV = 100% and -PV =
      75%. CONCLUSIONS: The Allen scale has not proved to be a valid instrument in
      stroke diagnosis due to its low sensitivity and specificity especially in cases
      of haemorrhagic stroke.

PMID- 8653605
TI  - [A descriptive epidemiological study of a neurological outpatient clinic].
AB  - OBJECTIVE: To evaluate the clinical, diagnostic, therapeutic and functional
      aspects of a Neurology Outpatient Clinic. MATERIAL AND METHOD: An epidemiological
      survey was made of 552 neurology patients first seen in the Neurology Outpatient
      Clinic during a three month period. RESULTS: There was a predominance of women
      (57.6%). The average age was 45.1 years in both sexes. 84.7% of the patients were
      sent by their family doctor. There was an average wait of nine days.
      Complementary investigations were asked for in 56% of the patients (cerebral CT
      scan in 13.7%, MR in 5%, EEG in 21%, ENG-EMG in 5.7%). The diagnostic groups were
      headache 30%, followed by vascular pathology (11.7%); psychiatric, syncopes,
      extrapyramidal syndromes, epilepsy and vertigo each made up 6-7% of the total.
      53% of patients attending for the first time received no treatment. The most
      commonly used drugs were: calcium antagonists (20%), antidepressives (15%),
      antiepileptics (10%), platelet antiaggregants (8.4%), anti-Parkinson drugs (7.3%)
      and beta-blockers (4.6%). CONCLUSIONS: Since there is a great demand for
      neurological attention (as with other specialties) more neurologists are
      required. Headache was the commonest reason for consultation. Improved selection
      of the patients, particularly the psychiatric patients and those with
      psychosomatic pathology, would considerably reduce the number of patients seen.

PMID- 8653607
TI  - [Neuropsychological evaluation of a case of organic personality disorder due to
      penetrating brain injury].
AB  - In this paper, an organic personality disorder case by penetrating brain injury,
      predominantly localized in the right frontal lobe, is presented.
      Neuropsychological and neuroimaging (CT scan studies) were performed. We assessed
      the main cognitive aspect: orientation, attention, memory, intelligence,
      language, visual-spatial functioning, motor functioning, executive functioning
      and personality. The results obtained, point out disorders in the patient's
      behavior and in the executive functions. Likewise, other cognitive functions as:
      attention, memory, language and visual-spatial functioning, show specific
      deficits.

PMID- 8653608
TI  - [Cephalic fibromuscular dysplasia and stroke in infancy: a case report] and
      review of literature].
AB  - Fibromuscular dysplasia (DFM) is an arterial lesion of unknown aetiology which
      affects medium sized arteries and is multifocal. In the cephalic form
      extracranial arteries may also be affected; the usual clinical finding is an
      ischaemic stroke related to arterial stenosis or obstruction, or to arterio
      arterial thrombo-embolism. Diagnosis of DFM in infancy is exceptional, and unlike
      the adult forms, affectation of the intracranial arteries is usual. Angiography
      of the cranial vessels is the most important diagnostic investigation, showing
      focal lesions with circular stenosis alternating with dilatations of the arterial
      wall and described as ?a pile of coins'; or there may be stenosis and obstruction
      of extracranial and intracranial arteries. We describe the case of an eleven-year
      old girl who presented with a motor deficit of sudden onset in relation to a
      parietal infarct, and in whom angiography of the supra-aortic and intra-cranial
      trunks showed evidence compatible with DFM of the extracranial internal carotid
      artery and carotid syphon. We also review the literature of all cases of
      infantile DFM published to date.

PMID- 8653609
TI  - [The organic and the functional, the neurotic and the psychologic, the endogenic
      and the exogenic].

PMID- 8653610
TI  - [Cerebellar infarction].

PMID- 8653611
TI  - [Management of intracranial hemorrhage].

PMID- 8653612
TI  - [Male sexual dysfunction: neuroanatomy, neurophysiology and semiology].

PMID- 8653613
TI  - [Disorders of erection and ejaculation. Diagnosis and management].

PMID- 8653614
TI  - [Diagnosis and treatment of the neurovegetative disorders: autonomic
      neuropathies].

PMID- 8653615
TI  - [Peripheral neuropathies: diagnosis and treatment].

PMID- 8653616
TI  - [Organization of a sleep center and sleep laboratory].

PMID- 8653618
TI  - [Neonatal seizures: diagnostic and therapeutic controversies].

PMID- 8653619
TI  - [Neuroepidemiology: study of epidemic forms of neuropathies].

PMID- 8653617
TI  - [Advances in the diagnostic and treatment of infantile epilepsy].

PMID- 8653620
TI  - [Nervous system infections by retroviruses].

PMID- 8653621
TI  - [New treatments for multiple sclerosis].

PMID- 8653623
TI  - [Pseudoaneurysm of galen's vein secondary to cerebral arterio-venous
      malformations].

PMID- 8653622
TI  - [Coob's syndrome: a new case].

PMID- 8653624
TI  - [Meningoencephalitis by Coxiella burneti].

PMID- 8653626
TI  - [Anterior ischemic optic neuropathy and increased intraocular pressure].
AB  - PURPOSE: To find out the occurrence of an increased intraocular pressure (IOP) in
      the anterior ischemic optic neuropathy (AION). METHODS: We studied 17 patients
      (10 men, 7 women, mean age 62.8 years) with AION. We measured the IOP at the
      beginning of observation and during the systemic corticosteroid therapy. RESULTS:
      We found an increased IOP in 4 patients (23.5%). CONCLUSIONS: The occurrence of
      an increased IOP in AION patients is higher than in a normal population. The
      increased IOP seems to be one of possible risk factors in the pathogenesis of
      AION.

PMID- 8653625
TI  - [Naclof in the treatment of chronic non-infectious conjunctivitis].
AB  - The group of 60 patients suffering from chronic non-infected reaction of
      conjunctivits, showing irritation, conjunctival hyperemia, pain and photophobia,
      have been treated in the open observational clinical trial comparing the
      efficiency, safety and local tolerance of diclofenac sodium eye drops 0.1%
      (Naclof) versus dexamethasone eye drops (Dexamethasone oph. 0.1%) during a period
      of 30 days. Both medications were locally well tolerated. Naclof caused some
      slight temporary burning slightly more frequently than dexamethasone but the
      difference was not statistically significant (Naclof 89.7% tolerability and
      Dexamethasone 89.1% tolerability). The two drugs were equally effective in the
      treatment of chronic non-infected conjunctivitis. All the patients have shown a
      gradual improvement of the symptoms as well as of the objective sings. The
      dexamethasone group showed an increase in intraocular pressure at the third and
      fourth visit. However, these differences are not statistically significant
      either.

PMID- 8653627
TI  - [Anterior ischemic optic neuropathy after electric injury].

PMID- 8653628
TI  - [Primary intraocular lens implantation after laser therapy in active diabetic
      retinopathy].
AB  - The author presents an account of the results and complications of cataract
      operations with primary implantation of a posterior chamber intraocular lens in
      10 eyes of 8 patients suffering from preproliferative diabetic retinopathy,
      partly treated by laser. After operation in nine eyes the visual acuity improved
      during a mean follow-up period of 22.7 months. As to postoperative complications,
      a late fibrinous reaction was important (4x posterior synechia of the iris, incl.
      iris capture syndrome in one case with subsequent secondary glaucoma). In three
      eyes within one year secondary fibrotic cataract developed, in one it was
      necessary to perform Nd-YAG laser membranotomy. In none of the eyes so far after
      supplementary laser coagulation progression of diabetic retinopathy was recorded.
      The authors recommend to carry out maximum laser coagulation of the retina before
      operation of the cataract, to remove during operation the total mass of the lens,
      to carry out preventive basal iridectomy and to complete panretinal laser
      coagulation as quickly as possible after operation.

PMID- 8653629
TI  - [Trabeculectomy with releasable sutures: initial experience].
AB  - The authors present an account on their first results of trabeculectomy with
      releasable sutures, as described by Osher. The intraocular pressure before
      operation was on average 21.7 mm Hg (23-40 mm Hg). During the last visit (on
      average 2.8 months after operation) it was 13.5 mm Hg (13-15 mm Hg), incl. six
      eyes without treatment. Only in two eyes during the early postoperative period a
      shallower anterior chamber was observed. The authors recommend more extensive use
      of the technique of releasable suture in trabeculectomy.

PMID- 8653630
TI  - [The Bratislava International Eye Bank--a member of the International Federation
      of Eye Banks].
AB  - The International Eye Bank in Bratislava has assembled during its two-year
      activities 1007 corneae with a 2mm scleral margin by excision performed in the
      donor in situ, 11 total eye-balls and 43 sclerae. From this total number 1331 eye
      tissues had to be eliminated because of serum positivity (115 HBsAg, 12 HCV, 2
      HIV 1,2 + HCV + HBsAg, 2 HBsAg + HCV, 2 HIV 1.2 + HBsAg). The most frequent cause
      of death in donors of corneae were carcinomas, injuries and cerebro- and
      cardiovascular diseases. Corneal grafts are stored at a temperature of +2 degrees
      C to +6 degrees C in Optisol GS medium. The most frequent indication for
      keratoplasty in Slovakia was keratopathia bullosa (28.6%), keratoconus (23.9%)
      and leukoma corneae (18.7%).

PMID- 8653631
TI  - [Contrast sensitivity].

PMID- 8653632
TI  - [Theoretical basis of error-free biometry].

PMID- 8653633
TI  - [The Molteno implant].
AB  - The authors describe their experience with Molteno implants in 21 patients. The
      most frequent types of glaucoma were congenital glaucoma--5 times--and glaucoma
      associated with pseudophakia--5 times. Before the implant as many as four
      operations of one eye were performed, in the whole group with Molteno implants 28
      operations had preceded, mostly trabeculectomies and cyclocryocoagulations. As to
      postoperative complications, expulsive haemorrhage on the first night after
      operation was most serious. The follow-up period is 1-15 months, on average 7.7
      months. The intraocular pressure before operation was on average 35.8 mm Hg, on
      discharge 9.7 mm Hg and during the last check-up examination (19 eyes) 19.1 mm
      Hg. It was under 21 mm Hg in 10 eyes, i.e. 52.6%, during the last check-up
      examination. Re-operations were made five times (26.3%). As compared with values
      before surgery, vision deteriorated in three eyes, incl. two because of
      complications of diabetes. The Molteno implant is an effective procedure in the
      treatment of complicated and refractory cases of glaucoma in high-risk eyes.

PMID- 8653634
TI  - Is the problem private care or managed care?

PMID- 8653635
TI  - Is the problem private care or managed care?

PMID- 8653636
TI  - Sex, lies and androgen insensitivity syndrome.

PMID- 8653637
TI  - Sex, lies and androgen insensitivity syndrome.

PMID- 8653638
TI  - Sex, lies and androgen insensitivity syndrome.

PMID- 8653639
TI  - Sex, lies and androgen insensitivity syndrome.

PMID- 8653640
TI  - Sex, lies and androgen insensitivity syndrome.

PMID- 8653642
TI  - Helping patients stop smoking: confrontation or caring?

PMID- 8653644
TI  - Cervical cancer screening: are the 1989 recommendations still valid? National
      Workshop on Screening for Cancer of the Cervix.
AB  - Although screening for cervical cancer has been shown to be effective in reducing
      the morbidity and mortality associated with this disease, and despite many
      attempts to encourage the development of provincial programs, as of 1995 no
      province had a comprehensive screening program for cervical cancer. Participants
      at the Interchange '95 workshop, held in Ottawa in November 1995, reviewed the
      recommendations of the 1989 National Workshop on Screening for Cancer of the
      Cervix and identified factors that have impeded their implementation.
      Participants discussed the need for comprehensive information systems, quality
      control and strategies to increase recruitment of unscreened and underscreened
      women. They concluded that the formation of a Cervical Cancer Prevention Network
      involving key stakeholders will facilitate the development and implementation of
      provincial programs to ensure optimal screening. They agreed that, in the
      interim, recommendations for practising physicians should remain as they were
      following the 1989 workshop.

PMID- 8653643
TI  - Prevention. How much harm? How much benefit? 2. Ten potential pitfalls in
      determining the clinical significance of benefits.
AB  - A preventive program is only of value if it has proven benefits that outweigh any
      adverse consequences; unfortunately, determination of the clinical significance
      of reported benefits is not always easy. The first article of this series
      discussed the confusion caused by reporting results in terms of relative rates.
      In this article, 10 other pitfalls that may lead to misunderstanding of the
      degree of benefits are reviewed. These pitfalls are: the type of outcome chosen
      (surrogate v. clinically significant), the risk level in the population screened,
      the interval between the intervention and the benefit, the duration of
      intervention required to achieve the benefit, the overshadowing of one benefit by
      another, the application of a benefit for one variant of a disease to another
      variant, lower benefits in community settings than in clinical trials,
      publication bias, preferential citation of studies showing beneficial effects and
      "false-negative" results of studies. These pitfalls are illustrated through
      examples from the current medical literature.

PMID- 8653645
TI  - A survey of population-based drug databases in Canada.
AB  - OBJECTIVE: To identify the population-based drug databases in Canada and to
      determine their comprehensiveness and accessibility for performing
      pharmacoepidemiologic and outcomes research. DESIGN: Survey (four-part mailed
      questionnaire). SETTING: Public and private third-party drug plans across Canada.
      PARTICIPANTS: All provincial and territorial drug plan or pharmacare managers as
      well as selected private plan managers including health benefit consultants,
      group insurers and claims adjudicators/pharmacy benefit managers (CA/PBMs).
      OUTCOME MEASURES: Patient, drug and pharmacy information; potential for
      electronic linkages to other provincial databases (e.g., physician, hospital,
      vital statistics); accessibility of information; population profile. RESULTS: Of
      the 32 recipients of the questionnaire 29 (91%) responded and 18 (56%) completed
      the survey. Most databases were reported to contain patient information (e.g.,
      patient identification number, age, sex and medication history) and prescription
      drug information (e.g., drug identification number, strength, quantity and cost).
      Six provinces and one territory reported the capability to link to other
      databases (e.g., hospital and physician databases). One CA/PBM reported some
      links to selected long-term disability data. All of the government databases
      except those in British Columbia and the Yukon Territory allowed use of the data
      for research purposes. Manitoba and Saskatchewan included all residents of the
      province in their database; the others included selected groups (e.g., residents
      65 years of age or older, people on social assistance or people covered by
      private group insurance). CONCLUSION: A number of public and private population
      based databases are available for use in pharmacoepidemiologic and outcomes
      research.

PMID- 8653646
TI  - Why is there no progress against cervical cancer?
AB  - The author reflects on the disheartening report given by Dr. E. Jean Parboosingh
      and associates on Canadian screening programs for cervical cancer (see pages 1847
      to 1853 of this issue). Although cancer of the cervix is one of the few
      preventable forms of cancer, little progress has been made toward the
      establishment of programs to control this disease. Barriers to progress include a
      lack of priority given to women's health issues, insufficient public awareness of
      cervical cancer, the absence of vocal lobby groups, poor understanding of the
      limitations of secondary prevention, uncertainty about professional jurisdiction
      and the financial commitment of government, a tendency for minutiae to deflect
      attention from essential aims and the sheer complexity of the task of prevention
      and control. Unless these barriers are overcome it is unlikely that there will be
      much progress toward the eradication of cervical cancer in Canada.

PMID- 8653647
TI  - The Ku autoantigen: cast in a new light.
AB  - With his associates at the University of Ottawa, Dr. Robert Hache has
      demonstrated that the Ku autoantigen, a protein that plays a role in DNA repair
      and in immunoglobulin gene recombination, also modifies the action of steroid
      hormones. This finding has potential implications for the treatment of tumours
      whose growth is influenced by steroid hormones. The researchers suggest that Ku
      could be involved in the control of gene expression through a mechanism involving
      protein phosphorylation. They hope that a better understanding of the role Ku
      plays in many cellular processes may improve our understanding of autoimmune
      diseases, diseases of immune deficiency and cancer.

PMID- 8653648
TI  - Internet addiction: a new disorder enters the medical lexicon.
AB  - The latest consequence of the information age may be addiction to the Internet. A
      psychologist who has established the Centre for Online Addiction in the US says
      the disorder causes the same type of social problems as other established
      addictions. Michael OReilly went on line to find physicians interested in
      discussing potential problems posed by the Internet.

PMID- 8653649
TI  - McGill-trained MD, experiment give June 20 shuttle flight strong Canadian
      flavour.
AB  - Family physician Robert Thirsk, an original member of the Canadian Space Agency's
      astronaut program, will be part of the seven-member crew when the space shuttle
      Columbia lifts off from Florida's Kennedy Space Centre June 20. In this special
      report, the 1982 McGill graduate outlines some of the physiologic and materials
      science experiments the crew will conduct. Thirsk, a payload specialist and crew
      medical officer, thinks the findings could have a significant impact on future
      space missions, medicine and the biotechnology industry.

PMID- 8653650
TI  - CMPA not alone in pursuing huge reserves, CMAJ survey of US firms reveals.
AB  - Although Canada and the US are two separate worlds when medical malpractice is
      considered, actuaries across North America are looking into their crystal balls
      in an attempt to set reserves for uncertain future claims. Given the relatively
      low rate of litigation in Canada, some feel the Canadian Medical Protective
      Association is hoarding cash as it continues to raise premiums even though it has
      close to $1 billion in reserves. However, some experts suggest that this is just
      a prudent way to do business in an unpredictable environment. Milan Korcok looks
      at the situation facing physicians on both sides of the border.

PMID- 8653651
TI  - Collaborative care receives stamp of approval in CMA, CNA study involving
      HIV/AIDS.
AB  - The CMA wants to work with national health care groups, such as the Canadian
      Nurses Association (CNA), to explore ways providers can work collaboratively to
      provide quality health care. A joint working group of the CMA and the CNA
      recently examined collaborative care, focusing on examples provided in HIV/AIDS
      care. The group developed principles to help people work collaboratively in a
      variety of settings.

PMID- 8653652
TI  - Pathophysiology of coronary artery disease.
AB  - Atherogenic risk factors provoke chronic injury to the endothelium in certain
      parts of the arterial tree leading to dysfunctional endothelium. Lipid
      accumulation, macrophage formation, and smooth muscle cell proliferation are key
      events in the initial slow progression of atherosclerotic lesions (phase 1). If
      extracellular lipid accumulation predominates, atherosclerotic process progresses
      into a more clinically relevant, advance lipid-rich lesion (phase 2)--the
      pathogenic basis for plaque rupture and thrombus formation. Small plaque fissures
      and mural thrombus formation may be responsible for the rapid, clinically silent
      progression of lesions (phase 3). Plaque rupture with large thrombus formation
      may be responsible for acute coronary syndromes (phase 4). Alternatively, if
      smooth muscle cell proliferation and collagen matrix synthesis predominate,
      atherosclerotic lesions may progress into advanced, stable sclerotic lesions
      (phase 5).

PMID- 8653653
TI  - Stress testing for coronary artery disease in the elderly.
AB  - The elderly constitute an increasing percentage of patients evaluated and treated
      for coronary artery disease. Clinical and noninvasive evaluation are important in
      both the diagnosis and prognosis of coronary disease in the elderly, and stress
      testing is an important part of that evaluation. For older individuals capable of
      vigorous treadmill or cycle exercise, the exercise electrocardiogram, either
      alone or combined with radionuclide or echocardiographic imaging, remains an
      excellent diagnostic and prognostic tool. For the large percentage of elderly
      patients unable to perform adequate exercise, pharmacologic stress testing with
      dipyridamole, adenosine, or dobutamine is a valuable alternative. The clinician's
      challenge is to choose the most appropriate cardiac stress test for his or her
      patient from among the many alternatives available. Future studies comparing the
      accuracy and cost-to-benefit ratio of various stress tests with regard to the
      elderly will help achieve this goal.

PMID- 8653655
TI  - Therapy for acute myocardial infarction.
AB  - Acute myocardial infarction occurs with increasing frequency with advancing age,
      and older patients with acute MI are at increased risk of a variety of
      complications including congestive heart failure, arrhythmias and conduction
      disturbances, myocardial rupture, cardiogenic shock, and death. Older patients
      thus comprise a high-risk subgroup of the MI population who consequently may
      derive substantial benefit from appropriately selected therapeutic interventions.
      At the same time, many interventions are associated with increased risks in the
      elderly, so that individualization of treatment is essential in all patients.
      Optimal therapy is thus based on a careful risk-benefit assessment of the
      available treatment options in conjunction with information on patient
      preferences and other relevant factors. Though many therapeutic trials of
      patients with acute MI have either excluded elderly patients or enrolled too few
      older subjects to permit definitive conclusions, sufficient data are available to
      make specific recommendations in several areas. As shown in Table 6, therapies of
      proven value in the acute-phase treatment of elderly patients with MI include
      aspirin and thrombolysis. Intravenous beta blockers are likely to be of benefit
      as well, and long-term oral beta blockade after MI is clearly beneficial. ACE
      inhibitors are of proven value in the long-term management of patients with left
      ventricular dysfunction (ejection fraction less than 40%), but initiation of an
      ACE inhibitor should probably be delayed for 48 to 72 hours in most cases. The
      role of other agents including nitrates, magnesium, diltiazem, and verapamil
      requires further clarification, but anti-arrhythmic drugs and dihydropyridine
      calcium antagonists should generally be avoided in the absence of specific
      indications for their use. Finally, though the role of catheterization and
      revascularization in elderly patients with acute MI requires additional study,
      current data indicate that age alone should not be considered a contraindication
      to these procedures. As the age of the population continues to rise, the number
      of older patients at risk of acute MI also increases. Though progressively more
      sophisticated interventions may ultimately result in sizable reductions in post
      MI morbidity and mortality, given the high risk of adverse outcomes in this
      population the best treatment is prevention. Thus, the greatest potential for the
      future, as well as the greatest challenge, is to develop more effective
      strategies for preventing atherosclerosis and for conquering the epidemic of
      coronary heart disease.

PMID- 8653654
TI  - Medical management of stable angina and unstable angina in the elderly with
      coronary artery disease.
AB  - Coronary artery disease is a major clinical problem in the elderly. This article
      discusses the medical management of stable and unstable angina pectoris. A review
      of the general measures and drug therapy used to treat these disorders,
      especially as they relate to the elderly patient are presented. In addition, new
      insights into the pathophysiologic mechanisms of chronic stable angina and
      unstable angina are reviewed.

PMID- 8653656
TI  - Management of postmyocardial infarction in the elderly patient.
AB  - Elderly patients have a significantly higher mortality and morbidity compared
      with younger patients in the postmyocardial infarction period and thus, with the
      appropriate management have a greater potential for benefit compared with younger
      patients. It has been shown in the large randomized trials that elderly patients
      with acute myocardial infarction benefit significantly from administration of
      beta-blocking agents and angiotensin-converting enzyme inhibitors. Aspirin and
      warfarin sodium (Coumadin) have been shown to benefit patients of all age groups.
      Secondary prevention with cessation of smoking, use of lipid-lowering agents,
      treatment of hypertension, and estrogen therapy in the postmenopausal woman have
      been shown to be effective. Elderly patients, therefore, who are free of general
      noncardiac disability and who can be expected to live meaningful lives should be
      offered a comprehensive program to reduce their cardiac morbidity and mortality
      after discharge following acute myocardial infarction.

PMID- 8653657
TI  - Percutaneous transluminal coronary angioplasty in the elderly.
AB  - Selected elderly patients, even the very elderly, can undergo percutaneous
      transluminal coronary angioplasty (PTCA) with a high expected rate of procedural
      success; however, procedural mortality is higher than in younger patients and,
      although long-term survival is very good, long-term relief of angina is less
      reliable. Patient selection is the key to optimal outcome.

PMID- 8653658
TI  - Coronary bypass surgery in the elderly.
AB  - The incidence and severity of coronary artery disease increase with age. Because
      the mortality and morbidity of patients over the age of 70 are higher than those
      for younger patients, many earlier studies comparing the effectiveness of bypass
      surgery to medical management deliberately excluded patients over the age of 65.
      Presently, however, there are many reports on the morbidity and mortality of
      patients having coronary bypass surgery who are over the age of 65 and 70 and
      even in some reports, over the age of 80. Compared with younger patients, the
      elderly have more severe disease, frequent comorbidity, and a slightly higher
      perioperative mortality and morbidity. In properly selected patients, that is
      patients in whom the major problem is the coronary artery disease and not
      multisystem failure, the benefit from coronary artery bypass surgery as far as
      relief of angina and improvement of physical activity is concerned is equal to
      the benefit that younger patients experience. Unlike younger patients, in
      patients over 75 years of age, the goal of surgery is not necessarily to prolong
      life, although in the appropriate patients this probably occurs, but to decrease
      or eliminate angina and return the patient to more normal activity and a better
      quality of life.

PMID- 8653660
TI  - Smoking and coronary artery disease.
AB  - This article discusses the specific effects of smoking on the heart and coronary
      arteries and demonstrates how these effects increase the risk for cardiovascular
      morbidity and mortality. The conflicting results of various studies concerning
      the association of smoking and coronary heart disease in older persons are
      reviewed, and possible explanations for the discrepancy are given. Recent trends
      in smoking habits in the United States and the effects of these changing trends
      on cardiovascular mortality are presented. Finally, data are presented that
      demonstrate the effects of physician-directed cessation programs and the health
      benefits of smoking cessation in elderly and younger persons.

PMID- 8653659
TI  - Exercise training for coronary artery disease in the elderly.
AB  - Treatment of the elderly cardiac patient poses a unique problem to the clinician.
      In addition to cardiovascular symptoms related to coronary artery disease, age
      related decrements in health, and physical function associated with
      musculoskeletal decline must also be addressed. Exercise training/physical
      activity has been shown to have a positive impact on health and function in
      primary and secondary prevention in young and elderly clinical populations.
      Although the components of and guidelines for prescribing an exercise program are
      similar for younger and older cardiac patients, the principles should be applied
      to meet the unique goals and demands of the elderly cardiac patient.

PMID- 8653661
TI  - Dyslipidemia and coronary artery disease in the elderly.
AB  - Risk factors that predict atherosclerotic cardiovascular disease in younger
      individuals also predict risk in older people. Although the relative risk of
      cardiovascular disease associated with any given risk factor may decrease as
      individuals get older, the absolute risk of morbidity and mortality increases
      markedly with age. Because the elderly carry the greatest burden of
      atherosclerosis, they should not be excluded automatically from cholesterol
      lowering interventions with either diet or drugs. Such interventions, however,
      should be undertaken with special attention to their potential adverse effects in
      the older population.

PMID- 8653662
TI  - Hypertension and coronary artery disease in the elderly.
AB  - Both hypertension and coronary artery disease are common in the geriatric
      population, and a variety of pathogenetic links exist between the two disorders.
      In the elderly patient, coronary artery disease is often asymptomatic and more
      difficult to recognize clinically. Antihypertensive therapy has been shown to
      reduce morbidity and mortality from coronary artery disease in the elderly to
      some extent. A more specific and individualized approach is more likely to
      increase these therapeutic benefits.

PMID- 8653663
TI  - Prevention and reduction of left ventricular hypertrophy in the elderly.
AB  - Left ventricular hypertrophy (LVH) is both a target organ response to arterial
      hypertension and a disorder that may be responsible for increasing risk of
      cardiovascular events, including coronary artery disease (CAD) events, in the
      elderly population. Hypertension and obesity are the strongest risk factors for
      LVH, and both disorders are more likely to occur with age. Not surprisingly, the
      prevalence of LVH markedly increases with age. Although LVH may initially be a
      compensatory mechanism to reduce ventricular wall stress, substantial data
      indicate that as LVH progresses, coronary flow reserve is reduced, and CAD events
      are increased. Furthermore, LVH leads to systolic and particularly, diastolic
      ventricular dysfunction, and an increase in the prevalence and complexity of
      ventricular dysrhythmias. All types of cardiovascular morbidity and mortality
      also are increased in patients with LVH. Pharmacologic and nonpharmacologic
      strategies that may decrease LVH and potentially reduce cardiovascular morbidity
      and mortality in the elderly are reviewed.

PMID- 8653664
TI  - Diabetes mellitus and coronary heart disease in the elderly.
AB  - Data from epidemiologic studies document the role of clinically manifest diabetes
      mellitus as a powerful risk determinant for an array of atherosclerotic
      cardiovascular outcomes including coronary heart disease (CHD), stroke, and
      peripheral arterial disease, particularly in the elderly. Although dyslipidemias
      and hypertension are quite prevalent in persons with diabetes mellitus and
      contribute heavily to the underlying atherosclerotic process, other factors
      involving alternative pathogenetic mechanisms are necessary to explain for the
      dramatic acceleration of atherogenesis observed in this condition. Myocardial
      ischemia may be silent and myocardial infarction (MI) may be either painless or
      atypical in presentation which further complicates both the diagnostic and
      therapeutic management of CHD in older diabetic patients. MI, in this context, is
      confounded by dual prognostic disadvantages of higher risk for MI-related
      complications attributable to both advanced age and diabetes mellitus. Because
      available evidence has yet to demonstrate that control of hyperglycemia, either
      by oral agents or by insulin, effectively forestalls either the development or
      complications of atherosclerosis, preventive management in older patients with
      diabetes requires critical attention to correcting coexisting cardiovascular risk
      factors.

PMID- 8653665
TI  - Physical inactivity and coronary heart disease in elderly patients.
AB  - Because physicians are viewed as reliable sources of health information, and
      because of the substantial number of physician contacts with elderly patients
      both with and without coronary heart disease, physician advice regarding the
      adoption of regular patterns of moderate-intensity physical activity has the
      potential to favorably improve coronary risk in the elderly. Guidelines for
      exercise programs for elderly individuals have been available for a number of
      years. The message should emphasize the adverse consequences of chronic
      inactivity and highlight that even modest increases in the level of habitual
      physical activity in older adults can limit decline in functional reserve,
      improve functional capacity, decrease coronary risk, and lessen mortality.

PMID- 8653666
TI  - Clinical manifestations and diagnosis of coronary artery disease.
AB  - Coronary atherosclerosis is very common in the elderly population with autopsy
      studies demonstrating the prevalence to be at least 70% in persons over the age
      of 70. These autopsy findings may be coincidental, with the disease clinically
      silent throughout the person's life, although 20% to 30% of persons over age 65
      years will demonstrate clinical manifestations of coronary heart disease (CHD).
      In most elderly persons, the disease will have manifested itself much earlier in
      their lives, however, in others the disease will be entirely silent until the
      person reaches his or her 70s or 80s. Unfortunately, even though CHD is prevalent
      in elderly persons, the disease is often not diagnosed or misdiagnosed in this
      age group. Failure to correctly diagnose the disease in the elderly may be due to
      the difference in the clinical manifestation in this age group compared with
      younger patients. Such differences may reflect a difference in the disease
      process between older and younger patients or it may be related to the
      superimposition of normal aging changes, plus the presence of concomitant
      diseases, which may mask the usual clinical manifestations.

PMID- 8653667
TI  - Functional circulation images by angio-CT in the assessment of small deep
      cerebral infarctions.
AB  - We analyzed circulation time (rABCT) and vascular volume density images obtained
      by angio-computerized tomography (angio-CT) in 63 patients with small deep
      cerebral infarctions. Abnormalities in the rABCT image were found in 88% of the
      patients and in the vascular volume image in 48%. Two groups with different
      clinical pictures were picked out by rABCT changes: one with major-vessel
      involvement, the other with small-vessel involvement. The perfusional changes
      found were mainly due to altered vascular canalization rather than to altered
      vasomotility. The hemodynamic theory could explain the spatial relations between
      perfusion changes and CT hypodense areas without needing assumptions linking
      blood flow and metabolism.

PMID- 8653668
TI  - Calcified pulmonary metastases from medullary carcinoma of the thyroid.
AB  - A case of calcified pulmonary metastases from medullary carcinoma of the thyroid
      is reported. This uncommon cause of multiple calcified pulmonary nodules is
      demonstrated on a computerized tomography (CT) scan and proven by pathology.

PMID- 8653669
TI  - Quantitative indices for ranking the severity of hepatocellular carcinoma.
AB  - A method for quantifying the severity of tumour burden based on fractional
      affected areas, weighted by their mean attenuation values relative to normal
      tissue, is presented. The procedure was applied retrospectively to routine
      computerized tomography (CT) scans of patients with hepatocellular carcinoma, and
      produced severity indices that reliably followed the ranking of an expert panel.

PMID- 8653670
TI  - Mucoepidermoid tumor of the lung: CT appearance.
AB  - Mucoepidermoid tumor of the lung is a rare endobronchial neoplasm with a wide
      spectrum of appearance. We present a case report and describe the plain film and
      computed tomography (CT) findings.

PMID- 8653671
TI  - Transjugular intrahepatic portosystemic shunt: correlation of portal vein
      velocity measurements and portosystemic pressure gradients.
AB  - To assess the relationship between portal vein velocity measurements and
      portosystemic gradients, color Doppler sonography was performed on 12 patients
      before and after transjugular intrahepatic portosystemic shunt placement. An
      additional patient was examined before and after shunt modification. The average
      maximum portal vein velocity increased from 15.7 cm s-1 before shunt placement to
      43.5 cm s-1 after shunt placement, while the average portosystemic gradient
      decreased from 22.0 mm Hg before shunt placement to 7.9 mm Hg after shunt
      placement. Flow was observed within the shunt in 11 of the 12 cases. Shunt
      velocity was measurable in nine patients, with an average value of 115.7 cm s-1.
      Reversal of intrahepatic portal vein flow was observed in 10 cases following
      shunt placement. Color Doppler sonography is a useful non-invasive tool in the
      evaluation of intrahepatic portosystemic shunts, and changes in portal vein
      velocity correlate well with changes in the portosystemic gradient.

PMID- 8653673
TI  - Cysts of the septum pellucidum.
AB  - A septum pellucidum cyst is defined as a cystic structure between the lateral
      ventricles, whose walls exhibit lateral bowing and are 10 mm apart or greater.
      This communication presents computerized tomography (CT) and magnetic resonance
      imaging (MRI) findings in six patients with septum pellucidum cysts, ages ranging
      from 1.5 to 47 yrs. The width of the cysts ranged from 13 to 23 mm, and their
      walls were laterally bowed. Only one patient had hydrocephalus, who was
      surgically treated. The remaining five patients only had intermittent headaches.
      It appears that further studies will be required to establish satisfactory
      diagnostic and therapeutic criteria for symptomatic or presumably symptomatic
      septum pellucidum cysts.

PMID- 8653672
TI  - MR imaging of atypical polypoid adenomyoma.
AB  - The magnetic resonance (MR) appearances of three cases of atypical polypoid
      adenomyoma are reported. The signal intensity of the tumor was similar to that of
      adenomyosis on T2-weighted MR Imaging (MRI). On contrast-enhanced study,
      irregular enhancement was seen in hyperintense areas on T2-weighted images.
      Atypical polypoid adenomyoma can be characterized as a hypointense polypoid mass
      with hyperintense foci on T2-weighted MR images, resembling the appearance of
      adenomyosis.

PMID- 8653674
TI  - MR vs CT in progressive supranuclear palsy.
AB  - Nine progressive supranuclear palsy (PSP) patients were studied with computerized
      tomography (CT) and magnetic resonance (MR) in order to determine the efficacy of
      each in detecting atrophy of the brainstem. Three additional PSP patients were
      evaluated with MRI for quantitative (electronic) measurements of the colliculi,
      pons and midbrain tegmentum. Both CT and MRI were equally effective in
      demonstrating midbrain atrophy. The MR was able to utilize the sagittal view to
      visualize thinning of the collicular (quadrigeminal) plate, a useful sign in PSP.
      Atrophy of the thinned collicular plate is more pronounced in the superior
      colliculus, one of the most common sites of pathology in PSP. The MR is able to
      make quantitative measurements of the degree of atrophy of the colliculi, pons
      and midbrain tegmentum.

PMID- 8653675
TI  - Methods of automatically acquiring images from digital medical systems.
AB  - Automated image acquisition plays an important role in a picture archiving and
      communication system (PACS). However, there is no single solution for automated
      data acquisition from existing digital medical imaging systems. We have gained a
      great deal of experience on automatic acquiring data by interfacing imaging
      scanners of major manufacturers. In this paper, we categorize the interface
      methods supported by the current image scanners. This categorization consists of
      five architectural models: (a) sequential chain; (b) direct interface; (c) memory
      access; (d) shared disk; and (e) interconnected network. The cost, rate of data
      transfer, and ease of implementation of each model are discussed. To ensure the
      integrity and availability of patient images in a PACS system, automated fault
      tolerance design in image acquisition is required. Based upon our field data, we
      report common scenarios which cause the acquisition to fail. We also describe
      techniques employed to automatically restart the operations which include
      recovery from acquisition processes' errors and traps, image acquisition computer
      down-time occurrence, and shutdown occurrence of medical imaging system.

PMID- 8653676
TI  - DNA methylation errors and cancer.

PMID- 8653677
TI  - Glucose catabolism in cancer cells: amplification of the gene encoding type II
      hexokinase.
AB  - Hexokinase type II is highly overexpressed in many cancer cells, where it plays a
      pivotal role in the high glycolytic phenotype. Here we demonstrate by Southern
      blot analysis and fluorescence in situ hybridization (FISH) that in the rapidly
      growing rat AS-30D hepatoma cell line, enhanced hexokinase activity is associated
      with at least a 5-fold amplification of the type II gene relative to normal
      hepatocytes. This amplification is located chromosomally, extends to the whole
      gene, and most likely occurs at the site of the resident gene. No rearrangement
      of the gene could be detected. Therefore, overexpression of hexokinase type II in
      AS-30D hepatoma cells may be based, at least in part, on a stable gene
      amplification. This is the first report describing the amplification of a
      hexokinase gene in a tumor cell line expressing the high glycolytic phenotype.

PMID- 8653678
TI  - Aberrant FHIT transcripts in Merkel cell carcinoma.
AB  - Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin which shares
      several features with small cell lung carcinoma. In a previous study, we reported
      a high frequency of abnormalities of the FHIT gene, located at 3p14.2, in small
      cell lung tumors. To determine the role of the FHIT gene in small cell
      neuroendocrine malignancies, 14 cases of Merkel cell carcinoma were analyzed by
      reverse transcription of FHIT mRNA followed by PCR amplification and sequencing
      of products. Eight of 14 tumors (57%) displayed abnormal FHIT products that
      lacked three or more exons of the FHIT gene. The pattern of abnormal transcripts
      was similar to that observed in small cell lung tumors, suggesting that FHIT
      abnormalities might be a common genetic marker of these two types of
      neuroendocrine tumors.

PMID- 8653679
TI  - Correlation of chloroethylnitrosourea resistance with ERCC-2 expression in human
      tumor cell lines as determined by quantitative competitive polymerase chain
      reaction.
AB  - We have developed a method to quantitate ERCC-2 gene expression in tumor cell
      lines. A mutant ERCC-2 DNA fragment (1-bp mutation) is used as a competitive DNA
      template in a coamplification PCR reaction with cDNA obtained by reverse
      transcribing DNase-free total RNA from six human tumor cell lines. The PCR
      products are separated on agarose gel by virtue of their differential banding
      pattern upon restriction enzyme digestion. Densitometric readings of the PCR
      products from a negative film of the gel are used to establish a linear
      regression curve, which in turn is used to quantitate ERCC-2 levels. Beta-actin
      expression is similarly quantitated. Normalized ERCC-2 gene expression (either to
      beta-actin or to total RNA) correlates with cytotoxicity of 1,3-bis-(2
      chloroethyl)-1-nitrosourea or (2-chloroethyl)-3-sarcosinamide-1-nitrosourea,
      suggesting that ERCC-2 may play an important role in drug resistance in these
      cell lines. This method is reliable and can be used to quantitate gene expression
      in clinical tumor specimens.

PMID- 8653680
TI  - Enhancement of cytolytic T lymphocyte precursor frequency in melanoma patients
      following immunization with the MAGE-1 peptide loaded antigen presenting cell
      based vaccine.
AB  - Identification of human melanoma-associated peptide antigens for CTLs has opened
      unprecedented opportunities for active specific immunotherapy for melanoma with
      synthetic peptide. We have shown that immunization with a MAGE-1 gene encoded
      nonapeptide (EADPT-GHSY)-pulsed autologous antigen presenting cell-based vaccine
      induces autologous melanoma-reactive and peptide-specific CTL response, in situ,
      at the vaccination site and at distant tumor deposits in patients who are HLA-A1+
      and whose melanoma cells express the MAGE-1 mRNA. Here, we show that such
      immunization is also capable of increasing the frequency of autologous melanoma
      reactive CTL precursors in the circulation. We further show that in vitro
      stimulation of the postimmunization peripheral blood lymphocytes with the MAGE-1
      nonapeptide-loaded antigen presenting cell and interleukin-2 leads to significant
      expansion of peptide-specific and autologous melanoma-reactive CTL response.

PMID- 8653681
TI  - Multiple head and neck tumors: evidence for a common clonal origin.
AB  - Patients with head and neck cancers have a high (2-3%/year) incidence of second
      primary lesions. Clinically, these new lesions are identified either
      simultaneously with the primary lesion (synchronous) or after a period of time
      (metachronous). This observation has been attributed to the concept of "field
      carcinogenesis," which is based on the hypothesis that prolonged exposure to
      carcinogens leads to the independent transformation of multiple epithelial cells
      at several sites. An alternative theory is based on the premise that any
      transforming event is rare; following initial transformation, the progeny of the
      transformed clone spread through the mucosa and give rise to geographically
      distinct but genetically related tumors. We analyzed the pattern of X-chromosome
      inactivation in multiple primary tumors from eight female patients with head and
      neck cancer. In addition, we used microsatellite analysis to examine the pattern
      of allelic loss on chromosomes 9p and 3p, identified as early events in the
      progression of head and neck malignancies. In four of four cases, multiple tumors
      demonstrated the same pattern of X-chromosome inactivation. In the remaining four
      cases, X-chromosome deletions prevented interpretation (n = 3), or the androgen
      receptor locus was noninformative (n = 1). In three of nine patients, multiple
      tumors displayed the same pattern of loss of heterozygosity, two with identical
      breakpoints on chromosome 9p. In one patient, there was an identical
      microsatellite alteration at a 3p locus, definitive evidence that these tumors
      arose from the same clone. Our findings suggest that in at least a proportion of
      patients with head and neck cancers, multiple primary tumors arise from a single
      clone.

PMID- 8653682
TI  - Genetic progression model for head and neck cancer: implications for field
      cancerization.
AB  - A genetic progression model of head and neck squamous cell carcinoma has not yet
      been elucidated, and the genetic basis for "field cancerization" of the
      aerodigestive tract has also remained obscure. Eighty-seven lesions of the head
      and neck, including preinvasive lesions and benign lesions associated with
      carcinogen exposure, were tested using microsatellite analysis for allelic loss
      at 10 major chromosomal loci which have been defined previously. The spectrum of
      chromosomal loss progressively increased at each histopathological step from
      benign hyperplasia to dysplasia to carcinoma in situ to invasive cancer. Adjacent
      areas of tissue with different histopathological appearance shared common genetic
      changes, but the more histopathologically advanced areas exhibited additional
      genetic alterations. Abnormal mucosal cells surrounding preinvasive and
      microinvasive lesions shared common genetic alterations with those lesions and
      thus appear to arise from a single progenitor clone. Based on these findings, the
      local clinical phenomenon of field cancerization seems to involve the expansion
      and migration of clonally related preneoplastic cells.

PMID- 8653683
TI  - Frequent loss of the P16INK4a gene product in human pituitary tumors.
AB  - Pituitary tumors develop at a high frequency in retinoblastoma (Rb)-knockout
      mice; however, defects in the Rb gene are not common in human pituitary tumors.
      The inverse correlation of Rb and p16 defects in certain human tumors has led us
      to investigate the expression of p16 in human pituitary tumors as an indirect
      mechanism of Rb inactivation. By Western blot analysis, the p16 gene product was
      undetectable in 25 human pituitary tumors, whereas high levels of p16 could be
      demonstrated in 10 normal human pituitary specimens under the same conditions of
      protein extraction and immunoblotting. Similar results were obtained at the mRNA
      level with low to undetectable levels of p16 mRNA in 13 of 14 pituitary tumors
      relative to 5 normal pituitary specimens. Single-strand conformation polymorphism
      analysis of p16 exons 1 and 2 revealed no mobility shifts in 25 tumors; however,
      a quantitative differential PCR analysis revealed diminished amplification of p16
      relative to a control gene in 3 of 25 tumors, suggesting homozygous p16 gene
      loss. We conclude that altered expression of the p16 gene product occurs at a
      high frequency in human pituitary tumors. This altered expression is not
      associated with frequent p16 mutation or gene loss, suggesting that alternative
      mechanisms of gene inactivation and/or altered regulation occur in the majority
      of these tumors.

PMID- 8653684
TI  - Novel germline p16 mutation in familial malignant melanoma in southern Sweden.
AB  - The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in
      10 melanoma kindreds from southern Sweden using single-stranded conformation
      polymorphism analysis of all three exons and flanking intron regions followed by
      sequence analysis. A novel germline mutation, constituting an in-frame 3-bp
      duplication at nucleotide 332 in exon 2, was identified in two families (Lund M2
      and M9). The mutation results in an insertion of Arg at codon 105, which
      interrupts the last of the four ankyrin repeats of the p16 protein, motifs which
      have been demonstrated as important in binding and inhibiting the activity of
      cyclin D-dependent kinases 4 and 6 in cell cycle G1 phase regulation. All five
      tested individuals of Lund M2 and M9 affected by melanoma were mutation carriers,
      as were five melanoma-free individuals. Other malignancies observed in gene
      carriers or obligate carriers included cervical, breast, and pancreatic
      carcinomas and a non-Hodgkin's lymphoma. Analysis of microsatellite markers
      adjacent to the p16 gene at chromosomal region 9p21 revealed that both families
      share a common haplotype, in keeping with a common ancestor.

PMID- 8653685
TI  - Frequent microsatellite instability in epithelial borderline ovarian tumors.
AB  - To further define the genetic events that could lead to the development of
      borderline ovarian tumors (BOTs), we analyzed 13 microsatellite markers on
      chromosomes 3p and q in 18 BOTs and compared the results to 31 serous invasive
      epithelia] ovarian cancers (IEOCs). Five of the 18 BOTs showed microsatellite
      instability (MSI) at one or more loci, compared to only 2 of the 31 IEOCs studied
      (P < 0.04). In two of these five BOTs, MSI was found in multiple loci. All BOTs
      with MSI were serous, while none of the mucinous type showed any alteration. Loss
      of heterozygosity was found in only 1 of the 18 BOTs, but in 12 of the 31 IEOCs
      (P < 0.01). This first report of a relatively high percentage of MSI in BOTs
      opens a wide spectrum of new hypotheses for borderline ovarian tumorigenesis as
      well as several new research avenues.

PMID- 8653686
TI  - Deletion of a nonconserved region of Bcl-2 confers a novel gain of function:
      suppression of apoptosis with concomitant cell proliferation.
AB  - The Bcl-2 protein coded by the proto-oncogene bcl-2 is expressed in a variety of
      embryonic and postnatal tissues and is overproduced in several types of tumours.
      Bcl-2 expression suppresses apoptosis induced by a multitude of stimuli in
      diverse cell types without exerting significant effects on cell proliferation,
      and is believed to contribute to oncogenesis by extending cell survival. In
      certain B-cell lymphomas, chromosomal translocations result in a gain of function
      of Bcl-2 by overexpression. Here, we report that a deletion of a nonconserved
      region of human Bcl-2 (residues 51-85) confers a novel gain of function that not
      only suppresses apoptosis induced by the tumor suppressor protein p53 and the Myc
      oncoprotein but also permits continued cell proliferation. Our result raises the
      possibility that mutations within the bcl-2 gene may contribute to oncogenesis by
      both suppressing apoptosis and facilitating cell proliferation.

PMID- 8653687
TI  - Accumulation of p16CDKN2A in response to ultraviolet irradiation correlates with
      late S-G(2)-phase cell cycle delay.
AB  - p16 is the product of the CDKN2A locus, which is mutated or deleted in many human
      tumors. In response to nonlethal UVC irradiation, HeLa cells accumulate elevated
      levels of p16. The accumulation of p16 is delayed 8-12 h following irradiation
      and correlates with S-phase and G2 delays, decreasing as the cells recover and
      recommence normal cell growth. The maximum levels of p16 correlated with G2
      delay. The UVC-induced cell cycle delay was absent in cell lines derived from
      HeLa that did not express p16 and in a melanoma line deleted for p16.

PMID- 8653688
TI  - The angiogenic factor midkine is expressed in bladder cancer, and overexpression
      correlates with a poor outcome in patients with invasive cancers.
AB  - Midkine (MK) is a member of a family of heparin-binding growth factors, which are
      reported to be angiogenic. We have investigated by RNase protection analysis the
      expression of MK in 47 primary bladder tumors and 7 normal bladder samples. MK
      mRNA transcripts were detectable in 46 (98%) of 47 of the tumors and in 5 (70%)
      of 7 of the normal bladder samples. However, median MK expression was 4-fold
      higher in tumors than in the normal bladder (P < 0.004). In eight tumors (17%),
      MK expression was elevated more than 10-fold compared with the median value of
      the normal bladder specimens. There was no statistically significant difference
      in expression between superficial and invasive tumors (P < 0.50). Seven (32 %) of
      22 patients with invasive cancers are alive at 1 year with no evidence of
      recurrence; in 5 (70%) of these patients, MK expression in the tumor was within
      the normal range at the time of presentation. By contrast, in only 2 (13%) of 15
      patients who died or whose tumors recurred or progressed was MK expression in the
      normal range (P < 0.01). Overall, median MK expression in invasive tumors that
      caused death, progressed, or recurred within 12 months was 3-fold higher than
      that found in the tumors of those patients who were clear of disease at 12 months
      (P < 0.04). Thus, overexpression of MK is associated with the development of
      bladder cancer and in invasive cancers predicts a poor clinical outcome in the
      short term.

PMID- 8653689
TI  - DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck
      squamous cell carcinoma.
AB  - DPC4, a candidate tumor suppressor gene, was identified recently at chromosome
      18q21.1. Frequent homozygous deletion or mutations of the gene were observed in
      pancreatic carcinomas. To investigate the role of this gene in head and neck
      squamous cell carcinomas (HNSCCs), we examined 16 HNSCC cell lines from 11
      patients and 20 primary HNSCCs for alterations of the gene by sequencing all 11
      exons of the gene. Fourteen cell lines from 10 patients showed monomers at marker
      D18s46 (l8q21.1). Full-length cDNA was detectable in all cell lines by reverse
      transcription-PCR. A nonsense mutation was identified at codon 526 (GAA to TAA,
      glutamine to termination) in two cell lines (UMSCC22A and UMSCC22B) derived from
      the primary tumor and lymph node metastasis of the same patient. Loss of
      heterozygosity was found in 7 of 15 (47%) informative primary tumors at D18s46,
      whereas only one polymorphism was observed in both tumor and normal tissues from
      the same patient (at codon 525; ATT to GTT, isoleucine to valine). Our data
      indicate that although DPC4 is altered infrequently in HNSCC, it may play some
      role in the tumorigenesis of a small subset of HNSCCs.

PMID- 8653690
TI  - Modulation of p53 expression by human recombinant interferon-alpha2a correlates
      with abrogation of cisplatin resistance in a human melanoma cell line.
AB  - G3361/CP cells, a cisplatin (CDDP)-resistant subclone of the human melanoma cell
      line G3361, overexpress wild-type p53 protein and demonstrate an increase in the
      percentage of cells in G0--G1 arrest compared to parental cells. Exposing
      G3361/CP cells to human recombinant IFN-alpha2a reduces the high basal levels of
      p53, releases G3361/CP cells from G0-G1 into S phase, and abrogates CDDP
      resistance. These findings suggest that recombinant IFN-alpha2a disrupts p53
      mediated cell cycle regulation to restore CDDP sensitivity in G3361/CP cells.

PMID- 8653691
TI  - DPC4 gene in various tumor types.
AB  - We recently identified a novel tumor-suppressor gene, DPC4, at chromosome 18q21.1
      and found that both alleles of DPC4 were inactivated in nearly one-half of the
      pancreatic carcinomas. Here, we analyzed 338 tumors, originating from 12 distinct
      anatomic sites, for alterations in the DPC4 gene. Sixty-four specimens were
      selected for the presence of the allelic loss of 18q and were further analyzed
      for DPC4 sequence alterations. An alteration of the DPC4 gene sequence was
      identified in one of eight breast carcinomas and one of eight ovarian carcinomas.
      These results indicate that whereas DPC4 inactivation is prevalent in pancreatic
      carcinoma (48%), it is distinctly uncommon (< 10%) in the other tumor types
      examined. The tissue restriction of alterations in DPC4, as in many other tumor
      suppressor genes, emphasizes the complexity of rate-limiting checkpoints in human
      tumorigenesis.

PMID- 8653692
TI  - Amount of interleukin 12 available at the tumor site is critical for tumor
      regression.
AB  - The C26 colon carcinoma is resistant to systemic recombinant interleukin 12 (rIL
      12) therapy. Transduction of C26 with genes encoding the two subunits of murine
      IL-12 to release 30-80 pg/ml resulted in delayed tumor onset after injection of 5
      x 10(4) cells into syngeneic BALB/c mice and in 40% tumor regression after
      injection into CD4-depleted mice. Here, we analyzed the activity of rIL-12 (1
      microgram/day) against C26 grown into CD4-depleted mice. Like in mice given
      injections of interleukin 12 (IL-12) gene-transduced C26 cells, depletion of CD4+
      cells led to tumor regression in 6 of 14 mice, and immumocytochemical
      characterization of tumor-infiltrating leukocytes showed abundant infiltration by
      CD8+ T cells and asialoGM1+ natural killer cells, which were scanty in tumors
      from nondepleted mice. On the basis of the percentage of tumor regression and
      leukocyte infiltration we can conclude that, in the C26 system, systemic rIL-12
      (1 pmicrogramg/day) produces the same results as 30-80 pg/ml IL-12 released at
      the tumor site. A new polycistronic retroviral vector was then used to increase
      the amount of IL-12 produced by C26-transduced cells. C26 cells releasing 5 ng/ml
      IL-12, nearly 100 times more than the above-mentioned transduced cells, were
      tumorigenic in less than 50% of the mice given injections of 5 x 10(4) cells. In
      mice given injections of 5 x 10(5) cells, an initial tumor take of 100% followed
      by a complete tumor regression. Tumor regression was associated with infiltration
      of CD8+ and asialoGM1+ cells, and mice that remained tumor free were immune to a
      rechallenge of nontransduced C26 cells. The results indicate that the amount of
      IL-12 made available at the tumor site may determine both the type and number of
      infiltrating leukocytes and the events leading to tumor regression as well as it
      may overcame host immunosuppression.

PMID- 8653693
TI  - Processing of a precursor of 72-kilodalton type IV collagenase/gelatinase A by a
      recombinant membrane-type 1 matrix metalloproteinase.
AB  - Membrane-type 1 matrix metalloproteinase that is associated with the proteolytic
      activation of progelatinase A was expressed as a recombinant fusion protein in
      Escherichia coli. The recombinant enzyme cleaved the propeptide sequence of
      gelatinase A in a sequence-specific manner. A mutant progelatinase A that has a
      substitution of Asn(66)-Leu to Ile-Val was not processed at all. The processing
      was blocked by tissue inhibitor of metalloproteinases-2 or BB-94 but not by
      tissue inhibitor of metalloproteinases-1. Thus, membrane-type 1 matrix
      metalloproteinase is a direct activator of progelatinase A without requiring
      additional proteases.

PMID- 8653694
TI  - Molecular modeling of the amino-terminal zinc ring domain of BRCA1.
AB  - The equine herpes virus zinc ring domain nuclear magnetic resonance structure was
      used for homology-based modeling of the amino-terminal zinc ring domain of the
      BRCA1 breast and ovarian cancer susceptibility gene. The zinc ring domain of
      BRCA1 is of particular interest because it is the location of significant and
      frequently occurring missense (Cys(61)Gly, Cys(64)Gly, and Cys(64)Tyr) and
      frameshift (185delAG) mutations observed in several high-risk kindreds. The BRCA1
      zinc ring domain possesses 54% sequence similarity with the equine herpes virus
      zinc ring domain. The model structure undergoes little conformational variance
      after 140 ps of solvated molecular dynamics. This model proposes BRCA1 zinc ring
      domain residues that may play a role in DNA binding and/or protein-protein
      interactions. These predictions provide a point of departure for the design of
      mutants to probe BRCA1 zinc ring domain functionality.

PMID- 8653695
TI  - Increase of a type of oxidative DNA damage, 8-hydroxyguanine, and its repair
      activity in human leukocytes by cigarette smoking.
AB  - To investigate the oxidative stress induced by cigarette smoking, the levels of a
      form of oxidative DNA damage, 8-hydroxyguanine (8-OH-Gua), and its repair
      activity in the leukocytes of current smokers, ex-smokers, and complete
      nonsmokers were measured. The mean level of 8-OH-Gua was 1.88-fold higher in
      smokers as compared to complete nonsmokers (the difference was statistically
      significant, P = 0.013). The mean 8-OH-Gua repair activity was 1.6-fold higher in
      smokers than complete nonsmokers (the difference was statistically significant, P
      = 0.0053). A positive association was observed for the 8-OH-Gua levels and its
      repair activity. Considerable interindividual variations in the 8-OH-Gua levels
      (current smokers, 3.5-fold; nonsmokers, 7.2-fold) and in its repair activity
      (current smokers, 7.5-fold; nonsmokers. 5.5-fold) were observed. These results
      demonstrate that not only smoking status but also life-style, environment, and
      genetic differences might have effects on the level of 8-OH-Gua and its repair
      activity in human leukocytes.

PMID- 8653696
TI  - The capability of rat colon tissue slices to metabolize the cooked-food
      carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
AB  - A major target tissue for carcinogenesis from the cooked-food carcinogen 2-amino
      l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rodents is the colon, yet the
      role of colon metabolism on the carcinogenicity of PhIP is not clearly
      understood. The mutagenic potency of PhIP is highly dependent upon cytochrome
      P450 N-hydroxylation. In the present study, the ability of rat colon tissue to
      activate PhIP to a mutagen was investigated in Salmonella typhimurium (strains
      TA98 and YGI024) and rat colon tissue slices. In the Ames/Salmonella assay, using
      rat colon S9 as the activating system, no mutations were evident from bacteria
      exposed to PhIP at any concentration tested. However, mutations were observed
      when bacteria were exposed to 2-aminoanthracene (2AA) and colon S9, indicating
      sufficient P450 activity in the S9 to activate 2AA but not PhIP. In rat colon
      slice preparations, the sulfotransferase and acetyltransferase inhibitors
      pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP) were used to
      modulate DNA adduct and metabolite formation. Incubations of 3-methylcholanthrene
      induced colon slices dosed with 50 microMolar [(3)H]PhIP produced no detectable
      metabolites. However, incubations of uninduced slices exposed to 10 microMolar of
      the reactive intermediate, [(3)H]2-(hydroxyamino)-l-methyl-6-phenylimidazo[4,5
      b]pyridine (N-hydroxy-PhIP), produced a single detectable metabolite, a
      glucuronide conjugate of N-hydroxy-PhIP. This metabolite decreased when PCP or
      DCNP was added to the incubation medium. DNA adducts were detected in colon
      slices exposed to N-hydroxy-PhIP at approximately 33 adducts/10(7) nucleotides.
      Interestingly, when PCP was added to the incubation mixture, an increase in DNA
      adduct levels was detected, whereas DCNP produced a decrease in adducts. Because
      these inhibitors are thought to have similar mechanisms with regard to
      sulfotransferase inhibition, the inverse relationship in DNA adduct levels due to
      PCP or DCNP treatment is at present unexplainable. The formation of DNA adducts
      and metabolites from colon slices exposed to N-hydroxy-PhIP but not PhIP implies
      that there is insufficient P450 activity in the rat colon to activate PhIP to
      hydroxylated metabolites, suggesting that the rat colon is a site of Phase II
      metabolism for PhIP and that the liver is the primary source for hydroxylation.

PMID- 8653697
TI  - Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a
      murine model of familial adenomatous polyposis.
AB  - Inducible cyclooxygenase (Cox-2), also known as prostaglandin H synthase 2 (PGH
      2) is a key enzyme in the formation of prostaglandins and thromboxanes. Cox-2 is
      the product of an immediate-early gene that is expressed in response to growth
      factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated
      with both human colon cancers and suppression of apoptosis in cultured epithelia]
      cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug,
      sulindac sulfide. To address the relationship between Cox-2, apoptosis, and tumor
      development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a
      fully penetrant dominant mutation in the Apc gene, leading to the development of
      gastrointestinal adenomas by 110 days of age. Min mice were fed AIN-76A chow diet
      and given sulindac (0.5 +/- 0.1 mg/day) in drinking water. Control Min mice and
      homozygous C57BL/6J-+/+ normal littermates lacking the Apc mutation (+/+) were
      fed AIN-76A diet and given tap water to drink. At 110 days of age, all mice were
      sacrificed, and their intestinal tracts were examined. Control Min mice had 11.9
      +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for sulindac-treated Min
      mice. As expected, +/+ littermates had no macroscopic tumors. Examination of
      histologically normal-appearing small bowel from Min animals revealed increased
      amounts of Cox-2 and prostaglandin E(2) compared to +/+ littermates. Using two
      different in situ techniques, terminal transferase-mediated dUTP nick end
      labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27
      47% decrease in enterocyte apoptosis compared to +/+ animals. Treatment with
      sulindac not only inhibited tumor formation but decreased small bowel Cox-2 and
      prostaglandin E(2) to baseline and restored normal levels of apoptosis. These
      data suggest that overexpression of Cox-2 is associated with tumorigenesis in the
      gastrointestinal epithelium, and that both are inhibited by sulindac
      administration.

PMID- 8653698
TI  - A comparison between the efficacy of somatostatin receptor scintigraphy and that
      of in situ hybridization for somatostatin receptor subtype 2 messenger RNA to
      predict therapeutic outcome in carcinoid patients.
AB  - Predictive tests for treatment with somatostatin analogues have been asked for by
      clinicians. We have shown previously that somatostatin receptor (sstr)
      scintigraphy may be used to predict therapeutic outcomes for carcinoid patients
      receiving somatostatin analogues. However, almost 20% of patients with
      pathological tracer uptake fail to respond to such treatment. To increase further
      the reliability and prognostic value of sstr identification, we investigated the
      presence of mRNA for the subtypes sstr1 and sstr2 by in situ hybridization on
      tumor specimen from 25 carcinoid patients (22 midgut, 2 foregut, and 1 hindgut),
      all receiving somatostatin analogue treatment (12 lanreotide, 8 octreotide, and 5
      octastatin) and compared this to the therapeutic response evaluated as inhibition
      of hormone secretion. Expression of sstr2 mRNA could be detected in 15 patients,
      all responding to somatostatin analogue treatment and showing pathological tracer
      uptake in tumor lesions at sstr scintigraphy. In the remaining 10 patients, no
      sstr2 mRNA could be detected, and none of the patients responded to somatostatin
      analogue treatment. Three of these 10 patients failed to accumulate tracer
      activity at sstr scintigraphy, whereas 7 had a pathological uptake of [(111)In
      DTPA-D-Phe(1)]-octreotide. We conclude that in this group of carcinoid patients,
      there was complete agreement between the presence of mRNA for sstr2 detected by
      in situ hybridization and therapeutic outcome. In patients with pathological
      tracer accumulation without expression of somatostatin sstr2 mRNA, other sstr may
      be present that can bind the somatostatin analogue but not inhibit hormone
      secretion.

PMID- 8653699
TI  - Engineered stromal layers and continuous flow culture enhance multidrug
      resistance gene transfer in hematopoietic progenitors.
AB  - We recently reported that in stroma-free cultures 11-33% of clonogenic cells
      derived from a bulk long-term culture [long-term culture-clonogenic cells (LTC
      CC)] could be transduced by supernatant exposure or coculture of human CD34+
      progenitors with MDR retroviral producer line A12M1. We reasoned that a stromal
      cell layer may generate niches in which LTC-CC could enter in the S-phase, thus
      becoming a more accessible target for gene delivery. In static culture studies in
      flasks, human engineered stromal cell line L87/4 or stromal murine M2-10B4 cells
      were used as feeder after irradiation, and CD34+ cells from either cord blood or
      peripheral blood of mobilized cancer patients were exposed to MDR supernatant for
      7 consecutive days before 5-week culture for LTC-CC evaluation. In continuous
      flow perfusion culture studies, CD34+ cells were seeded over irradiated stromal
      murine M2-1OB4 cells and exposed to MDR supernatant for 7 days before LTC-CC
      evaluation. In mock-transduced controls, <5% of LTC-CC were found to he viable
      after exposure to 10 ng/ml Taxol. In cells exposed to MDR supernatant in static
      stroma cultures, 68 +/- 4% of seeded LTC-CC were found to be drug resistant and
      express MDR mRNA as evaluated by reverse transcription-PCR analysis of single
      colonies. The addition of cytokines did not further enhance transfer efficiency.
      After MDR retroviral exposure in continuous flow cultures, 88 +/- 5% of LTC-CC
      were found to be drug resistant (P < 0.01 versus static stroma culture). P
      glycoprotein expression in CD34+ cells was evaluated using flow cytometry and
      found to he higher after continuous flow versus static cultures. Finally, very
      high levels of P-glycoprotein expression after MDR supernatant exposure in the
      presence of stroma were confirmed by APAAP staining of cultured cells. We
      conclude that engineered stromal cell layers and continuous flow culture
      conditions can significantly enhance retroviral-mediated gene transfer into human
      hematopoietic progenitor cells.

PMID- 8653700
TI  - Characterization of novel human leukemic cell lines selected for resistance to
      merbarone, a catalytic inhibitor of DNA topoisomerase II.
AB  - Merbarone is a catalytic inhibitor of DNA topoisomerase (topo) II that does not
      stabilize DNA-topo II cleavable complexes. Although the cytotoxicity of and
      resistance to complex-stabilizing topo II inhibitors, such as etoposide, is
      thought to be mediated through stabilization of these complexes, the mechanisms
      of cytotoxicity and resistance to catalytic inhibitors are not well known. To
      investigate this issue, we established 12 merbarone-resistant cell lines from
      human leukemia CEM cells, designated CEM/M70-B1 through -B12. Assessed by either
      growth inhibition or clonogenic assay, these cell lines are 3.5- to 6.6-fold
      resistant to merbarone, compared to the CEM parent cells. Karyotype analysis of
      three of the cell lines revealed that while CEM and drug-resistant cell lines had
      chromosome abnormalities in common, indicating a common origin, two of the
      merbarone-resistant lines (B1 and B8) each had unique structural markers. These
      novel cell lines are cross-resistant to complex-stabilizing topo II inhibitors,
      etoposide, teniposide, amsacrine, and doxorubicin, but not to other catalytic
      inhibitors, aclarubicin or SN-22995. Of considerable interest, these cell lines
      are cross-resistant to SN-38, a putative topo I inhibitor, but cross-resistance
      to other topo I inhibitors (camptothecin and topotecan) was lower and not seen in
      every cell line. In all 12 cell lines, there was a high correlation among drug
      resistance ratios between etoposide and teniposide and between merbarone and SN
      38. By contrast, there was a low correlation between merbarone and etoposide and
      between SN-38 and other topo I inhibitors. These results suggest that resistance
      to merbarone and cross-resistance to etoposide might be through different
      mechanisms, whereas cross-resistance to SN-38 might be through a merbarone
      related mechanism. Etoposide and SN-38 stabilized fewer DNA-topoisomerase
      complexes in CEM/M70-B cells than in CEM cells, but camptothecin stabilized more.
      Merbarone inhibited complex formation induced by etoposide in drug-sensitive and 
      resistant cells, but the degree of inhibition was lower in CEM/M70-B cells than
      in the parental cells. Moreover, merbarone did not affect complex formation
      stabilized by SN-38 or camptothecin. Immunoblot analysis of the CEM/M70-B cells
      showed decreased topo IIalpha, increased topo IIbeta, and no change of topo I
      protein, compared to CEM cells. We propose the hypothesis that decreased topo
      IIalpha may play a role in the resistance to merbarone that is different from
      that to complex-stabilizing drugs. Cross-resistance to catalytic inhibitors may
      be due to reduced complex formation as a consequence of decreased topo IIalpha.
      We also found that DNA-protein complexes stabilized by SN-38 might be different
      from those stabilized by topo II inhibitors and blocked by merbarone. Judging
      from both the high correlation of drug sensitivities and complex-formation
      assays, we postulate that mechanisms of cytotoxicity and cross-resistance of SN
      38 in CEM/M70-B cells might be similar to those of merbarone. We believe that the
      CEM/M70-B cells are the first to be selected and characterized for resistance to
      a catalytic inhibitor of topo II. This study provides novel cell lines with
      characteristics of resistances to topo II and topo I inhibitors.

PMID- 8653701
TI  - Increase of beta(III)- and beta(IVa)-tubulin isotopes in human prostate carcinoma
      cells as a result of estramustine resistance.
AB  - Estramustine (EM), an antimicrotubule agent, is effective against hormone
      refractory prostate cancer when used in combination with vinblastine or
      paclitaxel. To understand the effect of EM on beta-tubulin, a cellular target for
      this class of drugs, human prostate carcinoma cells (DU-145) were made resistant
      to EM, and two cell lines were selected at 12- (EM-12) and 15-microMolar (EM-15)
      concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to
      EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of
      the cells with beta-tubulin isotype-specific antibodies showed an approximately 6
      fold increase in the beta(III)-tubulin levels and moderate increase in overall
      beta-tubulin levels in EM-resistant cells when compared to DU-145 cells. This
      increase of beta(III) isotype was confirmed by Western analysis. A reverse
      transcriptase-PCR assay was also employed using beta-tubulin isotype-specific
      primers to quantify beta-tubulin isotype RNA. A 4-fold increase in beta(III) and
      a 3-fold increase in beta(IV alpha) transcript were seen in both EM-resistant
      cell lines. These results indicate that overexpression of specific beta-tubulin
      isotypes may play a role in the cellular defense against EM and other
      antimicrotubule agents.

PMID- 8653702
TI  - Interleukin 2 (IL-2) receptor expression and sensitivity to diphteria fusion
      toxin DAB389IL-2 in cultured hematopoietic cells.
AB  - The high-affinity interleukin 2 (IL-2) receptor is a heterotrimer consisting of
      alpha, beta, and gamma subunits. We examined the concentration of subunit mRNA
      for each of the three protein subunits on human hematopoietic cell lines, human
      peripheral blood mononuclear cells, and murine fibroblasts transfected with cDNAs
      encoding the human IL-2 receptor subunits. In most cultured hematopoietic cells,
      there was abundant gamma subunit message. In contrast, there was variable
      expression of both alpha and beta subunit message. Sensitivity of cells to the
      diphtheria fusion toxin DAB389IL-2 was not related to expression of any single IL
      2 receptor subunit mRNA. Rather, the greatest sensitivity was observed for cells
      possessing all three subunit mRNAs. Cells displaying beta and gamma subunit mRNA
      showed a reduced but significant sensitivity to the fusion toxin. In contrast,
      cells with alpha and gamma subunit mRNA, but missing the beta subunit mRNA, were
      insensitive to DAB389IL-2. The data correlate with the requirement for an
      intermediate or a high-affinity receptor for cell intoxication. A critical
      concentration of the beta subunit may be required for toxin internalization and
      killing.

PMID- 8653703
TI  - Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the
      mouse.
AB  - Based on the range of patient responses to treatment, and on animal studies, it
      is hypothesized that individual variation in sensitivity to bleomycin-induced
      pulmonary fibrosis is controlled genetically. A genetic model has been developed
      by (a) establishing a distinct difference in bleomycin-induced lung damage in two
      inbred strains of mice [parental generation: C57BL/6J (fibrosis-prone phenotype)
      and C3Hf/Kam (fibrosis-resistant phenotype)] and (b) characterizing inheritance
      of the fibrosing phenotype in the F1 (first filial) and F2 (F1 intercross; second
      filial) generations derived from the parental strains. Male mice received 100
      mg/kg and female mice 125 mg/kg of bleomycin via s.c. osmotic minipump. The
      animals were sacrificed 8 weeks after treatment or when their breathing rate
      indicated respiratory distress. The percentage of lung with fibrosis for each
      mouse was quantified with image analysis of a histological section of the left
      lung. The mean percentage of fibrosis for the C57BL/6J males was 8.4 +/- 0.8%
      (SE) and 4.4 +/- 0.8% for females, and the C3Hf/Kam mice of either sex did not
      present the fibrosing lesion (mean score, 0%). Significant difference (P = 6 x
      10(-6)) was measured in percentage of fibrosis between the two strains of F1
      males, but not F1 females (P = 0.38), suggesting the presence of an X-linked
      factor associated with the fibrosing phenotype. From an ANOVA the X-linked factor
      is estimated to contribute 19% of the fibrosis phenotype. A genetic model of two
      or three loci controlling the fibrosing phenotype is proposed from the data of
      the parental, F1, and F2 generations. The mouse model demonstrates that
      susceptibility to bleomycin-induced pulmonary fibrosis is a heritable trait
      controlled by a few genetic loci.

PMID- 8653704
TI  - Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M
      potassium oxonate (S-1) against human colon carcinoma orthotopically implanted
      into nude rats.
AB  - The purpose of this study was to establish a nude rat orthotopic (organ-specific)
      human colorectal cancer model as an in vivo secondary screen for general
      evaluation of new anticancer agents against colorectal cancer and to evaluate
      practically the antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4
      dihydroxypyridine-1 M potassium oxonate (S-1), a new p.o. fluoropyrimidine, in
      comparison to 1 M tegafur-4 M uracil [(UFT) effective on colorectal tumor in
      clinical]. After implantation of KM12C, a human colorectal cancer cell line, into
      the subserosal layer of the colon as a single-cell suspension, extensive local
      tumor growth and invasion to both the mucosal and the serosal sides were observed
      in all rats. Metastatic foci were also formed in both lymph nodes and lungs
      following local tumor growth in all of them. Using this method, an equitoxic dose
      of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was administered p.o. for 14
      consecutive days from 7 days after tumor cell implantation. S-1 showed a higher
      tumor growth inhibition than UFT did [S-1, 57% (significantly different from the
      tumor weight of the untreated group at P < 0.05) and UFT, 18% (P > 0.05)]. When
      both drugs were administered to nude rats bearing KM12C injected into the cecal
      wall for 28 consecutive days at equitoxic doses, the mean survival in the S-1
      group was 16 days longer than that in the untreated group (P < 0.01) but that in
      the UFT group was only 8 days longer (P > 0.05). After the administration of an
      equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various
      pharmacokinetic parameters as follows: area under the curve 0-24 h of 5
      fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of 5-fluorouracil
      incorporated into RNA in the tumor (1.3-fold), and thymidylate synthase
      inhibition rate (percentage) in the tumor (about 20%). Collectively, these
      findings suggested that this orthotopic human colorectal tumor model in nude rats
      is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for
      colorectal cancer, and that S-1 had a higher therapeutic effect on human
      colorectal tumor than UFT did.

PMID- 8653705
TI  - Dendritic epidermal T cells in ultraviolet-irradiated skin enhance skin tumor
      growth by inhibiting CD4+ T-cell-mediated immunity.
AB  - Chronic UV irradiation of the skin not only causes skin cancer in humans but
      modifies immune responses generated within the epidermis, resulting in impaired
      immunity against a variety of infectious as well as noninfectious agents. In
      mice, tumors induced by chronic UV irradiation grow faster when transplanted into
      mice that are immunosuppressed by UV irradiation. To investigate epidermal cells
      (EC) in UV-irradiated skin that inhibit the induction of immunity against tumors,
      the murine UV-induced LK2 regresser tumor was used. This tumor grows initially in
      vivo and then spontaneously regresses. In vivo T-cell depletion was used to
      determine that regression of LK2 tumors in unirradiated mice was mediated mainly
      by CD8+ T lymphocytes, with minor involvement of CD4+ T cells. Immunization of
      mice with tumor antigen-pulsed EC prepared from unirradiated mice enhanced
      immunity against subsequent inoculation of LK2 tumors, augmenting regression of
      the LK2 tumor due to increased activation of both CD4+ and CD8+ T-cell subsets
      against the tumor. By contrast, immunization with EC prepared from UV-irradiated
      skin inhibited the induction of antitumor immunity, enhancing LK2 tumor growth.
      This was caused by the dendritic epidermal T cells that remained within this UV
      irradiated EC preparation inhibiting activation of CD4+ T cells, without
      affecting CD8+ T cell function. Hence, during the development of murine UV
      induced skin tumors, dendritic epidermal T cell inhibition of CD4+ T cell
      activation may enable this skin tumor to escape immune-mediated destruction.

PMID- 8653706
TI  - Estrogen-induced proto-oncogene and suppressor gene expression in the hamster
      kidney: significance for estrogen carcinogenesis.
AB  - Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months
      induces a high frequency of estrogen-dependent renal cancers. We have proposed a
      sequential multistage scheme involving tubular cell damage, regenerative cell
      proliferation, aneuploidy, chromosomal imbalance, genetic instability, gene
      alteration, and amplification as essential steps for estrogen carcinogenesis in
      this model. A systematic study was undertaken to assess the expression of nuclear
      proto-oncogenes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by
      Northern blot analysis to further support this scheme. Hamster kidney RNA, taken
      at monthly intervals (1.0 to 6.0 months) from diethylstilbestrol (DES)-treated
      castrated male hamsters and corresponding age-matched untreated controls was used
      in these studies, as well as primary estrogen-induced renal tumor RNA, for
      reference. Although no significant changes in the expression of these proto
      oncogenes were detected in the first 4 months of estrogen treatment relative to
      age-matched controls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at
      5.0 and 6.0 months, respectively. Moreover, the expression of 2.2-kb c-fos
      transcript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression increased
      2.8- and 5.1-fold at these same respective estrogen treatment time intervals.
      Tumor suppressor gene expression, p53 and WT-1, was also evaluated in similar
      estrogen-exposed hamsters. Although no significant changes were found in hamster
      kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold
      at 6.0 months of estrogen treatment and more than 2.0-fold in the primary renal
      tumor. In contrast, no detectable changes in WT-1 expression were found during
      the first 6.0 months of DES treatment. However, a dramatic 7.0-fold increase in
      WT-1 expression was observed in the primary renal tumor. It is evident that two
      WT-1 transcripts reside in the hamster kidney; a lower molecular weight
      transcript was found in the normal adult kidney, and a higher molecular weight
      3.2-kb transcript was observed in the renal tumor, similar to that seen in the
      newborn mouse kidney. In summary, the estrogen-induced inappropriate gene
      expression, including p53, reported herein, is consistent with the view that the
      elevations seen in gene expression contribute to proliferative advantages of
      certain proximal tubular interstitial cells necessary for estrogen-driven tumor
      formation in the hamster.

PMID- 8653707
TI  - Inheritance of abnormal expression of SOS-like response in xeroderma pigmentosum
      and hereditary cancer-prone syndromes.
AB  - The time course of induction of SOS-like stress responses such as enhanced
      reactivation (ER) and enhanced mutagenesis (EM) has been investigated in UV-C
      irradiated skin fibroblasts from a xeroderma pigmentosum (XP) family, using
      herpes simplex virus type 1 as a probe. Similar ER studies were performed in a Li
      Fraumeni syndrome (LFS) family and in a family with a high incidence of breast,
      ovarian, and colon cancer. In two XP (complementation group B) patients, with a
      striking absence of skin tumors even at an age of >40 years, only induction of EM
      was observed, whereas ER was absent (XPER-). The ER- phenotype was inherited from
      the father, whereas cells from the mother exhibited normal expression of ER and
      EM. This suggests that the absence of ER is a hereditary trait that is not
      correlated with a repair-deficient phenotype. Abnormally high levels of ER were
      observed in UV-C-exposed skin fibroblasts from rive LFS patients. The inheritance
      of the ER response was studied in one LFS family. High levels of ER were observed
      only in cells derived from affected individuals carrying one mutated p53 allele,
      whereas cells from unaffected family members, carrying two wild-type p53 alleles,
      exhibited normal ER levels. This result shows that abnormally high levels of ER
      positively correlate with the occurrence of cancer in affected individuals from a
      LFS family. Interestingly, abnormally high levels of ER were observed in cells
      from afflicted as well as from unafflicted members of a family with a high
      incidence of breast, ovarian, colon, and stomach cancer. This suggests that these
      latter individuals have inherited a mutated, putative predisposing gene,
      resulting in abnormal expression of ER, but that cancer had not yet developed.
      The results indicate that the ER response can possibly be used as a prognostic
      marker to identify carriers in various hereditary cancer-prone syndromes at an
      early age.

PMID- 8653708
TI  - Resistance of a variant ras-transformed cell line to phenotypic reversion by
      farnesyl transferase inhibitors.
AB  - Pharmacological inhibitors of the housekeeping enzyme farnesyl transferase (FT)
      inhibit the growth of ras-transformed cells in vitro and in vivo without
      antiproliferative effects on normal cells. In one direction to analyze the basis
      for this selectivity and to study modes of drug resistance that arise in animals,
      we characterized a variant ras-transformed cell line, 749r-1, which was resistant
      to phenotypic reversion with FT inhibitors. The transformed phenotype, growth
      potential, and actin cytoskeleton of 749r-1 cells were unaffected by treatment
      with the FT inhibitor 1-739,749 at concentrations up to 30-fold higher than those
      sufficient to revert ras-transformed cells. Resistance correlated with a reduced
      ability of L-739,749 to inhibit the farnesylation of Ras and lamin B and with a
      reduction in the susceptibility of endogenous FT to drug inhibition. These
      effects were not due to mutation of the FT subunits, changes in intracellular
      drug accumulation, or amplification of the multiple drug resistance gene (MDR).
      However, a similar reduction in the ability of L-739,749 to inhibit Ras
      farnesylation was also seen in ras-transformed cells rendered resistant by
      ectopic expression of farnesyl-independent RhoB, suggesting some mechanistic
      overlap. We concluded that 749r-1 cells sustained a stable alteration that
      conferred drug resistance by a novel mechanism.

PMID- 8653709
TI  - Identification of murine p120 isoforms and heterogeneous expression of p120cas
      isoforms in human tumor cell lines.
AB  - p120cas (CAS) is a protein tyrosine kinase substrate that associates directly
      with the cytoplasmic tail of the cell-cell adhesion molecule E-cadherin. CAS is
      thus part of a multimolecular complex that, along with other cadherin-binding
      proteins (catenins), mediates interactions between E-cadherin and the actin
      cytoskeleton. Down-regulation of E-cadherin expression and defects in catenin
      function have been implicated in tumor metastasis, but the role of CAS in these
      processes has not been addressed. Recently, the study of CAS was complicated when
      new anti-CAS antibodies revealed the presence of at least four putative CAS
      isoforms that appeared to vary in abundance between cell types. Here, we identify
      the four major isoforms expressed in murine fibroblasts, and we show that they
      are products of alternative splicing. Analysis of CAS isoforms in a variety of
      murine cell lines indicates that motile cells like fibroblasts and macrophages
      preferentially express CAS1 (i.e., CAS1A and CAS1B isoforms), and epithelial
      cells preferentially express CAS2 (i.e., CAS2A and CAS2B isoforms), whereas
      nonadherent cells (e.g., B cells, T cells, and myeloid cells) do not express
      detectable levels of CAS. Interestingly, CAS1 expression is dramatically up
      regulated in a Src-transformed Madin-Darby canine kidney cell line, indicating
      that the pattern of isoform expression can be altered by cell transformation.
      Analysis of a variety of differentiated and metastatic human tumor cell lines
      reveals that CAS isoform expression in these cells is quite heterogeneous.
      Furthermore, several poorly differentiated cell lines fail to express particular
      isoforms that are typically observed in well-differentiated cell lines. These
      data raise the possibility that unbalanced expression of CAS isoforms in human
      carcinomas may influence cadherin function and contribute to malignant or
      metastatic cell phenotypes.

PMID- 8653710
TI  - PRG1: a novel early-response gene transcriptionally induced by pituitary
      adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line.
AB  - The rat pancreatic carcinoma cell line AR4-2J was screened for growth-associated
      genes linked to the mitogenic effect of the novel gut brain hormone, pituitary
      adenylate cyclase activating polypeptide (PACAP). Using the mRNA differential
      display technique, we identified and sequenced an unknown rat gene, PACAP
      responsive gene 1 (PRG1), which is highly homologous to gly96, a novel murine
      gene of unknown function. The PRG1 cDNA sequence of 1.1 kb encodes a 160-amino
      acid protein. Using targeted PCR, the gene structure of PRG1, constituting 0.6 kb
      of the promotor region, and the DNA coding region, including a single 107-bp
      intron, were established from rat genomic DNA. In AR4-2J cells, PACAP(1-38)
      increased PRG1 mRNA levels up to 10-fold in a rapid (30 min), transient (3-6 h),
      and dose-dependent (ED50, <1 nM) fashion. The growth-stimulating gastrointestinal
      hormones cholecystokinin and gastrin showed a similar degree of PRG1 induction,
      and the PACAP-related peptides vasoactive intestinal peptide and secretin were
      without effect. The transcriptional inhibitor actinomycin D, various protein
      kinase C inhibitors, and the calmodulin inhibitor W-7 strongly reduced PRG1
      induction by PACAP, whereas the translational inhibitor cycloheximide potently
      increased PRG1 mRNA levels in unstimulated and PACAP-stimulated cells. Feedback
      mediated hyperplasia of the rat exocrine pancreas induced by oral treatment of
      rats with the protease inhibitor camostate (FOY-305) was preceded by a 15-fold
      transient elevation of PRG1 mRNA levels. These data suggest that PRG1 is an early
      response gene linked to PACAP-induced growth of AR4-2J cells as well as to
      hyperplasia of the rat exocrine pancreas in vivo.

PMID- 8653711
TI  - In vivo ubiquitination and proteasome-mediated degradation of p53(1).
AB  - The levels of the tumor suppressor protein p53 are generally quite low in normal
      cells, due in part to its rapid turnover. Previous studies have implicated
      ubiquitin-dependent proteolysis in the turnover of wild-type p53 but have not
      established whether or not p53 is itself a substrate of the ubiquitin system. In
      this study, inhibitors of the 26S proteasome have been used to further explore
      the role of ubiquitin proteolysis in regulating p53 turnover. Increased levels of
      the tumor suppressor protein p53 were observed in normal cells, as well as in
      cells expressing the human papillomavirus 16 E6 oncoprotein, on exposure of the
      cells to proteasome inhibitors. Pulse-chase experiments indicated that the
      increased p53 levels resulted from stabilization of the protein. Furthermore,
      ubiquitin-p53 conjugates were detected in untreated as well as gamma-irradiated
      cells, indicating that ubiquitin-dependent proteolysis plays a role in the normal
      turnover of p53. Increased levels of the cyclin:cyclin-dependent kinase inhibitor
      p21, a downstream effector of p53 function, were also observed in proteasome
      inhibitor-treated cells, and this increase was due in part to an increase in p2l
      mRNA.

PMID- 8653712
TI  - Biallelic alterations of both ETV6 and CDKN1B genes in a t(12;21) childhood acute
      lymphoblastic leukemia case.
AB  - Recently, a new recurrent t(12;21)(pl3;q22) has been identified in a B-cell
      lineage childhood acute lymphoblastic leukemia (ALL). The translocation results
      in a fusion of two known genes, ETV6/TEL (12p13) and AML1 (21q22), previously
      shown to be involved in the pathogenesis of myeloid disorders. We report results
      of cytogenetic fluorescence in situ hybridization and molecular studies of a B
      cell childhood common ALL with a cryptic 12;21 translocation. Aberrations
      identified in this case involve both chromosomes 12 and include not only the ETV6
      AML1 gene fusion and two different microdeletions of ETV6 but also the hemizygous
      loss of CDKN1B, D12S119, and KRAS2 loci and a putative rearrangement of the
      second CDKN1B allele as a result of an inv(12)(p13q24). Moreover, it was shown
      that the AML1-ETV6 reciprocal chimeric transcript was not present in the
      malignant cells, and hence may not play a major role in leukemogenesis. In
      addition, the putative loss of wild-type function of CDKN1B and ETV6 could
      indicate a synergistic effect of both genes in the pathogenesis of this leukemia
      case.

PMID- 8653713
TI  - Augmentation of tumor metastasis by platelet-activating factor.
AB  - The effect of platelet-activating factor (PAF) on experimental pulmonary
      metastasis by the B16F10 murine melanoma and the possible involvement of PAF in
      the activities of tumor necrosis factor alpha (TNF-alpha) and interleukin 1alpha
      (IL-1alpha) in tumor metastasis were investigated. i.p. injection of PAF enhanced
      the lung colonization in a dose- and time-dependent manner. PAF enhanced lung
      colonization when it was administered after, but not before, B16F10 inoculation.
      Multiple injections of PAF were more effective than a single injection.
      Neutralization of endogenous PAF with PAF antagonist BN50739 decreased lung
      colonization, suggesting that endogenous PAF plays an important role in pulmonary
      metastases. A single i.p. injection of TNF-alpha or IL-1alpha caused a marked
      enhancement in lung colonization. TNF-alpha- and IL-1alpha-mediated enhancement
      in lung colonies was significantly inhibited by BN50739. These results
      demonstrate that PAF has a metastasis-enhancing effect and is a mediator of the
      metastatic activities of TNF-alpha and IL-1alpha.

PMID- 8653714
TI  - Epidermal growth factor-responsive and -refractory carcinomas initiated with N
      methyl-N-nitrosourea in rat urinary bladder.
AB  - We tested the role of epidermal growth factor (EGF) in the development of low
      grade superficial bladder tumors by using a heterotopically transplanted rat
      urinary bladder system. Weekly EGF administration (250 ng/0.5 ml of phosphate
      buffered 2.1% NaCl solution) for 28 weeks into heterotopically transplanted rat
      urinary bladders initiated with a low dose of N-methyl-N-nitrosourea resulted in
      a significant increase in the incidence (17 of 25 versus 6 of 30 rats; P < 0.001)
      and the mean number of tumors per bladder (1.08 versus 0.20; P < 0.001) as
      compared with those for a vehicle-only group. Changing to vehicle without EGF for
      the last 8 weeks resulted in tumors in 8 of 24 rats (P = 0.02 versus the EGF
      group), comparable to the rate for controls. Switching from vehicle to EGF for
      the last 8 weeks resulted in tumors in 15 of 24 rats, comparable to the rate in
      the 28-week EGF group. When tumors were divided into two groups according to size
      (>4.2 mm3 and </= 4.2 mm3), expression of EGF receptor (EGF-R) was found in 24 of
      25 "large" tumors as compared with 5 of 17 "small" tumors (P < 0.0001). The
      results of in situ hybridization for EGF-R correlated well with those of
      immunohistochemical study. These data suggest the possibility that recurrences of
      low-grade superficial bladder tumors are related to the continuing presence of
      EGF in the urine, and that blocking of EGF-R should be evaluated as a tumor
      inhibitor.

PMID- 8653715
TI  - Extent of tumor vascularization correlates with prognosis and hematogenous
      metastasis in gastric carcinomas.
AB  - To determine whether tumor angiogenesis correlates with prognosis and metastasis
      of patients with gastric carcinoma, we counted the microvessels within the
      primary carcinoma and compared their numbers with the patient's prognosis and
      mode of metastasis. Tumor specimens from 110 patients with gastric carcinoma, who
      had undergone curative resection more than 24 months before, were investigated.
      Intratumoral microvessels were stained with anti-CD34 and anti-von Willebrand
      factor monoclonal antibodies before being quantitated by light microscopy (x200).
      The antibody against von Willebrand factor often showed variability and stromal
      background staining, providing misleading low vessel counts. The data from three
      patients who died from nongastric carcinoma within 24 months after surgery were
      deleted. A total of 107 patients took part in the analysis examining the
      association between intratumoral microvessels and clinical outcomes. Vessel
      counts derived from CD34 expression were significantly higher in patients who
      experienced hematogenous or peritoneal metastasis after surgery than in patients
      with nonmetastatic tumors. No correlation between vessel counts and lymph node
      metastasis was found. The prevalence of hematogenous metastasis. but not
      peritoneal metastasis, increased as the vessel counts increased. Multivariate
      logistic regression and Cox hazards model analyses showed that the vessel counts
      obtained with CD34 staining correlated with the development of hematogenous
      recurrence but not peritoneal recurrence. It was the most important factor for
      predicting overall survival. These findings support the hypothesis that tumor
      angiogenesis is closely related to the development of hematogenous metastasis in
      human gastric carcinomas. Assessment of tumor vascularization may, therefore,
      prove valuable in identifying patients with gastric carcinoma at high risk for
      recurrence who would benefit from adjuvant therapy.

PMID- 8653716
TI  - Correspondence re: J.A. Knol et al., Incorporation of 5-bromo-2-deoxyuridine into
      colorectal liver metastases and liver in patients receiving a 7-day hepatic
      arterial infusion. Cancer Res., 55: 3687-3691, 1995.

PMID- 8653717
TI  - FTIR and laser-Raman spectra of oligosaccharides in water: characterization of
      the glycosidic bond.
AB  - Changes in conformation of oligosaccharides, and the constraints imposed by
      hydrogen bonding with the solvent, were studied by means of vibrational
      spectroscopy (FTIR-ATR and laser-Raman). Oligosaccharides differing in positions
      of the glycosidic bond, such as trehalose, sucrose, maltose, melibiose, lactose,
      maltotriose, raffinose, and stachyose, were investigated. FTIR spectra of
      oligosaccharides in aqueous solution at different concentrations allow
      differentiation of these molecules according to the types of glycosidic bonds
      present and the changes in conformation of their constituent monosaccharides.
      Characteristic spectral ranges influenced by the glycosidic linkage position,
      overall hydration, and concentration of the aqueous solution were found.
      Tentative assignment of the observed IR and Raman bands was achieved.

PMID- 8653718
TI  - Systematic synthesis of alpha-sialyl-(2 --> 3)- and -(2 --> 6)
      isoglobopentaosylceramides (V3Neu5AciGb5Cer and V6Neu5AciGb5Cer).
AB  - Systematic syntheses of the isoglobo-series gangliosides, alpha-sialyl-(2 --> 3)-
      and -(2 --> 6)-isoglobopentaosyl ceramides (21 and 24, V3Neu5AciGb5Cer and
      V6Neu5AciGb5Cer) are described. 2-(Trimethylsilyl)ethyl 2-O-benzyl-4,6-O
      benzylidene-alpha-D-galactopyranosyl-(1 --> 3)- 2,4,6,tri-O-benzyl-beta-D
      galactopyranosyl-(1--> 4) -2,3,6-tri-O-benzyl-bet a-D- glucopyranoside (4), the
      core structure of the isoglobo-series gangliosides was prepared by the
      glycosylation of 2-(trimethylsilyl)ethyl 2,4,6-tri-O-benzyl-(1 --> 4)-2,3,6-tri-O
      benzyl-beta-D-glucopyranoside (2) with methyl 3-O-acetyl-2-O-benzyl-4,6-O
      benzylidene-1-thio-beta-D-galactopyranoside (1), and subsequent O-deacetylation.
      Coupling of 4 and methyl 3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-1
      thio-beta-D- galactopyranoside gave an isoglobotetraoside derivative 6, from
      which the phthaloyl and O-acetyl groups were removed. N-Acetylation then gave a
      tetrasaccharide acceptor 7. Dimethyl(methylthio)sulfonium triflate-promoted
      coupling of 7 with methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy
      D-glycero-alpha-D- galacto)-(2 --> 3)-2,4,6-tri-O-benzoyl-1-thio-beta-D
      galactopyranoside or -(2 --> 6)-2,4-di-O-benzoyl-3-O-benzyl-1-thio-beta-D
      galactopyranoside gave the pentasaccharide derivative 9 and 14 in good yields.
      Compounds 9 and 14 were converted into the corresponding alpha-trichloroimidates
      12 and 17 which, on coupling with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3
      diol (18), gave the beta-glycoside 19 and 22 respectively, Finally, 19 and 22
      were transformed, via selective reduction of azide group, condensation with
      octadecanoic acid, O-deacylation, and hydrolysis of the methyl ester group into
      21 and 24, respectively.

PMID- 8653719
TI  - Synthesis of the methyl alpha-glycosides of some isomalto-oligosaccharides
      specifically deoxygenated at position C-3.
AB  - Methyl alpha-isomaltoside and methyl alpha-isomaltotrioside specifically
      deoxygenated at position C-3 of various glucopyranosyl units were synthesized by
      condensation of either 1,6-di-O-acetyl-2,4-di-O-benzyl-3-deoxy-alpha,beta-D-ribo
      hexopyranos e (7) or 1,6-di-O-acetyl-2,3,4-tri-O-benzyl-alpha,beta-D
      glucopyranose [mediated by silver perchlorate and tin(IV) chloride] with suitably
      blocked derivatives of methyl alpha-D-glucopyranoside, its 3-deoxy analog (6), or
      methyl 3'-deoxy alpha-isomaltoside (10), respectively.

PMID- 8653720
TI  - An efficient short-step total synthesis of ganglioside GM3: effective usage of
      the neighbouring group participation strategy.
AB  - We have developed an efficient methodology for highly stereoselective sialylation
      using 3-position substituted sialic acids and have prepared 2a having a 3 beta
      phenylthio group as a sialic donor. Glycosylation of suitably protected lactoside
      3 with 2a gave only the alpha-sialyl trisaccharide 16 in good yield. Condensation
      of the azidosphingosine 4 with the acetate 17 using promotors, DMTST or NIS-TfOH,
      afforded the glycolipid 18, which was directly transformed to 20 by reduction
      with Bu3P and subsequent acylation with octadecanoic acid in the presence of WSC.
      Removal of the protecting groups generated ganglioside GM3 (1).

PMID- 8653721
TI  - Inseparable iduronic acid-containing proteoglycan PG(IdoA) preparations of human
      skin and post-burn scar tissues: evidence for elevated levels of PG(IdoA)-I in
      hypertrophic scar by N-terminal sequencing.
AB  - Hypertrophic scarring is characterized by disordered collagen fibrils. In order
      to determine whether this is, in part, a result of changes in the population of
      proteoglycans that are thought to be involved in regulation of collagen fibril
      formation, we have compared PGs from post-burn normal and hypertrophic scar
      tissue, as well as from human dermis and epidermis. Efforts to separate the two
      major iduronic acid-containing proteoglycans, decorin [PG(IdoA)-II] and biglycan
      [PG(IdoA)-I], for quantitation were not successful. The different N-terminal
      sequences of these two iduronic acid-containing proteoglycans PG(IdoA-I and -II
      were utilized to estimate the relative amounts in the above PG(IdoA)
      preparations. Normal scar, dermis and epidermis were all found to contain
      primarily decorin with low (< 10%) levels of biglycan relative to decorin. In
      contrast, iduronic acid-containing proteoglycans from hypertrophic scar were
      found to be approximately 30% biglycan [PG(IdoA)-I]. This may be a proximal cause
      of altered collagen fibrils, or may result in alterations in the sequestration of
      growth factors, which then results in changes in collagen that effect the
      appearance of the scar. 1966 Elsevier Science Ltd.

PMID- 8653722
TI  - A new polysaccharide from a traditional Nigerian plant food: Detarium senegalense
      Gmelin.
AB  - The seed flour of an African leguminous plant, Detarium senegalense Gmelin, is
      used traditionally in Nigeria as a thickening agent in foods. Recent studies have
      shown that the detarium seed contains a large amount of water-soluble, non-starch
      polysaccharide (s-NSP), which suggests it has important nutritional properties.
      The aims of the present study were to characterise the structure and solution
      properties of purified s-NSP. The main monosaccharide residues of the extracted s
      NSP were glucose, xylose, and galactose in the ratio of 1.39:1.00:0.52,
      suggesting structural similarity to the xyloglucan group of cell wall storage
      polysaccharides. This was confirmed by comparing the oligosaccharides released on
      endo-(1 --> 4)-beta-D-glucanase digestion with those obtained from tamarind seed
      xyloglucan. The intrinsic viscosity [eta] of a sample of the detarium
      polysaccharide was found to be 8.9 dl/g, indicating that the sample was of high
      molecular weight, a result confirmed by light scattering. Histochemical
      examination of detarium seed using bright field and epifluorescence microscopy
      showed the presence of xyloglucan in highly thickened cell walls, which were
      particularly prominent at the cell junctions.

PMID- 8653723
TI  - Synthesis of 6-O-acetyl-2,3,4-tri-O-[(S)-2-methylbutyryl]sucrose and the three
      regioisomers of 6-O-acetyl-2,3,4-O-[(S)-2-methylbutyryl]-di-O-[(S)-3
      methylpentanoyl]su crose, naturally occurring fatty acid esters of sucrose found
      in tobacco.

PMID- 8653724
TI  - Synthesis of allyl beta-D-galactopyranoside from lactose using Streptococcus
      thermophilus beta-D-galactosidase.

PMID- 8653725
TI  - Reduced beat-to-beat changes of heart rate: an important risk factor after acute
      myocardial infarction.
AB  - The prognostic significance of heart rate variability derived from 24-hour
      electrocardiographic recordings was investigated in 250 patients with acute
      myocardial infarction. During a follow-up of 6 months 15 patients experienced a
      serious arrhythmic event. These patients showed a significantly reduced beat to
      beat variability (p = 0.006), a slightly reduced 5-min variability (p = 0.04) and
      no significant differences in the 24-hour variability compared to the patients
      free of arrhythmic events. Based on Cox proportional hazard analysis, beat to
      beat variability remained an independent risk factor (p = 0.0036) in addition to
      the presence or absence of ventricular late potentials (p = 0.0004) and history
      of previous infarction (p = 0.04).

PMID- 8653726
TI  - Transesophageal pulsed Doppler echocardiographic study of pulmonary venous flow
      in mitral stenosis.
AB  - For evaluation of pulmonary venous flow (PVF) in mitral stenosis, transthoracic
      and transesophageal echocardiography were performed in 33 patients with mitral
      stenosis and 20 normal controls. The peak systolic flow velocity of the PVF was
      significantly lower in patients with mitral stenosis and atrial fibrillation. The
      peak diastolic flow velocity of the PVF was significantly lower in the patients
      with mitral stenosis than in normal controls. The diastolic wave recorded as
      laminar flow in the mitral stenosis group showed a peak in the rapid filling
      phase with a gradually descending slope of velocity during mid to late diastole.
      There was a significant negative correlation between the peak diastolic flow
      velocity of the PVF and the pressure half time from transmitral flow obtained by
      continuous wave Doppler in the mitral stenosis group. These results demonstrate
      that evaluation of the PVF is helpful in understanding hemodynamic events between
      the left atrium and left ventricle in patients with mitral stenosis.

PMID- 8653727
TI  - Parasympathetic withdrawal precedes spontaneous blood pressure elevations in
      women with primary hypertension.
AB  - Exaggerated sympathetic activity is widely accepted as one of the fundamental
      mechanisms leading to primary hypertension and being responsible for frequent
      episodes of blood pressure elevation in hypertensive patients. Some data suggest
      also that basal parasympathetic tone in this entity is lowered. However, the
      effects of autonomic nervous activity on heart rate variability during
      spontaneous blood pressure elevations have not been yet evaluated. That is why we
      present the preliminary results of 24-hour electrocardiogram and blood pressure
      monitoring in 13 women with mild primary hypertension and with 25 episodes of
      blood pressure elevations. Time- and frequency domain measurements of heart rate
      variability found during the 24- and 10- hour daily periods were compared with
      those obtained during four 5-min records: 25-20, 15-10 min and immediately
      before, as well as immediately after the recording of blood pressure elevation.
      Significant decrease in parameters representing vagal tone was found during 5-min
      periods not only immediately preceding or following blood pressure elevations,
      but also 10 and 20 min before these episodes. Moreover, low-frequency component
      of heart rate variability was significantly lowered 10 min before and immediately
      after the recording of blood pressure elevation. These results suggest that among
      various pathogenetic mechanisms of spontaneous blood pressure elevations in women
      with primary hypertension, sudden withdrawal of parasympathetic tone should be
      taken into account.

PMID- 8653728
TI  - Predicting postinfarction left ventricular dysfunction based on the configuration
      of the QRS complex and ST segment in the initial ECG of patients with a first
      anterior wall myocardial infarction.
AB  - The objective of the study was to identify patients with anterior wall acute
      myocardial infarction (AMI) at high risk of postinfarction left ventricular
      dysfunction (LVD). This study population included all patients admitted with a
      diagnosis of anterior wall AMI (ST segment elevation of > 1 mm in 2 or more
      precordial leads) without history or ECG evidence of antecedent AMI,who underwent
      assessment of left ventricular ejection fraction (LVEF) during emergency
      hospitalization. ST segment deviation from baseline was measured manually 0.08 s
      after the J point in all leads. Patients (n = 81) were classified into two groups
      based on the configuration of the QRS complex and ST segment: ST > 1 mm with
      preserved (pattern A; n = 60) or distorted terminal QRS (emergence of the J point
      at a level above the lower half of the R wave or disappearance of the S wave in
      leads with an Rs configuration; pattern B; n = 21). LVD (LVEF < 40%) was
      significantly more prevalent in patients with pattern B than pattern A (48 vs.
      12%; p = 0.002). There was no correlation between the number of leads with ST
      segment elevation and LVD (p = 0.47). The sum of ST segment elevation in involved
      leads correlated weakly, yet significantly with LVEF (R = -0.22; p < 0.05). In
      conclusion, patients with anterior wall AMI and pattern B in the initial ECG are
      at high risk of post-AMILVD.

PMID- 8653729
TI  - Heterogeneous effect of quinidine on the ventricular depolarization process
      assessed by the spatial velocity electrocardiogram of the QRS complex.
      Preliminary report of a new investigative method.
AB  - The negative conduction effect of quinidine on each of the successive phases of
      the ventricular depolarization was investigated using an original noninvasive
      method: the spatial velocity electrocardiogram of the QRS complex (SVECG-QRS). We
      performed a randomized placebo-controlled trial in 10 healthy subjects with a
      single oral dose of quinidine (330 mg) or placebo. Electrocardiographic
      acquisition and processing (220 recordings for the complete trial) were performed
      using the Lyon vectorcardiographic program. For each SVECG-QRS curve, the
      position of seven specific points from A (onset of QRS) to G (end of QRS) were
      determined precisely. The six successive time intervals between these points (AB
      FG) and five velocity values (B-F) were then calculated. The QRS complex was
      longer under quinidine than placebo (102.4 +/- 1.6 vs. 100.3 +/- 1.5 ms). The
      difference was at the periphery of statistical significance (p = 0.05), and this
      lack of statistical difference may be mainly due to the low serum levels of
      quinidine obtained at the peak of the concentration (1.46 +/- 0.4 mg/1). All six
      QRS time intervals were longer under quinidine, but only the BC interval was
      significantly different (9.3 +/- 1.1 vs. 18.8 +/- 1.1 ms; p < 0.05) suggesting a
      more pronounced negative conduction effect at the onset of ventricular
      depolarization. No significant modifications were observed for the velocity
      values. We conclude that (1) the negative conduction effect of quinidine is
      heterogeneous, but a further study with a higher dose of quinidine (concentration
      dependent effect) is required to confirm this hypothesis and (2) the spatial
      velocity electrocardiogram of the QRS complex allows a detailed analysis of the
      ventricular conduction phases. The results of the measurement were found to be
      reproducible. This noninvasive tool could be used in clinical practice to assess
      effects of antiarrhythmic drugs on successive ventricular depolarization phases.

PMID- 8653730
TI  - Patterns of use and clinical utility of exercise thallium-201 single photon
      emission-computed tomography in a community hospital.
AB  - Single photon emission computed tomographic (SPECT) imaging with thallium-201 was
      evaluated in 492 consecutive, unselected patients to ascertain the patterns of
      use and additive value to the exercise electrocardiogram in the diagnosis of
      myocardial ischemia in a community hospital setting. Myocardial perfusion images
      were interpreted by a single observer employing visual and confirmatory
      quantitative analysis. The majority of patients (69%) were studied to evaluate
      the functional consequences of known coronary artery disease and not primarily to
      aid in diagnosis. Relationships among exercise electrocardiograms, SPECT
      information and coronary angiography were analyzed in 303 patients. The
      sensitivity was 92% and improved to 96% when multivessel disease was present.
      Overall, the positive predictive value of tomographic imaging in the detection of
      coronary disease was 94%. These findings demonstrate the changing pattern of use
      of myocardial perfusion imaging and confirm the value and applicability of this
      technique in routine clinical practice.

PMID- 8653731
TI  - Clinical significance of intracavitary spontaneous echo contrast in patients with
      dilated cardiomyopathy.
AB  - To assess the occurrence rate and major determinants of spontaneous echo contrast
      and to examine its impact on thromboembolic events and mortality in patients with
      dilated cardiomyopathy, 86 hospitalized patients (73 men and 13 women, mean age
      63 +/- 11 years) with dilated cardiomyopathy who underwent transthoracic and
      transesophageal echocardiographic examinations were followed up for a mean of 20
      +/- 13 months. Spontaneous echo contrast was observed in 36 patients (42%) and
      was detected only with the transesophageal approach. It was seen in the left
      atrium in 33 patients, in both right and left atria in 1 patient, in both left
      atrium and left ventricle in 1 patient, and in the descending aorta in 1 patient.
      Spontaneous echo contrast was more frequent in the presence of atrial
      fibrillation (p < 0.05), left atrial enlargement (p < 0.02) and severely
      depressed left ventricular function (p < 0.01), but was less common in patients
      with moderate to severe mitral regurgitation (p < 0.05). This imaging phenomenon
      was the only significant independent predictor of intracardiac thrombus formation
      and previous and subsequent thromboembolic events. During follow-up, there were
      26 deaths, and survival in patients with spontaneous echo contrast was
      significantly lower than in those without it (p < 0.02). A spontaneous echo
      contrast is commonly detected with transesophageal echocardiography in patients
      with dilated cardiomyopathy especially in the presence of atrial fibrillation,
      left atrial enlargement and severe left ventricular dysfunction. This imaging
      phenomenon represents an important marker for thromboembolic risk and may
      influence the treatment and clinical outcome of these patients.

PMID- 8653733
TI  - Acute filling pattern changes of the failing left ventricle after captopril as
      related to ventricular structure.
AB  - In congestive heart failure captopril modifies the left ventricular filling
      pattern mainly by unloading the heart. We investigated whether the structural
      characteristics of the left ventricle may influence the acute effects of
      captopril on this pattern in patients with untreated hypertensive (H group, 6
      patients) or idiopathic (I group, 14 patients) cardiomyopathy. We evaluated
      changes of pulsed Doppler mitral flow, of systemic arterial and wedge pulmonary
      pressures 40 min after 25 mg captopril administered sublingually, and correlated
      these changes with the M-mode echocardiographic relative wall thickness index
      (h/r). Baseline mean arterial pressure (H = 137 +/- 20 mm Hg, mean +/- SD, I = 95
      +/- 19 mm Hg; p < 0.001), and h/r (H = 0.38 +/- 0.03, I = 0.28 +/- 0.09; p <
      0.05) were greater in the high blood pressure group; wedge pressure,
      echocardiographic biplane ejection fraction, and Doppler indexes of the left
      ventricular filling were similar in the two populations. After captopril,
      ejection fraction did not change significantly, mean arterial pressure decreased
      significantly in hypertensive patients (H group, baseline = 137 +/- 20, captopril
      = 119 +/- 10, p = 0.02; I group, baseline = 95 +/- 19, captopril = 90 +/- 24, p =
      nonsignificant), and the wedge pressure was reduced by the same extent in both
      groups (H group, baseline = 27.7 +/- 3, captopril = 21 +/- 7, p < 0.05; I group,
      baseline = 20 +/- 12, captopril = 15 +/- 8, p < 0.05). In the H group early
      mitral flow increased [(E wave integral) x (mitral annulus area)] by 38 +/- 15%,
      and was almost steady in the I group (-1.3 +/- 30%; group H vs. I = p < 0.01);
      late mitral flow [(A wave integral) x (mitral annulus area)] showed a pattern
      exactly opposite to this (H = +0.4 +/- 40%, I = +38 +/- 19; p < 0.01). In the
      whole population there was a significant correlation between the early/late flow
      ratio variations and baseline h/r (r = 0.6, p < 0.05). In chronic congestive
      heart failure, changes in left ventricular filling with captopril are related to
      h/r: a higher index, as recorded in the H group, is associated with "true
      normalization' of the filling pattern after captopril; a lower index, as recorded
      in the I group, is associated with "pseudonormalization' despite a similar
      decrease of left ventricular filling pressure.

PMID- 8653732
TI  - Cardiopulmonary exercise response in patients with left ventricular dysfunction
      or heart failure: a noninvasive study by gas exchange and impedance cardiography
      monitoring.
AB  - We investigated the upright bicycle exercise cardiopulmonary response in 20
      patients with left ventricular dysfunction (LVD, secondary to previous myocardial
      infarction, left ventricular ejection fraction range 18-44%). Ten patients (48 +/
      7 years) asymptomatic (I NYHA class) without drug treatment (LVD group). The
      others (n = 10) (50 +/- 1 years) complained of dyspnea and/or fatigue despite
      therapy (NYHA II-III). They represented the heart failure (HF) group. Eight
      sedentary men (40 +/- 10 years) served as controls. Controls and patients
      performed stress testings under drug treatment, when administered. Anaerobic
      ventilatory threshold (ATge) was considered as an index of submaximal exercise
      while peak exercise VO2 (Peak VO2) was considered the maximal volitional exercise
      capacity. The ratio between minute ventilation (VE) to carbon dioxide release
      (VCO2) (VE/VCO2) was assessed to evaluate the ventilatory response during
      exercise. We coupled gas exchange assessment (2001, MGC) with noninvasive
      monitoring of stroke volume (SV) by impedance cardiography (NCCOM3, BOMED) and
      total systemic vascular resistances (TSVR; by auscultatory blood pressure
      measurement). In controls VO2 increase during exercise was related to higher
      heart rate (HR) and SV both from resting to ATge and from this point to the peak.
      TSVR declined during both steps. In patients with HF VO2 rose from resting to
      ATge (by faster HR and unchanged SV). VO2 increased slightly from this point to
      Peak VO2. This result was related to flat HR increase and unchanged SV as well as
      TSVR. In patients with LVD VO2 increased similarly to controls from resting to
      ATge and less above the threshold. In these patients both HR and SV increased
      during submaximal exercise. From ATge to Peak VO2 only HR increased. TSVR
      declined significantly similarly to controls. The VE/VCO2 ratio was higher at
      peak exercise in patients with HF compared to controls. Different determinants
      were demonstrated in patients with left ventricular dysfunction with mild or
      symptomatic chronic heart failure (CHF). These findings and the increased
      ventilatory response in patients with CHF can explain different changes of VO2 in
      these patients during submaximal and maximal voluntary exercise and contribute to
      explain exercise-induced exertion in these subjects.

PMID- 8653734
TI  - Beat-to-beat QRS amplitude variability during dobutamine infusion in patients
      with coronary artery disease.
AB  - The aim of this study was to investigate if provoked myocardial ischemia induces
      increased beat-to-beat QRS amplitude variability in patients with
      angiographically verified coronary artery disease. 15 patients (median age 62
      years, range 46-73 years) and 10 healthy controls (median age 25 years, range 22
      42 years) were studied. Dobutamine was infused intravenously at a low and at a
      high dose. The mean low dose of the drug was 10.0 micrograms/kg/min for both
      patients and controls, whereas the mean maximum dose was 31 +/- 2 for patients
      and 38 +/- 1 microgram/kg/min for controls. The total QRS amplitude beat-to-beat
      variance from 12 leads as well as individual variance scores in each single lead
      were evaluated. Before infusion, the total QRS variance did not differ between
      patients and controls, nor did the individual variance in 9 of the 12 ECG leads.
      Dobutamine elicited an increase (p < 0.01) in the total QRS variance, with
      significantly higher (p < 0.001) total variance in patients than in controls. At
      the high dose of the drug, the patients displayed significantly higher individual
      variance values in each ECG lead as well. During dobutamine infusion, 7 of 15
      patients developed ST depressions (> or = 0.1 mV in > or = 2 leads) in 12-lead
      ECG readings. Eleven of 15 patients developed chest pain (grade > or = 3 at the
      Borg's CR-10 scale). In conclusion, in patients with ischemic heart disease,
      dobutamine-provoked stress gives rise to increased QRS amplitude beat-to-beat
      variability, as a sign of electrical instability of the myocardium.

PMID- 8653735
TI  - Floating right heart thrombi and pulmonary embolism: diagnosis, outcome and
      therapeutic management.
AB  - The aim of this study was to analyze clinical and echographic findings and to
      assess therapeutic management in 14 floating right atrial thrombi diagnosed with
      systematic echocardiography in 200 consecutive patients with proven pulmonary
      embolism. Auscultatory findings were abnormal in 7 cases, 4 of them showing signs
      of tricuspid obstruction. Echocardiography displayed a mobile ovoid, polycyclic
      or worm-like right atrial mass, always associated with signs of cor pulmonale.
      Four patients (29%) died, 2 of them before any treatment could be started.
      Regarding the remaining 10 patients with favorable outcome, surgical embolectomy
      was carried out in 7. Our data suggest that echocardiographic examination is
      necessary in all suspected pulmonary embolisms and has to be done quickly for
      emergency treatment in patients with floating right atrial thrombus.

PMID- 8653737
TI  - Restoration of mechanical atrial function after electrical cardioversion of
      chronic atrial fibrillation in patients after surgical treatment of mitral valve
      disease--hemodynamic effects and prognostic value of maintenance of sinus rhythm.
AB  - There are controversies regarding the possibility of returning of A wave (mitral
      flow at left atrial contraction) after electroconversion (EC) in patients with
      persisting chronic atrial fibrillation in spite of successful surgical treatment
      of mitral valve disease. Twenty-four hours before successful EC, thereafter daily
      for 1 week and then on the 14th, 21st and 28th day and 6 months after EC, ECG, M
      mode, two-dimensional and Doppler echocardiography were performed in 55 patients.
      A wave (>0.1 m/s) appeared on the 1st day in 31 patients, on the 2nd day in the
      next 6, on the 3rd in 5 patients, on the 4th and 5th days in 1 patient and on the
      7th day in 4 patients. In 7 patients A wave did not restore. Maximum velocity of
      A wave increased from 0.48 +/- 0.22 to 0.86 +/- 0.28 m/s (p < 0.05) during the
      follow-up. In 92% of patients with A wave 24 h after EC, significant increases in
      stroke index from 35 +/- 12 to 47 +/- 15 ml/m2 (p < 0.04), ejection fraction from
      46 +/- 9 to 55 +/- 8% (p < 0.01) and pulmonary acceleration time from 94 +/- 26
      to 107 +/- 22 ms (p < 0.05) were observed. Sinus rhythm was still present on the
      28th day in 34 patients (62%) and after 6 months in 31 patients (57%), all of
      them with A wave. observation shows the increase in pulmonary acceleration time,
      the decrease in the left atrial area and the increase in its systolic function in
      patients with A wave. Appearance of A wave determined the hemodynamic
      improvement, but we did not observe a correlation between maximal velocity of A
      wave and hemodynamic improvement. Appearance of A wave had a low predictive value
      for maintaining sinus rhythm (sensitivity 58% and specificity 45%). Relative
      increase in A wave velocity during the 1st week after EC correlated positively
      with long-term maintenance of sinus rhythm (r = 0.62; p < 0.001).

PMID- 8653736
TI  - The deeper the negativity of the T waves recorded, the greater is the
      effectiveness of reperfusion of the myocardium.
AB  - We evaluated the time course of QT intervals and the amplitude of T waves, and
      their relationship to subsequent left ventricular regional wall motions in 88
      patients with successfully reperfused acute myocardial infarction (MI). The QTc
      intervals and the amplitude of inverted T waves of lead V3 in patients with
      anterior MI and of lead III in patients with inferior MI were measured for 1
      month after MI. Patients were classified as having severe T wave inversion or
      mild T wave inversion within 3 days of MI, based on a measurement of 0.5 mV in
      the anterior MI cases and 0.3 mV in the inferior MI cases. Chronicphase left
      ventriculography was performed 5 months later, and hypokinesis of the infarct
      site was measured using the centerline method. The T waves inverted after
      reperfusion in 86 patients (98%). The inverted T waves deepened twice, with the
      first negative peak about 48 h and the second negative peak about 18 days after
      MI. QTc intervals became prolonged as the T waves deepened. The extent of
      hypokinesis in the chronic phase correlated with the amplitude of inverted T
      waves and QTc intervals when the T waves were deepest. The group with severe T
      wave inversion had less extensive hypokinesis, a lower maximum serum creatine
      kinase level and a shorter time to reperfusion from the onset of symptoms than
      the group with mild inversion. We conclude that the degree of T wave inversion 48
      h after MI is predictive of abnormalities in left ventricular regional wall
      motions in the chronic phase. A deep inverted T wave in the acute phase of MI
      indicates an abundantly stunned myocardium.

PMID- 8653738
TI  - Intravascular ultrasound imaging of peripheral arteries as an adjunct to balloon
      angioplasty and atherectomy.
AB  - This article reviews many of the applications of intravascular ultrasound (US)
      imaging for peripheral arterial diseases. In vitro studies demonstrate an
      excellent correlation between ultrasound measurements of lumen and plaque cross
      sectional area compared with histologic sections. In vivo clinical studies reveal
      the enhanced diagnostic capabilities of this technology compared with
      angiography. Intravascular US imaging can provide valuable information on the
      degree, eccentricity, and histologic type of stenosis before intervention, and on
      the morphological changes in the arterial wall and the extent of excision after
      intervention. Intravascular US may also serve as a superior index for gauging the
      diameter of balloon, stent, laser probe, and/or atherectomy catheter appropriate
      for a proposed intervention. Significant new insights into the mechanisms of
      balloon angioplasty and atherectomy have been established by intravascular US
      findings. Intravascular US imaging has been shown to be a more accurate method
      than angiography for determining the cross-sectional area of the arterial lumen,
      and for assessing severity of stenosis. Quantitative assessment of the luminal
      cross-sectional area after the balloon dilatation should be more accurate than
      angiography as intimal tears or dissections produced by the dilatation may not be
      accurately evaluated with angiography. At the present time, intravascular US is
      still a controversial imaging technique. Outcome studies are currently being
      organized to assess the clinical value and cost effectiveness of intravascular
      ultrasound in the context of these interventional procedures.

PMID- 8653739
TI  - Covered self-expanding transhepatic biliary stents: clinical pilot study.
AB  - PURPOSE: We report our preliminary results with a new type of self-expanding
      covered stent for treatment of malignant biliary obstruction. METHODS:
      Wallstents, fully covered with high elasticity polyurethane, with an
      unconstrained diameter of 10 mm and a total length of 69 mm, were placed
      transhepatically under fluoroscopic guidance in five patients. The length of the
      biliary obstruction varied between 30-50 mm. At 1 and 3 months (82-98 days)
      clinical assessment, serum bilirubin measurement, and ultrasound examination of
      the biliary tree were performed. RESULTS: Initial uncomplicated deployment of the
      stents and internal drainage was possible in all patients. Distal stent migration
      resulted in early biliary reobstruction in one patient. At 3-month follow-up,
      partial reobstruction, most probably due to sludge formation, was found in
      another patient. CONCLUSION: Our initial results indicate that the covered, self
      expanding Wallstent endoprosthesis can be reliably and safely deployed
      transhepatically for malignant biliary obstruction.

PMID- 8653740
TI  - Nitinol esophageal stents: new designs and clinical indications.
AB  - PURPOSE: To evaluate the clinical use of covered and noncovered, knitted nitinol
      stents in patients presenting new stent indications. METHODS: Self-expandable,
      knitted nitinol stents were implanted in four patients for treatment of
      dysphagia. In two patients who had malignant strictures and had esophago
      respiratory fistulae and in one patient with an esophagocutaneous fistula,
      polytetrafluoroethylene (PTFE)-covered stents were implanted. One patient
      received a noncovered stent, but a retrograde approach through a percutaneous
      endoscopic gastrostomy (PEG) fistula had to be chosen for recanalization of an
      esophageal occlusion. Two patients received stents for treatment of benign
      strictures. RESULTS: Recanalization of the stricture and stent implantation were
      performed under fluoroscopic control without any procedure-related morbidity or
      mortality. Dysphagia improved in all patients and the esophageal fistulae could
      be sealed off by covered stents. During a maximum follow-up of 18 months, there
      was no stent migration or esophageal perforation. Complications observed were
      stent stenosis due to food impaction (1/4) and benign stent stenosis (2/2). Most
      complications could be treated by the interventional radiologist. CONCLUSION:
      Self-expandable, covered Nitinol stents provide an option for the treatment of
      dysphagia combined with esophageal fistulae. In combination with interventional
      radiology techniques, even complex strictures are accessible. For benign
      strictures, the value of stent treatment has not yet been proven.

PMID- 8653741
TI  - Portographic evaluation for recurrent esophagogastric varices following
      devascularization surgery.
AB  - PURPOSE: To investigate, by transhepatic portography, the changes in
      portosystemic collaterals and recurrent esophagogastric varices after
      devascularization surgery. METHODS: Thirty-five patients, who had undergone
      devascularization surgery 2-8 years previously, underwent follow-up portography
      and the collaterals and drainage routes were compared with preoperative
      portography results. RESULTS: Newly formed collaterals were present in 30 of 35
      patients and the origins and drainage routes differed from preoperative ones.
      Most common were new collaterals arising from the junction of the portal and
      superior mesenteric veins; the next most frequent arose from a main portal
      branch, the portal trunk, or the superior mesenteric vein. New collaterals with
      recurrent varices were seen in 20 patients and without varices in 10; 5 patients
      had no collaterals or varices. CONCLUSION: Since the development of new
      collaterals is common in portal hypertensive patients following devascularization
      surgery, regular follow-up for recurrent varices is necessary.

PMID- 8653742
TI  - One-shot percutaneous ethanol injection of liver tumors under general anesthesia:
      preliminary data on efficacy and complications.
AB  - PURPOSE: To verify the efficacy of ultrasound (US)-guided injection of large
      amounts of ethanol into large or multiple liver lesions, in a single session
      under general anesthesia (one-shot PEI) for percutaneous ablation of hepatic
      tumors. METHODS: Twenty-nine patients (27 with 51 hepatocellular carcinoma (HCC)
      nodules on cirrhosis, diameter range 1.0-9.0 cm; two patients with a single
      metastasis from the gastroenteric tract, 5.0 and 9.0 cm, respectively, in
      diameter) were treated with one-shot PEI. RESULTS: The total volume of alcohol
      delivered per patient ranged from 16 to 210 ml. Mean ethanol volume in all
      patients was 49 ml. Dynamic computed tomography (CT) examination showed complete
      necrosis in 41 of 50 lesions. Two patients died of hypovolemic shock due to
      massive upper gastrointestinal bleeding, 3 and 7 days, respectively, after the
      interventional procedure. All the remaining patients are alive (follow-up 5-14
      months) except one who died of liver failure 5 months after. New HCC nodules
      occurred in six patients within 6 months and one intralesional relapse was
      recorded. CONCLUSION: In this preliminary experience, one-shot PEI is as
      effective in inducing liver tumor necrosis as traditional PEI; its advantages are
      shorter treatment time and the capability of treating larger and multiple liver
      lesions.

PMID- 8653743
TI  - Budd-Chiari syndrome caused by obstruction of the hepatic inferior vena cava:
      immediate and 2-year treatment results of transluminal angioplasty and metallic
      stent placement.
AB  - PURPOSE: To assess the usefulness of percutaneous transluminal angioplasty (PTA)
      and expandable metallic stent (EMS) placement for treatment of Budd-Chiari
      syndrome (BCS). METHODS: Thirty-two patients with BCS were treated by PTA alone
      or by PTA and EMS placement. Among the 32 patients, a membranous obstruction was
      found in 24 and a segmental stenosis or occlusion in 8 patients. The follow-up
      period for PTA was 38-68 months (mean 52.2 months); for EMS it was 20-36 months
      (mean 24.3 months). RESULTS: Twenty-one patients underwent PTA as the primary
      treatment. Of these, one patient died of disseminated intravascular coagulation
      shortly after the procedure; 20 had good to excellent initial angiographic and
      clinical results. Of the 20, restenosis or reocclusion developed in 10 patients
      (48%), all before 27 months; 8 patients (38%) became symptomatic, and 2 remained
      symptom-free for a total recurrent obstruction rate of 50%. The EMS group of 17
      patients included 11 patients who underwent primary stenting and 6 patients with
      secondary stenting after recurrence following primary PTA; restenosis was
      demonstrated in only 2 patients (12%). CONCLUSIONS: We conclude that PTA alone
      produces excellent short-term results and about 50% sustained patency after 2
      years in patients with BCS; therefore it should remain the procedure of first
      choice. Stents should be reserved for primary or secondary PTA failures.

PMID- 8653744
TI  - Effort thrombosis: effective treatment with vascular stent after unrelieved
      venous stenosis following a surgical release procedure.
AB  - Acute symptomatic effort thrombosis in a 33-year-old male necessitated an
      aggressive approach consisting of thrombolysis, angioplasty, and surgical
      thoracic outlet release. The patient required postoperative placement of a
      Wallstent and was placed on anticoagulation. He has remained symptom free for the
      past 10 months, both clinically and sonographically.

PMID- 8653745
TI  - Iliocaval stenosis and iliac venous thrombosis in retroperitoneal fibrosis:
      percutaneous treatment by use of hydrodynamic thrombectomy and stenting.
AB  - A case of bilateral iliac stenosis and caval stenosis due to retroperitoneal
      fibrosis was treated by caval stenting and iliac balloon angioplasty, but was
      complicated by subsequent iliac thrombosis. Venous thrombectomy was successfully
      achieved by hydrodynamic thrombectomy, and iliac patency was stabilized by
      bilateral stent insertion.

PMID- 8653746
TI  - Embolization of an hepatic artery pseudoaneurysm following laparoscopic
      cholecystectomy.
AB  - Vascular injuries during laparoscopic cholecystectomy can occur in an analogous
      fashion to biliary injuries, with potential laceration, transection, and
      occlusion of blood vessels. A patient presented with symptomatic hemobilia 1
      month following laparoscopic cholecystectomy and was found to have a right
      hepatic artery pseudoaneurysm which communicated with the common bile duct. This
      was successfully embolized with several embolic agents, resulting in rapid
      resolution of all signs and symptoms. The patient has been free of symptoms
      during a follow-up period of 1 year. A brief discussion of hepatic artery
      pseudoaneurysms is presented.

PMID- 8653747
TI  - Selective arterial embolization of idiopathic priapism.
AB  - We report a case of idiopathic priapism that was only identified as high-flow or
      arterial priapism after drainage of the corpora cavernosa. Following failure of
      conservative and surgical treatment attempts, two consecutive embolizations of a
      unilateral penile artery were performed with gelgoam particles.

PMID- 8653748
TI  - Emergency balloon embolization for carotid artery rupture secondary to
      postoperative infection.
AB  - Two cases of carotid artery rupture due to postoperative infection were treated
      successfully with an emergency endovascular technique. A detachable balloon was
      attached to a 2 Fr microcatheter and was introduced through a 9 Fr guiding
      catheter. The balloons were detached at the rupture site and just proximal to the
      lesion. This technique has several advantages over surgical procedures.

PMID- 8653749
TI  - Post-TIPS hepatic encephalopathy treated by occlusion balloon-assisted retrograde
      embolization of a coexisting spontaneous splenorenal shunt.
AB  - A 51-year-old man with posthepatitis cirrhosis underwent a transjugular
      intrahepatic portosystemic shunt (TIPS) for bleeding of recurrent esophageal
      varices. The patient had a coexisting, spontaneous, splenorenal shunt. He
      subsequently developed hepatic encephalopathy, presumably due to excessive
      portosystemic shunting. Since medical management resulted in no significant
      improvement, the splenorenal shunt was embolized from the jugular vein approach
      via renal vein access during temporary balloon occlusion. Within a few days, the
      patient's hepatic encephalopathy resolved. Twelve months later the patient showed
      no recurrence of encephalopathy and had maintained a patent TIPS.

PMID- 8653750
TI  - Embolization of a high-output postnephrectomy aortocaval fistula with Gianturco
      coils and cyanoacrylate.
AB  - The authors describe the endovascular treatment of a high-output, large-caliber,
      postnephrectomy aortocaval fistula using a mixture of cyanoacrylate and lipiodol
      combined with Gianturco coil embolization. Thirty-nine coils were used to
      decrease the flow through the fistula so that a fast-polymerizing glue mixture
      could be injected into the fistula. During rapid polymerization, the N-butyl-2
      cyanoacrylate (NBCA) mixture was trapped within the coils, providing an easily
      controllable glue cast in the fistula, thereby preventing inadvertent
      embolization into the lungs. This approach can be of considerable benefit for the
      endovascular treatment of central high-output fistulas.

PMID- 8653751
TI  - Cesare Gianturco (1905-1995): a legend in his own time.

PMID- 8653752
TI  - Calcium-induced calcium release in neurones.
AB  - Neurones express several subtypes of intracellular Ca2+ channels, which are
      regulated by cytoplasmic calcium concentration ([Ca2+]c) and provide the pathway
      for Ca(2+)-induced Ca2+ release (CICR) from endoplasmic reticulum Ca2+ stores.
      The initial studies of CICR which employed several pharmacological tools (and in
      particular caffeine and ryanodine) demonstrated that: (i) caffeine induces
      intracellular calcium release in various peripheral and central neurones; and
      (ii) inhibition of CICR affects the parameters of depolarization-triggered
      [Ca2+]c responses. Experiments with caffeine demonstrated also that Ca2+ release
      from internal pools was incremental, suggesting the coexistence of several
      subpopulations of Ca2+ release channels with different sensitivity to caffeine.
      The CICR availability in neurones is controlled by both the Ca2+ content of the
      internal stores and the basal [Ca2+]c. Direct comparison of transmembrane Ca2+
      influx with plasmalemmal Ca2+ current and [Ca2+]c elevation performed on
      sympathetic, sensory and cerebellar Purkinje neurones revealed the gradual
      activation of CICR. The efficacy of CICR may be regulated by the newly discovered
      second messenger cADP ribose (cADPR), although the mechanism of signal
      transduction involving cADPR is still unknown. CICR in neurones may be important
      in creation of local [Ca2+]c signals and could be involved in a regulation of
      numerous neuronal functions.

PMID- 8653753
TI  - Age-related abnormalities in regulation of the ryanodine receptor in rat fast
      twitch muscle.
AB  - The tibialis anterior (TA) muscles of 6-month-old and 24-month-old male Wistar
      rats, after being characterized, at the fast motor unit level, for twitch
      properties, were dissected and processed by a procedure [Margreth A., Damiani E.,
      Tobaldin G. Biochem Biophys Res Commun 1993; 197: 1303-1311] aimed at obtaining a
      representative total membrane fraction comprising 70-80% of the total muscle
      content of sarcoplasmic reticulum (SR) and transverse tubule (TT) membranes
      (about 20 mg protein/g). Skeletal muscle membranes were analyzed for protein
      composition, and the content and functional properties of specific components of
      the free and junctional subcompartments of the SR and of junctional TT. Our
      results, while confirming a twitch prolongation in TA of old rats, do not
      demonstrate any associated age-related change concerning: (a) the overall number
      and functional properties of Ca2+ pumps, as characterized by kinetic parameters,
      Ca(2+)-dependency, and the protein isoform specificity of SR Ca(2+)-ATPase; (b)
      the number of functional junctional SR Ca(2+)-release channels, on the basis of
      Bmax values for high-affinity binding of [3H]-ryanodine to skeletal muscle
      membranes at optimal Ca2+; (c) the overall muscle dihydropyridine
      receptor/ryanodine receptor (RyR) ratio. We conclude from these findings, and the
      additional negative evidence for changes in membrane density of specific
      components of junctional SR, including 60 kDa Ca(2+)-calmodulin protein kinase,
      that this membrane domain, like the Ca(2+)-pump domain of the SR, are in no way
      basically altered at early stages of the aging process, as investigated here.
      Because of that, we allege particular significance to the occurrence of age
      related, specific abnormalities in regulation of RyR in rat TA. The main
      supportive evidence is as follows: (a) an increased sensitivity to Ca2+ of the
      RyR of old muscle, and, more importantly; (b) an increased sensitivity to
      caffeine of [3H]ryanodine binding to the RyR at optimal Ca2+ and also optimal for
      the activity of the Ca(2+)-release channel. The results reported here also
      demonstrate that there are two classes of caffeine sites in rat TA muscle, as
      defined by differences in EC50 values at resting (pCa 7) and at high Ca2+ (pCa 4
      5), that sites involved in stimulation of [3H]-ryanodine binding to the RyR are
      distinguished by a higher affinity (caffeine below mM), and that only these sites
      undergo age-related changes. Thus, although the underlying age-related
      abnormality of the RyR remains to be elucidated, it appears to satisfy the
      requirement for being regarded as a specific change, which in itself might argue
      for its being fundamentally related to the twitch prolongation of the muscle.

PMID- 8653754
TI  - Dual effects of fluoroaluminate on activation of calcium influx and inhibition of
      agonist-induced calcium mobilization in rat glomerulosa cells.
AB  - Results presented in this study demonstrate that, in rat glomerulosa cells,
      fluoroaluminate (AlF4-) alone stimulates both cAMP accumulation (maximal
      stimulation 10-fold, ED50, 24 mM) and total inositol phosphate accumulation
      (maximal stimulation 12-fold, ED50 14 mM). Despite a transient accumulation of
      Ins(1,4,5)P3 after AlF4- stimulation, no rapid and transient intracellular
      calcium mobilization was observed. In contrast to angiotensin II (Ang II) or
      vasopressin (AVP), AlF4- induces only a slow and sustained increase in
      intracellular Ca2+. We demonstrate that this increase results from a Ca2+ influx
      mediated by cAMP-protein kinase A (PKA) pathway since preincubation with H-89, a
      potent PKA inhibitor, inhibits this influx. Moreover, a short preincubation (15
      min at 37 degrees C) of cells with AlF4- or ACTH prevents the initial release of
      Ca2+ from intracellular stores induced by Ang II, but does not affect the amount
      of InsPs accumulated under Ang II stimulation. This rapid inhibition of Ang II
      action is mediated by ACTH- or AlF4(-)-stimulated cAMP production since
      pretreatment with H-89 leads to a complete reversal. cAMP most likely acts at the
      level of Ins(1,4,5)P3 receptors since an increase in intracellular cAMP blunts
      the calcium response induced by addition of exogenous Ins(1,4,5)P3 to
      permeabilized cells. These results point out that, in rat glomerulosa cells,
      activation of the cAMP pathway can induce a rapid desensitization of the
      phospholipase C pathway by acting downstream of inositol phosphate accumulation.

PMID- 8653755
TI  - The effect of extracellular polyvalent cations on bovine anterior pituitary
      cells. Evidence for a Ca(2+)-sensing receptor coupled to release of intracellular
      calcium stores.
AB  - We have investigated the effects of extracellular cations ([ION]ex) on cytosolic
      free calcium levels ([Ca2+]i) in bovine anterior pituitary (bAP) cells, using
      single-cell microfluorimetry. Increasing the [Ca2+]ex from 1 mM to 20 mM caused
      [Ca2+]i to increase in 64 +/- 14% of bAP cells. The [Ca2+]ex-induced [Ca2+]i
      increase was observed when cells were maintained in the presence of the voltage
      gated-calcium-channel antagonist nitrendipine, but not when cells were treated
      with thapsigargin. Addition of [La3+]ex (5-15 microM) decreased [Ca2+]i, whereas
      30 microM-1 mM caused a [Ca2+]i rise in 60.9 +/- 8.8% of bAP cells. [La3+]ex
      induced [Ca2+]i changes were abolished by treating bAP-cells with either
      thapsigargin or ionomycin, but not nitrendipine. [La3+]ex at 15 microM did not
      increase [Ca2+]i in any cells tested, but when cells were treated with
      thimerosal, [La3+]ex (15 microM) caused a [Ca2+]i increase in 62.5 +/- 12.2% of
      bAP cells. In the presence of 1 mM [Ca2+]ex, successive additions of La3+ caused
      successive [Ca2+]i rises, but in nominally [Ca2+]ex-free medium only the first
      addition of [La3+]ex caused a [Ca2+]i rise. Addition of thyroliberin (TRH) in the
      presence of 1 mM [Ca2+]ex, caused [Ca2+]i to increase in 70% of bAP cells;
      subsequent addition of [La3+]ex (1 mM) only caused [Ca2+]i increases in 75% of
      those cells which had already responded to TRH. However, all cells which
      responded to 1 mM [La3+]ex also responded subsequently to TRH. After treatment
      with TRH in medium that was nominally [Ca2+]ex free, addition of La3+ (0.5-1 mM)
      did not increase [Ca2+]i in any cells tested. The number of cells which showed
      [La3+]ex-induced [Ca2+]i increases decreased in culture: only 21.75 +/- 2.2%
      cells responded after 7-11 days. When cells were cultured for 7-11 days in the
      presence of tunicamycin, [La3+]ex failed to increase [Ca2+]i in any cells tested.
      [Mn2+]ex rapidly quenched the Fura-2 signal measured from all bAP cells, but at
      10 mM it also triggered a [Ca2+]i rise in about 60% of bAP cells. The Mn(2+)
      induced [Ca2+]i rise was specifically abolished in cells cultured in the presence
      of tunicamycin although quenching was still observed. From these data we suggest
      that bAP cells may express a polyvalent cation receptor coupled to the release of
      calcium from intracellular stores.

PMID- 8653756
TI  - Calcium signalling in granule neurones studied in cerebellar slices.
AB  - The cytoplasmic free calcium concentration ([Ca2+]i) was studied in Fura-2/AM
      loaded granule neurones in acutely prepared cerebellar slices isolated from
      neonatal (6 days old) and adult (30 days old) mice. Bath application of elevated
      (10-50 mM) KCl-containing extracellular solutions evoked [Ca2+]i rise which was
      dependent on extracellular Ca2+. The K(+)-induced [Ca2+]i elevation was inhibited
      to different extends by verapamil, nickel and omega-conotoxin suggesting the
      coexpression of different subtypes of plasmalemmal voltage-gated Ca2+ channels.
      Bath application of caffeine (10-40 mM) elevated [Ca2+]i by release of Ca2+ from
      intracellular stores. Caffeine-induced [Ca2+]i elevation was inhibited by 100
      microM ryanodine and 500 nM thapsigargin. Depletion of internal Ca2+ stores by
      caffeine, or blockade of Ca2+ release channels by ryanodine, did not affect
      depolarization-induced [Ca2+]i transients, suggesting negligible involvement of
      Ca(2+)-induced Ca2+ release in [Ca2+]i signal generation following cell
      depolarization. External application of 100 microM glutamate, but not
      acetylcholine (1-100 microM), carbachol (10-100 microM) or (1S,3R)-ACPD (100-500
      microM) evoked [Ca2+]i elevation. Part of glutamate-triggered [Ca2+]i transients
      in neurones from neonatal mice was due to Ca2+ release (presumably via inositol
      (1,4,5)-trisphosphate-sensitive mechanisms) from internal Ca2+ stores. In adult
      animals, glutamate-triggered [Ca2+]i elevation was exclusively associated with
      plasmalemmal Ca2+ influx via both voltage-gated and glutamate-gated channels.

PMID- 8653757
TI  - Calcium mobilization and isometric tension in bovine tracheal smooth muscle:
      effects of salbutamol and histamine.
AB  - We determined if decreases in relative free intracellular calcium concentration
      ([Ca2+]i) caused by salbutamol, a selective beta2-adrenoreceptor agonist, were
      paralleled by calcium egression from the cytosol in bovine trachealis muscle
      strips. [Ca2+]i, or tissue-surface extracellular calcium changes (Ts[Ca2+]ext),
      were monitored using Fluo-3 acetoxymethylester or Fluo-3 pentaammonium salt
      simultaneously with isometric tension. Salbutamol (1 microM) decreased histamine
      induced isometric tension from an average peak tension of 128.5 +/- 18.4 to -4.9
      +/- 0.3 mN/mm2, and reduced the associated sustained increases in [Ca2+]i from
      100% at peak to 20.4 +/- 7.6%. Both histamine-induced elevation in [Ca2+]i and
      isometric tension were reversed completely by forskolin (1 microM). In muscle
      strip at active resting tension, salbutamol caused a decrease (49.6 +/- 12.1%) in
      [Ca2+]i. Following precontraction with histamine, salbutamol caused an immediate
      and sustained increase in Ts[Ca2+]ext which was not seen in a Na(+)-free
      solution. Finally, propranolol (10 microM) blocked both increases in Ts[Ca2+]ext
      and muscle relaxation caused by salbutamol. These findings indicate that in
      bovine trachealis muscle, the effect of salbutamol to decrease [Ca2+]i and
      isometric tension is via a beta2-adrenoceptor, and the changes in [Ca2+]i are by
      an increase in calcium egression via the Na(+)/Ca2+ exchanger, and reuptake by
      myoplasmic stores.

PMID- 8653758
TI  - Calcium mobilisation modulates growth of lens cells.
AB  - The modulating effect of calcium cell signalling agonists on tissue growth was
      studied in a rabbit lens cell line (NN1003A). Calcium mobilisation was measured
      after Fura-2 incorporation and growth assayed either by direct Coulter counting
      or [3H]-thymidine incorporation. Transient increases in cytoplasmic calcium were
      elicited by rabbit serum, histamine, ATP and PDGF. Thapsigargin induced a
      prolonged increase and all of the above agonists failed to elicit a response
      after thapsigargin. Rabbit serum and PDGF both increased cell growth in a
      concentration-dependent manner. While histamine and ATP had little effect in
      serum-free medium, they reduced serum-stimulated growth. Acetylcholine and FGF
      did not produce a marked rise in cytoplasmic calcium and neither did they
      modulate growth. Both thapsigargin and caffeine greatly inhibited growth. These
      findings indicate that, in lens cells, agonists that mobilise calcium, whether by
      acting through G-protein or tyrosine kinase receptors, also modulate lens cell
      growth. Agents such as thapsigargin and caffeine that inactivate the same calcium
      store also inhibit growth.

PMID- 8653759
TI  - Effects of luminal Ca2+ on inositol trisphosphate-induced Ca2+ release: facts or
      artifacts?

PMID- 8653760
TI  - Levels of autistic behaviour among the mentally handicapped children in Zimbabwe.
AB  - The manifestation of autistic behaviours in relation to the Diagnostic and
      Statistical Manual of Mental Disorders (1987) Revised Criteria for Autism was
      investigated among 18 mentally handicapped children. The Autistic Behaviour
      Checklist and the Behaviour Rating Instrument for Autistic (and other Atypical)
      Children were used to collect data. All the three major categories of the DSM III
      R were observed in varying frequencies in the subjects. In addition other
      behaviours not described in the DSM III-R such as disturbances in perception and
      labile mood were also observed. Generally the DSM III-R categories are supported
      by empirical evidence as found in this and other studies. Consideration should be
      given to the inclusion of characteristics such as abnormal responses to sensory
      stimuli and disturbances in developmental rate in Category C of DSM III-R to make
      it more flexible to cater for non classical autism.

PMID- 8653761
TI  - Diagnostic and cost comparisons of a questionnaire against a chemical reagent
      strip test in identifying high risk communities for Schistosoma haematobium
      infection in northern Zambia.
AB  - A comparative study was conducted in northern Zambia in order to compare both the
      economical and diagnostic performance of a questionnaire with that of the
      chemical reagent strip test in diagnosing urinary schistosomiasis with a view to
      replacing the more economically expensive reagent strip test with the
      questionnaire in the identification of high risk communities. A total of 57
      schools participated in the study and each school was considered as a community.
      Among the symptoms and conditions of blood in urine, pain when passing urine and
      bilharzia for urinary schistosomiasis, blood in the urine was the best predictor
      for urinary schistosomiasis with 73.9 pc (95 pc CI 56.0 to 91.9 pc) sensitivity,
      82.4 pc (95 pc CI 69.5 to 95.2 pc) specificity and 78.9 pc (95 pc CI 68.4 to 89.5
      pc) diagnostic efficiency in the identification of schools with high levels of
      infection. A diagnostic questionnaire for urinary schistosomiasis was two times
      cheaper than the reagent strip test in economical terms. The questionnaire
      approach in identifying high risk communities for urinary schistosomiasis is
      promising and should be tried in other endemic areas.

PMID- 8653762
TI  - Lung function studies in some Nigerian bank workers.
AB  - Following complaints of cough and tightness in the chest by a group of treasury
      workers exposed to large quantities of old and dirty currency notes withdrawn
      from circulation as well as currency for circulation, lung function tests were
      performed to find the effects of this exposure on the ventilatory function status
      of the workers. Lung function tests were carried out on 72 treasury workers (62
      male and 10 female) aged 35.11 +/- 0.62 years (mean +/- SEM); range: (21 to 58
      years), height 1.68 +/- 0.17 m; (1.55 to 1.97 m) and body weight 60.61 +/- 0.65
      kg; (48 to 86 kg). The values were compared with a control group of age, height,
      weight and sex-matched Nigerians from the same area that were not exposed to any
      known air pollutant. The mean measured lung function values of the female workers
      were not significantly different from their control values. However, the mean
      measured values of FVC, FEV1 and PEFR of the males were significantly lower than
      their control values (p < 0.01; 0.05 and 0.001 respectively) which is indicative
      of a general restrictive ventilatory defect. We conclude that chronic exposure to
      large quantities of old and dirty currency notes withdrawn from circulation as
      well as new ones may impair the lung function of treasury workers.

PMID- 8653763
TI  - Nephroblastoma and renal dysplasia in a 40 year old Nigerian man with an atrophic
      contralateral foetal kidney.
AB  - This report concerns a 40 year old Nigerian man whose initial presentation
      mimicked acute pyelonephritis. He was subsequently found to have a renal tumour
      which turned out to be a nephroblastoma. In addition, there was marked renal
      dysplasia and the contralateral kidney was atrophic and foetal in configuration.
      The possible link between these observations is discussed.

PMID- 8653764
TI  - Congenital conjunctivo-limbo-corneal choristoma associated with marginal
      keratopathy.
AB  - We report a case of a three day old African baby who presented with a three day
      history of injected right eye. Examination disclosed an injected conjunctivo
      limbo-corneal choristoma with associated marginal keratitis. Investigation
      disclosed a high maternal titer of rubella antibodies. The marginal lesions
      responded well to topical corticosteroids. Clinical manifestations of ocular
      choristomas epidemiology, classification, pathogenesis and indications for
      surgical treatment are discussed. We assume that an embryological error was the
      cause for the development of the choristomatous lesion but we cannot exclude the
      possibility of occult rubella infection during the early stages of pregnancy.

PMID- 8653765
TI  - A case of the frontal lobe syndrome following head injury in Harare, Zimbabwe.
AB  - A 51 year old male, presented with recurrent outbursts of aggression,
      hypersexuality, sexual indiscretion and hoarding litter following a head injury
      sustained in a road traffic accident. His premorbid personality was described as
      energetic but quick tempered. He had no delusions or perceptual disturbances and
      cognitive functions were intact. Physical and detailed neurological examination
      were essentially normal, with the exception of disuse atrophy of the lower limb
      muscles. He lacked insight into his problems. This case illustrates the need for
      a multidisciplinary approach to assessment, management and rehabilitation of such
      cases.

PMID- 8653766
TI  - Congenital melanotic neuroectodermal tumour of infancy: report of a case.
AB  - A case of a congenital melanotic neuroectodermal tumour in a male neonate is
      described. Management consisted of wide excision of the tumour as opposed to
      simple enucleation.

PMID- 8653768
TI  - P-value in hypothesis testing and estimation: the need to standardize its
      reporting in the Central African Journal of Medicine.

PMID- 8653767
TI  - Gastro-intestinal lymphoma in southern Turkey.
AB  - One hundred sixty three patients with primary gastro-intestinal lymphoma
      diagnosed during the last 10 years were reviewed retrospectively. Seventy five of
      them were female and 88 were male, aged between 14 to 80 years. Mean age for
      women was 36.8 +/- 17.6 years and 39.4 +/- 14.8 years for men. In 142 patients
      the disease was diagnosed by surgical intervention and endoscopic biopsy was used
      as diagnostic tool in only 21 patients. Tumour was located in the stomach in 61
      cases in the mesenteric mass in 52 cases; in the small bowel in 42 cases; in the
      large bowel in seven cases and in the cases and esophagus in one case. Mean age
      for gastric lymphoma was 47.1 +/- 14.8; 42.2 +/- 14.3 for large bowel, 35.0 +/-
      13.6 for mesenteric mass and 32.7 +/- 13.5 in small bowel lymphoma patients. Only
      four of the patients had stage I disease; 100 of them stage II disease and 59 had
      stage II-high tumour burden. Using the Working Formulation, 45 pc of the cases
      had low grade, 32 pc intermediate grade and 8 pc had high grade lymphoma, in 15
      pc of the cases grading could not be achieved. In the low grade lymphoma stomach
      was the most common site and mesenteric mass in the intermediate grade lymphoma.
      One hundred and three cases were lost to follow up after surgery, so chemotherapy
      was given to 60 patients. Sixteen cases were lost to follow up in the early
      chemotherapy period and nine cases died while under chemotherapy. Three cases
      still receiving chemotherapy. Complete response was achieved in 32 cases. The
      stomach is the most common site for gastro intestinal lymphoma and occurs a
      decade earlier than other series in Southern Turkey. Low grade lymphoma accounts
      for 45 pc of the gastro-intestinal lymphoma. Chemotherapy is an important
      adjunctive therapy after an appropriate surgical intervention. Larger and further
      studies must be carried out on etiology, pathogenesis and management.

PMID- 8653769
TI  - Lower lung field tuberculosis in Yaounde, Cameroon.
AB  - Lower lung field tuberculosis was investigated in 273 consecutive adult patients
      with pulmonary tuberculosis admitted into the Chest Unit of the Jamot Hospital in
      Yaounde from December 1991 to July 1992. Twenty eight cases were found
      representing 10.3 pc of the total admissions with pulmonary tuberculosis. Twenty
      three (82.1 pc) of the patients were under 40 years of age and there were more
      women than men. Pregnancy, HIV infection and Diabetes mellitus were conditions
      frequently associated with lower lung field tuberculosis. The clinical symptoms
      were similar to those found in upper lobe disease. Radiographic changes were
      found mostly in the right lung and bilateral involvement was infrequent.
      Extensive homogeneous or patchy consolidation was found in 87.3 pc of the cases.
      Cavities and pleural effusion were respectively observed in 14 and four of the
      patients. Tuberculosis should always be considered as a diagnostic possibility in
      patients with lower lung field lesions.

PMID- 8653771
TI  - Appendicitis in Dar es Salaam, histological pattern.
AB  - Histology of 378 appendicectomy specimens submitted to the Histopathology
      Department of Muhimbili Medical Centre from its surgical wards over a 10 year
      period (1985 to 1994) were reviewed. There were 185 cases (48.9 pc) of acute
      appendicitis, 101 cases (26.7 pc) of chronic appendicitis, 74 (19.6 pc) normal
      appendices and 13 cases (3.5 pc) schistosomal appendicitis. There were two cases
      of tuberculous appendicitis and two cases of mucocele of the appendix. Apart from
      the high frequency of chronic appendicitis the histological findings in this
      study compare well with findings reported from other studies.

PMID- 8653770
TI  - HTLV-I infection in the Free State region of South Africa: a sero-epidemiologic
      study.
AB  - Human T-lymphotropic virus type I (HTLV-1) is associated with tropical spastic
      paraparesis (TSP) and adult T-cell leukemia/lymphoma. HTLV-I infection is endemic
      in certain parts of the Natal/KwaZulu region of South Africa. No studies on the
      seroprevalence of HTLV-I infection in the Free State (FS) have been published.
      This study was designed to determine the prevalence of HTLV-I antibodies among
      different patient groups in the FS. Sera from 863 patients were analyzed. There
      were: 178 asymptomatic rural Blacks, 200 asymptomatic urban Blacks, 50
      asymptomatic Whites, 60 patients with spastic myelopathy, 70 patients with other
      neurologic disorders, 12 patients with T-cell haematologic malignancies and 293
      human immunodeficiency virus (HIV) seropositive patients. Sera were tested for
      the presence of HTLV-I/II antibodies using an enzyme linked immunosorbent assay
      (ELISA). Positive results were confirmed using a modified Western blot assay.
      None of the asymptomatic Whites were HTLV-I antibody positive (95 pc confidence
      interval (CI): 0 to 7 pc), while 2 pc (95 CI: 0.5 to 5 pc) of asymptomatic urban
      Blacks and 1.1 pc (95 pc CI: 0.14 to 4 pc) of asymptomatic rural Blacks had HTLV
      I antibodies. Of the group of patients with spastic myelopathy 33.3 pc (95 pc CI:
      21.7 to 46.7 pc had HTLV-I antibodies, while none of the patients with T-cell
      haematologic malignancies (95 pc CI: 0 to 26.5 pc) or other neurologic disorders
      (95 pc CI: 0 to 5 pc) had HTLV-I antibodies. Of the HIV seropositive patients 6.1
      (95 pc CI: 4 to 9.5) were co-infected with HTLV-I. HTLV-I infection is present in
      the Free State. It is strongly associated with spastic myelopathy in this region.
      HIV seropositive patients have a high rate of HTLV-I co-infection.

PMID- 8653773
TI  - A 10 year retrospective evaluation of cases of post neonatal tetanus seen in a
      paediatric unit of a university teaching hospital in south western Nigeria (1985
      to 1994).
AB  - A review of 56 children with post neonatal tetanus admitted over a 10 year period
      (January 1985 t December 1994) was undertaken at the Wesley Guild Hospital,
      IIesa, South Western Nigeria. The male: female ratio was 1.8:1. About 64.3 pc of
      the cases were above six years of age (mean 7.6 years). Wounds on the lower limb
      were identified as portal of entry in 39.2 pc of cases and discharging Otitis
      media in 21.4 pc. Otitis media was the usual portal of entry among the pre-school
      children (six years) in 55 pc of the cases. The patients were managed with
      antibiotics, alternating does of diazepam, phenobarbitone and chlorpremazine and
      nasogastric tube feeding. It was noticed (in 1992) that the patients showed
      varying degrees of talkativeness and disinhibition during therapy, which tended
      to subside one to two weeks after discontinuation of chlorpremazine and
      phenobarbitone. One case had a relapse which occurred one week after complete
      cessation of the initial symptoms which had taken four weeks to nurse. Resolution
      of symptoms followed the removal of a foreign body from the left foot on the 58th
      day of admission. Mortality was recorded in 39.3 pc of cases. Only 12.5 pc of the
      survivors completed the scheduled immunization doses after discharge.

PMID- 8653772
TI  - Socio-economic status and serum vitamin A levels in Zambian children.
AB  - A vitamin A survey was conducted among school children attending primary schools
      located in urban residential compounds categorised according to their socio
      economic status based on average income, as well as in pre-school children from
      one compound. The study was done in order to find out the effect of socio
      economic status on the distribution of vitamin A levels and to ascertain whether
      vitamin A deficiency is a public health problem in Zambian children. A total of
      814 school going and 381 pre-school children were studied. The serum samples were
      analysed by High Pressure Liquid Chromatography (HPLC). Using a Chi square
      analysis there was a significant difference in the results between the more
      affluent areas with higher monthly average income and the less affluent ones (p <
      0.05) showing that the socio-economic status of communities is an important
      factor in interpreting the distribution of vitamin A levels in children. Vitamin
      A deficiency was found to be a public health problem only in the pre-school age
      group. Intervention efforts to reduce vitamin A deficiency should mainly target
      this group.

PMID- 8653774
TI  - Metastatic basal cell carcinoma of the spine.
AB  - A rather progressive case of basal cell carcinoma of the left zygoma which
      subsequently metastasized to spine and brain resulting in mortality is presented.
      Surgical management of spinal metastases should be prompt and radical.

PMID- 8653775
TI  - Myasthenia gravis (MG): a preliminary report.
AB  - Eighteen cases of MG admitted to the Neurology Unit, 7th April Hospital,
      Benghazi, Libya, over a period of three years October 1991 to December 1994 were
      reviewed. The female to male ratio was 2.6:1 (13 females and five males). The
      mean age of presentation was 13.3 years later for male patients compared to
      females (mean age of presentation in females was 26.5 years and in males 39.8
      years). The average time interval between the onset of symptoms and diagnosis was
      2.5 years. At the time of diagnosis 94.5 pc (17 cases) of the cases had
      generalized MG and 5.5 pc (one case) had ocular symptoms only. In 11.1 pc (two
      cases) of patients an association with thyroid disorder was observed. Repetitive
      nerve stimulation (RNS) test was abnormal in 83 pc (15 cases) of our cases. All
      cases were initially treated with anticholinesterase and 22.2 pc (four cases)
      also additionally required steroid therapy. Thymectomy was performed on eight
      cases, four of which had thymus hyperplasia. None of our cases had any thymoma.
      Of these eight cases, one case (12.5 pc) had complete remission, five cases (62.5
      pc) were doing well with a reduced dose of anticholinesterase and +/- steroids.
      However, two cases (25 pc) required intermittent plasmapharesis and
      immunosuppressants in addition to anticholinesterase and steroids. These patients
      are obviously being followed up for long term outcome.

PMID- 8653776
TI  - Reproductive and sexual health: a research and developmental challenge.
AB  - There is a growing awareness of the burden and implications of reproductive ill
      health as contributed by unsafe motherhood (during pregnancy, childbirth,
      abortion), reproductive tract infection (RTIs) and cancer, sexually transmitted
      infections (STIs) including the human immunodeficiency virus (HIV), poorly
      regulated fertility, infertility, unwanted pregnancy and adolescent/teenage
      sexuality and pregnancy. Sexual health further entails a state of well-being in
      expression of sexuality, prevention of unwanted pregnancies, prevention of STIs
      and AIDS and freedom from sexual abuse and violence. Reproductive health is
      increasingly being recognized as one of the corner stones of health and a major
      determinant and indicator of human social development. It is central to general
      health as it reflects health in childhood and adolescence and sets the stage for
      health and life expectancy beyond the reproductive years. It is affected by other
      health aspects such as nutrition and environment, low birth weight, neonatal and
      perinatal mortality and morbidity. According to the WHO, reproductive health
      problems account for more than one third of the total burden of disease in women
      and more than 10 pc of that in men. The challenges posed by the subordinate
      status of women, the exclusion of men in reproductive health programmes and the
      need for shaping adolescents' sexual knowledge and behaviour are viewed against
      today's poor reproductive and sexual health outcomes in the context of Africa.
      Education systems, employers and policy makers are challenged to provide adequate
      STI/HIV education and on-site (school, work, satellite, drop in) control
      services. Prevention interventions, disease and health trends and their outcome
      require systematic research in order to impact on policy. Reproductive health
      education should be universal, especially for adolescents, and its impact
      assessed against appropriate monitoring criteria such as reproductive morbidity,
      STI prevalence and abortion complications.

PMID- 8653777
TI  - The law of euthanasia?

PMID- 8653778
TI  - More regional cooperation in medicines?

PMID- 8653779
TI  - E2F and cell proliferation: a world turned upside down.

PMID- 8653780
TI  - Testing the agrin hypothesis.

PMID- 8653781
TI  - Moving membrane up to the front of migrating cells.

PMID- 8653782
TI  - Emotion: systems, cells, synaptic plasticity.

PMID- 8653783
TI  - Similar structural models of the transmembrane proteins of Ebola and avian
      sarcoma viruses.

PMID- 8653784
TI  - Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta
      superfamily.
AB  - Xenopus cDNAs homologous to the Drosophila Mad gene and C. elegans CEM genes have
      been cloned and functionally analyzed by microinjection into frog embryos. The
      results show that these genes (Xmad) encode intracellular proteins that act
      downstream of TGF beta superfamily ligands. Most interesting is the fact that
      different Xmad proteins produce distinct biological responses. Xmad1 produces
      ventral mesoderm, apparently transducing a signal for BMP2 and BMP4, whereas
      Xmad2 induces dorsal mesoderm like Vg1, activin, and nodal. These results suggest
      that an individual Xmad protein waits poised in the cytoplasm for instruction
      from a distinct subset of TGF beta ligands and then conveys specific information
      to the nucleus.

PMID- 8653785
TI  - MADR1, a MAD-related protein that functions in BMP2 signaling pathways.
AB  - Components of the signaling pathways that lie downstream of Ser/Thr kinase
      receptors and are required for signaling by the TGF beta superfamily have been
      poorly defined. The Drosophila gene Mothers against dpp (MAD) and the C. elegans
      sma genes are implicated in these signaling pathways. We show that MAD functions
      downstream of DPP receptors and is required for receptor signaling.
      Phosphorylation of MADR1, a human homolog of MAD, is tightly regulated and
      rapidly induced by BMP2, but not TGF beta or activin. This phosphorylation is
      necessary for function, since a point mutant that yields a null phenotype in
      Drosophila is not phosphorylated. BMP2 treatment results in accumulation of MADR1
      in the nucleus. MAD proteins may thus define a novel class of signaling molecules
      with nuclear function in Ser/Thr kinase receptor signaling pathways.

PMID- 8653786
TI  - The receptor tyrosine kinase MuSK is required for neuromuscular junction
      formation in vivo.
AB  - Formation of neuromuscular synapses requires a series of inductive interactions
      between growing motor axons and differentiating muscle cells, culminating in the
      precise juxtaposition of a highly specialized nerve terminal with a complex
      molecular structure on the postsynaptic muscle surface. The receptors and
      signaling pathways mediating these inductive interactions are not known. We have
      generated mice with a targeted disruption of the gene encoding MuSK, a receptor
      tyrosine kinase selectively localized to the postsynaptic muscle surface.
      Neuromuscular synapses do not form in these mice, suggesting a failure in the
      induction of synapse formation. Together with the results of an accompanying
      manuscript, our findings indicate that MuSK responds to a critical nerve-derived
      signal (agrin), and in turn activates signaling cascades responsible for all
      aspects of synapse formation, including organization of the postsynaptic
      membrane, synapse-specific transcription, and presynaptic differentiation.

PMID- 8653787
TI  - Agrin acts via a MuSK receptor complex.
AB  - Formation of th neuromuscular junction depends upon reciprocal inductive
      interactions between the developing nerve and muscle, resulting in the precise
      juxtaposition of a differentiated nerve terminal with a highly specialized patch
      on the muscle membrane, termed the motor endplate. Agrin is a nerve-derived
      factor that can induced molecular reorganizations at the motor endplate, but the
      mechanism of action of agrin remains poorly understood. MuSK is a receptor
      tyrosine kinase localized to the motor endplate, seemingly well positioned to
      receive a key nerve-derived signal. Mice lacking either agrin or MuSK have
      recently been generated and exhibit similarly profound defects in their
      neuromuscular junctions. Here we demonstrate that agrin acts via a receptor
      complex that includes MuSK as well as a myotube-specific accessory component.

PMID- 8653788
TI  - Defective neuromuscular synaptogenesis in agrin-deficient mutant mice.
AB  - During neuromuscular synapse formation, motor axons induce clustering of
      acetylcholine receptors (AChRs) in the muscle fiber membrane. The protein agrin,
      originally isolated from the basal lamina of the synaptic cleft, is synthesized
      and secreted by motoneurons and triggers formation of AChR clusters on cultured
      myotubes. We show here postsynaptic AChR aggregates are markedly reduced in
      number, size, and density in muscles of agrin-deficient mutant mice. These
      results support the hypothesis that agrin is a critical organizer of postsynaptic
      differentiation does occur in the mutant, suggesting the existence of a second
      nerve-derived synaptic organizing signal. In addition, we show that intramuscular
      nerve branching and presynaptic differentiation are abnormal in the mutant,
      phenotypes which may reflect either a distinct effect of agrin or impaired
      retrograde signaling from a defective postsynaptic apparatus.

PMID- 8653789
TI  - Tumor induction and tissue atrophy in mice lacking E2F-1.
AB  - The retinoblastoma tumor suppressor protein (pRB) is a transcriptional repressor
      that regulates gene expression by physically associating with transcription
      factors such as E2F family members. Although pRB and its upstream regulators are
      commonly mutated in human cancer, the physiological role of the pRB-E2F pathway
      is unknown. To address the function of E2F-1 and pRB/E2F-1 complexes in vivo, we
      have produced mice homozygous for a nonfunctional E2F-1 allele. Mice lacking E2F
      1 are viable and fertile, yet experience testicular atrophy and exocrine gland
      dysplasia. Surprisingly, mice lacking E2F-1 develop a broad and unusual spectrum
      of tumors. Although overexpression of E2F-1 in tissue culture cells can stimulate
      cell proliferation and be oncogenic, loss of E2F-1 in mice results in
      tumorigenesis, demonstrating that E2F-1 also functions as a tumor suppressor.

PMID- 8653790
TI  - E2F-1 functions in mice to promote apoptosis and suppress proliferation.
AB  - Members of the E2F transcription factor family (E2F-1-E2F-5) are believed to be
      critical positive regulators of cell cycle progression in eukaryotes although the
      in vivo functions of the individual E2Fs have not been elucidated. Mice were
      generated that lack E2F-1 and, surprisingly, these mice develop and reproduce
      normally. However, E2F-1-/- mice exhibit a defect in T lymphocyte development
      leading to an excess of mature T cells due to a maturation stage-specific defect
      in thymocyte apoptosis. As E2F-1-/- mice age they exhibit a second phenotype
      marked by aberrant cell proliferation. These findings suggest that while certain
      members of the E2F family may positively regulate cell cycle progression, E2F-1
      functions to regulate apoptosis and to suppress cell proliferation.

PMID- 8653791
TI  - Plant cells contain two functionally distinct vacuolar compartments.
AB  - The plant cell vacuole has multiple functions, including storage of proteins and
      maintenance of an acidic pH where proteases will have maximal activity. It has
      been assumed that these diverse functions occur in the same compartment. Here, we
      demonstrate that antibodies to two different tonoplast intrinsic proteins, alpha
      TIP and TIP-Ma27, label vacuole membranes of two different compartments within
      the same cell. These compartments are functionally distinct, because barley
      lectin, a protein stored in root tips, is exclusively contained within the alpha
      TIP compartment, while aleurain, a protease that serves as a marker for an
      acidified vacuolar environment, is exclusively contained within the TIP-Ma27
      compartment. As cells develop large vacuoles, the two compartments merge; this
      may represent a process by which storage products in the alpha-TIP compartment
      are exposed to the acidic lytic TIP-Ma27 compartment for degradation.

PMID- 8653793
TI  - The homeotic target gene centrosomin encodes an essential centrosomal component.
AB  - The centrosomin (cnn) gene encodes a protein associated with mitotic centrosomes
      in Drosophila melanogaster and is a target of homeotic gene regulation. Here we
      report that CNN is an essential component of the centrosome. Loss of zygotic cnn
      expression disrupts the development of the second midgut constriction, the
      gastric caeca, and the nervous system. Embryos that lack maternal as well as
      zygotic cnn expression display defects in nuclear division, chromosome alignment,
      and microtubule organization, while adult flies that are mosaic for cnn-cells
      exhibit defects indicative of a block in cell proliferation. We propose that cnn
      provides an example of homeotic genes directly regulating the accumulation of
      essential cellular proteins to carry out segment-specific morphogenetic
      functions.

PMID- 8653792
TI  - The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins
      Cdc42 and Rac1.
AB  - The 70 kDa ribosomol S6 kinase (pp70S6k) plays an important role in the
      progression of cells through G1 phase of the cell cycle. However, little is known
      of the signaling molecules that mediate its activation. We demonstrate that Rho
      family G proteins regulate pp70S6k activity in vivo. Activated alleles of Cdc42
      and Rac1, but not RhoA, stimulate pp70S6k activity in multiple cell types.
      Activation requires an intact effector domain and isoprenylation of Cdc42 and
      Rac1. Coexpression of Dbl, an exchange factor for Cdc42, also activates pp70S6k.
      Growth factor-induced activation of pp70S6k is abrogated by dominant negative
      alleles of Cdc42 and Rac1. In addition, Cdc42 and Rac1 form GTP-dependent complex
      with the catalytically inactive form of pp70S6k in vitro and in vivo, suggesting
      a mechanism by which these G proteins activate pp70S6k.

PMID- 8653794
TI  - Solution structure of a pair of calcium-binding epidermal growth factor-like
      domains: implications for the Marfan syndrome and other genetic disorders.
AB  - The nuclear magnetic resonance structure of a covalently linked pair of calcium
      binding (cb) epidermal growth factor-like (EGF) domains from human fibrillin-1,
      the protein defective in the Marfan syndrome, is described. The two domains are
      in a rigid, rod-like arrangement, stabilized by interdomain calcium binding and
      hydrophobic interactions. We propose a model for the arrangement of fibrillin
      monomers in microfibrils that reconciles structural and antibody binding data,
      and we describe a set of disease-causing mutations that provide the first clues
      to the specificity of cbEFG interactions. The residues involved in stabilizing
      the domain linkage are highly conserved in fibrillin, fibulin, thrombomodulin,
      and the low density lipoprotein receptor. We propose that the relative
      orientation of tandem cbEGF domains in these proteins is similar, but that in
      others, including Notch, pairs adopt a completely different conformation.

PMID- 8653795
TI  - Crystal structure of an ATP-dependent DNA ligase from bacteriophage T7.
AB  - The crystal structure of the ATP-dependent DNA ligase from bacteriophage T7 has
      been solved at 2.6 A resolution. The protein comprises two domains with a deep
      cleft running between them. The structure of a complex with ATP reveals that the
      nucleotide binding pocket is situated on the larger N-terminal domain, at the
      base of the cleft between the two domains of the enzyme. Comparison of the
      overall domain structure with that of DNA methyltransferases, coupled with other
      evidence, suggests that DNA also binds in this cleft. Since this structure is the
      first of the nucleotidyltransferase superfamily, which includes the eukaryotic
      mRNA capping enzymes, the relationship between the structure of DNA ligase and
      that of other nucleotidyltransferases is also discussed.

PMID- 8653796
TI  - Human platelet sulfotransferase shows seasonal rhythms.
AB  - Our study aimed to investigate the possible presence of seasonal changes in
      platelet phenolsulfotransferase (ST) in a group of 20 healthy, drug-free subjects
      of both sexes between 24 and 37 years of age. Blood samples were taken four times
      a year in the period immediately following the equinoxes and the solstices. The
      results showed that both Sts underwent seasonal changes: the lowest values were
      found in autumn and in winter, and the highest in the summer. A positive
      correlation between the two STs and the length of the photoperiod was observed in
      winter whereas in the spring we detected a negative correlation between the TL ST
      and the photoperiod length. Future studies should clarify whether platelet ST of
      patients with mood disorders shows a similar seasonality.

PMID- 8653797
TI  - Temporal (circadian) and functional relationship between atrial natriuretic
      peptides and blood pressure.
AB  - Long-acting natriuretic peptide, vessel dilator, and atrial natriuretic factor
      consisting of amino acids (a.a.) 1 to 30, 31 to 67, and 99 to 126 of the 126-a.a.
      atrial natriuretic factor (ANF) prohormone, respectively, circulate in humans and
      have potent vasodilatory properties. To determine if these atrial natriuretic
      peptides are directly related to blood pressure in clinically healthy
      normotensive humans, we obtained 24-h profiles of vessel dilator, long-acting
      natriuretic peptide, ANF, and blood pressure in 10 men in 1988 and 11 men in 1993
      (seven men were studied twice) to compare circulating concentrations of atrial
      natriuretic peptides with naturally occurring changes in blood pressure. Overall,
      vessel dilator, long-acting natriuretic peptide, and ANF each had significant
      (p<0.001) circadian rhythms, with peak concentrations late during sleep (at 04:00
      h) being nearly twice their concentrations in the afternoon and evening. This
      high-amplitude circadian change allowed for the refinement of normal limits for
      ANF peptides by computing 3-hourly tolerance intervals (chronodesms) against
      which to compare time-specified single samples for normality. Systolic,
      diastolic, and mean arterial blood pressure also had significant circadian
      rhythms (p<0.001) with peaks and troughs that were exactly opposite those of the
      ANF peptides. In addition to this inverse temporal relationship, there was a
      significant inverse correlation between absolute values for blood pressure and
      each ANF peptide (p<0.001), implying a functional relationship. These data
      suggest that in addition to other well-established neurochemical factors, the ANF
      peptides (vessel dilator, long-acting natriuretic peptide, and ANF) are important
      for the maintenance of blood pressure and modulation of its circadian rhythm.

PMID- 8653798
TI  - Effects of age and time of day on preferred work rates during prolonged exercise.
AB  - This study was designed to examine the effects of age and time of day on work
      rates during prolonged, self-paced exercise. Eight young (19-25 years of age) and
      eight old (48-62 years of age) endurance athletes volunteered for the study. At
      two times of day (07:00 and 17:00 h), subjects were asked to pedal on a Monark
      cycle ergometer (Varberg, Sweden) at a self-chosen exercise intensity that they
      believed they could sustain for exactly 80 min. This self-chosen work rate,
      rectal temperature, skin temperature (chest, arm, and lower leg), oxygen
      consumption (VO(2)), expired carbon dioxide (VCO(2)), minute ventilation (VE),
      heart rate, and perceived exertion (RPE) were recorded every 10 min during the
      exercise. Preexercise resting measures of rectal temperature, VO(2), and VE were
      less affected by the time of day in the older group than were those in the young
      subjects (p<0.05). In the morning, rectal temperature was 0.3 degrees C higher in
      the older subjects than in the young adults. Diurnal variation in mean work rate
      over the 80-min exercise period was not evident in the old group (p>0.10) but
      amounted to 10 W in the young group (p<0.05). Older subjects chose work rates 5.4
      W lower than did the young subjects in the morning test session (p>0.10). In the
      afternoon, age differences in work rate amounted to 14.3 W (p<0.05). For all
      subjects, work rates remained relatively constant throughout the exercise period
      in the morning. In the afternoon, subjects chose high work rates within the first
      40 min of exercise, after which work rate decreased sharply to values similar to
      those recorded in the morning (p<0.01). These changes were mirrored closely by
      changes in (VO(2)) and VCO(2). Perceived exertion increased linearly throughout
      exercise, irrespective of age or time of day. These results suggest that, in
      young adults, the mean work rate over 80 min of exercise is higher in the
      afternoon than in the morning, although the work rate decreased sharply toward
      the end of the afternoon exercise. In agreement with studies reporting age
      related increases in "morningness," age differences in work rate appeared to be
      least when exercise was performed in the morning.

PMID- 8653800
TI  - Light treatment for NASA shiftworkers.
AB  - Intense artificial light can phase-shift circadian rhythms and improve
      performance, sleep, and well-being during shiftwork simulations. In real
      shiftworkers, however, exposure to sunlight and other time cues may decrease the
      efficacy of light treatment, and occupational and family responsibilities may
      make it impractical. With these considerations in mind, we designed and tested
      light-treatment protocols for NASA personnel who worked on shifted schedules
      during two Space Shuttle missions. During the prelaunch week, treatment subjects
      self-administered light of approximately 10,000 lux at times of day that phase
      delay circadian rhythms. Treatment continued during the missions and for several
      days afterward. No treatment was administered to subjects in the control group.
      Treatment subjects reported better sleep, performance, and physical and emotional
      well-being than control subjects and rated the treatment as highly effective for
      promoting adjustment to their work schedules. Light treatment is both feasible
      and beneficial for NASA personnel who must work on shifted schedules during Space
      Shuttle missions.

PMID- 8653799
TI  - Day-night variations in the renal excretion of the antiarrhythmic agent
      tiracizine and its metabolites.
AB  - Daytime and nighttime urinary recovery as well as morning and evening trough
      serum levels of the antiarrhythmic agent tiracizine and three of its metabolites
      (M1, M2, and M3) were assessed during a 7-day multiple-dose study period (50 mg
      tiracizine twice daily) in eight healthy volunteers. A significantly lower mean
      steady-state urinary recovery was observed during the daytime as compared with
      during the nighttime (Ae (tot tau d)=42.0 +/- 15.7% vs. Ae (tot tau n)=51.2 +/-
      19.6%). This difference is mainly due to a substantial increase of M1 and a
      smaller increase of M2 urinary recovery by night. Results of additional in vitro
      investigations showed the ratio of the nonionic/ionic forms of M1 and M2 to be
      highly dependent on pH in the range of pH 5-pH 7. Therefore, the observed day
      night variations might be attributed to alterations of ionization, i.e., nonionic
      tubular reabsorption of the metabolites due to circadian differences in urinary
      pH. Trough serum levels of M1 and M2 tended to be higher at 7 P.M. as compared
      with 7 A.M. Due to the narrow therapeutic index of class I antiarrhythmics, the
      present results indicate the need for further investigations concerning the
      effect of urinary pH on the pharmacokinetics of tiracizine and its metabolites.

PMID- 8653801
TI  - Temporal variation in hepatic superoxide dismutase activity in mice.
AB  - Circadian variations in superoxide dismutase (SOD) activity were determined in
      liver homogenates of Balb-C mice that were synchronized under controlled
      environmental conditions with 12 h light:12 h dark. The activity of hepatic SOD
      exhibited a significant circadian rhythm, with a minimum at 01:00 h and a maximum
      at 10:00-13:00 h. It is concluded that fluctuations in hepatic SOD activity
      render mice more susceptible to the toxic effects of reactive oxygen radicals at
      particular times of the day.

PMID- 8653802
TI  - Investigation of natural genetic variation in the circadian system of Drosophila
      melanogaster. II. Biometrical analyses of locomotor activity rhythms recorded in
      constant darkness.
AB  - The locomotor activity rhythms of 24 isochromosomal strains of Drosophila
      melanogaster were recorded in constant conditions, using an experimental design
      suitable for the serial screening with so many strains using limited equipment.
      The data obtained were subjected to biometrical genetic analysis. The results
      show that four characteristics of the rhythms (period, phase, definition, and
      waveform) display genetically based variation in expression and that each appears
      to be affected by a range of genes.

PMID- 8653803
TI  - Circadian rhythms of dopamine and cholecystokinin in nucleus accumbens and
      striatum of rats--influence on dopaminergic stimulation.
AB  - The concentrations of cholecystokinin (CCK) and dopamine (DA) were determined in
      the nucleus accumbens (anterior, posterior) and striatum of rats every 2 h during
      a period of 24 h. For both substances, a circadian rhythm was found, which was
      best fitted by a dominant 24-h period superimposed by the second (12 h) and
      fourth (6 h) harmonics. The rhythms in CCK and DA were negatively correlated
      because of a difference in phase position by approximately 3 h. A dominant DA
      peak was found in the light phase coinciding with a trough in CCK and vice versa
      in the dark phase. Based on these data, CCK and DA were determined in rats
      treated with gamma-butyrolactone (GBL; inhibitor of DA release) or thyrotropin
      releasing hormone (TRH; stimulator of DA release) at 0900 h or 1300 h to study a
      putative time-dependency in drug effects. After GBL treatment, CCK as well as DA
      increased by up to 200% whereas TRH administration led to a rather complex
      alteration, inasmuch as CCK was increased or decreased, depending on circadian
      time, whereas the rhythmic pattern in DA remained relatively unaffected.
      Comparing the drug effects obtained at 0900 h with the response seen at 1300 h
      revealed significant quantitative as well as qualitative differences. The results
      demonstrate that the neurotransmission system investigated changed its level of
      activity depending on time of day. No changes were obtained that convincingly may
      be ascribed to colocalization of DA and CCK. It is concluded that the
      chronobiological data indicate a close interaction of CCK and DA in various areas
      of the rat brain, independent of colocalization.

PMID- 8653804
TI  - Metabolic effects of trifluoperazine in the liver and the influence of calcium.
AB  - The effects of trifluoperazine on hepatic cell metabolism were investigated using
      isolated perfused rat liver. The following effects of trifluoperazine were found:
      (1) trifluoperazine inhibited oxygen uptake, the site of action being the
      mitochondria. Half-maximal inhibition occurred at concentrations around 50
      microM; with 100 microM trifluoperazine the effect was already maximal. When Ca2+
      was withdrawn from the perfusion medium and the intracellular Ca2+ pools were
      exhausted, the inhibitory action on respiration was no longer observable. The
      reintroduction of Ca2+ restored inhibition. (2) Glycogenolysis and glycolysis
      were not significantly affected during the infusion of trifluoperazine. After
      stopping trifluoperazine infusion, however, glycogenolysis (glucose release)
      experienced a transitory stimulation. (3) Gluconeogenesis from lactate as the
      carbon source was inhibited by trifluoperazine. This inhibition was approximately
      proportional to the inhibition of oxygen uptake. Withdrawal of Ca2+ diminished,
      but it did not eliminate, inhibition of gluconeogenesis. (4) Ketogenesis was also
      inhibited in parallel with the inhibition of oxygen uptake. Withdrawal of Ca2+
      from the perfusion fluid also abolished this action. (5) The effects of
      trifluoperazine were reverted very slowly when its infusion was stopped. The
      recovery of oxygen uptake at 50 min after cessation of the infusion was only 30%.
      Uptake of the substance was very fast. Absence of Ca2+ did not affect uptake. It
      was concluded that inhibition of mitochondrial energy metabolism is one of the
      most prominent effects of trifluoperazine in the liver. The fact that this
      inhibition depends on Ca2+ is unique.

PMID- 8653805
TI  - Characterization of the molecular and structural properties of the transformed
      and nuclear aryl hydrocarbon (Ah) receptor complexes by proteolytic digestion.
AB  - Ligand-dependent differences in the molecular properties of the transformed
      cytosolic and nuclear aryl hydrocarbon receptor (AhR) were investigated using the
      proteolytic clipping band shift assay. AhR complexes were incubated with
      [32P]dioxin responsive element (DRE) (26-mer) or bromodeoxyuridine (BrdU)-DRE and
      the resulting protein-DNA or crosslinked protein-DNA complexes were treated with
      trypsin or V8 protease and analyzed by electrophoresis. The results showed that
      for several different AhR ligands including 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD), 2,3,7,8-tetrachlorodibenzofuran, 1,2,7,8-tetrachlorodibenzofuran and
      alpha-naphthoflavone, the pattern of degraded protein-DNA products were similar
      using transformed cytosolic or nuclear AhR complexes. In contrast, the
      proteolytic clipping band shift assay showed that there were significant
      differences in the pattern of degraded protein-DNA products using nuclear AhR
      complexes derived from mouse Hepa 1c1c7 cells treated with TCDD or 6-methyl-1,3,8
      trichlorodibenzofuran (MCDF). The differences detected in this in vitro assay
      parallel the in vivo and in vitro activities of these compounds in which TCDD is
      a potent AhR agonist whereas MCDF is a partial AhR agonist and antagonist.

PMID- 8653807
TI  - Peroxidase-catalyzed oxidation of 3,5-dimethyl acetaminophen causes cell death by
      selective protein thiol modification in isolated rat hepatocytes.
AB  - In this study we used a peroxidase model system (glucose/glucose oxidase and
      horseradish peroxidase) to investigate the effect of extracellularly generated
      reactive metabolites of 3,5-Me2-acetaminophen on cell viability and on cellular
      thiol levels. Incubation of hepatocytes with 3,5-Me2-acetaminophen in the
      presence of glucose/glucose oxidase and horseradish peroxidase caused a
      concentration-dependent loss of cell viability. Loss of viability was associated
      with decreased protein thiol levels. Addition of the reducing agent DTT, but not
      catalase, during the incubation restored cellular protein thiol levels and
      arrested the cell killing. Protein thiol depletion occurred selectively to the
      mitochondrial and microsomal fractions and was specific for a very limited number
      of protein bands. The data suggest that the oxidative modification of individual
      protein cysteine residues within the latter two organelle fractions is critically
      involved in the mechanism of toxicity.

PMID- 8653806
TI  - MNU affects mouse erythroleukemia cell differentiation at sub-cytotoxic doses.
AB  - MNU is a potent carcinogen and mutagen to various tissues. Molecular events
      during differentiation show particular sensitivity to MNU exposure. We have
      investigated the mouse erythroleukemia (MEL) cell differentiation in response to
      DMSO and the influence of subcytotoxic doses of MNU on this process to assess the
      role of MNU on the course of differentiation and specific gene expression in a
      single cell type. Differentiation was followed by determining the extent of
      hemoglobinization and beta-globin gene expression, which are representative
      measures of red cell maturation. In this study we have shown a delay and decrease
      in the extent of MEL cell differentiation by MNU exposure at the time of
      induction to differentiate, even at sub-lethal MNU concentrations. Once the
      differentiation process was initiated, exposure to MNU at sub-lethal doses showed
      a significantly smaller effect on the molecular course of events. Pre-treatment
      of MEL cells with MNU before DMSO induction did not affect differentiation. The
      MNU-induced delay in differentiation was reflected in the delayed appearance of
      beta-globin transcripts during the first 12 h post induction. However,
      transcription could not account for reduced hemoglobinization of the MNU-treated
      cells at 48 and 72 h post induction.

PMID- 8653808
TI  - Quinone-induced apoptosis in human colon adenocarcinoma cells via DT-diaphorase
      mediated bioactivation.
AB  - DT-diaphorase (DTD) activity has been related to bioactivation and cytotoxicity
      of antitumor quinones. A pair of human colon adenocarcinoma cell lines, HT29 and
      BE, were used in this study to examine the role of DTD in antitumor quinone
      induced apoptosis. HT29 cells have elevated levels of DTD whereas BE cells lack
      functional DTD due to a point mutation which results in a complete lack of DTD
      activity. MeDZQ, a quinone that is efficiently bioactivated by DTD, induced
      apoptosis both in HT29 and BE cells, but with a much higher incidence in HT29, as
      assessed by morphological criteria and the formation of oligonucleosomal
      fragments of DNA. Two other quinone compounds which are also substrates for DTD,
      i.e. streptonigrin and mitomycin C, also preferentially induced apoptosis in HT29
      cells, which could be inhibited by dicoumarol. Our data suggest that bioreductive
      activation of antitumor quinones by DTD results in induction of apoptosis in
      human colon carcinoma cells.

PMID- 8653809
TI  - Cadmium uptake by Caco-2 cells. Effect of some milk components.
AB  - The effect of some milk components on the cellular uptake of cadmium has been
      studied using a human intestinal cell line (Caco-2). Cadmium uptake by Caco-2
      cells increased with the concentration of this metal in the culture medium, in a
      saturable way. These cells were exposed to different concentrations of cadmium
      and the synthesis of metallothionein was studied by a cadmium-saturation method.
      The levels of metallothionein increased with the cadmium concentration in the
      medium up to 20 microM of metal. Supplementation of the culture medium with 10%
      bovine milk caused a 25% decrease in the uptake of cadmium with respect to that
      internalized by the cells maintained in the culture medium alone. However, the
      uptake of cadmium from the medium supplemented with 10% human milk was similar to
      that with serum-free medium. beta-Lactoglobulin interacted with cadmium when
      studied by equilibrium dialysis, showing a stoichiometric binding constant of 5 x
      10(4) l/mol. Interaction of lactoferrin with cadmium, however, was negligible.
      When Caco-2 cells were incubated in culture medium containing lactoferrin,
      cadmium uptake decreased with respect to that observed incubating the cells in a
      medium containing beta-lactoglobulin or in the free-protein medium. The
      inhibitory effect of lactoferrin on the uptake of cadmium might be due to a
      reduction of the cell surface charge, through its binding to the membrane.

PMID- 8653810
TI  - Safe use of iodized oil to prevent iodine deficiency in pregnant women. A
      statement by the World Health Organization.
AB  - The risks and expected benefits from iodized oil, given orally or by injection,
      to pregnant women in areas of severe iodine deficiency where iodized salt is not
      available were evaluated. The conclusions, which were approved by the
      International Council for Control of Iodine Deficiency Disorders (ICCIDD), showed
      that for preventing and controlling moderate and severe iodine deficiency, the
      giving of iodized oil is safe at any time during pregnancy. Maximum protection
      against endemic cretinism and neonatal hypothyroidism will be achieved when
      iodized oil is given before conception. The potential benefits greatly outweigh
      the potential risks in areas of moderate and severe iodine deficiency disorders,
      where iodized salt is not available and is unlikely to be made available in the
      short term (1-2 years).

PMID- 8653811
TI  - Administration of iodized oil during pregnancy: a summary of the published
      evidence.
AB  - This brief review of the available studies confirms that the administration of
      iodized oil before or during pregnancy prevents endemic cretinism and brain
      damage by correcting iodine deficiency and thyroid function in pregnant women,
      fetuses, neonates, infants and children. The potential benefits derived from
      using iodized oil immediately before or during pregnancy greatly outweigh the
      potential risks in areas of moderate and severe prevalence of iodine-deficiency
      disorders, where iodized salt is not yet available.

PMID- 8653812
TI  - Rapid and simple hepatitis assays: encouraging results from a blood donor
      population in Zimbabwe.
AB  - A rapid assay to detect antibodies to hepatitis C virus (HCV) in serum and two
      rapid/simple assays to detect hepatitis B surface antigen (HBsAg) in whole
      blood/serum were evaluated for their accuracy and suitability at the National
      Blood Transfusion Service, Harare, Zimbabwe. For this purpose, a total of 206
      sera (196 routinely collected and 10 frozen) were tested using the HCV-SPOT
      (Genelabs Diagnostics), the SimpliRED HBsAg test (AGEN), and the Dipstick-HBsAg
      (PATH/Immuno-Chemical Laboratories). The results were compared with those
      obtained using a routine HBsAg enzyme immunoassay (EIA) (Auszyme, Abbott) and an
      HCV IgG second-generation EIA (Abbott). An HCV IgM test (Abbott) was used for
      samples that produced discordant results, and all HCV-reactive samples were
      confirmed using the INNO-LIA HCV Ab III synthetic peptide assay (Innogenetics).
      Overall, the concordance between the HCV-SPOT and the HCV EIA was 97.6%
      (201/206). For the 193 sera that were true HCV negatives, the number of false
      positives was six with the HCV-SPOT test, while the HCV EIA produced three
      (specificity = 97.0% and 98.5%, resp.). Of these false positives, two were so in
      both tests. None of the false positives contained IgM antibodies to HCV, and
      there were no false negatives in the two HCV tests. The concordance between the
      two rapid HBsAg tests and the HBsAg EIA was 99.5% (205/206). All the rapid/simple
      tests were easy to perform and interpret, required no (or minimal) laboratory
      equipment, and could be taught easily to local laboratory personnel. The cost of
      these tests is equivalent to or less than that of routine EIA methods.

PMID- 8653814
TI  - Global eradication of poliomyelitis: benefit-cost analysis.
AB  - A benefit-cost analysis of the Poliomyelitis Eradication Initiative was
      undertaken to facilitate national and international decision-making with regard
      to financial support. The base case examined the net costs and benefits during
      the period 1986-2040; the model assumed differential costs for oral poliovirus
      vaccine (OPV) and vaccine delivery in industrialized and developing countries,
      and ignored all benefits aside from reductions in direct costs for treatment and
      rehabilitation. The model showed that the "break-even" point at which benefits
      exceeded costs was the year 2007, with a saving of US$ 13 600 million by the year
      2040. Sensitivity analyses revealed only small differences in the break-even
      point and in the dollars saved, when compared with the base case, even with large
      variations in the target age group for vaccination, the proportion of case
      patients seeking medical attention, and the cost of vaccine delivery. The
      technical feasibility of global eradication is supported by the availability of
      an easily administered, inexpensive vaccine (OPV), the epidemiological
      characteristics of poliomyelitis, and the successful experience in the Americas
      with elimination of wild poliovirus infection. This model demonstrates that the
      Poliomyelitis Eradication Initiative is economically justified.

PMID- 8653813
TI  - Operational problems of an iron supplementation programme for pregnant women: an
      assessment of UNRWA experience.
AB  - Assessed is a large-scale iron supplementation programme for the 70 000 pregnant
      refugee women cared for by the United Nations Relief and Works Agency for
      Palestine Refugees in the Near East (UNRWA). For this purpose, a retrospective
      survey of 1267 antenatal records was conducted in health centres located in the
      West Bank, Gaza, Syrian Arab Republic, Jordan, and Lebanon. The following
      operational problems were identified: late entry to antenatal care; high drop-out
      rate from antenatal care; low compliance in follow-up haemoglobin examinations;
      and misdirected continued testing of women who were not anaemic at registration.
      Routine iron supplementation of all pregnant women should be considered only in
      those countries where severe anaemia is prevalent and should always be coupled
      with additional interventions that are effective at improving iron deficiency
      anaemia in a given population. In most countries attention should be directed
      towards changing dietary habits to enhance the availability of local foodstuffs
      that are rich in iron. One initial haemoglobin test may help in focusing on the
      relatively few initially anaemic subjects who need further attention. Repeated
      testing during pregnancy is unwarranted.

PMID- 8653815
TI  - A rapid dipstick antigen capture assay for the diagnosis of falciparum malaria.
      WHO Informal Consultation on Recent Advances in Diagnostic Techniques and
      Vaccines for Malaria.
AB  - Recent advances in the diagnosis of Plasmodium falciparum infections have made it
      possible to consider supplementing light microscopy with a standardized dipstick
      antigen capture assay based on the detection of a parasite-specific protein,
      which is secreted by the asexual blood stages and immature gametocytes but not by
      the other stages. Field trials indicate that this dipstick assay provides
      consistently reproducible results, with a threshold of detection of P. falciparum
      parasitaemia similar to that obtained by high quality routine malaria microscopy
      and a specificity and sensitivity of around 90% compared with standard thick
      blood film microscopy. The stability, reproducibility, and ease of use of the
      assay clearly indicate that it has potential for application in the management of
      malaria, particularly at the peripheral health care level, provided its accuracy
      can be assured and that it can be made affordable. Consideration should be given
      to its wider use where operational requirements and resources so justify, and
      where decisions are based on adequate evaluation of the existing health delivery
      systems.

PMID- 8653816
TI  - Knowledge, practices, and perceptions about malaria in rural communities of
      Zimbabwe: relevance to malaria control.
AB  - A survey of 411 household heads was undertaken in Gokwe district, Zimbabwe, to
      assess villagers' knowledge, practices and perceptions about malaria and their
      implications for malaria control. Our results show that although the government
      has sustained an annual indoor insecticide spraying programme for over four
      decades, about 50% of respondents did not adequately understand its purpose, with
      26% believing that the programme was intended to kill domestic pests, not
      including mosquitos. During the 1991-92 spraying cycle, 72% of the villagers had
      their homes sprayed. However, 21% of such villagers refused to have some rooms in
      their homes sprayed. Householders' understanding of the function of the spraying
      programme was significantly related to their compliance with it (P < 0.05). A
      total of 82% of respondents reported not taking any measures to protect
      themselves from malaria. Taking preventive measures was significantly related to
      knowledge of the causes of malaria (P < 0.05). The study shows the importance of
      involving communities in a control programme intended to be to their benefit and
      of informing them about available options for protection against malaria.

PMID- 8653817
TI  - Anopheles minimus: its bionomics and role in the transmission of malaria in
      Assam, India.
AB  - Indoor, day-resting collections of Anopheles minimus mosquitos from human
      dwellings in the study area in Assam, India, indicated that these insects were
      prevalent throughout the year and that their maximum abundance occurred from
      March to August. A. minimus was identified as a vector of malaria, and sporozoite
      infections were recorded every month of the year, with the highest rating
      occurring in October. The mosquito was highly anthropophilic and fed on human
      hosts (indoor) all through the night, but feeding was more pronounced between
      01:00 and 04:00, the person-biting rate was 13.7 per night. Breeding occurred
      throughout the year in slow-flowing streams with grassy banks. A. fluviatilis was
      also identified as a vector of malaria in the study area but occurred in low
      density, and sporozoite infections were only seasonal.

PMID- 8653818
TI  - [Complementary nutrition for the young child following the devaluation of the CFA
      franc (African Financial Community): 2 case studies in the Congo and Senegal
      urban environment].
AB  - Developing countries frequently see their currency depreciated to varying
      degrees. The consequences of such monetary disturbances on the nutrition of young
      children are not well known, though children are the most vulnerable in
      nutritional terms. One year after the 50% devaluation of the CFA Franc
      (communaute financiere africaine, "African Financial Community"), which took
      place on 12 January 1994 simultaneously in fourteen countries, nine of which are
      on the UNDP list of least developed countries, we wanted to find out the long
      term effects of the devaluation, and the strategies that families had adopted to
      cope with it. In Brazzaville, Congo, in December 1994, an epidemiological survey
      was conducted on a representative sample of 893 children between the ages of 4
      and 12 months in two districts, and indicators of child nutrition were
      established. A comparable survey had been conducted in December 1993, before the
      devaluation. In Senegal, in the absence of a previous survey which could be used
      in comparison, a qualitative survey using RAP methodology, was conducted in
      January 1995 in two towns near the capital. In three districts in each of these
      towns, a cluster of ten plots was chosen at random and surveyed, with a
      combination of semi-structured individual interviews with mothers (n = 60) and
      group interviews with all the women together (n = 6). The information was put
      together with interviews of 25 local traders selling food. In the Congo,
      comparison of the two surveys shows that the practice of breast-feeding had
      hardly changed, nor had the age at which baby food was introduced (90% of
      children of 4-5 months take semi-solid and solid foods); on the other hand, more
      children are being given the ordinary family meal earlier, at 6-9 months. The
      proportion of baby foods based on commercially imported flour has fallen (from
      32% in 1993 to 18% in 1994), and has been replaced with local products based on
      maize; this change is more marked among poorer families. The low nutritional
      value of such preparations is in part compensated by the addition of sugar,
      though less milk is added (28% in 1994 as opposed to 43% in 1993). In Senegal,
      mothers do not seem to have changed their breast-feeding practices either, the
      age at which baby foods are introduced, or the number of times they are provided
      daily. The most important change is the drop in quality of food given to
      children, and the poorer family food for the older children. The partial switch
      from imported products to local produce was an expected consequence of
      devaluation; it is clearly confirmed here for nutrition of young children, with
      the consequent loss of nutritional quality (a reduction in energy density and in
      nutrients). The first thing needed is, therefore, an improvement in local
      manufacture of food supplements of good nutritional quality, for young children.
      Mothers also complain of the increased difficulty in managing a family diet so as
      to take account of economic needs, cultural values and nutrition. They therefore
      criticize a number of nutritional education messages that are clearly no longer
      appropriate to the new economic context. Finally the fact that young children are
      getting poorer quality nutrition is worrying for the future: if it lasts, the
      nutritional status of children will deteriorate; whenever possible, monitoring
      must be established so that measures can be taken when necessary to forestall any
      dramatic deterioration that would endanger the health of the children.

PMID- 8653820
TI  - Mass administration of DEC-medicated salt for filariasis control in the endemic
      population of Karaikal, south India: implementation and impact assessment.
AB  - DEC (diethylcarbamazine)-medicated salt, at a concentration of 0.1 to 0.2 mg per
      100 mg, was given to the entire population of Karaikal (119 978) in South India
      for a 4-year period from 1982. The per capita consumption of DEC in medicated
      salt was 13.3 grams for the entire period. The prevalence of microfilaraemia
      declined significantly from 4.5% in 1982 to 0.14% in 1985 and 0.4% in 1993.
      Vector infection declined from 0.6% in 1982 to zero after two years. The
      mechanism of preparation and regulated distribution of DEC-medicated salt in the
      locality is presented. Long-term follow-up suggests that DEC-medicated salt
      distribution is cheap, safe and efficient for the elimination of filariasis.

PMID- 8653819
TI  - Clinical and epidemiological evaluation of a live, cold-adapted influenza vaccine
      for 3-14-year-olds.
AB  - Reported is a study of live, cold-adapted (CA) reassortant mono-, di-, and
      trivalent influenza type A and B vaccines in a series of controlled clinical and
      epidemiological investigations involving nearly 130 000 children aged 3-15 years.
      The results of clinical, immunological, and morbidity investigations of the
      vaccinees and a control group over 6-months' follow-up indicated that the
      vaccines were completely attenuated by the children. Transient febrile reactions
      occurred in < 1% of the children after vaccination, including double seronegative
      individuals with low antibody titres. The type A reisolates examined were
      genetically stable. The reassortants did not suppress each other after
      simultaneous inoculation of children and stimulated antibody response to
      influenza virus strains A1, A3, and B. The incidence of influenza-like diseases
      was approximately 30-40% lower among the vaccinated group than among the control
      group. The study demonstrates, for the first time, the efficacy of CA vaccine
      against infections caused by influenza B virus.

PMID- 8653821
TI  - Leishmaniasis in AIDS patients: results of leukocytoconcentration, a fast
      biological method of diagnosis.
AB  - Leukocytoconcentration is an easy, fast and inexpensive technique for the
      diagnosis of leishmaniasis from peripheral blood. The technique involves
      concentration of blood parasites on a small surface of a microscope slide while
      the red blood cells are removed by lysis. The results, compared with those of
      other methods (examination of cultures of blood samples and bone marrow smears),
      were very good and accurate. All but one of our cases of leishmaniasis were
      patients with HIV co-infection. Leukocytoconcentration facilitates follow-up of
      cases and fast detection of any relapse.

PMID- 8653822
TI  - Eye disease in an onchocerciasis-endemic area of the forest-savanna mosaic region
      of Nigeria.
AB  - In a forest-saving mosaic zone of south-eastern Nigeria endemic for
      onchocerciasis, we identified eye disorders in 65.5% of a randomly selected
      population sample. Onchocerciasis-related eye disease was present in 13.7% of the
      study sample and constituted 21% of the total number of eye disorders. A total of
      78 (33.2%) of 235 subjects with visual impairment had onchocerciasis-related eye
      lesions, and of 35 who were blind in both eyes, onchocerciasis-induced eye
      disease was the cause in 28 (80%). The prevalence of bilateral blindness from all
      causes in the study area was 4.1%, while that from onchocerciasis-related causes
      was 3.3%. The commonest onchocerciasis-induced lesions that were responsible for
      visual impairment and blindness were choroidoretinitis and optic nerve disease.
      Sclerosing keratitis, an important causative lesion in onchocerciasis-endemic
      savanna regions, was encountered only one. Eye disease is therefore an important
      feature of onchocerciasis in the forest-savanna mosaic areas of Nigeria and
      should be borne in mind when planning and executing control programmes.

PMID- 8653823
TI  - Cholesterol screening in asymptomatic adults. No cause to change. Task Force on
      Risk Reduction, American Heart Association.

PMID- 8653824
TI  - Myocardial endothelin. Does it play a role in myocardial failure?

PMID- 8653825
TI  - Angiotensin-converting enzyme inhibition suppresses plasminogen activator
      inhibitor-1 expression in the neointima of balloon-injured rat aorta.
AB  - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1), an important regulator of
      fibrinolysis and extracellular matrix turnover, has been implicated in a number
      of vascular diseases. Studies demonstrating angiotensin II (Ang II) to be a
      potent stimulator of PAI-1 expression in cultured vascular cells suggests that
      the renin-angiotensin system may modulate vascular PAI-1 expression. METHODS AND
      RESULTS: We examined the effects of the ACE inhibitor captopril on PAI-1
      expression in control and balloon-injured rat aorta. Northern blot analysis
      demonstrated that aortic PAI-1 mRNA expression was 7.6-fold elevated 3 hours
      (P<.05) after balloon injury, back to baseline at 2 days, increased again at 4
      days, and by 7 days after balloon injury was 3.2-fold elevated (P<.05) when
      compared with control. In captopril-treated rats, the induction of PAI-1
      expression by balloon injury was significantly suppressed by 44% (P<.05) in the 7
      day group but was not altered in the 3-hour group. Captopril also reduced
      baseline aortic PAI-1 mRNA. In situ hybridization and immunohistochemistry
      revealed dense PAI-1 staining of 7-day neointima in untreated rats and a dramatic
      decrease in PAI-1 in neointima of captopril-treated rats. CONCLUSIONS: This
      report demonstrates that balloon injury results in both a rapid ACE inhibitor
      independent induction of aortic PAI-1 expression and a later increase in PAI-1 in
      the neointima that is significantly suppressed by captopril. This provides the
      first evidence that the renin-angiotensin system regulates neointimal PAI-1
      expression and that ACE inhibitors can reduce PAI-1 in the vessel wall in vivo.

PMID- 8653826
TI  - Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize
      to chromosomes 11q13 and 4q34, respectively.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) is an important regulator
      of endothelial cell proliferation, migration, and permeability during embryonic
      vasculogenesis as well as in physiological and pathological angiogenesis. The
      recently isolated VEGF-B and VEGF-C cDNAs encode novel growth factor genes of the
      VEGF family. METHODS AND RESULTS: Southern blotting and polymerase chain reaction
      analysis of somatic cell hybrids and fluorescence in situ hybridization (FISH) of
      metaphase chromosomes were used to assess the chromosomal localization of VEGF-B
      and VEGF-C genes. The VEGF-B gene was found on chromosome 11q13, proximal to the
      cyclin D1 gene, which is amplified in a number of human carcinomas. However, VEGF
      B was not amplified in several mammary carcinoma cell lines containing amplified
      cyclin D1. The VEGF-C gene was located on chromosome 4q34, close to the human
      aspartylglucosaminidase gene previously mapped to 4q34-35. CONCLUSIONS: The VEGF
      B locus in 11q13 and the VEGF-C locus in 4q34 are candidate targets for mutations
      that lead to vascular malformations or cardiovascular diseases.

PMID- 8653827
TI  - Thermal latency in radiofrequency ablation.
AB  - BACKGROUND: Progression of unintentionally induced atrioventricular delay is
      occasionally observed directly after termination of radiofrequency delivery in
      the vicinity of the atrioventricular node. We postulated that the application of
      a radiofrequency pulse may result in a tissue temperature rise that continues
      after the pulse. METHODS AND RESULTS: Using the thigh muscle preparation, 5-, 10
      , 20-, and 30-second pulses were applied as 30 to 40 W via a standard 4-mm tip
      electrode with 10-g contact pressure. Forty-one undisturbed pulses were delivered
      while recording intramural temperatures at 2-, 4-, and 7-mm depth. Maximal
      "thermal latency" was observed with the shortest pulse duration and at greatest
      depth. With 5-second applications, tissue temperature at 7-mm depth peaked 11.6
      seconds after termination of radiofrequency delivery and stayed above end-of
      pulse value as long as 34.5 seconds after the pulse. The additional rise in
      tissue temperature was 2.9 degrees C. If only recording within the lesion border
      zone were considered, the duration of latency was maximal with 10-second pulses:
      an additional gain in tissue temperature of 3.4 degrees C was observed 6.4
      seconds after the pulse while tissue temperature stayed above end-of-pulse value
      during 18.3 seconds. CONCLUSIONS: With relatively short applications, tissue
      temperature continues to rise after termination of radiofrequency delivery. This
      "thermal latency" may result in lesion growth after the pulse and may so explain
      the incidentally observed progression of conduction block after short pulses in
      the vicinity of the atrioventricular node. It also may explain the apparent
      discrepancy between lesion growth rate and intramural temperature rise studies.

PMID- 8653828
TI  - Expression of inducible nitric oxide synthase in human heart failure.
AB  - BACKGROUND: There is increasing evidence that alterations in nitric oxide
      synthesis are of pathophysiological importance in heart failure. A number of
      studies have shown altered nitric oxide production by the endothelial
      constitutive isoform of nitric oxide synthase (NOS), but there is very little
      information on the role of the inducible isoform. METHODS AND RESULTS: We
      analyzed inducible NOS (iNOS) expression in ventricular myocardium taken from 11
      control subjects (who had died suddenly from noncardiac causes), from 10 donor
      hearts before implantation, and from 51 patients with heart failure (24 with
      dilated cardiomyopathy [DCM], 17 with ischemic heart disease [IHD], and 10 with
      valvular heart disease [VHD]). Reverse transcription-polymerase chain reaction
      was used to confirm the presence of intact mRNA and to detect expression of iNOS
      and atrial natriuretic peptide (ANP). ANP was used as a molecular phenotypic
      marker of ventricular failure. iNOS was expressed in 36 of 51 biopsies (71%) from
      patients with heart failure and in none of the control patients (P<.0001). iNOS
      expression could also be detected in 50% of the donor hearts. All samples that
      expressed iNOS also expressed ANP. iNOS gene expression occurred in 67% of
      patients with DCM, 59% of patients with IHD, and 100% of patients with VHD. To
      determine whether iNOS protein was expressed in failing ventricles,
      immunohistochemistry was performed on three donor hearts and nine failing hearts
      with iNOS mRNA expression. Staining for iNOS was almost undetectable in the donor
      myocardium and in control sections, but all failing hearts showed diffuse
      cytoplasmic staining in cardiac myocytes. Expression of iNOS could be observed in
      all four chambers. Western blot analysis with the same primary antibody showed a
      specific positive band for iNOS protein in the heart failure specimens; minimal
      iNOS protein expression was seen in donor heart samples. CONCLUSIONS: iNOS
      expression occurs in failing human cardiac myocytes and may be involved in the
      pathophysiology of DCM, IHD, and VHD.

PMID- 8653829
TI  - Platelet-derived growth factor-A mRNA expression in fetal, normal adult, and
      atherosclerotic human aortas. Analysis by competitive polymerase chain reaction.
AB  - BACKGROUND: To understand which growth factors are important for growth of
      atherosclerotic plaques, it is necessary to know the factor's relative abundance
      and how its gene is regulated in relation to cell proliferation. We tested
      whether platelet-derived growth factor-A (PDGF-A) mRNA levels correlated with
      cell proliferation in developing aorta, normal adult aorta, and atherosclerotic
      plaques. METHODS AND RESULTS: We developed a competitive reverse transcription
      polymerase chain reaction (RT-PCR) assay to measure human PDGF-A mRNA levels in
      small tissue samples. A mutated PDGF-A synthetic RNA was used as an internal
      standard to compete with endogenous PDGF-A mRNA for amplification. The assay is
      highly sensitive and much more precise than routine RT-PCR. Correction for
      heteroduplex pairing between the endogenous and mutant PCR products correlates
      precisely with synthetic RNA standards and quantitative Northern blotting.
      Immunostaining with the proliferation marker (proliferating cell nuclear antigen)
      showed the following rank order of proliferation: fetal aorta >> atherosclerotic
      plaque > normal aortic media. PDGF-A mRNA levels, however, did not correlate with
      proliferation. Normal adult aorta contained the most PDGF-A mRNa (34.0+/-7.6
      amol/microgram total RNA). Fetal aortas were intermediate (10.2+/-1.6
      amol/microgram total RNA); advanced atherosclerotic plaques contained the least
      PDGF-A mRNA (0.3+/-0.1 amol/microgram total RNA). PDGF-A protein was readily
      detectable in normal media by immunostaining. Advanced plaques generally had less
      cell-associated PDGF-A protein, although A-chain was also detected in plaque
      matrix. CONCLUSIONS: PDGF-A mRNA and protein do not correlate with proliferation
      among these three groups. The significance of high levels of PDGF-A mRNA in the
      "quiescent" aortic media is unknown but it clearly does not promote cell
      replication.

PMID- 8653830
TI  - Ascorbic acid reverses endothelial vasomotor dysfunction in patients with
      coronary artery disease.
AB  - BACKGROUND: In the setting of atherosclerosis, endothelial vasomotor function is
      abnormal. Increased oxidative stress has been implicated as one potential
      mechanism for this observation. We therefore hypothesized that an antioxidant,
      ascorbic acid, would improve endothelium-dependent arterial dilation in patients
      with coronary artery disease. METHODS AND RESULTS: Brachial artery endothelium
      dependent dilation in response to hyperemia was assessed by high-resolution
      vascular ultrasound before and 2 hours after oral administration of either 2 g
      ascorbic acid or placebo in a total of 46 patients with documented coronary
      artery disease. Plasma ascorbic acid concentration increased 2.5-fold 2 hours
      after treatment (46+/-8 to 114+/-11 micromol/L, P=.001). In the prospectively
      defined group of patients with an abnormal baseline response (<5% dilation),
      ascorbic acid produced marked improvement in dilation (2.0+/-0.6% to 9.7+/-2.0%),
      whereas placebo had no effect (1.1+/-1.5% to 1.7+/-1.5%, P=.003 for ascorbic acid
      versus placebo). Ascorbic acid had no effect on hyperemic flow or arterial
      dilation to sublingual nitroglycerin. CONCLUSIONS: Ascorbic acid reverses
      endothelial vasomotor dysfunction in the brachial circulation of patients with
      coronary artery disease. These findings suggest that increased oxidative stress
      contributes to endothelial dysfunction in patients with atherosclerosis and that
      endothelial dysfunction may respond to antioxidant therapy.

PMID- 8653831
TI  - Patency of infarct-related artery. Effect of restoration of anterograde flow on
      vagal reflexes. ATRAMI (Automatic Tone and Reflexes After Myocardial Infarction)
      Investigators.
AB  - BACKGROUND: In post-myocardial infarction (MI) patients, the restoration of
      anterograde flow in the infarct-related artery (IRA) significantly improves
      survival. Limitation of infarct size and increased electrical stability of the
      myocardium are likely operating mechanisms for this beneficial effect. We tested
      the hypothesis that patency of the IRA may enhance vagal reflexes, a factor known
      to affect electrical stability of the infarcted myocardium. METHODS AND RESULTS:
      Analysis of angiographic data was performed in 359 of 1284 post-MI patients
      enrolled in a multicenter prospective study within 8 weeks after the index MI.
      All the patients underwent baroreflex sensitivity (BRS) assessment by the
      phenylephrine method. The BRS of the entire population averaged 8.2+/-5.5 ms/mm
      Hg and was significantly related to age but not to ejection fraction (EF). One-,
      two-, and three-vessel disease was present in 138, 96, and 99 patients,
      respectively, while no coronary stenosis was observed in 26. IRA patency was
      documented in 234 patients (65%), while in the remaining 125 (35%), the artery
      remained occluded. Patients with occluded IRAs had more extensive coronary
      disease (2 to 3 vessels, 71% versus 46%, P<.01) and more depressed left
      ventricular (LV) function (LVEF, 48+/-13% versus 53+/-12%, P<.001). Patency of
      the IRA was associated with higher BRS values (BRS, 8.9+/-5.8 versus 7.1+/-4.7
      ms/mm Hg, P<.005) and with a lower incidence (9% versus 18% P<.02) of markedly
      depressed BRS (<3 ms/mm Hg), a condition suggested by preliminary studies to be
      associated with an increased risk of post-MI mortality. The association between
      IRA patency and BRS was more evident in anterior than in inferior MI.
      Multivariate regression analysis showed that age of the patient and patency of
      the IRA were the major independent determinants of BRS, while LVEF was weakly
      related to BRS and only when analyzed as a categorized variable. CONCLUSIONS: The
      presence of an open IRA is associated with higher baroreflex sensitivity, and
      this effect is largely independent of limitation of infarct size by IRA patency.
      These data offer new insights into the mechanisms by which coronary artery
      patency may affect cardiac electrical stability and survival.

PMID- 8653832
TI  - Contributions of frequency distribution analysis to the understanding of coronary
      restenosis. A reappraisal of the gaussian curve.
AB  - BACKGROUND: Clinical restenosis after balloon angioplasty can be categorized by
      use of dichotomous terms based on the presence or absence of recurrent myocardial
      ischemia. In contrast, recent investigations have concluded that late luminal
      renarrowing, documented through angiographic imaging, occurs to a variable extent
      in nearly all stenoses. This process has been characterized by a gaussian or
      normal frequency distribution, with restenosis simply representing an extreme
      form of this delayed remodeling. In the current study, frequency distribution
      analysis was used to examine the process of coronary restenosis in a large cohort
      of patients at risk. METHODS AND RESULTS: Quantitative coronary angiographic
      analysis was applied to 9279 cineangiograms obtained in 3093 patients before and
      immediately after angioplasty and after 6-month follow-up. Late loss, defined as
      the change in minimum lumen diameter of the target stenosis from postdilation to
      follow-up, did not statistically conform to a normal distribution (P<.0001 by
      both chi2 statistic and Kolmogorov-Smirnov test), even after the exclusion of the
      236 stenoses that displayed total occlusions at follow-up angiography.
      Examination of deviation from a normal curve revealed an excessively high
      frequency of stenoses that experienced either little change (0.0+/-0.3 mm) or
      marked change (1.0 to 2.0 mm) in late loss, with a low frequency of stenoses with
      intermediate values (0.3 to 1.0 mm). Similarly, although the distribution of
      percent diameter stenosis of the target lesion was statistically normal
      immediately after dilation, this gaussian distribution disappeared during the
      follow-up period. Other angiographic indexes of restenosis also failed to
      approximate a normal curve. In an attempt to improve the goodness of fit, a
      probabilistic model of late loss was created on the basis of deconvolution of the
      observed data distribution. Two theoretical, discrete populations of stenoses
      were identified, one with and one without overall late luminal narrowing. Unlike
      the gaussian distribution, this model provided a good representation of the
      observed data (P=NS for lack of fit). CONCLUSIONS: The frequency distributions of
      angiographic indexes of restenosis often superficially resemble a gaussian curve,
      an appearance that is artifactually enhanced by the measurement imprecision of
      current quantitative techniques. Nevertheless, standard indexes of coronary
      restenosis fail to conform statistically to a normal distribution. The pattern of
      deviations observed supports the possible existence of discrete subpopulations of
      lesions, each with a different propensity toward the development of restenosis
      after coronary intervention.

PMID- 8653833
TI  - Heart transplantation-associated perioperative ischemic myocardial injury.
      Morphological features and clinical significance.
AB  - BACKGROUND: The frequency and clinical significance of perioperative ischemic
      myocardial injury (PIMI) after heart transplantation and the diagnostic features
      distinguishing PIMI from rejection are not well defined. METHODS AND RESULTS: We
      evaluated PIMI in the first four weekly endomyocardial biopsies and/or autopsy
      myocardium from 140 consecutive orthotopic heart transplantation recipients (1984
      to 1991) by grading the severity of coagulative myocyte necrosis (CMN) as absent,
      0; mild-focal, 1; moderate-multifocal, 2; or severe-confluent, 3, and determining
      the evolution of morphological features of its healing. CMN (often with
      contraction bands) was noted in 124 patients (89%); 24 patients (17%) had grade 3
      CMN, of which 4 died within 30 days of transplantation. Nevertheless, at 1 year
      after surgery, survival was similar in patients with and without severe injury.
      Increased cold ischemic time but neither donor age nor intensity of inotropic
      support correlated with more severe early ischemic injury. PIMI inflammation was
      characterized by a predominantly polymorphonuclear/histiocytic infiltrate that
      contained lymphocytes and plasma cells, expanding the interstitium but not
      encroaching upon and separable from adjacent viable myocytes. Histological
      features of PIMI developed and resolved more slowly than those of typical
      myocardial infarct necrosis in nonimmunosuppressed patients; at 4 weeks, CMN
      persisted in 20% of patients and residual healing in nearly half. Diagnostic
      rejection was observed concurrently with PIMI in 54 of 533 biopsies (10%).
      CONCLUSIONS: Diagnosed by conventional histological criteria, PIMI is prevalent
      early after heart transplantation and has a protracted healing phase that can
      mimic or coexist with rejection. Extensive PIMI has deleterious impact on short
      term survival, but the long-term impact of PIMI remains to be established.

PMID- 8653834
TI  - Distribution of hyaluronan during extracellular matrix remodeling in human
      restenotic arteries and balloon-injured rat carotid arteries.
AB  - BACKGROUND: The glycosaminoglycan hyaluronan (HA) is present in developing
      tissues and healing wounds and forms a loose, hydrated extracellular matrix (ECM)
      that promotes processes such as cell migration. To investigate the potential
      contribution of HA to the pathogenesis of restenosis, we studied (1) human
      lesions obtained by directional atherectomy and (2) experimentally induced
      neointima formation in balloon-injured rat carotid arteries. METHODS AND RESULTS:
      A biotinylated proteoglycan fragment that binds specifically to HA was used to
      stain atherectomy specimens from 29 human restenotic lesions (mean restenosis
      interval, 6.0+/-4.4 months) and 8 human primary lesions. The loose myxoid ECM
      typical of human restenotic arteries demonstrated intense, diffuse staining for
      HA. The intensity was inversely related to the density of immunostaining for
      collagen types I and III and was lowest in hypocellular primary atherosclerotic
      plaque. Among 24 rat carotid arteries retrieved 3, 7, 14, 28, 42, or 56 days
      after balloon injury and immunostained as well for proliferating cell nuclear
      antigen, staining for HA in the neointima reached a maximum 7 days after balloon
      injury and was associated with the presence of proliferating, PCNA-positive
      smooth muscle cells. CONCLUSIONS: Hyaluronan is a characteristic constituent of
      the loose myxoid ECM in human restenotic arteries and of the neointima in
      experimentally injured arteries. The presence of hyaluronan may be a marker for
      an initial phase of the extracellular matrix remodeling that occurs during the
      development of a fibroproliferative lesion and could facilitate biological
      processes such as cell migration.

PMID- 8653835
TI  - Plasma angiotensin II, predisposition to hypertension, and left ventricular size
      in healthy young adults.
AB  - BACKGROUND: We studied the correlates of left ventricular mass (LVM) in 84
      healthy young adults aged 16 to 24 years from the general population. Subjects
      were selected according to predisposition to hypertension into four groups with
      either high or low personal blood pressures and either high or low parental blood
      pressures. METHODS AND RESULTS: LVM was measured by echocardiography, and
      measurements of blood pressure, heart rate, body dimensions, and plasma
      concentrations of components of the renin-angiotensin system were made under
      resting conditions. LVM was similar in individuals predisposed to hypertension
      (high personal and parental blood pressures) and those with contrasting
      predisposition (low personal and parental pressures). Regression analysis of the
      combined groups showed that LVM correlated closely with body size, particularly
      lean body mass (r=.69, P<.0001) and systolic (r=.35, P<.0001) but not diastolic
      blood pressure. Plasma angiotensin II (r=.39, P<.0001), renin (r=.302, P<.01),
      and angiotensin-converting enzyme (r=.22, P<.05) showed significant correlation
      with LVM. Multiple regression analysis revealed that plasma angiotensin II was
      the most important component of the renin-angiotensin system and that its effect
      was independent of systolic blood pressure and body size. CONCLUSIONS: These
      findings provide evidence in humans that angiotensin II exerts a direct on
      myocardial size. This association may have important implications for the
      complications and treatment of left ventricular hypertrophy.

PMID- 8653836
TI  - C-type natriuretic peptide. An endogenous inhibitor of vascular angiotensin
      converting enzyme activity.
AB  - BACKGROUND: Atrial and B-type natriuretic peptide are both known to be
      antagonists of the renin-angiotensin system. C-type natriuretic peptide (CNP) is
      a new member of this family except that its principal source is the vascular
      endothelium. This study tested the hypothesis that CNP is a local inhibitor of
      vascular angiotensin-converting enzyme (ACE) activity. METHODS AND RESULTS:
      Vascular ACE activity was assessed by the differential vascular response to
      angiotensin I and angiotensin II. Healthy male volunteers were studied with the
      use of brachial artery infusions of angiotensin I and angiotensin II at two
      doses, with and without coinfusion of CNP at 500 pmol/min (n=8) and hydralazine
      at 10 microgram/min (n=8) (as a nonspecific vasodilator control). CNP alone and
      hydralazine alone caused similar increases in forearm blood flow (CNP+, 93.0+/
      14.8%; hydralazine+, 84.2+/-22.6%). CNP inhibited the vasoconstrictive effect of
      angiotensin I (reduction in overall effect with CNP, 56.8+/-12.9%, P<.001) but
      not that of angiotensin II. Hydralazine did not significantly inhibit the effect
      of either angiotensin I or angiotensin II. CONCLUSIONS: This evidence of a
      differential effect of CNP on the vascular response to angiotensin I but not to
      angiotensin II suggest that CNP acts as a local endogenous regulator of vascular
      ACE activity in the human forearm resistance vessels.

PMID- 8653837
TI  - Relation of mean right atrial pressure to echocardiographic and Doppler
      parameters of right atrial and right ventricular function.
AB  - BACKGROUND: A paucity of data exists as to the relation of mean right atrial
      pressure (RAP) to Doppler parameters of right atrial and ventricular filling.
      Furthermore, whether echocardiographic parameters of right atrial and right
      ventricular function and inferior vena cava improve the relation of Doppler
      filling dynamics with RAP has not been explored. METHODS AND RESULTS: Doppler and
      echocardiographic studies were performed simultaneously with measurements of mean
      RAP in consecutive patients who either had a central venous catheter in the
      Intensive Care Unit or underwent catheterization of the right side of the heart.
      The initial population consisted of 35 patients with a mean age (+/-SD) of 60+/
      15 years; 34% were on mechanical ventilation. Mean RAP averaged 9+/-5.7 mm Hg
      (range, 2 to 28 mm Hg). Among tricuspid inflow parameters, the strongest relation
      with RAP was observed with the ratio of early to late velocity (r=.66). For
      hepatic venous flow, systolic filling wave indexes had the best relation with
      atrial pressure, the highest being for systolic filling fraction (r=-.86). Weaker
      relations were noted with the use of right atrial volumes, right ventricular
      function, and inferior vena caval diameters. The addition of any of these
      variables did not improve the relation of systolic filling fraction with RAP. The
      regression equation (RAP=21.6-24 systolic filling fraction) was tested
      prospectively in the estimation of atrial pressure 50 patients. The correlation
      coefficient was .89 in the prospective group and .88 in the total group of 85
      patients. The mean difference between predicted and actual pressures in the whole
      population was -0.2+/-2.6 mm Hg. The sensitivity and specificity for mean RAP>8
      mm Hg were 86% and 92%, respectively. CONCLUSIONS: Among echocardiographic and
      Doppler parameters of right atrial and right ventricular function, hepatic venous
      flow dynamics relate best to mean atrial pressure and can be used clinically to
      estimate mean RAP.

PMID- 8653838
TI  - Sex differences in cardiac arrest survivors.
AB  - BACKGROUND: Important sex differences in the epidemiology of sudden death and in
      the results of electrophysiological testing in survivors of cardiac arrest have
      been identified. These differences are currently poorly understood. METHODS AND
      RESULTS: Three hundred fifty-five consecutive survivors of out-of-hospital
      cardiac arrest (84 women and 271 men) referred for electrophysiologically guided
      therapy were analyzed retrospectively for sex differences in underlying pathology
      and predictors of outcome. Women were significantly less likely to have
      underlying coronary artery disease than men (45% versus 80%) and more likely to
      have other forms of heart disease or structurally normal hearts (P<.0001). The
      mean left ventricular ejection fraction was higher in women (0.46+/-0.18 versus
      0.41+/-0.18, P<.05), and women were more likely to have no inducible arrhythmia
      at baseline electrophysiological testing (46% versus 27%, P=.002), although when
      the patients were stratified by coronary artery disease status, these sex
      differences were no longer present. The independent predictors of outcome
      differed between men and women. In men, a left ventricular ejection fraction of
      <0.40 was the most powerful independent predictor of total (relative risk, 2.8;
      95% CI, 1.6 to 5.0; P<.0001) and cardiac (relative risk, 6.3; 95% CI, 2.9 to
      13.5; P<.0001) mortality. In contrast, the presence of coronary artery disease
      was the only independent predictor of total (relative risk, 4.5; 95% CI, 1.5 to
      13.4; P=.003) and cardiac (relative risk, 4.4; 95% CI, 1.2 to 15.6; P=.012)
      mortality in women. CONCLUSIONS: Females survivors of cardiac arrest are less
      likely to have underlying coronary artery disease. The predictors of total and
      cardiac mortality differ between male and female survivors. Coronary artery
      disease status is the most important predictor in women, and impaired left
      ventricular function is the most important predictor in men.

PMID- 8653839
TI  - Direct evidence that initial oxidative stress triggered by preconditioning
      contributes to second window of protection by endogenous antioxidant enzyme in
      myocytes.
AB  - BACKGROUND: We tested the hypothesis that late preconditioning is associated with
      increased antioxidant enzyme activity induced by initial oxidative stress.
      METHODS AND RESULTS: Isolated rat myocytes were preconditioned either with two
      cycles of 5 minutes of anoxia and 5 minutes of reoxygenation or with exogenous
      superoxide anion (O2-) generated by reaction of xanthine oxidase with xanthine.
      Myocytes were allowed to recover for 60 minutes or 24 hours, after which they
      were subjected to 60 minutes of anoxia and 60 minutes of reoxygenation. After 60
      minutes or 24 hours, the protection was evidenced by decreased O2- production,
      increased Mn superoxide dismutase (Mn-SOD) activity, increased call viability,
      decreased LDH release, reduced malondialdehyde formation, high-energy phosphate
      preservation, and improved call morphology in preconditioned and O2(-)-treated
      myocytes. Immediately after treatment with O2- or repetitive, brief anoxia, O2-
      production was increased in myocytes. Longer anoxia resulted in loss of Mn-SOD
      activity in anoxic controls 24 hours later, whereas it was significantly
      increased in preconditioned and O2- -treated myocytes. O2- production was
      inhibited in preconditioned and O2(-)-myocytes. Myocytes treated with Mn-SOD
      during short, intermittent anoxia exhibited decreased activity of Mn-SOD and
      increased O2- production 24 hours later. Mn-SOD activity in late preconditioning
      was considerably higher than that in classic preconditioning. CONCLUSIONS: These
      results suggest that a burst of oxygen free radicals generated during the initial
      periods of brief, repetitive anoxia increases myocardial antioxidant activity 24
      hours later and that it contributes to the late cardioprotective effect of
      preconditioning.

PMID- 8653840
TI  - Human monocyte-endothelial cell interaction induces synthesis of granulocyte
      macrophage colony-stimulating factor.
AB  - BACKGROUND: Adhesion of monocytes to the endothelium is an initial step in the
      early stages of atherosclerosis and inflammation. Granulocyte-macrophage colony
      stimulating factor (GM-CSF) stimulates a range of functional activities of
      monocytes, including regulation of monocyte adhesion and induction of cytokine
      production. We investigated in this study whether CM-CSF synthesis was induced by
      the direct cell-to-cell interaction between human monocytes and human umbilical
      vein endothelial cells (ECs). METHODS AND RESULTS: The expressions of GM-CSF mRNA
      and protein were analyzed by Northern blotting and ELISA, respectively. Coculture
      of monocytes and ECs induced the high levels of GM-CSF mRNA expression, whereas
      culture of ECs or monocytes alone or coculture of neutrophils with ECs induced no
      GM-CSF mRNA expression. A large amount of GM-CSF was secreted into the
      supernatant upon coculture of monocytes with ECs. The supernatant from the
      coculture markedly stimulated 02- release in neutrophils, and this effect was
      significantly inhibited by anti-GM-CSF antibody (Ab). Immunohistochemistry and in
      situ hybridization revealed that GM-CSF protein and mRNA were clearly detectable
      in both ECs and monocytes adhered to ECs but not in nonadherent monocytes. The GM
      CSF production by the coculture was markedly inhibited by genistein and partially
      inhibited by Abs against interleukin-1 and tumor necrosis factor-alpha.
      CONCLUSIONS: The present results indicate that GM-CSF is produced by direct
      interaction between monocytes and ECs and suggest that GM-CSF produced locally by
      monocyte-EC adhesive interaction plays an important role in the pathogenesis of
      atherosclerosis and inflammation by modulating monocyte/macrophage functions in
      vivo.

PMID- 8653841
TI  - Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular
      proliferation after balloon angioplasty in atherosclerotic rabbits.
AB  - BACKGROUND: Thrombin may have a pivotal role in restenosis after angioplasty.
      Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after
      angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation
      is believed to be an important mechanism for restenosis and thrombin has been
      shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that
      the mechanism of the effect of hirudin on limiting luminal narrowing by plaque
      occurs via inhibition of cellular proliferation. METHODS AND RESULTS: Femoral
      atherosclerosis was induced in 108 rabbits, and balloon angioplasty was
      performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour
      infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group
      3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at
      7 or 28 days to determine cross-sectional area narrowing by plaque and cellular
      proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 hours
      after angioplasty, group 1 and 2 rabbits were injected with 3H-thymidine and
      killed 1 hour later, and labeling indexes were determined. A significant increase
      in the index of 3H-thymidine-labeled nuclei was observed in the intima of
      "ballooned" arteries compared with "nonballooned" atherosclerotic arteries at
      both 30 hours (0.06+/-0.05 versus 0.01+/-0.01, P<.01) and 72 hours (0.10+/-0.06
      versus 0.004+/-0.004, P<.01). By 7 days, the index of labeled cells was similar
      to baseline (0.04+/-0.03 versus 0.01+/-0.01, P=.12). Hirudin had no effect on the
      3H-thymidine labeling indexes at any of the time points studied despite the fact
      that hirudin treatment in group 3 rabbits resulted in less cross-sectional area
      narrowing by plaque at both 7 and 28 days after angioplasty (41+/-16 versus 24+/
      12 at 7 days and 60+/-21 versus 44+/-17 at 28 days, heparin versus hirudin;
      P<.03). CONCLUSIONS: Balloon angioplasty resulted in a marked increase in
      cellular proliferation that peaked at 72 hours. A 2-hour infusion of hirudin
      failed to reduce early 3H-thymidine labeling, suggesting that inhibition of cell
      proliferation within the first 7 days after angioplasty is not the predominant
      mechanism by which hirudin exerts its effect on limiting luminal narrowing by
      plaque 28 days after balloon angioplasty in this animal model.

PMID- 8653842
TI  - Increased shear stress overcomes the antithrombotic platelet inhibitory effect of
      aspirin in stenosed dog coronary arteries.
AB  - BACKGROUND: Shear stress is one of the known platelet activating mechanisms that
      leads to thrombosis. Increased shear stress has also been postulated to reverse
      the antithrombotic effect of some drugs such as aspirin (ASA). METHODS AND
      RESULTS: Experiments were conducted in five dogs to determine the minimal shear
      stress levels that produce acute platelet thrombus formation in mechanically
      stenosed arteries and the increase in shear required to reverse the
      antithrombotic effect of ASA. After intimal and medial damage, stenosis was
      produced in the circumflex coronary artery. We used the finite-difference
      numerical solution of the Navier-Stokes equation to determine the wall shear
      stresses in the area of stenosis. At 70+/-6% coronary diameter reduction, cyclic
      flow reductions (CFRs) caused by acute platelet thrombus formation were observed
      in the stenosed lumen. At this level of stenosis, the shear stress was 144+/-15
      Pa. ASA given at a dose of 5 mg/kg IV inhibited in vivo acute platelet-mediated
      thrombus formation and abolished CFRs in all dogs. However, increasing the
      stenosis level to 80+/-5% caused the CFRs to return. The shear stress increased
      with the increased level of stenosis to 226+/-22 Pa. Thus, an average 10%
      increase in diameter narrowing caused a 56+/-20% increase in shear stress
      (P<.005) and renewed platelet activation and thrombus formation despite ASA
      pretreatment. CONCLUSIONS: Individuals who take ASA daily to prevent coronary
      artery thrombus formation may not be well protected when a change in
      hemodynamics, such as an acute hypertensive episode, or an increase in stenosis
      severity due a ruptured atherosclerotic plaque causes an increase in shear
      stress.

PMID- 8653843
TI  - Optical coherence tomography for optical biopsy. Properties and demonstration of
      vascular pathology.
AB  - BACKGROUND: Optical coherence tomography (OCT) is an recently developed medical
      diagnostic technology that uses back-reflected infrared light to perform in situ
      micron scale tomographic imaging. In this work, we investigate the ability of OCT
      to perform micron scale tomographic imaging of the internal microstructure of in
      vitro atherosclerotic plaques. METHODS AND RESULTS: Aorta and relevant
      nonvascular tissue were obtained at autopsy. Two-dimensional cross-sectional
      imaging of the exposed surface of the arterial segments was performed in vitro
      with OCT. A 1300-nm wavelength, superluminescent diode light source was used that
      allows an axial spatial resolution of 20 microns. The signal-to-noise ratio was
      109 dB. Images were displayed in gray scale or false color, Imaging was performed
      over 1.5 mm into heavily calcified tissue, and a high contrast was noted between
      lipid- and water-based constituents, making OCT attractive for intracoronary
      imaging. The 20-microns axial resolution of OCT allowed small structural details
      such as the width of intimal caps and the presence of fissures to be determined.
      The extent of lipid collections, which had a low backscattering intensity, also
      were well documented. CONCLUSIONS: OCT represents a promising new technology for
      imaging vascular microstructure with a level of resolution not previously
      achieved with the use of other imaging modalities. It does not required direct
      contact with the vessel wall and can be performed with a catheter integrated with
      a relatively inexpensive optical fiber. The high contrast among tissue
      constituents, high resolution, and ability to penetrate heavily calcified tissue
      make OCT an attractive new imaging technology for intracoronary diagnostics.

PMID- 8653844
TI  - Endogenous endothelin-1 participates in the maintenance of cardiac function in
      rats with congestive heart failure. Marked increase in endothelin-1 production in
      the failing heart.
AB  - BACKGROUND: Although it was demonstrated that circulating endothelin-1 (ET-1)
      levels are elevated in congestive heart failure (CHF), the production and roles
      of ET-1 in the failing heart are not known. We investigated the production of ET
      1 in the heart and the density of myocardial ET receptors in rats with CHF. We
      also investigated the effects of intravenously infused BQ-123, an endothelin(A)
      (ETA) receptor antagonist, on both heart and myocardial contractility in rats
      with CHF. METHODS AND RESULTS: We used the left coronary artery-ligated rat model
      of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1
      concentration was significantly higher in the CHF rats than in the sham-operated
      rats (P<.01). In the left ventricle, the expression prepro-ET-1 mRNA was markedly
      higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1
      in the left ventricle was also significantly higher in the CHF rats than in the
      sham-operated rats (500+/-41 versus 102+/-10 pg/g tissue, P<.01). Myocardial ET
      receptors were significantly higher in the CHF rats than in the sham-operated
      rats (243+/-20 versus 155+/-17 fmol/mg protein, P<.05). In the CHF rats,
      intravenous BQ-123 infusion (0.1 mg x kg(-1) x min(-1) for 120 minutes)
      significantly decreased both heart rate (P<.01) and LV+dP x dt(max) (P<.05) but
      not mean blood pressure. BQ-123 infusion did not affect these hemodynamic
      parameters in the sham-operated rats. CONCLUSIONS: In the present study, we
      demonstrated that the production of ET-1 in the heart is markedly increased and
      that the density of myocardial ET receptors is significantly elevated in the CHF
      rats. Intravenous BQ-123 infusion significantly reduced both heart rate and
      LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the
      ET receptor-mediated signal transduction system in the heart appears to be
      markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the
      maintenance of the cardiac function in these rats.

PMID- 8653845
TI  - Myocardial contractile response to nitric oxide and cGMP.
AB  - BACKGROUND: Cardiac endothelium releases a number of factors that may modulate
      performance of underlying cardiac muscle. Nitric oxide (NO), which accounts for
      the biological activity of the vascular endothelium-derived relaxing factor and
      relaxes vascular smooth muscle by elevating intracellular cGMP, may be involved
      in this cardiac modulation. METHODS AND RESULTS: We examined the myocardial
      contractile effects of the NO-releasing nitrovasodilators sodium nitroprusside
      (SNP), 3-morpholino-sydnonimine (SIN-1), and S-nitroso-N-acetyl-penicillamine
      (SNAP); of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase
      inhibitor zaprinast in isolated cat papillary muscle. Modulation of these effects
      by endocardial endothelium (EE) and by cholinergic and adrenergic stimulation was
      also investigated. Concentration-response curves with addition of NO-releasing
      nitrovasodilators (SNP, SIN-1, SNAP) and 8-bromo-cGMP resulted in a biphasic
      inotropic response. Although administration of low concentrations induced a
      positive inotropic effect, higher concentrations induced a negative inotropic
      effect. Both NO-induced positive and negative inotropic effects were attenuated
      by methylene blue, suggesting a role for cGMP. The response to high
      concentrations of 8-bromo-cGMP was shifted to the right in muscles with damaged
      EE, whereas cholinergic stimulation shifted the curve leftward. Zaprinast caused
      a monophasic concentration-dependent positive inotropic effect; damaging the EE
      shifted the terminal portion of the curve upward. Concomitant cholinergic or
      adrenergic stimulation modified the response to zaprinast into a negative
      inotropic response. CONCLUSIONS: NO and cGMP induced a concentration-dependent
      biphasic contractile response. The myocardial contractile effects of NO and cGMP
      were modulated by the status of EE and by concomitant cholinergic or adrenergic
      stimulation.

PMID- 8653846
TI  - Basis for increased microtubules in pressure-hypertrophied cardiocytes.
AB  - BACKGROUND: We have shown the levels of the sarcomere and the cardiocyte that a
      persistent increase in microtubule density accounts to a remarkable degree for
      the contractile dysfunction seen in pressure-overload right ventricular
      hypertrophy. In the present study, we have asked whether these linked phenotypic
      and contractile abnormalities are an immediate and direct effect of load input
      into the cardiocyte or instead a concomitant of hypertrophic growth in response
      to pressure overloading. METHODS AND RESULTS: The feline right ventricle was
      pressure-overloaded by pulmonary artery banding. The quantity of microtubules was
      estimated from immunoblots and immunofluorescent micrographs, and their
      mechanical effects were assessed by measuring sarcomere motion during microtubule
      depolymerization. The biogenesis of microtubules was estimated from Northern and
      Western blot analyses of tubulin mRNAs and proteins. These measurements were made
      in control cats and in operated cats during and after the completion of right
      ventricular hypertrophy; the left ventricle from each heart served as a normally
      loaded same-animal control. We have shown that the alterations in microtubule
      density and sarcomere mechanics are not an immediate consequence of pressure
      overloading but instead appear in parallel with the load-induced increase in
      cardiac mass. Of potential mechanistic importance, both these changes and
      increases in tubulin poly A+ mRNA and protein coexist indefinitely after a new,
      higher steady state of right ventricular mass is reached. CONCLUSIONS: Because we
      find persistent increases both in microtubules and in their biosynthetic
      precursors in pressure-hypertrophied myocardium, the mechanisms for this
      cytoskeletal abnormality must be sought through studies of the control both of
      microtubule stability and of tubulin synthesis.

PMID- 8653847
TI  - Novel biochemical diagnostic method for aortic dissection. Results of a
      prospective study using an immunoassay of smooth muscle myosin heavy chain.
AB  - BACKGROUND: Aortic dissection is one of the most common aortic catastrophes.
      Although newer diagnostic methods as exemplified by image diagnostic techniques
      have greatly improved the diagnosis of aortic dissection, the diagnosis is still
      frequently missed today because the signs and symptoms of the disease are at
      times obscure. A reliable biochemical diagnostic method for aortic dissection
      would be beneficial. METHODS AND RESULTS: A novel biochemical diagnostic method
      for diagnosis of aortic dissection was developed that uses an immunoassay of
      monoclonal antibodies to smooth muscle myosin heavy chain. A prospective study
      was conducted to ascertain the usefulness of the method in the diagnosis of
      aortic dissection. Twenty-seven patients with aortic dissection admitted within
      the first 24 hours after onset were enrolled. Serial assay of serum smooth muscle
      myosin heavy chain showed significant elevations within the first 24 hours after
      onset of aortic dissection, with levels exceeding 10 ng/mL, with subsequent rapid
      reductions. The sensitivity of the assay within the first 12 hours was 90% with a
      specificity of 97%. Analysis of 65 patients with acute myocardial infarction
      showed that the method could accurately differentiate myocardial infarction from
      aortic dissection. CONCLUSIONS: The immunoassay of serum smooth muscle myosin
      heavy chain is a rapid and reliable biochemical method in the diagnosis of aortic
      dissection. The potential use of the method in clinical medicine is promising.

PMID- 8653848
TI  - Cardiac auscultation. A glorious past--but does it have a future?

PMID- 8653849
TI  - Images in cardiovascular medicine. Detection of normal pericardium and of
      pericardial effusion in the lateral chest radiograph.

PMID- 8653850
TI  - Inhibition of cyclic flow variations by von Willebrand factor-glycoprotein Ib
      binding domain.

PMID- 8653851
TI  - Serum-soluble interleukin-2 receptor, neopterin levels, and severity of dilated
      cardiomyopathy.

PMID- 8653852
TI  - Heart rate variability and sleep.

PMID- 8653853
TI  - Angiotensin-converting enzyme gene polymorphism in ischemic heart disease.

PMID- 8653854
TI  - QRS score and infarct size.

PMID- 8653855
TI  - Dobutamine induces a biphasic response in dysfunctional left ventricular regions.

PMID- 8653856
TI  - Sex differences in men and women after myocardial infarction.

PMID- 8653857
TI  - Management of patients with atrial fibrillation. A Statement for Healthcare
      Professionals. From the Subcommittee on Electrocardiography and
      Electrophysiology, American Heart Association.

PMID- 8653859
TI  - New treatments for acute ischemic stroke.

PMID- 8653858
TI  - Guidelines for perioperative cardiovascular evaluation for noncardiac surgery.
      Report of the American College of Cardiology/American Heart Association Task
      Force on Practice Guidelines. Committee on Perioperative Cardiovascular
      Evaluation for Noncardiac Surgery.

PMID- 8653860
TI  - Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases:
      a revisit.

PMID- 8653861
TI  - Aging and cardiovascular disease: a summary of the Eighth Munster International
      Arteriosclerosis Symposium.

PMID- 8653862
TI  - Potentiation of vasculopathy by insulin: implications from an NHLBI clinical
      alert.

PMID- 8653863
TI  - Thrombolysis in ischemic stroke: double or quits?

PMID- 8653864
TI  - Risk stratification in patients with unstable angina: 'deja vu all over again'?

PMID- 8653865
TI  - Angioplasty from bench to bedside to bench.

PMID- 8653866
TI  - Ischemic stroke and the gene for angiotensin-converting enzyme in Japanese
      hypertensives.
AB  - BACKGROUND: The ACE insertion/deletion (I/D) polymorphism is reported to be
      associated with myocardial infarction in both whites and Japanese. However, there
      have been no reports on the association of this polymorphism with stroke in each
      race. Furthermore, there are some racial differences in the demographics of
      cardiovascular disease. In Japanese, stroke (especially that which occurs in
      preexisting hypertension) is more common and coronary artery disease much less
      common than in whites. We propose that the ACE I/D polymorphism might be
      associated with hypertensive cerebrovascular disease in Japanese. METHODS AND
      RESULTS: To study the association between the ACE I/D polymorphism and
      hypertensive cerebrovascular disease, we identified the ACE I/D genotype in 228
      hypertensive and 104 normotensive Japanese subjects. Compared with its frequency
      (0.31) in the 90 hypertensives without lacunae detected by magnetic resonance
      imaging, the ACE*D allele frequency was significantly higher (0.47; P<.001) in
      the 138 hypertensives with silent or clinically overt ischemic stroke, whereas
      there was no significant difference between its frequency in hypertensives
      without lacunae and in 104 normotensive control subjects (0.34). The positive
      association between the ACE I/D genotype and ischemic stroke in hypertensive
      patients was independent of other risk factors. CONCLUSIONS: We found a positive
      association between the ACE*D allele and ischemic stroke in Japanese
      hypertensives in our study. The ACE*D allele may be an independent risk factor
      for the development of cerebrovascular disease in hypertensive patients.

PMID- 8653867
TI  - Thrombin activity and early outcome in unstable angina pectoris.
AB  - BACKGROUND: The blood coagulation system is frequently activated in the acute
      phase of unstable angina, but it is unknown whether the augmented function of the
      hemostatic mechanism may serve as a marker of increased risk for an early
      unfavorable outcome. METHODS AND RESULTS: Plasma concentrations and 24-hour
      urinary excretion of fibrinopeptide A were prospectively determined in 150
      patients with unstable angina. All patients underwent 24-hour Holter monitoring,
      during which time urine was collected; at the end of this period, a blood sample
      was taken and coronary arteriography was performed. The patients were followed up
      for the occurrence of cardiac events (death and myocardial infarction) until they
      underwent coronary revascularization or until they were discharged from the
      hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found
      to be abnormally elevated in 50% and 45% of the study population, respectively.
      During hospitalization, 11 patients developed myocardial infarction and 2
      patients died. Kaplan-Meier analysis demonstrated a significantly higher
      probability of developing cardiac events in patients with abnormal rather than
      normal plasma levels of fibrinopeptide A (P<.01), whereas no difference in
      outcome was observed between patients with normal and those with abnormal 24-hour
      urinary excretion. Cox regression analysis showed that the only variables
      independently related to an early unfavorable outcome were the presence of
      persistent ischemia during 24-hour Holter monitoring (P<.0001), the presence of
      intracoronary thrombosis at angiography (P=.016), and abnormal fibrinopeptide A
      plasma levels (P=.038). CONCLUSIONS: Patients with unstable angina pectoris and
      abnormal fibrinopeptide A plasma levels are at increased risk for an early
      unfavorable outcome.

PMID- 8653868
TI  - Leukocyte depletion attenuates reperfusion injury in patients with left
      ventricular hypertrophy.
AB  - BACKGROUND: Reperfusion injury can occur after a long period of aortic cross
      clamping in patients with left ventricular hypertrophy during open-heart surgery,
      even with the most up-to-date techniques of myocardial protection. In the present
      study, we examined whether leukocyte depletion as an adjunct to terminal blood
      cardioplegia (LDTC) attenuates reperfusion injury in patients with left
      ventricular hypertrophy (LV mass, >300 g; left ventricular end-systolic volume
      index, >100 mL/m2) in a group of 30 patients undergoing aortic valve replacement.
      METHODS AND RESULTS: We used basic cold potassium crystalloid cardioplegic
      solution. Terminal blood cardioplegic solution (TC) or LDTC was accomplished by
      mixing a cold potassium crystalloid cardioplegic solution with warm arterial
      blood obtained through cardiopulmonary bypass and administered to the aortic root
      for the first 10 minutes of reperfusion. During delivery of LDTC, warm arterial
      blood was passed through a leukocyte-removal filter. Patients were randomized
      into one of three groups for reperfusion: whole blood (WB) (n=10), TC (n=10), and
      LDTC (n=10). Left ventricular biopsies were obtained before ischemia, at the end
      of ischemia, and 15 minutes after reperfusion. Semiquantitative scoring for
      ultrastructural alterations indicated that the LDTC group achieved significantly
      better recoveries of both scores at reperfusion for myocyte damage and for
      endothelial cell damage of capillaries than did the WB and TC groups. The LDTC
      group had significantly fewer neutrophils adhering to endothelial cells at
      reperfusion and a lower level of malondialdehyde derived from myocardium than did
      the WB and TC groups. Regarding the clinical data, the LDTC group had a lower
      maximum creatine kinase-MB, a higher percentage of spontaneous defibrillation, a
      lower pulmonary capillary wedge pressure, and a lower requirement for dopamine
      that did the WB group, whereas the TC group failed to do better than the WB
      group. CONCLUSIONS: These results demonstrate that leukocyte-depleted reperfusion
      is potentially beneficial as an adjunct to terminal cardioplegia during cardiac
      surgery to attenuate reperfusion injury in patients with left ventricular
      hypertrophy.

PMID- 8653869
TI  - Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to
      oxidation in humans.
AB  - BACKGROUND: Oxidatively modified LDL has been shown to markedly impair
      endothelium-dependent dilation in experimental studies. The aim of the present
      study was to determine the relationship between the coronary vasomotor response
      to the endothelium-dependent agonist acetylcholine and the in vitro
      susceptibility of LDL to oxidation in patients. METHODS AND RESULTS: Endothelium
      dependent coronary vasomotion in response to acetylcholine (10(-8) to 10(-6)
      mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56 +/- 9
      years) after 1 year of therapy with either an American Heart Association Step 1
      diet (seven patients), lovastatin and cholestyramine (seven patients), or
      lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation
      was determined by measuring the lag phase of conjugated diene formation induced
      by Cu2+. Patients treated with lovastatin and probucol had prolongation of the
      lag phase (263 +/- 64 minutes) compared with diet- (91 +/- 22 minutes) or
      lovastatin and cholestyramine-(118 +/- 57 minutes) treated patients (P<.0001). By
      univariate analysis, the coronary vasomotor response to acetylcholine was
      significantly related to the lag phase of conjugated diene formation (P=.002),
      cholesterol-lowering therapy (P=.002), and serum cholesterol (P=.02). By
      multivariate analysis, the lag phase remained a significant predictor of the
      acetylcholine vasomotor response, independent of the effect of cholesterol
      lowering treatment. CONCLUSIONS: In patients treated with lipid-lowering agents,
      the vasodilator response to acetylcholine is related to the susceptibility of LDL
      to oxidation. These findings suggest that oxidative stress is an important
      determinant of the coronary endothelial dysfunction observed in patients with
      atherosclerosis and hypercholesterolemia.

PMID- 8653870
TI  - Relation between troponin T and the risk of subsequent cardiac events in unstable
      coronary artery disease. The FRISC study group.
AB  - BACKGROUND: Early risk assessment is important in patients with unstable coronary
      artery disease, ie, unstable angina or non-Q-wave myocardial infarction. Some
      previous small studies have indicated that patients with unstable angina and
      elevation of troponin T (tn-T) have worse short-term and long-term prognoses. In
      this study, the prognostic value of tn-T was evaluated and compared with other
      early available risk indicators. METHODS AND RESULTS: Nine hundred seventy-six
      patients participating in a randomized study of low-molecular-weight heparin in
      unstable coronary artery disease were followed for 5 months after the index
      episode. The risk of cardiac events increased with increasing maximal levels of
      tn-T obtained in the initial 24 hours. The lowest quintile (<0.06 microgram/L)
      constituted a low-risk group, the second quintile (0.06 to 0.18 microgram/L) an
      intermediate-risk group, and the three highest quintiles (> or =0.18 microgram/L)
      a high-risk group, with 4.3%, 10.5%, and 16.1% risk of either myocardial
      infarction or cardiac death, respectively. Troponin T level was identified
      together with age, hypertension, number of antianginal drugs, and ECG changes at
      rest as independent prognostic variables for myocardial infarction or cardiac
      death in a multivariate analysis. The prognostic value of tn-T was independent of
      the classification of index event into unstable angina or myocardial infarction.
      CONCLUSIONS: Troponin T determination is an inexpensive and widely applicable
      method for early risk assessment in patients with unstable coronary artery
      disease. The maximum tn-T value obtained during the first 24 hours provides
      independent and important prognostic information.

PMID- 8653871
TI  - Glucose uptake in the chronically dysfunctional but viable myocardium.
AB  - BACKGROUND: The regulation of glucose uptake in the dysfunctional but viable
      myocardium has not been studied previously in humans. METHODS AND RESULTS: Seven
      patients with an occluded major coronary artery but no previous infarction were
      studied twice with 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission
      tomography, once in the fasting state and once during hyperinsulinemic euglycemic
      clamping. Myocardial blood flow was measured with [(15)O]H2O. The myocardial
      region beyond an occluded artery that showed stable wall-motion abnormality
      represented chronically dysfunctional but viable tissue. Six of the patients were
      later revascularized, and wall-motion recovery was detected in the corresponding
      regions, which confirmed viability. A slightly reduced myocardial blood flow was
      detected in the dysfunctional than in the remote myocardial regions (0.81 +/-
      0.27 versus 1.02 +/- 0.23 mL x g(-1) x min(-1),P=.036). In the fasting state,
      glucose uptake was slightly increased in the dysfunctional regions compared with
      normal myocardium (15 +/- 10 versus 11 +/- 10 micromol/100 g per minute, P=.038).
      During insulin clamping, a striking increase in glucose uptake by insulin was
      obtained in both the dysfunctional and the normal regions (72 +/- 22 and 79 +/-
      21 micromol/100 g per minute, respectively; P<.001, fasting versus clamping).
      CONCLUSIONS: Contrary to previous suggestions, glucose uptake can be increased
      strikingly by insulin in chronically dysfunctional but viable myocardium. This
      demonstrates that insulin control over glucose uptake is preserved in the
      dysfunctional myocardium and provides a rational basis for metabolic
      intervention.

PMID- 8653872
TI  - Cardiac sympathetic nerve function in congestive heart failure.
AB  - BACKGROUND: Increased availability of norepinephrine (NE) for activation of
      cardiac adrenoceptors (increased cardiac adrenergic drive) and depletion of
      myocardial NE stores may contribute to the pathophysiology and progression of
      congestive heart failure. This study used a comprehensive neurochemical approach
      to examine the mechanisms responsible for these abnormalities. METHODS AND
      RESULTS: Subjects with and without congestive heart failure received intravenous
      infusions of [(3)H]NE. Cardiac spillover, reuptake, vesicular-axoplasmic
      exchange, and tissue stores of NE were assessed from arterial and coronary venous
      plasma concentrations of endogenous and [(3)H]-labeled NE and
      dihydroxyphenylglycol. Tyrosine hydroxylase activity was assessed from plasma
      dopa, and NE turnover was assessed from measurements of NE metabolites. NE
      release and reuptake were both increased in the failing heart; however, the
      efficiency of NE reuptake was reduced such that cardiac spillover of NE was
      increased disproportionately more than neuronal release of NE. Cardiac NE stores
      were 47% lower and the rate of vesicular leakage of NE was 42% lower in the
      failing than in the normal heart. Cardiac spillover of dopa and NE turnover were
      increased similarly in congestive heart failure. CONCLUSIONS: Increased neuronal
      release of NE and decreased efficiency of NE reuptake both contribute to
      increased cardiac adrenergic drive in congestive heart failure. Decreased
      vesicular leakage of NE, secondary to decreased myocardial stores of NE, limits
      the increase in cardiac NE turnover in CHF. Decreased NE store size in the
      failing heart appears to result not from insufficient tyrosine hydroxylation but
      from chronically increased NE turnover and reduced efficiency of NE reuptake and
      storage.

PMID- 8653874
TI  - Carnitine-related alterations in patients with intermittent claudication:
      indication for a focused carnitine therapy.
AB  - BACKGROUND: Carnitine metabolism is altered in peripheral arterial disease. L
      carnitine supplementation may correct these alterations and improve walking
      performance. METHODS AND RESULTS: Plasma levels of carnitine and its esters were
      measured at rest and after maximally tolerated exercise in 22 claudicant patients
      and 8 normal subjects. One week later, this protocol was repeated in patients
      after random administration of placebo or L-carnitine (500 mg IV as a single
      bolus). Two groups of patients emerged. In 10 patients (group IC1), the plasma
      level of acetylcarnitine at rest was 3.7 +/- 0.2 micromol/L and increased
      significantly (P<.01) at maximally tolerated exercise. In 12 patients (group
      IC2), the resting level of plasma acetylcarnitine was elevated (7.9 +/- 0.7
      micromol/L, P<.01) and decreased with exercise. Furthermore, group IC2 patients
      had a significantly lower walking capacity than group IC1 patients. In both
      groups, placebo did not affect the metabolic profile, nor did it improve exercise
      performance. Conversely, after L-carnitine administration, all but one patient in
      group IC2 (n=7) showed an increase in plasma acetylcarnitine concentration during
      exercise versus the decrease observed without L-carnitine. This metabolic effect
      was accompanied by a significant increase (P<.01) in walking capacity.
      Interestingly, in group IC1 patients (n=5), L-carnitine neither improved walking
      capacity nor modified the metabolic profile. Statistical analysis showed that
      changes in walking capacity with L-carnitine treatment were influenced
      exclusively by exercise-induced changes in plasma acetylcarnitine. CONCLUSIONS:
      In patients with intermittent claudication, assessment of plasma acetylcarnitine
      at rest and after exercise may be a means to select a target population for L
      carnitine therapy.

PMID- 8653873
TI  - Mean red cell volume as a correlate of blood pressure.
AB  - BACKGROUND: Clinical studies suggest that hypertensives have lower mean
      corpuscular volume (MCVs) than do normotensives. Epidemiological studies show no
      relation or higher MCVs. In the present study of elderly men (71 to 93 years of
      age) of the Honolulu Heart Program, elements of both findings are confirmed.
      METHODS AND RESULTS: Three groups are identified: (1) those receiving no
      hypertension treatment, (2) those receiving treatment with any diuretic, and (3)
      those receiving treatment with nondiuretics only. MCV is lower in group 3 than in
      group 1 (-0.85 fL, P<.001) but the same in groups 1 and 2. Within groups 1 and 3,
      inverse relations of -0.22 and -0.09 mm Hg/fL (P<.05) are noted for systolic
      (SBP) and diastolic (DBP) blood pressures. No relations are observed in group 2.
      MCV and red blood cell count (RBC) are inversely correlated (r=-.45). In group 2,
      adjustment for RBC unmasks a direct relation between MCV and SBP (0.5 mm Hg/fL,
      P=.02) and DBP (0.3 mm Hg/fL, P=.02). In groups 1 and 3, relations between SBP
      and MCV are lost after adjustment for RBC (0.005 mm Hg/fL). For DBP, adding RBC
      plus an MCV x RBC interaction is significant (P<.001). DBP is 5 mm Hg greater in
      the highest RBC quartile than in the lowest. A +3 mm Hg difference between
      extreme MCV quartiles is noted only at high RBC levels. CONCLUSIONS: The relation
      between blood pressure and red cell measures is probably mediated by whole blood
      viscosity. Hematocrit is a determinant of whole blood viscosity. Viscosity
      affects peripheral resistance to blood flow, and peripheral resistance affects
      DBP. At high RBC levels, MCV may be "downregulated." This may lower whole blood
      viscosity and partially reduce DBP without compromising flow.

PMID- 8653875
TI  - Electrophysiological mechanisms in successful radiofrequency catheter
      modification of atrioventricular junction for patients with medically refractory
      paroxysmal atrial fibrillation.
AB  - BACKGROUND: Mechanisms and changes of electrophysiological (EP) characteristics
      in successful radiofrequency (RF) modification of right midseptal and
      posteroseptal areas for controlling rapid ventricular response to atrial
      fibrillation (Af) are not clear. METHODS AND RESULTS: We studied 50 patients with
      medically refractory paroxysmal Af. Group 1 consisted of 40 patients without dual
      atrioventricular (AV) node physiology with modification sites located in the
      mid/posteroseptal area. Of the 40 patients, 36 had successful modification
      (follow-up of 14 +/- 8 months), and 3 had AV block. Late follow-up
      electrophysiological study (98 +/- 10 days) showed pattern 1 (67%) with
      prolongation of AV node effective refractory period (ERP, > or =40 milliseconds)
      and Wenckebach block cycle length (WBCL, > or =40 milliseconds); pattern 2 (22%)
      with prolongation of AH interval (> or =20 milliseconds), ERP, and WBCL; and
      pattern 3 (11%) without any change in AV node conduction parameter. Change in
      ventricular rate negatively correlated with change of WBCL in patterns 1 (r=
      .691, P=.019) and 2 (r=-.90, P=.01). Group 2 consisted of 10 patients with dual
      AV node pathway; elimination of slow pathway property was performed. Late follow
      up electrophysiological study (92+/-7 days) showed that change in ventricular
      rate negatively correlated with change in AV node ERP (r=-.926, P=.0001) and WBCL
      (r=-.969, P=.0001). Four patients without significant modification effect had
      success after RF energy was delivered to higher levels (follow-up, 15+/-7
      months). CONCLUSIONS: RF modification of right mid/posteroseptal area is feasible
      in 92% of patients with paroxysmal Af. Mechanisms of successful modification
      might be elimination of posterior input and/or partial injury of the compact
      node. Furthermore, simple elimination of slow pathway might be inadequate for
      control of ventricular rate in patients with little difference in conduction
      properties between fast and slow pathways.

PMID- 8653876
TI  - Latent hypoparathyroidism in children with conotruncal cardiac defects.
AB  - BACKGROUND: DiGeorge anomaly is characterized by hypoplasia or atresia of the
      thymus and parathyroid glands resulting in T cell-mediated deficiency,
      hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is
      associated with deletions of chromosomal region 22q11. We hypothesized that the
      stimulated (secretory reserve) but not the constitutive secretion of parathyroid
      hormone would be reduced in normocalcemic children with conotruncal cardiac
      defects but no overt immune deficiency and would be related to the presence of a
      deletion in the DiGeorge chromosomal region of 22q11. METHODS AND RESULTS: Blood
      ionized calcium and serum-intact parathyroid hormone were measured at baseline
      and seven more times during hypocalcemia induced during cardiopulmonary bypass in
      22 patients and 10 control subjects with an atrial septal defect. Chromosomal
      deletions were detected by fluorescent in situ hybridization and DNA dosage
      analysis. There were no differences in basal calcium and parathyroid hormone
      levels between patients and control subjects. All had increased parathyroid
      hormone in response to hypocalcemia; despite lower calcium levels, parathyroid
      hormone levels were lower in patients. The parathyroid hormone secretory reserve
      in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had
      deletions. CONCLUSIONS: A significant number of children with conotruncal cardiac
      defects have normocalcemia and a normal constitutive level of parathyroid hormone
      but deficient parathyroid hormone secretory reserve; about 30% also have 22q11
      deletions. Such children may be at risk for the later development of hypocalcemic
      hypoparathyroidism.

PMID- 8653877
TI  - Application of percutaneous transluminal coronary angioplasty to coronary
      arterial stenosis in Kawasaki disease.
AB  - BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) has rarely been
      performed on patients with coronary lesions that result from Kawasaki disease. In
      this study, we retrospectively evaluated the effectiveness of PTCA in five
      patients with coronary arterial stenosis that resulted from Kawasaki disease and
      reviewed previous reports for possible indicators of PTCA effectiveness. METHODS
      AND RESULTS: Five patients, ranging in age from 2 to 16 years (median 8 years)
      underwent conventional PTCA for localized stenosis. The lesion targeted for PTCA
      was located in the middle right coronary artery of three patients and in the left
      anterior descending artery in two patients. In four of the five patients, PTCA
      was angiographically effective, with stenosis rates improving from 84 +/- 10% to
      33 +/- 11% (P<.05). When the previously reported cases of six similar patients
      were taken into consideration, the only predictor of successful PTCA seemed to be
      the time elapsed between the onset of Kawasaki disease and performance of this
      procedure. CONCLUSIONS: In cases in which patients show significant localized
      stenosis as a result of Kawasaki disease, PTCA should be attempted within 6 to 8
      years of the onset of the disease. Additionally, intravascular ultrasound imaging
      was found to be a useful tool for evaluating internal morphology before and after
      PTCA. In older patients with coronary calcification, other alternatives to PTCA,
      such as the use of a rotablator or an atherectomy catheter, should be considered.

PMID- 8653878
TI  - Remodeling rather than neointimal formation explains luminal narrowing after deep
      vessel wall injury: insights from a porcine coronary (re)stenosis model.
AB  - BACKGROUND: Oversized balloon dilatation of normal porcine coronary arteries
      usually heals without stenosis formation. METHODS AND RESULTS: With the purpose
      of developing a stenotic model and examining the mechanisms of luminal narrowing
      after angioplasty, we produced a circumferential deep vessel wall injury by
      inflating and withdrawing an oversized chain-encircled angioplasty balloon in the
      left anterior descending coronary artery (LAD) of 20 pigs. Three pigs died and
      did not complete the study. In 8 pigs (group 1), serial coronary arteriography
      was performed. The lumen diameter (mean+/-SD) before dilation was 3.4 +/- .4 mm;
      after dilation, 4.2 +/- 0.6 mm; and at follow-ups 2 and 4 weeks later, 1.6 +/-
      0.4 mm (P<.0001). In 9 pigs (group 2) examined postmortem 3 weeks after
      dilatation, histology revealed that the injury was deep (out to adventitia) in
      all arteries and completely circumferential (360 degrees) in all but two
      arteries. Adventitia was markedly thickened as a result of neoadventitial
      formation. Injury correlated strongly with neointimal formation (middle LAD,
      r=.71, P=.00001, but neither injury nor neointima correlated with lumen size
      (r=.14, P=.46 and r=.34, P=.07, respectively); ie, neointimal formation did not
      explain late luminal narrowing. Lumen size, however, did correlate strongly with
      vessel size (r=.74, P=000005). The late loss in lumen diameter observed
      angiographically in group 1 substantially exceeded that caused by neointimal
      formation seen by histology in group 2. CONCLUSIONS: The chain-encircled
      angioplasty balloon produced a circumferential deep vessel wall injury that
      healed by luminal narrowing. In this porcine model, arterial remodeling was more
      important than neointimal formation in late luminal narrowing.

PMID- 8653879
TI  - Dichotomy of ischemic preconditioning: improved postischemic contractile function
      despite intensification of ischemic contracture.
AB  - BACKGROUND: Acceleration of ischemic contracture is conventionally accepted as a
      predictor of poor postischemic function. Hence, protective interventions such as
      cardioplegia delay ischemic contracture and improve postischemic contractile
      recovery. We compared the effect of ischemic preconditioning and cardioplegia
      (alone and in combination) on ischemic contracture and postischemic contractile
      recovery. METHODS AND RESULTS: Isolated rat hearts were aerobically perfused with
      blood for 20 minutes before being subjected to zero-flow normothermic global
      ischemia for 35 minutes and reperfusion for 40 minutes. Hearts were perfused at a
      constant pressure for 60 mm Hg and were paced at 360 beats per minute. Left
      ventricular developed pressure and ischemic contracture were assessed with an
      intraventricular balloon. Four groups (n=8 hearts per group) were studied:
      control hearts with 35 minutes of unprotected ischemia, hearts preconditioned
      with one cycle of 3 minutes of ischemia plus 3 minutes of reperfusion before 35
      minutes of ischemia, hearts subjected to cardioplegia with St Thomas' solution
      infused for 1 minute before 35 minutes of ischemia, and hearts subjected to
      preconditioning plus cardioplegia before 35 minutes of ischemia. After 40 minutes
      of reperfusion, each intervention produced a similar improvement in postischemic
      left ventricular development pressure (expressed as a percentage of its
      preischemic value: preconditioning, 44 +/- 2%; cardioplegia, 53 +/- 3%;
      preconditioning plus cardioplegia, 54 +/- 4% and control, 26 +/- 6%, P<.05).
      However, preconditioning accelerated whereas cardioplegia delayed ischemic
      contracture; preconditioning plus cardioplegia gave an intermediate result. Thus,
      times to 75% contracture were as follows: control, 14.3 +/- 0.4 minutes;
      preconditioning, 6.2 +/- 0.3 minutes; cardioplegia 23.9 +/- 0.8 minutes; and
      preconditioning plus cardioplegia 15.4 +/- 2.4 minutes (P<.05 preconditioning and
      cardioplegia versus control). In additional experiments, using blood- and
      crystalloid-perfused hearts, we describe the relationship between the number of
      preconditioning cycles and ischemic contracture. CONCLUSIONS: Although
      preconditioning accelerates, cardioplegia delays, and preconditioning plus
      cardioplegia has little effect on ischemic contracture, each affords similar
      protection of postischemic contractile function. These results question the
      utility of ischemic contracture as a predictor of the protective efficacy of anti
      ischemic interventions. They also suggest that preconditioning and cardioplegia
      may act through very different mechanisms.

PMID- 8653880
TI  - Coronary vasodilation induced by angiotensin-converting enzyme inhibition in
      vivo: differential contribution of nitric oxide and bradykinin in conductance and
      resistance arteries.
AB  - BACKGROUND: We studied in coronary conductance and resistance arteries the
      coronary vasodilator effects of the angiotensin-converting enzyme inhibitor
      ramiprilat and the contribution of nitric oxide, bradykinin, and prostaglandins
      to this vasodilation. METHODS AND RESEARCH: In seven anesthetized dogs, a Doppler
      guidewire was placed in the circumflex coronary artery to measure coronary flow
      velocity, and an ultrasound imaging catheter was introduced over the Doppler wire
      to measure coronary cross-sectional area. Drugs were infused directly into the
      left main coronary artery to minimize systemic effects. Ramiprilat increased both
      epicardial cross-sectional area and coronary blood flow velocity, resulting in an
      increase in absolute coronary blood flow. Pretreatment with N omega-nitro-L
      arginine methyl ester (100 micromol/L intracoronary) to block nitric oxide
      synthase attenuated ramiprilat-induced increase in epicardial coronary cross
      sectional area (P<.05) but not in coronary flow velocity or coronary blood flow.
      In contrast, pretreatment with the selective bradykinin antagonist HOE 140 (10
      micromol/L) attenuated ramiprilat-induced increase in flow velocity (P<.025) and
      coronary blood flow (P<.05) but not epicardial coronary cross-sectional area.
      Pretreatment with indomethacin (5 mg/kg body wt IV) did not alter ramiprilat
      induced increase in epicardial cross-sectional area, nor did it significantly
      influence coronary blood flow. CONCLUSIONS: Other than decreasing angiotensin II
      production, acute ramiprilat-induced vasodilation in canine coronary conductance
      arteries is mediated in part by nitric oxide. Ramiprilat-induced vasodilation in
      resistance arteries is in part mediated by the action of bradykinin.

PMID- 8653881
TI  - Oxidized LDL decreases L-arginine uptake and nitric oxide synthase protein
      expression in human platelets: relevance of the effect of oxidized LDL on
      platelet function.
AB  - BACKGROUND: Oxidized LDL (ox-LDL) promotes vasoconstriction and platelet
      activation. The present study was undertaken to determine the involvement of the
      L-arginine-nitric oxide (NO) pathway in ox-LDL-mediated platelet activation.
      METHODS AND RESULTS: Washed human platelets were incubated with native LDL or ox
      LDL for 1 hour at 37 degrees C followed by measurement of platelet function and
      indexes of the L-arginine-NO pathway. Ox-LDL but not native LDL caused a
      concentration-dependent increase in thrombin-induced platelet aggregation and 14C
      serotonin release. These effects of ox-LDL were inhibited by pretreatment of
      platelets with L-arginine, the precursor of NO. Ox-LDL also caused a
      concentration-dependent reduction in the uptake of 3H-L-arginine by platelets. In
      addition, NO synthase activity, measured as conversion of 3H-L-arginine to 3H-L
      citrulline, decreased on incubation of platelet cytosol with ox-LDL. Nitrite
      production was also reduced by treatment of platelets with ox-LDL. These effects
      of ox-LDL on NO synthase activity and nitrite production were reversed by
      pretreatment of platelets with L-arginine. Concurrent with the decrease in NO
      production, cytosolic cGMP was inhibited in ox-LDL-treated platelets. The
      inhibitory effects of ox-LDL were dependent in part on the increase of
      cholesterol in the platelets. Western blot analysis demonstrated approximately
      50% reduction in the expression of NO synthase protein in platelets treated with
      ox-LDL. CONCLUSIONS: These observations indicate that the L-arginine-NO pathway
      is involved in the effects of ox-LDL on platelet function and that ox-LDL
      stimulates platelet function primarily by diminishing NO synthase expression as
      well as decreasing the uptake of L-arginine.

PMID- 8653882
TI  - Atrial contractile dysfunction after short-term atrial fibrillation is reduced by
      verapamil but increased by BAY K8644.
AB  - BACKGROUND: Reduced atrial contractility occurs after cessation of atrial
      fibrillation. Its mechanism is unknown, and no pharmacological treatment exists.
      It has been hypothesized that this atrial contractile dysfunction results from
      intracellular calcium overload due to rapid depolarizations during fibrillation.
      Accordingly, we examined the effects of drugs that reduce or increase
      transsarcolemmal calcium influx on postfibrillation atrial dysfunction.
      Furthermore, we examined whether the dysfunction could be attributed to atrial
      ischemia. METHODS AND RESULTS: Atrial contractility after atrial fibrillation was
      examined in open-chest pigs paced with a constant ventricular rate after complete
      AV block. Atrial contractility was computed as systolic shortening of left atrial
      diameter divided by atrial preload. Three groups of six pigs each were subjected
      to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing.
      Verapamil or the calcium channel agonist BAY K8644 was administered intravenously
      before the second fibrillation period. The degree and duration of
      postfibrillation atrial contractile dysfunction were reduced with verapamil but
      increased with BAY K8644. In a control group, parallel changes occurred after the
      first and second fibrillation periods. Atrial tissue content of creatine
      phosphate declined slightly during fibrillation, whereas the tissue content of
      ATP and lactate remained unchanged. CONCLUSIONS: Atrial contractile dysfunction
      after short-term atrial fibrillation is reduced by the calcium antagonist
      verapamil, which suggests that transsarcolemmal calcium influx contributed to
      this dysfunction. The calcium agonist BAY K8644 increased postfibrillation atrial
      contractile dysfunction. Atrial ischemia was not observed during fibrillation.

PMID- 8653883
TI  - Cardiovascular disease epidemiology: a journey from the past into the future.

PMID- 8653884
TI  - Images in cardiovascular medicine. Superior vena caval thrombosis.

PMID- 8653886
TI  - A balanced budget--evaluating the iron economy.

PMID- 8653885
TI  - Report of the Expert Panel on Awareness and Behavior Change to the Board of
      Directors, American Heart Association.

PMID- 8653887
TI  - Screening newborns for hemoglobinopathies--enduring challenge.

PMID- 8653888
TI  - Recoveries cannot be used to authenticate thyroglobulin (Tg) measurements when
      sera contain Tg autoantibodies.

PMID- 8653889
TI  - Markers of activated coagulation and their usefulness in the clinical laboratory.
AB  - Currently, information on hypercoagulability can be achieved directly--through
      measuring the enzymatic forms of coagulation zymogens generated during
      coagulation activation--or indirectly--through measuring the activation peptides
      generated when zymogens are activated or the enzyme-inhibitor complexes formed by
      inhibition of the enzymes by their plasmatic inhibitors. On the basis of
      published results, markers of activated coagulation are considered useful for
      investigating mechanisms that regulate hemostasis. They can also be used to
      better characterize patients at increased thrombotic risk. However, they should
      be considered indices of hypercoagulability, not of the risk of thrombosis, until
      prospective studies can demonstrate that alterations of these markers can predict
      the occurrence of thrombosis. For diagnosing acute thrombosis, their usefulness
      is questionable; they are less effective than markers of fibrinolysis activation
      such as the D-dimer. Finally, their use to monitor anticoagulant treatment is
      still premature and needs investigation in well-designed clinical studies.

PMID- 8653890
TI  - Determination of shelf life and activation energy for tumor necrosis factor-alpha
      in cerebrospinal fluid samples.
AB  - The cytokine rumor necrosis factor-alpha (TNF-alpha) plays a prominent role in
      the inflammatory response and has been quantified in several kinds of body
      fluids. A safe method for keeping samples under the best storage conditions for
      later studies is clearly needed. We estimated TNF-alpha shelf life by using an
      accelerated stability testing protocol based on the Arrhenius equation. We
      investigated two kinds of samples: cerebrospinal fluid (CSF) normal pool (from
      patients without meningitis) and CSF pathological pool (from patients with
      pyogenic meningitis). Results of the stress protocol indicated that storing both
      normal and pathological CSF samples at -70 degrees C would maintain sample
      stability-i.e., retain at least 90% of the original TNF-alpha content-for
      approximately 5 years. At -20 degrees C and 4 degrees C, the projected stability
      time at which the same recovery would be obtained was 190 and 90 days,
      respectively.

PMID- 8653891
TI  - Ultrasensitive detection of prostate-specific antigen by a time-resolved
      immunofluorometric assay and the Immulite immunochemiluminescent third-generation
      assay: potential applications in prostate and breast cancers.
AB  - We report an ultrasensitive time-resolved immunofluorometric assay (TRIFA) for
      prostate-specific antigen (PSA). The assay is an improvement of our previous
      report (Clin Chem 1993;39:2108-14) and includes the utilization of two monoclonal
      antibodies and a one-step incubation period, which greatly reduces analysis time.
      The new method demonstrates a superior lower analytical limit of detection (< or
      = 1 ng/L), a wide dynamic range, absence of a hook effect at 10(6) ng/L PSA, and
      equimolarity for free PSA and PSA-antichymotrypsin complex. Also, we have
      compared several aspects of our TRIFA with a commercially available third
      generation assay (Immulite). An evaluation of breast tumor cytosol extracts from
      315 patients shows PSA immunoreactivity > 15 ng/g of total protein in 28% and 23%
      by TRIFA and Immulite analysis, respectively. Both methods demonstrate a
      significant association between breast tumor PSA immunoreactivity and
      progesterone and estrogen receptor positivity (P <0.001). Analysis of serum
      samples obtained for monitoring of postradical prostatectomy patients reveals
      significant PSA changes at concentrations undetectable by conventional methods.
      The significance of these results as well as the potential applications of
      ultrasensitive PSA assays in breast and prostate cancers are discussed.

PMID- 8653892
TI  - Urine trypsinogen-2 as marker of acute pancreatitis.
AB  - We examined the clinical utility of urine trypsinogen-2 as a marker of acute
      pancreatitis (AP). Fifty-nine patients with AP, 42 with acute abdominal diseases
      of extrapancreatic origin, and 63 without evidence of acute abdominal disease
      were studied. Urine trypsinogen-2 was determined by a time-resolved
      immunofluorometric assay. As reference methods we used serum trypsinogen-2, urine
      amylase, and serum amylase. The diagnostic accuracy of the markers was evaluated
      by receiver-operating characteristic (ROC) analysis. At admission, urine
      trypsinogen-2 differentiated patients with AP from controls with high accuracy.
      The area under the ROC curve (AUC) was 0.978, which was equal to that of serum
      trypsinogen-2 (0.998) and serum amylase (0.969) and significantly larger than
      that of urine amylase. For differentiation between severe and mild AP, urine
      trypsinogen-2 (0.730) was equal to serum trypsinogen-2 (0.721), and clearly
      better than amylase in serum and urine. These results suggest that determination
      of urine trypsinogen-2 is a useful test to detect AP and to evaluate disease
      severity.

PMID- 8653893
TI  - Physical activity releases prostate-specific antigen (PSA) from the prostate
      gland into blood and increases serum PSA concentrations.
AB  - Determination of prostate-specific antigen (PSA) is an established tool in
      detecting prostate cancer. However, the effect of physical activity on the PSA
      concentration in serum is controversial. We measured serum concentrations of PSA
      and prostatic acid phosphatase (PAP) in 301 healthy outpatients before and after
      they performed standardized exercise. Immediately after 15 min of exercise on a
      bicycle ergometer, their serum PSA concentrations increased by as much as
      threefold. The increase was age dependent and correlated to the PSA concentration
      before exercise. This increase was evident in both the free and complexed
      fractions of PSA. The amount of PSA secreted into blood depends on the volume of
      the prostate, whereas productivity of the prostate epithelium remains constant or
      increases slightly with age. We present cutoff values for clinical use. PAP was
      also increased, but to a lesser extent. The PSA and PAP secretion mechanisms
      differ. Our data suggest that extensive physical activity should be avoided
      before blood sampling for diagnostic purposes and, in case of an increase, the
      PSA concentration should be controlled after an exercise test.

PMID- 8653894
TI  - Fluorometric detection of HIV-1 genome through use of an internal control,
      inosine-substituted primers, and microtiter plate format.
AB  - We describe a PCR-based fluorometric assay for the detection of the HIV-1 genome.
      This technique consists of a reverse hybridization with oligonucleotide probes
      covalently coated onto a microtiter plate as a solid support. Several
      improvements to the PCR amplification and detection steps gave greater
      sensitivity and specificity for HIV-1 screening and resulted in a convenient and
      rapid technique. False-positive results were avoided by using uracyl DNA
      glycosylase. False-negative results from the presence of PCR inhibitors were
      detected by coamplifying an internal control with the viral sequence. False
      negative results from viral genome variability were limited by using two pairs of
      primers and by incorporating inosine at the primer positions corresponding to
      viral polymorphic nucleotides. Furthermore, the hybridization buffer and
      enzymatic reaction were optimized to increase the assay's sensitivity. The
      sensitivity and specificity of the fluorometric detection were similar to those
      of radioisotopic oligonucleotide solution hybridization; however, hands-on time
      was reduced, and the use of radioactivity was eliminated. We have used this
      technique routinely on 115 samples and obtained 100% specificity and high
      sensitivity (only one false-negative result) according to viral culture and (or)
      serological status of the patients.

PMID- 8653895
TI  - Automated HPLC screening of newborns for sickle cell anemia and other
      hemoglobinopathies.
AB  - Automated HPLC is used to test dried blood-spot specimens from newborns for
      hemoglobins (Hb) F, A, S, C, E, and D. We present the method and report on its
      performance determined during >4 years of testing 2.5 x 10(6) newborns. The
      method features automated derivation of presumptive phenotypes; quantitative
      quality control and proficiency testing; throughput of one specimen per minute;
      small sample volume; hemoglobin concentrations quantified with an interlaboratory
      CV of 14-18%; retention times with interlaboratory CV of <2% and matching, within
      +/- 0.03 min, of laboratories and reagent lots; control of peak resolution; 0.5%
      detection limit for Hb S and C, and 1.0% for Hb F, A, E, and D; few
      interferences; and negligible background and carryover. Shortcomings of the
      method are the absence of microplate barcode identification and the need for
      manually pipetting the sample eluate into the microplate.

PMID- 8653896
TI  - Impact of point-of-care testing on patients' length of stay in a large emergency
      department.
AB  - We prospectively investigated whether routine use of a point-of-care testing
      (POCT) device by nonlaboratory operators in the emergency department (ED) for all
      patients requiring the available tests could shorten patient length of stay (LOS)
      in the ED. ED patient LOS, defined as the length of time between triage (initial
      patient interview) and discharge (released to home or admitted to hospital), was
      examined during a 5-week experimental period in which ED personnel used a hand
      held POCT device to perform Na, K, Cl, glucose (Gluc), and blood urea nitrogen
      (BUN) testing. Preliminary data demonstrated acceptable accuracy of the hand-held
      device. Patient LOS distribution during the experimental period was compared with
      the LOS distribution during a 5-week control period before institution of the
      POCT device and with a 3-week control period after its use. Among nearly 15 000
      ED patient visits during the study period, 4985 patients (2067 during the
      experimental period and 2918 during the two control periods) had at least one Na,
      K, Cl, BUN, or Gluc test ordered from the ED. However, no decrease in ED LOS was
      observed in the tested patients during the experimental period. Median LOS during
      the experimental period was 209 min vs 201 min for the combined control periods.
      Stratifying patients by presenting condition (chest pain, trauma, etc.),
      discharge/admit status, or presence/absence of other central laboratory tests did
      not reveal a decrease in patient LOS for any patient subgroup during the
      experimental period. From these observations, we consider it unlikely that
      routine use of a hand-held POCT device in a large ED such as ours is sufficient
      by itself to impact ED patient LOS.

PMID- 8653897
TI  - Laboratory tests of iron status: correlation or common sense?
AB  - We demonstrate that simple correlation between the various tests of iron status
      is not sufficient for examining their value in diagnosing iron deficiency (ID).
      Three degrees of ID are recognized: Iron depletion (ID grade I) is defined by
      decreased total body iron and normal iron support to erythropoiesis, as diagnosed
      by decreased storage iron, decreased ferritin, normal sideroblast count, normal
      zinc protoporphyrin (ZPP), and transferrin saturation >15%. When the iron supply
      to erythropoiesis becomes insufficient, as diagnosed by transferrin saturation <
      or = 15%, increased ZPP, and decreased sideroblast count, iron-deficient
      erythropoiesis (ID grade II) occurs. When finally hemoglobin is below its normal
      range, iron-deficiency anemia (ID grade III) results. The various tests for ID
      cannot be compared without taking into account the severity of the deficiency.
      Depending on the grade of ID examined, the correlation of markers seen in our
      patients' data varied considerably. We conclude that a "best" marker of ID does
      not exist. However, the different tests efficiently complement each other by
      detecting different stages and individually show the clinical extent of ID.
      Ferritin reflects the iron stores. ZPP indicates whether the ID in a given
      patient is clinically relevant or not. Finally, the extent of a clinically
      relevant ID can be assessed by the measured ZPP, hemoglobin concentration, and
      red cell indices.

PMID- 8653898
TI  - Two-stage procedure for evaluating interassay carryover on random-access
      instruments.
AB  - A two-stage statistical procedure based on Dunnett's multiple comparison
      procedures with a control has been developed for detecting interassay carryover
      biases on the Abbott AxSYM(TM) System, a random- and continuous-access
      immunoanalyzer. With this procedure, every potential source of interassay
      carryover can be tested and estimated. In minimizing required sample sizes, the
      first stage is used primarily to detect and eliminate from further testing the
      assay reagent sources that do not cause carryover biases and the assay sources
      that cause very large carryover biases. Retested more extensively in the second
      testing stage are the cases where the data from the first testing stage are
      insufficient for judgment. An example data set from the Abbott AxSYM Free T4
      assay is used to illustrate the methodology.

PMID- 8653899
TI  - Variability in cholesterol measurements: comparison of calculated and direct LDL
      cholesterol determinations.
AB  - Calculated low-density lipoprotein cholesterol (LDL-C) concentrations determined
      from the Friedewald equation have a large intraindividual CV, in part because the
      calculation incorporates the variability of cholesterol, high-density lipoprotein
      cholesterol (HDL-C), and triglyceride measurements. We studied whether a new
      assay that measures LDL-C directly will reduce this variability and reduce the
      need for averaging serial specimens. Four blood samples were obtained 1 week
      apart from 35 mildly hypercholesterolemic subjects and analyzed for total
      cholesterol, triglycerides, and HDL-C. LDL-C was calculated by the Friedewald
      equation, and was also measured directly with a commercially available direct LDL
      C assay. The intraindividual CV for the direct and calculated LDL-C assays were
      similar [CV of direct LDL-C assay (mean +/- SE): 6.8 +/- 0.5% vs calculated LDL
      C: 7.3 +/- 0.6%; difference 0.44%, 95% confidence interval: -0.7-1.5%]. For both
      assays, at least two blood tests were required from each subject to reduce total
      variability of LDL-C to less than or equal to 5%. We conclude that the direct LDL
      C assay did not reduce the variability in LDL-C compared with the conventional
      LDL-C calculation. However, it may have a specific role in lipid disorder
      evaluation and (or) monitoring when triglycerides are increased or the LDL-C
      value alone is needed.

PMID- 8653901
TI  - Determination of ionized magnesium in platelets and correlation with selected
      variables.
AB  - We describe a method for determining the intracellular ionized magnesium
      concentration ([Mg2+]i) in platelets by using the fluorescent probe FURAPTRA. We
      determined the dissociation constant (KD) of FURAPTRA for Mg2+ (2.26 +/- 0.29
      mmol/L), within-day assay variability (CV = 6.8%), among-day intraindividual
      variability (CV = 11.0%), variability after a 4-h delay in processing the blood
      specimen (t = 1.2, P >0.2; F = 6.2, P <0.02), and the reference interval (0.23
      0.59 mmol/L) for this assay. We also evaluated the correlation between platelet
      [Mg2+]i and concentrations of selected serum electrolytes, proteins, and total
      cholesterol; age; body mass index; and gender. Only the inverse correlation
      between platelet [Mg2+]i and serum total cholesterol concentration in men was
      significant (r=-0.66, P <0.005).

PMID- 8653900
TI  - Three routine methods for measuring high-density lipoprotein cholesterol compared
      with the Reference Method.
AB  - We compared the performance of three methods for quantifying high-density
      lipoprotein cholesterol (HDL-C) with the Reference Method for HDL-C, using
      samples with a wide range of triglyceride (TG) concentrations (290-18000 mg/L).
      All three comparison assays-- utilizing a magnetic dextran sulfate precipitating
      reagent, a direct method, and a standard MgCl2-dextran sulfate reagent--were
      precise, with a run-to-run CV of less than or equal to 4.1%. However, the
      systematic error of these assays exceeded the National Cholesterol Education
      Program (NCEP) performance goal of less than or equal to 10% in half of the
      concentration ranges tested. Nevertheless, the total error of the assays
      generally meets the current 22% limit set by the NCEP. Although both the magnetic
      dextran sulfate precipitation reagent and the direct assay can be performed more
      rapidly than the MgCl2-dextran sulfate assay, the direct assay involves no sample
      preparation and requires only 4 microL of sample excluding the dead space.
      Although precipitation is frequently inadequate with the MgCl2-dextran sulfate
      reagent at TG concentrations >6000 mg/L, both the magnetic and the direct reagent
      show no interference from high TG concentrations as great as 18 000 mg/L.

PMID- 8653902
TI  - Serum total testosterone: immunoassay compared with negative chemical ionization
      gas chromatography-mass spectrometry.
AB  - We have developed an electron capture negative chemical ionization gas
      chromatography-mass spectrometry (GC-MS) procedure to quantify serum testosterone
      in the clinically relevant range 0.69-69.3 nmol/L and used this procedure to
      assess Ciba Corning Diagnostics ACS:180 testosterone immunoassay. The GC-MS
      method involves liquid-liquid extraction of serum samples and synthesis of a
      pentafluorobenzyloxime/silyl ether derivative of testosterone with excellent
      chromatographic and electron capturing properties. The ACS testosterone assay is
      the first fully automated nonradioactive testosterone immunoassay approved by the
      US Food and Drug Administration. Patients' specimens (101, 57 males, 44 females)
      were analyzed by both techniques. A plot of the GC-MS (x) vs ACS (y) testosterone
      concentrations for men was linear (y = 1.07x + 0.19 nmol/L), showing excellent
      correlation (r2 = 0.98) between the two assays. Agreement of the two assays for
      female specimens was poor (y = 0.72x + 1.2 nmol/L), with a poor correlation (r2 =
      0.31).

PMID- 8653903
TI  - HPLC method for measurement of purine nucleotide degradation products in
      cerebrospinal fluid.
AB  - We describe a convenient method for the separation and quantification of
      xanthine, hypoxanthine, and uric acid in 20 microL of cerebrospinal fluid (CSF)
      with use of HPLC and ultraviolet detection. The analysis is performed on a
      Sepharon SGX C18 column and the elution system consists of potassium phosphate
      buffer, pH 5.1, with 20 mL/L methanol. The lower limit of detection was 4 pmol
      for hypoxanthine and xanthine and 6 pmol for uric acid. Analytical recoveries of
      purine metabolites ranged from 98.6% to 102.9%. The intra- and interassay CVs
      were <3%. The applicability of the method is illustrated with the determination
      of micromolar concentrations of xanthine, hypoxanthine, and uric acid in CSF
      samples obtained from 113 patients with various neurological disorders.

PMID- 8653904
TI  - HPLC micromethod for amrinone and metabolites in patients receiving concurrent
      cephalosporin therapy.
AB  - Amrinone (AMR), a bipyridine derivative, is receiving increasing use in
      postoperative cardiac patients as an inotrope and vasodilator. The hemodynamic
      response to amrinone in adults is linearly related to AMR concentrations,
      warranting therapeutic drug monitoring. We report a rapid microsample HPLC method
      for monitoring AMR and its principal metabolites, N-acetyl (N-ac) and N-glycolyl
      (N-gly) AMR. Serum was precipitated with acetonitrile, and the supernatant fluid
      was then injected into a C18 narrow-bore column. The mobile phase consisted of a
      0.1 mol/L sodium phosphate buffer (pH 6) with a gradient of acetonitrile going
      from 50 to 100 mL/L of eluent. Detection with a diode-array detector (DAD)
      concurrently monitored the absorbances at 320 and 345 nm. Monitoring 320 nm
      allows optimal quantification of AMR, N-gly, and N-ac. Patients often receive
      concurrent cephalosporin therapy, which is detectable at 320 nm but not 345 nm.
      Because cephalosporins coelute with AMR or metabolites, monitoring at 345 nm
      allows separation of these antibiotics from AMR and metabolites while retaining a
      detection limit of 0.5 mg/L.

PMID- 8653905
TI  - ELISA for thyroglobulin in serum: recovery studies to evaluate autoantibody
      interference and reliability of thyroglobulin values.
AB  - An ELISA for measuring thyroglobulin (Tg) in serum was developed with polyclonal
      antibodies to Tg on the solid phase and two monoclonal antibodies to Tg as the
      second antibodies. The assay has a detection limit of 1 microgram/L, a within-run
      imprecision (CV) of <7%, and a between-run CV of < 10%. Parallelism of the assay
      was shown in dilution studies, in which the percent observed/expected values for
      n = 5 autoantibody-containing samples gave a mean of 99% (SD 13.1 %); for n = 5
      samples with undetectable autoantibody concentrations, the mean was 103% (SD
      11.8%). The correlation of the ELISA with an RIA for Tg in 46 normal samples was
      ELISA = 1.11(RIA) + 0.52, S y/x = 2.23, SD intercept = 0.54, SD slope = 0.03,
      range = 0 to 53 micrograms/L, r = 0.980. Comparison of the ELISA with a reference
      laboratory RIA for 29 clinical samples gave a correlation of: ELISA = 1.53(RIA) -
      0.48, S y/x = 9.00, SD intercept = 2.19, SD slope = 0.10, range = 0 to 98
      micrograms/L, r = 0.950. To provide additional information concerning the
      reliability of the Tg measurement in samples containing autoantibodies to Tg, we
      developed a procedure for determining the percent recovery. A percent recovery
      greater than or equal to 80% indicates minimal interference by autoantibodies in
      this assay. The assay is straightforward to perform, results can be posted within
      8 h, and the routinely good recovery of Tg in the presence of Tg autoantibodies
      indicates minimal autoantibody interference in this assay.

PMID- 8653906
TI  - Absorption of some aminoglycoside drugs by barrier gels in sampling tubes.

PMID- 8653907
TI  - Stability of plasma nonesterified arachidonate in healthy individuals in fasting
      and nonfasting states.

PMID- 8653908
TI  - Direct amplification of the CAG repeat of huntingtin without amplification of
      CCG.

PMID- 8653909
TI  - Liquid chromatography in diagnosis of rare hemoglobin variant (Hb Chicago) and
      its combination with HB S: Hb Chicago/S trait and Hb Chicago/sickle cell disease.

PMID- 8653910
TI  - Validity of Coat-A-Count insulin RIA kit for quantifying total and free humalog.

PMID- 8653912
TI  - Plasma dextran concentrations in trauma patients administered hypertonic saline
      dextran-70.

PMID- 8653911
TI  - Paramax triglycerides reagent: interference from high L-lactate and lactate
      dehydrogenase.

PMID- 8653913
TI  - Direct measurement of LDL cholesterol.

PMID- 8653914
TI  - Troponin T and troponin I after coronary artery bypass grafting: discordant
      results in patients with renal failure.

PMID- 8653915
TI  - Food and Drug Administration (FDA)'s impact on laboratory performance: FDA's
      perspective.
AB  - The Division of Clinical Laboratory Devices is responsible for the premarket
      review of in vitro diagnostic devices (laboratory tests). We currently process
      >1000 diverse applications per year. New versions of old devices are handled as
      premarket notifications, so-called 510(k) submissions. The review objective is to
      establish that the new product is "substantially equivalent" to its predicate.
      Fundamentally new devices are handled as premarket applications. The review
      objective is to establish de novo that the product is ?safe and effective.? A
      central regulatory issue over the past several years has been the development of
      a standardized model for scientific review. The Food and Drug Administration
      contributes to the quality of in vitro diagnostic devices by providing oversight
      and objective review, by setting thresholds for product safety and effectiveness,
      and by ensuring that organized data and appropriate labeling is present in
      support of a device's intended use.

PMID- 8653916
TI  - A critical review of personnel standards.
AB  - Qualified personnel are necessary to ensure quality results, but there is no
      evidence on what minimal educational requirements are necessary. In the future,
      cost-effectiveness analysis may be useful for policy questions such as the
      utility of personnel regulations. CLIA '88 regulations require explicit
      assessment of personnel competency. Survey evidence suggests that previously
      regulated laboratories tend to have highly formalized competency assessment
      programs, while physician office laboratory programs are minimal. Responding
      laboratory supervisors had no uniform definition of competency, but technical
      abilities, productivity, and professionalism were regarded as essential.
      Suggestions for contemporary strategies by laboratory professionals and their
      organizations in the current increasingly competitive managed care environment
      are described. Faced with limited empirical evidence on personnel, laboratory
      directors and supervisors should focus on the total testing process, the needs of
      clinicians, and the uses of testing information to guide personnel assignments.

PMID- 8653917
TI  - How to evaluate and implement new technologies in an era of managed care and cost
      containment.
AB  - New technologies often enable clinical laboratorians to overcome the challenges
      we face. These technologies sometimes become available with amazing punctuality,
      addressing recent problems and keeping the physician-customer satisfied for
      another day. Traditionally, developments such as a new cancer marker have been
      implemented into routine use with little circumspection because the benefits
      diagnostically and financially were perceived to far outweigh the risk that the
      new test or technology was not as effective as described. The notion of
      subsequently removing older tests inferior to the new one has hardly been
      considered. The challenges confronting clinical laboratorians today, however, are
      affecting that typical pattern dramatically. Four of the most pervasive
      challenges are comprehensively examined in the 1995 Clinical Chemistry Forum. One
      of these key areas--the proper implementation of modern technology in the form of
      new tests or new approaches to producing clinical laboratory results--is the main
      topic of this review.

PMID- 8653918
TI  - The case for cardiac troponin T: marker for effective risk stratification of
      patients with acute cardiac ischemia.
AB  - Availability of markers such as cardiac troponin T (cTnT) has brought new
      insights into ischemic heart disease (IHD). cTnT is a distinct protein that
      differs from other markers in biological function, molecular mass, and cytosolic
      pool. cTnT has been utilized for diagnosis of acute myocardial infarction (AMI)
      and risk stratification of patients with IHD. For AMI diagnosis, cTnT showed high
      sensitivity (94-100%) but generally lower specificity (46-99%), possibly because
      of increases in non-AMI patients with minor myocardial damage. Outcome studies
      have demonstrated that IHD patients with increased cTnT are at significantly
      greater risk for cardiac events; revascularization in patients with increased
      cTnT may improve outcome. Estimated costs for batched ES 300 cTnT results and for
      a cTnT rapid assay run "on demand" were $17.48 and $21.65, respectively. cTnT
      currently has no specific common procedure test code; expected reimbursement is
      $18.32 for the ES 300 and is not established for the rapid assay.

PMID- 8653919
TI  - Keeping up with new technology: new approaches to diagnosis of Chlamydia
      infection.
AB  - Chlamydia trachomatis infections are among the most common sexually transmitted
      infections in the US today. One of the keys to the prevention of C. trachomatis
      infection rests on the ability to make this diagnosis on the basis of accurate
      laboratory testing. For many years the standard for diagnosis of C. trachomatis
      infections has been isolation in tissue culture. Numerous nonculture methods,
      including enzyme immunoassay, have been used as an alternative to cell culture.
      The performance characteristics of these tests have all been compared with a
      standard, cell culture, which at best will detect 90% of positive specimens.
      Nucleic acid amplification techniques, including PCR and ligase chain reaction,
      have been recently introduced. The advantage of these tests is their ability to
      detect 10-20% more positive specimens when compared with culture or confirmed
      nonculture methods performed with a single specimen. The sensitivity of amplified
      tests also allows us to test specimens from multiple sites (endocervix, urethra,
      urine), which expands our standard from an infected sample to detection of an
      infected patient. Tests based on amplified nucleic acid technology have greatly
      improved our ability to diagnose urogenital C. trachomatis infection. The use of
      an expanded standard will help us accurately define the true performance and
      clinical utility of nonculture Chlamydia diagnostic tests.

PMID- 8653920
TI  - Why is the laboratory an afterthought for managed care organizations?
AB  - Market forces have dramatically influenced the environment in which healthcare is
      delivered, but these changes do not need to be interpreted negatively by
      community laboratorians. Only total vertical integration of laboratory medicine
      can control episode-of-care cost. Opportunities also exist for horizontal
      integration with community partners to provide geographical coverage and to
      compete favorably for managed care contracts. Lowering cost through "economies of
      scale" may apply to the procurement of supplies and equipment, but the delivery
      of services must be considered in the context of their overall effect on episode
      of-care cost. Laboratory services may make up 5% of a hospital's budget but
      leverage 60-70% of all critical decision-making such as admittance, discharge,
      and medication. Laboratory outreach can help the medical center's financial
      stability by: (a) providing tests and service that can reduce or avoid a hospital
      stay; (b) using the additional volume of testing to distribute existing fixed
      costs and lower unit cost; and (c) adding revenue as a direct contribution to
      margin. To successfully compete for contracted managed care services, the
      laboratory must network with other providers to demonstrate comprehensive access
      and capacity. Community hospital laboratories perform 50% of all laboratory tests
      in this country and have adequate excess capacity to fulfill the remaining
      community needs.

PMID- 8653921
TI  - Federal reimbursement to laboratories.
AB  - The change from a predominately fee-for-service payment environment to managed
      care has significantly reduced revenues for many clinical laboratories. Medicare
      is rapidly becoming the most favorable payor in areas with high managed-care
      penetration. This trend has not gone unnoticed by Congress, and congressional and
      regulatory initiatives are rapidly moving to reduce federal laboratory
      reimbursement. The efforts by both the private and public payors to further
      restrict payments could have a profound effect on the scope of testing offered by
      hospital-based laboratories. On-site nonemergent testing capability will be
      dependent on the cost to provide the service and the level of reimbursement.
      Laboratory providers have an opportunity to influence the extent of laboratory
      cost-reducing initiatives. To effect congressional or regulatory change requires
      an understanding of the federal Medicare payment system and a well-organized
      effort.

PMID- 8653922
TI  - Impact of cost cutting on laboratories: new business strategies for laboratories.
AB  - Cost reduction is the primary force driving healthcare reform. To survive and
      thrive in these tumultuous times, laboratories must adapt and implement new
      business strategies. Business paradigm shifts create opportunities for
      organizations with a plan; a wait-and-see attitude forecasts failure. Drawing
      upon an 11-year experience with the "ARUP business model," this work will
      highlight business strategies that have contributed to the success of this
      university-based reference laboratory. In the future, successful laboratories
      will implement new business strategies to become more effective members of the
      emerging integrated healthcare delivery teams. Within the laboratory, traditional
      organizational disciplinary boundaries, i.e., chemistry, microbiology, and
      hematology, are melding together to increase efficiency. Laboratorians must
      become influential members of institutional healthcare delivery teams formed to
      control utilization. Laboratory services are being adjusted to optimize patient
      care. Incremental pricing is only one of the strategies to be implemented to
      expand outpatient business to those in the region. Expanded computer
      capabilities, client services, specimen handling, marketing, and sales are also
      required. On a regional basis, service laboratories are increasingly joining
      forces to increase efficiency while at the same time improving the quality of
      patient care.

PMID- 8653923
TI  - Internet: road to heaven or hell for the clinical laboratory?
AB  - The Internet started as a research project by the Department of Defense Advanced
      Research Projects Agency for networking computers. Ironically, the networking
      project now predominantly supports human rather than computer communications. The
      Internet's growth, estimated at 20% per month, has been fueled by commercial and
      public perception that it will become an important medium for merchandising,
      marketing, and advertising. For the clinical laboratory, the Internet provides
      high-speed communications through e-mail and allows the retrieval of important
      information held in repositories. All this capability comes at a price, including
      the need to manage a complex technology and the risk of instrusions on patient
      privacy.

PMID- 8653924
TI  - How is telepathology being used to improve patient care?
AB  - Telepathology, as a subspecialty of telemedicine, involves the use of
      telecommunications technologies to transmit images to distant sites for the
      purpose of communicating diagnostic information or for teaching. Recent advances
      in technology have greatly increased the feasibility of performing diagnosis by
      telepathology, but there are still significant obstacles to implementation. In
      this review, I will discuss the technologies and organizations involved in
      telepathology, with examples of current practice in the US and abroad.

PMID- 8653925
TI  - A computer program that periodically monitors the ability to interpret the
      antinuclear antibody test.
AB  - Our laboratory has been developing computer programs that help medical
      technologists improve their performance of the microscope-based
      immunofluorescence assay for antinuclear antibodies (ANA). This image-based
      laboratory test has been associated with poor reproducibility. We have previously
      described our first program, ANA-Tutor, which systematically teaches the ANA test
      by using approximately 150 processed digital images of ANA test results. The
      program we describe here, Pattern Plus Auditor, is a logical extension to ANA
      Tutor. Pattern Plus Auditor tests the ability of laboratory personnel to
      interpret the ANA test, and tracks individual and laboratory performance over
      time. The program consists of image-based questions that test a variety of ANA
      staining patterns, including homogeneous, speckled, centromere, nucleolar, mixed
      patterns, and rare patterns. For each question, the program provides correct
      answers with explanations and color overlays that highlight key image features.
      By entering the proper password, users gain access to exam results for
      individuals and for the laboratory as a whole. Results are available for the
      current exam, any previous exam, or cumulatively on all exams to date.
      Intralaboratory testing with computer programs such as Pattern Plus Auditor might
      be a useful part of quality-assurance procedures for many image-based laboratory
      tests.

PMID- 8653926
TI  - Interleukin-6 and soluble interleukin-6 receptor in peritoneal fluid and serum of
      patients with endometriosis.
AB  - OBJECTIVE: Interleukin-6 (IL-6) and soluble Interleukin-6-receptor (sIL-6R)
      concentrations were investigated in patients with endometriosis and other benign
      gynecologic diseases. METHODS: During laparoscopy or laparotomy peritoneal fluid
      and serum were collected from 29 patients with endometriosis, 31 patients with
      benign ovarian masses and 4 patients with chronic inflammation or adhesions.
      Interleukin-6 (IL-6) concentrations were determined by Elisa-technique. RESULTS:
      Patients with endometriosis stage IV revealed slightly higher IL-6 concentrations
      in peritoneal fluid when compared to patients with stage I to II disease and
      ovarian masses/ chronic inflammation. IL-6 serum concentrations were higher in
      case of stage I and II when compared to stage III and IV and ovarian
      masses/chronic inflammation. Patients with endometriosis revealed significantly
      higher sIL-6 receptor concentrations in peritoneal fluid and serum as compared to
      patients with ovarian cysts and chronic inflammation. CONCLUSION: IL-6 and
      soluble IL-6 receptor may be considered to be involved in endometriosis. However,
      the patho-physiologic mechanism must be the subject of further investigation.

PMID- 8653927
TI  - Beta blockers in pregnancy and their effect on regional Doppler ultrasound and
      fetal weight.

PMID- 8653929
TI  - Prostaglandin F1a and prostaglandin E2 plasma levels after transvaginal cervical
      cerclage.
AB  - Plasma prostaglandin metabolites, prostaglandin F1a (PGF1a) and prostaglandin E2
      (PGE2) were measured in a serial set of maternal serum samples by
      radioimmunoassay after elective transvaginal cervical cerclage (Shirodkar) in 18
      patients early in the 2nd trimester (14-15 weeks of gestation) for a history of
      cervical incompetence. Eight patients received progesterone preoperatively as a
      myometrial suppressant. The basal PGF1a and PGE2 were 134.0 +/- 25.9 pg/ml and
      14.9 +/- 1.8 pg/ml, respectively. A gradual rise in both metabolites was observed
      within 1 hour after the operation (206.81 +/- 48.3 pg/ml and 16.7 +/- 1.6 pg/ml,
      respectively, p > .05), peaking at 6 hours (265.4 +/- 51.8 pg/ml, p < .01 and
      25.9 +/- 4.9 pg/ml, p < .05), and falling to basal levels within 24 hours (136.7
      +/- 26.5 pg/ml and 14.0 +/- 1.2 pg/ml, respectively, p > .05). The increase in
      PGF1a was proportionately greater than PGE2 metabolite (r = 0.838, p < .001). No
      differences were found in prostaglandin levels amongst patients who received
      progesterone as compared to the non-recipients for all the time intervals studied
      (p < .05). Our findings, further suggest that a temporary increase in
      prostaglandin production occurs following cervical cerclage, but its role remains
      unclear.

PMID- 8653930
TI  - Gynaecological emergency in surgical theatre. A case report.

PMID- 8653928
TI  - Nausea, vomiting and thyroid function before and after induced abortion in normal
      pregnancy.
AB  - Thyroid function in early pregnancy has been reported to be slightly different
      from that in second or third trimester. We assessed thyroid function before and
      after induced abortion in normal pregnant women. A significant increase in serum
      Free T4 and a decrease in serum TSH were observed before abortion and these
      changes, apart from the contemporary significance of serum hCG-beta, were
      especially marked in pregnant women with nausea and vomiting. On the other hand,
      an increased level of Free T4 and a reduced level of TSH returned to the normal
      ranges 7-10 days after induced abortion. Furthermore, serum hCG-beta was
      significantly reduced. These results suggest that, in normal early pregnancy,
      thyroid function may be related to serum hCG-beta concentration and its increased
      level, which induces gestational emesis.

PMID- 8653931
TI  - Topic and systemic administration of natural alfa interferon in the treatment of
      female and male HPV genital infections.
AB  - The aim of the study was to evaluate the effectiveness and tolerance of topic and
      systemic administration of natural alfa-interferon from normal human leukocytes
      in the treatment of HPV lesions of the lower genital tract. From May 1991 through
      May 1992, 70 women (mean age = 29; range 16-42) and 51 men (mean age = 28; range
      18-48) with histologically proven HPV genital lesions were studied. 43 patients
      and 32 male partners with subclinical infection underwent cream therapy (4
      applications/day for 30 days) composed of natural alfa interferon and containing
      1,000,000 IU/gr. 27 women and 19 men affected by florid infection underwent
      systemic i.m. therapy with natural alfa interferon in doses of 3,000,000 IU on
      alternate days for 30 days. The percentage of therapeutical success amounted to
      55.8% for women and 78.1% for men subjected to topic therapy; for the 27 patients
      and 19 male partners treated with systemic therapy the final percentages of
      success were 70.3% respectively. Natural alfa interferon from normal human
      leucocytes seems to be a drug of good efficacy and tolerance in the treatment of
      HPV genital pathology.

PMID- 8653932
TI  - Acute abdomen from pedicle torsion ectopic pelvic spleen. A case report and
      review of the literature.

PMID- 8653933
TI  - Vaginal ovarian cystectomy during vaginal hysterectomy. A case report.

PMID- 8653934
TI  - Postmaturity: how far is it a clinical entity in its own right?
AB  - In 1990 we adopted a protocol of antepartum testing for all booked pregnant
      patients, permitting healthy pregnancies to go beyond 42 completed weeks of
      gestation. This retrospective study regards 84 patients delivering after 42
      completed weeks of pregnancy and a control group of 1351 patients delivering
      after 37 completed and before 41 completed weeks of pregnancy. Records were
      revised for maternal age and parity, previous obstetric history, managing and
      complications of the actual pregnancy, labour and mode of delivery, neonatal
      biometric data and outcome. Only 4 patients delivered after 43 completed weeks of
      gestation, while none in the series delivered later than 44 completed weeks after
      the beginning of the last menstrual period. The overall frequency of caesarean
      birth was higher, but not significantly, in study group. Average neonatal
      birthweight and length were significantly greater in the study group. No
      significant difference in neonatal outcome was observed between study and control
      groups in terms of perinatal mortality. Low 1' Apgar score was significantly more
      frequent in the study group, but a similar frequency of 5' Apgar score and need
      for intensive care was observed in the two groups.

PMID- 8653935
TI  - Triplet pregnancy and fetal reduction counselling.
AB  - The aim of this study was to compare the fetal loss between triplet pregnancies
      that underwent fetal reduction to twins and triplets which continued in spite of
      reduction being suggested to all of them. During a five year period a total of
      3,518 cycles underwent ovarian stimulation with GnRH analogues, HMG, pure-FSH and
      HCG for the purpose of IVF; 2,918 women underwent ovarian aspiration leading to
      2,380 embryotransfers. A total of 560 clinical pregnancies were detected with 24
      clinical triplet pregnancies. Fourteen women continued their triplet pregnancy
      while 10 women underwent fetal reduction to twins. From 42 fetuses (14 triplets)
      starting the third trimester only 29 survived (total fetal loss 30.9%). From 14
      fetuses (7 twins) starting the third trimester all survived. Three twins were
      lost during the second trimester due to cervix incompetence. Fetal reduction to
      twins must be proposed to each multifetal pregnancy, considering the very serious
      high mortality rate.

PMID- 8653936
TI  - Comparison of cervical assessment, fetal fibronectin and fetal breathing in the
      diagnosis of preterm labour.
AB  - The management of threatened preterm labour is hampered by an inability to
      differentiate accurately true from false labour at an early stage. We compared
      the performance of vaginal assessment, fetal breathing movements and the
      detection of fetal fibronectin (Ffn) in the prediction of true preterm labour
      among 25 singleton pregnancies admitted with regular uterine activity, cervical
      dilatation < 4 cms and intact membranes at 25 to 35 weeks of gestation. A Bishop
      score of < 2 or a negative Ffn test was highly predictive (100%) of false preterm
      labour whereas fetal breathing movement detection was less reliable. The positive
      predictive value of cervical assessment alone was considerably improved with the
      addition of Ffn testing. The introduction of Ffn testing of cervico-vaginal
      secretions could result in a more rational use of tocolysis.

PMID- 8653937
TI  - Mesenteric panniculitis. A case report.
AB  - We reviewed the clinical history, and the physical, laboratory and
      ultrasonography examinations of a young female suffering from mesenteric
      panniculitis. In our case, as well as those described by other authors,
      definitive diagnosis was histological and our patient has had a benign course of
      the disease.

PMID- 8653939
TI  - Pulmonary manifestations of chronic liver disease.
AB  - Several lung disorders can occur as a consequence of chronic liver disease. In
      addition to the common findings of splanchnic and systemic vasodilatation in
      patients with chronic liver disease, pulmonary vasodilatation may also occur.
      This "hepatopulmonary syndrome' results in hypoxemia through pulmonary
      vasodilation and VA/Q mismatch, and in its advanced form leads to significant
      intrapulmonary arteriovenous shunting. Portal hypertension commonly results in
      the development of ascites, which may cause a restrictive lung pattern or pleural
      effusions. Rarely, thrombi formed in congested portal vein branches pass through
      portosystemic shunts and cause pulmonary hypertension, and plexogenic pulmonary
      hypertension may also occur in patients with portal hypertension. The autoimmune
      liver diseases, primary biliary cirrhosis and autoimmune hepatitis, may be
      accompanied by immune-mediated lung disease. These pulmonary abnormalities
      represent important extrahepatic manifestations of chronic liver disease.

PMID- 8653938
TI  - Pharmacologic prevention of colonic neoplasms. Effects of calcium, vitamins,
      omega fatty acids, and nonsteroidal anti-inflammatory drugs.
AB  - Dietary supplements of calcium, vitamins A, C, and E, carotenoids, and omega-3
      fatty acids can reduce the yield of experimental cancers in animals and reverse
      the pattern of abnormal epithelial proliferation in animals and humans.
      Epidemiological studies indicate that diets containing high amounts of these
      agents convey a protective effect against the development of colon cancer.
      Moreover, regular aspirin use in humans appears to reduce the risk of colon
      cancer and sulindac causes regression of polyps in patients with familial
      polyposis. These agents are promising for the prevention of human colorectal
      cancer, but their efficacy has not yet been shown in prospective, controlled
      trials. Thus, although it is tempting to speculate that in the future we may
      treat our patients who have a predisposition to colon polyps and cancer, or even
      healthy people at average risk, with such ordinary supplements as calcium,
      vitamins, fish oil, or aspirin, such advice at this time is premature.

PMID- 8653940
TI  - Risk factors for morbidity and mortality in pancreatitis.
AB  - The mortality of acute pancreatitis has steadily decreased over the last two
      decades while the incidence of acute pancreatitis has doubled, however, it still
      ranges from 5 to 10% in some university centers. Patients with chronic
      pancreatitis also have a diminished survival rate compared to the general
      population. Although there have been marked improvements in the mortality of
      acute pancreatitis and longevity in chronic pancreatitis, both are still
      substantial. Until improved therapies become available, recognition of the risk
      factors for mortality and rapid and intensive therapy are our best chance to
      decrease the mortality further.

PMID- 8653941
TI  - Obstruction of the hepatic veins or suprahepatic inferior vena cava.
AB  - Obstruction of the main hepatic veins or suprahepatic inferior vena cava is
      caused mainly by thrombosis or its fibrous sequela. One or several underlying
      thrombogenic disorders are usually present, the most common of which is an overt
      or occult primary myeloproliferative disorder. The major complications are
      ascites and gastrointestinal bleeding. A sizeable proportion of the cases are
      asymptomatic. Diagnosis is usually made at ultrasound or magnetic resonance
      imaging when collateral veno-venous circulation or endoluminal hepatic venous
      material are demonstrated. Natural history is poorly known. Overall, mortality is
      high in the early phase of the disease but once the acute episode is terminated,
      prognosis is good. Treatment includes anticoagulation to prevent recurrence or
      extension of thrombosis, nonspecific measures to control ascites and
      gastrointestinal bleeding, and procedures aiming to restore hepatic blood
      outflow. Portal-caval shunts are preferred when possible. In patients with
      obstructed inferior vena cava, the first choice is percutaneous angioplasty, and
      the second choice is portal-systemic shunts with the right atrium or superior
      vena caval circulation. Transplantation is proposed for patients with severe
      liver failure.

PMID- 8653942
TI  - Alternating sciatica while jogging: an early symptom of cauda equina tumor.
AB  - Three athletic patients with cauda equina or lumbosacral cord tumor noticed, as
      an early symptom of the disease, alternating bilateral sciatica synchronized with
      each stride while jogging. Comparison with athletic patients who developed lumbar
      disc hernia suggested that this symptom was significant. The authors speculated
      that the mechanism producing this symptom is the inertial force induced while
      jogging, which acts on the tumor in its early stage, when it is still quite
      mobile in the intradural space. The diagnostic role of this symptom in cauda
      equina and lumbosacral cord tumor should be recognized.

PMID- 8653943
TI  - Bilateral total hip arthroplasty: one stage versus two stage procedure.
AB  - The purpose of this study was to determine if any differences existed in the
      early complication rate, short term clinical outcome, and total length of
      hospital stay between patients who had bilateral total hip arthroplasty performed
      under a single anesthetic (during 1 patient visit to the operating room) and
      patients who had the procedure performed under 2 anesthetics (during 2 patient
      visits to the operating room). Patients operated on bilaterally were divided into
      3 groups: Group A (1 stage procedure)--hips that were operated on simultaneously
      (128 hips); Group B (2 stage procedure)--surgeries performed less than 6 weeks
      apart (126 hips); and Group C (2 stage procedure)--surgeries performed between 6
      weeks and 6 months apart (256 hips). All patients were evaluated after an average
      followup of 1.5 years. There were no differences in operative, early local, or
      general complications among the 3 groups. In particular, no higher incidence of
      pulmonary embolism or deep vein thrombosis was found in the 1 stage group.
      Preoperatively, very stiff hips (total range of motion < 50 degrees) gained
      significantly more motion in the 1 stage group than in the 2 stage groups,
      whereas hips with better preoperative motion (total range of motion > 50 degrees)
      improved the most in Group B, without a significant difference occurring between
      Groups A and C. The degree of pain reduction was the same in all groups, but
      patients in the 1 stage group had a significantly better capacity for walking
      after their procedure. Average total hospital stay was 5 to 6 days less for the
      patients in Group A than those in the other groups, which, combined with using
      the operating room only once, resulted in a reduction of overall hospital costs
      by more than 30% when using the 1 stage procedure.

PMID- 8653944
TI  - An electromyographic study of the hip muscles of transfemoral amputees in
      walking.
AB  - The aim of this study was to obtain insight into the electromyographic activity
      of the hip muscles after transfemoral amputation and to determine whether the
      cleaved hip muscles are still functional in locomotion. The electromyographic
      activity of the superficial hip muscles of both legs was studied in 11 men who
      had a unilateral transfemoral amputation. The intact muscles at the intact and
      amputated side showed the same sequence of activity as did those in healthy
      subjects, but during a longer period of time. The activity of the cleaved muscles
      with intact muscle fibers (gluteus maximus, tensor fasciae latae) was dependent
      on whether the iliotibial tract was reanchored. If the iliotibial tract was
      fixed, the same activity was found in the muscles of the patients as in those of
      healthy subjects. The activity of the cleaved, once biarticular, muscles
      (sartorius, rectus femoris, hamstring muscles, gracilis) was dependent on whether
      the muscles were reanchored and on the level of amputation. If the cleaved
      muscles were reanchored correctly, the muscles remained functional in locomotion
      in patients with an amputation in the distal half of the femur. In patients with
      high amputation levels, these muscles were almost continuously active; they
      probably play a role in fixing the socket.

PMID- 8653945
TI  - Ceramic femoral head fractures in total hip arthroplasty.
AB  - A failure analysis was performed of 4341 alumina ceramic heads articulating with
      2693 alumina ceramic and 1464 polymer sockets implanted over 20 years (1974 to
      1994). From 1974 to 1982, a mushroom shaped head with ceramic neck was used in
      1069 cases, and from 1982 to 1994 a ball type head was used in 3272 cases. In the
      ceramic/ceramic cases, the average followup was 11 years, and in the polymer
      pairing cases, the average followup was 6 years. In ceramic self pairing with the
      mushroom shaped head, the fracture rate was 0.4% (5 of 1069). With the ball type
      head, the fracture rate was 0.06% (1 of 1763). In articulation with polymer
      sockets, only 1 head fracture occurred (0.07%). In the group of cases with
      ceramic/ceramic pairing, the reason for fracture was direct trauma in 4 cases,
      recurrent neck impingement in 2 cases, and fatigue failure in 1 case. The only
      case with ceramic head fracture in polymer pairing also was caused by direct
      trauma. Fractures of the alumina ceramic heads cannot be avoided, but the use of
      ball type neckless heads brought the fracture rate close to 0. Under the aspect
      of material safety, it seems to be possible to use the great advantage of the
      superior low wear of the alumina/alumina couple with negligible fracture risk.

PMID- 8653946
TI  - How superior placement of the joint center in hip arthroplasty affects the
      abductor muscles.
AB  - This study examines the effects of a superiorly placed hip center on the strength
      of the abductor muscles. A 3-dimensional computer model of the hip and the
      surrounding musculature was used to calculate the moment arms, forces, and
      moments generated when the hip abductor muscles are maximally activated. A
      representation of a hip prosthesis was implanted into the computer model with
      altered hip center positions and a range of prosthetic neck lengths. Analysis of
      these simulated hip replacements demonstrated that superolateral placement of the
      hip center (2 cm superior and 2 cm lateral) decreases the moment arms of the hip
      abductor muscles by an average of 28%. This decrease in moment arm cannot be
      restored by increasing prosthetic neck length, resulting in an unrecoverable loss
      of abduction strength with superolateral displacement. By contrast, a 2-cm
      superior displacement of the hip center changes the moment arms and force
      generating capacities of the abductors by less than 10% if prosthetic neck length
      is increased to compensate for decreased muscle length. The results of this study
      suggest that superior positioning of the hip center, without lateral placement,
      does not have major, adverse effects on abduction moment arms or force generating
      capacities when the neck length is appropriately increased.

PMID- 8653947
TI  - Radioactive synoviorthesis in hemophilic hemarthrosis: materials, techniques, and
      dangers.
AB  - Radioactive synoviorthesis with 198Au, 90Y, 186Re, and 31P would seem to be the
      treatment of choice for recurrent hemarthroses in hemophilia. The clinical
      results, obtained by different centers, show a definite diminution of
      hemarthroses in 88% of cases. The advantages of radioactive synoviorthesis
      compared with surgical synovectomy are: better results, the requirement of
      substantially reduced antihemophilic factor, the possibility of performing the
      procedure on multiple cases concurrently on an ambulatory basis, no interference
      with articular range of movement, and the low cost of the procedure. In cases of
      failure, the procedure can be repeated after 6 months, and on as many as 3
      occasions. Studies performed on the chromosomal changes that could be attributed
      to the radioactive material show the disappearance of these alterations a few
      years after treatment. No physical changes have been found that could be
      attributed to cytogenic alteration (hematologic or other) in any reported
      patients.

PMID- 8653948
TI  - Muscle strength after successful total knee replacement: a 6- to 13-year
      followup.
AB  - This study investigated the long term results of muscle strength of the knee
      joint after total knee replacement. Isokinetic testings of 120 degrees and 180
      degrees per second and isometric testings at 30 degrees and 60 degrees knee
      flexion were studied on 1 healthy group and 3 groups of patients 6 to 13 years
      after total knee arthroplasty with prosthesis designs of total condylar, low
      contact stress meniscal bearing, or low contact stress rotating platform. The
      total condylar and low contact stress rotating platform prostheses were designed
      for use with a cut posterior cruciate ligament, whereas the low contact stress
      with meniscal bearing type was designed for use with a retained posterior
      cruciate ligament The muscle strength ratios of hamstring to quadriceps were
      compared among the prosthetic designs and there were no statistical differences
      among patient groups. Whether the posterior cruciate ligament was cut or retained
      did not affect the relative muscle strength of the quadriceps and hamstring. All
      hamstring to quadriceps ratios from the isokinetic testings of these 3 prostheses
      design groups were greater than those of the healthy group, but were quite close
      to those of patients with cut anterior cruciate ligaments or with lower levels of
      daily activity. The hamstring to quadriceps ratios after successful total knee
      replacement were not the same as those of the healthy group even after long term
      (6-13 years) functional adaptation.

PMID- 8653949
TI  - Osteonecrosis and resorption of the patella after total knee replacement: a case
      report.
AB  - A 54-year-old woman with a history of right total knee replacement had right knee
      pain and swelling for 6 months. Radiographs of the knee showed significant
      fragmentation and resorption of the patella consistent with osteonecrosis.
      Evidence of increased anteroposterior laxity was noted on physical examination.
      Revision surgery to a posterior stabilized prosthesis with excision of the
      patellar fragments resulted in a marked improvement in her symptoms and
      functional capabilities 2 years after surgery. The authors review the blood
      supply to the patella and how it may be disturbed by knee surgery and speculate
      that this patient's symptoms may have been worsened by the anteroposterior
      instability of her prosthesis.

PMID- 8653950
TI  - Anterior instability of the knee despite an intensive rehabilitation program.
AB  - To investigate if an intensive rehabilitation program has a positive influence on
      the late course of an old, isolated anterior cruciate ligament rupture, patients
      were evaluated at an average of 8 years after injury. Seventy-five percent had
      acquired the injury during sporting activities. After diagnostic arthroscopy,
      which was done at an average of 163 days after the injury, the patients
      immediately were assigned to an intensive rehabilitation program. At the followup
      examination, none of the patients had an excellent result as determined by the
      Swiss Knee Group Score; 6 patients had a good result; 13 had a fair result; and 8
      had a bad result. Fourteen patients had a partial meniscectomy during the
      followup period, and 4 had positive signs for meniscal lesions at the followup
      examination. In 52% of the patients gonarthrosis had advanced 2 stages, and in
      26% it had advanced 3 stages. There was a significant correlation between
      worsening of gonarthrosis and previous meniscectomy, poor evaluation scores, and
      clinical signs of instability. Even an intensive rehabilitation program cannot
      prevent secondary lesions of the meniscus with ensuing joint degeneration. Thus,
      immediate operative reconstruction of old ruptured anterior cruciate ligaments is
      recommended.

PMID- 8653951
TI  - Retrospective evaluation of graded stress examination of the ankle.
AB  - Stress radiography of the ankle commonly is used to evaluate talar tilt in
      patients with a history of inversion ankle sprains. Manual and instrumented
      procedures have been variously described in the literature. No reports have
      documented normative talar tilt as measured using the Telos ankle stress device
      in a large clinical population. In addition, little has been done to examine the
      value of using graded displacement forces compared with a single displacement
      force. Bilateral Telos examinations from 113 consecutive patients taken during a
      4-year period were evaluated for this study. No measurable talar tilt was
      observed in 65.8% of the ankles in this study. Talar tilt ranged from 1.7 degrees
      to 24.9 degrees in injured ankles. In patients with quantifiable talar tilt, all
      had greater talar tilt at the 15 kPa force than at all other forces. Because of
      the variability in talar tilt in injured and comparison ankles, clinical
      conclusions regarding injury severity cannot be made on measured talar tilt
      alone. The analysis suggests that inversion stress examination is helpful in
      documenting gross talar instability, but the discriminant value of the procedure
      to determine the anatomy and severity of lateral ligament injury is tenuous.

PMID- 8653952
TI  - Free tissue coverage of wound complications following Achilles tendon rupture
      surgery.
AB  - The purpose of this study was to examine the long term functional results
      following free tissue coverage in 4 patients who developed wound complications
      after surgical treatment of partial or total Achilles tendon rupture. Between
      1987 and 1993, 3 radial forearm flaps and 1 lateral arm flap were used. Two
      Achilles tendons were reinforced, 1 with palmaris longus tendon, and 1 with
      extensor carpi radialis and palmaris longus tendons. The patients were seen
      during followup an average of 3.1 years after the reconstruction. All patients
      were able to return to their preoperative level of activity within a year, and
      the aesthetic outcome was good in all cases. Isometric and isokinetic calf muscle
      performance was evaluated with a Lido Multi Joint II dynamometer, which showed
      the mean of isometric test values in 3 patients to be greater than 90% of that of
      the normal unaffected side, and probably abnormal (80%) in 1 patient. The mean
      isometric values obtained in 3 ankle positions, 20 degrees plantar flexion,
      neutral, and 10 degrees dorsiflexion, were 114%, 104%, and 94%, respectively.
      Isokinetic peak torque values were normal in 3 patients at a velocity of 30
      degrees per second, and in 2 at 90 degrees per second. The mean peak torque value
      was 90% of normal at both angle velocities. The cross sectional area of the calf
      muscle was greater than 90% of the normal unaffected side. Ultrasonography
      indicated that the diameters of 2 reinforced tendons were larger than those on
      the control sides. Posterior peritendinous fibrosis was found in the upper corner
      of the scar in 2 patients.

PMID- 8653953
TI  - External tibial torsion: an underrecognized cause of recurrent patellar
      dislocation.
AB  - Seventeen patients (18 knees) with recurrent patellar dislocation were identified
      with increased quadriceps angles secondary to excessive isolated external tibial
      torsion. Traditional realignment procedures attempted in these knees were
      unsuccessful because of failure to align the biomechanical axis of the extensor
      mechanism. Derotational osteotomies of the tibia just proximal to the patella
      tendon insertion were used to reduce the quadriceps angle to within normal limits
      to improve the biomechanics of the extensor mechanism. Seventeen (94%) knees were
      available for clinical and subjective followup at an average of 25 months (range,
      1-3.2 years). Overall, 13 of the 17 knees were graded as good to excellent (76%).
      Five of the 17 patients also had well established anterior knee pain in addition
      to recurrent dislocation and were treated with a combined derotational and Maquet
      type osteotomy, with 4 patients obtaining a good to excellent result. Knees that
      subjectively and functionally demonstrated less painful symptoms preoperatively
      were associated with excellent results. Poor outcomes were associated with knees
      that were operated on multiple times.

PMID- 8653954
TI  - Semiextended position of intramedullary nailing of the proximal tibia.
AB  - Over a 24 month period, 30 patients with proximal tibia fractures who were
      reviewed consecutively were treated by nonreamed, statically locked,
      intramedullary nailing. There were 16 open, 13 segmental, and 7 comminuted
      fractures (Winquist III, IV). The average distance from the fracture to the
      proximal locking screws was 24 mm (range, 0-65 mm). All procedures were performed
      while the patient's affected leg was on a radiolucent table without traction. The
      last 25 fractures were nailed using a partial (2/3) medial parapatellar incision
      while the leg was semiextended. This approach allowed the patella to be subluxed
      laterally availing the trochlear groove for use as a conduit for nail placement.
      Using only 15 degrees knee flexion eliminated the extension force of the
      quadriceps on the proximal fragment, which otherwise would have tended to cause
      anterior angulation at the fracture site. In the first 5 patients, the average
      anterior angulation was 8 degrees (range, 5 degrees-15 degrees). Of the 25
      patients who were treated while in the semiextended position, none had more than
      5 degrees anterior angulation and 19 had no anterior angulation. Fractures of 3
      of the 25 patients had greater than 5 degrees angulation in the coronal plane, 2
      of which were nailed in the semiextended position. This technique greatly
      facilitates intramedullary nailing of proximal tibia fractures.

PMID- 8653955
TI  - Hematomas within the iliopsoas muscles in hemophilic patients: the Latin American
      experience.
AB  - The majority of bleeding episodes in patients who have hemophilia occur within
      the musculoskeletal system, primarily in the joints, but approximately 30% occur
      within the muscles. Iliopsoas muscle bleeding episodes are often large in volume,
      causing muscular function inhibition, angular deformities, and nerve involvement.
      Recurrent hemorrhages are common (14.2%) and neural involvement is as high as
      37%. Three hundred patients are being observed in the authors' hemophilia center,
      63 of whom have suffered 127 hemorrhages. Absolute bed rest and long term factor
      replacement are the mainstay of therapy. The experiences of physicians in other
      countries are appendixed to this article.

PMID- 8653956
TI  - Thoracic spine fractures in patients older than 50 years.
AB  - The charts and radiographs of 70 patients older than 50 years of age with
      thoracic vertebral body collapse were reviewed retrospectively. Fifteen patients
      had traumatic fractures and 34 had osteoporotic collapse of thoracic vertebrae.
      Metastasis was the underlying disease process in 18 patients and multiple myeloma
      in the remaining 3 patients. Thirteen patients had fractures involving the upper
      half of the dorsal spine, of which 8 (61.5%) were metastatic, 4 (30.8%)
      osteoporotic, and 1 (7.7%) traumatic. All patients with osteoporotic fractures of
      the upper dorsal spine also had 1 or more fractures of the lower dorsal or lumbar
      spine. There were 11 metastatic, 80 osteoporotic, 14 traumatic, and 3 fractures
      secondary to multiple myeloma involving the lower dorsal spine. There were no
      infections or primary bone tumors. The difference in the frequency of metastatic
      fractures against other etiologies involving the upper versus the lower thoracic
      spine was highly statistically significant.

PMID- 8653957
TI  - Early, full weightbearing with flexible fixation delays fracture healing.
AB  - Secondary fracture healing is known to be accelerated by the process of
      periosteal callus formation that can be induced by flexible fracture fixation in
      connection with loading of the injured extremity. The purpose of this study was
      to compare the healing of experimental fractures of long bones in sheep under
      early weightbearing with that of fractures under delayed, steadily increasing
      weightbearing. Differences in the quality of fracture healing were described by
      biomechanical (rigidity of fracture, indentation stiffness of callus) and
      histologic methods. Prevention from early, full weightbearing resulted in a
      higher flexural rigidity of the fracture, an increased mechanical stiffness of
      the callus tissue, and an enhanced bone formation at the healing front. Although
      early loading of a fresh fracture initiated an enormous amount of periosteal
      callus, the healing of the osteotomy was significantly delayed, and the quality
      of the newly formed tissue was reduced as compared with fractures with a reduced
      loading situation. A reduction of load transfer by delaying full weightbearing is
      advantageous for the healing of fractures stabilized with flexible fixation
      systems.

PMID- 8653958
TI  - Hybrid external fixation of comminuted tibial plateau fractures.
AB  - Comminuted tibial plateau fractures present a surgical challenge to the
      orthopaedic surgeon. Over the years, treatment has ranged from traction to cast
      immobilization to open reduction and internal fixation. More recently, indirect
      reduction techniques with external fixation have been used. At the authors'
      institution, from 1990 to 1992, 18 Schatzker Types V and VI tibial plateau
      fractures were treated in 18 patients with indirect reduction and application of
      a Monticelli-Spinelli hybrid external fixation system. Two patients had
      additional internal fixation and were excluded from this review. All 16 patients
      were available for followup evaluation. The mean time to union was 4.5 months.
      There were no nonunions. Three patients developed a varus deformity. Fifteen had
      radiographic evidence of early degenerative changes at 1 year followup. There
      were 11 superficial pin tract infections in 4 patients; all resolved with local
      pin care and a short course of oral antibiotics. There were no deep infections.
      With the added advantages of minimal to no soft tissue stripping and early knee
      range of motion, this technique is recommended for treatment of these difficult
      fractures.

PMID- 8653959
TI  - Multicentric chondrosarcomas.
AB  - Multicentric chondrosarcomas, other than those from mesenchymal chondroma, are
      rare and difficult to differentiate from metastatic disease. Eight new patients
      with multicentric chondrosarcomas are reported. Five patients had chondrosarcomas
      that were monomelic, 3 had disseminated chondrosarcomas, 3 had synchronous
      involvement, and 5 had metachronous involvement; 1 patient had Ollier's disease.
      A bimodal age distribution was apparent: 4 patients were between 62 and 76 years
      old, and the remaining 4 were between 16 and 33 years old. Average duration of
      followup was 6 years, 4 months. Each of the patients with synchronous
      chondrosarcomas had single bone lower extremity involvement and presented with
      symptoms occurring at only 1 of the 2 sites of tumor. Each of the 5 patients with
      metachronous chondrosarcomas experienced involvement of a different bone when the
      second tumor presented. Only 1 of these metachronous chondrosarcomas was limited
      to the lower extremity. The second tumor occurred in all patients after excellent
      control of the primary tumor by wide excision. The average duration between
      diagnosis of the 2 tumors was 4 years, 4 months (range, 8 months-12 years, 9
      months). Patients who had nonmonomelic malignancies must be viewed with a
      considerably more guarded prognosis than those who had monomelic chondrosarcoma
      because each of the 2 deaths resulting from progressive disease occurred among
      the 3 patients with nonmonomelic chondrosarcoma. The nonmonomelic malignancies
      may represent metastatic chondrosarcoma with a rare predilection to bony
      involvement. Monomelic chondrosarcoma simply may represent lesions analogous to
      the skip lesions observed in osteosarcoma.

PMID- 8653960
TI  - Treatment of the femoral neck amd trochanteric benign lesions.
AB  - Thirty-five patients with a benign lesion of the femoral neck or trochanter were
      treated and seen in followup at the authors' institution from 1988 to 1991.
      Sixteen men and 19 women between the ages of 18 and 54 years (average, 27 years)
      were seen at an average followup of 3 years 6 months (range, 2-5 years). Eight
      patients had aneurysmal bone cyst; 14 had monostotic fibrous dysplasias; 2 had
      giant cell tumors; and 11 had simple bone cysts. Eleven patients had pathologic
      fractures. All patients were treated with curettage and bone grafting in
      conjunction with a sliding hip compression screw and plate. The bone grafting
      included a combination of a deep frozen allogenic cortical strut with autogenous
      iliac cancellous bone to fill the remaining defect space after lag screw and
      cortical strut had been implanted. At followup, all patients had good bony
      healing and incorporation of the implanted graft. There were no complications and
      no local recurrences. All of the functional results were excellent.

PMID- 8653961
TI  - Squamous cell carcinoma of the foot: two case reports.
AB  - Plantar keratoses and verrucous lesions are common foot problems in the
      orthopaedic, dermatologic, and podiatric practices. Treatment often is
      palliative. Two cases of squamous cell carcinoma are presented to draw attention
      to the potential for these lesions to deteriorate into malignant lesions. A high
      index of suspicion is necessary to make the early diagnosis of malignancy and
      prevent spread of lesions. An initial wide excision may prevent metastasis.
      Inadequate excision, recurrence, or tumor in the margins should be treated by
      amputation.

PMID- 8653962
TI  - Metastatic epidural bony tumor causing spinal cord compression: a case report.
AB  - The authors report the case of a patient with breast cancer who developed spinal
      cord compression due to the expansion of an epidural bony tumor from an
      osteoblastic vertebral metastasis into the spinal canal. Magnetic resonance
      imaging revealed an epidural mass that was compressing the spinal cord but that
      did not demonstrate the bony elements contained within the epidural mass. These
      bony elements were demonstrable only by computed tomography. The patient did not
      respond to radiotherapy but did recover after surgical decompression. Therefore,
      the authors recommend the use of computed tomography for patients who have
      osteoblastic vertebral metastases and epidural spinal cord compression diagnosed
      by MRI. Once an epidural bony mass expanding from a vertebral metastasis into the
      spinal canal is demonstrated by computed tomography, surgical decompression is
      indicated.

PMID- 8653963
TI  - Skeletal response to immobilization in Paget's disease of bone: a case report.
AB  - The authors discuss a case of Paget's disease of the forearm in which the Pagetic
      radius and non-Pagetic ulna responded differently to immobilization. The high
      turnover state of Pagetic bone is more sensitive to physical unloading than
      normal bone, and thus more rapidly develops osteopenia of immobilization. The
      different responses to immobilization between Pagetic bone and site controlled
      normal bone illustrate how physical and metabolic factors interact at a skeletal
      site to regulate bone remodeling and bone mass.

PMID- 8653964
TI  - Effects of etidronate and oophorectomy on the zeta potential of rat bone.
AB  - Recent clinical trials in osteoporotic patients show that cyclical etidronate
      therapy can increase vertebral bone mass and reduce the incidence of vertebral
      fractures. Stress generated potentials, which are theorized to participate in a
      negative feedback arrangement regulating bone and which are electrokinetic in
      origin, can be characterized in vitro by the zeta potential, a measure of
      electrical surface charge. Thus, the possible effects of etidronate and
      oophorectomy on the zeta potential of bone were investigated with respect to bone
      remodeling, pathophysiology, and osteoporosis. Thirty-two oophorectomized and 48
      sham oophorectomized rats received subcutaneous etidronate or saline. The zeta
      potential magnitude of the control group (sham oophorectomized, vehicle only)
      increased 23.6% from age 6 to 10 months, a period of bone growth. After 6 weeks
      of etidronate treatment, which decreased bone turnover, the zeta potential
      magnitude was decreased 14.9% (0.59 mV) compared with that of controls. Decreased
      zeta potential magnitudes with etidronate treatment also were observed in sham
      oophorectomized groups at 16 weeks and in oophorectomized groups at 6 and 16
      weeks, but the differences were not statistically significant. A large bolus of
      etidronate had no effect. The zeta potential of bone is a dynamic quantity that
      may correlate with bone growth or bone turnover. Whether it exerts a causative
      effect or is a marker remains unknown.

PMID- 8653965
TI  - Sports and hemophilia: antagonist or protagonist.
AB  - Until recent years the life for the person with hemophilia was dictated by the
      severity and frequency of bleeding episodes. Those with hemophilia tended to be
      overprotected and not allowed to participate in sporting activities normal to
      their peer group. The past 2 decades has seen a dramatic change in attitudes,
      mainly due to the introduction of factor replacement, home therapy, and
      comprehensive care programs. Those involved in the care of people with hemophilia
      now recognize that sport and exercise can reduce or prevent intraarticular
      hemorrhages. The arguments for and against sport as described in the literature
      from 1960 to 1990 are reviewed. Swimming, golf, and table tennis were recommended
      by doctors, whereas most contact sports, including football, were discouraged.
      The move toward more active pursuits brings with it an increase in sporting
      injuries, which is addressed in this article, but more importantly the prevention
      of injuries is highlighted.

PMID- 8653966
TI  - Evaluation of collagen ceramic composite graft materials in a spinal fusion
      model.
AB  - Autogenous bone graft is highly effective in inducing a bone healing response in
      most clinical settings. However, significant morbidity can occur related to the
      harvest of an autograft. This makes the development of synthetic or purified
      nontissue bone grafting materials highly desirable. Both purified bovine Type I
      collagen and calcium phosphate ceramics have been proposed as promising
      osteoconductive bone graft substitute materials. One collagen ceramic composite,
      Collagraft, is approved for use in acute long bone fractures. This study
      evaluated composites of purified bovine Type I fibrillar collagen and a granular
      biphasic hydroxyapatite/tricalcium phosphate ceramic in the posterior segmental
      canine spinal fusion model. Materials were compared based on union score and
      mechanical testing in 3 separate fusion sites (L1-2, L3-4, L5-6). All composites
      were found to be inferior in union score to an equal volume of autogenous
      cancellous bone. In addition, the combination of the collagen ceramic composite
      with autogenous cancellous bone graft reduced the effectiveness of the autogenous
      bone graft significantly. These data should be a caution to the clinician who may
      consider use of collagen ceramic composites similar to Collagraft for spinal
      fusion applications.

PMID- 8653967
TI  - Mechanical stamping: a cause of fatigue fracture.
AB  - Failure analysis of a retrieved flexible intramedullary nail was performed by
      standard optical and scanning electron microscopy. Results show that the
      corrosion fatigue at the stamped label caused the nail fracture. The authors
      strongly recommend that the American Society for Testing of Materials standard
      F86-91 be modified to exclude mechanical stamping from the repertoire for
      labeling implants. Surgeons also must avoid using mechanically stamped hardware
      that will be subject to cyclic loads in vivo.

PMID- 8653968
TI  - Adaptations of ligamentum teres in ischemic necrosis of human femoral head.
AB  - Little is known about the biomechanical properties of human ligamentum teres. To
      more fully understand the ligamentum teres, its dimensions and mechanical
      properties were measured in 22 cases of acute fracture of the femoral neck and 21
      cases of ischemic necrosis of the femoral head. The specimens first were
      preconditioned and then loaded to failure with a testing machine at a fast strain
      rate of 100% s(-1). The ischemic necrosis group had a significantly larger volume
      (3.09 +/- 1.81 ml versus 1.30 +/- 0.62 ml) and cross section area (65.3 +/- 59.1
      mm2 versus 30.6 +/- 27.2 mm2) than did the acute fracture group. The former also
      had a significantly greater ultimate load (234 +/- 168 N versus 130 +/- 111 N)
      and strain energy to failure (1.22 +/- 1.04 J versus 0.41 +/- 0.39 J), but a
      significantly smaller linear modulus (4.72 +/- 3.31 MPa versus 8.69 +/- 7.97 MPa)
      than did the latter. Histologic studies showed differences in the amount of
      organized collagen and components of subsynovial tissue between the 2 groups.
      Mechanical and morphologic adaptations of the ligamentum teres in a group of
      ischemic femoral heads are described, and a possible biomechanical role is
      suggested for the ligamentum teres in the hip joint in conjunction with the
      ischemic necrosis of the femoral head.

PMID- 8653969
TI  - Natural healing of anterior and posterior attachments of the rabbit meniscus.
AB  - The natural healing capacity of the anterior or posterior medial meniscal
      attachment after radial transection and the effect of such procedures on knee
      joint cartilage were investigated in 28 skeletally mature New Zealand white
      rabbits. Either the anterior (n = 14) or the posterior attachment (n = 14) was
      radially transected in the right knee joint. Fifty percent of the rabbits with
      each procedure were euthanized at 6 weeks and 50% at 12 weeks. The histologic
      characteristics of the healing tissue were evaluated, including
      immunohistochemical demonstration of nerve fibers. Histologic changes in the
      synovium and articular cartilage were graded for severity and extent. The
      concentration of proteoglycan fragments in joint fluid was analyzed before
      operation and at euthanasia. After both procedures, the transected attachment
      healed in a prolongated position resulting in peripheral displacement of the
      meniscus. The healing tissue at 6 weeks was composed mainly of granular tissue.
      By 12 weeks, the healing tissue at the anterior attachment had a ligament like
      structure, but at the posterior attachment, fibrocartilage like tissue had
      formed. Nerve fibers were found in the healing tissue, but connections to nerves
      in normal attachment or meniscal tissues were not found. Increased concentrations
      of proteoglycan fragments, articular cartilage degeneration, and synovitis were
      found in the operated knees. These data indicate that although the meniscal
      attachment can heal in a prolongated position, such a meniscus has lost its
      mechanical functions. Further, a joint protective function of the neoneurons is
      doubtful because of the lack of continuity with the adjacent meniscus. Rigid
      fixation of the attachment seems essential for a functional meniscal substitute.

PMID- 8653970
TI  - An axially loaded model of the ankle after pronation external rotation injury.
AB  - Using a testing apparatus that allows axial loading and displacement in the
      sagittal, axial, and coronal planes, 6 ankles were tested under experimental
      conditions intended to model the Lauge-Hansen pronation external rotation injury.
      All specimens were rotated through a continuous range of sagittal motion with the
      ankle under 300 N of axial load as the coupled motion of the ankle in the coronal
      and axial axes was recorded. Combinations of fibular osteotomy, disruption of the
      syndesmosis up to 6 cm above the plafond, and deltoid transection were tested to
      mimic Stages I to III of the pronation external rotation ankle fracture. The
      effects of stabilization of the fibula and syndesmosis also were examined.
      Neither fracture of the fibula 4 cm above the plafond nor disruption of the
      syndesmosis to 6.0 cm resulted in a significant change in coupled motion of the
      talus. When the superficial deltoid was sectioned, the ankle had increased
      external rotation in plantar flexion. When the deep deltoid was sectioned, the
      ankle dislocated in plantar flexion unless the fibula was stabilized. This
      prevented dislocation but failed to restore normal talar kinematics. This study
      found no biomechanical support for placement of a syndesmotic screw unless the
      medial side cannot be stabilized anatomically.

PMID- 8653971
TI  - Methotrexate eluted from bone cement: effect on giant cell tumor of bone in
      vitro.
AB  - The effectiveness of methotrexate eluted from polymethylmethacrylate on cell
      lines established from giant cell tumor of bone was investigated in vitro to
      determine the possible efficacy of this treatment. Elation of methotrexate from
      polymethylmethacrylate beads and boluses was shown in vitro to be dose dependent
      and limited by the size of the bolus. Cytocidal activity of methotrexate elated
      from polymethylmethacrylate beads prepared without monomer and of boluses of
      polymethylmethacrylate with the same dose of methotrexate prepared with monomer
      against 2 human giant cell tumor cell lines was statistically significant at 24
      hours in culture. Statistical significance occurred at 24 hours in culture.
      Activity was maintained in vitro after 17 days. These experiments showed that
      eluted methotrexate remained effective against tumor cells after exposure to
      thermal changes during polymerization of polymethylmethacrylate. While extensive
      curettage of giant cell tumor of bone followed by filling in the defect with
      polymethylmethacrylate has become a common treatment, a local adjuvant is
      necessary to reduce further risk of local recurrence. A potential alternative to
      cryosurgery or instillation of phenol is the use of methotrexate impregnated
      polymethylmethacrylate to treat residual microscopic disease after curettage.
      This method may provide locally effective chemotherapy without the risks of
      systemic toxicities.

PMID- 8653972
TI  - Ankle and foot pain in a 39-year-old man.

PMID- 8653973
TI  - Human immunodeficiency virus and the orthopaedic surgeon.
AB  - Human immunodeficiency virus is a devastating disease that ends in death. The
      fear that it engenders in healthworkers and patients may be out of proportion to
      the risks involved but an emotional response to the dangers is understandable.
      However, a careful study of the risks, the adoption of high standards of
      practice, and control of the clinical environment probably can eliminate most of
      the risk. There is a clear conflict of interest between the maintenance of
      confidentiality for the infected person and the right to information of those
      with whom they come into contact. Mandatory clinical testing for human
      immunodeficiency virus is likely to become the most contentious medicolegal issue
      of the next decade.

PMID- 8653974
TI  - Hemostasis: a practical review of conservative and operative care.
AB  - Progress in the treatment of persons with hemophilia has improved quality of life
      and made surgical intervention in these patients possible. Optimum management
      should include a facility equipped with a special coagulation laboratory, a
      hematologist proficient in the management of coagulation disorders, a surgeon
      with experience operating on persons with a clotting disorder, and a blood bank
      with experienced personnel. Persons with inhibitors should undergo elective
      procedures only after consultation between surgeon and hematologist. Replacement
      of deficient factor protein by the intravenous infusion of factor concentrates
      allows normal hemostasis. The manufacture of factor concentrates includes
      purification and viral attenuation procedures to limit exposure to other proteins
      and decrease the risk of transmission of viral infection. These concentrates may
      be delivered by bolus intravenous infusion or as a continuous intravenous
      infusion which allows for less total units of factor to be administered. In
      patients with mild hemophilia A, intravenous or intranasal desmopressin acetate
      may be used to increase the Factor VIII: coagulant level and eliminate exposure
      to blood products. With careful perioperative management, patients with
      hemophilia may undergo surgery safely without excessive bleeding. In the future
      because of prophylactic therapy, the need for orthopaedic procedures may be
      decreased substantially.

PMID- 8653975
TI  - Hemophilic ankle arthropathy.
AB  - Ankle arthropathy remains a frequent source of disability in the hemophilic
      patient. Bleeding into the ankle most commonly commences in the second decade,
      and, once established as a target joint, progressive damage leads to significant
      pain, stiffness, and deformity affecting general mobility and leisure and
      occupational pursuits. Review of cohorts of hemophilic patients at the Royal Free
      Hospital has monitored this deterioration and there is no evidence that, despite
      improvements in medical treatment, the pattern of insidious decline in hindfoot
      function has changed during the past 4 decades. Based on these observations, a
      combined clinical and radiologic scoring system has been developed, incorporating
      ankle specific features, such as talar tilt, tibial osteophytes, and talar dome
      flattening, which give a better correlation than traditional systems with
      objective measures, such as treadmill walking. There is no substitution for
      prophylactic treatment in arresting ankle function decline, and surgical
      interventions are rare. However, the types of potential procedures are numerous
      and choices must be made according to the degree of disability and state of
      overall damage to the joint and adjacent soft tissues.

PMID- 8653976
TI  - An account of an hemorrhagic disposition existing in certain families.

PMID- 8653978
TI  - Long term evaluation of septic arthritis in hemophilic patients.
AB  - Before 1983, septic arthritis was rare in patients with hemophilia. With the
      advent of human immunodeficiency virus infection in the hemophilia population,
      many centers noted an increasing incidence of patients with septic arthritis.
      Fifteen septic joints in 10 patients with severe hemophilia were documented.
      Eight patients were human immunodeficiency virus positive, 1 was human
      immunodeficiency virus negative, and 1 was not tested. The diagnosis was delayed
      in 5 patients because the symptoms are similar to an acute hemarthrosis. An
      elevated temperature was common. The white blood cell count was elevated in only
      1/3 of the infections, being modified by human immunodeficiency virus infection.
      Associated risk factors included infected angioaccess catheters (2), pneumonia
      (2), and generalized sepsis (1). All but 1 joint responded to appropriate
      antibiotics and either repeated aspiration or arthrotomy. However, 6 patients
      died of acquired immunodeficiency syndrome from 2 to 109 months after infection.
      Three patients are alive 29, 86, and 96 months, respectively, after infection.

PMID- 8653977
TI  - Arthroscopic synovectomy of the knee in hemophilia: 10-to-15 year followup.
AB  - Nine knees in 8 patients with severe hemophilia A and 1 patient with hemophilia B
      underwent arthroscopic synovectomy during the period of 1980 to 1985. This group
      of patients has been observed prospectively for the past 10 to 15 years. One
      complication occurred immediately postoperatively in an 8-year-old boy in whom a
      severe hemarthrosis developed that required arthroscopic evacuation. His
      postoperative recovery was compromised leading to significant loss of motion.
      Recurrent hemarthroses developed in only 1 patient after an injury to the knee. A
      second arthroscopic synovectomy was performed 45 months after the initial
      procedure. Other than the patient who lost motion after the postoperative
      complication, all patients initially regained or improved their range of motion.
      The latest followup, however, showed several patients losing motion which
      correlated with clinical and radiographic evidence of progressive changes of the
      hemophilic arthropathy. The 1 patient with Factor IX deficiency required a total
      knee replacement 8 years after synovectomy. Arthroscopic synovectomy was
      effective in reducing recurrent hemarthrosis and maintaining range of motion;
      however, joint deterioration continued to occur although probably at a slower
      rate.

PMID- 8653979
TI  - Multiple joint procedures in a single operative session on hemophilic patients.
AB  - Hemophilia is a coagulation disorder wherein frequent hemarthroses result in
      premature joint degradation. This hemophilic osteoarthropathy is polyarticular,
      and despite modern coagulation possibilities, acute hemarthroses and chronic
      synovitis are common. Because repair of a single joint in polyarthritic
      conditions may not improve the patient's functional ability a policy has been
      adopted to create a functional limb. This therapeutic protocol succeeded in
      gaining the objectives of a functional limb, and it was noted that the
      complication rate was less than expected and that the rehabilitation period was
      relatively short.

PMID- 8653980
TI  - Role of fibrin sealants in surgical procedures on patients with hemostatic
      disorders.
AB  - Fibrin sealants have until now been used to a very limited extent in patients
      with a bleeding diathesis. The authors have accumulated experience from 8 minor
      and 40 major surgical procedures, plus 10 circumcisions and 118 tooth extractions
      in 106 patients suffering from hemophilia A, B, or von Willebrand's disease. Most
      of the patients had the severe form of the disease. The authors were able to show
      a reduction of blood loss and of requirements for replacement therapy with factor
      concentrates. The literature on the application of fibrin sealants in this group
      of patients, which mainly deals with dental procedures, is reviewed and compared
      with data from the current study. The composition of the glue is of major
      significance and is discussed in detail.

PMID- 8653981
TI  - Effects of hemophilia on articulations of children and adults.
AB  - The majority of bleeding episodes in hemophilic patients occur within the joints.
      Of these hemarthroses, the knees, elbows, and ankles account for almost 80%.
      Should the bleeding persist, the synovium starts to hypertrophy and a vicious
      cycle of chronic synovitis develops, leading to joint destruction. In immature
      articulation, synovitis causes hypertrophy of the epiphyseal growth plates and
      significant structural deficiencies may rapidly develop. This stimulus to the
      growth plates results in bone hypertrophy, leg length discrepancy, and angular
      deformities. In mature articulation, hemophilia has a major detrimental effect on
      the joint cartilage. As it progressively exacerbates, joint function
      deteriorates. Loss of joint space is the most important radiographic finding
      related to range of motion. As the synovium becomes increasingly scarred, there
      is gradual conversion from friable hyperemic tissue to fibrotic scar tissue. This
      process is the natural course of hemophilic arthropathy. A phenomenon in adult
      hemophilic patients is that their joints, which radiographically appear severely
      destroyed, seem to function reasonably well for many years.

PMID- 8653982
TI  - Modern cement technique and the survivorship of total shoulder arthroplasty.
AB  - Thirty-eight consecutive Neer II total shoulder arthroplasties were performed in
      35 patients by one surgeon using the so called modem cement technique and
      followed for a mean of 5 years (range, 2-9.5 years). The preoperative diagnosis
      was osteoarthritis or avascular necrosis in 22 shoulders, rheumatoid arthritis in
      10 shoulders, and posttraumatic arthritis in 6 shoulders. The components were
      implanted using specific improved techniques for cement fixation initially
      described for total hip arthroplasty. Twenty-six metal-backed and 12 polyethylene
      glenoid components were used. The humeral component was implanted with cement in
      32 shoulders. There were no intraoperative fractures or postoperative
      neurapraxias. At most recent followup, 36 shoulders had no or slight pain with
      activity. The mean increase in active forward elevation was 38 degrees and in
      active external rotation was 29 degrees. There have been no revisions, and all
      components remain in place. With failure defined as definite radiographic
      loosening of the components, there was 97% survivorship at 5 years, and 93% at 8
      years. Radiolucent lines around more than 50% of the bone cement interface of the
      humeral component were present in only 3 shoulders. Radiolucent lines around more
      than 50% of the bone cement interface of the glenoid component were seen in only
      2 shoulders. Both components in 1 severely osteopenic shoulder had a complete
      radiolucent line and a change in position. Meticulous attention to cement
      technique may improve the long term survival of cemented total shoulder
      arthroplasty components.

PMID- 8653983
TI  - How much does inferior capsular shift reduce shoulder volume?
AB  - The purpose of this study was to quantitate the effect of inferior capsular shift
      on shoulder volume. Four fresh frozen cadaveric shoulders were analyzed. Volume
      before and after shift was determined using 3 techniques: (1) Magnetic resonance
      imaging sequences were digitized to computer and analyzed for volume via a 35-mm
      camera using Cue 2 software. The capsule was delineated by contrast between light
      and dark regions. Volume was calculated by summing the total area of respective
      slices. (2) Ultrasound images, obtained after surgical exposure of the capsule,
      were digitized. Volume was calculated using the formula for a prolate ellipsoid.
      (3) An 18-gauge needle was used to inject and evacuate saline via an anterior
      approach. Quantity of aspirated fluid provided a direct measure of volume.
      Inferior capsular shift was performed. After the operation, measurements were
      repeated. Inferior capsular shift reduced volume in all shoulders with each
      technique. On average, inferior capsular shift reduced joint volume by 57 %). A
      measurable reduction in shoulder joint volume is an effect of capsular shift.
      This measurement may have clinical application if volume is an indicator of
      instability or laxity.

PMID- 8653984
TI  - Description of new composite tissue transfer for salvage of a complex hand
      defect.
AB  - Leiomyosarcoma of the soft tissue involving bones is an extremely rare tumor. In
      the past, a hand tumor of this type required amputation. Presently, with improved
      chemotherapy and reconstruction, the hand and its dexterity sometimes can be
      saved. In this case, after chemotherapy, the authors opted for wide excision
      including the skin, tendons, muscles, and bones. The large defect was
      reconstructed with an iliac crest autograft and a dorsalis pedis free flap
      including tendons. Functional result was excellent in this patient. The
      pathologic results also were reviewed by histology, immunohistochemistry for
      muscle marker, and electron microscopy.

PMID- 8653985
TI  - Loss of elbow and wrist motion in hemophilia.
AB  - The longitudinal changes in elbow and wrist motion for 48 patients with
      hemophilia were reviewed to determine the effect of recurrent hemarthroses. The
      average age of the patients at the time of followup was 23 years 9 months. The
      average duration of followup was 10.8 years. The patients were divided into 3 age
      groups: younger than age 15 years (14 patients), age 15 to 25 years (11
      patients), and older than age 25 years (23 patients). For patients older than age
      25 years, pronation, supination, elbow flexion and extension, wrist flexion and
      extension, and ulnar deviation were significantly decreased relative to patients
      younger than age 15 years. Pronation was the first motion to show a significant
      change, decreasing by 19% in patients age 15 to 25 years and by 31% in patients
      older than age 25 years. Loss of elbow extension showed the greatest change. In
      cases of severe hemophilic arthropathy of the elbow, synovectomy and radial head
      excision decreased elbow pain and bleeding episodes and improved supination and
      pronation.

PMID- 8653986
TI  - Essential drugs and WHO Model List: addressing new issues. Report of a workshop
      focusing on the report of the World Health Organization Expert Committee on the
      Use of Essential Drugs.

PMID- 8653987
TI  - Are single-dose toxicology studies in animals adequate to support single doses of
      a new drug in humans?

PMID- 8653988
TI  - Response to Monro and Mehta proposal for use of single-dose toxicology studies to
      support single-dose studies of new drugs in humans.

PMID- 8653989
TI  - Phenobarbital minimally alters plasma concentrations of losartan and its active
      metabolite E-3174.
AB  - Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension,
      is metabolized to an active carboxylic acid metabolite, E-3174, which has a
      longer half-life. To investigate the effects of induction of cytochrome P450 on
      the metabolism of losartan, we evaluated the effects of phenobarbital on the
      plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects
      received a single 100 mg oral dose of losartan before and during phenobarbital
      administration (100 mg/day for 16 days), and five subjects received losartan
      before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative
      to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome
      P450 induction. The geometric mean area under the plasma concentration-time curve
      ratios (with/without phenobarbital and 90% confidence intervals) for losartan and
      its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820),
      respectively, indicating that phenobarbital treatment significantly but to a
      clinically minor extent reduced plasma concentrations of losartan and E-3174
      (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6
      beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital
      group (p < 0.001) and did not change appreciably in the placebo group.

PMID- 8653990
TI  - Safe coadministration of terbinafine and terfenadine: a placebo-controlled
      crossover study of pharmacokinetic and pharmacodynamic interactions in healthy
      volunteers.
AB  - The pharmacokinetic and pharmacodynamic interactions of terbinafine (Lamisil) and
      terfenadine (Seldane) were assessed in 26 healthy volunteers randomized to
      receive either terbinafine (250 mg tablet) or its placebo (terbinafine placebo),
      which were administered in a double-blind manner once daily for 18 days. On days
      12 through 18, terfenadine was coadministered (60 mg twice daily, unblinded).
      Pharmacokinetic profiles were obtained for terbinafine and its desmethyl
      metabolite on day 11 (in the absence of terfenadine), day 12, and day 18.
      Terfenadine and terfenadine acid metabolite levels were also assayed on days 12
      and 18. After a 4-week washout period, subjects were crossed over to the
      alternate treatment (terbinafine or terbinafine placebo). Pharmacodynamic
      measures were electrocardiographic (ECG) rhythm abnormalities, corrected QT
      interval (QTc), and plasma ALT levels. Terfenadine levels were evaluated;
      however, only eight of 1502 samples assayed were above the limit of quantitation.
      No effect of terbinafine administration on pharmacokinetic parameters for the
      terfenadine acid metabolite was observed, except for a decrease of approximately
      20% in through terbinafine concentrations (C0hr; p < 0.05) on the last day of
      terfenadine plus terbinafine coadministration. Pharmacokinetic parameters for
      terbinafine were unchanged on the first day of terfenadine coadministration, and
      only small increases in area under the plasma concentration versus time curve
      from 0 to 24 hours and peak plasma concentrations (16.1%[p < 0.01] and 6.63% [p <
      0.05]) were observed on the last day of terfenadine and terbinafine
      coadministration. Values for C0hr were also about 20% to 25% higher (p < 0.05).
      Steady-state levels of the terfenadine acid metabolite were achieved after 2 days
      of terfenadine coadministration, and steady-state levels of terbinafine and its
      desmethyl metabolite were achieved after 14 days of terbinafine administration.
      The incidence of ECG rhythm abnormalities was not significantly higher in any
      treatment group; however, the incidence of prolongation of QTc > 10% above
      baseline was significantly higher in the groups treated with terfenadine. No QTc
      prolongation occurred in the absence of terfenadine treatment. Both terbinafine
      and terfenadine were well tolerated when coadministered during this study, as
      indicated by the low incidence of complaints, abnormalities, and adverse events.
      The results of this study indicate that terbinafine and terfenadine can be safely
      coadministered.

PMID- 8653991
TI  - Validation of urine caffeine metabolite ratios with use of stable isotope-labeled
      caffeine clearance.
AB  - OBJECTIVE: A number of caffeine metabolite ratios have been proposed to measure
      CYP1A2 activity in vivo. The data to validate these ratios are scanty. The
      objective of this study was to validate urine caffeine metabolite ratios versus
      stable isotope-labeled caffeine clearance under different caffeine dosing
      conditions. STUDY DESIGN: Two experiments, one with nine nonsmoking subjects and
      the other with 12 cigarette smokers, were performed. We explored the relationship
      between caffeine clearance, measured by means of intravenous infusions of stable
      isotope-labeled caffeine, and a number of caffeine metabolite ratios during
      administration of different single or multiple doses of caffeine to smokers and
      nonsmokers on three different occasions over a 2-week period, using different
      durations of urine collections, including spot urines. The stable isotope
      technique allowed simultaneous oral dosing of caffeine and measurement of
      caffeine metabolite ratios and caffeine clearance, the latter reflecting CYP1A2
      activity. RESULTS: The caffeine metabolite ratio of AAMU + 1U +1X/17U (5
      acetylamino-6-amino-3-methyluracil + 1-methyluric acid + 1 methylxanthine/1,7
      dimethyluric acid) maintained a significant correlation with caffeine clearance
      for all the above conditions (gamma2 range, 0.4 to 0.9) except for dose. With
      high doses of caffeine (12 mg/kg), a significant relationship was not observed.
      AAMU + 1U + 1X/17U also correlated with the formation clearance of paraxanthine
      (gamma2 = 0.6, p = 0.002). Other reported caffeine metabolite ratios did not
      display the same robust correlation with caffeine clearance under all these
      different conditions. CONCLUSIONS: We conclude that AAMU+1U+1X/17U measured from
      a single spot urine collection is a valid measure of CYP1A2 activity except at
      very high levels of caffeine dosing. The validity of the other proposed caffeine
      metabolite ratios is questionable.

PMID- 8653992
TI  - The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy
      volunteers.
AB  - We evaluated the effect of water-soluble vitamin E (d-alpha-tocopheryl
      polyethylene glycol 1000 succinate [TPGS]; Liqui-E) on the oral pharmacokinetics
      of the cyclosporine, a poorly available (approximately 30%) drug, in healthy
      volunteers. Ten healthy subjects were given two doses of oral cyclosporine
      (10mg/kg) separated by a 7-day washout period. Oral TPGS (2.6 IU/kg) was
      administered concomitantly with one of the cyclosporine doses in a randomized
      order. A significant increase was observed in area under the blood concentration
      time curve (AUC;mean +/ SD) with concomitant TPGS administration (3908 +/- 2601
      versus 6296 +/- 5102 ng x hr/ml). Significant decreases were observed in apparent
      oral clearance (0.24 +/- 0.14 versus 0.15 +/- 0.08 L/hr/kg) and apparent oral
      steady-state volume of distribution (1.57 +/- 0.95 versus 1.07 +/- 0.73 L/kg). No
      significant changes were observed in the ratios of metabolites to parent drug AUC
      values. The comparable relative decreases in apparent oral clearance (38%) and
      apparent oral steady-state volume of distribution (30%) with TPGS are most likely
      explained by enhanced absorption, decreased counter transport back into the
      intestine by P-glycoprotein, or some unknown mechanism by which cyclosporine is
      protected from metabolism in the gut, thereby increasing bioavailability.

PMID- 8653993
TI  - Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and
      the S-mephenytoin oxidation in Tanzanians.
AB  - S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216
      tanzanians. The mephenytoin S/R ratio in urine ranged from <0.1 to 1.16. The
      distribution was skewed to the right, without evidence of a bimodal distribution.
      Ten subjects (4.6%, 2.2% to 8.3%, 95% CI) with an S/R mephenytoin ratio >0.9,
      were arbitrarily defined as poor metabolizers of mephenytoin. The
      chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant
      correlation between the mephenytoin S/R ratio and the chloroguanide/cycloguanil
      ratios (rs = 0.73; p<0.00001). This indicates that cytochrome P4502C19 or CYP2C19
      is a major enzyme that catalyzes the bioactivation of chloroguanide to
      cycloguanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity may
      lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty
      eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200
      mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria
      chemoprophylaxis study showed that there was significant correlation between the
      number of earlier breakthrough parasitemia episodes and the
      chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did
      not correlate with the S/R mephenytoin ratio. However, other factors, such as
      exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are
      probably more important.

PMID- 8653994
TI  - Oral contraceptive effects on methylprednisolone pharmacokinetics and
      pharmacodynamics.
AB  - OBJECTIVE: Oral contraceptive (OC) steroids alter the disposition of numerous
      drugs, including corticosteroids. We investigated the pharmacokinetics and
      pharmacodynamics of methylprednisolone. METHODS: Twelve women (six women used OC
      steroids and six women did not) received intravenous methylprednisolone (0.6
      mg/kg ideal body weight). Methylprednisolone disposition was assessed from plasma
      concentrations. Pharmacodynamic parameters measured were plasma cortisol, whole
      blood histamine (reflecting basophils), and blood helper T lymphocytes. RESULTS:
      Methylprednisolone clearance was significantly decreased in the women who used OC
      steroids (0.298 versus 0.447 L/hr/kg), resulting in a longer elimination half
      life (2.20 versus 1.72 hours). With use of indirect response models, significant
      differences were observed with the cortisol and basophil responses. A larger
      value for the concentration that inhibits the zero-order production rate by 50%
      (0.37 versus 0.11 ng/ml) was observed in the women who used OC steroids for
      suppression of cortisol secretion, indicating less sensitivity to the suppressive
      effects of methylprednisolone. Greater net suppression of basophils was observed
      in the users of OC steroids (area under the response curve, 694 versus 401 ng x
      hr/ml). No differences were observed for helper T-cell responses. CONCLUSION: OC
      steroids appear to inhibit methylprednisolone metabolism. However, mixed changes
      in several responses occur, indicating that women can probably receive similar
      doses of methylprednisolone irrespective of OC steroid use.

PMID- 8653996
TI  - Inhibition of sulfamethoxazole hydroxylamine formation by fluconazole in human
      liver microsomes and healthy volunteers.
AB  - Sulfamethoxazole toxicity is putatively initiated by the formation of a
      hydroxylamine metabolite by cytochromes P450. If this reaction could be
      inhibited, toxicity may decrease. We have studied--in vitro and in vivo-
      fluconazole, ketoconazole, and cimetidine as potentially suitable clinical
      inhibitors of sulfamethoxazole hydroxylamine formation. Both fluconazole and
      ketoconazole in human liver microsomal incubations competitively inhibited
      sulfamethoxazole N-hydroxylation, with the inhibitory constant (Ki) values of 3.5
      and 6 micromol/L, respectively. Cimetidine exhibited a mixed type of inhibition
      of sulfamethoxazole hydroxylamine formation in human liver microsomes, with IC 50
      values (the concentration required to decrease hydroxylamine formation by 50%) of
      80 and 800 micromol/L, the lower value being observed when cimetidine was
      preincubated with microsomes and reduced nicotinamide adenine dinucleotide
      phosphate. In an in vivo study in six healthy volunteers the inhibition of the
      cytochrome P450-mediated generation of the toxic metabolite in the presence of
      fluconazole was shown by a 94% decrease in the area under the plasma
      concentration-time curve of sulfamethoxazole hydroxylamine. In contrast, the
      recovery of hydroxylamine in urine decreased by only 60%. Total clearance of
      sulfamethoxazole was decreased by 26% by fluconazole, most likely because of the
      inhibition of unidentified P450 elimination pathways. There was close agreement
      between the predicted (87%) and observed inhibition (94%) of sulfamethoxazole
      hydroxylamine formation in vivo. Similarly, there was close agreement between in
      vivo and in vitro Ki values--1.6 and 3.5 micron/L, respectively.

PMID- 8653995
TI  - Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide,
      thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive
      metabolizers of dextromethorphan and mephenytoin.
AB  - Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of
      thioridazine and metabolites were measured in 21 patients who were receiving 100
      mg thioridazine for 14 days and who were comedicated with moclobemide (450
      mg/day). Two patients were poor metabolizers of dextromethorphan and one was a
      poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the
      formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably
      partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the
      formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant
      correlations between the mephenytoin enantiomeric ratio and concentrations of
      thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute
      to the biotransformation of thioridazine into yet-unknown metabolites, other than
      thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An
      enantioselectivity and a large interindividual variability in the metabolism of
      thioridazine have been shown: measured (R)/(S) ratios of thioridazine,
      thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE),
      thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and
      thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80),
      0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/-
      0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019
      (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively.
      CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)
      thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)
      thioridazine 5-SO(SE).

PMID- 8653997
TI  - Comparison of intranasal midazolam and sufentanil premedication in pediatric
      outpatients.
AB  - BACKGROUND: Intranasally administered midazolam was compared with sufentanil as a
      premedicant for 60 patients, aged 1/2 to 6 years, undergoing outpatient surgery
      of 2 hours or less. METHODS: Thirty minutes before anesthetic induction
      (halothane in 50% nitrous oxide/oxygen), patients were randomly assigned to
      receive either intranasal midazolam (0.2 mg/kg) or sufentanil (2 microg/kg). A
      "blinded" observer evaluated preoperative emotional state, response to
      premedication, induction, and emergence from anesthesia and side effects.
      RESULTS: Children who had not previously cried were more likely to cry when
      midazolam was administered compared with sufentanil (71% versus 20%, p = 0.0031).
      Of 31 midazolam patients, 20 experienced nasal irritation. Approximately 15 to 20
      minutes after drug administration, most patients in both groups could be
      comfortably separated from their parents. The sufentanil group appeared to be
      more sedated and more cooperative during induction of anesthesia. Vital signs and
      oxygen saturation did not change significantly with either medication before or
      after surgery, although two sufentanil patients had a moderate reduction in
      ventilatory compliance after anesthetic induction. Sufentanil was associated with
      more nausea and vomiting than midazolam (34% versus 6%, p < 0.02). CONCLUSION:
      Both intranasal midazolam and sufentanil provide rapid, safe, and effective
      sedation in small children before anesthesia for ambulatory surgery. Sufentanil
      provided somewhat better conditions for induction and emergence. Midazolam causes
      more nasal irritation during instillation, and sufentanil causes more
      postoperative nausea and vomiting. Both drugs enabled patients to be separated
      from their parents with a minimum of distress. Patients in the midazolam group
      were discharged approximately 40 minutes earlier (p <0.005).

PMID- 8653998
TI  - Etoposide combined with interferon alfa-2b: novel exploitation of established
      etoposide pharmacokinetics and pharmacodynamics.
AB  - PURPOSE: To construct an efficient pilot study design to determine whether
      interferon alfa-2b modifies the pharmacokinetics and pharmacodynamics of
      continuous-infusion etoposide. PATIENTS AND METHODS: A two-stage randomized 2 X 2
      factorial design was used to evaluate interferon alfa-2b at two doses (2 or 10
      MU/m2/day SQ for 3 days) and two schedules (interferon alfa-2b administered
      before or concurrent with 72-hour continuous-infusion etoposide). Etoposide was
      administered at 75, 100, or 125 mg/m2/day. In lieu of comparing the experimental
      arms to an etoposide-alone control arm to determine effect of interferon alfa-2b
      dose and schedule, a novel analytic approach was used. The effect of interferon
      alfa-2b on etoposide-induced leukopenia was assessed indirectly by comparison of
      the observed white blood cell (WBC) nadir to the nadir predicted from an
      established pharmacodynamic model for single agent etoposide. RESULTS: Based on
      29 patients, dose-normalized 24-hour total and estimated free etoposide
      concentrations did not differ with interferon alfa-2b dose or schedule. Patients
      treated with interferon alfa-2b before etoposide had, on average a WBC nadir 545
      +/- 225 cells microliter lower than that predicted by a pharmacodynamic model for
      etoposide alone. An optimal nonlinear model for leukopenia was defined by
      interferon alfa-2b schedule in addition to 24-hour etoposide concentration.
      CONCLUSION: A novel study design and statistical analysis provided an efficient
      preliminary evaluation of the combination of interferon alfa-2b with etoposide in
      a modest number of patients. Exploitation of a previously validated
      pharmacodynamic model allowed evaluation of interferon alfa-2b effect and
      eliminated the need for an etoposide-alone control arm. The pharmacokinetics of
      continuous-infusion etoposide at doses from 75 to 125 mg/m2/day appear to be
      unchanged by interferon alfa-2b at the doses and schedules tested and the
      combination appears to be feasible. We hypothesize that leukopenia may be
      enhanced when interferon alfa-2b is administered before etoposide, especially at
      a higher dose of interferon alfa-2b.

PMID- 8653999
TI  - A case of bleeding requiring hospitalization that was likely caused by an
      interaction between warfarin and levamisole.
AB  - Warfarin is one of the most commonly used oral anticoagulants. Many medications
      have been shown to influence the prothrombin time in patients treated with
      warfarin by various mechanisms. We observed a major bleeding episode that
      resulted from a probable interaction between levamisole (Ergamisol), 5
      fluorouracil, and warfarin. It is conceivable that many patients who are
      predisposed to thromboembolism because of cancer and surgery will be taking this
      combination of medications.

PMID- 8654000
TI  - Significant figures or significant nonsense?

PMID- 8654001
TI  - Colour Doppler energy (power) mode ultrasound.

PMID- 8654002
TI  - The role of radiology in the investigation and management of patients with
      haemoptysis.

PMID- 8654003
TI  - T2 relaxation times of hypervascular and non-hypervascular liver lesions: do
      hypervascular lesions mimic haemangiomas on heavily T2-weighted MR images?
AB  - AIM: To correlate the T2 relaxation times of liver lesions with their vascularity
      at angiography and to determine whether hypervascular lesions have similar signal
      intensity to haemangiomas on heavily T2-weighted MR images. PATIENTS AND METHODS:
      Thirty-four patients with histologically proven malignant liver lesions had both
      angiography and T2W (SE 3000/80,160) MR imaging (1.5 T) of the liver.
      Angiographically, the lesions were hypervascular in 15 and non-hypervascular in
      19 patients. Fifteen additional patients with proven haemangioma also had MR
      imaging during the same time period. The T2 relaxation time of a representative
      lesion was calculated for each patient and the results compared. RESULTS: The
      mean T2 time for hypervascular lesions was 76 +/- 21 ms compared with 79 +/- 18
      ms for non-hypervascular lesions (P = 0.61). The mean T2 relaxation time for
      haemangiomas was significantly longer than either group: 147 +/- 46 ms (P =
      0.0001). CONCLUSION: The T2 relaxation times of hypervascular and non
      hypervascular liver lesions are similar and are significantly shorter than those
      of haemangiomas. Therefore, hypervascular lesions should not mimic haemangiomas
      on heavily T2-weighted images.

PMID- 8654005
TI  - The value of serial Doppler imaging in central retinal vein occlusion:
      correlation with visual recovery.
AB  - A prospective study of 80 patients with central retinal vein occlusion (CRVO) was
      performed to determine whether Doppler flow measurements can predict visual
      outcome. All patients at presentation, had full ophthalmological examination,
      fluorescein angiography, relative afferent pupillary defect test and
      electroretinography to distinguish between ischaemic and non-ischaemic
      occlusions. In addition, all patients were examined at presentation with colour
      Doppler ultrasound using a 7.5 MHz linear array probe. Both the clinical
      examinations and colour Doppler ultrasound were repeated at one year following
      initial presentation in a smaller group of 20 patients. A significant reduction
      in velocity within the central retinal vein was noted in the ischaemic compared
      with non-ischaemic CRVO affected eye at the time of the baseline scan. The
      minimum venous velocity within the central retinal vein was most severely
      affected. No velocity difference was present within the ophthalmic artery. Follow
      up at one year with colour Doppler ultrasound showed an increase in blood
      velocity values within the central retinal vein in the CRVO affected eye but this
      was of no prognostic value and did not correlate with clinical outcome. Serial
      colour Doppler ultrasound examinations, therefore, have no clinical application
      in patients with CRVO and are of no prognostic value.

PMID- 8654004
TI  - Hyperattenuating rim on noncontrast CT of the liver: probable peritumoral sparing
      of fatty infiltration.
AB  - CT scans showing a hyperattenuating rim within the liver were retrospectively
      evaluated in 10 patients to clarify the character, aetiology and clinical
      significance. All patients had hepatic tumours (7 cavernous haemangiomas in 6
      patients, 3 metastatic tumours and 1 hepatocellular carcinoma) as well as fatty
      infiltration of the liver. Typical features of the hyperattenuating rim on
      noncontrast CT of the liver included (1) attenuation similar to that of the
      spleen, (2) a circular or semicircular shape, (3) a width of a few millimeters,
      (4) peritumoral localization and (5) loss of visualization with contrast
      enhancement. No such rims were noted around hepatic tumours unassociated with
      fatty infiltration. Peritumoral sparing of fatty infiltration was inferred. A
      hyperattenuating rim on noncontrast liver CT, although rare, suggests the
      presence of a hepatic tumour in fatty liver.

PMID- 8654006
TI  - Intraocular silicone oil for retinal detachment in AIDS: CT and MR appearances.
AB  - AIM: To describe the CT and MR features of intraocular silicone oil which is used
      to treat complex retinal detachments in patients with acquired immune deficiency
      syndrome (AIDS). PATIENTS AND METHODS: Seven male patients with AIDS were treated
      by pars plana vitrectomy and intraocular silicone oil injection for complex
      retinal detachments due to biopsy proven cytomegalovirus retinitis. Two patients
      had bilateral therapy. RESULTS: Silicone oil was hyperdense to muscle on CT with
      attenuation values of 106-139 HU (mean 115, SD 4.5). On MR, when compared with
      normal vitreous, intraocular silicone oil appeared hyperintense on T1-, proton
      density, and T2-weighted spin-echo sequences. A chemical shift artifact was seen
      on all MR images, being most marked on the T2-weighted images. CONCLUSION: The
      high attenuation value of silicone oil on CT and its hyperintensity on T1
      weighted MR images my cause diagnostic confusion with haemorrhage. These entities
      can be distinguished at CT by directly measuring the attenuation number (silicone
      oil > 100 HU; blood < 90 HU), and at MR by the presence of a chemical shift
      artifact.

PMID- 8654007
TI  - Use of resistance index for the diagnosis of breast tumours.
AB  - AIM: To determine whether the resistance index (RI) contributes to the
      differential diagnosis of breast masses. PATIENTS AND METHODS: In 56 breast
      tumours colour-coded Doppler sonography was performed and their resistance
      indices calculated from their spectral Doppler tracings. Histologic evaluation
      was obtained by excision biopsy. RESULTS: In seven of 28 benign tumours (25%) no
      lesion was seen on ultrasound. In another seven benign tumours, no intratumoral
      vessels were demonstrated. The resistance index of the remaining 14 lesions (50%)
      varied between 0.5 and 0.75 with a mean value of 0.62 (standard deviation 0.08).
      Ultrasound missed one of 28 carcinomas (3.5%) and in one other tumour (3.5%) no
      flow was demonstrable. The resistance index of 26 malignant tumours varied
      between 0.56 and 0.9 with a mean value of 0.7 (standard deviation 0.08).
      CONCLUSION: Breast malignancies have higher resistance indices with a wider range
      as assessed by colour-coded Doppler ultrasound (81% exceed 0.6) than do benign
      lesions. Due to the considerable overlap of the range of the resistance index,
      the measurements in any single patient may not be diagnostic. The absence of flow
      does not definitively exclude malignancy.

PMID- 8654008
TI  - Pure mucinous breast cancer-mammographic and ultrasound findings.
AB  - Aim to describe the mammographic and ultrasonographic features of pure mucinous
      breast cancer. PATIENTS AND METHODS: The mammographic features of 15 patients and
      ultrasonographic features of seven patients with pure mucinous breast cancer were
      reviewed retrospectively by three experienced breast radiologists. RESULTS: The
      commonest mammographic appearance was of a poorly defined (86%) lobulated (71%)
      mass which could contain calcification (14%). A well defined mass (14%) and
      suspicious calcifications without a mass (7%) were also seen. Ultrasound showed a
      mass lesion in all seven cases which was either hypoechoic (86%) or mixed
      echogenicity (14%); 86% had a heterogeneous internal echo pattern; 71% showed
      distal enhancement while none showed distal attenuation. CONCLUSION: The imaging
      features of pure mucinous cancer are different from more common types of breast
      carcinoma. It is possible to misinterpret the appearances of this slow growing
      tumour as a benign lesion due to rarity of speculation on mammography and distal
      attenuation on ultrasonography. Most cases do, however, show other features
      suggesting malignancy.

PMID- 8654009
TI  - Magnetic resonance imaging guided breast biopsy using a frameless stereotactic
      technique.
AB  - The high sensitivity but poor specificity of contrast enhanced magnetic resonance
      (MR) imaging for delineating malignant breast lesions is increasing the demand
      for MR guide breast biopsy. However, the poor patient access offered by
      conventional MR systems makes such procedures extremely difficult. We describe a
      method of performing breast biopsy outside the bore of the magnet using the 3-D
      MR imaging data. This involves a frameless stereotactic technique using an
      ultrasonic localizer. The position in space of the tip of a pointer with a handle
      which incorporates two ultrasound emitters can be tracked using an array of
      ultrasound detectors. MR visible marker beads (fiducials) placed on the breast
      and imaged at the same time are identified to the computer in relation to images
      of the breast. The ultrasonic localizer is used to register the position in space
      of the fiducials by touching them with the tip of the pointer. The image of the
      lesion within the breast can then be displayed in relation to the position of the
      tip of the pointer and the needle approach planned. Nine women with foci of
      enhancement on their dynamic contrast enhanced MR images underwent frameless
      stereotactic breast cytology. Needle placement within 2 mm of the lesion was
      achieved at first pass in eight out of nine (89%) cases: in one case the needle
      had to be re-positioned prior to sampling. This technique provides a means of
      targetting MR visible lesions using the MR imaging data whilst performing the
      procedure outside the magnet bore.

PMID- 8654010
TI  - CT findings in necrotising fasciitis--a report of four cases.

PMID- 8654011
TI  - Ultrasound features of folded lung.
AB  - The ultrasound features of folded lung (rounded atelectasis) have not been
      described previously. The US findings of folded lung in fourteen patients and
      correlation with computed tomography are presented. The principal US findings
      were a pleurally based 'mass' and thickening of the adjacent pleura and
      extrapleural fat. A highly echogenic line extending from the pleural surface into
      the mass was seen in 12 patients (86%). We believe this finding corresponds to
      the scarred invaginated pleura as demonstrated in pathological studies of this
      condition.

PMID- 8654012
TI  - Case report: intracystic papillary carcinoma of the breast in a male patient.

PMID- 8654013
TI  - Case report: the CT demonstration of soft tissue involvement in multicentric
      reticulohistiocytosis.

PMID- 8654014
TI  - Case report: successful internal iliac artery embolisation with glue in a case of
      massive obstetric haemorrhage.

PMID- 8654015
TI  - Case report: magnetic resonance imaging in cerebral fat embolism.

PMID- 8654016
TI  - Case report: ultrasound of primary generalised AL amyloid of the small bowel.

PMID- 8654017
TI  - Ultrasound training for non-radiologists.

PMID- 8654018
TI  - Ultrasound training for non-radiologists.

PMID- 8654019
TI  - Ultrasound training for non-radiologists.

PMID- 8654020
TI  - Plaque surface morphology on angiography.

PMID- 8654021
TI  - Genu varum and genu valgum in children: differential diagnosis and guidelines for
      evaluation.

PMID- 8654022
TI  - Evaluation and treatment of ankle sprains.

PMID- 8654023
TI  - Sjogren's syndrome.

PMID- 8654024
TI  - Needle arthroscopy: a new frontier in rheumatology.

PMID- 8654025
TI  - The adolescent with arthritis.

PMID- 8654026
TI  - Musculoskeletal tumour disorders.

PMID- 8654027
TI  - The myotonias: their diagnosis and treatment.

PMID- 8654028
TI  - Restorative treatment decisions from bitewing radiographs--performance of dental
      epidemiologists and general dental practitioners.
AB  - The object of the study was to compare the performance of a group of eight
      trained and standardized dental epidemiologists making restorative treatment
      decisions with that of a group of 20 general dental practitioners. Both groups
      read the same set of 15 pairs of simulated bitewing radiographs. For each
      approximal tooth surface image, the examiners were asked to record on a six-point
      rating scale the confidence with which they would or would not place a
      restoration. A histological gold standard was available, based on microscopic
      evaluation of sections of the extracted teeth used for study. The reference
      criterion was "caries into dentine". The only statistically significant
      differences in performance between the two groups were at the "definitely" plus
      "probably" restore rating level. For the proportions of correct decisions out of
      all treatment decisions at this level, the epidemiologists scored 89% compared
      with 86% for practitioners (P < 0.01) while for Youden's J index, the
      corresponding values were 0.44 and 0.34 (P < 0.05). The findings suggest that the
      benefits in improved performance from examiner training may be small.

PMID- 8654029
TI  - Dentists' variability in restorative decisions, microscopic and radiographic
      caries depth.
AB  - Restorative and dental caries depth decisions were recorded for 5168 un restored
      approximal tooth surfaces by 17 dentists who worked in the school dental clinics
      of the North York (Ontario) Public Health Department. Each dentist examined 15
      pairs of experimental bitewing radiographs for which true caries depth had
      previously been determined by microscopy of the sectioned teeth following
      production of the radiographs. The dentists independently recorded their
      restorative decisions and radiographic caries depth perceptions. The relationship
      between the variation in the dentists' restorative decisions and their
      perceptions of caries depth based on a re-reading of the bitewings on the one
      hand, and true caries depth on the other was also examined. The percentages of
      total variability in each dentist's restorative decisions attributable to
      radiographic and to microscopic caries depth were estimated using regression
      analyses. Large variations were found among the 17 dentists' distributions of
      overall restorative and depth decisions. The relationship between microscopic
      caries depth and the dentists' restorative decisions was, understandably, less
      strong than that of the dentists radiographic perceptions of caries depth and
      restorative decisions. Relative to true caries depth, high numbers of false
      positive and false negative restorative decisions were made. Overall, 50% of the
      variability in the dentists' restorative decisions was explained by the
      perceptions of radiographic caries depth; however, among individual dentists, the
      range was from 29% for one dentist to 69% for another. A much lower percentage of
      the overall restorative variation was explained by microscopic depth, 18%. Like
      the finding of the only two previous European studies that quantified the role of
      radiographs on clinical decisions, this study demonstrated that dentists'
      perceptions of dental caries depth using bitewing radiographs play a major but
      variable role in their restorative decisions for approximal tooth surfaces.

PMID- 8654030
TI  - Initial development of a scale to measure dental indifference.
AB  - Lack of concern about dental health contributes significantly to the reluctance
      of people to attend for dental check-ups and to implement preventive dental
      measures. The aim of this study was to develop and assess a questionnaire method
      of detecting this attitude which was described as dental indifference. The
      questionnaire was tested on 910 dentate adults in Scotland. A 62% response rate
      was obtained. Five hundred of the respondents were then sent a second copy of the
      questionnaire to assess its reliability, a 67% response rate was obtained. The
      Pearson correlation coefficient between the first and second completion of the
      dental indifference questionnaire was 0.79. The internal consistency measured by
      Chronbach's alpha was 0.71. High scores on the dental indifference questionnaire
      were significantly associated with being young, male and a manual worker. High
      scores had fewer teeth, on average, than the rest of the sample and more than
      half of them had no record of attending for dental care within 4 years. Those who
      did attend a dentist were more likely to have teeth filled or extracted. The
      dental indifference questionnaire may be useful for targeting groups who require
      oral health promotion activity and may prove to be a reliable means of
      identifying individuals who display behaviours which could be expected to be
      associated with a lack of interest in dental health, such as lack compliance with
      oral care instructions and failing to complete course of treatment.

PMID- 8654031
TI  - Dental health in Dutch drug addicts.
AB  - The aim of this study was to describe to dental health status of a group of Dutch
      20-40-yr-old drug addicts (n = 121) and to compare the results if DMFS with data
      of an age-comparable sample of the general adult population in the Netherlands (n
      = 1532). Mean DMFT of the addicted group was 16.9. ANOVA showed that the mean
      DMFS of the addicted group differed statistically significantly from the DMFS of
      the general population of the same age (= 52.1 versus 38.9) Statistically
      significant differences in DMFS were also found between the various age groups.
      The percentage of addicted subjects with more than cervical plaque on one or more
      teeth was 76.5%m 82.4% and 88.2% in the three youngest age groups. In almost all
      addicted subjects, bleeding of the gingiva was present Only 36% had visited the
      dentist less than a year ago and 18% brushed their teeth less than once a day. It
      is concluded that there is a large gap in dental health status and behavior
      between drug addicts and the general population. Dental care as an integral part
      of the care for drug addicts is advocated.

PMID- 8654033
TI  - A survey of reasons for extraction of permanent teeth in Singapore.
AB  - A survey was carried out to determine the reasons for tooth extractions of
      permanent teeth in Singapore. Data were obtained from 52 dentists practising
      general dentistry over a period of 12 months. At the end of the 12-month period,
      data were collected from 1276 patients, from whom a total 272 teeth were
      extracted. In this population group, the results showed that the percentage of
      teeth extracted due to periodontal reasons and caries were about the same, that
      is 35.8% and 35.4%, respectively. There was an increase in teeth extracted due to
      periodontal reasons with age. In patients above 40 yr, an average of 76% of teeth
      were lost due to periodontal reasons. An average of 26.7% of teeth were lost due
      to periodontal reasons in patients under 40 yr old. However, the trend for loss
      of teeth due to caries is reversed. Posterior teeth were more frequently extract
      compared to anterior teeth. Third molars accounted for 24.7% of all extractions
      carried out, whilst central incisors were 8.0% of all extractions. Molars were
      often lost due to caries and lower anterior teeth were most frequently lost due
      to periodontal reasons. The results of this study did not demonstrate one
      predominant reason for extraction. Both caries and periodontal reasons were
      equally common causes of tooth extraction.

PMID- 8654032
TI  - Differences in dental treatment plan and planning for drug-addicted and non-drug
      addicted patients.
AB  - This study investigated whether dental treatment plans and planning of general
      practitioners are different for addicted and identical non-addicted patients.
      Dental practitioners (n = 500) were sent a questionnaire with information on and
      questions about treatment for either an addicted or an identical non-addicted
      patient; response rate was 41 %. Loglinear analysis showed that after controlling
      for the influence of four demographic variables (sex, age number of patients and
      number of National Health Service insured patients), the treatment plans made for
      addicted patients were less elaborate than those for non-addicted. For the
      addicted, fillings or frames were proposed more often, whereas for non-addicted
      patients more often crowns or bridges were proposed. Extraction instead of
      filling was more often proposed for the addicted patient. Less elaborate
      treatment for addicted patients corresponds to the way dentists specialized in
      treating drug addicts work, with one exception: extraction should be avoided
      whether a patient is addicted or not. Treatment planning did not differentiate
      for addicted and non-addicted patients, whereas dentists specialized in treating
      addicted patients do recommend an adjusted treatment plan for the addicted.

PMID- 8654034
TI  - Self-assessed bleeding in monitoring gingival health among adolescents.
AB  - The purpose of this descriptive, cross-sectional community-based investigation
      was to assess the self-assessment of bleeding and plaque as methods to monitor
      gingival health among adolescents. Two study groups (n = 184 each) of 14-year-old
      Finnish school children performed either of self-assessment plaque or bleeding.
      Prior to that they were clinically examined by 10 dentists from the community
      dental service who recorded bleeding on probing from four surfaces of all teeth
      (BOP%) and Community Periodontal Index of Treatment Needs (CPITN) status. The
      self-assessment of plaque was not significantly correlated with a clinical
      bleeding on probing measurement (BOP%). The self-assessment of bleeding, based on
      observed bleeding after toothbrushing and after interproximal cleaning with
      toothpicks, exhibited statistically significant correlation with BOP% (r = 0.54,
      P < 0.001). Percent agreement was 75%, kappa agreement 0.33, sensitivity 31% and
      specificity 71%, respectively. In conclusion, the preliminary results suggest
      that the self-assessment of bleeding does not have sufficient validity for
      screening individuals but it could be a useful method for monitoring gingival
      health of populations, in particular, if the concurrent aim is to enhance
      periodontal awareness.

PMID- 8654035
TI  - Work stress, job satisfaction and emotional well-being among Canadian dental
      assistants.
AB  - Although dentistry is considered to be a stressful occupation, few data exist on
      work stress among dental assistants. In a previous paper, the extent and nature
      of work stress among this group was described and linked to a behavioural
      outcome; namely, intentions to change jobs or seek work outside of dentistry. In
      this paper the psychological outcomes of work stress, in the form of job
      satisfaction and emotional well-being, are examined. Using data collected by a
      mail survey, it was revealed that the main sources of dissatisfaction for dental
      assistants were low incomes, lack of opportunity to develop professionally and
      lack of recognition. Almost one-in-five had scores on a standard measure of
      emotional distress, which indicated a cause for concern. Work stress proved to be
      a significant predictor of job satisfaction, and work stress and job satisfaction
      emerged as significant predictors of emotional well-being. Social support while
      at work showed direct and interactive effects on job satisfaction but not
      emotional well-being. Role ambiguity, under-utilization of skills and low self
      esteem emerged as important issues. These results are of interest theoretically
      and have important implications for the way dental practice and dentistry are
      organized.

PMID- 8654036
TI  - Profile of work-related health complaints among Swedish dental laboratory
      technicians.
AB  - The purpose of the present investigation was to assess the prevalence and nature
      of occupation-related health problems among Swedish dental laboratory
      technicians. A 4-page questionnaire listing seven groups of health complaints was
      completed by 489 male and 242 female technicians, representing 56% of the active
      members of their organization. Similar information from 163 males and 160 females
      with other occupations was used for comparison. The biannual prevalence of health
      problems among the technicians was 79%, comprising musculoskeletal (68%), dermal
      (34%), respiratory 31%, neurological (26%), systemic (19%) and eyesight/hearing
      problems (15%). Job-specific ergonomic and stress factors were responsible for
      musculoskeletal and neurological (finger) reactions whereas chemical insults,
      grinding dusts and indoor climate caused dermal, respiratory and systemic
      reactions. There was no age prevalence as regards health complaints, but female
      technicians consistently showed a large prevalence of musculoskeletal, dermal
      systemic and neurological complaints than their male counterparts (P < 0.05,
      chi2). A similar sex difference was also present in the control group. A
      considerable part of the reactions were perceived to be of minor importance,
      bringing the total biannual prevalence down to 57%. However, the prevalence of
      job-related health complaints was still higher among the technicians than in
      control groups for all indicators except systemic and eyesight/hearing problems.
      The profile of health complaints among dental laboratory technicians was
      characterized by musculoskeletal, neurological and dermal reaction, underlining
      the importance of job-specific ergonomic and chemical hazards. Only a few of the
      technicians had consulted medical personnel.

PMID- 8654038
TI  - The tooth wear index: a flawed epidemiological tool in an ageing population
      group.
AB  - With a greater number of people living longer and tending to retain many natural
      teeth, the problems associated with tooth wear are likely to place greater
      demands upon dental professionals in the future. Several attempts have been made
      to develop an index to measure tooth wear, for use at both the individual and
      population level. A review of these indices is undertaken, and difficulties
      experienced with the tooth wear index (TWI) of Smith & Knight (1984) in a large
      adult dental health survey is discussed. In the elderly population the scoring
      criteria of the TWI proved to be difficult to apply without additional
      qualification, and in cases of extreme wear a five-point ordinal scale was found
      to be inadequate to describe the range of wear observed. The concept of
      "pathological" levels of wear proposed by the TWI are challenged and modification
      to the index suggested for use among the elderly population.

PMID- 8654037
TI  - Dentist service rates and distribution of practice styles over time.
AB  - Studies of dentist service rates have identified clusters of dentists with
      particular styles of practice, but these practice styles need to be investigated
      to determine whether patterns of care become established and remain
      characteristic among dentists. The aims of this study were to establish dentist
      practice styles and to assess the distribution of these styles of practice
      between 1983 and 1988. A total of 202 private general practitioners who provided
      service rate data in both 1983 and 1988 were used in a cluster analysis to group
      dentists into practice styles. For both 1983 and 1988 three clusters of dentists
      were obtained, characterized by service rates as "High Restorative", "Low Total
      Rates", and "High Diagnostic and Preventive". However, the distribution of
      cluster membership changed over time. The percentage of dentists in the "High
      Restorative" cluster decreased from 27.9% in 1983 to 16.6% in 1988, the "Low
      Total Rates" cluster decreased for 60.7% in 1983 to 49.2% in 1988, while the
      "High Diagnostic and Preventive" cluster increased from 11.4% in 1983 to 34.2% in
      1988. The distribution of dentists between these practice styles may be related
      to aging of dentists, practice maturation, population demographics, need or
      demand changes, or involve subtle differences in cluster classification over
      time.

PMID- 8654039
TI  - Influence of exposure to fluoridated water on socioeconomic inequalities in
      children's caries experience.
AB  - This study aimed to evaluate inequalities in children's dental caries experience
      among socioeconomic status (SES) groups and to investigate effects of exposure to
      fluoride in water on those inequalities. Cross-sectional data were obtained from
      6704 Queensland children aged 5-12 years and 6814 South Australian children aged
      5-15 years. School dental therapists and dentists recorded dmfs and DMFS data. A
      questionnaire to parents sought information about household SES and each child's
      lifetime exposure to fluoridated drinking water. SES fluoride exposure and
      multiplicative interactions between the two were used as explanatory variables in
      least squares models in which dmfs and DMFs were dependent variables. Additive
      interactions were evaluated by calculating the excess rate of disease. In both
      states, children from low SES groups (categorized by household income or parental
      education) had higher mean dmfs and DMFS values than children from high SES
      groups (P < 0.01). Independent effects of income and education remained
      significant (P < 0.01) after controlling for exposure to fluoride in drinking
      water. In Queensland, there was a significant multiplicative interaction whereby
      SES inequalities were lower among children exposed to fluoride: dmfs ratios
      between low- and high-income groups ranged among ages from 1.54 to 3.56 for
      children with no exposure to fluoride and from 0.84 to 2.07 for children with
      lifetime exposure to fluoride. Multiplicative interactions were not statistically
      significant in South Australia or when DMFS was the dependent variable. However,
      additive interactions were consistent and most pronounced for deciduous teeth in
      both States. Absolute differences in caries experience between low and high SES
      children were greater among non-exposed groups due to the higher underlying
      levels of caries experience of children with no exposure to fluoride in water.

PMID- 8654040
TI  - Formylmethionyl-leucyl-phenylalanine-induced chemiluminescence responses in
      bovine polymorphonuclear leukocytes.
AB  - Isolated bovine polymorphonuclear leukocytes (PMNL) show a biphasic luminol
      dependent chemiluminescence response, and when exposed to high concentrations (2
      x 10(-4) M) of the chemotactic peptide formylmethionyl-leucyl-phenylalanine (f
      Met-Leu-Phe), the second emission peak is enhanced. This response was increased
      in magnitude by incubating PMNL at room temperature before stimulation with f-Met
      Leu-Phe. Pre-exposure of bovine PMNL to myeloperoxidase (MPO) also enhanced their
      receptiveness to the chemotactic peptide, indicating that the MPO-hydrogen
      peroxide system can modulate the bovine PMNL response to chemotactic factors. The
      results demonstrate that bovine PMNL are stimulated by the chemotactic peptides
      to participate in inflammatory processes.

PMID- 8654041
TI  - Assessment of an indirect ELISA in milk for the diagnosis of ovine Brucellosis.
AB  - The possibility of using an ELISA for the diagnosis of ovine brucellosis in milk
      (M-ELISA) was investigated. The aim of the study was to establish whether the
      specificity and sensitivity of the M-ELISA would be high enough to detect low
      levels of Brucella antibodies in ewe milk. The diagnostic performances of the
      test under study were established by means of reference standards and compared
      with conventional screening and confirmatory tests under field conditions. The
      diagnostic specificity of the M-ELISA established on a number of samples from
      Brucella-free flocks was 100% while relative to RBT and CFT positive reactors the
      M-ELISA demonstrated sensitivity of 65 and 83% respectively. Its sensitivity
      relative to culture positive animals was of 92%. The course of Brucella
      antibodies in milk of positive sheep was evaluated in colostrum and in mature
      milk for a period of 30 days after delivery and it appeared that concentrations
      of immunoglobulins in milk tend to sharply decrease soon after parturition while
      in blood serum these remained constantly high. It was concluded that the M-ELISA
      for Brucella antibodies in ewe milk can be regarded as a complementary diagnostic
      tool for individual testing but it would be poorly viable if used as a screening
      test applied to pooled flock milks.

PMID- 8654042
TI  - Identification of the newly described Mycobacterium poriferae from tuberculous
      lesions of snakehead fish (Channa striatus).
AB  - A mycobacterium isolated form a cultured snakehead with nodular lesions was
      identified on the basis of high performance liquid chromatography (HPLC) profile
      of cell wall mycolic acids, and confirmed by conventional tests, as Mycobacterium
      poriferae, a species previously isolated only from a marine sponge. The profiles
      of M. poriferae, Mycobacterium aurum and Mycobacterium parafortuitum are here
      reported for the first time.

PMID- 8654043
TI  - A royal jelly as a new potential immunomodulator in rats and mice.
AB  - In order to study a possible immunomodulatory effect of the royal jelly (RJ)
      secreted by mandibular and hypopharingeal glands of the worker honeybee (Apis
      mellifera Linne.) we have used a well established rodent model. The CBA mice were
      given s.c. 0.1 ml of RJ, 7 days before, or immediately after, the immunization
      with sheep red blood cells (SRBC). The Y59 rats received i.m. 0.4 ml or i.v.
      0.025 ml of RJ once or twice at 7 day intervals. Serum levels of total proteins
      and immunoglobulins in the rats that received RJ once or twice within a 2-week
      period were significantly lower (P < or = 0.05) as compared with the nontreated
      animals. In mice which were immunized with 4 x 10(8) of SRBC 7 days after the
      application of RJ the number of plaque forming splenocytes was significantly
      higher (P < or = 0.05) than that in the controls. Both the weight of inguinal
      lymph node and the number of peripheral blood lymphocytes were increased (P < or
      = 0.05) in RJ-treated mice 3 or 5 days after the immunization, respectively.
      Neutrophils were decreased (P < or = 0.05) in the mice that were killed 5 or 10
      days after the RJ treatment. Overall these results indicate that RJ exhibited
      immunomodulatory properties by stimulating antibody production and
      immunocompetent cell proliferation in mice or depressing humoral immune functions
      in rats. Both phenomena, though species-related in this model, could probably be
      reversed by changing the dose or the route of RJ application.

PMID- 8654044
TI  - Passive immunization against somatostatin increases resistance to Eimeria
      vermiformis infection in susceptible mice.
AB  - The effect of in vivo immunoneutralization of somatostatin (SRIF) on Eimeria
      vermiformis intestinal infection was studied in resistant (BALB/c), and
      susceptible (C57BL/6) mouse strains. An anti-SRIF monoclonal antibody (MAb-SRIF)
      was used to passively immunize the mice by intraperitoneal injection. The animals
      were subsequently orally infected with oocysts of E. vermiformis. Individual
      fecal samples were collected daily for 21 days to monitor the kinetics of oocyst
      shedding. The fecal oocyst shedding was significantly higher in the C57BL/6
      strain than in the BALB/c strain (P < 0.01). Passive immunization with MAb-SRIF
      in the C57BL/6 mice significantly reduced the number of oocysts in feces (P <
      0.05), when compared to the infected non-immunized mice of the same strain.
      Infected BALB/c mice showed no difference in oocyst shedding in response to the
      passive immunoneutralization with MAb-SRIF. In conclusion, passive immunization
      with MAb-SRIF increased resistance to E. vermiformis-infection in the susceptible
      C57BL/6 mice, but not in the resistant BALB/c mice. This suggests that SRIF
      modulates gut immune function in parasitic infection.

PMID- 8654045
TI  - Some biochemical responses of buffalo PMN cells to various stimuli.
AB  - In view of great species differences in biology of polymorphonuclear cells, and
      non-availability of basic data on buffalo PMN cells for assessing their
      functional activity, the present work on the immuno-defence system involving
      protein synthesis and O2- production was undertaken to highlight the
      immunomodulatory role of thyroxine. Digitonin, LPS and Con-A activation generated
      superoxide, which was monitored by NBT reduction. The study suggested that
      concanvalin A (Con-A) and T4 were able to synergetically increase the production
      of superoxide and H2O2. The likely involvement of thyroxine in activation was
      studied by [125I]thyroxine incorporation, which was significantly increased due
      to activation. In contrast, aflatoxin B1 together with Con-A caused a significant
      decrease (P < 0.05) in incorporation of [125I]T4. Optimum time dependence in
      [14C]leucine incorporation by buffalo PMN cells was found to be 30 min and the
      factors like T4 (7.7 ng/ml) and glutathione (400 micrograms/ml) significantly
      enhanced the incorporation. In contrast, antiinflammatory agent, indomethacin (40
      micrograms/ml) inhibited protein synthesis in PMN cells; while puramycin also
      significantly lowered the [14C]leucine incorporation. Total [14C]leucine
      incorporation in acid extractable cationic proteins and peptides, known for their
      antibacterial properties was found to be 30-40% when separated on AU-PAGE. The
      studies revealed the in vitro immunomodulatory role of T4 in O2-, H2O2 production
      and cationic protein synthesis by the activated PMN cells of buffalos.

PMID- 8654046
TI  - Brucella abortus differs in the multiplication within bovine chorioallantoic
      membrane explants from early and late gestation.
AB  - The ability of Brucella to infect and grow within extraplacentomal
      chorioallantoic explants (CAMs) derived from early and late gestational cattle
      was compared. Following inoculation of CAMs with equal numbers of strain 2308 B.
      abortus, the infectivity was approximately the same in CAMs from both ages,
      however, bacterial replication was significantly greater in late gestational CAMs
      than in early gestational CAMs. Co-culture of both early and late gestation CAMs
      or culture of both types of CAMs in the presence of tissue culture media
      collected from either early or late B. abortus inoculated CAMs failed to alter B.
      abortus growth rates and/or cytopathic effects.

PMID- 8654047
TI  - Serology of Orthopoxvirus cameli infection in dromedary camels: analysis by ELISA
      and western blotting.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed, together with a
      Western blotting technique, for the detection of total and IgG and IgM antibodies
      to camelpox virus (Orthopoxvirus cameli) in camel (Camelus dromedarius) sera and
      for identifying the seroreactive antigens of the virus. A total of 520 camels
      from different regions in Libya were tested. The overall seropositivity rate in
      the examined herds was 9.8%, and varied between herds from 0 to 30%. Two viral
      antigenic determinants (31 and 35 kDa) were shared by the Western blotting
      patterns of all the positive camel sera tested. The developed ELISA assay showed
      ability to differentiate between orthopox and parapoxvirus infections in camels.
      It is considered that the ELISA technique is justified for serodiagnosis of
      camelpox in the camel and could be easily modified and usefully applied to other
      species at risk of poxvirus infection.

PMID- 8654048
TI  - Morphology and staining characteristics of Ehrlichia bovis.
AB  - Morphology and staining characteristics of Ehrlichia bovis were observed after
      staining with Romanowsky and Gimenez stains and fluorochroming with acridine
      orange. Ehrlichia bovis could be identified as elementary bodies, initial bodies
      and morulae in the host cell cytoplasm. The inclusions were solid and compact and
      resembled more closely those of E. canis (canine monocytic ehrlichia) than E.
      phagocytophilia or E. ondiri (bovine granulocytic ehrlichiae). The organisms
      usually took acidophilic shades with Romanowsky stains. Apart from morulae, the
      other forms sometimes resembled azurophil granules. While Gimenez staining and
      fluorochroming by Anderson and Greiff technique gave poor results, the organism
      stained well on fluorochroming with Lauer's technique.

PMID- 8654049
TI  - Study on immune response of goats vaccinated with a live strain of Mycobacterium
      paratuberculosis.
AB  - A study of the immune response of goats vaccinated with a live strain (316-F) of
      Mycobacterium paratuberculosis has been performed, taking into consideration both
      cellular and serological responses using a lymphocyte transformation assay (LTA)
      and a counterimmunoelectrophoresis test (CIET). The analyses made at three
      monthly intervals reveal an in vitro proliferative response of blood lymphocytes
      to specific antigen and lymphocytes T mitogen over a year of post-vaccination,
      but no humoral response was observed when CIET was used.

PMID- 8654050
TI  - A mathematical model for concentration of blood affecting erythrocyte
      sedimentation.
AB  - The rate at which red blood cells fall in vitro is used as a common clinical test
      for a number of pathological conditions. But this test becomes unreliable when
      one finds flaws in the model under consideration and these doubts raise the issue
      of aggregation of the red blood cells in concentration whose mathematical
      analysis is relatively unknown. However Huang et al. (Biorheology 8, 157-163,
      1971) made some efforts and their model resembles certain moving boundary
      problems. In the present work the modifications to this model have been suggested
      so far as the concentration of the blood is concerned, it being one of the
      important factors to decide ESR (Erythrocyte Sedimentation Rate). In the equation
      for nutrient concentration, to be more realistic, we have taken account of
      transfer of nutrient to the tissue from the blood. The exact solution has been
      obtained using Laplace transform. A finite element technique has been suggested
      which provides results closer to that of the exact solution. Our results for the
      blood concentration may be useful for conducting the ESR tests. A special case
      for an emergent patient when nutrient concentration falls down considerably and
      glucose is provided to improve the condition, has been shown graphically.

PMID- 8654051
TI  - Multiresolution biological transient extraction applied to respiratory crackles.
AB  - A method is proposed for the detection of transients in biological signals. The
      method is based on enhancing the transient-to-background ratio by a series of
      operations such as background whitening, wavelet-based multiresolution
      decomposition and application of Teager's energy operator. The transients are
      extracted by judiciously thresholding this processed signal. The proposed
      detector is applied to the discrimination of crackles in pathological respiratory
      sounds. It is shown that both the crackle detection performance and ability to
      extract the transient waveforms correctly are superior to existing detectors in
      the literature.

PMID- 8654052
TI  - Random selection algorithms for spatial and temporal sampling.
AB  - Seven BASIC programs are presented that use algorithms for selection of
      treatments and samples in spatial and temporal contexts. Program (1) takes a
      natural sequence of samples (such as logs cut from a tree trunk) and divides them
      into groups (equal to the number of samples divided by treatments), and then
      selects non-redundantly from each group a sample at random for each treatment.
      Program (2) matches items from different categories equally to any number of
      treatments in proportion to the numbers of items of each category. Program (3)
      selects sampling times or segment lengths of specified interval and number from
      within a time period or perimeter distance. These samples can be spaced apart by
      at least a specified amount of time or distance but otherwise are chosen at
      random. In program (4), a series of sample coordinates (x,y) are chosen at random
      from a rectangular area so that no points are closer than a specified minimum
      distance to any other. For each of the sample points, the Cartesian and polar
      coordinates are given. Program (5) generates any possible Latin square, while
      program (6) generates Latin cubes, and program (7) makes Graeco-Latin cubes.
      Examples of program use and output are presented for experiments with bark
      beetles (Coleoptera: Scolytidae) responding to pheromone blends and colonizing
      host trees.

PMID- 8654053
TI  - A computer-based statistical pattern recognition for Doppler spectral waveforms
      of intracranial blood flow.
AB  - A computer-based statistical pattern recognition system has been developed for
      the analysis of transcranial Doppler (TCD) spectral waveforms of the intracranial
      middle cerebral artery with varying degrees of increased intracranial pressure.
      This system extracts multidimensional features from TCD waveforms and performs a
      cluster analysis of those features. The system can automatically recognize the
      pattern of spectral waveform and classify it as a normal, abnormal, or borderline
      subclass of TCD spectral waveform. An optimum decision function was generated
      based on the Bayes Gaussian classifier. The accuracy of the Bayes Gaussian model
      the spectral waveforms reaches 100% by estimating posterior probability and using
      the resubstituting method of estimating misclassification in the training TCD
      data.

PMID- 8654054
TI  - Bone feature analysis using image processing techniques.
AB  - In order to establish the correlation between bone structure and age, and
      information about age-related bone changes, it is necessary to study
      microstructural features of human bone. Traditionally, in bone biology and
      forensic science, the analysis if bone cross-sections has been carried out
      manually. Such a process is known to be slow, inefficient and prone to human
      error. Consequently, the results obtained so far have been unreliable. In this
      paper we present a new approach to quantitative analysis of cross-sections of
      human bones using digital image processing techniques. We demonstrate that such a
      system is able to extract various bone features consistently and is capable of
      providing more reliable data and statistics for bones. Consequently, we will be
      able to correlate features of bone microstructure with age and possibly also with
      age related bone diseases such as osteoporosis. The development of knowledge
      based computer vision-systems for automated bone image analysis can now be
      considered feasible.

PMID- 8654055
TI  - Estimation of the size of the media necessary to construct a medical image
      database.
AB  - To estimate the size of the media necessary to construct a medical image
      database, a statistical analysis was made of the radiological data in our
      hospital information system database. The distribution of the total radiological
      image data storage required during one working day can be regarded as a normal
      distribution, and the distribution per patient was different from a normal one.
      Therefore, the mean amount required for the data storage of radiological images
      during one working day is very useful in estimating the data storage required for
      radiological images during a given number of working days.

PMID- 8654056
TI  - Fractal analysis of spinal dorsal horn neuron discharges by means of sequential
      fractal dimension D.
AB  - The present study describes a new method for converting a typical point process,
      such as a train of neuronal action potentials (spikes), into a planar curve which
      is then processed by means of a fast algorithm to calculate and display the
      fractal dimension D values of each of a sequence of blocks having an equal and
      preselectable number of interspike intervals, hence the term sequential fractal
      dimension D (SFD). This method is fast, does not require special computing
      facilities, and provides a continuous, high temporal resolution display of the
      neuronal discharge complexity along the course of spontaneous activity or event
      relating changes. The method affords insight into short duration changes in
      neuronal behaviour in a way independent of its discharge rate. SFD analysis of
      spike trains from spinal dorsal horn neurons suggests that the neuronal response
      to a given stimulus can be expressed as changes in the discharge pattern
      complexity, thus revealing a novel sensory coding strategy.

PMID- 8654057
TI  - Qualitative analysis of biochemical reaction systems.
AB  - The qualitative analysis of biochemical reaction systems is presented. A discrete
      event systems approach is used to represent and analyze bioreaction pathways. The
      approach is based on Petri nets, which are particularly suited to modeling
      stoichiometric transformations, i.e. the inter-conversion of metabolites in fixed
      proportions. The properties and methods for the analysis of Petri nets, along
      with their interpretation for biochemical systems, are presented. As an example,
      the combined glycolytic and pentose phosphate pathway of the erythrocyte cell is
      presented to illustrate the concepts of the methodology.

PMID- 8654058
TI  - Racial effects on the clinical presentation of alcoholics at a psychiatric
      hospital.
AB  - Despite the clinical importance of race effects on comorbidity and symptom
      patterns in recent community studies, little is known about such effects in
      various treatment facilities. This study evaluated the effect of race on the
      clinical profile of 604 alcoholics who presented for initial evaluation and
      treatment at a psychiatric hospital. The factor that most strongly distinguished
      the racial groups was socioeconomic status (SES). After controlling for SES and
      other factors, no significant difference was noted between ethnic groups in the
      prevalence of major depressive disorder (MDD) or antisocial personality disorder.
      However, after controlling for SES and other factors, alcohol and drug use were
      more severe in African-American alcoholics, along with four symptoms associated
      with alcohol and drug use. In contrast, reversed neurovegetative symptoms,
      anxiety-related symptoms, and some personality-related symptoms were more severe
      in white alcoholics.

PMID- 8654059
TI  - The tridimensional personality model: influencing variables in a sample of
      detoxified alcohol dependents. European Fluvoxamine in Alcoholism Study Group.
AB  - C.R. Cloninger proposed a biosocial model for personality, linking personality
      traits to patterns of responses to various external stimuli, including alcohol.
      The Tridimensional Personality Questionnaire (TPQ) was administered in a
      multicenter study to detoxified alcohol-dependent patients (N = 521). The
      objectives of the study were to evaluate (1) the expression of the three
      personality dimensions, novelty-seeking (NS), harm avoidance (HA), and reward
      dependence (RD), of the TPQ in this sample, and (2) the influence of different
      variables on these personality dimensions. The following variables were selected
      for a multiple and a stepwise regression analysis: sex, family history for major
      psychiatric disorders, marital status, occupation, age at study enrollment, age
      of onset of alcoholism, serum cholesterol level, intake of neuroleptics or
      benzodiazepines for detoxification, and severity of depression and anxiety. In
      comparison to Austrian normative data, both sexes of detoxified alcohol addicts
      scored higher in HA. The variables examined explain 23% of the variance of NS and
      35% of HA. Only one variable, namely age of onset, is significantly influencing
      NS (19% explained variance). HA is significantly influenced by three variables:
      anxiety state, anxiety trait, and sex (32% explained variance). RD is not
      influenced by any of the variables examined.

PMID- 8654060
TI  - A cluster analytic study of functional outcome after psychiatric hospitalization.
AB  - We report the initial results from a prospective study designed to assess
      patients' functional outcome and level of service utilization following
      psychiatric hospitalization. All patients admitted between March 31, 1993 and
      April 1, 1994 were interviewed at admission and discharge, and 350 consenting
      patients were reassessed 3 months postdischarge. Subgroups were created using
      cluster analysis (measures of outcome were rehospitalization, self-rated
      productivity and functioning, and satisfaction with living situation and
      employment/daily activities at the 3-month follow-up study), and these clusters
      were then validated using other variables. Four distinct outcome categories were
      identified. Cluster I contained patients with the greatest functional impairment
      and the highest rate of rehospitalization (28%). Cluster IV patients reported
      superior functioning and satisfaction and the lowest rate of rehospitalization
      (8%). Clusters II and III had intermediate outcomes, the first characterized by
      greater satisfaction with living situation, and the other by higher ratings for
      functioning and productivity. Outcome data are important to providers for program
      evaluation and patient care; if replicated in other samples, the four outcome
      categories reported may be useful for national mental health care policy and
      planning.

PMID- 8654061
TI  - Akathisia: a review and case report following paroxetine treatment.
AB  - Although akathisia is most commonly associated with neuroleptic medication, few
      cases of paroxetine-induced akathisia have been reported. A review of the
      authors' charts (C.F.B., A.N., S.N.G., and G.S.S.) was conducted to determine an
      estimated incidence for paroxetine-induced akathisia. Three cases of akathisia
      were reported in 67 patients treated with paroxetine. A case of akathisia
      secondary to paroxetine in an 18-year-old female is presented. Given the
      potential untoward effects of this syndrome, early diagnosis is essential.
      Clinical presentations and differential diagnoses are discussed.

PMID- 8654062
TI  - Psychosensorial and related phenomena in panic disorder and in temporal lobe
      epilepsy.
AB  - Since Cullen coined the term "neurosis" in the 18th century, medical
      investigators have searched the neural substrates of conditions we now classify
      as anxiety disorders. Harper and Roth in 1962 hypothesized that the temporal
      lobes might represent one such substrate for phobic-anxious patients with
      depersonalization-derealization (DD); the association between the presumed
      temporal lobe feature and phobic anxiety was so compelling that Roth (in 1959)
      described the condition as "phobic-anxiety-depersonalization" syndrome.
      Introduced into our current nosology as panic disorder-agoraphobia (PDA), this
      seemingly neuropsychiatric condition is nonetheless distinct from complex partial
      epilepsy (CPE), from which it is conventionally differentiated through clinical
      and anamnestic evaluation. Yet increasingly there are clinical-and laboratory
      hints of certain overlap between manifestations of the two disorders, hitherto
      based largely on evaluation of psychosensorial phenomena in PDA or affective
      phenomena in CPE. We located only one systematic study that monitored 24-hour
      electroencephalogram (EEG) abnormalities in PDA. Finally, recent epidemiologic
      data suggest a significantly greater than chance association between PDA and a
      history of seizures. To further explore these intriguing links, the present study
      directly compared a group of 91 PDA outpatients with a group of 41 CPE
      outpatients with respect to DD and other psychosensorial symptoms. The broad
      similarities discovered between psychosensorial and related phenomena provide
      further support for the hypothesis that there may be a common neurophysiological
      substrate linking CPE phenomena with PDA.

PMID- 8654063
TI  - Auditory startle response during exposure to war stress.
AB  - This report describes the immediate effect of war stress on physiological
      measures of the auditory startle responses (ASRs). Ten healthy Israeli subjects
      were examined 4 months before the Gulf war, during a missile alert on the first
      day of the war, and 8 months after the war. The magnitude and rate of habituation
      of orbicularis oculi electromyogram (EMG), heart rate (HR), and skin conductance
      (SC) responses to 15 consecutive presentations of 95-dB, 0-rise time, 1,000-Hz
      pure tones were recorded on each occasion, along with self-reports of anxiety.
      The group's anxiety scores were significantly higher during the war. ASRs, in
      contrast, remained stable across exposure conditions. However, a decrease in SC
      habituation was observed in few individuals during the war, and may illustrate a
      distinctive vulnerability to stress. The results are discussed in light of recent
      findings of abnormal startle response in posttraumatic stress disorder (PTSD).

PMID- 8654064
TI  - Family functioning in anxiety and eating disorders--a comparative study.
AB  - This study examines ratings of family functioning in families of origin and
      current (marital) families by patients with anxiety disorders (ADs) and compares
      them with known population means and with similar ratings by patients with eating
      disorders. Subjects were drawn from the Anxiety Disorders and Eating Disorders
      clinics of The Toronto Hospital, each group consisting of a consecutive sample.
      Family functioning was assessed using the general and self-rating scales of the
      Family Assessment Measure (FAM). Patients with ADs rated their families of origin
      less favorably than established population norms (general and self-rating scales,
      P < .001). Ratings by patients with ADs did not differ from comparable ratings by
      patients with eating disorders. AD patients' less favorable ratings of family of
      origin suggest a perception of significant family dysfunction. However, the
      similarity in ratings between AD and bulimia nervosa (BN) subjects suggests that
      this is unlikely to be specific to having an AD.

PMID- 8654066
TI  - A family study on outpatients with mood and personality disorders.

PMID- 8654065
TI  - Alexithymia in a normal elderly population.
AB  - The aim of the study was to determine the prevalence of alexithymia in an elderly
      Finnish population sample. Associations between alexithymia and sociodemographic
      factors were investigated, together with the relationship between alexithymia and
      perceived somatic health and self-reported psychic health. The study forms a part
      of the Turun Vanhustutkimus (TUR-VA) project, which is a longitudinal,
      prospective follow-up study dealing with psychosocial adaptation to retirement
      and to old age. The study group consisted of a population sample of 72-year-old
      people (N = 190). Alexithymia was measured with the 26-item version of the
      Toronto Alexithymia Scale (TAS-26). The prevalence of alexithymia was 34%.
      Alexithymia was associated with poor perceived somatic health. Alexithymia was
      associated with having a psychiatric disturbance (measured by the 36-item General
      Health Questionnaire [GHQ-36]), but this relationship disappeared when the
      influence of perceived somatic health was controlled for. Alexithymia was not
      associated with gender, marital status, social status, or residential area.

PMID- 8654067
TI  - Schizophrenia and affective disorder--distinct entities or continuum?: an
      analysis based on a prospective 6-year follow-up.
AB  - The purpose of this study was to determine whether the preponderance of data
      support a continuum hypothesis of the psychoses or a concept of separate,
      autonomous illnesses. Patients (N = 70) were hospitalized for nonmanic psychoses,
      given structured interviews and a dexamethasone suppression test (DST), and
      diagnosed according to the Research Diagnostic Criteria (RDC). Patients were then
      evaluated at 1 year and 6 years with a structured interview. Diagnoses were made
      at three points of time: intake, 1 year, and 6 years. The patients were divided
      into groups that had a consistent (over the three points) set of affective
      disorder diagnoses (affective disorder or schizoaffective disorder, mainly
      affective [AD group]) and those that had a consistent set of schizophrenic
      diagnoses (schizophrenic or schizoaffective disorder, mainly schizophrenic [S
      group]). A third group (inconsistently diagnosed) consisted of subjects who at
      one point were diagnosed in the AD group and at another in the S group. A series
      of discriminant function analyses suggested that the AD group differs widely from
      the S group; and the inconsistently diagnosed group most closely resembled the AD
      group. The family background of the inconsistent group was similar to that of the
      AD group. The DST and outcome showed that the inconsistent group was more like
      the AD group than the S group. Using the characteristics of the medical model
      clinical picture, outcome, laboratory tests, and family history-the group that
      was inconsistent with regard to diagnosis over time appeared similar to the AD
      group. Taking the follow-up evaluation into account, the data favor the
      possibility that patients who have a variable clinical diagnosis over time do not
      suffer from schizophrenia.

PMID- 8654068
TI  - An adoption study of drug abuse/dependency in females.
AB  - In a sample of 102 women who had been adopted at birth, drug abuse/dependency was
      found by log-linear analyses to have a major pathway of genetic etiology that
      started with a biologic parent with antisocial personality and led to an adoptee
      with conduct disorder and then through aggressivity to drug abuse/dependency, as
      well as from conduct disorder directly to drug abuse. This result was similar to
      findings from a male sample collected from the same agencies and at the same
      time, wherein antisocial biologic parents produced aggressive and conduct
      disordered off-spring, who in turn became drug abusers/dependents as adults.
      Results are compatible with family studies demonstrating that female drug abusers
      stem from deviant families and themselves demonstrate socially deviant behavior
      early in life. The present study shows that one element of familial factors is
      genetic, and that, in addition, the family environment directly affects behavior
      (aggressivity) that leads to drug abuse/dependency.

PMID- 8654069
TI  - Comorbidity of axis I and axis II diagnoses in a sample of Egyptian patients with
      neurotic disorders.
AB  - Neurosis and personality disorder (PD) are two of the most used but least
      clarified and understood terms in psychiatry. The separation of PD by the
      American Psychiatric Association in DSM-III and -IV as a discrete axis of
      classification has been a major advance in psychiatric nosology. Also with the
      advent of DSM-III and its multiaxial system, it was recognized that both PD and
      clinical syndromes can coexist, and in some cases this coexistence may have
      implications on treatment response and prognosis. This study was performed on 200
      neurotic patients in an attempt to investigate possible correlations between
      various neurotic subcategories and personality types. Our results confirm that PD
      and personality abnormality are significantly higher in neurotic patients than in
      controls and need to be considered in diagnostic assessment. Some comorbidity was
      shown between borderline PD and somatoform disorder; compulsive PD and obsessive
      compulsive disorder (OCD), and generalized anxiety disorder (GAD); and avoidant
      PD and phobia. However, our data failed to show a correlation between the
      presence of an additional PD and particular neurotic symptomatology. It seems
      that the association between neurotic disorders and PD should not be taken to
      indicate a direct causative relationship. It is likely that personality is just
      one of the predisposing factors that influence the individual response to
      psychological trauma and determine the form of neurosis. The most prevalent PD
      was found to be PD NOS, followed by borderline, compulsive, avoidant, and finally
      histrionic PDs. The term, multiple PD, should be given substance to characterize
      the diagnosis as a disorder, rather than leaving it at its current status of what
      seems to be a nondistinct clinical picture. Extensive research has to be
      undertaken in an attempt to decide which specific PDs most deserve to be included
      in the official nomenclature.

PMID- 8654070
TI  - Surfactants and experimental irritant contact dermatitis.
AB  - Surface-active agents (surfactants) are characterized by the possession of 2
      different moieties, both polar and non-polar regions on the same molecule.
      Surfactants are broadly classified as anionic, cationic, amphoteric, or non
      ionic, according to the nature of the hydrophile yielded in aqueous solution. In
      currently marketed household, personal, and industrial cleaners, anionic
      surfactants are the most common class because of their relative ability to
      solubilize fats and oils, lower the surface tension of aqueous solutions, or form
      microemulsions. Many surfactants elicit irritant reactions when applied to the
      skin, partially due to their relative ability to solubilize lipid membranes.
      Hence, surfactants have become important implements in skin irritation
      investigations. In general, the physicochemical properties of surfactants are a
      crucial factor in eliciting skin irritation. Anionic surfactants are broadly
      accepted as potent irritants to human and animal skin. Cationic surfactants are
      reputedly at least equally irritating, but more cytotoxic than anionic, while the
      irritation potential of non-ionic surfactants is considered the lowest. Such
      classification of innumerable surfactants is convenient and held in high
      practical esteem. however, the categorization does not permit the exact
      determination of irritation and cytotoxicity potential of each surfactant.
      Ranking of surfactant skin irritancy and cytotoxicity obtained by both in vitro
      and in vivo assays provides a helpful orientation for future work.

PMID- 8654071
TI  - Occupational allergic contact dermatitis in construction workers.
AB  - We report the patch test results of 449 construction workers who came as patients
      to the Occupational Dermatology Service of the Instituto Nacional de Medicina y
      Seguridad del Trabajo in Madrid between 1989 and 1993. 90.8% of them were patch
      tested, because they had cutaneous lesions or a clinical history suggestive of
      occupational dermatitis. 65.5% (268) of those patch tested showed one or more
      reactions connected with their work. Chromate at 42.1% was the main allergen,
      followed by cobalt, 20.5%, nickel, 10%, and epoxy resin, 7.5%. 25.9% (106) of
      patients showed sensitization to rubber components, the majority at 23.7% to
      thiuram mix, with TETD being the main allergen.

PMID- 8654072
TI  - Effect of occlusion on human skin.
AB  - In order to investigate the effect of occlusion on the skin, the flexor sides of
      both upper arms were covered with column-shaped with column-shaped closed
      chambers, 30 mm in outer diameter, 20 mm in inner diameter, and 5 mm in height,
      which were made of polyethylene foam. The tops of the chambers were sealed by
      plastic films with various levels of water vapor permeability to control moisture
      in each chamber. The raised chamber walls prevented direct contact between the
      skin and the plastic film. After 24 h of application, morphological changes of
      the skin surface were observed microscopically by the nitrocellulose-replica
      method. Although no visual alterations were found on all areas of occluded skin,
      microscopic evaluation showed that simple occlusion by films induced an increase
      in the number of deepened skin furrows on the skin surface. this increase was
      associated with lower water vapor permeability of the films, as well as with
      higher values of both temperature and humidity of the test day. Thus, since
      conditions which facilitate perspiration from the skin tend to cause skin
      irritation, prolonged exposure of the skin to sweat by simple occlusion may act
      as a primary skin irritant.

PMID- 8654073
TI  - Assessment of skin irritancy by 2 short tests compared to acute irritation
      induced by sodium lauryl sulfate.
AB  - Irritant contact dermatitis is a very common disease that is preventable by
      protective measures. The development of screening methods to identify subjects
      with increased susceptibility to irritants is essential to reduce the incidence
      of this disorder in the workplace. On the outlook for such methods, 2 quick non
      invasive tests for irritability of the skin were compared to reliable, but time
      consuming, patch testing with sodium lauryl sulfate (SLS). In 20 healthy
      volunteers, 0.5% SLS was applied on the medial 1.3 of the forearm for 23 h in
      order to induce experimental irritant contact dermatitis. On the same part of the
      forearm, 3 concentrations of dimethylsulfoxide (DMSO) and a solution of 0.2 mol/l
      NaOH were applied for 5 min. Assessment of skin irritability was made by visual
      scoring and measurement of transepidermal water loss. No correlation between the
      "quick tests" and SLS patch testing was found, indicating that these tests assess
      different mechanisms of irritation.

PMID- 8654074
TI  - Corticosteroid allergy.
AB  - Allergy to corticosteroids is becoming increasingly recognized. Diagnosis is
      difficult because of frequently false-negative patch tests. The optimum
      concentration and vehicle for patch testing with pure corticosteroid has still
      not been established. The patch test results of 19 patients with allergy to
      corticosteroids seen at the Skin and Cancer Foundation in Sydney, Australia, were
      analysed. It was found that patch testing with the patient's corticosteroid in
      the commercial cream base gave a greater yield of positive results than testing
      with the commercial corticosteroid ointment or with the pure corticosteroid in
      either petrolatum or in alcohol. Tixocortol pivalate, and to a lesser extent
      budesonide, were useful for detecting allergy to hydrocortisone, but not
      necessarily other corticosteroids. Delayed positive patch tests were often seen,
      showing the importance of carrying out a late reading. The repeat open
      application test (ROAT) with the patient's own corticosteroid was found to be a
      simple, useful diagnostic test.

PMID- 8654075
TI  - Contact allergy to Dermatophagoides in atopic dermatitis patients and healthy
      subjects.
AB  - To compare different house-dust-mite-derived allergenic materials and to
      correlate the presence of IgE to Dermatophagoides with patch test results, 313
      atopic dermatitis (AD) patients and 100 healthy volunteers (HV) underwent patch
      tests with: Dermatophagoides pteronyssinus (DPT) lyophilized purified alpha
      fraction in buffered saline/glycerol 50% and/or in petrolatum (Bayropharm); 50%
      DPT and 50% Dermatophagoides farinae (DF) whole bodies in petrolatum and
      petrolatum oil (Allergopharma-Bracco); DPT and DF whole bodies in petrolatum and
      petrolatum oil (Lofarma). We found 39% positive reactions among AD subjects and
      13% in HV. The presence of serum-specific IgE did not influence the patch test
      results. 38% of AD patch-test-positive patients and 4 of 13 HV, respectively,
      showed a positive prick test and/or RAST to Dermatophagoides. Similar
      sensitization rates were observed with the allergenic material from Bayropharm
      (54% positives) and Allergopharma-Bracco (51% positives), whereas the
      preparations from Lofarma gave a 20% response rate.

PMID- 8654076
TI  - Patch testing with preservatives at St John's from 1982 to 1993.
AB  - We have reviewed our patch test results for preservative allergy from 1982 to
      1993. 8 preservatives were included: formaldehyde, 2-bromo-2-nitropropane-1,3
      diol (Bronopol(TM)), quaternium-15 (Dowicil 200TM), imidazolidinyl urea (Germall
      115TM), diazolidinyl urea (Germall IITM), parabens, 5-chloro-2methyl-isothiazolin
      3-one (Kathon CG(TM)) and 1,2-dibromo-2,4-dicyanobutane (one of the constituents
      of Euxyl K 400TM). Whereas the allergy rate to formaldehyde is quite stable,
      there is a slight increase in the imidazolidinyl urea allergy rate. Quaternium
      15's rate is decreasing and 5-chloro-2-methyl-isothiazolin-3-one plus 2-methyl
      isothiazolin-3-one's rate, after a rapid rise, seems to have stabilized. Although
      very important constituents of cosmetics, preservatives not only induce allergies
      on the face but also on the hands, and, as expected, the allergy rate in men and
      women generally differs. Among the 5 formaldehyde-releasers, there are some
      favoured simultaneous reactions: quaternium-15 and formaldehyde, and diazolidinyl
      urea and imidazolidinyl urea. Concomitant reactions between 1-bromo-2
      nitropropane-1,3-diol and formaldehyde are not common, and those between 2-bromo
      2-nitropropane-1,3-diol and diazolidinyl urea, and formaldehyde are not very
      common. This supports the hypothesis that allergic reactions to the Germalls are
      directed toward the initial molecule rather than to formaldehyde.

PMID- 8654077
TI  - No evidence of contact sensitization to acyclovir in acute dermatitis of the lips
      following local application of Zovirax cream.
AB  - We report 4 patients with acute contact dermatitis of the lips following
      application of Zovirax cream. Patch tests with pure acyclovir, and combinations
      of the ingredients of the cream base, with and without acyclovir, provided no
      evidence of sensitization to any constituents of the cream.

PMID- 8654078
TI  - In vivo cytokine profiles in allergic and irritant contact dermatitis.
AB  - Local cytokine profiles in skin biopsies from allergic and irritant patch test
      reactions were determined by in vivo immunohistochemistry to differentiate
      between these 2 clinically identical afflictions especially at the same time of
      final reading in diagnostic patch testing. Biopsies were taken from established
      allergic persons after specific allergic patch tests to epoxy resin (1%), and
      formaldehyde (1%) and from non-allergic individuals with irritant patch tests to
      sodium lauryl sulfate (10%) and formaldehyde (8%). At 72 h after application of
      the agents, significantly enhanced frequencies of dermal infiltrating cells,
      producing IL-alpha, IL-2, and IFN-gamma per 100 infiltrating cells in the dermis,
      were observed in allergic as well as irritant test patch reactions, as compared
      to normal skin. Significantly higher frequencies of IL-1alpha producing cells
      were observed in biopsies from epoxy resin (1%) allergen-affected and
      formaldehyde (8%) irritant affected skin. The allergic and irritant patch test
      reactions showed similar levels of expression of the Th1 cytokines IL-2 and IFN
      gamma in the dermis, confirmed by probe based detection of IL-2 mRNA and IFN
      gamma mRNA. In conclusion, the described similarity shows that allergens and
      irritants can induce the same profile of IL-1alpha, TNF-alpha, IL-2, and IFN
      gamma production, resulting in the near impossibility of discriminating between
      allergic and irritant contact dermatitis at the time of patch test reading.

PMID- 8654079
TI  - Contact dermatitis due to a massage liniment containing Inula helenium extract.

PMID- 8654080
TI  - Lymphomatoid contact dermatitis due to nickel.

PMID- 8654081
TI  - Contact allergy to tiopronin: a case report.

PMID- 8654083
TI  - Contact dermatitis from carboxyvinyl polymer.

PMID- 8654082
TI  - Frequency of contact sensitivity to drugs and preservatives in patients with
      conjunctivitis.

PMID- 8654084
TI  - Contact dermatitis from usnic acid in vaginal ovules.

PMID- 8654085
TI  - Contact hypersensitivity to arsenic in a crystal factory worker.

PMID- 8654086
TI  - Occupational allergic contact dermatitis from oleyl alcohol and monoethanolamine
      in a metalworking fluid.

PMID- 8654087
TI  - Photosensitivity to simvastatin with an unusual response to photopatch and photo
      tests.

PMID- 8654089
TI  - Contact dermatitis from hydroxyethyl salicylate.

PMID- 8654088
TI  - Serum interferon-gamma level in a patient with carbamazepine-induced
      erythroderma.

PMID- 8654090
TI  - Multiple azo dye sensitization revealed by the wearing of a black "velvet" body.

PMID- 8654091
TI  - Allergic contact dermatitis from Pleurotus mushroom.

PMID- 8654092
TI  - Contact and photocontact sensitivity to sunscreens.

PMID- 8654093
TI  - An outbreak of irritant contact dermatitis from ethylene oxide among
      pharmaceutical workers.

PMID- 8654094
TI  - Allergic contact dermatitis from topical doxepin.

PMID- 8654096
TI  - Contact allergy with immediate and delayed photoaggravation to chromate and
      cobalt.

PMID- 8654095
TI  - Contact dermatitis due to imidazole antimycotics.

PMID- 8654097
TI  - Photocontact dermatitis from rue (Ruta montana L.).

PMID- 8654098
TI  - Contact allergy to tylosin and cobalt in a pig-farmer.

PMID- 8654099
TI  - Primary sensitization to a single accidental exposure to a flame retardant and
      subsequent allergic contact dermatitis.

PMID- 8654100
TI  - The chemistry of contact allergy.

PMID- 8654101
TI  - Impression tray not 'amalgam carrier'.

PMID- 8654102
TI  - Cholera toxin enhances taurine uptake in cultures of human retinal pigment
      epithelial cells.
AB  - Taurine uptake into cultures of human retinal pigment epithelial (HRPE) cells was
      monitored for 7 days after seeding. A culture medium containing 16% fetal bovine
      serum (FBS) was used for 2 days and switched to one with 8% FBS. Uptake of
      taurine (25 nM) was approximately 1.5 pmol/mg protein/15 min for 3 days, then
      decreased by 45% and was maintained at a decreased level till the 7th day. When
      the 16% FBS medium was used for the entire culture period, a similar profile of
      taurine uptake was observed but decrease of the uptake started on the 3rd day.
      Treatment of cells with 100 ng/ml cholera toxin (CT) for 24 h between the 6th and
      7th days returned taurine uptake to its high level observed at the beginning of
      the cell culture. A similar CT treatment of cells between the 2nd and 3rd days
      enhanced taurine uptake significantly but this enhancement was much smaller. CT
      increased taurine uptake in treatment-time and dose dependent manners. Forskolin
      (FSK) (10 mM) and 8-Bromocyclic adenosine 3',5'-monophosphate (1 mM) also
      increased taurine uptake. KT5720 at 1 microM, a selective inhibitor of cAMP
      dependent protein kinase (PKA), partially blocked CT-induced enhancement of
      taurine uptake. The level of cAMP was higher on the 3rd day than the 7th day but
      its response to 3-isobutyl-1-methyl-xanthine, FSK and CT was similar on both
      days. A kinetic analysis revealed that CT treatment decreases the apparent
      Michaelis-Menten constant of the taurine transporter while the drastic reduction
      of taurine uptake during the cell culture period is due to a decrease in the
      maximal velocity. The results show that cAMP elevated by CT treatment enhances
      taurine uptake via an increase in the affinity of the transporter. The decrease
      of taurine uptake during the culture period seems to be related to a decrease in
      the amount of the transporter.

PMID- 8654103
TI  - Calcium-activated potassium current in cultured rabbit retinal pigment epithelial
      cells.
AB  - Calcium-activated potassium current was studied in cultured rabbit retinal
      pigment epithelial (RPE) cells using whole-cell and single channel patch-clamp
      recording techniques. When K+ was the principal cation in the electrode,
      depolarizing voltage steps from a holding potential of -60 mV activated outwardly
      rectifying current. Outward K+ current was increased by the Ca2+ ionophore
      ionomycin and reduced when the extracellular Ca2+ concentration was decreased
      from 2.5 mM to 100 nM in the presence of ionomycin. Outward K+ current recorded
      in the presence of ionomycin was blocked by iberiotoxin and by charybdotoxin.
      Single channel recording from cell-attached and excised membrane patches revealed
      a large conductance Ca2+-activated K+ (K(Ca)) channel. Identification of K(Ca)
      channels was based on: 1) the voltage-dependence of channel opening; 2) the large
      unitary conductance (> 200 pS with symmetrical 130 mM K+); 3) the dependence of
      the reversal potential on the K+ gradient; and 4) increased channel opening after
      exposure of the cytosolic surface of excised membrane patches to elevated Ca2+.
      These results demonstrate that Ca2+-activated K+ channels are present in rabbit
      RPE cells and may play an essential role in the regulation of membrane potential
      and ion transport.

PMID- 8654104
TI  - Antimetabolite interactions with epidermal growth factor.
AB  - Antimetabolites such as 5-fluorouracil and mitomycin C are known to delay wound
      healing. Epidermal growth factor (EGF) has been shown to accelerate corneal
      epithelial wound healing. This study was designed to investigate the effects of
      EGF on corneal epithelial healing that has been modified by antimetabolite
      treatment. New Zealand White rabbits were pretreated with either saline
      (controls) or 5-fluorouracil (5FU) injected subconjunctivally, or mitomycin C
      (MMC) applied topically. Circular anterior stromal wounds were created, followed
      by a 6-hour perfusion of normal saline or 50 micrograms/ml of EGF.
      Subconjunctival saline or 5FU, or topical MMC treatments were continued after
      wounding for a total of 6 days. Corneas were photographed and quantitative
      morphometry of the wound site was performed. Compared with saline controls, MMC
      significantly delayed wound healing (P < 0.05) whereas 5FU did not (P > 0.05).
      Compared with 5FU, MMC significantly delayed wound healing with either normal
      saline or EGF perfusion (P < 0.05). In the presence of either 5FU or MMC, EGF
      perfusion had no significant effect on the corneal wound-healing rate (P > 0.05).
      Corneal wound healing is not affected by subconjunctivally injected 5FU while it
      is delayed by topically applied MMC. EGF treatment does not overcome the
      inhibitory effects of MMC. EGF therapy may not be useful in the treatment of
      complications related to antimetabolite therapy.

PMID- 8654105
TI  - Hypericin inhibits cell growth and induces apoptosis in retinal pigment
      epithelial cells: possible involvement of protein kinase C.
AB  - Proliferative vitreoretinopathy (PVR) is characterized by the proliferation and
      migration of retinal pigment epithelial (RPE) cells in the vitreous cavity. The
      drug hypericin, which is already in clinical use as an antidepressant, has shown
      promise as an antiviral and antineoplastic agent. To investigate the therapeutic
      potential of hypericin in PVR, we incubated RPE cells in standard medium with
      various serum concentrations containing 0.5 to 5 microM hypericin. In some
      experiments we studied the effects of hypericin in conjunction with the RPE
      growth stimulating cytokine tumor necrosis factor alpha (TNF-alpha). Dose
      dependent inhibition of RPE cell proliferation with IC50 values of 0.7 microM and
      3.3 microM in 1% and 5% serum respectively, was found. Even in conjunction with
      TNF-alpha, hypericin inhibited RPE proliferation with an IC50 value of 1.5
      microM. The drug inhibited PKC activity in cells treated with a 2.5 microM dose
      by 72% after 30 min and by 100% after 180 min. Finally, hypericin induced RPE
      cells to undergo apoptotic cell death, as shown by the presence of DNA laddering.
      These results suggest that hypericin may have potential as a therapeutic drug for
      PVR and that its antiproliferative and apoptotic effects on RPE cells in vitro
      are in part mediated by PKC.

PMID- 8654106
TI  - Common cryopreservation media deplete corneal endothelial cell plasma membrane
      Na+,K+ ATPase activity.
AB  - This study describes the effects of three cryopreservation media on the specific
      activity of corneal endothelial plasma membrane Na+,K+ ATPase activity, a
      transporter required for the fluid pump in the cornea. Bovine corneal endothelial
      cell cultures were used as a model system for these studies. Cryopreserved
      primary cells were thawed and passaged once to increase cell number. The specific
      activity plasma membrane Na+,K+ ATPase activity was subsequently measured on 4-6
      replicate cultures. One freeze/thaw cycle depleted the Na+,K+ ATPase specific
      activity of corneal endothelial cell cultures by approximately 90%, as compared
      to cells of equivalent passage which had not been cryopreserved. Cell morphology
      of the cryopreserved cultures was indistinguishable from that of control
      cultures. In other experiments, first passage cultures which had not been
      subjected to cryopreservation were incubated with a dimethyl sulfoxide-, glycerol
      , or propane diol-based freezing medium and Na+,K+ ATPase was measured on plasma
      membranes subsequently isolated from the cultures. Incubation of cells with
      cryopreservation media in the absence of the freezing process also depleted
      Na+,K+ ATPase by approximately 90%. Radiolabeled ouabain was used to measure
      Na+,K+ ATPase sites on cell cultures pretreated with dimethyl sulfoxide-based
      freezing media. A 4 h treatment with DMSO-based freezing medium had no effect on
      ouabain binding; treatment for 18 h reduced binding by only 50%. Thus, the method
      used to assess pump function (determination of Na+,K+ ATPase specific activity
      versus ouabain binding) may provide conflicting data concerning the level of pump
      function cultured cells. The cryoprotectants present in many common media used to
      freeze tissue culture cells appear to inhibit corneal endothelial Na+,K+ ATPase.
      Since the fluid pump of corneal endothelial cells is coupled to Na+,K+ ATPase
      activity, care must be taken to insure that pump function is not impaired during
      cryopreservation of cell cultures.

PMID- 8654107
TI  - Antioxidant enzymes of the human retina: effect of age on enzyme activity of
      macula and periphery.
AB  - The purpose of this research was to evaluate the effect of age on protective
      antioxidant enzyme activity of normal fresh cadaver human retina of the macula
      and periphery. Antioxidant enzymes were assayed in tissue extracts generated from
      5 mm trephined punches of retina obtained centered over the macula and the
      superior midperiphery of normal fresh human cadaver retina. Cadaver tissue was
      obtained from donors of a wide age range (age 7 to 85 years). The assays were
      performed within 6 h of enucleation and within 24 h of donor death. Antioxidant
      enzymes assayed included superoxide dismutase, catalase, glutathione peroxidase,
      and glutathione reductase. Hexokinase and glucose-6-phosphate dehydrogenase,
      enzymes not directly involved in protection against oxidative damage, were
      assayed for comparison. Enzyme specific activities were calculated for the macula
      and periphery using protein concentration of the extract as the denominator.
      Using linear regression analysis, over the age range of 25 to 75 years,
      superoxide dismutase activity of the periphery but not the macula tended to
      decline with age (p = 0.04, R2 = 0.21). Interindividual variability was high, and
      variability increased with age. The difference between the macular and peripheral
      enzyme activities for glutathione peroxidase tended to decline with increasing
      donor age (p = 0.025, R2 = 0.33). There was no effect of age on the specific
      activities of catalase, glucose-6-phosphate dehydrogenase, and glutathione
      reductase. The specific activity of hexokinase from the macula declined with
      increasing donor age (p = 0.022, R2 = 0.43). Time from death to enucleation or
      beginning of experiment was not a significant factor. In summary, age does not
      have an effect on the activity of major antioxidant enzymes of the macula in
      normal human retina. There is a tendency for an effect of age on peripheral
      superoxide dismutase activity and the difference between macular and peripheral
      glutathione peroxidase activity. High interindividual variability of antioxidant
      enzyme activity exists in humans.

PMID- 8654108
TI  - Identification and endocrine control of sex steroid binding sites in the lacrimal
      gland.
AB  - Previous research has indicated that the lacrimal gland may be a target organ for
      sex steroids and that androgen effects on this tissue may be inhibited by
      pituitary deficiency or diabetes. To extend these findings, the objectives of the
      current investigation were 3-fold: [a] to determine whether specific and high
      affinity binding sites for androgens and estrogens exist in rat lacrimal tissue;
      [b] to assess whether the number and affinity of androgen binding sites in the
      lacrimal gland may be influenced by hypophysectomy or acute diabetes; and [c] to
      examine whether androgen receptor mRNA may be detected in lacrimal tissues of a
      variety of species. Following the collection of lacrimal gland samples, tissues
      were processed for the conduct of equilibrium binding methods or molecular
      biological techniques. Our results demonstrated that a single class of saturable,
      high-affinity and stereochemically selective binding sites for androgens exist in
      lacrimal tissues of male and female rats. These sites possessed a dissociation
      constant of approximately 1 nM and were also present in isolated acinar
      epithelial cells. In contrast, we were unable to find any evidence for the
      presence of specific or high-affinity receptors for estrogens in the rat lacrimal
      gland. With regard to changes in the endocrine environment, hypophysectomy led to
      an increase in the number and affinity of androgen binding sites in rat lacrimal
      tissue cytosol, whereas diabetes reduced the total quantity of these sites. Of
      interest, androgen receptor mRNA was detected in lacrimal glands of mice, rats,
      hamsters, guinea pigs, rabbits and humans. Overall, our findings show that the
      lacrimal gland is a target organ for androgens and that androgen action in this
      tissue may be mediated through an interaction with specific and high-affinity
      binding sites.

PMID- 8654109
TI  - Lens opacity increase in a longitudinal study: comparison of the lens opacities
      classification system II and lensmeter 701.
AB  - We evaluated the ability of Lensmeter 701 (LOM) to detect changes in the
      transparency of the lens graded with the Lens Opacities Classification System II
      (LOCS II). In this prospective study 410 middle-aged Eastern Finnish men
      participating in the Kuopio Atherosclerosis Prevention Study were examined three
      times at eighteen month intervals, and lens opacities were graded with both LOM
      and LOCS II, the latter serving as the standard. Majority of the change in the
      LOM reading during the follow-up fell within the 95% tolerance interval of the
      apparatus (3.08 units). Only four eyes showing progression by LOCS II were
      detected by LOM. The association between LOM change and the change observed by
      LOCS II was not statistically significant, and the correspondence of the two
      methods was weak. It seems that the sensitivity of the LOM is not sufficient to
      detect small changes in the transparency of the lens over time.

PMID- 8654110
TI  - Apoptosis-related fas antigen on memory T cells in aqueous humor of uveitis
      patients.
AB  - To investigate the role of lymphocytes in the pathogenesis of uveitis, we
      analyzed the expression of memory markers, CD29 and CD45RO antigens, and
      apoptosis-related Fas antigen on T lymphocytes in the aqueous humor (AH) and
      peripheral blood (PB) from patients with uveitis. Using three-color flow
      cytometry, we assessed the number of T lymphocyte subsets that stained with
      fluorescence-conjugated anti-CD3, CD4, CD8, CD29, CD45RA, CD45RO, HLA-DR, and Fas
      monoclonal antibodies in the AH and PB from 19 patients with active uveitis who
      were diagnosed as having sarcoidosis, Vogt-Koyanagi-Harada disease, HLA-B27+
      uveitis, or idiopathic uveitis. Cells from AH and PB were evaluated by light and
      electron microscopy before and after 6 h of incubation. The majority of
      lymphocytes in AH but not in PB, were CD3+HLA-DR+ (activated) T cells. The
      percentage of CD4+ lymphocytes was significantly higher in uveitic AH than in PBL
      (P < 0.01). While the percentage of CD4+ CD45RA+ (naive) cells within T cells was
      much lower in uveitic AH than in PB, the percentage of CD4+CD29+ or CD4+CD45RO+
      (memory) cells was significantly higher in uveitic AH than in PBL (P < 0.01). Fas
      antigen was expressed preferentially on memory cells in uveitic AH. Apoptosis of
      cells in the AH was observed by microscopically following after incubation with
      no stimulation. Lymphocytes from the AH of patients with uveitis were more
      activated than those from PB. The majority of T lymphocytes from uveitic AH
      expressed memory markers and Fas antigen. Results suggest that an increase in the
      number of Fas+ memory T lymphocytes in AH is involved in the pathogenesis of
      uveitis.

PMID- 8654111
TI  - Molecular cloning of sheep connexin49 and its identity with MP70.
AB  - The nucleotide sequence of the sheep homologue of the lens-specific mouse
      connexin50, chicken connexin45.6, and human connexin50 has been obtained
      following screening of a sheep genomic library. This connexin comprises 1323
      nucleotides, coding for a protein of 440 amino acid residues and a predicted
      molecular weight of 49,160 daltons, so by convention is termed sheep connexin49.
      A connexin49 cDNA probe detected a single major band with a mobility of 6.8 kb in
      sheep lens RNA, but not in RNA isolated from five other sheep organs. The N
      terminal amino acid sequence of sheep connexin49 is identical to that of mouse
      connexin50 and closely matches that of MP70, indicating the identity of sheep
      connexin49 with MP70. The nucleotide and translated amino acid sequences of
      connexin49 have 69-87% and 76%-87% identity respectively with chicken
      connexin45.6, human connexin50 and mouse connexin50. Like other members of this
      lens connexin family, sheep connexin49 coding region is completely contained
      within one exon, and the sequence of the N-terminal region, the four
      transmembrane domains and the two extracellular loops are highly conserved.

PMID- 8654112
TI  - A comparison of binocular summation in young and older patients.
AB  - Binocular and monocular contrast sensitivities were measured at two spatial
      frequencies of 1 and 6 c/deg in 8 young (mean age 22.6 +/- 3.8 years) and 18
      older subjects with normal healthy eyes (mean age 58.4 +/- 7.3 years). Data were
      analysed as binocular summation ratios defined as binocular CS/"best eye' CS.
      Binocular summation ratios were higher for the younger group (1.46 and 1.48 for 1
      and 6 c/deg respectively) compared to the older group who demonstrated a spatial
      frequency dependence (1.31 and 1.13 at 1 c/deg and 6 c/deg respectively). The
      results are discussed in terms of age-related cortical cell loss and increased
      monocular sensitivity differences between the two eyes.

PMID- 8654113
TI  - Scanning electron microscopic study of episcleral arteriovenous anastomoses in
      the owl and cynomolgus monkey.
AB  - In the present study we have analyzed the architecture of the episcleral
      microvasculature in the owl and cynomolgus monkey using scanning electron
      microscopy of resin casts. Due to the topical pretreatment with nitroprusside the
      complete vasculature including segments of the aqueous humor outflow channels
      could be visualized. We found that 1-3 mm posterior to the limbus corneae the
      episcleral vessels form numerous arteriovenous anastomoses (AVA) in the size of
      small arterioles and venules. These AVA are also located at the collector
      channels near Schlemm's canal and at the episcleral venous plexus which drains
      the collector channels. It is assumed that the AVA might influence not only the
      circulation in the episcleral venous plexus but also in the aqueous humor outflow
      routes.

PMID- 8654114
TI  - Protein kinase C isoforms in iris sphincter smooth muscle: differential effects
      of phorbol ester on contraction and cAMP accumulation are species specific.
AB  - Objectives were to identify PKC isoforms in iris sphincter isolated from rabbit,
      cat, dog and bovine irides, to determine their subcellular distribution, and to
      investigate the effects of the phorbol ester, PDBu, on contraction and cAMP
      accumulation in this tissue. Using six isoform (alpha, beta, gamma, epsilon,
      delta, zeta)-specific polyclonal antibodies, PKC alpha, beta, epsilon, delta, and
      zeta were detected in the four species, whereas PKC gamma was detected only in
      dog and bovine. PKC alpha and epsilon are the most abundant isoforms in this
      tissue. PKC alpha is mainly cytosolic in rabbit and bovine and membrane
      associated in cat and dog. PKC gamma is equally distributed in cytosol and
      membrane fractions of bovine, but mostly cytosolic in dog. PKC beta, delta and
      epsilon are mainly membraneous and PKC zeta is mainly cytosolic in all species.
      PDBu (100 nM) induced a contractile response in rabbit- and cat-, but not in dog
      and bovine, sphincters, and increased cAMP accumulation in rabbit, cat, dog and
      bovine by 111, 130, 458 and 294%, respectively. Therefore, the lack of effect of
      PDBu on contraction in dog and bovine, as compared to rabbit and cat, may be due:
      (a) to the presence of PKC gamma isoform, and (b) to the stronger stimulatory
      effects of the phorbol ester on cAMP production in the non-contracting species.
      In addition to demonstrating the presence of various PKC isoforms in the iris
      sphincter and the activation of adenylyl cyclase by this protein kinase, we have
      shown that the distribution of the PKC isoforms in this tissue is species
      specific. Furthermore, our data suggest that there may be specific physiological
      functions associated with each of the PKC isoforms and that PKC is involved in
      the contractile response of some but not all smooth muscles.

PMID- 8654115
TI  - Expression of TGF-beta type I and type II receptors in rat eyes.
AB  - Transforming growth factor beta (TGF-beta) transduces signals through mediation
      of type I and type II serine/threonine kinase receptors. The expression of TGF
      beta type I (T beta R-I) and II (T beta R-II) receptors in rat eyes was
      investigated immunohistochemically. T beta R-I and T beta R-II immunoreactivity
      was detected in corneal and conjunctival epithelial cells, corneal endothelial
      cells, ciliary epithelial cells, lens epithelial cells, retinal pigment
      epithelial cells, and choroidal vessels. This co-expression of T beta R-I and T
      beta R-II indicates that the above cells respond to TGF-beta and, because TGF
      beta is reported to be produced in ocular tissues, that it may have important
      autocrine and/or paracrine roles in the growth and metabolism of ocular tissues
      in situ.

PMID- 8654116
TI  - High total TGF-beta 2 levels in normal human tears.
AB  - Mature and total TGF-beta 2 levels were determined in normal human tears, from 37
      volunteers, using a quantitative "sandwich' enzyme immunoassay technique. Since
      this ELISA method recognizes only mature TGF-beta 2, total TGF-beta 2 levels in
      tears were measured after acid activation. Aqueous humor samples from 9 patients
      with cataract were also tested as controls. Mature and total TGF-beta 2 in
      aqueous humor (AH) averaged 182 pg/ml and 737 pg/ml, respectively. The levels of
      mature TGF-beta 2 in normal human tears ranged from 36 to 71 pg/ml (mean: 55
      pg/ml). And the levels of total TGF-beta 2 ranged from 3446 to 14910 pg/ml (mean:
      7854 Pg/ml), a very high level. Percentage of mature TGF-beta 2 ranged 0.4 to
      1.3% (mean: 0.9%). It is reported for the first time that there are very high
      levels of total TGF-beta 2 in normal human tears.

PMID- 8654118
TI  - The selective effect of optical defocus on detection and resolution acuity in
      peripheral vision.
AB  - Detection and resolution acuity was measured at 30 degrees in the periphery for
      sinusoidal gratings under differing amounts of optical defocus. Within the range 
      2.0 to +2.5 diopters defocus, detection acuity was higher than resolution acuity.
      As defocus increased, detection acuity decreased continuously but resolution
      acuity was little affected until around 2.0 diopters defocus. The results
      indicate that resolution performance is sampling limited in peripheral vision,
      even for significant refractive error, and is more robust than detection acuity
      to the effects of optical defocus.

PMID- 8654117
TI  - Isolation of a cDNA encoding a taurine transporter in the human retinal pigment
      epithelium.
AB  - Reverse transcription-polymerase chain reaction (RT-PCR) was performed to amplify
      a cDNA encoding a taurine transporter in the human retinal pigment epithelium
      (HRPE). The coding region of a PCR product was found to be 1863 bp long,
      predicting a 620-amino acid protein (69,826 Da). This cDNA sequence is almost
      identical to those taurine transporters recently determined in the human thyroid
      and placenta: 12 and 1 base pair(s) different from the reported thyroid and
      placenta transporter clones, respectively. The injection of mRNA in vitro
      transcribed from the PCR product markedly increased taurine uptake in Xenopus
      laevis oocytes. Taurine uptake is Na+ and Cl- dependent. Unlabeled taurine, beta
      alanine and gamma-amino-n-butyric acid at 100 microM inhibited the uptake of
      radiolabeled taurine whereas 100 microM alpha-alanine and alpha-aminoisobutyric
      acid did not. A kinetic study showed that taurine uptake is mediated by a single
      carrier system with the apparent Michaelis-Menten constant of approximately 2
      microM. These results suggest that the PCR product encodes a functional taurine
      transporter whose characteristics are similar to those of taurine uptake observed
      in the original HRPE cells. A DNA encoding the reported placental transporter was
      made from the PCR product by site-directed mutagenesis but it was not functional
      in the oocyte expression. A similar RT-PCR was performed with poly (A)+ mRNA
      isolated from JAR human placenta choriocarcinoma cells. This PCR product was
      identical to that from the HRPE. In addition, the clone of the human thyroid
      transporter was obtained and re-sequenced. Its translation coding region was also
      identical to that of the PCR product from the HRPE, showing that taurine
      transporters are identical in the human RPE, thyroid and placenta.

PMID- 8654120
TI  - ABCDs of Melanoma.

PMID- 8654119
TI  - Myocardial viability.

PMID- 8654121
TI  - Allergic reaction to nonrubber products by testing with rubber mixes. Part IV:
      the carba mix.

PMID- 8654122
TI  - The treatment of acne. Part III: antibacterials.

PMID- 8654123
TI  - Scabies.

PMID- 8654124
TI  - Hepatitis C-associated cryoglobulinemia.
AB  - Leukocytoclastic vasculitis can be caused by a variety of infectious, neoplastic,
      and autoimmune processes. Cryoglobulinemia should be included in this
      differential diagnosis. Recently, many patients with "idiopathic"
      cryoglobulinemia have been found to have hepatitis C. We report the clinical and
      histopathologic features of a patient who presented with leukocytoclastic
      vasculitis and was found, after further investigation, to have cryoglobulinemia
      as well. This led to the identification of a previously undiagnosed hepatitis C
      infection. Dermatologists should be aware of this association because
      identification and treatment of hepatitis C in patients with cryoglobulinemia
      appears to have dramatic effect on prognosis.

PMID- 8654125
TI  - Angiolymphoid hyperplasia with eosinophilia and nephrotic syndrome.
AB  - We report a case of angiolymphoid hyperplasia with eosinophilia (ALHE) and
      nephrotic syndrome. The clinical and histologic features of ALHE are described
      and contrasted with Kimura's disease. Both ALHE and Kimura's disease may be
      associated with renal disease.

PMID- 8654126
TI  - Scurvy and panniculitis: a case report.
AB  - In most western countries, scurvy has become a rare clinical entity. However, it
      may still be encountered in selected situations. It can mimic connective tissue
      disease, because of multiorgan involvement. Panniculitis has not previously been
      described in association with scurvy.

PMID- 8654127
TI  - Rationale for the development of new topical treatments for acne vulgaris.
AB  - The development of new topical anti-acne therapies reflects the need for
      medications that address the requirements and concerns of an increasingly mature
      and demanding acne patient population. Some of the topical agents currently under
      investigation in the United States include several alpha-hydroxy acids (AHAs),
      the retinoids tazarotene and adapalene, and azelaic acid. All of these agents
      appear to exert their effect on acne through some effect on the process of
      keratinization and/or the thickness of the stratum corneum. Azelaic acid also has
      significant antimicrobial activity relevant to its efficacy in acne vulgaris.
      While azelaic acid has already been used successfully in many parts of the world
      for several years, the potential roles of the new retinoids in acne therapy are
      just beginning to be clarified. The properties of AHAs suggest that they may also
      be of value in the treatment of acne, but further systematic evaluation is
      needed.

PMID- 8654128
TI  - Efficacy and safety of topical azelaic acid (20 percent cream): an overview of
      results from European clinical trials and experimental reports.
AB  - Azelaic acid cream (20 percent) is a new topical treatment for acne with an
      additional therapeutic potential in rosacea and hyperpigmentation disorders.
      Azelaic acid (AzA; HOOC-(CH2)7-COOH) is a naturally occurring compound that
      interferes with acne pathogenesis by virtue of its antikeratinizing,
      antibacterial, and anti-inflammatory properties. Vehicle-controlled studies have
      verified that AzA exercises a significant and clinically relevant effect on both
      non-inflammatory and inflammatory acne lesions. Comparisons with clinically
      proven therapies have shown that 20 percent AzA cream is an effective monotherapy
      in mild to moderate forms of acne, with an overall efficacy comparable to that of
      tretinoin (0.05 percent), benzoyl peroxide (5 percent), and topical erythromycin
      (2 percent). In the treatment of moderate to severe acne, 20 percent AzA cream
      may be favorably combined with minocycline (90 percent good and excellent
      results), and may contribute towards reducing recurrences following
      discontinuation of systemic therapy (maintenance therapy with AzA cream).
      Particular advantages of AzA therapy include its favorable safety and side effect
      profile. It is non-teratogenic, is not associated with systemic adverse events or
      photodynamic reactions, exhibits excellent local tolerability, and does not
      induce resistance in Propionibacterium acnes.

PMID- 8654129
TI  - Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid,
      and other therapies.
AB  - Clinical studies of patients with melasma have shown that topical 20 percent
      azelaic acid is superior to 2 percent hydroquinone and as effective as 4 percent
      hydroquinone, without the latter's undesirable side effects. Tretinoin appears to
      enhance this effect of azelaic acid. Azelaic acid with tretinoin caused more skin
      lightening after three months than azelaic acid alone, and a higher proportion of
      excellent responders at the end of treatment. The effect of azelaic acid can be
      attributed to its ability to inhibit the energy production and/or DNA synthesis
      of hyperactive melanocytes, and partially to its antityrosinase activity. This
      may also account for the beneficial effect on postinflammatory hyperpigmentation.
      Destruction of malignant melanocytes by a combination of the same activities,
      enhanced by the greater permeability of tumoral cells to azelaic acid, may
      account for the clinical effects of azelaic acid observed in lentigo maligna and
      individual lesions of primary melanoma.

PMID- 8654130
TI  - New approaches in dermatology: a clinical profile of azelaic acid.

PMID- 8654131
TI  - An overview of acne and its treatment.
AB  - The pathophysiology of acne vulgaris results from the interplay of follicular
      hyperkeratinization, the presence of Propionibacterium acnes bacteria in the
      follicular canal, and sebum production. Several anti-acne agents are currently
      available that affect one or more of these pathogenic factors and are effective
      against one or more acne lesion types. The only currently available agent that is
      directly effective against comedones is tretinoin. Agents effective against
      inflammatory lesions include tretinoin, benzoyl peroxide, and topical and
      systemic antibiotics. Agents effective against nodules and cysts include oral
      antibiotics and isotretinoin. However, the successful utilization of the
      available agents and techniques is highly dependent on an accurate and thorough
      assessment of each patient's needs and concerns, followed by the implementation
      of an individualized treatment program that has been clearly communicated to the
      patient. Such a program may employ several different anti-acne agents and
      adjunctive treatments such as comedo extraction or intralesional injection.

PMID- 8654132
TI  - Endoscopic diagnosis and management of biliary complications following orthotopic
      liver transplantation.
AB  - Nonoperative management of biliary complications (BC) with endoscopic retrograde
      cholangiopancreatography (ERCP) is a natural sequel to the emergence of
      choledochocholedochostomy as the preferred biliary reconstruction for orthotopic
      liver transplantation (OLT). Overall, therapeutic ERCP's efficacy for
      posttransplant BC is difficult to assess because most published data are
      retrospective, anecdotal, or in abstract form, and there are no prospective,
      randomized studies. Thus, endoscopic management of posttransplant BC must be
      individualized. While T-tube-related late bile leaks and ductal calculi are
      amenable to endoscopic therapy, its efficacy for strictures is more difficult to
      define. Refined surgical technique has prevented many unifocal anastomotic
      lesions, while multifocal strictures (for which endoscopic therapeutic experience
      is minimal) are increasingly prevalent. Whether endoscopic sphincterotomy is
      appropriate for posttransplant sphincter of Oddi dysfunction is controversial,
      because the disorder may be transient and the risk significant. Multicenter,
      prospective studies are needed to determine more accurately the optimal role of
      endoscopic therapy after OLT.

PMID- 8654133
TI  - Hepatorenal syndrome. Long-term treatment with terlipressin as a bridge to liver
      transplantation.
AB  - In patients with hepatorenal syndrome (HRS), 4-hr administration of a vasopressin
      analog has recently been shown to benefit renal blood flow and renal function.
      However, long-term effects and tolerance of this treatment have not been
      reported. We report a case of HRS that was controlled by the vasopressin analog,
      terlipressin. Because HRS repeatedly relapsed when treatment was discontinued,
      terlipressin, 2 mg/day was administered for 67 days, until liver transplantation
      could be performed in a patient with normal renal function. Except for limited
      cutaneous necrosis at an injection point, prolonged treatment with this
      vasopressin analog was well tolerated.

PMID- 8654134
TI  - Differing proliferative responses in proximal and distal colons of growing rats
      fed food eaten by adenoma patients.
AB  - Animal dietary studies related to human colorectal carcinogenesis are usually
      based on AIN-76A diet, which is dissimilar to human food in source, preparation,
      and content. Our aim was to examine colonic epithelial proliferation in rats fed
      a diet based on the mean daily food intake of adenoma patients. Foods were
      prepared as reported by the adenoma patients and dehydrated; 64 Sprague-Dawley
      rats were fed either "human adenoma" or AIN-76A diet and every eight weeks, eight
      from each group were sacrificed. Both groups gained weight equally, had no
      colonic histological changes, but during the study showed progressive lengthening
      of colonic crypts (P < 0.01) and decreased proliferation (P < 0.05) in distal
      colons. Compared to controls, rats fed human adenoma diet had significantly
      longer crypts (P < 0.01) and more labeled cells (P < 0.05) at 32 weeks; overall
      they had increased proliferation (P < 0.01), most significantly in the distal
      colon. Thus, food eaten by adenoma patients induced hyperproliferative changes in
      the rat colon during growth and maturity, especially the distal colon, as found
      in humans at risk for neoplasia.

PMID- 8654135
TI  - Risk of pancreatic cancer associated with cholelithiasis, cholecystectomy, or
      gastrectomy.
AB  - Current data regarding an association between cholelithiasis, cholecystectomy, or
      gastrectomy and pancreatic cancer are conflicting. We evaluated the frequency
      with which these factors were present in 720 patients with newly diagnosed
      pancreatic cancer and in 720 matched controls. All subjects were interviewed
      personally and in detail about their clinical history. Cholelithiasis was present
      in 126 patients with pancreatic cancer (17.5%) and in 95 controls (13.2%),
      constituting a statistically significant association (odds ratio, 1.39; 95%
      confidence interval, 1.04-1.86); however, considering only the patients and
      controls in whom the diagnosis of cholelithiasis was made more than one year
      before cancer diagnosis or interview, the association was no longer significant
      (odds ratio, 1.04; 95% confidence interval, 0.75-1.44). Cholecystectomy had been
      performed in 93 patients with pancreatic cancer (12.9%) and in 71 controls
      (9.9%). When all subjects were considered, the odds ratio was mildly, although
      not significantly, increased (odds ratio, 1.35; 95% confidence interval, 0.97
      1.87); when only subjects who underwent cholecystectomy one year or more before
      the cancer diagnosis or interview were considered, the odds ratio fell to unity.
      Gastrectomy had been performed in 28 patients with pancreatic cancer (3.9%) and
      in 25 controls (3.5%); analysis revealed no significant association between these
      two factors (odds ratio, 1.14; 95% confidence interval, 0.64-2.05). In
      conclusion, our study, one of the largest on this topic, has found no evidence
      for an association between cholelithiasis, cholecystectomy, or gastrectomy and
      pancreatic cancer.

PMID- 8654136
TI  - Raf-1 kinase, epidermal growth factor receptors, and mutant Ras proteins in
      colonic carcinomas.
AB  - Epidermal growth factor receptors (EGFR) and ras mutations are known to play a
      significant role in controlling cell growth and tumor promotion. Both of them
      transmit mitogenic signals to the nucleus by activation of Raf-1 kinase. In this
      study, the expression of EGFR and mutant Ras proteins, and, for the first time,
      the expression, phosphorylation and kinase activity of Raf-1 kinase have been
      determined in paired samples of colorectal cancer and mucosa. The tumor and
      mucosa samples did not differ significantly with regard to Raf-1 kinase content
      and activity. A major difference between tumors and mucosa was found, however, in
      the phosphorylation of Raf-1. Most of the mucosa samples (13/20), but only 1/20
      of the cancer samples, contained hyperphosphorylated Raf-1. EGFR were
      significantly (p = 0.0025) decreased in the tumors. The decreased phosphorylation
      of Raf-1 in colonic carcinomas could be the result of activation of Raf-1
      phosphatases or inactivation of kinases phosphorylating Raf-1. New forms of
      treatment based on EGFR overexpression do not seem to be suitable for the
      majority of colonic cancers.

PMID- 8654137
TI  - Comparative effects of growth hormone on water and ion transport in rat jejunum,
      ileum, and colon.
AB  - Specific growth hormone (GH) receptors are located along the entire rat
      intestine. We have recently shown that GH induces water and ion absorption in the
      rat ileum. This raises the possibility that GH regulates water and ion transport
      throughout the intestine. To test this, we have evaluated the effects of GH
      administration on jejunal, ileal, and colonic water and ion transport, by the in
      vivo rat perfused intestine, and in vitro, in corresponding segments of intestine
      mounted in Ussing chambers. In vivo, GH increased water absorption by 250%, 180%,
      and 80% over baseline in the jejunum, ileum, and colon, respectively. The effect
      had similar kinetics in the three intestinal regions. In vitro, serosal GH
      administration induced a decrease in short-circuit current, consistent with an
      absorptive effect. The effect showed a proximal to distal decreasing pattern.
      These findings suggest that GH plays a role in the body fluid homeostatic
      control, promoting water and ion absorption.

PMID- 8654138
TI  - Myoelectric activity and absorptive capacity of rat small intestinal isografts.
AB  - The effect of transplantation on small intestinal absorption, digestive capacity,
      myoelectric activity, and morphology was assessed in inbred Lewis rats.
      Electrodes were sutured to the duodenum and isografted jejunoileum or to the
      native jejunoileum in controls. The frequency of migrating myoelectric complexes
      (MMCs) in the duodenum was 3.3 +/- 0.3/hr in controls and 1.8 +/- 0.4/hr in
      transplants (P < 0.05). MMC frequency in the jejunoileum was 5.1 +/- 1.3/hr in
      controls and 3.2 +/- 0.9/hr in transplants (P > 0.05). MMCs appeared to migrate
      from the duodenum to the jejunoileum 80 +/- 3% of the time in controls and 59 +/-
      7% of the time in transplant rats (P < 0.05). Absorption in the transplanted
      jejunoileum demonstrated a 35-40% decrease in glucose and electrolytes
      absorption. Villus height and number of nuclei per villus was reduced. Intestinal
      length (dry) was 103 +/- 6 cm for controls and 51 +/- 3 cm for transplant rats (P
      < 0.05). Brush border sucrase activity was unchanged. We conclude that small
      intestinal isografts display similar myoelectric activity as controls, but the
      decreased absorptive capacity and villus height may require longer segments of
      intestine to be transplanted in order to support normal nutrition.

PMID- 8654140
TI  - Does empiric esophageal dilation benefit dysphagia when endoscopy is normal?
AB  - Some patients referred for esophagogastroduodenoscopy (EGD) to evaluate symptoms
      of dysphagia have normal endoscopies. How best to manage these patients is
      unclear. We reviewed our experience with empiric esophageal dilation in this
      setting. Over a five-year period, 40 consecutive patients with esophageal
      dysphagia and normal EGD underwent empiric esophageal dilation at the time of
      their endoscopy. Postdilation follow-up was available in 37 of the 40. The
      patients were divided into two groups depending on whether their dysphagia was to
      solid food only or to both solids and liquids. The two groups were comparable as
      regards age, sex, and the frequency of heartburn. Complete resolution of
      dysphagia was seen in 19 of 20 patients (95%) with solid-food-only dysphagia. In
      contrast, only two of 17 patients (12%) with solid and liquid dysphagia had
      complete resolution with empiric dilation, although another six patients (35%)
      had partial improvement. The difference in response between the two groups was
      highly significant (P < 0.0001). The response to dilation in patients with
      dysphagia to solid food only was often long-lasting. Most patients with dysphagia
      to solid food only and a normal EGD benefit from empiric esophageal dilation
      performed at the time of their endoscopy. In contrast, few patients with
      dysphagia to both solids and liquids respond.

PMID- 8654139
TI  - Morphological characterization of the squamocolumnar junction of the esophagus in
      patients with and without Barrett's epithelium.
AB  - Barrett's esophagus is a metaplastic condition in which the normal stratified
      squamous epithelium of the distal esophagus is replaced by columnar epithelium.
      Our group has previously characterized a unique surface cell (the "distinctive
      cell") at the junction of squamous and Barrett's epithelium. This cell is notable
      for the simultaneous presence on its surface of both squamous and columnar cell
      features. The aims of our present study were, first, to evaluate prospectively
      the frequency with which Barrett's patients have the distinctive cell at the
      squamo-Barrett's junction; second, to further elucidate the characteristics of
      the distinctive cell; and third, to perform a combined morphological study of the
      squamo-Barrett's junction using scanning electron microscopy followed by
      transmission and light microscopy. We divided study patients into two groups:
      Group I consisted of Barrett's patients and group II of non-Barrett's control
      patients. Of eight group I Barrett's patients with junctional biopsies, three
      were noted to have the distinctive cell (37.5%). In contrast, this cell was not
      observed in any of the group II control patients. Biopsies in control patients as
      well as Barrett's patients without the distinctive cell revealed abrupt
      squamogastric or squamo-Barrett's junctions by scanning electron microscopy and
      light microscopy. In contrast, biopsies from the Barrett's patients with the
      distinctive cell revealed junctions that were not abrupt and had the distinctive
      cells overlying normal squamous epithelium. By scanning electron microscopy, the
      distinctive cells were flattened, polygonal cells with surface microvilli (a
      columnar cell feature) and were demarcated from one another by shallow
      depressions, or by intercellular ridges (a squamous cell feature). By
      transmission electron microscopy, the distinctive cells were cuboidal in shape
      with abundant apical microvilli and secretory vesicles. We have confirmed that
      distinctive cells are present in some Barrett's patients. This cell is a
      morphologic hybrid, sharing features of both squamous and columnar cells, and may
      be analogous to hybrid cells identified in other locations that undergo
      metaplasia (eg, the human cervix). Its origin may be the result of transformation
      of multipotential basal cells of squamous epithelial origin. We hypothesize that
      the distinctive cells may represent an intermediate stage in the development of
      Barrett's epithelium.

PMID- 8654141
TI  - Ambulatory esophageal pH testing. Referral patterns, indication, and treatment in
      a Canadian teaching hospital.
AB  - Over a 30-month period, 867 esophageal pH studies were conducted in a Canadian
      teaching hospital; of these, 315 tests were recorded in patients who were first
      time referrals having no chest or upper gastrointestinal surgery and taking no
      medication that would affect the results. Patients were referred by
      gastroenterologists, general surgeons, ENT surgeons, thoracic surgeons, and a
      miscellaneous group. Patients were classified based on: pH results [abnormal = %
      total time pH < 4.0 (ie, > 6.0%)], manometry (abnormal = LES resting pressure < 5
      mm Hg and/or abnormal peristalsis), and gender. Fifty-one percent (162/315) of
      the patient records demonstrated abnormal reflux. Intergroup comparisons of
      severity of reflux using two-way analysis of variance demonstrated no significant
      differences (P = 0.13). In the 162 patients who refluxed, 70% (N = 108) had
      normal motility studies; however, when the severity of reflux was compared,
      patients with abnormal motility (N = 54) demonstrated significantly more severe
      reflux (19.8 +/- 12.8 vs 16.2 +/- 11.3) P = 0.02. In those patients with abnormal
      manometry, no significant differences (P = 0.44) in the severity of reflux were
      found among those with abnormal peristalsis (N = 27), low resting pressure (N =
      17), or a combination of aperistalsis and low LES pressure (N = 10). Symptomatic
      patients with reflux (N = 107) demonstrated a significantly greater percent time
      pH < 4.0 than those with asymptomatic reflux (N = 55); 18.1 +/- 11.5% vs 16.2 +/-
      12.7%, P = 0.04. When the severity of reflux by gender was compared, no
      significant differences were found [18.3 +/- 11.9 (male) N = 91 vs 16.2 +/- 11.9
      (female) N = 71, P = 0.11]. The results from this study show that: (1) esophageal
      pH testing is important in subspecialties other than gastroenterology and that
      the clinical yield is high in all referring groups, (2) esophageal pH testing and
      manometry are complimentary tests, but that reflux occurs commonly in association
      with normal manometry, (3) asymptomatic reflux was found in 34% of the patients
      with abnormal reflux scores, and (4) the severity of reflux in male and female
      patients is similar.

PMID- 8654142
TI  - Short-term treatment of gastric ulcer. A meta-analytical evaluation of blind
      trials.
AB  - Gastric ulcer is relatively infrequent, and clinical trails are often based on
      small-sized samples. The aim of this study was to define the "gold standard"
      therapy of active gastric ulcer. We included all single- or double-blind clinical
      trials on the short-term treatment of gastric ulcer. All the articles published
      over the period 1977-1994 were reviewed. Meta-analysis was done with both fixed
      and random effect models; results were shown using Galbraith's radial plot. Forty
      eight papers comprising 52 studies were evaluated. Cimetidine, ranitidine, and
      famotidine proved significantly better than placebo [odds ratio (OR) and 95%
      confidence interval (CI 95%) at four to six weeks were: 2.67 (2.03-3.52), 3.94
      (2.28-6.80), 1.76 (1.08-2.88), respectively]. Cimetidine and ranitidine had
      results comparable with the newer H2 blockers [OR (CI 95%) at four weeks: 1.16
      (0.91-1.47), 1.11 (0.80-1.55), respectively]. H2 blockers were proved comparable
      with either sucralfate [OR (CI 95%) at eight weeks: 0.81 (0.37-1.79)] or bismuth
      [OR (CI 95%) at four to six weeks: 0.67 (0.37-1.20)]. Omeprazole is more
      effective than H2 blockers [OR (CI 95%) at four weeks: 2.00 (1.57-2.55)]. It is
      concluded that H2 blockers are preferred to either a placebo or sucralfate for
      short-term gastric ulcer treatment; the newer H2 blockers do not have significant
      advantages over the older types; omeprazole can be regarded as the "gold
      standard" for active gastric ulcer treatment.

PMID- 8654144
TI  - Rebamipide protects against activation of neutrophils by Helicobacter pylori.
AB  - Our objectives were to determine whether rebamipide, a unique antiulcer agent,
      would inhibit adhesive reactions between neutrophils and endothelial cells as
      well as the production of active oxygen species from neutrophils elicited by an
      extract of H. pylori. A water extract of H. pylori that was prepared from biopsy
      materials obtained from a patient with gastric ulcer increased the surface
      expression of CD18 on human neutrophils isolated from peripheral blood, the
      adhesion of neutrophil-endothelial cells, and the production of active oxygen
      species by neutrophils. Rebamipide, at concentrations of 10(-5) and 10(-6) M,
      reduced the adherence of neutrophils to endothelial cells as well as the CD18
      expression on neutrophils induced by this bacterial extract. Rebamipide also
      inhibited the production of active oxygen species from neutrophils stimulated by
      H. pylori extract. These results suggest that rebamipide protects against the
      gastric mucosal inflammation associated with H. pylori by inhibiting neutrophil
      function.

PMID- 8654143
TI  - Proliferative activity of gastric epithelium in progressive stages of
      Helicobacter pylori infection.
AB  - Helicobacter pylori (HP) infection is the main etiopathogenetic agent responsible
      for inflammatory and ulcerative changes in gastroduodenal mucosa and the basis
      for both intestinal and diffuse types of gastric carcinoma. In this latter case,
      intestinal metaplasia is the intermediary between gastritis and cancer. In this
      study we describe the proliferative activity of gastric epithelium in the
      progressive stages of HP infection. The expression of proliferating cell nuclear
      antigen (PCNA), which has proven to be a reliable method for this evaluation, was
      used as a marker. The study was performed on endoscopic biopsies of the gastric
      antrum of 40 patients, who were divided into five groups, eight in each group:
      normal histology and endoscopy, HP-; histological HP+ gastritis with normal
      endoscopy; histological HP+ gastritis with endoscopic evidence of chronic
      erosions; complete and incomplete intestinal metaplasia in a HP+ stomach. PCNA
      was detected by immunohistochemistry and expressed as labeling index, ie,
      percentage of positive nuclei either in the whole or upper third of foveolae. Our
      data show a progressive increase of epithelial proliferation in the successive
      stages of HP infection ranging from gastritis alone to the development of
      incomplete intestinal metaplasia, a well-known precancerous condition. The
      proliferative pattern tended to expand towards the upper foveolar third, which in
      normal conditions does not represent a site of epithelial renewal. These
      alterations may be related to the development of neoplastic transformations of
      gastric epithelium. It is well known that genetic mutations are facilitated in
      proliferating cells. Therefore, our results indicate that the high epithelial
      turnover, expressed by PCNA LI, may be an indicator of increased risk of
      neoplastic changes in long-standing untreated HP+ chronic gastritis.

PMID- 8654145
TI  - Safety of first trimester exposure to histamine H2 blockers. A prospective cohort
      study.
AB  - The objective of this study was to examine whether H2 blockers represent a major
      teratogenic risk. This prospective cohort study was done at the Motherisk
      Program, a Teratology Information Service, Toronto, Canada. The subjects included
      178 women who contacted Motherisk about gestational H2-blocker use, and 178
      controls matched for maternal age, smoking, and heavy alcohol consumption. The
      main outcome measures were primary--major malformations, and secondary--pregnancy
      outcome, method of delivery, gestational age, prematurity, birthweight, small for
      gestational age infants, neonatal health problems, and developmental milestones.
      No increase in major malformations was found following first trimester exposure
      to H2 blockers [2.1% vs 3.5% (controls), mean difference (95% CI) -1.4% (-5.2,
      +2.4)]. No other aspects of pregnancy outcome or neonatal health differed between
      groups. This study suggests that H2-blocker exposure during the first trimester
      does not represent a major teratogenic risk.

PMID- 8654146
TI  - Effects of pirenzepine on omeprazole-induced gastrin gene expression in rat
      antral tissues.
AB  - Pirenzepine has inhibitory effects on gastrin secretion both in vivo and in
      vitro. The aim of this study was to determine the mechanism responsible for the
      suppression of omeprazole-induced hypergastrinemia that occurs with pirenzepine
      treatment. The effects were measured in rats treated with oral omeprazole plus
      intraperitoneal pirenzepine or saline once daily for seven days in the antrum.
      The serum gastrin level increased significantly by more than sixfold with
      omeprazole treatment; additional treatment with pirenzepine suppressed this
      increase by 48%. Pirenzepine treatment did not change the level of gastrin mRNA
      but significantly increased the level of somatostatin mRNA. Combination treatment
      with omeprazole plus pirenzepine significantly decreased the gastrin mRNA level
      to half and significantly increased the somatostatin mRNA level up to 1.4-fold of
      the levels achieved with omeprazole treatment alone. These results suggest that
      the stimulatory effect of omeprazole on gastrin synthesis is partially blocked by
      pirenzepine via mediation of somatostatin synthesis in the antrum.

PMID- 8654147
TI  - Gastric injury induced by ethanol and ischemia-reperfusion in the rat. Differing
      roles for lipid peroxidation and oxygen radicals.
AB  - This study determined the role that oxygen-derived free radicals played in the
      production of gastric injury in rats challenged orally with concentrated ethanol
      or subjected to vascular compromise. In the ethanol study, rats were pretreated
      with a variety of free radical scavengers or enzyme inhibitors prior to exposing
      the stomach to 100% ethanol. At sacrifice, the degree of macroscopic damage to
      the glandular gastric mucosa was quantified. In separate studies, the effects of
      ethanol on gastric mucosal levels of enaldehydes (malondialdehyde and 4
      hydroxynonenal) were examined as an index of lipid peroxidation. Superoxide
      dismutase and catalase pretreatment were without benefit in reducing injury in
      our ethanol model, excluding potential contributory roles for the superoxide
      anion or hydrogen peroxide, respectively. Dimethyl sulfoxide and desferoxamine
      were likewise without protective capabilities, eliminating a role for the
      hydroxyl radical. Allopurinol, a xanthine oxidase inhibitor, provided no
      protection under acute conditions, even though partial protection was noted when
      administered chronically. Further, enaldehyde levels were not increased over
      control levels in alcohol-exposed mucosa, indicating no enhanced lipid peroxide
      formation. In contrast, in animals in which ischemia to the stomach was induced
      followed by reperfusion, marked gastric injury was observed in combination with
      enhanced enaldehyde levels. Prevention of enaldehyde formation by a 21
      aminosteroid concomitantly prevented injury induced by ischemia-reperfusion.
      These findings support the conclusion that ischemia-reperfusion injury to the
      stomach is an oxygen-derived free radical process whereas ethanol-induced injury
      clearly involved some other process. Although allopurinal was partially
      protective against ethanol damage when administered chronically, observations in
      other models of injury suggest that this action is independent of its inhibitory
      effect on xanthine oxidase.

PMID- 8654148
TI  - Effect of vitamin E and selenium on hypothermic restraint stress and chemically
      induced ulcers.
AB  - The present study was undertaken to determine the effect of a combination of
      selenium and vitamin E on stress and chemical-induced gastric ulcers in rats. The
      gastric mucosal lesions were produced by hypothermic restraint stress,
      indomethacin, reserpine, and mucosal damaging agents including 80% ethanol, 0.6 M
      HCl, 25% NaCl, and 0.2 M NaOH. The gastric secretion studies were undertaken
      using Shay's pylorus ligation model. The results of this study demonstrated that
      the treatment of rats with selenium or vitamin E significantly reduced the basal
      gastric acid secretions when given individually; however, the combination of
      these agents produced a better inhibition of gastric acid secretions as compared
      to their individual effect. Both selenium and vitamin E were found to protect
      gastric mucosa against the lesions produced by hypothermic restraint stress and
      chemicals, but a highly significant protection was observed when they were used
      concomitantly. Vitamin E alone and with selenium significantly inhibited ethanol
      induced depletion of gastric nonprotein sulfhydryl compounds. Our findings also
      showed that the combination of selenium and vitamin E provided better protection
      to gastric mucosa against hypothermic restraint-induced gastric wall mucus
      depletion. This study clearly suggests the feasibility of using selenium and
      vitamin E concurrently to achieve better gastroprotective effects.

PMID- 8654149
TI  - Role of endonuclease activity and DNA fragmentation in Ca2+ ionophore A23187
      mediated injury to rabbit isolated gastric mucosal cells.
AB  - In the current study, the role of endonuclease activity in calcium ionophore
      A23187-induced gastric mucosal cellular disruption was examined using rabbit
      gastric mucosal cells. Cell integrity was assessed using trypan blue dye
      exclusion and Alamar blue dye absorbance. Ionophore A23187 (1.6-25 microM)
      induced a concentration-dependent decrease in dye exclusion and cell metabolism
      in cells suspended in a medium containing Ca2+ (2 mM), while no such effect was
      observed in cells incubated in the absence of extracellular Ca2+. Cells that were
      pretreated with the endonuclease inhibitors aurintricarboxylic acid (ATCA; 0.2 or
      0.5 mM or Zn2+; 0.01 and 0.1 mM) exhibited significant reduction in the total
      extent of cell injury when incubated with A23187 in the presence of Ca2+. DNA
      fragmentation as assessed by measurement of [3H]thymidine liberation or gel
      electrophoresis was increased in response to ionophore A23187 (12.5 or 25 microM)
      treatment. A minimal degree of fragmentation was observed when cells were
      suspended in a Ca(2+)-free medium or incubated in the presence of ATCA or Zn2+.
      Addition of ethanol (8% w/v) induced a significant increase in cell injury, which
      was not affected by either removal of extracellular Ca2+ or ATCA pretreatment.
      Furthermore, treatment with the antioxidants catalase (50 micrograms/ml) or 2',2'
      dipyridyl (2 mM) reduced ionophore-induced cell injury but did not reduce the
      extent of DNA fragmentation. These data suggest that sustained increases in
      intracellular Ca2+ result in increased endonuclease activity in gastric mucosal
      cells, leading to extensive DNA lysis and cell damage. Ethanol-induced cell
      damage does not involve Ca2+ influx and therefore is not mediated by endonuclease
      activation. Furthermore, sustained increases in cellular Ca2+ may also mediate
      their effects via formation of reactive oxygen metabolites, but this mechanism of
      cell damage does not appear to involve DNA fragmentation.

PMID- 8654150
TI  - Protective effect of tauroursodeoxycholate against acute gastric mucosal injury
      induced by hydrophobic bile salts.

PMID- 8654151
TI  - Impact of aging on gastrointestinal mucosal immunity.
AB  - There is considerable evidence that the mucosal or secretory immune response in
      the gastrointestinal tract is compromised by aging. The generation of a mucosal
      immune response is an extremely complex process that involves antigenic
      stimulation of a specific subpopulation of immunologically competent cells in the
      Peyer's patches, differentiation and migration of these cells to the small
      intestinal lamina propria, initiation and regulation of local antibody production
      in the intestinal wall, and mucosal epithelial cell receptor-mediated transport
      of antibodies to the intestinal lumen. Available data suggest that
      gastrointestinal mucosal immunosenescence reflects deficits in: (1) the
      differentiation and/or migration (homing) of immunoglobulin A immunoblasts to the
      intestinal lamina propria, and (2) the initiation and/or regulation of local
      antibody production. The significant age-related increases in the incidence and
      severity of gastrointestinal infectious diseases, coupled with the potential for
      immunopharmacologic manipulation of the mucosal immune compartment, substantiate
      the merit of studies designed to resolve the etiology of mucosal immunodeficiency
      in the elderly.

PMID- 8654152
TI  - Time course of adaptive regulatory peptide changes following massive small bowel
      resection in the dog.
AB  - Basal and postprandial concentrations of gastrointestinal hormones were measured
      in 12 dogs before and at one and three months after a 75% small bowel resection.
      Five animals were studied again at six months. Concentrations of enteric hormones
      and neuropeptides, measured in the proximal jejunum and distal ileum adjacent to
      the anastomotic site at the time of euthanasia, were compared with concentrations
      in control tissues taken from each animal at the time of resection. Increased
      basal and postprandial levels of gastrin (P < 0.05), cholecystokinin (CCK, P <
      0.05), glucose-dependent insulinotropic peptide (GIP, P < 0.01), peptide YY (PYY,
      P < 0.001), and enteroglucagon (P < 0.001), were seen at one month after small
      bowel resection. In contrast, no significant changes were seen in concentrations
      of secretin, motilin, neurotensin, somatostatin, PP, or glucagon. Concentrations
      of enteroglucagon, GIP, and PYY remained high throughout the six-month study
      period. In contrast, gastrin and CCK had normalized by three months. Thus, only
      enteroglucagon, PYY, and GIP showed sustained elevations following enterectomy;
      the gastrin and CCK changes were transient. Following enterectomy, concentrations
      of vasoactive intestinal polypeptide (VIP) were reduced by about 50% in mucosal
      (P < 0.001) and muscle (P < 0.05) layers of proximal and distal gut. In contrast,
      calcitonin gene-related peptide (CGRP) was increased by about twofold in jejunal
      and ileal mucosa (P < 0.05), and CGRP elevations were even more marked in the
      muscle layers (P < 0.001). Somatostatin and neuropeptide Y (NPY) concentrations
      were similar to controls in all areas except for a small decrease in NPY in ileal
      mucosa (P < 0.05). These findings suggest that the increased motilin and PP
      concentrations previously reported after bowel resection in man are more likely
      to reflect underlying inflammatory bowel disease rather than enterectomy. The
      normalization of hypergastrinemia explains why the increased acid secretion after
      small bowel resection is transient. These results provide evidence for
      independent secretory control of enteroglucagon and PYY, which are both products
      of intestinal L cells. In addition, these studies reveal marked changes in
      enteric neuropeptide concentrations following bowel resection. VIP, which is
      thought to be a major inhibitory transmitter in the gut, is markedly reduced,
      while CGRP, which is mainly localized in sensory afferent fibers, is increased.
      These major neuropeptide changes are likely to be of importance in the adaptive
      responses to massive small bowel resection.

PMID- 8654153
TI  - Direct evidence of oxidative damage in acute and chronic phases of experimental
      colitis in rats.
AB  - During inflammatory colitis in man and experimental animals, the production of
      free radicals increases. This study evaluated the histological pattern and
      biochemical parameters of oxidative damage during acute and chronic colitis
      induced by 2,4,-trinitrobenzenesulfonic acid + ethanol in rats. On the samples of
      scraped mucosa of six groups of rats, one not treated, one killed after 1 hr, and
      those killed one, two, four, and eight weeks after the induced-damage, we
      determined the histological and superoxide dismutase activity and the
      concentration of lipoperoxides, malonyldialdheyde, and reduced glutathione. After
      1 hr, the mucosal damage and superoxide dismutase activity were slight;
      glutathione, lipoperoxides, and malonyldialdheyde were significantly increased.
      At one week, the histological damage was severe, decreasing progressively, and
      significantly correlated to superoxide dismutase activity. Lipoperoxides and
      malonyldialdheyde were high throughout the study. Glutathione was significantly
      increased at one and two weeks and dramatically decreased thereafter. Therefore,
      in experimental colitis the cascade of free-radical production induces a constant
      self-maintaining lipoperoxidation and consumes the cellular antioxidant
      capability.

PMID- 8654154
TI  - Unusual cause of fever and diarrhea in a patient with AIDS. Penicillium marneffei
      infection.
AB  - Penicillium marneffei is an opportunistic pathogen predominantly found in
      Southeast Asia. Systemic infection of Penicillium marneffei has protean
      manifestations including fever, weight loss, anaemia, skin lesions, and
      lymphadenopathy. We report a rare case of penicillium colitis in an AIDS patient
      who responded successfully to a course of amphotericin B therapy.

PMID- 8654155
TI  - Effect of beer, yeast-fermented glucose, and ethanol on pancreatic enzyme
      secretion in healthy human subjects.
AB  - The effect of beer, ethanol (4% v/v), and corresponding volumetric (water),
      caloric (glucose 5.76% w/v), and osmotic (glucose 11.5% w/v) control solutions on
      pancreatic enzyme output and release of gastrin and cholecystokinin (CCK) were
      studied in six healthy human subjects. As a simpler model of beer, yeast
      fermented glucose solution (11.5% w/v) was also studied and compared with
      unfermented glucose (11.5% w/v). Among the control solutions, the two glucose
      solutions, but not water, significantly (P < 0.05) increased the 150-min
      integrated trypsin and amylase output over basal levels. Beer and fermented
      glucose caused a significantly higher increase in trypsin and amylase output
      compared to water or glucose. Ethanol (4% v/v) failed to stimulate pancreatic
      enzyme output. Fermented glucose and beer, but not the control solutions,
      significantly increased plasma gastrin levels above basal values. Isotonic and
      hypertonic glucose, beer, and fermented glucose significantly increased plasma
      levels of cholecystokinin (CCK), but the effect was significantly higher after
      hypertonic glucose than after isotonic glucose, beer, or fermented glucose.
      Ethanol and water had no effect on plasma levels of gastrin and CCK. We conclude
      that: (1) in the doses studied intragastric beer and fermented glucose but not
      ethanol (4% v/v) stimulate pancreatic enzyme output and release of gastrin and
      CCK; (2) the lack of effect of ethanol indicates that nonalcoholic ingredients of
      beer and fermented glucose are responsible for this stimulatory effect; and (3)
      CCK could be one of the major mediators of the stimulation of pancreatic enzyme
      output after ingestion of beer and fermented glucose.

PMID- 8654157
TI  - Pancreatic arteriovenous malformation with duodenal ulcer. Demonstration by color
      Doppler ultrasonography.
AB  - We report the color Doppler ultrasonography features of arteriovenous
      malformation (AVM) of the pancreas, a very rare disease. The patient was a 52
      year-old man with congenital AVM of the pancreas and a duodenal ulcer that had
      been resistant to medication. Endoscopic color Doppler ultrasonography (color
      Doppler EUS) revealed many abnormal color signals showing pulsatile wave form at
      the portion of the duodenal wall involving the duodenal ulcer. Extracorporeal
      color Doppler ultrasonography revealed a mosaic-like color signal, caused by
      turbulent flow, in the portal trunk. Angiography demonstrated a vascular network
      with extensive proliferation at the pancreatic head and early portal filling. It
      is possible that the pancreatic AVM had caused the duodenal ulcer. Color Doppler
      EUS can be a useful modality for detection of vessel abnormalities of the
      gastrointestinal tract.

PMID- 8654156
TI  - Deficiency in antioxidant factors in patients with alcohol-related chronic
      pancreatitis.
AB  - Free radicals have been suspected to play a role in the pathogenicity of alcohol
      related chronic pancreatitis. The aim of this study was to determine the status
      of several antioxidant parameters in these patients and examine the factors that
      are likely to influence them. Thirty-five subjects (23 males and 12 females, mean
      age 48 +/- 8 years) with disease proven by endoscopic pancreatography and 14
      healthy controls (6 males and 8 females, mean age 44 +/- 7 years) were included
      in the study. Biochemical antioxidant parameters included: selenium, zinc, and
      copper levels in plasma; glutathione peroxidase in plasma and erythrocytes;
      plasma malondialdehyde concentrations assessed by thiobarbituric acid reactants;
      and serum vitamin E and A levels. Selenium and vitamin E oral intake was assessed
      by a five-day diet analysis. Hemoglobin (130 +/- 16 vs 143 +/- 15 g/liter),
      vitamin E (8 +/- 5 vs 16 +/- 9 mg/liter), vitamin A (30 +/- 11 vs 49 +/- 12
      micrograms/dl), selenium (54 +/- 20 vs 87 +/- 11 micrograms/liter), and plasma
      glutathione peroxidase (903 +/- 313 vs 1326 +/- 168 units/liter) were
      significantly lower in patients than in controls (P < 0.05). In contrast, white
      blood cell count, C-reactive protein, and plasma copper levels were significantly
      higher in patients than in controls. Cholesterol, triglycerides, iron, ferritin,
      total proteins, zinc, and malondialdehyde were not different. Vitamin E was lower
      in patients with steatorrhea, while vitamin A was lower in patients with
      concomitant diabetes mellitus. Dietary intakes were not different between
      patients and controls. In conclusion, patients with alcohol-related chronic
      pancreatitis have low blood levels in many antioxidant factors. Dietary intakes
      of some of them (selenium and vitamin E) are adequate, however. Such deficiencies
      are secondary to pancreatic insufficiency and probably to increased requirements
      related to enhanced oxidative stress.

PMID- 8654158
TI  - Heterotopic pancreas. A difficult diagnosis.
AB  - Heterotopic pancreas is seen in one of every 500 laparotomies or 0.55-13% of
      autopsies. Despite modern diagnostic procedures (endoscopy, endoscopic
      ultrasound) it is difficult to diagnose preoperatively. A 51-year-old patient
      with a 30-year history of recurrent gastric ulcers was diagnosed with a gastric
      wall tumor. Endoscopic biopsy sample showed normal gastric mucosa. Endoscopic
      ultrasound and contrast radiography were not able to specify the gastric wall
      tumor. The local excision and histologic preparation of the tumor showed
      heterotopic pancreatic tissue within the gastric submucosa without any signs of
      malignancy. Three years postoperatively the patient is without any complaints.
      There have been no further signs of gastric ulcers.

PMID- 8654159
TI  - Alpha but not beta interferon is useful in chronic active hepatitis due to
      hepatitis C virus. A prospective, double-blind, randomized study.
AB  - Interferon-alpha has been widely used in chronic hepatitis C, but controlled
      studies with intramuscular interferon-beta are lacking. We therefore performed a
      prospective, double-blind, randomized study comparing intramuscular IFN-alpha and
      -beta in patients with chronic hepatitis C. Sixty patients were randomly assigned
      to receive 3 MU thrice weekly intramuscularly of either recombinant IFN-alpha or
      leukocyte IFN-alpha or fibroblast IFN-beta for six months. Nine of 20 patients
      (45.0%) in the recombinant IFN, 5/19 (26.3%) in the leukocyte IFN, and none in
      the IFN-beta group had a complete response during therapy (recombinant IFN vs IFN
      beta: P < 0.01). Only in IFN-alpha-treated patients, was infection with a single
      HCV genotype (type 2a or 2b) associated with significantly better long-term
      outcome. IFN-alpha is useful in chronic hepatitis C while intramuscular IFN-beta
      interferon does not exert any beneficial effect. This is probably due to an
      insufficient bioavailability of IFN-beta when given intramuscularly.

PMID- 8654161
TI  - Preferential virological response to interferon-alpha 2a in patients with chronic
      hepatitis C infected by virus genotype 3a and exhibiting a low gamma-GT/ALT
      ratio.
AB  - Hepatitis C virus infection causes acute and often chronic hepatitis. Therapy
      with interferon-alpha has been shown to induce remission of the inflammatory
      process within the liver and also elimination of the virus. However, only about
      50% of treated patients respond in terms of at least a transient disappearance of
      viral RNA from the circulation below the limit of detection. In order to find
      prognostic factors for responsiveness, patients with chronic hepatitis C virus
      infection were analyzed for virus genotype and pretreatment biochemical liver
      parameters including serum AST, ALT, and gamma-GT activities. Whereas the initial
      biochemical response to interferon-alpha 2a was found not to be related to virus
      genotype, the initial virological response was found to be closely related to
      infection by genotype 3a and to a low pretreatment ratio of serum gamma-GT/ALT
      activity. These data confirm and extend the importance of virus genotype for
      responsiveness to interferon-alpha therapy and introduce an additional, host
      specific parameter with a potential predictive value, namely the pretreatment
      ratio of serum gamma-GT/ALT activity.

PMID- 8654160
TI  - Interferon as treatment for acute hepatitis C. A meta-analysis.
AB  - The efficacy of short-course (three months), low-dose (3 million units three
      times a week) interferon as treatment for acute hepatitis C was evaluated in a
      meta-analysis of controlled trials. Nine studies (five randomized and four
      nonrandomized) found by MEDLINE search were eligible for analysis. The outcomes
      assessed were the rate of patients with normal serum aminotransferases (all
      trials) and without HCV RNA in blood (five trials) after posttreatment follow-up.
      Eight trials compared interferon to no treatment, and one compared different
      schedules of interferon. The methodological quality of the studies was high.
      However, all trials had been planned for a short-term evaluation based on
      biochemical and virological outcomes alone. Significant differences were observed
      between interferon and control groups for both the assessable end points. Overall
      rate differences were +0.31 (P < 0.0001; 95% confidence interval +0.20 to +0.41)
      for aminotransferases normalization and +0.44 (P < 0.0001; 95% confidence
      interval +0.33 to +0.56) for HCV RNA clearance. In conclusion, a short course of
      low-dose interferon administered to patients with acute hepatitis C is
      significantly more effective than no treatment in obtaining viral clearance and
      normal aminotransferases 12 months after stopping treatment. Further long-term
      prospective cohort studies assessing outcomes of clinical relevance (ie, the rate
      of chronicity of infection and disease) are necessary before recommending
      interferon for acute hepatitis C.

PMID- 8654162
TI  - Effect of human immunodeficiency virus infection on hepatitis C virus infection
      in hemophiliacs.
AB  - Chronic liver disease due to hepatitis C virus (HCV) infection is a major problem
      in hemophiliacs. Recent reports suggested that hemophiliacs coinfected with
      hepatitis C virus and human immunodeficiency virus (HIV) have an increased
      incidence of liver failure but the mechanism of accelerated liver injury is not
      clear. We tested plasma from 100 hemophiliacs for anti-HCV by second generation
      ELISA, anti-HIV by EIA, and HCV RNA and HIV RNA by branched DNA and polymerase
      chain reaction assays to determine if hemophiliacs coinfected with HCV and HIV
      have higher HCV RNA levels and more active liver disease. Seventy-nine (79%)
      patients were anti-HCV positive, of whom 85% were HCV RNA positive. None of the
      anti-HCV-negative patients had detectable HCV RNA in plasma. Forty-two (42%)
      patients were anti-HIV positive, of whom 47% had detectable HIV RNA. All the anti
      HIV-positive patients were also anti-HCV positive. The prevalence of both anti
      HCV and anti-HIV increased significantly with age. There was no difference in HCV
      RNA levels between anti-HIV-positive and anti-HIV-negative patients (mean: 21 +/-
      4 vs 18 +/- 5 Meq/ml), although HCV RNA levels were significantly higher in anti
      HIV-positive patients with CD4 counts < 200/mm3 (P = 0.008). There was an inverse
      correlation between HCV RNA levels and CD4 counts but no correlation was found
      between HCV RNA and serum aminotransferase levels. We found a high prevalence of
      HCV and HIV coinfection in our hemophiliacs. Hepatitis C virus replication
      appears to be increased in patients with severe immunodeficiency secondary to
      progressive HIV infection. However, there was no correlation between HCV RNA and
      serum ALT level, suggesting that HCV is not directly cytopathic.

PMID- 8654163
TI  - Successful empiric treatment of HSV hepatitis in pregnancy. Case report and
      review of the literature.

PMID- 8654164
TI  - Effect of ursodeoxycholic acid on HCV replication in subtyped chronic hepatitis
      C.

PMID- 8654165
TI  - [Prevalence of Cryptosporidium sp and Isospora belli in patients with acquired
      immunodeficiency syndrome (AIDS) in Dakar (Senegal].
AB  - 72 patients with AIDS, having diarrhoea and admitted in the Unit of Infectious
      diseases, Fann Hospital from 1989 to 1991 were investigated for Cryptosporidium
      sp. and Isospora belli isolation by the modified Ziehl-Neelsen technique, after
      stolls' concentration by Ritchie technique. The prevalence were 13.9% for
      Cryptosporidium sp, and 15.3% for I. belli. In two patients (2.8%), these 2
      coccidiae were associated. Cryptosporidium sp. and I. belli were the single
      parasites found respectively in 6 (8.3% and 7 (9.7%) of the patients. In the
      other faecal samples with a positive result for Cryptosporidium sp. or I. belli,
      they were associated with A. lumbricoides, G. intestialis, E. histolytica or S.
      stecoralis. According to these results, Cryptosporidium sp. and I. belli were
      more frequently observed in AIDS patients from Dakar than those from Zaire, Congo
      and Cote d'Ivoire.

PMID- 8654166
TI  - [Purgative activity of Cassia italica].
AB  - Twenty guinea pigs were used to study the effects of Cassia italica leaves and
      pods extracts on intestinal motricity in vitro. The results obtained showed that
      the plant stimulate intestinal contractions with dose-dependent relation.
      Moreover, Cassia italica contractile activity was comparable to the acetylcholine
      one and was inhibited by atropine. According to these results, Cassia italica
      purgative activity is supported at least, by it's stimulating effect on
      intestinal motricity.

PMID- 8654168
TI  - [Embryo transfer in a Senegal village environment].
AB  - This study aims to identify the embryo transfer constraints and production costs
      at a village level in the district of Kolda (Senegal). Fifteen (15) donors cows
      were superovulated using 2500 UI PMSG (group A n = 8), 32 mg of FSH (group B n =
      3) and 36 mg of FSH (group C n = 4). The average number of yellow bodies that
      were palpated was 5.06 and the mean rates of collected embryos were 5.66 for
      group A, 2.5 for group B and 3.3 for group C. The average transferable embryos
      were 2.33 for group A, 0 for group B and 1.4 for group C. The identified
      constraints are nutritional, healthy, social and logistic nature. The average
      cost of a produced and transferred embryo amount respectively to 75.940 F CFA and
      99310 F CFA. Embryo transfer can fit in with a dairy production development plan
      in Senegal.

PMID- 8654167
TI  - [Control of reproduction in the female Ndama cow by Norgestomet (CRESTAR)].
AB  - The purpose of this experiment was to test the efficiency of the Norgestomet
      CRESTARND on 91 Ndama cows living in three different ecological zones. The
      results of the experiments showed an average rate of heat synchronisation of
      97.8%, an average heat time of 10.17 +/- 2.81 h with the intensity of these heat
      being essentially low or medium levels. The heats also occurred of mostly during
      the night. The time lag between the PGF2 alpha injection and the first signs of
      oestrus was 83.96 +/- 14.96 h and the one between removing the implant and the
      first heats was 34.78 +/- 14.9 h and the average blood's level of progesterone
      was 5 +/- 10.3 ng/ml. The efficiency of CRESTARND in the control of the sexual
      cycle of the Ndama cows was demonstrated by this study.

PMID- 8654169
TI  - [Frontal sinus mucoceles apropos of 35 cases].
AB  - 35 cases of frontal sinus mucoceles treated from 1977 to 1991 are reported. The
      average of age was 41 years with 74% of men. The clinical presentation was a
      frontal or fronto-orbital pyocele in 40% of the cases, with palpebral fistula in
      11 cases; one patient had visual loss. Unilateral exophtalmos was the initial
      complaint among five patients (14%). Surgical treatment, surrounded by massive
      antibiotherapy, required always curettage and aeration of the sinus by
      desobstruction of the nasofrontal duct and insertion of a tube in the duct to the
      nasal cavity. Exenteration was mandatory in one patient. Failure was due to
      recurrence in 3 cases. The gravity of paranasal sinuses mucoceles prescribe a
      correct evaluation of their usual predisposing factors.

PMID- 8654171
TI  - [Medico-social problems of young adolescents in Guediawaye (suburban area of
      Dakar-Senegal)].
AB  - A survey in the district of Guediawaye, towards teenagers from 12 to 16 years
      old, recruited according to a stratified risky method of sampling in 4 different
      areas has been carried out in order to evaluate their main medico-social
      problems. It ended up to the following findings: the majority live in hard socio
      economic conditions stamping by promiscuity, a weak family income and a low level
      of education of the parents. 39.2% have been placed under the guardianship of a
      relative other than the parents. 98.8% do not find spare time structures in their
      environment. The usage of tobacco and drug is respectively 14% and 1%; 79.4% of
      students have hardly access to the school stationery, while the teenagers in job
      apprenticeship have constraints linked to long hours of work (95%). The morbid
      affections are too varied, dominated by stomach aches (37.8%) far before
      traumatics (6%); the most frequent therapeutic is resort traditional or empiric
      treatment. The authors advocate the setting up of a medico-social center making
      interfere all persons, implied resources in the undertake of the teenagers.

PMID- 8654170
TI  - [Ocular hypertension after intra-capsular cataract extraction].
AB  - During 20 months, 593 intracapsular cataract extractions have been studied, the
      authors founded 10 cases of ocular hypertension representing 1.68%. These eyes
      did not present any ocular pathology before and the intraocular pressure was
      normal before the operation. Among the 10 cases, 4 developed pupillary block. In
      7 cases, the intraocular pressure was normalized within one month by local and
      general low pressure treatment, while 3 cases developed persistent ocular
      hypertension. The authors preconise to have a low pressure by premedication
      before surgery and to survey every day the intraocular pressure after
      intracapsular cataract extraction to prevent irreversible modifications of the
      optic nerve.

PMID- 8654172
TI  - [Effects of cholestatic bile acids on cytosolic calcium in isolated intrahepatic
      biliary cells].
AB  - In this study we measured biliary cytosolic calcium and examined the effect of
      cholestatic bile acids LCS and TLCS on intrahepatic isolated biliary cells
      cytosolic calcium. Cells have been isolated from bile duct ligated rats.
      Cytosolic calcium has been measured by using the Ca++ sensitive indicator Fura 2
      and a cytofluorimetric method. LCS and TLCS (200 microM and 300 microM) increased
      the cytosolic Ca++ concentration of the cells. In contrast, the bile acids
      cholate and urso-desoxycholate which are choleretic had no effect. The number of
      cells which have increased their cytosolic calcium was directly correlated with
      the biliary acid toxicity. The increase induced by LCS and TLCS was abolished by
      removing external calcium. It is suggested that the calcium increase results from
      external calcium influx. This cytosolic calcium increase is known to be toxic for
      cells so it is concluded that this calcium increase is probably involved in the
      toxicity of LCS and TLCS.

PMID- 8654173
TI  - [Intrauterine and extrauterine pregnancy association: apropos of 2 cases in
      gynecological and obstetrical clinical medicine].
AB  - The authors reviewed two cases of extra-uterine and intra-uterine pregnancies
      association. The frequency was higher than people expect. The diagnosis, usually
      done after surgery because of a very poor symptomatology, should benefit to the
      precious help of echography to make the prognosis better.

PMID- 8654174
TI  - [Paroxystic complications in vasculo-renal syndromes during pregnancy and
      puerperium at the CHU of Dakar].
AB  - In a comparative study issued in 1989 in Gynecology in Dantec (a Medical Hospital
      School) in Dakar (Senegal), the authors made a retrospective analysis of 206
      cases of abruptio placenta (3.3%) and 56 cases of eclampsia (0.9%). After a
      physiopathologic overview of the vascular renal syndromes, they point out the
      risk factors of paroxistic accidents represented mainly by the age and the
      parity, knowing that young age and primiparity appear as new risk factors for
      abruptio placenta. Finally, they insisted on the prevention of these accidents
      because of their impact on fetal and maternal mortalities.

PMID- 8654176
TI  - [Purulent pleurisy in the child].
AB  - We studied 122 cases of empyema in children. The mean age was 3 years. We found
      malnutrition in 33% of the patients. 60% of them had large pleural effusion and
      56% associated pneumonia. Staphylococcus aureus (51%) and Streptococcus
      pneumoniae (18%) were the most frequently isolated bacterias in pleural fluid.
      The mortality rate was 6.5%. 53% of the children had closed chest tube drainage.
      There were minor abnormalities in pulmonary function tests. The best treatment of
      empyema in children is closed chest tube drainage and an antimicrobial therapy
      with antistaphylococcus antibiotic.

PMID- 8654175
TI  - [Cervical adenophlegmon (apropos of 57 cases)].
AB  - Neck adenitis remain a frequent occurrence in our areas. Within one year only, 57
      cases were collected in the ORL department of University Hospital of Ouagadougou.
      Children were mostly affected (70% of cases) and the starting point or supposedly
      was mainly pharyngeal (67% of cases); streptococcus were the dominant microbes.
      Concerning the treatment, our preference was for wide antibiotherapy, in
      monotherapy but using wide spectrum, including staphylococcus aureus, due to its
      frequency in this pathology. But the primum movens remained the incision
      drainage. The post-operative period were regularly simple for our 57 patients.

PMID- 8654177
TI  - [Clinical aspects of Takayasu's disease: apropos of 4 cases].
AB  - We reported four cases of Takayasu's arteritis cases. Hypertension in only one
      arm was found in three of them. The other one were a reversed coarctation of the
      aorta. Diagnosis was made by clinical examination, vascular Doppler Echography,
      and, in one case, arteriography. Thus, were examined the etiology of this
      disease, it might probably due to tuberculosis, the outcome and therapy problems
      at the occlusive stage.

PMID- 8654178
TI  - [Biometric aspects of the lumbar canal in Senegalese of the African negro race
      (apropos of 21 autopsy parts)].
AB  - Because of frequency and seriousness of myelo radicular complications of narrow
      lumbar canal, the authors studied its radiological and anatomical measurements in
      order to specify the standards for senegalese negro african. For that purpose,
      they collected samples of 21 lumbosacral spines from new cadavers through medico
      legal necropsies. Pieces have been first X rayed, then treated. They measured the
      antero posterior diameter of vertebral corpse, the anterio posterior diameter of
      vertebral canal, the narrowest transversal diameter of vertebral corpse and the
      inter pedicular distance. The authors found no significant differences between
      radiological and anatomical measurements, but the latest changed from one stage
      to another. The variations also were not important comparatively to standards
      established by two authors.

PMID- 8654179
TI  - [Lumbar canal stenosis: apropos of 64 cases collected at the neurosurgical clinic
      of the CHU of Dakar].
AB  - From 1980 to 1990, 64 cases of Lumbar canal Stenosis have been recorded and
      operated on at the neurosurgical clinic. The male sex is prevailing and the
      breakdown by age groups showed a preponderance of the age sections between 31 and
      45 and 46 and 60 years. The sciatic pain was the most frequent starting symptom.
      As far as the physical signs are concerned, the areflexy of the tendon
      predominates. The saccoradiculography has established the diagnosis in most of
      the cases. The laminectomy associated with another technique has permitted to
      obtain the best result of the treatment. With the advent of the T scan, a better
      estimation of the lumbar canal will be possible, so as to replace the laminectomy
      by a more adaptable technique: the remeasurement of the lumbar canal.

PMID- 8654180
TI  - [Pupillary blockage after intracapsular cataract extraction in the adult apropos
      of 4 cases].
AB  - Intra capsular extraction is the most employed surgical technics for the
      treatment of senile cataract in developing countries. Nevertheless complications
      are usual, among them the pupillary block. The authors notified in 365 intra
      capsular cataract extractions, executed during 8 months, 4 cases of pupillary
      block occurred after operation without incident. The 3 cases had favorable
      evolution after an average of 4 days with medical treatment. 1 case had
      unfavorable evolution to aphakic glaucoma in spite of medical and surgical
      treatment. They point out in the necessity of strict post operative supervision
      and early treatment.

PMID- 8654181
TI  - [Anatomo-clinical study of chronic gastritis in Mali].
AB  - The aim of our study was to evaluate the frequency of chronic gastritis and its
      anatomoclinical aspects in Mali. Within thirteen months of prospective study, we
      have recorded seventy four chronic gastritis histologically confirmed which
      represented 3.28% of the total oesogastroduodenal pathologies registered during
      the same period (2256 cases). Chronic gastritis has been most observed between 31
      to 40 years (24.3%) and women were affected (sex ratio = 0.6). Households and
      civil servants were predominant. The precocious burning epigastralgy just after
      the meal was the main motive of the examination and chronic gastritis has been a
      fortuitous discovery. The basic alimentation included smoked or dried fish,
      peanuts, "to" and salt. The most frequent endoscopic aspect was the congestive
      one. The duodenogastric reflux was not negligible. The diffuse form and antral
      localisation were more frequent. Five displasiae and four intestinal metaplasiae
      have been found.

PMID- 8654182
TI  - [Folliculogenesis and endocrinology of superovulated Gobra cow].
AB  - During a study of folliculogenesis and progesterone profile in superovulated
      Gobra cows, the authors have superovulated 2 groups of 3 cows each, the first one
      with 32 mg of FSH during 4 days and the second with 2500 UI of PMSG. The
      reference heats observed with all six cows were obtained with Norgestomet
      implants. Superovulation responses were better with PMSG. The follicle dynamics
      observed with echography was stronger with PMSG compared to FSH. The progesterone
      profile had a variation inverse to follicle growth.

PMID- 8654183
TI  - [Artificial depigmentation practice of the skin in women of Dakar and analytical
      study of the cosmetic products used].
AB  - This survey which involved 6 salesman and 159 women, allowed us to carry out a
      study on the different cosmetic products used by women in Dakar to artificially
      bleach their skin. An analytical study has been conducted on those skin bleaching
      products through colorimetric identifications of hydroquinone, corticoids and
      mercurial derivates and the dosage of hydroquinone by High Performance Liquid
      Chromatography (HPLC). It was established that those products were essentially
      corticoids and hydroquinone based products and could induce serious
      dermatological troubles to users. This phenomenon, known in Wolof "xessal", and
      motivated by various factors, is facilitated by easy access to skin bleaching
      products available in the town market places. It affects an important part of the
      female population of all ages (educated, illiterate, married and single). In view
      of the importance of the phenomenon, emergency actions must be taken to eradicate
      it.

PMID- 8654184
TI  - [ Dietary intake of fluorine through of tea prepared by the traditional method in
      Senegal].
AB  - The consumption of tea in Senegal is known and called "trois normaux". The use of
      Thea sinensis as drink many times per day with a lot of sugar, may cause some
      public health problems. In the aim to face that situation, we have analysed the
      fluor level in the available tea samples in the senegalese market in respect of
      the ways of the preparation. The fluor level has been analysed by ionometric
      specific electrode. The concentrations were from 3.8 to 6.1 mg/l in the infusion
      and from 11.1 mg/l in the decoction. These results showed that the tea plant
      contain a high concentration of fluoride. In addition, the level of fluoride may
      be higher, when the water drink itself is rich in fluoride.

PMID- 8654185
TI  - [Cardiovascular manifestations of Marfan's syndrome apropos of 6 cases].
AB  - We reported six patients with Marfan's syndrome, studied retrospectively from May
      1990 to April 1992 in the department of Cardiology in Dakar. Morphological,
      cardiovascular, skeletal and ocular abnormalities have been reviewed. All the
      patients had been evaluated by echocardiography. Prevalence of Marfan's syndrome
      among congenital heart diseases during this period was 4.8%. The mean age was
      27.6 years. The mean height was 1.80 m (range 1.38-2.02 m) for a mean weight of
      62.8 kg. All the patients had dolichostenomely and arachnodactyly. Kyphosis or
      scoliosis was present in 5 cases. Chest deformities (pectus carinatum and
      excavatum) were present in 5 cases. 5 patients had hyperextensible joints. 5
      patients had ocular abnormalities. Cardiac pathology was found in 5: mitral
      prolapse with insufficiency in 2; mitral prolapse with aortic dystrophy in 2; and
      isolated dilatation of ascending aorta in an other. One patient with diffuse
      Marfan's syndrome died of cardiac failure. Our study confirm polymorphic
      manifestations of Marfan's syndrome and the frequency of cardiac abnormalities
      which are the major determinants of life-prognosis in these patients.
      Echocardiography is very useful as a noninvasive method for defining the extent
      of cardiovascular involvement and following its course, for more appropriate
      treatment.

PMID- 8654186
TI  - Use of gender and oxygenation as synonyms for sex and oxidation.

PMID- 8654187
TI  - Species similarities and differences in pharmacokinetics.
AB  - One of the fundamental challenges drug metabolism scientists face in drug
      discovery and development is the extrapolation of metabolic data and risk
      assessment from animals to humans. Although it is generally believed that data
      from animal studies can be reasonably extrapolated to humans with the application
      of appropriate pharmacokinetic principles, there are certainly some limitations.
      The purpose of this review is to show some species similarities and differences
      in absorption, distribution, metabolism, and excretion, with an attempt to
      address the questions of whether animal data can be extrapolated and what the
      limitations are. The underlying mechanisms responsible for these similarities and
      differences are discussed and examples given for illustration. In addition, the
      concepts of allometric and physiological models for extrapolation of kinetic data
      are briefly highlighted. In conclusion, although pharmacokinetics has been
      advanced greatly in recent years, it is not yet possible to predict all of the
      pharmacokinetic parameters of a drug in humans from animal studies. Nevertheless,
      under certain well-defined conditions, it may be possible to make reasonably good
      predictions. For example, the intrinsic absorption of a given drug across the
      wall of the gastrointestinal tract is probably similar among species, because the
      nature of the biomembrane of epithelial cells is similar in mammals and because
      the absorption process is basically an interaction between the drug and the
      biomembrane. However, other factors, such as pH-dependent solubility and first
      pass metabolism that affect the absorption, may differ from species to species
      resulting in species differences in absorption. Predicting the renal excretion of
      drugs in humans has been relatively successful using the glomerular filtration
      rate ratio between humans and animals. Similarity, if the elimination of a drug
      is mainly by the liver and the rate of elimination is limited by hepatic blood
      flow, one could predict the clearance of the drug in humans by the hepatic blood
      flow. However, biochemical parameters, such as protein binding and drug
      metabolism, are less predictable. These parameters vary considerably among
      species.

PMID- 8654188
TI  - Interindividual variation in carboxylesterase levels in human liver microsomes.
AB  - Microsomal carboxylesterase activities in 12 human livers were determined using
      10 kinds of carboxylesterase substrates (p-nitrophenylacetate, p
      nitrophenylpropionate, p-nitrophenylbutyrate, butanilicaine, isocarboxazid,
      palmitoyl-coenzyme-A, malathion, clofibrate, acetanilide, and phenacetin). There
      were large individual differences in the 12 humans based on experimental results
      in the past several years in our laboratory. We found that all human liver
      microsomes have RH1-immunoreactive carboxylesterase, and the carboxylesterase
      content in liver also showed large individual differences. The RH1-immunoreactive
      carboxylesterase concentration correlated well with those of p-nitrophenylesters,
      clofibrate, butanilicaine, and isocarboxazid, and anti-RH1 immunoglobulin G
      strongly inhibited human liver hydrolase activity. These findings indicate that
      one major carboxylesterase isozyme that is immunoreactive with anti-RH1 in human
      liver microsomes has catalytic activity on major carboxylesterase substrates, and
      thus hydrolase activity in human liver depends on the expression level of this
      carboxylesterase isozyme. These observations should be useful in understanding
      the action of carboxylesterases on drug metabolism in humans.

PMID- 8654189
TI  - Preclinical pharmacokinetic evaluation of the respiratory syncytial virus
      specific reshaped human monoclonal antibody RSHZ19.
AB  - A preclinical evaluation of RSHZ19, a respiratory syncytial virus-specific
      reshaped human monoclonal antibody (IgG1 framework), has included pharmacokinetic
      studies in rats, adult cynomolgus macaques, and infant baboons after intravenous
      (iv), subcutaneous, or intramuscular (im) administration. After iv administration
      to rats and monkeys (1 mg/kg dose), a biphasic decline in plasma concentration
      was observed. The dominant terminal phase was characterized by an 11-day half
      life in rats and a 21- to 24-day half-life in monkeys. Plasma clearances of 0.3
      ml/hr/kg in the rat and 0.1-0.2 ml/hr/kg in the monkey were estimated. In the
      macaque, based on area under the curve, no evidence of significant nonlinearity
      in the pharmacokinetics was observed over a 200-fold dose range (1-200 mg/kg). In
      rat and monkey, absorption after extravascular administration was rapid relative
      to elimination (apparent half-lives < or = 24 hr), and bioavailability was high
      (> or = 82%). After iv or im administration to macaques (> or = 40 mg/kg), 1 of 3
      animals in each group developed anti-RSHZ19 antibodies, and this resulted in
      rapid elimination of RSHZ19 from plasma. After the administration of a second im
      dose to macaques, no additional animals developed anti-RSHZ19 antibodies.
      Multiple-dose iv kinetics (5-day repeat dose) in infant baboons were modeled
      accurately by adult macaque data, suggesting that these species handled RSHZ19
      similarly. The pharmacokinetic characteristics of RSHZ19 should support a
      convenient regimen for treatment or prophylaxis of human respiratory syncytial
      virus infection.

PMID- 8654190
TI  - Human liver lauric acid hydroxylase activities.
AB  - Nine male and five female human liver microsomal sample were examined for laurate
      11- and 12-hydroxylase activities. The mean specific activities for the 11- and
      12-hydroxylation reactions were 0.78 +/- 0.33 and 1.07 +/- 0.12 nmol/min/mg
      protein, respectively. Antibody inhibition experiments, using a polyclonal
      antibody to a cytochrome P450 (P450) isolated from diethylhexyl phthalate-treated
      rats, which recognizes forms P4504A1, P4504A2, and P4504A3 of the rate, inhibited
      the 12-hydroxylase activity by 65%, but did not affect 11-hydroxylase activity.
      Western-blot analyses of the 14 human liver microsomal samples identified one
      major protein band at 52 kDa that comigrated with human form 4A11. A correlation
      coefficient of only 0.19 was calculated when comparing laurate 12-hydroxylase
      activities and the densitometric values of the immunochemically reactive protein
      bands in the human liver microsomal samples, which strongly suggests that
      additional P450 forms also support the 12-hydroxylation of lauric acid. Laurate
      11-hydroxylase activity was inhibited by diethyldithiocarbamate, an inhibitor of
      P4502E1-mediated reactions, and by chlorzoxazone, a P4502E1 substrate. A
      comparison of laurate 11-hydroxylase activities with densitometric values of the
      P4502E1 protein bands indicated a strong correlation existed (0.82). An analysis
      of microsomal samples containing expressed human forms P4501A2, P4502A6, P4502C8,
      P4502C9, P4502D6, P4502E1, and P4503A4 showed that only form P4502E1 supported
      the 11-hydroxylation reaction.

PMID- 8654191
TI  - Renal catabolism of recombinant human soluble CD4 after intravenous
      administration to male Sprague-Dawley rats.
AB  - Recombinant soluble CD4 (sT4; mol. wt. 45,000) has been studied extensively in
      Sprague-Dawley rats, and substantial renal processing has been indicated. In rats
      and monkeys, renal filtration and precipitation of sT4 in the distal nephron
      caused tubular cast nephropathy. Intravenous pharmacokinetics in the rat
      demonstrated that sT4 plasma clearance exceeded the glomerular filtration rate.
      In an effort to determine quantitatively the extent to which kidney and other
      tissues were responsible for sT4 catabolism, sT4 was labeled with trace amounts
      of dilactitol-[125I]tyramine and administered intravenously to Sprague-Dawley
      rats (1 mg/kg). Dilactitol-tyramine accumulates in lysosomes at the site of
      protein degradation. It has been used primarily to demonstrate hepatic catabolism
      of endogenous proteins. Blood samples were drawn for pharmacokinetic analysis,
      and selected tissues were removed to assess radiolabel distribution. Comparison
      of pharmacokinetic parameters derived from total plasma radiolabel and functional
      ELISA were not significantly different. Thus, covalent modification of sT4 with
      dilactitol-tyramine did not appreciably change the rate of clearance. From 3 to
      24 hr after intravenous administration, 81.5 +/- 0.1% of the total administered
      radioactivity was found in the kidney. Approximately 8-13% of the administered
      dose was recovered in the liver. Macroscopic autoradiography of the kidney
      demonstrated accumulation of radiolabel in the cortex. Light microscopic
      autoradiography of the kidney following intravenous administration of directly
      radioiodinated sT4 confirmed cortical processing, because radiolabel was located
      primarily in epithelial cells of P1 and P2 segments of the proximal tubule after
      low intravenous doses (0.4-4 mg/kg). At 40 mg/kg, distal tubules and cortical
      collecting ducts were labeled as well. Thus, sT4 was filtered by the glomerulus,
      reabsorbed in the proximal tubule, and degraded in the lysosomal compartment.

PMID- 8654192
TI  - Metabolism of mofarotene in hepatocytes and liver microsomes from different
      species. Comparison with in vivo data and evaluation of the cytochrome P450
      isoenzymes involved in human biotransformation.
AB  - The arotinoid mofarotene is a novel potent anticancer compound. The metabolic
      profiles obtained from rat, dog, and human plasma showed a good correlation with
      the corresponding in vitro profiles observed with liver microsomes and
      hepatocytes. Interspecies differences in its metabolism were investigated using
      microsomes prepared from the livers of the mouse, rat, dog, cynomolgus monkey,
      and humans. These in vitro experiments showed that, both qualitatively and
      quantitatively, the metabolic profiles obtained with cynomolgus monkey liver
      samples were similar to those observed with human liver material. However, rat
      and dog were also confirmed to be suitable species for assessing the safety of
      mofarotene, and were used in toxicology. The involvement of cytochrome P450 (CYP)
      in the metabolism of mofarotene was examined with human liver microsomes. CYP3A4
      plays a major role in the metabolism, and CYP1A2 might be responsible for a minor
      pathway. Finally, the potential induction by mofarotene of four major CYP
      isoenzymes was investigated in rats. These experiments showed that CYP1A1 was
      clearly induced, whereas a slight induction of CYP3A and CYP2B was observed.
      Repeated administration of mofarotene had no effect on CYP2E1. These studies with
      liver microsomes and hepatocytes aided the selection of appropriate species for
      toxicology, and have provided information that will help to predict potential
      drug-drug interactions in clinical trials.

PMID- 8654193
TI  - Xenopus laevis: a model system for the study of embryonic retinoid metabolism.
      III. Isomerization and metabolism of all-trans-retinoic acid and 9-cis-retinoic
      acid and their dysmorphogenic effects in embryos during neurulation.
AB  - These investigations provide data pertaining to the metabolism and disposition of
      exogenous 9-cis-retinoic acid and all-trans-retinoic acid during neurulation in
      Xenopus embryos. Each isomer elicited malformations of the heart, eye, and brain,
      but approximately 2-fold higher concentrations of all-trans-retinoic acid than 9
      cis-retinoic acid were required to produce qualitatively and quantitatively
      similar dysmorphogenic effects. The dymorphogenic effects of all-trans-retinoic
      acid could not be attributed to the isomerization of all-trans-retinoic acid to 9
      cis-retinoic acid. Evidence is provided that all-trans-retinoic acid and 9-cis
      retinoic acid are both direct-acting dysmorphogens. After Xenopus embryos were
      exposed to all-trans-retinoic acid, elevated levels of 4-oxo-all-trans-retinoic
      acid, 4-oxo-13-cis-retinoic acid, all-trans-retinoyl-beta-glucuronide, and 13-cis
      retinoic acid were detected in the embryos, whereas embryonic levels of 9-cis
      retinoic acid were actually slightly lower than endogenous levels during early
      neurulation. After embryos were exposed to 9-cis-retinoic acid during
      neurulation, elevated levels of 4-oxo metabolites, glucuronides and 9,13-di-cis
      retinoic acid were observed in the embryos. At equivalent concentrations, 4-oxo
      13-cis-retinoic acid and 13-cis-retinoic acid elicited fewer severe multiple
      malformations than all-trans isomers 9,13-di-cis isomers, or 9-cis isomers. The
      dysmorphogenic effect of 9,13-di-cis-retinoic acid may be caused by its
      isomerization to 9-cis-retinoic acid. All-trans retinoyl-beta-glucuronide was
      only marginally teratogenic at the highest concentrations tested.

PMID- 8654194
TI  - Microdialysis sampling for hepatic metabolism studies. Impact of microdialysis
      probe design and implantation technique on liver tissue.
AB  - Microdialysis sampling of liver tissue was performed using several probe
      geometries. The extent of tissue damage and response in vivo caused by
      implantation and indwelling of the probe was evaluated by histological
      examination of the tissue. A linear probe, implanted using fused silica tubing,
      was less damaging than other probe designs and implantation procedures tested. A
      series of time points up to 48 hr after implantation ere histologically examined.
      Infiltration of inflammatory cells, predominantly polymorphonuclear leukocytes
      (PMNs), was evident adjacent to the probe membrane after approximately 8 hr.
      Mixed inflammatory infiltration, mainly PMNs but including some macrophages, was
      observed in tissue slices 18 hr after implantation. At 48 hr, the mixed
      inflammatory infiltration was still present, with some degeneration of PMNs. In
      implantations of longer than 12 hr, some necrosis appeared at eh implantation
      site. The rate of delivery of phenol via the probe was stable for at least 30 hr,
      despite changes in the surrounding tissue.

PMID- 8654195
TI  - Human breast adenocarcinoma MCF-7/0 cells electroporated with cytosolic class 3
      aldehyde dehydrogenases obtained from tumor cells and a normal tissue exhibit
      differential sensitivity to mafosfamide.
AB  - The cytosolic class aldehyde dehydrogenase (ALDH-3) present in human normal
      tissues/secretions is apparently much less able to catalyze the oxidation
      aldophosphamide to carboxyphosphamide than is the ALDH-3 present in human tumor
      cells/tissues, suggesting that the former may be less able to protect cells from
      the cytotoxic action of cyclophosphamide, mafosfamide, and other
      oxazaphosphorines. To test this notion, relatively large and approximately equal
      amounts of human normal stomach mucosa ALDH-3 and catechol-induced human breast
      adenocarcinoma MCF-7/0 ALDH-3 were first electroporated into cells (MCF-7/0) that
      constitutively express only very small amounts of the enzyme. The resultant
      preparations were then tested for sensitivity to mafosfamide. ALDH-3 activities
      (NADP-dependent catalysis of benzaldehyde oxidation) were 1.7, 212, and 183
      mlU/10(7) cells in sham-electroporated MCF-7/0 cells, and MCF-7/0 cells
      electroporated with stomach mucosa ALDH-3 and catechol-induced MCF-7/0 ALDH-3,
      respectively. LC90 values (concentrations of mafosfamide required to effect a 90%
      cell kill) were 62, 417, and >1,000 microM, respectively. The three preparations
      were equisensitive to phosphoramide mustard (LC90 = approximately 850 microM).
      Inclusion of benzaldehyde in the drug exposure medium fully restored the
      sensitivity of MCF-7/0 cells electroporated with either enzyme to mafosfamide.
      These observations support the notions that 1) cellular sensitivity to the
      oxazaphosphorines decreases as the cellular content of ALDH-3 increases, 2) the
      foregoing is the consequence of ALDH-3-catalyzed oxidation (thus detoxification)
      of aldophosphamide, and 3) the ALDH-3 present in at least some tumor
      cells/tissues is a slight variant of the ALDH-3 present in normal
      tissues/secretions. Furthermore, they illustrate the utility of electroporation
      used as a tool to determine whether a given enzyme, or even more generally,
      protein or other macromolecule, is a determinant of cellular sensitivity to a
      given cytotoxic agent.

PMID- 8654196
TI  - Verlukast (MK-0679) conjugation with glutathione by rat liver and kidney cytosols
      and excretion in the bile.
AB  - Verlukast (MK-0679) is a potent leukotriene D4 antagonist that was under
      development for the treatment of bronchial asthma. A previously uncharacterized
      metabolite of verlukast was formed in incubations using rat liver cytosol
      fortified with glutathione (GSH). The metabolite was detected by HPLC and
      characterized by UV spectroscopy (photodiode array detection after HPLC) and
      capillary HPLC continuous flow-liquid secondary-ion mass spectrometry. After a
      large-scale incubation and isolation, it was further characterized by 500 MHz
      proton NMR. The metabolite is a 1,4-Michael addition product in which GSH has
      added to position 12 of the styryl quinoline double bond of verlukast. There is
      no apparent stereoselectivity because a mixture of the two possible isomers, in
      equal amounts, was observed by NMR. Although there was spontaneous chemical
      addition of GSH to verlukast (0.18 nmol/min), the reaction was shown to be enzyme
      catalyzed in studies using three different preparations of rat liver cytosol at
      pH 7.4. Using Lineweaver-Burk analysis of experiments in which the effect of
      verlukast concentration on the rate of conjugation was studied, the apparent KM
      and Vmax were determined to be 107 +/- 22 microM (SD, N=3) and 0.66 +/- 0.21
      nmol/min/mg protein, respectively. In similar studies with GSH as the variable
      substrate, the apparent KM and Vmax were 2.32 +/- 0.68 mM and 0.69 +/- 0.14
      nmol/min/mg protein, respectively. Incubations with kidney cytosol produced the
      GSH, cysteinylglycine, and cysteine conjugates of verlukast. In bile collected
      from rats dosed intravenously with 50 mg/kg of verlukast, approximately 80% of
      the dose was recovered up to 4 hr postdose. The GSH conjugate accounted for 16.5%
      of the dose. The cysteinylglycine, cysteine, and N-acetylcysteine conjugates were
      observed and together accounted for 7.5%. Verlukast accounted for 14.5%, and the
      remainder of the metabolites (40.5%) were oxidation or acyl glucuronide
      metabolites.

PMID- 8654197
TI  - Minimal effects of two aldose reductase inhibitors, AL-1576 and AL-4114, after
      subacute topical-ocular dosing on xenobiotic biotransformation in rabbits.
AB  - Aldose reductase is believed to be involved in teh etiology of diabetic
      complications, including cataractogenesis, nephropathy, and neuropathy. AL-1576
      and AL-4114, two spirohydantoin aldose reductase inhibitors, were specifically
      developed for prevention of diabetic cataractogenesis. This study has determined
      whether AL-1576 and AL-4114 are inducers of biotransformation by assaying the
      activities of some phase I and phase II enzymes in the liver, kidney, intestine,
      and five ocular tissues (cornea, lens, iris-ciliary body, retina, and choroid).
      The aldose reductase inhibitors were administered topically (the intended route
      for use in preventing cataractogenesis) in two concentrations (0.5 and 5.0%) each
      3 times/day to both eyes of New Zealand white rabbits for 14 days. Lenticular
      aldose reductase activity was decreased by 30-75% by the aldose reductase
      inhibitors. Monooxygenase activity toward benzo(a)pyrene, ethoxyresorufin, and
      methoxycoumarin was not increased by AL-1576 or AL-4114 treatment in any tissue.
      Activities of 1-chloro-2,4-dinitrobenzene glutathione S-transferase, 2-naphthol
      sulfotransferase, and 1-naphthol UDP-glucuronosyltransferase were not
      significantly induced in the eight tissues. Clearly, ocular dosing with AL-4114
      and AL-1576 for 14 days had little effect on hepatic, intestinal, and ocular
      biotransformation.

PMID- 8654198
TI  - Stereoselective disposition of naproxen glucuronide in the rat.
AB  - The disposition of R- and S-naproxen glucuronides were investigated after
      intravenous administration (approximately 1.5 mg/kg) to normal male Sprague
      Dawley rats and to rats pretreated with phenylmethylsulfonylfluoride, an
      inhibitor of esterases. The relative stability of the two glucuronides also was
      measured in vitro. Both diastereomers were hydrolyzed rapidly in vivo, liberating
      naproxen, but R-naproxen glucuronide was hydrolyzed faster than the corresponding
      S-diastereomer. This difference resulted in a larger plasma AUC(Nap):AUC(Nap-G)
      ratio for the R-glucuronide. There was, however, no marked difference in the
      apparent clearance of the R- and S-diastereomers. Administration of
      phenylmethylsulfonylfluoride had no significant effect on the disposition of the
      two diastereomers. In 0.15 M phosphate buffer (ph 7.4) at 37 degree C, the
      fastest degradation process for both diastereomers in vitro was acyl migration.
      Our results show that R-naproxen glucuronide is more labile than S-naproxen
      glucuronide in vivo and in vitro, and suggest that hydrolysis, rather than
      biliary excretion, is the major process leading to elimination of R-naproxen
      glucuronide in vivo in the rat. These results demonstrate that the rat may in
      certain situations be an inadequate model for studying the disposition of acyl
      glucuronides and that the metabolic disposition, and possibly toxicities, of
      diastereomeric metabolites of chiral drugs can be quite different even when the
      individual diastereomers have similar apparent clearances.

PMID- 8654199
TI  - Disposition of DMP 811 (L-708,404), a potent angiotensin II receptor antagonist,
      in the rat, monkey, and chimpanzee.
AB  - DMP 811 {4-ethyl-2-n-propyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)
      methyl]imidazole-5-carboxylic acid; L-708,404} is a highly potent angiotensin II
      receptor antagonist. The physiological disposition of DMP 811 was examined in the
      Sprague-Dawley rat, rhesus monkey, and pan troglodytes chimpanzee. Plasma
      concentrations of DMP 811 were determined by an HPLC assay with fluorescence
      detection. After intravenous administration of DMP 811 to rats (1 mg/kg), monkeys
      (0.5 mg/kg), and chimpanzees (0.5 mg/kg), the plasma clearance was 1.3, 1.8, and
      0.3 ml/min/kg, respectively. The corresponding volumes of distribution were 0.16,
      0.10, and 0.10 liters/kg, and the value for the terminal half-life was 3.0, 2.4,
      and 10.1 hr in the respective species. After oral administration to rats (5
      mg/kg), monkeys (2 mg/kg), and chimpanzees (2 mg/kg), DMP 811 was 8.4%, 10.2%,
      and 8.0% bioavailable, respectively. The mass balance of [14C]DMP 811 was
      investigated in rats and monkeys. In rats, the radiolabeled dose was excreted
      primarily in feces (79% intravenous; 99% oral) with <1% of the dose in urine. In
      monkeys, the intravenous radiolabeled dose was excreted in both urine (48%) and
      feces (42%), whereas the oral dose was excreted largely in feces (79%), with an
      additional 6% in urine. In summary, DMP 811 was cleared slowly in all three
      species. The oral bioavailability of DMP 811 was low, but consistent across
      species. Pharmacokinetic data suggest that the low oral bioavailability was not
      caused by first-pass metabolism, but probably caused by limited absorption.

PMID- 8654200
TI  - Liver volume as a determinant of drug clearance in children and adolescents.
AB  - Many drugs eliminated by the liver exhibit age-related differences in systemic
      clearance, necessitating different dosage requirements in children and adults.
      However, the physiological basis for these age-related changes is not well
      defined, including the importance of liver size in determining systemic
      clearance. Therefore, magnetic resonance imaging was used to determine liver
      volume in pediatric and adolescent patients, in whom systemic clearance of three
      model substrates [lorazepam (0.03 mg/kg), antipyrine (10 mg/kg), and indocyanine
      green (ICG; 0.5 mg/kg)] was also determined. In 16 children (ages 3.3-18.8 years;
      8 boys), liver volume ranged from 469 to 1640 ml (median 937), and was
      significantly related to age, body weight, and body surface area (BSA). Younger
      children had larger liver normalized to body weight (ml/kg), but there was no
      difference when liver volume was normalized to BSA (ml/m2). Unnormalized
      lorazepam and ICG clearances (ml/min) were significantly related to absolute
      liver volume (r2 = 50.2% and 31.4%, respectively), whereas unnormalized
      antipyrine clearance was not. Lorazepam, ICG, and antipyrine clearance normalized
      to BSA did not exhibit age-related changes, nor did lorazepam or ICG clearance
      normalized to body weight decreased significantly with increasing age (r2 =
      36.9%, p=0.012), as did antipyrine clearance relative to liver volume. Thus, age
      related changes in drug clearance and the importance of liver volume may differ
      based on the principal hepatic mechanisms involved in drug elimination.

PMID- 8654201
TI  - Metabolism and pharmacokinetics of N1,N11-diethylnorspermine.
AB  - The pharmacokinetics and metabolism of N1,N11-diethylnorspermine (DENSPM) is
      described. When administered to dogs as an intravenous bolus, DENSPM was shown to
      have a plasma half-life of 72.8 +/- 11.8 min, with an early distribution phase
      half-life of approximately 4 min and an apparent volume of distribution of 0.216
      +/- 0.032 liter/kg. The renal clearance half-life was 59.7 +/- 7.6 min, with 48.8
      +/- 12.5% of the drug recovered in the urine between 0-4 hr unchanged. In three
      other experiments, the drug was administered to dogs by constant rate intravenous
      infusion over periods ranging from 10 min to 2 hr. Analysis of plasma
      concentration-time data and urinary excretion data yielded pharmacokinetic
      parameters in general agreement with the intravenous bolus experiments. DENSPM
      metabolites were identified in both beagle dog and mouse tissues. Tissues were
      sampled from a single beagle 24 hr posttreatment, and rodent samples were
      examined at 12, 24, 48, and 96 hr posttreatment. Both the concentration of DENSPM
      and the metabolic profile were shown to vary in the lung, liver, spleen, and
      kidney. Although all the tissues examined contained DENSPM and its metabolites,
      the liver and kidney had the highest level of metabolites that included N1
      ethylnorspermine, N1-ethylnorspermidine, N1-ethyl-1,3-diaminopropane, and
      norspermidine. These data suggest that DENSPM is metabolized by N-deethylation
      and step-wise removal of aminopropyl equivalents by spermine/spermidine N1
      acetyltransferase/polyamine oxidase, a metabolic pathway unique to the
      polyamines.

PMID- 8654202
TI  - Identification of human cytochrome P450 isozymes responsible for the in vitro
      oxidative metabolism of finasteride.
AB  - Finasteride, a prescription drug for the treatment of benign prostatic
      hypertrophy and alleviation of symptoms associated with benign prostatic
      hypertrophy and alleviation of symptoms associated with benign prostatic
      hypertrophy, has been shown to be metabolized in rat hepatic microsomes by
      hydroxylation at the t-butyl group (omega-OH finasteride), followed by further
      oxidation to the corresponding acid (omega-oic acid finasteride), with omega
      aldehyde finasteride as an intermediate. In this study, we identified specific
      human cytochrome P450 (CYP) isozyme(s) involved in the in vitro metabolism of
      [14C]finasteride using CYP isozyme-selective inhibitors and microsomes containing
      specific recombinant human CYP isozymes (expressed in human AHH-1 TK+/-cells).
      Each of the three steps of the oxidative pathway was examined separately by using
      [14C]finasteride and its consecutive metabolites (omega-OH finasteride and omega
      aldehyde finasteride) as substrates, and human liver microsomes or expressed
      recombinant CYP isozymes as the enzyme source. Gestodene, a mechanism-based
      inhibitor of CYP3A isozymes, showed a concentration-dependent inhibition of the
      oxidative metabolism of [14C]finasteride. In addition, the respective omega-OH
      finasteride and omega-oic acid finasteride metabolites were generated only by
      microsomes containing recombinant CYP3A4, but not the other isozymes (CYP1A1,
      CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP2E1). Similar results were obtained for
      the oxidation of omega-OH finasteride to omega-aldehyde finasteride, suggesting
      that human CYP3A isozymes were involved in the oxidation of omega-OH finasteride.
      When omega-aldehyde finasteride was incubated with human liver microsomes in the
      presence of an NADPH regenerating system, both the omega-oic acid finasteride and
      the omega-OH finasteride were detected, suggesting that oxidative and reductive
      reactions were occurring simultaneously and that they were NADPH- or NADP
      dependent. Inhibitors of CYP3A isozymes inhibited the oxidation of omega-aldehyde
      finasteride in a concentration-dependent manner; an increase in the reduction was
      also observed, presumably caused by inhibition of the competitive oxidative
      reaction. Other selective CYP inhibitors for CYP1A1/2 (alpha-naphthoflavone),
      CYP2C8-10 (sulfaphenazole), CYP2D6 (quinidine), and CYP2E1 (diallylsulfone)
      showed minor or no effects on both reactions. Consistent with these results, only
      microsomes containing human recombinant CYP3A4 catalyzed the oxidation of omega
      aldehyde finasteride to omega-oic acid finasteride. These results indicate that
      the oxidation of omega-aldehyde finasteride was NADPH-dependent and was mediated
      at least in part by CYP3A4. In addition, NAD-dependent enzymes in cytosolic,
      microsomal, and mitochondrial fractions were capable of oxidizing omega-aldehyde
      finasteride to omega-oic acid finasteride. Other cellular fractions, particularly
      mitochondria, were shown to convert finasteride to omega-oic acid finasteride in
      a similar fashion.

PMID- 8654203
TI  - Metabolism as a determinant of species susceptibility to 2,3,5-(triglutathion-S
      yl)hydroquinone-mediated nephrotoxicity. The role of N-acetylation and N
      deacetylation.
AB  - 2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] is a potent
      nephrotoxicant when administered to male rats. We now report that significant
      species differences exist in susceptibility to 2,3,5-(triGSyl)HQ-mediated
      nephrotoxicity. Metabolism of glutathione conjugates involves cleavage of teh
      glutamate and glycine moieties by gamma-glutamyltranspeptidase (gamma-GT) and
      dipeptidases, respectively, and the nephrotoxicity of 2,3,5-(triGSyl)HQ can be
      prevented by the inhibition of renal gamma-GT. The resulting cysteine conjugate
      exhibits a balance between N-acetylation, and N-deacetylation of the mercapturic
      acid biosynthesis in various species contribute to species susceptibility to
      2,3,5-(triGSyl)HQ. Renal gamma-GT activity toward 2,3,5-(triGSyl)HQ was highest
      in the rat (Fischer 344 and Sprague-Dawley) and consistent with the sensitivity
      of this species to 2,3,5-(triGSyl)HQ (20 micromol/kg iv)-mediated nephrotoxicity.
      The gamma-GT-mediated hydrolysis of 2,3,5-(triGSyl)HQ was similar in B6C3F1 and
      BALB/c mice and guinea pigs. In these species, the gamma-GT activity ranged
      between 30-45% of the activity measured in rats. Although, the activity of gamma
      GT was similar in mice and guinea pigs, only guinea pigs were susceptible to
      2,3,5-(triGSyl)HQ (200 micromol/kg iv)-induced renal necrosis. The gamma-GT
      mediated hydrolysis of 2,3,5-(triGSyl)HQ was lowest in the hamster, and this
      species were not susceptible to the renal toxicity of this conjugate. Thus,
      factors in addition to gamma-GT activity probably contribute to species
      susceptibility to 2,3,5-(triGSyl)HQ nephrotoxicity. The kinetics of the AT-125
      mediated inhibition of gamma-GT differed between species, indicative of potential
      differences in the regulation of gamma-GT. Consistent with this view, the ratio
      between the hydrolysis and transpeptidation of 2,3,5-(triGSyl)HQ varied 10-fold
      between the species examined, and was highest in the guinea pig (0.48) and lowest
      in the hamster (0.05). Guinea pigs also exhibited the highest renal cytosolic N
      deacetylase activity and the lowest N-acetylase activity. The ratios of N
      deacetylation to N-acetylation in guinea pigs, BALB/c mice, B6C3F1 mice,
      hamsters, Fischer 344 rats, and Sprague-Dawley rats were 4.57, 0.16, 0.14, 0.04,
      0.03, and 0.02, respectively. Because quinol-cysteine conjugates seem to undergo
      oxidation more readily than the corresponding mercapturates, the balance of N
      deacetylase and N-acetylase in the guinea pig may contribute to the
      susceptibility of this species to 2,3,5-(triGSyl)HQ nephrotoxicity.

PMID- 8654204
TI  - In vitro hepatic metabolism of ABT-418 in chimpanzee (Pan troglodytes). A unique
      pattern of microsomal flavin-containing monooxygenase-dependent stereoselective
      N'-oxidation.
AB  - Metabolism of the cholinergic channel activator [N-methyl-3H]ABT-418 was studied
      using precision-cut tissue slices and microsomes (+/- cytosol) prepared from a
      single chimpanzee liver. In both cases, the products of C-oxidation (lactam) and
      N'-oxidation (cis > trans) were detected. In the presence of chimpanzee liver
      microsomes and cytosol, which had been characterized with respect to the levels
      of aldehyde oxidase (N1-methylnicotinamide oxidase), NADPH-dependent flavin
      containing monooxygenase (FMO; N, N-dimethylaniline N-oxidase), and various
      cytochrome P450 (CYP)-dependent monooxygenase activities, ABT-418 lactam and N'
      oxide formation was found to be largely dependent on CYP/aldehyde oxidase and
      FMO, respectively. The rank order of total (trans + cis) FMO-dependent N'
      oxidation in liver microsomes was dog > rat > rabbit > chimpanzee > or =
      cynomolgus monkey > human. It is concluded that the metabolic profile of ABT-418
      in the chimpanzee is unique. First, the C-/N'-oxidation ratio in liver slices
      (0.43) is similar to that of the rat and dog and dissimilar to that of the rat
      and dog and dissimilar to that of the two other primate species studied; human
      and cynomolgus monkey (C-/N'-oxidation ratio > or = 9.4). Second, the pattern of
      ABT-418 N'-oxidation observed with chimpanzee liver microsomes, and liver slices
      (trans:cis = 1:3), differs from that of rat, rabbit, and dog liver microsomes,
      rat and human kidney S-9 (trans >> cis), human liver microsomes (trans:cis
      approximately 1:1), and cynomolgus monkey (trans:cis approximately 2:1) liver
      microsomes. Lack of stereoselective N'-oxidation by human FMO was confirmed with
      cDNA-expressed FMO3.

PMID- 8654205
TI  - Identification of the human and rat P450 enzymes responsible for the
      sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-ME). The terminal step
      in the bioactivation of disulfiram.
AB  - The present study investigated the role of rat and human cytochrome P450 enzymes
      in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-Me) to S-methyl
      N,N-diathylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the putative active
      metabolite of disulfiram. DETC-Me sulfoxidation by microsomes from male and
      female rats treated with various cytochrome P450-enzyme inducers suggested that
      multiple enzymes can catalyze this reaction, and these include, CYP1A1/2,
      CYP2B1/2, and CYP3A1/2. All cDNA-expressed human cytochrome P450 enzymes examined
      catalyzed the sulfoxidation of DETC-Me. The turnover rates (min-1) of DETC-Me
      sulfoxidation by the cDNA-expressed cytochrome P450 enzymes ranked as follows:
      CYP3A4 > CYP2A6 = CYP2C9 > CYP1A2 > CYP2B6 = CYP2E1 > CYP1A1 > CYP2D6.
      Interestingly, CYP3A4 ranked first or last, depending on whether or not
      additional NADPH-cytochrome P450 reductase was coexpressed in the lymphoblastoid
      cells. This complicated estimates of the contribution of CYP3A4 to DETC-Me
      sulfoxidation by human liver microsomes. The sample-to-sample variation in DETC
      Me sulfoxidation by bank of human liver microsomes (N=13) correlated highly with
      coumarin 7-hydroxylation (r=0.88) and testosterone 6beta-hydroxylation (r=0.90),
      suggesting that CYP2A6 and CYP3A4/5 contribute to the sulfoxidation of DETC-Me by
      human liver microsomes. Although, chlorzoxazone 6-hydroxylation (a marker for
      CYP2E1) correlated poorly with DETC-Me sulfoxidation, the correlation improved
      from r=0.07 to r=0.44 when DETC-Me sulfoxidation was studied in the presence of
      the CYP2A6 inhibitor, coumarin. Similarly, when DETC-Me sulfoxidation was studied
      in the presence of diethyldithiocarbamate (DDTC), the inhibited DETC-Me
      sulfoxidase activity correlated better (r=0.50) with chlorzoxazone 6-hydroxylase,
      compared with DETC-Me sulfoxidase activity in the absence of DDTC (r=0.09).
      Polyclonal antibodies against CYP2E1 caused a modest inhibition (30%) of DETC-Me
      sulfoxidation by human liver microsomes. Anti-CYP3A1 antibodies completely
      inhibited DETC-Me sulfoxidation by cDNA-expressed CYP3A4. Under similar
      conditions, DETC-Me sulfoxidation by human liver microsomes was only partially
      inhibited by anti-CYP3A1 antibodies. Although studies with the rat and cDNA
      expressed cytochrome P450 enzymes suggested that CYP1A2 contributed to DETC-Me
      sulfoxidation, this reaction was not inhibited by either furafylline ( a
      mechanism-based inhibitor of CYP1A2) or antibodies against CYP1A1/2. A
      significant role for CYP2C9 was excluded by the inability of sulfaphenazole to
      inhibit the sulfoxidation of DETC-Me by human liver microsomes. Collectively,
      these data suggest that multiple cytochrome P450 enzymes can catalyze the
      sulfoxidation of DETC-Me. In human liver microsomes the CYP2A6, CYP2E1, and
      CYP3A4/5 all contribute significantly to the sulfoxidation of DETC-Me. It is
      interesting to note that DDTC, the reduced metabolite of disulfiram, is known to
      inhibit these same enzymes. The ability of DDTC to block the formation of DETC-Me
      sulfoxide may explain why the dose of disulfiram required to produce a disulfiram
      ethanol reaction in alcoholics is so variable and often inadequate.

PMID- 8654206
TI  - Identification of the human liver cytochrome P450 enzymes involved in the
      metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott
      66193.
AB  - In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP)
      forms involved in the oxidative metabolism of [14C]zileuton (ABT-077) and its N
      dehydroxylated metabolite, [14C]Abbott-66193, by human liver microsomes. The two
      compounds were metabolized by parallel pathways to form the corresponding ring
      hydroxylated and diastereomer sulfoxide metabolites. Results suggested that
      whereas the metabolism of zileuton and Abbott-66193 were mediated by the same CYP
      forms, the CYP forms responsible for hydroxylation (CYP1A2 and CYP2C9/10) were
      distinct from those involved in sulfoxidation (CYP3A > CYP2C9/10). Sulfoxidation
      (zileuton, Km = 0.82 +/- 0.40 mM, Vmax = 39.1 +/- 21.8 pmol/min/mg; Abbott-66193,
      Km = 0.23 +/- 0.06 mM, Vmax = 507 +/- 215 pmol/min/mg; mean +/- SD, N=3) was
      highly correlated with the CYP3A-specific erythromycin N-demethylase activity
      (r=0794-0.856; p<0.01, N=11) in human microsomes and was inhibited (32-67%) by
      ketoconazole and troleandomycin. In addition, purified recombinant human
      CYP3A4/rat NADPH-P450 reductase fusion protein catalyzed only the sulfoxidation
      of zileuton and Abbott-66193; no hydroxylated metabolites were detected. On the
      other hand, hydroxylation of the two compounds (zileuton, Km = 0.34 +/- 0.25 mM,
      Vmax = 17.8 +/- 5.58 pmol/min/mg; Abbott-66193,Km = 0.39 +/- 0.14 mM, Vmax = 1061
      +/- 220 pmol/min/mg) was significantly correlated with 7-ethoxyresorufin O
      deethylase (CYP1A2; r=0.652-0.762; p<0.01, N=11) and tolbutamide methyl
      hydroxylase (CYP2C9/10; r=0.863-0.935; p<0.01, N=10) activity in human liver
      microsome, and was inhibited (26-51%) by well-known CYP1A2 inhibitors
      (furafylline and alpha-naphthoflavone). Furthermore, microsomes from human B
      lymphoblastoid cells expressing CYP1A2 catalyzed only the hydroxylation of
      zileuton and Abbott-66193; sulfoxide were not formed. Abbott-66193 was a better
      substrate for CYP2C9/10, when compared with zileuton: 1) the effect of
      sulfaphenazole on hydroxylation in human liver microsomes was more pronounced for
      Abbott-66193 than zileuton (56% vs. 9% inhibition); and 2) the rate of Abbott
      66193 hydroxylation by purified CYP2C9 was almost 30-fold greater than that of
      zilueton.

PMID- 8654207
TI  - Determination of nicotine metabolites in rat brain after peripheral radiolabeled
      nicotine administration: detection of nornicotine.

PMID- 8654208
TI  - Influence of lipophilicity on the bioavailability and disposition of orally
      active 3-hydroxypyridin-4-one metal chelators.

PMID- 8654210
TI  - Women and coronary heart disease.

PMID- 8654209
TI  - Pre-conception, pregnancy and prescribing.

PMID- 8654211
TI  - Advising patients about air travel.

PMID- 8654212
TI  - [Sphincter of Oddi disfunction in "idiopathic" recurrent pancreatitis].
AB  - OBJECTIVE: As the pathogenesis of acute recurrent pancreatitis remains unclear in
      30% of patients, it was the aim of this study to find out whether and how often
      changes in sphincter of Oddi motility is present in these patients and whether
      endoscopic treatment promises success. PATIENTS AND METHODS: 18 patients (three
      men, 15 women; mean age 41.5 [30-56] years) with "idiopathic" acute recurrent
      pancreatitis seen consecutively between April 1991 and November 1995, were
      included in the study. In none had laboratory examinations, sonography, computed
      tomography and endosonography (n = 11) demonstrated any unusual findings. Neither
      exocrine (pancreaolauryl test in 8, secretin-pancreozymin test in 10 patients),
      nor endocrine (oral glucose tolerance test) pancreatic insufficiency had been
      found. Endoscopic retrograde cholangiopancreatography had excluded morphological
      changes in the biliary-pancreatic system. All patients underwent endoscopic
      manometry. When a basal sphincter of Oddi pressure > or = 40 mm Hg was
      demonstrated in the pancreatic sphincter segment, combined endoscopic
      sphincterotomy was done of both the biliary and the pancreatic component.
      RESULTS: Nine patients had a raised basal sphincter pressure in the pancreatic
      segment of the sphincter, but in only four in the biliary one as well. The phasic
      sphincter motility was normal in all patients. In four patients iatrogenic
      pancreatitis developed after the procedure (mild in three, moderately severe in
      one). Eight of the nine patients who had a sphincterotomy remained symptom-free
      during a mean follow-up period of 21 months, but only three of the nine with
      normal manometric findings. CONCLUSION: Half of the patients with acute recurrent
      pancreatitis of unknown cause have sphincter of Oddi dysfunction, usually limited
      to the pancreatic segment of the sphincter, Endoscopic sphincterotomy can prevent
      recurrent pancreatitis in most of the patients.

PMID- 8654213
TI  - [Cardiosurgical therapy of coronary heart disease in terminal kidney
      insufficiency].
AB  - OBJECTIVE: To determine retrospectively the complications and long-term results
      of aortocoronary bypass grafting in patients with end-stage renal disease.
      PATIENTS AND METHODS: 65 patients with coronary heart disease (CHD) and on
      dialysis (54 men, 11 women; average age 56.9 +/- 8.1 years) underwent
      aortocoronary bypass grafting between 1982 and 1992. Mean duration of dialysis
      (haemo- or peritoneal) was 41.1 +/- 45.0 (1-215) months. All patients had had
      haemofiltration treatment in conjunction with the bypass operation. RESULTS:
      Coronary angiography demonstrated triple-vessel disease in 40 patients (62%).
      Average number of bypasses was 2.8 per patient. Perioperative death rate was
      4.6%. 95% of survivors were free of symptoms 6 months postoperatively. Long-term
      survival rate was 71% after 3 years and 55% after 5 years. CONCLUSION:
      Aortocoronary bypass grafting for CHD in patients with end-stage renal disease
      can be performed with a low perioperative mortality rate and significantly
      improves symptoms.

PMID- 8654214
TI  - [Solar retinopathy. Rare cause of acute loss of vision].
AB  - HISTORY AND CLINICAL FINDINGS: A 15-year-old girl was admitted to hospital for
      acute bilateral visual deterioration and central scotoma of two days' duration.
      It became known on the third day that she had looked into the sun on several
      occasions, for several minutes at a time. INVESTIGATIONS: In addition to the
      scotoma there was a visual loss to 0.05 in the right and 0.1 in the left eye.
      Neurological examination and imaging of the head were unremarkable. At first the
      visual evoked potential was prolonged (122 ms on right, 130 ms on left), but all
      other electrophysiological tests were normal. Fundoscopy at first showed macular
      oedema and pigment changes in the macula. TREATMENT AND COURSE: Local application
      of prednisolone (0.5 mg five times daily) gradually improved the vision and it
      returned to normal after 8 weeks. The initially prolonged visual evoked potential
      restored to normal either. No pathophysiological reason for this was found.
      CONCLUSION: In case of acute loss of vision in the absence of other neurological
      findings, external factors should be considered in the differential diagnosis.

PMID- 8654215
TI  - [Therapy of carotid stenosis].

PMID- 8654217
TI  - [Examination of patients in medical documents during psychiatric treatment.
      Decision of the Saarbrucken regional court of September 20, 1995].

PMID- 8654216
TI  - [Cytokines: biology and therapeutic relevance].

PMID- 8654218
TI  - [Early summer meningoencephalitis].

PMID- 8654219
TI  - [Persistent pericardial effusion].

PMID- 8654220
TI  - [Awareness during general anesthesia].

PMID- 8654221
TI  - [Diagnostic ultrasound imaging in municipal health care centers].

PMID- 8654222
TI  - [Matti Ayrapaa Award. Production of drug proteins in bioreactors].

PMID- 8654223
TI  - [Single umbilical artery].

PMID- 8654224
TI  - [The treatment of non-Hodgkin lymphoma in elderly patients].

PMID- 8654225
TI  - [The diagnosis of asthma caused by cow hair epithelium].

PMID- 8654226
TI  - [Pyomyositis].

PMID- 8654228
TI  - [Immediate-type hypersensitivity to chlorhexidine].

PMID- 8654227
TI  - [Resistance to thyroid hormone].

PMID- 8654229
TI  - [Surgery in Crohn's disease].

PMID- 8654230
TI  - [Magnetic resonance imaging and intravertebral disk protrusion].

PMID- 8654231
TI  - [Avoiding certainty while treating the pain].

PMID- 8654232
TI  - [Rehabilitation of patients with brain injuries in the Helsinki area].

PMID- 8654233
TI  - [Euthanasia and logic].

PMID- 8654234
TI  - [Antidepressants, melatonin and seasonal depression].

PMID- 8654235
TI  - [Does reading strain the eyes?].

PMID- 8654236
TI  - [Left ventricular remodeling and its role following myocardial infarction].

PMID- 8654237
TI  - [Nobel Prize to a supporter of young scientists].

PMID- 8654238
TI  - [Rewarded articles in 1994: from hepatitis in hemophiliacs to infertility].

PMID- 8654239
TI  - [Human insulin-like growth factor I and treatment in diabetes].

PMID- 8654240
TI  - [The value of health].

PMID- 8654241
TI  - [Effects of hyperventilation-induced brain ischemia on central nervous system
      mediator substances in pigs].

PMID- 8654242
TI  - [Skeletal muscle weakness in a young woman].

PMID- 8654243
TI  - [The activation of lupus in pregnancy and its successful immunological
      treatment].

PMID- 8654244
TI  - [Facial nerve palsy as initial symptom of parotid gland cancer].

PMID- 8654245
TI  - [Severe tetanus following a minor injury].

PMID- 8654246
TI  - [Fever, hemorrhagic diathesis and pancytopenia in a middle-aged woman].

PMID- 8654247
TI  - [Euthanasia in The Netherlands].

PMID- 8654248
TI  - [Between two levels--chief physician and young doctor discuss the stumbling
      blocks of intercollegiality. Interview by Hannu Sariola].

PMID- 8654249
TI  - [Do research physicians escape from the university?].

PMID- 8654250
TI  - [Medicine in developing countries and Finland].

PMID- 8654251
TI  - [Who is ill and what are the diseases in Finland?].

PMID- 8654252
TI  - [Development in primary care does not preclude the personal physician approach].

PMID- 8654253
TI  - [Challenges and hazards within maternal--child health centers].

PMID- 8654254
TI  - [Competition in Finnish health care!].

PMID- 8654255
TI  - [Prioritization of health care: is there room for selection or risk?].

PMID- 8654257
TI  - [What is quality care?].

PMID- 8654256
TI  - [110 years of Duodecim].

PMID- 8654258
TI  - [Quality assurance].

PMID- 8654259
TI  - [Why does Finland not have a Nobel Prize winner in medicine?].

PMID- 8654261
TI  - [Alternative medicine].

PMID- 8654260
TI  - [Public funding of medical research].

PMID- 8654262
TI  - [Challenges for medical education at the beginning of the new millennium].

PMID- 8654263
TI  - [Civilized physicians].

PMID- 8654264
TI  - [Patients' right and physicians' power].

PMID- 8654265
TI  - [Who is interested in the health of the nation?].

PMID- 8654266
TI  - [The risk genes of familial breast cancer can be identified].

PMID- 8654267
TI  - [Risk-benefit evaluation of mammographic breast cancer screening].

PMID- 8654268
TI  - [Polymerase chain reaction assay of HSV in the rapid diagnosis of encephalitis].

PMID- 8654269
TI  - [Role of bibliometrics in the evaluation of medical research].

PMID- 8654270
TI  - [Clinical measurement of serum transferrin receptor--a promising new measure for
      the diagnosis of anemia].

PMID- 8654271
TI  - [para-esophageal hernia--a poorly recognised form of hiatal hernia].

PMID- 8654272
TI  - [A severe puerperal infection caused by group A streptococci in a previously
      healthy mother].

PMID- 8654273
TI  - [Lung findings, large spleen and retardation in a young child].

PMID- 8654274
TI  - [Tailgut cyst].

PMID- 8654275
TI  - [Autoimmune oophoritis].

PMID- 8654276
TI  - [The clinical use of CRP measurements].

PMID- 8654277
TI  - [Are the benefits of videoscopic inguinal hernioplasty weighed?].

PMID- 8654278
TI  - [Psychosocial support of a cancer patient--theory and reality].

PMID- 8654279
TI  - [Welfare clinic's operation has been evaluated].

PMID- 8654280
TI  - [Orogenital sex and pregnancy].

PMID- 8654282
TI  - [Genetic background of diastrophic dysplasia has been solved].

PMID- 8654281
TI  - [Should beta-adrenergic blockade be part of drug therapy for heart failure?].

PMID- 8654283
TI  - [Physical activity in childhood may have advantages even in older age].

PMID- 8654284
TI  - [Effectiveness of cervical cancer screening in Finland].

PMID- 8654285
TI  - [Fast-acting insulin analogs in the treatment of juvenile diabetes].

PMID- 8654286
TI  - [The ROC curve in the measurement of the diagnostic value of tests].

PMID- 8654287
TI  - [Hydatidiform mole and live fetus--a happy ending in a hopeless pregnancy].

PMID- 8654288
TI  - [Critical pulmonary edema following cesarean section].

PMID- 8654289
TI  - [Pseudoxanthoma elasticum--a rare hereditary connective tissue disease].

PMID- 8654290
TI  - [Can indomethacin prolong arthritis?].

PMID- 8654291
TI  - [A single sting of wasp and bee as a cause of fatal anaphylaxis].

PMID- 8654292
TI  - [Epidural anesthesia in the treatment of painful diabetic neuropathy].

PMID- 8654293
TI  - [Critical lower extremity ischemia].

PMID- 8654294
TI  - [European fats recommendations].

PMID- 8654295
TI  - [Family education is gone, population responsibility began--will family planning
      services for youth suffer?].

PMID- 8654296
TI  - [Will surgical wounds and pain be history?].

PMID- 8654297
TI  - [Measurement and importance of heart rate variability].

PMID- 8654298
TI  - [Male infertility can be treated].

PMID- 8654299
TI  - [Has the prevalence of mental health problems increased during the recession?].

PMID- 8654300
TI  - [Feather allergy--rarer than formerly thought].

PMID- 8654301
TI  - [A recurrence of rickets--prevalence, diagnosis and treatment].

PMID- 8654302
TI  - [Long-term fever and light-chain myeloma].

PMID- 8654303
TI  - [Chylothorax and chylous ascites as symptoms of Castleman's disease].

PMID- 8654304
TI  - [Aggravation of supraventricular tachycardia symptoms during pregnancy].

PMID- 8654305
TI  - [Tracheobronchial malacia in patients with obstructive sleep apnea].

PMID- 8654306
TI  - [Perianal infection caused by group A beta-hemolytic Streptococcus on children].

PMID- 8654307
TI  - [Which operations can be done without general anesthesia?].

PMID- 8654308
TI  - Fetal hepatic alpha-fetoprotein mRNA expression in fetuses with trisomy 21 and 18
      at 12-15 weeks gestation.
AB  - In this study we examined alpha-fetoprotein (AFP) mRNA expression in fetal liver
      at 12-15 weeks of gestation in trisomy 21 (n = 13), trisomy 18 (n = 5) and
      control fetuses (n = 24). No significant difference was found in the steady-state
      level of fetal liver AFP mRNA levels in either of the two trisomy groups studied.
      These findings suggest that the decrease in maternal serum AFP concentration
      found in trisomic pregnancies is unlikely to be the consequence of impaired
      transcription of the AFP gene by the fetal liver.

PMID- 8654309
TI  - Chest circumference as an indicator of intrauterine growth retardation.
AB  - Three hundred and fifty six intrauterine growth retarded (IUGR) and 356
      appropriate birth weight (ABW) babies were studied for a range of different
      anthropometric measurements. Birth weights was highly correlated with chest
      circumference (r = 0.64, P < 0.001; r = 0.76, P < 0.001), length (r = 0.71, P <
      0.001; r = 0.68, P < 0.001), and head circumference (r = 0.49, P < 0.001; r =
      0.53, P < 0.001) either in IUGR and ABW babies, respectively. There were weak
      statistically significant correlations between birth weight and mid-upper arm
      circumference (MUAC) (r = 0.65, P < 0.001; r = 0.15, P < 0.001), MUAC/head
      circumference (r = 0.43, P < 0.001; r = 0.13, P < 0.001), triceps skinfold
      thickness (r = 0.31, P < 0.001; r = 0.14, P < 0.001), and ponderal index (r =
      0.23, P < 0.001, r = 0.33, P < 0.001) in IUGR and ABW babies. All anthropometric
      measurements had a statistically significant sensitivity and specificity for
      identifying intrauterine growth retardation (IUGR). However, chest circumference
      < or = 29.0 cm; length < or = 47.5 cm; and head circumference < or = 33.0 cm has
      the highest sensitivity, specificity and predictive power. Chest circumference
      seems to be the easiest, cheapest and most reliable anthropometric measurement to
      assess IUGR.

PMID- 8654310
TI  - Blood pressure and heart rate response to head-up position in full-term newborns.
AB  - The reactions of heart rate (HR), systolic (sBP) and diastolic (dBP) blood
      pressure were studied in response to passive head-up tilting (successively to +45
      degrees and +90 degrees) in a group of 83 full-term, 1- to 7-day-old newborns who
      were quiet and awake. A significant mean increase of HR was noted for the whole
      group, from 121 +/- 14 beats/min to 124 +/- 15 beats/min at +45 degrees and to
      127 +/- 17 beats/min at +90 degrees, while sBP rose from 65 +/- 9 mmHg to 67 +/-
      12 mmHg at +45 degrees and to 70 +/- 13 mmHg at +90 degrees tilts, respectively
      (5th post-tilt min). A negative correlation (r = -0.41, P < 0.01) was found
      between basal supine values of HR and their post-tilt increments after +45
      degrees tilting. After +90 degrees tilting, dBP correlated negatively (r = -0.33,
      P < 0.003) with the supine values, as well as HR (r = -0.30, P < 0.01). Breaking
      down the whole group according to age has shown that in 1-day-old babies (N =
      11), the only one significant mean change was an increase of HR by 7 +/- 10
      beats/min after the +45 degrees tilt. At the age of 2 days (N = 36), the group
      mean values showed a rise of sBP only by 5 +/- 12 mmHg after the +90 degrees
      tilt. In 3-day-old babies (N = 18), increased values were noted in both the HR
      (by 6 +/- 18 beats/min) and sBP (by 5 +/- 15 mmHg) even after the +45 degrees
      tilt. The increase of all the variable: HR by 7 +/- 12 beats/min, sBP by 6 +/- 8
      mmHg, dBP by 2 +/- 4 mmHg after 5 min of +90 degrees tilt was present only in 4-
      to 7-day-old neonates (N = 18). It seems that the evolution of orthostatic
      circulatory regulation is a component of the evolution in the overall
      responsiveness of the cardiovascular system to external stimuli and becomes
      apparent after a relative stabilization of the neonatal blood volume on the 2nd
      3rd postnatal day.

PMID- 8654311
TI  - Mode of delivery and perinatal cerebral blood flow.
AB  - OBJECTIVE: To ascertain whether the perinatal cerebral blood flow velocity
      differed between vaginally delivered appropriate for gestational age (vag. AGA)
      term babies, AGA babies delivered by Caesarean section (C.s. AGA), and small for
      gestational age (C.s. SGA) babies also delivered by Caesarean section. STUDY
      DESIGN: Forty-five babies were examined by Doppler ultrasound of the middle
      cerebral artery prior to and immediately after delivery, and at 1 h and 24 h
      after birth. The pulsatility index (PI) and time-averaged maximum velocity
      (TAMXV) were calculated. RESULTS: No differences in TAMXV were found between the
      vag. AGA and C.s. AGA groups at any of the four recordings. A significantly
      higher PI value was found in the C.s. AGA group 1 h after birth. The C.s. SGA
      group had lower PI values before and just after birth, but did not differ
      significantly from the C.s. AGA group at 1 h or 24 h after birth. CONCLUSIONS:
      The results suggest mode of delivery to have a transitory effect on cerebral
      vascular resistance in healthy term AGA babies. The C.s. SGA group differed in
      the initial recording just after birth, but later manifested similar blood flow
      velocities in middle cerebral artery as the C.s. AGA group.

PMID- 8654312
TI  - Cardiac and respiratory patterns during sleep in cocaine-exposed neonates.
AB  - Four-hour recordings of heart rate and respiration during spontaneous sleep and
      wakefulness were obtained from 17 cocaine-exposed and 14 control infants at 2
      weeks of age. The median values for heart and respiratory rate and variability
      were determined for each 1-min epoch of quiet and active sleep. Overall mean
      rates and variabilities were determined for each state. The cocaine-exposed
      infants showed significantly greater sleep state effects on heart rate relative
      to the control infants. Recency of cocaine exposure was not a factor in the
      differences; even those cocaine-exposed infants who tested negative for the drug
      perinatally differed significantly from those who had never been exposed. Heart
      rate variability was increased in cocaine-exposed infants relative to controls in
      both sleep states. Respiratory rate and variability were not significantly
      different in the cocaine-exposed and control infants. These results suggest
      differences in cardiovascular control in infants of cocaine-abusing mothers
      compared to infants without cocaine exposure. The mechanism responsible for these
      differences is unclear and may reflect cocaine-induced changes in the autonomic
      physiology of developing infants or some indirect effect of maternal cocaine use.

PMID- 8654313
TI  - Rhythmical leg movements in low-risk and brain-damaged preterm infants.
AB  - The characteristics of rhythmical kicking movements of preterm infants with
      documented brain damage (BD), who later showed a severe motor impairment, are
      described and compared with those of low-risk (LR) preterm infants. Spontaneous
      movements were videotaped for 60 min in the incubator or in a warmer. A first
      group of 6 BD and 6 LR infants was observed at 31-35 weeks of postmenstrual age
      (PMA) and a second group (6 BD, 6 LR) at 37-39 weeks. Bouts of rhythmical kicks,
      defined as leg movements repeated in the same form at least three times at
      regular short intervals, were analysed during periods of activity. The results
      indicated non-significant differences between BD and LR infants at 31-35 weeks of
      PMA. In contrast, some differences were observed at 37-39 weeks. These
      differences were not due to leg movement frequency, but to inter-leg coordination
      and to temporal organisation of the kicking cycles. LR infants exhibited more
      alternate-leg movements and fewer semi-both-leg movements (simultaneous flexion
      and non-simultaneous extension) than BD infants. In LR cases the duration of the
      pause between flexion and extension was shorter, whereas flexion and extension
      periods were similar for all infants. Although there were significant
      differences, quantitative analysis of kicking characteristics was not clinically
      useful because of the large overlap in findings between the two groups. On the
      other hand Gestalt evaluation of general movements of the same videorecordings
      showed a closer correlation with the presence of brain lesions and with
      neurological outcome.

PMID- 8654314
TI  - Long-chain polyunsaturated fatty acid content in Dutch preterm breast milk;
      differences in the concentrations of docosahexaenoic acid and arachidonic acid
      due to length of gestation.
AB  - Recognizing the important role of long-chain polyunsaturated fatty acids (LCP)
      particularly in preterm infant nutrition, we studied the fatty acid composition
      of breast milk from 65 mothers of very preterm ( < 31 weeks of gestation) and
      preterm ( > or = 31 and < 36 weeks of gestation) infants. Fatty acids were
      determined as fatty acid methyl esters by capillary gas chromatography. In
      accordance with other studies, the increase of capric acid, lauric acid and
      myristic acid during lactation is influenced by prematurity. Unsaturated fatty
      acids had the inclination to decrease. Our interest was mainly focused on
      docosahexaenoic acid (DHA) and arachidonic acid (AA). Accelerated brain growth
      during the last trimester of gestation requires an extra need for these LCPs. In
      our study, preterm milk after a gestation period of at least 32 weeks contained
      the highest amounts of DHA and AA. The Western maternal diet is considered to be
      low in omega 3 fatty acids, that is why the concentration of DHA in our preterm
      milk can be regarded as a low amount. As it is the milk of their mothers, and
      because the amounts are higher than normally found in Western full term breast
      milk, the contribution of DHA to preterm milk fat (0.34%) might be considered,
      for the time being, as a safe natural guideline for formulas for preterm infants.

PMID- 8654315
TI  - Sensorineural hearing loss in survivors of neonatal extracorporeal membrane
      oxygenation.
AB  - From February 1989 to January 1994, nine of 63 (14.3%) survivors of neonatal
      extracorporeal membrane oxygenation developed bilateral sensorineural hearing
      loss. Seven of nine children were tested and passed initial or repeat clinical
      auditory brainstem response evaluation completed before discharge from neonatal
      intensive care. Hearing loss was suspected and confirmed between 6-36 and 10-48
      months of age, respectively. We recommend regular audiologic follow-up for these
      high-risk infants until bilateral thresholds for hearing can be obtained.

PMID- 8654316
TI  - Alcohol withdrawal tremor.
AB  - It is well known that during the withdrawal period after chronic alcohol intake,
      tremor is one of the symptoms that disturb patients. Alcohol withdrawal tremor
      might be a variant of enhanced physiological tremor, most often caused by anxiety
      or emotional stress. The aim of this investigation was to establish the EMG
      pattern of alcoholic tremor and to compare it with the well known pattern of
      enhanced physiological tremor caused by anxiety or emotional stress. Forty
      patients 20-43 years old were investigated by a neurologist and psychiatrist 1-10
      days after acute alcohol withdrawal. They all met the criteria for chronic
      alcoholism. Thirty three patients 26-43 years old with the complaint of tremor
      and anxiety or emotional stress were also investigated. An electromyographic
      investigation was performed to evaluate the pattern, frequency and amplitude of
      tremor. Results revealed that both groups of patients had 8-12 Hz low amplitude
      postural tremor with synchronous activity in antagonist muscles. Patients with
      alcohol withdrawal tremor had significantly higher amplitude tremor compared with
      patients with anxiety and emotional stress. No other clinical or
      electromyographic differences existed between both groups. In conclusion alcohol
      withdrawal tremor is a variant of enhanced physiological tremor. Both types of
      tremor could be distinguished only by the circumstances responsible for tremor
      occurrence.

PMID- 8654317
TI  - Somatosensory evoked potentials following voluntary movement during upper arm
      compression.
AB  - We examined the modulation of somatosensory evoked potentials (SEPs) during upper
      arm compression and following voluntary movement during upper arm compression.
      Most SEPs were significantly decreased, although some SEPs showed a slight, non
      significant diminution. SEPs are mediated not only by myelinated fibers but also
      by mixed nerves and afferents from cutaneous, joints, and deep tissues, these
      being dependent upon the dorsal column-medical lemniscal system. Therefore, most
      of the diminution in SEPs found here may have been due to afferent occlusion from
      muscle, cutaneous, joints, and deep tissues, since normal SEPs are selectively
      modulated, corresponding to motor or mental tasks, regardless of whether gating
      is centrifugal or centripetal. In addition, the present experiments showed that
      all the SEPs at FZ, C3' and CZ were significantly decreased following voluntary
      movement at a pressure 25%-30% higher than the subject's systolic blood pressure.
      Comparing SEPs during upper arm compression and those following voluntary
      movement during upper arm compression at these pressures, we found that the SEPs
      at C3' were significantly diminished following voluntary movement during upper
      arm compression, with other SEPs showing slight, non-significant attenuation. In
      conclusion, it is possible that the diminution in SEPs following voluntary
      movement could be responsible for sensory inputs, however, when sensory inputs
      are present, centrifugal modulation would also be responsible for this
      diminution.

PMID- 8654318
TI  - Early detection of neurological involvement in diabetes mellitus.
AB  - The aim of this study was to investigate diabetic patients to obtain
      electrophysiological data of possible neurological abnormalities even in the
      absence of neuropathy symptoms, taking into account metabolic control. Fifty five
      diabetic patients and twenty healthy subjects were included in this study. Motor
      and sensory nerve conduction velocities (CV), F wave and somatosensory evoked
      potentials (SEP) were recorded. Metabolic data about glycemia and HbA1c were
      collected. 49.1% of the patients had peripheral nerve conduction slowing. 56.4%
      of the patients had SEP abnormalities, and among them 38.7% did not have any
      peripheral nerve alterations. 40% of diabetic patients had F wave abnormalities
      and 22.7% peripheral nerve conduction was within normal limits. 33.7% of our
      patients had carpal tunnel syndrome and 38.8% of these were asymptomatic. There
      was a significant association between electrophysiological parameters and
      metabolic control. In diabetic patients it is essential to determine the presence
      and distribution of neuropathy.

PMID- 8654319
TI  - Nerve conduction changes in asymptomatic HIV-1 seropositive individuals in the
      absence of other risk factors for neuropathy.
AB  - The major problem in determining the role of HIV-1 infection in the pathogenesis
      of peripheral neuropathy is the difficulty in separating possible effects of
      confounding factors such as other infections, malnutrition, neurotoxic
      medication, drug abuse and antiretroviral treatment. We therefore selected 28
      neurologically asymptomatic HIV-seropositive homosexual men (category A, CDC
      1993) without other recognized reasons for peripheral nerve disease and 20 age,
      sex and height matched healthy controls for a prospective nerve conduction study.
      Nine (32%) HIV-seropositive patients had single nerve conduction abnormalities
      and 2 (7%) had at least two abnormalities considered to be indicative of
      subclinical neuropathy. Even patients with normal CD4 cell counts showed
      significantly lower mean sural nerve conduction velocities and higher tibial
      distal motor latencies compared to controls (ANOVA; p < 0.05). There was an
      overall trend toward more frequent nerve conduction changes in subgroups with
      abnormal CD4 cell counts, lymphocyte responsiveness or beta 2-microglobulin
      levels. Using strict selection criteria subclinical nerve conduction changes can
      be found even in the absence of symptomatic HIV-disease or potential confounding
      factors suggesting that HIV-1 plays a direct role in the pathogenesis of
      associated peripheral nervous system disease.

PMID- 8654320
TI  - Acute multifocal motor neuropathy with early spontaneous recovery: a distinct
      syndrome from Guillain-Barre syndrome?
AB  - We describe a case of acute multifocal motor neuropathy with normal sensory
      conduction studies in the nerve segments of severe motor conduction block.
      Antiganglioside antibodies were not detected in serum and the patient recovered
      spontaneously. The clinical picture and course of time of the illness allowed the
      diagnosis of a Guillain-Barre syndrome (GBS). The electrophysiological findings
      closely matched the typical findings of chronic multifocal motor neuropathy with
      persistent conduction block. From these similarities, we conclude that acute and
      chronic forms of acquired demyelinating motor neuropathies have to be accepted as
      variants of acute GBS and chronic inflammatory demyelinating polyneuropathy
      (CIDP), respectively. We suggest that the conduction block cannot always be
      attributed to antiganglioside antibodies, as chronic cases without
      antiganglioside antibodies have also been reported and further elevation of
      antibody titres has been seen after spontaneous recovery.

PMID- 8654321
TI  - Involvement of the autonomic nervous system in patients with syringomyelia--a
      study with the sympathetic skin response.
AB  - In order to determine the function of the autonomic nervous system in
      syringomyelia, the sympathetic skin response (SSR) was performed in 13 patients
      with syringomyelia and 20 healthy controls. SSR was recorded from both palms and
      soles. In patients with syringomyelia, we found absent responses, prolonged
      latencies and reduced amplitudes. SSRs could be recorded in 15 out of the
      examined 26 upper extremities. The latencies were prolonged in 12 of these cases.
      In the lower limbs, 11 SSRs could be obtained. In 4 of these cases the latencies
      were prolonged. The SSR latencies recorded from the palms and soles were both
      significantly prolonged (p < 0.05) and the amplitudes were reduced (p < 0.05) as
      compared to normal persons. Our data strongly suggest involvement of the
      autonomic nervous system in syringomyelia as assessed by the SSR response (in
      upper and lower extremities). In our patients, the extent of autonomic
      dysfunction was not related to the stage or the duration of disease.

PMID- 8654322
TI  - Evidence of deterministic chaos in the myoelectric signal.
AB  - Our aim was to study whether the myoelectric signals can be better modelled as
      outputs of a nonlinear dynamic system rather than as random stochastic signals.
      Both the nonlinear predictability and the dimensionality of the signals were
      studied using methods of nonlinear dynamics. The signals were measured from the
      biceps brachii muscle during both fatiguing and non-fatiguing isometric
      contractions at low load levels. The myoelectric signals were found to be
      nonlinear and to have a structure statistically distinguishable from random
      noise. The correlation dimension describing the dimensionality of the myoelectric
      signal decreased during local muscular fatigue. The results support the use of
      the theory of nonlinear dynamics for the modelling of the myoelectric signals.

PMID- 8654323
TI  - Effect of postural and load variation on the coordination of the leg muscles in
      concentric jumping movement.
AB  - Coordination of the lower extremity muscles was studied under different load
      conditions (40-110% of the body weight). Skilled male subjects performed vertical
      jumps with maximum effort in four body postures (105-165 degree angle of the hip
      joint) without any balance requirements. The maximum peak force values closely
      followed the variation in the body weight (p < 0.001). Furthermore, a more erect
      body posture reduced the force level during the first half and increased it
      during the second half of the jump (p < 0.001) in consequence of the force-length
      relationship of the thigh muscles. The shift toward an erect body posture
      significantly increased the activity of the rectus femoris (p < 0.001) and
      slightly that of the vasti muscles (n.s.). On the other hand, the gastrocnemius
      medialis reacted clearly (p < 0.01) and the gluteus maximus and gastrocnemius
      lateralis muscle slightly to the variation in body weight. Hence, the concentric
      jump conditions divided the agonist muscles into two categories: the posture
      sensitive muscles guided by the rectus femoris and the load sensitive muscles
      guided by the gastrocnemius medialis. The central nervous system (CNS) seems
      basically to favour the muscle coordination of an erect body posture through the
      function of two-joint muscle extending the knee joint. In addition according to
      the requirements of the increasing load, the CNS postpones the timing of the
      concentration of the activity of the hip and ankle joint agonists. But in the
      vertical jump as a whole, the activity pattern of the leg muscles was not
      essentially influenced by the different posture or load conditions (n.s.).

PMID- 8654324
TI  - Electrophysiology of the palmomental reflex in normal and parkinsonian subjects.
AB  - The palmomental reflex (PMR), obtained by mechanical stimulation of the skin of
      the thenar and hypothenar eminences of the hand and recording the surface EMG
      response from the chin muscles homolateral and contralateral to the side of
      stimulation, was studied in normal subjects and in a group of akinetic
      parkinsonians, both de novo and treated. PMR was present in most subjects of both
      groups. No differences regarding the incidence of the PMR homolateral to
      stimulation of the thenar eminence was found between controls and patients, and
      it was non-habituating in both groups. When the hypothenar eminence was
      stimulated, the PMR was present in about half of the subjects of both groups. PMR
      was present contralaterally in both normal and patients, whereas bilateral PMR
      prevailed in parkinsonians. Latency and duration of the reflex were significantly
      shorter in parkinsonians than in controls. The data are discussed in the light of
      the pathophysiology of the PMR putative pathways in normal subjects and in
      Parkinson's disease.

PMID- 8654325
TI  - Dietary fibres: effects on lipid metabolism and mechanisms of action.

PMID- 8654326
TI  - The Malmo Food Study: the reproducibility of a novel diet history method and an
      extensive food frequency questionnaire.
AB  - OBJECTIVE: To assess the reproducibility of two diet assessment methods, an
      extensive quantitative food frequency questionnaire (method A) and a novel
      shorter quantitative food frequency questionnaire with a 14 day food record
      (method B). DESIGN: A randomized prospective cohort study. SETTING: General
      community. SUBJECTS: 241 residents of the town of Malmo, aged between 50-69
      years, 126 men and 115 women who completed the methods one year apart. METHODS:
      Both diet methods were designed to cover the whole diet and portion sizes were
      estimated using a booklet with 120 photographs; method A comprised 250 items and
      method B combined a two-week food record measuring lunch and dinner meals and a
      shorter 130 item quantitative food frequency questionnaire for average
      consumption of foods, snacks and beverages during the past year; RESULTS: The
      percent difference between estimated energy intake one year apart were for men
      10.7% for method A and 0.2% for method B, corresponding values for women 13.7%
      and 1.1%. Method B showed a good agreement between measurements for energy
      providing nutrients, micronutrients and major food groups, i.e. meat products,
      edible fats, milk, fish, fruits and vegetables with correlation coefficients
      between 0.70-0.90 for women. The percent difference of average intake of edible
      fat was about 10%. Average energy-adjusted Pearson's correlation coefficients
      were of the order of 0.50-0.80 for most nutrients including 14 fatty acids. The
      correlation for the ratio between polyunsaturated and saturated fatty acids were
      about 0.70 for men and 0.80 for women; CONCLUSION: A modified diet history method
      combining a food record and a food frequency questionnaire shows good
      reproducibility.

PMID- 8654327
TI  - The Malmo Food Study: the relative validity of a modified diet history method and
      an extensive food frequency questionnaire for measuring food intake.
AB  - OBJECTIVE: To assess the relative validity of two diet assessment methods, an
      extensive quantitative food frequency questionnaire (method A) and a novel
      shorter quantitative food frequency questionnaire with a 14 day food record
      (method B). DESIGN: A randomized prospective cohort study. SETTING: General
      community. SUBJECTS: 206 residents of the town of Malmo, aged between 50-69
      years, 101 men and 105 women who completed the methods during one year. METHODS:
      Both diet methods were designed to cover the whole diet and portion sizes were
      estimated using a booklet with 120 photographs; method A comprised 250 items and
      method B combined a two-week food record measuring lunch and dinner meals and a
      shorter 130 item quantitative food frequency questionnaire for average
      consumption of foods, snacks and beverages during the past year. An 18 day
      dietary record comprising six 3-day weighed records evenly distributed over one
      year served as a reference method. RESULTS: Pearson's correlation coefficients
      varied from 0.25 for fat intake to 0.84 for milk products for method A and from
      0.32 for fish to 0.88 for meat for method B. Correlations for most food groups
      ranged between 0.50-0.80, and were higher for method B. Only small changes were
      noted after adjustment for energy intake. On average for most food groups
      categorization of subjects into quartiles, 55% of subjects belonging to the
      lowest quartile, and 57-59% of those belonging to the highest quartile for method
      A and B were correctly classified. CONCLUSION: A combined food record with a
      quantitative food frequency questionnaire is a better tool for food assessment
      than an extensive food frequency questionnaire.

PMID- 8654328
TI  - Twenty-four-hour energy expenditure and urinary catecholamines of humans
      consuming low-to-moderate amounts of medium-chain triglycerides: a dose-response
      study in a human respiratory chamber.
AB  - OBJECTIVE: To determine whether medium-chain triglycerides, in low-to-moderate
      amounts consumed with meals (at breakfast, lunch and dinner), can increase daily
      energy expenditure (EE) and 24-h urinary excretion of catecholamines in humans.
      DESIGN: Dose-response study conducted under double-blind randomised design.
      SETTING: Respiratory chamber at the Faculty of Medicine, University of Geneva.
      SUBJECTS: Eight healthy young men were recruited from the student population by
      advertisement in our Faculty. METHODS: 24-h EE and urinary catecholamines were
      measured in each subject during stay in a respiratory chamber on four separate
      occasions. These were randomised between four different combinations of medium
      chain triglycerides (MCT) and long-chain triglycerides (LCT), a total 30g/day,
      which was consumed with their habitual diet in three equal parts (10g each) at
      breakfast, lunch, and dinner in the following ratio of MCT: LCT (g/g) 0:30, 5:25,
      15:15 and 30:0. RESULTS: 24-h EE increased significantly with increasing MCT:LCT
      ratio (ANOVA, P < 0.001), with the diet providing a total of 15-30 g MCT per day
      stimulating 24-h EE by 5%: this corresponds to a mean absolute increase in daily
      EE of approximately 500kJ, with individual values varying between 268 kJ and 756
      kJ. No significant differences were observed in respiratory quotient nor in
      urinary nitrogen losses across diets, but 24-h urinary noradrenaline was
      significantly increased (ANOVA, P < 0.025), whereas adrenaline and dopamine were
      unaltered. CONCLUSIONS: This study suggests that relatively low-to-moderate
      intake of MCT (15-30 g per day) as part of habitual diet may play a role in the
      control of human body composition by enhancing daily EE, and that this effect is
      mediated at least in part through activation of the sympathetic nervous system.

PMID- 8654329
TI  - Evaluation of multiple frequency bioelectrical impedance and Cole-Cole analysis
      for the assessment of body water volumes in healthy humans.
AB  - OBJECTIVE: To assess the application of a Cole-Cole analysis of multiple
      frequency bioelectrical impedance analysis (MFBIA) measurements to predict total
      body water (TBW) and extracellular water (ECW) in humans. This technique has
      previously been shown to produce accurate and reliable estimates in both normal
      and abnormal animals. DESIGN: The whole body impedance of 60 healthy humans was
      measured at 496 frequencies (ranging from 4 kHz to 1 MHz) and the impedance at
      zero frequency, Ro, and at the characteristic frequency, Zc, were determined from
      the impedance spectrum, (Cole-Cole plot). TBW and ECW were independently
      determined using deuterium and bromide tracer dilution techniques. SETTING: At
      the Dunn Clinical Nutrition Centre and The Department of Biochemistry, University
      of Queensland. SUBJECTS: 60 healthy adult volunteers (27 men and 33 women, aged
      18-45 years). RESULTS: The results presented suggest that the swept frequency
      bioimpedance technique estimates total body water, (SEE = 5.2%), and
      extracellular water, (SEE = 10%), only slightly better in normal, healthy
      subjects than a method based on single frequency bioimpedance or anthropometric
      estimates based on weight, height and gender. CONCLUSIONS: This study has
      undertaken the most extensive analysis to date of relationships between TBW (and
      ECW) and individual impedances obtained at different frequencies ( > 400
      frequencies), and has shown marginal advantages of using one frequency over
      another, even if values predicted from theoretical bioimpedance models are used
      in the estimations. However in situations where there are disturbances of fluid
      distribution, values predicted from the Cole-Cole analysis of swept frequency
      bioimpedance measurements could prove to be more useful.

PMID- 8654330
TI  - Physical measures of recovery from anorexia nervosa during hospitalised re
      feeding.
AB  - OBJECTIVE: To examine the relationship between weight gain, changes in body
      composition and physiological characteristics of fitness during the recovery from
      anorexia nervosa. DESIGN: Longitudinal over eight weeks of intensive inpatient re
      feeding (Wk 0-8). SETTING: The London Hospital Medical College. SUBJECTS: Ten
      female patients who agreed to participate. Seven completed the protocol.
      INTERVENTIONS: Dual-energy X-ray absorptiometry (dexa) and skinfold thickness
      measures at Wk 0 and 8. Weekly measures of peak expiratory flow rate and cycle
      ergometry (several variables relating to aerobic work recorded at rest and during
      cycling at low loads (0-60 W)). Blood samples for lactate and potassium measures,
      taken during cycling at Wk 0, 4 and 8 only. RESULTS: (1) Body composition: Mean
      weight gain over eight weeks was 9.6 kg, dexa and skinfold measures showing fat
      gain to contribute 62% and 54%, respectively. Both methods showed significant
      changes in percentage body fat with refeeding (P < 0.01 and P < 0.001,
      respectively), however there were significant differences in results between
      methods before (P < 0.01) but not after (P = 0.2) refeeding. (2) Physiological
      function: Between weeks 0 and 8, mean peak expiratory flow rate rose to 85% of
      predicted values, cycle ergometry performance improved in six subjects (three
      never reached 60 W load), mean respiratory exchange ratio (RER) during cycling
      fell at 0 W and 20 W loads (both P < 0.05), and oxygen pulse increased at rest
      and 0 W load cycling (both P < 0.05), Wk 8 values being well below normal. Oxygen
      uptake at rest and all loads increased in line with body weight gain only. No
      significant changes were seen in heart rate or blood lactate and potassium
      levels. CONCLUSIONS: (1) Lean body and fat mass increased significantly during
      eight weeks of refeeding. The methodological difference in initial body fat
      measurements requires further investigation. (2) The women had severely impaired
      physiological function. Variables studied were only slowly improving with
      refeeding, and work capacity was still well below normal.

PMID- 8654331
TI  - Large differences in nutritional status between fully weaned and partially breast
      fed children beyond the age of 12 months.
AB  - OBJECTIVE: To assess the effect of prolonged (partial) breastfeeding into the
      second and third year of life on the nutritional status of children. DESIGN,
      SETTING AND SUBJECTS: The analysis is based on data collected in the first two
      rounds of the nationally representative Ghana Living Standards Survey, held in
      1987/88 (GLSS-I) and 1988/89 (GLSS-II), with both surveys covering approximately
      3000 households. For the youngest child in each household the dataset provides
      information on mode of feeding and nutritional status, as well as on several
      household and individual level socio-economic characteristics. For both GLSS
      rounds, the actual sample for analysis, which focuses on children 13-36 months,
      consisted of approximately 500 children. METHOD: Bivariate analysis was used to
      assess the relationship between prolonged (partial) breastfeeding and children's
      nutritional status. Multiple regression was used to estimate parameters, to
      determine levels of significance, and to control for confounding factors. RESULTS
      AND CONCLUSION: The data reveal a considerably lower nutritional status of
      children who continue to receive breastfeeding into their second and third year
      in comparison with fully weaned children of the same age. Differences in
      nutritional status between breastfed and nonbreastfed children cannot (only) be
      explained on the basis of differences in socio-economic conditions of households.
      It is hypothesized that, under conditions where infectious disease pressure is
      relatively low and where post-weaning child feeding practices are satisfactory,
      prolonged breastfeeding, either directly or indirectly, contributes to a lower
      nutritional status of children receiving prolonged breastfeeding in comparison
      with fully weaned children of the same age.

PMID- 8654332
TI  - Body protein in prepubertal children with phenylketonuria.
AB  - OBJECTIVE: To assess body protein and protein deposition in prepubertal children
      with phenylketonuria (PKU). DESIGN: Cross-sectional study with nested
      longitudinal cohort. SETTING: A tertiary referral paediatric hospital. SUBJECTS:
      37 PKU patients (3.9-11.0 years) and 27 unselected healthy controls (4.0-11.5
      years) of whom 29 PKU patients and 17 controls were followed longitudinally.
      INTERVENTIONS: All had measurements of height, weight, body fat and total body
      nitrogen (TBN) by neutron capture analysis; PKU patients and their unaffected
      siblings (n = 16) also had measurements of four day weighed food record and
      plasma amino acids by HPLC. RESULTS: The children with PKU compared with the
      controls were significantly shorter (height SD score -0.42 +/- 0.89 vs 0.17 +/-
      0.94, respectively, P < 0.02) and had a lower TBN (575 +/- 200 vs 710 +/- 215g,
      respectively, P < 0.02). TBN in the controls was significantly correlated with
      lean body mass (LBM), weight, height and age (r = 0.97, 0.95, 0.95, 0.88,
      respectively, P < 0.001). The children with PKU had significantly lower TBN when
      predicted from LBM, weight and age (93%, 92%, 92% of predicted, respectively),
      but normal TBN predicted from height (102% of expected). The annual accretion of
      nitrogen was similar for the PKU and controls (86 +/- 45 and 77 +/- 58 g/y,
      respectively). There was no difference between the two groups in protein intake
      or plasma amino acids except for phenylalanine. CONCLUSION: The children with PKU
      had a deficit in height and body protein despite a normal to higher accretion of
      protein. If the deficit occurs early in life, amino acid supplementation and
      other nutritional practices used at this time need to be reviewed.

PMID- 8654333
TI  - Urinary iodine excretion in mothers and their breast-fed children in relation to
      other childhood nutritional parameters.
AB  - OBJECTIVE: There is currently no coordinated policy on the epidemiology and
      control of iodine deficiency disorders (IDD) in many parts of Africa even where
      these disorders are endemic. Assessment of the urinary iodine excretion is
      believed to give the best index of the prevalence of IDD in the community. This
      study aimed to establish whether: (i) the breast-fed child of an iodine replete
      mother was protected from IDD and, (ii) infants at risk of IDD and in need of
      immediate iodine supplementation could easily be identified through simple
      screening methods. DESIGN: Randomized, cross-sectional study. SETTING: A tertiary
      care infant welfare clinic in Ibadan, South-western Nigeria, a geographical area
      recognised to be outside Nigeria's endemic goitre belt (goitre prevalence <
      5.0%). SUBJECTS: 68 healthy mother-child pairs. The children were all aged 9-18
      months and breast-fed almost exclusively. INTERVENTIONS: Nil. METHODS: The
      relationships of anthropometric, iodine status (casual urinary iodine (I) and
      iodine/creatinine ratio (I/Cr)) and nutritional indices (weights, haematocrits)
      of the mothers with those of their breast-fed children were assessed, as well as
      how these parameters differed between the children classified on the basis of
      their mid-upper arm circumference, MUAC, as: (A) borderline malnourished, MUAC <
      13.5 cm and, (B) well nourished, MUAC > 13.5 cm. RESULTS: The maternal values for
      I and I/Cr were significantly (p < 0.001) greater than those of their breast-fed
      infants, although the respective mother-child pair values correlated positively
      (I, r 0.47; I/Cr, 0.21; both p < 0.05). There was thus a gradient in iodine
      status between the mother and her breast-fed infant that is unfavourable to the
      growing child; the latter may thus require iodine supplementation in spite of the
      fact that the mother is iodine replete. Among the children, those considered well
      nourished (Group B) had similar iodine status parameters as those considered
      poorly nourished (Group A) suggesting that malnutrition alone should not be the
      determinant of the prioritization (or otherwise) of iodine supplementation in a
      population with coexistent iodine deficiency and malnutrition. Mean values for
      (I) in all the children (9.9 micrograms/dl) fell in the iodine deficiency range (
      < 10 micrograms/dL), although all the mothers were iodine replete (mean urinary
      (I) 14.5 micrograms/dL), despite the fact that all resided in a non iodine
      deficient area. CONCLUSION: The study suggests that: (i) the breast-fed child of
      an iodine replete mother resident in a non-iodine deficient area may be iodine
      deficient and in need of iodine supplementation; (ii) malnutrition, as defined by
      the simple community screening method of measuring the MUAC, will not accurately
      identify those infants in immediate need of iodine supplementation. These
      observations have important implications for planning IDD control programmes in
      Africa.

PMID- 8654334
TI  - Serum selenium values in healthy children aged 1-18 years in NE Slovenia.
AB  - OBJECTIVE: The objective of the paper was to establish the serum Se status in
      healthy children in the north-eastern region of Slovenia. SUBJECTS: In 71 healthy
      children of the age group 1-18 years the serum Se values were determined by means
      of atomic spectrometry. RESULTS: The results obtained show that the serum Se
      values depend on the age of the children. Thus the serum Se level in the youngest
      age group (1-2 years) was 74.9 +/- 9.7 micrograms/l; in the pre-school age group
      (3-5 years) it was 85.5 +/- 10.0 micrograms/l; and in the group of school
      children (11-13 years) it was 93.9 +/- 9.3 micrograms/l. The difference between
      the serum Se values in the youngest age group and all the other groups was
      statistically significant (P < 0.05). CONCLUSIONS: The serum Se levels rise
      gradually so that by the time the children reach school age their serum Se levels
      equal those found in healthy adult persons in Italy and several Western European
      countries, e.g. The Netherlands.

PMID- 8654336
TI  - Behavioral and sociocultural perspectives on ethnicity and health: introduction
      to the special issue.

PMID- 8654335
TI  - Anti-oxidant vitamin status of Russian children and elderly.

PMID- 8654337
TI  - Epidemiology of minority health.
AB  - Collecting epidemiologic data by ethnicity and race is a highly useful
      undertaking; but "bench mark" comparisons relative to majority Americans should
      not take priority over defining the determinants of health status within a
      minority group. Thus, it is necessary to identify factors contributing to the
      measured health status and to modify the environment, lifestyles, and behaviors
      to diminish the likelihood of undesirable health outcomes. This article presents
      an overview of the health status of African Americans, Asians and Pacific
      Islanders, and Hispanics. The goals are to provide a framework for the rational
      interpretation of both health status data and its determinants both within and
      between minority groups. This approach recognizes the heterogeneity of health
      status that exists within a minority group and encourages investigators to place
      more emphasis on the within-group health status differentials as they search for
      modifiable factors that underlie the risk for undesirable health outcomes.

PMID- 8654338
TI  - Macrosocial and environmental influences on minority health.
AB  - Ethnic minority populations show patterns of health, health care use, and
      mortality that differ from the overall U.S. population. Each of the broad groups
      of minorities (Asian Hispanic, Native, and African Americans) has a unique
      background of sociocultural factors that influence these patterns. Thus, the
      larger social environment for ethnic populations, including political,
      environmental, historical, and economic factors, is a major variable in possible
      health outcomes. The individual portions in this panel report of the conference
      seek to identify such factors for each ethnic group and to suggest those
      macrosocial influences that are most important for observed health effects.

PMID- 8654339
TI  - Behavioral risk factors related to chronic diseases in ethnic minorities.
AB  - This article reviews the evidence on 5 risk behaviors: cigarette smoking, dietary
      intake, being overweight, limited exercise, and alcohol consumption among African
      Americans, Asian/Pacific Islanders, Latinos, and Native Americans. Although there
      is little basis for believing that these high-risk behaviors are any less
      significant as contributors to chronic disease risk in any ethnic group, the
      limited information available, especially for Asian/Pacific Islanders and Native
      Americans, indicates that there may be significant within- and between-group
      differences in the prevalence of these behaviors. Therefore, some of the ethnic
      group differences in morbidity and mortality for chronic diseases are partly
      attributable to differences in behavioral risk profiles. Limited basic health
      behavior information on most ethnic minority groups delay the development of
      effective health promotion interventions.

PMID- 8654340
TI  - Risk-taking and abusive behaviors among ethnic minorities.
AB  - The health status and health outcomes of many ethnic minorities have remained
      poor, or have deteriorated, despite massive health promotion campaigns. Multiple
      factors that encourage ethnic minorities to engage in high-risk behaviors and
      those that discourage health promotive behaviors must be closely examined before
      any health interventions are likely to be successful in decreasing substance
      abuse, high-risk sex, accidental deaths and injuries, and violence. Cultural and
      contextual factors may put some ethnic minorities in jeopardy and at higher risk
      for poorer health than their White counterparts (B. W. K. Yee, 1995, in press).
      This review article identifies contributing factors in high-risk behaviors and
      highlights research gaps for Americans of African, Indian, Asian and Pacific
      Islander, and Hispanic descent.

PMID- 8654341
TI  - Adaptive health behaviors among ethnic minorities.
AB  - Race, ethnicity, and cultural attitudes and practices are among the variables
      that influence health behaviors, including adaptive health behaviors. The
      following discussions highlight the important role of social conditions in
      shaping health behaviors and the central role of family in promoting health
      across the Asian, Hispanic, Native American, and African American ethnic groups.
      Factors that may lead to health-damaging behaviors are also discussed. The need
      for additional research that identifies correlations among physiological, social,
      and behavioral factors and health behaviors, as well as underlying mechanisms, is
      called for.

PMID- 8654343
TI  - Cyclosporine A and the equine cornea.

PMID- 8654342
TI  - Ethnic minorities, health care systems, and behavior.
AB  - This article presents an overview of research on health care use and provider
      behavior, on doctor-patient relationships, adherence to medical regimens, self
      care, practices and avoidance health care behaviors, and attitudes of 4
      ethnoracial groups: African Americans, American Indians, Asian Americans, and
      Latinos. Although issues within the groups varied, common themes between the
      groups emerged. It became apparent, after discussion, that whatever the issues
      and health problems, these can be resolved most effectively when addressed within
      the social contexts of each ethnoracial group.

PMID- 8654344
TI  - Monozygotic triplets in the mare.

PMID- 8654345
TI  - Steroid production by equine fetal gonads: a speculative view.

PMID- 8654346
TI  - Ophthalmic cyclosporine in equine keratitis and keratouveitis: 11 cases.
AB  - Topical cyclosporine A was safely used in a series of 11 cases of equine
      keratitis and keratouveitis and appeared to be an effective anti-inflammatory
      agent in 9 cases. The clinical diagnoses included interstitial keratouveitis,
      endotheliitis, multifocal punctate keratopathy and a melting stromal ulcer. In
      most cases, the presence or absence of insidious bacterial infection was not
      conclusively determined. Topical cyclosporine A had no deleterious effects in
      this series of cases. The authors suggest that topical cyclosporine in both
      aqueous and lipid base vehicles should be investigated and evaluated as an
      alternative mode of achieving ocular immunosuppression.

PMID- 8654347
TI  - Localisation of 15-hydroxy prostaglandin dehydrogenase (PGDH) and steroidogenic
      enzymes in the equine placenta.
AB  - 15-hydroxy prostaglandin dehydrogenase (PGDH) is the critical enzyme that
      determines metabolism of primary prostaglandins. Its expression is determined in
      part by steroid hormones, particularly progesterone, formed from delta(5)
      steroids through 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity. To
      assess whether the regulation of PGDH might occur in a paracrine, autocrine or
      intracrine fashion, we used immunohistochemistry (IHC) to determine the
      localisation of key steroidogenic enzymes in the equine placenta and compared
      these patterns to the distribution of immunoreactive (IR-) PGDH. Placental tissue
      was obtained from pony or Thoroughbred mares at about Days 150, 250-280 and >300
      of pregnancy (term 320 to 360 days; n=5-8 each group). IR-PGDH, 3beta-HSD,
      cholesterol side chain cleavage enzyme (P450(scc)) and 17-hydroxylase/lyase
      (P450(C17)) were localised using specific antibodies and the avidin-biotin
      peroxidase technique and visualised using diaminobenzidine as substrate. IR
      P450(scc) was present in trophoblast cells, but not in maternal tissues of the
      microcotyledons. In contrast, at Days 150 and 280, IR-PGDH was present in
      maternal epithelial and interstitial cells in the microcotyledons, but was not
      detected in trophoblast epithelium, chorioallantois or endometrial glands. After
      Day 300, IR-PGDH was present in the maternal epithelium and interstitial cells of
      the placenta and it was also present in trophoblast cells in some specimens.

PMID- 8654348
TI  - Modulation of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in the
      equine placenta by pregnenolone and progesterone metabolites.
AB  - The purpose of this study was to measure 3beta-HSD activity in the equine
      placenta and to assess the effect of fetal and maternal blood plasma progestagens
      on 3beta-HSD activity was measured in 8 late gestation (collected by caesarian
      section at 250 to 320 days) and 7 term (collected by caesarian section at 250 to
      320 days) and 7 term (collected at birth) equine placentae using a tritium
      release assay with [3alpha-3H] pregnenolone as substrate. Mean +/- s.d. Km(app)
      and Vmax for term placentae were in general higher than for late gestation
      placentae (0.129 +/- 0.217 micromol/l and 23.85 +/- 9.1 nmol/mg/h respectively
      vs. 0.016 +/- 0.048 micromol/l and 17.36 +/- 20.9 nmol/mg/h) but there was no
      statistical difference between them. Inhibition studies were performed on 3 term
      placentae and 3 late gestation ones. Steroid concentrations used for inhibition
      studies were close to blood plasma concentrations (0.5 to 2 micromol/l). 3beta
      hydroxy compounds (5alpha-pregnene-3beta, 20alpha-diol and 3beta-hydroxy-5alpha
      pregnan-20-one) showed noncompetitive or mixed inhibition. Mean Ki(app) of 0.7
      micromol/l. Inhibition was competitive with 20alpha-hydroxy-5alpha-pregnan-3-one
      with a mean Ki(app) of 0.1 micromol/l.

PMID- 8654349
TI  - Tendonitis of the deep digital flexor tendon in the distal metacarpal/metatarsal
      region associated with tenosynovitis of the digital sheath in the horse.
AB  - Twenty-four horses with ultrasonographic evidence of tendonitis of the deep
      digital flexor tendon in the metacarpal/metatarsal region were seen over a 7 year
      period. Most horses had mild to moderate lameness and distension of the digital
      flexor tendon sheath in the affected limb. Intrasynovial analgesia of the digital
      flexor tendon sheath consistently improved the degree of lameness.
      Ultrasonography most commonly revealed small, distinct, often circular, focal
      hypoechoic areas within the deep digital flexor tendon which usually extended
      less than 1 cm proximodistally. The degree of lameness and swelling generally
      improved with box rest and controlled exercise, however, exacerbation of the
      clinical signs and ultrasonographic lesions was common when affected horses were
      returned to work or allowed free exercise at pasture. Of 24 cases, only 7 horses
      made a full recovery and returned to their intended athletic activity.

PMID- 8654350
TI  - Comparison of polysulphated glycosaminoglycan and sodium hyaluronate with placebo
      in treatment of traumatic arthritis in horses.
AB  - A randomised double blind and placebo controlled clinical study was carried out.
      Standardbred trotters (n=77), age 3-4 years) with moderate to severe lameness
      were grouped according to number of affected joints and, within each group, were
      randomised for treatment with polysulphated glycosaminoglycan (PSGAG), sodium
      hyaluronate (SH) or placebo for 3 weeks. The horses were inspected weekly with a
      final examination 2-4 weeks after the end of treatment. Mean initial lameness
      score was significantly reduced during treatment and at the last examination in
      all 3 groups (P<0.01). Additionally, the prevalence of sound horses increased
      significantly from 1 to 3 weeks of treatment and to the last examination in all 3
      groups (P < or = 0.03). Comparison of the 2 treatment groups with regard to
      development of the lameness curve and time until soundness indicated a small, non
      significant difference in favour of SH. No significant difference was detected
      between the 2 treatment groups in the prevalences or cumulative incidence of
      soundness. The study detected a superior effect of the 2 drugs compared with
      placebo for reduction in lameness score during the treatment period (P=0.03) and
      the total study period (P<0.01), time until soundness (P=0.04) and the prevalence
      of sound horses at the last examination (P<0.01). All 3 treatments affected
      traumatic arthritis in horses, but the SH and PSGAG gave better results than the
      placebo.

PMID- 8654351
TI  - Descriptive epidemiological study of equine laminitis.
AB  - A descriptive and matched case-control study of laminitis was conducted in 7
      private practices and at the Texas Veterinary Medical Centre (TVMC) between May
      1992 and July 1993. Out of 108 horses with laminitis, 19 acute (49%) and 20
      chronic (51%) cases were seen in private practice and 16 acute (23%) and 53 (77%)
      cases at the TVMC. Gastrointestinal disease was the most common problem in 19/35
      horses (54%), occurring just prior to the onset of acute laminitis in all
      hospitals. Among all horses in the study, most commonly used drugs were
      phenylbutazone (68%), acepromazine (34%), dimethyl sulphoxide (DMSO) (27%),
      antibiotics of various types (19%) and flunixin meglumine (19%). Acepromazine,
      DMSO and flunixin meglumine were used more commonly in acute cases of laminitis
      compared to chronic cases. In acutely affected horses, DMSO and flunixin
      meglumine were used significantly more often at the TVMC. In chronic cases,
      phenylbutazone and antibiotics were used more often in private practice. Shoeing
      and trimming were more commonly part of the treatment protocol for chronic cases.
      There were no significant associations between age, breed, sex or weight and the
      occurrence of acute laminitis. Horses with chronic laminitis were significantly
      older (P=0.04) and more females tended to be affected (P=0.08).

PMID- 8654352
TI  - Harem stability and reproductive success of Misaki feral mares.
AB  - The stability of relationships between harem stallions and mares (consort
      relations) was investigated and the durations of inter partum intervals were
      determined in order to establish if there was any correlation between the
      stability of consort relation and reproductive success of mares in Misaki feral
      horses. Thirty-four mares were observed continuously for more than 5 years. The
      lifetime stability was 80-100% (mean 92.4%) for 16 mares, 60-79% (mean 70.4%) for
      10 mares and 0-59% (mean 27.9%) for 8 mares. The continuous length (years) of
      specific consort relations was 2-10 years and was found to correlate
      significantly with lifetime stability. There was a significant positive
      correlation of lifetime stability with lifetime reproductive success for 34 mares
      observed, and the correlation was higher when the data of 8 wandering mares (<60%
      in lifetime stability) were omitted. The mean +/- s.d. delivery interval of 25
      stable mares was 364.5 +/- 11.0 days, whereas that of 8 unstable mares and stable
      mares who changed stallions was 387.0 +/- 40.2 days. There was a significant
      difference between delivery intervals of stable and unstable mares. Significant
      correlations between the stability of consort relations and both the foaling
      rates and delivery intervals suggest that mares may obtain major reproductive
      advantages if they maintain long term and stable consort relations with a
      particular stallion throughout their reproductive life span.

PMID- 8654353
TI  - Small intestinal herniation through the epiploic foramen: 53 cases (1987-1993).
AB  - The incidence of epiploic entrapment of the small intestine in horses undergoing
      celiotomy for colic was 5%. The condition was more prevalent in older (mean 9.81
      years) gelding and Thoroughbred horses. Preoperative peritoneal protein level was
      a good prognostic indicator as it was significantly greater in the nonsurvivor
      (39.4 +/- 5.10) group than in the survivor group (26.6 +/- 14.0) (P<0.05).
      Abdominal ultrasonography allowed earlier diagnosis and surgical intervention in
      nonpainful cases with inconclusive rectal findings. Surgery was completed in 46
      horses and 44 horses recovered from anaesthesia. Nine horses were either
      subjected to euthanasia in surgery (7 horses) or died in recovery (2 horses).
      Repeat laparotomies were pursued in 27% (12/44) of the horses. Seven horses (16%)
      showed post operative adynamic ileus which was the most common post operative
      complication. The incidence (6%) of adhesion formation was lower than previously
      reported. Other post operative complications included gastric ulceration, liver
      disease, diarrhoea and weight loss. Short and long term survival rates were 79%
      (35/44) and 70% (31/44) respectively. Improved rates were attributed to earlier
      referral and diagnosis and prompt surgical intervention. The aggressive use of
      repeat celiotomy and a more effective treatment of the endotoxic horse in the
      perioperative period contributed to survival.

PMID- 8654354
TI  - Ultrastructure of the secretory endometrium during oestrus in young maiden and
      foaled mares.
AB  - Cyclical accumulation of uterine fluid occurs during oestrus and is often seen in
      excessive volumes in mares considered susceptible to endometritis. Since the
      mechanisms behind the formation of free uterine fluid remain to be clarified, the
      fine structure of the secretory equine endometrium was studied in biopsies
      collect during videoendoscopy from 14 endometritis-free, 4-9-year-old mares
      during oestrus. A distinct oedema of the tunica mucosa was evident. The surface
      epithelium had both ciliated and nonciliated cells and, particularly at the
      uterine body, often presented intra-epithelial macrophages. The epithelial cells
      of the gland duct were similar to the surface epithelium, except that the
      nonciliated cells lacked secretory vesicles in the non ciliated cells. This
      glandular epithelium presented clear signs of secretory activity with conspicuous
      secretory vesicles holding electron-dense granula in the adluminal cytoplasm and
      a well developed supranuclear Golgi apparatus. Secretory products as well as cell
      debris were commonly found in the lumen of the glands. No clear signs of apocrine
      secretion were found and it seemed therefore, that the mechanism of secretion is
      merocrine, i.e. by exocytosis. The endometrial oedema and intense secretory
      activity, both under oestrogenic influence, contribute to the building up of the
      uterine fluid during oestrus. No differences in morphology of the secretory
      endometrium could be noticed between nulliparous mares and mares that had had 1
      or 2 foals.

PMID- 8654355
TI  - Role of navicular bone shape in the pathogenesis of navicular disease: a
      radiological study.
AB  - From progeny lists of 30 Dutch Warmblood sires, 586 3-year-old females by these
      stallions were randomly selected, each progeny group aimed at 20 animals for
      statistical reasons. The front feet of the sires and female progeny were examined
      radiographically using lateromedial and dorsopalmar upright pedal projections.
      The radiological features associated with navicular disease were classified 0-4
      using a standardised classification, grades 3 and 4 representing the more severe
      changes. The shape of the proximal articular border of the navicular bone outline
      on the dorsopalmar view was classified 1-4; 1=concave; 2=undulating; 3=straight;
      4=convex. A significant shape-grade association was found, the highest grades 3
      and 4 incidence demonstrated by shape 4. In shapes 1 and 2, navicular bones
      grades 3 and 4 features were mainly characterised by inverted flask-shaped
      channels. In shape 3, navicular bones grades 3 and 4 were dominated by
      enthesiophytes. These findings indicate an apparent shape predisposition to
      radiological changes associated with navicular disease. The shape of the
      navicular bone in the offspring was on average the same as the sire, indicating
      an hereditary element in navicular bone shape.

PMID- 8654356
TI  - Identical triplets in a thoroughbred mare.

PMID- 8654357
TI  - Recognition of bronchopulmonary dysplasia in a newborn foal.

PMID- 8654358
TI  - A pathogenic bacterium triggers epithelial signals to form a functional bacterial
      receptor that mediates actin pseudopod formation.
AB  - Enteropathogenic E. coli (EPEC) belongs to a group of bacterial pathogens that
      induce actin accumulation beneath adherent bacteria. We found that EPEC adherence
      to epithelial cells mediates the formation of fingerlike pseudopods (up to 10
      microm) beneath bacteria. These actin-rich structures also contain tyrosine
      phosphorylated host proteins concentrated at the pseudopod tip beneath adherent
      EPEC. Intimate bacterial adherence (and pseudopod formation) occurred only after
      prior bacterial induction of tyrosine phosphorylation of an epithelial membrane
      protein, Hp90, which then associates directly with an EPEC adhesin, intimin.
      These interactions lead to cytoskeletal nucleation and pseudopod formation. This
      is the first example of a bacterial pathogen that triggers signals in epithelial
      cells which activates receptor binding activity to a specific bacterial ligand
      and subsequent cytoskeletal rearrangement.

PMID- 8654359
TI  - AChR phosphorylation and aggregation induced by an agrin fragment that lacks the
      binding domain for alpha-dystroglycan.
AB  - Agrin induces both phosphorylation and aggregation of nicotinic acetylcholine
      receptors (AChRs) when added to myotubes in culture, apparently by binding to a
      specific receptor on the myotube surface. One such agrin receptor is alpha
      dystroglycan, although binding to alpha-dystroglycan appears not to mediate AChR
      aggregation. To determine whether agrin-induced AChR phosphorylation is mediated
      by alpha-dystroglycan or by a different agrin receptor, fragments of recombinant
      agrin that differ in affinity for alpha-dystroglycan were examined for their
      ability to induce AChR phosphorylation and aggregation in mouse C2 myotubes. The
      carboxy-terminal 95 kDa agrin fragment agrin-c95(A0B0), which binds to alpha
      dystroglycan with high affinity, failed to induce AChR phosphorylation and
      aggregation. In contrast, agrin-c95(A4B8) which binds less strongly to alpha
      dystroglycan, induced both phosphorylation and aggregation, as did a small 21 kDa
      fragment of agrin, agrin-c21(B8), that completely lacks the binding domain for
      alpha-dystroglycan. We conclude that agrin-induced AChR phosphorylation and
      aggregation are triggered by an agrin receptor that is distinct from alpha
      dystroglycan.

PMID- 8654360
TI  - RAP, a specialized chaperone, prevents ligand-induced ER retention and
      degradation of LDL receptor-related endocytic receptors.
AB  - The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP)
      forms a complex with a receptor-associated protein (RAP) within the secretory
      pathway. RAP inhibits ligand binding to LRP and is required for normal functional
      expression of LRP in vivo, suggesting a physiological function as a specialized
      chaperone. We have used RAP-deficient mice, generated by gene targeting, to
      investigate the role of RAP in the biosynthesis and biological activity of LRP
      and other members of the LDL receptor gene family in various organs and in
      embryonic fibroblasts. Our results demonstrate that RAP is required for the
      proper folding and export of the receptors from the endoplasmic reticulum (ER) by
      preventing the premature binding of co-expressed ligands. Overexpression of
      apolipoprotein E (apoE), a high affinity ligand for LRP, results in dramatically
      reduced cellular LRP expression, an effect that is prevented by co-expression of
      RAP. RAP thus defines a novel class of molecular chaperones that selectively
      protect endocytic receptors by binding to newly synthesized receptor
      polypeptides, thereby preventing ligand-induced aggregation and subsequent
      degradation in the ER.

PMID- 8654361
TI  - A novel Hsp70 of the yeast ER lumen is required for the efficient translocation
      of a number of protein precursors.
AB  - The yeast genome sequencing project predicts an open reading frame (YKL073) that
      would encode a novel member of the Hsp70 family of molecular chaperones. We
      report that this 881 codon reading frame represents a functional gene expressing
      a 113-119 kDa glycoprotein localized within the lumen of the endoplasmic
      reticulum (ER). We therefore propose to designate this gene LHS1 (Lumenal Hsp
      Seventy). Our studies indicate that LHS1 is regulated by the unfolded protein
      response pathway, as evidenced by its transcriptional induction in cells treated
      with tunicamycin, and in various mutants defective in precursor processing (sec11
      7, sec53-6 and sec59-1). LHS1 is not essential for viability, but an Lhs1 null
      mutant strain exhibits a coordinated induction of genes regulated by the unfolded
      protein response indicating a role for Lhs1p in protein folding in the ER.
      Furthermore, the null mutation is synthetically lethal in combination with
      (delta)ire1, thus activation of the unfolded protein response pathway is
      essential for cells to tolerate loss of Lhs1p. Synthetically lethality is also
      seen with mutations in KAR2, strongly suggesting that Kar2p and Lhs1p have
      overlapping functions. The Lhs1 null mutant exhibits a severe constitutive defect
      in the translocation of several secretory preproteins. We therefore propose that
      Lhs1p is a molecular chaperone of the ER lumen involved in both polypeptide
      translocation and subsequent protein folding.

PMID- 8654362
TI  - Co-translational trimerization of the reovirus cell attachment protein.
AB  - The reovirus cell attachment protein, sigma1, is a trimer with a 'lollipop'
      structure. Recent findings indicate that the N-terminal fibrous tail and the C
      terminal globular head each possess a distinct trimerization domain. The region
      responsible for N-terminal trimerization (formation of a triple alpha-helical
      coiled-coil) is located at the N-terminal one-third of sigma1. In this study, we
      investigated the temporality and ATP requirement of this trimerization event in
      the context of sigma1 biogenesis. In vitro co-synthesis of the full-length (FL)
      and a C-terminally truncated (d44) sigma1 protein revealed a preference for
      homotrimer over heterotrimer formation, suggesting that assembly at the N
      terminus occurs co-translationally. This was corroborated by the observation that
      polysome-associated sigma1 chains were trimeric as well as monomeric. Truncated
      proteins (d234 and d294) with C-terminal deletions exceeding half the length of
      sigma1 were found to trimerize post-translationally. This trimerization did not
      require ATP since it proceeded normally in the presence of apyrase. In contrast,
      formation of stable FL sigma1 trimers was inhibited by apyrase treatment.
      Collectively, our data suggest that assembly of nascent sigma1 chains at the N
      terminus is intrinsically ATP independent, and occurs co-translationally when the
      ribosomes have traversed past the midpoint of the mRNA.

PMID- 8654363
TI  - The CXXC motif: imperatives for the formation of native disulfide bonds in the
      cell.
AB  - The rapid formation of native disulfide bonds in cellular proteins is necessary
      for the efficient use of cellular resources. This process is catalyzed in vitro
      by protein disulfide isomerase (PDI), with the PDI1 gene being essential for the
      viability of Saccharomyces cerevisiae. PDI is a member of the thioredoxin (Trx)
      family of proteins, which have the active-site motif CXXC. PDI contains two Trx
      domains as well as two domains unrelated to the Trx family. We find that the gene
      encoding Escherichia coli Trx is unable to complement PDI1 null mutants of
      S.cerevisiae. Yet, Trx can replace PDI if it is mutated to have a CXXC motif with
      a disulfide bond of high reduction potential and a thiol group of low pKa. Thus,
      an enzymic thiolate is both necessary and sufficient for the formation of native
      disulfide bonds in the cell.

PMID- 8654364
TI  - Differential requirement for the mitochondrial Hsp70-Tim44 complex in unfolding
      and translocation of preproteins.
AB  - The mitochondrial heat shock protein Hsp70 is essential for import of nuclear
      encoded proteins, involved in both unfolding and membrane translocation of
      preproteins. mtHsp70 interacts reversibly with Tim44 of the mitochondrial inner
      membrane, yet the role of this interaction is unknown. We analysed this role by
      using two yeast mutants of mtHsp70 that differentially influenced its interaction
      with Tim44. One mutant mtHsp70 (Ssc1-2p) efficiently bound preproteins, but did
      not show a detectable complex formation with Tim44; the mitochondria imported
      loosely folded preproteins with wild-type kinetics, yet were impaired in
      unfolding of preproteins. The other mutant Hsp70 (Ssc1-3p') bound both Tim44 and
      preproteins, but the mitochondria did not import folded polypeptides and were
      impaired in import of unfolded preproteins; Ssc1-3p' was defective in its ATPase
      domain and did not undergo a nucleotide-dependent conformational change,
      resulting in permanent binding to Tim44. The following conclusions are suggested.
      (i) The import of loosely folded polypeptides (translocase function of mtHsp70)
      does not depend on formation of a detectable Hsp70-Tim44 complex. Two
      explanations are possible: a trapping mechanism by soluble mtHsp70, or a
      weak/very transient interaction of Ssc1-2p with Tim44 that leads to a weak force
      generation sufficient for import of loosely folded, but not folded, polypeptides.
      (ii) Import of folded preproteins (unfoldase function of mtHsp70) involves a
      reversible nucleotide-dependent interaction of mtHsp70 with Tim44, including a
      conformational change in mtHsp70. This is consistent with a model that the
      dynamic interaction of mtHsp70 with Tim44 generates a pulling force on
      preproteins which supports unfolding during translocation.

PMID- 8654365
TI  - Crystal structure of human lithostathine, the pancreatic inhibitor of stone
      formation.
AB  - Human lithostathine (HLIT) is a pancreatic glycoprotein which inhibits the growth
      and nucleation of calcium carbonate crystals. The crystal structure of the
      monomeric 17 kDa HLIT, determined to a resolution of 1.55 angstroms, was refined
      to a crystallographic R-factor of 18.6%. Structural comparison with the
      carbohydrate-recognition domains of rat mannose-binding protein and E-selectin
      indicates that the C-terminal domain of HLIT shares a common architecture with
      the C-type lectins. Nevertheless, HLIT does not bind carbohydrate nor does it
      contain the characteristic calcium-binding sites of the C-type lectins. In
      consequence, HLIT represents the first structurally characterized member of this
      superfamily which is not a lectin. Analysis of the charge distribution and
      calculation of its dipole moment reveal that HLIT is a strongly polarized
      molecule. Eight acidic residues which are separated by regular 6 angstrom
      spacings form a unique and continuous patch on the molecular surface. This
      arrangement coincides with the distribution of calcium ions on certain planes of
      the calcium carbonate crystal; the dipole moment of HLIT may play a role in
      orienting the protein on the crystal surface prior to the more specific
      interactions of the acidic residues.

PMID- 8654366
TI  - A conserved family of cellular genes related to the baculovirus iap gene and
      encoding apoptosis inhibitors.
AB  - The baculovirus inhibitor of apoptosis gene, iap, can impede cell death in insect
      cells. Here we show that iap can also prevent cell death in mammalian cells. The
      ability of iap to regulate programmed cell death in widely divergent species
      raised the possibility that cellular homologs of iap might exist. Consistent with
      this hypothesis, we have isolated Drosophila and human genes which encode IAP
      like proteins (dILP and hILP). Like IAP, both dILP and hILP contain amino
      terminal baculovirus IAP repeats (BIRs) and carboxy-terminal RING finger domains.
      Human ilp encodes a widely expressed cytoplasmic protein that can suppress
      apoptosis in transfected cells. An analysis of the expressed sequence tag
      database suggests that hilp is one of several human genes related to iap.
      Together these data suggest that iap and related cellular genes play an
      evolutionarily conserved role in the regulation of apoptosis.

PMID- 8654367
TI  - Human hsp27, Drosophila hsp27 and human alphaB-crystallin expression-mediated
      increase in glutathione is essential for the protective activity of these
      proteins against TNFalpha-induced cell death.
AB  - Expression of small stress proteins (shsp) enhances the survival of mammalian
      cells exposed to heat or oxidative injuries. Recently, we have shown that the
      expression of shsp from different species, such as human hsp27, Drosophila hsp27
      or human alphaB-crystallin protected murine L929 cells against cell death induced
      by tumor necrosis factor (TNFalpha), hydrogen peroxide or menadione. Here, we
      report that, in growing L929 cell lines, the presence of these shsp decreased the
      intracellular level of reactive oxygen species (ROS). shsp expression also
      abolished the burst of intracellular ROS induced by TNFalpha. Several downstream
      effects resulting from the TNFalpha-mediated ROS increment, such as NF-kappaB
      activation, lipid peroxidation and protein oxidation, were inhibited by shsp
      expression. We also report that the expression of these different shsp raised the
      total glutathione level in both L929 cell lines and transiently transfected NIH
      3T3-ras cells. This phenomenon was essential for the shsp-mediated decrease in
      ROS and resistance against TNFalpha. Our results therefore suggest that the
      protective activity shared by human hsp27, Drosophila hsp27 and human alphaB
      crystallin against TNFalpha-mediated cell death and probably other types of
      oxidative stress results from their conserved ability to raise the intracellular
      concentration of glutathione.

PMID- 8654368
TI  - A retrovirus carrying the promyelocyte-retinoic acid receptor PML-RARalpha fusion
      gene transforms haematopoietic progenitors in vitro and induces acute leukaemias.
AB  - The promyelocyte (PML)-retinoic acid receptor alpha (RARalpha) fusion gene
      results from a t(15;17) chromosome translocation in acute promyelocytic
      leukaemia. We have analysed the oncogenic potential of the human fusion PML
      RARalpha product in chicken using retrovirus vectors. We show that PML-RARalpha
      transforms very early haematopoietic progenitor cells in vitro and induces acute
      leukaemias. Neither PML nor RARalpha domains alone achieve such a transformation.
      The PML-RARalpha viruses recovered from the transformed cells carry two point
      mutations in the PML domain, one of which alters both the pattern of
      intracellular localization of the fusion protein and its functional interference
      with AP-1, thus defining an essential domain in PML for oncogenic transformation.

PMID- 8654369
TI  - Molecular heterogeneity of RET loss of function in Hirschsprung's disease.
AB  - The RET proto-oncogene encodes a receptor with tyrosine kinase activity (RET)
      that is involved in several neoplastic and non-neoplastic diseases. Oncogenic
      activation of RET, achieved by different mechanisms, is detected in a sizeable
      fraction of human thyroid tumors, as well as in multiple endocrine neoplasia
      types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinoma
      tumoral syndromes. Germline mutations of RET have also been associated with a non
      neoplastic disease, the congenital colonic aganglionosis, i.e. Hirschsprung's
      disease (HSCR). To analyse the impact of HSCR mutations on RET function, we have
      introduced into wild-type RET and activated RET(MEN2A) and RET(MEN2B) alleles
      three missense mutations associated with HSCR. Here we show that the three
      mutations caused a loss of function of RET when assayed in two model cell
      systems, NIH 3T3 and PC12 cells. The effect of different HSCR mutations was due
      to different molecular mechanisms. The HSCR972 (Arg972-->Gly) mutation, mapping
      in the intracytoplasmic region of RET, impaired its tyrosine kinase activity,
      while two extracellular mutations, HSCR32 (Ser32-->Leu) and HSCR393 (Phe393-
      >Leu), inhibited the biological activity of RET by impairing the correct
      maturation of the RET protein and its transport to the cell surface.

PMID- 8654370
TI  - Engineering human interleukin-6 to obtain variants with strongly enhanced
      bioactivity.
AB  - Interleukin-6 (IL-6) triggers the formation of a high affinity receptor complex
      with the ligand binding subunit IL-6Ralpha and the signal transducing chain
      gp130. Since the intracytoplasmic region of the IL-6Ralpha does not contribute to
      signaling, soluble forms of the extracytoplasmic domain (sIL-6Ralpha), potentiate
      IL-6 bioactivity and induce a cytokine-responsive status in cells expressing
      gp130 only. This observation, together with the detection of high levels of
      circulating soluble human IL-6Ralpha (shIL-6Ralpha) in sera, suggests that the
      hIL-6-shIL-6Ralpha complex is an alternative form of the cytokine. Here we
      describe the generation of human IL-6 (hIL-6) variants with strongly enhanced
      shIL-6Ralpha binding activity and bioactivity. Homology modeling and site
      directed mutagenesis of hIL-6 suggested that the binding interface for hIL
      6Ralpha is constituted by the C-terminal portion of the D-helix and residues
      contained in the AB loop. Four libraries of hIL-6 mutants were generated by each
      time fully randomizing four different amino acids in the predicted AB loop. These
      libraries were displayed monovalently on filamentous phage surface and sorted
      separately for binding to immobilized shIL-6Ralpha. Mutants were selected which,
      when expressed as soluble proteins, showed a 10- to 40-fold improvement in shIL
      6Ralpha binding; a further increase (up to 70-fold) was achieved by combining
      variants isolated from different libraries. Interestingly, high affinity hIL-6
      variants show strongly enhanced bioactivity on cells expressing gp13O in the
      presence of shIL-6Ralpha at concentrations similar to those normally found in
      human sera.

PMID- 8654371
TI  - Differential V region mutation of two transfected Ig genes and their interaction
      in cultured B cell lines.
AB  - We have established B cell culture systems in which transfected and stably
      integrated Ig constructs spontaneously undergo high rates of variable (V) region
      mutation. Mutation rates were determined using reversion analysis of an Ig V
      region nonsense codon (Vn). A construct (Vn/gamma2a) in which a Vn was associated
      with the gamma2a constant region and its intervening and immediate flanking
      sequences mutated at a high rate of 2.2 x 10(-4)/bp/generation in the NSO myeloma
      cell line. This same Vn, when associated with the mu constant region (Vn/mu),
      mutated at a 1000-fold lower rate in NSO. The Vn/gamma2a construct also mutated
      at high rates in the 18.81 pre-B and the S107 myeloma cell lines and at a low
      rate in the J558 myeloma cell line. In NSO, the presence of the gamma2a construct
      raised the mutation rate of the mu construct and the mu decreased the mutation
      rate of gamma2a. These results suggest that there is both positive and negative
      regulation of V region mutation and that different cell lines express different
      combinations and/or amounts of trans-acting factors that are involved in the
      mutational process.

PMID- 8654372
TI  - The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle
      arrest through induction of cyclin-dependent kinase inhibitors.
AB  - While oncoproteins encoded by small DNA tumor viruses and Epstein-Barr virus
      (EBV) latent antigens facilitate G1/S progression, the EBV lytic switch
      transactivator Zta was found to inhibit growth by causing cell cycle arrest in
      G0/G1 in several epithelial tumor cell lines. Expression of Zta results in
      induction of the tumor suppressor protein, p53, and the cyclin-dependent kinase
      inhibitors, p21 and p27, as well as accumulation of hypophosphorylated pRb. Up
      regulation of p53 and p27 occurs by post-transcriptional mechanisms while
      expression of p21 is induced at the RNA level in a p53-dependent manner.
      Inactivation of pRb by transient overexpression of the human papillomavirus E7
      oncoprotein indicates that pRb or pRb-related proteins are key mediators of the
      growth-inhibitory function of Zta. These findings suggest that EBV plays an
      active role in redirecting epithelial cell physiology to facilitate the viral
      replicative program through a Zta-mediated growth arrest function.

PMID- 8654373
TI  - Selective interaction of JNK protein kinase isoforms with transcription factors.
AB  - The JNK protein kinase is a member of the MAP kinase group that is activated in
      response to dual phosphorylation on threonine and tyrosine. Ten JNK isoforms were
      identified in human brain by molecular cloning. These protein kinases correspond
      to alternatively spliced isoforms derived from the JNK1, JNK2 and JNK3 genes. The
      protein kinase activity of these JNK isoforms was measured using the
      transcription factors ATF2, Elk-1 and members of the Jun family as substrates.
      Treatment of cells with interleukin-1 (IL-1) caused activation of the JNK
      isoforms. This activation was blocked by expression of the MAP kinase phosphatase
      MKP-1. Comparison of the binding activity of the JNK isoforms demonstrated that
      the JNK proteins differ in their interaction with ATF2, Elk-1 and Jun
      transcription factors. Individual members of the JNK group may therefore
      selectively target specific transcription factors in vivo.

PMID- 8654374
TI  - Interaction of the co-activator CBP with Myb proteins: effects on Myb-specific
      transactivation and on the cooperativity with NF-M.
AB  - The oncoprotein v-Myb is a potent inducer of myeloid leukemias, and its cellular
      homolog c-Myb plays a crucial role in the regulation of hematopoiesis. Both
      proteins function as transcriptional regulators. We demonstrate that this
      function is mediated at least in part by the nuclear co-activator CREB binding
      protein (CBP). This protein interacts directly with both c-Myb and v-Myb and
      potentiates Myb-specific transcription as measured on the mim-1 promoter. In
      contrast, dominant negative mutants of CBP lead to repression, as does E1A, an
      antagonist of CBP function. Phosphorylation of c-Myb does not appear to be
      required for interaction with CBP, thus indicating that the binding may be
      constitutive. Furthermore, the C/EBP family member NF-M, which cooperates with c
      Myb in transactivating the mim-1 promoter through an adjacent DNA binding site,
      is co-activated by CBP in a Ras-dependent manner. Not only the individual
      activities of c-Myb and NF-M are stimulated by CBP, but also their synergistic
      transcriptional function, while it is negatively regulated by dominant negative
      forms of CBP. These data suggest that CBP is recruited by both Myb proteins and
      NF-M and potentiates their transcriptional activity. We suggest that CBP can
      bridge between c-Myb and NF-M, thus providing an explanation for the strong
      synergism between these two proteins.

PMID- 8654375
TI  - The B cell coactivator Bob1 shows DNA sequence-dependent complex formation with
      Oct-1/Oct-2 factors, leading to differential promoter activation.
AB  - We have shown previously that both octamer binding transcription factors, namely
      the ubiquitous Oct-1 and the B cell-specific Oct-2A protein, can be enhanced in
      transcriptional activity by their association with the B cell-specific
      coactivator protein Bob1, also called OBF-1 or OCA-B. Here we study the
      structural requirements for ternary complex formation of DNA-Oct-Bob1 and
      coactivation function of Bob1. In analogy to DNA-bound transcription factors,
      Bob1 has a modular structure that includes an interaction domain (amino acids 1
      65) and a C-terminal domain (amino acids 65-256), both important for
      transcriptional activation. A mutational analysis has resolved a region of seven
      amino acids (amino acids 26-32) in the N-terminus of Bob1 that are important for
      contacting the DNA binding POU domain of Oct-1 or Oct-2. In contrast to the viral
      coactivator VP16 (vmw65), which interacts with Oct-1 via the POU homeosubdomain,
      Bob1 association with Oct factors requires residues located in the POU-specific
      subdomain. Because the same residues are also involved in DNA recognition, we
      surmised that this association would affect the DNA binding specificity of the
      Oct-Bob1 complex compared with free Oct factors. While Oct-1 or Oct-2 bind to a
      large variety of octamer sequences, Bob1 ternary complex formation is indeed
      highly selective and occurs only in a subset of these sequences, leading to the
      differential coactivation of octamer-containing promoters. The results uncover a
      new level in selectivity that furthers our understanding in the regulation of
      cell type-specific gene expression.

PMID- 8654376
TI  - Nitrogen metabolite signalling involves the C-terminus and the GATA domain of the
      Aspergillus transcription factor AREA and the 3' untranslated region of its mRNA.
AB  - AREA is a GATA transcription factor which mediates nitrogen metabolite repression
      in Aspergillus nidulans in response to intracellular glutamine levels. We have
      identified and localized three elements important to modulation of AREA function:
      a region of 13 residues within the DNA-binding GATA domain which forms a putative
      extended loop structure, the 12 C-terminal residues, and sequences within a 218
      nucleotide region of the 3' UTR. The 12 C-terminal residues are also required for
      transcriptional activation at a subset of loci under areA control. Specific
      deletions within the 3' UTR and the C-terminus cause similar levels of
      derepression and the mutations are additive, implicating two principal signal
      transduction pathways. The contribution of the 3' UTR to AREA modulation is
      effected at the level of transcript stability such that the areA mRNA is at least
      five times more stable under nitrogen-derepressing conditions than it is under
      repressing growth conditions.

PMID- 8654377
TI  - Deletion of rpoB reveals a second distinct transcription system in plastids of
      higher plants.
AB  - The plastid genome in higher plants encodes subunits of an Escherichia coli-like
      RNA polymerase which initiates transcription of plastid genes from sequences
      resembling E.coli sigma70-type promoters. By deleting the gene for the essential
      beta subunit of the tobacco E.coli-like RNA polymerase, we have established the
      existence of a second plastid transcription system which does not utilize E.coli
      like promoters. In contrast to the E.coli-like RNA polymerase, the novel
      transcription machinery preferentially transcribes genetic system genes rather
      than photosynthetic genes. Although the mutant plants are photosynthetically
      defective, transcription by this polymerase is sufficient for plastid maintenance
      and plant development.

PMID- 8654378
TI  - Utilizing the GCN4 leader region to investigate the role of the sequence
      determinants in nonsense-mediated mRNA decay.
AB  - In the yeast Saccharomyces cerevisiae, premature translation termination promotes
      rapid degradation of mRNAs. Accelerated decay requires the presence of specific
      cis-acting sequences which have been defined as downstream elements. It has been
      proposed that the role of the downstream element may be to promote translational
      reinitiation or ribosomal pausing. The GCN4 gene produces an mRNA that contains
      four short upstream open reading frames (uORFs) preceding the GCN4 protein-coding
      region in which translational initiation and reinitiation events occur. It was
      anticipated that these uORFs would function in a manner analogous to nonsense
      codons, promoting rapid degradation of the mRNA. However, the GCN4 transcript was
      not degraded by the nonsense-mediated mRNA decay pathway. We have investigated
      the role of the leader region of the GCN4 transcript in an effort to identify
      possible sequence elements that inactivate this decay pathway. We show that the
      GCN4 leader region does not harbor a downstream element needed to promote mRNA
      decay. In addition, using hybrid GCN4-PGK1 transcripts, we demonstrate that if a
      translational reinitiation signal precedes a downstream element, the mRNA will no
      longer be sensitive to nonsense-mediated decay. Furthermore, we demonstrate that
      the downstream element is functional only after a translational initiation and
      termination cycle has been completed but is unable to promote nonsense-mediated
      mRNA decay if it is situated 5' of a translational initiation site. Based on
      these results, the role of the downstream element will be discussed.

PMID- 8654379
TI  - A long-range pseudoknot is required for activity of the Neurospora VS ribozyme.
AB  - Four small RNA self-cleaving domains, the hammerhead, hairpin, hepatitis delta
      virus and Neurospora VS ribozymes, have been identified previously in naturally
      occurring RNAs. The secondary structures of these ribozymes are reasonably well
      understood, but little is known about long-range interactions that form the
      catalytically active tertiary conformations. Our previous work, which identified
      several secondary structure elements of the VS ribozyme, also showed that many
      additional bases were protected by magnesium-dependent interactions, implying
      that several tertiary contacts remained to be identified. Here we have used site
      directed mutagenesis and chemical modification to characterize the first long
      range interaction identified in VS RNA. This interaction contains a 3 bp
      pseudoknot helix that is required for tertiary folding and self-cleavage activity
      of the VS ribozyme.

PMID- 8654380
TI  - The growth defect in Escherichia coli deficient in peptidyl-tRNA hydrolase is due
      to starvation for Lys-tRNA(Lys).
AB  - The existence of a conditional lethal temperature-sensitive mutant affecting
      peptidyl-tRNA hydrolase in Escherichia coli suggests that this enzyme is
      essential to cell survival. We report here the isolation of both chromosomal and
      multicopy suppressors of this mutant in pth, the gene encoding the hydrolase. In
      one case, the cloned gene responsible for suppression is shown to be lysV, one of
      three genes encoding the unique lysine acceptor tRNA; 10 other cloned tRNA genes
      are without effect. Overexpression of lysV leading to a 2- to 3-fold increase in
      tRNA(Lys) concentration overcomes the shortage of peptidyl-tRNA hydrolase
      activity in the cell at non-permissive temperature. Conversely, in pth, supN
      double mutants, where the tRNA(Lys) concentration is reduced due to the
      conversion of lysV to an ochre suppressor (supN), the thermosensitivity of the
      initial pth mutant becomes accentuated. Thus, cells carrying both mutations show
      practically no growth at 39 degrees C, a temperature at which the pth mutant
      grows almost normally. Growth of the double mutant is restored by the expression
      of lysV from a plasmid. These results indicate that the limitation of growth in
      mutants of E.coli deficient in Pth is due to the sequestration of tRNA(Lys) as
      peptidyl-tRNA. This is consistent with previous observations that this tRNA is
      particularly prone to premature dissociation from the ribosome.

PMID- 8654381
TI  - The crystal structure of the ternary complex of T.thermophilus seryl-tRNA
      synthetase with tRNA(Ser) and a seryl-adenylate analogue reveals a conformational
      switch in the active site.
AB  - The low temperature crystal structure of the ternary complex of Thermus
      thermophilus seryl-tRNA synthetase with tRNA(Ser) (GGA) and a non-hydrolysable
      seryl-adenylate analogue has been refined at 2.7 angstrom resolution. The
      analogue is found in both active sites of the synthetase dimer but there is only
      one tRNA bound across the two subunits. The motif 2 loop of the active site into
      which the single tRNA enters interacts within the major groove of the acceptor
      stem. In particular, a novel ring-ring interaction between Phe262 on the
      extremity of this loop and the edges of bases U68 and C69 explains the
      conservation of pyrimidine bases at these positions in serine isoaccepting tRNAs.
      This active site takes on a significantly different ordered conformation from
      that observed in the other subunit, which lacks tRNA. Upon tRNA binding, a number
      of active site residues previously found interacting with the ATP or adenylate
      now switch to participate in tRNA recognition. These results shed further light
      on the structural dynamics of the overall aminoacylation reaction in class II
      synthetases by revealing a mechanism which may promote an ordered passage through
      the activation and transfer steps.

PMID- 8654382
TI  - Variant minihelix RNAs reveal sequence-specific recognition of the helical
      tRNA(Ser) acceptor stem by E.coli seryl-tRNA synthetase.
AB  - Aminoacylation rate determinations for a series of variant RNA minihelix
      substrates revealed that Escherichia coli seryl-tRNA synthetase (SerRS)
      recognizes the 1--72 through 5--68 base pairs of the E.coli tRNA(Ser) acceptor
      stem with the major recognition elements clustered between positions 2--71 and 4-
      69. The rank order of effects of canonical base pair substitutions at each
      position on kcat/Km was used to assess the involvement of major groove functional
      groups in recognition. Conclusions based on the biochemical data are largely
      consistent with the interactions revealed by the refined structure of the
      homologous Thermus thermophilus tRNA(Ser)-SerRS complex that Cusack and
      colleagues report in the accompanying paper. Disruption of an end-on hydrophobic
      interaction between the major groove C5(H) of pyrimidine 69 and an aromatic side
      chain of SerRS is shown to significantly decrease kcat/Km of a minihelix
      substrate. This type of interaction provides a means by which proteins can
      recognize the binary information of 'degenerate' sequences, such as the purine
      pyrimidine base pairs of tRNA(Ser). The 3--70 base pair is shown to contribute to
      recognition by SerRS even though it is not contacted specifically by the protein.
      The latter effect derives from the organization of the specific contacts that
      SerRS makes with the neighboring 2--71 and 4--69 acceptor stem base pairs.

PMID- 8654383
TI  - Crystal structure of tRNA-guanine transglycosylase: RNA modification by base
      exchange.
AB  - tRNA-guanine transglycosylases (TGT) are enzymes involved in the modification of
      the anticodon of tRNAs specific for Asn, Asp, His and Tyr, leading to the
      replacement of guanine-34 at the wobble position by the hypermodified base
      queuine. In prokaryotes TGT catalyzes the exchange of guanine-34 with the queuine
      (.)precursor 7-aminomethyl-7-deazaguanine (preQ1). The crystal structure of TGT
      from Zymomonas mobilis was solved by multiple isomorphous replacement and refined
      to a crystallographic R-factor of 19% at 1.85 angstrom resolution. The structure
      consists of an irregular (beta/alpha)8-barrel with a tightly attached C-terminal
      zinc-containing subdomain. The packing of the subdomain against the barrel is
      mediated by an alpha-helix, located close to the C-terminus, which displaces the
      eighth helix of the barrel. The structure of TGT in complex with preQ1 suggests a
      binding mode for tRNA where the phosphate backbone interacts with the zinc
      subdomain and the U33G34U35 sequence is recognized by the barrel. This model for
      tRNA binding is consistent with a base exchange mechanism involving a covalent
      tRNA-enzyme intermediate. This structure is the first example of a (beta/alpha)
      barrel protein interacting specifically with a nucleic acid.

PMID- 8654384
TI  - Developmentally programmed DNA deletion in Tetrahymena thermophila by a
      transposition-like reaction pathway.
AB  - We provide a molecular description of key intermediates in the deletion of two
      internal eliminated sequences (IES elements), the M and R regions, during
      macronuclear development in Tetrahymena thermophila. Using a variety of PCR-based
      methods in vivo, double-strand breaks are detected that are generated by
      hydrolytic cleavage and correspond closely to the observed chromosomal junctions
      left behind in the macronuclei. The breaks exhibit a temporal and structural
      relationship to the deletion reaction that provides strong evidence that they are
      intermediates in the deletion pathway. Breaks in the individual strands are
      staggered by 4 bp, producing a four nucleotide 5' extension. Evidence is
      presented that breaks do not occur simultaneously at both ends. The results are
      most consistent with a deletion mechanism featuring initiation by double-strand
      cleavage at one end of the deleted element, followed by transesterification to
      generate the macronuclear junction on one DNA strand. An adenosine residue is
      found at all the nucleophilic 3' ends used in the postulated transesterification
      step. Evidence for the transesterification step is provided by detection of a 3'
      hydroxyl that would be liberated by such a step at a deletion boundary where no
      other DNA strand ends are detected.

PMID- 8654385
TI  - Structural adaptations in the interaction of EcoRI endonuclease with methylated
      GAATTC sites.
AB  - We have studied the interaction of EcoRI endonuclease with oligonucleotides
      containing GAATTC sites bearing one or two adenine-N6-methyl groups, which would
      be in steric conflict with key protein side chains involved in recognition and/or
      catalysis in the canonical complex. Single-strand methylation of either adenine
      produces small penalties in binding free energy (deltadeltaG0(S) approximately
      +1.4 kcal/mol), but elicits asymmetric structural adaptations in the complex,
      such that cleavage rate constants are strongly inhibited and unequal in the two
      DNA strands. The dependences of cleavage rate constants on the concentration of
      the Mg2+ cofactor are unaltered. When either adenine is methylated on both DNA
      strands, deltadeltaG0(S) (approximately +4 kcal/mol) is larger than the expected
      sum of the deltadeltaG0(S) values for the single-strand methylations, because the
      asymmetric adaptations cannot occur. Cleavage rate constants are reduced by 600
      000-fold for the biologically relevant GAmATTC/CTTmAAG site, but the
      GmAATTC/CTTAmAG site forms only a non-specific complex that cannot be cleaved.
      These observations provide a detailed thermodynamic and kinetic explanation of
      how single-strand and double-strand methylation protect against endonuclease
      cleavage in vivo. We propose that non-additive effects on binding and structural
      'adaptations' are important in understanding how DNA methylation modulates the
      biological activities of non-catalytic DNA binding proteins.

PMID- 8654386
TI  - The RNA 3' cleavage factors CstF 64 kDa and CPSF 100 kDa are concentrated in
      nuclear domains closely associated with coiled bodies and newly synthesized RNA.
AB  - The cleavage stimulation factor (CstF), and the cleavage and polyadenylation
      specificity factor (CPSF) are necessary for 3'-terminal processing of
      polyadenylated mRNAs. To study the distribution of 3' cleavage factors in the
      nuclei of human T24 cells, monoclonal antibodies against the CstF 64 kDa subunit
      and against the CPSF 100 kDa subunit were used for immunofluorescent labelling.
      CstF 64 kDa and CPSF 100 kDa were distributed in a fibrogranular pattern in the
      nucleoplasm and, in addition, were concentrated in 1-4 bright foci. Double
      immunofluorescence labelling experiments revealed that the foci either overlapped
      with, or resided next to, a coiled body. Inhibition of transcription with alpha
      amanitin or 5,6-dichloro-beta-D-ribofuranosyl-benzimidazole (DRB) resulted in the
      complete co-localization of coiled bodies and foci containing 3' cleavage
      factors. Electron microscopy on immunogold double-labelled cells revealed that
      the foci represent compact spherical fibrous structures, we named 'cleavage
      bodies', intimately associated with coiled bodies. We found that approximately
      20% of the cleavage bodies contained a high concentration of newly synthesized
      RNA, whereas coiled bodies were devoid of nascent RNA. Our results suggest that
      the cleavage bodies that contain RNA are those that are adjacent to a coiled
      body. These findings reveal a dynamic and transcription-dependent interaction
      between different subnuclear domains, and suggest a relationship between coiled
      bodies and specific transcripts.

PMID- 8654388
TI  - Lens crystallins of invertebrates--diversity and recruitment from detoxification
      enzymes and novel proteins.
AB  - The major proteins (crystallins) of the transparent, refractive eye lens of
      vertebrates are a surprisingly diverse group of multifunctional proteins. A
      number of lens crystallins display taxon-specificity. In general, vertebrate
      crystallins have been recruited from stress-protective proteins (i.e. the small
      heat-shock proteins) and a number of metabolic enzymes by a gene-sharing
      mechanism. Despite the existence of refractive lenses in the complex and compound
      eyes of many invertebrates, relatively little is known about their crystallins.
      Here we review for the first time the state of knowledge of invertebrate
      crystallins. The major cephalopod (squid, octopus, and cuttlefish) crystallins (S
      crystallins) have, like vertebrate crystallins, been recruited from a stress
      protective metabolic enzyme, glutathione S-transferase. The presence of
      overlapping AP-1 and antioxidant responsive-like sequences that appear functional
      in transfected vertebrate cells suggest that the recruitment of glutathione S
      transferase to S-crystallins involved response to oxidative stress. Cephalopods
      also have at least two taxon-specific crystallins: omega-crystallin, related to
      aldehyde dehydrogenase, and omega-crystallin, related to a superfamily of lipid
      binding proteins. L-crystallin (probably identical to O-crystallin) is the major
      protein of the lens of the squid photophore, a specialized structure for emitting
      light. The use of L/omega-crystallin in the ectodermal lens of the eye and the
      mesodermal lens of the photophore of the squid contrasts with the recruitment of
      different crystallins in the ectodermal lenses of the eye and photophore of fish.
      S-and omega-crystallins appear to be lens-specific (some S-crystallins are also
      expressed in cornea) and, except for one S-crystallin polypeptide (SL11/Lops4;
      possibly a molecular fossil), lack enzymatic activity. The S-crystallins (except
      SL11/Lops4) contain a variable peptide that has been inserted by exon shuffling.
      The only other invertebrate crystallins that have been examined are in one marine
      gastropod (Aplysia, a sea hare), in jellyfish and in the compound eyes of some
      arthropods; all are different and novel proteins. Drosocrystallin is one of three
      calcium binding taxon-specific crystallins found selectively in the acellular
      corneal lens of Drosophila, while antigen 3G6 is a highly conserved protein
      present in the ommatidial crystallin cone and central nervous system of numerous
      arthropods. Cubomedusan jellyfish have three novel crystallin families (the J
      crystallins); the J1-crystallins are encoded in three very similar intronless
      genes with markedly different 5' flanking sequences despite their almost
      identical encoded proteins and high lens expression. The numerous refractive
      structures that have evolved in the eyes of invertebrates contrast markedly with
      the limited information on their protein composition, making this field as
      exciting as it is underdeveloped. The similar requirement of Pax-6 (and possibly
      other common transcription factors) for eye development as well as the diversity,
      taxon-specificity and recruitment of stress-protective enzymes as crystallins
      suggest that borrowing multifunctional proteins for refraction by a gene sharing
      strategy may have occurred in invertebrates as did in vertebrates.

PMID- 8654387
TI  - In vitro binding of clathrin adaptors to sorting signals correlates with
      endocytosis and basolateral sorting.
AB  - To analyze the interaction of sorting signals with clathrin-associated adaptor
      complexes, we developed an in vitro assay based on surface plasmon resonance
      analysis. This method monitors the binding of purified adaptors to immobilized
      oligopeptides in real time and determines binding kinetics and affinities. A
      peptide corresponding to the cytoplasmic domain of wild-type influenza
      hemagglutinin, an apical membrane protein that is not endocytosed, did not
      significantly bind adaptor complexes. However, peptide sequences containing a
      tyrosine residue that has previously been shown to induce endocytosis and
      basolateral sorting were specifically recognized by adaptor complexes. The in
      vitro rates of adaptor association with these peptides correlated with the
      internalization rates of the corresponding hemagglutinin variants in vivo.
      Binding was observed both for purified AP-2 adaptors of the plasma membrane and
      for AP-1 adaptors of the Golgi, with similar apparent equilibrium dissociation
      constants in the range 10(-7)-10(-6) M. Adaptor binding was also demonstrated for
      a sequence containing a C-terminal di-leucine sequence, the second major motif of
      endocytosis/basolateral sorting signals. These results confirm the concept that
      interaction of cytoplasmic signals with plasma membrane adaptors determines the
      endocytosis rate of membrane proteins, and suggest the model that clathrin-coated
      vesicles of the trans-Golgi network are involved in basolateral sorting.

PMID- 8654389
TI  - The structure of the semenogelin gene locus--nucleotide sequence of the
      intergenic and the flanking DNA.
AB  - The sequence of 15.7 kb from the human semenogelin gene locus has been
      determined. Together with previously published sequences, this gives the
      structure of a 28-kb region encompassing the two semenogelin genes. The two
      transcription units are separated by 11616 bp intergenic DNA comprising more than
      40% repetitive DNA sequences, predominantly located to a 4-kb block of L1 and Alu
      repeats. Two more blocks of L1 sequences are present in the DNA flanking the
      genes, so that approximately 20% of the completed sequence consists of long
      interspersed repeated sequences, so called LINES. A comparison of the SgI gene
      and the SgII gene suggests that they evolved by the duplication of an
      approximately 8 kb DNA segment about 61 million years ago, probably by a
      mechanism involving recombination between L1 elements.

PMID- 8654390
TI  - cDNA cloning of a novel protein containing two zinc-finger domains that may
      function as a transcription factor for the human heme-oxygenase-1 gene.
AB  - Heme oxygenase 1 is an essential enzyme in heme catabolism that cleaves heme to
      form biliverdin, iron, and carbon monoxide. The human heme-oxygenase-1 gene is
      transcriptionally activated through the cis-regulatory element (MTE), GTCATATGAC
      (positions -156 to -147), during 12-O-tetradecanoylphorbol 13-acetate (TPA)
      induced differentiation of myelomonocytic cell lines, such as THP-1, to
      macrophages. MTE is responsible for the myelomonocytic-specific induction of heme
      oxygenase-1 gene expression, and is bound by ubiquitous and myelomonocytic cell
      line-restricted proteins. In this study, we cloned the cDNA segments coding for a
      portion of a protein that binds to MTE by a Southwestern procedure from a THP-1
      cDNA expression library; we subsequently isolated putative full-length cDNAs by a
      conventional hybridization procedure. The deduced protein, termed MTB-Zf,
      consists of 1482 amino acid residues, has a molecular mass of about 162 kDa, and
      contains the two widely separated zinc-finger domains located near the N- and C
      termini. MTB-Zf possesses other structural features characteristic of
      transcription factors, including a long stretch of acidic amino acids (amino
      acids 67 - 95), a proline-rich region (positions 733-849), a region rich in basic
      amino acids (positions 1161-1247), and a leucine repeat-like region (positions
      486-514). We show that a portion of MTB-Zf, including an N-terminal zinc-finger
      domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA
      leads to transactivation of the heme-oxygenase-1 gene promoter. Since the 6.5 kb
      MTB-Zf is expressed in various human cell lines of different lineages, MTB-Zf may
      represent a ubiquitous MTE-binding protein. Furthermore, the MTB-Zf gene has been
      mapped to human chromosome 1p35-36.1 by fluorescence in situ hybridization, a
      region which is frequently deleted in various solid tumors, including neurogenic
      tumors. We found remarkable differences in the expression patterns of MTB-Zf mRNA
      and two other hybridizable mRNAs of 5kb and 8.5 kb when human brain and primary
      brain tumors were compared. Both MTB-Zf and the 8.5-kb mRNAs were abundantly
      expressed in the five primary brain tumors examined, but only the 5-kb mRNA was
      detectable in the human brain. These results suggest that MTB-Zf is a
      transcription factor and may also play an important role in cell growth or
      differentiation.

PMID- 8654391
TI  - The incorporation of arachidonic acid into triacylglycerol in P388D1 macrophage
      like cells.
AB  - When 388D1 cells are incubated in media containing 10 microM [3H]arachidonic acid
      (delta4Ach), the label is rapidly incorporated into phospholipids and
      triacylglycerol. However, incorporation of [3H]delta4Ach into phospholipids
      clearly precedes incorporation into triacylglycerol, indicating that the
      phospholipid pool constitutes the primary metabolic fate of the delta4Ach via a
      remodelling pathway. In contrast, [3H]delta4Ach is incorporated into
      triacylglycerol almost exclusively via de novo synthesis, as evidenced by studies
      using propranolol, a phosphatidate phosphohydrolase inhibitor. This compound
      induced a time-dependent and concentration-dependent increase in the levels of
      [3H]delta4Ach-containing phosphatidate that is directly correlated with a
      decrease in the levels of [3H]delta4Ach-containing triacylglycerol. In addition,
      no change in the levels of [3H]delta4Ach-containing diacylglycerol and
      monoacylglycerol were apparent along the time course of fatty acid incorporation
      into triacylglycerol. However, a sharp and transient accumulation of cell
      associated free [3H]delta4Ach was detected shortly after exposure of the cells to
      the radioactive fatty acid. Collectively, the results reported herein suggest
      that free delta4Ach availability determines the patterns of incorporation and
      distribution of this fatty acid among the various lipid classes of P338D1 cells.

PMID- 8654392
TI  - Overexpression of RII beta regulatory subunit of protein kinase A in human colon
      carcinoma cell induces growth arrest and phenotypic changes that are abolished by
      site-directed mutation of RII beta.
AB  - LS-174T human colon carcinoma cells that contain approximately equal amounts of
      cAMP-dependent protein kinase (PKA) isozymes, PKA-I and PKA-II, were infected
      with retroviral vectors coding for regulatory (R) and catalytic (C) subunits of
      human PKA. In cells overexpressing RII alpha, RII beta and RII beta-P (a RII beta
      mutant at the autophosphorylation site), PKA-II levels increased while PK-A
      levels decreased. PKA-I was almost completely eliminated in cells overexpressing
      RII beta or RII beta-P. In contrast, overexpression of either RI alpha or C alpha
      had little or no effect on PKA isozyme levels. Although all infectants expressed
      high levels of PKA subunit mRNAs in accordance with gene introduction, the R
      subunit protein expression was reflected in PKA isozyme levels rather than in
      subunit mRNA levels. Only RII beta infectants demonstrated marked growth
      inhibition in monolayer culture, reduced thymidine incorporation into DNA, and
      inability to grow in semisolid medium or in serum-free medium. Conversely, all
      other infectants displayed growth properties similar to uninfected parental
      cells. The growth-retardation properties of RII beta infectants were reflected in
      their altered phenotypic appearances. Our findings that the mutant RII beta-P
      could not mimic the growth-inhibitory effect of RII beta suggest the functional
      importance of the authophosphorylation site in RII beta. Our results suggest a
      role for RII beta in the suppression of neoplastic cell growth, and thus abnormal
      expression of R subunit isoforms of PKA may be involved in neoplastic
      transformation.

PMID- 8654393
TI  - The association of focal adhesion kinase with a 200-kDa protein that is tyrosine
      phosphorylated in response to platelet-derived growth factor.
AB  - Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase implicated in the
      signal transduction pathways initiated by integrins. However, we have previously
      found that platelet-derived growth factor (PDGF) could stimulate the association
      of FAK with phosphatidylinositol 3-kinase in NIH 3T3 cells [Chen, H.-C. & Guan,
      J.-L. (1994) J. Biol. Chem 269, 31229-31223], suggesting that FAK might
      participate in some of the cellular effects of the growth factors in modulating
      cell morphology and migration. In this report, we describe the association of FAK
      with a 200-kDa protein (pp200) that is tyrosine phosphorylated in response to
      PDGF stimulation in NIH 3T3 cells. Although the identity of pp200 is unknown at
      present, we have excluded the possibilities that it is the PDGF receptor beta,
      tension, talin, myosin or the guanosine-triophosphatase-activating-protein
      associated p190 protein. Furthermore, we found that the tyrosine phosphorylation
      of FAK-associated pp200 upon PDGF stimulation is largely independent of cell
      adhesion or the integrity of the cytoskeleton. Therefore, pp200 and its
      interaction with FAK may also be involved in growth-factor-induced cellular
      effects such as the modulation of cell adhesion or cell migration via
      cytoskeletal reorganization or disruption of focal adhesions.

PMID- 8654394
TI  - Molecular cloning and functional expression of the alpha1A-adrenoceptor of Medaka
      fish, Oryzias latipes.
AB  - A genomic DNA encoding a subtype adrenoceptor (AR) was cloned from Medaka fish,
      Oryzias latipes, using an oligonucleotide probe corresponding to the consensus
      sequence of mammalian alpha-AR and beta-AR. The gene spans at least 9kbp, and the
      coding region consists of two exons split by an intron of 7.2 kbp located at the
      same position as those of mammalian alpha1B-AR genes. The gene encodes 470 amino
      acid residues, the sequence of which shows the highest similarity to that of
      mammalian alpha1A-AR (61%) and significant but lower similarities to other alpha
      AR and beta-AR proteins (31-45%), indicating that the gene encodes a Medaka
      homolog of alpha1A-AR. To characterize the encoded protein, the mRNA was
      synthesized in vitro and injected into Xenopus oocytes. As a result, the oocytes
      responded to 100 nM epinephrine evoking a Ca2 + -dependent C1- current in the
      order of microamperes, which was not observed for oocytes injected with water
      alone. The response was reversibly inhibited by an alpha1-selective antagonist,
      WB4101 (2-[2,6-dimethoxphenoxyethyl]aminomethyl)-1,4-benzodioxane). Similar
      experiments using several adrenergic agonists revealed that Medaka alpha1A-AR
      responds to the following agonists in the order: epinephrine > or = (
      )norepinephrine > oxymetazoline > or = methoxamine, which is similar to the
      responses of rat alpha1A receptor expressed in COS cells. The results indicate
      that fish contains adrenoceptor systems similar to those of mammals in terms of
      primary structure and pharmacological properties.

PMID- 8654395
TI  - The gene, protein and glycan structures of laccase from Pleurotus ostreatus.
AB  - A member of the laccase multigene family in Pleurotus ostreatus has been cloned
      and sequenced. The gene structure has been determined by comparison with the
      corresponding cDNA, synthesized by reverse transcription/PCR amplification. The
      gene encode a laccase isoenzyme of 533 amino acids which has already been
      purified and characterized [Palmieri, G., Giardina, P., Marzullo, L., Desiderio,
      B., Nitti, G., Cannio, R. & Sannia, G.(1993) Appl. Microbiol. Biotechnol. 39, 632
      636]. More than 92% of the protein sequence, including the N and C termini, has
      been verified by fast-atom-bombardment mass spectrometry, thus confirming the
      correspondence between the gene and its protein product. The protein was N
      glycosylated Asn444. Glycan analysis showed the presence of only a high-mannose
      structure containing varying numbers of mannose residues. The presence of O
      linked oligosaccharides as well as other post-translational modification could be
      ruled out by the mass analysis.

PMID- 8654396
TI  - The C-terminal bisphosphorylated proenkephalin-A-(209-237)-peptide from adrenal
      medullary chromaffin granules possesses antibacterial activity.
AB  - The chromaffin granules have been shown to be an excellent model to study the
      processing of proenkephalin-A and chromogranins. Recently, we reported a study
      dealing with the processing of chromogranin B/secretogranin I and the occurrence
      of the C-terminal chromogranin B-derived peptide 614-626 which was shown to have
      antibacterial activity [Strub, J.M., Garcia-Sablone, P., Looning, K., Taupenot,
      L., Hubert, P., Van Dorsselaer, A., Aunis, D. & Metz-Boutigue, M.H. (1995) Eur.
      J. Biochem. 229, 356-368]. We also observed that this new antibacterial activity
      present in chromaffin granules was associated with other endogenous protein
      derived fragments yet to be characterized. The present study reports the
      isolation and characterization of a peptide which possesses antibacterial
      activity and which corresponds to the C-terminal 209-237 sequence of
      proenkephalin-A. A detailed study using microsequencing and matrix-assisted-laser
      desorption time-of-flight mass spectrometry (MALD-TOF MS) allowed us to correlate
      the antibacterial activity of this peptide named enkelytin
      (FAEPLPSEEEGESYSKEVPEMEKRYGGFM) with post-translational modifications. Endogenous
      bisphosphorylated proenkephalin-A-(209-237) was active on Micrococcus luteus and
      Bacillus megaterium killing bacteria in the 0.2 - 0.4 microM range but was
      inactive in similar conditions towards Escherichia coli. Enkelytin shares
      sequence and structural similarities with the antibacterial C-terminal domain of
      diazepam-binding inhibitor. According to this similarity, a prediction of
      secondary structure is proposed for enkelytin and discussed in relationship to
      its biological activity.

PMID- 8654397
TI  - Solid-state 13C-NMR of [(3-13C)Pro]bacteriorhodopsin and [(4
      13C)Pro]bacteriorhodopsin: evidence for a flexible segment of the C-terminal
      tail.
AB  - The configuration of an Xaa-Pro bond can be determined by solid-state magic-angle
      sample-spinning (MASS)-13C-NMR spectroscopy since the chemical shifts of C beta
      and Cgamma of the proline ring are sensitive to the isomerization state of the
      preceding peptide bond. (3-13C)Pro and (4-13C)Pro have been chemically
      synthesized; the former by means of an asymmetric synthesis. The 13C-labeled Pro
      residues were biosynthetically incorporated into bacteriorhodopsin with a yield
      of 80%. The solid-state-MASS-13C-NMR spectra of [(3-13C)Pro]bacteriorhodopsin and
      [(4-13C)Pro]bacteriorhodopsin revealed isotropic chemical shifts at 29.8 ppm and
      25.5 ppm, respectively. From the chemical-shift values we conclude that all Xaa
      Pro peptide bonds are in the trans configuration confirming previous results from
      solution-NMR studies on solubilized bacteriorhodopsin in organic solvents [Deber,
      M.C., Sorrell, B.J. & Xu, G.Y. (1990) Biochem. Biophys. Res. Commun. 172, 862
      869]. Inversion-recovery experiments could differentiate between three classes of
      Pro residues distinguished by their relaxation time t1. Tentatively, these three
      distinct groups of Pro residues could be assigned to the helical, the loop, and
      the C-terminal parts of the protein. The resonances of the two C-terminal Pro
      could be identified by removing the C-terminus by proteolysis. Although they are
      separated by only one Glu they occupy different chemical environments and possess
      different flexibilities. These results indicate that the first part of the C
      terminal tail is constrained. Pro238 marks the position where the tail becomes
      freely mobile. It is proposed that the C-terminus is fixed to the membrane via
      salt bridges between divalent cations and negative charges of the C-terminus as
      well as interhelical loops.

PMID- 8654398
TI  - Hybrids of chicken cystatin with human kininogen domain 2 sequences exhibit novel
      inhibition of calpain, improved inhibition of actinidin and impaired inhibition
      of papain, cathepsin L and cathepsin B.
AB  - Chicken cystatin and human kininogen domain 2 are members of the cystatin
      superfamily of protein-type cysteine proteinase inhibitors. They show structural
      and functional similarities, but only human kininogen domain 2 inhibits calpain.
      Using recombinant chicken cystatin as a scaffold for hybrid cassette analysis,
      the known reactive-site regions (N-terminus, first hairpin loop and second
      hairpin loop) were substituted by the corresponding sequences of human kininogen
      domain 2 in a single and combined manner. Seven hybrids were expressed, purified
      to homogeneity, characterized protein-chemically, and their inhibition of papain,
      actinidin, human cathepsin B, human cathepsin L and calpain (80-kDa subunit of
      rabbit skeletal muscle calpain II and porcine erthrocyte calpain 1) was
      determined. Strong but temporary inhibition of calpain by chicken cystatin
      hybrids carrying the N-terminus alone (variant sc1-KD2) or the N-terminus
      together with the first hairpin loop (variant sc1/2-KD2) was observed; hybrids of
      the second hairpin loop (sc3-KD2, sc1/3-KD2, sc2/3-KD2, sc1/2/3-KD2) were less
      strong calpain inhibitors. These data indicate that the inhibiton of calpain by
      human kininogen domain 2 requires the correct conformation and combination of
      several contact sites, and suggest that the N-terminus and the first hairpin loop
      play a major role in this ensemble. Remarkably, hybrid sc2-KD2 exhibited 5 or 150
      times stronger inhibition of actinidin compared to native chicken cystatin or to
      proteolytically isolated human kininogen domain 2, respectively. This indicates
      an important role of the first hairpin loop of cystatins in the interaction with
      actinidin. Along with the impaired inhibition of cathepsin L, papain, actinidin,
      cathepsin B and calpain by the hybrids sc1/3-KD2, sc2/3-KD2 and sc1/2/3-KD2,
      these results support our hypothesis that all three predicted contact regions of
      kininogen domain 2 contribute to binding in the active-site clefts of papain-like
      enzymes in a finely balanced manner.

PMID- 8654399
TI  - Backbone dynamics of a domain of protein L which binds to immunoglobulin light
      chains.
AB  - Protein L is a multidomain protein expressed at the surface of some strains of
      the anaerobic bacterial species Peptostreptococcus magnus. The molecule interacts
      with the variable domain of immunoglobulin (Ig) light chains through five
      repeated homologous domains denoted B1 to B5. The fold of the Ig-light-chain
      binding B1 domain of protein L (PLB1) has been shown to comprise an alpha-helix
      packed against a four-stranded beta-sheet and therefore resembles the structure
      of the IgG-binding domains of streptococcal protein G. In the present study,
      amide-proton exchange and 15N-relaxation NMR measurements were performed on the
      B1 domain to investigate its backbone mobility. It was shown that the folded
      portion of PLB1 is rigid with no regions of significantly higher flexibility than
      average. The N-terminus, however, is highly flexible consistent with earlier
      studies on the solution structure of PLB1. Comparison of the amide-proton
      exchange data with similar measurements performed on the IgG-binding domains of
      protein G indicates that the two proteins have different exchange behaviors in
      their second beta-strands. Both protein G and L employ this region of their
      structures for binding to immunoglobulins since the interaction of protein G and
      protein L with IgG Fab and the Ig light chain, respectively, involves residues
      from the second beta-strand.

PMID- 8654400
TI  - Relationship between type II phosphatidylinositol 4-kinase activity and protein
      tyrosine phosphorylation in membranes from normal and sickle red cells.
AB  - To assess the origin of the previously reported higher type II
      phosphatidylinositol 4-kinase (PtdIns 4-kinase) activity of sickle-red-cell
      membranes [Rhoda-Hardy-Dessources, M.D., de Neef, R.S., Merault, G.& Giraud, F.
      (1993) Biochim. Biophs. Acta 1181, 90-96], we have investigated the possible
      involvement of protein kinase C and tyrosine kinases in the regulation of the
      lipid kinase activity. Both protein kinase activities were found to be markedly
      higher in membranes from the pathological cells. When isolated normal-red-cell or
      sickle-red-cell membranes were assayed, phosphatidylinositol phosphorylation
      activity was not significantly modified after phorbol ester modulation of protein
      kinase C. In contrast, stimulation (with sodium orthovanadate) or inhibiton (by
      tyrphostin) of tyrosine phosphorylation led respectively, to increased or
      decreased PtdIns 4-kinase activity in membranes from both cell types. Moreover,
      immunoprecipitations of membrane extracts from normal and sickle red cells types
      with anti-PtdIns 4-kinase antibody 4C5G, followed by immunoblotting with an anti
      phosphotyrosine Ig, revealed a 56-kDa band migrating with PtdIns 4-kinase
      activity. Taken together, these findings indicate that PtdIns 4-Kinase in red
      blood cells is a phosphotyrosine-containing protein and could be regulated by a
      mechanism involving tyrosine phosphorylation, and the increase in PtdIns 4-Kinase
      activity of sickle-red-cell membranes is at least in part mediated by their
      intrinsic tyrosine kinase activity.

PMID- 8654401
TI  - Secretory non-pancreatic phospholipase A2 and cyclooxygenase-2 expression by
      tracheobronchial smooth muscle cells.
AB  - Lipid mediators of inflammation, contribute to airway hyper-reactivity in asthma.
      Since production of lipid mediators is largely regulated by phospholipase A2
      (PLA2), and since PLA2 expression in mesenchymal cells is induced by cytokines
      and other signals, we examined PLA2 expression by rat tracheobronchial smooth
      muscle cells (TBSMC). PLA2 expression in TBSMC cultures was markedly increased by
      tumour-necrosis factor (TNF) alpha (130-fold) and interleukin-1beta (IL-1beta)
      (7.4-fold). Lipopolysaccharide (LPS;100 ng/ml) resulted in a 51-fold increase in
      extracellular PLA2 activity. PLA2 expression by LPS-stimulated or cytokine
      stimulated cells was downregulated by dexamethasone. Whereas forskolin or
      dibutyrl cAMP increased PLA2 activity, inhibition of protein kinase A but not
      tyrosine kinase reduced PLA2 expression. Northern blot analysis showed that TNF
      alpha and IL-1beta increased both PLA2 and inducible cyclooxygenase (Cox-2) mRNA
      transcription. Addition of dexamethasone substantially blunted the increase in
      PLA2 and Cox-2 mRNA. In contrast, the level of Cox-1 mRNA was very low and did
      not change with the various treatments. Since proinflammatory lipid mediators
      have been implicated in the pathogenesis of asthma and PLA2 activity regulates
      generation of these lipid mediators, cytokine-stimulated synthesis and release of
      PLA2 by airway smooth cells may contribute to the potentiation of airway
      inflammation in asthma.

PMID- 8654402
TI  - The role of the intralysosomal pH in the control of autophagic proteolytic flux
      in rat hepatocytes.
AB  - Current methods to estimate changes in intralysosomal pH in hepatocytes do not
      discriminate between lysosomes and other intracellular acidic compartments. To
      obtain selective information on the change in lysosomal function in response to a
      change in lysosomal pH we have used the liberation of fluorescent 4-methoxy-2
      naphthylamide from low concentrations of lysyl-alanyl-4-methoxy-2-naphthylamide,
      a substrate of lysosomal dipeptidylpeptidase II. Using permeabilized and intact
      hepatocytes, the activity of this enzyme in response to manipulations meant to
      increase the intralysosomal pH was compared with intralysosomal protein
      degradation and with the accumulation of [14C]chloroquine as a pH indicator of
      intracellular acidic compartments. The data show that changes in intralysosomal
      pH are indicated by changes in dipeptidylpeptidase II activity and that these are
      mainly due to a pH-dependent change in substrate accumulation in the lysosomes.
      Subsequently, the method was applied to establishing the extent to which an
      increase in intralysosomal pH can contribute to the inhibition of autophagic
      proteolysis in intact hepatocytes caused by a decrease in intracellular ATP, by
      an increase in amino acid concentration and by hypo-osmotic cell swelling. The
      following observations were made. (a) Moderate changes in intracellular ATP do
      not affect the lysosomal pH. (b) Hypo-osmotic cell swelling, which promotes
      inhibition of proteolysis by amino acids in freshly isolated hepatocytes, does
      not affect the lysosomal pH. (c) In addition to their known inhibitory effect on
      autophagic sequestration, amino acids (leucine in particular) can increase the
      lysosomal pH and thus inhibit intralysosomal protein degradation directly. (d)
      Low concentrations of the acidotropic agent methylamine increase the lysosomal pH
      without having an effect on autophagic proteolytic flux. It is concluded that
      autophagic proteolysis is not controlled by changes in the lysosomal pH.

PMID- 8654403
TI  - Protease inhibitor studies and cloning of a serine carboxypeptidase cDNA from
      germinating seeds of pea (Pisum sativum L.).
AB  - The nature of the proteolytic activity found within the germinating pea (Pisum
      sativum) seed, 4 days from the initiation of imbibition, was determined by the
      use of specific protease inhibitors. These studies have shown most of the
      activity to belong to metallo or metal-activated and serine proteases. In order
      to investigate further the serine protease activity, a pea cotyledon germination
      cDNA library was, therefore, screened with a wheat cDNA (2437) [Baulcombe, D.C.,
      Barker, R.F. & Jarvis, M.G. (1987) J. Biol. Chem. 262, 13726-13735] which had
      extensive similarity to the yeast serine carboxypeptidase Y gene. A positive cDNA
      clone (pNY551) was obtained which had extensive similarity to the four
      carboxypeptidases, Arabidopsis thaliana carboxypeptidase Y-like protein, rice
      serine carboxypeptidase III, barley serine carboxypeptidase III and wheat serine
      carboxypeptidase III precursor. Northern-blot analysis showed mRNA homologous to
      pNY551 to be expressed in late developmental pea seed and again during
      germination.

PMID- 8654404
TI  - Depolarization-induced tyrosine phosphorylation of paxillin in PC12h cells.
AB  - Treatment of PC12h cells with a high concentration of KC1 induces depolarization
      of the plasma membrane and Ca2+ influx into the cells. We have previously shown
      that KC1 induced tyrosine phosphorylation of cellular proteins of 120, 110, 68,
      44 and 42 kDa. In the present study, we found that the 68-kDa protein is
      paxillin, a tyrosine kinase substrate associated with the actin cytoskeleton. A
      calcium ionophore, A23187, also induced tyrosine phosphorylation of the 68-kDa
      protein, while KC1 did not in the presence of EGTA or nifedipine, indicating that
      the effect of KC1 was due to the Ca2+ influx into the cells. Tyrosine
      phosphorylation of paxillin was also induced by nerve growth factor and epidermal
      growth factor, but its migration patterns on an SDS/polyacrylamide gel were
      different, that is, nerve growth factor and epidermal growth factor caused upward
      shifts of the bands, while KC1 did not. However, both forms could associate with
      Csk and Crk. The effect of KC1 was blocked by cytochalasin D, indicating that
      tyrosine phosphorylation required the integrity of actin filaments. These results
      suggest that tyrosine phosphorylation of paxillin may be involved in Ca2+ 
      dependent events in neuronal and neuroendocrine cells.

PMID- 8654405
TI  - A tobacco nuclear protein that preferentially binds to unmethylated CpG-rich DNA.
AB  - The methylation of cytosine residues in CpG dinucleotides of eukaryotic DNA is an
      important mechanism for the regulation of gene expression. Higher plants have a
      high content of methylated cytosine residues in CpG as well as CpNpG sites, and
      experimental evidence suggests a role in gene expression for DNA methylation. In
      this article, we describe a tobacco nuclear protein whose binding to various DNA
      sequences is positively correlated with the CpG density of the probes. This
      protein, CpG-binding protein 1 (CGBP-1), has reduced affinity for DNA when the
      CpG sites are methylated. Ribonuclease treatment also reduces the formation of
      the CGBP-1 complex. The binding characteristics of CGBP-1 make it an interesting
      protein with respect to methylation-mediated gene expression in plants.

PMID- 8654406
TI  - The presence of tandem repeats and the initiation of replication in rabbit
      mitochondrial DNA.
AB  - The non-coding region of rabbit mitochondrial DNA (mtDNA) exhibits two sets of
      tandem repeats between conserved sequence block 1 (CSB1) and the tRNA Phe gene.
      Both repeated sequences, short repeated (SR) and long repeats (LR), which contain
      20 and 153 nucleotides, respectively, are involved in the generation of a high
      degree of mitochondrial heteroplasmy. Due to the location of these sequences in
      the regulatory region and their properties in terms of variable conformations,
      they could affect the initiation of replication of the heavy-strand DNA (H-strand
      DNA) and subsequently would influence the efficiency of mtDNA replication. The
      extremities of the displacement loop (D-loop) DNA strand and the 5' ends of RNA
      primers initiating the H-strand DNA synthesis were characterized in individual
      rabbits. Mapping at the nucleotide level of the 5' and 3' ends of the D-loop DNA
      strands indicates that both extremities are heterogeneous. The H-strand
      replication origin OH is located close to the conserved sequence block CSB1 as in
      other mammals. In all of the individuals studied so far, DNA molecules with a 5'
      end 1-2 nucleotides downstream of CSB1 were always present. As H-strand DNA
      replication is believed to be primed by RNA transcribed from the light-strand
      promoter (LSP), RNA mapping was carried out to identify the 5' end of H-strand
      RNA. Neighbouring initiation sites were identified at the nucleotide level in an
      (A+T)-rich region at nucleotide 1841 and in a stretch of cytosine residues at
      nucleotides 1849-1852, which are located at the beginning of the first long
      repeat. A detailed RNA analysis indicates that H-strand RNA molecules are
      initiated in each long repeat. The amplification of the regulatory region has
      produced multiple initiation transcription sites and a family of RNA primers of
      various lengths. These variations in length and the ensuing secondary structures
      are not critical for their potential function as H-strand DNA replication
      primers.

PMID- 8654407
TI  - Construction of a multifunctional pneumococcal murein hydrolase by module
      assembly.
AB  - A chimeric trifunctional pneumococcal peptidoglycan hydrolase (CHL) has been
      constructed by fusing a choline-binding domain with two catalytic modules that
      provide lysozyme and amidase activity. The chimeric enzymes behaves as a choline
      dependent enzyme and its activity is comparable to that of the parent enzymes.
      Site-directed mutagenesis of CHL produced a mutated enzyme [D9A,36A]CHL) that
      only exhibited an amidase activity. Comparative biochemical analyses of CHL and
      [D9A, E36A]CHL strongly suggest that the lysozyme catalytic module confers 88% of
      the total activity of CHL, whereas 12% of the activity can be ascribed to the
      amidase module. Both enzymatic activities are affected by the process of
      activation or conversion induced by choline suggesting that the conversion
      process is produced by a conformational change in the choline-binding domain. Our
      findings demonstrate that the three modules can acquire the proper folding
      conformation in the-three domain chimeric CHL enzyme. This experimental evidence
      supports the modular theory of protein evolution, and demonstrates that modular
      assembly of functional domains can be a rational approach to construct fully
      active chimeric enzymes with novel biological or biotechnological properties.

PMID- 8654408
TI  - X-ray absorption spectroscopy study of zinc coordination in tetanus neurotoxin,
      astacin, alkaline protease and thermolysin.
AB  - Tetanus and botulinum neurotoxins constitute a new group of Zn-endopeptidases
      which has been recently actively investigated with the purpose of correlating
      their biochemical properties to their neurobiocytosis inhibitory capacity.
      Crystallographic data show that Zn-endopeptidases are characterized by an active
      site with a Zn atom coordinated to two histidines and glutamate-bound water
      molecule. The two histidines and glutamate resides belong to the HEXXH motif
      which is characteristic of most Zn-endopeptidases. A forth metal ligand is a
      glutamate in thermolysin-like proteinases, but it is an histidine in the astacin
      family of proteinases and in alkaline protease. Astacin and alkaline protease
      possess a tyrosine as fifth Zn ligand, whose position in the case of alkaline
      protease could not be determined by X-ray crystallography. Not much is known
      about the atom arrangement around the active site in tetanus neurotoxin. In this
      work X-ray absorption spectroscopy has been used to obtain information on the Zn
      coordination mode in tetanus neurotoxin. The near-edge and extended fine
      structure absorption spectra of this toxin are compared with those of astacin,
      alkaline protease and thermolysin. The present data and sequence information
      suggest a new pattern of Zn coordination in tetanus neurotoxin with one water
      molecule and three aromatic residues as metal ligands. These residues are the two
      histidines of the characteristic motif and a tyrosine which is tentatively
      identified with Tyr242, on the basis of sequence comparison and mutagenesis
      experiments. The mean distances of the Zn from the nearest coordinated atoms is
      reported. Our results indicate that alkaline protease, like astacin, also
      possesses a tyrosine as a fifth ligand.

PMID- 8654409
TI  - In vitro protein folding by ribosomes from Escherichia coli, wheat germ and rat
      liver: the role of the 50S particle and its 23S rRNA.
AB  - Ribosomes from a number of prokaryotic and eukaryotic sources (e.g. Escherichia
      coli, wheat germ and rat liver) can refold a number of enzymes which are
      denatured with guanidine/HC1 prior to incubation with ribosomes. In this report,
      we present our observations on the refolding of denatured lactate dehydrogenase
      from rabbit muscle and glucose-6-phosphate dehydrogenase from baker's yeast by
      ribosomes from E. coli, wheat germ and rat liver. The protein-folding activity of
      E. coli ribosomes was found to be present in 50S particles and in 23S rRNA. The
      30S particle or 16S rRNA did not show any protein-folding activity. The protein
      folding activity of 23S rRNA may depend on its tertiary conformation. Loss of
      tertiary structure, by incubation with low concentrations of EDTA, inhibited the
      protein-folding activity of 23S rRNA. This low concentration of EDTA had no
      effect on folding of the denatured enzymes by themselves.

PMID- 8654410
TI  - H-NMR signal of Arenicola marina myoglobin in vivo as an index of tissue
      oxygenation.
AB  - Key questions on how intertidal animals adapt to hypoxic stress center on the
      high energy phosphate response to decreasing oxygenation. With recent 1H/31P-NMR
      techniques to monitor mammalian tissue metabolism, a novel approach has emerged
      to observe potentially the intracellular oxygen interaction in invertebrates. The
      present study indicates that Arenicola marina, a standard model for intertidal
      animals, exhibits a distinct set of Mb 1H-NMR signals in vivo, corresponding to
      the two isolated Mb isoforms. Specifically both deoxy-Mb I and deoxy-Mb II
      exhibit paramagnetically shifted signals at 93.4 ppm and 92.5 ppm at 25 degrees
      C, respectively, which arise from the proximal histidyl NdeltaH. These signals
      reflect the cellular oxygenation state and indicate clearly that the
      phosphotaurocyamine level begins to drop at the onset of anoxia and declines
      gradually to 50% of control after 3.5 h. 1H Mb spectra indicate protein
      heterogeneity originating from heme as well as structural disorder.

PMID- 8654411
TI  - Backbone dynamics of the 269-residue protease Savinase determined from 15N-NMR
      relaxation measurements.
AB  - Backbone dynamics of Savinase, a subtilisin of 269 residues secreted by Bacillus
      lentus, have been studied using 15N relaxation measurements derived from proton
      detected dimensional 1H-15N-NMR spectroscopy. 15N spin-lattice rate constants
      (R1), spin-spin relaxation-rate constants(R2), and 1H-15N nuclear Overhauser
      effects (NOE) were determined for 84% of the backbone amide 15N nuclei. The model
      free formalism [Lipari, G. & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559]
      was used to derive values for a generalized order parameter, S2, interpretable as
      a measure of the amplitude of motion on the picosecond-nanosecond timescale, for
      each N-H bond vector. Additional terms used to fit the data include an effective
      correlation time for internal motions (taue) and an exchange term (Rex) to
      account for exchange contributions to R2. The overall rotational correlation time
      (taum) is 9.59 +/- 0.02 ns; the average order parameter (S2) is 0.90 +/- 0.07,
      indicative of a rigid structure consistent with Savinase's high degree of
      secondary structure and compact tertiary fold. Residues S125-S128, located in the
      substrate-binding region, represent the longest stretch of protein which exhibits
      disorder on the picosecond-nanosecond timescale. These residues also exhibit
      significant exchange terms, possibly indicative of motion on the microsecond
      millisecond timescale, which could also be influenced by the proximity of the
      phenyl ring of the substituted aryl boronic acid inhibitor used in this study.
      S103 and G219 in the substrate-binding region, represent the longest stretch of
      protein which exhibits disorder on the picosecond-nanosecond timescale. These
      residues also exhibit significant exchange terms, possibly indicative of motion
      on the microsecond-millisecond timescale, which could also be influenced by the
      proximity of the phenyl ring of the substituted aryl boronic acid inhibitor used
      in this study. S103 and G219 in the substrate-binding region also show
      flexibility on the picosecond-nanosecond timescale. There is also significant
      motion in the turn, G258-T260, of a small solvent-exposed loop region which may
      make the protein vulnerable autolysis at that point. Some residues in both
      calcium-binding sites and nearby also show mobility.

PMID- 8654412
TI  - Phosphate-binding sites in phosphorylating glyceraldehyde-3-phosphate
      dehydrogenase from Bacillus stearothermophilus.
AB  - The two anion-binding sites of the glycolytic glyceraldehyde-3-phosphate
      dehydrogenase (GraP-DH), the Ps and Pi sites, were originally proposed by Moras
      et al. [Moras, D., Olsen, K.W., Sabesan, M.N., Buehner, M., Ford, G.C. &
      Rossmann, M. G. (1975) J. Biol. Chem. 250, 9137-9162] to bind the C3 phosphate of
      the glyceraldehyde 3-phosphate and the inorganic phosphate respectively. Ps site
      mutants T179A, and T179M, and R231L, and the Pi site mutants T150A and T208 of
      the Bacillus stearothermophilus GraP-DH were constructed by site-directed
      mutagenesis and their kinetic properties were determined and compared with those
      of mutants R195L and R231G, already described [Corbier, C., Michels, S.,
      Wonacott, A. & Branlant, G. (1994) Biochemistry 33, 3260-3265]. Taking advantage
      of the opportunity to study both the oxidoreduction and the phosphorylation step
      independently and the fact that the phosphorylation becomes rate determining for
      most of the mutants, the relative energetic contribution of each mutated amino
      acid to the phosphorylation step was evaluated. It was concluded that (a) Ps
      amino acids contribute more than the Pi amino acids to the stabilisation of the
      transition state relative to the ground state and (b) the side chain of arginine
      contributes more than that of the threonine residue. It was also concluded that
      the differences observed in the efficiency of the phosphorylation step for Ps and
      Pi mutants is a consequence of the orientation of the thioester bond of the
      thioacyl] intermediate relative to the attacking inorganic phosphate and not of a
      change in the intrinsic electrophilic property of the thioacyl intermediate.
      Furthermore, the kinetic results on the overall steps leading to the acyl-enzyme
      formation provided supplementary evidence that the C3 phosphate moiety of the
      glyceraldehyde 3-phosphate interacts with the Pi site during these steps and thus
      are consistent with the findings of Skarzynski et al. [Skarzynski, T., Moody, P.
      C. E. & Wonacott, A. J. (1987) J. Mol Biol. 193, 171-183] and Corbier et al.
      [Corbier, C., Michels, S., Wonacott, A. & Branlant, G. (1994) Biochemistry 33,
      3260-3265] that recommended the reconsideration of the first definition of the Ps
      and Pi sites.

PMID- 8654413
TI  - Changes in plasma phospholipids in the presence and absence of erythrocytes 31P
      NMR time-course studies.
AB  - Whole human blood and plasma were incubated at 37 degrees C and 31P-NMR spectra
      were acquired from aliquots of plasma dissolved in sodium cholate. The narrow
      resonances of phospholipids were well resolved, allowing identification and
      accurate quantification of the various phospholipid classes. During the course of
      plasma incubation, the rate of increase in 2-lysphosphatidylcholine (2
      LysoPtdCho) corresponded closely to the rate of decrease in phosphatidylcholine.
      However, little or no change was observed in the sphingomyelin concentrations.
      The rate of cholesteryl ester formation in plasma was also determined using HPLC
      and was observed to be similar to the rate of 2-LysoPtdCho increase in plasma;
      this is consistent with the rate of acyl transfer from phosphatidylcholine to
      free cholesterol catalysed by lecithin:cholesterol acyltransferase. However,
      during the course of whole blood incubation, the rate of 2-LysoPtdCho increase in
      plasma was significantly lower than the rate of 2-LysoPtdCho production during
      incubation of plasma alone (31 +/- 4 micromol x 1(-1) x h(-1) and 80 +/- 8
      micromol x 1(-1) x h(-1), respectively). The difference between the rates can be
      attributed to the action of enzymes present in blood cells including those in the
      erythrocytes that catalyse acylation or hydrolysis of 2-LysoPtdCho.

PMID- 8654414
TI  - Methylcobalamin: coenzyme M methyltransferase isoenzymes MtaA and MtbA from
      Methanosarcina barkeri. Cloning, sequencing and differential transcription of the
      encoding genes, and functional overexpression of the mtaA gene in Escherichia
      coli.
AB  - Methanosarcina barkeri is known to contain two methyltransferase isoenzymes, here
      designated MtaA and MtbA, which catalyze the formation of methyl-coenzyme M from
      methylcobalamin and coenzyme M. The genes encoding the two soluble 34-kDa
      proteins have been cloned and sequenced. mtaA and mtbA wee found to be located in
      different parts of the genome, each forming a monocystronic transcription unit.
      Northern blot analysis revealed that mtaA is preferentially transcribed when M.
      barkeri is grown on methanol and the mtbA gene when the organism is grown on
      H2/CO2 or trimethylamine. Comparison of the deduced amino acid sequences revealed
      the sequences of the two isoenzymes to be 37% identical. Both isoenzymes showed
      sequence similarity to uroporphyrinogen III decarboxylase from Escherichia coli.
      The mtaA gene was tagged with a sequence encoding six His placed bp before the
      mtaA start codon, and was functionally overexpressed in E. coli. 25% of the E.
      coli protein was found to be active methyltransferase which could be purified in
      two steps to apparent homogeneity with a 70% yield.

PMID- 8654415
TI  - The CO stretching mode infrared spectrum of substrate-free cytochrome P-450cam
      CO: the effect of solvent conditions, temperature, and pressure.
AB  - The effect of pH, glycerol, temperature, and pressure on the carbon monoxide (CO)
      stretch mode of substrate-free cytochrome P-450cam (CYP101) was studied. Complex
      spectra of overlapping bands have been observed. CO stretch bands centered at
      about 1911-1918 cm-1 (band I), 1927-1931 cm-1 (band II), 1940-1942 cm-1 (band
      III), 1950-1953 cm-1 (band IV), 1960-1963 cm-1 (band V) and 1966-1973 cm-1 (band
      VI) are obtained from the fitting analyses independently of the lineshape model
      used. Only two or three bands are dominant in each spectrum. Compared to bands I,
      II and III, the bands IV and V are assigned to correspond to a weaker polar
      contact between the CO ligand and a polar group in the heme pocket (probably
      Thr252) because of the opposite effect of glycerol (osmotic pressure) and
      hydrostatic pressure on the intensity and frequency of these bands. The different
      CO stretch bands are interpreted as indicating conformational substates of the
      protein. It is suggested that water in the heme pocket plays an important role
      for the substate equilibrium. This substate equilibrium freezes in at the glass
      transition temperature, Tg, of the protein/solvent mixture. For the temperature
      region above Tg the thermodynamic parameters and volumes for the substates have
      been determined by a global fit analysis of the temperature- and pressure
      dependent populations and they are compared to the respective values for camphor
      bound cytochrome P-450cam.

PMID- 8654417
TI  - Regulation of glutamate dehydrogenase expression in the developing rat liver:
      control at different levels in the prenatal period.
AB  - To study the regulation of the expression of glutamate dehydrogenase (Glu-DH) in
      rat liver during development, the Glu-DH mRNA concentration in the liver of rats
      ranging in age from 14 days prenatal development to 3 months after birth was
      determined. This concentration increased up to two days before birth, decreased
      rapidly between two days before and one day after birth and increased again in
      the second and third postnatal week. The ratio of Glu-DH mRNA/protein decreased
      more than 10-fold in the prenatal period, whereas it did not change significantly
      after birth. Thus, whereas the ratio between the Glu-DH monomer protein molecules
      and Glu-DH mRNA molecules is found to be approximately 1400 at 14 days of
      prenatal development, it is approximately 1700 four weeks after birth. We argue
      than an increase in the translational efficiency after birth is the most likely
      cause of the observed developmental changes in Glu-DH mRNA/protein ratio. Our
      results suggest that the expression after birth is predominantly regulated at the
      pretranslational level, whereas the prenatal Glu-DH expression is regulated both
      at the translational level and at the pretranslational level.

PMID- 8654416
TI  - Translocation of microfilament-associated inhibitory guanine-nucleotide-binding
      proteins to the plasma membrane in myeloid differentiated human leukemia (HL-60)
      cells.
AB  - The cytoskeletal localization of inhibitory guanine-nucleotide-binding (Gi)
      proteins and the coupling of these proteins to formyl peptide receptors were
      studied in myeloid differentiated human leukemia (HL-60) cells. Treatment of HL
      60 cells with cytochalasin B or botulinum C2 toxin, which leads to the disruption
      of microfilaments, increased the binding of the stable GTP analogue guanosine
      5'[gamma-thio]triphosphate (GTPS[S]) to permeabilized cells by about 30%. In
      contrast, the microtubule-disrupting agents colchicine and vinblastine, and
      cytochalasin B treatment of isolated HL-60 membranes did not affect GTP[S]
      binding. The stimulatory effect of cytochalasin B treatment was concentration and
      time dependent, with maximal increases observed at 5 micrograms/ml cytochalasin B
      and an incubation time of 10 min, and was counteracted by the F-actin-stabilizing
      toxin phalloidin. Cytochalasin B treatment increased the amount of G proteins
      activated by chemoattractant receptors by about 25%. Furthermore, the number of
      Gi-protein-coupled receptors for the chemoattractant, N-formyl-Met-Leu-Phe, was
      increased by about 25% upon cytochalasin B treatment. Based on these functional
      data, which suggest an association of G proteins with actin filaments, the Triton
      X-100 (1%)-insoluble cytoskeleton was analyzed for the presence of G proteins.
      Gia subunits were detected in the cytoskeleton preparations, both by specific
      antisera and by pertussis-toxin -catalyzed ADP-ribosylation. Cytochalasin B
      pretreatment depleted the cytoskeleton in Gialpha, with an approximately 20%
      concomitant increase in membrane Gialpha content. In conclusion, evidence is
      presented that part of the cellular Gia is localized at actin filaments in HL-60
      cells. After filament disruption, these Gia subunits seem to be translocated to
      the plasma membrance, where they can productively interact with chemoattractant
      receptors.

PMID- 8654418
TI  - Differential developmental and tissue-specific regulation of expression of the
      genes encoding three members of the flavin-containing monooxygenase family of
      man, FMO1, FMO3 and FM04.
AB  - We have previously described the isolation and sequencing of cDNA clones encoding
      flavin-containing monooxygenases (FMOs) 1 and 4 of man [Dolphin, C., Shephard, E.
      A., Povey, S., Palmer, C. N. A., Ziegler, D. M., Ayesh, R., Smith, R. L. &
      Phillips, I. R. (1991) J. Biol. Chem. 266, 12379-12385; Dolphin, C., Shephard E.
      A., Povey, S., Smith, R. L. & Phillips, I. R. (1992) Biochem. J. 287, 261-267].
      We present here the isolation of a cDNA for FM03 of man. The sequence of this
      CDNA and the amino acid sequence deduced from it differ substantially from those
      previously reported for this member of the FMO family of man. In addition, we
      have investigated, by quantitative RNase protection assays, the expression in
      several foetal and adult human tissues of genes encoding FMO1, FMO3 and FMO4, Our
      results demonstrate that, in the adult, FMO1 is expressed in kidney but not in
      liver, whereas in the foetus it is expressed in both organs. The lack of
      expression of FMO1 in adult human liver is in marked contrast to the situation in
      other mammals, such as pig and rabbit, in which FMO1 constitutes a major form of
      the enzyme in the liver of the adult animal. The mRNA encoding FMO3 is abundant
      in adult liver and is also present, in low abundance, in some foetal tissues.
      Thus, FMO1 and FMO3 are both subject to developmental and tissue-specific
      regulation, with a developmental switch in the expression of the genes taking
      place in the liver. FMO4 mRNA is present in low abundance in several foetal and
      adult tissues and thus the corresponding gene appears to be expressed
      constitutively.

PMID- 8654419
TI  - Characterization of the gene encoding quinohaemoprotein ethanol dehydrogenase of
      Comamonas testosteroni.
AB  - The gene encoding quinohaemoprotein ethanol dehydrogenase type I (QH-EDHI) from
      Comamonas testosteroni has been cloned and sequenced. Comparison of the amino
      acid sequence deduced from this with that determined for the N-terminal amino
      acid stretch of purified QH-EDHI, suggests that the gene also contains a leader
      sequence of 31 residues. Based on this information, the molecular mass of the apo
      enzyme, i.e. the enzyme without the cofactors pyrroloquinoline quinone (PQQ) and
      haem c, and without the Ca2+, appears to be 73 200 Da. Alignment of the deduced
      amino acid sequence to that of other PQQ-containing dehydrogenases showed that
      good similarity (up to 43% identity) exists with most of them. This also showed
      that the amino acid residues presumed to be involved in PQQ and Ca2+ binding and
      in the typical features of structure and catalysis of methanol dehydrogenase, are
      conserved at the same positions in QH-EDHI. The C-terminal part of the protein,
      containing the haem c, exhibited some similarity to cytochromes C553 from
      cyanobacteria and algae. Correct processing of the qhedh gene appeared to occur
      in Escherichia coli strain JM 109 in which the gene was placed under control of
      the lac promoter, as judged from a positive reaction with antibodies raised
      against authentic QH-EDHI, the size of the protein, the presence of haem c in it,
      and the specific activity value obtained after reconstitution with PQQ. The qhedh
      gene seems to form part of an operon which is organized in a way different from
      that of the genes required for methanol oxidation in methylotrophic bacteria.

PMID- 8654420
TI  - Dissection of the basic subdomain of the c-Jun oncoprotein: a structural analysis
      of two peptide fragments by CD, Fourier-transform infrared and NMR.
AB  - In a previous paper, we reported on the structural properties of a 35-residue
      peptide corresponding to a modified basic subdomain (bSD) of the basic zipper
      protein c-Jun (residues 252-281) as determined by combined use of 1H-NMR,
      circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopies
      [Krebs, D., Dahmani, B., El Antri, S., Monnot, M., Convert, O,. Mauffret, O.,
      Troalen, F. & Fermandjian, S. (1995) Eur. J. Biochem. 231, 370-380]. The
      fragments NP and CP (the N-terminal residues 1-19 and C-terminal residues 16-35
      of bSD, respectively) proved to be particularly useful for the assignment of the
      1H-NMR spectra of the full-length bSD, which has been achieved completely in
      aqueous solution and partially in trifluoroethanol. Here, we report on the
      structural properties of NP and CP in aqueous solution and under varying
      H2O/trifluoroethanol conditions, again using 1H-NMR, CD and FT-IR experiments.
      Both CD and FT-IR results established that the fragments are weakly structured in
      aqueous solution. Addition of trifluoroethanol to aqueous solutions of the
      peptides produced their stabilization into helix, following a profile sigmoidal
      for NP and nearly linear for CP. Quantitative NOEs, secondary Halpha chemical
      shifts, NH temperature coefficients and 3JalphaN coupling constants for the
      peptides in aqueous solutions provided indications for weak helix features
      (nascent helices) manifested within two sites (continuous dNN NOEs) in both NP
      and CP. For each peptide, an excellent agreement was observed between experiments
      and predictions with the AGADIR program for the location of these nascent helices
      in the sequences. Trifluoroethanol provoked both the alpha-helix stabilization
      within these sites and the alpha-helix propagation to adjacent amino acid
      residues. Finally, our results reflected the high flexibility and helix potential
      of the NP and CP fragments, these two properties seeming crucial for the
      accommodation of c-Jun to its specific DNA targets. The results demonstrated also
      the fragmentation's benefits in dissecting a protein or a complex peptide into
      smaller fragments and analyzing their structure individually.

PMID- 8654421
TI  - The Gly74-->Ser and Ser3-->Ala mutations in Rhodobacter sphaeroides Y
      thioredoxin: effects on active site reactivity and protein interaction.
AB  - In this study, we report the effects of two different substitutions in
      Rhodobacter sphaeroides thioredoxin on two regions of the protein: the N-terminus
      end and the hydrophobic area implicated in protein/protein interactions. We have
      produced by site-directed mutagenesis R. sphaeroides thioredoxin single and
      double mutants in which the glycine residue at position 74 is changed to a serine
      and the serine at position 3 is changed to an alanine; the three mutant proteins
      have been purified. The two substitutions are not equivalent. Substitution of
      serine by alanine increased the pI from 5.2 to 6.1; this pI value was the same in
      the double-mutated protein, which demonstrates the presence of a local
      conformational change. In vivo studies showed that the Gly74-->Ser substitution
      completely prevented phage T3/T7 growth whereas the Ser3-->Ala substitution had
      no effect. This finding was corroborated by the large decrease (100-fold) of
      polymerase activity for the double mutant in the in vitro measurement of phage T7
      DNA polymerase activity with the corresponding pure proteins. Although marginal
      (within a factor of two), the effects of the two substitutions on the catalytic
      activities of the thioredoxin reductase reaction confirmed their difference.
      Substitution of serine by alanine had no effect on the Km and resulted in an
      improvement in the catalytic efficiency. In contrast, the second substitution
      increased the Km value, without improving the catalytic efficiency. The following
      can be concluded (a) glycine74 of R. sphaeroides thioredoxin has a direct role in
      the binding of T7 gene 5 protein and the hydrophobic area of thioredoxin; (b) the
      N-terminus plays a role in maintaining the conformational integrity of the active
      site; (c) the flexibility of Gly74 in the hydrophobic region involved in
      protein/protein interaction is the operative factor in the case of the activity
      of thioredoxin in the T7 DNA polymerase.

PMID- 8654422
TI  - Structure of the B-Myb DNA-binding domain in solution and evidence for multiple
      conformations in the region of repeat-2 involved in DNA binding: implications for
      sequence-specific DNA binding by Myb proteins.
AB  - A range of double and triple resonance heteronuclear NMR has been used to obtain
      nearly complete sequence-specific 15N, 13C and 1H resonance assignments for a 110
      residue protein corresponding to the B-Myb DNA-binding domain (B-MybR2R3) and to
      determine its secondary structure in solution. The protein was found to contain
      two stable helices in repeat-2 (R2) and three in repeat-3 (R3), involving
      residues K12-K24 (R2-1), W30-H36 (R2-2), E64-V76 (R3-1), W81-L87 (R3-2) and D93
      K105 (R3-3). In addition, the chemical shift and nuclear Overhauser effect data
      suggest that amino acids Q44-W49 near the C-terminus of R2 form an unstable or
      nascent helix, which could be stabilised on binding to a specific DNA target
      site. The two N-terminal helices in R2 and R3 occupy essentially identical
      positions in the two domains, consistent with the high level of sequence
      similarity between these regions. In contrast, the C-terminal region forming the
      third helix in R3 shows low sequence similarity with R2, accounting for the
      differences in secondary structure. In the case of B-MybR2R3, there is a clear
      chemical shift and line-broadening evidence for the existence of multiple
      conformations in the C-terminal region of R2, which is believed to form one half
      of the DNA-binding site. We propose that conformational instability of part of
      the DNA-binding motif is a way of increasing the specificity of Myb proteins for
      a relatively short (6-bp) DNA target site by reducing their affinity for non
      specific DNA sequences compared to specific sites.

PMID- 8654423
TI  - Molecular cloning and characterization of a novel mammalian protein kinase
      harboring a homology domain that defines a subfamily of serine/threonine kinases.
AB  - The cDNA of a novel protein kinase (referred to as SNRK) was isolated from a rat
      fat cell cDNA library with a probe generated by a cloning approach based on the
      polymerase chain reaction. The encoded polypeptide (746 amino acids, Mr=81627)
      contains all conserved subdomains characteristic of the protein serine/threonine
      kinase family. A recombinant fusion protein with glutathione S-transferase
      catalysed autophosphorylation as well as phosphorylation of histone, confirming
      that SNRK has indeed protein kinase activity. By Northern blot hybridization, a 5
      kb mRNA was detected in brain, heart, fat cells, intestine, testis, ovary,
      adrenal gland and thymus. In 3T3-L1 cells. SNRK was specifically expressed in the
      differentiated, adipocyte-like phenotype, whereas its mRNA was not detected in
      fibroblasts. Sequence comparisons of its catalytic domain relate SNRK to the SNF1
      family of protein kinases. The noncatalytic domain comprises several intriguing
      structural features, including a glycine-rich region, two PEST sequences, and a
      bipartite nuclear localization signal which is preceded by a stretch of ten
      consecutive acidic residues. This part of the sequence exhibits no extended
      similarity with other proteins. In addition, we detected a high degree of
      sequence similarity with other SNF1-related proteinases in a small region (30-35
      amino acids) flanking the C-terminus of the catalytic domain. This domain
      (designated the SNH domain) appears to define the subfamily of SNF1-related
      protein kinases and might represent a new type of regulatory domain of protein
      kinases.

PMID- 8654424
TI  - Cloning, sequencing and expression in Escherichia coli of two Rhizobium sp. genes
      encoding haloalkanoate dehalogenases of opposite stereospecificity.
AB  - A 6.5-kp EcoRI fragment of genomic DNA from a Rhizobium sp. cloned into pUC19 was
      able to endow Escherichia coli K-12 with the novel ability to grow at the expense
      of 2-chloropropionic acid. Subcloning showed that this property was a consequence
      of two dehalogenases encoded on a 2.2-kb PstI fragment. Further subcloning of the
      PstI fragment led to two constructs that encoded, separately, dehalogenase
      activity that acted stereospecifically on D-2-chloropropionic acid and L-2
      cloropropionic acid, respectively. The genes encoding these two stereospecific
      dehalogenases have been sequenced and shown to be separated by 177 bp of non
      coding DNA. Expression of the dehalogenase genes involved the vector promoter,
      suggesting that the anticipated Rhizobium sp. regulatory sequences were not
      functional in E. coli. Comparison of the deduced amino acid sequences of the two
      dehalogenases (18% identity) indicated with any other 2-chloropropionic acid
      dehalogenase studied so far.

PMID- 8654425
TI  - A receptor for the import of proteins into human mitochondria.
AB  - We have characterised a 16.3-kDa human protein that functions as a receptor for
      the import of preproteins into mitochondria. Based on amino acid sequence
      alignments, the protein (hMas20p) is 41% similar to Mas20p (20-kDa mitochondrial
      assembly protein) from yeast Saccharomyces cerevisiae and 38% similar to MOM19
      (19-kDa mitochondrial outer-membrane protein) from Neurospora crassa. hMas20p has
      a putative N-terminal transmembrane sequence of 29 amino acids and an acidic C
      terminus. A 13-kDa fragment [des-(1-29)-hMas20p], which lacks the 29-amino acid
      putative N-terminal transmembrane domain, is soluble when expressed in
      Escherichia coli. Antibodies produced against this domain crossreacted with a
      protein of 16 kDa in outer membranes of mitochondria from rat liver and inhibited
      import of protein into isolated mitochondria from rat liver. In addition, the
      recombinant soluble domain folds into a functional structure as it competes with
      hMas20p on the mitochondrial surface for precursor binding, confirming the
      functional role of hMas20p in the import of preproteins into mitochondria.

PMID- 8654426
TI  - Requirements for maturation of Bradyrhizobium japonicum cytochrome c550 in
      Escherichia coli.
AB  - Various forms of Bradyrhizobium japonicum cytochrome c550 (the cycA gene product)
      were overexpressed in Escherichia coli cells grown under different conditions.
      Antibodies directed against a synthetic cytochrome c550 peptide were used as
      tools to detect both, apoprotein and holoprotein. Complete maturation of the
      apoprotein into its holo form with haem covalently bound to the polypeptide was
      observed only under anaerobic growth conditions and in E. coli K12 derivatives,
      whereas haem binding did not occur in the E. coli BL21 host. When maturation was
      complete, holocytochrome c550 was found exclusively in the periplasmic fraction.
      A cycA-expressing plasmid construct lacking the genetic information for the
      signal sequence produced apoprotein that was rapidly degraded without further
      maturation. Mutations in the haem-binding site resulted in products that were
      translocated through the cytoplasmic membrane, but apparently became degraded.
      Our results support the view that attachment of haem to the apoprotein is not a
      prerequisite for cleavage of the signal sequence and occurs on the periplasmic
      side of the membrane, subsequent to translocation of the apoprotein precursor.

PMID- 8654427
TI  - Purification, characterization and partial amino acid sequencing of two new
      aspartic proteinases from fresh flowers of Cynara cardunculus L.
AB  - Two new aspartic proteinases have been isolated from stigmas of the cardoon
      Cynara cardunculus L. by a two-step purification procedure including extraction
      at low pH, gel filtration on Superdex 200, and ion-exchange chromatography on
      Mono Q. To follow the conventional nomenclature for aspartic proteinases, we have
      named these proteinases cardosin A and cardosin B. On SDS/PAGE, cardosin A
      migrated as two bands with apparent molecular masses of 31 000 Da and 15 000 Da
      whereas the chains of cardosin B migrated as bands of 34 000 Da and 14 000 Da.
      The partial amino acid sequences of the two cardosin revealed that they are
      similar but not identical, and that they differ from the previously reported
      cardoon proteinases named cynarases, which were assumed to be derived from a
      common precursor. Although the cardosins show some degree of similarity to each
      other, we could detect no immunological crossreactivity between them. Both
      cardosins were active at low pH and were inhibited by pepstatin, with Ki values
      of 3 nM for cardosin A and 1 nM for cardosin B, indicating that they belong to
      the class of aspartic proteinases. Significant differences between the two
      enzymes were also found for the Kcat/km values for the hydrolysis of two
      chromophoric synthetic peptides. The active-site ionization constants, pKe1 and
      pKe2, for cardosin A are 2.5 +/- 0.2 and 5.3+/- 0.2, whereas for cardosin B they
      are 3.73 +/- 0.09 and 6.7 +/- 0.1. The results herein described on the structural
      and kinetic properties of the cardosins indicate that they are the products of
      distinct genes which have probably arisen by gene duplication. A scheme for the
      proteolytic processing of the two enzymes is also proposed.

PMID- 8654428
TI  - ATP synthesis by the F0F1 ATP synthase from thermophilic Bacillus PS3
      reconstituted into liposomes with bacteriorhodopsin. 1. Factors defining the
      optimal reconstitution of ATP synthases with bacteriorhodopsin.
AB  - Optimal conditions for the reconstitution of bacteriorhodopsin and H+
      transporting ATP synthase from thermophilic Bacillus PS3 (TF0F1) were determined.
      Phosphatidylcholine/phosphatidic acid liposomes prepared by reverse-phase
      evaporation were treated with various amounts of Triton X-100, octyl glucoside,
      octaethylene glycol n-dodecylether, sodium cholate or sodium deoxycholate and the
      incorporation of proteins by these detergents was studied at each step of the
      solubilization process. After removal of detergent by means of SM-2 Bio-Beads,
      the light-driven ATP synthase activities of the resulting proteoliposomes were
      analyzed at 40 degrees C. The nature of the detergent used for reconstitution was
      important for determining the mechanism of protein insertions. The most efficient
      reconstitutions were obtained with octyl glucoside or Triton X-100 by insertion
      of the proteins into detergent-saturated liposomes. The conditions for
      reconstitutions were further optimized with regard to functional coupling between
      bacteriorhodopsin and TF0F1. It was demonstrated that one of the main factors
      limiting the production of efficient reconstituted proteoliposomes was related to
      activation of the highly stable TFO-F1. Activation was accomplished by total
      solubilization of phospholipids and proteins in a Triton X-100/octyl glucoside
      mixture containing 20 mM octyl glucoside, leading to a threefold stimulation of
      the ATP synthase activity. Final ATP synthase activities depended greatly on the
      lipid/bacteriorhodopsin and the lipid/TF0F1 ratios as well as on the phospholipid
      used. In particular, light-driven ATP synthesis depended upon the presence of
      negatively charged phospholipids. Cholesterol was found to induce a fourfold
      increase in ATP synthase activity with a concomitant 65% decrease in the Km for
      ADP, suggesting that sterols can modulate catalytic events mediated by F1.
      Preparations obtained by this step-by-step reconstitution procedure displayed
      activities up to 20-fold higher (500-800 nmol ATP x min(-1) x mg TF0F1(-1) in the
      presence of cholesterol) than the maximal values reported in the literature for
      light-driven ATP synthesis TF0F1 measured under similar conditions. This study
      also allowed rationalization of the different parameters involved in
      reconstitution experiments and the present simple method is shown to be of
      general use for preparation of efficient proteoliposomes containing
      bacteriorhodopsin and choloroplast or mitochondrial F0F1-type ATP synthases.

PMID- 8654429
TI  - ATP synthesis by the F0F1 ATP synthase from thermophilic Bacillus PS3
      reconstituted into liposomes with bacteriorhodopsin. 2. Relationships between
      proton motive force and ATP synthesis.
AB  - The correlation between the rate of ATP synthesis and light-induced proton flux
      was investigated in proteoliposomes reconstituted with bacteriorhodopsin and ATP
      synthase from thermophilic Bacillus PS3. By variation of the actinic light
      intensity it was found that ATP synthase activity depended in a sigmoidal manner
      on the amplitude of the transmembrane light-induced pH gradient. Maximal rates of
      ATP synthesis (up to to 200 nmol ATP x min(-1) x mg protein (-1) were obtained at
      saturating light intensities under a steady-state pH gradient of about pH 1.25.
      It was demonstrated that this was the maximal deltapH attainable at 40 degrees C
      in reconstituted proteoliposomes, due to the feedback inhibition of
      bacteriorhodopsin by the proton gradient it generates. In the absence of
      valinomycin, a small but significant transmembrane electrical potential could
      develop at 40 degrees C, contributing to an increase in the rate of ATP
      synthesis. The H+/ATP stoichiometry was measured at the static-head (equilibrium)
      conditions from the ratio of the phosphate potential to the size of the light
      induced pH gradient and a value of about four was obtained under the maximal
      electrochemical proton gradient. Increasing the amount of bacteriorhodopsin in
      the proteoliposomes at a constant F0F1 concentration led to a large increase in
      the rate of ATP synthesis whereas the magnitude of delta pH remained the same or,
      at very high bacteriorhodopsin levels, decreased. Consequently the H+/ATP
      stoichiometry was found to increase significantly with increasing
      bacteriorhodopsin content. Reconstitutions with mixtures of native and impaired
      bacteriorhodopsin (Asp96-->Asn mutated bacteriorhodopsin) further demonstrated
      that this increase in the coupling efficiency could not be related to protein
      protein interactions but rather to bacteriorhodopsin donating H+ to the ATP
      synthase. Increasing the amount of negatively charged phospholipids in the
      proteoliposomes also increased the coupling efficiency between bacteriorhodopsin
      and ATP synthase at a constant transmembrane pH gradient. Similar results were
      obtained with chloroplast ATP synthase. Furthermore, ATP synthase activities
      induced by delta pH/delta psi transitions were independent of bacteriorhodopsin
      or anionic lipid levels. These observations were interpreted as indicating that,
      in bacteriorhodopsin/ATP synthase, proteoliposomes, a localized pathway for
      coupling light-driven H+ transport by bacteriorhodopsin to ATP synthesis by F0F1
      might exist under specific experimental conditions.

PMID- 8654430
TI  - Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene
      transcription in cultured fetal rat hepatocytes.
AB  - In the rat, the gene for liver mitochondrial carnitine palmitoyltransferase I
      (CPT I), though dormant prior to birth, is rapidly activated postnatally. We
      sought to elucidate which hormonal and/or nutritional factors might be
      responsible for this induction. In cultured hepatocytes from 20-day-old rat
      fetus, the concentration of CPT I mRNA, which initially was very low, increased
      dramatically in a dose-dependent manner after exposure of the cells to dibutyryl
      cAMP (Bt2cAMP). Similar results were obtained when long-chain fatty acids (LCFA),
      but not medium-chain fatty acids, were added to the culture medium. The effects
      of Bt2cAMP and LCFA were antagonized by insulin, also dose dependently. In
      contrast, CPT II gene expression, which was already high in fetal hepatocytes,
      was unaffected by any of the above manipulations. Bt2cAMP stimulated CPT I gene
      expression even when endogenous triacylglycerol breakdown was suppressed by
      lysosomotropic agents suggesting that the actions of cAMP and LCFA were distinct.
      Moreover, half-maximal concentrations of Bt2cAMP and linoleate produced an
      additive effect CPT I mRNA accumulation. While linoleate and Bt2cAMP stimulated
      CPT I gene transcription by twofold and fourfold, respectively, the fatty acid
      also increased the half-life of CPT I mRNA (50%). When hepatocytes were cultured
      in the presence of 2-bromopalmitate, (which is readily converted by cells into
      its non-metabolizable CoA ester) CPT I mRNA accumulation was higher than that
      observed with oleate or linoleate. Similarly, the CPT I inhibitor,
      tetradecylglycidate, which at a concentration of 20 microM did not itself
      influence the CPT I mRNA level, enhanced the stimulatory effect of linoleate. The
      implication is that induction of the CPT I message by LCFA does not require
      mitochondrial metabolism of these substrates; however, formation of their CoA
      esters is a necessary step. Unlike linoleate, the peroxisome proliferator,
      clofibrate, increased both CPT I and CPT II mRNA levels and neither effect was
      offset by insulin. It thus appears that the mechanism of action of LCFA differs
      from that utilized by clofibrate, which presumably works through the peroxisome
      proliferator activated receptor. We conclude that the rapid increase in hepatic
      CPT I mRNA level that accompanies the fetal to neonatal transition in the rat is
      triggered by the reciprocal change in circulating insulin and LCFA
      concentrations, coupled with elevation of the liver content of cAMP.

PMID- 8654431
TI  - Mechanisms by which fatty-acyl-CoA esters inhibit or activate glucose-6
      phosphatase in intact and detergent-treated rat liver microsomes.
AB  - We have studied the effects of fatty-acyl-CoA esters on the activity of glucose-6
      phosphatase (Glc6Pase) in untreated and detergent-treated liver microsomes. Fatty
      acyl-CoA esters with chain lengths less than or equal to nine carbons do not
      inhibit Glc6Pase. Medium-chain fatty-acyl-CoA esters (10-14 carbons) inhibit
      Glc6Pase of untreated microsomes in a dose-dependent manner in the range 1-20
      microM. The inhibitory effect is also dependent on the acyl-chain length. The
      higher the chain length, the stronger the inhibitory effect. It is also dependent
      on the microsomal protein concentration. The higher the protein concentration,
      the lower the inhibitory effect. Fatty-acyl-CoA esters with longer chain length
      (equal to or higher than 16 carbons) inhibit Glc6Pase of untreated microsomes
      within the range 1-2 microM. However, the inhibitory effect is either partially
      or totally cancelled, or even changed into an activation effect at higher
      concentrations. This is due to the release of mannose-6-phosphatase latency. The
      inhibition is fully reversible in the presence of bovine serum albumin. The
      mechanism of the Glc6Pase inhibition in untreated microsomes is uncompetitive (Ki
      for myristoyl-CoA = 1.2 +/- 0.3 microM, mean +/- SD, n = 3). Glc6Pase of
      detergent-treated microsomes is also inhibited by fatty-acyl-CoA esters, albeit
      less efficiently. In this case, the mechanism is non-competitive (Ki for
      myristoyl-CoA = 29 +/- 3 microM).

PMID- 8654432
TI  - NMR studies of the mode of binding of corepressors and inducers to Escherichia
      coli trp repressor.
AB  - The binding of the corepressors tryptophan and 5-methyltryptophan and of the
      inducers 3-indolepropionate, 3-indoleacrylate and 5-methylindole to the
      Escherichia coli trp repressor have been studied by 1H-NMR spectroscopy.
      Identification of the resonances of the protons of bound ligands and their NOEs
      to protons of the protein (measured as transferred NOE) was greatly facilitated
      by the use of samples of the protein in which the hydrogens of all residues
      except alanine, isoleucine and threonine was replaced by deuterium. Chemical
      shift changes of protein-backbone resonances and side-chain-amide resonances on
      ligand binding were measured with generally or selectively 15N-labelled protein.
      The patterns of changes in the chemical shifts of protein resonances and,
      particularly, ligand resonances distinguish the corepressors from the inducers,
      indicating, in agreement with earlier work, that corepressors and inducers bind
      to the protein in different ways. The NOEs observed for the bond ligands have
      been used to determine the position of the ligands in the crystallographically
      determined binding site, by means of a simulated-annealing molecular-dynamics
      protocol. The structures obtained show that the orientation in the binding site
      of the indole rings of tryptophan and 5-methyltryptophan and of 3
      indolepropionate and 3-indoleacrylate differ by approximately 180 degrees in
      solution (in agreement with the crystallographic data for complexes of the trp
      repressor with tryptophan or with 3-indolepropionate). The value and limitations
      of calculating ligand positions based on transferred NOE are discussed.

PMID- 8654433
TI  - Photoaffinity labeling of the head-activator receptor from hydra.
AB  - A photoaffinity ligand for the head-activator (HA) receptor from hydra was
      synthesized using solid-phase peptide synthesis and coupling of two HA peptides
      over their epsilon-amino groups of Lys7 with succinimidyl esters. The new ligand,
      Bpa-HA-HA bipeptide, contains one normal HA peptide and another where p
      benzoylphenylalanine (Bpa) was added at the amino terminus to allow ultraviolet
      activation and Tyr11 instead of Phe11 for radioiodination. The 125I-Bpa-HA-HA
      bipeptide bound with nanomolar affinity to the HA receptor from the multiheaded
      mutant of Chlorohydra viridissima as measured in a filter assay. After
      photoaffinity labeling of the hydra membrane fraction, a 200-kDa band was
      detected using reducing or non-reducing SDS/PAGE and autoradiography. Unlabeled
      HA derivatives, but no other neuropeptides, inhibited the labeling. Competition
      experiments with HA-HA homobipeptide in the nanomolar range indicate that
      predominantly the low-affinity and not the high-affinity HA receptor was
      photolabeled. Further evidence that the labeled molecule is the HA receptor comes
      from specific photoaffinity labeling with a second ultraviolet-activatable ligand
      containing p-nitrophenylalanine. The HA receptor could be functionally
      solubilized with Triton X-100 or Chaps. In the solubilizate the 200-kDa HA
      receptor was photolabeled specifically by both ligands. Liquid-phase isoelectric
      focussing of the solubilizate indicated a pI of about 5.4 of the photolabeled
      molecule. After chemical deglycosylation with trifluoromethanesulfonic acid, the
      apparent molecular mass of the labeled molecule was decreased to 180 kDa,
      indicating that the receptor is glycosylated.

PMID- 8654434
TI  - The defective secretion of a naturally occurring alpha-1-antichymotrypsin variant
      with a frameshift mutation.
AB  - A newly found variant alpha-1-antichymotrypsin (ACT), ACT Isehara-2, has a
      deletion of two bases (AA) at codon 391 near the carboxyl terminus. This
      frameshift mutation caused a change in the amino acid sequence and generated 10
      extra amino acids (408 amino acids total) [Tsuda, M., Sei, Y., Matsumoto, M.,
      Kamiguchi, H., Yamamoto, Y., Shinohara, Y., Igarashi, T. & Yamamura, M. (1992)
      Hum. Genet. 91. 467-468]. The serum ACT levels in three unrelated heterozygotes
      with this mutant ACT gene were 37% 49% and 54% that of the normal individuals. To
      examine the reduced serum levels, the normal ACT and the mutant ACT created by
      site-directed mutagenesis were transfected into COS-7 cells for comparison. The
      value for the retention rate (intracellular ACT/total ACT) was apparently higher
      in the cells expressing mutant ACT Isehara-2 than those bearing the normal gene.
      In the pulse-chase experiments, the secretion of the synthesized mutant ACT into
      the medium was not observed, whereas the normal ACT was mostly secreted as a 64
      kDa form. The endoglycosidase H digestion and an electron microscopic analysis
      indicated that the retained mutant ACT was present in the endoplasmic reticulum.
      These results provide the biochemical basis for the decreased serum ACT level of
      individuals with ACT Isehara-2, and suggest the importance of the carboxyl
      terminal region for its secretion.

PMID- 8654435
TI  - Inhibition of phosphatidylinositol 3-kinase blocks T cell antigen receptor/CD3
      induced activation of the mitogen-activated kinase Erk2.
AB  - The production of 3-phosphorylated inositol phospholipids is implicated in
      regulation of cell growth and transformation. To explore the role of these lipids
      in T cell antigen receptor (TCR)/CD3-induced signaling, we have examined the
      effects of a specific phosphatidylinositol 3-kinase (PtdIns3K) inhibitor,
      wortmannin, and overexpression of two PtdIns3K constructs on the activation of
      down-stream effectors in anti-CD3 treated T cells. We report that treatment of
      cells with wortmannin blocked anti-CD3-induced activation of the mitogen
      activation kinase Erk2 while not affecting phorbol-ester-induced Erk2 activation.
      An inactive analog of wortmannin, WM12, did not affect TCR/CD3-induced Erk2
      activation, and wortmannin had no effect on the activity of Erk2 when added
      directly to the in vitro assays. Expression of a disruptive PtdIns3K construct
      also reduced Erk2 activation, while a construct that stimulates PtdIns3K enhanced
      the activation of Erk2. Receptor-induced activation of other Ser/Thr kinases,
      such as c-Raf, B-Raf, Mek1, Mek2, Mekk, was not affected by wortmannin. Our
      results suggest that the production of 3-phosphorylated inositol phospholipids is
      involved in the activation of Erk2, but does not regulate the enzymes that are
      thought to be upstream of Erk2.

PMID- 8654436
TI  - Deep soft-tissue infections caused by Streptococcus pneumoniae.
AB  - Three cases of deep soft-tissue infections caused by Streptococcus pneumoniae are
      presented. All patients were previously healthy adults. The first case was a man
      with a protracted illness in whom pelvic and inguinal abscesses developed at the
      site of a scar from a traumatic injury several years earlier. The second patient,
      a woman, had mastitis with systemic symptoms. The third patient was a woman who
      developed a gluteal abscess after an intramuscular injection of a contraceptive.
      Cellulitis and deep soft-tissue infections caused by Streptococcus pneumoniae are
      uncommon, but may occur even in immunocompetent adults.

PMID- 8654437
TI  - Two cases of infected atherosclerotic aneurysms and a comparison with infective
      endocarditis.
AB  - Two cases of infected atherosclerotic aneurysms thought to have arisen following
      haematogenous seeding of atheromatous lesions are described. Although infective
      endocarditis also arises by the haematogenous route, there are striking contrasts
      in both the range and therefore likely source of organisms, together with a
      perceived difference in the rate of blood-culture positivity. This case report
      provides a focus for discussion of these observations.

PMID- 8654438
TI  - Rapid growth of Helicobacter pylori.
AB  - The ability of six variants of a new charcoal medium and Skirrow's medium to grow
      Helicobacter pylori in 3 and 5 days was studied using 20 different strains of
      Helicobacter pylori. The main admixtures for the charcoal media were serum, whole
      blood, and egg yolk emulsion. For this purpose, serum was significantly better
      and egg yolk emulsion significantly worse than whole blood. The addition of Iso
      Vitalex resulted in significantly improved growth on the charcoal media.
      Skirrow's medium showed very poor performance after three days of incubation and
      needed a long incubation time.

PMID- 8654439
TI  - Concordance between polymerase chain reaction and antibody detection in the
      diagnosis of human immunodeficiency virus type 1 infection.
AB  - A highly sensitive nested polymerase chain reaction (PCR) protocol was used to
      detect human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood
      mononuclear cells from 271 HIV-1-seropositive patients, 240 HIV-1-seronegative
      subjects at increased risk for HIV-1 infection, 51 serologically indeterminate
      individuals, and 120 healthy blood donors. PCR was carried out in a multiplex
      nested configuration with pol and env region primer sets. HIV-1 DNA was detected
      in all of the HIV-1 seropositive patients. In contrast, HIV-1 DNA was not
      detected in any of the either seronegative or serologically indeterminate
      subjects. Only one of 37 seronegative regular sexual partners of HIV-1-infected
      patients who were followed longitudinally was found to seroconvert to HIV-1.
      However, HIV-1 DNA and antibody results were concordant in the four samples
      obtained from this subject prior to and after seroconversion. These results show
      an excellent concordance between HIV-1 DNA and antibody detection for diagnosis
      of HIV-1 infection and suggest that long-term HIV-1 infection in the absence of
      detectable antibody is likely to occur at a very low frequency.

PMID- 8654440
TI  - Bacillus circulans infection of a proximal interphalangeal joint after a clenched
      fist injury caused by human teeth.

PMID- 8654441
TI  - Septic shock due to Vibrio vulnificus serogroup 04 wound infection acquired from
      the Baltic Sea.

PMID- 8654442
TI  - Evaluation of direct immunofluorescence, dot-blot enzyme immunoassay, and shell
      vial culture for detection of respiratory syncytial virus in patients with
      bronchiolitis.

PMID- 8654444
TI  - Influence of human immunodeficiency virus type 1 infection on the natural course
      of chronic parenterally acquired hepatitis C.
AB  - The aim of the present study was to investigate the possible role of human
      immunodeficiency virus (HIV) infection in the natural course of chronic hepatitis
      C. Seventy-six adult patients with chronic parenterally acquired hepatitis C
      virus (HCV) infection examined from 1989 to 1993 were enrolled; of these 32
      (42.1%) were HIV positive and 44 (57.9%) were HIV negative. Serum HCV RNA
      quantitation was carried out by polymerase chain reaction in a well-characterized
      group (n = 20; 11 HIV positive and 9 HIV negative). Distribution of histological
      findings in liver biopsies from both HIV-infected and noninfected patients was
      similar. However, within 15 years after initial HCV infection, 8 of 32 (25%) HIV
      positive patients developed cirrhosis, in comparison with only 2 of 31 (6.5%)
      patients in the HIV-negative group (p < 0.05); similar incidences of cirrhosis
      were found in both patient groups within 5 and 10 years after HCV infection. Most
      of the HIV-negative cirrhotic patients (9 of 11) developed cirrhosis in a time
      interval longer than 15 years. Finally, HCV load was almost ten times higher (1
      10-fold dilution) in the HIV-positive group, but this difference did not reach
      statistical significance in this small study population. These results suggest
      that HIV infection can alter the natural course of chronic parenterally acquired
      hepatitis C, causing an unusually rapid progression to cirrhosis.

PMID- 8654445
TI  - Seroepidemiological study of hepatitis E virus in different population groups.
AB  - In order to determine the seroprevalence of hepatitis E virus, 1,993 sera (453
      from healthy pregnant women, 491 from Moroccan subjects, 492 from blood donors,
      321 from children, and 236 from intravenous drug users) were studied. IgG was
      measured by enzyme immunoassay (EIA), and positive results were confirmed by
      Western blot. The EIA detected antibodies in 3.96% of the subjects (5.6% of the
      Moroccans and drug users and 1.8% of the children). Fifty-four percent of these
      results were confirmed by Western blot, 11.4% were found to be negative, and
      34.2% indeterminate. The overall prevalence after confirmation by Western blot
      decreased to 2.15%. When studying the Western blot pattern of the positive
      samples, 95% showed antibodies to SG-3, 65% to 8-5, and only 9.3% to CKS fusion
      protein. In the indeterminate Western blots, the results for these proteins were
      96.3%, 62.9%, and 37%, respectively. When the epidemiological data were analysed,
      no statistically significant differences between women and men or between
      different age groups were found.

PMID- 8654446
TI  - Epidemiologic analysis of glycopeptide-resistant Enterococcus strains in
      neutropenic patients receiving prolonged vancomycin administration.
AB  - Vancomycin-resistant enterococci have been isolated with increasing frequency
      since 1988. Thus far, most of these resistant enterococci have belonged to the
      Enterococcus faecium species, and epidemiological studies have shown a wide
      diversity among interhospital and intrahospital isolates. This report presents an
      epidemiologic investigation of 25 vancomycin-resistant Enterococcus strains--24
      Enterococcus faecium and one Enterococcus gallinarum--isolated from the stools or
      blood of adult patients receiving intravenous vancomycin prophylaxis during
      neutropenia and hospitalized in a single hematologic unit. Macrorestriction
      patterns of total DNA and of ribosomal DNA regions were used to analyze the
      strains. Strains produced different total DNA restriction fragment length
      polymorphism patterns after SmaI digestion. Ribotyping was less discriminative
      than pulsed-field gel electrophoresis. The results confirmed the genetic
      unrelatedness of the strains. Prolonged vancomycin administration, commonly used
      in hematologic units, could be involved in the selection of endogenous resistant
      enterococcal strains.

PMID- 8654443
TI  - Haemophilus influenzae: then and now.
AB  - Haemophilus influenzae has long been recognised as a major cause of serious
      infection and mortality in children less than 5 years old. Prior to the
      introduction of Haemophilus influenzae type b (Hib) immunisation, the incidence
      of a child suffering an invasive Haemophilus infection was 20-50/100,000 in
      industrialised countries and up to ten times higher in developing regions. The
      introduction of a Hib vaccine programme results in a rapid and dramatic decline
      in the incidence of Hib infection in the susceptible childhood population. For
      example, within two years of the introduction of routine Hib vaccination of
      infants in the UK, the risk of serious Hib infection had fallen from 1:600 to
      1:30,000 by 5 years of age. Many other European countries have introduced, or are
      in the process of introducing, a routine Hib immunisation programme. Because the
      epidemiology of Haemophilus influenzae infection is changing so dramatically, it
      is opportune to review Haemophilus influenzae as it was perceived in the pre
      vaccine era (the past) and during vaccine implementation (the present), and how
      its role may change in the post-vaccination era (the future). This review will
      summarise the historical landmarks that have led to our present-day understanding
      of Haemophilus influenzae pathogenicity, the concerns about antibiotic
      resistance, the features of the host immune response to Haemophilus influenzae,
      and the introduction of the Hib vaccine. Furthermore, the possible importance of
      this organism in the future will be discussed.

PMID- 8654447
TI  - Emergence of resistance to beta-lactam agents in Pseudomonas aeruginosa with
      group I beta-lactamases in Spain.
AB  - The contribution of induction and stable derepression of chromosomal class I beta
      lactamases to beta-lactam antibiotic resistance was studied in clinical isolates
      of Pseudomonas aeruginosa collected from patients treated with beta-lactam
      antibiotics. Multiple isolates from the same patient were characterized by O
      serotyping as a primary screen, combined with pyocin typing. Sonicated extracts
      of cells were assayed for chromosomal and plasmid-mediated beta-lactamases by
      isoelectric focusing and cloxacillin inhibition studies. The specific beta
      lactamase activity, basal and induced, with cefoxitin was determined to
      differentiate strains with inducible or derepressed production of the enzyme.
      Beta-lactamase induction was performed in each strain against the beta-lactam
      agents used in the therapy of each patient. The observations showed that
      induction against older penicillins such as penicillin, amoxicillin, and
      amoxicillin/clavulanate resulted in a moderate to strong increase in beta
      lactamase activity, whereas the results obtained with first-generation
      cephalosporins varied with the beta-lactam agent tested. Third-generation
      cephalosporins were weak inducers of beta-lactamases, and their use as therapy
      preceded the appearance of strains that produce chromosomal group I beta
      lactamases constitutively. These strains showed a remarkable reduction in
      sensitivity to ureidopenicillins, carboxipenicillins, third-generation
      cephalosporins, and monobactams, but not to carbapenems.

PMID- 8654448
TI  - Activity of beta-lactamase inhibitor combinations on Escherichia coli isolates
      exhibiting various patterns of resistance to beta-lactam agents.
AB  - The efficacy of the clinically available beta-lactam/beta-lactamase inhibitor
      combinations (amoxicillin/clavulanic acid (CA), ticarcillin/CA,
      amoxicillin/sulbactam, and piperacillin/tazobactam) was evaluated on 300
      amoxicillin-resistant Escherichia coli isolates having the main patterns of beta
      lactam resistance. The patterns, which reflect the production of various beta
      lactamase enzymes, were analyzed by a principal component analysis of
      susceptibility to 11 beta-lactam antibiotics or beta-lactam/beta-lactamase
      inhibitor combinations. Sixty-two percent of strains were not very susceptible to
      penicillins, cephalothin, or any beta-lactam/beta-lactamase inhibitor
      combinations except for piperacillin/tazobactam; these strains may represent high
      level broad-spectrum beta-lactamase (so-called penicillinase) production
      phenotype or inhibitor-resistant TEM-like enzyme production phenotype. Of the
      strains, 14.7% were resistant to amoxicillin and ticarcillin compatible with low
      level broad-spectrum beta-lactamase production phenotype; 5.7% were cefoxitin
      resistant and were postulated to present a high-level cephalosporinase production
      phenotype; and 2.6% were resistant to cephalothin only, attributable to a low
      level cephalosporinase production phenotype. Three percent of strains were
      intermediate or resistant to cefotaxime and may produce an extended-spectrum beta
      lactamase, and the remaining strains (12 %), resistant to all tested antibiotics
      except for cefotaxime and piperacillin/tazobactam, were hypothesized to produce
      both broad-spectrum beta-lactamase plus cephalosporinase. The minimal inhibitory
      concentration (MIC) for these phenotype patterns indicated that combinations of
      CA plus amoxicillin or ticarcillin, or sulbactam plus amoxicillin, restored the
      activity of penicillins against phenotype 1 strains, whereas these combinations
      remained inactive against the other phenotype strains. Piperacillin plus
      tazobactam showed the best in vitro effect against the strains of all resistance
      phenotypes.

PMID- 8654449
TI  - Lack of additive effect between mechanisms of resistance to carbapenems and other
      beta-lactam agents in Pseudomonas aeruginosa.
AB  - Eighty-nine clinical isolates resistant (n = 61) or susceptible (n = 28) to
      imipenem and exhibiting the main patterns of susceptibility to other beta-lactam
      agents (wild type pattern, penicillinase pattern, constitutive cephalosporinase
      pattern) were studied in order to investigate (i) the mechanism of resistance
      involved and (ii) whether resistance to carbapenems affects the level of
      resistance to other beta-lactam agents and, conversely, if resistance to other
      beta-lactam agents affects the level of resistance to carbapenems. For this
      purpose, the presence of OprD protein in the cell wall was detected by Western
      blot and beta-lactamase activity by spectrophotometric assay and isoelectric
      focusing. OprD expression was not detectable in the imipenem-resistant (MIC > or
      = 16 micrograms/ml) strains. It was decreased in half the strains for which MICs
      of imipenem were 2 to 8 micrograms/ml and was close to a normal level in the most
      susceptible strains (MIC < or = 1 microgram/ml), thus demonstrating a direct
      correlation between the level of susceptibility to imipenem and the level of OprD
      expression. No imipenemase activity was detected in imipenem-resistant strains.
      Synergy between imipenem or meropenem and BRL 42715 was observed for all of the
      strains, demonstrating the role of cephalosporinase in carbapenem resistance.
      Within each pattern of susceptibility, the mean MICs of beta-lactam agents other
      than carbapenems were similar, whether the strains were susceptible or resistant
      to imipenem. Conversely, the mean MICs of imipenem or meropenem for either the
      imipenem-resistant or the imipenem-susceptible strains were similar, regardless
      of the susceptibility of these strains to the other beta-lactam agents. Thus,
      when several mechanisms of resistance to beta-lactam agents are present in the
      same strain of Pseudomonas aeruginosa, there is no additive effect between these
      mechanisms.

PMID- 8654450
TI  - Use of pulsed-field gel electrophoresis for investigation of an outbreak of
      Clostridium difficile infection among geriatric patients.
AB  - A six-month outbreak of Clostridium difficile infection among elderly residents
      of a middle-term-care facility was investigated. Pulsed-field gel electrophoresis
      was used to genotype 22 outbreak strains and 30 epidemiologically unrelated
      strains. A prospective case-control study was conducted to identify risk factors
      for epidemic Clostridium difficile-associated diarrhea. All epidemiologically
      unrelated Clostridium difficile strains of the same serogroup could be
      differentiated by their DNA patterns with two restriction enzymes (SmaI and
      KspI). Among clustered strains, two epidemic serogroups (C and K) were
      identified. Two different DNA patterns were identified among serogroup C strains
      and three among serogroup K strains. Multivariate analysis showed that the risk
      of Clostridium difficile infection increased with antimicrobial chemotherapy
      (beta-lactam agents and pristinamycin) and the presence of a feeding tube. This
      study confirms the high discriminative power of restriction fragment length
      polymorphism analysis by pulsed-field gel electrophoresis to describe Clostridium
      difficile epidemiology. The typing results confirm that infection was principally
      exogenous in this outbreak. Furthermore, they indicate the need to improve all
      measures limiting transmission of infection.

PMID- 8654451
TI  - Infection rate of Ixodes ricinus ticks with Borrelia afzelii, Borrelia garinii,
      and Borrelia burgdorferi sensu stricto in Slovenia.
AB  - In spring 1993, Ixodes ricinus ticks were collected from six regions of Slovenia
      to determine their overall rate of infection with Borrelia burgdorferi sensu lato
      and to assess the frequency of individual species in these tick populations.
      Ticks were dissected and midgut tissue inoculated into modified Barbour-Stoenner
      Kelly (BSK II) medium. Borrelia isolates were differentiated into separate
      species using species-specific polymerase chain reaction (PCR) primers and by
      large restriction fragment pattern (LRFP) analysis. Infected ticks were found in
      all six regions surveyed. Spirochaetes were isolated from 69 of 363 ticks (19%):
      the isolation rate from adult female ticks was 35% (23/66 ticks cultured), from
      adult male ticks 22% (20/91), and from nymphal ticks 13% (26/206). Determination
      of the species of 60 isolates revealed that 32 were Borrelia afzelii (53%), 20
      were Borrelia garinii (33%), and 8 were Borrelia burgdorferi sensu stricto (13%).
      In the Ljubljana region Borrelia afzelii and Borrelia garinii predominated (43%
      and 40%, respectively), whereas Borrelia burgdorferi sensu stricto constituted
      only 17% of isolates. In three other regions of the country Borrelia afzelii was
      isolated exclusively, although the number of isolates investigated was small.
      This study demonstrates the presence of all three European species of Borrelia
      burgdorferi sensu lato within the Slovenian tick population and also within a
      geographic area of less than 100 m2.

PMID- 8654452
TI  - Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast
      agent for magnetic resonance imaging.
AB  - The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10
      tetraazacyclo  dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd
      chelate for use as an extracellular contrast agent in magnetic resonance imaging
      (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with
      a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg
      and the distribution volume of 0.23 l/kg suggested an extracellular distribution.
      Biodistribution experiments in rats revealed that only a very small amount
      (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable
      amounts of Gd could be detected only in the liver, kidneys and bones. The
      osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the
      range of other low osmolality contrast media for MRI. Only very little
      interaction with biologically relevant molecules was suggested by a histamine
      release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice
      combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and
      6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In
      preliminary imaging experiments, gadobutrol caused high enhancement in different
      lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical
      clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in
      lesions of this type.

PMID- 8654453
TI  - Effects of iodinated contrast agents in MR imaging.
AB  - PURPOSE: To investigate the effects of iodinated contrast agents in MRI. MATERIAL
      AND METHODS: Twenty patients were examined with MRI immediately, 8 and 24 h after
      lumbar myelography. Signal intensities and calculated T1- and T2-relaxation times
      of different iodinated contrast agents, a dilution row of iopamidol, and a
      mixture of CSF and iotrolan were compared with physiological saline solution
      using different T1- and T2-weighted sequences. 1H-spectroscopy was performed with
      several solutions containing iodine or other substances. RESULTS: A fluid-fluid
      level of the CSF existed in the lumbar dural sac in all patients immediately
      after lumbar myelography with a non-ionic iodinated contrast agent. Increased
      signal intensity on T1-weighted and decreased signal intensity on T2-weighted
      sequences was found for all contrast agents, as well as for the dilution row,
      compared with physiological saline solution. The structure of the side chains of
      the contrast agents is responsible for the T1- and T2-shortening effect.
      CONCLUSION: It is important to be aware of the effect of iodinated contrast
      agents in MRI. To avoid misinterpretation of atypical findings, MRI of the spine
      should not be performed earlier than 24 h after myelography.

PMID- 8654454
TI  - Grading medial collateral ligament injury: comparison of MR imaging and
      instrumented valgus-varus laxity test-device. A prospective double-blind patient
      study.
AB  - PURPOSE: The role of MR imaging in grading medial collateral ligament (MCL)
      injury of the knee in comparison to other grading methods (clinical findings and
      instrumental measurement) is hardly documented in the literature. The purpose of
      this study is to compare the results of MR imaging in grading acute MCL injuries
      to the results of a clinical grading by an instrumented valgus-varus laxity
      tester (VVLT). MATERIALS AND METHODS: Twenty-one patients clinically suspected of
      acute MCL injury were tested by VVLT, a well documented and instrumented test
      device. All patients subsequently underwent MR imaging of the knee. MCL injury
      was graded independently by VVLT and MR imaging using a classification method
      with reference to Petermann. RESULTS: Nineteen patients had corresponding grading
      results by VVLT and MR imaging (kappa, 0.83; S.E., 0.10); 14 patients had a Grade
      I, four a Grade II and two patients had a Grade III MR imaged MCL injury.
      Associated lesions were also depicted on MR imaging (bone contusion (n = 3), ACL
      disruption (n = 2) and medial meniscal rupture (n = 1)). CONCLUSIONS: This study
      shows a very high degree of agreement between the results in grading acute MCL
      injuries with MR imaging and an instrumented valgus-varus laxity tester (VVLT).
      MR imaging depicted important, clinically undetected, additional lesions which
      can determine the treatment of MCL injury.

PMID- 8654455
TI  - Spin-echo and 3D gradient-echo imaging of the knee joint: a clinical and
      histopathological comparison.
AB  - OBJECTIVE: A clinical and histopathological comparison of 2D spin-echo (SE) and
      3D gradient-echo (3DGE) sequences was undertaken for the knee joint. The purpose
      of the study was to evaluate the clinical results and to explain the different
      appearances of meniscal abnormalities on both 2DSE and 3DGE images. PATIENTS,
      MATERIALS AND METHODS: The clinical study comprised 45 patients with
      arthroscopically correlated MR imaging results. For the histopathological
      correlation, seven cadaveric knee joints were examined with the same 2DSE and
      3DGE (FISP) imaging protocol and sliced in sagittal sections according to the MR
      images. Different stainings were used. RESULTS: For the detection of meniscal
      tears, accuracy (82.2%) and positive predictive value (70.7%) of the 3DGE
      sequence were limited due to a high number of false positive findings.
      Cartilaginous lesions were more easily visible on 3DGE than on 2DSE images
      (sensitivity: 63.1% vs. 52.6%, respectively). As in the clinical study, the
      meniscal signal abnormalities of the cadaveric knee joints were much more
      extensive on the 3DGE images than on the 2DSE images. The 3DGE findings
      correlated better with degenerative meniscal changes which were visible
      microscopically. CONCLUSION: The high sensitivity of the 3DGE sequence for
      degenerative meniscal changes explains the lack of specificity for the
      differentiation between meniscal degeneration and tears with this sequence. The
      MR grading system for meniscal lesions is of limited value for the evaluation of
      3D FISP images.

PMID- 8654456
TI  - Magnetic resonance imaging of cartilaginous tumors: a retrospective study of 79
      patients.
AB  - OBJECTIVE: Hyaline cartilaginous tumors are characterized by extremely high
      signal intensity on T2-weighted images. Recently, some distinctive MR features of
      cartilaginous bone tumors were reported in small series. Low signal intensity
      septa surrounding high signal intensity cartilage lobules were seen on T2
      weighted images in low-grade chondrosarcomas. On spin-echo T1-weighted images
      after Gd contrast injection, marked 'septal' or 'ring-and-arc' enhancement was
      observed in low-grade chondrosarcomas and enchondromas. The purpose of this study
      was to determine sensitivity and specificity of these MR findings in diagnosis of
      cartilaginous tumors, and to assess the value of MR in diagnostic workup of these
      lesions. MATERIALS AND METHODS: Retrospective evaluation of MR findings in 79
      cartilaginous tumors and in 79 non-cartilaginous tumors. All lesions were biopsy
      proven. Each MR examination was independently reviewed by two experienced
      radiologists without knowledge of clinical data, radiographic and/or CT findings,
      or histological diagnosis. All lesions were evaluated for morphology (lobular or
      non-lobular), presence of a high signal intensity mass on T2-weighted images,
      presence of low signal intensity septa separating high signal intensity lobules
      on T2-weighted images, and evidence of septal ('ring-and-arc') enhancement.
      RESULTS: None of the reviewed parameters is useful in diagnosing osteochondromas.
      Since osteochondromas have a characteristic appearance on plain radiography, the
      value of MR imaging in the workup of these lesions remains limited. MR findings
      in enchondromas have a low specificity and a low sensitivity. Low-grade
      chondrosarcomas, often hard to diagnose on plain radiography and difficult to
      differentiate from enchondromas, are characterized by the MR tandem of 'low
      signal intensity septa on T2-weighted images' together with 'septal or ring-and
      arc enhancement' (sensitivity 92.3%, specificity 76.5%). High-grade
      chondrosarcomas are easily recognized on plain radiography. CONCLUSIONS: In
      differentiating cartilaginous from non-cartilaginous tumors, MR features are
      highly specific but lack sensitivity. Grading potentials of MR parameters are
      promising due to the high accuracy in diagnosing low-grade chondrosarcomas.

PMID- 8654457
TI  - Hemorrhage in cavernous hemangioma of the adrenal gland: US, CT and MRI
      appearances with pathologic correlation.

PMID- 8654458
TI  - Mycobacterial respiratory infection in leukemic children.

PMID- 8654459
TI  - Measurement of femoral anteversion by magnetic resonance imaging--evaluation of a
      new technique in children and adolescents.
AB  - Anteversion of the femoral neck was measured by magnetic resonance imaging (MRI)
      in 19 children (37 hips) preoperatively before femoral rotation osteotomies. The
      results of this new technique were compared with values for anteversion obtained
      by computed-tomographic (CT) scanning and ultrasound. In order to determine the
      correlation between the three different methods and to assess their reliability,
      the measurements were performed independently by two observers at different
      times. There was a high correlation (Pearson's correlation coefficient) between
      MRI results and CT scan (r = 0.77) as well as MRI and sonography (r = 0.81),
      although the mean anteversion angles obtained by computerized tomography (34.0
      degrees, range 5-82 degrees) and ultrasound (25.6 degrees, 10-40 degrees) were
      larger than the MRI values (23.2 degrees, 0-65 degrees), which can be explained
      by the different measurement techniques. Mean inter-rater as well as intra-rater
      reliability was high for MRI (r = 0.97 and r = 0.97) and CT (r = 0.99 and r =
      0.96) but slightly less for sonography (r = 0.88 and r = 0.88). MRI is a novel
      method for evaluating femoral anteversion that does not require ionizing
      radiation, allows a precise anatomical measurement and reliable results. MRI is
      recommended for preoperative planning of pediatric femoral rotation osteotomy
      cases.

PMID- 8654460
TI  - Mandibulofacial dysostosis: CT findings of the temporal bones.
AB  - Six patients of two families with clinically suspected and genetically proven
      Treacher Collins syndrome and hearing loss were studied by CT of the temporal
      bone. The objective of this study was to detect the abnormalities and to show the
      variation of expression of abnormalities. We found a high incidence of asymmetry
      in the different ear malformations and a slightly lower incidence of some other
      classical features, probably due to our patient selection.

PMID- 8654461
TI  - Acinar cell carcinoma of the pancreas: a rare case of an alpha-fetoprotein
      producing cystic tumor.

PMID- 8654463
TI  - A ROC study of AMBER and conventional chest imaging in the detection of simulated
      interstitial lung disease.
AB  - PURPOSE: The aim of this study was to compare the detection of simulated
      interstitial lung disease with Advanced Multiple Beam Equalization Radiography
      (AMBER) and conventional wide latitude screen-film radiography. MATERIALS AND
      METHODS: Interstitial disease of varying severity was simulated with overlays on
      an anthropomorphic chest phantom. A total of 60 images per modality was used in a
      Receiver Operating Characteristic (ROC) study. RESULTS: AMBER performed
      significantly better than conventional radiography for all readers (P < 0.02).
      The difference was even more significant for the radiologist readers (P = 0.001).
      In each case the difference in ROC areas was between 5% and 9%. CONCLUSION: AMBER
      is superior to conventional wide latitude screen-film imaging in detecting the
      subtle patterns used to simulate interstitial lung disease.

PMID- 8654464
TI  - Radiation exposure to the hands of operators during angiographic procedures.
AB  - The hands of those undertaking angiographic studies are close to the X-ray beam
      and may receive high doses. However, during recent years little information is
      available on these doses. The exposure to the left and right hand was measured
      with thermoluminescent dose meters during several conventional angiographic
      procedures. Mean doses to the left hand ranged from 0.24 to 0.96 mSv and to the
      right hand from 0.12 to 0.71 mSv, related to the type of procedure performed. The
      protection provided by new flexible lead gloves was estimated. The dose reduction
      with the glove was 19.5%. Operators can approach the dose limit to hands set by
      the International Commission on Radiological Protection (ICRP) during high
      workload. The data presented emphasize the importance of wearing lead gloves.

PMID- 8654462
TI  - Laryngeal schwannomas.
AB  - As laryngeal schwannomas are a threat to breathing, they must be removed. CT and
      MR provide an accurate pre-operative work-up of these lesions. The clear
      delineation of the tumoral attachment to the larynx proved to be very useful in
      the difficult management of our second patient. Our two laryngeal schwannomas
      exhibited a similar appearance which differed from those of the few other
      laryngeal nerve sheath tumors reported in the literature The low attenuating
      outer part correlated with Antoni B areas. The denser enhancing inner part
      correlated with Antoni A areas containing large vessels. This unusual tumoral
      appearance, which has been observed in some other peripheral schwannomas, must
      bring this diagnostic possibility to mind. However, this clearly contrasting
      distribution of the two components of schwannomas is not the most commonly
      observed in other locations. More reports are needed to establish whether this
      special appearance is characteristic of laryngeal location.

PMID- 8654465
TI  - Intraductal carcinoma (DCIS) of the breast. Risk-adapted tumor surgery with
      axillary lymphadenectomy?
AB  - Between 1963 and April 1994, 3823 women were treated both at the Universitats
      Frauenklinik Berlin-Charlottenburg as well as at the I. Frauenklinik der
      Universitat Munchen, for a malignant condition of the breast gland. 161 of these
      (4.2%) exhibited an intraductal carcinoma stage pTis, whilst 99 (61.5%) were
      axillary lymphadenectomised. During the observation time-span of up to 24 years,
      9 patients (5.6%) developed local recurrence. In neither patients of the group
      with axillary nor without axillary dissection could a regional recurrence be
      observed within this period. Also, a generalisation of this condition was not
      recorded in any patient. On the basis of our own results and those from the
      literature we postulate that, under the auspices of a risk adapted tumor surgery,
      axillary lymphadenectomy is no longer necessary under certain conditions in non
      invasive breast carcinoma.

PMID- 8654466
TI  - Urokinase plasminogen activator in ovarian cancer.
AB  - Invasion and metastasis require the destruction of the extracellular matrix and
      basement membranes to facilitate growth or migration of tumor cells into vascular
      and lymphatic spaces. These processes are mediated by proteolytic enzymes.
      Malignant cells produce urokinase which is a protease known to enhance the
      invasiveness of many tumor cells. The relationship between urokinase and various
      prognostic factors was investigated in 16 patients with epithelial ovarian
      cancer. Tissue concentrations of urokinase were measured in tumor cytosols using
      enzyme-linked immunoassays. Urokinase levels were lower in ovarian tumors of low
      malignant potential (median 9.5, range 3.5-18.3 pg/mg protein, n = 4) than
      invasive cancers (median 44.6, range 16.1-210.6 pg/mg protein, n = 12), p < 0.01.
      In the invasive carcinomas urokinase levels did not vary significantly with tumor
      stage or cell type. Grade 3 tumors had higher levels of urokinase (median 120.4,
      range 21.4-397.1 pg/mg protein, n = 6) than grade 1 and 2 tumors (median 29.2,
      range 16.1-51.8 pg/mg protein, n = 6), p < 0.05. Urokinase levels were higher in
      recurrent (median 120.4, range 51.8-210.6 pg/mg protein, n = 4) than in primary
      (median 29.2, range 16.1-97.1 pg/mg protein, n = 8) tumors, p < 0.05. These
      results support the hypothesis that urokinase plays a role in invasion and
      metastasis of ovarian epithelial cancers and suggest that tissue levels of
      urokinase may have prognostic value.

PMID- 8654467
TI  - Improved control of nausea and emesis with a new bromazepam-containing
      ondansetron regimen in ovarian cancer patients receiving chemotherapy with
      carboplatin and cyclophosphamide.
AB  - BACKGROUND: Ondansetron was found to be effective as an antiemetic in numerous
      clinical trials of highly emetogenic combination-chemotherapy regimens that
      included cisplatin. Its role in milder emetogenic regimes has not been fully
      defined. METHODS: This study investigated the efficacy of two different
      antiemetic regimes in thirty-five patients with ovarian cancer receiving 68
      cycles of chemotherapy with carboplatin (350 mg/m2) and cyclophosphamide (600
      mg/m2). Ondansetron (3 x 8 mg i.v.) was compared to a bromazepam-containing
      ondansetron regimen. RESULTS: Nausea was absent in 65% of chemotherapy courses in
      patients receiving the combination of ondansetron and bromazepam and in 38% of
      chemotherapy courses in patients receiving ondansetron alone. Complete control of
      emesis was achieved in 93% of the courses in patients receiving the combination
      and in 81% of the courses using ondansetron alone. CONCLUSIONS: The addition of
      bromazepam to ondansetron, and the extension of antiemetic prophylaxis to the day
      before and the day after chemotherapy improves the control of nausea and emesis
      compared to ondansetron monotherapy in patients with ovarian cancer.

PMID- 8654468
TI  - Cytologic assessment of metastatic ovarian carcinoma.
AB  - Significance of routine cytologic examination in the diagnosis of metastatic
      ovarian carcinoma was assessed. Twenty-one cases of metastatic carcinoma of the
      ovary were examined both pathologically and cytologically. Primary sites of the
      carcinoma were the stomach, breast, large bowel and uterine corpus. Cytology
      specimens were taken from the portio, endocervix and endometrium of the uterus,
      ascites and vaginal surgical stump. Malignant cells were detected in the samples
      from the portio, endocervix and endometrium in two, three and eight cases,
      respectively. One of the portio and endocervix and two of the endometrial
      specimens indicated the cases to be from endometrial primary sites. Primary sites
      of the remaining cases were the stomach and breast. Preoperative and
      intraoperative cytology of ascites were done in 16 cases and positive results
      were obtained in 11 cases. Postoperative recurrence was found cytologically in
      the surgical stump and ascites in two cases. Preoperative routine cytology of the
      uterus is considered to have diagnostic potential and ascite cytology to be an
      accurate index of intra-peritoneal spread in the case of metastatic ovarian
      carcinoma.

PMID- 8654469
TI  - Urinary, climacteric and sexual symptoms one year after treatment of endometrial
      and cervical cancer.
AB  - Data regarding urinary, climacteric and sexual symptoms among women before and
      one year after treatment of endometrial (n = 30) and cervical cancer (n = 26)
      were selected by a questionnaire, survey of medical records and semistructured
      interviews. The results were compared with similar data from hysterectomized
      women (n = 30). Urinary and climacteric symptoms were frequent in all three
      groups of women one year after treatment. In the cancer group the occurrence of
      urinary incontinence was significantly more frequent among women with vaginal
      dryness than among those without. Sexual symptoms were common in the endometrial
      and cervical group but not in the hysterectomy group one year after treatment.
      The results from medical records were not always in accordance with the results
      from questionnaire. Finally, the prospective interview study proved an
      appropriate method for collecting relevant data concerning the women's sexual
      life.

PMID- 8654470
TI  - Serous surface papillary carcinoma.
AB  - Three cases of serous surface papillary carcinoma of the abdominopelvic
      peritoneum are presented. All of the patients were subjected to a relatively
      homogeneous management consisting of primary surgery and cisplatin based
      chemotherapy regimen. The second look procedures of two patients were found to be
      negative. Although these tumors are known to have a poor prognosis, aggressive
      surgery and cisplatin based chemotherapy seem to have promising results.

PMID- 8654471
TI  - Deciduoma of the sigmoid colon in a nulliparous woman. A case report.

PMID- 8654472
TI  - Squamous cell carcinoma arising in dermoid cyst.
AB  - Since malignant transformation in a dermoid cyst is extremely rare, the
      clinicopathological characteristics of patients with squamous carcinoma arising
      in dermoid cyst are evaluated in the hope of offering a more rational therapy.
      Our first patient was lost to follow-up after surgery. In the second patient,
      with a gross stage III disease, after extensive surgery and multiagent
      chemotherapy we were able to achieve a remission period of 42 months. In the
      third patient with pelvic lymph node metastases, adjuvant radiation and
      chemotherapy was administered following surgical staging. She was free of disease
      6 months after surgery. Malignant transformation in a dermoid cyst is a rare
      complication observed especially in older age groups. Thus, a frozen section in
      these decades may improve detection of this complication allowing a more accurate
      staging. Although poor prognosis is reported, an aggressive approach with
      cisplatinum based chemotherapy and radiation and even with secondary
      cytoreduction, long-term remission may be achieved.

PMID- 8654473
TI  - Chemotherapy and cervical cancer: present trends.
AB  - A clinical case of cervical carcinoma Stage Ib is described. We treated a 48-year
      old woman with grade 2 carcinoma, using cisplatin at a dose of 40 mg/mq on the
      1st and 4th days, bleomycin at a dose of 15 mg/mq on the 1st and 8th days, and
      anti-emetic for two cycles. On the basis of the low ratio T4/T8 we also
      administered along with chemotherapy, alpha natural interferon at a dose of
      3,000,000 i.u. three times a week for four weeks. At the end of the
      chemotherapeutic treatment the lesion was reduced in size and the biopsy was
      pathognomically of a microinvasive cancer. In spite of the encouraging biopsy
      results, the patient was submitted to a simple hysterectomy, with random
      lymphoadenectomy. Today, two years after her treatment, the patient is free of
      disease. At present there is discussion as to the efficacy of neoadjuvant
      chemotherapy in the first stages of the neoplasia in relation to conventional
      treatment, which reserves chemotherapy to stages IV and IVb and to relapses, in
      the light of both the lesion and the disposability of the patient to treatment
      and successive follow-up.

PMID- 8654474
TI  - Choriocarcinoma following term pregnancy by transvaginal color Doppler
      ultrasound. A two case report.

PMID- 8654475
TI  - Gynecologic oncology as a specialty. Current status.

PMID- 8654476
TI  - Bartholin's gland metastases from breast cancer: a case report.
AB  - Only three cases of breast cancer metastatic to the vulva have been reported in
      the English literature. The present report is the fourth, and the first reported
      metastatic to the Bartholin's gland.

PMID- 8654477
TI  - Patient compliance with prolonged oral altretamine treatment in relapsed ovarian
      cancer.
AB  - Using an 'intelligent' tablet bottle which, unknown to the patient,
      electronically records the times of opening, we have assessed the compliance of
      patients with prescribed oral altretamine for ovarian cancer. During the periods
      of compliance monitoring the physical and mental state of the patients was also
      monitored by means of self-assessed diary cards. 11 patients were assessed over
      21 monitoring periods, each of 14 days, representing a total of 294 days. The
      Overall Compliance (OC), which we define as the number of bottle openings in a
      monitoring period as a percentage of that number expected on the assumption of
      perfect compliance, had a mean (SD) of 97.4 (6.9)% over the 21 periods. The OC
      was not related to any of the diary card measures, or to the cycle number (range
      1-5) of the treatment. The high level of compliance is encouraging and is in line
      with our previous reports in patients with lymphoma and with small cell lung
      cancer.

PMID- 8654478
TI  - Clinical features and mortality in patients with early-onset Alzheimer's disease.
AB  - In a population-based study of 198 patients with probable early-onset Alzheimer's
      disease (AD), we studied the occurrence of extrapyramidal signs (tremors and
      rigidity), myoclonus, psychosis and seizures, as well as their predictive value
      for mortality. The presence of tremors was significantly associated with the
      presence of rigidity. The occurrence of myoclonus was significantly associated
      with the occurrence of seizures. Psychosis and seizures in AD patients were not
      associated with mortality. The occurrence of extrapyramidal signs and myoclonus
      at any point in time during the course of AD increased the risk of mortality
      significantly. When evaluating their relative importance, extrapyramidal signs
      appeared to be the most important predictor of mortality.

PMID- 8654479
TI  - Abnormal enhancement of the left putamen on brain MRI in a case of proven
      Creutzfeldt-Jakob disease.

PMID- 8654480
TI  - Hemisensory deficit in a patient with Creutzfeldt-Jakob disease.

PMID- 8654481
TI  - Moclobemide in the prophylactic treatment of migraine. A retrospective analysis
      of 44 cases.

PMID- 8654482
TI  - Migrainous stroke: are antiphospholipid antibodies pathogenetic, a biological
      epiphenomenon, or an incidental laboratory aberration?

PMID- 8654483
TI  - Neurosyphilis presenting as complex partial status epilepticus.

PMID- 8654484
TI  - Corneomental reflex in early herniation.

PMID- 8654485
TI  - Migrainous stroke and antiphospholipid antibodies: are they pathogenetically
      linked?

PMID- 8654486
TI  - Ischemic stroke: treatment on the horizon.

PMID- 8654487
TI  - Isolated symptomatic stenosis of the middle cerebral artery in younger adults. A
      clinical and ultrasonic follow-up study of eight patients.
AB  - We studied 8 symptomatic patients aged 32-56 years with isolated stenosis of the
      middle cerebral artery who had TIAs or minor strokes. Angiography showed MCA
      stenosis in the M1 segment in 7 patients, and proximal M1 occlusion that later
      recanalized with persistent stenosis in 1 patient, without evidence of more
      widespread atherosclerotic disease. A potential cardiac source of embolism was
      detected in only 2 patients with mitral valve prolapse. During follow-up for 39
      82 months, no further ischemic events occurred, and transcranial Doppler showed
      unchanged or decreased stenosis in 6 patients. We conclude that isolated MCA
      stenosis in younger patients may be a unique pathologic entity with a benign long
      term course, although previous embolism with partial recanalization appears
      possible in some patients.

PMID- 8654488
TI  - Development of subtle neurological signs after systemic illness in HIV-infected
      individuals.
AB  - Thirty human immunodeficiency virus (HIV) infected individuals entered a
      longitudinal study without signs of dysfunction of the central nervous system
      (CNS). Nine of these individuals developed a systemic illness between study
      visits, and 7 of these 9 patients (78%) had neurological signs at the next
      examination (e.g., action-intention tremors, abnormal gait, release signs,
      abnormal deep tendon reflexes). Only 2/21 (9.5%) of the subjects who did not
      develop systemic illness showed such signs. These data are consistent with the
      hypothesis that other factors (e.g. cytokines) as well as the HIV may cause
      subtle CNS dysfunction.

PMID- 8654489
TI  - Ischemia-induced migraine from paradoxical cardioembolic stroke.
AB  - Although little is known on the pathophysiologic mechanism of migraine-related
      stroke, the prevailing attitude is that vasoconstriction and activation of
      clotting factors play a primary role. In 2 female patients presenting with
      migraine and stroke, risk profiles and history were consistent with this
      pathophysiologic mechanism. Cerebro- and cardiovascular workup, however, led to a
      diagnosis of paradoxical cardioembolic stroke through a patent foramen ovale.
      Since there is hardly any evidence in the literature that migraine acts as a risk
      factor for stroke on its own, these case reports emphasize the importance of
      complete cardiovascular evaluation in patients with suspected migrainous stroke.

PMID- 8654490
TI  - Multiple sclerosis in childhood: report of 16 cases.
AB  - Sixteen children with definite multiple sclerosis (MS; aged 6-17 years, mean 11.4
      +/- 2.7; 8 boys, 8 girls) were reviewed. Cerebellar symptoms and signs were
      frequent at initial presentation. Among laboratory studies, the cerebrospinal
      fluid (CSF) IgG index or oligoclonal bands were informative in 75%, evoked
      potentials in 70%, electroencephalography (EEG) in 83%, magnetic resonance
      imaging in 80% and computed tomography in 45%. When compared with patients with
      other neurological disorders and similar presentation (non-MS group, n = 13), MS
      patients were more likely to recover from the first attack without significant
      sequelae. CSF protein was usually normal in MS and high in non-MS patients. The
      CSF IgG index and/or oligoclonal bands were also helpful in differentiating these
      two groups. The absence of female preponderance, the frequency of EEG
      abnormalities and the lower yield from CSF analysis are particularly interesting
      in this childhood series. Different pathogenetic mechanisms may be involved in MS
      from different ages, genetic backgrounds, or environments.

PMID- 8654491
TI  - A positive relation between high hemoglobin values and the risk of ischemic
      stroke. Progetto 3A Investigators.
AB  - We examined the relationship between the hemoglobin concentration and the risk of
      ischemic stroke using data from a hospital-based case-control study. A total of
      143 patients (age 30-69 years) with a diagnosis of cerebral infarction confirmed
      by computerized tomography scan and 143 age- and sex-matched controls entered the
      study. Hemoglobin was higher in the patients with stroke (14.2 +/- 1.6 g/l, mean
      +/- SD) than in controls (13.7 +/- 1.6 g/l; p < 0.05). Compared with subjects
      with hemoglobin levels of less than 13 g/l (reference category), the relative
      risk of ischemic stroke, after allowance for potential risk factors, was 2.0 (95%
      CI 0.8-4.9) for the 13-13.9 g/l quartile, 2.8 (95% CI 1.2-6.5) for the 14-14.9
      g/l quartile, and 3.2 (95% CI 1.4-7.4) for the 14 + g/l quartile (chi 2 for
      linear trend 7.27, p < 0.01). We conclude that the hemoglobin concentration may
      be an indicator of risk for ischemic stroke.

PMID- 8654492
TI  - Inclusion body myositis: atypical clinical presentations.
AB  - Inclusion body myositis affects primarily the proximal muscles but distal limb
      muscles are involved too in this chronic myopathy. Characteristic histopathologic
      findings include "rimmed vacuoles', inflammation and typical cytoplasmic and
      nuclear filamentous inclusions. The patients are usually unresponsive to
      steroids. We present four inclusion body myositis patients with atypical clinical
      presentations: one with scapuloperoneal syndrome, one with post-polio-like
      syndrome and two with associated immune-mediated diseases (one with undefined
      autoimmune disorder and the second with scleroderma). Two patients responded to
      high-dose steroid therapy. We suggest that the clinical spectrum of inclusion
      body myositis is wider than previously appreciated.

PMID- 8654493
TI  - Dementia characterized by abundant neurofibrillary tangles and scarce senile
      plaques: a quantitative pathological study.
AB  - We report an elderly case who had demonstrated progressive memory disturbance and
      disorientation for 4 years. The clinical features were indistinguishable from
      late-onset dementia of the Alzheimer type (DAT). Neuropathologically, however,
      senile plaques (SPs) were almost absent throughout the brain. In contrast,
      numerous neurofibrillary tangles (NFTs) were observed in the hippocampus and
      neighboring regions, with much higher density than age-matched normal controls.
      The immunohistochemical and ultrastructural properties of the NFTs were identical
      to those of typical DAT. The present case is histologically different from DAT
      because of the scarce SPs and indicates that numerous NFTs in the hippocampal
      region can be formed independently of the existence of SPs.

PMID- 8654494
TI  - Ragged red or ragged blue fibers.
AB  - Fibers called ragged red fibers are generally considered the morphological
      characteristic of mitochondrial encephalomyopathies. These fibers appear red in
      the modified Gomori trichrome (Tri) stain due to subsarcolemmal and
      interfibrillar increase in mitochondrial number and volume. Other accepted
      morphological abnormalities include partial cytochrome c oxidase deficiency and
      subsarcolemmal increase in succinate dehydrogenase and NADH tetrazolium reductase
      stain. We were interested to see which of these abnormalities would be the most
      specific for mitochondrial cytopathies such as Kearns-Sayre syndrome and chronic
      progressive external ophthalmoplegia. We analyzed five patients and found 74
      fibers compatible with mitochondrial abnormalities as defined above. The modified
      Gomori Tri stain turned out to be the most specific and reliable technique.

PMID- 8654495
TI  - Differential intrastromal invasion by normal ocular surface epithelia is mediated
      by different fibroblasts.
AB  - For most mucosal epithelia including the ocular surface, it is generally believed
      that wound healing is executed by epithelial migration on the plane of erosion or
      ulceration. In explant cultures, we incidentally observed the phenomenon of
      intrastromal invasion by corneal, limbal and conjunctival epithelial cells even
      when cell migration on plastics was promoted. Homotypic and heterotypic tissue
      recombinants between corneal and conjunctival epithelial cells and their stroma
      revealed that this phenomena was dependent on viable mesenchymal cells and was
      more active in conjunctival stroma than corneal stroma. Using organotypic
      cultures in which 3T3 fibroblasts were incorporated in collagen gel, we noted
      that this phenomenon was fibroblast-dependent and up-regulated by lifting the
      culture to the air-fluid interphase. The extent of intrastromal invasion was
      decreased if 3T3 fibroblasts were treated with increasing concentrations of
      mitomycin C. The invading epithelial islands retained the same basal and
      suprabasal epithelial phenotypes as those of the surface epithelial layers using
      several anti-keratin monoclonal antibodies. Using 5-fluorouracil (5-FU) to
      eliminate the rapid-cycling, i.e. transient amplifying progenitor basal cells, we
      further noted that this phenomenon could still be produced by 5-FU-resistant slow
      cycling progenitor cells of corneal, limbal and conjunctival explants. In
      organotypic cultures, conjunctival fibroblasts were more active than corneal
      fibroblasts in inducing corneal or conjunctival epithelial invasion. As such
      intrastromal invasion can experimentally be produced by normal non-transformed
      adult epithelial cells and mediated by fibroblasts, this in vitro phenomenon may
      be useful for studying the epithelial-mesenchymal interactions operating during
      embryonic development and post-natal wound healing.

PMID- 8654496
TI  - Immortalization of cat iris sphincter smooth muscle cells by SV40 virus: growth,
      morphological, biochemical and pharmacological characteristics.
AB  - The purpose of this study was to establish immortalized cell cultures of cat iris
      sphincter smooth muscle cells for a model investigating ocular receptors and
      their signal transduction pathways. Cultured cat iris sphincter muscle cells were
      immortalized by viral transformation with SV40 virus and the morphological and
      immunocytochemical properties of the normal and immortalized cells were
      investigated. The transformed cell clone, SV-CISM-2, was further characterized
      biochemically and pharmacologically. The normal muscle cells showed
      characteristics of smooth muscle cells, as judged by their growth and the
      presence of smooth muscle alpha-actin and desmin. After seven passages the normal
      cells ceased to proliferate. In contrast, the immortalized cells retained their
      proliferative ability for more than 220 population doublings over 55 passages.
      The transformation phenotype in these cells was confirmed by their expression of
      the large T-antigen, the incorporation of viral DNA into cellular DNA, growth in
      agarose and in low-serum medium, and complete loss of contact inhibition. The
      immortalized cells expressed smooth muscle alpha-actin, desmin and MLC protein.
      Biochemical and pharmacological studies on the SV-CISM cells revealed the
      presence of several functional receptors including muscarinic cholinergic, beta
      adrenergic, peptidergic (substance P and endothelin). Platelet-activating factor,
      and prostaglandin (PG). Muscarinic stimulation of these cells resulted in: (a) a
      dose-dependent increase in the release of arachidonic acid (AA) and (PGs) and
      enhancement in the production of inositol trisphosphate (IP3); and (b) a
      substantial increase in MLC phosphorylation (118%), an indicator of smooth muscle
      contractility. The stimulatory effects of carbachol on these responses were
      completely blocked by atropine, a muscarinic receptor antagonist. This study
      constitutes the first successful immortalization of iris sphincter smooth muscle
      cells. The SV-CISM-2 cells can serve as an important model system for
      investigations on the biochemical and pharmacological properties of receptors and
      their signal transduction pathways in smooth muscle. The advantage of these cells
      over normal iris sphincter cells is that they can be propagated over many
      generations without alterations in their morphological, biochemical and
      physiological characteristics.

PMID- 8654497
TI  - Blood-retinal barrier breakdown following experimental retinal ischemia and
      reperfusion.
AB  - The purpose of this study was to examine the effects of acute ischemia and
      reperfusion on blood-retinal barrier (BRB) function in the rabbit eye.
      Hydrostatic pressure (140 mmHg) was used to create total retinal ischemia for
      intervals of 20, 40, 60, 80 or 100 min in the rabbit eye. The location, size and
      permeability-surface-area product normalized to the area of retinal leakage (PS')
      of ischemia-induced BRB lesions were then measured using contrast-enhanced
      magnetic resonance imaging (MRI) after various intervals of reperfusion. Diffuse
      outer BRB leakage occurred in most eyes subjected to 80 or 100 min of ischemia. A
      posterior region of outer BRB sparing was found in eyes that underwent lesser
      durations of ischemia. On day 1 after retinal ischemia, a linear relationship was
      found between mean PS' and duration of ischemia for periods of ischemia between
      20 and 100 min [slope: 5.65 x 10(-6) to 5.96 x 10(-6) cm min-1 (min ischemia)-1;
      r2 > or = 0.69]. Lesion size also increased between 20 and 100 min of ischemia.
      In a longitudinal study, eyes exposed to 60 min of ischemia showed a decrease in
      PS' and a lesion size over an 8-week period of observation. However, leakage was
      still present on post-ischemia day 57 in two of three eyes examined. Data
      obtained in these experiments are expected to prove useful in future studies
      aimed at understanding how BRB damage relates to neuroretinal damage after
      ischemia-reperfusion injury.

PMID- 8654498
TI  - The effects of endothelin-1 on isolated bovine ciliary muscles.
AB  - The effects of endothelin-1 on bovine ciliary muscle were investigated in vitro
      using muscle strips prepared in two different directions (longitudinal and
      circular). Fifty-two bovine ciliary muscle strips (4 x 6 mm) were prepared.
      Chemicals were added to both types of strips suspended in an organ chamber, and
      their changes in isometric tension were recorded. The concentration-response
      relationship of endothelin-1 (n = 20), the magnitudes of contractions caused by
      endothelin-1 and carbachol (n = 12), and the effects of an endothelin receptor
      subtype A antagonist BQ123 (n = 4) and an endothelin receptor subtype B agonist
      IRL1620 (n = 4) were studied. The cumulative addition of endothelin-1 caused
      relaxation at low concentrations (10(-11) and 10(-10) M), while it caused
      contraction of the ciliary muscles at high concentrations (10(-9), 10(-8) and 3 x
      10(-8) M). The magnitude of the contraction caused by 10(-8) M endothelin-1 was
      about 30% in the longitudinal muscle strips and 29% in the circular muscle
      strips, relative to the contraction caused by 10(-5) M carbachol, a muscarinic
      agonist. The contractile response caused by 10(-8) M endothelin-1 was abolished
      and converted to relaxation by pretreatment with BQ123, a selective endothelin
      receptor subtype A antagonist. Single addition of IRL1620, a selective endothelin
      receptor subtype B agonist, caused only relaxation. These results suggest that,
      endothelin-1 causes not only contraction at high concentrations, but also
      relaxation at low concentrations in bovine ciliary muscle. Also, it suggested
      that the relaxation is mediated by endothelin receptor subtype B, whereas the
      contraction is mediated by endothelin receptor subtype A.

PMID- 8654499
TI  - Verapamil increases outflow facility in the human eye.
AB  - Verapamil, a calcium channel antagonist, causes a reduction of intraocular
      pressure in humans. This study investigated whether verapamil's effect on
      intraocular pressure was related to increased outflow facility. Six pairs of
      human eyes were dissected and anterior segments were perfused under constant
      pressure with concentrations of verapamil HCl ranging from 10(-10)-10(-3) M. The
      maximal increase of outflow facility over baseline was 64% at 10(-9) M. These
      results indicate that verapamil causes a dose related increase in outflow
      facility in human eyes, which may account for the reduced intraocular pressure
      following topical administration of verapamil.

PMID- 8654500
TI  - Alligator rhodopsin: sequence and biochemical properties.
AB  - We sequenced selected peptides of alligator rhodopsin that accounted for about
      half of the total protein. These sequences were confirmed when the total primary
      structure of alligator rhodopsin was deduced from the cDNA sequence. Differences
      in the amino-terminal region, compared to that of bovine rhodopsin, account for
      failure of cross-reactivity of several anti-bovine rhodopsin monoclonal
      antibodies. Differences in the carboxyl-terminal region give rise to limited
      antibody cross-reactivity and may also account for a slightly reduced ability of
      alligator rhodopsin to be phosphorylated by bovine rhodopsin kinase. Alligator
      rhodopsin regenerates much faster than bovine rhodopsin. The pseudo-first-order
      rate constant for alligator rhodopsin regeneration is approximately 25 times that
      of bovine. Phylogenetic analysis of 17 rhodopsin sequences indicates that the
      alligator is more closely related to the chicken than to the other species
      examined.

PMID- 8654501
TI  - An ultrastructural analysis of the epithelial-fiber interface (EFI) in primate
      lenses.
AB  - The purpose of this study was to conduct a comprehensive ultrastructural analysis
      of the epithelial-fiber interface (EFI) in normal adult primate (Macaque
      nemestrina and fascicularis; 6-9 years old, n = 10) lenses. Scanning electron
      microscopy (SEM) was used to initially characterize the gross size, shape and
      three-dimensional organization of central zone (cz) epithelial cells and the
      anterior ends of elongating fibers beneath these cells. This fiducial information
      was essential to properly orient lens pieces in freeze fracture specimen carriers
      for the production of replicas with unambiguously identifiable EFI. Transmission
      electron microscopy (TEM) of replicas and thin-sectioned material were used to
      ultrastructurally analyse the cz EFI. TEM thin-sectioned material was also used
      to ultrastructurally analyse the pregerminative (pgz), germinative (gz) and
      transitional zone (tz) EFI. Correlative SEM and TEM of cz EFI components revealed
      that the apical membrane of both epithelial and elongating fiber cells were
      irregularly polygonal in shape, and aligned in parallel as smooth, concave-convex
      surfaces. However, whereas epithelial cell apical surfaces had minimal size
      variation, elongating fibers were larger and considerably variable in size.
      Quantitative analysis of > 10000 micron2 cz elongating fiber apical surfaces
      failed to detect any gap junctions defined in freeze fracture replicas as
      complementary aggregates of transmembrane proteins (connexons) conjoined across a
      narrowed extracellular space. However, a comparable frequency of vesicular events
      was noted in this region as quantified previously in adult and embryonic chick
      lens. Correlative TEM analysis > 1500 linear micrometers of thin-sectioned EFI
      from this region confirmed the presence of epithelial-epithelial gap junctions,
      elongating fiber-elongating fiber gap junctions, and an extreme paucity of
      epithelial-elongating fiber gap junctions. In contrast, TEM analysis of > 1000
      linear micrometers of thin-sectioned pgz, gz and tz EFI, confirmed the presence
      of epithelial-epithelial gap junctions, elongating fiber-elongating fiber gap
      junctions, numerous epithelial-elongating fiber adherens junctions and a few
      epithelial-elongating fiber gap junctions. Thus, the results of this and previous
      quantitative morphological and physiological studies (electronic and dye
      coupling) demonstrate that there is limited coupling between cz epithelial cells
      and underlying elongating fibers. Furthermore, the absence of gap junctional
      plaques in cz EFI freeze-fracture replicas and either pentalaminar or
      septalaminar profiles in correlative thin-sections, suggests that this limited
      coupling could be mediated via isolated gap junction channels. However, the
      results of this and previous quantitative studies further show that a greater
      degree of coupling exists across the pgz, gz and tz regions of the EFI and that
      this coupling is likely to be mediated by gap junction plaques. Finally, this and
      other studies continue to demonstrate that transcytotic processes play a role in
      lens physiology at the EFI.

PMID- 8654502
TI  - Misrouting of tyrosinase with a truncated cytoplasmic tail as a result of the
      murine platinum (cp) mutation.
AB  - Mice homozygous for the platinum (cp) allele at the albino locus manifest severe
      oculocutaneous albinism despite the presence in vitro of tyrosinase activity at
      25% wild-type levels. We demonstrate that the cp allele results from an A-->T
      substitution, changing a lysine residue at position 489 to a termination codon,
      with truncation of tyrosinase's cytoplasmic tail. In choroidal melanocytes of
      neonatal mutant mice, tyrosinase activity could be detected in the trans Golgi
      network, but was absent from melanosomes. Instead, it was detected in vesicles in
      the cell periphery and dendrites, and on the extracellular surface. In the
      retinal pigment epithelium, activity was present on the extracellular apical and
      basolateral surfaces. Our results demonstrate misrouting of a mutant tyrosinase
      lacking its cytoplasmic tail, providing an explanation for the severe effect of
      this mutation on ocular and cutaneous pigmentation.

PMID- 8654503
TI  - Leukemic glaucoma: the effects on outflow facility of chronic lymphocytic
      leukemia lymphocytes.
AB  - The purpose of this study was to investigate the mechanisms of the leukemic
      glaucoma. We established a cell culture from leukemic cells collected from the
      aqueous humor of a living patient with chronic lymphocytic leukemia (CLL) and
      glaucoma secondary to the leukemia. We then perfused 16 pairs of fresh cadaver
      normal human eyes at a constant pressure of 10 mmHg at 37 degrees C. We delivered
      as a bolus either cultured CLL cells or cultured normal lymphocytes, using 3 x
      10(2), 3 x 10(3), 3 x 10(4) or 3 x 10(5) cells in Barany's solution, into one eye
      of each pair. The other eye of the pair served as a control, receiving a sham
      bolus of Barany's solution alone. In addition, CLL and normal lymphocytes were
      perfused through 0.2, 0.6, 2, and 3 microns millipore filters. Following
      perfusion, the tissue and the filters were examined histopathologically by light,
      transmission and scanning electron microscopy. Cultured leukemic lymphocytes
      perfused into normal cadaver eyes caused a significantly more profound reduction
      in outflow facility than normal lymphocytes (P < 0.05); however, there was no
      significant difference in the effect on outflow facility between leukemic and
      normal lymphocytes when they were perfused through the millipore filters.
      Histopathology confirmed the presence of lymphocytes in the trabecular meshwork
      and Schlemm's canal, deforming on passage through the inner wall. Our results
      suggest that leukemic lymphocytes in CLL may reduce outflow facility by means of
      a biological interaction with the tissues of the outflow pathways, rather than by
      mechanical obstruction due to a lack of distensibility. Questions remain as to
      the nature of this biological interaction.

PMID- 8654504
TI  - The effect of phenazine methosulphate on intermediary pathways of glucose
      metabolism in the lens at different glycaemic levels.
AB  - In this study changes in alternative pathways of glucose metabolism are examined
      in the rat lens using radiolabelled glucose in a 1 hr in vitro incubation of 50
      mM or 10 mM glucose with or without 0.1 mM phenazine methosulphate (PMS). PMS
      which reoxidizes NADPH ensures that the pentose phosphate pathway (PPP) is not
      limited by the supply of NADP+. The data shows that maximal activation of the PPP
      (with PMS) is 40% greater at high glucose concentrations than normal glucose.
      This difference in maximal stimulation may be explained by the increase glucose
      uptake in the hyperglycaemic incubation. In the high-glucose incubation with PMS,
      hexokinase activity and the glucose 6-phosphate pool is not limiting for the PPP.
      Under these conditions, PMS alter the NAD+/NADH and NADP+/NADPH ratio. The change
      in the redox state alters the flux through the polyol pathway, the glycerol 3
      phosphate shuttle and the glycolytic control sites, glyceraldehyde 3-phosphate,
      pyruvate and lactate dehydrogenases. These results are discussed in relation to
      hyperglycaemia-induced oxidative stress.

PMID- 8654505
TI  - Endotoxin induced uveitis in the mouse: susceptibility and genetic control.
AB  - Endotoxin induced uveitis in the mouse provides a useful animal model for acute
      anterior uveitis in humans. We have investigated the susceptibility of endotoxin
      induced uveitis among various mouse strains, and have examined the relationship
      between genetic background and the resultant inflammatory response to endotoxin.
      We studied ten strains with differing major histocompatibility-2 genes,
      lipopolysaccharide response gene, and strains with mast cell depletion and its
      sham control. Anterior uveitis was induced by injecting 300 micrograms of
      Salmonella typhimurium endotoxin into one hind footpad. Mice were then killed 8,
      12, 16, 20, 24, 48 and 72 hr after endotoxin injection, and vertical sections of
      the eyes through the pupil-optic nerve axis were evaluated for ocular
      inflammation. C3H/HeN mice developed severe uveitis. In contrast, C3H/HeJ mice
      (lipopolysaccharide response gene-) did not develop uveitis even though it has
      the same genetic background and shares the same major histocompatibility-2
      haplotype with C3H/HeN mice (lipopolysaccharide response gene+). The strain that
      was mast-cell deficient (W/Wv) developed minimal uveitis; however, W/+ mice, with
      mast cells, developed more inflammation at 48 and 72 hr after endotoxin
      injection. C3H.SW and FVB/N mice also developed severe uveitis, and BALB/C,
      CBA/J, and B10.A developed mild uveitis. In conclusion, there is a wide variation
      in the magnitude and susceptibility to endotoxin among mouse strains. Multiple
      factors appear to influence this variability, including non-histocompatibility-2
      genetic background, the lipopolysaccharide response gene, and the presence of
      mast cells.

PMID- 8654506
TI  - Glucose supply and enzyme activities in the lens.

PMID- 8654507
TI  - A non-lens member of the beta gamma-crystallin superfamily in a vertebrate, the
      amphibian Cynops.

PMID- 8654508
TI  - Canine homolog and exclusion of retinal degeneration slow (rds) as the gene for
      early retinal degeneration (erd) in the dog.

PMID- 8654509
TI  - Identification of SPARC in the anterior lens capsule and its expression by lens
      epithelial cells.

PMID- 8654510
TI  - Capture-recapture methods in epidemiology: methods and limitations.

PMID- 8654511
TI  - Epidemiology of menstruation and its relevance to women's health.

PMID- 8654512
TI  - Menopause: its epidemiology and potential association with chronic diseases.
AB  - While there are weak indications that the decline in estradiol levels with
      menopause has ramifications for the expression of overt disease in women, the
      associations are not clearly characterized with the exception of osteoporosis.
      The lack of well-characterized associations is undoubtedly due to the same
      limitations previously described: difficulty in defining the menopausal stages
      and difficulty in doing serum hormone sampling. Added to these limitations are
      other impediments. Chronic diseases will not be expressed within a few short
      months of the menopause, so the temporal sequence of hormone change with clinical
      disease expression is difficult to establish. Furthermore, it is likely that
      menopause is an "enabling" state that allows for the subsequent disease in women
      with other risk factors. Until sufficient data are available to explore the
      menopause as both an effect modifier and confounder, inconclusive results are
      likely to be reported. Future studies of the association between chronic diseases
      and the menopause need to consider issues similar to those that have arisen
      relative to studies in symptomatology. There needs to be a more concise
      definition of menopausal status. Potential confounders, including race/ethnicity,
      body size, and socioeconomic status, must be considered in both design and
      analysis. Studies need to be designed to separate the effects of age from those
      of menopause. Finally, women with medically induced menopause should be evaluated
      separately from those with natural menopause.

PMID- 8654513
TI  - Emergence of cryptococcal disease: epidemiologic perspectives 100 years after its
      discovery.

PMID- 8654514
TI  - Review of the factors modulating dengue transmission.

PMID- 8654515
TI  - Risk factors for age-related cataracts.
AB  - Cataracts, the world's leading cause of blindness, are an enormous public health
      problem in both developing and industrialized countries. Identifying the risk
      factors responsible for cataract formation is a difficult and complicated problem
      because a realistic causal model in cataract formation would not be a simple
      linear sufficient cause paradigm (e.g., one exposure-one cataract type). A more
      complex model depicting each risk factor as a component cause, or part of a
      sufficient cause such as the sufficient/component cause model proposed by Rothman
      (62), is a more realistic way to summarize how multiple risk factors act in
      cataract etiology. Moreover, even this model has shortcomings, especially in
      explaining cataract etiology. It ignores the obvious importance of time to
      cataract formation and the way different component causes may act on different
      etiologic branches of cataract formation, e.g., nuclear sclerosis, posterior
      subcapsular cataracts, and mixed. Despite the complexity in identifying cataract
      risk factors, attempting to do so provides new hope in dealing with the
      morbidity, mortality, and cost of this disease. The evidence is overwhelming that
      age, trauma, and intraocular inflammation are important cataract risks. However,
      these exposures either are inevitable or are not major contributors to the
      population attributable risk. On the basis of both coherence and predictive
      performance, undernutrition is an important risk factor that can be altered.
      However, work still needs to be done in two areas related to this risk. First,
      regarding individuals in developing nations, the question must be asked about
      which nutrients (or lack thereof) are the culprits. The epidemiologic evidence
      that antioxidants are the missing nutrients is far from overwhelming. For
      developed nations, the obvious question still to be answered is whether the
      results of the Linxian Cataract Studies (11) and the India-US Case-Control Study
      (12) can be generalized to industrial nations. To help answer this question, an
      intervention study sponsored by the National Institutes of Health is now underway
      (K. Kupfer, Director, National Eye Institute of the USA, Bethesda, Maryland,
      personal communication, 1993). Ultraviolet radiation, especially ultraviolet B
      radiation, is an important risk for cortical cataracts, and one study (27) has
      even demonstrated a dose-response relation. However, the public health
      implication of this finding is not clear. Isolating the risk of ultraviolet B
      radiation exposure as a cause of cortical cataracts (and, in general, not of
      other types) indicates that the risk is small on a public health scale. This is
      because cortical cataracts are well tolerated and frequently require no treatment
      at all. The evidence that links ultraviolet B radiation to other cataract types
      comes mainly from ecologic studies and needs to be verified by analytic studies
      that are specifically designed to study the association. The strength of the
      association, consistency of studies, coherence, and biologic plausibility all
      indicate that both systemic and topical steroids are significant risk factors for
      the formation of posterior subcapsular cataracts. Given that most people are not
      chronic steroid users, the population attributable risk is low; however, the
      relative risk of those unfortunate enough to require chronic steroid use is high.
      The evidence is accumulating that cataracts can be added to the list of illnesses
      that are at least partially attributed to smoking. Although consistency among
      studies has not been obtained, this is certainly a plausible cause, and dose
      response relations have been demonstrated (53). At this point, nuclear sclerosis
      is the most important cataract type associated with smoking. More work needs to
      be done to assess the role of smoking on other cataract types and to assess the
      risk of those who stop smoking. Retrospective studies that examine diabetes as a
      risk for cataracts are almost inevitably marred by hte selection bia

PMID- 8654516
TI  - Epidemiology of age-related maculopathy.

PMID- 8654517
TI  - Epidemiology of intracerebral hemorrhage.

PMID- 8654518
TI  - Etiology of brain tumors in adults.

PMID- 8654519
TI  - Etiology of Wilms' tumor.
AB  - Present knowledge of the pathogenesis of Wilms' tumor can be used to plan further
      epidemiologic investigations in a logical manner. Table 3 summarizes the
      epidemiologic evidence presently available that implicates various exposures. The
      proportion of cases of Wilms' tumor that arise from germline mutations is
      unknown. Future case-control studies could contribute to providing such
      information by systematically collecting and preserving constitutional genetic
      material from cases and their parents and neoplastic genetic material from their
      tumors. The studies that have demonstrated germline mutations so far have
      involved small numbers of subjects, being the equivalent of "case reports" (36,
      37, 45-47, 50, 53). The techniques of molecular biology will be necessary to
      distinguish germline mutations or equivalent events that have been transmitted by
      parents from those that have arisen de novo. (Since it has already been shown
      that phenotypically unaffected parents can transmit relevant mutations to
      offspring who become affected (45, 46), the presence or absence of phenotypic
      abnormalities in the parents cannot be used to infer whether germinal mutations
      have arisen de novo.) Such studies will be laborious and expensive. The best
      strategy to minimize cost and labor would be restriction on age; the cases
      diagnosed relatively early in life (before the age of 2-3 years) are more likely
      to have arisen from germline mutations than those diagnosed later (34). The
      existence of de novo germline mutations relevant to the development of Wilms'
      tumor should prompt epidemiologists to search for causal exposures before
      conception. Preliminary evidence suggests that males have a higher germinal
      mutation rate (48). On the basis of the epidemiologic evidence to date, Olshan et
      al. have suggested the following: "paternal preconceptional exposures may play a
      more important role in the etiology of Wilm's tumor than maternal
      factors"(8,p.943). Pathologic and molecular biologic studies have shown that
      Wilm's tumor arises from nephrogenic rests that represent renal stem cells, the
      development of which has been arrested before normal differentiation occurs
      (2,44). Exposures that occur during intrauterine life are likely to be relevant
      to this process; these can be studied with epidemiologic methods, and clues have
      emerged (7,86,89). It is important to realize, however, that the fetus may be
      exposed in utero to substances to which the mother was exposed prior to
      conception, if these substances are excreted slowly or not at all, such as the
      persistent organochlorine pesticides (96,98). Study of the determinants of the
      growth behavior of nephrogenic rests (persistence, regression, generalized
      growth, or malignant transformation (2)) may be possible only in an animal model
      of Wilm's tumor, if one can be found in which nephroblastoma arises from
      nephrogenic rests. Ethylnitrosurea, an alkylating agent, causes renal tumors
      identical to Wilm's tumor in the opossum when given early in postnatal life (103)
      and in the rabbit when given transplacentally (104). Nephroblastoma in animals is
      one of the very few types of tumors that is inducible by chemicals via the
      transplacental route. This mode of induction should be regarded as as an
      etiologic possibility in humans as well as animals (105). As Hard, however, has
      pointed out, "nodular renal blastema [now known as nephrogenic rests] or
      nephroblastomatosis...have [sic] never been described in conjunction with
      nephroblastoma of animals" (105,p.184). the renal stem cells that give rise to
      Wilm's tumor normally disappear 4-6weeks prior to birth (19). If they persist
      after birth, as nephrogenic rests or otherwise, postnatal exposures could
      contribute to the development of Wilm's tumor. Cases diagnosed later, especially
      those presenting with lower stage disease, are more likely to have arisen from
      mutations occurring after birth. Potential carcinogens in children's diet and the
      home environment are worthy of close study.

PMID- 8654520
TI  - Epidemiology of testicular cancer.

PMID- 8654521
TI  - Traumatized rat striatum produces neurite-promoting and neurotrophic activities
      in vitro.
AB  - We have previously reported that ciliary neurotrophic factor (CNTF) mRNA is
      upregulated in the rat striatum following trauma and that its peak is coincident
      with a peak in the number of GFAP-positive astrocytes. CNTF, or other
      neurotrophic factors present in the traumatized striatum, may be involved in the
      dopaminergic fiber sprouting seen following cavitation or graft implantation in
      animal models of Parkinson's disease. This study was undertaken in order to
      further characterize the neurotrophic activity present following trauma through
      the use of bioassays. Adult rats underwent stereotaxic biopsy of the right
      striatum, and gelatin sponge [gelfoam (GF)] was placed in the resultant cavity.
      GF was collected from 1 to 30 days following trauma and homogenized. GF extracts
      (with equal protein concentrations) were assayed using dorsal root ganglion (DRG)
      explants, dissociated ciliary ganglia (CG), and human dopaminergic neuroblastoma
      cell (SH-SY5Y) cultures. The GF extracts had significant neurite-promoting
      activity (NPA) for DRG, CG, and SH-SY5Y cells, with the maximum effect seen 7
      days after trauma. NPA was not blocked by anti-nerve growth factor (NGF) Ab, but
      anti-brain-derived neurotrophic factor (BDNF) Ab significantly blocked the
      activity for DRG. The GF extracts protected the SH-SY5Y cells from the
      neurotoxins 6-OHDA and MPP+, as did NGF and BDNF. This neuroprotective effect of
      GF was not blocked by anti-NGF Ab. This study suggests that the neurotrophic
      activity in GF extracts has CNTF-like and BDNF-like components as well as
      another, undefined component.

PMID- 8654522
TI  - Lack of evidence for neutrophil participation during infarct formation following
      focal cerebral ischemia in the rat.
AB  - The involvement of neutrophils in the pathogenesis of cerebral ischemic injury in
      two rat models of focal ischemia was investigated. In Experiment I, a model of
      focal ischemia with partial reperfusion was used. Although significant and
      discrete ischemic damage within the neocortex was nearly maximal at 12 h
      postocclusion, no elevation in neutrophils was seen at this time point. Even
      after 21 h postocclusion, only a subtle increase in neutrophils within the
      ischemic tissue was observed. To further investigate the possible role of
      neutrophils in cerebral ischemia, the effect of cyclophosphamide-induced
      neutropenia was investigated (Experiment II). While a marked reduction (>98%) in
      systemic neutrophils was achieved in advance of and during the ischemic
      challenge, no reduction in the volume of ischemic damage was observed. In
      Experiment III, variations in the rat model of focal ischemia were made to
      produce a larger area of ischemic damage, as well as to permit complete
      reperfusion of blood to the affected cortex. While more neutrophils were seen in
      this variation of the model, very few were observed (< 1 per field) prior to the
      time that maximal ischemic damage had already occurred. Together, these
      experiments revealed that substantial brain necrosis occurred prior to the
      appearance of neutrophils, under conditions of partial, as well as complete,
      reperfusion. Moreover, at the time points when elevations in neutrophils were
      observed, no further increase in volume of ischemic damage was noted. Finally,
      pharmacologic removal of neutrophils prior to ischemia did not alter the size of
      the ischemic region. These data therefore fail to support the hypothesis that
      neutrophils play a general and essential role in infarct formation following
      focal brain ischemia and argue that further studies are required to more clearly
      elucidate the conditions under which neutrophils might participate in ischemic
      pathogenesis.

PMID- 8654523
TI  - The recovery of 5-HT immunoreactivity in lumbosacral spinal cord and locomotor
      function after thoracic hemisection.
AB  - To determine the role of serotonin (5-HT) in recovery from spinal cord injury, we
      examined spinal cord 5-HT immunohistologically and assessed locomotor recovery
      after thoracic (T8) spinal cord hemisection in 68 rats. Forty eight rats had
      laminectomy and hemisection, while the remaining 20 rats received laminectomy
      only. All rats were evaluated every other day for 4 weeks, using a 0-14 point
      scale open field test. Hemisection markedly reduced mean hindlimbs scores from 14
      to 1.5 +/- 0.32 and 5.6 +/- 0.31 (mean +/- standard error of mean) in the
      ipsilateral and contralateral side, respectively. The rats all recovered
      apparently normal walking by 4 weeks. The 5-HT immunohistological study revealed
      a marked reduction of 5-HT-containing terminals in the ipsilateral but not the
      contralateral lumbosacral cord by 1 week after hemisection. By 4 weeks after
      hemisection, 5-HT immunoreactive fibers and terminals returned to the ipsilateral
      lumbosacral cord, with many 5-HT fibers crossing over the central canal at
      thoracic level. We estimated the recovery of 5-HT neural elements in lumbosacral
      ventral horn by ranking 5-HT staining intensity and counting 5-HT terminals. The
      return of 5-HT immunoreactivity of the lumbosacral ventral horn correlated with
      locomotor recovery. Locomotory recovery invariably occurred when the density of 5
      HT terminals approached 20% of control values. These results indicate that return
      of 5-HT fibers and terminals predict the time course and extent of locomotory
      recovery after thoracic spinal cord hemisection.

PMID- 8654524
TI  - Altered motor function and graft survival produced by basic fibroblast growth
      factor in rats with 6-OHDA lesions and fetal ventral mesencephalic grafts are
      associated with glial proliferation.
AB  - Basic fibroblast growth factor (bFGF) promotes the survival and growth of
      dopaminergic neurons. We have investigated the effect of treating fetal ventral
      mesencephalon with bFGF or nerve growth factor (NGF) on the subsequent survival
      and function of grafted dopaminergic neurons implanted into the striatum of rats
      with a unilateral 6-hydroxydopamine lesion. Animals implanted with fetal ventral
      mesencephalon mixed with bFGF, but not with NGF, displayed more rapid
      compensation in motor behavior up to 9 weeks after graft implantation. bFGF, but
      not NGF, produced an increase in the number of tyrosine hydroxylase (TH)-positive
      neurons, a larger graft volume, and longer neurite outgrowth in comparison to
      control grafts. bFGF also increased the number of glial fibrillary acidic protein
      (GFAP)-positive astrocytes within the grafts. The increased number of GFAP
      positive astrocytes induced by bFGF correlated with the increase in the number of
      TR-positive neurons, with graft volume and with neurite outgrowth. These findings
      support the use of bFGF to promote the functional integration of fetal ventral
      mesencephalon grafts into the denervated host brain and and suggest that its
      action may be indirectly mediated through glial cells.

PMID- 8654525
TI  - First trimester development of the human nigrostriatal dopamine system.
AB  - The aim of the present study was to characterize the morphological and
      neurochemical differentiation of mesencephalic dopaminergic neurons in human
      embryos, derived from elective first trimester abortions. Embryonic brain tissue
      was taken for analysis of tyrosine hydroxylase (TH) by immunohistochemistry and
      Western blot, and for analysis of endogenous dopamine (A) content using HPLC-ED.
      TH expression was first detected at 3.5 weeks of gestational age (Carnegie stage
      11) by immunohistochemical staining of the primordial sympathetic trunk along
      both sides of the neural tube. In sagittal sections of the intact 4.5-week-old
      embryo, a small, distinct population of rounded, densely packed TH-immunoreactive
      perikarya with short primary processes was seen in the midbrain. During the
      latter half of the first trimester, the number of TH-stained cells as well as the
      length and number of axonal processes projecting toward and into the developing
      neostriatum increased rapidly. At the end of the first trimester, varicose fibers
      could be detected in the striatal anlage. In order to verify that TH was the
      antigen recognized by the antibodies used for immunohistochemistry on human
      tissue specimens, mesencephalic tissue of 5-10 weeks gestation was analyzed by
      Western blot technique. A single, homogeneous band with the apparent molecular
      weight of approximately 60 kDa was clearly detected at 5 weeks of age. The amount
      of TH/mg total protein increased at least 10-fold between 5-10 weeks of
      gestation. For comparison, the mesencephalon and the forebrain/basal ganglia were
      analyzed for endogenous DA content using HPLC-ED. DA was first detected at 5.5
      weeks of gestational age in both mid- and forebrain, and DA levels were found to
      increase exponentially from 7 to 7.5 weeks of age, reaching 4-5.5 ng
      DA/mesencephalon and 50-75 ng DA/g caudate nucleus-putamen anlage at the end of
      the first trimester. Together, morphological and biochemical data presented here
      constitute evidence for a very early appearance, migration, and differentiation
      as well as functional development of human mesencephalic dopaminergic neurons and
      their projections into target areas during the first trimester.

PMID- 8654526
TI  - Tubulization increases axonal outgrowth of rat sciatic nerve after crush injury.
AB  - It is important to develop methods which increase nerve regeneration since
      restoration of function following injury to peripheral nerves often requires
      outgrowth of the injured axons over long distances. In this study, axonal
      outgrowth after bilateral crush injury to the sciatic nerve of the rat was
      measured. One group with large-diameter nonpermeable silicone tubes and one group
      with large diameter permeable silicone tubes applied around the crush site on one
      side had regeneration following nerve injury compared to controls on the other
      side. The length of regeneration of the regenerating axons were then measured 4,
      5, and 6 days following the crush injury using the "pinch reflex test." The
      presence of axons at the pinch level was confirmed by immunocytochemical staining
      for neuro-filaments. The length of regeneration for rats with nonpermeable tubes
      was significantly greater than that of the contralateral control side and was so
      at all times (p < 0.05). The effect was present but not that pronounced where
      permeable tubes were used. We conclude that the outgrowth of regenerating sensory
      axons after sciatic nerve crush injury in the rat can be increased by enclosing
      the regeneration site in a silicone tube. The observed effect may be due to local
      mechanisms such as macrophage invasion or prevention of rapid wash-out of fluid
      from the crush zone.

PMID- 8654527
TI  - Graded histological and locomotor outcomes after spinal cord contusion using the
      NYU weight-drop device versus transection.
AB  - Injury reproducibility is an important characteristic of experimental models of
      spinal cord injuries (SCI) because it limits the variability in locomotor and
      anatomical outcome measures. Recently, a more sensitive locomotor rating scale,
      the Basso, Beattie, and Bresnahan scale (BBB), was developed but had not been
      tested on rats with severe SCI complete transection. Rats had a 10-g rod dropped
      from heights of 6.25, 12.5, 25, and 50 mm onto the exposed cord at Tl 0 using the
      NYU device. A subset of rats with 25 and 50 mm SCI had subsequent spinal cord
      transection (SCI + TX) and were compared to rats with transection only (TX) in
      order to ascertain the dependence of recovery on descending systems. After 7-9
      weeks of locomotor testing, the percentage of white matter measured from myelin
      stained cross sections through the lesion center was significantly different
      between all the groups with the exception of 12.5 vs 25 mm and 25 vs 50 mm
      groups. Locomotor recovery was greatest for the 6.25-mm group and least for the
      50-mm group and was correlated positively to the amount of tissue sparing at the
      lesion center (p < 0.0001). BBB scale sensitivity was sufficient to discriminate
      significant locomotor differences between the most severe SCI (50 mm) and
      complete TX (p < 0.01). Transection following SCI resulted in a drop in locomotor
      scores and rats were unable to step or support weight with their hindlimbs (p <
      0.01), suggesting that locomotor recovery depends on spared descending systems.
      The SCI + TX group had a significantly greater frequency of HL movements during
      open field testing than the TX group (p < 0.005). There was also a trend for the
      SCI + TX group to have higher locomotor scores than the TX group (p > 0.05).
      Thus, spared descending systems appear to modify segmental systems which produce
      greater behavioral improvements than isolated cord systems.

PMID- 8654528
TI  - Alterations in CNS gene expression in a rodent model of moderate traumatic brain
      injury complicated by acute alcohol intoxication.
AB  - The combined effects of acute alcoholic intoxication and moderate traumatic brain
      injury (TBI) on zif/268, glial fibrillary acidic protein (GFAP), and
      preproenkephalin (PPE) mRNA expression were examined. Adult male Wistar rats
      received ip injections of a 5% alcohol solution (2.4 g/kg in a final volume of 20
      ml isotonic saline) 10 min prior to fixed-head, mechanical injury. Using Northern
      analysis, a transient three- to fourfold induction of zif/268 mRNA levels was
      observed 45 min after injury in both TBI and alcohol-treated rats. This induction
      occurred in regions close to the impact site, namely, the olfactory bulb (OB) and
      frontal cortex (FTCTX) but not in the more distal piriform/amygdala cortex (P/A).
      No PPE mRNA changes were observed at 45 min for any experimental group. By 6 h,
      zif/268 transcript levels returned to or fell below basal levels in the OB and
      FTCTX while GFAP mRNA levels began to increase in TBI rats. At 24 h, GFAP mRNA
      levels were greatly increased in all three brain regions of TBI rats. However,
      alcohol inhibited the temporal induction of GFAP mRNA in the FTCTX and P/A
      triggered by TBI at 6 and 24 h. These results suggest that although acute alcohol
      intoxication prior to TBI does not influence gene expression patterns immediately
      after injury, it may minimize the transcriptional activation of astrocytes
      particularly in more distant brain regions that were influenced by the impact in
      nonintoxicated rats.

PMID- 8654529
TI  - Parvalbumin-immunoreactive neurons are not affected by trimethyltin-induced
      neurodegeneration in the rat hippocampus.
AB  - The present study investigates, by immunocytochemistry, the behavior of different
      neuronal subpopulations of the rat hippocampus in neurodegenerative processes
      induced by the neurotoxicant trimethyltin. The calcium-binding proteins calbindin
      and parvalbumin are used as selective markers of different neuronal
      subpopulations. The effects of the neurotoxicant were apparent 21 days after a
      single i.p. administration with severe neuronal loss, which was significant in
      CAI and CA3, as revealed by cell counts after cresyl violet staining.
      Immunolabeling with calbindin D28-k (CB) and parvalbumin (PV) indicated severe
      cell loss of CB-containing neurons, essentially reflecting the generalized
      neuronal loss, while PV-containing neurons appeared to be selectively spared by
      the neurotoxicant-induced degeneration.

PMID- 8654530
TI  - Synaptic evoked potentials from regenerating dorsal root axons within fetal
      spinal cord tissue transplants.
AB  - Previously injured dorsal roots were electrically stimulated to determine if
      regenerating sensory axons can form physiologically active synaptic contacts with
      neurons within fetal spinal cord tissue transplants. Dorsal rootlets, sectioned
      at their spinal cord entry zone, were apposed to intraspinal transplants of fetal
      spinal cord tissue grafted along each side of a nerve growth factor treated
      nitrocellulose implant. Two to six months later, the rootlets were transected
      between the spinal cord and their respective ganglia and electrically stimulated.
      Evoked potentials were recorded from the dorsal surface of the transplant, but
      were absent from adjacent ipsilateral and contralateral spinal cord regions. A
      glass micropipette was advanced through the transplant and used to record
      intramedullary field potentials evoked by dorsal root stimulation. Maximal
      negative potentials occurred 400-700 micron below the dorsal surface of the
      transplant, shifting to positive potentials deeper into the transplant.
      Additionally, both spontaneous and electrically evoked single neuronal action
      potentials were observed along the microelectrode track. Evoked potentials were
      abolished following transaction of the rootlets between the stimulation site and
      the transplant. Immunocytochemical evidence of the production of fos protein
      following electrical stimulation of the regenerated dorsal rootlets was
      demonstrated within transplant neurons and some ventrally located host neurons,
      providing an anatomical correlate to the electrophysiological recordings of
      synaptic activation. These results provide evidence of the structural and
      functional integration of regenerated sensory axons with both transplant and host
      neurons.

PMID- 8654531
TI  - Delayed nociceptive response following cold-water swim in the formalin test:
      possible mechanisms of action.
AB  - Exposure of animals to aversive events produces stress-induced analgesia. A
      common method of producing stress in animals is the cold-water swim (CWS). The
      present series of experiments examines the effect of CWS on tonic pain, as
      measured by the formalin test, and explores possible mechanisms of action.
      Experiment 1 demonstrates that a 3.5-min swim in 2 degrees C water produces a
      delayed nociceptive response (DNR), characterized by a prolonged period of no
      formalin responding which then begins and continues during the time when control
      animals, which have not received the CWS, are finished responding. The delayed
      response begins at 50-60 min postformalin injection, peaks at 80 min, and is
      still present at 120 min. Experiment 2 indicates that paw temperature effects are
      not responsible for the DNR, although core body temperature effects are a
      possible mechanism. However, systematic delays in the formalin injection
      following the CWS (Experiment 3) drastically altered the DNR even though core
      body temperature remained unchanged, suggesting that a decrease of core body
      temperature is insufficient to account for the DNR. Experiment 4 demonstrates
      that the NMDA antagonist MK-801 administered prior to the CWS dramatically
      reduces the DNR. The present experiment is the first study that reports a delay
      as long as 60 min in pain responding. It is concluded that the delayed response
      to formalin injection is the result of complex interactions involving peripheral
      mechanisms and central neuronal plasticity in which activity initiated by a
      noxious input persists after the cessation of the input as a consequence of a
      stressful event such as the cold-water swim.

PMID- 8654532
TI  - Restraint reduces formalin-test pain but the effect is not influenced by lesions
      of the hypothalamic paraventricular nucleus.
AB  - Previous research indicates that the paraventricular nucleus of the hypothalamus
      (PVN) plays an important role in the development of stress-induced analgesia
      (SIA). Research implicating the PVN in SIA has generally employed the cold-water
      swim as the stressor and a phasic pain test, such as the tail-flick test, as the
      pain model. The present study, using the formalin test for tonic pain,
      investigated the effect of PVN lesions on (1) tonic pain responses and (2) SIA
      caused by 30 min of restraint. Male Long-Evans rats were randomly assigned to one
      of four groups. Two groups received electrolytic lesions of the PVN and two
      additional groups served as sham-operated controls. One group which received PVN
      lesions and one group which was sham-operated were exposed to 30 min of restraint
      immediately prior to a 0.05-ml injection of 2.5% formalin into the planter
      surface of one hindpaw. The remaining groups which either received PVN lesions or
      were sham-operated received the formalin injection without prior exposure to
      restraint. During the first phase of the formalin response, PVN lesions did not
      alter duration of paw elevation scores, but significantly increased duration of
      paw licking scores. A 30-min period of restraint had no effect on duration of paw
      elevation scores, but significantly decreased duration of paw licking scores. PVN
      lesions did not alter the significant decrease in paw licking scores as a result
      of restraint. During the second phase of the formalin response, PVN lesions did
      not alter either the duration of paw elevation scores or the duration of paw
      licking scores. A 30-min period of restraint significantly decreased duration of
      paw elevation scores, but had no effect on duration of paw licking scores. PVN
      lesions did not alter the significant decrease in paw elevation scores as a
      result of restraint. The results indicate that PVN lesions increase paw licking
      only during the first phase of the formalin response, with no other alterations
      in paw licking or duration of paw elevation. In addition, a 30-min period of
      restraint can produce short-term and long-term SIA for tonic pain. The short-term
      SIA is reflected as a decrease in paw licking, whereas the long-term SIA is
      reflected as a decrease in paw elevation. In addition, PVN lesions failed to
      alter SIA during both phases of the formalin test. The differential effect of
      restraint on pain responses during the two phases of the formalin test and the
      lack of effect of PVN lesions on SIA for tonic pain suggest that stress engages
      multiple endogenous pain inhibitory systems.

PMID- 8654533
TI  - Peripheral nerve allograft preservation improves regeneration and decreases
      systemic cyclosporin A requirements.
AB  - Peripheral nerve allografting is limited by the need for long-term systemic
      immunosuppression. The purpose of this study was to determine if nerve allograft
      preservation reduced the requirements for systemic Cyclosporin A (CsA)
      immunosuppression. One hundred twenty Lewis rats were randomized to one of seven
      experimental groups. Group 1 received a 2-cm Lewis posterior tibial nerve
      autograft. Groups 2-7 received 2-cm ACI posterior tibial nerve allografts. The
      allograft group was then further subdivided into three groups of two receiving
      daily subcutaneous injections of 0, 2.5, or 5.0 mg/kg of CsA for 12 weeks. Within
      each CsA dose, one group received a fresh while the other received a preserved
      allograft. Preserved grafts were stored in University of Wisconsin solution for 7
      days at 5 degrees C prior to implantation. Animals from each group were
      sacrificed at 6, 12, and 20 weeks postoperatively. Evaluations included
      histomorphometry, electrophysiology, and serial walking track analysis. Histology
      revealed varying degrees of nerve regeneration in all groups at 6, 12, and 20
      weeks. For a given CsA dose, the group receiving the preserved graft revealed
      evidence of better nerve regeneration by all histomorphometric parameters
      including fiber width and density, percentage neural tissue, and total fiber
      number. There was no statistical difference in walking track analysis between
      groups at 4 weeks. By 20 weeks, functional recovery statistically poorer than
      autograft was seen only in the fresh allograft groups receiving 0 or 2.5 mg/kg of
      CsA. Identical electrophysiologic findings were seen at 20 weeks. These results
      suggest that nerve graft preservation may decrease systemic immunosuppression
      requirements while improving functional recovery. As well, storage of nerve
      grafts is feasible and would facilitate elective surgery and less costly
      reconstructive repair.

PMID- 8654534
TI  - Morphological analysis of the early development of the chick neural tube
      separated from the floor plate and notochord.
AB  - When the neural tube of avian embryos is separated from the notochord and floor
      plate, motoneurons in the spinal cord fail to develop. In order to investigate
      the factors involved in this phenomenon, cell proliferation activity and cell
      death were observed following paramedian incision of the neural tube at the level
      of the segmental plate using colchicine, BrdU, and TUNEL methods. If the
      notochord and/or floor plate produces a substance(s) that promotes cell division
      in the basal plate neuroepithelium or that supports the survival of the
      motoneuron's neuroblasts, mitotic figures should not be present in the
      neuroepithelium nor should substantial cell death be observed in the ventral
      aspect of the notochord- and floor plate-deprived neural tube. Surprisingly,
      however, neither result was observed in the present experiments, with the
      exception of a considerable amount of homogeneously distributed cell death.
      Neuroepithelial cells continued to proliferate and gave rise to neuroblasts.
      Nevertheless, motoneurons failed to develop, and the neural tube was enveloped by
      only the basement membrane of the alar plate (S. Hirano and H. Tanaka, 1994, Dev.
      Growth Differ: 36, 481-488). These morphological results revealed that the cause
      of the development of the anterior horn lacking a neural tube in the notochord-
      and neural tube-eliminated embryos is not the elimination of the source of the
      surviving factor(s) of the motoneuron's neuroblasts, but rather the elimination
      of the signals to induce the motoneurons, derived from the notochord and/or floor
      plate. The larger amount of cell death in the neural tube on the experimental
      side suggests that a nonspecific survival factor(s), necessary for the survival
      of a variety of types of neuroblasts, is also produced by the notochord and/or
      floor plate.

PMID- 8654535
TI  - Environment, social interaction, and physical activity as determinants of
      functional outcome after cerebral infarction in the rat.
AB  - Rats housed in an enriched environment allowing both social interaction and
      physical activity improve more than rats housed in standard laboratory cages
      after focal brain ischemia. To determine the relative importance of social and
      physical activity, rats that sustained ligation of the middle cerebral artery
      were kept in an enriched environment with opportunities for various activities
      (group A), housed together in the same size of cage as group A but with no
      activity-stimulating equipment (group B), or housed in individual cages with a
      running wheel (group C). There was no significant difference in infarct size
      between the groups. Limb placement, climbing, balance on an inclined plane, and
      ability to traverse a beam and a rotating pole were repeatedly tested 2-13 weeks
      after the operation. During the entire postoperative period, group A performed
      significantly better than group C in all tests and better than group B on the
      rotating pole. With time they also performed significantly better than group B in
      limb placement, climbing, and on the inclined plane. Group B performed
      significantly better than group C on the inclined plane and in climbing at all
      times, and by 13 weeks also in the limb placement test and on the beam. Thus,
      social interaction was superior to wheel-running but an enriched environment
      allowing free physical activity combined with social interaction resulted in the
      best performance.

PMID- 8654536
TI  - The neuronal voltage-gated sodium channel, Scn8a, is essential for postnatal
      maturation of spinal, but not oculomotor, motor units.
AB  - Mice with a nontargeted transgene insertion at the motor endplate disease (med)
      locus (med(tg)) contain a deletion of a novel gene encoding a neuronal voltage
      gated sodium channel, designated Scn8a. We characterized severe skeletal muscle
      atrophy beginning by Postnatal Day 10 (P10) and death by P20 in the med(tg)
      mouse. Denervation was functional, rather than structural, since the Scn8a
      mutation was not accompanied by retraction of neuromuscular contacts, motoneuron
      death, or decreased motoneuron soma diameter. Although pathology consistent with
      denervation was seen in both hindlimb and forelimb musculature, the postnatal
      maturation of the extraocular muscles was not altered. The onset of paralysis is
      likely coincident with the time that the Scn8a sodium channel normally assumes a
      critical role in the initiation and/or propagation of action potentials in spinal
      motoneurons. By contrast, the lack of consequences for extraocular muscle
      suggests that the Scn8a voltage-gated sodium channel may be of relatively minor
      importance for oculomotor motoneurons.

PMID- 8654537
TI  - Alveolar hydatid cyst (AHC): inflammation-induced reactive gastrointestinal (GL)
      amyloidosis in AHC-infected mice and chemical characterization of the GL amyloid.
AB  - A high incidence of GI amyloidosis has been described in patients with various
      forms of systemic amyloidosis but its evolution and progression in different
      subregions of the GI tract are not well documented. These aspects including the
      chemical nature of GI amyloid were examined in the AHC mouse model of
      inflammation-associated reactive amyloidosis. C57BL/6 mice were infected
      intraperitoneally with 250 AHC. Paraffin sections from the stomach and the small
      and large intestines of AHC mice were stained at different time intervals with
      Congo red or immunocytochemically with monospecific RAA. The submucosal blood
      vessels at 1 week postinfection were found to be the first target of amyloid
      deposition. With time the amyloid deposits extended to the mucosa and the Peyer's
      patches and immunoreacted with RAA; ileum was the most severely affected region.
      Amyloid was extracted from the GI tract and purified by size exclusion
      chromatography using 5 M guanidine-formic acid, pH 3. The purified amyloid was
      identified by Western blotting using RAA and by partial N-terminal
      microsequencing up to 10 cycles. The GI amyloid showed homology with murine SAA2,
      although SAA2 mRNA is not expressed in murine GI tract. These results shows that
      (a) the GI amyloid is derived, similar to that of splenic/hepatic amyloid, from
      circulating SAA2 and (b) the GI tract submucosal blood vessels are the first
      target of AA deposition. The data also suggest that AA-mediated damage to the
      submucosal blood capillaries may lead to SAA leakage followed by cascading of AA
      deposition in other layers of the GI tract.

PMID- 8654538
TI  - Trypanosoma congolense: B-lymphocyte responses differ between trypanotolerant and
      trypanosusceptible cattle.
AB  - Trypanosomiasis is a serious constraint to livestock production in sub-Saharan
      Africa. Some breeds of cattle are genetically more resistant to the pathogenic
      effects of trypanosome infection. We measured B-cell activation and the quantity
      and isotype of antibody produced at the cellular level in six trypanotolerant
      N'Dama and five trypanosusceptible Boran cattle. The frequencies of spleen cells
      secreting total and parasite-specific IgM and IgG were measured prior to and 16,
      28, and 35 days after a primary challenge with Trypanosoma congolense. Boran
      cattle had higher frequencies of splenic cells secreting IgM specific for
      trypanosome-derived variable surface glycoprotein (VSG), cysteine protease
      (congopain, CP), and heat shock protein (hsp 70/BiP) and the nonparasite antigen,
      ovalbumin, than did N'Dama cattle. In contrast, the number of VSG-specific IgG
      secreting cells was significantly greater in N'Dama than in Boran cattle. During
      infection, low titers of anti-VSG IgM were detected transiently in the serum of
      all animals. However, N'Dama had significantly more VSG-specific IgG in blood
      than Boran during infection. The peripheral blood mononuclear cell population of
      N'Dama cattle contained a higher percentage of surface IgM-positive B-cells prior
      to and throughout infection than were found in the blood of Boran. In addition,
      during infection N'Dama cattle had more circulating lymphocytes that could be
      activated in vitro to undergo differentiation into IgM- and IgG-secreting cells.
      These findings demonstrate differences in the frequency of trypanosome-specific
      antibody-secreting cells in the spleen and in the activation state of B-cells in
      the blood between N'Dama and Boran cattle during a primary infection with T.
      congolense.

PMID- 8654540
TI  - Glycosidases in Leishmania and their importance for Leishmania in phlebotomine
      sandflies with special reference to purification and characterization of a
      sucrase.
AB  - Culture forms of Leishmania (Leishmania) amazonensis (IFLA/BR/67/PH8) produce an
      extracellular enzyme that hydrolyzes sucrose molecules into their component
      monosaccharides. This is important because phlebotomine sand flies, the
      invertebrate hosts of Leishmania, ingest plant sap or aphid and coccid honeydew
      rich in sucrose between blood meals and Leishmania promastigotes cannot uptake
      sucrose. The sucrase was purified and characterized; its molecular weight,
      estimated by gel filtration chromatography and SDS-PAGE electrophoresis, was
      about 73 kDa. K(m) and V(max) measured with sucrose as substrate were
      respectively 4.4 mM and 6.9 mumole glucose.min-1 (mg sucrase)-1, with maximum pH
      activity at pH 5.5. A series of natural and p-nitrophenyl-derived substrates were
      assayed, characterizing the enzyme as a highly specific beta-D-fructofuranoside
      fructohydrolase. When 11 species of Leishmania and 7 genera of trypanosomatids
      were screened, only the species of the genus Trypanosoma did not produce an
      enzyme with saccharolytic activity. These data are in agreement with the fact
      that the latter vectors do not acquire sucrose or raffinose in their meals.
      Searching for glycolytic enzymes other than sucrase, we found an N-acetyl-beta-D
      galactosaminolytic activity. This N-acetyl-galactosaminidase, here described for
      the first time, might have a role in peritrophic membrane disruption. The
      importance of sucrase and N-acetyl-beta-D-galactosaminidase in the Leishmania
      life cycle is discussed.

PMID- 8654539
TI  - Plasmodium vivax: favored gene frequencies of the merozoite surface protein-1 and
      the multiplicity of infection in a malaria endemic region.
AB  - In this study, we present an analysis of the Plasmodium vivax MSP-1 polymorphic
      region 5 and identify a new recombinant gene element. In clinical isolates from
      Papua New Guinea (PNG), the P. vivax MSP-1 gene type was characterized by
      restriction fragment length polymorphisms and by Southern blot oligonucleotide
      hybridizations using probes to type-specific sequences. There were three pairs of
      dimorphic gene elements in the MSP-1 polymorphic region 5; four of the eight
      potential different combinations of sequence elements for this region have been
      identified. The center gene segment was the most polymorphic, especially for the
      glutamine (Q) repeat element with virtually every gene containing a different
      length of Q repeats, a finding consistent with database sequence information. The
      frequencies of all of the polymorphic MSP-1 gene elements were approximately
      equal except for the first segment, which was biased 10:1 for the Type II (Sal-1
      type) versus Type I (Belem type) gene segment. In fact, only one combination
      (I/Q/S) of the genetic elements containing the type I gene segment for
      polymorphic region 5 was identified, a finding consistent with sequences reported
      to gene data banks. Considering only the multiplicity of MSP-1 gene types, 38% of
      the patients were identified as having multiple infections; when correlated with
      the circumsporozoite protein and the Duffy antigen binding protein gene types,
      the multiple infection rate increased to 65% of 23 isolates characterized.
      Increased age was the only clinical parameter that positively correlated with
      multiclonal infections and there was no other apparent bias or linkage of gene
      types among the three loci. These data identify multiple clonal populations of P.
      vivax in the PNG population and potentially a high rate of concurrent infections
      in clinical cases. The extreme polymorphism of the MSP-1 polymorphic region 5
      suggests that frequent recombination occurs within this gene. The bias in
      frequency for one recombinant gene motif indicates that intrinsic host or
      parasite factors may engender increased frequency of one genetic element over
      another. Failure to identify this type of discrete clonal marker as well as
      reliance on a single marker can mask the true multiclonal nature of an infection
      and lead to underestimation of the multiplicity of infection.

PMID- 8654541
TI  - Theileria annulata: altered gene expression and clonal selection during
      continuous in vitro culture.
AB  - Kept in continuous in vitro culture, the protozoan parasite Theileria annulata
      gradually loses virulence when inoculated into cattle. These attenuated cell
      lines form the basis of the in vitro live vaccines which have been used
      successfully to control tropical theileriosis in several endemic regions. In the
      study reported here, events occurring during in vitro culture of an Indian
      (Hisar) cell line, which may be associated with the reduction in virulence, have
      been investigated. Hybridization with two polymorphic DNA probes following
      Southern blotting showed that selection of particular parasite genotypes occurs
      very rapidly with culture; a novel hybridization pattern is observed with both
      probes after 50-100 passages in vitro. In addition to this selection process,
      immunofluorescence studies using a monoclonal antibody which specifically
      recognizes virulent T. annulata revealed alterations in antibody reactivity
      following in vitro culture. This loss of reactivity was observed in three cloned
      cell lines derived from the early, virulent Hisar line and implies that
      phenotypic changes resulting from alterations to parasite gene expression are
      taking place during the attenuation process. When considered with the results
      from in vivo infections with serial passages of this cell line, it can be
      proposed that both altered gene expression and selection may be involved in the
      loss of pathogenicity of T. annulata during continuous in vitro culture.

PMID- 8654543
TI  - Plasmodium falciparum: isolation of large numbers of parasite clones from
      infected blood samples.

PMID- 8654542
TI  - Trypanosoma brucei: analysis of cytoplasmic Ca2+ during differentiation of
      bloodstream stages in vitro.
AB  - The highly regulated intracellular concentration of calcium (Ca2+) is a well
      described regulator of diverse cellular events, including cell cycle control. In
      the present study we have addressed the regulation of cytosolic Ca2+ in
      differentiation events in the life cycle of the protozoan parasite Trypanosoma
      brucei. Bloodstream form (BSF) trypanosomes include the mitotically active long
      slender forms (LS) which differentiate to two nondividing stages--intermediate
      (INT) which transform into short stumpy (SS) forms. An axenic in vitro culture
      system was used to cultivate LS to a density greater than 1.0 x 10(6)
      cells/ml/day. Populations of the intermediate BSF (INT) and SS were derived from
      cultured LS by treatment with difluoromethyl ornithine (DFMO, 100 microM) for 2
      and 4 days, respectively. A semiquantitative reverse transcriptase-coupled
      polymerase chain reaction protocol (SQ-RT-PCR) was developed to objectively
      distinguish the three BSF by monitoring the relative levels of stage-specific
      mRNAs--cytochrome oxidase II (COXII), variant surface glycoprotein, and procyclin
      during the differentiation of LS to SS, showing an increase in COXII and
      procyclin mRNA expression during this process of differentiation. Basal cytosolic
      Ca2+ levels [Ca2+]i of populations of LS, INT, and SS were studied using Indo-1
      dual emission fluorometry. [Ca2+]i was maximal in dividing LS cells and was shown
      to decrease coincidentally with early events in the process of differentiation to
      INT and SS. Thapsigargin (1 microM), reported to cause the release of Ca2+ from
      the endoplasmic reticulum, elevated [Ca2+]i by about 30-60 nM in all BSF;
      however, the total thapsigargin-releasable stores decreased in parallel with the
      decrease in basal [Ca2+]i. Control treatments verified that elevations in [Ca2+]i
      in response to thapsigargin were intracellular in origin. These results may
      reflect the cessation of cytosolic Ca2+ transients involved in the regulation of
      mitosis as the parasite exits from the cell cycle and differentiates from rapidly
      dividing LS to the nondividing SS.

PMID- 8654544
TI  - Leishmania and Sauroleishmania: the use of random amplified polymorphic DNA for
      the identification of parasites from vertebrates and invertebrates.
AB  - We used the RAPD-PCR method for distinguishing the main Old World Leishmania
      parasites Leishmania tropica, L. major, and L. infantum and applied it to
      Sauroleishmania species from Iran. Twelve out of 21 tested primers were suitable
      for identification of these parasites. The Jaccard similarity index was 0.30 for
      L. tropica and L. infantum as well as for L. major and L. infantum. The
      similarity coefficient for L. major and L. infantum was 0.22 and for L. tropica
      and L. major it was 0.26. These data agree well with established phylogenetic/
      taxonomic classification. The index between different isolates derived from
      various hosts and sandfly vectors for the same Leishmania species was 1,
      indicating that this method is suitable for epidemiological analysis.

PMID- 8654545
TI  - Leptomonas seymouri, Trypanosoma brucei: a method for isolating trypanosomatid
      nuclear factors which bind T. brucei single-stranded g-rich telomere sequence.
AB  - Sequential expression of variant surface glycoproteins (VSG) in Trypanosoma
      brucei is the basis of antigenic variation which is essential for parasite
      survival. Telomere distal copies of VSG genes, so-called basic copies, provide a
      repository of VSG sequence information for variability, but actively expressed
      copies are found only at subtelomeric regions of chromosomes. Of eight or so
      expression sites (ES) in the T. brucei genome, only one is active at one time.
      Movement of a basic copy VSG gene to an ES requires a recombination event of
      unknown mechanism. The properties of telomeres have been speculated to be
      important for control of VSG expression or basic copy mobilization, prompting us
      to begin to investigate telomere-binding proteins in trypanosomatids. The T.
      brucei telomere sequence is known, facilitating design of synthetic telomeric
      DNAs. Here we describe a method for preparation of active trypanosomatid nuclear
      extracts. We show that in T. brucei and Leptomonas seymouri, factors can be
      detected which bind a g-rich single-strand telomere sequence based on the T.
      brucei telomere. The L. seymouri telomere-binding factor, LST-1, dissociates in
      the presence of high salt to produce a core factor, LST-2, migrating similarly to
      the T. brucei telomere-binding factor TBT-1. The affinity of LST-2 and TBT-1 for
      DNA under high salt conditions is characteristic of telomere proteins.

PMID- 8654546
TI  - Trypanosoma cruzi: expression of interleukin-2 utilizing both supercoiled
      plasmids and linear DNAs.

PMID- 8654547
TI  - Onchocerca volvulus: development of a species specific polymerase chain reaction
      based assay.

PMID- 8654548
TI  - Giardia lamblia: increased UDP-N-acetyl-D-glucosamine and N-acetyl-D
      galactosamine transferase activities during encystation.
AB  - The cyst wall of Giardia lamblia is essential for survival of the parasite
      outside the host. N-acetyl-D-glucosamine (GalNAc) has been reported as a major
      terminal sugar of cyst wall glycoproteins and N-acetyl-D-galactosamine (GalNAc)
      as the major sugar of the fibrous insoluble cyst wall fraction. Therefore, we
      measured UDP-glycosyltransferase activities as the incorporation of [3H]UDP-sugar
      into an alcohol-insoluble product. We found that during encystation only UDP
      GlcNAc and UDP-GalNAc transferase (UDP-GT) activities increased approximately
      three- to five-fold compared to nonencysting trophozoites. These activities were
      distributed approximately equally in the pellet and soluble fractions. The
      apparent K(m) and V(max) of UDP-GT in these fractions were similar. The
      activities from both fractions were dependent on Mn2+; however, the pellet
      enzymes were also partially activated by other metal ions. Both pUDP-GT and sUDP
      GT were inhibited by uridine, UDP, and UDP sugars, but not by GlcNAc or GalNAc.
      Isolation and analysis of the reaction products suggest that pUDP-GT incorporate
      GlcNAc and GalNAc into glycoproteins, since the products were proteinase
      sensitive. In contrast, sUDP-GT products were resistant to proteinase treatment.
      Hydrolysis of the product of UDP-GlcNAc-T incorporation by trifluoroacetic acid
      released only glucosamine, while both glucosamine and galactosamine were released
      from UDP-GalNAc-T products, supporting the presence of an epimerase in Giardia
      which can convert GalNAc to GlcNAc during incorporation. This study suggests that
      at least two UDP-GT activities are induced during encystation, which are
      responsible for the transfer of GlcNAc and GalNAc from UDP-GlcNAc or UDP-GalNAc
      into both proteinase-sensitive and proteinase-resistant components of the Giardia
      cyst wall.

PMID- 8654549
TI  - Dirofilaria immitis: ultrastructural localization, molecular characterization,
      and analysis of the expression of p27, a small heat shock protein homolog of
      nematodes.
AB  - A cDNA fragment encoding the complete coding region of a 27-kDa protein (p27) of
      Dirofilaria immitis was cloned. Antibody to the recombinant p27 bound to
      hypodermal tissues of third (L3) and fourth stage larvae (L4) of D. immitis and
      to both the hypodermis and the cuticle of L3s of Onchocerca volvulus, as
      visualized by immunoelectronmicroscopy. The deduced amino acid sequence of the
      central and C-terminal regions of p27 (amino acids S83 to H222) is 18-36%
      identical to members of the sHsp/alpha-crystallin family of proteins. The
      homologous region is thought to be responsible for the molecular chaperone
      activity of members of this family. The p27 cDNA does not encode a hydrophobic
      signal peptide. At least two homologous yet distinct p27 genes were identified in
      the D. immitis genome by Southern hybridization using the p27 cDNA as a probe.
      The p27 transcript was 0.9 kb in length on Northern blots. The expression of p27
      in L3s of D. immitis was neither upregulated by heat shock (43 degrees C) nor by
      incubation at the physiologic temperature of 37 degrees C. Pulse-labeling
      experiments of both D. immitis and Brugia malayi L3s during the L3-L4 molt in
      vitro showed that synthesis of p27 is also not upregulated during this
      developmental phase. However, p27 is expressed constitutively throughout the D.
      immitis L3-L4 molt and therefore by both larval stages. In addition, both female
      and male adult worms of this species express p27 constitutively. P27, or an
      allomorph thereof, was detected in each of nine species representing four
      nematode superfamilies, thus indicating that this molecule is ubiquitous within
      the phylum Nematoda. In view of the hypodermal localization of p27, its
      constitutive expression, and its retention among nematodes, the function of this
      protein in essential housekeeping roles such as that of molecular chaperone
      during the molting process is discussed.

PMID- 8654550
TI  - Schistosoma mansoni: influence of infection on mouse behavior.
AB  - Schistosoma mansoni infection in humans and animals induces abnormal
      neurobehavioral responses following granuloma formation. In mice, granulomas in
      the liver are observed 8 weeks after infection, while after 15-20 weeks, the
      presence of eggs and granulomas in the brain has been reported. In this study,
      outbred CD-1 female mice were infected with S. mansoni and examined in several
      behavioral tests (open field, novel object investigation, black/white box, and
      hot plate) 8 and 15 weeks after infection. The detected effects of schistosome
      infection were a reduction of body weight in 8-week infected mice, marked changes
      in exploration/activity, rearing, and wall-rearing in 8- and 15-week infected
      mice, an enhancement of sniffing and grooming in 8-week infected mice, and
      finally an increase in the threshold of pain response to the hot plate in 15-week
      infected mice. The results of the present study indicate that S. mansoni
      infection markedly alters exploratory behavior of mice, affecting particularly
      the vertical movements of the animals, and suggests that the differences in
      behavioral abnormalities between 8- and 15-week infected mice might be associated
      with modifications in the levels of nerve growth factor and cytokines induced by
      granulomas.

PMID- 8654551
TI  - L ferritin accumulation in macrophages infiltrating the lung during rat
      Angiostrongylus cantonensis infection.
AB  - A 22-kDa protein was increased quantitatively, as measured by sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis techniques, in lung microsomes
      prepared from Angiostrongylus cantonensis-infected rats. However, it was almost
      absent in normal rats. The protein was purified by sequential chromatography on
      Superdex 200 columns and identified chemically and immunologically as ferritin.
      Using isoelectric focusing and anion exchange chromatography, it was identified
      as L ferritin. Distribution of this 22-kDa protein in the lung tissue of A.
      cantonensis-infected rate was studied by immunocytochemistry. Positively stained
      cells were mainly infiltrated macrophages. Our results suggest that L ferritin
      accumulation in the macrophages may be related to the proliferation of connective
      tissue elements and the inflammatory response to A. cantonensis dwelling in the
      pulmonary arteries of the rat.

PMID- 8654552
TI  - Trypanosoma cruzi: polymerase chain reaction-based detection in dried feces of
      Triatoma infestans.
AB  - PCR was employed to detect Trypanosoma cruzi DNA in Triatoma infestans dry fecal
      spots collected on filter papers. Both insects fed on experimentally infected
      monkeys and insects collected in a Paraguayan endemic area for Chagas' disease
      were examined. When the insects fed on a chronically infected monkey with low
      parasitemia as revealed by direct microscopic observation (DMO), T. cruzi was
      detected in the insect feces by PCR as soon as 2 days postfeeding. When the same
      experiment was performed on monkeys with parasitemia levels below the limit of
      detection by DMO, the degree of positivity found through PCR-Southern
      hybridization, applied on Day 8 postfeeding, was superior to that obtained
      through xenoculture. These results suggest that PCR can be used to speed the
      xenodiagnosis results with great sensitivity. On the other hand, when applied to
      the feces of triatomines collected in the field, 84% were positive by PCR
      Southern hybridization, whereas only 26% were positive by DMO. Therefore, PCR
      could also be applied to the monitoring of the infection status of triatomines
      which infest rural dwellings by examining only the feces left on paper sensors
      hung on the walls of the houses.

PMID- 8654553
TI  - Eimeria tenella: role of carbohydrates on sporozoite at the penetration into
      cultured cells.
AB  - The effects of carbohydrates on the penetration of Eimeria tenella sporozoites
      into cultured cells were investigated. Eight different carbohydrates that have
      been known to be on the surfaces of animal cells were added to culture medium
      during the penetration period. D-Galactose alone inhibited sporozoite penetration
      into primary chicken kidney cells. When kidney cells were pretreated with D
      galactose and infected with E. tenella sporozoites, the penetration was
      suppressed significantly, but not when the sporozoites were pretreated. In
      addition, the penetration of sporozoites was suppressed when pretreated with
      peanut lectin that specifically recognizes D-galactose residues at a
      concentration of 50 micrograms/ml. The present results suggested that D-galactose
      residues on E. tenella sporozoite surfaces and the lectin-like receptors that
      recognize D-galactose of host cells are important factors for penetration.

PMID- 8654554
TI  - Schistosoma mansoni: evidence for a 28-kDa membrane-anchored protease on
      schistosomula.
AB  - Transformation of cercariae of Schistosoma mansoni into schistosomula is
      accompanied by release of a soluble 28-kDa serine protease (s28) from the
      acetabular glands. The postulated activities of s28 include cleavage of skin
      connective tissue proteins (elastin, etc.), release of the cercarial glycocalyx,
      and cleavage of complement proteins. Our previous results demonstrated the
      presence of an antigenically cross-reactive protein on the surface of
      mechanically transformed schistosomula. As shown here, schistosomula express on
      their surface a 28-kDa serine protease (m28) which can be immunoprecipitated with
      anti-s28 antibodies. m28 eluted from the schistosomular tegumental membrane with
      NP-40 was purified to homogeneity in one step by adsorption on a chymotrypsin
      inhibitor column: 6-aminocaproyl-D-tryptophan methyl ester-Sepharose. Proteolytic
      activity of m28 was completely inhibited by the chymotrypsin inhibitor N-succinyl
      Ala-Ala-Pro-Phe-chloromethyl ketone. Efficient removal of m28 from schistosomula
      was achieved with NP-40, deoxycholate, cholate, Tween 20, and phospholipases A2
      and C, but not with papain, trypsin, pronase, or proteinase K. Furthermore,
      treatment with phosphatidyl inositol-specific phospholipase C (PI-PLC) followed
      by hydroxylamine also released m28. Anti-cross-reactive determinant antibodies
      which recognize a neo epitope exposed in glycosyl phosphatidyl inositol
      containing molecules cleaved by PI-PLC bind to purified m28. The latter results
      suggest that m28 is anchored to the tegumental membrane of schistosomula by a
      lipid anchor and that perhaps some of the m28 molecules are bound via
      glycosylphosphatidyl inositol. Based on inhibitor sensitivity and antigenic cross
      reactivity, it is conceivable that s28 and m28 are related, if not identical,
      proteins. Finally, m28 was detected antigenically also on lung-stage and adult
      worms of S. mansoni.

PMID- 8654556
TI  - Leishmania amazonensis: cultivation and characterization of axenic amastigote
      like organisms.
AB  - Extracellular amastigote-like forms of Leishmania amazonensis can be maintained
      in axenic culture at 32 degrees C, pH 4.6, with a generation time of
      approximately 17 hr. This species of Leishmania is of particular interest since
      it has been associated with cutaneous, diffuse cutaneous, and mucocutaneous forms
      of the disease. Immunofluorescence, Western and Northern blot analyses, and
      immunoprecipitation have been used to estimate the expression levels of
      amastigote or promastigote antigens in axenically cultured amastigotes. In these
      analyses, monoclonal antibodies (mAbs) specific for either the amastigote (A-1, A
      2, P-2, P-4, P-5, P-8) or promastigote (M-2, P-9, and F-4) and a DNA probe that
      was specific for the amastigote gene encoding the protein reactive with mAb P-4
      have been employed. The amastigote-like organisms were infective for peritoneal
      and J774.G8 macrophages and BALB/c mice. While amastigote-like forms maintained
      at pH 4.6, 32 degrees C transformed to promastigotes when transferred to pH 7.3,
      24 degrees C, transformation of promastigotes to amastigote-like organisms
      required a period of growth at pH 4.6 24 degrees C prior to transfer to 32
      degrees C. This is the first report of the axenic cultivation of L. amazonensis
      amastigote-like organisms. This species grows in continual culture at a lower pH
      than any other species characterized to date. These organisms will prove useful
      in further studies of the biochemistry, immunology, developmental biology, and
      molecular biology of this parasite.

PMID- 8654555
TI  - Trypanosoma cruzi and erythrocyte agglutinins: a comparative study of occurrence
      and properties in the gut and hemolymph of Rhodnius prolixus.
AB  - The activity of agglutinins found in the gut tissues and hemolymph of Rhodnius
      prolixus was tested using rabbit erythrocytes, Trypanosoma cruzi, or Trypanosoma
      rangeli as test particles. In addition, investigations were made of the influence
      of parasitic infection and insect diet on the agglutination titers. A range of
      physicochemical tests and carbohydrate-binding studies were performed and
      inhibitors were subsequently found for both the crop agglutinin (p-nitrophenol
      derived sugars) and the hemolymph agglutinin (galactose-type sugars). As a
      result, affinity chromatography was utilized for an attempted purification of
      these agglutinins, and a one-step purification protocol for the R. prolixus
      hemolymph agglutinin has been developed. Preliminary results of some biological
      and physicochemical characteristics of this pure agglutinin are described. These
      results represent a starting point for future studies of lectin/parasite
      interaction in this reduviid-trypanosome model.

PMID- 8654557
TI  - Bifurcated ubihydroquinone oxidation in the cytochrome bc1 complex by proton
      gated charge transfer.
AB  - The unique bifurcation of electron flow at the ubihydroquinone-oxidation center
      of the cytochrome bc1 complex is the energy-conserving reaction of the
      protonmotive Q- cycle and is prerequisite to vectorial proton translocation. The
      widely accepted Q-cycle reaction scheme describes the overall electron and proton
      pathways, but does not address the detailed chemistry of this central step. Based
      on a model of the ubihydroquinone-oxidation pocket containing two ubiquinone
      molecules in a stacked configuration, a detailed model for the reactions during
      steady-state catalysis is proposed. In this proton-gated charge-transfer
      mechanism the reaction is controlled by the deprotonation of the substrate
      ubihydroquinone.

PMID- 8654558
TI  - Tailoring echistatin to possess higher affinity for integrin alpha(IIb)beta(3).
AB  - A mutant of echistatin, a disintegrin with a high affinity for the integrins, was
      constructed by substituting CRGDC for ARGDD in the Arg-Gly-Asp (RGD) region. The
      mutant was chemically synthesized, subjected to a folding process with air
      oxidation, and purified by reverse-phase HPLC. The peptide mapping and mass
      spectrometric analyses revealed that the two Cys residues introduced in the
      mutant are linked to each other, without any effect on the mode of the four
      disulfide bonds present in native echistatin, as expected. The mutant strongly
      inhibited the binding of human fibrinogen to its receptor, integrin
      alpha(IIb)beta(3) with an IC(50) value of 0.12 nM. This value shows that the
      mutant is twice as potent as the native form (IC(50) = 0.23 nM). These results
      indicate that the native disintegrin molecule, which has been considered to
      possess the optimum affinity for the integrins, can be tailored to exhibit even
      higher affinity by introducing the conformational constraint into the RGD region.
      Monte Carlo simulations of KRCRGDCMD, the RGD region in the mutant, suggested
      that the disulfide bond constrains the RGD region to assume a type II' beta-turn,
      with Gly and Asp in positions 2 and 3 of the turn.

PMID- 8654559
TI  - A monoclonal antibody that causes the heterotrimeric G-protein G(o) to release
      its beta gamma subunits.
AB  - Heterotrimeric (alpha beta gamma) guanine nucleotide binding proteins (G
      proteins) dissociate into their constituent subunits in the course of signal
      transduction. Exposure of the G-protein G(o) to the alpha(o)-specific monoclonal
      antibody 3E7 results in recovery of alpha(o) alone. We identified the 3E7 epitope
      as ERSKAIEKNL (positions 14-23) using synthetic peptides and phage display. G(o)
      isolated with alpha(o)-specific monoclonal antibodies MONO and 3C2 dissociates
      and releases its beta gamma subunits when exposed to 3E7. Exposure to 3E7, but
      not MONO or 3C2, results in the displacement of beta gamma from trimers, in the
      absence of added activators of G-proteins (GTPgammaS, Mg2+AlF4-). We propose that
      stable binding of 3E7 to alpha(o) requires displacement of beta-gamma and occurs
      in the absence of guanine nucleotide exchange.

PMID- 8654560
TI  - Translational fusion of heat labile enterotoxin chain B and beta-subunit of human
      chorionic gonadotropin: periplasmic expression in Escherichia coli and its
      immunogenicity.
AB  - A fusion gene was constructed consisting of heat labile enterotoxin chain B (LTB)
      of E. coli genetically linked at its C-terminus to the beta-subunit of human
      chorionic gonadotropin in translational fusion, under the control of tac promoter
      and LTB signal sequence. Expression of the fusion gene (about 5 microgram/ml) in
      E. coli was confirmed by immunoblot analysis using both anti-LTB and anti-betahCG
      polyclonal antibodies. The fusion protein was efficiently processed and exported
      to the periplasmic space. LTB in the fusion protein retained its ability to bind
      to GM1 ganglioside receptor. Mice immunized with the fusion protein produce
      antibodies that recognize recombinant betahCG and the native hCG suggesting its
      potential use as a contraceptive vaccine.

PMID- 8654561
TI  - Calnexin: its molecular cloning and expression in the liver of the frog, Rana
      rugosa.
AB  - A 2.2-kb cDNA clone encoding the endoplasmic reticulum (ER) resident protein,
      calnexin (CLX), was isolated from the frog Rana rugosa liver cDNA library and
      sequenced. The sequence encoded 622 amino acids and was 77% similar to mammalian
      CLXs and 56% to mouse CLX-t. In the phylogenetic tree, mouse CLX-t was clearly
      diverged from other CLXs including frog. The amino acid sequence of CLX showed
      regions similar to those in frog calreticulin (CLT), although CLX, but not CLT,
      contained a histidine-rich region at the NH2-terminus. CLX gene expression was
      observed only in the liver among various tissues examined. Additionally, its
      expression was strong in the liver in 2-month post-metamorphosis frogs, but very
      weak in adults. The results suggest that the CLX gene is expressed in a tissue-
      and stage-dependent manner in the frog, R. rugosa, and that CLX is widely
      distributed in eukaryotic organisms.

PMID- 8654562
TI  - Correlated behavior of the EPR signal of cytochrome b-559 heme Fe(III) ligated by
      OH- and the multiline signal of the Mn cluster in PS-II membrane fragments.
AB  - EPR signals of Cyt b-559 heme Fe(III) ligated by OH- and the multiline signal of
      the Mn cluster in PS-II membrane fragments have been investigated. In 2,3-dicyano
      5,6-dichloro-p-benzoquinone-oxidized PS-II membrane fragments the light-induced
      decrease of the EPR signal of the heme Fe(III)-OH- is accompanied by the
      appearance of the EPR multiline signal of the Mn cluster. Addition of F- ions,
      which act as a stronger ligand for heme Fe(III) than OH-, decreases to the same
      extent the dark- and light-induced signal of the heme Fe(III)-OH- and the light
      induced multiline signal of the Mn cluster. These results are discussed in terms
      of the light-induced formation of a bound OH' radical shared between the Cyt b
      559 heme Fe and the Mn cluster as a first step of water oxidation.

PMID- 8654563
TI  - Expression and initial characterization of recombinant mouse thrombospondin 1 and
      thrombospondin 3.
AB  - To analyze the function of TSP family members, we have expressed and purified
      mouse TSP1 and TSP3 encoded by recombinant baculoviruses in Spodoptera frugiperda
      cells and compared these TSPs to mouse TSP2 prepared in a similar way. Yields of
      purified TSP1 and TSP3 were 5-15 and 2-4 micrograms, respectively, per ml of
      conditioned medium. Mature, secreted mouse T41 and TSP3 had the previously
      predicted NH2-terminal sequences of DHVKDTSFDLFSI, and SQDLQVIDLLT, respectively.
      Analysis by SDS-PAGE and rotary shadowing electron microscopy indicated that TSP1
      and TSP2 are disulfide bonded trimers whereas TSP3 is a disulfide-bonded
      pentamer. Binding assays with 45Ca2+ as ligand and immobilized TSP1, TSP2 and
      TSP3 demonstrated that all three TSPs are calcium-binding proteins. These results
      are consistent with previous studies of TSP structure and demonstrate that
      Spodoptera cells process and secrete TSPs having the same subunit organizations
      and structure as the native vertebrate molecules.

PMID- 8654564
TI  - Efficient binding to the MHC class I K(d) molecule of synthetic peptides in which
      the anchoring position 2 does not fit the consensus motif.
AB  - Peptides eluted from the MHC class I K(d) molecule are generally nonamers that
      display a strong preference for Tyr in position 2 and Ile or Leu in position 9.
      We investigated the binding ability of several synthetic peptides which did not
      fit this consensus motif. In our peptides, Tyr(2) was substituted by other amino
      acids, i.e. LeU, Ile or Met. These peptides were variants of the 252-260 K(d)
      restricted peptide SYIPSAEKI derived from the Plasmodium berghei circumsporozoite
      protein. They bound to purified K(d) molecules in vitro with intermediate
      affinity. One of them was tested for in vivo stimulation of T cells and induced a
      cytotoxic response. These results demonstrate the importance of binding motif
      refinement to discover new binding characteristics and new ligands such as low
      affinity peptides.

PMID- 8654565
TI  - Down-regulation of non-L-, non-N-type (Q-like) Ca2+ channels by Lambert-Eaton
      myasthenic syndrome (LEMS) antibodies in rat insulinoma RINm5F cells.
AB  - The action exerted on non-L-, non-N-type (Q-like) Ca 2+ channels by
      immunoglobulins G (IgGs) obtained from two patients with Lambert-Eaton myasthenic
      syndrome (LEMS) was investigated in the rat insulinoma RINm5F cell line. LEMS
      IgGs reduced by 30-36% the whole-cell Ba2+ currents through Q-like Ca2+ channels
      at +10 mV without significantly modifying their voltage dependence and activation
      kinetics. Single- and multiple-channel recordings in cell-attached and outside
      out patches of cells treated with LEMS IgGs showed no significant changes of the
      channel elementary properties but rather a decreased number of active channels
      per patch. This suggests that Q-like current depression by LEMS autoantibodies is
      mostly due to a down-regulation of functioning Ca2+ channels. In agreement with
      previous observations, LEMS IgGs also reduced by 20-33% the dihydropyridine
      sensitive (L-type) Ba2+ current. The suggested down-regulation of Q-like channels
      by LEMS IgGs in RINm5F cells may have a functional correlation with the
      depressive action of LEMS autoantibodies on the P/Q-type Ca2+ channels
      controlling acetylcholine release from mammalian neuromuscular junctions.

PMID- 8654566
TI  - Basal phosphorylation of mu opioid receptor is agonist modulated and Ca2+
      dependent.
AB  - The mu opioid receptor was shown to be phosphorylated at a basal rate in the
      absence of agonist, measured in permeabilized HEK293 cells transfected with an
      epitope tagged mu receptor (EE-mu) [Arden, J., Segredo, V., Wang, Z., Lameh, J.
      and Sadee, W. (1995) J. Neurochem. 65, 1636-1645]. In the present study, basal
      phosphorylation was found to be Ca2+ dependent; however, several inhibitors of
      protein kinase C and Ca2+-calmodulin dependent kinases failed to affect basal mu
      receptor phosphorylation. Thus, the basal mu receptor phosphorylating activity
      differed from the main kinases involved in receptor regulation. The general
      kinase inhibitor H7 (100 microM) suppressed basal mu receptor phosphorylation.
      Pretreatment with the agonist morphine, followed by drug removal, resulted in a
      sustained increase of basal mu receptor phosphorylation. The gradual agonist
      dependent modulation of basal mu receptor phosphorylation suggests a novel
      regulatory mechanism which may play a role in narcotic tolerance and dependence.

PMID- 8654567
TI  - Reaction of human alpha2-antiplasmin and plasmin stopped-flow fluorescence
      kinetics.
AB  - The interaction of human plasmin with human alpha2-antiplasmin was measured in
      the presence and absence of lysine-binding ligands using the corresponding active
      site fluorescence changes. The stopped-flow method allows for direct
      determination of reliable values of the second order rate constant for the fast
      association step of plasmin and alpha2-antiplasmin in the absence of another
      interacting compound, e.g. a plasmin substrate. At pH 7.4, 25 degrees C, k1 = 2.2
      x 10(7) M(-1)s(-1) was obtained. Substantial reductions in k1 were seen in the
      presence of trans-4-(aminomethyl)cyclohexane-1-carboxylic acid at concentrations
      corresponding to lysine-binding site interactions at kringle 4 of plasmin; at
      saturation the rate constant is reduced 20-fold, whereas the effect of saturation
      of kringle 1 is only a 2-fold reduction. It is thus found that the interaction of
      alpha2-antiplasmin with the lysine-binding site of kringle 1 is of little
      importance compared with that of kringle 4 in regulating the inhibition reaction
      of plasmin with alpha2-antiplasmin. Similar results were recently obtained for
      the bovine plasmin-bovine alpha2-antiplasmin reaction (Christensen et al. (1995)
      Biochem. J. 305, 97-102).

PMID- 8654568
TI  - Analysis of basic fibroblast growth factor in rats with inherited retinal
      degeneration.
AB  - In RCS rats, photoreceptors degenerate between postnatal days 20 and 60,
      secondary to a genetic defect expressed in the neonatal retinal pigmented
      epithelium (RPE). Previous work has shown delay of the photoreceptor degeneration
      in this model by intraocular injection of basic fibroblast growth factor (bFGF).
      Evidence is presented here, from bFGF immunostaining and Northern analysis of
      bFGF mRNA, for reduced bFGF expression in uncultured RPE of dystrophic RCS pups.
      It is also shown that in the mutant eyes angiogenesis in the underlying choroid,
      which normally occurs between postnatal days 7 and 10, is markedly delayed, with
      irregular distribution of vessels, consistent with a reduction in this known
      angiogenesis factor. Mutational analysis of the bFGF transcript and gene by
      denaturing gradient gel electrophoresis and Southern analysis did not, however,
      reveal abnormalities in the coding sequence of this gene in RCS rats.

PMID- 8654569
TI  - Reoxidation of the NADPH produced by the pentose phosphate pathway is necessary
      for the utilization of glucose by Kluyveromyces lactis rag2 mutants.
AB  - Kluyveromyces lactis mutants defective in the glycolytic enzyme phosphoglucose
      isomerase are able to grow in glucose media and to produce ethanol, but they
      depend on a functional respiratory chain and do not grow in glucose-antimycin
      media. We postulate that this is due to the necessity of reoxidizing, in the
      mitochondria, the NADPH produced by the pentose phosphate pathway, which may be
      highly active in these mutants in order to bypass the blockade in the
      phosphoglucose isomerase step. This oxidation would be mediated by a cytoplasmic
      side mitochondrial NAD(P)H dehydrogenase that would pass the electrons to
      ubiquinone. Data supporting this hypothesis are provided.

PMID- 8654570
TI  - The purification of ammonia monooxygenase from Paracoccus denitrificans.
AB  - The heterotrophic nitrifier Paracoccus denitrificans expresses a membrane
      associated ammonia monooxygenase. The active enzyme has been solubilized in the
      detergent dodecyl-beta-D-maltoside and purified by standard chromatographic
      techniques. This is the first purification of an ammonia monooxygenase. The
      enzyme consists of two subunits with molecular masses of 38 and 46 kDa. The
      purified enzyme is a quinol oxidase, is inhibited by light and a variety of
      chelating agents and is activated by cupric ions. These properties indicate that
      this enzyme has similarities to a family of enzymes including the ammonia
      monooxygenase from Nitrosomonas europaea and the particulate methane
      monooxygenase from Methylococcus capsulatus (Bath).

PMID- 8654571
TI  - Characterization of a high-affinity and specific binding site for Gas6.
AB  - We have purified a novel growth-potentiating factor and demonstrated that the
      factor is coded by the gas6 gene. Moreover, we have suggested the presence of a
      Gas6 receptor on rat vascular smooth muscle cells. In this study, we further
      analyzed the binding of Gas6 to its receptor. Tissue and cellular distribution of
      the binding activity of (125)I-labeled Gas6 showed that the binding site existed
      in many but a limited range of tissues and cell types. Further characterization
      of the binding of [(125)I]Gas6 using HOS cells demonstrated that the specific
      binding was dependent on the presence of Ca(2+). Chemical cross-linking of
      [(125)I]Gas6 to HOS cells resulted in the formation of a high-molecular-mass
      complex, suggesting the presence of a high-molecular-weight receptor.

PMID- 8654572
TI  - Prevention of growth arrest-induced cell death of vascular smooth muscle cells by
      a product of growth arrest-specific gene, gas6.
AB  - We have purified Gas6 as a growth-potentiating factor for vascular smooth muscle
      cells (VSMCs) [Nakano, T. et al. (1995) J. Biol. Chem. 270, 5702-5705]. However,
      specific production of Gas6 in growth-arrested cells raises an intriguing
      question as to the physiological function of Gas6. In this study, we found that
      serum-starved VSMCs secreted some survival factors and depletion of the factors
      induced cell death of VSMCs. Finally, we demonstrated that cell death was
      prevented by the addition of Gas6, suggesting that one of the major biological
      activities of Gas6 is protection of growth-arrested VSMCs from death.

PMID- 8654573
TI  - Exciton delocalization in the antenna of purple bacteria: exciton spectrum
      calculations using Z-ray data and experimental site inhomogeneity.
AB  - Electron absorption and circular dichroism spectra of the peripheral light
      harvesting complex (LH2) of photosynthetic purple bacteria were calculated taking
      into account the real-life spatial arrangement and experimental inhomogeneous
      broadening of bacteriochlorophyll molecules. It was shown that strong excitonic
      interactions between 18 bacteriochlorophyll molecules (BCh1850) within the
      circular aggregate of the LH2 complex result in an exciton delocalization over
      all these pigment molecules. The site inhomogeneity (spectral disorder)
      practically has no influence on exciton delocalization. The splitting between two
      lowest exciton levels corresponds to experimentally revealed splitting by hole
      burning studies of the LH2 complex.

PMID- 8654574
TI  - Calcium transported to isolated rat liver nuclei by nicotinamide adenine
      dinucleotide is insensitive to thapsigargin.
AB  - Calcium uptake by isolated nuclei was mediated by nicotinamide adenine
      dinucleotide. Oxidized nicotinamide nucleotide analogues were more effective
      mediators of nuclear calcium uptake. Thapsigargin inhibited ATP-mediated nuclear
      calcium transport without affecting NAD-mediated nuclear calcium uptake. Whilst
      DBHQ did not influence ATP-induced calcium transport, it did stimulate NAD
      mediated nuclear calcium entry. Calcium channel blockers did not influence the
      action of NAD. This study provides a further mechanism for nuclear calcium
      transport regulated by changes in the cytosolic NAD(+)/NADH ratio.

PMID- 8654575
TI  - Characterization of the NHA1 gene encoding a Na+/H+-antiporter of the yeast
      Saccharomyces cerevisiae.
AB  - The NHA1 gene (2958 nt) encoding a putative Na(+)/H(+) antiporter (986 aa) in
      Saccharomyces cerevisiae was cloned by selection based on increased NaCl
      tolerance. The putative protein is highly similar to sodium/proton antiporters
      from Schizosaccharomyces pombe (gene sod2), and Zygosaccharomyces rouxii (gene Z
      SOD2). Overexpression of the NHA1 gene results in higher and partially pH
      dependent tolerance to sodium and lithium; its disruption leads to an increased
      sensitivity towards these ions.

PMID- 8654576
TI  - Evolution of legumin genes: loss of an ancestral intron at the beginning of
      angiosperm diversification.
AB  - The polymerase chain reaction was used to survey gymnosperm legumin genes.
      Characterization of 46 cloned amplificates, differing in sequence and size (1.2
      1.6 kb), revealed the ubiquitous occurrence of legumin genes and their
      organization in small subfamilies in the 22 species investigated. The 3' portions
      of the genes, coding for the legumin beta-polypeptides, show a highly conserved
      intron/exon structure divergent from those of angiosperms: an additional intron
      (intron IV) uniformly interrupts the region coding for the C-terminal part of the
      beta-polypeptides. Phylogenetic analysis of the respective coding sequences as
      well as the organization of the Magnolia B14 legumin gene also investigated here
      both indicate that intron IV is ancestral and was lost during early angiosperm
      evolution. Taking into account the intron/exon structures from all legumin genes
      known, our results suggest that legumin genes evolved by subsequent loss of
      introns, providing also further evidence for a common origin of legumins and
      vicilins.

PMID- 8654577
TI  - The structure of the O-linked carbohydrate chain of bovine seminal plasma protein
      PDC-109 revised by H-NMR spectroscopy A correction.

PMID- 8654578
TI  - Heat-labile uracil-DNA glycosylase: purification and characterization.
AB  - A uracil-DNA glycosylase (UNG) from a psychrophilic marine bacterium (BMTU 3346)
      has been purified to apparent homogeneity. The enzyme has a molecular weight of
      23400 Da. It is stable in complex buffers (containing glycerol/BSA), whereas it
      is heat-labile in dilute buffers (free of stabilizers) with a half-life of 2 min
      at 40 degrees C. Due to the thermolability, uracil-DNA glycosylase is suitable
      for application in the carryover prevention technique showing less residual
      activity and/or a slower reactivation rate than the usually applied UNG from
      Escherichia coli.

PMID- 8654579
TI  - Immunolocalization of an inwardly rectifying K+ channel, K(AB)-2 (Kir4.1), in the
      basolateral membrane of renal distal tubular epithelia.
AB  - Immunolocalization of K(AB)-2 (Kir4.1), an inwardly rectifying K+ channel with a
      putative ATP-binding domain, was examined in rat kidney where expression of K(AB)
      2 mRNA was previously shown. Anti-K(AB)-2 antibody was raised in rabbit and then
      affinity-purified. An immunohistochemical study revealed that K(AB)-2
      immunoreactivity was detected specifically in the basolateral membrane of distal
      tubular epithelia. Therefore, K(AB)-2 is the first K+ channel shown to be
      localized in the basolateral membrane of renal epithelia. The finding suggests
      that K(AB)-2 may contribute to supplying K+ to the Na(+)-K+ pump, which is
      abundant in the basolateral membrane of distal tubular epithelia, as well as to
      maintenance of the deep negative membrane potential of these cells.

PMID- 8654580
TI  - Detection of living cells that express AP1 using a fluorolabeled DNA probe.
AB  - Activator protein 1 (AP1) is a complex of Fos and Jun, and it regulates the
      transcription of genes possessing the AP1-binding sequence. The purpose of this
      study was to detect living cells that express AP1 after stimulation with a tumor
      promoter. The Fos and Jun components of AP1 were induced rapidly and transiently
      in PC12 cells following the addition of phorbol ester (phorbol 12-myristate 13
      acetate, PMA). The DNA fragment containing the AP1-binding sequence was combined
      with ethidium bromide, which was used as a fluorescent probe. The probe was
      transfected into the cells using cationic liposomes. Fluorescence in the
      transfected cells was observed using a fluorescence microscope. The nuclei of
      transfected cells emitted strong fluorescence in the presence of PMA, whereas
      weak fluorescence was retained in the cytoplasm in its absence. The former
      phenomenon is evidence that AP1 combined with the fluorescent probe was
      transported into the nuclei. This study suggests that such a fluorolabeling
      method is feasible to detect living AP1-expressed neurons.

PMID- 8654581
TI  - Ligand dependence of cytochrome P450c17 protection against proteolytic
      inactivation: structural, methodological and functional implications.
AB  - Rate constants for the subtilisin-catalyzed proteolytic inactivation of
      cytochrome P450c17 (CYP17), the endoplasmic reticulum membrane-bound limiting
      enzyme of gonadal androgen synthesis, have been determined in the absence and
      presence of various CYP17 ligands and correlated with fractional enzyme
      saturation (Y). Extrapolation to Y = 1 reveals 15.1-, 4.0- and 7.4-fold enzyme
      stabilization with progesterone (substrate-type ligand), testosterone (product
      type ligand) and ketoconazole (imidazole-type inhibitory ligand), respectively.
      Structural features of ligand accommodation can therefore be monitored by the
      susceptibility of target enzymes to proteolysis. It is further proposed that
      specific protection of a membrane protein by ligand binding during proteolytic
      digestion may assist in the purification of that protein. Evidence is finally
      presented that the gonadotropin-induced rapid CYP17 down-regulation is not
      promoted by an elevation of steroid hormone levels.

PMID- 8654582
TI  - Effects of phorbol esters on insulin-induced activation of phosphatidylinositol 3
      kinase, glucose transport, and glycogen synthase in rat adipocytes.
AB  - In rat adipocytes, phorbol ester-induced activation of PKC did not inhibit
      insulin signalling through IRS-1-dependent phosphatidylinositol (PI) 3-kinase
      activation. Moreover, phorbol esters alone provoked an increase in membrane PI 3
      kinase activity. These findings may be relevant to the failure of phorbol esters
      to inhibit insulin effects on glucose transport and glycogen synthesis in rat
      adipocytes.

PMID- 8654583
TI  - Antigen binding of antiganglioside antibodies in vitro is strongly influenced by
      the ganglioside composition of the sample.
AB  - The ability of antiganglioside antibodies to detect their respective antigens in
      various environments was studied. In contrast to sensitive detection of pure
      ganglioside standards by ELISA, antibody binding to mixtures of gangliosides was
      drastically reduced. This loss of sensitivity also occurred with immunostaining
      of gangliosides absorbed to silica gel. Moreover, absorption of antibodies to
      antigen-containing lipid vesicles failed, if the vesicles were prepared together
      with other gangliosides. These data indicate that antigen accessibility is
      strongly influenced by surrounding gangliosides. This should be considered
      whenever gangliosides are traced by antibodies. The ELISA procedure appears
      useful to test for such properties.

PMID- 8654584
TI  - The N-terminal half of a mitochondrial presequence peptide inserts into
      cardiolipin-containing membranes. Consequences for the action of a transmembrane
      potential.
AB  - The orientation of a mitochondrial-presequence peptide, associated with anionic
      lipid-containing model membranes, was investigated. The peptide inserts with its
      N-terminal alpha-helical part into cardiolipin (CL) monolayers so that the N
      terminal 14 residues are protected from proteinase K. In phosphatidylglycerol
      (PG) monolayers the inserted peptide was fully accessible to the protease. A
      consequence of the different orientations of the peptide was that membrane
      potential-dependent protection from trypsin was much faster for the peptide bound
      to PG-containing vesicles compared to CL-containing membranes, suggesting that in
      the mitochondrial protein import process other components of the import apparatus
      are involved in the efficient potential-driven translocation of presequences
      across the inner mitochondrial membranes.

PMID- 8654585
TI  - Porcine polypyrimidine tract-binding protein stimulates translation initiation at
      the internal ribosome entry site of foot-and-mouth-disease virus.
AB  - The cDNA for porcine polypyrimidine tract-binding protein (sPTB) was cloned. The
      sPTB amino acid sequence is highly homologous to the human PTB sequence (97%
      identity), and the sPTB sequence corresponds to that of the longest human PTB,
      PTB4. The specificity of binding in the UV-crosslink of sPTB to the internal
      ribosome entry site (IRES) of foot-and-mouth-disease virus (FMDV) is similar to
      that of human PTB. Purified recombinant sPTB efficiently stimulates internal
      translation initiation directed by the FMDV IRES in a rabbit reticulocyte lysate
      translation system from which the internal PTB had been depleted.

PMID- 8654587
TI  - Redox-linked conformational changes in cytochrome c oxidase.
AB  - The CD spectrum of oxidized cytochrome oxidase in the wavelength region 185-260
      nm shows that the secondary structure of the protein consists of close to 60%
      alpha-helix and slightly less than 20% beta-structure. CD spectra of oxidized
      cytochrome oxidase, of half and fully reduced carboxycytochrome oxidase as well
      as of fully reduced cytochrome oxidase, have been recorded in the wavelength
      region 200-260 nm. The results demonstrate a conformational change on going from
      the oxidized to the half reduced state in carboxycytochrome oxidase; no further
      change occurs on full reduction. A conformational change is also seen in the
      fully reduced enzyme without bound CO. The conformational transitions are
      suggested to be part of the proton pumping mechanism of cytochrome oxidase.

PMID- 8654586
TI  - Two different respiratory Rieske proteins are expressed in the extreme
      thermoacidophilic crenarchaeon Sulfolobus acidocaldarius: cloning and sequencing
      of their genes.
AB  - We have isolated two genes encoding Rieske iron sulfur proteins from the genomic
      DNA of the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius (DSM 639).
      One of the genes, named soxL, codes for the previously isolated novel Rieske-I
      protein. The second gene (soxF) 121 codes for the Rieske-II protein associated
      with the second terminal oxidase of Sulfolobus. Both proteins exhibit only 24%
      identical residues. The Rieske-I protein shows a number of unusual features. (i)
      The distance between the two cluster binding sites is significantly larger than
      in all known proteins. (ii) An unexpected Pro --> Asp exchange in one of the
      cluster binding sites. (iii) It shows some resemblance to the mitochondrial and
      plastidic Rieske proteins insofar as the soxL gene codes for a pre-sequence which
      is no longer present in the mature Rieske-I protein. Both proteins cluster
      together on a separate branch of the phylogenetic tree. To our knowledge this is
      the first proven case of two significantly different Rieske proteins in a
      prokaryote.

PMID- 8654588
TI  - Association of yeast SAP1, a novel member of the 'AAA' ATPase family of proteins,
      with the chromatin protein SIN1.
AB  - The yeast SIN1 protein is a nuclear protein that together with other proteins
      behaves as a transcriptional repressor of a family of genes. In addition, sin1
      mutants are defective in proper mitotic chromosome segregation. In an effort to
      understand the basis for these phenotypes, we employed the yeast two-hybrid
      system to identify proteins that interact with SIN1 in vivo. Here, we demonstrate
      that SAP1, a novel protein belonging to the 'AAA' family of ATPases, is able to
      directly interact with SIN1. Furthermore, we show, using recombinant molecules in
      vitro, that a short 27 amino acid sequence near the N-terminal of SIN1 is
      sufficient to bind SAP1. Previous experiments defined different domains of SIN
      that interact with other proteins and with DNA. The C-terminal domain of SIN1 was
      shown to be responsible for interaction with a protein that binds the regulatory
      region of HO, a gene whose transcription is repressed by SIN1. The central 'HMG1
      like region' of SIN1 binds DNA, while the N-terminal of SIN1 can bind CDC23, a
      protein that regulates chromosome segregation. These data, taken together with
      the results presented here, suggest that SIN1 is a multifunctional chromatin
      protein that can interact with a number of different proteins that are involved
      in several different cellular functions.

PMID- 8654589
TI  - Asp-285 of the metal-tetracycline/H+ antiporter of Escherichia coli is essential
      for substrate binding.
AB  - The transposon Tn10-encoded metal-tetracycline/H+ antiporter (TetA(B)) was
      preferentially photolabeled when [3H]tetracycline was irradiated in the presence
      of energized inverted membrane vesicles containing the TetA protein. The degree
      of labeling depended on the duration of irradiation and the energization of the
      membrane. Photolabeling was not observed in vesicles containing the Asp-285 -->
      Asn mutant TetA protein, indicating that Asp-285 participates in the substrate
      binding or the step(s) prior to substrate binding.

PMID- 8654590
TI  - In vitro characterization of the ORF1-ntrBC promoter of Rhizobium etli.
AB  - Rhizobium sigma vegetative-dependent promoters are different from those of
      enteric bacteria and have never been characterized before. We report here the
      biochemical characterization of the ORF1-ntrBC promoter of Rhizobium etli. The
      minimal promoter region was located by means of a transcriptional fusion and
      further characterized by in vitro transcription and gel retardation experiments.
      Oligonucleotides used as DNA competitors in runoff transcription experiments
      allowed the precise localisation of the promoter region. Protein extracts from an
      ntrC+, but not from an ntrC- strain, inhibited in vitro transcription. The NtrC
      protein was found to bind specifically to the promoter, where an NtrC binding
      site overlapping the transcription initiation site, is present.

PMID- 8654591
TI  - Molecular determinants of external barium block in Shaker potassium channels.
AB  - Mutations in the outer pore region of Shaker K+ channels (T449 and D447) can
      influence external Ba2+ block. Substitution of T449 by A, V or Y differentially
      reduced Ba2+ block primarily by decreasing the blocking rate. Substitution of
      D447 by N resulted in a non-conducting channel with apparently normal gating
      currents. External Ba2+ can speed the OFF gating current of a different non
      conducting mutant, W434F; this effect was markedly attenuated by the D447N
      substitution. These results suggest that D447 contributes to an external Ba2+
      binding site while T449 imposes a barrier to the access of that site.

PMID- 8654592
TI  - NMR investigations of the structural properties of the nodulation protein, NodF,
      from Rhizobium leguminosarum and its homology with Escherichia coli acyl carrier
      protein.
AB  - Heteronuclear NMR methods have been used to elucidate the secondary structure and
      the general tertiary fold of the protein NodF from Rhizobium leguminosarum. A
      similarity to acyl carrier proteins of the fatty acid synthase system had been
      suggested by the presence of a phosphopantetheine prosthetic group and a short
      stretch of sequence homology near the prosthetic group attachment site. NMR
      results suggest that the structural homology extends well beyond this region.
      Both proteins have three well-formed helices which fold in a parallel
      antiparallel fashion and a prosthetic group attachment site near the beginning of
      the second helix.

PMID- 8654593
TI  - Kinetic differentiation between ligand-induced and pre-existent asymmetric
      models.
AB  - Negative cooperativity can be accounted for either by the pre-existent asymmetry
      model or by the ligand-induced sequential model. It is virtually impossible to
      deduce the mechanism of negatively cooperative interaction solely from the
      binding curves. Distinguishing between these two possible mechanisms for negative
      cooperativity usually requires experiments other than equilibrium binding. In the
      present communication, a kinetic method is proposed to distinguish between these
      two possible mechanisms for negative cooperativity. As an example of use of the
      new method, experimental data for the modification of creatine kinase by 5,5'
      dithiobis-2-nitrobenzoic acid were taken from literature and reanalyzed by using
      the present method. The result indicates that under conditions in which creatine
      kinase forms the postulated 'transition state analogue' complex, the two subunits
      in the enzyme molecule have different tertiary structures and behave as different
      types of subunit.

PMID- 8654594
TI  - New forms of HMW MAP2 are preferentially expressed in the spinal cord.
AB  - The high molecular weight forms of microtubule-associated protein 2 (MAP2a and b)
      play a central role in the specification of dendrites. RT-PCR amplification of a
      portion of the N-terminal and middle MAP2b domains of rat spinal cord cDNAs
      allowed identification of new variants containing both exon 8 (246 bp) and a new
      exon, 7A (237 bp), located at the beginning of the middle MAP2b region. The brain
      and the spinal cord express transcripts containing exon 8, whereas exon 7A alone
      or exons 7A+8 were detected, whatever the developmental stage, only in the spinal
      cord.

PMID- 8654595
TI  - Peroxisomal beta-oxidation of 2-methyl-branched acyl-CoA esters: stereospecific
      recognition of the 2S-methyl compounds by trihydroxycoprostanoyl-CoA oxidase and
      pristanoyl-CoA oxidase.
AB  - Trihydroxycoprostanoyl-CoA oxidase and pristanoyl-CoA oxidase, purified from rat
      liver, both catalyse the desaturation of 2-methyl-branched acyl-CoAs. Upon
      incubation with the pure isomers of 2-methylpentadecanoyl-CoA, both enzymes acted
      only on the S-isomer. The R-isomer inhibited trihydroxycoprostanoyl-CoA oxidase
      but did not affect pristanoyl-CoA oxidase. The activity of both enzymes was
      suppressed by 3-methylheptadecanoyl-CoA. Valproyl-CoA and 2-ethylhexanoyl-CoA,
      however, did not influence the oxidases. Although only one isomer of 25R,S
      trihydroxycoprostanovl-CoA was desaturated by trihydroxycoprostanoyl-CoA oxidase,
      isolated peroxisomes were able to act on both isomers, suggesting the presence of
      a racemase in these organelles. Given the opposite stereoselectivity of the 26
      cholesterol hydroxylase and of the oxidase, the racemase is essential for bile
      acid formation.

PMID- 8654596
TI  - The importance of volume for outcome in cancer surgery--an overview.

PMID- 8654597
TI  - The influence of surgeon case volume on outcome in site-specific cancer surgery.

PMID- 8654598
TI  - The importance of volume in colorectal cancer surgery.

PMID- 8654599
TI  - The potential of NSAIDs in the treatment of oesophageal carcinoma.

PMID- 8654600
TI  - The influence of age on the surgical management of carcinoma of the stomach.
AB  - The medical records of 31,808 patients with gastric cancer registered with the
      West-Midlands Cancer Registry between 1957-1981 were reviewed to determine the
      influence of age on presentation, stage assessment, management, survival and
      mortality rates. When analysed by stage, and excluding post-operative deaths,
      survival was similar in all age groups. This study confirms stage of disease to
      be the single most important prognostic factor. The inverse relationship between
      laparotomy and age implies inadequate assessment of stage in the elderly. The
      poor prognosis in unresected cases suggests that increased precise staging by
      laparotomy or laparoscopy will have minimal adverse effects. On the other hand
      this may result in increased resections and survival.

PMID- 8654601
TI  - Oesophageal cancer composed of mixed histological types.
AB  - Glandular or adenoid cystic differentiation and sarcomatous features are
      sometimes encountered in oesophageal cancer and such histological variants often
      coexist with ordinary squamous cell carcinoma. So far no serial evaluation of
      such mixed histological types of oesophageal cancer has ever been performed, we
      therefore clinicopathologically investigated such cases While an
      immunohistochemical study of the p53 protein was also done on four available
      cases in order to discuss the histogenesis of these tumours. Among the 600
      patients with surgically resected oesophageal cancer, seven cases were found to
      have a mixture of histological variants with ordinary SCC (squamous cell
      carcinoma) (adenocarcinoma 1, adenoid cystic cancer 3, sarcomatous component 2,
      basaloid cystic cancer and sarcomatous component 1). All but one case had an
      elevated type tumour while the predominant components of protrusion were not SCC
      but variant histological types. Six tumours were restricted to the submucosal
      layer. An immunohistochemical study of the p53 protein revealed that two of four
      cases were positive in both the SCC and variant patterns. Mixed histological
      types of oesophageal cancer composed of SCC and other variants often occur and
      thus the carcinogenesis of both histological types are considered to be aspects
      of the same mechanism.

PMID- 8654602
TI  - Favourable prognosis of cystadeno- over adenocarcinoma of the pancreas after
      curative resection.
AB  - This report details nine patients after curative surgical resection of
      histologically proven mucinous cystadenocarcinoma of the pancreas and compares
      the prognosis with ductal adenocarcinomas. Cystadenocarcinomas represented 2.1%
      (10/ 466) of a total of 466 patients who underwent surgical exploration and 5.5%,
      of all curatively resected carcinomas of the exocrine pancreas at Hanover Medical
      School from 1971 to 1994. Forty percent of adenocarcinomas and 90% of
      cystadenocarcinomas were resectable. A curative R0 resection was possible in all
      patients with cystadenocarcinoma and 85 % with adenocarcinoma. Six of the
      patients with cystadenocarcinoma were female and three were male. Their median
      age was 54 +/- 12 years (range: 44 to 81 years). Four cystic neoplasms were
      located in the head, one in the head and body, three in the tail, and one in the
      body and tail of the pancreas. There was no hospital mortality in this group. The
      prognosis after resection of cystadenocarcinomas was significantly better
      compared to ductal adenocarcinomas of the pancreas. The Kaplan-Meier survival was
      89% vs 52% after 1 year, and 56% vs 13% at 5 years. Our results indicate the
      favourable prognosis of cystadeno- over ductal adenocarcinomas of the pancreas in
      a cohort of patients with curative tumour resection.

PMID- 8654603
TI  - Malignant ascites: a 2-year review from a teaching hospital.
AB  - In this retrospective review of 164 consecutive patients with malignant ascites
      it has been shown that ovarian ascites accounts for 28% of the total and is
      associated with a significantly improved survival compared with other groups
      (P<0.001). Non-ovarian ascites is associated with a very poor prognosis and many
      patients in this group are unsuitable for aggressive treatment. In 49% of
      patients, ascites will be the presenting feature requiring further investigation
      to ascertain the primary tumour. Thorough investigation of female patients should
      be performed in order to identify all patients with an ovarian primary so that
      appropriate chemotherapy can be given. However, thorough investigation in male
      patients is not justifiable.

PMID- 8654605
TI  - Magliant melanoma of the oral cavity: report of 14 cases from a regional cancer
      centre.
AB  - Fourteen patients with oral mucosal malignant melanomas seen at a regional cancer
      centre over a 10-year period were analysed. All the patients presented with
      symptoms of short duration, with extensive local disease at initial evaluation in
      11 patients. The palate was the commonest site involved. Ten patients had
      regional nodal disease and of these four also had distant metastases to the liver
      and/or the lung. Coincidental melanosis was identified clinically in three
      patients and histologically confirmed in two patients. Only four patients
      underwent radical surgery. Of the five patients who received DTIC-based
      chemotherapy, only one achieved a complete response. No significant correlation
      between stage of the disease at presentation, histological features or type of
      treatment and survival could be seen as the number of cases is small.

PMID- 8654604
TI  - Psychosocial adaptation after liver transplantation with particular reference to
      recipients aware of their cancer.
AB  - This study investigated the Psychosocial adjustment in 40 patients who received
      orthotopic liver transplantation (OLT) for several endstage liver diseases.
      Twenty patients were grafted because they suffered from liver Cancer as well as
      cirrhosis. Particular attention was paid to evaluating whether cancer could
      affect recipients' coping with transplant. Each patient underwent a semi
      structured interview to obtain information on their psychosocial life,
      relationship with the donor, organ acceptance and life expectancy. Interview was
      performed I year after transplantation. A psychodiagnostic evaluation was also
      performed using a Minnesota Multiphasic Personality Inventory (MMPI) and a Human
      Figure Test. Psychosocial adaptation in everyday life following liver
      transplantation seemed good in most of the patients, whatever the indication for
      transplantation might be. It can he seen that by replacing the diseased organ a
      high percentage of oncological patients overcame their fear of cancer.

PMID- 8654606
TI  - Management of accidentally found pathological lymph nodes on routine screening
      mammography.
AB  - Normal lymph nodes in the anterior part of the axilla are readily seen on routine
      mammography. It is important, however, to recognize pathological lymph nodes,
      characterized by increased attenuation, high density, a round or irregular shape
      and lack of fat in the hilus, as they often indicate significant diseases. We
      examined the final diagnosis in 22 patients referred for clinical examination
      from a mammographic screening programme because of pathological lymph nodes
      without concomitant breast malignancy. Ten of them were found to have a malignant
      lesion, and one had sarcoidosis. None of the malignancies had been diagnosed
      before screening. Among women with abnormal but impalpable nodes, only one
      malignancy was found (in a woman with previous breast cancer), whereas nine of 13
      women with palpable nodes had malignancies. Seven malignant lymphomas were
      discovered, but among all 60 women of the age group in question with newly
      diagnosed lymphomas in the region, only 13 had pathological axillary nodes.
      Mammography cannot therefore be used as a screening method for lymphoma. We
      conclude that mammographically pathological lymph nodes in the axilla should be
      examined clinically and propose a simple programme for patient management.

PMID- 8654607
TI  - Integrin expression in breast cancer cytology: a novel predictor of axillary
      metastasis.
AB  - The integrins are heterodimeric transmembrane receptors of varying alpha and beta
      subunits that modulate cell adhesion to each other and to the extracellular
      matrix. Loss of integrin expression on primary breast cancer frozen sections
      measured by immunohistochemistry may be related to the presence of axillary
      metastasis. The clinical application of this finding would be increased if
      integrin expression could also be shown to be reliably measured on breast cancer
      cells obtained by fine needle aspiration cytology. Axillary operations may be
      planned as a single stage procedure from outpatients, and neoadjuvant therapy
      protocols may be developed without surgery to the axilla. Expression of the alpha
      1, alpha 2, alpha 3, alpha 6, alpha v, beta 1, beta 3 and beta 5 integrin
      subunits were measured by immunohistochemistry and immunocytochemistry in 58
      patients. Integrin measurement by both these methods were found to be closely
      associated using the kappa-test. Loss of expression of the alpha 1, alpha 2,
      alpha 3, alpha 6, alpha v, beta 1 and beta 5 integrin subunits measured by
      cytology and histology were each related to positive nodal status (chi(2) test).
      Measuring integrin expression on cytology is of clinical value and may prove to
      have prognostic significance.

PMID- 8654608
TI  - A CD44 variant exon 6 epitope as a prognostic indicator in breast cancer.
AB  - The CD44 variant exon 6 sequence is associated with metastasizing clones of rat
      pancreatic and mammary carcinoma. In human breast and colorectal carcinoma
      epitopes on the cell surface encoded by exon v6 have been shown to predict poor
      chances of survival. Breast cancers in 55 patients whose clinical follow-up was
      available for 6 to 8 years were immunophenotyped for the presence of the CD44
      exon v6 epitope and the results were correlated with survival. There was a
      difference in survival in the first 2.5 years following surgery: of the eight
      patients with negative tumours none had died during this period. The advantage of
      the negative group faded at later time points. However, the log-rank analysis
      revealed that differences between CD44 exon v6-negative and -positive groups were
      just below statistical significance. Studies with a larger number of patients are
      needed to establish the role of this CD44 variant as an early prognostic
      indicator in metastatic dissemination of breast cancer.

PMID- 8654609
TI  - Patients' psychological and cosmetic experience after immediate breast
      reconstruction.
AB  - Immediate breast reconstruction was introduced in 1990 at the Karolinska
      Hospital. A semistructured interview with 20 patients operated on between 1991
      and 1994 was undertaken to evaluate patients' degrees of satisfaction regarding
      pre-operative information, the need for psychological support and the opinion
      about the cosmetic outcome. During the pre-operative period, 18 patients felt
      that they were engaged in the decision-making whereas two patients felt that the
      surgeon alone was responsible for the decision. Regarding pre-operative
      information given, 7/20 were satisfied, 5/20 were mostly satisfied, 5/20 were
      unsatisfied and 3/20 had no opinion. During the early post-operative period (<3
      months), five patients felt anxiety or depression and 10 patients felt a need of
      additional psychological support. Within 6 weeks 19/20 patients returned to their
      occupational level. During the late post-operative period (>3 months), 19/20
      patients were generally satisfied with the reconstructive procedure. Eight
      patients thought the final result exceeded their initial expectations and 11/17
      accepted the new breast as an integrated part of their body. The results confirm
      that immediate breast reconstruction plays an important role in the surgical
      management of breast cancer. The need for pre-operative information and
      continuous psychological support in terms of an empathetic behaviour cannot be
      underestimated.

PMID- 8654610
TI  - Conservation treatment in subareolar breast cancers.
AB  - The results of centromammary conservation in 37 patients with 20 mm-median-size
      breast cancer, located in the subareolar area (SAA), with an infiltration of the
      nipple-areolar-complex (NAC) in 12 patients and a retraction in 24, are reported.
      Breast conservative surgery was initially performed in 30 patients; five patients
      were first treated with chemotherapy; two patients received initial tamoxifen.
      Surgery comprised tumorectomy plus axillary dissection, with complete resection
      of the NAC (20 patients), or partial resection (nine patients), or without
      resection (eight patients). Post-operatively, all patients received 50 Gy
      external radiotherapy, with an additional external electron boost in 13 patients;
      14 patients received adjuvant tamoxifen and two patients adjuvant chemotherapy.
      With a median follow-up of 49 months, one patient experienced a local failure and
      four a metastatic failure; 5-year overall actuarial survival and disease-free
      survival rates were 97%, and 75%. Cosmetic results were excellent in three
      patients, good in 25, and poor in seven. Breast conservation appears a satisfying
      treatment in small breast cancer located in SAA.

PMID- 8654611
TI  - The technique of sentinel node biopsy.
AB  - Fifty-five consecutive patients with localized melanoma and clinically definable
      regional nodal basin who had undergone sentinel node biopsy were reviewed. The
      technique described by Morton et al was applied with the following modifications:
      (1) injection of a larger amount of isosulfan blue dye initially, i.e. 3 ml, on
      the side of the primary lesion facing the nodal group; (2) elevation of the
      primary site, for 5 min; (3) incision over the regional nodal group and exposure
      of the nodes with sharp dissection; (4) identification of either the blue-stained
      node(s) or adjacent colored lymphatics first and demonstration of their
      continuity. The sentinel node was identified in 51/55 (93%); specifically 33/36
      (92%) in the axilla, 17/18 (93%) in the groin, and 1/1 in the supraclavicular
      area. It was positive in 12/51 (24%). Morton's technique of sentinel node biopsy
      is reproducible and can provide correct identification of the sentinel node in
      over 90% of the patients without the aid of radiolabelled materials.

PMID- 8654612
TI  - Differentiated thyroid cancer: surgical treatments of 190 patients.
AB  - Between 1968 and 1991, 190 patients (51 men, 139 women) with a mean age of 46.3
      years underwent surgery for differentiated thyroid cancer (148 papillary and 42
      follicular carcinomas). In 29.5% of the cases a concomitant goitre was
      histologically demonstrated. These patients were significantly older (mean: 54.7
      years) (P<0.01). The patients who had previously received cervical radiotherapy
      were significantly younger (mean: 29.7 years) (P<0.01). The analysis of
      historical and clinical findings failed to identify predictive factors of
      biological aggressiveness. Hyperthyroidism occurred in 5.7% of patients: this
      subgroup did not show any difference in clinical behaviour. Occult carcinoma
      (14.7%) and multifocality (9.4%) were found more frequently in the glands with a
      pre-existent goitre (P<0.05), but the clinical significance of these aspects is
      uncertain. The surgical treatment of choice was total thyroidectomy (135
      patients); more conservative procedures were performed only in younger patients
      with small lesions, without a difference in survival. Post-operatively a
      permanent recurrent laryngeal nerve injury occurred in four patients (2.1%) and
      nine patients (4.7%) required a permanent calcium supplementation. Among patients
      in follow-up (91.6%), those who underwent a total thyroidectomy were studied
      using a total body scinti scan. A poor prognosis was associated with age (>40
      years), pT, stage, pM and symptomatic metastases.

PMID- 8654613
TI  - Pelvic and periaortic pertioneal closure or non-closure at lymphadenectomy in
      ovarian cancer: effects on morbidity and adhesion formation.
AB  - The effects of pelvic and periaortic peritoneal closure or (non-closure) on
      morbidity and adhesion formation were prospectively compared in 102 patients with
      ovarian cancer who had undergone a pelvic and periaortic lymphadenectomy.
      Hysterectomy with bilateral salpingoophorectomy, bilateral pelvic and periaortic
      lymphadenectomy, omentectomy, appendectomy and lysis of pelvic adhesions for the
      standardization of initial adhesion scores was performed on all patients. The
      pelvic and periaortic peritoneum were re-approximated in group I (n = 50)
      patients, and left open in group II (n = 52) patients. The groups were similar
      for mean age, previous surgery, tumour histology and disease stage. Morbidity
      characteristics such as blood loss, transfusion rate, post-operative infectious
      and non-infectious complications, and total hospital stay were also similar.
      After six courses of PAC (cisplatin 50 mg/m(2), Adriamycin 50 mg/m(2),
      cyclophosphamide 500 Mg/M(2)) chemotherapy, all patients underwent a second-look
      laparotomy. Persistent cancer was detected in 49 of 102 (48.03%) patients.
      Adhesion scores were detected at the time of second-look laparotomy. Adhesion
      scores for group I (8.9 +/- 2.9) were significantly higher than the group II
      (peritoneum non-closure) (5.8 +/- 2.3) (P<0.01). Closing the pelvic and
      periaortic peritoneum did not effect morbidity, but leaving the pelvic and
      periaortic peritoneum open significantly decreased the adhesion formation.

PMID- 8654614
TI  - II--Cancer cachexia: treatments strategies.

PMID- 8654615
TI  - Is nutritional support in patients with cancer undergoing surgery beneficial?

PMID- 8654616
TI  - Ampullary somatostatinoma associated with von Recklinghausen's neurofibromatosis
      presenting as obstructive jaundice.
AB  - A case of von Recklinghausen's disease associated with a somatostatinoma of the
      pancreas causing obstructive jaundice is described. Discussion on the association
      of von Recklinghausen's disease with somatostatinoma is presented.

PMID- 8654617
TI  - Gastric carcinoma in siblings with Friedreich's ataxia.
AB  - Friedreich's ataxia is a hereditary neurological condition characterized by
      severe ataxia. We report the cases of two siblings with this condition, both of
      whom developed signet ring cell adenocarcinoma of the stomach at a young age.
      This association has not been previously described and it suggests the presence
      of an unidentified aberrant gene.

PMID- 8654618
TI  - An unusual case of spinal metastasis from a liposarcoma.
AB  - A 58-year-old man presented with spinal cord compression due to a metastatic
      liposarcoma of the thoracic spine. There was no evidence of vertebral bone
      involvement radiographically. This rare case is presented and its clinical
      features and diagnosis are discussed.

PMID- 8654619
TI  - VIII Symposium Mammographicum.

PMID- 8654620
TI  - Carcinoid tumour of the breast.

PMID- 8654621
TI  - Mini-symposium on breast cancer surgery.

PMID- 8654623
TI  - A skeleton in the closet? Bone health and therapy for endometriosis revisited.

PMID- 8654622
TI  - Estrogen biosynthesis--regulation, action, remote effects, and value of
      monitoring in ovarian stimulation cycles.
AB  - OBJECTIVE: To review current knowledge regarding estrogen biosynthesis, its
      regulation and action, specifically concerning local as opposed to remote effects
      of this hormone, and to examine the effectiveness and prognostic value of
      monitoring hormone concentrations and endometrial response in cycles of
      controlled ovarian hyperstimulation. DATA IDENTIFICATION AND SELECTION: Studied
      that relate specifically to estrogen biosynthesis, enzymatic pathways, estrogen
      receptor physiology, and the clinical aspects of estrogen monitoring were
      identified through literature and Medline searches. RESULTS: Folliculogenesis is
      the basic unit of ovarian activity, which has a dual purpose: oocyte maturation
      and steroid production. Steroidogenic granulosa and theca cells cooperate under
      gonadotropin control to produced estrogens by stimulating synthesis of
      steroidogenic enzyme messenger RNAs. Steroid synthesis is amplified further by
      local growth factors and follicular cell multiplication. Estrogen synthesis is
      directed by FSH, and only small amounts of LH are needed to amplify the
      follicular estrogenic potential. However, the growth of preovulatory follicles
      can proceed without LH, under FSH regulation only, even in the presence of low
      peripheral estrogen levels. Oocyte maturation and fertilization may proceed
      independently of ambient estrogen levels, leading to the assumption that estrogen
      exerts a minimal autocrine-paracrine function. The notable effect of follicular
      estrogen production is to promote adequate receptive endometrium for embryo
      implantation. Clinical treatment cycles may be monitored more effectively by
      evaluating end-organ response to estrogen rather than by evaluating absolute
      serum E2 concentrations or sonographic follicular measurements. CONCLUSION:
      Follicular estrogen production is regulated by a complex set of signals that
      synergize to produce optimal steroidogenesis. Most importantly, the effect of
      estrogen is truly an endocrine effect, as it prepares the endometrium for
      implantation. Therefore, the goal of effective treatment and monitoring
      strategies should focus on direct assessment of the biologic activity of estrogen
      as it optimizes endometrial receptivity in anticipation of subsequent
      implantation.

PMID- 8654624
TI  - The first giant step for males.

PMID- 8654625
TI  - Spontaneous reversibility of bone loss induced by gonadotropin-releasing hormone
      analog treatment.
AB  - OBJECTIVE: To verify if a 6-month period of hypoestrogenism due to chronic
      treatment with GnRH analogue (GnRH-a) causes irreversible bone loss in young
      women. DESIGN: Controlled clinical study in volunteer women. SETTING: Department
      of Obstetrics and Gynecology, University of Cagliari, Cagliari, Italy. PATIENTS:
      Twenty-eight women (mean age +/- SE 81.1 +/- 0.99 years) with endometriosis
      diagnosed by laparoscopy and 25 healthy, normally cycling women of the same age
      (28.3 +/- 1.14 years). INTERVENTIONS: In women with endometriosis, six SC
      implants of the GnRH-a compound, 3.6 mg goserelin acetate depot, were
      administered every 28 days starting within 15 days of laparoscopy. Compounds
      interfering with bone metabolism or hormonal formulations were not taken by
      control women during the entire period of the study. MAIN OUTCOME MEASURE:
      Evaluation of lumbar bone mineral density at the start of the study and 6, 12,
      and 30 months later. RESULTS: At the onset of the study, lumbar bone mineral
      density did not differ in women with endometriosis and control women. Lumbar bone
      mineral density values significantly decreased after 6 months of GnRH-a
      treatment. This reduction was still evident 6 months after GnRH-a interruption.
      However, 24 months after treatment withdrawal, bone mineral density reduction
      disappeared and bone mineral density values were completely superimposable (+/-
      O.4 percent) to those observed before treatment. In contrast, control women
      lumbar bone mineral density values did not change during the entire period of
      observation. CONCLUSIONS: These data suggest that GnRH-a treatment for 6 months
      is not associated with long-term effects on lumbar bone density.

PMID- 8654626
TI  - Ovarian response to recombinant human follicle-stimulating hormone in luteinizing
      hormone-depleted women: examination of the two cell, two gonadotropin theory.
AB  - OBJECTIVE: To evaluate the relative contribution of FSH to ovarian estrogen
      production. DESIGN: Nonrandomized, prospective study. SETTING: University of
      Toronto teaching hospital reproductive biology unit. PATIENTS: Five women who had
      been treated with depot GnRH agonist with hormonal add-back for 4 to 48 months
      and who were confirmed to be gonadotropin depleted by both bioassay and RIA.
      INTERVENTIONS: Subjects received 75 IU SC recombinant human FSH daily for 7 days
      followed by 150 IU daily for 7 days and 225 IU daily for the third week. MAIN
      OUTCOME MEASURE: Serum steroid determination and vaginal sonography for follicle
      size and endometrial thickness were performed serially and follicular fluid
      hormone levels were measured in two subjects. RESULTS: Bioactive LH and FSH
      activity were less than the detection limit of the assay (0.1 mIU/mL; conversion
      factor to SI units, 1.00 for LH and FSH) before recombinant FSH treatment in all
      five women. In all subjects, at least one preovulatory follicle developed by the
      end of two to three weeks. Endometrial thickness increased to between 7 and 9 mm
      in four women. Mean serum E2 in the five subjects increased from 17 pg/mL (range:
      5 to 33 pg/mL; conversion factor to SI unit, 3.671) at baseline to 230 pg/mL
      (range: 37 to 489 pg/mL) at the end of the study. Follicular fluid E2
      concentrations ranged from 44,296 to 69,367 pg/mL in the four follicles
      aspirated. CONCLUSION: Our results indicate that LH is not necessary for ovarian
      E2 production. We speculate that the granulosa cells, in the absence of
      detectable LH bioactivity, can use circulating adrenal androgens or constitutive
      or FSH-stimulated thecal androgens, to produce intrafollicular E2.

PMID- 8654627
TI  - Seasonal changes in pituitary function: amplification of midfollicular
      luteinizing hormone secretion during the dark season.
AB  - OBJECTIVE: To analyze the effect of season on the pulsatility of gonadotropin
      secretion in women living in an area with a large annual variability in daylight
      length. DESIGN: A prospective study. Pulse studies were carried out in each
      subject during both the dark and light season. SETTING: The gynecologic endocrine
      research unit of the University Central Hospital of Oulu. PARTICIPANTS: Eleven
      ovulatory, healthy women volunteering for the study. INTERVENTIONS: Serum samples
      were collected at 10-minute intervals for 6 hours on days 7 to 9 of the cycle.
      MAIN OUTCOME MEASURES: Serum LH and FSH concentrations were measured and the data
      were analyzed with an algorithm computer-based program. RESULTS: The mean area of
      LH pulses analyzed was significantly higher during the dark season than the light
      season (49.1 +/- 3.1 versus 38.5 +/- 1.7 mIU/mL; conversion factor to SI unit,
      1.00), while in the amplitude (1.9 +/- 0.1 versus 1.8 +/- 0.1 mIU/mL), number of
      pulses (5.2 +/- 0.3 versus 4.4 +/- 0.6), and the mean level (9.6 +/- 0.5 versus
      9.4 +/- 0.9 mIU/mL) the difference did not reach statistical significance. The
      number (5.2 +/- 0.5 versus 5.2 +/- 0.4,), amplitude (1.0 +/- 0.05 versus 1.1 +/-
      0.07 mIU/mL; conversion factor to SI unit, 1.00), area (29.9 +/- 2.4 versus 29.6
      +/- 3.1 mIU/mL), and the mean level of FSH (5.4 +/- 0.6 versus 6.0 +/- 0.8
      mIU/mL) during the dark and light seasons were identical, showing no seasonal
      variability. CONCLUSIONS: The results indicate increased pituitary LH secretion
      in the midfollicular phase during the dark season that may be related to
      increased melatonin secretion and decreased ovarian activity at this time of the
      year.

PMID- 8654628
TI  - Evidence for diminished midcycle ovarian androgen production in older
      reproductive aged women.
AB  - OBJECTIVE: To test the hypothesis that reproductive aging is associated with
      menstrual cycle-related decreases in androgen secretion. DESIGN: Comparison of
      cross-sectional data. SETTING: University teaching hospital. PATIENTS: Two groups
      of seven women were studied; midreproductive aged (19 to 37 years old) and older
      reproductive aged (43 to 47 years old). All patients were cycling regularly and
      had normal PRL and TSH. INTERVENTIONS: Patients underwent blood sampling during
      selected days of the menstrual cycle. MAIN OUTCOME MEASURE: After establishing
      the date of the midcycle surge, specimens were measured on selected days for
      androstenedione (A), total T, free T, and sex hormone-binding globulin (SHBG)
      using commercially available reagents. RESULTS: Sex hormone-binding
      concentrations did not vary across the menstrual cycle and did not differ between
      older and younger women. Total T did not differ significantly at any cycle stage
      between older and younger women. However, the midcycle rise in free T and A seen
      in younger women was consistently and significantly absent in the older women.
      CONCLUSIONS: In the absence of significant changes in SHBG associated with older
      reproductive age, the finding of diminished concentrations of both free T and A
      suggests that these hormones are produced in lesser quantity at midcycle in older
      women. Because the changes we noted depended on menstrual cycle stage, our
      findings suggest that an ovarian and not adrenal process is involved.

PMID- 8654629
TI  - Effects of a single contraceptive Silastic implant containing nomegestrol acetate
      on ovarian function and cervical mucus production during 2 years.
AB  - OBJECTIVE: To study the mechanism of action of Uniplant (South to South
      Corporation in Reproductive Health, Salvador, Brazil), a single Silastic capsule
      containing nomegestrol acetate (Lutenyl, Theramex, France) in women during 2
      years. DESIGN: Comparison between the hormonal levels, follicular development,
      cervical mucus (CM) production, and endometrial thickness in the menstrual cycle
      before implant insertion and at 1, 6, 12, 18, and 24 months after implant
      insertion. PARTICIPANTS: A total of 15 women of reproductive age were enrolled
      for the 1st year of use. Twelve of these women continued for a 2nd year of
      Uniplant use. MAIN OUTCOME MEASURES: Hormonal plasma levels were measured in
      control cycles and at 1, 6, 12, 18, and 24 months of Uniplant use. Cervical
      mucus, follicular development, and endometrial thickness also were evaluated.
      RESULTS: In this study, Uniplant blocks ovulation in 86 percent of cycles
      studied. Disturbances in follicular growth were observed also. Cervical mucus was
      scanty and viscous in all women during this study. Endometrial thickness was <8
      mm in all cycles studied. CONCLUSION: This study shows that Uniplant is a long
      acting contraceptive that probably acts at the hypothalamic-pituitary levels, on
      the ovary, on CM production, and on the endometrium. These properties suggest the
      use of Uniplant as a contraceptive agent, especially if one considers the lack of
      androgenic and metabolic effects and the maintenance of periodic bleeding similar
      to menstruation.

PMID- 8654630
TI  - Ectopic pregnancy: histopathology and assessment of cell proliferation with and
      without methotrexate treatment.
AB  - OBJECTIVE: To evaluate tubal morphology, trophoblast proliferation, and
      inflammatory reaction in response to methotrexate (MTX) treatment of ectopic
      pregnancy (EP). DESIGN: Nonrandomized controlled study. SETTING: Academic
      hospital. PATIENTS: Archival specimens from 10 EP unsuccessfully treated with MTX
      and 10 cases primarily treated by surgery. INTERVENTIONS: Ki67/hCG and Ki67/human
      placental lactogen double immunohistochemical methods were used to examine
      trophoblastic spread, placentation, hormone production, decidualization, vascular
      invasion, hemorrhage, rupture, and proliferative index of the cytotrophoblast. B
      and T-lymphocyte responses were evaluated by CD3 and CD20. RESULTS: Trophoblastic
      spread and placentation were confined to the tubal mucosa after MTX treatment,
      whereas invasion of the muscularis and subserosa was common in the controls. The
      proliferative index was reduced (19 percent versus 93 percent), although a high
      proliferative index was found in two of three cases complicated by rupture. Polar
      proliferation of Ki67-positive cytotrophoblast toward the implantation site was
      abolished in MTX-treated cases. Decidual reaction was not observed. No
      correlation was observed between the above-mentioned findings and gestational
      age, level of beta-hCG, dose of MTX, or interval to surgery. CONCLUSION:
      Trophoblastic spread, differentiation, and invasion were compromised by MTX
      treatment. Methotrexate seems to decrease cytotrophoblast proliferation. Whether
      a missing decrease in proliferation index reflects treatment failure awaits a
      larger population-based study.

PMID- 8654631
TI  - Intrafollicular insulin-like growth factor-II levels in normally ovulating women
      and in patients with polycystic ovary syndrome.
AB  - OBJECTIVE: To investigate intrafollicular insulin-like growth factor II (IGF-II)
      in patients affected with polycystic ovary syndrome (PCOS) in comparison with
      normal women. DESIGN: Insulin-like growth factor-II was determined in 103
      follicular fluids (FF) from normally ovulating women and in 102 FF from patients
      with PCOS. Ribonucleic acid was extracted from granulosa cells of follicles
      obtained from control and PCOS patients and from tissue from polycystic ovaries.
      SETTING: Procedures were performed in a university laboratory. PATIENTS: Twenty
      nine normally ovulating women and 19 patients with PCOS underwent ovulation
      induction for IVF-ET with LH-releasing hormone (LH-RH) analog and gonadotropins.
      Eleven of them, 4 to 8 months later, underwent ovulation induction with
      approximately the same dosage of gonadotropins plus a standard dosage of GH. MAIN
      OUTCOME MEASURES: Intrafollicular IGF-II, IGF-I, epidermal growth factor (EGF),
      transforming growth factor beta 2, (TGF-beta 2), inhibin, and steroids were
      evaluated by appropriate RIA, immunoenzymatic assay (EIA), and ELISA assays. The
      expression of the gene encoding IGF-II was analyzed by Northern blot. RESULTS:
      Intrafollicular IGF-II was lower in PCOS than in controls. Accordingly, IGF-II
      messenger RNA expression was lower in PCO than in normal granulosa cells. Several
      differences in FF IGF-I, EGF, inhibin, and TGF-beta 2 concentrations were
      observed between PCOS and controls. CONCLUSIONS: Both IGF-II and IGF-I were
      reduced in PCOS, confirming a possible role of an IGF imbalance in the
      development of this disease.

PMID- 8654632
TI  - Endometrial wavelike movements during the menstrual cycle.
AB  - OBJECTIVE: To qualify and quantify endometrial waves in regularly cycling women.
      DESIGN: A prospective transvaginal ultrasound study was performed throughout 23
      cycles of 16 healthy women. Wave type and wave frequency were evaluated. SETTING:
      Normal human volunteers in an academic research environment. PATIENTS: Sixteen
      healthy regularly cycling women. RESULTS: Of 23 cycles, 19 proved to be
      ovulatory. Five types of endometrial waves could be distinguished. Waves from
      cervix to fundus and opposing waves were seen predominantly periovulatorily.
      Waves from fundus to cervix were absent in the postovulatory phase. Endometrial
      wavelike activity was most pronounced in the periovulatory phase. CONCLUSIONS:
      Standardized qualification and quantification of endometrial waves, as described
      in this study, might shed new light on the underlying mechanisms in selected
      cases of hitherto unexplained subfertility.

PMID- 8654633
TI  - Ultrastructural aspects of endometrium in infertile women with septate uterus.
AB  - OBJECTIVES: To evaluate the endometrial surface morphology in patients with
      septate uterus and primary infertility in an attempt to throw light on the
      question of whether endometrial anomalies are involved in the pathogenesis of
      infertility in women with mullerian malformations. DESIGN: Endometrial biopsies
      were performed in eight women with septate uterus and primary infertility during
      hysteroscopy scheduled in the preovulatory phase of the cycle (when a follicle >
      17 mm was identified by ultrasonography and E2 levels were >200 pg/mL [conversion
      factor to SI unit, 3.671]). Two samples were obtained from each patient, one from
      endometrium covering the septum and the other from endometrium lining the lateral
      wall of the uterus. All specimens were examined by scanning electron microscopy.
      MAIN OUTCOME MEASURES: The number of glandular ostia, the ciliated:nonciliated
      cell ratio, and the number of cilia on ciliated cells were analyzed in
      endometrial specimen from both the covering of the septum and the corresponding
      uterine lateral wall. RESULTS: In five patients septal endometrium showed the
      following defective preovulatory changes with respect to endometrium of the
      lateral uterine wall: a reduced number of glandular ostia, irregular nonciliated
      cells with rare microvilli, incomplete ciliogenesis on ciliated cells, and
      decrease in the ciliated:nonciliated cell ratio (1:52 +/- 11 versus 1:21 +/- 8).
      CONCLUSIONS: Our results indicate a decrease in the sensitivity of endometrium
      covering the septa of malformed uteri to preovulatory hormonal changes. This
      could play a role in the pathogenesis of primary infertility in patients with
      septate uterus.

PMID- 8654634
TI  - Ultrasound studies of vascular and morphological changes in the human corpus
      luteum during the menstrual cycle.
AB  - OBJECTIVE: To determine changes in corpus luteum (CL) volume, echogenicity,
      vascularity, and P production relative to a positive test result for urinary LH
      and day 1 of next menses. SUBJECTS: Thirteen healthy volunteers (age 23 to 32
      years). INTERVENTIONS: All women underwent transvaginal ultrasonography on cycle
      day 11 and a urinary LH self-test was used daily. The plan was to rescan all
      women immediately after a positive test result and then at least every 48 hours
      (until day 6 of the next cycle); samples of peripheral blood were taken for
      analysis. MAIN OUTCOME MEASURES: The times of follicular rupture, a positive
      urinary LH test, and the start of menses; CL volume and echogenicity, maximum
      peak systolic velocity and minimum impedance, the circulating levels of serum P,
      E2, LH, and FSH. RESULTS: Nine women fulfilled criteria for an ovulatory cycle.
      There was a good correlation between peak systolic velocity, CL volume, and the
      concentration of serum P from day 4 to 10 after a positive LH test. Peak systolic
      velocity reached a maximum value between days 7 and 9 relative to a positive
      urinary LH test and started to decline from day 1 of menses minus 3, 4 days.
      CONCLUSION: Changes in peak systolic velocity from the time of a positive urinary
      LH self-test might be a useful adjunct for monitoring CL function.

PMID- 8654635
TI  - Clomiphene citrate with intrauterine insemination: is it effective therapy in
      women above the age of 35 years?
AB  - OBJECTIVES: To evaluate the influence of female age on clomiphene citrate (CC)
      with IUI therapy and to compare the efficacy of this therapy between patients
      with ovulatory and anovulatory infertility. SETTING: A university fertility
      clinic. SUBJECTS: Six hundred sixty-four CC with IUI cycles from 290 women aged
      22 to 48 years. MAIN OUTCOME MEASURES: Cumulative and clinical pregnancy rates
      (PRs). RESULTS: Both cumulative and clinical PRs declined substantially in women
      > 35 years when compared with those < or = 35 years. In addition, no difference
      in these parameters was noted between patients with ovulatory and anovulatory
      infertility diagnoses. The vast majority of pregnancies occurred within the first
      four treatment cycles, irrespective of age or ovulatory versus anovulatory
      infertility diagnoses. CONCLUSIONS: The age-related decline in clinical PR is
      most rapid beginning at the age of 35 years. For any given age group, CC with IUI
      therapy has similar cumulative and clinical PRs for both ovulatory and
      anovulatory infertility diagnoses. This therapy usually should not extend beyond
      four cycles. Couples should be counseled about the dramatic fall in PRs occurring
      beyond the age of 35 years.

PMID- 8654636
TI  - Donor insemination: a comparison of lesbian couples, heterosexual couples and
      single women.
AB  - OBJECTIVE: To compare single women, lesbian couples, and heterosexual couples
      receiving therapeutic donor insemination (TDI). DESIGN: Chart review followed by
      anonymous mail questionnaires to donor insemination recipients and their
      partners. SETTING: Infertility clinic in a university hospital. PATIENTS: One
      hundred fifteen women receiving donor insemination were identified by chart
      review. RESULTS: Too few single women responded for reliable comparison. Lesbian
      women were similar to married women in age, education, duration, and outcome of
      donor insemination. When considering alternatives to TDI, married women were more
      likely to consider adoption and lesbians were most likely to consider using a
      known semen donor or having intercourse with a man aware of their desire to have
      a child. Married couples were less likely to tell others, including the child,
      about conception by donor insemination. They were also less likely to support
      disclosing identifying data about the donor to the child. Lesbians were more
      likely to report stress in their relationships as a result of TDI. Married men
      were most likely to support mandatory counseling before TDI initiation.

PMID- 8654637
TI  - Effect of the postcoital test on the sexual relationship of infertile couples: a
      randomized controlled trial.
AB  - OBJECTIVE: To investigate the impact of the postcoital test (PCT) on the sexual
      relationship and functioning of infertile couples. DESIGN: Randomized controlled
      study. SETTING: University hospital. PATIENTS: New infertility patients were
      randomized to an infertility work-up with (PCT group) or without (non-PCT group)
      postcoital test as integral part of the investigation. INTERVENTION: Performance
      of the PCT. MAIN OUTCOME MEASURE: Both partners completed a questionnaire on
      their sexual relationship and functioning at the initial visit and after 3
      months. RESULTS: Of 500 consecutive new couples, 304 fulfilled inclusion criteria
      and 290 consented to participate (PCT group: 152; non-PCT group: 138). Answers to
      both the first and second questionnaire were obtained from 84 couples (PCT: 43;
      non-PCT: 41). After 3 months, couples in the PCT group were at least as satisfied
      with their sexual relationship as couples in the non-PCT group with little
      difference having occurred in the 3 months of investigation. CONCLUSION: Overall,
      the influence of the PCT on the sexual relationship of infertile couples is more
      positive than negative.

PMID- 8654638
TI  - Endometrial response to hormone replacement therapy as assessed by expression of
      insulin-like growth factor-binding protein-1 in the endometrium.
AB  - OBJECTIVE: To assess endometrial response to parenteral levonorgestrel in hormone
      replacement therapy by means of morphological criteria and immunohistochemical
      staining of insulin-like growth factor-binding protein-1 (IGFBP-1). DESIGN:
      Endometrial samples were collected from 35 postmenopausal women after 12 to 22
      months of continuous combined estrogen-progestin therapy. All subjects were
      treated with parenteral progestin. A group of 8 women was treated with a
      subdermal levonorgestrel-releasing implant, and 27 women had a levonorgestrel
      releasing intrauterine device (IUD). Sections of formalin-fixed paraffin-embedded
      biopsies were used for immunohistochemistry and after hematoxylin-eosin staining
      for routine histologic examination. RESULTS: Atrophic epithelium with pronounced
      decidual reaction in the stroma was detected by histologic examination in all
      endometrial samples obtained from 27 women treated with the levonorgestrel
      releasing IUD. In contrast, the endometrium was proliferative in seven of eight
      (87.5 percent) biopsies obtained from women treated with the levonorgestrel
      releasing implant. Immunoreactive IGFBP-1 was detected in decidualized stromal
      cells in all endometrial samples obtained during intrauterine levonorgestrel
      therapy, whereas only one of eight samples obtained from women treated with
      subdermal levonorgestrel exhibited weak staining for IGFBP-1. CONCLUSIONS: Our
      data show that both the morphological and biochemical response of post-
      menopausal endometrium to parenteral levonorgestrel was strikingly different,
      depending on the route of progestin administration, and that the decidual
      reaction and epithelial atrophy induced by intrauterine levonorgestrel were
      associated with expression IGFBP-1 in decidualized stromal cells.

PMID- 8654639
TI  - The age-related decline in female fecundity: a quantitative controlled study of
      implanting capacity and survival of individual embryos after in vitro
      fertilization.
AB  - OBJECTIVE: To determine strictly comparable rates per embryo of implantation and
      birth of a baby related to the woman's age, which would be representative of
      natural fertility at least in relative terms. DESIGN: Comparative study of IVF-ET
      results controlling for confounding variables including cause and duration of
      infertility, history of previous pregnancy, hormonal treatment, rank cycle of
      treatment, and numbers of embryos transferred and available. SETTING: University
      comprehensive fertility service. PATIENTS: All couples (n = 561) in their first
      cycle of treatment reaching oocyte collection, women with normal uterus and
      ovulatory cycles, and men with normal sperm. INTERVENTIONS: Standardized methods
      of pituitary desensitization, ovarian stimulation, and IVF-ET, and maximum of
      three embryos transferred. MAIN OUTCOME MEASURES: Oocytes, pregnancies, and live
      births per cycle; fertilization and cleavage rates; embryo implantation and live
      baby rates. RESULTS: The numbers of oocytes and consequent embryos declined with
      age but fertilization and cleavage rates rose slightly. Embryo implantation rates
      were reduced when no more than three embryos were available (9.3 percent),
      especially in women aged 35 to 39 years (6.2 percent) or older compared with four
      or more embryos (17.1 percent) but were equally low in all women over 40 years
      even with more embryos (6.1 percent). In the age bands 25 to 29, 30 to 34, 35 to
      39, and 40 to 44 years, the rates per embryo of implantation were 18.2 percent,
      16.1 percent, 15.3 percent, and 6.1 percent, respectively, and of a live baby
      were 15.7 percent, 12.1 percent, 12.0 percent, and 3.5 percent. CONCLUSIONS:
      Embryo implanting ability and survival decline gradually after 30 years of age,
      but by more than two thirds after 40 years and in younger women with reduced
      ovarian capacity.

PMID- 8654640
TI  - Comparison of reoperation for moderate (stage III) and severe (stage IV)
      endometriosis-related infertility with in vitro fertilization-embryo transfer.
AB  - OBJECTIVE: To evaluate the efficacy of reoperation for stage III or IV
      endometriosis-related infertility versus IVF-ET. DESIGN: Retrospective analysis.
      SETTING: In vitro fertilization-embryo transfer unit and tertiary infertility
      clinic. PATIENTS: Twenty-three couples with stage III or IV endometriosis-related
      infertility undergoing IVF-ET and 18 women undergoing reoperation for stage III
      or IV disease, both groups undergoing treatment after failed initial surgery to
      restore fertility. RESULTS: The cumulative pregnancy rate (CPR) after reoperation
      for stage III or IV endometriosis-related infertility after 3, 7, and 9 months
      was 5.9 percent, 18.1 percent and 24.4 percent, respectively. The cumulative PR
      after one and two cycles of IVF-ET with stage III or IV endometriosis was 33.3
      percent and 69.6 percent, respectively. The cumulative PR after one cycle of IVF
      ET was higher than with reoperation 33.3 percent versus 24.4 percent. After two
      cycles the cumulative PR was significantly higher than reoperation 69.6 percent
      versus 24.4 percent. The mean number of oocytes retrieved was 8.5 +/- 4.6, the
      mean number of embryos was 4.8 +/- 2.9, and the fertilization rate was 64 percent
      +/- 21.8 percent. The PR per cycle, per oocyte retrieval and per ET was 38
      percent, 42 percent, and 44 percent, respectively, with the implantation rate
      being 16 percent. The live birth rate per oocyte retrieval and per ET was 29.7
      percent and 34.4 percent, respectively. No statistically significant difference
      could be demonstrated with regard to the fertilization, implantation, nor
      pregnancy or live birth rates, as compared with IVF-ET outcome with tubal
      infertility. CONCLUSION: If initial surgery fails to restore fertility in
      patients with moderate (stage III) or severe (stage IV) endometriosis-related
      infertility, IVF-ET is an effective alternative; reoperation for asymptomatic
      patients offers little added benefit.

PMID- 8654641
TI  - Use of the flare-up protocol with high dose human follicle stimulating hormone
      and human menopausal gonadotropins for in vitro fertilization in poor responders.
AB  - OBJECTIVE: To analyze the effect of high dose human FSH in combination with hMG
      with a flare-up leuprolide acetate (LA) protocol in patients undergoing IVF at
      risk for a poor response. DESIGN: Prospective. SETTING: Free-standing ambulatory
      IVF center. PATIENTS: Two hundred eighty-four patients underwent a LA screening
      test for IVF. Patients with a lack of flare response were considered at risk for
      a poor response and underwent ovarian stimulation with the flare-up LA protocol
      in combination with high dose human FSH and hMG. RESULTS: The poor responder
      group was compared with the good responders on the flare-up LA protocol and to
      patients undergoing ovulation induction with a luteal phase LA protocol. There
      were 53 poor responder flare-up LA cycles, 177 good responder flare-up LA cycles,
      and 54 luteal phase LA cycles. The cancellation rate was higher in poor flare-up
      LA responders (11.3 percent) compared with good flare-up LA responders (1.1
      percent) and luteal phase LA cycles (1.8 percent). Peak E2 levels, number of
      oocytes, and number of embryos were significantly higher in the good flare-up LA
      responders. Fertilization rate was similar in all groups. Ongoing pregnancy rate
      per retrieval was 28 percent in good responders, 29 percent in poor responders,
      and 33 percent in luteal phase LA patients. Only one patient (0.4 percent) was
      hospitalized for severe ovarian hyperstimulation. CONCLUSION: The flare-up
      protocol with high-dose human FSH and hMG is a very good alternative for patients
      who are at high risk for a poor response. Although peak E2 and number of oocytes
      were significantly lower in this group, the patients who responded had the same
      fertilization and pregnancy rate as the good responders. Cancellation rate
      remains high in poor responders.

PMID- 8654642
TI  - Double-blind placebo controlled study: human biosynthetic growth hormone for
      assisted reproductive technology.
AB  - OBJECTIVE: To study whether the effect of cotreatment with human biosynthetic GH
      improves the outcome of poor IVF responders. DESIGN: A double-blind placebo
      controlled study using a GnRH agonist (GnRH-a) and gonadotropin in a "boost"
      flare-up protocol for ovarian stimulation together with either placebo, 4, or 12
      IU of human GH followed by oocyte retrieval and IVF-ET. PATIENTS: Twenty-two
      patients with previously demonstrated poor responses in at least two assisted
      reproductive technology cycles were recruited. INTERVENTIONS: Pretreatment and
      post-treatment blood samples and daily morning blood samples during ovarian
      stimulation were collected after an overnight fast. Human GH or placebo and GnRH
      a were administered SC; gonadotropin was administered IM. Oocytes were collected
      by ultrasound-guided transvaginal aspiration of follicles. Embryos were cultured
      in vitro and transferred transcervically. MAIN OUTCOME MEASURES: Serum E2, FSH,
      GH, insulin-like growth factor-I (IGF-1), IGF binding protein 1 (IGFBP-1), and
      IGFBP-3 concentrations. Number of FSH ampules, follicles, oocytes, embryos, and
      pregnancies. RESULTS: No improvement in cycle outcome was demonstrated with daily
      adjuvant human GH administration with either 4 or 12 IU. Serum IGF-I levels were
      highest in the 12 IU human GH group and lowest in the placebo group. Serum IGFBP
      3 levels increased 2 days after IGF-I levels in the 12 IU human GH group only.
      Serum IGFBP-1 levels were unchanged in all groups. CONCLUSION: Poor IVF
      responders do not benefit from cotreatment with human GH during their ovarian
      stimulation.

PMID- 8654643
TI  - Prediction of oocyte recovery rate by transvaginal ultrasonography and color
      Doppler imaging before human chorionic gonadotropin administration in in vitro
      fertilization cycles.
AB  - OBJECTIVE: To detect and quantify follicular vascularity before hCG
      administration in women undergoing IVF-ET. To correlate follicular vascularity
      with the oocyte recovery rate after direct follicle aspiration. DESIGN: A
      prospective, longitudinal study of consecutive women undergoing IVF-ET at the
      assisted conception unit of King's College Hospital, London and having at least
      20 follicles between the two ovaries on the day of hCG administration.
      INTERVENTIONS: An Acuson 128XP1O computed sonography system (Acuson Ltd.,
      Uxbridge, United Kingdom) was used to measure follicular diameters, indices of
      blood flow impedance (pulsatility index), peak systolic velocities (Vmax), and
      the proportion of follicles demonstrating pulsatile vascularity, i.e., follicular
      vascularity index. For the purpose of analysis, each woman was classified into
      one of four groups (I to IV) based on their oocyte recovery rate. RESULTS: The
      mean age, duration of infertility, Dmax, pulsatility index, and Vmax were similar
      in the four groups, but the follicular vascularity index was higher in the groups
      with the highest oocyte recovery rates. Furthermore, there was a positive
      correlation between the follicular vascularity index and the oocyte recovery
      rate. CONCLUSION: The follicular vascularity index correlates positively with
      oocyte recovery rates. Detection and quantification of follicular vascularity
      with color Doppler imaging can therefore be used to predict oocyte recovery rate
      and hence may be useful in determining the most appropriate time to administer
      hCG to optimize oocyte recovery rates.

PMID- 8654644
TI  - Influence of smoking on fertility in women attending an in vitro fertilization
      program.
AB  - OBJECTIVE: To investigate the influence of cigarette smoking of women on the
      fertilization and pregnancy rates obtained by IVF treatment. PATIENTS: One
      hundred ninety-seven infertile, otherwise healthy women who entered an IVF
      program for the first time. SETTING: Fertility unit at the Women's University
      hospital of the University of Ulm, Ulm, Germany. INTERVENTIONS: The study
      population consisted of 197 women (23 to 39 years old) who were divided into the
      following groups: nonsmokers (n = 68), passive smokers (n = 26), and active
      smokers (n = 103) according to the cotinine concentration measured in follicular
      fluid. The reason for infertility was strictly a tubal factor with apparently
      normal ovulatory cycles. To guarantee an objective recording of tobacco smoke
      exposure, the smoking habit was not determined by questionnaires, but by
      cotinine, the principal metabolite of nicotine. RESULTS: There were no
      significant differences in fertilization and pregnancy rates between the
      different groups. The E2 serum levels were decreased significantly in women who
      smoked when compared with the results obtained from nonsmokers and passive
      smokers. Overall, a strong negative correlation of the cotinine and E2 levels was
      observed (r = -0.65). CONCLUSION: The results suggest that there is no clinically
      detectable impairment of fertilization potential due to female smoking and that
      there is a greater influence on the outcome of IVF by other factors.

PMID- 8654645
TI  - Attitudes of in vitro fertilization and intrauterine insemination couples toward
      multiple gestation pregnancy and multifetal pregnancy reduction.
AB  - OBJECTIVE: To determine attitudes regarding multiple pregnancy and multifetal
      pregnancy reduction in couples embarking on gonadotropin therapy. DESIGN:
      Questionnaire given to couples initiating gonadotropin therapy. SETTING:
      University hospital-based infertility unit. PATIENTS: Twenty-seven couples
      undergoing IVF and 50 couples undergoing IUI. RESULTS: The groups' responses
      tended to be quite similar, with all groups reporting declining favorability
      ratings as the fetal order increased. The IUI group did feel more favorable than
      the IVF group toward all gestational outcomes and less favorable toward
      multifetal pregnancy reduction. A history of live births and length of
      infertility had no significant impact on the results. CONCLUSION: Couples
      undergoing gonadotropin therapy have an overall favorable attitude toward
      multiple gestational pregnancies of triplets or twins and an increased
      willingness to consider multifetal pregnancy reduction for quadruplets and more.

PMID- 8654646
TI  - Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
      normal men.
AB  - OBJECTIVE: To determine contraceptive efficacy of hormonally induced sperm
      suppression to severe oligozoospermia or azoospermia. DESIGN: Prospective,
      noncomparative contraceptive efficacy study. SETTING: Multicenter study in 15
      centers in nine countries. PARTICIPANTS: Three hundred ninety-nine normal,
      healthy, fertile men requesting a male contraceptive method. INTERVENTION: Weekly
      IM injection of 200 mg T enanthate. MAIN OUTCOME MEASURE: Incidence of
      pregnancies in efficacy when couples relied on T injections alone for
      contraception. RESULTS: Four pregnancies occurred during 49.5 person-years
      involving men with oligozoospermia (0.1 to 3 x 10(6)/mL) and none during 230.4
      person-years in azoospermic men: pregnancy rates 8.1 (95 percent confidence
      interval [CI] 2.2 to 20.7) and 0.0 (95 percent CI, 0.0 to 1.6) per 100 person
      years, respectively, or 1.4 (95 percent CI, 0.4 to 3.7) per 100 person-years for
      oligozoospermia and azoospermia (O to 3 x 10(6)/mL) combined. Pregnancy rates
      were related to sperm concentration. Inadequate suppression of spermatogenesis
      occurred in eight men and escape from suppression occurred in four.
      Discontinuations were due to personal reasons (50 men, cumulative annual life
      table rate 12.2 percent [95 percent CI, 9.1 percent to 16.1 percent]) and dislike
      of the injection schedule (21 men, 5.1 percent [95 percent CI, 3.2 percent to 7.9
      percent]). Thirty-five men discontinued for medical reasons (9.4 percent [95
      percent CI, 6.7 percent to 13.2 percent]), with no serious treatment-related side
      effects. After stopping injections, sperm output recovered; additionally,
      fertility was demonstrated in 33 couples. CONCLUSION: Suppression of
      spermatogenesis to azoospermia or severe oligozoospermia (< or = 3 x 10(6)/mL)
      induced by weekly T enanthate injections results in sustained, reversible
      contraception with good efficacy and minimal short-term side effects. New
      hormonal regimens with more convenient delivery and improved spermatogenic
      suppression would provide practical male contraception.

PMID- 8654647
TI  - Gonadal function and response to growth hormone (GH) in boys with isolated GH
      deficiency and to GH and gonadotropins in boys with multiple pituitary hormone
      deficiencies.
AB  - OBJECTIVE: [corrected] To evaluate spermatogenesis in patients with isolated GH
      deficiency and multiple pituitary hormone deficiencies. DESIGN: Treatment of
      isolated GH-deficient patients with recombinant human GH (weekly dose of 0.7
      IU/kg) for 5.3 +/- 0.4 (mean +/- SD) years and cotreatment of multiple pituitary
      deficient patients with GH at the same dosage for 8.0 +/- 0.4 years and hCG
      (2,000 IU, three times per week) and hMG (500 IU, two times per week) for 13.7 +/
      1.1 months. SETTING: Endocrine Pediatric Unit. PATIENTS: Eight patients affected
      by isolated GH deficiency and seven by multiple pituitary hormone deficiencies.
      MAIN OUTCOME MEASURES: Serum LH, FSH, and T, testicular volume, semen volume,
      density, count, and motility. RESULTS: Patients with isolated GH deficiency
      completed their pubertal development in 19.0 +/- 3.5 months and patients with
      multiple pituitary hormone deficiencies in 13.7 +/- 1.1 months. At the end of
      puberty, the two groups of patients had similar testicular volume, penis size,
      sperm concentration, motility, and morphology, although T levels and seminal
      volume were lower in isolated GH-deficient patients than in multiple pituitary
      deficient patients. CONCLUSIONS: The two groups of patients, treated specifically
      for their identified hormonal deficiencies, in the end had similar satisfactory
      reproductive results.

PMID- 8654648
TI  - Cigarette smoking and semen quality.
AB  - OBJECTIVE: To determine whether cotinine levels provide stronger evidence for an
      association between smoking and semen quality than the number of cigarettes
      smoked per day or years smoked controlling for potential confounders and effect
      modifiers. DESIGN: Cross-sectional study. SETTING: Male volunteers at the
      Reproductive Endocrinology-Fertility Laboratory. PARTICIPANTS: Eighty-eight men
      (ages 18 to 35 years) provided a semen, urine, and blood specimen and completed a
      self-administered questionnaire concerning smoking and demographic information as
      well as caffeine and alcohol consumption. Urine, blood, and semen cotinine levels
      were analyzed via RIA. MAIN OUTCOME MEASURE: Standard clinical semen analysis.
      RESULTS: Number of cigarettes smoked per day, years smoked, and log-transformed
      cotinine levels were associated negatively with semen quality (density, total
      count, and motility). The association was evident among men age > or = 22 years.
      For example, the correlation coefficient for the overall association between
      logged urine cotinine and logged sperm density was -0.23; those stratified by age
      were 0. 13 (age < 22 years) and - 0. 39 (age > or = 22 years). Potential
      confounders included in regression models did not diminish the associations.
      CONCLUSIONS: Smoking is associated with lowered semen quality.

PMID- 8654649
TI  - Fluorescence-labeled fucolectins are superior markers for flow cytometric
      quantitation of the human sperm acrosome reaction.
AB  - OBJECTIVE: To evaluate the binding of three fluorescein (FITC)-labeled fucose
      specific lectins, Anguilla anguilla agglutinin (AAA), Tetragonolobus purpureas
      agglutinin (TPA), and Ulex europaeus-1 agglutinin (UEA-1), to unfixed, acrosome
      intact and acrosome-reacted (AR) human sperm by flow cytometry and to compare the
      results with those found using FITC-labeled Pisum sativum agglutinin (PSA) and
      Arachis hypogaea agglutinin (PNA). DESIGN: The binding of five FITC-labeled
      lectins (PSA, PNA, AAA, TPA, and UEA-1) to capacitated, calcium ionophore A23187
      (CaI)-treated, or solvent-treated human sperm was quantitated by fluorescence
      flow cytometry. The binding of FITC-labeled lectins was compared with the binding
      of anti-CD46 monoclonal antibody (mAb), a marker for the human sperm AR. The
      effect of fucose alpha-1->2-, alpha-1->3-, and alpha-1->4-linked oligosaccharides
      to inhibit the binding of FITC-fucolectins to AR sperm also was tested. SETTING:
      University of Oklahoma Health Sciences Center, a tertiary care referral center.
      RESULTS: The average percentage of fluorescing, solvent-treated sperm labeled
      with PSA, PNA, AAA, TPA, or UEA-1 was 98 percent, 97 percent, 15 percent, 13
      percent, and 17 percent, respectively. The corresponding values for CaI-treated,
      lectin-labeled sperm were 98 percent, 98 percent, 89 percent, 91 percent, and 92
      percent, respectively. The increase in mean fluorescence intensity for the
      binding of the five lectins to CaI-treated versus solvent-treated sperm was 2.9-,
      6.4-, 34.5-, 22-, and 36.7-fold, respectively. The binding site of the
      fucolectins was confined to the equatorial segment of the AR sperm. High positive
      correlations were observed between the percentage of AR sperm detected using
      three FITC-labeled fucolectins (AAA, TPA, and UEA-1) and anti-CD46 mAb (r2 =
      0.87, 0.99, and 0.99, respectively). Fucolectin binding to AR sperm was sensitive
      to competitive inhibition by fucose alpha-1->2-linked lacto-N-fucopentaose I and
      fucoidan. CONCLUSIONS: Fucosylated glycans are expressed on AR human sperm.
      Fluorescence-labeled fucolectins markedly improved the signal:noise ratio in the
      detection of acrosomal loss of human sperm when compared with FITC-PSA or FITC
      PNA. Fluorescence-labeled fucolectins can be used as specific markers for flow
      cytometric quantitation of unfixed AR sperm in suspension.

PMID- 8654650
TI  - Adhesion formation from release of dermoid contents in the peritoneal cavity and
      effect of copious lavage: a prospective, randomized, blinded, controlled study in
      a rabbit model.
AB  - OBJECTIVES: To determine, in a rabbit model, whether peritoneal exposure to
      dermoid cyst material produces inflammation and adhesions above control levels
      and whether saline lavage reduces the degree of peritoneal reaction. DESIGN: A
      prospective, randomized, blinded, controlled study of adhesion formation. Thirty
      New Zealand white female rabbits were assigned randomly to five experimental
      groups: [1] laparoscopy with intraperitoneal injection of human dermoid material,
      [2] laparoscopy with intraperitoneal injection of human dermoid material and
      subsequent lavage to clear all visible dermoid material, [3] laparoscopy with
      saline lavage, [4] laparoscopy with intraperitoneal injection of human follicular
      fluid (antigenic control), and [5] laparoscopy alone. MAIN OUTCOME MEASURES: Six
      weeks after initial laparoscopy, inflammation and adhesions were scored in
      several categories via visual assessment (range 0 to 15) and histologic
      microscopic evaluation (range 0 to 24). Data were evaluated using Kruskal-Wallis
      and Mann-Whitney U nonparametric tests. RESULTS: For groups 1, 2, 3, 4, and 5,
      respectively, mean +/- SEM total inflammation-adhesion scores were 13.85 +/-
      0.55, 2.90 +/- 1.15, 0 +/- 0, 1.50 +/- 1.00, and 0 +/- 0 for clinical evaluation
      and 16.83 +/- 1.22, 7.33 +/- 1.76, 0 +/- 0,0 +/- 0, and 0 +/- 0 for histologic
      evaluation. Using nonparametric tests, significant differences were found between
      groups in clinical and histologic scores. CONCLUSIONS: Dermoid material produces
      a significant peritonitis. Results of the clinical evaluation demonstrate that
      saline lavage brings inflammation and adhesion formation close to control levels.
      However, results of the histologic evaluation suggest that the decrement in
      inflammation as a result of lavage may be less dramatic than that found by
      clinical evaluation.

PMID- 8654652
TI  - Reproductive outcome after tubal reversal in women 40 years of age or older.
AB  - OBJECTIVE: To determine the reproductive outcome of women who received a
      microsurgical tubal anastomosis operation at age 40 years or older. DESIGN:
      Multicenter retrospective cohort study. SETTING: Four university teaching
      hospitals. PATIENTS: Fifty-two women having undergone tubal sterilization
      reversal at age > or = 40 years. MAIN OUTCOME MEASURES: Pregnancy and live birth
      rate. RESULTS: Of the 52 women, 10 were lost to follow-up. Of those traced, 18 of
      42 (42.8 percent) conceived. Of those 18, 6 patients had a live birth, 10
      patients had a first trimester spontaneous abortion, 1 patient had an ectopic
      pregnancy, and 1 patient had an elective termination. Overall, the live birth
      rate was 14.3 percent, spontaneous abortion rate was 23.8 percent, and ectopic
      pregnancy rate was 2.4 percent. CONCLUSIONS: Microsurgical tubal anastomosis is a
      justifiable alternative to IVF-ET in women age 40 years or older.

PMID- 8654651
TI  - Pharmacokinetics and endometrial effects of the vaginal administration of
      micronized progesterone in an oil-based solution to postmenopausal women.
AB  - OBJECTIVE: To study the pharmacokinetics of the transvaginal absorption of 100 mg
      micronized P from an oil-based solution in postmenopausal women before and after
      the estrogenization of the vaginal mucosa and to evaluate the endometrial effects
      of 10 days of once daily P vaginal administration. DESIGN: Prospective clinical
      trial. SETTING: University Medical School. PATIENTS: Nine postmenopausal women
      undergoing hormone replacement therapy. INTERVENTIONS: A micronized P (100 mg)
      oil-based solution currently available on the market for IM use was administered
      vaginally by means of a Teflon cannula without the aid of a speculum.
      Subsequently, the women received 4 weeks 0.1 mg/d transdermal E2 treatment
      combined on the last 10 days with the once daily vaginal administration of P in
      the same way as before. MAIN OUTCOME MEASURES: At the first (before estrogen) and
      second (during estrogen therapy) P administrations, P serum levels were measured
      at time 0, and then after 15, 30, 45, 60, 120, 240, 480, and 1440 minutes.
      Endometrial samples were collected at the end of treatment. RESULTS: After the
      first administration, a mean Cmax of 5.40 +/- 0.92 ng/mL (mean +/- SD) was
      reached at a Tmax of 45 minutes (range 30 to 480 minutes). The serum
      concentrations returned to their initial values after 24 hours. The second P
      administration reached a mean Cmax of 5.30 +/- 1.04 ng/mL at a Tmax of 60 minutes
      (range 30 to 240 minutes); after 24 hours, the serum P levels still were
      significantly higher than at baseline and at the same time after the first
      administration. None of the women complained of significant vaginal losses. No
      signs of vaginal phlogosis or irritation were observed. In all subjects,
      histologic evaluation showed clear endometrial secretory changes. CONCLUSIONS:
      The daily vaginal administration of one vial of micronized P for 10 days allowed
      useful serum P levels to be reached, especially after estrogen therapy, and
      induced clear secretory changes in the endometrium.

PMID- 8654653
TI  - Presentation of a mullerian anomaly with outflow obstruction after tubal
      ligation.
AB  - OBJECTIVE: To report an unusual presentation of a patient with unicornuate uterus
      and a noncommunicating functional rudimentary horn and discuss related patient
      management issues. SETTING: University hospital. PATIENT: A 27-year-old woman who
      presented with cyclic abdominal pain after a postpartum tubal ligation.
      INTERVENTION: Diagnostic studies followed by a laparotomy and resection of the
      rudimentary horn. RESULTS: Resolution of patient's symptoms. CONCLUSIONS:
      Patients with a unicornuate uterus and a rudimentary horn recognized for the
      first time during a tubal ligation require individualized management depending in
      part on the precise nature of the horn.

PMID- 8654654
TI  - The effect of routine breast examination on serum prolactin levels.
AB  - OBJECTIVE: To evaluate the effect of a routine breast examination on serum PRL
      levels. DESIGN: Prospective clinical study. SETTING: University-based
      reproductive endocrinology unit. PATIENTS: Eleven nonlactating, euprolactinemic
      women of reproductive age with a history of regular menstrual cycles and
      currently taking no medications. INTERVENTIONS: Breast examination using standard
      technique. MAIN OUTCOME MEASURE: Changes in serum PRL levels after breast
      examination. RESULTS: Baseline PRL levels ranged from 3.64 to 19.23 ng/mL (mean
      7.17 ng/mL; conversion factor to SI unit, 1.00). There were no significant
      increases in PRL levels after breast examination, with mean PRL levels after 15,
      30, and 45 minutes of 6.59, 6.84, and 6.45 ng/mL, respectively. CONCLUSION:
      Routine breast examination does not alter acutely serum PRL levels in normal
      women.

PMID- 8654655
TI  - Does large loop excision of the transformation zone of the cervix predispose to
      the development of antisperm antibodies in women?
AB  - OBJECTIVE: To determine whether large loop excision of the transformation zone of
      the uterine cervix for cervical intraepithelial neoplasia predisposes to the
      development of female isoimmunity to human spermatozoa. DESIGN: A prospective,
      controlled study. SETTING: Colposcopy and Andrology units at the John Radclife
      and Churchill Hospitals, Oxford, United Kingdom. INTERVENTIONS: Serum samples
      were collected from 33 women before large loop excision of the transformation
      zone of the cervix and repeated at a minimum time interval of 4 months after the
      procedure. Women were questioned regarding the procedure and subsequent
      reproductive function. A control population of 30 women not undergoing cervical
      surgery also underwent serial serum screening for antisperm antibodies. MAIN
      OUTCOME MEASURE(S): The detection of serum antisperm antibodies by flow
      cytometry. RESULTS: None of the serum samples before large loop excision of the
      cervical transformation zone had clinically significant levels of antisperm
      antibodies. There was, however, a significant rise in antisperm antibody levels
      in women following large loop excision of the transformation zone. Apparent risk
      factors for the development of antisperm antibodies included a short duration of
      sexual abstinence and the use of nonbarrier contraception after surgery. There
      was no rise in antisperm antibody levels in the control population. CONCLUSION:
      Large loop excision of the transformation zone of the cervix is a risk factor for
      the development of antisperm antibodies in women. Women should be advised to use
      barrier contraception or avoid sexual intercourse until complete healing of the
      cervix has occurred.

PMID- 8654656
TI  - Intrafollicular hemodynamics before the administration of human chorionic
      gonadotropin in women at risk of the ovarian hyperstimulation syndrome.
AB  - OBJECTIVE: To test the hypothesis that alteration of intrafollicular hemodynamics
      precedes the ovarian hyperstimulation syndrome (OHSS). DESIGN: A prospective
      study. SETTING: The IVF unit and the Doppler imaging laboratory of King's College
      Hospital, London. PATIENTS: Twenty-four women undergoing IVF and considered to
      have an exaggerated response to ovarian stimulation and hence at risk of OHSS.
      INTERVENTIONS: Transvaginal Doppler imaging of the intrafollicular blood flow was
      performed before hCG administration to determine the indexes of intrafollicular
      hemodynamics. MAIN OUTCOME MEASURES: Moderate or severe OHSS. RESULTS: There was
      no statistically significant difference in mean age (32.63 +/- 1.77 versus 31.48
      +/- 3.87), duration of infertility (6.00 +/- 2.19 versus 5.29 +/- 2.73), maximum
      peak systolic velocity (0.25 +/- 0.16 versus 0.26 +/- 0.21 m/s), mean of six
      maximal peak systolic velocity (0.15 +/- 0.04 versus 0.21 +/- 0.10), minimum
      pulsatility index (0.76 +/- 0.26 versus 0.59 +/- 0.23), mean of six minimal
      pulsatility indexes (0.89 +/- 0.30 versus 0.79 +/- 0.14), minimum resistance
      index (0.47 +/- 0.06 versus 0.41 +/- 0.10), and mean of six minimal resistance
      indexes (0.56 +/- 0.05 versus 0.53 +/- 0.06) of intrafollicular blood flow
      between the women who developed moderate or severe OHSS and matched controls.
      CONCLUSION: Measurement of intrafollicular hemodynamics before hCG administration
      does not predict the development of the OHSS.

PMID- 8654657
TI  - Fertilization after intracytoplasmic sperm injection with cryopreserved
      testicular spermatozoa.
AB  - OBJECTIVE: To assess the possibility of cryopreserving testicular tissue
      extracted sperm for intracytoplasmic sperm injection (ICSI). DESIGN: A report of
      two cases. Our study was approved by the Ethical Committee at the Instituto
      Valenciano de Infertilidad. SETTING: In vitro fertilization program at the
      Instituto Valenciano de Infertilidad. PATIENTS: Two azoospermic patients with
      severe spermatogenic failure but with focal spermatogenesis on testicular
      biopsies. In both cases, a first ICSI attempt with fresh testicular biopsy
      extracted sperm was unsuccessful. INTERVENTIONS: Cryopreservation of testicular
      spermatozoa in 100-micro L "pills." Intracytoplasmic sperm injection with thawed
      testicular spermatozoa. MAIN OUTCOME MEASUREMENTS: Fertilization rate, cleavage
      rate, embryo quality, clinical pregnancy. RESULTS: Fertilization rates were 36
      percent and 100 percent after ICSI with fresh testicular spermatozoa, and 63
      percent and 57 percent after ICSI with cryopreserved testicular sperm. In both
      cases, cleavage rates and embryo quality were similar when using fresh and
      cryopreserved testicular spermatozoa. No clinical pregnancies were achieved.
      CONCLUSION: High fertilization rates can be obtained after ICSI with frozen
      thawed testicular tissue extracted spermatozoa. Cryopreservation of testicular
      sperm may avoid repetition of testicular biopsies in azoospermic patients in whom
      the only source of spermatozoa is the testicle.

PMID- 8654658
TI  - Impact of in vitro fertilization culture media on peroxidative damage to human
      spermatozoa.
AB  - OBJECTIVE: To compare different culture media for their effects on sperm motility
      and lipid peroxidation. DESIGN: The ability of four different culture media to
      sustain the motility of human spermatozoa during an overnight incubation was
      examined in relation to the induction of lipid peroxidation. The role of
      transition metals in the genesis of peroxidative damage was investigated in
      experiments involving the addition of iron or the chelating reagent
      ethylenediamine tetra acetic acid (EDTA). SETTING: Academic research institute.
      MAIN OUTCOME MEASURES: The generation of malondialdehyde and 4-hydroxyalkenals
      after the addition of a ferrous ion promoter and the measurement of sperm
      motility. RESULTS: Spermatozoa incubated in Ham's F-10 medium (GIBCO, Paisley,
      Scotland) exhibited a marked loss of motility in association with a significant
      increase in peroxidative damage. Addition of EDTA to Ham's F-10 medium
      significantly reduced the degree of lipid peroxidation and induced a simultaneous
      increase in sperm motility. CONCLUSIONS: Ham's F-10 medium is a suboptimal medium
      for the long-term culture of human spermatozoa because it induces peroxidative
      damage and a concomitant decline of sperm motility.

PMID- 8654659
TI  - AN electronic bulletin board for instruction in reproductive endocrinology in a
      residency in obstetrics and gynecology.
AB  - OBJECTIVE: To explore the role of an electronic bulletin board as a means of
      computer-based learning in reproductive endocrinology for residents in obstetrics
      and gynecology. DESIGN: An electronic bulletin board was networked to all
      residents to present a formal lecture series in reproductive endocrinology and an
      informal question, answer, and discussion session after each lecture. Ten
      lectures were presented, one each month, throughout the academic year followed by
      question, answer, and discussion sessions. All lectures could be stored in an
      electronic file folder or printed as hard copy for review. A questionnaire was
      distributed at the conclusion of the project to assess previous resident
      experience with computers, resident response to, and utilization of the bulletin
      board. SETTING: A residency program in obstetrics and gynecology in a major
      medical center. PARTICIPANTS: Twenty-four residents in a 4-year program. MAIN
      OUTCOME MEASURES: Previous computer experience, ease of use, resident
      participation, and satisfaction with the bulletin board. RESULTS: Sixty-five
      percent of the residents considered themselves computer literate and 33 percent
      previously had taken a course in computer technology. Computer experience in word
      processing, spreadsheet, and database management was related by 55 percent, 40
      percent, and 25 percent of the residents, respectively. Ninety-five percent of
      the residents accessed the bulletin board for the lectures and found this system
      a convenient means of review. Sixty percent reviewed the lectures and stored them
      in an electronic file folder for later review. Forty percent printed the lecture
      on hard copy. On a scale of 1 to 5 (1 = lowest; 5 = highest), overall resident
      satisfaction was high at 4.5. CONCLUSION: Our data suggest a potential role for
      electronic bulletin boards as a complement to standard teaching protocols in
      resident education. The relative ease of use and satisfaction suggest that these
      techniques are feasible and offer an effective method of on-line instruction.

PMID- 8654660
TI  - Laparoscopic-assisted transvaginal metroplasty for the treatment of bicornuate
      uterus: a case study.
AB  - OBJECTIVE: To introduce a combined laparovaginal metroplasty approach to the
      treatment of bicornuate uterus. DESIGN: Case report. SETTING: Private community
      hospital. PATIENT: A nulliparous patient with three recurrent spontaneous
      midtrimester abortions and a double uterus on hysterosalpingogram was evaluated
      laparoscopically. INTERVENTIONS: A laparoscopic-assisted transvaginal wedge
      metroplasty for the surgical correction of a symptomatic bicornuate uterus was
      performed. Intraoperative hysteroscopy also was used. MAIN OUTCOME MEASURES: Term
      pregnancy, uterine integrity. RESULTS: Hysteroscopic transillumination of the
      uterine horns delineated the uterine cavities while a laparoscopic wedge incision
      was initiated with a unipolar needle. The uterus was delivered through a
      posterior colpotomy, the wedge excision and uterine unification were completed
      transvaginally, the uterus was replaced into the pelvis, and the colpotomy was
      closed. The patient subsequently became pregnant, carried to term without
      complications, and delivered a healthy infant by cesarean section. The
      metroplasty scar was noted to be intact. CONCLUSIONS: Laparoscopic-assisted
      transvaginal metroplasty is a logical and useful minimally invasive alternative
      to laparotomy for the treatment of symptomatic bicornuate uterus and has
      potential utility for the treatment of complicated septate uterus and the
      correction of uterine perforation not amenable to laparoscopic suturing occurring
      during hysteroscopic septal resection.

PMID- 8654661
TI  - "Leveling the playing field".

PMID- 8654662
TI  - Not all assays are equal.

PMID- 8654663
TI  - Parallel induction of cecropin and lysozyme in larvae of the silkworm, Bombyx
      mori.
AB  - Lysozyme activity in the hemolymph of Bombyx mori increased in parallel with
      cecropin activity after injection of the larvae with soluble peptidoglycan or UV
      killed bacteria. The lysozyme and cecropin A genes were expressed in parallel in
      the fat body after injection of peptidoglycan as detected by northern blot
      hybridization. The elicitor specificity for lysozyme induction was identical to
      that for cecropin, suggesting a common mechanism for recognition of bacteria and
      following signal transduction introducing to the simultaneous synthesis of
      cecropin and lysozyme. Bacterial cells killed by UV-irradiation were also
      effective as elicitor when added to the fat body culture, suggesting that
      phagocytosis of bacteria by hemocytes may not be an essential process for the
      induction of antibacterial protein synthesis in the silkworm.

PMID- 8654664
TI  - Evidence for a family of schistosome glycan-binding lectins in Biomphalaria
      alexandrina.
AB  - A novel family of isolectins that selectively recognize a schistosome-associated
      fucosyllactose determinant was identified in the hemolymph of Biomphalaria
      alexandrina, a snail vector of Schistosoma mansoni. Three lectins of this family
      were purified by serial affinity chromatography on a column of L-fucose and
      elution with a gradient of 0.1-1 M L-fucose (designated BaSII and BaSIII),
      followed by a column of D-glucose and elution with 0.3 M D-glucose (designated
      BaSI). Assessment of the structural characteristics by one- and two-dimensional
      gels indicated that, inspite of similarities in native molecular weights, the
      three lectins were tetramers of noncovalently-associated subunits that were of
      different sizes and pIs in BaSI, and of equal size but distinct pIs in BaSII and
      BaSIII. Comparisons of two-dimensional gels of the glycosylated and
      deglycosylated forms were consistent with the presence of an invariant alpha
      subunit (13.2 kDa, pI 7.2) constituting the three deglycosylated lectins, which
      associates with other subunits unique to each lectin, namely a beta subunit (10.1
      kDa, pI 5.8) in BaSI, an alpha 1 subunit (13.2 kDa, pI 6.8) in BaSII and BaSIII,
      and an alpha 2 subunit (13.2 kDa, pI 7.0) in BaSIII. Each of these subunits is
      subjected to differential post-translational N-linked glycosylations, which
      accounts for the additional heterogeneity expressed by the glycosylated lectins.
      Based on miracidial glycoprotein binding and inhibition assays, the three lectins
      exhibited optimum binding at similar pH and temperature, but were distinct in
      their binding affinities towards the fucose moiety constituting the
      fucosyllactose target. These observations indicate that an oligomorphic family of
      recognition molecules may have evolved to regulate the snails' response to
      schistosomes.

PMID- 8654665
TI  - Proliferation of undifferentiated blood cells from the solitary ascidian, Ciona
      intestinalis in vitro.
AB  - The proliferative responses of the cytotoxic blood cell population of the
      solitary ascidian, Ciona intestinalis, were investigated by autoradiography and
      tritiated thymidine (3H-TdR) incorporation following treatment with mitogens or
      co-culture with allogeneic cells in vitro. A small number of mitotic figures were
      seen in untreated circulating blood cells and pulse labelling with 3H-TdR showed
      that only the undifferentiated "lymphocyte-like" cells within the enriched
      cytotoxic cell population undergo spontaneous cell division and DNA synthesis in
      the circulation. Treatment of the cells, cultured for 4 days, with concanavalin A
      (con A), phytohaemagglutinin-B (PHA-B) or lipopolysaccharide (LPS) produced
      significantly increased 3H-TdR incorporation, although there were differences in
      the sensitivity of the cells to mitogen concentration. Significantly enhanced
      proliferation was also observed following incubation with mitomycin C-treated
      cells from allogeneic individuals. These results show that the cytotoxic blood
      cell population of C. intestinalis is capable of mitogen-induced proliferation as
      well as mixed lymphocyte-type responses and therefore shares some proliferative
      characteristics with vertebrate lymphocytes.

PMID- 8654666
TI  - Immunoregulation in fish II: intermolecular-induced suppression of antibody
      responses studied by haptenated antigens in atlantic salmon (Salmo salar L).
AB  - Here we report evidence for T cell dependent intermolecular-induced suppression
      of antibody responses in fish, using a panel of T cell dependent (TD) and T cell
      independent (TI) hapten-carrier antigens. Atlantic salmon were immunized
      intraperitoneally either with protein antigens: Limulus polyphemus hemocyanin
      (LPH), chicken gammaglobulin (CGG), A. salmonicida surface A-layer protein
      (ALPAsal) or lipopolysaccharide (LPS) antigens isolated from A. salmonicida and
      Escherichia coli. The various antigens were given as a mixture of the native and
      haptenated (4-hydroxy-3-iodo-5-nitrophenyl-acetic acid, NIP; 2,4,6-trinitrophenyl
      acetic acid, TNP; fluorescein-5-iso-thiocyanate, FITC) forms. The salmon immune
      system responded to the antigen mixtures by eliciting high anti-hapten titers
      whereas the antibody titers against protein determinants were low (suppress 65
      95%) as determined by ELISA. The suppression was induced between haptens (NIP and
      FITC) and between heterologous antigens (NIP-CGG and LPH) indicating that the
      mechanisms involved were non-specific. Moreover, suppression was induced by TD
      antigens only, indicating that the mechanism was T cell dependent. Injection of
      antigen mixtures containing variable amounts of the competing antigens showed
      that the kinetics of suppression was dose-ratio and dose dependent. In a time
      course study it was found that the suppressed anti-LPH response was unchanged
      until native LPH was injected almost 2 years after the primary immunization,
      showing that permanent tolerance had not been induced. Sequential immunization
      showed that the antibody response was most sensitive to suppression during the
      initial 10 days after immunization. Moreover, the carrier antigen was also able
      to induce suppression of hapten epitopes, but only if the anti-carrier response
      was allowed to develop for 14 days before the hapten-carrier antigen was
      injected. This shows that AIS in fish is elicited as a result of the immune
      response to the dominant antigen, and can be induced against either antigens if
      the temporal order of administration is reversed. A possible model for AIS as a
      normal immunoregulatory process in fish is proposed and discussed.

PMID- 8654667
TI  - The development of peripheral TNP-tolerance and suppressor function in Xenopus
      laevis, the South African clawed toad.
AB  - In adult Xenopus laevis, inducer- and effector-suppressor functions are located
      in the spleen. These peripheral suppressor functions must be established at this
      location near the end of metamorphosis, since both functions are in the thymus in
      premetamorphic and in developmentally-blocked metamorphosing larvae. This study
      examined whether TNP-conjugated self-antigens resulting from exposure to
      trinitrobenzene sulfonic acid (TNBS), will stimulate TNP-tolerance in
      premetamorphic, metamorphic, and in developmentally-blocked metamorphosing
      larvae. Premetamorphic and developmentally-blocked larvae produce little TNP
      tolerance or peripheral suppressor function. However, when TNBS exposure includes
      the late stages of the metamorphic period, both TNP-tolerance and splenic anti
      hapten suppressor function are demonstrable. Removal of suppressor function with
      cyclophosphamide prevents expression of tolerance, thus, they are functionally
      related. Suppressor function and tolerance both differentiate during the late
      metamorphic stages when new adult antigens are being expressed and incorporated
      into a library of self.

PMID- 8654668
TI  - Identification of cDNA clones encoding HMG 2, a major protein of the mexican
      axolotl hydrocortisone-sensitive thymocytes.
AB  - We have identified and analyzed cDNA clones encoding a major 26 kDa protein of
      the HMG1-2 family which is abundant in the cytoplasm and nucleus of axolotl
      hydrocortisone-sensitive thymocytes. The axolotl HMG2 protein is very similar to
      proteins belonging to the HMG1-2 family, from teleost fish to mammals. All the
      molecular features of the HMG1-2 proteins are conserved, including the high
      proportion of basic and aromatic residues, and the characteristic acidic C
      terminus tail. The 3'-untranslated region of the HMG2 axolotl cDNA is also
      similar to the avian and mammalian HMG2 3'-UT sequences, suggesting that some
      selective events have acted at the DNA level to conserve this region, which could
      be important in the differential expression of the HMG1 and HMG2 genes. The
      axolotl HMG2 protein contains the two well conserved HMG boxes which are thought
      to be the DNA-binding domains of the molecule. Axolotl thymocytes and spleen
      cells contain almost identical amounts of HMG2 mRNAs but HMG2 polypeptide is
      undetectable in spleen cells using anti-26 kDa antibodies. The reason for the
      accumulation of HMG1-2 molecules in vertebrate hydrocortisone-sensitive
      thymocytes is discussed, as well as their possible role in apoptosis.

PMID- 8654669
TI  - MHC expression in nonlymphoid tissues of the developing embryo: strongest class I
      or class II expression in separate populations of potential antigen-presenting
      cells in the skin, lung, gut, and inter-organ connective tissue.
AB  - We define expression of major histocompatibility complex (MHC) antigens in the
      nonlymphoid tissues of the developing rat. Antibodies to class I heavy and light
      chains (b2-m), and to class II MHC proteins were used. Strongest MHC expression
      was by individual cells in the skin, lung, gut, and inter-organ connective
      tissue. The class I+ and class II+ cells were distinct populations, differing in
      morphology, distribution, and expression of macrophage-associated antigens. A
      nonimmunologic role for MHC proteins in development has been proposed. Yet the
      distributions and antigenic profiles lead us to emphasize immunologic functions
      that may be served by the early presence of MHC+ cells outside the forming
      lymphoid organs. Potential contributions to establishment of extrathymic or
      maternal/fetal tolerance are discussed. Localization of strongest MHC expression
      to individual connective tissue cells of the developing organs, rather than
      parenchymal cells, is of clinical relevance to transplantation of fetal tissue.

PMID- 8654670
TI  - Mechanism of inhibition of hepatic gluconeogenesis by bacterial endotoxin: a role
      for nitric oxide?

PMID- 8654671
TI  - Hepatic inducible nitric oxide synthase: regulation and function.

PMID- 8654672
TI  - Effects of endotoxin on lipid metabolism.
AB  - Endotoxin, via cytokines, induces marked changes in lipid metabolism which are
      now considered part of the acute phase response. The endotoxin induced
      hyperlipidemia may represent a nonspecific immune response that can decrease the
      toxicity of a variety of harmful biological and chemical agents and serve to
      redistribute nutrients to cells important in host defense. The endotoxin induced
      changes in lipid metabolism may therefore be beneficial.

PMID- 8654673
TI  - Muscle protein metabolism during sepsis.

PMID- 8654674
TI  - Role of nitric oxide in the vascular dysfunction of septic shock.

PMID- 8654675
TI  - Cell signalling events involved in mediating the induction of nitric oxide
      synthase in macrophages and vascular smooth muscle cells.

PMID- 8654676
TI  - Production of humanized monoclonal antibodies for in vivo imaging and therapy.

PMID- 8654677
TI  - Human and humanized monoclonal antibodies: preclinical studies and clinical
      experience.

PMID- 8654678
TI  - Therapeutic monoclonals.

PMID- 8654679
TI  - Antibody-directed enzyme prodrug therapy (ADEPT) for treatment of major solid
      tumour disease.

PMID- 8654680
TI  - Anti-platelet monoclonal antibodies for the prevention of arterial thrombosis:
      experience with ReoPro, a monoclonal antibody directed against the platelet
      GPIIb/IIIa receptor.

PMID- 8654681
TI  - Clinical trials with CAMPATH-I and other monoclonal antibodies.

PMID- 8654683
TI  - Antibody fragments for controlled delivery of therapeutic agents.

PMID- 8654682
TI  - Anti-respiratory syncytial virus monoclonal antibodies show promise in the
      treatment and prophylaxis of viral disease.

PMID- 8654684
TI  - Immunoliposome-mediated targeting of anti-cancer drugs in vivo.

PMID- 8654685
TI  - Chimaeric T-cell receptors specific to a B-lymphoma idiotype: a model for tumour
      immunotherapy.

PMID- 8654686
TI  - Structure and dynamics of ion channel polypeptides from amide exchange analysis
      and dynamics simulations.

PMID- 8654687
TI  - Application of SPR & FTIR spectroscopy to the study of protein-biomaterial
      interactions.

PMID- 8654688
TI  - Distribution and clustering of rare codons in Escherichia coli genes.

PMID- 8654689
TI  - Specificity of integrin I-domain-ligand binding.

PMID- 8654690
TI  - Inhibition of integrin-ligand binding by recombinant kistrins.

PMID- 8654691
TI  - Conformation and function of fibrillin 8-cysteine motifs.

PMID- 8654692
TI  - Isolation and characterisation of a novel non-haem extracellular peroxidase
      produced by the thermophilic actinomycete Thermonospora fusca BD25.

PMID- 8654693
TI  - High pressure cryofixation for immuno-electron microscopy of human cartilage.

PMID- 8654694
TI  - Dissection of the FMN-binding site in trimethylamine dehydrogenase.

PMID- 8654695
TI  - Tyrosine 495 is a key residue in the active site of galactose oxidase.

PMID- 8654697
TI  - Identification of a key structural element in VCAM-1.

PMID- 8654696
TI  - Inhibitors of trypanothione reductase as potential antitrypanosomal drugs.

PMID- 8654698
TI  - Structure and organisation of type VIII collagen.

PMID- 8654699
TI  - Structural implications of alternative splicing in type VI collagen.

PMID- 8654700
TI  - The proteins of proteodermatan and proteokeratan sulphates (decoron and
      fibromodulon/lumicon) are horseshoe shaped, resembling ribonuclease inhibitor.

PMID- 8654701
TI  - Regulation of extracellular matrix deposition by the C-propeptide domain of
      fibrillar collagens.

PMID- 8654702
TI  - Collagen IX isoforms in the intervertebral disc.

PMID- 8654703
TI  - Diabetic complications and the mechanism of the hyperglycaemia-induced damage to
      the mt DNA of cultured vascular endothelial cells: (I) Characterisation of the
      4977 base pair deletion and 13 bp flanking repeats.

PMID- 8654704
TI  - Diabetic complications and the mechanism of the hyperglycaemia-induced damage to
      the mt DNA of cultured vascular endothelial cells: (II) The involvement of
      protein kinase C.

PMID- 8654705
TI  - Expression of yeast mitochondrial F1F0 ATPase subunit 9 in E. coli as fusion
      constructs: Sec-independent membrane insertion ?

PMID- 8654706
TI  - Rapid-scan FTIR spectroscopic studies on the photolysis and recombination of the
      cyanide adduct of fully reduced bovine cytochrome c oxidase.

PMID- 8654707
TI  - Purification of F0F1 ATP synthase from bovine heart mitochondria.

PMID- 8654708
TI  - Purification of F1-ATPase from bovine heart mitochondria.

PMID- 8654709
TI  - Iron chelation, respiratory chain function and tubular necrosis in renal
      transplantation.

PMID- 8654710
TI  - An investigation into the effect of hepatic transplantation on cerebral
      oxygenation and haemodynamics.

PMID- 8654711
TI  - The use of a critikon cerebral redox research monitor model 2001 for assessing
      tissue viability during reconstructive surgery.

PMID- 8654712
TI  - Changes in hepatic mitochondrial metabolic parameters following transplantation.

PMID- 8654713
TI  - The alpha beta dimer-catalytic unit of the F1-ATPase.

PMID- 8654714
TI  - Mucin expression in colon adenocarcinoma cell lines.

PMID- 8654715
TI  - Quantitation of MCA, CA 19.9, CA 125 and TSA levels in lung cancer.

PMID- 8654716
TI  - Muc2 in ulcerative colitis: a quantitative study.

PMID- 8654717
TI  - Mucin secretion mediated by the cystic fibrosis gene protein, CFTR.

PMID- 8654718
TI  - Human gastric mucins--a major population identified as MUC5.

PMID- 8654719
TI  - Human tracheal mucins--is MUC5 more prominent in the epithelial surface than in
      the submucosa?

PMID- 8654720
TI  - The insoluble glycoprotein complex from human colon contains two MUC2 subunits of
      different size.

PMID- 8654721
TI  - Expression of mucin genes in ulcerative colitis.

PMID- 8654722
TI  - Secreted and membrane bound ocular mucins from normal and dry eye dogs.

PMID- 8654723
TI  - Lectin probe analysis of the glycosylation of human parotid salivary
      glycoproteins.

PMID- 8654725
TI  - Effect of vitamin A-CoMP on heme catabolism.

PMID- 8654724
TI  - Effect of metalloporphyrin on blood chemistry.

PMID- 8654726
TI  - Fluoride or GTP-gamma-S markedly stimulate lipid peroxidation catalysed by
      endogenous iron in rat liver microsomes.

PMID- 8654727
TI  - Histidine dipeptide levels in exercised and hypertensive rat muscles.

PMID- 8654728
TI  - Garlic can induce both GTP cyclohydrolase and nitric oxide synthase activity in
      choriocarcinoma cells.

PMID- 8654729
TI  - Effects of somatostatin-28 on plasma glucose-dependent insulinotropic polypeptide
      and serum insulin concentrations.

PMID- 8654731
TI  - Lead-cobalt mesoporphyrin alters heme regulatory enzymes.

PMID- 8654730
TI  - Wortmannin influences insulin regulation of gene 33 expression in rat hepatoma
      cells.

PMID- 8654732
TI  - The interaction of the neurodegenerative fragment of the beta-amyloid peptide
      with phospholipid membranes.

PMID- 8654733
TI  - Penems as research tools to investigate the activity of E.coli leader peptidase.

PMID- 8654734
TI  - Chemical modification of aminopeptidase P: identification of a critical histidyl
      residue.

PMID- 8654735
TI  - Characterisation of porcine aminopeptidase A: a type II integral membrane
      protein.

PMID- 8654736
TI  - Purification and characterization of the angiotensin converting enzyme secretase.

PMID- 8654738
TI  - Histamine-stimulated Cl- transport in HeLa cells.

PMID- 8654737
TI  - Identification of the site of cleavage in angiotensin converting enzyme by its
      secretase.

PMID- 8654739
TI  - Interaction of a signal peptide with phospholipid vesicles: the kinetics of
      binding, insertion and structural changes.

PMID- 8654740
TI  - Investigation of fusion complex assembly from placental clathrin coated vesicle
      membranes.

PMID- 8654741
TI  - The effect of anions on interfacial binding and activation of secretory
      phospholipase A2.

PMID- 8654742
TI  - Reaction mechanism of Hsc70.

PMID- 8654743
TI  - A characterisation of the peptide transport system in barley seeds.

PMID- 8654744
TI  - The inhibition of Na(+)-Pi cotransport and Pi self-exchange mechanisms in
      lactating rat mammary tissue.

PMID- 8654746
TI  - Interaction of cationic liposomes with skin bacteria.

PMID- 8654745
TI  - Functional integration of a polytopic membrane protein of E. coli requires the
      bacterial signal recognition particle.

PMID- 8654747
TI  - Using beta-lactams to investigate the existence of a protein complex, involving
      the Escherichia coli penicillin-binding proteins 1a/1b, 3 and 5.

PMID- 8654748
TI  - The soluble form of Escherichia coli penicillin-binding protein 4 observed in
      over-expressing strains is an artefact of the system.

PMID- 8654749
TI  - Characterisation of Krp1, an endopeptidase that is essential for cell viability
      in fission yeast.

PMID- 8654751
TI  - Isolation of the plc1 gene from the fission yeast Schizosaccharomyces pombe.

PMID- 8654750
TI  - Characterisation of Sxa2, a protease involved in pheromone communication in
      fission yeast.

PMID- 8654752
TI  - Evidence for a high affinity, Na(+)-dependent glutamate transport system in
      lactating rat mammary tissue.

PMID- 8654753
TI  - The use of the Rank electrode for the detection of the activity of liposomally
      encapsulated enzymes.

PMID- 8654754
TI  - The effect of dioleoylglycerol on cytosolic phospholipase A2 activity using a
      continuous fluorescence displacement assay.

PMID- 8654755
TI  - Reconstitution of hexose phosphate transport in membranes isolated from
      developing wheat endosperm amyloplasts.

PMID- 8654756
TI  - Identification of two types of Ca2+ transport ATPases in pig brain by specific
      antibodies.

PMID- 8654757
TI  - Influence of trifluoperazine on tegument membranes in Hymenolepis diminuta.

PMID- 8654758
TI  - Mastoparan induces inositol phospholipid changes and plasmolysis in carrot cells.

PMID- 8654760
TI  - The effect of cyclic AMP on the biliary secretion of taurocholic acid in the
      perfused rat liver.

PMID- 8654761
TI  - Neutral cholesteryl ester hydrolase activity in rat peritoneal macrophages:
      regulation by cyclic AMP.

PMID- 8654759
TI  - Characterisation of inositol 1,4,5-trisphosphate receptors from Chenopodium
      rubrum.

PMID- 8654762
TI  - Peroxisomes and plasmalogens along the intestine villus.

PMID- 8654763
TI  - Gastric mucosal peroxisomes and plasmalogen biosynthesis.

PMID- 8654764
TI  - Effects of growth hormone on mammary cholesterol metabolism in the lactating rat.

PMID- 8654765
TI  - The effect of okadaic acid and calyculin A on cholesterol esterification in rat
      hepatocytes.

PMID- 8654767
TI  - A novel inositol-lipid in plant-bacteria symbiosis.

PMID- 8654766
TI  - Nuclear Ca(2+)-fluxes and phosphoinositides in plants.

PMID- 8654768
TI  - Adsorption of immunoliposomes to bacterial biofilms.

PMID- 8654769
TI  - Breast cancer-associated antibody LU BCRU G7 recognises the terminal disaccharide
      Gal beta 1-3GlcNAc and can be used to isolate tumour cells from body fluids by an
      immunomagnetic bead procedure.

PMID- 8654770
TI  - Dichloroacetate increases cell and product yields in hybridoma batch cultures.

PMID- 8654771
TI  - Multiple forms of endo-1,4-beta-D-glucanase in the extracellular cellulase system
      of Fusarium oxysporum.

PMID- 8654772
TI  - Evaluation of the cellulase system produced by three strains of Clostridium
      thermocellum on cellobiose and Avicel.

PMID- 8654773
TI  - Variation of intracellular distribution of mRNAs expressed from transfected cDNAs
      -a study by FISH.

PMID- 8654774
TI  - Hormone regulation of gene transcription in human breast cancer cells.

PMID- 8654775
TI  - Effect of the thiazolidinedione BRL49653 and genetic obesity on hepatic gene
      expression in the Zucker rat.

PMID- 8654777
TI  - CCK-8 sulphate inhibits intestinal glucose transport.

PMID- 8654776
TI  - A novel cell growth inhibitor produced by macrophages.

PMID- 8654778
TI  - Effects of insulin secretagogues on phosphoprotein phosphatase 1 and 2A
      activities in rat islets of Langerhans.

PMID- 8654779
TI  - Alzheimer's disease, herpes simplex virus type 1, cold sores and apolipoprotein
      E4.

PMID- 8654780
TI  - Characterising the Huntington's disease gene product.

PMID- 8654781
TI  - Media composition modulates glutamate-induced cell death in rat cerebellar
      granule cells.

PMID- 8654782
TI  - Sustained activation of NF kappa B and transient I kappa B alpha degradation
      induced by tumour necrosis factor in 1321N1 human astrocytoma.

PMID- 8654783
TI  - Usage of gallium as a model for aluminium localisation in human neuroblastoma
      cells.

PMID- 8654784
TI  - Excitatory amino acid-induced neuronal cell death in rat cerebellar granule cell
      cultures.

PMID- 8654785
TI  - Serotonergic profiles of lobar atrophies.

PMID- 8654786
TI  - Non-serotonergic profiles of lobar atrophies.

PMID- 8654787
TI  - Excitotoxic neurotoxicity in an in vitro brain slice model.

PMID- 8654788
TI  - Analysis of urinary pterins in autism.

PMID- 8654789
TI  - The role of aldehyde oxidase in the in vivo metabolism of benzothiazole.

PMID- 8654791
TI  - Clinical evaluation of copper and ceruloplasmin levels in effusions of malignant
      and benign origin.

PMID- 8654790
TI  - NADH oxidoreductase activity in human and mouse cells treated with free radical
      generating agents.

PMID- 8654792
TI  - Novel inhibitors of 3-phosphoglycerate kinase.

PMID- 8654793
TI  - Different effects of platelet derived growth factor isoforms on DNA synthesis and
      migration in human vascular smooth muscle cells.

PMID- 8654794
TI  - Effect of Cleome arabica leaves extract on inflammatory cells response in rat.

PMID- 8654795
TI  - Prevention of the inactivation of glutathione reductase by fructation using human
      alpha-crystallin.

PMID- 8654796
TI  - The helix Ia rod domain of desmin: antibody and molecular modeling studies.

PMID- 8654797
TI  - Limited interpretation of changes in the FTIR spectrum of beta-lactoglobulin with
      temperature.

PMID- 8654798
TI  - NMR lipids profiles of common mushrooms.

PMID- 8654799
TI  - Lipidic mimetics as inhibitors of pancreatic phospholipase A2.

PMID- 8654800
TI  - Effect of cyclosporin A, FK506 and rapamycin on proliferation and soluble IL-2
      receptor release from mitogenically stimulated rat spleen cells.

PMID- 8654802
TI  - Studies of lymphocyte trafficking in a microvascular rat model of acute
      pancreatitis.

PMID- 8654801
TI  - Xanthine oxidase activity and subcellular localisation in human mammary
      epithelial cells.

PMID- 8654803
TI  - Is there a relationship between raised plasma osmolarity and the onset of acute
      pancreatitis.

PMID- 8654804
TI  - Nucleoside spiroxiranes as suicide inhibitors of the human immunodeficiency
      virus.

PMID- 8654805
TI  - Identification of the binding site for the allosteric inactivator UTP in
      mammalian CPS II.

PMID- 8654806
TI  - Are all four yeast PRS genes essential?

PMID- 8654807
TI  - Site directed mutagenesis of human cytosolic serine hydroxymethyltransferase.

PMID- 8654808
TI  - Translational control of rabbit cytosolic serine hydroxymethyltransferase
      expression.

PMID- 8654809
TI  - Overexpression of human cytosolic serine hydroxymethyltransferase in E. coli.

PMID- 8654810
TI  - Molecular studies of the mitochondrial isoform of serine
      hydroxymethyltransferase.

PMID- 8654811
TI  - Protective effect of histidine by inhibition of gossypol on rat's liver LDH-5.

PMID- 8654812
TI  - Effect of differential growth conditions on the dTTP pool size in herpes simplex
      virus-infected Vero cells.

PMID- 8654813
TI  - Influence of molybdenum complexes on the activity of (ADP-ribose)polymerase.

PMID- 8654814
TI  - Molecular mechanism of the multifunctional enzyme L-delta-(alpha-aminoadipoyl)-L
      cysteinyl-D-valine (ACV) synthetase.

PMID- 8654815
TI  - Molecular and functional studies of copper amine oxidase from Arabidopsis
      thaliana.

PMID- 8654816
TI  - A Drosophila early embryonic ventral transcript encoding a protein phosphatase-1
      binding protein.

PMID- 8654817
TI  - Purification and partial sequence of an alpha 3-gliadin.

PMID- 8654818
TI  - A partial sequence of an IgG light chain using continuous flow HPLC-FAB mass
      spectroscopy.

PMID- 8654819
TI  - Analysis of acylcarnitines by gas chromatography-electron impact mass
      spectrometry.

PMID- 8654820
TI  - Oxygen free radicals and red blood cell damage in acute renal failure.

PMID- 8654821
TI  - Adventures with membrane lipids.

PMID- 8654822
TI  - Protein hydration, stability and unfolding.

PMID- 8654823
TI  - Lattice models of protein folding.

PMID- 8654824
TI  - Mass mapping of extracellular matrix assemblies.

PMID- 8654825
TI  - Refined solution structure of p17, the HIV matrix protein.

PMID- 8654826
TI  - Structural and dynamic characterization of an SH2 domain-phosphopeptide complex
      by NMR approaches.

PMID- 8654827
TI  - Brian Beechey: an appreciation.

PMID- 8654828
TI  - Probing interactions of the Escherichia coli F0F1 ATP synthase beta and gamma
      subunits with disulphide cross-links.

PMID- 8654829
TI  - Nucleotide-binding sites in F1-ATPase: different pockets for different types of
      nucleotide analogues.

PMID- 8654830
TI  - Catalytic mechanism of Escherichia coli F1-ATPase.

PMID- 8654831
TI  - A model for ATP hydrolysis catalysed by F1-ATPases based on kinetic and
      structural considerations.

PMID- 8654833
TI  - Correlations of structure and function in subunit c of Escherichia coli F0F1 ATP
      synthase.

PMID- 8654832
TI  - ATP synthase from a cyanobacterial Synechocystis 6803 mutant containing the
      regulatory segment of the chloroplast gamma subunit shows thiol modulation.

PMID- 8654835
TI  - On the way towards the Na(+)-binding site within the F1F0 ATPase of
      Propionigenium modestum.

PMID- 8654834
TI  - Conformational changes in the gamma and epsilon subunits are integral to the
      functioning of the Escherichia coli H(+)-pumping ATPase (ECF1F0).
AB  - ATP synthesis and ATP hydrolysis by F1F0-type ATPases involve conformational
      changes transmitted from the catalytic site regions to the proton channel, a
      distance of more than 100 A. Our studies focus attention on the gamma and epsilon
      subunits that provide a part of the stalk region in the energy-coupling process
      within the complex. There are conformational changes in the gamma subunit, and
      translocations of the epsilon unit, linked to nucleotide-binding changes in
      catalytic sites, which might be expected to alter the interaction of this
      subunits with c subunits and, hence, be linked to proton translocation.

PMID- 8654836
TI  - Thioredoxin and control of F0F1: function and distribution.

PMID- 8654837
TI  - The structure of the H(+)-ATPase from chloroplasts by electron cryomicroscopy.

PMID- 8654838
TI  - Escherichia coli H(+)-ATPase (ATP synthase): catalytic site and roles of subunit
      interactions in energy coupling.

PMID- 8654839
TI  - Protein and peptide inhibitors of the F1-ATPase.

PMID- 8654840
TI  - Human mucin glycoproteins: varied structures predict diverse properties and
      specific functions.
AB  - It has been clear for some time now that mucin glycoproteins have extensive,
      highly glycosylated tandem repeat domains. What is becoming increasingly
      apparent, however, is the diversity of unique sequences present on different
      mucins. Variations in mucin-unique sequences clearly result in major differences
      in physical and biological properties. MUC1-unique sequences are needed for
      membrane binding, while MUC2-unique sequences apparently mediate polymerization.
      As the sequences of other mucins are determined, undoubtedly additional
      structures will be determined that confer specific properties and functions upon
      this interesting class of glycoconjugates.

PMID- 8654841
TI  - Human mucin genes: genomic organization and expression of MUC4, MUC5AC and MUC5B.

PMID- 8654842
TI  - Biosynthesis and molecular architecture of gel-forming mucins: implications from
      an amphibian model system.

PMID- 8654843
TI  - Regulation of mucin exocytosis from intestinal goblet cells.

PMID- 8654844
TI  - Biosynthesis of intestinal mucins: MUC1, MUC2, MUC3 and more.

PMID- 8654845
TI  - Mucin biosynthesis and macromolecular assembly.

PMID- 8654846
TI  - Involvement of the cell surface-bound mucin, episialin/MUC1, in progression of
      human carcinomas.

PMID- 8654847
TI  - MUC1, endometrium and embryo implantation.

PMID- 8654848
TI  - Modulation of the hyaluronan receptor, CD44, by its transmembrane and cytoplasmic
      domains.

PMID- 8654849
TI  - Interactions between human respiratory mucins and pathogens.

PMID- 8654850
TI  - Glycosylation patterns of mucins in colonic disease.

PMID- 8654851
TI  - 'Soluble' and 'insoluble' mucins--identification of distinct populations.

PMID- 8654852
TI  - Phosphoinositide signalling in plant and algal responses to physiological
      stimuli.

PMID- 8654853
TI  - Ligand- and voltage-gated calcium release channels at the vacuolar membrane.

PMID- 8654854
TI  - Inositol lipid signal transduction in phytoalexin elicitation.

PMID- 8654855
TI  - Diacylglycerol- and phosphatidic acid-kinase studies in plant cell suspension
      cultures.

PMID- 8654857
TI  - Enzymes of nucleotide biosynthesis: differences between intact and lysed cells as
      well as between species and tissues can be important.

PMID- 8654856
TI  - The functional relationship of plant lipid-derived second messengers and plant
      lipid-activated protein kinase.

PMID- 8654858
TI  - The carbamoyl-phosphate synthase family and carbamate kinase: structure-function
      studies.

PMID- 8654859
TI  - Thymidylate synthase as a target in cancer chemotherapy.

PMID- 8654860
TI  - Inhibitors of dihydro-orotase, amidophosphoribosyltransferase and IMP
      cyclohydrolase as potential drugs.

PMID- 8654861
TI  - Structures of glutamine amidotransferases from the purine biosynthetic pathway.

PMID- 8654862
TI  - Key enzymes in the biosynthesis of purines and pyrimidines: their regulation by
      allosteric effectors and by phosphorylation.

PMID- 8654863
TI  - Mouse ribonucleotide reductase: from genes to proteins.

PMID- 8654864
TI  - Tandem mass spectrometric characterization of modified peptides and proteins.

PMID- 8654865
TI  - Characterization of chemokine proinflammatory proteins by combined liquid
      chromatography-mass spectrometry.

PMID- 8654866
TI  - Peptide sequencing by matrix-assisted laser desorption ionization/time-of-flight
      mass spectrometry.

PMID- 8654867
TI  - Different strategies for recombinant protein characterization using mass
      spectrometry.

PMID- 8654869
TI  - Disruption of the mouse oestrogen receptor gene: resulting phenotypes and
      experimental findings.

PMID- 8654868
TI  - Characterizing biomolecules by electrospray ionization-mass spectrometry coupled
      to liquid chromatography and capillary electrophoresis.

PMID- 8654870
TI  - Oestrogen receptor activation in the absence of ligand.

PMID- 8654871
TI  - Anti-inflammatory mechanisms of glucocorticoids.

PMID- 8654873
TI  - Antagonism of nuclear factor-kappa B functions by steroid hormone receptors.

PMID- 8654872
TI  - Glucocorticoid receptor-activator protein-I interactions in drug design.

PMID- 8654874
TI  - Biophysics of the membrane interface.
AB  - It is clear that the interface is a highly complex region of the bilayer. In
      summary: (i) anionic lipids can interact in a stoichiometric way with charged
      protein residues; (ii) proteins are induced into 'molten globule' states on
      interaction with the membrane surface; (iii) local pH and hydration of the
      surface is not uniform and does not reflect the bulk properties; (iv) the
      contributions to the energetics of protein or peptide interaction are not well
      resolved and may not be readily measured; (v) as a result of electrostatic
      interactions between proteins and lipids, biomembranes may contain laterally
      separated domains that, at their interfaces, provide mismatched regions capable
      of permitting passage of components through the bilayer; (vi) the mode of
      insertion, folding and translocation may be determined directly by the surface
      properties of the biomembrane. Much still needs to be done to enable a complete
      description of the biophysics (mechanisms and energetics) of protein folding,
      insertion and translocation, and how this is affected by the bilayer surface, the
      initial site of interaction of such species. More experimental evidence, as well
      as theory to understand the results, is required before the measured
      thermodynamic parameters meet with descriptions of the various contributions for
      the process. Deuterium NMR is one direct and highly sensitive experimental
      approach to help in the understanding of such electrostatics at membrane
      interfaces.

PMID- 8654875
TI  - Membrane protein anchors and polytopic determinants.

PMID- 8654876
TI  - A molecular model for the specific cardiolipin-presequence interactions.

PMID- 8654877
TI  - The interactions of signal sequences with membranes.

PMID- 8654878
TI  - The membrane-interactive properties of the low-molecular-mass penicillin-binding
      proteins of Escherichia coli.

PMID- 8654879
TI  - SecA, a novel ATPase that converts chemical energy into a mechanical force to
      drive precursor protein translocation.

PMID- 8654880
TI  - Translocation of folded proteins across bacterial outer membranes: a novel
      secretory phenomenon.

PMID- 8654882
TI  - Bacterial endotoxin effects on carbohydrate utilization and transport.

PMID- 8654881
TI  - Hepatic cellular interactions in endotoxaemia and sepsis.

PMID- 8654884
TI  - Female genital mutilation: a reproductive health concern.

PMID- 8654883
TI  - Meeting the needs of young adults.
AB  - As they mature and become sexually active, more young people face serious health
      risks. Most face these risks with too little factual information, too little
      guidance about sexual responsibility, and too little access to health care.
      Meeting young adults' diverse needs challenges parents, communities, health care
      providers, and educators. Despite urgent needs, program efforts have been slight
      and slowed by controversy.

PMID- 8654885
TI  - Reaching young adults through entertainment.

PMID- 8654886
TI  - A novel chloride channel localizes to Caenorhabditis elegans spermatids and
      chloride channel blockers induce spermatid differentiation.
AB  - Caenorhabditis elegans spermatogenesis is especially suited for studies of
      nonrandom cytoplasmic segregation during cellular differentiation. Spermatocytes
      separate from an anuclear cytoplasmic core and undergo two sequential divisions.
      During the second division, intracellular organelles segregate specifically to
      spermatids as they bud from an anuclear residual body. We have applied patch
      clamp techniques in order to investigate membrane protein distribution during
      these asymmetric divisions. We show that membrane components, as assayed by
      voltage-dependent ion channel activity, follow a specific distribution pattern
      during sperm development. Several voltage-sensitive ion channel activities are
      observed in spermatocytes and residual bodies, but only a single-channel type can
      be detected in spermatids, indicating that other channel activities are excluded
      from or inactivated within these cells as they form. The channel that is observed
      in spermatids is an inward-rectifying chloride channel (Clir), as indicated by
      its sensitivity to chloride channel inhibitors and Cl-dependent shifts in its
      conductance. Treatment of spermatids with Cl channel blockers induce their
      differentiation into spermatozoa, suggesting that Clir plays a role during this
      developmental step. These studies are the first application of patch-clamp
      electrophysiology to C. elegans development.

PMID- 8654887
TI  - Thyroid hormone controls the onset of androgen sensitivity in the developing
      larynx of Xenopus laevis.
AB  - Gonadal differentiation, the onset of androgen-stimulated laryngeal growth and
      the genesis of a sex difference in laryngeal innervation, all temporally coincide
      with thyroid hormone (TH)-induced metamorphosis in Xenopus laevis. To explore the
      role TH plays in the ontogeny of the Xenopus androgen-sensitive vocal
      neuromuscular system, we examined gonadal and laryngeal development in tadpoles
      in which metamorphosis had been blocked by treatment with the thyroxine synthesis
      inhibitor propylthiouracil (PTU). PTU treatment did not arrest gonadal
      differentiation. Testes from PTU-treated male tadpoles had seminiferous tubules
      and advanced stage male germ cells, while in females stage 1 oocytes were
      present. In contrast to the gonads, PTU did block morphological development of
      the larynx. Tadpoles treated with PTU for 50 or 100 days had larynges which
      structurally resembled those of stage 54 control tadpoles. PTU-treated animals
      did not exhibit the extensive development of the laryngeal cartilage seen in
      untreated animals. Laryngeal cartilages of hypothyroid tadpoles exhibited low
      density and minimal patterning of chondrocytes; the complex lumen and marked
      expansion of the dilator muscles characteristic of 50- and 100-day untreated
      animals were absent. Laryngeal growth evoked by exposure to exogenous androgen
      (dihydrotestosterone) was entirely prevented by PTU treatment. Hypothyroid
      tadpoles did not exhibit the decline in laryngeal nerve axon number
      characteristic of age-matched controls, nor were laryngeal nerve axon numbers
      sexually dimorphic. PTU treatment also interfered with the myelination of
      laryngeal axons. We conclude that while gonadal differentiation is independent of
      TH, androgen sensitive laryngeal development and sexually dimorphic laryngeal
      innervation require exposure to secreted TH.

PMID- 8654888
TI  - A novel angiogenic molecule produced at the time of chondrocyte hypertrophy
      during endochondral bone formation.
AB  - Angiogenesis is a pivotal event in endochondral ossification. Vessels grow into
      the hypertrophic cartilage and erode it to produce a scaffold on which
      osteoblasts settle to produce woven bone. A new culture system was used to
      determine whether growth-plate chondrocytes produce an angiogenic molecule.
      Chondrocytes from primary growth plates of bovine fetuses were separated into
      maturationally distinct subpopulations. When cultured these cells produce an
      extensive extracellular matrix and the prehypertrophic cells mature to express
      the hypertrophic phenotype defined by the synthesis of type X collagen and matrix
      calcification. The culture medium collected from the hypertrophic cells contains
      a chemoattractant, nonmitogenic molecule for bovine endothelial cells which can
      induce angiogenesis in vivo in the rabbit cornea model. This molecule has a Mr of
      approximately 120 x 10(3). The production of this molecule by hypertrophic cells
      is enhanced by both 1,25-(OH)2 vitamin D3 and 24,25-(OH)2 vitamin D3 at 10(-8)
      10(-12) M, but only in pre- and early hypertrophic cells. In contrast, these
      metabolites have either no effect or an inhibitory effect on the more mature
      hypertrophic cells. These results describe for the first time the production of
      an angiogenic molecule by hypertrophic chondrocytes. They demonstrate an
      important role for vitamin-D3 metabolites in regulating hypertrophy and
      angiogenesis during normal skeletal growth and differentiation. Thus, a defective
      regulation of these processes, due to the lack of vitamin-D metabolites, may
      explain the observed enlargement of the hypertrophic zone and impairment of
      skeletal growth in rickets which is induced clinically and experimentally by a
      deficiency of vitamin D.

PMID- 8654889
TI  - PDGF-A is required for normal murine cardiovascular development.
AB  - Several lines of evidence suggest that platelet-derived growth factor A chain
      (PDGF-A) is required for normal embryonic cardiovascular development. To test
      this directly, we introduced anti-PDGF-A neutralizing antibodies into mouse
      deciduas in utero at Embryonic Days (E) 8.5, 9.5, and 10.5. This resulted in the
      selective disruption of PDGF-A ligand-receptor interactions in vivo for a period
      of 18-24 hr and allowed us to assess both if PDGF-A is required for
      cardiovascular development and when it is required. Embryos collected 48 hr after
      antibody treatment displayed severe cardiovascular abnormalities. These included
      both atrial and ventricular myocardial hypertrophy, epicardial and endocardial
      abnormalities, and aortic dilation, among others. Although heart abnormalities
      were observed in embryos treated at all three ages, they were more common in
      embryos treated at E8.5. In contrast, only embryos treated at E10.5 exhibited
      significant aortic dilation. This work (1) demonstrates directly for the first
      time that PDGF-A is required for normal cardiovascular development, (2)
      identifies several processes that require PDGF-A, and (3) defines discreet
      developmental periods during which these PDGF-A-dependent processes require the
      factor.

PMID- 8654890
TI  - Wingless signaling induces nautilus expression in the ventral mesoderm of the
      Drosophila embryo.
AB  - The segregation of founder cells from the somatic mesoderm is a prerequisite for
      the formation of body wall muscles in the Drosophila embryo. The myogenic basic
      helix-loop-helix protein, Nautilus (Nau), is expressed in a subset of these
      founder cells in medial and lateral positions in the somatic mesoderm. Mutations
      in the wingless (wg) gene, which encodes a secreted growth factor, lead to the
      complete loss of Nau-expressing medial muscle precursor cell clusters, but not
      lateral clusters. Using the GAL4/UAS system, we demonstrate that the wg-derived
      signal can originate from either ectoderm or mesoderm to influence nau
      expression. By using a temperature-sensitive wg allele, we also show that wg
      function is required during and after gastrulation for the formation of Nau
      expressing medial muscle precursor cell clusters. Our results, combined with
      recent studies from chick, suggest a conserved role for Wg signaling pathways
      during muscle development.

PMID- 8654891
TI  - Early embryonic induction in C. elegans can be inhibited with polysulfated
      hydrocarbon dyes.
AB  - During embryogenesis of Caenorhabditis elegans cellular interactions are
      necessary to determine the fate of blastomeres. In one of these interactions,
      taking place in the 4-cell stage, the germline cell P2 induces longitudinal
      orientation of the cleavage spindle in the neighboring EMS cell, its asymmetric
      division, and the establishment of a gut lineage. Application of several
      polysulfated hydrocarbon dyes (e.g., trypan blue, TB) in the 1- to 4-cell stages
      inhibits induction of the gut precursor cell. However, dye application from the
      late 4-cell stage onward does not interfere with gut induction, supporting the
      earlier finding of a short time window for this interaction. We also tested the
      effect of TB on the induction of pharyngeal muscle cells by the MS blastomere,
      which appears to involve a surface receptor-ligand interaction. We found that
      this process is inhibited as well. These and additional data indicate that
      polysulfated hydrocarbon dyes are suitable tools to generally interfere with cell
      cell interactions in the nematode embryo.

PMID- 8654892
TI  - Cellular interactions that guide sensory and motor neurites identified in an
      embryo slice preparation.
AB  - We used cultured cross sections ("slices") of avian embryos to identify
      interactions that guide neurites during their encounters with seven tissues that
      impose a stereotyped gross anatomical nerve pattern. We show that cultured slices
      retain tissue morphology, molecular distribution patterns, and guidance cues.
      They also allow us to directly visualize responses of labeled sensory and motor
      neurons deposited on the slice's surface. This assay has high predictive power.
      Contact-mediated avoidance or stimulation and long-range attraction or repulsion
      are each distinguishable because each predicts different neurite lengths and
      trajectories. The analysis shows that all but one of these mechanisms contributes
      to guidance. Three tissues similarly stimulated neurite elongation, suggesting
      common responses to a contact-mediated stimulation. Four tissues similarly
      elicited avoidance on contact, suggesting a common contact-mediated inhibition.
      Neurite orientations implicate a previously unsuspected long-distance attraction
      to one tissue, dorsal anterior sclerotome. Long-range repulsion plays no
      detectable role. Each tissue elicits the same response in two different neural
      populations, sensory and motor neurons. These results suggest that a small set of
      repeated mechanisms mediates responses to tissues that axons contact serially
      during pathfinding.

PMID- 8654893
TI  - Identification of cis-acting sequences that control nanos RNA localization.
AB  - The generation of anterior-posterior polarity during development in Drosophila
      requires the localization of determinant molecules to the anterior and posterior
      poles of the embryo. Localization of the maternally synthesized nanos RNA to the
      posterior pole of the embryo is essential to provide a source for a gradient of
      Nanos protein that directs abdomen formation. nanos RNA localization occurs
      during oogenesis and requires the function of at least nine genes. cis-acting
      sequences that direct nanos RNA localization lie within the nanos 3'UTR. In this
      analysis, we have used nanos 3'UTR deletion mutants to define the localization
      signal more precisely. Our results indicate that the nanos RNA localization
      signal is large and complex and that targeting of nanos RNA may be achieved by
      the combined effects of multiple, partially independent sequences. This idea is
      supported by evolutionary conservation, both in sequence and in function, of the
      nanos 3'UTRs of Drosophila melanogaster and Drosophila virilis.

PMID- 8654894
TI  - Nuclear localization of type II cAMP-dependent protein kinase during limb
      cartilage differentiation is associated with a novel developmentally regulated A
      kinase anchoring protein.
AB  - Differentiation of chicken limb cartilage is accompanied by a rise in
      intracellular cyclic AMP, an inducer of cartilage-specific gene expression. A
      basic approximately 35-kDa protein, designated p35, is the major nuclear
      substrate for cAMP-dependent protein kinase (PKA) during this process. Here we
      show that whereas both precartilage and cartilage nuclei contain p35, only
      precartilage nuclei contain PKA. The phosphorylation of p35 in isolated cell
      fractions was used as an index of changes in the cellular compartmentalization of
      components of PKA during chondrogenesis. Both the catalytic subunit and type II
      regulatory subunit (RII) of PKA were present in the precartilage nuclear
      fraction, but were undetectable or present in only trace amounts in the cartilage
      nuclear fraction. Furthermore, a novel approximately 150-kDa A-kinase anchoring
      protein (AKAP), which binds to RII, was detected in the nuclear matrix of
      precartilage nuclei but, like RII, was virtually absent in the nuclei of fully
      differentiated cartilage cells. In limb mesenchymal cells undergoing
      chondrogenesis in culture a corresponding set of changes occurred: cartilage
      differentiation was accompanied by a marked reduction in the amounts of both
      nuclear RII and nAKAP150. These observations indicate that type II PKA holoenzyme
      is imported into the mesenchymal cell nucleus prior to chondrogenesis, an event
      that appears to depend on the activity of the developmentally regulated nAKAP150.

PMID- 8654895
TI  - Immortalized Hensen's node cells secrete a factor that regulates avian neural
      crest cell fates in vitro.
AB  - The derivatives of the neural crest are regionally specified with respect to the
      anterior-posterior axis of the avian embryo. We have shown previously that young
      Hensen's node can act in vitro to regulate the expression of certain region
      specific phenotypes in trunk neural crest cells. To study potential factors
      acting on the neural crest, we have generated an immortalized cell line from
      young Hensen's node. Here we show that a factor produced by these cells
      stimulates the expression of two cranial-specific phenotypes (fibronectin and
      smooth muscle actin) in trunk neural crest cells and decreases their expression
      of a trunk-specific phenotype (melanin). The active factor is a secreted protein
      with a molecular weight >30 kDa. Clonal studies suggest that the factor acts by
      changing the phenotypic fates of individual neural crest cells, rather than by
      selective effects on cell proliferation or survival. Previous work has shown that
      TGF-betas can mimic the effects of Hensen's node cells on neural crest
      differentiation. Results from the present study suggest that the factor in the
      conditioned medium of the immortalized node cell line is not a TGF-beta isoform.
      However, the cranial phenotype-inducing activity of the conditioned medium factor
      requires the presence of neural crest cell-derived TGF-betas.

PMID- 8654897
TI  - Exogenous tau RNA is localized in oocytes: possible evidence for evolutionary
      conservation of localization mechanisms.
AB  - The multistep pathway leading to intracellular RNA localization is known to
      involve cis-acting signals in targeted mRNAs, which are presumably recognized by
      specific RNA-binding proteins and interact with a functional cytoskeleton. Tau
      RNA is localized to the proximal hillock of rat axons, and this movement requires
      intact microtubules. Because Xenopus oocytes demonstrate a clear polarity
      involving microtubule-mediated RNA localization, we have studied the distribution
      of tau RNA injected into oocytes. We find that a fragment from the 3'
      untranslated region of tau RNA is localized to the vegetal cortex of stage III/IV
      oocytes in a distribution indistinguishable from Vg1 RNA, a vegetally localized
      oocyte mRNA. A fragment from the tau RNA coding region, however, is homogeneously
      distributed in oocytes. Tau RNA contains a functional binding site for Vg1 RBP, a
      Xenopus microtubule-associated protein that binds vegetally localized oocyte RNAs
      with high affinity, and this binding correlates with vegetal localization
      ability. The present studies demonstrate, for the first time, localization of
      heterologous RNA in oocytes. Given the role of Vg1 RBP as a mediator of specific
      RNA-microtubule interactions, these results are strong evidence that Vg1 RBP is
      involved in the vegetal localization of RNAs in oocytes and raise the intriguing
      possibility of the existence of proteins with similar function in neurons.

PMID- 8654896
TI  - VEGF121 induces proliferation of vascular endothelial cells and expression of flk
      1 without affecting lymphatic vessels of chorioallantoic membrane.
AB  - We have studied the effect of VEGF(121) homodimer and VEGF(121/165) heterodimer
      on the chorioallantoic membrane (CAM) of 13-day-old chick embryos. The factors
      were applied in doses of 2-4 micrograms and the effects were evaluated
      macroscopically after 2 and 3 days. Histological studies were performed on semi-
      and ultrathin sections. Proliferation was studied according to the BrdU-anti-BrdU
      method on whole mounts and sections. The labeling density was quantified in whole
      mounts. The fractal dimension, D, of the vascular tree was assessed as a value
      for vascular bifurcation density. Both forms of VEGF induce brush-like vessel
      formation in the precapillary region. New capillaries are found in the stroma of
      the CAM, which normally does not contain capillaries. Our results show that
      VEGF(121) is a specific endothelial cell mitogen. A fourfold increase of BrdU
      labeled endothelial cells is found after VEGF(121) application. The fractal
      dimension of the vascular tree increases from 1.26 in the controls to 1.44
      (VEGF(121)) and 1.41 (VEGF(121/165)). The endothelial cells of the newly formed
      capillaries possess many mitochondria and micropinocytotic vesicles, but no
      fenestrations. These capillaries are obviously formed by intussusceptive
      microvascular growth. Signs of sprouting are almost absent. An effect on the
      lymphatic vessels of the CAM is not detectable. Compared to VEGF(165) and
      VEGF(121/165), VEGF(121) diffuses over a slightly greater distance. Using in situ
      hybridization, VEGF receptor-2 (flk-1/Quek1) and the homologous flt-4 (Quek2)
      receptor were studied in the CAM of normal quail embryos and after VEGF(121)
      application on the CAM of 11-day-old quail embryos. During normal development,
      flk-1 expression becomes restricted to vascular endothelial cells of large
      vessels in the stroma of the CAM. VEGF(121) application induces expression of flk
      1 in capillaries that normally do not express the receptor. In the normal
      development of the CAM, flt-4 becomes restricted to endothelial cells of vessels
      that appear to be lymphatic vessels. Application of VEGF(121) does not alter flt
      4 expression.

PMID- 8654898
TI  - Characterization of a SpAN promoter sufficient to mediate correct spatial
      regulation along the animal-vegetal axis of the sea urchin embryo.
AB  - In order to investigate how the maternally specified animal-vegetal axis of the
      sea urchin embryo is established, we have examined the molecular basis of
      regulation of several genes transcribed differentially in nonvegetal and vegetal
      domains of the very early blastula. Here we present an initial characterization
      of the regulatory region of one of these, SpAN, which encodes a protease in the
      astacin family related to Drosophila tolloid and vertebrate BMP-1 (Reynolds et
      al., Development 114, 769-786). Tests of SpAN promoter function in vivo show that
      high-level activity and correct not-vegetal expression are mediated by sequences
      within 300 bp upstream of the basal promoter. In vitro studies have identified
      six protein binding sites serviced by at least five different proteins.
      Comparison of the structure of the SpAN promoter to that of SpHE, whose
      expression pattern is identical, shows that both promoters contain multiple
      positively acting upstream elements close to the basal promoter. We show that two
      elements are critical for high-level transcription of SpAN, since exact
      replacement of either results in 10- to 20-fold reduction in promoter strength.
      These shared elements are, however, not essential for spatially correct SpHE gene
      transcription. We conclude that the coordinate strong activities of the SpAN and
      SpHE promoters in the nonvegetal domain of the embryo rely primarily on different
      transcription factor activities.

PMID- 8654900
TI  - Effects of channel-to-electrode mappings on speech reception with the ineraid
      cochlear implant.
AB  - OBJECTIVE: Research was conducted to assess multichannel saliency with the
      Ineraid cochlear prosthesis. The goal was to determine whether tonotopically
      ordered stimulation benefits speech reception. DESIGN: In a single high
      performing subject, changes in speech reception were studied during two dramatic
      alterations to the normal (tonotopic) mapping between the sound-processors's four
      filter channels and the intracochlear electrode array: In one alteration, the
      four filter outputs were summed and delivered to one electrode; this single
      channel mapping was worn for 7 days. In another alteration, the four filter
      outputs were connected in reverse tonotopic order to four intracochlear
      electrodes; this reversed mapping was worn for 3 days. RESULTS: When using the
      implant in conjunction with speechreading, all three mappings provided large
      gains over speechreading alone on the recognition of words in sentences. When
      using the implant alone (without speechreading), tests of consonant and vowel
      recognition, and the recognition of words in isolation and in sentences all
      showed substantial decreases in performance across the three mapping conditions:
      normal > single-channel > reversed. The patterns of segmental confusions and the
      relations among scores on different tests were highly consistent. Finally, the
      performance with the altered mappings was, in some ways, remarkably good. With
      single-channel mapping, 15% word recognition was obtained, much less than the 54%
      obtained with the normal mapping, but demonstrative of some open-set speech
      reception. With the reversed mapping, high levels of consonantal voicing and
      manner information were received, indicating good reception of time-intensity
      cues, but open-set word recognition was near zero. CONCLUSIONS: Despite the
      extensive spread of current associated with monopolar intracochlear stimulation,
      the Ineraid electrode array affords a degree of perceptual selectivity that
      substantially aids speech reception.

PMID- 8654899
TI  - Longitudinal assessment of physiological and psychophysical measures in cochlear
      implant users.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of long-term
      electrical stimulation on human cochlear implant users. DESIGN: Repeated measures
      of electrically evoked auditory brain steam response (EABR) threshold, slope of
      the EABR growth function, and behavioral measures of threshold and dynamic range
      were made for a group of 22 Ineraid cochlear implant users and 19 Nucleus
      cochlear implant users over a 3- to 5-yr period. RESULTS: Data from both Ineraid
      and Nucleus cochlear implant users suggest that EABR threshold, slope of the EABR
      growth function, and behavioral measures of threshold and dynamic range remain
      reasonably stable for periods up to 5 yr postimplant. CONCLUSIONS: The results of
      this study show little evidence that prolonged electrical stimulation through
      daily use of a cochlear implant has deleterious effects on the auditory system.

PMID- 8654901
TI  - Effects of talker familiarity on communication breakdown in conversations with
      adult cochlear-implant users.
AB  - This investigation had three objectives: a) to determine the types of repair
      strategies that cochlear-implant users implement to rectify communication
      breakdowns during ongoing conversation when talking to either familiar or
      unfamiliar communication partners, b) to determine how communication partners
      respond to particular types of repair strategies, and c) to describe the use of
      conversational behaviors that might circumvent communication difficulties. In
      Experiment 1, cochlear-implant subjects were videotaped while talking to familiar
      and then unfamiliar communication partners. In Experiment 2, a second group of
      cochlear-implant subjects were videotaped while speaking with an unfamiliar
      partner for 6.5 minutes. Analysis of the videotapes revealed that the cochlear
      implant subjects in the two experiments most commonly asked "what?," "huh," or
      "pardon?" after not recognizing a spoken message (e.g., following a communication
      breakdown), regardless of whether the communication partner was familiar or
      unfamiliar. Communication partners' more common response to this repair strategy
      was to repeat the original message. When cochlear-implant subjects repeated back
      the segment of a message that they understood, communication partners most often
      confirmed or corrected them. When they requested information, communication
      partners usually provided it. The cochlear-implant subjects were more likely to
      use controlling conversational behaviors when interacting with unfamiliar than
      familiar communication partners. We conclude that repair strategy-response
      adjacency pairs may emerge during spontaneous conversations. Use of both specific
      and nonspecific repair strategies may indicate cochlear-implant users' adherence
      to a cooperative principle.

PMID- 8654902
TI  - Lexical effects on spoken word recognition by pediatric cochlear implant users.
AB  - OBJECTIVE: The purposes of this study were 1) to examine the effect of lexical
      characteristics on the spoken word recognition performance of children who use a
      multichannel cochlear implant (CI), and 2) to compare their performance on
      lexically controlled word lists with their performance on a traditional test of
      word recognition, the PB-K. DESIGN: In two different experiments, 14 to 19
      pediatric CI users who demonstrated at least some open-set speech recognition
      served as subjects. Based on computational analyses, word lists were constructed
      to allow systematic examination of the effects of word frequency, lexical density
      (i.e., the number of phonemically similar words, or neighbors), and word length.
      The subjects' performance on these new tests and the PB-K also was compared.
      RESULTS: The percentage of words correctly identified was significantly higher
      for lexically "easy" words (high frequency words with few neighbors) than for
      "hard" words (low frequency words with many neighbors), but there was no lexical
      effect on phoneme recognition scores. Word recognition performance was
      consistently higher on the lexically controlled lists than on the PB-K. In
      addition, word recognition was better for multisyllabic than for momosyllabic
      stimuli. CONCLUSIONS: These results demonstrate that pediatric cochlear implant
      users are sensitive to the acoustic-phonetic similarities among words, that they
      organize words into similarity neighborhoods in long-term memory, and they use
      this structural information in recognizing isolated words. The results further
      suggest that the PB-K underestimates these subjects' spoken words recognition.

PMID- 8654903
TI  - Dichotic listening, event-related potentials, and interhemispheric transfer in
      the elderly.
AB  - OBJECTIVE: To determine the basis for the large, age-related asymmetries in
      dichotic listening performance scores reported by Jerger et al. (1994). DESIGN:
      Behavioral and electrophysiologic responses to dichotic listening tasks in both
      verbal and nonverbal paradigms were obtain in four groups of subjects: young
      adults with normal hearing, elderly persons with presbyacusis, elderly persons
      with presbyacusis and marked dichotic deficits, and patients with lesions of the
      corpus callosum. RESULTS: In comparison with the young group the two elderly
      groups showed an increasing left-ear deficit on the verbal task, and an
      increasing right-ear deficit on the nonverbal paradigm. The pattern of results
      obtained in the elderly persons with marked dichotic deficits was similar to the
      pattern of results in the group with callosal lesions. CONCLUSIONS: With age,
      there may be a significant loss of efficiency of interhemispheric transfer of
      auditory information through the corpus callosum. Such age-related deficit might
      have important implications for the effective use of binaural information by
      elderly person.

PMID- 8654904
TI  - The automated prediction of hearing thresholds in sleeping subjects using
      auditory steady-state evoked potentials.
AB  - OBJECTIVE: To examine the relationship between auditory steady-state evoked
      potentials (SSEPs) and behavioral thresholds in sleeping subjects. DESIGN: 60
      adults and children with hearing thresholds ranging from normal to profound were
      selected on the basis of appropriate audiograms. Behavioral audiograms were
      determined at the octave frequencies 250-4000 Hz. These behavioral thresholds
      were then compared with the SSEP thresholds obtained during natural sleep for
      adults, or natural or sedated sleep for children. RESULTS: A strong relationship
      between behavioral and SSEP thresholds was observed. The strength of the
      relationship increased with increasing frequency and increasing degree of the
      loss. On the basis of these data, the prediction of behavioral thresholds from
      SSEP levels was determined. It was found that the standard deviation of the error
      in this prediction decreased with increasing frequency and increasing degree of
      the loss. There was no significant age effect in the results obtained at any of
      the frequencies. CONCLUSION: The results suggest the SSEP technique can be used
      as a predictor of behavioral threshold in adults and children at the frequencies
      250-4000 Hz.

PMID- 8654905
TI  - Analog and digital filtering of ABR: ipsi- and contralateral derivations.
AB  - OBJECTIVE: In audioneurological evaluations, peak latency is an important
      parameter regarding the determination of possible wave delays. Digital filtering
      entails suppression of less informative low-frequency components without phase
      distortion, thus accentuating the peak readings. Ipsi- and contralateral
      recordings have improved the reliability as regards the identification of ABR
      waves. This applies specifically to the wave IV-V complex. The purpose of this
      study has been to compare 1) analog and digitally filtered waveforms and 2) ipsi-
      and contralateral derivations. DESIGN: Two-channel ABR data were collected from
      120 unselected subjects referred for assessment of possible retrocochlear
      diseases. The analog filter bandwidth was 30 to 3000 Hz. Each response was
      subsequently digitally filtered with a bandwidth of 300 to 2500 Hz, and a
      comparison of wave identification between the analog and digitally filtered
      responses was performed. Wave identification was also compared between the
      digitally filtered ipsi- and contralateral responses, and the differences of the
      wave latencies between the two derivations were calculated. RESULTS AND
      CONCLUSIONS: Digital filtering improves ABR wave identification. For the
      digitally filtered waveforms, a better wave identification is found ipsilaterally
      for waves I to III, whereas the opposite is found for wave IV. Wave V
      identification is identical in both derivations. Furthermore, significant ipsi-
      and contralateral latency difference were found for all waves except for wave IV.
      This must be taken into consideration if ipsi- and contralateral derivations are
      to be summed.

PMID- 8654906
TI  - The contribution of spontaneous otoacoustic emissions to the click evoked
      otoacoustic emissions.
AB  - OBJECTIVE: This investigation determines whether spontaneous otoacoustic
      emissions (SOAE) contribute to click evoked otoacoustic emissions (EOAE). DESIGN:
      Bilateral SOAEs and click EOAEs were recorded for 81 normal-hearing subjects by
      using an ILO88 Otodynamic Analyzer. RESULTS: Results suggest that several factors
      from COAEs contribute to the level and the shape of the click EOAE. The number,
      frequency, and level of SOAEs all appear to affect the click EOAE. In addition,
      as the number of SOAEs increased, the click EOAE response level significantly
      increased. For the majority of subjects with SOAEs in only one ear, the click
      EAOE response level was higher in the same ear. CONCLUSIONS: These findings
      suggest that SOAEs add to the overall EOAE response level. This likely occurs
      from the synchronous capturing of SOAEs during click EOAE data collection.
      Therefore, SOAEs play an important role in the click EOAE measurement.

PMID- 8654907
TI  - COAEs and SSOAEs in adults with increased age.
AB  - OBJECTIVE: The purpose of this study was to compare click-evoked otoacoustic
      emissions (COAEs) of subjects having similar auditory thresholds but different
      age ranges. It is well known that elevated hearing thresholds are common with
      increasing age and that deterioration of outer hair cells is often noted in cases
      of hearing loss due to increased age. It has also been reported that evoked
      otoacoustic emissions (EOAEs) decrease with increased age. However, there is
      still some question whether changes in EOAEs with aging are associated with the
      increased hearing threshold or whether there is some additional effect of aging
      that enfluences EOAEs. DESIGN: COAE input/output functions and synchronized
      spontaneous OAEs (SSOAEs) were measured in two groups of subjects having similar
      auditory thresholds, one ranging in age from 19 to 29 yr, the other ranging in
      age from 40 to 61 yr. Mixed-model ANOVAs were performed to determine whether
      there were any statistically significant differences in COAEs based on age group.
      RESULTS: There were no statistically significant differences in COAE level or
      COAE threshold between age groups. Significant differences in COAEs were found
      for subjects based on whether they had measurable SSOAEs, regardless of age.
      CONCLUSIONS: Age does not significantly reduce COAE level nor increase COAE
      threshold. Other factors, such as presence of SSOAEs and hearing loss,
      undoubtedly have more influence on COAEs than the factor of age.

PMID- 8654908
TI  - The effect of multichannel compression on vowel and stop-consonant discrimination
      in normal-hearing and hearing-impaired subjects.
AB  - OBJECTIVE: Multichannel compression (MCC) processing can alter the speech
      spectrum, perhaps reducing spectral contrasts that are important for the
      discrimination of certain speech sounds. The effect of MCC processing on the
      discrimination of vowels and voiced stop consonants was studied. DESIGN: Vowels
      and voiced stop consonants were MCC-processed in two ways: 1) FLAT MCC having the
      same compression ratio in each channel, and 2)SHAPED MCC having compression
      ratios in each channel adjusted to the auditory area of the particular subject.
      The stimuli were processed both ways using 2, 4, 8, 16, and 31 independent
      compression channels. Unprocessed and linearly amplified stimuli were used as
      control conditions. Normal-hearing and hearing-impaired subjects were tested for
      changes in discrimination performance as a function of the MCC processing
      parameters. RESULTS: When the MCC processing was adjusted specifically for an
      individual hearing impared subject, no negative effect of increasing numbers of
      channels (2 to 31)was found. In the case of FLAT MCC processing, increasingly
      degraded discrimination performance was found for both subject groups as the
      compression ratio increased and as the number of channels increased. There was
      also a strong interaction between the effects of the number of channels and the
      compression ratio, with the negative effects of increasing numbers of channels
      being much greater at the highest compression ratio. CONCLUSIONS: Negative
      effects of MCC were found only for very extreme MCC conditions. MCC processing
      with compression ratios adjusted in each channel for the individual subject, and
      having as many as 31 channels, revealed no negative effects on vowel or voiced
      stop-consonant discrimination. These results do not support the prevalent view
      that MCC with more than two or three channels will be detrimental and should
      encourage further research on MCC processing with larger numbers of channels.

PMID- 8654909
TI  - Repeated DNA sequences isolated by microdissection. I. Karyotyping of barley
      (Hordeum vulgare L.).
AB  - We report on microdissection, cloning and sequence, and Southern and fluorescence
      in situ hybridization (FISH) analysis of one moderately and one highly amplified
      repetitive DNA element, pHvMWG2314 and pHvMWG2315, respectively, isolated from
      barley (Hordeum vulgare L.) chromosome arm 3HL. The pHvMWG2315 sequence
      hybridizes to all 14 telomeric or subtelomeric regions of the barley chromosomes
      as determined by FISH. The 50 different hybridization sites that include
      intercalary signals allow the discrimination of all 14 chromosome arms and the
      construction of a kariotype of barley. The tandemly repeated subtelomeric element
      of 331 bp exists in all Triticeae species tested (H. vulgare, Agropyron
      elongatum, Secale cereale, Triticum tauschii, T. turgidum, and T. aestivum). It
      is AT rich (66%), exibits 84% sequence homology to subfragments of the D genome
      ?specific? 1-kb element pAs1 of T. tauscii and 75% homology to interspersed
      genome-specific DNA sequence pHcKB6 from H. chilence. The repetitive sequence
      pHvMWG2314 is moderately amplified in barley and highly amplified in hexaploid
      wheat. The in situ experiments revealed no distinct signals on barley
      chromosomes, indicating a dispersed character for the sequence. The significance
      of the results for the identification of chromosomes and chromosome aberrations
      in FISH experiments are discussed.

PMID- 8654910
TI  - Genetic and cytological mapping of a "Y-2" translocation in the Mediterranean
      fruit fly Ceratitis capitata.
AB  - In this paper we analyze genetically and cytologically a Y-chromosome 2
      translocation with several markers, some of which are potentially useful for
      large scale sex separation. The breakpoint of this Y-2 translocation is located
      at region 6B on the trichogene polytene chromosome map. It is found that, in
      strains carrying this TY-2, only 40% of the fertilized eggs survived to the adult
      stage, 26% of them dying as embryos, 27% as larvae, and 7% as pupae. Early
      lethality is explained by the nonviability of adjacent-1 products of meiosis
      containing a deletion of section 1A-6B. The reciprocal segregation products,
      carrying this chromosome segment in triplicate, survive until late stages. By
      analyzing the phenotype of the individuals we conclude that all markers used in
      this study are located outside the triplicated region and that the male
      determining factor is not included in the piece of the Y chromosome translocated
      to chromosome 2. The male recombination frequencies of several genes located on
      chromosome 2 relative to the breakpoint of translocation T5038 have also been
      studied here.

PMID- 8654911
TI  - Cloning of a DNA repeat element from horse: DNA sequence and chromosomal
      localization.
AB  - A DNA repeat element, revealed initially by digestion of horse DNA with TaqI, was
      cloned and characterized by Southern and in situ hybridization studies and
      nucleotide sequencing. The clone, e4/1, consisted of 32 tandem reiteration of a
      unit repeat of 21-22 bp, and produced multilocus DNA fingerprinting profiles that
      were useful for parentage analysis in horses. The tandem repeat element was shown
      by in situ hybridization to be localized in the centromeres of the acrocentric
      but not metacentric classes of horse chromosomes.

PMID- 8654912
TI  - Analysis of the genetic composition of anther-derived potato by randomly
      amplified polymorphic DNA and simple sequence repeats.
AB  - Randomly amplified polymorphic DNA (RAPD) and simple sequence repeat (SSR)
      analyses were used to characterize the genetic composition of anther-derived
      plants of a diploid potato clone, CP2 (Solanum chacoense 80-1 x S. phureja 1-3).
      The ploidy of anther-derived plants was first determined by flow cytometry. A
      total of 44 decamer primers was screened for RAPD polymorphism. The loci that
      segregated were selected and scored. The monoploids had less than half as many
      loci carrying RAPD markers compared with the anther donor. Among 14 anther
      derived diploids, 5 were identified as homozygous by marker frequency similar to
      monoploids and 9 as heterozygous. Five of seven SSRs obtained from published
      potato sequences were polymorphic in CP2. CP2 was found to be heterozygous with
      two alleles at four SSR loci (TC/TA, AAG, AGA, CTT) and three alleles at a ACTC
      locus. Primer pairs flanking each of the five polymorphic SSRs revealed that
      monoploids had only the allele contributed by S. chacoense 80-1. Homozygous
      diploids had only one band per SSR locus, whereas heterozygous diploids displayed
      more than one allele for at least one SSR locus. Results of the SSR analysis
      supported the findings based on RAPD markers; the same five diploid clones were
      characterized as homozygous by both SSR and RAPD markers.

PMID- 8654913
TI  - Frequency of microsatellite sequences in rice (Oryza sativa L.).
AB  - This study was undertaken to estimate the relative frequencies of 13
      microsatellite motifs in the rice genome as a basis for efficient development of
      a microsatellite map. Two dinucleotide, seven trinucleotide, and four
      tetranucleotide repeat motifs were end labelled and used as hybridization probes
      to screen genomic and cDNA libraries of rice, cv. IR36. Optimal washing
      temperatures for identification of clones containing specific microsatellite
      motifs were estimated based on washing temperatures near Td (dissociation
      temperature; Td = Tm - 7.6 degrees C). Sequencing of 20 putatively positive
      clones corresponding to each of 4 microsatellite motifs suggested that while Td
      provides a useful predictor of washing stringency for most of the repeats
      studied, those with a very high GC or AT content were most prone to error. The
      results from screening the rice genomic library suggest that there are an
      estimated 1360 poly(GA)n and 1230 poly(GT)n microsatellites in the rice genome,
      and that the relative frequency of different repeats decreased with increasing
      size of the motif. The most frequently observed microsatellites in the cDNA
      library were the same as for genomic library, but no poly(CGG)n, poly(ATC)n, or
      tetranucleotide motifs were observed among cDNA in this study.

PMID- 8654914
TI  - Cloning and characterization of the majority of repetitive DNA in cotton
      (Gossypium L.).
AB  - Repetitive DNA elements representing 60-70% of the total repetitive DNA in
      tetraploid cotton (Gossypium barbadense L.) and comprising 30-36% of the
      tetraploid cotton genome were isolated from a genomic library of DNA digested
      with a mixture of four blunt-end cutting restriction enzymes. A total of 313
      clones putatively containing nuclear repetitive sequences were classified into
      1103 families, based on cross hybridization and Southern blot analysis. The 103
      families were characterized in terms of genome organization, methylation pattern,
      abundance, and DNA variation. As in many other eukaryotic genomes, interspersed
      repetitive elements are the most abundant class of repetitive DNA in the cotton
      genome. Paucity of tandem repeat families with high copy numbers (>10(4)) may be
      a unique feature of the cotton genome as compared with other higher plant
      genomes. Interspersed repeats tend to be methylated, while tandem repeats seem to
      be largely unmethylated in the cotton genome. Minimal variation in repertoire and
      overall copy number of repetitive DNA elements among different tetraploid cotton
      species is consistent with the hypothesis of a relatively recent origin of
      tetraploid cottons.

PMID- 8654915
TI  - Genomic organization of 57 ribosomal protein genes in rice (Oryza sativa L.)
      through RFLP mapping.
AB  - Four hundred cDNA clones from rice (Oryza sativa L.) callus and root cDNA
      libraries, with a high similarity to about 70 kinds of ribosomal proteins (r
      protein) in eukaryotic as well as procaryotic organisms, were identified by their
      deduced amino acid sequences. Southern hybridization of 114 independent cDNA
      clones with total rice genomic DNA showed 77 distinct and specific hybridization
      patterns. Of the 77 clones representing the above hybridization patterns, copies
      of 67 clones corresponding to 57 r-proteins could be estimated and, among these,
      only 6 clones were single copy, indicating that almost 90% of these r-proteins in
      rice were encoded by small multigene families. Loci of 36 r-protein genes could
      be mapped on the rice linkage map by using 30 full-length cDNA clone sequences
      from specific RELP bands. Another 21 expressed gene loci were mapped using 3'
      untranslated region specific cDNA probes amplified from the multicopy cDNA clones
      representing 17 of the r-protein multicopy gene families. The above 57 loci were
      mapped from 51 cDNA clones and 41 of these r-protein genes mapped to regions that
      did not show any clustering, while in 5 cases, pairs of r-protein genes
      cosegregated or linked closely. The r-protein genes in rice were located
      throughout the 12 chromosomes and it was found that more than one copy within a
      multigene family may be expressed simultaneously.

PMID- 8654916
TI  - Variations of two repetitive DNA sequences in several Triticeae genomes revealed
      by polymerase chain reaction and sequencing.
AB  - Genomes of Triticeae were analyzed using PCR with synthesized primers that were
      based on two published repetitive DNA sequences, pLeUCD2 (pLe2) and 1-E6hcII-1
      (L02368),which were originally isolated from Thinopyrum elongatum. The various
      genomes produced a 2240 bp PCR product having high homology with the repetitive
      DNA pLe2. The PCR fragments produced from different genomes differed mainly in
      amplification quantity and in base composition at 89 variable sites. On the other
      hand, amplification products from the primer set for L02368 were of different
      sizes and nucleotide sequences. These results show that the two repetitive DNA
      sequences have different evolutionary significance. ple2 is present in all
      genomes tested, although differences in copy number and nucleotide sequence are
      notable. L02368 is more genome specific, i.e., fewer genomes possess this family
      of repetitive sequences. It was concluded that the repetitive sequence pLe2
      family is an ancient one that existed in progenitor genome prior to divergence of
      annual and perennial genomes. In contrast, sequences similar to L02368 have only
      evolved following genome divergence.

PMID- 8654917
TI  - Molecular and cytological characterization of a highly repeated DNA sequence in
      Raphanus sativus.
AB  - A highly repeated DNA sequence with a repeat unit of ca. 180 bp was found in
      genomic DNA HindIII-digests of Raphanus sativus. The repeating units of six
      isolated, independent clones were sequenced. These units have 177 or 178 bp, are
      36% G+C in their DNA base composition, and show 90% sequence homology. The copy
      number of this 180-bp repeat unit is about 0.5 x 10(6) per diploid genome. In
      situ hybridization analysis with the repeating units as the probe and C-banding
      analysis indicated that the repeated DNA sequence of R. sativus is closely
      associated with the major C-heterochromatins in the proximal regions of all 18
      chromosomes at mitotic metaphase.

PMID- 8654918
TI  - Microsatellite sequences in a conifer, Pinus sylvestris.
AB  - Scots pine (Pinus sylvestris) genomic libraries were constructed and screened
      with oligonucleotides probes (GT)10, (CT)10, and (AT)10. Eight microsatellites
      were identified from 6000 clones screened. The longest microsatellite stretch
      found, (CT)9(N)21(AT)24, was amplified from bud and single pollen grain samples.
      In order to clarify the complex amplification pattern revealed, two PCR products
      were sequenced. The size differences were caused both by varying repeat numbers
      of the microsatellite stretches and by differences in other parts of the
      amplified sequence. This kind of complex molecular basis of microsatellite
      amplification within a species has been previously reported. Microsatellite
      sequences were used as PCR primers to detect polymorphisms and to estimate the
      abundance of microsatellites.

PMID- 8654920
TI  - Families of tandemly repeated DNA elements from horse: cloning, nucleotide
      sequence, and organization.
AB  - DNA repeats, revealed initially by digestion of horse DNA with restriction
      enzymes, were cloned and characterized by cross-hybridization studies and
      nucleotide sequencing. The Sau-like family of tandem repeats contained two
      classes of repetitive elements with unit repeats of about 80 bp that shared no
      sequence similarity. Both unit repeats were present, frequently in tandem, in
      cloned segments of horse DNA of less than 600 bp. Evidence is presented, based on
      their ladderlike patterns of hybridization to horse DNA and their high level of
      similarity to published sequences of satellites from equine DNA, suggesting that
      they are centromerically located in the horse genome. The Sau-like tandem repeat
      families were specific to Equidae. Another class of repeats, GATA-like elements,
      which did not appear to have a centromeric distribution, was also cloned and
      sequenced.

PMID- 8654919
TI  - FokI DNA repeats in the genome of Vicia faba: species specificity, structure,
      redundancy modulation, and nuclear organization.
AB  - Tandemly repeated DNA sequences about 60 bp in length, which may be isolated by
      digestion with FokI restriction endonuclease, were studied by means of molecular
      and cytological hybridization in Vicia faba and other Vicia species. The results
      obtained can be summarized as follows: (i) FokI repeats are almost species
      specific to V. faba, since they hybridize to a minimum extent to genomic DNA of
      only two out of five related species; (ii) these tandemly repeated elements
      display variability in structure even within one and the same array, where
      different repeats may share not more than 71% homology; (iii) their redundancy in
      the genome of V. faba is remarkably high and varies largely between land races
      (copy numbers per haploid, 1C, genome range from 21.51 x 10(6) to 5.39 x 10(6));
      (iv) FokI repeats are clustered in differing amounts in each subtelocentric pair
      of the chromosome complement and are missing or present in a nondetectable amount
      in the submetacentric pair; (vi) chromosome regions that bear these repeats
      associate closely to varying degrees in interphase nuclei. These results are
      discussed in relation to possible functional roles that tandemly repeated DNA
      sequences such as the FokI elements might play.

PMID- 8654921
TI  - Inositols do it all.

PMID- 8654922
TI  - p53: puzzle and paradigm.

PMID- 8654923
TI  - The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with
      substrate specificities similar to those of the human CPP32 protease.
AB  - The Caenorhabditis elegans cell-death gene ced-3 encodes a protein similar to
      mammalian interleukin-1beta-converting enzyme (ICE), a cysteine protease
      implicated in mammalian apoptosis. We show that the full-length CED-3 protein
      undergoes proteolytic activation to generate a CED-3 cysteine protease and that
      CED-3 protease activity is required for killing cells by programmed cell death in
      C. elegans. We developed an easy and general method for the purification of CED
      3/ICE-like proteases and used this method to facilitate a comparison of the
      substrate specificities of four different purified cysteine proteases. We found
      that in its substrate preferences CED-3 was more similar to the mammalian CPP32
      protease than to mammalian ICE or NEDD2/ICH-1 protease. Our results suggest that
      different mammalian CED-3/ICE-like proteases may have distinct roles in mammalian
      apoptosis and that CPP32 is a candidate for being a mammalian functional
      equivalent of CED-3.

PMID- 8654924
TI  - p150Ship, a signal transduction molecule with inositol polyphosphate-5
      phosphatase activity.
AB  - The production, survival, and function of monocytes and macrophages is regulated
      by the macrophage colony-stimulating factor (M-CSF or CSF-1) through its tyrosine
      kinase receptor Fms. Binding of M-CSF to Fms induces the tyrosine phosphorylation
      and association of a 150-kD protein with the phosphotyrosine-binding (PTB) domain
      of Shc. We have cloned p150 using a modified yeast two-hybrid screen. p150
      contains one SH2 domain, two potential PTB-binding sites, an ATP/GTP-binding
      domain, several potential SH3-binding sites, and a domain with homology to
      inositol polyphosphate-5-phosphatases. p150 antibodies detect this protein in FDC
      P1 myeloid cells, but the same protein is not detectable in fibroblasts. The
      antibodies immunoprecipitate a 150-kD protein from quiescent or M-CSF-stimulated
      FDC-P1 cells that hydrolyzes PtdIns(3,4,5)P3, to PtdIns(3,4)P2. This activity is
      observed in Shc immunoprecipitates only after M-CSF stimulation. Retroviral
      expression of p15O in FD-Fms cells results in strong inhibition of cell growth in
      M-CSF and a lesser inhibition in IL-3. Ectopic expression of p150 in fibroblasts
      does not inhibit growth. This novel protein, p150(ship) (SH2-containing inositol
      phosphatase), identifies a component of a new growth factor-receptor signaling
      pathway in hematopoietic cells.

PMID- 8654925
TI  - ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to
      fatty acid metabolism.
AB  - Adipocyte determination and differentiation-dependent factor 1 (ADD1) is a member
      of the basic helix-loop-helix leucine zipper (bHLH-LZ) family of transcription
      factors that binds to two distinct DNA sequences and has been associated with
      both adipocyte development and cholesterol homeostasis (where it has been termed
      SREBP1). To investigate the biological role of ADD1, we expressed wild-type and
      dominant negative forms of this protein with retroviral vectors in preadipocytes
      and nonadipogenic cells. A dominant-negative form of ADD1 with a point mutation
      in the DNA-binding domain sharply represses the differentiation of 3T3-L1 cells
      as observed morphologically or by the expression of adipocyte-specific mRNAs.
      When NIH-3T3 cells ectopically expressing ADD1 are cultured under hormonal
      conditions not favoring differentiation, they do not overtly differentiate but
      still activate expression of mRNAs for fatty acid synthase (FAS) and lipoprotein
      lipase (LPL), two key genes that regulate fatty acid metabolism. Under culture
      conditions permissive for differentiation including a PPAR activator, 15%-20% of
      the cells expressing ADD1 undergo adipogenesis while 2%-3% of cells containing a
      control vector differentiate. Simultaneous expression of ADD1 with PPARgamma
      increases the transcriptional activity of this adipogenic nuclear hormone
      receptor, suggesting involvement of ADD1 in this pathway. These data indicate
      that ADD1 plays an important role in fat cell gene expression and
      differentiation, and suggest that it may function by augmenting a step in
      PPARgamma-mediated transcription.

PMID- 8654926
TI  - Pollux, a novel Drosophila adhesion molecule, belongs to a family of proteins
      expressed in plants, yeast, nematodes, and man.
AB  - Adhesion molecules have pivotal roles in cellular processes critical to the
      development and maintenance of multicellular organisms. Here we describe a new
      member of the adhesive repertoire encoded by the Drosophila pollux (plx) gene.
      Marked by a novel 74-amino-acid domain, Plx belongs to a highly conserved family
      with members in plants, yeast, nematodes, and man, including the human
      oncoprotein TRE17. Essential for viability, plx mutant analysis indicates that
      larval death is attributable to asphyxiation brought on by fluid-congested
      tracheal tubes. Ultrastructural examination of mutant tracheae reveals defects in
      cell-extracellular matrix contacts. During embryogenesis, Plx uniformly covers
      the apical surface of cellular blastoderm cells. It is later found regionally
      concentrated along subsets of central nervous system axon pathways and on the
      apical surface of the trachea's tubular epithelium. Cell attachment assays
      demonstrate that Plx can serve as a ligand for cell surface integrins. Plx also
      contains a motor neuron-selective adhesive site, multiple proteoglycan-binding
      motifs, and a leucine zipper: all suggest possible associations with additional
      components of the adhesion complex.

PMID- 8654927
TI  - Posterior patterning by the Caenorhabditis elegans even-skipped homolog vab-7.
AB  - Patterning of the posterior end in animals is not well understood. Homologs of
      Drosophila even-skipped (eve) have a similar posterior expression pattern in many
      animals, and in vertebrates they are linked physically to the "posterior" ends of
      homeotic clusters (HOM-C), suggesting a conserved role in posterior development.
      However, the function of this posterior expression is not known. Here I show that
      the Caenorhabditis elegans gene vab-7 encodes an eve homolog that is required for
      posterior development and expressed in a pattern strikingly similar to that of
      vertebrate eve genes. Using a four-dimensional recording system, I found that
      posterior body muscles and the posterior epidermis are patterned abnormally in
      vab-7 mutants, but commitment to muscle and epidermal fates is normal.
      Furthermore, vab-7 activity is required for the complete expression of the most
      posterior HOM-C gene egl-5 in muscle cells, supporting the idea that eve homologs
      may act with the HOM-C to determine posterior cell fates. The conservation of
      sequence and expression pattern between vab-7 and eve homologs in other animals
      argues that most eve genes have posterior mesodermal and ectodermal patterning
      functions.

PMID- 8654928
TI  - Activation of transcription in Drosophila embryos is a gradual process mediated
      by the nucleocytoplasmic ratio.
AB  - We have observed that zygotic transcription does not initiate at a single point
      in Drosophila embryos. Rather, a gene initiates transcription in a few nuclei of
      a fraction of embryos. During succeeding cycles, the frequency of transcribing
      embryos, and of nuclei transcribing in those embryos, gradually increases. For
      the fushi tarazu (ftz) gene, the timing of this process is regulated by the
      concentration of the maternally loaded, repressing transcription factor tramtrack
      (ttk). Altering the dose of Ttk protein in embryos shifts the activation of ftz
      transcription either forward or backward during development but does not effect
      Kruppel (Kr) activation. We have observed that the transcription of several
      genes, including ftz, is triggered in embryos at a critical nuclear density;
      therefore, we suggest that titration of transcription factors like ttk by the
      nucleocytoplasmic ratio triggers zygotic transcription in Drosophila.

PMID- 8654929
TI  - The RNA-binding protein HF-I, known as a host factor for phage Qbeta RNA
      replication, is essential for rpoS translation in Escherichia coli.
AB  - The rpoS-encoded sigma(S) subunit of RNA polymerase in Escherichia coli is a
      global regulatory factor involved in several stress responses. Mainly because of
      increased rpoS translation and stabilization of sigma(S), which in nonstressed
      cells is a highly unstable protein, the cellular sigma(S) content increases
      during entry into stationary phase and in response to hyperosmolarity. Here, we
      identify the hfq-encoded RNA-binding protein HF-I, which has been known
      previously only as a host factor for the replication of phage Qbeta RNA, as an
      essential factor for rpoS translation. An hfq null mutant exhibits strongly
      reduced sigma(S) levels under all conditions tested and is deficient for growth
      phase-related and osmotic induction of sigma(S). Using a combination of gene
      fusion analysis and pulse-chase experiments, we demonstrate that the hfq mutant
      is specifically impaired in rpoS translation. We also present evidence that the H
      NS protein, which has been shown to affect rpoS translation, acts in the same
      regulatory pathway as HF-I at a position upstream of HF-I or in conjunction with
      HF-I. In addition, we show that expression and heat induction of the heat shock
      sigma factor sigma(32) (encoded by rpoH) is not dependent on HF-I, although rpoH
      and rpoS are both subject to translational regulation probably mediated by
      changes in mRNA secondary structure. HF-I is the first factor known to be
      specifically involved in rpoS translation, and this role is the first cellular
      function to be identified for this abundant ribosome-associated RNA-binding
      protein in E. coli.

PMID- 8654930
TI  - Restriction of the activity of the recombination site dif to a small zone of the
      Escherichia coli chromosome.
AB  - The recombination site dif is the target on the Escherichia coli chromosome of
      the site-specific recombinases XerC and XerD. The dif/XerC-D system plays a role
      during the cell cycle, probably by favoring sister chromosome monomerization or
      separation. A phenomenon of regional control over dif activity, also analyzed in
      this issue, is demonstrated here by translocation of dif to a series of loci
      close to the normal locus. We found that the site is physiologically active only
      within a narrow zone around its natural position. Competence for dif activity
      does not depend on the sequence of the normal dif activity zone (DAZ), because
      delta(dif) deletions larger than the DAZ result in Dif+ bacteria when dif is
      reinserted at the junction point. Although dif maps where replication normally
      terminates, termination of replication is not the elicitor. A strain with a large
      inversion that places dif and its surrounding region close to oriC remains Dif+,
      even when a Tus- mutation allows replication to terminate far away from it.
      Preliminary data suggest the possibility that specialized sequences separate the
      competent zone from the rest of the chromosome. We suspect that these sequences
      are members of a set of sequences involved in a polarized process of
      postreplicative reconstruction of the nucleoid structure. We propose that this
      reconstruction forces catenation links between sister chromosomes to accumulate
      within the DAZ, where they eventually favor recombination at dif.

PMID- 8654931
TI  - Use of a transposon (Tndif) to obtain suppressing and nonsuppressing insertions
      of the dif resolvase site of Escherichia coli.
AB  - The dif locus is a RecA-independent recombination site, located in the terminus
      region of the chromosome of Escherichia coli. This site functions to reduce
      circular dimer chromosomes to monomers before cell division. Strains lacking this
      site exhibit the Dif phenotype, in which a fraction of the cells form extended
      filaments with abnormal nucleoids, and the SOS system is induced. We have used a
      transposon (Tndif), as well as linear transformation, to position dif in 19
      locations around the chromosome. All of the suppressing insertions that we
      obtained were within 10 kb of the normal site, even in strains in which the
      normal symmetry, between the origin of replication and dif had been altered by
      200 kb. We also observed that the nonsuppressing insertions in the terminus
      region became suppressing if a deletion occurred that extended from the ectopic
      site up to or past the normal location of dif. We propose that dif is normally
      located at the center of converging polarities in the terminus region and that
      deletions that restore suppression do so by placing ectopic sites once again at
      the center of this polarity. Similar results and conclusions are described in
      this issue.

PMID- 8654932
TI  - Functional analysis of a mosquito gamma-aminobutyric acid receptor gene promoter.
AB  - A single point mutation in the insect gamma-aminobutyric acid receptor (GABAR)
      encoding gene (Rdl) confers high levels of resistance to cyclodienes in
      Drosophila and other insects. We were interested in studying the promoter of this
      gene for two reasons. Firstly, to define the elements underlying Rdl expression.
      Secondly, to identify the minimum set of regulatory elements necessary for
      construction of a functional Rdl minigene. Such an insecticide-resistance
      associated minigene should form a strong selectable marker for use in the genetic
      transformation of non-drosophilid pest insects, such as mosquitoes. Here, we
      report the identification of the region containing the rdl promoter, via
      transient expression of a luc reporter gene following micro-injection into
      embryos of the mosquito Aedes aegypti. Promoter activity is contained within a
      2.53-kb fragment immediately upstream from the rdl start codon. Primer extension
      shows three closely linked sites for transcript initiation within this region and
      sequence analysis reveals anumber of putative consensus regulatory sequences
      shared by other genes expressed in the nervous system. The implications for
      construction of a functional minigene and the identification of cis-acting
      control elements underlying ion-channel gene regulation are discussed.

PMID- 8654934
TI  - Polymorphism of the mouse E2A gene due to an intronic deletion of 536 bp.
AB  - Examination of genetic polymorphism of the transcription factor-encoding gene E2A
      in laboratory and wild mice by Southern blotting has revealed the presence of two
      alleles. The most frequent allele is found in Mus musculus (Mm) musculus, as well
      as Mm domesticus. The less common allele is restricted to the Mm domesticus
      subspecies. Characterisation of these alleles has shown that the less common
      allele contains a deletion of approx. 500 bp located within a 1.8-kb intron
      immediately upstream from the E12 basic helix-loop-helix exon. DNA sequencing
      determined the deletion to span 536 bp including nucleotides 1045-1580 of the
      intron within the common allele. The deleted region includes several sequences
      with similarity to gene regulatory motifs; however, expression of E12 and intron
      splicing appeat unaltered. The occurrence of an identical deletion in mice from
      different geographical regions suggests that the uncommon allele may have a long
      evolutionary history.

PMID- 8654933
TI  - Alternative splicing of the Drosophila melanogaster rotundRacGAP gene.
AB  - The rotund (rn) gene in Drosophila melanogaster codes for a RacGTPase-activating
      protein, RnRacGAP. Cellular studies have shown that RacGAP proteins function as
      negative regulators of substrate Rac proteins which, in turn, control the
      localization and polymerization state of actin within the cell. Previous sequence
      analysis of rn genomic DNA and incomplete cDNA clones suggested that at least two
      differentially spliced forms of the transcript exist, rnRacGAP(1) and
      rnRacGAP(2). Using nested reverse transcription-polymerase chain reaction (RT
      PCR) methods, we have cloned missing exon and intron sequences, and detected
      differences between rnRacGAP(1) and rnRacGAP(2) involving 24 nucleotides (nt) of
      coding sequences and 119 nt of 3'UTR. This translates to a difference of seven
      amino acids at the C-termini of the polypeptide products. Utilization, in RT-PCR
      analysis, of form-specific primers provided a simple assay for the tissue
      specificity of expression of the two forms. rnRacGAP(1) is the predominant
      species in the testes and is expressed at a low level in the ovary and somatic
      tissues. rnRacGAP(2) is only very weakly expressed and is detectable solely in
      the testes.

PMID- 8654935
TI  - Activation of mts1 transcription by insertion of a retrovirus-like IAP element.
AB  - The mechanism of activation of mestatasis-associated mts1 gene transcription in
      the mouse myelomonocytic leukaemia WEHI-3 cell line is described. Northern blot
      analysis showed that WEHi-3 cells expressed two types of mts1-specific mRNA:
      standard (550 nt) and additional (about 800 nt). The steady-state expression
      level of the 800-nt RNA was isolated and sequence analysis showed that it
      contained a 357-bp fragment represented by long terminal repeat (LTR) sequences
      and a 5' untranslated region of the gag gene of the intracisternal A-particle
      (IAP) element. The chimeric IAP::mts1 800-nt mRNA is initiated from the 5' LTR
      promoter. The rearranged and normal loci of mts1 were cloned and partially
      sequenced. The results suggested that the insertion of the IAP sequences into the
      first intron of mts1 brings the gene under control of the strong IAP promoter.
      The additional chimeric 800-nt IAP::mts1 RNA transcript was the result of a
      splicing event linking IAP sequences with the coding part of mts1. We suggest
      that the chimeric IAP::mts1 RNA is capable of producing a functional Mts1
      protein.

PMID- 8654936
TI  - A mouse kidney- and liver-expressed cDNA having homology with a prokaryotic
      parathion hydrolase (phosphotriesterase)-encoding gene: abnormal expression in
      injured and polycystic kidneys.
AB  - To investigate abnormalities in gene expression associated with cyst formation in
      polycystic kidney disease, differential cDNA library screening was carried out
      using RNA from normal and cystic kidneys of the C57BL/6J-cpk mouse. Among a
      number of genes found to be abnormally expressed was one (cDNA clone 56-1) that
      was significantly underexpressed in cystic kidneys. Hybridization analyses
      revealed that the 56-1 mRNA is expressed primarily in kidney and liver, and that
      the kidney expression begins postnatally and continues in the adult. Expression
      of this mRNA was found to be significantly decreased upon acute renal injury
      induced by a single intraperitoneal injection of folic acid, and to return to
      normal levels upon recovery of kidney function. Analysis of the cDNA sequence
      predicted a protein of 349 amino acids (aa), which was confirmed by in vitro
      translation of a sense-strand transcript, producing a protein of approx. 39 kDa.
      The aa sequence shows similarity to Flavobacterium sp. and Pseudomonas diminuta
      parathion hydrolase (phosphotriesterase or PTE), an enzyme that hydrolyzes toxic
      organophosphates and other phosphotriesters, and to the predicted product of an
      Escherichia coli open reading frame of unknown function (phosphotriesterase
      homology protein or PHP). Use of optimal alignment programs demonstrated a
      significant overall homology between the bacterial and mouse sequences, with
      greater than 50% aa sequence similarity. This cDNA represents the first
      eukaryotic sequence showing similarity to these prokaryotic genes. Based on this
      apparent homology, it has been named mpr56-1 (for mouse phosphotriesterase
      related 56-1).

PMID- 8654937
TI  - Two versatile eukaryotic vectors permitting epitope tagging, radiolabelling and
      nuclear localisation of expressed proteins.
AB  - Two versatile eukaryotic expression vectors have been developed which permit the
      production of an epitope-tagged cDNA insert by transient transfection in
      mammalian cells or by in vitro transcription-translation. The first vector,
      pCATCH, can be used to clone cDNA inserts in three different frames via eight
      unique restriction sites in a multiple cloning site (MCS) located downstream from
      both the FLAG epitope and the specific heart muscle kinase phosphorylation site,
      conferring the possibility of in vitro radiolabelling. A specific protease
      cleavage site enables the removal of the FLAG epitope, simplifying affinity
      purification of recombinant CATCH proteins. pCATCH possesses stop codons in all
      three reading frames at the 3' terminal end of the MCS. A derivate of this
      vector, pCATCH-NLS, was constructed by incorporating an SV40 nuclear localisation
      signal upstream from the MCS, for directed localisation of the tagged proteins.

PMID- 8654938
TI  - An autonomously replicating eukaryotic expression vector with a tetracycline
      responsive promoter.
AB  - The control elements of the tetracycline-resistance operon encoded in Tn10 of
      Escherichia coli have previously been utilized by Gossen and Bujard [ Proc. Natl.
      Acad. Sci. 89 (1992) 5547-5551] to establish an efficient transcription
      regulatory system in mammalian cells. We describe here a modification of this
      vector system that encodes all required elements, including a neomycin-resistance
      gene, on an autonomously replicating episome. This, thereby, allows for improved
      transfection frequency and episome stability, providing an easily selectable
      marker gene and a promoter whose activity can be easily modulated to control gene
      expression.

PMID- 8654939
TI  - pHIVTATA-CAT, a versatile vector to study transcriptional regulatory elements in
      mammalian cells.
AB  - We have constructed a vector, pHIVTATA-CAT, that contains the Escherichia coli
      cat gene, encoding chloramphenicol acetyltransferase, under the control of a
      minimal promoter consisting of the HIV TATA box and the adenovirus major late
      promoter initiator element. Putative transcriptional elements can be inserted
      either directly upstream from the TATA box or downstream from the reporter gene
      in an enhancer position. Transcription can be monitored enzymatically or by RNase
      protection mapping. An analysis of mRNAs generated from pHIVTATA-CAT constructs
      revealed that transcription starts at the transcription start point and no read
      through transcripts are generated.

PMID- 8654940
TI  - Cloning, sequence determination and functional expression of the genes encoding
      adenovirus type-4 polymerase and the terminal protein precursor.
AB  - Sequences of the open reading frames encoding adenovirus type 4 (Ad4) DNA
      polymerase and the terminal protein precursor were determined. Sequence
      comparisons with the corresponding genes and proteins from Ad2 and Ad5 show high
      overall identity, but significant differences in those portions of the two
      proteins thought to be essential for their biological activities. Both Ad4
      proteins were functionally expressed in insect cells from the corresponding
      cDNAs.

PMID- 8654941
TI  - Sequence of the mouse adenovirus type-1 DNA encoding the 100-kDa, 33-kDa and DNA
      binding proteins.
AB  - The genomic nucleotide sequence for the region of 66 to 77 map units (m.u.) of
      mouse adenovirus type 1 (MAV-1) was determined and predicted to encode proteins
      homologous to the human adenovirus (Ad) 100-kDa, 33kDa and DNA-binding proteins
      (DBP). The putative MAV-1 100-kDa protein has 65-70% amino-acid similarity to 100
      kDa proteins from five different human Ad serotypes. The mRNA for the putative 33
      kDa protein is internally spliced within the coding sequence, as are its human Ad
      counterparts [Oosterom-Dragon and Anderson, J. Virol 45 (1983) 251-263]. The N
      terminal region of the putative MAV-1 33-kDa protein has 41-44% similarity to two
      human Ad 33-kDa N-termini, and the C-terminal regions are more conserved, with 60
      65% similarity. The MAV-1 DBP is predicted to be encoded in this region and was
      compared to six different human Ad DBP N-and C-termini. The N-termini of the MAV
      1 and Ad DBP were 33-48% similar and the C-termini were 56-60% similar. The MAV-1
      DBP contains conserved regions (CR) 1,2 and 3, and it retains important residues
      for a putative zinc finger (Zf) motif identified in Ad DBP [Eagle and Klessig,
      Virology 187 (1992) 777-787]. Additional sequence features of these proteins have
      also been identified.

PMID- 8654942
TI  - Sequence and expression of a bovine herpesvirus-1 gene homologous to the
      glycoprotein K-encoding gene of herpes simplex virus-1.
AB  - In the bovine herpes virus-1 (BHV-1) genome, a gene equivalent to the
      glycoprotein k (gK)-encoding gene of other herpesviruses was identified and
      sequenced. The primary translation product is predicted to comprise 338 amino
      acids (aa) and to exhibit a molecular mass of 37.5 kDa. It possesses
      characteristics typical for membrane glycoproteins including a potential
      cleavable signal sequence, three transmembrane domains and two potential N-linked
      glycosylation sites. Comparison to the gK proteins of the other herpesviruses
      revealed aa sequence homologies of 46, 44, 53, 43, and 46% with the gK
      counterparts of herpes simplex viruses-1 and 2 (HSV-1 and 2), equine herpesvirus
      1 (EHV-1), Marek's disease virus (MDV) and varicella zoster virus (VZV),
      respectively. A 30-kDa primary translation product was identified following in
      vitro translation of in vitro transcribed mRNA. When canine microsomal membranes
      were added to the translation reaction, a 38-kDa glycosylated protein was
      detected. Treatment with endoglycosidase F or H (endo or H) removed the glycosyl
      groups and reduced the apparent molecular mass of the 38-kDa glycoprotein.

PMID- 8654943
TI  - Efficiency of different viral promoters in directing gene expression in mammalian
      cells: effect of 3'-untranslated sequences.
AB  - We compared (i) the enhancer/promoter (mCMV promoter) from the murine
      cytomegalovirus (CMV) major immediate early gene,(ii) the enhancer/promoter from
      human CMV major immediate early gene, containing a short promoter (h1CMV) or a
      long stretch of 5' untranslated region (UTR) from the gene promoter (h2CMV) and
      (iii) the simian virus 40 (SV40) enhancer/early region promoter (SV2) for their
      ability to direct foreign gene expression in transiently transfected mammalian
      cell lines. Two series of recombinant plasmids containing the different viral
      promoters fused to the cat reporter gene and 3'-UTR for processing of transcripts
      from either the SV40 early region or the rabbit Beta 1-globin-encoding gene (Glb)
      were also analyzed for their effect on transient gene expression. The mCMV was
      the most active in dihydrofolate reductase-deficient Chinese hamster ovary
      (CHOdhfr-) cells and BALB/3T3 clone A31 mouse embryo cells. The h2CMV was more
      active than the other promoters in Bowes human melanoma cells and in Vero African
      green monkey kidney cells. In human hepatoma (Hep G2) cells, similar levels of
      CAT synthesis were observed with the h2CMV- and the mCMV-based vectors. In Hep G2
      and Bowes cells, 3'-UTR from the SV40 early region resulted in consistently
      higher levels of cat expression, as compared to the rabbit beta 1-Glb gene, while
      the converse was true in BALB/3T3 clone A31 and Vero cells. SV40 early region and
      rabbit beta1-Glb gene 3'-UTR resulted in similar cat expression in CHOdhfr-
      cells.

PMID- 8654945
TI  - Cloning, characterization and chromosomal location of a satellite DNA from the
      Pacific oyster, Crassostrea gigas.
AB  - We report the cloning and characterization of a high-copy-number, tandem-repeat
      satellite DNA sequence from the genome of the Pacific oyster, Crassostrea gigas
      (Cg). The monomeric unit was found to be 166 (+/- 2) bp in length with 79-94%
      homology between monomers of the array. The sequence is A+T-rich (60%) and lacks
      internal repetition and substructural features. The repeat was estimated to
      account for 1-4% of the Cg genome. Fluorescence in situ hybridization (FISH)
      studies mapped the repeat to two distinct heterochromatic regions of two pairs of
      homologous chromosomes on Cg embryonic metaphases. Also, the number of metaphase
      chromosomes containing this repeat varied with the ploidy of the cell.

PMID- 8654944
TI  - Simplified plasmid rescue of host sequences adjacent to integrated proviruses.
AB  - We have previously described a Moloney murine leukemia retroviral (MoMLV) vector
      useful for the generation of anchored long-range maps of complex mammalian
      genomes. We now report the development of a modified vector carrying the ColE1
      origin of replication and the chloramphenicol-resistance (CmR) gene to facilitate
      the recovery of genomic sequences adjacent to integrated proviruses. We
      demonstrate the utility of this new vector for the rescue in plasmid form of a 6
      kb human fragment containing portions of an Alu element adjacent to the proviral
      3'-LTR from an infected human primary fibroblast clone. We generated a sequence
      tagged site (STS) from the derived sequence outside the Alu element, and used a
      somatic cell hybrid mapping panel to assign this STS to human chromosome 10 by a
      polymerase chain reaction-based assay. We suggest that this new CmR vector will
      be useful for recovering sequences of genes interrupted by proviral insertion, to
      generate directional maps with respect to the inserted provirus using the single
      cleavage sites within the vector, and to generate site-specific STS for defining
      and mapping the integration site.

PMID- 8654946
TI  - The zebrafish Fgf-3 gene: cDNA sequence, transcript structure and genomic
      organization.
AB  - We report the isolation and characterization of genomic and cDNA clones encoding
      zebrafish fibroblast growth factor 3 (FGF3). An initial cDNA clone was generated
      by PCR amplification using degenerate oligo primers corresponding to a conserved
      region of protein found in the mouse and human homologues. Screening a cDNA
      library made from 30-33-h-old zebrafish embryos with this PCR product led to the
      isolation of two cDNA clones. Sequence analysis of the longest cDNA insert (1810
      bp) revealed a 256-amino-acid (aa) orf. The central region, composed of approx.
      155 aa, shares 78% identity with the analogous region of Xenopus laevis FGF3 and
      72% identity with the product of the more distantly related human gene. However,
      the N-and C-terminal domains of zebrafish FGF3 are very different from those of
      other known homologues. The cDNA was used as a probe on genomic DNA to create a
      physical map of the locus and to isolate a genomic clone encompassing the entire
      coding region and 5' sequences. DNA sequencing and RNase protection analyses
      indicate that zebrafish Fgf-3 (ZFgf-3) is structurally analogous to the mouse
      gene and regulated through two different promoters. The transcription start point
      of the proximal promoter aligns to that of mouse promoter P3 and lies within a
      conserved region of sequence.

PMID- 8654947
TI  - Expression of cDNAs encoding mouse cardiac troponin T isoforms: characterization
      of a large sample of independent clones.
AB  - We have isolated 52 mouse cardiac troponin-T-encoding cDNA clones (TnT) by
      specific antibody screening of a lambda ZAPII expression library. Sequencing data
      from the large sample of independent cDNAs demonstrated relationships among the
      expression of four alternatively-spliced exons of the cardiac TnT gene, producing
      seven classes of cDNAs encoding four protein isoforms differing in two variable
      regions. In the N-terminal variable region and next to the embryonic-specific
      exon 4, an alternatively spliced exon 3a was identified in 20% of the adult
      isoforms. The alternatively spliced exon 12, corresponding to a central variable
      region between the two functional domains of TnT, was found in approx. 79% of the
      52 mouse cardiac TnT cDNAs with a single base mutation completely abolishing the
      splicing at an internal acceptor site. Three novel alternative splicing acceptor
      sites in the 5'-untranslated portion of exon 2 have been identified with
      different frequencies.

PMID- 8654948
TI  - Complete nucleotide sequence of the mouse CTLA8 gene.
AB  - The gene encoding the mouse cytotoxic T-lymphocyte-associated antigen 8 (CTLA8)
      has been cloned and its complete nucleotide (nt) sequence determined. Sequence
      and polymerase chain reaction (PCR) analysis indicated that the published CTLA8
      sequence[Rouvier et al., J. Immunol. 150 (1993), 5445-5456] was of rat rather
      than mouse origin. The mouse CTLA8 gene contains two exons and one intron. The
      5'flanking region contains several consensus motifs for binding to transcription
      factors and the 3' untranslated region (UTR) has AU-rich motifs associated with
      RNA instability. The putative exon sequences predict that the full-length mouse
      CTLA8 molecule contains 147 amino acids (aa) and shares 88% aa identity with rat
      CTLA8 and 57% aa identity to HSV13, an open reading frame (ORF) from herpesvirus
      saimiri (HVS).

PMID- 8654949
TI  - Cloning of the cDNA encoding the mouse ATBF1 transcription factor.
AB  - We have isolated a mouse ATBF1 cDNA which is 12-kb long and capable of encoding a
      406-kDa protein containing four homeodomains and 23 zinc-finger motifs. Mouse
      ATBF1 is 94% homologous to the human ATBF1-A transcription factor. Northern blot
      and RNase protection analysis showed that levels of ATBF1 transcripts were low in
      adult mouse tissues, but high in developing brain, consistent with a role for
      ATBF1 in neuronal differentiation.

PMID- 8654950
TI  - Isolation and characterization of the mouse (Mus musculus) somatostatin receptor
      type-4-encoding gene (mSSTR4).
AB  - We have isolated and sequenced the mouse somatostatin receptor subtype-4-encoding
      gene (mSSTR4). The mSSTR4 gene encodes 384 amino acids (aa). The deduced mouse
      SSTR4 has 95 and 89% aa identity with the deduced rat and human SSTR4,
      respectively, while it has lower aa identity with the other mouse subtypes
      (mSSTR1, 60%; mSSTR2, 47%; mSSTR3, 42%). Using an RT-PCR technique, we show that
      the mSSTR4 gene is expressed in brain, but not in liver, heart, spleen or kidney
      of the adult mouse.

PMID- 8654951
TI  - An element upstream from the human delta-globin-encoding gene specifically
      enhances beta-globin reporter gene expression in murine erythroleukemia cells.
AB  - We have previously shown that a DNA-binding factor specific to adult
      hematopoietic cells (polypryrimidine-binding factor, PYBF) binds to a pyrimidine
      rich region 1 kb upstream from the human delta-globin-encoding gene (HBD). The
      developmental stage-specificity of PYBF and the location of its binding site
      between the fetal and adult beta-globin (HBB)-like genes suggest that PBYF and
      its binding site may function in fetal-to-adult globin gene switching. Here, we
      describe the effect of 383-bp (delta383) and 99-bp (delta99) sequences containing
      the PYBF-binding site on transcription from various globin and non-globin
      promoters, using a transient assay with the cat reporter gene in murine
      erythroleukemia (MEL) cells, a cell line with abundant PYBF activity. We show
      that both delta383 and delta99 specifically enhance expression of cat for
      plasmids containing a human adult globin (HBB) promoter, whereas expression of
      similar constructs using human fetal (A gamma-) globin (HBG1) or simian virus 40
      (SV40) promoters is not enhanced. The results suggest that PYBF and the
      pyrimidine-rich region upstream from HBD can specifically enhance HBB
      transcription in adult erythroid cells.

PMID- 8654953
TI  - Cloning of the cDNAs coding for cat growth hormone and prolactin.
AB  - Characterization of the prolactin (PRL) amino acid (aa) or cDNA sequences has not
      been reported for any member of the Felidae family. We cloned cat growth hormone
      (cGH) and cat PRL (cPRL) cDNA sequences from a feline pituitary cDNA library.
      High homology between species allowed bovine PRL(bPRL) and bGH cDNA clones to be
      used to identify clones encoding the 229-aa cPRL and 216-aa cGH sequences. The
      cGH protein is most homologous to pig and dog GH. Similarly, cPRL shares the most
      aa identity to pig PRL (pPRL). Northern blot analysis revealed the mRNA size for
      cGH and cPRL to be approx. 1 and 1.1 kb, respectively. These results reveal that
      GH and PRL from the Felidae family are highly conserved to other families of GH
      and PRL.

PMID- 8654952
TI  - Cloning and expression of the cDNA encoding rat tissue inhibitor of
      metalloproteinase 3 (TIMP-3).
AB  - We have cloned the cDNA encoding the rat tissue inhibitor of metalloproteinase 3
      (TIMP-3) by a PCR cloning method. Sequence analysis reveals an open reading frame
      containing 211 amino acids that show 99% identity to mouse TIMP-3 and 95%
      identity to human TIMP-3, respectively. High-level expression of TIMP-3 was
      detected in rat kidney, lungs and heart.

PMID- 8654955
TI  - Prokaryotic production of the human T cell receptor Vbeta2 chain and binding to
      toxic-shock syndrome toxin-1.
AB  - The human T-cell receptor Vbeta2-, D- and J-encoding domains were PCR-amplified
      from MOLT-4 total cDNA and subcloned in Escherichia coli. The V/D/J fragment was
      subsequently transferred to a prokaryotic expression vector in frame with a
      polyhistidine-encoding prosequence which enabled us to affinity-purify the fusion
      protein with IMAC (immobilized metal-ion affinity chromatography [correction of
      chromatorgraphy]). Since the recombinant (re-) human T-cell receptor Vbeta2
      fusion protein (Vbeta2 sol) produced in E.coli was found to be insoluble,
      purification was carried out under denaturating conditions. The purified and
      renatured re-protein, Vbeta2 sol, was immunoreactive with an anti-Vbeta2
      monoclonal antibody in an ELISA assay. The specificity of Vbeta2 sol was shown by
      its binding in vitro to the staphylococcal superantigen TSST-1, but not to the
      Staphylococcus aureus exotoxin-1 (SEA).

PMID- 8654954
TI  - Canine brain glucose transporter 3: gene sequence, phylogenetic comparisons and
      analysis of functional sites.
AB  - There has been a sparsity of various mammalian neuronal glucose transporter 3
      encoding sequences(Glut3) available for the purposes of alignment studies. We
      report here a 2355-bp sequence of canine Glut3 that encodes a deduced protein of
      496 amino acids (aa). The full-length canine aa sequence was compared to those of
      the human, mouse and rat glucose transporter 3 (Glut3), and found to be 88.3,
      84.9 and 84.3% identical, respectively. However, while mouse and rat identical C
      termini, the canine nd human C-termini share markedly little identity or
      similarity to one another, or to that of rat/mouse. The canine Glut3 sequence
      also exhibits 74.5% aa identity with a non-mammalian chicken Glut3 sequence.
      These differences in the C-termini of Glut3 among the species may result in
      kinetic or mechanistic differences in transport of glucose. Computer searches
      were made for conserved functional motifs, and a brief review of ten sites is
      provided. This review includes the determination of their locations in two
      transmembrane (TM) motifs that have been proposed for glucose transporters. The
      nucleotide (nt) sequence of the 5'-untranslated region (UTR) of canine Glut3 was
      aligned with the comparable human glut3 region and was shown to be 70% identical
      over a region of 129 nt just prior to the ATG start codons. A similar comparison
      of the 3'-UTR shows 74% identity over 350 nt immediately following the stop
      codons. An adenosine-uridine-binding factor (AUBF) region, which has been
      identified as a region of importance in mRNA stabilization, is conserved in the
      3'-UTR of both canine and human Glut3. The conservation in the UTR suggests that
      Glut3 may be post-transcriptionally regulated.

PMID- 8654956
TI  - A 28-bp negative element with multiple factor-binding activity controls
      expression of the vimentin-encoding gene.
AB  - The promoter of the human vimentin-encoding gene (VIM) contains two enhancers
      separated by a negative region. The distal and proximal enhancers bind the
      transcription factors, AP-1 and NK-kappaB, respectively, which contribute to
      serum induction of Vim synthesis. We were interested in looking for particular
      regulatory elements that might be responsible for tissue-specific extinction and
      culture-dependent activation of human VIM. We have identified a 48-bp sequence in
      the distal enhancer which had not been reported before. This sequence includes a
      negative element, NE2, which confers transcriptional repression in transfection
      experiments and binds at least two factors in vitro. NE2 may participate in the
      differentiation-stage-specific control of VIM expression which involves multiple
      regulatory sequences and several positive and negative trans-acting factors.

PMID- 8654957
TI  - Cloning of a gene encoding a DNase I-like endonuclease in the human Xq28 region.
AB  - To contribute to the isolation of genes within the q-24-qter region of the human
      X chromosome,we screened three cDNA libraries (human fetal brain, liver and
      skeletal muscle) with a cosmid clone containing a CpG island previously mapped in
      the q28 region. A full-length 2.1-kb cDNA clone was isolated (XIB); DNA databank
      searches revealed identity with an EST fragment (XAP-1), residing between the
      RCP/GCP and G6PD loci. The XIB coding region (909 bp) showed 44% amino acid (aa)
      identity to pig DNase I. Several conserved residues have been observed between
      these two genes including aa in the active site. XIB expressed a single
      transcript in adult heart and skeletal muscle, whereas, in some fetal tissues,
      two different-sized transcripts were seen. Zoo blot analysis showed a remarkable
      cross-species conservation. Expression and sequence of this novel gene are
      reported.

PMID- 8654958
TI  - The cDNA sequence of murine Nkx-2.2.
AB  - We isolated and sequenced a 2026-bp murine Nkx-2.2 cDNA clone that contains an
      open reading frame encoding 273 amino acids (aa). The 273-aa protein includes a
      homeobox, an NK-2 box and a N-terminal decapeptide found in other Nk family
      members.

PMID- 8654959
TI  - The cDNA cloning of the hamster homologue of the human L6 gene.
AB  - The cDNA cloning and sequencing of a Syrian hamster gene that produces a surface
      antigen on cells transformed by the SV40 or BK virus are described. Sequence
      analysis showed that this gene is a member of the transmembrane 4 superfamily
      (TM4SF) and encodes the Syrian hamster counterpart of the human and the murine L6
      antigens. The amino-acid sequences are highly conserved, being 71% identical
      among three species.

PMID- 8654960
TI  - A cDNA encoding canine muscle-type phosphofructokinase.
AB  - The canine muscle-type-phosphofructokinase-encoding gene (M-PFK) was sequenced by
      using a combination of cDNA cloning and RT-PCR amplification. The canine M-PFK
      sequence shares 88 and 90% identity with rabbit and human M-PFK, respectively.
      The canine ORF was determined to be 6-bp longer than either human or rabbit M-PFK
      due to a 6-bp insertion at the end of exon 13.

PMID- 8654961
TI  - A human cDNA encoding the 110-kDa A subunit of RNA polymerase II transcription
      factor elongin.
AB  - A full-length cDNA encoding a human homolog of the approx. 110-kDa subunit
      (elongin A; El A) of the RNA polymerase II transcription factor, elongin, was
      isolated and sequenced. Comparison of the open reading frames of the human el A
      cDNA and the previously characterized rat El A cDNA [Aso et al., Science 269
      (1995) 1439-1443] indicates that they are 84% conserved in nucleotide sequence
      and encode 84% identical proteins.

PMID- 8654963
TI  - Parametric genome rearrangement.
AB  - Algorithms inspired by comparative genomics calculate an edit distance between
      two linear orders based on elementary edit operations such as inversion,
      transposition and reciprocal translocation. All operations are generally assigned
      the same weight, simply by default, because no systematic empirical studies exist
      verifying whether algorithmic outputs involve realistic proportion of each. Nor
      do we have data on how weights should vary with the length of the inverted or
      transposed segment of the chromosome. In this paper, we present a rapid algorithm
      that allows each operation to take on a range of weights, producing an relatively
      tight upper bound on the distance between single-chromosome genomes, by means of
      a greedy search with look-ahead. The efficiency of this algorithm allows us to
      test random genomes for each parameter setting, to detect gene order similarity
      and to infer the parameter values most appropriate to the phylogenetic domain
      under study. We apply this method to genome segments in which the same gene order
      is conserved in Escherichia coli and Bacillus subtilis, as well as to the gene
      order in human versus Drosophila mitochondrial genomes. In both cases, we
      conclude that it is most appropriate to assign somewhat more than twice the
      weight to transpositions and inverted transpositions than to inversions. We also
      explore segment-length weighting for fungal mitochondrial gene orders.

PMID- 8654962
TI  - Comparison of the human genomic structure of the Runt domain-encoding
      PEBP2/CBFalpha gene family.
AB  - We cloned the human cDNA corresponding to the cDNA (PEBP2alphaB-451) encoding the
      mouse polyomavirus enhancer-binding protein 2alphaB-451, representing a major
      splice variant from acute myeloid leukemia gene 1 (AML1). Genomic DNA clones of
      AML1 were also isolated and the exon/intron structure was determined.
      Furthermore, we determined and compared the genomic structures of three mammalian
      Runt domain-containing genes, PEBP2alphaA,AML/PEBE2alphaB and PEBP2alphaC.

PMID- 8654965
TI  - A general method for fast multiple sequence alignment.
AB  - We have developed a fast heuristic algorithm for multiple sequence alignment
      which provides near-to-optimal results for sufficiently homologous sequences. The
      algorithm makes use of the standard dynamic programming procedure by applying it
      to all pairs of sequences. The resulting score matrices for pair-wise alignment
      give rise to secondary matrices containing the additional charges imposed by
      forcing the alignment path to run through a particular vertex. Such a constraint
      corresponds to slicing the sequences at the positions defining that vertex, and
      aligning the remaining pairs of prefix and suffix sequences separately. From
      these secondary matrices, one can compute-for any given family of sequences
      suitable positions for cutting all of these sequences simultaneously, thus
      reducing the problem of aligning a family of n sequences of average length l in a
      Divide and Conquer fashion to aligning two families of n sequences of
      approximately half that length. In this paper, we explain the method for the case
      of 3 sequences in detail, and we demonstrate its potential and its limits by
      discussing its behaviour for several test families. A generalization for aligning
      more than 3 sequences is lined out, and some actual alignments constructed by our
      algorithm for various user-defined parameters are presented.

PMID- 8654964
TI  - Coordinate positioning of MEF2 and myogenin binding sites.
AB  - The MEF2 and MyoD families of transcriptional regulatory factors both play
      central roles in the terminal differentiation of skeletal muscle. Further,
      binding sites for the two families often occur nearby, and there have been a
      number of indications that members of the two families may bind coordinately. The
      present study provides evidence that known binding sites for the two occur with
      precise geometric restrictions related to the DNA helical repeat unit, that pairs
      of putative sites following these restrictions are indicative of skeletal muscle
      specific transcriptional regulatory regions, and that the geometric relationship
      can help provide a consistent interpretation for data that has until now been
      difficult to explain.

PMID- 8654966
TI  - Adapting EcoCyc for use on the World Wide Web.
AB  - The World Wide Web (WWW) offers the potential to deliver specialized information
      to an audience of unprecedented size. Along with this exciting new opportunity
      comes a challenge for software developers: instead of rewriting our software
      applications to operate over the WWW, how can we maximize software reuse by
      retrofitting existing applications? We have developed a Web server tool, written
      in Common Lisp, that allows existing graphical user interface applications
      written using the Common Lisp Interface Manager (CLIM) to hook easily into the
      WWW. This tool-CWEST (CLIM-WEb Server Tool, pronounced "quest")-was developed to
      operate with EcoCyc, an electronic encyclopedia of the genes and metabolism of
      the bacterium E. coli. EcoCyc consists of a database of objects relevant to E.
      coli biochemistry and a user interface, implemented in CLIM, that runs on the X
      window system and generates graphical displays appropriate to biological objects.
      Each query to the EcoCyc WWW server is treated as a command to the EcoCyc
      program, which dynamically generates an appropriate CLIM drawing. CWEST
      translates that drawing, which can be a mixture of text and graphics, into the
      HyperText Markup Language (HTML) and/or the Graphics Interchange Format (GIF),
      which are returned to the client. Sensitive regions embedded in the CLIM drawing
      are converted to hyperlinks with Universal Resource Locators (URLs) that generate
      further EcoCyc queries. This tight coupling of CLIM output with Web output makes
      CLIM a powerful high-level programming tool for Web applications. The flexibility
      of Common Lisp and CLIM made implementation of the server tool surprisingly easy,
      requiring few changes to the existing EcoCyc program. The results can be seen at
      URL http: @www.ai.sri.com/ecocyc/browser.html. We have made CWEST available to
      the CLIM community at large, with the hope that it will spur other software
      developers to make their CLIM applications available over the WWW.

PMID- 8654967
TI  - Characterization of Tn1547, a composite transposon flanked by the IS16 and IS256
      like elements, that confers vancomycin resistance in Enterococcus faecalis
      BM4281.
AB  - A 64-kb genetic element harboring a vanB vancomycin-resistance (VmR) gene cluster
      was shown to translocate from the chromosome of Enterococcus faecalis BM4281 into
      the hemolysin (Hly) plasmid, pIP964. Sequence analysis of the resulting junction
      fragments indicated that the VmR genes were carried by a composite transposon,
      Tn1547, bounded by two distantly related insertion sequences (IS), designated
      IS256-like and IS16, in a direct orientation. IS256-like (1324 bp) was identical
      to IS256, except for two nucleotide (nt) transitions in the putative transposase
      gene. IS16 (1466 bp) contained a large open reading frame (ORF) that was 61%
      identical to the gene encoding the putative transposase of IS256. There was 58%
      identity between the deduced amino acid (aa) sequences of the putative
      transposases of IS256-like (390 aa) and IS16 (395 aa). IS16 was delineated by
      imperfect inverted repeats (IR) (18 out of 26 bp) which were related (23/26 bp
      identity) to their respective imperfect IR counterparts in IS256. The difference
      between the IS was not a barrier for transposition of Tn1547 which generated an 8
      bp duplication at the target site. Dissemination of VanB-type resistance among
      enterococci results from two mechanisms: (i) large conjugative elements
      translocate from chromosome to chromosome following inter-strain transfer; and
      (ii) as described in this report, the VmR genes transpose from replicon to
      replicon within the same strain as part of composite transposons that are
      internal to the conjugative elements.

PMID- 8654968
TI  - An unusual gene arrangement for the putative chromosome replication origin and
      circadian expression of dnaN in Synechococcus sp. strain PCC 7942.
AB  - In eubacteria, the clustering of DnaA boxes around the dnaN (beta subunit of DNA
      polymerase III) and dnaA genes usually defines the chromosome replication origin
      (oriC). In this study, the dnaN locus from the cyanobacterium Synechococcus sp.
      strain PCC 7942 was sequenced. The gene order in this region is cbbZp-dnaN-orf288
      purL-purF which contrasts with other eubacteria. A cluster of eleven DnaA boxes
      (consensus sequence: TTTTCCACA) was found in the intergenic region between dnaN
      and cbbZp. We also found a 41-bp sequence within this region that is 80%
      identical to the proposed oriC of Streptomyces coelicolor. Therefore, we propose
      that this intergenic region may serve as an oriC in Synechococcus. Using
      bacterial luciferase as a reporter, we also showed that dnaN is rhythmically
      expressed, suggesting that DNA replication could be under circadian control in
      this organism.

PMID- 8654969
TI  - Identification of a native Dichelobacter nodosus plasmid and implications for the
      evolution of the vap regions.
AB  - Studies on the role of various virulence factors of the ovine pathogen,
      Dichelobacter nodosus, have suffered from the absence of a mechanism for the
      introduction of DNA into this organism. As an initial step in the development of
      genetic methods, we have identified and cloned a native 10-kb plasmid, pJIR896,
      from a clinical isolate. This plasmid was found to be a circular form of vap
      region 1/3 that is found in the reference strain, A198. However, pJIR896 lacked
      the duplicated region present in the A198 sequence and instead contained a 1.7-kb
      putative insertion sequence, IS1253, which shared similarity to a number of
      unusual IS elements. A model is proposed for the evolution of vap region 1/3
      which involves the integration of a plasmid, such as pJIR896, and subsequent
      rearrangements resulting from the deletion or transposition of IS1253.

PMID- 8654970
TI  - Sequence analysis of the L-lactate dehydrogenase-encoding gene of Deinococcus
      radiodurans, a suitable mesophilic counterpart for Thermus.
AB  - A gene encoding L-lactate dehydrogenase (LDH; EC 1.1.1.27) from Deinococcus
      radiodurans (Dr) was cloned and sequenced. The deduced amino acid (aa) sequence
      was compared to those of the Thermus aquaticus (Ta) and T. caldophilus (Tc) LDH.
      The similarity of the G + C contents between the Dr and Thermus genes permits the
      comparison of the aa sequences of LDH without considering the difference in the G
      + C contents. Compared to the mesophilic Dr LDH, increased numbers of hydrophobic
      aa, together with hydrophilic Arg, were found in the LDH from Ta and Tc,
      suggesting that these features would contribute to protein thermostability in
      part via hydrophobic and electrostatic interactions in the protein globule.
      Deinococcus would be a suitable mesophilic counterpart for Thermus to investigate
      the thermostability of proteins.

PMID- 8654971
TI  - The 3-phosphoglycerate kinase of the hyperthermophilic archaeum Pyrococcus woesei
      produced in Escherichia coli: loss of heat resistance due to internal translation
      initiation and its restoration by site-directed mutagenesis.
AB  - Heterologous expression of the gene coding for 3-phosphoglycerate kinase (PGK) of
      the hyperthermophilic archaeum, Pyrococcus woesei (Pw), in Escherichia coli (Ec)
      yielded only low recovery of recombinant PGK (re-PGK) in heat-precipitated crude
      extracts. Moreover, we noticed contamination with a 28-kDa protein, from which
      PGK could hardly be separated, even under stringent conditions after tagging the
      re-PGK with a His6-tag. The preparations contaminated with the 28-kDa protein
      showed an unexpectedly low thermal stability. Under the same conditions (85
      degrees C, 30 min), however, the enzyme from the original organism was completely
      resistant to heat inactivation. As shown by size-exclusion chromatography, re-PGK
      forms tight associations with the 28-kDa protein, which was found to represent a
      C-terminal fragment of PGK and to arise as a product of internal translation
      initiation within the pgk gene. Mutations changing the internal ribosome-binding
      site effectively suppressed the production of the 28-kDa protein and restored the
      thermal stability of the Pw re-PGK.

PMID- 8654972
TI  - Isolation of an HSP12-homologous gene of Schizosaccharomyces pombe suppressing a
      temperature-sensitive mutant allele of cdc4.
AB  - Defects in the Schizosaccharomyces pombe (Sp) cell cycle-controlling genes
      prevent the cell cycle progression. Mutations in one of the late septation genes,
      cdc4, cause Sp cells to arrest at cytokinesis and result in an elongated cellular
      morphology. By functional complementation of one of the temperature-sensitive
      (ts) mutant alleles of cdc4, cdc4-31, with a Sp cDNA library, a novel gene, scf1,
      which suppresses the elongated ts phenotype of cdc4-31, was isolated. DNA
      sequence analysis of the cDNA revealed homology with a small heat-shock protein
      family, HSP12, of Saccharomyces cerevisiae (Sc). Expression of this gene is
      highly induced, both at 37 degrees C and in the stationary phase of cell growth.
      It is likely that scf1 is expressed in stress conditions such as heat-shock or
      nutritional limitation. The phenotypic suppression of cdc4-31 by a small HSP12
      homolog, Scf1, suggests that the functional loss of cdc4, which is involved in
      formation of the F-actin contractile ring, can be prevented or repaired by one of
      the small HSP. This implies that an HSP might be involved in late cell plate
      formation or in stabilization of the Sp F-actin contractile ring structure.

PMID- 8654973
TI  - Low- and high-copy-number shuttle vectors for replication in the budding yeast
      Kluyveromyces lactis.
AB  - Four sets of plasmid vectors for the budding yeast Kluyveromyces lactis (Kl) have
      been constructed. All plasmids are pUC19-based shuttle vectors having multiple
      unique sites in their multiple cloning site (MCS) within the bacterial lacZ gene.
      The first set of vectors contains Klori, the origin of replication for Kl
      isolated from Kluyveromyces plasmid pKD1, and one of the selectable nutritional
      markers, URA3, TRP1 or LEU2. These markers from the yeast, Saccharomyces
      cerevisiae (Sc), can complement the uraA1, trp1 and leu2 mutations of Kl. The
      second set of vectors, in addition to Klori, contains the ARS (autonomously
      replicating sequence) and centromeric sequences of Sc, and are able to replicate
      in both Sc and Kl. The third group of plasmids is centromeric vectors that are
      maintained in Kl at low copy number. The last family of vectors was designed for
      gene overexpression. As they contain the bacterial kanamycin-resistance-encoding
      gene (kan), plasmid copy number can be amplified to over 100 copies per cell in
      Kl by growing cells in the presence of the antibiotic G418 (Geneticin). This type
      of vector has been used to study the high-copy-lethality phenotype of a truncated
      version of the Kl MGI2 gene encoding the alpha-subunit of the mitochondrial F1F0
      ATP synthase.

PMID- 8654974
TI  - Candida albicans CDK1 and CYB1: cDNA homologues of the cdc2/CDC28 and
      cdc13/CLB1/CLB2 cell cycle control genes.
AB  - Major transitions in the eukaryotic cell cycle are regulated by the cyclin
      dependent protein kinases (CDK). In particular, the G2/M transition is initiated
      by the activity of a complex formed by a CDK of the Cdc2/Cdc28 family and B-type
      cyclins of the Cdc13/C1b family in the yeasts, Schizosaccharomyces pombe (Sp) and
      Saccharomyces cerevisiae (Sc). To study the molecular mechanisms that control the
      G2/M transition in the dimorphic pathogenic yeast, Candida albicans, we have
      cloned and characterized cDNAs corresponding to CDK1 and CYB1. The CDK1 cDNA
      encodes a 317-amino-acid (aa) protein that shares 76.8 and 62.3% identity with
      the Sc CDC28 and Sp cdc2 gene products, respectively. The CYB1 cDNA encodes a 493
      aa protein that is 34.8, 34.4 and 35.5% identical to Sc C1b1 and C1b2, and to Sp
      Cdc13, respectively. Cyb1 contains characteristic mitotic destruction and cyclin
      boxes. The CDK1 and CYB1 cDNAs are functional homologues, as they are able to
      complement Sp cdc2 and cdc13 temperature-sensitive (ts) mutations, respectively,
      and their gene products interact in vivo in Sc to form an active histone H1
      kinase.

PMID- 8654975
TI  - Missense mutations at the FKBP12-rapamycin-binding site of TOR1.
AB  - The TOR genes were first identified in Saccharomyces cerevisiae by the isolation
      of mutants which exhibit dominant resistance to the immunosuppressive and
      antifungal drug rapamycin (Rm). The originally characterized Rm-resistant (RmR)
      TOR1-1 and TOR2-1 alleles contain an Arg in place of a conserved Ser residue,
      which lies adjacent to the phosphatidylinositol (PI) kinase-related domain of TOR
      (Ser1972 in TOR1; Ser1975 in TOR2). Additional spontaneous RmR mutants containing
      Lys, Ile or Asn substitutions were subsequently isolated. As this Ser is a
      potential site for protein kinase C phosphorylation, we were interested in
      determining whether the observed RmR is due to steric hindrance of the FKBP12-Rm
      TOR interaction or whether phosphorylation at this site is required to mediate
      the interaction. Using site-directed mutagenesis, we replaced the Ser1972 residue
      of TOR1 with either a conservative residue, Ala, an alternative potential
      phosphorylation site, Thr, or Asp to mimic phosphorylation. The TOR1 (S1972A)
      mutant protein retained Rm sensitivity (RmS), whereas both the Thr and Asp
      substitutions conferred RmR. RmS correlated with the ability to interact with
      FKBP12-Rm in a two-hybrid assay: both wild-type TOR1 and the S1972A mutant
      retained the ability to interact with FKBP12-Rm, whereas the S1972T, S1972D and
      S1972R mutants failed to interact. All mutant TOR1 proteins were able to
      complement the growth defect of tor1 null alleles, suggesting that the Ser1972
      residue may not be required for TOR1 function in cycling cells. Since a
      TOR1(S1972A) mutant protein confers a RmS phenotype, interacts with FKBP12-Rm in
      a two-hybrid assay, and functions in vivo, we conclude that phosphorylation at
      Ser1972 is not necessary for the interaction between TOR1 and FKBP12-Rm.

PMID- 8654976
TI  - Isolation and sequence analysis of the cDNA encoding delta 1-pyrroline-5
      carboxylate reductase from Zalerion arboricola.
AB  - A cDNA encoding delta 1-pyrroline-5-carboxylate reductase (P5CR) was isolated
      from the pneumocandin (Pmo)-producing fungus, Zalerion arboricola (Za), by
      complementation of a P5CR-deficient mutant (pro3) of Saccharomyces cerevisiae
      (Sc). The cloned cDNA was placed under control of the Sc galactokinase (GAL1)
      promoter and restored P5CR activity to the pro3 mutant. Sequence analysis
      revealed that the Za P5CR-encoding cDNA encodes an approx. 35 kDa protein with
      substantial amino acid (aa) identity to P5CR from another filamentous fungus,
      Neurospora crassa (Nc). Za P5CR exhibits a moderate degree of aa identity to P5CR
      from plants, bacteria, human and Sc. This is the first gene to be isolated from
      Za.

PMID- 8654977
TI  - Identification of a Hydra homologue of the beta-catenin/plakoglobin/armadillo
      gene family.
AB  - The beta-catenin/plakoglobin/armadillo gene family encodes a group of highly
      conserved proteins which play important roles in cadherin-mediated cell adhesion
      and in signal transduction mechanisms involved in regulating development. This
      gene family previously had been isolated only from higher metazoans. Here, we
      describe the isolation and characterization of a beta-catenin (beta Ctn)
      homologue from Hydra magnipapillata, a diploblastic lower metazoan. Comparison of
      the putative amino acid (aa) sequence of Hydra beta Ctn, with its homologues in
      higher metazoans, shows that a repeating 42-aa motif present in its central
      domain is highly conserved throughout the metazoa. This suggests that beta Ctn
      appeared very early in metazoan evolution, possibly when primitive multicellular
      animals started to form epithelial cell layers.

PMID- 8654978
TI  - Nucleotide sequence of the gene presumably encoding the adsorption protein of
      filamentous phage phi Lf.
AB  - A 1170-nucleotide fragment of phi Lf DNA was sequenced. This fragment contains an
      open reading frame, ORF367, encoding a protein of 367 amino acids (aa) (36710
      Da). ORF367 is located downstream from the gene encoding the major coat protein
      (gVIIIp) and a Rho-independent termination signal. Sequence analysis revealed
      that the gene product has a Gly-rich domain (70 aa) at the center and a
      hydrophobic region (26 aa) at the C terminus. These structural features suggest
      that ORF367 may encode the adsorption protein of phi Lf.

PMID- 8654979
TI  - Construction of improved vectors for protein production in Pseudomonas
      aeruginosa.
AB  - We report the construction of two cloning vectors that are based on the
      Pseudomonas-Escherichia shuttle vector, pUCP19. The new vectors, pUCPKS and
      pUCPSK, contain a significantly expanded multiple cloning site (MCS) with an
      adjacent T7 promoter sequence. In conjunction with specifically engineered host
      strains encoding an inducible T7 RNA polymerase, these vectors allow the
      controlled production of plasmid-encoded proteins in both Escherichia coli and
      Pseudomonas aeruginosa to analyse the spectrum of products encoded by cloned
      segments of DNA. The usefulness of these vectors was demonstrated by expressing
      the chloramphenicol acetyltransferase (CAT)-encoding gene.

PMID- 8654980
TI  - Cloning of the Pseudomonas aeruginosa gene encoding CDP-diglyceride synthetase.
AB  - The CDP-diglyceride synthetase (CDS)-encoding gene (cds) from Pseudomonas
      aeruginosa PAO1 was cloned and sequenced. The gene possessed an open reading
      frame of 813 bp capable of encoding a putative polypeptide of 271 amino acids
      (aa) (28 699 Da). The deduced aa sequence of CDS revealed a 67% similarity (45%
      identity) to Escherichia coli CDS.

PMID- 8654981
TI  - The LYS5 gene of Saccharomyces cerevisiae.
AB  - The LYS2 and LYS5 genes of Saccharomyces cerevisiae together encode the 180-kDa
      alpha-aminoadipate reductase (AAR) in the biosynthetic pathway of lysine. The 4.8
      kb LYS2 gene encodes the 155-kDa subunit of AAR. The complete nucleotide (nt)
      sequence of the 1.1-kb LYS5 gene is presented in this report. It contains a
      single continuous open reading frame of 816 nt encoding a 272-amino-acid, 30.6
      kDa polypeptide.

PMID- 8654982
TI  - Construction of a CUP1 promoter-based vector to modulate gene expression in
      Saccharomyces cerevisiae.
AB  - We report the construction and characterization of a yeast shuttle-expression
      vector that can be used to express genes in yeast in a modulated form. This
      vector is centromeric, with a polylinker that optionally can provide an ATG start
      of translation. Expression features are based on the CUP1 yeast metallothionein
      gene promoter, which can be tightly modulated by copper.

PMID- 8654983
TI  - The effect of Srb, a homologue of the mammalian SRP receptor alpha-subunit, on
      Bacillus subtilis growth and protein translocation.
AB  - To determine the signal recognition particle (SRP)-SRP receptor (Srb) system in
      Bacillus subtilis (Bs), we cloned the Bs srb gene, which encodes a homologue of
      the mammalian SRP receptor alpha-subunit [Oguro et al., DNA Res. 2 (1995) 95
      100]. We sequenced a 6098-bp DNA containing srb and analyzed the gene
      organization. Primer extension experiment and Northern blot analysis revealed
      that srb constitutes an operon with two additional ORFs. A database search of
      known proteins revealed that one encodes a homologue of Escherichia coli RNase
      III [36.0% identical amino acids (aa)] and the other encodes a homologue of yeast
      Smc1 (26.6% identical aa). We then constructed a Bs mutant in which srb
      expression was induced by IPTG. The depletion of Srb caused a defect in the cell
      growth and the cells became filamentous and twisted. Furthermore, pulse-chase
      experiments using this mutant revealed that the 17% of the beta-lactamase
      precursor accumulated in the cell after a 4-min chase in the absence of IPTG,
      although almost all of the precursors were converted into the mature from after a
      1-min chase in the presence of IPTG.

PMID- 8654984
TI  - The alpha-glucuronidase-encoding gene of Trichoderma reesei.
AB  - The Trichoderma reesei cDNA coding for alpha-glucuronidase (GLRI), which releases
      glucuronic acid attached to xylose units of xylan, was cloned and sequenced. The
      deduced N-terminal amino acid (aa) sequence of the protein was verified by
      sequencing of the purified GLRI. The aa sequence of the GLRI displayed no
      similarity with any aa sequence available in the data bases.

PMID- 8654985
TI  - Sequences upstream and downstream from the glutamine-dependent carbamoyl
      phosphate synthetase-encoding gene from the protozoan Babesia bovis.
AB  - In the protozoan parasite, Babesia bovis, the glutamine-dependent carbamoyl
      phosphate synthetase-encoding gene (CPSII) contains contiguous amidotransferase-
      and synthetase-encoding sequences. Unlike the organisation in most eukaryotes,
      the gene is not fused with other genes encoding enzymes of pyrimidine
      biosynthesis de novo. The nucleotide sequences immediately upstream and
      downstream from the gene contain motifs which may be involved in regulating its
      expression.

PMID- 8654986
TI  - Heterodimerization between two classes of homeodomain proteins in the mushroom
      Coprinus cinereus brings together potential DNA-binding and activation domains.
AB  - The A mating type-genes of the mushroom, Coprinus cinereus, encode two classes of
      homeodomain-containing proteins distinguished as HD1 and HD2 on the basis of
      conserved, but distinctly different motifs. Compatible mating partners bring
      together versions of the proteins that can heterodimerize, thereby generating an
      active transcription factor complex that commits mated cells to sexual
      development. We have previously described a rare mutation in which an HD2::HD1
      gene fusion generates a 'fused dimer' lacking much of HD1 including the
      homeodomain yet capable of constitutively promoting development [Kues et al.,
      EMBO J. 13 (1994b) 4054-4059]. Here, we exploit this mutation to help identify
      contributions made by each protein class to normal heterodimer function. We show
      that the HD2 homeodomain is essential; deletion within the HD1 homeodomain can be
      tolerated in a normal heterodimer, as well as in the mutant fusion protein, but
      not substitution of a critical amino acid. We define, by deletion analysis, an
      essential C-terminal region of the HD1 and demonstrate its potential activation
      function by the ability to activate transcription in yeast when fused to the GAL4
      DNA-binding domain. We also identify a potential role in transcriptional
      repression for the predicted C-terminal helix of HD1 proteins.

PMID- 8654987
TI  - Expression of genes encoding two major Theileria annulata merozoite surface
      antigens in Escherichia coli and a Salmonella typhimurium aroA vaccine strain.
AB  - The genes, Tams1-1 and Tams1-2, encoding the 30-and 32-kDa major merozoite
      surface antigens of Theileria annulata (Ta), have recently been cloned and
      characterized. Both genes encode a protein of 281 amino acids (aa) containing a
      putative hydrophobic N-terminal signal peptide. Another hydrophobic stretch is
      predicted at the C terminus which probably functions to anchor the protein in the
      membrane of the merozoite and piroplasm. Here, we report the successful
      expression of both Tams1-1 and Tams1-2 in Escherichia coli (Ec) using gene
      fragments lacking both hydrophobic domains. Attempts to produce high amounts of
      the entire recombinant (re-) protein, or a fragment containing the N terminus
      only, were unsuccessful. This is presumably due to the toxicity of these re
      proteins. The internal part of both genes was also expressed in Salmonella
      typhimurium (St) aroA vaccine strain SL3261. We employed a dual-plasmid
      expression system based on an invertible promoter and selected the most stable St
      construct in vitro using liquid cultures and a macrophage-like cell line. The re
      Tams1-1 protein produced in Ec, as well as in St, was recognized by monoclonal
      antibody (mAb) 5E1 specific to the 30-kDa protein. Both re-Tams1-1 and re-Tams1-2
      were recognized by Ta immune calf serum.

PMID- 8654988
TI  - Cloning and characterization of the MamI restriction-modification system from
      Microbacterium ammoniaphilum in Escherichia coli.
AB  - The genes encoding a class-IIN restriction-modification (R-M) system (MamI,
      sequence specificity [symbol: see text] from Microbacterium ammoniaphilum have
      been cloned in Escherichia coli. The vector used for cloning was plasmid pUC18
      modified by the inclusion of three MamI recognition sites. Recombinant clones
      containing the mamIM gene in its genomic context became fully methylated in vivo
      and remained completely resistant against digestion with the R.MamI restriction
      endonuclease (ENase). Determination of the nucleotide (nt) sequence revealed
      three open reading frames with lengths of 1089 bp (ORF1), 276 bp (ORFc) and 927
      bp (ORF2). On the basis of expression and deletion experiments, the 1089-bp ORF1
      was assigned to mamIM encoding the M.MamI DNA methyltransferase (MTase). By amino
      acid sequencing of the N terminus of R.MamI and comparison of the deduced nt
      sequence with ORF2, the 927-bp ORF2 was identified as the mamIR gene encoding
      R.MamI. The 276-bp ORFc, located between mamIR and mamIM, is part of the DNA
      sequence downstream from mamIM shown to be necessary for controlled mamIM
      expression.

PMID- 8654989
TI  - Novel specific endonuclease activity recognizing a 10-bp sequence.
AB  - We report here the generation of a novel restriction endonuclease (ENase)
      activity with the 10-bp recognition sequence, [symbol: see text]. This
      specificity could be achieved by first methylating a substrate DNA with M.MamI in
      vivo, followed by in vitro R.DpnI restriction.

PMID- 8654990
TI  - BstF5I, an unusual isoschizomer of FokI.
AB  - BstF5I, a new restriction endonuclease (ENase) from Bacillus stearothermophilus
      F5, has been discovered. This enzyme recognizes 5'-GGATG-3' and cleaves DNA,
      generating a 2-base 3'extension: 5'-GGATG NN[symbol: see text]-3' 3'
      CCTAC[symbol: see text]NN-5' BstF5I is an isoschizomer of FokI and seems to be
      evolutionarily close to other nonpalindromic-recognizing ENases from thermophilic
      bacilli.

PMID- 8654991
TI  - M13-102: a vector for facilitating construction and improving quality of M13
      shotgun libraries.
AB  - A modified vector, M13-102, is described which utilizes the previously reported
      M13-100 direct selection strategy for shotgun cloning [Guilfoyle and Smith,
      Nucleic Acids Res. 22 (1994) 100-107]. In these vectors, direct selection
      replaces the need for phosphatase treatment of vector DNA and is achieved by
      insertional inactivation of M13 gene X. When not inactivated, the engineered
      overproduction of the M13 gene X product mediates phage replication repression.
      M13-102 contains two new additions: (1) a sequence enabling triple-helix-mediated
      affinity capture (TAC) for purification of linearized vector DNA, and (2)
      universal primer sequences for wider compatibility with commercial instruments
      that support fluorescence-based sequencing. Using a biotinylated homopyrimidine
      oligodeoxyribonucleotide as third-strand probe, TAC is performed on streptavidin
      coated magnetic beads [Ji et al., Genetics Analysis: Techniques and Applications
      11 (1994) 43-47], and serves as a rapid and efficient alternative to gel
      purification. To reduce tandem insertions, phosphatase treatment of insert DNA
      was easily invoked without sacrificing cloning efficiency. The combined
      capabilities of direct selection, TAC purification and phosphatase treatment of
      inserts should facilitate library construction and improve overall library
      quality.

PMID- 8654992
TI  - Phage display vectors for in vivo recombination of immunoglobulin heavy and light
      chain genes to make large combinatorial libraries.
AB  - New phage display vectors for in vivo recombination of immunoglobulin (Ig) heavy
      (VH) and light (VL) chain variable genes, to make single-chain Fv fragments
      (scFv), were constructed. The VH and VL genes of monoclonal antibody (mAb) EP
      5C7, which binds to both human E- and P-selectin, were cloned into a pUC19
      derived plasmid vector, pCW93, and a pACYC184-derived phagemid vector, pCW99,
      respectively. Upon induction of Cre recombinase (phage P1 recombinase), the VH
      and VL genes were efficiently recombined into the same plasmid via the two loxP
      sites (phage P1 recombination sites), one located downstream from a VH gene in
      pCW93 and another upstream from a VL gene in pCW99. In the resulting phagemid,
      the loxP sequence also encodes a polypeptide linker connecting the VH and VL
      domains to form a scFv of EP-5C7. Whether expressed on the phage surface or as a
      soluble form, the EP-5C7 scFv showed specific binding to human E- and P-selectin.
      This phagemid vector system provides a way to recombine VH and VL gene libraries
      efficiently in vivo to make extremely large Ig combinatorial libraries.

PMID- 8654993
TI  - A pBRINT family of plasmids for integration of cloned DNA into the Escherichia
      coli chromosome.
AB  - Plasmid pBRINT is an efficient vector for chromosomal integration of cloned DNA
      into the lacZ gene of Escherichia coli [Balbas et al., Gene 136(1993) 211-213]. A
      family of related plasmids containing different antibiotic-resistance markers
      (CmR or GmR or KmR) and a larger multiple cloning site (MCS) has been
      constructed. This set of plasmids, whose integration efficiencies are as good as
      those obtained with the prototype plasmid pBRINT, constitutes a collection of
      tools that allow rapid and easy integration of cloned DNA, at the chromosomal
      level. Their functionality as integration vectors has been ascertained by
      integrating the Vitreoscilla sp. hemoglobin-encoding gene and the Photobacterium
      leiognathi lux genes. To evaluate the level of expression obtained after
      chromosomal integration, we constructed strains carrying one or two copies of the
      cat gene integrated in the chromosome, and compared their enzymatic activities
      with those obtained from a strain carrying cat on a multicopy plasmid.

PMID- 8654994
TI  - Determination of the cos sequence of the mature genome of S2/HP1 type B
      bacteriophage of Haemophilus influenzae.
AB  - The cos region of Haemophilus influenzae phage HP1/S2 type B has been cloned and
      its nucleotide (nt) sequence determined. The nt sequence of the cohesive ends
      (cos) and whole cos site of type-B phage have been compared to corresponding
      sequences of the HP1c1 phage. The results of a search for symmetry elements and
      IHF-binding sites in this region are presented.

PMID- 8654995
TI  - The amb2 locus from Serratia entomophila confers anti-feeding effect on larvae of
      Costelytra zealandica (Coleoptera: Scarabaeidae).
AB  - Serratia entomophila (Se) causes amber disease in the soil-dwelling pest,
      Costelytra zealandica (Cz). The disease presents two main signs: anti-feeding
      effect (AFE) and development of amber coloration (AC). To identify the genetic
      loci involved in pathogenicity, non-pathogenic (Path-) Se mutants were created by
      transposon (TnphoA) mutagenesis [Upadhyaya et al., J. Bacteriol. 174 (1992) 1020
      1028]. The mutant UC24 lost the ability to produce amber disease signs and it was
      shown to contain a single TnphoA insertion. The TnphoA insertion site was mapped
      in a 5.3-kb DNA fragment, which was named amb2 locus. Cosmids containing amb2
      fully restored AFE and partially restored AC in UC24. Escherichia coli (Ec) HB101
      bearing the amb2 locus was able to cause AFE in a multiple-dose bioassay. SDS
      PAGE analysis of the amb2 gene products produced in minicells showed the
      synthesis of two proteins of 16 and 19.5 kDa, named AnfA and AnfB. The genes
      encoding these proteins were mapped by deletion analysis. Pathogenicity tests
      with insect larvae fed with bacteria carrying the anfA and anfB gene regions
      separately showed that both regions are essential for AFE. It is proposed that
      the AnfA and AnfB proteins are virulence factors (toxin-like proteins) causing
      AFE in Cz.

PMID- 8654996
TI  - VTR expression cassettes for engineering conditional phenotypes in Pseudomonas:
      activity of the Pu promoter of the TOL plasmid under limiting concentrations of
      the XylR activator protein.
AB  - A simplified procedure to construct recombinant Pseudomonas putida (Pp) and
      related bacteria, which transcribe conditionally specific genes inserted into
      their chromosome in response to lac inducers such as IPTG, has been developed.
      The method is based on the so-called VTR expression cassettes. These are three
      small (1.98-kb) DNA segments engineered as NotI restriction fragments that
      include a lacIq gene along with the hybrid trp/lac promoter, Ptrc, followed by an
      optimised translation initiation region with a leading ATG and a multiple cloning
      site in each of the three reading frames. This arrangement allows the chromosomal
      insertion of the conditionally expressed genes of interest through its transfer
      to any of the mini-Tn5 transposon vectors available. VTR cassettes permit
      construction of specialized strains that are instrumental to address, by genetic
      means, otherwise intractable regulatory problems observed in biodegradative
      pathways of Pp. In this context, the VTR system was employed to examine the
      effect of the intracellular concentration of XylR, the main regulator of the TOL
      (toluene biodegradation) plasmid pWW0, on the exponential silencing of the
      promoter of the upper operon, Pu. Increasing concentrations of XylR resulted in
      more intense induction of the system that, however, remained silent during fast
      cell growth regardless of activator levels.

PMID- 8654998
TI  - Inhibition of Serratia marcescens nuclease secretion by a truncated nuclease
      peptide.
AB  - The production of extracellular nuclease (Nuc) from the Serratia marcescens nucA
      chromosomal locus is inhibited in cells producing the N-terminal portion of Nuc
      from a multicopy plasmid. This inhibition in trans is not at the level of nucA
      expression, but rather at the level of secretion of the Nuc protein. Production
      of the periplasmic protein beta-lactamase (Bla) does not inhibit Nuc production
      unless fused to the nucA signal peptide and expressed from nucAp. Inhibition by
      either the truncated Nuc peptide (delta Nuc) or a Bla fusion protein is promoter
      specific and observed when expressed from nucAp; little inhibition is observed
      when the same protein is expressed from the lacZpo promoter-operator. This
      promoter specificity is also true for the secretion of Nuc itself.

PMID- 8654997
TI  - Characterization of Streptomyces argillaceus genes encoding a polyketide synthase
      involved in the biosynthesis of the antitumor mithramycin.
AB  - Mithramycin (Mtm) is an aromatic polyketide which shows antibacterial and
      antitumor activity. From a chromosomal cosmid library of Streptomyces
      argillaceus, a Mtm producer, a clone (cosAR7) was isolated by homology to the
      actI/III region of S. coelicolor and the strDEM genes of S. griseus. From this
      clone, a 5.3-kb DNA region was sequenced and found to encode six open reading
      frames (designated as mtmQXPKST1), five of them transcribed in the same
      direction. The deduced products of five of these genes resembled components of
      type-II polyketide synthases. The mtm genes would code for an aromatase (mtmQ), a
      polypeptide of unknown function (mtmX), a beta-ketoacylsynthase (mtmP) and a
      related 'chain length factor' (mtmK), an acyl carrier protein (mtmS) and a beta
      ketoreductase (mtmT1). The involvement of this gene cluster in Mtm biosynthesis
      was demonstrated by the Mtm non-producing phenotype of mutants generated in two
      independent insertional inactivation experiments.

PMID- 8654999
TI  - Cloning, sequencing and analysis of the ggh-A gene encoding a 1,4-beta-D-glucan
      glucohydrolase from Microbispora bispora.
AB  - The ggh-A gene, encoding a 1,4-beta-D-glucan glucohydrolase/beta-glucosidase, of
      Microbispora bispora (Mb) was subcloned and expressed from a 4.0-kb XhoI DNA
      fragment. The nucleotide sequence of this fragment was determined. Analysis of
      the sequence revealed one open reading frame (ORF) which encodes a 986-amino-acid
      (aa) protein with a calculated molecular weight of 107,510. The ggh-A ORF has
      features typical of an actinomycete gene including high GC content (70.5%) and
      corresponding biased codon usage. Comparison of the aa sequence of the Mb 1,4
      beta-D-glucan glucohydrolase (Mbggh-A) with other glycosidases reveals high
      overall homology to several beta-glucosidases and a 1,4-beta-D-glucan
      glucohydrolase belonging to the glycosyl hydrolase family 3. The aa sequence
      alignments of Mbggh-A and beta-glucosidases show that the active site region
      potentially involves two Asp residues. The aa sequence homology studies revealed
      a potential two-domain structure for Mbggh-A and other beta-glucosidases.
      Furthermore, Mbggh-A has localized homology to a cellulose-binding domain present
      in some xylanases. This report is significant, as, to date, 1,4-beta-D-glucan
      glucohydrolases have rarely been reported, though they are assumed to have a
      critical role in cellulolysis.

PMID- 8655001
TI  - [Cooperation between surgeons and anesthesiologists studied by the Polish Society
      of Surgery].

PMID- 8655000
TI  - Expression and functional characterisation of the clpC gene of Mycobacterium
      leprae: ClpC protein elicits human antibody response.
AB  - This paper reports the expression of a previously described gene [Nath and Laal,
      Nucleic Acids Res. 18 (1990) 4935], currently identified as the clpC gene of
      Mycobacterium leprae, using an in vitro rabbit reticulocyte lysate-coupled
      transcription/translation system. The produced protein moved as a 95-kDa band on
      SDS-PAGE. An additional band of 79 kDa was seen which may have resulted from a
      GTG codon downstream to the initiating ATG in the clpC sequence. A threefold
      increase in synthesis of the 95-kDa protein was achieved by altering the
      translation codon context sequence of the ATG start codon. The ClpC (caseinolytic
      protease C) amino acid sequence, which contained two nucleotide-binding sites,
      exhibited in vitro ATP binding. Of functional significance was its
      immunoreactivity in human subjects with mycobacterial infection. Leprosy and
      tuberculosis patients with active disease had antibodies which recognised ClpC in
      dot ELISA.

PMID- 8655002
TI  - [Comparison of Doppler examination results for utero-placental blood flow and
      plate-villous index--morphologic determinant of placental barrier in pregnant
      patients with diabetes].
AB  - The resistance index (RI) of the uteroplacental blood flow of both uterine
      arteries was evaluated in diabetic women in the perinatal period. Consecutively
      morphometric examination of placenta was proceeded after the delivery and the
      average number of epithelial plates in villi was calculated (so called "plate
      villous index"). The correlation between the uterine arteries' blood flows and
      the plate-villous indices was calculated since the number of the epithelial
      plates determines the placenta barrier. There was poor correlation found between
      resistance indices and the average number of epithelial plates.

PMID- 8655003
TI  - [Usefulness of vaginal ultrasonography for evaluation of cervix sufficiency in
      pregnancy].
AB  - 73 expectant mothers from 7 to 37 weeks of pregnancy were divided into 4 groups
      according to their pregnant age. The women were clinically and sonography
      examined with endovaginal transducer. The main aim of these examinations was
      comparison of the results of cervix efficiency. In this sonography scanning were
      estimating the length, the width of the cervix canal and the width of internal
      os. Having done the examinations we discovery interdependence the cervix
      parameters of the age of pregnancy it also proved the great worth of endovaginal
      ultrasonography as a verification of the clinical examination.

PMID- 8655004
TI  - [Comparison of prolactin levels in first, second and multiple physiological
      pregnancy].
AB  - Serum prolactin level was estimated by radioimmunological method (RIA) in women
      during the first, the second and the multiple normal pregnancy. The value of
      prolactin was compared in the successive pregnancies and in the successive weeks
      of pregnancy. The dependence between concentration of prolactin and successive
      pregnancy was observed. A significant increase of prolactin was noted in the 4
      week of multiple pregnancy. The increased level of prolactin was observed in the
      10th, 12th, 14th, 40th and 42nd weeks of the first normal pregnancy.

PMID- 8655005
TI  - [Evaluation of newborn maturation and gestational age using the Ballard-Klimka
      scale].
AB  - Results of prospective studies of 1404 consecutive vaginal and cesarean
      deliveries of newborns weighted > or = 2500 g were analyzed in relation to their
      maturity. It was stated that Ballard Maturation Score is a valid accurate
      assessment tool for precise interpretation of the degree of fetal maturity, but
      not of the calendar length of gestation, especially beyond 36 weeks. Therefore it
      was reasonable to propose a constant distribution of scores: 39 +/- 3 points
      within the period from 37% to 43% weeks while at the 28th week: 10 +/- 2 points
      (Ballard-Klimek scale of pregnancy dating) instead of therefore used J. L.
      Ballard rule that only newborns at 44 weeks can have scores of 50 and infants
      with shorter gestational age have lower values, e.g. 33 at the 37th week.

PMID- 8655006
TI  - [Evaluation of ambroxol given prenatally and postnatally on gas exchange in the
      newborn with respiratory distress syndrome].
AB  - 160 newborns were observed to compare the influence of combine treatment with
      ambroxol (Lasolvan-Boehringer Ingelheim) (antenatal and postnatal) versus
      postnatal administration of this drug on gas exchange and reduction of
      ventilatory settings in newborns with RDS. In 53% of cases the preparation was
      given both: pre- and postnatal and 47% of newborns were treated only postnatal.
      The results of stimulation of lung maturity "before and after" versus "after"
      delivery were better in the first group, however in some parameters we did not
      found statistical differences.

PMID- 8655007
TI  - [Stamey-Lorenz operation for treatment of stress urinary incontinence in women].
AB  - The Stamey-Lorenz operation was presented as a new method for treatment of stress
      urinary incontinence in women. During operation the urethra is suspended by using
      special needles and under cystoscopic control, thus proper vesico-urethral angle
      is restored. 10 incontinent women were cured using this method, 8 with good
      results. In two cases we failed.

PMID- 8655008
TI  - [Teratoma of the ovary. Analysis of prognostic factors].
AB  - Forty-one patients with teratoma of the ovary were operated in the Center of
      Oncology in Krakow. The five-year disease-free survival for all patients was
      68.3%. The histological grading appear to be an important prognostic factor. The
      five-year disease-free survival for patients with grade 0 was 100%, grade I--80%,
      grade II and III--14.3%.

PMID- 8655009
TI  - [Occurrence of antinuclear antibodies in women with endometriosis and unexplained
      infertility].
AB  - The relationship between female infertility, endometriosis and antinuclear
      antibodies (ANA) in the blood of women without clinical symptoms of autoimmune
      disease is described. ANA in the titre of 1:40 and more, was detected in 63%
      women with endometriosis, 70.4% women with idiopathic infertility, 3.3% women
      with hypothalamic-pituitary dysfunction and 5.6% healthy nonpregnant women. The
      occurrance of ANA in endometriosis and idiopathic infertility was more frequently
      connected with negative postkoital test and the number of spontaneous abortions.
      We suggest, that (auto)immunological mechanisms play an important role in
      endometriosis and unexplained infertility.

PMID- 8655010
TI  - [Pregnancy course in women with terminal kidney failure treated with
      hemodialysis].
AB  - According to the European Dialysis and Transplantation Association at least 250
      patients on each 1 million of inhabitants in Europe is treated with renal
      replacement therapy. One can assumed that if only half of above mentioned are
      women then from 5 to 10 of them can conceive pregnant. It's likely that number of
      pregnant women with end-stage renal disease depending on different forms of renal
      replacement therapy will increase. These facts determined us to present study
      concerning to course of pregnancy in women with end-stage renal disease treated
      with haemodialysis.

PMID- 8655011
TI  - [The value of computer tomography for diagnosis of seminal vesicle cysts].
AB  - Presented report deals with the case of a giant cyst of the left seminal vesicle
      with major diagnostic difficulties. After urography, cystoscopy, and computer
      tomography all symptoms in patient with cyst disappeared, and the tumor was not
      stated during physical examination. Six months later all symptoms in the patient
      exaggerated. Among diagnostic procedures used only computer tomography visualized
      giant cyst of the seminal vesicle which occupied the whole pelvis. After surgical
      excision of the cyst the patient had and erectile dysfunction.

PMID- 8655012
TI  - [Effect of mestranol on pharmacokinetics of phenazone in the rabbit].
AB  - There was studied the influence of mestranol on the pharmacokinetics parameters
      of phenazone. There was proved the decrease AUC abridgement the period of semi
      duration for elimination phase and increase total clearance. On the base of these
      experiments there was able to make a conclusion that estrogens influence on the
      phenazone's pharmacokinetic probably by induction of microsomal enzymes of liver.

PMID- 8655013
TI  - [Intensive therapy of puerperal disorders with a life-threatening state caused by
      sepsis].
AB  - The paper reviews intensive, complex therapeutical procedure introduced in 19
      critically ill puerperal women due to severe sepsis. In 6 cases only the
      generative organ was the primary source of infection. It is underlined that
      sepsis can predispose to various complications and multiorgan failure.

PMID- 8655014
TI  - [C-reactive protein in normal pregnancy].
AB  - Serum C-reactive protein levels (CRP) were measured by means of the
      immunoturbidimetric assay technique in 33 healthy pregnant women (38-42 week of
      gestation) and 32 healthy women in labour at term. CRP values for pregnant women
      ranged from 0.15 to 1.5 mg/dl with the median value 0.2 mg/dl. The 95th
      percentile for CRP in these pregnant women was 1.2 mg/dl. CRP values for women in
      labour at term ranged from 0.15 to 2.7 mg/dl. The median CRP value for these
      women was 0.8 mg/dl; the 95th percentile was 1.9 mg/dl. CRP values for women in
      labour at term were significantly higher than CRP values for pregnant women (p <
      0.001). C-reactive protein levels in normal pregnancies appear to be higher than
      standardized values for nonpregnant individuals, and CRP values are further
      elevated in labour.

PMID- 8655015
TI  - [Major risk factors for endometrial carcinoma].
AB  - Our results were compared with the results from numerous recent studies
      concerning important risk factors for the endometrial carcinoma. We revealed that
      only age more then 50 with conjunction with obesity is the important risk factor.
      We didn't proved the protection role of the pregnancy emphasized in the
      literature. The role of others epidemiologic risk factors for the endometrial
      carcinoma remains still unequivocally explained.

PMID- 8655016
TI  - [Hydroxyproline urine excretion--potential marker of cervical ripening?].
AB  - Urinary hydroxyproline excretion does not change significantly within last two
      weeks of gestation among 89 healthy patients. Decreased hydroxyproline
      concentration found in cervices of pregnant women in the course of labor has not
      been accompanied by increased urinary excretion of this particular amino acid.

PMID- 8655017
TI  - [Bacterial flora of the vagina and the effect of endogenous and exogenous factors
      on its changes].
AB  - The paper describes composition of the bacterial vaginal flora and its basic
      mechanisms enabling coexistence of different bacterial species residing in this
      region. A role of the dominant bacteria in maintaining stability of the
      microflora was stressed. Also various factors influencing ecological balance of
      the vaginal flora were presented.

PMID- 8655018
TI  - [Effect of fetal and neonatal growth on the occurrence of some diseases in
      adults].
AB  - The findings of many authors show that reduced fetal growth is followed by
      increased mortality from cardiovascular disease in adult life. They are further
      evidence that cardiovascular disease originates, among other risk factors,
      through programming of the bodies structure and metabolism during fetal and early
      post-natal life. Wrong maternal nutrition may have an important influence on
      programming.

PMID- 8655019
TI  - [A rare case of appendicitis in pregnancy].
AB  - It has been described a case of appendicitis in atypical appendix localisation
      complicated by perforation with coexisting pleuropneumonia on the right side in
      21 year old primipara in 33 week of gestation. It has been performed cesarean
      section with simultaneous surgical intervention.

PMID- 8655020
TI  - [Meckel-Gruber syndrome].
AB  - Two cases of the Meckel-Gruber syndrome were described at two subsequent
      pregnancies. Suspicion of this syndrome was established by ultrasonography and
      confirmed by histopathological findings. Both of the pregnancies were terminated
      by premature induced delivery.

PMID- 8655021
TI  - [A case of acute renal failure in pregnancy complicated by Henoch-Schoenlein
      purpura requiring hemodialysis therapy].
AB  - The secondary kidney's diseases may be a cause of the acute renal failure in
      pregnancy. Pregnancy may be a factor which reveal earlier existence of the
      disease. We reported the case of 18-year-old woman (gravida 1) in whom the first
      symptoms of the Henoch-Schoenlein purpura occurred in 23rd week of pregnancy. In
      32nd week of pregnancy appeared hypertension, anasarca, oliguria and acute renal
      failure. In this case hemodialysis appeared as an effective procedure which saved
      mother's and child's life.

PMID- 8655022
TI  - [Uncomplicated course of pregnancy after previous ligation of both internal iliac
      arteries and left ovarian artery].
AB  - The described case is the mature pregnancy in a patient with previously ligated
      both internal iliac arteries and the left ovarian artery due to the haemorrhage
      complicating the last delivery. The course of the pregnancy was uncomplicated.
      The results of the CTG tracings, USG of the fetus and Doppler measurements of the
      blood flow in the umbilical artery have not revealed any abnormalities. The
      pregnancy was terminated by elective cesarean section. A healthy baby weighing
      2970 g was born.

PMID- 8655023
TI  - [Promotion of breast feeding. Needs and recommendations].

PMID- 8655024
TI  - [Analysis of therapeutic methods used in puerperium complicated by hemorrhagic
      shock].
AB  - Methods of intensive treatment of puerperium with severe haemorrhagic shock of a
      dramatic course are analysed in the paper. In 20% of patients shock occurred due
      to non-obstetric reasons. It is stated, that haemorrhagic shock predisposes to
      various complications, which in turn require multidirectional treatment. It is
      stressed, that monitored therapy by means of adequately selected fluids should be
      supplemented by immediate and appropriate oxygen therapy.

PMID- 8655025
TI  - Comprehensive treatment of inflammatory diseases of parodontium by antiseptic and
      antiinflammatory agents made in Bulgaria.

PMID- 8655026
TI  - Clinical investigations of Bulgarian toothpastes.

PMID- 8655027
TI  - Denture implants.

PMID- 8655028
TI  - Endodontial treatment of primary teeth by carbamide-formaldehyde agents.

PMID- 8655029
TI  - Modern aspects in the treatment of dental hyperesthesia.

PMID- 8655030
TI  - On the effect of some agents for local prophylactics of caries.

PMID- 8655031
TI  - On the anesthetic effect of low-power infrared lasers with different mode of
      irradiation in complications after stomatologic treatment.

PMID- 8655032
TI  - Scientific achievements of the Higher Medical Institute, Plovdiv.

PMID- 8655033
TI  - Megatubules in renomedullary (RIC) and Leydig's (LIC) interstitial cells in rats.

PMID- 8655034
TI  - Morphological aspects of periostal osteogenesis.

PMID- 8655035
TI  - Exfoliative cytology in experimental pharmacology and toxicology.

PMID- 8655036
TI  - Frequency of sperm antibodies in different populations of infertile persons.

PMID- 8655037
TI  - Microstructure, ultrastructure and reactivity of the venous wall in experimental
      action with sex hormones.

PMID- 8655038
TI  - Determination of some bioactive substances in cosmetic products and half-
      finished products.

PMID- 8655039
TI  - Comparative study of zona pellucida in vertebrate animals.

PMID- 8655040
TI  - Identification of the thymic stromal populations which participate in the
      negative selection of double positive thymocytes.

PMID- 8655041
TI  - Study on the cell expression of human A, B and H blood-group antigens.

PMID- 8655042
TI  - Synthesis and study of derivatives of cyclic carbamides with antiviral and
      antimicrobial action.

PMID- 8655043
TI  - Tolerance, drug dependence and withdrawal syndrome in antiepileptic drugs.

PMID- 8655045
TI  - Methodologic approach for integral assessment of the immune state.

PMID- 8655044
TI  - New enterocytic peptides with morphogenic effect.

PMID- 8655046
TI  - Etiopathogenetic, diagnostic, therapeutic and labour-expertise investigations in
      acute viral hepatitis.

PMID- 8655047
TI  - Disorders in metabolism and granulocyte function in acute intoxications with
      phosphororganic pesticides.

PMID- 8655048
TI  - Double inversibly phased palestesiometer.

PMID- 8655049
TI  - Angiographic changes in vibration disease.

PMID- 8655050
TI  - Rational use of clinical laboratory tests.

PMID- 8655051
TI  - Modern clinical, diagnostic and therapeutic approaches in characterization of the
      autosomal dominant polycystic kidney disease.

PMID- 8655052
TI  - Molecular and genetic studies of 22 Bulgarian families with autosomal dominant
      polycystic kidney disease (ADPKD). Extrarenal clinical manifestations of ADPKD
      compared with data from DNA analysis.

PMID- 8655053
TI  - Thrombolytic therapy for acute myocardial infarction--yesterday, today, tomorrow.

PMID- 8655054
TI  - Diagnosis and treatment of first stage acute hepatic insufficiency.

PMID- 8655055
TI  - Renal disorders and calcium phosphorus tubular dysfunctions in multiple myeloma.

PMID- 8655056
TI  - Determination of the level of tumour markers (CA-15-3, CA-125, CA-19-9, NSE, SCC,
      SP-1, CEA, AEP, ferritin, hCG) in cancer patients undergoing radiotherapy,
      surgery or a combined therapy.

PMID- 8655057
TI  - Postoperative radiotherapy of patients with supratentorial astroglial tumours.

PMID- 8655058
TI  - Clinical results from the treatment of erysipelas with heparin.

PMID- 8655059
TI  - Blood gases, electrolytes and metabolic monitoring in children with acute failure
      of vital functions.

PMID- 8655060
TI  - Hormones of the thyroid gland in children with non-thyroid diseases.

PMID- 8655061
TI  - Juvenile struma--prognosis and treatment.

PMID- 8655062
TI  - Results of twenty-year experience from studying polygenic inheritance in some
      internal diseases.

PMID- 8655063
TI  - Increased IgE--diagnostic value of the index in children with bronchial
      obstruction.

PMID- 8655064
TI  - Breathing disorders in sleep.

PMID- 8655065
TI  - Bronchoscopy with persistent tracheobronchial lavage in acute intoxications with
      pulmonary affection.

PMID- 8655067
TI  - The HLA system--central link in immunopathogenesis of type B viral hepatitis.

PMID- 8655066
TI  - Benzacilin compositum viewed in the light of the cost-effectivity problem in in
      patient children's wards.

PMID- 8655068
TI  - Reactivity of the cells of the adrenal cortex under experimental conditions.

PMID- 8655069
TI  - Cultures in diffusion chambers from malignant eye tumors.

PMID- 8655070
TI  - On some modern approaches for cerebral haemodynamics examination by
      rheoencephalographic and carotid sphigmographic methods.

PMID- 8655071
TI  - Ulcer--suggestions for a new classification.

PMID- 8655072
TI  - DNA methylation pattern in Angelman syndrome.

PMID- 8655073
TI  - Selection of an appropriate panel for immunophenotyping of cells in acute
      leukaemias.

PMID- 8655075
TI  - Digital subtraction angiographic equipment--main aspects and clinical
      application.

PMID- 8655074
TI  - A clinical expression in structural chromosomal aberrations.

PMID- 8655076
TI  - Hypertoxic haemorrhagic form of diphtheria.

PMID- 8655077
TI  - Neurologic complications in patients with chronic alcohol dependance.

PMID- 8655078
TI  - Acute ischemic disturbances of the cerebral blood circulation with complete
      clinical recovery.

PMID- 8655079
TI  - Daily rhythmicity of temperature and pulse in patients with schizophrenia, maniac
      depressive psychoses and neuroses.

PMID- 8655080
TI  - Prophylaxis of epilepsy.

PMID- 8655081
TI  - Biological markers in affective disturbances.

PMID- 8655082
TI  - Phobic and anxiety conditions--diagnosis and therapy.

PMID- 8655083
TI  - Diagnoses of narcolepsy and sleep apnea syndrome.

PMID- 8655084
TI  - Achievements of the paediatric surgery clinic in the last five years.

PMID- 8655085
TI  - Malignant tumors of the eyeball and its accessories.

PMID- 8655086
TI  - Laparostomy in the treatment of acute purulent peritonitis.

PMID- 8655087
TI  - An original method and metal plates for surgical stabilization of movable
      thoracal cover.

PMID- 8655088
TI  - Treatment of ruptures of Achilles' tendons by an external fixator.

PMID- 8655089
TI  - Epidemiology, diagnostics, clinical manifestations, prophylaxis and fight against
      Lyme borreliosis in Bulgaria.

PMID- 8655090
TI  - A scale for evaluation of the health status of labour active population.

PMID- 8655091
TI  - On the epidemiology of some acute respiratory infections and the accompanying
      nonbacterial pneumonia in children.

PMID- 8655092
TI  - A study of the toxic hazard that might be associated with the consumption of
      green potato tops.
AB  - Eating green potatoes has reportedly led to poisoning attributed to potato
      glycoalkaloids (PGA), primarily alpha-solanine and alpha-chaconine.
      Concentrations of PGA increase during the greening of potatoes but are reportedly
      much higher in potato tops (leaves). As it is known that members of the UK
      Bangladeshi community consume potato tops, a study of the toxic hazard that may
      be associated with the consumption of green potato tops has been carried out. PGA
      in seven potato varieties were determined by HPLC. Tubers protected from light
      contained 0.05-0.65 mg/100 g alpha-solanine and 0.3-0.63 mg/100 g alpha
      chaconine. Concentrations in leaf samples ranged from 0.64 to 22.6 mg alpha
      solanine/100 g and 0.06 to 55.7 mg alpha-chaconine/100 g. Aqueous leaf extracts
      were cytotoxic to Chinese hamster ovary cells and lysed human, rat and hamster
      blood cells with no difference in sensitivity among species. Oral administration
      of potato tops to rats, mice and Syrian hamsters had no adverse effects at the
      highest practicable dose. A mixture of alpha-solanine and alpha-chaconine (1:1,
      w/w) given orally at doses of up to 50 mg/kg body weight to hamsters had no
      effect, but a single ip injection of 25 mg/kg body weight or greater was lethal,
      with bleeding in the gut. High concentrations of cytotoxic PGA were found in some
      potato tops, but their effect in laboratory animals was minimal. It is concluded
      that the consumption of moderate quantities of potato tops (2-5 g/kg body
      weight/day) is unlikely to represent an acute health hazard to humans.

PMID- 8655093
TI  - An evaluation of the antioxidant and antiviral action of extracts of rosemary and
      Provencal herbs.
AB  - Extracts of herbs and spices are increasingly of interest in the food industry
      because they retard oxidative degradation of lipids. There is also increasing
      interest in the antiviral activity of plant products. A liquid, deodorized
      rosemary extract and an oily extract of a mixture of Provencal herbs were tested
      for antioxidant and antiviral action in vitro. The rosemary extract (Herbor 025)
      and the extract of Provencal herbs (Spice Cocktail) inhibited peroxidation of
      phospholipid liposomes with 50% inhibition concentration values of 0.0009% (v/v)
      and 0.0035% (v/v), respectively. Herbor 025 and the spice cocktail (at 0.2%, v/v)
      reacted with trichloromethylperoxyl radical with calculated rates of 2.7 x 10(4)
      s-1 and 1.5 x 10(3) s-1, respectively. The main active components in the herbal
      preparations, carnosol and carnosic acid, at 0.05% (v/v) react with rate
      constants of (1-3) x 10(6) M-1 sec-1 and 2.7 x 10(7) M-1 sec-1, respectively.
      Both extracts show good antioxidant activity in the Rancimat test, especially in
      lard. Herbor 025 and the spice cocktail inhibited human immunodeficiency virus
      (HIV) infection at very low concentrations which were also cytotoxic. However,
      purified carnosol exhibited definite anti-HIV activity at a concentration (8
      microM) which was not cytotoxic. Both preparations promoted some DNA damage in
      the copper-phenanthroline and the bleomycin-iron systems. The two herbal
      preparations possess antioxidant properties that may make them useful in the food
      matrix.

PMID- 8655094
TI  - Quantification of genistein and genistin in soybeans and soybean products.
AB  - It has been suggested that the isoflavone, genistein,, may have some role as a
      chemopreventive agent against cancer in humans. Levels of genistein and its beta
      glucoside conjugate, genistin, ingested in soybeans and related bean products by
      the Japanese were quantified by HPLC, to estimate daily intake of these
      compounds. Amounts of genistein and genistin in soybeans, soy nuts and soy powder
      were in the range of 4.6 to 18.2 and 200.6 to 968.1 micrograms/g food,
      respectively. The values for soy milk and tofu (bean curd) were 1.9 to 13.9 and
      94.8 to 137.7 micrograms/g food, respectively. Levels of isoflavones in fermented
      soybean products, miso (bean paste) and natto (fermented soybeans), were 38.5 to
      229.1 micrograms/g food for genistein and 71.7 to 492.8 micrograms/g food for
      genistin. Thus, the level of genistein in the fermented soybean products was
      higher than in soy beans and soybean products such as soy milk and tofu. From
      these observations, it is suggested that the beta-glycosyl bond of genistin is
      cleaved to produce genistein by microbes during fermentation to yield miso and
      natto. Soy sauce was also found to contain both isoflavones, but at levels lower
      than in miso and natto. On the basis of these data for average annual consumption
      of soybeans and related products, daily intake of genistein and genistin by the
      Japanese is calculated to be 1.5-4.1 and 6.3-8.3 mg/person, respectively. These
      levels are much higher than those for Americans or Western Europeans, whose
      mortality rates for breast, colon and prostate cancers are greater than the
      Japanese.

PMID- 8655095
TI  - Lack of carcinogenicity of tamarind seed polysaccharide in B6C3F1 mice.
AB  - The carcinogenic potential of tamarind seed polysaccharide was examined in both
      sexes of B6C3F1 mice. Groups of 50 male and 50 female animals were given diets
      containing 0, 1.25 and 5% of tamarind seed polysaccharide for 78 wk. Body weight
      retardation was exhibited by the females in the 1.25 and 5% groups from 34 wk to
      termination. However, there were no treatment-related clinical signs or adverse
      effects on survival rate, food and water consumption, haematology findings or
      organ weights. Detailed histopathological examination also revealed no treatment
      related increase in the incidence of any non-neoplastic or neoplastic lesions.
      These results demonstrated that tamarind seed polysaccharide is not carcinogenic
      in B6C3F1 mice of either sex.

PMID- 8655096
TI  - Induction of hepatic and renal P4502E1 of neonatal rats exposed
      translactationally to ethanol.
AB  - The effect of maternal ethanol intake during lactation on neonatal cytochrome
      P4502E1 was investigated in Sprague-Dawley rats. Dams were exposed to 15% (v/v)
      ethanol in drinking water from day 1 of lactation to 4, 7 or 14 days postpartum.
      Significant (P < 0.01) enhancement of both hepatic and renal N
      nitrosodimethylamine (NDMA) demethylase, an activity of P4502E1, was observed in
      lactating mothers given ethanol in drinking water. Demethylase activity also
      significantly increased (P < 0.01) in the 7- and 14-day livers of both female and
      male pups and in the 7- and 14-day female and 14-day male kidneys exposed to
      ethanol through the transmammary route. Cytochrome P4502E1 protein content,
      assayed by immunoblotting, increased in the maternal liver and kidney of all
      groups consuming ethanol. Neonatal P4502E1 protein content increased in the 7-
      and 14-day livers of both sexes and 14-day female kidneys exposed
      translactationally to ethanol. No effect of ethanol on enzyme activity or protein
      content of P4502E1 was observed in the liver or kidney of 4-day-old neonates.
      These results demonstrate the translactational effect of ethanol on neonatal
      P4502E1 enzyme, which is involved in the metabolism of many low molecular weight
      xenobiotics, and indicate the possibility of alterations occurring in the
      kinetics of neonatal drug and xenobiotic metabolism and also in processes
      connected with perinatal carcinogenesis.

PMID- 8655097
TI  - Study of the embryofoetotoxicity of alpha-terpinene in the rat.
AB  - alpha-Terpinene (1-isopropyl-4-methyl-1,3-cyclohexadiene) (TER) is a monoterpene
      found in the essential oils of a large variety of useful plants. Despite the
      widespread use of plants and essential oils containing TER in folk medicine
      potions and cosmetics, and as a flavouring food additive, toxicity studies of
      this monoterpene are scarce. The present study was undertaken to provide data on
      the embryofoetotoxic potential of TER in the rat. TER (30, 60, 125 and 250 mg/kg
      body weight) in corn oil was given by gavage to female Wistar rats from day 6 to
      15 of pregnancy. Caesarean sections were performed on day 21 of pregnancy. The
      number of implantation sites, living and dead foetuses, resorptions and corpora
      lutea were recorded. All foetuses were weighed, examined for externally visible
      malformations, numbered with a marker pen and fixed in 5% formalin solution. One
      third of the foetuses of each litter, chosen at random, were evaluated for
      visceral anomalies by a microsectioning technique. Heart, lungs, thymus, liver,
      spleen and kidneys of foetuses that were microdissected were also weighed. The
      remaining foetuses were examined for skeletal malformations after clearing with
      potassium hydroxide and staining with Alizarin Red S. A reduction in body weight
      minus uterine weight at term indicated that the two highest doses tested [125 and
      250 mg TER/kg body weight orally] were maternally toxic. No increase in the ratio
      of resorptions/implantations was observed over the dose range tested. The highest
      dose of TER (250 mg/kg body weight) reduced the ratio of pregnant/treated female.
      A decrease in foetal body weight and an increase in foetal kidney weights were
      noted at 250 mg TER/kg body weight. Signs of delayed ossification (poorly
      ossified and not ossified bones as well as irregular spongy bones) and a higher
      incidence of minor skeletal malformations were observed at doses of 60 mg/kg body
      weight or more. These findings indicate that the no-observed-adverse-effect level
      for TER-induced embryofoetotoxicity can be set at 30 mg/kg body weight by the
      oral route.

PMID- 8655098
TI  - In vitro percutaneous absorption of the fragrance ingredient musk xylol.
AB  - The percutaneous absorption of the fragrance fixative musk xylol was measured in
      vitro in human and hairless guinea pig skin. For comparison, musk xylol was
      applied to skin in an oil-in-water emulsion or the volatile solvent, methanol.
      After 24 hr, total absorption of musk xylol in hairless guinea pig skin was 55%
      from the emulsion vehicle and 45% from the methanol vehicle. With human skin,
      permeation of musk xylol from both vehicles decreased to 22% of the applied dose.
      When human studies were continued for an additional 6 days after skin surface
      washing, only 6% of the applied dose remained in skin. The data suggest that most
      of the absorbed musk xylol in skin at 24 hr will be systemically absorbed in vivo
      within 1 wk. Throughout the 24-hr absorption study, absorbed musk xylol was not
      metabolized. A permeability constant for musk xylol permeation through hairless
      guinea pig skin was determined by a modified procedure for the lipophilic
      compound. At each time point, some diffusion cells were terminated so that skin
      and receptor fluid levels could be determined. Under steady-state absorption the
      permeability constant was 6.86 x 10(-5) cm/hr. The amount of musk xylol
      penetrating skin from three types of cosmetic products was also calculated on the
      basis of actual conditions of use. Products that are applied to large areas of
      the body and remain on the skin for long periods will result in the greatest
      absorption of musk xylol.

PMID- 8655099
TI  - Investigation of regional glutathione levels in a model of chemically-induced
      renal papillary necrosis.
AB  - The effect of diphenylamine on renal cortical, outer medullary and inner
      medullary glutathione (GSH) concentrations and the effect of GSH depletion on the
      nephrotoxicity of diphenylamine were investigated in male Syrian hamsters. A dose
      dependent decrease in renal cortical GSH was observed within 1 hr of a single
      oral dose of diphenylamine (200, 400 or 600 mg/kg body weight), but statistically
      significant changes in outer medullary or papillary GSH were not observed.
      Reduction of renal papillary GSH to 29% of basal concentration [by prior
      treatment with L-buthionine sulfoxime (500 mg/kg body weight, ip)] did not
      increase the papillotoxicity of a non-toxic dose of diphenylamine (400 mg/kg)
      administered orally. The findings indicate that diphenylamine-induced renal
      papillary necrosis in the Syrian hamster is not associated with a decrease in
      renal papillary or outer medullary GSH nor mediated by oxidative cell injury.

PMID- 8655100
TI  - Preclinical skin sensitization testing of antihistamines: guinea pig and local
      lymph node assay responses.
AB  - Preclinical test methods for allergic contact sensitivity have been widely used
      for sensitization hazard identification and, with consideration of human exposure
      conditions, have also been valuable tools for sensitization risk assessment. For
      many years, the guinea pig has been the test species of choice with a variety of
      test methods developed to assess the sensitization response. More recently the
      local lymph node assay (LLNA) in mice has been developed to provide a more
      objective index of sensitization potential. The standardized methods have proven
      to be very well suited to most situations in which potential skin sensitization
      of a chemical needs to be assessed before human exposure. A potential difficulty
      with all these relatively limited exposure preclinical test methods, however, is
      in the ability to detect weak contact allergens that prove to be significant
      clinical allergens due to chronic topical exposure, exposure to compromised skin,
      and/or highly exaggerated exposure through transdermal delivery. This has been
      shown with the transdermal drug clonidine and might also be the case for topical
      antihistamines. The latter are considered significant clinical contact allergens,
      although predictive preclinical test data are minimal or lacking. A series of
      guinea pig (modified Buehler) tests with two common antihistamine compounds
      (triprolidine and diphenhydramine) and LLNA on these and two other compounds
      (chlorpheniramine and promethazine) was conducted. Positive Buehler test results
      required use of penetrating vehicle systems and a modified nine-induction patch
      regimen. Positive LLNA responses were obtained with all four materials (to
      varying degrees) only if the application site was pre-abraded or a penetrating
      vehicle (dimethylformamide) was used. These data support the notion that
      preclinical sensitization test methods can be modified to increase sensitivity.
      This may be critical for preclinical assessment of topical/transdermal drugs or
      other materials with chronic or high-concentration exposures in man.

PMID- 8655101
TI  - [The development and testing of a new NiTi-SE-steel uprighting spring].
AB  - The uprighting spring presented here consists of a combination of superelastic
      material which is connected with a steel were by means of a crimped connector.
      Pseudo-elastic areas of such a spring can be used well by combining superelastic
      material with steel. The uprighting spring presented here yields the following
      advantages: 1. The uprighting moment of the molar is between 10 and 20 N with a
      40 degree tipping of molar.2. The uprighting springs exhibit a large plateau in
      the area of 8 to 15 Nmm depending on a bending-in of an alpha-bend. 3. An
      intrusive force of approximately 0.5 to 1.0 N can be produced by varying the
      alpha-bend. The preformed uprighting spring in combination with a cross tube can
      be affixed without any problems, because only the alpha-activation must be bent
      in. 5. Practically, a reactivation during uprighting is not required. 6. An
      enlargement of the alpha-moment to produce an intrusive force makes great demands
      on the anchoring element. For this reason, one must check in each individual
      case, if an anchoring segment displays the required stability. 7. By lengthening
      the SE material at the crimped connector, the alpha and beta-moments become
      smaller, as does the intrusive (extrusive) force applied to molars.

PMID- 8655102
TI  - [The clinical use of the new NiTi-SE-steel uprighting spring].
AB  - In clinical practice the NiTi steel uprighting spring presented in this study has
      been employed up until now to upright 30 molars. The advantage of this spring is
      that in large areas the pseudoelastic part of the spring transfers constant
      moments and forces to the molars. In addition, the steel part makes it possible
      to simply and easily adjust and fasten alpha-bends. Because of the relatively
      small uprighting moments of 10 up a maximum of 25 Nmm such an uptighting spring
      can also be applied without any modifications in cases in which the molars are
      tipped up to 50 degrees. Going beyond this our study determined that it is
      possible to exert intrusive forces of 0.4 N over the entire uprighting area by
      bending-in an 45 degrees alpha-bend. From a 15 degrees tipping on up the
      uprighting moments applied to molars remain relatively constant and they are only
      dependent on the bent alpha-activation. An uprighting by intrusive force on the
      molars can also be achieved through an alpha-activation of 0 degree (90 degrees +
      40 degrees), when the vertical length of the pegs is enlarged. An on average 1.43
      mm per month root mesialization of the uprighting spring with the Memory Maker,
      should such for whatever reason be considered desirable, take place only in the
      final stage. In almost every case of molar uprighting it is possible to fasten a
      figure eight ligature from the molar to the cross tube. The uprighting spring
      presented here combined with a cross tube proves to be an effective method for
      achieving a fast and trouble free uprighting of molars.

PMID- 8655103
TI  - [The therapeutic effects after the dentoalveolar compensation of skeletal open
      bite in adults. The skeletal and dental parameters].
AB  - In the following study 20 adult skeletal open-bite patients were analysed after
      they had undergone dental compensation to camouflage the underlying skeletal
      discrepancy. The initial and final cephalometric records were analysed to
      determine the factors that led to the desired goal. The results showed no
      significant difference in the skeletal relationship. Molar intrusion was not
      recorded. The open-bite was correct mostly by reclining the upper incisors and by
      changing their position. Significant differences existed between the obtained
      results and the mechano-therapy employed. The geometrical model developed on the
      of the above makes it possible to predict and predetermine the targeted vertical
      dimension. Furthermore the results show extrusion of the front teeth as another
      dominant factor.

PMID- 8655104
TI  - [Findings in the panoramic tomogram in orthodontic patients with functional
      disorders].
AB  - In our study of 107 patients, for whom data derived from clinical functional
      analysis, axiography and, in part magnet resonance imaging, were present, we were
      able to show that in routine orthodontic diagnosis the use of panoramic X-ray in
      the normal course of a general examination of the mandibular joint can also
      provide important indications of the presence of cranio-mandibular disorders. The
      panoramic X-ray revealed that in patients with Angle class II and front deep and
      open bite there were significantly mor changes in the form of the condyles. A
      definite morphologic finding of a retracted fovea pterygoidea was found
      frequently in patients with anterior disk replacement with or without reduction.
      Lastly, the panoramic X-ray showed that a change in form of the condyles, with in
      some cases a serious arthrosis, occurs significantly most frequent in patients
      with anterior displacement without reduction.

PMID- 8655105
TI  - [How effective is asymmetrical headgear in practical use?].
AB  - The asymmetrical face bow with internal hinge was successfully employed in the
      treatment of all examined patients. It finds application as an individual
      appliance, in combination with removable appliances, and in conjunction with the
      fixed appliance technique. The major advantage of the face bow is that during a
      check-up visit, because it is already in place, it presents itself as a proven
      means for the treatment of asymmetries by adding a hinge on the side not to be
      distalized and by shortening the external arm on the same side. It is not
      necessary to employ a new, special face bow or even to change the orthodontic
      bands. In addition, in the case of an intermaxillary midline correction, no
      anchorage loss occurs. In the case of more extensive molar rotations, a
      pretreatment with a palatal archwire is recommended to rotate the molars. Because
      in 4% of the patients a cross bite or a cross bite tendency arises on the side
      distally treated, at the beginning of treatment the use of bands with attachments
      for palatal archwires should be considered. Relatively sizable distal forces in
      the range of 2:1 to 4:1 are exerted on the molar. This should be taken into
      account when selecting the forces of the external arm. It is recommended to apply
      on each of both sides a distal force of no more than 4 to 5 N. Decoupling of
      forces and movements through the internal hinge makes it possible for the
      practitioners to check the asymmetrical effect of the face bow by pulling out
      carefully the lingual archwire from the right or left tube. As long as the hinge
      still folds down, when the face bow is applied, the geometrics of the face bow
      should be altered. The following procedures can be recommended: 1. Further
      shortening of the already shortened arm; 2. outward bending of the long external
      arm; 3. use of an additional stop tube at the lingual archwire on the side that
      must be distalized. During the use of related low-pulls, the molars are subjected
      to diverse forces as a result of preferred sleeping positions, head bearings, and
      extensive friction, To avoid these non-calculable asymmetries, it is recommended
      to use gliding low-pulls. Because of the excellent results achieved throughout
      the use of the asymmetrical headgear with the lingual archwire, it can be
      recommended that it become a standard appliance in clinical practice.

PMID- 8655106
TI  - [The dental and skeletal changes in early Class II treatment with a Klammt open
      activator].
AB  - In order to evaluate the initiation of treatment of Angle class II malocclusion
      at an early age, seventy-six patients, 34 girls aged on average 10.1 years and 42
      boys, average age 11.3 years, were selected for the study. For the treatment we
      used the Klammt open activator. For evaluation purposes we used casts and
      cephalograms taken before and after treatment. The results showed distinctive
      differences between Angle class II/1 and II/2. The sagittal correction in class
      II/1 was a result of the reduction of the SNA angle, the mandibular protrusion,
      and the retrusion of the upper incisors. The face high index was normalized. No
      labial inclination of the lower incisors was registered. In the Angle class II/2
      cases the SNA angle was unchanged. The sagittal correction was brought about
      exclusively through mandibular translation. The deep bite and the retrusion of
      the upper incisors weren't markedly improved. The lower incisors showed a labial
      tip. The incisor angle was unchanged. Our study showed that the ANB reduction on
      an annual basis is highest, when treatment is initiated at an age of 10 to 11
      years for girls and 12 years for boys. On the growth curve this is a point in
      time below the accelerated growth phase of puberty.

PMID- 8655107
TI  - [The GTR technic within the framework of combined periodontal-orthodontic
      treatments. A case report].
AB  - Periodontal defects in adolescents or young adults are often an incidental
      finding within the framework of orthodontic treatment. Often these patients are
      suffering from a special form of periodontal disease, juvenile periodontitis.
      Guided tissue regeneration (GTR) offers a technique for long-term therapy in such
      cases. In the case presented here, the periodontal problems were aggravated by
      malpositioning of the affected teeth. Orthodontic and periodontal treatment
      enabled the malpositioning to be corrected and the osseous defects to be largely
      regenerated. Controls on regular bases up to now revealed a stable status over 2
      years.

PMID- 8655108
TI  - In-vitro study of the adhesive strengths of brackets on metals, ceramic and
      composite. Part 2: Bonding to porcelain and composite resin.
AB  - In addition to part 1 of the study, the present paper investigated more than 25
      resin/conditioner combinations with respect to their bond strengths to porcelain
      and composite resin. For that purpose stainless steel lingual buttons were bonded
      with the various adhesives and their shear bond strengths and types of bond
      failure were determined after 24 hours. All specimens were air-abraded with 50
      microns Al2O3 for 2 or 4 seconds by means of a Microetcher before bonding.
      Results show that, on the porcelain, and composite under investigation, several
      materials yield bond strengths which are similar to or higher than what is
      achieved with the conventional acid etch technique on enamel. Maximum adhesive
      strength is not always desirable, however, for bonding brackets. The type of bond
      failure and the risk of irreversible damage to the bonded material have also to
      be taken into consideration.

PMID- 8655109
TI  - The Orthosystem--a new implant system for orthodontic anchorage in the palate.
AB  - The present report describes the design and first clinical experiences of a newly
      developed endosseous orthodontic implant anchor system (Orthosystem, Institut
      Straumann, Waldenburg, Switzerland) for palatal anchorage. The 1-piece fixture
      made of titanium consists of a screw-type endosseous implant body (sandblasted,
      acid-etched, diameter 3.3 mm, lengths: 4 and 6 mm), a cylindrical polished
      transmucosal neck and an abutment. Clamp-caps provide attachment of square
      commercially available orthodontic wires (0.032 x 0.032 inch, SS) to the abutment
      (transpalatal bars). In a pilot study 1 fixture (implant body length: 6 mm) was
      inserted into the midsagittal anterior palatal region in each of 6 adult patients
      with Angle class II malocclusion (distocclusion 7 to 8 mm, overjet: approximately
      9 mm). The treatment plan included extraction of the first maxillary premolars
      and retraction of the anterior teeth based on maximum anchorage of the posterior
      teeth without using compliance-dependent anchorage aids (headgear, class II
      elastics). Due to the design of the fixture only 1 simple surgical procedure was
      required for insertion (nonsubmerged method, 1-stage surgery). Accordingly the
      need for surgical exposure of the abutment for connection and wire insertion was
      eliminated. Thus, inconvenience to patients was reduced to a minimum. The
      patients are now at varying active treatment stages. The course of treatment of
      the most advanced case is described. Evaluation of the clinical and radiological
      findings after 12 months of treatment (3 months implant healing, 9 months active
      orthodontic treatment which is equal to the implant loading period) revealed no
      implant mobility/dislocation, favourable peri-implant soft tissue conditions, no
      marked mesial movement (approximately 0.5 mm) of the implant/transpalatal bar
      supported posterior teeth, and 8 mm retraction of the anterior teeth. Retrieval
      of the fixture and post-operative wound healing were uncomplicated. In the
      treatment of this case, no compliance-dependent extraoral anchorage was used, and
      the well aligned mandibular dentition was not bonded provide anchorage support
      (class II elastics).

PMID- 8655110
TI  - Effects of information-giving and communication during orthodontic consultation
      and treatment. Part 3: Optimized orthodontist-patient communication.
AB  - Effective, orthodontist-patient communication must meet certain minimum
      requirements whose importance might vary, depending on the individual case and
      stage of treatment. In the course of treatment the following tasks are of primary
      importance: 1. Before the start of treatment, during preliminary consultation,
      information tailored in extent and quality to the individual patient has to be
      provided, a professional assessment of treatment needs made, and a relationship
      of mutual trust established. 2. In the initial phase of treatment, the individual
      shaping and optimisation of treatment needs is a matter of priority if initial
      acceptance of the appliance is to be assured. The patient should be advised how
      to meet the treatment needs in his individual situation. 3. In the further course
      of treatment, the fulfillment of the demands has to be repeatedly clarified.
      Feedback with regard to patient cooperation should be handled with caution. A
      tight recall schedule, a time-keeping record and involvement of the parents are
      obvious interventions in cases of inadequate cooperation. The treatment may also
      have to be reevaluated.

PMID- 8655111
TI  - Three-dimensional interpretation of labiolingual bone width of the lower
      incisors. Part II.
AB  - For quantitative evaluation of the different imaging quality of cephalograms and
      computed tomography in the region of the lower incisors, the macroscopic and
      histological findings of specimens were compared with the corresponding
      radiological findings. After removal of the soft tissue from 11 mandibular
      dentate segments, 15 artificial bone defects of different dimensions were
      produced in the region of the lower incisors. In comparison with the microscopic
      jaw measurements, the mean labiolingual diameter of the frontal alveolar process
      of the single incisors was overestimated in the cephalograms by 0.3 to 1.2 mm.
      Most of the anatomical-radiological correlations of the cephalometric
      measurements was insignificant. Individual metric assessment of the labiolingual
      bone width or of the facial/lingual cortical bone plates or the identification of
      the artificial defects of lower incisors in the cephalograms were generally not
      possible. In the CT-images the mean labiolingual diameter of the frontal alveolar
      process of the single incisors was overestimated by 0.1 to 0.5 mm, but the
      correlations were highly significant. The facial/lingual cortical bone plates of
      the lower incisors were evaluated and measured in the CT-scans. Thirteen of 15
      artificial bone defects (80%) were identified in the CT-scans. CT-scanning is the
      only imaging technique offering three-dimensional quantitative evaluation of the
      labiolingual alveolar bone width and the facial/lingual cortical bone plates.

PMID- 8655112
TI  - Cephalometric investigations concerning the geometry of the viscerocranium of
      human anencephalic fetuses.
AB  - Cephalometric investigations were carried out on 16 macerated skulls of
      anencephalic fetuses aged around 6 months and compared with the values obtained
      from a group of 18 normally developed specimens. The skull geometry of the
      anencephalic fetuses was different from normal proportions: anencephalic fetuses
      showed a clear mandibular prognathism, and a maxilla tilted in anterior
      direction. The values describing length of maxilla and length of the anterior
      cranial base, and NS-Ba angle were found to be within the normal range. From the
      results it can be concluded that the defective development of the forebrain seems
      to have no effects on the length development of the anterior cranial base
      although it does influence the form of the surrounding bony structures. The
      formation of the mandibular prognathism cannot be brought into direct connection
      with the defective brain development.

PMID- 8655113
TI  - Orthodontic space closure without compensatory extractions in missing second
      lower premolars and Class I molar relationship.
AB  - In a case of missing second lower premolars and class I molar relationship a good
      aesthetic and functional treatment result was achieved without compensatory
      extractions. The treatment method is described and the result discussed.

PMID- 8655114
TI  - [Endocrine crises--acute life threatening aspects].

PMID- 8655115
TI  - [Thyrotoxic crisis. Pitfalls in diagnosis--intensive therapy].
AB  - Thyroid storm--a dramatic exacerbation of existing hyperthyroidism of sudden
      onset associated with hyperthermia, tachycardia and CNS symptomatology--remains a
      life-threatening disease. On account of an overlapping of the symptoms of
      precipitating conditions, and complications, e.g. thromboembolism, the clinical
      diagnosis is not easy, and is often established "too late'. Since an additional
      role is often played by exposure to iodine, treatment is also rendered more
      difficult, for antithyroid drugs inhibit only de novo synthesis, but not the
      secretion of stored thyroxin. Treatment requires the use of thyroid-specific and
      numerous adjuvant measures, and the patient must be admitted to an intensive care
      unit with relevant experience.

PMID- 8655116
TI  - [Hypercalcemic crisis. Exacerbation of an existing hypercalcemia syndrome].
AB  - Acute hypercalcemic crisis is the life-threatening exacerbation of an existing
      hypercalcemia syndrome, which is characterized by additional cerebral symptoms
      such as clouding of consciousness, somnolence and coma as well as rapid
      deterioration of renal function. Possible causes are diseases associated with
      severe hypercalcemia, such as malignant diseases, primary and tertiary
      hyperparathyroidism, vitamin D poisoning and treatment with calcium, vitamin D
      and calcium-containing ion exchangers in renal insufficiency. Nowadays the
      specific diagnosis can usually be established quickly and simply, since only in
      primary and tertiary hyperparathyroidism are calcium and the intact parathormone
      elevated. The aim of treatment is to bring about an effective reduction in serum
      calcium by inhibiting bone resorption and increasing calcium excretion in the
      urine. Today, the substances calcitonin, biphosphonate, mithramycin (plicamycin)
      and glucocorticoids, each with a different mode of action, are available. In
      patients with underlying malignant diseases these substances are used to
      supplement the treatment of the malignancy, while in hyperparathyroidism they are
      administered prior to operative parathyroidectomy.

PMID- 8655117
TI  - [Check list for publications on drug treatment studies].

PMID- 8655118
TI  - [Magnesium deficiency after kidney transplantation and cyclosporine therapy].

PMID- 8655120
TI  - [Thyrotoxic crisis: a dangerous rarity. Interview by E. B. Moosmann].

PMID- 8655119
TI  - [Alzheimer disease: anti-inflammatory agents could be of therapeutic value.
      Interview by Elisabeth B. Moosmann].

PMID- 8655121
TI  - [Respiratory tract infections: seven days antibiosis in general practice].

PMID- 8655122
TI  - [Ancient Chinese prescriptions for hay fever. Herbs and acupuncture instead of
      desensitizing Western medicine?].

PMID- 8655123
TI  - [Calcium antagonist protects the heart from ischemia and thrombosis].

PMID- 8655124
TI  - [Correlation between symptoms and diagnosis in pharmacotherapeutic decision
      process].
AB  - Evaluation of influence of psychopathological symptoms (AMDP System) and
      diagnosis (ICD-9) on the choice of drug therapy (neuroleptics or antidepressants)
      for psychiatric in-patients was the aim of this work. Statistical analysis of
      3745 patients led to three different decision-making procedures. These procedures
      are based on symptoms or diagnoses alone or on both symptoms and diagnosis. CART
      Analysis was used for statistical analysis. Reclassification errors for
      neuroleptics were always larger than reclassification errors for antidepressants.
      The results show that both symptoms (error neuroleptics 20.2%, respectively
      antidepressants 15.0%) and diagnosis (20.8%, resp. 11.9%) alone are not
      sufficient to explain the choice of drug therapy. Lowest error rates were gained
      in a hierarchical model for the choice of drug treatment where both diagnosis and
      symptoms were used (17.1%, resp. 10.1%).

PMID- 8655125
TI  - [Chronic fatigue syndrome--psychiatric aspects].
AB  - Diagnosis of the chronic fatigue syndrome depends on various somatic and
      psychopathological symptoms. Somatic symptoms of the syndrome have been subject
      of an extensive body of literature. In comparison, psychiatric aspects have
      caught relatively less attention. Psychiatric aspects of etiological, diagnostic,
      and therapeutic concepts are essential for evaluation of the syndrome.
      Application of CDC-criteria to a well known disease does not solve the
      nosological problem, but may define the syndrome more accurately. In this
      respect, issues including psychiatric comorbidity and specificity of
      neuropathological symptoms are discussed. Psychological variables seem to have a
      high predictor value for time course and outcome of the symptoms. Etiological
      concepts emphasize on biological or psychosocial factors. Alterations of
      biological parameters including immune functions, sleep regulation, and
      hypothalamic-pituary-adrenocortical function have been reported. The role of
      cultural factors has been discussed extensively. Somatic and psychological stress
      may result in the same clinical syndrome via psychoimmunological mechanisms. An
      integrated, interdisciplinary approach to further refine diagnostic criteria,
      understanding of etiology and development of adequate therapeutic measures seems
      necessary.

PMID- 8655126
TI  - [Craving--an adequately defined concept?].
AB  - Many addicts report on craving--a strong desire to consume the drugs again.
      Craving is attributed by many addicts to be the main reason for relapse or for
      the failure to become abstinent. In the recent years some drugs with an "anti
      craving" effect have been developed. In this context a review of the complex
      concept "craving" seems to be urgent. In this paper the psychological conditions
      of craving and biochemical phenomena possibly underlying craving are reviewed.
      Basing on the recently available data a new psychobiological concept of craving
      with two prototypes (craving in early withdrawal and craving during abstinence)
      has been developed. This model is discussed with regards to possible therapeutic
      implications.

PMID- 8655127
TI  - [Dissection of the carotid artery and vertebral artery--diagnosis and therapy].
AB  - Carotid and vertebral artery dissections typically occur in young adults after
      major trauma, although they can arise spontaneously or after trivial injury. Many
      patients with carotid dissections have minor symptoms such as a subject bruit or
      Horner's syndrome. Cephalic pain is also frequent and often inaugural in carotid
      dissection. However, extracranial dissection is a well recognised cause of
      ischaemic stroke. The diagnosis of dissection was based on angiographic findings.
      Noninvasive imaging also allows prompt and reliable diagnosis. Our goal was to
      demonstrate the spectrum of neuroradiologic (CT, MR and angiographic) findings in
      craniocervical arterial dissection and compare the diagnostic utility of CT, MR,
      MR angiography. Clinical data imaging studies, and outcome were reviewed and
      compared with the results in four patients with carotid artery dissection.

PMID- 8655128
TI  - Genetic deficiencies of the glycogen phosphorylase system.
AB  - Several types of glycogen storage disease attributable to a deficiency of
      phosphorylase or phosphorylase kinase have been described. These diseases have
      been divided according to clinical symptoms, mode of inheritance, and affected
      tissue. However, this classification is questionable, as the clinical symptoms of
      these different diseases are similar, the mode of inheritance is often difficult
      to establish, and the biochemical assays are subject to several technical
      problems. A better classification would be based upon the identification of
      mutations in the respective disease genes. The molecular heterogeneity, however,
      is large, and at least 10 genes are involved. Mutations have been found in the
      muscle phosphorylase gene in patients with muscle phosphorylase deficiency, in
      the gene encoding the liver alpha subunit of phosphorylase kinase in patients
      with X-linked liver glycogenosis, and in the gene for the muscle alpha subunit of
      phosphorylase kinase in a patient with muscle phosphorylase kinase deficiency. We
      review here the different deficiencies of the phosphorylase system.

PMID- 8655129
TI  - A novel point mutation in congenital erythropoietic porphyria in two members of
      Japanese family.
AB  - The molecular basis of the uroporphyrinogen III synthase (UROIIIS) deficiency was
      investigated in two members of a Japanese family. This defect in heme
      biosynthesis is responsible for a rare autosomal recessive disease: congenital
      erythropoietic porphyria (CEP) or Gnther's disease. The first patient was
      homoallelic for a novel missense mutation: a T to C transition of nucleotide 634
      that predicted a serine to proline substitution at residue 212 (S212P). The
      second patient appeared heteroallelic, carrying the same missense mutation and a
      nonsense mutation: a C to T change at nucleotide 745, resulting in a premature
      stop at codon 249, instead of a glutamine (Q249X). The corresponding mutated
      proteins were expressed in Escherichia coli and no residual activity was
      observed. A family study was also performed to determine the carrier status.

PMID- 8655130
TI  - Assignment of the human ST2 gene to chromosome 2 at q11.2.
AB  - The human St2 locus has been assigned to chromosome 2, using a human ST2 cDNA
      clone, by a human/rodent somatic cel hybrid mapping panel. The St2 locus has also
      been mapped to chromosome 2q11.2, using a human ST2 genomic DNA clone, by in situ
      hybridization. The locus is very tightly linked to the Il-1r1 locus. Together
      with the structural similarity of ST2 to IL-1RI, these data suggest functional
      relationships between these two genes.

PMID- 8655131
TI  - Coarctation of the aorta and renal hypoplasia in a boy with Turner/Noonan surface
      anomalies and a 46,XY karyotype: a clinical model for the possible impairment of
      a putative lymphogenic gene(s) for Turner somatic stigmata.
AB  - This paper describes a 12-year-old Japanese boy with coarctation of the aorta,
      renal hypoplasia, Turner/Noonan surface anomalies, and a 46,XY karyotype.
      Although the patient might represent an exceptional case of Noonan syndrome, the
      combination of the somatic stigmata appears to be consistent with a mutation of
      the putative lymphogenic gene(s) for Turner somatic stigmata.

PMID- 8655132
TI  - Tetrasomy 18p de novo: identification by FISH with conventional and
      microdissection probes and analysis of parental origin and formation by short
      sequence repeat typing.
AB  - We report a de novo supernumerary isochromosome 18p in a child with tetrasomy
      18p, analyzed by a straightforward combination of cytogenetic and molecular
      cytogenetic methods. The diagnostic procedure consisted of standard banding
      techniques and fluorescence in situ hybridization (FISH) with centromere and
      library DNA probes for chromosome 18, and 18p-specific FISH probes prepared by
      chromosome dissesction and in vitro amplification. The maternal origin as well as
      the most probable cell stages of formation of the supernumerary isochromosome
      were determined by typing of short sequence repeats (SSRs). The pattern of
      allelic distribution suggests a nondisjunction during meiosis followed by a
      centromeric misdivision in an early postzygotic mitosis as the most probable mode
      of isochromosome 18p formation. The combination of the applied methods represents
      a powerful tool to investigate the nature and the origin of de novo marker
      chromosomes.

PMID- 8655133
TI  - Differential underacetylation of histones H2A, H3 and H4 on the inactive X
      chromosome in human female cells.
AB  - It has previously been shown that the acetylated forms of histone H4 are depleted
      or absent in both constitutive, centric heterochromatin and in the facultative
      heterochromatin of the inactive X chromosome (Xi) in female cells. By
      immunostaining of metaphase chromosomes from human lymphocytes with antibodies to
      the acetylated isoforms of histones H2A and H3, we now show that these histones
      too are underacetylated in both Xi and centric heterochromatin. Xi shows two
      prominent regions of residual H3 acetylation, one encompassing the
      pseudoautosomal region at the end of the short arm and one at about Xq22. Both
      these regions have been shown previously to be sites of residual H4 acetylation.
      H2A acetylation on Xi is higher overall than that of H3 or H4 and is particularly
      high around the pseudoautosomal region, but not at Xq22. The results suggest that
      the acetylated isoforms of H3 and H4 have at least some effects on chromosomal
      structure and function that are not shared by acetylated H2A.

PMID- 8655134
TI  - Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the
      APC gene. A clue for understanding the function of the APC protein.
AB  - The identification of germline mutations in a large number of clinically well
      characterised patients with familial adenomatous polyposis (FAP) has allowed the
      unravelling of several genotype-phenotype relationships that can now be
      interpreted in the light of the structure and functional domains of the
      adenomatous polyposis coli (APC) protein. An attenuated phenotype has been found
      to be associated with mutations at the 5' end of the gene, while a severe
      clinical expression was found in patients with the most common mutation at codon
      1309. So far, only few mutations in the 3' half of the gene have been published.
      We report on two families with a rather mild phenotype due to a frameshift
      mutation at codon 1597. These families may represent a clue for defining a 5'
      border for the occurrence of a second region of attenuated FAP that is localised
      in the 3' part of the APC gene. We propose a model to explain the relationship
      between the severity of the disease and the size of the mutant APC protein.

PMID- 8655135
TI  - Malignant familial hypertrophic cardiomyopathy in a family with a 453Arg-->Cys
      mutation in the beta-myosin heavy chain gene: coexistence of sudden death and end
      stage heart failure.
AB  - Recent genotype-phenotype correlation studies in familial hypertrophic
      cardiomyopathy (FHC) have revealed that some mutations in the beta- myosin heavy
      chain (BMHC) gene may be associated with a high incidence of sudden death and a
      poor prognosis. Coexistence of sudden death and end-stage heart failure in
      several families with FHC has recently being reported; however, the genetic basis
      of such families has not been clearly demonstrated. A three-generation Chinese
      familial hypertrophic cardiomyopathy (FHC) family (family HLI) with two cases of
      end-stage heart failure and three cases of sudden death was analyzed. The average
      age of death in the affected members in this family was 34 years old. Genetic
      linkage analysis using polymorphisms in the (alpha- and beta-myosin heavy chain
      genes revealed that FHC in this family is significantly linked to the BMHC gene
      without recombinations. Single-strand conformation polymorphism analysis of exons
      8, 9 and 13 to 23 in the BMHC gene showed a polymorphic band on exon 14 that is
      in complete linkage with the disease status in this family. DNA sequencing
      analysis in the affected members revealed an 453Arg-->Cys mutation in the BMHC
      gene. To our knowledge this is the first reported mutation of FHC in Chinese. Our
      data suggest that the 453Arg-->Cys mutation is associated with a malignant
      clinical course in FHC due not only to sudden death but also to end-stage heart
      failure.

PMID- 8655136
TI  - Reevaluation of the exact CAG repeat length in hereditary cerebellar ataxias
      using highly denaturing conditions and long PCR.
AB  - Hereditary cerebellar ataxias, including spinocerebellar ataxia type I (SCA1),
      dentato-rubro-pallidoluysian atrophy (DRPLA), and Machado-Joseph disease (MJD),
      have been associated with unstable CAG repeats. The length of the CAG repeat is a
      major factor in determining the age of onset of these diseases. In
      electrophoresis through acrylamide gels with formamide, the CAG repeat length
      following the polymerase chain reaction (PCR) coincides with the sequence
      determined repeat length after subcloning. However, without formamide, PCR
      products with long CAG repeats appear 1-4 repeats shorter than when
      electrophoresed with formamide, and the repeat lengths are variable. In addition,
      the larger the CAG repeats are, the more difficult are the PCR reactions. A
      mixture containing thermostable Taq and Pwo DNA polymerases (so-called "long
      PCR") is much more sensitive than that with Taq polymerase alone in detecting-
      expanded CAG repeats. Therefore, highly denaturing conditions, especially
      formamide gel electrophoresis, and the "long PCR" protocol should be used to
      evaluate the exact CAG repeat length. We have used these principles to detect
      unstable CAG repeats. The normal ranges are 14-34 repeats for MJD, 6-31 repeats
      for DRPLA, and 21-32 repeats for SCA1.

PMID- 8655137
TI  - SRY-negative true hermaphrodites and an XX male in two generations of the same
      family.
AB  - Two 46,XX true hermaphrodites and one XX male without genital ambiguities are
      reported. They coexist in two generations of the same pedigree, with paternal
      transmission and in the absence of SRY (sex-determining region, Y chromosome).
      These familial cases provide evidence to support the hypothesis that these
      disorders are alternative manifestations of the same genetic defect, probably an
      autosomal dominant mutation (with incomplete penetrance) or an X-linked mutation
      (limited by the presence of the Y chromosome).

PMID- 8655138
TI  - Fanconi anaemia in Italy: high prevalence of complementation group A in two
      geographic clusters.
AB  - Cell fusion studies using lymphoblastoid cell lines from Fanconi anaemia (FA)
      patients have identified five complementation groups (FA-A to FA-E) among
      European FA patients. In Italy, of the 45 FA families referred to the Italian
      Registry of Fanconi Anaemia (RIAF), 15 took part in a project for the
      identification of complementation groups. Since three immortalized lymphoblast
      lines were resistant to a cross-linking agent, we analysed only 12 patients by
      complementation analysis and found that 11 belong to complementation group A.
      Four and seven families came from two geographic clusters in the Veneto and
      Campania regions, respectively, which are thought to consist of aggregates of
      related families in reproductive isolation. The clinical characteristics of the
      patients showed both intra- and interfamilial heterogeneity, although overall the
      disease had a relatively mild course. Since the populations in both Veneto and
      Campania are likely to represent genetic isolates, our finding predicts linkage
      disequilibrium for markers flanking the FAA gene. DNAs from these FA families may
      thus be utilized for positional cloning of this gene through haplotype
      disequilibrium mapping.

PMID- 8655139
TI  - Generation of sequence-tagged sites from Xp22.3 by isolating common Alu-PCR
      products of radiation hybrids retaining overlapping human X chromosome fragments.
AB  - Several human diseases have been mapped to Xp22.3 on the distal short arm of the
      human X chromosome, and many genes in this area have been found to be expressed
      from the inactive X chromosome. To facilitate physical mapping and
      characterization of this interesting region, we have constructed a battery of
      radiation hybrids containing human X chromosomal fragments, and isolated two
      hybrid clones A with overlapping fragments of Xp22.3. Alu-PCR on these hybrids
      and identification of sequences common to both hybrids allowed the isolation of
      six sequences-tagged sites (STSs) from Xp22.3. Five of the STSs were mapped+ to
      individual YACs comprising a recently constructed contig of this region. These
      novel STSs are useful markers for further physical characterization of this part
      of the genome.

PMID- 8655140
TI  - A novel polymorphism in the coding region of CYBB, the human gp91-phox gene.
AB  - We have identified a rare polymorphism (G to C at nucleotide 1102) in CYBB, which
      codes for gp91-phox, a component of NADPH oxidase. Polymorphonuclear leukocytes
      with this enzyme produced normal amounts of superoxide anion.

PMID- 8655141
TI  - Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor
      gene: identification of two naturally occurring receptor variants and association
      analysis in schizophrenia.
AB  - A statistically significant association between a silent mutation (102T/C) in the
      serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported
      in a sample of Japanese patients and healthy controls. This finding suggests that
      genetic predisposition to schizophrenia may be affected by a functional 5-HT2A
      receptor variant that is in linkage disequilibrium with 102T/C. In the present
      study, we have sought to identify genetic variation in the 5-HT2A receptor gene
      by screening genomic DNA samples from 91 unrelated subjects comprising 45
      patients with schizophrenia and 46 healthy controls by using single-strand
      conformation analysis. We have identified four nucleotide sequence variants. Two
      sequence changes would result in protein alterations: a substitution of threonine
      by asparagine at position 25 (Thr25Asn), and a substitution of histidine by
      tyrosine at position 452 (His452Tyr). In order to test for a possible
      contribution to the development of schizophrenia, we have determined allele
      frequencies in extended samples of unrelated patients and healthy controls. The
      two amino acid substitutions are found with similar frequencies in patients and
      controls, indicating that the presence of these variants is not causally related
      to the development of schizophrenia. However, the reported association of the non
      coding polymorphism 102T/C with the disease has also been detected in our sample
      (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623).

PMID- 8655142
TI  - The human lanosterol synthase gene maps to chromosome 21q22.3.
AB  - In order to contribute to the development of the transcriptional map of human
      chromosome 21 (HC21) we have used exon trapping to identify portions of HC21
      genes. Using pools of random HC21-specific cosmids from the LL21NC02-Q library
      and cosmids from 21q22.3 we have identified five different coding regions with
      strong homology to the lanosterol synthase genes of rat and yeast. This enzyme
      catalyzes the cyclization of squalene-2,3-epoxide lanosterol, which is the
      parental compound of all steroids in mammals. Using somatic cell hybrids and HC21
      yeast artificial chromosomes (YACS) and cosmids, we mapped the human lanosterol
      synthase cDNA gene to 2lq22.3 between markers D21S25 and 21qter. Cosmid Q7G8 from
      the LL21NC02-Q library and YAC 145D8 from the CEPH HC21 contig contain this human
      gene. We cloned a portion of the human lanosterol synthase cDNA (almost 85% of
      the coding region) from a brain cDNA library and determined its nucleotide
      sequence. The predicted human protein shows 83% identity to its rat and 40% to
      its yeast homolog. No obvious candidate human disease exists for lanosterol
      synthase deficiency and the role (if any) of triplication of this gene in the
      various phenotypes of trisomy 21 is unknown.

PMID- 8655144
TI  - Screening for mutations in the neurofibromatosis type 2 (NF2) gene in sporadic
      meningiomas.
AB  - Meningiomas are benign tumors of the central nervous system. They are usually
      sporadic but can also occur associated with the neurofibromatosis type 2 (NF2)
      syndrome. The gene responsible for NF2, recently isolated from chromosome 22,
      encodes a membrane-organizing protein that shows high sequence homology to a
      protein family thought to link the cytoskeleton with membrane proteins. Mutations
      of the NF2gene have been described in sporadic meningiomas, exclusively in tumors
      that show loss of heterozygosity (LOH) of 22q. These preliminary results indicate
      that the NF2 gene is involved in the pathogenesis of at least a subset of
      meningiomas, where it does indeed behave as a tumor suppressor gene. In order to
      characterize better the role of the NF2 gene in the genesis of meningiomas we
      have examined the entire coding sequence of the gene in 125 meningiomas by single
      strand conformational polymorphism analysis; furthermore, LOH analysis for
      markers of 22q has been carried out. Inactivating mutations were identified in
      30% of our samples, all of which also showed LOH of 22q. The majority of
      mutations identified were frameshifts and nonsense mutations, which are predicted
      to produce a truncated or nonfunctional protein. We also found two missense and
      three in-frame deletions that may pinpoint specific regions of the protein
      critical to its function. Furthermore, the distribution of mutations throughout
      the gene, suggested that exons 2, 3, 5, 11 and 13 are more frequently involved.
      Our results reconfirm the importance of the NF2 gene in the pathogenesis of
      meningiomas and also suggest that there may be a nonrandom clustering of
      mutations throughout the gene.

PMID- 8655143
TI  - Characterization of the human p57KIP2 gene: alternative splicing,
      insertion/deletion polymorphisms in VNTR sequences in the coding region, and
      mutational analysis.
AB  - We have isolated human cDNA and genomic clones of a gene termed p57KIP2, which is
      related to the p2I WAFI and p27 KIP1 genes that encode inducible inhibitors of
      cyclin-dependent kinase activity. The p57 gene contains three GC-rich introns of
      166 bp, 566 bp, and 83 bp, and two of the four exons correspond to coding
      regions. Alternative splicing generates the heterogeneity in the translational
      initiations. As this gene has been localized to chromosomal band 11pI5.5, a
      region thought to be the location of a tumor suppressor gene(s) for carcinomas of
      the breast, bladder, and liver, we have examined a large number of tumors for
      genetic alterations of p57. Although no somatic mutation has been detected, we
      have found several normal variations in this gene, including four types of 12-bp
      in-frame deletions in the proline/alanine repeating domain, in which nearly 40
      motifs, viz., 5'-CCGGCC-3', are tandemly repeated.

PMID- 8655145
TI  - Analysis of the neurofibromatosis type 2 gene in different human tumors of
      neuroectodermal origin.
AB  - The autosomal dominant syndrome neurofibromatosis type 2 (NF2) is characterized
      by the development of bilateral vestibular schwannomas, meningiomas, ependymomas
      and gliomas. The NF2 gene, recently isolated from chromosome 22, is mutated in
      both sporadic and NF2 tumors such as schwannomas, meningiomas and ependymomas.
      Mutations of the gene have been described not only in the neoplasms usually
      associated with NF2, but also in 30% of the melanomas and 41 % of the
      mesotheliomas analyzed. In particular, the finding of mutations in melanomas
      supports the hypothesis that the NF2 gene is involved in the genesis of several
      tumor types that arise from the embryonic neural crest. In this study we
      examined, by single-strand conformational polymorphism (SSCP) analysis, 41 tumors
      of the central nervous system (11 schwannomas and 30 gliomas), 19 melanomas and
      15 Merkel cell carcinoma specimens for mutations in the coding sequence of the
      NF2 gene. We found three inactivating mutations of the NF2 gene in schwannomas.
      No alterations of the gene were detected by SSCP analysis of the other tumors.
      These results confirm the role of NF2 in pathogenesis of schwannomas, but do not
      define its significance in the genesis of the other neuroectodermal tumors
      studied.

PMID- 8655146
TI  - Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie
      Tooth type-1 neuropathy.
AB  - Autosomal dominant Charcot-Marie-Tooth type-1A neuropathy (CMT1A) is a
      demyelinating peripheral nerve disorder that is commonly associated with a
      submicroscopic tandem DNA duplication of a 1.5-Mb region of 17p11.2p12 that
      contains the peripheral myelin gene PMP22. Clinical features of CMT1A include
      progressive distal muscle atrophy and weakness, foot and hand deformities, gait
      abnormalities, absent reflexes, and the completely penetrant electrophysiologic
      phenotype of symmetric reductions in motor nerve conduction velocities (NCVs).
      Molecular and fluorescense in situ hybridization (FISH) analyses were performed
      to determine the duplication status of the PMP22 gene in four patients with rare
      cytogenetic duplications of 17p. Neuropathologic features of CMT1A were seen in
      two of these four patients, in addition to the complex phenotype asociated with
      17p partial trisomy. Our findings show that the CMT1A phenotype of reduced NCV is
      specifically associated with PMP22 gene duplications, thus providing further
      support for the PMP22 gene dosage mechanism for CMT1A.

PMID- 8655147
TI  - Distribution of mosaicism in human placentae.
AB  - Traditional first trimester chorionic villus sampling (CVS) for prenatal
      diagnosis can be performed by cytogenetic analysis of cytotrophoblast or
      chorionic villous stroma. Approximately 2% of pregnancies studied by CVS show
      confined placental mosaicism (CPM) involving either cytotrophoblast, stroma or
      both. We present the results of a cytogenetic study of nine term placentae from
      pregnancies with prenatally diagnosed CPM. The aneuploid++ cell lines involved
      trisomies for chromosomes 7,9,16, and X. The cytotrophoblast and villous stroma
      from multiple biopsies of these placentae were examined using a combination of
      interphase and metaphase cytogenetic analysis. CPM was detected in all nine of
      the term placentae and both tissue-specific and site-specific patterns of
      mosaicism could be discerned. These results indicate that the analysis of villous
      stroma and cytotrophoblast from multiple placental biopsies is necessary to
      improve our understanding of the evolution of CPM during pregnancy and its effect
      on the fetus.

PMID- 8655148
TI  - Human chromosome 1 localization of the gene for a prostaglandin F2alpha receptor
      negative regulatory protein.
AB  - A protein that copurifies with the bovine prostaglandin F2alpha (FP) receptor has
      been isolated and the corresponding rat cDNA has been cloned. Transfection
      experiments suggest that this protein inhibits binding of [3H]prostaglandin
      F2alpha ([3H]PGF2alpha) to FP. Histologically, this protein (FP regulatory
      protein or FPRP) shows a distribution coinciding well with those cells and
      tissues that respond to PGF2alpha. A portion of the 3' untranslated region of the
      human homolog to fprp was subcloned, sequenced, and oligonucleotide primers
      chosen that allow polymerase chain reaction (PCR) amplification specifically of
      the human fprp sequence. These primers were then used in a PCR-based mapping
      protocol. The human fprp gene was first socalized through human/rodent somatic
      cell hybrids to human chromosome 1 (100% concordance), and further through yeast
      artificial chromosome (YAC) pools to region 1p13.1-q21.3 (level 1 mapping). In
      view of the specific histologic localization of this negative regulator, possible
      pathological conditions are mentioned that may cosegrepate with this chromosomal
      region.

PMID- 8655149
TI  - Cartographic study: breakpoints in 1574 families carrying human reciprocal
      translocations.
AB  - Reciprocal translocations (rcp) are among the most common constitutional
      chromosomal aberrations in man. Using a European database of 1574 families
      carrying autosomal rcp, a cartographic study was done on the breakpoints
      involved. The breakpoints are non-randomly distributed along the different
      chromosomes, indicating "hot spots". Breakpoints of rcp that result in
      descendants that are unbalanced chromosomally at birth are more frequent in a
      distal position on chromosomal arms, and 65% of them are localised in R-bands.
      Among the R-bands, bands rich in GC islands and poor in Alu repetitive sequences
      are more frequently the site of breakpoints, as well as bands that include a
      fragile site. This result suggests that the variation in degree of methylation in
      GC islands could be involved in chromosomal breakage and hence in chromosomal
      rearrangements. The heterogeneity of the human chromosomal structure has been
      demonstrable by metaphase banding techniques since 1970. In contrast to G-bands,
      R-bands are sites of high gene concentration (Korenberg et al. 1978), are
      relatively rich in cytosine plus guanine (GC), and in Alu repetitive DNA
      sequences (Korenberg and Rykowski 1988). More recently Holmquist (1992) has
      proposed four types of R-bands, depending on their relative richness in GC and
      Alu DNA sequences. R-bands rich in GC correspond almost exactly to T-bands
      (Dutrillaux 1977). They contain 65% of all genes while they represent only 15% of
      the genome (Holmquist 1992). The aim of this study is to analyse the distribution
      of the breakpoints along chromosomes from a European database of autosomal rcp in
      order to relate it to the specificity of different chromosomal regions.

PMID- 8655150
TI  - An additional allelic variant of the CYP2D6 gene causing impaired metabolism of
      sparteine.
AB  - The identification of a novel CYP2D6 allele from a healthy Caucasian poor
      metabolizer was achieved by using a previously described polymerase chain
      reaction/single-strand conformation polymorphism strategy. Among the four point
      mutations that this allele carries, a missense mutation in exon 1 (212 G-->A or
      D6-H) seems to be responsible for the loss of CYP2D6 function. Although the
      mutation D6-H has a low prevalence in a randomly selected population of healthy
      Caucasians, its identification should further increase the phenotype prediction
      rate by genotyping.

PMID- 8655151
TI  - Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies):
      genetic analysis of three unrelated SCA2 families.
AB  - Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative
      disorders that are clinically and genetically heterogeneous. We report here a
      genetic linkage study, with five chromosome 12q markers, of three Martinican
      families with ADCA type 1, for which the spinocerebellar ataxia 1 (SCA1) locus
      was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lead
      score of 6.64 at theta = 0.00 with marker D12S354. Recombinational events
      observed by haplotype reconstruction demonstrated that the SCA2 locus is located
      in an approximately 7-cM interval flanked by D12S105 and D12S79. Using the z(max)
      1 method, multipoint analysis further reduced the candidate interval for SCA2 to
      a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM,
      which suggests a founder effect, whereas a different haplotype segregated with
      the disease in the third family. Finally, a mean anticipation of 12+/-14 years
      was found in parent-child couples, with no parental sex effect, suggesting that
      the disease might be caused by an expanded and unstable triplet repeat.

PMID- 8655152
TI  - Genotypes with the apolipoprotein epsilon4 allele are predictors of coronary
      heart disease mortality in a longitudinal study of elderly Finnish men.
AB  - Earlier we reported that allelic variation in the gene coding for apolipoprotein
      (apoE is a significant predictor of variation in the risk of coronary heart
      disease (CHD) death in a longitudinal study of elderly Finnish men. Here we
      address the question: which of the apoE genotypes confers the risk information in
      these men, and whether such information persists after other CHD risk factors are
      considered? We followed two cohorts of elderly Finnish men aged 65 to 84 years,
      one in Eastern (n = 281) and the other in the Southwestern (n = 344) Finland for
      5 years during which 26 (9.3%) of the men from the Eastern cohort and 40 (11.6%)
      of the men in the Southwestern cohort died from CHD. Baseline high density
      lipoprotein (HDL) cholesterol and (HDL cholesterol)2 in the Eastern cohort and
      age, and total and HDL cholesterol and smoking status in the Southwestern cohort
      were significant predictors of CHD death (P < 0.05). The apoE genotypes were
      significant predictors in the Southwestern cohort at P = 0.02 and in the Eastern
      cohort at P = 0.18. In multivariable models, information about apoE genotypes
      improved the prediction at P = 0.1O level of statistical significance in both
      cohorts. When genotypes were considered separately, the episilon2/4 combined with
      the epsilon4/4 in the Eastern cohort (odds ratio = 7.69, 95% CI = 1.67-35.52) and
      the epsilon 3/4 in the Southwestern cohort (odds ratio = 2.44, 95% CI = 1.165.10)
      had sigificantly greater odds of CHD death compared to the common F3/3 genotype.
      We conclude that apoE genotypes confer risk information about CHD death in two
      cohorts of elderly Finnish men in a longitudinal study, and this information
      persists after adjustment for other CHD risk factors. Because different genotypes
      were predictors in these two cohorts, we further conclude that the utility of a
      particular genotype as a predictor of CHD death in other populations may depend
      on the distribution of risk factor profiles at baseline, geographically defined
      environmental exposures, the CHD mortality history, and the evolutionary history
      of background genotypes in the population considered.

PMID- 8655153
TI  - A new point mutation affecting the fourth transmembrane domain of PMP22 results
      in severe de novo Charcot-Marie-Tooth disease.
AB  - A novel T-->G mutation in exon 4 of the PMP22 gene was identified heterozygously
      in a girl with severe, de novo CMT1A disease. Duplication of the chromosomal
      17p11-12 region, encompassing the PMP22 gene, was ruled out. This is the only
      known mutation that specifically affects the human fourth transmembrane (TM)
      domain of PMP22. It results in a substitution of a non-polar amino acid by a
      polar one (Leu147-->Arg), similar to the nearby Gly150-->Asp substitution,
      underlying the severe Trembler phenotype in the mouse. These mutations suggest
      that the fourth TM domain plays a crucial role in the normal function of PMP22.
      The new mutation also augments previous observations that diseases caused by
      mutations in PMP22 are more severe than those caused by the duplication of 17p11
      12.

PMID- 8655154
TI  - A novel sequence polymorphism in the promoter region of the human B2-bradykinin
      receptor gene.
AB  - The distribution of a nucleotide polymorphism in the core promoter of the human
      B2-bradykinin receptor gene was examined in the population of southern Germany.
      The allelic frequencies were 0.595 for C allele and 0.405 for the T allele. The
      allele frequencies were in Hardy-Weinberg equilibrium. This new marker provides a
      valuable tool to assess the risk for putative bradykinin-associated disorders
      with genetic determinism.

PMID- 8655155
TI  - Mapping of the variegate porphyria (VP) gene: contradictory evidence for linkage
      between VP and microsatellite markers at chromosome 14q32.
AB  - The gene for variegate porphyria (VP), an autosomal dominant disease with a high
      prevalance in South Africa, evidently due to a founder effect, was previously
      mapped to chromosome 14q32. In the current study this localization was evaluated
      by linkage and haplotype analyses using microsatellite markers spanning a region
      of more than 20 cM on chromosome 14q32. In many recent studies linkage
      disequilibrium between disease and marker loci has been utilized to map genes in
      founder populations, but we could not find any association between VP and the
      markers used in this study. Our data suggest that the allocation of VP to
      chromosome 14q32 may be incorrect.

PMID- 8655156
TI  - A novel emerin mutation in a Japanese patient with Emery-Dreifuss muscular
      dystrophy.
AB  - Sequencing of the STA gene in a patient with Emery-Dreifuss muscular dystrophy
      showed a 1-bp deletion of C at nucleotide 672 or 673. This deletion causes a
      frameshift, changing the amino acid sequence (amino acids 206-235) and generating
      an early stop codon.

PMID- 8655157
TI  - New allele variants of the immunoglobulin switch (Salpha) regions.
AB  - In this report we define ten Salpha1 IGHA1 (*S5-*S14) and nine Salpha2 IGHA2
      (*S10-*S18) newly found alleles of the human immunoglobulin switch alpha 1 and
      switch alpha 2 regions, respectively, in Colombian Indian, Black and Mestizo
      populations, and a complete list of the SacI and PvuII alleles so far identified
      as given.

PMID- 8655158
TI  - A new XmnI polymorphism in the regulatory region of the corticotropin releasing
      hormone gene.
AB  - We describe the first polymorphism in the 5' flanking region of the corticotropin
      releasing hormone (CRH) gene. DNA sequencing analysis identified a T --> G base
      substitution in the 5' flanking region of the gene. This substitution leads to
      the loss of an XmnI site at position 255 of the Genbank entry X67661. The
      frequency analysis in 32 Caucasians revealed that it is a rare polymorphism, with
      only three observed heterozygous individuals for this polymorphism.

PMID- 8655159
TI  - AIDS survival and progression in black Africans living in south London, 1986
      1994.
AB  - OBJECTIVES: To describe the rate of progression to AIDS and survival following
      AIDS diagnosis in HIV-infected Africans living in London. To identify factors
      influencing progression and outcome of disease. DESIGN: Retrospectively
      constructed prevalent cohort. SETTING: Outpatient clinic population, London.
      SUBJECTS: HIV-infected individuals of African origin presenting between January
      1986 and October 1994. MAIN OUTCOME MEASURES: AIDS indicator illness; cumulative
      survival probabilities to AIDS diagnosis and from AIDS diagnosis to death; rate
      of progression to AIDS. RESULTS: Ninety six patients (57 women) provided 166
      person years of follow up. Median CD4 lymphocyte count at presentation was 205
      (90% range 20-577) x 10(6)/l. Kaplan-Meier estimates of the proportion (95%
      confidence interval) of patients developing AIDS from the time of enrollment were
      18 (9 to 27)% at 12 months and 44 (30 to 58)% at 36 months. Only CD4 count at HIV
      diagnosis was independently associated with a faster rate of progression to AIDS
      (adjusted relative hazard 9.18%, 95% confidence interval 2.84 to 29.67, p <
      0.001). The proportion (95% confidence interval) surviving following AIDS
      diagnosis was estimated to be 73 (55 to 91)% at 12 months and 25 (0 to 52)% at 36
      months. CONCLUSIONS: HIV-infected people of sub-Saharan African origin living in
      London present with advanced disease. When compared with published studies, their
      survival experience is comparable to that observed in HIV-infected individuals
      born in developed countries.

PMID- 8655160
TI  - Pilot study of azithromycin in the treatment of genital donovanosis.
AB  - OBJECTIVES: To determine the effectiveness of azithromycin, an azalide antibiotic
      with long tissue half-life, in a pilot study of patients with genital donovanosis
      in the Northern Territory, Australia. DESIGN: Patients with histologically
      confirmed donovanosis were randomised to receive one of two open-label
      azithromycin dosage regimens: Regimen A--1.0 g once weekly for 4 weeks; or
      Regimen B--500 mg daily for 7 days. Patients were assessed at 6 weeks and
      classified as either "cured", "improved" or "failed". RESULTS: Seven patients
      received regimen A and 4 received regimen B. Six weeks after commencing treatment
      the genital ulcers of four patients receiving regimen A and one patient receiving
      regimen B had healed; the lesions of the other six patients (3 in each regimen)
      were "improved". No patient failed to respond and no significant adverse reaction
      was recognised. The eleven patients were reviewed after completing the six-week
      trial; all lesions had re-epithelialised without further antibiotic treatment, no
      relapses had occurred, the longest follow-up period being seven months. A further
      17 patients with donovanosis who were unable to meet the entry criteria were also
      treated successfully with azithromycin during the study period. CONCLUSIONS: This
      is the first time that azithromycin has been shown to have clinical activity
      against donovanosis. Poor compliance with prolonged courses of antibiotics is one
      of the major barriers to control of the disease. Intermittent or short-course
      therapy, made possible by the long tissue half-life of the drug, could facilitate
      control of donovanosis in endemic populations if the high cost of medication can
      be addressed.

PMID- 8655161
TI  - Ups and downs--and ups in the antiviral therapy of HIV infection.

PMID- 8655162
TI  - Genital chlamydial infection among women in Nicaragua: validity of direct
      fluorescent antibody testing, prevalence, risk factors and clinical
      manifestations.
AB  - OBJECTIVE: To validate the performance of a direct fluorescence antibody (DFA)
      test and to determine the prevalence, risk factors and clinical manifestations of
      cervical chlamydia infection in different groups of women in Nicaragua. STUDY
      POPULATION: 926 women, 863 routine clinic attenders (mean age 27 years) and 63
      sex workers (mean age 25 years) attending health centres in Leon, Corinto,
      Matagalpa and Bluefields. METHODS: Cervical specimens were examined using the
      Syva MicroTrak test system with a cut-off of 10 or more elementary bodies (EBs).
      The DFA results were validated by a one-step polymerase chain reaction (PCR)
      assay. Discordant results were further examined in nested PCR assays directed at
      two different target genes. An interviewer-administered questionnaire and a
      standard gynaecological examination were completed. RESULTS: Sensitivity of DFA
      was 80.1%, specificity 98.3%, and positive and negative predictive values 62.5%
      and 99.3%, respectively. Values were lower in locations where samples thawed
      because of electricity breaks and higher among sex workers. The majority of
      discordant results was confirmed as positive in nested PCR assays. Prevalence of
      cervical chlamydia infection based on positivity in DFA and/or PCR ranged from 2%
      among routine clinic attenders aged 35 years or older, to 8% among adolescent
      clinic attenders, and to 14% among sex workers. Among routine clinic attenders,
      young age (odds ratio [OR] 3.6, 95% confidence intervals [95% CI] 1.4-8.9 for
      women aged 15-19 years as compared with 1 in women 25 years of age or older) and
      use of oral contraceptives (OR 4.0, 95% CI 1.7-9.6) were the only statistically
      significant risk factors identified in multivariate logistic regression analysis.
      Presence of mucopurulent cervical discharge (OR 5.9, 95% CI 3.0-11.5) and
      presence of ectropion (OR 2.6, 95% CI 1.1-6.5) were the clinical signs
      independently associated with infection. CONCLUSIONS: Our results indicate that
      the DFA test was sensitive and specific while the performance of the PCR assay
      depends on adequate storage of samples. Genital C trachomatis infection is a
      common health problem among women in Nicaragua. The wide implementation of
      syndromic STD management algorithms together with health education programmes
      aimed at young people is the most promising approach to control STD in Nicaragua.

PMID- 8655164
TI  - The relationship between knowledge about sexually transmitted diseases and actual
      sexual behaviour in a group of teenage girls.
AB  - PURPOSE: To assess longitudinally the relationship between knowledge about
      sexually transmitted diseases (STDs) and sexual behaviour, contraceptive use, STD
      protection and social class in a group of Swedish teenage girls. METHODS: Girls
      starting their upper secondary school education were invited to attend a teenage
      clinic during a period of 2 years (5 visits). Questions were asked about family
      situation, sexual activity, contraceptives, STD protection and knowledge about
      STD. Gynaecological examinations were performed on entry and completion, and when
      necessary during the observation period. RESULTS: Eighty-eight girls completed
      all visits during the observation period. At 16 years of age there were no
      significant differences in knowledge about various STD and STD protection between
      girls from different social classes or with respect to coital experience, age of
      coitarche and the subsequent number of sexual partners at 18 years of age. At 18
      years of age there was a better knowledge about STDs and the need for STD
      protection (p < 0.01) among girls with coital experience compared with those who
      had no coital experience. Girls reporting many lifetime partners were best
      informed, but in spite of solid knowledge they did not protect themselves from
      infection. Even though 34% of the girls with coital experience were found to
      harbour a STD during the course of this study, almost all girls denied the
      possibility of having acquired or transmitted an infection. CONCLUSIONS: Although
      girls were well-informed about sexually transmitted diseases and knew how to
      avoid infections this knowledge had little influence on behaviour.

PMID- 8655163
TI  - Reference ranges and sources of variability of CD4 counts in HIV-seronegative
      women and men.
AB  - BACKGROUND: CD4 lymphocyte counts are used to monitor immune status in HIV
      disease. An understanding of the variability of CD4 counts which occurs in the
      absence of HIV infection is essential to their interpretation. The sources and
      degree of such variability have not been extensively studied. OBJECTIVES: To
      establish reference ranges for CD4 counts in HIV-seronegative women and
      heterosexual men attending a genitourinary medicine (GUM) clinic, and to identify
      possible differences according to gender and cigarette smoking and, in women, any
      effect of the menstrual cycle, oral contraceptive use and cigarette smoking.
      DESIGN: Female and heterosexual male patients attending a GUM clinic and
      requesting an HIV-antibody test were recruited prospectively. Results from an
      earlier study of CD4 counts in homosexual men were available for comparison.
      METHODS: Lymphocyte subpopulation analysis on whole blood by flow cytometry.
      RESULTS: The absolute CD4 count and percentage of CD4 cells (CD4%) were
      significantly higher in women (n = 195) than heterosexual men (n = 91)
      [difference between the means 111 x 106/1 (95% CI 41, 180) and 3.1% (1.30,
      4.88)]. The absolute CD4 count and CD4% were also significantly higher in smokers
      (n = 143) than non-smokers (n = 140) [difference 143 (79, 207) and 2.1% (0.43,
      3.81)]. Reference ranges for absolute CD4 counts (geometric mean +/- 2SD) were
      calculated on log transformed data as follows; female smokers 490-1610, female
      non-smokers 430-1350, heterosexual male smokers 380-1600, heterosexual male non
      smokers 330-1280. Among other variables examined, combined oral contraceptive
      pill use was associated with a trend towards a lower absolute CD4 count. Changes
      were seen in CD4% with the menstrual cycle. CD4 counts and CD4% did not differ
      significantly between heterosexual men and homosexual men (n = 45). CONCLUSION:
      There is a significant gender and smoking effect on CD4 counts. The effects of
      oral contraceptive use and the menstrual cycle warrant further investigation.

PMID- 8655165
TI  - Changes in sexual behaviour of patients attending an HIV testing centre: a
      prospective study 1988-1994.
AB  - OBJECTIVE: To evaluate the sexual behaviour changes in patients attending HIV
      testing during the period July 1988 to June 1994. DESIGN: In a prospective study,
      6824 face-to-face interviews were carried out before the HIV test was performed.
      The frequency of condom use and the number of sexual partners during the 6
      previous months were recorded annually from July to June. The data were analysed
      according to gender, age class and sexual orientation. SETTING: Strasbourg, Bas
      Rhin, France. SUBJECTS: Patients attending the HIV testing centre of Strasbourg.
      RESULTS: There was a striking increase in the number of attenders of this centre
      from 358 patients in 1988/89 to 2421 in 1993/94. We observed a significant
      decrease of homosexuals having more than five partners (p < 0.05) whereas
      multipartner sex remained unchanged in heterosexuals. There was no change in the
      proportion of patients having only one partner, except a slight raise in patients
      under 20 years. All groups showed a very significant increase in condom use,
      which was especially marked in young heterosexuals aged under 30 years.
      Nevertheless, condom use remained higher in homosexuals than in heterosexuals in
      1993/94. In addition, there was a striking fall of past sexually transmitted
      disease in heterosexual patients under 20 years during the study period, and a
      fall in the HIV positivity rate from 1.96% to 0.42%. CONCLUSIONS: A major
      increase was noted in condom use in all groups and a reduction of multipartner
      sex in some patients. These data are encouraging in the younger patients, but
      prevention efforts should also be concentrated on middle aged patients who did
      not show major sexual changes, although having important risk factors for HIV
      infection.

PMID- 8655166
TI  - Sexual behaviour in travellers abroad attending an inner-city genitourinary
      medicine clinic.
AB  - OBJECTIVE: To investigate frequency of sexual encounters with new partners abroad
      in patients attending a genitourinary clinic (GUM). METHODS: In a case series 464
      attenders at a genitourinary medicine clinic completed an anonymous self
      administered questionnaire, if they had been abroad recently, enquiring about
      sexual behaviour abroad. RESULTS: 28.4% of subjects admitted to sex with a new
      partner abroad with only 41.7 per cent consistently using condoms. There were no
      significant differences in condom use for gender, ethnicity or type of visit and
      relationship. Twenty-nine per cent of those admitting to sex abroad had more than
      one partner. The risk of multiple partners was not associated with gender,
      ethnicity, type of visit (holiday or business) or type of relationship
      (heterosexual or homosexual). The first partner abroad for 63% of men and 62.5%
      of women was of a nationality other than that of United Kingdom residents. Non
      Caucasians and homosexuals were significantly more likely to have first partners
      abroad from outside the UK than Caucasians and heterosexuals respectively.
      CONCLUSION: The occurrence of casual sex abroad in GUM attenders suggests that
      further research is needed to establish targetable risk factors for this type of
      behaviour amendable to change through health promotion.

PMID- 8655168
TI  - Accessibility of genitourinary medicine clinics.
AB  - OBJECTIVES: to examine and compare the accessibility and acceptability of a range
      of genitourinary medicine (GUM) clinics. DESIGN: five GUM clinics representing
      different types of locations in the West Midlands Region were selected. All
      patients attending over the sampling period were included, with data collected by
      anonymous self completed questionnaire. RESULTS: 297 completed questionnaires
      were obtained from 360 attendees; 87.4% of attendees had taken 30 minutes or less
      to get to the clinic, and 66% had used public transport, with variations found
      between locations. The majority (72.5%) of attendees visited the clinics during
      their preferred part of the day. Examination of narrower time preferences showed
      that those wanting to visit in the evening were less likely to be seen during
      their preferred time than those wanting daytime visits (32% compared with 90%).
      Of the attendees 98.6% found clinic staff to be friendly and 97.5% did not feel
      they were being judged because of their sexual activities. The most common
      reasons for choosing a clinic were recommendation (38.2%) and proximity (36.4%).
      CONCLUSIONS: the clinics were generally found to be physically accessible,
      although clinic opening hours need to be reconsidered. Further work is needed on
      the acceptability of the service in relation to expectations.

PMID- 8655167
TI  - Sexual health and use of condoms among local and international sex workers in
      Sydney.
AB  - OBJECTIVES: To compare indicators of sexual health and predictors of condom use
      for commercial sex among local and international female sex workers first
      attending an STD clinic. SETTING: A public STD clinic in Sydney, Australia.
      SUBJECTS: All sex workers first attending between June 1991 and May 1993.
      METHODS: Cross-sectional analysis of demographic, behavioural and morbidity data
      from proforma medical records. RESULTS: 91 local sex workers and 123
      international sex workers (predominantly from Thailand, Malaysia and China) first
      presented during the study period. There were significantly higher prevalences of
      chlamydia (0 v. 15%, p = 0.0002), gonorrhoea (0 v. 14%, p = 0.0006), syphilis (0
      v. 10%, p = 0.006) and clinical genital herpes (0 v. 5%, p = 0.04) among
      international sex workers. The only case of HIV infection was in an international
      sex worker. Inconsistent condom use for commercial sex was significantly more
      common among international sex workers (RR = 4.5; 95% CI 3.1-6.5). On
      multivariate analysis, inconsistent condom use in international sex workers was
      associated with a recent history of prostitution outside Australia (p = 0.04),
      while inconsistent condom usage among local sex workers was associated with
      increasing age (p = 0.003). CONCLUSIONS: These data illustrate the efficacy of
      condoms and the success of targeted education programmes in local sex workers in
      Sydney. By contrast, international sex workers continued to be at high risk of
      STDs. The international sex industry in Sydney requires enhanced culture-specific
      interventions. Immigration laws as they affect sex workers should also be
      reviewed.

PMID- 8655169
TI  - Partner referral as a component of integrated sexually transmitted disease
      services in two Rwandan towns.
AB  - OBJECTIVE: To document partner referral rates at health centres with improved STD
      services, and to determine factors contributing to successful referral. METHODS:
      Partner referral was initiated as part of the upgrading of STD services in
      primary care health facilities in two semi-urban Rwanda towns. After syndromic
      management of the presenting complaint, index patients received prevention
      education and condom demonstration, and were urged to refer sexual partners to
      the health centre for a free examination. Partner referral coupons linked by code
      number to the symptomatic index patient were given to facilitate referral; no
      identifying information was collected on partners from the index patients.
      RESULTS: Three quarters of the symptomatic patients seen at the two primary
      health care facilities were women. Overall, the ratio of referred partners to
      index patients was 26%. Only 58% of index patients accepted partner referral
      coupons. The referral rate for those who did accept coupons was 45%. Partner
      referral worked best for regular partners. Most index patients and partners were
      married and only four index patients referred more than one partner. Women index
      patients, especially when pregnant, were more successful in referring partners
      than men. Index patients who referred partners tended to be older than those who
      did not. Awareness of STD symptoms in the partner, and diagnosis of cervicitis
      were associated with a higher rate of STD symptoms in the partner, and diagnosis
      of cervicitis were associated with a higher rate of partner referral.
      CONCLUSIONS: Efforts to improve rates of partner referral should begin at the
      clinic level with improved counselling to convince more index patients of the
      importance of partner referral. Partner symptom recognition may be useful for
      increasing rates of partner referral. Supplementary strategies are needed to
      reach non-regular partners. When syndromic management is used, counselling should
      take into account the lower predictive values of identifying STD in women in
      order to avoid partner accusation. Despite limitations, patient referral of
      sexual partners can be an effective strategy for reaching a population at high
      risk for STD with minimal additional investment in health worker staff time.

PMID- 8655170
TI  - Undergraduate teaching of genitourinary medicine in Britain--what are the issues?

PMID- 8655171
TI  - Sexually acquired metronidazole-resistant trichomoniasis in a lesbian couple.
AB  - A lesbian couple in a monogamous relationship each presented with vaginal
      discharge demonstrable on culture to contain Trichomonas vaginalis. Their
      symptoms had failed to respond to standard regimens of metronidazole, and
      subsequent microbiological sensitivities confirmed resistance of the trichomonads
      to metronidazole (minimum inhibitory concentrations in aerobic conditions > 8
      mcg/ml). In addition, the couple denied use of penetrative sex toys or recent
      male partners, supporting the concept of transmission through mutual
      masturbation.

PMID- 8655172
TI  - Fatal haemorrhage following liver biopsy in patients with HIV infection.
AB  - A retrospective review of all 248 liver biopsies performed in patients with HIV
      infection at two referral centres in London over a 12 year period revealed five
      cases of major bleeding following biopsy, with four deaths. The risk of major
      bleeding was 2.0%, and mortality was 1.6% following liver biopsy. The risk of
      bleeding as much higher than in published series of biopsies done in patients
      without HIV infection, owing in part to the high prevalence of thrombocytopaenia
      and clotting abnormalities in patients with HIV infection. HIV infection per se
      may also increase the risk of bleeding following liver biopsy.

PMID- 8655173
TI  - Male duct ectasia associated with HIV infection.
AB  - The incidence of male duct ectasia (periductal mastitis) is extremely rare, only
      eight cases having been reported. The underlying cause (as in females) is
      uncertain. Two cases in HIV positive males of recurrent unilateral nipple lesions
      are reported with histology consistent with duct ectasia. At presentation neither
      patient had an AIDS defining illness. An impaired immunity secondary to HIV
      infection may result in an increased susceptibility to repeated nipple
      infections, and the clinical as well as histological features of duct ectasia.
      The consideration of HIV infection in future cases of male duct ectasia may be
      warranted.

PMID- 8655174
TI  - Case report: foreign body in male penile urethra.

PMID- 8655175
TI  - Recurrent perianal warts and anal carcinoma.

PMID- 8655176
TI  - Photodynamic therapy for condylomata acuminata with local application of 5
      aminolevulinic acid.

PMID- 8655177
TI  - Systemically administered interferon alfa-2a prevents recurrence of condylomata
      acuminata following CO2-laser ablation. The influence of the cyclic low-dose
      therapy regimen. Results of a multicentre double-blind placebo-controlled
      clinical trial.

PMID- 8655178
TI  - Herpes simplex virus infection in women: viral subtypes and epidemiological
      features in a district hospital.

PMID- 8655179
TI  - Successful treatment of donovanosis with ciprofloxacin.

PMID- 8655180
TI  - Gonorrhoea in HIV seropositive homosexual men attending an East London
      genitourinary medicine clinic.

PMID- 8655181
TI  - The silent suffering women.

PMID- 8655182
TI  - Syndromic management of genital ulcer disease--a reply.

PMID- 8655183
TI  - Community-based respiratory viral infections in HIV positive patients with lower
      respiratory tract disease: a prospective bronchoscopic study.
AB  - OBJECTIVES: To evaluate the contribution of community-based respiratory virus
      infections to lower respiratory tract disease in HIV-1 infected individuals.
      DESIGN: Prospective clinical cohort study. SETTING: Specialist in-patient unit
      for HIV and AIDS, University College London Hospitals, London. SUBJECTS: 44
      consecutive HIV-1 antibody positive patients who underwent 47 diagnostic
      bronchoscopies for evaluation of the symptoms and signs of lower respiratory
      tract disease. TIME: Winter months of 1994/95. MAIN OUTCOME MEASURES: Detection,
      in bronchoscopic alveolar lavage fluid, of infection with influenza A and B,
      respiratory syncytial virus (RSV), parainfluenza 1, 2 and 3 (by
      immunofluorescence and cell culture) and adenovirus and enteroviruses (by cell
      culture). RESULTS: No evidence of influenza, RSV, parainfluenza, adenovirus, or
      enterovirus infection was detected. CONCLUSIONS: Despite a marked increase in RSV
      and influenza B infection in the general population over the winter of 1994-95,
      respiratory virus infections were not detected in this cohort of HIV infected
      patients. As the organisms causing lower respiratory tract disease were related
      to immunosuppression, this study questions the value of routine identification of
      community-based respiratory viruses in this patient group.

PMID- 8655184
TI  - Primase structure and function.
AB  - Primase is the ssDNA-dependent RNA polymerase that synthesizes RNA primers during
      DNA replication. In common with all DNA and RNA polymerases, primase has
      structural and functional features involved in polymer elongation. As RNA
      polymerase, it has structural and functional features for initiating chain
      synthesis. As a primase, it has structural and functional features for initiating
      chain synthesis on ssDNA. Using amino acid sequence analysis the structure of
      Escherichia coli primase responsible for binding zinc, at least three magnesium,
      and DnaB helicase has been identified. One of the magnesium binding motifs
      resembles the ?active magnesium? motif found in all DNA and RNA polymerases. This
      motif can be considered to be involved in phosphodiester bond formation. The
      region with the putatuve zinc binding motif is the most highly conserved portion,
      including more than 25% of identical residues among bacterial primases. The
      function of the zinc finger may be to bind ssDNA in a sequence-specific manner.
      Primase has ?RNAP? motif, a sequence found in all RNA polymerases which may be
      involved in chain initiation. Many of the observations concerning primer
      synthesis initiation in vivo have been reproduced by several of the in vitro
      assay systems. Important among these is that Okazaki fragments are initiated in
      vivo from d(CTG) most of the time. This trinucleotide initiation specificity has
      been shown to be an intrinsic property of pure primase in vitro. Using artificial
      ssDNA templates, primase has been shown to be the slowest and most error-prone
      polymerase yet studied. The rate-determining step is the first phosphodiester
      bond formed. Any protein which can influence either the dinucleotide synthesis
      rate or primase-ssDNA binding affinity will also play a key role in the
      regulation of primer synthesis initiation.

PMID- 8655185
TI  - Regulation of NK susceptibility by target cell class I MHC molecules.

PMID- 8655186
TI  - Conformational dynamism in d-(GAATTCCGTTATT) containing the complementary Myb
      responsive element d-CCGTTA: NMR and MD investigations.
AB  - Conformational features of the DNA segment d-(GAATTCCGTTATT) containing the
      complementary Myb responsive element CCGTTA has been studied by NMR and molecular
      dynamics calculations with a view to see the role of 3D structure in specific DNA
      recognition. From the low field imino proton NMR spectra, the DNA sequence is
      seen to exist as a duplex with pyrimidine mismatches in the centre. The 2D NMR
      spectra however show that teh molecule exhibits substantial dynamism even at 1
      degree C. Several extra cross peaks, more than the expected number, are seen in
      particular regions in all the spectra. These observations indicate that the
      duplex undergoes slow transitions between base-paired and unbase-paired states
      due to mismatches in the centre. Hence, to characterise those transitions a
      restrained verlet dynamics has been performed for 50ps using X-PLOR force field.
      Structural intermediates at regular intervals have been analysed, and we see that
      the dynamism in the molecule results in substantial fluctuations in the different
      torsion angles. The mismatch sites are seen to exhibit the highest degree of
      fluctuations, with the bases stacking in and looping out of the duplex. The sugar
      geometry is seen to be fairly steady around the S domain for most of the
      residues.

PMID- 8655187
TI  - Synthetic peptides related to the delta-receptor agonist, dermorphin gene
      associated peptide.
AB  - The delta-receptor selective dermorphin gen associated peptide (DGAP) and five of
      its analogues having structural modifications at positions 2, 4 and 5 were
      synthesized by the solid phase method using 9-fluorenylmethoxycarbonyl amino acid
      trichlorophenyl esters as coupling agents and rho-benzyloxybenzyl alcohol resin
      as the solid support. The delta-receptor selectivity of these peptides was
      determined by guinea pig ileum and mouse vas deferens assays. The latter assay
      was carried out using modified Kreb's solution aerated with pure oxygen instead
      of carbogen. All the synthetic peptides were found to be delta-receptor
      selective.

PMID- 8655188
TI  - Structural alterations induced by photodynamic action of hematoporphyrin
      derivative (HpD) in plasma membrane of glioblastoma (U-87MG) cells: time
      dependent fluorescence spectroscopic study.
AB  - Photodynamic action of hematoporphyrin derivative (HpD) on the plasma membrane of
      human glioblastoma U-87MG cells was investigated using lipid and protein specific
      fluorescent probes trimethylammonium-1,6-diphenyl 1,3,5-hexatriene (TMA-DPH) and
      N-(1-pyrene)-maleimide (PM) respectively. Steady state anisotropy, decay time and
      time dependent anisotropy of these probes in U-87MG cells were measured. Light
      irradiation caused an increase in the steady state anisotropy of TMA-DPH in cells
      treated with HpD; however, no change in decay time was observed. Time dependent
      anisotropy measurements were performed and the data were analyzed using wobbling
      in cone model. A decrease in the rotational relaxation time (phi) as well as the
      cone angle (theta(c)) and an increase in the order parameter (S) of TMA-DPH were
      observed on photosensitization of cells. A decrease in the order parameter (S) of
      TMA-DPH were observed on photosensitization of cells. A decrease in the steady
      rate anisotropy and the rotational relaxation time (phi) of PM and enhancement in
      the lipid peroxidation were also observed. Our results show that the photodynamic
      action of HpD increases the order in the lipid bilayer and the mobility of the
      proteins in the plasma membrane of cells.

PMID- 8655189
TI  - Conformational structure of some beta 1-blockers, their partitioning in lipid and
      the role of parasubstituents.
AB  - The conformational structure of beta1-blockers metoprolol, atenolol and practolol
      has been investigated by PCILO method. The aminoalkanol moiety adopts the same
      conformation in all these compounds. These beta-antagonists differ only in the
      conformation adopted by the substituent para to the aminoalkanol moiety. The
      graphical representation of the B1-antagonists for the final conformation reveals
      that only in the S-form, three interacting sites, namely, aromatic moiety, the
      beta-hydroxyl group and the -NH2(+) groups of aminoalkanol moiety are available
      for interactions with the receptor. The interaction of the aryloxy oxygen of the
      beta-antagonists with water molecule has also been taken into account. A linear
      relationship was obtained between log K (the partitioning of the beta-blocker in
      DMPC and also in octanol/water) and the potencies of these beta1-antagonists.
      Possibly, the role of para substituent is to act as an anchor by partitioning in
      the lipid bilayer so that the beta1-antagonist adopts the proper orientation for
      binding to the receptor.

PMID- 8655190
TI  - A soluble preparation from developing groundnut seeds (Arachis hypogaea)
      catalyzes de novo synthesis of long chain fatty acids.
AB  - A 100,000 x g supernatant fraction prepared from developing groundnut seeds (30
      35 days after flowering) catalyzed the synthesis of fatty acids from [l
      14C]acetate at a rate of 120nmoles of acetate incorporated per hr per gram fresh
      weight of tissue. 90% of this incorporated label was associated with fatty acids.
      The major fatty acids formed were stearic- (77%) and palmitic acids (14%) with 4%
      of oleic acid. The fatty acid synthetase activity was stable when stored at 0-4
      degrees C for at least fifteen days. It is concluded from these results that
      acetyl-coA carboxylase and all the enzymes of fatty acid synthetase from
      developing groundnut seeds are soluble.

PMID- 8655191
TI  - Studies on the surface properties of human lymphocytes by photon correlation
      spectroscopy technique.
AB  - Electrokinetic behaviour of human lymphocytes was studied by photon correlation
      spectroscopy technique on laser IR-spectrometer. The electrophoretic mobilities
      (EPMs) were measured for peripheral blood lymphocytes (PBL) and CEM-C12 T cell
      line in 1:1 electrolyte at 22 degrees C. Plots of mobility vs ionic strength in
      the range 0.001-0.1 M were compared with theoretical curves calculated from (i)
      the Smoluchowsky formula, (ii) the simplified form of the Dukhin-Deryaguin
      equation which takes into account the fact that the mobility decreases due to the
      relaxation effect and (iii) the equation suggested by Donath and Pastushenko,
      which takes into account the influence of cell glycoprotein layer (GPL) on the
      EPM values. It has been found that the first two equations describe the
      experimental data with the assumption that surface charge density (sigma)
      decreases and width of the hydrodynamically immobile layer (L) increases with
      decreasing ionic strength; the relaxation effect turns out to be insignificant
      for the cell charges and sizes under consideration. In agreement with these
      findings, the third equation is approximately consistent with experimental data
      on the condition that GPL is allowed to expand with decreasing ionic strength,
      with simultaneous decrease of its full charge density (sigma(f)). The results are
      compared with relevant evidence for erythrocytes. The possible applications of
      the inferences arrived at in electrophoretic studies of cell behaviour are also
      discussed.

PMID- 8655192
TI  - Spectrophotometric titration of phenoxyl groups of sheep brain tubulin.
AB  - Spectrophotometric titration of phenoxyl group of sheep brain tubulin carried out
      in 6M guanidine hydrochloride indicated 36 tyrosine residues per dimer of
      tubulin. A plot of log alpha/(1-alpha) versus pH showed that 26 residues titrated
      with apparent pK of 10.4 and 10 residues titrated with apparent pK of 11.0. The
      high pK value of tyrosine could be attributed to the possibility that the
      molecules containing tyrosine residues were not completely utilised as these
      residues could have been partially shielded from the solvent. Alternatively, they
      could have proximal negative charges.

PMID- 8655193
TI  - Phaco triples: are we crossing the limit?

PMID- 8655194
TI  - Principles and paradigms of pediatric cataract management.
AB  - Propensity for increased postoperative inflammation and capsular opacification, a
      refractive state that is constantly in a state of flux due to growth of the eye,
      difficulty in documenting anatomic and refractive changes due to poor compliance,
      and a tendency to develop amblyopia, makes management of cataract in the child
      different from that in the adult. The recent past has unraveled several caveats
      of pediatric cataract management-the importance of atraumatic surgery and
      complete removal of lens matter, benefits of in-the-bag intraocular lens (IOL)
      implantation, role of titrating IOL power to counter refractive changes due to
      growth of the eye, prudery of continuously following these eyes for early
      detection of aphakic glaucoma and benefits of some surgical innovations. Although
      these promise to significantly improve our management of pediatric cataract,
      their long-term benefits are yet to be determined. We will also have to harness
      newer techniques, especially in the areas of wound construction and capsule
      management, and will have to develop effective strategies for the refractive
      management of infantile aphakia.

PMID- 8655195
TI  - Changing trends in the intraocular lens acceptance in rural Tamil Nadu.
AB  - A retrospective analysis spanning a 3-year period (1992-1994) was done to
      determine the rate of acceptance and affordability of intraocular lenses among
      the rural population of Tamil Nadu. The acceptance rate increased at an average
      of almost 70 to 100% as compared to a 17 to 20% increase in the total number of
      cataract surgeries performed per year. Analysing by mode of admission, the
      proportion of intraocular lens acceptance was more among the patients who
      directly presented at the hospital than the patients referred from eye camps. The
      overall acceptance rate was high and the ophthalmologist should be prepared to
      meet the likelihood of greater demand for intraocular lens from this population.

PMID- 8655196
TI  - Colour of the nucleus as a marker of nuclear hardness, diameter and central
      thickness.
AB  - Hundred and thirty patients, aged above 40 years, with senile cataract were
      examined. Age and colour were selected as the probable preoperative indicators of
      nuclear hardness. The lens material collected after manual extracapsular
      extraction was washed and the nucleus isolated. The diameter and central
      thickness of the nucleus were measured; the mean diameter and mean central
      thickness were 7.13 mm +/- 0.76 and 3.05 mm +/- 0.48, respectively. The hardness
      of the nucleus was measured with a lens guillotine designed by us. Regression
      analysis was applied to the parameters measured and these were compared with the
      colour and age. The parameters measured had the following relationship: Colour vs
      hardness (r value = 0.7569) (p < 0.001) Colour vs diameter (r value = 0.3962) (p
      < 0.001) Colour vs central thickness (r value = 0.4785) (p < 0.001) Age vs
      hardness (r value = -0.0499) (p > 0.05) Age vs diameter (r value = 0.0987) (p >
      0.05) Age vs central thickness (r value = 0.1700) (p > 0.05) The values showed
      that colour had a statistically significant relationship with all the 3
      parameters (p < 0.001), while age had no significant relationship with the same
      parameters. The results indicated that colour can be used more reliably to
      predict physical characteristics of the cataractous lens nucleus, the
      preoperative knowledge of which would help the surgeon in planning small-incision
      surgery including phacoemulsification.

PMID- 8655197
TI  - Capsulorhexis: its safe limits.
AB  - We undertook this study to determine the safe limits of capsulorhexis during
      nucleus expression in 40 eyes of patients undergoing extracapsular cataract
      extraction (ECCE) with a posterior chamber intraocular lens (PCIOL) implantation
      and in 30 cadaver eyes. In group I (patient eyes), capsulorhexis of 4.5 to 7.5 mm
      was performed and the nucleus was expressed by hydrodissection. The nuclei
      measured 4.5 to 9.0 mm. One relaxing incision at 12 o'clock position had to be
      placed in 9 patients. In group II (cadaver eyes), continuous curvilinear
      capsulotomies of 4.0, 4.5, 5.0, 5.5, 6.0 and 6.5 mm were made in 5 eyes each. No
      relaxing incisions were placed. In both the groups, nuclei of all sizes could be
      safely delivered through intact capsulotomies measuring 5.5 mm or more. In two
      patient eyes, posterior capsule rupture occurred with rhexis measuring 4.5 and
      5.0 mm, respectively. In the cadaver eyes, intracapsular extraction occurred in 4
      eyes with rhexis measuring 5.0 mm or less. We conclude that a rhexis less than
      5.5 mm is not safe for nucleus delivery during ECCE.

PMID- 8655198
TI  - Endophthalmitis caused by anaerobic bacteria.
AB  - A retrospective analysis of 22 patients who underwent pars plana vitrectomy for
      endophthalmitis and had culture-proven anaerobic bacteria, was done. Elimination
      of infection with attached retina and recovery of ambulatory vision > or = 2/60
      were considered as anatomic success and functional success, respectively. Mean
      follow-up period was 12.7 months (range, 2 to 48 months). Anatomic success was
      attained in 14 (63.6%) eyes and functional success in 12 (54.6%) eyes. A poor
      preoperative visual acuity was found to be associated with poor functional
      outcome (p < 0.046). In endophthalmitis, a routine anaerobic culture of
      intraocular specimen is recommended.

PMID- 8655199
TI  - Retained wooden foreign bodies in the orbit: a case report.

PMID- 8655200
TI  - Rhodotorula causing chronic dacryocystitis: a case report.

PMID- 8655201
TI  - Progressive growth in melanocytoma of the optic nerve head.

PMID- 8655202
TI  - Complications of cataract surgery.

PMID- 8655203
TI  - Biochemical profiles and serotypes of nosocomial Enterobacter cloacae strains in
      Northern Norway: biochemical identification problems with commercial test
      systems.
AB  - During a period of 2 years, 118 strains of Enterobacter cloacae were collected
      consecutively in connection with nosocomial infections in Northern Norway;
      identified by conventional methods and by the API 20E system. The API 20E profile
      3305573 predominated and was present in 73 of 118 strains. Among 96 serotyped
      strains, 73 were serotypable, 20 nontypable and two polyagglutinable.
      Predominating serotypes were 3 (29 strains), 8 (21 strains) and 23 (nine
      strains). When the API 20E profiles of the 118 strains were read in the new ATB
      (automated computer-assisted) 20E data base system, 97 of 118 (82.2%) strains
      were identified as E. cloacae. The 118 strains were tested in the new ATB Rapid
      ID 32E and ATB ID 32E (ATB system, bioMerieux, France) systems. Only 69 of 118
      (58.5%) strains were identified as E. cloacae in both systems. The ATB Rapid ID
      32E identified 97 of 118 strains (82.2%), and the ATB ID 32E only 80 of 118
      strains (67.8%). Among 73 serotypable strains, the ATB Rapid ID 32E identified
      79.5% as E. cloacae, while the ATB ID 32E identified only 64.4%. Among 40
      serotypable strains with API 20E profile 3305573, all 40 were identified as E.
      cloacae by the ATB Rapid ID 32E, while only 27 (67.5%) by the ATB ID 32E system.
      Further improvements may increase the value of biochemical identification of E.
      cloacae in diagnostic work.

PMID- 8655204
TI  - Pharmacokinetics of orally administered zidovudine in HIV-infected children and
      adults.
AB  - The pharmacokinetics of oral zidovudine in HIV-infected children and adults are
      reported. Fourty-six patients were investigated. For data analysis three groups
      of similar size were formed: young children 4 months-4 years, n = 15 (group 1),
      older children up to 13 years, n = 16 (group 2) and young adults, n = 15 (group
      3). After a single oral dose repeated blood samples were taken 1/2 hourly during
      a period of 4 hours and zidovudine concentrations in plasma were determined by
      high performance liquid chromatography. For better comparison of dose dependent
      parameters peak concentrations (Cmax) and the area under the time-concentration
      curves (AUC) were normalized either to the dose/body weight (bw) or the dose/body
      surface area (bs), respectively. Time to reach peak concentrations and mean
      terminal elimination half-life times (t1/2 beta = 63.4 +/- 47.6, 74.9 +/- 54.9
      and 56.9 +/- 16.4 min in group 1, 2 and 3, respectively, mean +/- SD) were not
      significantly different between the three groups. With normalization to dose/bw
      young children in comparison to adults had significantly lower Cmax (2.7 +/- 1.3
      vs. 4.6 +/- 2.4 mumol/l, p = 0.016) and AUC (226 +/- 108 vs. 373 +/- 224
      mumol.min/l, p = 0.038). Group 2 gave intermediate values. However, with
      normalization to dose/bs differences in Cmax (6.5 +/- 3.3, 7.3 +/- 4.2 and 6.8 +/
      3.6 mumol/l, in group 1, 2, and 3, respectively) and AUC (563 +/- 313, 691 +/-
      351 and 555 +/- 342 mumol.min/l, in group 1, 2 and 3) were not significant
      between the three groups. It is likely that changes in body water content with
      age may account for most of these differences observed. In conclusion, a similar
      pharmacokinetic profile was found in children older than 3 months as compared to
      older children or adults.

PMID- 8655205
TI  - A randomized study of imipenem compared to cefotaxime plus piperacillin as
      initial therapy of infections in granulocytopenic patients.
AB  - The objective of the presented, randomized study was to compare the efficacy of
      antimicrobial monotherapy with imipenem (3 x 0.5g/d) to a combination therapy
      with cefotaxime (3 x 2g/d) plus piperacillin (3 x 4g/d) for empirical treatment
      of infections in neutropenic patients. In 165 patients, 237 infectious episodes
      were evaluable. The overall response rate of patients treated with cefotaxime
      plus piperacillin was 67/115 (58%), of those treated with imipenem 66/122 (54%).
      In patients not responding to the initial therapy regimen within 2 or 3 days, the
      antimicrobial therapy was modified. After therapy modification 85/100 patients
      were cured. Fever of unknown origin (FUO) showed the most favourable course
      compared to other infection types, with a response in 46/59 (78%) and in 35/50
      (70%) cases, respectively. In comparison, pneumonias were successfully treated in
      only 3/21 (14%) and 7/37 (19%) cases. Even including patients with modified
      therapy, only 66% (21/32) of pneumonia episodes responded. The unfavourable
      results in pneumonias is mainly due to the high rate of 13 systemic mycoses in
      this group (22%). Overall, a similar response was observed in patients treated
      with cefotaxime plus piperacillin in comparison with imipenem. In primary
      bacteremias however, an advantage was observed in patients treated with imipenem
      (20/27; 74%) compared with cefotaxime plus piperacillin (11/23; 48%).

PMID- 8655206
TI  - Pharmacokinetics of azithromycin in normal and impaired renal function.
AB  - Plasma and urine levels of 12 healthy subjects and 30 patients with renal
      insufficiency of different degrees were examined after oral administration of
      four 250 mg capsules azithromycin (total daily dose 1,000 mg). The concentrations
      were determined by cup plate method. The pharmacokinetic parameters were
      determined model-dependent and noncompartmentally. Neither the area under the
      plasma concentration curve nor the distribution volume in steady state (16 l/kg
      body weight) nor the maximal plasma concentration were significantly affected by
      renal insufficiency. Thus the dosage regimen of azithromycin in renal impairment
      may (and should) be the same as in patients with normal renal function. The
      nonrenal clearance is not affected by renal insufficiency, but the concentration
      of the substance in the tubular lumen (the "tubular load") may be increased.

PMID- 8655207
TI  - Clinical and microscopical features of small-intestinal microsporidiosis in
      patients with AIDS.
AB  - Intestinal microsporidiosis by Enterocytozoon bieneusi is an increasingly
      recognized infection in AIDS patients. We report eight cases of microsporidiosis.
      All patients were severely immunodepressed. Clinical features were highly
      variable. Patients were followed up for a mean period of 7.8 months. All patients
      had persistent infection during the follow-up and spore excretion remained
      constant. Two patients became asymptomatic during the follow-up. None of the
      patients presented clinical and echographic signs of biliary involvement.
      Treatment with albendazole, metronidazole or paromomycin failed to produce a
      durable clinical response or to eradicate the organism. Cases were identified by
      stool examination and additionally investigated with light and electron
      microscopy. It was found that light microscopy was a sensitive method, while
      electron microscopy was less sensitive but allowed the definition of the
      infecting species. The modified trichrome stain was a satisfactory method for
      diagnosis on fecal smears. The calcofluor stain and the combination of DAPI with
      calcofluor was a rapid and simple staining method for screening.

PMID- 8655208
TI  - First case of HIV-1 subtype 0 infection in Germany.

PMID- 8655210
TI  - Comparison of BacT/Alert blood culture bottles with lytic media for culture of
      peritoneal dialysis fluid.
AB  - A comparison was made between the Septi-Chek "Release" system containing
      saponins, standard BacT/Alert blood culture bottles and FAN BacT/Alert blood
      culture bottles for culturing CAPD fluids. Seventy-seven CAPD effluent specimens
      were tested. No differences could be found. Therefore, lytic agents are not
      necessary when dialysates are cultured in blood culture media.

PMID- 8655209
TI  - Salicylate-enhanced exposure of Klebsiella pneumoniae subcapsular components.
AB  - The capsular polysaccharide (CPS) of Klebsiella pneumoniae is an important
      virulence factor. Salicylate, which inhibits CPS production, was used to expose
      subcapsular antigens and components that may play an important role in host
      defense. Salicylate treatment greatly increased phagocytosis of five O1 serotypes
      by human polymorphonuclear leukocytes with normal rabbit serum and rabbit
      antisera against purified O1 lipopolysaccharide (O1LPS) as opsonins (p < 0.01 or
      < 0.05). Similar results were obtained with rabbit antiserum against a non
      encapsulated isogenic strain. To further determine how salicylate increases
      susceptibility to phagocytosis, the binding of monoclonal antibodies against
      O1LPS or the LPS core and the binding of complement component C3b were measured
      by ELISA. The data indicate that salicylate reduced the barrier of CPS in
      serotypes O1:K1, O1:K10, and O1:K16 and unmasked subcapsular antigenic components
      in serotypes O1:K2 and O1:K66 so that bound opsonins could react with receptors
      on phagocytes. Serum bactericidal assays supported this conclusion. Therefore,
      decapsulating agents such as salicylate accentuate phagocytosis of K. pneumoniae
      by making subcapsular antigens and components accessible to immune and nonimmune
      host defences and vaccination with subcapsular antigens may exhibit optimal
      protection against lethal infection when combined with salicylate therapy.

PMID- 8655211
TI  - Incidence and mechanisms of aminoglycoside resistance in Pseudomonas aeruginosa
      serotype O11 isolates.
AB  - Mechanisms of resistance to five aminoglycoside antibiotics: gentamicin (G),
      tobramycin (T), netilmicin (N), amikacin (A) and isepamicin (I), were assessed in
      16 clinical isolates of Pseudomonas aeruginosa serotype O11, originating from
      five hospitals in Bratislava. All isolates were in vitro highly resistant to all
      mentioned aminoglycoside antibiotics (MIC > 32 mg/l). Thirteen isolates produced
      three aminoglycoside-modifying enzymes (AGME), responsible for resistance to the
      respective aminoglycosides: AAC(6')-I (T, N, A); APH (2") (G, T); APH (3')-VI
      (I). In addition to this, in four isolates a production of AAC(3)-II (G, T, N)
      was observed. In three isolates no production of AGME was observed. The strains
      studied were isolated mainly from urine. Several isolates were able to transfer
      aminoglycoside resistance by bacterial conjugation to P. aeruginosa 1008 rifr
      recipient. The transconjugants from these transfers expressed the same resistance
      pattern and nearly the same mechanisms of resistance as the donor strains.

PMID- 8655212
TI  - In vitro activity of cefpirome against selected clinical enterobacterial isolates
      with beta-lactamase-mediated resistance.
AB  - Previous studies have shown that there is a high incidence of resistance to
      cephalosporins among enterobacteria isolated in Greek hospitals. This resistance
      is mainly due to either the derepression of chromosomal cephalosporinases or the
      acquisition of plasmids coding for SHV-5 type beta-lactamase. In the present
      study the activity of cefpirome against a number of enterobacteria (Escherichia
      coli, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes and
      Serratia marcescens) possessing the mechanisms mentioned above was examined.
      Cefpirome was found active against all the strains characterized by stable
      derepression of chromosomal class-C enzymes. The antibiotic was less potent
      against strains expressing SHV-5 type beta-lactamase due to its hydrolysis by the
      enzyme. Also cefpirome exhibited good activity against E. aerogenes strains with
      reduced susceptibility to imipenem. These in vitro data suggest that cefpirome
      might be useful in treating infections caused by these resistant microorganisms
      that are frequently encountered in Greek hospitals.

PMID- 8655213
TI  - Lymphedema as a presenting sign of toxocariasis.
AB  - Toxocariasis in children is usually an asymptomatic infection and those with
      clinical illness have non-specific systemic or local manifestations. We present a
      24-month-old boy with bilateral lymphedema of the feet as the main clinical
      manifestation of toxocariasis. The child presented with limping and nonpitting
      edema of both feet. Laboratory investigation revealed leucocytosis of <
      20,000/mm3 with a differential count of < 50% eosinophils. No other cause of
      edema was found. The ELISA for toxocariasis revealed a high titer of > or =
      1:4,096. The limping and the lymphedema disappeared during the third week of his
      illness. We suggest that toxocariasis should be considered as a possible cause of
      lymphedema and eosinophilia in young children.

PMID- 8655214
TI  - Haemophilus parainfluenzae: an unusual case of psoas abscess.
AB  - A case of Haemophilus parainfluenzae psoas abscess in a previously healthy 36
      year-old man is reported here. The absence of any bowel pathology indicates that
      abscess formation occurred secondary to haematogenous spread of the organism.

PMID- 8655215
TI  - Re: M. G. Bergeron, M. Ouellette--diagnosing bacterial infectious diseases in one
      hour: an essential upcoming revolution (infection 23 [1995] 69-72)

PMID- 8655216
TI  - Treatment of systemic neonatal candidiasis with fluconazole.

PMID- 8655217
TI  - Meningitis caused by Alcaligenes (Achromobacter) xylosoxidans associated with
      epidural catheter.

PMID- 8655218
TI  - Isolation of Arcanobacterium haemolyticum from throat culture samples in the
      Czech Republic.

PMID- 8655219
TI  - The correlation between protein catabolic rate and Kt/V in hemodialysis is not a
      mathematical artifact.
AB  - To test whether the demonstrated correlation between Kt/V urea and normalised
      protein catabolic rate (NPCR) is caused by a mathematical artifact, we examined
      12 adult and 8 paediatric haemodialysis patients. Kt/V was determined by the
      classical method. As an equivalent of NPCR we measured normalised urea generation
      rate (NUGR) by a one-week collection of dialysate and urine using total body
      water estimated by bioelectrical impedance for normalisation. The correlation
      between Kt/V and NUGR was 0.58 (all), 0.55 (adults), and 0.62 (children). Since
      the determination of Kt/V and NUGR are not interdependent, we conclude that the
      correlation between Kt/V and protein catabolism is not artifactual.

PMID- 8655220
TI  - The production of platelet-activating factor (PAF) during hemodialysis with
      cuprophane membrane. Does the calcium concentration in the dialysate play any
      role on it?
AB  - There is evidence that PAF may be produced during hemodialysis (HD) mainly when
      using cuprophane membrane (CU). It is also known that PAF production is dependent
      on the amount of extracellular calcium (ECa2+). In the present study, we
      investigated the production of PAF during HD with CU as well as the role of the
      Ca2+ in the dialysate with respect to PAF production. Five hemodialyzed patients
      were studied in two consecutive HD sessions (the first performed using dialysate
      without Ca2+ and the second with a Ca2+ concentration of 3.25 mEq/L) and at
      different times during the sessions the circulating PAF levels as well as the
      leukocyte and platelet counts were measured. The results demonstrated that a) PAF
      was indeed produced during HD with CU, b) the highest PAF levels in blood were
      observed between 5 and 15 minutes from the beginning of HD, at which time the
      lowest circulating leukocyte and platelet count were measured and c) PAF levels
      in blood were inversely proportional to the Ca2+ concentration in the dialysate
      (with the exceptional case of the 15 minutes), although we expected the opposite
      results.

PMID- 8655221
TI  - Is Ace inhibitor treatment a possible cause of better cardiovascular remodelling
      in well functioning kidney transplant?
AB  - Diseases of the cardiovascular system are a common cause of death in renal
      transplanted patients. In this study we assessed the echocardiographic
      morphological and functional findings after renal transplantation of two
      homogenous groups of transplanted patients with normal renal function. The first
      (A) with spontaneously normotensive patients, the second (B) with moderate
      hypertension treated mainly with Ace inhibitors. Analysis of these data
      highlights two noteworthy results: the similar left ventricle hypertrophy found
      in both groups and the existence of better diastolic compliance among the
      hypertensive transplanted patients. If this is confirmed by studies currently in
      progress, the importance of Ace-inhibitors treatment in remodelling cardiac
      dysfunction after long term dialysis treatment might be seriously considered.

PMID- 8655222
TI  - Hemolysis with the F21 hemopump.
AB  - The aim of this study was to determine the influence of mechanical factors on
      free hemoglobin using an F21 hemopump cannula. These factors (flow, rotary speed,
      reduction of the cross section area of the silicone tube and foreign material on
      the screw) were tested in a mock circulation with ox blood. Irrelevant increase
      in free hemoglobin were induced by foreign bodies either in the inlet or on the
      screw. The hemopump flow was easily affected and almost suppressed by small
      amounts of foreign bodies on the screw. Other reasons for elevated concentrations
      of plasma free hemoglobin may imply a general disorder of the pump,
      anticoagulation, renal function, red cells or a combination of these factors.

PMID- 8655224
TI  - Ventricular flow dynamic past bileaflet prosthetic heart valves.
AB  - To characterise hydrodynamic properties of prosthetic heart valves in mitral
      position, ultrasonic velocity measurements were performed using a cardiovascular
      simulator. A Duromedics and a Saint-Jude Medical bileaflet heart valve were
      tested. The Saint-Jude valve was oriented first in an anatomical position, i.e.
      the tilt axis parallel to the septal wall, and then in an anti-anatomical
      position. In the anti-anatomical position, from mid diastole to mid systole, two
      contrarotative vortices are generated in the ventricle by the interaction between
      the flow directed by the leaflets downstream from the lateral orifices and the
      ventricular wall motions. In the anatomical position, the mitral flow penetrates
      the ventricle principally through the lateral orifice proximal to the septal
      wall, due to the vortex in the atrial chamber. The mitral inflow then circulates
      along the septal wall to the apex, and produces a large ventricular vortex during
      systole. In the anatomical position, the Saint-Jude thus provides a better
      ventricular washout during this phase. The mitral inflow through the Duromedics
      in the anti-anatomical position produces two contrarotative vortices in the
      ventricle, but in the opposite sense than downstream the Saint-Jude valve; the
      flows that penetrate through the lateral orifices are directed to the ventricular
      walls and then recirculate to the centre of the ventricle, providing a very
      fluctuating flow near the apex. Thus, a slight difference in valve design
      produces a significant difference in the ventricular flow fields.

PMID- 8655223
TI  - Metabolic response of blood cells to synthetic graft-materials with special
      reference to a Fluoromer Passivated Dacron graft. An in vitro study using
      microcalorimetry.
AB  - Microcalorimetry was used to study in vitro the metabolic response from human
      platelets and leukocytes when incubated with three different synthetic graft
      materials. The graft to be studied primarily was Fluoromer Passivated Dacron
      (FPD) which was compared with ePTFE and with a knitted Teflon graft. A rapid
      increase in the metabolic activity of platelets was observed, followed by a
      steady-state for more than one hour, while the platelet metabolism did not differ
      among the various graft-materials. Leukocytes incubated with FPD showed a high
      initial metabolism, with a peak after about 15 minutes. After 60 minutes the
      metabolic response had reached control values. ePTFE and Teflon grafts differed
      significantly from FPD, without causing any peak metabolic activity. It may be
      concluded that FPD and ePTFE grafts, as evaluated in vitro, activate platelets to
      the same extent, while FPD causes a more extensive leukocyte activation. Whether
      these findings can be interpreted as differences in thrombogenicity and
      inflammatory responses has not been proven, but seems probable. This in vitro
      method should make it possible to further study human responses to synthetic
      materials a method possibly more reliable than animal experiments.

PMID- 8655225
TI  - In vitro removal of human IgG by pseudobiospecific affinity membrane filtration
      on a large scale. A preliminary report.
AB  - We have developed a pseudobiospecific affinity membrane device for selective
      removal of human IgG from plasma or serum in vitro for clinical apheresis
      application. The pseudobiospecific affinity ligand L-histidine was immobilized
      through an ether linkage onto poly(ethylenevinyl alcohol) hollow fiber cartridge.
      The obtained affinity membranes showed high selectivity for IgG adsorption from
      untreated human serum. These membranes are able to adsorb IgG1, IgG2, IgG3 if
      Mops buffer is used, and more selectively IgG1, and IgG3 in Tris-HCl buffer. With
      respect to the binding capacity, the pseudobiospecific affinity membrane used
      showed a higher capacity as compared to protein A-membranes described in the
      literature. Due to the high capacity, specificity and stability of the histidine
      affinity membranes, in addition to their lower cost, the approach proposed in
      this paper may offer a useful alternative to protein A based devices in the
      treatment of immune-related diseases.

PMID- 8655226
TI  - Non-machinery-based system for cell-free, concentrated autogenous ascitic fluid
      reinfusion.
AB  - A non-machinery-based system for the reinfusion of ascitic fluid was developed
      and assessed. In fundamental studies utilizing bovine serum, this procedure
      proved economical, quick and useful. The most suitable filter was PS-R (#405-2).
      Bovine serum with a protein concentration below 3.0 g/dl was treated using this
      system. Samples containing blood (prepared to 0.5% hematocrit) were also treated,
      but the treatment time required was double that of serum with the same protein
      concentration. In both cases the protein recovery ratios were about 90%. We
      conducted clinical studies on 62 occasions (machinery-based system; 31 times, non
      machinery-based system; 31 times) on 19 cases of ascites refractory to treatment
      with various drugs including diuretics. Clarification of the differences between
      the non-machinery-based system, indicated the former to be superior. This new
      procedure is easier because of its use of no machinery, and the high protein
      recovery ratio proved its usefulness.

PMID- 8655227
TI  - Skin hazards of the marine aquarium industry.

PMID- 8655228
TI  - Itch and pain.

PMID- 8655229
TI  - Nehushtan: equity, the law of the funnel, and the publication process.

PMID- 8655230
TI  - Psoriasis and pregnancy: hormone and immune system interaction.
AB  - BACKGROUND: Various hormonal states are known to be associated with the waxing
      and waning of psoriasis. Patients with psoriasis commonly experience changes in
      their cutaneous disease during pregnancy or post partum. OBJECTIVE: We evaluated
      100 women with psoriasis by questionnaire and interview. The women had been seen
      at the Baylor Psoriasis Center, Dallas, and had experienced a pregnancy while
      having psoriasis. The answers were sorted and tabulated. In addition, we reviewed
      the literature to ascertain possible causes of clinical changes in psoriasis
      during pregnancy. RESULTS: Ninety questionnaires were completed. Sixty-nine women
      (76.7%) described a change in their psoriasis during pregnancy with 57 (63.3%)
      noting improvement. Seventy-nine patients (87.7%) had a postpartum flare, most
      within 4 months of delivery. CONCLUSIONS: The majority of women with psoriasis,
      who become pregnant, experience a change, usually an improvement, in their
      cutaneous disease. Pregnancy is associated with hormonal changes in estrogens and
      progesterone resulting in a state of altered immune surveillance.

PMID- 8655231
TI  - Supplemental tests in the evaluation of occupational hand dermatitis in soldiers.
AB  - BACKGROUND: Hand dermatitis in soldiers is a considerable problem. The purpose of
      the study was to evaluate appropriate screening tests to improve the diagnosis of
      hand dermatitis in soldiers. MATERIALS AND METHODS: A group of 111 soldiers with
      occupational dermatitis from contact with fuels and oils underwent "tailored
      patch tests" with allergens relevant to their field of work and their
      environment. The control group consisted of 24 soldiers with various jobs similar
      to those of civilian life, who had not been exposed to oils and fuels. Seventy
      three civilian patients, attending the clinic for patch testing, were also
      included. Twenty soldiers, who had a history of intensive contact with oil and
      fuels, but no contact dermatitis, and who were admitted because of various skin
      diseases (fungal infections, acne, etc.) also underwent the supplemental testing
      and served as an additional control group. RESULTS: Of the soldiers, 31 (29%)
      showed one or more positive skin tests of the oil series and 30 patients of this
      group one or more positive reactions to the standard patch tests trays. No
      patient of the control groups had a positive test to the oil series. CONCLUSIONS:
      Our results show the value of the supplementary tests as a first-step screening
      test for detection of oil allergy in soldiers and automobile-mechanics or in
      workers handling other gasoline- or diesel-powered engineering equipment. The
      test method appears to be practical, easy to perform, reliable and giving clear
      and accurate results, with a negligible rate of false positive reactions.

PMID- 8655232
TI  - Sensitization to para-tertiary-butylphenolformaldehyde resin.
AB  - BACKGROUND: Phenolformaldehyde resins, especially the para-tertiary
      butylphenolformaldehyde resin (PTBP-FR), are widely used in industry and in
      numerous materials of everyday use, such as glues, adhesives, or inks. They can
      cause many occupational and nonoccupational cases of dermatitis. PATIENTS AND
      METHODS: Forty-one patients with positive patch test results to PTBP-FR were
      selected for this study. They were patch-tested with a series of chemically
      related compounds and cross-reactions were noted. RESULTS: Phenolformaldehyde
      resin (PF-R) was frequently positive (65.8%), whereas other compounds gave a much
      smaller number of positive results. Cases of occupational exposure (24.4%),
      location of the dermatitis (hands were involved in 46.3% of cases), and possible
      sources of exposure (shoes were the responsible agent in 12.2% of cases) were
      evaluated. CONCLUSIONS: Phenolformaldehyde resins are an important cause of
      contact dermatitis and must be studied chemically and clinically to improve the
      prognosis of sensitized patients.

PMID- 8655233
TI  - Clinical-epidemiologic study of alopecia areata.
AB  - BACKGROUND: Alopecia areata is a common disease and may be associated with
      autoimmune disease, atopy, Down syndrome, emotional stress, and foci of sepsis.
      METHODS: Seven cases of alopecia areata were diagnosed among workers in the Water
      and Effluent Treatment Sector (WETS) of a paper factory, representing a 0.6%
      incidence, when the value for the population at large is 0.1%. Three of these
      workers are assigned to the WETS on a permanent basis and four provide
      maintenance services. One of the latter patients had alopecia areata that fully
      regressed. Because biologic treatment of water and effluents involves saprophytic
      bacteria and fungi as well as chemical substances such as acrylamide, a clinical
      examination and laboratory tests were performed on all workers assigned
      permanently to the WETS (N = 9) and on 25% of the workers, selected at random
      providing services to the sector (N = 14). RESULTS: There was no association
      between alopecia areata and atopy, dermatophytosis, or bacteria isolated.
      Toxicologic evaluation revealed an acrylamide-like substance in 7 workers with
      alopecia areata, with a statistically significant correlation. Measures were
      taken at the workplace to decrease worker contact with the mists (probably
      containing acrylamide) in the pulp-pressing room; no other cases of alopecia
      areata had been detected 1 year after the study. CONCLUSIONS: A survey of the
      literature did not show reports of alopecia areata as an occupational dermatosis,
      but our conclusion is, that this dermatosis could be due to the professional
      activities of the workers at the paper factory studied.

PMID- 8655234
TI  - Diagnosis of cutaneous tuberculosis by polymerase chain reaction using a species
      specific gene.
AB  - BACKGROUND: Diagnosis of tuberculosis (TB), especially cutaneous TBC, by
      conventional microbiologic methods is still a very laborious process and the
      results are usually inconclusive. Our purpose was to identify M. tuberculosis
      bacilli in uncultured clinical samples from skin lesions by means of the rapid,
      specific, and sensitive polymerase chain reaction (PCR). METHODS: The PCR, using
      a set of species-specific primers, was performed on biopsies and fluid secretions
      from lesions. RESULTS: A positive amplification reaction was observed in three of
      the four samples studied. For one of the samples, the result was confirmed by a
      positive culture in Lowenstein-Jensen medium and for the other two, by molecular
      hybridization and the clinical course of the patients after treatment. Samples
      obtained from a patient with panniculitis of Christian-Weber and a normal skin
      biopsy were included as negative controls. CONCLUSIONS: We propose the PCR method
      as a tool for the diagnosis of cutaneous TBC. The presence of the M. tuberculosis
      in an erythema induratum of Bazin suggests a revision of the concept of this
      disease as a tuberculide reaction.

PMID- 8655235
TI  - False negative patch test reaction caused by testing with dental composite
      acrylic resin.

PMID- 8655236
TI  - Complications following industrial liquid silicone injection.

PMID- 8655237
TI  - Transformed cutaneous T cell lymphoma and biclonal gammopathy.

PMID- 8655238
TI  - Contact pemphigus.

PMID- 8655239
TI  - Pustular psoriasis limited to the penis.

PMID- 8655240
TI  - Subcutaneous and superficial granuloma pyogenicum.

PMID- 8655241
TI  - Rheumatoid neutrophilic dermatitis.

PMID- 8655243
TI  - Isotretinoin for acne vulgaris.
AB  - BACKGROUND: The clinical efficacy of oral isotretinoin in the treatment of severe
      acne is now well established and so are the clinical and laboratory adverse
      effects of the drug. Isotretinoin was first introduced in Saudi Arabia late in
      1987. In this 7-year retrospective study, efficacy and side effects of
      isotretiunoin are reviewed in Saudi patients with acne vulgaris seen in a
      university skin clinic in Riyadh, Saudi Arabia. MATERIALS AND METHODS: A total of
      262 patients had been treated with isotretinoin. Their case records were studied
      with reference to demographic data, clinical findings, dosage of isotretinoin,
      response to the drug, and the prevalence and severity of clinical and laboratory
      adverse effects. RESULTS: Only 156 case records (69.9% women) could be evaluated.
      Most patients received 0.60 to 0.75 mg of isotretinoin per kg per day for a
      period ranging from 16 to 35 weeks (mean +/- SD: 21.2 +/- 3.3 weeks); a total
      cumulative dose of 75 to 146 mg per kg (mean +/- SD: 104 +/- 10.6 mg per kg).
      Approximately 56% of the patients had therapy-resistant moderate acne and only
      14% had nodulocystic acne. Of the patients, 90.4% had an excellent response and
      3.8% were poor responders. Adverse effects occurred in 99% of the patients, but
      in no case did they lead to discontinuation of the drug. Except for minor
      differences in prevalence, the clinical side effects were similar to those
      reported in the literature. Elevation of plasma triglyceride levels was the most
      significant laboratory adverse effect. CONCLUSIONS: This is the first report on
      the experience with isotretinoin in the treatment of acne in the Middle East.
      Moderate doses of isotretinoin are well tolerated and produce excellent results
      in Saudi patients with acne.

PMID- 8655242
TI  - Treatment of acne vulgaris: combination of 3% erythromycin and 5% benzoyl
      peroxide in a gel compared to clindamycin phosphate lotion.

PMID- 8655244
TI  - Effect of systemic administration of isotretinoin on blood lipids and fatty acids
      in acne patients.
AB  - BACKGROUND: In many studies, an increase in total cholesterol and triglycerides
      with isotretinoin therapy have been shown and investigators have commented on
      potential cardiovascular risk. A low intake of linoleic acid, the main essential
      fatty acid in man, may act as an independent risk factor for coronary heart
      disease. In vitro etretin alters both the incorporation of extracellular fatty
      acids into cell membranes and the fatty acid composition of the cell membrane
      itself. It is, therefore, important to establish whether isotetinoin has any
      effect on the metabolism of polyunsaturated fatty acids. METHODS: The effect of
      treatment with isotretinoin for 4 months on the metabolism of polyunsaturated
      fatty acids in patients with acne was assessed. Quantitative total cholesterol
      and triglycerides as well as plasma phospholipid, triglycerides, and cholesteryl
      ester fatty acids were measured in 12 patients and red cell
      phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol fatty
      acids were measured in 13 patients before and after isotretinoin therapy.
      RESULTS: There was a significant increase in the concentrations of cholesterol (P
      < 0.02) and triglycerides (P < 0.04) during treatment. There was no significant
      difference is plasma phospholipids, triglycerides, and cholesterol esters, or in
      the red cell phosphatidylethanolamine, phosphatidylcholine, and
      phosphatidylinositol during isotretinoin therapy. CONCLUSIONS: This study failed
      to demonstrate any effect of isotretinon on the metabolism of polyunsaturated
      fatty acids. There was a significant increase in total cholesterol and
      triglyceride levels following isotretinoin therapy supporting the findings of
      many previous studies.

PMID- 8655245
TI  - Syringomas: new approach to an old technique.
AB  - BACKGROUND: Syringomas are common, benign periorbital adnexal tumors that pose a
      cosmetic dilemma for both patients and physicians alike. Many therapeutic
      modalities can potentially cause scarring and recurrences are common. The
      objective was to develop a treatment method that minimizes scarring and
      subsequent recurrences. METHODS: Each syringoma is treated with short bursts of
      low voltage electrodesiccation, delivered with an epilating needle that is
      inserted deeply into the skin at the level of the reticular dermis. RESULTS: A
      patient treated by intralesional electrodesiccation of her long-standing
      periorbital syringomas remains lesion-free for over 24 months after therapy.
      CONCLUSIONS: Intralesional electrodesiccation is a safe, nonscarring and reliable
      method that can be used to eradicate periorbital syringomas.

PMID- 8655246
TI  - Active cutaneous tuberculosis after therapy of squamous cell carcinoma of the
      skin, a PCR study.

PMID- 8655248
TI  - Cutaneous leishmaniasis in the north of Italy.

PMID- 8655247
TI  - Giant basal cell carcinoma.

PMID- 8655249
TI  - "Guboow': medico-religious practice simulating nonaccidental injury in Somalia.

PMID- 8655250
TI  - Malignant melanoma in situ in a Japanese psoriatic patient treated with
      phototherapy.

PMID- 8655251
TI  - Anetoderma secondary to the application of leeches.

PMID- 8655252
TI  - Simultaneous assessment of muscle and skin blood fluxes with the laser-Doppler
      technique.
AB  - The laser-Doppler technique was used to assess local muscle and skin blood fluxes
      at the lower limb in 20 healthy volunteers. After puncturing the anterior tibial
      muscle with a steel cannula, a single-fibre probe with a diameter of 0.5 mm was
      inserted into the muscle. Simultaneously, the skin blood flux was measured at
      calf and foot. The muscle blood flux at rest was 3.5 to 4 times higher than the
      skin blood flux at calf or foot. The spatial variability of the muscle blood flux
      at three different sites of measurement was considerable and tended to be higher
      than in the skin of the calf. After an arterial occlusion lasting 3 min, peak
      flux was reached in the muscle after 18.7 +/- 9.8 s, in the skin of the calf
      after 16.8 +/- 9.3 s, and in the skin of the foot after 22.9 +/- 14.6 s (NS). The
      relative flux increase during reactive hyperaemia was significantly lower in the
      muscle (2.7 +/- 1.3) than in the skin of the calf (3.9 +/- 1.9; p<0.05) or the
      foot (5.1 +/- 3.5; p<0.005). The reproducibility of reactive hyperaemia response
      in muscle was excellent with unchanged probe position, but exhibited a marked
      variability on different days. The laser-Doppler technique provides the
      possibility for simultaneous measurement of flow dynamics in muscle and skin with
      a high temporal resolution. Methodological problems include differences in probe
      geometry of the single-fibre compared to standard probes and differences in
      optical properties of the tissues. Direct comparison of flux values may,
      therefore, be subject to criticism, but not the comparative analysis of relative
      flux changes. The influence of tissue trauma on muscle blood flux has to be
      considered for the analysis of flux data.

PMID- 8655253
TI  - Transcutaneous oxygen and carbon dioxide during treatment of critical limb
      ischemia with iloprost, a prostacyclin derivative.
AB  - The effect of intravenous iloprost treatment (median rate: 1.6; range 1-2
      ng/kg/min; 6 h daily over 4 weeks) on transcutaneous pO2 and pCO2 was studied in
      8 patients with bilateral peripheral obstructive arterial disease and monolateral
      critical limb ischemia. Tensiometric determinations were obtained at both
      metatarsi in the supine and dependent position. In critically ischemic limbs,
      supine transcutaneous p)2 changed erratically during iloprost treatment,
      increasing in only three out of eight lower limbs. At variance with its
      inconsistent behavior in the supine position, dependent pO2 increased during drug
      administration (p<0.02). Transcutaneous pCO2 was unchanged by iloprost. In the
      contralateral, non-symptomatic limb, both supine and dependent pO2 values were
      increased by the drug, suggesting that systemic hemodynamic changes may
      participate in its effect on transcutaneous gas tension, even at infusion rates
      clinically titrated to avoid evident changes in blood pressure and heart rate.

PMID- 8655254
TI  - Normal cutaneous microcirculation in gaiter zone (ulcer-susceptible skin) versus
      nearby regions in healthy young adults.
AB  - Skin just proximal to the medial malleolus ('gaiter' zone) is the usual site for
      venous ulceration in later life, whereas shin and dorsum of the foot are
      generally unaffected. We studied the microcirculation of these regions in 6
      healthy young adults to see whether any premorbid, constitutional differences in
      microvascular physiology or anatomy exist between local leg sites even in normal
      subjects. Capillary density was assessed by capillaroscopy (native and
      fluorescein) and local flow by laser Doppler fluxmetry, in supine and upright
      positions and during reactive hyperaemia. Supine capillary densities in
      supramedial malleolar skin (SMMS) averaged 31038 mm(-2) (fluorescein and native
      count means, respectively) and was not statistically significantly different from
      those in the dorsum of the foot (36.0-36.2 mm(-2) or shin 30-51 mm(-2)).
      Dependency did not alter the counts significantly, but the fluorescein transport
      time from antecubital vein to capillary increased by 16-69% (SMMS 40%). In the
      supine position, red cell flux in SMMS was only 42-43% of the flux in skin over
      the shin and dorsum of the foot (p<0.04, 2-way analysis of variance) and
      cumulative reactive hyperaemia in SMMS was also less marked. Basal flux and
      reactive hyperaemia at all sites fell to closely similar levels in dependency
      (veni-arteriolar response). In relative terms, however, the posturally induced
      vasoconstriction was weaker in SMMS (flux reduction by 29% of supine value) than
      at other sites (reductions 61-61% of supine value). The results showed that even
      in young healthy legs the cutaneous microcirculation is not physiologically
      homogeneous, raising the possibility that constitutional factors might influence
      the siting of overt pathology if chronic venous insufficiency develops in later
      life.

PMID- 8655255
TI  - Vascular impairment in patients with primary biliary cirrhosis.
AB  - Experimental and clinical observation suggest that patients with primary biliary
      cirrhosis (PBC) have endothelial dysfunction. Postischemic digital blood flow,
      nailfold capillaroscopy, von Willebrand factor (vWf) and tissue-type plasminogen
      activator (t-PA) plasma levels were examined in 59 PBC patients. Forty-six
      subjects (15 with liver diseases other than PBC, 11 hypercholesterolemics, 20
      healthy subjects) served as controls. PBC versus healthy controls (209.8 +/- 1.4%
      and 16.54 +/- 1.44 ng/ml vs. 120.2 +/- 1.4% and 9.91 +/- 1.49 ng/ml; p<0.001) and
      related to bilirubin (r = 0.38, p<0.02; r = 0.47, p<0.0005, respectively). vWf
      was also increased in other liver diseases (249.9 +/- 1.7%; p<0.001) and related
      to bilirubin (r = 0.59, p<0.05). Postischemic finger blood flow negatively
      correlated with vWf(p<0.05 or less). Our data indicate that PBC patients have
      microvascular disease. Whether vessels other than those of the fingers were
      involved remained unclear. vWf and t-PA might reflect a dysfunction of teh
      hepatic vascular endothelium.

PMID- 8655256
TI  - Soluble E-selectin levels in acute human myocardial infarction.
AB  - It has been suggested that leukocyte adhesion mechanisms play a key role in
      experimental myocardial infarction. We have recently shown that E-selectin, an
      adhesion molecule belonging to the selectin family, is involved in the
      pathogenesis of experimental myocardial ischemia. We investigated the circulating
      levels of E-selectin, studied as a marker of endothelial dysfunction, in acute
      myocardial infarction. Our study was carried out in 60 patients, 20 hospitalized
      for acute myocardial infarction, 20 suffered from angina pectoris and 20 healthy
      control subjects. Patients with acute myocardial infarction had increased serum
      levels of soluble E-selectin (sE-selectin = 255 +/- 12 ng/ml) compared to both
      patients with angina pectoris (sE-selectin = 51 +/- 14 ng/ml). Thrombolytic
      therapy with urokinase (1,000,000 IU as an intravenous bolus in 5 min, followed
      by producing reperfusion and reduced the serum levels of sE-selectin (71 +/- 19
      ng/ml). Our results confirm previous experimental data and indicate that adhesion
      mechanisms supporting leukocyte-endothelium interaction may also be operative in
      human acute myocardial infarction.

PMID- 8655258
TI  - Effects of calcium channel blockers on cold-induced vasodilatation and elevated
      sympathetic tone in the canine internal maxillary artery bed.
AB  - This study was concerned with the interactive effects of cold-induced
      vasodilatation, blockade of voltage-sensitive Ca2+ channels and sympathetic nerve
      stimulation in the nasal vascular bed of anesthetized dogs. To estimate the
      distribution of the internal maxillary artery blood flow to capillaries and to
      arteriovenous anastomoses (AVA), the microsphere technique in combination with
      electromagnetic flowmetry was used. Intraarterial infusion of verapamil resulted
      in a dose-dependent vasodilatation and a redistribution of the internal maxillary
      artery blood flow. Simultaneously applied electrical stimulation of the cervical
      sympathetic trunk resulted in a significant fall in blood flow, caused mainly by
      a decrease in capillary flow. Verapamil infusion combined with cold exposure led
      to a simultaneous elevation of the AVA and capillary flows. When electrical
      stimulation of the cervical sympathetic trunk was also applied, the AVA and
      capillary flows were affected in different manners, depending on the sequence of
      the stimulations. Analysis of capillary flow data in the various nasal and facial
      tissue compartments indicates that cold exposure, blockade of the voltage
      dependent Ca2+ channels and an elevated sympathetic tone modify the local
      nutritive blood flow.

PMID- 8655259
TI  - An exploration of the carers' perceptions of caregiving and caring
      responsibilities in Chinese families.
AB  - This qualitative study carried out with 10 Chinese families in Hong Kong
      describes caregiving and caring from the perceptions of the primary carers. Semi
      structured interviews were carried out to gain personal accounts of experiences
      of primary carers caring for dependent family members. The analysis resulted in
      categories identifying and explaining the needs of primary carers. Suggestions
      for practice are made.

PMID- 8655257
TI  - Kinetics of white blood cell staining by intravascular administration of
      rhodamine 6G.
AB  - Rhodamine 6G is a vital dye accumulating in the mitochondria of cells. It is used
      in intravital fluorescence microscopy for contrast enhancement of white blood
      cells (WBC), enabling visualization of WBC in the microvasculature even at high
      center flow velocity. The aim of this study was to examine the kinetics of WBC
      staining after intravascular administration of rhodamine 6G in Lewis rats, Syrian
      golden hamsters and BALB/c mice. For this purpose, WBC were isolated from whole
      blood and the percentage of cells stained positively as well as their
      fluorescence intensity were measured by flow cytometry 5, 15, 30 and 60 min after
      dye administration. Injection of 0.06-0.2 mg/kg body weight of rhodamine 6G
      resulted in staining practically all granulocytes and monocytes over the entire
      observation period of 60 min. Fluorescence intensity of WBC was adequate to be
      detected in an experimental setup for intravital fluorescence microscopy in the
      hamster dorsal skinfold chamber. The degree of WBC staining was different in the
      species studied, yielding a higher percentage of stained lymphocytes in rats than
      in mice and hamsters. Staining of lymphocytes declined within 60 min after
      rhodamine application, the loss of fluorescent label being most pronounced in
      hamster cells. After 15-30 min, relative fluorescence intensity of stained
      lymphocytes had decreased considerably, indicating the need for reinjection of
      the dye or limiting microscopic analysis to approximately 15 min after rhodamine
      6G administration. While the intravascular injection of rhodamine 6G results in
      adequate staining of granulocytes and monocytes, only a fraction of lymphoid
      cells are stained.

PMID- 8655260
TI  - The quality of life of renal dialysis patients: trying to find the missing
      measurement.
AB  - The physiological status of the individual renal patient is monitored regularly
      to ensure adequate dialysis is maintained, however, the psychosocial status of
      the renal patient is not subject to the same amount of attention. This study
      aimed to determine the Quality of Life and psychosocial needs of a sample of
      renal dialysis patients (n = 170), and to consider methods of routine clinical
      assessment and evaluation. Difficulties with psychosocial adjustment and physical
      symptoms were demonstrated. These findings provide evidence for the need to
      routinely assess psychosocial status in this patient population. There are some
      scales which could be incorporated into standard settings and used as outcome
      measures to assess the effectiveness of interventions, and for planning and
      resource allocation purposes.

PMID- 8655261
TI  - Towards a conceptual model of 'quality care'.
AB  - A model of multi-dimensional concept 'Quality Care' was constructed from data
      generated inductively from a concept analysis (Attree, 1993). The construction of
      a model was intended to assist in the clarification of this complex and abstract
      concept, and permit the exploration of postulated relationships between the
      elements. The theoretical model could also be used to construct more acceptable
      and credible measures which would adequately represent the multiple dimensions
      and perspectives of 'Quality Care'. It was anticipated that attainment of these
      initial theoretical stages would form a basis for the development of nursing
      theory and research relating to 'Quality Care'.

PMID- 8655262
TI  - The development of Taiwanese Elderly Stressor Inventory.
AB  - The purpose of this study was to develop a stressor inventory for use with a
      population of elderly Taiwanese people that allows the respondent to rate the
      degree of stressfulness of each stressor experienced, based on a transactional
      stress model. Thirty-three subjects identified stressors experienced from age 65
      onwards. Seventy-three stressors were identified and listed in the instrument.
      Inter-rater agreement on the content was > or = 0.90. The psychometric properties
      of the instrument was established among 351 elderly Taiwanese subjects. In
      determining the stability of stressfulness, the generalizability coefficient for
      the relative decisions was 0.90 and generalizability coefficient for the absolute
      decision was 0.90. As to stability of stressor frequency, the generalizability
      coefficients for both the relative and absolute decisions was 0.72. Construct
      validity of the instrument was provided by a correlation of 0.59 with state
      anxiety, of 0.56 with negative affect, and -0.28 with positive affect. Further
      refinement of the toll is in progress.

PMID- 8655263
TI  - Development, refinement and future usage of the scale: "attitudes toward learning
      in pregnancy".
AB  - Given the continued lack of research and evaluation in relation to antenatal
      education and the real concern for early parenting influences on childhood
      development, this research surveyed 705 midwives. Their attitudes were analysed
      and categorised into six themes which were associated with antenatal education,
      learning and decision making during pregnancy and the midwife's role in antenatal
      education. The initial finding was that a sizeable minority (up to 30%) of
      registered midwives has negative attitudes to the woman's ability to learn during
      pregnancy. In response to this finding, the data were factor analysed and
      refined. Three factors resulted from this process and were named: cognition,
      motivation and professional issues. The 30-item ATLIP questionnaire accounted for
      36% of the total variance. Professional and further research issues arising from
      this research were discussed.

PMID- 8655264
TI  - Information sources used in decision making: considerations for simulation
      development.
AB  - Simulation tasks, together with think aloud techniques are often used to research
      the cognitive processes individuals go through when making a decision or solving
      a problem. They have been utilised to a certain degree within nursing. A study
      was carried out to try and identify the sources of information nurses in acute
      medical and surgical wards used to make assessment judgements. A sample of 114
      nurses were interviewed, and their responses analysed using content analysis.
      Four main sources of information were identified, with verbal interaction being
      the source of information most frequently mentioned by the subjects. The content
      of material presented in simulations is normally tested using techniques such as
      expert panels. However, this paper suggests that of equal importance may be the
      form of presentation or source of that information. It is suggested that in order
      to increase the validity of information obtained from simulation tasks, the form
      of presentation of information to the subject should also be considered.

PMID- 8655266
TI  - The role of the nurse in patient-focused care: models of competence and
      implications for education and training.
AB  - This article explores implications of Patient-Focused Care (PFC) for the
      education and training of nurses. It does so by examining various models of
      competence and their strengths and limitations as bases for developing training
      programmes. It cautions against attempting to transpose an approach to training
      based on the U.S.A. model of PFC without modification, given the differing
      nursing roles in the U.K. PFC setting. It argues for a broad-based definition of
      competence rather than a narrower focus on training in specific skills alone.

PMID- 8655265
TI  - Knowledge and beliefs about hypertension among Jamaican female clients.
AB  - Hypertension is a major health problem in the Caribbean Region. If health
      promotion programs are to be appropriate and effective, the clients' knowledge
      and beliefs regarding this chronic health problem need to be identified. The
      purpose of this study was to determine the knowledge level and beliefs about
      hypertension among female clients attending primary health care clinics in
      Jamaica, West Indies. Data were collected from 240 female clients with the use of
      a pretested interview schedule. Findings indicated that the respondents were of
      low socio-economic status, lacked knowledge regarding the predisposing factors
      and characteristics of the disease and had a number of misconceptions surrounding
      the illness. Implications for nurses and health care providers are discussed with
      suggestions for future research.

PMID- 8655267
TI  - Accelerated versus traditional nursing students: a comparison of stress, critical
      thinking ability and performance.
AB  - A high demand for graduate nurses and a dwindling pool of nursing school
      applicants have led several collegiate nursing programs to adopt innovative
      programs to increase the number of eligible applicants. One option is the
      development of accelerated nursing program. Because of the relative newness of
      these programs, the need to ascertain data about accelerated students and their
      success in these programs is vital. This prospective study examines the
      differences in stress levels, critical thinking ability, and performance of
      traditional and accelerated nursing students. A voluntary convenient sample (n =
      94) was used from nursing students enrolled in the Associate Degree Nursing (ADN)
      program. The State-Trait Anxiety Inventory and the Scale of Judgmental Abilities
      were used to measure the two independent variables. The grade point average in
      nursing courses and the National Council Licensure Exam scores were employed to
      measure performance of students. Results revealed that accelerated students
      showed consistently higher stress levels than those of the traditional students.
      Moreover, the accelerated group had significantly higher grade averages in
      nursing courses than traditional students. Implications for nurse educators and
      recommendations for further studies were made.

PMID- 8655268
TI  - Culture, age and gender: effects on quality of predicted self and colleague
      reactions.
AB  - Ethnocentrism on the part of health care workers has been documented in the
      literature and has led to misdiagnosis, mistreatment and undertreatment of
      culturally diverse individuals worldwide. Aversive Insidious Racism and Ingroup
      Favoritism theories were used as the guiding framework for this study. Two
      hundred and sixty-eight female nurses from a large, urban, multi-service hospital
      in the United States were surveyed to identify those psychosocial variables (age,
      gender and culture status of the client) which enhanced and/or inhibited their
      predicted reactions with clients and which have the power to contribute to
      unethical decision making and less than ethical client care. The findings of this
      study, which is the first to examine nurses' predicted self and colleague
      reactions to multiple client variables concurrently, demonstrated that Client
      Gender as a main effect was not significant in itself when examining self and
      colleague predictions. Client Age as a main effect was significant for self
      predictions, p < 0.006, and for colleague predictions, p < 0.000. Client Culture
      as a main effect was significant for self predictions, p < 0.001 and for
      colleague predictions, p < 0.001. Many two-way and three-way interaction effects
      were significant. Subjects consistently predicted more favorable self reactions
      than colleague reactions, supporting Aversive Insidious Racism theory. Study
      findings did not consistently support Ingroup Favoritism theory. Subjects did not
      predict most favorable reactions with Caucasian female clients.

PMID- 8655269
TI  - Nursing: a ghettoized profession relegated to women's sphere.
AB  - Feminists have suggested that the predominance of women in professions such as
      social work and nursing has led to their identification with that other domain of
      female exclusivity, the housewife, and has reduced, rather than enhanced choices
      for women (Clifford, 1988). If so, has this identification led to a ghettoization
      that prevents nurses from joining and reaping the benefits from the mainstream of
      the feminist movement? The concepts of ghettoization and women's sphere will be
      used to explore nursing's relationship to the women's movement, the medical
      profession, and the larger society.

PMID- 8655270
TI  - [Principles and strategies of gene therapy].

PMID- 8655271
TI  - [Gene therapy concepts in coronary stenoses].

PMID- 8655272
TI  - [Gene therapy approaches in metabolic diseases].

PMID- 8655273
TI  - [Using the thymidine kinase gene in therapy of solid tumors].

PMID- 8655274
TI  - [Immunotherapy with genetically modified tumor cells].

PMID- 8655275
TI  - [Ethical evaluation of somatic gene therapy].

PMID- 8655277
TI  - [Therapy refractory continuous tachycardia of many years in a 40-year-old woman].

PMID- 8655278
TI  - [The CK-MB isoenzyme is higher than creatine kinase].

PMID- 8655279
TI  - [How can improved effectiveness of the loop diuretic furosemide be explained when
      the same dosage is administered 2 x daily (morning and noon)?].

PMID- 8655276
TI  - [A rare cause of cardiopulmonary insufficiency].

PMID- 8655280
TI  - [Estrogens in menopause--therapy and prevention. I. Hormone substitution in
      climacteric and postmenopause].

PMID- 8655282
TI  - [Estrogens in menopause--therapy and prevention. III. Estrogen replacement in
      menopause: uses and risks in prevention and therapy of cardiovascular diseases].

PMID- 8655283
TI  - [HIV infections in Switzerland].

PMID- 8655281
TI  - [Estrogens in menopause--therapy and prevention. II. Estrogens and osteoporosis].

PMID- 8655284
TI  - [Drug treatment of tumor pain].

PMID- 8655285
TI  - Immunological characterization and functional importance of human heart mast
      cells.
AB  - Mast cells are present in normal and even more abundant in diseased human heart
      tissue and their localization is of particular relevance to their function.
      Within heart tissue mast cells lie between myocytes and in close contact with
      blood vessels. They are also found in the coronary adventitia and in the shoulder
      regions of a coronary atheroma. The density of cardiac mast cells is markedly
      higher in some patients with myocarditis and dilated cardiomyopathy than in
      accident victims without cardiovascular diseases. More importantly, in some of
      these conditions there is in situ evidence of mast cell activation. We have
      described an original technique to isolate and purify HHMC for in vitro study.
      This procedure gives viable cells and after stimulation with immunological or non
      immunological stimuli they release performed (histamine and tryptase) and newly
      generated mediators (PGD2 and LTC4). We have demonstrated that HHMC differ from
      those in other anatomical districts in that they are activated by specific
      immunological and non-immunological stimuli, and in their relation to the
      arachidonic acid metabolism, suggesting that the local microenvironment can
      influence their phenotypic and biochemical characteristics. Our own and other
      findings suggest that HHMC have complex and significant roles in different
      pathophysiological conditions involving the cardiovascular system. Direct
      activation of HHMC by therapeutic and diagnostic substances injected
      intravenously explains some of the anaphylactoid reactions caused by these
      agents. HHMC possess Fc epsilon RI and IgE bound to the surface and C5a
      receptors, which could explain how cardiac mast cells are involved in systemic
      and cardiac anaphylaxis. Cardiac mast cells and those in human coronary arteries
      also play a role in the early and late stages of atherogenesis and during
      ischemic myocardial injury. In conclusion, although studies of HHMC are in their
      infancy, their in vitro isolation may be useful in identifying additional
      mediators synthesized and released, stimuli relevant to human pathophysiology,
      and pharmacological agents selectively modulating the activation of these cells
      and their mediators. Drugs specifically acting on HHMC or on their mediators may
      eventually be useful in treating different cardiovascular diseases.

PMID- 8655286
TI  - Downregulation of silicone-induced chronic arthritis by gastric administration of
      type II collagen.
AB  - We previously demonstrated that intra-articular injection of silicone in rats
      induced acute arthritis followed by chronic destructive joint inflammation in
      which T cells played a role. To investigate whether the model of T cell-mediated
      chronic silicone-induced arthritis (SIA) is modified by oral administration of
      type II collagen (CII), rats were fed CII either before or after intra-articular
      injection of silicone. We found that feeding CII either before or after intra
      articular injection of silicone markedly suppressed the development of chronic
      arthritis. The early phase of acute joint inflammation was not affected by the
      oral antigen. There were no proliferative responses to CII of lymph node cells
      from rats with SIA. The proliferation to CII of lymph node cells from CII-primed
      rats was markedly suppressed by the addition of spleen cells from animals fed
      CII. Furthermore, the proliferative response to keyhole limpet hemocyanin (KLH)
      of KLH-sensitized lymph node cells was also suppressed by the addition of CII
      plus spleen cells from CII-fed animals. Injection of the spleen cells into rats
      followed by intra-articular injection of silicone inhibited the development of
      chronic SIA. These results indicate that T cell-mediated chronic arthritis may be
      downregulated by oral administration of CII and that the downregulation of joint
      inflammation may be due to the generation of CII-specific regulatory lymphocytes
      that react to CII abundant in cartilage.

PMID- 8655287
TI  - Thalidomide increases the synthesis of IL-2 in cultures of human mononuclear
      cells stimulated with Concanavalin-A, Staphylococcal enterotoxin A, and purified
      protein derivative.
AB  - Thalidomide significantly increases the quantity of extracellular IL-2 in
      cultures of human mononuclear cells stimulated with mitogens or antigen. Cells
      from 7 donors exposed for 2 h to 4.0 micrograms/ml of thalidomide and stimulated
      for 16-18 h with 20 micrograms/ml of Concanavalin-A (Con-A) averaged producing
      187 +/- 49% more IL-2 than cells stimulated with Con-A alone. In similar
      experimental procedures and comparisons the pg/ml of IL-2 secreted by thalidomide
      treated cells from five donors stimulated with 50 ng/ml of Staphylococcal
      enterotoxin A (SEA) increased by 159 +/- 32%, and the pg/ml of IL-2 secreted by
      thalidomide-treated cells from 2 donors stimulated with 5.0 micrograms/ml of
      purified protein derivative of Mycobacterium tuberculosis increased by 120 +/-
      4%. Thalidomide also significantly increases the quantity of intracellular IL-2
      in cells stimulated with mitogens. Cells exposed to thalidomide and stimulated
      with Con-A had an increase in intracellular IL-2 of 130% after 8 h and 157% after
      12 h in culture; cells stimulated with SEA had an increase in intracellular IL-2
      of 120% after 8 h and 182% after 12 h in culture. Thalidomide did not alter the
      percent of lymphocytes expressing the alpha-chain of IL-2 receptor, nor did it
      significantly increase incorporation of [3H]thymidine by cells.

PMID- 8655288
TI  - Methylxanthines with adenosine alter TNF alpha-primed PMN activation.
AB  - Methylxanthines are best known as phosphodiesterase inhibitors that cause a rise
      in intracellular cAMP. One would expect the two methylxanthines, caffeine and
      pentoxifylline, to have similar actions on neutrophils (PMN). However, caffeine
      stimulated and pentoxifylline inhibited PMN oxidative activity. Micromolar
      concentrations of pentoxifylline decreased native and recombinant tumor necrosis
      factor-alpha (TNF alpha)-primed formyl met-leu-phe (fMLP)-stimulated PMN
      chemiluminescence, superoxide production and myeloperoxidase (MPO) release. In
      contrast, equal concentrations of caffeine increased chemiluminescence and MPO
      release with no effect on superoxide production. These activities of the
      methylxanthines were only observed in the presence of physiological
      concentrations of adenosine, and were abolished by the treatment of the PMN with
      adenosine deaminase. The activities of adenosine, pentoxifylline and caffeine on
      PMN activity could not be readily explained by changes in PMN [cAMP]. Thus for
      TNF alpha-primed PMN, pentoxifylline decreases PMN activity by enhancing the
      effect of adenosine on degranulation and superoxide production; whereas caffeine
      increases PMN activity by counteracting the effect of adenosine on degranulation.

PMID- 8655289
TI  - Effect of bismuth salts on systemic and mucosal immune responses to orally
      administered cholera toxin.
AB  - While the antimicrobial and antisecretory effects of bismuth salts are well
      documented, little is known regarding their effects on immune responses to
      enterotoxins such as that of V. cholerae or to orally administered vaccine
      antigens. To evaluate the effects of Pepto Bismol (PB) on the induction of
      systemic and mucosal immune responses to cholera toxin (CT), C57BL/6 mice were
      orally administered 10 micrograms CT and PB, or mice were pretreated with PB 30
      min prior to CT administration. When co-administered with CT, PB attenuated serum
      IgG1, IgG2a, IgG2b and IgG3 anti-CT responses in a dose-dependent manner and also
      reduced levels of circulating anti-CT IgA and total serum IgE. Similarly, anti-CT
      intestinal IgA responses were also decreased. However, when administered 30 min
      prior to CT, PB had little to no effect on serum or intestinal anti-CT
      immunoglobulin responses. Administration of bismuth subsalicylate (BSS), the
      active component of PB, or sodium salicylate did not reduce immune responses to
      CT, suggesting that the combination of BSS plus other constituents contained
      within PB contributed to the decreased immune response to CT. Moreover, bismuth
      subgallate alone inhibited antibody responses to CT. Our data are consistent with
      the hypothesis that, when administered orally with CT, PB and bismuth subgallate
      create a physical barrier to antigen uptake.

PMID- 8655290
TI  - Different pathways of in vitro ethanol-induced apoptosis in thymocytes and
      splenic T and B lymphocytes.
AB  - To investigate the intracellular pathways leading to ETOH-induced apoptosis,
      thymocytes and splenic T and B cells were cultured 16 h with or without ETOH and
      different stimuli, and apoptotic cell death was determined. At concentrations of
      0.4%-2% in culture, ETOH induced apoptosis in all three types of cells, but it
      had a more profound effect on thymocytes and B cells as compared with its effect
      on T cells. In thymocytes, ETOH-induced apoptosis was abrogated by chelation of
      extracellular calcium with EGTA, and inhibition of protein synthesis with CHX, or
      of PKC with H7 but not of PKA with HA 1004. ETOH potentiated the apoptosis of
      thymocytes induced with the calcium ionophore A23187 and suboptimal doses of PMA,
      but it had negligible effect on dAMP- and PGE2-induced apoptosis of thymocytes.
      In contrast to findings in thymocytes, the ETOH-induced apoptosis of T and B
      cells was almost completely abrogated by PMA, but not by H7 or CHX. In spleen
      cells, calcium chelation with EGTA triggered apoptosis. ETOH significantly
      inhibited EGTA-induced apoptosis of B cells but had little effect on EGTA-induced
      apoptosis of T cells. IL-4 reduced the ETOH-induced apoptosis of B and T cells,
      but it was not effective in the prevention of apoptosis of thymocytes. Inhibition
      of the calcium-dependent neutral protease calpain I did not rescue cells from
      apoptosis. Moreover, treatment with CI-I potentiated ETOH-induced apoptosis in T
      cells. These results suggest that both thymocytes and splenic T and B cells have
      relevant apoptotic pathways that can be induced by ETOH, but the mechanisms of
      ETOH-induced apoptosis differ in these cells.

PMID- 8655291
TI  - Exogenous and endogenous opioids as biological response modifiers.
AB  - Narcotic opioid compounds are among the most widely prescribed drug interventions
      for individuals suffering pain. Among the unwarranted side effects of respiratory
      depression, constipation, and physical dependence are the immunosuppressive
      qualities, particularly those which affect cell-mediated immunity. The
      immunosuppressive characteristics of opioid narcotics (e.g., morphine) have
      recently come into focus with the advent of acquired immune deficiency syndrome
      (AIDS) and the putative causative agent, human immunodeficiency virus type 1 (HIV
      1). Specifically, a vast reservoir of HIV-1-infected individuals exists among
      drug abusers. Moreover, experimental evidence would suggest narcotic opioids may
      increase viral load in infected individuals by modifying the cellular machinery
      of activated leukocytes. Likewise, investigators have shown that opioids modify
      tumor growth and development. In this review, a comparison between endogenous
      opioid peptides and exogenous opiates on cell-mediated immunity and its
      relationship to viral infection and tumors is described.

PMID- 8655292
TI  - Stimulation of human immunodeficiency virus type 1 infected cells with superoxide
      enhances the chemotactic motile response of CD4+ human T cells: implication for
      virus transmission by cell-to-cell interaction.
AB  - We previously showed that superoxide (O2-) significantly enhanced human
      immunodeficiency virus type 1 (HIV-1)-induced syncytia formation in co-cultured
      infected and uninfected human T cells. In this study, we describe a novel
      chemotactic response of uninfected CD4+ T cells by stimulating infected T cells
      with O2-. Syncytia formation was amplified only when persistently infected cells
      were stimulated by O2-. When the infected cells in lower well of microplate were
      cultured with uninfected cells in the upper well of a Boyden chamber with 8.0
      microns pores, uninfected cell migration to the porous membrane was significantly
      amplified by stimulating infected cells with O2-. In contrast, similar functions
      were slight under the same assay conditions in the presence of known chemokines
      such as human RANTES and macrophage inflammatory protein 1 (MIP-1 alpha and
      beta), which all activate T lymphocytes. In addition, it is unlikely that the O2(
      )-induced chemotactic response is due to soluble HIV-1 proteins from infected
      cells or to amplified expression levels of cell surface functional molecules such
      as CD4 and LFA-1 (CD11a and CD18) as well as HIV-1 Env gp120 on uninfected and/or
      infected cells. Thus, an unknown chemotactic factor could be generated from
      infected T cells by stimulation with O2- and it might contribute to viral
      transmission by activating cell-to-cell interactions.

PMID- 8655293
TI  - Pentoxifylline therapy in HIV seropositive subjects with elevated TNF.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is thought to induce cachexia in subjects
      infected with human immunodeficiency virus (HIV), and it has been suggested that
      HIV-seropositive patients would benefit from treatment with pentoxifylline, a
      known suppressor of TNF-alpha production. The purpose of the present study was to
      examine how pentoxifylline at a dose of 800 mg thrice daily would influence the
      cellular immune system in HIV-seropositive persons with elevated TNF-alpha. Six
      HIV-seropositive subjects with elevated amounts of TNF-alpha in plasma at least
      at two occasions were included in an open, controlled, randomized, cross-over
      study consisting of a 6 week treatment period and a 6 week control period. Blood
      samples were collected before and at the end of each period. Pentoxifylline
      treatment did not influence the concentration of plasma-TNF-alpha, subpopulations
      of blood mononuclear cells, the proliferative responses nor the natural killer
      (NK), and lymphokine activated killer (LAK) cell activities. Furthermore,
      pentoxifylline treatment did not influence the weight, temperature, well being,
      or tiredness of the subjects. However, the patients frequently reported
      gastrointestinal side effects. In vitro, however, pentoxifylline at
      suprapharmacological concentrations inhibited the blood mononuclear cell (BMNC)
      proliferative responses, NK, and LAK cell activities.

PMID- 8655294
TI  - Interferon-gamma-activated macrophages release interleukin-1 alpha to increase
      tube formation from endothelial cells of rat aorta.
AB  - Interferon (IFN)-gamma (160 and 460 pM)-treated peritoneal macrophages (M phi)
      increase tube formation from subcultured aortic endothelial cells (EC) of rat in
      type I collagen gel (Kobayashi et al., Immunopharmacology, 27: 23, 1994). The
      present study was carried out to identify factors released from these M phi.
      Interleukin (IL)-1 alpha, platelet-derived growth factor (PDGF)-BB and basic
      fibroblast growth factor (bFGF) increased tube formation, and their 50% effective
      concentrations were 0.46, 6.4 and 140 pM, respectively. A polyclonal anti-mouse
      IL-1 alpha antibody (0.33%) inhibited 57.7 +/- 6.5% of the activity of
      conditioned medium (CM) from IFN-gamma-treated M phi, but not from medium of
      basal M phi or EC. A monoclonal anti-human bFGF antibody (20 ng/ml) inhibited
      both the activities of CM from IFN-gamma-treated and basal M phi by 43.2 +/-
      15.0% and 46.7 +/- 15.9%, respectively. However, a polyclonal anti-human PDGF-BB
      antibody (0.33%; 3.3 micrograms/ml) did not inhibit either activity of M phi.
      These results demonstrate that the effect of IFN-gamma-treated M phi on tube
      formation was caused by released IL-1 alpha. The release of IL-1 alpha was
      dependent on the action of IFN-gamma, a different mechanism from those of bFGF
      and PDGF-BB.

PMID- 8655295
TI  - Needs assessment: taking stock.
AB  - In 1994, the Scottish Needs Assessment Programme (SNAP) carried out a stocktaking
      review of all needs assessment reports in 14 topic areas produced in Scotland on
      the previous three years. National needs assessment documents from England in the
      relevant topic areas were also reviewed. The review identified two particular
      points for comment. First, in respect of content, the definition of need as "the
      ability to benefit'-while appropriate for NHS purchasing- must be balanced by a
      greater emphasis on the wider concerns for the public's health. At the same time,
      relevant economic and costing information should be incorporated. Secondly, the
      process of information collation for purchasing could be made more efficient.
      Closer links between clinical experts and public health specialists would ensure
      assessments based on timely opportunities for change. National reviews should
      provide generally applicable intelligence and comparative analyses; short local
      reports can then focus on local quantification and priority setting.

PMID- 8655296
TI  - Patients' desire for information about anaesthesia: change in Scottish attitudes
      over five years.
AB  - In 1989, 49 general surgical in-patients in our hospital completed a preoperative
      questionnaire concerning their desire for information about anaesthesia. We have
      now repeated the study.

PMID- 8655297
TI  - The value of skin testing in patients with chronic rhinitis.
AB  - The value of skin prick testing in the management of patients with chronic
      rhinitis has still to be established. The aim of the study was to determine how
      accurately atopic status could be predicted from the clinical history of allergy.
      We carried out a prospective audit of 103 patients undergoing skin tests in three
      ORL departments over a three-month period. Of 73 patients with a history of
      allergy or an atopic family history, 44 (60%) had a positive skin test. Twenty
      one out of 30 (70%) with no history had a negative skin test. In subjects where a
      negative atopic history to inhaled allergens is combined with a negative family
      history, the incidence of negative skin test results was 79%. Skin prick testing
      is of questionable clinical value in the absence of positive atopic feature in
      the personal or family history of the patient.

PMID- 8655298
TI  - Can information on breast pathology reports be used to audit the UK Breast
      Screening Programme?

PMID- 8655299
TI  - The smoke-free policies of Lanarkshire general practices.
AB  - A telephone survey was performed to examine the smoke-free policies at
      Lanarkshire general practices sited outwith health centres. Forty-nine practices
      were contacted and all agreed to take part. Thirty-three practices (67%) reported
      that there was a complete ban on smoking within the building. The remaining 16
      practices (33%) reported that the building was largely no-smoking with smoking by
      staff restricted to designated smoking areas. No practices permitted patients to
      smoke within the main practice premises. Few practices reported experiencing any
      difficulties with either the implementation or operation of the smoke-free
      policies. Although it is possible that problems may not have been recognised or
      not reported, these results are encouraging. They suggest that smoking in
      surgeries is the exception rather than the rule. The finding that patients
      largely respect the smoking ban in practice premises also suggests that the
      health service exemplar role is being recognised by the public. Practices that
      currently have no smoking restrictions should review their policy. Practices that
      do impose restrictions must recognise the needs of staff who smoke and offer
      appropriate support to help them to stop.

PMID- 8655300
TI  - Wide variation in the use of thrombolytic therapy among junior doctors in south
      and central Scotland.
AB  - OBJECTIVES: (a) To assess the practice of junior doctors who administer
      thrombolytic therapy in acute myocardial infarction. (b) To assess whether wider
      implementation of current guidelines is indicated. DESIGN: Postal questionnaire
      survey. Each questionnaire was followed by a reminder. SETTING: Teaching and
      district general hospitals in Central and Southern Scotland. SUBJECTS: Two
      hundred and twelve junior doctors (excluding JHO's) regularly involved in the
      early assessment and management of patients with acute myocardial infarction.
      RESULTS: One hundred and ten questionnaires were returned (response rate 52%).
      There was wide inter-individual variation in clinical practice regardless of
      whether subjects worked in teaching or district general hospitals or as
      cardiologists or non-cardiologists. As many as 12% of respondents administer
      thrombolytic therapy in the absence of ST elevation or bundle branch block on the
      presenting ECG. A high percentage of subjects considered diabetic retinopathy,
      but not a previous history of cerebrovascular disease, a contraindication to
      thrombolytic therapy. Only 29% and 32% respectively worked in institutions where
      formal policies existed for streptokinase readministration and rt-PA
      administration in preference to streptokinase. The administration of thrombolytic
      therapy in Accident and Emergency departments is not a popular strategy, and the
      full efficacy of rt-PA is not realised due to inappropriate use or failure to use
      intravenous heparin. CONCLUSIONS: There is wide variation in clinical practice
      among junior doctors who administer thrombolytic therapy for acute myocardial
      infarction. Wider implementation and firmer current national guidelines would
      ensure that patients presenting with suspected acute myocardial infarction
      receive optimal therapy.

PMID- 8655301
TI  - The utilisation of hepatitis A vaccine 1992-1994.
AB  - OBJECTIVES: To assess the utilisation of hepatitis A vaccine in Scotland since it
      was licensed and also any impact this had on the utilisation of immunoglobulin
      prophylaxis. DESIGN: Collation and analysis of information obtained from the
      Pharmacy Practice Division and the Scottish National Blood Transfusion Service
      (SNBTS). SETTING: Scotland. 1992 to 1994 inclusive. SUBJECTS: All
      supplies/persons for whom hepatitis A vaccine or Human normal immunoglobulin
      (commercial or via SNBTS) was prescribed or dispensed in Scotland 1992-94.
      RESULTS: Hepatitis A vaccine started to be utilised very shortly after it became
      available. Utilisation has increased progressively since April 1992 with nearly
      65,000 "courses' being prescribed in 1994. There has been no obvious impact on
      the use of immunoglobulin which has increased during this period. New
      formulations of the vaccine, e.g. paediatric and one dose courses have been
      rapidly assimilated by practitioners into their practice. Both vaccine and
      immunoglobulin utilisation follow a marked seasonal pattern with a peak every
      June. CONCLUSION: Statistics from the Pharmacy Practice Division proved useful in
      monitoring utilisation of this prescribed vaccine. The increasing utilisation of
      hepatitis A vaccine is a significant financial outlay for the NHS in Scotland.
      There may be significant non-compliance with the recommendations for restricting
      its use. The cost effectiveness of this immunisation for travellers has been
      recently called in question. The changing epidemiology of endemic infection is
      referred to in respect of possible immunisation programmes and the likely decline
      in efficacy of immunoglobulin. The need for more research on the incidence of
      hepatitis A antibody in the Scottish population is highlighted.

PMID- 8655302
TI  - Assessing continuing care needs: findings from the Fife Healthcare Assessment for
      Placement Project for elderly people.
AB  - Previous surveys of elderly patients in different continuing care settings
      suggest considerable overlap between settings. However, re-analysis of this data
      in terms of patients' profiles of dependency reveals a somewhat different
      picture, suggesting that overlap is not such a general phenomenon. Further data
      from new surveys in Fife confirm this view. The findings of these studies raise
      questions about some of the previous research on "misplacement' of people in long
      stay care, and suggest that planners may need to be more discriminating in their
      analysis of which types of patient to transfer and what continuing care resources
      might be required. Failure to address these issues may lead to undue pressure on
      many of the continuing care placements.

PMID- 8655303
TI  - Acute psychiatric problems in an A&E Department.
AB  - A study of patients with psychiatric problems attending the Accident & Emergency
      Department at the Western Infirmary, Glasgow was performed over a four month
      period. Those requiring admission to other specialties for treatment were
      excluded (e.g. overdoses). Forty-seven patients presented during the study period
      and all were self-referred. Seventy-seven per cent had a past history of
      psychiatric illness. Sixty-six per cent of cases presented with self harm. Eighty
      one per cent of cases presented after normal working hours. Alcohol intoxication
      was a contributing factor in only one quarter of patients presenting. Of all
      cases seen, 62% were referred to a duty psychiatrist. In this group 38% were
      admitted and 45% were discharged with psychiatric follow-up, three absconded and
      two were referred back to their general practitioners. Results indicated that the
      majority of patients referred to the psychiatric services from Accident &
      Emergency needed some form of psychiatric input. In the self harm group results
      showed a correlation between known risk factors for suicide and a need for
      admission or follow up. Due to local psychiatric referral policies, patients were
      referred to four different psychiatric hospitals in the area. After initial
      assessment by the duty psychiatrist, 52% of these patients were subsequently
      discharged with or without psychiatric follow up. Availability of an on site
      psychiatrist would alleviate many of the present delays in obtaining definitive
      management.

PMID- 8655305
TI  - The pattern of increase in emergency hospital admissions in Scotland.

PMID- 8655304
TI  - Major paediatric trauma in Glasgow 1980-1989: implications for services.
AB  - The experience of major paediatric trauma presenting both directly and indirectly
      over ten years to a Paediatric Teaching Hospital is presented. Of the 185
      patients assessed and treated in the Resuscitation Room, 131 were considered to
      have sustained significant trauma: 99 being admitted to the Intensive Therapy
      Unit and 32 transferred to the regional Neurosurgical centre. Road traffic
      accidents were responsible for the majority of serious injuries and eight of the
      11 deaths, emphasising the need for further preventative measures. There were 95
      interhospital transfers amongst the 131 patients judged to have sustained
      significant trauma. The potential benefits of centralisation of services to
      manage major paediatric trauma, in terms of both a reduction in interhospital
      transfers and early involvement of experienced staff, are proposed.

PMID- 8655306
TI  - The Chief Scientist reports. ... Mental health hearings for elderly people with
      dementia.
AB  - The aim of the study reported here was to examine the feasibility of mental
      health hearings, modelled along the lines of the Children's Hearings, for
      handling legal and ethical problems that arise in managing the personal and
      financial affairs of elderly people with dementia. The study involved interviews
      with professionals, as well as a postal survey. The findings indicated that
      technically irregular solutions to problems were commonplace. Over half of the
      professionals surveyed thought that mental health hearings would help solve
      disputes.

PMID- 8655307
TI  - [Indications for psychosomatically-oriented dermatologic rehabilitation].
AB  - Dermatological rehabilitation treatment can take different forms: climato
      therapy, baths, phototherapy and psychosomatic treatments. Which of these
      treatments is of most benefit to any one patient depends on his or her illness.
      Accordingly, a psychosomatic approach to dermatological illness is indicated
      mainly when a psychological disorder and a dermatological disease coincide. In
      addition, dermatoses with psychological triggers or overlays, and also
      depression, pre-existing emotional disorders and special motivation for
      psychotherapy should be considered for psychosomatic treatment. Finally, patients
      who are having trouble accepting or confronting malignant skin tumours may also
      benefit.

PMID- 8655308
TI  - [Selective photothermolysis of superficial varicose veins telangiectasias of the
      lower extremity].
AB  - Leg venectasia is a common problem. Although there are a variety of therapeutic
      modalities, none of them gives satisfactory results. The effects of sclerotherapy
      in the treatment of telangiectasia with a small diameter are poor.
      Electrocoagulation and argon laser treatment often result in scarring. We studied
      the effectiveness of the flashlamp pumped pulsed dye laser at a wavelength of 585
      nm in the treatment of leg venectasia. After repeated treatments using this laser
      system, only 30% of the vessels that looked blue on clinical examination could be
      removed; we obtained better lightening of smaller red, telangiectatic vessels
      with a diameter up to 0.4 mm. However, hyperpigmentation frequently developed
      after treatment. In post-treatment biopsies, occlusion of the vessels was found.
      Based on these results, we recommend a combined therapy for leg venectasia.
      Larger diameter vessels should be treated with sclerotherapy, while finer
      telangiectasia can be treated with the flashlamp pumped pulsed dye laser.

PMID- 8655309
TI  - [Incident light microscopic characterization of vascular patterns in skin
      tumors].
AB  - The search for vascular structures in skin tumors by incident light microscopy
      has revealed a surprisingly high proportion of vascularized tumours.
      Characteristic vascular patterns, in some cases highly tumour-specific, have been
      defined. The vascular structure is a valuable feature for characterization and
      differentiation of skin tumours, especially for amelanotic malignant melanoma. We
      propose a flowchart procedure for analysis and diagnosis of skin tumours using
      incident light microscopy, which appears to be valuable for advanced image
      analytic techniques.

PMID- 8655310
TI  - [Umbilical reconstruction after excision of melanomas in the area of the
      umbilicus].
AB  - Reconstruction of the navel after tumour excision with subsequent navel resection
      is of great aesthetic importance for the patient. Methods of navel reconstruction
      are found in the literature but do not provide an elegant solution to the
      problem. Our method permits reconstruction of the navel during wound closure, by
      creation of two opposing trapezoidal skin flaps at the excision margin in the
      midline of the body; the umbilical fossa is then restored by jointly anchoring
      these flaps to the linea alba. Reconstruction has been successfully carried out
      in this way after melanoma excision in 7 patients.

PMID- 8655311
TI  - [Measuring capillary resistance values in atopic dermatitis].
AB  - For over 100 years many different methods have been used to determine capillary
      resistance as a measure of small vessel fragility. There is still no firm
      agreement as to the most suitable method; the procedure is not standardized and
      an objective system for measurement is lacking. We have developed a computerized
      system that makes it possible to count petechiae and determine their area without
      the results varying with different examiners. Although we tried to keep the
      conditions for our examinations constant, we found a wide individual spread. In
      spite of this, the capillary resistance of atopic subjects was significantly
      lower than that of healthy persons.

PMID- 8655313
TI  - [Microcystic adnexal carcinoma of the skin. An underestimated tumor].
AB  - Microcystic adnexal carcinoma is a rare semimalignant cutaneous neoplasm
      characterised by slow but locally aggressive growth. Its histogenesis and
      nomenclature are still a subject of controversy. Under-recognition and the
      tumor's bland cytologic features lead to frequent misdiagnoses. In addition,
      subclinical tumour invasion explains the high incidence of local recurrence.
      Thus, the tumour makes great demands on the planning of its surgical removal. We
      report the case of an 81-year-old woman with a microcystic adnexal carcinoma of
      the lower lip, which was treated by micrographic surgery. On the basis of this
      case, differential diagnoses, histogenesis and micrographic surgery as the
      treatment of choice are discussed.

PMID- 8655312
TI  - [Acetylsalicylic acid as an augmentation factor in food allergy].
AB  - A 39-year-old female patient presented with an intense allergic reaction and
      shock after ingesting sunflower seeds and simultaneously acetylsalicylic acid
      (ASA). Skin tests and CAP specific. IgE demonstrated an IgE-mediated
      sensibilization to sunflower seeds. When sunflower seeds were eaten alone, only
      discrete paresthesia of the oral mucosa occurred. Surprisingly, an oral challenge
      with ASA was well tolerated. The supplementary contribution of ASA to the
      allergic reaction was dose-dependent. The quantity of the allergen also modified
      the intensity of the symptoms. This surprising effect of ASA may be attributed to
      increased gastric resorption of the allergens. During the course of this
      reaction, eosinophil-cationic-protein was released.

PMID- 8655314
TI  - [Microangiopathic changes and functional disorders of nail fold capillaries in
      dermatomyositis].
AB  - We report on a 70-year-old female patient with dermatomyositis. The connective
      tissue vascular bed was studied with capillaroscopy to evaluate morphological and
      functional changes of skin capillaries. Capillaroscopic findings showed
      morphological alterations such as rarefication of capillaries, avascular fields
      and tortuosity of nailfold capillaries. In addition, fluorescence-videomicroscopy
      showed pathologically increased transcapillary diffusion of dye in the apex
      region of nutritive skin capillaries. Increased capillary leakage probably
      contributed to the development of oedema in our patient. Immunosuppressive
      therapy combined with intensified manual lymphatic drainage was successful.

PMID- 8655315
TI  - [Cutaneous large cell anaplastic Ki-1 (CD 30) positive T-cell lymphoma].
AB  - A 72-year-old female patient presented with a large ulceration on the lower half
      of her right abdomen. Cutaneous anaplastic large-cell lymphoma was diagnosed
      based upon histopathological and immunohistochemical features. There were no
      signs of extracutaneous involvement by the lymphoma. Complete remission was
      achieved by local electron beam radiation, followed by chemotherapy.

PMID- 8655316
TI  - [Giant cell fibroblastoma. A rare soft tissue tumor in childhood].
AB  - We report on a 9-year-old girl with a giant cell fibroblastoma of the right
      anterior chest wall. This rare soft tissue tumour occurs predominantly in the
      first two decades of life. The typical clinical presentation is a solitary,
      usually 2-6 cm large, non-tender mass of blue-greyish colour which is mostly
      located on the back, anterior chest wall, thigh or groin. The histology shows a
      loose infiltrate of predominantly bland spindle cells in dermis and subcutis.
      Characteristic elements of the tumour are large angiectoid branching spaces
      lacking any endo- or epithelium, and relatively small multinucleated cells
      (floret cells). The recurrence rate is high if the tumour is not excised with
      adequate safety margins. Metastases are not reported. It is of pre-eminent
      importance to differentiate this rare benign tumor from sarcomas, in order to
      avoid an inappropriately aggressive therapy.

PMID- 8655317
TI  - [Perifollicular fibroma of the skin and colonic polyps: Hornstein-Knickenberg
      syndrome].
AB  - The syndrome of perifollicular fibromas and colonic polyps was delineated 20
      years ago by Hornstein and Knickenberg; it probably occurs more frequently than
      suggested by the literature. Multiple perifollicular fibromas were found in a
      mother and daughter. The mother also had colonic polyps. This dermo-intestinal
      syndrome varies in its clinical manifestations, but it is probably an autosomal
      dominant trait. We believe that the Horn-stein-Knickenberg syndrome and the Birt
      Hogg-Dube syndrome are identical. If perifollicular fibromas are observed and
      cannot be explained as postinflammatory sequelae of acne, the patient should be
      examined for colonic polyps as an appropriate from of cancer screening.

PMID- 8655318
TI  - [Value of dental treatment in interdisciplinary management of a child with
      epidermolysis bullosa dystrophica hereditaria (Hallopeau-Siemens)].
AB  - Severe dystrophic epidermolysis bullosa with oral involvement often leads to
      dental destruction and restricted food intake, resulting in malnutrition and
      maldevelopment. The patients become handicapped and have a poor prognosis. We
      report on a now 13-year-old Turkish child with normal secondary dentition who had
      severely damaged primary dentition. The teeth were treated surgically and then by
      continuous dental hygiene measures over the next 7 years. This care also resulted
      in an improvement in the nutritional state, associated anemia and the incidence
      of skin infections. Although cutaneous blistering and scarring has been
      progressive, with resulting mutilation of the fingers, the child is socially well
      adjusted in school and family. Its clinical course demonstrates that the fate of
      patients with severe dystrophic epidermolysis bullosa can be improved through
      multidisciplinary management.

PMID- 8655319
TI  - [Alpha hydroxy acids in acne therapy].

PMID- 8655320
TI  - [Sperm intolerance as a possible cause for infertility?].

PMID- 8655321
TI  - [Sunscreens popular with children].

PMID- 8655323
TI  - Four decades for HPS.

PMID- 8655322
TI  - [Metal dermatoses I].

PMID- 8655324
TI  - Present concept on current water protection and remediation activities for the
      areas contaminated by the 1986 Chernobyl accident.
AB  - The results of radiation monitoring data and migration pathway analysis of water
      bodies within areas affected by the 1986 Chernobyl accident provide a unique
      opportunity for decision-makers working in other extensively contaminated regions
      to optimize their approaches to surface and groundwater protection. Most
      engineering measures within the Chernobyl 30-km exclusion zone were focused on
      preventing secondary contamination of surface and groundwater from entering the
      Pripyat River and the Kiev Reservoir. However, implementation of these measures
      required huge financial and human resources. Therefore, lessons about post
      accidental water protection activities can be learned from the Chernobyl example.

PMID- 8655325
TI  - The results of selective cytogenetic monitoring of Chernobyl accident victims in
      the Ukraine.
AB  - Selective cytogenetic monitoring of the highest priority groups of Chernobyl
      disaster victims has been carried out since 1987. In 1992-1993, 125 liquidators
      (irradiated mainly in 1986) and 42 persons recovering from acute radiation
      sickness of the second and third degrees of severity were examined. Cytogenetic
      effects (an elevated level of unstable as well as stable markers of radiation
      exposure) were found in all groups, which showed a positive correlation with the
      initial degree of irradiation severity even 6-7 y after the accident. Comparative
      scoring of conventional staining vs. G-banding in 10 liquidators showed the
      identical rate of unstable aberrations. At the same time, the yield of stable
      aberrations for G-banded slides exceeded the frequency for conventional staining.
      In order to study possible mutagenic activity of chronic low levels of
      irradiation, the cytogenetic monitoring of some critical groups of the population
      (especially children and occupational groups--tractor drivers and foresters)
      living in areas of the Ukraine contaminated by radionuclides was carried out. In
      all the examined groups, a significant increase in the frequency of aberrant
      metaphases, chromosome aberrations (both unstable and stable), and chromatid
      aberrations was observed. Data gathered from groups of children reflect the
      intensity of mutagenic impact on the studied populations and demonstrate a
      positive correlation with the duration of exposure. Results of cytogenetic
      examination of adults confirmed the importance of considering the contribution of
      occupational radiation exposure to genetic effects of Chernobyl accident factors
      on the population of contaminated areas. Results of our investigations
      demonstrated the possibility of evaluating the mutagenic impact of acute and long
      term irradiation of different intensities on somatic cells of persons undergoing
      radiation exposure due to the Chernobyl accident and confirmed the need to
      introduce new informative genetic methods [especially fluorescence in situ
      hybridization (FISH)] for reliable retrospective cytogenetic dosimetry of
      radiation exposure in Chernobyl accident victims.

PMID- 8655326
TI  - The influence of water potassium concentration on 137Cs excretion from fish.
AB  - Results are reported of the investigation on the peculiarities of 137Cs release
      from carp (Cyprinus carpio L.) acclimatized to different potassium concentrations
      in water. The dynamics of radiocesium release are characterized by slow and fast
      components. The 137Cs release rates observed in the experiments with different
      water potassium concentrations were not markedly different from the point of view
      of middle-term radioecological predictions.

PMID- 8655327
TI  - Internal doses to Ukrainian populations using Dnieper River water.
AB  - The dynamics of internal doses from 137CS and 90Sr as a consequence of the use of
      Dnieper River water were calculated. Local peculiarities of municipal tap,
      irrigation, and fish consumption in the Ukraine were considered. The dynamics of
      90Sr accumulation in human bone as a result of the use of Dnieper water is
      simulated. The dose predictions are based on de facto data and the stochastic
      forecast of radionuclide concentrations in Dnieper reservoirs. A large array of
      statistical data on the age-structures of exposed populations, food consumption
      rate, agricultural production, fish contamination, and site-specific parameters
      were used. Exposures are estimated for 12 regions of the Dnieper basin and the
      Crimea Republic. The maximal individual annual committed effective doses are 1.7
      X 10(-5) and 2.7 X 10(-5) Sv from 90Sr and 137Cs, respectively, due to the use of
      water in 1986 by members of the population in the Kievska region. Commercial
      fishermen on the Kievska reservoir, who consumed 360 kg y(-1) of fish in 1986,
      received 4.7 X 10(-4) and 5 X 10(-3) Sv from 90Sr and 137Cs, respectively. The
      contributions to the collective (over 70 y) effective dose of irrigation,
      municipal tap water, and fish consumption for members of the general public,
      respectively, are 18%, 43%, 39% in the Kievska region; 8%, 25%, 67% in the
      Poltavska region; 50% 50%, 0% (no Dnieper fish consumed) in the Crimea Republic.
      The predicted contribution of 90Sr to collective dose resulting from the use of
      water is 80%. The collective dose to the population of the Dnieper regions (32.5
      million people) is 3,000 person-Sv, due to the use of water.

PMID- 8655328
TI  - The Chernobyl accident and the resultant long-term relocation of people.
AB  - Following the Chernobyl accident, large areas of the former USSR with populations
      in the millions were polluted, to varying extent, with long-lived radionuclides.
      Within the framework of the USSR state legislation still in force in the newly
      formed independent states of Belorussia, Russia, and Ukraine, relocation of
      nearly one million people from these areas was prescribed to avoid exposure to
      low levels of irradiation; this measure was obviously groundless, both medically
      and socially. Additionally, four million people from the three affected states
      were needlessly included in post-Chernobyl legislation; their exposure did not
      exceed the natural background levels characteristic of many inhabited regions
      around the world. Finally, these millions of people were falsely identified as
      the major victims of the accident. This evoked worldwide concern and played an
      important role in limiting the development of nuclear power production in a
      number of countries. This article focuses on the social aspects of the Chernobyl
      aftermath that ordinarily escape scientific attention. In particular, it
      considers the public health-related realities of "pre-Chernobyl" and "post
      Chernobyl, Soviet society, both political and psychological, that not only
      blocked implementation of proper radiation protection measures, but also put
      inappropriate measures into action.

PMID- 8655329
TI  - Cancer risk estimation in Belarussian children due to thyroid irradiation as a
      consequence of the Chernobyl nuclear accident.
AB  - The thyroid doses received by the juvenile population of Belarus following the
      Chernobyl accident ranged up to about 10 Gy. The thyroid cancer risk estimate
      recommended in NCRP Report No. 80 was used to predict the number of thyroid
      cancer cases among children during 1990-1992 in selected Belarussian regions and
      cities. The results obtained using this risk estimate show an excess of thyroid
      cancer cases being registered vs. the predicted cases. Thyroid cancer incidence
      rate among boys under investigation is higher than among girls in the
      postaccident period. The excess of the observed over the expected incidence in
      the general juvenile population is caused by the high thyroid cancer incidence
      rate among boys. These results, which can be considered part of the first stage
      of a thorough thyroid cancer risk estimation after the Chernobyl accident,
      demonstrate the critical need to complete these studies in depth.

PMID- 8655330
TI  - Doses to workers in the United States nuclear weapons program due to external
      irradiation at the dawn of the atomic era (1940-1960).
AB  - Radiation doses to workers at the Manhattan Engineer District (MED) and Atomic
      Energy Commission (AEC) sites due to external irradiation during 1940-1960 are
      reviewed. Categorized radiation dose data were available from AEC annual reports
      for some years. Annual individual radiation dose data for nine MED/AEC sites for
      all years were available from the U.S. Department of Energy's Comprehensive
      Epidemiologic Data Resource. These data are combined to produce an estimate of
      external collective dose equivalent to 1,720 person-Sv for 1940-1960. During this
      period there were 19 criticality incidents; 41 persons in a workforce of several
      hundred thousand were accidentally overexposed in these and other incidents,
      including three men who died due to acute radiation syndrome.

PMID- 8655331
TI  - The Chelyabinsk data base: current Russian legislation on databases and
      intellectual property and its implications for international scientific
      collaboration.
AB  - The Chelyabinsk data base contains medical and radiation dosimetry data from the
      archives (handwritten paper files) dating from the early 1950's at the Urals
      Research Center for Radiation Medicine (URCRM). The original medical records of
      the off-site population (about 100,000 people) exposed to radiation due to at
      least three nuclear events in the Urals are stored in the archives.

PMID- 8655332
TI  - Environmental monitoring in the vicinity of the Mayak atomic facility.
AB  - The goal of radiation monitoring in the zone influenced by the operation of the
      Mayak Production Association is to provide information for activities aimed at
      environmental preservation in that territory. The priority tasks of the
      radioecological monitoring system are measuring all parameters of radiation
      impact on the environment (which contribute up to 95% of the total population
      exposure dose), and estimating all parameters required to support effective
      decision-making. The basic methods for radioecological monitoring are:
      unification and standardization of field and laboratory techniques for
      radionuclide analysis; measurement of gamma-irradiation dose rate; measurement of
      137Cs, 90Sr, and plutonium concentrations in soils; measurement of radionuclide
      concentration in surface and ground waters and the atmosphere; study of the
      pathways of horizontal and vertical migration of radionuclides in natural media;
      and establishment of data bases including ecological mapping. Based on the
      information obtained, assessment of contamination and forecasts of the future
      radiation situation are prepared using models.

PMID- 8655333
TI  - An approach to dose reconstruction for the Urals population.
AB  - Population exposure in the Urals region occurred due to the releases of
      radionuclides by the Mayak plutonium facility in the 1950's. The major sources of
      radioactive contamination were the discharges of liquid wastes into the Techa
      river (1949-1956); an explosion in the storage facility for high level
      radioactive wastes which formed the East Urals Radioactive Trace in 1957; and
      gaseous aerosol releases within the first decade of the facility's operation
      (1949-1957). The problems of dose reconstruction for the population exposed on
      the Techa river banks and East Urals Radioactive Trace are outlined. The initial
      data sets and basic models for dose reconstruction are described. The main tasks
      of the Techa River Dosimetry System Project and the approaches to individual
      internal and external dose reassessment are formulated.

PMID- 8655334
TI  - Cancer mortality among Techa River residents and their offspring.
AB  - This paper analyzes the data on leukemia and solid cancers of all types among
      28,000 people exposed due to discharges of radioactive waste into the Techa River
      in the South Urals. Cancer mortality rates for the 33-y period since the
      beginning of the exposure have been estimated. In addition, the paper discusses
      malignancy cases among the first generation offspring of the exposed people. In
      comparison with matched control groups, an increased incidence of malignant
      neoplasms was observed among the exposed population. The leukemia risk, estimated
      on the basis of the linear model of absolute risk, was 0.85 per 10,000 person-y
      Gy of the dose accumulated in red bone marrow. Solid cancer risk (except
      osteosarcoma), estimated using linear model of relative risk, was 0.65 per Gy of
      dose accumulated in soft tissues. No increase in cancer mortality has been
      documented for the offspring of the exposed individuals.

PMID- 8655335
TI  - Estimation of the temporal distribution and dose dependency of lung cancers among
      workers of nuclear fuel reprocessing plants.
AB  - Lung cancer mortality among 4,279 workers at the Mayak nuclear complex who were
      exposed to chronic irradiation both externally and internally from incorporation
      of plutonium was analyzed in terms of a linear relative risk model. It is
      estimated that excess lung cancer risk is about 1.9 Sv(-1), with an average
      latent period of 24 y.

PMID- 8655336
TI  - Mortality among workers with chronic radiation sickness.
AB  - This study is based on a registry containing medical and dosimetric data of the
      employees who began working at different plants of the Mayak nuclear complex
      between 1948 and 1958 who developed chronic radiation sickness. Mayak is the
      first nuclear weapons plutonium production enterprise built in Russia and
      includes nuclear reactors, a radiochemical plant for plutonium separation, and a
      plutonium production plant. Workers whose employment began between 1948 and 1958
      exhibited a 6-28% incidence of chronic radiation sickness at the different
      facilities. There were no cases of chronic radiation sickness among those who
      began working after 1958. Data on doses of external whole-body gamma-irradiation
      and mortality in workers with chronic radiation sickness are presented.

PMID- 8655337
TI  - Risks from radionuclide migration to groundwater in the Chernobyl 30-km zone.
AB  - Remediation of contaminated groundwater in the Chernobyl 30-km evacuation zone is
      frequently identified as a priority by technical experts and Chernobyl site
      officials in Ukraine. In order to evaluate the health risk basis for this
      groundwater remediation, we have estimated both on-site and off-site health risks
      caused by radionuclide migration to the groundwater and compared these risks with
      those from exposure to radioactive contamination on the ground surface. A simple
      and conservative analytical model was developed to assess radionuclide transport
      to the groundwater from the soil surface contaminated by radioactive fallout.
      90Sr, the primary radioactive contaminant of concern for the groundwater
      migration exposure pathway, was evaluated in the analysis. The estimated health
      risk to hypothetical, self-sufficient residents in the 30-km zone is dominated by
      external and internal irradiation (due primarily to ingestion of agricultural
      products) from 137Cs, which is present in soils of the 30-km zone in roughly
      equal proportion with 90Sr. The estimated risk from contaminated groundwater is
      approximately an order of magnitude lower. Analysis of 90Sr migration via
      groundwater to surface water and down-river population centers shows that,
      despite generally unfavorable environmental conditions in the 30-km exclusion
      zone, radionuclide transport via the groundwater pathway has potential to
      contribute only marginally to the off-site radiological risk, which is governed
      by wash-out of radionuclides from the contaminated river flood plain and
      catchment areas by surface water during spring snowmelt and rains. Health risks
      due to off-site radionuclide migration via groundwater are below the level
      requiring application of counter-measures. This analysis implies that, relative
      to other exposure pathways, there is little current or future health risk basis
      for the proposed complex and costly groundwater remediation measures in the 30-km
      zone. Therefore, these activities should be abandoned in favor of more pressing
      health issues caused by the Chernobyl accident.

PMID- 8655339
TI  - High-energy gamma rays at Hiroshima and Nagasaki.

PMID- 8655338
TI  - Mortality among personnel who worked at the Mayak complex in the first years of
      its operation.
AB  - Epidemiological studies revealed increased cancer mortality among persons who
      began working at the Mayak complex during the period 1948-1958. Estimation of
      cancer risk was carried out for the sites of cancer that showed increased
      mortality and dependence on dose of external gamma- or internal alpha
      irradiation.

PMID- 8655340
TI  - Plasterboard as an emergency EPR dosimeter.

PMID- 8655341
TI  - Electromagnetic interference and medical devices. An update on the use of
      cellular telephones and radio transmitters in healthcare facilities.

PMID- 8655342
TI  - Blood leakage from the female Luer connector of a Datascope intra-aortic balloon
      catheter.

PMID- 8655343
TI  - Failure of drive belt assembly on Tranas (Ferno-Washington) Model 9651 Patient
      Transport System.

PMID- 8655344
TI  - Materials management information systems.
AB  - The hospital materials management function--ensuring that goods and services get
      from a source to an end user--encompasses many areas of the hospital and can
      significantly affect hospital costs. Performing this function in a manner that
      will keep costs down and ensure adequate cash flow requires effective management
      of a large amount of information from a variety of sources. To effectively
      coordinate such information, most hospitals have implemented some form of
      materials management information system (MMIS). These systems can be used to
      automate or facilitate functions such as purchasing, accounting, inventory
      management, and patient supply charges. In this study, we evaluated seven MMISs
      from seven vendors, focusing on the functional capabilities of each system and
      the quality of the service and support provided by the vendor. This Evaluation is
      intended to (1) assist hospitals purchasing an MMIS by educating materials
      managers about the capabilities, benefits, and limitations of MMISs and (2)
      educate clinical engineers and information system managers about the scope of
      materials management within a healthcare facility. Because software products
      cannot be evaluated in the same manner as most devices typically included in
      Health Devices Evaluations, our standard Evaluation protocol was not applicable
      for this technology. Instead, we based our ratings on our observations (e.g.,
      during site visits), interviews we conducted with current users of each system,
      and information provided by the vendor (e.g., in response to a request for
      information [RFI]). We divided the Evaluation into the following sections:
      Section 1. Responsibilities and Information Requirements of Materials Management:
      Provides an overview of typical materials management functions and describes the
      capabilities, benefits, and limitations of MMISs. Also includes the supplementary
      article, "Inventory Cost and Reimbursement Issues" and the glossary, "Materials
      Management Terminology." Section 2. The MMIS Selection Process: Outlines steps to
      follow and describes factors to consider when selecting an MMIS. Also includes
      our Materials Management Process Evaluation and Needs Assessment Worksheet (which
      is also available online through ECRInet(TM)) and a list of suggested interview
      questions to be used when gathering user experience information for systems under
      consideration. Section 3A. MMIS Vendor Profiles: Presents information for the
      evaluated systems in a standardized, easy-to-compare format. Profiles include an
      Executive Summary describing our findings, a discussion of user comments, a
      listing of MMIS specifications, and information on the vendor's business
      background. Section 3B. Discussion of Vendor Profile Conclusions and Ratings:
      Presents our ratings and summarizes our rationale for all evaluated systems. Also
      includes a blank Vendor Profile Template to be used when gathering information on
      other vendors and systems. We found that, in general, all of the evaluated
      systems are able to meet most of the functional needs of a materials management
      department. However, we did uncover significant differences in the quality of
      service and support provided by each vendor, and our ratings reflect these
      differences: we rated two of the systems Acceptable--Preferred and four of the
      systems Acceptable. We have not yet rated the seventh system because our user
      experience information may not reflect the vendor's new ownership and management.
      When this vendor provides the references we requested, we will interview users
      and supply a rating. We caution readers against basing purchasing decisions
      solely on our ratings. Each hospital must consider the unique needs of its users
      and its overall strategic plans--a process that can be aided by using our Process
      Evaluation and Needs Assessment Worksheet. Our conclusions can then be used to
      narrow down the number of vendors under consideration...

PMID- 8655345
TI  - [Pathophysiology and therapy of mucoviscidosis].

PMID- 8655346
TI  - [Therapeutic guidelines for acute treatment of penetrating and blunt neck
      trauma].

PMID- 8655347
TI  - [Benzamil and mucoviscidosis. Primary culture of nasal mucosa as an
      electrophysiologic in vitro model].
AB  - The genetic disease cystic fibrosis (CF) is characterized by a defect in the gene
      encoding for an epithelial chloride channel. This gene product, cystic fibrosis
      transmembrane conductance regulator (CFTR), in turn leads to a decreased chloride
      secretion. When this occurs sodium absorption is increased drastically because of
      an up-regulation of the epithelial sodium channel. In airway epithelia these
      changes in ion permeabilities result in dehydration of the mucus blanket and
      impaired mucociliary clearance, and subsequently lead to chronic infections of
      the airways. In this study we established a primary cell culture of human nasal
      epithelium from CF and non-CF patients. The increased transepithelial potential
      in CF exclusively was due to the greater sodium absorption. In previous studies,
      amiloride was found to specifically block the epithelial sodium channel.
      Inhalation of nebulized amiloride has been used clinically in the treatment of CF
      to inhibit sodium absorption and exert a secondary effect on water withdrawal. In
      the present cell culture model benzamil, an amiloride analogue, was found to
      inhibit sodium absorption completely, but at strikingly lower concentrations than
      amiloride. This raises the possibility of using benzamil for inhalation and to
      provide better efficacy in the symptomatic therapy of patients with CF.

PMID- 8655348
TI  - [Current aspects in diagnosis and therapy of carotid artery kinking].
AB  - Elongation, coiling and/or kinking of the interal carotid artery occur in 10-25%
      of the population. While coiling of the internal carotid artery is ascribed to
      embryological causes, elongation and kinking are due to atherosclerosis or
      fibromuscular dysplasia. Seventy-seven patients with carotid kinking were
      examined using different diagnostic imaging methods. Of these, 64 underwent
      surgery because of cerebrovascular symptoms that ranged from local disturbances,
      vertigo, diplopia and cerebrovascular insufficiency producing ischemic attacks or
      infarction. The treatment of choice was surgical correction of the carotid
      kinking in symptomatic cases and, if indicated, endarterectomy of atherosclerotic
      lesions of the internal carotid artery to prevent ischemic stroke. Because of the
      anatomical position of the interal carotid artery kink there is a potential risk
      of complications in head and neck surgery. For this reason, the presence of
      carotid kinking should be excluded preoperatively by means of non-invasive
      diagnostic imaging, such as afforded by ultrasonic testing. The merits of the
      different diagnostic imaging methods to diagnose internal carotid artery disease
      were compared and discussed.

PMID- 8655349
TI  - [Mucociliary clearance of radically operated maxillary sinuses and effect of
      endoscopic ethmoid bone revision on the mucociliary system].
AB  - Twenty-six maxillary sinuses (of 20 patients) were studied following Caldwell-Luc
      procedures. Surgery had been performed between 1 to 27 years previously. Follow
      up studies included nasal endoscopy, coronal computed tomography and camera
      sequence scintigraphy. Findings demonstrated that normalization of disturbed
      mucosal function was possible after surgery. Indications for revision endoscopic
      sinus surgery are discussed, as are the limitations of surgery.

PMID- 8655350
TI  - [Transfacial approach, craniofacial resection and midfacial degloving in surgery
      of malignant tumors of the anterior cranial base and adjacent paranasal sinuses].
AB  - Malignancies of the nose, paranasal sinuses and anterior skull base are
      characterized by their hidden locations and late clinical manifestation. This
      explains why most of the patients at the University of Tubingen were diagnosed in
      an advanced tumor stage (15 T1/T2; 33 T3/T4). Surgical treatment was possible in
      35 cases and depended on tumor location and extent. A lateral rhinotomy for a
      transfacial approach was performed in 8 tumors of the middle level and 6 tumors
      of the upper level as described by Sebileau. An advantage of this procedure was
      the exposure provided with a working direction parallel to skull base and orbit
      allowing a secure en bloc resection. In 9 cases the malignant growth was
      localized in the upper level infiltrated the anterior skull base and required a
      craniofacial resection. An alternative to transfacial resection of nasal and
      sinus tumors was the midfacial degloving technique. Without creating visible
      facial scars we were able to resect reliably 5 malignancies of the middle level
      that extended in part to the sphenoid sinus and the nasopharynx. Complications
      occurred in 2 cases. When also considering non-malignant tumors (n = 42), the
      following complications occurred with this technique: stenosis of the lacrimal
      duct, stenosis of the nasal vestibule and a perceptive disorder of the
      infraorbital nerve. Endonasal surgery was restricted to small malignancies of the
      nasal cavity. In contrast, surgical treatment of advanced tumors required a wide
      and clear three-dimensional exposure for an oncologically secure resection.

PMID- 8655351
TI  - [Use of self-organizing neural networks (Kohonen maps) for classification of
      voice acoustic signals exemplified by the infant voice with and without time
      delayed auditory feedback].
AB  - Subjective and auditory assessment of the voice is now more commonly being
      replaced by objective voice analysis. Because of the amount of data available
      from computer-aided voice analysis, subjective selection and interpretation of
      single data sets remain a matter of experience of the individual investigator.
      Since neuronal networks are widely used in telecommunication and speech
      recognition, we applied self-organizing Kohonen networks to classify voice
      patterns. In the phase of "learning," the Kohonen map is adapted to patterns of
      the primary signals obtained. If, in the phase of using the map, the input signal
      hits the field of the primary signals, it will resemble them closely. In this
      study, we recorded newborn and young infant cries using a DAT recorder and a high
      quality microphone. The cries were elicited by wearing uncomfortable headphones
      ("cries of discomfort"). Spectrographic characteristics of the cries were
      classified by 20-step bark spectra and then applied to the neuronal networks. It
      was possible to recognize similarities of different cries of the same children
      and interindividual differences, as well as cries of children with profound
      hearing loss. In addition, delayed auditory feedback at 80 dB SL was presented to
      27 children via headphone using a three-headed tape-recorder as a model for
      induced individual cry changes. However, it was not possible to classify short
      term changes as in a delayed feedback procedure. Nevertheless, neuronal networks
      may be helpful as an additional tool in spectrographic voice analysis.

PMID- 8655353
TI  - [Sensible applications of modern hearing aid technology].

PMID- 8655352
TI  - [A case of "midline granuloma" in a 29-year-old patient].
AB  - The term "(lethal) midline granuloma" originates from the disease's clinical
      presentations, including various granulomatous, inflammatory and destructive
      changes as well as necrosis of the midface. The present paper discusses the case
      of a 29-year-old woman with a midline granuloma involving the left palatal cleft
      and affecting the nose and naso-maxillary sinus. In terms of the currently
      available literature the difficulties are shown in diagnosing "midline granuloma"
      from other possible diseases using histomorphological criteria. Various therapies
      are discussed, including those used in the present case.

PMID- 8655354
TI  - Longitudinal induced IL-2 mRNA monitoring in renal transplant patients
      immunosuppressed with cyclosporine and in unmodified canine renal transplant
      rejection.
AB  - Immune monitoring of transplant patients to define optimal immunosuppression
      continues to be important, as rejection occurs despite adjustment of dosaging of
      CsA or even FK506 to achieve "therapeutic-range" blood levels. Because CsA is
      known to inhibit upregulation of IL-2 mRNA transcription, we prospectively
      sequentially measured (induced) IL-2 mRNA in PHA-stimulated PBMC cultures from
      transplant recipients of kidneys from living-related donors (n = 15) using a
      quantitative PCR assay, with a potential 24-hour turnaround time, to define
      immunologic events in real time. Reproducible individual patient sensitivity or
      refractoriness to CsA was determined pretransplant, by adding a range of CsA
      concentrations to the PBMC cultures and constructing induced IL-2 mRNA regression
      inhibition curves. However, this was not predictive of rejection episodes, but
      did correlate well with individual differences in IL-2 mRNA levels
      posttransplant, despite similar maintenance trough blood concentrations of CsA
      between patients. In this prospective study, seven patients experienced rejection
      episodes despite therapeutic CsA trough levels. Three of these, plus one not
      receiving CsA therapy, who happened to be prospectively tested at the time that
      rejection was clinically diagnosed, had a decrease in induced IL-2 mRNA before
      treatment was instituted. As a correlation to this observation in patients,
      induced IL-2 mRNA levels in unmodified rejection were sequentially measured in
      PBMC cultures in autologous vs allogeneic canine renal transplants and IL-2, IL
      10, TNF-alpha, and IFN-gamma mRNA were also measured in kidney biopsies.
      Sequential PHA lymphoproliferation assays of [3H] thymidine incorporation on
      patient and dog PBMC cultures were also performed. Similar to the observations in
      patients, unmodified rejection in the canine renal allograft model also was
      accompanied by a decline of PHA-induced IL-2 mRNA in PBMCs as the serum
      creatinine concentrations became elevated. In the dog kidney biopsies at later
      phases of rejection, IL-10 mRNA levels were also significantly elevated (p =
      0.032).

PMID- 8655355
TI  - Trafficking of major histocompatibility complex class II molecules through
      intracellular compartments containing HLA-DM.
AB  - The endosomal site(s) where MHC class II molecules become competent to bind
      antigenic peptide has not been completely characterized. We identified endocytic
      compartments through which newly synthesized MHC class II molecules move prior to
      their expression on the plasma membrane. The compartments co-sediment with
      lysosomes in the most dense regions of Percoll gradients. The appearance of
      proteolytic fragments of the invariant chain (I chain), namely leupeptin-induced
      proteins (LIPs) and class-II-associated invariant chain peptides (CLIP), in this
      region of the gradient suggests that the release of MHC class II molecules from I
      chain association occurs within these vesicles. The formation of SDS-stable alpha
      beta dimers indicated that MHC class II molecules contained within these
      compartments are receptive to peptide binding. A majority of the HLA-DM protein
      was found in the same region of the Percoll gradient, consistent with its
      established function in MHC class-II-restricted antigen presentation.
      Immunoelectron micrographs of dense-sedimenting compartments indicated that I
      chain, MHC class II, and DM molecules are contained within both multivesicular
      and multilamellar vesicles. The final stages of I chain dissociation from MHC
      class II molecules and DM-mediated peptide loading probably occur in these
      compartments.

PMID- 8655356
TI  - Association of celiac disease with microsatellite polymorphisms close to the
      tumor necrosis factor genes.
AB  - Celiac disease is tightly linked to the MHC class II region on chromosome 6. We
      have studied two highly polymorphic microsatellite loci, TNFa and b, near the TNF
      genes in the class III region of the MHC, for evidence of their association to
      CD, as compared to a control population. Our findings show that the
      microsatellite allele most significantly associated with the disease is TNFb3,
      which is found in 86.3% of CD patients versus 24.5% of controls, with allele
      frequencies of 0.5392 and 0.1290, respectively (p < 0.001). The TNFa2 allele had
      a frequency of 0.6122 in CD patients and 0.2627 in controls (p < 0.001), with
      phenotype frequencies of 87.8% and 50.0%, respectively. TNFa6 and -a11 and TNFb5
      have significantly reduced frequencies in CD patients. TNFb3 shows a maximal
      level of linkage disequilibrium with HLA-DQB1*0201 in celiac patients. However,
      while the DQB1*0201/TNFa2 haplotype was strongly associated with CD, DQB1*0201
      was not significantly in linkage disequilibrium with TNFa2, suggesting that TNFa2
      is independently associated with CD. This association could have functional
      significance as TNFa2 has been correlated with high TNF production.

PMID- 8655357
TI  - HLA-B*1303: a new example of poor correlation between serology and structure.
AB  - The HLA-B locus discloses a higher number of alleles and more complex serologic
      patterns than those observed for the HLA-A locus. In this article we describe the
      molecular structure and serologic details of a novel HLA-B allele, B*1303. B*1303
      has been serologically defined as a B21 Bw4-associated molecule, whereas its
      primary structure is closely related to B13 alleles. In fact, only three
      nucleotide and two amino acid substitutions were found with respect to the
      Caucasian B*1302 allele. In contrast, there were 10, 14, and 16 amino acid
      substitutions when compared to B*4901, B*5001, and B*4005, respectively.
      Serologic analysis definitively supports the essential role of leucine 145 within
      the B13-specific epitope. Furthermore, the involvement of glutamic 163 in the
      definition of both the specific B21 and polyspecific B15,B57 epitopes is
      suggested. B*1303 constitutes a new example of how serology can give a distorted
      point of view of the structural relationship among alleles.

PMID- 8655358
TI  - DRB1*1316: evolutionary and functional implications of a novel polymorphism at
      codon 86.
AB  - HLA-DRB1 molecules contain extensive polymorphism localized to specific
      functional regions of the antigen binding site (ABS). Position 86 of HLA-DRB1
      molecules modulates a hydrophobic pocket in the ABS which acts as a peptide
      anchoring site [1]. We report the nucleotide sequence of HLA-DRB1*1316 which is
      identical to HLA-DRB1*1301 and *1302 except at codon 86. The novel allele encodes
      aspartate rather than valine or glycine at position 86. Val86 and Gly86 have been
      exclusively observed in thousands of oligotyped specimens; thus Asp86 is a rare
      polymorphism which is significant with respect to hypotheses concerning evolution
      and structure-function relationships of HLA-DRB1 molecules.

PMID- 8655359
TI  - The toxic shock syndrome toxin-1 induces anergy in human T cells in vivo.
AB  - TSST-1 is a Staphylococcus aureus-derived superantigen which has been implicated
      in the pathogenesis of toxic shock syndrome. In mice, superantigen-induced
      proliferation is followed by deletion or anergy of reactive T cells. So far,
      superantigen-induced T-cell anergy has not been observed in humans. We therefore
      examined PBMCs derived from a 15-year-old patient suffering from severe toxic
      shock syndrome. Markedly elevated levels of circulating TSST-1-reactive T cells
      were found by cytofluorometric analysis. Upon in vitro restimulation with TSST-1,
      hyporesponsiveness of TSST-1-responsive V beta 2+ T cells was detected, thus
      confirming results obtained in the murine system.

PMID- 8655360
TI  - Uniparental maternal disomy 6 in a renal transplant patient.
AB  - HLA analysis of the family of a renal transplant patient revealed an extremely
      rare condition. On repeated typings the only demonstrable HLA antigens shown in
      the propositus were from the maternal haplotype, HLA-A11,-B46,-CW1,-DR14,-DQ1. No
      paternal antigens could be demonstrated either by serologic or by DNA-typing
      methods. A paternity investigation was carried out to exclude the possibility of
      the legal father not being the biological father. The results of this
      investigation showed a paternity index I = > 20000 and a fatherhood probability W
      = > 99.995%. Karyotyping of the patient showed two normal chromosomes 6 and no
      other chromosomal abnormalities. Maternal isodisomy was demonstrated from the
      analysis of polymorphic DNA markers, involving the short as well as the long arm
      of chromosome 6. These data are consistent with this patient having the first
      uniparental maternal disomy 6 reported (inheritance of two identical chromosome 6
      haplotypes from the mother and none from the father).

PMID- 8655361
TI  - Identification and DNA typing of two Cw7 alleles (Cw*0702 and Cw*0704) in
      Japanese, with the corrected sequence of Cw*0702.
AB  - Two alleles encoding HLA-Cw7 antigens, tentatively called C7J1 and C7J2, have
      been identified in Japanese using a PCR-SSCP method. The nucleotide sequence of
      full-length C7J1 cDNAs showed a high degree of homology to the reported Cw*0702
      sequence except in exon 1. We then resequenced the allele carried by the cell
      line JY in which Cw*0702 was first identified, according to a request from the
      WHO Nomenclature Committee. The results revealed complete identity between the
      corrected Cw*0702 sequence and the C7J1 sequence. On the other hand, the C7J2
      sequence was completely identical to the reported Cw*0704 sequence. Sequences
      specific for Cw*0702 and Cw*0704 were confirmed using PCR-RFLP and PCR-SSO
      methods. Moreover, association analysis with other HLA locus alleles showed
      positive associations of Cw*0702 with HLA-B7, -B39, and -B67 and of Cw*0704 with
      HLA-B70 in Japanese.

PMID- 8655362
TI  - The 8.5-kb PstI allele of the stress protein gene, Hsp70-2: an independent risk
      factor for systemic lupus erythematosus in African Americans?
AB  - SLE is dramatically more prevalent in persons of African descent than in other
      populations. Several genes in the class III region of the MHC have been
      considered as potential susceptibility loci for this disorder, but the primary
      association(s) remains unknown. The stress protein gene, hsp70-2, is of special
      interest in this regard because it encodes a protein functionally relevant to
      antigen processing and presentation and has itself been identified as a putative
      susceptibility locus in organ-specific autoimmune diseases in Caucasians. To
      clarify the relationship of the hsp70-2 gene to SLE in African Americans, genomic
      DNA from 46 patients and 42 appropriately matched control subjects was analyzed
      for an RFLP of the hsp70-2 gene using the probe pH2.3 and the restriction
      endonuclease PstI, which identifies alleles of 8.5 and 9.0 kb. The 8.5-kb hsp70-2
      allele was associated with SLE in this population (X2 = 8.2473, p = 0.0044). This
      association was not due to linkage disequilibrium with the C4A deletion or with
      HLA-DR3, as has been reported in Caucasians with IDDM. These data suggest that
      the 8.5-kb hsp70-2 allele may be an independent susceptibility marker for SLE in
      African Americans.

PMID- 8655363
TI  - Cytolytic effector mechanisms of human CD4+ cytotoxic T lymphocytes.
AB  - To elucidate mechanisms by which human CD4+ cells mediated cytolytic activity, we
      studied the expression of cytolytic proteins and the effects of inhibitors and
      mAbs on T-cell clones. Of seven cytolytic CD4+ clones, three were specific for
      the HLA-DR17, while four recognized DR18. Anti-HLA-DR mAb and anti-CD4 mAb
      blocked lysis. In addition, N alpha-p-tosyl-L-lysine chloromethylketone (TLCK), a
      serine esterase inhibitor, as well as cytochalasin B and monensin, antagonists of
      secretory pathways, inhibited CD4+ CTLs, whereas the absence of extracellular
      Ca+2 or the presence of Ca+2 channel blockers partially inhibited cytotoxicity.
      CD4+ CTLs induced apoptosis of target cell nuclei and membrane damage
      simultaneously. The CD4+ clones synthesized perforin and granzyme B and expressed
      the granule-associated protein TIA-1. Our studies indicate that two distinct
      mechanisms may contribute to cytolysis by CD4+ clones: (1) a Ca+2-dependent
      mechanism associated with the cytotoxic granules and (2) a Ca+2-insensitive
      mechanism.

PMID- 8655364
TI  - Evolution of the Radiation Therapy Oncology Group clinical trials for head and
      neck cancer.
AB  - During the past 25 years, the Radiation Therapy Oncology Group (RTOG) has played
      a major role in head and neck cancer clinical research. The major research themes
      for recent and currently active trials have been: (a) combined modality therapy,
      (b) altered fractionation radiotherapy, (c) hypoxic cell sensitizers, (d) organ
      preservation, (e) chemoprevention, and (f) clinical/laboratory correlations. For
      advanced operable disease, the RTOG showed improved local-regional control with
      postoperative radiotherapy as compared to preoperative radiotherapy for carcinoma
      of the supraglottic larynx and hypopharynx. This established the use of surgery
      followed by postoperative radiotherapy as the standard treatment in subsequent
      RTOG and Intergroup trials for operable disease. For advanced inoperable disease,
      the RTOG demonstrated the feasibility of testing altered fractionation
      radiotherapy in a multiinstitutional clinical trials setting. A Phase III trial
      comparing hyperfractionation and accelerated fractionation to conventional
      fractionation is now in progress. Phase I/II combined modality studies
      established the efficacy of concurrent high-dose cisplatin and radiotherapy in
      the treatment of advanced disease and provided the basis for further testing in
      Phase III trials for nasopharyngeal carcinoma, larynx preservation, and high-risk
      advanced operable disease. Analysis of the extensive RTOG Head and Neck Cancer
      database established the incidence of second malignancies and their adverse
      impact on patients whose initial tumors were cured by radiotherapy, and provided
      the basis for chemoprevention trials. Recursive partitioning analysis identified
      6 distinct prognostically homogeneous patient groups based on pretreatment tumor
      or patient characteristics and/or treatment variables. Retrospective analysis
      identified tumor p105 antigen density as an independent prognostic indicator in
      patients irradiated for head and neck cancer. Future trials will continue to
      focus on the reduction of morbidity and mortality, and improvement of the quality
      of life of head and neck cancer patients through innovative radiotherapy
      delivery, multimodality approaches, use of chemical and biological modifiers, and
      other novel therapies, identification of clinical and biological prognostic
      indicators, and prevention or diminution of acute morbidity and late
      complications of the disease and its treatment.

PMID- 8655365
TI  - Local control of T3 carcinomas after accelerated fractionation: a look at the
      "gap".
AB  - PURPOSE: To study the effects of midcourse treatment break or gaps related to the
      local control of T3 carcinoma of the oropharynx and larynx following accelerated
      hyperfractionated radiation therapy. METHODS AND MATERIALS: All patients were
      treated at the Massachusetts General Hospital from 1979 through 1994 with
      treatment consisting of 1.6 Gy per traction, two fractions a day for the
      treatment of T3 carcinoma of the oropharynx and larynx. They were entered in the
      head and neck data base. Their treatment dates, treatment breaks, and doses vs.
      local control were analyzed and compared. A p-value of 0.05 was considered
      statistically significant. RESULTS: A total of 162 patients were available for
      review. Due to the acute severe mucosal effects, most of the patients required a
      midcourse pause or "break" after a dose of 38.4-48 Gy before treatment could be
      resumed and completed. The data indicate that (a) prolongation of the treatment
      gap for more than 14 days, (b) total treatment course longer than 45 days, (c)
      total dose less than 67 Gy, and (d) male gender adversely affected local control.
      In spite of the gaps, the female patients with advanced carcinomas enjoyed the
      benefits of improved local control after the accelerated hyperfractionated
      radiation therapy. CONCLUSIONS: Accelerated hyperfractionation radiation therapy
      using 1.6 Gy per fraction/twice-a-day (b.i.d.) for a total dose of 70.4 Gy in 6
      weeks is effective in achieving high local control of T3 squamous cell carcinoma
      of the oropharynx and larynx. The midcourse treatment gap should be as short as
      possible with the projected total dose and time. Should the gaps be unduly
      prolonged due to various circumstances, further increase in the total dose, for
      example, 72-75 Gy, and/or increase of the fraction sizes, for example, 1.8-2.0
      Gy/f b.i.d. after the gap may be necessary to compensate for the adverse effects
      of the tumor regeneration from the prolonged gap.

PMID- 8655366
TI  - Management of minor salivary gland carcinomas.
AB  - PURPOSE: To assess the role of radiotherapy alone or in combination with surgery
      in the treatment of patients with malignant minor salivary gland carcinomas.
      METHODS AND MATERIALS: Between October 1964 and November 1992, 95 patients with
      minor salivary gland carcinomas of the head and neck received radiotherapy with
      curative intent. Eighty-seven patients were previously untreated, and 8 were
      treated for postsurgical recurrence. Fifty-one patients were treated with
      radiotherapy alone, and 44 were treated by surgical resection plus radiotherapy.
      Patients were staged according to the 1983 American Joint Committee on Cancer
      (AJCC) staging criteria for squamous cell carcinomas. RESULTS: The 20-year
      actuarial rate of local control was 57% with no significant difference according
      to histologic type. When tumor stage was taken into consideration, there were no
      significant differences in local control according to tumor site. The 12-year
      actuarial probability of distant metastases was 40% (19% as the only site of
      failure). In multivariate analyses, local control was significantly affected only
      by tumor stage and treatment type (combined therapy better than radiotherapy
      alone); tumor stage was a significant predictor of cause-specific survival and
      freedom from relapse. Freedom-from-relapse rates were higher for patients who
      received combined treatment (p = 0.068). CONCLUSIONS: Treatment of minor salivary
      gland carcinomas is usually by combined surgery and radiotherapy, but there are
      situations where surgery alone or radiotherapy alone may be used. The ability to
      control these tumors with radiotherapy alone is not widely recognized. In the
      present series, the tumor was locally controlled in 20 patients with previously
      untreated primary lesions after radiotherapy alone (2.5 to 21 years) and in 4
      other patients who were treated by radiotherapy alone for postsurgical recurrent
      tumor (3.5 to 14 years after radiotherapy). Contrary to the widely held belief
      that local recurrence after radiotherapy eventually develops in all patients with
      adenoid cystic carcinoma, local control has been maintained in 13 patients after
      radiotherapy alone; 5 of the 13 patients have been observed for 10 to 17 years.

PMID- 8655367
TI  - Comparison between normal tissue reactions and local tumor control in head and
      neck cancer patients treated by definitive radiotherapy.
AB  - PURPOSE: This study was conducted to test for the relationship between tumor and
      normal tissue radiosensitivity, by comparing local tumor control to the severity
      of acute and late normal tissue reactions in head and neck cancer patients
      treated by definitive radiotherapy. METHODS AND MATERIALS: Two hundred eighty-six
      patients with head and neck cancer who were treated at the University of Texas M.
      D. Anderson Cancer Center between 1983 and 1993 were selected for the study. Of
      these, 124 (43%) were treated by a concomitant boost regimen and 162 (57%) by
      hyperfractionation. All patients had at least 1 year of follow-up. The tumor
      stage distribution according to the 1992 American Joint Committee on Cancer
      (AJCC) staging system was as follows: T1, 3%; T2, 53%; T3, 40%; T4, 4%. The
      average doses delivered were 71.2 Gy and 76.2 Gy for the concomitant boost and
      hyperfractionation regimens, respectively, with no significant variation between
      patients. Acute and late reactions were recorded using the Radiation Therapy
      Oncology Group (RTOG)/European Organization for Research on Treatment of Cancer
      (EORTC) grading system (0 to 4). The median follow-up period was 38 months
      (range: 12-107 months). The time to local tumor recurrence was analyzed in
      relation to the severity of acute and late reactions expressed as the maximum
      recorded grades, and to the time intensity of acute mucositis, expressed as the
      area under the curve of mucositis grade vs. time. Univariate and multivariate
      analyses also included T stage, N stage, and site of origin as other prognostic
      variables, and were carried out using a proportional hazards model. RESULTS:
      Fifty-four patients (19%) suffered local failure. T stage was found to
      significantly influence local control (p = 0.009). There was a nonsignificant
      trend for higher failure rates in patients with maximum Grade 1 or 2 vs. those
      with Grade 3 or 4 acute mucositis (28 and 18%, respectively; p = 0.17). No
      correlation was found between the severity of late reactions and local tumor
      control after radiotherapy. Analysis by time intensity of mucositis revealed a
      wide variation between individuals with a nonsignificant trend for higher local
      failure rates in patients with low mucositis time intensity scores. CONCLUSIONS:
      These clinical results suggest a possible relationship between normal tissue and
      tumor radiosensitivity. However, additional studies with a larger numbers of
      patients, and using refined normal tissue endpoints that incorporate a time
      function are needed to fully elucidate this question.

PMID- 8655368
TI  - Preliminary results of a randomized trial comparing neoadjuvant chemotherapy
      (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in
      stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive
      effect on progression-free survival.
AB  - PURPOSE: Our Phase II trial using bleomycin, epirubicin, and cisplatin (BEC)
      protocol in the treatment of loco-regionally advanced undifferentiated
      nasopharyngeal carcinoma (UCNT) patients has shown encouraging results with high
      objective response, disease-free survival, and overall survival rates. To
      establish the value of this BEC regimen as neoadjuvant chemotherapy, we initiated
      in 1989 a large international Phase III trial. It compares three cycles of BEC
      followed by radiotherapy to radiotherapy alone. METHODS AND MATERIALS: From
      November 1989 to October 1993, 339 patients with negative metastases workup,
      stratified by accrual center have been randomized, 168 to radiotherapy alone and
      171 to chemotherapy plus radiotherapy. All patients characteristics were well
      balanced in both arms. There was a quality control/data verification by
      specialist panel (radiology, histology, radiotherapy, chemotherapy) and external
      policy board expert every 60-80 patients having completed treatment. RESULTS:
      With a median follow-up of 49 months (range: 23-70), despite an excess of
      treatment-related deaths in the neoadjuvant chemotherapy arm (8 vs. 1%), there is
      a significant difference in disease free survival favoring the chemotherapy arm
      (p < 0.01). The proportion of local and/or regional metastases was comparable in
      both arms. No difference in overall survival is seen but the numbers of events
      needed for analysis has not yet been reached. CONCLUSIONS: BEC type neoadjuvant
      chemotherapy has a significant impact in the natural history of UCNT. Further
      follow-up is needed to establish an eventual overall survival difference.

PMID- 8655369
TI  - Potential doubling time and clinical outcome in head and neck squamous cell
      carcinoma treated with 70 GY in 7 weeks.
AB  - PURPOSE: To study the predictive value of pretreatment potential doubling time
      and labeling index, as measured by flow cytometry in patients with head and neck
      squamous cell carcinoma treated with conventional radiotherapy. METHODS AND
      MATERIALS: 70 patients with a squamous cell carcinoma of the oropharynx and 4
      patients with another involved head and neck site were entered in this
      prospective study. The duration of the S phase (TS), the labeling index (LI), and
      the potential doubling time (Tpot) were obtained by flow cytometry measurements
      of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine to
      the patient. The treatment consisted of 70 Gy in 7 weeks, 2 Gy per fraction and
      five fractions per week. RESULTS: The mean and median LI were 7.7% (standard
      deviation, SD: 5.0) and 6.3%, respectively. The mean and median TS were 9.3 h
      (SD: 3.6) and 8.3 h, respectively. The mean and median Tpot were 5.6 days (SD:
      5.4) and 4.6 days, respectively. No significant relationship was found between
      the Tpot or LI and the tumor stage (T), nodal status (N), histological grade, and
      the site of the primary within the oropharynx. The only parameter significantly
      associated with an increased risk of local relapse was the tumor stage (p <
      0.001). The mean Tpot for the group of tumors that relapsed locally was 5.3 days
      (SD: 3.3), compared to 6.1 days (SD: 4.08) for those who did not relapse locally
      (NS). Two parameters were significantly associated with a decrease in disease
      free (DFS) and overall survival, namely the tumor stage (p < 0.005, and p <
      0.001, respectively, for DFS and overall survival) and nodal involvement (p =
      0.02 and (p < 0.005, respectively, for DFS and overall survival). The TS, LI, DNA
      index, and Tpot were not significantly associated with local relapse, DFS, and
      survival, either in the univariate or in the multivariate analysis. CONCLUSIONS:
      The method used to evaluate tumor cell kinetics did not provide clinically
      relevant kinetic parameters for this type of cancer. The classic prognostic
      factors (tumor stage and nodal status) were strongly associated with clinical
      outcome.

PMID- 8655370
TI  - Squamous cell carcinoma of the pharyngeal walls treated with radiotherapy.
AB  - PURPOSE: To assess the impact of fractionation schedule, chemotherapy, and tumor
      location on local control and survival in patients treated with definitive
      irradiation for carcinoma of the pharyngeal walls. METHODS AND MATERIALS: Between
      May 1971 and December 1991, 74 patients with previously untreated squamous cell
      carcinoma of the pharyngeal walls (excluding nasopharynx, tonsil, and pyriform
      sinus) were treated with radical megavoltage irradiation with or without
      chemotherapy at Oregon Health Sciences University. RESULTS: Two-year local
      control rates by stage were: T1: 100%, T2: 55%, T3: 31%, and T4: 29% . Twice-a
      day irradiation improved local control rates as compared with once-a-day
      irradiation for patients with Stage T3 lesions, with 5 out of 7 (71.4%) vs. 4 out
      of 19 (21%) patients controlled at 2 years (p = 0.015). No improvement was seen
      in 2-year local control of all stages when chemotherapy was used in conjunction
      with once-a-day fractionation; however, six of eight patients (75%) treated with
      twice-a-day irradiation combined with either induction or concurrent chemotherapy
      had local control. The 2-year local control rate of 100% (6 out of 6) for the
      group of patients treated with concurrent chemotherapy and b.i.d. irradiation
      (all with Stage T3 and T4 tumors) is a dramatic improvement over the 2-year local
      control rate of 30% (10 out of 33) for our entire group of patients with Stage T3
      and T4 tumors. Local control rates did not differ by tumor location on the
      pharyngeal walls. Adjusted disease-specific survival rates by stage were: 1:
      100%, II: 85%, III: 58%, IV: 40%. Overall survival rates by stage were: I: 75%,
      II: 67%, III: 33%, IV: 30%. CONCLUSION: We advocate radical irradiation as the
      primary therapy for pharyngeal wall carcinomas with the use of twice-a-day
      fractionation for Stages T2-T4. Our preliminary results with concurrent
      chemotherapy and b.i.d. irradiation for advanced T3 and T4 tumors appear to be
      comparable to reported results with hyperfractionated radiation alone. The
      relative contribution of chemotherapy to b.i.d. irradiation cannot be determined
      from this small retrospective series; however, in view of the relatively poor
      results for patients with advanced stage disease, we feel this treatment
      combination deserves further investigation.

PMID- 8655371
TI  - Nasopharyngeal carcinoma in children: retrospective review of 50 patients.
AB  - PURPOSE: To report a retrospective analysis of epidemiologic, clinical, and
      therapeutic aspects of 50 children with newly diagnosed nasopharyngeal carcinoma
      who were treated in a single institution over a period of 18 years. METHODS AND
      MATERIALS: Thirty-two male and 18 female children ranging from 5 to 16 years,
      accounted for 7.2% of all nasopharyngeal carcinoma cases and 52% of childhood
      nasopharyngeal malignancies. Histopathology was World Health Organization Type 3
      carcinoma in 45, World Health Organization Type 2 in 4, and World Health
      Organization Type 1 in one patient. Two of the patients had missing information
      for staging and treatment evaluation. Disease extent was T1 (n = 4), T2 (n = 9),
      T3 (n = 21), and T4 (n = 14); N0 (n = 1), N1 (n = 6), N2 (n = 12), and N3 (n =
      29). Six patients had base of skull invasion, two had cranial nerve palsies, and
      six had both. One patient had M1 disease on admission. Twenty-three patients were
      treated with irradiation only. Thirteen patients received adjuvant, and 12 had
      neoadjuvant chemotherapy in addition to radiotherapy. Patients received 50-72 Gy
      to the primary tumor and involved nodes, and 45-50 Gy to uninvolved regions.
      Chemotherapy consisted of combinations including cisplatin, bleomycin,
      epirubicin, 5-fluoroucil, and cyclophosphamide. RESULTS: Thirty-eight (79%)
      patients attained locoregional control. Overall, 22 patients are alive without
      relapse 6-195 months from diagnosis. Thirteen patients had 21 relapses, at local
      and/or regional sites (43%), distant sites (48%), or both (9%). The median time
      for first relapse was 8 months. Overall, the 5-and 10-year survival rates were 52
      and 52%, respectively, and the failure-free survival rates were both 53%. The
      results of three distinct treatments given in subsequent time periods were not
      statistically different. Three second malignancies occurred 33-156 months
      following nasopharyngeal carcinoma diagnosis. CONCLUSION: In the current series,
      nasopharyngeal carcinoma patients under the age of 16 accounted for 7.2% of all
      nasopharyngeal carcinoma cases. Whereas the impact of chemotherapy on long-term
      survival remains to be determined by randomized studies, the results suggest that
      more effective treatment regimens and long-term follow-up are necessary for
      children with nasopharyngeal carcinoma.

PMID- 8655372
TI  - Radiosurgery for hemangioblastoma: results of a multiinstitutional experience.
AB  - PURPOSE: Between June 1988 and June 1994. 38 hemangioblastomas were treated with
      stereotactic radiosurgery (SR) at three SR centers to evaluate the efficacy and
      potential toxicity of this therapeutic modality as an adjuvant or alternative
      treatment to surgical resection. METHODS AND MATERIALS: SR was performed using
      either a 201-cobalt source unit or a dedicated SR linear accelerator. Of the 18
      primary tumors treated, 16 had no prior history of surgical resection and were
      treated definitively with SR and two primary lesions were subtotally resected and
      subsequently treated with SR. Twenty lesions were treated with SR after prior
      surgical failure (17 tumors) or failure after prior surgery and conventional
      radiotherapy (three tumors). Eight patients were treated with SR for multifocal
      disease (total, 24 known tumors). SR tumor volumes measured 0.05 to 12 cc
      (median: 0.97 cc). Minimum tumor doses ranged from 12 to 20 Gy (median: 15.5 Gy).
      RESULTS: Median follow-up from the time of SR was 24.5 months (range: 6-77
      months). The 2-year actuarial over-all survival was 88 +/- 15% (95% confidence
      interval). Two-year actuarial freedom from progression was 86 +/- 12% (95%
      confidence interval). The median tumor volume of the lesions that failed to be
      controlled by SR was 7.85 cc (range: 3.20-10.53 cc) compared to 0.67 cc (range:
      0.05-12 cc) for controlled lesions (p - 0.0023). The lesions that failed to be
      controlled by SR received a median minimum tumor dose of 14 Gy (range: 13-17 Gy)
      compared to 16 Gy (range: 12-20 Gy) for controlled lesions (p = 0.0239). Seventy
      eight percent of the surviving patients remained neurologically stable or
      clinically improved. There were no significant permanent complications directly
      attributable to SR. CONCLUSIONS: This report documents the largest experience in
      the literature of the use of SR in the treatment of hemangioblastoma. We conclude
      that SR: (a) controls the majority of primary and recurrent hemangioblastomas;
      (b) offers the ability to treat multiple lesions in a single treatment session,
      which is particularly important for patients with Von Hippel-Lindau Syndrome; and
      that (c) better control rates are associated with higher doses and smaller tumor
      volumes.

PMID- 8655373
TI  - Treatment results for 149 medulloblastoma patients from one institution.
AB  - PURPOSE: Retrospective analysis of patients with medulloblastoma to determine the
      effectiveness of previous treatments for medulloblastoma and plan for future
      management strategies. METHODS AND MATERIALS: During the period March 1976 to
      December 1991, 172 patients with cerebellar medulloblastoma were referred to King
      Faisal Specialist Hospital and Research Center. One hundred and forty-nine
      patients were treated with curative intent. There were six postoperative deaths,
      and 10 patients planned for radiotherapy treatment failed to complete the
      prescribed course. One hundred and thirty-three patients completed a course of
      radiotherapy after surgery. Adjuvant chemotherapy was not used routinely (six
      patients only). Tumors were staged retrospectively according to the Chang staging
      system. There were no T1 patients, 32 patients had T2 tumors, 76 had T3 tumors,
      and 29 had T4 tumors. The T stage could not be allocated in 12 patients. Ninety
      nine patients required a shunting procedure either pre- or postoperatively. Forty
      six patients had complete resection of tumor, 91 had incomplete resection, and 6
      patients had biopsy only. The extent of resection could not he determined in six
      patients. The median radiation dose for the whole brain was 34 Gy, spine 32.5 Gy,
      and posterior fossa 52.8 Gy. Fraction sizes ranged from 1.7-1.8 Gy for
      craniospinal fields and 2 Gy for the posterior fossa boost. Seventy percent
      completed the prescribed course within 7 weeks. RESULTS: Actuarial survival for
      the whole group of 149 patients was 53% at 5 years and 38% at 10 years. On
      univariate analysis, patients with T2 tumors did significantly better as compared
      to patients with T3 and T4 tumors. Survival of patients who had clinical and
      radiological complete resection of tumor at surgery was significantly better than
      patients with incomplete tumor removal. The presence of a ventriculoperitoneal
      (VP) shunt had a significant negative impact on survival. Treatment failure by
      site was analyzed with respect to the radiation dose. Doses greater than 50 Gy
      for the posterior fossa, and greater than 30 Gy for craniospinal axis, resulted
      in significantly better survival. On multivariate analysis, the only significant
      prognostic factor was the presence of a VP shunt in patients with T2 tumors.
      CONCLUSION: T stage, VP shunt, radiation doses and extent of surgery were
      important prognostic factors. In this study, radiation doses of more than 50 Gy
      to the posterior fossa and 30 Gy to the craniospinal axis resulted in improved
      survival.

PMID- 8655374
TI  - Radiotoxic effect and dosimetry of 67GA in multicellular spheroids as compared to
      single cells of the lymphoma cell line U715.
AB  - PURPOSE: The purpose of the present study was to investigate if there were
      differences between U715 spheroids and single cells in the radiotoxic effect of
      67Ga on cell growth and clonogenic capacity in vitro and to generate dosimetric
      approaches for the multicellular tumor model. METHODS AND MATERIALS: Human
      lymphoma U715 cells were cultured in vitro as single cells and multicellular
      spheroids, grown with the use of a combination of fibrin clot technique, spinner
      flasks, and liquid-overlay culture. Cells were incubated with 2.96-8.88 MBq/ml
      67Gallium for 4 days. Spheroids were dispersed to single cells by treatment with
      plasmin. Residual proliferative and clonogenic capacity after 67Ga incubation
      were assayed using the MTT-test and clonogenic test, respectively.
      Autoradiography was performed with 1 microm sections and Ilford L4 liquid
      photographic emulsion. Dosimetric approaches were made, based on the MIRD
      approach. RESULTS: During 67Ga incubation proliferation was inhibited. The
      residual proliferative or clonogenic capacity was inhibited by 8.88 MBq/ml for 39
      and 88%, respectively. For single cells with 6.66 MBq/ml these inhibitions were
      64 and 96%, respectively. Autoradiography showed an homogeneous distribution of
      67Ga in spheroids and single cells. In single cells a 2.1-3.5 times higher 67Ga
      uptake/cell than in spheroids produced an equitoxic effect. The uptake parameters
      were implemented in new dosimetric approaches and showed that the efficacy of
      intracellular 67Ga was two times higher in spheroid clusters than in single cells
      due to energy deposition of internal conversion electrons within the cell
      clusters with a mean diameter size of nine cells. Both for proliferative and
      clonogenic capacity the exponential survival curves were superimposed.
      CONCLUSIONS: With the new approaches made in our dosimetric model the discrepancy
      found between 67Ga accumulation and radiotoxic effect in spheroids as compared to
      single cells can be explained by additional effects of the crossfire of internal
      conversion electrons within clusters of about nine cells in diameter in
      spheroids. Only twice as much 67Ga was needed to reach equitoxic absorbed doses
      in spheroids than was needed in single cells. Such might be important for the use
      of 67Ga treatment of small metastasis of malignant lymphoma.

PMID- 8655375
TI  - Concurrent cisplatin-vindesine and hyperfractionated thoracic radiotherapy in
      locally advanced nonsmall cell lung cancer.
AB  - PURPOSE: Local failure is a major problem in locally advanced nonsmall cell lung
      cancer. The main objective of this Phase II trial was to test the feasibility of
      a combined concurrent radiotherapy and chemotherapy approach in an attempt to
      improve local control. METHODS AND MATERIALS: From December 1989 to December
      1992, 34 patients were included. The treatment schedule consisted of
      hyperfractionated radiotherapy (60 Gy in 48 fractions and 6 weeks with two daily
      sessions of 1.25 Gy), cisplatin (6 mg/m2 every day of radiotherapy), and
      vindesine (2.5 mg/m2 once weekly). After a 3-week rest period, two full cycles of
      cisplatin (120 mg/m2 on weeks 10 and 14) and vindesine (2.5 mg/m2 on weeks 11,
      12, and 13) were given. Treatment evaluation with thoracic computed scan,
      bronchoscopy, and bronchial biopsies was performed 3 months after completion of
      radiation therapy. Failure rates were estimated using a competing risk approach.
      RESULTS: The complete response rate was 50%. Local failure rates at 1 and 3 years
      were 53 and 56%, respectively. Distant metastases rates at 1 and 3 years were
      26.5 and 29%. Overall survival rates at 1, 2, and 3 years were respectively 53,
      33, and 12%. Severe esophagitis was observed in three patients (9%). Lethal
      toxicity was observed in two patients. CONCLUSION: This Phase II trial confirms
      the feasibility of this type of approach with specific dose reduction and
      suggests that it may improve local control compared to conventional approaches.

PMID- 8655376
TI  - A prospective study of cognitive functions following conventional radiotherapy
      for supratentorial gliomas in young adults: 4-year results.
AB  - PURPOSE: To evaluate the effects of limited field conventional cerebral
      radiotherapy (RT) on cognitive functions of adults. METHODS AND MATERIALS: A
      prospective neuropsychological study was performed on 17 patients who underwent
      conventional limited field RT for a low-grade glioma or for a good-prognosis
      anaplastic glioma. Results were compared with 14 control patients with low-grade
      gliomas who did not receive radiotherapy. RESULTS: A transient significant
      decrease of performances for the Reaction Time test was observed at 6 months in
      the irradiated group with return to baseline values 12 months post-RT.
      Subsequently, no other significant changes were observed over a 48-month follow
      up period in the irradiated and nonirradiated groups. Nonetheless, when the
      scores of each patient were considered over time instead of the mean values of
      the group, one irradiated patient (5.8%) experienced progressive deterioration
      while two irradiated patients (11.7%) experienced long-lasting improvement.
      Individual changes did not occur in the control group. CONCLUSION: This study
      suggests that a transient early delayed drop of neuropsychological performances
      at 6 months is frequent following limited field conventional RT, but the risk of
      long-term cognitive dysfunction after irradiation is low, at least in the first 4
      years after RT and when it is administered alone in young adults.

PMID- 8655377
TI  - Quantification of salivary gland function in thyroid cancer patients treated with
      radioiodine.
AB  - PURPOSE: Damage to salivary gland function following external irradiation has
      been documented. However, the extent of damage following radioiodine (131I)
      therapy for thyroid cancer has not been adequately studied. We evaluated salivary
      dysfunction in Ca-thyroid patients treated with therapeutic doses of 131I.
      METHODS AND MATERIALS: A simple acquisition and analysis protocol using 99mTcO4-
      (pertechnatate) and a gamma camera computer system was planned. The uptake of
      99mTcO4- by the salivary glands at 10 min and percent of excretion of 99mTcO4-
      from the glands in response to a sialogogue (lemon juice) was studied in 33
      patients treated with 1.369-38.702 GBq of 131I (Mean = 10.16 GBq, standard
      deviation = 7.659 GBq) in addition to 14 athyreotic controls. RESULTS:
      Significant damage to the salivary gland in terms of abnormal percent uptake or
      excretion was noted in 72.73% of the patients. Forty-eight percent of the
      patients treated with 131I showed asymmetrical involvement of the salivary
      complexes as opposed to none of the controls. Reduction in uptake of 99mTc4- or
      response to sialogogue was dose dependent, being more marked with higher
      radioiodine doses. Parotid glands were more affected than submandibular glands
      following 131I therapy. CONCLUSIONS: 131I therapy produces a significant effect
      on salivary gland function that is dose related and becomes evident over a period
      of several months after treatment.

PMID- 8655378
TI  - Operation and permanent low activity 125I brachytheraphy for recurrent high-grade
      astrocytomas.
AB  - Twenty-two adult patients with recurrent high grade astrocytomas [18 glioblastoma
      multiforme (GBM) and 4 anaplastic astrocytoma (AA) at time of implant] underwent
      therapy at the University of Washington from October 1991 through March 1995,
      with repeat craniotomy, maximal debulking of tumor, and placement of permanent
      low activity 125I seeds. Median age was 41 years and median Karnofsky performance
      status was 90. Median survival for the entire group was 65 weeks from the time of
      implant. For the subgroup of GBM patients, median survival was 64 weeks from the
      time of implant. One-year survival from the date of implant was 57% for the
      entire group and 59% for those with GBM. The site of first failure after implant
      was local (within 2 cm of the resection cavity) in 70%, distant (noncontiguous,
      beyond 2 cm) in 18% and concurrently local and distant in 12%. There was one case
      of symptomatic radiation injury that resolved with steroid therapy, and no
      patient required repeat craniotomy for parenchymal necrosis. For patients with
      recurrent GBM, treatment with resection and permanent low activity 125I
      brachytherapy yielded improved survival compared to an internal historical
      control group treated with resection and chemotherapy (p = 0.023). Craniotomy
      with maximal tumor debulking and placement of low activity 125I seeds yields
      encouraging results with minimal morbidity in patients with recurrent high-grade
      astrocytomas.

PMID- 8655379
TI  - Dose-volume histogram analysis of high dose rate intracavitary brachytherapy for
      uterine cervix cancer.
AB  - PURPOSE: We retrospectively analyzed the relationship between dose distribution
      and local control using a dose-volume histogram (DVH) in patients with cancer of
      the uterine cervix treated by definitive radiotherapy including intracavitary
      brachytherapy. METHODS AND MATERIALS: Twenty-five patients with squamous cell
      carcinoma of the uterine cervix who underwent definitive radiotherapy between
      August 1987 and April 1994 were selected for the present study. They included 15
      patients with local control and 10 patients with local recurrence. In principle,
      these patients were treated with 50 Gy of external beam pelvic radiotherapy and a
      point A dose of 24 Gy, in four fractions, of intracavitary brachytherapy. The
      DVHs of tumor volumes were calculated by superimposing three-dimensional (3D)
      dose distributions on computed tomography (CT) images taken before brachytherapy.
      RESULTS: Differential DVHs revealed a tendency for the portion of the total tumor
      volume to which the delivered dose was low to be larger in patients with local
      recurrence. The tumor volumes and the absolute dose volumes of which the absorbed
      dose was less than 24 Gy [DV (< 24 Gy)] were significantly larger in patients
      with local recurrence than those in local control patients (p = 0.02 and 0.03,
      respectively). The percent DV (<24 Gy) was not significantly different in the two
      groups. In patients with larger tumor volume, the absolute DV (<24 Gy) was also
      larger and a strong linear correlation was noted between them. CONCLUSIONS: The
      analysis of dose distribution of brachytherapy using DVH was useful to evaluate
      the quality of dose distribution quantitatively. The absolute dose volume was
      considered more important than the percent dose volume for evaluation of the
      clinical outcome. Our study suggested that unfavorable dose distribution for the
      tumor volume in brachytherapy was one of the reasons of poor local control in
      patients with large tumor volume.

PMID- 8655380
TI  - Computed tomography slice-by-slice target-volume delineation for stereotactic
      proton irradiation of large intracranial arteriovenous malformations: an
      iterative approach using angiography, computed tomography, and magnetic resonance
      imaging.
AB  - PURPOSE: Target-volume delineation for stereotactic irradiation is problematic
      for large and irregularly shaped arteriovenous malformations (AVMs). The purpose
      of this report is to quantify modifications in the target volume that result from
      iterative treatment planning that incorporates multimodality imaging data.
      METHODS AND MATERIALS: Stereotactic neuroimaging procedures were performed for 20
      consecutive patients with AVM volumes > 10 cm3. Angiographically defined extrema
      were transformed into computed tomography (CT) space. The resulting target
      contours were then modified by a multidisciplinary treatment planning team after
      iterative review of angiographic, CT, and magnetic resonance imaging (MRI) data.
      Volumes of interest and dose-volume histograms for proton irradiation were
      calculated before and after iterative target delineation. RESULTS: Initial
      (angiographically defined) target volumes ranged from 15.3 to 96.1 cm3 (mean,
      43.6 cm3). Final (iteratively defined) target volumes ranged from 10.7 to 114.0
      cm3 (mean, 38.4 cm3). The volume of presumed normal tissue excluded by iterative
      planning ranged from 2.6 to 47.0 cm3 (mean, 15.5 cm3). Initially untargeted AVM,
      most commonly obscured by embolization material, was identified in all cases
      (range, 0.3 to 57.8 cm3; mean, 10.3 cm3). Corresponding dose-volume histograms
      demonstrated marked differences regarding lesion coverage and sparing of normal
      tissue structures. CONCLUSIONS: Iterative target-volume delineation resulted in
      significant modifications from initial, angiographically defined target volumes.
      Substantial amounts of apparently normal tissue were excluded from the final
      target, and additional abnormal vascular structures were identified for
      incorporation. We conclude that an iterative multimodality approach to target
      volume delineation may improve the overall results for stereotactic irradiation
      of large and complex AVMs.

PMID- 8655381
TI  - Shape recovery and volume calculation from biplane angiography in the
      stereotactic radiosurgical treatment of arteriovenous malformations.
AB  - PURPOSE: A model for calculating the three-dimensional volume of arteriovenous
      malformations from biplane angiography. METHODS AND MATERIAL: Three-dimensional
      (3D) volume reconstruction is easily feasible with axial, coronal, or sagittal
      computer tomography (CT) and nuclear magnetic resonance (NMR) scans. On the other
      hand, radiosurgical treatment of arteriovenous malformations (AVM) is exclusively
      based on two orthogonal stereotactic projections, obtained with angiographic
      procedures. Most commonly, AVM volumes have been calculated by assimilating the
      nidus volume to a prolate ellipsoid. We present an algorithm dedicated to 3D
      structure reconstruction starting from two orthogonal stereotactic projections.
      This has been achieved using a heuristic approach, which has been widely adopted
      in the artificial intelligence domain. RESULTS: Tests on phantom of different
      complexity have shown excellent results. CONCLUSION: The importance of the
      algorithm is considerable. As a matter of fact: (a) it allows calculations of
      complex structures far away from regular ellipsoid; (b) it permits shape
      recovery; (c) it provides AVM visualization on axial planes.

PMID- 8655382
TI  - Use of a 1 mm collimator to test the accuracy of stereotactic radiotherapy.
AB  - PURPOSE: To develop a method of measuring locations of the center of dose in
      stereotactic radiotherapy relative to the center of the target, and thereby
      obtain a test of the accuracy of stereotactic radiotherapy (SRT). METHODS AND
      MATERIALS: An insert was mounted in an SRT collimator on a 6 MV linear
      accelerator to provide a photon beam approximately 1 mm in diameter at isocenter,
      and a method of measuring radiation center coordinates of arced SRT beams. To
      simulate a small intracranial target, two halves of a Barium paste column were
      embedded in two adjacent slabs of a humanoid phantom. A film was placed between
      the slabs to image the radiation relative to the target center. A surgical head
      ring and computerized tomography (CT) localizer were attached to the phantom and
      CT scans were obtained. The scans were entered in a three-dimensional
      computerized treatment-planning system and radiation isocenter coordinates
      determined by iteratively moving the 90% isodose surface center of arced beam
      dose distributions to coincide with the target center. The phantom was bolted to
      an SRT floorstand with isocenter coordinates obtained from the treatment plan,
      and then irradiated in two sets of experiments. The first set applied five 1 mm
      noncoplanar arced beams with and without offsets of the planned coordinates in
      the transverse plane. The second set applied one large transverse arc coplanar to
      the film with and without offsets in the craniocaudal direction. Irradiations
      with coordinate offsets tested the sensitivity of the method. Films were
      developed and digitized with a high resolution film scanner to measure the
      location of the radiation relative to the target center. RESULTS AND CONCLUSION:
      The radiation center was found from 0.0 to 0.3 mm of the target center, within
      requirements of our clinical quality assurance program. The measurement and
      evaluation of coincidence of radiation and target centers are, thus, proposed as
      elements of radiosurgery facility acceptance and annual quality assurance.

PMID- 8655383
TI  - A dual computed tomography linear accelerator unit for stereotactic radiation
      therapy: a new approach without cranially fixated stereotactic frames.
AB  - PURPOSE: To perform stereotactic radiation therapy (SRT) without cranially
      fixated stereotactic frames, we developed a dual computed tomography (CT) linear
      accelerator (linac) treatment unit. METHODS AND MATERIALS: This unit is composed
      of a linac, CT, and motorized table. The linac and CT are set up at opposite ends
      of the table, which is suitable for both machines. The gantry axis of the linac
      is coaxial with that of the CT scanner. Thus, the center of the target detected
      with the CT can be matched easily with the gantry axis of the linac by rotating
      the table. Positioning is confirmed with the CT for each treatment session.
      Positioning and treatment errors with this unit were examined by phantom studies.
      Between August and December 1994, 8 patients with 11 lesions of primary or
      metastatic brain tumors received SRT with this unit. All lesions were treated
      with 24 Gy in three fractions to 30 Gy in 10 fractions to the 80% isodose line,
      with or without conventional external beam radiation therapy. RESULTS: Phantom
      studies revealed that treatment errors with this unit were within 1 mm after
      careful positioning. The position was easily maintained using two tiny metallic
      balls as vertical and horizontal marks. Motion of patients was negligible using a
      conventional heat-flexible head mold and dental impression. The overall time for
      a multiple noncoplanar arcs treatment for a single isocenter was less than 1 h on
      the initial treatment day and usually less than 20 min on subsequent days.
      Treatment was outpatient-based and well tolerated with no acute toxicities.
      Satisfactory responses have been documented. CONCLUSION: Using this treatment
      unit, multiple fractionated SRT is performed easily and precisely without
      cranially fixated stereotactic frames.

PMID- 8655384
TI  - A comparison of intensity modulated conformal therapy with a conventional
      external beam stereotactic radiosurgery system for the treatment of single and
      multiple intracranial lesions.
AB  - PURPOSE: To compare the stereotactic radiosurgery treatment plans generated by a
      conventional radiosurgery treatment system with the plan generated by a system
      using intensity modulated beams. METHODS AND MATERIALS: Optimized conformal
      radiation treatment plans were generated for both single and multiple
      intracranial lesions using a conventional radiosurgery treatment-planning system
      computer and the Peacock treatment-planning computer. The Peacock system is a
      conformal therapy system that uses intensity modulated beams, back projection,
      and the simulated annealing optimization technique. The dose delivered to
      critical structures and the target volume were compared by means of dose volume
      histograms between plans generated by the two different systems. The Radiation
      Therapy Oncology Group (RTOG) stereotactic radiosurgery criteria were also used
      to evaluate each plan. RESULTS: (a) For a single small target, radiosurgery plans
      generated by the conventional radiosurgery system and the Peacock system were
      comparable. (b) For two separate small targets, where nonoverlapping arcs could
      be used, plans generated by the two systems were also comparable. (c) For a
      single large (>4 cm) irregular-shaped target, the Peacock system appeared to be
      able to generate a treatment plan superior to that of the conventional
      radiosurgery system. CONCLUSIONS: A treatment plan generated using intensity
      modulated beams appears to be superior to a multiple isocenter plan using a
      conventional radiosurgery system, for the treatment of a large irregular shaped
      intracranial target.

PMID- 8655385
TI  - Dosimetric evaluation of lead and tungsten eye shields in electron beam
      treatment.
AB  - PURPOSE: The purpose of this study is to report that commercially available eye
      shields (designed for orthovoltage x-rays) are inadequate to protect the ocular
      structures from penetrating electrons for electron beam energies equal to or
      greater than 6 MeV. Therefore, a prototype medium size tungsten eye shield was
      designed and fabricated. The advantages of the tungsten eye shield over lead are
      discussed. METHODS AND MATERIALS: Electron beams (6-9 MeV) are often used to
      irradiate eyelid tumors to curative doses. Eye shields can be placed under the
      eyelids to protect the globe. Film and thermoluminescent dosimeters (TLDs) were
      used within a specially constructed polystyrene eye phantom to determine the
      effectiveness of various commercially available internal eye shields (designed
      for orthovoltage x-rays). The same procedures were used to evaluate a prototype
      medium size tungsten eye shield (2.8 mm thick), which was designed and fabricated
      for protection of the globe from penetrating electrons for electron beam energy
      equal to 9 MeV. A mini-TLD was used to measure the dose enhancement due to
      electrons backscattered off the tungsten eye shield, both with or without a
      dental acrylic coating that is required to reduce discomfort, permit
      sterilization of the shield, and reduce the dose contribution from backscattered
      electrons. RESULTS: Transmission of a 6 MeV electron beam through a 1.7 mm thick
      lead eye shield was found to be 50% on the surface (cornea) of the phantom and
      27% at a depth of 6 mm (lens). The thickness of lead required to stop 6-9 MeV
      electron beams is impractical. In place of lead, a prototype medium size tungsten
      eye shield was made. For 6 to 9 MeV electrons, the doses measured on the surface
      (cornea) and at 6 mm (lens) and 21 mm (retina) depths were all less than 5% of
      the maximum dose of the open field (4 x 4 cm). Electrons backscattered off a
      tungsten eye shield without acrylic coating increased the lid dose from 85 to
      123% at 6 MeV and 87 to 119% at 9 MeV. For the tungsten eye shield coated with 2
      3 mm of dental acrylic, the lid dose was increased from 85 to 98.5% at 6 MeV and
      86 to 106% at 9 MeV. CONCLUSION: Commercially available eye shields were
      evaluated and found to be clearly inadequate to protect the ocular structures for
      electron beam energies equal to or greater than 6 MeV. A tungsten eye shield has
      been found to provide adequate protection for electrons up to 9 MeV. The increase
      in lid dose due to electrons backscattered off the tungsten eye shield should be
      considered in the dose prescription. A minimum thickness of 2 mm dental acrylic
      on the beam entrance surface of the tungsten eye shield was found to reduce the
      backscattered electron effect to acceptable levels.

PMID- 8655386
TI  - Collimator (head) scatter at extended distances in linear accelerator-generated
      photon beams.
AB  - PURPOSE: A calculation formalism is proposed to predict variation of head scatter
      as a function of field size and treatment distance. METHODS AND MATERIALS:
      Assuming that the head scatter for the linear accelerator studied was contributed
      predominantly by the flattening filter, a formalism was devised to predict beam
      intensity as a function of distance from the target position. The method used the
      concept of an equivalent collimator field in which a given field at any distance
      can be equated to a field at the isocenter such that the extent of the flattening
      filter seen at the two positions is the same. RESULTS: The equation derived from
      the concept of equivalent collimator field size predicated change in head scatter
      with distance to within 0.5% for collimator field sizes ranging from 8 x 8 to 40
      x 40 cm and distances up to 300 cm from the target. CONCLUSIONS: Considering
      flattening filter to be the main source of head scatter, the observed deviation
      from inverse square law for extended treatment distances can be accounted for by
      an equivalent collimator field size, which sees the same extent of the flattening
      filter at the isocenter as the field at the given distance.

PMID- 8655387
TI  - Past and present of radiation oncology in Italy.

PMID- 8655388
TI  - The history of radiotherapy in The Netherlands.
AB  - Soon after the discovery of x-rays by W. C. Roentgen in 1895, a publication on
      fluoroscopy and x-ray pictures/films appeared in the Dutch medical literature in
      February 1896. The present article reviews the subsequent developments in the
      field of therapeutic radiology in The Netherlands and, in particular, the
      evolution of radiation oncology as a distinct medical specialty.

PMID- 8655389
TI  - A history of radiation oncology in Switzerland.

PMID- 8655390
TI  - Alternative fractionation schemes -- is the "gap" the way ?

PMID- 8655391
TI  - Management of minor salivary gland carcinomas.

PMID- 8655392
TI  - What TPOT is not.

PMID- 8655393
TI  - Comments on ocular globe topography in Radiotherapy by Karlsson et al. IJROBP
      33(3):705-712;1995.

PMID- 8655394
TI  - Reirradiation for recurrent pterygia.

PMID- 8655395
TI  - Regarding Smith and Ling, IJROBP 33(5):977; 1995.

PMID- 8655397
TI  - Morphological and morphometric study of early changes in the ageing golden
      hamster testis.
AB  - The histological and morphometric features of the aged golden hamster testis were
      examined and compared with those of adult animals. Three age groups (6, 12 and 18
      months) were studied by light microscopy, and testosterone levels were
      determined. The observations showed a progressive involution of the seminiferous
      tubules, beginning to be perceptible at 12 months with slight hypospermatogenesis
      and desquamation. In 18-month-old specimens degeneration was more significant and
      histopathological lesions could be classified on a 6-point scale, ranging from
      slight hypospermatogenesis to absence of germ cells. These involutive changes
      were not homogeneously distributed in the testis; affected tubules close to
      seeming normal ones were present. The morphometric results point to a progressive
      diminution, in the 3 age groups, in vas deferens spermatozoa, pachytene
      spermatocytes, and Sertoli and Leydig cells (the latter significantly diminished
      only in the 18-month-old group). For morphometric purposes a 7-point scale of
      tubule degeneration was used, showing a significant increase, with age, in the
      presence of more degenerated tubule stages. Several correlations were found
      between the morphometric variables, outlining existing relations between age and
      the associated diminution of several testis cell types, and lumen diameter. No
      significant differences were found between groups in serum testosterone levels.
      In conclusion, histological changes related to age are evident in 18-month-old
      animals, while at 12 months a diminution in germ cell numbers and sperm
      production is detectable.

PMID- 8655396
TI  - If you assume, you can make an ass out of u and me': a decade of the disector for
      stereological counting of particles in 3D space.
AB  - The year 1984 was a watershed in stereology. It saw the introduction of highly
      efficient and unbiased design-based methods for counting the number of arbitrary
      objects in 3-dimensional (3D) space using 2D sectional images. The only
      requirement is that the objects be unambiguously identifiable on parallel
      sections or successive focal planes. The move away from the ?assumption-based'
      and ?model-based' methods applied previously has been a major scientific advance.
      It has led to the resolution of several problems in different biomedical areas.
      The basic principle which makes possible 3D counting from sections is the
      disector. Here, we review the disector principle and consider its impact on the
      counting and sizing of biological particles. From now on, there can be no excuse
      for applying the biased counting methods of yesteryear. Their continued use,
      despite the availability of unbiased alternatives, should be seen as paying
      homage to History rather than advancing Science.

PMID- 8655399
TI  - Development of the vomeronasal organ in Rousettus leschenaulti (Megachiroptera,
      Pteropodidae).
AB  - A functional vomeronasal organ (VNO) is known to be lacking in adult bats of the
      suborder Megachiroptera, family Pteropodidae, studied to date. However, whether
      the VNO every forms during ontogeny in megachiropterans has not been addressed.
      We report here on the development of the VNO in megachiropterans via study of 8
      stages of rousette fruit bat Rousettus leschenaulti, ranging from an early limb
      bud embryo to a young specimen attached to the nipple. A vomeronasal primordium
      appears in the 4 youngest stages (7-14 mm crown-rump length), but there is no
      sign of any of the components of the vomeronasal system (neuroepithelial tube,
      nerves, sinuses, glands, or trough-like cartilage) in the septal region of the 4
      oldest stages examined, or in the adult. Given the number of genera investigated
      to date and their taxonomic diversity, a conclusion that a VNO is entirely
      lacking in Megachiroptera seems reasonable. However, final confirmation awaits
      study of the additional 27 genera not yet reported (out of a total of 41).

PMID- 8655398
TI  - Distribution in human tissues of the synovial lining-associated epitope
      recognised by monoclonal antibody 67.
AB  - Murine monoclonal antibody Mab 67 was originally shown on histochemical screening
      to bind to synovial intimal fibroblasts (SIF), cells in lymphoid follicles and
      elastic fibres. As part of a programme to isolate the antigen recognised by Mab
      67 and determine its function, a wider histochemical study was performed.
      Cryostat sections were prepared from normal human adult synovium, skin, placenta,
      amnion, kidney, tonsil, breast, thyroid, colon and pericardium, fetal limb
      tissues and rheumatoid arthritic synovium. Sections were stained with Mab 67,
      anti-CD3, as isotype matched control, and anti-VCAM-1 using alkaline phosphatase 
      anti-alkaline phosphatase. Selected sections were double labelled for nonspecific
      esterase activity. Staining by Mab 67 of SIF, identified as NSE-negative intimal
      cells, and follicle centre cells was confirmed. Staining with Mab 67 was also
      seen on Bowman's capsule and juxtaglomerular apparatus, stratum granulosum of
      skin, pulmonary alveolar cells, amniotic epithelium, chorionic villi, fetal
      synovium, bone marrow stromal cells and epidermis, and interstitial elastic
      fibres in most tissues, but not at other sites in these tissues or in
      pericardium, muscle, colon, breast, thyroid, salivary gland or vein. The staining
      pattern with Mab 67 suggests that the antigen is pericellular. Its distribution
      does not match any molecule known to us but overlaps at several sites with VCAM-1
      (SIF, follicle centres, Bowman's capsule and bone marrow stroma). We suggest that
      the antigen involved may possible by similarly involved in cell-matrix
      interaction.

PMID- 8655400
TI  - RNA and protein synthesis in the nonspermatozoal cells of normal human semen.
AB  - A series of semen samples from recently fertile men was obtained by masturbation.
      They were washed and placed in short term culture in BWW medium, and labelled
      either with tritiated uridine or tritiated tyrosine. Control samples were
      labelled in the presence of actinomycin D and puromycin respectively, and
      examined by light and electron microscopy. Ejaculated spermatocytes, spermatids
      of various stages and certain anucleate bodies proved to be labelled with
      tritiated tyrosine and hence to be protein synthetic. Ejaculated spermatocytes
      were also active in RNA synthesis. Macrophages and neutrophil leucocytes both
      heavily incorporated tritiated uridine and tritiated tyrosine. The significance
      of these results is discussed in relation to the possible role of exfoliated
      sperm precursors in ejaculates.

PMID- 8655401
TI  - The innervation of the chromaffin cells in the head kidney of the carp, Cyprinus
      carpio; regional differences of the connections between nerve endings and
      chromaffin cells.
AB  - Nerve fibres and their connections with chromaffin cells in the carp head kidney
      were studied by light and electron microscopy. Some nerve bundles entered the
      head kidney from the dorsal aspect along veins. Many unmyelinated axons emerged
      from the nerve bundles to invade the clusters of chromaffin cells, the
      distribution of which was restricted to the neighbourhood of the venous trunks
      and their tributaries. Most of the nerve endings were attached to a chromaffin
      cell by synaptic junctions and were generally invaginated into the cell. Some
      nerve endings were flattened in shape and connected with two chromaffin cells.
      Occasional exocytotic figures of synaptic vesicles opening into the intercellular
      space, or synaptic junctions along the course of the nerve fibre were observed.
      The percentage of the chromaffin cells supplied by nerve endings in the head
      kidney as a whole was similar to that in primitive amphibians. The distribution
      of the chromaffin cells and the frequency of their innervation suggest that carp
      chromaffin cells are phylogenetically similar to those of amphibians. The
      frequencies of synaptic connections in the carp head kidney showed regional
      differences. The number in dorsal portion was significantly higher than that in
      two ventral portions. It is suggested that chromaffin cells in the head kidney
      are separable into two populations: one (in the dorsal portion) shows closer and
      the other (in the ventral portions) less contact with nerve fibres. The fine
      structure of the nerve endings indicates that catecholamine secretion of carp
      chromaffin cells is partially modulated by nerve fibres (probably preganglionic
      cholinergic fibres). However, the low frequency of synaptic connections on the
      chromaffin cells and their distribution suggest that carp chromaffin cells are
      mainly modulated by the endocrine system via the bloodstream.

PMID- 8655402
TI  - Expression of tenascin in joint-associated tissues during development and
      postnatal growth.
AB  - The extracellular matrix protein, tenascin, is selectively expressed in a variety
      of connective tissues during development. In this study, the distribution of
      tenascin in tissues contributing to the knee joint during embryonic development
      and postnatal growth in the rat has been investigated by immunohistochemistry. In
      recently formed embryonic knee joints, tenascin expression was abundant in the
      territorial matrix of superficial articular cartilage. Site of attachment of
      cruciate and patellar ligaments to cartilage were strongly stained; staining of
      ligaments weakened with distance from the attachment site. In rapidly growing 4
      wk-old rats, tenascin was present in a fine line on the surface of articular
      cartilage, but at 10 wk of age tenascin staining was absent from most of the
      articular surface. In postnatal rats, there was strong tenascin staining of the
      synovial lining, but not of subintimal tissue. Cruciate ligaments were
      histologically fibrocartilaginous in 4 and 10-wk-old rats; within these ligaments
      strong pericellular tenascin staining was seen in association with rounded
      chondrocyte-like cells. Tenascin was absent from the cartilaginous growth plates
      of 4 and 10-wk-old rats, but intense tenascin staining was seen at the junction
      between epiphyseal bone and growth plate. Within the metaphysis, tenascin
      staining on bone surfaces increased with distance from the hypertrophic
      chondrocytes. Osteocytes within epiphyseal trabecular bone were strongly stained
      for tenascin, whereas those in the metaphysis were mostly unstained. The results
      presented here demonstrate that tenascin expression in joint-associated tissues
      changes markedly with cell type and stage of differentiation.

PMID- 8655403
TI  - Modification of tooth size and shape in Down's syndrome.
AB  - Individuals with Down's syndrome (DS) tend to display a reduction in size of
      permanent teeth, and reduced intercuspal distances in molars. A total of 51
      permanent maxillary 1st molars of 26 DS children were examined from dental casts,
      65 permanent maxillary 1st molars of normal children were examined from dental
      casts of 33 individuals. The following measurements were performed on both right
      and left molars (teeth 16 and 26 respectively): (1) all intercusp distance
      (distobuccal, db; distolingual, dl; mesiobuccal, mb; mesiolingual, ml); (2) the
      db-mb-ml, mb-db-ml, db-ml-mb, dl-mb-db, mb-dl-db, and dl-db-mb angles; (3) the
      area of the quadrangle shaped by connecting the cusp tips. All the intercusp
      distances were significantly smaller in the DS group. Stepwise logistic
      regression, applied to all the intercusp distances, was used to build a
      multivariate probability model for DS and normals. The mb-dl and mb-ml distances
      of the upper right molar (tooth 16) were sufficient to discriminate between DS
      and normal teeth: [table: see text] The probability for DS is higher when mb-ml
      is relatively higher in the mb-ml/mb-dl ratio. Another logistic analysis based on
      groups of angles revealed a combination of 3 angles which gave highly
      statistically significant discrimination between both groups: the mb-db-dl angle
      was higher in DS, the mb-dl-db angle was slightly smaller in DS, and the mb-ml-db
      angle was slightly smaller in DS. The dl cusp was located closer to the centre of
      the tooth. The change in size occurs at an early stage, while the change in shape
      occurs in a later stage of tooth formation in DS population. Our probability
      model for DS teeth is simple and practical because it requires only 2 intercusp
      distances to be put into the formula.

PMID- 8655404
TI  - Degenerating and regenerating skeletal muscles contain several subpopulations of
      macrophages with distinct spatial and temporal distributions.
AB  - Macrophages of different phenotypes can be detected using a panel of antibodies.
      We have used such antibodies to demonstrate that the macrophages in freeze
      lesioned skeletal muscles are heterogeneous, with each subtype having a distinct
      location within the lesion as well as distinct times of arrival and departure
      from the lesion. ED1+ monocytes and macrophages began invading the lesion within
      3 h and were abundant until necrotic tissue had been removed. In some
      macrophages, the ED1 antigen aggregated into a single or a few clumps and such
      cells persisted in the regenerated area for at least 21 d. ED2+/Ox6-/ED1-/RM1-
      cells are one of the major subpopulations of resident macrophages within skeletal
      muscle. Cells of this phenotype accumulated in the epimysia and perimysia
      surrounding the lesions but did not penetrate into the lesion until extensive
      phagocytosis had occurred (usually 1 or 2 d). ED2+ cells were subsequently
      concentrated in the regenerating connective tissues and empty remnants of
      phagocytosed fibres. They only rarely invaded necrotic tissue, even when
      immediately adjacent to it, suggesting that this type of macrophage has a
      specialised function which is unrelated to removal of damaged tissue. The ED2+
      macrophages were CD4+ and it is probably that macrophages of this type have been
      previously misclassified as CD4+ T cells. Skeletal muscles also contain numerous
      Ox6(Ia)+/ED2- resident macrophages. Unlike ED2+ macrophages, Ox6+ macrophages
      invaded the damaged muscles half a day after lesioning and were abundant in
      necrotic tissue. As regeneration occurred, the Ox6+ macrophages became restricted
      to the connective tissues of the muscle, which is their normal location.

PMID- 8655405
TI  - The periepiglottic space: topographic relations and histological organisation.
AB  - Important aspects of histological organisation and topographic relations of the
      pre-epiglottic space are not fully understood. This region was therefore
      reinvestigated in plastinated serial sections of 19 human adult specimens. The
      cranial part of the pre-epiglottic space is homogenously filled with adipose
      tissue and extends around the epiglottis in a horseshoe fashion. Therefore, the
      term periepiglottic space (PES) is a more accurate description of this region.
      The cranial border of the PES is constituted by the hyoepiglottic membrane, which
      extends between the epiglottis and the tongue, and the hyoepiglottic ligament.
      The ligament consists of a cranial fibre layer anchored within the lingual
      muscles, and a caudal layer attached to the hyoid bone. Anterior to the lingual
      surface of the epiglottis, both fibre layers become apposed to form a dense
      collagenous mass, which may stabilise the epiglottis during deglutition.
      Contractions of the infrahyoid muscles will be transmitted to the thyrohyoid
      membrane anterior to the PES by numerous collagenous septa which originate from
      the membrane and radiate into the muscles. In contrast, the pre-epiglottic
      adipose tissue is not connected to the thyrohyoid membrane. The caudal part of
      the PES is subdivided by two paramedian sagittal collagenous septa. They include
      a medial compartment bordered by the epiglottis posteriorly and the
      thyroepiglottic ligament inferiorly. The two lateral subdivisions of the PES
      extend between the glands of the vestibular folds and towards the aryepiglottic
      folds, but a distinct confining collagenous layer is absent there.
      Posterolaterally, the PES is separated from the paraglottic space by the
      thyroarytenoid muscle and by a cranial extension of the fibrous sheet of the
      muscle. This collagenous tissue is often split into several layers and displays
      gaps which may facilitate the spread of malignancies.

PMID- 8655406
TI  - Structural changes in fluorosed dental enamel of red deer (Cervus elaphus L.)
      from a region with severe environmental pollution by fluorides.
AB  - A macroscopic, microradiographic and scanning electron microscope study was
      performed on the structure of fluorosed dental enamel in red deer from a fluoride
      polluted region (North Bohemia, Czech Republic). As was revealed by analysis of
      mandibular bone fluoride content, the rate of skeletal fluoride accumulation in
      the fluorotic deer was about 6 times that in controls taken from a region not
      exposed to excessive fluoride deposition. In all fluorosed mandibles, the 1st
      molar was consistently less fluorotic than the other permanent teeth. This was
      related to the fact that crown formation in the M1 takes place prenatally and
      during the lactation period. Fluorosed teeth exhibited opaque and posteruptively
      stained enamel, reduction or loss of enamel ridges, moderately to grossly
      increased wear and, in more severe cases, also enamel surface lesions of partly
      posteruptive, partly developmental origin. Microradiographically, fluorosed
      enamel was characterised by subsurface hypomineralisation, interpreted as a
      result of fluoride interference with the process of enamel maturation. In
      addition, an accentuation of the incremental pattern due to the occurrence of
      alternating bands with highly varying mineral content was observed in severely
      fluorosed teeth, denoting fluoride disturbance during the secretory stage of
      amelogenesis. A corresponding enhancement of the incremental pattern was also
      seen in the dentine. The enamel along the more pronounced hypoplasias consisted
      of stacked, thin layers of crystals arranged in parallel, indicating that the
      ameloblasts in these locations had lost the distal (prism-forming) portions of
      their Tomes processes. The findings of the present study indicate that red deer
      are highly sensitive bioindicators of environmental pollution by fluorides.

PMID- 8655407
TI  - Lectin histochemistry of pregnant rat uterine tissues.
AB  - Glycoconjugate residues were examined in the rat uterus at days 10, 12 and 15 of
      pregnancy using 17 biotinylated lectins with specificities for a variety of
      carbohydrate moieties. A wide variety of glycoconjugate residues were detected in
      the cytoplasm of some antimesometrial and mesometrial decidual cells with lectins
      from Canavalia ensiformis (Con A), Lens culinaris (LcH) culinaris (LcH), Pisum
      sativum (PSA), Griffonia simplicifolia II (GS-II), Triticum vulgaris (WGA),
      Griffonia simplicifolia I (GS-I), Maclura pomifera (MPA) and Phaseolus vulgaris
      (PHA-E and PHA-L). Reactivity with some of these lectins was also pericellular
      and the glycoconjugate residues detected may be related to extracelluar matrix
      produced by decidual cells. Reactivity with PHA-E, demonstrating complex
      carbohydrates, was most intense in the mesometrial decidua closest to the
      trophoblastic giant cells and may demonstrate glycoconjugates involved in
      maintaining integrity at this maternotrophoblast interface. Lectins derived from
      Helix pomatia (HPA), Vicia villosa (VVA), Glycine max (SBA) and Arachis hypogaea
      (PNA) reacted only with occasional small cells in antimesometrial or mesometrial
      decidua, probably demonstrating alpha and/ or beta-linked N-acetylgalactosamine
      residues on lymphocytes or monocytes. The glycoprotein granules of granulated
      metrial gland (GMG) cells in the decidua basalis and the metrial gland reacted
      strongly with WGA, MPA and PHA-L demonstrating complex carbohydrates including
      sialic acid residues and tri/tetra-antennary, nonbisected N-linked glycans. GMG
      cell cytoplasm reacted diffusely with Con A, LcH, PSA, WGA, PHA-E and PHA-L. In
      some GMG cells reactivity with WGA was apparently localised to the Golgi region
      indicating involvement in granule formation. Pericellular reactivity of some GMG
      cells with WGA may relate to migratory activity. The lectin reactivity of
      fibroblast-like stromal cells in the material gland was similar to that of the
      extracellular matrix and it is likely that many matrix molecules are produced by
      the stromal cells. A range of lectins (Con A, LcH, PSA, GS-II GS-I and PHA-L)
      reacted with some blood vessels in the metrial gland at day 12 of pregnancy: this
      may indicate activation changes associated with the transendothelial passage of
      GMG cells at this stage. Lectins derived from Dolichos biflorus (DBA), Bauhinia
      purpurea (BPA), Lotus tetragonolobus (LTA) and Ulex europaeus-I (UEA-I) did not
      react with decidual and metrial gland regions. Lectin binding profile studies can
      provide further information on the events occurring in the uterus in pregnancy:
      investigations at the ultrastructural level are required to resolve further intra
      and extracellular changes.

PMID- 8655408
TI  - Precondylar tubercles on the basiocciput of adult human skulls.
AB  - The basiocciput of 265 Indian adult human skulls was examined for precondylar
      tubercles, which are single or paired osseous formations anterior to the
      occipital condyles and foramen magnum. Of the 14% of skulls displaying these
      tubercles unilaterally or bilaterally, 5.3% demonstrated ridges, 4.9% showed
      spines and 3.8% exhibited processes. Sexual dimorphism was evident with female
      skulls showing a higher incidence (8.7%) compared with male skulls (5.3%). The
      corresponding atlas vertebrae were normal. These craniovertebral anomalies may
      have clinical relevance for lesions at the foramen magnum.

PMID- 8655409
TI  - Ultrastructural observations on the peritoneum in the mouse.
AB  - The serous mesothelium of the serosa and mesentery of the small intestine in the
      mouse were examined by scanning and transmission electron microscopy. The serosa
      consisted of a single layer of flattened microvilli-bearing cells containing
      nuclei, caveolae and micropinocytotic vesicles. The observations in this study
      differed from previous reports on mesothelial surfaces in two respects. A surface
      layer of amorphous material was present over parts of the serosa. This layer
      probably represents serous fluid trapped by the mesothelial microvilli but is
      unaffected by prefixation rinsing in saline or ultrasonic cleaning. The layer is
      lost following osmication and routine processing for transmission electron
      microscopy. The possibility that a serous fluid layer may be preserved in this
      way may be useful in assessing changes in the peritoneum. Stomata were observed
      in the mesentery but there was no evidence of a connection with the lymphatic
      system. The presence of mesenteric stomata may explain the difference in
      permeability reported between parietal peritoneum and mesentery.

PMID- 8655410
TI  - Mastoid canals in adult human skulls.
AB  - Mastoid canals (tunnels) were observed in 41 (7.7%) of 265 dry human skulls. The
      canals were 2-27 mm long. This feature has not been reported before. dissection
      of 30 mastoid regions in cadavers showed that the canals contained a branch of
      the occipital artery and a vein. It is possible that during development of the
      mastoid process the squamous temporal bone ossifies over the vessels, giving rise
      to the canals.

PMID- 8655411
TI  - A warning against revival of the classic tenets of gross anatomy related to nerve
      muscle specificity.

PMID- 8655412
TI  - The nerve supply to extensor carpi radialis brevis.

PMID- 8655413
TI  - Ultrastructural study on the plical epithelium of the bursa of Fabricius in chick
      embryos: influence of partial decerebration and hypophyseal allografts.
AB  - The bursa of Fabricius of 18 day normal and partially decerebrated chick embryos,
      and partially decerebrated embryos bearing a hypophyseal allograft was analysed
      by scanning and transmission electron microscopy, focusing on the ultrastructural
      characterisation of the plical epithelium. The plicae of the normal bursa consist
      of interfollicular (IFE) and follicle associated epithelium (FAE). The FAE is
      composed of typical polygonal cells and is supported by a layer of epithelial
      cells which appears as a continuation of the corticomedullary epithelium.
      Bordering cells lie between the FAE and IFE. The IFE is composed of 4 cell types:
      (1) undifferentiated, (2) goblet, at various stages of maturity, (3) prismatic,
      and (4) globular light cells. Partially decerebrated embryos showed a gross
      impairment of plical epithelium development and the complex of FAE and IFE cells
      was largely undifferentiated. Partially decerebrated embryos with a hypophyseal
      allograft displayed the same cellular types as observed in controls, thus
      indicating a restored differentiation of plical epithelium. These findings
      suggest that the hypophysis affects the differentiation of plical epithelium
      during ontogenesis.

PMID- 8655414
TI  - Behaviour of two IgG subclasses in transport of immunoglobulin across the human
      placenta.
AB  - The human IgG subclasses are a family of highly related yet distinct molecules.
      Each of these four subclasses performs a discrete function within the human
      immune system. Previous studies have shown that one of these molecules, hIgG2,
      may be discriminated against in transport across the human placenta. We have
      aimed to elucidate the mechanism of this discrimination in order to gain a more
      comprehensive understanding of the process of transport of immunoglobulin across
      the human placenta. We have used a combination of immunocyctochemical
      localisation and biochemical analysis to detail the behaviour of hIgG2. Confocal
      laser scanning microscopy was used to compare the localisation of hIgG1 (chosen
      as representative of the efficiently transported subclasses) and hIgG2 in term
      and first trimester chorionic villi. Complementary evidence was provided from
      immunoblot analysis of isolated placental coated vesicles. The data presented
      here suggest that the hIgG2 is transported into the syncytiotrophoblast and
      appears to accumulate in the stroma of the villi. This leads us to the hypothesis
      that the fetal capillary endothelium is the cellular impediment to the transport
      of hIgG2 into the fetal circulation.

PMID- 8655416
TI  - Anatomy of the ostia venae hepaticae and the retrohepatic segment of the inferior
      vena cava.
AB  - In 30 normal adult livers the retrohepatic segment of inferior vena cava had a
      length of 6.7 cm and was totally encircled by liver substance in 30% of cases.
      Altogether 442 ostia venae hepaticae were found, averaging 14.7 per liver and
      classified as large, medium, small and minimum. The localisation of the openings
      was studied according to the division of the wall of the retrohepatic segment of
      the inferior vena cava into 16 areas.

PMID- 8655415
TI  - The gyrification of mammalian cerebral cortex: quantitative evidence of
      anisomorphic surface expansion during phylogenetic and ontogenetic development.
AB  - Describing the shapes of 3D objects has proved to be as problematical in biology
      as in other areas. In an attempt to tackle this problem, established
      stereological methods (the Cavalieri principle and vertical sectioning) have been
      used to estimate a 3D shape-dependent quantity which can detect anisomorphic
      changes and is related to the degree of cortical convolution or gyrification.
      This isomophy factor is employed to assess phylogenetic and ontogenetic changes
      in the mammalian cerebral cortex. Gross anatomical differences between cerebral
      hemispheres of adult domestic mammals (horses, oxen, pigs, goats, dogs, cats and
      rabbits) were tested by paying attention to species, laterality and sex
      differences. Human fetal brains were also studied. Mean body weights of domestic
      mammals varied from 4 kg to 460 kg and brain weights from 10 g to 636 g. Fetuses
      weighed 39-610 g (crown-rump lengths 85-185 mm) and brain volumes were 4-56 cm3.
      Isomorphy factors were derived from estimates of hemisphere volumes and cortical
      surface areas. Hemisphere shape varied between species but no lateral or sex
      differences were detected. It is concluded that these mammalian brains are, in
      terms of their gross anatomy, symmetric and not sexually dimorphic. Fetal brains
      became more convoluted during uterine development. The isomorphy factor offers a
      convenient measure of gyrification which demonstrates that brains become more
      convoluted as they enlarge.

PMID- 8655418
TI  - A study of the ultrastructure of developing human umbilical vessels.
AB  - Electron microscopic techniques were used to examine the ultrastructure of
      developing human umbilical arteries and vein (8-12, 13-17 and 37-40 wk
      gestational age). These showed that with increasing age there is (1) an increase
      in the size of the lumen and the thickness of the media; (2) an increase in the
      ratio of contractile smooth muscle phenotypic cells; (3) an increase in the
      myofilament content of the smooth muscle cells and the number of Weibel-Palade
      bodies; (4) a decrease in the glycogen content; (5) an appearance of microvilli
      on the luminal surface of the endothelium. Lipid vesicles, nerves and vasa
      vasorum were not observed in any region of the umbilical vein or arteries.

PMID- 8655417
TI  - Expression of insulin-like growth factor II (IGF)-II) and H19 in murine
      teratocarcinomas derived from embryonic stem (ES) cells.
AB  - Insulin-like growth factor II (IGF-II) is expressed during embryogenesis in
      rodents and humans, but is not produced in most adult tissues. This pattern of
      expression is closely shared by the gene H19, which lies 3' to IGF-II. This,
      together with the fact that the genes are reciprocally imprinted, has led to the
      proposal that the genes are under common transcriptional control by the H19
      enhancers during development. In the present study, embryonic stem (ES) cells
      have been used to generate teratocarcinomas in mice. These tumours generate a
      wide range of differentiated tissues which have been subjected to hybridisation
      histochemistry with RNA probes to H19 and IGF-II. Coexpression of the two genes
      was found in a range of tissues, a pattern consistent with the idea of common
      transcriptional control. However, there were some areas in which H19 was
      expressed strongly in comparison with IGF-II and vice versa suggesting the
      existence of further control elements other than the H19 enhancers.

PMID- 8655419
TI  - Normal and healing ligament vascularity: a quantitative histological assessment
      in the adult rabbit medial collateral ligament.
AB  - Normal and healing adult rabbit medial collateral ligaments (MCL) have been
      assessed for microvascular anatomy using a quantitative image analysis
      methodology. MCL preparation by ink-gelatin perfusion enabled acceptable
      visualisation of microvascular channels within the tissue. Fifteen adult rabbits
      were studied; 3 normal rabbits formed an external time-zero control group; 12
      animals received a standardised gap injury to the right MCL. The ligament injury
      was permitted to heal for 3, 6, 17 or 40 wk (3 animals in each healing group).
      Results confirmed that the normal MCL is hypovascular (about 1.46% vascularity by
      area) and that microvascular channels are highly organised and oriented
      longitudinally deep within the tissue. Healing MCL scar becomes twice as vascular
      as normal ligament early on, but returns to near normal values by 40 wk.
      Microvascular channels appear less organised in scar than in contralateral
      controls, but remodel with time. The directional scatter and spatial extent of
      ligament microvascular channels is quantifiable in normal and healing tissues.

PMID- 8655421
TI  - Herbert Windsor Mumford, 1871-1938: a brief biography.

PMID- 8655420
TI  - Localisation of immunoreactive factor VIII, nitric oxide synthase, substance P,
      endothelin-1 and 5-hydroxytryptamine in human postmortem middle cerebral artery.
AB  - This pre-embedding electron-immunocytochemical study investigated the
      localisation of endothelial (type III) and neuronal (type I) isoforms of nitric
      oxide synthase, substance P, endothelin-1 and 5-hydroxytryptamine in the human
      middle cerebral artery taken up to 40 h postmortem. To ?recover' from the anoxic
      period some of the vessels were incubated in oxygenated Krebs solution prior to
      the immunoprocedure. At this long postmortem time, immunoreactivity to type III
      and type I nitric oxide synthase, substance P, endothelin-1 and 5
      hydroxytryptamine was found in a subpopulation of intact cells present in the
      vessel intima; immunoreactivity to type I nitric oxide synthase was also observed
      in a subpopulation of adventitial perivascular nerve fibres. Cultures of the
      cells from the intima of the postmortem vessels showed that the cells were
      proliferating and positive immunoreactivity to factor VII identified them as
      endothelial cells. The results therefore indicate that even after up to 40 h
      postmortem, endothelium of human middle cerebral artery is immunoreactive for a
      number of vasoactive agents and perivascular nerve fibres show nitric oxide
      synthase immunoreactivity.

PMID- 8655423
TI  - Injection-site lesions: incidence, tissue histology, collagen concentration, and
      muscle tenderness in beef rounds.
AB  - The national incidence and extent of injection-site lesions in the muscles of the
      round were determined via audits conducted at retail stores and in purveying
      establishments. Two additional experiments were conducted to examine the
      subsequent effects of pharmaceutical administration on tissue histology, soluble
      and insoluble collagen concentration, and muscle tenderness in beef bottom
      rounds. Injection-site lesion incidence in beef round cuts audited at retail (n =
      3,538) and in steak-cutting facilities (n = 15,464) was 8.45 and 10.04%,
      respectively, with an average lesion-trim of 314.7 and 191.59 g, respectively, in
      these two studies. Lesion classification revealed that 93.20 and 99.91% of
      lesions reported for the retail and purveyor audits, respectively, were
      chronologically aged lesions. Overall, 19,002 round cuts were examined, and
      injection-site lesion incidence (nationally) was 9.74%, whereas lesion-trim
      averaged 211.8 g. Warner-Bratzler shear measurements taken near lesions and in
      areas 7.62 cm from the lesions were higher (P < .001) for lesioned, than for
      control bottom-round steaks. Warner-Bratzler shear values for lesion cores were
      3.5 times greater than those in paired control (non-affected) steaks.
      Concentrations of insoluble and soluble collagen were much higher (P < .001) at
      the site of the lesion center in lesion-afflicted vs control steaks. Histological
      determinations of the relative proportions of muscle, connective tissue and fat
      to a distance of 5.08 cm from the site of the lesion center confirmed that severe
      disruption of muscle tissue constituents and architecture had occurred. Injection
      site lesions occur at an unacceptable frequency in the muscles of the round, and
      severe tissue changes accompany these lesions that can dramatically affect
      tenderness of those cuts.

PMID- 8655422
TI  - Feedlot performance and carcass characteristics of Holstein steers as affected by
      source of dietary protein and level of ruminally protected lysine and methionine.
AB  - The objective of this study was to determine the effects of source of dietary CP
      and level of ruminally protected lysine and methionine (RPLM) on feedlot
      performance and carcass characteristics of Holstein steers during a growing
      finishing trial (266 d). A total of 168 Holstein steers (182.7 +/- 27.5 kg) were
      used in a completely randomized design experiment (eight treatments; three pens
      of seven steers/treatment). Steers were given ad libitum access to high
      concentrate diets (13% CP) containing 71% whole shelled corn, 10% corn silage, 4%
      condensed distillers solubles, and 15% protein supplements (DM basis). Treatments
      were arranged as a 2 x 4 factorial. The main factors were two sources of dietary
      CP and four levels of RPLM. The sources of dietary CP were soybean meal (SBM) or
      SBM and urea (SBM-U). Urea-N replaced 50% of SBM-N in the SBM-U diet. The levels
      of RPLM were 0, 5, 10, and 15 g per steer daily. No interactions (P > .10)
      between source of dietary CP and level of RPLM were observed for feedlot
      performance or carcass characteristics. Feedlot performance showed an advantage
      (P < .10) to feeding SMB during the first 84 d of the trial and an advantage to
      feeding SBM-U during the last 98 d of the trial. However, feedlot performance for
      the whole trial and carcass characteristics (except for fat thickness) were not
      affected (P > .10) by the source of dietary CP. Steers fed diets containing SBM-U
      had 12% less (P < .10) fat thickness than those fed diets containing SBM.
      Supplementation of diets with increasing levels of RPLM did not affect (P > .10)
      ADG or carcass characteristics. However, DMI and gain:feed showed cubic (P < .10)
      responses to increasing dietary level of RPLM. Supplementation of RPLM at the 10
      g/d level improved gain:feed by 12% during the last 98 d of the trial, and this
      was a direct response to the cubic effects of RPLM on DMI. Results suggest a cost
      advantage for replacing 50% of SBM-N with that from urea in high-corn diets
      without negative effects on feedlot performance or carcass characteristics of
      growing-finishing Holstein steers with extended feeding periods (266 d). These
      types of diets seem to meet the amino acid requirements and are not limiting in
      lysine and methionine.

PMID- 8655424
TI  - Comparison of Landim and Africander cattle in southern Mozambique: I. Body
      weights and growth.
AB  - The growth performance of Landim and Africander breeds was compared using data
      collected from 1968 to 1981 at the Chobela Research Station in Mozambique.
      Animals from both breeds were managed together in groups by age and sex, except
      when separated for breeding. Growth traits were body weights at birth, weaning at
      7 mo, 18 mo, and first calving, and pre- and postweaning daily growth rates.
      These traits were analyzed using a mixed-effects least squares model containing
      breed, year-season of birth, sex, the nested effect of parity within breed, a
      linear regression on dam's age, and the random effect of sire within breed.
      Africander calves were 16, 9, and 7% heavier (P < .01) than Landim calves at
      birth, weaning, and 18 mo (18 +/- 6 kg heavier than the 237-kg Landim average).
      However, there was no detectable difference for age-adjusted weight at first
      calving and postweaning daily growth rate. Diminishing weight and growth
      differences with advancing age may indicate adaptation by the Landim to the
      prevailing environmental limitations in southern Mozambique, especially through
      younger ages at puberty and at first calving.

PMID- 8655425
TI  - Comparison of Landim and Africander cattle in southern Mozambique: II. Female
      fertility, reproduction, and beef offtake.
AB  - Fertility and reproductive performance of Landim and Africander females were
      compared using data collected from 1968 to 1981 at the Chobela Research Station
      in Mozambique. Breeds were managed together and grouped by age and sex, except
      when separated for breeding. Traits were relative fertility (probability of
      fertile females calving from the first breeding season), age at first calving,
      first calving interval, and subsequent calving intervals. calving rates were
      tested by x2 procedures with equal expected frequencies in each subclass. The
      statistical model included breed, the random effect of sire within breed, year
      season of birth or calving, and calving group within breed. Landim survivors were
      more fertile (P < .05) than the Africander ones throughout their recorded
      lifetimes. Landim females were 1.32 +/- .21 mo (or 3%) younger at first calving
      and had a 48 +/- 12 d (or 11%) shorter interval between first and second calving
      than the Africander average of 473 d. When reproductive and growth information
      were combined to compute an annual index of beef offtake expressed as 18-mo calf
      yield per unit of dam's weight at first calving, Landim cows annually yielded 30%
      more calf weight (P < .001) than Africander cows per kilogram of their own body
      maintenance despite lighter body weights at 18 mo. Superior fertility of Landim
      females led to greater beef offtake from higher calving rates. Greater fertility
      and relatively less feed to maintain the reproducing herd are probable mechanisms
      for a population to adapt to nutrient-limiting environments such as the one in
      southern Mozambique.

PMID- 8655426
TI  - Survival, body weights, feed efficiency, and carcass traits of 3/4 white
      composite and 1/4 Duroc, 1/4 Meishan, 1/4 Fengjing, or 1/4 Minzhu pigs.
AB  - Pigs were the progeny of White Composite (WC) boars mated to F1 Duroc x WC,
      Meishan x WC, Fengjing x WC, and Minzhu x WC gilts. Meishan and Fengjing crosses
      had more (P < .05) nipples than Duroc and Minzhu crosses. Meishan and Minzhu
      crosses had a higher survival rate at birth (P < .05) than Duroc and Fengjing
      crosses, but breed types did not differ significantly (P approximately .29) for
      survival to 14 or 28 d of age. Duroc crosses were heavier (P < .05) than Fengjing
      and Minzhu crosses at 0, 28, 56, 70, 98, 126, and 154 d of age; they were heavier
      (P < .05) than Meishan crosses at 0, 28, 98, 126, and 154 d of age. Chinese
      crosses had similar weights at most ages, although Meishan crosses were heavier
      (P < .05) than Fengjing and Minzhu crosses at 126 and 154 d of age. Breed types
      did not differ significantly (P approximately .27) for feed efficiency during the
      nursery period. Over the entire finishing period, Duroc-cross gilts (.3310) were
      less efficient (P < .05) than Meishan (.3436), Fengjing (.3454), or Minzhu
      crosses (.3466); among barrows Meishan crosses (.3176) were least efficient (P <
      .05), Fengjing crosses (.3263) were most efficient (P < .05), and Duroc (.3211)
      and Minzhu (.3209) were intermediate but not significantly different from the
      Meishan or Fengjing crosses. At a constant age, Duroc crosses had longer
      carcasses, greater longissimus muscle area, and heavier slaughter weight, carcass
      weight, and weight of untrimmed cuts and trimmed cuts than the Chinese crosses (P
      < .05). There were few significant differences among breed types for carcass
      traits at a constant carcass weight. Results show that, relative to one-half
      Duroc females, incorporation of one-half Chinese females into a crossbreeding
      program will result in progeny with a significant decrease in rate of growth
      (approximately 9% for weight at 154 d of age) and a small, nonsignificant
      decrease in yield of trimmed lean cuts (approximately 5%) at a constant carcass
      weight.

PMID- 8655427
TI  - Reducing pig mortality through supervision during the perinatal period.
AB  - A study was undertaken on a commercial swine farm to investigate methods of
      reducing perinatal mortality. During a 12-wk period, 251 sows and gilts were
      assigned randomly to one of four treatment groups in a 2 x 2 factorial design: 1)
      supervised/induced, 2) supervised/non-induced, 3) unsupervised/induced, and 4)
      unsupervised/non-induced. Supervised groups of sows and their litter were
      observed constantly for a minimum of 3 h before and until 3 d after farrowing.
      The onset of farrowing was induced with 250 micrograms of cloprostenol
      administered into the vulvo-vestibular mucosa. There was an increase (P = .012)
      in the number of pigs weaned from supervised (10.17 pigs/litter) relative to
      unsupervised group (9.44 pigs/litter). This increase was due to a reduction (P =
      .001) in both the number of stillborn pigs and the mortality of live-born pigs (P
      = .026). The latter resulted from fewer pigs that died (P = .003). Induction did
      not influence the mortality of pigs in the perinatal period in unsupervised
      groups. Induced sows farrowed an average of .43 d earlier than non-induced sows
      (P = .029). The mean interval from prostaglandin treatment to farrowing was 23.87
      h (SD = 10.96). The results of this study suggest that a controlled farrowing
      system, coupled with good supervision, can improve pig survival. Financial
      analyses, based on improvements in pig survival resulting from additional labor
      in the farrowing house, suggested that this method of reducing preweaning
      mortality is a viable option for improving the profitability of commercial pig
      farms.

PMID- 8655428
TI  - Effects of feeding wash-water solids on health and performance of ewes and lambs.
AB  - Diets containing 0, 10, or 20% dried wash-water solids (WWS) from a milk
      processing plant were fed to 48 Hampshire crossbred wews (average weight 58.1 kg)
      for 3 yr. Data were obtained on BW gains, hematology, tissue elements, and
      survival for ewes and BW gains, tissue elements and survival for their lambs.
      Ewes fed 20% WWS gained less (P < .05 ) BW during gestation and lactation in yr 1
      and had lower BW (P < .05) in yr 2 and 3 than those fed 0 or 10% WWS. Lambs from
      ewes fed 20% WWS gained less (P < .05) BW in yr 2 and 3. Hematology variables of
      ewes, survival of ewes and survival of lambs were not effected by diet. Although
      WWS-containing diets contained high concentrations of Ca, P, Mn, and Fe and
      moderate concentrations of Mo, Mg, and Zn, diets had few effects on tissue
      elements in ewes and lambs. Concentrations of some tissue elements were less (P <
      .05) in lambs in yr 2 and 3 than in yr 1. Wash-water solids can be incorporated
      into ruminant diets, providing a disposal alternative that recycles and conserves
      nutrients. Long-term feeding posed only minor or negligible health of safety
      problems. Because fo low energy and N availability and high ash content, WWS
      probably should be limited to 10% or less of conventional diets.

PMID- 8655429
TI  - Energy metabolism in young pigs as affected by mixing.
AB  - The effect of mixing on energy metabolism was studied in 8-wk-old pigs. In each
      of two trials, two clusters of 20 pigs (two litters of 10 pigs) were randomly
      assigned to one of two treatments: control or mixing. Each cluster was housed in
      two pens. In each trial, after a preliminary period od 2 wk, the two litters
      within the mixing treatment were mixed at the start of a 2-wk experimental
      period. During mixing, the five heaviest pigs of each litter were put together in
      one pen, and the five lightest pigs of each litter were put together in the other
      pen. In the control treatment, the social structure of both litters in one
      climatic chamber was not altered. After mixing, a short-term effect on total heat
      production and activity-related heat production was present. Both were increased
      (P < .01) only during the 1st h after mixing. Only 57.3% of this increased total
      heat production was caused by an increased activity. However, no long-term
      effects of mixing on energy partitioning were present during the total
      experimental period. The absence of a long-term mixing effect might be caused by
      the optimal conditions at the moment of mixing. In the preliminary period the
      transposition of GE into ME increased 1.3% (P < .05), and ME for maintenance
      decreased 80 kJ.kg(-.75).d(-1) (P < .01) between wk 1 and 2. These large
      alterations in energy metabolism are probably a carry-over effect of the
      transportation of the pigs and (or) the changes in housing environment.

PMID- 8655430
TI  - Breed affects thermoregulation and epithelial morphology in imported and native
      cattle subjected to heat stress.
AB  - The objective of this study conducted in tropical Brazil was to characterize some
      physiological responses to heat stress in imported Bos taurus, native Bos taurus,
      and native Bos indicus cattle. Imported Simmental (n = 107) native Simmental (n =
      99), and native Bos indicus cattle (n = 121) (42 to 80 mo of age) were evaluated.
      Animals were walked 7 km at 37 degrees C and 60 to 65% relative humidity during
      midday. Rectal temperatures and respiration rates were taken before and after the
      walk. A .01-cm2 sample of cutaneous tissue from the lateral cervical region was
      obtained from each animal. Slices were stained with hematoxylin-eosin solution,
      and the epithelial strata were counted. Perimeter of the sweat glands was also
      calculated. Rectal temperatures before the walk were greater (P < .001) in
      imported Simmental (40.52 +/- .04 degrees C) than in native Simmental (38.92 +/-
      .04 degrees C) or Bos indicus (38.90 +/- .04 degrees C). Rectal temperatures
      after the walk were greater (P < .001) in native Simmental (39.87 +/- .05 degrees
      C) than in Bos indicus (39.46 +/- .05 degrees C). Because of the heat, imported
      Simmental were not capable of finishing the drive, and rectal temperatures could
      not be taken. Respiration rates before and after the walk were greater (P < .001)
      in imported Simmental (64.3 +/- .6; 95.8 +/- .8) than in native Simmental (35.0
      +/- .6; 56.8 +/- .8) or Bos indicus (15.0 +/- .2; 33.2 +/- .8). Sweat gland
      perimeter was greater (P < .001) in Bos indicus (540.5 +/- 19.1 mm) than in
      native Simmental (382.0 +/- 27.6 micrograms) or imported Simmental 497.2 +/- 17.4
      micrograms). Native Bos indicus were environmentally adapted, native Simmental
      had elevated body temperatures and respiration rates, and imported Simmental had
      dramatically increased body temperatures and respiration rates. Native Bos
      indicus cattle were environmentally adapted and differed in skin histology, sweat
      gland histometry, and number of epithelial strata.

PMID- 8655431
TI  - Effects of growth hormone and ovariectomy on performance, serum hormones, insulin
      like growth factor-binding proteins, and muscle fiber properties of prepubertal
      Friesian heifers.
AB  - Sixteen prepubertal Friesian heifers were used to examine the effect of bovine
      growth hormone (GH) and ovariectomy (OVX) at 2.5 mo of age (2 x 2 factorial
      design) on growth, carcass quality, and fiber types, capillarization, and
      metabolic potentials of the longissimus muscle, and serum concentrations of
      estradiol-17beta (E2beta), insulin, GH, IGF-I, and IGF-binding proteins (IGFBP).
      Treatment with GH (15 mg/d) started at 147 +/- 3 kg BW and lasted for 15 wk.
      Heifers were fed a mixed roughage-based diet. Growth hormone increased ADG (P <
      .001), improved gain:feed (P < .007), and had a small but positive influence on
      lean accretion. Growth hormone reduced fat thickness (P < .009), carcass fat trim
      (P < .009) and i.m. fat (P < .09). Ovariectomy did not affect performance but
      increased dressing percentage (P < .03), full rib weight (P < .003), and fat
      thickness (P < .04). Ovariectomy reduced E2beta (P < .001) and insulin (P < .02),
      and increased the 32-kDa IGFBP (IGFBP-2) (P < .09). Growth hormone treatment
      increased GH, IGF-I, the 28-kDa IGFBP, and the 40- to 43-kDa IGFBP (IGFBP-3) (P <
      .004 or P < .001). Neither GH nor ovariectomy affected the proportion and
      relative area of the individual muscle fiber types, but GH tended to increase
      type I fiber area (P < .10). Number of capillaries per fiber increased in OVX GH
      treated heifers (GH x OVX interaction, P < .02). Activities of citrate synthetase
      were higher in GH-treated (P < .05) and OVX (P < .02) heifers, indicating
      increased oxidative capacity of the longissimus muscle. The effects of GH on
      performance and carcass fattening were in accordance with the observed hormonal
      changes. When slaughter occurs before puberty, ovariectomy has no effect on
      performance, only few effects on carcass quality, and small effects on hormone
      concentrations.

PMID- 8655432
TI  - Growth performance, carcass characteristics, and sensory attributes of boars
      administered porcine somatotropin by sustained-release implant for different
      lengths of time.
AB  - We investigated the effect of sustained-release implant administration of porcine
      somatotropin (pST) (4 mg/d) to male pigs for different lengths of time before
      slaughter. Crossbred white boars were assigned to six groups (n = 10/ group); B0,
      non-implanted boars; B6, boars implanted from 22 to 28 wk of age; B12, boars
      implanted from 16 to 28 wk of age; B18, boars implanted from 10 to 28 wk of
      age;C0, non-implanted castrates; and C18, castrates implanted from 10 to 28 wk of
      age. Castration was at 65 d of age. All pigs were slaughtered at 28 wk of age,
      and measures of offal and carcass components were recorded. Loin chops were
      collected for sensory evaluation. During the trial the pigs were maintained in
      individual pens with ad libitum access to water and a 19% CP corn-soybean meal
      diet containing 1.08% calculated lysine. Although pST reduced feed intake in
      castrates (P < .01), the effect in boars was nonsignificant. Slaughter weight was
      increased in a linear (P < .04) manner with length of pST treatment of boars, and
      slaughter weights of castrates given pST were greater (P < .01) than those of
      control castrates. The product of the changes in feed intake and gain resulted in
      greater efficiency of gain in pST-treated pigs than in control pigs (P < .01). A
      linear effect (P < .06) of length of pST treatment on trimmed lean cut weights of
      boars was noted. The weights of trimmed lean cuts produced by castrates treated
      for 18 wk with pST and boars treated for 12 or 18 wk were similar. Boars given
      pST for 18 wk had improved (P < .10) boar taint scores compared with untreated
      boars. Boars and castrates given pST for 18 wk had a similar rates of gain and
      weights of trimmed lean cuts. Efficiencies of gain were greater in pST-treated
      boars and castrates than in untreated boars, which were superior to untreated
      castrates in efficiency of gain.

PMID- 8655433
TI  - A muscle hypertrophy condition in lamb (callipyge): characterization of effects
      on muscle growth and meat quality traits.
AB  - The present experiment was conducted to determine the effect of the callipyge
      phenotype on traits affecting muscle growth and meat tenderness. Dorset wethers
      (N = 40) that were either carriers or non-carriers were fed grain and slaughtered
      at 169 d of age. Callipyge phenotype did not affect (P > .05) slaughter weight,
      hot carcass weight, or weights of the heart, spleen, viscera, kidney-pelvic fat,
      head, and pelt; however, callipyge lambs had a higher dressing percentage and
      lighter lungs, liver, and kidneys (P < .01). Callipyge lambs had reduced fat
      thickness and marbling score and higher leg scores and longissimus area (34%).
      Adductor (30%), biceps femoris (42%), gluteus group (31%), longissimus (32%),
      psoas group (20%), quadriceps femoris (18%), semimembranosus (38%), and
      semitendinosus (26%) weights were higher in the callipyge phenotype (P < .01);
      however, phenotype did not affect (P > .05) weights of infraspinatus or
      supraspinatus. Longissimus pH and temperature declines were not affected (P >
      .05) by phenotype. Longissimus myofibril fragmentation index was lower at 1
      (27%), 7 (35%), and 21 (37%) d postmortem and Warner-Bratzler shear force was
      higher at 1, 7, and 21 d postmortem in the callipyge phenotype (P < .01). Shear
      force values of callipyge lambs at 21 d postmortem tended to be greater (P = .12)
      than shear force values of non-carriers at 1 d postmortem . Activities of
      calpastatin (83%) and m-calpain (45%) were higher in the callipyge (P < .01);
      however mu-calpain activity was not affected (P > .05). Longissimus and
      semitendinosus RNA concentration, DNA content, RNA content, protein content, and
      the RNA:DNA ratio were higher (P < .05), but DNA concentration, protein
      concentration, and protein:DNA were not affected in the callipyge phenotype. The
      higher calpastatin activity associated with callipyge suggests that protein
      degradation may be reduced in the live animal. Additionally, the increased muscle
      DNA content associated with the callipyge phenotype suggests an increase in
      satellite cell proliferation, and results in an increased capacity of skeletal
      muscle to accumulate and maintain myofibrillar protein. These results suggests
      that both reduced rate of protein degradation and higher capacity for protein
      synthesis are consequences of the callipyge condition.

PMID- 8655434
TI  - Relationship of restriction fragment length polymorphisms (RFLP) at the bovine
      calpastatin locus to calpastatin activity and meat tenderness.
AB  - Restriction fragment length polymorphisms (RFLP) have been identified at the
      bovine calpastatin locus. The objective of the present study was to determine
      whether these polymorphisms are related to variations in calpastatin activity or
      beef tenderness in unrelated animals of mixed breeding. A sample of 83 crossbred
      steers from sires representing eight different breeds was examined to determine
      this relationship. A 2.2-kb cDNA coding for domains 2 through 4 plus a 3'
      untranslated region of bovine skeletal muscle calpastatin was used as a probe for
      calpastatin RFLP. Polymorphisms were found using the restriction enzymes BamHI
      and EcoRI. Polymorphic restriction fragments for BamHI were 9.0 and 5.0 kb and
      for EcoRI were 6.0 and 4.0 kb. Allelic frequencies for BamHI restriction
      fragments were .53 for the 9.0-kb allele and .47 for the 5.0-kb allele. Allelic
      frequencies for EcoRI restriction fragments were .43 for the 6.0-kb allele and
      >57 for the 4.0-kb allele. No polymorphisms were identified using the restriction
      enzymes BglII, DraI, or PstI. No associations between EcoRI and BamHI RFLP and 24
      h calpastatin activity of Warner-Bratzler shear force at 14 d postmortem were
      detected. Therefore, the polymorphic EcoRI and BamHI restriction sites within the
      bovine calpastatin locus do not detect DNA sequence differences responsible for
      variation in calpastatin activity or tenderness of aged beef. Therefore, these
      polymorphisms cannot be used to predict tenderness of aged beef from unrelated
      animals of mixed breeding. These results do not exclude the possibility that
      other DNA sequences in or near the bovine calpastatin gene are responsible for
      variation in calpastatin activity or meat tenderness. The lack of a relationship
      between these calpastatin RFLP and meat tenderness must be distinguished from the
      well-documented relationship between calpastatin activity and meat tenderness.
      Therefore, further development of calpastatin-based methods for predicting beef
      tenderness in unrelated animals of mixed breeding should focus on basic factors
      influencing calpastatin activity at the molecular and cellular level.

PMID- 8655435
TI  - Feedlot performance, carcass traits, and palatability traits of Hereford and
      Hereford x Brahman steers.
AB  - Short-yearling steer of known genotypes-straightbred Hereford (100H, n = 80) 75%
      Hereford x 25% Brahman (75H:25B, n = 80), and 50% Hereford x 50% Brahman
      (50H:50B, n = 80) were sampled serially at four time-on-feed endpoints (84, 98,
      112, 126 d) to compare feedlot performance and carcass and palatability traits of
      Hereford and Hereford x Brahman steers. After slaughter, USDA yield grade and
      quality grade factors were recorded, and a portion of the longissimus muscle was
      removed from the left side of each carcass and fabricated into four 2.54-cm
      steaks for palatability analyses. Paired steaks from each carcass were aged (6
      and 18 d after death), and sensory panel and shear force evaluations were
      performed. At a constant live weight, 100H steers had higher ADG and produced
      less mature carcasses with smaller longissimus muscle areas and higher marbling
      scores than did 75H:25B and 50H:50B steers. The 50H:50B steers had the highest (P
      < .05) values for dressing percentage. Loin steak tenderness and juiciness
      decreased (P < .05) and shear force values increased (P < .05) as the percentage
      of Brahman breeding increased. EXtending the postmortem aging period from 6 to 18
      d improved shear force values by 20% and panel tenderness ratings by
      approximately 14%. Beef from steers of the three breeds responded similarly to
      aging. When Certified Hereford Beef (CHB) specifications were applied, steaks
      from 100H steers and 75H:25B steers had similar shear force values, suggesting
      that beef from quarter-blood Brahman crossbred steers could be included in the
      CHB Program without detrimental effects on product tenderness.

PMID- 8655436
TI  - Pork characteristics as affected by two populations of swine and six crude
      protein levels.
AB  - Previous research has investigated the effect of genetic line and dietary CP on
      gilt growth and carcass composition. The aim of this research was to characterize
      lean tissue composition, color, tenderness, and water-holding capacity as
      affected by protein level and genetic lines. Thirty-six Gene Pool pigs, a
      population with low lean growth potential, and 36 Hampshire pigs, a population
      with a high lean growth potential, had ad libitum access to diets consisting of
      10, 13, 16, 19, 22, or 25% CP. Longissimus muscles of Hampshire pigs were
      lighter, more red, and more yellow than those from Gene Pool pigs (P< .01).
      Redness and yellowness of longissimus muscles decreased linearly (P < .01) as
      protein level increased. Chops from Hampshire pigs required less force and less
      total energy to shear but had lower cooking yields and water-holding capacity
      than chops from Gene Pool pigs (P < .01). Chops from pigs fed 19 and 22% protein
      required greater force (quadratic, P < .01) and more total energy (quadratic, P <
      .05) to shear. Objective color differences revealed that restructured, cured hams
      from Hampshire pigs were lighter, less red, and had less intense cured color (P <
      .01). The Hampshire line of gilts produced pork muscle that was leaner, more pale
      in color, more tender, and lower in water-holding capacity than the Gene Pool
      line. Level of dietary CP caused alterations in tenderness and lean composition,
      especially when diets contained less protein.

PMID- 8655437
TI  - Development and evaluation of a regression equation of prediction for fat-free
      soft tissue in heterogenous populations of cattle.
AB  - Regression equations to predict kilograms of fat-free soft tissue (the sum of
      water and protein from chemical analyses) were developed from data collected on
      526 steers and heifers. Straightbred animals representing Angus, Braunvieh,
      Charolais, Gelbvieh, Hereford, Limousin, Pinzgauer, Red Poll, and Simmental
      breeds of cattle contributed to the data set. Cattle ranged in slaughter weight
      and age from approximately 350 to 575 kg and from 13 to 23 mo, respectively.
      Diets (100% ground alfalfa, 67% ground alfalfa and 33% ground corn or 33% ground
      alfalfa and 67% ground corn) were cross-classified with breed and sex. Estimative
      traits included in the equation were warm carcass weight, fat depth at the 12th
      rib, and body impedance. Carcass soft-tissue samples were taken for determination
      of chemical constituents. The prediction equation accounted for 94% of the
      variation in fat-free soft tissue of the carcass. Adjusting for breed-sex-diet
      contemporary groups increased the R2 value by 2% units. The prediction model was
      evaluated using data collected on 65 steers sired by Charolais or by Hereford
      bulls at the Ft Keogh Livestock and Range Research Laboratory (Miles City, MT).
      Postweaning feeding strategies and slaughter ages varied among these animals.
      Carcass weight, back fat depth, and resistive impedance measures were recorded.
      Carcass soft-tissue samples were taken for determination of chemical
      constituents. Values of estimator variables recorded at Ft. Keogh were used in
      the regression equation to predict fat-free soft tissue for each animal. The
      values for kilogram of fat-free soft tissue determined from chemical analysis
      were regressed on predicted fat-free soft tissue. the results indicate that fat
      free soft tissue of carcasses can be accurately predicted using estimative traits
      that do not diminish carcass value.

PMID- 8655438
TI  - Restaurant consumer acceptance of beef loin strip steaks tenderized with calcium
      chloride.
AB  - Beef strip loins from either the right or left side of 22 carcasses of Bos
      indicus-type steers were injected with 200 mM calcium chloride (CaCl2) solution
      at 5% (wt/wt) to determine its effect on tenderness and other selected quality
      traits of steaks. Loins from opposite sides of the carcasses were untreated and
      served as the control. The steaks were evaluated for tenderness, juiciness,
      flavor intensity, tenderness acceptability, and overall acceptability by 62
      restaurant consumers over a 6-wk period. The CaCl2 injection improved (P < .05)
      tenderness and flavor intensity ratings by the restaurant consumers. Tenderness
      acceptability and overall acceptability were improved 23 and 17%, respectively,
      by the CaCl2 injection. Flavor was not compromised by the CaCl2 injection. The
      CaCl2-treated steaks were rated superior(P < .05) for flavor compared to the
      control steaks. Restaurant consumers preferred the beef loin strip steaks
      injected with 200 mM CaCl2 at 5% (wt/wt). The results of this study are
      interpreted to indicate that, from a restaurant consumer perspective, CaCl2
      injection is an acceptable means of making beef a more consistently tender
      product.

PMID- 8655439
TI  - In vitro fermentation of cellulose, beet pulp, citrus pulp, and citrus pectin
      using fecal inoculum from cats, dogs, horses, humans, and pigs and ruminal fluid
      from cattle.
AB  - We evaluated the influence of gastrointestinal tract microflora from several
      species on fiber fermentation characteristics in vitro. Selected fibrous
      substrates (cellulose, beet pulp, citrus pulp, and citrus pectin) were incubated
      for 6, 12, 24, and 48 h with ruminal fluid from cattle or feces from dogs, cats,
      pigs, horses, or humans. When data were pooled across all substrates and
      fermentation times, OM disappearance (29.4%) and acetate, propionate, butyrate,
      and total short-chain fatty acid (SCFA) production (1.09, .41, .12, and 1.61
      mmol/g of OM, respectively) were lowest (P < .05), and lactate production (.23
      mmol/g of OM) was greatest (P < .05) for horse fecal microflora compared with
      samples from the other species. The greatest (P < .05) acetate production
      resulted when substrates were fermented by cat fecal microflora (2.38 mmol/g of
      OM). The greatest (P < .05) propionate productions resulted from pig fecal and
      cattle ruminal microflora (.88 and .83 mmol/g of OM, respectively), and the
      greatest (P < .05) butyrate productions resulted from human and pig fecal
      microflora (.39 and .40 mmol/g of OM, respectively). Total SCFA production was
      greatest (P < .05) for cat fecal microflora (3.38 mmol/g of OM). When data were
      pooled across the species, substrate OM disappearance and SCFA production ranked
      from least to greatest in the following order: cellulose < beet pulp < citrus
      pulp < citrus pectin. The fermentability of different fibrous substrates by fecal
      or ruminal microflora from various species seems to be dependent not only on the
      fermentative activity of the microbial population but on other factors as well,
      perhaps lag time and rate of digesta passage.

PMID- 8655440
TI  - Relationship of rate of lean tissue growth and other factors to concentration of
      urea in plasma of pigs.
AB  - The objectives of this study were 1) to investigate the relationship between
      plasma urea N concentrations (PUN) and lean tissue growth and 2) to compare the
      value of different variables, related to lean growth and renal function, to
      correct the relationship between dietary lysine concentration and PUN response
      for variation not related to amino acid adequacy. Forty-eight gilts (64.8 kg BW)
      were individually penned (blocks based on initial BW) for 50 d: a 10-d
      adjustment, a 35-d pretreatment, and a 5-d treatment period. During the
      pretreatment period, ADFI, urine specific gravity (SG), serum creatinine (SC),
      PUN, and daily fat-free carcass lean (DFFCL), empty body protein (DEBP), total
      carcass fat (DCF), and empty body lipid (DEBLI) depositions were measured.
      Partial correlation coefficients (ADFI effect removed) indicated a strong and
      inverse relationship between PUN and lean growth (DFFCL and DEBP) (r = -.88 and 
      .91, respectively, P < .01) and a positive relationship between PUN and fat
      deposition (DCF and DEBLI) (r = .66 and .54; respectively, P < .22). Treatments
      consisted of six dietary lysine concentrations (.475, .550, .625, .700, .775, and
      .850%). Initial and final BW in the treatment period were 103.3 and 107.7 kg,
      respectively. Pretreatment PUN (PUNO) was the pretreatment variable with the
      greatest R2 and the smallest MSE when used in the model describing the response
      of PUN (PUN1) to dietary lysine. The estimated lysine requirements from the PUN1
      response corrected with either PUN0 or with the combination of PUN0, ADFI, DFFCL,
      DCF, SG, and SC were not (P > .05) different (.656 vs > 678%, respectively). We
      conclude that 1) PUN concentrations have a potential value as an indicator of the
      efficiency of lean tissue growth and 2) pretreatment PUN is a useful variable to
      correct treatment PUN for variation not related to amino acid adequacy.

PMID- 8655441
TI  - Plasma protein for pigs weaned at 19 to 24 days of age: effect on performance and
      plasma insulin-like growth factor I, growth hormone, insulin, and glucose
      concentrations.
AB  - Three experiments were conducted to evaluate spray-dried porcine plasma (SDPP)
      protein in diets for early weaned pigs. In Exp. 1, 144 weanling pigs (24 +/- 4 d
      of age) were used to determine the effects of replacing dried skim milk (DSM)
      with either 4% SDPP or 2.75% spray-dried blood meal (SDBM) in Phase 1 diets (d 0
      to 14 postweaning). During 0 to 14, pigs fed SDPP or SDBM had higher ADG (P <
      .05) and ADFI (P < .1) than those fed DSM. Pigs fed SDPP had greater (P < .05)
      ADG and ADFI (P < .1) than those fed SDBM. In Exp. 2, performance was similar in
      pigs fed two plasma protein sources (AP-820 and MP-722). In Exp.3, 18 weanling
      pigs (19 to 20 d of age) were used to determine the effects of feeding high
      levels of SDPP on performance and on plasma IGF-I, growth hormone, insulin, and
      glucose concentrations. Pigs were fed either a control diet containing 21.5%
      soybean meal (SBM) or a diet containing 14% SDPP. Treatments were applied for 14
      d (Phase 1). During d 0 to 14, pigs fed a SDPP had a greater ADG and ADFI (P <
      .05) than pigs fed SBM. Replacing SBM with SDPP did not affect plasma IGF-I and
      glucose concentrations. However, SDPP replacement increased (P < .06) plasma
      growth hormone concentrations. Insulin levels were greater (P < .06) in pigs fed
      SBM than in those fed SDPP. These results indicate that SDPP and SDBM are
      effective alternatives to DSM or SBM in Phase 1 diets and the two plasma protein
      sources will produce similar performance. The factor(s) responsible for this
      improved performance does not seem to involve a change in plasma IGF-I.

PMID- 8655442
TI  - The effect of dietary methionine and its relationship to lysine on growth
      performance of the segregated early-weaned pig.
AB  - Two experiments were conducted to determine the dietary methionine requirement
      and the appropriate methionine:lysine for the segregated early weaned-weaned pig.
      In Exp. 1, 435 crossbred pigs (9.5 +/- 4 d of age and 3.5 kg BW) were fed diets
      (1.8% lysine, .62% cystine) containing 10% spray-dried plasma protein (SDPP) and
      1.75% spray-dried blood meal (SDBM) from day 0 to 21 postweaning. Pigs were feed
      one of six dietary treatments from .36% to .56% total dietary methionine (.317 to
      .517% apparent digestible methionine). From d 0 to 7 and d 0 to 21 postweaning,
      ADG and gain:feed ratio (G/F) increased (linear, P < .01, P < .05, respectively)
      as dietary methionine increased. In Exp. 2, 350 crossbred pigs (9.0 +/- 2 d of
      age and 3.8 kg BW) were used to determine the appropriate methionine:lysine ratio
      for the segregated early-weaned pig in a 2 x 5 factorial arrangement. Two lysine
      levels (1.8 and 1.4%) and five methionine levels within each lysine level were
      used to obtain methionine:lysine ratios ranging from 21.5 to 33.5%. From d 0 to
      21 postweaning, pigs were assigned to one of 10 dietary treatments containing 25%
      dried whey, 12% lactose, 7.5% SDPP, 6.0% select menhaden fish meal, and 1.75%
      SDBM. No methionine x lysine interactions were observed (P > .10). From d 0 to 7
      postweaning, increasing dietary methionine improved (quadratic, P < .01) ADG and
      ADFI regardless of dietary lysine. From d 0 to 14 postweaning, increasing dietary
      methionine improved ADG (quadratic, P < .01), ADFI quadratic, P =.02), and G/F
      (quadratic, P < .10). Inflection point analysis projected maximum ADG at
      methionine:lysine ratios of 27 and 27.5% for pigs fed 1.4 and 1.8% lysine,
      respectively. Cumulative (d 0 to 21 postweaning) ADG, ADFI, and G/F were improved
      (quadratic, P < .05) by increasing dietary methionine. Increasing dietary lysine
      improved (P < .01) ADG and G/F from d 0 to 7, from d 0 to 14, and for the overall
      experiment. In conclusion, a diet with 1.8% total lysine that includes spray
      dried blood products must contain .48 to .52% total dietary methionine (.437 to
      .477% apparent digestible) or 27.5% of total lysine to maximize growth
      performance of pigs from d 0 to 21 postweaning (3.5 to 12 kg BW).

PMID- 8655443
TI  - Endocrine and metabolic response to muscarinic stimulation and inhibition in the
      ruminant: effects of slaframine.
AB  - The influence of slaframine (SF), a parasympathomimetic compound isolated from
      the fungus Rizoctonia leguminicola, on circulating metabolic hormone
      concentrations was investigated in goats. In Exp. 1, SF was administered i.v. at
      0 (CONT), 50 (LSF), 100 (MSF), or 150 (HSF) microgram/kg.75 BW in four mature
      Spanish-cross does (average BW 36 +/- 7 kg) fitted with indwelling jugular vein
      catheters in a 4 x 4 Latin square design. Plasma glucose peaked (P < .06) at 120
      min with LSF and at 180 min with HSF and was higher (P <.06) than the CONT at
      these times. Glucose exhibited a quadratic response (P < .03) to SF. Area under
      the response curve for glucose differed (P < .02) in HSF from CONT and MSF.
      Insulin peaked (P < .01) at 240 min with MSF and at 180 min with HSF. Plasma
      triiodothyronine was maintained at a higher level (P < .03) with HSF. Thyroxine
      peaked (P < .06) at 120 min with MSF and 300 min with HSF. Plasma NEFA and
      somatotropin concentrations were not affected (P > .10) by SF. In Exp. 2, four
      mature Spanish-cross wethers (average BW 27 +/- 2 kg) fitted with jugular vein
      catheters were administered SF (0 and 114 micrograms/kg.75 BW) and 4
      diphenylacetoxy-N-methylpiperidine methiodide (4DAMP; 0 and 258 micrograms/kg.75
      BW), a M3-muscarinic receptor antagonist, i.v. in a 4 x 4 Latin square design
      with a 2 x 2 factorial arrangement of treatments. With SF, glucose peaked (P <
      .06) at 60 min and insulin peaked (P < .05) at 180 min. Plasma triiodothyronine
      levels were maintained (P < .05) with SF but declined with other treatments.
      Plasma NEFA and thyroxine concentrations remained unchanged regardless of
      treatment. Slaframine administration induced hyperglycemia and hyperinsulinemia
      in goats; however, these changes were blocked by preadministration of isomolar
      quantities of the M3-muscarinic receptor antagonist, 4DAMP.

PMID- 8655444
TI  - Exogenous oxytocin decreases interestrous interval of cyclic gilts.
AB  - Oxytocin (OT) stimulates pulsatile secretion of uterine PGF2 alpha in ruminants,
      but the role of OT in regulation of the estrous cycle of pigs is not clear. four
      experiments were performed to examine the effect of exogenous OT on interestrous
      interval of intact cyclic and hysterectomized gilts. In Exp. 1, i.v. injections
      of 20 USP units (equivalent to 20 IU) of OT, once/day via an ear vein on d 10,
      12, 14, and 16 after estrus, decreased (P < .01) interestrous interval (19.9 +/-
      .2 d) compared with vehicle-injected control gilts (20.8 +/- .2 d), without
      affecting ovulation rate (12.1 vs. 12.0 +/- .7 corpora lutea; OT vs control
      gilts) at subsequent estrus. In Exp. 2, i.v. infusions of 20 USP units of OT,
      twice/day via an indwelling jugular catheter on d 10 to 16 after estrus, did not
      alter interestrous interval (20.6 +/- .3 d) compared with control gilts (20.4 +/-
      .3 d). Concentrations of progesterone in jugular vein plasma did not differ
      between treatment groups on d 9 to 21 after estrus. In Exp. 3, i.m. injections of
      20 USP units of OT, twice/day on d 10 to 16 after estrus, decreased (P < .05)
      interestrous interval (20.6 +/- .4 d) compared with control gilts (22.3 +/- .4
      d). In Exp. 4, i.m. injections of 20 USP units of OT, twice/day on d 10 to 16
      after estrus, decreased (P < .05) interestrous interval (20.7 +/- .3 d) compared
      with control injections in uterine-intact gilts (21.8 +/- .3 d). None of the
      gilts hysterectomized on d 7 and treated on d 10 to 16 after estrus with either
      OT or control injections returned to estrus by d 28, and all had increased plasma
      progesterone on d 21 to 27. Mean weight of individual corpora lutea (502 vs 449
      +/- 28 mg; OT vs control gilts) and total weight of corpora lutea (5,758 vs.
      5,126 +/- 298 mg; OT vs control gilts) of hysterectomized gilts did not differ
      between treatment groups at ovariectomy on d 28. These results indicate that 1)
      exogenous OT administered on d 10 to 16 shortened the interestrous interval of
      intact cyclic gilts and 2) the effect of OT was uterine-dependent.

PMID- 8655445
TI  - An evaluation of estrus synchronization programs in reproductive management of
      dairy herds.
AB  - The objectives of this experiment were to evaluate the effect of various estrus
      synchronization programs on estrus detection rate (EDR) and pregnancy rate (PR)
      in lactating cows. Spring-calving, lactating dairy cows (n = 3,096) were
      allocated to one of six treatments: 1) PG (n = 514), estrus detection for 10 d
      before the onset of the breeding season (BS), cows detected in estrus received
      PGF2 alpha (PGF) 8 d after estrus, and all cows to be bred by d 11 of BS; 2)
      PG+EBZ (n = 510), as in PG plus cows treated with PGF received 1 mg of estradiol
      benzoate 48 h later; 3) C (n = 522), progestogen (controlled intravaginal drug
      release; CIDR) inserted per vaginum 10 d before BS for 8 d, PGF treatment on the
      day before CIDR removal, and AI within 6 d after CIDR withdrawal; 4) C+EBZ (n =
      520), as in C, plus 10 mg of estradiol benzoate 10 d before BS; 5) C+BUS (n =
      517), as in C plus 10 micrograms of buserelin on the day of CIDR insertion; or 6)
      CON (n = 513), no treatment, and a 32-d period of AI. Relative to other CIDR
      treated groups, estradiol benzoate at the time of CIDR insertion reduced (P <
      .05) the EDR (C, 85.0%;C+EBZ, 75.9%; C+BUS, 88.5%). The PR to first AI was
      reduced (P < .05) by C compared with other treatments (PG, 60.9%; PG+EBZ, 57.2%;
      C, 46.6%; C+EBZ, 60.5%; C+BUS, 57.9%; CON, 60.1%). The interval from the onset of
      BS to AI and pregnancy was reduced (P < .05) by up to 9 d by estrus
      synchronization relative to controls (PG, 5.5 +/- .2 d; PG+EBZ, 5.2 +/- .2 d; C
      1.7 +/- .1 d; C+EBZ, 2.3 +/- .1 d; C+BUS, 106 +/- .04d, CON, 10.4 +/- .3 d). In
      conclusion an 8-d progestogen-buserelin-PGF treatment resulted in the best
      overall estrus detection and pregnancy rates, which would be beneficial to a
      compact calving program.

PMID- 8655447
TI  - The effect of breeding facility and sexual stimulation on plasma cortisol in
      boars.
AB  - Nine boars were used to evaluate effects of breeding facility design and sexual
      activity on plasma cortisol concentrations . In one breeding facility
      (conventional), boars were housed individually in small pens, and female pigs
      were mated in those boar pens. In another breeding facility (Detection-Mating
      Area [DMA] system), boars were housed individually in stalls, and female pigs
      were mated in a specific mating pen adjacent to the front of stalls where boars
      were housed. After 51 d of housing treatment, a catheter was surgically implanted
      in the cephalic vein for collection of blood samples. Daytime profiles (hourly
      collections from 0900 to 1700) of cortisol did not differ among boars in the two
      treatment groups. Cortisol was greater (P < .01) in the morning than in the
      afternoon. Administration of ACTH increased (P < .001) plasma cortisol in boars,
      but breeding facility did not affect the ACTH-induced changes in cortisol
      concentrations. There was a treatment x time interaction (P < .02) for cortisol
      after sexual stimulation, and the magnitude and duration of increase in cortisol
      were greater (P < .05) in the DMA treatment group. Cortisol was greater (P <
      .001) after than before mating for both treatment groups. An acute increase in
      plasma cortisol concentration in boars seems to be a normal biological response
      to sexual activity. However, magnitude and duration of the increase in cortisol
      may be influenced by breeding facility design and mating procedure. There is no
      evidence, based on physiological data, that housing boars in stalls in the DMA
      system has any adverse effects on their welfare.

PMID- 8655446
TI  - Feed deprivation of mares: plasma metabolite and hormonal concentrations and
      responses to exercise.
AB  - Twelve light horse mares were fed a control diet that provided 100% of their
      maintenance protein and energy requirements for 7 d and were then either
      continued on the control diet or totally deprived of feed (with access to water)
      for 3 d . Plasma samples were drawn twice daily throughout the experiment, at 15
      min intervals for 9 h beginning 45 h after feed removal, and at 10-min intervals
      around an exercise bout beginning 73 h after feed removal. Feed deprivation
      increased (P < or = .06) whole blood beta-hydroxybutyrate and plasma NEFA, urea
      N, L-lactate, and glucagon concentrations, decreased (P = .02) IGF-I
      concentrations, and did not change (P > .1) plasma glucose insulin, prolactin,
      triiodothyronine, and thyroxine concentrations. Exercise increased (P < .05)
      plasma NEFA, prolactin, and growth hormone (GH) concentrations in all mares.
      Plasma NEFA concentrations increased (P < .001) after exercise and remained
      increased in fed mares, but rapidly decreased in deprived mares (time x diet
      interaction, P = .006). Plasma glucose concentrations following exercise
      increased in deprived mares but decreased in fed mares (time x diet interaction,
      P = .07). The plasma prolactin response after exercise also differed between
      groups (P = .09). Feed-deprived mares had greater (P = .02) plasma GH
      concentrations before exercise (73 h after feed withdrawal) and had a greater (P
      < .001) GH peak at 10 min after initiation of exercise. The increase in secretion
      rate o GH due to feed deprivation in these mares was similar to that reported for
      other domestic species but was not nearly as great in magnitude.

PMID- 8655448
TI  - Parturition and periparturient reproductive and metabolic hormone concentrations
      in prenatally androgenized beef heifers.
AB  - Primiparous Angus x Simmental heifers (n = 43) in a single-calf heifer (SCH)
      system (i.e., heifers are bred, calved, and placed in drylot pens with their
      calves at side and fed to slaughter weights) were studied to evaluate the effects
      of prenatal androgenization on parturition and on periparturient reproductive and
      metabolic hormone concentrations. Seven prenatally androgenized (PA) and seven
      control (C) heifers were used for blood collection to characterize parturient and
      lactation endocrine profiles; all heifers were used for blood collection to
      characterize postpartum ovarian cyclicity. Serum concentrations of progesterone,
      estradiol, testosterone, 13,14-dihydro-15-keto-PGF2 alpha (PGFM), and prolactin
      from 10 d before to 3 d after parturition were similar for PA and C heifers. Calf
      birth weights (34.7 +/- .9 kg) and calving ease scores (1.34 +/- .14) were
      similar between treatments. Postpartum ovarian cyclicity was similar; only 6 of
      22 PA (27.3%) and 3 of 21 C (14.3%) heifers were cyclic by 70 d postpartum, based
      on weekly serum progesterone concentrations. Serum concentrations of insulin,
      triiodothyronine (T3), and prolactin at 35, 70, and 105 d of lactation were
      similar for PA and C heifers; thyroxine (T4) concentrations were similar at 35
      and 70 d but greater (P < .01) at 105 d of lactation in PA heifers than in C
      heifers. Although mean serum concentrations of insulin, T3, and T4 were similar
      between treatments, prolactin concentrations were greater (P < .05) in C than in
      PA lactating heifers. We conclude that PA heifers are similar to C heifers with
      respect to parturition and to periparturient reproductive and metabolic hormone
      concentrations. Therefore, management requirements of PA primiparous beef heifers
      seem to be similar to those of C primiparous beef heifers, and PA heifers can be
      used successfully in a SCH system.

PMID- 8655449
TI  - Effects of insulin-like growth factor I and insulin on proliferation and on basal
      and luteinizing hormone-induced steroidogenesis of bovine thecal cells:
      involvement of glucose and receptors for insulin-like growth factor I and
      luteinizing hormone.
AB  - The objective of the present study was to determine the effects of IGF-I and
      insulin on cell proliferation, LH receptors, and basal and LH-induced
      progesterone and androstenedione production by bovine thecal cells. Cells from
      large (> or = 8mm) bovine follicles were cultured for 1 or 2 d in medium
      containing 10% fetal calf serum (FCS) and treated for 1 or 2 d in serum-free
      medium with IGF-I, insulin, and(or) LH. Treatment with 30 and 100 ng/mL of IGF-I
      for 1 or 2 d increased thecal cell numbers in the absence of LH regardless of
      whether treatments were initiated after 1 or 2 d of exposure to 10% FCS. Co
      treatment with LH reduced the stimulatory effect of IGF-I on thecal cell numbers.
      Insulin at 10 and 100 ng/mL increased cell numbers in the presence of LH. Both
      IGF-I and insulin were ineffective at stimulating thecal cell progesterone or
      androstenedione production in the absence of LH. However, IGF-I and insulin
      increased (P < .05) androstenedione and progesterone production in the presence
      of LH. Alone, LH had little or no effect on androstenedione and progesterone
      production, whereas in the presence of 30 and 100 ng/mL IGF-I or 1 to 100 ng/mL
      insulin, LH stimulated (P < .05) androstenedione production. The stimulatory
      effects of IGF-I on cell proliferation and progesterone production were not
      detected in the presence of 100 ng/mL insulin. However, co-treatment with various
      doses of IGF-I and 100 ng/mL insulin further increased androstenedione production
      above that seen with insulin alone. In glucose-deficient medium, 25 to 75 mg/dL
      of glucose increased (P < .05) thecal cell proliferation, progesterone
      production, and androstenedione production. In the absence or presence of
      glucose, insulin (100 ng/mL) increased (P < .05) thecal cell proliferation,
      progesterone production, and androstenedione production. Treatment with 3, 10, or
      100 ng/mL LH had no effect (P > .10) on the numbers of IGF-I binding sites on
      thecal cells but increased (P < .05) androstenedione production. Treatment with
      10 and 100 ng/mL IGF-I increased (P <.01) numbers of LH/hCG binding sites. These
      results indicate that IGF-I and insulin may each play a significant role in
      thecal cell mitogenesis and LH-induced thecal cell steroidogenesis during
      follicular development in cattle and that glucose enhances these effects.
      Furthermore, the synergism between IGF-I and LH on increasing steroidogenesis
      does not seem to be mediated through increased binding sites for IGF-I in bovine
      thecal cells but rather, in part, through increased binding sites for LH.

PMID- 8655450
TI  - Acute shifts in relaxin, progesterone, prolactin, and growth hormone secretion in
      Chinese Meishan gilts during late pregnancy and after hysterectomy.
AB  - Pregnant and hysterectomized Chinese Meishan gilts were used to investigate
      mechanisms regulating the production and secretion of relaxin, progesterone,
      prolactin (PRL), and growth hormone (GH) during different reproductive states.
      Gilts were bred to Meishan boars on the 1st d of the second observed estrus, and
      unmated gilts were hysterectomized on d 8 (estrus = d 0). Blood samples (10 mL)
      were collected twice daily (0800 and 2000) from d 9 to 120 and every 20 min
      within a 3-h period on d 112 to 116. Relaxin plasma concentrations were
      consistently greater in hysterectomized than in pregnant (6 vs 2 ng/mL, P < .05)
      gilts on d 99 to 109. The surge relaxin release on d 114 was greater in pregnant
      (66 ng/mL) than in hysterectomized gilts (34 ng/mL, P < .05). Thereafter, relaxin
      remained consistently increased (12 ng/mL) in hysterectomized gilts, whereas it
      was basal (< .5 ng/mL) during lactation. Progesterone concentrations decreased by
      half from d 109 to 115 and remained at 16 ng/mL through d 120 in hysterectomized
      pigs, whereas in pregnant pigs progesterone became basal after parturition.
      Prolactin in hysterectomized gilts remained at 4 ng/mL throughout the study
      period, whereas in pregnant gilts PRL increased steadily from 16 ng/mL on d 99 to
      39 ng/mL at parturition and remained increased during lactation. Growth hormone
      concentrations were similar in hysterectomized and pregnant gilts from d 99 to
      114; however, GH concentrations were consistently greater (P < .05) in lactating
      than in hysterectomized gilts (2.6 vs 1.0 ng/mL, respectively). These results
      indicate that PRL and GH secretions differ in pregnant and hysterectomized pigs
      because of the physiological changes necessitated by the onset of lactation.

PMID- 8655452
TI  - Cattle grazing a riparian mountain meadow: effects of low and moderate stocking
      density on nutrition, behavior, diet selection, and plant growth response.
AB  - Twelve ruminally cannulated and six intact crossbred beef steers were used in a
      randomized complete block design to evaluate the effects of stocking density of a
      riparian pasture in the Sierra Nevada mountains on grazing behavior, dietary
      selection, forage intake, digesta kinetics, and growth rates of Carex
      nebraskensis and Juncus balticus. Nine .5-ha pastures were assigned to one of
      three treatments: ungrazed (CON) or grazed to leave either 1,500 kg/ha (LOW) or
      1,000 kg/ha (MOD). Two collections were conducted during the summer of 1992
      (following winter drought) and 1993 (following above-average winter
      precipitation). Standing crop biomass was greater (P < .05) in grazed pastures
      than in CON pastures at initiation of grazing in 1992 but not in 1993. After
      grazing in both 1992 and 1993, a treatment x intrapasture location interaction
      was noted (P < .05). Tiller growth rates in both 1992 and 1993 were affected (P <
      .05) by a treatment x growth period interaction. Stocking density did not alter
      (P > .10) botanical or chemical composition of the diet in 1992, and only minor
      differences were noted (P < .05) in 1993. Forage intake, passage rate measures,
      and total time spent loafing did not differ (P > .10) between LOW and MOD steers.
      Within the mid-meadow area in 1992, loafing time was greater (P< .05) for MOD
      steers than for LOW steers. In 1993, a treatment x trial interaction was noted
      for loafing time in all three areas. Total time spent grazing was greater (P <
      .05) for MOD steers than for LOW steers in 1992 and was affected (P < .05) by a
      treatment x trial interaction in 1993. In 1992 grazing time along the streamside
      was greater (P < .05) for LOW steers than for MOD steers, and significant
      treatment x trial interactions were noted for grazing time spent along the forest
      edge and mid-meadow areas. In 1993, only streamside grazing time was influenced
      by treatment being greater (P < .05) for MOD steers than for LOW steers. In
      general, our data suggest that management decisions to reduce stocking densities
      may force cattle to congregate along streambanks and to concentrate grazing and
      loafing activities in those areas.

PMID- 8655451
TI  - Fate of the dominant follicle, embryonal survival, and pregnancy rates in dairy
      cattle treated with prostaglandin F2 alpha and progestins in the absence or
      presence of a functional corpus luteum.
AB  - Our objective was to examine the role of progestin type on serum concentrations
      of progesterone (p4) and estradiol-17 beta (E2), ovarian follicular dynamics, and
      fertility in cattle in the presence or absence of a corpus luteum (CL) in an
      estrus synchronization scheme using progestin and PGF2 alpha. In Exp. 1, 325 cows
      and heifers were given one injection of PGF2 alpha (d 0) and then assigned
      randomly within parity to five treatments: to receive a second PGF2 alpha
      injection 14 d later (control); to receive norgestomet (NORG) for 7 d beginning
      on d 8, with a second PGF2 alpha injection given either 1 d (NORG + no CL) or 6 d
      (NORG + CL) after insertion; or to receive a P4-releasing intravaginal device
      (PRID) in lieu of norgestomet at comparable times. Presence or absence of a CL
      was based on concentrations of serum P4 on d 14. Pregnancy rates after
      insemination were greater (P < .01) with luteal treatments than with nonluteal
      treatments. Embryonal survival between two stages of pregnancy was 87.6%. In Exp.
      2, ovarian structures in 50 cows were examined daily using ultrasonography and
      the same five treatments. Diameter of the ovulatory follicle was greater (P <
      .05) with the nonluteal treatments (NORG and PRID + no CL) than with the control
      and luteal treatments (PRID and NORG + CL). Replacement of the dominant follicle
      during progestin treatment was altered by treatment (luteal status) and stage of
      the estrous cycle. Fertility was not enhanced by exogenous progestins when a CL
      was present. In the absence of a CL, progestin (P4 less than NORG at the doses
      used) reduced fertility by increasing E2 and the diameter of the ovulatory
      follicle and decreasing turnover of dominant follicles.

PMID- 8655453
TI  - Influence of ruminal or abomasal starch hydrolysate infusion on pancreatic
      exocrine secretion and blood glucose and insulin concentrations in steers.
AB  - Seven Holstein steers (234 +/- 6.4 kg) surgically fitted with pancreatic
      cannulas, ruminal and abomasal infusion cannulas, and hepatic-portal vein
      catheters were used in a 4 x 7 incomplete Latin square design experiment to
      examine the influence of ruminal and abomasal carbohydrate infusion on enzyme
      secretion and composition of pancreatic juice. Four treatments were arranged in a
      2 x 2 factorial: 1) ruminal starch hydrolysate (SH; 34.2 g/[h.site]) or abomasal
      water and 2) abomasal SH or ruminal water. Starch hydrolysate is raw cornstarch
      that has been partially digested by a heat-stable alpha-amylase. Experimental
      periods were 14 d with 9 to 10 d of adaptation, 4 d of pancreatic collection, and
      blood collection on d 14. Abomasal SH infusion tended (P < .10) to increase
      pancreatic fluid secretion. The pH of pancreatic juice was higher (P < .01) for
      ruminal SH infusion, and abomasal SH infusion tended (P < .10) to result in lower
      pH of pancreatic juice. alpha-Amylase concentrations (units/milliliter and
      units/milligram of protein) and secretion (units/hour) were less (P < .002) for
      abomasal SH infusion. Chymotrypsin concentration (units/liter; P < .01) and
      secretion (units/hour; P < .10) were less for abomasal SH infusion; however, a
      rumen x abomasal interaction was found (P < .05). Chloride concentration
      (milligrams/deciliter) and secretion (milligrams/hour) were increased (P < .01)
      for abomasal SH infusion. Abomasal SH infusion resulted in increased (P < .01)
      portal blood glucose concentrations; however, portal plasma insulin concentration
      was not affected (P > .10). Abomasal SH infusion altered alpha-amylase secretion
      in steers, but ruminal SH infusion had minimal effect on alpha-amylase secretion.
      These changes suggest abosamal infusion of SH may negatively impact secretion of
      pancreatic alpha-amylase.

PMID- 8655454
TI  - In vitro ouabain-sensitive respiration and protein synthesis in rumen epithelial
      papillae of Hereford steers fed either timothy hay or timothy hay supplemented
      with cracked corn once daily.
AB  - Rumen epithelial papillae samples, acquired from the Central sac of six adult
      Hereford steers (585 +/- 17 kg) fed either timothy hay plus soybean meal (T) or
      timothy hay plus cracked corn and soybean meal (TC) once daily (0900), were used
      in a crossover design to study the daily pattern of O2 consumption and protein
      synthesis. Tissue samples were acquired at 0900, 1200, 1800, and 2400 over a 10-d
      sampling period. Additionally, ruminal fermentation characteristics (pH, ammonia,
      VFA, and osmolality) were measured at 0430, 0900, 1030, 1200, 1500, 1800, 2100
      and 2400. Total, ouabain-insensitive (OIO2), and cycloheximide-insensitive (CIO2)
      O2 consumption were greatest at 2400 (P < .01, P < .06, and P < .02
      respectively). Additionally, steer fed TC had a greater CIO2 at 2400. In
      conjunction with a temporal effect on ruminal fermentation patterns, after an
      initial decline, there was an increase (P < .05) in total O2, ouabain-sensitive
      (OSO2), OIO2, and CIO2 consumption throughout the day. Fractional rates of
      protein synthesis were not different at any time point between diets. Rumen
      epithelial metabolism exhibits a temporal pattern in cattle fed once daily.

PMID- 8655455
TI  - Mineral and nitrogen balance in lambs implanted with zeranol.
AB  - Fourteen crossbred wether lambs (average BW, 28 kg +/- 2.3) were either implanted
      (12 mg of zeranol) or not implanted and group-fed an 86% concentrate diet for 21
      d. Lambs were then moved to metabolism stalls and fed .8 kg/d for a 10-d stall
      adjustment followed by a 7-d total collection of feces and urine. Feed, feces and
      urine were analyzed for Ca, P, Mg, Zn, Mn, Cu, and N. Apparent absorption of Mn,
      Cu, and N, were similar for implanted and nonimplanted lambs. Zeranol did not
      affect (P > .10) the retention of Mn or Cu. Zeranol decreased fecal excretion of
      CA 22% (P < .01), P 27% (P < .05), Mg 11% (P < .03) and Zn 9% (P < .10). This
      increased apparent absorption of CA 88% (P < .01), P 193% ( P < .05), Mg 9% (P <
      .05) and Zn 45% (P < .10) in zeranol-treated lambs. Urinary excretion of all
      nutrients analyzed was similar for implanted and control lambs with the exception
      of N, which was reduced by 24% (P < .06) in implanted lambs. The amount of Ca,
      Mg, and Zn retained increased 98% (P < .01), 138% (P < .03), and 60% (P < .10),
      respectively, in implanted lambs compared with controls. These results indicate
      that zeranol improved N balance and enhanced the absorption and retention of Ca,
      P, Mg, and Zn in lambs.

PMID- 8655456
TI  - Rapid communication: restriction fragment length polymorphism in amplification
      products of the bovine growth hormone-releasing hormone gene.

PMID- 8655457
TI  - Rapid communication: a TaqI restriction fragment length polymorphism in the
      bovine calpastatin gene.

PMID- 8655458
TI  - Refractory multiple myeloma: recent advances in therapy.

PMID- 8655460
TI  - VLA-4-dependent adhesion in follicular non-Hodgkin's lymphomas.
AB  - The cellular contact between B cells and follicular dendritic cells (FDCs) in the
      germinal center is thought to play a key role in B-cell maturation and
      proliferation. The adhesion pathway through the very late antigen 4 (VLA-4) on
      the B cells and the vascular cell adhesion molecule 1 (VCAM-1) on the FDCs
      support this binding process. The neoplastic follicular centers in follicular non
      Hodgkin's lymphomas (FNHLs) have similar structures and cellular components to
      those of normal germinal centers, but their interaction between B cells and FDCs
      may be functionally disturbed. In view of this we analyzed the interaction
      between VLA-4 and VCAM-1 molecules in the germinal center microenvironment, both
      in neoplastic and normal follicles. The structural characterization of FNHLs and
      reactive lymph nodes was studied with indirect immunohistochemical stainings
      using monoclonal antibodies against VLA-4, VCAM-1, and fibronectin, with special
      reference to the reaction pattern in the normal and neoplastic follicles. In the
      reactive follicular centers most B cells did not show a positive reaction for VLA
      4, except for moderate reaction products in the B cells of the light zone. In
      FNHLs, on the other hand, most follicular center B cells were positive for VLA-4.
      The reaction patterns of VCAM-1 and fibronectin in both normal and neoplastic
      follicular centers were not basically different. To investigate the interaction
      of VLA-4 with VCAM-1 in both neoplastic and normal follicular centers, we
      performed a frozen-section binding assay, which found decreased binding between
      VLA-4 and VCAM-1 in FNHLs. The results of this study indicated that the
      microenvironment in neoplastic follicular centers is different from that in their
      normal counterparts, in terms of the characteristic distribution pattern of the
      VLA-4-positive B cells, and the functional deterioration of the VCAM-1 on FDCs.

PMID- 8655459
TI  - Nonradioactive detection of monoclonal immunoglobulin heavy chain gene
      rearrangement with PCR-SSCP.
AB  - The rearrangement of the immunoglobulin heavy chain gene can be used as a marker
      of B-cell lineage and clonality. By using polymerase chain reaction (PCR) with
      variable-region and joining-region specific primers it is possible to detect the
      rearrangement of a small amount of clonal B cells, as described by several
      groups. The specific PCR product can be detected after amplification with gel
      electrophoresis and ethidium bromide staining. The DNA fragments obtained from
      different clones are, however, approximately of the same size, making it
      difficult to distinguish between the clones by simple electrophoresis and
      ethidium bromide staining, as described in many reports. Single-strand
      conformational polymorphism (SSCP) was evaluated as a method to detect specific
      clonal amplicons in a mixture of PCR-amplified products. Unique patterns were
      obtained for different B-cell clones, detectable in mixtures of 0.25% clonal
      cells in normal cells. It is concluded that SSCP is a valuable method for the
      specificity control of PCR in B-lymphocyte clonality analyses. The advantages of
      the described method over previously published techniques are increased
      specificity, simplicity without radioactivity, and rapidity.

PMID- 8655461
TI  - Absence of somatic changes in p21 gene in non-Hodgkin's lymphoma and chronic
      myelogenous leukemia.
AB  - p21 is induced by and mediates the effects of p53 in response to DNA damage
      arresting the cell in G1 or G2, by inhibiting multiple cyclin-cyclin-dependent
      kinases (CDK) or binding to proliferating-cell nuclear antigen (PCNA),
      respectively. To determine whether p21 mutants occur in tumors we examined DNA
      from 188 primary non-Hodgkin's B-cell lymphoma (NHL) tumors and 84 chronic
      myelogenous leukemia samples for mutational changes in the coding region of p21
      by single-strand conformation polymorphism (SSCP) analysis and direct sequencing
      of polymerase chain reaction (PCR)-amplified DNA. We did not find mutations in
      the coding region in these two tumor types. We identified a polymorphic
      nucleotide change in codon 31 in which a transversion from C to A substituted
      amino acid arginine for serine. Three of 188 NHL tumors were homozygous for this
      change, but they were not identified in 84 CMLs or in 97 normal controls. On the
      other hand, in one CML case a transition from G to A in codon 64 substituted
      amino acid threonine for alanine. These data do not indicate that derangements in
      the coding region of p21 contribute to the initiation and/or progression of these
      tumors.

PMID- 8655462
TI  - Identification of proerythroblasts in tissue sections of bone marrow.
AB  - In paraffin-embedded sections of bone marrow fixed in B5-formalin,
      proerythroblasts from patients with marked erythroid hyperplasia displayed a
      characteristic nuclear chromatin pattern. This pattern consisted of an "arm" of
      chromatin extending from the center of the nucleus to the inner aspect of the
      nuclear envelope. In some instances the arm showed an "elbow bend." Depending on
      the plane of section, approximately 30% of proerythroblasts demonstrated these
      chromatin patterns. Ultrastructurally a similar "arm" of chromatin was seen in
      proerythroblasts. Embedded within the chromatin was a nucleolus. Although the
      significance of this pattern is as yet unknown, it provides a morphologic clue to
      identification of proerythroblasts in tissue sections.

PMID- 8655463
TI  - High-dose methylprednisolone, low-dose cytosine arabinoside, and mitoxantrone in
      children with myelodysplastic syndromes.
AB  - High-dose methylprednisolone (HDMP) has been shown to induce differentiation of
      myeloid leukemic cells with a remarkable antileukemic effect in children with
      various subtypes of acute myeloblastic leukemia (AML), therefore we used HDMP in
      the treatment of four children with myelodysplastic syndrome (MDS). Two patients
      had refractory anemia with an excess of blasts in transformation (RAEB-t) with
      extramedullary infiltration (EMI), one had chronic myelomonocytic leukemia with
      pleural effusion, and one had RAEB. HDMP was administered orally at a single dose
      of 20-30 mg/kg/day combined with low-dose cytosine arabinoside (LD Ara-C) (10
      mg/m2, 12-hourly s.c.) for 2 weeks. The treatment continued with mitoxantrone (10
      mg/m2, i.v.) and Ara-C (5 mg/kg, i.v.) once a week for four doses followed by
      maintenance chemotherapy. All patients achieved hematologic remission 2-4 weeks
      after initiation of treatment. Extramedullary infiltration disappeared in all
      cases within 2 weeks to 3 months after initiation of therapy. With the exception
      of two patients who relapsed 6 and 24 months after remission, treatment could be
      stopped in others who remained in remission for 36 months without evidence of
      EMI; 6 months later one of them developed myelodysplastic relapse (RAEB). No side
      effects related to HDMP treatment were noted, but hyperleukocytosis developed in
      two patients who initially had high WBC counts. We suggest that the addition of
      HDMP with or without LD Ara-C to cytotoxic chemotherapy offers a promising
      alternative in cases not considered suitable for bone marrow transplantation.

PMID- 8655464
TI  - Hypocellular acute myeloid leukemia: the Rochester (New York) experience.
AB  - Fourteen patients with hypocellular acute leukemia (HAL) were reviewed. The
      median age was 72 years, with an equal male-to-female ratio. Severe
      granulocytopenia with marrow hypocellularity and increased marrow blasts and
      absence of physical findings were common features. The median peripheral blood
      blast count was 2%. All except 3 cases of erythroleukemia had marrow blast count
      that exceeded 30% of all nucleated marrow cells. All cases were classifiable with
      the FAB criteria. FAB classification revealed a preponderance of the M1 category
      followed by M2 and M6 types. The majority of blasts were type I and the median
      myeloperoxidase positivity was 14%. Immunophenotyping of bone marrow cells by
      flow cytometry in 9 cases showed expression of myeloid antigens (CD13, CD33); 6
      cases also expressed CD34 antigen. Significant dysplasia involving erythroid and
      megakaryocytic lineages was seen in most of the cases. Trilineage dysplasia was
      observed in 5 cases. Median survival of the entire group was 10.5 months. Eleven
      patients underwent induction therapy consisting of daunorubicin and cytosine
      arabinoside +/- 6 thioguanine; 8 patients achieved complete remission (72.6%).
      Remission duration was 14.5 months. Three patients (27.4%) died secondary to
      infections during induction therapy. Higher frequencies of trilineage dysplasia
      and FAB M6 type together with low percentage of peripheral blasts and presence of
      antecedent hematologic disorders suggest that some of these cases might represent
      the hypocellular form of acute myeloid leukemia with trilineage dysplasia.

PMID- 8655465
TI  - Expression of renin and angiotensin-converting enzyme in human hearts.
AB  - To understand the significance of the tissue renin-angiotensin system in the
      heart, we examined the expression of renin and angiotensin-converting enzyme
      (ACE) in autopsied human hearts. Samples were taken from organs obtained at
      autopsy from 15 patients without heart disease and 3 patients with heart disease
      (old myocardial infarctions, acute myocardial infarctions, and hypertrophic
      cardiomyopathy). We examined the expression of renin and ACE mRNA by using the
      reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR showed the
      expression of renin in the right atria in all patients. However, expression of
      renin mRNA in the left ventricles was not found in any of the 15 hearts without
      heart disease. In contrast, renin mRNA was detected in the left ventricles in
      hearts with heart disease. ACE mRNA was detected in both the atria and the
      ventricles in normal hearts, and its expression did not alter in diseased hearts.
      These findings suggest that renin mRNA is expressed mainly in the right atria in
      normal hearts, but that its expression in the left ventricle can be activated in
      some pathological conditions.

PMID- 8655468
TI  - Myocardial recovery during post-ischemic reperfusion: optimal concentrations of
      Na+ and Ca2+ in the reperfusate and protective effects of amiloride added to
      cardioplegic solution.
AB  - The effects of Na+ and Ca2+ concentrations in the reperfusate on post-ischemic
      myocardial recovery were examined. Also, the myocardial protective effects of
      amiloride, an inhibitor of the Na+/Ca2+ and Na+/H+ exchange systems, added to
      cardioplegic solutions were assessed, using an isolated working rat heart
      perfusion system. Global myocardial ischemia was induced by 30-min normothermic
      cardioplegic arrest, using St. Thomas' solution. The concentration of Na+ in the
      reperfusate varied, stepwise, from 75 to 145 mM/l, and that of Ca2+, from 0.1 to
      2.5 mM/l. In this study post-ischemic functional recovery was best at 110mM/l Na+
      and 1.2-1.8 mM/l Ca2+ in the reperfusate. A significantly greater post-ischemic
      functional recovery and a lower creatine kinase release were observed when
      amiloride was added to the cardioplegic solution. Ca2+ overload via Na+/Ca2+ and
      Na+/H+ exchange systems would, thus, appear to be due, at least in part, to post
      ischemic reperfusion injury.

PMID- 8655469
TI  - Long-term results of aortic valve translocation for mycotic periannular abscess:
      comparative study of Danielson's original method and our threadless method.
AB  - Between June, 1983, and October, 1992, we performed Danielson's original
      translocation method in four patients (group I) and our translocation method in
      seven patients (group II), for the treatment of active periannular abscess. There
      were no perioperative or hospital deaths in either group. The long-term results
      of these two groups are compared in this report. There were four late deaths
      (mortality rate 100%) in group I, and three late deaths (mortality rate 43%) in
      group II. The causes of death were cardiac in six patients and noncardiac in one
      patient. Vein graft failure occurred in one group I patient (25%) and in two
      group II patients (28%). Rupture or aortic pseudoaneurysm formation occurred in
      three group I patients (75%). These findings suggest that our threadless method
      may be superior to Danielson's original translocation method. Therefore, with
      close observation, especially of saphenons vein great (SVG) failure, arterial
      graft use could be acceptable for translocation.

PMID- 8655466
TI  - Hypoxic preconditioning in isolated rat hearts: non-involvement of activation of
      adenosine A1 receptor, Gi protein, and ATP-sensitive K+ channel.
AB  - Activation of the adenosine A1(A1) receptor, Gi protein, and ATP-sensitive K+
      (KATP)-channel system has been shown to play an important role in the
      cardioprotective effects of ischemic preconditioning in dogs. The present study
      was undertaken to elucidate the possible involvement of this system in hypoxic
      preconditioning, which ameliorates injury induced by prolonged ischemia and
      subsequent reperfusion in perfused rat hearts. Ten minutes of hypoxic
      preconditioning resulted in an appreciable improvement of post-ischemic cardiac
      contractile recovery. This was associated with a significant reduction in the
      release of creatine kinase (CK) from reperfused hearts. Hypoxic preconditioning
      shortened the time to ischemic contracture onset and prevented a further rise in
      left ventricular end-diastolic pressure (LVEDP) during reperfusion. Neither the
      selective A1 receptor antagonist, 8-cyclopentyltheophylline (CPT) nor the KATP
      channel blocker, glibenclamide, altered the beneficial effects of hypoxic
      preconditioning. In vivo pretreatment with an inhibitor of Gi protein, pertussis
      toxin (PTX), also did not diminish the preconditioning effect. The results
      suggest that, although hypoxic preperfusion ameliorates post-ischemic contractile
      dysfunction, neither the activation of the A1 receptor, nor the opening of the
      KATP-channel, nor transduction through Gi protein are involved in the post
      ischemic functional recovery of hypoxic preconditioning in the perfused rat
      heart.

PMID- 8655467
TI  - Human heart-type cytoplasmic fatty acid-binding protein as an indicator of acute
      myocardial infarction.
AB  - Human heart-type cytoplasmic fatty acid-binding protein (HH-FABPc) has been
      proposed as an early biochemical indicator of acute myocardial infarction (AMI).
      However, skeletal muscles also contain HH-FABPc identical to that found in the
      heart. Before HH-FABPc can be clinically employed as an indicator of AMI, its
      content in various tissues other than the heart must be known. Accordingly, we
      measured the HH-FABPc content of various human muscles and organs, using a
      sandwich enzyme-linked immunosorbent assay (ELISA) for HH-FABPc. HH-FABPc was
      abundant in the ventricles (0.46 mg/g wet weight and 1.5% of the cytoplasmic
      protein in the left ventricle), while the atria contained slightly less HH-FABPc
      (0.25 mg/g wet weight and 0.7% of the cytoplasmic protein in the left atrium). Of
      the skeletal muscles tested, the diaphragm contained about one-quarter of the HH
      FABPc content of the heart, but other skeletal muscles contained very low levels
      of this protein. Other than the muscles, the kidneys contained less than one
      tenth of the HH-FABPc in the heart, and negligible amounts were found in the
      liver and small intestine. The distribution of HH-FABPc in the heart and skeletal
      muscles was comparable to that of cardiac-specific creatine kinase (CK-MB)
      activity, and was inverse to the distribution of myoglobin. The plasma
      myoglobin/HH-FABPc ratio, determined in patients with AMI and those without AMI,
      closely reflected that in the heart and skeletal muscles. These findings indicate
      that HH-FABPc may be useful as a specific indicator of AMI, and the plasma
      myoglobin/HH-FABPc ratio could provide valuable information for the diagnosis of
      AMI.

PMID- 8655470
TI  - Percutaneous transvenous mitral commissurotomy immediately restores quick
      response of VO2 to mild exercise despite insignificant increases in peak VO2.
AB  - Percutaneous transvenous mitral commissurotomy (PTMC) increases peak oxygen
      uptake (VO2) chronically, but not acutely, despite early symptomatic
      improvements. Analysis of transient VO2 responses to submaximal exercise (an
      exercise regimen more comparable to the patients' daily activities than that
      provided by maximal exercise testing), may be sensitive in detecting the acute
      hemodynamic benefits of PTMC. Since no methods are available to accurately
      estimate the transient response of VO2, we developed a new technique, using
      random exercise. In 15 patients who underwent successful PTMC, we repeated the
      conventional maximal exercise test and the random exercise test before and within
      a few days after PTMC. For the random exercise test, we intermittently imposed
      upright bicycle exercise at 50 W, according to a random binary sequence, while
      measuring breath-by-breath VO2. After determining the transfer function relating
      workload to VO2, we computed the high resolution VO2 response to a hypothetical
      step increase in exercise. Despite improvements in resting hemodynamics and New
      York Heart Association (NYHA) Class, peak VO2 improved insignificantly (952 +/-
      271 vs 1,029 +/- 342 ml/min, P = 0.063) shortly after successful PTMC. In
      contrast, the amplitude of the VO2 step response increased significantly in the
      early-to-mid portion (28-76s; P < 0.01-0.05). The remaining portion was
      unchanged. Consequently, the time constant shortened from 64 +/- 26 to 48 +/- 22s
      (P < 0.05). The maximal Borg scale value during random exercise decreased
      significantly (13.1 +/- 1.8 vs 11.4 +/- 1.1; P < 0.01). We conclude that the VO2
      step response, using the random exercise test, is more sensitive than peak VO2 in
      detecting the functional improvement that is coupled with the hemodynamic
      improvement immediately after PTMC.

PMID- 8655471
TI  - Magnetic resonance imaging of cardiac hemangiopericytoma.
AB  - We report a patient with hemangiopericytoma, a rare soft tissue sarcoma,
      involving the left ventricle. T1- and T2-weighted magnetic resonance imaging
      (MRI) revealed a high signal mass invading the left ventricular wall. A biopsied
      specimen obtained from the metastatic subcutaneous tumor in the right popliteal
      fossa showed pathologic findings consistent with hemangiopericytoma.

PMID- 8655472
TI  - Cold shock and cold acclimation proteins in the psychrotrophic bacterium
      Arthrobacter globiformis SI55.
AB  - The psychrotrophic bacterium Arthrobacter globiformis SI55 was grown at 4 and 25
      degrees C, and the cell protein contents were analyzed by two-dimensional
      electrophoresis. Cells subjected to cold shocks of increasing magnitude were also
      analyzed. Correspondence analysis of protein appearance distinguished four groups
      of physiological significance. Group I contained cold shock proteins (Csps)
      overexpressed only after a large temperature downshift. Group II contained Csps
      with optimal expression after mild shocks. Group III contained proteins
      overexpressed after all cold shocks. These last proteins were also overexpressed
      in cells growing at 4 degrees C and were considered to be early cold acclimation
      proteins (Caps). Group IV contained proteins which were present at high
      concentrations only in 4 degrees C steady-state cells and appeared to be late
      Caps. A portion of a gene very similar to the Escherichia coli cspA gene
      (encoding protein CS7.4) was identified. A synthetic peptide was used to produce
      an antibody which detected a CS7.4-like protein (A9) by immunoblotting two
      dimensional electrophoresis gels of A. globiformis SI55 total proteins. Unlike
      mesophilic microorganisms, this CS7.4-like protein was still produced during
      prolonged growth at low temperature, and it might have a particular adaptive
      function needed for balanced growth under harsh conditions. However, A9 was
      induced at high temperature by chloramphenicol, suggesting that CS7.4-like
      proteins have a more general role than their sole implication in cold acclimation
      processes.

PMID- 8655473
TI  - delta psi-mediated signalling in the bacteriorhodopsin-dependent photoresponse.
AB  - It has been shown previously that the proton-pumping activity of
      bacteriorhodopsin from Halobacterium salinarium can transmit an attractant signal
      to the bacterial flagella upon an increase in light intensity over a wide range
      of wavelengths. Here, we studied the effect of blue light on phototactic
      responses by the mutant strain Pho8l-B4, which lacks both sensory rhodopsins but
      has the ability to synthesize bacteriorhodopsin. Under conditions in which
      bacteriorhodopsin was largely accumulated as the M412 bacteriorhodopsin
      photocycle intermediate, halobacterial cells responded to blue light as a
      repellent. This response was pronounced when the membrane electric potential
      level was high in the presence of arginine, active oxygen consumption, or high
      background long-wavelength light intensity but was inhibited by an uncoupler of
      oxidative phosphorylation (carbonyl cyanide 3-chlorophenylhydrazone) and was
      inverted in a background of low long-wavelength light intensity. The response to
      changes in the intensity of blue light under high background light was
      asymmetric, since removal of blue light did not produce an expected suppression
      of reversals. Addition of ammonium acetate, which is known to reduce the pH
      gradient changes across the membrane, did not inhibit the repellent effect of
      blue light, while the discharge of the membrane electric potential by
      tetraphenylphosphonium ions inhibited this sensory reaction. We conclude that the
      primary signal from bacteriorhodopsin to the sensory pathway involves changes in
      membrane potential.

PMID- 8655475
TI  - Conformational change of the hexagonally packed intermediate layer of Deinococcus
      radiodurans monitored by atomic force microscopy.
AB  - Both surfaces of the hexagonally packed intermediate (HPI) layer of Deinococcus
      radiodurans were imaged in buffer solution by atomic force microscopy. When
      adsorbed to freshly cleaved mica, the hydrophilic outer surface of the HPI layer
      was attached to the substrate and the hydrophobic inner surface was exposed to
      the stylus. The height of a single HPI layer was 7.0 nm, while overlapping edges
      of adjacent single layers adsorbed to mica had a height of 14.7 nm. However,
      double-layered stacks with inner surfaces facing each other exhibited a height of
      17.4 nm. These stacks exposed the outer surface to the stylus. The different
      heights of overlapping layers and stacks are attributed to differences in the
      interaction between inner and outer surfaces. At high resolution, the inner
      surface revealed a protruding core with a central pore connected by six emanating
      arms. The pores exhibited two conformations, one with and the other without a
      central plug. Individual pores were observed to switch from one state to the
      other.

PMID- 8655474
TI  - Cloning, sequencing, and expression of clustered genes encoding beta
      hydroxybutyryl-coenzyme A (CoA) dehydrogenase, crotonase, and butyryl-CoA
      dehydrogenase from Clostridium acetobutylicum ATCC 824.
AB  - The enzymes beta-hydroxybutyryl-coenzyme A (CoA) dehydrogenase (BHBD), crotonase,
      and butyryl-CoA dehydrogenase (BCD) from Clostridium acetobutylicum are
      responsible for the formation of butyryl-CoA from acetoacetyl-CoA. These enzymes
      are essential to both acid formation and solvent formation by clostridia.
      Clustered genes encoding BHBD, crotonase, BCD, and putative electron transfer
      flavoprotein alpha and beta subunits have been cloned and sequenced. The
      nucleotide sequence of the crt gene indicates that it encodes crotonase, a
      protein with 261 amino acid residues and a calculated molecular mass of 28.2 kDa;
      the hbd gene encodes BHBD, with 282 residues and a molecular mass of 30.5 kDa.
      Three open reading frames (bcd, etfB, and etfA) are located between crt and hbd.
      The nucleotide sequence of bcd indicates that it encodes BCD, which consists of
      379 amino acid residues and has high levels of homology with various acyl-CoA
      dehydrogenases. Open reading frames etfB and etfA, located downstream of bcd,
      encode 27.2- and 36.1-kDa proteins, respectively, and show homology with the
      fixAB genes and the alpha and beta subunits of the electron transfer
      flavoprotein. These findings suggest that BCD in clostridia might interact with
      the electron transfer flavoprotein in its redox function. Primer extension
      analysis identified a promoter consensus sequence upstream of the crt gene,
      suggesting that the clustered genes are transcribed as a transcriptional unit and
      form a BCS (butyryl-CoA synthesis) operon. A DNA fragment containing the entire
      BCS operon was subcloned into an Escherichia coli-C. acetobutylicum shuttle
      vector. Enzyme activity assays showed that crotonase and BHBD were highly
      overproduced in cell extracts from E. coli harboring the subclone. In C.
      acetobutylicum harboring the subclone, the activities of the enzymes crotonase,
      BHBD, and BCD were elevated.

PMID- 8655476
TI  - Succinate:quinone oxidoreductase (complex II) containing a single heme b in
      facultative alkaliphilic Bacillus sp. strain YN-2000.
AB  - Succinate:quinone oxidoreductase (EC 1.3.5.1) was first purified from the
      facultative alkaliphilic Bacillus sp. strain YN-2000 in the presence of Triton X
      100. The isolated enzyme showed high succinate-ubiquinone oxidoreductase activity
      at pH 8.5. The Km for ubiquinone 1 and the Vmax of the enzyme were determined to
      be about 5 microM and 48 micromol of ubiquinone 1 per min per mg, respectively.
      The catalytic activity of the enzyme was 50% inhibited by 9 microM 2
      thenoyltrifluoroacetone or 0.8 microM 2-n-heptyl-4-hydroxyquinoline- N-oxide. The
      enzyme consisted of three kinds of subunits with molecular masses of 66, 26, and
      15 kDa, respectively, and contained 1.28 mol of covalently bound flavin adenine
      dinucleotide, 0.9 mol of heme b, 1.35 mol of menaquinone, 8.3 mol of nonheme
      iron, and 7.5 mol of inorganic sulfide per mol of enzyme. The enzyme showed
      symmetrical alpha absorption peaks at 556.5 and 554 nm in the reduced state at
      room temperature and 77 K, respectively. The potentiometric analysis of the
      enzyme yielded an Em,7 of heme b of about -64 mV (n = 1). Furthermore, the
      content of the enzyme was increased up to fivefold when the bacterium was grown
      at pH 10 compared with pH 7. These results indicate that the succinate:quinone
      oxidoreductase with a single heme b is involved in the respiratory chain of the
      alkaliphile at a very alkaline pH.

PMID- 8655477
TI  - Redundant homosexual F transfer facilitates selection-induced reversion of
      plasmid mutations.
AB  - F plasmids use surface exclusion to prevent the redundant entry of additional F
      plasmids during active growth of the host cells. This mechanism is relaxed during
      stationary phase and nonlethal selections, allowing homosexual redundant plasmid
      transfer. Homosexual redundant transfer occurs in stationary-phase liquid
      cultures, within nongrowing populations on solid media, and on media lacking a
      carbon source. We examined the relationship between homosexual redundant
      transfer, which occurs between F+ hosts, and reversion of a plasmid-encoded lac
      mutant allele, lacI33omegalacZ. Sodium dodecyl sulfate (SDS) and mutations that
      prevent normal transfer to F- cells reduced redundant transfer and selection
      induced reversion of the lacI33omegalacZ allele. A recA null mutation reduced
      redundant transfer and selection-induced reversion of the lacI33omegalacZ
      mutation. Conversely, a recD null mutation increased redundant transfer and
      selection-induced reversion of the lacI33omegalacZ allele. These results suggest
      an explanation for why SDS and these mutations affect reversion of the plasmid
      lacI33omegalacZ allele. However, a direct causal relationship between transfer
      and reversion remains to be established. These results suggest that Rec proteins
      play an active role in redundant transfer and/or that redundant transfer is
      regulated with the activation of recombination. Redundant homosexual plasmid
      transfer during a period of stress may represent a genetic response that
      facilitates evolution of plasmid-encoded functions through mutation,
      recombination, reassortment, and dissemination of genetic elements present in the
      populations.

PMID- 8655478
TI  - Dihydrolipoamide dehydrogenase from the halophilic archaeon Haloferax volcanii:
      homologous overexpression of the cloned gene.
AB  - The gene encoding dihydrolipoamide dehydrogenase from the halophilic archaeon,
      Haloferax volcanii, has been subcloned and overexpressed in the parent organism
      by using the halophilic archaeal rRNA promoter. The recombinant protein has been
      purified to homogeneity and characterized with respect to its kinetic, molecular,
      and salt-dependent properties. A dihydrolipoamide dehydrogenase-minus mutant of
      H. volcanii has been created by homologous recombination with the subcloned gene
      after insertion of the mevinolin resistance determinant into the protein-coding
      region. To explore the physiological function of the dihydrolipoamide
      dehydrogenase, the growth properties of the mutant halophile have been examined.

PMID- 8655479
TI  - Biotinylation in vivo as a sensitive indicator of protein secretion and membrane
      protein insertion.
AB  - Escherichia coli biotin ligase is a cytoplasmic protein which specifically
      biotinylates the biotin-accepting domains from a variety of organisms. This in
      vivo biotinylation can be used as a sensitive signal to study protein secretion
      and membrane protein insertion. When the biotin-accepting domain from the 1.3S
      subunit of Propionibacterium shermanii transcarboxylase (PSBT) is translationally
      fused to the periplasmic proteins alkaline phosphatase and maltose-binding
      protein, there is little or no biotinylation of PSBT in wild-type E. coli.
      Inhibition of SecA with sodium azide and mutations in SecB, SecD, and SecF, all
      of which slow down protein secretion, result in biotinylation of PSBT. When PSBT
      is fused to the E. coli inner membrane protein MalF, it acts as a topological
      marker: fusions to cytoplasmic domains of MalF are biotinylated, and fusions to
      periplasmic domains are generally not biotinylated. If SecA is inhibited by
      sodium azide or if the SecE in the cell is depleted, then the insertion of the
      MalF second periplasmic domain is slowed down enough that PSBT fusions in this
      part of the protein become biotinylated. Compared with other protein fusions that
      have been used to study protein translocation, PSBT fusions have the advantage
      that they can be used to study the rate of the insertion process.

PMID- 8655480
TI  - A new cell surface proteinase: sequencing and analysis of the prtB gene from
      Lactobacillus delbruekii subsp. bulgaricus.
AB  - Investigation of the chromosomal region downstream of the lacZ gene from
      Lactobacillus delbrueckii subsp. bulgaricus revealed the presence of a gene
      (prtB) encoding a proteinase of 1,946 residues with a predicted molecular mass of
      212 kDa. The deduced amino acid sequence showed that PrtB proteinase displays
      significant homology with the N termini and catalytic domains of lactococcal PrtP
      cell surface proteinases and is probably synthesized as a preproprotein. However,
      the presence of a cysteine near the histidine of the PrtB active site suggests
      that PrtB belongs to the subfamily of cysteine subtilisins. The C-terminal region
      strongly differs from those of PrtP proteinases by having a high lysine content,
      an imperfect duplication of 41 residues, and a degenerated sequence compared with
      the consensus sequence for proteins anchoring in the cell walls of gram-positive
      bacteria. Finally, the product of the truncated prtM-like gene located
      immediately upstream of the prtB gene seems too short to be involved in the
      maturation of PrtB.

PMID- 8655481
TI  - Identification and characterization of BpH2, a novel histone H1 homolog in
      Bordetella pertussis.
AB  - A basic protein, BpH2, with an apparent molecular mass of 18 kDa was purified
      from Bordetella pertussis, and the corresponding gene, bph2, was cloned. Sequence
      analysis revealed some homology to the H1 class of eukaryotic histones and to
      AlgP protein of Pseudomonas aeruginosa. BpH2 binds both single- and double
      stranded DNA in a nonspecific manner. Deletion of the corresponding gene in B.
      pertussis generated a BpH2 null mutant with an altered growth rate in which the
      expression of two virulence factors, adenylate cyclase-hemolysin (CyaA) and
      filamentous hemagglutinin (FhaB), was reduced. It is suggested that BpH2 may
      exhibit specific regulatory functions through its interaction with chromosomal
      DNA.

PMID- 8655482
TI  - Growth suppression in early-stationary-phase nutrient broth cultures of
      Salmonella typhimurium and Escherichia coli is genus specific and not regulated
      by sigma S.
AB  - We have studied the growth suppression seen in early-stationary-phase LB broth
      cultures of Salmonella typhimurium. Multiplication of small numbers of an
      antibiotic-resistant S. typhimurium mutant was prevented when the mutant was
      added to 24-h cultures of the antibiotic-sensitive parent strain, whereas an
      antibiotic-resistant mutant of an Escherichia coli strain added to the same
      culture grew well. A 24-h E. coli culture produced a similar specific
      bacteriostatic inhibition against E. coli. In older cultures, a specific
      bactericidal effect similar to that observed by M. M. Zambrano and R. Kolter (J.
      Bacteriol. 175:5642-5647, 1993) was also observed. Whether incubated statically
      or shaken, sufficient nutrients were present in the filtered supernatants of 24-h
      cultures for small inocula of the same strain to multiply to ca. 10(9) CFU/ml
      after reincubation. Introduction of the rpoS mutation had no effect on the
      specific bacteriostatic inhibition. Similar specific inhibition was also observed
      in strains of Citrobacter freundii, Klebsiella pneumoniae, Enterobacter
      agglomerans, and Shigella spp. Experiments in which the 24-h culture was
      physically separated from the antibiotic-resistant mutant by using a dialysis
      membrane were carried out. These results indicated that the inhibition might be
      mediated by a diffusible but labile chemical mediator.

PMID- 8655484
TI  - The role of specific surface loop regions in determining the function of the
      imipenem-specific pore protein OprD of Pseudomonas aeruginosa.
AB  - Pseudomonas aeruginosa OprD is a specific porin which facilitates the uptake of
      basic amino acids and imipenem across the outer membrane. In this study, we
      examined the effects of deletions in six of the proposed eight surface loops of
      OprD on the in vivo and in vitro functions of this protein. Native OprD formed
      very small channels in planar lipid bilayers, with an average single-channel
      conductance in 1.0 M KCl of 20 pS. When large numbers of OprD channels were
      incorporated into lipid bilayer membranes, addition of increasing concentrations
      of imipenem to the bathing solutions resulted in a progressive blocking of the
      membrane conductance of KCl, indicating the presence of a specific binding
      site(s) for imipenem in the OprD channel. From these experiments, the
      concentration of imipenem value of resulting in 50% inhibition of the initial
      conductance was calculated as approximately 0.6 microM. In contrast, no decrease
      in channel conductance was observed for the OprDdeltaL2 channel upon addition of
      up to 2.4 microM imipenem, confirming that external loop 2 was involved in
      imipenem binding. Deletion of four to eight amino acids from loops 1 and 6 had no
      effect on antibiotic susceptibility, whereas deletion of eight amino acids from
      loops 5, 7, and 8 resulted in supersusceptibility to beta-lactams, quinolones,
      chloramphenicol, and tetracycline. Planar lipid bilayer analysis indicated that
      the OprDdeltaL5 channel had a 33-fold increase in single-channel conductance in 1
      M KCl but had retained its imipenem binding site. The disposition of these loop
      regions in the interior of the OprD channel is discussed.

PMID- 8655485
TI  - Efficient homologous recombination in fast-growing and slow-growing mycobacteria.
AB  - Although homologous recombination is a major mechanism for DNA rearrangement in
      most living organisms, it has been difficult to detect in slowly growing
      mycobacteria by a classical suicide vector approach. Among the possible reasons
      for this are the low levels of transformation efficiency, the relatively high
      levels of illegitimate recombination, and the peculiar nature of the recA gene in
      slowly growing mycobacteria. In this report, we present an efficient homologous
      recombination system for these organisms based on the use of replicative plasmids
      which facilitates the detection of rare recombination events, because the
      proportions of recombined molecules increase over time. Intraplasmid homologous
      recombination in Mycobacterium smegmatis and Mycobacterium bovis BCG was easily
      selected by the reconstitution of an interrupted kanamycin resistance gene.
      Chromosomal integration via homologous recombination was selected by the
      expression of the kanamycin resistance gene under the control of a chromosomal
      promoter that was not present in the plasmid before recombination. This technique
      was termed STORE (for selection technique of recombination events). All the
      clones selected by STORE had undergone homologous recombination, as evidenced by
      PCR analyses of the kanamycin-resistant clones. This technique should be
      applicable to all organisms for which homologous recombination has been difficult
      to achieve, provided the gene of interest is expressed.

PMID- 8655483
TI  - A new type of cohesin domain that specifically binds the dockerin domain of the
      Clostridium thermocellum cellulosome-integrating protein CipA.
AB  - The cellulosome-integrating protein CipA, which serves as a scaffolding protein
      for the cellulolytic complex produced by Clostridium thermocellum, comprises a
      COOH-terminal duplicated segment termed the dockerin domain. This paper reports
      the cloning and sequencing of a gene, termed sdbA (for scaffoldin dockerin
      binding), encoding a protein which specifically binds the dockerin domain of
      CipA. The sequenced fragment comprises an open reading frame of 1,893 nucleotides
      encoding a 631-amino-acid polypeptide, termed SdbA, with a calculated molecular
      mass of 68,577 kDa. SAA comprises an NH2-terminal leader peptide followed by
      three distinct regions. The NH2-terminal region is similar to the NH2-terminal
      repeats of C. thermocellum OlpB and ORF2p. The central region is rich in lysine
      and harbors a motif present in Streptococcus M proteins. The COOH-terminal region
      consists of a triplicated sequence present in several bacterial cell surface
      proteins. The NH2-terminal region of SdbA and a fusion protein carrying the first
      NH2-terminal repeat of OlpB were shown to bind the dockerin domain of CipA. Thus,
      a new type of cohesin domain, which is present in one, two, and four copies in
      SdbA, ORF2p, and OlpB, respectively, can be defined. Since OlpB and most likely
      SdbA and ORF2p are located in the cell envelope, the three proteins probably
      participate in anchoring CipA (and the cellulosome) to the cell surface.

PMID- 8655487
TI  - Modeling and measuring the elastic properties of an archaeal surface, the sheath
      of Methanospirillum hungatei, and the implication of methane production.
AB  - We describe a technique for probing the elastic properties of biological
      membranes by using an atomic force microscope (AFM) tip to press the biological
      material into a groove in a solid surface. A simple model is developed to relate
      the applied force and observed depression distance to the elastic modulus of the
      material. A measurement on the proteinaceous sheath of the archaebacterium
      Methanospirillum hungatei GP1 gave a Young's modulus of 2 x 10(10) to 4 x 10(10)
      N/m2. The measurements suggested that the maximum sustainable tension in the
      sheath was 3.5 to 5 N/m. This finding implied a maximum possible internal
      pressure for the bacterium of between 300 and 400 atm. Since the cell membrane
      and S-layer (wall) which surround each cell should be freely permeable to methane
      and since we demonstrate that the sheath undergoes creep (expansion) with
      pressure increase, it is possible that the sheath acts as a pressure regulator by
      stretching, allowing the gas to escape only after a certain pressure is reached.
      This creep would increase the permeability of the sheath to diffusible
      substances.

PMID- 8655486
TI  - Cloning and expression of the first anaerobic toxin gene from Clostridium
      bifermentans subsp. malaysia, encoding a new mosquitocidal protein with
      homologies to Bacillus thuringiensis delta-endotoxins.
AB  - A gene (cbm71) encoding a 71,128-Da mosquitocidal protein (Cbm71) was obtained by
      screening a size-fractionated XbaI digest of total genomic DNA from Clostridium
      bifermentans subsp. malaysia CH18 with two gene-specific oligonucleotide probes.
      The sequence of the Cbm71 protein, as deduced from the sequence of cbm71,
      corresponds to that of the 66-kDa protein previously described as one of the
      mosquitocidal components of C. bifermentans subsp. malaysia. Cbm71 shows limited
      similarities with Bacillus thuringiensis delta-endotoxins, especially in the four
      first conserved blocks. However, Cbm71 was not immunologically related to any of
      the Cry toxins and thus belongs to a novel class of mosquitocidal protein. The
      cbm71 gene was expressed in a nontoxic strain of B. thuringiensis, and Cbm71 was
      produced during sporulation and secreted to the supernatant of culture.
      Trichloroacetic-precipitated supernatant preparations were toxic for mosquito
      larvae of the species Aedes aegypti, Culex pipiens, and Anopheles stephensi.

PMID- 8655488
TI  - Role of FlgM in sigma D-dependent gene expression in Bacillus subtilis.
AB  - The alternative sigma factor sigma D directs transcription of a number of genes
      involved in chemotaxis, motility, and autolysis in Bacillus subtilis (sigmaD
      regulon). The activity of SigD is probably in contrast to that of FlgM, which
      acts as an antisigma factor and is responsible for the coupling of late flagellar
      gene expression to the assembly of the hook-basal body complex. We have
      characterized the effects of an in-frame deletion mutation of flgM. By
      transcriptional fusions to lacZ, we have shown that in FlgM-depleted strains
      there is a 10-fold increase in transcription from three different sigmaD
      dependent promoters, i.e., Phag, PmotAB, and PfliDST. The number of flagellar
      filaments was only slightly increased by the flgM mutation. Overexpression of
      FlgM from a multicopy plasmid under control of the isopropyl-beta-D
      thiogalactopyranoside-inducible spac promoter drastically reduced the level of
      transcription from the hag promoter. On the basis of these results, we conclude
      that, as in Salmonella typhimurium, FlgM inhibits the activity of SigD, but an
      additional element is involved in determining the number of flagellar filaments.

PMID- 8655489
TI  - Regulatory proteins and cis-acting elements involved in the transcriptional
      control of Rhizobium etli reiterated nifH genes.
AB  - In Rhizobium etli the nitrogenase reductase genes are reiterated. Strain CE3 has
      three copies; nifHa and nifHb form part of nifHDK operons with the nitrogenase
      structural genes, while nifHc is linked to a truncated nifD homolog. Their
      sequences are identical up to 6 residues upstream from a sigma54-dependent
      promoter. A remarkable difference among them is the absence of canonical NifA
      binding sites upstream of nifHc while a canonical binding site is located 200 bp
      upstream of nifHa and nifHb. To evaluate the transcriptional regulation of the
      reiterated nifH genes, we constructed fusions of nifHa and nifHc with the lacZ
      gene of Escherichia coli. Both genes were expressed at maximum levels under 1%
      oxygen in free-living cultures, and their expression declined as the oxygen
      concentration was increased. This expression was dependent on the integrity of
      nifA, and nifHc was expressed at higher levels than nifHa. The same pattern was
      observed with root nodule bacteroids. Expression of both genes in E. coli
      required sigma54 in addition to NifA bound to the upstream activator sequence. In
      vivo dimethyl sulfate footprinting analyses showed that NifA binds to the
      canonical site upstream of nifHa and to a TGT half-site 6 nucleotides further
      upstream. NifA protected an imperfect binding site upstream of nijHc at position
      85 from the promoter. The integration host factor stimulated each gene
      differently, nifHa being more dependent on this protein. The above results
      correlate the asymmetric arrangement of cis-acting elements with a differential
      expression of the reiterated nifH genes, both in culture and during symbiosis
      with bean plants.

PMID- 8655490
TI  - The proton motive force generated in Leuconostoc oenos by L-malate fermentation.
AB  - In cells of Leuconostoc oenos, the fermentation of L-malic acid generates both a
      transmembrane pH gradient, inside alkaline, and an electrical potential gradient,
      inside negative. In resting cells, the proton motive force ranged from -170 mV to
      -88 mV between pH 3.1 and 5.6 in the presence Of L-malate. Membrane potentials
      were calculated by using a model for probe binding that accounted for the
      different binding constants at the different pH values at the two faces of the
      membrane. The delta psi generated by the transport of monovalent malate, H-malate
      , controlled the rate of fermentation. The fermentation rate significantly
      increased under conditions of decreased delta psi, i.e., upon addition of the
      ionophore valinomycin in the presence of KCl, whereas in a buffer depleted of
      potassium, the addition of valinomycin resulted in a hyperpolarization of the
      cell membrane and a reduction of the rate of fermentation. At the steady state,
      the chemical gradient for H-malate- was of the same magnitude as delta psi.
      Synthesis of ATP was observed in cells performing malolactic fermentation.

PMID- 8655492
TI  - Effect of CO2 on the fermentation capacities of the acetogen Peptostreptococcus
      productus U-1.
AB  - The fermentative capacities of the acetogenic bacterium Peptostreptococcus
      productus U-1 (ATCC 35244) were examined. Although acetate was formed from all
      the substrates tested, additional products were produced in response to CO2
      limitation. Under CO2-limited conditions, fructose-dependent growth yielded high
      levels of lactate as a reduced end product; lactate was also produced under CO2
      enriched conditions when fructose concentrations were elevated. In the absence of
      supplemental CO2, xylose-dependent growth yielded lactate and succinate as major
      reduced end products. Although supplemental CO2 and acetogenesis stimulated cell
      yields on fructose, xylose-dependent cell yields were decreased in response to
      CO2 and acetogenesis. In contrast, glycerol-dependent growth yielded high levels
      of ethanol in the absence of supplemental CO2, and pyruvate was subject to only
      acetogenic utilization independent of CO2. CO2 pulsing during the growth of CO2
      limited fructose cultures stopped lactate synthesis immediately, indicating that
      CO2-limited cells were nonetheless metabolically poised to respond quickly to
      exogenous CO2. Resting cells that were cultivated at the expense of fructose
      without supplemental CO2 readily consumed fructose in the absence of exogenous
      CO2 and formed only lactate. Although the specific activity of lactate
      dehydrogenase was not appreciably influenced by supplemental C02 during
      cultivation, cells cultivated on fructose under CO2-enriched conditions displayed
      minimal capacities to consume fructose in the absence of exogenous CO2. These
      results demonstrate that the utilization of alternative fermentations for the
      conservation of energy and growth of P. productus U-1 is augmented by the
      relative availability of CO2 and growth substrate.

PMID- 8655491
TI  - Site-directed mutagenesis of conserved amino acids in the alpha subunit of
      toluene dioxygenase: potential mononuclear non-heme iron coordination sites.
AB  - The terminal oxygenase component of toluene dioxygenase from Pseudomonas putida
      F1 is an iron-sulfur protein (ISP(TOL)) that requires mononuclear iron for enzyme
      activity. Alignment of all available predicted amino acid sequences for the large
      (alpha) subunits of terminal oxygenases showed a conserved cluster of potential
      mononuclear iron-binding residues. These were between amino acids 210 and 230 in
      the alpha subunit (TodC1) of ISP(TOL). The conserved amino acids, Glu-214, Asp
      219, Tyr-221, His-222, and His-228, were each independently replaced with an
      alanine residue by site-directed mutagenesis. Tyr-266 in TodC1, which has been
      suggested as an iron ligand, was treated in an identical manner. To assay toluene
      dioxygenase activity in the presence of TodC1 and its mutant forms, conditions
      for the reconstitution of wild-type ISP(TOL) activity from TodC1 and purified
      TodC2 (beta subunit) were developed and optimized. A mutation at Glu-214, Asp
      219, His-222, or His-228 completely abolished toluene dioxygenase activity. TodC1
      with an alanine substitution at either Tyr-221 or Tyr-266 retained partial enzyme
      activity (42 and 12%, respectively). In experiments with [14C]toluene, the two
      Tyr-->Ala mutations caused a reduction in the amount of Cis-[14C]-toluene
      dihydrodiol formed, whereas a mutation at Glu-214, Asp-219, His-222, or His-228
      eliminated cis-toluene dihydrodiol formation. The expression level of all of the
      mutated TWO proteins was equivalent to that of wild-type TodC1 as judged by
      sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot
      (immunoblot) analyses. These results, in conjunction with the predicted amino
      acid sequences of 22 oxygenase components, suggest that the conserved motif Glu
      X3-4,-Asp-X2-His-X4-5-His is critical for catalytic function and the glutamate,
      aspartate, and histidine residues may act as mononuclear iron ligands at the site
      of oxygen activation.

PMID- 8655493
TI  - Evidence that SbcB and RecF pathway functions contribute to RecBCD-dependent
      transductional recombination.
AB  - A role for the RecF, RecJ, and SbcB proteins in the RecBCD-dependent
      recombination pathway is suggested on the basis of the effect of null recF, recJ,
      and sbcB mutations in Salmonella typhimurium on a "short-homology" P22
      transduction assay. The assay requires recombination within short (approximately
      3-kb) sequences that flank the selected marker and lie at the ends of the
      transduced fragment. Since these ends are subject to exonucleolytic degradation,
      the assay may demand rapid recombination by requiring that the exchange be
      completed before the essential recombining sequences are degraded. In this assay,
      recF, recJ, and sbcB null mutations, tested individually, cause a small decrease
      in recombinant recovery but all pairwise combinations of these mutations cause a
      10- to 30-fold reduction. In a recD mutant recipient, which shows increased
      recombination, these pairwise mutation combinations cause a 100-fold reduction in
      recombinant recovery. In a standard transduction assay (about 20 kb of flanking
      sequence), recF, recJ, and sbcB mutations have a very small effect on recombinant
      frequency. We suggest that these three proteins promote a rate-limiting step in
      the RecBC-dependent recombination process. The above results were obtained with a
      lysogenic recipient strain which represses expression of superinfecting phage
      genomes and minimizes the contribution of phage recombination functions. When a
      nonlysogenic recipient strain is used, coinfecting phage genomes express
      functions that alter the genetic requirements for recombination in the short
      homology assay.

PMID- 8655495
TI  - The Agrobacterium tumefaciens VirB7 lipoprotein is required for stabilization of
      VirB proteins during assembly of the T-complex transport apparatus.
AB  - The Agrobacterium tumefaciens virB7 gene product is a lipoprotein whose function
      is required for the transmission of oncogenic T-DNA to susceptible plant cells.
      Three lines of study provided evidence that VirB7 interacts with and stabilizes
      other VirB proteins during the assembly of the putative T-complex transport
      apparatus. First, a precise deletion of virB7 from the pTiA6NC plasmid of wild
      type strain A348 was correlated with significant reductions in the steady-state
      levels of several VirB proteins, including VirB4, VirB9, VirB10, and VirB11;
      trans expression of virB7 in the delta virB7 mutant partially restored the levels
      of these proteins, and trans coexpression of virB7 and virB8 fully restored the
      levels of these proteins to wild-type levels. Second, modulation of VirB7 levels
      resulted in corresponding changes in the levels of other VirB proteins in the
      following cell types: (i) a delta virB7 mutant expressing virB7 and virB8 from
      isopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible Plac and other virB genes
      from acetosyringone (AS)-inducible PvirB; (ii) a delta virB operon mutant
      expressing virB7 and virB8 from Plac and virB9, virB10, and virB11 from PvirB;
      and (iii) a delta virB operon mutant expressing virB7 from IPTG-inducible Pklac
      and virB9 from an AS-inducible PvirB. Third, the synthesis of a VirB7::PhoA
      fusion protein in strain A348 was correlated with a significant reduction in the
      steady-state levels of VirB4, VirB5, and VirB7 through VirB11; these cells also
      exhibited a severely attenuated virulence phenotype, indicating that synthesis of
      the fusion protein perturbs the assembly of VirB proteins into a stabilized
      protein complex required for T-complex transport. Extracts of AS-induced cells
      electrophoresed under nonreducing conditions possessed undetectable levels of the
      32-kDa VirB9 and 4.5-kDa VirB7 monomers and instead possessed a 36-kDa complex
      that cross-reacted with both VirB7 and VirB9 antisera and accumulated as a
      function of virB7 expression. Our results are consistent with a model in which
      VirB7 stabilizes VirB9 by formation of a covalent intermolecular cross-link; in
      turn, the VirB7-VirB9 heterodimer promotes the assembly of a functional T-complex
      transport machinery.

PMID- 8655494
TI  - The Agrobacterium tumefaciens virB7 gene product, a proposed component of the T
      complex transport apparatus, is a membrane-associated lipoprotein exposed at the
      periplasmic surface.
AB  - The Agrobacterium tumefaciens virB7 gene product contains a typical signal
      sequence ending with a consensus signal peptidase II cleavage site characteristic
      of bacterial lipoproteins. VirB7 was shown to be processed as a lipoprotein by
      (i) in vivo labeling of native VirB7 and a VirB7::PhoA fusion with [3H]palmitic
      acid and (ii) inhibition of VirB7 processing by globomycin, a known inhibitor of
      signal peptidase II. A VirB7 derivative sustaining a Ser substitution for the
      invariant Cys-15 residue within the signal peptidase II cleavage site could not
      be visualized immunologically and failed to complement a delta virB7 mutation,
      establishing the importance of this putative lipid attachment site for VirB7
      maturation and function. VirB7 partitioned predominantly with outer membrane
      fractions from wild-type A348 cells as well as a delta virB operon derivative
      transformed with a virB7 expression plasmid. Expression of virB7 fused to phoA,
      the alkaline phosphatase gene of Escherichia coli, gave rise to high alkaline
      phosphatase activities in E. coli and A. tumefaciens cells, providing genetic
      evidence for the export of VirB7 in these hosts. VirB7 was shown to be
      intrinsically resistant to proteinase K; by contrast, a VirB7::PhoA derivative
      was degraded by proteinase K treatment of A. tumefaciens spheroplasts and
      remained intact upon treatment of whole cells. Together, the results of these
      studies favor a model in which VirB7 is topologically configured as a monotopic
      protein with its amino terminus anchored predominantly to the outer membrane and
      with its hydrophilic carboxyl domain located in the periplasmic space. Parallel
      studies of VirB5, VirB8, VirB9, and VirB10 established that each of these
      membrane-associated proteins also contains a large periplasmic domain whereas
      VirB11 resides predominantly or exclusively within the interior of the cell.

PMID- 8655496
TI  - Characterization of the cytoplasmic filament protein gene (cfpA) of Treponema
      pallidum subsp. pallidum.
AB  - Treponema pallidum and other members of the genera Treponema, Spirochaeta, and
      Leptonema contain multiple cytoplasmic filaments that run the length of the
      organism just underneath the cytoplasmic membrane. These cytoplasmic filaments
      have a ribbon-like profile and consist of a major cytoplasmic filament protein
      subunit (CfpA, formerly called TpN83) with a relative molecular weight of
      approximately 80,000. Degenerate DNA primers based on N-terminal and CNBr
      cleavage fragment amino acid sequences of T. pallidum subsp. pallidum (Nichols)
      CfpA were utilized to amplify a fragment of the encoding gene (cfpA). A 6.8-kb
      EcoRI fragment containing all but the 5' end of cfpA was identified by
      hybridization with the resulting PCR product and cloned into Lambda ZAP II. The
      5' region was obtained by inverse PCR, and the complete gene sequence was
      determined. The cfpA sequence contained a 2,034-nucleotide coding region, a
      putative promoter with consensus sequences (5'-TTTACA-3' for -35 and 5'-TACAAT-3'
      for -10) similar to the sigma70 recognition sequence of Escherichia coli and
      other organisms, and a putative ribosome-binding site (5'-AGGAG-3'). The deduced
      amino acid sequence of CfpA indicated a protein of 678 residues with a calculated
      molecular mass of 78.5 kDa and an estimated pI of 6.15. No significant homology
      to known proteins or structural motifs was found among known prokaryotic or
      eukaryotic sequences. Expression of a LacZ-CfpA fusion protein in E. coli was
      detrimental to survival and growth of the host strain and resulted in the
      formation of short, irregular filaments suggestive of partial self-assembly of
      CfpA. The cytoplasmic filaments of T. pallidum and other spirochetes appear to
      represent a unique form of prokaryotic intracytoplasmic inclusions.

PMID- 8655497
TI  - Isolation of cmr, a novel Escherichia coli chloramphenicol resistance gene
      encoding a putative efflux pump.
AB  - A novel gene designated cmr, which mapped to 18.8 min of the Escherichia coli K
      12 genome, was shown to mediate resistance to chloramphenicol when it was
      expressed from a multicopy vector. The accumulation of chloramphenicol was
      significantly less in cells overexpressing cmr than in control cells harboring
      the vector without insert. After the addition of a proton motive force blocker,
      the level of accumulation of chloramphenicol in the resistant cells rapidly
      approached the levels found in sensitive cells carrying only the chromosomal cmr.
      Northern (RNA) blot analyses revealed that the cmr gene is expressed as a 1.3-kb
      transcript. This size corresponds very well with a predicted size of 1,293
      nucleotides (nt) based on the mapping of the transcription initiation site to a G
      residue 24 nt upstream of the start codon and the presence of a putative rho
      independent terminator sequence ending 36 nt downstream of the 1,233-nt open
      reading frame encoding the putative Cmr protein. The 411-residue-long derived
      amino acid sequence contains 12 putative transmembrane segments and displays
      significant sequence similarities to several known drug resistance protein
      sequences of the major facilitator family. We provide evidence strongly
      suggesting that the resistance mediated by Cmr involves active exclusion of
      chloramphenicol.

PMID- 8655498
TI  - Analysis of the traLEKBP sequence and the TraP protein from three F-like
      plasmids: F, R100-1 and ColB2.
AB  - The sequence of a region of the F plasmid containing the traLEKBP genes involved
      in plasmid transfer was compared to the equivalent regions of two IncFII
      plasmids, R100-1 and ColB2. The traLEK gene products of all three plasmids were
      virtually identical, with the most changes occurring in TraE. The TraB genes were
      also nearly identical except for an 11-codon extension at the 3' end of the R100
      1 traB gene. The TraP protein of R100-l differed from those of F and ColB2 at its
      N terminus, while the ColB2 TraP protein contained a change of sequence in a
      predicted loop which was shown to be exposed in the periplasmic space by TnphoA
      mutagenesis. The effect of the altered TraP sequences was determined by
      complementing a traP mutant with clones expressing the traKBP genes of F, R100-1,
      and ColB2. The traP mutation in pOX38 (pOX38-traP474), a derivative of F, was
      found to have little effect on pilus production, pilus retraction, and
      filamentous phage growth and only a moderate effect on transfer. The transfer
      ability of pOX38-traP474 was shown to be affected by mutations in the rfa
      (lipopolysaccharide) locus and in ompA in the recipient cell in a manner similar
      to that for the wild-type pOX38-Km plasmid itself and could be complemented with
      the traP analogs from R100-1 and ColB2 to give an F-like phenotype. Thus, the
      TraP protein appears to play a minor role in conjugation and may interact with
      TraB, which varies in sequence along with TraP, in order to stabilize the
      proposed transmembrane complex formed by the tra operon products.

PMID- 8655499
TI  - mioC transcription, initiation of replication, and the eclipse in Escherichia
      coli.
AB  - The potential role of mioC transcription as a negative regulator of initiation of
      chromosome replication in Escherichia coli was evaluated. When initiation was
      aligned by a shift of dnaC2(Ts) mutants to nonpermissive temperature (40 degrees
      C), mioC transcript levels measured at the 5' end or reading through oriC
      disappeared within one mass doubling. Upon return to permissive temperature (30
      degrees C), the transcripts reappeared coordinately about 15 min after the first
      synchronized initiation and then declined sharply again 10 min later, just before
      the second initiation. Although these observations were consistent with the idea
      that mioC transcription might have to be terminated prior to initiation, it was
      found that the interval between initiations at permissive temperature, i.e., the
      eclipse period, was not influenced by the time required to shut down mioC
      transcription, since the eclipse was the same for chromosomes and minichromosomes
      which lacked mioC transcription. This finding did not, in itself, rule out the
      possibility that mioC transcription must be terminated prior to initiation of
      replication, since it might normally be shut off before initiation, and never be
      limiting, even during the eclipse. Therefore, experiments were performed to
      determine whether the continued presence of mioC transcription during the process
      of initiation altered the timing of initiation. It was found that minichromosomes
      possessing a deletion in the DnaA box upstream of the promoter transcribed mioC
      continuously and replicated with the same timing as those that either shut down
      expression prior to initiation or lacked expression entirely. It was further
      shown that mioC transcription was present throughout the induction of initiation
      by addition of chloramphenicol to a dnaA5(Ts) mutant growing at a semipermissive
      temperature. Thus, transcription through oriC emanating from the mioC gene
      promoter is normally inhibited prior to initiation of replication by the binding
      of DnaA protein, but replication can initiate with the proper timing even when
      transcription is not shut down; i.e., mioC does not serve as a negative regulator
      of initiation. It is proposed, however, that the reappearance and subsequent
      disappearance of mioC transcription during a 10-min interval at the end of the
      eclipse serves as an index of the minimum time required for the establishment of
      active protein-DNA complexes at the DnaA boxes in the fully methylated origin
      region of the chromosome. On this basis, the eclipse constitutes the time for
      methylation of the newly formed DNA strands (15 to 20 min at 30 degrees C)
      followed by the time for DnaA protein to bind and activate oriC for replication
      (10 min).

PMID- 8655500
TI  - Exchange of genetic markers at extremely high temperatures in the archaeon
      Sulfolobus acidocaldarius.
AB  - When cells of two auxotrophic mutants of Sulfolobus acidocaldarius are mixed and
      incubated on solid medium, they form stable genetic recombinants which can be
      selected, enumerated, and characterized. Any of a variety of auxotrophic markers
      can recombine with each other, and the phenomenon has been observed at
      temperatures of up to 84 degrees C. The ability to exchange and recombine
      chromosomal markers appears to be an intrinsic property of S. acidocaldarius
      strains. It occurs between two cell lines derived from the same parent or from
      different parents and also between a recombinant and its parent. This is the
      first observation of chromosomal marker exchange in archaea from geothermal
      environments and provides the first functional evidence of generalized,
      homologous recombination at such high temperatures.

PMID- 8655501
TI  - Thermoregulation of kpsF, the first region 1 gene in the kps locus for polysialic
      acid biosynthesis in Escherichia coli K1.
AB  - The kps locus for biosynthesis of the capsular polysialic acid virulence factor
      in Escherichia coli K1 contains at least two convergently transcribed operons,
      designated region 1 and regions 2 plus 3. On the basis of DNA sequence analysis,
      kpsF appeared to be a good candidate for the first gene of region 1 (M. J.
      Cieslewicz, S. M. Steenbergen, and E. R. Vimr, J. Bacteriol. 175:8018-8023,
      1993). A preliminary indication that kpsF is required for capsule production is
      the capsule-negative phenotype of an aph T insertion in the chromosomal copy of
      kpsF. The present communication describes the isolation and phenotypic
      characterization of this mutant. Although transcription through kpsF was required
      for capsule production, complementation analysis failed to indicate a clear
      requirement for the KpsF polypeptide. However, since E. coli contains at least
      two other open reading frames that could code for homologs of KpsF, the apparent
      dispensability of KpsF remains provisional. DNA sequence analysis of 1,100 bp
      upstream from the kpsF translational start site did not reveal any open reading
      frames longer than 174 nucleotides, consistent with kpsF being the first gene of
      region 1. Since kpsF appeared to be the first gene of a region whose gene
      products are required for polysialic acid transport and because capsule
      production is known to be thermoregulated, primer extension analyses were carried
      out with total RNA isolated from cells grown at permissive (37 degrees C) and
      nonpermissive (20 degrees C) temperatures. The results revealed a potentially
      complex kpsF promoter-like region that was transcriptionally silent at the
      nonpermissive temperature, suggesting that thermoregulation of region 1 may be
      exerted through variations in kpsF expression. Additional evidence supporting
      this conclusion was obtained by demonstrating the effects of temperature on
      expression of the gene kpsE, immediately downstream of kpsF. Chloramphenicol
      acetyltransferase assays were carried out with constructs containing the kpsF 5'
      untranslated region fused to a promoterless cat cassette, providing further
      evidence that kpsF is thermoregulated. Although the function of KpsF is unclear,
      primary structure analysis indicated two motifs commonly observed in regulatory
      proteins and homology with glucosamine synthase from Rhizobium meliloti.

PMID- 8655502
TI  - Global negative regulation of Streptomyces coelicolor antibiotic synthesis
      mediated by an absA-encoded putative signal transduction system.
AB  - Streptomycete antibiotic synthesis is coupled to morphological differentiation
      such that antibiotics are produced as a colony sporulates. Streptomyces
      coelicolor produces several structurally and genetically distinct antibiotics.
      The S. coelicolor absA locus was defined by four UV-induced mutations that
      globally blocked antibiotic biosynthesis without blocking morphological
      differentiation. We show that the absA locus encodes a putative eubacterial two
      component sensor kinase-response regulator system. All four mutations lie within
      a single open reading frame, designated absA1, which is predicted to encode a
      sensor histidine kinase. A second gene downstream of absA1, absA2, is predicted
      to encode the cognate response regulator. In marked contrast to the antibiotic
      deficient phenotype of the previously described absA mutants, the phenotype
      caused by disruption mutations in the absA locus is precocious hyperproduction of
      the antibiotics actinorhodin and undecylprodigiosin. Precocious hyperproduction
      of these antibiotics is correlated with premature expression of XylE activity in
      a transcriptional fusion to an actinorhodin biosynthetic gene. We propose that
      the absA locus encodes a signal transduction mechanism that negatively regulates
      synthesis of the multiple antibiotics produced by S. coelicolor.

PMID- 8655503
TI  - Sequence of plasmid pGT5 from the archaeon Pyrococcus abyssi: evidence for
      rolling-circle replication in a hyperthermophile.
AB  - The plasmid pGT5 (3,444 bp) from the hyperthermophilic archaeon Pyrococcus abyssi
      GE5 has been completely sequenced. Two major open reading frames with a good
      coding probability are located on the same strand and cover 85% of the total
      sequence. The larger open reading frame encodes a putative polypeptide which
      exhibits sequence similarity with Rep proteins of plasmids using the rolling
      circle mechanism for replication. Upstream of this open reading frame, we have
      detected an 11-bp motif identical to the double-stranded origin of several
      bacterial plasmids that replicate via the rolling-circle mechanism. A putative
      single-stranded origin exhibits similarities both to bacterial primosome
      dependent single-stranded initiation sites and to bacterial primase (dnaG) start
      sites. A single-stranded form of pGT5 corresponding to the plus strand was
      detected in cells of P. abyssi. These data indicate that pGT5 replicates via the
      rolling-circle mechanism and suggest that members of the domain Archaea contain
      homologs of several bacterial proteins involved in chromosomal DNA replication.
      Phylogenetic analysis of Rep proteins from rolling-circle replicons suggest that
      diverse families diverged before the separation of the domains Archaea, Bacteria,
      and Eucarya.

PMID- 8655505
TI  - Tet(M)-promoted release of tetracycline from ribosomes is GTP dependent.
AB  - Tet(M) protein, which displays homology to elongation factor G (EF-G), interacts
      with the protein biosynthetic machinery to render this process resistant to
      tetracycline in vivo and in vitro. To clarify the basis of the resistance
      mechanism, the effects of Tet(M) on several reactions which occur during protein
      synthesis were examined. The mechanism of action of Tet(M) has been clarified by
      two observations. The protein relieves tetracycline inhibition of factor
      dependent tRNA binding and dramatically reduces the affinity of ribosomes for
      tetracycline when GTP is present. This reduction in drug affinity appears to be
      due to a large increase in the rate of tetracycline dissociation. Addition of
      Tet(M) to ribosome-tetracycline complexes results in displacement of bound drug.
      And, while Tet(M) and EF-G GTPase activities are tetracycline resistant, the two
      proteins differ in their sensitivities to fusidic acid, with the latter activity
      inhibited by the drug. Furthermore, while Tet(M) protects translation from
      tetracycline inhibition in a defined system, it is unable to substitute for
      either EF-G or elongation factor Tu.

PMID- 8655504
TI  - The Streptomyces peucetius drrC gene encodes a UvrA-like protein involved in
      daunorubicin resistance and production.
AB  - The drrC gene, cloned from the daunorubicin (DNR)- and doxorubicin-producing
      strain of Streptomyces peucetius ATCC 29050, encodes a 764-amino-acid protein
      with a strong sequence similarity to the Escherichia coli and Micrococcus luteus
      UvrA proteins involved in excision repair of DNA. Expression of drrC was
      correlated with the timing of DNR production in the growth medium tested and was
      not dependent on the presence of DNR. Since introduction of drrC into
      Streptomyces lividans imparted a DNR resistance phenotype, this gene is believed
      to be a DNR resistance gene. The drrC gene could be disrupted in the non-DNR
      producing S. peucetius dnrJ mutant but not in the wild-type strain, and the
      resulting dnrJ drrC double mutant was significantly more sensitive to DNR in
      efficiency-of-plating experiments. Expression of drrC in an E. coli uvrA strain
      conferred significant DNR resistance to this highly DNR-sensitive mutant.
      However, the DrrC protein did not complement the uvrA mutation to protect the
      mutant from the lethal effects of UV or mitomycin even though it enhanced the UV
      resistance of a uvrA+ strain. We speculate that the DrrC protein mediates a novel
      type of DNR resistance, possibly different from the mechanism of DNR resistance
      governed by the S. peucetius drrAB genes, which are believed to encode a DNR
      antiporter.

PMID- 8655506
TI  - Anaerobic biosynthesis of enterobactin Escherichia coli: regulation of entC gene
      expression and evidence against its involvement in menaquinone (vitamin K2)
      biosynthesis.
AB  - In Escherichia coli, isochorismate is a common precursor for the biosynthesis of
      the siderophore enterobactin and menaquinone (vitamin K2). Isochorismate is
      formed by the shikimate pathway from chorismate by the enzyme isochorismate
      synthase encoded by the entC gene. Since enterobactin is involved in the aerobic
      assimilation of iron, and menaquinone is involved in anaerobic electron
      transport, we investigated the regulation of entC by iron and oxygen. An operon
      fusion between entC with its associated regulatory region and lacZ+ was
      constructed and introduced into the chromosome in a single copy. Expression of
      entC-lacZ was found to be regulated by the concentration of iron both aerobically
      and anaerobically. An established entC::kan mutant deficient in enterobactin
      biosynthesis was found to grow normally and synthesize wild-type levels of
      menaquinone under anaerobic conditions in iron-sufficient media. These results
      led to the demonstration of an alternate isochorismate synthase specifically
      involved in menaquinone synthesis encoded by the menF gene. Consistent with these
      findings, the entC+ strains were found to synthesize enterobactin anaerobically
      under iron-deficient conditions while the ent mutants failed to do so.

PMID- 8655507
TI  - Cloning and molecular genetic characterization of the Escherichia coli gntR,
      gntK, and gntU genes of GntI, the main system for gluconate metabolism.
AB  - Three genes involved in gluconate metabolism, gntR, gntK, and gntU, which code
      for a regulatory protein, a gluconate kinase, and a gluconate transporter,
      respectively, were cloned from Escherichia coli K-12 on the basis of their known
      locations on the genomic restriction map. The gene order is gntU, gntK, and gntR,
      which are immediately adjacent to asd at 77.0 min, and all three genes are
      transcribed in the counterclockwise direction. The gntR product is 331 amino
      acids long, with a helix-turn-helix motif typical of a regulatory protein. The
      gntK gene encodes a 175-amino-acid polypeptide that has an ATP-binding motif
      similar to those found in other sugar kinases. While GntK does not show
      significant sequence similarity to any known sugar kinases, it is 45% identical
      to a second putative gluconate kinase from E. coli,gntV. The 445-amino-acid
      sequence encoded by gntU has a secondary structure typical of membrane-spanning
      transport proteins and is 37% identical to the gntP product from Bacillus
      subtilis. Kinetic analysis of GntU indicates an apparent Km for gluconate of 212
      microM, indicating that this is a low-affinity transporter. Studies demonstrate
      that the gntR gene is monocistronic, while the gntU and gntK genes, which are
      separated by only 3 bp, form an operon. Expression of gntR is essentially
      constitutive, while expression of gntKU is induced by gluconate and is subject to
      fourfold glucose catabolite repression. These results confirm that gntK and gntU,
      together with another gluconate transport gene, gntT, constitute the GntI system
      for gluconate utilization, under control of the gntR gene product, which is also
      responsible for induction of the edd and eda genes of the Entner-Doudoroff
      pathway.

PMID- 8655508
TI  - Characterization of heterologously produced carbonic anhydrase from
      Methanosarcina thermophila.
AB  - The gene encoding carbonic anhydrase from Methanosarcina thermophila was
      hyperexpressed in Escherichia coli, and the heterologously produced enzyme was
      purified 14-fold to apparent homogeneity. The enzyme purified from E. coli has
      properties (specific activity, inhibitor sensitivity, and thermostability)
      similar to those of the authentic enzyme isolated from M. thermophila; however, a
      discrepancy in molecular mass suggests that the carbonic anhydrase is
      posttranslationally modified in either E. coli or M. thermophila. Both the
      authentic and heterologously produced enzymes were stable to heating at 55
      degrees C for 15 min but were inactivated at higher temperatures. No esterase
      activity was detected with p-nitrophenylacetate as the substrate. Plasma emission
      spectroscopy revealed approximately 0.6 Zn per subunit. As judged from the
      estimated native molecular mass, the enzyme is either a trimer or a tetramer.
      Western blot (immunoblot) analysis of cell extract proteins from M. thermophila
      indicates that the levels of carbonic anhydrase are regulated in response to the
      growth substrate, with protein levels higher in acetate than in methanol- or
      trimethylamine-grown cells.

PMID- 8655509
TI  - Ti plasmid-encoded genes responsible for catabolism of the crown gall opine
      mannopine by Agrobacterium tumefaciens are homologs of the T-region genes
      responsible for synthesis of this opine by the plant tumor.
AB  - Agrobacterium tumefaciens NT1 harboring pSaB4, which contains the 14-kb BamHI
      fragment 4 from the octopine/mannityl opine-type Ti plasmid pTi15955, grew well
      with agropine (AGR) but slowly with mannopine (MOP) as the sole carbon source.
      When a second plasmid encoding a dedicated transport system for MOP was
      introduced, these cells grew well with both AGR and MOP. Transposon insertion
      mutagenesis and subcloning identified a 5.7-kb region of BamHI fragment 4 that
      encodes functions required for the degradation of MOP. DNA sequence analysis
      revealed seven putative genes in this region: mocD (moc for mannityl opine
      catabolism) and mocE, oriented from right to left, and mocRCBAS, oriented from
      left to right. Significant identities exist at the nucleotide and derived amino
      acid sequence levels between these moc genes and the mas genes that are
      responsible for opine biosynthesis in crown gall tumors. MocD is a homolog of
      Mas2, the anabolic conjugase encoded by mas2'. MocE and MocC are related to the
      amino half and the carboxyl half, respectively, of Mas1 (MOP reductase), the
      second enzyme for MOP biosynthesis. These results indicate that the moc and mas
      genes evolved from a common origin. MocR and MocS are related to each other and
      to a putative repressor for the AGR degradation system encoded by the rhizogenic
      plasmid pRiA4. MocB and MocA are homologs of 6-phosphogluconate dehydratase and
      glucose-6-phosphate dehydrogenase, respectively. Mutations in mocD and mocE, but
      not mocC, are suppressed by functions encoded by the chromosome or the 450-kb
      megaplasmid present in many Agrobacterium isolates. We propose that moc genes
      derived from genes located elsewhere in the bacterial genome and that the tumor
      expressed mas genes evolved from the bacterial moc genes.

PMID- 8655510
TI  - A Ti plasmid-encoded enzyme required for degradation of mannopine is functionally
      homologous to the T-region-encoded enzyme required for synthesis of this opine in
      crown gall tumors.
AB  - The mocC gene encoded by the octopine/mannityl opine-type Ti plasmid pTi15955 is
      related at the nucleotide sequence level to mas1' encoded by the T region of this
      plasmid. While Mas1 is required for the synthesis of mannopine (MOP) by crown
      gall tumor cells, MocC is essential for the utilization of MOP by Agrobacterium
      spp. A cosmid clone of pTi15955, pYDH208, encodes mocC and confers the
      utilization of MOP on strain NT1 and on strain UIA5, a derivative of NT1 lacking
      the 450-kb cryptic plasmid pAtC58. NT1 or UIA5 harboring pYDH208 with an
      insertion mutation in mocC failed to utilize MOP as the sole carbon source.
      Plasmid pSa-C, which encodes only mocC, complemented this mutation in both
      strains. This plasmid also was sufficient to confer utilization of MOP on NT1 but
      not on UIA5. Computer analysis showed that MocC is related at the amino acid
      sequence level to members of the short-chain alcohol dehydrogenase family of
      oxidoreductases. Lysates prepared from Escherichia coli cells expressing mocC
      contained an enzymatic activity that oxidizes MOP to deoxyfructosyl glutamine
      (santhopine [SOP]) in the presence of NAD+. The reaction catalyzed by the MOP
      oxidoreductase is reversible; in the presence of NADH, the enzyme reduced SOP to
      MOP. The apparent Km values of the enzyme for MOP and SOP were 6.3 and 1.2 mM,
      respectively. Among analogs of MOP tested, only N-1-(1-deoxy-D-lyxityl)-L
      glutamine and N-1-(1-deoxy-D-mannityl)-L-asparagine served as substrates for MOP
      oxidoreductase. These results indicate that mocC encodes an oxidoreductase that,
      as an oxidase, is essential for the catabolism of MOP. The reductase activity of
      this enzyme is precisely the reaction ascribed to its T-region-encoded homolog,
      Mas1, which is responsible for biosynthesis of mannopine in crown gall tumors.

PMID- 8655512
TI  - Mutational analysis of the active site of Pseudomonas fluorescens pyrrolidone
      carboxyl peptidase.
AB  - On the basis of chemical inhibition studies and a multiple alignment of four
      pyrrolidone carboxyl peptidase (Pcp) amino acid sequences, seven conserved
      residues of the Pseudomonas fluorescens Pcp, which might be important for enzyme
      activity, have been modified by site-directed mutagenesis experiments. Wild-type
      and mutant Pcps were expressed in Escherichia coli, purified, and characterized
      by the ability to cleave the synthetic chromogenic substrate pyroglutamyl-beta
      naphthylamide and the dipeptide pyroglutamyl-alanine. Substitution of Glu-10 and
      Glu-22 by Gln led to enzymes which displayed catalytic properties and
      sensitivities to 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide similar to those
      of the wild-type Pcp. These residues are not essential for the catalytic
      activity. Replacement of Asp-89 by Asn and Ala resulted in enzymes which retained
      nearly 25% of activity and which had no activity, respectively. Substitution of
      the Cys-144 and His-166 residues by Ala and Ser, respectively, resulted in
      inactive enzymes. Proteins with changes of Glu-81 to Gln and Asp-94 to Asn were
      not detectable in crude extract and were probably unstable in bacteria. Our
      results are consistent with the proposal that Cys-144 and His-166 constitute the
      nucleophilic and imidazole residues of the Pcp active site, while residue Glu-81,
      Asp-89, or Asp-94 might constitute the third part of the active site. These
      results lead us to propose Pcps as a new class of thiol aminopeptidases.

PMID- 8655511
TI  - Borrelia burgdorferi supercoiled plasmids encode multicopy tandem open reading
      frames and a lipoprotein gene family.
AB  - DNA sequencing and Southern blot analyses of a Borrelia burgdorferi DNA fragment
      encoding a signal sequence led to the discovery of a genetic locus, designated
      2.9, which appears to be present in at least seven copies in virulent B.
      burgdorferi 297. DNA sequence analysis of these regions revealed that each 2.9
      locus contained an operon of four genes (ABCD) and open reading frames designated
      rep+ (positive strand) and rep- (negative strand) which encoded multiple repeat
      motifs. Downstream of the rep+ gene(s) in six of the completely cloned and
      sequenced 2.9 loci also were lipoprotein (LP) genes possessing highly similar
      signal sequences but encoding variable mature polypeptides. The lipoproteins
      could he separated into two classes on the basis of hydrophilicity profiles,
      sequence similarities, and reactivity with specific antibodies. The 2.9 loci were
      localized to two (20- and 30-kb) supercoiled plasmids in B. burgdorferi 297.
      Northern (RNA) blot analysis established that the 2.9 ABCD operon was only
      minimally expressed, whereas the rep- gene(s) and at least three of the seven LP
      genes were expressed by B. burgdorferi in vitro. A single putative promoter
      element was identified by RNA primer extension analysis upstream of the ABCD
      operon, whereas a number of potential promoter regions existed upstream of the LP
      genes. The combined data indicate that the ABCD operon, rep+ and rep- genes, and
      LP genes are separately transcribed during in vitro growth. The 2.9 loci possess
      a repetitiveness, diversity, and complexity not previously described for B.
      burgdorferi; differential expression of these genes may facilitate the
      spirochete's ability to survive in diverse host environments.

PMID- 8655513
TI  - Elements of signal transduction in Mycobacterium tuberculosis: in vitro
      phosphorylation and in vivo expression of the response regulator MtrA.
AB  - A putative two-component system, mtrA-mtrB, was isolated from M. tuberculosis
      H37Rv by using phoB from Pseudomonas aeruginosa as a hybridization probe. The
      predicted gene product of mtrA displayed high similarity with typical response
      regulators, including AfsQ1, PhoB, PhoP, and OmpR. The predicted gene product of
      mtrB displayed similarities with the histidine protein kinases AfsQ2, PhoR, and
      EnvZ and other members of this class of proteins. Expression analysis in the T7
      system showed that mtrA encoded a polypeptide with an apparent molecular mass of
      30 kDa. MtrA was overproduced, purified, and demonstrated to participate in
      typical phosphotransfer reactions using a heterologous histidine protein kinase,
      CheA, as a phosphoryl group donor. Mycobacterium bovis BCG, harboring an mtrA-gfp
      (green fluorescent protein cDNA) transcriptional fusion, was used to monitor mtrA
      expression in infected J774 monolayers. Flow cytometric and fluorescence
      microscopic analyses indicated that the mtrA promoter was activated upon entry
      and incubation in J774 macrophages. In contrast, the hsp60-gfp fusion displayed
      no change in expression under the growth conditions tested. These results suggest
      a potential role for mtrA in adaptation of the M. tuberculosis complex organisms
      to environmental changes which may include intracellular conditions.

PMID- 8655514
TI  - Comamonas testosteroni 3-ketosteroid-delta 4(5 alpha)-dehydrogenase: gene and
      protein characterization.
AB  - Comamonas testosteroni delta 4(5 alpha)- and delta1-dehydrogenases
      [delta4(5alpha)- and delta1DH] are key enzymes in the degradation of steroids
      having an A:B ring fusion in a trans configuration. We previously reported the
      isolation of the delta1dh gene (P. Plesiat, M. Grandguillot, S. Harayama, S.
      Vragar, and Y. Michel Briand, J. Bacteriol. 173:7219-7227, 1991). In this study,
      the gene encoding delta 4(5 alpha)DH was cloned in Escherichia coli on a 16-kbp
      BamHI fragment by screening a genomic bank of C. testosteroni ATCC 17410 with a
      probe derived from delta1dh. Subcloning experiments in plasmid pUC19 mapped delta
      4(5 alpha)dh immediately downstream of delta1dh. The enzyme was overexpressed 18
      fold in cells of E. coli JM109 carrying a 2.5-kbp cloned fragment (plasmid
      pXE25). However, much higher levels of enzymatic activity (264-fold) were
      obtained in Pseudomonas putida KT2440, using pMMB208 as an expression vector.
      Studies with crude lysates of KT2440 showed that delta4(5alpha)DH exhibits higher
      specificity and higher activity toward delta  l-androstene-3,17-dione than toward
      the saturated derivative 5 alpha-androstane-3,17-dione. The reaction was found to
      be irreversible and to use efficiently typical flavoprotein electron acceptors;
      optimal conditions for the enzyme activity were pH 8 and 40 degrees C. Analysis
      of the nucleotide sequence of the insert of pXE25 revealed an open reading frame
      of 1,593 bp preceded by a putative ribosome-binding site and followed by a
      potential transcription terminator. The amino acid sequence of the deduced
      peptide showed a typical flavin adenine dinucleotide-binding site in its N
      terminal region, confirming the flavoproteinic structure of delta 4(5 alpha)DH.
      The predicted molecular mass was consistent with that of the enzyme expressed in
      a T7 polymerase system (60 kDa). Alignment between delta 4(5 alpha)dh and
      delta1dh indicated that both genes, though coding for functionally related
      enzymes, do not derive from a common ancestor.

PMID- 8655515
TI  - Cyclic AMP receptor protein positively controls gyrA transcription and alters DNA
      topology after nutritional upshift in Escherichia coli.
AB  - The expression of a transcriptional gyrA-lacZ gene fusion throughout the
      Escherichia coli growth cycle and the effect that mutation delta crp39 had on
      this expression were studied. The data obtained indicate that the expression of
      gyrA is growth phase dependent and under the positive control of the cyclic AMP
      receptor protein (CRP). Complementation analysis of gyrA-lacZ expression with
      wild-type CRP or variant CRP pc (with a T-to-A mutation at position 158) in a CRP
      deficient background suggests that this CRP action is mediated by a class I or
      class II CRP-dependent promoter(s). Our results also indicate that CRP may be
      involved in the modulation of DNA topology in the transition from the lag period
      to the exponential phase of growth.

PMID- 8655516
TI  - Molecular cloning and site-specific mutagenesis of a gene involved in
      arylsulfatase production in Campylobacter jejuni.
AB  - The arylsulfatase gene from Campylobacter jejuni 81-176 encodes a predicted
      protein of 69,293 Da which shows no sequence similarity with other known
      arylsulfatases. The gene hybridizes to other Ast+ strains of C. jejuni and
      Campylobacter sputorum subsp. bubulus, as well as to many Ast- strains of C.
      jejuni.

PMID- 8655517
TI  - Molecular cloning of the Haemophilus influenzae gmhA (lpcA) gene encoding a
      phosphoheptose isomerase required for lipooligosaccharide biosynthesis.
AB  - We have determined that gene HI#1181 of Haemophilus influenzae is a homolog of
      Escherichia coli gmhA (previously designated lpcA) (J. S. Brooke and M. A.
      Valvano, J. Biol. Chem. 271:3608-3614, 1996), which encodes a phosphoheptose
      isomerase catalyzing the first step of the biosynthesis of ADP-L-glycero-D-manno
      heptose. Mutations in this gene are associated with a heptoseless core
      lipopolysaccharide which determines an increased outer membrane permeability to
      hydrophobic compounds. The cloned H. influenzae gmhA restored the synthesis of a
      complete core in the gmhA-deleted E. coli strain chi711. Amino acid sequence
      comparisons of the GmhA proteins of E. coli and H. influenzae with other proteins
      in the databases revealed the existence of a novel family of phosphosugar a1do
      keto isomerases.

PMID- 8655518
TI  - Genes associated with meningococcal capsule complex are also found in Neisseria
      gonorrhoeae.
AB  - A homolog of the meningococcal cps locus region E has been identified in
      Neisseria gonorrhoeae immediately upstream of the gonococcal region D locus.
      Region E has no detectable function in capsule biosynthesis in Neisseria
      meningitidis or in lipopolysaccharide biosynthesis in either organism. The open
      reading frame is homologous to proteins of unknown function in Escherichia coli
      and Haemophilus influenzae. Further analysis of the N. meningitidis cps cluster
      has identified a second copy of region D encoding three additional open reading
      frames, including homologs of DNA methyltransferases. The organization of the
      region D and E genes in N. gonorrhoeae and N. meningitidis in relation to the cps
      genes provides some insight into the evolutionary origin of encapsulation in N.
      meningitidis.

PMID- 8655519
TI  - Membrane topology of the outer membrane protein OprH from Pseudomonas aeruginosa:
      PCR-mediated site-directed insertion and deletion mutagenesis.
AB  - The 21-kDa outer membrane protein OprH from Pseudomonas aeruginosa is
      overexpressed under Mg2+ starvation conditions and when overproduced causes
      resistance to polymyxin B, gentamicin, and EDTA. By circular dichroism analysis,
      OprH revealed a calculated beta-sheet structure content of 47.3%. PCR-based site
      directed deletion and epitope insertion mutagenesis was used to test a
      topological model of OprH as an eight-stranded beta-barrel. Three permissive and
      seven nonpermissive malarial epitope insertion mutants and four permissive and
      four nonpermissive deletion mutants confirmed the general accuracy of this model.
      Thus, OprH is the smallest outer membrane protein to date to be confirmed as a
      beta-stranded protein.

PMID- 8655520
TI  - Pseudomonas aeruginosa PAO1 ceases to express serotype-specific
      lipopolysaccharide at 45 degrees C.
AB  - Most Pseudomonas aeruginosa strains are able to produce two distinct
      lipopolysaccharide (LPS) O-polysaccharide types, A-band (common-antigen) and B
      band (serotype-specific) LPSs. The relative expression levels of these two LPS
      types in P. aeruginosa PAO1 (O5 serotype) at various growth temperatures were
      investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
      silver staining or Western blotting (immunoblotting) with monoclonal antibodies
      specific for each O polysaccharide. A-band and B-band LPSs were expressed
      concurrently when the cells grew at 15, 25, and 35 degrees C; however, growth at
      45 degrees C resulted in a surface deficiency in B-band LPS as determined by
      immunoblotting and agglutination with B-band-specific monoclonal antibody.
      Transfer of these cells (expressing A-band LPS but deficient in B-band LPS) [A+B
      ]) to a lower temperature (at which the division time was comparable) resulted in
      a rapid resumption of normal A-band and B-band expression. B-band LPS was
      detectable by immunoblotting before measurable growth of the culture had
      occurred.

PMID- 8655521
TI  - Stereospecific dihydroxylation of the styrene vinyl group by purified naphthalene
      dioxygenase from Pseudomonas sp. strain NCIB 9816-4.
AB  - Naphthalene dioxygenase (NDO) from Pseudomonas sp. strain NCIB 9816-4 adds both
      atoms of the dioxygen molecule to styrene to form (R)-l-phenyl-1,2-ethanediol.
      Product formation is tightly coupled to dioxygen consumption and NADH oxidation.
      NDO oxidizes styrene-d8 at almost the same initial rate as styrene. The results
      indicate that dioxygen activation by NDO is different from that by cytochrome P
      450 and other monooxygenases, which oxidize styrene to styrene 1,2-oxide.

PMID- 8655522
TI  - Analysis of linear plasmid dimers in Borrelia burgdorferi sensu lato isolates:
      implications concerning the potential mechanism of linear plasmid replication.
AB  - The Borrelia genome is composed of a linear chromosome and a number of variable
      circular and linear plasmids. Atypically large linear plasmids of 92 to 105 kb
      have been identified in several Borrelia burgdorferi sensu lato isolates and
      characterized. These plasmids carry the p27 and ospAB genes, which in other
      isolates reside on a 50-kb plasmid. Here we demonstrate that these plasmids are
      dimers of the 50-kb ospAB plasmid (pAB50). The 94-kb plasmid from isolate VS116,
      pVS94, was an exception and did not hybridize with any plasmid gene probes. When
      this plasmid was used as a probe, homologous sequences in other isolates were not
      detected, suggesting that it is unique to isolate VS116. These analyses provide
      insight into the mechanism of linear plasmid replication and the mechanisms by
      which plasmid variability can arise.

PMID- 8655523
TI  - Identification and characterization of the pckA gene from Staphylococcus aureus.
AB  - The Staphylococcus aureus pckA gene was identified and characterized. A pckA
      mutant lacked detectable phosphoenolpyruvate carboxykinase activity and grew
      poorly in the absence of glucose. Both enzymatic activity and pckA promoter
      activity in wild-type cells grown in the absence of glucose were at least 22-fold
      greater than activities in cells grown in the presence of glucose.

PMID- 8655524
TI  - Purification and characterization of 2-oxoglutarate:ferredoxin oxidoreductase
      from a thermophilic, obligately chemolithoautotrophic bacterium, Hydrogenobacter
      thermophilus TK-6.
AB  - 2-Oxoglutarate:ferredoxin oxidoreductase from a thermophilic, obligately
      autotrophic, hydrogen-oxidizing bacterium, Hydrogenobacter thermophilus TK-6, was
      purified to homogeneity by precipitation with ammonium sulfate and by
      fractionation by DEAE-Sepharose CL-6B, polyacrylate-quaternary amine,
      hydroxyapatite, and Superdex-200 chromatography. The purified enzyme had a
      molecular mass of about 105 kDa and comprised two subunits (70 kDa and 35 kDa).
      The activity of the 2-oxoglutarate:ferredoxin oxidoreductase was detected by the
      use of 2-oxoglutarate, coenzyme A, and one of several electron acceptors in
      substrate amounts (ferredoxin isolated from H. thermophilus, flavin adenine
      dinucleotide, flavin mononucleotide, or methyl viologen). NAD, NADP, and
      ferredoxins from Chlorella spp. and Clostridium pasteurianum were ineffective.
      The enzyme was extremely thermostable; the temperature optimum for 2-oxoglutarate
      oxidation was above 80 degrees C, and the time for a 50% loss of activity at 70
      degrees C under anaerobic conditions was 22 h. The optimum pH for a 2
      oxoglutarate oxidation reaction was 7.6 to 7.8. The apparent Km values for 2
      oxoglutarate and coenzyme A at 70 degrees C were 1.42 mM and 80 microM,
      respectively.

PMID- 8655525
TI  - Sequence of the bchG gene from Chloroflexus aurantiacus: relationship between
      chlorophyll synthase and other polyprenyltransferases.
AB  - The sequence of the Chloroflexus aurantiacus open reading frame thought to be the
      C. aurantiacus homolog of the Rhodobacter capsulatus bchG gene is reported. The
      BchG gene product catalyzes esterification of bacteriochlorophyllide a by
      geranylgeraniol-PPi during bacteriochlorophyll a biosynthesis. Homologs from
      Arabidopsis thaliana, Synechocystis sp. strain PCC6803, and C. aurantiacus were
      identified in database searches. Profile analysis identified three related
      polyprenyltransferase enzymes which attach an aliphatic alcohol PPi to an
      aromatic substrate. This suggests a broader relationship between chlorophyll
      synthases and other polyprenyltransferases.

PMID- 8655526
TI  - The sre gene (ORF469) encodes a site-specific recombinase responsible for
      integration of the R4 phage genome.
AB  - The sre gene (ORF469) of the R4 phage encodes a protein similar to the resolvase
      DNA invertase family proteins. Insertional gene disruption of sre prevented a
      lysogen from entering the lytic cycle, implying that Sre protein is a site
      specific recombinase needed for excision of the R4 prophage genome (M. Matsuura,
      T. Noguchi, T. Aida, M. Asayama, H. Takahashi, and M. Shirai, J. Gen. Appl.
      Microbiol. 41:53-61, 1995). To determine whether this sre gene is also necessary
      for the integration reaction, we studied its function by integration plasmid
      analysis. When deletions, frameshifts, and site-directed mutations that caused an
      amino acid substitution of Ser-17 for Ala were introduced into the sre structural
      gene, transformation efficiency of Streptomyces parvulus 2297 with these plasmid
      DNAs was severely reduced. However, an adenine insertion just before the possible
      initiation codon of the sre gene did not significantly decrease the efficiency.
      These data suggest that the Sre protein is a site-specific recombinase
      responsible for integration of the R4 phage genome.

PMID- 8655527
TI  - Site-directed mutational analysis of the osmotically regulated proU promoter of
      Salmonella typhimurium.
AB  - We carried out PCR mutagenesis of the proU promoter of Salmonella typhimurium, in
      order to identify sequences important for its osmotic control. We obtained five
      mutations in the -35 element: two decreased the promoter strength, one increased
      it, and the others had no effect. However, none abolished osmotic control,
      suggesting that the sequence of the -35 element is not crucial for osmotic
      control.

PMID- 8655528
TI  - Analysis of suppressor mutations of spoIVCA mutations: occurrence of DNA
      rearrangement in the absence of site-specific DNA recombinase SpoIVCA in Bacillus
      subtilis.
AB  - The spoIVCA gene of Bacillus subtilis encodes a site-specific recombinase, which
      excises a 48-kb skin element from the chromosomal DNA by DNA rearrangement and
      creates a new composite gene, sigK, on the chromosome. From spoIVCA mutants, we
      have isolated Spo+ revertants which have no skin element but have an intact sigK
      gene. This result suggests that the DNA rearrangement can occur in the absence of
      spoIVCA.

PMID- 8655529
TI  - Cloning, sequencing, and analysis of aklaviketone reductase from Streptomyces sp.
      strain C5.
AB  - DNA sequence analysis of a region of the Streptomyces sp. strain C5 daunomycin
      biosynthesis gene cluster, located just upstream of the daunomycin polyketide
      biosynthesis genes, revealed the presence of six complete genes. The two genes
      reading right to left include genes encoding the potentially translationally
      coupled gene products, an acyl carrier protein and a ketoreductase, and the four
      genes reading divergently, left to right, include two open reading frames of
      unknown function followed by a gene encoding an apparent glycosyltransferase and
      dauE, encoding aklaviketone reductase. Extracts of Streptomyces lividans TK24
      containing recombinant DauE catalyzed the NADPH-specific conversion of
      aklaviketone, maggiemycin, and 7-oxodaunomycinone to aklavinone, epsilon
      rhodomycinone, and daunomycinone, respectively. Neither the product of dauB nor
      that of the ketoreductase gene directly downstream of the acyl carrier protein
      gene demonstrated aklaviketone reductase activity.

PMID- 8655530
TI  - Isolation and characterization of a gene from Streptomyces sp. strain C5 that
      confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans
      TK24.
AB  - DNA sequence analysis of a region of the Streptomyces sp. strain C5 daunomycin
      biosynthesis gene cluster, located between the daunomycin polyketide biosynthesis
      gene cluster and a dnrI (transcriptional activator) homolog, revealed the
      presence of a gene encoding a P-450-like enzyme with a deduced Mr of 46,096.
      Expression of this gene, named herein doxA, in Streptomyces lividans TY24
      resulted in in vivo bioconversion of daunomycin to doxorubicin. DoxA showed
      specificity for only daunomycin and 13-dihydrodaunomycin, both of which were
      converted to doxorubicin. Daunomycinone (daunomycin aglycone), carminomycin, 13
      dihydrocarminomycin, idarubicin, and aklavin were not apparent substrates for
      DoxA. In vector controls or in vectors in which doxA was poorly expressed, S.
      lividans catalyzed the reduction of daunomycin and other 13-oxo-anthracyclines
      and -anthracyclinones to their 13-dihydro homologs.

PMID- 8655531
TI  - Differential antibiotic sensitivity determined by the large ribosomal subunit in
      thermophilic archaea.
AB  - Hybrid ribosomes obtained by mixing the ribosomal subunits of the extremely
      thermophilic archaea Sulfolobus solfataricus and Desulfurococcus mobilis were
      tested for their sensitivity to selected antibiotics. It is shown that structural
      differences in the large ribosomal subunits determine qualitatively and
      quantitatively the patterns of response to alpha-sarcin and paromomycin in these
      species.

PMID- 8655532
TI  - Phenotypic differentiation of "smart" versus "naive" bacteriophages of Bacillus
      subtilis.
AB  - The temperate bacteriophages of Bacillus subtilis differ dramatically in their
      response to the induction of the SOS system during the development of competence
      and following DNA damage. While all temperate bacteriophages are induced
      following DNA damage, the "naive" bacteriophages (i.e., phi105 and SPO2) are also
      induced during the development of competence. On the other hand, "smart"
      bacteriophages (i.e., phi3T and SPbeta) are not induced during the development of
      competence, and furthermore, once competence has developed, these prophages can
      no longer be induced by DNA damage.

PMID- 8655533
TI  - redD and actII-ORF4, pathway-specific regulatory genes for antibiotic production
      in Streptomyces coelicolor A3(2), are transcribed in vitro by an RNA polymerase
      holoenzyme containing sigma hrdD.
AB  - redD and actII-ORF4, regulatory genes required for synthesis of the antibiotics
      undecylprodigiosin and actinorhodin by Streptomyces coelicolor A3(2), were
      transcribed in vitro by an RNA polymerase holoenzyme containing sigma hrdD.
      Disruption of hrdD had no effect on antibiotic production, indicating that redD
      and actII-ORF4 are transcribed in vivo by at least one other RNA polymerase
      holoenzyme. These data provide the first experimental evidence that HrdD can
      function as a sigma factor.

PMID- 8655534
TI  - The tamA gene of Aspergillus nidulans contains a putative zinc cluster motif
      which is not required for gene function.
AB  - Expression of many nitrogen catabolic enzymes is controlled by nitrogen
      metabolite repression in Aspergillus nidulans. Although the phenotypes of tamA
      mutants have implicated this gene in nitrogen regulation, its function is
      unknown. We have cloned the tamA gene by complementation of a new tamA allele.
      The tamA sequence shares significant homology with the UGA35/DAL81/DURL gene of
      Saccharomyces cerevisiae. In vitro mutagenesis of sequences encoding a putative
      zinc cluster DNA binding domain indicated that this motif is not required for in
      vivo TamA function.

PMID- 8655535
TI  - The catabolite repressor/activator (Cra) protein of enteric bacteria.

PMID- 8655536
TI  - The histone-like protein H-NS acts as a transcriptional repressor for expression
      of the anaerobic and growth phase activator AppY of Escherichia coli.
AB  - The transcriptional activator AppY is required for anaerobic and stationary-phase
      induction of the cyx-appA and hya operons of Escherichia coli, and expression of
      the appY gene itself is induced by these environmental conditions. The sequence
      of the appY gene and its promoter region is unusually AT rich. The nucleoid
      associated protein H-NS has a DNA-binding specificity for intrinsically curved AT
      rich DNA. Using a single-copy transcriptional appY-lacZ fusion, we have shown
      that appY gene expression is derepressed in hns mutants during aerobic
      exponential growth. In the hns mutant, growth phase and growth rate regulation
      under aerobic conditions was maintained, while ArcA-dependent anaerobic induction
      was greatly diminished. Judged by two-dimensional gel electrophoresis, the appY
      promoter fragment exhibits the features characteristic of curved DNA. Gel
      retardation assays showed that purified H-NS protein bound with high affinity to
      two different segments of the appY promoter region. The role of H-NS in the AppY
      regulatory cascade is discussed and compared with its function in the regulatory
      cascades of the AppY homologs CfaD and VirF.

PMID- 8655537
TI  - Identification of major and minor chaperone proteins involved in the export of
      987P fimbriae.
AB  - The 987P fimbriae of Escherichia coli consist mainly of the major subunit, FasA,
      and two minor subunits, FasF and FasG. In addition to the previously
      characterized outer membrane or usher protein FasD, the FasB, FasC, and FasE
      proteins are required for fimbriation. To better understand the roles of these
      minor proteins, their genes were sequenced and the predicted polypeptides were
      shown to be most similar to periplasmic chaperone proteins of fimbrial systems.
      Western blot (immunoblot) analysis and immunoprecipitation of various fas mutants
      with specific antibody probes identified both the subcellular localizations and
      associations of these minor components. FasB was shown to be a periplasmic
      chaperone for the major fimbrial subunit, FasA. A novel periplasmic chaperone,
      FasC, which stabilizes and specifically interacts with the adhesin, FasG, was
      identified. FasE, a chaperone-like protein, is also located in the periplasm and
      is required for optimal export of FasG and possibly other subunits. The use of
      different chaperone proteins for various 987P subunits is a novel observation for
      fimbrial biogenesis in bacteria. Whether other fimbrial systems use a similar
      tactic remains to be discovered.

PMID- 8655538
TI  - Functional analysis of promoters in the nisin gene cluster of Lactococcus lactis.
AB  - The promoters in the nisin gene cluster nisABTCIPRKFEG of Lactococcus lactis were
      characterized by primer extension and transcriptional fusions to the Escherichia
      coli promoterless beta-glucuronidase gene (gusA). Three promoters preceding the
      nisA, nisR, and nisF genes, which all give rise to gusA expression in the nisin
      producing strain L. lactis NZ9700, were identified. The transcriptional
      autoregulation of nisA by signal transduction involving the sensor histidine
      kinase NisK and the response regulator NisR has been demonstrated previously (0.
      P. Kuipers, M. M. Beerthuyzen, P. G. G. A. de Ruyter, E. J. Luesink, and W. M. de
      Vos, J. Biol. Chem. 270: 27299-27304, 1995), and therefore the possible nisin
      dependent expression of gusA under control of the nisR and nisF promoters was
      also investigated. The nisR promoter was shown to direct nisin-independent gusA
      expression in L. lactis MG 1363, which is a nisin-transposon- and plasmid-free
      strain. L. lactis NZ9800, which does not produce nisin because of a deletion in
      the nisA gene, containing the nisF-gusA fusion plasmid, gave rise to beta
      glucuronidase production only after induction by nisin. A similar regulation was
      found in L. lactis NZ3900, which contains a single copy of the nisR and nisK
      genes but no other genes of the nisin gene cluster. In contrast, when the nisK
      gene was disrupted, no beta-glucuronidase activity directed by the nisF promoter
      could be detected even after induction with nisin. These results show that, like
      the nisA promoter, the nisF promoter is nisin inducible. The nisF and nisA
      promoter sequences have significant similarities and contain a conserved region
      that could be important for transcriptional control.

PMID- 8655539
TI  - Cloning, nucleotide sequencing, and expression of the Azospirillum brasilense lon
      gene: involvement in iron uptake.
AB  - The lon gene of Escherichia coli encodes the lon (La) protease, which is
      associated with cellular protein degradation. A lon gene homolog from
      Azospirillum brasilense, a nitrogen-fixing soil bacterium which lives in
      association with the roots of cereal grasses, was cloned and characterized. The
      nucleotide sequence of the A. brasilense lon gene was determined. It contains an
      open reading frame that encodes a protein of 810 amino acids with a predicted
      molecular mass of about 90 kDa. The deduced amino acid sequence showed a high
      level of homology with the sequences of all the known lon gene products. An open
      reading frame homologous to the E. coli clpX gene was found in front of the lon
      gene. Transcriptional analysis showed that the lon gene of A. brasilense is
      induced by heat shock and that the mRNA is monocistronic. An A. brasilense
      mutant, with Tn5 inserted in the lon gene, was shown to be defective in iron
      uptake and failed to express two membrane proteins that are induced by iron
      starvation in the parental strain.

PMID- 8655540
TI  - Topology of the membrane protein LamB by epitope tagging and a comparison with
      the X-ray model.
AB  - We previously developed a genetic approach to study, with a single antibody, the
      topology of the outer membrane protein LamB, an Escherichia coli porin with
      specificity towards maltodextrins and a receptor for bacteriophage lambda. Our
      initial procedure consisted of inserting at random the same reporter epitope (the
      C3 neutralization epitope from poliovirus) into permissive sites of LamB (i.e.,
      sites which tolerate insertions without deleterious effects on the protein
      activities or the cell). A specific monoclonal antibody was then used to examine
      the position of the inserted epitope with respect to the protein and the
      membrane. In the present work, we set up a site-directed procedure to insert the
      C3 epitope at new sites in order to distinguish between two-dimensional folding
      models. This allowed us to identify two new surface loops of LamB and to predict
      another periplasmic exposed region. The results obtained by random and directed
      epitope tagging are analyzed in light of the recently published X-ray structure
      of the LamB protein. Study of 23 hybrid LamB-C3 proteins led to the direct
      identification of five of the nine external loops (L4, L5, L6, L7, and L9) and
      led to the prediction of four periplasmic loops (I1, I4, I5, and I8) of LamB.
      Nine of the hybrid proteins did not lead to topological conclusions, and none led
      to the wrong predictions or conclusions. The comparison indicates that parts of
      models based on secondary structure predictions alone are not reliable and points
      to the importance of experimental data in the establishment of outer membrane
      protein topological models. The advantages and limitations of genetic foreign
      epitope insertion for the study of integral membrane proteins are discussed.

PMID- 8655541
TI  - The tolZ gene of Escherichia coli is identified as the ftsH gene.
AB  - Escherichia coli tolZ mutants are tolerant to colicins E2, E3, D, Ia, and Ib (Tol
      ), can grow on glucose but not on succinate or other nonfermentable carbon
      sources (Nfc-), and show temperature-sensitive growth (Ts). A 1.8-kb DNA fragment
      that complemented the tolZ mutation was cloned. The DNA fragment was sequenced,
      and one open reading frame was found. This frame was identical to a part of the
      E. coli FtsH protein, an ATP-dependent metalloprotease that binds to the
      cytoplasmic membrane. The tolZ gene was located at 69 min on the E. coli genetic
      map, and the mutation was complemented by a plasmid carrying the ftsH gene,
      indicating that the tolZ gene is identical to the ftsH gene. The mutated tolZ21
      gene was also cloned and sequenced and was found to have a single base change
      that caused an amino acid alteration of His-418 to Tyr in the FtsH protein. The
      tolZ21 mutant showed Hfl- (high frequency of lysogenization) and Std- (stop
      transfer-defective) pheno-types, both of which are due to a mutation in the ftsH
      (hflB) gene. However, the ftsH1, ftsH101, and hflB29 mutants did not show Tol-
      and Nfc phenotypes. The tolZ21 mutant was found to have a suppressor mutation,
      named sfhC, which allowed cells to survive. The sfhC mutation alone caused no Tol
      , Nfc-, Ts, or Hfl- phenotypes in the tolZ21 mutant.

PMID- 8655542
TI  - HrpXv, an AraC-type regulator, activates expression of five of the six loci in
      the hrp cluster of Xanthomonas campestris pv. vesicatoria.
AB  - hrp genes, basic pathogenicity genes of the pepper and tomato pathogen
      Xanthomonas campestris pv. vesicatoria, are regulated dependent on environmental
      conditions. We isolated the hrpXv gene, which was found to be outside the large
      hrp cluster comprising the six loci hrpA to hrpF. The predicted HrpXv protein is
      476 amino acids long and has a molecular mass of 52.5 kDa. HrpX is highly
      conserved among xanthomonads and is a member of the AraC family of regulatory
      proteins. An hrpXv insertion mutant has a typical hrp phenotype and no longer
      allows induction of the five hrp loci hrpB to hrpF in the new hrp induction
      medium XVM2, indicating that HrpXv is the positive regulator of these loci. An
      hrpXv mutant could be partially complemented by the related hrpB gene of
      Burkholderia solanacearum, the protein product of which shows 40 and 58% amino
      acid identity and similarity, respectively, to HrpXv. The hrpXv gene itself has a
      low basal level of expression that is enhanced in XVM2. Expression of hrpXv as
      well as that of the hrpA locus is independent of the hrpXv gene. The
      transcription start site of hrpXv was mapped. Comparison between the hrpXv
      promoter and the corresponding region of the hrpXc gene from X. campestris pv.
      campestris revealed sequence conservation up to position -84. A putative helix
      turn-helix motif in the C-terminal region of HrpXv and its possible interaction
      with a conserved hrp promoter element, the plant-inducible promoter box, are
      discussed.

PMID- 8655543
TI  - G1n3p is capable of binding to UAS(NTR) elements and activating transcription in
      Saccharomyces cerevisiae.
AB  - When readily used nitrogen sources are available, the expression of genes
      encoding proteins needed to transport and metabolize poorly used nitrogen sources
      is repressed to low levels; this physiological response has been designated
      nitrogen catabolite repression (NCR). The cis-acting upstream activation sequence
      (UAS) element UAS(NTR) mediates Gln3p-dependent, NCR-sensitive transcription and
      consists of two separated dodecanucleotides, each containing the core sequence
      GATAA. Gln3p, produced in Escherichia coli and hence free of all other yeast
      proteins, specifically binds to wild-type UAS(NTR) sequences and DNA fragments
      derived from a variety of NCR-sensitive promoters (GDH2, CAR11 DAL3, PUT1, UGA4,
      and GLN1). A LexA-Gln3 fusion protein supported transcriptional activation when
      bound to one or more LexAp binding sites upstream of a minimal CYC1-derived
      promoter devoid of UAS elements. LexAp-Gln3p activation of transcription was
      largely independent of the nitrogen source used for growth. These data argue that
      Gln3p is capable of direct UAS(NTR) binding and participates in transcriptional
      activation of NCR-sensitive genes.

PMID- 8655544
TI  - Gliding motility in slide cultures of Myxococcus xanthus in stable and steep
      chemical gradients.
AB  - A method was devised to construct stable and steep chemical gradients in slide
      cultures to study the movements of gliding cells. The movement of Myxococcus
      xanthus individual cells and small swarms was studied in these gradients. There
      was no response to gradients of Casitone and yeast extract that were previously
      reported to stimulate a positive chemotactic response with M. xanthus.

PMID- 8655545
TI  - Role of DNA repair in Bacillus subtilis spore resistance.
AB  - Wet-heat or hydrogen peroxide treatment of wild-type Bacillus subtilis spores did
      not result in induction of lacZ fusions to three DNA repair-related genes (dinR,
      recA, and uvrC) during spore outgrowth. However, these genes were induced during
      outgrowth of wild-type spores treated with dry heat or UV. Wet-heat, desiccation,
      dry-heat, or UV treatment of spores lacking major DNA-binding proteins (termed
      alpha-beta- spores) also resulted in induction of the three DNA repair genes
      during spore outgrowth. Hydrogen peroxide treatment of alpha-beta-spores did not
      result in induction of dinR- and rerA-lacZ but did cause induction of uvrC-lacZ
      during spore outgrowth. Spores of a recA mutant were approximately twofold more
      UV sensitive and approximately ninefold more sensitive to dry heat than were wild
      type spores but were no more sensitive to wet heat and hydrogen peroxide. In
      contrast, alpha-beta- recA spores were significantly more sensitive than were
      alpha-beta- spores to all four treatments, as well as to desiccation.
      Surprisingly, RecA levels were quite low in dormant spores, but RecA was
      synthesized during spore outgrowth. Taken together, these data (i) are consistent
      with previous suggestions that some treatments (dry heat and UV with wild-type
      spores; desiccation, dry and wet heat, hydrogen peroxide, and UV with alpha-beta-
      spores) that kill spores do so in large part by causing DNA damage and (ii)
      indicate that repair of DNA damage during spore outgrowth is an important
      component of spore resistance to a number of treatments, as has been shown
      previously for UV.

PMID- 8655547
TI  - Purification and properties of an amidase from Rhodococcus erythropolis MP50
      which enantioselectively hydrolyzes 2-arylpropionamides.
AB  - An enantioselective amidase from Rhodococcus erythropolis MP50 was purified to
      homogeneity. The enzyme has a molecular weight of about 480,000 and is composed
      of identical subunits with molecular weights of about 61,000. The NH2-terminal
      amino acid sequence was significantly different from previously published
      sequences of bacterial amidases. The purified amidase hydrolyzed a wide range of
      aliphatic and aromatic amides, The highest enzyme activities were found with
      amides carrying hydrophobic residues, such as pentyl or naphthoyl. The purified
      enzyme converted racemic 2-phenylpropionamide, naproxen amide [2-(6-methoxy-2
      naphthyl) propionamide], and ketoprofen amide [2-(3'-benzoylphenyl)propionamide]
      to the corresponding S-acids with an enantiomeric excess of >99% and an almost
      50% conversion of the racemic amides. The enzyme also hydrolyzed different alpha
      amino amides but without significant enantioselectivity.

PMID- 8655546
TI  - In situ visualization of high genetic diversity in a natural microbial community.
AB  - Simultaneous in situ visualization of seven distinct bacterial genotypes, all
      affiliated with the phylogenetically narrow group of beta-1 Proteobacteria, was
      achieved in activated sludge. This finding indicates that the high diversity
      found in the same sample by direct rRNA sequence retrieval was indeed present in
      this complex community. By the combination of comparative rRNA sequence analysis,
      in situ hybridization with fluorescently labeled, rRNA-targeted oligonucleotides
      and confocal laser scanning microscopy several microbial populations can be
      analyzed for abundance, relative spatial distribution and phylogeny directly at
      their site of action without prior cultivation.

PMID- 8655549
TI  - Identification and characterization of a gene cluster involved in manganese
      oxidation by spores of the marine Bacillus sp. strain SG-1.
AB  - The marine Bacillus sp. strain SG-1 forms spores that oxidize manganese(II) as a
      result of the activities of uncharacterized components of its spore coat.
      Nucleotide sequence analysis of chromosomal loci previously identified through
      insertion mutagenesis as being involved in manganese oxidation identified seven
      possible genes (designated mnxA to mnxG) in what appears to be an operon. A
      potential recognition site for the sporulation, mother-cell-specific, RNA
      polymerase sigma factor, sigmaK, was located just upstream of the cluster, and
      correspondingly, measurement of beta-galactosidase activity from a Tn917-lacZ
      insertion in mnxD showed expression at mid-sporulation to late sporulation
      (approximately stage IV to V of sporulation). Spores of nonoxidizing mutants
      appeared unaffected with respect to their temperature and chemical resistance
      properties and germination characteristics. However, transmission electron
      microscopy revealed alterations in the outermost spore coat. This suggests that
      products of these genes may be involved in the deposition of the spore coat
      structure and/or are spore coat proteins themselves. Regions of the deduced
      protein product of mnxG showed amino acid sequence similarity to the family of
      multicopper oxidases, a diverse group of proteins that use multiple copper ions
      to oxidize a variety of substrates. Similar regions included those that are
      involved in binding of copper, and the addition of copper at a low concentration
      was found to enhance manganese oxidation by the spores. This suggests that the
      product of this gene may function like a copper oxidase and that it may be
      directly responsible for the oxidation of manganese by the spores.

PMID- 8655548
TI  - A family of genes located on four separate 32-kilobase circular plasmids in
      Borrelia burgdorferi B31.
AB  - We have identified four loci in Borrelia burgdorferi B31 that contain open
      reading frames capable of encoding six proteins that are related to the antigenic
      proteins OspE and OspF. We have designated these proteins Erp, for OspEF-related
      protein, and named their respective genes erp. The erpA and erpB genes are
      linked, as are erpC and erpD, and the pairs probably constitute two operons. The
      erpG and erpH genes appear to be monocistronic. The ErpA and ErpC proteins are
      expressed by B. burgdorferi B31 in culture and are recognized by a polyclonal
      antiserum raised against the OspE protein of B. burgdorferi N40. The four erp
      loci are each located on different 32-kb circular plasmids that contain
      additional DNA sequences that are homologous to each other and to an 8.3-kb
      circular plasmid of B. burgdorferi sensu lato Ip2l. All four 32-kb plasmids can
      be maintained within a single bacterium, which may provide a model for the study
      of plasmid replication and segregation in B. burgdorferi.

PMID- 8655550
TI  - Splicing of a group II intron involved in the conjugative transfer of pRS01 in
      lactococci.
AB  - Analysis of a region involved in the conjugative transfer of the lactococcal
      conjugative element pRS01 has revealed a bacteria] group II intron. Splicing of
      this lactococcal intron (designated Ll.ltrB) in vivo resulted in the ligation of
      two exon messages (ltrBE1 and ltrBE2) which encoded a putative conjugative
      relaxase essential for the transfer of pRS01. Like many group II introns, the
      Ll.ltrB intron possessed an open reading frame (ltrA) with homology to reverse
      transcriptases. Remarkably, sequence analysis of ltrA suggested a greater
      similarity to open reading frames encoded by eukaryotic mitochondrial group II
      introns than to those identified to date from other bacteria. Several insertional
      mutations within ltrA resulted in plasmids exhibiting a conjugative transfer
      deficient phenotype. These results provide the first direct evidence for splicing
      of a prokaryotic group II intron in vivo and suggest that conjugative transfer is
      a mechanism for group II intron dissemination in bacteria.

PMID- 8655551
TI  - Purification and characterization of an oxygen-sensitive, reversible 3,4
      dihydroxybenzoate decarboxylase from Clostridium hydroxybenzoicum.
AB  - A 3,4-dihydroxybenzoate decarboxylase (EC 4.1.1.63) from Clostridium
      hydroxybenzoicum JW/Z-1T was purified and partially characterized. The estimated
      molecular mass of the enzyme was 270 kDa. Sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis gave a single band of 57 kDa, suggesting that the enzyme
      consists of five identical subunits. The temperature and pH optima were 50
      degrees C and pH 7.0, respectively. The Arrhenius energy for decarboxylation of
      3,4-dihydroxybenzoate was 32.5 kJ . mol(-1) for the temperature range from 22 to
      50 degrees C. The Km and kcat for 3,4-dihydroxybenzoate were 0.6 mM and 5.4 x
      10(3) min(-1), respectively, at pH 7.0 and 25 degrees C. The enzyme optimally
      catalyzed the reverse reaction, that is, the carboxylation of catechol to 3,4
      dihydroxybenzoate, at pH 7.0. The enzyme did not decarboxylate 2-hydroxybenzoate,
      3-hydroxybenzoate, 4-hydroxybenzoate, 2,3-dihydroxybenzoate, 2,4
      dihydroxybenzoate, 2,5-dihydroxybenzoate, 2,3,4-trihydroxybenzoate, 3,4,5
      trihydroxybenzoate, 3-F-4-hydroxybenzoate, or vanillate. The decarboxylase
      activity was inhibited by 25 and 20%, respectively, by 2,3,4- and 3,4,5
      trihydroxybenzoate. Thiamine PPi and pyridoxal 5'-phosphate did not stimulate and
      hydroxylamine and sodium borohydride did not inhibit the enzyme activity,
      indicating that the 3,4-dihydroxybenzoate decarboxylase is not a thiamine PPi-,
      pyridoxal 5'-phosphate-, or pyruvoyl-dependent enzyme.

PMID- 8655552
TI  - The cryptic general secretory pathway (gsp) operon of Escherichia coli K-12
      encodes functional proteins.
AB  - Systematic sequencing of the Escherichia coli K-12 chromosome (GenBank entry
      U18997) has revealed the presence of an apparently complete operon of genes (the
      gspC-0 operon) similar to genes coding for components of the main terminal branch
      of the general secretory pathway (e.g., the Klebsiella oxytoca pulC-0 pullulanase
      secretion operon) and to related genes required for type IV pilus biogenesis. For
      example, the last gene in the gsp operon, gspO (formerly hopD), encodes a protein
      which is similar to several type IV prepilin peptidases. Expression of gspO from
      lacZp promotes cleavage of two known prepilin peptidase substrates in E. coli K
      12: Neisseria gonorrhoeae type IV prepilin and K. oxytoca prePulG protein. gspO
      also complements a mutation in the corresponding gene (pulO) of the pullulanase
      secretion operon when it is expressed from lacZp. Another gene in the gsp operon,
      gspG (formerly hopG), encodes a protein similar to prePulG, a component of the
      pullulanase secretion pathway. Expression of gspG from lacZp leads to production
      of a protein which (i) is recognized by PulG-specific antiserum (and by antiserum
      against the Pseudomonas aeruginosa PulG homolog XcpG [formerly XcpT]), (ii) is
      processed in cells expressing gspO, and (iii) restores secretion in cells
      carrying a pulG mutation. The chromosomal copies of gspG and gspO are apparently
      not expressed, probably because of very weak transcription from the upstream
      region, as measured by using a chromosomal gspC-lacZ operon fusion. Thus, the gsp
      operon of E. coli K-12 includes at least two functional genes which, together
      with the rest of the operon, are probably not expressed under laboratory
      conditions.

PMID- 8655553
TI  - In vivo stability of the Umu mutagenesis proteins: a major role for RecA.
AB  - The Escherichia coli Umu proteins play critical roles in damage-inducible SOS
      mutagenesis. To avoid any gratuitous mutagenesis, the activity of the Umu
      proteins is normally kept to a minimum by tight transcriptional and
      posttranslational regulation. We have, however, previously observed that compared
      with an isogenic recA+ strain, the steady-state levels of the Umu proteins are
      elevated in a recA730 background (R. Woodgate and D. G. Ennis, Mol. Gen. Genet.
      229:10-16, 1991). We have investigated this phenomenon further and find that
      another coprotease-constitutive (recA*) mutant, a recA432 strain, exhibits a
      similar phenotype. Analysis revealed that the increased steady-state levels of
      the Umu proteins in the recA* strains do indeed reflect an in vivo stabilization
      of the proteins. We have investigated the basis for the phenomenon and find that
      the mutant RecA* protein stabilizes the Umu proteins by not only converting the
      labile UmuD protein to the much more stable (and mutagenically active) UmuD'
      protein but by directly stabilizing UmuD' itself. In contrast, UmuC does not
      appear to be directly stabilized by RecA* but is instead dramatically stabilized
      in the presence of UmuD'. On the basis of these observations, we suggest that
      formation of a UmuD'C-RecA*-DNA quaternary complex protects the UmuD'C proteins
      from proteolytic degradation and as a consequence helps to promote the switch
      from error-free to error-prone mechanisms of DNA repair.

PMID- 8655554
TI  - Regulation of sugar uptake via the phosphoenolpyruvate-dependent
      phosphotransferase systems in Bacillus subtilis and Lactococcus lactis is
      mediated by ATP-dependent phosphorylation of seryl residue 46 in HPr.
AB  - By using both metabolizable and nonmetabolizable sugar substrates of the
      phosphoenolpyruvate-dependent phosphotransferase system (PTS), we show that PTS
      sugar uptake into intact cells and membrane vesicles of Lactococcus lactis and
      Bacillus subtilis is strongly inhibited by high concentrations of any of several
      metabolizable PTS sugars. Inhibition requires phosphorylation of seryl residue 46
      in the phosphocarrier protein of the PTS, HPr, by the metabolite-activated, ATP
      dependent protein kinase. Inhibition does not occur when wild-type HPr is
      replaced by the S46A mutant form of this protein either in vesicles of L. lactis
      or B. subtilis or in intact cells of B. subtilis. Nonmetabolizable PTS sugar
      analogs such as 2-deoxyglucose inhibit PTS sugar uptake by a distinct mechanism
      that is independent of HPr(ser-P) and probably involves cellular
      phosphoenolpyruvate depletion.

PMID- 8655555
TI  - Genetic analysis of the Mycobacterium smegmatis rpsL promoter.
AB  - The DNA sequence of the promoter region of the Mycobacterium smegmatis rpsL gene,
      which encodes the S12 ribosomal protein, was determined. Primer extension
      analysis and S1 nuclease protection experiments identified the 5' end of the rpsL
      mRNA to be 199 bp upstream of the translation initiation codon. The rpsL promoter
      contained sequences upstream of this start point for transcription that were
      similar to the canonical hexamers found at the -10 and -35 regions of promoters
      recognized by Esigma70, the major form of RNA polymerase in Escherichia coli. To
      define the promoter of the rpsL gene, DNA fragments containing progressive
      deletions of the upstream region of the rpsL gene were inserted into a plasmid
      vector containing a promoterless xylE gene. These insertions revealed that the
      200 bp of DNA sequence immediately upstream from the translation initiation codon
      was not essential for promoter function. In addition, 5' deletions removing all
      but 34 bp upstream of the transcription start point retained greater than 90%
      promoter activity, suggesting that the -35 hexamer was not essential for promoter
      activity. To determine which nucleotides were critical for promoter function,
      oligonucleotide-directed mutagenesis and mutagenic PCR amplification were used to
      produce point mutations in the region upstream of the start point of
      transcription. Single base substitutions in the -10 hexamer, but not in the -35
      hexamer, severely reduced rpsL promoter activity in vivo. Within the -10 hexamer,
      nucleotide substitutions causing divergence from the E. Coli sigma70 consensus
      reduced promoter activity. The DNA sequence immediately upstream from the - 10
      hexamer contained the TGn motif described as an extended -10 region in
      prokaryotic promoters. Mutations in this motif, in combination with a transition
      at either the -38 or -37 position within the -35 hexamer, severely reduced
      promoter activity, indicating that in the absence of a functional -35 region, the
      rpsL promoter is dependent on the TGn sequence upstream from the -10 hexamer.
      Comparison of the nucleotide sequence of the rpsL promoter region of M. smegmatis
      with the homologous sequences from Mycobacterium leprae, Mycobacterium bovis, and
      Mycobacterium tuberculosis showed the presence in these slowly growing
      mycobacterial species of conserved promoter elements a similar distance upstream
      of the translation initiation codon of the rpsL gene, but these other
      mycobacterial promoters did not contain the extended -10 motif.

PMID- 8655556
TI  - Evidence that the hanA gene coding for HU protein is essential for heterocyst
      differentiation in, and cyanophage A-4(L) sensitivity of, Anabaena sp. strain PCC
      7120.
AB  - The highly pleiotropic, transposon-generated mutant AB22 of Anabaena sp. strain
      PCC 7120 exhibits slow growth, altered pigmentation, cellular fragility,
      resistance to phage A-4(L), and the inability to differentiate heterocysts.
      Reconstruction of the transposon mutation in the wild-type strain reproduced the
      phenotype of the original mutant. Sequencing of the flanking DNA showed that the
      transposon had inserted at the beginning of a gene, which we call hanA, that
      encodes Anabaena HU protein (R. Nagaraja and R. Haselkorn, Biochimie 76:1082
      1089, 1994). Mapping of the transposon insertion by pulsed-field gel
      electrophoresis showed that hanA is located at ca. 4.76 Mb on the physical map of
      the chromosome and is transcribed clockwise. Repeated subculturing of AB22
      resulted in improved growth and loss of filament fragmentation, presumably
      because of one or more compensatory mutations; however, the mutant retained its A
      4(L)r Het- phenotype. The mutation in strain AB22 could be complemented by a
      fragment of wild-type DNA bearing hanA as its only open reading frame.

PMID- 8655557
TI  - Heterologous growth phase- and temperature-dependent expression and H2O2 toxicity
      protection of a superoxide-inducible monofunctional catalase gene from
      Xanthomonas oryzae pv. oryzae.
AB  - Catalase is an important protective enzyme against H2O2 toxicity. Here, we report
      the characterization of a Xanthomonas oryzae pv. oryzae catalase gene (katX). The
      gene was localized and its nucleotide sequence was determined. The gene codes for
      a 77-kDa polypeptide. The deduced katX amino acid sequence shares regions of high
      identity with other monofunctional catalases in a range of organisms from
      bacteria to eukaryotes. The transcriptional regulation of katX was atypical of
      bacterial monofunctional kat genes. Northern (RNA) analysis showed that katX
      transcription was highly induced by treatments with low concentrations of
      menadione, a superoxide generator, and methyl methanesulfonate, a mutagen. It was
      only weakly induced by H2O2. Unlike in other bacteria, a high level of catalase
      in Xanthomonas spp. provided protection from the growth-inhibitory and killing
      effects of H2O2 but not from those of organic peroxides and superoxide
      generators. Unexpectedly, heterologous expression of katX in Escherichia coli was
      both growth phase and temperature dependent. Catalase activity in E. coli kat
      mutants harboring katX on an expression vector was detectable only when the cells
      entered the stationary phase of growth and at 28 degrees C. The patterns of
      transcription regulation, heterologous expression, and physiological function of
      katX are different from previously studied bacterial kat genes.

PMID- 8655558
TI  - Cloning and genetic organization of the bacteriocin 31 determinant encoded on the
      Enterococcus faecalis pheromone-responsive conjugative plasmid pYI17.
AB  - The conjugative plasmid pYI17 (57.5 kb) isolated from Enterococcus faecalis YI717
      confers a pheromone response on the host and encodes the bacteriocin 31 gene.
      Bacteriocin 31 is active against E. hirae 9790, E. faecium, and Listeria
      monocytogenes. pYI17 was mapped physically by restriction enzyme analysis and the
      relational clone method. Deletion mutant and sequence analyses of the EcoRI
      fragment B cloned from pYl17 revealed that a 1.0-kb fragment contained the
      bacteriocin gene (bacA) and an immunity gene (bacB). This fragment induced
      bacteriocin activity in E. faecalis OG1X and E. hirae 9790. The bacA gene is
      located on the pYI17 physical map between 3.37 and 3.57 kb, and bacB is located
      between 3.59 kb and 3.87 kb, bacA encodes 67 amino acids, and bacB encodes 94
      amino acids. The deduced amino acid sequence of the bacA protein contained a
      series of hydrophobic residues typical of a signal sequence at its amino
      terminus. The predicted mature bacA protein (43 amino acids) showed sequence
      homology with the membrane-active class II bacteriocins of lactic acid bacteria.
      Analysis of Tn5 insertion mutants and the resulting transcripts indicated that
      these genes are transcribed as an operon composed of bacA, bacB, and an open
      reading frame located downstream of bacB designated ORF3.

PMID- 8655560
TI  - NBU1, a mobilizable site-specific integrated element from Bacteroides spp., can
      integrate nonspecifically in Escherichia coli.
AB  - NBU1 is an integrated Bacteroides element that can he mobilized from Bacteroides
      donors to Bacteroides recipients. Previous studies have shown that a plasmid
      carrying the internal mobilization region of NBU1 could be transferred by
      conjugation from Bacteroides thetaiotaomicron to Escherichia coli. In this
      report, we show that NBU1 can integrate in E. coli. Whereas integration of NBU1
      in B. thetaiotaomicron is site specific, integration of NBU1 in E. coli was
      relatively random, and the insertion frequency of NBU1 into the E. coli
      chromosome was 100 to 1,000 times lower than the frequency of integration in B.
      thetaiotaomicron. The frequency of NBU1 integration in E. coli could be increased
      about 10- to 70-fold, to a value close to that seen with B. thetaiotaomicron, if
      the primary integration site from B. thetaiotaomicron, BT1-1, was provided on a
      plasmid in the E. coli recipient or the NBU1 integrase gene, intN1, was provided
      on a high-copy-number plasmid to increase the amount of integrase available in
      the recipient. When the primary integration site was available in the recipient,
      NBU1 integrated site specifically in E. coli. Our results show that NBUs have a
      very broad host range and are capable of moving from Bacteroides spp. to
      distantly related species such as E. coli. Moreover, sequence analysis of NBU1
      integration sites provided by integration events in E. coli has helped to
      identify some regions of the NBU1 attachment site that may play a role in the
      integration process.

PMID- 8655559
TI  - The Bacteroides mobilizable insertion element, NBU1, integrates into the 3' end
      of a Leu-tRNA gene and has an integrase that is a member of the lambda integrase
      family.
AB  - NBU1 is a 10.3-kbp integrated Bacteroides element that can be induced to excise
      from the chromosome and can be mobilized to a recipient by trans-acting functions
      provided by certain Bacteroides conjugative transposons. The NBU1 transfer
      intermediate is a covalently closed circle, which is presumed to be the form that
      integrates into the recipient genome. We report here that a 2.4-kbp segment of
      NBU1 was all that was required for site-specific integration into the chromosome
      of Bacteroides thetaiotaomicron 5482. This 2.4-kbp region included the joined
      ends of the NBU1 circular form (attN1) and a single open reading frame, intN1,
      which encoded the integrase. Previously, we had found that NBU1 integrates
      preferentially into a single site in B. thetaiotaomicron 5482. We have now shown
      that the NBU1 target site is located at the 3' end of a Leu-tRNA gene. The NBU1
      integrase gene, intN1, was sequenced. The predicted protein had little overall
      amino acid sequence similarity to any proteins in the databases but had limited
      carboxy-terminal similarity to the integrases of lambdoid phages and to the
      integrases of the gram-positive conjugative transposons Tn916 and Tn1545. We also
      report that the intN1 gene is expressed constitutively.

PMID- 8655562
TI  - Polar allele duplication for transcriptional analysis of consecutive essential
      genes: application to a cluster of Escherichia coli fatty acid biosynthetic
      genes.
AB  - The genes encoding acyl carrier protein and several key fatty acid biosynthetic
      enzymes are clustered at min 24 of the Escherichia coli chromosome. This cluster
      of genes is not transcribed as a classical operon, but rather multiple promoters
      are present and each gene is cotranscribed with at least one other gene.
      Transcripts specific for single genes ar also present. Transcription of acpP, the
      gene encoding acyl carrier protein, has been studied in detail. The acpP gene was
      shown to be transcribed from at least two different promoters by Northern (RNA)
      blot, primer extension, and deletion analyses, and the major promoter was mapped.
      We tested whether multiple promoters are necessary to produce acyl carrier
      protein by use of a new method whereby a transcriptional terminator was
      integrated into the chromosome upstream of the intact acpP gene. By use of this
      method (called polar allele duplication), we demonstrate that the promoter
      located immediately upstream of the coding sequence is sufficient for synthesis
      of this very abundant protein.

PMID- 8655561
TI  - Involvement of the DnaK-DnaJ-GrpE chaperone team in protein secretion in
      Escherichia coli.
AB  - We used depletion studies designed to further investigate the role of the DnaK,
      DnaJ, and GrpE heat shock proteins in the SecB-dependent and SecB-independent
      secretion pathways. Our previous finding that SecB-deficient strains containing
      the grpE280 mutation were still secretion proficient raised the possibility that
      GrpE was not involved in this secretory pathway. Using depletion studies, we now
      demonstrate a requirement for GrpE in this pathway. In addition, depletion
      studies demonstrate that while DnaK, DnaJ, and GrpE are involved in the secretion
      of the SecB-independent proteins (alkaline phosphatase, ribose-binding protein,
      and beta-lactamase), they are not the primary chaperones in this process.

PMID- 8655563
TI  - Modulation of development, growth dynamics, wall crystallinity, and infection
      sites in white clover root hairs by membrane chitolipooligosaccharides from
      Rhizobium leguminosarum biovar trifolii.
AB  - We used bright-field, time-lapse video, cross-polarized, phase-contrast, and
      fluorescence microscopies to examine the influence of isolated
      chitolipooligosaccharides (CLOSs) from wild-type Rhizobium leguminosarum bv.
      trifolii on development of white clover root hairs, and the role of these
      bioactive glycolipids in primary host infection. CLOS action caused a threefold
      increase in the differentiation of root epidermal cells into root hairs. At
      maturity, root hairs were significantly longer because of an extended period of
      active elongation without a change in the elongation rate itself. Time-series
      image analysis showed that the morphological basis of CLOS-induced root hair
      deformation is a redirection of tip growth displaced from the medial axis as
      previously predicted. Further studies showed several newly described infection
      related root hair responses to CLOSs, including the localized disruption of the
      normal crystallinity in cell wall architecture and the induction of new infection
      sites. The application of CLOS also enabled a NodC- mutant of R. leguminosarum
      bv. trifolii to progress further in the infection process by inducing bright
      refractile spot modifications of the deformed root hair walls. However, CLOSs did
      not rescue the ability of the NodC- mutant to induce marked curlings or infection
      threads within root hairs. These results indicate that CLOS Nod factors elicit
      several host responses that modulate the growth dynamics and symbiont
      infectibility of white clover root hairs but that CLOSs alone are not sufficient
      to permit successful entry of the bacteria into root hairs during primary host
      infection in the Rhizobium-clover symbiosis.

PMID- 8655564
TI  - Transposon mutagenesis affecting thiosulfate oxidation in Bosea thiooxidans, a
      new chemolithoheterotrophic bacterium.
AB  - Transposon insertion mutagenesis was used to isolate mutants of Bosea thiooxidans
      which are impaired in thiosulfate oxidation. Suicide plasmid pSUP5011 was used to
      introduce the transposon Tn5 into B. thiooxidans via Escherichia coli S17.1
      mediated conjugation. Neomycin-resistant transconjugants occurred at a frequency
      of 2.2 X 10(-4) per donor. Transconjugants defective in thiosulfate oxidation
      were categorized into three classes on the basis of growth response, enzyme
      activities, and cytochrome patterns. Class I mutants were deficient in cytochrome
      c, and no thiosulfate oxidase activity was detected. Class II mutants retained
      the activities of key enzymes of thiosulfate metabolism, although at reduced
      levels. Mutants of this class grown on mixed-substrate agar plates deposited
      elemental sulfur on the colony surfaces. Class III mutants were unable to utilize
      thiosulfate, though they had normal levels of cytochrome c. The transposon
      insertions occurred at different chromosomal positions, as confirmed by Southern
      blotting of chromosomal DNA of mutants deficient in thiosulfate oxidation, a
      deficiency which resulted from single insertions of Tn5.

PMID- 8655565
TI  - Heat shock activation of the groESL operon of Agrobacterium tumefaciens and the
      regulatory roles of the inverted repeat.
AB  - Deletions were constructed in the conserved inverted repeat (IR) found in the
      groESL operon of Agrobacterium tumefaciens and in many other groE and dnaK
      operons and genes in eubacteria. These deletions affected the level of expression
      of the operon and the magnitude of its heat shock activation. The IR seems to
      operate at the DNA level, probably as an operator site that binds a repressor
      under non-heat shock conditions. The IR was also found to function at the mRNA
      level, since under non-heat shock conditions transcripts containing deletions of
      one side of the IR had longer half-lives than did transcripts containing the wild
      type IR. Under heat shock conditions, the half-life of the mRNA was unaffected by
      this deletion because of heat shock-dependent cleavage. However, the groESL
      operon was found to be heat shock activated even after most of the IR was
      deleted. This observation, together with the fact that the groESL operon of A.
      tumefaciens was heat shock activated in Escherichia coli and vice versa, suggests
      that a heat shock promoter regulates the heat shock activation of this operon.
      The primary role of the IR appears to be in reducing the MRNA levels from this
      promoter under non-heat shock conditions.

PMID- 8655567
TI  - H-NS regulates OmpF expression through micF antisense RNA in Escherichia coli.
AB  - H-NS is a major constituent of the Escherichia coli nucleoid. Expression of the
      major outer membrane proteins, OmpC and OmpF, is influenced by hns mutations such
      that OmpC expression increases whereas OmpF expression decreases irrespective of
      the osmolarity of the medium (K. A. Graeme-Cook, G. May, E. Bremer, and C. F.
      Higgins, Mol. Microbiol. 3:1287-1294, 1989). In this study we show that the
      effect of an hns::neo mutation on OmpF expression is largely diminished in a
      deletion mutant carrying the micF gene that encodes the ompF mRNA-specific
      antisense RNA. In addition, the micF transcript levels in the hns::neo mutation
      are high compared with transcript levels in wild-type cells. On the basis of
      these results, we provide evidence for a link between OmpC/OmpF expression and
      the regulatory function of H-NS. We suggest that H-NS most likely affects OmpC
      expression directly at the level of transcription, but OmpF expression is
      indirectly regulated by micF antisense RNA.

PMID- 8655566
TI  - Oxidative stress response and its role in sensitivity to isoniazid in
      mycobacteria: characterization and inducibility of ahpC by peroxides in
      Mycobacterium smegmatis and lack of expression in M. aurum and M. tuberculosis.
AB  - Mycobacterium tuberculosis is a natural mutant with inactivated oxidative stress
      regulatory gene oxyR. This characteristic has been linked to the exquisite
      sensitivity of M. tuberculosis to isonicotinic acid hydrazide (INH). In the
      majority of mycobacteria tested, including M. tuberculosis, oxyR is divergently
      transcribed from ahpC, a gene encoding a homolog of the subunit of alkyl
      hydroperoxide reductase that carries out substrate peroxide reduction. Here we
      compared ahpC expression in Mycobacterium smegmatis, a mycobacterium less
      sensitive to INH, with that in two highly INH sensitive species, M. tuberculosis
      and Mycobacterium aurum. The ahpC gene of M. smegmatis was cloned and
      characterized, and the 5' ends of ahpC mRNA were mapped by S1 nuclease protection
      analysis. M. smegmatis AhpC and eight other polypeptides were inducible by
      exposure to H2O2 or organic peroxides, as determined by metabolic labeling and
      Western blot (immunoblot) analysis. In contrast, M. aurum displayed differential
      induction of only one 18-kDa polypeptide when exposed to organic peroxides. AhpC
      could not be detected in this organism by immunological means. AhpC was also
      below detection levels in M. tuberculosis H37Rv. These observations are
      consistent with the interpretation that ahpC expression and INH sensitivity are
      inversely correlated in the mycobacterial species tested. In further support of
      this conclusion, the presence of plasmid-borne ahpC reduced M. smegmatis
      susceptibility to INH. Interestingly, mutations in the intergenic region between
      oxyR and ahpC were identified and increased ahpC expression observed in deltakatG
      M. tuberculosis and Mycobacterium bovis INH(r) strains. We propose that mutations
      activating ahpC expression may contribute to the emergence of INH(r) strains.

PMID- 8655568
TI  - Differential domain accessibility to monoclonal antibodies in three different
      morphological assemblies built up by the S-layer protein of Thermus thermophilus
      HB8.
AB  - A collection of 27 monoclonal antibodies (MAbs) against the S-layer protein
      (P100) of Thermus thermophilus HB8 has been obtained. They have been classified
      according to their ability to recognize S-layer regions expressed in E. coli from
      plasmids containing different fragments of its coding gene, slpA. The
      accessibility of the binding sites in hexagonal, trigonal, or tetragonal
      assemblies of P100 was analyzed by enzyme-linked immunosorbent assays with six of
      these MAbs and their respective Fab fragments. When packed hexagonally as the
      native S-layer (S1 assemblies), only a small region located near the amino
      terminus of the P1OO was accessible. However, when P1OO was assembled into
      trigonal (pS2 assemblies) or tetragonal (S2 assemblies) arrays, most of the
      protein domains analyzed were easily detected, thus suggesting that P1OO is
      assembled in S2 and pS2 in a similar way and that these two arrangements are
      quite different from the S1 assembly. Relationships between accessibility and
      sequence predictions are discussed.

PMID- 8655569
TI  - Characterization of the major citrate synthase of Bacillus subtilis.
AB  - The major citrate synthase of Bacillus subtilis (CS-II) was purified to near
      homogeneity and shown to correspond to the product of the citZ gene. Accumulation
      of CS-II during exponential growth and stationary phases paralleled expression of
      the citZ gene. The physical and kinetic properties of CS-II were similar to those
      of citrate synthase enzymes from Bacillus megaterium and from eukaryotic cells
      but differed from those of citrate synthases from many gram-negative bacteria.

PMID- 8655570
TI  - Genetic analysis of plasmid determinants for microcin J25 production and
      immunity.
AB  - Microcin J25 (MccJ25) is a small peptide antibiotic produced by an Escherichia
      coli strain isolated from human feces. The genetic determinants for MccJ25
      synthesis and immunity have been cloned from the low-copy-number wild-type
      plasmid pTUC1OO into the compatible vectors pBR322 and pACYC184. Physical and
      phenotypical analysis of insertion mutations and complementation tests defined
      three contiguous genes involved in MccJ25 production which span a region of about
      2.2 kb. Immunity to the antibiotic is provided by an additional gene adjacent to
      the production region.

PMID- 8655571
TI  - Gene inactivation in the oral spirochete Treponema denticola: construction of an
      flgE mutant.
AB  - Treponema denticola is implicated in the etiology of periodontal diseases. We now
      report the construction of a specific flgE mutant of T. denticola ATCC 35405
      following electroporation utilizing an erythromycin resistance cassette inserted
      into an flgE DNA fragment. The resulting mutant displays no visible motility and
      lacks periplasmic flagella as would be predicted from inactivation of the gene
      for the flagellar hook protein.

PMID- 8655572
TI  - General stress transcription factor sigmaB of Bacillus subtilis is a stable
      protein.
AB  - The sigmaB subunit of Bacillus subtilis RNA polymerase governs the expression of
      a large general stress regulon. The results of pulse-chase and
      immunoprecipitation experiments showed that sigmaB is stable both in the presence
      and in the absence of the RsbW anti-sigma factor, the principal regulator of
      sigmaB in response to environmental signals.

PMID- 8655573
TI  - Conservation of PcaQ, a transcriptional activator of pca genes for catabolism of
      phenolic compounds, in Agrobacterium tumefaciens and Rhizobium species.
AB  - In Agrobacterium tumefaciens A348, control of five genes for catabolism of the
      phenolic compound protocatechuate to beta-ketoadipate is exerted by the gene
      pcaQ. The product of pcaQ is a transcriptional activator which is distinct from
      regulators of the beta-ketoadipate pathway characterized in other bacterial
      groups. An investigation of whether pcaQ is present and conserved in related
      Rhizobium species employed Southern hybridization and an agrobacterial pcaD::LacZ
      promoter probe plasmid. These studies revealed that homologs of the activator are
      widespread among members of the family Rhizobiaceae, being present in Rhizobium
      leguminosarum, Rhizobium fredii, Rhizobium meliloti, Rhizobium etli, and
      Rhizobium tropici.

PMID- 8655574
TI  - Multiple features of the p59fyn src homology 4 domain define a motif for immune
      receptor tyrosine-based activation motif (ITAM) binding and for plasma membrane
      localization.
AB  - The src family tyrosine kinase p59fyn binds to a signaling motif contained in
      subunits of the TCR known as the immune-receptor tyrosine-based activation motif
      (ITAM). This is a specific property of p59fyn because two related src family
      kinases, p60src and p56lck, do not bind to ITAMs. In this study, we identify the
      residues of p59fyn that are required for binding to ITAMs. We previously
      demonstrated that the first 10 residues of p59fyn direct its association with the
      ITAM. Because this region of src family kinases also directs their fatty
      acylation and membrane association (Resh, M.D. 1993, Biochim. Biophys. Acta
      1155:307-322; Resh, M.D. 1994. Cell. 76:411-413), we determined whether fatty
      acylation and membrane association of p59fyn correlates with its ability to bind
      ITAMs. Four residues (Gly2, Cys3, Lys7, and Lys9) were required for efficient
      binding of p59fyn to the TCR. Interestingly, the same four residues are present
      in p56lyn, the other src family tyrosine kinase known to bind to the ITAM,
      suggesting that this set of residues constitutes an ITAM recognition motif. These
      residues were also required for efficient fatty acylation (myristoylation at Gly2
      and palmitoylation at Cys3), and plasma membrane targeting of p59fyn. Thus, the
      signals that direct p59fyn fatty acylation and plasma membrane targeting also
      direct its specific ability to bind to TCR proteins.

PMID- 8655575
TI  - A new pathway for protein export in Saccharomyces cerevisiae.
AB  - Several physiologically important proteins lack a classical secretory signal
      sequence, yet they are secreted from cells. To investigate the secretion
      mechanism of such proteins, a representative mammalian protein that is exported
      by a nonclassical mechanism, galectin-1, has been expressed in yeast. Galectin-1
      is exported across the yeast plasma membrane, and this export does not require
      the classical secretory pathway nor the yeast multidrug resistance-like protein
      Ste6p, the transporter for the peptide a factor. A screen for components of the
      export machinery has identified genes that are involved in nonclassical export.
      These findings demonstrate a new pathway for protein export that is distinct from
      the classical secretory pathway in yeast.

PMID- 8655576
TI  - Differential distribution of alpha subunits and beta gamma subunits of
      heterotrimeric G proteins on Golgi membranes of the exocrine pancreas.
AB  - Heterotrimeric G proteins are well known to be involved in signaling via plasma
      membrane (PM) receptors. Recent data indicate that heterotrimeric G proteins are
      also present on intracellular membranes and may regulate vesicular transport
      along the exocytic pathway. We have used subcellular fractionation and
      immunocytochemical localization to investigate the distribution of G alpha and G
      beta gamma subunits in the rat exocrine pancreas which is highly specialized for
      protein secretion. We show that G alpha s, G alpha i3 and G alpha q/11 are
      present in Golgi fractions which are > 95% devoid of PM. Removal of residual PM
      by absorption on wheat germ agglutinin (WGA) did not deplete G alpha subunits. G
      alpha s was largely restricted to TGN-enriched fractions by immunoblotting,
      whereas G alpha i3 and G alpha q/11 were broadly distributed across Golgi
      fractions. G alpha s did not colocalize with TGN38 or caveolin, suggesting that G
      alpha s is associated with a distinct population of membranes. G beta subunits
      were barely detectable in purified Golgi fractions. By immunofluorescence and
      immunogold labeling, G beta subunits were detected on PM but not on Golgi
      membranes, whereas G alpha s and G alpha i3 were readily detected on both Golgi
      and PM. G alpha and G beta subunits were not found on membranes of zymogen
      granules. These data indicate that G alpha s, G alpha q/11, and G alpha i3
      associate with Golgi membranes independent of G beta subunits and have
      distinctive distributions within the Golgi stack. G beta subunits are thought to
      lock G alpha in the GDP-bound form, prevent it from activating its effector, and
      assist in anchoring it to the PM. Therefore the presence of free G alpha subunits
      on Golgi membranes has several important functional implications: it suggests
      that G alpha subunits associated with Golgi membranes are in the active, GTP
      bound form or are bound to some other unidentified protein(s) which can
      substitute for G beta gamma subunits. It further implies that G alpha subunits
      are tethered to Golgi membranes by posttranslational modifications (e.g.,
      palmitoylation) or by binding to another protein(s).

PMID- 8655577
TI  - Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell
      death.
AB  - In the accompanying paper by Weil et al. (1996) we show that staurosporine (STS),
      in the presence of cycloheximide (CHX) to inhibit protein synthesis, induces
      apoptotic cell death in a large variety of nucleated mammalian cell types,
      suggesting that all nucleated mammalian cells constitutively express all of the
      proteins required to undergo programmed cell death (PCD). The reliability of that
      conclusion depends on the evidence that STS-induced, and (STS + CHS)-induced,
      cell deaths are bona fide examples of PCD. There is rapidly accumulating evidence
      that some members of the Ced-3/Interleukin-1 beta converting enzyme (ICE) family
      of cysteine proteases are part of the basic machinery of PCD. Here we show that Z
      Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a cell-permeable, irreversible,
      tripeptide inhibitor of some of these proteases, suppresses STS-induced and (STS
      + CHX)-induced cell death in a wide variety of mammalian cell types, including
      anucleate cytoplasts, providing strong evidence that these are all bona fide
      examples of PCD. We show that the Ced-3/ICE family member CPP32 becomes activated
      in STS-induced PCD, and that Bcl-2 inhibits this activation. Most important, we
      show that, in some cells at least, one or more CPP32-family members, but not ICE
      itself, is required for STS-induced PCD. Finally, we show that zVAD-fmk
      suppresses PCD in the interdigital webs in developing mouse paws and blocks the
      removal of web tissue during digit development, suggesting that this inhibition
      will be a useful tool for investigating the roles of PCD in various developmental
      processes.

PMID- 8655578
TI  - Constitutive expression of the machinery for programmed cell death.
AB  - In the presence of cycloheximide (CHX) to inhibit protein synthesis, a high
      concentration of staurosporine (STS) induces almost all cells in explant cultures
      of 8/8 types of newborn mouse organs and 3/3 types of adult mouse organs to die
      with the characteristic features of apoptosis. Eggs and blastomeres also die in
      this way when treated with STS and CHX, although they are less sensitive to this
      treatment than trophectoderm or inner cell mass cells whose sensitivity resembles
      that of other developing cells. Human red blood cells are exceptional in being
      completely resistant to treatment with STS and CHX. As (STS plus CHX)-induced
      cell deaths have been shown to display the characteristic features of programmed
      cell death (PCD), we conclude that all mammalian nucleated cells are capable of
      undergoing PCD and constitutively express all the proteins required to do so. It
      seems that the machinery for PCD is in place and ready to run, even though its
      activation often depends on new RNA and protein synthesis.

PMID- 8655579
TI  - Subunit composition of neurofilaments specifies axonal diameter.
AB  - Neurofilaments (NFs), which are composed of NF-L, NF-M, and NF-H, are required
      for the development of normal axonal caliber, a property that in turn is a
      critical determinant of axonal conduction velocity. To investigate how each
      subunit contributes to the radial growth of axons, we used transgenic mice to
      alter the subunit composition of NFs. Increasing each NF subunit individually
      inhibits radial axonal growth, while increasing both NF-M and NF-H reduces growth
      even more severely. An increase in NF-L results in an increased filament number
      but reduced interfilament distance. Conversely, increasing NF-M, NF-H, or both
      reduces filament number, but does not alter nearest neighbor interfilament
      distance. Only a combined increase of NF-L with either NF-M or NF-H promotes
      radial axonal growth. These results demonstrate that both NF-M and NF-H play
      complementary roles with NF-L in determining normal axonal calibers.

PMID- 8655580
TI  - Sequence and transmembrane topology of MEC-4, an ion channel subunit required for
      mechanotransduction in Caenorhabditis elegans.
AB  - The process by which mechanical stimuli are converted into cellular responses is
      poorly understood, in part because key molecules in this mode of signal
      transduction, the mechanically gated ion channels, have eluded cloning efforts.
      The Caenorhabditis elegans mec-4 gene encodes a subunit of a candidate
      mechanosensitive ion channel that plays a critical role in touch reception.
      Comparative sequence analysis of C. elegans and Caenorhabditis briggsae mec-4
      genes was used to initiate molecular studies that establish MEC-4 as a 768-amino
      acid protein that includes two hydrophobic domains theoretically capable of
      spanning a lipid bilayer. Immunoprecipitation of in vitro translated mec-4
      protein with domain-specific anti-MEC-4 antibodies and in vivo characterization
      of a series of mec-4lacZ fusion proteins both support the hypothesis that MEC-4
      crosses the membrane twice. The MEC-4 amino- and carboxy-terminal domains are
      situated in the cytoplasm and a large domain, which includes three Cys-rich
      regions, is extracellular. Definition of transmembrane topology defines regions
      that might interact with the extracellular matrix or cytoskeleton to mediate
      mechanical signaling.

PMID- 8655581
TI  - Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF
      kappa B activation by glutathione peroxidase overexpression.
AB  - We report here that both kappa B-dependent transactivation of a reporter gene and
      NF-kappa B activation in response to tumor necrosis factor (TNF alpha) or H2O2
      treatments are deficient in human T47D cell transfectants that overexpress seleno
      glutathione peroxidase (GSHPx). These cells feature low reactive oxygen species
      (ROS) levels and decreased intracellular ROS burst in response to TNF alpha
      treatment. Decreased ROS levels and NF-kappa B activation were likely to result
      from GSHPx increment since these phenomena were no longer observed when GSHPx
      activity was reduced by selenium depletion. The cellular contents of the two NF
      kappa B subunits (p65 and p50) and of the inhibitory subunit I kappa B-alpha were
      unaffected by GSHPx overexpression, suggesting that increased GSHPx activity
      interfered with the activation, but not the synthesis or stability, of Nf-kappa
      B. Nuclear translocation of NF-kappa B as well as I kappa B-alpha degradation
      were inhabited in GSHPx-overexpressing cells exposed to oxidative stress.
      Moreover, in control T47D cells exposed to TNF alpha, a time correlation was
      observed between elevated ROS levels and I kappa B-alpha degradation. We also
      show that, in growing T47D cells, GSHPx overexpression altered the isoform
      composition of I kappa B-alpha, leading to the accumulation of the more basic
      isoform of this protein. GSHPx overexpression also abolished the TNF alpha
      mediated transient accumulation of the acidic and highly phosphorylated I kappa B
      alpha isoform. These results suggest that intracellular ROS are key elements that
      regulate the phosphorylation of I kappa B-alpha, a phenomenon that precedes and
      controls the degradation of this protein, and then NF-kappa B activation.

PMID- 8655582
TI  - Motogenic and morphogenic activity of epithelial receptor tyrosine kinases.
AB  - Receptor tyrosine kinases play essential roles in morphogenesis and
      differentiation of epithelia. Here we examined various tyrosine kinase receptors,
      which are preferentially expressed in epithelia (c-met, c-ros, c-neu, and the
      keratin growth factor [KGF] receptor), for their capacity to induce cell motility
      and branching morphogenesis of epithelial cells. We exchanged the ligand-binding
      domain of these receptors by the ectodomain of trkA and could thus control
      signaling by the new ligand, NGF. We demonstrate here that the tyrosine kinases
      of c-met, c-ros, c-neu, the KGF receptor, and trkA, but not the insulin receptor,
      induced scattering and increased motility of kidney epithelial cells in tissue
      culture. Mutational analysis suggests that SHC binding is essential for
      scattering and increased cell motility induced by trkA. The induction of motility
      in epithelial cells is thus an important feature of various receptor tyrosine
      kinases, which in vivo play a role in embryogenesis and metastasis. In contrast,
      only the c-met receptor promoted branching morphogenesis of kidney epithelial
      cells in three-dimensional matrices, which resemble the formation of tubular
      epithelia in development. Interestingly, the ability of c-met to induce
      morphogenesis could be transferred to trkA, when in a novel receptor hybrid COOH
      terminal sequences of c-met (including Y14 to Y16) were fused to the trkA kinase
      domain. These data demonstrate that tubulogenesis of epithelia is a restricted
      activity of tyrosine kinases, as yet only demonstrated for the c-met receptor. We
      predict the existence of specific substrates that mediate this morphogenesis
      signal.

PMID- 8655584
TI  - Activities of the Wnt-1 class of secreted signaling factors are antagonized by
      the Wnt-5A class and by a dominant negative cadherin in early Xenopus
      development.
AB  - When overexpressed in Xenopus embryos, Xwnt-1, -3A, -8 and -8b define a
      functional class of Wnts (the Wnt-1 class) that promotes duplication of the
      embryonic axis, whereas Xwnt-5A, -4, and -11 define a distinct class (the Wnt-5A
      class) that alters morphogenetic movements (Du, S., S. Purcell, J. Christian, L.
      McGrew, and R. Moon. 1995. Mol. Cell. Biol. 15:2625-2634). Since come embryonic
      cells may be exposed to signals from both functional classes of Wnt during
      vertebrate development, this raises the question of how the signaling pathways of
      these classes of Wnts might interact. To address this issue, we coexpressed
      various Xwnts and components of the Wnt-1 class signaling pathway in developing
      Xenopus embryos. Members of the Xwnt-5A class antagonized the ability of ectopic
      Wnt-1 class to induce goosecoid expression and a secondary axis. Interestingly,
      the Wnt-5A class did not block goosecoid expression or axis induction in response
      to overexpression of cytoplasmic components of the Wnt-1 signaling pathway, beta
      catenin or a kinase-dead gsk-3, or to the unrelated secreted factor, BVg1. The
      ability of the Wnt-5A class to block responses to the Wnt-1 class may involve
      decreases in cell adhesion, since ectopic expression of Xwnt-5A leads to
      decreased Ca2+-dependent cell adhesion and the activity of Xwnt-5A to block Wnt-1
      class signals is mimicked by a dominant negative N-cadherin. These data
      underscore the importance of cell adhesion in modulating the responses of
      embryonic cells to signaling molecules and suggest that the Wnt-5A functional
      class of signaling factors can interact with the Wnt-1 class in an antagonistic
      manner.

PMID- 8655583
TI  - Endoglin modulates cellular responses to TGF-beta 1.
AB  - Endoglin is a homodimeric membrane glycoprotein which can bind the beta 1 and
      beta 3 isoforms of transforming growth factor-beta (TGF-beta). We reported
      previously that endoglin is upregulated during monocyte differentiation. We have
      now observed that TGF-beta itself can stimulate the expression of endoglin in
      cultured human monocytes and in the U-937 monocytic line. To study the functional
      role of endoglin, stable transfectants of U-937 cells were generated which
      overexpress L- or S- endoglin isoforms, differing in their cytoplasmic domain.
      Inhibition of cellular proliferation and downregulation of c-myc mRNA which are
      normally induced by TGF-beta 1 in U-937 cells were totally abrogated in L
      endoglin transfectants and much reduced in the S-endoglin transfectants.
      Inhibition of proliferation by TGF-beta 2 was not altered in the transfectants,
      in agreement with the isoform specificity of endoglin. Additional responses of U
      937 cells to TGF-beta 1, including stimulation of fibronectin synthesis, cellular
      adhesion, platelet/endothelial cell adhesion molecule 1 (PECAM-1)
      phosphorylation, and homotypic aggregation were also inhibited in the endoglin
      transfectants. However, modulation of integrin and PECAM-1 levels and stimulation
      of mRNA levels for TGF-beta 1 and its receptors R-I, R-II, and betaglycan
      occurred normally in the endoglin transfectants. No changes in total ligand
      binding were observed in L-endoglin transfectants relative to mock, while a 1.5
      fold increase was seen in S-endoglin transfectants. The degradation rate of the
      ligand was the same in all transfectants. Elucidating the mechanism by which
      endoglin modulates several cellular responses to TGF-beta 1 without interfering
      with ligand binding or degradation should increase our understanding of the
      complex pathways which mediate the effects of this factor.

PMID- 8655585
TI  - Demonstration of a dynamic, transcription-dependent organization of pre-mRNA
      splicing factors in polytene nuclei.
AB  - We describe the dynamic organization of pre-mRNA splicing factors in the intact
      polytene nuclei of the dipteran Chironomus tentans. The snRNPs and an SR non
      snRNP splicing factor are present in excess, mainly distributed throughout the
      interchromatin. Approximately 10% of the U2 snRNP and an SR non-snRNP splicing
      factor are associated with the chromosomes, highly enriched in active gene loci
      where they are bound to RNA. We demonstrate that the splicing factors are
      specifically recruited to a defined gene upon induction of transcription during
      physiological conditions. Concomitantly, the splicing factors leave gene loci in
      which transcription is turned off. We also demonstrated that upon general
      transcription inhibition, the splicing factors redistribute from active gene loci
      to the interchromatin. Our findings demonstrate the dynamic intranuclear
      organization of splicing factors and a tight linkage between transcription and
      the intranuclear organization of the splicing machinery.

PMID- 8655586
TI  - Metazoan rDNA enhancer acts by making more genes transcriptionally active.
AB  - Enhancers could, in principle, function by increasing the rate of reinitiation on
      individual adjacent active promoters or by increasing the probability that an
      adjacent promoter is activated for transcription. We have addressed this issue
      for the repetitive metazoan rDNA enhancer by microinjecting Xenopus oocytes with
      enhancer-less and enhancer-bearing genes and determining by EM the frequency that
      each gene type forms active transcription units and their transcript density. We
      use conditions where transcription requires the normal rDNA promoter and is
      stimulated 30-50-fold by the enhancer. (In contrast, at saturating template
      conditions as used in previous EM studies, an aberrant mode of transcription is
      activated that is not affected by the rDNA enhancer or by the generally
      recognized rDNA promoter). The active transcription units on enhancer-less genes
      are found to be as densely packed with nascent transcripts and polymerases as
      those on enhancer-bearing genes and on the endogenous rRNA genes. Significantly,
      the enhancer-bearing genes are approximately 30-50-fold more likely to form such
      active transcription units than enhancer-less genes, consistent with their
      amounts of transcript. Complementary studies confirm that the enhancer does not
      affect elongation rate, the stability of the transcription complex, or transcript
      half-life. These data demonstrate that the repetitive metazoan rDNA enhancer
      causes more genes to be actively transcribed and does not alter the reinitiation
      rate on individual active genes.

PMID- 8655587
TI  - Nuclear proteins of quiescent Xenopus laevis cells inhibit DNA replication in
      intact and permeabilized nuclei.
AB  - Quiescent cells from adult vertebrate liver and contact-inhibited or serum
      deprived tissue cultures are active metabolically but do not carry out nuclear
      DNA replication and cell division. Replication of intact nuclei isolated from
      either quiescent Xenopus liver or cultured Xenopus A6 cells in quiescence was
      barely detectable in interphase extracts of Xenopus laevis eggs, although Xenopus
      sperm chromatin was replicated with approximately 100% efficiency in the same
      extracts. Permeabilization of nuclei from quiescent Xenopus liver or cultured
      Xenopus epithelial A6 cells did not facilitate efficient replication in egg
      extracts. Moreover, replication of Xenopus sperm chromatin in egg extracts was
      strongly inhibited by a soluble extract of isolated Xenopus liver nuclei; in
      contrast, complementary-strand synthesis on single-stranded DNA templates in egg
      extracts was not affected. Inhibition was specific to endogenous molecules
      localized preferentially in quiescent as opposed to proliferating cell nuclei,
      and was not due to suppression of cdk2 kinase activity. Extracts of Xenopus liver
      nuclei also inhibited growth of sperm nuclei formed in egg extracts. However, the
      rate and extent of decondensation of sperm chromatin in egg extracts were not
      affected. The formation of prereplication centers detected by anti-RP-A antibody
      was not affected by extracts of liver nuclei, but formation of active replication
      foci was blocked by the same extracts. Inhibition of DNA replication was
      alleviated when liver nuclear extracts were added to metaphase egg extracts
      before or immediately after Ca++ ion-induced transition to interphase. A
      plausible interpretation of our data is that endogenous inhibitors of DNA
      replication play an important role in establishing and maintaining a quiescent
      state in Xenopus cells, both in vivo and in cultured cells, perhaps by negatively
      regulating positive modulators of the replication machinery.

PMID- 8655588
TI  - A GTPase distinct from Ran is involved in nuclear protein import.
AB  - Signal-dependent transport of proteins into the nucleus is a multi-step process
      mediated by nuclear pore complexes and cytosolic transport factors. One of the
      cytosolic factors, Ran, is the only GTPase that has a characterized role in the
      nuclear import pathway. We have used a mutant form of Ran with altered nucleotide
      binding specificity to investigate whether any other GTPases are involved in
      nuclear protein import. D125N Ran (XTP-Ran) binds specifically to xanthosine
      triphosphate (XTP) and has a greatly reduced affinity for GTP, so it is no longer
      sensitive to inhibition by nonhydrolyzable analogues of GTP such as guanosine 5'
      O-(3-thiotriphosphate) (GTP gamma S). using in vitro transport assays, we have
      found that nuclear import supported by XTP-Ran is nevertheless inhibited by the
      addition of non-hydrolyzable GTP analogues. This in conjunction with the
      properties of the inhibitory effect indicates that at least one additional GTPase
      is involved in the import process. Initial characterization suggests that the
      inhibited GTPase plays a direct role in protein import and could be a component
      of the nuclear pore complex.

PMID- 8655591
TI  - Excess protein in nuclei isolated from heat-shocked cells results from a reduced
      extractability of nuclear proteins.
AB  - An excellent correlation has been established between the quantity of protein
      associated with nuclei isolated from heat-shocked cells and the level of
      hyperthermic cell killing. However, controversy remains about whether increases
      in nuclear-associated protein result from a heat-induced migration of cytoplasmic
      proteins into the nucleus or because hyperthermia reduces the solubility of
      nuclear proteins in the detergent buffers commonly used to isolate nuclei. To
      address this controversy, the nuclear protein content was measured in whole and
      detergent-extracted cells before and following hyperthermia. It was found that
      hyperthermia caused no significant change in the nuclear protein content of
      whole, unextracted cells, and when fluorescently labeled proteins were
      microinjected into the cytoplasm no gross change in the selective permeability of
      the nuclear membrane to soluble proteins was observed during or following
      hyperthermia. Measurements in extracted cells showed that the detergent buffers
      removed protein from both the nucleus and cytoplasm of control, nonheated cells
      and that hyperthermia reduced the extractability of both nuclear and cytoplasmic
      proteins. The amount of protein found in nuclei isolated from heated cells
      approached that observed in nuclei within nonheated whole cells as the
      hyperthermic exposure was increased. Thus, the dose-dependent, two- to threefold
      increase in the protein content of nuclei isolated from heated cells represents a
      heat-induced reduction in the extractability of proteins normally present within
      cell nuclei and does not result from a mass migration of cytoplasmic proteins
      into the nucleus, although some specific proteins (e.g., the 70 KDa heat shock
      protein) do migrate to the nucleus following heat shock. Differential scanning
      calorimetry (DSC) measurements of whole cells, isolated nuclei, cytoplasts, and
      karyoplasts supported these conclusions and suggested that most of the detergent
      insoluble proteins remaining in the nuclei and cytoplasm of heated cells are in
      their native state. Thus, a relatively small amount of denatured protein may be
      sufficient to initiate and sustain insoluble protein aggregates comprised of
      mostly native proteins. Analyses of the DSC data also implied that the previously
      identified critical target proteins, predicted to have a Tm of 46.0 degrees C,
      are present in both the nucleus and cytoplasm.

PMID- 8655590
TI  - Signal transduction by the polymeric immunoglobulin receptor suggests a role in
      regulation of receptor transcytosis.
AB  - Many membrane traffic events that were previously thought to be constitutive
      recently have been found to be regulated by a variety of intracellular signaling
      pathways. The polymeric immunoglobulin receptor (pIgR) transcytoses dimeric IgA
      (dIgA) from the basolateral to the apical surface of polarized epithelial cells.
      Transcytosis is stimulated by binding of dIgA to the pIgR, indicating that the
      pIgR can transduce a signal to the cytoplasmic machinery responsible for membrane
      traffic. We report that dIgA binding to the pIgR causes activation of protein
      kinase C (PKC) and release of inositol 1,4,5-trisphosphate (IP3). The IP3 causes
      an elevation of intracellular Ca. Artificially activating PKC with phorbol
      myristate acetate or poisoning the calcium pump with thapsigargin stimulates
      transcytosis of pIgR, while the intracellular Ca chelator BAPTA-AM inhibits
      transcytosis. Our data suggest that ligand-induced signaling by the pIgR may
      regulate membrane traffic via well-known second messenger pathways involving PKC,
      IP3, and Ca. This may be a model of a general means by which membrane traffic is
      regulated by receptor-ligand interaction and signaling pathways.

PMID- 8655589
TI  - Evidence using a green fluorescent protein-glucocorticoid receptor chimera that
      the Ran/TC4 GTPase mediates an essential function independent of nuclear protein
      import.
AB  - The Ran/TC4 GTPase is required for the nuclear accumulation of artificial
      karyophiles in permeabilized cell assays. To investigate Ran function in a
      physiologically intact setting using mammalian cells, we examined the effects of
      several Ran mutants on cell growth and on the nuclear translocation of a
      glucocorticoid receptor-green fluorescent protein fusion (GR-GFP). Glucocorticoid
      receptor is cytosolic in the absence of ligand, but translocates to the nucleus
      on binding the agonist dexamethasone. After transfection into baby hamster kidney
      cells (BHK21), GR-GFP was detectable in living cells by direct fluorescence
      microscopy. Addition of dexamethasone caused a rapid translocation of the
      chimeric protein from the cytosol into the nucleus (t1/2 approximately 5 min).
      Cotransfection with epitope-tagged, wild-type Ran led to expression of HA1-Ran
      that was approximately 1.6-fold higher than the level of the endogenous protein,
      but it had no deleterious effect on nuclear import of the GR-GFP. However,
      expression of the Ran mutants G19V, T24N, or a COOH-terminal deletion (delta C)
      mutant dramatically reduced the accumulation of GR-GFP in the nuclei. An L43E
      mutant of Ran was without significant effect on nuclear GR-GFP import. Identical
      results were obtained following micro-injection of recombinant Ran mutants into
      cells expressing GR-GFP. Significantly, all of the Ran mutants, including L43E,
      strongly inhibited cell growth. These results demonstrate the use of GR-GFP in
      real-time imaging of nuclear transport. They also show that multiple types of Ran
      mutant exert dominant effects on this process, and that normal Ran function
      requires cycling between the GTP- and GDP-bound states of the protein. Most
      importantly, the results with the L43E Ran mutant provide strong evidence that
      Ran mediates a function essential to cell viability that is independent of
      nuclear protein import.

PMID- 8655592
TI  - Nongenomic regulation of protein kinase C isoforms by the vitamin D metabolites 1
      alpha,25-(OH)2D3 and 24R,25-(OH)2D3.
AB  - Prior studies have shown that vitamin D regulation of protein kinase C activity
      (PKC) in the cell layer of chondrocyte cultures is cell maturation-dependent. In
      the present study, we examined the membrane distribution of PKC and whether 1
      alpha,25-(OH)2D3 and 24R,25-(OH)2D3 can directly regulate enzyme activity in
      isolated plasma membranes and extracellular matrix vesicles. Matrix vesicle PKC
      was activated by bryostatin-1 and inhibited by a PKC-specific pseudosubstrate
      inhibitor peptide. Depletion of membrane PKC activity using isoform-specific anti
      PKC antibodies suggested that PKC alpha is the major isoform in cell layer
      lysates as well as in plasma membranes isolated from both cell types; PKC zeta is
      the predominant form in matrix vesicles. This was confirmed in Western blots of
      immunoprecipitates as well as in studies using control peptides to block binding
      of the isoform specific antibody to the enzyme and using a PKC zeta-specific
      pseudosubstrate inhibitor peptide. The presence of PKC zeta in matrix vesicles
      was further verified by immunoelectron microscopy. Enzyme activity in the matrix
      vesicle was insensitive to exogenous lipid, whereas that in the plasma membrane
      required lipid for full activity. 1,25-(OH)2D3 and 24,25-(OH)2D3 inhibited matrix
      vesicle PKC, but stimulated plasma membrane PKC when added directly to the
      isolated membrane fractions. PKC activity in the matrix vesicle was calcium
      independent, whereas that in the plasma membrane required calcium. Moreover, the
      vitamin D-sensitive PKC in matrix vesicles was not dependent on calcium, whereas
      the vitamin D-sensitive enzyme in plasma membranes was calcium-dependent. It is
      concluded that PKC isoforms are differentially distributed between matrix
      vesicles and plasma membranes and that enzyme activity is regulated in a membrane
      specific manner. This suggests the existence of a nongenomic mechanism whereby
      the effects of 1,25-(OH)2D3 and 24,25-(OH)2D3 may be mediated via PKC. Further,
      PKC zeta may be important in nongenomic, autocrine signal transduction at sites
      distal from the cell.

PMID- 8655593
TI  - Transforming growth factor beta (TGF-beta) expression in isolated and cultured
      rat hepatocytes.
AB  - It is still a subject of debate whether hepatocytes have the ability to express
      TGF-beta. Therefore, we investigated in freshly isolated and in monolayer
      cultures of rat hepatocytes the expression of TGF-beta isoform s at the RNA and
      protein level applying RT-PCR, immunocytochemistry, immunoblotting, and
      functional assays of TGF-beta. TFG-beta 1, -beta 2, and -beta 3 transcripts were
      detected in cultured cells, and the level of m RNA increased up to 48/72 h, but
      TGF-beta 1 transcripts were absent in freshly isolated cells. Using APAAP
      stainings the proteins of all three TGF-beta isoforms were observed in hepatocyte
      cultures from 5-96 h, but in hepatocytes in the liver in situ and in freshly
      isolated cell suspensions TGF-beta staining was negative. SDS-PAGE under reducing
      conditions followed by Western blotting detected in cell lysates the subunit of
      mature TGF-beta at about 13 kd. Analysis of TGF-beta bioactivity with the mink
      cell (Mv1Lu) proliferation inhibition assay and competitive radioligand assay
      confirmed in activated (i.e., acidified and subsequently neutralized) hepatocyte
      conditioned media the presence of TGF-beta, which, however, is almost entirely in
      the latent form. It is concluded that TGF-beta can be expressed in cultured
      hepatocytes and that the level of expression is quickly upregulated under
      abnormal, not yet known, microenvironmental conditions.

PMID- 8655594
TI  - Deletion of specific protein kinase C subspecies in human melanoma cells.
AB  - It has been shown that tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol
      13-acetate (TPA), stimulates the proliferation of normal human melanocytes,
      whereas it inhibits the growth of human melanoma cell lines. The expression of
      protein kinase C (PKC) subspecies, the major intracellular receptors for TPA, was
      examined in normal melanocytes and the four melanoma cell lines HM3KO, MeWo, HMV
      1, and G361. PKC was partially purified and then separated into subspecies by
      column chromatography on Mono Q and hydroxyapatite successively, and finally
      subjected to immunoblot analysis using antibodies specific for the PKC
      subspecies. Of the PKC subspecies examined, delta-, epsilon-, and zeta-PKC were
      detected in both normal melanocytes and the four melanoma cell lines. In
      contrast, both alpha-PKC and beta-PKC were expressed in normal melanocytes,
      whereas either alpha-PKC or beta-PKC was detected in melanoma cells.
      Specifically, HM3KO, MeWo, and HMV-1 cells were shown to contain alpha-PKC but
      not beta-PKC, while G361 cells expressed beta-PKC but not alpha-PKC. The growth
      of these melanoma cells was suppressed by TPA treatment, and the growth of the
      G361 cells lacking alpha-PKC was inhibited more efficiently than the other
      melanoma cell lines which lacked beta-PKC. It was further shown that beta-PKC was
      not detected in freshly isolated human primary or metastatic melanoma tissues.
      These results suggest that the expression of alpha-PKC or beta-PKC may be altered
      during the malignant transformation of normal melanocytes and that loss of alpha
      PKC or beta-PKC may be related to the inhibitory effect of TPA on the growth of
      melanoma cells.

PMID- 8655595
TI  - Control of retinoic acid receptor expression in mouse melanoma cells by cyclic
      AMP.
AB  - Retinoic acid receptor (RAR) alpha and gamma mRNAs were constitutively expressed
      in B16 melanoma cells with or without retinoic acid (RA) treatment. RAR beta
      mRNA, however, was significantly expressed only after exposure to RA. Induction
      of RAR beta by RA occurred within 1 h and was not inhibited by cycloheximide
      (i.e., did not require new protein synthesis). All three RAR mRNA levels were
      dramatically decreased with 8-bromo-cyclic AMP treatment and could not be rescued
      by addition of RA. Analysis of RAR gamma revealed that this decrease occurred
      within 1 h of exposure to 8-bromo-cyclic AMP and was not blocked by simultaneous
      treatment with cycloheximide. The stability of RAR gamma mRNA was not altered by
      cyclic AMP treatment. Nuclear extracts from 8-bromo-cyclic AMP-treated cells
      showed a large decrease in protein binding to a retinoic acid response element
      (RARE) oligonucleotide compared to control cells. This correlated with a marked
      reduction of RA-stimulated RARE-reporter gene activity in transfected cells which
      were treated with cyclic AMP. Pretreatment of B16 cells with cyclic AMP prior to
      RA addition dramatically reduced induction of PKC alpha, an early marker of RA
      induced cell differentiation. Thus, cyclic AMP can antagonize the action of RA
      most likely via its ability to inhibit RAR expression.

PMID- 8655596
TI  - Upregulation of molecular motor-encoding genes during hepatocyte growth factor-
      and epidermal growth factor-induced cell motility.
AB  - Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are known to
      stimulate the locomotion of epithelial cells in culture. However, the molecular
      mechanisms which mediate these important changes are poorly understood. Here we
      have determined the effects of HGF and EGF on hepatocyte morphology, cytoskeletal
      organization, and the expression of molecular motor-encoding genes. Primary
      cultures of hepatocytes were treated with 10 ng/ml of HGF or EGF and observed
      with phase and fluorescence microscopy at 10, 24, and 48 h after treatment. We
      found that, over time, treated cells spread and became elongated after 24 h of
      treatment while forming long processes with dramatic alterations in the
      microtubule and actin cytoskeletons by 48 h. Quantitative Northern blot analysis
      was performed to measure expression of cytoskeletal-(beta-actin, alpha-tubulin)
      and molecular motor-(dynein, kinesin, and myosin I alpha and II) encoding genes
      which may contribute to this change in form. We observed the highest increase in
      levels of expression for myosin II (3.3-fold), kinesin (2.7-fold), myosin I alpha
      (2.2-fold), and alpha-tubulin (1.9-fold) after only 2 h of treatment with HGF. In
      contrast, EGF upregulated the expression of myosin I alpha (2.4-fold), kinesin
      (1.5-fold), and dynein (1.5-fold) at 10 h. The expression of the beta-actin gene
      remained constant in HGF-treated cells, while EGF induced a slight upregulation
      after 10 h of treatment. These results show for the first time that a selective
      upregulation of molecular motor-encoding genes correlates with alterations in
      cell shape and motility induced by HGF and EGF.

PMID- 8655597
TI  - Hepatocellular carcinoma cells resist necrosis during anoxia by preventing
      phospholipase-mediated calpain activation.
AB  - Although hepatocellular carcinoma (HCC) cells are more resistant to anoxic injury
      than normal hepatocytes, the mechanisms responsible for this differential
      sensitivity remain obscure. Because enhanced calpain protease activity
      contributes to hepatocyte necrosis, we tested the hypothesis that HCC cells
      resist anoxia by preventing calpain activation. Cell viability in two rat HCC
      cell lines (N1S1 and McA-RH7777 cells) was fourfold greater compared to rat
      hepatocytes after 4 h of anoxia. Although calpain activity increased twofold in
      rat hepatocytes during anoxia, no increase in calpain activity occurred in HCC
      cells. Western and Northern blot analysis revealed greater or equivalent
      expression of calpains and calpastatin in HCC cells compared to hepatocytes.
      Because increases in cytosolic free Ca++ (Cai++) and phospholipid degradation
      products regulate calpains in vitro, we measured Cai++ and phospholipid
      degradation. Ca++i did not change in any cell types during 60 min of anoxia. In
      contrast, phospholipid degradation was fourfold greater in hepatocytes compared
      to HCC cells. Melittin, a phospholipase A2 activator, increased calpain activity
      and cell necrosis in all cell types; melittin-induced cell necrosis was
      ameliorated by a calpain protease inhibitor. In summary, these data demonstrate
      for the first time 1) calpain activation without a measureable increase in Ca++i,
      2) phospholipase-mediated calpain activation in hepatocytes and HCC cells, and 3)
      the adaptive mechanism responsible for the resistance of HCC cells to anoxia-an
      inhibition of phospholipid-mediated calpain activation. Interruption of
      phospholipase-mediated calpain activation may be a therapeutic strategy for
      preventing anoxic cell injury.

PMID- 8655598
TI  - Basic fibroblast growth factor (FGF-2) protects rat cochlear hair cells in
      organotypical culture from aminoglycoside injury.
AB  - Given the evidence that basic fibroblast growth factor (FGF-2) can protect neural
      and retinal cells from degeneration, we evaluated the potential of this growth
      factor to protect sensory cells in the inner ear. When sensory cells of the organ
      of Corti are exposed to aminoglycoside antibiotics such as neomycin either in
      vivo or in vitro, significant ototoxicity is observed. The in vitro cytotoxic
      effects of neomycin are dose and time dependent. In neonatal rat organ of Corti
      cultures, complete inner and outer hair cell destruction is observed at high (mM)
      concentrations of neomycin while inner hair cell survival and severely damaged
      outer hair cells are noted at moderate (microM) concentrations, with a maximal
      effect observed after 2 days of culture. Approximately 50% of cochlear outer hair
      cells are lost at a dose of 35 microM neomycin, and most surviving cells show
      disorganized stereocilia. Inner hair cells show primarily disorganization of
      their stereocilia. A significant protective effect is observed when the organ of
      Corti is pre-treated with FGF-2 (500 ng/ml) for 48 hours, and then FGF-2 is
      included with neomycin in the culture medium. A greater extent of outer hair cell
      survival and a significant decrease in stereociliary damage are noted with FGF-2.
      However, disorganization of inner hair cell stereocilia is unaffected by FGF-2.
      The protective effect of FGF-2 is specific, since interleukin-1B, nerve growth
      factor, tumor necrosis factor, and epidermal growth factor are ineffective, while
      retinoic acid and transforming growth factor alpha show only a moderate
      protective effect. These results confirm the potential of molecules like FGF-2
      for preventing cell death due to a variety of causes.

PMID- 8655599
TI  - Synergistic stimulation of gamma-glutamyl transpeptidase and alkaline phosphatase
      activities by retinoic acid and astroglial factors in immortalized rat brain
      microvessel endothelial cells.
AB  - The immortalized rat brain microvessel endothelial cell line RBE4 was used to
      investigate the in vitro regulation of two blood-brain barrier specific enzymes,
      gamma-glutamyl transpeptidase (GTP) and alkaline phosphatase (ALP). The effects
      of bFGF, astroglial factors, and retinoic acid (a cell differentiation agent) on
      GTP and ALP activities were separately or simultaneously studied in order to
      define optimal culture conditions for induction of these two specific enzymes of
      the blood-brain barrier. In the present study, a phenotypically distinct
      subpopulation of endothelial cells has been shown to develop from confluent
      cobblestone monolayers of RBE4 immortalized cerebral endothelial cells. These
      distinct cells were present within multicellular aggregates and specifically
      exhibited GTP and ALP activities. Addition of bFGF, astroglial factors, or
      retinoic acid induced the formation of these three-dimensional structures and in
      consequence an increase in GTP and ALP activities. For retinoic acid and
      astroglial factors, this increase could also be explained by the stimulation of
      either GTP or ALP expression in the phenotypically distinct positive cells
      associated with aggregates. Simultaneous treatment with retinoic acid and
      astroglial factors had a synergistic effect on GTP and ALP expression and thus
      may allow these distinct cells to evolve toward a more differentiated state.
      Since such results were also obtained with physiological concentrations of
      retinoic acid, we suggest that addition of this agent might contribute to greater
      differentiation of cells in in vitro blood-brain barrier models where endothelial
      cells are cocultured with astrocytes.

PMID- 8655600
TI  - Mitogenic effect of erythropoietin on neonatal rat cardiomyocytes: signal
      transduction pathways.
AB  - The mitogenic effect of recombinant human erythropoietin (rHuEpo) on primary
      cultures of neonatal rat cardiac myocytes was observed. rHuEpo triggered a dose
      dependent increase in myocyte proliferation. The hormone effect over optimally
      grown control culture 1 day after addition was maximum with 0.5 U/ml and was
      inhibited with anti-rHuEpo. Inhibitors of enzymatic pathways known to be involved
      in the cytokines intracellular mechanism such as genistein (tyrosine kinase
      inhibitor), 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (phospholipase C [PLC]
      inhibitor), and 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (protein kinase C
      [PKC] inhibitor) prevented the mitogenic action of rHuEpo. Also the inhibition of
      Na(+)-K(+)-ATPase activity by ouabain blunted the stimulatory action of rHuEpo on
      cell proliferation. The mitogenic action of the hormone was correlated with
      cardiac membrane paranitrophenylphosphatase (pNPPase) and PKC activity, since
      concentrations of rHuEpo that stimulate DNA synthesis increased pNPPase and PKC
      activity. Moreover, the enzymatic inhibition of tyrosine kinase, PLC, and PKC
      attenuated the stimulatory action of rHuEpo upon cardiac pNPPase activity. In
      this paper we demonstrate a non-hematopoietic action of rHuEpo showing both
      mitogenic and enzymatic effect upon primary myocyte cell culture and on pNPPase
      activity of neonatal rat heart. These effects are related to the capacity of
      rHuEpo to stimulate Na(+)-K(+)-ATPase activity and appear to be secondary to the
      activation of tyrosine kinase and PKC, indicating that in the rHuEpo mediated
      mitogenic action on cardiomyocytes involves the activation of the same enzymatic
      pathways that have been described by other cytokines in different tissues.

PMID- 8655601
TI  - Hypoxia decreases constitutive nitric oxide synthase transcript and protein in
      cultured endothelial cells.
AB  - Endothelial cell-generated nitric oxide (NO) accounts in large part for the
      labile vasodilator termed endothelium-derived relaxing factor. Two distinct types
      of NO synthase exist: a "constitutive' type (cNOS), found in endothelial cells,
      and an "inducible' enzyme. Endothelial cells sense pO2 levels in the range of 70
      20 torr and respond to this hypoxia by inducing transcription of genes which
      encode the vasoactive proteins PDGF-B and endothelin-1. Exposure of human or
      bovine endothelial cells to low oxygen tensions results in a profound decrease in
      the transcript for cNOS and a corresponding fall in cNOS protein levels. The
      ability of endothelial cells exposed to hypoxia to produce NO in response to
      bradykinin, a stimulator of cNOS activity, was coordinately impaired. Cobalt
      inhibited the expression of cNOS transcripts, suggesting a mechanism comparable
      to that by which oxygen tension regulates expression of other vasoregulatory
      genes. In the presence of actinomycin-D, hypoxia had no effect on cNOS
      transcripts, suggesting that new gene transcription is required for cNOS
      suppression. The reducing agents PDTC and N-Ac did not mimic cNOS gene
      suppression by hypoxia, suggesting that this suppression is not related to the
      redox state of the intracellular environment. Thus, regulation of cNOS function
      in response to environmental factors can occur at the level of gene expression as
      well as at the level of enzyme activation.

PMID- 8655602
TI  - Lipoxygenase metabolites induced expression of adhesion molecules and
      transendothelial migration of monocyte-like HL-60 cells is linked to protein
      kinase C activation.
AB  - Studies have shown that, among lipoxygenase metabolites examined, 15(S)
      hydroperoxy-5,8,11,13-eicosa-tetraenoic acid (15[S]-HPETE), at micromolar
      concentrations, selectively causes injury to cultured endothelial cells. We
      investigated whether physiologically relevant concentrations of lipoxygenase
      metabolites affected the expression of cell adhesion molecules (CAMs) involved in
      the adhesion of leukocytes and/or the accumulation of leukocytes in the vascular
      endothelium, these being the initial events in endothelial cell injury. Among
      lipoxygenase metabolites, 15(S)-HPETE and 12(S)-HETE, at nanomolar
      concentrations, induced surface expression of a subset of cell adhesion molecules
      (CAM), ICAM-1, ELAM-1, and VCAM-1, in human umbilical vein endothelial cells
      (HUVEC), which is associated with an increased binding activity of the
      transcription factor, NF-kappa B, to the consensus motif common to the CAM genes
      in the HUVEC nuclear extracts. Furthermore, 15(S)-HPETE (1 nM) caused a threefold
      increase in the rate of transendothelial migration of vitamin D3-differentiated
      HL-60 monocyte-like cells and showed a thirtyfold increase in the phosphorylation
      of PECAM-1, an adhesion molecule involved in endothelial cell-cell adhesion. Both
      an antibody to PECAM-1 and the protein kinase C inhibitor, GF 109203X, reduced
      15(S)-HPETE-induced transmigration of monocyte-like HL-60 cells by approximately
      75% and 85%, respectively. Treatment of HUVEC with a phosphatase inhibitor,
      calyculin A, augmented both the phosphorylation of PECAM-1 and transmigration of
      monocyte-like HL-60 cells induced by 15(S)-HPETE. Our results show that 15(S)
      HPETE, at physiological concentrations, induced activation of protein kinase C in
      HUVEC and leads to the phosphorylation of PECAM-1, thus facilitating the
      migration of monocyte-like HL-60 cells across the endothelial cell monolayer. It
      is suggested that phosphorylation/dephosphorylation events in PECAM-1 are
      important in regulating the trafficking of monocytes across the endothelial cell
      monolayer.

PMID- 8655603
TI  - Inhibition of cellular proliferation and modulation of insulin-like growth factor
      binding proteins by retinoids in a bovine mammary epithelial cell line.
AB  - Retinoids are potent inhibitors of growth and tumor progression in many mammary
      carcinoma cell lines, though regulation of growth in nontumorigenic mammary
      epithelial cells by retinoids is less clear. Here, we have characterized the
      inhibition of MAC-T (a nontransformed bovine mammary epithelial cell line)
      cellular proliferation by retinoids and their role in regulating insulin-like
      growth factor binding proteins (IGFBPs). Retinoic acid (RA) (100 nM) was a potent
      inhibitor of MAC-T cell proliferation. Retinol was 10-100 times less effective.
      Neither retinoid could completely arrest growth at noncytotoxic concentrations.
      Retinoic acid inhibited cellular proliferation by 1 h (P < .05), but inhibition
      was fivefold greater by 24 h (P < .01). This second stage of growth inhibition
      (after 12 h) was dependent upon protein synthesis. However, RA-induced inhibition
      of cellular proliferation did not persist, with thymidine incorporation
      increasing toward control levels by 4 days in culture. Retinoic acid was less
      effective in inhibiting thymidine incorporation when cells were stimulated with
      insulin, des(1-3) IGF-I, or Long(R3) IGF-I when compared to cells stimulated with
      native IGF-I or serum. Inhibition of proliferation by RA was associated with
      increased levels of IGFBP-2 in conditioned media and in plasma membrane
      preparations. Treatment with insulin or des(1-3) IGF-I resulted in the appearance
      of IGFBP-3 in conditioned media and on the cell surface. However, RA
      significantly reduced IGFBP-3 levels in conditioned media and eliminated IGFBP-3
      associated with the plasma membrane. Thus, RA is a potent but transient inhibitor
      of bovine mammary epithelial cell proliferation, and this growth inhibition is
      correlated with increased IGFBP-2 accumulation and inhibition of IGF-I stimulated
      IGFBP-3 protein secretion.

PMID- 8655604
TI  - Protein kinase C mediates up-regulation of urokinase and its receptor in the
      migrating keratinocytes of wounded cultures, but urokinase is not required for
      movement across a substratum in vitro.
AB  - Both in cell culture and in vivo, keratinocytes that are migrating in response to
      a wound express enhanced levels of both urokinase-type plasminogen activator
      (uPA) and the uPA cell surface receptor (uPA-R). To explore the mechanism of this
      up-regulation, keratinocyte cultures were treated proir to wounding with a
      variety of metabolic and growth factor inhibitors in order to evaluate their
      effect on uPA and uPA-R expression. Actinomycin D and cycloheximide inhibited the
      up-regulation of both uPA and uPA-R, as determined by immunohistochemistry,
      indicating that RNA and protein syntheses are required for their induction in
      migrating keratinocytes. Neither removal of protein growth factors from the
      medium nor addition of inhibitory antibodies to a number of growth factors
      depressed uPA or uPA-R induction; these findings suggest that a variety of
      exogenous or endogenous growth factors [i.e., basic fibroblast growth factor
      (bFGF), epidermal growth factor (EGF), transforming growth factor-alpha (TGF
      alpha), amphiregulin, and tumor necrosis factor-alpha (TNF-alpha) do not have a
      critical role in the induction of uPA or uPA-R. In contrast, when protein kinase
      C (PKC) was either down-regulated with bryostatin 5 or inhibited with Ro31-8220
      or staurosporine, the expression of both uPA and uPA-R was greatly decreased in
      migrating keratinocytes. Furthermore, pharmacologic activation of PKC enhanced
      uPA levels in non-wounded cultures. These data suggest that the enhanced
      expression of uPA and uPA-R in migrating keratinocytes is mediated by selective
      activation of PKC in these cells, perhaps secondary to alterations in the
      cytoskeleton induced by wounding. To test the requirement for uPA during
      keratinocyte migration in vitro, the extent of migration was quantified in the
      presence and absence of a variety of inhibitors in the wounded culture model.
      Migration was not altered by actinomycin D, cycloheximide, any of the above
      growth factor inhibitors, anti-uPA antibodies, a variety of inhibitors of uPA or
      plasmin enzymatic activity, or exogenous uPA. The independence of keratinocyte
      migration in vitro from uPA was further suggested by experiments which combined
      the phagokinetic assay of migration and the zymographic assay for pericellular
      uPA activity; no relationship was observed between pericellular uPA activity and
      the motility of individual cells.

PMID- 8655605
TI  - Expression of hydrogen peroxide and glutathione metabolizing enzymes in human
      skin fibroblasts derived from donors of different ages.
AB  - We have examined the activities and mRNA abundance of two hydrogen peroxide
      metabolizing enzymes (glutathione peroxidase and catalase), glutathione
      concentration, and the activities of several enzymes that influence glutathione
      concentration, including glutathione reductase (GR), glucose-6-phosphate
      dehydrogenase (G-6-PD), and gamma-glutamylcysteine synthetase (gamma-GCS), in 29
      skin fibroblast lines derived from donors ranging in age from 14 gestational
      weeks to 94 years of age. H2O2 metabolizing enzyme activities and mRNA abundances
      were greater in skin fibroblast cultures established from postnatal donors than
      in fetally derived cultures. There were no significant differences in either of
      these parameters in cell lines established from postnatal donors of different
      ages. Total glutathione concentration decreased with age, but GR activity
      appeared to be unaffected by age. In order to estimate the ability of the
      cultures to produce NADPH (an important component of cellular redox status and a
      cofactor for GR), we determined glucose-6-phosphate dehydrogenase activity and
      mRNA abundance. We were unable to directly measure gamma-GCS activity or mRNA
      abundance in any of the skin lines or in fetal lung fibroblast; however, we were
      able to indirectly demonstrate the presence of this enzyme by stimulating fetal
      lung fibroblasts with H2O2 following treatment with L-buthionine-S,R-sulfoximine
      (BSO), an inhibitor of gamma-GCS activity. These results show that some, but not
      all, age-associated differences in antioxidant defense levels are maintained in a
      culture environment and are consistent with the hypothesis that developmental
      stages of life are associated with lower antioxidant defense levels than are
      present in postnatal phases of life.

PMID- 8655606
TI  - Differentiation potential of conditionally immortalized mesenchymal progenitor
      cells from adult marrow of a H-2Kb-tsA58 transgenic mouse.
AB  - Primary cultures were initiated from marrow, spleen, and bone explants of an
      adult H-2Kb-tsA58 transgenic mouse (immortomouse). All cultures were initiated in
      immortalizing conditions, and an additional marrow culture was first incubated
      for 1 week in standard conditions and then switched to immortalizing conditions.
      Marrow cells immediately immortalized were designated the marrow immediate
      population (MIP); those immortalized after 1 week were termed the marrow delayed
      population (MDP). MIP and MDP cells both contained a mixture of fibroblastic or
      flattened cells, and the MIP cells contained an additional subpopulation of
      adipocytic (Oil Red-O positive) cells. Alkaline phosphatase expression was
      induced by dexamethasone (10(-7) M) in MDP cells while MIP, spleen, and bone
      explant cells had only a low level of expression. MDP and MIP cells
      differentiated into bone when combined with porous calcium phosphate ceramics and
      implanted subcutaneously into nude mice while bone- and spleen-derived cells did
      not. Clones were isolated from the MDP and MIP cell populations and tested for
      differentiated phenotypes. Some MIP-derived clones exhibited adipocytic
      characteristics while MDP-derived subclones were negative. Histologic examination
      of porous ceramic implanted clones showed that all of the clones had osteogenic
      potential. Clones exposed to either dexamethasone, human recombinant bone
      morphogenetic protein-2, or horse serum plus hydrocortisone showed differences in
      expression of adipocytic or osteogenic markers. These immortalized cultures have
      retained both adipocytic and osteogenic potential even after 1 year of continuous
      culture, and provide a model system for clonal analysis of the developmental
      potential of marrow-derived mesenchymal precursor cells.

PMID- 8655607
TI  - Zinc transport across an endothelium includes vesicular cotransport with albumin.
AB  - Bovine pulmonary arterial endothelial cells (BPAEC) were grown on permeable
      polycarbonate membrane filters suspended between two compartments representing
      the blood vessel lumen and the interstitium. This in vitro model of an
      endothelium was subjected to a battery of tests to unravel the mechanisms of zinc
      transport from the blood into peripheral tissues. Transport of 65Zn across BPAEC
      from media containing zinc concentrations up to 50 mumol/L exhibited both
      saturable and nonsaturable kinetics. Vmax of the saturable component was 246 +/-
      43 pmol/(h x cm2) and Km was 2.3 +/- 1.3 mumol/L. Transport was pH and
      temperature sensitive and substantially influenced by albumin and histidine
      concentrations, but not influenced by analogous minerals or metabolic inhibitors.
      Inhibition of coated vesicle formation by depletion of intracellular potassium
      reduced 65Zn transport. Albumin carrying a zinc ion crossed the endothelium more
      rapidly than zinc-free albumin. When evaluated together, this body of evidence
      supports the existence of two major pathways of zinc transport across the
      pulmonary endothelium, but neither involves entry into the endothelial cells. One
      pathway involves receptor-mediated cotransport with albumin by transcytotic
      vesicles. The other is nonsaturable and involves cotransport with albumin and low
      molecular weight ligands, principally histidine, through intercellular junctions
      and nonselective, bulk-fluid transcytosis.

PMID- 8655608
TI  - Actin polymerization in human eosinophils, unlike human neutrophils, depends on
      intracellular calcium mobilization.
AB  - Eosinophils represent major effector cells in the allergic inflammation. In
      contrast to neutrophils, the mechanism of eosinophil activation during the
      inflammatory response is poorly understood. In this study, the relation between
      calcium fluxes, chemotaxis, and actin polymerization in eosinophils from healthy
      non-atopic donors was investigated. Pre-incubation of eosinophils with the
      intracellular calcium chelator BAPTA dose-dependently prevented an increase in
      the intracellular calcium concentration ([Ca2+]i), whereas the depletion of
      extracellular calcium in the test medium had no effect. The chemotactic response
      of eosinophils, which was measured by the modified boyden chamber technique upon
      stimulation with RANTES, C5a and PAF, was dose-dependently inhibited by the
      chelation of intracellular calcium as well as inactivation of the cells in Ca2+ 
      depleted medium. To evaluate whether other cell functions which are involved in
      the migratory response of eosinophils might be dependent on intracellular and
      extracellular calcium, actin polymerization was investigated. Flow-cytometric
      measurement of F-actin with NBD-phallacidin revealed that actin polymerization in
      human eosinophils in response to RANTES, C5a, and PAF was dose-dependently
      inhibited by the intracellular calcium chelator BAPTA. Since it is well known
      that actin polymerization in neutrophils is not affected by chelation of
      intracellular calcium, actin polymerization in these cells was investigated under
      the same conditions as for eosinophils. In contrast to eosinophils, BAPTA did not
      inhibit actin polymerization in neutrophils. In summary, these data demonstrate
      that intracellular calcium fluxes represent a prerequisite for eosinophil
      chemotaxis and actin polymerization in human eosinophils. Furthermore, regulation
      of actin polymerization in eosinophils differed from that of neutrophils on the
      level of intracellular calcium fluxes.

PMID- 8655609
TI  - Regulation of human dermal papilla cell production of insulin-like growth factor
      binding protein-3 by retinoic acid, glucocorticoids, and insulin-like growth
      factor-1.
AB  - Insulin-like growth factor-1 (IGF1) has been reported to stimulate hair
      elongation and to facilitate maintenance of the hair follicle in anagen phase.
      However, little is known about IGF1 signaling in the hair follicle. In this study
      we investigate the effects of IGF1, glucocorticoids, and retinoids on dermal
      papilla (DP) cell production of insulin-like growth factor binding proteins
      (IGFBPs). IGFBPs comprise a family of IGF binding proteins that are produced and
      released by most cell types. They bind to IGFs to either enhance or inhibit IGF
      activity. In the present report we identify IGFBP-3 as being produced and
      released by cultured human dermal papilla (DP) cells. IGFBP-3 levels are
      increased fivefold by retinoic acid, eightfold by dexamethasone, and tenfold by
      IGF1. DP cells are known to produce IGF1, and so the observed stimulation of DP
      cell IGFBP-3 production by IGF1 is consistent with the idea that DP cells possess
      the IGF transmembrane receptor kinase and are autoregulated by IGFs. The level of
      another IGFBP, tentatively identified as IGFBP-2, is, in contrast, not regulated
      by these agents. IGFBP-3 has been shown to inhibit the activity of IGFs in a
      variety of systems. Our results are consistent with a model in which retinoids
      and glucocorticoids inhibit IGF action on DP cells and surrounding matrix cells
      by stimulating increased DP cell production of IGFBP-3. The IGFBP-3, in turn,
      forms a complex with free IGF1 to reduce the concentration of IGF1 available to
      stimulate hair elongation and maintenance of anagen phase.

PMID- 8655610
TI  - Mechanisms of alpha-thrombin, histamine, and bradykinin induced endothelial
      permeability.
AB  - alpha-Thrombin, bradykinin, and histamine are endogenous mediators that increase
      endothelial permeability. We examined the mechanism by which these three
      vasoactive mediators could alter permeability to albumin of human umbilical vein
      endothelial cells (HUVEC). HUVEC were grown to confluence on Transwell membranes
      and we monitored the flux of fluorescein isothiocyanate-labeled human serum
      albumin across the membrane from the upper to lower chamber of the Transwell.
      Addition of alpha-thrombin, bradykinin, or histamine increased the permeability
      coefficient of the HUVEC monolayer. At 30 min the permeability coefficient for
      alpha-thrombin was 4.92 x 10(-6) cm/sec while histamine was 4.47 x 10(-6) cm/sec.
      Maximum changes in the permeability coefficient were about three-fold control
      baseline values (1.59 x 10(-6) cm/sec). There was also a temporal difference in
      the magnitude of the permeability coefficient. alpha-Thrombin and bradykinin
      induced HUVEC permeability was increased for the first 90 min after which it
      returned to control levels. In contrast, histamine increased the permeability of
      the HUVEC monolayer throughout the 2 h experiment. To determine a possible
      intracellular mechanism of the altered permeability coefficients, HUVEC were
      labeled with FURA-2 and intracellular calcium was monitored by digital
      fluorescence ratio imaging. Maximum intracellular calcium in HUVEC was increased
      by alpha-thrombin (245 +/- 20 nM) and histamine (210 +/- 22 nM), but not by
      bradykinin (70 +/- 7 nM) as compared to control (69 +/- 10). Fluorescent
      photomicrographs of HUVEC stimulated with the three agonists indicated that alpha
      thrombin and histamine substantially altered HUVEC f-actin arrangement, while
      bradykinin had no effect on HUVEC f-actin distribution. These data support
      previous in vitro and in vivo studies demonstrating increased permeability by all
      three agonists. These data also show, for the first time, that histamine and
      alpha-thrombin increased permeability by calcium-dependent intracellular
      pathways, but bradykinin operates through a calcium-independent mechanism.

PMID- 8655611
TI  - History of rest and motion and the scientific basis for early continuous passive
      motion.
AB  - The history of rest, early motion, and CPM is described. The success of CPM stems
      from two main factors: basic research has validated the concept, and the clinical
      applications of CPM for various joints of the extremities have produced very
      satisfactory results.

PMID- 8655612
TI  - Continuous passive motion use in hand therapy.
AB  - This paper discusses the indications and contraindications of continuous passive
      motion (CPM) in hand therapy. The pros and cons of portable and stationary CPMs
      available for the hand, wrist, forearm, elbow, and shoulders are reviewed.

PMID- 8655613
TI  - Psychological management of postsurgical pain and patient adherence.
AB  - The advantages of proper management of postsurgical pain include fewer
      postoperative complications; increased early ambulation and mobilization;
      decreased opportunity for chronic pain syndromes to occur; shorter, less
      complicated rehabilitation; greater patient satisfaction; and increased patient
      adherence to prescribed regimens. In turn, greater adherence positively affects
      pain management and, therefore, patients, satisfaction with their surgeon. A
      variety of approaches may be used for the management of acute pain, and the
      "psychological preparation" of the patient prior to surgery plays a significant
      role. Specific approaches include (1) cognitive-behavioral (such as diaphragmatic
      breathing, positive visualization rehearsal, and autogenic training); (2)
      hypnosis; (3) biofeedback; and (4) microelectrostimulation. Some of these
      approaches to pain management apply during surgery and the recovery and
      rehabilitation periods. Many of the approaches can be carried out relatively
      easily by the physician and his or her staff; in some cases, specialists, such as
      psychologists trained in behavioral medicine, are needed. Variables that affect
      patient adherence, both positively and negatively, include patient motivations,
      the nature and chronicity of the disorder, treatment variables, and the quality
      of the patient-doctor relationship. Physician behaviors may encourage or
      discourage patient adherence.

PMID- 8655614
TI  - Effects of early motion on healing of musculoskeletal tissues.
AB  - One of the most important advances in the promotion of musculoskeletal healing
      has come from understanding that treatment of injuries with prolonged rest may
      delay recovery and adversely affect normal tissues and that controlled early
      resumption of activity can promote restoration of function. Experimental studies
      of the past several decades confirm and help explain the deleterious effects of
      prolonged rest and the beneficial effects of activity on the musculoskeletal
      tissues. They have shown that maintenance of structure and composition of normal
      bone, tendon and ligament, articular cartilage and muscle, requires repetitive
      use and that changes in the patterns of tissue loading can strengthen or weaken
      normal tissues. Although all the musculoskeletal tissues can respond to
      repetitive loading, they vary in the magnitude and type of response to specific
      patterns of activity. Furthermore, their responsiveness may decline with
      increasing age. Skeletal muscle and bone demonstrate the most apparent response
      to changes in activity in individuals of any age. Cartilage and dense fibrous
      tissues also can respond to loading, but the responses are more difficult to
      measure. The effects of loading on healing tissues have been studied less
      extensively but the available evidence indicates that repair and remodeling
      tissues respond to loading and that, like immature normal tissues, repair tissues
      may be more sensitive to cyclic loading and motion than mature normal tissues.
      Early motion and loading of injured tissues is not without risks, however.
      Excessive or premature loading and motion of repair tissue can inhibit or stop
      healing. Unfortunately, the optimal methods for facilitating healing by early
      application of loading and motion have not been defined. Nonetheless,
      experimental studies and newer clinical investigations document the benefits of
      early controlled loading and motion in the treatment of musculoskeletal injuries,
      and show that optimal restoration of musculoskeletal function following injury or
      surgery requires early controlled activity.

PMID- 8655615
TI  - Medical management of pain for early motion in hand and wrist surgery.
AB  - Pain control is a prerequisite to early motion. It can best be accomplished with
      a combination of drugs given around the clock, rather than on an as-needed basis.

PMID- 8655616
TI  - Orthopaedia: or, the art of correcting and preventing deformities. 1743.

PMID- 8655617
TI  - The treatment of fractures by mobilization and massage. 1908.

PMID- 8655619
TI  - Early motion after hand and wrist reconstruction.
AB  - There is substantial evidence to support the fact that early motion is beneficial
      for bones, joints, ligaments, tendons, and muscles. An Early Mobilization Program
      was designed to provide early motion for all these structures after hand and
      wrist reconstruction.

PMID- 8655618
TI  - Splinting the hand. 1952.

PMID- 8655620
TI  - Early motion protocols in hand and wrist rehabilitation.
AB  - Early motion programs establish gliding, decrease unwanted adhesions, and enhance
      the healing process and return to normal function of injuries. This article
      elaborates on how to best incorporate early motion programs into the
      rehabilitation process.

PMID- 8655621
TI  - Early motion after flexor tendon surgery.
AB  - Flexor tendon rehabilitation means control of the tendon healing process. It is
      therefore important to appreciate the physiological and biomechanical nuances of
      flexor tendon healing.

PMID- 8655622
TI  - Early motion after extensor tendon surgery.
AB  - Early motion programs for extensor tendon lacerations and repairs are relatively
      new and are proving to be extremely beneficial in the rehabilitation process.
      This article discusses when these programs are indicated and the details of how
      to provide a good early motion program.

PMID- 8655623
TI  - Early motion in the treatment of fractures and dislocations in the hand and
      wrist.
AB  - The concept of early motion is valuable in the treatment of fractures of the hand
      and wrist. It is a means to an end, however, and should be employed principally
      when the benefits outweigh the risks. The goal is a hand that functions as near
      to normally as possible, considering the injury. All treatments need to be
      tailored to the individual patient.

PMID- 8655624
TI  - Early motion after arthroplasty.
AB  - Early controlled motion after arthroplasty in the MP and PIP joints allows for
      collagen remodeling during the encapsulation process that creates a stable joint.
      Motion generally is begun within the first few days after surgery and must be
      supervised carefully. Dynamic splinting is an important component in achieving
      early motion in the MP joints and often is a useful adjunct in the PIP joints.
      Early motion after total wrist arthroplasty depends on surgical fit of the
      prosthesis. Only a tight fit allows early motion. The potential for complications
      resulting from early motion in the wrist is greater than in the MP or PIP joints
      and may involve increased wear, fracture, or component loosening. The benefits of
      early motion after arthroplasty, therefore, must be weighed against potential
      risks. Although generally necessary in the MP and PIP joints to achieve
      satisfactory results, early motion after total wrist arthroplasty has limited
      applications and significant risks.

PMID- 8655625
TI  - Early motion after wrist surgery.
AB  - This article reviews general considerations for therapists when initiating early
      motion after wrist surgery. Various early range of motion techniques and
      splinting are discussed in detail for the radiocarpal joint and distal radioulnar
      joint.

PMID- 8655626
TI  - Early motion after replantation.
AB  - Early motion should be begun as soon as possible after replantation but must be
      tailored to the specific injury. It is important to move joints and glide tendons
      and nerves within a safe short arc range of motion. This technique prevents many
      of the deleterious effects of immobilization, stiffness, and adhesion formation,
      at the same time protecting tendon, nerve, and vascular repairs. A well thought
      out clinical plan for mobilization combined with a considerate and compassionate
      approach to the emotional, financial, and social needs of the patient ensures a
      good result.

PMID- 8655627
TI  - SV40 T antigen increases the expression and activities of p34cdc2, cyclin A, and
      cyclin B prior to immortalization of human diploid fibroblasts.
AB  - SV40 T antigen induces karyotype instability soon after it is expressed in human
      diploid fibroblasts and ultimately promotes cell immortalization and
      tumorigenesis. Protein levels and activities of mitotic cell cycle proteins have
      been shown to be elevated in several immortal cell lines relative to their normal
      parental cells, suggesting a possible role for the aberrant regulation of mitosis
      in karyotype instability. We show here that IMR-90 human diploid lung fibroblasts
      expressing the SV40 tumor antigens display increased protein levels and
      associated enzymatic activities of cyclin A, cyclin B, and p34cdc2 long before
      crisis and immortalization. These elevations cannot be explained by faster cell
      growth or altered cell cycle distributions. Increased protein levels were not
      totally accounted for by elevated levels of the corresponding mRNA, indicating
      that T antigen modulates expression at least partially by posttranscriptional
      mechanisms. These results indicate that perturbation of mitotic regulatory
      proteins precedes crisis, and imply that altered mitotic control is a direct
      consequence of T antigen expression rather than an outcome of secondary events
      associated with immortalization.

PMID- 8655628
TI  - Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 12-O-tetradecanoylphorbol-13
      acetate and 17 beta-estradiol on estrogen receptor regulation in MCF-7 human
      breast cancer cells.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exhibits remarkably potent
      antiestrogenic activity. To further elucidate the role of estrogen receptor (ER)
      regulation in this response, we examined the effects of exposure to TCDD in MCF-7
      human breast cancer cells on ER mRNA levels by using an RNase protection assay,
      on ER accumulation by using an ER immunocytochemical essay (ER-ICA), and on ER
      function by competitive binding assays under conditions of saturating 17 beta
      estradiol (E2). Comparative studies were conducted with E2 and 12-O
      tetradecanoylphorbol-13-acetate (TPA), as both compounds are known to suppress ER
      expression. Our results indicate that 1 nM E2 and 100 nM TPA both suppress ER
      mRNA levels as early as 4 h after exposure and to 33.6% and 16.5% of control
      levels, respectively, after 72 h. In contrast, no significant effect on ER mRNA
      levels was attributed to exposure to 10 nM TCDD. A greater than 50% reduction in
      positive staining was observed by ER-ICA after 72 h exposure to 1 nM E2 and to
      100 nM TPA, while only an 11% reduction in positive staining was observed with 10
      nM TCDD. Specific binding of [3H]E2 under saturating conditions (10 nM E2) in
      whole cells was reduced by 50% in cultures exposed to 100 nM TPA, although no
      effect on binding was observed with exposure to 10 nM TCDD. In contrast, specific
      binding using subsaturating 1 nM [3H]E2 was depressed by 49% in MCF-7 cells
      exposed to 10 nM TCDD for 72 h. This depression was inhibited by a 1-h treatment
      with 5 microM alpha-naphthoflavone, which inhibits TCDD-induced, P450-mediated,
      E2 metabolism, and subsequent E2 depletion. In conclusion, while TPA and E2
      effectively down-regulate ER expression, TCDD, under antiestrogenic conditions,
      has little if any effect on total ER levels in MCF-7 cells, and thus ER
      modulation is probably not necessary for the suppression of estrogenic activity
      in MCF-7 cells by TCDD.

PMID- 8655629
TI  - Contraction of fibrillar type I collagen by endothelial cells: a study in vitro.
AB  - The formation of microvascular sprouts during angiogenesis requires that
      endothelial cells move through an extracellular matrix. Endothelial cells that
      migrate in vitro generate forces of traction that compress (i.e., contract) and
      reorganize vicinial extracellular matrix, a process that might be important for
      angiogenic invasion and morphogenesis in vivo. To study potential relationships
      between traction and angiogenesis, we have measured the contraction of fibrillar
      type I collagen gels by endothelial cells in vitro. We found that the capacity of
      bovine aortic endothelial (BAE) cells to remodel type I collagen was similar to
      that of human dermal fibroblasts--a cell type that generates high levels of
      traction. Contraction of collagen by BAE cells was stimulated by fetal bovine
      serum, human plasma-derived serum, bovine serum albumin, and the angiogenic
      factors phorbol myristate acetate and basic fibroblast growth factor (bFGF). In
      contrast, fibronectin and immunoglobulin from bovine serum, several nonserum
      proteins, and polyvinyl pyrrolidone (a nonproteinaceous substitute for albumin in
      artificial plasma) were not stimulatory. Contraction of collagen by BAE cells was
      diminished by an inhibitor of metalloproteinases (1,10-phenanthroline) at
      concentrations that were not obviously cytotoxic. Zymography of proteins secreted
      by BAE cells that had contracted collagen gels revealed matrix metalloproteinase
      2. Subconfluent BAE cells that were migratory and proliferating were more
      effective contractors of collagen than were quiescent, confluent cells of the
      same strain. Moreover, bovine capillary endothelial cells contracted collagen
      gels to a greater degree than was seen with BAE cells. Collectively, our
      observations indicate that traction-driven reorganization of fibrillar type I
      collagen by endothelial cells is sensitive to different mediators, some of which,
      e.g., bFGF, are known regulators of angiogenesis in vivo.

PMID- 8655630
TI  - Instability of endogenous MRP/proliferin transcripts in the nucleus of mouse
      embryo fibroblasts contrasts with their stability when produced during transient
      transfections.
AB  - The mitogen regulated protein/proliferin (MRP/PLF) gene is transcribed in primary
      mouse embryo fibroblasts (MEFs), but the pre-mRNA is not properly converted into
      a stable cytoplasmic mRNA and instead is rapidly degraded, apparently in the
      nucleus [Malyankar et al. (1994): Proc Natl Acad Sci USA 91:335-359]. In 3T3
      cells derived from the MEFs by the standard 3T3 immortalization protocol, stable
      MRP/PLF mRNA is produced. We show here that the processing of intron sequences is
      similar in the two cell types and that some of the MRP/PLF transcripts are
      polyadenylated in the MEFs. We also document the production of stable MRP/PLF
      mRNA generated by transcription of various plasmid constructs containing
      different portions of the MRP/PLF3 gene after calcium phosphate-mediated
      transfection into the MEFs. We conclude that the inability of the MRP/PLF mRNA to
      accumulate in the MEFs is unlikely to result solely from a single localized
      sequence in the primary transcript (or the mRNA) that causes it to be subject to
      rapid breakdown; possibly export of the mRNA from the MEF nucleus is defective or
      some aspect of the transcriptional process marks the transcript for degradation.

PMID- 8655631
TI  - Tissue inhibitor of metalloproteinase-2 (TIMP-2) mRNA is constitutively expressed
      in bovine, human normal, and osteoarthritic articular chondrocytes.
AB  - Tissue inhibitors of metalloproteinases (TIMPs) inhibit the extracellular matrix
      (ECM) metalloproteinases (MMPs). To determine the source of TIMPs in synovial
      fluids of patients with osteoarthritis (OA), the ability of chondrocytes to
      express TIMP-2 and its regulation by agents found in inflammed joints was
      investigated. The constitutive TIMP-2 mRNA expression was demonstrated in
      chondrocytes from normal bovine, human OA and normal cartilage. The cross
      hybridization of human and bovine TIMP-2 suggested its evolutionary conservation.
      Serum, IL-1, IL-6 and TGC-beta were unable to augment considerably the basal
      expression of TIMP-2 mRNA. TIMP-1 RNA expression in chondrocytes from human OA
      cartilage was elevated compared to non-OA chondrocytes, while TIMP-2 mRNA levels
      were similar in both. IL-1 beta, IL-6 and TGF-beta did not affect TIMP-2
      expression but TGF-beta induced TIMP-1 mRNA in human OA chondrocytes. TIMP-2 and
      TIMP-1 are therefore differentially regulated in chondrocytes and the basal TIMP
      2 levels may be needed for the cartilage ECM integrity.

PMID- 8655632
TI  - Okadaic acid, sphingosine, and phorbol ester reversibly modulate heat induction
      on protein kinase FA/GSK-3 alpha in A431 cells.
AB  - Exposure of A431 cells to a rapid and sudden increase from 37 degrees C to 46
      degrees C for 30 min could induce an increase in protein level and cellular
      activity of protein (kinase FA/GSK-3 alpha) up to approximately 200% of control
      level. However, when cells were first treated with 500 nM tumor promoter phorbol
      ester TPA at 37 degrees C for 30 min to activate cellular protein kinase C (PKC)
      or with 400 nM okadaic acid at 37 degrees C for 30 min to inhibit cellular
      protein phosphatases followed by heat shock at 46 degrees C for another 30 min,
      the heat induction on kinase FA/GSK-3 alpha was found to be completed blocked. In
      sharp contrast, when cells were first treated with 1 microM TPA at 37 degrees C
      for 24 h or with 5 microM sphingosine at 37 degrees C for 30 min to down-regulate
      cellular PKC, the heat induction on kinase FA/GSK-3 alpha was found to be
      reversely promoted up to approximately 250% of control level, demonstrating that
      kinase FA/GSK-3 alpha may not represent a constitutively active/mitogen
      inactivated protein kinase as previously conceived. Taken together, the results
      provide initial evidence that TPA/sphingosine and okadaic acid could reversibly
      modulate the heat induction on kinase FA/GSK-3 alpha in A431 cells, suggesting
      that phosphorylation/dephosphorylation mechanisms are involved in the regulation
      of the heat-shock induction of kinase FA/GSK-3 alpha, representing a new mode of
      signal transduction for the regulation of this multisubstrate protein kinase and
      a new mode of signaling pathway modulating the heat-induction process.

PMID- 8655633
TI  - Shedding of the 67-kD laminin receptor by human cancer cells.
AB  - The 67-kD laminin receptor (67LR) is a cell membrane-associated molecule
      exhibiting high affinity for the basement membrane glycoprotein, laminin. While
      export of the 67LR toward the extracellular matrix has been recently suggested by
      electron microscopy studies, there is to date no evidence of shedding of the 67LR
      from cells. Using two monoclonal antibodies directed against the 67LR, we
      developed a double-determinant radioimmunoassay that demonstrates that the 67LR
      is released from cancer cells into the culture medium. The shed molecule
      exhibited the same apparent molecular weight as that of the membrane-associated
      67LR, suggesting that no proteolytic cleavage is involved in the process.
      Furthermore, we demonstrate that the 67LR is not anchored to the membrane through
      a glycolsyl-phosphatidylinositol bridge. However, the observation that lactose
      increased the release of 67LR suggests that a lectin-type interaction is involved
      in the cell membrane association of this laminin binding protein and the cell
      surface. Interestingly, the released 67LR recovered after HPLC gel filtration was
      found free as well as associated to high molecular weight complexes. The free
      67LR retained its ability to bind to the cell surface. Our study is the first
      demonstration that the 67LR is effectively shed by cancer cells. The released
      free 67LR could play an important role in modulating interactions between cancer
      cells and laminin during tumor invasion and metastasis.

PMID- 8655635
TI  - Loss and shedding of surface markers from the leukemic myeloid monocytic line THP
      1 induced to undergo apoptosis.
AB  - Previous studies have established that a relationship exists between apoptosis
      and cell surface (ecto-) peptidase activity. Thus dose-dependent increases were
      found both in ectopeptidase activities and in the proportion of cells undergoing
      apoptosis in HeLa cell monolayers after exposure to UV and other perturbants
      causing arrest of DNA synthesis (indirectly or directly as a result of DNA
      damage). The nature of the correlation made no distinction as to whether an
      increase in peptidase activity was causal of, or consequential to apoptosis, nor
      whether the increase was a general response by all cells. As a wider approach to
      understanding the possible role played by ectopeptidases in apoptosis, we report
      the effect on expression of a known ectopeptidase, aminopeptidase N (CD13), by a
      myelomonocytic cell line induced to undergo apoptosis. Using THP-1 cultures
      exposed to low concentrations of ethanol, we used FACS technology to sort for
      early apoptotic cells that have an increased ability to sequester the vital dye
      Hoechst 33342 while excluding nonvital dyes. Apoptosis was verified by light,
      fluorescence, and transmission electron microscopy, and the presence of DNA
      fragmentation. These early apoptotic cells showed a significant loss in CD13
      labeling. Another surface marker, CD33, behaved similarly, whereas CD14 was lost
      globally, and not just by the apoptotic cells. Peptidase assays confirmed that an
      aminopeptidase was shed into the bathing media and that this activity was
      inhibitable both by bestatin and by a CD13 neutralizing monoclonal antibody. In
      treated cells, there was no evidence for an increase in cell surface protease
      activity directed toward a highly aliphatic nonapeptide substrate used as a model
      for TGF-alpha scission from its precursor form. However, other cell surface
      proteases of different specificity are presumably responsible for the observed
      shedding of CD13.

PMID- 8655634
TI  - Tyrosine kinase but not phospholipid/Ca2+ signaling pathway is involved in
      interferon-gamma stimulation of Ia expression in macrophages.
AB  - The specific signal transduction pathway(s) involved in the induction of the
      expression of the MHC class II molecule, Ia, on macrophages by interferon-gamma
      (IFN-gamma) is unclear. In this paper, we assessed the role of several signal
      transduction pathways including calcium mobilization, phospholipase C, protein
      kinase C and cyclic nucleotide-dependent protein kinase, and the tyrosine kinase
      pathways. IFN-gamma was unable to mobilize intracellular calcium, unlike platelet
      activating factor, which stimulated a threefold increase in cytosolic Ca2+
      concentration in macrophages. Inhibition of the phospholipase C pathway by U73122
      or ET-180CH3 and of phosphatidic acid phosphohydrolase by propranolol did not
      suppress IFN-gamma-induced Ia expression. In addition, inhibition of protein
      kinase C by calphostin C or cyclic nucleotide-dependent protein kinase by HA1004
      did not suppress Ia expression. However, IFN-gamma-induced Ia expression was
      significantly suppressed when the tyrosine kinase pathway was inhibited with
      herbimycin A and genestein. In addition, those two inhibitors suppressed tyrosine
      phosphorylation of several proteins in macrophages that may or may not be
      involved in the induction of Ia expression. Thus, IFN-gamma used only the
      tyrosine kinase signaling pathway, but not the phospholipid/Ca2+ signaling
      pathways, to induce Ia expression in macrophages.

PMID- 8655636
TI  - Estrogen pretreatment increases arachidonic acid release by bradykinin stimulated
      normal human osteoblast-like cells.
AB  - Eicosanoids are multifunctional autocrine/paracrine regulators of bone that are
      enzymatically derived from arachidonic acid (AA). The rate-limiting step in the
      eicosanoid biosynthetic pathways may be the release of AA from membrane
      glycerophospholipids by activated phospholipases. Free AA can serve as the
      substrate for cyclooxygenase(s) or lipoxygenases that catalyze the commitive
      steps in eicosanoid synthesis; alternatively, free AA may be used in reacylation
      processes, resulting in its reincorporation into cellular lipids. The hormones 17
      beta-estradiol (17 beta-E2), dexamethasone (a synthetic glucocorticoid), and 1,25
      dihydroxyvitamin D3 (1,25(OH)2D3) have been identified as regulators of AA
      metabolism, at various levels, in several tissues including bone. The possibility
      that these osteotropic steroids modulate the availability of free AA in bone
      cells was studied in the human osteoblast-like (hOB) cell model system. Following
      a 48-h steroid pretreatment, bradykinin or the calcium ionophore A23187 were used
      as agonists to stimulate hOB cell release of AA. The principal findings from
      these investigations were that (1) 17 beta-E2 pretreatment potentiated the
      appearance of free AA following bradykinin stimulation of the cells but, did not
      alter their response to A23187 stimulation; (2) dexamethasone pretreatment
      limited bradykinin-induced increases in free AA levels but did not alter cell
      response to A23187 stimulation; (3) hOB cells derived from different trabecular
      bone compartments (manubrium of the sternum, femoral head) differed
      quantitatively in their responses to bradykinin stimulation of AA release; and
      (4) 1,25(OH)2D3 did not effect AA release stimulated by either agonist. The
      ability of the steroids to modulate AA release by hOB cells suggests that these
      hormones may indirectly mediate bone cell responses to other osteotropic hormones
      that act through eicosanoid-dependent processes.

PMID- 8655637
TI  - Heterogeneous distribution and organization of cytoskeletal proteins drive
      differential modulation of metabolic fluxes.
AB  - On the basis of experimental data obtained in vitro, we propose that differential
      segregation of actin and tubulin in the cytoplasm may be a regulatory mechanism
      of metabolic fluxes. The results presented point out that the same enzymes may be
      differentially modulated at different locations in the cytoplasm, depending on
      the cytoskeletal protein present at that location, its concentration, polymeric
      status, or geometric arrangement. Essentially, actin or microtubular protein
      would exert their effect on enzymatic catalysis through displacement of the
      equilibrium of enzyme oligomers either to active or less active species. The
      latter was corroborated by mathematical modeling of the dynamic coupling between
      microtubular protein assembly-disassembly and pyruvate kinase activity. From
      these results, a precise biochemical meaning can be given to the putative linkage
      existing between the mechanisms by which cells rearrange their cytoplasmic
      architecture and the dynamics of biochemical reactions taking place
      concomitantly.

PMID- 8655638
TI  - Involvement of protein phosphatase 2A in PKC-independent pathway of neutrophil
      superoxide generation by fMLP.
AB  - We examined the effects of okadaic acid, a protein phosphatase 1 and 2A
      inhibitor, on superoxide generation in human neutrophils. Superoxide generation
      induced by fMLP was inhibited by low-dose okadaic acid (10-100 nM), but it had no
      effect on superoxide synthesis by PMA, and the fMLP-induced rise of the
      intracellular Ca2+ concentration was not affected by low-dose okadaic acid. These
      findings suggested that the inhibitory mechanism of okadaic acid might involve
      PKC-independent and Ca(2+)-independent pathways in fMLP induced NADPH oxidase
      activation. Both fMLP-stimulated phosphorylation of serine residues in p47phox
      and its translocation to the plasma membrane were suppressed by low-dose okadaic
      acid. On the other hand, PMA-induced phosphorylation and translocation of p47phox
      were not affected by such a low dose of okadaic acid. These findings suggested
      that fMLP induced phosphorylation of serine residues in p47phox was regulated by
      protein phosphatase 2A, and its phosphorylation was necessary for translocation
      and superoxide generation in fMLP-activated human neutrophils.

PMID- 8655639
TI  - Exploring nuclear pore complex structure and function in molecular detail.
AB  - Bidirectional molecular trafficking between the nucleus and the cytoplasm of
      eukaryotic cells occurs through the nuclear pore complexes (NPCs), approximately
      120 megadalton supramolecular assemblies embedded in the double-membraned nuclear
      envelope. Significant progress has been made in elucidating the three-dimensional
      (3-D) architecture of the NPC, and in identifying, characterizing, and cloning
      and sequencing NPC proteins. Several of these have now been localized within the
      3-D structure of the NPC. Nevertheless, there still remain major questions
      relating to the conformation, molecular composition and functional roles of
      distinct NPC components. Here we review recent structural studies from our group
      and others which have contributed toward dissecting the molecular architecture of
      the NPC. We also present our results on the molecular characterization of some
      NPC components, and on the elucidation of their functional roles in mediated
      nucleocytoplasmic transport.

PMID- 8655640
TI  - The role of PRP8 protein in nuclear pre-mRNA splicing in yeast.
AB  - The removal of introns from precursor messenger RNAs occurs in a large complex,
      the spliceosome, that contains many proteins and five small nuclear RNAs
      (snRNAs). The snRNAs interact with the intron-containing substrate RNA and with
      each other to form a dynamic network of RNA interactions that define the intron
      and promote splicing. There is evidence that protein splicing factors play
      important roles in regulating RNA interactions in the spliceosome. PRP8 is a
      highly conserved protein that is associated in particles with the U5 snRNA and
      directly binds the substrate RNA in spliceosomes. UV crosslinking has been used
      to map the binding sites, and shows extensive interaction between PRP8 protein
      and the 5' exon prior to the first step of splicing and with the 3' splice site
      region subsequently. It is proposed that PRP8 protein may stabilize fragile
      interactions between the U5 snRNA and exon sequences at the splice sites, to
      anchor and align them in the catalytic centre of the spliceosome.

PMID- 8655641
TI  - Molecular analysis of the coiled body.
AB  - There is increasing interest in studying how specific metabolic activities within
      the nucleus are organised into functional domains. The best known example is the
      nucleolus where rRNA genes are transcribed and rRNA processed and assembled into
      ribosomal units. Other subnuclear domains have been known for many years through
      morphological studies but are only recently being analysed at the molecular
      level. Here we focus on an evolutionarily conserved nuclear domain, called the
      coiled body, which contains splicing snRNPs. We review recent literature on the
      coiled body and discuss a possible model for its biological function.

PMID- 8655642
TI  - The influence of 5' and 3' end structures on pre-mRNA metabolism.
AB  - The 5' cap structure of RNA polymerase II transcripts and the poly(A) tail found
      at the 3' end of most mRNAs have been demonstrated to play multiple roles in gene
      expression and its regulation. In the first part of this review we will
      concentrate on the role played by the cap in pre-mRNA splicing and how it may
      contribute to efficient and specific substrate recognition. In the second half,
      we will discuss the roles that polyadenylation has been demonstrated to play in
      RNA metabolism and will concentrate in particular on an elegant mechanism where
      regulation of polyadenylation is used to control gene expression.

PMID- 8655643
TI  - Protein kinases in the control of mitosis: focus on nucleocytoplasmic
      trafficking.
AB  - The eukaryotic cell nucleus is a highly dynamic organelle. This is illustrated
      most dramatically during mitosis, when the nuclear envelope breaks down, the
      nuclear lamina disassembles, chromosomes condense, and a microtubule-based
      spindle apparatus distributes sister chromatids to the dividing daughter cells.
      Many of these dramatic changes in nuclear architecture and microtubule
      organization are controlled by phosphorylation and dephosphorylation events.
      Whereas the cardinal role of cyclin-dependent kinases (CDKs) in the regulation of
      mitosis is well established, there is now clear evidence for the requirement of
      additional mitotic protein kinases. Studies into the regulation of CDKs and other
      mitotic kinases have revealed that these enzymes undergo cell cycle dependent
      changes in subcellular distribution, suggesting that localization may contribute
      to regulating their activities. This article describes some recent findings
      relating to the nucleocytoplasmic translocation of CDK/cyclin complexes at the
      onset of mitosis. In addition, it summarizes recent information on two novel
      human protein kinases which have been implicated in the control of mitotic
      progression.

PMID- 8655644
TI  - The regulation of euchromatin and heterochromatin by histones in yeast.
AB  - Yeast chromosomes may lack the linker histone H1 (normally required to compact 10
      nm beads-on-a-string fiber into the 30 nm fiber) and there is no cytological
      evidence for higher order fiber structure but they do contain regions which
      correspond to euchromatin and heterochromatin of higher eukaryotes. Both
      euchromatin and heterochromatin contain nucleosomal particles (composed of two
      molecules each of H2A, H2B, H3 and H4), however histones have been shown to
      regulate genes in these regions in quite different ways. The mechanisms by which
      such regulation occurs are the topic of this paper.

PMID- 8655645
TI  - Studies of DNA methylation in animals.
AB  - We have been studying the evolution and function of DNA methylation in vertebrate
      animals using three related approaches. The first is to further characterise
      proteins that bind to methylated DNA. Such proteins can be viewed as 'receptors'
      of the methyl-CpG 'ligand' that mediate downstream consequences of DNA
      modification. The second approach involves CpG islands. These patches of non
      methylated DNA coincide with most gene promoters, but their origin and functional
      significance have only recently become the subject of intensive study. The third
      approach is to trace the evolution of DNA methylation. Genomic methylation
      patterns of vertebrates are strikingly different from those of invertebrates. By
      studying methylation in animals that diverged from common ancestors near to the
      invertebrate/vertebrate boundary, we will assess the possibility that changes in
      DNA methylation contributed causally to the evolution of the complex vertebrate
      lineage.

PMID- 8655646
TI  - Characterization of the execution phase of apoptosis in vitro using extracts from
      condemned-phase cells.
AB  - Apoptotic cell death is characterized by a dramatic morphological transformation
      during which apparently healthy cells suddenly initiate a comprehensive program
      of motility changes and degradative activities that culminates in disassembly of
      the cell into membrane-enclosed vesicles. The mechanism of the cellular changes
      during this spectacular execution phase of apoptosis is just now yielding to
      biochemical analysis. In our laboratory, we have applied a novel in vitro system
      to the study of these events. In this system, nuclei isolated from healthy cells
      undergo the characteristic changes of apoptosis rapidly and synchronously. Using
      this system we have identified the first substrates for interleukin-1 beta
      converting enzyme (ICE)-like proteinases during apoptotic execution. One of
      these, the nuclear enzyme poly (ADP-ribose) polymerase is cleaved very early in
      the apoptotic process. A second class of proteins, the nuclear lamins, is cleaved
      later in the pathway. Lamin cleavage requires a second ICE-related proteinase,
      and is essential for the complete dissolution of nuclei into apoptotic bodies.
      Studies with our cell-free extracts reveal that the various proteinases and
      nucleases that operate during the execution phase of apoptosis do so largely in
      independent parallel biochemical pathways. However, all of these pathways require
      the action of ICE-related proteinases for their initiation.

PMID- 8655647
TI  - Analysis of the temporal program of replication initiation in yeast chromosomes.
AB  - The multiple origins of eukaryotic chromosomes vary in the time of their
      initiation during S phase. In the chromosomes of Saccharomyces cerevisiae the
      presence of a functional telomere causes nearby origins to delay initiation until
      the second half of S phase. The key feature of telomeres that causes the
      replication delay is the telomeric sequence (C(1-3)A/G(1-3)T) itself and not the
      proximity of the origin to a DNA end. A second group of late replicating origins
      has been found at an internal position on chromosome XIV. Four origins, spanning
      approximately 140 kb, initiate replication in the second half of S phase. At
      least two of these internal origins maintain their late replication time on
      circular plasmids. Each of these origins can be separated into two functional
      elements: those sequences that provide origin function and those that impose late
      activation. Because the assay for determining replication time is costly and
      laborious, it has not been possible to analyze in detail these 'late' elements.
      We report here the development of two new assays for determining replication
      time. The first exploits the expression of the Escherichia coli dam methylase in
      yeast and the characteristic period of hemimethylation that transiently follows
      the passage of a replication fork. The second uses quantitative hybridization to
      detect two-fold differences in the amount of specific restriction fragments as a
      function of progress through S phase. The novel aspect of this assay is the
      creation in vivo of a non-replicating DNA sequence by site-specific pop-out
      recombination. This non-replicating fragment acts as an internal control for copy
      number within and between samples. Both of these techniques are rapid and much
      less costly than the more conventional density transfer experiments that require
      CsCl gradients to detect replicated DNA. With these techniques it should be
      possible to identify the sequences responsible for late initiation, to search for
      other late replicating regions in the genome, and to begin to analyze the effect
      that altering the temporal program has on chromosome function.

PMID- 8655648
TI  - On the structure of replication and transcription factories.
AB  - Recent experiments suggest that active polymerases are concentrated in large
      structures, 'factories', within eukaryotic nuclei. Data concerning the structure
      of these factories is reviewed.

PMID- 8655649
TI  - Stepwise assembly of initiation complexes at budding yeast replication origins
      during the cell cycle.
AB  - DNA replication is a pivotal event in the cell cycle and, as a consequence, is
      tightly controlled in eukaryotic cells. The initiation of DNA replication is
      dependent upon the completion of mitosis and upon the commitment to complete the
      cell cycle made during G(1). Characterisation of the protein factors required for
      initiating DNA replication is essential to understand how the cell cycle is
      regulated. Recent results indicate that initiation complexes assemble in multiple
      stages during the cell cycle. First, origins are bound by the multisubunit origin
      recognition complex (ORC) which is essential for DNA replication in vivo. ORC,
      present at little more than one complete complex per replication origin, binds to
      origins immediately after initiation in the previous cell cycle. ORC binding
      occurs by the recognition of a bipartite sequence that includes the essential ARS
      consensus sequence (ACS) and the functionally important B1 element adjacent to
      the ACS. A novel pre-replicative complex (pre-RC) assembles at origins at the end
      of mitosis in actively cycling cells and remains at origins until DNA replication
      initiates. Finally, Dbf4, which is periodically synthesised at the end of G(1),
      interacts with replication origins. Dbf4-origin interaction requires an intact
      ACS strongly suggesting that interaction occurs through ORC. Dbf4 interacts with
      and is required for the activation of the Cdc7 protein kinase and together, Dbf4
      and Cdc7 are required for the G(1)-S transition. Separate regions of Dbf4 are
      required for Cdc7- and origin-interaction suggesting that Dbf4 may act to recruit
      Cdc7 to replication origins where phosphorylation of some key component may cause
      origin firing.

PMID- 8655650
TI  - Recognition and processing of damaged DNA.
AB  - Base excision-repair, which is required for correction of spontaneous hydrolytic
      and oxidative damage to DNA as well as lesions inflicted by alkylating agents, is
      a relatively well understood repair pathway. Mammalian factors involved in this
      pathway are reviewed, with emphasis on current uncertainties. Most DNA
      replication and repair enzymes in mammalian cell nuclei, e.g. DNA polymerases
      alpha, beta, delta, and epsilon, have direct counterparts in yeast. In contrast,
      the abundant enzymes in mammalian cell nuclei that bind and are activated
      specifically by DNA strand interruptions, poly(ADP-ribose) polymerase and DNA
      dependent protein kinase, have not been detected in yeast; nor has p53, which is
      elevated in response to DNA strand breaks. We have found a family of four
      distinct DNA ligases in human cell nuclei, whereas only a single DNA ligase has
      been detected in yeast. It would appear that the cellular responses to DNA strand
      breaks may differ markedly between higher and lower eukaryotes.

PMID- 8655651
TI  - Appearance of apparently ubiquitin-conjugated I kappa B-alpha during its
      phosphorylation-induced degradation in intact cells.
AB  - NF-kappa B is a dimeric protein that serves to initiate gene transcription in
      higher eukaryotic cells in response to mainly pathogenic stimuli. Its activity is
      controlled by a third inhibitory subunit, called I kappa B. When I kappa B is
      bound, NF-kappa B cannot bind to DNA or enter the nucleus but is stored in a
      latent cytoplasmic form. Upon stimulation of cells I kappa B is released, which
      allows the activation of NF-kappa B. We have analyzed the molecular mechanism
      underlying the removal of I kappa B-alpha. Distinct extracellular stimuli lead to
      a phosphorylation of I kappa B-alpha of serines 32 and 36 by a yet unidentified
      kinase. These modifications do not directly dissociate I kappa B from NF-kappa B
      but render the inhibitor highly susceptible for proteolytic degradation by,
      presumably, the proteasome. In this paper, we report for the first time that
      higher molecular mass forms of I kappa B-alpha occur under conditions that lead
      to a phosphorylation of I kappa B-alpha and activation of NF-kappa B. These I
      kappa B-alpha variants had discrete molecular masses and were most prominent in
      cells overexpressing I kappa B-alpha, suggesting the covalent modification of I
      kappa B-alpha by ubiquitin conjugation. The proteasome inhibitor Cbz-Ile-Glu(O-t
      Bu)-Ala-leucinal (PSI), which stabilizes the phospho form of I kappa B-alpha,
      only slightly increased the amount of conjugates indicating that the conjugation
      of I kappa B-alpha with ubiquitin was the rate-limiting step in I kappa B-alpha
      degradation, and not its phosphorylation or proteolysis. Our data suggest that
      conjugation of I kappa B-alpha with ubiquitin is an intermediate reaction in the
      phosphorylation-controlled degradation of I kappa B-alpha and the subsequent
      activation of NF-kappa B.

PMID- 8655652
TI  - Regulation of cell proliferation and differentiation by Myc.
AB  - Myc is a nuclear phosphoprotein which controls cellular proliferation, most
      likely by regulating gene activity. The finding that the neuronal model cell line
      PC12 lacks the Myc DNA binding partner, the Max protein, and the demonstration
      that Myc is a repressor of gene activity as well as a transactivator, lead to
      models for Myc action in regulating cell growth.

PMID- 8655653
TI  - Regulation of transcription by E2F1/DP1.
AB  - The E2F1 transcription factor, in co-operation with DP1, controls the expression
      of several S-phase specific genes. This activity is most likely responsible for
      the oncogenic and S-phase inducing properties of E2F1, suggesting that this
      transcription factor plays a key role in regulating the cell cycle. The
      transcriptional activation functions of E2F1 are resident in a small C-terminal
      domain which can independently activate transcription. Here we review the protein
      protein interactions which impinge upon and regulate this activation domain and
      put forward some models on their mechanism of action.

PMID- 8655654
TI  - Does the Wilms' tumour suppressor gene, WT1, play roles in both splicing and
      transcription?
AB  - The Wilms' tumour suppressor gene (WT1) encodes a protein(s) with 4 zinc fingers
      that is essential for the development of the genitourinary system. A considerable
      body of evidence exists to support the idea that WT1 binds DNA and functions as a
      transcription factor. However, we have shown recently by confocal microscopy and
      immunoprecipitation studies that a significant proportion of WT1 is associated
      with splice factors in kidney cell lines, fetal tissues and transfected Cos
      cells. Different isoforms of WT1 are produced by an alternative splice that leads
      to the presence or absence of a 3 amino acid insertion (KTS) between zinc fingers
      3 and 4. We have shown that these different forms localise differently in the
      nucleus. The +KTS form mainly localises with splice factors, the -KTS form mainly
      with transcription factors. Here we propose a model to account for these
      different localisations. Also, we discuss the possible significance of these
      findings.

PMID- 8655655
TI  - Somatisation in children.
AB  - This review summarises recent work on somatisation in childhood. Minor
      physiological dysfunction may play a part in a number of cases and associated
      psychiatric disorders are commonly though not universally found. Contributory
      family factors include high rates of health problems and of parental
      psychological distress and there is some evidence for the role of family
      modelling and reinforcement of illness behaviour. There is suggestive evidence
      linking somatisation to emotional closeness in families, to family togetherness
      around health matters and to anomalies in children's social relationships.
      Somatisation in children can respond to treatments involving cognitive
      behavioural and family techniques as well as to sensitive, psychologically sound
      advice from paediatricians.

PMID- 8655656
TI  - Classification of child and adolescent psychopathology.
AB  - This review will consider some of the major issues in the classification of child
      and adolescent psychopathology. The central issue will be the value of
      classification systems in child and adolescent psychopathology research. Some
      comment will also be made on the value of the existing classifications in
      clinical practice.

PMID- 8655657
TI  - Epidemiology of childhood disorders in a cross-cultural context.
AB  - The present report summarizes the epidemiologic research on childhood
      psychopathology that has been carried out in different cultural settings over the
      past 15 years from either an empirical or a diagnostic perspective. Prevalence
      and risk factor findings are summarized and contrasted. Some controversies
      surrounding cross-cultural research are discussed and methodological
      recommendations applicable to cross-cultural epidemiologic research are provided.

PMID- 8655658
TI  - Executive functions and developmental psychopathology.
AB  - In this paper, we consider the domain of executive functions (EFs) and their
      possible role in developmental psychopathologies. We first consider general
      theoretical and measurement issues involved in studying EFs and then review
      studies of EFs in four developmental psychopathologies: attention deficit
      hyperactivity disorder (ADHD), conduct disorder (CD), autism, and Tourette
      syndrome (TS). Our review reveals that EF deficits are consistently found in both
      ADHD and autism but not in CD (without ADHD) or in TS. Moreover, both the
      severity and profile of EF deficits appears to differ across ADHD and autism.
      Molar EF deficits are more severe in the latter than the former. In the few
      studies of more specific EF tasks, there are impairments in motor inhibition in
      ADHD but not in autism, whereas there are impairments in verbal working memory in
      autism but not ADHD. We close with a discussion of implications for future
      research.

PMID- 8655659
TI  - Autism: towards an integration of clinical, genetic, neuropsychological, and
      neurobiological perspectives.
AB  - Autism constitutes one of the best validated child psychiatric disorders.
      Empirical research has succeeded in delineating the key clinical phenomena, in
      demonstrating strong genetic influences on the underlying liability, and in
      identifying basic cognitive deficits. A range of neurobiological abnormalities
      has also been found, although the replicability of specific findings has not been
      high. An understanding of the causal processes leading to autism, and accounting
      for the marked variability in its manifestations, requires an integration across
      these different levels of enquiry. Although this is not yet possible, a partial
      integration provides a useful strategy for identifying key research questions,
      the limitations of existing hypotheses, and future research directions that are
      likely to prove fruitful. The research findings for each research level are
      critically reviewed in order to consider how to move towards an integration
      across levels.

PMID- 8655660
TI  - Variations of the left and middle hepatic veins: application in living related
      hepatic transplantation.
AB  - The anatomic variations of the middle hepatic vein (MHV) and left hepatic vein
      (LHV) in 200 patients with normal liver function were analyzed using
      ultrasonography to clarify the feasibility of resecting the left lobe or left
      lateral segment in living subjects for living related hepatic transplantation
      (LRHT). The MHV and LHV form a common trunk in 70% of cases but drain
      independently into the inferior vena cava (IVC) in 30%. In 7% of cases, the left
      median vein (LMV) drains into the MHV, in 32% of cases the anterior superior
      segmental vein (ASSV) that drains segment 8 flows into the MHV. The distance
      between the two confluence points (LHV flows into MHV or IVC and LMV flows into
      the MHV) ranged from 0.3 cm to 2.5 cm with an average of 0.75 cm. The diameter of
      the LMV at the point that flows into MHV ranged from 0.3 cm to 0.9 cm. with an
      average of 0.61 cm. The distance from the IVC to the confluence of the MHV and
      LHV ranged from 0 cm to 3.5 cm with an average of 1.5 cm in those cases whose MHV
      and LHV presented as common trunks. Preoperative delineation of this complex
      venous anatomy is of paramount importance because the hepatic veins have to be
      transected in the cutting plane of the liver. The location of this plane is
      determined by the optimal graft volume required, and both the graft and the
      remnant liver have to retain perfect function. The venous anatomy would change
      the cutting plane in the living donor and the surgical method of anastomosis for
      the recipient.

PMID- 8655661
TI  - Gallbladder compression sign: an indicator of small isoechoic hepatic tumors.
AB  - A small isoechoic liver mass is difficult to detect with ultrasound. Gallbladder
      compression indicates the presence of the lesion. To assess the clinical
      significance of the gallbladder compression (GBC) sign, we report on 9 cases of
      small isoechoic hepatic masses (less than 3 cm in diameter) detected by the GBC
      sign. The final diagnoses of these small hepatic masses was 3 hepatomas, 2
      hemangiomas, 2 nodular regenerations, 1 liver abscess, and 1 normal liver lobule.
      The gallbladder compression sign was not seen in 4992 normal volunteers. In
      conclusion, the GBC sign is an useful guide for the detection of a small
      isoechoic mass in the liver, but the nature of the mass cannot be determined.

PMID- 8655662
TI  - The effect of the amount of feedback on anxiety levels during ultrasound
      scanning.
AB  - This study examined the influence of different levels of feedback and of other
      situational and buffering variables on the psychological effects of ultrasound
      examinations of 211 pregnant women. The patients were randomly assigned to two
      different experimental conditions: high feedback and low feedback. The subjects'
      levels of anxiety (both trait- and state-anxiety) were measured immediately
      before and after the ultrasound examination. Overall, there was a significant
      decrease in the level of state-anxiety, which could not be explained by the
      different levels of feedback provided. Situational and buffering variables were
      not found to be related to the degree of psychological benefit produced by the
      scan.

PMID- 8655663
TI  - Sonographic diagnosis of fatty liver using a histogram technique that compares
      liver and renal cortical echo amplitudes.
AB  - Accurate diagnosis of fatty liver using ultrasonography was attempted based on
      the difference between the echo intensities of the liver and kidney determined
      from ultrasonic histograms. Livers were then classified as having fatty
      infiltration, normal histology, or intermediate histology based on CT ratios
      established previously in earlier work comparing non-contrast-enhanced liver and
      spleen. The hepatorenal difference was significantly greater in the fatty liver
      group than in the normal liver group (8.9 +/- 2.0 dB vs 2.5 +/- 4.5 dB, p <
      0.001). When a hepatorenal difference of > or = 7.0 dB was taken as the
      criterion, this method had a sensitivity of 91.3%, a specificity of 83.8%, and an
      accuracy of 86.7% for the diagnosis of fatty liver. Thus, quantitative ultrasonic
      diagnosis of fatty liver can be performed using echo intensity histograms.

PMID- 8655664
TI  - Transvaginal sonography of the yolk sac in normal and abnormal pregnancy.
AB  - A cross-sectional study comprising 117 consecutive first trimester singleton
      pregnancies was performed using transvaginal sonography (TVS) to evaluate size
      abnormalities of the secondary yolk sac (YS) vis-a-vis pregnancy outcome. In
      normal pregnancy outcome (NPO) the YS diameter showed an increase from the 5th to
      the 11th week, menstrual age, followed by a decrease and its disappearance after
      12 weeks. A YS of abnormal size was statistically significant (p < 0.001) in
      spontaneous abortion (SA) versus NPO, with a sensitivity of 68.7%, a specificity
      of 99%, a positive predictive value of 91.6% and a negative predictive value of
      95.2%. These preliminary results indicate that a measurement of the YS very early
      in gestation may be a useful marker of pregnancy outcome.

PMID- 8655665
TI  - Color doppler ultrasound of liver lesions: signal enhancement after intravenous
      injection of the ultrasound contrast agent Levovist.
AB  - Patients with focal liver lesions (hemangioma, focal nodular hyperplasia,
      adenoma, hepatocellular carcinoma, metastatic lesions, focal fatty lesion)
      received the ultrasound contrast agent Levovist (300 mg/mL and 400 mg/mL)
      intravenously. This ultrasound contrast agent (a suspension of micrometer-sized
      microparticles of galactose and microscopic gaseous bubbles) can pass through the
      lungs without impairment. After the administration of Levovist, increased color
      flow signals were detected in the liver. Five of 6 patients with metastatic liver
      lesions showed previously undetected blood flow in the rim of the tumor. In 4
      patients with hepatocellular carcinoma, enhanced signal intensity was observed in
      the vessels of the rim and in 3 of those patients in the center of the tumor. One
      patient with adenoma and one patient with focal nodular hyperplasia showed signal
      enhancement in the central area of the tumor. No signal enhancement was observed
      in hemangiomas, a focal fatty lesion, or in a carcinoid metastatic lesion.
      Levovist increased the echointensity of normal and tumor vessels in liver
      lesions. This new ultrasound contrast agent led to the detection of tumor vessels
      previously not detectable by conventional color flow imaging.

PMID- 8655666
TI  - Prenatal diagnosis of non-iatrogenic hematoma of the umbilical cord.

PMID- 8655667
TI  - Endoscopic ultrasonography in corrosive injury of the upper gastrointestinal
      tract by hydrochloric acid.

PMID- 8655668
TI  - Occult post-thoracentesis hematoma presenting as a pleural mass.

PMID- 8655669
TI  - Subhepatic appendix with fecalith mimicking acute cholecystitis with gallstone.

PMID- 8655670
TI  - A twin gestation complicated by gastroschisis in both twins.

PMID- 8655671
TI  - Audit of continuing medical education for pathologists: strategies and
      implications.

PMID- 8655672
TI  - Detection and widespread distribution of Chlamydia pneumoniae in the vascular
      system and its possible implications.
AB  - AIMS: To attempt to detect Chlamydia pneumoniae DNA in atheromatous vascular
      tissue. METHODS: A modification of an existing polymerase chain reaction (PCR)
      assay and immunofluorescence staining with a monoclonal antibody directed against
      C pneumoniae were used to detect C pneumoniae. Specimens from 32 patients
      undergoing abdominal aortic aneurysm repair were examined. Vascular tissue,
      ostensibly normal, from six liver transplant donors was also examined for
      comparison. Altogether, 43 vessels from these 38 subjects (age range 36-85 years)
      were examined. RESULTS: C pneumoniae was detected in 11 (44%) of 25 aortas, five
      (55%) of nine iliac arteries, two (40%) of five femoral arteries, and one of two
      iliac veins. Immunofluorescence staining supported positive PCR results in three
      of 12 cases in which it was used. Overall, C pneumoniae was detected in the
      arteries of 14 (44%) of the patients undergoing vascular surgery and three (50%)
      of the donors. CONCLUSIONS: This study is the first in the UK in which C
      pneumoniae organisms have been found in atherosclerotic vessels and the tendency
      for the organisms to be present most often in such vessels exhibiting chronic
      inflammatory changes suggests that a search for them in various forms of
      arteritis may also be rewarding.

PMID- 8655673
TI  - Detection of Helicobacter pylori in gastric biopsy and resection specimens.
AB  - AIMS: To compare the sensitivity of detecting Helicobacter pylori in gastric
      biopsy and resection specimens using tinctorial and silver impregnation stains,
      immunohistochemistry and the polymerase chain reaction (PCR). METHODS: Formalin
      fixed, paraffin wax embedded tissue from 33 gastric biopsy specimens (26 showing
      chronic gastritis and seven showing low grade mucosa associated lymphoid tissue
      (MALT) lymphoma) together with blocks of uninvolved mucosa from gastrectomy
      specimens for MALT lymphoma (five cases) were studied. Consecutive sections were
      stained using haematoxylin and eosin, Giemsa, the Warthin-Starry silver stain,
      and a polyclonal antibody directed against H pylori using an immunoperoxidase
      technique following heat induced antigen retrieval. PCR analysis of DNA extracted
      from a further section was carried out using primers which amplified a 411 base
      pair fragment of the urease A gene. RESULTS: H pylori was detected in 14 (37%)
      sections stained with haematoxylin and eosin, 21 (55%) with Giemsa, 23 (61%) with
      Warthin-Starry, and 25 (66%) stained with the antibody. Seventeen (45%) cases
      were positive on PCR. Immunohistochemistry was positive in all cases in which H
      pylori was detected by other methods. CONCLUSION: Immunohistochemistry using an
      immunoperoxidase technique following heat induced antigen retrieval for detecting
      H pylori in gastric biopsy and resection specimens is highly sensitive and easy
      to use.

PMID- 8655674
TI  - Inverse relation of serum Helicobacter pylori antibody titres and extent of
      intestinal metaplasia.
AB  - AIMS: To clarify the relation between the serum titre of anti-Helicobacter pylori
      (H pylori) antibody and the extent of intestinal metaplasia of the gastric
      mucosa. METHODS: The serum anti-H pylori IgG titres of 95 asymptomatic
      individuals (mean age 65 years) undergoing an annual health examination were
      measured and compared with the extent of intestinal metaplasia (absent, moderate,
      or extensive), determined by examination of multiple endoscopic mucosal biopsy
      specimens. Serum pepsinogen I (PGI) levels, as a marker for gastric atrophy, were
      also measured. RESULTS: The prevalence of seropositivity for H pylori antibody
      was high (> 80%), regardless of the extent of metaplasia. However, there was a
      negative association between the extent of metaplasia and the anti-H pylori
      titre: 75% of the subjects in the group without metaplasia had high (3+) antibody
      levels, as did 43% with moderate, and 37% with extensive metaplasia (absent v
      extensive). The inverse relation between the titre and the extent of metaplasia
      was evident when examined in those with normal PGI (> 30 ng/ml), whereas no such
      relation was apparent in subjects with low PGI (< or = 30 ng/ml). CONCLUSIONS:
      The anti-H pylori titre correlates inversely with the extent of intestinal
      metaplasia, particularly in subjects with less marked gastric atrophy.

PMID- 8655675
TI  - Comparison of the ligase chain reaction with cell culture for the diagnosis of
      Chlamydia trachomatis infection in women.
AB  - OBJECTIVE: To determine the sensitivity and specificity of ligase chain reaction
      (LCR) analysis of cervical and urine specimens from women compared with cell
      culture of cervical and urethral specimens for the diagnosis of genitourinary
      chlamydial infection. METHODS: Women (n = 624) attending the Genitourinary
      Medicine Clinic at University College London Hospitals, were enrolled. Patients
      who had received antibiotics within the previous two weeks were excluded.
      Specimens were obtained from the urethra and cervix for chlamydial culture, and
      from the cervix for LCR. A specimen of first void urine was also obtained for
      LCR. Discrepancies were resolved by direct immunofluorescence or a major outer
      membrane protein targeted LCR, or both. RESULTS: The prevalence of Chlamydia
      trachomatis in 600 patients, using an expanded standard of a positive cell
      culture or two confirmed positive non-culture tests, was 13.2% (79/600). Cervical
      culture detected 68.4% and urethral culture 62% of all positive results compared
      with 81% detected by cervical LCR and 69% by urine LCR. Cervical and urethral
      culture combined detected 87.3% whereas cervical and urine LCR combined detected
      91.1% of positive cases. Specificity of LCR was 100% in the cervix and 99.8% in
      urine. CONCLUSION: This study demonstrates that LCR analysis of cervical and
      urine specimens is a reliable method for the diagnosis of chlamydial genital
      infection in women. However, the study also demonstrates that no single test will
      detect all chlamydial infections. Conventional non-culture tests and cell culture
      may grossly underestimate the prevalence of chlamydial infection. LCR analysis of
      a cervical specimen was superior to conventional cell culture without blind
      passage as a single test for diagnosing chlamydial infection in women, followed
      by LCR of a urine specimen.

PMID- 8655676
TI  - Lipoproteins in pregnant women before and during delivery: influence on neonatal
      haemorheology.
AB  - AIMS: To investigate whether the lipid profile of pregnant women during
      parturition differs from the profile at previous stages of pregnancy and to
      determine the effects of maternal lipid changes on fetal or neonatal
      haemorheology. METHODS: Sixty pregnant women were studied, divided into two
      groups. Group 1 contained 30 women of mean age of 27 (SD 3) years and gestational
      age > 38 weeks in whom delivery had not yet begun; all these pregnancies followed
      an uncomplicated course and there was no evidence of any fetal pathology from
      previous obstetric examinations. All the women reached term and birth weight was
      3340 (350) g. Group 2 contained women of mean age 26 (4) years, in whom delivery
      was ongoing, all of whose pregnancies reached term. The following variables were
      determined in all cases: total cholesterol, triglycerides, high density
      lipoproteins (HDL), low density lipoproteins (LDL), free fatty acids and
      phospholipids, and apoprotein A (apo-A) and apoprotein B (apo-B). Serum and
      plasma viscosity was measured with a capillary viscosimeter. RESULTS: The apo
      B/apo-A and HDL/apo-A ratios increased during delivery, indicating that in
      pregnant women these atherogenic indices are raised during delivery compared with
      previous gestational stages. Significant correlation coefficients were obtained
      between maternal lipids (triglycerides, total cholesterol, LDL, total
      cholesterol/HDL, and LDL/HDL) and plasma viscosity in the neonate. CONCLUSIONS:
      Plasma atherogenic indices increase progressively until birth. These changes have
      implications for neonatal haemorheology because they cause an increase in plasma
      viscosity.

PMID- 8655677
TI  - Measurement of extent of spread of oesophageal squamous carcinoma by serial
      sectioning.
AB  - OBJECTIVES: (1) To examine the prevalence and extent of intramural metastasis in
      squamous cell carcinomas of the oesophagus so as to delineate the resection
      margins for these tumours; (2) to devise an appropriate method for measurement of
      these lesions which takes into account of the contraction of the specimens after
      resection. METHODS: Oesophagectomy specimens were prospectively collected from 96
      patients (87 males, nine females) with primary oesophageal squamous cell
      carcinoma over a two year period. The sizes of the tumours were measured in situ,
      after resection and after application of muscle relaxant (to regain their in situ
      length). The specimens were then serially sectioned for histological examination.
      RESULTS: The sizes of the tumours measured after application of muscle relaxant
      roughly corresponded to those measured in situ. Intramural metastasis was
      observed in 26% of the cases. Sixty four per cent (16 cases) of these were on the
      oral side, 72% (18 cases) on the gastric side, and 25% (nine cases) on both sides
      of the tumours. The most distant extent of intramural metastasis from the primary
      tumour was from 0.5 cm to 7.7 cm (mean = 3.4 cm) on the oral side, and 0.5 to 9.5
      cm (mean 4 cm) on the gastric aspect of the tumour. Intramural metastasis was
      seen only in patients in whom the primary cancer had deep muscle infiltration.
      Multiple neoplastic lesions could be detected in 33% of the patients. Both
      intramural metastasis and multiple neoplastic lesions were associated with
      extensive lymph node infiltration. However, they had different histological
      features and extent of infiltration. CONCLUSIONS: Intramural metastasis was
      frequently observed in oesophageal squamous cell carcinoma. This implies that
      excision with wide margins should be considered for local control of the disease.

PMID- 8655678
TI  - Observer variability in histopathological reporting of non-small cell lung
      carcinoma on bronchial biopsy specimens.
AB  - AIMS: To evaluate the ability of histopathologists to sub-classify non-small cell
      lung carcinomas on bronchial biopsy material using the current World Health
      Organisation (WHO) classification. METHODS: Twelve histopathologists each
      reviewed 100 randomly selected bronchial biopsy specimens which had originally
      been reported as showing non-small cell lung carcinoma. For each case, two
      sections were circulated, one stained by haematoxylin and eosin and the other by
      a standard method for mucin (alcian blue/periodic acid Schiff). The participants
      were allowed to indicate their degree of confidence in their classification of
      each case. A standard proforma was completed and the results were analysed using
      kappa statistics. RESULTS: Where the participants were confident in their
      classification, they were actually quite good at sub-classifying the non-small
      cell carcinoma sections (kappa = 0.71, standard error = 0.058). Overall, however,
      the results were only fair (kappa = 0.39, standard error = 0.034). CONCLUSIONS:
      The majority of non-small cell lung carcinomas can be correctly categorised on
      adequate bronchial biopsy material. Where a confident diagnosis was made, both
      squamous carcinoma (kappa = 0.73) and adenocarcinoma (kappa = 0.83) were well
      recognised.

PMID- 8655679
TI  - Correlation of apoptosis with tumour cell differentiation, progression, and HPV
      infection in cervical carcinoma.
AB  - AIMS: To clarify the significance of apoptosis in the progression of uterine
      cervical neoplasias, including cervical intraepithelial neoplasia (CIN),
      microinvasive carcinoma (MIC), and invasive squamous cell carcinoma (ISCC)
      categories, in relation to cell proliferation and human papilloma virus (HPV)
      infection. METHODS: Forty six cases of CIN I/II, 75 of CIN III, 16 of MIC, and 44
      of ISCC were examined using formalin fixed and paraffin wax embedded samples. The
      TdT mediated dUTP-biotin nick end labelling (TUNEL) method for detection of
      apoptotic cells was performed along with Ki-67 immunohistochemistry. Presence of
      HPV-DNA was confirmed by PCR-RFLP assay. RESULTS: Apoptotic labelling indices,
      calculated after counting positive nuclei among at least 2000 nuclei, showed
      significant positive correlation with histological malignant grading in CIN and
      tumour cell invasion into stroma. In contrast, similar Ki-67 labelling index
      values were found in CIN, MIC, and ISCC. Although HPV-DNA was detected in 35/46
      CIN I/II (76.1%), 53/74CIN III (71.6%), 9/16 MIC (56.3%), and 36/44 ISCC (81.8%),
      there was no apparent relation with the apoptotic labelling indices. CONCLUSIONS:
      Apoptosis in cervical neoplasias may be closely related to tumour cell
      differentiation and progression. It also seems unlikely that HPV itself is
      directly related to pathways regulating apoptosis.

PMID- 8655680
TI  - Neuroendocrine differentiation in cervical carcinoma.
AB  - AIMS: To examine neuroendocrine differentiation, as shown by chromogranin A (CGA)
      expression, in cervical carcinomas. METHODS: Sixty seven cervical carcinomas were
      studied and were classified as adenocarcinomas, adenosquamous carcinomas or
      squamous cell carcinomas based on the assessment of haematoxylin and eosin
      staining and stains for mucin. Where features of glandular differentiation were
      identified, sections were also stained for evidence of intestinal type mucin. CGA
      immunostaining was done and the results were graded on a three point scale: 0, +
      (1-5% of cells positive) and ++ (> 5% of cells positive). These findings were
      then analysed with respect to lymph node status, tumour differentiation and
      clinical outcome. RESULTS: There were 32 adenocarcinomas, 18 adenosquamous
      carcinomas and 17 squamous cell carcinomas. Positive staining was seen in 14
      (20.9%) cases, of which four were strongly positive. All but one case were either
      adenocarcinomas or adenosquamous carcinomas. There was a trend for CGA positivity
      to be related to intestinal differentiation but this failed to reach statistical
      significance. No correlation could be demonstrated between CGA staining and lymph
      node status, tumour differentiation and clinical outcome. CONCLUSIONS:
      Neuroendocrine differentiation is common in cervical carcinomas where there is
      evidence of glandular differentiation. Whilst the numbers in this study are
      relatively small, the presence of neuroendocrine cells in otherwise typical
      carcinomas does not seem to have any association with clinical behaviour.

PMID- 8655681
TI  - Value of quantitative pathological variables as prognostic factors in advanced
      ovarian carcinoma.
AB  - AIMS: To evaluate correlations among clinical, pathological, morphometric,
      stereological, and DNA flow cytometric variables and their prognostic value in
      advanced ovarian cancer. METHODS: Tissue was collected from 180 patients with
      advanced ovarian cancer. All 180 had undergone debulking surgery and were being
      treated with cisplatin. Long term follow up was available for all patients. The
      mitotic activity index (MAI), volume % of epithelium (VPE), mean nuclear area
      (MNA), standard deviation of the nuclear area (SDNA), estimates of volume
      weighted mean nuclear volume (nu v), and variables obtained from minimum spanning
      tree (MST) analysis were assessed in the least differentiated tumour section in
      each case. DNA flow cytometry was also performed. RESULTS: Quantitative
      pathological features differed significantly with respect to histological grade.
      The MAI, MNA, SDNA, and the number of points connected to three neighbours
      differed significantly among the different DNA ploidy groups. The VPE and number
      of points connected to two or three neighbours differed significantly between
      FIGO stages III and IV. Fifty two (29%) patients survived. FIGO stage, residual
      disease and SDNA had prognostic significance on both univariate and multivariate
      survival analysis. In patients with FIGO III stage disease and residual tumour
      nodes < or = 2 cm in diameter (67 patients, 29 (43%) survivors) a prognostic
      index was established based on SDNA and of the line length of the MST. The median
      survival time was not reached in a subgroup of patients with favourable prognosis
      (overall survival 57%). Median survival was 32 months for patients with an
      unfavourable index score (overall survival 28%). CONCLUSION: Morphometric
      variables have important additional value in predicting prognosis in patients
      with advanced ovarian cancer.

PMID- 8655682
TI  - Pathology of deaths associated with "ecstasy" and "eve" misuse.
AB  - AIMS: To study the postmortem pathology associated with ring substituted
      amphetamine (amphetamine derivatives) misuse. METHODS: The postmortem findings in
      deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl
      amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve)
      were studied in seven young white men aged between 20 and 25 years. RESULTS:
      Striking changes were identified in the liver, which varied from foci of
      individual cell necrosis to centrilobular necrosis. In one case there was massive
      hepatic necrosis. Changes consistent with catecholamine induced myocardial damage
      were seen in five cases. In the brain perivascular haemorrhagic and hypoxic
      changes were identified in four cases. Overall, the changes in four cases were
      the same as those reported in heart stroke, although only two cases had a
      documented history of hyperthermia. Of these four cases, all had changes in their
      liver, three had changes in their brains, and three in their heart. Of the other
      three cases, one man died of fulminant liver failure, one of water intoxication
      and one probably from a cardiac arrhythmia associated with myocardial fibrosis.
      CONCLUSIONS: These data suggest that there is more than one mechanism of damage
      in ring substituted amphetamine misuse, injury being caused by hyperthermia in
      some cases, but with ring substituted amphetamines also possibly having a toxic
      effect on the liver and other organs in the absence of hyperthermia.

PMID- 8655684
TI  - Comparison of histological and biochemical hepatic iron indexes in the diagnosis
      of genetic haemochromatosis.
AB  - AIMS: To compare a histological hepatic iron index with a biochemical hepatic
      iron index, derived from atomic absorption spectroscopy measurements of hepatic
      iron content, for the diagnosis of genetic haemochromatosis (GH). METHODS:
      Histological sections of liver biopsy specimens from 70 subjects, who had
      previously had their biochemical hepatic iron index measured, were examined. The
      iron stores were scored to derive a histological hepatic iron index and were also
      graded from 0 to 4 by a standard grading system. The case history of each patient
      was then reviewed to establish a definitive clinical diagnosis and patients were
      classified as GH, non-GH or indeterminate. RESULTS: There were 26 cases of GH, 40
      cases of non-GH and four indeterminate cases in whom a definite clinical
      diagnosis was not established. Using a biochemical hepatic iron index cut off
      level of 2.0, two cases were misclassified, with one case of GH having a
      biochemical hepatic iron index of 1.8 and one non-GH case having a biochemical
      hepatic iron index of 3.1. This could not have been improved by altering the cut
      off level. Using the recommended cut off level of 0.15, the histological hepatic
      iron index was raised in all cases of GH, but was also increased in 11 of the 40
      non-GH patients. The specificity of this histological index can be improved by
      increasing the cut off level to 0.30. A histological iron grade of > or = 3 is
      more specific than the histological index but has a lower sensitivity, which
      particularly affects the diagnosis of younger patients with GH. CONCLUSIONS: The
      biochemical hepatic iron index is a reliable method for establishing a diagnosis
      of homozygous GH. In contrast, the histological hepatic iron index as originally
      described is non-specific and does not reliably distinguish patients with GH from
      others with a raised hepatic iron index due to other causes. The specificity of
      this index can be improved by increasing the cut off level used, but the
      discrimination provided by the histological index is still inferior to that
      provided by the biochemical hepatic iron index.

PMID- 8655683
TI  - Expression of TIA-1 and TIA-2 in T cell malignancies and T cell lymphocytosis.
AB  - OBJECTIVE: To investigate the reactivity with TIA-1 and TIA-2, two monoclonal
      antibodies that recognise, respectively, granular structures in T lymphocytes and
      the T cell receptor chain in cells from a variety of T cell disorders. METHODS:
      Cytoplasmic staining with TIA-1 and TIA-2 was carried out by the immunoalkaline
      phosphatase anti-alkaline phosphatase technique in 67 cases with a T cell
      disorder: 31 large granular lymphocyte (LGL) leukaemia, nine T-prolymphocytic
      leukaemia (T-PLL), five Sezary syndrome, four peripheral T cell lymphoma (PTCL),
      13 T cell lymphocytosis, and five T-acute lymphoblastic leukaemia (T-ALL). All
      had over 75% abnormal T cells which were CD2+, CD3+, CD5+, CD7+, and negative
      with B cell markers. RESULTS: TIA-1 was positive in 77% cases of LGL leukaemia
      and half of the PTCL and T-ALL, whereas it was negative in all Sezary syndrome
      and most T-PLL (8/9) and reactive T-lymphocytosis (10/13). In LGL leukaemia, TIA
      1 was positive irrespective of the membrane phenotype, whether CD8+, CD4- or
      CD4+, CD8-, and was more often positive in cases where cells were CD16+, CD56+,
      or CD57+. TIA-2 was positive in 60% of cases encompassing all diagnostic types of
      T cell disorder. There was no correlation between TIA-2 expression and that of
      other T cell markers, activation antigens, and natural killer markers.
      CONCLUSIONS: The pattern of TIA-1 expression in T cell malignancies may help in
      the differential diagnosis among LGL leukaemia (high expression), T cell
      lymphocytosis and other T cell diseases (low expression). As TIA-2 is expressed
      in over 95% mature T lymphocytes and thymic cells, its assessment may be useful
      to demonstrate aberrant phenotypes which can be exploited for detecting minimal
      residual disease.

PMID- 8655685
TI  - Inflammatory pseudotumour of the mouth and maxilla.
AB  - AIM: To describe the clinicopathological and immunophenotypical findings of two
      cases of inflammatory pseudotumour in the oral cavity. METHODS AND RESULTS: The
      patients presented with a short history of swelling in the cheek and the maxilla
      respectively. Magnetic resonance imaging or computerised tomography scan showed
      space occupying lesions with infiltrative margins which were interpreted as
      aggressive malignant neoplasms. Histological examination showed fascicles of
      spindle cells in a background of chronic reactive inflammatory cells including
      plasma cells, typical of inflammatory pseudotumour. The spindle cells were
      positive for vimentin, smooth muscle actin and CD68, but were negative for
      follicular dendritic cell markers. The lymphocytes showed no light chain
      restriction. CONCLUSIONS: Inflammatory pseudotumour in the oral cavity is
      completely benign and simple excision is curative. However, it may be confused
      with a malignant tumour on clinical and radiographic grounds, and histologically
      the appearances can also be misinterpreted as those of a more aggressive lesion.
      Its correct recognition by the surgical pathologist is important to avoid
      unnecessarily radical and potentially mutilating surgery.

PMID- 8655686
TI  - Blood ferritin concentrations in newborn infants and the sudden infant death
      syndrome.
AB  - Liver iron concentrations have been shown to be higher in victims of SIDS than in
      postmortem controls suggesting that high levels of tissue iron may be implicated
      in SIDS. To determine whether infants who subsequently die from SIDS are born
      with greater iron stores than those who do not, the iron stores in newborn
      infants were assessed retrospectively by measuring blood ferritin concentration
      in spots from Guthrie cards (collected from almost all infants born in the UK in
      the first week of life). A method for extracting and measuring ferritin from
      stored blood spots is described. Eighteen cases of SIDS were identified in South
      Glamorgan along with four controls for each case. Ferritin concentrations did not
      differ in SIDS victims and controls suggesting that victims of SIDS are not born
      with abnormal concentrations of stored iron. If iron stores are found to be
      higher in SIDS victims than in healthy live infants of the same age then it is
      more likely that the iron will have been acquired after birth.

PMID- 8655687
TI  - Sleeping position and upper airways bacterial flora: relevance to cot death.
AB  - The hypothesis that the prone sleeping position is associated with accumulation
      of upper airways secretions and increased bacterial growth was investigated in
      adults. Ten subjects with upper respiratory tract infection lay prone for one
      hour and then supine for one hour. Nasal swabs after the prone period yielded
      higher bacterial counts than swabs obtained after the supine period. This result
      could be relevant to sudden infant death syndrome (SIDS), as infants who sleep in
      the prone position are at increased risk of SIDS and one theory is that death is
      caused by toxins produced by bacterial overgrowth in the upper respiratory tract
      following a viral infection.

PMID- 8655689
TI  - Gastroenteritis caused by Aeromonas trota in a child.
AB  - A case of acute diarrhoea caused by Aeromonas trota (formerly HG 13 group) in a
      Spanish child is reported. The strain was isolated in the faeces using the CIN
      agar (cefsulodin-irgasan-novobiocin) culture media. The strain was initially
      identified as A sobria by the commercial GNI card and API 20E biochemical
      systems. The strain was, however, VogesProskauer and sucrose negative, so
      complementary tests of cellobiose fermentation and gluconate oxidation were
      performed. These tests, together with the strain susceptibility to ampicillin
      (MIC 1 microgram/ml) and carbenicillin (MIC < 16 micrograms/ml) led to the final
      identification of A trota. The microbiological characteristics of this new
      species and the principal tests required for its identification are presented.
      The isolation, for the first time, of A trota in the Mediterranean area confirms
      the suspected worldwide distribution of this species.

PMID- 8655688
TI  - Nosocomial empyema caused by Clostridium difficile.
AB  - Pleural infection with Clostridium difficile is extremely rare. A case of
      nosocomial empyema following chest drain insertion in a 46 year old man is
      described. The potential of C difficile to cause extra-intestinal infections
      should be recognised and its isolation from other sites should not be ignored.

PMID- 8655690
TI  - Helicobacter pylori infection in patients with Barrett's oesophagus: a
      prospective immunohistochemical study.
AB  - The prevalence of Helicobacter pylori infection in patients with Barrett's
      oesophagus was studied prospectively. A sensitive immunohistochemical staining of
      H pylori was performed in oesophageal and gastric biopsies of 73 patients from a
      surveillance group with this condition. H pylori was detected in 11 cases of
      Barrett's mucosa (15%) and in 26 gastric mucosa specimens (35.6%). All cases
      positive in Barrett's mucosa were also positive in the stomach. In Barrett's
      oesophagus, H pylori was never found on specialised epithelium. The percentage of
      Barrett's mucosa showing inflammatory changes was similar in specimens with and
      without H pylori, both for chronic (81% v 79%) and acute (9% v 10%) infiltrates.
      These results indicate that H pylori infection does not play an aetiological role
      in Barrett's oesophagus and that colonisation of the metaplastic mucosa by this
      bacteria is related with the presence of gastric type mucosa in the oesophagus
      and of H pylori infection in the stomach.

PMID- 8655691
TI  - Use of buffered formaldehyde in the enzymatic digestion of inflamed mucosa.
AB  - Mucosal inflammation is associated with altered expression of cell membrane
      molecules. Disaggregation of tissue for flow cytometry may introduce artefactual
      changes. In an attempt to prevent the induction of artefacts, cells were fixed
      prior to isolation. The addition of 0.1% buffered formaldehyde to the
      collagenase/dispase digestion of mucosal biopsy specimens from patients with
      inflammatory bowel disease enhances detection of CD3, CD11b, CD16, CD63, and
      CD14. No significant effect was noted for CD19, CD67 or CD45. The expression of
      CD3, CD11b and CD45 correlated with the degree of endoscopic inflammation. Dilute
      buffered formaldehyde may be a useful adjunct to the enzymatic isolation of cells
      from mucosal specimens, by protecting surface antigens from digestion or
      alterations in expression.

PMID- 8655692
TI  - The absence of a B allele in acquired B blood group phenotype confirmed by a DNA
      based genotyping method.
AB  - A case of an 87 year old woman with carcinomatous sigmoid colon, found to be of
      group A1 with acquired B status, is reported. The acquired B phenotype was
      confirmed by the absence of a B allele in the patient using denaturing gradient
      gel electrophoresis of a DNA fragment amplified from the ABO locus by the
      polymerase chain reaction.

PMID- 8655693
TI  - POEMS syndrome and Waldenstrom's macroglobulinaemia.
AB  - A 58 year old man presented with a three year history of impotence, night sweats
      and ankle swelling. On examination, the patient fulfilled the diagnostic criteria
      for POEMS syndrome, but was unusual in that he also had underlying Waldenstrom's
      macroglobulinaemia with IgM kappa paraproteinaemia. The patient was treated with
      intermittent chlorambucil and made a good recovery. POEMS syndrome has been
      described in association with osteosclerotic myeloma and Castleman's disease. The
      paraprotein involved is usually IgG or IgA with lambda light chains. This case
      indicates that the presence of lambda light chains is not essential for the
      pathogenesis of POEMS syndrome. It also emphasises the diversity of plasma cell
      dyscrasias that can manifest as POEMS syndrome.

PMID- 8655694
TI  - Giant cell hepatitis associated with systemic lupus erythematosus.
AB  - Giant hepatocytes are commonly found in several neonatal and infantile liver
      diseases, but are rarely found in adult liver disease. A 42 year old white woman
      presented with a five month history of paraesthesia and numbness of both the
      upper and lower limbs and with vague abdominal pain. Abnormal liver function was
      noted on routine screening. Ultrasound scan of the abdomen showed gallstones;
      barium enema, ERCP and computed tomography scan were all normal. IgG antibodies
      to double stranded DNA were present at a titre of 40 units. Anti-cardiolipin
      antibodies, anti-mitochondrial antibodies and rheumatoid factor were not
      detected. Serology for hepatitis A, B, C, and paramyxoviruses was negative, as
      was the Paul Bunnell test. A clinical diagnosis of systemic lupus erythematosus
      (SLE) with an axonal sensory polyneuropathy was made, the latter confirmed on
      biopsy of the sural nerve. Giant cells were noted on liver biopsy. The patient
      was treated with corticosteroids; liver function had improved after two years of
      follow up. When extensive giant cell transformation is noted on liver biopsy,
      particularly when neuropathy is also a feature, the possibility of an association
      with SLE should be considered.

PMID- 8655695
TI  - Chaetomium pneumonia in patient with acute myeloid leukaemia.
AB  - A patient with relapsed refractory acute myeloid leukaemia developed typical
      fungal lung lesions despite intravenous amphotericin B prophylaxis. Chaetomium
      globosum was cultured from the resected right lower lobe. Histology showed
      branching hyphae negative for common Aspergillus species by immunohistochemical
      staining. Previous reports of invasive disease caused by Chaetomium and some
      applications of immunohistochemical staining for Aspergillus are discussed.

PMID- 8655696
TI  - ACP Broadsheet No 145--Investigation of patients with autoimmune haemolytic
      anaemia and provision of blood for transfusion.

PMID- 8655697
TI  - Macroscopic examination of prostatic specimens.

PMID- 8655698
TI  - Mycological techniques.

PMID- 8655699
TI  - Recommendations for reference method for haemoglobinometry in human blood (ICSH
      standard 1995) and specifications for international haemiglobinocyanide standard
      (4th edition).

PMID- 8655700
TI  - Stability of haemiglobincyanide standards.

PMID- 8655701
TI  - Lipid screening in an elderly population: difficulty in interpretation and in
      detection of occult metabolic disease.
AB  - AIMS: To determine lipid profiles and associations with other metabolic disease
      in a representative British elderly population. METHODS: Part of a prevalence
      survey of dementia in all 75+ year olds conducted from the large general practice
      serving the town and surrounding area of Melton Mowbray, Leicestershire (the M
      old study). Patients (n = 224) aged from 75 to 98 years, and representative of
      the overall population, also provided pre-prandial blood samples on which various
      age and nutrition related analytes were determined. These included documented
      medical history, thyroid stimulating hormone (TSH), glucose, immunoglobulins, and
      lipid profile in plasma. RESULTS: Cholesterol and lipid variables showed wide
      scatter, with some negative trends but no significant associations with age for
      total cholesterol, high density lipoprotein (HDL) cholesterol, the ratio of total
      to HDL cholesterol or triglycerides. Women had significantly higher
      concentrations of total and HDL cholesterol at all ages. Serum TSH was above 6.0
      mU/1 in 10/205 patients, random glucose was above 11.2 mmol/l in nine of 207
      patients, borderline dysglobulinaemia was present in four of 210 patients, all
      without correlation with cholesterol concentrations. CONCLUSION: This British
      data is consistent with an inverse correlation between survival and cholesterol,
      but wide scatter restricts reliance on single result lipid data in individual
      patient management. Random lipid screening is also unhelpful, inefficient and
      without added value in revealing other age related and unrecognised occult
      metabolic disease.

PMID- 8655702
TI  - Seasonal differences in biochemical parameters of bone remodelling.
AB  - AIMS: To compare bone remodelling parameters in late autumn and early spring in
      20 post-menopausal women. METHODS: The parameters measured were serum osteocalcin
      and its apparent degree of carboxylation (measured by hydroxyapatite binding),
      total and bone specific alkaline phosphatase and urinary bone resorption markers,
      (pyridinoline and deoxypyridinoline). RESULTS: Serum osteocalcin concentrations
      were lower in autumn than in spring but the degree of carboxylation was similar.
      Total and bone specific alkaline phosphatase activities in serum were higher in
      autumn than in spring. These results support previous observations. However,
      notable and previously unreported changes in urinary bone resorption markers were
      observed. Pyridinoline concentrations were lower and deoxypyridinoline higher in
      autumn compared with spring. The ratio of pyridinoline:deoxypyridinoline was
      therefore very different between the seasons. CONCLUSIONS: The results clearly
      demonstrate that seasonal changes in these variables of bone remodelling must be
      taken into consideration when designing, reporting or analysing studies of bone
      metabolism in vivo.

PMID- 8655703
TI  - Single-tube nested PCR in the diagnosis of tuberculosis.
AB  - AIMS: To evaluate the usefulness of a single-tube nested polymerase chain
      reaction (PCR) assay in the diagnosis of tuberculosis in 1497 pulmonary and 536
      extrapulmonary specimens. METHODS: A single-tube nested PCR, utilising two sets
      of primers with different melting temperatures (88 degrees C for external
      primers; 70 degrees C for internal primers) to augment sensitivity and
      specificity without increasing the risk of amplicon contamination, was evaluated.
      Specimens were initially tested for the repetitive IS6110 sequences and if
      negative, retested for the universal 38 kilodalton sequence and for inhibitors.
      dUTP/Uracil-N-glycosylase and Instagene treatment were used to minimise
      contamination and the effect of inhibitors, respectively. RESULTS: Using culture
      as the gold standard, the overall sensitivity of the assay was 89% for pulmonary
      and 42% for extrapulmonary specimens. Sensitivity varied greatly with respect to
      sample type (92% for follow up specimens from a chest hospital and 70% for non
      follow up specimens from a general hospital). The smear positivity rates were 15%
      for extrapulmonary specimens, and 69% and 45%, respectively, for follow up and
      non-follow up specimens from pulmonary sites. Specificity was 99.7%. Inhibitors
      were present more frequently in extrapulmonary than in pulmonary specimens (13.4%
      v 2.7%). CONCLUSION: Despite the high sensitivity of the PCR assay for the
      diagnosis of tuberculosis in pulmonary specimens, it was less effective in the
      extrapulmonary samples. This is probably because of the lower bacterial load in
      extrapulmonary specimens, the presence of more inhibitors adversely affecting the
      PCR assay and the higher volume of specimens used for culture.

PMID- 8655704
TI  - Use of specific ELISA for the detection of antibodies directed against p53
      protein in patients with hepatocellular carcinoma.
AB  - AIMS: To analyse the significance of antibodies to p53 protein as a serological
      marker for changes in p53 gene expression in patients with hepatocellular
      carcinoma. METHODS: Thirty eight patients with hepatocellular carcinoma, 19
      showing accumulation of p53 protein by immunohistochemistry and 19 having no
      accumulation, were studied. The presence of anti-p53 was tested using a novel
      ELISA utilising a recombinant p53 protein as a capture system and verified by
      western blotting. p53 gene mutations were sought by single strand conformational
      polymorphism and DNA sequencing analyses. RESULTS: Of 19 patients with p53
      protein accumulation in tumour tissue, 10 (52%) had antibodies to p53 in serum by
      ELISA. Four patients with p53 negative immunohistochemistry also had detectable
      anti-p53. Western blot analysis confirmed the specificity of the ELISA positive
      serum samples. The presence of anti-p53 was independent of serum alpha
      fetoprotein and was detected in 50% of small tumours while only 8% were alpha
      fetoprotein positive. Mutations affecting exons 5 and 6 seem to be more
      frequently associated with development of anti-p53, than mutations in exons 7 or
      8. CONCLUSIONS: The ELISA for anti-p53 is a convenient and specific tet for the
      detection of humoral response to alterations in p53 gene expression and could be
      of value in the diagnosis and characterisation of patients with hepatocellular
      carcinoma.

PMID- 8655705
TI  - Detection of exfoliated carcinoma cells in colonic luminal washings by
      identification of deranged patterns of expression of the CD44 gene.
AB  - AIMS: To investigate whether colonic cancer cells exfoliated into the lumen of
      the organ can be detected by identification of their abnormal CD44 gene products.
      METHODS: Exfoliated cells were obtained by centrifugation of saline wash-outs of
      27 surgically resected colon specimens obtained from 15 patients with carcinoma,
      seven with ulcerative colitis and five with Crohn's disease. After extracting
      cellular mRNA, amplification by the reverse transcription-polymerase chain
      reaction (RT-PCR) technique and analysis by Southern blot hybridisation was
      carried out to examine the levels and patterns of transcription of exons 11(v6),
      and 12(v7) and intron 9 of the CD44 gene. The transcription of these CD44
      components was also examined by RT-PCR of snap-frozen solid tissue specimens from
      11 of the above patients with colorectal carcinoma, seven with ulcerative colitis
      and five with Crohn's disease. RESULTS: Abnormal expression of exons 11(v6) and
      12(v7) was detected in exfoliated cells from 11 (73%) of 15 patients with
      carcinoma, but not in any patients with inflammatory bowel disease (IBD). The
      retention of intron 9 in CD44 mRNA transcripts was detected in washings from four
      (27%) carcinoma specimens but not in washings from non-malignant specimens. It
      was confirmed that in solid tissue samples from the same carcinomas there was
      abnormal over-expression of numerous alternatively spliced CD44 species
      containing transcripts of exons 11 and 12 and retention of intron 9. Low level
      expression of these exons was detected in tissue from inflammatory lesions from
      five of seven patients with ulcerative colitis and four of five with Crohn's
      disease. The retention of intron 9 was not seen in normal mucosa nor IBD.
      CONCLUSION: Abnormal expression of the variant exons and of intron 9 of the CD44
      gene in tumour cells exfoliated into the colonic lumen may be helpful markers for
      the early, non-invasive, diagnosis of colorectal cancer.

PMID- 8655706
TI  - Herpes virus-like sequences are specifically found in Kaposi sarcoma lesions.
AB  - AIM: To detect the prevalence of herpes virus-like DNA sequences in AIDS
      associated Kaposi sarcoma (KSHV) lesions and normal tissue. METHODS: KSHV
      detection was performed by polymerase chain reaction (PCR) using four different
      sets of primers. PCR products were cloned, sequenced, and analysed. RESULTS: All
      of four biopsies of Kaposi sarcoma lesions and all of three paraffin embedded
      Kaposi sarcoma tissues were positive for KSHV, while normal tissue from the same
      patients was negative. Sequence analysis of amplification products revealed
      polymorphisms that result in amino acid changes of the predicted sequence.
      CONCLUSIONS: KSHV is prevalent in tissues from Kaposi sarcoma, suggesting a role
      in the development of the tumour. On this basis, anti-herpes virus agents should
      be considered to control Kaposi sarcoma.

PMID- 8655708
TI  - Aneurysmal and haemangiopericytoma-like fibrous histiocytoma.
AB  - AIM: To describe the clinicopathological features of 33 aneurysmal fibrous
      histiocytomas (AFH), including five cases with a haemangiopericytoma-like
      pattern. METHODS: Thirty three cases of AFH were studied by using routine
      histology and immunohistochemistry for factor XIIIa, the "cell activity marker"
      E9 (anti-metallothionein), NK1C3 (CD57), smooth muscle actin (SMA), factor VIII,
      ulex europaeus agglutinin, JC70A (CD31), and QBEND10 (CD34). The time dependent
      variation in histopathological features was evaluated by statistical methods
      (Pearson chi 2, likelihood ratio chi 2). RESULTS: Of the AFHs, 29 of 33 occurred
      on the extremities of adults (age range 30 to 50 years), six of which were
      associated with rapid growth, probably caused by trauma, and pain. Twenty one
      lesions were thought to be vascular and/or melanocytic lesions, including two
      melanomas, because of a bluish-black and/or cystic appearance. Histologically,
      large areas of haemorrhage, up to 50% of the tumour bulk, lacking an endothelial
      lining were seen in otherwise typical fibrous histiocytomas. Five cases resembled
      nodular stages of Kaposi's sarcoma. Variable haemosiderin deposition in
      histiocytes (18/33) and giant cells (11/33) was suggestive of haemosiderotic
      histiocytoma. A haemangiopericytoma-like pattern was seen in five otherwise
      indistinguishable cases. On immunohistochemistry, variable reactivity was seen
      for factor XIIIa (18/30), with E9 (18/30), NK1C3 (19/30), and for SMA (14/30),
      but labelling for vascular markers was not detected. Early lesions without iron
      deposition were factor XIIIa positive; late lesions with iron deposition were
      factor XIIIa negative. Labelling for SMA correlated with prominent sclerosis.
      CONCLUSION: AFHs, including a haemangiopericytoma-like variant, have a
      characteristic time dependent histological and immunophenotypic profile, clearly
      different from nodular type Kaposi's sarcoma.

PMID- 8655707
TI  - Parietal cells in the duodenal bulb and their relation to Helicobacter pylori
      infection.
AB  - AIM: To investigate the prevalence, and relation to Helicobacter pylori, of
      parietal cells in the duodenal bulb using a monoclonal antibody directed against
      H+,K(+)-ATPase (HK12.18). METHODS: Twenty six patients with duodenal ulcer
      disease and 16 healthy controls were studied. H pylori status was determined by
      gastric histology and culture and by the 13C-urea breath test. Four biopsy
      specimens were taken from the duodenal bulb and stained with HK12.18. The
      presence/absence and number of parietal cells in the duodenal bulb were assessed
      blindly by a histopathologist. RESULTS: The overall prevalence of parietal cells
      in the duodenal bulb was 31% (13/42) and was similar in patients with duodenal
      ulcer and in controls, and in H pylori positive and negative subjects. The median
      (range) number of parietal cells in the duodenal bulb was 7.5 (4-20) parietal
      cells/subject, and was similar in all four groups. CONCLUSIONS: The prevalence of
      parietal cells in the duodenal bulb (31%) is notably higher than previously
      reported in endoscopic studies, and is in keeping with reports from studies on
      necropsy/operative specimens. There was no difference in the prevalence or number
      of parietal cells in the duodenal bulb between patients with duodenal ulcer and
      controls, regardless of H pylori status. These findings suggest that parietal
      cells in the duodenal bulb do not contribute to the pathogenesis of duodenal
      ulcer.

PMID- 8655709
TI  - Diagnostic difficulty arising from rectal recovery in ulcerative colitis.
AB  - AIMS: To ascertain whether the dogma that a normal rectal biopsy precludes a
      diagnosis of ulcerative colitis is correct. METHODS: Rectal biopsy specimens from
      a prospective group of 24 asymptomatic patients, with an established diagnosis of
      ulcerative colitis, were examined in a blinded study alongside 10 normal rectal
      biopsy specimens from an age and sex matched patient cohort without ulcerative
      colitis. Each biopsy specimen was assessed by three pathologists and ascribed to
      one of four categories: normal; borderline abnormality (one or more minor
      nonspecific abnormalities which, when combined, did not fulfil the minimal
      acceptable criteria for a diagnosis of ulcerative colitis); minimal features of
      chronic ulcerative colitis; and unequivocal ulcerative colitis. RESULTS: Two
      patients with ulcerative colitis had normal biopsy specimens; nine specimens were
      categorised as borderline abnormality, one as showing the minimal changes of
      chronic ulcerative colitis, and 12 as having the typical changes of chronic
      ulcerative colitis. Thus, 11 (46%) of the 24 patients had a rectal biopsy
      specimen that was devoid of the acceptable attributes on which a diagnosis is
      established, despite a confident previous diagnosis. Ten of these 11 cases had
      disease limited to the rectum. Review of all previous histological biopsy
      specimens (n = 164) and clinical data, including drug treatment, failed to
      identify any attributes that might be prognostic markers for future rectal
      mucosal healing. CONCLUSIONS: A normal rectal biopsy specimen, though uncommon,
      may occur in longstanding colitis. Moreover, in 46% of these asymptomatic but
      established cases the degree of healing may preclude a diagnosis of ulcerative
      colitis without comprehensive clinical and radiological details. Pathologists
      need to be aware of this minimal end of the spectrum of disease.

PMID- 8655710
TI  - Treatment of benign prostatic hyperplasia with 5-alpha-reductase inhibitor:
      morphological changes in patients who fail to respond.
AB  - AIMS: To describe the prostatic adenectomy specimens of six patients with
      symptomatic benign prostatic hyperplasia (BPH) who failed to respond to long term
      treatment with a 5-alpha-reductase inhibitor, finasteride. METHODS: Histological
      sections from six cases of BPH who had been treated with finasteride were
      investigated. Five patients were prescribed 5 mg finasteride daily for six months
      and one patient 5 mg daily for 12 months. The patients underwent adenectomy as
      their urethral obstruction failed to resolve. Twenty cases of untreated BPH
      served as controls. RESULTS: In patients taking finasteride for six months the
      prostatic adenectomy specimens showed a reduction in the size of the prostate and
      an increase in the stroma:epithelial and stroma:lumen ratios compared with
      controls. The size of the ducts and acini was not as uniform as in the controls.
      In particular, some ducts and acini were still lined by a bistratified epithelium
      similar to that found in controls but lacked undulations at the epithelial
      border; other ducts/acini were atrophic. Some scattered clusters of small acini
      with a focally fragmented basal cell layer were observed in two of the five
      treated cases. One prostatic adenectomy specimen, from the patient treated for
      one year, showed extensive lobular atrophy and diffuse squamous and transitional
      cell metaplasia. At the periphery of the transition zone, there was a complex
      intra-acinar papillary-cribriform proliferation of clear cells without nuclear
      atypia, similar to clear cell papillary hyperplasia. The periurethral region
      showed stromal nodules in both patients and controls. CONCLUSIONS: Morphological
      evaluation of finasteride treated BPH showed changes in the lobules of the
      transition zone, but not in the periurethral stroma.

PMID- 8655711
TI  - beta hCG as a prognostic marker in adenocarcinoma of the prostate.
AB  - AIMS: To assess the importance of immunohistological detection of beta-human
      chorionic gonadotrophin (beta hCG) in localised prostatic adenocarcinoma with
      regard to prognosis and clinical applications. METHODS: Eighty consecutive cases
      of clinically localised adenocarcinoma of the prostate were studied
      retrospectively. Immunohistological analysis on formalin fixed, paraffin wax
      embedded prostate tissue from transurethral resections was related to clinical
      outcome and survival. Prognosis was also related to tumour grade. RESULTS: beta
      hCG was detected in 12 cases. Nine of these patients were found to have
      metastases (75%) at follow up and 11 (92%) were dead within 18 months. There was
      no correlation with grade and prognosis in this group. Of the 68 beta hCG
      negative cases, 21 had developed metastases (31%) and 25 (37%) had died within 18
      months. In the beta hCG negative group there was an association between
      histological grade and survival. CONCLUSION: The demonstration of beta hCG in
      prostatic adenocarcinoma identifies a group of patients with poor prognosis,
      irrespective of histological grade. This additional information will be extremely
      valuable in the subsequent clinical management of such patients.

PMID- 8655712
TI  - Diagnosis of lymphoma in paraffin wax sections by nested PCR and
      immunohistochemistry.
AB  - AIMS: To investigate whether nested polymerase chain reaction (PCR) and
      immunohistochemistry can be used to diagnose malignant lymphoma. METHODS:
      Paraffin wax embedded tissue sections from 31 patients with malignant lymphoma
      were analysed by nested PCR and immunohistochemistry using standard protocols.
      RESULTS: Nested PCR amplification of 1 pg DNA confirmed monoclonality in B cell
      lymphoma; PCR amplification of 10 pg DNA confirmed monoclonality in T cell
      lymphoma. Twenty seven (87%) samples were diagnosed as malignant lymphoma by
      nested PCR, and 24 (77%) by immunohistochemistry. Seven samples were diagnosed as
      malignant lymphoma by nested PCR, but not by immunohistochemistry, whereas the
      use of both procedures gave a diagnosis of malignant lymphoma in all 31 samples.
      CONCLUSIONS: A combination of immunohistochemistry and nested PCR can be used to
      diagnose malignant lymphoma in routine paraffin wax embedded sections.

PMID- 8655714
TI  - Hypomagnesaemic tetany.
AB  - Hypomagnesaemic tetany (hypomagnesaemic tetany with secondary hypocalcaemia) is a
      rare inherited form of hypomagnesaemia. Initial reports involved affected males
      only; however, affected females have also been reported. The case of a child with
      hypomagnesaemic tetany is described, the biochemical and genetic aspects of this
      condition are reviewed and the importance of the assessment of renal magnesium
      excretion in patients presenting with hypomagnesaemia is highlighted.

PMID- 8655713
TI  - Cell growth and p53 expression in primary acquired melanosis and conjunctival
      melanoma.
AB  - AIMS: To evaluate cell growth and the pattern of p53 suppressor gene expression
      in atypical primary acquired melanosis (PAM) and in recurrent conjunctival
      melanoma. METHODS: Eighteen specimens of PAM with atypia and 24 specimens,
      comprising early and late lesions, from 12 patients with conjunctival melanoma
      were stained for the proliferating cell nuclear antigen using the PC10 antibody,
      and for the p53 gene product using the BP53-12-1, 1801 and DO7 clones. The
      immunoreactive cells were counted manually and the data evaluated statistically.
      RESULTS: Seven of nine PAM specimens progressing to melanoma expressed PC10. None
      of these lesions expressed the p53 gene product. The number of proliferating
      cells was higher in the late than in the early lesions of conjunctival melanoma.
      Four of the 12 recurrent melanomas displayed focal, but minimal, p53 expression.
      The proliferating cell count in the p53 positive tumours was very similar to that
      of the p53 negative conjunctival melanomas. CONCLUSION: Examination of the
      expression of proliferating cells in atypical PAM may be used as an adjunct to
      predict which lesions will progress to melanoma. The increase in the number of
      proliferating cells over time in recurrent conjunctival melanomas probably
      reflects more aggressive behaviour and may be used to monitor recurrence. The
      absence of p53 expression in PAM and minimal staining of conjunctival melanomas
      did not correlate with cell growth, suggesting that alterations in the p53 tumour
      suppressor gene are uncommon and late events in conjunctival melanoma, and that
      p53 expression is unlikely to be a useful prognostic indicator.

PMID- 8655715
TI  - Necropsy findings in lysinuric protein intolerance.
AB  - Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of
      metabolism, characterised by defective transport of the cationic amino acids
      lysine, arginine and ornithine. To date there are few reported necropsy cases.
      This report describes the necropsy findings in a 21 year old female patient
      originally diagnosed as having LPI in 1973. Liver function tests deteriorated and
      immediately before death jaundice, hyperammonaemia, coma, metabolic acidosis, and
      a severe bleeding diathesis developed. At necropsy, there was micronodular
      cirrhosis of the liver with extensive fatty change in hepatocytes. The lungs
      showed pulmonary alveolar proteinosis. Immunofluorescence and electron microscopy
      revealed the presence of a glomerulonephritis with predominant IgA deposition.
      These necropsy findings reflect the spectrum of lesions reported in LPI,
      providing further evidence of an association between this condition and pulmonary
      alveolar proteinosis, cirrhosis and glomerulonephritis.

PMID- 8655716
TI  - Intimal sarcoma of the right brachiocephalic vein presenting as the superior vena
      caval syndrome.
AB  - A case of an 84 year old man presenting with obstruction of the superior vena
      cava caused by an intimal sarcoma of the right brachiocephalic vein is reported.
      The tumour morphology was similar to intimal sarcomas arising in major arteries,
      a more common primary site, and showed malignant fibrous histiocytoma-like
      features. Immunohistochemistry was suggestive of myofibroblastic differentiation.

PMID- 8655717
TI  - Alpha-fetoprotein production by a malignant mixed mullerian tumour of the uterus.
AB  - A case of alpha-fetoprotein production by a uterine malignant mixed mullerian
      tumour is described. The patient was a 68 year old woman who developed
      intraabdominal recurrence of a stage 1 uterine tumour which had been treated
      surgically seven years previously. Her serum alpha-fetoprotein was raised at
      21,000 micrograms/l (normal < 10 micrograms/l) and staining with immunoperoxidase
      confirmed that the tumour was the site of alpha-fetoprotein production. The
      patient was treated with combination chemotherapy but died two weeks after the
      first course. This is believed to be only the second such case reported.

PMID- 8655718
TI  - An unusual association of Felty syndrome and TCR gamma delta lymphocytosis.
AB  - Felty syndrome, comprised of neutropenia, rheumatoid arthritis and splenomegaly,
      occurs in approximately 1% of patients with rheumatoid arthritis. Up to one third
      of these patients have an increased number of large granular lymphocytes. The
      usual immunophenotype of these cells is CD3+, CD8+, CD57+, T cell receptor (TCR)
      alpha beta. A patient with Felty syndrome and large granular lymphocytosis, who
      had an unusual immunophenotype CD3+, CD4-, CD8-, TCR gamma delta, is described.
      Her neutropenia responded to treatment with granulocyte colony stimulating factor
      (G-CSF), which was given in order to raise her neutrophil count prior to
      bilateral knee replacement surgery. Thus, Felty syndrome with large granular
      lymphocytosis is a heterogeneous condition, one in which TCR gamma delta large
      granular lymphocytosis may be found, and also shows a response to treatment with
      G-CSF.

PMID- 8655719
TI  - Flow cytometry and Kleihauer tests.

PMID- 8655720
TI  - Cutaneous malacoplakia: a report of two cases and review of the literature.
AB  - Malacoplakia, an inflammatory disease characterized by accumulations of
      phagocytic macrophages, occurs primarily in immunocompromised individuals.
      Cutaneous involvement is rare. Two men, each with a renal allograft, had
      expanding nodules on the temple and perianal area (case 1) and perianal,
      inguinal, and scrotal skin (case 2). Lesions resolved after combined surgical and
      antibiotic therapy. Histopathologic examination showed dense infiltration with
      large phagocytic macrophages containing round, concentric, laminar Von Kossa
      stain-positive inclusion bodies. Histiocytes had positive results for CD 68,
      lysozyme, and alpha 1-antitrypsin. Electron microscopic examination demonstrated
      rare intracytoplasmic inclusion bodies with concentric electron-dense laminations
      of calcium (Michaelis-Gutmann bodies.) Cutaneous malacoplakia should be
      considered in the differential diagnosis of nodules or draining ulcers,
      particularly in immunocompromised patients. Because Michaelis-Gutmann bodies are
      difficult to identify, specimens should be evaluated for cutaneous malacoplakia
      by immunohistochemical or electron microscopic means.

PMID- 8655721
TI  - Chronic herpes gestationis and antiphospholipid antibody syndrome successfully
      treated with cyclophosphamide.
AB  - Herpes gestationis shares many features with other bullous diseases, especially
      bullous pemphigoid. Treatments of benefit in bullous pemphigoid may also be
      effective for herpes gestationis. Cyclophosphamide, azathioprine, and other
      immunosuppressive agents have been used successfully in refractory cases of
      bullous pemphigoid. We describe a patient with severe and persistent herpes
      gestationis in the postpartum period and the antiphospholipid antibody syndrome,
      both of which were refractory to high-dose corticosteroid therapy. Treatment with
      pulsed-dose intravenous cyclophosphamide produced an excellent clinical response.

PMID- 8655722
TI  - Multimodal management of diffuse neonatal hemangiomatosis.
AB  - Diffuse neonatal hemangiomatosis is a rare, frequently fatal disorder. We
      describe the case of a neonate with numerous cutaneous and ocular hemangiomas.
      Hepatic hemangiomas were noted at 4 weeks of age, associated with congestive
      heart failure resulting from hepatic arteriovenous shunting. This condition was
      controlled by treatment with prednisone, interferon alfa-2b and hepatic
      embolization. Treatment of cutaneous hemangiomas with the tunable dye laser
      prevented hemorrhage, facilitated routine skin care, and allowed uninhibited
      intravenous access during hospitalization.

PMID- 8655723
TI  - Bacillus piliformis infection (Tyzzer's disease) in a patient infected with HIV
      1: confirmation with 16S ribosomal RNA sequence analysis.
AB  - Bacillus piliformis is a long, rod-shaped bacterium that has never been grown in
      cell-free medium and whose taxonomic classification is uncertain. B. piliformis
      is the causative agent of Tyzzer's disease, which is frequently reported in
      laboratory, wild, and domesticated animals. The spectrum and severity of this
      disease is wide in animals. Although many infections are rapidly fatal,
      subclinical infections are also common. To date, there have been no reports of B.
      piliformis infection in human beings, although elevated antibody levels have been
      reported in pregnant women. We describe the first case of human B. piliformis
      infection, in a man with HIV-1 infection and chronic, localized, crusted
      verrucous lesions. The diagnosis was confirmed by ribosomal RNA sequencing. The
      spectrum of organisms leading to infection and the spectrum of diseases caused by
      these organisms continue to expand, as new infections are identified and as
      patients with HIV-1 live longer with more severe immune suppression. The extreme
      difficulty in culturing B. piliformis and the lack of clinical and
      histopathologic experience with this organism in human beings mean that B.
      piliformis is potentially another infectious agent to be considered in human
      beings. Also, when an infectious organism is a strong clinical consideration,
      silver stains may be of use when results of routine bacterial staining are
      negative.

PMID- 8655724
TI  - Chrysiasis after low-dose gold and UV light exposure.
AB  - We describe a case of chrysiasis in a 54-year-old woman. The diagnosis was
      confirmed by light microscopy, transmission electron microscopy, and radiographic
      microanalysis. The condition developed after a relatively low dose of gold. We
      propose that chrysiasis developed because of the patient's exposure to the
      intense UV light in Australia.

PMID- 8655725
TI  - Extraabdominal desmoid tumor.
AB  - An extraabdominal desmoid tumor of the shoulder occurring in a middle-aged woman
      without Gardner's syndrome is described. Two punch biopsy specimens from the
      tumor were initially interpreted as representing scar tissue; a third incisional
      biopsy specimen demonstrated the characteristic features of a desmoid tumor.
      Because desmoid tumors are locally aggressive, early diagnosis and treatment are
      crucial to minimize morbidity and mortality. Typical clinical and histologic
      findings characteristic of an extraabdominal desmoid tumor are described, and
      treatment options are reviewed.

PMID- 8655726
TI  - Eczematous halo reaction in atypical nevi.
AB  - Meyerson's nevus has been described as a melanocytic nevus with an associated
      eczematous halo reaction. We describe four patients with eczematous halos
      developing around atypical nevi, a finding not previously reported. Biopsy
      specimens revealed eosinophilic spongiosis in addition to the previously reported
      spongiotic dermatitis.

PMID- 8655727
TI  - Possible origin of pancreatic fat necrosis as a septal panniculitis.
AB  - We describe pancreatic subcutaneous fat necrosis in a man with alcoholism and
      pancreatitis. The initial specimen, from a 2-day-old lesion, showed a septal
      inflammatory infiltrate in the subcutis. A second specimen, from a 5-day-old
      lesion, showed the lobular pattern of enzymatic fat necrosis diagnostic for
      pancreatic panniculitis. We suggest that the histologic appearance of
      subcutaneous pancreatic fat necrosis evolves from an early septal reaction to a
      fully developed lobular panniculitis.

PMID- 8655728
TI  - Cutaneous ulcerations and pustular psoriasis flare caused by recombinant
      interferon beta injections in patients with multiple sclerosis.
AB  - Seven patients with multiple sclerosis who were receiving subcutaneous injections
      of recombinant interferon beta had pain followed by ulceration at the injection
      site. An eighth patient had a pustular flare of her usually mild psoriasis. No
      evidence of infection or contaminated medication was found.

PMID- 8655729
TI  - CD7-positive Sezary syndrome with a Th1 cytokine profile.
AB  - Sezary syndrome is a leukemic variant of cutaneous T-cell lymphoma characterized
      by the appearance of numerous CD4+ cells with cerebriform nuclei in the
      peripheral blood. Recent observations have suggested that Sezary cells lack CD7
      molecules on their surface and are analogous to murine Th2 cells. It remains
      unclear, however, whether these two properties are actually common features of
      Sezary cells. We describe a case of Sezary syndrome in which more than 98% of the
      peripheral blood mononuclear cells expressed CD7 as well as a homogeneous T-cell
      receptor V alpha 2V beta 17, indicative of the expression of CD7 in the Sezary
      cells. Although the circulating Sezary cells continuously bore CD7 molecule on
      their surface throughout the patient's clinical course, the intensity of CD7
      expression was variable in skin-infiltrating and in vitro cultured cells.
      Peripheral blood mononuclear cells from the patient proliferated well to a V beta
      17-relevant superantigen (staphylococcal enterotoxin B) but not to irrelevant
      superantigens; produced interleukin-2, interferon gamma, and tumor necrosis
      factor-alpha, but not interleukin-4; and transcribed messenger RNA for
      interleukin-2 and interferon gamma but not interleukin-4 or interleukin-10. This
      represents an unusual case of a CD7+ Sezary syndrome with a cytokine profile
      characteristic of Th1 cells.

PMID- 8655730
TI  - Leukemia cutis: Darier's sign in a neonate with acute lymphoblastic leukemia.
AB  - Infantile leukemia accounts for only 3% of childhood leukemia. Leukemia cutis
      occurs in 25% to 30% of infants with congenital leukemia and is more frequently
      associated with acute myeloid leukemia than with acute lymphoblastic leukemia. We
      describe an infant in whom hyperpigmented macules that developed when the patient
      was 2 weeks old demonstrated Darier's sign when he was 4 weeks old. Acute
      lymphoblastic leukemia, early pre-B-cell type, was diagnosed when the patient was
      10 weeks old. Examination at that age revealed 1 to 2 cm, firm, mildly tender
      nodules clustered on the scalp, face, and extremities, less severe involvement of
      the trunk, and marked induration of the face and eyelids. Darier's sign was
      elicited from the less infiltrated truncal lesions. Histologic examination
      revealed a dense monomorphous infiltrate consisting of pleomorphic,
      undifferentiated cells. No mast cells were revealed by Giemsa staining. This case
      is to our knowledge the first reported example of leukemia cutis demonstrating
      Darier's sign.

PMID- 8655731
TI  - Ichthyosiform dermatosis with superficial blister formation and peeling: evidence
      for a desmosomal anomaly and altered epidermal vitamin A metabolism.
AB  - We describe a man with generalized congenital ichthyosiform dermatosis, severe
      cheilitis, and palmar and plantar hyperkeratosis with superficial blistering. Low
      dose acitretin therapy induced areas of peeling skin, similar to that seen in the
      peeling skin syndrome. Histologically, the skin was moderately hyperkeratotic and
      the palmar blisters were subcorneal. Electron microscopy revealed that the
      splitting occurred within the desmosomal plaque. Ultrastructural and biochemical
      investigations indicated epidermal hypervitaminosis A, probably related to
      alteration of epidermal retinoic acid metabolism. This disease is proposed as a
      hitherto unreported variant of the peeling skin syndrome.

PMID- 8655732
TI  - Primary plasmacytoma of the skin.
AB  - Primary plasmacytoma of the skin without evidence of bone marrow plasmacytosis is
      a rare disorder belonging to the heterogenous spectrum of plasma cell neoplasms.
      With immunohistochemical techniques, differentiation from benign plasma cell
      aggregates can be accomplished by demonstrating the monoclonality of tumor cells.
      We describe a patient in whom a solitary primary cutaneous plasmacytoma developed
      on the left thigh. Immunohistochemically, plasma cells showed restriction of
      immunoglobulin lambda-chain expression. Underlying multiple myeloma was excluded
      by serum protein and immunoglobulin electrophoresis, roentgenographic skeletal
      survey, and bone marrow biopsy. The tumor responded well to local electron-beam
      radiotherapy. Whereas multiple primary cutaneous plasmacytomas seem to carry a
      significant early mortality rate, the prognosis of solitary lesions is likely to
      be more favorable.

PMID- 8655733
TI  - Vesicle formation in dermatomyositis associated with gynecologic malignancies.
AB  - Vesicle formation in dermatomyositis is rare. We describe two women with
      dermatomyositis and vesicle formation on their extremities. Both had an ovarian
      cancer and histologic examinations revealing subepidermal vesicles. In both
      patients, direct immunofluorescence did not reveal deposition of immunoglobulin
      in the basement membrane zone. Of our two patients and the 17 previously reported
      to have dermatomyositis with vesicle formation, 10 had an internal malignant
      disease. Of these 10 patients, eight women had gynecologic malignant disease and
      two men had gastric cancer and lung cancer, respectively. Vesicle formation in
      dermatomyositis is strongly related to the presence of an internal malignant
      process, especially gynecologic malignant disease in female patients.

PMID- 8655734
TI  - Milkability of Murciano-Granadina dairy goats. Milk partitioning and flow rate
      during machine milking according to parity, prolificacy and mode of suckling.
AB  - A total of 78 lactations (25 primiparous and 53 multiparous) in a herd of
      Murciano-Granadina dairy goats were studied over 3 years. Animals were allocated
      to two experimental groups: suckling (S) goats were milked once daily until
      weaning (week 7) and thereafter twice daily; milking (M) goats were milked twice
      daily from 2 d after parturition. Milk partitioning during milking (machine and
      machine stripping milk fractions) was recorded every week and the residual milk
      every 2 weeks. Milk flow rate was studied in 63 lactations on three consecutive
      days during week 12 or 13. Average machine and machine stripping milk fractions
      over 210 d were 1.09 and 0.23 l/d for the S and 1.23 and 0.28 l/d for the M group
      respectively. Machine milk volume and percentage were smaller in the S group
      during the first 7 weeks of lactation, while the machine stripping fraction was
      unaffected by group, indicating that this fraction was constant. The average
      residual milk was 11.1 and 9.2% of total milk in the S and M groups. Goats in
      their third lactation had the least residual milk (8.9%). Milk flow and total
      machine milk volume (but not milking time) were affected by parity, second and
      third lactation goats having higher values. Positive correlations were found
      between daily milk yield and milk flow characteristics. Residual milk was
      positively correlated with the machine stripping but not with the machine milk
      fraction. The results indicated that Murciano-Granadina goats can readily be
      machine milked, since > 80% of the milk can be obtained without massage or
      stripping.

PMID- 8655735
TI  - Effect of propylene glycol supplementation around parturition on milk yield,
      reproduction performance and some hormonal and metabolic characteristics in dairy
      cows.
AB  - Thirty-nine multiparous Holstein cows were used to measure the effect of
      propylene glycol treatment around parturition on milk yield, reproductive
      efficiency and some hormone and metabolite concentrations. Cows were assigned
      randomly to control (n = 19) or propylene glycol treated (n = 20) groups.
      Propylene glycol (300 g) was administered directly mixed with the diet from day
      10 prior to the expected calving date until parturition (day 0) and orally after
      dilution in 1 l water on days 3, 6, 9 and 12. Blood samples were collected on
      days -20, -5, 0, 3, 10, 25 and 50 while milk samples were taken weekly until 13
      weeks post partum. Body condition scores, recorded on days -20, 15 and 50, were
      not affected by propylene glycol administration. Propylene glycol did not
      significantly affect milk yield or composition but linear somatic cell score
      measured from the first 13 weeks post partum was reduced by propylene glycol
      administration (P < 0.01). Moreover, propylene glycol reduced milk urea (-25
      mg/l, P < 0.05), especially during the first 9 weeks post partum. Plasma insulin
      concentrations were similar in both groups during the experiment while insulin
      like growth factor I (P < 0.05) and insulin-like growth factor-binding protein 3
      (P < 0.001) levels were higher on days 10, 25 and 50 post partum in the propylene
      glycol group. Propylene glycol administration decreased plasma non-esterified
      fatty acid concentrations (P < 0.05 to P < 0.01) but increased total cholesterol
      levels (P < 0.01) after parturition while 3-hydroxybutyrate levels were
      unaffected by the treatment. Changes in the hormone and metabolic concentrations
      after propylene glycol administration in the last few days of gestation and the
      first week of lactation seem to indicate that energy balance in the treated group
      was probably more positive than in the control group. There was also evidence
      that propylene glycol administration prevented fatty liver syndrome and hastened
      the resumption of oestrous cycles (P < 0.001).

PMID- 8655736
TI  - Effect of high hydrostatic pressure on the enzymic hydrolysis of beta
      lactoglobulin B by trypsin, thermolysin and pepsin.
AB  - Hydrolysis of beta-lactoglobulin B (beta-lg B) by pepsin, a process slow at
      ambient conditions, is facilitated at a moderately high hydrostatic pressure such
      as 300 MPa, corresponding to an apparent volume of activation delta V# = -63 ml
      mol-1 at pH 2.5, 30 degrees C and gamma/2 = 0.16. Digestion of beta-lg by trypsin
      and thermolysin is likewise enhanced by pressure, and the pressure effect has
      been traced to pressure denaturation of beta-lg B, which by high-pressure
      fluorescence spectroscopy has been shown to have a large negative volume of
      reaction, delta V(o) = -98 ml mol-1, at pH 6.7, 30 degrees C and gamma/2 = 0.16.
      Pressure denaturation is only slowly reversed following release of pressure and
      the enhanced digestibility is maintained at ambient pressure for several hours.

PMID- 8655737
TI  - Bovine milk procathepsin D and cathepsin D: coagulation and milk protein
      degradation.
AB  - Cathepsin D is an indigenous aspartic proteinase in bovine milk. By competitive
      enzyme-linked immunosorbent assay the amount of immunoreactive cathepsin D and
      procathepsin D in bovine skim milk was estimated to be 0.4 microgram/ml.
      Immunoreactive cathepsin D purified from whey consisted of a small fraction of
      mature cathepsin D, but the major form was the proenzyme procathepsin D. A
      preparation of bovine milk procathepsin D was, like mature cathepsin D, able to
      degrade purified alpha s1-, alpha s2-, beta- and kappa-casein and alpha
      lactalbumin, while beta-lactoglobulin was resistant to cleavage. The cleavage
      sites in these proteins were determined and compared with those of chymosin.
      Cathepsin D was capable of generating the alpha s1-I, beta-I, beta-II and beta
      III fragments originally described from the action of chymosin on the respective
      caseins, and these fragments were subjected to further proteolysis. Cathepsin D
      was also able to liberate the caseinomacropeptide from purified kappa-casein, and
      to coagulate bovine skim milk. This demonstrated that milk contains an indigenous
      coagulation enzyme present mainly in the whey fraction.

PMID- 8655738
TI  - Purification of tributyrin esterase from Lactococcus lactis subsp. cremoris E8.
AB  - A tributyrin esterase was purified from Lactococcus lactis subsp. cremoris E8
      using FPLC chromatography. This was the major esterase activity observed in
      strain E8 and was associated with a single protein with a subunit molecular mass
      of 29 kDa and a holoenzyme of molecular mass 109 kDa. The enzyme was active
      against tributyrin and p-nitrophenyl butyrate. The N-terminal sequence of the
      enzyme was determined. The enzyme had a pH optimum in the neutral range, was
      stable on freezing at -20 degrees C, and had a half life of 1 h at 50 degrees C.

PMID- 8655739
TI  - Cholesterol oxidation in butter and dairy spread during storage.
AB  - In a dairy spread (800 g lipid/kg, 10 g salt/kg) based on 750 g milk fat/kg and
      250 g rapeseed oil/kg fat in 15 g extruded catering packaging, there was a more
      significant accumulation of cholesterol oxidation products than in butter
      (minimum 800 g lipid/kg, 12 g salt/kg) in 10 g extruded catering packaging when
      stored at 4 or at 20 degrees C. There was a lag phase of 7 weeks in cholesterol
      oxidation in dairy spread stored at 4 degrees C, while no lag phase was observed
      for storage at 20 degrees C. Total concentrations of oxysterols were, however,
      very similar for dairy spread stored at 4 and 20 degrees C after 13 weeks storage
      (approximately 12 micrograms/g milk lipid); storage at -18 degrees C almost
      prevented cholesterol oxidation (approximately 4 micrograms/g milk lipid). For
      butter, cholesterol oxidation was less pronounced at 4 degrees C (<3 micrograms/g
      milk lipid) than at -18 degrees C (approximately 4 micrograms/g milk lipid) and
      20 degrees C (approximately 7 micrograms/g milk lipid). 7-Ketocholesterol was the
      dominant oxidation product, with 1.3 and 5.7 micrograms/g milk lipid in butter
      and dairy spread respectively after 13 weeks storage at 4 degrees C.

PMID- 8655740
TI  - Effect of microwave heating on vitamins A, E, B1, B2 and B6 in milk.

PMID- 8655741
TI  - Evidence for an interaction between cationic and neutral amino acids at the blood
      facing aspect of the lactating rat mammary epithelium.
AB  - The transport of lysine by perfused lactating rat mammary tissue has been
      examined using a rapid, paired-tracer dilution technique. This experimental
      approach allowed the characteristics of lysine transport across the blood-facing
      aspect of the mammary epithelium to be studied. The clearance of lysine from the
      perfusate was influenced by the extracellular lysine concentration in a fashion
      consistent with the presence of carrier-mediated transport. Replacing
      extracellular Na+ with N-methyl-D-glucamine had no significant effect on lysine
      transport. Lysine uptake was inhibited by extracellular leucine and glutamine but
      not by alpha-(methylamino)isobutyric acid. Leucine interacted with lysine
      transport under Na+(-)free conditions. It appears that the system for cationic
      acid transport which is situated in the blood-facing aspect of the lactating rat
      mammary epithelium may also accept neutral amino acids as substrates.

PMID- 8655742
TI  - Occurrence of five alpha s1-casein variants in ovine milk.
AB  - Five ovine alpha s1-casein variants (A-E) were identified in an Italian
      population sample using gel electrophoresis at alkaline pH, gel isoelectric
      focusing, two dimensional gel electrophoresis, and immunoblotting with polyclonal
      antibodies against alpha s1-casein. Each casein sample produced two peaks by fast
      reversed-phase HPLC. Gel isoelectric focusing and electrospray mass spectrometry
      were used to demonstrate that the first HPLC peak contained the 191 residue alpha
      s1-casein molecular species and the second the 199 residue species, in
      proportions of approximately 20:80. Only in the case of the sample containing
      alpha s1-casein CE was the method for the separation of the single short and long
      forms of each variant unsuccessful. Both two dimensional electrophoresis followed
      by staining with polyclonal antibodies against alpha s1-casein and electrospray
      mass spectrometry showed a heterogeneity consistent with that expected from a
      protein chain with three levels of phosphorylation and two different lengths.
      However, especially for alpha s1-caseins D and E, a further uncharacterized
      heterogeneity was detected.

PMID- 8655743
TI  - Comparative study of methods for the isolation and purification of bovine kappa
      casein and its hydrolysis by chymosin.
AB  - kappa-Casein was purified from a single batch of whole acid casein (kappa-A
      variant) using different methods in order to compare their merits in producing a
      purified material with a carbohydrate and phosphate heterogeneity representative
      of the whole kappa-casein complement in milk. Ion-exchange methods of
      purification gave products of higher purity than precipitation techniques
      involving final purification by ethanol fractionation, but all methods resulted
      in kappa-caseins of apparently similar heterogeneity and chemical composition.
      The purified kappa-caseins were hydrolysed with chymosin and the derived
      macropeptides isolated. These were all virtually identical as determined by
      reversed-phase chromatography and gel electrophoresis. Some observations on
      chymosin hydrolysis of kappa-casein were made. In addition to formation of the
      major para-kappa-casein (Glu1-Phe105) and macropeptide (Met106-Val169), chymosin
      hydrolysis at pH 6.6 also resulted in two minor para-kappa-caseins with N-termini
      corresponding to Phe18 and Ser33 of kappa-casein. At pH 5.5 and 4.5 para-kappa
      casein was rapidly hydrolysed into at least six fragments, one of which had an N
      terminus corresponding to Trp76 of kappa-casein. At pH 6.6, 5.5 and 4.5 the kappa
      casein macropeptide was stable to chymosin, but at pH 2.3 it was hydrolysed by
      chymosin into fragments with N-termini corresponding to Met106, Ile125, Ala138,
      Val139, Thr145 and Glu147 of kappa-casein.

PMID- 8655745
TI  - The maltreatment of infants.

PMID- 8655744
TI  - Effects of physicochemical factors on the secondary structure of beta
      lactoglobulin.
AB  - Fourier transform infrared spectroscopy and differential scanning calorimetry
      were used as complementary techniques to study changes in the secondary structure
      of beta-lactoglobulin under various physicochemical conditions. The effects of pH
      (3-9), NaCl (0-2 M), and lactose, glucose and sucrose (100-500 g/l) in the
      temperature range 25-100 degrees C on the conformation sensitive amide I band in
      the i.r. spectrum of beta-lactoglobulin in D2O solution were examined. The 1692
      cm-1 band in the amide I band profile had not been definitively assigned in
      previous studies of the i.r. spectrum of beta-lactoglobulin. The decrease in this
      band at ambient temperature with time or upon mild heating was attributed to slow
      H-D exchange, indicating that it was due to a structure buried deep within the
      protein. The disappearance of the 1692 cm-1 band on heating was accompanied by
      the appearance of two bands at 1684 and 1629 cm-1, assigned to beta-sheets. The
      1692 cm-1 band was therefore attributed to a beta-type structure. beta
      Lactoglobulin showed maximum thermal stability at pH 3 and was easily denatured
      at pH 9. On denaturation, the protein unfolded into more extensive random coil
      structures at pH 9 than at pH 3. After 10 h at pH 9 (25 degrees C), beta
      lactoglobulin was partly denatured. Heating to 60-80 degrees C generally resulted
      in the loss of secondary structure. At all pH values studied, two new bands at
      1618 and 1684 cm-1, characteristic of intermolecular beta-sheet structure and
      associated with aggregation, were observed after the initial denaturation.
      Differential scanning calorimetry studies indicated that the thermal stability of
      beta-lactoglobulin was enhanced in the presence of sugars. The Fourier transform
      i.r. results obtained provide evidence that sugars promoted the unfolding of beta
      lactoglobulin via multiple transition pathways leading to a transition state
      resisting aggregation.

PMID- 8655746
TI  - Tooth color improvement for children and teens: enamel microabrasion and dental
      bleaching.
AB  - Enamel microabrasion and carbamide peroxide-dentist supervised home applied
      dental bleaching are conservative methods of improving the appearance of teeth.
      Children and teens can benefit from these procedures. This article describes the
      step-by-step clinical technique of enamel microabrasion and a protocol for custom
      tray-applied, home tooth-bleaching. Representative case histories are documented
      with photographs.

PMID- 8655747
TI  - Clinical and ultrastructural study of the natal tooth: enamel and dentin
      assessments.
AB  - A natal tooth, the lower left central primary incisor, extracted from a twenty
      eight-day-old boy was the subject of a clinical and ultrastructural (S.E.M.,
      T.E.M., H.R.T.E.M.) study. The right one having been lost shortly after birth,
      the places of the natal teeth were taken by two hyperplastic structures which
      disappeared one year later, ejecting two little pearls of hard tissue. Scanning
      electron microscopic investigation of the extracted natal tooth showed a reduced
      enamel thickness corresponding to the development stage of the tooth as well as
      the absence of Hunter-Schreger bands and of an outer prism-free layer probably
      related with amelogenesis perturbations. Transmission electron microscopy
      disclosed characteristic ultrastructure of the enamel rods, the morphology of the
      enamel crystals evaluated by their width-to-thickness ratio taking logically
      place between fetal and adult enamel. A central dark line, which is thought to be
      in relation to the initial growth process, was observed in enamel crystals.
      Dentin aspects did not reveal significant perturbations compared to normal
      primary teeth.

PMID- 8655748
TI  - Computed tomography in pediatric oral and maxillofacial surgery.
AB  - The use of computed tomography (C.T.) in the diagnosis and management of
      developmental and pathological conditions of the jaws in children was evaluated.
      CT was found to be superior to plain film radiography in estimation of the three
      dimensional morphology of the abnormality in the jaws, in determining spatial
      relationship and proximity to vital structures. It is valuable by allowing
      accurate planning of the surgical procedure, estimation of the extent of the
      surgery and prediction of outcome as well as complications and prognosis. CT in
      the appropriate circumstances, is a very useful diagnostic tool in pediatric
      maxillofacial surgery. Tissue preservation and precision are of utmost
      importance, especially in children where many structures have not reached their
      final dimensions. Careful consideration should be given to risk benefit ratios
      due to higher exposure to radiation.

PMID- 8655749
TI  - The effect of training on the ability of children to use dental floss.
AB  - The effect of training on the ability to use dental floss was evaluated in a
      study involving forty-eight children in the 6.5 to 7.5 age-group. Using a dental
      plaque index for the proximal surfaces, we observed significantly superior
      average results for the trained group (five weekly sessions) relative to the
      group with no training. We also observed a significant average difference
      favoring the male trained group relative to the female trained group.

PMID- 8655750
TI  - Nursing-bottle syndrome: risk factors.
AB  - The paper is based on data obtained from a study of all new patients under six
      years of age, seeking consultation in a period of thirty months because of
      nursing-bottle syndrome. The information was obtained from questionnaires
      completed by the parents of the children. The children attended the Odontological
      Pediatric Service of the children's hospital in Nice, France. The syndrome
      affected 10.73 percent of the children under six years of age presenting to the
      service for consultation. Included in the discussion are the risk-prone family,
      the medical history and general state of health of the child at risk, feeding
      habits, oral hygiene, and use of fluorides.

PMID- 8655751
TI  - The development of formocresol as a medicament for primary molar pulpotomy
      procedures.
AB  - The development of formocresol as a pulpotomy medicament is charted from the 19th
      Century to the present day. While the solution has come in and out of vogue, few
      agents can seriously challenge its efficacy. Doubts about its toxicity,
      mutagenicity, and carcinogenicity have led, however, to a call for a more dilute
      formulation as well as a review of alternative medicaments. Problems arise in
      deriving an appropriate formula for a dilute version from existing formulations,
      which appear to have misinterpreted the concentration of constituents in the
      original solution.

PMID- 8655752
TI  - Almost 19 million childhood injuries result in 11 thousand deaths.
AB  - Details are provided from a series of government and private agency reports on
      the accidents and related deaths of children and the effectiveness of efforts
      being made to reduce the incidence of these tragedies. In 1992 there were 83,000
      accidental deaths and more than 17 million disabling injuries in the United
      States costing $399 billion. The death rate was down 10 percent from 1991, and
      also the lowest recorded in recent years. Included in these statistics are 19
      million injured children and 11 thousand dead children. The leading cause of
      death of children less than ten years of age was an unintentional injury. The
      author presents details on the accidents and related deaths, as well as the
      effectiveness of efforts to reduce the incidence of these accidents. From the
      youngest ages to the teen years, a greater number of males than females are
      injured and die from accident-related causes. The number of accidental deaths of
      children, ages five to nine years, almost equalled the number of deaths from
      natural causes. For children ten to fourteen years old, the number of accidental
      deaths was one third greater than the number from natural causes. Statistics
      regarding death and injury from motor vehicles, firearms, consumer products, and
      poison are presented.

PMID- 8655754
TI  - Art and science, culture and dental research.

PMID- 8655753
TI  - The health of our children continues to improve--but... (a litany of change--Part
      III).
AB  - The National Center for Health Statistics supplies extensive and detailed survey
      results that support the general underlying perspective of an improving trend in
      the health status of children in the United States. Included in the survey were
      47,000 households with more than 17,000 children, less than eighteen years of
      age. Nevertheless, there were several negative trends in children's health and
      safety in the 1980s. The negative trends included (1) failure to maintain the
      level of women getting prenatal care set in the 1970s; (2) the infant mortality
      rate in 1990 of 9.2 per 1000 of live births is higher than that in twenty-three
      industrialized countries; (3) injuries have emerged as the major cause of
      childhood mortality, morbidity, and disability; (4) disparities along racial and
      income-related lines continue at a serious level. The author also discusses the
      dental needs of children and the use of dental services.

PMID- 8655755
TI  - Additives to cereals and other foods to control dental caries.

PMID- 8655756
TI  - Michael Buonocore and the Eastman Dental Center: a historic perspective on
      sealants.
AB  - Dr. Michael Buonocore is known for his innovative research on the preparation of
      the enamel surface with a weak acid to enhance adhesion of an organic plastic
      chemical sealant and the polymerization in situ of a sealant with ultraviolet
      light. His co-workers at Eastman Dental Center aided and extended his research
      findings. The purpose of his original research was the development of a sealant
      to prevent occlusal caries on posterior teeth. However, the major impact of his
      work has been the development of adhesive restorative techniques. Although it has
      been demonstrated that (i) bacteria tend to die out and caries does not progress
      if early caries lesions are inadvertently sealed, (ii) sealant retention rates
      are favorable, and (iii) sealants are cost-effective, the use of sealants by the
      profession is still far short of early expectations.

PMID- 8655757
TI  - Cariogenicity depends more on diet than the prevailing mutans streptococcal
      species.
AB  - This review aims to compare the occurrence and distribution of mutans
      streptococci in Africa, Europe, and North America and in addition will try to
      offer explanations for existing relationships among salivary mutans streptococci
      counts, dietary patterns, and dental caries. The literature reveals that salivary
      mutans streptococci counts in child populations of the three continents are
      comparable. The distribution of mutans streptococci species, with a predominance
      of S. mutans followed by S. sobrinus, and the virtual absence of other mutans
      streptococci species are also comparable. Although it is widely believed that
      diet has an important effect on mutans streptococci counts, this review provides
      evidence that this does not hold true when variations in dietary patterns are
      moderate, as they normally are in real-life situations. Since the diets of the
      child populations in the three continents vary moderately, a strong dietary
      induced effect on salivary mutans streptococci counts cannot be expected. The
      observed analogous salivary mutans streptococci counts in these child populations
      are thus 'not surprising' but are in accordance with the conceptual expectation.
      The differences in caries experience in children of the three continents cannot
      be explained by the prevailing mutans streptococci species but instead should be
      attributed to differences in the cariogenicity of the various diets. The fact
      that the cariogenicity of the diet determines the development of dental caries
      while hardly affecting the mutans streptococci counts explains the limited value
      of the latter as an indicator of dental caries. The reviewed literature shows
      that mutans streptococci are ubiquitous in children aged 7 years and older in
      Africa, Europe, and North America. Mutans streptococci should therefore be
      considered as belonging to the indigenous microflora of the human mouth.

PMID- 8655758
TI  - Sleep bruxism: validity of clinical research diagnostic criteria in a controlled
      polysomnographic study.
AB  - The clinical validity of diagnostic criteria for sleep orofacial motor activity-
      more specifically, bruxism--has never been tested. Polysomnographic recordings
      from 18 bruxers and 18 asymptomatic subjects, selected according to American
      Sleep Disorders Association criteria, were analyzed (1) to discriminate sleep
      bruxism from other orofacial motor activities and (2) to calculate sensitivity,
      specificity, and predictive values of research criteria. Clinical observations
      and reports revealed that all 18 bruxers reported frequent tooth-grinding during
      sleep. Tooth wear was noted in 16 out of 18 bruxers and jaw discomfort reported
      by six of them. These findings were present in none of the controls. The analysis
      of polysomnographic data showed that the asymptomatic subjects presented a mean
      of 1.7 +/- 0.3 bruxism episodes per hour of sleep (sustained or repetitive
      bursting activity in jaw closer muscles), while bruxers had a significantly
      higher level of activity: 5.4 +/- 0.6. Controls exhibited 4.6 +/- 0.3 bruxism
      bursts per episode and 6.2 (from 0 to 23) bruxism bursts per hour of sleep,
      whereas bruxers showed, respectively, 7.0 +/- 0.7 and 36.1 (5.8 to 108). Bruxism
      like episodes with at least two grinding sounds were noted in 14 of the 18
      bruxers and in one control. The two groups exhibited no difference in any of the
      sleep parameters. Based on the present findings, the following polysomnographic
      diagnostic cut-off criteria are suggested: (1) more than 4 bruxism episodes per
      hour, (2) more than 6 bruxism bursts per episode and/or 25 bruxism bursts per
      hour of sleep, and (3) at least 2 episodes with grinding sounds. When the
      polysomnographic bruxism-related variables were combined under logistic
      regression, the clinical diagnosis was correctly predicted in 81.3% of the
      controls and 83.3% of the bruxers. The validity of these clinical research
      criteria needs now to be challenged in a larger population, over time, and in
      subjects presenting various levels of severity of sleep bruxism.

PMID- 8655759
TI  - Inflammatory lesions of the tooth pulp induce changes in brainstem neurons of the
      rat trigeminal subnucleus oralis.
AB  - Neuroplastic changes are known to occur in the CNS in response to injury of
      peripheral nerves. Previous investigation has demonstrated neuroplasticity in
      second-order neurons of the subnucleus oralis (SO) of the trigeminal (V) nuclear
      complex in association with aseptic injury to the tooth pulp. A question arises,
      therefore, as to whether similar changes occur in response to injury associated
      with inflammation induced by tooth pulp infection. The effects of tooth pulp
      infection on the mechanoreceptive fields (RFs) of SO neurons were examined in
      rats. Infection was established by exposure and removal of the coronal pulp of
      the mandibular first molar, which was left open to the oral environment for 7 (n
      = 5) or 28 (n = 6) days. Neurons in SO were then electrophysiologically
      characterized in chloralose/urethane-anesthetized rats. The RF and the response
      properties of 118 low-threshold mechanoreceptive (LTM) neurons from seven-day-old
      rats and 149 LTM neurons from 28-day-old rats were compared with those of 204 LTM
      neurons tested in 11 untreated (control) rats. Significant differences were noted
      in RF size and location when control, seven-day-old, and 28-day-old groups were
      compared. Radiographic examination revealed inconsistencies among examiners in
      the interpretation of periapical lesions < 2 mm in diameter and general agreement
      in the identification of periapical lesions > 2 mm in diameter. Histological
      examination of teeth with pulp exposure revealed superficial necrosis and
      inflammation without periapical extension in the seven-day-old animals and total
      pulp necrosis with periapical inflammation, abscess formation, and alveolar bone
      resorption in the 28-day-old animals. The results indicate that neuroplastic
      changes in LTM oralis neurons can develop subsequent to tooth pulp infection and
      that there may be a correlation between the incidence of these changes and the
      extension of the attending inflammation from the pulp to the dental supporting
      tissues.

PMID- 8655760
TI  - Interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha, epidermal growth
      factor, and beta 2-microglobulin levels are elevated in gingival crevicular fluid
      during human orthodontic tooth movement.
AB  - Bone remodeling is a complex process regulated by several mediators. Recent work
      has revealed that cytokines and growth factors have significant effects on bone
      cell metabolism. However, little information is available concerning the
      production of cytokines during orthodontic tooth movement in human subjects, and
      there is no non-invasive model for determining the production of cytokines.
      Therefore, the purpose of this study was to identify and quantify the various
      cytokines in human gingival crevicular fluid (GCF), and to investigate the
      changes in their levels during orthodontic tooth movement. Twelve patients (mean
      age, 14.4 years) were used as subjects. An upper canine of each patient having
      one treatment for distal movement served as the experimental tooth, whereas the
      contralateral and antagonistic canines were used as controls. The GCF around the
      experimental and the two control teeth was taken from each subject immediately
      before activation, and at 1, 24, and 168 hr after the initiation of tooth
      movement. Cytokine levels were determined by ELISAs. The concentrations of
      interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha, epidermal growth
      factor, and beta 2-microglobulin were significantly higher in the experimental
      group than in the controls at 24 hr after the experiment was initiated. All the
      cytokines remained at baseline levels throughout the experiment for the two
      control groups. In contrast to cytokine alteration, the amount of total protein
      in the GCF exhibited a gradual increase, but no significant difference was
      observed between the control and experimental groups. Since all cytokines in GCF
      play an important role in the bone remodeling processes in vitro, the present
      results indicate that the changes in cytokines in GCF are associated with
      orthodontic tooth movement.

PMID- 8655761
TI  - Protection of gingival epithelium against complement-mediated damage by strong
      expression of the membrane attack complex inhibitor protectin (CD59).
AB  - Adult periodontitis (AP) is a chronic inflammatory disease of the tooth
      supporting apparatus. Activation products of the inflammation-inducing complement
      system have been detected in the gingival crevicular fluid at the site of
      gingival inflammation. In the present study, we examined whether evidence for
      ongoing complement activation in gingival tissues of patients with AP can be
      obtained. In light of the potential tissue-damaging effects of the complement
      system, we also examined how the gingival tissue is protected against the
      cytolytic activity of complement. Surgical and autopsy samples of AP (n = 18) and
      healthy (n = 11) gingiva were analyzed for the expression or deposition of the
      complement regulators protectin (CD59) and vitronectin (S-protein) and complement
      components C3d and C9 by indirect immunofluorescence microscopy with specific
      antibodies. In healthy gingiva, protection was strongly expressed on the
      membranes of epithelial cells and on the vascular endothelia of the underlying
      connective tissue. In AP, protectin was also strongly expressed by endothelial
      cells, but in the epithelia the expression was granular and weaker than in the
      healthy gingiva. Coarse granular deposits of complement components were seen in
      the subepithelial tissues of 61% (C3d), 39% (C9), and 33% (vitronectin) of AP
      patients, compared with 9% (one case in 11) in healthy controls. In addition,
      deposits of C3d, C9, and vitronectin were observed on the basement membranes of
      both pocket and oral epithelium of healthy and AP gingiva but not at sites of
      protectin expression. The results suggest an increased turnover of the complement
      system in the gingival tissues of AP patients. The gingival epithelium and
      connective tissue endothelia are well-protected against damage by the membrane
      attack complex of complement (MAC). Protection of the underlying connective
      tissue is insufficient, however, and may allow for deposition of MAC and
      autologous tissue damage in AP.

PMID- 8655762
TI  - Regulation of mucous acinar exocrine secretion with age.
AB  - Denny and co-workers (Navazesh et al., 1992) recently reported decreased
      concentrations of MG1 and MG2 mucins in resting and stimulated whole human saliva
      with age. The current study was therefore conducted to examine whether there is a
      corresponding attenuation with age in stimulus secretion coupling regulating
      mucous cell exocrine secretion. We utilized an in vitro model system, isolated
      rat sublingual acini, to evaluate the regulation of mucous cell exocrine
      secretion. Rat sublingual glands are similar to human sublingual and minor mucous
      glands, both histologically and in terms of their pattern of innervation, which
      is predominantly parasympathetic. Mucin secretion is thus activated primarily by
      muscarinic cholinergic agonist and to a lesser extent by vasoactive intestinal
      peptide (VIP), which is co-localized with acetylcholine in parasympathetic nerve
      terminals. We isolated sublingual mucous acini from five-month-old and 24-month
      old rats and compared the concentration responses for mucin secretion induced by
      VIP and the muscarinic agonist, arecaidine propargyl ester (APE). Concentration
      response curves for VIP were nearly identical for mucous acini from the five
      month-old and 24-month-old animals. Values for basal secretion, maximal
      secretion, and EC50 (approximately equal to 200 nmol/L VIP) were statistically
      equivalent between both age groups. Concentration-response curves for APE were
      also very similar between age groups, with no statistically significant
      difference in basal secretion or EC50 values (approximately equal to 50 nmol/L
      APE). Maximal secretion was slightly less but statistically different for 24
      month-old vs. five-month-old animals, 158% vs. 169% above basal secretion,
      respectively. Collectively, we found no substantial age-related changes in the
      secretory responsiveness of salivary mucous cells.

PMID- 8655763
TI  - Immunoreactivity of tenascin-C in dentin matrix in dentinogenesis imperfecta
      associated with osteogenesis imperfecta.
AB  - Osteogenesis imperfecta (OI) is a heterogeneous group of heritable connective
      tissue disorders, assigned to different mutations in type I collagen genes. A
      variety of structural abnormalities of dentin have been described in
      dentinogenesis imperfecta (DI) associated with OI. To clarify further the
      constitution of the dentin matrix in OI, we immunostained frozen and paraffin
      sections of deciduous teeth from four patients, each from a different family,
      with two monoclonal antibodies (MAbs) to the matrix glycoprotein tenascin-C (TN
      C). One of the MAbs recognizes an epitope common to all TN-C isoforms (BC-4), and
      the other is specific for a splicing variant (BC-2). Normal teeth, oral mucosa,
      and skin were analyzed for comparison. Staining patterns with the two MAbs did
      not differ markedly. Normal dentin matrix and odontoblasts were lacking
      reactivity, but the pulp stained clearly. TN-C reactivity was present in the
      dentin matrix of all teeth obtained from two patients with different OI
      phenotypes and DI, and in one out of three teeth from one patient who also had
      DI. The reactivity was distributed in layers, but the staining patterns varied
      from one patient to another and from tooth to tooth. Intratubular staining seen
      in a tooth from the patient with clinically and histologically normal teeth was
      comparable with that present in normal deciduous teeth. The variation in TN-C
      expression suggests that, besides genetic heterogeneity, epigenetic factors could
      influence the composition of the dentin matrix in OI.

PMID- 8655764
TI  - Evaluation of sodium fluorescein for quantitative diagnosis of root caries.
AB  - The diagnosis of root caries, in particular the judgment of the activity of a
      visually observed lesion, is difficult. Quantitative determination of lesion
      severity would allow the lesion to be monitored with time, so that an indication
      of lesion activity could be obtained. This paper describes a step in the
      development of a method that provides such a quantitative determination.
      Specifically, fluorescein sodium salt is used as a penetrating dye, the subject
      of study being the relationship between dye concentration and porosity in
      demineralized root dentin. Fourteen human third molars were demineralized in
      vitro (lactic acid CMC-gel, pH 5; in each of 6 groups for 4, 7, 11, 14, 18, and
      21 days). Fluorescein sodium salt (0.2 g/L) was applied for 2 min. Thin slices
      (+/- 130 microns) were cut from the root surfaces without water cooling. The dye
      fluorescence radiance in the demineralized dentin was determined by means of a
      micro-Raman spectroscope and compared with the mineral loss profiles measured
      with transverse microradiography (TMR). The TMR data were corrected for the
      difference in measurement area between the two measurement systems. Corrected TMR
      profiles were compared with the corresponding fluorescence scans, showing linear
      correspondence. The correlation coefficient was r = 0.96. We conclude that, after
      uptake of fluorescein sodium salt for 2 min, the dye concentration in an
      artificially produced root-surface caries lesion is proportional to the amount of
      mineral lost from that lesion.

PMID- 8655765
TI  - Long-term use of nicotine chewing gum and mercury exposure from dental amalgam
      fillings.
AB  - In experimental studies, chewing gum has been shown to increase the release rate
      of mercury vapor from dental amalgam fillings. The aim of the present study was
      to investigate the influence of long-term frequent chewing on mercury levels in
      plasma and urine. Mercury levels in plasma (P-Hg) and urine (U-Hg), and urinary
      cotinine were examined in 18 subjects who regularly used nicotine chewing gum,
      and in 19 referents. Age and number of amalgam surfaces were similar in the two
      groups. Total mercury concentrations in plasma and urine were determined by means
      of cold vapor atomic absorption spectrometry. Urinary cotinine was determined by
      gas chromatography-mass spectrometry. The chewers had been using 10 (median)
      pieces of gum per day for the past 27 (median) months. P-Hg and U-Hg levels were
      significantly higher in the chewers (27 nmol/L and 6.5 nmol/mmol creatinine) than
      in the referents (4.9 nmol/L and 1.2 nmol/mmol creatinine). In both groups,
      significant correlations were found between P-Hg or U-Hg on the one hand and the
      number of amalgam surfaces on the other. In the chewers, no correlations were
      found between P-Hg or U-Hg and chewing time per day or cotinine in urine.
      Cotinine in urine increased with the number of pieces of chewing gum used. The
      impact of excessive chewing on mercury levels was considerable.

PMID- 8655766
TI  - Shear strength of composite bonded to Er:YAG laser-prepared dentin.
AB  - An Er:YAG laser coupled with a cooling stream of water effectively removes dental
      hard tissues. However, before such a system can be deemed clinically viable, some
      safety and efficacy issues must be addressed. We compared the bonding of
      composite to dentin following the preparation of the dentinal surface with either
      an Er:YAG laser (lambda = 2.94 microns) or a standard dental bur and with and
      without a subsequent acid-etching treatment. The crowns of extracted human molars
      were removed, revealing the underlying dentin. We removed an additional thickness
      of material with either a dental handpiece or an Er:YAG laser (350 mJ/pulse at 6
      Hz) by raster-scanning the samples under a fixed handpiece or laser. Comparable
      surface roughnesses were obtained. Several samples from each group received an
      acid-conditioning treatment. A cylinder of composite was bonded onto the prepared
      surfaces. The dentin-composite bond was then shear-stressed to failure on a
      universal testing apparatus. The results indicate that laser-irradiated samples
      had improved bond strengths compared with acid-etched and handpiece controls. SEM
      photographs of the surfaces show exposed tubules following the laser treatment:
      tubules could also be exposed with acid etching. We conclude that Er:YAG laser
      preparation of dentin leaves a suitable surface for strong bonding or an applied
      composite material.

PMID- 8655767
TI  - New surface-active comonomer for adhesive bonding.
AB  - Previous studies have indicated that chemical and physical characteristics of
      aromatic amines can be influenced by the nature of their substituents. The
      experimental question examined in the present study relates to the effects of
      replacing specific hydrogen atoms with methyl groups in a surface-active
      comonomer utilized in adhesive bonding protocols. N-2-propionic acid-N-3-(2
      hydroxy-1-methacryloxy)propyl-3,5-dimethylaniline sodium salt (N35A) was
      synthesized by an addition reaction of glycidyl methacrylate with the sodium salt
      of N-reaction of glycidyl methacrylate with the sodium salt of N-(3,5
      dimethylphenyl)alanine, which was formed by alkaline hydrolysis of ethyl-N-(3,5
      dimethylphenyl)alanate that was prepared by condensation of ethyl-2
      bromopropionate with 3,5-dimethylaniline. 1H and 13C NMR spectra and analysis by
      mass spectroscopy were consistent with N35A after it had been recrystallized from
      acetone. Color stability and adhesion-promoting capability of N35A were compared
      with those of N-2-acetic acid-N-3-(2-hydroxy-1-methacryloxy)propyl-4
      methylanaline sodium salt (Na-NTG-GMA), the latter being widely used in
      commercial bonding formulations. Both N35A and Na-NTG-GMA polymerized within a
      few minutes at 23 degrees C when dissolved in aliquots from a stock solution
      containing benzene 85 wt%, ethanol 14 wt%, and benzoyl peroxide 1.0 wt%; but with
      each at 0.018 molal concentration, the N35A suspension was more color-stable than
      that of the Na-NTG-GMA. In the protocol used, shear bond strengths of a hybrid
      composite to human dentin with N35A were 30.2 MPa, SD = 7.5 MPa, and with Na-NTG
      GMA, 29.7 MPa, SD = 11.8 MPa(n = 7 each; t test, p = 0.93).

PMID- 8655768
TI  - Syndromes, syndromes, and more syndromes.

PMID- 8655769
TI  - Ins and outs of antimicrobial resistance: era of the drug pumps.
AB  - Over the past five years, concerns have heightened over the escalating numbers of
      pathogenic micro-organisms isolated that are resistant to many antibiotics and
      drugs. This phenomenon poses major problems in the treatment of patients with
      hospital- or community-acquired infections caused by bacteria, fungi, or
      parasitic organisms. Microbial cells have acquired resistances to specific
      antibiotics and drugs by mechanisms that include antibiotic inactivation, target
      alteration, or drug exclusion. More recently, the importance of another
      mechanism, that of drug expulsion, has been recognized as contributing
      significantly to antibiotic and drug resistance in microbes. Drug expulsion,
      mediated by membrane-associated drug efflux pumps, can protect cells from a range
      of toxic compounds and therefore may confer single-step multidrug resistance. It
      is imperative that new drugs be designed or discovered that will poison the pumps
      or bypass the efflux mechanisms.

PMID- 8655770
TI  - Analysis of tempering stresses in metal-ceramic disks.
AB  - Previous studies showed that residual compressive stresses induced by thermal
      tempering retarded the growth of surface cracks in bilayered porcelain disks. The
      objectives of the present study were: (1) to determine whether thermal tempering
      by air blasting reduces the length of cracks induced by microhardness indentation
      in metal-ceramic disks, and (2) to use visco-elastic finite element analyses to
      calculate transient and residual stresses in metal-ceramic disks. Ni-Cr-Be disks,
      16 mm in diameter and 0.3 mm in thickness, were prepared with a 0.5-mm-thick
      layer of opaque porcelain and a 1.5-mm-thick layer of body porcelain. Metal
      porcelain combinations were selected to provide a range of thermal contraction
      mismatch values. The disks were fired to the maturing temperature of body
      porcelain and then were subjected to three cooling procedures: (1) slow cooling
      in a furnace (SC), (2) cooling in air (FC), and (3) air tempering (T) by blasting
      the surface of the body porcelain with compressed air. The lengths of cracks
      induced in the surface of the body porcelain by a microhardness indenter were
      measured immediately after indentation at 20 points along diametral lines. The
      results of Tukey's multiple-contrast analyses indicated that the mean crack
      lengths of air-tempered specimens were significantly smaller (p < or = 0.05) than
      the crack lengths of the fast-cooled and slow-cooled groups. Except for one case,
      there were no statistically significant differences in the mean crack lengths
      between FC and SC specimens independent of thermal contraction mismatch. Residual
      tensile stresses were calculated for SC and FC specimens for all thermal
      contraction mismatch cases, with the largest values being associated with
      combinations containing the body porcelain with the smaller contraction
      coefficient. Calculations by use of the model confirmed that tempering induces
      large residual compressive stresses in the surface of body porcelain for all of
      the thermal contraction mismatch cases included in this study.

PMID- 8655771
TI  - Analysis of edge-losses in reflectance measurements of pigmented maxillofacial
      elastomer.
AB  - Edge-losses occur during reflectance measurements of pigmented maxillofacial
      elastomer when light is scattered within a sample beyond that part of the surface
      exposed to the observation system of the optical device. A custom sample-holder
      is presented which redirects light that would not be measured during conventional
      reflectance measurement back into the sample. The amount of edge-loss occurring
      within thin layers of maxillofacial elastomer with tan pigment on black-and-white
      backings was found to depend on sample thickness, the backing, the beam size used
      during conventional reflectance measurement, and the optical term bS = (2KS +
      K2)1/2. Data analysis revealed a significant interaction among these four
      factors. Additionally, the edge-loss occurring during the tristimulus reflectance
      measurement of thick samples of maxillofacial elastomer with various
      concentrations of tan and black pigment was found to be linearly related to bS up
      to a limiting value, with no additional edge-loss occurring for bS values above
      this limiting value. Edge-loss is an important consideration during the matching
      of the optical characteristics of pigmented maxillofacial material to those of
      human skin.

PMID- 8655773
TI  - The influence of dft index on sealant success: a 48-month survival analysis.
AB  - Early loss of pit and fissure sealants is considered to be primarily dependent on
      inadequate isolation of the tooth from salivary contamination during application.
      Gradual additional loss is considered to be caused by occlusal wear, shearing
      forces, and marginal failure. Our hypothesis is that the caries risk of the child
      may be an additional factor in sealant loss. The objective of this study was to
      analyze the influence of caries history in primary teeth (dft index) on the
      success of sealants. Delton light-polymerized sealant was applied in 104 six- to
      eight-year-old children, followed for four years on a six-month-visit basis. All
      sound permanent first molars were sealed during the study. A survival analysis
      was used to describe sealant success over time. A Cox proportional hazards
      regression model was built to test the influence on sealant success of the dft
      index and site of sealant application (mandibular occlusal surface, maxillary
      fossae, and maxillary distolingual fissure), controlling for some potential
      confounders. Sealant half-life was 46 months. Site and dft index were related to
      sealant survival. The maxillary fossae showed the best retention, followed by the
      mandibular occlusal site and the maxillary disto-lingual fissure. The higher the
      dft, the higher the risk of sealant failure. This study has implications for
      sealant study designs and public sealant programs.

PMID- 8655772
TI  - Design and development of isocyanatoacrylates as dental adhesives.
AB  - During the last 12 years, significant progress has been made in the development
      of dental adhesive systems. Some of the more promising systems are based on
      multifunctional structures that contain polymerizable vinyl double bonds and
      reactive isocyanate groups. The utility of compounds with such structures as
      adhesives arises in part because their isocyanate functionality is available for
      reaction independently, without compromising the reactivity of the vinyl groups.
      The hypotheses tested in this investigation were: (1) that the monomer reactivity
      ratios (r1, r2) for the free-radical-initiated copolymerization of ethyl alpha
      isocyanatoacrylate (alpha-EIA) and 2-isocyanatoethyl methacrylate (IEM) with
      selected vinyl monomers can be determined; (2) that these reactivity ratios can
      be used to establish Q (reactivity) and e (polarity) values for alpha-EIA and
      IEM; and (3) that these reactivity parameters can be useful in designing
      copolymers with controlled compositions for dental adhesive applications. The
      free-radical copolymerization characteristics of alpha-EIA and IEM were studied.
      The isocyanate monomers were copolymerized at seven comonomer ratios with n-butyl
      acrylate (NBA), methyl methacrylate (MMA), and styrene (STY). Reactivity ratios,
      r1 and r2, were calculated for each of the copolymer systems, giving:IEM (r1) =
      0.38 and STY (r2) = 0.44; IEM (r1) = 1.19 and MMA (r2) = 0.84; IEM (r1) = 2.50
      and NBA (r2) = 0.40; alpha-EIA (r1) = 2.20 and STY (r2) = 0.06; alpha-EIA (r1) =
      7.00 and MMA (r2) = 0.10; and alpha-EIA (r1) = 23.50 and NBA (r2) = 0.04. The Q
      (reactivity) and e (polarity) values for IEM and alpha-EIA were calculated from
      r1 and r2 with use of the Alfrey-Price equations, giving, for IEM, Q = 0.89 and e
      = 0.60, and, for alpha-EIA, Q = 7.64 and e = 0.74. These reactivity parameters
      are useful for tailoring copolymers with controlled compositions and properties.
      Based on these calculated reactivity parameters, several copolymers of IEM [for
      example, IEM/2-hydroxyethyl methacrylate (HEMA)] are currently being prepared and
      evaluated as adhesives.

PMID- 8655774
TI  - Relationships between clinician variability and radiographic guidelines.
AB  - This study evaluated the replicability of clinical measurements under careful
      calibration of multiple dentists and how the replicability can relate to their
      use as selection criteria in guidelines for prescribing dental radiographs. For
      48 consenting patients, three dentists clinically examined each patient and
      recorded the presence of all clinical findings using standardized selection
      criteria. The examinations were performed independently of each other, but with
      periodic conferences of the dentists to clarify general measurement criteria. The
      degree of agreement among the dentists is described by the interrater agreement
      kappa for several standard clinical indications such as rating of caries,
      periodontal disease, and tooth mobility. Almost perfect agreement was obtained
      for tooth status, restoration size, and restoration material. Moderate agreement
      resulted for measures of caries, defective restoration presence, and gingival
      recession presence. Only fair agreement was obtained for other periodontal
      disease measures. The relationship between extent of agreement and guidelines'
      results was examined for the FDA Guidelines. The differences among the dentists'
      clinical measurements resulted in considerable differences among the radiographs
      that were selected by the FDA Guidelines' criteria. Even so, the missed disease
      rates for 490 patients in a larger study of the FDA Guidelines' efficacy were
      very low and did not vary greatly among the three dentists. We conclude that
      guidelines' criteria can be quite robust to variation from dentists' clinical
      measurement differences, as seen from the FDA Guidelines applied under the
      idealized setting where the dentists are periodically recalibrated through group
      discussions of the clinical measurements' definitions and interpretations.

PMID- 8655775
TI  - Incidence of and risk factors for tooth loss in a population of older Canadians.
AB  - Data on the incidence of tooth loss in community-dwelling older Canadians have
      not previously been reported. Since recent US studies of older adults were
      conducted in predominantly rural communities, their results may not be
      generalizable to Canada, where the majority of older adults live in major
      metropolitan or urban settings. This paper describes a study designed to estimate
      the incidence of tooth loss in older Canadians and to identify factors predictive
      of that loss. Using personal interviews and clinical examinations, we obtained
      baseline and three-year follow-up data from 491 dentate subjects. Overall, 23.2%
      lost one or more teeth between baseline and follow-up. Only six, or 1.2%, became
      edentulous. Twelve baseline factors were significantly associated with the
      probability of loss. However, in a logistic regression analysis, only five had
      significant independent effects. These were gender, marital status, self-rating
      of oral health status, the number of decayed root surfaces, and a mean
      periodontal attachment loss of 4 mm or more. The predictive ability of the model
      was poor, largely because tooth loss is a complex outcome which depends on
      decisions taken by dentists and patients. Since this decision-making process
      cannot be captured in epidemiological studies, observational studies are needed
      to cast further light on tooth loss in this population.

PMID- 8655776
TI  - A meta-analysis of clinical studies on the caries-inhibiting effect of
      chlorhexidine treatment.
AB  - A meta-analysis was performed on published data on the caries-inhibiting effect
      of chlorhexidine treatment. The results of the various studies are difficult to
      evaluate because of various treatment procedures, dissimilar features of
      participants, and different presentations of study results. A meta-analysis
      provides a more structured approach than the traditional review, due to
      systematic analysis and numerical processing of the available information. The
      objectives of this meta-analysis were: (1) to assess a more accurate estimate of
      the caries-inhibiting effect of chlorhexidine treatment than provided by
      individual studies, and (2) to explore factors potentially modifying the effect
      of chlorhexidine treatment in caries prevention, i.e., the application method,
      application frequency, target population, the fluoride regime, and caries
      criteria. Caries reduction was expressed by the prevented fraction, indicating
      the percentage reduction of caries incidence in the chlorhexidine group. For all
      prevented fractions, 95% confidence intervals were calculated. The overall caries
      inhibiting effect of the chlorhexidine treatment studies was 46% (95% CI = 35% -
      57%). Multiple-regression analysis showed no significant influence on the
      prevented fractions for the variables "application method", "application
      frequency", "caries risk", "fluoride regime", "caries diagnosis", and "tooth
      surface".

PMID- 8655777
TI  - Serum cotinine levels, smoking, and periodontal attachment loss.
AB  - Cigarette smoking and tobacco use have been the subjects of numerous studies for
      many years. Smoking has also been associated with periodontal disease. However,
      no relationship between a reliable biochemical marker and increased severity of
      the periodontal condition has yet been described. It was thus the aim of this
      study to apply the measurement of cotinine, the major metabolite of nicotine, as
      a quantitative method to assess levels of smoking, and to correlate serum levels
      of cotinine with severity of periodontal disease. The degree of association
      between smoking and periodontal attachment loss was investigated in a study
      including 79 patients 25 to 64 years old suffering from periodontitis. Patients
      were examined and the following parameters recorded: Gingival Assessment (GA),
      Probing Pocket Depth (PPD), Clinical Attachment Level (CAL), and Bone Crest
      Height (BCH). In addition, self-reported histories of tobacco use as well as
      blood samples for quantitative analysis of serum levels of cotinine were taken.
      The serum samples were analyzed for cotinine content by means of a competitive
      inhibition ELISA technique. The differences in mean cotinine levels were
      statistically significant (p = 0.0001) between smokers and non-smokers, showing
      no overlap between the groups. Severity of periodontal attachment loss was
      positively correlated with serum levels of cotinine for both measures of
      periodontal disease (CAL p = 0.005; BCH p = 0.008). Results from the present
      study indicate that serum cotinine levels used as a biochemical marker of smoking
      status are correlated with severity of periodontal attachment loss.

PMID- 8655778
TI  - Temporal and compositional characteristics of salivary protein adsorption to
      hydroxyapatite.
AB  - Salivary proteins bind to enamel surfaces and hydroxyapatite in a highly
      selective manner. Numerous studies have identified these proteins as primarily
      proline-rich proteins, cystatins, statherin, and histatins. Previously, the
      hydroxyapatite-binding potential of these proteins had been characterized in
      systems consisting of singly purified protein and adsorbent. The purpose of this
      study was to investigate the adsorption of each protein in the presence of
      complete salivary secretion. Proteins, shown to adsorb to hydroxyapatite, were
      purified, biotinylated, and added back to the remaining proteins to form a series
      of reconstituted secretions. The adsorption of each biotinylated protein in the
      reconstituted secretion to hydroxyapatite was then measured as a function of
      time. Results indicated that three different adsorption patterns occur. A simple
      hyperbolic pattern is characteristic of amylase, glycosylated proline-rich
      protein (PRG), and cystatin. A faster adsorption process is observed for PRP-3,
      PRP-4, PIF-f, and statherin. A more complex pattern, exhibiting a rapid phase
      followed by a slower phase, is characteristic of PRP-1, PRP-2, PIF-s, and
      histatins. These results suggest that there are different adsorption processes
      involved in the binding of salivary proteins to hydroxyapatite. Two possible
      mechanisms are direct adsorption of protein to hydroxyapatite and indirect
      adsorption of protein by interacting with other proteins already bound to
      hydroxyapatite.

PMID- 8655779
TI  - Co-adhesion of oral microbial pairs under flow in the presence of saliva and
      lactose.
AB  - Co-aggregation (interactions between two suspended micro-organisms) between oral
      microbial pairs has been studied extensively and is believed to be an important
      factor in dental plaque formation. However, co-adhesion (interactions between
      suspended and already-adhering micro-organisms) may well be equally important.
      The aim of this paper was to determine the influence of saliva and lactose on the
      co-adhesion of streptococci (S. oralis 34 and S. sanguis PK1889) to actinomyces
      (A. naeslundii T14V-J1 or 5951) adhering on glass under flow from buffer and
      saliva in the absence and presence of lactose. The kinetics of co-adhesion as
      well as co-adhesion in a stationary end-point of co-aggregating and non-co
      aggregating pairs was studied in a parallel plate flow chamber by analysis of the
      spatial arrangement of co-adhering micro-organisms as a function of time. For co
      aggregating pairs, initial deposition rates of streptococci in the immediate
      vicinity of adhering actinomyces (local initial deposition rates) were up to 5 to
      10 times higher than the non-local initial deposition rates in buffer and in
      saliva, respectively. In a stationary end-point of co-adhesion, 5 to 6 times more
      streptococci co-adhered with the adhering actinomyces than averaged over the
      entire substratum surface. A non-co-aggregating pair showed only minor
      preferential (co-)adhesion near the adhering actinomyces. Co-adhesion in buffer
      was fully lost when lactose was added. However, addition of lactose to saliva did
      not inhibit co-adhesion, but co-adhesion became more reversible. Detachment of
      micro-organisms from the substratum due to the passage of an air-liquid
      interface, as occurs in the oral cavity during eating, drinking, and speaking,
      was minimal when deposition was carried out from buffer to bare glass. Major
      detachment of streptococci adhering to the substratum occurred when adhesion was
      mediated through a salivary conditioning film on the glass, while detachment of
      adhering actinomyces and streptococci co-adhering with them remained low. It is
      suggested that, in the development of dental plaque, adhering actinomyces may act
      as strongholds for other micro-organisms, like streptococci, to adhere.

PMID- 8655780
TI  - The inhibiting effect of aqueous Azadirachta indica (Neem) extract upon bacterial
      properties influencing in vitro plaque formation.
AB  - The purpose of this investigation was to examine the inhibitory effects of
      aqueous extracts derived from the bark-containing sticks (Neem stick) of
      Azadirachta indica upon bacterial aggregation, growth, adhesion to
      hydroxyapatite, and production of insoluble glucan, which may affect in vitro
      plaque formation. Neem stick extracts were screened for minimal bacterial growth
      inhibition (MIC) against a panel of streptococci by means of a broth dilution
      assay. Initial bacterial attachment was quantified by the measurement of the
      adhesion of 3H-labeled Streptococcus sanguis to saliva-conditioned synthetic
      hydroxyapatite. The effect of the Neem stick extract upon insoluble glucan
      synthesis was measured by the uptake of radiolabeled glucose from 14C-sucrose.
      Aggregating activity of the Neem stick extracts upon a panel of streptococci was
      also examined. No inhibition of bacterial growth was observed among the
      streptococcal strains tested in the presence of < or = 320 micrograms/mL of the
      Neem stick extract. The pre-treatment of S. sanguis with the Neem stick extract
      or the gallotannin-enriched extract from Melaphis chinensis at 250 micrograms/mL
      resulted in a significant inhibition of the bacterial adhesion to saliva
      conditioned hydroxyapatite. Pre-treatment of saliva-conditioned hydroxyapatite
      with the Neem stick or gallotannin-rich extract prior to exposure to bacteria
      yielded significant reductions in bacterial adhesion. The Neem stick extract and
      the gallotannin-enriched extract from Melaphis chinensis inhibited insoluble
      glucan synthesis. Incubation of oral streptococci with the Neem stick extract
      resulted in a microscopically observable bacteria aggregation. These data suggest
      that Neem stick extract can reduce the ability of some streptococci to colonize
      tooth surfaces.

PMID- 8655781
TI  - Proceedings of a symposium, toward responsible research conduct: the role of
      scientific societies.

PMID- 8655782
TI  - The moral foundations of scientific ethics and responsibility.
AB  - Any significant involvement of AADR/IADR in ensuring responsible research among
      their members must be grounded in a widely accepted consensus that there are good
      moral reasons for such involvement. One important source of such reasons is
      AADR/IADR's identity as a scientific research, a professional, and a dental
      association. These identities and the commitments to society and to clients
      implicit in them generate several mutually reinforcing reasons for taking
      responsibility for the reliability of members' research. With regard to
      scientific research, these reasons arise from what it means to do such research,
      and from the various ways the larger society supports that activity. With regard
      to the professional dimension, the reasons arise from what it means to be a
      profession in this society and can be best seen in relation to the four major
      characteristics of professions. With regard to AADR/IADR's being a dental
      profession, such reasons arise from dental researchers' specific role in the
      dental family of professions' goal of delivering optimal care to the clients of
      practitioners. The clients' perspective, specifically the need to be able to
      trust that one will receive the best care possible, is a final source for such
      reasons. Two current issues, the sharing of findings and commercial/industrial
      support for research, give new urgency to this question of the Association's role
      in ensuring responsible research.

PMID- 8655783
TI  - Developing ethical standards for responsible research: Why? Form? Functions?
      Process? Outcomes?
AB  - Any profession that is considering the development of ethical standards should
      give serious attention to the intended purposes of such standards, what form they
      should take, what functions they will serve, how the process for developing them
      should be organized, what outcomes are sought, and what values are central to the
      mission and performance of the profession. The profession serves as a normative
      reference group for individual practitioners and through ethical standards
      clarifies, for both its members and outsiders, the norms that ought to govern
      professional behavior. Such standards may be aspirational, educational, or
      regulatory, and may perform many functions, nine of which are discussed. The
      process of developing standards is assessed because of the role it plays in
      gaining consensus on professional values and ethical norms. Finally, several
      outcomes likely to increase the value and utility of ethical standards are
      identified.

PMID- 8655784
TI  - Process and procedures for dealing with misconduct: a necessity or a nightmare?
AB  - After a scientific and professional association has developed a code of ethics,
      it must develop a set of procedures to investigate, adjudicate, and enforce the
      code's provisions. The author, who is a scientist and an attorney, describes and
      discusses the fundamental legal principles that must be adhered to so that
      complaints against members can be adjudicated fairly, objectively, and with
      little legal risk to the association. The paper defines the concept of due
      process as it applies to private, non-profit associations and provides an example
      of how one professional and scientific association actually goes about
      adjudicating claims of misconduct against its members. It also informs
      associations about the liability risks that may confront them when they enforce a
      code of ethics, offers suggestions of how to manage those risks successfully, and
      concludes by cataloguing some of the financial burdens enforcement entails.

PMID- 8655785
TI  - On being a scientist in a rapidly changing world.
AB  - The practice of biological science has changed dramatically since mid-century,
      reshaped not only by a rapid series of landmark discoveries, but also by
      governmental directives, institutional policies, and public attitudes. Until
      1964, the major influences were the mentor, who provided direction and
      indoctrination into the culture of science, and in dentistry, the newly
      established NIDR, which fueled the research engine with an expanding research and
      training program. The 1965-74 period witnessed the advent of the Institutional
      Review Board, an increased social involvement of biological scientists, and a
      recognition of the need for biological and physical safeguards in the conduct of
      research. The most turbulent years were 1975-89, when there was a confluence of
      animal rights activism and regulation, growing concerns with scientific fraud and
      publication malpractice, and the stresses and strains (and opportunities)
      resulting from the rapid expansion of the academic-industrial complex. The
      current period is characterized by rapid pace, high volume, and an increased
      depth and breadth of knowledge-a major change in scale in the conduct of science.
      It is an exciting time but one in which ethical issues are multiplying. Attention
      must be paid.

PMID- 8655786
TI  - Survey of ethical issues in dental research.
AB  - The American Association for Dental Research (AADR) surveyed its leaders to
      determine their perceptions of the prevalence of problematic research practices
      and the possible roles AADR should play in promoting scientific integrity.
      Seventy-six of the 98 program chairs and Association officers (1990-1995)
      surveyed responded. In general, these respondents did not think that serious
      misconduct or sloppy science occurred more often in AADR than in other scientific
      disciplines. Overall, respondents rated practices that undermine the
      trustworthiness of science (falsifying or fabrication of research data,
      retaliation, failure to present negative results, failure to disclose involvement
      with commercial enterprises, failure to maintain research records, etc.) as more
      serious, but less prevalent, than practices considered disrespectful of the work
      of others (gift authorship, citing sources without reading them, dividing a
      project into many small units, etc.). All respondents said that they had observed
      each of the less serious problematic practices one or more times, whereas 10%
      reported having observed retaliation, 30% reported having observed falsification,
      and 54% reported having observed plagiarism one or more times. AADR leaders had
      observed many more instances of misconduct and other problematic research
      practices than had faculty surveyed by Swazey et al. (1993), supporting
      conclusions by Greenberg and Goldberg (1994) that status and years of experience
      are associated with more frequent observations of misconduct. With respect to the
      possible roles the AADR might play in promoting research integrity, 88% thought
      that AADR should develop ethics cases and materials for educational use, 78%
      thought that AADR should create a process for addressing allegations of
      misconduct, 72% thought that the Association should develop an ethics committee
      or consultation service, 55% thought it should create a yearly ethics symposium,
      and 45% thought that the AADR should develop a more specific code of ethics to
      complement the general code recently developed by the IADR.

PMID- 8655787
TI  - The role of the AADR in promoting research integrity: perspectives and consensus
      statements.

PMID- 8655788
TI  - Spatial periodicity in the cochlea: the result of interaction of spontaneous
      emissions?
AB  - In this study the results of simulations with a nonlinear macromechanical model
      of the human cochlea are presented. In this model it is possible to investigate
      the interactions between large numbers of spontaneous emissions. The focus of
      this study is on the effect of a local maximum in emission strength on its direct
      surroundings. The suppression that such an emitter causes depends on the distance
      between suppressor and suppressee in a strongly nonmonotonic manner. This
      nonmonotonicity leads to natural minimal distances between emission frequencies,
      without additional assumptions about the mechanics of the cochlea. The origin of
      this nonmonotonicity in the suppression lies in reflection of the generated
      energy at the stapes. The fact that these minimum distances correspond to
      distances observed between measured SOAE frequencies in adults, but not in
      newborns, suggests that the nonmonotonicity may play a role in the development of
      the cochlea in the early years of childhood.

PMID- 8655789
TI  - The ipsilaterally evoked olivocochlear reflex causes rapid adaptation of the 2f1
      f2 distortion product otoacoustic emission.
AB  - The onset behavior of the distortion product otoacoustic emission (DPOAE) at 2f1
      f2 in anesthetized cats was measured with temporal resolution finer than 70 ms.
      The amplitude of the DPOAE adapts after onset of the primary tones by as much as
      6 dB for monaural stimulation and 10 dB when the primaries are presented
      binaurally. DPOAE adaptation consists of a large, rapid component, with a time
      constant of roughly 100 ms, and a small, slower component with a time constant of
      roughly 1000 ms. The rapid component disappears when only the crossed
      olivocochlear bundle (OCB) is cut, whereas the slow adaptation persists after
      complete OCB section. The loss of rapid adaptation upon OC section is accompanied
      by a concomitant increase in the steady-state amplitude of the DPOAE. Thus an
      intact OC reflex can significantly alter DPOAEs obtained during routine
      measurement. Rapid adaptation of the monaurally evoked 2f1-f2 DPOAE is probably
      mediated by reflex activity in ipsilaterally responsive OC neurons innervating
      outer hair cells. The effects of this ipsilateral reflex on DPOAE amplitudes are
      typically twice as large as those of the contralateral reflex, presumably because
      there are twice as many ipsilaterally responsive OC neurons. Tests for the
      ipsilateral OC reflex based on the phenomenon of rapid adaptation should be both
      feasible and useful in human subjects.

PMID- 8655790
TI  - The periodogram and Allan variance reveal fractal exponents greater than unity in
      auditory-nerve spike trains.
AB  - Auditory-nerve spike trains exhibit fractal behavior, and therefore traditional
      renewal-point-process models fail to describe them adequately. Previous measures
      of the fractal exponent of these spike trains are based on the Fano factor and
      consequently cannot exceed unity. Two estimates of the fractal exponent are
      considered which do not suffer from this limit: one derived from the Allan
      variance, which was developed by the authors, and one based on the periodogram.
      These measures indicate that fractal exponents do indeed exceed unity for some
      nerve-spike recordings from stimulated primary afferent cat auditory-nerve
      fibers.

PMID- 8655791
TI  - Responses of ventral cochlear nucleus units in the chinchilla to amplitude
      modulation by low-frequency, two-tone complexes.
AB  - For a tone that is amplitude modulated by two tones (fmod1 and fmod2), neither
      the stimulus waveform nor the half-wave rectified waveform has spectral energy at
      the envelope beat frequency (fmod2-fmod1). The response of ventral cochlear
      nucleus units in the chinchilla were recorded for best frequency tones that were
      amplitude modulated by low-frequency, two-tone complexes. Fourier analysis of
      poststimulus time histograms shows spectral peaks at fmod2-fmod1 in addition to
      the peaks at fmod1 and fmod2. The peaks in the neural spectra arise from
      compressive nonlinearities in the auditory system. The magnitudes of these
      spectral peaks are measures of synchrony at each frequency component. For all
      units, synchrony at fmod1 and fmod2 is greater than the synchrony at fmod2-fmod1.
      For a given unit, synchrony at fmod1 and fmod2 remains relatively constant as a
      function of overall level, whereas synchrony at fmod2-fmod1 decreases as the
      level increases. Synchrony was quantified in terms of the Rayleigh statistic (z),
      which is a measure of the statistical significance of the phase locking. In terms
      of z, phase locking at fmod1 and fmod2 is largest in chopper units, whereas onset
      chopper units and primarylike units having sloping saturation in their rate-level
      functions show the smallest amount of phase locking. Phase locking at fmod2-fmod1
      is also largest in chopper units, and smallest in onset-chopper units and
      primarylike units with sloping saturation.

PMID- 8655792
TI  - Acoustic elements of speechlike stimuli are reflected in surface recorded
      responses over the guinea pig temporal lobe.
AB  - Auditory evoked potentials measured from the guinea pig temporal lobe surface
      reflect acoustic elements of synthesized speech syllables. Eliciting stimuli
      included a four formant anchor stimulus /ba/, with a 40-ms formant transition
      duration. The other stimuli differed from /ba/ along simple acoustic dimensions.
      The /pa/ stimuli differed on a VOT continuum; /da/ stimuli had a higher frequency
      F2 onset; /wa/ had a longer (80 ms) formant transition duration; and /bi/
      differed in three vowel formant frequencies. The /ba/ and /da/ onset response
      latencies decreased systematically with increasing F2 onset frequency. The
      response to the /pa/ voicing increased in latency with increasing VOT and showed
      a physiologic discontinuity at VOT of 15-20 ms. Responses to /ba/ and /wa/ showed
      similar onset morphology but significant amplitude differences at latencies
      corresponding to vowel onset. Significant amplitude differences in /ba/ and /bi/
      responses corresponded in latency to both consonant and vowel portions of the
      syllables. Similar to previous reports in the awake monkey for VOT, these results
      demonstrate in the anesthetized guinea pig that acoustic elements essential to
      speech perception are reflected in aggregate response of ensembles of cortical
      neurons.

PMID- 8655793
TI  - A quantitative model of the "effective" signal processing in the auditory system.
      I. Model structure.
AB  - This paper describes a quantitative model for signal processing in the auditory
      system. The model combines a series of preprocessing stages with an optimal
      detector as the decision device. The present paper gives a description of the
      various preprocessing stages and of the implementation of the optimal detector.
      The output of the preprocessing stages is a time-varying activity pattern to
      which "internal noise" is added. In the decision process, a stored temporal
      representation of the signal to be detected (template) is compared with the
      actual activity pattern. The comparison amounts to calculating the correlation
      between the two temporal patterns and is comparable to a "matched filtering"
      process. The detector itself derives the template at the beginning of each
      simulated threshold measurement from a suprathreshold value of the stimulus. The
      model allows one to estimate thresholds with the same signals and psychophysical
      procedures as those used in actual experiments. In the accompanying paper [Dau et
      al., J. Acoust. Soc. Am. 99, 3623-3631 (1996)] data obtained for human observers
      are compared with the optimal-detector model for various masking conditions.

PMID- 8655794
TI  - A quantitative model of the "effective" signal processing in the auditory system.
      II. Simulations and measurements.
AB  - This and the accompanying paper [Dau et al., J. Acoust. Soc. Am. 99, 3615-3622
      (1996)] describe a quantitative model for signal processing in the auditory
      system. The model combines several stages of preprocessing with a decision device
      that has the properties of an optimal detector. The present paper compares model
      predictions for a variety of experimental conditions with the performance of
      human observers. Simulated and psychophysically determined thresholds were
      estimated with a three-interval forced-choice adaptive procedure. All model
      parameters were kept constant for all simulations discussed in this paper. For
      frozen-noise maskers, the effects of the following stimulus parameters were
      examined: signal frequency, signal phase, temporal position and duration of the
      signal within the masker under conditions of simultaneous masking, masker level,
      and masker duration under conditions of forward masking, and backward masking.
      The influence of signal phase and the temporal position of the signal, including
      positions at masker onset, was determined for a random-noise masker and compared
      with corresponding results obtained for a frozen noise. The model describes all
      the experimental data with an accuracy of a few dB with the following exceptions:
      forward-masked thresholds obtained with brief maskers are too high and the change
      in threshold with a change in signal duration is too small. Both discrepancies
      have their origin in the adaptation stages in the preprocessing part of the
      model. On the basis of the wide range of simulated conditions we conclude that
      the present model is a successful approach to describing the detection process in
      the human auditory system.

PMID- 8655795
TI  - Extents of laterality and binaural interference effects.
AB  - Extents of laterality produced by ongoing interaural time delays (ITDs) within
      high-frequency sinusoidally amplitude-modulated (SAM) target tones were measured
      in the presence or absence of a second, spectrally remote, diotic, SAM tone. The
      spectrally remote SAM tones had recently been shown to reduce sensitivity to ITDs
      conveyed by a 4-kHz SAM tone in a previous experiment employing the same
      listeners [L. M. Heller and C. Trahiotis, J. Acoust. Soc. Am. 97, 1808-1816
      (1995)]. All SAM tones were 100% modulated at 250 Hz and were presented at 77 dB
      SPL for a duration of 250 ms. The SAM target tone was centered at 4 kHz and the
      lower-frequency SAM tones were centered at either 500 Hz, 1 kHz, or 2 kHz. The
      data indicate that spectrally remote, diotic, SAM tones "pull" the lateral
      position of a 4-kHz SAM tone toward the midline, even when the 4-kHz SAM tone
      contains an ITD of up to 400 or 600 microseconds. This means that effects of
      spectrally remote information are not confined to tasks which require that
      listeners detect, or discriminate between, threshold amounts of ITD. Analyses
      revealed that changes in lateral position, as measured by an acoustic pointing
      task, cannot in and of themselves account for the interference effects found in
      discrimination tasks with similar stimuli. It was found, however, that Buell and
      Hafter's [J. Acoust. Soc. Am. 90, 1894-1990 (1991)] weighted-combination model,
      when augmented to include measures of laterality as well as measures of
      discriminability, could provide reasonably accurate predictions of the amounts of
      interference obtained in the discrimination task.

PMID- 8655796
TI  - Cues for discrimination of envelopes.
AB  - Thresholds for detection of sinusoidal amplitude modulation at a signal
      modulation frequency were measured in the presence of a masker modulation
      frequency, with broadband noise carriers. Broad tuning for modulation frequency
      was observed. For maskers half or twice the signal frequency, thresholds depended
      on the relative phases of the signal and masker. These results were used to
      determine what aspects of envelopes listeners might be using in making decisions.
      Simulations were performed using an envelope detector model, consisting of
      bandpass filtering, half-wave rectification, and low-pass filtering. Decisions
      were based on envelope statistics that have been used to predict other data.
      These statistics were (1) rms power, (2) ratio of maximum to minimum amplitude
      (max/min), (3) crest factor, (4) fourth moment, and (5) average slope. The
      max/min statistic was successful at predicting the major trends in the data,
      without requiring the presence of channels tuned to modulation frequency.

PMID- 8655798
TI  - Detection of decrements and increments in sinusoids at high overall levels.
AB  - Thresholds for the detection of decrements in level of sinusoidal signals were
      measured as a function of duration (2, 4, 6, 10, and 14 ms), level (70, 80, and
      90 dB SPL) and frequency (250, 500, 1000, 2000, and 4000 Hz). Seven normally
      hearing listeners were tested at each frequency (with different subjects for each
      frequency). Thresholds for detecting a 10-ms increment in level were also
      measured. The sinusoids were presented in a background noise low-pass filtered at
      5 kHz, which was intended to mask spectral splatter associated with the decrement
      or increment. Performance improved with increasing frequency for all decrement
      and increment durations. Performance also tended to improve with increasing level
      at 2000 and 4000 Hz. The results were analyzed using a four-stage model
      consisting of an auditory filter centered on the signal frequency, a compressive
      nonlinearity, a sliding temporal integrator and a decision mechanism. The
      analysis indicated that the improved performance with increasing frequency and
      increasing level could be attributed partly to off-frequency listening; for the
      two highest center frequencies, subjects probably made use of the output of an
      auditory filter centered above the signal frequency, where changes in excitation
      level associated with an increment or decrement were magnified. The measurements
      at 4000 Hz were repeated using a broadband background noise (15-kHz bandwidth),
      which would prevent the use of information from auditory filters centered far
      above the signal frequency. Performance was poorer than when low-pass noise was
      used, but still improved somewhat with increasing level. The slight improvement
      in performance with increasing level can be accounted for by a reduced
      compressive linearity at high levels. A good fit to the data could be obtained by
      assuming that the equivalent rectangular duration (ERD) of the temporal
      integrator was invariant with level, but that the compressive nonlinearity varied
      with level in a similar way to basilar-membrane input-output functions. The
      nonlinearity appears to be somewhat less compressive at 250 Hz than at higher
      center frequencies. The ERD is about 7 ms regardless of center frequency.

PMID- 8655797
TI  - Vowel discrimination in cats: acquisition, effects of stimulus level, and
      performance in noise.
AB  - The ability of cats to discriminate accurately among different synthetic, steady
      state vowels was examined across a range of stimulus levels and in background
      noise. Cats were trained to press and hold down a lever to produce a pulsed train
      of a standard vowel stimulus, and to release the lever only when a different
      vowel sound occurred. Five synthetic vowels were tested (/e/, /ae/, /a/, /o/, and
      /u/) at levels of 30, 50, 70, and 90 dB SPL. In separate experiments, each of
      these vowels served in turn as the standard vowel. All cats discriminated among
      the vowels accurately, and in general performed at least as well at high stimulus
      levels as at low levels. Where differences in vowel discriminability occurred,
      they were correlated with the relative changes in first and second formant peaks.
      Cats appear to predominantly utilize upward frequency changes in either the first
      or second formants of the vowels to make the discriminations; downward formant
      changes produced considerably lower discrimination performances. In background
      noise, high vowel discriminability was still maintained at an average
      signal/noise ratio of -12.3 dB. Thus cats can discriminate among vowels at high
      signal levels and in background noise, despite the fact that the neural
      representations of vowels based on rate responses in the auditory nerve can be
      severely degraded under these conditions.

PMID- 8655799
TI  - On the externalization of sound images.
AB  - Listeners perceive the sounds of the real world to be externalized. The sound
      images are compact and correctly located in space. The experiments reported in
      this article attempted to determine the characteristics of signals appearing in
      the ear canals that are responsible for the perception of externalization. The
      experiments used headphones to gain experimental control, and they employed a
      psychophysical method whereby the measurement of externalization was reduced to
      discrimination. When the headphone signals were synthesized to best resemble real
      world signals (the baseline synthesis) listeners could not distinguish between
      the virtual image created by the headphones and the real source. Externalization
      was then studied, using both discrimination and listener rating, by
      systematically modifying the baseline synthesis. It was found that
      externalization depends on the interaural phases of low-frequency components but
      not high-frequency components, as defined by a boundary near 1 kHz. By contrast,
      interaural level differences in all frequency ranges appear to be about equally
      important. Other experiments showed that externalization requires realistic
      spectral profiles in both ears; maintaining only the interaural difference
      spectrum is inadequate. It was also found that externalization does not depend on
      dispersion around the head; an optimum interaural time difference proved to be an
      adequate phase relationship.

PMID- 8655800
TI  - Placement of observations for the efficient estimation of a psychometric
      function.
AB  - Psychometric functions for different psychophysical tasks describe the
      relationship between physical stimuli and subjects' responses. Although a
      psychometric function is of considerable value, characterizing the function is
      time consuming and, hence, is not carried out routinely in psychophysical
      experiments. A principal reason for the lack of efficiency in characterizing the
      psychometric function is the use of unimodal (e.g., Gaussian and uniform)
      sampling methods. As an alternative, a multimodal four-point sampling method is
      proposed. A psychometric function is then fitted to the four data points (each
      with several trials) to estimate the threshold and slope parameters of the
      psychometric function. Results from three examples demonstrate that a 60% savings
      in data-collection time can be achieved.

PMID- 8655801
TI  - Some acoustic features of nasal and nasalized vowels: a target for vowel
      nasalization.
AB  - In order to characterize acoustic properties of nasal and nasalized vowels, these
      sounds will be considered as a dynamic trend from an oral configuration toward an
      [n]-like configuration. The latter can be viewed as a target for vowel
      nasalization. This target corresponds to the pharyngonasal tract and it can be
      modeled, with some simplifications, by a single tract without any parallel paths.
      Thus the first two resonance frequencies (at about 300 and 1000 Hz) characterize
      this target well. A series of measurements has been carried out in order to
      describe the acoustic characteristics of the target. Measured transfer functions
      confirm the resonator nature of the low-frequency peak. The introduction of such
      a target allows the conception of the nasal vowels as a trend beginning with a
      simple configuration, which is terminated in the same manner, so allowing the
      complex nasal phenomena to be bounded. A complete study of pole-zero evolutions
      for the nasalization of the 11 French vowels is presented. It allows the
      proposition of a common strategy for the nasalization of all vowels, so a true
      nasal vowel can be placed in this nasalization frame. The measured transfer
      functions for several French nasal vowels are also given.

PMID- 8655802
TI  - Two cross-linguistic factors underlying tongue shapes for vowels.
AB  - Desirable characteristics of a vocal-tract parametrization include accuracy, low
      dimensionality, and generalizability across speakers and languages. A low
      dimensional, speaker-independent linear parametrization of vowel tongue shapes
      can be obtained using the PARAFAC three-mode factor analysis procedure [Harshman
      et al., J. Acoust. Soc. Am. 62, 693-707 (1977)]. Harshman et al. applied PARAFAC
      to midsagittal x-ray vowel data from five English speakers, reporting that two
      speaker-independent factors are required to accurately represent the tongue shape
      measured along anatomically normalized vocal-tract diameter grid lines.
      Subsequently, the cross-linguistic generality of this parametrization was brought
      into question by the application of PARAFAC to Icelandic vowel data, where three
      nonorthogonal factors were reported [Jackson, J. Acoust. Soc. Am. 84, 124-143
      (1988)]. This solution is shown to be degenerate; a reanalysis of Jackson's
      Icelandic data produces two factors that match Harshman et al.'s factors for
      English vowels, contradicting Jackson's distinction between English and Icelandic
      language-specific "articulatory primes". To obtain vowel factors not constrained
      by artificial measurement grid lines, x-ray tongue shape traces of six English
      speakers were marked with 13 equally spaced points. PARAFAC analysis of this
      unconstrained (x,y) coordinate data results in two factors that are clearly
      interpretable in terms of the traditional vowel quality dimensions front/back,
      high/low.

PMID- 8655803
TI  - Functional data analyses of lip motion.
AB  - The vocal tract's motion during speech is a complex patterning of the movement of
      many different articulators according to many different time functions.
      Understanding this myriad of gestures is important to a number of different
      disciplines including automatic speech recognition, speech and language
      pathologies, speech motor control, and experimental phonetics. Central issues are
      the accurate description of the shape of the vocal tract and determining how each
      articulator contributes to this shape. A problem facing all of these research
      areas is how to cope with the multivariate data from speech production
      experiments. In this paper techniques are described that provide useful tools for
      describing multivariate functional data such as the measurement of speech
      movements. The choice of data analysis procedures has been motivated by the need
      to partition the articulator movement in various ways: end effects separated from
      shape effects, partitioning of syllable effects, and the splitting of variation
      within an articulator site from variation from between sites. The techniques of
      functional data analysis seem admirably suited to the analyses of phenomena such
      as these. Familiar multivariate procedures such as analysis of variance and
      principal components analysis have their functional counterparts, and these
      reveal in a way more suited to the data the important sources of variation in lip
      motion. Finally, it is found that the analyses of acceleration were especially
      helpful in suggesting possible control mechanisms. The focus is on using these
      speech production data to understand the basic principles of coordination.
      However, it is believed that the tools will have a more general use.

PMID- 8655804
TI  - Three-dimensional tongue surface shapes of English consonants and vowels.
AB  - This paper presents three-dimensional tongue surfaces reconstructed from multiple
      coronal cross-sectional slices of the tongue. Surfaces were reconstructed for
      sustained vocalizations of the American English sounds [symbol: see text].
      Electropalatography (EPG) data were also collected for the sounds to compare
      tongue surface shapes with tongue-palate contact patterns. The study was
      interested also in whether 3-D surface shapes of the tongue were different for
      consonants and vowels. Previous research and speculation had found that there
      were differences in production, acoustics, and linguistic usage between the two
      groups. The present study found that four classes of tongue shape were adequate
      to categorize all the sounds measured. These classes were front raising, complete
      groove, back raising, and two-point displacement. The first and third classes
      have been documented before in the midsagittal plane [cf. R. Harshman, P.
      Ladefoged, and L. Goldstein, J. Acoust. Soc. Am. 62, 693-707 (1976)]. The first
      three classes contained both vowels and consonants, the last only consonants.
      Electropalatographic patterns of the sounds indicated three categories of tongue
      palate contact: bilateral, cross-sectional, and combination of the two. Vowels
      used only the first pattern, consonants used all three. The EPG data provided an
      observable distinction in contact pattern between consonants and vowels. The
      ultrasound tongue surface data did not. The conclusion was that the tongue
      actually has a limited repertoire of shapes and positions them against the palate
      in different ways for consonants versus vowels to create narrow channels, divert
      airflow, and produce sound.

PMID- 8655805
TI  - Acoustic characteristics of less-masculine-sounding male speech.
AB  - This study compared samples of less-masculine-sounding (LMS) and more-masculine
      sounding (MMS) male speech to identify acoustic characteristics, other than
      fundamental frequency, that might contribute to the perception of these
      categories. In the first phase, audiorecorded speech samples provided by 35 males
      were presented to 35 female listeners in a paired-comparison perceptual
      experiment. Nineteen of the male speech samples were judged reliably to fall
      within the LMS or MMS categories. Within those 19 samples, 8 speakers (4 LMS and
      4 MMS) exhibited similar distributions of habitual fundamental frequency values
      in connected speech and in sustained phonation. In the second phase of the
      experiment, various acoustic measures of these eight connected speech samples
      were conducted. Significant differences between measures of fundamental frequency
      contours, vowel formant midpoint values, and in the first, third and fourth
      spectral moments of two fricatives were revealed. These findings may be useful in
      creating stylized synthetic speech that varies on the dimension of masculinity,
      and they may have clinical relevance for patients wishing to modify the
      perception of masculinity invoked by their speech.

PMID- 8655806
TI  - Effects of spectral contrast on perceptual compensation for spectral-envelope
      distortion.
AB  - Features in a sound's spectral envelope are important for perceptual
      identification but they are likely to be accompanied by spurious features due to
      distortion by the transmission channel between source and listener. Previous
      experiments have demonstrated that there is perceptual compensation for this
      distortion, and the present experiments ask whether the compensation involves a
      separation of spurious and salient features. Listeners identified words
      containing a vowel test sound in an /aept/ to /ppt/ continuum, with a carrier
      phrase before each word. Effects of transmission channels were simulated by
      filtering the carrier and the /pt/ following the test sound. Filters were pairs
      with frequency responses that were the difference of the spectral envelopes from
      the end-point vowels. Contrasts were altered by multiplying decibel values of the
      carrier filter's frequency response or the test sound's spectral envelope by a
      positive number. This keeps features such as peaks at the same frequencies but
      changes the difference in level between peaks and valleys. When the contrasts of
      the carrier filters and test sound were the same, the continuum's phoneme
      boundary was shifted in a manner consistent with a perceptual compensation for
      the filters that affects the neighboring test sound. However, this shift
      decreased when the carrier-filter's contrast was less than that of the test
      sound, and increased slightly when the test-sound's contrast was less than the
      carrier-filter's contrast. Therefore, the amount of compensation increases with
      the amount of distortion, even when spectral features such as peaks are kept at
      the same frequencies. So compensation seems to occur before any perceptual
      extraction of these features.

PMID- 8655807
TI  - Consonant recognition for spectrally degraded speech as a function of consonant
      vowel intensity ratio.
AB  - Normal-hearing subjects' recognition of spectrally degraded speech was evaluated
      under conditions in which the consonant-vowel (C-V) intensity ratio was modified.
      Subjects identified 22 consonants presented in an /a-Consonant-a/ format at
      suprathreshold and near threshold conditions. Prior to C-V ratio modification,
      the stimuli were processed to limit spectral information. In the suprathreshold
      experiment, stimuli were presented at the natural C-V ratio and at six modified C
      V ratios. C-V ratio manipulations had dramatic effects on recognition scores for
      some groups of consonants. Scores for glides and sibilant fricatives increased
      with increasing C-V ratio, while scores for nasals and weak fricatives were best
      at low C-V ratios. Recognition scores for the stops and affricates were generally
      independent of C-V ratio. For nearly all consonants, changes in recognition
      scores as a function of C-V ratio were associated with changes in a general
      response bias toward those sounds. Performance was poor when the spectrally
      smeared VCVs were presented at low SN ratios in a second experiment. The
      influence of C-V ratio on percent correct scores was generally similar to the
      suprathreshold results, but consonant audibility, which was not a factor in the
      suprathreshold experiment, appeared to alter the effect of C-V ratio modification
      for some consonants.

PMID- 8655808
TI  - Modeling formant frequency discrimination of female vowels.
AB  - The present investigations were designed to establish the features of vowel
      spectra that mediate formant frequency discrimination. Thresholds for detecting
      frequency shifts in the first and second formants of two steady-state vowels were
      initially measured for conditions in which the amplitudes of all harmonics varied
      in accordance with a model of cascade formant synthesis. In this model, changes
      in formant frequency produce level variations in components adjacent to the
      altered formant as well as in harmonics spectrally remote from the shifted
      resonant frequency. Discrimination thresholds determined with the cascade
      synthesis procedure were then compared to difference limens (DLs) obtained when
      the number of harmonics exhibiting level changes was limited to the frequency
      region surrounding the altered formant. Results indicated that amplitude
      variations could be restricted to one to three components near the shifted
      formant before significant increases in formant frequency DLs were observed. In a
      second experiment, harmonics remote from the shifted formant were removed from
      the stimuli. In most cases, thresholds for these reduced-harmonic complexes were
      not significantly different from those obtained with full-spectrum vowels.
      Preliminary evaluation of an excitation-pattern model of formant frequency
      discrimination indicated that such a model can provide good accounts of the
      thresholds obtained in the present experiments once the salient regions of the
      vowel spectra have been identified. Implications of these findings for
      understanding the mechanism mediating vowel perception are discussed.

PMID- 8655809
TI  - The processing of duration and intensity cues to prominence.
AB  - This paper presents results from two experiments designed to show how duration
      and intensity are processed during speech perception. Duration and intensity are
      two physical dimensions which are known to interact psychoacoustically in the
      perception of both length (a term that will be used for perceived duration) and
      loudness. The first experiment, a selective attention task, shows that length and
      loudness are processed as a unit [integrally, in the terms of Garner, The
      Processing of Information and Structure (Erlbaum, Potomac, MD, 1974)], but that
      the integrality is asymmetric: Extracting length information appears to be easier
      than extracting loudness information. The results of the first experiment make
      the prediction that listeners would not use loudness by itself in making
      prominence judgments, since the extraction of loudness in the presence of
      duration variation appears to require a (relatively) high processing load. The
      second experiment, a traditional trading relation experiment in which duration
      and intensity were varied orthogonally, appears to bear out this prediction.
      Listeners' responses were predicted from computed measures of length and loudness
      in a linear multiple regression analysis. Results show a negligible independent
      contribution of loudness to listeners' responses. Listeners' behavior is best
      predicted by computed measures of length.

PMID- 8655810
TI  - Compensation to articulatory perturbation: perceptual data.
AB  - The perceptual adequacy of vowels, stop consonants, and fricatives produced under
      conditions of articulatory perturbation was explored. In a previous study
      [McFarland and Baum, J. Acoust. Soc. Am. 97, 1865-1873 (1995)], acoustic analyses
      of segments produced in two subtests (immediate compensation and
      postconversation) revealed small but significant changes in spectral
      characteristics of vowels and consonants under bite-block as compared to normal
      conditions. For the vowels only, adaptation increased subsequent to a period of
      conversation with the bite block in place, suggesting that compensation may
      develop over time and that consonants may require a longer period of adaptation.
      The present follow-up investigation examined whether the acoustic differences
      across conditions were perceptually salient. Ten listeners performed an
      identification and a quality rating task for stimuli from the earlier acoustic
      study. Results revealed reductions in identification scores and quality ratings
      for a subset of the vowels and consonants in the bite-block conditions relative
      to the normal condition in the immediate compensation subtest. In the
      postconversation subtest, quality ratings for the fricatives in the bite-block
      condition remained low as compared to those in the normal condition. Perceptual
      results are compared to the previous acoustic data gathered on these stimuli.

PMID- 8655811
TI  - Statistics of the log-compressed echo envelope.
AB  - Log compression of A lines to produce B-scan images in clinical ultrasound
      imaging systems is a standard procedure to control the dynamic range of the
      images. The statistics of such compressed images in terms of underlying scatterer
      statistics have not been derived. The statistics are analyzed for partially
      formed speckle using a general K distribution model of envelope statistics to
      derive the density function for the log-compressed envelope. This density
      function is used to elucidate the relation between the moments of the compressed
      envelope, the compression parameters, and the statistics of the scatterers. The
      analysis shows that the mean of the log-compressed envelope is an increasing
      function of both the backscattered energy and the effective scatterer density.
      The variance of the log-compressed envelope is a decreasing function of the
      effective scatterer density and is independent of the backscattered energy.

PMID- 8655813
TI  - Anisotropy of the slope of ultrasonic attenuation in formalin fixed human
      myocardium.
AB  - Clinical implementation of quantitative ultrasonic tissue characterization is
      likely to require imaging the heart with sound propagating at varying angles
      relative to the fibers of the heart. Under these circumstances, the variation of
      the ultrasonic properties of myocardium with the angle of propagation relative to
      the myofibers may represent a significant source of potential misinterpretation.
      In the present study, the systematic approach of assessing the impact of
      anisotropy on quantitative myocardial tissue characterization is extended by
      reporting results of a recent in vitro study to measure the anisotropy of the
      slope of ultrasonic attenuation in specimens of formalin fixed human myocardium.
      Data obtained from regions of remote infarct are presented and compared to data
      acquired from regions identified to be free of infarct. The slope of attenuation
      for both regions exhibit a sinusoid-like dependence on angle that is
      approximately doubled for propagation parallel to the fibers as compared to
      perpendicular. These results are, in turn, compared to an earlier study from the
      laboratory that examined the effects of myocardial infarction on ultrasonic
      attenuation and interstitial collagen content in freshly excised canine hearts.
      Discussion regarding the analysis and interpretation of measurements of slope of
      attenuation is presented as well as a discussion of the possible influence of
      formalin fixation on our results.

PMID- 8655812
TI  - Anisotropy of the transverse mode ultrasonic properties of fixed tendon and fixed
      myocardium.
AB  - This study investigates the influence of the fiber-reinforced nature of
      myocardium and tendon on the propagation of transverse mode ultrasonic waves.
      Formalin fixed specimens of normal human left ventricular cardiac muscle and
      bovine Achilles tendon were prepared for this study in such a way that transverse
      mode ultrasonic waves could be propagated perpendicular to the fiber axis of the
      tissue with the polarization oriented either parallel or perpendicular to the
      fiber axis. Measurements of velocity and attenuation were made at 3 MHz to assess
      the degree of anisotropy in these parameters for both tissues. Formalin fixed
      tendon exhibited a significant anisotropy whereas formalin fixed myocardium
      displayed a similar trend of more modest magnitude. Results of these measurements
      were used to compute two elastic stiffness coefficients for each tissue, yielding
      c44 = 37.2 MPa and c66 = 18.0 MPa for formalin fixed tendon, and c44 = 8.97 MPa
      and c66 = 8.45 MPa for formalin fixed myocardium. To validate this approach,
      additional studies were conducted to measure the transverse mode ultrasonic
      properties of silicone rubber and motor oil.

PMID- 8655814
TI  - Acoustic reflectivity of a dolphin.
AB  - Backscatter measurements were made on a stationary Atlantic bottlenosed dolphin
      under controlled conditions. Three sets of measurements were made: (1) broadside
      aspect target strength as a function of frequency from 23 to 80 kHz; (2) relative
      target strength as a function of the polar angle about the animal using a short
      click signal having a peak frequency of 67 kHz; and (3) relative reflective
      strength of different portions of the animal's body. The mean target strength at
      the broadside aspect decreased from -11 to -24 dB as the frequency increased from
      23 to 45 kHz. As the frequency increased from 45 kHz, the target strength rose to
      a local maximum of -18 dB at 66 kHz and then decreased to -23 dB at 79 kHz.
      Maximum target strength was measured at the broadside aspect and exceeded the
      minimum (tail aspect) target strength by 21 dB. The target strength at the head
      aspect was 5 dB below that of the broadside aspect. Most acoustic energy was
      reflected from the area between the dorsal and pectoral fins, corresponding to
      the location of the dolphin's lungs.

PMID- 8655815
TI  - Barriers to research utilization.

PMID- 8655816
TI  - From research to practice: one organizational model for promoting research-based
      practice.
AB  - This paper describes a framework used by the National Institute for Nursing in
      Oxford to integrate research, development and practice. With the increasing
      attention given to the topic of how research findings are implemented into
      clinical practice, it was felt important to share the challenges that have arisen
      in attempting to combine traditional research activities with more practice-based
      development work. The emerging conceptual framework, structures and functions are
      described, highlighting the variety of partnerships to be established in order to
      achieve the goal of integrating research into practice. While the underpinning
      principles of the framework-generating knowledge, implementing research into
      practice and evaluating the effectiveness of programmes-are not new, it is the
      way they have been combined within an organizational structure that could be
      helpful to others considering such a strategy. Both the strengths and weaknesses
      of the framework are discussed, a number of conclusions drawn as to its
      robustness and consideration given to its replication.

PMID- 8655817
TI  - Validity in qualitative health care research: an exploration of the impact of
      individual researcher perspectives within collaborative enquiry.
AB  - The authors of the present paper are a team of workers undertaking an empirical
      study of the definitions of quality in nursing used by National Health Service
      managers and others. At an early stage in that work, their concern to enhance the
      validity of the findings led them to participate in the exercise reported in this
      paper. Their purpose was to answer the question 'what is the effect of the
      researcher's perspective on the interpretation of the analysis of interview
      data?'. This paper reports an exploration of the problem of validity in
      qualitative enquiry and a review of published strategies for analysing interview
      data. It then outlines the strategy chosen by the team-the use of a framework
      which addresses validity in terms of adequacy of description. The experience of
      using this framework is described and some empirical evidence of the way that
      individual perspectives influence the analysis is presented. This gives rise to
      four principles which are considered to be of value in team working in
      qualitative enquiry, whether the team is a large one or consists of research
      student and supervisor alone. The paper concludes with practical suggestions as
      to how these principles may be built in to the project planning cycle.

PMID- 8655818
TI  - Grounded theory as feminist research methodology.
AB  - Feminist research is evolving, and with it new methods of doing science. In this
      feminist post-positivist era, grounded theory, while less inclusive and
      descriptive than ethnography, allows for complex analysis of complex questions.
      While Glaser & Strauss (the originators of this methodology) have written about
      grounded theory in an esoteric way, others have written extensively about this
      method in a much clearer and less rigid fashion. In this paper we discuss how
      grounded theory could be used in a creative and constantly evolving manner for
      feminist research.

PMID- 8655819
TI  - Action research as a professionalizing strategy: issues and dilemmas.
AB  - This paper identifies the need for a debate about the appropriateness of action
      research for nursing as it seeks to achieve the status of a research-based
      profession. It also identifies a related need to inform such a debate by bringing
      together three sets of writings that are not normally united in the nursing
      research literature-those of action research, organizational culture and
      professionalization. In nursing, as in education, action research is being
      deployed as part of a professionalizing strategy, since amongst other things it
      seems to offer a means of developing reflective practitioners and of producing
      knowledge for practice. The increasing popularity of action research amongst
      nurse researchers suggests that it is seen to reflect the attributes to which
      nursing aspires as a profession, including a concern to realize humanistic
      values. Action research was embraced by the teaching profession before nursing,
      and nurse researchers are increasingly drawing on the ideas of influential
      educationalists in defining action research as an emancipatory strategy and a
      form of collaborative enquiry rooted in reflective practice. This paper argues
      that in the managerialist context of the British National Health Service action
      research may be reduced from a participatory methodology into a method for
      getting people to collaborate with managerial goals and internalize the values of
      the corporate culture. The danger is that in the name of reflective practice
      nursing work may become increasingly individualized. The challenge for action
      research in nursing is how to respond to this dilemma, and this may require
      looking critically at the managerial values underpinning the NHS reforms and at
      the organizational context in which action research strategies are deployed.

PMID- 8655820
TI  - Swedish midwives' awareness of, attitudes to and use of selected research
      findings.
AB  - Members of a county division of the Midwives' Association of Sweden were surveyed
      to examine their awareness of, attitudes to and use of selected research
      findings. A total of 14 findings from research within the midwifery field were
      identified from midwives' dissertations and the journal Jordemodern using the
      criterion of physical availability. Questionnaires were mailed according to the
      membership list (n = 146). The response rate was 74% (n = 118). The results
      demonstrated that 75% of the midwives were aware of research findings, 65% were
      convinced of their usefulness and 63% used findings at least sometimes. According
      to the stages of Rogers' innovation-decision model the midwives were in the
      'persuasion' stage, which is consistent with the result in Brett's 1987 study.
      The results indicate that research findings are used when midwives believe that
      the findings provide good care for mothers and babies. Even though the midwife in
      Sweden is considered to be an independent practitioner she is a member of a
      limiting social system. With regard to the interests influencing the health care
      system there is a need to examine the innovation-decision process from an
      organizational perspective to effectively improve the quality of care.

PMID- 8655821
TI  - The organization of clinical supervision within the nursing profession: a review
      of the literature.
AB  - There is a considerable amount of literature available on the subject of
      supervision within the nursing profession. However, there appears to be little
      structure regarding how this subject is organized within the professional
      literature. Thus, although the subject of supervision appears within the nursing
      literature as a fairly consistent theme, there has been little or no attempt by
      the profession to give structure to either its underpinning theory or its
      practice. It is apparent that the term 'supervision' within the nursing
      profession has different meanings for different individuals and groups. In an
      attempt to explore the literature relating to the United Kingdom, the author has
      developed a structure for the review, based upon his reading of the literature
      and his own experience within the profession. The review covers five areas. The
      first area is that of examining the need for clinical supervision within the
      practice of nursing. The second area of the review identifies the various ways in
      which the concept of supervision is used in practice, particularly identifying
      the variety of terminology. The third area of the review is that of the
      profession's perception of good practice regarding supervision. The fourth area
      of the review seeks to identify various models of supervision as they are used
      within the nursing profession. Lastly, the preparation and training for the role
      of supervisor is reviewed.

PMID- 8655822
TI  - A critical reflection on the personal impact of managerial hegemony within nurse
      education.
AB  - This paper, written by two male nurse teachers, describes and analyses their
      experience of working in a nurse education culture permeated by the philosophy of
      business management. The introduction of business management practices to nurse
      education is discussed as a reflection of the current political hegemony of
      market forces and individualism. The authors discuss the implications for nurse
      teachers of being continually exposed to these politically motivated forces which
      increasingly provide the paradigm for service developments within the United
      Kingdom health services. In discussing the impact of this exposure it is argued
      that at the personal level individual teachers are experiencing a degree of
      apathy and personal dissonance which undermines their professional value system,
      resulting in emotional distress and a crisis of identity. It provides a critical
      reflection on the way organizational dynamics and power relations influence the
      subjective sense-making of individuals. The authors use a multiplicity of
      perspectives, including those provided by individual psychology, power relations,
      feminism and personhood, to argue for the need to develop an alternative paradigm
      which is characterized by the valuing of individual persons, empathic sensitivity
      and the fostering of creativity.

PMID- 8655823
TI  - Information needs and sources of information for women with breast cancer: a
      follow-up study.
AB  - This paper reports a study which examined the specific information needs and
      sources of information for 105 women with breast cancer at two time points, the
      time of diagnosis and a mean of 21 months from diagnosis. At diagnosis the
      priority information needs concerned survival issues. Further from diagnosis
      survival issues were still a concern, but information about the risk to family
      members of getting breast cancer showed a significant increase in importance.
      Information about sexual attractiveness was ranked last at both the newly
      diagnosed and follow-up stages. Information sources at the time of diagnosis
      centred around the specialist breast care service, while further from diagnosis
      few professional or voluntary sector sources were utilized, with women receiving
      most of their information from media sources such as women's magazines. The
      relevance of these findings for nurses and other health care professionals is
      discussed.

PMID- 8655824
TI  - Women's experience of living with cancer.
AB  - This paper is drawn from a piece of empirical research which set out to give
      three women the opportunity to speak on their own behalf about how they
      experience having cancer in a sexual organ, using a feminist methodology to
      produce autobiographical stories. The stories describe the process of diagnosis
      and treatment and also convey the catastrophic nature of a diagnosis of cancer,
      which leads to a painful, existential crisis and feelings of bewilderment,
      powerlessness and isolation. The work was prompted by attendance at a workshop
      about cancer, body image and sexuality for sufferers and carers, which had
      indicated a depth of pain greater than is usually acknowledged. This pain
      suggested a fundamental link between body image and the posited concept of woman
      image; the existence of a common identity through the category woman as it is
      traditionally structured in society. This link is explored in relation to the
      evident changes in body image and the compromised sexualities of the women. The
      disabling consequences of female sexual stereotyping are elaborated and discussed
      as synergistic with the more fundamental stigma shadow cast by the prospect of
      dying. The paper discusses possible reasons for this in the context of a
      transformative rather than restorative model of living with cancer. It suggests
      that being thrown into self-conscious living could be a source of energy for
      renegotiation for women especially. The inadequacy of the medical model of
      disease is exposed and a more holistic approach is shown to be essential to
      address the needs of cancer patients, as is a critical appraisal and adjustment
      of existing social attitudes and relations.

PMID- 8655825
TI  - The pre- and postsurgical nursing of women with stress incontinence.
AB  - The aim of the present study was to evaluate subjective and objective methods
      used for the investigation of stress urinary incontinence (SUI) and to compare
      the outcome of two different surgical techniques regarding cure rate,
      postoperative nursing, bladder drainage and postoperative pain relief. The study
      included 45 women with SUI, randomized either to retropubic urethrocystopexy (n =
      30) or pubococcygeal repair (n = 15). The assessment included medical history,
      gynaecological examination, urine analysis and culture, residual urine, pad test,
      frequency-continence charts, water urethrocystoscopy, continence test, and
      cystometry with micturition analysis. Moreover, Beck's Depression Inventory and
      the Eysenck Personality Inventory were used before surgery. One year after
      surgery no significant difference in subjective cure rate was found between the
      two surgical methods (73% vs. 80%, respectively). According to pad tests, 67% of
      the women in the urethrocystopexy group and 47% in the pubococcygeal repair group
      had ceased to leak urine. The bladder volume increased significantly in both
      groups. Sixty-three per cent of the women in the urethrocystopexy and 33% in the
      pubococcygeal repair group experienced severe to very severe postoperative pain.
      In these groups, significantly more dysphoric women were found as compared with
      the group of women with less postoperative pain. Furthermore, the women with more
      severe pain scored higher on the neuroticism scale. These findings indicate the
      importance of personality factors in the treatment and nursing women with SUI.

PMID- 8655826
TI  - The effects of terminal illness on patients and their carers.
AB  - As part of a larger study, this paper describes the development and design of a
      project looking at the experiences of the relatives and carers of terminally ill
      patients in one health authority, as a replication of a similar study undertaken
      in another area. Following a description of the problems associated with studies
      into the problems of dying people and of the method used here, the results
      indicate that there are quite important effects on the household and carers,
      which include the problem of obtaining a diagnosis of terminal illness, and the
      actual process of dying. The study also highlights some of the effects of the
      terminal illness on the patients and their carers. In particular the results
      indicate that it was usually a spouse or the daughter who bore the brunt of the
      care, but that most preferred to retain their independence of the services as
      long as possible. Often, carers (and the patients) were not fully appraised that
      a terminal stage had been reached. Some doctors seemed reluctant (or found it
      difficult) to admit that such a stage had been reached. For many, the experience
      of dying was a very slow, distressing and often painful period, with serious
      limitations on their lifestyle imposed by the illness. A number of these
      limitations could have been reduced if earlier diagnosis had been made or if
      community nursing or social services had been called in sooner.

PMID- 8655827
TI  - Client views on periodic health examinations: opinions and personal experience.
AB  - Clients' views on periodic health examinations (PHEs) were examined in a
      questionnaire study in Tampere, Finland. A sample of 240 clients aged 45 years
      looked back at their recent experiences of PHE screening and counselling sessions
      with a public health nurse. According to the clients' accounts, the discussions
      and counselling had dealt with living habits and, to a lesser extent, diseases,
      symptoms and the prevention of illness. The vast majority of the respondents
      appreciated the friendly and considerate manner in which the nurse dealt with the
      situation. About half of them felt that the discussion was personally important
      to them. Virtually all respondents saw the PHE programme as beneficial for
      everyone. Opinions were more divided on the benefits of the health examination
      sessions compared with medical help from a physician or with laboratory tests.
      The dimensions of client opinions were extracted by means of factor analysis. One
      of the factors emerging in the analysis demanded access to health examinations
      from the vantage point of individual rights or entitlement. In women, a factor
      emphasizing self-care was also discerned. The interpretation of the factors was
      based on the social tradition of community-based health services in Finland by
      means of the concept of social representation.

PMID- 8655828
TI  - An exploratory study of recipients' perceptions of bone marrow transplantation.
AB  - Bone marrow transplantation (BMT) is now an established form of treatment for a
      wide range of malignant and non-malignant diseases. Research has led
      understanding and effective treatment of many side-effects of BMT. However,
      relatively little is known about how patients' perceive BMT, and how they view
      their experiences during transplantation. The purpose of this study was to
      describe the perceptions of a small group of BMT recipients. Audio-taped
      interviews were undertaken with six recipients of BMT who were well and in
      remission. This provided in-depth descriptive data of these individuals'
      experiences, which were analysed using latent content analysis. Five broad
      categories were identified under which data were grouped and discussed: mortality
      and death; luck; 'prison' (protective isolation); relationships; and physical
      effects. These revealed that patients attached relatively little importance to
      the physical effects of BMT, possibly because of the effectiveness of treatment.
      However, this led to a focus on other concerns, which the categories reflect. The
      importance of family members, particularly spouses, in sharing the burden of BMT,
      and the strengthening of family relationships were highlighted. The value of
      nurses was also emphasized. Protective isolation was found to be a stressor in
      two different ways. All of those interviewed reported concern with thoughts of
      their own mortality and possible death before and during BMT. Recommendations for
      nurses working in BMT units and suggestions for the direction of future research
      are made.

PMID- 8655829
TI  - An investigation into the application and maintenance of Hamilton Russell
      traction on three orthopaedic wards.
AB  - This study is concerned with the application and maintenance of Hamilton Russell
      traction, a form of vectored skin traction. It may be used in the treatment of
      fractures of the femur for the purposes of immobilization and for pain relief
      prior to surgery. A preliminary questionnaire demonstrated a poor level of
      knowledge in nurses working in an orthopaedic area. It was therefore speculated
      that application and maintenance of the traction would be inaccurate. The angles
      making up the resultant traction forces were measured in 11 systems. The
      theoretical traction force was established using mathematics. The actual force
      was measured using a goniometer. A comparison was then made. The results in all
      11 systems demonstrated a highly statistically significant difference between the
      theoretical and actual positions of the traction force (P < 0.0005). The
      practical implications of this are discussed and recommendations for a protocol
      of application and maintenance suggested. Areas for further research are
      identified.

PMID- 8655830
TI  - Perceptions of physical fitness and exercise activity among older adults.
AB  - The purpose of this research was to examine older adults' perceptions of physical
      fitness and exercise. This qualitative study was divided into four stages as
      described by Berg (1989): identification of the concept of the study; development
      of the interview guide; collection of data; and data analysis. Twenty-three older
      adults, aged 63-82 years (9 females, 14 males), participated in the interviews.
      Transcripts were analysed using content analysis. Three major themes emerged as
      the participants viewed physical fitness in terms of: functional independence
      ('being able to do'); holism ('mind-body works together'); and age reference (
      for people my age'). Nine elements which impeded or enhanced physical activity
      were identified. Implications for education, research and practice are discussed.

PMID- 8655831
TI  - Bladder instillations and bladder washouts in the management of catheterized
      patients.
AB  - Considerable controversy exists over the instillation of solutions into the
      bladder of catheterized patients. The main purpose of this paper is to present
      existing research-based evidence on the potential advantages and disadvantages of
      their use to assist practitioners to clarify the issues and to make informed
      decisions during client care.

PMID- 8655832
TI  - An investigation into nurses' perceptions of secluding patients on closed
      psychiatric wards.
AB  - Seclusion continues to be used in the care of acutely disturbed psychiatric
      patients despite often emotionally charged debate about its appropriateness
      within mental health services. Powerful legal and moral arguments about the use
      of seclusion emphasize an urgent need to critically examined its role into the
      care of mentally ill people. This paper examines the use of seclusion on closed
      psychiatric wards in the management of acutely disturbed patients. Seven
      psychiatric nurses working in two closed wards in an Australian teaching hospital
      were interviewed in relation to their perceptions of the role of seclusion. Data
      were analysed using grounded theory methodology revealing the core conceptual
      category 'controlling' and two sub-categories 'watching out for' and 'watching
      over'. Seclusion was found to be used as an adjunctive treatment in the care of
      individuals considered to be 'out of control'. Clinicians expressed comfort with
      the use of seclusion, citing a strict protocol that provided parameters for its
      use. Whilst expert therapeutic interventions were described by clinicians, they
      are contextualized within a framework of power and control - a framework that
      stands in stark contrast to contemporary philosophies of nursing care, providing
      impetus for a reconsideration of the use of constraining practices in the care of
      mentally ill people.

PMID- 8655833
TI  - A critique of multiculturalism in heath care: the challenge for nurse education.
AB  - This paper is concerned with the way in which discussions of the health status of
      people from minority ethnic groups and the delivery of health care to such groups
      has been constructed, in the nursing literature in particular, within a
      culturalist framework which has many serious drawbacks. The paper reviews the
      argument for a 'multicultural' approach to health care and also discusses some of
      the main implications of this analysis for the education of health professionals.
      It suggests that health workers and those responsible for the education of such
      workers, need to reassess learning needs in the light of a critique of the
      effects of an analysis based on 'cultural pluralism' and 'ethnic sensitivity'.
      The paper suggests ways in which the nursing curriculum must be broadened to take
      into account the limitations of a culturalist approach and to debate the
      interplay of racism and other structures of inequality and their influence on
      health and on a service delivery.

PMID- 8655834
TI  - Critical care nurse satisfaction with levels of involvement in clinical
      decisions.
AB  - This research reports the results of a survey of 230 Australian critical care
      nurses. The respondents were asked to rate how frequently they were involved in
      10 common critical care decisions and their levels of satisfaction with their
      involvement for each decision task. It was found that level of task satisfaction
      was positively correlated with level of task involvement, thus supporting the
      hypothesis that nurse task decision autonomy is associated with nurse task
      satisfaction. The paper argues for the importance of differentiation between task
      satisfaction and work satisfaction in research of these issues.

PMID- 8655835
TI  - The learning career in the community setting: a phenomenological study of a
      Project 2000 placement.
AB  - The findings of one element of an English National Board-funded research study
      conducted in two phases between 1989 and 1992 are discussed. The study examined
      one aspect of the new Project 2000 courses introduced in 13 'demonstration
      districts' in England in the autumn of 1989. During Phase 2 of the study (1991
      1992). 14 district nursing sisters and 12 of the students they supervised were
      interviewed. Data were re-transcribed and interpreted in 1993; the interpretation
      was based on a phenomenological paradigm which focused on the subjective
      perceptions of students and supervisors. Participants identified 'learning', as
      it took place in the community setting, as a sequential process, which is
      referred to here as the 'learning career'. Using terminology adopted by
      participants themselves; the authors identify the stages of the 'learning career'
      as:'encountering reality'; 'having a go' 'gaining confidence'; 'thinking through
      and understanding'; 'developing ideas'; 'being independent'; and 'being
      assessed'. Supervisors could ease their students' passage through this complex
      and anxiety-provoking sequence of events in a number of ways. They could
      demonstrate their practice and provide opportunities for students to gain
      experience for themselves; they could teach their students about nursing, and
      enable them to reflect on their own practice; and they could also monitor and
      assess their students' work.

PMID- 8655836
TI  - New meanings: a qualitative study of change in nursing education.
AB  - This paper reports on the experiences of teachers in one college of nursing and
      midwifery in South East England during a period of profound and complex change.
      Personal perceptions and reactions are studied in the context of professional
      organizational influences. A phenomenological approach was used to identify and
      portray the personal perspectives and meanings of the respondents. Fifty semi
      structured interviews with a purposeful sample of the college staff were
      supplemented with participant observation and documentary analysis. The data were
      analysed inductively, and emergent categories were confirmed and clarified
      through respondent validation. Findings relating to organizational, professional
      and personal perceptions are presented alongside the major themes of belonging,
      knowing and controlling. The conclusions and implications of this exploratory
      study are discussed, together with aspects of the researcher's role and areas for
      future research.

PMID- 8655837
TI  - International comparison of baccalaureate nursing degrees: collaboration in
      qualitative analysis.
AB  - This paper describes a study which investigated the perceived similarities and
      differences of a selection of baccalaureate nursing degrees from different
      continents. An international research team was formed, and by using a modified
      version of the Delphi process and nominal group techniques the group undertook a
      qualitative analysis of curriculum documents. The major areas analysis were:
      aims, content, methods and assessment. Under these headings the group produced a
      list of key issues supported by a number of indicative statements by collating
      the independent analyses undertaken by each of the team members. Examples of
      findings are that critical thinking and personal development are most obvious in
      aims but that the progression of curricula may not achieve this, there are
      differences in 'western' and 'asian' orientations to the concept of personal
      autonomy. Sciences are valued more than arts or humanities. The lecture method as
      well as practice placement dominate the teaching methods. Transcultural nursing
      is not significant except where there are two therapeutic ideologies in
      existence. Assessment methods are largely summative. The findings have
      application in the development of credit transfer and international exchange
      schemes. The conclusions highlight areas of special considerations when designing
      such schemes.

PMID- 8655838
TI  - Nurse teacher's clinical work: a survey report.
AB  - This paper reports on the results of a survey of nurse teachers in four colleges
      of nursing in England (n = 126). Data were collected using a questionnaire
      survey. In this survey a five-point Likert scale was developed from an earlier
      study, to explore nurse teachers' perception of this clinical role. The findings
      indicate that a number of factors may be influential in the way in which nurse
      teachers approach their clinical activity. This includes personal factors such as
      age, educational grade and the length of time spent working in nurse education.
      Organizational factors also appear to make a difference in the teacher who worked
      in an organizational model which ensured a smaller number link ward areas were
      more likely to exhibit a positive and orientation towards clinical work. Factor
      analysis of the clinical scale resulted in loading of items relating to
      confidence in clinical role, preparation for the role, influence in clinical area
      and supervision of students in clinical areas. The implications of these findings
      are discussed.

PMID- 8655839
TI  - An investigation into how the health care assistants perceive their role as
      'support workers' to the qualified staff.
AB  - This qualitative study investigates the support worker's role as perceived by
      health care assistants (HCAs) who have undergone some training and National
      Vocational Qualification assessments. The findings suggest that the HCAs consider
      that they support the trained nurses by acting as a link in the communication
      chain between the patient and carers, and by providing 'time' for the trained
      nurse to use in therapeutic activities. The indications are that the HCAs
      perceive little difference between their roles and those of qualified nurses, and
      they experience ambiguity as to their proper role. The researcher sought to apply
      role theory in an inductive approach to data interpretation, from which it is
      posited that the HCAs' role ambiguity arises because the qualified nurses' own
      role lacks clarity and this affects their expectations of the HCA's role. Having
      had some training, the roles are more ambiguous now than before as the HCAs are
      no longer untrained carers but nor are they qualified professionals. It is also
      suggested that the qualified nurses perceive the HCAs as a threat to their own
      roles in that the HCAs are seen as depriving them of their 'real' nursing role;
      thus they are experiencing 'role deprivation'. Recommendations to clarify role
      expectations and reduce role ambiguities are suggested to alleviate an avoidable
      source of stress for both the qualified nurse and the HCA.

PMID- 8655840
TI  - Postgraduate education in nursing: a case study.
AB  - This paper describes the integrated postgraduate programmed recently introduced
      by the University of Ulster which includes the first Doctor of Nursing Science
      (DNSc) programme in Europe. It has three exist points: with a Postgraduate
      Diploma in Advanced Nursing or Midwifery, a Master of Science in Advanced Nursing
      or Midwifery or the DNSc. It aims to develop nurses who have the necessary
      knowledge and skills to function as advanced practitioners and, concurrently, to
      prepare nurses able to undertake high quality research which will contribute to
      the knowledge and theoretical base of nursing. Some of the issues which
      influenced the planning are discussed and demographic characteristics,
      expectations of the course, and comments of the first two cohorts of students are
      presented. Anticipated benefits for nursing knowledge and practice as well as
      potential difficulties with such a programmed are identified.

PMID- 8655842
TI  - III European Congress of Gerontology held at the RAI Conference Centre,
      Amsterdam, The Netherlands, 30 August-2 September 1995.

PMID- 8655841
TI  - A history of nursing: a history of caring?
AB  - The history of nursing is, itself, a fit subject for research. It is unclear what
      would constitute history in this case, its time frame or its methodology. It is
      also the case that the purpose of history needs exploration, since it can meet
      many goals, including the goal of professionalization. This paper explores these
      issues in some detail, using examples from the literature in the history of
      nursing. It explores historical inquiry and purpose and the problems of sources.
      The paper also addresses the relationship between the history of nursing and
      nursing theory and questions whether existing historical scholarship is
      integrated with or is outwith mainstream nursing theory. The paper questions the
      relevance of the history of nursing and suggests that the history of caring may
      offer one way through history to nursing theory.

PMID- 8655843
TI  - Nursing in the year 2000.

PMID- 8655844
TI  - Legal and ethical issues. Flexibility and faithfulness.

PMID- 8655845
TI  - Education. Is tenure still viable today?

PMID- 8655846
TI  - History. Care versus cure--examining the dichotomy through a historical lens.

PMID- 8655847
TI  - International affairs. The harsh reality of community care.

PMID- 8655848
TI  - Measuring the leadership styles and scholarly productivity of nursing department
      chairpersons.
AB  - Self-perceived leadership styles of nursing department chairpersons were
      correlated with their scholarly productivity. The sample consisted of the 106
      nursing department chairpersons from National League for Nursing (NLN)-accredited
      baccalaureate and higher-degree programs in 10 midwestern states. Hersey and
      Blanchard's Situational Leadership Model was used as the conceptual framework.
      Their LEAD-Self instrument was used to measure leadership styles, range, and
      adaptability. In addition, the Scholarly Productivity Index (SPI) was used to
      measure the nursing chairpersons' involvement in prepublication and research,
      publication, editorial, and other scholarly activities. College size and status
      (public or private) were among the variables examined to assess a relationship or
      group differences. A majority of nursing department chairpersons viewed
      themselves as having a "participating" leadership style. Most of the remaining
      chairpersons viewed themselves as having a "selling" leadership style. Study
      participants viewed their backup leadership styles to be in a reverse order from
      their primary leadership styles with the "selling" leadership style the most
      frequently used backup style and "participating" the second most frequently used
      style. Chairpersons from public nursing schools reported significantly greater
      numbers of scholarly activities than did chairpersons from private nursing
      schools. Chairpersons who had held their positions for less than 5 years tended
      to have a "participating" leadership style. A majority of nursing department
      chairpersons in the study reported that they felt institutional pressure to
      engage in scholarly activities.

PMID- 8655849
TI  - Advanced practice in nursing: conceptual issues.
AB  - The issue of defining advanced practice nursing roles is increasingly a subject
      of national discussion and debate. Central to this discussion has been the issue
      of merging nurse practitioner (NP) and clinical nurse specialist (CNS) roles and
      the tendency for the term "nurse practitioner" to replace that of "clinical nurse
      specialist" in denotation of these roles. The authors note the lack of any
      attempt to use a broader conceptual approach in these discussions. In this
      article, the development of each role is reviewed, and the strengths and
      weaknesses of each role in current practice and education are evaluated. The
      authors conclude that inadequate justification exists for continuing both roles,
      but that the answer is not in simply replacing the CNS with the NP. Ongoing
      careful and thoughtful dialogue should be used to guide the merging of these two
      roles.

PMID- 8655850
TI  - Consortia arrangements and educational telecommunication.
AB  - Revolutionary and rapid changes are required in nursing programs and products to
      fit with the developing health care system. Many present-day nurses and nursing
      faculty will require changes in their areas of expertise. Nursing colleges that
      have faculty qualified in the areas of greatest need should explore the use of
      consortia for delivering distance education. In this way, quality can be
      controlled, and the conflict of interest involved in schools trying to change the
      preparation of their own faculty can be reduced or resolved. Organizing consortia
      is complex, with problem areas in administration, personnel, and resources.
      Selected television satellite networks are offered as examples of how to manage
      the problem areas or as possible vehicles for course delivery.

PMID- 8655851
TI  - Earning a Master's of Science in Nursing through distance education.
AB  - The increased availability of telecommunications technology has made possible the
      offering of degree programs via distance education. Such programs make courses
      and degrees more readily accessible to a wider range of students than has
      traditionally been the case. The University of Tennessee, Memphis, College of
      Nursing has undertaken to offer a Master's of Science in Nursing degree entirely
      by distance education. The challenges, successes, and technology of the program
      are discussed.

PMID- 8655852
TI  - Multicultural ethics in nursing education: a potential threat to responsible
      practice.
AB  - If nurses are to make the kind of contribution they are capable of making to the
      betterment of human health, then they must critically examine the moral
      injunctions and tenets of multicultural ethics that are being widely promulgated
      in nursing education. Such an examination, undertaken in this article, shows that
      responsible nursing practice cannot be realized under multicultural ethics. An
      alternate ethical basis for practice, a transcultural ethics grounded in moderate
      realism, is described and recommended because it provides principles that permit
      the realization of responsible practice.

PMID- 8655853
TI  - Integration into professional nursing by graduates of an innovative entry-level
      MSN program.
AB  - Recently, nursing programs that admit nonnurse college graduates to graduate
      study in nursing have emerged around the country. The University of Texas at
      Austin has such a program called the Alternate Entry Master of Science in Nursing
      (AEMSN) program. Using a grounded theory approach, 13 telephone interviews were
      conducted with alumni of the AEMSN program to examine the socialization of these
      nontraditional graduates into the profession of nursing. Participants reported
      some anxiety as they approached graduation. They were particularly aware of a
      disconnection between their academic credentials and their limited professional
      nursing experience. To manage others' and their own expectations of them, the
      participants chose various strategies, such as using positive self-talk and
      seeking a manager who understood and favored the AEMSN program. Eventually the
      graduates found places where they felt comfortable and where they could hone
      their skills. As they began to function in roles that they believed were
      consistent with master's level nursing, the AEMSN graduates began to embrace the
      identity of master's-prepared nurses.

PMID- 8655854
TI  - Tapping into the culture of homelessness.
AB  - This article describes the problem of homelessness from a cultural perspective.
      Three health and human service agencies located in Pennsylvania were investigated
      to ascertain whether the needs of the homeless as a culture were being met. The
      findings of this qualitative investigation conclude that the strategies of
      survival inherent in the culture of homelessness are rarely considered by social
      and health agencies in providing services to the homeless. Implications for
      improving health and other services provided for the homeless from a cultural
      perspective are discussed in the concluding remarks of the report.

PMID- 8655855
TI  - Diagnostic oddities of the strangest form.
AB  - It's called Munchausen's syndrome, after an 18th-century German soldier known for
      fabricating fabulous stories. Most clinical descriptions of this intriguing
      oddity are found in the medical literature, although examples of patients
      feigning dental diseases also have been documented.

PMID- 8655856
TI  - Is peroxide a hazard?

PMID- 8655857
TI  - Misleading your patients.

PMID- 8655858
TI  - A question on crowns.

PMID- 8655859
TI  - Electronic claims.

PMID- 8655860
TI  - HMO expenses.

PMID- 8655861
TI  - Radiographic guidelines.

PMID- 8655862
TI  - Mouthguards, headgear not worn regularly.

PMID- 8655863
TI  - Preparing patients for cancer therapy.

PMID- 8655864
TI  - Dentistry and government: evolution of a relationship.

PMID- 8655865
TI  - State leaders share their thoughts on government relations.

PMID- 8655866
TI  - The impact of edentulousness on food and nutrient intake.
AB  - The authors collected dietary intake data about the food and nutrient intake of
      49,501 male health professionals. Edentulous participants consumed fewer
      vegetables, less fiber and carotene, and more cholesterol, saturated fat and
      calories than participants with 25 or more teeth. These factors could increase
      the risks of cancer and cardiovascular disease. Mean differences in intake ranged
      from 2 to 13 percent, independent of age, smoking, exercise and profession.
      Longitudinal analyses suggest that tooth loss may lead to detrimental changes in
      diet.

PMID- 8655867
TI  - Digital enhancement of radiographs: can it improve caries diagnosis?
AB  - Unlike traditional radiographs, digital images are electronically alterable and
      offer the potential for enhancing diagnostic information. The authors conducted a
      small-scale study to examine differences in clinicians' diagnoses of caries using
      traditional radiographs and digitized images vs. microscopic diagnosis. Two
      general dentists and one oral-maxillofacial radiologist scored the images for
      caries. This study suggests that digital enhancements may aid some clinicians in
      caries diagnosis.

PMID- 8655868
TI  - Clinical assessment of bad breath: current concepts.
AB  - Bad breath typically originates in the mouth, often from the back of the tongue.
      Nasal problems also can cause bad breath; odor generated in this manner can be
      easily distinguished from mouth odor by comparing the odor exiting the mouth and
      nose. In most cases, good professional oral care combined with a daily regimen of
      oral hygiene--including interdental cleaning, deep tongue cleaning and optional
      use of an efficacious mouthrinse---will lead to improvement. This article
      discusses common causes of oral malodor as well as methods to assess the extent
      of the problem.

PMID- 8655869
TI  - Assessing abuse and neglect and dental fear in women.
AB  - Little is known about how specific life stressors, such as sexual, physical and
      emotional abuse and neglect, might be factors in the establishment or maintenance
      of dental fears or might affect routine dental treatment. The authors collected
      data from 462 female members of a large urban health maintenance organization
      about their dental fear and histories of childhood and adult traumas. According
      to these data, a history of trauma appears to be significantly associated with
      elevated dental fear, although multiple factors play a major role in the
      establishment and maintenance of these phobias.

PMID- 8655870
TI  - ADA advertising++ standards.

PMID- 8655871
TI  - Hereditary gingival fibromatosis: identification, treatment, control.
AB  - Hereditary gingival fibromatosis, or HGF, is characterized by varying degrees of
      attached gingival hyperplasia. The authors describe a case of generalized severe
      hereditary gingival fibromatosis involving the maxillary and mandibular arches.
      Removal of excess gingival tissue by conventional gingivectomy dramatically
      improved the patient's appearance.

PMID- 8655872
TI  - Tooth sensitivity related to Class I and II resin restorations.

PMID- 8655873
TI  - Dentists' personal values: an exploratory investigation.
AB  - A sample of 367 dentists, all licensed to practice in Oregon, provided data for
      an investigation of the personal values of dentists. The authors found that the
      dentists' values differed in several particulars from those of the general
      population. On the other hand, they found that the values of younger and older
      dentists were highly similar, as were the values of male and female dentists.

PMID- 8655874
TI  - Accessing MEDLINE from the dental office.
AB  - Electronic access to on-line information is now available for dentists. One such
      resource is MEDLINE, a database of more than 7,500,000 biomedical references
      indexed by the National Library of Medicine. MEDLINE searching can be performed
      on-line or locally using a CD-ROM drive. Dentists should evaluate equipment
      requirements, availability of training, extent of the bibliographic database,
      ease of using the searching software and adequacy of documentation before
      selecting a mode of MEDLINE access.

PMID- 8655875
TI  - The war on oral cavity and pharyngeal cancer.

PMID- 8655876
TI  - Does the dentist have an ethical duty to report child abuse?

PMID- 8655877
TI  - Oral prednisone therapy in experimental rhinovirus infections.
AB  - This study was designed to test the effects of oral steroid therapy on the kinin
      levels and symptoms of experimental rhinoviral colds. Forty-seven men were
      randomized to receive prednisone (20 mg) or placebo. Therapy was administered
      three times a day for 5 days, after one dose was given 11 hours before
      inoculation with rhinovirus. Viral titers, symptom scores, and kinin and albumin
      concentrations in nasal washes were monitored. The mean kinin levels were lower
      in the steroid group (287 vs 449 pg/ml, p = 0.005) with significant differences
      in kinin levels on days 3 and 4 (p < 0.01). No significant difference in total
      symptom scores was seen between the two groups. Except for increased sneezing (p
      < 0.01) and mucus weights (p < 0.05) on day 1 in patients treated with
      prednisone, there were no significant differences in individual symptom scores.
      Headache tended to be less prominent in steroid recipients. Mean viral titers
      were higher in the steroid group (1.13 vs 0.79, p = 0.03) with significant
      differences in the daily viral titers on days 3 (p < 0.05) and 4 (p < 0.01).
      Steroids reduced kinin levels in rhinoviral infections, but that reduction was
      not associated with a significant reduction in symptoms. This study also provides
      evidence for the enhancement of viral growth in steroid recipients.

PMID- 8655878
TI  - Human immune response to pneumococcal polysaccharides: complement-mediated
      localization preferentially on CD21-positive splenic marginal zone B cells and
      follicular dendritic cells.
AB  - A functionally intact spleen with a marginal zone, containing B cells with high
      density of surface C3d-receptors (CD21), is essential for the ability to induce a
      primary immune response to thymus-independent type 2 (TI-2) antigens. Main
      representatives of natural TI-2 antigens are capsular pneumococcal
      polysaccharides (PPSs). In this study the localization of different types of PPS
      antigen is determined in human spleen tissue. Our findings indicate that a main
      type of TI-2 antigen, PPS, localizes preferentially in the marginal zone. PPSs
      show co-localization with C3, presumably C3d, at the surface of strongly CD21+ B
      cells equipped for rapid activation. This enables a rapid primary humoral
      response. The other main PPS localization at follicular dendritic cells in
      germinal centers, relevant for isotype switching of anti-PPS antibodies, does not
      seem to be dependent on the presence of specific immunoglobulin. This may explain
      the finding of specific IgG in an early stage after antigenic challenge. It seems
      likely that complement C3 fragments (likely C3d), bound to PPSs, enable PPS
      localization at B-cell and follicular dendritic cell surfaces by binding to CD21,
      the C3d receptor.

PMID- 8655879
TI  - Occupational asthma caused by imbuia wood dust [case report].

PMID- 8655880
TI  - Hypersensitivity pneumonitis: problems in diagnosis.

PMID- 8655881
TI  - Systemic reactions to immunotherapy: comparisons between two large allergy
      practices.

PMID- 8655882
TI  - The eosinophil: a cytokine-producing cell?

PMID- 8655883
TI  - Type 1 allergic reactions to plant-derived food: a consequence of primary
      sensitization to pollen allergens.

PMID- 8655884
TI  - Vaccines: new approaches and concepts.

PMID- 8655885
TI  - Cat antigen in homes with and without cats may induce allergic symptoms.
AB  - Although Fel d 1, the major cat allergen, has been found in settled dust samples
      from homes both with and without cats, the clinical relevance of this allergen
      has never been studied. In this study we measured airborne concentrations of Fel
      d 1 in homes both with and without cats and then attempted to relate these levels
      to those obtained in our experimental cat challenge model to assess their
      clinical significance. In baseline samples we found measurable levels of airborne
      Fel d 1 in all 37 homes with cats (range, 1.8 to 578 ng/m3; median, 45.9 ng/m3)
      and in 10 of the 40 homes without cats (for detectable samples: range, 2.8 to
      88.5 ng/m3; median, 17 ng/m3). Fel d 1 was present in the settled dust of 38 of
      40 homes without cats (range, 39 to 3750 ng/gm; median, 258 ng/gm), although
      these levels were only weakly predictive of airborne levels. Repeat samples
      obtained weekly from 12 homes without cats yielded measurable airborne levels.
      Fel d 1 in at least one of the four samples from all homes. When compared with
      challenges performed in our cat room facility at low levels of airborne Fel d 1
      (<500 ng/m3), these home levels are within the range capable of causing upper and
      lower respiratory symptoms in subjects allergic to cats. We therefore conclude
      that the low level cat exposure that occurs in many homes without cats is capable
      of inducing symptoms in some patients who are sensitive to cats. The assessment
      of cat exposure should not be based solely on the presence or absence of a cat in
      the home.

PMID- 8655886
TI  - Fluticasone propionate aqueous nasal spray compared with terfenadine tablets in
      the treatment of seasonal allergic rhinitis.
AB  - BACKGROUND: Comparative studies with topical corticosteroids and antihistamines
      for treatment of allergic rhinitis have not always demonstrated clear
      distinctions between the two on the basis of therapeutic efficacy. OBJECTIVE:
      This study was designed to compare the efficacy and tolerability of fluticasone
      propionate aqueous nasal spray with those of terfenadine in the treatment of
      seasonal allergic rhinitis. METHODS: Three hundred forty-eight patients with
      allergic rhinitis were given fluticasone propionate aqueous nasal spray (200
      micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 4
      weeks in a multicenter, randomized, double-blind, double-dummy, parallel-group
      study. RESULTS: Clinician-rated total nasal symptom scores after 1, 2, 3, and 4
      weeks of therapy and patient-rated total nasal symptom scores throughout
      treatment were significantly (p <0.05) lower in the fluticasone propionate group
      compared with the terfenadine group or the placebo group. Terfenadine was not
      statistically different from placebo on the basis of clinician-related nasal
      symptom scores, except for sneezing. Total nasal airflow, measured by
      rhinomanometry, significantly (p <0.05) improved in the fluticasone propionate
      group compared with the terfenadine group or the placebo group. More fluticasone
      propionate-treated patients compared with placebo-treated patients had reduced
      nasal mucosal eosinophil counts after 4 weeks of therapy (p <0.05). No serious or
      unusual drug-related adverse events were reported. Morning plasma cortisol
      concentrations after 4 weeks of therapy did not differ among groups. CONCLUSION:
      Fluticasone propionate aqueous nasal spray is more effective than terfenadine
      tablets for treatment of seasonal allergic rhinitis.

PMID- 8655887
TI  - Association of skin test reactivity, specific IgE, total IgE, and eosinophils
      with nasal symptoms in a community-based population study. The Dutch ECRHS Group.
AB  - BACKGROUND: Skin prick tests and measurement of specific IgE are important
      markers of the possible causes of disorders of the upper respiratory tract.
      OBJECTIVE: In this study we investigated the association of skin test reactivity
      and specific IgE positivity to five common aeroallergens separately and of total
      serum IgE and eosinophil count with nasal allergy symptoms in a random sample of
      the adult population in the Netherlands. METHODS: A cross-sectional study was
      carried out in a sample of 2167 subjects, aged 20 to 70 years, stratified by age
      and gender. Nasal allergy symptoms were differentiated into three categories:
      symptoms after exposure to indoor allergens only, symptoms after exposure to
      outdoor allergens only, and symptoms after exposure to both indoor and outdoor
      allergens. Associations were investigated by multiple logistic regression
      analyses with adjustment for area of residence, gender, age, and smoking status.
      RESULTS: Skin test and specific IgE reactivity to indoor and outdoor allergens
      were significantly related to their corresponding nasal symptom groups. Odd
      ratios increased with increasing number of positive skin test results or
      increasing levels of specific IgE to allergens in all three nasal symptom groups.
      For each allergen, a positive skin test result together with a positive specific
      IgE measurement were the strongest predictors of nasal symptoms. Sensitization to
      house dust mite was the most prevalent in our study population, whereas the
      association of skin test reactivity and specific IgE positivity with nasal
      symptoms was strongest for cat allergen. Skin test and specific IgE reactivity to
      Cladosporium species were not significantly related to the prevalence of nasal
      symptoms. Total serum IgE was related to nasal symptoms only in subjects who
      reported symptoms in response to both indoor and outdoor allergens and only at
      high levels of IgE. Eosinophil count was associated with nasal symptoms in all
      nasal symptom groups. CONCLUSION: Our findings confirm the close relationship of
      skin test positivity with reported symptoms of nasal allergy in a general
      population. Specific IgE positivity also shows a close relationship with nasal
      symptoms in response to allergen exposure in a general population. Skin testing
      and specific IgE measurement may be considered complementary to one another in
      diagnosing allergic rhinitis. Total IgE may be considered an indicator of greater
      dysregulation of the immune system in atopic allergy. Eosinophil count is
      associated with nasal symptoms, regardless of type and extent of nasal symptoms.

PMID- 8655888
TI  - Adverse reactions to local anesthetics: analysis of 197 cases.
AB  - BACKGROUND: Adverse drug reactions to local anesthetics are frequently reported.
      However, little is known about the underlying mechanisms. Therefore we
      investigated 177 patients with a history of 197 events after application of these
      drugs. METHODS: The diagnostic approach included prick and intracutaneous tests,
      provocative challenge tests with causative and unrelated local anesthetics, and
      in selected cases, radioimmunoassays to detect specific IgE. In addition, tests
      were performed with preservatives, including sodium metabisulfite and
      parahydroxybenzoic acid ester. RESULTS: Results of prick and intracutaneous tests
      with local anesthetics were all negative. Only three patients reacted after
      subcutaneous challenge with the causative drug (local anesthetics of the amide
      type). Although one patient showed a delayed-type response to mepivacaine, two
      patients had immediate-type reactions to articaine and lidocaine. However, in
      both cases no specific IgE could be detected. In five patients with positive skin
      test reactions to preservatives, challenge test results remained negative.
      CONCLUSION: Two immediate-type reactions were not IgE-mediated. In only one of
      197 reported adverse reactions were we able to prove delayed-type allergic
      response. Therefore true allergic reactions caused by local anesthetics are
      extremely rare.

PMID- 8655889
TI  - Airway responsiveness after a single dose of salmeterol and during four months of
      treatment in children with asthma.
AB  - BACKGROUND: Inhalation of a single dose of the long-acting beta 2-adrenoceptor
      agonist salmeterol protects against methacholine-induced airway obstruction and
      other bronchoconstricting stimuli for at least 12 hours. Hypothetically, twice
      daily dosing of salmeterol may result in continuous protection. OBJECTIVE: This
      study was designed to investigate the protective effect of a single dose of
      salmeterol and of continuous twice daily treatment on airway responsiveness to
      methacholine. METHODS: In a double- blind, parallel study, salmeterol 50
      micrograms twice daily was compared with salbutamol 200 micrograms twice daily.
      Thirty children with mild asthma, who had little or no bronchial obstruction and
      were hyperresponsive to methacholine (PD20 < or = 150 micro g) were allocated to
      receive either salmeterol or salbutamol. Airway responsiveness was measured
      before study entry, 12 hours after a single dose of drug was given, and monthly
      during 4 months of daily treatment. Measurements were always performed at the
      same time of the day, 12 hours after the last dose of medication was
      administered. RESULTS: No significant differences in FEV 1 were found between
      treatments at any time point. PD20 significantly increased after the first dose
      of salmeterol was given (geometric mean, 100 micro g). Geometric mean PD20 values
      were significantly better during salmeterol treatment than during salbutamol
      treatment, 52 and 25 micro g, respectively (p = 0.005). CONCLUSION: The
      protection provided by salmeterol during maintenance treatment was less than that
      provided after the first dose (p <0.001). However, protection did not diminish
      during the 4-month treatment period and remained significant compared with
      baseline (p = 0.003).

PMID- 8655890
TI  - Nasal neutrophilia and release of myeloperoxidase induced by nasal challenge with
      platelet activating factor: different degrees of responsiveness in atopic and
      nonatopic subjects.
AB  - BACKGROUND: Nasal challenge with platelet activating factor (PAF) is able to
      induce local neutrophilia, with a different degree of responsiveness in atopic
      subjects and in nonatopic subjects. We investigated whether nasal accumulation of
      neutrophils induced by PAF is accompanied by the release of neutrophil-derived
      mediators. METHODS: Nasal lavages were performed before and after challenge with
      PAF (500 nmol), lyso-PAF (500 nmol), and saline solution in 10 patients with
      allergic rhinitis and 10 normal subjects to evaluate changes in neutrophil counts
      and the release of myeloperoxidase (MPO) and immunoreactive leukotriene B4.
      RESULTS: PAF caused neutrophilia, which appeared after 30 minutes in atopic
      subjects and after 3 hours in nonatopic subjects. Furthermore, when compared with
      saline insufflation, PAF caused a significant release of MPO in the nasal lavage
      fluids collected 30 minutes, 3 hours, and 24 hours after challenge in atopic
      subjects and 3 hours after challenge in nonatopic subjects, with higher values in
      the former than in the latter. Neutrophil counts correlated with MPO levels in
      the nasal lavages collected after PAF challenge. A lower degree of neutrophilia
      was found 3 hours after stimulation with lyso-PAF in both groups of subjects,
      with a marginal release of MPO in atopic subjects only. No significant increase
      of immunoreactive leukotriene B4 levels in nasal lavages was found after
      challenge with either PAF or lyso-PAF. CONCLUSION: These results indicate that
      PAF-induced neutrophilia in the nose is accompanied by the release of MPO, which
      appears earlier and is more marked in atopic subjects than in nonatopic subjects.

PMID- 8655891
TI  - CD4 T-lymphocyte activation is associated with peak expiratory flow variability
      in childhood asthma.
AB  - BACKGROUND: Asthma has been recognized as a chronic inflammatory disorder of the
      airway. We have investigated the relationships among the activation markers on
      lymphocytes, eosinophils, their serum products in the peripheral blood, and the
      variability of airway obstruction in childhood asthma. METHODS: Twenty-two
      patients with atopic asthma (mean age, 12 years) were treated regularly and asked
      to measure their peak expiratory flow (PEF) twice daily for 7 days, Peripheral
      venous blood was obtained on day 8. RESULTS: The absolute counts of CD4 T
      lymphocytes expressing the activation marker CD25 in the peripheral blood on day
      8 correlated significantly with the values of the coefficient of variation (CV)
      of both morning PEF (p < 0.01) and night PEF (p < 0.05) obtained over 7 days, but
      those of CD8+/CD25+ T lymphocytes, those of CD23+ B lymphocytes, and the serum
      concentrations of soluble CD25 did not. The absolute counts of peripheral blood
      eosinophils also demonstrated a significant correlation with the CV values of
      both morning PEF (p < 0.01) and night PEF (p <0.05). CONCLUSION: CD4 T-lymphocyte
      activation and increased counts of eosinophils in peripheral blood correlate with
      CV of PEF in patients with asthma, suggesting that CV of PEF is a good marker for
      assessing not only the variability of airway obstruction but also the degree of
      airway inflammation.

PMID- 8655892
TI  - Specific depletion of the house dust mite allergen Der p 1 cereal flour
      prolamins.
AB  - BACKGROUND: Quantitation of Der 1 and Der 2 in dust samples by specific
      monoclonal antibodies is a method used increasingly to evaluate mite allergen
      exposure. The level of Der 1 has been proposed as a risk factor for
      sensitization. AIM: We report a drastic decrease in the Der 1/Der 2 ratio when
      dust samples are collected in bakeries. METHODS: Wheat flour and purified mites
      were extracted simultaneously; levels of Der p 1 and Der p 2 and cysteine
      protease activity were determined by ELISA and inhibition experiments. RESULTS:
      High titers of Der 2, but only trace amounts of Der p 1, were detected in dust
      collected from bakeries. Both the level and proteolytic activity of Der p 1
      appeared greatly decreased when mites and wheat flour were coextracted.
      CONCLUSION: Group 1 protein was found to be masked by flour components, resulting
      in an underestimation of the mite content in bakery dust. This problem was not
      found for group 2 allergen.

PMID- 8655893
TI  - Compartmentalization of eosinophil granulocyte-macrophage colony-stimulating
      factor expression in patients with asthma.
AB  - BACKGROUND: In patients with asthma the endobronchial instillation of an allergen
      induces recruitment of granulocyte-macrophage colony-stimulating factor (GM-CSF)
      messenger RNA-positive eosinophils into the airway. OBJECTIVE: The goal of the
      study was to determine whether peripheral blood (as opposed to bronchoalveolar
      lavage) eosinophils express GM-CSF mRNA and protein. METHODS: We performed in
      situ hybridization and immunocytochemistry on peripheral blood eosinophils,
      obtained at 0, 4, and 24 hours after either inhalation of diluent, inhalation of
      allergen, or endobronchial instillation of allergen. RESULTS: Each study subject
      (n = 6) had both an immediate and late-phase response to allergen inhalation but
      not to diluent inhalation. Allergen, but not diluent, challenge induced a
      significant increase in the number of peripheral blood eosinophils at 24 hours.
      In situ hybridization of peripheral blood eosinophils with a sulfur 35-labeled GM
      CSF RNA riboprobe and immunostaining with a GM-CSF monoclonal antibody revealed
      that neither pre- nor postchallenge (allergen or diluent) peripheral blood
      eosinophils expressed GM-CSF mRNA or protein. In contrast, both bronchoalveolar
      lavage eosinophils and mononuclear cells expressed GM-CSF mRNA and protein.
      CONCLUSION: These studies suggest that the expression of GM-CSF by eosinophils
      after allergen inhalation is compartmentalized to the lungs.

PMID- 8655894
TI  - Laboratory determinations in Anisakis simplex allergy.
AB  - BACKGROUND: Anaphylactic reactions caused by the fish nematode, Anisakis simplex,
      after ingestion of parasitized fish, have been described. OBJECTIVE: This study
      was undertaken to confirm, by histamine release tests, that A. simplex is able to
      trigger IgE-mediated reactions and to describe the serologic profiles in this
      sensitization. METHODS: Twelve patients who had anaphylactic symptoms after
      ingestion of cooked fish and positive prick test results and determinations of
      IgE to A. simplex were studied by indirect IgG ELISA and IgG and IgE
      immunoblotting. Sera from subjects parasitized with other nematodes, patients
      with fish allergy, and healthy donors were included as controls. A histamine
      release test was performed in a representative case. RESULTS: IgE immunoblotting
      was a specific test to detect A. simplex allergy. IgE-reacting bands were found
      in serum samples from 11 of our patients. Specific IgG antibodies were found by
      ELISA and immunoblotting, but this response was less specific. Histamine release
      was positive with A. simplex extract and negative with fish. CONCLUSION: A
      specific and intense immune response to an A. simplex extract was found in our
      patients. A. simplex is able to elicit anaphylactic reactions, and A. simplex
      allergy should be suspected in patients with allergic symptoms after ingestion of
      fish. A positive prick test response to A. simplex and a negative response to
      fish is a good indication for a diagnosis of A. simplex allergy.

PMID- 8655895
TI  - Evaluation of the gut mucosal barrier: evidence for increased antigen transfer in
      children with atopic eczema.
AB  - BACKGROUND: Intestinal antigen handling determines subsequent immune response to
      the antigen. Antigens are absorbed across epithelium along two functional
      pathways. The main pathway is degradative, which reduces the immunogenicity of
      the antigen. A minor pathway allows the transport of intact proteins, which is
      crucial for antigen-specific immune responses. The Ussing chamber method allows
      the quantitative measurement of protein transfer across the intestinal mucosa.
      OBJECTIVE: This study was designed to explore the theory that altered antigen
      transfer across the intestinal mucosa is a factor in the pathogenesis of atopic
      eczema, characterized by hyperactivity to environmental antigens. METHODS: The
      absorption and degradation of horseradish peroxidase (molecular weight, 40,000 d)
      were studied in vitro in Ussing chambers. Eighteen biopsy specimens of upper
      small intestinal mucosa from 14 patients (aged 0.5 to 8 years) with atopic eczema
      and 18 specimens from 15 age-matched control subjects were examined. RESULTS: The
      mean (95% confidence interval) absorption of intact horseradish peroxidase was
      significantly higher in children with atopic eczema than in control subjects: 242
      (81-404) pmol . hr(-1) . cm(-2) versus 23 (12-33) pmol . hr(-1) . cm(-2); t =
      2.86, p = 0.007. The absorption of degraded horseradish peroxidase was 972 (732
      1213) pmol . hr(-1) . cm(-2) in patients with atopic eczema and 672 (532-811)
      pmol . hr(-1) . cm(-2) in control subjects; t = 2.29, p = 0.03. CONCLUSIONS: Our
      results may reflect a primarily altered antigen transfer in patients who have
      atopic eczema, which may initiate and perpetuate prompt immune responses to
      common environmental antigens, including foods.

PMID- 8655896
TI  - Single doses of intravenous protamine result in the formation of protamine
      specific IgE and IgG antibodies.
AB  - BACKGROUND: Protamine reactions are a well-recognized and serious complication of
      intravenous protamine administration. IgE-mediated anaphylaxis occurs after
      initial sensitization and subsequent re-exposure to antigens. Subcutaneous
      protamine in insulin preparations is associated with protamine-specific IgE and
      IgG antibody production. In contrast, the influence of intravenous protamine
      administration on protamine-specific IgE and IgG antibody formation has never
      been investigated. METHODS: Sera from 93 patients were analyzed for protamine
      specific IgE and IgG antibodies both before and 4 to 6 weeks after exposure to
      single doses of intravenous protamine. Specific clinical variables were assessed
      by univariate and multivariate analyses to determine independent predictors of
      protamine-specific antibody production. RESULTS: In patients who were previously
      seronegative, intravenous protamine administration resulted in protamine-specific
      IgE and IgG antibody production in 17 of 93 (18%) and 15 of 93 (16%) patients,
      respectively. As determined by multivariate analysis, male gender (p = 0.06) and
      insulin-dependent diabetes mellitus (p = 0.002) were associated with protamine
      specific IgG but not IgE antibody production. CONCLUSION: Single-dose intravenous
      protamine resulted in protamine-specific IgE and/or IgG antibody production in 26
      of 93 (28%) of patients. Seroconversion was associated with male gender and
      insulin-dependent diabetes mellitus. Patients responding immunologically to
      protamine may be at increased risk for experiencing reactions on subsequent
      exposure.

PMID- 8655897
TI  - C-1-inhibitor binding monoclonal immunoglobins in three patients with acquired
      angioneurotic edema.
AB  - The syndrome of acquired angioneurotic edema (AAE) is characterized by the adult
      onset of angioedema, the lack of evidence for inheritance of the disorder, and
      the frequent association of the C1-inhibitor (C1-INH) deficiency with
      lymphoproliferative or other malignant diseases. Recently, a new type of AAE
      (type II AAE) has been described. The two major biologic differences of this new
      syndrome compared with all other previously reported AAE cases (type I AAE) are
      the presence in patients' sera of both anti-C1-INH autoantibodies, often
      monoclonal, and a circulating low molecular weight (95 kd) C1-INH protein. From
      the clinical point of view, the absence of underlying lymphoproliferative disease
      is the hallmark of type II AAE compared with type I AAE. However, the distinction
      between type I and type II AAE may not be so clear-cut. We report three patients
      with monoclonal gammopathies and AAE for whom the initial diagnosis was type I
      AAE. The demonstration by ELISA of the C1-INH binding ability of their monoclonal
      immunoglobulins in addition to the presence of 95 kd C1-INH protein enables us to
      change the diagnosis to type II AAE. From the therapeutic point of view, it is
      crucial to detect the anti-C1-INH antibody and to analyze the C1-INH size to
      distinguish type I and type II AAE, especially if patients have a monoclonal
      gammopathy, to give the appropriate treatment (attenuated androgens vs
      immunosuppressive regimen, respectively) to prevent a fatal outcome.

PMID- 8655898
TI  - ADA applauds addition of nutrition screening requirement to new older Americans
      Act reporting guidelines.

PMID- 8655899
TI  - Bringing home the mission of the Fourth World Conference on Women.
AB  - The objective of the Public Initiative of The American Dietetic Association's
      1996-1999 Strategic Framework (see page 559 of this issue for details) is to
      influence the public's access to sound, scientifically based nutrition
      information. One way the ADA is promoting this objective is by identifying and
      targeting the nutrition needs and concerns of specific populations. In June 1993,
      the ADA became a major player in the effort to improve the health of America's
      women by launching the Nutrition & Health Campaign for Women. To target the
      nutrition needs of women most effectively, information about how women live is
      fundamental.

PMID- 8655900
TI  - Elder care and Medicare.

PMID- 8655901
TI  - Successful recruitment and interview techniques of free-living elderly.

PMID- 8655902
TI  - Weight gain and increased concentrations of receptor proteins for tumor necrosis
      factor after patients with symptomatic HIV infection received fortified nutrition
      support.
AB  - OBJECTIVE: To determine whether certain nutrients and dietary factors act as
      modulators of the immune system and improve the nutritional status of
      immunocompromised patients. DESIGN: Controlled, double-blind, crossover phase
      trials of the effects of a fortified formula in patients infected with the human
      immunodeficiency virus (HIV). Patients consumed a control formula for 4 months
      and a study formula for 4 months. SUBJECTS: Ten men with symptomatic HIV
      infection who were following stable medication regimens and had no malignancies,
      mycobacteriosis, or additional virus infection requiring systemic treatment.
      INTERVENTION: Formula fortified with alpha-linolenic acid (1.8 g/day), arginine
      (7.8 g/day), and RNA (0.75 g/day) and a standard formula. MAIN OUTCOME MEASURES:
      Nutritional status determined by anthropometric, bioelectrical, biochemical, and
      dietary assessment; energy expenditure determined by indirect calorimetry;
      disease progression; CD4 lymphocyte counts; HIV p24 antigen plasma
      concentrations; tumor necrosis factor (TNF) receptor proteins; and compliance
      control parameters. STATISTICAL ANALYSES PERFORMED: Student's t tests for paired
      and unpaired data. RESULTS: Fortified nutrition resulted in a weight gain (+ 2.9
      kg/4 months vs -0.5 kg/4 months with the control formula, P < .05), an
      incorporation of eicosaenoic acid into erythrocyte cell membranes (+ 47% of
      baseline values, P < .05), and increased plasma arginine concentrations (96.8 +/-
      45.1 vs 51.8 +/- 20.9 mumol/L, P < .01). The serum concentrations of the soluble
      tumor necrosis factor receptor (sTNFR) proteins increased during the study period
      (sTNFR 55 = + 0.23 vs -0.40 ng/mL, P < .001; sTNFR 75 = + 0.90 vs -0.36 ng/mL, P
      < .01), whereas no changes in CD4+ lymphocyte counts were observed. CONCLUSION:
      Increasing dietary intakes of n-3 polyunsaturated fatty acids, L-arginine, and
      RNA increased body weight, possibly by modulating the negative effects of TNF.

PMID- 8655903
TI  - Meals-on-wheels applicants are a population at risk for poor nutritional status.
AB  - OBJECTIVE: To identify older adults with poor nutritional status among the
      independent-living elderly applying for meals-on-wheels, and to compare how a
      self-assessment tool and more traditional criteria identify nutritional risk.
      DESIGN: Descriptive study. SUBJECTS/SETTING: Meals-on-wheels applicants (n = 230
      between 60 and 90 years of age (mean age = 77.4 +/- 7 years) who were free from
      terminal illness. Nutrition assessment data were collected in the home of each
      participant. MAIN OUTCOME MEASURES: Risk assessment for poor nutritional status
      was determined using anthropometric, dietary, and laboratory data and with a
      Nutrition Screening Initiative (NSI) self-assessment tool-the "DETERMINE Your
      Nutritional Health" checklist. STATISTICAL ANALYSES: Differences were assessed
      using Student's t test for unpaired data. RESULTS: Seventy-four percent of study
      participants were found to be at risk for poor nutritional status according to
      the study criteria, and 98% were at risk for poor nutritional status according to
      the NSI self-assessment tool. CONCLUSIONS: The majority of the applicants for
      meals-on-wheels were at risk for poor nutritional status. Thus, many independent
      living older adults may need additional nutrition assessment and intervention to
      remain independent and in good nutritional status.

PMID- 8655904
TI  - Monitoring dietary change in a low-fat diet intervention study: advantages of
      using 24-hour dietary recalls vs food records.
AB  - OBJECTIVE: The purpose of the study was to evaluate two methods of dietary
      assessment for monitoring change in fat intake in a low-fat diet intervention
      study. DESIGN: The two dietary assessment methods were a 4-day food record (4DFR)
      and an unannounced 24-hour dietary recall conducted by telephone interview
      (referred to as a telephone recall [TR]). Subjects were assigned randomly to
      either a low-fat diet intervention group or a control group that received no
      counseling about fat intake. Dietary data were collected at baseline, 6 months,
      and 12 months. SUBJECTS: Two hundred ninety postmenopausal women with localized
      breast cancer were recruited at seven clinical centers in the United States.
      STATISTICAL ANALYSIS: Analysis of variance was used to test for significant
      differences in mean fat and energy intakes. RESULTS: Three sources of error were
      identified: (a) an instrument effect, suggesting underreporting at baseline of
      approximately 8% in mean energy intake and 11% in mean fat intake in the TR group
      compared with the 4DFR group (P = .0001); (b) a repeated measures effect observed
      for the 4DFR, suggesting underreporting of approximately 7% for energy intake and
      14% for fat intake in the control group at 6 and 12 months compared with baseline
      values (P < .001); and (c) an adherence effect (or compliance bias), suggesting
      greater compliance to the low-fat intervention diet when subjects were keeping
      food records than when estimates were based on the unannounced TR. Compared with
      the TR, the 4DFR overestimated the extent of fat reduction in the low-fat diet
      intervention group by 41% (P = .08) and 25% (P = .62) at 6 and 12 months,
      respectively. APPLICATION: Multiple days of unannounced 24-hour recalls may be
      preferable to multiple-day food records for monitoring dietary change in diet
      intervention studies.

PMID- 8655905
TI  - Relationship of social roles and nutrition beliefs to fat avoidance practices:
      investigation of a US model among Danish women.
AB  - OBJECTIVE: This study was designed to investigate the associations among women's
      social roles, their nutrition beliefs, and their dietary fat avoidance practices.
      Role theory and prior qualitative research among US women provided the
      theoretical framework. DESIGN/SUBJECTS: A random-sample mail survey (76%
      response) was used to gather information on the usual pattern of dietary fat use,
      nutrition beliefs, and social positions of Danish women aged 30 to 60 years. A
      fat avoidance score was calculated for each respondent on the basis of 12 fat
      consumption practices. Sequential multiple linear regression was used to develop
      an explanatory model for fat avoidance using responses from 594 women. RESULTS:
      Interactions between nutrition attitudes and beliefs and social roles suggested
      that the roles themselves did not influence fat avoidance practices, but the
      nutrition beliefs associated with particular roles did have an influence. Among
      employed women, fat avoidance was lower among those who perceived many barriers
      to healthful eating. Among women who were not employed, fat avoidance was lower
      among those who perceived little social support for healthful eating. The
      association of fat avoidance with caretaking responsibility varied by age group.
      Caretaking was positively associated with fat avoidance among women in their
      forties, but not in older or younger age groups. CONCLUSIONS: Nutrition messages
      should be tailored to fit women's unique social roles and the beliefs associated
      with them. Nutrition professionals in Denmark and the United States can adapt
      these findings to their own cultural context.

PMID- 8655906
TI  - Development of an objective method for assessing viscosity of formulated foods
      and beverages for the dysphagic diet.
AB  - OBJECTIVE: To develop and validate a practical, economical, and objective
      viscosity assessment tool, the line-spread test, for foods and beverages
      formulated for the dysphagic diet. The line-spread test is based on the measure
      of product dispersion over a flat surface. DESIGN: Viscosity-altering
      formulations for a selection of soups and beverages commonly served to patients
      with dysphagia at a local hospital were developed under controlled conditions.
      The samples were presented to a trained sensory panel for evaluation by
      quantitative descriptive analysis and were measured by the line-spread test.
      Numeric results of the two tests were compared. SETTING: The Food Research
      Laboratory with private sensory booths at Mount Saint Vincent University. MAIN
      OUTCOME MEASURES: Results of the sensory evaluation and the line-spread test
      would strongly correlate, indicating predictive validity, but the line-spread
      test would be more reliable and show variability in measurement. STATISTICAL
      ANALYSES PERFORMED: Correlation, analysis of variance (ANOVA), and standard
      deviations (calculated from the within-group mean square error of the ANOVAs).
      RESULTS: ANOVA showed that both the sensory panel results and the line-spread
      test values indicated significant differences among the samples. Standard
      deviations indicated less variability in line-spread values. There was a strong
      positive correlation (r = .90 to .97) between the two types of results, which
      indicated strong predictive validity for the line-spread test. APPLICATIONS: The
      line-spread test is a reliable and valid tool to assess viscosity of formulated
      foods and beverages for the dysphagic diet and can be readily and economically
      adapted to any dietary department for product development and quality control.

PMID- 8655907
TI  - Psychological consequences of food restriction.
AB  - A review of the literature and research on food restriction indicates that
      inhibiting food intake has consequences that may not have been anticipated by
      those attempting such restriction. Starvation and self-imposed dieting appear to
      result in eating binges once food is available and in psychological
      manifestations such as preoccupation with food and eating, increased emotional
      responsiveness and dysphoria, and distractibility. Caution is thus advisable in
      counseling clients to restrict their eating and diet to lose weight, as the
      negative sequelae may outweigh the benefits of restraining one's eating. Instead,
      healthful, balanced eating without specific food restrictions should be
      recommended as a long-term strategy to avoid the perils of restrictive dieting.

PMID- 8655908
TI  - Perspectives on history: army dietetics in southwest Asia during Operation Desert
      Shield/Desert Storm.
AB  - The Army dietitians deployed during Operation Desert Shield and Operation Desert
      Storm exemplified the commitment, dedication, patriotism, and professionalism of
      their predecessors. Although some were continuously on the move and all dealt
      with the extremes of a desert environment, were frequently handicapped with
      equipment shortages, and coped constantly with the monotony of limited ration
      variety, throughout their experiences these professionals expressed pride in
      participating in this national undertaking. The purposes of this article are to
      familiarize members of The American Dietetic Association with the responses of
      their colleagues in the US military to another of their nation's calls, to relate
      some aspects of Army dietetics experienced in Southwest Asia, and to identify the
      lessons learned in that engagement.

PMID- 8655909
TI  - Perspectives on history: Army dietitians in the European, North African, and
      Mediterranean theaters of operation in World War II.
AB  - World War II necessitated the mobilization of hundreds of dietitians to serve in
      military hospitals in the United States and in theaters of war all over the
      globe. Although initially military dietitians had civilian status, on December
      22, 1942, Congress passed Public Law 828, which authorized military status for
      Army dietitians with relative rank in the Medical Department for the duration of
      the war and 6 months thereafter. This article chronicles the role of Army
      dietitians who supported the allied troops in military hospitals in England,
      Europe, and North Africa during World War II. Recollections of military
      dietitians who served in the war are included to illustrate the circumstances
      under which these professionals lived and the dedication with which they worked.

PMID- 8655910
TI  - Evaluation of the appropriate use of parenteral nutrition in an acute care
      setting.

PMID- 8655911
TI  - Preference for and consumption of fat-free and full-fat cheese by children.

PMID- 8655913
TI  - Nutrition and food industry professionals' opinions about the nutrition label and
      its components.

PMID- 8655912
TI  - Nutrient intakes in a frail homebound elderly population in the community vs a
      nursing home population.

PMID- 8655914
TI  - Timely statement of The American Dietetic Association: nutrition guidance for
      child athletes in organized sports.

PMID- 8655915
TI  - Timely statement of The American Dietetic Association: nutrition guidance for
      adolescent athletes in organized sports.

PMID- 8655916
TI  - Another look at competency-based education in dietetics.

PMID- 8655917
TI  - Regional and temporal fluctuations in the incidence of congenital hypothyroidism
      in Israel.
AB  - It is well known that the incidence of congenital hypothyroidism (CH) differs
      significantly among different parts of the world. Northern Israel has been shown
      to be an iodine deficient area with a relatively high incidence of CH. This study
      aimed to compare the incidence of CH between different regions of Israel and to
      examine the temporal fluctuations of this disease in each region. All 303 primary
      CH infants born in Israel during the 10-year period between April 1978 and March
      1988 were classified by hospital of birth and place of residence. Using these
      data we calculated the incidence of CH in the different subdistricts and
      districts of Israel. We also calculated the annual incidence of CH in each
      district. The incidence of CH in each hospital was compared to the filter paper
      T4 levels of all newborns born in that hospital during 1993. The incidence of CH
      decreased gradually from northern to southern Israel. This trend was also
      observed for thyroid agenesis, but the incidence of ectopic thyroid was highest
      in central Israel. Dyshormonogenesis (DHG) was on average 3.5 fold more frequent
      in the Arab compared to the Jewish populations, but did not show any clear
      geographic pattern. A significantly increased CH incidence in north-central
      Israel in 1985 was opposed by a low incidence in the South. A clear correlation
      exists between the incidence of CH in each hospital and the mean newborns' T4
      level in that hospital. The incidence of primary CH in general, and of thyroid
      agenesis and ectopic thyroid specifically, has a clear regional-temporal pattern.
      Thus, some of the factors causing CH in Israel may be local factors that show
      local annual fluctuations.

PMID- 8655918
TI  - The pH dependence of interleukin-1 beta effects on insulin secretion in HIT
      cells.
AB  - We have examined a hypothesis that the effects of recombinant human interleukin-1
      beta (IL-1) on insulin secretion may depend upon the condition of intracellular
      pH levels in hamster clonal beta-cell line, HIT-T 15 cells. In the first
      experiment, the addition of 5 and 20 microM monensin, a Na+/H+ electroneutral
      exchange ionophore, did not attenuate a short-stimulatory effect of IL-1 on
      insulin secretion at 0-4 h period. At the concentration of 20 microM, monensin
      deleted the IL-1-induced reduction of insulin secretion at 4-24 h period, while 5
      microM did not. Furthermore, 100 microM monensin blocked the bimodal effects of
      IL-1 on insulin secretion. In the second experiment, IL-1 significantly
      stimulated insulin secretion, although it did not affect cyclic AMP production at
      0-4 h period. At 4-24 h period, IL-1 dose-dependently inhibited cyclic AMP
      production, accompanied with a significant reduction of insulin secretion.
      Alkalinization of circumstantial pH levels to 8.0 deleted the IL-1 effects on
      insulin secretion at 4-24 h period. However, alkalinization to pH 8.0 failed to
      attenuate the reduction of cyclic AMP production by IL-1. These data indicated
      that maintaining adequate intracellular pH levels may be important in the IL-1
      effects on insulin secretion by the mechanism in which cyclic AMP may not be
      involved.

PMID- 8655919
TI  - Thyroid homeostasis and retinol circulating complex relationships in a severe
      iodine-deficient area of Senegal.
AB  - In adult subjects living in a severely iodine-deficient area (median urinary
      iodine 10 microgram/L), we evaluated the biochemical parameters of protein
      malnutrition in relation to thyroid homeostasis. Serum transthyretine (TTR),
      retinol binding protein (RBP) and retinol, all components of the retinol
      circulating complex (RCC), as well as ceruloplasmin levels, were determined in 63
      subjects (44 F/19 M). These comprised 21 controls, 31 who were euthyroid with
      goiter WHO stage 2 or 3 and 11 who met the criteria of hypothyroidism (i.e. FT4 <
      8 pmol/L and TSH > 4.13 mU/L) with goiter stage no more than 1b. No differences
      in the values of TTR and RBP were found between males and females, whereas the
      retinol values were slightly higher in males. The mean retinol binding protein
      values were lower than the normal range in all three groups but were
      significantly lower (p < 0.01; < 0.05) in hypothyroid subjects than in the other
      two groups. All hypothyroid subjects exhibited reduced retinol binding protein
      levels and 1/3 of them showed a marked decrease. The circulating levels of
      transthyretine were also lower than the normal range for western countries. 45%
      of the hypothyroid, 26% of goitrous and 9% of control subjects exhibited a
      transthyretine lower than 12 mg/dl, but the mean values were not dissimilar. The
      mean retinol values were within the normal range in all three groups but were
      lower in hypothyroid as compared to the controls (< 0.01). The resulting
      retinol/RBP ratio was over 1 in both the whole sample and in the subgroups.
      Ceruloplasmin levels were in the normal range in all groups. The data indicated
      that hypothyroid subjects had reduced retinol binding protein and retinol
      circulating complex network compared to euthyroid subjects.

PMID- 8655920
TI  - Doppler echocardiographic patterns in patients with acromegaly.
AB  - Cardiovascular problems have long been recognized as responsible for an increased
      morbidity and mortality in patients with acromegaly. The aim of the present study
      was to evaluate echocardiographically the prevalence of cardiomyopathy in a
      cohort of acromegalic patients and to analyze the results in relation to
      demographic, clinical and hormonal data. This study, a retrospective controlled
      clinical trial, was performed in 25 acromegalic patients, 12 men and 13 women
      aged 26-66 years (mean: 52.6). Fifteen patients had an active disease, 10 were
      cured by previous pituitary surgery. The same echocardiographic parameters were
      analyzed in 50 healthy subjects aged 30-70 years (mean: 51.4). Serum GH was
      determined on at least 4 samples drawn over 24 hours and plasma IGF-I on a single
      point. Standardized parameters of diastolic and systolic function were evaluated
      by real-time Doppler echocardiography. Twelve patients with active acromegaly
      underwent also 48-hour ECG registering. Left ventricular (LV) hypertrophy was
      found in 14/25 patients (56%). No difference was found between patients with
      active disease (53%) and patients with cured acromegaly (60%). LV mass index was
      significantly increased in acromegalics in comparison with healthy subjects (137
      +/- 43 g/m2 vs 96 +/- 16 g/m2, p < 0.01) and also the indices of LV diastolic
      function were significantly impaired. Asymmetric septal hypertrophy was found
      only in one patient. Hypertension was detected in 9/25 patients (36%) without
      difference between patients with active or cured disease (40% vs 30%, NS). No
      significant correlation was found between hormonal or clinical data and
      echocardiographic findings. During Holter monitoring, heart rate of acromegalics
      was not significantly different from that of controls (78 +/- 12 bpm vs 72 +/- 10
      bpm, NS) and only isolated supraventricular or ventricular premature complexes
      (Lown class 1) were detected. In conclusion, this study provides evidence of
      subclinical LV dysfunction in acromegaly in the absence of other known causes of
      heart disease and no significant difference in echocardiographic pattern was
      apparent between active or cured acromegalics.

PMID- 8655921
TI  - Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing
      hormone in juvenile obesity before and after hypocaloric diet.
AB  - This study was performed on 36 obese subjects aged 8.5-17.4 yr, 14 boys and 22
      girls (prepubertal: 5 boys and 5 girls [stage I, according to Tanner]; BMI: 35.5
      +/- 1.4 [mean +/- SEM] and 35 +/- 1.3 respectively; pubertal: 9 boys and 17 girls
      [stage IV-V]; BMI: 36.2 +/- 1.8 and 36 +/- 1.5 respectively) before and after 8
      weeks of a 1000 kCal/day diet. The responses of serum TSH and PRL to TRH (200
      micrograms iv as a bolus) were evaluated as Area Under the Curve (AUC) and net
      increase in respect to basal values (delta TSH and delta PRL). Serum T4, fT4 and
      rT3 were assayed at the baseline and T3 and fT3 at the baseline and 120' after
      TRH injection. A similar analysis was performed on 14 age- and sex-matched lean
      subjects as controls. In females at baseline fT4 serum levels were greater than
      controls and were significantly reduced after weight loss; rT3 increased after
      weight loss in the whole study group. In patients of both sexes the PRL peak
      after TRH injection was earlier but not greater (15') than in controls (30').
      After weight loss PRL peak after TRH was found at 30' (as controls) in females
      only. Taking into consideration the stage of pubertal development, the results
      were the following: a) in puberal girls, after weight loss, TSH and PRL peaks
      after TRH were delayed with respect to baseline and to the other considered
      subgroups; b) in prepubertal girls TSH and PRL peaks, delta TSH, delta PRL, AUC
      TSH and AUC-PRL were blunted with respect to pubertal ones; c) the other
      considered variables were unchanged after the period of caloric deprivation. No
      correlation between BMI and the AUC of TSH and PRL was found. These data suggest
      that thyroid function is substantially normal in adolescent obese subjects and
      not influenced by a prolonged period of caloric restriction, even though a
      reduced hypothalamic dopaminergic tone on pituitary thyreotrophs and lactotrophs
      could cause subtle alterations on TSH and PRL release, partially influenced by
      gender and sexual development.

PMID- 8655922
TI  - Binding of GC (VDBP) to membranes of human B lymphocytes following stripping of
      extant protein.
AB  - The presence of Gc (vitamin D binding protein) has been consistently demonstrated
      on the membrane of B lymphocytes. This protein appears to be spatially associated
      with surface immunoglobulins. The origin of this surface protein has not yet been
      determined and the purpose of the present paper was to investigate if Gc may bind
      to human lymphocytes after immunoglobulin (Ig) capping. For this purpose the
      presence of Gc on B lymphocytes was examined by three different approaches.
      First, when cells were examined by immunofluorescence and quantified by flow
      cytometry, membrane Ig capping was followed by a dramatic decrease in positivity
      for Gc when compared to native cells. In addition, incubation of capped cells
      with purified Gc was followed by a significant increase in fluorescence,
      indicating that this protein had been able to bind again. Second, analysis of
      solubilized lymphocytes by Western blotting showed that native lymphocytes and
      capped cells incubated with purified Gc contained a large quantity of a 56kDa
      protein which was immunoreactive with anti Gc antibodies. This protein band was
      much weaker on blots from capped cells not treated with Gc. Third, radiobinding
      assays indicated that, following capping, cells were able to bind Gc in saturable
      fashion. These results suggest that membrane Gc could play a role in the entry of
      vitamin D metabolites into lymphocytes.

PMID- 8655923
TI  - Effects of abstinence on sex hormone profile in alcoholic patients without liver
      failure.
AB  - Excessive ethanol ingestion induces hypoandrogenism in male subjects. To confirm
      its presence and to study its relationship with the degree of liver damage and
      alcohol abstinence, plasma sex hormones were measured in alcoholic patients
      without liver failure, after two different abstinence periods. Patients were 30
      male chronic alcoholics admitted to the Alcoholism Ward for treatment of their
      addiction. On admission, we measured: testosterone (T), estradiol (E), follicle
      stimulating hormone (FSH), luteinizing hormone (LH) and sex-hormone binding
      globulin (SHBG). A liver biopsy was also performed. These measurements were
      repeated at discharge and were also done in 15 normal volunteers. On admission
      (mean abstinence 1.9 +/- 1.7 days) total T was similar to controls, FSH was lower
      (p < 0.02) and high levels of SHBG were found (3.5 fold increase, as compared to
      controls). Histologically, 9 patients had normal liver; 14 had moderate
      alterations and 7 showed marked alterations. Hormonal values were not different
      in these 3 groups. At discharge, 11.1 +/- 4.7 days after admission, T, E and FSH
      did not show significant changes but LH decreased (8.2 +/- 5.2 mIU/ml vs 12.9 +/-
      4.1, p < 0.001); SHBG also decreased (65.4 +/- 21.6 nmol/l vs 117.2 +/- 33.3, p <
      0.001) to values that still were twice those of controls. It is concluded that
      alcoholic patients without clinical signs of liver failure have normal plasma
      testosterone levels, irrespective of their histologic liver alterations and high
      plasma SHBG levels that decreased significantly after a short abstinence. The
      concomitant LH decrease suggests that hypoandrogenism is likely in these
      patients. Fast changes in SHBG levels rise the possibility that this protein is
      candidate marker of alcoholism.

PMID- 8655925
TI  - Virilization associated with choriocarcinoma.
AB  - We demonstrate here two autopsy-proven cases of virilization associated with
      choriocarcinoma. The first patient was a 27-year-old woman with a 7-year history
      of metastatic choriocarcinoma who presented with left hemiparesis and
      virilization. Serum testosterone concentration was 18 nmol/l, free testosterone
      471 pmol/l, dehydroepiandrosterone sulphate (DHEA-sulphate) 1.7 mumol/l, sex
      hormone binding globulin 12.3 nmol/l, estradiol (E2) 1,843 pmol/l, and hCG 1.6 x
      10(5) IU/l. The second patient was a 21-year-old virilized woman with metastatic
      choriocarcinoma who presented in semicomatose state. Limited endocrine
      investigation revealed serum testosterone 27 nmol/l and hCG 2.7 x 10(5) IU/l.
      Both patients died despite chemotherapy and radiation therapy. Autopsy findings
      revealed choriocarcinoma with brain and multiple organ metastasis in both.
      Pathology of the ovaries of both patients demonstrated hyperplasia of luteinized
      theca cells and lutein cells. We postulate that an association of virilization
      and choriocarcinoma resulted from long-standing stimulation of ovary by hCG
      causing theca cell hyperplasia with subsequent hypertestosteronemia and
      virilization.

PMID- 8655924
TI  - Relationship between 17-beta-estradiol and prolactin in the regulation of natural
      killer cell activity during progression of endometriosis.
AB  - Endometriosis is an estrogen-dependent disease affecting women during their
      reproductive years. An abnormal immune function and, in particular, a decreased
      natural killer (NK) cell activity have been found in endometriosis, suggesting a
      role of the immune system in the pathophysiology of the disease. We have recently
      evidenced a significant inverse relationship between 17-beta-estradiol plasma
      levels and NK cytotoxicity in endometriosis patients. In this study we have
      investigated the combined role of 17-beta-estradiol (E2) and prolactin (PRL) in
      the regulation of NK cell activity during the progression of endometriosis, by
      evaluating the correlation among E2, PRL, and other immunomodulating
      neurohormones on both the cytotoxic activity and the number of NK cells in women
      at different stages of endometriosis. The early stages (I/II) of endometriosis
      are characterized by increased plasma levels of either E2 or PRL without
      significant alterations of NK cell activity in comparison with healthy subjects.
      The progression to advanced stages (III/IV) of the disease is associated with a
      further increase of E2 levels, a decrease of PRL plasma concentrations (with an
      increase of E2/PRL ratio), and an impairment of NK cytotoxicity. The plasma
      levels of both E2 and PRL and the E2/PRL ratio are significantly correlated with
      the values of NK cytotoxicity in advanced stages of endometriosis. Either the
      absolute number or the relative percentage of CD16+ or CD56+ peripheral
      lymphocytes are not significantly different between patients at either stages
      I/II or III/IV and healthy controls. Plasma levels of progesterone (P) and
      luteinizing hormone (LH), are not significantly changed in different stages of
      endometriosis with respect to healthy controls. The significant decrease of
      follicle-stimulating hormone (FSH) plasma levels found in either stages I/II or
      III/IV endometriosis patients is not correlated with the NK cell activity. In
      conclusion, at advanced stages of endometriosis the impairment of NK cell
      activity occurs with increased E2, and decreased PRL plasma levels. Additional
      studies are required to determine whether the E2/PRL ratio represents a possible
      biochemical marker of endometriosis.

PMID- 8655926
TI  - Paroxystic hypertension in a long-term hemodialyzed patient. Successful
      adrenalectomy for a dopamine-producing pheochromocytoma.
AB  - Pheochromocytoma (Pheo) is an uncommon neoplasm producing blood pressure troubles
      and it may be undiagnosed in chronic dialyzed patients in whom hypertension is a
      common finding. The symptoms in Pheo syndrome depends on the prevalent
      catecholamine released, the most common being epinephrine (E) and norepinephrine
      (NE). Recently, a particular clinical picture has been described for dopamine
      (DA)-producing Pheos, in whom a normo-hypotensive status is more often observed.
      The authors report a case of mainly dopamine-producing Pheo in a long-term
      dialyzed patient, successfully treated with adrenalectomy. The main steps in
      diagnosis and preoperative management are described and debated also in view of
      the particular background produced by the end-stage renal failure. The common
      imaging techniques adopted for adrenal medullary neoplasms (US, CT, MIBG
      scintiscan) confirmed to be decisive for diagnosis; HPLC assay of plasma
      catecholamines is the only biochemical test available in these patients although
      its significance is questionable due to the poor knowledge of catecholamine
      metabolism in chronic renal failure. The clinical findings observed in this case
      seem in disagreement with those already reported in DA producing Pheos. Pheo in
      hemodialyzed patients is a rare event and it may be hidden by other more common
      causes of hypertension. However, more awareness from the medical staff allows to
      diagnose the neoplasm correctly by the currently available methods and to plan a
      safe surgical therapy also in high-risk patients.

PMID- 8655927
TI  - Diabetes insipidus for five years preceding the diagnosis of hypothalamic
      Langerhans cell histiocytosis.
AB  - We report a case of an adult male with Langerhans cell histiocytosis (LCH), in
      which the hypothalamic involvement went undetected by radiology and who was
      diagnosed as having central diabetes insipidus for 5 years before the skin
      lesions and the hypothalamic mass became evident on a CT scan. The skin lesions
      spontaneously disappeared but relapsed 12 months later. The hypothalamic mass
      disappeared six months after low dose radiotherapy with persistence of diabetes
      insipidus and loss of thirst sensation. We did not observe relapse of the
      hypothalamic mass within the five years of post-radiotherapy follow-up. Despite
      the fact that patients with LCH may experience spontaneous remissions and
      exacerbations in their clinical manifestations, the patient's long-term evolution
      suggested the mass was cured. We would like to draw the attention of clinicians
      to the necessity of long-term follow-up in patients initially diagnosed of
      idiopathic central diabetes insipidus. Furthermore, low dose radiotherapy is a
      successful treatment for LCH-dependent masses in the hypothalamus; however,
      normalization or regression of CT abnormalities after radiotherapy did not affect
      the clinical diabetes insipidus status.

PMID- 8655928
TI  - Effectiveness of different crystalloid i.v. solutions in establishing urine flow.
AB  - There are several situations in Emergency Medicine when it is desirable to
      promote a prompt diuresis to fill the bladder or obtain urine for diagnostic
      tests. We attempted to determine which of 3 commonly used intravenous solutions
      is most effective in establishing urine flow. In a prospective, randomized double
      blind crossover study of 12 healthy male volunteers, we rapidly infused 20 cc/kg
      of D5W, D51/2NS, or 1/2NS immediately after voiding. Voided urine volumes were
      then recorded at 30, 60, 90, and 120 min postinfusion and the degree of
      glycosuria, if any, was noted. Total mean urine volume after D5W was 1181 ml,
      significantly greater than after 1/2NS (825 ml) and 1/2NS (630 ml), which did not
      differ between each other. Mean urine volume was greater at every time interval
      for the D5W group, and glycosuria was common in both D5-containing groups. We
      conclude that in healthy subjects, D5W is more effective in promoting rapid
      diuresis than are sodium-containing solutions.

PMID- 8655929
TI  - Memo.

PMID- 8655930
TI  - An unusual presentation of urinary retention.
AB  - Patients with urinary retention frequently present to the emergency department
      (ED) for evaluation and treatment. Urinary retention is seen most often in males
      secondary to mechanical causes. However, other etiologies must be considered. We
      present an unusual case of a 35-year-old male who developed postcoital urinary
      retention secondary to urogenital diaphragm spasm.

PMID- 8655931
TI  - An emergency department-based domestic violence intervention program: findings
      after one year.
AB  - This article reports findings from the first year of operation of an emergency
      department-based domestic violence intervention program in one of Canada's major
      metropolitan areas. The program has established methods for identifying,
      treating, and following up battered women. Information on several key variables
      is now available for the group of 279 individuals who were the program's first
      patients. Two out of three (68%) of the patients seen were assaulted by their
      current spouse. Nine percent (9%) were abused by former spouses from whom they
      were separated or divorced. Twelve percent (12%) were assaulted by someone they
      were dating. Women in the program who were abused by a former or current spouse
      experienced severe violence, with 81% being kicked, bitten, or hit; 60% being
      pushed, grabbed, or shoved; 55% being threatened; and 30% being choked. Follow-up
      connection could only be made with 140 women (50%), highlighting the need for
      focused interventions during the emergency department visit. The findings confirm
      that women are being injured, often seriously, by those with whom they have close
      relationships. We present a program for addressing the needs of battered women
      seen in emergency departments.

PMID- 8655932
TI  - Acute bilateral adrenal hemorrhage secondary to rough truck ride.
AB  - Acute bilateral adrenal hemorrhage secondary to indirect trauma is rare. This
      condition may mimic an acute surgical abdomen. We present such a patient in whom
      the anatomic diagnosis was confirmed by serial computed tomographic (CT) scans,
      and adrenal insufficiency by biochemical tests. The response to steroid
      replacement therapy was remarkable. Although the patient had normal coagulation
      parameters at the time of presentation, subtle changes resulting from earlier
      anticoagulation may have been a contributing factor.

PMID- 8655933
TI  - AIDS in the elderly: New York City vital statistics.
AB  - The HIV infection primarily affects young adults, but older adults are also
      susceptible. The number of AIDS cases among persons aged 50 or greater is growing
      and is of major concern. As our awareness of the prevalence of HIV-related
      illnesses presenting to the emergency department improves in the younger
      population, we must not ignore the disease in older patients. Early recognition
      of HIV infection will ensure the greatest opportunity for treatment and
      prevention of many of the consequences of opportunistic infections. We present a
      case of HIV in an elderly patient in order to heighten awareness of the
      possibility of HIV infection in older patients presenting to the emergency
      department. We also review the epidemiological, diagnostic, and therapeutic
      aspects of AIDS in older adults.

PMID- 8655934
TI  - Fatal vascular catastrophe in Ehlers-Danlos syndrome: a case report and review.
AB  - The Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue
      disorders that are characterized by abnormalities of the skin, joints, and a
      diversity of other phenotypic manifestations. An awareness of the disease is
      vital for optimal outcome in this rare group of patients who may present with a
      variety of life-threatening illnesses. Ehlers-Danlos type IV has been associated
      with vascular catastrophes, perforated viscous, ruptured uterus, and pneumothorax
      (1-4). We present a case of aneurysmal formation and spontaneous rupture of the
      great vessels in a 15-year-old male with EDS type IV, who remained undiagnosed
      until the time of autopsy.

PMID- 8655935
TI  - Fatal pneumococcal septicemia in a patient with a connective tissue disease.
AB  - Fulminant pneumococcal sepsis is a rare but life-threatening illness usually
      occurring in patients with known splenic absence (postsplenectomy) or dysfunction
      (sickle cell anemia). Several medical illnesses, not typically recognized as
      being associated with abnormal spleen function, may be complicated by fulminant
      pneumococcal sepsis. We report a case of fatal pneumococcal sepsis in a patient
      diagnosed with mixed connective tissue disease who likely had systemic lupus
      erythematosus and unsuspected splenic fibrosis. Medical illnesses associated with
      functional asplenia, hematological findings suggesting splenic dysfunction, and
      confirmatory tests of hyposplenism are discussed.

PMID- 8655936
TI  - Paroxysmal supraventricular tachycardias.
AB  - Paroxysmal supraventricular tachycardia (PSVT) is a distinct clinical syndrome.
      Most patients present with the abrupt onset of palpitations, dizziness, dyspnea,
      or chest pain. The electrocardiogram (ECG) demonstrates a fast heart rate (150
      250 beats per min), a regular rhythm, and most often, a narrow QRS complex. The P
      wave is usually hidden within the QRS complex. PSVT is caused by reentry, and the
      tachycardias are classified, electrophysiologically, according to the anatomic
      location of the reentry circuit. Atrioventricular nodal reentry is the most
      common form of PSVT. In A-V nodal reentry, there are two conducting pathways
      (alpha and beta) that have different conduction times and refractory periods;
      both pathways are confined to the A-V nodal and perinodal atrial tissue. The
      other common form of PSVT, termed atrioventricular reciprocating tachycardia,
      depends on an anatomically distinct, or "accessory," pathway that may conduct
      impulses between the atria and the ventricles, while bypassing the AV node. The
      two forms of PSVT may be distinguished in many cases by examining the 12-lead
      electrocardiogram. In the majority of cases of A-V nodal reentry, the atria and
      ventricles are depolarized simultaneously, and the P waves are hidden in the QRS
      complex. If the reentry circuit includes an accessory pathway, the P wave always
      follows the QRS, and usually the R-P interval exceeds 70 msec. Several principles
      should guide the management of PSVT: (a) Unstable patients require emergent
      electrical cardioversion; (b) A 12-lead ECG should be obtained immediately to
      confirm that the tachycardia has a narrow complex (ventricular tachycardia may
      masquerade as PSVT if only a single lead is examined); (c) Vagal maneuvers may be
      attempted (the Valsalva maneuver is safer and more efficacious, especially in the
      elderly); and (4) In most patients, adenosine is the first-line agent to treat
      PSVT. Contraindications to adenosine and drug interactions are noted in this
      article. In addition, the use of adenosine in wide complex tachycardias and the
      indications for admission and referral for electrophysiologic evaluation are
      discussed.

PMID- 8655937
TI  - Aortocaval fistula secondary to mediastinitis.
AB  - Aortocaval fistula is a rare entity usually associated with a preexistent
      atherosclerotic abdominal aortic aneurysm or trauma. We present a case of an
      aortocaval fistula secondary to the subdiaphragmatic progression of a
      mediastinitis. The pathogenesis, clinical presentation, and treatment are
      discussed.

PMID- 8655938
TI  - Ruptured hemidiaphragm: unusual late presentation.
AB  - Diaphragmatic injuries may be undiagnosed in the acute posttraumatic period and
      may remain unrecognized despite a variety of chronic symptoms, until eventual
      emergency department presentation with an intestinal obstruction. We present a
      case of a female who experienced chronic chest pain during coitus that eventuated
      in an acute admission with an intrathoracic mesentero-axial volvulus of the
      stomach, 8 months after a motor vehicle accident. The literature regarding
      delayed presentation of a ruptured hemidiaphragm is reviewed.

PMID- 8655939
TI  - Emergency department pregnancy testing.
AB  - The rapid and accurate diagnosis of pregnancy is a necessity for emergency
      physicians. Physicians of the 1990s are fortunate to have available inexpensive,
      rapid pregnancy tests with virtually no false positives or negatives. The current
      basis of endocrine pregnancy tests is detection of Human Chorionic Gonadotrophin
      (HCG) in the serum or urine. The single HCG tests in combination with ultrasound,
      as well as serial HCGs, are also useful in the diagnosis of ectopic pregnancy.
      Serum progesterone, although at present not widely used in the emergency
      department, shows great promise as a test useful in the often difficult task of
      distinguishing ectopic and abnormal pregnancies from viable intrauterine
      pregnancies.

PMID- 8655940
TI  - The analgesic efficacy of ketorolac for acute pain.
AB  - Ketorolac is a nonsteroidal anti-inflammatory drug, available in both oral and
      parenteral forms, that possesses significant analgesic potency. Its analgesic
      efficacy has been studied extensively for the treatment of moderate-to-severe
      pain in many clinical settings. Although ketorolac possesses significant
      analgesic potency, it has limited utility as an analgesic for the acute treatment
      of moderate-to-severe pain in the emergency department. Oral ketorolac has been
      shown to provide analgesia that is the same or better than aspirin,
      acetaminophen, and dextropropoxyphene with acetaminophen, and equal analgesia to
      most other commonly available oral analgesics, including ibuprofen and
      acetaminophen with codeine. Intramuscular ketorolac provides analgesia equivalent
      to commonly used doses of meperidine and morphine. However, its utility in acute
      pain, when rapid relief is necessary, is limited due to a prolonged onset to
      analgesic action (30-60 min) and a significant number of patients who exhibit
      little or no response, more than 25% in most studies. The use of intravenous
      ketorolac has been less well studied. It has analgesic potency but its utility in
      patients with moderate-to-severe pain is also limited because there is a
      significant percentage of patients who fail to obtain adequate relief. Ketorolac
      may be most useful in supplementing parenteral opiates.

PMID- 8655941
TI  - Intraorbital air in a patient status post facial trauma.

PMID- 8655942
TI  - Percivall Pott: tuberculous spondylitis.
AB  - Tuberculous spondylitis, also known as Pott's disease, is an entity that produces
      a characteristic kyphotic deformity, and was described by Sir Percivall Pott in
      1779 and 1782. The majority of his patients were infants and young children.
      Although the incidence of tuberculosis in the industrialized world has since
      declined dramatically, the number of cases of extrapulmonary disease, though
      small, has remained relatively unchanged. In developing countries, spondylitis is
      still generally a disease of children, but in Europe and North America, it more
      commonly involves older adults. Pott's spondylitis represents a reactivation of
      latent disease, frequently years after the initial infection. Clinical findings
      include complaints of back pain and symptoms of fever, chills, weight loss,
      malaise, and fatigue. Characteristically a late finding, paraplegia is
      occasionally the initial indicator of spinal involvement. There is an average
      delay of a year between the onset of symptoms and patient presentation. Plain
      spinal radiographs usually are the initial diagnostic modality utilized. Computed
      tomography scanning and magnetic resonance imaging can be used to further define
      the process. The differential diagnosis includes neoplasm, pyogenic or
      disseminated fungal infection, and sarcoid arthritis.

PMID- 8655943
TI  - A voice from the night.

PMID- 8655944
TI  - Prescription drug noncompliance: a clear and present danger.

PMID- 8655945
TI  - Cervicofacial and mediastinal emphysema as the result of a dental procedure.
AB  - Cases of cervicofacial subcutaneous emphysema occurring during dental treatment
      often result from the use of air-water cooled dental drills during tooth
      extraction. A case is presented in which a compressed air syringe, used to dry
      the field, caused diffuse cervicofacial emphysema with retropharyngeal and
      mediastinal extension. The point of entry appeared to be a 4 mm superficial
      laceration of the buccal mucosa. Despite the size of the wound, a significant
      amount of air was able to enter the tissues and spread quite distantly. Though
      many cases of subcutaneous emphysema go unnoticed, diffuse extension, especially
      with involvement of deep neck structures and with thoracic extension, must be
      recognized as they can be potentially life-threatening.

PMID- 8655946
TI  - Emergency medicine cyberspace.

PMID- 8655947
TI  - Laughter in the temple of pain and illness.

PMID- 8655948
TI  - Laughter and loyalty.

PMID- 8655949
TI  - Disaster medicine in Europe.

PMID- 8655950
TI  - Disaster medicine in Europe.

PMID- 8655951
TI  - Objectives to direct the training of emergency medicine residents on off-service
      rotations: surgery, Part 3.
AB  - This is the 36th and final article in a series of objectives to direct emergency
      medicine resident experiences on off-service rotations. An understanding of the
      principles of surgical diagnosis and treatment is an essential component of the
      practice of emergency medicine. Emergency medicine residents rotating on surgical
      services require specific objectives to maximize their learning potential,
      emphasize early patient assessment, identify the possible need for surgery, and
      gain a basic understanding of definitive management. This article approaches
      surgical problems from the presenting complaint. It concludes with procedures not
      covered in the goals and objectives for traumatology.

PMID- 8655952
TI  - Late-onset hepatic failure: clinical features, serology and outcome following
      transplantation.
AB  - A further series of 41 adult patients with late-onset hepatic failure was
      investigates with respect to aetiological factors, particularly hepatitis C and
      E, which have been identified since our earlier report of this condition. The
      increased use of transplantation and its impact on survival overall is assessed.
      Comparison is made with 64 patients admitted over the same period with fulminant
      hepatic failure of non-A, non-B aetiology. Screening for the hepatitis viruses
      revealed three cases of hepatitis A and one case of Epstein Barr virus hepatitis.
      There were no cases of hepatitis C or hepatitis E virus detected by enzyme
      immunoassay and reverse transcriptase/polymerase chain reaction techniques,
      although three patients had positivity for IgG anti-hepatitis E virus,
      demonstrating previous exposure. Serum autoantibodies in a titre greater than or
      equal to 1:40 were present in 29% of samples tested and in three cases, titres of
      SMA or ANF were greater than 1:320. In a further five cases, a potentially
      hepatotoxic agent had been given within 3 months of the onset of symptoms,
      leaving the majority of patients (29) with no identifiable cause for their
      disease. The frequency of symptoms, however, including nausea, abdominal
      discomfort with the subsequent development of ascites, encephalopathy and renal
      impairment suggest a similar disease process in these patients. Analysis of liver
      biopsy material showed similar patterns on all cases of map-like necrosis with
      nodular regeneration and without other additional features of aetiological
      significance. Differences in clinical and histological changes for the non-A, non
      B fulminant hepatic failure comparison group reflect the tempo of disease process
      rather than the nature and cause of the liver damage. The introduction of
      transplantation has led to a marked improvement in survival (39% overall in the
      earlier series). In the 21 patients in whom transplantation was carried out, the
      1-year actuarial survival is currently 55%. Treatment of late-onset hepatic
      failure with corticosteroids and the use of Prostaglandin E1 and interferon in
      individual cases has been disappointing, and the emphasis in management should be
      placed on teh early referral of such patients to a centre offering
      transplantation.

PMID- 8655953
TI  - Liver transplantation for Wilson's disease.
AB  - BACKGROUND/AIMS: As has been the case with other metabolic diseases of the liver
      in the last decade, orthotopic liver transplantation has been applied to the
      treatment of Wilson's disease with increasing frequency. The experience at the
      University of Pittsburg with orthotopic liver transplantation for Wilson's
      disease is reported. METHODS: Between February 1981 and December 1991, 51
      orthotopic liver transplants were performed on 39 patients (16 pediatric, 23
      adults) with Wilson's disease. Twenty-two patients were transplanted because of a
      presentation co-existent with fulminant hepatic failure. Seventeen presented with
      chronic advanced liver disease with (n=9) or without (n=8) associated neurologic
      dysfunction. RESULTS: The rate of primary graft survival (n-39) was 73% and
      patient survival was 79.4%. No patient mortality occurred beyond 3 weeks post
      orthotopic liver transplantation. Survival was butter for those with a chronic
      advanced liver disease presentation (90%) than it was for those with a fulminant
      hepatic failure (73%) presentation, but the difference was not statistically
      significant. CONCLUSIONS: 1) Currently, orthotopic liver transplantation is the
      treatment of choice for Wilson's disease presenting as fulminant hepatic hepatic
      failure; 2) orthotopic liver transplantation should be considered for patients
      with Wilson's disease with advanced, chronic liver disease for whom no other
      therapy is possible; 3)orthotopic liver transplantation only partially corrects
      the underlying metabolic defect of patients with Wilson's disease and converts
      the copper kinetics from that characteristic of an individual affected with a
      homozygous disease to that of an individual who is an obligate heterozygote,
      thereby effecting a phenotypic cure.

PMID- 8655954
TI  - Autoantibody against 70 kD heat shock protein in patients with autoimmune liver
      diseases.
AB  - BACKGROUND/AIMS: It has recently been suggested that heat shock proteins are
      implicated in the pathogenesis and teh pathophysiology of various immunological
      disorders, and the presence of antibodies against heat shock proteins has been
      reported in several autoimmune diseases. METHODS: We investigated autoantibodies
      against the two major human heat shock proteins (hsp70 and hsp90) in sera from
      patients with primary biliary cirrhosis and autoimmune hepatitis, the two major
      autoimmune liver disease. Reactivity with human heat shock proteins obtained from
      phytohemagglutinin stimulated cells was investigated by immunoblots with sera at
      1:20 dilution. RESULTS: Reactivity with human hsp90 was not found in any sera
      from patients or normal controls. In contrast, reactivity with human hsp70 was
      found in 16 of 35 (45.7%) primary biliary cirrhosis patients and in 9 of 17
      (52.9%) autoimmune hepatitis patients, but similar reactivity was found in only 2
      of 15 patients with chronic hepatitis B and 1 of 13 patients with chronic
      hepatitis C. All the normal controls showed a negative reaction. Two-dimensional
      immunoblots and immunoabsorption experiments established that the autoantibody
      recognized only human hsc70 (73 kD/pI 5.5), a constitutive form of the hsp70
      family. CONCLUSIONS: Although the pathological significance of the autoantibody
      against hsc70 in these autoimmune liver diseases remains unknown, the serum
      autoantibody detected in primary biliary cirrhosis patients is closely related to
      clinical variables including serum total bilirubin, alanine aminotransferase,
      IgG, IgM, titers of antimitochondrial antibodies, and major symptoms (pruritus
      and/or icterus). These observations may suggest that the anti-hsc70 antibody is
      an indicator for the disease activity of primary biliary cirrhosis.

PMID- 8655955
TI  - Plasma endotoxin and tumor necrosis factor-alpha in the hyperkinetic state of
      cirrhosis.
AB  - BACKGROUND/AIMS: The factors which trigger the hyperdynamic circulation in
      cirrhosis remain poorly defined. Plasma levels of the potent vasodilators
      endotoxin and tumor necrosis factor-alpha may be elevated in patients with
      cirrhosis, and therefore the potential role of these substance was assessed in
      the hyperkinetic circulation in cirrhosis. METHODS: Forty-nine patients in stable
      condition underwent systemic and hepatic hemodynamic measurements, and right
      atrial blood sampling for endotoxin and tumor necrosis factor-alpha assays.
      Patients were divided into three groups according to the severity of the disease:
      group 1 consisted of eight patients with normal liver or mild hepatic fibrosis,
      and groups 2 and 3 contained 17 and 24 patients with Child A and Child B or C
      cirrhosis, respectively. RESULTS: Systemic vascular resistance decreased and
      cardiac index increased from group 1 to 3: 1530 +/- 196 dyn.s.cm-5 to 990 +/- 72
      dyn.s.cm-5 (mean +/- S.E.; p<0.05) and 3.1 +/- 0.3 l.min-1.m-2 to 4.2 +/- 0.2
      l.min-2.m-2, respectively. Endotoxin was not detectable in any of the groups and
      tumor necrosis factor-alpha was increased in one patient from group 1, six from
      group 2 and six from group 3. Mean tumor necrosis factor-alpha levels were not
      different among the groups (10 +/- 5, 18 +/- 5 and 17 +/- 7 pg/ml in groups 1, 2
      and 3, respectively). Systemic vascular resistance and cardiac index were not
      correlated to plasma tumor necrosis factor-alpha levels; patients with increased
      levels of this cytokine did not have worse hyperdynamic circulation in any of the
      groups. CONCLUSIONS: These results suggest that tumor necrosis factor-alpha and
      endotoxin do not play a role in the maintenance of the hyperkinetic state of
      cirrhosis.

PMID- 8655956
TI  - Increased in vitro production and serum levels of the soluble lipopolysaccharide
      receptor sCD14 in liver disease.
AB  - Elevated concentrations of lipopolysaccharide have been found in serum of
      patients with severe parenchymal liver disease and its toxic effect is thought to
      involved in hemodynamic disturbances seen in cirrhosis. A soluble form of the
      receptor (sCD14) for lipopolysaccharide is present in serum and is released by
      stimulated macrophages, indicating macrophage activation. We investigated sCD14
      serum levels and in vitro production by lipopolysaccharide stimulated peripheral
      blood monocytes in patients with various liver diseases. In acute viral hepatitis
      serum sCD14 levels were significantly higher during the first 2 weeks after onset
      of jaundice (n=11; 3.6 +/- 0.9 microg /ml (mean +/- SD)) than in healthy control
      individuals (n=52; 2.5 +/- 0.7 microg/ml; p<0.001). These elevated serum levels
      corresponded to enhanced in vitro production of sCD14 by lipopolysaccharide
      stimulated peripheral blood monocytes (n=11; 365 +/- 262 ng/ml) as compared to
      control monocytes (n=52; 228 +/- 74 ng/ml; p=0.02). Similarly, patients with
      alcoholic cirrhosis had significantly increased sCD14 serum levels (n=31; 4.5 +/-
      3.2 microg/ml; p<0.001) and in vitro sCD14 production by lipopolysaccharide
      stimulated monocytes (291 +/- 153 ng/ml; p=0.014). Serum sCD14 levles correlated
      with the severity of disease (Child A: 2.6 +/- 1.0 microg/ml; Child B: 4.4 +/-
      2.1 microg/ml; Child C: 7.8 +/- 5.1 micro/ml; Anova: p=0.001). Patients with
      chronic viral hepatitis had only slightly elevated serum sCD14 levels (n=17; 2.9
      +/- 0.7 microg/ml; p=0.01) and increased in vitro production of sCD14 by
      peripheral blood monocytes (320 +/- 128 ng/ml; p<0.001). The elevated serum
      concentration of sCD14 in alcoholic cirrhosis and acute and chronic viral
      hepatitis points to an incrased macrophage activation in these diseases. sCD14
      from serum is able to associate with cells not expressing membrane CD14, such as
      endothelial cells, allowing those cells to bind and respond to
      lipopolysaccharide. Elevated levels of sCD14 could in this way contribute to the
      toxic effects of lipopolysaccharide in severe liver disease.

PMID- 8655957
TI  - Quantitative analysis of hepatitis C virus RNA in liver biopsies by competitive
      reverse transcription and polymerase chain reaction.
AB  - BACKGROUND/AIMS: The determination of HCV-RNA concentration in liver samples is
      likely to provide interesting insights for the study of disease progression and
      for evaluation of the efficacy of anti-viral therapy. METHODS: A procedure was
      developed for the precise quantification of HCV-RNA in liver biopsies, based on
      the competitive reverse transcription-polymerase chain reaction technology. This
      competitive assay consists of the co-amplification of the target RNA with known
      amounts of a competitor RNA molecule containing the same sequence as the target
      plus an insertion in the middle, allowing resolution of the two amplification
      products by gel electrophoresis. RESULTS: The amounts of HCV-genomic-RNA and beta
      actin mRNA (the latter being used as an internal standard to overcome the problem
      of reproducibility of quantitative RNA extraction) were evaluated in liver
      biopsies of 15 patients affected by hepatitis C virus-positive chronic liver
      disease at the time of diagnosis. All the patients underwent alpha-interferon
      therapy for 6 months and were subsequently followed for at least 1 further year
      after the end of treatment. Viral RNA concentration (which ranged from 2 to 2.7 x
      10(5) HCV-RNA molecules per 10(6) beta-actin molecules) directly correlated with
      the efficacy of treatment, indicating that low levels of viral replication in the
      liver are associated with a poor response to therapy. CONCLUSIONS: This study
      suggests that the determination of viral load in the liver is an important
      prognostic tool for the prediction of the efficacy of alpha-interferon therapy.

PMID- 8655958
TI  - Low incidence of p53 mutations in European hepatocellular carcinomas with
      heterogeneous mutation as a rare event.
AB  - BACKGROUND/AIMS: The aim of this study was to evaluate the role of p53 mutations
      in European hepatocarcinogenesis. METHODS: DNA extracts from 20 microdissected
      tumor samples were investigated. Nucleotide sequence analysis of subcloned
      polymerase chain reaction-fragments of the conserved domain exons 5-8 was
      performed in order to detect heterogeneous distribution of p53 mutated cells
      within the tumors. In a screening procedure four clones of each exon 5-8 were
      analyzed. To confirm the observed mutations polymerase chain reaction and
      subcloning was repeated. RESULTS: Sequence analysis confirmed a mutation in only
      two cases (10%). One at codon 220 (exon 6) was a homogeneous transition in nearly
      all clones from TAT to TGT. The other mutation was a transition from cGG to CAG
      at the known hot spot codon 248 (exon 7). It was found in 30% of the clones. We
      conclude that the other mutations from the first step were artefacts due to the
      infidelity of the taq-polymerase. All tumors had wild type sequence at the
      reported hot spot codon 249. The minor importance of p53 gene alterations in
      European hepatocarcinogenesis was further confirmed at the protein level by
      immunohistochemistry. Only the tumors with the heterogeneous p53 mutation at
      codon 248 showed a p53 overexpression in nearly 30% of the nuclei. None of the
      other tumors showed higher levels of p53 expression. CONCLUSIONS: We therefore
      conclude that the incidence of p53 mutations in European hepatocellular
      carcinomas is very low. Generally there may be no heterogeneous distribution of
      p53 mutated cells within a tumor. The contribution of this genetic alteration to
      hepatocarcinogenesis in Europe seems of little importance.

PMID- 8655959
TI  - Gallstone recurrence after successful lithotripsy.
AB  - We report the recurrence rate of gallstone within 5 years after successful
      lithotripsy. One hundred and fifty consecutive patients (solitary stones, 102
      patients; multiple stones, 48 patients) were followed up for a median of 42
      months (range 6-72) after stone clearance and cessation of bile acid therapy. No
      patient received any therapy to prevent recurrence. Thirty-seven patients
      developed recurrent gallstones. Probabilities of recurrence were (mean +/- SD)
      6.6% +/- 2%, 15.7% +/- 3%, 22.8% +/- 3.6%, 29.7% +/- 4.5%, 32.2% +/- 5% at 1, 2,
      3, 4 and 5 years, respectively. The recurrence rate was lower in patients who had
      solitary stones than in patients with multiple stones (26.1% versus 47% at 5
      years, respectively; p<0.009 - log rank test). Only five patients developed
      recurrent symptoms or stone complication (14%). We conclude that the recurrence
      rate after successful lithotripsy is lower than expected from dissolution
      studies, due to a low recurrence rate in patients who had solitary stones.

PMID- 8655960
TI  - Synthesis of insulin-like growth factor binding proteins and of the acid-labile
      subunit of the insulin-like growth factor ternary binding protein complex in
      primary cultures of human hepatocytes.
AB  - BACKGROUND/AIMS: The liver is the main source of circulating insulin-like growth
      factor binding proteins. In man, the cellular origin of insulin-like growth
      factor binding proteins has remained obscure. METHODS: Human hepatocytes isolated
      from surgical specimens were purified and cultured using a collagen gel
      immobilization technique. Gene expression of individual insulin-like growth
      factor binding proteins and of the acid-labile subunit of the insulin-like growth
      factor binding proteins by Western ligand blotting and immunoblot analysis.
      Neutral size chromatography of medium samples was used to detect insulin-like
      growth factors binding protein complexes. RESULTS: In cultured hepatocytes
      transcripts for insulin-like growth factor binding protein-1, -2, -3, -4 and for
      acid labile subunit could be demonstrated. Ligand blotting revealed the secretion
      of insulin-like growth factor binding proteins of molecular weights of 24 kD, 30
      kD, 34 kD, 43 kD and 46 kD, respectively. Using polyclonal antisera, these
      proteins were identified as insulin-like growth factor binding protein-1, -2 and
      the insulin-like growth factor binding protein-3 doublet. Neural size
      chromatography of culture supernatants showed the presence of an insulin-like
      growth factor binding protein complex of approximately 40 kD, but absence of the
      high molecular weight ternary complex of 150 kD. CONCLUSIONS: It is concluded
      that in man parenchymal liver cells have to be regarded as a source of acid
      labile subunit and of circulating insulin-like growth factor binding proteins
      including insulin-like growth factor binding protein-3.

PMID- 8655961
TI  - Regulation of ferritin expression by alcohol in a human hepatoblastoma cell line
      and in rat hepatocyte cultures.
AB  - Serum ferritin increases in chronic alcoholism, without clear explanation. We
      have previously shown that alcohol increases ferritin levels in a human
      hepatoblastoma cell line (HepG2). The aims of the present work were: 1) To extend
      our results in normal rat hepatocyte cultures, and 2) To determine the mechanism
      by which alcohol enhances ferritin levels. In HepG2 cells, high alcohol
      concentrations (300 mM) during long exposure (4 days) increased the synthesis of
      H and L ferritin subunits, in association with increased levels of ferritin
      mRNAs. In rat hepatocyte cultures, the synthesis of L ferritin increased after 24
      h of exposure to lower alcohol concentrations (10 mM); alcohol had no effect on
      ferritin mRNAs levels. In both cell types, the alcohol effect was not related to
      an increase in iron intracellular incorporation. In HepG2 cells, desferrioxamine
      (Df), a potent iron chelator, abolished ferritin synthesis in the presence or
      absence of alcohol, and abolished the alcohol induction of ferritin mRNAs. In rat
      hepatocytes, Df decreased ferritin synthesis to a similar level in the presence
      or absence of alcohol. Alcohol increased ferritin synthesis differently in HepG2
      cells and in normal rat hepatocyte cultures. In the latter case, the alcohol
      effect was observed at low concentration. Despite a striking inhibiting effect of
      Df on ferritin synthesis, in both cellular models a mechanism accounting for
      increased ferritin synthesis independently of iron is suggested. Globally, these
      data strongly suggest that hyperferritinemia in chronic alcoholism could be
      related to the induction of ferritin by alcohol.

PMID- 8655962
TI  - Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in
      rats.
AB  - To clarify the contribution of P-glycoprotein to the biliary excretion of
      vincristine in rats, the effects of induction of hepatic P-glycoprotein by a
      phenothiazine treatment on the biliary excretion of [3H]vincristine were
      investigated. Immunoblot analysis using C219, a monoclonal antibody to P
      glycoprotein, demonstrated that the phenothiazine treatment increased the P
      glycoprotein level in isolated bile canalicular membrane vesicles approximately
      6.5-fold. Transport of [3H]vincristine to canalicular membrane vesicles from the
      phenothiazine-treated and control rats revealed ATP-dependency, with an overshoot
      that results from the consumption of medium ATP. The maximum ATP-dependent uptake
      was increased in canalicular membrane vesicles from the phenothiazine-treated
      rats approximately 2-fold compared to the control. The biliary excretion of
      [3H]vincristine was further studied using an indicator dilution method in a
      single-pass perfused liver. The ratios of the cumulative amount of
      [3H]vincristine excreted into the bile ot the amount of [3H]vincristine taken up
      by the liver at 15, 30 and 90 min were significantly increased in the
      phenothiazine-treated rats by 60, 45 and 25%, respectively, compared to the
      control rats. Furthermore, the corrected mean residence time of [3H]vincristine
      in hepatocytes in the phenothiazine-treated rats was reduced to 21 min from that
      in the control rats (30 min), supporting the contention that the induction of
      hepatic P-glycoprotein on the bile canalicular membrane function sas a
      transporter not only in the isolated membrane but also in the more physiological
      perfused liver system. One must be cautious in the interpretation of the data,
      however, since phenothiazine can induce other proteins which might affect the
      behavior of [3H]vincristine.

PMID- 8655964
TI  - The overexpression of proliferating cell nuclear antigen in biliary cirrhosis in
      the rat and its relationship with epidermal growth factor receptor.
AB  - Chronic bile duct obstruction in the rat leads to biliary cirrhosis but
      maintained hepatocellular mass. We have previously demonstrated translocation of
      epidermal growth factor receptor to nuclei. It remained unclear, however, whether
      this was due to hepatocyte proliferation and/or altered handling of epidermal
      growth factor receptor. Therefore, in the present investigation we
      stereologically estimated expression of proliferating cell nuclear antigen, a
      marker of the S phase of teh cell cycle at 1, 2, 3, 7, 14, 21 and 28 days after
      bile duct ligation. Proliferating cell nuclear antigen positive hepatocytes
      averaged 2.1 +/- 3.6% in sham-operated control animals. This increased to 20.7 +/
      6.4, 26.8 +/- 18.7, 31.3 +/- 23.9, 42.3 +/- 16.6 and 24.7 +/- 28.0% 3, 7, 14, 21
      and 28 days after bile duct ligation, respectively (p<0.005 by ANOVA). This was
      correlated with the number of epidermal growth factor receptor positive nuclei
      (rs = 0.737) and inversely with the maximal binding capacity of epidermal growth
      factor to a crude plasma membrane fraction (rs = 0.697) reported previously. We
      conclude that bile duct ligation in the rat induces a significant hepatocellular
      proliferation as assessed by proliferating cell nuclear antigen expression and
      that this process could, at least in part, be related to increased nuclear
      expression of the epidermal growth factor receptor.

PMID- 8655963
TI  - Experimental biliary fibrosis correlates with increased numbers of fat-storing
      and Kupffer cells, and portal endotoxemia.
AB  - In the present study, we have investigated the correlation between hepatic
      fibrosis in rats subjected to bile duct ligation, the numbers of Kupffer and fat
      storing cells, and the level of endotoxin in both the portal and systemic
      circulation. The extent of hepatic fibrosis was measured by morphometry. Kupffer
      cells were identified by indirect immunoperoxidase staining using ED-2 anti
      macrophage antibody. Fat-storing cells were stained with DE-B-5 anti-desmin
      antibody. Endotoxin levels were determined by the Limulus Lysate test. Following
      bile duct ligation, connective tissue septa rapidly developed in periportal
      areas. After 1 week, the volume density of connective tissue had increased from
      0.6 +/- 0.1% in control animals to 3.8 +/- 1.1%. After 2 weeks, this volume
      increased to 19.9 +/- 1.3%, and after 3 weeks to 34.3% +/- 2.7%. The number of
      periportal fat-storing cells increased 2.8-fold during the first 2 weeks, whereas
      pericentral fat-storing cells increased only 1.7-fold. After 2 weeks, no further
      increase was observed. During the first week of bile duct ligation, the number of
      Kupffer cells increased nearly two-fold. Thereafter, no further increase was
      detected. In control rats, only two of ten rats showed low amounts of endotoxin
      in the portal blood. Portal endotoxemia increased with time after bile duct
      ligation. After 3 weeks, all rats were positive. The measured endotoxin levels
      were approximately 7 times higher than in control rats. We conclude that the
      development of fibrosis secondary to experimental bile duct ligation is
      accompanied by protal endotoxemia, and increases in the numbers of Kupffer and
      periportal fat-storing cells. We found a significant correlation between portal
      endotoxemia, the number of Kupffer and fat-storing cells, and the extent of
      fibrous septa, supporting the view that high endotoxemia levels coincide with
      Kupffer cell activation and fibrogenesis.

PMID- 8655965
TI  - Nicotinamide methylation and hepatic energy reserve: a study by liver perfusion
      in vitro.
AB  - BACKGROUND/AIMS: The synthesis of pyridine nucleotides from nicotinamide requires
      adenosine triphosphate. In man when exogenous nicotinamide is poorly utilized in
      this synthesis, the excess follows a dissipative metabolic pathway and is
      excreted in urine as N-methylnicotinamide. In human cirrhosis N
      methylnicotinamide serum levels are higher than normal, in basal condition and
      after nicotinamide oral load. The aim of this study was to verify N
      methylnicotinamide production in relation to hepatic content of adenosine
      triphosphate during in vitro perfusion of rat liver, in normal conditions and
      after adenosine triphosphate depletion by metabolic stress. METHODS: "Stress" was
      obtained by pre-washing with saline for 15 min before the perfusion with
      nutritive medium. RESULTS: The adenosine triphosphate decrease in the stressed
      liver was 38% after pre-washing with saline and 80% at the end of nutritive
      perfusion. In control liver the corresponding decreases were 1% after pre-washing
      with nutritive medium and 65% at the end of perfusion with the same medium. The
      total nicotinamide adenine dinucleotide decreases were 44% and 56% in the
      stressed liver, and 19% and 52% in the control liver. The output levels of N
      methylnicotinamide at 90 min of rat liver nutritive perfusion were 31.50 +/- 4.72
      nmol/g for normal liver and 66.40 +/- 13.17 for stressed liver (p<0.001). Liver
      adenosine triphosphate was inversely related to N-methylnicotinamide production
      (r=0.93; p<0.001). CONCLUSIONS: These data suggest that nicotinamide methylation
      may be enhanced when there is hepatic adenosine triphosphate decrease and energy
      failure induced by hypoxia or metabolic stress, similar to that obtained in vitro
      by saline washing before perfusion with nutritive medium. This study shows that
      the evaluation of N-methylnicotinamide production in man (before and after
      nicotinamide load) might be useful to explore the energy state of diseased liver.

PMID- 8655967
TI  - Liver transplantation for alcoholic liver disease.

PMID- 8655966
TI  - Endogenous pulmonary nitric oxide production measured from exhaled air is
      increased in patients with severe cirrhosis.
AB  - BACKGROUND/AIMS: Endogenous pulmonary nitric oxide production may be increased in
      severe cirrhosis and contribute to pulmonary vasodilation. This study assessed
      pulmonary nitric oxide production by measuring nitric oxide in the exhaled air in
      patients with severe cirrhosis and examined the relationship between exhaled
      nitric oxide and pulmonary hemodynamics in these patients. METHODS: Nitric oxide
      concentrations and production were measured in the exhaled air in six Child-Pugh
      class C patients with cirrhosis and 21 non-smoking healthy controls. Systemic and
      pulmonary hemodynamics were measured in patients only. RESULTS: Nitric oxide
      concentration (32.0 +/- 1.7 (mean +/- SEM) vs. 8.9 +/- 1.0 ppb) and production
      (9.2 +/- 1.3 vs. 3.1 +/- 0.3 nmol/min) in exhaled air were significantly higher
      in patients than in controls. Patients had high cardiac output (8.5 +/- 0.9
      l/min), low pulmonary and systemic vascular resistance (57 +/- 10 and 767 +/- 93
      dyn.s.cm-5, respectively) under baseline conditions. A significant negative
      correlation was found between pulmonary vascular resistance and exhaled nitric
      oxide production (r=0.943, p=0.05) but not between cardiac output or systemic
      vascular resistance and nitric oxide measured in exhaled air. CONCLUSIONS:
      Endogenous pulmonary nitric oxide production measured from exhaled air is
      increased in patients with cirrhosis and liver failure. Increased in patients
      with cirrhosis and liver failure. Increased nitric oxide production may also
      contribute to cirrhosis-induced pulmonary vasodilatation.

PMID- 8655968
TI  - Low prevalence of hepatitis C virus antibody in Turkish children with chronic
      hepatitis B infection.

PMID- 8655969
TI  - Infection with hepatitis B or C virus of peripheral blood mononuclear cells in
      serologically negative chronic alcoholic patients.

PMID- 8655970
TI  - Anamnestic responses of infants after regular or reduced doses of hepatitis B
      vaccine.

PMID- 8655971
TI  - Pentoxifylline-induced acute hepatitis.

PMID- 8655972
TI  - Parkinson's disease: a new risk factor for gallstone disease?

PMID- 8655973
TI  - Anthony Blunt and Guy Burgess, gay spies.
AB  - Anthony Blunt and Guy Burgess were prominent figures in the Cambridge spy ring
      operating on behalf of the USSR from the 1930s into the 1960s. The essay
      describes the complex personalities of Blunt and Burgess, whose homosexuality and
      communism were related aspects of a rebellious, antibourgeois culture in 1930s
      leftist Britain. The focus is on male homosexuality, and the question is put
      whether, and in what sense, Blunt and Burgess served the left, and whether they
      can be role models for gays at the end of this century.

PMID- 8655974
TI  - Between Marxism and psychoanalysis: antifascism and antihomosexuality in the
      Frankfurt School.
AB  - In their efforts to utilize individualist psychoanalysis as a tool for
      understanding mass behavior, the social theorists associated with the Frankfurt
      School increasingly came to rely on a static, essentializing construction of
      sexuality which ultimately led to an equation of fascism and homosexuality.
      Heretofore unexamined in studies of the Frankfurt School, this equation will here
      serve as the starting point for a fundamental critique of the concept of
      sexuality developed by this influential circle of Marxist thinkers. While
      directed at the concept of sexuality, such a critique more importantly opens up
      the underlying understanding of the social and psychological realms advanced by
      Critical Theory. Attending to the equation of homosexuality and fascism as the
      central point of concern, this essay will first trace the introduction of
      psychoanalysis into Critical Theory through Erich Fromm and then investigate the
      extent of Fromm's influence on the concept of sexuality propounded by his
      colleagues, especially Max Horkheimer and Theodor W. Adorno. Finally, it will
      take up a frequently overlooked essay by Herbert Marcuse which promoted a vision
      of sexuality radically different from that of his associates.

PMID- 8655975
TI  - Homosexuality and the American left: the impact of Stonewall.
AB  - Following the Stonewall Riots in New York City in June 1969, the left had to
      reassess negative appraisals of homosexuality that prevailed among virtually all
      leftist currents. Pressure for change came from within and from without. By the
      mid-1970s, three approaches had emerged: (1) radical support for sexual
      liberation and acceptance of same-sex love as being on a par with
      heterosexuality; (2) liberal support for the civil rights of homosexuals but
      without challenging heterosupremacy; and (3) continued adherence to the
      (Stalinist) view that homosexuality is a form of "bourgeois decadence" alien to
      the working class. This essay assesses the ways in which the left adapted to the
      new challenges that confronted it, with particular focus on attitudes toward the
      nature of homosexuality and its relation to the broader goals of the left.

PMID- 8655976
TI  - The Church, the Stasi, and socialist integration: three stages of lesbian and gay
      emancipation in the former German Democratic Republic.
AB  - Organized groups of homosexuals began forming in the East German Protestant
      Church beginning in 1982. They constituted a rapidly spreading nucleus for a
      lesbian and gay emancipation movement. As such, they were viewed with suspicion
      by the state security apparatus which heavily infiltrated them. As an attempt to
      out maneuver the church groups and raise political capital, the East German state
      by the last years of its existence in the late eighties embarked on a program of
      tolerance and integration of homosexuals into socialist society.

PMID- 8655977
TI  - From revolution to involution: the disappearance of the gay movement in France.
AB  - This essay sketches the development of the modern French gay movement in relation
      to its political context, in particular to the French Socialist Party. The author
      argues that its curvilinear development the movement started very modestly in the
      1950s, spread within small, radical left-wing circles in the late 1960s and early
      1970s, peaked around 1980, and declined rapidly in the course of the 1980s can be
      explained by the ups and downs in political repression on the one hand and
      political support and success on the other.

PMID- 8655979
TI  - Comparable growth of virulent and avirulent Mycobacterium tuberculosis in human
      macrophages in vitro.
AB  - The relative virulence and avirulence of Mycobacterium tuberculosis strains H37Rv
      and H37Ra were previously defined using animal infection models. To investigate
      host species' specificity of mycobacterial virulence, growth of the 2 M.
      tuberculosis strains in human monocyte-derived macrophages in vitro was studied.
      Mycobacterial growth was evaluated by acid-fast staining, electron microscopy,
      and colony-forming units (cfu) assay. As expected, the 2 strains demonstrated
      significantly different growth rates in mouse macrophages in vitro (53 h for
      H37Rv, 370 h for H37Ra). In marked contrast, in human macrophages the average
      division times of the strains were nearly equal (80 h for H37Rv and 76 h for
      H37Ra by cfu measurement, and 96 h for H37Rv and 104 h for H37Ra by acid-fast
      staining). These findings indicate that observations of mycobacterial virulence
      in murine systems may not necessarily translate to the human system, in which
      different mechanisms to control mycobacterial growth may be expressed.

PMID- 8655978
TI  - Factors affecting treatment responses to interferon-alpha in chronic hepatitis C.
AB  - Parameters have been studied to predict responses to interferon (IFN) therapy for
      chronic hepatitis C, but the definition of a response, the times at which
      responses were assessed, and the pretreatment parameters considered differ
      markedly from study to study. Thus, 113 patients with chronic hepatitis C were
      treated 3-6 months with 3 MU of IFN-alpha 2a three times a week and assessed for
      pretreatment parameters predictive of responses to IFN. In a multivariate
      analysis, a biochemical response (normal aminotransferase activity) at the end of
      treatment was significantly associated with low body weight, normal gamma
      glutamyl transpeptidase activity, and a pretreatment hepatitis C virus (HCV)
      genotype other than 1. Six months after the end of treatment, a low virus burden
      and a lack of anti-HCV IgM core antibodies were independently associated with
      sustained virologic response (i.e., normal aminotransferase activity and HCV RNA
      negativity). Therefore, these pretreatment parameters should be taken into
      account when individual treatment protocols are designed.

PMID- 8655980
TI  - Immune responses stimulated by percutaneous and intradermal bacille Calmette
      Guerin.
AB  - Healthy volunteers were randomized to receive percutaneous or intradermal bacille
      Calmette-Guerin (BCG) vaccination. Delayed-type hypersensitivity (DTH) to
      tuberculin, as well as proliferative and interferon-gamma responses in peripheral
      blood mononuclear cells stimulated by whole cell lysates and culture filtrates of
      Mycobacterium tuberculosis and Mycobacterium avium-intracellulare, were compared
      before and after vaccination. Positive DTH reactions were detected in 83% of
      intradermal and 40% of percutaneous BCG recipients 3 months after vaccination (P
      < .004). M. tuberculosis-specific proliferation was increased after intradermal
      BCG (P < .01) but not after percutaneous BCG compared with prevaccination
      responses. In addition, M. tuberculosis-specific interferon-gamma production was
      increased after intradermal BCG compared with both prevaccination responses (P <
      .04) and those measured after percutaneous BCG (P < .05). Predominant immune
      responses stimulated by BCG were directed against antigens present in
      mycobacterial whole cell lysate. These results indicate that the BCG vaccination
      route can affect both in vivo and in vitro immune responses.

PMID- 8655981
TI  - The role of nitric oxide in bacterial meningitis in children.
AB  - To investigate the role of nitric oxide (NO) in bacterial meningitis,
      concentrations in serum, cerebrospinal fluid (CSF), or both of the precursor (L
      arginine) and degradation products of NO (nitrate, nitrite) and tumor necrosis
      factor (TNF)-alpha were measured in 35 patients and 30 controls. CSF nitrate
      levels were significantly elevated, mainly due to increased blood-brain barrier
      permeability, and are therefore not a good parameter for gauging endogenous NO
      production in the CSF compartment. CSF NO/nitrite levels were significantly
      elevated in patients. NO/nitrite levels decreased over time (26%/6 h; P < .001).
      CSF levels of NO/nitrite correlated with those of TNF-alpha (r = .55; P = .001)
      and glucose (r = -.43; P = .02). CSF levels of L-arginine were lower in patients
      than in controls (P < .001). Dexamethasone did not exert a significant effect on
      NO metabolism. In conclusion, enhanced NO production may contribute to anaerobic
      glycolysis and neurologic damage in bacterial meningitis.

PMID- 8655982
TI  - Evidence for a beta 1 integrin fibronectin receptor in Candida tropicalis.
AB  - The binding of Candida tropicalis to fibronectin (FN) was studied in order to
      characterize the FN receptor in this species. FN binding was saturable at a
      concentration of 1.8 x 10(-9) M and exhibited a Kd of 2.3 x 10(-9) M and a
      receptor density of 854 receptors per cell. Extracts of C. tropicalis cell
      membrane at dilutions of 1:100-1:1000 significantly inhibited the binding of 3H
      labeled FN to C. tropicalis cells (P < .03). Purified FN, antibodies to the
      integrin alpha 5 beta 1 (FN receptor on human placenta), and antibodies specific
      for the integrin beta 1 subunit recognized a C. tropicalis membrane protein of
      125 +/- 25 kDa on immunoblots. Immunoprecipitation of radiolabeled proteins from
      C. tropicalis with purified human FN yielded a protein of 105 +/- 15 kDa. Thus,
      C. tropicalis expresses a protein with antigenic and functional similarity to the
      vertebrate beta 1 integrin FN receptor.

PMID- 8655983
TI  - Oral immunization of mice against candidiasis.
AB  - Oral immunization with live Candida albicans evoked antibody- and cell-mediated
      immune responses in gnotobiotic C.B-17 and BALB/c mice. No deaths or systemic
      candidiasis of endogenous origin were evident in these C. albicans-colonized
      (pure culture) mice. Histologic examination showed minimal to no infection of the
      stomach, esophagus, or tongue by C. albicans. Not only were orally immunized mice
      more resistant to systemic candidiasis (intravenous challenge) than were germfree
      (nonimmunized) controls, but immunity could be transferred to susceptible mice
      with immune spleen cells. Oral immunization elicited a Th1-type response in
      spleen cells and a Th2 response in Peyer's patch lymphocytes. The alimentary
      tracts of these orally immunized mice remained chronically colonized with C.
      albicans in spite of the presence of both antibody- and cell-mediated immune
      responses to C. albicans.

PMID- 8655984
TI  - Genetic diversity at the internal transcribed spacer regions of the rRNA operon
      among isolates of Pneumocystis carinii from AIDS patients with recurrent
      pneumonia.
AB  - The opportunistic fungal pathogen Pneumocystis carinii sp. f. hominis is a
      frequent cause of pneumonia in the immunocompromised host. Analysis of genetic
      variation among isolates of P. carinii sp. f. hominis from 12 human
      immunodeficiency virus (HIV)-infected persons with single and multiple episodes
      of P. carinii pneumonia was undertaken at the internal transcribed spacer (ITS)
      regions of the nuclear rRNA operon. In samples from 24 episodes of pneumonia, 10
      different types of P. carinii sp. f. hominis were identified. More than 1
      sequence type was observed in 8 samples, indicating that mixed infection with
      different types of P. carinii sp. f. hominis is not uncommon. In 4 of 7 patients
      with recurrent episodes of pneumonia, the sequence types observed at the second
      episode were different from those of the first, suggesting the occurrence of both
      reactivation of a previously acquired infection and reinfection from an exogenous
      source.

PMID- 8655985
TI  - Humoral and mucosal IgA antibody response to a recombinant 52-kDa cysteine-rich
      portion of the Entamoeba histolytica galactose-inhibitable lectin correlates with
      detection of native 170-kDa lectin antigen in serum of patients with amebic
      colitis.
AB  - Humoral and mucosal IgA responses to a recombinant cysteine-rich portion
      (designated LC3) of the Entamoeba histolytica galactose-inhibitable lectin's 170
      kDa subunit were determined in patients with amebic colitis. All patients had 170
      kDa amebic antigen in serum, compared with 1 of 50 cyst passers and 1 of 31
      controls (P < .01). Seven days after treatment, serum and fecal 170-kDa antigen
      became undetectable in 12 of the 13 patients (P < .001). Serum anti-LC3 IgA was
      found in 83.8% of colitis patients, compared with 2% of controls and 12% of
      asymptomatic cyst passers (P < .001). Salivary and fecal anti-LC3 IgA levels were
      higher in patients than in cyst passers (P < .001). In conclusion, in amebic
      colitis, development of humoral and mucosal IgA responses to the recombinant LC3
      encoded protein correlates with detection of amebic 170-kDa antigen in serum and
      feces.

PMID- 8655986
TI  - Lamivudine in children with human immunodeficiency virus infection: a phase I/II
      study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency
      Virus Working Group.
AB  - The safety, tolerability, pharmacokinetic profile, and preliminary activity of
      lamivudine (2'-deoxy-3'-thiacytidine), a novel cytidine nucleoside analogue with
      antiretroviral activity, in human immunodeficiency virus (HIV)-infected children
      beyond the neonatal period were studied. Ninety children received dosages of 1-20
      mg/kg/day. Pharmacokinetic evaluation demonstrated serum and cerebrospinal fluid
      concentrations that increased proportionally to dose. As of January 1994, 11
      children had been withdrawn from study for disease progression and 10 because of
      possible lamivudine-related toxicity, and 6 had died. CD4 and CD8 cell counts
      remained stable over 24 weeks in therapy-naive children and decrease slightly in
      previously treated children. Quantitative immune complex-dissociated p24 antigen
      and HIV RNA were decreased significantly at 12 and 24 weeks. In vitro resistance
      to lamivudine was documented in sequential virus isolates from some patients by
      12 weeks. Lamivudine was well-tolerated and exhibited virologic activity in
      children, although future use in children is likely to be in combination
      antiretroviral regimens.

PMID- 8655988
TI  - Identification of humoral antigenic determinants in the hepatitis C virus NS3
      protein.
AB  - Immunoblot analysis on serum samples from 90 patients with chronic hepatitis C
      virus infection revealed four putative immunogenic regions within the NS3 protein
      of the virus: E (around aa 1250/ 1251), A (within aa 1250-1334), A/B (around aa
      1323 and 1334), and B/C (around aa 1407 and 1412). Among them, region E was most
      immunodominant, and region A was recognized much less frequently by patients with
      cirrhosis than by those with chronic hepatitis (10% vs. 46%, chi 2 = 12.05, P <
      .01). The results suggest that region A might be a potential prognostic marker to
      differentiate chronic hepatitis from cirrhosis.

PMID- 8655987
TI  - Schistosomiasis japonica in the Philippines: the long-term impact of population
      based chemotherapy on infection, transmission, and morbidity.
AB  - The long-term impact of annual case-finding and chemotherapy with praziquantel on
      schistosomiasis japonica was examined in an 8-year longitudinal study in the
      Philippines. The prevalence, incidence, and intensity of infection and
      schistosome-induced hepatomegaly significantly decreased within 3-4 years of
      treatment and then stabilized despite continual population-based chemotherapy.
      Hepatomegaly rapidly developed in acutely infected persons, with 82% of subjects
      developing hepatic enlargement within 2 years of reinfection. These data suggest
      that abrupt discontinuation of current control measures in the Philippines may
      result in a rapid rebound in morbidity. Age-dependent acquired resistance to
      reinfection also developed in subjects chronically exposed to schistosomiasis
      japonica, suggesting that a vaccine may represent an alternative approach for
      control of this parasitic infection.

PMID- 8655989
TI  - Detection of a cluster of hepatitis C infections in a renal transplant unit by
      analysis of sequence variation of the NS5a gene.
AB  - Hepatitis C virus (HCV) genotype 1 isolates from 31 patients on dialysis or with
      renal transplants were studied for evidence of patient-to-patient spread of
      infection. Nucleotide sequences from a variable region (NSSV) of the NSSa
      (nonstructural 5a) gene and the hypervariable region of the second envelope gene.
      (env2) were compared. Investigation of phylogenetically related isolates of HCV
      type 1a with identical derived amino acid sequences in the NS5V led to
      recognition of a cluster of 4 patients who had received renal transplants within
      an 8-day period in 1984. This demonstrates the value of molecular epidemiologic
      techniques in reconstructing routes of infection and adds to the evidence for
      nosocomial transmission of HCV by routes other than blood transfusion.

PMID- 8655990
TI  - High prevalence of GB virus C infection in a group of Italian patients with
      hepatitis of unknown etiology.
AB  - Prevalence of the recently discovered GB virus C(GBV-C) was evaluated in a cohort
      of 49 Italian patients with acute or chronic hepatitis of unknown etiology (non-A
      E hepatitis) and in a control group of 100 healthy blood donors. The GBV-C
      genomes could be detected by polymerase chain reaction (PCR) with reverse
      transcription in 35% of the acute and 39% of the chronic hepatitis patients; only
      1 of the control subjects had a positive response. All PCR products hybridized
      with a specific probe in a colorimetric assay, and the analysis of the sequences
      of the amplified cDNAs fully confirmed the specificity of the assay. Furthermore,
      the alignment of the predicted translation products identified two recurrent
      amino acid substitutions in 6 patients, suggesting the possible existence of at
      least 2 different GBV-C subtypes. Thus, GBV-C may be an important agent,
      contributing, at least in Italy, to a significant number of the cases of
      hepatitis of unknown etiology.

PMID- 8655991
TI  - Cytomegalovirus glycoprotein B groups associated with retinitis in AIDS.
AB  - To determine if cytomegalovirus (CMV) retinitis occurs more frequently in
      patients infected with certain strains CMV isolates from the blood of 44 patients
      with advanced human immunodeficiency virus disease were grouped by the DNA
      sequence or the restriction endonuclease digest pattern of a portion of the
      glycoprotein B (gB) gene. Forty-two patients (95%) were followed clinically until
      the development of CMV retinitis or death. Fourteen (78%; 95% confidence
      interval, 7%-39%) of 26 with isolates belonging to other gB groups developed CMV
      retinitis (P = .002). Viremia caused by gB group 2 CMV strains is associated with
      higher risk of CMV retinitis than viremia due to other CMV gB groups. The
      association of CMV gB gene with retinitis suggests this gene, or one linked to
      it, is a virulence factor for CMV strains causing infection in AIDS patients.

PMID- 8655992
TI  - Low plasma concentrations achieved with conventional schedules of administration
      of ganciclovir in patients with AIDS.
AB  - Plasma concentration of ganciclovir was studied prospectively in 15 AIDS patients
      treated for acute cytomegalovirus (CMV) retinitis. Ganciclovir was administered
      at a mean dose of 10.3 +/- 0.6 mg/kg/day. The mean trough plasma concentration
      was 0.6 +/- 0.3 mg/L (n = 24), and the mean peak concentration was 7.2 +/- 2.4
      mg/L (n = 6). In 12 patients, trough concentrations were below the range that has
      been associated with effective treatment. Low trough concentrations were
      associated with treatment failure in 6 patients. Following an increase in the
      daily dose, improvement was observed in 4 of the 6 patients. These results
      suggest that low plasma ganciclovir levels are associated with the failure of
      therapy. Monitoring the plasma concentration of ganciclovir may thus be useful
      before considering the virus to be resistant to the drug or before switching from
      ganciclovir to foscarnet.

PMID- 8655993
TI  - Variation in plasma RNA levels, CD4 cell counts, and p24 antigen levels in
      clinically stable men with human immunodeficiency virus infection.
AB  - Short-term variability in CD4 cell counts, plasma RNA levels, and p24 antigenemia
      was measured in clinically stable men with human immunodeficiency virus
      infection. Blood samples were obtained three times in each of 2 weeks 4 weeks
      apart. Differences between duplicate assays were considered to be due to
      technical factors; variation among visits was attributed to physiologic factors.
      Median enrollment values of CD4 cell counts, plasma RNA levels, and immune
      complex-dissociated (ICD) p24 antigenemia were 400 cells/mm3, 3.4 log10
      copies/mL, and 38 pg/mL, respectively. Median absolute differences between
      duplicate CD4 cell counts, plasma RNA levels, and ICD p24 antigen were 16
      cells/mm3, 0.21 log10 copies/mL, and 9.3 pg/mL. Median intraindividual ranges
      were 119 cells/mm3, 0.83 log10 copies/mL, and 18 pg/mL. Above 500 copies/mL,
      plasma RNA levels have a variability of 0.5 log10; the test is unreliable below
      this level.

PMID- 8655994
TI  - Primary infection with zidovudine-resistant human immunodeficiency virus type 1
      does not adversely affect outcome at 1 year. Sydney Primary HIV Infection Study
      Group.
AB  - Human immunodeficiency virus type 1 (HIV-1) variants with reduced in vitro
      sensitivity to zidovudine, conferred by specific mutations in the viral reverse
      transcriptase, emerge during prolonged therapy. Late-stage disease and declining
      CD4 cell count are associated with more rapid emergence of these resistant
      variants. Isolates of HIV-1 from seroconverters were screened for the zidovudine
      resistance marker mutation at codon 215. HIV-1 with the altered genotype was
      detected in 5 (8.2%) of 61 patients soon after onset of symptomatic primary
      illness and from the sex partner of 1 patient. These transmitted resistant
      viruses were either replaced by strains susceptible to zidovudine within a few
      months of infection or persisted for up to 1 year in the absence of prolonged
      zidovudine therapy. The resistant genotype persisted in 3 of 5 seroconverters but
      in 2 patients had reverted to wild type at 48 and 52 weeks. Primary infection
      with zidovudine-resistant variants of HIV-1 was not associated with a more severe
      symptomatic primary illness or more rapid CD4 cell decline at 1 year after
      infection.

PMID- 8655995
TI  - Pseudouridine and 1-ribosylpyridin-4-one-3-carboxamide (PCNR) serum
      concentrations in human immunodeficiency virus type 1-infected patients are
      independent predictors for AIDS progression.
AB  - A prospective study was conducted with 161 human immunodeficiency virus (HIV)
      positive patients to investigate the prognostic role of 10 serum-modified
      nucleosides with regard to some of the most widely used parameters of AIDS
      progression. Serum concentrations of pseudouridine (> 3.77 nmol/mL) predicted
      progression to AIDS in CDC stage A2 HIV-infected patients much better than did
      other widely used parameters (hazard ratio, 2.7; 95% confidence interval, 1.29
      6.35; P = .01; median permanence time in stage A2, 17 vs. 30.5 months; P = .03).
      Serum concentrations of 1-ribosylpyridin-4-one-3-carboxamide (PCNR) and beta 2
      microglobulin and the CD4:CD8 cell ratio, in decreasing order and used in
      combination, differentiated the overall survival time probability of AIDS
      patients; PCNR was the best and a new independent predictor (overall survival
      time, > 31 months, no positive parameters; 19.3 months, one positive parameter;
      and 5.5 months, two positive parameters.

PMID- 8655996
TI  - Treatment of human immunodeficiency virus infection with hydroxyurea: virologic
      and clinical evaluation.
AB  - To assess the efficacy of the therapeutic use of inhibitors of ribonucleotide
      reductase for the treatment of human immunodeficiency virus (HIV) type 1
      infection, 7 consecutive patients were enrolled in a clinical trial involving
      monotherapy with hydroxyurea for 8-19 weeks. During therapy, patients were
      evaluated for clinical status and immunologic, hematologic, and quantitative
      virologic parameters, including determinations of viremia and the number of
      provirus-containing cells by competitive polymerase chain reaction. In all
      patients, these parameters were not modified during the course of therapy. The
      number of CD4 cells remained generally unchanged or showed a tendency to further
      decline. No sign of improvement in HIV disease was detected in any patient. These
      observations indicate that monotherapy with hydroxyurea does not provide
      therapeutic benefit to HIV-1-infected patients.

PMID- 8655997
TI  - Lysis of human immunodeficiency virus type 1 antigen-expressing cells by CD4 and
      CD8 T cells ex vivo.
AB  - The aim of this study was to investigate the extent of lysis mediated by
      cytotoxic T lymphocytes (CTL) directed against human immunodeficiency virus (HIV)
      type 1 gag protein and envelope glycoprotein in peripheral blood mononuclear
      cells (PBMC) from HIV-1-infected subjects and to compare it with nonspecific
      envelope glycoprotein-directed cytotoxicity involving CD4 T cells. Most
      seropositive subjects exhibited antigen-specific cytotoxicity directed at one or
      both viral antigens in unstimulated or in vitro-stimulated PBMC (or both)
      mediated by CD8 T cells. In addition, all donors, including seronegative control
      persons, exhibited nonspecific calcium-independent cytotoxicity involving CD4 T
      cells and envelope glycoprotein-expressing cells. No calcium-dependent, antigen
      specific CD4 T cell-mediated cytolysis was detected. In seropositive subjects,
      the vigor of nonspecific cytotoxicity was comparable to lysis by antigen-specific
      CD8 CTL and suggests that it may contribute to lysis of HIV-infected cells in
      vitro and in vivo.

PMID- 8655998
TI  - In vitro inhibition of the replication of human immunodeficiency virus type 1 by
      beta-mercaptoethylamine (cysteamine).
AB  - This study investigates the effects of cysteamine alone and in association with
      zidovudine or didanosine on the replication of human immunodeficiency virus type
      1 (HIV-1). More than 90% viral inhibition was obtained by 200 microM cysteamine
      in lymphocytes and 100 microM cysteamine in macrophages against 4 primary
      isolates and 2 laboratory strains of HIV-1. Polymerase chain reaction analysis
      demonstrated that cysteamine interferes with early steps of HIV-1 replication,
      before proviral DNA formation. The use of cysteamine in conjunction with
      zidovudine or didanosine brought about an additive antiviral effect without
      concomitant increases in toxicity. The concentrations of cysteamine that are
      effective against HIV-1 in vitro have been well tolerated over long periods by
      patients under treatment for cystinosis, an inherited disorder. These
      observations suggest that cysteamine alone or in combination with zidovudine or
      didanosine could be a new potential treatment of HIV-1 infection.

PMID- 8655999
TI  - Diagnosis of neurosyphilis in patients infected with human immunodeficiency virus
      type 1.
AB  - Establishing the diagnosis of neurosyphilis may be particularly difficult in
      human immunodeficiency virus type 1 (HIV)-infected persons. Polymerase chain
      reaction (PCR) was used to detect Treponema pallidum DNA in cerebrospinal fluid
      (CSF) from 81 HIV-infected patients. On the basis of reactive serum and CSF-VDRL
      tests, 2 patients were diagnosed as having neurosyphilis. T. pallidum DNA was not
      consistently detected in any sample, even when the CSF-VDRL was reactive. CSF
      pleocytosis, elevated protein, or depressed glucose concentration was not
      significantly associated with a history of exposure to or infection with T.
      pallidum. On the basis of results of routine CSF measurements and T. pallidum PCR
      results, no evidence was found for undiagnosed neurosyphilis in HIV-infected
      patients. T. pallidum DNA PCR on CSF did not provide more information than
      conventional CSF analysis. Further study is needed to determine the utility of
      this test in the diagnosis and treatment of neurosyphilis.

PMID- 8656000
TI  - Role of bird migration in the long-distance dispersal of Ixodes dammini, the
      vector of Lyme disease.
AB  - To evaluate the role of migratory birds in the long-distance dispersal of Ixodes
      dammini ticks and in the spread of Lyme disease, a 6-year study of migrating
      birds to an offshore New England island was conducted during 1989-1994. I.
      dammini are not endemic on this island, therefore allowing assessment of long
      distance tick dispersal rather than local infestation. Of 11,324 spring migrants
      examined, 1.2% were infested with I. dammini. Of 8607 fall migrants examined,
      0.2% were infested. Of nymphal ticks examined, 20% were infected with Borrelia
      burgdorferi. OspB DNA sequencing of 6 B. burgdorferi isolates was identical to
      sequences of 2 strains common in coastal Maine. It is evident that bird migration
      allows for long-distance dispersal of I. dammini from areas where they are
      endemic to areas where they are not and that a few bird species account for the
      majority of tick dispersal. The likelihood of establishment of enzootic Lyme
      disease by this mechanism is discussed.

PMID- 8656001
TI  - Effects of granulocyte colony-stimulating factor in cirrhotic rats with
      pneumococcal pneumonia.
AB  - A rat model was used to study the effects of granulocyte colony-stimulating
      factor (G-CSF) on the pathogenesis of pneumococcal pneumonia in cirrhosis. G-CSF
      or 5% dextrose in water was administered subcutaneously to cirrhotic and control
      rats before or after transtracheal infection with type 3 Streptococcus
      pneumoniae. In both groups, G-CSF significantly increased the total number and
      percentage of polymorphonuclear leukocytes (PMNL) in peripheral blood (P < .002)
      and bronchoalveolar lavage fluid (P < .01). An in vivo phagocytosis assay
      revealed no increase in uptake of pneumococci by PMNL within the lungs of
      cirrhotic or control rats receiving G-CSF. G-CSF administered before infection
      did not protect cirrhotic or control rats, but G-CSF treatment after infection
      significantly reduced mortality in control (P = .04) but not cirrhotic rats.
      These data suggest that despite increasing numbers of circulating and pulmonary
      PMNL, G-CSF does not protect against fatal pneumococcal pneumonia in cirrhotic
      rats.

PMID- 8656002
TI  - Effect of interferon-gamma in experimental Cryptosporidium parvum infection.
AB  - The activity of recombinant murine interferon-gamma (IFN-gamma) against infection
      by Cryptosporidium parvum was evaluated in immunosuppressed rats. Daily
      intraperitoneal doses of at least 125,000 U/kg significantly (P < .05) reduced
      the intensity of subsequent ileal infection. In addition, daily administration of
      500,000 U/kg significantly (P < .05) inhibited colonization of the biliary tract.
      When administered for 11 days to rats with established C. parvum infection, IFN
      gamma significantly (P < .05) reduced the number of parasites in the small
      intestine, but this treatment was ineffective against infection of the biliary
      tract and large intestine. Although the parasite loads in the common bile duct
      and large intestine were not significantly reduced, there were fewer cases of
      infection among the treated rats than in the control group. The data suggest that
      treatment with IFN-gamma may limit cryptosporidiosis of the small intestine.

PMID- 8656003
TI  - The molecular epidemiology of Giardia lamblia: a sequence-based approach.
AB  - Animals are commonly considered to be potential sources for Giardia lamblia
      infections in humans, but the extent of zoonotic transmission of G. lamblia
      remains controversial because of inadequate understanding of its epidemiology. A
      better understanding of the epidemiology of G. lamblia may be facilitated by a
      more effective means for classifying G. lamblia isolates. To develop a sequence
      based classification system, the gene encoding the metabolic enzyme triose
      phosphate isomerase (tim) was sequenced from a number of G. lamblia isolates of
      various host origins. Restriction enzymes were identified that can distinguish
      among isolates without the need for sequencing, simplifying the application of
      this approach to the epidemiologic investigation of giardiasis. Isolates from a
      previously reported epidemic of giardiasis were accurately classified by this
      technique, further verifying its utility for epidemiologic investigation.

PMID- 8656004
TI  - Serology of human papillomavirus type 16 infections: where angels fear to tread?

PMID- 8656005
TI  - Racial differences in herpes zoster and age at onset of varicella.

PMID- 8656006
TI  - Iron overload as a mechanism for the lowered survival in AIDS patients receiving
      dapsone-iron protoxalate for secondary prophylaxis of Pneumocystis carinii
      pneumonia.

PMID- 8656007
TI  - The changing epidemiology of pneumococcal bacteremia in human immunodeficiency
      virus infection.

PMID- 8656008
TI  - False-negative polymerase chain reaction-based diagnosis of human
      immunodeficiency virus (HIV) type 1 in children infected with HIV strains of
      African origin.

PMID- 8656009
TI  - No evidence for a role of enteroadherent Escherichia coli in diarrhea in human
      immunodeficiency virus-infected patients.

PMID- 8656010
TI  - Factors influencing human immunodeficiency virus type 1 transmission by blood
      transfusion. Transfusion Safety Study Group.
AB  - One hundred thirty-two recipients of blood components that retrospectively tested
      positive for antibody to human immunodeficiency virus type 1 (anti-HIV-1) were
      identified. Fourteen (11%) remained seronegative throughout follow-up. Donor and
      recipient characteristics that could have influenced transmission were examined.
      Attributes did not differ for infected and uninfected recipients. Peripheral
      blood mononuclear cells (PBMC) from uninfected recipients were HIV-1-negative by
      DNA amplification and culture but were susceptible to in vitro infection.
      Transmitting and nontransmitting donors at donation differed only for HIV-1 RNA
      positivity. By immunocapture reverse transcriptase-polymerase chain reaction, 6
      of 11 transmitters and 0 of 11 nontransmitters tested RNA-positive (P = .02). A
      more sensitive quantitative RNA assay detected RNA in all donation sera, but
      median levels were higher in transmitting than nontransmitting sera (P = .01).
      Median CD4 cell counts were lower for transmitting than nontransmitting donors at
      enrollment (P = .02). Level of viremia is an important determinant of HIV
      infection by blood transfusion.

PMID- 8656011
TI  - Human immunodeficiency virus type 1 (HIV-1)--and Epstein-Barr virus--specific
      cytotoxic T lymphocyte precursors exhibit different kinetics in HIV-1--infected
      persons.
AB  - The frequencies of human immunodeficiency virus type 1 (HIV-1) Gag- and Epstein
      Barr virus (EBV)-specific cytotoxic T lymphocyte precursors (CTLp) were studied
      longitudinally in peripheral blood mononuclear cells from 9 HIV-1-infected
      persons. By antigen-specific stimulation, HIV-1 Gag-specific CTLp were detected
      in vitro throughout the course of HIV-1 infection, even after the onset of overt
      disease. In 4 patients, however, HIV-1 Gag-specific CTLp frequencies declined
      over time in the presence of maintained EBV-specific CTLp. This decline was
      correlated with decreasing CD4 (r = .38; P < .05) and CD8 (r = .75; P < .001)
      cell numbers. The maintenance of EBV-specific CTLp in patients with low CD4 cell
      numbers indicated that EBV-specific CTL-mediated immunity may remain longer
      unaffected by HIV-1-induced immune dysfunction. Consistent with this observation,
      the growth of EBV-specific CTL could be supported in vitro by EBV-infected
      lymphoblastoid B cell lines, independent of both CD4 cells and exogenous
      cytokines.

PMID- 8656012
TI  - Molecular analysis of decreased interleukin-12 production in persons infected
      with human immunodeficiency virus.
AB  - Human immunodeficiency virus (HIV) disease is associated with loss of type 1
      responses, including interleukin (IL)-12 production. The dramatic drop in p70
      production seen at early stages of disease was found not to be associated with a
      similarly decreased p40 mRNA expression. p35 mRNA expression was more extensively
      reduced than p40 mRNA expression at these early stages. Monocytes infected in
      vitro with HIV displayed decreased p35 expression and p70 production, suggesting
      that such decreased IL-12 expression may contribute to reduced IL-12 production
      in HIV-positive patients' cells. In addition, treatment of cells with IL-10
      increased IL-10 mRNA expression and decreased p40 expression in both HIV-positive
      and -negative cells, while neutralization of IL-10 increased p40 mRNA levels.
      These observations, together with the observed hyperproduction of IL-10 in HIV
      positive patients, may explain the dysregulation of IL-12 production seen in HIV
      disease.

PMID- 8656013
TI  - Engagement of adhesion molecules (CD18, CD11a, CD45, CD44, and CD58) enhances
      human immunodeficiency virus type 1 replication in monocytic cells through a
      tumor necrosis factor-modulated pathway.
AB  - Engagement of monocytic cell membrane proteins was shown to enhance human
      immunodeficiency virus type 1 (HIV-1) replication in monocytic cells. Cross
      linking of CD18, CD11a, or CD45 by immobilized antibodies produced up to an 11
      fold enhancement of HIV-1 release in the OM10.1 monocytic cell line in a tumor
      necrosis factor-alpha (TNF-alpha)-dependent manner. In addition, adhesion of
      OM10.1 cells to immobilized intercellular adhesion molecule-1 (ligand for
      CD18/CD11a) induced similar TNF-alpha-dependent enhancement of HIV-1 replication.
      After phenotypic differentiation of OM10.1 cells, engagement of cell membrane
      proteins CD18, CD11a, CD44, CD45, or CD58 by soluble antibodies enhanced HIV-1
      replication in a TNF-alpha-dependent manner. These data suggest that cross
      linkage of monocytic cell membrane proteins during cell-cell interaction and
      specifically during antigen presentation to CD4 T cells may enhance HIV-1
      replication, facilitating infection of adjacent cells.

PMID- 8656014
TI  - Inhibition of immunoreactive tumor necrosis factor-alpha by a chimeric antibody
      in patients infected with human immunodeficiency virus type 1.
AB  - Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to
      stimulate human immunodeficiency virus type 1 (HIV-1) replication, has been
      implicated in the pathogenesis of HIV-1 infection. Inhibition of TNF-alpha by a
      chimeric humanized monoclonal antibody, cA2, was investigated in 6 HIV-1-infected
      patients with CD4 cell counts < 200/mm3. Two consecutive infusions of 10 mg/kg 14
      days apart were well tolerated, and a prolonged serum half-life for cA2 (mean,
      257 +/- 70 h) was demonstrated. Serum immunoreactive TNF-alpha concentrations
      fell from a mean prestudy value of 6.4 pg/mL (range, 4.2-7.9) to 1.1 pg/mL
      (range, 0.5-2.2) 24 h after the first infusion and returned to baseline within 7
      14 days. A similar response was seen after the second infusion. No consistent
      changes in CD4 cell counts or plasma HIV RNA levels were observed over 42 days.
      Future studies evaluating the therapeutic utility of long-term TNF-alpha
      suppression using anti-TNF-alpha antibodies are feasible and warranted.

PMID- 8656015
TI  - Cytomegalovirus inhibits CD14 expression on human alveolar macrophages.
AB  - Cytomegalovirus (CMV) infection in transplant patients is associated with an
      increased incidence of gram-negative pneumonia; the mechanism for this is
      unknown. Human alveolar macrophages (HAM) are an important part of the response
      of the lung to gram-negative bacteria. They interact with lipopolysaccharide
      (LPS) via the surface receptor CD14. The effect of CMV on CD14 expression by HAM
      was examined. HAM were obtained from normal volunteers by bronchoalveolar lavage,
      and some were exposed to CMV. CD14 expression was assessed by immunofluorescent
      microscopy and flow cytometry. CMV inhibited the surface expression of CD14 on
      HAM. Release of soluble CD14 was also reduced from infected cells, and Northern
      blot analysis revealed that CD14 mRNA was reduced in CMV-exposed cells. These
      findings were specific for CD14 expression. These results demonstrate that CMV
      inhibits the ability of HAM to express CD14.

PMID- 8656016
TI  - The repertoire of human antibodies to the carbohydrate capsule of Streptococcus
      pneumoniae 6B.
AB  - Antibodies to Streptococcus pneumoniae 6B capsular polysaccharide (PS) induced
      with a 23-valent PS vaccine among 25 adults were examined. The magnitude of
      antibody responses among different subjects was highly correlated with the amount
      of anti-6B antibodies expressing IgG (r = 0.98) and lambda (r = 0.93) isotypes.
      Most individuals produced one or two dominant IgG antibody clones as identified
      by their isoelectric points. Two antibody clones with unique amino acid sequences
      could be readily purified, and the sequences of their light chains match those of
      A1/A17 V kappa and hslv2046 V lambda genes. Anti-6B antibodies isolated from
      different subjects used various VL genes and differed in their cross-reactivity
      with 6A PS. An isoelectric focusing study suggests that some IgG antibodies
      induced with 6B PS bind 6A PS with lower avidity.

PMID- 8656017
TI  - Detection of group C rotavirus in infants with extrahepatic biliary atresia.
AB  - The purpose of this retrospective study was to examine liver tissue from patients
      with cholestatic disease for the presence of group C rotavirus RNA. The reverse
      transcriptase-polymerase chain reaction (PCR) for genes 5 and 6 was used, and the
      PCR products were subjected to liquid hybridization with a 32P-labeled probe. A
      second amplification with nested primers was also used. Samples from 32 subjects
      (20 with biliary atresia or choledochal cyst and 12 controls) were tested. Ten of
      20 biliary atresia patients were positive for group C rotavirus RNA; no controls
      were positive (P < .003). Three of the positive patients were positive for both
      genes 5 and 6. Six of the 10 had > 1 sample that was positive. These data suggest
      a possible relationship between group C rotavirus and extrahepatic biliary
      atresia in the 10 patients in whom virus RNA was detected.

PMID- 8656018
TI  - Collagen binding of Staphylococcus aureus is a virulence factor in experimental
      endocarditis.
AB  - The role of Staphylococcus aureus collagen binding in the development of
      experimental endocarditis was studied. Two isogenic strains of S. aureus, 1
      carrying an insertional inactivation of the gene encoding collagen-binding
      protein, were compared in a rat model of catheter-induced infective endocarditis
      (i.e.). Separate groups of rats with traumatized aortic valves were intravenously
      challenged with 1 of the strains. In rats sacrificed 24 h after inoculation, the
      collagen-binding strain significantly outnumbered the mutant strain (P < .001);
      however, 1 h after challenge, there was no difference in numbers of the 2
      strains. The results were substantiated, using a 1:1 mixture of the parent strain
      and the mutant as an inoculate. Our findings suggest that collagen binding of S.
      aureus is important in the sustenance of experimental IE and plays a limited role
      during the initial attachment of the microorganism to traumatized aortic valves.

PMID- 8656019
TI  - A clinical validation of Bordetella pertussis and Bordetella parapertussis
      polymerase chain reaction: comparison with culture and serology using samples
      from patients with suspected whooping cough from a highly immunized population.
AB  - The aim of this study was to validate the performance of the polymerase chain
      reaction (PCR) assay for Bordetella pertussis and Bordetella parapertussis in
      comparison with both culture and serology. The number of samples positive in PCR
      was 2.4-fold higher than the number of samples positive in culture. In
      serologically confirmed cases, the sensitivity of PCR and culture depended on the
      duration of disease and the age of the patient, being less sensitive in older age
      and later in disease. The sensitivity of the PCR in patients with < 10 days of
      symptoms was 70%, 50%, and 10% in the age groups < 1 year, 1-4 years, and > or =
      5 years, respectively. Evidence suggested that the effect of age on sensitivity
      may be due to differences in immune responses. The low IgA response in the < 1
      year age group may be related to the high number of samples positive in PCR and
      culture, even late in disease.

PMID- 8656020
TI  - Binding of human urokinase type plasminogen activator and plasminogen to Borrelia
      species.
AB  - Borrelia burgdorferi binds human urokinase plasminogen activator (uPA), which
      cleaves plasminogen (Pgn) to plasmin. The ability of other Borrelia species to
      bind uPA, Pgn, or both was investigated. Borrelia coriacae, Borrelia garinii,
      Borrelia parkeri, Borrelia anserina, and Borrelia turicatae were compared with
      infectious and noninfectious B. burgdorferi isolates. All Borrelia species lacked
      endogenous proteases capable of digesting casein, but all species bound human uPA
      and Pgn, generating Pgn-dependent proteolytic activity. There were no significant
      differences in the amount of plasmin, Pgn, or uPA bound per spirochete of the
      different species. On unfixed borreliae, fluorochrome-conjugated uPA bound to all
      species. Early binding was at the terminus of B. burgdorferi, whereas diffuse
      binding was observed on B. coriacae, B. garinii, B. parkeri, and B. turicatae.
      These studies demonstrate that binding of human uPA and Pgn to borreliae occurs
      on multiple species with apparent differences in surface distribution.

PMID- 8656021
TI  - From yesterday to today.

PMID- 8656022
TI  - Extrapancreatic nerve plexus invasion by carcinoma of the head of the pancreas.
      Diagnosis with intraportal endovascular ultrasonography.
AB  - CONCLUSION: The intraportal endovascular ultrasonography (IPEUS) could diagnose
      the second portion of the extrapancreatic nerve plexus invasion and provide
      precise information in operative strategy. But, the first portion was not
      visualized clearly owing to poor tissue penetration of the ultrasound beam, which
      may have reduced diagnostic accuracy. Improvement of the scanning area is
      expected to make intraportal endovascular US even more useful. BACKGROUND:
      Pancreatic cancer easily invades the retroperitoneal tissue, especially the
      extrapancreatic nerve plexus. We evaluated the extrapancreatic nerve plexus
      invasion of the pancreatic cancer with IPEUS. IPEUS was performed
      intraoperatively in 20 consecutive resected cases with carcinoma of the head of
      the pancreas. METHODS: IPEUS was performed with an 8-French, 20 MHz intravascular
      ultrasound catheter. IPEUS visualized the inferior pancreaticoduodenal artery
      (IPDA) in the extrapancreatic nerve plexus. The high-echoic area around the IPDA
      corresponds to the second portion of the extrapancreatic nerve plexus. The
      sonographic criterion for detection of the extrapancreatic nerve plexus invasion
      is low-echoic infiltration around the IPDA. RESULTS: Extrapancreatic nerve plexus
      invasion was confirmed with resected specimens in 10 patients. The IPDA could not
      be visualized in two patients. In 18 patients, the diagnostic accuracy of
      invasion was evaluated. For diagnosis of extrapancreatic nerve plexus invasion
      with intraportal endovascular US, the sensitivity, specificity, and overall
      accuracy were 87.5, 90, and 88.7%, respectively.

PMID- 8656023
TI  - Risk of death from acute pancreatitis. Role of early, simple "routine" data.
AB  - CONCLUSIONS: The analysis of all the data available in 192 patients at 24 h from
      admission shows that only serum glucose above 250 mg/dL (13.88 mmol/L) and serum
      creatinine above 2 mg/dL (176.8 mumol/L) are prognostic factors of death (P <
      0.0001). When, however, pathological chest X-rays are also considered in a subset
      of 149 patients, these and serum creatinine are prognostic factors of death with
      odd ratios of 2.9 (95% CL 1.3-6.3) and 9.4 (95% CL 2.2-40.7), respectively (P <
      0.0001). BACKGROUND: In patients suffering from acute pancreatitis, neither
      Ranson scores nor Glasgow criteria evaluation at 24 h yield a sufficiently
      reliable prognosis of the risk of death from the first acute attack. METHODS:
      After excluding posttraumatic, postsurgical, and post-ERCP acute pancreatitis, we
      selected 192 consecutive patients admitted in the first instance to our center
      for a first attack, distinguishing between patients who died and patients who
      survived. We used Cox's model to analyze the prognostic weight of variables
      available within 24 h of admission (sex, age, alcohol intake, smoking habits, 17
      biochemical tests, body mass index, chest X-rays, body temperature, and shock
      status). RESULTS: Seventeen (8.8%) patients died; mortality showed a decreasing
      trend over the period of years considered and was correlated, among other things,
      with necrotizing type of pancreatitis, idiopathic etiology, and shock status on
      admission.

PMID- 8656024
TI  - Expression and potential role of E-cadherin in pancreatic carcinoma.
AB  - CONCLUSION: Our results indicate that loss of E-cadherin might be associated with
      a more invasive phenotype in pancreatic cancer. BACKGROUND: A reduced expression
      of the calcium-dependent E-cadherin cell-cell adhesion molecule on tumor cells
      has been described as an important factor for tumor invasion and metastasis.
      METHODS: Pancreatic tissues (carcinoma, chronic pancreatitis, and normal) as well
      as 12 pancreatic tumor cell lines were investigated for E-cadherin expression by
      immunohistochemistry. To correlate the motility of pancreatic tumor cells in
      vitro with E-cadherin expression, we used a Boyden chamber assay. RESULTS: In
      pancreatic carcinoma tissues, diffuse growing tumor cells showed a decrease or
      loss of E-cadherin expression, whereas in areas of compact tumor growth, only a
      slight decrease of E-cadherin was observed compared to normal pancreas or chronic
      pancreatitis. No correlation between the E-cadherin expression and the grading of
      the tumor cells, the tumor stage, or the disease progression was detectable. Of
      four tumor cell lines that migrated in the Boyden chamber, three were
      predominantly E-cadherin negative. In contrast, seven of eight cell lines that
      did not migrate in vitro revealed E-cadherin expression.

PMID- 8656025
TI  - Pancreatic adenocarcinoma cell line, MDAPanc-28, with features of both acinar and
      ductal cells.
AB  - CONCLUSION: We established a new human pancreatic adenocarcinoma cell line,
      MDAPanc-28. Studies on this new line indicate that it expressed both acinar and
      ductal gene products suggesting that the patterns of gene expression in the
      pancreatic adenocarcinoma from which this cell line arose have features similar
      to those of the protodifferentiated cells hypothesized by Rutter and his
      colleagues for the developing pancreas (1,2). BACKGROUND: The cell line arose
      from a tumor that, like most pancreatic adenocarcinomas, was ductal on the basis
      of its histological appearance. METHODS: Once the cell line was established in
      culture, they were subjected to cytogenetic analysis and tested for their ability
      to grow in nude mice. RNA from the cells was analyzed by Northern blot analysis
      and PCR of reverse transcribed cDNA for the expression of both acinar and duct
      cell gene products. DNA was analyzed for the presence of mutated K-ras at codon
      12. RESULTS: The cell line expressed trypsin and ribonuclease RNA, which are
      considered to be acinar cell markers, and carbonic anhydrase II (CAII), which is
      considered to be a duct-cell markers. The histological appearance of xenografts
      in nude mice was similar to that of the tumor from which the cell line was
      established. The chromosome number varied between 46 and 60.

PMID- 8656027
TI  - The effect of chronic intraperitoneal infusion of bacterial endotoxin on exocrine
      pancreas function in rats.
AB  - CONCLUSION: This study demonstrated that LPS infusion can induce tissue lesions
      and impair the exocrine protein secretion of the pancreas in rats. BACKGROUND:
      The effect of chronic ip infusion of lipopolysaccharide (LPS) on the exocrine
      pancreas function was studies in rats. METHODS: Four milligrams per kilogram per
      day of Salmonella typhi LPS were infused intraperitoneally by means of surgically
      implanted osmotic pumps. Rats were studied after 7-d LPS infusion. RESULTS:
      Plasma fibrinogen and amylase activity increased significantly in LPS-treated
      rats when compared with control rats. Histological examination of the pancreas
      showed congestion, infiltration, and focal necrosis in LPS-treated rats. The
      pancreas wet weight, as well as DNA and total soluble protein contents were
      significantly increased in LPS-treated animals when compared with controls. The
      pancreas protein output was significantly decreased in pure pancreatic juice,
      whereas the pancreatic juice flow rate was significantly increased in LPS-treated
      animals, when compared with controls. Electrophoretic patterns showed a marked
      decrease in digestive enzyme contents, whereas there was an increased content of
      15 kDa protein.

PMID- 8656026
TI  - Adenylate cyclase activity in human pancreatic adenocarcinoma cell lines.
AB  - CONCLUSION: BxPC-3, Hs 766T, Capan-2, Panc-1, and Capan-1 cells possess receptors
      for VIP and beta-adrenergic agonists that are functionally coupled to adenylate
      cyclase. In this respect, they resemble pancreatic duct cells. However, we
      speculate that the process of neoplastic transformation has either downregulated
      the expression of secretin receptors or led to a defect in the receptor itself,
      placing a question mark over the usefulness of these adenocarcinoma cell lines as
      models of the pancreatic ductal epithelium BACKGROUND: Because of the importance
      of ducts in pancreatic disease, we wished to establish which duct cells receptors
      are functional on adenocarcinoma cell lines. METHODS: We investigated the
      expression of agonist-stimulated adenylate cyclase activity in six human
      pancreatic adenocarcinoma cell lines. Known stimulants of pancreatic ductal
      secretion, VIP, PHI, secretin, beta-adrenergic, and dopamine, were tested.
      RESULTS: For responsive cell lines, VIP was the most effective stimulant followed
      by adrenaline, isoprenaline, PHI, and secretin. Dopamine was without effect.
      Since high concentrations of PHI and secretin were required to stimulate cyclase
      activity, their effect is probably mediated by VIP receptors. Based on the degree
      of stimulation observed with the individual agonist, Hs 766T and BxPC-3 were the
      most responsive cell lines, followed by Capan-2 and Capan-1, and finally Panc-1.
      MIAPaCa-2 cells did not respond to any of the agonists tested.

PMID- 8656028
TI  - Aprotinin inhibits unspecific degradation of collagen in rat and human pancreas.
AB  - CONCLUSION: Addition of aprotinin in human and rat pancreatic extracts
      inactivates nonspecific proteases that completely degrade collagen. BACKGROUND:
      We sought to clarify the relative roles of collagenase and nonspecific proteases
      in the breakdown of collagen by the pancreas. METHODS: The degradation of [3H]
      collagen fibrils by pancreatic extracts to small fragments of low molecular
      weight was determined by SDS-electrophoresis and autoradiography. Aprotinin (0.14
      mg/mL) was added to inhibit nonspecific protease activity. RESULTS: Rat and human
      pancreas extracts contained a high collagenolytic activity that was demonstrated
      to be the result of the combined action of collagenase and other pancreatic
      proteases. Seventy percent of the total collagenolytic activity in rat pancreas
      extracts was inhibited by aprotinin. The same aprotinin concentration had no
      effect on two commercially available collagenases. The electrophoretic pattern
      obtained from [3H] collagen treated with rat and human pancreatic extracts
      containing aprotinin confirmed the presence of a true specific collagenase in the
      pancreas.

PMID- 8656030
TI  - Lymphoepithelial cyst of the pancreas. Report of two cases and review of the
      literature.
AB  - CONCLUSION: Lymphoepithelial cyst of the pancreas (LC) is a very rare benign
      lesion and preoperative diagnosis is difficult. Conservative surgery seems to be
      the appropriate therapy in symptomatic patients or when a precise preoperative
      diagnosis is not achieved. The benign behavior of all reported cases suggests
      that the asymptomatic patients with a certain morphological preoperative
      diagnosis might be clinically followed up. The histogenesis of LC remains to be
      elucidated. BACKGROUND: LC of the pancreas is a cyst that is histologically
      characterized by a fibrous tissue, a lymphoid component and a lining squamous
      epithelium. METHODS: Clinical and pathological findings of two personal cases are
      reported with review of the literature. RESULTS: A 56-yr-old man, complaining of
      epigastric pain, and a 47-yr-old man, with a history of alcohol abuse, were
      admitted to hospital. In both cases the lesion was detected with abdominal
      ultrasound but a certain diagnosis was obtained only after histological
      examination of the resected cysts.

PMID- 8656029
TI  - Oxidative stress in rodent closed duodenal loop pancreatitis.
AB  - CONCLUSION: Production of excited oxygen species is earlier in the liver than in
      the pancreas and could contribute to damage in a reflux model. Treatment with SOD
      could attenuate 59% light emission in pancreas, but did not modify serum enzyme
      levels or pancreatic edema, resulting as an insufficient isolated therapy.
      Unexpectedly, it was found an increased plasma antioxidant capacity that was
      related to total bilirubin levels, and declined at late stages probably denoting
      other circulating antioxidant consumption. BACKGROUND: Oxidative stress has been
      shown to play a role in different models of acute pancreatitis, although it has
      not been studied in the severe necrohemorrhagic model produced by closed duodenal
      loop pancreatitis. METHODS: We studied Sprague Dawley female rats in two groups:
      a closed duodenal loop pancreatitis group and a control, sham-operated group. In
      order to evidence the oxygen excited species production, in situ spontaneous
      chemiluminescence from living and naturally perfused pancreas and liver was
      measured at 0, 0.5, 1.5, 3, 6, 12, and 24 h after the duodenal ligature. Blood
      pancreatic amylase and aminotransferases levels were determined as expression of
      tissue damage in pancreas and liver. At the same time, plasma antioxidant
      capacity was measured by the peroxyl radical trapping capability of plasma
      samples compared to that of Trolox (synthetic analog of vitamin E), and results
      are expressed as Trolox equivalence. Bovine superoxide dismutase (SOD) was
      administered to attenuate oxygen free radicals activity at the beginning of the
      peroxidation chain and also as a therapeutic tool. RESULTS: The experimental
      procedure induced a severe pancreatitis, as evidenced by pancreatic enzymes that
      rose markedly in the early hours of disease and remained heightened throughout
      the experiment. The results show early light emission from the liver at 3 h and
      peak levels at 12 h, whereas in the pancreas, luminescence increased at 6 h and
      doubled later at 12 h, both returning to control levels at 24 h.

PMID- 8656032
TI  - To tell the truth: will the real CD36 please stand up?

PMID- 8656031
TI  - The use of spiral computed tomography in the evaluation of vessel encasement for
      pancreatic cancer.
AB  - CONCLUSIONS: Spiral CT allows for a noninvasive evaluation of the mesenteric
      arterial and venous vessels. This test can be performed quicker, with less
      expense, and with a reduced radiation and contrast load than angiography.
      Comparison studies of angiography and spiral CT are needed in patients with
      pancreatic cancer to determine the best method of evaluating possible vessel
      involvement. BACKGROUND: Preoperative imaging of patients with pancreatic cancer
      is crucial in determining resectability and planning management. Computed
      tomography (CT) remains the diagnostic procedure of choice for the evaluation of
      the primary tumor and angiography is the gold standard to evaluate vessel
      encasement. This case evaluates the usefulness of spiral computed tomography in
      determining vessel encasement. METHODS: A 53-yr-old female presented with vague
      abdominal complaints and evaluation revealed a mass in the pancreas. CT suggested
      portal vein involvement and collateralization was noted in the upper abdomen.
      Spiral CT revealed normal arterial anatomy and near complete obstruction of the
      portal vein at the superior mesenteric vein (SMV) splenic vein (SV) confluence.
      RESULTS: Operative findings confirmed the involvement of the portal vein at the
      confluence of the SMV and SV. Pancreatico-duodenectomy with portal vein resection
      and primary anastomosis was performed. The patient's postoperative course was
      uneventful and she was discharged home on the 13th postoperative day.

PMID- 8656033
TI  - Adenosine deaminase isoenzymes and pleural tuberculosis.

PMID- 8656034
TI  - Endocrine regulation of food intake and body weight.

PMID- 8656035
TI  - Recombinant ribosomal P2 protein can unmask anti-ribosomal P autoantibodies from
      healthy adults.
AB  - Autoantibodies to ribosomal P proteins (anti-P) are detected almost exclusively
      in the serum samples from patients with systemic lupus erythematosus when
      conventional enzyme-linked immunosorbent assay and immunoblotting techniques are
      used. Anti-P are not detected in serum samples from healthy adults by these
      techniques. By treating serum from healthy adults with ribosome-coated beads, we
      unexpectedly unmasked anti-P in virtually all individuals. This unmasking of anti
      P occurs by the displacement of an antibody inhibitor from anti-P. We wanted to
      determine whether anti-P from healthy adults could also be unmasked by treatment
      of their serum or plasma with isolated ribosomal P proteins. Recombinant human
      ribosomal P2 protein was produced in bacteria as a TrpE fusion protein, resolved
      by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, blotted onto
      nitrocellulose membranes, and isolated as strips of membranes corresponding to
      the size of the P2 fusion protein. Serum or plasma from six healthy adults and
      three patients with systemic lupus erythematosus were incubated with these strips
      overnight rather than for 2 hours, as is done in conventional immunoblots. Acid
      eluates were obtained from the strips and analyzed for antibody activity by
      immunoblot. Eluates from healthy adults and patients contained antibodies
      reactive with recombinant ribosomal P2 protein. They also reacted with the three
      ribosomal P proteins in purified rabbit ribosomes. Their anti-P activity was
      completely inhibited by a peptide corresponding to the immunodominant linear
      epitope of the ribosomal P proteins. The antibodies in the eluate were
      immunoglobulin G. We conclude that anti-P autoantibodies from healthy adults can
      be unmasked by affinity purification on denatured, recombinant ribosomal P
      proteins and that antigen excess is sufficient for inhibitor displacement.

PMID- 8656036
TI  - CD36-positive stress reticulocytosis in sickle cell anemia.
AB  - Vasoocclusive episodes in sickle cell anemia may be initiated by adherence of
      erythrocytes to endothelium, one mechanism of which involves thrombospondin
      binding to CD36 on the red blood cell (RBC). We compared CD36 expression and its
      relationship to stress reticulocytosis in patients with sickle cell anemia and
      other chronic hemolytic disorders, including some after splenectomy. Adults with
      sickle cell anemia had significantly more CD36-positive cells (4.1% +/- 3.4%,
      mean +/- SD, n = 12) in unfractionated blood than did normal adults, who had
      almost none (0.13% +/- 0.15%, n = 8, p < 0.05). In density-fractionated blood,
      sickle samples contained significantly more CD36-positive cells (39.8% +/- 21.9%,
      n = 10) in the lowest density layers than did splenectomized high-reticulocyte
      controls (8.5% +/- 6.4%, n = 4, p < 0.05). "Stress" reticulocytes (identified by
      their unique morphology) were significantly more frequent in low-density layers
      from sickle blood (44.3% +/- 23.9%, n = 10) than from nonsplenectomized high
      reticulocyte controls (10.5% +/- 14.8%, n = 5, p < 0.05). There was a strong
      correlation (r = 0.92) between stress reticulocyte count and number of CD36
      positive cells for all patients except thalassemics, in whom CD36-positive cells
      were more frequent than stress reticulocytes. Flow cytometry confirmed that the
      maximal CD36 signal was found on immature reticulocytes. We conclude that CD36
      positive stress reticulocytes occur more frequently in sickle cell anemia than in
      other chronic hemolytic states, even after surgical splenectomy, suggesting that
      this enhanced CD36-positive stress reticulocytosis does not simply reflect absent
      splenic function. These results explain why RBCs from high-reticulocyte control
      patients fail to show the significant CD36-dependent thrombospondin-mediated
      adhesion to endothelium that is exhibited by sickle red cells.

PMID- 8656037
TI  - Adenosine deaminase isozymes in tuberculous pleural effusion.
AB  - Total adenosine deaminase (ADA) activity and its isozyme (ADA1 and ADA2)
      activities were measured in pleural effusions and serum samples from patients
      with tuberculosis and in those from patients with lung cancer as controls. To
      analyze the cellular source of ADA isozymes in tuberculous pleural effusions, ADA
      isozyme activities in CD2+ T lymphocytes purified from tuberculous pleural
      effusions and cultured human cell lines derived from hematopoietic tumors were
      measured. Tuberculous pleural effusions had a much higher ADA activity than
      cancerous effusions, and high ADA activity mainly originated from the increase in
      ADA2 activity. Further, total ADA activity in tuberculous pleural effusions
      decreased after antituberculosis treatment, because of the decrease in ADA2
      activity. On the other hand, measurement of ADA and ADA isozyme activities in T
      lymphocytes purified from tuberculous pleural effusions and human hematopoietic
      cell lines showed dominant expression of ADA1 in total ADA activity. In
      conclusion, we found that ADA2 is a dominant component of tuberculous pleural
      effusions and that ADA1 is a major component of lymphoid cells. These results
      suggest that elevation of ADA activity in tuberculous pleural effusions does not
      always reflect the activation of cell-mediated immunity.

PMID- 8656038
TI  - Analysis of the lipids of normal and Gaucher bone marrow.
AB  - Quantitative chemical shift magnetic resonance imaging (QCSI) is currently being
      utilized for measuring the extent of bone marrow involvement and its response to
      enzyme replacement therapy in patients with Gaucher's disease. Quantitation of
      the major lipid species in human bone marrow is required to accurately interpret
      QCSI data on bone marrow composition. The major lipid species in bone marrow
      specimens from normal individuals and from patients with type 1 Gaucher's disease
      were analyzed by thin-layer and high-pressure liquid chromatography. In normal
      marrow (N = 5), triglycerides were by far the most abundant lipid (278 +/- 70
      mg/gm wet wt), with other non-polar lipids and phospholipids totaling less than
      20 mg/gm wet weight. The concentration of glucocerebroside in normal marrow was
      0.061 +/- 0.06 mg/gm wet weight. Gaucher marrow (N = 9) had dramatically lower
      triglyceride levels (51 +/- 53 mg/gm wet wt), and as expected, it had markedly
      elevated levels of glucocerebroside (7.1 +/- 3.4 mg/gm wet wt). The other major
      non-polar lipids and phospholipids were measured in selected specimens, but none
      were found that differed so profoundly between normal and Gaucher's disease.
      These data support a model of bone marrow alteration in Gaucher's disease in
      which triglyceride-rich adipocytes are progressively replaced by storage cells,
      leading to an overall reduction in total lipid content. This phenomenon provides
      an explanation for the changes in proton signal intensity observed in QCSI
      studies of Gaucher bone marrow.

PMID- 8656039
TI  - Polymerase chain reaction for the detection of Mycobacterium tuberculosis DNA in
      tissue and assessment of its utility in the diagnosis of hepatic granulomas.
AB  - A polymerase chain reaction (PCR) assay for the rapid identification of
      Mycobacterium tuberculosis, based on amplification of the IS6110 insertion
      sequences, was tested in paraffin-embedded tissue from 64 biopsy samples with
      either positive or negative cultures for Mycobacterium tuberculosis. The utility
      of this PCR assay in the diagnosis of tuberculosis among patients with hepatic
      granulomas (HGs) was then tested by examining 43 liver biopsy samples. They were
      classified as either having definitive or probable tuberculosis or as being of
      nontuberculous origin, on the basis of clinical and microbiologic data and on
      their response to antituberculous treatment. PCR was 100% sensitive in the
      diagnosis of culture-positive M. tuberculosis infection in the lymph node, lung,
      and liver. The sensitivity of the PCR in the diagnosis of HG of definitive
      tuberculous origin was 58%, and the specificity was 96%. PCR is a valuable test
      for the demonstration of mycobacterial DNA in tissues. Although it is not highly
      sensitive, the DNA amplification method may also be more sensitive than culture
      in the diagnosis of M. tuberculosis-associated HG.

PMID- 8656040
TI  - Polymorphonuclear leukocyte opsonic receptor expression after
      hypoxia/reoxygenation.
AB  - We investigated the effects of hypoxia/reoxygenation (H/R) and subsequent
      stimulation of polymorphonuclear leukocytes (PMNs) with either formyl-methionyl
      leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA) on CD32, CD16,
      CD35, and CD11b/CD18 expression and on degranulation and superoxide anion
      production. H/R primed both adherent and fluid-phase PMNs for subsequent up
      regulation of CD32 and CD16 (Fcgamma receptors) when stimulated with FMLP and
      primed both Fcgamma and complement (CD35, CD11b/CD18) receptors when stimulated
      with PMA. Kinetics assays demonstrated maximal up-regulation of CD32 and CD16
      induced by H/R plus FMLP after 30 minutes of reoxygenation, whereas maximal
      receptor stimulation by H/R plus PMA occurred within 15 minutes of reoxygenation.
      Neither actinomycin D nor cycloheximide abrogated the effect of H/R with
      subsequent stimulation of PMNs on receptor expression; however, 10(-5) to 10(-8)
      mol/L concentrations of either taxol or phalloidin completely abrogated the
      effect of H/R plus FMLP or PMA on opsonic receptor expression. The effect of H/R
      plus FMLP on CD32 and CD16 expression was blocked by pertussis toxin, whereas
      staurosporine, H-7, H-9, and genistein had no effect. Conversely, the effect of
      H/R plus PMA on CD32, CD16, CD35, and CD11b/CD18 expression was blocked by
      staurosporine and H-7 but not by H-9, pertussis toxin, or genistein. The up
      regulation of CD32, CD16, CD35, and CD11b/CD18 induced by H/R plus FMLP or PMA in
      the presence or absence of matrix proteins resulted in the increased rosetting of
      E-anti-CD32, E anti-CD16, E-Con A, EC3b, and EC3bi, respectively. Reduced
      nicotinamide adenine dinucleotide phosphate oxidase inhibition with
      diphenyleneiodonium blocked the effect of H/R on receptor expression,
      degranulation, and superoxide anion production. These results demonstrate that
      H/R primes PMNs for subsequent receptor up-regulation by divergent intracellular
      signal transduction pathways and that the receptors induced to the cell surface
      are biologically active.

PMID- 8656041
TI  - Inhibitory effect of platelet factor 4 on human erythroleukemic cells is
      dependent on cell surface heparan sulfate.
AB  - We have previously reported that platelet factor 4 (PF4) inhibits human
      erythroleukemic (HEL) cell growth in a dose-dependent fashion in vitro and that
      PF4 binds to HEL cells in a specific, saturable, and concentration-dependent
      manner. In this article we demonstrate that the binding of PF4 on HEL cells and
      its inhibitory effect on HEL cell growth were mediated by heparan sulfate. We
      found that binding of iodine 125-labeled PF4 to HEL cells was inhibited by
      heparin, heparan sulfate, and dermatan sulfate and to a smaller extent by
      chondroitin sulfate. Ninety percent of 125I-labeled PF4 bound to HEL cells was
      released by cells after exposure to heparin and heparan sulfate. Treatment of
      cells with heparitinase and heparinase induced a decrease in the binding of 125I
      labeled PF4 to cells. Binding of 125I-labeled PF4 was partially inhibited by the
      presence of increasing concentrations of protamine sulfate and basic fibroblast
      growth factor. To test whether PF4 bound to cell surface proteoglycans,
      proteoglycan synthesis was inhibited by using 4-methylumbelliferyl-beta-D
      xyloside. The binding of 125I-labeled PF4 on treated cells was decreased, and
      xyloside treatment of cells abrogated the biologic activity of PF4 in a plasma
      clot culture system. The inhibitory effect of PF4 was retained in a serum-free
      agar culture system, which indicates that the binding of PF4 to HEL cells induces
      cell growth inhibition in a direct fashion. Taken together, these findings
      suggest that PF4 directly acts on HEL cell growth by fixation on heparan sulfate
      proteoglycans on the HEL cell surface.

PMID- 8656042
TI  - Thiocyanate induces vasoconstriction in rat-tail artery primed with
      norepinephrine.
AB  - The vasoregulating effects of thiocyanate (SCN-) were studied by means of a new
      rat tail artery perfusion model that uses constant driving pressure (1000 mm
      H2O). When a 30 mm long artery was perfused with 20 micromol/L verapamil, the
      flow rate increased 6%. Norepinephrine (10 to 1000 nmol/L) caused a dose
      dependent flow inhibition. SCN- alone (0.05 to 5 mmol/L) had a slight, if any,
      effect on the arterial flow. However, when the artery was pretreated with
      norepinephrine (1000 nmol/L) for 10 minutes, followed by a basal-medium washout
      that left a 13% norepinephrine-induced flow inhibition, 0.05 to 5 mmol/L SCN-
      caused a marked flow rate reduction of between 20.4% +/- 9.8% and 28.0% +/-
      21.8%, as calculated for the entire test perfusion. The decrease in flow rate
      correlated with the SCN- concentration (p < 0.05) and showed a clear
      reversibility. A similar SCN(-)-induced (0.05 mmol/L) vasoconstriction (p < 0.05)
      was seen when the artery was given a basal tone by continuous perfusion with low
      dose norepinephrine, 10 nmol/L. Nifedipine (100 nmol/L) abolished the effect of
      0.05 mmol/L SCN- but did not affect the norepinephrine priming. We conclude that
      SCN- amplifies the norepinephrine-induced vascular smooth muscle tone and that
      this may be caused by an altered calcium channel activity.

PMID- 8656043
TI  - Alveolar macrophages accumulate iron and ferritin after in vivo exposure to iron
      or tungsten dusts.
AB  - Extracellular iron present in alveolar structures may contribute to oxidative
      lung injury induced by toxic mineral dusts by enhancing dust-induced generation
      of hydroxyl radicals. Alveolar macrophages (AMs) can sequester iron within
      ferritin and limit generation of hydroxyl radicals. In the current study we
      sought to assess whether AMs accumulate iron and ferritin after in vivo exposure
      to a dust with high iron content, to iron oxide, or to an inflammatory dust,
      calcium tungstate. We performed lung lavage 1, 7, 14, 28, 42, and 56 days after
      intratracheal instillation of mineral dust in saline solution or instillation of
      saline solution alone and quantitated cell recovery and AM content of iron and
      ferritin. Instillation of iron oxide increased neutrophil recovery only on a day
      1 when compared with results in controls, whereas calcium tungstate increased
      neutrophil recovery through day 14. AMs recovered after instillation of iron
      oxide contained increased amounts of iron and ferritin, beginning on day 1 and
      progressing through day 56 after treatment (7.57 +/- 0.38 microgram iron per
      10(6) AMs vs 1.54 +/- 0.28 microgram iron per 10(6) AMs for controls, p < 0.001;
      and 5908 +/- 768 ng ferritin per 10(6) AMs vs 395 +/- 20 ng ferritin per 10(6)
      AMs, p < 0.001). AMs recovered after calcium tungstate instillation also
      contained increased amounts of iron and ferritin beginning 14 days after
      treatment, with greatest content 42 days after treatment (4.85 +/- 0.68 microgram
      iron per 10(6) AMs, p < 0.001, and 2274 +/- 736 ng ferritin per 10(6) AMs, p <
      0.001). Tumor necrosis factor, which can enhance iron accumulation by
      macrophages, was spontaneously released by AMs recovered from tungsten-treated
      rats. These studies indicate that AMs accumulate iron and ferritin in response to
      both iron loading of the lungs with iron oxide exposure and lung inflammation
      induced by calcium tungstate exposure.

PMID- 8656044
TI  - Soluble extracellular antigen-specific T cell immunoproteins.
AB  - Some T cells release proteins that bind specifically to antigens that have not
      been processed by antigen-presenting cells. These soluble immunoproteins induce
      or effect antigen-specific T cell functions in immunoregulation and/or
      hypersensitivity. After certain immunization regimens, T cell immunoproteins
      specific for the immunogen rise in serum, and therefore may be an antigen
      specific, humoral manifestation of the activation of some T cells during an
      immune response. Although non-MHC (major histocompatibility complex)-associated
      antigen is bound, soluble antigen-specific T cell immunoproteins share variable
      and constant region epitopes and some amino acid sequence with the T cell
      receptor for antigen alpha or beta chains, and their expression depends on T cell
      receptor structural genes. Herein, the properties of extracellular antigen
      specific T cell immunoproteins are reviewed and it is suggested that these
      molecules are a soluble analogue of the T cell receptor for antigen and provide
      an amplifying element for some T cell functions.

PMID- 8656045
TI  - The secretion of preformed granules by macrophages and neutrophils.
AB  - The ability of macrophages and neutrophils to defend tissue homeostasis and
      participate in inflammatory responses depends on their ability to mobilize
      granule-membrane proteins and granule content into their external milieu and into
      phagosomes by regulated secretory processes. Many laboratories have invested much
      time and effort into furthering our understanding of vesicular transport and
      secretion. A surge of interest in phagocytosis and phagosomal maturation is also
      apparent (e.g., the March 1995 issue of Trends in Cell Biology was entirely
      devoted to phagocytosis). The signaling and the regulation of the secretory
      response are most likely different for secretion into phagosomes than for
      secretion into the external milieu. However, these differentially targeted
      secretory processes rely both upon proteins in vesicular membranes, plasma
      membrane/phagosomal membrane, and cytosol and upon their interactions with
      cytoskeletal structures. It is the complex molecular interactions between these
      components that form the basis for regulation and control of secretion. In the
      following, the signaling role of granular and cytosolic pH in phagocyte lysosomal
      secretion is discussed and the current literature on regulated secretion by
      macrophages and neutrophils is reviewed.

PMID- 8656046
TI  - Interleukin-12 protects thermally injured mice from herpes simplex virus type 1
      infection.
AB  - Severe burn injury is associated with increased susceptibility to severe
      herpesvirus infections. Type 2 cytokines [interleukin (IL)-4 and IL-10] released
      from burn-associated CD8+ type 2 T cells (BA-type 2 T cells) have been shown to
      play a role in the increased susceptibility of thermally injured mice (TI-mice)
      to herpes simplex virus type 1 (HSV-1) infection. Because IL-12 has been shown to
      inhibit the generation of type 2 T cells, murine rIL-12 was injected into TI-mice
      exposed to HSV-1 to determine whether IL-12 could influence HSV-1 infections in
      individuals bearing type 2 T cells. rIL-12 improved the resistance of TI-mice or
      mice inoculated with T6S cells (a BA-type 2 T cell clone) against HSV-1
      infection. Type 2 cytokines were detected in sera of TI-mice or mice inoculated
      with T6S cells (T6S-mice). However, treatment of TI-mice or T6S-mice with rIL-12
      inhibited type 2 cytokine production in the sera of these mice. All TI-mice
      exposed to a lethal dose of HSV-1 survived when they were treated with a mixture
      of monoclonal antibodies (mAbs) against type 2 cytokines. Staphylococcal
      enterotoxin A [an interferon-gamma (IFN-gamma) inducer] stimulated serum IFN
      gamma production in TI-mice and T6S-mice treated with rIL-12, whereas no IFN
      gamma was produced in mice treated with saline. These results suggest that IL-12
      has the potential to protect TI-mice infected with a lethal dose of HSV-1 via a
      shift to type 1 T cell responses from type 2 T cell responses.

PMID- 8656047
TI  - In vivo labeling of neutrophils using a fluorescent cell linker.
AB  - To study neutrophil circulation time and trafficking in vivo requires labeling
      the cells so that their movement can be followed temporally and spatially.
      Labeling procedures used to date, however, have relied on ex vivo separation and
      labeling methods, an undesired consequence of which may be neutrophil activation.
      Moreover, the labeled cells preferentially stick in the pulmonary circulation for
      several hours upon reinjection into the host. Therefore, we devised an alternate
      labeling procedure that relied on intra-arterial infusion of the fluorescent
      phagocytic cell linker PKH26. We infused PKH26 (5.5 x 10(-6) M for 1 h) into six
      awake sheep and measured systemic and pulmonary hemodynamics and lung lymph
      dynamics continuously for 3-4 h after the infusion. We collected simultaneous
      arterial and venous blood samples hourly for 4 h, and again 24 h after the
      infusion ended, for white blood cell and neutrophil differential counts and to
      identify labeled cells in fresh smears by fluorescence and differential
      interference contrast (DIC) microscopy. Infusion of PKH26 had minimal and
      transient physiologic effects on systemic and pulmonary artery pressure, lung
      lymph flow, and leukocyte counts. Labeled cells were present in venous blood
      after the infusion for at least 24 h. DIC microscopy observation of the blood
      smears indicated that the fluorescently labeled cells were exclusively
      neutrophils. Unstimulated superoxide anion release from neutrophils isolated 2
      and 24 h after PKH26 infusion was not different from baseline release. Phorbol
      myristate acetate-stimulated release was not affected either. The labeled
      neutrophils responded to chemoattractants by migrating to extravascular sites.
      Our results indicate that neutrophils can be selectively labeled in vivo, after
      which trafficking of the labeled neutrophils can be determined.

PMID- 8656048
TI  - Augmentations of glucose uptake and glucose transporter-1 in macrophages
      following thermal injury and sepsis in mice.
AB  - Glucose is the primary metabolic substrate of macrophages, which are critical
      components of the host response to injury and infection. We have carried out a
      series of studies to examine macrophage glucose uptake and the status of glucose
      transporter 1 (GLUT1) at both the mRNA and protein level. Peritoneal macrophages
      that were obtained from mice undergoing sham burned (S), 15%TBSA burn (B) +/-
      Pseudomonas aeruginosa burn infection (B + I) and lipopolysaccharide (LPS) or
      tumor necrosis factor-alpha (TNF-alpha) administration. [3H]deoxyglucose uptake
      was significantly increased (B, 157 +/- 9%; B + I, 243 +/- 19%; S + LPS, 231 +/-
      24%; S + TNF-alpha, 379 +/- 18%; B + LPS, 230 +/- 13%; and B + TNF, 305 +/- 23%,
      P< 0.01 vs. sham). GLUT1 mRNA and protein levels were increased as well (mRNA: B,
      135 +/- 13%; B + I, 250 +/- 33%; S + LPS, 282 +/- 29%; S + TNF-alpha, 193 +/-
      19%; B + LPS, 378 +/- 20%; and B + TNF-alpha, 204 +/- 16%; protein: B, 159 +/-
      27%; B + I, 181 +/- 17%; S + LPS, 219 +/- 26%; S + TNF-alpha, 343 +/- 51%; B +
      LPS, 366 +/- 41%; and B + TNF-alpha, 415 +/- 44, P< 0.01 vs. sham). Macrophages
      co-cultured with LPS or TNF-alpha in vitro demonstrated a similar response
      pattern. Following burn injury and infection, macrophages augment their cellular
      glucose uptake, which is facilitated by an increased GLUT1 mRNA and protein
      levels. TNF-alpha elicited by LPS may mediate this enhanced carbohydrate
      metabolism at the point of glucose entry into the cell.

PMID- 8656049
TI  - Competition between lymphocyte function-associated antigen 1 (CD11a/CD18) and Mac
      1 (CD11b/CD18) for binding to intercellular adhesion molecule-1 (CD54).
AB  - Both human integrin receptors Mac-1 (CD11b/CD18,CR3)and lymphocyte function
      associated antigen (LFA)-1 (CD11a/CD18) have been demonstrated to bind human
      intercellular adhesion molecule-1 (ICAM-1) (CD54). Here we show that LFA-1 and
      Mac-1 can bind to ICAM-1 in the mouse as well. Interestingly, we observed that
      binding of murine LFA-1 dominates over Mac-1 for binding to ICAM-1. Using three
      different murine macrophage cell lines that express distinct levels of LFA-1 and
      Mac-1 on their cell surface, we could only detect Mac-1-dependent adhesion to
      ICAM-1 when little or no LFA-1 is expressed on the cell surface. When LFA-1 and
      Mac-1 are expressed at similar levels, the LFA-1/ICAM-1 interaction dominates
      over Mac-1/ICAM-1 interaction, indicating that there is a competition of LFA-1
      and Mac-1 for ICAM-1 binding.

PMID- 8656050
TI  - Integrin-mediated epithelial-T cell interaction enhances nitric oxide production
      and increased intracellular inhibition of Chlamydia.
AB  - T cell-mediated immunity against Chlamydia in mice is mediated at least in part
      by T cell-derived interferon-gamma (IFN-gamma) induction of the nitric oxide
      synthase (iNOS) system in infected epithelial cells. Although IFN-gamma alone
      could stimulate nitric oxide (NO) production from epithelial cells and inhibit
      the intracellular growth of Chlamydia, the effectiveness was less than when
      infected epithelial cells were co-cultured with IFN-gamma-producing T cell
      clones. In co-cultures containing T cells and infected epithelial cells,
      additional NO produced by activated T cells could augment chlamydial killing;
      however, T cell-derived NO was insufficient to account for the total NO present
      in the co-culture and therefore could not explain the dramatic increase in
      chlamydial inhibition under those conditions. To determine whether direct cell-to
      cell interaction involving adhesion molecules was involved in increased NO
      induction, the ability of neutralizing monoclonal antibodies directed against
      intercellular adhesion molecule type 1 (ICAM-1) and leukocyte function antigen-1
      (LFA-1) to suppress NO production and lower intracellular chlamydial inhibition
      was investigated. It was found that monoclonal antibodies against ICAM-1/LFA-1
      could significantly reduce the capacity of a protective CD4+ type 1 (Thl) clone
      (clone 2.14-0) to inhibit the intracellular growth of the C. trachomatis agent of
      mouse pneumonitis (MoPn). The suppression of the anti-chlamydial action of the
      clone by antibodies correlated with approximately 50% decrease in NO production.
      Also, paraformaldehyde-fixed clone 2.14-0 could enhance NO induction and
      chlamydial inhibition mediated by IFN-gamma, and this effect could be reversed by
      anti-ICAM-1/LFA-1 antibodies. The results indicated that epithelial-T cell
      interaction via adhesion molecules enhances NO production and increased
      chlamydial inhibition by IFN-gamma-secreting T cells.

PMID- 8656051
TI  - PLA2 promotes fusion between PMN-specific granules and complex liposomes.
AB  - Neutrophil stimulation results in the activation of a variety of phospholipases,
      including phospholipase A2 (PLA2), which releases arachidonic acid from the 2
      position of membrane phospholipids, leaving a lysophospholipid. Because
      arachidonic acid is known to be a potent fusogen in vitro, we examined the effect
      of metabolism by PLA2 on the fusion of complex liposomes (liposomes prepared with
      a phospholipid composition similar to that found in neutrophil plasma membrane).
      We observed that PLA2 augmented the fusion of complex liposomes with each other
      as well as with specific granules isolated from human neutrophils, lowering the
      Ca2+ requirement for fusion by three orders of magnitude. Furthermore, although
      lysophospholipids inhibited fusion, the incorporation of arachidonic acid into
      liposome membranes overcame the inhibitory effects of the lysophospholipids. Thus
      with PLA2 and annexins we were able to obtain fusion of complex liposomes at
      concentrations of Ca2+ that are close to physiological. Our data suggest that the
      activation of PLA2 and the generation of arachidonic acid may be the major fusion
      promoting event mediating neutrophil degranulation.

PMID- 8656052
TI  - Effect of adenosine on the expression of beta(2) integrins and L-selectin of
      human polymorphonuclear leukocytes in vitro.
AB  - Adenosine has been shown to inhibit the adhesion of polymorphonuclear leukocytes
      (PMNL) to the vascular endothelium. Because the underlying molecular mechanisms
      have not been fully understood, the present study characterizes the effect of
      adenosine on the expression of adhesion molecules of human PMNL. When PMNL were
      activated by N-formyl-methionyl-leucyl-phenylalanine the number of cell surface
      beta2 integrins increased fivefold, whereas L-selectin molecules were completely
      shed. Activation-dependent numerical up-regulation Of beta2 integrins and
      shedding of L-selectin were inhibited by exogenously applied adenosine receptor
      agonists in a concentration-dependent fashion. The rank order of potencies of
      adenosine receptor agonists, measured by the agonists' half-maximal inhibitory
      concentrations, revealed that adenosine inhibited the numerical up-regulation of
      beta2 integrins and shedding of L-selectin most likely via an A2(a) receptor
      site. When extracellular concentrations of endogenously formed adenosine were
      enhanced by the nucleoside uptake inhibitor dipyridamole, up-regulation of beta2
      integrins, and shedding of L-selectin was again inhibited. Both effects were
      reversed by the enzyme adenosine deaminase, which degrades active adenosine to
      inactive inosine, suggesting that endogenously formed adenosine may play an
      important role in the regulation of beta2 integrins and L-selectin of human PMNL.

PMID- 8656054
TI  - The lectin jacalin triggers CD4-mediated lymphocyte signaling by binding CD4
      through a protein-protein interaction.
AB  - The lectin jacalin specifically stimulates lymphocytes expressing the CD4
      antigen. Recent studies have also demonstrated that this lectin interacts with
      CD4, inhibits in vitro HIV infection, and triggers cell signaling directly via
      CD4. Jacalin as a lectin was suggested to trigger CD4-mediated cell signaling by
      interacting with the oligosaccharide side chains of CD4 located on Asn271 and
      Asn3OO. Such a hypothesis was of importance because it implied that the
      glycosylated chains could represent a functional domain directly involved in CD4
      related cell activation. We analyzed this possibility by studying the effect of
      hapten sugars on jacalin-induced CD4 cell signaling and jacalin/CD4 interaction,
      and by studying the binding capacities of the lectin toward glycosylated,
      deglycosylated, and unglycosylated CD4. The results presented in this study
      provide evidence that jacalin does not recognize the CD4 oligosaccharide chains
      and actually binds CD4 through a specific protein-protein interaction; as a
      consequence these results rule out the involvement of the CD4 saccharide moieties
      in CD4-mediated cell signaling triggered by the lectin.

PMID- 8656053
TI  - Differential regulation of Ia expression and antigen presentation by
      listeriolysin-producing versus non-producing strains of Listeria monocytogenes.
AB  - Listeria monocytogenes is an intracellular bacterial pathogen. A single gene
      product, listeriolysin (LLO), is critical for the induction of protective
      immunity. We now show that listeria that produce functional LLO augment Ia
      expression by macrophages and are better presented to a Th1, CD4+ anti-listeria T
      cell line. We used two genetically engineered strains of listeria which differed
      only in their ability (Ly+) or inability (Ly-) to produce functional LLO. Ia
      negative murine macrophages ingested either Ly+ or Ly-, and then were stimulated
      by interferon-gamma (IFN-gamma). Increasing numbers of live Ly+, but not Ly-,
      augmented IFN-gamma-induced Ia expression. Ly+ by itself did not induce Ia
      expression. Heat-killed Ly+ and Ly- did not augment IFN-gamma-induced Ia
      expression. The abundance of Ia on the macrophage cell surface is one major
      determinant of antigen presentation to CD4+ T cells. Consistent with their
      ability to augment la expression, Ly+ were better presented than Ly- to a CD4+,
      Th1, anti-listeria T cell line. When macrophages and T cells were from different
      inbred mouse strains, antigen presentation required identity at the class II
      region of the MHC gene complex. This indicated that antigen presentation occurred
      via Ia molecules. The increased ability of macrophages to present Ly+ is a
      product of the macrophage-listeria interaction, not a property of the T cell tine
      86. If Ia-negative macrophages ingested Listeria and were then stimulated by IFN
      gamma, Ly+ was presented more efficiently than Ly-. On the other hand, if Ia
      positive macrophages ingested Listeria, then Ly+ and Ly- were presented equally
      well to T cells. Altogether our data is consistent with the hypothesis that
      macrophages interact differently with Ly+, and that this contributes to the
      ability of only live Ly+ to induce protective immunity.

PMID- 8656055
TI  - Development and characterization of a novel monoclonal antibody (mNI-11) that
      induces cell adhesion of the LPS-stimulated human monocyte-like cell line U937.
AB  - A monoclonal immunoglobulin G1 (IgG1) antibody (mAb), designated mNI-11, was
      produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte
      like cell line U937. The reactivity of mNI-11 was tested by the indirect
      immunofluorescence method. The antigen defined by mNI-11 was found to be
      expressed on U937 cells, LPS-stimulated U937 cells, normal CD14+ cells
      (monocytes/macrophages), and human umbilical vein endothelial cells (HUVECs).
      Expression of the antigen defined by mNI-11 on HUVECs slightly increased in
      response to exposure to tumor necrosis factor-alpha (TNF-alpha) and phorbol
      myristate acetate (PMA). When the reactivity of mNI-11 and mAbs binding human
      differentiation antigens such as CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23,
      CD28, CD29, CD31, CD43, CD44, CD45RA, CD49d, CD50, CD54, CD58, CD80, CD102,
      CD106, HLA-class I, or HLA-class II antigen was compared, no mNI-11 reactivity
      resembling that of these mAbs was found. mNI-11 markedly induced homotypic cell
      aggregation of U937 cells when they were stimulated with LPS. The mNI-11-induced
      aggregation of LPS-stimulated U937 cells, referred to as LPS-U937 cells, required
      neither Fc receptor engagement nor cross-linking of the antigen defined by mNI-11
      because aggregation was induced by both F(ab')2 fragments and monovalent F(ab')
      fragments of mNI-11. The mNI-11-induced aggregation was blocked by the addition
      of ethylenediaminetetraacetate, and also when incubated at 4 degrees C. mAbs to
      CD11a/CD18 (lymphocyte-function associated antigen-1; LFA-1) and CD54
      (intercellular adhesion molecule-1; ICAM-1) completely blocked the LPS-U937 cell
      aggregation induced by mNI-11. The LPS-U937 cell aggregation induced by mNI-11
      was partially but not completely blocked by the protein kinase C inhibitors
      sphingosine and H-7, and was completely blocked by the protein-tyrosine kinase
      inhibitor genistein. Interestingly, mNI-11 markedly promoted LPS-U937 cell
      adhesion to HUVECs. The mNI-11-induced LPS-U937 cell adhesion to HUVECs was not
      reduced in the presence of LFA-1 (CD11a/CD18) or ICAM-1 (CD54) mAbs. On the other
      hand, LPS-U937 cells, whether treated with mNI-11 or not, sufficiently adhered to
      the extracellular matrix protein fibronectin, but not to laminin or collagen type
      I. However, mNI-11 did not markedly promote LPS-U937 cell adhesion to
      fibronectin. Adhesion of LPS-U937 cells treated with mNI-11 to fibronectin was
      completely blocked by CD29 (beta chain of very late antigens) mAb. The surface
      antigen recognized by mNI-11 had a molecular size of approximately 97 kDa under
      non-reducing conditions and approximately 117 kDa under reducing conditions, as
      determined by immunoblotting analysis. We found that mNI-11 recognizes an
      adhesion-associated molecule distinct from any previously reported in terms of
      its pattern of cellular distribution and molecular weight, and also found that
      mNI-11 has activity which induces cell adhesion/aggregation of U937 cells when
      stimulated with LPS.

PMID- 8656056
TI  - Priming of human peripheral blood mononuclear cells with lipopolysaccharides for
      enhanced arachidonic acid release and leukotriene synthesis.
AB  - In a previous study, we have shown that the ability of lipopolysaccharides (LPS)
      to prime isolated neutrophils for enhanced leukotriene B4 (LTB4) synthesis was
      dependent on the presence of plasma and involved the CD 14 antigen. In the
      present study, we have investigated the priming of human peripheral blood
      mononuclear cells (PBMC) with LPS for the subsequent release and metabolism of
      arachidonic acid. When PBMC were incubated with LPS for up to 2 h or when freshly
      isolated PBMC were stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP)
      or with LPS alone, little or no synthesis of 5-lipoxygenase products nor
      arachidonic acid liberation were detected. However, the preincubation of PBMC
      with LPS for as little as 5 min primed cells for the subsequent synthesis of LTB4
      upon stimulation with fMLP. Maximal priming was observed following a 15-min
      preincubation period and the priming effect was transient as cells preincubated
      with LPS for 90 min or more were no longer primed for leukotriene synthesis.
      Monocytes were found to be responsible for the enhanced response to fMLP since
      purified lymphocytes did not produce LTB4 nor LTC4 in contrast to monocyte
      enriched suspensions. The priming for leukotriene synthesis coincided with an
      increased capacity for the release of free arachidonic acid as measured by mass
      spectrometry; LPS-primed cells released 8-15 times more arachidonic acid than
      unprimed cells within 1 min of stimulation with fMLP. Priming was observed with
      as little as 0.001-0.01 microg LPS/mL when cells were incubated in the presence
      of 10% autologous plasma. Interestingly, in the absence of plasma, priming was
      only observed at LPS concentrations of 0.1 microg/mL or greater. Pretreatment of
      cells with anti-CD14 antibodies significantly decreased the priming effect
      observed with 0.01 microg/mL LPS but did not affect priming with 1 microg/mL LPS.
      These results indicate that the priming of human PBMC with LPS for the subsequent
      synthesis of arachidonic acid metabolites via the 5-lipoxygenase pathway is
      dependent on plasma and CD14 at lower concentrations of LPS (0.001-0.01
      microg/mL) but not at LPS concentrations of 0.1 microg/mL or greater.

PMID- 8656057
TI  - Identification of factors from rat neutrophils responsible for cytotoxicity to
      isolated hepatocytes.
AB  - Activated polymorphonuclear neutrophils (PMNs) have been shown to be cytotoxic to
      rat hepatic parenchymal cells in vitro. This cytotoxicity could be observed
      without direct cell-cell contact, since the conditioned medium from PMNs
      activated with formyl-Met-Leu-Phe (fMLP) was effective in hepatocyte killing. To
      identify the toxic factor(s) released by PMNs, degranulation was induced by fMLP
      in PMNs pretreated with cytochalasin B. The contents released from the phagocytes
      were subjected to gel filtration on a Sephadex G-100 column. Resulting fractions
      were tested for cytotoxicity to isolated hepatocytes by using release of alanine
      aminotransferase as a marker for hepatocyte injury. Cytotoxicity was associated
      with fractions containing cathepsin G and elastase and not with other fractions,
      including those containing myeloperoxidase. The former two enzymes were purified
      to homogeneity with a carboxymethyl cellulose column. Each of these enzymes
      demonstrated concentration-dependent cytotoxicity to hepatocytes at
      concentrations > 2 microgram/mL. Moreover, they exhibited an additive cytotoxic
      effect. Effective concentrations for the combined cathepsin G and elastase in the
      incubation mixture were similar to the concentrations of these enzymes in PMN
      conditioned medium that produced cytotoxicity to hepatocytes. Cytotoxicity of
      either purified enzyme or of conditioned medium could be prevented by plasma
      alpha-1-antitrypsin or soybean trypsin-chymotrypsin inhibitor, which were also
      potent inhibitors of enzymic activity of both cathepsin G and elastase. By
      contrast, the serine protease inhibitors, aprotinin and 4-(2-aminoethyl)-benzene
      sulfonyl fluoride, were less effective in inhibiting cathepsin G and elastase
      activities as well as cytotoxicity caused by the purified proteases or PMN
      conditioned medium. These results support the hypothesis that cathepsin G and
      elastase are important mediators of hepatic parenchymal cell killing produced by
      activated PMNs in vitro.

PMID- 8656058
TI  - IFN-alpha-mediated suppression of low-affinity FC(epsilon) receptors on Peyer's
      patch lymphocytes and augmentation of soluble CD23: implications for IgE
      responses.
AB  - The ability of interleukin (IL)-6 or interferon-alpha (IFN-alpha) to regulate
      expression of low-affinity Fc(epsilon) receptor (CD23) and serum levels of CD23
      was studied in benzylpenicilloyl-keyhole limpet hemocyanin-sensitized BALB/c mice
      at the peak of a hapten-specific immunoglobulin E (IgE) antibody-forming cell
      (AFC) response. These responses are analogous to those observed in human atopic
      disease. To induce peak IgE responses, mice were injected intraperitoneally with
      BPO-KLH (10 micrograms) in aluminum hydroxide gel (alum) on days 0, 21, and 42.
      On day 44, mice were injected subcutaneously with IL-6 (100-1000 U) or IFN-alpha
      (1000-10,000 U). On day 46, numbers of CD23+ lymphocytes in Peyer's patches (PP),
      mesenteric lymph nodes (MLN), and spleen and levels of soluble CD23 in serum were
      determined (flow microfluorimetry and enzyme-linked immunosorbent assay,
      confirmed by competition assay). Data are expressed as percent total cells or as
      optical density at 490 nm. IFN-alpha treatment strongly suppressed (up to 100%)
      numbers of CD23+ cells exclusively in PP (i.e., numbers of CD23+ cells in MLN and
      spleen were unchanged) whereas serum levels of soluble CD23 were dramatically
      increased (60%). IL-6 treatment had no effect on either numbers of CD23+
      lymphocytes or on serum levels of soluble CD23. The data suggest that the
      mechanism(s) by which IFN-alpha, but not IL-6, regulates IgE responses involves
      suppression of CD23 expression on lymphocytes in PPs and supports a central role
      for these organs in regulation of IgE responses in vivo.

PMID- 8656059
TI  - IL-13 restores an in vitro specific cytolytic response of spleen cells from tumor
      bearing rats.
AB  - In a model of colon cancer, spleen cells from tumor-bearing rats are neither
      cytotoxic nor proliferative in vitro in the presence of tumor cells. Interleukin
      13 (IL-13) induced an in vitro cytolytic activity of spleen cells from tumor
      bearing rats in response to the tumor they bore, but had no effect on spleen
      cells from normal rats. This cytotoxic response was dependent on both adherent
      and non- adherent cells, involving both an antigen-presenting activity that was
      enhanced by IL-13 and a cytolytic activity of lymphocytes. So, IL-13 reversed the
      tumor-induced immunosuppression.

PMID- 8656060
TI  - Transcriptional regulation of LDL receptor-related protein by IFN-gamma and the
      antagonistic activity of TGF-beta(1) in the RAW 264.7 macrophage-like cell line.
AB  - Low density lipoprotein receptor-related protein (LRP) is a major receptor for
      multiple ligands, including chylomicron and VLDL remnants, bacterial toxins,
      viruses, proteinases, lipoprotein lipase, and activated alpha2-macroglobulin
      (alpha2M). In this study, we used Northern blot analyses and nuclear run-on
      experiments to demonstrate that interferon-gamma (IFN-gamma) causes a
      concentration-dependent decrease in steady-state LRP mRNA expression and gene
      transcription rate in RAW 264.7 cells. IFN-gamma also markedly increased
      expression of inducible nitric oxide synthase (NOS), as expected; however, the
      increase in nitric oxide was not responsible for the down-regulation of LRP
      expression since the NOS inhibitor, N(G)-monomethyl-L-arginine, did not preserve
      LRP expression in IFN-gamma-treated cells. Transforming growth factor-beta1 (TGF
      beta1; 2.5 ng/mL) had no independent effect on LRP expression and did not modify
      the response to IFN-gamma when the two cytokines were added simultaneously to
      cultures. When TGF-beta1 was added 24 h prior to IFN-gamma, the extent of LRP
      down-regulation was significantly reduced. Specific binding of the LRP ligand,
      activated (125)I-alpha2M, was decreased by 76 +/- 5% in cells treated with 100
      U/mL IFN-gamma, but only by 45 +/- 7% in cells treated with 100 U/mL IFN-gamma
      after TGF-beta1-pretreatment. The antagonistic activity of TGF-beta1 on the IFN
      gamma response in RAW 264.7 cells did not result from a change in LRP mRNA
      stability or IFN-gamma receptor expression, as determined by Northern blot
      analyses and (125)I-IFN-gamma binding experiments. The studies presented here
      suggest that the balance between IFN-gamma and TGF-beta1 may be critical in
      determining LRP expression at sites of infection and inflammation.

PMID- 8656061
TI  - Binding affinities of the SH2 domains of ZAP-70, p56lck and Shc to the zeta chain
      ITAMs of the T-cell receptor determined by surface plasmon resonance.
AB  - The zeta chains of the T cell receptor complex play a critical role in the
      initiation of proximal signaling events upon T cell activation. Three pairs of
      potential tyrosine phosphorylation sites are located within the cytoplasmic
      domains of the zeta chains. Subsequent to engagement of the T cell receptor, one
      or more of these tyrosine residues is phosphorylated. The phosphotyrosine
      residues, along with flanking amino acids, form an activation motif (and are
      shared by signaling subunits in the TCR, B cell receptor, and FcgammaRI) termed
      tyrosine-based activation motifs (ITAMs). ITAMs serve as binding sites for SH2
      domain-containing proteins. Recent evidence suggests that the zeta chains provide
      docking space for several key signal transduction molecules such as ZAP-70,
      p56lck, and Shc. To determine if ZAP-70, p56lck, and Shc bind to particular zeta
      chain ITAM sequences, quantitative free-solution measurements of binding
      affinities (Kd) were obtained by use of surface plasmon resonance technology. The
      results indicate that binding affinities of distinct SH2 domains to individual
      and paired phosphorylation sites greatly differ, and may dictate the sequence of
      signal transduction events.

PMID- 8656062
TI  - Beta2 integrins mediate protein tyrosine phosphorylation in human neutrophils.
AB  - Tyrosine kinases play a prominent role in various intracellular signal
      transduction pathways. In this study, beta2 integrin (CD11/CD18)-mediated
      adhesive interactions of human neutrophils (PMN) were mimicked by antibody cross
      linking of CD11/CD18. Cross-linking of CD18 induced tyrosine phosphorylation of
      several proteins with apparent molecular masses of approximately 120, 78, 72, 65,
      and 56 kDa, respectively, as shown by anti-phosphotyrosine immunoblotting of
      whole cell lysates. Cross-linking of the alpha-subunits of the beta2 integrins
      demonstrated that only cross-linking of Mac-1 but not LFA-1 or gp150/95 triggered
      tyrosine signaling. The tyrosine phosphorylations showed a rapid and transient
      time course. Comparison of the CD18-mediated tyrosine phosphorylation patterns
      with those induced by chemoattractants gave similar results. The observed
      tyrosine phosphorylation was specific, since binding and non-binding irrelevant
      primary antibodies had no effect. Furthermore, F(ab')2 fragments of the anti-CD18
      antibody IB4 and addition of F(ab')2 fragments of secondary antibody were
      sufficient to induce tyrosine phosphorylation. Inhibition of tyrosine kinases by
      herbimycin A resulted in partial inhibition of the CD18-mediated tyrosine
      phosphorylation of the 120- and 65-kDa proteins and in complete inhibition of
      tyrosine phosphorylation of the 78- and 56-kDa proteins. In unstimulated PMN, the
      tyrosine phosphatase inhibitor sodium orthovanadate had no effect on tyrosine
      phosphorylation of the 120-kDa protein, but induced phosphorylation of the 78-,
      72-, 65-, and 56-kDa proteins. These results indicate that the beta2 integrin
      mediated intracellular signaling cascade involves different tyrosine
      phosphorylation (and dephosphorylation) events, which may play a role in the
      regulation of PMN functions during inflammation.

PMID- 8656063
TI  - Okadaic acid inhibits the signal responsible for activation of the NADPH-oxidase
      in neutrophils stimulated with serum-opsonized yeast.
AB  - The effects of the phosphatase inhibitor okadaic acid (OA) on human neutrophil
      phagocytic activity were investigated. The chemiluminescence response was found
      to be greatly reduced in OA-treated neutrophils during phagocytosis of serum
      opsonized yeast particles in comparison to control cells. However, the OA-treated
      neutrophils phagocytosed yeast particles to the same extent as control cells and
      the engulfment of the prey was accompanied by phagolysosomal formation in both OA
      treated and nontreated cells. We thus found that the OA effect was selective in
      the sense that it inhibits the NADPH-oxidase activity in neutrophils
      phagocytosing yeast particles but not uptake of the prey or phagolysosomal
      formation. Based on the fact that the NADPH-oxidase activity induced by the
      chemoattractant formyl-methionyl-leucyl-phenylalanine was not reduced but
      elevated in OA-treated neutrophils, we conclude that the state of phosphorylation
      has no direct effect on the oxidase, but is of importance for the NADPH-oxidase
      activating signal(s) generated during phagocytosis of the yeast particles.

PMID- 8656064
TI  - Cloning and expression of a second human natural killer cell granule tryptase,
      HNK-Tryp-2/granzyme 3.
AB  - Cytotoxic lymphocytes possess a number of serine proteases (granzymes) usually
      localized in cytoplasmic granules. To date, the DNA sequences of four human
      granzymes have been reported. A fifth human granzyme (granzyme 3) has been
      biochemically purified and its N-terminal amino acid sequence has been reported.
      This enzyme was described as possessing tryptase activity, cleaving synthetic
      substrates after arginine or lysine. We recently cloned a rat granzyme tryptase
      (RNK-Tryp-2), and used this cDNA to screen human cDNA libraries. Isolation of
      cDNA fragments of a human gene could be overlapped to provide a complete cDNA
      sequence, which we designated HNK-Tryp-2. The N-terminal amino acid sequence
      deduced from HNK-Tryp-2 was identical to that reported for granzyme 3. This gene
      appears to be a single copy gene that is expressed in isolated natural killer
      cells and T cells as well as in tissues containing these cells.

PMID- 8656065
TI  - Identification and quantitation of cholest-5-ene-3 beta,4 beta-diol in rat liver
      and human plasma.
AB  - Cholest-5-ene-3 beta,4 beta-diol (4 beta-hydroxycholesterol) was identified in
      human plasma and rat liver by gas-liquid chromatography-mass spectrometry. An
      assay based on isotope dilution-mass spectrometry with a deuterium-labeled
      internal standard was developed for quantitation of this compound. The
      concentration of cholest-5-ene-3 beta,4 beta-diol in plasma from healthy subjects
      was 36 +/- 4.3 ng/ml (mean +/- SD, n = 8). The concentration in rat liver was
      0.62 +/- 0.19 microgram/g wet weight (mean +/- SD, n = 6). These levels are of
      the same order of magnitude as other common oxysterols.

PMID- 8656066
TI  - Differential regulation of macrophage scavenger receptor isoforms: mRNA
      quantification using the polymerase chain reaction.
AB  - There are two isoforms of the macrophage scavenger receptor (MSR I and II). Both
      are expressed on macrophages and mediate internalization of oxidized lipoproteins
      and several other ligands. MSR expression is regulated by cytokines but the
      individual regulation of each isoform is not well documented. We have therefore
      developed a PCR method to quantify mRNA levels of MSR isoforms. The analysis is
      based on relating the amount of reverse transcribed and amplified human
      macrophage MSR transcripts to a synthetic internal standard, using a 32P-labeled
      5'-primer to allow quantitation of the products. Each MSR isoform and its
      corresponding standard amplified with equal efficiency and the amount of MSR mRNA
      could be determined from 1 to 100 ng of total RNA. Using this method, we
      estimated that each monocyte-derived macrophage contains 10-130 molecules of MSR
      I and 30-640 copies of MSR II mRNA. Both isoforms were down-regulated by
      bacterial endotoxin (LPS), but the effect was more pronounced for MSR II
      transcripts. However, cycloheximide induced a selective degradation of MSR I
      transcripts, leaving MSR II levels unaltered. This suggests that both
      transcriptional and posttranscriptional control mechanisms are important in the
      regulation of MSR expression.

PMID- 8656068
TI  - Regulation of neutral cholesterol esterase activity by phospholipids containing
      negative charges in substrate liposome.
AB  - The effect of phospholipids on cholesteryl ester hydrolysis by neutral
      cholesterol esterase in alveolar macrophages was studied. Among the phospholipids
      used as emulsifiers, those with a negative charge, such as phosphatidylserine,
      phosphatidic acid, phosphatidylinositol, and cardiolipin, gave a higher level of
      hydrolysis by neutral cholesterol esterase than other less negatively charged
      phospholipids, such as phosphatidylcholine, lysophosphatidylcholine,
      phosphatidylethanolamine, and sphingomyelin. Phospholipase D treatment of
      liposomes emulsified with phosphatidylcholine produced phosphatidic acid and
      enhanced cholesteryl ester hydrolysis. Phospholipase A2 treatment produced
      lysophosphatidylcholine and decreased the hydrolysis. The hydrolysis of
      cholesteryl ester in lipid droplets obtained from cholesterol-laden macrophages
      elicited by thioglycollate in the rat peritoneal cavity was low compared to
      artificial liposomes emulsified with phosphatidylcholine. The reason for this was
      speculated to be that lipid droplets were low in total phospholipids and poor in
      phospholipids with strong negative charges but rich in phosphatidylethanolamine
      and sphingomyelin. These results suggest that the polar heads of phospholipids
      may play an important role in cholesteryl ester hydrolysis by neutral
      cholesterolesterase.

PMID- 8656067
TI  - Identification and cholesterol quantification of low density lipoprotein
      subclasses in young adults by VAP-II methodology.
AB  - Low density lipoprotein (LDL) particles are heterogeneous in size, density, and
      chemical composition; small, dense LDL may be more atherogenic than large,
      buoyant LDL. We have developed a rapid microscale method called LDL VAP-II
      (Vertical Auto Profile-II) for quantification of cholesterol in LDL subclasses.
      The method is based upon a short (1 h) single vertical spin density-gradient
      ultracentrifugation and on-line VAP-II analyzer. LDL VAP-II is rapid and
      reproducible. Using this method five LDL subclasses, designated as LDL-1 (most
      buoyant) through LDL-5 (most dense), have been identified in a population
      consisting of 195 medical students (ages, 22-29 years). The Rf (relative position
      of the major LDL peak in the density gradient; the higher the Rf value, the lower
      the peak density) was significantly positively correlated with cholesterol levels
      of high density lipoprotein (HDL) (r = 0.594), HDL3 (0.350) and HDL2 (0.625), and
      significantly negatively correlated with triglycerides (TG) (-0.355) and
      cholesterol levels of very low density lipoprotein (VLDL) (-0.386) and
      intermediate density lipoprotein (IDL) (-0.432). These results are consistent
      with those obtained by other investigators. The Rf value was significantly
      correlated with peak particle diameter as determined by non-denaturing gradient
      gel electrophoresis (r = 0.859). In a forward stepwise multivariate analysis
      comparing Rf with sex, VLDL, LDL, Lp[a], IDL, HDL3, HDL2, and triglyceride, only
      HDL2 remained in the model.

PMID- 8656069
TI  - Fatty acid composition of brain capillary endothelial cells: effect of the
      coculture with astrocytes.
AB  - We have investigated the fatty acid composition of brain capillary endothelial
      cells cultured alone or in coculture with astrocytes, using an in vitro model in
      which endothelial cells and astrocytes were grown from one part of a filter to
      another. We found that the fatty acid composition of the cocultured cerebral
      endothelial cells was markedly different from that of non-cocultivated
      endothelial cells. The most striking difference was the increase of arachidonic
      acid (20:4n-6) at the expense of its precursor, linoleic acid (18:2n-6). Similar
      modifications were found for the n-3 family of fatty acids with an increase of
      docosahexaenoic acid (22:6n-3) at the expense of its precursors, but the
      differences were less than within the n-6 fatty acids. These changes induced by
      the coculture were observed only in endothelial cell phospholipids, especially
      the phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine
      classes, but were not detected in phosphatidylinositols and in other lipid
      classes. Only the composition of the n-3 series fatty acids was altered in
      another capillary endothelial cell type (from adrenal cortex) cocultured with
      astrocytes under the same conditions. The fatty acid changes observed might be
      biologically relevant as they tended to make the fatty acid composition of the
      brain capillary endothelial cells more closely resemble that of brain
      microvessels.

PMID- 8656070
TI  - Quantitation of atherosclerosis in murine models: correlation between lesions in
      the aortic origin and in the entire aorta, and differences in the extent of
      lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient
      mice.
AB  - Murine strains susceptible to atherosclerosis provide valuable models to study
      factors involved in atherogenesis. In some murine models, limited
      hypercholesterolemia can be achieved and lesions develop primarily in the aortic
      origin, in the vicinity of the aortic valve. In other models such as LDL receptor
      deficient and apoE-deficient mice, diet-induced or spontaneous
      hypercholesterolemia and atherogenesis are much greater. To determine whether
      lesion formation in the aortic origin, where particular pathogenic conditions may
      exist, correlates with lesion formation throughout the entire aorta, we measured
      the extent of atherosclerosis in both areas in 8 apoE- and 11 LDL receptor
      deficient mice fed cholesterol-rich diets for 3-6 months, as well as in 9 C57BL/6
      mice fed an atherogenic diet for a year, using two different morphometric
      methods. Both apoE-deficient and LDL receptor-deficient mice developed extensive
      lesions throughout the aorta, and in these models a significant correlation was
      observed between the extent of lesions in the entire aorta (measured as percent
      of surface area) and that at the aortic origin (measured as averaged lesion area
      per cross-section) (r = 0.77, P < 0.0001). In contrast, the plasma cholesterol
      levels achieved in C57BL/6 mice were much lower, and atherosclerotic lesions were
      found almost exclusively in the aortic origin. These results demonstrate that in
      murine models developing extensive aortic lesions, both morphometric methods
      provide valid and complementary information on the degree and distribution of
      atherosclerosis, and suggest that under severe atherogenic conditions lesion
      formation throughout the aorta is determined by the same pathological factors, in
      each model. Comparison of the extent of atherosclerosis in the entire aorta
      between genders also showed that male LDL receptor-deficient mice had
      significantly more lesions than females (29.2 vs. 14.8%, P < 0.005, n = 16). A
      similar trend was also seen in apoE-deficient mice.

PMID- 8656072
TI  - Role of lecithin:cholesterol acyltransferase and apolipoprotein A-I in
      cholesterol esterification in lipoprotein-X in vitro.
AB  - Lipoprotein-X (Lp-X) is an abnormal particle present in the plasma of patients
      with familial lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes or
      cholestatic liver disease. Compared to other lipoproteins, Lp-X contains a high
      content of unesterified cholesterol (30%, w/w) to phosphatidylcholine (60%, w/w).
      The objective of this study was to evaluate the role of LCAT and apolipoprotein A
      I (apoA-I) in Lp-X metabolism in vitro and to elucidate the regulation of
      cholesterol esterification in this unique lipoprotein. Lp-X isolated from sera of
      patients with obstructive jaundice had a high content of unesterified cholesterol
      and phosphatidylcholine and contained apolipoprotein E, apoCs, and albumin.
      Although human recombinant LCAT used as an enzyme source did bind to isolated Lp
      X, no cholesterol esterification was detected. However, addition of human apoA-I
      in the presence of albumin resulted in significant cholesterol esterification in
      Lp-X (Vmax 0.25 +/- 0.04 nmol/h per microgram LCAT protein). Exogenous apoA-I did
      not change the size of Lp-X particle as determined by quasi-elastic light
      scattering analysis. A reduction in Lp-X size was observed when both apoA-I and
      LCAT were included in the reaction mixture (from 47 nm to 42 nm). Furthermore,
      addition of apoA-I (but not HDL) dramatically changed the electrophoretic
      mobility of Lp-X from cathodic to anodic migration. Such changes are not due to
      displacement of apoC or apoE proteins from Lp-X by apoA-I. While increasing apoA
      I concentration (up to 35 micrograms/ml) in the reaction mixture stimulated
      cholesterol esterification in Lp-X, addition of apoA-I at the concentration of 8
      micrograms/ml inhibited cholesterol esterification in VLDL, LDL, and HDL by more
      than 50%. Albumin was required for the LCAT reaction to Lp-X. Our results suggest
      that while LCAT binds to isolated Lp-X, apoA-I is needed for the LCAT reaction to
      proceed. The presence of apoA-I does not result in the displacement of apoCs and
      apoE from Lp-X and addition of apoA-I changes the electrophoretic mobility but
      not the size of Lp-X.

PMID- 8656071
TI  - Two novel point mutations in the lecithin:cholesterol acyltransferase (LCAT) gene
      resulting in LCAT deficiency: LCAT (G873 deletion) and LCAT (Gly344-->Ser).
AB  - We investigated the genetic defects in two patients with familial
      lecithin:cholesterol acyltransferase (LCAT) deficiency. Their clinical
      manifestations including corneal opacities, anemia, proteinuria, and
      hypoalphalipoproteinemia were identical for familial LCAT deficiency. Their LCAT
      activities and the cholesterol esterification rate (CER) were nearly zero, and
      their LCAT masses were below 10% of normal control values. Sequence analysis of
      the amplified DNA of case 1 revealed one base deletion of G at base 873 (first
      position of Val264) in exon 6, leading to a premature termination by frameshift.
      Sequence analysis of amplified DNA of case 2 revealed a single G to A converting
      Gly (GGT) to Ser (AGT) substitution at residue 344. When COS-1 cells were
      transfected with these mutants, LCAT activity in the medium was nearly zero, and
      the LCAT mass was undetectable (< 0.01 microgram/ml). In contrast, LCAT activity
      in the medium of COS-1 cells, transfected with wild-type LCAT, was 1.7 nmol/h per
      ml and the LCAT mass was 0.09 micrograms/ml. The LCAT mass in the cell lysates of
      the mutants was less than 12% of control for case 1 and 18% of control for case
      2. Northern blot analysis of the mRNA of COS-1 cells transfected with the mutants
      showed the same amounts of LCAT mRNA as compared with wild-type LCAT.
      Biosynthesis of mutant LCATs was analyzed by pulse-chase and immunocytochemistry
      in transfected baby hamster kidney cells. SDS-PAGE/fluorography demonstrated that
      wild-type LCAT was synthesized as a high-mannose type of 56 kDa, which was very
      slowly converted to a mature form of 67 kDa and was secreted into the media. In
      contrast to the wild-type LCAT, the mutant precursors were not processed into the
      mature form but slowly degraded along with chase times. On steady and continuous
      labeling in the case of wild-type LCAT, the mature 67 kDa form was observed in
      both the cell lysate and media, whereas no mature form was detected in the cell
      lysates and media which were transfected mutant LCATs. These data suggest that
      the mutant LCATs are actually synthesized in an amount comparable to that of wild
      type, but they are slowly degraded without being processed into the mature form.
      The immunocytochemistry revealed that mutant LCATs were mainly retained in the
      endoplasmic reticulum. These data suggest that these two mutations may disrupt
      the mutant LCATs' transport from the endoplasmic reticulum into Golgi apparatus,
      resulting in LCAT deficiency.

PMID- 8656073
TI  - Secretion of biologically active human proapolipoprotein A-I in a baculovirus
      insect cell system: protection from degradation by protease inhibitors.
AB  - Studies of the structure and function of apolipoprotein A-I (apoA-I) often
      require its purification by delipidation of high density lipoprotein isolated
      from large quantities of human plasma and separation of apoA-I from other plasma
      apolipoproteins. To reduce the need for extensive purification procedures, we
      have developed an insect cell/baculovirus expression system for the production
      and secretion of human proapoA-I. The recombinant baculovirus containing full
      length human apoA-I cDNA, when introduced into Spodoptera frugiperda, directs the
      synthesis of preproapoA-I, which is subsequently secreted into the growth medium
      as proapoA-I, indicating correct processing of the signal peptide during
      secretion. To prevent the extensive degradation of secreted proapoA-I, leupeptin
      and pepstatin A were added to the serum free cell culture medium. The protein was
      simply purified by filtration of the medium, which contained up to 80 mg/l
      proapoA-I, followed by chromatography on phenyl-sepharose CL-4B. The resultant
      proapoA-I was found to bind lipid and to activate lecithin:cholesterol
      acyltransferase as effectively as apoA-I from human plasma. The advantage of this
      expression system is the ease of purification of intact, biologically active apoA
      I in high yield.

PMID- 8656074
TI  - Structural features in lipoprotein lipase necessary for the mediation of
      lipoprotein uptake into cells.
AB  - Lipoprotein lipase (LpL) has been shown to mediate the uptake of lipoproteins
      into cells. The uptake is initiated by binding of LpL to cell surface
      proteoglycans and to the low density lipoprotein (LDL) receptor-related protein.
      This ability of LpL is independent of catalytic activity and depends on the
      intact dimeric structure of the lipase and functional residues in the C-terminal
      domain. The goal of this study was to identify structural features in LpL that
      are essential in the mediation of lipoprotein uptake. Naturally occurring
      variants and LpL mutants produced by site-directed mutagenesis were cloned and
      expressed in COS-cells. A combination of immunoassays and separation on heparin
      Sepharose columns was used to determine the molar ratio of monomeric to dimeric
      LpL in the expression media. The mutants were tested for their ability to mediate
      the uptake of 125I-labeled beta-VLDL in cultured Hep3b cells in direct comparison
      with wild type LpL. We found that the concentration of monomer in the media
      correlated negatively with the effect on the uptake mediated by the dimeric form
      of LpL. A mutation affecting the catalytic activity (Asp 156Gly) resulted in no
      significant reduction in the lipase-mediated beta-VLDL uptake. Point mutations in
      the proposed lipid binding region Trp390Ala or Trp393Ala and the substitution of
      390-393 with the homologous hepatic lipase (HL) sequence were also normal, while
      the deletion of 390-393 reduced the ability to mediate the uptake by about 60% in
      comparison to wild type. A mutation known to impair heparin binding (Arg294Ala)
      was also less efficient than the wild type in mediating uptake. In conclusion, it
      is important to determine the monomer/dimer ratio in mutant preparations as the
      presence of monomers inhibits the uptake mediated by the dimeric LpL. Moreover,
      sites involved in heparin and lipid binding between residues 390-421 are
      important for LpL-mediated lipoprotein uptake.

PMID- 8656075
TI  - Rat GP-3 is a pancreatic lipase with kinetic properties that differ from colipase
      dependent pancreatic lipase.
AB  - The pancreas contains three homologous proteins, colipase-dependent pancreatic
      lipase (PL) and two recently described pancreatic lipase-related proteins, PLRP1
      and PLRP2. Rat (r) PLRP2 was first identified as a zymogen granule membrane
      protein, GP-3. Subsequently, we showed that rPLRP2 could cleave fatty acids from
      triglycerides, but the kinetic properties of rPLRP2 have not been further
      investigated. To further characterize rPLRP2, we expressed the recombinant enzyme
      in a baculovirus system, purified the secreted protein, and measured its kinetic
      properties. rPLRP2 had a broad pH optimum and the curve was similar to that of
      rPL. At pH 7.5, rPLRP2 cleaved short, medium, and long chain triglycerides by a
      kinetic mechanism that did not include interfacial activation. The activity
      against these substrates was not affected by bile salts. In particular, rPLRP2
      did not show the bile salt inhibition typical of PL. Although colipase increased
      rPLRP2 activity in the presence of bile salts, the increase was only 2- to 5-fold
      compared to the absolute requirement for colipase that rPL had under these
      conditions. Finally, rPLRP2 could hydrolyze phospholipids, a substrate poorly
      hydrolyzed by PL. Our characterization of rPLRP2 demonstrates clear differences
      among the kinetic properties of rPLRP2 and rPL, rPLRP2, and PLRP2 homologues
      isolated from guinea pig and coypu pancreas. These findings have important
      implications for the physiological function of rPLRP2.

PMID- 8656076
TI  - Oxidative modification and antioxidant protection of human low density
      lipoprotein at high and low oxygen partial pressures.
AB  - Oxidative modification of low density lipoprotein (LDL) in the subendothelial
      space of the arterial wall has been implicated as an initial process in
      atherosclerosis. In vitro studies of LDL oxidation are usually done at ambient
      oxygen partial pressure (pO2; approximately 160 torr, or 21% O2), which is
      considerably higher than arterial tissue pO2 (30-70 torr, and as low as 20 torr,
      or 2.5% O2, in atherosclerotic lesions). In addition, beta-carotene acts as an
      efficient free radical scavenger only at low pO2. Therefore, we investigated the
      effects of high (20%) and low (2%) pO2 on the kinetics of LDL oxidation, and the
      effectiveness of beta-carotene compared to other physiological antioxidants in
      preventing LDL oxidation. At low pO2, the rate of Cu(2+)-induced oxidative
      modification of LDL was lower than at high pO2. Furthermore, at high pO2 there
      was a distinct lag phase preceding the propagation phase of lipid peroxidation in
      Cu(2+)-exposed LDL, as measured by cholesteryl ester hydroperoxide formation; in
      contrast, there appeared to be no distinct lipid peroxidation lag phase in LDL
      incubated with Cu2+ at low pO2. Elevating alpha-tocopherol levels in LDL about 5
      fold resulted in significant antioxidant protection: the lipid peroxidation lag
      phase at high pO2 increased by 45% (from 58 +/- 11 to 84 +/- 3 min, P < 0.05),
      and the initial rate (0-1 h) of lipid hydroperoxide formation at low pO2 was
      reduced by 52% (from 11.6 +/- 1.9 to 5.6 +/- 1.0 nmol/mg LDL protein/h, P <
      0.01). In contrast, increasing LDL beta-carotene levels about 6-fold did not
      inhibit LDL oxidation at either pO2. Most remarkably, low concentrations of
      ascorbic acid (30 microM) drastically reduced LDL oxidation, regardless of pO2:
      the lipid peroxidation lag phase at high pO2 increased more than 7-fold (from 46
      +/- 11 min to > 360 min, P < 0.001), and at low pO2 no lipid hydroperoxides could
      be detected for at least 6 h of incubation. These results show that at low
      physiological pO2, Cu(2+)-induced LDL oxidation occurs at a significantly lower
      rate than at ambient pO2. At both high and low pO2, beta-carotene cannot inhibit
      LDL oxidation, whereas alpha-tocopherol has a moderate protective effect, and low
      physiological concentrations of ascorbic acid very strongly suppress LDL
      oxidation.

PMID- 8656078
TI  - Intestinal triacylglycerol storage pool size changes under differing
      physiological conditions.
AB  - The intestinal mucosal triacylglycerol storage pool consists of triacylglycerol
      that is predominantly transported from the intestine via the portal vein rather
      than in chylomicrons (Am. J. Physiol. 1991. 261: G530-G538). Here we examined the
      size of the storage pool under varying physiological conditions. Four groups of
      rats were infused intraduodenally for 4 h. Group A was fasted; group B was
      infused with trioleoylglycerol, 135 mumol/h; group C was infused with
      trioleoylglycerol, 135 mumol/h plus phosphatidylcholine, 9 mumol/h; and group D
      was bile-diverted and infused with trioleoylglycerol, 135 mumol/h. The amount of
      triacylglycerol in the mucosa increased from groups A to D (A > B > C > D) but
      the storage pool triacylglycerol was least in groups A and C and greatest in
      groups B and D. The percentage of trioleoylglycerol in mucosal triacylglycerol
      was greater in groups B and D than in group A and greater in all groups than the
      percentage of oleate in the total fatty acids. We conclude that the
      triacylglycerol storage pool size varies inversely with the efficiency of
      lymphatic lipid output, which is greatest in rats infused with trioleoylglycerol
      plus phosphatidylcholine (group C) and least in bile-diverted rats infused with
      trioleoylglycerol (group D).

PMID- 8656077
TI  - Distinct mechanisms of plasma LDL lowering by dietary fiber in the guinea pig:
      specific effects of pectin, guar gum, and psyllium.
AB  - Pectin (PE), guar gum (GG), and psyllium (PSY) lower plasma low density
      lipoprotein (LDL) cholesterol concentrations in guinea pigs with different orders
      of magnitude by inducing defined alterations in hepatic cholesterol homeostasis
      (Fernandez et al. 1994. Am. J. Clin. Nutr. 59: 869-879; 61: 127-134 and 1995. J.
      Lipid Res. 36: 1128-1138). To further explore specific mechanisms responsible for
      the differences in plasma and hepatic cholesterol lowering, the effects of these
      fibers were evaluated on cholesterol absorption, hepatic cholesterol 7 alpha
      hydroxylase activity, the rate-limiting enzyme of bile acid synthesis, and in
      vivo LDL transport to target specific primary and secondary mechanisms accounting
      for the observed responses. Fibers were fed with physiological (0.04%), low
      cholesterol (LC), or pharmacological high cholesterol (HC) (0.25%) levels to
      assess whether cholesterol intake influences plasma LDL lowering mechanisms.
      Intake of PE, GG, or PSY with LC or HC diets lowered plasma and hepatic
      cholesterol concentrations (P < 0.001). PE and PSY up-regulated 7 alpha
      hydroxylase activity 3-fold with LC and PE by 5-fold with HC diets. In contrast,
      GG intake had no effect on 7 alpha-hydroxylase activity. Cholesterol absorption
      was reduced 30% by PE intake while no differences were found between control and
      PSY groups. GG reduced cholesterol absorption only with HC diets. Intake of PE,
      GG, or PSY with HC diets resulted in faster plasma LDL fractional catabolic rates
      (FCR) (P < 0.01) with no effect on LDL apoB flux rates (FR) or pool size,
      suggesting that fiber reduced LDL cholesterol concentration without decreasing
      the number of LDL particles. In addition to reducing LDL apoB FR, PE and PSY
      increased LDL FCR with HC diets while GG effects were limited to lowering LDL
      apoB FR. These results indicate that the distinctive reductions in hepatic
      cholesterol induced by PE, GG, and PSY associated with plasma cholesterol
      lowering result from different mechanisms specific to each fiber and that the
      levels of dietary cholesterol contribute to the different metabolic responses.

PMID- 8656079
TI  - Identification of 19-nor-5,7,9(10)-cholestatrien-3 beta-ol in patients with Smith
      Lemli-Opitz syndrome.
AB  - We have identified the third unknown sterol in the plasma and tissues of Smith
      Lemli-Opitz homozygotes as 19-nor-5,7,9(10)-cholestatrien-3 beta-ol. The
      structure was established from capillary gas-liquid chromatography retention
      index and characteristic fragmentation pattern by mass spectrometry that were
      identical to a synthetic reference standard. Evidence is presented that 19-nor
      5,7,9(10)-cholestatrien-3 beta-ol is not an artifact formed during the chemical
      isolation of the relatively unstable 7-dehydrocholesterol. It is possible that 19
      nor-5,7,9(10)-cholestatrien-3 beta-ol may contribute to the clinical
      abnormalities in patients with Smith-Lemli-Opitz syndrome.

PMID- 8656080
TI  - Hormonal regulation of the cholesterol 7 alpha-hydroxylase gene (CYP7).
AB  - The transcriptional regulation of the rat cholesterol 7 alpha-hydroxylase gene
      (CYP7) by hormones and signal transduction pathways was studied by transient
      transfection assay of the promoter activity. HepG2 cells were transfected with
      deletion mutants of the CYP7 upstream region linked to the luciferase reporter
      gene. The transcription of CYP7/luciferase chimeric genes was higher in confluent
      than in subconfluent cultures of HepG2 cells. Glucocorticoid receptors, in the
      presence of dexamethasone, up-regulated the CYP7 gene through two regions located
      between -3262 and -2803, and between -344 and -222, respectively. Thyroid
      hormones did not have any effect on the promoter activity. Insulin inhibited the
      promoter activity through sequences located between -344 and -222, and abolished
      the stimulation by dexamethasone. Hence, the insulin effect was dominant over
      that of glucocorticoids. Treatment of transfected HepG2 cells with phorbol 12
      myristate 13-acetate (PMA), a known activator of protein kinase C (PKC), resulted
      in a time-dependent inhibition of the CYP7 promoter activity. The negative
      phorbol ester-response sequences were mapped between -344 and -222, and between 
      200 and -161, respectively. The CYP7 promoter activity was induced nearly 5-fold
      by all-trans-retinoic acid through sequences in the region from -200 to -129.
      Finally, cyclic AMP and protein kinase A (PKA) stimulated the expression of the
      CYP7/luciferase gene through multiple sequences in the distal and proximal
      regions, and both positive and negative response regions were mapped. Our results
      revealed that the -416 fragment of the rat CYP7 gene confers the activation by
      glucocorticoids and retinoic acid, and inhibition by insulin, phorbol esters and
      cAMP. It appears that this proximal promoter may contain a pleiotropic domain
      that regulates the effects of multiple signals.

PMID- 8656081
TI  - Docosahexaenoic acid synthesis in human skin fibroblasts involves peroxisomal
      retroconversion of tetracosahexaenoic acid.
AB  - The purpose of this study was to determine whether the formation of
      docosahexaenoic acid in human cells occurs through a pathway that involves 24
      carbon n-3 fatty acid intermediates and retroconversion. Normal human skin
      fibroblasts synthesized radiolabeled docosahexaenoic acid from [1-(14)C]18:3n-3,
      [3-(14)C]22:5n-3, [3-(14)C]24:5n-3, and [3-(14)C]24:6n-3. The amount of
      docosahexaenoate formed was reduced in fibroblasts defective in peroxisomal
      biogenesis, by 90-100% in Zellweger's syndrome and by 50-75% in infantile
      Refsum's disease. Fatty acid elongation and desaturation were intact in these
      mutant cells. No decrease in radiolabeled docosahexaenoic acid production
      occurred in mutant fibroblasts defective in peroxisomal alpha-oxidation or
      mitochondrial beta-oxidation, or in normal fibroblasts treated with methyl
      palmoxirate to inhibit mitochondrial beta-oxidation. Therefore, the
      retroconversion step in docosahexaenoic acid formation occurs through peroxisomal
      beta-oxidation in normal human cells. These results demonstrate that the pathway
      for docosahexaenoic acid synthesis in human cells involves 24-carbon
      intermediates. The limited ability to synthesize docosahexaenoic acid may
      underlie some of the pathology that occurs in genetic diseases involving
      peroxisomal beta-oxidation.

PMID- 8656082
TI  - Lipoxygenase mRNA in cultured human epidermal and oral keratinocytes.
AB  - Although 15-lipoxygenase has not been purified from cultured human keratinocytes
      nor has cDNA coding for the protein been isolated from this source, this enzyme
      activity is implied by the finding of its stereospecific product in in vitro
      experiments. Based on two primer pairs derived from human reticulocyte 15
      lipoxygenase cDNA, we detected approximately 260 bp and approximately 370 bp cDNA
      fragments that were indistinguishable by gel electrophoresis and Southern
      hybridization from those derived from reticulocyte 15-lipoxygenase cDNA. The
      approximately 260 bp polymerase chain reaction (PCR) fragment from a keratinocyte
      plasmid cDNA library was cloned and determined, by sequencing, to contain 262 bp
      that were 100% identical to the corresponding reticulocyte 15-lipoxygenase cDNA.
      These two reticulocyte-type 15-lipoxygenase PCR fragments were also detected from
      oral keratinocytes. Using platelet-type 12-lipoxygenase cDNA primers, we derived
      a 264 bp cDNA fragment from keratinocyte mRNA. By sequence analysis, this
      fragment was determined to be 99.6% identical to that from platelet-type 12
      lipoxygenase cDNA. The same fragment was also observed from two amplified
      keratinocyte cDNA libraries, and from oral keratinocyte mRNA. This is the first
      demonstration of reticulocyte-type 15-lipoxygenase cDNA derived from the mRNA of
      cultured human keratinocytes.

PMID- 8656083
TI  - Quantification of mucin in human gallbladder bile: a fast, specific, and
      reproducible method.
AB  - It is generally accepted that gallbladder mucin (GBM) plays an important role in
      the pathogenesis of cholesterol gallstone (ChG) disease. However, it remains
      unclear whether ChG patients have higher GBM concentrations than controls.
      Discrepant findings regarding biliary mucin concentrations may be due to
      methodological problems with the assays commonly used. The methods currently used
      to quantitate mucin in bile have not been systematically evaluated. To establish
      a reliable method for mucin quantification in bile, we evaluated three mucin
      assays: the classic Pearson-PAS (periodic acid Schiff) assay, a direct
      fluorometric assay, and a new PAS or fluorometric assay with the following
      modifications of the Pearson assay: preincubation of bile samples with TBS
      containing KSCN and sodium taurocholate and micellation of biliary lipids during
      gel chromatographic fractionation using 25 mM sodium taurocholate in the elution
      buffer. SDS-PAGE and monoclonal anti-human-GBM (GBM59) were used to identify
      mucin. Highly specific and reproducible mucin isolation was achieved with the
      modified method. We found considerable loss of mucin during the different
      purification steps in the Pearson method. The direct fluorometric assay showed
      unspecific fluorometric signal with low molecular constituents of bile. Our
      experiments showed that human-GBM can be accurately measured after a simple
      modified chromatographic fractionation followed by a PAS or fluorometric assay.

PMID- 8656084
TI  - A simple chemical synthesis of the ether analog of lysophosphatidylcholine and
      platelet-activating factor.
AB  - A simple chemical procedure for synthesis of 1-O-alkyl-(rac or sn)-glycero-3
      phosphocholine (alkyl analog of lysophosphatidylcholine, II) and platelet
      activating factor (PAF), 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (III) has
      been described. The key step of the method is the decomposition of 1-O-hexadecyl
      3-diazohydroxyacetone (A. K. Hajra, T. V. Saraswathi and A. K. Das, 1983. Chem.
      Phys. Lipids. 33: 179-193) with phosphocholine to synthesize 1-O-hexadecyl
      dihydroxyacetone-3-phosphocholine (I). Conditions for this phosphorolysis were
      studied with respect to the reaction medium, temperature, and optimum proportion
      of the reactants. Compound (I) was quantitatively reduced with NaBH4 to
      synthesize (II) which was acetylated to prepare compound (III). Phospholipase A2
      hydrolysis of compound (III) followed by separation of the products afforded the
      unreacted sn-3-hexadecyl isomer (III) and sn-1-hexadecyl isomer (II) which was
      acetylated to PAF. The structures of the compounds were verified by NMR and FAB
      MS spectra, and their biological activities were determined by measuring the
      release of serotonin from rabbit blood platelets in response to different doses
      of these compounds. The suitability of the method as a general technique for
      synthesis of different ether phosphoglycerides is discussed.

PMID- 8656085
TI  - [Role of the hemostasis laboratory in the etiologic approach to deep vein
      thrombosis].
AB  - Thrombophilia is characterized by an inherited or acquired defect in the blood
      coagulation pathway leading to an increased risk for thrombosis. The etiological
      approach following confirmed venous thrombotic events should rule out medical or
      chirurgical risk factors. Thrombophilia should be sought by laboratory tests. The
      recent discovery of a blood coagulation defect: inherited resistance to activated
      protein C which is found to 20% of patients with former thrombotic events has
      changed current laboratory approach. Deficiencies of one of the anticoagulant
      proteins (antithrombin III, protein C, protein S) are found in 10% of the
      patients, similar to the frequency of antiphospholipid antibodies. These tests
      may be difficult to interpret immediately after the thrombotic event because of
      various factors such as inflammatory states or anticoagulant treatments.
      Therefore this abnormal tests should be confirmed on a later sample analysis far
      from the event. The discovery of an inherited blood coagulation pathway defect
      may affect the duration of treatment, prophylaxis in situations with
      circumstantial risk factors and requires familial analysis. Inherited resistance
      to activated protein C may be associated with another inherited defect leading to
      an increased risk for thrombosis.

PMID- 8656086
TI  - [Magnetic resonance contract agents and perfusion imaging].
AB  - Contrast agents may be categorised as non-specific or specific agents. Non
      specific agents are freely diffusible in the extracellular and extravascular
      compartment with the exception of the brain where only blood brain barrier
      lesions enables the contrast agent to pass. In the specific agent group, a new
      class of products has been developed, that of blood pool contrast agent, which
      are distributed in the total intravascular volume and are slowly cleared from the
      blood. Crossing the healthy capillary wall is limited and depends both on the
      pathological state of the endothelial permeability tissue of the organ under
      interest and on the characteristics of the contrast agent (size, charge,
      molecular shape...). The diagnostic efficacy in perfusion imaging including
      cerebral perfusion is modulated by the pharmacokinetic profile of the blood pool
      contrast agent. One way to improve the vascular residence time, consists in
      binding a vector such as synthetic polymer or a biological macromolecule and a
      lanthanide like Gd3+, Mn2+, Dy3+ or metal ions. A second way is the synthesis of
      ultrasmall iron oxide nanoparticles which could escape rapid recognition by the
      monocyte macrophage phagocytic system mainly of liver and spleen. Because of
      their cristalline structure and the large number of non-paired spins, five
      electrons for the iron metal, the nanoparticles behave as magnetic domain when an
      external field is applied. They consequently have a high dipolar magnetic moment,
      and can produce a T2 effect in vivo, resulting in a drop in the magnetic
      resonance signal. Possible interests and developments toward perfusion imaging
      are demonstrated in experimental models studies.

PMID- 8656087
TI  - [Diagnosis of venous thrombosis and/or pulmonary embolism by determination of d
      dimers using ELISA. Review based on a study of 80 consecutive patients
      hospitalized in an emergency unit].
AB  - The sensitivity and specificity of an ELISA method (Fibrinostika Fbdp Organon
      Teknika) for assay of D-dimers in the diagnosis of deep vein thrombosis and/or
      pulmonary embolism was studied in 80 consecutive patients seen at an emergency
      unit. Fifty-six of the patients presented clinical signs of deep vein thrombosis.
      Diagnosis was confirmed in 26 of the 56 patients with a D-dimer level above 370
      ng/ml (sensitivity 92.3%) and 370 ng/ml for 13 of 30 patients with a negative
      venous ultrasound Doppler examination (specificity 43.3%). The positive
      predictive value was 58.5% and the negative predictive value was 87%. There was a
      significant difference in the level of D-dimers between distal and proximal deep
      vein thrombosis. In 40 cases with suspected pulmonary embolis, either alone or
      with suspected deep vein thrombosis, diagnosis was made in only 4 of 9 with a
      highly or intermediately probable ventilation/perfusion scan. D-dimer level was
      always above 3,000 ng/ml. Coupling the ELISA dimer test with noninvasive
      explorations improves negative predictive value but can also avoid invasive
      explorations (venography, pulmonary angiography) in certain patients. A D-dimer
      test as sensitive as the ELISA test and as rapid as the latex test remains to be
      described.

PMID- 8656088
TI  - [Surgical treatment of superficial vascular malformations. Indications for tissue
      expansion].
AB  - The aim of this work was to demonstrate the feasibility of surgical exeresis of
      superficial vascular malformations using tissue expansion. A retrospective
      analysis of data from 15 patients who underwent surgery over a 9 year period for
      arteriovenous (n = 6) and venous malformations of the trunk and limbs was made.
      Indications for treatment were pain in six patients or complications of an
      arteriovenous malformation. Twenty-eight expanders were used in 15 patients. Most
      of the complications observed (25% of the cases) were minor. The program had to
      be interrupted due to complications in only one case (7%). Mean duration of
      tissue expansion was 105 days (30-165). Mean delay to cicatrization was 40 days
      and mean duration of the treatment program was 156 days. Indication for surgical
      exeresis of superficial vascular malformations can be widened due the
      contribution of tissue expansion. With acquired experience, the risk of
      complications has been reduced. The duration of the treatment protocol is the
      main drawback.

PMID- 8656089
TI  - [Risk of development of false aneurysm and graft infection after aorta-femoral
      bypass graft. Retrospective study. Report of 211 cases].
AB  - Anastomotic aneurysm and infection of arterial graft are complications that occur
      late after aorto-femoral bypass graft surgery. The objective of this paper is to
      calculate the percentage of patients free of these complications after 10 years.
      From 1966 to 1983, 211 patients were operated on consecutively to treat
      aortoiliac atherosclerotic obstructive disease. There were 173 (82%) men and 38
      (18%) women of mean age 54.7 +/- 9.1 years. Forty-one percent of patients were
      operated on for limb salvage. Aorto-bi-femoral bypass was performed in 196
      (92.9%) patients; the unilateral aorto-femoral bypass in 8 (3.8%) and the aorto
      femoral to one side and aorto-iliac to the order in 7 (3.3%). In 28 patients, the
      bypass was associated with femoro-popliteal bypass (21 patients) or
      reconstruction of visceral arteries (7 patients). The anastomosis was end-to-side
      both in the aorta and in the femoral arteries, made of synthetic sutures.
      Diagnosis of the complications was made by physical examination, ultrasonography,
      CT scan or arteriography. The Kaplan-Meier method was used to determine the
      percentage of patients without complications. After 24, 60 and 120 months, 98.5%,
      92.6% and 85.4% of the patients were free of anastomotic aneurysm, respectively
      and after the same periods, 97.3%, 90.4% and 75.2% of the patients respectively
      were free of graft infection (table 2). We conclude that the risk of developing
      complications is a permanent risk and increases with time, but the use of grafts
      cannot be invalidated.

PMID- 8656090
TI  - [Comparison between the CHIVA cure and stripping in the treatment of varicose
      veins of the legs: follow-up of 3 years].
AB  - OBJECTIVE: To assess three-year results following "CHIVA". DESIGN: Comparison
      between our results and data in the literature following stripping. SETTING:
      Phlebologic Surgery, 46 Datini Street, Florence, Italy. PATIENTS: 148 consecutive
      operated patients suffering from varicose veins (166 procedures). INTERVENTIONS:
      "CHIVA", as described by Franceschi and Bailly. MAIN OUTCOME MEASURES: The
      presence of visible varicose veins, graded in three categories, according to
      Hobbs and Einarsson, as shown by clinical examination. RESULTS: Very good results
      were obtained in 100 cases, who presented without any finding of varicose veins
      throughout the follow-up. Of the remaining 66, in 1 case we found a new varicose
      network completely developed, whereas in 65 cases only some visible residual or
      recurrent vessels were present. CONCLUSIONS: Significantly better results were
      observed in the CHIVA group compared with stripping groups (P < 0,001).

PMID- 8656091
TI  - [Pseudothromboangiitis obliterans and qualitative protein C deficiency: report of
      a case].
AB  - Thromboangiitis obliterans is a segmental obliterating inflammatory arteritis,
      usually found in young (below 40) smoking males. Its diagnosis relies on patient
      history, clinical features, arterial angiography, and more rarely on pathological
      findings, though none of these is specific of the disease, and on the absence of
      other diseases such as early atheroma, thromboembolic processes, vascular
      malformation, trauma, collagen or blood disorders. Raynaud's phenomenon, digital
      arteritis, superficial and often migrating venous thromboses are further
      arguments for the disease. However, such associations can also occur during other
      diseases, especially congenital or acquired deficits in coagulation factors
      (antiphospholipid syndrome, S protein deficiency...). In our patient with
      suspected thromboangiitis obliterans, the occurrence of superior longitudinal and
      right lateral sinus thrombosis led to the discovery of a qualitative C protein
      defect. This observation stresses the need for careful elimination of a
      coagulation disorder before confirming the diagnosis of thromboangiitis
      obliterans.

PMID- 8656092
TI  - [Livedo vasculitis: report of a case].
AB  - Livedo vasculitis is an occlusive thrombotic hyalinizing vessel disease
      characterized by parietal hyalinization, endothelial proliferation, fibrin
      deposits and formation of thrombi within the superficial and deep dermal vessels.
      Diagnosis, essentially clinical, emphasizes the clinical and histopathological
      features of livedo vasculitis. We conducted an etiological investigation in our
      case, as required to diagnose idiopathic livedo vasculitis. Several therapies
      have been suggested with inconstant results and recurrence after withdrawal. In
      our case, treatment with recombinant tissue plasminogen activator was successful
      but was unable to prevent recurrence.

PMID- 8656093
TI  - [Outlook for clinical hemorheology].
AB  - Harvey may be considered to be the precursor of modern hemorheology, but it was
      not until the pioneering work of Loewenhoeck, Poiseuille, Fahraeus and Copley
      that the essential role of the hemorheological properties of blood and its
      cellular components was recognized. Before the advent of modern hemorheology in
      the 70s, studies were mainly focussed on microcirculation and validation of
      global hemorheological equations applied to blood circulation. Parallel studies
      on the microrheological properties (erythrocyte deformability and aggregation)
      explained analytically the non-Newtonian behavior of blood, and the essential
      contribution of these parameters to the understanding hyperviscosity syndromes.
      The development of clinical hemorheology in fact started at the international
      conferences held in Reykjavik (1966) and Heidelberg (1969), and with the
      initiation of the periodical European Microcirculation (since Nancy in 1960) and
      Clinical Hemorheology (since Nancy in 1979) Conferences. The current main avenues
      of research involve flow modelling, studies of cell-cell interaction mechanisms
      (aggregation and adhesion), in relation to the associated pathophysiological
      phenomena, such as cellular activation (platelets and leukocytes in particular),
      gene expression linked to blood flow (e.g. endothelial cells)... Clinically and
      therapeutically, it is crucial that pathophysiological studies be undertaken on
      the relationship existing between rheological parameters and objective clinical
      data (local flow rates, ischemic markers, hemostatic parameters, tissue oxygen,
      clinical symptoms,...). The main clinical application fields are cardiovascular
      diseases, thrombosis, diabetes, hypercholesterolemia... Also, studies on new
      therapeutics or on biomaterials should also be given priority.

PMID- 8656094
TI  - Proceedings of the 20th annual ISCE conference. Research and Technology Transfer
      in Computerized Electrocardiology. Amelia Island Plantation, Florida, April 29
      May 4, 1995.

PMID- 8656095
TI  - Mechanisms of defibrillation. Critical points and the upper limit of
      vulnerability.
AB  - The upper limit of vulnerability hypothesis for defibrillation states that a
      successful defibrillation shock must both stop the fibrillation wave fronts on
      the heart at the time that the shock is delivered and not start new wave fronts
      that will lead to reentrant circuits being formed, causing the heart to
      refibrillate. Mapping studies have demonstrated that defibrillation shocks can
      halt all wave fronts on the heart but fibrillation will begin again with an
      initial activation pattern that is different from the activation pattern on the
      heart just before the shock is delivered. In a fashion similar to the
      reinitiation of fibrillation following a failed defibrillation shock, properly
      sized and timed shocks can be delivered to the heart during paced rhythm to
      induce functional reentry that will initiate fibrillation. If the shocks are made
      incrementally larger, a shock level will be reached that is high enough not to
      start fibrillation in regular rhythm regardless of when it is delivered during
      the cardiac cycle. This shock level is called the upper limit of vulnerability.
      In this study, the formation of reentrant circuits with defibrillation-sized
      shocks and how this formation of reentrant circuits may be related to mechanism
      of defibrillation, via the upper limit of vulnerability hypothesis are discussed.

PMID- 8656096
TI  - Interpolation of body surface potential maps.
AB  - The performance of four methods for interpolation of body surface potential maps
      (BSPMs) for different electrode grid densities was assessed. This study is part
      of a research project on the influence of the variability of 12-lead
      electrocardiograms on computer interpretation due to small electrode position
      changes. Interpolated BSPMs can be used to simulate this variability. The set of
      BSPMs studied, derived from a 117-electrode grid with relatively many electrodes
      on the left precordial part of the thorax, consisted of 232 cases without
      abnormalities, 277 with infarction, and 237 with left ventricular hypertrophy.
      The interpolation methods used were fast Fourier transforms, Chebyshev
      polynomials, linear functions, and cubic splines (CS). In the horizontal plane, a
      reference signal was first interpolated and, thereafter, resampled using 11
      different sets of electrodes with the number of electrodes ranging from 18 down
      to 8. In the vertical direction, five grids with electrodes only on the front of
      the thorax and nine grids with electrodes on the front and back were examined. As
      a performance measure for interpolation, mean absolute error (MAE) was used: the
      absolute differences between the reference signal and the interpolated signal,
      averaged over the QRS on all maps. All methods showed deteriorating performance
      for decreasing grid density. In the horizontal direction, CS proved to be
      slightly superior to other methods for the left precordial electrodes for all but
      the densest grid (e.g., MAE = 22.8 microV vs MAE > 24.8 microV for a 12-electrode
      grid). For electrodes not in that area, CS performed the best as well (MAE = 16.1
      microV for the same grid), with differences with the other methods being small
      (MAE > 16.4 microV). In the vertical direction, CS showed the best results on the
      front, both for the dense nonperiodic (MAE = 19.1 microV vs MAE > 26.6 microV for
      a 6-electrode grid) and periodic grids (MAE = 25.1 microV vs MAE > 26.6 microV
      for a 12-electrode grid). Linear functions performed best for sparse nonperiodic
      grids and sparse periodic grids for electrodes on the back, with the difference
      with CS for the last case being small. The method CS performed best overall, and
      is recommended for interpolating BSPMs.

PMID- 8656098
TI  - Map representation and diagnostic performance of the standard 12-lead ECG.
AB  - The diagnostic information contained in the standard 12-lead electrocardiogram
      was assessed by comparing the classification results produced by the standard
      leads for various clinical settings, such as normal versus myocardial infarction
      or versus left ventricular hypertrophy to those achieved by 120-lead data or body
      surface potential maps (BSPMs). Separately, optimal signal leads were extracted
      from the BSPM by ranking all leads in function of their capability of
      reconstructing the BSPM. Ranking was achieved by deriving eigenvalues from the
      covariance matrix calculated from all leads and corresponding measurements. Thus,
      while comparing the results from the standard leads (diagnostic leads) to those
      from the original raw map data, a comparison was also performed with respect to
      the best signal leads, namely the four best and the eight best. From the results
      observed for all bi- and multigroup classifications, it appeared that the
      diagnostic yield of the 12 standard leads matched those obtained with a number of
      signal leads lying between 4 and 8. This indicated that a large overlap still
      existed between the leads composing the 12-lead ECG (in fact, only 8 independent
      leads). Another interesting observation resulted from this investigation:
      although classifiers (discriminating variables) used for classification were
      identical, whether they originated from the raw standard leads (derived from the
      raw maps) or from standard leads reconstructed with four or eight signal leads,
      reconstructed measurements performed better than original measurements. This
      paradox can be explained by looking at the respective F values. Indeed, since
      increased F values result from higher ratios between the difference of group
      means and the composite variance from the pooled groups, higher differences
      and/or smaller variances produce larger ratios and hence, better group
      separations.

PMID- 8656097
TI  - The state of body surface mapping in Japan.
AB  - In Japan, body surface mapping (BSM) started in 1974. A huge amount of data has
      been accumulated regarding basic researches and clinical applications. Recent
      work on BSM in Japan is summarized here, with the goals of establishing a normal
      database and diagnostic criteria by using the standardized mapping system. The
      standard systems used in Japan are the HPM-7100 and the VCM-3000, manufactured by
      Fukuda-Denshi (Tokyo, Japan) under the supervision of a committee of the Japanese
      Circulation Society. The number of leads in this system is 87 (59 on front, 28 on
      back). As a basic study, a computer simulation was carried out on bundle branch
      block with myocardial infarction (MI), on late potentials in MI, and finally, on
      the solution of the inverse problem. The database of 606 normal subjects was
      established regarding age and sex, and a "departure index" (the grade of
      deviation from normal: the difference between a patient's data the normal mean
      divided by the normal SD) was proposed. Using the departure index, diagnostic
      criteria were proposed for the ischemic site, MI site, hypertrophic site of the
      ventricle, etc. The origin of the ventricular premature contractions was
      determined by the site of minima and maxima of the QRS and QRST isointegral maps.
      The site of accessory pathways was determined by the site of minimum less than 
      0.15 mV on the BSM. For the prediction of patients prone to ventricular
      tachycardia (VT), several approaches were tried such as multipolar patterns of
      QRST isointegral maps, Wigner distribution, late potentials with relation to endo
      or epicardial delayed potentials, body surface distribution of specific
      frequency band (25-50 Hz) obtained from fast Fourier transform analysis, and
      nondipolarity of the QRST isointegral map. To improve the ablation procedure of
      VT, the author developed a technique to determine the precise location of the VT
      focus in pace mapping using a correlation matrix between VT and pace maps. To
      ensure the longevity of the BSM, a reduction of the number of leads has been
      proposed. The usefulness of BSM has been confirmed and the technique accepted in
      Japan for daily clinical diagnosis.

PMID- 8656099
TI  - Time-related perturbations of repolarization.

PMID- 8656100
TI  - Role of M cells in acquired long QT syndrome, U waves, and torsade de pointes.

PMID- 8656101
TI  - Different circadian behavior of the apex and the end of the T wave.

PMID- 8656102
TI  - T wave changes following right ventricular pacing.

PMID- 8656103
TI  - Clinical aspects of cardiac memory revisited.

PMID- 8656104
TI  - Numerical analysis of electrical defibrillation. The parallel approach.
AB  - Numerical modeling offers a viable tool for studying electrical defibrillation,
      allowing the behavior of field quantities to be observed easily as the different
      system parameters are varied. One numerical technique, namely the finite-element
      method, has been found particularly effective for modeling complex thoracic
      anatomies. However, an accurate finite-element model of the thorax often requires
      a large number of elements and nodes, leading to a large set of equations that
      cannot be solved effectively with the computational power of conventional
      computers. This is especially true if many finite-element solutions need to be
      achieved within a reasonable time period (eg, electrode configuration
      optimization). In this study, the use of massively parallel computers to provide
      the memory and reduction in solution time for solving these large finite-element
      problems is discussed. Both the uniform and unstructured grid approaches are
      considered. Algorithms that allow efficient mapping of uniform and unstructured
      grids to data-parallel and message-passing parallel computers are discussed. An
      automatic iterative procedure for electrode configuration optimization is
      presented. The procedure is based on the minimization of an objective function
      using the parallel direct search technique. Computational performance results are
      presented together with simulation results.

PMID- 8656105
TI  - Repolarization gradients derived by subtraction of monophasic action potential
      recordings in the human heart. Studies incorporating altered mechanical loading
      and ischemia.
AB  - Information derived from the analysis of the electrocardiographic waveform
      remains one of the most valuable diagnostic aids in modern cardiology.
      Paradoxically, although changes in the ST-T segment probably have the widest
      clinical application, it is the analysis of this repolarization phase that has
      been surrounded by the greatest difficulties in interpretation.

PMID- 8656106
TI  - Prediction of the location and time of spontaneous termination of reentrant
      ventricular tachycardia for radiofrequency catheter ablation therapy.
AB  - Ventricular tachycardia caused by reentrant excitation can lead to cardiac arrest
      and sudden death. Drug treatment and surgical procedures have been used with
      limited effectiveness. Catheter ablation methods are more promising because they
      are less invasive than surgery. Although ablation has come to be highly effective
      in the treatment of supraventricular tachycardias, the overall success rate
      remains low for ventricular tachycardias, which may be due in part to an
      inaccurate localization of the reentrant pathway. The authors hypothesize that a
      site in the myocardium exists that is critical for the maintenance or reentry and
      that when ablated, will result in permanent cessation of the tachycardia. The
      authors also hypothesize that this is the same site where the reentrant impulse
      blocks during spontaneous termination of tachycardia. A series of experiments has
      been designed to determine if there are specific properties of extracellular
      electrograms recorded from reentrant circuits that would enable the circuits to
      be identified without activation maps and, more specifically, allow the site of
      block causing spontaneous termination to be localized. For quantitative analysis
      of electrograms, a paradigm is developed to characterize electrogram morphology
      using a canine infarct model. Changes in morphology (shape, size, and location of
      signal deflections) can be considered (1) motions of a coordinate system and/or
      (2) conformational changes of shape. To a first approximation, stationarity over
      short time segments is assumed so that the motions and conformations can be
      parameterized. These parameters were extracted for 50 cardiac cycles during an
      episode of nonsustained ventricular tachycardia, in which 196-bipolar electrode
      pairs were positioned in an array format across the epicardial surface of the
      heart. The results of these studies of changes in electrogram morphology suggest
      that during cycles 5 to 49 of ventricular tachycardia, in many electrograms near
      the circuit, the cycle length increases linearly, the amplitude increases, and
      the duration of activation decreases. During cycles 50 to 54, the cycle length
      increases much more markedly, the amplitude decreases, and the duration of
      activation increases. These observations suggest that cycle lengthening may be an
      important property of some spontaneous terminations, and moreover that other
      morphologic characteristics are affected differently at different stages of cycle
      lengthening. Further, all motion parameters tended to oscillate from cycle to
      cycle in either an alternans pattern or longer oscillation. The variations in
      morphology were typically only a few percent from cycle to cycle. Such
      variability would not be evident using only ruler-and-caliper measurements made
      by hand because of the lack of precision and the sheer volume of data. It is
      expected that this approach for characterization of electrogram morphology will
      be extremely useful clinically to (1) increase speed and accuracy of ablation
      site selection and (2) reduce multichannel electrogram recording complexity
      during ablation site selection.

PMID- 8656107
TI  - Cardiac responses to premature monophasic and biphasic field stimuli. Results
      from cell and tissue modeling studies.
AB  - Experimental and clinical observations confirm that certain biphasic (BP)
      defibrillation shocks are significantly more efficacious than equivalent
      monophasic (MP) shocks, yet the mechanisms underlying these improvements are
      still not well understood. The authors used two separate, but related, computer
      models to investigate in detail the excitation responses of active cardiac cells
      and tissue to idealized premature extracellular MP and BP field stimuli. The
      results revealed a large disparity in MP and BP excitation responses to low
      strength, but not high-strength, fields. In particular, at these low-strength
      levels, the polarity reversal within BP shocks effectively extends excitability
      to earlier cellular refractory states than can be achieved with simple MP shocks.
      Moreover, whereas low-strength MP shocks induce a distinct all-or-none excitatory
      response to varying shock prematurities, the excitatory response to equivalent BP
      shocks remains highly graded. In tissue simulations where such field stimuli
      intersected propagating wave fronts, the all-or-none excitatory response elicited
      by low-strength MP shocks created a postshock discontinuity in the spatial
      transmembrane voltage profile, which initiated a new propagation wave front. In
      contrast, the graded excitatory response elicited by BP waveforms effectively
      prevented the formation of postshock wave fronts. High-strength MP and BP stimuli
      prevented renewed propagation equally well. In conclusion, these results suggest
      a new mechanisms for BP defibrillation superiority over MP waveforms: that the
      graded excitatory response to BP stimuli at low-field strengths effectively
      prevents the formation of large spatial transmembrane voltage gradients, which
      can lead to renewal of propagated wave fronts.

PMID- 8656108
TI  - Simulation of cardiac memory in a computer model using capacitive coupling.

PMID- 8656109
TI  - Body surface ECG potential maps in acute myocardial infarction.
AB  - An algorithm for the early detection of acute myocardial infarction (MI) using
      body surface electrocardiographic potential mapping has been developed. The
      mapping system consists of a 64-hydrogel electrode harness applied rapidly to the
      anterior chest, from which electrocardiographic signals are stored on a memory
      card and processed by computer. At each of the 64 points, QRS and ST-T
      isointegrals and 10 other features of the QRST segment are measured. Using these
      measurements, new variables are derived that express the shape of the three
      dimensional geometric surface of the map. The isointegrals, features, and shape
      variables are used in a variety of techniques to discriminate between MI and
      control subjects. Maps were recorded from 69 patients at initial presentation of
      chest pain suggestive of acute MI and from 80 healthy control subjects. Using a
      multiple logistic regression technique, 14 variables were identified that
      correctly classified 79 of the 80 control subjects (specificity, 98.8%) and 65 of
      the 69 MI patients (sensitivity, 94.2%). The algorithm based on these 14
      variables was applied prospectively to maps recorded on a further 48 control
      subjects and 59 patients with acute MI. Of the MI patients, 31 had inferior, 13
      inferoposterior, 10 anterior, 2 posterior, 1 lateral, 1 inferior with right
      bundle branch block, and 1 anterior non Q wave MI. The algorithm correctly
      classified all 48 control subjects (specificity, 100%) and 57 of the 59 MI
      patients (sensitivity, 96.6%). Marked differences in the three-dimensional
      geometric map surfaces between the control subjects and MI patients were
      demonstrated. Variables derived from these surfaces form the basis of an
      algorithm with a high sensitivity and specificity for the automated detection of
      acute MI. The design of adaptive algorithms and their application to patients
      with chest pain and atypical electrocardiographic changes, particularly ST
      depression, may lead to the earlier detection of MI and greater numbers of
      patients receiving thrombolytic therapy.

PMID- 8656110
TI  - Why are some antiarrhythmic drugs proarrhythmic? Cardiac arrhythmia study by
      bifurcation analysis.
AB  - This study employs a bifurcation analysis approach to elucidate the effect of the
      key ion channels on cardiac arrhythmias and thereby explain the efficacy of
      antiarrhythmic drugs in controlling arrhythmias. The model used for the analysis
      contains the key ion channels involved in the ventricular action potential--fast
      sodium, slow calcium, and background potassium channels. The cardiac tissue is
      modeled by a ring structure. The bifurcation diagram reveals that at a certain
      ring size, the amplitude of the action potential suddenly shrinks and the
      conduction velocity (CV) becomes unstable. Instability in CV leads to termination
      of reentrant arrhythmias. This ring size (ie, the critical ring size [CRS])
      depends of the type of channel blocker. Blocking of the sodium channel leads to a
      decrease in the CRS, which in turn enhances stable reentry (proarrhythmia).
      Although calcium channel blockers do not alter the CV, they can exert the
      proarrhythmic effect by drastically shortening the CRS. The potassium channel
      blockers, on the other hand, are effective in controlling reentry in ventricular
      tissues by lengthening the CRS. Near blocking of the potassium channel, however,
      brings about another type of arrhythmia--the formation of ectopic foci. In the
      neighborhood of the CRS, the cycle length oscillates with an interesting pattern
      that depends on ring size and drug type. Although a critical reentrant loop
      length for stable reentrant excitation has been investigated for a long time,
      this study is the first demonstration of how the key ion channels in the plasma
      membrane affect the loop length. Furthermore, the analysis approach provides a
      theoretical basis for the increased mortality associated with class I drug use in
      the Cardiac Arrhythmia Suppression Trial Team.

PMID- 8656112
TI  - Dispersion of repolarization. Relation to heart rate and repolarization duration.
AB  - Repolarization duration is highly dependent on heart rate. A major concern when
      evaluating dispersion of repolarization is the possible influence of heart rate
      on the magnitude of dispersion. Another consideration relates to a potential
      relationship between overall duration of repolarization and the magnitude of
      dispersion, that is, whether patients with longer repolarization duration present
      with increased or decreased dispersion of repolarization. Therefore, the
      following relationships were studied in 380 normal subjects, 68 coronary artery
      disease (CAD) patients, and 41 long QT syndrome (LQTS) patients: the magnitude of
      dispersion (JTd) versus cycle length (R-R) and dispersion versus repolarization
      duration (QTc interval). Dispersion of repolarization (JTd), measured as the
      maximal difference in JT interval duration between precordial leads, was
      significantly higher in LQTS patients than in normal subjects or CAD patients
      (120 +/- 72 vs 53 +/- 42 and 48 +/- 22 ms, respectively). In neither normal
      subjects, CAD patients, or LQTS patients were there significant relationships
      between the magnitude of dispersion and the R-R interval (r = .094, .158, and
      .233, respectively; not significant) and between the magnitude of dispersion and
      QTc duration (r = .0443, -.094, and .126, respectively; not significant). In
      normal subjects, CAD patients, and LQTS patients, the magnitude of dispersion is
      not significantly related to heart rate, indicating that there is no need for
      heart rate adjustment of dispersion parameters. In addition, there is no
      significant association between the magnitude of dispersion and duration of
      repolarization.

PMID- 8656111
TI  - Analysis of alternans in late potentials. Correlations between epicardial and
      body surface recordings.
AB  - The methodical performance of the signal-averaged electrocardiogram is strongly
      influenced by the beat-to-beat reproducibility of late potentials (LPs).
      Especially at higher heart rates, epicardial recordings from infarct regions show
      progressive beat-to-beat prolongations with alternating conduction block. To
      analyze the influence of beat-to-beat-alternans of LPs on the signal-averaging
      process, epicardial and body surface recordings were studied at different heart
      rates and extrastimulation. Epicardial and body surface recordings were obtained
      from dogs with 4-day postligation of the left anterior descending coronary artery
      (Harris model). Body surface potentials were averaged in different modes to a
      final noise level of 0.3 microV (rms) and digitally bandpass filtered (40-250
      Hz). Modulation of the heart rate was performed by atrial or His-bundle pacing
      and by atrial premature extrastimulation. Pacing up to heart rates close to 180
      beats/min produced no significant changes in the duration of LPs in epicardial
      and averaged body surface recordings; however, at higher pacing rates,
      considerable prolongation of LPs with different patterns in the epicardial leads
      was observed. In these cases, averaging of all beats revealed only a slight
      prolongation of LPs, as seen from the body surface. Selective averaging of beats
      with prolonged epicardial LPs showed the prolongation or absence of LPs, as seen
      in the epicardial recordings. Similar observations were made using an atrial
      extrastimulation technique, whereby the average of the premature beats was
      compared to the average of all normal sinus beats. Selective beat averaging of
      body surface potentials can unmask the prolongation of LPs due to atrial pacing
      or extrastimulation, as seen in recordings from the infarcted epicardium. The
      evidence of this modulation of LPs may improve the positive predictive value of
      the signal-averaged electrocardiogram.

PMID- 8656113
TI  - QTc behavior during treadmill exercise as a function of the underlying QT-heart
      rate relationship.
AB  - A mathematic description of the behavior of the Bazett-corrected QTc interval
      during exercise was developed from the underlying relationship between the
      unadjusted QT interval and heart rate in 94 normal men. Measurements were made
      from digitized precordial lead V5 complexes that were averaged by computer over
      20-second periods at upright control (mean rate, 78 beats/min), during moderate
      exercise (mean rate, 125 beats/min), and at peak effort (mean rate, 162
      beats/min), using a gently graded treadmill protocol that produces small heart
      rate increments between 2-minute stages. Although the group mean QTc interval
      increased during early exercise and decreased during higher exercise workloads,
      the mean unadjusted QT interval decreased throughout exercise in a strongly
      linear relationship with increasing heart rate: QT[ms] = 481 - 1.32HR, R2 = .99,
      where HR stands for heart rate. As a consequence of this linearity, the behavior
      of the QTc interval over a range of heart rates generally found during exercise
      could be modeled as a function of the slope (m) and intercept (b) of the observed
      relationship, since the Bazett relationship QTc = QT[ms]/R-R0.5 can, in this
      context, be rewritten simply as QTc = (481 - 1.32HR)/(60/HR)0.5, which reproduces
      the observed biphasic QTc interval behavior. Plots of the generalized equation
      QTc = (b - mHR)/(60/HR)0.5 allow theoretical exploration of QTc interval behavior
      that might result from varied disorders with different slopes (m) and intercepts
      (b), and these regression-based descriptors of the QT-heart rate relationship may
      provide useful, additional definitions of normal and abnormal QT interval
      behavior during exercise.

PMID- 8656115
TI  - Value of a derived 12-lead ECG for detecting transient myocardial ischemia.

PMID- 8656114
TI  - Increased defibrillation threshold due to ventricular fibrillation duration.
      Potential mechanisms.
AB  - The duration of ventricular fibrillation (VF) that precedes a high energy shock
      has been recognized as a critical determinant of defibrillation outcome. Factors
      such as metabolic acidosis or alkalosis do not affect outcome. The authors
      hypothesized that release of myocardial adenosine during VF could potentially
      mediate the time-dependent effects of VF duration on defibrillation.
      Defibrillation threshold (DFT) was therefore determined in dogs during concurrent
      infusion of adenosine and dipyridamole (a nucleoside transport blocker).
      Transthoracic DFT increased by approximately 50%, whereas transmyocardial DFT
      increased by approximately 100% in a separate group of dogs. These effects of
      adenosine on DFT were abolished when the dogs were autonomically denervated,
      suggesting that the deleterious effects of adenosine on DFT are due to its
      antiadrenergic mechanism of action. These data indicate that adenosine release
      during VF can markedly increase DFT. Since adenosine myocardial release during VF
      is time dependent, it is likely that adenosine plays a significant role in
      mediating the increase in threshold that is dependent on the duration of VF.

PMID- 8656117
TI  - The signal-averaged high-resolution ECG.

PMID- 8656116
TI  - Computer simulation of the electrotonic modulation of pacemaker activity in the
      sinoatrial node by atrial muscle.
AB  - Electrotonic interaction between the sinoatrial (SA) node and surrounding atrial
      muscle was investigated in a computer simulation using a modified Oxsoft HEART
      model (Oxsoft, Oxford, UK). When an SA node cell model was coupled to a passive
      atrial membrane model (RC circuit) with various coupling conductances (Gc), there
      was a Gc-dependent prolongation of spontaneous cycle length (SCL). At a
      sufficiently high value of Gc, the spontaneous activity was finally stopped. A
      nonlinear relationship between Gc and SCL was obtained, similar to that observed
      in experiments on rabbit SA node cells. When the muscarinic potassium current
      (iK,ACh) was activated in the SA node cell model, the coupling-induced inhibition
      of pacemaker activity was potentiated. Although coupling current and iK,ACh were
      additive, their effects on SCL were more than additive because of the nonlinear
      dependence of SCL on net current. A decrease in the input resistance of the
      atrial membrane model to stimulate the activation of iK,ACh in atrial muscle was
      also shown to potentiate the coupling-induced inhibition of SA node spontaneous
      activity.

PMID- 8656118
TI  - Changes in high-frequency QRS components during prolonged coronary artery
      occlusion in humans.

PMID- 8656119
TI  - Frequency content and sex difference of the Frank lead signal-averaged ECG in a
      population with significant coronary artery disease. Comparison with concurrent
      12-lead ECG morphology.
AB  - The 12-lead electrocardiogram (ECG) and a 100-beat signal-averaged Frank lead ECG
      (SAECG) at a sampling rate of 1,000 Hz and with 16-bit resolution were recorded
      from 52 women and 256 men with significant coronary artery disease presenting for
      coronary artery revascularization. The QRS portion of each Frank lead was
      digitally filtered in four bandwidths: 0-10, 10-60, 60-150, and 150-250 Hz. The
      root-mean-square (RMS) voltage of each filtered signal was calculated as an
      absolute value and normalized as a percentage of the sum of the four filters,
      creating 27 variables. Three groups were formed using the presenting 12-lead ECG:
      N-ECG, ST-ECG, and MI-ECG. Despite variation in 12-lead morphology, concordance
      was dominant in the RMS values of the SAECG in sex comparisons within and between
      groups. There was significant sex difference of the RMS values in 6 of the 15
      absolute RMS variables within the three groups. Women had no significant between
      group difference, and men had a significant between-group differences in five
      absolute values and one normalized RMS value. P was considered significant at <
      .05.

PMID- 8656120
TI  - Intra-QRS high-frequency ECG changes with ischemia. Is it possible to evaluate
      these changes using the signal-averaged Holter ECG in dogs?
AB  - The purpose of this experiment is to study the possibility of intra-QRS high
      frequency electrocardiographic (HFECG) changes for the evaluation of and recovery
      from myocardial ischemia in both the time-domain and spectral-turbulence analyses
      on the signal-averaged ECG using the Holter ECG monitoring (Holter SAECG) system.
      A balloon catheter was inserted into the left anterior descending coronary artery
      (LAD of 8 mongrel dogs and was maintained inflated for 2 hours to occlude the LAD
      and then was deflated to allow for reperfusion. The cardiac signal from the three
      orthogonal leads of the surface ECG (X, Y, and Z) was recorded and analyzed with
      a Del Mar Avionics (model 459, Irvine, CA) recorder and analyzer (model 563). The
      Holter SAECG was assessed before the LAD occlusion phase (control), during the
      coronary occlusion phase (ischemia), after the reperfusion phase (recovery). To
      evaluate intra-QRS ECG changes in the time-domain analysis, root-mean-square
      (RMS) voltage of the entire QRS in 40-250 HZ (40 RMS), 100-250 Hz (100 RMS), and
      150-250 Hz (150 RMS) were studied and the vector magnitude of the QRS was
      depicted. In the spectral-turbulence analysis and spectrocardiogram to study the
      discordance of the ECG wave front velocity by fast Fourier transformation
      analysis, the interslice correlation mean (IC mean) and interslice correlation
      standard deviation (IC SD), which were calculated as the mean and standard
      deviation of the Pearson correlation coefficient of each time slice with its
      neighbor, were investigated. In the time-domain analysis, the LAD occlusion by
      balloon catheter at ischemia produced a reduction in 40 RMS, 100 RMS, and 150
      RMS, while a restoration was seen at recovery in 40 RMS and 100 RMS. In the
      spectral-turbulence analysis, LAD occlusion at ischemia caused a decrease in IC
      mean and an increase in IC SD. The waveform of the vector magnitude and the
      spectrocardiogram seen at control showed changes with ischemia and was restored
      at recovery with the coronary reperfusion. It was thought possible to capture the
      intra-QRS HFECG changes that occur during myocardial ischemia and recovery from
      it in the time-domain analysis and spectral-turbulence analysis on the Holter
      SAECG system in spite of the limitation of this methodology. To evaluate
      myocardial ischemia and recovery, this method should be useful clinically.

PMID- 8656121
TI  - Analysis of high-frequency signal-averaged ECG measurements.
AB  - Analysis of high frequency (150-250 Hz) in the signal-averaged electrocardiogram
      (SAECG) is one of the emerging methods for detecting vessel patency in acute
      myocardial infarction following thrombolytic therapy and angioplasty. Root-mean
      square voltage (RMSV) of the filtered QRS has been used in earlier studies to
      detect reperfusion; however, previous analysis indicated that RMSV is sensitive
      to residual noise in the SAECG and errors in QRS delineation (onset/offset). A
      new measurement is proposed, high-frequency energy (HFQE), and the robustness of
      the RMSV and HFQE was evaluated for simulated errors in QRS delineation. In this
      study, two measures (RMSV and HFQE) were tested on 24 control subjects and 21
      patients undergoing thrombolytic therapy. Results indicate that unfiltered QRS
      duration is more stable than filtered QRS duration for the control subjects and
      patients and that HFQE had less fluctuation than RMSV in thrombolytic therapy
      patients. In the control group, HFQE was sensitive to the amplitude variation of
      the filtered SAECG. Therefore, another new measurement is proposed high-frequency
      integral of absolute value (HFAV), for reducing the sensitivity to amplitude
      changes in the filtered SAECG. This new feature was tested on control subjects
      and was found to be more stable than HFQE. In the thrombolitic therapy group,
      HFAV provided similar information as HFQE. These three measurements-RMSV, HFQE,
      and HFAV-provide a comprehensive analysis of the high-frequency SAECG for
      detecting vessel patency and reocclusion. Relative merits of these measures need
      to be evaluated on a larger database of patients undergoing thrombolysis and
      angioplasty for acute myocardial infarction.

PMID- 8656122
TI  - Personal reflections of the president on the 1994 ISCE meeting and progress
      report on the 1995 meeting.

PMID- 8656123
TI  - Threshold reduction with biphasic defibrillator waveforms. Role of charge
      balance.
AB  - Mechanism underlying improved defibrillation efficacy of biphasic waveforms at
      low shock intensities remain poorly understood. Recent studies suggest that
      biphasic waveforms produce a longer mean postshock response throughout the
      ventricle. This prolongs the cellular refractory period, blocks fibrillation wave
      fronts, and causes fibrillation to cease. Previous studies showed that
      hyperpolarizing monophasic waveforms, delivered during the refractory period, can
      shorten action potential duration (APD90), which would be deleterious for
      defibrillation. This study tested the hypothesis that a balanced-charge biphasic
      waveform produces a longer mean total mean APD than a comparable monophasic
      waveform by preventing this shortening in hyperpolarized regions as well as by
      prolonging APD in depolarized regions. To test this hypothesis, the authors
      examined transmembrane potential changes produced by hyperpolarizing and
      depolarizing monophasic and balanced-charge symmetrical biphasic waveforms using
      a computer model of the ventricular action potential. Shock intensities within
      the low-intensity "window," where biphasic waveforms defibrillate with higher
      efficacy than monophasic waveforms (1.5-3 times diastolic threshold), were used.
      Results show that biphasic S2 produced a significantly longer response both under
      hyperpolarizing and depolarizing conditions. The hyperpolarizing/depolarizing
      biphasic S2 produced a prolonged response with a well-defined plateau. Following
      the depolarizing/hyperpolarizing S2, APD90 did not shorten as with the
      hyperpolarizing monophasic S2. Rather, repolarization continued near the original
      S1 times course, but with slight prolongation of S1 APD90. These results suggest
      that biphasic waveforms enhance the prolonged refractory periods required for
      defibrillation throughout the heart, including regions exposed to both anodal and
      cathodal stimulation.

PMID- 8656124
TI  - In memoriam Jos Willems, MD, PhD (1939-1994).

PMID- 8656125
TI  - The P wave signal-averaged ECG.
AB  - The P wave signal-averaged electrocardiogram is designed to predict the
      development of atrial fibrillation. This review will discuss the methodology and
      summarize the published experience with the P wave signal-averaged
      electrocardiogram.

PMID- 8656126
TI  - Analysis of high-resolution ECG changes during percutaneous transluminal coronary
      angioplasty.
AB  - The authors have hypothesized that low-level, electrocardiographic changes may
      accompany transient ischemia induced by percutaneous transluminal coronary
      angioplasty. Altered repolarization may manifest as subclinical changes in ST-T
      morphology. Changes in depolarization may manifest as low-amplitude notches and
      slurs, a phenomenon the authors term abnormal intra-QRS potentials. The initial
      aim of this study was to characterize changes in high-resolution
      electrocardiograph signals that might be linked to ischemic involvement of the
      ventricular myocardium.

PMID- 8656127
TI  - Karhunen-Loeve transform as a tool to analyze the ST-segment. Comparison with QT
      interval.
AB  - The spatial and temporal courses of ventricular repolarization are quite
      sensitive to the biochemical and biophysiologic environment of the myocardial
      cells, and are therefore often an early marker of heart disease, particularly of
      ischemia. The detailed morphology of the surface electrocardiogram contains
      considerable information about the repolarization process. The ST-segment changes
      with ischemia, injury, and drugs. The QT interval is affected by drugs, heart
      rate, and autonomic tone, and in some situations may identify individuals at high
      risk for arrhythmias and sudden death. Variability in the shape, including
      duration, of the ST-T waves reflects autonomic nervous system activity and may
      identify high-risk patients. Automated methods for quantitatively characterizing
      ST-T complexes are important in studying long-term electrocardiographic records.
      Two computer-based measurement procedures for characterizing the repolarization
      period were comparatively analyzed: Karhunen-Loeve (KL) transform representation
      of the ST-T shape and measurement of beat-to beat durations of repolarization (QT
      intervals). The results of KL transform representation and time-domain QT
      measurement algorithms for studying the repolarization period of the
      electrocardiogram on the European ST-T database are presented. It was found that
      about 20% of the records present a quasiperiodic KL pattern of ischemic ST-T
      activity and another 20% exhibit repetitive but not clearly periodic patterns of
      ischemic ST-T changes. From these ischemic records, 50% showed QT variations in
      at least one lead associated with the ischemic episodes.

PMID- 8656128
TI  - Effect of noise in maximum likelihood analysis of late potentials.

PMID- 8656129
TI  - Improved time-frequency filtering of signal-averaged ECGs.
AB  - A recently proposed time-frequency filtering technique has shown promising
      results for the enhancement of signal-averaged electrocardiograms. This method
      weights the short-time Fourier transform of the ensemble-averaged signal,
      analogous to the spectral domain Wiener filtering of stationary signals. In
      effect, it is a self-designing, time-varying Wiener filter applied to the high
      resolution electrocardiogram (HRECG). In this study, the authors empirically show
      that the performance of the proposed technique is about 2-3 dB lower over the
      critical late-potential portion of the HRECG than the optimal fixed-window, time
      frequency filter based on ideal a priori knowledge of statistics. Although this
      ideal knowledge and performance is unattainable in practice, these results
      suggest that there remains potential for modest improvement. To narrow this gap
      in performance, improvements based on alternative structures for the time
      frequency filter, including time-varying short-time Fourier transform windows,
      are proposed. Simulation results show that an improved fixed-window technique can
      potentially yield an improvement of about 1-1.5 dB. By using properly chosen time
      varying windows, the performance could potentially be improved of about 1-1.5 dB.
      By using properly chosen time-varying windows, the performance could potentially
      be improved even further. Thus, the improved techniques could produce an HRECG
      using fewer averages than the existing method, or that could tolerate a lower
      initial signal-to-noise ratio.

PMID- 8656131
TI  - Nonlinear forecasting and the dynamics of cardiac rhythm.
AB  - Since the initial development of the electrocardiogram, cardiologists have made
      dramatic advances in the description and understanding of cardiac arrhythmias.
      Despite these successes, the analysis of cardiac rhythm has remained largely
      descriptive. Recently, the principles of nonlinear dynamics, or chaos theory,
      have been applied to the quantitative analysis of cardiac rhythm in a variety of
      diverse situations. In chaos theory, three types of signals can be defined:
      periodic signals, which repeat themselves over some finite time interval, chaotic
      signals, which, while deterministic, demonstrate complex behavior and do not
      repeat themselves, and random signals, which are unpredictable and
      nondeterministic. The technique of nonlinear forecasting defines trajectories in
      a suitably defined phase space and uses the future evolution of trajectories that
      are close to each other over short distances to make predictions for times
      further into the future. The ability to reliably predict the future evolution of
      the trajectories derived from any signal is an important characteristic of the
      underlying dynamics of the signal and can therefore used to determine those
      dynamics. The foundation of nonlinear forecasting is reviewed, and an algorithm
      is described that can be used to determine the underlying dynamics of a signal
      and has been applied to the analysis of R-R interval data.

PMID- 8656130
TI  - Fractal mechanisms and heart rate dynamics. Long-range correlations and their
      breakdown with disease.
AB  - Under healthy conditions, the normal cardiac (sinus) interbeat interval
      fluctuates in a complex manner. Quantitative analysis using techniques adapted
      from statistical physics reveals the presence of long-range power-law
      correlations extending over thousands of heartbeats. This scale-invariant
      (fractal) behavior suggests that the regulatory system generating these
      fluctuations is operating far from equilibrium. In contrast, it is found that for
      subjects at high risk of sudden death (e.g., congestive heart failure patients),
      these long-range correlations break down. Application of fractal scaling analysis
      and related techniques provides new approaches to assessing cardiac risk and
      forecasting sudden cardiac death, as well as motivating development of novel
      physiologic models of systems that appear to be heterodynamic rather than
      homeostatic.

PMID- 8656132
TI  - Animated images of cardiac membrane voltage during defibrillation.
AB  - Optical recording using voltage-sensitive dyes has been used to investigate the
      mechanisms of defibrillation because it (1) is immune to the artifacts produced
      by high-voltage shocks, (2) provides the time course of the membrane action
      potential, and (3) can be used to make simultaneous recordings at many sites. The
      authors used the laser scanning technique to optically record action potentials
      from 100 sites with 1-ms resolution on the surface of the isolated, perfused
      rabbit heart during defibrillation. The data were typically analyzed by
      constructing maps of impulse propagation and examining individual recordings from
      sites of interest. Described here is a new analysis method that creates
      millisecond-by-millisecond images of the spatial distribution of membrane
      potentials. The experimental protocol applied a test shock to the fibrillating
      heart, followed by a rescue shock and a paced beat. Optical recordings were
      calibrated to yield membrane voltage as a percentage of the resting and overshoot
      levels of the postrescue stimulated action potential. The positions of the
      recording sites and the membrane voltage levels for all 100 sites during a single
      1-ms interval were used to interpolate membrane voltage levels at points within a
      128 x 128 pixel frame using the biharmonic interpolation method. The level of
      membrane potential was encoded by pixel color and surface elevation. Sequential
      frames were viewed as a face-on two dimensional or as a three-dimensional
      perspective of the colored surface. Animation of membrane voltage distributions
      enabled the visualization of the interaction between the shock-induced
      electrophysiologic response and the propagation of electrical activity preceding
      and following a defibrillation shock. Successful defibrillation shocks
      synchronized repolarization across the surface of the heart following the shock.

PMID- 8656133
TI  - Fractal dimension predicts arrhythmia recurrence in patients being treated for
      life-threatening ventricular arrhythmias. ESVEM Investigators.

PMID- 8656134
TI  - Numeric processing of Lorenz plots of R-R intervals from long-term ECGs.
      Comparison with time-domain measures of heart rate variability for risk
      stratification after myocardial infarction.
AB  - The so-called "Lorenz plots" are scatterplots that show the R-R interval as a
      function of the preceding R-R intervals. Repeatedly, it has been proposed that
      these plots might be used for visualizing the variability of the heart rate and
      that the assessment of heart rate variability (HRV) from these plots might be
      superior to conventional measures of HRV. However, a precise numeric evaluation
      of the images of Lorenz plots have never been suggested. To classify the images
      of Lorenz plots, a computer package that measures their density was developed.
      For each rectangular area of the plot, the relative number of R1/R2 samples in
      that area is established and a function is created that assigns the maximum
      relative number of samples (i.e., the maximum density) to each size of an area of
      the plot. Plots that are very compact result in a sharply falling density
      function, while plots that are more diffuse lead to a flat density function. The
      distinction between such types of density function may be expressed as a
      logarithmic integral of the density function to express the "compactness" of the
      plot numerically. As the computational demands of this approach are intensive, an
      approximate method that restricts the measurement of the density to the area
      around the peak of the plot was also developed. The results of this approximate
      method correlate strongly with the full results (r = .98), and approximate
      measurement of one plot requires less than 1 minute of computer time. The
      approximate method has been applied to a set of 24-hour Holter records obtained
      from 637 survivors of acute myocardial infarction. For each record, the SDNN and
      SDANN values were also calculated as conventional measures of HRV. Both the
      density of the Lorenz plots and the conventional measures of HRV were used to
      investigate the differences among 48 patients who suffered an arrhythmic event
      (sudden death or sustained symptomatic ventricular tachycardia) during a 2-year
      follow-up period and the remaining 589 patients without arrhythmic postinfarction
      complications. At a sensitivity of 30%, the Lorenz plot density distinguished the
      patients with events with a positive predictive accuracy of 58%, while the SDNN
      and SDANN led to a positive predictive accuracy of only 23 and 18%, respectively.
      Thus, a detailed analysis of Lorenz plots is feasible and more clinically useful
      than the conventional measures of HRV.

PMID- 8656135
TI  - Improved analysis of heart rate variability by methods of nonlinear dynamics.
AB  - The traditional analysis of heart rate variability (HRV) in the time and
      frequency domains seems to be an independent predictive marker for sudden cardiac
      death. Because the usual applied methods of HRV analysis describe only linear or
      strong periodic phenomena, the authors have developed new methods of HRV analysis
      based on nonlinear dynamics. In that way, parameters are extracted that quantify
      more complex processes and their complicated relationships. These methods are
      symbolic dynamics that describes the beat-to-beat dynamics and renormalized
      entropy that compares the complexity of power spectra on a normalized energy
      level. In an initial investigation, the HRV of 35 healthy subjects and 39 cardiac
      patients have been analyzed. Using discriminant functions, the authors found an
      optimal (100%) differentiation between the group of healthy subjects (even using
      only an age-matched subgroup of 12 subjects) and that of patients after
      myocardial infarction with a high electrical risk (Lown 4b). Applying this
      discriminant function to a group of patients with low electrical risk, four
      patients show the same behavior indicative of a high risk score, which might be a
      sign for a hidden high risk, two patients show healthy behavior, and the
      remaining patients show a separate pattern. The use of new methods of nonlinear
      dynamics in combination with parameters of the time and frequency domains in HRV
      offers possibilities for improved classification of HRV behavior. It is suggested
      that this could lead to a more detailed classification of individual high risk.

PMID- 8656136
TI  - Estimating ECG distributions from small numbers of leads.
AB  - The utility of body surface potential mapping to improve interpretation of
      electrocardiographic information lies in the presentation of thoracic surface
      distributions to characterize underlying electrophysiology less ambiguously than
      that afforded by conventional electrocardiography. Localized cardiac disease or
      abnormal electrophysiology presents itself electrocardiographically on the body
      surface in a manner in which pattern plays an important role for identifying or
      characterizing these abnormalities. Thus, in myocardial infarction, transient
      myocardial ischemia, Wolff-Parkinson-White syndrome, or ventricular ectopy,
      observation of electrocardiographic potential patterns, their extrema, and their
      magnitudes permits localization and quantization of the abnormal activity.
      Conventional electrocardiography assesses pattern information incompletely and
      does not use information of distribution extrema locations or magnitudes. Thus,
      increases or decreases in the magnitudes of electrocardiographic features (ST
      segment potential displacement, amplitude, or morphology of Q, R, S, or T waves)
      associated with changes in cardiac sources (ischemia, infarction, conduction
      abnormalities, etc.) as measured from fixed leads have a high likelihood of being
      misinterpreted if the distribution itself is changing. In this study, the authors
      demonstrate the utility of estimating distributions from small numbers of
      optimally selected leads, including conventional leads, to reduce uncertainty in
      the interpretation of electrocardiographic information. This issue is highly
      relevant when thresholds are used to detect significance of potential levels
      (exercise testing, detection of myocardial infarction, and continuous monitoring
      to assess ST-segment changes). Significance of this work lies in improved
      detection and characterization of abnormal electrophysiology using conventional
      or enhanced leadsets and methods to estimate thoracic potential distributions.

PMID- 8656137
TI  - Errors in ECG parameter estimation from standard leadsets.
AB  - With the availability of low-cost, high-speed computers with (relatively) vast
      amounts of storage has come something of an explosion in the application of
      "quantitative electrocardiography." A search of the Medline medical reference
      database on the subject string "quantitative AND electrocardiography" reveals no
      less than 509 citations, suggesting that the term has gained widespread
      acceptance. However, while quantitative techniques are, in general, to be
      welcomed to clinical medicine and research, their use as a diagnostic or patient
      monitoring tool begs a careful examination of just what is being counted and how
      it is being linked to physiology. In this study, the authors focus on the use of
      standard electrocardiographic lead systems as the basis for quantitative patient
      evaluation and attempt to highlight some limitations in the ability to extract
      meaningful parameters with such a limited sampling of human thoracic electrical
      activity.

PMID- 8656138
TI  - Platelet-activating factor: antagonists, terminators, molecular mimics, and
      microbial opportunism.

PMID- 8656139
TI  - Primary Sjogren's syndrome: the challenge for classification of disease
      manifestations.
AB  - A new model for classifying the clinical disease manifestations of primary
      Sjogren's syndrome is introduced. Three "exocrine' and four "nonexocrine'
      subgroups of disease manifestations are defined. Accordingly, "surface exocrine
      disease' includes the diagnostic features from eyes, mouth, and the
      manifestations from the upper airways, skin and genital tract. Involvement of the
      excretory parenchyma of the lungs, hepatobiliary system, pancreas,
      gastrointestinal tract and kidneys is designated "internal organ exocrine
      disease'. We suggest "monoclonal B lymphocyte disease' to be an exocrine disease
      manifestation because it originates mostly from the immunoinflammatory foci of
      the autoimmune exocrinopathy. The nonexocrine manifestations are subgrouped into
      "inflammatory vascular disease'. "noninflammatory vascular disease', "mediator
      induced disease' and "autoimmune endocrine disease'.

PMID- 8656140
TI  - A new model for classification of disease manifestations in primary Sjogren's
      syndrome: evaluation in a retrospective long-term study.
AB  - OBJECTIVES: The clinical features of 80 patients with primary Sjogren's syndrome
      (PSS) were revised in order to evaluate the descriptive and analytical facilities
      of a newly proposed model for classification of the exocrine and nonexocrine
      disease manifestations in PSS. DESIGN: Retrospective, long-term (median 7.5 years
      follow-up) observational, clinical study. SETTING: Patients were recruited from
      our Department, which is a tertiary referral centre for PSS patients. SUBJECTS:
      Eighty patients fulfilling the Copenhagen criteria for keratoconjunctivitis sicca
      and/or xerostomia and followed between 1972 and 1991 were studied. RESULTS: All
      patients had 'surface exocrine disease' and in 31% this was the only disease
      manifestation. 'Internal organ exocrine disease' was found in 25% of the
      patients, whilst 2.5% developed 'monoclonal B lymphocyte disease' (non-Hodgkin's
      lymphoma). 28% displayed 'inflammatory vascular disease', 25% 'noninflammatory
      vascular disease', 41% "mediator-induced disease' and 2.5% 'autoimmune endocrine
      disease' (thyroiditis). In patients with 'internal organ exocrine disease' the
      frequencies of "mediator-induced disease' (70%; P < 0.01) and 'inflammatory
      vascular disease, (50%; P < 0.03) were significantly higher than expected by
      chance. The level of immunoinflammatory activity (assessed by plasma IgG, serum
      ANA and focus scoring of minor labial salivary gland biopsies) correlated with
      the extent of clinical disease as assessed by the model. CONCLUSIONS: We conclude
      that this theoretically based model for classification of disease manifestations
      in PSS contains descriptive and analytic powers which may assist the clinical
      handling of these patients.

PMID- 8656141
TI  - Urolithiasis and distal renal tubular acidosis preceding primary Sjogren's
      syndrome: a retrospective study 5-53 years after the presentation of
      urolithiasis.
AB  - OBJECTIVES: Distal renal tubular acidosis (dRTA) can be associated with
      autoimmune diseases such as primary Sjogren's syndrome (SS). Our objective was to
      study SS-associated symptoms, autoantibodies and renal histopathology in patients
      with urolithiasis and dRTA. SETTING: The patients were from the Departments of
      Nephrology and Rheumatology. University Hospital of Linkoping, which is a
      tertiary referral hospital, as well as a secondary referral centre for the
      immediate area around the city of Linkoping. SUBJECTS: Ten female patients with
      dRTA, who presented with urolithiasis and not with subjective sicca symptoms,
      were from the Department of Nephrology, University Hospital, Linkoping.
      Autoantibodies were detected in eight of these patients, and they were studied
      with respect to clinical and laboratory evidence of SS (urolithiasis group).
      Fifteen women with SS, who presented with sicca symptoms and not with
      urolithiasis or dRTA, served as the reference group. RESULTS: In the urolithiasis
      group, all of the eight patients had anti-SS-A antibodies, and SS (or possible
      SS) developed in seven of the eight patients 1-48 (mean 15) years after the onset
      of urolithiasis. Histological features of tubulointerstitial nephritis were found
      in four of five biopsied patients in the urolithiasis group, and in two of four
      patients (with dRTA) in the reference group. CONCLUSIONS: Urolithiasis and dRTA
      can precede subjective sicca symptoms, and patients with dRTA may have SS in the
      absence of subjective sicca symptoms. Anti-SS-A antibodies are common in patients
      with urolithiasis and dRTA. Therefore, we hypothesize the possibility of a
      Sjogren-related renal disease in these patients.

PMID- 8656142
TI  - Cardiovascular risk groups and mortality in an urban swedish male population: the
      Malmo Preventive Project.
AB  - OBJECTIVES: To describe the size, overlap and mortality of four cardiovascular
      risk groups, in order to give a scientific background for the prevention of
      cardiovascular disease in a representative urban population. SETTING: Section of
      Preventive Medicine, Department of Medicine, Malmo University Hospital, Malmo,
      Sweden. SUBJECTS: Between 1974 and 1984 22444 men born between 1949 and 1921,
      constituting 75% of the total male population in these age groups, took part in a
      comprehensive screening examination aimed at detecting risk factors for
      cardiovascular disease. INTERVENTIONS: Those at high-risk of developing
      cardiovascular disease were referred to their general practitioner or to special
      clinics for hypertension, hyperlipidaemia and diabetes. The follow-up, which
      lasted until the end of 1991, averaged 12.2 years. MAIN OUTCOME MEASURES: Total
      death (n = 1450) and death from ischaemic heart disease (IHD) (n = 471). RESULTS:
      Hypertension was found in 13%, hypercholesterolaemia in 19% and diabetes mellitus
      in 2.6% of the subjects; 49% of the subjects smoked. Multiple risk factors were
      found in over 17% of the total cohort. Despite the intervention, all-cause
      mortality during follow-up was increased three-fold in smokers and in men with
      hypercholesterolaemia, four-fold in hypertensive men and five-fold in men with
      diabetes, compared to men with no risk factors. The vast majority of deaths (81%)
      occurred in men who smoked, had hypertension or had high serum cholesterol.
      Ischaemic heart disease (IHD) was increased five-fold in smokers, seven-fold in
      men with hypercholesterolaemia, nine-fold in hypertensive men and 12-fold in men
      with diabetes. Again, the vast majority of IHD deaths (86%) occurred in the first
      three categories. Combinations of risk factors substantially increased total
      mortality as well as IHD mortality. CONCLUSIONS: The large proportion (64%) of
      the population with risk factors for cardiovascular disease and the substantially
      (5-12-fold) increased IHD mortality in those risk groups, calls for actions aimed
      at preventing premature IHD deaths. Such action should include measures directed
      towards the whole population and comprehensive treatment programmes for high-risk
      individuals, including intervention to stop smoking. The substantial overlap
      between risk factors calls for one high-risk clinic caring for all risk groups.

PMID- 8656143
TI  - Fibrinogen, coronary heart disease and mortality from all causes in smokers and
      nonsmokers. The study of men born in 1933.
AB  - OBJECTIVES: To analyse the relation between fibrinogen concentration and
      incidence of coronary heart disease and mortality from all causes. A secondary
      aim was to investigate whether the effect of fibrinogen, as in previous cross
      sectional analyses from this population, was restricted to nonsmokers. DESIGN:
      Prospective population study. SETTING: City of Goteborg, Sweden. SUBJECTS: A
      total of 664 men from a population sample of 1016 men aged 50 in 1983, without
      prior myocardial infarction. MAIN OUTCOME MEASURES: Development of coronary heart
      disease (myocardial infarction, coronary death or, in men with angina,
      revascularization, or scintigraphic evidence of coronary disease) and death from
      all causes, in relation to fibrinogen concentration and smoking status at
      baseline, during 9 years' follow-up. RESULTS: Rates of coronary heart disease
      during follow-up in the lowest, middle and highest third of the fibrinogen
      distribution were 4.6, 6.4 and 10.3%, respectively, but this did not remain
      significant after controlling for smoking and other risk factors (adjusted odds
      ratio [OR] for the highest, compared to the lowest third 1.5 [0.7-3.4]).
      Percentages of men who died from any cause were 3.2, 5.9 and 10.7 in the lowest,
      middle and highest thirds of fibrinogen, respectively. After adjustment for
      smoking and other risk factors, this difference remained significant (relative
      risk 2.6 [1.2-5.9]). In men who were smokers at baseline, fibrinogen was not
      significantly related to coronary heart disease or mortality. Men who did not
      smoke in the lowest, middle, and highest third of the fibrinogen distribution had
      rates of coronary heart disease of 1.8, 3.6 and 10.3%, respectively, and of
      deaths from all causes of 1.8, 2.9 and 8.4%, respectively. The adjusted OR
      remained significant at 5.4 (1.4-20.0) for coronary heart disease, as did the
      adjusted relative risk for mortality at 3.8 (1.01-14.4). CONCLUSION: Plasma
      fibrinogen is an independent predictor of premature death, and also of coronary
      heart disease, in middle-aged men and in nonsmokers. A high fibrinogen
      concentration, particularly in a nonsmoker, deserves attention.

PMID- 8656144
TI  - Thrombocytopenia induced by noncytotoxic drugs in Denmark 1968-91.
AB  - OBJECTIVES: To analyse the distribution of noncytotoxic drugs reported as cause
      of thrombocytopenia during a 24-year period, and to draw attention to the most
      commonly involved drugs in modern clinical practice. DESIGN/SETTING:
      Retrospective study of spontaneous case reports from the Danish reporting system
      on adverse drug reactions. SUBJECTS: A total of 309 critically reviewed cases of
      drug-induced thrombocytopenia reported during the period from 1968 to the end of
      1991. RESULTS: Sodiumaurothiomalate and the combination sulfamethoxazole with
      trimethoprim were the most commonly reported single drugs, and nonsteroid anti
      inflammatory drugs were the most frequently reported category of drugs. A
      pronounced shift in the spectrum of causal drugs was observed due to the
      introduction of new drugs and alterations in drug consumption. At present,
      valproic acid and measlesmumps-rubella vaccine are most numerously reported. The
      still-growing list of thrombocytopenia-inducing agents contained 110 different
      drugs. At present, 20% of reported cases concern drugs not previously registered
      as causing thrombocytopenia in Denmark. Twenty-five per cent of all cases were
      caused by drugs which appeared only sporadically in the material. CONCLUSIONS:
      The spectrum of drugs reported as causing drug-induced thrombocytopenia is
      broadening and changing progressively, reflecting changes in drug consumption.
      The most frequently reported drugs at present are valproic acid and measlesmumps
      rubella vaccine.

PMID- 8656145
TI  - Thyroid antibodies in northern Norway: prevalence, persistence and relevance.
AB  - OBJECTIVES: To investigate the prevalence and persistence of thyroid
      autoantibodies in a population sample and to assess the development of
      biochemical hypothyroidism (defined as an elevated serum thyrotropin [TSH]
      concentration) in relation to their presence. DESIGN AND SETTING: A cross
      sectional and longitudinal study based on the Tromso Study in 1979-80 and 1986
      87. SUBJECTS AND MAIN OUTCOME MEASURES: From 2551 random participants in 1979-80
      aged 34 +/- 8.4 (mean +/- SD) years, sera were available in 2513 and 2504 persons
      for determination by passive haemagglutination of the antibody to thyroid
      microsomal antigen (anti-Tm) and of the antibody to thyroglobulin (anti-Tg).
      Total thyroxine (TT4) and TSH were measured in 114 of 176 antibody-positive
      subjects and in 101 controls. After 7 years, anti-Tm and anti-Tg were remeasured
      in 1939 and 1931 subjects, and TT4 and TSH in 92 of the initially antibody
      positive subjects and in 69 controls. RESULTS: Anti-Tm occurred more frequently
      than anti-Tg (in 6.1 vs. 2.8%; P < 0.001). Anti-Tm (P < 0.001) and anti-Tg (P =
      0.027) were both more common in women than in men. The prevalence of anti-Tm (P =
      0.025), but not of anti-Tg, increased with age. Changes in titre levels after 7
      years were mostly small or moderate. Both in women (P = 0.005) and in men (P <
      0.001) the TSH concentrations increased with increasing levels of anti-Tm,
      whereas in men, the concentrations also increased with increasing anti-Tg levels
      (P < 0.001). Biochemical hypothyroidism developed with a 2.7% yearly incidence
      only in antibody-positive subjects, all except one of whom had anti-Tm.
      CONCLUSIONS: The prevalences of thyroid antibodies were comparable to those found
      in similar studies in other areas. Their presence was associated with the
      development of biochemical hypothyroidism.

PMID- 8656146
TI  - Comparison of standardized initial doses of two antithyroid drugs in the
      treatment of Graves' disease.
AB  - OBJECTIVES: To obtain a simple standard regimen, suitable for general practice,
      and based upon the addition of antithyroid drug plus thyroxine for attaining
      euthyroidism in patients with Graves' disease. DESIGN: Prospective, randomized
      trial of patients with Graves' disease followed for 3 months after the initiation
      of therapy with an antithyroid drug and combined with the later addition of
      triiodothyronine to keep the patient euthyroid. The patients were randomized,
      according to birth date, between methimazole and propylthiouracil. Three dose
      schemes were tested for each antithyroid drug. SETTING: The study was performed
      at the thyroid outpatient units of two general hospitals, with the patients
      having been referred from primary care. SUBJECTS: Ninety-four patients with
      Graves' disease who were suitable for treatment with antithyroid drugs.
      INTERVENTIONS: The patients were allocated into six groups. Three groups received
      methimazole (10 mg every 6th, 8th or 12th h) and three received propylthiouracil
      (100 mg every 6th, 8th or 12th h). Twenty micrograms of triiodothyronine was
      added when the patients were euthyroid to avoid hypothyroidism. MAIN OUTCOME
      MEASURES: The lowest serum free thyroxine level within 3 months of the initiation
      of the antithyroid treatment. RESULTS: Fourteen per cent of the patients on
      methimazole 10 mg every 12th h and 29% on propylthiouracil 100 mg every 12th h
      did not achieve euthyroidism within the 3-month observation period. All but one
      patient on methimazole 10 mg every 8th h or propylthiouracil 100 mg every 8th h
      reduced the free serum thyroxine levels to the normal or hypothyroid range within
      the observation period. All of the patients on methimazole 10 mg every 6th h and
      56% on propylthiouracil 100 mg every 6th h reduced the serum T4 values into the
      hypothyroid range within the period. CONCLUSION: A standard regimen, based upon
      the addition of methimazole 10 mg every 8th or 6th h or propylthiouracil 100 mg
      every 8th or 6th h and followed by the addition of thyroxine or triiodothyronine
      when euthyroid to avoid hypothyroidism, seems to be suitable for attaining
      euthyroidism within 3 months in patients with Graves' disease. A dose scheme
      based on methimazole 10 mg every 12th h or propylthiouracil 100 mg every 12th h
      were found to be unsuitable due to an unacceptably high incidence of failure to
      attain euthyroidism or hypothyroidism within 3 months.

PMID- 8656147
TI  - Neurofibromatosis complicated with XXX syndrome and renovascular hypertension.
AB  - A 25-year-old woman with neurofibromatosis was admitted to our hospital for
      evaluation of hypertension. When she was 6 years old, she was diagnosed as having
      neurofibromatosis and XXX syndrome because of multiple cafe-au-lait spots,
      neurofibromas of the skin and mental retardation. Chromosome analysis revealed
      that her karyotype was 46, XX/47, XXX. Renal arteriography disclosed aneurysmal
      change and stenosis of the right renal artery. After right-side nephrectomy and
      aneurysmectomy, the kidney was autotransplanted in the left iliac fossa. Surgical
      procedure resulted in marked amelioration of the hypertension without medical
      treatment. Thus, aortorenal bypass and renal autotransplantation have emerged as
      the preferred revascularization operations. This is the first report of a
      chromosomal linkage between neurofibromatosis which is thought to be an autosomal
      dominant disease and the XXX syndrome.

PMID- 8656148
TI  - Predialysis calcitriol administration: effects on pre- and post-transplant renal
      osteodystrophy.
AB  - Twins with parallel loss of kidney function and moderate hyperparathyroid bone
      disease were participants in a double-blind study where twin A was given placebo
      and twin B calcitriol. After 8 months. A's bone disease had not improved, while
      B's bone had normalized. Thereafter, both received calcitriol until kidney
      transplantation 11 months later, when both had normal bone structure. Two years
      after transplantation, both twins had hyperparathyroid bone disease, but A had
      more pronounced changes. This report illustrates our findings in larger series:
      When started early in the course of renal failure, calcitriol can reverse pre
      transplant hyperparathyroid bone disease and also influence post-transplant bone
      disease.

PMID- 8656149
TI  - Cognitive sequence knowledge: what is learned?
AB  - In 4 experiments, participants performed running-arithmetic tasks. These tasks
      involved a sequential ordering of individual operations and a structure of
      subgoals that defined how calculations fit together in purpose. Consistent
      transitions between adjacent steps facilitated performance only when subgoal
      structures were relatively simple. When subgoal structures were more complex,
      consistent mapping of operations to serial locations produced a slight benefit.
      Consistency of subgoal structure produced a substantial benefit in both speed and
      accuracy, and some knowledge of subgoal structure integrated with knowledge of
      the sequence of operations. Apparently, a task's subgoal structure imposes
      demands that either facilitate or obscure benefits of sequence consistencies. The
      benefits are attributed to increased efficiency in using working memory.

PMID- 8656150
TI  - Effects of color and pattern on implicit and explicit picture memory.
AB  - The degree to which repetition priming is perceptually specific is informative
      about the mechanisms of implicit memory as well as of perceptual processing. In 2
      sets of experiments with pictures as stimuli, we tested the effects of color and
      pattern manipulations between study and test on implicit memory (i.e., naming
      facilitation) and explicit memory (i.e., 2 forms of recognition). These
      manipulations did not affect priming. However, participants were able to
      explicitly detect stimulus changes at above-chance levels. Changes in color also
      produced small decrements in participants' ability to judge that repeated stimuli
      were old on a recognition test. Experiment 2 showed diminished priming with
      changes in the stimulus exemplar (i.e., a different picture of the same named
      object) from study to test, which demonstrated that the picture-naming paradigm
      is sensitive to changes in physical attributes. The results suggest that physical
      attributes that are not essential to the formation of a shape representation do
      not influence repetition priming in a basic identification paradigm. Suggestions
      for how priming may be mediated are discussed.

PMID- 8656151
TI  - A syntactic complexity effect with visual patterns: evidence for the syntactic
      nature of the memory representation.
AB  - In a series of 3 experiments, participants learned visual patterns that contained
      the same number of visual features but varied in the complexity of the
      interrelations among the features. The results indicate a large and orderly
      effect of the pattern's syntactic complexity on recognition speed. Evidence is
      provided that this effect was not due to physical characteristics, target-foil
      similarity, speed-accuracy trade-off, or level of pattern learning. A multiple
      encoding explanation of the effect is described. According to this framework,
      there is an initial, automatically generated encoding of the pattern as a short
      term pictorial representation that becomes the basis for the construction of a
      second syntactic-propositional encoding. In this model, the participant's "sense
      of familiarity" for a particular stimulus is associated only with the syntactic
      propositional encoding.

PMID- 8656152
TI  - No enemies in the neighborhood: absence of inhibitory neighborhood effects in
      lexical decision and semantic categorization.
AB  - The effect of neighborhood density on visual word recognition was found to be
      facilitatory for words but inhibitory for nonwords in 3 lexical-decision
      experiments. However, the facilitation virtually disappeared when the task was
      changed to semantic categorization (animal vs. nonanimal), despite the presence
      of a strong frequency effect. None of these experiments showed a consistent
      inhibitory effect of a higher frequency neighbor. The absence of inhibitory
      effects suggests that competition does not play a key role in visual word
      recognition. The data also suggest that the neighborhood density effect is not an
      access effect but is a task-dependent effect instead.

PMID- 8656153
TI  - Reliability of prosodic cues for resolving syntactic ambiguity.
AB  - Although previous research has shown that listeners can use prosody to resolve
      syntactic ambiguities in spoken sentences, it is not clear whether naive,
      untrained speakers in experimental situations ordinarily produce the prosodic
      cues necessary for disambiguating such sentences. In a series of experiments, the
      authors found that neither professional nor untrained speakers consistently
      produced such prosodic cues when simply reading ambiguous sentences in a
      disambiguating discourse context. Speakers who were aware of the ambiguities and
      were told to intentionally pronounce the sentences with one meaning of the other,
      however, did produce sufficient prosodic cues for listeners to identify the
      intended meanings.

PMID- 8656154
TI  - Category-based predictions: influence of uncertainty and feature associations.
AB  - Four experiments examined how people make inductive inferences using categories.
      Subjects read stories in which 2 categories were mentioned as possible identities
      of an object. The less likely category was varied to determine if people were
      using it, as well as the most likely category, in making predictions about the
      object. Experiment 1 showed that even when categorization uncertainty was
      emphasized, subjects used only 1 category as the basis for their prediction.
      Experiments 2-4 examined whether people would use multiple categories for making
      predictions when the feature to be predicted was associated to the less likely
      category. Multiple categories were used in this case, but only in limited
      circumstances; furthermore, using multiple categories in 1 prediction did not
      cause subjects to use them for subsequent predictions. The results increase the
      understanding of how categories are used in inductive inference.

PMID- 8656155
TI  - Structural alignment in induction and similarity.
AB  - According to a structural alignment view, representational commonalities
      contribute to the perception of similarity, whereas nonshared attributes related
      to commonalities are candidate inferences in induction. This view was tested in 5
      experiments. Novel animal pairs varying in the number of attributes and relations
      they shared were used to assess the relationship between induction and
      similarity. In Experiments 1 and 2, the number of shared attributes and the
      presence of 2 kinds of causal relations between attributes varied. Shared
      attributes increased both similarity and inductive strength judgments. Shared
      causal relations, possessed by both animals, influenced perceived similarity, but
      binding causal relations, which connected a shared attribute to a candidate
      inference in the induction task, were important for inductive strength. In
      Experiments 3-5, these results were extended through use of a noncausal relation
      and familiar animal categories.

PMID- 8656156
TI  - Temporal discounting and utility for health and money.
AB  - In 3 experiments, choices for hypothetical amounts of future health and money
      showed that, contrary to normative discounted utility theory, the temporal
      discount rate, or annual percentage increase in value needed to offset a delay,
      differed for the 2 domains. Domain independence, defined as the low correlation
      between health and money discount rates relative to the consistency within each
      domain, was not due to different utility functions for health and money.
      Consistent with other research, these results suggest that decision domain
      affects the cognitive processes used. Despite this domain difference, there were
      some similarities between the 2 domains. Both health and money decisions revealed
      that discount rates were larger for short delays, small magnitudes, and gains as
      compared with losses.

PMID- 8656158
TI  - Marilyn.

PMID- 8656157
TI  - "Remembering" words not presented in lists: relevance to the current
      recovered/false memory controversy.
AB  - H.L. Roediger and K.B. McDermott (1995) found that when participants studied a
      list of words with a common but not presented associate, participants frequently
      falsely reported remembering the never presented associated word as part of the
      list. Roediger and McDermott suggest that this finding is generalizable to the
      current controversy surrounding contested memories of child abuse. The present
      authors urge caution in making such a generalization, arguing that there are
      critical differences between Roediger and McDermott's findings and contested
      memories of abuse.

PMID- 8656159
TI  - Risk assessment after acute upper GI hemorrhage.

PMID- 8656160
TI  - Uncertain value of electronic fetal monitoring.

PMID- 8656161
TI  - Validation of decision rules for radiography in knee injuries.

PMID- 8656163
TI  - Home treatment of deep venous thrombosis.

PMID- 8656162
TI  - Treating depression in alcoholics.

PMID- 8656164
TI  - Water precautions in children with tympanostomy tubes.

PMID- 8656165
TI  - Treatment of Helicobacter pylori infection.

PMID- 8656166
TI  - Diet and the progression of renal disease.

PMID- 8656167
TI  - Family involvement in routine health care: a survey of patients' behaviors and
      preferences.
AB  - BACKGROUND: The purpose of this study was to assess the behavior and preferences
      of patients regarding family involvement in their routine health care visits.
      METHODS: A self-administered questionnaire was given to a convenience sample of
      patients visiting a family medicine center for an appointment. RESULTS: Thirty
      nine percent of patients came to the physician's office with a family member or
      friend. Married patients and those with higher emotional involvement scores were
      significantly more likely to come to the office with someone. Two thirds of
      accompanied patients reported that this person came into the examination room
      with them. One third of the accompanied patients, however, thought that their
      physician was unaware that someone had accompanied them to the office. The
      majority (55%) of patients indicated that they would prefer to have a friend or
      family member in the examination room with them for some of their visits. No
      patient indicated that they never wanted a family member or friend to come into
      the examination room. CONCLUSIONS: Patients prefer direct family involvement in
      their health care more often than what occurs in practice. Physicians can easily
      address this discrepancy by asking patients whether and in what way they would
      like others to be involved in their health care.

PMID- 8656168
TI  - Number-needed-to-treat analysis of the prevention of myocardial infarction and
      death by antidyslipidemic therapy.
AB  - BACKGROUND: Atherosclerosis of the coronary arteries is the most common cause of
      death in the United States for persons over the age of 45. Dyslipidemia is one of
      the risk factors for the development of coronary atherosclerosis. Recent studies
      suggest that treating dyslipidemia in persons with coronary atherosclerosis may
      decrease morbidity and mortality. METHODS: A meta-analysis of 33 studies on the
      clinical and angiographic benefits of treating dyslipidemia in the prevention of
      morbidity and mortality from cardiovascular disease was performed. These benefits
      are quantitated in the form of "number needed to treat" (NNT) as an estimate of
      the public health benefit. The NNT is defined as the number of people that need
      to be treated to prevent one event. RESULTS: Treatment of dyslipidemia in persons
      with multiple atherosclerosis risk factors alone, ie, primary prevention, was
      effective in preventing myocardial infarction and all-cause death. In six trials
      of primary prevention, excluding the British cooperative trial using clofibrate,
      the NNT was 53 to prevent a nonfatal MI and 190 to prevent all-cause death (4.8
      years treatment with total cholesterol reduction of 15%). Treatment of
      dyslipidemia in people with known atherosclerosis, ie, secondary and tertiary
      prevention, was also effective in preventing myocardial infarctions and death
      from all causes. For 23 trials of secondary and tertiary prevention, the NNT was
      37 to prevent death from any cause (4.9 years treatment with total cholesterol
      reduction of 18%). In the trials with quantitative angiography, the NNT was 7 to
      prevent progression of coronary atherosclerosis and 10 to induce regression of
      coronary atherosclerosis (2.5 years treatment with a low-density lipoprotein
      cholesterol reduction of 28%). Similar benefits were observed in those trials
      employing HMG CoA reductase inhibitors. Benefits may be similar with niacin or
      dietary therapy, but these therapies did not reach significance in all categories
      of benefits, potentially due to beta error. These treatment benefits are
      comparable to other secondary prevention measures such as aspirin or beta
      blockers. The benefits appeared to extend to persons over 65, with less clearly
      defined benefits for women. CONCLUSIONS: These results support the overall
      clinical benefit of treating dyslipidemia, both in persons with and without known
      atherosclerosis.

PMID- 8656169
TI  - Pediatrician and family physician agreement with and adoption of universal
      hepatitis B immunization.
AB  - BACKGROUND: The purpose of this study was to assess (1) rates of agreement with
      and adoption of the universal hepatitis B vaccine recommendation among practicing
      pediatricians and family physicians in nine selected states; (2) physicians'
      attitudes related to hepatitis B immunization; and (3) physicians' perceptions of
      parental attitudes regarding the hepatitis B vaccine series. METHODS: Self
      administered questionnaires were mailed to 3014 pediatricians and family
      physicians in selected metropolitan areas and non-metropolitan areas of nine
      states. Outcome variables were agreement with and adoption of the hepatitis B
      vaccine recommendation. Predictor variables included physicians' characteristics,
      practice type and location, and proportion of managed care and Medicaid patients.
      Other variables that were studied include physicians' attitudes related to
      hepatitis B immunization, sources of immunization recommendation information,
      personal completion of the hepatitis B immunization series, and physicians'
      impressions of parental attitudes about the vaccine. RESULTS: Pediatricians were
      more likely than family physicians to report that they knew "a lot" about the
      recommendation (95% vs 84%), agreed with it (83% vs 57%), and have adopted it
      into practice (90% vs 64%). More physicians in both specialties had adopted the
      recommendation than actually agreed with it. Doubt about long-term protection
      from the vaccine was a strong predictor of not agreeing with or adopting the
      recommendation. Parental resistance to or request for hepatitis B vaccine
      affected the likelihood of physicians adopting it. CONCLUSIONS: Pediatricians and
      family physicians continue to differ in both agreement with and adoption of
      universal hepatitis B immunization. Two years after the recommendation was made,
      less than two thirds of all family physicians have adopted this recommendation.
      Adoption is likely influenced by practice policy, physician attitudes, and
      perceived parental opinions. We recommend that as new vaccines are approved and
      recommended, research be conducted to explore and address issues germane to
      physician agreement and adoption.

PMID- 8656170
TI  - Women's use of over-the-counter antifungal medications for gynecologic symptoms.
AB  - BACKGROUND: Over-the-counter (OTC) antifungal products for vulvovaginal
      candidiasis (VVC) have gained tremendous popularity, as evidenced by staggering
      increases in sales since the products were switched from prescription-only to OTC
      status. The rapid escalation in the sale of these products may imply that women
      are using them inappropriately. The purposes of this study were to determine (1)
      whether women could correctly diagnose VVC and common genitourinary tract
      problems after reading classic case scenarios, (2) whether women could correctly
      select the appropriate treatment for these cases, and (3) whether a previous
      diagnosis of VVC by a clinician had any effect on a woman's ability to self
      diagnose and self-treat VVC. METHODS: Women 16 years of age and older were
      recruited from medical and community sites to complete a 63-question survey
      instrument designed to assess their knowledge of the symptoms and signs of pelvic
      inflammatory disease, bacterial vaginosis, acute cystitis, vaginal
      trichomoniasis, and vulvovaginal candidiasis after reading classic case
      scenarios. RESULTS: A total of 601 women completed the questionnaire, 552
      subjects and 49 medically trained women who served as a criterion standard for
      comparison. Of the 552 subjects, 365 reported a prior diagnosis of VCC and 154
      reported no such prior diagnosis. The medically trained cohort was more accurate
      in diagnosing VVC (83.7% correct) than were subjects who had received a prior
      diagnosis of VVC (34.5% correct), and more accurate than subjects without a
      previous diagnosis of VVC (11.0% correct, P < .001). A greater percentage of
      subjects in whom VVC had been previously diagnosed, as compared with the
      medically trained cohort, would use OTC agents inappropriately for pelvic
      inflammatory disease (6.7% vs 4.3%, respectively; P = NS), bacterial vaginosis
      (14.6% vs 6.4%, respectively; P = .028), urinary tract infection (2.0% vs 0%,
      respectively; P < .001), and vaginal trichomoniasis (11.8% vs 6.6%, respectively;
      P = .048). CONCLUSIONS: A minority of women were able to correctly diagnose VVC
      from a classic case scenario. A prior clinical diagnosis of VVC had only a
      moderate positive effect on subjects' ability to correctly diagnose a classic
      case. Based on our findings, women likely use OTC antifungals inappropriately to
      treat gynecologic conditions that are similar but potentially more severe.
      Numerous adverse consequences may result from misdiagnosis. Improved patient
      education by health care providers and the manufacturers of OTC antifungal drugs
      might improve this diagnostic problem.

PMID- 8656171
TI  - Effectiveness of erythromycin in the treatment of acute bronchitis.
AB  - BACKGROUND: Clinical trials have not shown a consistent benefit of treating
      bronchitis with antibiotics. Many physicians, however, treat acute bronchitis
      with antibiotics because of the possibility of Mycoplasma pneumoniae or other
      pathogens. The objectives of this study were to determine the effectiveness of
      erythromycin treatment in patients with acute bronchitis and to determine whether
      a newly developed rapid M pneumoniae antibody test is useful in predicting which
      patients will respond to therapy. METHODS: We conducted a randomized, double
      blind, placebo-controlled clinical trial at three primary care centers in North
      Carolina. A convenience sample of 140 patients presenting with acute bronchitis
      were tested for M pneumoniae, 91 of whom were treated with either erythromycin
      250 mg four times daily for 10 days or an identical-appearing placebo. RESULTS:
      Patients treated with erythromycin missed an average of only 0.81 +/- 1.1 days of
      work compared with 2.16 +/- 3.2 days for placebo-treated patients (P < .02).
      There were no significant differences in cough, use of cough medicine, general
      feeling of well-being, or chest congestion between the erythromycin and placebo
      groups. Twenty-five percent of the patients tested positive for M pneumoniae.
      There were no differences in response to erythromycin based on whether the
      patient had a positive test for M pneumoniae. CONCLUSIONS: Erythromycin is
      effective in significantly reducing lost time from work, but it is not effective
      in reducing cough or other symptoms in patients with acute bronchitis, regardless
      of the outcome of the M pneumoniae antibody test.

PMID- 8656172
TI  - Consent form readability in university-sponsored research.
AB  - BACKGROUND: Consent forms are required in most biomedical research involving
      human subjects. In recent years, a number of studies from different disciplines
      have reported problems related to consent form readability. METHODS: We analyzed
      284 consent forms submitted to and approved by five institutional review boards
      (IRBs) (schools of Medicine, Nursing, Academic Affairs, Dentistry, and Public
      Health) at one university and one IRB at another. We examined consent form
      readability scores and factors that might relate to readability. RESULTS: The
      average reading level of all consent forms was high: 12.2, which corresponds
      roughly to a 12th-grade reading level. Less than 10% of all consent forms were
      written at a 10th grade reading level or below. Thirty-two percent of all consent
      forms had no evidence of revisions, and less than 2% of consent forms were
      revised more than once. Readability scores were not related to consent form
      revisions, the type of IRB, the year of study, or the university where the
      research was conducted. CONCLUSIONS: Poor readability of consent forms probably
      occurs in all university-related research. We recommend that IRBs require
      readability checks for research consent forms before researchers submit their
      proposals to an IRB.

PMID- 8656173
TI  - Metformin: a new treatment option for non-insulin-dependent diabetes mellitus.
AB  - Metformin is a biguanide that can used alone or in combination with sulfonylureas
      or insulin in the treatment of non-insulin-dependent diabetes mellitus (NIDDM).
      Since biguanides do not increase pancreatic insulin secretion, they are referred
      to as antihyperglycemic agents, as opposed to hypoglycemic agents. Biguanides
      reduce hyperglycemia by increasing, insulin sensitivity, decreasing glucose
      absorption, and inhibiting hepatic gluconeogenesis. Advantages of metformin
      include achieving glycemic control without exacerbating weight gain or
      hyperinsulinemia and beneficially affecting serum cholesterol concentrations.
      Although metformin has the potential to cause lactic acidosis, the incidence is
      significantly lower compared with phenformin. Risk factors for lactic acidosis
      include renal serum creatinine > 1.5 mg/dL and cardiovascular, pulmonary, and
      hepatic disease. Metformin should be temporarily discontinued prior to surgery
      and before administration of radiologic intravenous contrast, and in patients
      with sepsis, severe gastrointestinal disease, trauma, and acute cardiovascular
      events.

PMID- 8656174
TI  - Dementia and Down syndrome.
AB  - Through deinstitutionalization, more adults with mental retardation are living in
      the community under the care of family physicians. Patients with Down syndrome
      are at high risk for early Alzheimer's disease. This case report describes a 43
      year-old woman with Down syndrome whose progressive functional decline over 3
      years was attributed to dementia of the Alzheimer type.

PMID- 8656175
TI  - Patient support networks.

PMID- 8656176
TI  - Who is a "specialist"?

PMID- 8656177
TI  - Parental grieving after infant death.

PMID- 8656178
TI  - Panic attack or CVD?

PMID- 8656179
TI  - Acute diverticulitis and obesity in young adults.

PMID- 8656180
TI  - Producing STR locus patterns from bloodstains and other forensic samples using an
      infrared fluorescent automated DNA sequencer.
AB  - Short tandem repeat (STR) analysis is increasingly being used in forensic case
      analysis because of the large number of STR loci in the human genome and their
      highly polymorphic nature. An automated DNA sequencer using high sensitivity
      infrared (IR) fluorescence technology was used to detect STR allele patterns from
      simulated forensic samples. The amplification strategy used a 19 base pair
      extension on the 5' end of one of the PCR primers. This sequence is identical to
      the sequence of a universal M13 Forward sequencing primer which is included in
      the amplification reaction. Allelic bands were detected by incorporation of the
      M13 primer-fluorescent dye conjugate into PCR products thus eliminating the need
      for direct conjugation of fluorescent dye to individual STR primers. By using an
      IR-based automated DNA sequencer and Tth DNA polymerase, polymorphic STR alleles
      were detected on-line rapidly and efficiently from bloodstains using only a high
      temperature incubation to extract DNA from blood cells. Five STR loci were also
      amplified using Chelex extracted DNA from simulated forensic samples.
      Multiplexing of three primer pairs in a single PCR mixture for amplification was
      accomplished using Taq polymerase. This system combines IR fluorescence chemistry
      and laser technology thus eliminating the need for radioactivity and the gel
      handling required with silver staining and fluor detection systems. Real-time
      detection permits immediate visualization of the data and STR alleles are
      displayed as familiar autoradiogramlike images that can be analyzed by computer.
      By loading a 64 lane gel twice and multiplexing with three primer pairs, forensic
      scientists can type at least three loci from 120 samples in one day.

PMID- 8656181
TI  - Continuous river monitoring of the diatoms in the diagnosis of drowning.
AB  - The diagnosis of drowning is one of the most difficult in forensic pathology.
      Diatom analysis has been proposed to provide supportive evidence of drowning but
      the reliability and applicability of quantitative and qualitative diatom analysis
      in the diagnosis of drowning is still disputed in the literature. In order to
      further examine such cases, the authors report the development of a water
      monitoring system based on algae performed each month at three aquatic locations
      where drowning victims are frequently found. Water samples and stones were taken
      from the surface and from the bed of the river. This protocol was performed
      during 1993 with analyses both on water samples and human tissue samples (30
      bodies). The diatom profile of the drowning sites was compared with the tissue
      analysis. The extraction of diatoms from the tissues was performed with an
      enzymatic digestion method using Proteinase K. Results indicate that the
      monitoring of river diatom populations is an accurate method of generating
      profiles of the river flora, which can then be compared with the diatom genera
      found in tissues.

PMID- 8656182
TI  - Histological criteria for diagnosis of amanita phalloides poisoning.
AB  - Five fatal cases of poisoning from ingestion of Amanita phalloides, a very common
      mushroom in central Italy, are reported. The fact that four of the cases occurred
      simultaneously enabled uniform collection of clinical, pathology and toxicology
      data, which is presented with particular emphasis on the histological aspects.
      The fifth case involved a six-year-old girl, and is discussed with reference to
      differential diagnosis with respect to Reye's syndrome, which was the initial
      diagnosis, demonstrated incorrect by the histology, pathology and toxicology
      findings. The typical liver and kidney alterations of Amanita phalloides
      poisoning, consisting of massive hepatic central lobular cell necrosis and acute
      tubular necrosis of the kidney are described. Outside the liver, there was often
      general hemorrhagic diathesis and severe brain edema. Although poisoning by
      Amanita phalloides is rare, these cases confirm the requirement for as complete a
      comparison as possible between circumstantial histopathological and toxicological
      data for the purposes of forensic diagnosis.

PMID- 8656183
TI  - Pulmonary histopathology and survival period in morphine-involved deaths.
AB  - For an evaluation of the survival period in morphine-involved deaths, changes of
      pulmonary histopathology were investigated in a total of 90 morphine-associated
      fatalities. Although pulmonary histopathology proved to be heterogeneous, several
      distinctive histological patterns emerged. While the subgroup with short courses
      of intoxication ( < 1 h, n = 15) was mostly characterized by slight/moderate
      alveolar edema (12/15), severe hemorrhages (12/15) and marked acute emphysema
      (9/15), the phenomena of massive edema (8/15), missing/slight hemorrhages (8/15)
      and absent/slight emphysema (11/15) dominated in the group with intermediate
      survival times (1-24 h, n = 15). Intravascular leukocyte accumulations (shock
      equivalent) occurred in the first group only once, but in the group with the
      longer survival time in 10 of 15 cases. Delayed deaths ( > 24 h, n = 4) were
      mainly characterized by purulent bronchitis/pneumonia. Those fatalities (n = 56)
      that could not be classified by anamnestic data were assessed by histological
      criteria. In comparison with the evaluation of the survival period by
      toxicological analyses, concordance was found in 46 cases. Pulmonary
      histopathology is not a tool for an exact graduation of survival time, but the
      combination of several key parameters can provide criteria for a differentiation
      between short ( < 1 h) and longer courses of intoxication.

PMID- 8656184
TI  - Mechanisms of unexpected death in infants and young children following foreign
      body ingestion.
AB  - Fatal foreign body ingestion in childhood usually results in sudden and
      unexpected death from acute upper airway occlusion. The most common age range for
      such episodes is one to three years. However, a variety of different mechanisms
      of death due to ingested foreign bodies may occur in children, including
      hemorrhage, acute cardiac tamponade, arrhythmia, centrally mediated respiratory
      arrest and sepsis. Sudden death may follow a protracted asymptomatic period and
      may also be due to foreign bodies impacted in the esophagus. A review of cases
      has been undertaken (N = 10; age = three and one-half months to seven years; M:F
      = 9:1), which demonstrates the variety of lethal processes that may occur, the
      range of materials involved and the different anatomical sites where problems can
      result.

PMID- 8656185
TI  - An investigation of medical examiner cases in which methadone was detected,
      Harris County, Texas, 1987-1992.
AB  - In 1991, media reports of an increase in the number of deaths attributed to
      methadone toxicity in Harris County, Texas, raised public concern about the
      safety of methadone. This concern was heightened by publicity surrounding the
      closure of three Harris County methadone maintenance treatment programs due to
      their poor compliance with federal methadone regulations. In response to this
      concern, the Texas Department of Public Health requested that the Centers for
      Disease Control and Prevention (CDC) assist in an epidemiologic study to
      determine the extent of methadone-related mortality in Harris County during 1991
      and to determine the role of methadone maintenance treatment in these deaths. We
      reviewed cases investigated by the Harris County Medical Examiner's Office from
      1987 through 1992 in which methadone was detected by postmortem drug testing. The
      autopsy reports for cases occurring in 1991 were also reviewed by three
      independent forensic pathologists who were asked to determine the role of
      methadone in the death. In addition, we attempted to document Harris County
      methadone maintenance treatment program enrollment for each decedent. We
      identified 91 decedents in whom methadone was detected at the time of death, with
      the largest number of cases occurring in 1991 (n = 27). Other substances,
      including alcohol, were detected in 85% of the cases. The Harris County Medical
      Examiner attributed 11 of the deaths to methadone toxicity. No more than three
      cases per year from 1987 through 1992 were attributed to methadone toxicity. In
      contrast, 34 deaths were attributed to polydrug toxicity, the largest number
      occurring in 1991 (n = 11). There was good agreement between the results of the
      independent review and the opinions of the Harris County Medical Examiner. Only
      20% of the decedents were found to have been enrolled in a Harris County
      methadone maintenance treatment program at the time of death. Four people died of
      drug toxicity shortly after enrolling in a methadone maintenance treatment
      program. We found an increase in the number deaths occurring in Harris County,
      Texas, in 1991 in which methadone was detected. We also found that methadone
      blood levels were higher among decedents identified for 1991 and 1992 than among
      those identified in the previous years studied. However, we did not find evidence
      that the cause of these deaths could be attributed solely to methadone toxicity.
      Instead, for all years studied, the use of multiple drugs was the leading cause
      of death among people in whom methadone was detected. This finding points out the
      difficulties involved in determining the role of methadone as a cause of death.

PMID- 8656186
TI  - Mortality from Hurricane Andrew.
AB  - Hurricane Andrew, a category 4 storm, made landfall in South Florida on August
      24, 1992, and caused extensive structural and environmental damage. The Dade
      County Medical Examiner Department investigated 15 deaths directly related to the
      storm and another 15 natural deaths indirectly related to the storm. The
      aftermath of the hurricane continued to create circumstances that lead to 32
      accidental deaths, five suicides, and four homicides over the next six months.
      Traffic fatalities due to uncontrolled intersections accounted for one-third of
      the post-storm accidental deaths. Dyadic deaths (homicide-suicide) doubled in
      rate for the six months following the storm. The limited number of direct
      hurricane deaths is attributed to advance storm warnings, its occurrence on a
      weekend, the storm's passage through less populated areas of the county, and the
      relatively modest amount of accompanying rainfall.

PMID- 8656187
TI  - Methamphetamine and driving impairment.
AB  - Following a review of the effects of methamphetamine on human performance, actual
      driving and behavior were evaluated in 28 cases in which drivers arrested or
      killed in traffic accidents had tested positive for methamphetamine. The
      circumstances surrounding the arrest or accident were examined, together with any
      observations by the arresting officer regarding behavioral irregularities. The
      investigators also made a determination of culpability. Most of the arrests
      resulted from accidents in which the driver was determined to be culpable.
      Typical driving behaviors included drifting out of the lane of travel, erratic
      driving, weaving, speeding, drifting off the road, and high speed collisions.
      Behavioral manifestations of methamphetamine use in arrestees included rapid or
      confused speech, rapid pulse, agitation, paranoia, dilated pupils, violet or
      aggressive attitude. Combined alcohol and methamphetamine use was uncommon,
      however use of marijuana was evident in about one third of the cases. In addition
      to impairing judgment and increasing risk taking, the effects of withdrawal from
      methamphetamine use including fatigue, hypersomnnolence, and depression are
      likely contributors to many of these accidents. A consideration of the literature
      and the cases discussed here, leads to the conclusion that methamphetamine at any
      concentration is likely to produce symptoms that are inconsistent with safe
      driving.

PMID- 8656188
TI  - Stability and spontaneous production of blood cyanide during heating.
AB  - To investigate the effects of heat on blood cyanide concentrations, in vitro
      experiments were performed using a headspace gas chromatographic method. Cyanide
      concentrations were determined for solutions of human hemoglobin (Hb) at
      neutrality, and for blood which was sealed in a vial and incubated at 25, 50, 63,
      75 and 90 degrees C for 1 h. Spontaneous cyanide production was also measured.
      Nearly all of the added cyanide was recovered in both the Hb and for blood
      samples which were heated below 63 degrees C. Cyanide recovery in Hb decreased in
      a temperature-dependent manner at temperatures above 75 degrees C, and more than
      half of the recovered cyanide was found to be in the free form. In contrast,
      cyanide in blood disappeared more rapidly, and a major portion of it existed in
      the bound form. Cyanide concentrations in Hb solutions which were heated at 90
      degrees C dropped in the two phases; a rapid initial phase, followed by a slower
      process. Spontaneous cyanide production was observed at temperatures above 50
      degrees C for Hb and above 63 degrees C for blood. Under optimal conditions (75
      degrees C heating), about 0.2 mmol of cyanide was produced per mol heme of Hb.

PMID- 8656189
TI  - Attribution of hand bones to sex and population groups.
AB  - Forensic anthropologists assign sex and population group (race) to individuals on
      the basis of skeletal remains. While the most useful bones for these
      determinations are cranial and pelvic, these are not always available. The
      purpose of this paper is to provide models for classification using metacarpals
      and hand phalanges. Four samples of 40 individuals each (black and white males
      and females) form the dataset. Measurements include lengths and radioulnar and
      dorsopalmar widths of the 19 bones of each hand. The large number of total
      variables necessitated separate models for metacarpal and phalangeal categories;
      due to the considerable number of significant differences between corresponding
      right and left hand variables, separate models were created for right and left
      sides. A stepwise discriminant procedure was used to select variables, with some
      highly correlated (r > 0.85) variables subsequently removed. The model for left
      hand metacarpals has the greatest power of discrimination (89.4%); that for right
      hand middle phalanges, the least (71.7%). Metacarpals assign approximately 87
      89%, proximal phalanges 76-79%, middle phalanges 72-79%, and distal phalanges 81
      83% of individuals to their correct sex and population groups. Models exchanging
      variables selected from one side for corresponding variables on the other show
      discriminating power ranging from 72.3 to 85.6%. Thus roughly 70-90% of
      individuals are correctly classified by these models; more conservative
      "jackknife" estimates yield a success rate of approximately 67-82%. When these
      models are used for classification of sex alone, 89.9-94.4% ("jackknife" range,
      88.7%-94.4%) of cases are correctly classified; for race alone, 80.5-98.1%
      ("jackknife" range, 77.4-96.9%).

PMID- 8656190
TI  - DNA profiling in two Alaskan Native populations using HLA-DQA1, PM, and D1S80
      loci.
AB  - Two Native Alaskan populations were sampled and DNA profiles were generated for
      201 individuals. Ninety two blood samples were collected from the North Slope
      Borough region of Alaska and the remaining 109 blood samples came from Native
      Alaskans in the Bethel and Wade Hampton areas. Allele and genotype frequencies
      were established for the HLA-DQA1, LDLR, GYPA, HBGG, D7S8, Gc, and D1S80 loci.
      Native Alaskans are slightly less polymorphic than Caucasians at the HLA-DQA1
      locus. In contrast, the PM loci appear to be nearly as informative in the Native
      Alaskan populations as in Caucasians for identity testing. The data clearly
      demonstrate that all the loci tested are highly informative for the Alaskan
      populations and fall well within Hardy-Weinberg expectations. There is little
      evidence for departure from expectation of independence of alleles across loci.
      The data demonstrate that estimates of multiple locus profile frequencies can be
      obtained from Native Alaskan populations using the product rule under the
      assumption of independence of loci. In addition, Native Alaskan databases were
      more similar to each other and to other Native American databases than they were
      to U.S. Caucasians and African Americans.

PMID- 8656191
TI  - PCR-based human leukocyte antigen (HLA) DQ alpha typing of blood stained light
      and dark blue denim fabric.
AB  - Obtaining typable PCR products from DNA purified from blood stained blue denim
      has been difficult since inhibitors of PCR in blue denim apparently co-purify
      with the DNA. Organic and chelex extraction methods were tested for their ability
      to purify typable DNA from either light or dark blue denim fabric both stained
      with blood. DNA purified from the light blue denim using either method was
      successfully used in obtaining correct HLA-DQ alpha typing results. The chelex,
      but not the organic, procedure was able to yield typable DNA when the dark blue
      denim was the substrate. Therefore, the chelex method may be more effective than
      the organic method in preventing compounds that inhibit PCR from co-purifying
      with the DNA.

PMID- 8656192
TI  - Confirmation of PM typing protocols for consistent and reliable results.
AB  - A recent report in the Perkin Elmer "Forensic Forum" bulletin described a
      modification to the previously published PM typing protocol indicating that in
      order to obtain consistent and reliable PM and DQA1 typing results, disodium EDTA
      should be added to the post-amplification mixture before denaturation of the DNA
      fragments. The analysis and validation of this suggestion is described in the
      accompanying paper. We report the evaluation of this additional step when typing
      for PM alleles and conclude that the standard operating procedures currently
      enforced at the Palm Beach County Sheriff's Office and Indian River crime
      laboratories do not necessitate the need for the addition of disodium EDTA to the
      PM amplified products prior to the heat denaturation step. Further, depending on
      an individual laboratory's PM protocol, the recommendation by Perkin Elmer to add
      disodium EDTA to PM amplified products before typing has merit and should be
      carefully considered when determining laboratory PM typing protocols.

PMID- 8656193
TI  - Post-amplification primer extension of heat-denatured AmpliType PCR products:
      effects on typing results.
AB  - Alleles of the HLA, DQA1, LDLR, GYPA, HGBB, D7S8 and GC loci, which are amplified
      using the AmpliType(R) PM PCR Reaction Mix and Primer Set, can be detected using
      sequence-specific oligonucleotide probes immobilized on a nylon membrane strip.
      Using reagents supplied in AmpliType PCR Amplification and Typing Kits, patterns
      of blue dots corresponding to particular alleles are visualized on the DNA probe
      strips. Frequently, the correct interpretation of typing results is dependent not
      only on the presence of probe signals but also on their relative intensities. The
      relative probe signal intensities obtained from an undegraded DNA sample
      extracted from a single individual will be different from those obtained from
      degraded DNA and from samples containing DNA from more than one source. Because
      probe signal intensity is an essential consideration for interpretation, factors
      that can influence it need to be identified. Clearly, the time and temperature of
      the assay steps and the salt concentration in the typing solutions can affect
      probe signal intensity. Also, if heat-denatured PCR products are allowed to cool
      for several minutes, the strands will reanneal and become unavailable for binding
      to the probes immobilized on the strips. However, the selective loss of GC B and
      HLA DQA1 4.1 probe signals observed after shorter cooling times cannot be
      explained by these factors. We demonstrate that following heat denaturation of PM
      PCR products there is sufficient residual Taq DNA polymerase activity to extend
      primers as the solution cools and that this primer extension occurs at a more
      rapid rate than PCR product reannealing. Primer extension across probe binding
      sites will prevent hybridization of the PCR product to complementary probes on
      the strip. The extent of signal reduction is dependent on the position of the
      probe binding site relative to the 3' ends of the primers and on the strand to
      which the probe is complementary. We recommend a simple modification to the
      AmpliType typing protocol to ensure all probe binding sites will be available for
      hybridization to PM and HLA DQA1 DNA probe strips.

PMID- 8656194
TI  - Drug and alcohol use in fatally injured drivers in Washington State.
AB  - Blood and/or urine from fatally injured drivers in Washington State were
      collected and tested for the presence of drugs and alcohol. Drug and/or alcohol
      use was a factor in 52% of all fatalities. Among single vehicle accidents,
      alcohol use was a factor in 61% of cases versus 30% for multiple vehicle
      accidents. Drugs most commonly encountered were marijuana (11%), cocaine (3%),
      amphetamines (2%), together with a variety of depressant prescription
      medications. Trends noted included an association of depressant use with higher
      blood alcohol levels, while marijuana use was associated with lower blood alcohol
      levels. Marijuana use was noted to be most prominent in the 15-30 year age group,
      stimulant use in the 21-40 year old group, and prescription depressant use was
      more prevelant in the 45 + age group. Drug use demographics in this population
      are consistent with those noted in other jurisdictions.

PMID- 8656195
TI  - Elimination of fluconazole interference in gas chromatography/mass spectrometric
      confirmation of benzoylecgonine, the major metabolite of cocaine using
      pentafluoropropionyl derivative.
AB  - Cocaine is a widely abused drug and causes death from overdose. Benzoylecgonine,
      the major metabolite of cocaine in urine is usually confirmed after
      derivatization by gas chromatography/mass spectrometry to demonstrate cocaine
      abuse. Recently, Wu et al. demonstrated that fluconazole coelutes with
      benzoylecgonine after conversion to trimethylsilyl analogs and causes false
      negative result in the confirmation test. However, fluconazole did not interfere
      with the screening assay using a enzyme multiplied immunoassay technique. We
      demonstrated that by converting benzoylecgonine to the corresponding
      pentafluoropropionyl derivative, the interference of fluconazole can be
      completely eliminated. The pentafluoropropionyl derivative of benzoylecgonine
      eluted at 14.7 min while the derivatized fluconazole eluted at 15.6 min. The mass
      spectral fragmentation pattern of derivatized benzoylecgonine was distinctively
      different from the mass spectral features of derivatized fluconazole in both
      electron ionization and chemical ionization mode of operation of mass
      spectrometers. The quantitation of benzoylecgonine in positive urine specimens
      has not affected when the specimens were supplemented with 50 micrograms/mL of
      fluconazole.

PMID- 8656196
TI  - Radiographic reconstruction of root morphology in skeletonized remains: a case
      study.
AB  - This is a case study in the application of a laboratory technique first described
      by Dr. Brion C. Smith in the Journal of Forensic Sciences in January 1992. Our
      study evaluated a human skull that showed perimortem and/or postmortem tooth
      loss. It was discovered in 1991 and deemed to have no usable dental information
      due to severe alveolar bone destruction. In 1994, using minor modifications of
      Dr. Smith's technique, we sealed off the open tooth sockets and injected a
      radiopaque material which, after radiographic analysis, revealed previously
      unobserved dental information. This report demonstrates that root morphology can
      be reconstructed. This yields radiographic information that may be useful in the
      identification of unknown human remains.

PMID- 8656197
TI  - Facial casting as a method to help identify severely disfigured corpses.
AB  - The authors apply a previously reported method for facial casting of severely
      disfigured corpses, which allowed a three-dimensional cast to be made. This
      method involved several stages: face restoration, casting by elastomer, then
      three-dimensional positive image building. This technique seems to be useful in
      all cases of severe disfiguration of the face, particularly by trauma.

PMID- 8656198
TI  - Unexpected deaths due to colloid cysts of the third ventricle.
AB  - Colloid cysts of the third ventricle are rare central nervous system tumors that
      are a recognized cause of unexpected death in young, otherwise healthy adults and
      children. We report three adults and one child who died from colloid cysts of the
      third ventricle. Our report illustrates the difficulties of diagnosing these
      tumors premortem.

PMID- 8656199
TI  - The detection of a metabolite of alpha-benzyl-N-methylphenethylamine synthesis in
      a mixed drug fatality involving methamphetamine.
AB  - A 37-year-old, white male collapsed at his home following a party. He reportedly
      had a history of unspecified cardiac arrhythmia. The ambulance crew found him
      unresponsive and an ECG revealed ventricular tachycardia/fibrillation. Following
      one hour of resuscitative efforts in the ambulance and emergency room of a local
      hospital, he was pronounced dead. An antemortem urine toxicology screen performed
      at the hospital was "positive" for benzodiazepines, cocaine and
      amphetamine/methamphetamine. At autopsy, there was generalized organ congestion
      with no evidence of trauma or other significant pathology except mild, left
      ventricular hypertrophy. Quantitation by gas chromatography/mass spectrometry
      (GC/MS) of methamphetamine in bile, blood, urine and gastric contents yielded
      21.7, 0.7, 32.0 and 2.9 mg/L, respectively. Liver and brain contained 2.2 and 2.7
      mg/kg, respectively. A trace amount of p-OH-alpha-benzyl-N-methylphenethylamine
      (p-OH-BNMPA), a metabolite of alpha-benzyl-N-methylphenethylamine (BNMPA), an
      impurity of illicit methamphetamine synthesis, was also detected in the urine.
      Since these impurities can be characteristic of a particular synthetic method,
      their presence in seized samples or their detection in biological samples from
      methamphetamine users can further be used to monitor the sales of precursor
      chemicals, group seized compounds to common sources of illicit production or
      provide links between manufacturers, dealers and users.

PMID- 8656200
TI  - Two fatal cases of dichloromethane or chloroform poisoning.
AB  - The two cases presented here involve deaths that were due to dichloromethane or
      chloroform poisoning. The dichloromethane and chloroform were determined in
      biological specimens by headspace gas chromatography with mass spectrometric
      detector. In one case, dichloromethane concentrations found were 252 mg/L
      (blood), 75 mg/kg (brain) and 30 mg/kg (heart). From the case investigation, it
      was determined that the death was accidental but related to the dichloromethane
      poisoning. In the other case, chloroform concentrations were 60 mg/kg (blood) and
      14 mg/kg (lungs), respectively. This case, the cause of death was chloroform
      poisoning by forced inhalation in addition to oronasal obstruction.

PMID- 8656201
TI  - The relationship of HIV status, type of coagulation disorder, and school
      absenteeism to cognition, educational performance, mood, and behavior of boys
      with hemophilia.
AB  - Psychological and educational data were analyzed for all school-aged males with
      hemophilia at the Hemophilia Center of Central Pennsylvania (N = 66). Mean IQ
      (113.5) was higher than normal, and 2.4 times as many boys with hemophilia were
      enrolled in gifted programming than is the state average for boys. However, there
      was a disproportionately high prevalence of attention-deficit/hyperactivity
      disorder (ADHD; 28.3%), learning disability (LD; 15.8%), and graphomotor
      weakness. These were not significantly associated with HIV status or type and
      severity of coagulation disorder. School absenteeism was high but was not
      significantly related to academic achievement, IQ/achievement discrepancy, need
      for educational intervention, or diagnosis of ADHD or LD.

PMID- 8656202
TI  - Enmity in males at four developmental levels: cognitive bases for disliking
      peers.
AB  - The goal of this study was to determine whether, at different age levels, males
      cite different bases as reasons for disliking peers. Male preschoolers, primary
      graders, preadolescents, and young adults were asked to name and give reasons for
      disliking an actual same-sex peer. Participants from preschool through
      preadolescence frequently cited aggression and aberrant behavior as reasons for
      disliking, a finding that suggests that both dimensions serve as major sources of
      enmity across childhood. Although aggression was not cited frequently by the
      young adults, aberrant behavior persisted as a significant basis for disliking
      across all four developmental levels. Lack of general play and rule violation
      constituted reliable bases for disliking only at the preschool level, whereas
      lack of help was cited frequently by both the primary-grade and preadolescent
      participants. The preadolescents and the young adults also specified negative
      evaluation as a major basis of enmity, whereas lack of genuineness was cited at
      above-chance levels only by the young adults.

PMID- 8656203
TI  - Combat-related trauma as measured by ego developmental indices of defenses and
      identity achievement.
AB  - The relation between combat-related trauma experience and male ego development
      and the impact of such trauma on subsequent employment, marital, and legal
      behavior were investigated empirically. Vietnam combat veterans (N = 52)
      diagnosed with post-traumatic stress disorder (PTSD) completed the Defense Style
      Questionnaire (DSQ), the Ego Identity Scale (EIS), and the Impact of Event Scale
      (IES); 45 noncombat Vietnam-era veterans (not diagnosed with PTSD) completed the
      DSQ and the EIS. Combat veterans were found to use more maladaptive defenses and
      have lower levels of identity achievement. Failed marriages, employment problems,
      and the tendency to experience legal difficulties were more prevalent among the
      combat veterans. Data analyses showed that identity and defenses do indeed
      correlate, suggesting that these constitute a unified construct that can be
      subsumed under the rubric of ego development.

PMID- 8656204
TI  - Delay of gratification: mothers' predictions about four attentional techniques.
AB  - Mothers' predictions about the ability of their own children to delay
      gratification using different techniques were investigated. Fifty-one mothers of
      children 4 to 6 years old were asked to evaluate distraction, thinking about the
      incentive, tasting the incentive, and a control. These conditions were derived
      from the research of Mischel and his associates (1974), who demonstrated the
      effectiveness of distraction in aiding children's delay behavior. Parents were
      predicted to expect delay to be enhanced by the distraction technique and
      hampered by the thinking about the incentive and tasting the incentive
      techniques, with the latter being the least effective. Contrary to our
      predictions, mothers failed to predict effectiveness of distraction compared with
      the two incentive-focused techniques. Reasons are advanced for more research on
      parents' knowledge and valuing of metacognitive strategies appropriate for their
      children.

PMID- 8656205
TI  - Girls' relational self in Sri Lanka and the United States.
AB  - The self-conceptions of 100 girls (11-17 years old) from Sri Lanka and the United
      States were studied from the traditional Western perspective of identity
      development as a process in which adolescents become increasingly independent and
      autonomous. This perspective is based on male development in Western countries
      and may not adequately describe the experience of girls of non-Western
      adolescents, for whom relationships with others may be central to identity
      formation. The participating girls drew self-portraits and either answered the
      question "How would you describe yourself to yourself?" or completed the sentence
      "I am..." 20 times. The results indicate that relationships and independence are
      important themes for the girls from the United States and from Sri Lanka. Older
      girls differed from younger girls in that greater maturity was associated with
      greater interest in interpersonal relationships and future lives.

PMID- 8656206
TI  - Preschoolers' inferred self-esteem: the Behavioral Rating Scale of presented self
      esteem in young children.
AB  - Teachers of 94 preschoolers (in Head Start and university-based programs)
      assessed the children's inferred self-esteem using the Behavioral Rating Scale of
      Presented Self-Esteem in Young Children. The instrument was found to have
      excellent internal consistency. Factor analysis yielded a two-factor solution:
      approach confidence and social-emotional expression. There were no significant
      program differences in inferred self-esteem, but girls scored significantly
      higher than boys. Implications for learning opportunities in the preschool years
      are discussed.

PMID- 8656207
TI  - Self-reported narcissism and perceived parental permissiveness and
      authoritarianism.
AB  - The hypothesis that inadequate parenting promotes the development of pathological
      narcissism was tested in a sample of 370 undergraduate students. They responded
      to the O'Brien (1987) Multiphasic Narcissism Inventory (OMNI) and to measures of
      parental permissiveness, authoritarianism, and authoritativeness. Perceived
      parental permissiveness and authoritarianism served as independent predictors of
      greater narcissistic tendencies. The students who scored high on the OMNI were
      also less likely to evaluate both of their parents as having been especially
      strong in their use of the adjustment-promoting authoritative style. Theoretical
      efforts to link narcissism with inadequate parenting therefore may have merit and
      may deserve additional research attention.

PMID- 8656208
TI  - Exogenous nitric oxide causes collapse of retinal ganglion cell axonal growth
      cones in vitro.
AB  - We show that nitric oxide (NO) from applied NO-donating chemicals induces
      collapse of ganglion cell axonal growth cones extending from explants of tadpole
      retina in culture. Peroxynitrite, a neurotoxic product of NO and superoxide
      reaction, did not induce collapse, and oxyhemoglobin, which binds NO, blocked the
      highly effective collapsing activity of the NO donor S-nitrosocysteine. Membrane
      permeable analogs of cyclic guanosine monophosphate had no collapsing activity.
      Inhibitors of NO synthase did not induce collapse. NO is a potential retrograde
      messenger through which postsynaptic neurons signal to their inputs to modify
      synaptic efficacy following NMDA receptor activation. Our results suggest a role
      for NO as such a messenger during development of the retinotectal projection.

PMID- 8656209
TI  - Conotoxin-sensitive and conotoxin-resistant Ca2+ currents in fish retinal
      ganglion cells.
AB  - Using whole-cell patch-clamp methods, we tested whether omega-toxins from Conus
      block voltage-gated Ca2+ currents in teleost central neurons. The fractions omega
      CTx-GVIA and omega-CTx-MVIIC, together with omega-toxins from Agelenopsis, the
      dihydropyridine BAY-K-8644, and voltage steps, produced effects indicating three
      types of Ca2+ current in dissociated goldfish retinal ganglion cells. One was
      activated by depolarization of most cells beyond -65 mV, primed at -95 mV but not
      at -45 mV, reduced by Ni2+, and unchanged by conotoxins, agatoxins, or BAY-K
      8644. The second type constituted more than three-quarters of the total Ca2+
      current in all cells, and at test potentials more positive than -30 mV, was
      reduced consistently by omega-CTx-GVIA, omega-CTx-MVIIC, and omega-Aga-IA, but
      not omega-Aga-IVA. The third Ca2+ current type was augmented by BAY-K-8644 at
      test potentials as negative as -45 mV, even in the presence of omega-CTx-GVIA.
      Replacement of extracellular Ca2+ by Ba2+ augmented current amplitude and slowed
      current decay. Conditioning depolarizations reduced Ca2+ current amplitude less
      than did omega-CTx-GVIA, and slowed current decay to imperceptible rates. These
      results provide the first description of conotoxin-sensitive, voltage-gated Ca2+
      current recorded from teleost central neurons. Although most of the high
      threshold Ca2+ current in these cells is blocked by omega-CTx-GVIA, it is also
      Ni(2+)-sensitive, and relatively resistant to omega-Aga-IIIA. The voltage
      sensitivities of low-and high-threshold Ca2+ current may suit current recruitment
      in situ after light-evoked hyperpolarizations end, and after light-evoked
      depolarizations begin, respectively.

PMID- 8656210
TI  - Ontogeny of odorant receptor gene expression in zebrafish, Danio rerio.
AB  - We cloned three putative odorant receptor (OR) genes from the zebrafish to use as
      in situ hybridization probes to follow the temporal patterns of neurons
      expressing OR genes through a developmental progression from embryo (12 h
      postfertilization) to adult. The identification of these genes is supported by
      sequence homology to previously reported ORs and by the morphology and location
      of labeled cells in in situ hybridization experiments. Cells expressing OR mRNA
      were first observed in the olfactory placodes between 31 and 38 h after
      fertilization (fish reared at 26 degrees C). Initially, only single cells were
      observed to hybridize the probe; the number of labeled cells increased throughout
      the remainder of embryogenesis and through postembryonic growth and morphogenesis
      of the olfactory organ. At all ages, the positively hybridizing cells were
      scattered throughout the olfactory epithelium but not in the nonsensory
      epithelium of the olfactory organ.

PMID- 8656211
TI  - Glomerular organization in developing olfactory and accessory lobes of American
      lobsters: stabilization of numbers and increase in size after metamorphosis.
AB  - Olfactory glomeruli are columnar and radially arranged at the periphery of the
      primary chemosensory areas, the olfactory lobes (OLs), in the American lobster
      Homarus americanus. The number of olfactory glomeruli reaches nearly 100/lobe in
      midembryonic life, increases rapidly during larval life, and stabilizes at about
      200 in juvenile and adult lobsters. The accessory lobes (ALs), higher order
      integration areas, are composed of cortical columns and of spherical glomeruli.
      Two populations of spherical glomeruli are defined, the cortical glomeruli
      located at the bases of the columns, and the medullary glomeruli scattered
      throughout the ALs. Both cortical columns and spherical glomeruli are seen for
      the first time in the second larval stage. There are about 1000 cortical columns
      and 1700 glomeruli/AL in the postlarva and these numbers remain constant during
      the life of the lobster. In both OLs and ALs, it is the size of the
      interglomerular spaces and of the glomeruli themselves that increases. Therefore,
      the data suggest that in both OLs and ALs the glomeruli were already generated
      when the lobster metamorphoses (stage III to IV) and switches from a planktonic
      to a benthic existence, and that the new sensory neurons that are formed at each
      molt in the antennulae grow into existing olfactory glomeruli. Stability of the
      glomerular population in the primary olfactory centers, once the full complement
      of glomeruli is acquired, has also been reported in insects, fish, and mammals.

PMID- 8656212
TI  - Development of the catecholaminergic innervation of the song system of the male
      zebra finch.
AB  - Catecholamines (CA) have been proposed to have neuromodulatory actions,
      particularly on attention and learning, in a number of neural systems. Because
      several of the interconnected brain nuclei that mediate song learning and
      production in the adult male zebra finch (Taeniopygia guttata) contain these
      neurotransmitters, we investigated the appearance of the catecholaminergic
      innervation of the song nuclei of male zebra finches during posthatch
      development, specifically during the period in which song learning occurs. We
      studied the development of immunoreactivity for tyrosine hydroxylase (TH) in the
      song nuclei HVc, RA, NIf, LMAN, and Area X in young males aged 20, 35, and 60
      days as well as in adults (> 90 days). We also visualized catecholamines directly
      in Area X using CA histofluorescence. Both TH immunoreactivity and CA
      histofluorescence were initially low in Area X relative to their levels in the
      surrounding parolfactory lobe (LPO), and then increased during development to
      become more intense than in LPO by days 60-90. Similarly, TH immunoreactivity in
      HVc was initially low relative to that in the surrounding neostriatum, then
      increased during development to become more intense than that in the surround by
      day 60. TH immunostaining also increased markedly in NIf, RA, and LMAN over the
      same period. These results show that the levels of catecholamines and their major
      synthetic enzyme increase in song nuclei during development and thus raise the
      possibility that these transmitters contribute to the development of the song
      system or to song learning.

PMID- 8656213
TI  - Axons of Xenopus neural tube respond to reversals of neural tube orientation.
AB  - Axonal trajectories of the Kolmer-Agduhr (KA) neurons of Xenopus embryos, were
      observed after anterior-posterior (A-P) inversions of neural tube grafts to
      determine whether KA axons follow cell-inherent directional cues, cues from their
      immediate environment, or rostrocaudal signals from the embryo. KA axons form one
      of the earliest ascending spinal pathways in Xenopus and are visible in the
      lateral marginal zone of whole mounts processed for GABA immunoreactivity. Grafts
      were made at trunk levels at stages 22-24, 3-5 h before the first KA neurons were
      detectable and prior to axonal out-growth. Embryos were fixed and immunostained 6
      36 h later. KA trajectories within and adjacent to reversed grafts were compared
      to those of nonrotated control grafts and to neural tube lengths comparable in
      position and in length in unoperated embryos. Most KA axons within rotated grafts
      followed the graft's orientation. However, others changed direction, taking novel
      routes, including turning to conform to the orientation of the host embryo.
      Reorientations were most common near the posterior host/graft interface. Some
      host KA cells also reoriented, always within a few hundred microns of the graft
      interface. Taken together, these growth patterns show that most KA axons within
      the grafts grow normally with respect to the original polarity of the graft
      neural tube and maintain that direction even into tissue of opposite polarity,
      suggesting that their routes are mainly determined by cell-intrinsic and/or local
      tissue factors. However, the reorientation of many other axons, particularly near
      graft seams, implies that KA axons can respond to local fluctuations in
      directional or segment identity signals generated in both host and graft after
      this perturbation.

PMID- 8656214
TI  - Brain-derived neurotrophic factor transiently stabilizes silent synapses on
      developing neuromuscular junctions.
AB  - A general feature of the developing nervous system is the activity-dependent
      rearrangement of genetically defined, synaptic connections. A parallel process
      occurs at the developing neuromuscular junction as activity-dependent synapse
      withdrawal reduces the initial polyneuronal innervation of individual muscle
      fibers to a mononeuronal innervation within the first few weeks after birth.
      Because members of the neurotrophin gene family influence motor neuron
      differentiation and survival, we examined whether or not they also influence
      synaptic rearrangements in neonatal muscles. We found that treatment with brain
      derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5
      (NT-4/5) causes the transient retention of multiple synaptic contacts on neonatal
      myofibers. However, the combination of both electrophysiological and histological
      assays revealed that the majority of such supernumerary synaptic contacts are
      functionally inactive or "silent." There also occurs an increase in the number of
      retracting axons. Because BDNF mRNA is expressed in developing muscle and the
      trkB tyrosine kinase receptor for BDNF is expressed by neonatal motor neurons,
      our results suggest that BDNF may play an endogenous role in the refinement of
      synaptic connectivity that occurs in skeletal muscles after birth.

PMID- 8656215
TI  - Optic nerve-dependent changes in adult frog tectal cell phenotypes.
AB  - Optic nerve activity helps determine the placement of retinal ganglion cell
      terminals in the optic tectum of the frog. We investigated whether the presence
      of this nerve might also influence a characteristic of its target structure,
      neurotransmitter biosynthesis. We performed unilateral optic nerve transections
      on adult animals and assayed the percent and intensity of substance P- and
      serotoninlike immunoreactive (SP-ir and 5-HT-ir, respectively) cells in the
      deafferented and afferented tectal lobes. Regeneration of the optic nerve was
      prevented. The percent of SP-ir cells in the afferented tectal lobes was
      significantly less than that in the deafferented ones either 6 weeks or 5 months
      following optic nerve lesion. Comparison to normal animals indicated that the
      change in SP-ir expression was due to a decrease in the percent of immunoreactive
      cells in the afferented tecta ipsilateral to the optic nerve lesion. The
      serotoninlike immunoreactivity of tectal cells was also significantly different
      in the two lobes following optic nerve lesions. This difference resulted from an
      increase in the percent of 5-HT-ir cells in the deafferented tectum. In addition,
      the intensity of 5-HT-ir cells in the deafferented lobe was significantly greater
      than in the afferented one. The staining intensity of SP-ir cells underwent only
      a transient, relative decrease in the deafferented tectum. We conclude that the
      optic nerve does regulate substance P and serotonin expression in the tectum, but
      that this regulation likely occurs through different pathways.

PMID- 8656216
TI  - Steroid control of muscle remodeling during metamorphosis in Manduca sexta.
AB  - During metamorphosis in the tobacco hornworm, Manduca sexta, the abdominal body
      wall muscle DEO1 is remodeled to form the adult muscle DE5. The degeneration of
      muscle DEO1 involves the dismantling of its contractile apparatus followed by the
      degeneration of muscle nuclei. As some nuclei are degenerating, others begin to
      incorporate 5-bromodeoxyuridine (BrdU), indicating the onset of nuclear
      proliferation. This proliferation is initially most evident at the site where the
      motoneuron contacts the muscle remnant. The developmental events involved in
      muscle remodeling are under the control of the steroid hormones, the
      ecdysteroids. The loss of the contractile elements of the larval muscle requires
      the rise and fall of the prepupal peak of ecdysteroids, whereas the subsequent
      loss of muscle nuclei is influenced by the slight rise in ecdysteroids seen after
      pupal ecdysis. Incorporation of BrdU by muscle nuclei depends on both the adult
      peak of the ecdysteroids and contact with the motoneuron. Unilateral axotomy
      blocks proliferation within the rudiment, but it does not block its subsequent
      differentiation into a very thin muscle in the adult.

PMID- 8656217
TI  - Petr Skrabanek and the Lancet.

PMID- 8656218
TI  - A brief history of medicine's war on responsibility.

PMID- 8656219
TI  - Twentieth century paradigms that threaten both scientific and humane medicine in
      the twenty-first century.

PMID- 8656220
TI  - Medical hubris and the public health: the ethical dimension.

PMID- 8656221
TI  - The scope and nature of epidemiology.

PMID- 8656222
TI  - Biostatistics in epidemiology: a view from the faultline.

PMID- 8656223
TI  - The contribution of the case-control approach to vaccine evaluation: Pneumococcal
      and Haemophilus influenzae type B PRP vaccines.
AB  - Case-control studies have had an increasing role in the postlicensure evaluation
      of vaccine efficacy. We review the contribution of case-control studies to the
      evaluation of vaccines for Streptococcus pneumoniae (pneumococcus) and
      Haemophilus influenzae type b (Hib) and compare these studies with clinical
      trials of these vaccines. We located one clinical trial and eight case-control
      studies of Hib PRP vaccine efficacy and three clinical trials and four case
      control studies of pneumococcal vaccine efficacy. The pooled estimate of Hib PRP
      vaccine efficacy based on the case-control studies (0.38, 95% CL = 0.15-0.55) was
      lower than the efficacy of the clinical trial conducted in Finland (0.8, 95% CL =
      0.57-0.98). The pooled estimate of pneumococcal vaccine efficacy based on the
      case-control studies (0.56, 95% CL = 0.44-0.66) was also lower than the pooled
      efficacy of the South African clinical trials (0.79, 95% CL = 0.69-0.86).
      Although the clinical trials provided crucial evidence that these vaccines worked
      in selected international settings, the direct evidence of efficacy in the United
      States rests largely on the case-control results. The utility of the case-control
      approach is supported.

PMID- 8656225
TI  - Epidemiologic research in an integrated regional medical care system: the
      Marshfield Epidemiologic Study Area.
AB  - To capitalize on Marshfield Clinic's advantages for population-based health
      research, we developed the Marshfield Epidemiologic Study Area (MESA). Marshfield
      Clinic is an integrated system consisting of a large multispecialty clinic and 23
      affiliated clinics. Clinic physicians provide virtually all of the medical care,
      both inpatient and outpatient, for residents of the area. MESA consists of 14 ZIP
      codes in which over 95% of the 50,000 residents and most significant health
      events are captured in Marshfield Clinic databases, including all deaths, 94% of
      hospital discharges, and 92% of medical outpatient visits. MESA exemplifies the
      research potential of integrated medical care systems and the efforts required to
      realize that potential. Because it is representative of a defined population and
      provides an unselected sample of patients, MESA is well suited for epidemiologic
      research and research elucidating the clinical spectrum and natural history of
      diseases and the effectiveness of treatment.

PMID- 8656224
TI  - Age-standardized incidence and prevalence of Parkinson's disease in a Swedish
      community.
AB  - Parkinson's disease (PD) shows a geographical variation. All prescriptions for
      anti-parkinsonian drugs were recorded for a half-year in a region with low L-dopa
      consumption. Hospital and outpatient records were studied and physicians were
      asked to supply details of PD patients in the region, with 147,777 inhabitants.
      The crude prevalence was 115 PD per 100,000 inhabitants, based on 170 cases. In
      contrast to other studies we report an age-standardized prevalence, which was 76
      per 100,000, using the European Standard Population as reference. The
      corresponding approximate incidences were 11.0 (crude) and 7.9 (age-standardized)
      per 100,000 person-years. Male preponderance appeared in all age groups. Mean age
      at onset was 65.6 years, the highest figure reported. Variation between studies
      for age at onset, differences in prevalence, and male preponderance suggest
      environmental risk factors to be of importance for PD.

PMID- 8656226
TI  - A computer-assisted telephone interview technique for assessment of asthma
      morbidity and drug use in adult asthma.
AB  - This study concerns an analysis of the feasibility, validity, and repeatability
      of telephone interviews for the collection of data concerning health-related
      quality of life in asthma and patient reports of their use of asthma therapy. A
      computer-assisted hierarchical interview algorithm was developed that allowed
      rapid and precise recording of all aspects of asthma medication including drug,
      dose, and delivery system. This questionnaire was used together with the Symptoms
      and Impacts components of the St. George's Respiratory Questionnaire (SGRQ) in
      one face-to-face and then in three computer-assisted telephone interviews (CATIs)
      that took place 1, 3, and 13 weeks later. One hundred patients with asthma who
      had received inhaled steroids within the previous year were identified from
      general practice records. The intraclass correlation between the face-to-face
      interview and the first CATI for the SGRQ scores and the daily dose of inhaled
      steroid was approximately 0.8. For daily bronchodilator use, this value was 0.56.
      The intraclass correlation obtained between two CATIs 3 months apart was a little
      lower: SGRQ scores, 0.78; inhaled steroid dose, 0.67; bronchodilator use, 0.58.
      Telephone interviews can provide repeatable and efficient measurements of health
      and patient-reported drug use in asthma.

PMID- 8656227
TI  - Diet and plasma lipids in women. I. Macronutrients and plasma total and low
      density lipoprotein cholesterol in women: the Framingham nutrition studies.
AB  - This study examined relationships between diet and plasma total and LDL
      cholesterol levels in a population-based sample of 695 premenopausal and 727
      postmenopausal women participating in the Framingham Offspring/Spouse Study.
      Regression analyses controlled for age, caloric intake, apolipoprotein E isoform
      type, estrogen use, and important CVD risk factors indicated that plasma total
      and LDL-cholesterol levels were directly associated with consumption of saturated
      fat and inversely associated with total calorie intake. In contrast, dietary
      cholesterol was not a predictor of plasma total or LDL cholesterol levels. Total
      cholesterol levels were also directly associated with total fat, oleic acid, and
      animal fat, and inversely associated with carbohydrate intake. Stepwise
      regressions with key nutrients indicated that saturated fat was consistently
      associated with total and LDL cholesterol levels in Framingham women. These
      analyses suggest that diet explains 2% of the variability in these lipid levels
      in a cross-sectional sample of women; the full model explains 22-27%.

PMID- 8656229
TI  - High uric acid: a metabolic marker of coronary heart disease among alcohol
      abstainers.
AB  - The association between serum uric acid level and risk of coronary heart disease
      (CHD) over 21 years was investigated among 6411 middle-aged Japanese-American men
      who were participants in the Honolulu Heart Program. In an age-stratified Cox
      regression model, high serum uric acid (quartile 4 [>6.7 mg/dl], relative to
      quartile 1 [<5.0 mg/dl]) was a significant predictor of definite CHD (RR = 1.33;
      95% confidence interval = 1.08-1.63; p = 0.006). However, when adjustment for
      confounders (body mass index, heavy alcohol consumption, triglycerides, diastolic
      blood pressure, blood glucose, and the ratio of animal to vegetable protein) was
      made, the association of high uric acid with coronary events was substantially
      reduced and became nonsignificant (RR = 1.14; 95% confidence interval = 0.92
      1.42; p = 0.21). There was a significant interaction between serum uric acid and
      drinking status (P = 0.03). Thus, the risk of definite CHD associated with high
      urate levels (quartile 4), relative to low levels (quartile 1), was elevated in
      the abstainers (RR = 1.40; 95% confidence interval = 1.01-1.93; p = 0.02), but
      not in light and moderate drinkers (RR = 1.1 1; 95% confidence interval = 0.79
      1.55; p = 0.58) or among the heavy drinkers (>40 ml of ethanol/day; RR = 0.57;
      95% confidence interval = 0.27-1.21; p = 0.08). It is concluded that elevated
      uric acid may be associated with higher CHD among alcohol abstainers. Whether
      raised urate is an etiological factor for CHD or a manifestation of existing
      arterial disease in nondrinkers deserves further investigation.

PMID- 8656228
TI  - Diet and plasma lipids in women. II. Macronutrients and plasma triglycerides,
      high-density lipoprotein, and the ratio of total to high-density lipoprotein
      cholesterol in women: the Framingham nutrition studies.
AB  - This study examined relationships between macronutrients and plasma
      triglycerides, HDL, and the total-to-HDL cholesterol ratio (T/H ratio) in a
      population-based sample of 695 premenopausal and 727 postmenopausal women
      participating in the Framingham Offspring/Spouse Study. Multivariate regression
      analyses revealed that plasma triglycerides were inversely related to protein,
      fiber, and polyunsaturated fat and directly related to saturated fat and oleic
      acid. Alcohol intake was directly related to HDL cholesterol and inversely
      related to the T/H ratio in all subgroups of women, except for postmenopausal
      women with the 3/2 or 2/2 apolipoprotein E phenotype. Similarly, a direct
      relationship between dietary fat and HDL cholesterol was limited to this single
      subgroup of postmenopausal women. Since dietary fat and alcohol do not appear to
      have consistent effects on plasma lipids in all groups of women, it is important
      to consider the genetic contribution to diet/lipid relationships in
      epidemiological studies and when evaluating lipid-lowering interventions.

PMID- 8656230
TI  - Clinical correlates of advanced retinopathy in type II diabetic patients:
      implications for screening. The CODIAB-INSERM-Zeneca Pharma Study Group.
AB  - The clinical correlates of advanced retinopathy were determined in a sample of
      427 type II diabetic outpatients, aged 35 to 74 years, recruited in eight centers
      from all parts of France. The presence of retinopathy was assessed by fluorescein
      angiography with centralized interpretation. Advanced retinopathy (proliferative
      and/or macular edema) was independently linked with nephropathy, peripheral
      neuropathy, and insulin therapy. Prevalence of advanced retinopathy was 1.6% in
      the absence of signs of nephropathy and/or peripheral neuropathy, 10.4% in
      patients with mild signs, and 17.5% in patients with moderate to severe signs.
      Overall, 87% of the patients with advanced retinopathy had signs of nephropathy
      and/or peripheral neuropathy. In conclusion, patients showing signs of
      nephropathy and/or peripheral neuropathy should be sent in priority to an
      ophthalmologist. Prospective data are necessary to determine if screening is
      necessary in patients with no signs of nephropathy or peripheral neuropathy.

PMID- 8656231
TI  - Can protocol-specified doses of chemotherapy and radiotherapy be used as a
      measure of treatment actually received? A CCG/NIH study on long-term survivors of
      acute lymphocytic leukemia.
AB  - In a cohort of 593 long-term survivors of acute lymphocytic leukemia identified
      through the Children's Cancer Group (CCG), treatment abstracts were obtained and
      compared to protocol information on radiation therapy and intravenous
      chemotherapy. This was done in order to evaluate the actual compliance to
      protocol-specified treatment, and assess if protocol-specified doses can be used
      in studies of late effects of treatment. The compliance to protocol-specified
      type of treatment ranged between 95.3% (intrathecal methotrexate) and 98.6%
      (adriamycin) for chemotherapy, and between 94.1% (cranial radiation) and 97.0%
      (extended field radiation) for radiation. Concordance with the protocol-specified
      chemotherapy dose (+/- 25%) was 57.5% for adriamycin, 91.3% for daunomycin, and
      48.5% for cyclophosphamide. When concordance was low, most patients received
      doses that were lower than expected. Concordance with chemotherapy was
      significantly lower for high-dose regimens than for low-dose regimens.
      Concordance with protocol-specified radiation dose (+/- 10%) was 87.4% for
      cranial radiation, 87.8% for spinal radiation, and 85.7% for extended field
      radiation. Concordance with treatment did not differ by gender, relapse status,
      or age at diagnosis. In this cohort of leukemia survivors, the validity of type
      of treatment was greater than the validity of dosage. Great care should be used
      when drawing conclusions about effects of treatment dosage. Although costly and
      time consuming, it appears that chart reviews are the most appropriate way to
      collect information about dose-related effects of therapy.

PMID- 8656232
TI  - Effects of adjustment on the case-finding potential of cognitive tests.
AB  - Adjustment of a cognitive test for an expected level of performance improves the
      discrimination between brain-diseased and healthy subjects. However, this
      improvement is subject to severe limitations and may be worthwhile only in
      clinical settings, where test results tend to be low regardless of disease
      status. The objective of this study was to provide an empirical demonstration of
      these principles, applied to the detection of dementia with the Mini-Mental State
      Examination (MMSE). The subjects, derived from a population-based sample,
      consisted of 36 cases of dementia (23 diagnosed shortly after testing and 13 at
      follow-up 1 year later) and 301 nondemented subjects defined by a negative follow
      up diagnosis. A simulated group of 179 clinically suspect normals was obtained by
      selecting all cases with an MMSE score below 27. Adjustment was based on the
      Dutch version (DART) of the National Adult Reading Test (NART), which was highly
      correlated (0.53) with the MMSE score of nondemented subjects. The results were
      in accordance with the predictions. We conclude that adjustment is unlikely to
      improve case finding in representative samples, but can be profitable in clinical
      practice, where it will be especially helpful in ruling out cerebral disease.

PMID- 8656233
TI  - Cognitive processes and the decisions of some parents to forego pertussis
      vaccination for their children.
AB  - Public health analyses suggest that, in spite of the possibility that pertussis
      vaccine may cause rare cases of neurological injury, catastrophic risks to
      individual children are lower if they are vaccinated. A number of parents,
      however, choose not to vaccinate their children. The purpose of this study was to
      investigate the decision processes of some parents who choose to vaccinate and
      some parents who choose not to do so. Surveys were mailed to 500 randomly
      selected subscribers of Mothering magazine. Two hundred and ninety-four completed
      questionnaires were returned (59%). In addition to well-recognized factors in
      vaccination decisions, perceived dangers of the vaccine, and of the disease and
      susceptibility to the disease, several cognitive processes not previously
      considered in vaccination decision studies were found to be important predictors
      in this population of parents: perceived ability to control children's
      susceptibility to the disease and the outcome of the disease; ambiguity or doubts
      about the reliability of vaccine information; a preference for errors of omission
      over errors of commission; and recognition that if many other children are
      vaccinated, the risk to unvaccinated children may be lowered. Although perhaps
      most cases of undervaccination for pertussis reflect more general problems of
      health care access, some parents choose to forego vaccination for their children
      for other reasons. Traditional risk-benefit arguments alone will be unlikely to
      persuade these parents to reassess their decisions. Efforts to increase childhood
      vaccination must incorporate an understanding of the cognitive processes that
      help drive these decisions.

PMID- 8656234
TI  - Epidemiologic and economic impact of advanced heart failure.
AB  - As the final common pathway in many forms of cardiovascular disease, heart
      failure is a major public health problem in the United States. It is the only
      cardiovascular condition that is increasing in incidence, prevalence, and
      mortality. The economic impact of heart failure is staggering and is likely to
      escalate as increasing numbers of people are saved from premature death
      attributable to coronary heart disease. This article reviews the incidence,
      prevalence, prognosis, risk factors, and economic impact of this common and
      usually lethal condition.

PMID- 8656235
TI  - Physiologic changes in heart failure--"What's new".
AB  - The physiologic changes that accompany heart failure are complex and evolve over
      time. Adaptations to an initial insult include both central (myocardial) and
      peripheral mechanisms that attempt to maintain adequate cardiac output at rest,
      as well as during increased metabolic demands such as exercise. Physiologic
      models provide insight into these complex changes and are necessary to design and
      evaluate the efficacy of pharmacologic and nonpharmacologic interventions. Recent
      advances in ventricular remodeling and changes in myocardial adrenergic receptors
      are presented as are alterations in vasodilatory response, skeletal muscle
      structure, function, and metabolism.

PMID- 8656236
TI  - Maximizing therapy in the advanced heart failure patient.
AB  - Heart failure is a common clinical syndrome in which left ventricular dysfunction
      results in vasoconstriction, volume overload, activity intolerance, reduced
      quality of life, and high mortality. Recognition of the role of neurohormonal
      activation in the progression of heart failure has led to more effective
      treatment. Integral to optimal treatment of heart failure is maximization of both
      pharmacologic and nonpharmacologic therapy. This article presents information
      important to maximizing both types of therapy in the advanced heart failure
      patient. The importance of effective patient and family education is emphasized.

PMID- 8656237
TI  - Nonpharmacologic interventions in the treatment of heart failure.
AB  - Chronic heart failure represents a significant challenge to caregivers because
      these patients are fragile, care is complex, and the numbers of patients are
      increasing dramatically. The anticipated illness trajectory is also rapidly
      changing due to the advent of pharmacologic interventions that offer greatly
      improved outcomes and quality of life for these patients. Despite such advances,
      mortality and morbidity remain high. Therefore, an important goal is to develop
      and evaluate nonpharmacologic interventions as adjuvant therapy to the
      traditional pharmacologic approach. Although relatively few studies have examined
      nonpharmacologic treatment strategies, it appears that many patients with heart
      failure may benefit significantly from participation in long-term aerobic
      exercise conditioning programs. Psychological and biobehavioral interventions
      also have the potential to substantially enhance treatment outcomes and quality
      of life for patients with chronic heart failure. This article reviews the
      available literature about nonpharmacologic strategies in the treatment of heart
      failure along with specific recommendations for practice.

PMID- 8656238
TI  - When to transplant: Recipient selection for heart transplantation.
AB  - Heart transplantation is an accepted therapeutic alternative for patients with
      end-stage heart failure. The most common diagnoses of patients who require heart
      transplantation are ischemic and nonischemic cardiomyopathy. Evaluation for heart
      transplantation involves an examination of the patient's heart disease including
      left ventricle ejection fraction, hemodynamic status, presence of ventricular
      ectopy, New York Heart Association functional class, symptoms, exercise
      tolerance, and sympathetic nervous system activation. In addition, absolute and
      relative contraindications must be identified to determine their influence on a
      patient's candidacy. Care must be taken to determine the best use of a donor
      heart, a scarce resource, with regard to posttransplant morbidity, mortality, and
      quality of life.

PMID- 8656239
TI  - Team management of congestive heart failure across the continuum.
AB  - Despite an increased incidence of congestive heart failure and frequency of
      hospital admissions for the Medicare population, there is little information
      available on improving outcomes for these patients. As changes in health care
      lead toward capitation, efficient care with limited use of expensive inpatient
      hospital resources is a necessity. The coordination of three critical components-
      inpatient, outpatient, and home care--can lead to positive outcomes in terms of
      functional capacity changes, length of stay, readmission rates, patient self-care
      knowledge, and patient satisfaction.

PMID- 8656240
TI  - Agency for health care policy and research: Clinical practice guidelines for
      heart failure.
AB  - The Agency for Health Care Policy and Research (AHCPR) and Rand Corporation
      convened a panel of experts to review published studies on care of the patient
      with heart failure. The outcome was the Clinical Practice Guideline for the
      evaluation and care of patients with left ventricular systolic dysfunction,
      published in June 1994. This article reviews key points in the clinical practice
      guideline and summarizes important areas for future research to improve patient
      outcomes.

PMID- 8656241
TI  - Health-related quality of life as an outcome for patients with heart failure.
AB  - The Agency for Health Care Policy and Research Clinical Practice Guidelines on
      heart failure recommends that providers assess patients' health-related quality
      of life (HRQOL) and recommends using HRQOL information to modify treatment and
      guide patient and family teaching to facilitate adaptation to heart failure. This
      research column reviews eight studies that measured HRQOL as an outcome for
      patients with medically managed heart failure.

PMID- 8656242
TI  - One hundred thirteen men with hormone-refractory prostate cancer died today.

PMID- 8656243
TI  - Chemotherapy with mitoxantrone plus prednisone or prednisone alone for
      symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with
      palliative end points.
AB  - PURPOSE: To investigate the benefit of chemotherapy in patients with symptomatic
      hormone-resistant prostate cancer using relevant end points of palliation in a
      randomized controlled trial. PATIENTS AND METHODS: We randomized 161 hormone
      refractory patients with pain to receive mitoxantrone plus prednisone or
      prednisone alone (10 mg daily). Nonresponding patients on prednisone could
      receive mitoxantrone subsequently. The primary end point was a palliative
      response defined as a 2-point decrease in pain as assessed by a 6-point pain
      scale completed by patients (or complete loss of pain if initially 1 +) without
      an increase in analgesic medication and maintained for two consecutive
      evaluations at least 3 weeks apart. Secondary end points were a decrease of > or
      = 50% in use of analgesic medication without an increase in pain, duration of
      response, and survival. Health-related quality of life was evaluated with a
      series of linear analog self-assessment scales (LASA and the Prostate Cancer
      Specific Quality-of-Life Instrument [PROSQOLI]), the core questionnaire of the
      European Organization for Research and Treatment of Cancer (EORTC), and a disease
      specific module. RESULTS: Palliative response was observed in 23 of 80 patients
      (29%; 95% confidence interval, 19% to 40%) who received mitoxantrone plus
      prednisone, and in 10 of 81 patients (12%; 95% confidence interval, 6% to 22%)
      who received prednisone alone (P = .01). An additional seven patients in each
      group reduced analgesic medication > or = 50% without an increase in pain. The
      duration of palliation was longer in patients who received chemotherapy (median,
      43 and 18 weeks; P < .0001, log-rank). Eleven of 50 patients randomized to
      prednisone treatment responded after addition of mitoxantrone. There was no
      difference in overall survival. Treatment was well tolerated, except for five
      episodes of possible cardiac toxicity in 130 patients who received mitoxantrone.
      Most responding patients had an improvement in quality-of-life scales and a
      decrease in serum prostate-specific antigen (PSA) level. CONCLUSION: Chemotherapy
      with mitoxantrone and prednisone provides palliation for some patients with
      symptomatic hormone-resistant prostate cancer.

PMID- 8656244
TI  - Simultaneous retroperitoneal, thoracic, and cervical resection of
      postchemotherapy residual masses in patients with metastatic nonseminomatous germ
      cell tumors of the testis.
AB  - PURPOSE: We report our experience with simultaneous resection of residual masses
      above and below the diaphragm in patients with metastatic nomseminomatous germ
      cell tumor (NSGCT) of the testis. MATERIALS AND METHODS: Twenty-four patients
      underwent simultaneous resection of residual postchemotherapy masses in the
      retroperitoneum and chest, including three who also had radical neck dissection.
      All had been heavily pretreated with chemotherapy and five had undergone previous
      retroperitoneal lymph node dissections (RPLNDs). RESULTS: The combined procedure
      was performed with no mortality and low morbidity. The median length of the
      procedure was 5 hours 45 minutes, median blood loss 500 mL, and median length of
      hospital stay 9 days. Complications included one patient with chylous ascites and
      one with a prolonged air leak, both of which resolved with conservative
      management. Eighteen patients had similar pathologic findings in all sites: 13
      with necrosis only and five with teratoma only. Six patients had discordant
      pathology in the abdomen and chest, including one with viable tumor in the chest
      only and two with viable tumor in the abdomen only. The overall actuarial 5-year
      survival rate for all patients was 79%. CONCLUSION: Simultaneous resection of
      neck, chest, and abdominal residual masses after chemotherapy for germ cell
      tumors is both a feasible and safe alternative to staged excision in selected
      patients who require surgical intervention at multiple sites and fulfills the
      objective of rendering patients disease-free in a single operative procedure.

PMID- 8656245
TI  - Critical analysis of the ability of the endorectal coil magnetic resonance
      imaging scan to predict pathologic stage, margin status, and postoperative
      prostate-specific antigen failure in patients with clinically organ-confined
      prostate cancer.
AB  - PURPOSE: To determine whether there is a role for endorectal coil magnetic
      resonance imaging (erMRI) in the prediction of pathologic stage, margin status,
      and/or postoperative prostate-specific antigen (PSA) failure in patients with
      clinically organ-confined prostate cancer. PATIENTS AND METHODS: Using erMRI, the
      radiologic-pathologic correlation of extracapsular extension (ECE) and seminal
      vesicle invasion (SVI) was evaluated in 445 surgically managed patients. Logistic
      regression multivariable analysis was applied to the clinical stage, PSA, biopsy
      Gleason grade, and erMRI findings to assess the outcomes of ECE, SVI, positive
      surgical margins (PSM), and postoperative PSA failure. RESULTS: The accuracy of
      erMRI to predict for ECE and SVI numerically decreased with both increasing PSA
      and biopsy Gleason score because of the increasing false-negative scans in cases
      of microscopic transcapsular or seminal vesicle disease. Of patients who could
      not be categorized into low or high risk for postoperative PSA failure on the
      basis of clinical stage, preoperative PSA, and biopsy Gleason score, a negative
      or positive erMRI for ECE or SVI stratified these patients into groups with a 78%
      versus 21% (P < .0001) 3-year rate of actuarial freedom from PSA failure. In this
      subgroup, the overall accuracy of the erMRI was 70% +/- 6% and 94% +/- 2% for ECE
      and SVI, respectively. The most significant predictor on multivariable analysis
      of PSM was the erMRI finding of ECE (P = .0001). CONCLUSION: This initial report
      suggests that a preoperative erMRI can identify clinically organ-confined
      prostate cancer patients at high risk for having ECE, SVI, and PSM that otherwise
      would be missed on the basis of the clinical stage, preoperative PSA, and biopsy
      Gleason score. Confirmatory studies are needed.

PMID- 8656246
TI  - Prediction of response to treatment in superficial bladder carcinoma through
      pattern of interleukin-2 gene expression.
AB  - PURPOSE: Superficial bladder carcinoma, treated by resection and intravesical
      administration of bacillus Calmette-Guerin (BCG), yields a remission rate that
      approaches 70%. We examined whether expression of interleukin-2 (IL-2) or
      interferon-gamma (IFN-gamma) genes can serve to predict response. PATIENTS AND
      METHODS: During BCG treatment, we analyzed induction of IL-2 and IFN-gamma mRNA
      in peripheral-blood mononuclear cells (PBMC) from 73 patients: 51 with papillary
      tumors and 22 with carcinoma-in-situ (CIS). Results were correlated with
      remission, relapse, or tumor persistence over a 4-year follow-up period. RESULTS:
      Independent of tumor type, induction of IL-2 mRNA was observed for patients who
      responded with remission, but not for those who relapsed (P = .0001).
      Multivariate logistic analysis showed that inducibility of IL-2 mRNA is the
      discriminating parameter, which yields a predictive value of 97% for remission.
      Of 23 patients with relapse/persistence, 22 lacked inducibility of IL-2 mRNA
      (sensitivity, 95.6%), while 35 of 50 patients in remission exhibited inducibility
      (specificity, 70%). For patients with carcinoma-in-situ, in which remission or
      failure depends solely on response to BCG, sensitivity and specificity were 88%
      and 86%, respectively; for patients with papillary tumors, they were 100% and
      64%. IFN-gamma mRNA, by contrast, was clearly inducible in PBMC from all patients
      (P = .51). The disease-free interval increased progressively with inducibility of
      IL-2 mRNA; this trend was highly significant (P = .0001). CONCLUSION: IL-2 gene
      expression is essential for mounting an antitumor response in superficial bladder
      carcinoma. Inducibility of IL-2 mRNA is an independent prognostic parameter and
      useful predictive indicator of remission versus relapse.

PMID- 8656247
TI  - Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with
      advanced colon cancer.
AB  - PURPOSE: A phase I/II study was designed to determine the maximum-tolerated dose
      (MTD) of iodine 125-labeled monoclonal antibody A33 (125I-mAb A33), its limiting
      organ toxicity, and the uptake and retention of radioactivity in tumor lesions.
      PATIENTS AND METHODS: Patients (N = 21) with advanced chemotherapy-resistant
      colon cancer who had not received prior radiotherapy were treated with a single
      125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2
      increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I
      mAb A33 administration. RESULTS: All 20 patients with radiologic evidence of
      disease showed localization of 125I to sites of disease. Twelve of 14 patients,
      who underwent imaging studies 4 to 6 weeks after antibody administration, had
      sufficient isotope retention in tumor lesions to make external imaging possible.
      No major toxicity was observed, except in one patient with prior exposure to
      mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope
      showed variable uptake in the normal bowel, gastrointestinal symptoms were mild
      or absent, and in no case did stools become guaiac-positive. The MTD was not
      reached at 125I doses up to 350 mCi/m2. However, cytotoxicity assays demonstrated
      that patients treated with the highest dose had sufficiently high serum levels of
      125I-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients,
      carcinoembryonic antigen (CEA) levels returned to normal in one patient and
      decreased by 35% and 23%, respectively, in two patients; one additional patient
      had a mixed response on computed tomography. Additional, significant responses
      were observed in those patients treated with chemotherapy [carmustine [BCNU],
      vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the
      125I-mAb A33 study. CONCLUSION: Low-energy emission radioimmunotherapy with doses
      of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity.
      The modest antitumor activity in these heavily pretreated patients is encouraging
      because of lack of toxicity at the doses studied. The long radioactivity
      retention in tumors suggests that isotopes with a long half-life may have a
      therapeutic advantage, based on calculated dose delivery to tumor versus normal
      tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb
      A33 are warranted, and controlled studies must be conducted to evaluate the
      combination of radioimmunotherapy and chemotherapy.

PMID- 8656248
TI  - Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal
      malignancies: influence of serum carcinoembryonic antigen and tumor bulk on
      pharmacokinetics.
AB  - PURPOSE: COL-1 is a high-affinity murine monoclonal antibody (MAb) specific for
      carcinoembryonic antigen (CEA). A phase I trial was conducted in which a uniform
      quantity of antibody labeled with escalating doses of iodine 131 (131I) was
      administered to patients with advanced gastrointestinal (GI) malignancies to
      evaluate tolerance and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients
      with advanced, assessable GI malignancies (16 colon, one pancreas, and one
      gastric) previously treated with conventional chemotherapy (but no pelvic
      radiation) received 20 mg of COL-1 labeled with 131I, with doses from 10 mCi/m2
      to 75 mCi/m2. In this cohort, the baseline serum CEA level ranged from 6 to 2,739
      ng/mL (mean +/- SD, 500 +/- 639). RESULTS: Nuclear imaging detected at least one
      tumor site in all 18 patients; 82% of all tumor involved organs were positive and
      58% of all lesions > or = 1.0 cm were detected. Immune complexes were detected in
      89% of patients 5 minutes after completion of infusion, and levels correlated
      with CEA levels (r = .71). Elevated CEA (> 500 ng/mL) and tumor bulk (total tumor
      area > 150 cm2) correlated directly with clearance of serum radioactivity and
      inversely with serum half-life and cumulative serum radioactivity parameters.
      Nonhematologic toxicity was mild and non-dose-limiting. Hematologic toxicity,
      particularly thrombocytopenia, was both dose-related and dose-limiting. The
      maximal-tolerated dose is 65 mCi/m2. The correlation between dose (millicuries
      per square meter) and thrombocytopenia was made stronger, by accounting for
      either variation in pharmacokinetics, or variation in serum CEA and tumor bulk.
      CONCLUSION: 131I-COL-1 is well tolerated, except for hematologic toxicity. These
      data suggest that patients with highly elevated circulating CEA levels and/or
      increased tumor bulk may clear 131I-labeled COL-1 more rapidly from the
      circulation and experience less myelosuppression.

PMID- 8656249
TI  - Prognostic significance of bone marrow micrometastases in patients with gastric
      cancer.
AB  - BACKGROUND: Monoclonal antibodies (mabs) against components of the cytoskeleton
      such as cytokeratins allow single disseminated epithelial carcinoma cells to be
      detected in the bone marrow. The aim of this study was to examine the prognostic
      relevance of these cells in patients with gastric cancer and to evaluate by
      multivariate analysis their predictive value compared with conventional risk
      factors. PATIENTS AND METHODS: A total of 1 x 10(6) cells from bone marrow
      aspirates were screened immunoctochemically for the presence and absolute number
      of disseminated tumor cells using mab CK2 to cytokeratin component no. 18.
      Patients were monitored prospectively for 30.6 +/- 15.2 months. RESULTS: Between
      one and 122 CK2-positive cells per 1 million mononuclear bone marrow cells were
      present in 95 of 180 patients (53%). A similar prevalence of 51% was found in
      curatively operated patients (55 of 109). Comparison with conventional prognostic
      risk factors showed a correlation of cell dissemination with pathohistologic
      tumor (pT) stage (P = .07) and Bormann classification (P = .022). Tumor-cell
      content in the bone marrow predicted disease-free and overall survival in
      curatively resected patients (P = .007 and P = .049, respectively). Multivariate
      analysis, which included established risk factors, showed that extent of tumor
      cell dissemination was an independent prognostic parameter for disease-free
      survival in T1/2 tumors (P = .014; relative risk [RR], 1.84; 95% confidence
      interval [CI], 1.35 to 2.52), in intestinal type carcinomas according to Lauren
      (P = .008; RR, 1.62; 95% CI, 1.23 to 2.12), and in patients without lymph node
      involvement (P = .004; RR, 2.43; 95% CI, 1.22 to 4.82). CONCLUSION: Presence of
      disseminated tumor cells in bone marrow is indicative of systemic disease even in
      early-stage gastric cancer. The extent of tumor-cell presence in bone marrow
      correlates with prognosis in curatively resected patients. Therefore, a positive
      bone marrow finding may be a selection criteria for adjuvant treatment because of
      minimal residual tumor load.

PMID- 8656250
TI  - Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative
      FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous
      fluorouracil.
AB  - PURPOSE AND METHODS: We identified patients with gastric cancer at high risk for
      recurrence before therapy using endoscopic ultrasonography (EUS). Neoadjuvant
      therapy using the fluorouracil, doxorubicin, and metrotrexate (FAMTX) regimen was
      given for three courses before planned laparotomy with the intention to perform
      curative resection. Postoperatively, intraperitoneal (IP) cisplatin and
      fluorouracil (FU) and intravenous (i.v.) FU were administered to patients
      undergoing resection. RESULTS: Fifty-six assessable patients were treated.
      Preoperative FAMTX therapy was tolerable, with the major toxicity being
      neutropenic fever. One treatment-related death was seen. Eighty-nine percent of
      patients underwent surgical exploration and 61% had potentially curative
      resections. There were two postoperative deaths. Comparison of pathologic tumor
      (pT) stage with EUS-predicted tumor stage showed apparent downstaging in 51% of
      patients. Postoperative IP chemotherapy was delivered to 75% of eligible
      patients. Toxicity was acceptable. There was no increase in operative morbidity
      or mortality compared with concurrent nonstudy patients undergoing a similar
      operative procedure and not receiving preoperative therapy. With a median follow
      up time of 29 months, the median survival duration was 15.3 months. For patients
      who underwent potentially curative resections, the median survival duration was
      31 months. Peritoneal failure was seen in 16% of patients. CONCLUSION:
      Chemotherapy with the FAMTX regimen is tolerable in patients with locally
      advanced gastric cancer, without an increase in operative morbidity or mortality.
      IP therapy can be successfully delivered to most resected patients. The
      intraabdominal failure pattern appears to be decreased compared with expected.
      This approach is an appropriate investigational arm to pursue in future studies.

PMID- 8656251
TI  - Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors.
AB  - PURPOSE: To evaluate the therapeutic effect of iodine-131-labeled
      metaiodobenzylguanidine (131I-MIBG) and unlabeled MIBG in patients with carcinoid
      tumor. MATERIALS AND METHODS: A therapeutic dose of 7.4 GBq (200 mCi) 131I-MIBG
      infused over 4 hours was administered to 30 patients with either carcinoid
      syndrome (n = 20) or tumor symptoms such as pain and fever due to carcinoid tumor
      (n = 10). In general, two courses were given, 6 weeks apart. Due to
      radioactivity, patients had to be isolated for 5 to 7 days. Subsequently, we
      studied the effect of unlabeled MIBG based on the possible pharmaceutic activity
      of MIBG and to avoid the isolation procedure. A doseescalation study of 8.5, 17,
      and 34 mg/m2 MIBG infused over 4 hours at 4-week intervals was performed in 20
      patients with carcinoid syndrome who were not suitable for treatment with the
      radioactive compound. RESULTS: Following 131I-MIBG treatment, symptomatic
      responses were observed in 60% of patients (median duration, 8 months; maximum, 2
      years). Side effects were mild and rapidly reversible in 16 patients, and were
      related to the isolation procedure in seven of these patients. Unlabeled MIBG
      resulted in symptomatic improvement in 60% of patients (median duration, 4.5
      months). Side effects, which included changes in blood pressure, were mild and
      transient. Symptomatic responses were not accompanied by biochemical responses.
      CONCLUSION: Both MIBG treatment regimens were equally effective in the palliation
      of symptoms, but duration of response tended to be much longer with the
      radioactive compound. However, the unlabeled compound provided a simpler
      treatment, eg, in elderly patients and those in poor condition, without the need
      for isolation.

PMID- 8656252
TI  - CD34-positive cells isolated from cryopreserved peripheral-blood progenitor cells
      can be expanded ex vivo and used for transplantation with little or no toxicity.
AB  - PURPOSE: The objectives of this phase I study were to assess the feasibility of
      using cryopreserved peripheral-blood progenitor cells (PBPC) for large-scale CD34
      selection and subsequent expansion, and the safety of their use for reinfusion
      following chemoradiotherapy. PATIENTS AND METHODS: For 10 patients with
      nonmyeloid malignancy, an aliquot from a PBPC harvest was recovered from liquid
      nitrogen, and CD34 selected using the Isolex system (Baxter Healthcare, Newbury,
      United Kingdom) and expanded for 8 days ex vivo in a medium free of animal
      proteins but supplemented with autologous serum, stemcell factor (SCF),
      interleukin-1 beta (IL-1 beta), IL-3, IL-6, and erythropoietin. RESULTS: The mean
      increase for cell number was 21-fold, for colony-forming units
      granulocyte/macrophage (CFU-GM) 139-fold, and for burst-forming units-erythroid
      (BFU-E) 114-fold. The expanded cells were reinfused in tandem with unmanipulated
      material (> or = 25 x 10(4) CFU-GM/kg). The patients did not experience any
      adverse effects immediately on cell infusion or within 48 hours. The 10 index
      patients were compared with 10 historical controls for parameters of
      myelosuppressive morbidity. In this small study, there were no differences in
      either neutrophil or platelet recovery between the patients who received expanded
      cells and historical controls. CONCLUSION: These data demonstrate that CD34 cells
      can successfully be selected from cryopreserved material, expanded ex vivo on a
      large scale, and safely reinfused following myeloablative conditioning regimens.

PMID- 8656253
TI  - Metabolic characterization of breast tumors with positron emission tomography
      using F-18 fluorodeoxyglucose.
AB  - PURPOSE: To evaluate the diagnostic value of position emission tomographic (PET)
      imaging with F-18 fluorodeoxyglucose (FDG) in differentiating between benign and
      malignant breast tumors. PATIENTS AND METHODS: Fifty-one patients, with
      suspicious breast lesions newly discovered either by physical examination or by
      mammography, underwent PET imaging before exploratory surgery. FDG-PET images of
      the breast were analyzed visually and quantitatively for objective assessment of
      regional tracer uptake. RESULTS: Primary breast cancer was identified visually
      with a sensitivity of 68% to 94% and a specificity of 84% to 97% depending on
      criteria used for image interpretation. Quantitative analysis of FDG uptake in
      tumors using standardized uptake values (SUV) showed a significant difference
      between benign (1.4 +/- 0.5) and malignant (3.3 +/- 1.8) breast tumors (P < .01).
      Receiver operating characteristic (ROC) curve analysis exhibited a sensitivity of
      75% and a specificity of 100% at a threshold SUV value of 2.5. Sensitivity
      increased to 92% with a corresponding specificity of 97% when partial volume
      correction of FDG uptake was performed based on independent anatomic information.
      CONCLUSION: PET imaging allowed accurate differentiation between benign and
      malignant breast tumors providing a high specificity. Sensitivity for detection
      of small breast cancer ( < 1 cm) was limited due to partial volume effects.
      Quantitative image analysis combined with partial volume correction may be
      necessary to exploit fully the diagnostic accuracy. PET imaging may be helpful as
      a complimentary method in a subgroup of patients with indeterminate results of
      conventional breast imaging.

PMID- 8656254
TI  - Multicenter, randomized comparative study of two doses of paclitaxel in patients
      with metastatic breast cancer.
AB  - PURPOSE AND METHODS: The objective of this multicenter study was to compare the
      therapeutic index of two different doses of paclitaxel given as a 3-hour infusion
      in patients with metastatic breast cancer (MBC), who had failed to respond to
      previous chemotherapy. A total of 471 patients with MBC were randomized to
      receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks.
      RESULTS: Better treatment results were achieved with high-dose (HD) versus low
      dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete
      response (CR) rate, 5% versus 2% (P = .088); median time to disease progression,
      4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5
      months (P = .321). Patients previously exposed or resistant to anthracyclines
      were as likely to respond as those without such prior exposure. Treatment was
      well tolerated, as documented by the number of administered treatment courses
      (median, six v five; range, one 17 v one to 18), the low frequency of dose
      reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn
      = 5 or 2%) who required treatment discontinuation for adverse reactions. The
      incidence and severity of neutropenia and peripheral neuropathy were dose
      related. After quality-of-life-adjusted time-to-progression analysis, the HD arm
      (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). CONCLUSION: The
      results of this trial substantiate the activity of paclitaxel in the treatment of
      MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2
      suggests a dose-effect relationship. The clinical activity in anthracycline
      resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs
      further evaluation in large trials that use combination chemotherapy and involve
      earlier disease stages.

PMID- 8656255
TI  - Clinical significance of bone marrow metastases as detected using the polymerase
      chain reaction in patients with breast cancer undergoing high-dose chemotherapy
      and autologous bone marrow transplantation.
AB  - PURPOSE: The present study evaluates the clinical significance of detection of
      cytokeratin 19 (K19) in the bone marrow of patients with breast cancer undergoing
      high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT).
      PATIENTS AND METHODS: We studied retrospectively cryopreserved bone marrow
      aspirates from 83 patients with high-risk stage II, III, and IV breast cancer
      obtained before bone marrow harvest but after induction chemotherapy. All samples
      were histologically negative for metastases. Polymerase chain reaction (PCR) for
      K19 was performed according to methods described previously and results were
      correlated with the probability of relapse following HDCT and ABMT. RESULTS: The
      incidence of occult metastases as defined by PCR for K19 message was 52% for 19
      stage II, 57% for 14 stage III, and 82% for 50 stage IV patients (two-tailed P =
      .0075, chi 2 test). The probability of relapse at 3 years after ABMT was 32% and
      94% for K19-positive stage II/III and stage IV patients, respectively, versus 10%
      and 14% for K19-negative stage II/III and stage IV patients, respectively. The
      difference was significant for stage IV patients (two-tailed P = .0002).
      CONCLUSION: It has been shown that PCR is a highly sensitive method to detect K19
      message in the bone marrow. The incidence of K19 positivity in bone marrow
      increases significantly with advancing stage. In patients with breast cancer,
      especially metastatic breast cancer, undergoing HDCT and ABMT, the presence of
      K19 is associated with a poor prognosis.

PMID- 8656257
TI  - Duration and reintroduction of adjuvant chemotherapy for node-positive
      premenopausal breast cancer patients.
AB  - PURPOSE: The optimal duration and timing of adjuvant chemotherapy for breast
      cancer patients remain uncertain and were prospectively studied. PATIENTS AND
      METHODS: We randomly assigned 1,554 premenopausal breast cancer patients with
      node-positive disease in a 2 x 2 factorial design to receive the following: (A)
      cyclophosphamide, methotrexate, and fluorouracil for 6 consecutive courses on
      months 1 to 6 (CMF x 6); (B) CMFx6 plus three single courses of reintroduction
      CMF given on months 9, 12, and 15; (C) CMF for three consecutive courses on
      months 1 to 3 (CMFx3); or (D) CMFx3 plus three single courses of reintroduction
      CMF given on months 6, 9, and 12. Accrual was between July 1986 and April 1993. A
      total of 1,475 patients (95%) were eligible and assessable. The median follow-up
      duration was 60 months. RESULTS: Patients who received CMFx3 without
      reintroduction had a 5-year disease-free survival (DFS) rate of 53% compared with
      58% for the other three treatment groups (hazards ratio [HR], 1.20; 95%
      confidence interval [CI], 1.00 to 1.45; P = .04). The increased risk of relapse
      with CMFx3 was more marked for women aged less than 40 years (308 patients; HR,
      1.32; 95% CI, 0.94 to 1.84; P = .11) and for patients with estrogen receptor (ER)
      negative tumors (455 patients; HR, 1.45; 95% CI, 1.06 to 2.00; P = .02).
      Reintroduction chemotherapy provided additional benefit (HR, 0.86; 95% CI, 0.73
      to 1.01; p = .07), especially for women > or = 40 years of age (1,167 patients;
      HR, 0.82; 95% CI, 0.68 to 0.99; P = .04). CONCLUSION: Three courses of adjuvant
      CMF chemotherapy are not sufficient compared with longer duration CMF
      chemotherapy, especially in younger women and in patients with ER-negative
      primary tumors. Reintroduction chemotherapy showed some evidence of additional
      benefit, but remains investigational.

PMID- 8656256
TI  - Ninety-six-hour paclitaxel infusion after progression during short taxane
      exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic
      breast cancer.
AB  - PURPOSE: A phase II trial of paclitaxel infused over 96 hours in patients with
      metastatic breast cancer with demonstrated disease progression (PD) during short
      infusion taxane treatment was performed to evaluate schedule-dependent activity
      with prolonged drug exposure. The tolerability of this strategy and its
      pharmacokinetic profile and pharmacodynamic correlates were also investigated.
      PATIENTS AND METHODS: Paclitaxel was administered to 26 patients with metastatic
      breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three
      patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during
      1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel.
      Twenty-one patients (81%) had no prior response to the short taxane infusion
      (primary resistance) and five (19%) had prior partial responses (PRs) of brief
      duration before PD (secondary resistance). Plasma paclitaxel concentrations were
      assessed at 24, 48, 72, and 96 hours. RESULTS: After delivery of 195 cycles,
      seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%)
      had major objective responses, with a median response duration of 6 months
      (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or =
      3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no
      significant hypersensitivity reactions occurred. The median steady-state
      paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L
      (range, .023 to .176). Patients who experienced grade 4 neutropenia had
      significantly decreased paclitaxel clearance and higher Css than those with grade
      1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was
      associated with delayed clearance (P < .01) and increased myelo-suppression and
      mucosal toxicity. CONCLUSION: Paclitaxel demonstrates activity against metastatic
      breast cancer when administered over 96 hours to patients with disease that
      recently had progressed during short taxane exposure. Delayed paclitaxel
      clearance and consequent increased toxicity occurred in patients with hepatic
      dysfunction. The activity observed supports preclinical data that suggest
      variability in efficacy and resistance patterns to paclitaxel based on duration
      of exposure.

PMID- 8656258
TI  - Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the
      Gynecologic Oncology Group.
AB  - PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and
      paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS
      AND METHODS: Patients underwent initial surgical assessment and tumor debulking.
      Patients with stage III/IV disease received six cycles of chemotherapy on a
      planned 21-day cycle. Carboplatin dose was calculated based on projected area
      under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to
      determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as
      a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs)
      were required at selected dose levels or could be added based on hematologic
      toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity
      and response. Dose-limiting toxicity (DLT) was hematologic, primarily
      neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour
      infusion were associated with either grade 4 thrombocytopenia or febrile
      neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471
      mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3
      hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120
      mg/m2 was associated with excessive single-cycle and cumulative myelosuppression,
      and was not further evaluated. Measured carboplatin AUC agreed well with the
      calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate
      among 24 patients with measurable disease was 75%, with a median progression-free
      survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with
      paclitaxel using a dose formula based on projected renal clearance. The
      recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2
      over 3 hours without initial G-CSF. This treatment safely achieved a greater dose
      intensity of carboplatin than would have been achieved with conventional dosing
      based on body-surface area.

PMID- 8656259
TI  - Therapeutic monitoring of continuous infusion etoposide in small-cell lung
      cancer.
AB  - PURPOSE: To investigate the feasibility of therapeutic monitoring of etoposide at
      different plasma concentrations of the drug, and the resulting pharmacodynamic
      effects of such an approach. PATIENTS AND METHODS: Forty-nine previously
      untreated small-cell lung cancer (SCLC) patients received single-agent etoposide
      every 3 weeks by continuous infusion over 5 days. Plasma etoposide concentrations
      were monitored 18 and 66 hours into the infusion to permit dose modification. The
      first cohort of 15 patients began treatment with etoposide 2 micrograms/mL, with
      dose escalation to 3 micrograms/mL for cycles 3 and 4 and 4 micrograms/mL for
      cycles 5 and 6, toxicity permitting. The second cohort of 34 patients commenced
      at 3 micrograms/mL, with dose escalation to 4 and 5 micrograms/mL on cycles 3 and
      5, respectively. RESULTS: Mean plasma etoposide concentration during the first
      treatment cycle was 93.4% +/- 26.6% of the target level at 18 hours (57% of
      patients within +/- 20% of the target) and 98.9% +/- 14.5% of the target level at
      66 hours (82% of patients within +/- 20%). Hematologic toxicity was more
      pronounced in those treated with 3 micrograms/mL versus 2 micrograms/mL (median
      nadir neutrophil count, 1.3 v 2.6 x 10(9)/L, P = .032). Tumor responses,
      typically documented by the third cycle, were similar in each cohort (71% in
      patients commenced at 2 micrograms/mL and 70% at 3 micrograms/mL). Treatment
      cohort was not independently predictive of survival. CONCLUSION: Therapeutic
      monitoring of infusional etoposide is feasible and dramatically reduces
      interpatient pharmacokinetic variability. Although this was a small nonrandomized
      trial, the observation of different hematologic toxicity at the two starting
      concentrations but similar antitumor activity further suggests that these effects
      may be associated with different plasma etoposide concentrations.

PMID- 8656260
TI  - Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer:
      a report of high response rates and prolonged survival.
AB  - PURPOSE: Based on preclinical and clinical studies that suggested amifostine may
      potentiate the effects of cytotoxic drugs, we conducted a phase II trial of
      amifostine, cisplatin, and vinblastine (ACV) in patients with metastatic non
      small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with
      metastatic NSCLC received amifostine (740 or 910 mg/m2) before 120 mg/m2 of
      cisplatin on day 1, plus weekly 5 mg/m2 of vinblastine without amifostine. Cycles
      were repeated every 4 weeks. Patients were required to have good performance
      status, no prior chemotherapy or biologic therapy, adequate organ function, and
      measurable disease. RESULTS: Sixteen of 25 assessable patients had an objective
      response documented by computed tomographic (CT) scan (64%; 95% confidence
      interval, 45% to 85%). With a median duration of follow-up of 19.2 months, the
      estimated median survival is 17 months and 1-year survival is 64% (+/- 10%).
      Toxicities included grades 3 and 4 neutropenia (8% and 92%, respectively) and
      nausea and vomiting (32% and 4%, respectively). Reversible grade 3 nephrotoxicity
      occurred in 12% of patients, although only one of 13 patients (7%) who received >
      or = four cycles of therapy had > or = 40% reduction in creatinine clearance.
      Grade 3 neuropathy was observed in seven patients at cumulative cisplatin doses
      that ranged from 324 to 660 mg/m2; grade 3 ototoxicity occurred in three patients
      at cumulative cisplatin doses that ranged from 390 to 450 mg/m2. Four patients
      (16%) required early stopping of an amifostine infusion due to hypotension.
      CONCLUSION: ACV appears to be a highly active regimen in metastatic NSCLC. Acute
      toxicities were generally reversible and the data suggest that amifostine may
      protect against long-term renal insufficiency from cumulative doses of cisplatin.
      Although the sample size of this trial is small, the results are significantly
      encouraging to warrant confirmation in randomized multiinstitutional trials.

PMID- 8656261
TI  - Response of recurrent medulloblastoma to low-dose oral etoposide.
AB  - PURPOSE: The outcome for patients with recurrent medulloblastoma has historically
      been poor, with most patients dying of disseminated disease. Here, we report on
      seven patients with recurrent medulloblastoma, most heavily pretreated with a
      variety of chemotherapeutic agents, including parenteral etoposide (VP-16), who
      showed responses to the administration of repeated courses of low-dose oral VP
      16. PATIENTS AND METHODS: Seven patients age 4 to 16 years were treated with VP
      16 after neuroradiographic and clinical evidence of tumor progression. Six had
      received prior irradiation. All seven had been pretreated with a variety of
      chemotherapeutic agents and schedules, including parenteral VP-16. VP-16 was
      administered orally as repeated 21-day courses at 50 mg/m2/d with a 7-day
      interval between courses. Evaluation consisted of neuroradiographic and clinical
      examination after completion of every two courses of therapy. Complete blood cell
      counts were performed weekly. RESULTS: The major toxicity of oral VP-16 was
      hematologic, with two patients requiring platelet transfusions due to
      thrombocytopenia and two requiring RBC transfusions. All seven patients developed
      treatment-related neutropenia. Two patients were supported with granulocyte
      colony-stimulating factor (G-CSF) between courses. One patient developed
      infectious epididymitis after course 2 and required intravenous antibiotics; this
      illness was complicated by Clostridium difficile colitis. There was one episode
      of fever associated with neutropenia. There were no treatment-related deaths. Of
      seven patients assessed, six have demonstrated partial responses (PRs) and the
      remaining patient had stable disease (SD). CONCLUSION: This report demonstrates
      the activity of oral VP-16 in the treatment of a small cohort of pretreated
      patients with recurrent medulloblastoma. This form of administration of oral VP
      16 was well tolerated and produced modest toxicity.

PMID- 8656262
TI  - Mediastinal tumor size and response to chemotherapy are the only prognostic
      factors in supradiaphragmatic Hodgkin's disease treated by ABVD plus
      radiotherapy: ten-year results of the Paris-Ouest-France 81/12 trial, including
      262 patients.
AB  - PURPOSE: To identify prognostic factors in 262 patients with supradiaphragmatic
      Hodgkin's disease (HD), clinical stages (CS) I and II, prospectively treated
      between 1981 and 1988 according to the Paris-Ouest-France (POF) 81/12 protocol by
      three 1-month cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus
      methylprednisone (ABVD-MP) followed by subtotal nodal irradiation (RT). PATIENTS
      AND METHODS: The size of mediastinal tumor (MT) was measured in all patients: 66
      did not have MT (NoMT); 105 had a small-size MT (SSMT), ie, mediastinal mass
      ratio (MMR) less than 0.33; 58 had a medium-size MT (MSMT), ie, MMR > or = 0.33
      and less than 0.45; and 33 had a bulky MT (BuMT), ie, MMR > or = 0.45. All
      patients received three cycles (CS IA, one cycle only) of ABVD-MP; patients in
      partial remission (PR) or complete remission (CR) after chemotherapy (CT)
      received supradiaphragmatic RT (involved fields, 40 Gy; adjacent fields, 30 Gy)
      plus lumboaortic and splenic RT (30 Gy); patients not in CR or PR after CT
      received salvage CT. RESULTS: Two hundred seventeen patients (82.8%) entered CR
      after CT and 258 (98.5%) after RT. Ten-year freedom-from-progression (FFP) and
      survival rateswere 88.6% and 89.4%, respectively. According to univariate
      analysis, MT size and post-CT status were the only factors to influence both FFP
      and survival. For patients with NoMT or SSMT, those with MSMT, and those with
      BuMT, FFP rates were 94.1%, 87.0%, and 63.0% (P < .001), respectively, while
      corresponding survival rates were 92.6%, 87.2%, and 78.2% (P < .05). FFP rates
      were significantly different between the patients who achieved CR and those who
      did not achieve CR after CT: 94.6% versus 65.3% (P < .001); corresponding
      survival rates were 89.9% and 73.7% (P < .01). Multivariate analysis confirmed
      that MT size and post-CT status were the only two prognostic factors for FFP; for
      survival, the same two characteristics, as well as age (< 40 v > or = 40 years),
      significantly affected prognosis. We were thus able to identify three groups. The
      33 patients (12.6%) with a BuMT had 10-year FFP and survival rates of 63.0% and
      78.2%, respectively. Of 229 patients without BuMT, the 195 who attained CR after
      CT had an optimal prognosis (FFP, 96.6%; survival, 93.6%), while those who failed
      to achieve CR after CT had an intermediate prognosis (FFP, 68.8%; survival,
      77.6%). CONCLUSION: These results demonstrate the independent impact on HD
      prognosis of tumor burden and post-CT status.

PMID- 8656263
TI  - Utility of gallium-67 scintigraphy in low-grade non-Hodgkin's lymphoma.
AB  - PURPOSE: Low-grade non-Hodgkin's lymphoma (LGNHL) has traditionally been
      considered non-gallium-avid. The sensitivity of gallium 67 (67Ga) scintigraphy
      when using modern equipment and techniques in patients with LGNHL was
      investigated. MATERIALS AND METHODS: Fifty-seven consecutive patients with LGNHL
      underwent 67Ga scintigraphy at initial presentation (n = 40), when tumor
      progression occurred during treatment (n = 3), and at suspected disease
      recurrence after continuous clinical remission (CCR) (n = 14). Planar and
      tomographic images were obtained with either a very large field-of-view or a dual
      head digital camera. Of 45 patients with Ga-avid LGNHL, 30 underwent 93 follow-up
      scans (one to six studies per patient). Scan findings were correlated with
      clinical and computed tomographic (CT) findings and with patient outcomes.
      RESULTS: 67Ga scintigraphy was positive in 45 of 57 patients (sensitivity, 79%)
      and in 113 of 164 disease sites (sensitivity, 69%). The sensitivity was higher in
      the more common types of LGNHL: follicular, predominantly small cleaved cell
      (FSC), and follicular, mixed small cleaved and large cell (FM) (84% and 91% in
      patients and 72% and 71% in disease sites, respectively). Sensitivity was lower
      in patients with mucosa-associated lymphoid tissue lymphoma (MALT) and small
      lymphocytic lymphoma (SL). Among 28 patients with disease recurrence after CCR
      (14 with and 14 without baseline studies), 67Ga scan was positive in 25, for a
      sensitivity of 89% for detection of disease recurrence. CONCLUSION: When modern
      technology is used, 67Ga scintigraphy has good sensitivity in patients with
      LGNHL. It therefore can be used to monitor response to therapy and to provide
      early detection of disease recurrence in these patients.

PMID- 8656264
TI  - Spontaneous regression of lymphoproliferative disorders in patients treated with
      methotrexate for rheumatoid arthritis and other rheumatic diseases.
AB  - PURPOSE: To determine the clinicopathologic features of lymphoproliferative
      disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for
      rheumatic diseases (RD) and to define the relationship between the presence of
      Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX
      withdrawal. PATIENTS AND METHODS: In addition to nine new cases, we analyzed 28
      cases previously reported in the literature of LPD in patients receiving MTX for
      RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19
      patients, azathioprine in three, and cyclosporine in one. Extranodal disease was
      identified in 16 patients, but none had CNS involvement. Pathologic findings
      included five cases of Hodgkin's disease and seven low-grade lymphomas. The
      remaining patients had intermediate or aggressive lymphomas. In situ
      hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27
      patients (44%). RESULTS: Among 37 patients, 16 were initially observed after MTX
      withdrawal without additional antitumor therapy. Six achieved a spontaneous
      complete remission (CR), three had a partial response (PR), one had a minimal
      response, and six had no response to MTX withdrawal. Of 10 responding patients,
      EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one
      patient had a CR despite the absence of EBV by PCR and one had a CR but did not
      have viral assays performed. Only one of six patients with negative EBV by ISHS
      or PCR responded to MTX withdrawal. CONCLUSION: MTX withdrawal and observation
      for a short period should be considered in the initial management of patients who
      develop LPD while on MTX therapy. Responses were consistently observed, but not
      limited to patients in whom EBV was detected by ISHS or PCR. Further studies are
      required to confirm these findings and to evaluate the role for EBV in LPD that
      occur in patients receiving MTX.

PMID- 8656265
TI  - Port site recurrences after laparoscopic and thoracoscopic procedures in
      malignancy.
AB  - PURPOSE AND METHODS: A review of the literature was performed to determine the
      number of cases of port site recurrences (PSR) after laparoscopy or thoracoscopy.
      CANCERLINE and MEDLINE were searched, as were citings from retrieved and related
      papers. RESULTS: There have been 35 reported cases of PSR after laparoscopic
      colectomy for colorectal carcinoma, and 23 cases after thoracoscopic procedures
      for lung neoplasms. All of these have been reported since 1993. Since 1991, 12
      cases have been described after laparoscopic cholecystectomy of unsuspected
      gallbladder carcinoma, and another case after biopsy of a known gallbladder
      carcinoma. Ten cases of PSR have been reported after laparoscopic procedures for
      ovarian lesions, often in the presence of peritoneal seeding at diagnosis. Other
      rare PSRs have been documented after several procedures in various malignancies.
      CONCLUSION: Enrollment of patients onto the ongoing intergroup study evaluating
      open versus laparoscopic resection of colon cancer should be encouraged. Until
      valid prospective data on PSR frequency are available, laparoscopic or
      thoracoscopic resection of malignancy off-protocol should be undertaken with
      circumspection.

PMID- 8656266
TI  - Update of recommendations for the use of hematopoietic colony-stimulating
      factors: evidence-based clinical practice guidelines. American Society of
      Clinical Oncology.

PMID- 8656267
TI  - Tobacco control: reducing cancer incidence and saving lives. American Society of
      Clinical Oncology.
AB  - INTRODUCTION: The American Society of Clinical Oncology (ASCO) supports the
      elimination of tobacco products. Toward that goal, ASCO urges the adoption of
      national policy that strengthens regulation of the sale, promotion, and
      distribution of such products. To reduce cancer mortality, our regulatory
      policies must recognize that the nicotine within tobacco is an addictive
      substance, the use of which leads to 30% of all cancer deaths and a total of
      419,000 deaths each year. RESTRICTING ADVERTISING AND PROMOTION: Tobacco-related
      advertising and promotion should be banned. At a minimum, national policies
      should: ban billboards; limit advertising to black and white text only; prohibit
      the sale or giveaway of products that contain tobacco brand names or logos;
      prohibit brand name sponsorship of sporting or entertainment events; and require
      stronger and more prominent warning labels on all tobacco products. RESTRICTING
      ACCESS BY CHILDREN AND TEENAGERS: Despite existing state laws prohibiting sale of
      tobacco products to minors, children are able to buy such products easily.
      National regulation of the sale and distribution of tobacco products is necessary
      to eliminate children's access to tobacco. Where sales are permitted, they should
      be limited to face-to-face purchases by individuals 18 and older. Vending
      machines and other means of distributing tobacco without a face-to-face purchase
      should be outlawed. ENHANCING PUBLIC EDUCATION: To the extent tobacco sales are
      allowed to continue, the federal government should mandate that the tobacco
      industry contribute substantial funds for a national public education campaign to
      prevent young people from smoking and other tobacco use. RAISING TOBACCO EXCISE
      TAXES: ASCO has long advocated a substantial increase (in the range of $2) in the
      federal excise tax on cigarettes and other tobacco products- a measure known to
      decrease consumption, particularly among children. Revenue from a tax on tobacco
      products should be used to support retraining for tobacco farmers, biomedical
      research, health care delivery, and antitobacco education. CONTROLLING TOBACCO
      EXPORTS: United State trade policies should discourage the export of tobacco
      products and manufacturing to foreign markets. At a minimum, United States
      tobacco companies selling or manufacturing tobacco products in foreign markets
      that have not developed comparable health warning labels should be required to
      retain United States warning labels. TAKING RESPONSIBILITY AS HEALTHCARE
      PROFESSIONALS: Physicians, nurses, and other health care professionals-especially
      those in primary care disciplines-have the opportunity and responsibility to
      assist patients' efforts to quit tobacco use and to ensure that nonsmokers
      continue to avoid the addiction. Oncology specialists should discuss the causal
      relationship between tobacco use and cancer as well as a variety of other chronic
      diseases and assist, as required, the patient and family members to end tobacco
      dependency. In addition, health care professionals must advocate that public and
      private insurers be required to provide health care coverage for medically
      necessary interventions, such as counseling and nicotine transdermal systems.

PMID- 8656269
TI  - Prostate interstitial implantation: half the solution.

PMID- 8656268
TI  - Treatment-related fatal sepsis from topotecan/cisplatin and topotecan/paclitaxel.

PMID- 8656270
TI  - Prostate brachytherapy: importance of technique.

PMID- 8656271
TI  - Clinical prognostic factors in adjuvant melanoma trial.

PMID- 8656272
TI  - Adjuvant interferon alfa-2b for high-risk melanoma.

PMID- 8656273
TI  - Neural agrin activates a high-affinity receptor in C2 muscle cells that is
      unresponsive to muscle agrin.
AB  - During synaptogenesis, agrin, released by motor nerves, causes the clustering of
      acetylcholine receptors (AChRs) in the skeletal muscle membrane. Although muscle
      alpha-dystroglycan has been postulated to be the receptor for the activity of
      agrin, previous experiments have revealed a discrepancy between the biological
      activity of soluble fragments of two isoforms of agrin produced by nerves and
      muscles, respectively, and their ability to bind alpha-dystroglycan. We have
      determined the specificity of the signaling receptor by investigating whether
      muscle agrin can block the activity of neural agrin on intact C2 myotubes. We
      find that a large excess of muscle agrin failed to inhibit either the number of
      AChR clusters or the phosphorylation of the AChR induced by picomolar
      concentrations of neural agrin. These results indicate that neural, but not
      muscle, agrin interacts with the signaling receptor. Muscle agrin did block the
      binding of neural agrin to isolated alpha-dystroglycan, however, suggesting
      either that alpha-dystroglycan is not the signaling receptor or that its
      properties in the membrane are altered. Direct assay of the binding of muscle or
      neural agrin to intact myotubes revealed only low-affinity binding. We conclude
      that the signaling receptor for agrin is a high-affinity receptor that is highly
      specific for the neural form.

PMID- 8656274
TI  - Determinants of competitive antagonist sensitivity on neuronal nicotinic receptor
      beta subunits.
AB  - We constructed a series of chimeric and mutant neuronal nicotinic acetylcholine
      receptor beta subunits to map amino acid residues that determine sensitivity to
      competitive antagonists. The beta 2 and beta 4 subunits form pharmacologically
      distinct receptors when expressed in combination with the alpha 3 subunit in
      Xenopus oocytes. At equipotent acetylcholine concentrations, alpha 3 beta 2 is 56
      fold more sensitive to blockage by dihydro-beta-erythroidine than is alpha 3 beta
      4. The alpha 3 beta 2 combination is also sensitive to long-term blockade by
      neuronal bungarotoxin, whereas alpha 3 beta 4 is not. Pharmacological analysis of
      receptors formed by chimeric beta subunits reveals that amino acid residues that
      determine both dihydro-beta-erythroidine and neuronal bungarotoxin sensitivity
      are located within several sequence segments. The major determinant of
      sensitivity to both competitive antagonists is located between residues 54 and
      63. A minor determinant of sensitivity to both antagonists lies between residues
      1 and 54, whereas a minor determinant of NBT sensitivity lies between residues 74
      and 80. Within region 54-63 of beta 2, mutant beta 2 subunits were used to
      identify threonine 59 as a residue critical in determining competitive antagonist
      sensitivity. Changing threonine 59 to lysine, as occurs in beta 4, causes a 9
      fold decrease in dihydro-beta-erythroidine sensitivity and a 71-fold decrease in
      neuronal bungarotoxin sensitivity. Changing polar threonine 59 to negatively
      charged aspartate causes a 2.5-fold increase in neuronal bungarotoxin sensitivity
      and has no effect on dihydro-beta-erythroidine sensitivity.

PMID- 8656275
TI  - [3H]dihydrorotenone binding to NADH: ubiquinone reductase (complex I) of the
      electron transport chain: an autoradiographic study.
AB  - Abnormalities of mitochondrial energy metabolism may play a role in normal aging
      and certain neurodegenerative disorders. In this regard, complex I of the
      electron transport chain has received substantial attention, especially in
      Parkinson's disease. The conventional method for studying complex I has been
      quantitation of enzyme activity in homogenized tissue samples. To enhance the
      anatomic precision with which complex I can be examined, we developed an
      autoradiographic assay for the rotenone site of this enzyme. [3H]dihydrorotenone
      ([3H]DHR) binding is saturable (KD = 15-55 nM) and specific, and Hill slopes of 1
      suggest a single population of binding sites. Nicotinamide adenine dinucleotide
      (NADH) enhances binding 4- to 80-fold in different brain regions (EC50 = 20-40
      microM) by increasing the density of recognition sites (Bmax). Nicotinamide
      adenine dinucleotide phosphate also increases binding, but NAD+ does not. In
      skeletal muscle, heart, and kidney, binding was less affected by NADH. [3H]DHR
      binding is inhibited by rotenone (IC50 = 8-20 nM), meperidine (IC50 = 34-57
      microM), amobarbitol (IC50 = 375-425 microM), and MPP+ (IC50 = 4-5 mM),
      consistent with the potencies of these compounds in inhibiting complex I
      activity. Binding is heterogeneously distributed in brain with the density in
      gray matter structures varying more than 10-fold. Lesion studies suggest that a
      substantial portion of binding is associated with nerve terminals. [3H]DHR
      autoradiography is the first quantitative method to examine complex I with a high
      degree of anatomic precision. This technique may help to clarify the potential
      role of complex I dysfunction in normal aging and disease.

PMID- 8656276
TI  - The taste of monosodium glutamate: membrane receptors in taste buds.
AB  - Receptor proteins for photoreception have been studied for several decades. More
      recently, putative receptors for olfaction have been isolated and characterized.
      In contrast, no receptors for taste have been identified yet by molecular
      cloning. This report describes experiments aimed at identifying a receptor
      responsible for the taste of monosodium glutamate (MSG). Using reverse
      transcriptase (RT)-PCR, we found that several ionotropic glutamate receptors are
      present in rat lingual tissues. However, these receptors also could be detected
      in lingual tissue devoid of taste buds. On the other hand, RT-PCR and RNase
      protection assays indicated that a G-protein-coupled metabotropic glutamate
      receptor, mGluR4, also is expressed in lingual tissues and is limited only to
      taste buds. In situ hybridization demonstrated that mGluR4 is detectable in 40
      70% of vallate and foliate taste buds but not in surrounding nonsensory
      epithelium, confirming the localization of this metabotropic receptor to
      gustatory cells. Expression of mGluR4 in taste buds is higher in preweaning rats
      compared with adult rats. This may correspond to the known higher sensitivity to
      the taste of MSG in juvenile rodents. Finally, behavioral studies have indicated
      that MSG and L-2-amino-4-phosphonobutyrate (L-AP4), a ligand for mGluR4, elicit
      similar tastes in rats. We conclude that mGluR4 may be a chemosensory receptor
      responsible, in part, for the taste of MSG.

PMID- 8656277
TI  - Null mutation of c-fos impairs structural and functional plasticities in the
      kindling model of epilepsy.
AB  - It has been suggested that expression of the immediate early gene c-fos links
      fleeting changes in neuronal activity to lasting modifications of neuronal
      structure and function in the mammalian nervous system. To test this idea, we
      examined behavioral and electrophysiological indices of kindling development and
      kindling-induced sprouting of hippocampal granule cell axons in wild-type (+/+),
      heterozygous (+/-), and homozygous (-/-) mice carrying a null mutation of c-fos.
      The rate of kindling development was significantly attenuated in -/- compared
      with +/+ mice, as evidenced by both electrophysiological and behavioral measures.
      Kindling-induced granule cell axon sprouting as measured by the Timm stain was
      also attenuated in homozygous null mutants compared with +/+ mice, with an
      intermediate effect in +/- mice. The impairment of kindling-induced axonal
      sprouting in the null mutants could not be attributed to either detectable loss
      of dentate hilar neurons or reduced activation of the dentate granule cells by
      seizures. Instead, our data are consistent with the hypothesis that the null
      mutation of c-fos attenuates a pathological activity-determined functional
      plasticity (kindling development) as well as a structural plasticity (mossy fiber
      reorganization). We favor the hypothesis that this "fos-less phenotype" is
      attributable to impaired seizure-induced transcriptional activation of one or
      more growth-related genes.

PMID- 8656278
TI  - Temporal representations of odors in an olfactory network.
AB  - The responses of projection neurons in the antennal lobe of the locust brain (the
      functional analog of mitral-tufted cells in the vertebrate olfactory bulb) to
      natural blends and simple odors were studied with multiple intra- and
      extracellular recordings in vivo. Individual odors evoked complex temporal
      response patterns in many neurons. These patterns differed across odors for a
      given neuron and across neurons for a given odor, but were stable for each neuron
      over repeated presentations (separated by seconds to minutes) of the same odor.
      The response of individual neurons to an odor was superimposed on an odor
      specific coherent oscillatory population activity. Each neuron usually
      participated in the coherent oscillations during one or more specific epochs of
      the ensemble activity. These epochs of phase locking were reliable for each
      neuron over tens of repeated presentations of one odor. The timing of these
      epochs of synchronization differed across neurons and odors. Correlated activity
      of specific pairs of neurons, hence, generally occurred transiently during the
      population response, at times that were specific to these pairs and to the odor
      smelled. The field potential oscillations, therefore, fail to reveal a
      progressive transformation of the synchronized ensemble as the response to the
      odor unfolds. We propose that (1) odors are represented by spatially and
      temporally distributed ensembles of coherently firing neurons, and (2) the field
      potential oscillations that characterize odor responses in the olfactory system
      occur, at least in this animal, in parallel with a slower dynamic odor
      representation.

PMID- 8656279
TI  - Muscarinic activation of a voltage-dependent cation nonselective current in rat
      association cortex.
AB  - The ionic mechanism underlying the acetylcholine-induced depolarization of layer
      V pyramidal neurons of rat prefrontal cortex was examined using whole-cell
      recording in in vitro rat brain slices. Consistent with previous results,
      pressure application of acetylcholine to layer V pyramidal neurons elicited a
      strong depolarization. Pharmacological analysis of this response indicated that
      it was mediated by the stimulation of muscarinic receptors as it was mimicked by
      muscarinic agonists, but not by nicotine, and was blocked by atropine. The inward
      current responsible for the depolarization resulted from the activation of a
      voltage-dependent, cation nonselective current. Thus, the amplitude of the
      current was critically dependent on extracellular sodium concentration but not on
      extracellular potassium or chloride concentration. Examination of the I-V
      relationship for the muscarinic current using voltage clamp revealed that the
      current reversed near -15 mV and exhibited a strong voltage dependence, turning
      off rapidly in the subthreshold range. The voltage dependence of the current led
      to the appearance of a current associated with a conductance decrease when
      examined using steady-state voltage- or current-clamp measurements. This might
      have led to earlier misidentification of this response as mediated by a decrease
      in potassium conductance. These results question the traditional interpretation
      that muscarinic depolarization in cortex is mediated by a decrease in potassium
      conductance. They indicate that the fundamental mechanism responsible for
      muscarinic depolarization in prefrontal cortex involves the activation of a
      voltage-dependent, cation nonselective current. This current might represent a
      previously unsuspected mechanism capable of mediating slow depolarization in the
      central nervous system.

PMID- 8656280
TI  - Layer-specific properties of the transient K current (IA) in piriform cortex.
AB  - Piriform cortex in the rat is highly susceptible to induction of epileptiform
      activity. Experiments in vivo and in vitro indicate that this activity originates
      in endopiriform nucleus (EN). In slices, EN neurons are more excitable than layer
      II (LII) pyramidal cells, with more positive resting potentials and lower spike
      thresholds. We investigated potassium currents in EN and LII to evaluate their
      contribution to these differences in excitability. Whole-cell currents were
      recorded from identified cells in brain slices. A rapidly inactivating outward
      current (IA) had distinct properties in LII (IA,LII) versus EN (IA,EN). The peak
      amplitude of IA,EN was 45% smaller than IA,LII, and the kinetics of activation
      and inactivation was significantly slower for IA,EN. The midpoint of steady-state
      inactivation was hyperpolarized by 10 mV for IA,EN versus IA,LII, whereas
      activation was similar in the two cell groups. Other voltage-dependent potassium
      currents were indistinguishable between EN and LII. Simulations using a
      compartmental model of LII cells argue that different cellular distributions of
      IA channels in EN versus LII cells cannot account for these differences. Thus, at
      least some of the differences are intrinsic to the channels themselves. Current
      clamp simulations suggest that the differences between IA,LII and IA,EN can
      account for the observed difference in resting potentials between the two cell
      groups. Simulations show that this difference in resting potential leads to
      longer first spike latencies in response to depolarizing stimuli. Thus, these
      differences in the properties of IA could make EN more susceptible to induction
      and expression of epileptiform activity.

PMID- 8656281
TI  - Homeostasis of synaptic transmission in Drosophila with genetically altered nerve
      terminal morphology.
AB  - We present a new test of the hypothesis that synaptic strength is directly
      related to nerve terminal morphology through analysis of synaptic transmission at
      Drosophila neuromuscular junctions with a genetically reduced number of nerve
      terminal varicosities. Synaptic transmission would decrease in target cells with
      fewer varicosities if there is a relationship between the number of varicosities
      and the strength of synaptic transmission. Animals that have an extreme
      hypomorphic allele of the gene for the cell adhesion molecule Fasciclin II
      possess fewer synapse-bearing nerve terminal varicosities; nevertheless, synaptic
      strength is maintained at a normal level for the muscle cell as a whole. Fewer
      failures of neurotransmitter release and larger excitatory junction potentials
      from individual varicosities, as well as more frequent spontaneous release and
      larger quantal units, provide evidence for enhancement of transmitter release
      from varicosities in the mutant. Ultrastructural analysis reveals that mutant
      nerve terminals have bigger synapses with more active zones per synapse,
      indicating that synaptic enlargement and an accompanying increase in synaptic
      complexity provide for more transmitter release at mutant varicosities. These
      results show that morphological parameters of transmitting nerve terminals can be
      adjusted to functionally compensate for genetic perturbations, thereby
      maintaining optimal synaptic transmission.

PMID- 8656282
TI  - Brain-derived neurotrophic factor and neurotrophin-4/5 stimulate growth of axonal
      branches from regenerating retinal ganglion cells.
AB  - To investigate the influences of growth factors on axonal regeneration in the
      mammalian CNS, we used intracellular tracers to quantitate the effects of brain
      derived neurotrophic factor (BDNF), neurotrophin (NT)-4/5, or NT-3 on individual
      retinal ganglion cell (RGC) axons in the retinas of adult rats after optic nerve
      transection. A single injection of BDNF or the prolonged administration of NT-4/5
      by mini-pump increased axon branch median lengths by eightfold but had no effect
      on the number of branches formed by the RGC axons. NT-3 did not significantly
      influence axonal regrowth. These specific in vivo effects of BDNF and NT-4/5 on
      axonal regeneration from injured RGCs may be used to promote growth and expand
      the abnormally small terminal arbors observed when RGCs regrow into their CNS
      targets.

PMID- 8656283
TI  - Nerve growth factor (NGF)-mediated protection of neural crest cells from
      antimitotic agent-induced apoptosis: the role of the low-affinity NGF receptor.
AB  - Prevention by nerve growth factor (NGF) of apoptotic death in neural cells has
      been variously ascribed to binding of NGF to its low-affinity (p75) or high
      affinity (trkA) receptor or to a cooperative interaction between the two. In a
      series of studies using, in turn, neuroblastoma cell lines that express only p75,
      mutant NGF species that bind selectively to either p75 or trkA, and a polyclonal
      antibody that binds to the NGF-binding domain of p75, we demonstrate that NGF
      binding to p75 is both necessary and sufficient for the abrogation of apoptosis
      in neuroblastoma cells treated with antimitotic agents.

PMID- 8656284
TI  - Characterization of Drosophila tyramine beta-hydroxylase gene and isolation of
      mutant flies lacking octopamine.
AB  - Octopamine is likely to be an important neuroactive molecule in invertebrates.
      Here we report the molecular cloning of the Drosophila melanogaster gene, which
      encodes tyramine beta-hydroxylase (TBH), the enzyme that catalyzes the last step
      in octopamine biosynthesis. The deduced amino acid sequence of the encoded
      protein exhibits 39% identity to the evolutionarily related mammalian dopamine
      beta-hydroxylase enzyme. We generated a polyclonal antibody against the protein
      product of T beta h gene, and we demonstrate that the TBH expression pattern is
      remarkably similar to the previously described octopamine immunoreactivity in
      Drosophila. We further report the creation of null mutations at the T beta h
      locus, which result in complete absence of TBH protein and blockage of the
      octopamine biosynthesis. T beta h-null flies are octopamine-less but survive to
      adulthood. They are normal in external morphology, but the females are sterile,
      because although they mate, they retain fully developed eggs. Finally, we
      demonstrate that this defect in egg laying is associated with the octopamine
      deficit, because females that have retained eggs initiate egg laying when
      transferred onto octopamine-supplemented food.

PMID- 8656285
TI  - Synchronous GABA-mediated potentials and epileptiform discharges in the rat
      limbic system in vitro.
AB  - Application of 4-aminopyridine (4AP, 50 microM) to combined slices of adult rat
      hippocampus-entorhinal cortex-induced ictal and interictal epileptiform
      discharges, as well as slow field potentials that were abolished by the mu-opioid
      agonist [D-Ala2,N-Me-Phe4,Gly-ol5] enkephalin (DAGO, 10 microM) or the GABAA
      receptor antagonist bicuculline methiodide (BMI, 10 microM); hence, they
      represented synchronous GABA-mediated potentials. Ictal discharges originated in
      the entorhinal cortex and propagated to the hippocampus, whereas interictal
      activity of CA3 origin was usually recorded in the hippocampus. The GABA-mediated
      potentials had no fixed site of origin or modality of propagation; they closely
      preceded (0.2-5 sec) and thus appeared to initiate ictal discharges. Only ictal
      discharges were blocked by the antagonist of the NMDA receptor 3,3-(2
      carboxypiperazine-4-yl)propyl-1-phosphonate (CPP, 10 microM), whereas the non
      NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM)
      abolished all epileptiform activities. The GABA-mediated potentials continued to
      occur synchronously in all regions even after concomitant application of CNQX and
      CPP. [K+]o elevations were recorded in the entorhinal cortex during the ictal
      discharge (peak values = 13.9 +/- 0.9 mM) and the synchronous GABA-mediated
      potentials (peak values = 4.2 +/- 0.1 mM); the latter increases were presumably
      attributable to postsynaptic GABAa-receptor activation because they were
      abolished by DAGO or BMI. Their role in initiating ictal activity was
      demonstrated by using DAGO, which abolished both GABA-mediated synchronous
      potentials and ictal discharges. These data indicate that NMDA-mediated ictal
      discharges induced by 4AP originate in the entorhinal cortex; such a conclusion
      is in line with clinical evidence obtained in temporal lobe epilepsy patients.
      4AP also induces GABA-mediated potentials that spread within the limbic system
      when excitatory transmission is blocked and may play a role in initiating ictal
      discharge by increasing [K+]o.

PMID- 8656286
TI  - Cloning and functional characterization of a novel dopamine receptor from
      Drosophila melanogaster.
AB  - A cDNA clone is described that encodes a novel G-protein-coupled dopamine
      receptor (DopR99B) expressed in Drosophila heads. The DopR99B receptor maps to
      99B3-5, close to the position of the octopamine/tyramine receptor gene at 99A10
      B1, suggesting that the two may be related through a gene duplication. Agonist
      stimulation of DopR99B receptors expressed in Xenopus oocytes increased
      intracellular Ca2+ levels monitored as changes in an endogenous inward Ca2+
      dependent chloride current. In addition to initiating this intracellular Ca2+
      signal, stimulation of DopR99B increased cAMP levels. The rank order of potency
      of agonists in stimulating the chloride current is: dopamine > norepinephrine >
      epinephrine > tyramine. Octopamine and 5-hydroxytryptamine are not active (< 100
      microM). This pharmacological profile plus the second-messenger coupling pattern
      suggest that the DopR99B receptor is a D1-like dopamine receptor. However, the
      hydrophobic core region of the DopR99B receptor shows almost equal amino acid
      sequence identity (40-48%) with vertebrate serotonergic, alpha 1- and beta
      adrenergic, and D1-like and D2-like dopaminergic receptors. Thus, this Drosophila
      receptor defines a novel structural class of dopamine receptors. Because DopR99B
      is the second dopamine receptor cloned from Drosophila, this work establishes
      dopamine receptor diversity in a system amenable to genetic dissection.

PMID- 8656287
TI  - Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by
      calcium and cAMP.
AB  - Understanding the mechanisms involved in the biogenesis of N
      arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine is important in
      view of the possible role of these lipids as endogenous cannabinoid substances.
      Anandamide (which activates cannabinoid CB1 receptors) and N
      palmitoylethanolamine (which activates a CB2-like receptor subtype in mast cells)
      may both derive from cleavage of precursor phospholipid, N
      acylphosphatidylethanolamine (NAPE), catalyzed by Ca(2+)-activated D-type
      phosphodiesterase activity. We report here that the de novo biosynthesis of NAPE
      is enhanced in a Ca(2+)-dependent manner when rat cortical neurons are stimulated
      with the Ca(2+)-ionophore ionomycin or with membrane-depolarizing agents such as
      veratridine and kainate. This reaction is likely to be mediated by a neuronal N
      acyltransferase activity, which catalyzes the transfer of an acyl group from
      phosphatidylcholine to the ethanolamine moiety of phosphatidylethanolamine. In
      addition, we show that Ca2+-dependent NAPE biosynthesis is potentiated by agents
      that increase cAMP levels, including forskolin and vasoactive intestinal peptide.
      Our results thus indicate that NAPE levels in cortical neurons are controlled by
      Ca2+ ions and cAMP. Such regulatory effect may participate in maintaining a
      supply of cannabimimetic N-acylethanolamines during synaptic activity, and prime
      target neurons for release of these bioactive lipids.

PMID- 8656288
TI  - Maternal glucocorticoid secretion mediates long-term effects of prenatal stress.
AB  - There is growing evidence that stressors occurring during pregnancy can impair
      biological and behavioral adaptation to stress in the adult offspring. Mechanisms
      by which stress in the pregnant rat can influence development of the offspring
      are still unknown. In the present study, we investigated the involvement of
      maternal corticosterone secretion during pregnancy on the hypothalamo-pituitary
      adrenal axis activity of adult offspring. We investigated stress-induced
      corticosterone secretion and hippocampal type I and type II corticosteroid
      receptors in male adult rats submitted to prenatal stress born to either mothers
      with intact corticosterone secretion or mothers in which stress-induced
      corticosterone secretion was blocked by adrenalectomy with substitutive
      corticosterone therapy. Repeated restraint during the last week of pregnancy was
      used as prenatal stressor. Furthermore, the specific role of an injection of
      corticosterone before the restraint stress on adrenalectomized mothers with
      substitutive corticosterone treatment was also studied. We report here that
      blockade of the mother's stress-induced glucocorticoid secretion suppresses the
      prolonged stress-induced corticosteroid response and the decrease in type I
      hippocampal corticosteroid receptors usually observed in prenatally stressed
      adults. Conversely, corticosterone administered during stress, to mothers in
      which corticosterone secretion is blocked, reinstates the effects of prenatal
      stress. These results suggest for the first time that stress-induced increases in
      maternal glucocorticoids may be a mechanism by which prenatal stress impairs the
      development of the adult offspring's glucocorticoid response.

PMID- 8656289
TI  - Modulation of a neural network by physiological levels of oxygen in lobster
      stomatogastric ganglion.
AB  - Although a large body of literature has been devoted to the role of O2 in the
      CNS, how neural networks function during long-term exposures to low but
      physiological O2 partial pressure (PO2) has never been studied. We addressed this
      issue in crustaceans, where arterial blood PO2 is set in the 1-3 kPa range, a
      level that is similar to the most frequently measured tissue PO2 in the
      vertebrate CNS. We demonstrate that over its physiological range, O2 can
      reversibly modify the activity of the pyloric network in the lobster Homarus
      gammarus. This network is composed of 12 identified neurons that spontaneously
      generate a triphasic rhythmic motor output in vitro as well as in vivo. When PO2
      decreased from 20 to 1 kPa, the pyloric cycle period increased by 30-40%, and the
      neuronal pattern was modified. These effects were all dose- and state-dependent.
      Specifically, we found that the single lateral pyloric (LP) neuron was
      responsible for the O2-mediated changes. At low PO2, the LP burst duration
      increased without change in its intraburst firing frequency. Because LP inhibits
      the pyloric pacemaker neurons, the increased LP burst duration delayed the onset
      of each rhythmic pacemaker burst, thereby reducing significantly the cycling
      frequency. When we deleted LP, the network was no longer O2-sensitive. In
      conclusion, we propose that (1) O2 has specific neuromodulator-like actions in
      the CNS and that (2) the physiological role of this reduction of activity and
      energy expenditure could be a key adaptation for tolerating low but physiological
      PO2 in sensitive neural networks.

PMID- 8656290
TI  - Synaptic vesicle movements monitored by fluorescence recovery after
      photobleaching in nerve terminals stained with FM1-43.
AB  - We used the fluorescence recovery after photobleaching technique to monitor
      movements of synaptic vesicles in top views of living frog motor nerve terminals
      that had been prestained with the fluorescent dye FM1-43. In each experiment, a
      small portion of a single stained vesicle cluster was bleached with a laser and
      monitored subsequently for signs of recovery as neighboring, unbleached vesicles
      moved into the bleached region. In resting terminals, little or no recovery from
      photobleaching occurred. Repetitive nerve stimulation, which caused all
      fluorescent spots to grow dim as dye was released from exocytosing vesicles, did
      not promote recovery from photobleaching. Pretreatment with botulinum toxin (type
      A, C, or D) blocked exocytosis and destaining, but intense nerve stimulation
      still did not cause significant recovery in bleached regions. These results
      suggest that lateral movements of synaptic vesicles are restricted severely in
      both resting and stimulated nerve terminals. We tested for laser-induced
      photodamage in several ways. Bleached regions could be restained fully with FM1
      43, and these restained regions could be destained fully by nerve stimulation.
      Partially bleached regions could be destained, although the rate of destaining
      was lower than normal. Brisk recovery from photobleaching occurred after
      treatment with okadaic acid, which disrupts synaptic vesicle clusters and causes
      vesicles to spread throughout the nerve terminal. These results suggest that
      vesicle translocation and recycling machinery was intact in photobleached
      regions.

PMID- 8656291
TI  - Visual stimulation regulates the expression of transcription factors and
      modulates the composition of AP-1 in visual cortex.
AB  - It is believed that long-term changes in neuronal function are orchestrated by
      transcription factors, such as AP-1 and ZIF 268, which are in turn regulated by
      synaptic stimulation. To further our understanding of the functional effects of
      such expression, we have examined the DNA-binding activities of both AP-1 and ZIF
      268 by way of electrophoretic mobility shift assays (EMSA) on nuclear extracts
      from visual cortices of rats treated with selective light exposure. Visual
      stimulation after dark rearing increased the DNA-binding activities of both AP-1
      and ZIF 268 to their highest levels within 2 hr. ZIF 268 thereafter dropped to
      levels similar to that observed in naive animals, whereas AP-1 DNA-binding
      activity continued to remain elevated even after 24 hr of stimulation. The
      components of the AP-1 complex, when assessed by EMSA-supershift analysis, showed
      considerable variability under different conditions of exposure. FosB and JunD
      were the major constituents of AP-1 in both naive and dark-reared animals. Brief
      visual stimulation (2 hr) added c-Fos, c-Jun, and JunB to this complex, whereas
      prolonged stimulation (6-24 hr) reduced c-Fos and c-Jun levels significantly,
      leaving only FosB, JunB, and JunD as the major components of AP-1. These results
      suggest that transcriptional control by AP-1 may be generated by selective
      combinatorial interactions of different members of the Fos and Jun families and
      that are guided by activity-dependent processes.

PMID- 8656292
TI  - Schwann cell apoptosis during normal development and after axonal degeneration
      induced by neurotoxins in the chick embryo.
AB  - In the present work, we show that chick embryo Schwann cells die by apoptosis
      both during normal development and after axonal degeneration induced by
      neurotoxin treatment. Schwann cell apoptosis during development takes place
      during a period roughly coincidental with normally occurring motoneuron death.
      Administration of NMDA to chick embryos on embryonic day 7 induces extensive
      excitotoxic motoneuronal damage in the spinal cord without any apparent effects
      on neurons in the dorsal root ganglia (DRG). The death of Schwann cells in
      ventral nerve roots after NMDA treatment causes degenerative changes that display
      ultrastructural features of apoptosis and exhibit in situ detectable DNA
      fragmentation. By contrast, NMDA treatment does not increase the death of Schwann
      cells in dorsal nerve roots. In situ detection of DNA fragmentation in
      combination with the avian Schwann cell marker 1E8 antibody demonstrates that
      dying cells in ventral nerve roots are in the Schwann cell lineage.
      Administration of cycloheximide does not prevent the toxic effects of NMDA on
      motoneurons, but dramatically reduces the number of pyknotic Schwann cells and
      DNA fragmentation profiles in the ventral nerve roots. In ovo administration of
      various tissue extracts (muscle, brain, and spinal cord) from the chick embryo or
      of the motoneuron conditioned medium fails to prevent Schwann cell apoptosis in
      NMDA-treated embryos. Intramuscular administration of the snake toxin beta
      bungarotoxin produces a massive death of both lateral motor column motoneurons
      and DRG neurons, resulting in a substantial increase in the number of pyknotic
      Schwann cells in both ventral and dorsal nerve roots. It is concluded that during
      development, axonal-derived trophic signals are involved in the regulation of
      Schwann cell survival in peripheral nerves.

PMID- 8656293
TI  - Expression of NGF and NT3 mRNAs in hippocampal interneurons innervated by the
      GABAergic septohippocampal pathway.
AB  - We used in situ hybridization for the detection of nerve growth factor (NGF),
      brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT3) mRNAs combined
      with immunocytochemistry against the calcium-binding proteins parvalbumin (PARV),
      calbindin 28k (CALB), and calretinin (CALR) to determine the expression of
      neurotrophins in functionally distinct subsets of hippocampal interneurons. Most
      PARV-immunoreactive neurons in the hippocampus were NGF mRNA-positive (82%),
      which corresponds to 71% of NGF-positive neurons in the hippocampus proper and in
      the dentate gyrus (excluding granule cells). In contrast, only a subset of CALB-
      and CALR-immunoreactive interneurons (24% and 23%, respectively) displayed
      hybridization signals for NGF. Small subsets of PARV- and CALR-positive cells
      expressed NT3 mRNA, but we did not find hippocampal interneurons expressing BDNF
      mRNA. These results show that NGF and NT3 genes are differentially regulated in
      distinct subsets of GABAergic cells, and these interneurons are a major source of
      NGF production in the hippocampus. We also addressed whether hippocampal
      interneurons expressing neurotrophins were targets of the GABAergic
      septohippocampal pathway. We developed a triple-labeling method that combines
      anterograde tracing of this pathway by means of Phaseolus vulgaris
      leucoagglutinin injections, with in situ hybridization for the detection of
      neurotrophins, and immunocytochemistry for calcium-binding proteins. Virtually
      every PARV-positive neuron innervated by GABAergic septohippocampal baskets
      expressed NGF mRNA (86%), whereas 39-59% of CALR- and CALB-positive interneurons
      that were contacted by GABAergic septohippocampal axons showed NGF gene
      expression. A small subset of NT3 mRNA-expressing interneurons was also
      innervated by septohippocampal baskets. These findings show that the GABAergic
      septohippocampal pathway preferentially terminates on interneurons expressing NGF
      mRNA, suggesting that this neurotrophic factor might be involved in the
      specification of this connection and in its maintenance and normal function in
      the adult brain.

PMID- 8656294
TI  - Analysis of the globose basal cell compartment in rat olfactory epithelium using
      GBC-1, a new monoclonal antibody against globose basal cells.
AB  - The olfactory epithelium (OE) supports ongoing neurogenesis throughout life and
      regenerates after experimental injury. Although evidence indicates that
      proliferative cells within the population of globose (light) basal cells (GBCs)
      give rise to new neurons, little is known about the biology of GBCs. Because GBCs
      have been identifiable only by an absence of staining with reagents that mark
      other cell types in the epithelium, we undertook to isolate antibodies that
      specifically react against GBCs and to characterize the GBC compartment in normal
      and regenerating OE. Monoclonal antibodies were produced using mice immunized
      with regenerating rat OE, and a monoclonal antibody designated GBC-1, which
      reacts against GBCs of the rat OE, was isolated. In immunohistochemical analyses,
      antibody GBC-1 was found to label GBCs in both normal and regenerating OE as we
      are currently able to define them: basal cells that incorporate the mitotic
      tracer bromodeoxyuridine and fail to express cytokeratins or neural cell adhesion
      molecule. During epithelial reconstitution after direct experimental injury with
      methyl bromide, expression of the GBC-1 antigen overlaps to a limited extent with
      expression of cell-specific markers for horizontal basal cells, Bowman's gland
      and sustentacular cells, and neurons. These data suggest that GBC-1 may mark
      multipotent cells residing in the GBC compartment, which are prominent during
      regeneration. However, a limited number of cells in the regenerating OE with
      other phenotypic characteristics of GBCs lack expression of the GBC-1 antigen.
      GBC-1 has revealed novel aspects of GBC biology and will be useful for studying
      the process of olfactory neurogenesis.

PMID- 8656295
TI  - A dynamic network simulation of the nematode tap withdrawal circuit: predictions
      concerning synaptic function using behavioral criteria.
AB  - The nematode tap withdrawal reflex demonstrates several forms of behavioral
      plasticity. Although the neural connectivity that supports this behavior is
      identified (Integration of mechanosensory stimuli in Caenorhabditis elegans,
      Wicks and Rankin, 1995, J Neurosci 15:2434-2444), the neurotransmitter
      phenotypes, and hence whether the synapses in the circuit are excitatory or
      inhibitory, remain uncharacterized. Here we use a novel strategy to predict the
      polarity configuration, i.e., the array of excitatory and inhibitory connections,
      of the nematode tap withdrawal circuit using an anatomically and physiologically
      justifiable dynamic network simulation of that circuit. The output of the modeled
      circuit was optimized to the behavior of animals, which possessed circuits
      altered by surgical ablation by exhaustively enumerating an array of synaptic
      signs that constituted the modeled circuit. All possible polarity configurations
      were then compared, and a statistical analysis was used to determine whether, for
      a given synaptic class, a particular polarity was associated with a good fit to
      behavioral data. The results from four related experiments were used to predict
      the polarities of seven of the nine cell classes of the tap withdrawal circuit.
      In addition, the model was used to assess possible roles for two novel
      mechanosensory integration neurons: DVA and PVD.

PMID- 8656296
TI  - Functional mapping of human learning: a positron emission tomography activation
      study of eyeblink conditioning.
AB  - Regional cerebral blood flow (rCBF) was measured using positron emission
      tomography during eyeblink conditioning in young adults. Subjects were scanned in
      three experimental conditions: delay conditioning, in which binaural tones
      preceded air puffs to the right eye by 400 msec; pseudoconditioning, in which
      presentations of tone and air puff stimuli were not correlated in time; and
      fixation rest, which served as a baseline control. Compared with fixation,
      pseudoconditioning produced rCBF increases in frontal and temporal cortex, basal
      ganglia, left hippocampal formation, and pons. Learning-specific activations were
      observed in conditioning as compared with pseudoconditioning in bilateral frontal
      cortex, left thalamus, right medial hippocampal formation, left lingual gyrus,
      pons, and bilateral cerebellum; decreases in rCBF were observed for bilateral
      temporal cortex, and in the right hemisphere in putamen, cerebellum, and the
      lateral aspect of hippocampal formation. Blood flow increased as the level of
      learning increased in the left hemisphere in caudate, hippocampal formation,
      fusiform gyrus, and cerebellum, and in right temporal cortex and pons. In
      contrast, activation in left frontal cortex decreased as learning increased.
      These functional imaging results implicate many of the same structures identified
      by previous lesion and recording studies of eyeblink conditioning in animals and
      humans and suggest that the same brain regions in animals and humans mediate
      multiple forms of associative learning that give meaning to a previously neutral
      stimulus.

PMID- 8656297
TI  - Systemic NMDA receptor antagonist CGP-40116 does not impair memory acquisition
      but protects against NMDA neurotoxicity in rhesus monkeys.
AB  - A widely accepted hypothesis is that long-term potentiation (LTP) is a synaptic
      mechanism of memory. NMDA receptors are critically involved in induction but not
      maintenance of LTP; therefore, their blockade should impair memory acquisition
      but not retrieval. In Experiment 1, we investigated the effect of a systemic NMDA
      receptor antagonist, CGP-40116 [D-isomer of CGP-37849: (E)-2-amino-4-methyl-5
      phosphono-3-pentenoic acid (6 mg/kg, i.m.) 60 min before the testing session] on
      memory acquisition and retrieval by monkeys in the "object-in-place" visual
      memory task, an analog of human episodic memory. Only a small increase in error
      rate was produced (< 3%), and this increase was observed in both retention and
      acquisition tests. This deficit is substantially smaller than the previously
      reported deficit after fornix transection in the same task, and is not specific
      to memory acquisition. In Experiment 2, we investigated the neuroprotective
      effect of CGP-40116. NMDA (68 nmol) was injected into the right hippocampus, then
      CGP-40116 (6 mg/kg) was given intramuscularly, and then NMDA was injected into
      the left hippocampus. The area of cell loss in CA1 and CA3 fields was smaller in
      both hemispheres compared with unprotected monkeys (without CGP-40116). Thus, CGP
      40116 provides both retrograde and anterograde protection against NMDA
      neurotoxicity. These data (1) demonstrate that acquisition of episodic memories
      remains almost intact when an NMDA receptor antagonist is given in a dose
      sufficient to block NMDA receptors in the hippocampus, and (2) indirectly oppose
      the hypothesis that NMDA receptor-dependent LTP plays the key role in memory.

PMID- 8656298
TI  - Banking on cord blood.

PMID- 8656299
TI  - Follow-up home care.

PMID- 8656300
TI  - Toxic shock syndrome.

PMID- 8656301
TI  - Fetal complications related to minor maternal trauma.
AB  - The active lifestyle of pregnant women, in combination with the increased
      incidence of violence in society, place women at greater risk for accidental
      injury during pregnancy. This identification of increased risk has altered the
      health care management of mother and fetus after injury. The health care provider
      treating this patient population must perform thorough maternal-fetal assessments
      and be suspicious of fetal compromise, even in the face of maternal stability.

PMID- 8656302
TI  - Family care related to alpha-fetoprotein screening.
AB  - A family's coping repertoire may be challenged when the result of a standard
      prenatal maternal serum alpha-fetoprotein screening is not within a normal range.
      Abnormal screening results can cause families to experience anxiety and confusion
      at a time when they may need to make difficult decisions. The nurse's role is to
      provide information and emotional support and to coordinate health care services
      for optimal family coping.

PMID- 8656303
TI  - Pregnancy after cardiac transplantation: principles of nursing care.
AB  - The number of cardiac transplants for chronic end-stage disease, congenital heart
      disease, and primary pulmonary hypertension has increased during the past 20
      years. Decreased symptoms, decreased incidence of rejection, and greater
      tolerance of medical regimens have improved the quality of life for heart
      transplant recipients. Women of childbearing age who have undergone cardiac
      transplantation may now consider pregnancy. The principles of nursing care for
      pregnant women who have undergone heart transplantation are presented in this
      article. A case report of pregnancy after cardiac transplantation is included.

PMID- 8656304
TI  - Evaluation of a fetal monitoring education program.
AB  - OBJECTIVE: To evaluate the effectiveness of a fetal monitoring education program
      in increasing nurses' knowledge and clinical skills. DESIGN: Multicenter
      randomized control trial. SETTING: Twelve hospitals in eastern Ontario, Canada.
      PARTICIPANTS: One hundred nine volunteer registered nurses randomly assigned,
      within each hospital, to an experimental (n = 47) or control (n = 62) group.
      Ninety-six nurses (40 in the experimental group and 56 in the control group)
      completed the 6-month follow-up (88% retention). INTERVENTIONS: The experimental
      group participated in a 1-day fetal monitoring workshop and a review session 6
      months later. MAIN OUTCOME MEASURES: Performance on a 45-item knowledge test and
      a 25-item skills checklist. The passing score was at least 75% correct on each
      test. RESULTS: The percentage of nurses in the experimental group passing both
      the knowledge and the clinical skills tests after the workshop was significantly
      higher (p < 0.01) than that of the nurses in the control group: 68.1% versus
      6.5%, respectively. A large difference between the groups remained at the 6-month
      follow-up (experimental, 45%; control, 6.5%). The performance of the nurses in
      the experimental group improved to an 85% pass rate after they attended the 6
      month review session. CONCLUSION: This comprehensive, research-based program is
      effective in increasing fetal monitoring knowledge and clinical skills.

PMID- 8656305
TI  - Holding on: parents' perceptions of premature infants' transfers.
AB  - OBJECTIVE: To describe parents' perceptions of their infants' transfers within a
      regional system of perinatal care. DESIGN: Qualitative; grounded theory
      methodology. SETTING: Interviews were conducted in an office adjacent to a
      neonatal intensive care unit (NICU), in an intermediate care unit (IMCU), and in
      the homes of parents. PARTICIPANTS: Fifteen parents of premature infants were
      recruited and interviewed during the 3 days before their infants were transferred
      from a NICU to an IMCU or home. The 15 parents were interviewed again during the
      5 days after the initial interview to learn their feelings about the transfer.
      DATA COLLECTION: After consent was obtained, unstructured interviews were
      recorded and transcribed. Analyses of the data were ongoing, and the second
      interviews with parents were more focused. RESULTS: Parents identified four
      phases that described their transfer experience. Within the four phases, four
      categories were identified to depict parents experiences further. The core
      category of holding on reflected the belief that transfer home would become a
      reality and normal family life eventually would ensue. CONCLUSIONS: Nurses in
      NICUs and IMCUs have a responsibility to educate the parents of infants at high
      risk. Nurses sensitive to parental perceptions of neonatal transfer can better
      facilitate a positive transfer experience.

PMID- 8656306
TI  - Blood pressure measurement during pregnancy: auscultatory versus oscillatory
      methods.
AB  - OBJECTIVE: To determine the equivalence of auscultatory and oscillatory blood
      pressure measurements. SETTING: Inner-city prenatal clinic. PARTICIPANTS: Eighty
      one women in their 2nd to 9th month of pregnancy. DESIGN: Participants were
      assessed for systolic and diastolic blood pressures on left and right arms using
      auscultatory (manual) and oscillatory (electronic) methods. A correlational study
      design was used. MAIN OUTCOME MEASURES: Differences in pressures related to arm
      and method of measurement. RESULTS: The oscillatory method produced consistently
      higher readings for both systolic (F[1,80] = 45.9, p < 0.001) and diastolic
      (F[1,80] = 25.79, p < 0.001) pressure readings. Correlations between estimates
      generally treated as substitutable all fell below the recommended level of 0.80
      for measurement equivalence. CONCLUSIONS: Results suggest the need for caution
      when interpreting blood pressure estimates as interchangeable. This is
      particularly important when patients move from clinic settings, where
      auscultatory methods predominate, to inpatient settings, where oscillatory
      methods of measurement are used.

PMID- 8656307
TI  - Prenatal and postnatal attachment: a modest correlation.
AB  - OBJECTIVE: To determine whether a correlation exists between prenatal and
      postnatal attachment. DESIGN: Prospective, correlational study with data
      collected during the second half of pregnancy and again 1-2 months after
      delivery. SETTING/PARTICIPANTS: Two hundred twenty-eight women were recruited
      from childbirth education classes. The women were generally young, white, well
      educated, married, and employed. MAIN OUTCOME MEASURES: The Prenatal Attachment
      Inventory (PAI) was used to measure attachment before birth. The Maternal
      Attachment Inventory (MAI), the How I Feel About my Baby Now Scale, and the
      Maternal Separation Anxiety Scale were used to measure attachment after birth.
      RESULTS: One hundred ninety-six women completed all the measures. A correlation
      was found between PAI and MAI scores (r = 0.41, p < 0.001). CONCLUSIONS: A
      correlation between prenatal and postnatal attachment was found. However, the
      modest size of the correlation indicated that other factors also influenced
      postnatal scores. Thus, caution should be exercised when promoting increased
      prenatal attachment in hopes of improving postnatal attachment.

PMID- 8656308
TI  - The comfort and discomfort of infertility.
AB  - Infertility has been described as a life crisis by many authors. Nursing has a
      major role in assisting couples through the infertility diagnosis and treatment
      regimen. The role of nurses is expanding as technologic advances expand and
      families are created using donor eggs, donor sperm, expanded male infertility
      techniques, host uteri, and preimplantation genetic diagnosis. A framework for
      nurses to use to provide comfort in infertility is provided, as are suggestions
      regarding nursing interventions to assist infertile patients through the
      physical, social, psychospiritual, and environmental contexts. The couple using
      advanced reproductive technologies proceeds through the stages of grief to, it is
      hoped, resolution. Kolcaba's matrix can be used as a framework for nursing
      interventions to move couples along the continuum of ease, relief, and
      transcendence.

PMID- 8656309
TI  - Discomforts of the perimenopause.
AB  - The transition to menopause is associated with multiple discomforts that affect
      the whole physical and psychologic self. The physiology of perimenopausal
      discomforts, treatment modalities, and self-help measures are described. Nurses
      can teach women about these multisystem effects and promote comfort and a healthy
      life-style during this time.

PMID- 8656310
TI  - Special needs related to the pain and discomfort of patients with gynecologic
      cancer.
AB  - Patients with gynecologic malignancies can experience pain associated with a
      variety of causes. Chronic pain associated with the disease or treatment presents
      the most problems. Chronic cancer-related pain is associated with negative mood
      states and a decrease in the patient's quality of life. Clinicians must conduct
      pain assessments on a routine basis to accurately diagnose the specific pain
      syndrome in patients with gynecologic cancer. An overview of how to conduct a
      pain assessment with such patients is provided. The etiology, clinical
      manifestations, and treatment strategies for the most common pain syndromes seen
      in patients with gynecologic cancer are reviewed. The use of nonpharmacologic
      interventions with this patient population is discussed.

PMID- 8656311
TI  - Experimental personality designs: analyzing categorical by continuous variable
      interactions.
AB  - Theories hypothesizing interactions between a categorical and one or more
      continuous variables are common in personality research. Traditionally, such
      hypotheses have been tested using nonoptimal adaptations of analysis of variance
      (ANOVA). This article describes an alternative multiple regression-based approach
      that has greater power and protects against spurious conclusions concerning the
      impact of individual predictors on the outcome in the presence of interactions.
      We discuss the structuring of the regression equation, the selection of a coding
      system for the categorical variable, and the importance of centering the
      continuous variable. We present in detail the interpretation of the effects of
      both individual predictors and their interactions as a function of the coding
      system selected for the categorical variable. We illustrate two- and three
      dimensional graphical displays of the results and present methods for conducting
      post hoc tests following a significant interaction. The application of multiple
      regression techniques is illustrated through the analysis of two data sets. We
      show how multiple regression can produce all of the information provided by
      traditional but less optimal ANOVA procedures.

PMID- 8656312
TI  - Delay of gratification, psychopathology, and personality: is low self-control
      specific to externalizing problems?
AB  - We assessed the delay of gratification behavior of 428 twelve- and thirteen-year
      old boys, half of whom were known to manifest symptoms of behavioral disturbance.
      Consistent with the hypothesis that low self-control is a risk factor specific to
      externalizing (aggressive and delinquent) disorders, boys who showed signs of
      externalizing disorders tended to seek immediate gratification in a laboratory
      task more often than both nondisordered boys and boys who showed signs of
      internalizing (anxious and depressed) disorders. In addition, children who were
      able to delay immediate gratification were described by their mothers as ego
      controlled, ego resilient, conscientious, open to experience, and agreeable.
      These results suggest that poor delay of gratification may be one of a select
      number of specific risk factors for externalizing disorder, and that good delay
      of gratification is linked to multiple adaptive tendencies in early adolescence.

PMID- 8656313
TI  - Private and public self-consciousness and articulation of the ought self from
      private and public vantages.
AB  - The current research included two studies that examined whether private and
      public self-consciousness predicts the extent to which individuals schematically
      articulate the ought self from private and public vantages. Each study assessed
      private and public self-consciousness, and tested recognition memory of trait
      adjectives, which participants had rated according to either private/ought (Study
      1) or public/ought (Study 2) self-descriptiveness. Across the studies, the
      convergent and discriminant patterns of false alarms supported the hypotheses
      that (a) the private and public facets of the ought self resemble bipolar
      schemas, and (b) private and public self-consciousness, respectively, predicts
      the extent to which individuals articulate the ought self from either a private
      or a public vantage.

PMID- 8656314
TI  - The relations of dispositional regulation and emotionally to elder's empathy
      related responding and affect while volunteering.
AB  - Researchers recently have proposed that various empathy-related reactions are
      differentially related to individual differences in emotional intensity and
      regulation. This idea was tested with a sample of elderly hospital volunteers. As
      predicted, dispositional sympathy was associated with high levels of both
      dispositional regulation and negative emotional intensity. Personal distress was
      linked with low regulation and high negative emotional intensity, and cognitive
      perspective taking was associated with high regulation. Perspective taking
      moderated the relation of emotional intensity to sympathy and personal distress.
      In addition, elders' negative affect when volunteering at a hospital was
      correlated with low regulation and high levels of regulation and dispositional
      sympathy. The results demonstrate the findings pertaining to vicarious emotional
      responding are generalizable to nonstudent populations engaged in planned,
      sustained helping behavior.

PMID- 8656315
TI  - Affect intensity and individual differences in informational style.
AB  - Although individuals differ widely in the typical intensity of their affective
      experience, the mechanisms that create or maintain these differences are unclear.
      Larsen, Diener, and Cropanzano (1987) examined the hypothesis that individual
      differences in affect intensity (AI) are related to how people interpret
      emotional stimuli. They found that high AI individuals engaged in more
      personalizing and generalizing cognitions while construing emotional stimuli than
      low AI individuals. The present study extends these findings by examining
      cognitive activity during a different task-the generation of information to
      communicate about life events. Participants provided free-response descriptions
      of 16 life events. These descriptions were content coded for five informational
      style variables. It was found that the descriptive information generated by high
      AI participants contained significantly more references to emotional arousal,
      more focus on feelings, and more generalization compared to participants low in
      AI. These results are consistent with the notion that specific cognitive activity
      may lead to, or at least be associated with, dispositional affect intensity. In
      addition, the informational style variables identified in this study were stable
      over time and consistent across situations. Although men and women differ in AI,
      this difference becomes insignificant after controlling for informational style
      variation. Overall results are discussed in terms of a model of various
      psychological mechanisms that may potentially create or maintain individual
      differences in affect intensity.

PMID- 8656316
TI  - Depressive tendencies and susceptibility to anxiety: differential personality
      correlates.
AB  - Although the constructs of depression and anxiety are conceptually and clinically
      separable, they have been difficult to separate psychometrically. The present
      study is an attempt to statistically disentangle the two constructs and to
      evaluate their differential correlates. A common factor analysis of the items in
      a depression and an anxiety inventory was conducted using data collected from two
      samples-208 college students and eighty-seven 18-years-old participating in the
      Block Longitudinal Study. In both samples two factors, interpreted as depressive
      tendencies and susceptibility to anxiety, were found; the factor loadings on each
      factor were highly correlated across the two samples. No sex differences were
      found in these factor structures. Factor-based scores comprised of well
      differentiating items were computed for participants in the Block sample. Using
      partial correlation analyses, observer-measured as well as self-report-based
      personality correlates of the specific variance associated with depressive
      tendencies and with susceptibility to anxiety, respectively, were contrasted. The
      results indicated that a strong interpersonal component discernible in depression
      was less noticeable in anxiety.

PMID- 8656317
TI  - Personal influences on professional work: an empirical case study of B.F.
      Skinner.
AB  - This study addresses the hypothesis that individuals have characteristic ways of
      looking at the world that are revealed not only in their life story but also in
      their professional work. It seeks to provide the first empirical test of this
      hypothesis using systematic methods for data selection, interpretation, and
      matching, as applied to the case of B. F. Skinner. Using the salience identifier
      "primacy" (Alexander, 1990), Skinner's first research design and the first
      paragraph of his autobiography were selected for analysis. Adopting a
      personological approach to interpretation, "scripts" (Tomkins, 1987) were derived
      from these materials by blind and independent coders. A matching task (Allport,
      1961) then indicated that the scripts derived from Skinner's work and life were
      substantially similar and significantly more similar than random pairs of scripts
      . A search through other autobiographical and professional writings by Skinner
      revealed that the elements of the discovered script appear recurrently in his
      imagery.

PMID- 8656318
TI  - Transition from the early 40s to the early 50s in self-directed women.
AB  - How does personality type moderate personality change in middle age? Answers to
      this question were sought with three observer-based measures of self-directedness
      (autonomy, hypersensitivity, and willfulness) scored from the California Q-set
      when the participants in the Mills longitudinal study were age 43. From their
      early 40s to early 50s, high scorers on autonomy (healthy self-directedness)
      increased on California Psychological Inventory measures of impulse control and
      agency, and continued their involvement in high-status occupational careers.
      Despite increases in impulse control, the hypersensitive women had not increased
      in agency and expressed boredom in major social roles. In their early 50s, high
      scorers on willfulness increased in agency but not impulse control. In social
      roles, they perceived themselves as stimulating and creative.

PMID- 8656319
TI  - Assessment and prediction of stress-related growth.
AB  - This article reports the development of the Stress-Related Growth Scale (SRGS)
      and its use in a study examining determinants of stress-related positive outcomes
      for college students. Study 1 analyses showed that the SRGS has acceptable
      internal and test-retest reliability and that scores are not influenced by social
      desirability. Study 2 analyses showed that college students' SRGS responses were
      significantly related to those provided by friends and relatives on their behalf.
      Study 3 analyses tested the determinants of stress-related growth longitudinally.
      Significant predictors of the SRGS were (a) intrinsic religiousness; (b) social
      support satisfaction; (c) stressfulness of the negative event; (d) positive
      reinterpretation and acceptance coping; and (e) number of recent positive life
      events. The SRGS was also positively related to residual change in optimism,
      positive affectivity, number of socially supportive others, and social support
      satisfaction, lending further support to the validity of this new scale. Results
      have implications for current theory on stress-related positive outcomes.

PMID- 8656320
TI  - The effect of perceived challenges and skills on the quality of subjective
      experience.
AB  - This article investigates the effects that perceived challenges and skills in
      activities have on the quality of everyday life experience. Based on flow theory
      it was predicted that quality of daily experience would depend on the challenge
      experienced and skill required in specific situations, as well as on the balance
      between challenge and skill. The Experience Sampling Method (ESM) was used on a
      sample of 208 talented adolescents to measure daily variations in four dimensions
      of experience (concentration, wish to do the activity, involvement, and
      happiness) in four contexts (in school, with relatives, with friends, and in
      solitude). The four dimensions of experience were regressed on the predictors
      challenges, skills, and their absolute difference expressing the
      balance/imbalance of challenges and skills. Hierarchical linear modeling,
      explained in detail herein, was conducted on a 1-week sample of experiences.
      Findings confirm the prediction of flow theory that the balance of challenges and
      skills has a positive and independent effect on the quality of experience. Yet
      some differences of parameter estimates were found between dimensions of
      experience and between social contexts. These heterogeneities call for a further
      improvement of the flow model.

PMID- 8656321
TI  - Comparing the accuracy of personality judgements by the self and knowledgeable
      others.
AB  - In this article we compare the accuracy of personality judgements by the self and
      by knowledgeable others. Self- and acquaintance judgements of general personality
      attributes were used to predict general, videotaped behavioral criteria. Results
      slightly favored the predictive validity of personality judgements made by single
      acquaintances over self-judgements, and significantly favored the aggregated
      personality judgements of two acquaintances over self-judgements. These findings
      imply that the most valid source for personality judgements that are relevant to
      patterns of overt behavior may not be self-reports but the consensus of the
      judgement of the community of one's peers.

PMID- 8656322
TI  - Repressive coping style and the experience and recall of emotion: a naturalistic
      study of daily affect.
AB  - Research shows that people characterized as repressors display inhibited recall
      for unpleasant memories. In this study, the relationship between repressive
      coping style and the recall of affect near the time of the experience was
      compared to delayed recall. An experience sampling technique was used to collect
      affect data twice daily for 4 weeks. Repressive coping style was found to be
      related to low levels of average daily unpleasant affect and lowered delayed
      recall of unpleasant affect. Unlike repressors, high anxious individuals
      overestimated unpleasant affect during delayed recall. Repressors did not exhibit
      isolation of the dominant unpleasant affect from nondominant unpleasant affect in
      daily reporting. The overall pattern of results suggests that the effect of
      repressive coping style is to diminish the encoding of all unpleasant affect,
      whereas trait anxiety appears to promote overestimation in the recall of
      unpleasant affect.

PMID- 8656323
TI  - Self-concept clarity and preferred coping styles.
AB  - This study examined the relation between self-concept clarity and (a) preferred
      general coping styles, (b) coping with a specific event, and (c) coping with a
      specific ongoing situation in 175 undergraduate students. The results of the
      regression analyses for general coping styles indicated that self-concept clarity
      made a reliable but weak positive contribution to active coping styles (e.g.,
      planning and taking action) and a strong negative contribution to passive coping
      styles (e.g, denial). The unique negative contribution of self-concept clarity to
      passive coping was replicated with respect to coping with a specific event and to
      coping with a specific ongoing situation. However, the weaker positive
      contribution of self-concept clarity to active coping was not replicated with
      respect to coping with specific events or specific ongoing situations.

PMID- 8656324
TI  - Beliefs in realistic and unrealistic control: assessment and implications.
AB  - Scales were constructed to measure perceived control over controllable events
      (realistic control) and perceived control over uncontrollable events (unrealistic
      control). Internal reliability, test-retest reliability, and discriminant
      validity of both scales were adequate. Study 1 measured perceived personal
      control over hassles that judges rated on general controllability. For hassles
      very high in controllability, perceived personal control was related to belief in
      realistic control but not to belief in unrealistic control; for hassles very low
      in controllability, perceived personal control was related to belief in
      unrealistic control but not to belief in realistic control. Study 2 showed that
      participants high in unrealistic control belief (but not those high in realistic
      control belief) persevered more on a task that was in part uncontrollable. Study
      3 showed that the combination of low realistic control belief and high
      unrealistic control belief predicted poorer future health, particularly for
      participants who have reported the experience of many negative events and/or
      hassles. The conditions under which unrealistic control results in maladaptive
      outcomes are discussed.

PMID- 8656325
TI  - Social-emotional adjustment and patterns of alcohol use among young adults.
AB  - Individual differences in social-emotional adjustment, jointly defined by levels
      of distress and self-restraint, were used to evaluate (a) patterns of alcohol
      use, (b) reasons for use, and (c) associated problems in two college samples of
      young adults (N = 287 and N = 215). As hypothesized, low self-restraint was
      associated with high levels of alcohol use, drinking to increase positive affect,
      and high levels of alcohol-related problems. Subjective distress was not related
      to levels of use; however, it was associated with drinking to escape negative
      moods and social discomfort and with excessive alcohol-related problems. Both
      high distress and low self-restraint predicted problem drinking beyond what could
      be accounted for by quantity or frequency of alcohol use or by peers' use. Within
      Weinberger and Schwartz's (1990) six-group typology, reactive individuals (high
      distress-low restraint) were especially likely to be problem drinkers, even when
      compared to groups with equivalent alcohol use. In a separate study,
      knowledgeable peers' reports validated the differences between reactive and
      repressive individuals, the two groups most likely to have inaccurate self
      reports.

PMID- 8656326
TI  - Perfectionism and suicidal preoccupation.
AB  - One hundred twenty-nine undergraduate students were assessed for suicidal
      preoccupation, using the Alabama Adolescent Health Survey (AAHS) and selected
      cards from the Thematic Apperception Test (TAT). They were also administered the
      Multidimensional Perfectionism Scale (MPS) to assess perfectionistic tendencies.
      Objective scoring of the TAT was found to be highly reliable. Canonical
      correlational analyses were nonsignificant for a relationship between
      perfectionism and suicidal themes on the TAT. However, the more direct questions
      of the AAHS relating to suicide were significantly related to perfectionism.
      Results suggest that passive perfectionists who procrastinate out of fear of
      making mistakes are more likely to be preoccupied with suicide, unlike
      perfectionists whose strivings produce achievement. High personal standards and
      parental expectations do not appear related to suicidal preoccupations.

PMID- 8656327
TI  - The prejudiced personality, racism, and anti-Semitism: the PR scale forty years
      later.
AB  - The relationship of prejudiced personality traits with racism and anti-Semitism
      was examined with 150 Asian American and White university students. The Prejudice
      (PR) scale, composed of 32 items from the Minnesota Multiphasic Personality
      Inventory, was administered along with the McConahay racism scale and the
      Selznick and Steinberg Anti-Semitism scale. Results indicated that for Whites,
      the PR scale was significantly correlated with old-fashioned and modern racism
      and anti-Semitism, replicating Gough's 1951 study (Gough, 1951b) with the PR
      scale. However, no such relationship was observed for the Asian American group.
      This suggests that personality traits of prejudicial attitudes may be relatively
      stable for Whites but may not be related to outgroup bias for other racial or
      ethnic groups.

PMID- 8656328
TI  - Clinician diagnoses of personality disorders: evidence of a hierarchical
      structure.
AB  - This study examined whether clinicians employ a hierarchical model in the
      diagnosis of personality disorders. Using a methodology developed by Morey and
      Ochoa (1989), the study compared how clinicians diagnose patients (clinical
      diagnoses) to the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.,
      rev.; American Psychiatric Association, 1987) criteria they endorsed for each
      patient (criterion diagnoses). A national sample of 320 clinicians served as
      subjects. When cases were examined in which the patients met diagnostic criteria
      for two or more personality disorders, clinicians used the diagnosis of
      borderline personality disorder more frequently. They failed to use other
      diagnoses whose criteria these patients met. Narcissistic personality disorder
      also appeared to have diagnostic dominance, although somewhat less striking than
      for borderline. These results suggest that clinicians do view the personality
      disorders as hierarchical, with borderline clearly identified as the dominant
      disorder.

PMID- 8656329
TI  - Self-liking and self-competence as dimensions of global self-esteem: initial
      validation of a measure.
AB  - Three studies were conducted to validate the conceptualization of global self
      esteem as consisting of two dimensions: a sense of social worth, or self-liking,
      and a sense of personal efficacy, or self-competence. In Study 1, confirmatory
      factor analysis was used to test the a priori structure of the Self-Liking/Self
      Competence Scale, a self-report instrument designed to measure the two
      dimensions. In Study 2, a second structural analysis showed the dimensionality of
      Rosenberg's (1965) Self-Esteem Scale to parallel the proposed dichotomy. In Study
      3, self-liking and self-competence were related to several theoretically linked
      constructs--depression, self-perceived abilities, and perceived parental approval
      -with the resulting pattern of correlations supporting their conceptualization as
      substantively distinct dimensions. The implications of these findings for
      understanding global self-esteem are discussed.

PMID- 8656330
TI  - Sex, sex roles, and sexual attitudes: figure gender in the Draw-A-Person test
      revisited.
AB  - A study of 116 subjects examined the relationships among subject sex,
      experimenter sex, sex roles, and sexual attitudes as predictors of drawing the
      same-sex figure on the Draw-A-Person test (DAP). Results indicate that subject
      and experimenter sex are consistent and significant predictors of picture sex.
      Masculinity and sexual attitudes also predict but only for female picture
      attributes. The subjects' response to current, historically determined attitudes
      toward gender and gender roles must be seen as strong influences on the sex of
      the drawn picture. A model of some determinants of the sex of the drawn figure is
      offered.

PMID- 8656331
TI  - Parental representations among preschoolers and fourth-grade children:
      integrating object relational and cognitive developmental frameworks.
AB  - The aim of this research was the empirical study of the development of object
      representations among preschool and fourth-grade children. Psychometric
      properties and age differences on structural and qualitative dimensions of
      parental descriptions are reported. The relationships between the dimensions of
      object representations and children's self-perceptions and interpretations of
      situations depicting typical interferences of ongoing parent-child relations were
      explored. Our findings point to multidimensional representations, underlying the
      importance of the structural dimensions of the representation. More mature
      representations were related to more advanced conflict resolution strategies.
      More positive perceptions of self in middle childhood and less idealized self
      concept among preschoolers were associated to higher conceptual levels of
      parental representations. The constraints, as well as the possibilities, inherent
      to research based on narrative models of object representations are discussed.

PMID- 8656333
TI  - Identified and introjected forms of political internalization: extending self
      determination theory.
AB  - Canadian voters' reasons for following political events were assessed prior to
      the 1992 Constitutional Referendum and the 1993 federal election. Results showed
      that reasons reflecting identification were endorsed more frequently than those
      reflecting introjection, and distinctive patterns of cognitions, emotions, and
      actions were associated with the 2 types of internalization. Identification was
      associated with actively seeking information about political events, possessing a
      complex set of political attitudes, and being more likely to actually vote.
      Introjection was associated with relying on the influence of important others,
      experiencing conflicted emotions about political outcomes, and vulnerability to
      persuasion. The study also provided evidence that identification and introjection
      toward politics are distinguishable from intrinsic motivation and amotivation.

PMID- 8656334
TI  - Who lies?
AB  - Seventy-seven undergraduates and 70 demographically diverse members of the
      community completed 12 individual differences measures hypothesized to predict
      lie-telling in everyday life and then kept a diary every day for a week of all of
      their social interactions and all of the lies that they told during those
      interactions. Consistent with predictions, the people who told more lies were
      more manipulative, more concerned with self-presentation, and more sociable.
      People who told fewer lies were more highly socialized and reported higher
      quality same-sex relationships. Manipulative people, less highly socialized
      people, and people with less gratifying same-sex relationships also told
      especially more self-serving lies, whereas people with higher quality same-sex
      relationships told relatively more other oriented lies.

PMID- 8656332
TI  - Interpersonal control and cardiovascular reactivity: goals, behavioral
      expression, and the moderating effects of sex.
AB  - Cardiovascular responses to stressful stimuli have been implicated in the
      development of cardiovascular disease. However, the effects of social stressors
      on short-term changes in blood pressure and heart rate (i.e., cardiovascular
      reactivity [CVR]) are not well understood. The independent effects of an
      incentive to exert interpersonal influence and the expression of socially
      controlling behavior on CVR were examined in 96 undergraduates. For men, both the
      incentive to exert influence and the enactment of a controlling interpersonal
      style produced larger increases in systolic blood pressure. By contrast, although
      the incentive to be influential increased women's CVR, the enactment of a
      cooperative role produced the largest increases in blood pressure among women.
      The effects of social dominance on CVR, sex differences in CVR, and interpersonal
      approaches to the study of these psychophysiological mechanisms are discussed.

PMID- 8656335
TI  - Conceptual analysis and measurement of the construct of ego-resiliency.
AB  - This investigation explored the meaning, measurement, and validity of the ego
      resiliency construct (ER, J.H. Block & J Block) in 3 samples. Study 1 explored
      the internal structure of ER in observer and self-report data, and the
      development of a self-report measure is described. Study 2 tested convergent and
      discriminant relations of ER with personality attributes. Study 3 investigated
      implications of ER for adjustment and effective functioning in adulthood.
      Components of ER obtained through exploratory factor analyses--confident
      optimism, productive and autonomous activity, interpersonal warmth and insight,
      and skilled expressiveness--formed a unitary construct and mirrored the relations
      found between ER and other trait domains. Across samples, there were strong
      relations between ER and effective functioning in diverse areas of life. ER is
      discussed in relation to generally accepted criteria of adjustment and effective
      functioning.

PMID- 8656336
TI  - Reliability shifts in measurement reactivity: driven by content engagement or
      self-engagement?
AB  - Self-report measures require respondents to comprehend the inquiry and then
      engage the self. Two studies investigated how these 2 processes affect the
      answers produced. In Study 1,480 participants completed a locus-of-control scale
      describing themselves, their best friend, or Bill Cosby. Item answers became more
      reliable as the items moved from the beginning to the end of the measure. The
      similar increase for self, friend, and Cosby suggested that exposure to the
      content, rather than self-engagement, was driving the reliability shift. Self
      engagement did activate an actor-observer difference in scale means. Study 2
      focused on the content engagement process. With more item experience, respondents
      were better able to distinguish that prototypic items belonged to the locus-of
      control scale and that distractor items did not. These studies imply that early
      questions clarify the meaning of a measure and improve the reliability of later
      answers.

PMID- 8656337
TI  - Events and subjective well-being: only recent events matter.
AB  - The effect of life events on subjective well-being (SWB) was explored in a 2-year
      longitudinal study of 115 participants. It was found that only life events during
      the previous 3 months influenced life satisfaction and positive and negative
      affect. Although recent life events influenced SWB even when personality at Time
      1 was controlled, distal life events did not correlate with SWB. SWB and life
      events both showed a substantial degree of temporal stability. It was also found
      that good and bad life events tend to covary, both between individuals and across
      periods of the lives of individuals. Also, when events of the opposite valence
      were controlled, events correlated more strongly with SWB. The counterintuitive
      finding that good and bad events co-occur suggests an exciting avenue for
      explorations of the structure of life events.

PMID- 8656338
TI  - What do connectionism and social psychology offer each other?
AB  - Social psychologists can benefit from exploring connectionist or parallel
      distributed processing models of mental representation and process also can
      contribute much to connectionist theory in return. Connectionist models involve
      many simple processing units that send activation signals over connections. At an
      abstract level, the models can be described as representing concepts (as
      distributed patterns of activation), operating like schemas to fill in typical
      values for input information, reconstructing memories based on accessible
      knowledge rather than retrieving static representations, using flexible and
      context-sensitive concepts, and computing by satisfying numerous constraints in
      parallel. This article reviews open questions regarding connectionist models and
      concludes that social psychological contributions to such topics as cognition
      motivation interactions may be important for the development of integrative
      connectionist model.

PMID- 8656339
TI  - Insult, aggression, and the southern culture of honor: an "experimental
      ethnography".
AB  - Three experiments examined how norms characteristic of a "culture of honor"
      manifest themselves in the cognitions, emotions, behaviors, and physiological
      reactions of southern White males. Participants were University of Michigan
      students who grew up in the North or South. In 3 experiments they were insulted
      by a confederate who bumped into the participant and called him an "asshole".
      Compared with northerners--who were relatively unaffected by the insult-
      southerners were (a) more likely to think their masculine reputation was
      threatened, (b) more upset (as shown by a rise in cortisol levels), (c) more
      physiologically primed for aggression (as shown by a rise in testosterone
      levels), (d) more cognitively primed for aggression, and (e) more likely to
      engage in aggressive and dominant behavior. Findings highlight the insult
      aggression cycle in cultures of honor, in which insults diminish a man's
      reputation and he tries to restore his status by aggressive or violent behavior.

PMID- 8656340
TI  - Lying in everyday life.
AB  - In 2 diary studies of lying, 77 college students reported telling 2 lies a day,
      and 70 community members told 1. Participants told more self-centered lies than
      other-oriented lies, except in dyads involving only women, in which other
      oriented lies were as common as self-centered ones. Participants told relatively
      more self-centered lies to men and relatively more other-oriented lies to women.
      Consistent with the view of lying as an everyday social interaction process,
      participants said that they did not regard their lies as serious and did not plan
      them much or worry about being caught. Still, social interactions in which lies
      were told were less pleasant and less intimate than those in which no lies were
      told.

PMID- 8656341
TI  - Discrepancies in pharmacokinetic parameter estimation between bolus and infusion
      studies in the perfused rat hindlimb.
AB  - Isolated, perfused rat hindlimb consists of skeletal muscle, skin, bone, and
      adipose. Hence, it is a heterogeneous preparation composed of slowly
      equilibrating tissues of different characteristics and fractional flow rates.
      This paper shows how caution should be exercised in interpreting the results
      following bolus administration and subsequent statistical moment analysis of
      intravascular markers (51Cr-erythrocytes and 125I-albumin) and lipophilic
      barbiturates. For the intravascular markers, the events in the hindlimb are
      overshadowed by events in the connecting tubing and cannulas, due to their
      comparable volumes. For the barbiturates, these estimates appear to apply to
      short-term effects as the volume estimates obtained following infusion to steady
      state are greater than after bolus administration. For the extravascular markers,
      14C-sucrose, 14C-urea, and 3H-water, no such time dependency was shown. However,
      it is only from the outflow profiles following bolus administration that events
      in the tissue beds can be elucidated.

PMID- 8656343
TI  - Pharmacokinetic parameter estimations by minimum relative entropy method.
AB  - For estimating pharmacokinetic parameters, we introduce the minimum relative
      entropy (MRE) method and compare its performance with least squares methods.
      There are several variants of least squares, such as ordinary least squares
      (OLS), weighted least squares, and iteratively reweighted least squares. In
      addition to these traditional methods, even extended least squares (ELS), a
      relatively new approach to nonlinear regression analysis, can be regarded as a
      variant of least squares. These methods are different from each other in their
      manner of handling weights. It has been recognized that least squares methods
      with an inadequate weighting scheme may cause misleading results (the "choice of
      weights" problem). Although least squares with uniform weights, i.e., OLS, is
      rarely used in pharmacokinetic analysis, it offers the principle of least
      squares. The objective function of OLS can be regarded as a distance between
      observed and theoretical pharmacokinetic values on the Euclidean space RN, where
      N is the number of observations. Thus OLS produces its estimates by minimizing
      the Euclidean distance. On the other hand, MRE works by minimizing the relative
      entropy which expresses discrepancy between two probability densities. Because
      pharmacokinetic functions are not density function in general, we use a
      particular form of the relative entropy whose domain is extended to the space of
      all positive functions. MRE never assumes any distribution of errors involved in
      observations. Thus, it can be a possible solution to the choice of weights
      problem. Moreover, since the mathematical form of the relative entropy, i.e., an
      expectation of the log-ratio of two probability density functions, is different
      from that of a usual Euclidean distance, the behavior of MRE may be different
      from those of least squares methods. To clarify the behavior of MRE, we have
      compared the performance of MRE with those of ELS and OLS by carrying out an
      intensive simulation study, where four pharmaco-kinetic models (mono- or
      biexponential, Bateman, Michaelis-Menten) and several variance models for
      distribution of observation errors are employed. The relative precision of each
      method was investigated by examining the absolute deviation of each individual
      parameter estimate from the known value. OLS is the best method and MRE is not a
      good one when the actual observation error magnitude conforms to the assumption
      of OLS, that is, error variance is constant, but OLS always behaves poorly with
      the other variance models. On the other hand, MRE performs better than ELS and
      OLS when the variance of observation is proportional to its mean. In contrast,
      ELS is superior to MRE and OLS when the standard deviation of observation is
      proportional to its mean. In either case the difference between MRE and ELS is
      relatively small. Generally, the performance of MRE is comparable to that of ELS.
      Thus MRE provides as reliable a method as ELS for estimating pharmacokinetic
      parameters.

PMID- 8656342
TI  - Risk assessment of adverse pulmonary effects induced by adrenaline beta-receptor
      antagonists and rational drug dosage regimen based on receptor occupancy.
AB  - To clarify the beta-1 selectivity of beta-adrenergic receptor blocking agents
      (beta-blocking agents) after typical oral doses, the relationships between the
      effects on exercise heart rate or FEV1 and beta-1 or beta-2 receptor occupancies
      (phi 1, phi 2) of seven beta-blocking agents, acebutolol, atenolol, metoprolol,
      oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively.
      Nonlinear relationships between the pharmacologic effect and phi 1 and between
      the pulmonary adverse effect and phi 2 were obtained. Based on these findings, a
      new index of cardiovascular selectivity is proposed, given by the ratio of beta-1
      receptor occupancy to beta-2 receptor occupancy (phi 1/phi 2). Using this new
      index, there was a little difference in beta-1 selectivity between acebutolol and
      pindolol (3.1:1.0), in contrast to a marked difference in beta-1 selectivity
      (320:1) as a conventional index between these two drugs. This finding indicates
      that even beta-1 selective drugs must be administered carefully to patients with
      pulmonary disease. Furthermore, the relationship between the pharmacologic or
      pulmonary effects and phi 1 or phi 2 has been analyzed quantitatively with a
      ternary complex model and used to develop rational dosage regimens for beta-1
      selective beta-blocking agents, such as atenolol, to obtain the desired
      pharmacologic effects with minimum adverse pulmonary effects.

PMID- 8656344
TI  - A nonlinear mixed-effects pharmacokinetic model comparing two formulations of
      cyclosporine in stable renal transplant patients.
AB  - A nonlinear mixed-effects model simultaneously modeled two pharmacokinetic (PK)
      variables in patients administered cyclosporine twice daily: (i) concentration of
      drug in blood at the end of the 12-hr dosing interval (C12) and (ii) area under
      the concentration-time curve within the dosing interval (AUC). For two
      formulations (Neoral and Sandimmune), the model assessed the following:
      nonlinearity with respect to dose, interoccasion (intraindividual) variability,
      interindividual variability, and within- and across-individual correlation
      between C12 and AUC. Data were pooled from six clinical studies in stable renal
      transplant patients administered each formulation. PK samples on two occasions
      were taken usually for each formulation. Each individual's random effect was
      eight-dimensional consisting of two PK variables for each formulation on two
      occasions. An ANOVA-like partitioning worked well and reduced the variance matrix
      for the random effect to a known function of 13 parameters to be estimated,
      thereby making a numerically intensive computation feasible. Simulations were
      used to check the model fit, to compute standard errors, and to account for
      peculiarities in the residual analysis. Outcomes of tests comparing formulations,
      most of which were statistically significant, favored Neoral (dose proportional,
      lower interoccasion variability, lower interindividual variability, and higher
      correlation between C12 and AUC).

PMID- 8656345
TI  - Development of limited sampling strategies for characteristics of a
      pharmacokinetic profile.
AB  - New approaches for empirical and model-based development of constrained, limited
      sampling strategies for the estimation of one or more characteristics of a
      pharmacokinetic (PK) profile are evaluated. The methods (i) permit a
      specification of an overall risk function weighted by each estimation objective,
      (ii) require only a few sampling times for each of one or more new individuals,
      (iii) permit tight time constraints, such as those imposed by outpatients, and
      (iv) recognize variations across individuals, but determine optimal sampling
      times that are the same for all individuals. The methods are applied to a 4-way
      crossover pharmacokinetic study of two formulations of cyclosporin G, under fed
      and fasted conditions, in renal transplant patients. This application used
      average percentage absolute error for estimating AUC and Cmax with an overall
      risk function that first put all weight on the error for estimating AUC and
      second put equal weights on the errors for estimating AUC and Cmax. Empirical and
      model-based methods identified constrained, 3-point designs with acceptable
      precision for estimating either AUC alone or AUC and Cmax simultaneously. Model
      based sampling times were obtained by software for minimizing a general objective
      function subject to linear constraints where the objective function was evaluated
      by computer-intensive sampling under a nonlinear mixed-effects model. The model
      based approach permitted a direct comparison of the precision of limited and full
      sampling strategies.

PMID- 8656346
TI  - Two year clinical study of a soft acrylic intraocular lens.
AB  - PURPOSE: To assess the efficacy and safety of a soft acrylic intraocular lens
      (IOL) in small incision cataract surgery. METHODS: Sixty-four eyes of 64 patients
      (mean age 71.0 +/- 7.7 [SD] years) who had phacoemulsification and implantation
      of a soft acrylic IOL were followed for 2 years. RESULTS: At day 1, 96.9% of
      patients had corrected visual acuity of 20/40 or better, and 50.0% had 20/20 or
      better. At 2 years postoperatively, 100% had 20/40 or better, and 86.3% had
      20/20. Surgically induced keratometric cylinder remained quite stable throughout
      the 2 year follow-up period, with axis-based astigmatism of +/- 0.3 diopters.
      Flare intensity measured with the laser flare-cell meter was less than that with
      other type of IOLs measured, including poly(methyl methacrylate) and silicone.
      Neodymium:YAG laser capsulotomy was performed in seven cases (11.1%). without
      causing damage to the optic. No other postoperative complications were
      encountered. CONCLUSION: Soft acrylic IOLs have clinically apparent advantages in
      small incision cataract surgery.

PMID- 8656347
TI  - Clinical evaluation of a five-zone refractive multifocal intraocular lens.
AB  - PURPOSE: To evaluate the clinical performance of a five-zone refractive
      multifocal intraocular lens (AMO, model MPC-25NB, Array). METHODS: We performed a
      retrospective clinical trial of 31 cataract patients (mean age 64.3 years). The
      parameters studied were intraoperative and postoperative complications, distance
      and near visual acuity, spectacle use, decreased number of corneal endothelial
      cells, contrast sensitivity, percentage of glare disability, near binocular
      vision, and depth of focus. RESULTS: Intraoperatively, iris damage occurred in
      two eyes (4.2%), vitreous loss in one eye (2.1%), and consecutive rupture of
      Zinn's zonule and vitreous in one eye (2.1%). Postoperatively, posterior capsule
      opacification was observed in two eyes (4.2%), temporary intraocular pressure
      increase in one eye (2.1%), and cystoid macular edema in one eye (2.1%).
      Uncorrected distance visual acuity of 20/40 or better was achieved by 34 of 37
      eyes (91.9%) with less than 1.5 diopters of preoperative keratometric
      astigmatism; best corrected distance acuity of 20/20 or better was achieved by 41
      of 45 eyes (91.1%). Near visual acuity with distance correction of 20/40 or
      better was achieved by 29 of 43 eyes (67.4%). These data were compared
      retrospectively with data from control patients who received monofocal lenses,
      and no significant differences in the decreased number of corneal endothelial
      cells were found. Mean contrast sensitivities were within normal range for all
      spatial frequencies. Percentage of glare disability and near binocular vision
      were within normal limits. CONCLUSIONS: Eyes implanted with the five-zone
      refractive multifocal lens showed better near visual acuity than control eyes and
      compared favorably in other aspects of visual function, indicating that these
      lenses are effective and safe.

PMID- 8656348
TI  - Evaluation of intraocular lens power calculation formulas in the triple
      procedure.
AB  - PURPOSE: To determine whether the choice of intraocular lens (IOL) power formula
      improves IOL power predictions and whether personalized constants within the IOL
      power formula are critical factors in improving refractive predictions after
      combined penetrating keratoplasty, cataract extraction, and IOL implantation.
      METHODS: Records of 46 patients who had the triple procedure between January 1988
      and December 1992 were evaluated using the SRK II, SRK/T, Holladay, and Hoffer Q
      formulas to predict the postoperative spherical equivalent refractions for
      implanted lens power. Calculations were carried out with and without the use of
      personalized constants. The predictive accuracy of each formula was assessed by
      comparing the actual postoperative spherical equivalent refractive error with
      that predicted by the formulas. The predictive error and the distribution of
      predictive errors were used to assess predictive accuracy. RESULTS: There was no
      difference in the mean absolute predictive errors and the distribution of
      predictive errors for the four formulas evaluated (P > .05). The use of
      personalized formula constants significantly reduced the mean absolute predictive
      error for the SRK II, SRK/T, and Holladay formulas (P < .05) and approached
      significance for the Hoffer Q formula. CONCLUSION: The findings suggest that the
      choice of IOL power formula does not affect IOL power predictions in the corneal
      triple procedure; however, personalized constants within a formula appears to be
      a critical factor in improving postoperative refractive predictions.

PMID- 8656349
TI  - Algorithm for determining equivalent A-constants and surgeon factors.
AB  - PURPOSE: To describe statistical algorithms for determining surgeon factors and
      corresponding A-constants and compare them to empirical data. METHODS: The
      Holladay and SRK/T equations are rearranged to develop a series of equations
      expressing the surgeon factor as a function of the A-constant or, alternatively,
      the A-constant as a function of the surgeon factor. These expressions are
      statistically manipulated using keratometric and axial length distributions to
      determined clinically equivalent A-constant-surgeon factor pairs. Predictions
      made by this algorithm are fit to a linear equation that accurately relates
      surgeon factors to equivalent A-constants and are compared to a set of
      corresponding A-constants and surgeons factors used by the Food and Drug
      Administration for labeling purposes. Algorithm performance is assessed by
      calculating the difference between the Holladay and SRK/T intraocular lens power
      equations, establishing equivalence criteria. These calculations are performed
      using clinically equivalent A-constant-surgeon factor pairs with an axial length
      and average corneal curvature corresponding to the population mean. RESULTS: The
      difference calculation is less than or equal to 0.02 diopter (D) for A-constants
      ranging between 110.0 and 120.0. A comparison of the algorithm with empirically
      derived corresponding A-constant-surgeon factor pairs shows that the two methods
      are identical for A-constants ranging between 117.0 and 119.0; however,
      differences in equivalent surgeon factors predicted by these methods increase
      with decreasing A-constants. The magnitude of this difference is 0.44 mm at an A
      constant of 110.0, resulting in a difference of 0.45 D in equivalence criteria.
      CONCLUSIONS: These data demonstrate that the statistical algorithm provides an
      improvement in A-constant-surgeon factor equivalent for A-constants less than
      117.0. The structure of this algorithm can easily be adapted to interrelate other
      pairs of personal constants and serves as a theoretical method to standardize
      personal constants.

PMID- 8656350
TI  - Effect of peripheral subepithelial fibrosis on corneal transplant topography.
AB  - Subepithelial fibrosis in the area of peripheral suture placement is an often
      overlooked phenomenon of healing following uneventful penetrating keratoplasty
      surgery. Three affected cornea transplant patients whose sutures had been removed
      were studied using videophotokeratoscopy before and after stripping of the
      subepithelial tissue with cellulose sponges and jeweler's forceps. All three
      showed relative flattening in the involved hemimeridian prior to treatment.
      Removal of the fibrotic tissue produced relative steepening in the same area.
      Overall graft astigmatism was essentially unchanged following the procedure in
      each patient. However, average central keratometric readings increased
      approximately 1 to 2 diopters in each patient, demonstrating that these
      peripheral changes have a direct influence on corneal power. The surface
      regularity index and surface asymmetry index values improved in two of the three
      patients and manifest spectacle visual acuity improved in each patient.

PMID- 8656351
TI  - Neodymium:YAG laser optical opening for retained Descemet's membrane after
      penetrating keratoplasty.
AB  - A 78-year-old woman who had intracapsular cataract extraction and anterior
      chamber intraocular lens implantation 8 years earlier presented with decreased
      visual acuity (20/400) and discomfort of 2 years duration in the operated eye.
      Penetrating keratoplasty was done to improve visual function and reduce
      discomfort; however, at 6 months postoperative, visual acuity was 20/800, due in
      part to retained opacified host corneal tissue. A retrograft (duplicate) membrane
      was identified at the posterior aspect of the graft/host junction. The
      neodymium:YAG laser was used to create a central 3.5 mm circular opening in the
      duplicate membrane. There were no complications from the laser treatment. The
      donor cornea remained thin and clear, and visual acuity improved to 20/40 with
      spectacle correction. It is imperative to confirm complete removal of host
      corneal tissue before implanting donor tissue; however, vision can be restored,
      and a corneal graft can remain clear following laser membranotomy.

PMID- 8656352
TI  - Modified trabeculectomy/trabeculotomy with no-stitch cataract surgery.
AB  - This study combined a modified trabeculectomy and trabeculotomy with no-stitch
      cataract surgery as a safe and effective combined surgical procedure for
      cataracts and glaucoma. One hundred consecutive patients were followed for a
      minimum of three months to a maximum of three years, between July 1991 and
      September 1994. We found the procedure to be effective in controlling intraocular
      pressure and restoring vision while eliminating the occurrence of flat anterior
      chambers.

PMID- 8656353
TI  - Wessely-type immune ring following phototherapeutic keratectomy.
AB  - Immune rings following photorefractive keratectomy (PRK) have been reported but
      have not been described in detail. This case report describes an immune ring
      after phototherapeutic keratectomy (PTK) in a patient with long-standing
      superficial corneal scars. A dense white ring formed in the peripheral cornea on
      the fourth day following surgery. The patient was treated with antibiotics until
      negative cultures were reported 48 hours later. A biopsy was taken and examined
      by light microscopy using hematoxylin-eosin and Mason's trichrome staining. The
      stroma showed focal keratocyte depopulation with nuclear fragments, occasional
      polymorphonuclear leucocytes, and an active fibroblastic reaction. No lymphocytes
      or plasma cells were seen. Clinically, the immune ring faded slowly and was still
      apparent 9 months after the PTK. Studies of similar cases are required to clarify
      the mechanisms responsible for this phenomenon.

PMID- 8656354
TI  - Localized bullous separation of Descemet's membrane after previous cataract
      surgery.
AB  - This paper describes four cases of localized bullous separation of Descemet's
      membrane that occurred from more than 1 year to 7 years after cataract surgery.
      In all eyes, fluid resembling a hypopyon (pseudohypopyon) filled the space
      created by the separation. In three cases, the fluid was white. In one of these,
      pathological examination of the fluid showed mostly necrotic but a few viable
      squamous epithelial cells. In the fourth case in which the fluid was whitish red,
      there were many capillaries along the edge of the separation and there was
      evidence of injury to the nearby epithelium. The one case with poor visual acuity
      improved after the fluid was removed.

PMID- 8656355
TI  - Implantation of a Staar silicone intraocular lens with the anterior chamber
      maintainer.
AB  - A method for performing phacoemulsification and implantation of a foldable lens
      (Staar AA 4203) with an anterior chamber maintainer is described. The procedure
      eliminates the need for viscoelastics, preventing postoperative pressure
      elevation and reducing costs. The incision is kept sealed during the implantation
      with the injector, and the anterior chamber remains deep. Making a small incision
      under positive intraocular pressure pressure prevents the development of high
      astigmatism. I have implanted more than 500 lenses using this method, with very
      good results.

PMID- 8656356
TI  - Modified stretch technique for small pupil phacoemulsification with topical
      anesthesia.
AB  - I present an atraumatic technique for small pupil phacoemulsification using
      topical anesthesia. Fifty consecutive small pupil phacoemulsification cases were
      performed with topical anesthesia and mild intravenous sedation. Viscoelastic
      combined with a modified two instrument stretch was used for pupillary
      enlargement adequate for phacoemulsification. After preoperative cycloplegia, two
      or more multidirectional stretches were used for 3.0 to 5.0 mm pupils; three or
      more multidirectional stretches were used for pupils less than 3.0 mm. Pain and
      proprioceptive responses were avoided by reducing the stretch length, leaving the
      angle structures and ciliary body untouched. Sodium hyaluronate (Healon GV)
      created additional expansive power. Of 50 successfully implanted cases, 45 (90%)
      had acceptable pupillary form and function postoperatively. The 5 (10%) with
      enlarged, atonic pupils had past injury or inflammatory disease. This technique
      minimizes anterior segment trauma, instrumentation, and operating time.

PMID- 8656357
TI  - Optimal capsulorhexis technique in pediatric eyes.

PMID- 8656358
TI  - Initial results of automated lamellar keratoplasty for correction of myopia: one
      year follow-up.
AB  - PURPOSE: To report our initial results with automated lamellar keratoplasty (ALK)
      to correct myopia and to evaluate the short-term efficacy, safety, and
      predictability of this procedure. METHODS: A prospective series of 128 eyes of 81
      consecutive patients who had ALK were reviewed for a mean follow-up of 13.6
      months (range 12 to 19 months). Preoperative data, intraoperative parameters, and
      postoperative visual acuity, refraction, keratometric readings, and complications
      at 1 day, 1 week, 1, 3, and 6 months, 1 year, and last follow-up visit were used
      for analysis. The procedure was performed for myopia in 120 eyes (-4.50 to -13.25
      diopters [D]) and for residual myopia following radial keratotomy (RK) in eight
      eyes (-1.75 D to -3.75 D). A hinged-flap technique was used in 17 cases (13%)
      once this method was introduced. RESULTS: Preoperative mean uncorrected visual
      acuity was 0.04 +/- 0.05 (20/500). Postoperatively (12 to 19 months), overall
      uncorrected visual acuity was 20/40 or better in 86.4% of eyes with a mean
      uncorrected acuity of 0.68 +/- 0.22 (20/30) 76.2% of eyes were within 1.00 D of
      emmetropia and 93.6%, within 2.00 D. After the initial ALK procedure, 77% of eyes
      had RK or astigmatic keratotomy (AK). Among the 29 eyes with ALK alone, 86% had
      20/40 or better uncorrected visual acuity, with mean uncorrected acuity and mean
      corrected acuity of 0.69 +/- 0.21 (20/30) and 0.95 +/- 0.10 (20/21),
      respectively; 72% of eyes were within 1.00 D of emmetropia and 90%, within 2.00
      D. In 4%, astigmatism increased more than 1.00 D from the preoperative value and
      4% of eyes (5/128) had persistent irregular astigmatism. Four percent of eyes
      (5/128) had overcorrection, with a final spherical equivalent greater than +1.00
      D. Epithelial growth in the interface requiring surgical removal occurred in 2%
      of cases. One eye with residual myopia from a previous RK lost the cap after ALK.
      A homologous donor graft was performed, which resulted in 20/30 uncorrected
      visual acuity. Best corrected visual acuity of two lines or more was lost in 6.3%
      of eyes (8/128). This was caused by irregular astigmatism in 63% of cases.
      CONCLUSIONS: The results of our initial experience indicate that ALK is a
      reasonably safe, effective, and predictable procedure for correction of high
      myopia and myopia following previous RK. With additional enhancement with RK/AK,
      good visual and refractive outcome can be expected.

PMID- 8656359
TI  - Perilimbal anesthesia.

PMID- 8656360
TI  - Lid speculum for surgery without lid block.

PMID- 8656361
TI  - Corneal epithelial permeability after excimer laser photorefractive keratectomy.
AB  - PURPOSE: To evaluate the effect of excimer laser photorefractive keratectomoy
      (PRK) on the corneal epithelial barrier function. METHOD: Corneal uptake of 5,6
      carboxyfluorescein (CF) was measured by Bernal and Ubels' method after excimer
      laser PRK in New Zealand white rabbits (N = 40). One cornea in each rabbit was
      treated, and the fellow cornea was used as a control. In both eyes, the central
      7.0 mm of the corneal epithelium was removed. Myopic PRK treatments were
      performed at 37.75 microns (3.3 diopters [D]) and at 52.50 microns (5.0 D). The
      animals were euthanized and the eyes placed in CF for 5 minutes at 3 days, and at
      1, 2, and 4 weeks following PRK. The corneas were then excised and dialyzed in
      balanced salt solution. The CF concentration in the dialysate was measured by
      fluorometry. Four corneas were also prepared for transmission electron microscopy
      using fixative containing ruthenium red. RESULTS: Three days after PRK, CF uptake
      increased in all study eyes compared with normal eyes (n = 5). One week after
      PRK, the control corneas showed a decreased CF uptake while the study corneas
      still had an increased CF uptake (P < .05). Two weeks after PRK, CF uptake in
      corneas with a 5.0 D ablation remained increased but decreased in corneas with a
      3.3 D ablation (P < .05). Four weeks after PRK, CF uptake returned to normal in
      all corneas. The ruthenium red penetrated into the deeper layers of the corneal
      epithelium 1 week after PRK; only the superficial cell layer was stained 4 weeks
      after PRK. CONCLUSIONS: Excimer laser PRK affected the corneal epithelial barrier
      function at 1 and 2 weeks postoperatively even though the corneal epithelium
      covered the ablated area. Deeper laser ablations showed higher corneal CF uptake
      for longer periods than shallower ablations.

PMID- 8656362
TI  - Measuring structures within the eye.

PMID- 8656363
TI  - Efficacy and safety of excimer laser photorefractive keratectomy and radial
      keratotomy for bilateral myopia.
AB  - PURPOSE: To compare the safety and efficacy of radial keratotomy (RK) and
      photorefractive keratectomy (PRK) to correct myopia. METHODS: In this randomized,
      prospective, parallel-group study, 33 patients with bilateral myopia of 1.00 to
      5.00 diopters (D) had PRK in one eye and RK in the other. The order of surgeries
      and treatment assignments were randomized, and the bilateral surgeries were
      within 1 week for each patient. Data were collected using standardized
      procedures. Clinical measurements and satisfaction surveys were taken in masked
      fashion. RESULTS: Eyes that had PRK had statistically significantly more residual
      myopia than RK-treated eyes at 3, 6, and 12 months postoperatively. This result
      was attributed to the use of an older excimer laser PRK algorithm that was used
      at the initiation of the study. No eye that had PRK was overcorrected by 0.50 D
      or more at 1 year postoperatively, while seven eyes that had RK were
      overcorrected by at least 0.50 D and six were overcorrected by 1.00 D. Eyes that
      had PRK had a statistically significant mean shift in the myopic direction
      between 6 and 12 months postoperatively; two RK eyes had hyperopic shifts of 1.00
      D. Three RK eyes and two PRK eyes failed to achieve an uncorrected visual acuity
      of 20/40 or better by 12 months postoperatively. No eye lost any best corrected
      visual acuity. CONCLUSION: The two procedures were comparably safe and effective
      in treating mild to moderate myopia under this protocol. Eyes that had PRK were
      somewhat more myopic at 1 year after surgery, attributable to the older PRK
      ablation algorithm. Adoption of newer (current) laser algorithms has improved the
      predictability of PRK. There was also evidence of reduced variability of outcome
      in the PRK group. The PRK eyes did not exhibit hyperopic shifts during the 1 year
      follow-up.

PMID- 8656364
TI  - Effect of occlusive pressure patching on the rate of epithelial wound healing
      after photorefractive keratectomy.
AB  - PURPOSE: This study measured the effect of pressure patching on the rate of
      epithelial wound healing in 41 myopic patients after photorefractive keratectomy
      (PRK). METHODS: On day 0, mechanical debridement was done to remove the central
      6.5 mm diameter of epithelium. Subsequently, a 5.0 mm diameter photoablation was
      performed, the depth of ablation being proportional to the degree of myopia (-1.0
      to -6.0 diopters). The patients were discharged with an application of
      antibiotic/steroid ointment (A/S) followed by pressure patching. On day 1, the
      epithelial defects were stained with fluorescein and photographed. The patients
      were then randomized prospectively into two groups: Group 1 was pressure patched
      after application of A/S ointment; Group 2 received A/S ointment twice a day
      without patching. A photograph of the remaining epithelial defect was taken on
      day 2. The area of the epithelial defect was measured with a computerized image
      analyzer. Wound diameter (radius) was used to calculate the epithelial healing
      rate (EHR). RESULTS: Between days 1 and 2, the mean EHR in Group 1 was 0.072 +/-
      0.005 mm/hr and in Group 2, 0.056 +/- 0.004 mm/hr (P < 0.05). There was no
      correlation between the EHR and patient gender or the degree of myopia. However,
      a correlation was noted between patient age and wound size on day 1. CONCLUSION:
      Pressure patching significantly accelerated the EHR following PRK.

PMID- 8656365
TI  - Challenge of world blindness.

PMID- 8656366
TI  - Long-term endothelial cell loss following phacoemulsification through a temporal
      clear corneal incision.
AB  - PURPOSE: To evaluate central endothelial cell loss (ECL) following clear corneal
      cataract surgery using two different incision sizes and the effect of ultrasound
      time (UST) and power on postoperative ECL and various cell parameters. METHODS:
      Fifty-eight patients had phacoemulsification through temporal, two-step clear
      corneal tunnel incisions. In Group A (n = 28), a one-piece, plate-haptic foldable
      silicone intraocular lens (IOL) was implanted through a 3.5 mm sutureless
      incision. In Group B (n = 30), a poly(methyl methacrylate) IOL was implanted
      through a 5.0 mm incision with one radial suture. The central endothelial cell
      counts were recorded preoperatively and postoperatively at 2 to 5 days, after 6
      months, and after 1 year. Color-coded, computer-assisted specular microscopy was
      used for special cell analysis after 1 year. RESULTS: Collective data showed an
      ECL of 7.9 +/- 4.1% (mean +/- standard deviation) at 2 to 5 days postoperatively,
      6.7 +/- 2.9% after 6 months, and 7.3 +/- 3.3% after 1 year. A direct linear
      relationship was found between ECL and UST and power: ECL increased as UST and
      power increased. After 1 year, ECL in Group A was 4.2% with UST < or = 11/2
      minutes, 6.7% with UST > 11/2 to 21/2 min, and 9.6% with UST > 21/2 to 31/2 min;
      in Group B it was 6.0%, 7.5%, and 11.4%, respectively. Specular microscopy showed
      normal, age-related cell parameters 1 year postoperatively. CONCLUSIONS:
      Phacoemulsification with 3.5 mm clear corneal incisions produced slightly less
      ECL (6.7%) than phacoemulsification with 5.0 mm incisions (7.9%). Total ECL of
      7.3% at 1 year postoperatively compared favorably with ECL rates of other
      cataract extraction methods.

PMID- 8656367
TI  - Long-term course of induced astigmatism after clear corneal incision cataract
      surgery.
AB  - PURPOSE: To determine whether a small clear corneal temporal incision produces
      less surgically induced astigmatism than a larger incision. METHODS: One hundred
      three consecutive cases of postoperative astigmatism after clear corneal incision
      cataract surgery were studied for a minimum of 1 year. Only self-sealing
      incisions from the temporal side were made as follows: 3.2 mm (Group A); 4.0 mm
      (Group B); 5.2 mm (Group C). We considered the amount and axes of the
      keratometric readings at different times as well as their course over time.
      Induced astigmatism was calculated using three methods. Axial changes were also
      analyzed. RESULTS: Immediately after the surgery, there was a small, surgically
      induced, with-the-rule astigmatic shift in all groups, which in most cases
      decreased to near preoperative levels with time. One year postoperatively. mean
      induced astigmatism was 0.09 diopter (D) in Group A, 0.26 D in Group B, and 0.54
      D in Group C. Most cases had minimal axial changes. In Group A, 86% had an axial
      change of fewer than 30 degrees; in Group B, 76%; and Group C, 73%. CONCLUSIONS:
      The smallest incision group had the least surgically induced astigmatism and
      axial change. All incision groups remained stable and had satisfactory clinical
      results.

PMID- 8656368
TI  - Posterior limbal incision.
AB  - BACKGROUND: Sutureless cataract incisions should ideally remain sealed with
      increased intraocular pressure and be able to withstand increased external
      pressure to the posterior aspect. Cadaver eye studies have shown that meeting
      these criteria requires an internal corneal lip of at least 1.5 mm and a square
      wound. Scleral incisions can meet these criteria but sacrifice aesthetics and
      surgical efficiency. Clear corneal incisions provide aesthetics and surgical
      efficiency but not wound stability. An ideal incision would combined stability
      with aesthetics and efficiency. METHODS: We tested a posterior limbal incision to
      assess its stability, aesthetics, and efficiency. The incision originated at the
      posterior limbus within the conjunctiva, gaining about 1.0 mm in tunnel length
      over a clear corneal incision. This was enough to obtain a square profile for 3.0
      x 3.0 mm wide incisions, while providing the aesthetics and surgical efficiency
      of a clear corneal incision. We compared a 3.0 x 2.0 mm posterior limbal with a
      3.0 x 2.0 mm clear corneal incision. Each was tested in stepped, paracentesis,
      and hinged profiles. CONCLUSIONS: When compared with the clear corneal incision,
      the posterior limbal incision is equal in aesthetics and surgical efficiency,
      slightly superior in patient comfort, and far more stable.

PMID- 8656369
TI  - Consultation section. What would you advise for a patient who has had episodic
      pupillary capture?

PMID- 8656370
TI  - After-cataract formation in newborn rabbits implanted with intraocular lenses.
AB  - PURPOSE: Comparison of the after-cataract formation in newborn rabbits implanted
      with a heparin-surface-modified (HSM) intraocular lens (IOL), a silicone IOL, or
      no IOL. METHODS: Two groups of 3-week-old rabbits were used. In Group 1 (n = 11),
      lensectomy was performed in both eyes. One eye was selected at random and an HSM
      IOL was implanted in the capsular bag; the other eye was left aphakic. In Group 2
      (n = 13), lensectomy was performed in both eyes. An HSM IOL was implanted in one
      eye, a silicone IOL in the other. The wet mass of the dissected after-cataract
      was determined 3 months after surgery in both groups. RESULTS: In Group 1, the
      wet mass of the dissected after-cataract was 17.0 +/- 6.5 mg (mean +/- SEM) in
      eyes implanted with an HSM IOL and 159.7 +/- 17.0 mg in aphakic eyes. This
      difference was statistically significant (P < .01). In Group 2, the wet mass of
      the dissected after-cataract was 18.3 +/- 4.3 mg in eyes implanted with an HSM
      IOL and 25.7 +/- 5.2 mg in eyes implanted with a silicone IOL. No statistically
      significant difference was found. CONCLUSIONS: In young rabbits, implantation of
      an IOL in the capsular bag following lensectomy reduced cell proliferation.

PMID- 8656371
TI  - Continuous curvilinear capsulorhexis and intraocular lens biocompatibility.
AB  - PURPOSE: To study the influence of continuous curvilinear capsulorhexis (CCC) on
      poly(methyl methacrylate) (PMMA) intraocular lens (IOL) biocompatibility.
      METHODS: Biocompatibility was assessed by measuring the postoperative blood
      aqueous barrier breakdown and the cellular reaction at the anterior capsule-IOL
      interface. In a prospective study, 30 consecutive eyes, normal except for having
      extracapsular cataract extraction (ECCE) with CCC by a single surgeon, has laser
      flare and cell measurements and specular microscopy of the anterior IOL surface
      at 1 day, 1 week, and 1 and 3 months postoperatively. RESULTS: In addition to the
      foreign-body reaction previously described in eyes that had other capsulotomy
      types, the eyes in this study also had a lens epithelial cell (LEC) reaction. The
      severity of the foreign-body reaction and postoperative aqueous flare and cells
      was significantly less in eyes with an intact CCC than in those with rim tears in
      the capsulorhexis and in those having an ECCE with a linear or can-opener
      capsulotomy, as previously reported. CONCLUSIONS: Continuous curvilinear
      capsulorhexis improves the biocompatibility of PMMA IOLs to a degree that could
      be of clinical benefit. In eyes with CCC, most cells seen on the anterior IOL
      surface were LECs.

PMID- 8656373
TI  - Enter with caution.

PMID- 8656372
TI  - Capsulorhexis size and posterior capsule opacification.
AB  - PURPOSE: Posterior capsule opacification (PCO) after intraocular lens (IOL)
      implantation has a multifactored pathogenesis. Capsulorhexis and capsular bag
      implantation of a one-piece, biconvex poly(methyl methacrylate) (PMMA) IOL are
      likely to reduce the PCO incidence. This study was performed to determine whether
      an ideal capsulorhexis size able to reduce PCO incidence exists. METHODS: A
      retrospective study of 107 patients who had extracapsular cataract extraction
      with capsulorhexis and capsular bag IOL implantation was carried out. The PCO
      site (central, paracentral, and peripheral) and degree (mild, moderate, and
      severe) were evaluated in relation to the capsulorhexis edge location relative to
      the IOL optic. Slitlamp biomicroscopy and photography and examination with a
      three-mirror Goldmann lens were performed. Patients were divided into three
      groups. Group 1: capsulorhexis free edge located on the IOL optic for 360
      degrees; Group 2: capsulorhexis free edge located asymmetrically on and
      peripherally to the IOL optic; Group 3: capsulorhexis free edge located
      peripherally to IOL optic for 360 degrees. Each group was divided into two
      subgroups; one received polyHema IOLs and the second, PMMA IOLs. RESULTS: In
      Groups 1 and 2, the capsular transparency was higher than in Group 3 (P < .04).
      Central opacification percentage was lower in Group 1 than in Groups 2 and 3 (P <
      .04). No statistically significant differences between the polyHema and the PMMA
      subgroups were seen. CONCLUSIONS: Capsulorhexis with a slightly smaller diameter
      than the IOL optic appears to be better than a large-size capsulorhexis in
      reducing the incidence of PCO.

PMID- 8656374
TI  - Delivery of perilimbal anesthesia.

PMID- 8656375
TI  - Delivery of topical anesthesia.

PMID- 8656376
TI  - Topical anesthesia technique.

PMID- 8656377
TI  - Silicone sleeve defects.

PMID- 8656378
TI  - Consultation Section: contraindications in use of foldable intraocular lenses.

PMID- 8656379
TI  - Avoiding complications associated with iris retractor use in small pupil cataract
      extraction.
AB  - While there are several options for managing the small pupil during cataract
      surgery, adjustable iris retractors are beneficial when there is a risk of
      cutting or tearing the iris, such as with rubeosis. Appropriate use of this new
      surgical tool includes proper placement of the parcenteses and a gradual and
      limited enlargement of the pupil, perhaps to no more than 5.0 mm.

PMID- 8656380
TI  - Use of the anterior chamber maintainer in anterior segment surgery.
AB  - Over a 12 month period, we used the anterior chamber maintainer (ACM) in cataract
      surgery in 258 patients; ages ranged from 15 to 95 years (mean 73 years). Surgery
      was performed using general or local anesthesia. The procedures were standard
      extracapsular cataract extraction (ECCE), mini-nuc ECCE, vectis extraction of the
      endonucleus, manual phacofragmentation, phacoemulsification, phacotrabeculectomy,
      repositioning the IOL, and anterior segment revision. We recorded our subjective
      assessment of the degree of anterior chamber (AC) maintenance and control of the
      position of the posterior capsule during surgery. We also kept clinical notes of
      the practical aspects of the procedures. The AC was well maintained in all
      patients throughout the surgery; posterior position of the posterior capsule was
      maintained during irrigation/aspiration. Five patients required the use of a
      viscoelastic agent at some stage. Our subjective assessment is that use of the
      ACM increased surgical control of the anterior chamber depth and position of the
      posterior capsule during surgery. Provided that it is used correctly, the ACM may
      offer increased safety during anterior segment surgery and require less use of
      viscoelastic agents.

PMID- 8656381
TI  - Posterior chamber myopia lenses in phakic eyes.
AB  - OBJECTIVE: To determine the best technique for implanting a hypernegative
      intraocular lens (IOL) in the posterior chamber of phakic eyes to neutralize high
      myopia and its results. SETTING: Robert Koch Hospital, Hannover-Gehrden, Germany.
      METHODS: We implanted the Chiron-Adatomed silicone myopia IOL in 69 eyes of 37
      patients between June 1992 and August 1994 and followed them prospectively.
      RESULTS: To avoid marked decentration, the IOL should merely touch the ciliary
      sulcus. Its best length should equal the horizontal diameter of the cornea (white
      to white). Iritis from implantation trauma was avoided by intravenous
      administration of 250 mg prednisone preoperatively. When inserting the Chiron
      Adatomed myopia IOL, we avoided putting pressure on the crystalline lens with the
      spatula. In 53 eyes, the difference between precalculated postoperative
      refraction and achieved postoperative refraction at 3 months was +0.07 +/- 1.05
      diopters (D) (mean +/- SD). No eye deviated more than 2.80 D. Eleven of 69 eyes
      had a follow-up of fewer than 6 months and 13 had marked preoperative cortical
      opacities. Eight of the remaining 45 eyes with clear or almost clear cortexes
      showed a central subcapsular opacity after 1 to 2 years, probably IOL induced.
      CONCLUSION: Use of the Chiron-Adatomed IOL should be confined to older patients
      with early cataract until its role as the cause of opacities has been clarified
      by further observation.

PMID- 8656382
TI  - Chronic subclinical inflammation in phakic eyes with intraocular lenses to
      correct myopia.
AB  - PURPOSE: To evaluate whether either of two anterior chamber intraocular lenses
      (IOLs) implanted in myopic, phakic eyes induced an inflammatory response that was
      measurable with a laser flare-cell meter but that could not be measured by other
      methods. SETTING: Jimenez-Diaz Foundation and San Carlos University Hospital,
      Madrid, Spain. METHODS: Thirty eyes with a Worst-Fechner IOL and 30 eyes with a
      Baikoff ZB5M IOL were evaluated using the flare mode of a laser flare-cell meter.
      Patients in each group were divided into three subgroups of 10 eyes each
      according to when the postoperative flare measurements were done: 12 months, 18
      months, and 24 months. Thirteen phakic eyes with myopia greater than -6.00
      diopters were used as controls. RESULTS: Postoperative flare in the Worst-Fechner
      group was 27.05 +/- 19 photons per millisecond (photons/ms) (mean +/- SD) at 12
      months, 18.09 +/- 17.38 photons/ms at 18 months, and 31.03 +/- 28.8 photons/ms at
      24 months. Postoperative flare in the Baikoff group was 21.1 +/- 5.9 photons/ms
      at 12 months, 16.13 +/- 8.3 photons/ms at 18 months, and 21.05 +/- 23.5
      photons/ms at 24 months. Flare in the control group was 4.24 +/- 2.8 photons/ms.
      Postoperative flare values were significantly higher in both IOL groups than in
      the control group at all follow-ups (Mann-Whitney test, P < .05). Postoperative
      flare values in the Worst-Fechner group were higher than in the Baikoff group at
      12, 18, and 24 months, although the difference was not significant (Mann-Whitney
      test, P > .05). CONCLUSIONS: Our study shows chronic subclinical inflammation
      between 1 and 2 years after implantation of both IOL types.

PMID- 8656383
TI  - Specular microscopy of the corneal endothelium after excimer laser
      photorefractive keratectomy.
AB  - PURPOSE: To evaluate endothelial cell morphology and density after excimer laser
      photorefractive keratectomy (PRK). METHODS: We used a noncontact specular
      microscope to examine the central corneal endothelium of 50 eyes of 50 patients
      who had PRK for an attempted correction between -2.5 and -17.0 diopters (D) (mean
      -7.8 D) beginning 18 to 24 hours postoperatively. RESULTS: After a follow-up of
      11.4 +/- 6.1 months (mean +/- standard deviation), mean endothelial cell density
      was 2577.6 +/- 402.0 cells/mm2 with rare signs of polymegathism and pleomorphism.
      Preoperative and untreated fellow eye endothelial cell density values were used
      as a control. Paired Student's t-test and analysis of variance results were not
      significant (P > .05). CONCLUSION: Excimer laser PRK did not significantly change
      cell density and morphology.

PMID- 8656384
TI  - Regression after photorefractive keratectomy for myopia.
AB  - OBJECTIVE: To evaluate the effect of topical steroid treatment in eyes that
      showed refractive regression after photorefractive keratectomy (PRK) to correct
      myopia. SETTING: Mater Private Hospital, Dublin, Republic of Ireland. METHODS: In
      this prospective study with a minimum of 6 months follow-up, 289 eyes were
      treated over 2 1/2 years. Of these eyes, 23 had myopic regression of 0.75
      diopters (D) or more. Topical steroid treatment was given to reverse the
      regression. Refraction and uncorrected visual acuity before and after treatment
      were measured. RESULTS: Twelve eyes in the regression group had at least 18
      months of follow-up. At the final examination, eight of these eyes had an
      uncorrected visual acuity of 20/40 or better; six were within 1.00 D of intended
      refraction. CONCLUSION: Refractive regression after PRK for myopia was
      permanently reversed in some eyes; final stable refraction was close to the
      intended value in about half.

PMID- 8656385
TI  - Corneal optical irregularity after excimer laser photorefractive keratectomy. The
      Summit Photorefractive Keratectomy Topography Study Group.
AB  - PURPOSE: To assess the influence of corneal surface microirregularities on
      objective and subjective visual performance after photorefractive keratectomy
      (PRK). SETTING: Multicenter clinical trial. METHODS: The alpha version of the
      Potential Corneal Acuity (PCA) computer program, currently under development, was
      used to qualitatively and quantitatively analyze the corneal surface of 176 eyes
      of 176 patients 1 year after PRK. Color maps of corneal surface irregularities
      were reviewed and quantitative values (PCA) predicting best spectacle-corrected
      visual acuity (BSCVA) as limited by the cornea were evaluated for associations
      with qualitative topography patterns, optical zone decentration, and clinical
      outcomes of BSCVA, uncorrected visual acuity (UCVA), subjective patient
      satisfaction, and a subjective glare/halo index. RESULTS: Qualitatively, corneas
      after PRK were generally characterized by a ring of optical irregularity at the
      juncture of the ablation zone and untreated cornea. Standard corneal topography
      maps graded as irregular after PRK had a significantly higher PCA value than
      those graded as regular. There was a trend toward higher PCA values with greater
      optical zone decentration that was not statistically significant. Actual BSCVA
      was identical to that which the PCA value predicted in 32% of patients and was
      within one Snellen line in 71%, within two lines in 89%, and within three lines
      in 94%. The correlation between the PCA and the glare/halo index and with
      subjective patient satisfaction was statistically significant. The relationship
      between PCA and UCVA was not significant. CONCLUSIONS: A ring of optical
      microirregularity of the corneal surface can appear at the juncture of the
      treated and untreated cornea after PRK, indicating that the optical zone edge
      might affect objective and subjective postoperative visual outcomes. Further
      understanding of corneal surface topography and refinement of the PCA program
      should help explain visual outcome after PRK.

PMID- 8656386
TI  - Scheimpflug anterior segment photography assessment of wound healing after myopic
      excimer laser photorefractive keratectomy.
AB  - PURPOSE: To describe a method for analyzing Scheimpflug anterior segment images
      for a new measure of the cornea's response to excimer laser photoablation.
      SETTING: Mericos Eye Institute, Scripps Memorial Hospital, La Jolla, California.
      METHODS: Digitized Scheimpflug anterior segment photographs of operated and
      unoperated eyes were obtained in 17 patients 1 to 15 months after photorefractive
      keratectomy (PRK). The images were analyzed to determine their dimensions. Each
      imaged opacity was compared with corneal haze observed by slitlamp biomicroscopy,
      intended ablation depth, postoperative corneal thickness, and refractive error
      change. RESULTS: All postoperative corneas displayed a nonhomogeneous, meniscus
      shaped pattern in the ablated area that ranged from 17 to 40% of corneal
      thickness. This pattern correlated poorly with intended laser ablation depth.
      CONCLUSION: This technique provides a new assessment of corneal response to PRK.
      Improvements in software analysis may facilitate quantitative assessment.

PMID- 8656387
TI  - Miyake analysis of anterior vitrectomy techniques.
AB  - PURPOSE: To study the efficacy and safety of anterior vitrectomy with the Miyake
      system. SETTING: Miyake Laboratory, IOLAB, Claremont, California. METHODS: Four
      pig eyes and three human eyes were transected equatorially. The anterior segments
      were glued to a glass slide and placed on a stage for anterior and posterior
      videography. Phacoemulsification was performed, and the posterior capsule was
      intentionally ruptured. Three different vitrectomy techniques were studied:
      anterior vitrectomy with coaxial infusion sleeve, anterior vitrectomy with
      separate limbal infusion, and pars plana vitrectomy with limbal infusion.
      RESULTS: All techniques showed that vitreous could be safely and effectively
      removed without undue stress on the retina whenever the vitrectomy instrument was
      held directly beneath the iris and not placed peripherally to the iris root. Only
      the pars plana site allowed access to the entire posterior aspect of the iris for
      removal of vitreous gel. CONCLUSION: Anterior vitrectomy can be performed safely
      and effectively with any of the three approaches studied. The pars plana
      technique permitted removal of gel beneath the superior iris. This has important
      clinical implications because iridovitreous adhesions tend to form superiorly
      after limbal vitrectomy.

PMID- 8656388
TI  - Extracapsular cataract extraction after vitrectomy.
AB  - OBJECTIVE: To ascertain the reliability, safety, and effectiveness of
      extracapsular cataract extraction (without the use of pars plana infusion) in
      eyes that have had vitrectomy. SETTING: The Manchester Royal Eye Hospital.
      METHODS: A retrospective analysis of surgical and postsurgical complications and
      visual acuity change in 41 patients who had one or more vitreoretinal procedures,
      followed by extracapsular cataract extraction and intraocular lens implantation
      at a subsequent date. RESULTS: No significant operative complications were
      encountered using an extracapsular technique without pars plana infusion. Thirty
      eyes (73.2%) had a significant increase in visual acuity, 10 (24.4%) did not
      change, and 1 worsened. CONCLUSIONS: A modified form of extracapsular extraction,
      with control of intraocular fluid flow but without the use of a pars plana
      infusion, is safe and effective in post-vitrectomy eyes.

PMID- 8656389
TI  - Treatment of anterior vitreous before suturing and intraocular lens to the
      ciliary sulcus.
AB  - PURPOSE: To clarify the relationship between suturing an intraocular lens (IOL)
      and residual vitreous after vitrectomy and transscleral IOL suturing. SETTING:
      Toranomon Hospital, Tokyo, Japan. METHODS: Enucleated pigs' eyes were fixed to
      the observation device. Three methods for removing the crystalline lens and the
      vitreous were tested; and IOL was then sutured to the ciliary sulcus. Miyake's
      posterior approach and an endoscope were used to observe the movement of
      fluorescein-stained residual vitreous during these procedures. RESULTS:
      Considerable residual vitreous and extensive vitreous entwinement with the IOL
      were seen when IOL suturing followed anterior vitrectomy through a limbal
      incision. These were absent when IOL suturing followed careful pars plana
      vitrectomy and capsulectomy. CONCLUSIONS: Our findings indicate that suturing the
      IOL to the ciliary sulcus should be followed by the removal of as much anterior
      vitreous and lens capsule as possible to prevent such postoperative complications
      as tractional retinal detachment and cystoid macular edema.

PMID- 8656390
TI  - Evaluation of intraocular pressure with Healon and Healon GV in sutureless
      cataract surgery with foldable lens implantation.
AB  - PURPOSE: To evaluate transient increases in intraocular pressure (IOP) after use
      of high-viscosity viscoelastic agents in cataract surgery. SETTING: Military
      Hospital, Ulm, Germany. METHODS: In a prospective, randomized study, we evaluated
      IOP following cataract surgery using two different viscoelastic substances
      (Healon, Healon GV). The viscosity of Healon GV is 10 times higher than that of
      Healon because of higher concentration and molecular weight. Patients having
      identical phacoemulsification procedures (sutureless clear corneal tunnel
      incision with foldable silicone lens implantation) (N = 60) and identical
      viscoelastic removal were assigned to groups of 15 based on viscoelastic used and
      removal time (20 or 40 seconds). Intraocular pressure was measured preoperatively
      and at 6, 24, 36, and 48 hours and 1 month postoperatively. RESULTS: The highest
      mean IOP elevations in both viscoelastic groups were obtained at 24 hours
      postoperatively (2.9 mm Hg +/- 4.3 [SD] with Healon and 3.3 +/- 6.3 mm Hg with
      Healon GV). There were no statistically significant differences between the two
      viscoelastics and the two removal times during the entire follow-up period
      (unpaired t-test), but standard deviations were higher in the Healon GV groups at
      6 and 24 hours. Two patients in the Healon groups and three in the Healon GV
      groups required medical treatment for IOP within the first 24 postoperative
      hours; however, all five patients had an IOP lower than 22 mm Hg on the second
      postoperative day. CONCLUSIONS: Based on postoperative IOP, both viscoelastics
      can be equally well removed from the anterior chamber. Incidence of high IOP
      using high-viscosity hyaluronic acid is minimized by the described removal
      technique.

PMID- 8656391
TI  - Phacoemulsification with intraocular lens implantation in high myopia.
AB  - PURPOSE: To assess phacoemulsification and posterior chamber intraocular lens
      (IOL) implantation in highly myopic eyes and to compare the results of sutureless
      scleral tunnel incision and sutured scleral incision techniques. SETTING: The Eye
      Institute of Utah, Salt Lake City. METHODS: A series of 109 highly myopic eyes
      (axial length over 26.00 mm) were reviewed at a mean postoperative follow-up of
      27 months. RESULTS: Postoperative corrected visual acuity was 20/40 or better in
      94% of eyes, and uncorrected visual acuity was 20/40 or better in 77% of eyes.
      Posterior capsule opacification developed in 50% of eyes; 95% of these had
      neodymium:YAG (Nd:YAG) laser capsulotomy. Cystoid macular edema occurred in two
      eyes, and one eye developed retinal detachment following Nd:YAG capsulotomy. Eyes
      that had sutureless scleral tunnel incisions attained earlier postoperative
      rehabilitation of visual acuity and stabilization of astigmatism than did
      patients who had sutured scleral incisions. CONCLUSIONS: The results of this
      study of highly myopic eyes indicate that treating retinal pathology
      preoperatively and using the sutureless procedure, phacoemulsification, and in
      the-bag IOL placement lead to good visual outcome, a lower rate of retinal
      complications, and a more stable wound.

PMID- 8656392
TI  - Flexible open-loop anterior chamber intraocular lens implantation after posterior
      capsule complications in extracapsular cataract extraction.
AB  - OBJECTIVES: To analyze 50 cases of flexible open-loop anterior chamber
      intraocular lens (IOL) implantation after posterior capsule rupture and vitreous
      loss and compare the results with those of other published series. SETTING: North
      Riding Infirmary, Cleveland, England. METHODS: This retrospective study, with a
      follow-up between 3 and 81 months, comprised all patients who had a flexible open
      loop anterior chamber IOL implanted because of significant posterior capsule
      problems during extracapsular cataract extraction. The incidence of postoperative
      complications and best corrected visual acuity results were determined. RESULTS:
      Three patients with cystoid macular edema achieved final best corrected visual
      acuity of 6/9 (20/30). There was one retinal detachment and one traumatic
      incision rupture with IOL loss 6 weeks postoperatively and subsequent retinal
      detachment and phthisis. Seventy-two percent achieved a best corrected visual
      acuity of 6/9 (20/30). CONCLUSIONS: Our results agree with those of other
      published series. Implantation of a flexible open-loop anterior chamber IOL as a
      primary lens is still an acceptable way of treating posterior capsule
      complications in cataract surgery.

PMID- 8656393
TI  - Secondary implantation of angle-supported anterior chamber and scleral-fixated
      posterior chamber intraocular lenses.
AB  - PURPOSE: To compare the results of secondary implantation of angle-supported
      anterior chamber intraocular lenses (IOLs) and scleral-fixated posterior chamber
      lenses. SETTING: Eye Clinic, University of Verona, Italy. METHODS: This study of
      68 eyes of 60 patients comprised two groups. In Group A (n = 35), an angle
      supported anterior chamber IOL was implanted and in Group B (n = 33), a scleral
      fixated posterior chamber IOL. Follow-up was from 12 to 45 months. RESULTS: In
      Group A, one eye developed a retinal detachment and another, pseudophakic bullous
      keratopathy. In Group B, one eye had a major intraoperative choroidal hemorrhage
      and two developed a retinal detachment postoperatively. All other complications
      were minor. CONCLUSIONS: Although the rate of sight-threatening complications was
      about 6% for both groups, scleral-fixated posterior chamber IOLs were associated
      with more intraoperative and postoperative complications than angle-fixated
      anterior chamber IOLs, and surgery took longer. Thus, anterior chamber IOL
      implantation should be considered for older patients with relatively good
      endothelial cell counts.

PMID- 8656394
TI  - No-stitch phacotrabeculectomy.
AB  - PURPOSE: To describe and evaluate no-stitch trabeculectomy combined with
      phacoemulsification and intraocular lens implantation. SETTING: Arnold Cataract
      Center, Springfield, Missouri. METHODS: Results of two groups that had combined
      phacoemulsification/trabeculectomy were compared. One group had a standard, "two
      stitch" phacotrabeculectomy in which the scleral tunnel incision was secured with
      sutures. In the no-stitch group, no scleral "flap" was created. The scleral
      tunnel (pocket) was left intact over the trabeculectomy, and no sutures were used
      to close the scleral incision. One episcleral suture was used to secure the
      conjunctiva at the limbus. RESULTS: Mean intraocular pressure (IOP) reduction in
      the no-stitch group (n = 66) was 9.7 mm Hg; 88% of eyes required no glaucoma
      medication after a mean of 13.2 months. At the last examination, 95% had an IOP
      of 21 mm Hg or less and 73%, 16 mm Hg or less. A detectable bleb was present in
      92%. These results, comparable to those of the two-stitch group, were consistent
      in eyes followed over 2 years. CONCLUSION: No-stitch phacotrabeculectomy is a
      simple, safe, effective way to combine phacoemulsification and trabeculectomy
      that might lead to better filtration without the risks of other techniques (e.g.
      releasable sutures, suturelysis, antimetabolite therapy.

PMID- 8656395
TI  - Cataract surgery in Fuchs' heterochromic uveitis: past, present, and future.

PMID- 8656396
TI  - Total anterior capsule closure after silicone intraocular lens implantation.
AB  - An 84-year-old man with a nuclear cataract had phacoemulsification, continuous
      curvilinear capsulorhexis, and implantation of a silicone intraocular lens. Two
      months later, the patient had vision loss and severe anterior capsule fibrosis,
      leading to complete posterior chamber lens encapsulation. After a capsular
      opening was created with a neodymium:YAG laser, visual acuity returned to the
      preoperative level of 20/30.

PMID- 8656397
TI  - Explantation of endocapsular posterior chamber lens after spontaneous posterior
      dislocation.
AB  - The management of spontaneous posterior dislocation of an intraocular lens (IOL)
      (11.0 mm in overall diameter) encapsulated within the remaining lens capable is
      presented. The patient was a 55-year-old man who had had phacoemulsification
      following continuous curvilinear capsulotomy for monocular cataract 3 years
      earlier. The dislocated, encapsulated IOL was lifted up by hooking the fibrotic
      capsular opening with a bent disposable needle following vitrectomy and then
      explanted. A conventional posterior chamber lens with modified C-loops was
      inserted and sutured in the ciliary sulcus. This technique may be an alternative
      treatment for a posteriorly dislocated IOL. Histopathological examination clearly
      revealed that lens epithelial cell migration stopped at the planoconvex optic
      edge. This finding may be consistent with reports that the incidence of posterior
      capsule opacification with the planoconvex IOL is lower than with the bioconvex
      IOL.

PMID- 8656398
TI  - Microsurgical replantation of avulsed scalps.
AB  - Four cases of extensive scalp avulsion were successfully replanted in this
      reported series. All patients were female, with the youngest 3 years of age. All
      replanted scalps survived, with some marginal necrosis due to tissue destruction.
      Postoperative venous congestion of the involved ear in one patient was managed
      with anticoagulant therapy. Another patient underwent severe congestion of the
      whole replanted scalp and was treated with thin skin-graft shaving in the
      parietal area. In the follow-up period, all patients obtained hair growth in the
      scalp with light touch sensation.

PMID- 8656399
TI  - Orthotopic vascularized osteochondral allografts in an immunosuppressed rat
      model.
AB  - This study examined the survival of orthotopic, vascularized, osteochondral
      allografts, following 12 weeks of immunosuppression and transfer into a naive,
      allograft host up to 14 weeks later, and compared the results with those
      previously reported for similar grafts in a heterotopic position. Knee-joint
      allografts between DA (donor) and Lewis (recipient) rat strains were assessed by
      quantitative histology up to 6 months after transplantation, and graft
      microcirculation was examined by India-ink infusion. Graft repopulation was
      assessed by re-transferring the graft to a naive, non-suppressed allograft host
      12 to 26 weeks after the initial transplantation. Isografts survived for as long
      as grafts were examined (6 months) and showed good healing of the graft/host bone
      junction, although long-term isografts showed some deterioration of the growth
      plate. Non-suppressed allografts rejected within 2 weeks. Allografts in hosts
      immunosuppressed for 12 weeks remained healthy and healed in a similar manner to
      the isografts. Following cessation of immunosuppression, allografts progressively
      deteriorated, with mononuclear cell infiltration apparent in graft bone marrow
      and muscle in the later stages examined. Transfer to second non-suppressed hosts
      resulted in rapid rejection of the allografts, indicating that, as shown
      previously in heterotopic, osteochondral allografts, little or no graft
      repopulation by host-derived cells had occurred during the protected period in
      the first host.

PMID- 8656400
TI  - Mechanical evaluation of anastomotic tension and patency in arteries.
AB  - This study quantified arterial anastomotic tension, evaluated subsequent patency
      rates, and examined the degree of tension reduction with vessel mobilization. The
      study was divided into two components. In part I, a mechanical analysis was
      undertaken to evaluate tension, based on the determination of the force required
      to deflect a cable (vessel) laterally, and its resulting lateral displacement.
      Six Sprague-Dawley rats with 12 femoral arteries were divided into two subgroups:
      1) no mobilization; and 2) axial mobilization by ligation and transection of
      superficial epigastric and gracilis muscular branches. The tension of femoral
      arterial anastomoses was calculated in vessels with no segmental defect and with
      1.5-, 3-, 4.5-, 6-, and 7.5-mm defects. In part II, patency was evaluated. Fifty
      five rats with 110 femoral arteries were divided into two sub-groups as defined
      in part I: 1) no mobilization; and 2) axial mobilization by ligation and
      transection of superficial epigastric and gracilis muscular branches.
      Microvascular anastomoses were performed with no segmental defect and with 1-, 2
      , 3-, 4-, 5-, 6-, 7-, 8-, 9-, and 10-mm segmental vessel defects. Patency was
      evaluated 24 hr postoperatively. Part I of the study revealed that anastomotic
      tension gradually increased along with an increase in the length of the vessel
      defect, from 1.9 to 11.34 g in the no-mobilization group and from 1.97 to 8.44 g
      in the axial-mobilization group. Comparison of tension linear regression
      coefficient showed a significant difference between the two groups (p < 0.05). In
      part II of the study, the maximum length of femoral artery defects still able to
      maintain 100 percent patency of anastomoses was 4 mm (tension approximately 6 g)
      in the no-mobilization group and 6 mm in the axial-mobilization group (tension
      approximately 6.48 g). Microanastomotic tension was related to the size of the
      vessel defect, with increasing tension leading to thrombosis. Axial mobilization
      significantly reduced the tension in vessels with segmental defects and decreased
      thrombosis rates.

PMID- 8656401
TI  - A new suction device for microsurgery.
AB  - A new suction device for microsurgical procedures is presented. This device is
      made of soft, compliant PVC, which enables all fluids to be evacuated from the
      surgical field without damaging the surrounding soft tissue. The device is
      designed with front and radial ports that allow placement onto the blood vessel
      or nerve while the anastomosis is being performed. There is a tapered end
      providing the surgeon with fine control of the suction. Unlike other bulky
      suction devices, this one readily fits into the operative field without
      inhibiting operative procedures. It also readily fits varying sizes of
      conventional Frazier-type tips. The device has been used in over 100
      microsurgical procedures and it has served well.

PMID- 8656402
TI  - Facial contouring surgery with the scapular osteo-adipo-fascial flap.
AB  - Recently, deepithelialized scapular or parascapular flaps have been used for
      reconstruction of facial contour. The authors used a scapular osteo-adipo-fascial
      flap, based on the subscapular vascular system, accompanied with scapular bone on
      the angular branch, for surgical correction of facial contour in two cases. At
      follow-up, both patients showed aesthetic improvements, and were pleased with the
      results. The scapular osteo-adipo-fascial flap provides a technique to
      reconstruct facial contour, including the bony structure as well as the soft
      tissue.

PMID- 8656403
TI  - Split nerve grafting.
AB  - Twenty-five patients with severe brachial plexus lesions (having a rather poor
      prognosis in general), were subjected to a variety of split nerve graft
      procedures, with 22 achieving useful functional recovery. Thirty-eight nerves
      were reconstructed, with 32 of them achieving useful recovery. Results in these
      patients were no better nor worse than those obtained with other types of nerve
      grafts (e.g., free cutaneous nerve grafts, vascularized nerve grafts, etc.). The
      technique of splitting the nerve for the use of split fascicle groups as free
      nerve grafts is nevertheless recommended as an alternative to the application of
      the ulnar nerve as a vascularized nerve graft. The plexiform arrangement of the
      fascicles within the ulnar nerve apparently does not preclude the possibility of
      harvesting sufficiently long nerve grafts.

PMID- 8656404
TI  - Functional transfer of pronator quadratus free flap for thenar muscle loss.
AB  - A case of functional replacement for traumatic thenar muscle loss using an
      innervated pronator quadratus free flap is reported. The pronator quadratus
      matched the damaged thenar muscle in size and excursion and provided satisfactory
      thumb opposition in long-term follow-up.

PMID- 8656405
TI  - Some problems in wrist reconstruction after tumor resection with vascularized
      fibular-head graft.
AB  - Restoration of wrist function was attempted in six patients with aggressive or
      malignant bone tumor of the distal end of the radius with free vascularized
      fibular graft including the fibular head, and following wide resection of tumor.
      There was no local recurrence in all six cases. In one case, pulmonary metastasis
      occurred, but was successfully treated. Secondary bone graft was necessary in two
      cases for non-union. Additional procedures, such as partial or total wrist
      fusion, were necessary in three cases due to collapse of the grafted fibular
      head. Corrective osteotomy or a Sauve-Kapandji procedure were also needed in two
      cases for improvement of forearm rotation. Grip strength ranged from 41 to 68
      percent of the contralateral side, with an average of 54.6 percent in five cases;
      it was only 6 percent in one patient because of flexion contracture at the wrist
      joint. Final functional results, evaluated by a modified system of Enneking,
      ranged from 73 to 92 percent, with an average of 83.2 percent. Indications for
      this procedure seem to be limited to patients engaged in non-heavy manual work,
      in whom the proximal carpal row can be preserved during tumor resection, and who
      have given consent for additional secondary procedures, if they prove necessary.

PMID- 8656406
TI  - Liability of recipient vessels distal to the zone of injury when used for
      extremity free flaps.
AB  - The selection of recipient vessels distal to an extremity defect can be
      tantalizing option, offering the potential advantage of rapid accessibility to
      relatively large vessels that, in turn, would simplify revascularization of any
      desired microsurgical tissue transfer. However, such a maneuver contradicts the
      traditional dictum that any microanastomosis should be proximal to the zone of
      injury. A retrospective review of experiences with free flaps to the extremities
      corroborated this predilection for proximally-based flaps, which were successful
      in 115 of 136 cases (84.6 percent). Eleven distally-based flaps were also
      attempted: four were converted intraoperatively to proximally-based flaps; one
      was moved to an even more distal site, necessitating an interposition vein graft;
      and one totally failed. Although six (54.5 percent) distally-based flaps were
      ultimately successful, the incidence of problems encountered overall negated most
      benefits, so that this option for recipient vessels would rarely be justified.

PMID- 8656407
TI  - One-stage repair of skin and tendon digital defects using the arterialized venous
      flap with palmaris longus tendon: an additional four cases.
AB  - The use of the arterialized venous flap with a palmaris longus tendon transfer
      has previously been reported. Further trials of this technique were conducted in
      four patients to reconstruct complicated finger injuries involving loss of skin
      and extensor tendon. In contrast to the results of previous cases, those of
      recent cases are more encouraging. This technique may be the procedure of choice
      in patients with digital skin defects, where there are associated extensor tendon
      defects with exposed bone.

PMID- 8656408
TI  - Cross-facial nerve grafting for facial reanimation: effect on normal hemiface
      motion.
AB  - Reinnervation of the paralyzed hemiface with a cross-facial nerve graft (CFNG)
      required division of facial nerve branches on the normal hemiface to serve as
      axon donors. There is therefore concern about whether any impairment of normal
      hemiface motion occurs in the postoperative period. To minimize the likelihood of
      donor-side impairment, donor branches are chosen from the bucco-zygomatic region
      which was extensive cross branching, as opposed to be the single temporal or
      marginal mandibular branches. This study chose to determine quantitatively if
      this practice does, in fact, adversely affect the normal side hemiface motion
      governed by these branches, viz., eye closure, pucker, and smile. Since surgical
      procedures near the facial nerve (such as superficial parotidectomy) may leave
      the patient with transient facial weakness, even in the absence of nerve
      transection, the hypothesis was that hemiface motion would be impaired on the
      donor side during the early postoperative period (first month) secondary to edema
      and/or neuropraxia. However, based on the clinical observation that donor-side
      facial motion is not demonstrably impaired late after surgery, a further
      hypothesis was that any early facial motion is not demonstrably impaired late
      after surgery, a further hypothesis was that any early facial motion impairment
      would return to normal by 3 months postoperatively. Seven patients underwent
      sural CFNG as a primary or secondary component of their facial animation
      procedure. Their facial motion was quantified preoperatively and in serial
      postoperative examinations using the Maximal Static Response Assay (MSRA) of
      facial motion. Careful selection of redundant bucco-zygomatic branches of the
      facial nerve on the normal side for CFNG did not ultimately ( > or = 3 months
      postoperative) impair the important motions of eye closure, smile, or pucker.
      Early postoperative ( < or = 1 month) weakness of the smile was seen on both X
      and Y axes, indicating that both the risorius and zygomatic muscles were
      transiently weakened. The ability to elevate the lower eyelid was unaffected at
      any postoperative time point. Movement of the normal hemiface did not appear to
      be permanently affected by CFNG when a careful choice of redundant bucco
      zygomatic donor branches was made.

PMID- 8656409
TI  - Gas embolism in obstetrics and gynecology. A review.
AB  - OBJECTIVE: To review gas embolism in the field of obstetrics and gynecology, with
      an emphasis on the pathophysiology, clinical presentation and treatment options.
      STUDY DESIGN: A review of the world literature on gas embolism. CONCLUSION: Gas
      embolism is an unusual complication and has increased in frequency since the
      introduction of new invasive procedures. Since the clinical presentation of gas
      embolism has many faces, it is important to identify it as early as possible:
      timely treatment may be life saving, while a delay may have serious consequences.

PMID- 8656410
TI  - Surveillance of growth-retarded fetuses with computerized fetal heart rate
      monitoring combined with Doppler velocimetry of the umbilical and uterine
      arteries.
AB  - OBJECTIVE: To define guidelines for surveillance of growth-retarded fetuses with
      a computerized fetal heart rate (FHR) monitor and Doppler device. STUDY DESIGN:
      Eighty-one growth-retarded fetuses with birth weights < 10th percentile and
      lacking major anomalies were studied. One hundred ninety-two tests (one to six
      per patient), including computerized FHR monitoring and Doppler studies of the
      umbilical and uterine arteries, were performed. The relationship between Doppler
      velocimetry or FHR variation and fetal outcome was examined. RESULTS: Fetuses
      with an abnormal FHR variation or abnormal Doppler velocimetry had a
      significantly higher rate of cesarean deliveries for fetal distress and a higher
      number of admissions to the neonatal intensive care unit (NICU) as compared with
      fetuses with normal results on both tests. The best distinction was noted when
      the growth-retarded fetuses were partitioned into four analytic groups based on
      the presence of normal or abnormal FHR variation or Doppler velocimetry. The
      group with the poorest results was composed of fetuses with abnormal umbilical
      flow velocity and reduced FHR variation. These fetuses had significantly lower
      birth weights (1,250 g) and significantly higher rates of cesarean deliveries for
      fetal distress (92%) and admission to the NICU (100%). Thirty percent of these
      fetuses died. CONCLUSION: Fetal surveillance with Doppler and computerized FHR
      monitoring allows better understanding of the management of fetuses that are
      small for gestational age.

PMID- 8656411
TI  - Tamoxifen-induced growth of leiomyomas. A case report.
AB  - BACKGROUND: Tamoxifen, a nonsteroidal estrogen agonist-antagonist, is used in the
      treatment of breast cancer. CASE: A postmenopausal woman, aged 73, while being
      treated with Tamoxifen, developed continuous growth of her myomatous uterus,
      became symptomatic and required surgery. CONCLUSION: Tamoxifen at a dose of 40
      mg/d has been associated with endometrial carcinoma. The growth of myomas seen
      with Tamoxifen in this patient seems to be a result of its direct agonist
      properties.

PMID- 8656412
TI  - Massive vulvar edema complicating tocolysis in a patient with twins. A case
      report.
AB  - BACKGROUND: Severe vulvar edema is an extremely rare complication of pregnancy.
      One other case of tocolysis-induced vulvar edema has been reported, as have five
      cases of postpartum vulvar edema, associated with an 80% maternal mortality rate.
      CASE: A multipara with a twin gestation presented with premature labor at 31
      weeks. The patient had no history of trauma, lymphatic obstruction, venous
      obstruction or infection. On the fifth day of tocolysis with magnesium sulfate,
      nifedipine, terbutaline and betamethasone, edema developed in both labia. The
      following day the vulvar edema had increased and spread to the sacrum. The
      patient was normotensive and afebrile. Resolution occurred in spite of continuous
      tocolytic therapy, which was stopped at 35 weeks. Two days later, on hospital day
      27, the patient spontaneously delivered two healthy, male infants. CONCLUSION:
      The two reported cases of tocolysis-induced vulvar edema were not fatal and
      resolved after repositioning the patient in one case and by cesarean section in
      the other. However, since maternal death has occurred with postpartum vulvar
      edema, the patient with vulvar edema merits special attention. The WBC count
      should be determined and the patient's circulatory status evaluated to rule out
      hypovolemia.

PMID- 8656413
TI  - Spontaneous ruptured subcapsular liver hematoma associated with pregnancy. A case
      report.
AB  - BACKGROUND: Spontaneous rupture of a subcapsular liver hematoma in pregnancy is a
      rare and potentially life-threatening complication of preeclampsia. The incidence
      is approximately 1 in 45,000 live births. The liver hematoma is often not
      suspected until it ruptures. CASE: A 32-year-old female developed severe shoulder
      pain at 33 weeks' gestation while in the hospital with preeclampsia. Liver
      involvement was suspected, and cesarean delivery was performed. Over the first
      two postpartum days the patient had rising liver enzyme and falling hematocrit
      levels. A ruptured subcapsular liver hematoma was discovered at emergency
      laparotomy. Both mother and infant survived. CONCLUSION: A patient with a liver
      hematoma will usually experience right upper quadrant or epigastric pain.
      However, shoulder pain should also be regarded with suspicion in patients with
      preeclampsia.

PMID- 8656414
TI  - Laparoscopic surgery in patients with a ventriculoperitoneal shunt. A case
      report.
AB  - BACKGROUND: Ventriculoperitoneal shunts have afforded many patients the
      opportunity to expect a normal lifespan. Since laparotomy is more likely to be
      associated with adhesion formation, potentially reducing the functional capacity
      of ventriculoperitoneal shunts, laparoscopy may be a preferable surgical
      alternative. CASE: A 64-year-old woman presented with a pelvic mass requiring
      surgical evaluation to rule out ovarian cancer. She had a ventriculoperitoneal
      shunt. Diagnostic laparoscopy was performed without complication. However, due to
      the significant adhesions from previous surgery, the mass could not be safely
      evaluated, and the procedure was completed by laparotomy. CONCLUSION: This is the
      first report of laparoscopy for a pelvic mass in an adult with a
      ventriculoperitoneal shunt. Laparoscopy is preferable to laparotomy for the
      replacement or repair of ventriculoperitoneal shunts. Also, laparoscopy should be
      considered for other problems requiring surgical intervention.

PMID- 8656415
TI  - Prenatal diagnosis of fetal bladder and cloacal exstrophy by ultrasound. A report
      of three cases.
AB  - BACKGROUND: Bladder and cloacal exstrophy can be diagnosed with prenatal
      ultrasound. CASES: Three cases of bladder and cloacal exstrophy were diagnosed
      prenatally by ultrasound and confirmed at birth. The ultrasound findings were a
      soft tissue mass in the lower abdominal wall (which appeared larger and more
      heterogeneous in cloacal exstrophy than in bladder exstrophy), absent bladder,
      malformation of the external genitalia and normal kidneys along with normal
      amniotic fluid volume. CONCLUSION: Prenatal diagnosis of these defects will allow
      appropriate referrals prior to birth.

PMID- 8656416
TI  - Endoscopic ultrasound. A new instrument for laparoscopic surgery.
AB  - OBJECTIVE: Although laparoscopy is an important tool for evaluating pelvic
      pathology, visualization is limited to the surface of structures. A method of
      seeing below the surface during laparoscopy could be useful. We report on our
      early experience with new laparoscopic ultrasound. STUDY DESIGN: Following
      diagnostic laparoscopy the pelvis is filled with fluid to obtain optimal imaging.
      A 10-mm ultrasound probe is introduced through the umbilical trocar and the
      uterus and adnexa examined. RESULTS: High-resolution images can be obtained to
      delineate such abnormalities as suspected ovarian cysts and uterine myomata.
      CONCLUSION: Endoscopic ultrasound is a new instrument that allows the surgeon to
      evaluate and define pelvic pathology suspected at the time of laparoscopy.
      Endoscopic ultrasound may augment the diagnosis of subtle pathologic findings
      during laparoscopy.

PMID- 8656417
TI  - Same-day Dilapan insertion before second-trimester dilatation and evacuation for
      a fetal anomaly or death.
AB  - OBJECTIVE: To evaluate the efficacy of same-day Dilapan insertion prior to
      nonelective second-trimester dilatation and evacuation. STUDY DESIGN: Eighty
      women had Dilapan inserted six to eight hours prior to surgery. Degree of
      cervical dilatation was assessed after Dilapan was removed. RESULTS: Seventy
      eight of 80 women had adequate cervical dilatation from a single, same-day
      Dilapan insertion. There were no major complications. CONCLUSION: Same-day
      Dilapan insertion prior to planned second-trimester dilatation and evacuation is
      safe and effective.

PMID- 8656418
TI  - Expanded polytetrafluoroethylene surgical membrane in ovarian surgery on the
      rabbit. Biocompatibility, adhesion prevention properties and ability to preserve
      reproductive capacity.
AB  - OBJECTIVE: To evaluate the biocompatibility, adhesion prevention properties and
      ability to preserve reproductive capacity of polytetrafluoroethylene surgical
      membrane in ovarian surgery on the rabbit. STUDY DESIGN: In two groups of female
      rabbits a standard lesion was made on each ovary. In group 1, one ovary was
      partially covered with a flat sheet of the surgical membrane, and the other was
      left uncovered so that each rabbit served as its own control. In group 2, one
      ovary was again left uncovered to serve as an internal control, and the other was
      completely covered with a "cap" of the surgical membrane. Laparotomies were
      performed several weeks postoperatively after the rabbits were mated with fertile
      males; adhesions were evaluated, and the number of cornual pregnancies was
      determined. RESULTS: In group 1, 67.9% of the control ovaries and 7.1% of the
      partially covered ovaries had adhesions (P < .001); in the uterine horn on the
      control side, 32.1% of the rabbits exhibited cornual pregnancies (1.14 +/- 1.72
      [mean +/- SD] pregnancies per rabbit), whereas on the experimental side, 89.3% of
      the rabbits exhibited cornual pregnancies (3.89 +/- 1.58 per rabbit). In group 2,
      83.3% of the control ovaries and 11.1% of the covered ovaries had adhesions (P <
      .001); in the uterine horn on the control side, 23.5% of the rabbits exhibited
      cornual pregnancies (2 +/- 1.1 per rabbit), whereas on the experimental side,
      100% of the rabbits exhibited cornual pregnancies (4.8 +/- 0.9 per rabbit).
      CONCLUSION: The surgical membrane is an excellent device for preventing the
      formation of adhesions to the ovary after surgery in rabbits, preserving the
      reproductive capacity of the ovary.

PMID- 8656419
TI  - Maternal plasma and amniotic fluid cortisol and progesterone concentrations
      between women with and without term labor. A comparison.
AB  - OBJECTIVE: The purpose of the present study was to determine the amniotic fluid
      and maternal plasma concentrations of cortisol and progesterone in nonlaboring
      women at term and to compare them to those in women with active labor at term.
      STUDY DESIGN: A prospective, cross-sectional study. Soroka Medical Center of
      Kupat Holim, Faculty of Health Sciences, Ben-Gurion University of the Negro, Beer
      Sheva, Israel. Thirty-five healthy women with normal term pregnancies were
      classified according to labor status into two groups: group A (16 women with
      spontaneous, active labor at term) and group B (19 women not in labor). RESULTS:
      We found a significant increase in the median concentration of plasma cortisol in
      women at term in active labor in comparison to those not in labor. In addition,
      the median concentration of cortisol in amniotic fluid in women in labor was also
      significantly higher than that in women not in labor. In contrast, no significant
      changes in median maternal plasma or amniotic fluid progesterone concentrations
      were detected between the groups. CONCLUSION: Human parturition is associated
      with a significant increase in the concentration of cortisol in both maternal
      plasma and amniotic fluid. These findings suggest that cortisol plays an
      important but still-undetermined role in human parturition.

PMID- 8656420
TI  - Pregnancy outcome in women with low midtrimester maternal serum unconjugated
      estriol.
AB  - OBJECTIVE: To determine if unexplained low second-trimester maternal serum
      unconjugated estriol (MSuE3) is a useful predictor of complications of pregnancy.
      STUDY DESIGN: Between February 1, 1990, and January 3, 1993, 10,492 patients
      underwent prenatal screening using second-trimester maternal serum alpha
      fetoprotein (MSAFP), maternal serum human chorionic gonadotropin (MShCG) and
      MSuE3. One hundred ninety-five patients with complete obstetric history/delivery
      records and with < 0.4 multiples of the median (MoM) second-trimester MSuE3
      values were matched with 261 controls with complete obstetric history/delivery
      records and normal second-trimester MSAFP, MSuE3 and MShCG. RESULTS: The relative
      risk of pregnancy loss, as compared to that in controls, was 3.7 (1.4-9.1
      confidence interval [CI], P < .0001) in patients with 0.2-0.4 MoM MSuE3 and 19.3
      (6.1-60.5 CI, P < .0001) in patients with < 0.2 MoM MSuE3. After exclusion of
      patients with low and high MSAFP and MShCG, the relative risk of pregnancy loss
      for the remaining patients with low MSuE3 was 3.3 (1.3-8.5 CI, P < .008).
      CONCLUSION: The data suggest that patients with unexplained low second-trimester
      MSuE3 have an increased risk of pregnancy loss that may not be associated with a
      high or low MSAFP, MShCG or higher incidence of pregnancy-induced hypertension,
      gestational diabetes, premature rupture of membranes or premature onset of labor.

PMID- 8656421
TI  - Association of endogenous steroid levels with high and low density lipoprotein
      concentrations in the human maternal-fetoplacental unit at term.
AB  - OBJECTIVE: To determine the concentrations of high density lipoprotein
      cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), estradiol (E2),
      dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in both
      maternal and venous cord blood upon delivery at term; to determine the degree of
      association between lipoprotein cholesterol concentrations and concentrations of
      selected steroid hormones, thus indicating correlations between regulatory
      mechanisms mediating steroid biosynthesis and cholesterol homeostasis in the
      maternal-fetoplacental unit; and to determine the efficacy of both heparin
      manganese precipitation and agarose-gel electrophoresis techniques for
      quantitation of HDL-C and LDL-C in fetal and maternal plasma. STUDY DESIGNS:
      Steroids were quantitated by radioimmunoassay in maternal and umbilical cord
      venous blood collected from 56 patients upon delivery. Correlation analysis and
      ANOVA were utilized to determine the degree of association between quantitative
      parameters in the total study population and differences in regard to fetal sex,
      respectively. RESULTS: Values determined for all parameters measured fell within
      previously established normal ranges. HDL-C concentrations in the cord blood of
      female newborns were higher than those of males, while LDL-C concentrations were
      unchanged in regard to fetal sex. Concentrations of both LDL-C and all steroids
      measured in the maternal periphery were unchanged in regard to fetal sex, but HDL
      C concentrations were higher in plasma of women bearing female fetuses. Further,
      LDL-C levels in cord blood positively correlated with maternal DHEAS levels and
      negatively correlated with maternal E2 levels. Cord E2 concentrations correlated
      highly with cord levels of both DHEA and DHEAS, and maternal E2 levels
      correlated, although to a lesser degree, with maternal DHEA concentrations.
      CONCLUSION: The results indicated both positive and negative correlations of
      lipoprotein cholesterol levels with concentrations of the various steroid
      hormones associated with human pregnancy and illustrate the complicated interplay
      of mechanisms regulating steroid/lipoprotein metabolism in the maternal
      fetoplacental unit. Changes in lipoprotein levels in the maternal-fetoplacental
      unit may suggest changes in steroid metabolism associated with fetal sex. Both
      heparin-manganese precipitation and agarose-gel electrophoresis techniques proved
      adequate for the quantitation of plasma lipoprotein cholesterol in both maternal
      and fetal plasma.

PMID- 8656422
TI  - Testosterone maintenance therapy. Effects on vulvar lichen sclerosus treated with
      clobetasol propionate.
AB  - OBJECTIVE: To evaluate the possible effects of topical testosterone as
      maintenance therapy after clobetasol propionate treatment. STUDY DESIGN: Thirty
      two patients with biopsy-proven vulvar lichen sclerosus (LS), after 24 weeks of
      treatment with 0.05% clobetasol propionate cream, were randomly distributed into
      two groups of 16 each and treated for a further length of time (24 weeks) with
      testosterone 2% ointment or a cream-based preparation (placebo). The patients
      were examined before and after treatment for symptoms, gross aspects and
      histologic features. RESULTS: With clobetasol propionate all patients had a
      marked improvement (P < .001) in both clinical and histologic parameters. After
      clobetasol propionate therapy, the 16 testosterone-treated patients had
      significant worsening of their symptoms (P < .05%) and no evident changes in
      gross aspects (P = NS). The placebo-treated group had good symptomatic control of
      their disease, with no significant changes in symptoms or gross aspects (P = NS).
      CONCLUSION: After the good results obtained with clobetasol propionate, treatment
      with testosterone appeared to have a negative effect, while a regularly provided
      emollient cream was useful in symptom control.

PMID- 8656423
TI  - Mutations of non-canonical base-pairs in the 3' major domain of Escherichia coli
      16 S ribosomal RNA affect the initiation and elongation of protein synthesis.
AB  - Three single-point mutations and two multibase substitutions were introduced into
      the lower half of the 3' major domain of Escherichia coli 16 S ribosomal RNA. The
      three single mutations were located in helix 29 (U1341C) or in helix 43 (U1351C
      or A1357C) and replaced highly conserved non-canonical base-pairs with Watson
      Crick base-pairs. The two multibase substitutions were located at the base of
      helix 42, where they transformed an irregular portion into a Watson-Crick
      [correction of Waston-Crick] segment. Each of the single mutations could be
      expressed in vivo from the rrnB operon of a multicopy plasmid under control of
      constitutive promoters, and none of them affected growth-rate. However, mutation
      A1357C, but not U1341C or U1351C, severely retarded cell growth, when expressed
      together with another mutation in the upper half of the 3' major domain, C1192U.
      The latter mutation is located in helix 34 and abolishes the binding of
      spectinomycin, a protein synthesis inhibitor. The proportion of mutated ribosomes
      was high in polysomes, suggesting that the A1357C and C1192U double mutation did
      not affect the initiation but rather the elongation of protein synthesis. The
      effect of the double mutation reveals a functional interplay between helices 34
      and 43. Furthermore, an interaction between helices 34 and 43 was also suggested
      by studies of protection by spectinomycin against chemical attack, that showed
      that the binding site of spectinomycin was restored with ribosomes bearing
      another double mutation, U1351C and C1192U. In contrast to the single mutations,
      the multiple mutations in helix 42 could not be expressed in vivo under control
      of the strong constitutive promoters, but could be expressed under control of the
      weaker, thermoinducible lambda PL promoter. They did not affect cell growth,
      whether expressed in the absence or the presence of the C1192U mutation. However,
      under conditions where protein synthesis depended exclusively on ribosomes with
      plasmid-encoded rRNA, cells transformed with plasmids altered in helix 42 could
      not grow. Analysis of the plasmid-borne 16 S rRNA distribution in bacteria
      transformed with these mutant plasmids showed that mutant 16 S rRNA was present
      in a high proportion in the free 30 S subunits but was underrepresented in 70 S
      ribosomes and polysomes. Extension inhibition assays (toeprinting) demonstrated
      that this altered distribution resulted from an impaired capacity of the mutant
      30 S subunits to form translation initiation complexes.

PMID- 8656424
TI  - Selection of RNAs that bind to duplex DNA at neutral pH.
AB  - RNA that are capable of binding duplex DNA in a site-specific manner have
      potential applications in gene therapy strategies. Such RNAs might be targeted to
      DNA sequences in a gene promoter and prevent initiation of transcription by
      occluding transcription factors and/or RNA polymerases. RNA oligonucleotides that
      bind homopurine/homopyrimidine DNA sequences by forming triple-helical complexes
      involving T.A.T and C+.G.C base-triplets can be rationally designed. However, the
      formation of such pyrimidine motif triple helices typically requires mildly
      acidic conditions. In addition, the proper oligonucleotide sequence must be
      optimally presented within a longer RNA transcript if it is to be synthesized in
      vivo. To address these issues, RNAs were selected from pools of random sequences
      for binding to a homopurine/homopyrimidine DNA sequence. RNAs selected for
      binding the duplex DNA target between pH 6.5 and pH 7.4 were characterized by
      sequence analysis and binding studies. All RNAs isolated by selection and
      amplification were found to contain a pyrimidine recognition sequence for binding
      the duplex DNA target via conventional triple helix formation. The selected
      approximately 85 nt RNAs have dissociation constants that approach, but do not
      surpass, the binding affinity of a 21 nt RNA oligonucleotide that binds the DNA
      target sequence by forming a canonical triple helix. The presence of a pyrimidine
      recognition sequence within a longer RNA transcript is not sufficient for high
      affinity. Experimental data and secondary structure predictions suggest that the
      context of the pyrimidine recognition sequence within selected RNAs is a very
      important determinant of DNA binding affinity. These studies provide insight into
      the development of RNA transcripts that may function as gene-specific repressors
      by forming triple helices with DNA in vivo.

PMID- 8656425
TI  - Functional analysis of conserved motifs in EcoP15I DNA methyltransferase.
AB  - EcoP15I DNA methyltransferase recognizes the sequence 5'-CAGCAG-3' and transfers
      a methyl group to N-6 of the second adenine residue in the recognition sequence.
      All N-6 adenine methyltransferases contain two highly conserved sequences, FxGxG
      (motif I), postulated to form part of the S-adenosyl-L-methionine binding site
      and (D/N/S)PP(Y/F) (motif IV) involved in catalysis. We have altered the second
      glycine residue in motif I to arginine and serine, and substituted tyrosine in
      motif IV with tryptophan in EcoP15I DNA methyltransferase, using site-directed
      mutagenesis. The mutant enzymes were overexpressed, purified and characterized by
      biochemical methods. The mutations in motif I completely abolished AdoMet binding
      but left target DNA recognition unaltered. Although the mutation in motif IV
      resulted in loss of enzyme activity, we observed enhanced crosslinking of S
      adenosyl-L-methionine and DNA. This implies that DNA and AdoMet binding sites are
      close to motif IV. Taken together, these results reinforce the importance of
      motif I in AdoMet binding and motif IV in catalysis. Additionally, limited
      proteolysis and UV crosslinking experiments with EcoP15I DNA methyltransferase
      imply that DNA binds in a cleft formed by two domains in the protein. Methylation
      protection analysis provides evidence for the fact that EcoP15I DNA MTase makes
      contacts in the major groove of its substrate DNA. Interestingly,
      hypermethylation of the guanine residue next to the target adenine residue
      indicates that the protein probably flips out the target adenine residue.

PMID- 8656426
TI  - Tubular crystals of a photosystem II core complex.
AB  - An oxygen evolving photosystem II core complex containing all three extrinsic
      proteins (33, 23, 17 kDa) was isolated from spinach and reconstituted into
      tubular two-dimensional crystals of 72.9 nm diameter and 1-2 micrometers length.
      While the 17 and 23 kDa polypeptides were lost during crystallization, the
      extrinsic 33 kDa protein was retained. The optical spectrum of the crystallized
      core was characteristic of an intact PSII core complex. Immunoelectron microscopy
      revealed that the lumenal surface of the PSII complex was exposed at the outside
      of the cylindrical tubes. The projection of the complex was determined from
      flattened tubular crystals by negative stain electron microscopy and image
      analysis to 2.0 nm resolution. Rhombic unit cells (a = 16.2 nm, b = 13.7 nm;
      gamma = 142.4 degrees) contained one PSII complex.

PMID- 8656428
TI  - The structures of Salmonella typhimurium LT2 neuraminidase and its complexes with
      three inhibitors at high resolution.
AB  - The structure of Salmonella typhimurium LT2 neuraminidase (STNA) is reported here
      to a resolution of 1.6 angstroms together with the structures of three complexes
      of STNA with different inhibitors. The first is 2-deoxy-2,3-dehydro-N-acetyl
      neuraminic acid (Neu5Ac2en or DANA), the second and third are phosphonate
      derivatives of N-acetyl-neuraminic acid (NANA) which have phosphonate groups at
      the C2 position equatorial (ePANA) and axial (aPANA) to the plane of the sugar
      ring. The complex structures are at resolutions of 1.6 angstroms, 1.6 angstroms
      and 1.9 angstroms, respectively. These analyses show the STNA active site to be
      topologically inflexible and the interactions to be dominated by the arginine
      triad, with the pyranose rings of the inhibitors undergoing distortion to occupy
      the space available. Solvent structure differs only around the third phosphonate
      oxygen, which attracts a potassium ion. The STNA structure is topologically
      identical to the previously reported influenza virus neuraminidase structures,
      although very different in detail; the root-mean-square (r.m.s) deviation for 210
      C alpha positions considered equivalent is 2.28 angstroms (out of a total of 390
      residues in influenza and 381 in STNA). The active site residues are more highly
      conserved, in that both the viral and bacterial structures contain an arginine
      triad, a hydrophobic pocket, a tyrosine and glutamic acid residue at the base of
      the site and a potential proton-donating aspartic acid. However, differences in
      binding to O4 and to the glycerol side-chain may reflect the different kinetics
      employed by the two enzymes.

PMID- 8656429
TI  - Conformation, protein-carbohydrate interactions and a novel subunit association
      in the refined structure of peanut lectin-lactose complex.
AB  - The structure of the complex of the tetrameric peanut lectin with lactose has
      been refined to an R-value of 16.4% using 2.25 angstroms resolution X-ray
      diffraction data. The subunit conformation in the structure is similar to that in
      other legume lectins except in the loops. It has been shown that in the tertiary
      structure of legume lectins, the short five-stranded sheet plays a major role in
      connecting the larger flat six-stranded and curved seven-stranded sheets.
      Furthermore, the loops that connect the strands at the two ends of the seven
      stranded sheet curve toward and interact with each other to produce a second
      hydrophobic core in addition to the one between the two large sheets. The protein
      lactose interactions involve the invariant features observed in other legume
      lectins in addition to those characteristic of peanut lectin. The "open"
      quaternary association in peanut lectin is stabilised by hydrophobic, hydrogen
      bonded and water-mediated interactions. Contrary to the earlier belief, the
      structure of peanut lectin demonstrates that the variability in quaternary
      association in legume lectins, despite all of them having nearly the same
      tertiary structure, is not necessarily caused by covalently bound carbohydrate.
      An attempt has been made to provide a structural rationale for this variability,
      on the basis of buried surface areas during dimerisation. A total of 45 water
      molecules remain invariant when the hydration shells of the four subunits are
      compared. A majority of them appear to be involved in stabilising loops.

PMID- 8656427
TI  - Conserved features in papillomavirus and polyomavirus capsids.
AB  - Capsids of papilloma and polyoma viruses (papovavirus family) are composed of 72
      pentameric capsomeres arranged on a skewed icosahedral lattice (triangulation
      number of seven, T = 7). Cottontail rabbit papillomavirus (CRPV) was reported
      previously to be a T = 7laevo (left-handed) structure, whereas human wart virus,
      simian virus 40, and murine polyomavirus were shown to be T = 7dextro (right
      handed). The CRPV structure determined by cryoelectron microscopy and image
      reconstruction was similar to previously determined structures of bovine
      papillomavirus type 1 (BPV-1) and human papillomavirus type 1 (HPV-1). CRPV
      capsids were observed in closed (compact) and open (swollen) forms. Both forms
      have star-shaped capsomeres, as do BPV-1 and HPV-1, but the open CRPV capsids are
      approximately 2 nm larger in radius. The lattice hands of all papillomaviruses
      examined in this study were found to be T = 7dextro. In the region of maximum
      contact, papillomavirus capsomeres interact in a manner similar to that found in
      polyomaviruses. Although papilloma and polyoma viruses have differences in capsid
      size (approximately 60 versus approximately 50 nm), capsomere morphology (11 to
      12 nm star-shaped versus 8 nm barrel-shaped), and intercapsomere interactions
      (slightly different contacts between capsomeres), papovavirus capsids have a
      conserved, 72-pentamer, T = 7dextro structure. These features are conserved
      despite significant differences in amino acid sequences of the major capsid
      proteins. The conserved features may be a consequence of stable contacts that
      occur within capsomeres and flexible links that form among capsomeres.

PMID- 8656430
TI  - Native and non-native structure in a protein-folding intermediate: spectroscopic
      studies of partially reduced IGF-I and an engineered alanine model.
AB  - The structure of a metastable folding intermediate of human insulin-like growth
      factor I (IGF-I) and an engineered model are investigated by circular dichroism
      and two-dimensional 1H NMR spectroscopy. The intermediate, which contains two of
      three native disulfide bonds, was trapped by acid quenching and isolated by
      reverse-phase HPLC. The reduced cysteine residues were mapped to residues 47 and
      52 (corresponding to A6-A11 in insulin). In the native state this disulfide
      bridge anchors an adjoining amphipathic alpha-helix (helix 2; residues 42 to 49)
      against the hydrophobic core. Comparison of CD and 1H-NMR spectra demonstrates
      that the acid-quenched intermediate is partially folded and contains elements of
      native secondary and tertiary structure. Spectra are similar to those of an
      equilibrium model in which the reduced cysteine residues are replaced by alanine.
      Complete 1H-NMR sequential assignment of the alanine model has been obtained and
      demonstrates that removal of the disulfide bond is associated with local
      unfolding of the adjoining alpha-helix. Native secondary structure (including
      helices 1 and 3) is otherwise retained and defines a folded subdomain. Long-range
      nuclear Overhauser effects (NOE) within this subdomain are similar to those of
      native IGF-I; no non-native NOE is observed. Our results support the hypothesis
      that folding of the insulin motif is directed by a subset of native structural
      elements and that these elements form at an early step in the pathway. Formation
      of helix 2, despite its prominence in the native state, is likely to represent a
      late step. Hydrophobic collapse of this segment appears to precede helix
      formation.

PMID- 8656431
TI  - Another look at induction chemotherapy for organ preservation in patients with
      head and neck cancer.

PMID- 8656433
TI  - Hospice services feel the pinch of managed care.

PMID- 8656432
TI  - Fiber and breast cancer: another piece of the puzzle--but still an incomplete
      picture.

PMID- 8656434
TI  - Palliative treatment needs stronger research basis.

PMID- 8656435
TI  - New trial empowers patients in their end-of-life care.

PMID- 8656436
TI  - START cancer database starts up in Europe.

PMID- 8656437
TI  - Basic research plays a key role in new patient treatments.

PMID- 8656438
TI  - "Two-in-one" surgery works for some stage I lung cancers.

PMID- 8656439
TI  - A model protocol for evaluating the behavioral and psychosocial effects of BRCA1
      testing.

PMID- 8656440
TI  - Testicular nonseminoma and seminoma in relation to perinatal characteristics.
AB  - BACKGROUND: Testicular cancer incidence peaks during the third decade of life,
      and an increasing trend in the occurrence of this disease has been seen in many
      countries. Few risk factors have been established for testicular cancer, but
      evidence suggests that causal factors operate early in life, perhaps even in
      utero. PURPOSE: We performed a case-control study to evaluate specific perinatal
      characteristics as risk factors for the two main histopathologic types of
      testicular cancer: seminomas and nonseminomas. METHODS: Two hundred thirty-two
      case patients with invasive testicular cancer and 904 individually matched
      control subjects (all singleton births), nested in a cohort of men born at 10
      hospitals in Sweden from 1920 through 1978, were included in the study. Perinatal
      information about the study subjects and their parents was obtained from birth
      records. For the mothers, information was recorded concerning age at menarche,
      marital status, parity, age at delivery, maternal weight at delivery and at first
      visit to a maternal-care center, education and/or profession, and any medical
      problems encountered during pregnancy or after delivery. For the fathers,
      information was obtained concerning age at delivery and education and/or
      profession. For the study subjects, information was recorded about the following:
      gestational age, birth length and weight, placental weight, method of delivery
      (normal, cesarean section, or with forceps or vacuum extractor), medical problems
      during hospital stay, presence of jaundice, method of feeding at discharge, and
      duration of hospital stay after birth. Individuals diagnosed with testicular
      cancer were identified through the Swedish National Cancer Registry and the
      Uppsala Regional Cancer Registry. The data were analyzed by use of conditional
      logistic regression modeling. RESULTS: When testicular cancer was modeled as a
      single entity, significantly elevated risks were associated with neonatal
      jaundice (adjusted odds ratio [OR] = 2.30; 95% confidence interval [CI] = 1.07
      4.94) and with either low (< 2500 g) or high (> or = 4000 g) birth weight (OR =
      2.59; 95% CI = 1.05-6.38 and OR = 1.58; 95% CI = 1.10-2.29, respectively). When
      seminomas and nonseminomas were analyzed separately, high maternal socioeconomic
      status (OR = 2.54; 95% CI = 1.05-6.12), neonatal jaundice (OR = 3.96; 95% CI =
      1.47-10.69), and low birth weight (OR = 7.62; 95% CI = 1.59-36.60) were
      associated with nonseminomas, whereas high placental weight (OR = 3.50; 95% CI =
      0.97-12.62) suggested increased risk for seminomas. CONCLUSIONS AND IMPLICATIONS:
      Perinatal exposures appear to influence the risk of testicular cancer, and
      seminomas and nonseminomas may have somewhat different risk profiles. Future
      epidemiologic studies should consider the possibility of etiologic heterogeneity
      in the development of seminomas and nonseminomas.

PMID- 8656441
TI  - Larynx preservation in pyriform sinus cancer: preliminary results of a European
      Organization for Research and Treatment of Cancer phase III trial. EORTC Head and
      Neck Cancer Cooperative Group.
AB  - BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation
      is considered to be the standard treatment for cancer of the hypopharynx, thus
      sacrificing natural speech. In most patients, surgery includes removal of the
      larynx. PURPOSE: A prospective, randomized phase III study was conducted by the
      European Organization for Research and Treatment of Cancer (EORTC) starting in
      1990 to compare a larynx-preserving treatment (induction chemotherapy plus
      definitive, radiation therapy in patients who showed a complete response or
      surgery in those who did not respond) with conventional treatment (total
      laryngectomy with partial pharyngectomy, radical neck dissection, and
      postoperative irradiation) in previously untreated and operable patients with
      histologically proven squamous cell carcinomas of the pyriform sinus or
      aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly
      assigned to one of two treatment arms: 1) immediate surgery with postoperative
      radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given
      as a bolus intravenous injection on day 1, followed by infusion of fluorouracil
      [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after
      each cycle of chemotherapy. After two cycles, only partial and complete
      responders received a third cycle. Patients with a complete response after two or
      three cycles of chemotherapy were treated thereafter by irradiation (70 Gy);
      nonresponding patients underwent conventional surgery with postoperative
      radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed
      after chemotherapy and irradiation. The trial was designed to test the
      equivalence of the two treatment arms; i.e., the induction chemotherapy treatment
      would be judged equivalent to immediate surgery if the relative risk of death for
      induction chemotherapy compared with immediate surgery was significantly less
      than 1.43 using a one-sided hypothesis test at the .05 level of significance.
      RESULTS: Two hundred two patients entered the trial and were randomly assigned;
      only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in
      the induction-chemotherapy arm). In the induction-chemotherapy arm, complete
      response was seen in 52 (54%) of 97 patients with local disease (primary tumor)
      and in 31 (51%) of 61 patients with regional disease (involvement of the neck).
      Treatment failures at local, regional, and second primary sites occurred at
      approximately the same frequencies in the immediate-surgery arm (12%, 19%, and
      16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%,
      respectively). In contrast, there were fewer failures at distant sites in the
      induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%,
      respectively; P = .041). The median duration of survival was 25 months in the
      immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since
      the observed hazard ratio was 0.86 (logrank test, P = .006), which was
      significantly less than 1.43, the two treatments were judged to be equivalent.
      The 3- and 5-year estimates of retaining a functional larynx in patients treated
      in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%)
      and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND
      IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible
      in patients with cancer of the hypopharynx. On the basis of these observations,
      the EORTC has now accepted the use of induction chemotherapy followed by
      radiation as the new standard treatment in its future phase III larynx
      preservation trials.

PMID- 8656442
TI  - Wheat bran and psyllium diets: effects on N-methylnitrosourea-induced mammary
      tumorigenesis in F344 rats.
AB  - BACKGROUND: Experimental and epidemiologic evidence suggests that increased
      dietary fiber is associated with decreased breast cancer risk. Little is known
      about the role played by different types of fiber and, particularly, mixtures of
      soluble and insoluble fibers similar to those consumed by human populations in
      reducing breast cancer risk. High intake of fiber may suppress bacterial
      hydrolysis of biliary estrogen conjugates to free (absorbable) estrogens in the
      colon and thus may decrease the availability of circulating estrogens necessary
      for the development and growth of breast cancers. PURPOSE: The purpose of this
      study was to evaluate the effect of wheat bran (an insoluble fiber) and psyllium
      (a soluble fiber) alone and in combination on overall estrogen status, on fecal
      bacterial beta-D-glucuronidase (a key diet-responsive estrogen-deconjugating
      enzyme) activity, and on the induction of mammary tumors in rats treated with N
      methylnitrosourea (MNU). METHODS: One hundred fifty virgin female F344 rats were
      fed the NIH-07 diet from 28 days of age until 50 days of age; they were then
      given a single dose (40 mg/kg of body weight) of MNU by tail vein injection.
      Three days later, they were randomly assigned to one of five experimental dietary
      groups (30 animals per group). Soft, white wheat bran (45% dietary fiber content)
      and psyllium (80% dietary fiber content) were added to a modified (high-fat)
      American Institute of Nutrition (AIN)-76A diet at the following percents,
      respectively: 12% + 0% (group 1), 8% + 2% (group 2), 6% + 3% (group 3), 4% + 4%
      (group 4), and 0% + 6% (group 5). Blood, urine, and feces were collected and
      analyzed by radioimmunoassay techniques for estrogens. Cecal contents were
      analyzed for bacterial beta-D-glucuronidase activity. After 19 weeks on the
      experimental diets, the rats were killed, and mammary tumors were counted and
      classified by histologic type. Cumulative tumor incidence was evaluated by the
      Kaplan-Meier life-table method and the logrank test. Tumor number was evaluated
      by the chi-squared test of association, and tumor multiplicity was evaluated by
      the Mantel-Haenszel chi-squared test. All statistical tests were two-tailed.
      RESULTS: As the level of psyllium relative to that of wheat bran increased, the
      total tumor number and multiplicity of mammary adenocarcinomas in rats decreased
      as a statistically significant linear trend across groups 1-5 (P < .05). Compared
      with the group given wheat bran alone, the group given the 1:1 (wheat
      bran:psyllium) combination had maximum protection against mammary tumorigenesis,
      while the groups given the 4:1 or 2:1 (wheat bran:psyllium) combination or
      psyllium alone had intermediate protection. No statistically significant
      differences in circulating estrogens or urinary estrogen excretion patterns were
      observed among the five experimental groups. Fecal estrogen excretion, however,
      decreased with increasing levels of psyllium (P < .01), and cecal beta-D
      glucuronidase activity exhibited a decreasing trend with respect to the
      increasing psyllium content of the diet across groups 1-5 (P < .01). CONCLUSIONS:
      The addition of a 4%:4% mixture of an insoluble (wheat bran) fiber and a soluble
      (psyllium) fiber to a high-fat diet provided the maximum tumor-inhibiting effects
      in this mammary tumor model. Although increasing levels of dietary psyllium were
      associated with decreased cecal bacterial beta-D-glucuronidase activity, these
      changes were not reflected in decreased circulating levels of tumor-promoting
      estrogens. Therefore, the mechanism(s) by which mixtures of soluble and insoluble
      dietary fibers protect against mammary tumorigenesis remains to be clarified.

PMID- 8656443
TI  - Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate
      cancer cells.
AB  - BACKGROUND: Diethylstillbestrol (DES) and diethylstilbestrol diphosphate (DESdP)
      are effective agents for the treatment of advanced prostate cancers. Tumor
      inhibiting effects of DES and DESdP are presumed secondary to suppression of
      androgen production in vivo. Little is known, however, about the direct cellular
      mechanisms of the tumor inhibition. Estrogens have been reported not only to
      stimulate growth but also to disrupt microtubule formation in prostate cancer
      cells. PURPOSE: The study was designed to examine and compare mechanisms of in
      vitro growth inhibition of DES and DESdP in human androgen-insensitive prostate
      cancer cells (DU145, 1-LN, and PC-3) and human androgen-sensitive prostate cancer
      cells (LNCaP) and to examine estrogen receptor modulation of such effects.
      METHODS: The cytotoxic effects of DES and DESdP were examined in vitro by use of
      a standard microculture tetrazolium assay to quantitate numbers of viable cells.
      Immunofluorescence microscopy, DNA fragmentation analysis, and fluorescence flow
      cytometry were used to investigate microtubules, the induction of apoptosis, and
      changes in cell cycle distribution. The degree of estrogen receptor positivity of
      untreated and treated cells was determined by immunohistochemistry and
      quantitative image analysis. RESULTS: LD50 levels (the dose at which 50% of cells
      are no longer viable) in the concentration range of 19-25 microM were observed
      for both DES and DESdP in all cell lines examined. DESdP-induced growth
      inhibition was found to be dependent on heat-labile phosphatases present in fetal
      calf serum. DES-induced cytotoxicity was not affected by the presence of 17 beta
      estradiol, and it was not dependent on the presence of estrogen receptor.
      Estrogen receptor-positive cells and estrogen receptor-negative cells were
      equally responsive to DES. PC-3 cells stained with fluorescent anti-tubulin,
      phalloidin (actin stain), and 4',6-diamidino-2-phenylindole (DNA stain) showed no
      inhibition of microtubules or actin filaments but revealed the presence of
      apoptotic bodies in the nuclei. Fluorescence flow cytometry of nuclear DNA
      content of propidium iodide-stained nuclei from androgen-insensitive prostate
      cancer cells treated with 15 or 30 microM DES or DESdP revealed an increase in
      relative numbers of hypodiploid (apoptotic) nuclei, a depletion of G1- and S
      phase cells, and an accumulation of cells in G2/M phase. Conversely, androgen
      sensitive cells contained a lower percentage of hypodiploid nuclei but no
      accumulation of cells in G2/M phase. CONCLUSIONS: Direct cytotoxic effects of DES
      in prostate cancer cells are estrogen receptor independent and do not involve
      disruption of microtubule architecture but do involve the promotion of cell cycle
      arrest and apoptosis. These are the first data confirming direct cytotoxic
      effects of DES and DESdP in prostate cancer cells via an apoptotic mechanism.
      IMPLICATIONS. These results suggest that DES and DESdP have potential value as
      agents against androgen-insensitive prostate neoplasms through induction of an
      apoptotic cascade.

PMID- 8656444
TI  - Radiotherapy-related lung fibrosis enhanced by tamoxifen.
AB  - BACKGROUND: Tamoxifen is an anti-estrogen with proven efficacy and low toxicity
      in the treatment of breast cancer. However, tamoxifen has been shown to exert a
      number of nonhormonal as well as hormonal effects. One nonhormonal effect of
      tamoxifen is the induction of transforming growth factor-beta (TGF-beta)
      secretion. TGF-beta has been implicated in the pathogenesis of radiation-induced
      fibrosis. PURPOSE: We investigated the development of lung fibrosis in breast
      cancer patients who were treated after mastectomy with radiotherapy, with or
      without simultaneous adjuvant treatment with tamoxifen. METHODS: Data from 196
      women were included in the analysis. Eighty-four women were postmenopausal
      patients who participated in a randomized trial testing tamoxifen as an adjuvant
      to postmastectomy radiotherapy. The radiotherapy technique employed an 8-MV
      photon field covering the axillary and the infraclavicular and supraclavicular
      regions of the affected side of the chest; the chest wall was treated with an
      abutted electron field. Optical density changes in pretreatment and post
      treatment chest x-ray films were used to monitor the development of lung
      fibrosis; lung reactions were assessed in the photon-irradiated field only.
      Logistic regression analysis was used to explore relationships between radiation
      dose and the development of lung fibrosis in patients either receiving or not
      receiving tamoxifen. All P values are from two-sided tests. RESULTS: Among the 84
      women who participated in the randomized trial of radiotherapy plus tamoxifen (n
      = 38) versus radiotherapy alone (n = 46), there was a significant association
      between tamoxifen treatment and the incidence of marked lung fibrosis (relative
      risk = 2.0; 95% confidence interval [CI] = 1.2-3.5; P = .01). When logistic
      regression analysis was used to evaluate data from all 196 patients, a highly
      significant relationship was found between the incidence of lung fibrosis and
      total radiation dose (P = .0005). In the full analysis, an increased risk of
      marked lung fibrosis was found again for patients who received tamoxifen
      simultaneously with radiotherapy (with patients receiving radiotherapy alone as
      the referent, odds ratio = 2.9; 95% CI = 1.3-6.3; P = .007). Patient age and
      menopausal status did not significantly influence the results. CONCLUSION:
      Tamoxifen treatment during postmastectomy radiotherapy enhances the risk of
      radiation-induced lung fibrosis. IMPLICATIONS: In view of pre-existing data, we
      hypothesize that tamoxifen mediates the enhancement of radiation-induced lung
      fibrosis through the induction of TGF-beta secretion. If this hypothesis is
      correct, new strategies might be devised for preventing or reducing radiation
      induced fibrosis. Because we studied a relatively small portion of the irradiated
      lung, we cannot recommend changes in current therapeutic measures; however, we
      strongly encourage additional studies of lung fibrosis in patients receiving
      tamoxifen and radiotherapy.

PMID- 8656445
TI  - Re:Randomized trial of adjuvant human interferon gamma versus observation in high
      risk cutaneous melanoma: a Southwest Oncology Group study.

PMID- 8656446
TI  - Clinical immunotoxicity of pesticides.
AB  - Because of the wide use of pesticides for domestic and industrial purposes, the
      evaluation of their immunotoxic effects is of major concern for public health.
      Despite the large amount of experimental data describing pesticide-induced
      immunosuppression, evidence that pesticides may severely impair immune functions
      in humans is lacking or scarce. Contact hypersensitivity is a well-identified
      immunotoxic effect of pesticides but remains a rare complaint in pesticide
      exposed workers. By contrast, immunologically mediated systemic reactions have
      been described only as debatable case reports. The association between autoimmune
      diseases and pesticide exposure has more recently been suggested. Despite the
      lack of convincing human data, a potential risk for the immune system should not
      be excluded, especially during chronic exposure to pesticides or in otherwise
      (immuno) compromised patients (malnutrition, children, old patients).
      Epidemiological studies including markers of exposure and the assessment of
      immune competence in exposed individuals, or registries of sentinel diseases
      related to immunosuppression (e.g., non-Hodgkin's lymphoma, opportunistic
      infections) or autoimmunity (e.g. lupus erythematosus, rheumatoid arthritis), are
      warranted.

PMID- 8656447
TI  - On interspecies correlations of carcinogenic potencies.
AB  - It has been established in the literature that constraints on the designs of
      experiments used to estimate carcinogenic potencies cause overestimation of true
      biological interspecies correlations of such potencies. This article explores the
      potential for appreciable underestimation of interspecies correlations, due to
      the experimental error that occurs in the estimation of carcinogenic potencies.

PMID- 8656448
TI  - Evaluation of selenium exposure in copper refinery workers.
AB  - Concentrations of selenium in plasma and urine and activity of glutathione
      peroxidase in erythrocytes were determined in workers exposed to selenium and in
      a control group. Plasma selenium concentrations were significantly lower in
      exposed workers compared to the controls. Erythrocyte glutathione peroxidase
      activity in selenium workers was significantly higher than in the control
      subjects. Urine selenium concentrations were not statistically different between
      the two groups. There was a significant positive correlation between plasma
      selenium concentrations and urine selenium concentrations in workers exposed to
      selenium. A weak significant positive correlation was found between plasma
      selenium concentrations and erythrocyte glutathione peroxidase activity in
      exposed workers. Our results suggest that the lower plasma selenium
      concentrations in selenium workers may be attributed to an increase of urinary
      selenium excretion.

PMID- 8656449
TI  - Role of arsenic as a reproductive toxin with particular attention to neural tube
      defects.
AB  - Arsenic has been recognized as a human toxicant for over 2000 years. More
      recently it has been readily accepted as a human carcinogen. Animal research has
      demonstrated arsenic's ability to have profound detrimental effects on the
      developing embryo in avian and mammalian species. This article comprehensively
      reviews the human and animal literature on the subject of the reproductive
      toxicity of arsenic. A variety of endpoints are considered, including spontaneous
      abortion, cardiovascular defects, and arsenic's role in the causation of neural
      tube defects (NTDs). A summary of the literature that has examined the various
      postulated mechanisms by which arsenic may produce NTDs is also considered. In
      addition, a discussion of literature relative to the presence of arsenic in the
      general environment and in the workplace is presented. This article reaches the
      conclusion that while further research is clearly needed, particularly on the
      potential toxicity of organic arsenical compounds, the current literature
      suggests it may be prudent and appropriate to treat inorganic arsenic as a
      probable human reproductive toxin.

PMID- 8656451
TI  - Evaluation of acoustic rhinometry and posterior rhinomanometry as tools for
      inhalation challenge studies.
AB  - Objective measures of upper respiratory function are needed to understand the
      effects of inhaled toxicants on the nasal passages. Acoustic rhinometry (AR) is a
      simple new technique that determines nasal volume by measuring the cross
      sectional area of the upper airway as a function of the distance along the nasal
      passage. This study compares acoustic rhinometry with the more traditional
      posterior rhinomanometry (NAR) and correlates these objective measures with the
      symptom of nasal congestion. Healthy young adults (n = 29) were studied on 4
      days, each separated by at least 1 wk, in a climate-controlled environmental
      chamber for 6 h, with exposure to clean air or sidestream tobacco smoke (SS) (2
      h, 1, 5, and 15 ppm CO). The coefficient of variation for single measurements was
      8-15% (AR) and 4% (NAR); for across-day measurements it was 15-25% (AR) and 13
      15% (NAR); and for between days it was 19-27% AR and 17-21% (NAR). These
      coefficients were similar in subjects with a history of environmental tobacco
      smoke sensitivity (ETS-S) and those with no history of ETS sensitivity (ETS-NS).
      At baseline, the perception of unilateral nasal congestion was significantly
      correlated with unilateral nasal dimensions or nasal resistance; the symptom of
      baseline bilateral nasal congestion (estimated for both nasal passages
      simultaneously) correlated less well with objective measures of nasal patency.
      Under challenge conditions (SS at 1-15 ppm CO), there were typically significant
      correlations between changes in unilateral congestion and both unilateral
      rhinomanometry and acoustic rhinometry, but correlations of bilateral congestion
      and measurable dimensions were much lower. ETS-S and ETS-NS subjects differed in
      correlations between bilateral subjective and objective measures: ETS-S subjects
      showed significant correlation between baseline congestion and NAR; in contrast,
      ETS-NS subjects showed significant correlation between baseline congestion and
      acoustic rhinometry. These results indicate that NAR and AR are complementary
      tests for use in inhalation challenge studies and have different correlations
      with nasal congestion under baseline and challenge conditions.

PMID- 8656450
TI  - Pneumotoxicity and hepatotoxicity of styrene and styrene oxide.
AB  - The purpose of this study was to investigate the toxicity of styrene and styrene
      oxide in the lung in comparison to the toxicity in the liver. Pneumotoxicity
      caused by styrene or styrene oxide was measured by elevations in the release of
      gamma-glutamyltranspeptidase (GGT) and lactate dehydrogenase (LDH) into
      bronchoalveolar lavage fluid (BALF), while hepatotoxicity was measured by
      increases in serum sorbitol dehydrogenase (SDH) in non-Swiss Albino (Hsd:NSA)
      mice. Intraperitoneal administration of styrene at doses of 500-1000 mg/kg caused
      consistent dose-dependent increases in both sets of biomarkers with the hepatic
      effect appearing earlier than the pulmonary effect. Pyridine, phenobarbital, and
      beta-naphthoflavone, inducers of CYP2E1, CYP2B, and CYP1A, respectively,
      increased the toxicity of styrene. Pyridine and phenobarbital treatments
      increased mortality due to styrene. Styrene oxide exists in two enantiomeric
      forms: (R)- and (S)-styrene oxide, and the differential toxicities of the two
      enantiomers and racemic styrene oxide were compared. In all studies, (R)-styrene
      oxide caused greater toxicity than the (S) enantiomer, especially in the liver.
      Trichloropropene oxide, an epoxide hydrolase inhibitor, was used to inhibit
      styrene oxide detoxification and increased its hepatotoxicity, while buthionine
      sulfoxamine, a glutathione depletor, did not. These results demonstrated the
      greater role of epoxide hydrolase in styrene oxide detoxification.

PMID- 8656452
TI  - Inhibition of protein synthesis in a cell-free system and Vero cells by okadaic
      acid, a diarrhetic shellfish toxin.
AB  - Okadaic acid, a diarrhetic shellfish toxin, is a potent promoter of tumors in
      mouse skin and a specific inhibitor of protein phosphatases 1 and 2A. In the
      present study, we investigated its effects on protein synthesis in Vero cells and
      rabbit reticulocyte lysate. Protein synthesis was inhibited by okadaic acid in
      Vero cells in a concentration-dependent manner (IC50 = 3.3 x 10(8) M-1). DNA
      synthesis was also inhibited by okadaic acid in Vero cells in a concentration
      dependent manner (IC50 = 5.3 x 10(8) M-1). DNA synthesis inhibition in Vero cells
      occurred only after 8 h or longer. RNA synthesis was inhibited with an IC50 of
      8.2 x 10(8) M-1. The time lag before DNA and RNA synthesis inhibition occurred
      was longer than the time lag before protein synthesis inhibition occurred in the
      same cells (4 h), indicating that protein synthesis is probably the main target
      and the first of okadaic acid's cytotoxic effects. Moreover, the inhibition of
      DNA and RNA synthesis is probably a consequence of the inhibition of protein
      synthesis. Since okadaic acid does not impair the uptake of the precursor of
      protein synthesis, it is assumed that the inhibition is due to a direct effect on
      one of the components of the protein synthesis machinery. We then used a cell
      free system of rabbit reticulocyte lysate in which specific mRNA is translated
      into globin to ensure that protein synthesis is a direct target of okadaic acid
      in vitro. In rabbit reticulocyte lysate, okadaic acid inhibited protein synthesis
      in a concentration-dependent manner (IC50 = 6.3 x 10(12) M-1) with a correlation
      coefficient for percent inhibition values of r = .918. The molecular target of
      okadaic acid inside the cell whereby protein synthesis is inhibited remains to be
      discovered.

PMID- 8656453
TI  - Trauma care reimbursement in rural hospitals: implications for triage and trauma
      system design.
AB  - American College of Surgeons triage guidelines recommend rapid identification and
      transfer of seriously injured patients to regional trauma centers, bypassing
      local hospitals if necessary. This approach raises concerns about the potential
      negative financial impact of implementing such triage strategies on already
      strained rural hospitals. OBJECTIVE: The purpose of this study was to determine
      the association between injury severity and reimbursement for trauma care in
      rural hospitals. It was our hypothesis that the seriously injured would be high
      cost and relatively low reimbursement patients, and thus be a significant
      financial liability to the rural hospital. This would imply that concerns by the
      rural hospital about triage of such patients to trauma centers would be
      unfounded. METHODS: Data on every injured patient seen in the emergency
      department during two 3-month periods were obtained from three rural hospitals in
      the state using the American College of Surgeons Trauma Registry data base.
      RESULTS: One thousand six hundred thirty patients had complete data available for
      analysis. The analyses demonstrated that as the injury severity increased, there
      was an increase in hospital charges, length of stay, and risk of dying. In
      contrast, the reimbursement changed little as the charges and severity increased.
      Thus, hospital losses increased in an exponential fashion as injury severity
      increased above 15. CONCLUSION: The study demonstrates that as injury severity
      increases, costs and charges increase, but reimbursement does not keep pace with
      these increased charges. The rural hospital was projected to lose an average of
      $25,000 for each patient with an Injury Severity Score over 15. This study
      supports the rapid triage and transport of the seriously injured patient from the
      rural hospital to the regional trauma center both for improved patient outcome
      and for the hospital's best interest. The potential impact of such a system on
      the trauma center also needs to be addressed.

PMID- 8656454
TI  - Delayed diagnosis of pancreatic transection after blunt abdominal trauma.
AB  - A case of delayed diagnosis of a pancreatic transection after blunt abdominal
      trauma is presented. The cause of diagnostic delay as well as measures to avoid
      future errors in diagnosis are outlined.

PMID- 8656455
TI  - Spontaneous recanalization of the pancreatic duct: case report and review.
AB  - An eight-year-old boy received a grade 3 pancreatic injury as a result of a
      bicycle handlebar accident. Endoscopic retrograde cholangiopancreatography (ERCP)
      showed a proximal pancreatic duct transection. At laparotomy, a complete
      transection of the gland and duct was visualized; however, only debridement and
      external fistulization were performed. Follow-up ERCP performed 3 months
      postoperatively showed recanalization of the pancreatic duct without further
      operative intervention. At 1-year follow-up, the patient is pain free and
      tolerating a regular diet.

PMID- 8656456
TI  - Motor-scooter handlebar syndrome: blunt traumatic injury of the femoral artery.
AB  - We present a case of "motor-scooter handlebar syndrome," i.e., intimal injury to
      the common femoral artery caused by a direct blow from a motorcycle handlebar,
      and review other potential mechanisms for similar arterial injuries. Our case is
      unique in that a clinical diagnosis was made before vascular studies or arterial
      occlusion. The mechanism of injury combined with physical examination findings of
      localized swelling, tenderness, and an overlying bruit prompted early
      heparinization with subsequent radiographic studies and surgical repair.

PMID- 8656457
TI  - Aortic balloon control of a traumatic aortoenteric fistula after damage control
      laparotomy: a case report.
AB  - Aortoenteric fistula is a rare complication of abdominal trauma. We present a
      case of a patient with multiple gunshot wounds to the abdomen and thorax in whom
      control of injury required staged operations. An aortoenteric fistula developed,
      presenting a diagnostic and therapeutic challenge. The operative control of
      aortic bleeding was by a retroperitoneal approach to the aorta and facilitated by
      the use of percutaneous aortic balloon catheters. The patient survived to leave
      hospital. This case highlights a rare trauma complication, the use of "damage
      control" for the severely injured abdomen and the technique of intra-arterial
      balloon control of bleeding from inaccessible locations.

PMID- 8656458
TI  - Lung injury with pleuropericardial rupture successfully treated by video-assisted
      thoracoscopy: case report.
AB  - We present a case of lung injury with pleuropericardial rupture resulting from
      blunt chest trauma. A conclusive diagnosis and successful treatment was achieved
      by video-assisted thoracoscopy. The value of diagnostic modalities and the role
      of video-assisted thoracoscopy in the management of these challenging patients
      are discussed.

PMID- 8656459
TI  - Hypothermia induced by continuous arteriovenous hemofiltration as a treatment for
      adult respiratory distress syndrome: a case report.

PMID- 8656460
TI  - Aspirated tooth removal from airway through tracheotomy and flexible
      bronchoscopy.
AB  - Aspiration of a tooth in facial trauma is a known complication. A complicated
      case of tooth aspiration with a compromised airway in a 28-year-old woman is
      described. The tooth was in the left main bronchus. A special technique involving
      flexible bronchoscopy, Fogarty catheter, and tracheotomy was used to extract the
      tooth.

PMID- 8656461
TI  - Volar transscaphoid perilunate fracture dislocation: case report and review.

PMID- 8656462
TI  - Paradoxical bullet embolism: case report and literature review.
AB  - Bullet embolization through the arterial or venous systems, although unusual,
      often causes diagnostic confusion. Paradoxical emboli are even more unusual. We
      present a case of a paradoxical bullet embolism from the left external iliac vein
      to the left common iliac artery via a patent foramen ovale.

PMID- 8656463
TI  - Evolution in the management of duodenal injuries.

PMID- 8656464
TI  - Thoracoscopy in the trauma patient: what is its role?

PMID- 8656465
TI  - Role of echocardiography in the diagnosis of occult penetrating cardiac injury.

PMID- 8656466
TI  - Quantitative sensitivity of ultrasound in detecting free intraperitoneal fluid.

PMID- 8656467
TI  - Buckshot colic.

PMID- 8656468
TI  - Regional trauma systems.

PMID- 8656469
TI  - Reengineering trauma care: the challenge of the nineties.

PMID- 8656470
TI  - Attrition of cognitive and trauma management skills after the Advanced Trauma
      Life Support (ATLS) course.
AB  - OBJECTIVE: To test the attrition of cognitive and trauma management skills among
      practising physicians after the Advanced Trauma Life Support (ATLS) course.
      DESIGN, MATERIALS, AND METHODS: Sixty practising physicians who completed the
      ATLS course had comparative assessment of cognitive skills (with multiple choice
      questions, MCQ) pre-ATLS, immediately post-ATLS, at 6 months (group A), 2 years
      (group B), 4 years (group C), and 6 years (group D) after the course. Trauma
      management skills were also compared using eight Objective Structured Clinical
      Examination (OSCE) trauma stations completed by the four groups of physicians.
      MEASUREMENTS AND MAIN RESULTS: Pre-ATLS MCQ scores (54.2 +/- 4.2 to 59.8 +/-
      5.3%) and immediately post-ATLS MCQ scores (85.9 +/- 5.1 to 87.7 +/- 5.3%) were
      similar in all four groups. Follow-up MCQ scores were 77.8 +/- 3.6% at 6 months
      70.6. +/- 1.9% at 2 years, 69.4 +/- 1.7% at 4 years, and 68.9 +/- 2.0% at 6
      years. OSCE scores out of a maximum of 20 were 16.8 +/- 0.3 at 6 months, 13.9 +/-
      0.1 at 2 years, 12.0 +/- 0.1 at 4 years, and 11.9 +/- 0.1 at 6 years. Adherence
      to-priorities scores (maximum, 7) were 6.6 +/- 0.2 at 6 months, 6.8 +/- 0.1 at 2
      years, 6.6 +/- 0.1 at 4 years, and 6.6 +/- 0.1 at 6 years. Organized-approach
      scores (maximum, 5) were 4.8 +/- 0.1 at 6 months, 4.6 +/- 0.2 at 2 years, 4.7 +/-
      0.2 at 4 years, and 4.6 +/- 0.2 at 6 years. Using the MCQ 80% pass mark
      criterion, at least 50% of physicians fail by 6 months and all fail this
      cognitive test thereafter. CONCLUSIONS: Whereas cognitive and trauma management
      skills decline after the ATLS, these skills are maintained at similar levels
      between 4 and 6 years after ATLS. A 50% failure rate occurs within 6 months and
      maximum attrition of cognitive skills occurs within 2 years of ATLS completion.
      Major principles of adherence to priorities and maintenance of an organized
      approach to trauma care are preserved for at least 6 years after ATLS.

PMID- 8656471
TI  - Emergent abdominal sonography as a screening test in a new diagnostic algorithm
      for blunt trauma.
AB  - Although there is an interest in emergent abdominal sonography (EAS), the
      clinical utilization of EAS in North America is minimal. The purpose of this
      study was to develop a new diagnostic algorithm for blunt abdominal injury based
      on a prospective blinded comparison of EAS, diagnostic peritoneal lavage (DPL),
      and computed tomography (CT). EAS (+ = fluid, - = no fluid) was performed before
      the DPL or CT, in 400 patients with a mean Injury Severity Score of 26; 293 had a
      CT and 107 had a DPL. The EASs required 2.6 +/- 1.2 minutes with 82% < or = 3
      minutes. The accuracy of EAS for free fluid was 94% with a positive and negative
      predictive value of 82 and 96%, respectively. Only 1 of 338 patients with EAS-
      had an acute therapeutic laparotomy. Three patients with EAS- had a delayed
      laparotomy based on evolving clinical findings. The radiologists interpretation
      of the EAS video disagreed with the clinician sonographer in only 3% of cases.
      Based on these results, a diagnostic algorithm was developed using EAS as a
      screening test with selective use of DPL and CT. Emergent abdominal sonography
      performed by clinician sonographers is a rapid and accurate test for peritoneal
      fluid in blunt trauma victims, and the need for laparotomy in patients with a
      negative EAS is rare. Our study supports the routine use of EAS as a screening
      test in a diagnostic algorithm for the evaluation of blunt abdominal trauma.

PMID- 8656472
TI  - A prospective evaluation of abdominal ultrasound in blunt trauma: is it useful?
AB  - OBJECTIVE: The purpose of this study is to evaluate the utility and feasibility
      of abdominal ultrasound (US) in blunt trauma patients. DESIGN: This prospective
      study examined the operational issues and the diagnostic accuracy of US in
      selected blunt trauma patients triaged to a Level 1 trauma center. MATERIALS AND
      METHODS: All patients were evaluated by an attending trauma surgeon and our usual
      criteria for objective evaluation of the abdomen were applied. US was performed
      by US technicians and interpreted by the trauma surgeon. We prospectively
      evaluated the availability (time to arrival), the ease with which the US could be
      integrated into the resuscitation (minutes to start after arrival), and the time
      required to perform the study. The US results were compared to diagnostic
      peritoneal lavage and computed tomography findings, clinical course, operative
      findings, and to repeat US examinations to determine sensitivity, specificity,
      and usefulness. MEASUREMENTS AND MAIN RESULTS: A total of 800 US studies were
      performed over 15 months. In four cases (0.5%), the US was incomplete for
      technical reasons. The results in the remaining 796 studies were as follows:
      [table: see text] The average time to arrival of the US was 17.3 minutes (range 0
      120) and the average minutes to start after arrival was 7.0 (range 1-49). The
      average time required to perform the study was 10.6 minutes (range 2-26).
      CONCLUSIONS: This study demonstrates that US can be obtained rapidly, integrated
      into the resuscitation, and completed quickly. US provides a highly accurate,
      noninvasive method to evaluate the abdomen in the blunt trauma patient, and has
      supplanted the previously used methods at this institution.

PMID- 8656473
TI  - Effects of recombinant bactericidal/permeability-increasing protein (rBPI23) on
      neutrophil activity in burned rats.
AB  - Bactericidal/permeability-increasing protein (BPI) is a neutrophil granule
      protein with potent bactericidal and lipopolysaccharide (LPS)-neutralizing
      activities. The purpose of this study was to determine if a human recombinant BPI
      product, rBPI23, would influence neutrophil (PMN) sequestration into various
      tissues in a rat burn injury model. Leukosequestration may produce local tissue
      injury from proteases and high-energy oxygen species released from PMNs. Rats
      received tracheostomy and venous cannulation, then received 17 to 20% total body
      surface area full-thickness contact burns and resuscitation with 20 ml, of
      intraperitoneal saline. Ten mg/kg body weight rBPI23 in saline was given by
      intravenous injection immediately after burn injury, followed by intravenous
      doses of 2 mg/kg at 2 and 4 hours. Control animals received intravenous saline
      only. PMN retention in lung, liver, spleen, gut, skin, muscle, kidney, and brain
      tissues was determined by removing (before burn injury) and differentially
      radiolabeling PMNs (111In) and erythrocytes (51Cr), reinfusing cells 4.5 hours
      after burn injury, and measuring tissue radioactivity 30 minutes later. Edema was
      estimated by measuring extravasated 125I-labeled albumin in the various tissues,
      30 minutes after injection. Peripheral blood PMNS were analyzed for intracellular
      H2O2 content by flow cytometry using a fluorescent dye that reacts with H2O2.
      Radioisotope studies demonstrated significant (p < 0.05) leukosequestration into
      lung, liver, gut, kidney, and skin tissues at 5 hours after burn injury. Tissue
      edema, manifested by radiolabeled albumin retention, was not observed in any
      tissues. Postburn PMN deposition in lungs and skin was decreased (p < 0.05) by
      the immediate administration of rBPI23 after burn injury. Flow cytometry showed
      increased intracellular H2O2 content in peripheral blood PMNs 5 hours after burn
      injury (p < 0.05), which was unaffected by administration of rBPI23. Since
      sequestration of metabolically active PMNs may induce tissue injury, therapies
      that block leukosequestration after burn injury may improve clinical outcomes by
      limiting remote tissue injury.

PMID- 8656474
TI  - Expression of interleukin-1alpha, interleukin-6, and basic fibroblast growth
      factor by cultured skin substitutes before and after grafting to full-thickness
      wounds in athymic mice.
AB  - OBJECTIVES: Cultured skin substitutes (CSSs), consisting of human keratinocytes
      and human fibroblasts attached to collagen-glycosaminoglycan substrates, have
      been demonstrated to cover wounds, and may release detectable quantities of
      growth factors that promote wound healing. MATERIALS AND METHODS: Basic
      fibroblast growth factor (bFGF), interleukin-1alpha (IL-1alpha), and interleukin
      6 (IL-6) were assayed by enzyme linked immunosorbent assay and
      immunohistochemistry in CSSs in vitro and at days 1, 3, 7, 14, and 21 after
      grafting to full-thickness wounds in athymic mice. MEASUREMENTS AND MAIN RESULTS:
      When isolated cells were tested, IL-1alpha was found to come primarily from the
      keratinocytes, whereas bFGF was from the fibroblasts. Combinations of both cell
      types in the CSSs resulted in a synergistic enhancement of IL-6 expression.
      Quantities of all three cytokines from CSSs were greater in vitro compared with
      in vivo levels at all time points after grafting. bFGF increased from day 1 to
      day 7, and then remained relatively constant until day 21. At day 3 maximal
      levels of IL-1alpha were observed. By day 7, IL-1alpha decreased to approximately
      40% of maximal levels, and subsequently increased until day 21. IL-6 levels were
      highest at day 7 after grafting. All cytokines had reached elevated levels during
      the time of wound revascularization (days 3-7). CONCLUSIONS: The sequence of
      cytokine synthesis in the wounds (i.e., rapid IL-1alpha increase followed by IL-6
      expression) parallels serum levels reported after a septic challenge. These
      findings support the hypothesis that the wound is a source of systemic cytokines.

PMID- 8656475
TI  - Elevated transforming growth factor-beta concentration correlates with posttrauma
      immunosuppression.
AB  - OBJECTIVE: To determine whether trauma induces an increase in the concentration
      of circulating transforming growth factor-beta (TGF-beta), and whether there is a
      temporal correlation between plasma TGF-beta concentration and the development of
      posttrauma cellular immunosuppression. MATERIALS AND METHODS: Male Sprague-Dawley
      rats were anesthetized, subjected to bilateral femur fractures or sham injury,
      and killed 1, 3, or 5 days later. Plasma TGF-beta levels, splenocyte phenotypes,
      mitogen-induced proliferation, interleukin-2 (IL-2) production, and IL-2 receptor
      (IL-2R) expression were determined at each time point. MEASUREMENTS AND MAIN
      RESULTS: Splenocyte proliferation increased on day 1 postinjury without
      corresponding change in IL-2 or plasma TGF-beta levels. Splenocyte proliferation
      and IL-2 production were suppressed on day 3 postinjury, while plasma TGF-beta
      levels peaked. No differences were observed between trauma and control groups on
      day 5. Splenocyte phenotypes and IL-2R expression were similar in injured and
      control rats at all times. CONCLUSIONS: Suppression of lymphocyte proliferation
      and IL-2 production after trauma occurs concomitantly with a rise in plasma TGF
      beta. The immune response is restored with normalization of TGF-beta
      concentration. These observations suggest that TGF-beta may contribute to
      posttrauma immunosuppression.

PMID- 8656476
TI  - Different pattern of local and systemic release of proinflammatory and anti
      inflammatory mediators in severely injured patients with chest trauma.
AB  - BACKGROUND: Excessive release of proinflammatory cytokines has been involved in
      pathogenesis of acute respiratory distress syndrome. DESIGN: Since injured
      patients with chest trauma reveal a high risk for posttraumatic acute respiratory
      distress syndrome, local and systemic release of proinflammatory cytokines and
      their naturally occurring inhibitors were determined in the early posttraumatic
      period. MATERIALS AND METHODS: Proinflammatory and anti-inflammatory mediators
      were measured in plasma and bronchoalveolar lavage fluid (BALF) from 16 patients
      with multiple injuries including severe chest injury (Injury Severity Score of
      34.4 +/- 2.3 points) and compared with healthy volunteers (n = 17). RESULTS:
      Tumor necrosis factor-alpha was detectable neither in plasma nor in BALF.
      Interleukin-1beta and interleukin-8 were significantly increased in BALF from
      injured patients, while plasma levels were similar in both groups. Soluble tumor
      necrosis factor receptors p55 and p75 and interleukin-1ra were markedly elevated
      in plasma (p < or = 0.01) and BALF (p < or = 0.001) from injured patients
      compared with controls. CONCLUSION: Highly increased concentrations of
      proinflammatory cytokines in BALF, but not in circulation, indicate a strong
      local inflammatory response early after multiple injuries combined with chest
      injury rather than severe systemic inflammation. In contrast, anti-inflammatory
      mechanisms seem to be activated locally and systemically.

PMID- 8656477
TI  - Uncontrolled hemorrhage from parenchymal injury: is resuscitation helpful?
AB  - Fluid resuscitation increases blood pressure and may increase hemorrhage. We
      tested this hypothesis in a model of liver injury. After standardized injury,
      rats were randomized into four groups: no resuscitation (NR, n = 30), small
      volume lactated Ringer's solution (SVLR, 4 mL/kg, n = 30), large volume lactated
      Ringer's solution (LVLR, 24 mL/kg, n = 30), and hypertonic saline (HS, 4 mL/kg, n
      = 30). Terminal circulating volume was estimated using controlled hemorrhage
      experiments. Survival times and mortality rates were significantly lower in HS
      animals (10%) than in NR (50%) or SVLR (47%) animals. Blood pressure was
      significantly higher after HS, and this difference was sustained. Intraperitoneal
      blood volume was significantly higher with HS (26.0 +/- 0.7 mL/kg) and LVLR (26.9
      +/- 0.6 mL/kg) compared with NR (21.5 +/- 0.7 mL/kg) and SVLR (22.5 +/- 0.7
      mL/kg). Estimated terminal blood volume was significantly decreased in LVLR (29.3
      +/- 0.6 mL/kg) compared with NR (33.3 +/- 0.7 mL/kg), SVLR (33.7 +/- 0.8 mL/kg),
      and HS (31.7 +/- 0.7 mL/kg). CONCLUSION: Vigorous resuscitation increases
      bleeding from solid viscus injury. Small volume HS improves blood pressure and
      survival compared with no resuscitation. Results of large vessel hemorrhage
      models may not apply to parenchymal viscus injury.

PMID- 8656478
TI  - Predicting the need to pack early for severe intra-abdominal hemorrhage.
AB  - OBJECTIVE: To determine if the decision to pack for hemorrhage could be refined.
      MATERIALS AND METHODS: Seventy consecutive trauma patients for whom packing was
      used to control hemorrhage were studied. The patients had liver injuries,
      abdominal vascular injuries, and bleeding retroperitoneal hematomas. Preoperative
      variables were analyzed and survivors compared with nonsurvivors. RESULTS:
      Packing controlled hemorrhage in 37 (53%) patients. Significant differences (p <
      0.05) between survivors and nonsurvivors were Injury Severity Score (29 vs. 38),
      initial pH (7.3 vs. 7.1), platelet count (229,000 vs. 179,000/mm3), prothrombin
      time (14 vs. 22 seconds), partial thromboplastin time (42 vs. 69 seconds), and
      duration of hypotension (50 vs. 90 minutes). Nonsurvivors received 20 units of
      packed red blood cells before packing compared to 13 units for survivors.
      CONCLUSION: Patients who suffer severe injury, hypothermia, refractory
      hypotension, coagulopathy, and acidosis need early packing if they are to
      survive. Failure to control hemorrhage is related to severity of injury and delay
      in the use of pack tamponade. A specific protocol that mandates packing when
      parameters reach a critical limit should be considered.

PMID- 8656479
TI  - Decreased cerebral glucose utilization in rats during the ebb phase of thermal
      injury.
AB  - OBJECTIVE: Thermal injury is associated with the development of encephalopathy.
      The mechanism(s) for the development of this condition have not been established.
      In the present study, the effects of thermal injury were determined on rat brain
      glucose utilization (Rg), using 2-[18F]fluoro-2-deoxy-D-glucose (18FDG). DESIGN:
      Four types of studies were performed. In one group of rats, the effect of thermal
      injury on total rat brain glucose utilization (Rg) was determined at 6 hours, 24
      hours, and 3 weeks after injury. The brains of thermally injured rats were also
      assayed for hexokinase and glucose-6-phosphatase activities, since these enzyme
      activities are responsible for the phosphorylation and dephosphorylation of the
      18FDG. We also measured total body oxygen consumption in the thermally injured
      rats. We wanted to compare the changes produced by thermal injury on rat brain
      glucose utilization (Rg) with the effects produced by compounds known to modify
      energy metabolism and/or rat brain glucose utilization (Rg). For that reason, in
      a second group of rats, an inflammatory state was produced by lipopolysaccharide
      injection, and rat brain glucose utilization (Rg) was determined. In the third
      group of rats, overall metabolism in rats was reduced by pentobarbital injection,
      followed by hypothermia, and rat brain glucose utilization (Rg) was determined.
      In the fourth group of rats, overall metabolism in rats was stimulated by 2,4
      dinitrophenol injection, and rat brain glucose utilization (Rg) was determined.
      MATERIALS AND METHODS: Glucose utilization (Rg) by the brains of these treated
      rats was determined using 18FDG. Oxygen consumption in vivo, as well as glucose-6
      phosphatase and hexokinase activity in vitro, were measured by standard
      procedures. MEASUREMENTS AND MAIN RESULTS: Glucose utilization (Rg) by rat brain
      was significantly reduced (p < 0.01) at 6 and 24 hours after injury, but returned
      to normal values 3 weeks after injury. These reductions were associated with
      decreases in rat brain hexokinase activity, increases in rat brain glucose-6
      phosphatase activity, and decreased oxygen consumption by rats in vivo.
      Pentobarbital injection followed by hypothermia reduced rat brain glucose
      utilization (Rg) (p < 0.01), while 2,4-dinitrophenol treatment elevated rat brain
      glucose utilization (Rg) (p < 0.01). In contrast, LPS treatment had no effect on
      rat brain glucose utilization (Rg). CONCLUSIONS: These data indicate that thermal
      injury decreases glucose utilization (Rg) in rat brain during the hypometabolic
      phase. This effect can be explained, at least in part, by alterations in
      hexokinase and glucose-6-phosphatase activities, as well as reductions in oxygen
      consumption. Thus, the changes in brain glucose utilization (Rg) appear to be
      associated with the ebb phase of the thermal injury. The present results observed
      in burned rats may provide evidence to explain the encephalopathy observed in
      burned patients.

PMID- 8656480
TI  - Effects of increased intra-abdominal pressure upon intracranial and cerebral
      perfusion pressure before and after volume expansion.
AB  - OBJECTIVE: To study the effects of elevated intra-abdominal pressure (IAP) upon
      intracranial (ICP) and cerebral perfusion pressure (CPP) before and after
      intravascular volume resuscitation. MATERIALS AND METHODS: Intra-abdominal
      pressure was increased in five anesthetized swine by inflating an intraperitoneal
      balloon until the IAP was 25 mm Hg above baseline. Intravascular volume was then
      expanded and finally abdominal decompression was performed. Changes in ICP and
      systemic and pulmonary hemodynamic parameters secondary to increasing IAP were
      measured. The effect upon CPP was derived from these measurements. PaO2 and PaCO2
      were maintained relatively constant by increasing ventilatory rate. MEASUREMENTS
      AND MAIN RESULTS: Elevated IAP significantly increased ICP (7.6 +/- 1.2 vs. 21.4
      +/- 1.0), pleural pressure and central venous pressure; whereas cardiac index and
      CPP (82.2 +/- 6.3 vs. 62.0 +/- 10.0) decreased significantly. Intravascular
      volume expansion further significantly increased ICP (27.8 +/- 1.0), and
      significantly increased both mean arterial pressure (83.4 +/- 14.0 versus 103.4
      +/- 8.9) and CPP (75.6 +/- 9.0). Abdominal decompression returned ICP (11.2 +/-
      1.8) toward baseline and further increased CPP (79.8 +/- 9.7). CONCLUSIONS:
      Elevated IAP increases ICP and decreases CPP and cardiac index. Volume expansion
      further increases ICP yet improves CPP via its greater positive effect upon mean
      arterial pressure (*p < 0.05, analysis of variance. All measurements are mean +/-
      SEM in mm Hg).

PMID- 8656481
TI  - The Injury Severity Score is unable to differentiate between poor care and severe
      injury.
AB  - The Injury Severity Score (ISS) has been the most frequently used tool for
      stratifying injured patients. The primary hypothesis of this study was that ISS
      fails to differentiate between severe injury and mismanagement. METHODS: Data
      models were generated for mismanaged and ideally managed patients for isolated
      injuries for each body system. Flow charts of care, outcomes, and Abbreviated
      Injury Scale (AIS) and ISS scores were generated for each model. RESULTS:
      Multiple models demonstrated that minor injuries that were mismanaged would
      result in AIS and ISS scores that were the same as ideally managed severe
      injuries. Three examples are summarized as follows: A comparison of two patients
      with splenic injuries demonstrates that ISS is unable to differentiate between
      mismanagement of a minor splenic laceration as compared to a severely lacerated
      spleen. In the case of the minor injury to the spleen (initial AIS = 2) that was
      missed by the treating physicians and allowed to bleed into shock and near arrest
      because of massive hemorrhage that could have been prevented by early recognition
      and treatment, the final AIS is coded as 4 in this mismanaged patient, the same
      AIS and ISS as a severely lacerated spleen (AIS = 4) managed well. Both result in
      a discharge ISS of 16. Similarly, the ISS at discharge is the same for a well
      managed severe head injury (AIS = 4) and a mismanaged minor head injury that is
      unrecognized, progresses and leads to coma (AIS = 4). Finally AIS, ISS does not
      differentiate between a well-managed cervical fracture with complete cord injury
      and a mismanaged cervical spine fracture that initially does not involve a cord
      injury, but because of mismanagement and lack of immobilization, progresses to
      complete cord injury because of poor care. Both result in the same injury
      severity assessment (AIS = 5, ISS = 25 in both). CONCLUSIONS: This study
      demonstrates a fact that should be recognized by all who rely upon the ISS for
      comparing quality of care: ISS fails to differentiate severe injury from
      mismanagement of injury. Because the ISS mixes outcome data with injury severity,
      ISS incorrectly assigns increased severity to the lesser injuries of mismanaged
      patients. These findings have important implications for use of the ISS in
      quality of care assessments.

PMID- 8656482
TI  - Abbreviated Injury Scale does not reflect the added morbidity of multiple lower
      extremity fractures.
AB  - OBJECTIVES: To determine if patients with multiple lower extremity fractures have
      worse outcomes than do patients with isolated femur fractures, and to determine
      if the Abbreviated Injury Scale (AIS) should distinguish between single and
      multiple lower extremity fractures. DESIGN: A retrospective study. MATERIALS AND
      METHODS: All blunt trauma patients at least 15 years of age treated at a level 1
      trauma center from January 1990 through December 1993. Three groups of patients
      were selected. Group 1 included 50 patients whose only significant injury was a
      diaphyseal femur fracture. They had no other long bone fractures, minimal
      injuries to other body areas, and an Injury Severity Score (ISS) < or = 14. Group
      2 was consisted of 29 patients with a femur fracture, at least one other
      diaphyseal lower extremity fracture, and also an ISS < or = 14. Group 3 consisted
      of 23 patients who had fracture patterns similar to those of group 2, but also
      had more severe nonextremity injuries (ISS > or = 15). Hospital morbidity and
      mortality rates were compared with t tests or chi-square analysis. Type 1 error
      probability was established at p < 0.05. MEASUREMENTS AND MAIN RESULTS: Compared
      with patients in group 1, patients in group 2 had an identical ISS (10.1 vs.
      10.6, respectively), but had higher transfusion requirements (0.3 vs. 3.9 units),
      more days in the intensive care unit (ICU) (0.02 vs. 1.4), a higher incidence of
      adult respiratory distress syndrome (ARDS) (0 vs. 14%), longer hospital stays
      (6.0 vs. 14.8 days), greater disability at discharge (disability score 2.2 vs.
      3.2), and a higher mortality rate (0 vs. 3.4%; p < 0.05 all variables). Patients
      in group 3 had worse outcomes than the other two groups: ISS = 30.1; transfusions
      = 11.9 units; ICU days = 9.1; ARDS incidence = 26%; hospital days = 29.9;
      disability score = 3.9; mortality = 26% (p < 0.05). CONCLUSIONS: Although AIS and
      ISS appropriately reflect the impact of extraskeletal injuries in patients with
      femur fractures, they do not adequately reflect the increased morbidity
      associated with multiple lower extremity fractures. The AIS-Extremity Score may
      need to be upgraded for multiple long bone fractures of the lower extremities.

PMID- 8656483
TI  - Improved accuracy of burn wound assessment using laser Doppler.
AB  - The utility of the laser Doppler for determining burn depth has been questioned
      because of problems with technology and methodology. This study prospectively
      evaluates the ability of a new laser Doppler technique to predict burn healing
      time. Using the Periflux System 4000 laser Doppler, readings were taken on 305
      burns (147 patients) on postburn day 3 or 4. Sixty-six wounds were used to derive
      a predictive function (phase I) and 152 wounds were used to test the function
      (phase II). Blood flow dynamics (flux), microvascular dilation capacity of the
      wounds to beat stress, and flow motion wave pattern (vasomotion) were studied
      using the laser Doppler, and seven parameters were evaluated to determine their
      relative contribution to the prediction of healing time. These parameters are
      hyperemic flux (flux value after heating to 42 degrees C), average hyperemic wave
      amplitude (AHWA), number of average flux units >100(F100), number readings with
      wave amplitude 75 (A5), average flux change (AFC), percentage of average flux
      increase, and relative flow capacity (RFC = AFC/average hyperemic flux). After
      readings were made, the wounds were observed and divided into two groups: those
      that healed in less than 14 days and those that healed or were grafted after 14
      days. A step-wise discriminant analysis was used to assess the relative
      contribution of the Doppler-derived measures to healing time prediction. AHWA,
      F100, and RFC were included in the final discriminant function explaining 72% of
      the healing time variance (Wilks' lambda value 0.28; p value <0.0001). Predicted
      outcome = 0.05(AHWA) + 0.31(F100) + 5.0(RFC) - 2.3. With this derived function,
      there is 94% accuracy in the prediction of burn wound healing time compared with
      a physician predictive accuracy of 70%.

PMID- 8656484
TI  - Rectal pH measurement in tracking cardiac performance in a hemorrhagic shock
      model.
AB  - OBJECTIVE AND DESIGN: We evaluated the utility of rectal mucosal pH measurement
      for tracking cardiac performance in hemorrhagic shock as compared with gastric
      tonometry. MATERIALS AND METHODS: Hemorrhagic shock was induced in five adult
      swine to a mean arterial pressure of 45-65 mm Hg. Hypotension was maintained for
      30 minutes, resuscitation was accomplished with the shed blood and lactated
      Ringer's solution (3x blood volume). Gastric tonometry, rectal pH, and oxygen
      transport data were obtained at baseline, 0, and 30 minutes after onset of
      hypotension and after resuscitation. RESULTS: Intramucosal pH readings from
      gastric tonometry and rectal mucosal pH both showed a significant change from
      baseline to 0 and 30 minutes after onset of hypotension. Data after resuscitation
      were found to be statistically the same as baseline values. CONCLUSIONS: Rectal
      mucosal pH tracks cardiac performance as well as does gastric tonometry in
      hemorrhagic shock without as many limitations.

PMID- 8656485
TI  - Carotid and vertebral artery occlusion after blunt cervical injury: the role of
      MR angiography in early diagnosis.
AB  - The early diagnosis of cervical vascular trauma is critical in the prevention of
      cerebral ischemia. Traumatic blunt carotid or vertebral artery dissection is rare
      and frequently associated with other injuries. Diagnosis is often delayed,
      limiting treatment options and contributing to a poor outcome. The clinical
      findings and investigation of 14 patients are presented with special reference to
      the last three who had magnetic resonance imaging angiography. Treatment options
      are discussed and it is suggested that with modern methods of investigation and
      management, the prognosis of this condition may be improved.

PMID- 8656486
TI  - Transverse abdominis musculo-peritoneal (TRAMP) flap for the repair of large
      duodenal defects.
AB  - Definitive surgical management of major acute injuries to the second and third
      portions of the duodenum has been enigmatic. Sometimes, the defect is so large
      that it is unwise to do primary repair, and resection at this critical portion of
      the intestinal tract is technically hazardous or impossible. A serosal or mucosal
      patch technique has been used to repair this kind of duodenal defect with
      encouraging results. Since the use of this technique has proved effective, such a
      defect was not necessarily treated with the more complicated
      pancreaticoduodenectomy and was managed with less morbidity and mortality. But
      these techniques are still controversial. So, we tried a pedicle flap, called the
      transverse abdominis musculo-peritoneal (TRAMP) flap, for repair of large
      duodenal defect. We have used this flap in 25 rabbits, and the specimens were
      followed up to a period of 3 months. The flap showed satisfactory results and is
      presented as another option for repair of large duodenal defects.

PMID- 8656487
TI  - Experimental flail chest: ventilatory function with fixation of flail segment in
      internal and external position.
AB  - The effect on ventilatory function of fixation of a flail segment in internal
      (FIP) and external (FEP) position and oxygen administration was studied in an
      experimental flail chest with pleural indemnity. Variations of tidal volume (TV),
      respiratory rate (RR), minute volume (MV), and arterial blood gases are reported.
      These parameters were measured in nine dogs in control and flail conditions (FC).
      The effect of FIP, FEP, and oxygen administration were studied. RESULTS:
      Significant differences were found: TV decreased from control values to FC and
      from FC to FIP, but increased from FC to FEP. RR values increased from control to
      FC and from FC to FIP, but decreased from FC to FEP. MV values decreased from FC
      to FEP. TV, RR, and MV were not changed under oxygen administration. Hypoxemia or
      hypercapnia were not observed. It was concluded that FIP is deleterious for
      respiratory mechanics, whereas FEP improves ventilatory parameters.

PMID- 8656488
TI  - Nailing versus plating in thoracic trauma: an experimental study in sheep.
AB  - In this study, femoral intramedullary pressure, fat embolization, and pulmonary
      response were measured during reamed and unreamed nailing and plating of femoral
      fractures after blunt thoracic trauma. Intramedullary peak pressures of 425 mm Hg
      (mean 205 mm Hg) occurred in the reamed nail group (group I) during reaming with
      the 9-mm reamer, while in the unreamed nail group (group II) peak values were
      seen during nail insertion (330 mm Hg) with a mean of 203 mm Hg. Plating never
      led to a pressure rise over 67 mm Hg (mean 37 mm Hg). In reamed nailing, the most
      intense embolism was identified under ultrasound imaging with the large awl and
      with the 9.0-mm reamer (mean 2.2) and in the unreamed nail group during nail
      insertion (mean 2.8). Minimal echoes appeared during plating. The pulmonary
      arterial pressure did not vary significantly postoperatively between the three
      groups (p < 0.08). Our findings indicate that intramedullary fracture fixation
      causes a higher increase of intramedullary pressure and more fat and bone marrow
      embolization than extramedullary ones. Nevertheless, only minimal differences in
      the pulmonary hemodynamic response (pulmonary arterial pressure) were noted even
      in the presence of thoracic trauma.

PMID- 8656489
TI  - Operative treatment for delayed union and nonunion of midshaft clavicular
      fractures: AO reconstruction plate fixation and early mobilization.
AB  - Fourteen patients were treated operatively for delayed union and nonunion of
      midshaft clavicular fractures from 1986 to 1994. Radiographically, nine nonunions
      were atrophic and five hypertrophic. The operative technique included opening the
      medullary canal, bone grafting, and fixation with an AO reconstruction plate.
      Postoperative mobilization started within one week. The mean follow-up was 60
      months (range, 16 to 101 months). Consolidation was observed radiologically after
      10 to 30 weeks. All patients were asymptomatic after 10 weeks and had a normal
      range of shoulder motion. One patient sustained a fractured clavicle following
      adequate trauma. Operative treatment for delayed union and nonunion of clavicular
      fractures with AO reconstruction plate fixation, bone grafting, and early
      postoperative mobilization yields excellent results.

PMID- 8656490
TI  - Unstable closed tibial shaft fractures: a prospective evaluation of surgical
      treatment.
AB  - OBJECTIVE: To define the roles of the rigid interlocking nail and the semirigid
      Ender nail in the treatment of closed unstable tibia] shaft fractures. DESIGN:
      Randomized, clinical, prospectively study with detailed comparison of parameters.
      MATERIALS AND METHODS: Data on 116 unstable closed tibial shaft fractures were
      collected. Randomly, 60 tibiae were fixed with interlocking nails and 56 tibiae
      were fixed with Ender nails. The follow-up period was 24 (16-32) months.
      MEASUREMENTS AND MAIN RESULTS: In the interlocking nail group, the average blood
      loss was 189 cc, operation time was 51 minutes, length of hospital stay was 7
      days, and union time was 14.2 weeks. In the Ender nail group, the average blood
      loss was 95 cc, operation time was 30 minutes, length of hospital stay was 5.0
      days, and union time was 16.9 weeks. Student's t test was used for statistical
      significance. CONCLUSIONS: For more comminuted unstable tibial shaft fractures,
      an interlocking nail is undoubtedly a better choice, but an Ender nail still is
      effective in some aspects of treatment in the less comminuted unstable tibial
      shaft fractures.

PMID- 8656491
TI  - Are type IIIC lower extremity injuries an indication for primary amputation.
AB  - There are few large series of the long-term results of severe devascularized,
      open fractures to the lower extremity. Therefore, we retrospectively reviewed our
      experience with 35 consecutively admitted patients who sustained Gustilo Type
      IIIC injuries and who presented to our Reimplantation Center between 1984 and
      1987. To our knowledge, this group of patients represents the largest series of
      this injury reported to date. The review included 21 patients who required
      primary amputation and 14 patients who underwent vascular, orthopedic, and
      delayed soft tissue reconstruction. This report details the treatment protocol
      used to result in our 93% success rate in the 14 patients with Type IIIC injuries
      who were successfully revascularized. Our initial management approach to the
      devascularized lower limb includes immediate revascularization with temporary
      shunts to minimize ischemia time, followed by revascularization with vein grafts
      beyond the zone of injury and external fixation. Subsequent management included
      liberal use of microsurgical free transplantation to overcome soft tissue
      defects; bone grafting as soon as infection and soft tissue coverage permitted
      and delayed wound closure. Our approach differs in that definitive wound closure
      is avoided for 4 to 6 weeks to allow resolution of myonecrosis secondary to
      initial ischemia and subsequent reperfusion injury. Contraindications to this
      aggressive revascularization approach are poor patient health before injury,
      completely severed limb, segmental tibial loss greater than 8 cm, ischemia time
      greater than 6 hours, and severance of the posterior tibial nerve.

PMID- 8656492
TI  - Skiing injuries in children and adolescents.
AB  - OBJECTIVE: A study of major skiing injuries in children and adolescents. DESIGN
      AND MATERIALS AND METHODS: A 5-year retrospective study of patients 18 years old
      and under admitted to a pediatric trauma center after skiing accidents. A follow
      up questionnaire was used to obtain additional information. MEASUREMENTS AND MAIN
      RESULTS: Thirty-eight patients, of which 34 were male. Age range was 5 to 18
      years. Fifty-eight percent of the accidents were collisions with stationary
      objects. Alcohol and drugs were not implicated. Helmet use was negligible. Head
      injuries, especially skull fractures, were very common (27), followed by
      extremity fractures (13), facial fractures (8), and abdominal (6), thoracic (5),
      and spinal injuries (2). One third had multiple injuries. The average cost was
      $22,000. There were no deaths, but 26% had long-term sequelae. The skill
      breakdown was 26% beginner, 29% intermediate, 45% advanced. Willingness to accept
      responsibility for the accident correlated inversely with skill level.
      CONCLUSIONS: Prevention efforts must target excessive speed and loss of control.
      Beginners must be well supervised on appropriate terrain. The frequency of skull
      fractures suggests that helmet use should be encouraged for young recreational
      skiers.

PMID- 8656493
TI  - Triiodothyronine and cardiac surgery.

PMID- 8656494
TI  - Frequency of prenatal care visits and perinatal outcome.

PMID- 8656495
TI  - Breast implants and connective-tissue disease.

PMID- 8656496
TI  - Breast implants and connective-tissue disease.

PMID- 8656497
TI  - Breast implants and connective-tissue disease.

PMID- 8656498
TI  - Breast implants and connective-tissue disease.

PMID- 8656499
TI  - A 61-year-old man with Parkinson's disease.

PMID- 8656500
TI  - A 61-year-old man with Parkinson's disease.

PMID- 8656501
TI  - Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter
      Hemophilia Cohort Study.
AB  - OBJECTIVE: To determine if the long-term incidence of the acquired
      immunodeficiency syndrome (AIDS) is related to human immunodeficiency virus type
      1 (HIV-1) RNA levels measured early in HIV-1 infection. DESIGN: Epidemiologic
      cohort study. SETTING: Five hemophilia treatment centers in the United States.
      SUBJECTS: A total of 165 subjects with hemophilia and HIV-1 infection (age at HIV
      1 seroconversion, 1-66 years) followed from 1979 to 1995. METHODS: The HIV-1 RNA
      level was measured by polymerase chain reaction over a range of 200 to 1 million
      or more HIV-1 RNA copies/mL in archived serum specimens collected 12 to 36 months
      (median, 27 months) after the estimated date of HIV-1 seroconversion. Kaplan
      Meier methods were used to examine the risk of AIDS and proportional hazards
      models were used to estimate relative hazards. RESULTS: The HIV-1 RNA values were
      similar in subjects younger than 17 years at seroconversion (median, 5214
      copies/mL) and those 18 to 34 years old (median, 4693 copies/mL), but higher in
      those 35 years or older (median, 12069 copies/mL) (P = .02 compared with each
      younger group). At 10 years after seroconversion, the proportions of subjects
      with AIDS were 72% among subjects with 100,000 or more HIV-1 RNA copies/mL
      measured 12 to 36 months after HIV-1 seroconversion (n = 9), 52% among subjects
      with 10,000 to 99,999 copies/mL (n = 55), 22% among subjects with 1000 to 9,999
      copies/mL (n = 82), and 0% among subjects with fewer than 1000 copies/mL (n = 19)
      (P < .001). The age-adjusted relative hazard for AIDS for subjects with 10,000 or
      more copies/mL was 14.3 (95% confidence interval, 1.9-105.6) compared with
      subjects with fewer than 1000 copies/mL. CONCLUSIONS: The HIV-1 RNA level during
      early chronic HIV-1 infection is a strong, age-independent predictor of clinical
      outcome; low levels define persons with a high probability of long-term AIDS-free
      survival.

PMID- 8656502
TI  - Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine
      experienced patients. A randomized controlled comparison with zidovudine
      monotherapy. Lamivudine European HIV Working Group.
AB  - OBJECTIVE: To compare the safety and efficacy of 2 doses of lamivudine given in
      combination with zidovudine with continued zidovudine monotherapy. DESIGN: Double
      blind, randomized, multicenter, comparative trial of 223 patients treated for 24
      weeks. SETTING: Patients from 32 hospitals in Europe were enrolled throughout a 1
      year period. PATIENTS: Adult human immunodeficiency virus type 1 (HIV-1)
      positive, zidovudine-experienced ( > or = 24 weeks prior zidovudine) patients
      with CD4+ cell counts between 0.10 and 0.40 x 10(9)/L (100-400 cells/microL).
      INTERVENTION: Patients received either 200 mg of zidovudine every 8 hours, 150 mg
      of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12
      hours plus zidovudine for 24 weeks. All patients were then allowed to receive
      zidovudine and open-label lamivudine combination therapy. Twelve patients
      withdrew because of adverse events during the 24-week treatment period. MAIN
      OUTCOME MEASURES: Efficacy was measured by evaluating immunological and viral
      load changes, and safety was assessed by evaluating clinical manifestations and
      laboratory indexes of toxic effects. RESULTS: Patients receiving low- or high
      dose combination therapy had greater treatment effects compared with patients
      receiving continued zidovudine monotherapy during the first 24 weeks as
      documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02 x 10(9)/L,
      respectively; P < .001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs
      -0.77 vs +0.07 copies/mL, respectively; P < .001) or log10 HIV-1 RNA measured by
      the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06
      vs -0.02 copies/mL, respectively; P < .011); and immune-complex dissociated (ICD)
      p24 antigen (-74% vs -68% vs +27%, respectively; P < .001). There were no
      statistically significant differences in viral measurements, in CD4+ cell counts,
      or in safety profile between the groups receiving 2 doses of lamivudine in
      combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen
      were sustained throughout 48 weeks for patients continuing combination therapy.
      Patients switching to combination therapy at week 24 showed improvement.
      CONCLUSION: In zidovudine-experienced HIV-1-infected patients, combination
      treatment with lamivudine and zidovudine is well tolerated and provides greater
      and more sustained increases in CD4+ cell counts and decreases in viral load than
      continued zidovudine monotherapy.

PMID- 8656503
TI  - Safety and efficacy of lamivudine-zidovudine combination therapy in
      antiretroviral-naive patients. A randomized controlled comparison with zidovudine
      monotherapy. Lamivudine European HIV Working Group.
AB  - OBJECTIVE: To compare safety and efficacy of lamivudine-zidovudine combination
      therapy with zidovudine monotherapy in treating human immunodeficiency virus type
      1 (HIV-1)-infected, antiretroviral therapy-naive patients. DESIGN: Double-blind,
      randomized, multicenter, comparative trial of 129 patients throughout 24 weeks
      followed by 24 weeks of open-label lamivudine in combination with zidovudine.
      SETTING: Outpatients from 14 hospitals in Belgium, France, Germany, Spain, and
      the United Kingdom were enrolled within 6 months. PATIENTS: HIV-1-positive,
      antiretroviral-naive ( < or = 4 weeks prior zidovudine use) patients aged atleast
      18 years with CD4+ cell counts between 0.10 x 10(9)/L and 0.40 x 10(9)/L (100
      400/microL). INTERVENTION: Patients received either 300 mg of lamivudine every 12
      hours in combination with 200 mg of zidovudine every 8 hours for 24 weeks or
      zidovudine monotherapy for 24 weeks. All patients were then allowed to receive
      zidovudine in combination with open-label lamivudine (300 mg every 12 hours).
      MAIN OUTCOME MEASURES: Efficacy was assessed by changes in CD4+ cell counts beta
      2-microglobulin, neopterin, HIV-1 immune-complex dissociated (ICD) p24
      antigenemia, and HIV-1 viral load. Safety was assessed by incidence of adverse
      clinical events and defined laboratory-measured toxic effects. RESULTS:
      Combination therapy showed superior treatment effects compared with monotherapy
      during the first 24 weeks as documented by changes in CD4+ cell counts (increase
      of 0.08 x 10(9)/L vs 0.02 x 10(9)/L; P < .001), ICDp24 (-88% vs -49%; P = .04),
      cellular viremia (-1.27 vs -0.20 log10 median tissue-culture infected dose
      [TCID50] per 10(6) peripheral blood mononuclear cells; P = .001), and viral load
      measured by HIV-1 RNA polymerase chain reaction using a Roche method (-1.33 vs 
      0.57 log10 copies/mL; P = .001) or an immune-capture method (-0.6 vs -0.14log10
      copies/mL; P = .008). Observed changes were sustained to 48 weeks for patients
      continuing to receive combination therapy. Patients switching to receive
      combination therapy at week 24 showed improvements in CD4+ cell count and viral
      load to week 48. Mutation results suggested that mutations associated with
      zidovudine resistance may have developed more slowly over the first 24 weeks in
      patients receiving combination therapy. In contrast, mutations associated with
      lamivudine resistance appeared to develop rapidly, despite sustained antiviral
      treatment effect. However, the number of patients evaluated for genotypic changes
      was small, and confirmation of these results is needed in larger studies. No
      statistically significant differences in incidence or severity of clinically
      manifested or laboratory-measured toxic effects were noted between treatment
      groups. CONCLUSIONS: The combination of lamivudine and zidovudine results in a
      potent and sustained antiviral effect in antiretroviral-naive patients that is
      superior to that observed with zidovudine monotherapy.

PMID- 8656504
TI  - Prevalence of HIV infection in the United States, 1984 to 1992.
AB  - OBJECTIVE: To estimate the number of persons infected with the human
      immunodeficiency virus (HIV) living in the United States and the change in HIV
      infection prevalence since 1984. DESIGN: We estimated HIV prevalence from 3 data
      sources. We estimated past HIV infection rates from a statistical procedure based
      on national acquired immunodeficiency syndrome (AIDS) case surveillance data and
      estimates of the time from HIV infection to AIDS diagnosis. We also analyzed HIV
      prevalence data from 2 national surveys, a survey of childbearing woman and a
      household survey of current health status. We used other data sources to adjust
      these survey estimates to include groups not covered in the surveys. RESULTS:
      Approximately 0.3% of US residents (650,000-900,000 persons) were infected with
      HIV in 1992. Approximately 0.6% of men (including adolescent boys > or = 13 years
      of age) were infected, including approximately 2% of non-Hispanic black men and
      1% of Hispanic men. Approximately 0.1% of women (including adolescent girls > or
      = 13 years of age) were infected, including approximately 0.6% of non-Hispanic
      black women. Approximately half of all infected persons were men who had sex with
      men, and one fourth were injecting drug users. The prevalence of HIV infection
      increased from 1984 to 1992, with a greater relative increase among women than
      men. CONCLUSIONS: The 3 different data sources and methods are consistent in
      estimating that 650,000 to 900,000 persons were infected with HIV in the United
      States in 1992. Among adolescents and adults of both sexes, the proportion
      infected was substantially higher among non-Hispanic blacks and Hispanics than
      among non-Hispanic whites. HIV-related illness will be a major clinical and
      public health problem in the United States for years to come.

PMID- 8656505
TI  - Economic impact of treatment of HIV-positive pregnant women and their newborns
      with zidovudine. Implications for HIV screening.
AB  - OBJECTIVES: To estimate the economic impact of (1) treating pregnant women who
      are human immunodeficiency virus (HIV)-positive with zidovudine and (2) voluntary
      screening programs for pregnant women for HIV infection and offering treatment
      with zidovudine to those found to be HIV-positive. MAIN OUTCOME MEASURES: Number
      of cases of pediatric HIV infection and costs of screening, zidovudine treatment,
      and pediatric HIV infection treatment. DESIGN: Health care costs associated with
      treatment of HIV-positive pregnant women and their newborns are estimated as the
      costs of zidovudine and its administration and the reduction in costs of treating
      pediatric HIV infection. The lifetime costs of pediatric HIV infection are
      derived from the published literature. Estimates of the reduction in maternal-to
      fetal transmission rates are taken from the AIDS [acquired immunodeficiency
      syndrome] Clinical Trials Group (ACTG) Protocol 076. Costs of a voluntary
      screening program include costs of screening tests and counseling. Sensitivity
      and threshold analyses are performed to determine the impact of changes in input
      parameter values including zidovudine treatment costs, efficacy of treatment,
      costs of pediatric HIV infection, prevalence of HIV infection in pregnant women,
      screening test sensitivity and specificity, and pregnancy termination rates on
      the results. RESULTS: Assuming transmission rates are reduced from 25.5% to 8.3%
      as found in the ACTG 076 trial, treatment costs of $104,502 for 100 HIV-positive
      pregnant women and their newborns are offset by the reduction of $1,701,333
      associated with fewer cases of pediatric HIV infection for a net savings of
      $1,596,831. The sensitivity and threshold analyses show that overall cost savings
      from treatment of HIV-positive pregnant women and their newborns are achieved for
      a wide range of possible maternal treatment costs, efficacy rates, and lifetime
      pediatric HIV treatment costs. In the base-case analysis for the voluntary
      screening program, overall cost savings are seen when HIV prevalence rate among
      pregnant women is greater than 4.6 per 1000. However, this threshold prevalence
      rate is sensitive to changes In parameter value-especially pediatric HIV
      treatment costs, counselling costs, efficacy of treatment, and years of
      additional HIV treatment for the pregnant women. CONCLUSIONS: Offering zidovudine
      treatment to pregnant women known to be HIV-positive will decrease the number of
      cases of pediatric HIV infection and reduce health care costs. Voluntary
      screening programs for pregnant women will further decrease the number of cases
      of pediatric HIV infection. The effect of a screening program on health care
      costs varies according to HIV prevalence and the costs associated with the
      screening program.

PMID- 8656506
TI  - Cost-effectiveness of short-course zidovudine to prevent perinatal HIV type 1
      infection in a sub-Saharan African Developing country setting.
AB  - OBJECTIVE: To evaluate the cost-effectiveness of a short-course zidovudine
      program to prevent perinatal transmission of human immunodeficiency virus (HIV)
      type 1 in sub-Saharan African country settings. DESIGN AND SETTING: Several
      clinical trials of short-course zidovudine during pregnancy for prevention of
      perinatal transmission of HIV are under way in developing countries in sub
      Saharan Africa. A decision model was used to examine the cost-effectiveness of
      zidovudine programs in a hypothetical 1-year birth cohort in a sub-Saharan
      African setting from the perspective of the health care system and of society. A
      completed short course of zidovudine was assumed to reduce perinatal HIV
      transmission from 25% to 16.5%, approximately one half of the effect of the
      longer-course zidovudine. Estimates of program costs, lifetime HIV-related health
      care costs, and lost productivity costs were derived from the published
      literature and from preliminary data available from sites of planned clinical
      trials. Sensitivity analyses were conducted on all relevant parameters. MAIN
      OUTCOME MEASURES: Medical costs, lost productivity costs, program costs, cost
      savings, and incremental cost-effectiveness, expressed as cost per infant HIV
      infection prevented. RESULTS: The model estimated that a national zidovudine
      program in a setting with 12.5% HIV seroprevalence would reduce perinatal HIV
      incidence by 12% (4.9 infections per 1000 births). The costs to the health care
      system would be $3748 per infant HIV infection prevented. When productivity
      losses were included in the model, the cost decreases to $1115 per infant HIV
      infection prevented. The cost to implement a national zidovudine program
      including the cost of counseling, testing, and drugs, would be $2 million per
      100,000 births or $20 per pregnant woman. In the base case, decreases in the cost
      of counseling and testing and increases in maternal HIV prevalence, zidovudine
      efficacy, and medical and lost productivity costs improved cost-effectiveness of
      the zidovudine program. CONCLUSIONS: Assuming demonstrable efficacy of short
      course zidovudine prevention of perinatal HIV, a national perinatal HIV
      prevention program with zidovudine in most sub-Saharan African country settings
      would reduce the incidence of infant HIV infection and, in some settings, provide
      societal savings; however, substantial initial investment in such programs will
      be required. Where health care resources are limited, as in these regions,
      allocation of resources to a perinatal zidovudine program will need to be
      considered in the context of resources required for other pressing medical care
      needs.

PMID- 8656508
TI  - AIDS in 1996. Much accomplished, much to do.

PMID- 8656509
TI  - Importance of surrogate markers in evaluation of antiviral therapy for HIV
      infection.

PMID- 8656507
TI  - Antiretroviral therapy for HIV infection in 1996. Recommendations of an
      international panel. International AIDS Society-USA.
AB  - OBJECTIVE: To provide clinical recommendations for antiretroviral therapy for
      human immunodeficiency virus (HIV) disease with currently (mid 1996) available
      drugs. When to start therapy, what to start with, when to change, and what to
      change to were addressed. PARTICIPANTS: A 13-member panel representing
      international expertise in antiretroviral research and HIV patient care was
      selected by the international AIDS Society-USA. EVIDENCE: Available clinical and
      basic science data, including phase 3 controlled trials, clinical endpoint data,
      virologic and immunologic endpoint data, interim analyses, studies of HIV
      pathophysiology, and expert opinions of panel members were considered.
      Recommendations were limited to drugs available in mid 1996. PROCESS: For each
      question posed, 1 or more member(s) reviewed and presented available data.
      Recommendations were determined by group consensus (January 1996); revisions as
      warranted by new data were incorporated by group consensus (February-May 1996).
      CONCLUSIONS: Recent data on HIV pathogenesis, methods to determine plasma HIV
      RNA, clinical trial data, and availability of new drugs point to the need for new
      approaches to treatment. Therapy is recommended based on CD4+ cell count, plasma
      HIV RNA level, or clinical status. Preferred initial drug regimens include
      nucleoside combinations; at present protease inhibitors are probably best
      reserved for patients at higher progression risk. For treatment failure or drug
      intolerance, subsequent regimen considerations include reasons for changing
      therapy, available drug options, disease stage, underlying conditions, and
      concomitant medication(s). Therapy for primary (acute) infection, high-risk
      exposures to HIV, and maternal-to-fetal transmission are also addressed.
      Therapeutic approaches need to be updated as new data continue to emerge.

PMID- 8656511
TI  - Issue dedicated to HIV/AIDS research.

PMID- 8656510
TI  - Surrogate markers in AIDS research. Is there truth in numbers?

PMID- 8656512
TI  - HIV guide for primary care physicians stresses patient-centered prevention.

PMID- 8656513
TI  - Penicillium marneffei part of Southeast Asian AIDS.

PMID- 8656515
TI  - Switch to inactivated polio vaccine recommended.

PMID- 8656514
TI  - Conference explores ethics of animal research with critical thinking and balanced
      argument.

PMID- 8656516
TI  - From the Centers for Disease Control and Prevention. Update: provisional public
      health service recommendations for chemoprophylaxis after occupational exposure
      to HIV.

PMID- 8656517
TI  - From the Centers for Disease Control and Prevention. Scopolamine poisoning among
      heroin users--New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996.

PMID- 8656518
TI  - The changing face of AIDS in Argentina.

PMID- 8656519
TI  - A piece of my mind. Shadow bands.

PMID- 8656520
TI  - Incidence of HIV infection in a New York City methadone maintenance treatment
      program.

PMID- 8656523
TI  - Military medicine responds to terrorism.

PMID- 8656522
TI  - A piece of my mind. A jack of all trades.

PMID- 8656524
TI  - Appeals board exonerates Baltimore, Imanishi-Kari.

PMID- 8656521
TI  - Transmission of HIV-1 subtype E in the united states.

PMID- 8656525
TI  - Physicians put promise of telemedicine to the test: reports from rural
      practitioners, anesthesiologists.

PMID- 8656526
TI  - Increasing use of computerized recordkeeping leads to legislative proposals for
      medical privacy.

PMID- 8656527
TI  - From the Centers for Disease Control and Prevention. Lyme disease--United States,
      1995.

PMID- 8656528
TI  - From the Centers for Disease Control and Prevention. Heat-Wave-related mortality-
      Milwaukee, Wisconsin, July 1995.

PMID- 8656529
TI  - Death certificate completion by physicians.

PMID- 8656531
TI  - Death certificate completion by physicians.

PMID- 8656530
TI  - Death certificate completion by physicians.

PMID- 8656532
TI  - Hepatitis C: watch for the many or treat for the few?

PMID- 8656533
TI  - Employment status of physicians completing training.

PMID- 8656534
TI  - Employment status of physicians completing training.

PMID- 8656535
TI  - Adolescent pregnancy.

PMID- 8656536
TI  - Adolescent pregnancy.

PMID- 8656537
TI  - Adolescent pregnancy.

PMID- 8656538
TI  - HIV counseling and testing of pregnant women.

PMID- 8656539
TI  - Nosocomial pneumonia and mortality.

PMID- 8656540
TI  - Screening for mild thyroid failure at the periodic health examination: a decision
      and cost-effectiveness analysis.
AB  - OBJECTIVE: To estimate the cost-effectiveness of periodic screening for mild
      thyroid failure by measurement of serum thyroid stimulating hormone (TSH)
      concentration. DESIGN: Cost-utility analysis using a state-transition computer
      decision model that accounted for case finding, medical consequences of mild
      thyroid failure, and costs of care during 40 years of simulated follow-up.
      SETTING: Periodic health examinations in offices of primary care physicians.
      PATIENTS: Hypothetical cohorts of women and men screened every 5 years during the
      recommended periodic examination, beginning at age 35 years. INTERVENTIONS:
      Adding the serum TSH assay to total serum cholesterol screening was compared to
      cholesterol screening alone. MAIN OUTCOME MEASURES: Discounted quality-adjusted
      life years (QALYs) and direct medical costs from a societal perspective. RESULTS:
      The cost-effectiveness of screening 35-year-old patients with a serum TSH assay
      every 5 years was $9223 per QALY for women and $22595 per QALY for men. The cost
      effectiveness became more favorable when age at first screening was increased for
      both sexes and was always more favorable for women than men. Reduced progression
      to overt hypothyroidism and relief of symptoms increased QALYs, but did not
      substantially reduce direct medical costs. Finding hypercholesterolemia induced
      by mild thyroid failure reduced direct medical costs, but did not substantially
      increase QALYs. The cost of a TSH assay and the importance to patients of
      symptoms associated with thyroid failure were the most influential factors in
      sensitivity analyses. CONCLUSIONS: The cost-effectiveness of screening for mild
      thyroid failure compares favorably with other generally accepted preventive
      medical practices. Physicians should consider measuring serum TSH concentration
      in patients aged 35 years and older undergoing routine periodic health
      examinations. The cost-effectiveness of screening is most favorable in elderly
      women.

PMID- 8656541
TI  - Cross-national epidemiology of major depression and bipolar disorder.
AB  - OBJECTIVE: To estimate the rates and patterns of major depression and bipolar
      disorder based on cross-national epidemiologic surveys. DESIGN AND SETTING:
      Population-based epidemiologic studies using similar methods from 10 countries:
      the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon,
      Taiwan, Korea, and New Zealand. PARTICIPANTS: Approximately 38000 community
      subjects. OUTCOME MEASURES: Rates, demographics, and age at onset of major
      depression and bipolar disorder. Symptom profiles, comorbidity, and marital
      status with major depression. RESULTS: The lifetime rates for major depression
      vary widely across countries, ranging from 1.5 cases per 100 adults in the sample
      in Taiwan to 19.0 cases per 100 adults in Beirut. The annual rates ranged from
      0.8 cases per 100 adults in Taiwan to 5.8 cases per 100 adults in New Zealand.
      The mean age at onset shows less variation (range, 24.8-34.8 years). In every
      country, the rates of major depression were higher for women than men. By
      contrast, the lifetime rates of bipolar disorder are more consistent across
      countries (0.3/100 in Taiwan to 1.5/100 in New Zealand); the sex ratios are
      nearly equal; and the age at first onset is earlier (average, 6 years) than the
      onset of major depression. Insomnia and loss of energy occurred in most persons
      with major depression at each site. Persons with major depression were also at
      increased risk for comorbidity with substance abuse and anxiety disorders at all
      sites. Persons who were separated or divorced had significantly higher rates of
      major depression than married persons in most of the countries, and the risk was
      somewhat greater for divorced or separated men than women in most countries.
      CONCLUSIONS: There are striking similarities across countries in patterns of
      major depression and of bipolar disorder. The differences in rates for major
      depression across countries suggest that cultural differences or different risk
      factors affect the expression of the disorder.

PMID- 8656542
TI  - Atrial fibrillation following coronary artery bypass graft surgery: predictors,
      outcomes, and resource utilization. MultiCenter Study of Perioperative Ischemia
      Research Group.
AB  - OBJECTIVE: To determine the incidence, predictors, and cost of atrial
      fibrillation and flutter (AFIB) following coronary artery bypass graft (CABG)
      surgery. DESIGN: Prospective observational study (MultiCenter Study of
      Perioperative Ischemia). SETTING: Twenty-four university-affiliated hospitals in
      the United States from 1991 to 1993. SUBJECTS: A total of 2417 patients
      undergoing CABG with or without concurrent valvular surgery selected using a
      systematic sampling interval. MEASUREMENTS: Detailed preoperative,
      intraoperative, and postoperative data collected on standardized reporting forms.
      RESULTS: The overall incidence of postoperative AFIB was 27 percent. Independent
      predictors of postoperative AFIB included advanced age (odds ratio [OR], 1.24 per
      5-year increase; 95 percent confidence interval [CI], 1.18-1.31); male sex (OR,
      1.41; 95 percent CI, 1.09-1.81); a history of AFIB (OR, 2.28; 95 percent CI, 1.74
      3.00); a history of congestive heart failure (OR, 1.31; 95 percent CI, 1.04
      1.64); and a precardiopulmonary bypass heart rate of more than 100 beats per
      minute (OR, 1.59; 95 percent CI, 1.00-2.55). Surgical practices such as pulmonary
      vein venting (OR, 1.44; 95 percent CI, 1.13-1.83); bicaval venous cannulation
      (OR, 1.40; 95 percent CI, 1.04-1.89); postoperative atrial pacing (OR, 1.27; 95
      percent CI, 1.00-1.62); and longer cross-clamp times (OR, 1.06 per 15 minutes; 95
      percent CI, 1.00-1.11) also were identified as independent predictors of
      postoperative AFIB. Patients with postoperative AFIB remained an average of 13
      hours longer in the intensive care unit and 2.0 days longer in the ward when
      compared with patients without AFIB. CONCLUSION: Postoperative AFIB is common
      after CABG surgery and has a significant effect on both intensive care unit and
      overall hospital length of stay. In addition to expected demographic factors,
      certain surgical practices increase the risk of postoperative AFIB. Randomized
      controlled trials are necessary to determine if modification of these surgical
      practices, especially in patients at high risk, would decrease the incidence of
      postoperative AFIB.

PMID- 8656543
TI  - Reported cholera in the United States, 1992-1994: a reflection of global changes
      in cholera epidemiology.
AB  - OBJECTIVE: To describe US cholera surveillance data from 1992 to 1994 and the
      domestic impact of the epidemics of Vibrio cholerae O1 in Latin America and V
      cholerae O139 in Asia. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of
      surveillance data from all cases of cholera reported to the Centers for Disease
      Control and Prevention (CDC) from January 1, 1992, through December 31, 1994, in
      the United States and its territories. MAIN OUTCOME MEASURES: Clinical,
      epidemiologic, and laboratory surveillance data. RESULTS: From 1992 through 1994,
      160 cases of cholera were reported to CDC by 20 states and 1 territory. This is a
      marked increase: only 136 cases were reported from 1965 through 1991. Outbreaks
      affecting 75 passengers on an airplane from Latin America and 5 passengers on a
      cruise ship in Southeast Asia accounted for 50 percent of cases. Vibrio cholerae
      O139 caused 6 cases (4 percent). The proportion of V cholerae O1 isolates
      resistant to at least 1 antimicrobial agent rose from 3 percent in 1992 to 93
      percent in 1994. Of 158 patients whose location of exposure was known, 151 (96
      percent) acquired infection abroad (125 in Latin America, 26 in Asia). Of 105
      persons whose reason for travel was known, 31 (30 percent) were US residents who
      had returned to their country of origin to visit family or friends, and 65 (62
      percent) were non-US residents visiting the United States from cholera-affected
      countries. The cholera rate among persons arriving in the United States from
      cholera-affected regions was 0.27 case per 100000 air travelers, not
      substantially increased from earlier estimates. CONCLUSIONS: Cholera has
      increased in the United States since 1991, reflecting global changes in cholera
      epidemiology, and is now primarily travel associated and antimicrobial resistant.
      Most travelers were not traditional tourists; reaching them with prevention
      measures may be difficult. The risk of cholera to the individual traveler remains
      extremely low.

PMID- 8656544
TI  - Integration of behavioral and relaxation approaches into the treatment of chronic
      pain and insomnia. NIH Technology Assessment Panel on Integration of Behavioral
      and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia.
AB  - OBJECTIVE: To provide physicians with a responsible assessment of the integration
      of behavioral and relaxation approaches into the treatment of chronic pain and
      insomnia. PARTICIPANTS: A nonfederal, nonadvocate, 12-member panel representing
      the fields of family medicine, social medicine, psychiatry, psychology, public
      health, nursing, and epidemiology. In addition, 23 experts in behavioral
      medicine, pain medicine, sleep medicine, psychiatry, nursing, psychology,
      neurology, and behavioral and neurosciences presented data to the panel and a
      conference audience of 528 during a 1 1/2-day public session. Questions and
      statements from conference attendees were considered during the open session.
      Closed deliberations by the panel occurred during the remainder of the second day
      and the morning of the third day. EVIDENCE: The literature was searched through
      MEDLINE, and an extensive bibliography of references was provided to the panel
      and the conference audience. Experts prepared abstracts with relevant citations
      from the literature. Scientific evidence was given precedence over clinical
      anecdotal experience. ASSESSMENT PROCESS: The panel, answering predefined
      questions, developed their conclusions based on the scientific evidence presented
      in open forum and the scientific literature. The panel composed a draft statement
      that was read in its entirety and circulated to the experts and the audience for
      comment. Thereafter, the panel resolved conflicting recommendations and released
      a revised statement at the end of the conference. The panel finalized the
      revisions within a few weeks after the conference. CONCLUSIONS: A number of well
      defined behavioral and relaxation interventions now exist and are effective in
      the treatment of chronic pain and insomnia. The panel found strong evidence for
      the use of relaxation techniques in reducing chronic pain in a variety of medical
      conditions as well as strong evidence for the use of hypnosis in alleviating pain
      associated with cancer. The evidence was moderate for the effectiveness of
      cognitive-behavioral techniques and biofeedback in relieving chronic pain.
      Regarding insomnia, behavioral techniques, particularly relaxation and
      biofeedback, produce improvements in some aspects of sleep, but it is
      questionable whether the magnitude of the improvement in sleep onset and total
      sleep time are clinically significant.

PMID- 8656545
TI  - Intranasal lidocaine for treatment of migraine: a randomized, double-blind,
      controlled trial.
AB  - OBJECTIVE: To evaluate the effectiveness of intranasal lidocaine for treatment of
      acute migraine headache. DESIGN: Prospective, randomized, double-blind, placebo
      controlled trial. SETTING: Community urgent care department. PATIENTS: A total of
      81 patients (67 women and 14 men; median age, 42 years; range, 19-68 years) with
      a chief complaint of headache who fulfilled criteria of the International
      Headache Society for migraine participated. Patients were excluded if headache
      had lasted more than 3 days or if the frequency of severe headache was more than
      once per week. INTERVENTION: Patients were randomized in a 2:1 ratio to receive a
      4 percent solution of intranasal lidocaine or saline placebo, respectively. MAIN
      OUTCOME MEASURES: The primary outcome measure was at least 50 percent reduction
      of headache within 15 minutes after treatment. Secondary measures include
      reduction in nausea and photophobia, use of rescue medication, relapse of
      headache, and change in headache disability scores. RESULTS: Of 53 patients who
      received intranasal lidocaine, 29 (55 percent) had at least a 50 percent
      reduction of headache compared with 6 (21 percent) of 28 controls (P=.004).
      Nausea and photophobia were significantly reduced (P=.03 and P=.001,
      respectively). Rescue medication for headache relief was needed in 15 (28
      percent) of 53 patients in the lidocaine group vs 20 (71 percent) of 28 controls
      (P<.001). Among those with initial relief of headache, relapse of headache
      occurred in 10 (42 percent) of 24 in the lidocaine group vs 5 (83 percent) of 6
      in the control group (P=.17), usually within the first hour after treatment.
      CONCLUSIONS: Intranasal lidocaine provides rapid relief of headache in
      approximately 55 percent of ambulatory patients with migraine. Relapse of
      headache is common and occurs early after treatment.

PMID- 8656547
TI  - Evidence-based medicine meets cost-effectiveness analysis.

PMID- 8656546
TI  - Effects of organizational change in the medical intensive care unit of a teaching
      hospital: a comparison of 'open' and 'closed' formats.
AB  - OBJECTIVE: To compare the effects of change from an open to a closed intensive
      care unit (ICU) format on clinical outcomes, resource utilization, teaching, and
      perceptions regarding quality of care. DESIGN: Prospective cohort study;
      prospective economic evaluation. SETTING: Medical ICU at a university-based
      tertiary care center. For the open ICU, primary admitting physicians direct care
      of patients with input from critical care specialists via consultation. For the
      closed ICU, critical care specialists direct patient care. PATIENTS: Consecutive
      samples of 124 patients admitted under an open ICU format and 121 patients
      admitted after changing to a closed ICU format. Readmissions were excluded. MAIN
      OUTCOME MEASURES: Comparison of hospital mortality with mortality predicted by
      the Acute Physiology and Chronic Health Evaluation II (APACHE II) system;
      duration of mechanical ventilation; length of stay; patient charges for
      radiology, laboratory, and pharmacy departments; vascular catheter use; number of
      interruptions of formal teaching rounds; and perceptions of patients, families,
      physicians, and nurses regarding quality of care and ICU function. RESULTS: Mean
      +/- SD APACHE II scores were 15.4 +/- 8.3 in the open ICU and 20.6 +/- 8.6 in the
      closed ICU (P=.001). In the closed ICU, the ratio of actual mortality (31.4
      percent) to predicted mortality (40.1 percent) was 0.78. In the open ICU, the
      ratio of actual mortality (22.6 percent) to predicted mortality (25.2 percent)
      was 0.90. Mean length of stay for survivors in the open ICU was 3.9 days, and
      mean length of stay for survivors in the closed ICU was 3.7 days (P=.79). There
      were no significant differences between periods in patient charges for radiology,
      laboratory, or pharmacy resources. Nurses were more likely to say that they were
      very confident in the clinical judgment of the physician primarily responsible
      for patient care in the closed ICU compared with the open ICU (41 percent vs 7
      percent; P<.Ol), and nurses were the group most supportive of changing to a
      closed ICU format before and after the study. CONCLUSIONS: Based on comparison of
      actual to predicted mortality, changing from an open to a closed ICU format
      improved clinical outcome. Although patients in the closed ICU had greater
      severity of illness, resource utilization did not increase.

PMID- 8656548
TI  - Trends in the supply of medical personnel in the Russian Federation.

PMID- 8656550
TI  - Does the cell wall skeleton from Bacille Calmette-Guerin directly induce
      interferon-gamma, independent of interleukin-12?
AB  - Interleukin-12 (IL-12), known to be a strong inducer of interferon-gamma (IFN
      gamma), plays a vital role in activating the immune surveillance system against
      intracellular pathogens and malignant tumors. The authors have found that cancer
      patients showing marked IFN-gamma induction after inoculation with BCG-CWS (the
      cell wall skeleton from Bacille Calmette-Guerin) have a good prognosis. The
      present study was undertaken to determine whether the level of IL-12 is increased
      prior to, or along with, IFN-gamma induction in the serum of patients inoculated
      with BCG-CWS. Unexpectedly, we found no detectable amount of IL-12 in the serum
      throughout the entire time course. This suggests that a novel IFN-gamma inducing
      factor (IGIF) or another unknown IFN-gamma inducer may be working in place of IL
      12 in the BCG-CWS system.

PMID- 8656549
TI  - Expression of type IV collagen-degrading metalloproteinases and tissue inhibitors
      of metalloproteinases in newly established human oral malignant tumor lines.
AB  - We have established 11 human oral tumor lines maintained as in subcutaneous
      xenografts in BALB/c athymic nude mice, and examined their metastatic and
      invasive characteristics, and expression of type IV collagen-degrading
      metalloproteinases and their intrinsic inhibitors (TIMPs). These tumor lines have
      approximately maintained the histological appearance of the parental tumors.
      Generally, human tumors maintained subcutaneously in nude mice metastasize only
      very rarely. However, one mesenchymal tumor line, a malignant melanoma designated
      MTN, was found to metastasize spontaneously to the lung and a lysate of the MTN
      cells had a high level of type IV collagenolytic activity. Among epithelial tumor
      lines, SKH, derived from squamous cell carcinoma, showed high expression of TIMP
      1 in Northern blotting and had low type IV collagenolytic activity. SN, derived
      from squamous cell carcinoma, also showed low type IV collagenolytic activity.
      These two squamous cell carcinoma lines showed a non-invasive growth pattern when
      they were implanted orthotopically into the tongues of athymic nude mice. By
      contrast, tumor lines which showed higher type IV collagenolytic activity had a
      tendency to grow invasively in mouse tongue. These findings suggest that our 11
      newly established tumor lines may provide useful systems for studies of tumor
      biology and therapy.

PMID- 8656552
TI  - Treatment of multiple early gastric cancer.
AB  - To investigate the treatment of multiple early gastric cancer, 82 cases were
      compared with 829 single early gastric cancers. Univariate analyses with respect
      to eight clinicopathological factors--age, sex, family history of gastric cancer,
      macroscopic appearance, histologic type, depth of tumor invasion, tumor location,
      and lymph node metastasis--were performed. Age, male sex, elevated and
      differentiated-type tumors, frequent occurrence in the lower third, and mucosal
      cancers were correlated significantly with multiple early gastric cancer.
      However, there was no significant difference in the frequency of node
      involvement. Multiple early gastric cancer, limited to the mucosal layer, was not
      associated with node involvement. Therefore, endoscopic mucosal resection may be
      feasible for the treatment of multiple early gastric cancer when there is no
      evidence of submucosal invasion in any of the lesions and none exceed 2.0 cm in
      diameter. Upon examination of the long-term results for patients with multiple
      early gastric cancer, two (3.0%, 2/66) had died of recurrence due to hematogenous
      spread, and one (1.9%, 1/52) had developed cancer of the remnant stomach. Other
      primary malignancies were observed in 12 patients (18.2%, 12/66). In particular,
      lung cancer was the major neoplasm occurring after gastrectomy. These results
      suggest the importance of systemic surveillance for the detection of other
      malignancies as well as cancer of the remnant stomach and recurrence after
      gastrectomy for multiple early gastric cancer.

PMID- 8656551
TI  - Retrospective analysis of the treatment of patients with small cell lung cancer
      showing poor performance status.
AB  - To assess the feasibility of treatments for patients with small cell lung cancer
      (SCLC) showing a poor performance status (PS, Eastern Cooperative Oncology Group;
      ECOG 3 or 4), we retrospectively reviewed the outcome for 13 SCLC patients
      showing poor PS treated at the National Cancer Center Hospital between January
      1984 and May 1994. The main factors which contributed to poor prognosis were
      superior vena cava (SVC) syndrome, massive pleural effusion, tracheal stenosis
      due to lymph node swelling, pericardial effusion and pulmonary fibrosis (causing
      dyspnea in combination), brain metastasis resulting in neurological disturbance,
      cachexia, Eaton-Lambert syndrome causing muscle weakness, retroperitoneal lymph
      node metastasis causing abdominal pain, peritoneal effusion due to abdominal
      lymph node swelling, vertebral metastasis causing paraplegia, and
      dermatomyositis/polymyositis (DM/PM) causing muscle weakness. All of the patients
      received chemotherapy with or without radiotherapy. The PS of 8 patients improved
      with treatment, but no improvement was seen in 5. We analyzed these 13 patients
      and considered the treatments for those with poor PS. Chemo-radiotherapy was
      tolerable in SCLC patients showing PS 3, and improved their PS if severe
      conditions or combined disease did not arise concurrently. It was further
      suggested that PS 4 patients with severe conditions or combined disease should
      not be given the treatments.

PMID- 8656553
TI  - Gastric carcinoma in young adults.
AB  - Among 4608 patients with gastric carcinoma treated during a 20-year period from
      1971 to 1990, 328 (7.1%) were less than 40 years of age. The clinicopathologic
      features and treatment results in this young group were compared with those for
      older gastric carcinoma patients (40-79 years of age, control group). In the
      young group, the male/female ratio and the prevalence of tumors in the lower
      third of the stomach were both lower than in the control group, and
      undifferentiated-type adenocarcinomas with diffusely infiltrative growth
      predominated. The TNM stage distribution and the proportion of curative
      resections were similar in the two groups. The overall cumulative 5-year survival
      rates were also similar, although that of patients who underwent curative
      resection was higher in the young group, due probably to the low rate of death
      from other causes. There was no difference in the recurrence rates after curative
      resection between the two groups. Contrary to widely held belief, the prognosis
      of young patients with gastric carcinoma is not poorer than that of older
      patients if the disease is diagnosed at a reasonably early stage.

PMID- 8656554
TI  - Clinical and pathological features of cutaneous malignant melanoma: a
      retrospective analysis of 124 Japanese patients.
AB  - A review of mainly histopathologic factors associated with the survival of
      patients with malignant melanoma was carried out in a retrospective study of 124
      Japanese patients treated at the National Cancer Center Hospital between July
      1962 and December 1992. There were 60 females and 64 males, and the median follow
      up period was 52.7 months (range, 1.1 to 235.3 months). The histologic features
      included tumor thickness, level of invasion, histologic subtype, ulceration,
      pigmentation, and cell type. Melanomas thicker than 1.5 mm (P<0.01) and with
      ulceration (P<0.001) had a significantly worse prognosis. With regard to
      histologic type, ten-year survival was 65.1% for acral lentiginous melanoma,
      50.7% for nodular melanoma, and 47.0% for superficial spreading melanoma (SSM),
      there being no significant differences among them. We suggest that the prognosis
      was affected not by histologic type but by the large radial or vertical growth
      component. With regard to clinical features, the clinicopathological stage,
      patient age, and year when the disease was diagnosed were reflected in the
      prognosis (P<0.001). Multifactorial analysis showed that the most significant
      prognostic variables were histopathologic type (SSM or other), stage (I and II or
      III and IV), and patient age (<70 or > or = 70 yr).

PMID- 8656555
TI  - Comparison of the clinicopathological characteristics of premenopausal and
      postmenopausal endometrial carcinomas: analysis of endocrinologically evaluated
      cases.
AB  - A study was performed to clarify the clinicopathological differences between
      premenopausal endometrial carcinoma, which occurs during the reproductive period,
      and postmenopausal endometrial carcinoma. We analyzed 76 patients with
      endometrial carcinoma treated in our department between January 1984 and July
      1994. Using classification criteria which included menstrual history and results
      of endocrinological tests (serum FSH, LH and estradiol), 50 (65.7%) patients were
      defined as postmenopausal, 16 (21.0%) as premenopausal, and 10 (13.1%) as
      unclassified. From an epidemiologic viewpoint, the incidence of nulliparity was
      higher in the premenopausal (37.5%) than in the postmenopausal (10%) patients.
      However, no significant differences were observed between the two groups with
      regard to the incidence of obesity, diabetes and hypertension. The results of our
      clinicopathological study revealed that premenopausal endometrial carcinoma had a
      significantly higher incidence of well differentiated (63.1%) and relatively less
      advanced (31.1% of cases at stages III and IV) cancers than postmenopausal
      carcinoma (38% and 46%, respectively). These features were positively correlated
      with prognosis, i.e., premenopausal patients in general had a much better
      prognosis than postmenopausal patients.

PMID- 8656556
TI  - Clinical usefulness of serum carboxyterminal propeptide of type I procollagen and
      pyridinoline cross-linked carboxyterminal telopeptide of type I collagen in
      patients with prostate cancer.
AB  - A study was undertaken to evaluate the clinical usefulness of measurements of
      serum concentrations of the carboxyterminal propeptide of type I procollagen
      (PICP) and the pyridinoline cross-linked carboxyterminal telopeptide of type I
      collagen (ICTP) as parameters of bone metastasis in patients with prostate
      cancer. Serum PICP, ICTP, prostate-specific antigen (PSA), and alkaline
      phosphatase (ALP) were evaluated in 82 patients with prostate cancer and 26
      patients with benign prostatic hyperplasia (BPH). These markers were measured
      serially in 16 prostate cancer patients during treatment. The serum levels of
      PICP, ICTP, ALP, and PSA were significantly higher in prostate cancer patients
      with bone metastasis than in patients with either BPH or prostate cancer without
      bone metastasis. Although the rate of detection of bone metastasis with PICP and
      ICTP was slightly lower than that with PSA determined by the receiver operating
      characteristic curve, the correlation between both PICP and ICTP and the extent
      of disease was much higher than that of PSA. PICP and ICTP levels varied with ALP
      and PSA levels, the patient's clinical course after the start of endocrine
      therapy and the progression of bone metastasis. The levels of PICP and ICTP did
      not change substantially in patients who developed local regrowth or lymph node
      metastasis, and decreased as bone metastases responded to radiotherapy. PICP and
      ICTP thus reflect the metastatic burden in bone and are useful for monitoring the
      response of bone metastasis to therapy.

PMID- 8656557
TI  - A randomized cross-over trial of granisetron and dexamethasone versus granisetron
      alone: the role of dexamethasone on day 1 in the control of cisplatin-induced
      delayed emesis.
AB  - We studied the role of dexamethasone (DEX) administered on day 1 in controlling
      cisplatin-induced delayed emesis. Forty patients were randomly allocated to
      receive either granisetron (GRN) and DEX on day 1, or the same dose of GRN alone.
      On days 2-5, all the patients received metoclopramide and DEX. They were crossed
      over to the other antiemetic regimen with their second course of chemotherapy.
      Thirty-one patients were evaluable for efficacy. The mean visual analogue scale
      scores for nausea on days 1 and 2 were 9.1 and 18.8 mm for GRN and DEX, and 16.3
      and 28.5 mm for GRN alone, respectively (P<0.05 on day 2). The mean numbers of
      emetic episodes on days 1-3 were 0.036, 0.46 and 0.36 for GRN and DEX, and 0.39,
      0.89 and 0.57 for GRN alone, respectively (P<0.01 on day 1). Hiccups and
      restlessness were noted in 38% and 33% of cycles, respectively. Addition of DEX
      to GRN on day 1 thus enhanced the control of delayed emesis.

PMID- 8656558
TI  - A working hospice in Tennessee. Interview by Kaoru Kubota, letter.

PMID- 8656559
TI  - Results of radiation therapy for hypopharyngeal carcinoma: impact of accelerated
      hyperfractionation on prognosis.
AB  - We reviewed the results of treatment in 52 patients with hypopharyngeal carcinoma
      who underwent radical radiation therapy using a two-fractionation scheme-
      conventional fractionation (CF) and accelerated hyperfractionation (AHF)--in
      order to evaluate the impact of the fractionation scheme on prognosis. The 5-year
      survival rate for the 52 patients was 19.5%, and a significantly better rate was
      obtained with AHF (44.4%) than with CF (12.4%). Of 27 patients who showed a
      complete response (CR), a higher CR rate (61%) was achieved with AHF than with CF
      (47%). A similar trend was also observed for T3 and T4 tumors (55% with AHF vs.
      36% with CF). Multivariate analysis demonstrated that neck node status was a
      significant factor related to local control, and that local response and the
      fractionation scheme employed were significant prognostic factors for survival.
      The recurrence rate and recurrence within the radiation field in the AHF group
      was lower than in the CF group (27% vs. 50%), although the time to recurrence in
      the two groups did not differ greatly. Voice preservation was achieved in 20% of
      the patients. Considering the better survival and local control rate compared
      with conventional fractionation, accelerated hyperfractionation seems a
      preferable treatment for hypopharyngeal carcinoma.

PMID- 8656560
TI  - Malignant soft tissue sarcoma of the hypopharynx successfully treated by
      radiotherapy alone.
AB  - Sarcoma of the hypopharynx has been reported very rarely in the literature, only
      six cases having been found among all head and neck malignancies reported to SEER
      (Surveillance, Epidemiology, and End Results) during 1973-1987. We report a 14
      year-old boy with a huge malignant soft tissue sarcoma arising from the
      hypopharynx. Tracheostomy and feeding gastrostomy were performed as emergency
      life-saving procedures. Surgical resection had been attempted, but abandoned.
      Because of the rapidity of tumor growth, we gave the patient a course of
      accelerated radiotherapy (170 cGy/fraction, two fractions per day) with a total
      dose of 7140 cGy within one month. A series of endoscopy and imaging studies
      demonstrated complete regression of the tumor, and the patient is currently alive
      without evidence of disease 3.5 years after treatment. We conclude that for an
      unresectable tumor without distant metastasis, radiation therapy may be tried.
      The time, dose, and fractionation of radiotherapy should be carefully designed
      and individualized.

PMID- 8656561
TI  - Six-year follow-up of primary small cell carcinoma of the esophagus showing a
      complete response: a case report.
AB  - Six-year follow-up of a case of small cell carcinoma of the esophagus showing a
      complete response is reported. The small cell pattern appeared intermingled with
      areas of invasive squamous cell carcinoma and carcinoma in situ. A neoadjuvant
      polychemotherapy regimen was used, followed by radiation therapy and adjuvant
      chemotherapy. This therapeutic combination resulted in complete response of the
      disease, as confirmed by computed tomography, endoscopy and biopsy. The patient
      is currently still alive, 6 years after the diagnosis, without any sign of
      relapse. A review of the literature reveals that this patient has survived longer
      than any others with this disease after treatment by chemoradiotherapy. The
      authors suggest that this therapy should be considered for patients with limited
      small cell carcinoma of the esophagus.

PMID- 8656562
TI  - Ancient schwannoma of the oral floor and ventricular portion of the tongue: a
      case report and review of the literature.
AB  - We report a case of ancient schwannoma, which is a rare benign neoplasm of the
      oral floor and ventricular portion of the tongue. Only two cases have previously
      been reported in the English literature. The present tumor, measuring 5.5 x 3.0 x
      3.0 cm, was the largest of the three. To differentiate ancient schwannoma from
      schwannoma with malignant transformation, it is important to confirm the absence
      of abrupt transition between areas of apparently typical schwannoma and areas
      composed of atypical large cells with pleomorphic and hyperchromatic nuclei, as
      well as the absence of mitoses, necrosis, and invasiveness. In the present case,
      calcification was not detected, nor was hyalinization extensive, although many of
      the neoplastic Schwann cells showed degenerative nuclear atypia.

PMID- 8656564
TI  - Japanese endoscopy: reflections of a British gastroenterologist.

PMID- 8656563
TI  - Retropharyngeal abscess after radiation therapy and cis-platinum, 5-fluorouracil
      treatment for nasopharyngeal carcinoma with collagen disease: report of two
      patients and a review of the literature.
AB  - Collagen disease are frequently associated with malignant tumors. Recently,
      radiotherapy combined with chemotherapy has been recommended for improving the
      efficacy of treatment for nasopharyngeal carcinoma. Two patients with
      nasopharyngeal carcinoma complicated by collagen diseases (dermatomyositis in
      one, and Sjogren's syndrome with mixed connective tissue disease in the other)
      were given radiotherapy combined with chemotherapy consisting of cis-platinum and
      5-fluorouracil. Following this combination therapy, both patients developed
      retropharyngeal abscess and ulceration of the mucosal membrane on the posterior
      wall of the oropharynx; there was no tumor cell involvement. Because these
      injuries were more severe than would have been expected from radiotherapy alone,
      it is recommended that special attention be paid to combination therapy in
      patients with nasopharyngeal carcinoma complicated by collagen disease.

PMID- 8656565
TI  - [Gastric mucosal atrophy and prevalence of Helicobacter pylori in reflux
      esophagitis of the elderly].
AB  - This study is aimed at a role of Helicobacter pylori (HP) infection in reflux
      esophagitis of the elderly. 46 patients with reflux esophagitis aged at older
      than 60 years are selected for this study with informed consent. 43 patients
      without reflux esophagitis, peptic ulcer, and gastric cancer are used as a
      control group. In reflux esophagitis, gastric mucosal atrophy is judged as closed
      type of endoscopic findings in all cases. In control, 27 of 43 patients were
      judged as open type. Serum pepsinogen I, II ratio is 4.73 +/- 1.28 which is
      higher significantly than 3.39 +/- 1.69 in control. Serological positive rate of
      HP antibody is 39.1% in reflux esophagitis. This rate is significantly lower than
      62.7% in control. In conclusion, low frequency of chronic HP infection protects
      gastric mucosa from atrophy, and keeps secretion of gastric acid, resulting in
      reflux esophagitis of the elderly accompanied with various abnormal esophago
      gastric functions.

PMID- 8656566
TI  - [Effect of endoscopic sclerotherapy with esophageal varices on esophageal
      motility].
AB  - We investigated esophageal motility in 12 patients with esophageal varices by
      esophagography, scintigraphy and manometry before and after endoscopic
      sclerotherapy. In the manometric study, the appearance rates of the primary wave
      and the deglutitive relaxation decreased gradually after sclerotherapy, and the
      former improved within 3 months after discharge, while the latter tended to have
      a prolonged recovery period. The pressure of the lower esophageal sphincter was
      not significantly different before and after sclerotherapy. The length of the
      lower esophageal high pressure zone was greater than normal range before
      sclerotherapy, but it gradually shortened after sclerotherapy and improved by 3
      months after sclerotherapy. The inducing rates of gastroesophageal reflux by
      abdominal compression was significantly higher at 3 months after sclerotherapy
      than before. In radiologic study, the esophageal transit time tended to prolong
      early after sclerotherapy, and it improved only slowly. We concluded that we need
      contrive to prevent from motility disorder of esophagus at the time of endoscopic
      sclerotherapy for patients with esophageal varices.

PMID- 8656567
TI  - [Evaluation of the number of clones and the degree of nucleotide diversity of the
      HCV genome by FSSA (fluorescence single strand conformation polymorphism and
      sequence analysis) in patients with chronic active hepatitis C receiving
      interferon therapy].
AB  - We evaluated the number of clones and the degree of nucleotide diversity in the
      HVR of the HCV genome in patients with chronic active hepatitis C who were
      treated with IFN (interferon). We could not obtain the nucleotide sequence per se
      of the HCV genome but were able to evaluate the degree of diversity in the
      nucleotide sequence of the HCV genome using FSSA. Nonresponders to IFN therapy
      showed significant diversity in the nucleotide sequence, even if their number of
      HCV clones are small. Responders showed little diversity in the nucleotide
      sequence, which suggests that their viral clones were composed of populations
      with less variability in the HVR. IFN therapy had more impact on diversity in the
      nucleotide sequence than on the number of HCV clones.

PMID- 8656568
TI  - [A case of early cancer which consecutively spread on the stomach and duodenum].

PMID- 8656569
TI  - [An adult case of intussusception due to inverted Meckel's diverticulum
      accompanied by angiolipoma].

PMID- 8656570
TI  - [A case of autoimmune hepatitis with multinucleated giant hepatocytes].

PMID- 8656571
TI  - [A case of chronic hepatitis C developing drug induced intrahepatic cholestasis
      due to anti-inflammatory drug during interferon therapy].

PMID- 8656572
TI  - [A case of the hypoplasia of the hepatic left lobe complicated with
      cholangiocarcinoma].

PMID- 8656574
TI  - [The growth process of nodular-invasive gallbladder cancer observed by
      ultrasonography: a case report].

PMID- 8656573
TI  - [A case of hepatocellular carcinoma with obstructive jaundice successfully
      treated by biliary stent endoprosthesis].

PMID- 8656575
TI  - [A case of pancreatic pseudocyst with splenic infarction].

PMID- 8656576
TI  - [A case of idiopathic orthostatic hypotension manifesting sick sinus syndrome due
      to sympathetic nervous dysfunction].
AB  - A 67-year-old woman with idiopathic orthostatic hypotension was presented. The
      patient started to experience faintness on standing since 1993. During a physical
      examination, her systolic blood pressure fell from 148 to 50 mmHg on standing.
      Blood pressure responses to the mental arithmetic test and hyperventilation
      stress were normal. However, cold pressor test failed to increase blood pressure.
      These observations, with the finding that phase IV response on Valsalva's
      maneuver was absent, indicate afferent sympathetic nervous dysfunction.
      Peripheral neuropathy including diabetes mellitus and involvement of central
      nervous system such as multiple system atrophy were excluded. Holter ECG
      examination revealed a 3.9 second sinus arrest and bradycardia (total beats
      88901/day). the blunted responses of the heart rate to atropine as well as
      isoproterenol further suggested the presence of sick sinus syndrome. Amezinium
      administration significantly improved her orthostatic hypotension and eliminated
      sinus arrest. These findings indicate that sympathetic nervous dysfunction could
      account for at least a part of the sick sinus syndrome in this patient.

PMID- 8656577
TI  - [A case of abnormal hemoglobin (HbJ Cape Town) with high serum levels of HbAlc].
AB  - We describe a case of hemoglobinopathy detected on admission for examination for
      high blood glucose levels and abnormal liver function. In 1991, it was pointed
      out that he had postprandial hyperglycemia. In 1994, at age 60, he had lassitude
      and anorexia. He was admitted to our hospital on the suspicion of diabetes
      mellitus and liver disease. Glycosylated hemoglobin levels was very high, but the
      75 gram oral glucose tolerance test result was within the normal range. After
      abstinence from alcohol, his glutamic oxaloacetic transaminase, glutamic pyruvic
      transaminase and gamma glutamyl traspeptidase became normal. Diabetes was
      excluded and abnormal hemoglobinopathy had been suspected. We analyzed his
      abnormal hemoglobin. In isoelectro-phoresis a fast moving variant was detected
      suggesting the presence of abnormal hemoglobin at the cathode. We fractionated
      hemolytic globin by CM-chromatography and detected an abnormal peak before the
      alpha chain band. Subsequently, we sequenced isolated abnormal alpha chain and
      detected the substitution of Ariginine for Glutamamine at position 92 (Hb J Cape
      Town). So far he has not demonstrated any symptoms or signs of HbJ Cape Town.
      Hemoglobinopathy is not uncommon in aged people.

PMID- 8656579
TI  - [Effect of apolipoprotein E phenotype on cerebrospinal fluid levels of tau in
      patients with dementia of Alzheimer type].

PMID- 8656578
TI  - [Normalization of hypercholesterolemia in a female stroke patient after switching
      from enteral tube feeding to oral feeding].
AB  - A 70-year-old female was admitted to a general hospital in a rural area due to
      left putamenal cerebral hemorrhage in December 1994. She had right hemiplegia and
      was totally aphasic. In May 1995, she was moved to Tokyo where her son lives, and
      she was admitted to Tokyo Metropolitan Geriatric Hospital in order to prepare a
      home care system. her family's support (serving her favorite dishes) allowed
      enteral tube feeding to be halted. After one month she could absorb enough energy
      to maintain her serum albumin level. The total calories ingested orally was
      comparable to that of enteral feeding but the fat composition was 62% of that of
      enteral feeding (fat was 19.6% and 31.7% of the total calories in the two diets,
      respectively). Her cholesterol level decreased from 286 mg/dl to 197 mg/dl.
      Nutrient-balanced tube feeding is useful, but may disturb lipid metabolism in
      patients used to having vegetable-rich diets.

PMID- 8656580
TI  - [Cancer medicine and aged people].

PMID- 8656581
TI  - [ENT practice for the aged].

PMID- 8656582
TI  - [The relationship between office and ambulatory blood pressure in elderly
      patients in a non-academic setting].
AB  - We investigated the relationship between clinic blood pressure (BP) and
      ambulatory blood pressure (ABP) in 297 elderly patients who underwent 24 hour ABP
      monitoring as a non-academic clinical references. Among 107 cases who were
      normotensive in office BP measurements, 33 cases (30.8%) proved to be
      hypertensive with more than 140 mmHg in ambulatory systolic BP. Those patients
      should be referred to as home hypertension or white coat normotension. On the
      other hand, among 187 patients who were hypertensive in the clinic, 78 cases
      (41.7%) turned out to be white coat hypertension with an ambulatory daytime
      systolic BP of less than 140 mmHg. Ambulatory systolic BP in white coat
      hypertension was comparable with that in the non-hypertensive group although
      their BP in the clinic was significantly higher than the latter (p < 0.02).
      Ambulatory systolic BP in the home hypertension group was significantly higher
      than that in the normotension but was comparable with that in true hypertension.
      The number of the antihypertensive drugs prescribed in the white coat
      hypertensive group tended to be greater than that in other groups although that
      in the home hypertensive group was similar to the other groups. The incidence of
      cerebro vascular disease in each group was similar.

PMID- 8656583
TI  - [Sociomedical study of centenarians in Nagoya City].
AB  - The purpose of this study was to assess the background to the longevity of 36
      centenarians in Nagoya city and to compare 14 institutionalized centenarians out
      of those 36 with 202 individuals in the 70-99 age group in our special nursing
      home, particularly with regard to blood chemistry and immunity tests. The reasons
      for their social longevity in terms of profile appeared to be attention to eating
      habits, abstention from smoking and drinking, occupations with adequate exercise.
      The incidence of dementia was 65.6% among them. We evaluated centenarians from
      the viewpoint of Hasegawa's Dementia Scale (HDS) and comprehensive functional
      assessment of the elderly consisted of the revised version of Hasegawa's Dementia
      Scale (HDSR), and examination of activity of daily living (ADL), physical
      perception, and social life. All were positively associated. Thus centenarians
      independent of physical assistance demonstrated significantly higher systolic
      blood pressure, and respective scores for HDS, HDSR, ADL, physical perception and
      social life than their dependent counterparts, were less likely to be
      institutionalized and suffered from fewer disorders. In particular none were
      diagnosed as positive for cerebral hemorrhage, infarction and dementia. Age
      demonstrated significant positive or negative correlation with the following
      values in blood chemistry and immunity tests: blood cell counts, hemoglobin
      concentration, hematocrit value, albumin, total protein, total cholesterol, low
      density lipoprotein cholesterol, creatinine, blood cell nitrogen, uric acid,
      helper T cell, and IgA immunoglobulin.

PMID- 8656585
TI  - [In vitro antimicrobial activity of a new quinolone, levofloxacin, against
      atypical mycobacteria].
AB  - We measured th in vitro antimicrobial activity of a new quinolone, levofloxacin
      (LVFX) against seven clinically isolated species of atypical mycobacteria,
      including 30 strains of M. avium complex. 8 of M. fortuitum, 4 of M.
      scrofulaceum, 2 of M. kansasii, 2 of M. gordonae, and 1 of M. chelonae (subsp
      chelonae). LVFX showed a potent antimicrobial activity against M. kansasii, M.
      gordonae and M. chelonae (subsp chelonae). In addition, it was suggested that
      LVFX may be effective for the treatment of infections caused by M. avium complex,
      since satisfactory antimicrobial activity was displayed against some strains of
      M. avium complex. Considering the fact that LVFX shows good concentration levers
      in sputum, this drug could be used in the chemotherapy against the infection with
      M. avium complex.

PMID- 8656584
TI  - [Cerebral hemodynamics in patients with dementia].
AB  - Cerebral blood flow (CBF) at rest was measured by 123I-IMP SPECT and the standing
      test was conducted by 99mTc-HMPAO SEPCT in patients with dementia of Alzheimer's
      type (DAT) and vascular dementia (VD) in order to evaluate cerebral
      autoregulation and to consider the diagnostic significance of this determination
      and test. CBF at rest decreased significantly in all regions in the DAT and VD
      groups compared to the control groups (healthy aged persons, group C). The value
      of mean CBF also decreased significantly in the DAT (40.1 micromilligrams/100
      g/min) and VD groups (41.3) as compared to group C (51.0). In the DAT groups, the
      CBF was significantly lower in the parietal region compared to VD groups, and CBF
      and Hasegawa's dementia score showed a positive correlation in the temporal and
      parietal regions. Decreases in blood pressure upon standing were about 10 mmHg in
      all three groups, but the decrease rate in mean CBF was significantly greater in
      the VD groups (20.2%) than in the C (5.0%) and DAT groups (4.0%). The
      dysautoregulation index (D.I. delta; % CBF mmHg), used as a measurement of
      cerebral autoregulation, was significantly higher in the VD groups (1.7) than in
      the C(0.5) and DAT groups (0.3). This index made it possible to make differential
      diagnosis in some patients in whom it was impossible using CBF at rest, probably
      due to impaired cerebral autoregulation and atherosclerotic changes in VD
      patients. Our findings suggest that D.I. provides information on the condition of
      patients that cannot be obtained with CBF at rest and assists in differential
      diagnosis.

PMID- 8656586
TI  - [A clinical study of non-tuberculous pulmonary mycobacteriosis].
AB  - We studied the clinical features of sixty-one patients with non-tuberculous
      pulmonary mycobacteriosis (NTM), who were newly diagnosed at five national
      hospitals in Kinki area during 1993. The study subjects were composed of 31
      patients with M. avium complex (MAC) disease (20 males and 15 females), 21 with
      M. kansasii (MK) disease (19 males and 3 females), 2 males with M. szulgai (MS)
      disease and 2 females with M. chelonae (MC) disease. The rate of NTM to all
      culture proven mycobacteriosis was 20.2% and the rate of NTM to all culture
      proven, newly discovered mycobacteriosis was 18.2% and the rates were higher than
      Sakatani's report in 1994 (14% in 1991). The ratio of MK to MAC was 22:35, and
      the ratio of MK was higher than the report of Sakatani. The mean age of patients
      with MK was 57.9 in male and 76.7 in female, that with MAC was 71.0 in male and
      70.1 in female, that with MS was 57.0 in male and that 72.5 with MC in female.
      The proportion of elderly patients was higher than the former reports in Japan,
      especially in female with MK. The main lesions on chest X-ray was found in
      bilateral S1, 2(S1+2), particularly in the cases with cavitary lesions, but right
      middle lobe and left lingular lobe were mainly affected in some patients with MAC
      and S6 was often affected in elderly patients with MK. The chemotherapy with
      isoniazid, rifampicin, ethambutol and/or streptomycin (or kanamycin) w as highly
      effective in case with MK and MS disease, the efficacy was similar to pulmonary
      tuberculosis. Some patients with MAC were treated with combination of anti
      tuberculosis drugs and new quinolons and/or clarythromycin, but the efficacy was
      not yet revealed.

PMID- 8656587
TI  - [Isolation of nontuberculous mycobacteria during colonoscopy].
AB  - We conducted a survey on nontuberculous mycobacteria (NTM) isolated in
      association with colonscopy at two hospitals. NTM was isolated from the fluid
      phase of colonic contents in 17.6% of the specimens obtained at hospital A and in
      46.3% at hospital B. The rate of isolation from the preexamination suction fluid
      was 9.5% and 43.3% at hospital A and B, respectively. Tap water samples from both
      hospitals were examined and proved to be free from contamination with NTM. The
      mycobacterial species isolated at hospital A were M. chelonae subsp. abscessus,
      M. chelonae subsp. chelonae, M. fortuitum, and M. gordonae. M. chelonae subsp.
      abscessus was the only mycobacterial species isolated at hospital B. M. avium
      complex was not isolated at either hospital. By an additional procedure to cleans
      and decontaminate the endoscopes by suction with Maskin ethanol solution, the
      incidence of isolation of NTM from the fluid-phase of colonic contents was
      significantly reduced. None of the patients from whom NTM was isolated exhibited
      positive signs of colonic NTM infection by the endoscopic examination and non had
      any underlying diseases which might induce immune suppression. We suspect that
      most of the NTM isolates have originated from the contaminated endoscope. In
      conclusion, when a colonscopic examination is carried out in suspicion of NTM
      disease in intestine, it is essential to reassess the possibility of
      mycobacterial contamination of the colonscopes and implement appropriate steps
      for cleansing and sterilization of them.

PMID- 8656588
TI  - [The role of some cellular components of bacterial parasites in determining the
      incidence of tuberculosis: studies on mycobacterial antigens, with special
      reference to mycobacterial immunoreactive ribosomal and secreted proteins].
AB  - Tuberculosis remains as major disease, affecting more than 20 million people. The
      elimination of the disease with vaccination, rapid diagnosis, and and efficient
      therapy is an important objective of our study. To realize the objective, the
      characterization of antigens is essential. We have chosen two kinds of antigens
      for our study, the ribosomal antigens and and an antigenic proteins secreted by
      mycobacteria. The biochemical and immunological characterization of ribosomal
      fraction was carried out. Ribosomal proteins were purified and assessed for DTH
      reaction. The N-terminal amino acids sequences were determined. Total structures
      of S19, S7 and S12 in 30S and L7/L12 in 50S subunits were elucidated. L7/L12 had
      66% homology with analogue from S. griseus which showed GTPase activity in
      protein synthesis. This protein was secreted in culture medium and induced strong
      DTH. Secreted antigenic proteins are of great interest for us. Secreted antigens
      may be recognized rapidly by immune system and therefore may induce rapid and
      high level immune response. It is also expected that it may contain protective
      antigens, since live BCG protect disease more efficiently than heat killed BCG.
      We have determined and published the total structure of four proteins (MPB64,
      MPB70, MPB57 and alpha antigen). We attempted to utilize this antigen for the
      diagnosis and the design of vaccine. The structures of alpha antigens from M.
      avium, M. intracellulare, M. scrofulaceum, M. kansasii and BCG were determined
      and its potential for application to diagnosis was presented. Using the operon of
      M. kansasii, alpha antigen and V3 region of HIV-1 were expressed by recombinant
      BCG which induced CTL in mice.

PMID- 8656589
TI  - [The mode of infection of tuberculosis--analysis using molecular epidemiologic
      methods].
AB  - In the 1950's, evidence showed that INH-resistant Mycobacterium tuberculosis
      organisms were attenuated in both virulence and pathogenicity in animals, and it
      was postulated that these bacilli might also be attenuated in their virulence to
      humans. Subsequent studies, however, indicated that all INH-resistant strains
      should not be considered as being attenuated in their virulence to humans. The
      general conclusion was that patients excreting INH-resistant organisms are
      somewhat less infectious to their contacts than patients excreting INH
      susceptible organisms. Insertion sequences are suitable tools for the diagnosis
      and epidemiology of tuberculosis because of the highly variable copy number and
      variability of insertion sites in the chromosome. This variability allows the
      subtyping of M. tuberculosis strains by restriction fragment length polymorphism
      (RFLP) analysis. Patients with the same RFLP pattern constitute an
      epidemiologically linked cluster. Clustering indicates recent infection and rapid
      progression to clinical illness. Nearly one thirds of new cases of tuberculosis
      in San Francisco are the result of recent infection. In Thailand, tuberculosis
      has now emerged as the most common opportunistic disease associated with HIV
      infection. Cluster analysis showed the risk of progression to active tuberculosis
      among individuals infected with HIV. Ther have been numerous outbreaks of
      multidrug-resistant tuberculosis in the United States. Most of such outbreaks
      have primarily involved persons infected with HIV, who are thought to have been
      exposed to the strains in medical or correctional facilities.

PMID- 8656590
TI  - [The mechanism of induction and expression of protective immunity with special
      reference to the role of cytokines].
AB  - The mechanism of induction of protective T cells mediating the anti-tuberculous
      immunity is not well elucidated. Using viable and killed cells of Mycobacterium
      bovis BCG and Listeria monocytogenes, which differ in the ability to induce
      specific protection in mice, we have found that the difference is mainly due to
      the different ability to induce several cytokines especially IFN-rho not due to
      the difference in antigenic property. It was shown that the induction of
      protective T cells is highly dependent upon various cytokines produced by the
      host at the early stage of immunization. Based on our own experimental result in
      mice, the relative contribution of several cytokines to the induction and
      expression of cell-mediated immune protection was discussed.

PMID- 8656591
TI  - [Clinical comparison of pulmonary tuberculosis with pulmonary M. avium complex
      disease].
AB  - At first, we reviewed radiographic findings of primary pulmonary tuberculosis,
      secondary pulmonary tuberculosis, pulmonary M. avium complex (MAC) disease
      without predisposing conditions, and pulmonary tuberculosis in AIDS patient.
      Infiltrates in lower field, mediastinal lymphadenopathy, and pleural effusion
      were the characteristics for primary pulmonary tuberculosis, while multiple
      nodular shadow with/without cavitation in S1,2,6 were the characteristics for
      secondary pulmonary tuberculosis. In pulmonary MAC disease without predisposing
      conditions, lesions progressed slowly from a cluster of a small nodules to cystic
      bronchiectasis with collapse of the segment or the lobe, and it took usually more
      than 10-years for the whole process interval. The characteristics of pulmonary
      tuberculosis in AIDS patient were nearly the same as those of primary pulmonary
      tuberculosis. Secondly, we compared clinical characteristics between pulmonary
      tuberculosis and pulmonary MAC disease. We reviewed the medical records of
      hospitalized patients who were diagnosed as pulmonary tuberculosis or pulmonary
      MAC disease. Systemic compromised host defense, such as diabetes mellitus or
      malignancy, played a more important predisposing factors in the development of
      pulmonary MAC disease. The average age of patients with MAC disease was found to
      be older than those with tuberculosis. By gender women were predominant in MAC
      disease, while men were predominant in tuberculosis.

PMID- 8656592
TI  - Removal of foreign bodies in the nasopharynx.

PMID- 8656594
TI  - Orbital fat prolapse in the dog.
AB  - Five dogs presented with varying degrees of subconjunctival swelling and
      enophthalmos. Biopsy revealed the subconjunctival tissue to be fat. Surgical
      excision in two cases resulted in resolution of the clinical signs and
      demonstrated that the fat came from the retrobulbar region.

PMID- 8656593
TI  - Uterine, cervical and vaginal microflora of the normal bitch throughout the
      reproductive cycle.
AB  - Samples for microbiological culture were collected from the uterus of bitches
      using transcervical uterine cannulation (31 samples, 23 bitches) and from the
      uterus, cervix and vagina post mortem (19 bitches) at all stages of the
      reproductive cycle. Samples were cultured for aerobic and anaerobic bacteria and
      for aerobic mycoplasmas. Bacteria were always found in the uterus during pro
      oestrus and oestrus (12 positive in 12 cultures) and rarely at other stages of
      the reproductive cycle: during anoestrus (one in 14) and other stages (none in
      24). When microorganisms were detected at three sites post mortem, those found in
      the cervix and vagina were always of the same species as those found in the
      uterus. In six out of 13 instances, microorganisms were found in the cervix or
      vagina when none were found in the uterus. The mean number of isolates, number of
      bacteria seen in uterine cytology and bacterial growth were greater (P < 0.005)
      during oestrus and pro-oestrus than at other stages. Bacteria isolated from the
      uterus, in order of frequency, were Escherichia coli, Haemophilus species, alpha
      haemolytic streptococci, Corynebacterium species, Streptococcus canis,
      Alcaligenes faecalis, Bacteroides species, Pasteurella species and Proteus
      mirabilis. No mycoplasmas were cultured from the samples. This study indicates
      that the uterus of the normal bitch has a uterine microflora during pro-oestrus
      and oestrus that is similar to that of the vagina and cervix.

PMID- 8656595
TI  - Clinical usefulness of fructosamine measurements in diagnosing and monitoring
      feline diabetes mellitus.
AB  - Fructosamines are glycated serum proteins that reflect long-term serum glucose
      concentrations in humans and several animal species. In the present study, blood
      samples were drawn from three populations of diabetic cats: untreated diabetic
      cats with clinical symptoms prevailing only a few days (n = 1), untreated
      diabetic cats with symptoms lasting more than two weeks (n = 6) and clinically
      well stabilised diabetic cats receiving insulin twice daily which showed no signs
      of disease (n = 4). All untreated diabetic cats showed elevated fructosamine
      measurements. Based on fructosamine measurements, clinically well stabilised
      diabetic cats could be subdivided further according to the degree of glycaemic
      control. Diabetic cats with satisfactory glycaemic control revealed fructosamine
      concentrations within or close to the reference range (146 to 271 mumol/liter),
      whereas fructosamine concentrations above 400 mumol/liter indicated insufficient
      glycaemic control. This study suggests that the fructosamine assay reflects
      persistently elevated serum glucose concentrations in cats and is a useful
      parameter for diagnosing and monitoring diabetes mellitus in cats.

PMID- 8656596
TI  - Heart rate variability in relation to severity of mitral regurgitation in
      Cavalier King Charles spaniels.
AB  - Heart rate variability was measured in 81 Cavalier King Charles spaniels to
      investigate if it could be used to evaluate the severity of mitral regurgitation
      and to predict decompensation. Heart rate variability was assessed by the natural
      logarithm of the variance of the R-R intervals for 20 consecutive beats obtained
      from electrocardiographic recordings. Twenty-two of the dogs were clinically
      normal and 59 had mitral regurgitation caused by chronic valvular disease. The
      severity of mitral regurgitation was evaluated by echocardiography and thoracic
      radiography. Heart rate variability was found to be reduced (P < 0.001) among
      dogs with severe left atrial and ventricular dilatation and clinical signs of
      congestion. No significant differences in heart rate variability were found among
      normal dogs, dogs with only cardiac murmur, and dogs with echoradiographic
      evidence of slight to moderate left atrial and ventricular dilatation. Overall,
      an association was found between heart rate variability and left atrial to aortic
      root ration and left ventricular end diastolic diameters (r = 0.72 and 0.64,
      respectively, P < 0.001), as well as heart and respiratory rate (r = 0.80 and
      0.69, respectively, P < 0.001). Multiregression analysis showed that, in order of
      importance, heart rate, left atrial diameter and respiratory rate had significant
      effects on heart rate variability. Among these parameters, heart rate variability
      and left atrial diameter were found to be most efficient in separating
      decompensated dogs from compensated. It is concluded that heart rate variability
      may provide the clinician with valuable information when assessing the severity
      of mitral regurgitation caused by chronic valvular disease.

PMID- 8656597
TI  - Romifidine as a premedicant to propofol induction and infusion anaesthesia in the
      dog.
AB  - The effects of premedication with four different intravenous doses of romifidine
      (20, 40, 80 and 120 micrograms/kg bodyweight) and a saline placebo were compared
      in a group of 20 adult beagles of both sexes, undergoing anaesthesia with
      propofol for a clinical dental procedure. Anaesthesia was induced 10 minutes
      after premedication and maintained by intravenous infusion of propofol for a
      period of 30 minutes. Romifidine had a marked synergistic effect with propofol
      and reduced the required induction and infusion doses by more than 60 per cent
      for a standard level of anaesthesia; the synergistic effect was dose related.
      Following premedication, propofol produced no significant alteration of
      respiratory rate, heart rate or rectal temperature. Anaesthesia was found to be
      more stable following romifidine premedication at all doses studied. The quality
      of induction was unaltered by the dose of the romifidine. Recovery from
      anaesthesia was smooth and of a similar quality in all cases. There were no
      differences in the recovery times between the unpremedicated group and the dogs
      premedicated with any dose of romifidine studied. There were no adverse effects
      noted following this anaesthetic regimen. The marked dose-related synergism with
      propofol induction and infusion anaesthesia is relevant should romifidine be used
      in the dog in clinical veterinary practice.

PMID- 8656598
TI  - Canine conjunctival papilloma: a review of five cases.
AB  - Five cases of unilateral bulbar conjunctival papillomata are reported in five
      different breeds of dog. The dogs ranged from six to nine years of age, four were
      female and one was male. In all but one case the mass was an incidental finding.
      The morphology and histopathology are described. The authors have been unable to
      find any details or descriptions of this type of papilloma in the veterinary
      literature.

PMID- 8656599
TI  - Pancreatic injuries in rats with fecal peritonitis: protective effect of a new
      synthetic protease inhibitor, sepinostat mesilate (FUT-187).
AB  - To evaluate the effects of sepsis on the exocrine pancreas, we studied (1) serum
      amylase levels, pancreatic water and trypsin content; (2) pancreatic histological
      changes; (3) pancreatic subcellular distribution of lysosomal enzyme in the
      acinar cells; and (4) protective effects of a new synthetic protease inhibitor,
      FUT-187 against the pancreatic injuries in sepsis of rats induced by cecal
      ligation and puncture. Elevated serum amylase levels, increased pancreatic water
      and trypsin content, were observed in rats with fecal peritonitis induced by
      cecal ligation and puncture. Subcellular redistribution of lysosomal enzyme,
      cathepsin B, activity from the lysosomal fraction to the zymogen fraction was
      also observed. FUT-187 was found to significantly prevent these pancreatic
      injuries induced by fecal peritonitis. These results indicate that the exocrine
      pancreas is injured during sepsis, and that some unknown protease activities,
      which are present during sepsis and are susceptible to the inhibition of FUT-187,
      seem to play an important role in the pathogenesis of the pancreatic injuries
      induced by fecal peritonitis. These results also indicate the important
      pathological role of lysosomal enzymes in the pancreatic injuries induced by
      sepsis.

PMID- 8656600
TI  - Renal artery smooth muscle is refractory to contraction by angiotensin II.
AB  - The vasomotor responses of vascular smooth muscle from different vascular smooth
      muscle beds have not been well characterized. The purpose of this study was to
      compare the contractile responses of vascular smooth muscle from two vascular
      beds, the peripheral vascular bed (carotid artery) and the visceral vascular bed
      (renal artery) to vasoactive agonists. Fresh bovine carotid and renal artery
      smooth muscle contractile responses to serotonin, endothelin, angiotensin, and
      dopamine were determined in a muscle bath. Serotonin and dopamine cause rapidly
      developing sustained contractions in carotid and renal artery smooth muscle. The
      magnitude of the contractile response to serotonin is significantly greater in
      carotid artery and the magnitude of the response to dopamine is similar between
      carotid and renal artery. Endothelin induces a slowly developing sustained
      contraction of greater magnitude in renal artery. Angiotensin II causes transient
      contractile responses in carotid artery but renal artery smooth muscle is
      uniquely refractory to angiotensin stimulation. This lack of response to
      angiotensin II may be protective in the role of the kidney in regulating blood
      pressure through the renin-angiotensin system. Differences in receptor expression
      or affinity or in postreceptor cellular signaling events may account for these
      differential responses to endogenous vasoactive agonists.

PMID- 8656601
TI  - A new approach to the treatment of experimental septic shock.
AB  - Previous work has shown that disseminated intravascular coagulation (DIC) may
      produce multiple organ failure, including adult respiratory distress syndrome, by
      obstruction of visceral micro circulation by microclots DIC can be produced by
      sepsis. This study tests the ability of a plasminogen activator to prevent death
      from an intravenous injection of killed Escherichia coli by causing lysis of the
      microclots. Subjects were two groups of 8 pigs each with body weight of 60-70
      lbs. Killed Escherichia coli were injected IV in 16 pigs. Invasive monitoring was
      used to record physiologic data during the 5.0-hr experimental period. Urokinase
      injected 20 min after the injection of Escherichia coli organisms significantly
      prevented mortality, acidosis, and development of blood incoagulability. We
      conclude that plasminogen activator can significantly prevent fatal Escherichia
      coli (septic) shock without causing bleeding.

PMID- 8656602
TI  - Effect of human growth hormone on human pancreatic carcinoma growth, protein, and
      cell cycle kinetics.
AB  - The role of human growth hormone (hGH) as a nutritional adjunct for cancer
      patients is controversial because of its potential mitogenic effects on tumor
      growth. No studies to date have examined the effect of hGH on human tumor
      response in vivo. In Vitro: Athymic mice were injected (s.c.) daily with hGH (GH,
      n=14) or saline (CTL, n=14). On Day 10, serum was collected and added to human
      pancreatic carcinoma cells in culture. In Vivo: Athymic mice were inoculated
      (s.c.) with human pancreatic carcinoma cells. On Day 14, mice were randomized to
      receive daily either hGH (GH, n=14) or saline (CTL, n=12). On Day 29, animals
      received [3H]phenylalanine for tissue protein fractional synthetic rate (FSR)
      measurement. Tumors were excised and cell cycle kinetics analyzed. Data are
      expressed as mean +/- SEM. Statistical analysis was performed by unpaired t test
      and/or ANOVA where appropriate. In Vitro: Serum from GH-treated animals had
      elevated IGF-1 levels (287 +/- 34 ng/ml vs 157 +/- 53 ng/ml, P<0.001) and
      significantly stimulated cell growth (No. cells x 10(3)/well) compared with CTL
      serum (925 +/- 31 vs 747 +/- 38, P<0.001). In Vivo: Serum for GH-treated animals
      had elevated IGF-1 levels (287 +/- 34 ng/ml vs 157 +/- 53 ng/ml, P<0.001) and
      significantly stimulated cell growth (No. cells x 10(3)/well) compared with CTL
      serum (925 +/- 31 vs 747 +/- 38, P<0.001). In Vivo: Growth hormone had no
      significant effect on tumor growth rate (mm3/day) (1.45 +/- 0.47 CTL vs 1.57 +/-
      0.66 GH), final tumor weight (mg) (0.19 +/- 0.15 CTL vs 0.17+/- 0.06 GH), DNA
      Index (1.5 +/- 0.1 CTL vs 1.5 +/- 0.1 GH), percent S phase (20.3 +/- 3.3 CTL vs
      22.1 +/- 3.0 GH), or tumor FSR (%/day) (51.1 +/- 17.8 CTL vs 70.2 +/- 61.1 GH).
      Growth hormone significantly elevated serum IGF-1 levels (ng/ml) (176 +/- 48 CTL
      vs 222 +/- 53 GH, P<0.005) and liver FSR (%/day) (62.8 +/- 17.8 CTL vs 79.7 +/-
      12.7 GH, P<0.005). Serum of GH-treated mice increased human pancreatic cell
      growth in vitro. In vivo, GH administration raised serum IGF-1 levels and
      increased liver protein FSR, without tumor growth, cell cycle kinetics, or
      protein FSR.

PMID- 8656603
TI  - c-MYC oncoprotein production in experimental vein graft intimal hyperplasia.
AB  - PURPOSE: The expression of c-MYC oncoprotein in proliferating smooth muscle cells
      (SMCs) was analyzed in an experimental model of vein graft intimal thickening.
      METHODS: Superficial epigastric vein grafts were inserted into the femoral
      arteries of male Sprague-Dawley rats. The vein grafts were harvested at 6 hr, 2
      days, 1 week, 2 weeks, and 4 weeks after grafting and were rapidly frozen in
      liquid nitrogen. Immunohistochemical labeling and morphologic analysis of vein
      graft sections with a double staining technique were used to identify c-MYC/alpha
      SMC actin and proliferating cell nuclear antigen (PC10)/alpha SMC actin within
      intimal cells. c-MYC/alpha SMC actin and PC10/alpha SMC actin positive cells were
      quantitated in the perianastomotic area (R-1) and the body of the graft (R-2) for
      each time period. Total wall and intimal thickness of perfusion fixed vein grafts
      were measured with a computer digitized system. RESULTS: Intimal and total wall
      thickening in the R-1 region peaked at 1 week (27.4 and 579.4 microns
      respectively) and were significantly thicker (P < 0.01) than the same region at 6
      hr after graft implantation (6.0 and 113.5 microns respectively). Staining for c
      MYC and PC10 in R-1 was also significantly higher (P < 0.05) at 1 week (5.75 and
      7.00 positive cells/10 cells, respectively) compared with that at 6 hr (1.5 and
      1.33, respectively). The R-1 region stabilized and remodeled over the following 3
      weeks, while c-MYC and PC10 staining progressively decreased. In the R-2 region,
      intimal thickness significantly increased (P < 0.05) from 6 hr (4.0 micrometers)
      to 1 week (12.0 micrometers) and stabilized, while total wall thickness increased
      throughout the first week and the difference became significant at 2 weeks (P <
      0.05). Staining for c-MYC and PC10 paralleled the staining in R-1 with a
      significant peak at 1 week (P < 0.05). CONCLUSIONS: c-MYC oncoprotein is
      expressed early after experimental vein grafting, with peak expression at 1 week.
      This occurs during a period of maximal intimal thickening, SMC proliferation, and
      increased expression of PC10. Expression of c-myc protooncogene may contribute to
      the induction and regulation of SMC proliferation, producing intimal hyperplasia.

PMID- 8656604
TI  - Effect of maturation on alpha-adrenoceptor activity in newborn piglet mesentery.
AB  - To characterize the mesenteric alpha1- and alpha2-adrenoceptor populations in
      newborn piglets, an extracorporeal circuit was established to control intestinal
      blood flow in 0- to 2-day old and 10- to 14-day old animals. In both groups,
      alpha-adrenoceptor activation was first documented by observing dose-dependent
      increases in mesenteric perfusion pressure after intramesenteric arterial
      injection of alpha-adrenoceptor agonists. In the 10- to 14-day old piglets,
      mesenteric vasoconstrictor responses to alpha1-adrenoceptor agonists (methoxamine
      and norepinephrine) and an alpha2-adrenoceptor agonist (BHT-933) were each
      blunted (P < 0.05, analysis of variance) by peripheral intravenous injections of
      prazosin (an alpha1-adrenoceptor antagonist) and yohimbine (an alpha2
      adrenoceptor antagonist), respectively. The mesenteric vasoconstrictor responses
      to those agonists were not significantly attenuated by prazosin or yohimbine in 0
      to 2-day old animals, nor were they blunted by YM-12617 (alpha1-adrenoceptor
      antagonist) or idazoxan (alpha2-adrenoceptor antagonist)--compounds that are
      structurally unrelated to prazosin and yohimbine, respectively. In addition,
      mesenteric vasoconstrictor responses to other known vasoconstrictor agents-
      angiotensin II, neuropeptide Y, and a thromboxane A2 mimic (U-46619)--were not
      effected in either age group by prazosin or yohimbine, implying these agents act
      independently of alpha-adrenoceptor mechanisms. These data suggest that (1) there
      exists functional mesenteric alpha1- and alpha2-adrenoceptor-like activity in 10-
      to 14-day old piglets that, in 0- to 2-day old animals, is not specifically
      expressed; and (2) mesenteric alpha-adrenoceptor function becomes more selective
      as newborn piglets mature.

PMID- 8656605
TI  - Water transport in native and transplanted porcine jejunum.
AB  - Adequate absorptive function of transplanted small intestine is essential for
      success of this procedure. This study compared water transport under basal and
      meal stimulated conditions in the transplanted swine jejunum to native jejunum.
      Six female adolescent Yorkshire swine were randomized to undergo construction of
      either a 25-cm native proximal jejunal Thiry-Vella Fistula (TVF), n=3, or a 25-cm
      proximal jejunal allograft TVF, n=3. Immunosuppression in the transplanted
      animals was accomplished with intravenous methylprednisolone, azathioprine, and
      cyclosporin. Jejunal absorption studies, each 4 hr long, were performed utilizing
      14C-polyethylene glycol to calculate net water flux. Each animal underwent at
      least three fasting and three postprandial studies. New water flux was negative,
      i.e., secretory, in both the native and transplanted proximal swine jejunum. In
      the basal state, integrated hourly water transport was more secretory in the
      native bowel vs the transplanted bowel during the 2nd, 3rd, and 4th experimental
      hr (-4.6 +/- .8 vs -2.1 +/- .7 cc, P = 0.034; -4.4 +/- .7 vs -1.8 +/- .6 cc, P =
      0.012; and -4.7 vs 1.3 +/- .5 cc, P < 0.005), respectively. In native jejunum,
      integrated hourly water transport was less secretory 2 and 3 hr postprandially
      compared to basal (-1.9 +/- .5 vs -4.4 +/- .7 cc, P = 0.016; and -2.0 +/- .5 vs 
      4.7 +/- .7 cc, P = 0.021), respectively. This postprandial proabsorptive response
      did not occur in the transplanted jejunum. Native and transplanted jejunal water
      flux in the postprandial state did not differ significantly. We conclude that
      there is higher secretion in native vs transplanted jejunum during fasting. The
      postprandial proabsorptive response of the proximal porcine jejunum is abolished
      by transplantation.

PMID- 8656606
TI  - Increased proliferation in keloid fibroblasts wounded in vitro.
AB  - A keloid is a pathological overgrowth of scar expanding beyond the boundaries of
      the initiating skin wound. Ultimately, this expansive scar is a result of excess
      collagen synthesized by fibroblasts within the wound. The processes that lead to
      this collagen excess remain unknown. An in vitro wound model was developed to
      test the hypothesis that fibroblasts isolated from keloid tissue and wounded in
      vitro might proliferate more rapidly that similarly wounded normal dermal
      fibroblasts. Keloid fibroblasts (KF) and normal human dermal fibroblasts (NDF)
      were grown to confluence and quiescence in flexible-bottomed culture plates.
      Wounds were created in a standardized fashion using a specially designed jig. The
      jig utilized a 25 gauge needle to reproducibly ablate 16-20% of cells from
      confluent cell sheets. Wounded and nonwounded cells were labeled with 3H
      thymidine at 24, 48, 72 and 96 hr postwounding to measure DNA synthesis. Wounded
      KF and NDF demonstrated increased 3H-thymidine incorporation compared to
      nonwounded control cultures, and wounded KF demonstrated significantly higher
      levels of 3H-thymidine incorporation than wounded NDF both 24 and 48 hr after
      wounding. A similar trend was seen in cell counts. The wounded KF also showed a
      statistically greater labeling index quantitated by autoradiography than did
      wounded NDF. The increased commitment to DNA synthesis in response to wounding in
      vitro in keloid fibroblasts correlates with pathology seen in vivo. Keloid
      fibroblasts may have a lower inherent threshold for S phase entry than do normal
      fibroblasts contributing to the increased proliferation of keloid fibroblasts in
      response to wounding in vitro.

PMID- 8656607
TI  - Effects of granulocyte colony stimulating factor in a nonneutropenic rodent model
      of Escherichia coli peritonitis.
AB  - Despite improved antimicrobials and advances in caring for critically ill
      patients, mortality from sepsis is still unacceptably high. Upregulation of the
      cellular immune system is one strategy for decreasing mortality in subjects with
      severe sepsis, which appears to be promising. Granulocyte colony stimulating
      factor (G-CSF) has been used successfully to decrease mortality in neutropenic
      subjects with sepsis. In this study, we have investigated whether pretreatment
      with G-CSF decreases mortality in non-neutropenic rodents with lethal Escherichia
      coli peritonitis. We implanted agar pellets impregnated with 5 x 10(8) cfu of
      Escherichia coli into the peritoneal cavities of rats pretreated with 50
      micrograms/kg of G-CSF or an equal volume of 5% dextrose in water (D5W). Survival
      of these animals increased from 38 to 78% with G-CSF pretreatment. We also
      demonstrated an 11-fold increase in the number of polymorphonuclear leukocytes
      (PMNs) in animals treated with G-CSF. This increase in cells was seen initially
      only in the peripheral circulation. Twenty-four hours after induction of
      peritonitis, however, there was a three-fold greater increase in number of PMNs
      recovered from the peritoneal cavities of animals pretreated with G-CSF as
      compared to those treated with D5W. PMNs recovered from the peritoneal cavities
      of these animals had significantly elevated bactericidal activity (74% killing vs
      53% killing) as compared to those cells recovered from the peritoneal cavities of
      control animals. These results indicate that G-CSF pretreatment improves survival
      of non-neutropenic animals with lethal Escherichia coli peritonitis by enhancing
      the cellular arm of the immune response.

PMID- 8656608
TI  - Cardiac allograft tolerance induction with limited immunosuppression.
AB  - We evaluated the efficacy and systemic toxicity of cyclosporine G, rapamycin, and
      cyclosporine A with multiple donor-specific blood transfusions in the stringent
      ACI to Lewis heterotopic cardiac transplant model. In addition, all animals
      received a 28-day post-operative course of cyclosporine A. Systemic toxicity was
      assessed by measuring recipient body weight at 30 and 60 days posttransplantation
      and at the time of graft rejection. Preengraftment cyclosporine G (10 mg/kg)
      resulted in a mean graft survival of 7.31 +/- 1.09 days (n=13; N.S. vs Control).
      A 10-day course of the novel immunosuppressant rapamycin (d4-14) combined with
      our standard 28-day cyclosporine A protocol resulted in a mean graft survival of
      206.0 +/- 143.6 days (n=5; P < 0.05 vs Control). Furthermore, the rapamycin
      injection vehicle was found to have no intrinsic immunosuppressive activity or
      systemic toxicity. The addition of pre- (d-1) and post- (d7, 14, 21) engraftment
      donor-specific transfusion resulted in a mean allograft survival of 131.2 +/-
      43.9 days. No significant difference in interval weight was observed in any of
      the experimental groups. We conclude that cyclosporine G is of little value in
      this experimental model. However, rapamycin combined with cyclosporine A provides
      effective immunosuppressive synergy without significant toxicity or the
      sensitization risk inherent in donor-specific blood transfusions.

PMID- 8656609
TI  - Effects of cold preservation and reperfusion on microsomal cytochrome P-450
      linked monooxygenase system of the rat liver.
AB  - The effects of cold preservation and reperfusion of the liver on the hepatic
      microsomal cytochrome P-450-linked monooxygenase system (P-450 system) were
      investigated. Rat livers were preserved with cold University of Wisconsin
      solution for 0, 12, 24, 36, and 48 hr. Half of them in 0-, 24-, and 48-hr groups
      were reperfused for 1 hr at 37 degrees C with oxygenated Krebs-Henseleit buffer.
      After preservation or reperfusion, the liver microsomes were prepared and the
      concentration of each component of the P-450 system [NADPH-cytochrome b5
      reductase (b5 reductase), cytochrome b5 (b5), NADPH-cytochrome P-450 reductase (P
      450 reductase) and cytochrome P-450 (P-450)] and their drug metabolizing
      activities and concentration of apo-cytochrome P-450 2E1 (apo-P-450 2E1) were
      measured. After 48-hr preservation, b5 concentration did not decrease, whereas
      the concentration of P-450, P-450 reductase, and b5 reductase decreased from
      0.865 to 0.676 nmole/mg protein, from 0.262 to 0.233 micromole/mg protein/min and
      from 5.34 to 4.86 micromole/mg protein/min, respectively. During cold
      preservation, the activities of p-nitroanisole O-demethylase and aniline p
      hydroxylase did not change. Aminopyrine N-demethylase activity was inhibited from
      4.45 to 3.34 nmole/mg protein/min after 48-hr cold preservation. Apo-P-450 2E1
      was gradually decreased during cold preservation. Reperfusion caused a further
      decrease in the activities and concentration of the components of the P-450
      system and concentration of apo-P-450 2E1 to 80-90% after 1-hr reperfusion. It
      was suggested that the prolonged preservation caused deterioration of the P-450
      system and the loss of the abilities of metabolism and detoxication of
      xenobiotics.

PMID- 8656610
TI  - The effect of lovastatin on [3H]thymidine uptake in HTC-4 and LLC-L1 tumor cells.
AB  - Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been
      shown to inhibit the in vitro and in vivo growth of a number of different cell
      lines. However, the mechanism by which lovastatin exerts its effect is not clear.
      In this experiment, we investigated the effect of lovastatin on the incorporation
      of [3H]thymidine by Hepatoma Tissue Culture-4 (HTC-4) and Lewis Lung Carcinoma L
      1 (LLC-L1) tumor cells. Tumor cells were grown under standard conditions and
      treated with four different concentrations of lovastatin. Cell growth was
      evaluated by daily hemacytometer cell counts. On Day 4, the plates were pulsed
      with 10 microCi [3H]thymidine. After 24 hr, the plates were harvested and
      [3H]thymidine incorporation was measured by scintillation counting. Lovastatin
      inhibited both HTC-4 and LLC-L1 cell growth in a dose-dependent manner. At the
      highest lovastatin dose, both LLC-L1 and HTC-4 cell growth was slowed to less
      than 15% of control. Remarkably, however, both cell lines showed a paradoxical,
      dose related, increase in [3H]thymidine uptake. Cell cycle analysis using flow
      cytometry was performed on Day 5 in the LLC-L1 cell line. As the lovastatin
      concentration increased, a lower percentage of cells was found in the G1 phase of
      the cell cycle and a higher percentage of cells was found in the S and G2 phases.
      These findings suggest that these tumor cells are undergoing brisk DNA repair or
      that lovastatin is more effectively blocking cell division than cellular DNA
      replication.

PMID- 8656611
TI  - Ischemic injury of the small intestine studied by 31P-MRS.
AB  - In order to examine the efficacy of phosphorus-31 nuclear magnetic resonance
      spectroscopy (31P-MRS) of the small intestine during superior mesenteric artery
      occlusion (SMAO) and reperfusion, we compared the beta-ATP level measured by in
      vivo 31P-MRS and the ATP level measured by high performance liquid chromatography
      (HPLC) in a rat model. The rat small intestines were subjected to 30 or 90 min of
      SMAO followed by reperfusion. 31P-nuclear magnetic resonance spectra were taken
      every 10 min during SMAO and subsequent reperfusion. Specimens for HPLC were
      taken every 30 min. Metabolite levels measured by 31P-MRS and HPLC demonstrated a
      linear correlation. This result shows that 31P-MRS can determine the ATP content
      of the small intestine as well as HPLC. Additionally, the changes of beta-ATP,
      inorganic phosphate (Pi) and tissue pH in the small intestine during SMAO and
      reperfusion were examined by 31P-MRS in detail. beta-ATP decreased with longer
      SMAO times, and the recovery rate of beta-ATP after reperfusion also decreased
      with longer SMAO times. Therefore, the ATP level measured by 31P-MRS may provide
      a clinical parameter of tissue damage and organ viability. The levels of Pi and
      tissue pH changed greatly, but reached a plateau in the early phase of SMAO.
      Their levels after reperfusion reflected the time of SMAO, and therefore may also
      provide a clinical parameter of organ viability.

PMID- 8656612
TI  - Small intestinal function following syngeneic transplantation in the rat.
AB  - Improvements in immunosuppression have led to the use of small intestinal
      transplantation clinically. Previous studies have suggested that the
      transplantation process and immunosuppression with cyclosporin independently
      affect small intestinal function. This study describes the effects of syngeneic
      small intestinal transplantation and cyclosporine in rats on intestinal
      permeability and nutrient transport. Orthotopic transplantation of the small
      intestine was performed between syngeneic (Lewis) rats. Transplanted animals
      received chronic treatment with cyclosporine (10 mg/kg) or vehicle on alternate
      days. Sham operated controls received treatment with vehicle. Animals were
      followed for 60 days monitoring weight gain, feed intake, intestinal
      permeability, in vivo absorption of dietary fat and carbohydrate, and at
      sacrifice in vitro transmural flux of 3-O-methyl-D-glucose. Weight gain, feed
      intake, and absorption of fat and carbohydrate from the diet were not altered by
      intestinal transplantation alone; transplantation plus cyclosporine treatment
      caused a slight reduction in dietary fat absorption. Both the transplant and
      transplant plus cyclosporine groups demonstrated increased permeability to 51Cr
      EDTA and mannitol but not lactulose. Jejunal and ileal 3-O-methyl-D-glucose net
      transmural flux was decreased in both transplant and transplant plus cyclosporin
      groups. Intestinal transplantation and cyclosporin treatment reduce mucosal
      glucose transport and increase intestinal permeability. These altered transport
      characteristics could affect dietary choices and the selection of
      immunosuppressive drugs during clinical transplantation efforts, however, the
      overall impact on animal well-being was minimal, and support the continued study
      of intestinal transplantation for clinical application.

PMID- 8656613
TI  - Evaluation of functional recovery of regenerating rat liver after partial
      hepatectomy using 31P-NMR spectroscopy.
AB  - Using 31P-NMR spectroscopy, we studied the process of the functional recovery of
      the regenerating rat liver at 1-5 weeks after a 65% partial hepatectomy from the
      viewpoint of phosphate metabolism. Portal vein clamping (20 min) or fructose
      administration (250 mg/kg body weight) was performed to temporarily reduce
      adenosine triphosphate (ATP) content in the remnant liver. Changes in ATP level
      were observed for 60 min after declamping the portal vein or after fructose
      administration. Significant differences in the increased ATP levels after
      declamping the portal vein or after fructose administration were observed in each
      hepatectomized group. Until 3 weeks after hepatectomy, ATP levels during 60 min
      after declamping the portal vein or after fructose administration were
      significantly lower than those in the nonresected control rats. However, the
      increase in ATP in the 4-week group was almost identical to the increase in the
      control group throughout the 60 min. Remnant liver weight already returned to the
      nonresected control level 1 week after hepatectomy, and remained constant
      thereafter. On the other hand, the final ATP levels 60 min after declamping the
      portal vein or after fructose administration returned to the nonresected control
      level only after 4 weeks following hepatectomy. These results demonstrate that
      from the viewpoint of ATP synthesis, functional recovery of the regenerating
      liver to normal can be observed within 4 weeks after partial hepatectomy.

PMID- 8656614
TI  - In vivo metabolic response of glucose to dichloroacetate in humans.
AB  - Hyperglycemia is common in severely ill patients and is related principally to an
      increase in glucose production. Dichloroacetate (DCA), which is known to increase
      the rate of pyruvate oxidation, has been shown to lower plasma glucose
      concentrations in normal fasting subjects and in diabetics and thus may be
      efficacious in treating stress induced hyperglycemia. However, the mechanism by
      which DCA lowers the plasma glucose concentration in humans has not been
      elucidated. To examine the human in vivo metabolic alterations induced by DCA,
      six fasting volunteers were infused with 6,6-D2-glucose and indirect calorimetry
      was performed prior to and following DCA administration. Glucose, lactate, and
      alanine net balance across the leg were also quantitated. Following DCA
      administration, plasma glucose concentrations decreased by 9% due to a
      proportional decrease in the rate of glucose production (P < 0.05). DCA had no
      affect on glucose clearance or leg net balance; however, the rate of glucose
      oxidation increased by 24% from baseline (P < 0.05). This increase in glucose
      oxidation without a compensatory change in peripheral glucose consumption
      suggests an improved efficiency in peripheral glucose utilization induced by DCA.
      Plasma concentrations of lactate and alanine were also lowered by DCA (56% for
      lactate, 66% for alanine, P < 0.05) without a significant alteration in leg net
      balance. These results suggest that DCA may decrease gluconeogenesis by limiting
      the availability of the precursor substrates lactate and alanine. Thus
      dichloroacetate may be an appropriate alternative to insulin in correcting mild
      elevations in plasma glucose concentrations. Furthermore, DCA may be especially
      effective in severely ill patients where hyperglycemia is largely due to
      increases in gluconeogenesis.

PMID- 8656616
TI  - Endoluminal aortic grafting: a preliminary animal study of graft-healing.
AB  - Our purpose was to evaluate the placement, long term performance, and healing of
      a transluminally delivered endoluminal graft and attachment system, in an animal
      model using large adult sheep. Nineteen sheep in the weight range of 105-125 kg
      were entered into this study. Under fluoroscopic guidance in anesthetized
      animals, an endoluminal delivery system was inserted through a common femoral
      arteriotomy into the infrarenal aorta, and the graft and attachment system were
      deployed. Fixation of the proximal and distal ends of the graft to the aortic
      wall was achieved by hooks on the self expanding attachment system, and seated by
      balloon expansion. Explantation of the prosthesis was performed prior to
      euthanasia at 1-, 3-, and 6-month intervals. Aortograms were obtained before and
      after implantation and before explantation for evaluation of placement, patency,
      anastomotic seal, migration, and graft infolding. In situ gross examination of
      the prosthesis under anesthesia prior to sacrifice was performed in all animals.
      Histologic sections were obtained from both attachment sites ("anastomoses"),
      from the midgraft and hook insertion sites, and from normal aorta inferior and
      superior to the endoluminal prosthesis. Scanning electron microscopy was
      performed randomly on specimens derived from the superior and inferior
      anastomotic sites at each time point. Selected intervals of healing were 1 month
      (N=5), 3 months (N=5), and 6 months (N=8). One sheep was euthanized at 1 week due
      to paraplegia. At all intervals, all prostheses were patent, were well
      incorporated at the aortic wall-anastomotic sites, and were without mural
      thrombus. The attachment hooks penetrated the aortic adventitia in all animals.
      There was no graft migration. At one month, initial pannus formation covered the
      anastomoses and the entire luminal graft, yet the endothelial-like surface
      coverage was incomplete. At 3 months and at 6 months, the anastomoses and luminal
      surfaces displayed more uniform pannus and endothelial-like surface coverage. We
      conclude that this endoluminal delivery system, passed through a femoral
      arteriotomy, can effectively deploy an endoluminal graft with self expanding
      attachment system having consistent patency, secure fixation, and incorporation
      of the anastomoses with the aortic wall in this animal model.

PMID- 8656615
TI  - Gastric injury and protection against alcohol and acid: influence of
      perturbations in glutathione metabolism.
AB  - This study assessed the role that inhibition of glutathione (GSH) synthesis and
      decreased GSH peroxidase (GPX) activity in the rat played in modulating gastric
      injury induced by ethanol and acid and its prevention by 16,16-dimethyl PGE2
      (dmPGE2) and the mild irritant, 25% ethanol. Although numerous studies have
      proposed that GSH may be important in maintaining gastric mucosal defense, the
      exact role of this antioxidant in protecting the stomach from injury remains
      undefined. The present study addressed this consideration by blocking the
      synthesis of GSH and altering the major pathway by which it exhibits its
      antioxidant activity and determining the effect of these perturbations on gastric
      injury and protection. Four to six rats were used for each experimental group.
      GSH synthesis was blocked by the potent and specific inhibitor L-buthionine
      sulfoximine (BSO), 2 or 6 mmole/kg intraperitoneally. The activity of the major
      form of GPX, which is selenium dependent and utilizes GSH as a substrate to
      detoxify hydrogen peroxide and other hydroperoxides, was inhibited by placing
      animals on a selenium-deficient diet for 6 weeks. Gastric damage was induced by
      100% ethanol, 50% ethanol in 150 mM HCl, and 0.75 M HCl. Prevention of such
      injury was accomplished with oral pretreatment using 25% ethanol or dmPGE2 (5
      microgram/kg). The damaging effects of 100% ethanol, 50% ethanol/150 mM HCl, or
      0.75% M HCl were not adversely affected by BSO pretreatment even though GSH
      synthesis was inhibited by as much as 80%. Similarly, inhibition of GPX activity
      by 58% in adult rats and 98% in weanling rats failed to potentiate the damaging
      effect of 100% ethanol. Furthermore, with both perturbations in GSH metabolism,
      the protective action of dmPGE2 and 25% ethanol was maintained. Our results
      indicate that profound alterations in gastric GSH metabolism by themselves do not
      aggrevate the injurious effects of ethanol or acid, nor do they prevent the
      protective action of a prostaglandin or mild irritant.

PMID- 8656617
TI  - Effect of histologic preparation on the cross-sectional area of arterial rings.
AB  - Histometric studies are useful for correlating mechanical properties of tissues
      with morphological characteristics. However, fixation and embedding can cause
      volume changes and may cause tissue distortion. This study examined 24 rings of
      unpressurized arteries fixed with formalin, glutaraldehyde, or McDowell's
      solution and then embedded in paraffin or glycol methacrylate. A ring of each
      artery was also studied in the fresh state. The tissues were projected at 22X
      magnification and cross-sectional areas were measured. The dimensions of the
      fixed rings were compared with that of the fresh tissue. Results showed that
      embedding with paraffin produced 19-25% shrinkage with all three fixatives,
      whereas embedding with glycol methacrylate produced 4 to 13% volume expansion
      with the three fixatives. The least volume expansion occurred with McDowell's
      solution fixation (4%) and glutaraldehyde fixation (8%). These findings suggest
      that, when performing histometric studies, one should consider using glycol
      methacrylate for embedding in order to cause the least volume change.

PMID- 8656618
TI  - Neural isolation of the jejunoileum. Effect on tissue morphometry, mucosal
      disaccharidase activity, and tissue peptide content.
AB  - The aim of this study was to determine the effects of a model of intestinal
      extrinsic denervation on mucosal structure and function. Six dogs underwent in
      situ neural isolation of the jejunoileum (Group 2); six other dogs served as
      operated controls (Group 1), and five nonoperated dogs were naive controls (Group
      3). Thirty-centimeter segments of proximal jejunum and distal ileum were excised
      before (time zero) and at 2 weeks and 8 weeks postoperatively in Groups 1 and 2,
      while similar regions were removed at time zero in Group 3. Tissues were analyzed
      for morphology with quantitative morphometry, mucosal disaccharidase activities
      (sucrase, maltase, and lactase), and tissue content of selected regulatory
      peptides in transmural, mucosa/submucosa, and muscularis regions. In situ neural
      isolation had no significant or consistent effects on morphology/morphometry or
      on mucosal disaccharidase activities. Tissue content of neuropeptide Y decreased
      markedly (P < 0.002) in all layers of the jejunal and ileal walls, but tissue
      content of vasoactive inhibitory polypeptide, substance P, cholecystokinin,
      neurotensin, met-enkephalin, neurokinin A, somatostatin, and calcitonin gene
      related peptide demonstrated only minor changes. The physiologic effects of
      intestinal transplantation (extrinsic denervation and disruption of intrinsic,
      enteric neural continuity, and lymphatic drainage) have little effect on
      morphology, mucosal disaccharidase activity, and tissue content of most
      regulatory peptides. How these minor alterations might affect enteric function,
      however, needs to be investigated.

PMID- 8656619
TI  - Production of extracellular virulence factors by Pseudomonas aeruginosa isolates
      obtained from tracheal, urinary tract, and wound infections.
AB  - This study was conducted to determine the effect of the local environment within
      the host on the ability of P. aeruginosa to produce different extracellular
      virulence factors (elastase, phospholipase C, toxin A, and exoenzyme S). A total
      of 105 P. aeruginosa isolates was obtained from patients with tracheal, urinary
      tract, and wound infections. Quantitative analysis of the virulence factors was
      done by growing the isolates in vitro in different defined media. Single colonies
      of each isolate were inoculated from the primary isolation plates into the
      defined medium. All four virulence factors were produced by most isolates.
      However, depending on the location of their isolation, the isolates varied in the
      level of virulence factors they produced. High levels of elastase and
      phospholipase C were produced by most isolates obtained from trachea, urinary
      tract, and wounds. A significantly higher level of toxin A was produced by wound
      isolates, while a significantly higher level of exoenzyme S was produced by wound
      and urinary tract isolates. Some P. aeruginosa strains were frequently isolated
      from the same site of infection (persistent infection isolates). Comparative
      analysis of virulence factors produced by these isolates showed that, regardless
      of the isolation site, subsequent isolates produced higher levels of exoenzyme S.
      These results suggest that: (1) elastase, phospholipase C, toxin A, and exoenzyme
      S are produced by P. aeruginosa isolates from different sites of infection; (2)
      the production of higher levels of elastase and phospholipase C is important in
      all types of infections, while the production of toxin A and exoenzyme S is
      important in wound infection; (3) persistent infection with P.aeruginosa may
      enhance exoenzyme S production.

PMID- 8656620
TI  - Infectious sequelae in the use of polyglycolic acid mesh for splenic salvage with
      intraperitoneal contamination.
AB  - Salvage of the injured spleen is important in the trauma patient. Loss of the
      spleen can result in both early and late infectious complications due to
      immunologic and phagocytic deficits. Splenic salvage techniques include the use
      of polyglycolic acid (PGA) mesh to wrap and tamponade the damaged and bleeding
      spleen. However, the use of mesh may increase the incidence of infection in the
      presence of intraperitoneal contamination. We examined whether mesh in the
      contaminated field increases the infection rate compared to splenectomy in a
      murine model. Sixty male Sprague-Dawley rats were divided into three groups of 20
      each: splenectomy, splenic wrap with PGA, and control (with splenic
      mobilization). All rats were subjected to a standard inoculum of enteric bacteria
      at the time of celiotomy. Sixteen (80%) of the splenectomy rats, 10 (50%) of the
      PGA mesh wrapped rats, and four (20%) of the control rats expired (P < 0.5). In
      surviving rats, necropsy at 7 days demonstrated abscess formation in all four
      (100%) of splenectomy, four of 10 (40%) in PGA mesh wrapped, and two of 16 (13%)
      of control rats. All of the abscesses in the wrap group involved the mesh.
      Overall infection rates (including fatal peritonitis, abscess formation, and
      empyema) were 100% for splenectomy, 75% for PGA mesh wrapped, and 30% for control
      rats (P < 0.05). We conclude in this experimental model that the use of PGA mesh
      wrap does increase susceptibility to infection, but much less so than splenectomy
      in the presence of intraperitoneal contamination.

PMID- 8656621
TI  - Postprandial responses of liver blood flow prior to and following hepatectomy in
      conscious dogs.
AB  - The responses of the portal and hepatic arterial blood flows to various diets and
      nutrients were measured simultaneously in conscious dogs prior to and following
      hepatic resection. Prior to hepatectomy, the increase in the portal blood flow
      was significantly larger in response to an elemental diet, fats, or amino acids
      than to glucose or water. The peak increase was 60.2 +/- 14.4 ml for water, 144.7
      +/- 22.1 ml for a 150-cal elemental diet, 168.5 +/- 16.1 ml for a 300-cal
      elemental diet, 86.7 +/- 14.0 ml for a glucose solution, 159.3 +/- 16.7 ml for an
      amino acid meal, and 188.5 +/- 25.3 ml for a fat meal. Following partial
      hepatectomy, fats and amino acids induced an increase in the portal blood flow
      similar to that prior to hepatectomy. Glucose and the elemental diet, on the
      other hand, induced a significantly larger increase in portal blood flow
      following the surgery although water did not. The peak increase was 144.4 +/-
      27.8 ml for glucose (166% of the peak increase prior to hepatectomy) and 221.8 +/
      32.5 ml for the 300-cal elemental diet (132%). The postprandial response of the
      hepatic artery to every diet was quite different among the dogs and there were no
      significant changes both prior to and following surgery. The different response
      of the portal flow to intraluminal glucose following partial hepatectomy may be
      due to alterations in glucose metabolism following hepatectomy. We have shown
      that the postprandial response of the portal blood flow varies with the type of
      nutrient, and it can be altered by hepatectomy.

PMID- 8656622
TI  - Pulmonary vascular smooth muscle relaxation by cAMP-mediated pathways.
AB  - Adenosine 3',5'-cyclic monophosphate (cAMP)-mediated pulmonary vascular smooth
      relaxation is a principle mechanism of pulmonary vasomotor control. The purpose
      of this study was to compare the potency and efficacy of the following receptor
      linked pathways of pulmonary vasorelaxation which are mediated by cAMP: (1) beta2
      adrenergic receptor activation (response to isoproterenol) (2) Adenosine A2
      receptor activation (response to adenosine) (3) Prostaglandin EP2-receptor
      activation (response to prostaglandin E1) (4) Histamine H2-receptor activation
      (response to the H2-receptor agonist dimaprit) and (5) Purinergic P2-receptor
      activation (response to ADP). Cumulative concentration-response curves were
      generated in isolated rat pulmonary artery rings suspended on individual
      tensiometers. Five rats/ten pulmonary artery rings were studied for each agonist.
      Relaxation by beta2-adrenergic receptor activation was most effective as complete
      ring relaxation was achieved at 10(-6) M isoproterenol with a median effective
      dose of 10(-7) M. A2, P2, and EP2-receptor activation all achieved complete ring
      relaxation at concentrations up to 10(-3) M. Relaxation by H2-receptor activation
      was least effective as 30% ring tension remained at a concentration of 10(-3) M.
      We conclude that these receptor-linked pathways, although all mediated through
      cAMP, have significant differences in potency and efficacy.

PMID- 8656623
TI  - Effect of octreotide on pancreatic endocrine function in partial pancreatectomy.
AB  - Octreotide acetate (Sandostatin), a long-acting somatostatin analogue, has been
      demonstrated to inhibit pancreatic exocrine secretion. The effect of octreotide
      acetate on pancreatic endocrine function in patients undergoing pancreas surgery
      or pancreas transplantation has not been as well described, nor have the clinical
      implications been studied as systematically. This study was designed to
      investigate the effects of octreotide acetate on glucose metabolism and endocrine
      function in a partial pancreatectomized canine model, simulating reduced islet
      cell reserve. Serum levels of glucose, insulin, and glucagon were determined at
      intervals over 2 hr following an intravenous glucose tolerance test (0.5 g/kg
      intravenous bolus of 50% glucose) in: normal animals (Group A, n = 5), normal
      animals pretreated with an intravenous bolus of 400 micrograms of octreotide
      acetate (Group B, n = 5), partial pancreatectomized animals (Group C, n = 5), and
      partial pancreatectomized animals pretreated with an intravenous bolus of 400
      micrograms of octreotide acetate (Group D, n = 5). Peak glucose concentration was
      significantly increased in Group D when compared to Group C (Group C = 304.2 +/-
      13.5 mg/dl vs Group D = 353.2 +/- 12.9 mg/dl, P < 0.05), indicating an impairment
      of glucose metabolism by octreotide. In addition, octreotide significantly
      decreased peak insulin release in the partial pancreatectomy groups (Group C =
      129 +/- 12.9 micro U/ml vs Group D = 47.5 +/- 6.8 micro U/ml, P < 0.05). There
      were no significant differences in the rate of glucose utilization or glucagon
      concentrations among the groups. These results demonstrate that octreotide does
      result in insulin suppression, with a resultant increase in stimulated glucose
      concentrations, in a canine model of reduced islet cell mass. Further studies are
      required to determine the mechanism of action of octreotide on endocrine function
      in the setting of pancreas transplant.

PMID- 8656624
TI  - Doxorubicin-induced disturbance of the energy metabolism after hepatectomy.
AB  - This study was designed to clarify effects of gamma-glutamylcysteine ethyl ester,
      a prodrug of glutathione, on doxorubicin-induced changes in liver energy
      metabolism after hepatectomy. Rats were divided into two major groups dependent
      on whether hepatectomy had been performed. Rats undergoing hepatectomy were
      subdivided into three groups: the control group, 70% of the liver was resected;
      the doxorubicin group, after hepatectomy 2 mg/kg body weight doxorubicin was
      administered intraperitoneally; and the doxorubicin + gamma-glutamylcysteine
      group, 30 min before hepatectomy 50 mg/kg body weight of gamma-glutamylcysteine
      ethyl ester was injected intravenously and other procedures were performed as in
      the doxorubicin group. In the group not undergoing hepatectomy, 2 mg/kg body
      weight doxorubicin was administered intraperitoneally after a sham operation.
      Rats in each group were sacrificed 24, 72, and 120 hr after hepatectomy or sham
      operation, and the remnant liver was isolated. Liver mitochondrial function,
      adenine nucleotide concentrations, and glutathione and glutathione peroxidase
      activities were determined. Doxorubicin did not show any significant effects on
      parameters measured in rats not undergoing hepatectomy. Liver mitochondrial
      function was increased significantly 24 hr after hepatectomy, and significant
      decreases in adenine nucleotide concentrations were observed 24 and 72 hr after
      hepatectomy. Doxorubicin inhibited the increase in mitochondrial function
      associated with hepatectomy and delayed recovery of liver adenine nucleotide
      concentrations. Significant increases in tissue glutathione concentrations were
      observed 24 and 72 hr after hepatectomy. These significant increases in
      glutathione concentrations were not observed in rats treated with doxorubicin 72
      hr after hepatectomy. Furthermore, doxorubicin decreased glutathione peroxidase
      activity after hepatectomy. Administration of gamma-glutamylcysteine ethyl ester
      lessened these doxorubicin-induced changes. These results indicate that changes
      in the glutathione redox system might be involved in the doxorubicin-induced
      deterioration of the remnant liver energy metabolism. Clinical application of
      gamma-glutamylcysteine ethyl ester might be expected.

PMID- 8656625
TI  - Hypoxia/reoxygenation of human endothelium activates PMNs to detach endothelial
      cells via a PAF mechanism.
AB  - Our previous in vivo studies have implicated phospholipase A2 activation and
      platelet-activating factor (PAF) production as an important mediator of
      neutrophil (PMN) priming after mesenteric ischemia/reperfusion. Furthermore, our
      in vitro studies demonstrate that PAF priming of PMN enhances PMN respiratory
      burst and increases PMN adherence to human umbilical vein endothelial cell
      cultures (HUVEC). Others have shown that cytokine stimulated HUVEC can activate
      quiescent PMNs to provoke endothelial cell (EC) monolayer disruption via EC
      detachment by a noncytolytic PMN protease mechanism. Hypoxia and reoxygenation
      (H/R) of HUVEC can also directly stimulate PAF production. Consequently, we
      hypothesized that HUVEC H/R can activate quiescent PMNs to disrupt the EC
      monolayer (detachment) through a PAF mediated mechanism. HUVEC were labeled with
      51 chromium (51Cr) and subjected to 45 min hypoxia (95% N2/5% CO2). PMNs freshly
      isolated by Percoll gradient centrifugation were added to HUVEC and reoxygenated
      for 120 min. Additionally, H/R HUVEC with PMN pretreated with WEB2170 (a PAF
      receptor antagonist) was compared to control (non-H/R HUVEC incubated with PMNs).
      Wells were washed at end incubation, and adherent ECs counted. Detachment =
      [total counts - sample counts]/total counts X 100. H/R HUVEC plus PMN provoked a
      29.3 +/- 1.6% detachment of EC compared to 9.3 +/- 2.9% detachment in control
      (non-H/R HUVEC with PMNs). In contrast, H/R HUVEC with PMNs preincubated with
      WEB2170 had 9.9 +/- 3.8% detachment of EC. In summary, HUVEC H/R activated
      quiescent PMNs to disrupt an EC monolayer (detachment) via a PAF mechanism.

PMID- 8656626
TI  - Inhibition of NO synthase prevents acute collateral artery dilation in the rat
      hindlimb.
AB  - The role of endothelium-derived nitric oxide (EDNO) in the initial opening and
      sustained dilation of collateral vessels in the peripheral circulation was
      investigated. Abrupt arterial occlusion was produced by clamping the rat
      superficial femoral artery (SFA). Arterial pressures were measured proximal (MAP)
      and distal (PD) to the occlusion site. In one group (INITIAL DILATION), the clamp
      was removed after PD reached a plateau, and then the nitric oxide synthase
      inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), was administered and
      the occlusion repeated in the same limb to evaluate the role of nitric oxide in
      the initial opening of collateral vessels. In another group (SUSTAINED DILATION),
      L-NAME was administered after acute compensation to SFA occlusion had occurred to
      determine if inhibition of nitric oxide synthase would reverse any acute
      compensation. Collateral dilation was evaluated by recovery in PD relative to MAP
      (PD-%MAP) and by the percent of total resistance in the collateral-dependent
      circuit due primarily to collaterals (%Rc). The acute compensation indicated by
      an increase in PD-%MAP (14 +/- 1.9% to 27 +/- 2.6%) and decrease in %Rc (86 +/-
      1.9 to 73 +/- 2.6%) in the INITIAL DILATION group was prevented by L-NAME (P <
      0.0005). L-NAME also reversed the compensation in the SUSTAINED DILATION group;
      PD-%MAP decreased from 28 +/- 2.3% to 11 +/- 1.9% and %Rc increased from 72 +/-
      2.3% to 93 +/- 1.1% after administration of L-NAME. Although collateral flow was
      not measured, the results are consistent with the hypothesis that acute
      collateral dilation is mediated by increases in flow or shear stress which
      stimulate the release of EDNO.

PMID- 8656627
TI  - Mechanism of protection of verapamil by preventing neutrophil infiltration in the
      ischemic rat kidney.
AB  - In this study, we tested if the mechanism of protection of a calcium channel
      blocker, Verapamil (VER), was due to modulation of neutrophil infiltration after
      ischemia/reperfusion injury, in a rat renal ischemic model. Forty-four Sprague
      Dawley rats were subjected to 75 min of warm ischemia and immediate contralateral
      nephrectomy. The animals were divided into two groups: the ischemic control (IC)
      group, which received normal saline, and the experimental group that received VER
      1.25 mg/kg. The drug was administrated intravenously after ligation of the renal
      pedicle, before reperfusion. Survival was followed for 7 days. Laboratory tests
      included renal function tests, with serum creatinine (SCr) and blood urea
      nitrogen (BUN), light histology and neutrophil infiltration, measured by the
      myeloperoxidase test in renal tissue. Better survival rate was observed in the
      VER group (85% at 7 days vs control 50%) (P = 0.08). SCr and BUN at 48 and 72 hr
      showed a statistical significant difference between the two groups (VER lower
      than IC P < 0.05). Histological damage was significantly less in the VER group (P
      < 0.05). Neutrophil infiltration was significantly decreased in the VER group
      when compared to the IC group (P < 0.05). We concluded then, that VER had a
      downregulating effect on neutrophil infiltration and this might be an important
      mechanism of protection during the development of renal ischemic damage.

PMID- 8656628
TI  - Effects of hyaluronic acid on fibroblast behavior in peritoneal injury.
AB  - The process of intraperitoneal adhesion formation is affected by macrophages and
      fibroblasts which are major components of postsurgical peritoneal repair.
      Hyaluronic acid (HA) has been shown to affect cellular behavior. We studied the
      effects of HA on experimental adhesions in vivo and its in vitro effect on
      cultured postsurgical macrophages and fibroblasts. Experimental adhesions were
      facilitated by laparotomy and localized peritoneal controlled trauma in two
      groups of rats (A, B). Postoperatively, group A received intraperitoneal (ip)
      treatment by HA (1 mg/kg) for 7 days, and group B, ip saline. The rats were then
      reoperated upon, and adhesions scored. In vitro studies were performed on
      postsurgical macrophages and fibroblasts. Fibroblasts were obtained using a
      single-cell suspension technique by debridement of adhesions. The fibroblasts
      were cultured for 7 days, and their metabolic activity was assessed by the uptake
      of [3H]thymidine. Postoperative macrophages were obtained from the peritoneal
      fluid of the rats operated on, and their effect upon fibroblast [3H]thymidine
      uptake was studied in mixed cultures. The adhesion score of the HA-treated rats
      was smaller than the score of the saline-treated group. This observation suggests
      that ip treatment by HA may decrease adhesion formation in this rat model.
      [3H]Thymidine uptake by cultured postsurgical fibroblasts was significantly lower
      in the HA-treated group compared to that of controls. In vitro addition of HA to
      cultured "saline fibroblast" resulted in a significant decrease in [3H]thymidine
      uptake, suggesting a direct effect of HA on postsurgical fibroblast metabolism.
      However, [3H]thymidine uptake by fibroblasts in mixed cultures with macrophages
      obtained from HA-treated rats was significantly increased. These observations
      suggest that HA may affect the process of peritoneal healing by direct effect on
      fibroblast metabolic activity, and indirectly via modification of the macrophage
      fibroblast interrelationship.

PMID- 8656630
TI  - The microvascular structure of the normal colon in rats and humans.
AB  - The colonic microcirculation may be expected to have a central role in the
      absorptive, secretory, and protective functions of the colon. To characterize the
      microvascular structure of the colon in rats and humans, microvascular casts were
      prepared and examined by scanning electron microscopy. Quantitative measures of
      the microvasculature were obtained from histological sections. The overall
      organization of microvessels was found to be similar in the rat and human colon.
      Capillaries in the colonic mucosa formed a honeycomb-like network around each of
      the mucosal glands. This capillary plexus was supplied by arterioles which divide
      into their capillary branches at the level of the submucosa. Mucosal capillaries
      drain into venules at the luminal surface of the mucosa. Venules then pass to
      submucosal veins without receiving further capillary branches. Examination of
      vascular casts also showed that in both the rat and the human colon, there was an
      increased density of subluminal capillaries in the cecum and proximal colon
      compared to that of the rest of the colon. This was supported by quantitative
      measures which indicated a significantly greater microvascular surface area in
      the rat cecum (24.1 mm2/mm3) compared to that of the midcolon (19.8 mm2/mm3) (P =
      0.04) and the distal colon (19.1 mm2/mm3) (P = 0.03). Similarly in the human
      colon there was a significantly greater total microvascular volume in the
      proximal colon (13.4%) compared to that of the distal colon (7.7%) (P < 0.0005)
      and there was a significantly greater total microvascular surface area in the
      proximal colon (22.4 mm2/mm3) compared to that of the distal colon (17.5
      mm2/mm3)(P=0.032). This study details quantitative vascular data for the colon in
      rats and humans which has not previously been documented, despite its important
      role in the absorptive function of the colon and in many disease processes
      affecting the colon. These data provide the normal values with which pathological
      conditions of the colon which affect the vasculature can be compared.

PMID- 8656629
TI  - The endothelium-dependent response of human hepatic artery after preservation
      with the UW solution.
AB  - The University of Wisconsin's (UW) solution has been used commonly for current
      liver transplantation. However, its effect on the vascular endothelium remains
      unclear. Experiments were designed to study the effects. Human hepatic arteries
      harvested from patients with hepatocellular carcinoma undergoing liver resection
      were preserved in 4 degree C physiological solution (group 1, the content showed
      on the text) and UW solution (group 2) for 1 hr. Segments of preserved and
      control (group 3) hepatic arteries were suspended in organ chamber to measure the
      isometric force. The relaxations to acetylcholine (ACH) and adenosine diphosphate
      in segments of hepatic artery with endothelium were significantly greater than
      those segments without endothelium. The maximal relaxation to ACH in arterial
      segments with endothelium of group 2 was significantly different from those of
      group 1 and 3 (group 1 to group 3, 82 +/- 2%, 57 +/- 6%, and 83 +/- 4% of the
      initial tension contracted by neoepinephrine (3 X 10-7 mole/l, P < 0.05). The
      maximal relaxation to adenosine diphosphate was similar to the response to ACH.
      Perfusate hypoxia (oxygen tension 30 +/- 5 mmHG) caused endothelium-dependent
      contraction of the arterial segments (group 1 to group 3, 233 +/- 32%, 276 +/-
      35%, and 251 +/- 40% of the initial tension, P < 0.05). Endothelium-independent
      relaxation and contraction of human hepatic artery to sodium nitroprusside and
      norepinephrine were not altered by UW solution. In summary, the impaired
      endothelium-dependent relaxation by UW solution and prominent endothelium
      dependent contraction to hypoxia of human hepatic artery would favor vasospasm
      and thrombus formation after liver transplantation.

PMID- 8656631
TI  - Hepatic morphonuclear alterations following portacaval shunt in the rat.
AB  - Portacaval shunt (PCS) induced major biochemical alterations to rat liver. We
      characterized the chromatin status in the rat hepatocyte at various times after
      this surgical procedure. The samples studied were from histological imprint
      smears of liver tissue. Nuclear assessments were computed on Feulgen-stained
      nuclei by means of a cell-image processor. We described the distribution values
      of the ploidy, of the percentage of diploid and tetraploid cells per case, of the
      size of nuclei, and of the chromatin pattern. At the 18th hr post-PCS we observed
      a complete inversion in the ratio of diploid and tetraploid cells. The size of
      nuclei increased after PCS and returned progressively to normal values at the
      72nd hr post-PCS. The chromatin pattern revealed a mirror image between the small
      and large dense chromatin clumps (SRL and LRL parameters). Twenty-four hours
      postsurgery, we observed the minimum value for SRL together with the maximum
      value for LRL, and these two parameters remained to the normal values within 72
      hr post-PCS. Our results show that chromatin organization level is changed during
      portacaval shunt. They also suggest that the value of SRL and LRL parameters are
      important in the description of normal or neoplasic cells.

PMID- 8656632
TI  - Impairment of the brain beta-adrenergic system during experimental endotoxemia.
AB  - Brain dysfunction is observed clinically in patients suffering from prolonged
      endotoxic shock. However, the etiology of brain dysfunction during sepsis is not
      clear. Certain researchers have reported that the decrease in brain
      catecholamines concentration during septic shock might be etiologically important
      in brain dysfunction. Therefore, we hypothesized that the beta-adrenergic
      receptor system undergoes a change during septic shock, and plays a role in the
      pathogenesis of septic encephalopathy. In this study, we examined two models of
      septic shock in rats, each of which has a different time course for the shock
      state. Male Wistar rats were divided into four groups: (1) Control--0.9% saline
      vehicle, (2) Lipopolysaccharide (LPS) i.v.-- Escherichia coli endotoxin 1.0 mg/ml
      i.v. bolus, (3) Sham-operated, and (4) Cecal ligation and puncture (CLP) model.
      The rats were killed by decapitation at 3, 12, or 24 hr after the treatments, and
      the brains were removed and subdivided into three areas: the forebrain,
      cerebellum, and brain stem. In the LPS i.v. group, the brain tissue
      norepinephrine (NE) concentration had decreased in the forebrain and brain stem
      and the tissue epinephrine (E) concentration had decreased in the brain stem by 3
      hr after treatment. In the CLP group, the brain tissue NE concentration had
      decreased in the forebrain, cerebellum, and brain stem (P < 0.05), and the tissue
      E concentration had decreased in the forebrain and brain stem by 24 hr after
      treatment (P < 0.05). An alteration in beta-adrenergic receptor density in the
      forebrain was observed at 24 hr in the CLP group (control, 237.0 +/- 14.0
      fmole/mg protein; LPS i.v., 233.2 +/- 3.0 fmole/mg protein; sham-operated, 236.0
      +/- 3.0 fmole/mg protein; CLP, 177.0 +/- 4.2 fmole/mg protein). These alterations
      in transmitter concentrations and beta-adrenergic density in the forebrain may be
      an important factor in septic encephalopathy.

PMID- 8656633
TI  - Sequential changes of energy charge, lipoperoxide level, and DNA synthesis rate
      of the liver following biliary obstruction in rats.
AB  - To clarify the effects of obstructive jaundice on the liver, sequential changes
      of hepatic energy charge, the concentrations of adenine nucleotides and
      malondialdehyde, DNA synthesis rate, and histology of the liver were examined on
      the day before and Days 1, 2, 4, 7, and 14 after biliary obstruction in rats and
      compared with those of sham-operated controls. Foci of necrotic hepatocytes were
      present on Days 1 and 2 and mitoses of the hepatocytes were frequently observed
      with a peak on Day 2 in the jaundiced liver. Marked proliferation of bile
      ductules were subsequently observed on Days 7 and 14, resembling biliary
      cirrhosis. The DNA synthesis rate was significantly activated after bile duct
      obstruction with its peak on Day 2, more than nine times higher than the control
      value and returned to the control level on Day 14. Hepatic ATP concentration and
      energy charge gradually declined with prolonged jaundice and significantly lower
      levels persisted after Day 7 compared with the controls. The malondialdehyde
      level in the jaundiced liver gradually increased and became significantly higher
      on Day 14. We conclude that obstructive jaundice decreases hepatic energy charge
      and increases the lipoperoxide level. In the initial stage of obstructive
      jaundice, the hepatocytes proliferate associated with activated DNA synthesis
      probably to compensate hepatic damage; however, prolonged obstructive jaundice
      induces functional hepatic injury possibly necessitating biliary drainage.

PMID- 8656634
TI  - Effects of donor position on harvested lung quality.
AB  - Potential lung donors are frequently maintained in one position for prolonged
      periods of time prior to harvest. This study was designed to determine if the
      effects of gravity induced by maintaining an animal model in the supine position
      for 24 hr would have adverse effects on the harvested lung. Group 1 pigs were
      anesthetized, instrumented, mechanically ventilated, and the lungs harvested
      within 90 min. Group 2 pigs were anesthetized, instrumented, and mechanically
      ventilated in an identical manner then maintained in the same dorsal-spinal
      recumbency position for 24 hrs. Hemodynamic and respiratory parameters were
      stable and not statistically different between the two groups for the baseline
      and 1 hr time period measurements. There were no significant differences between
      the two groups for shunt fractions, wet/dry ratios, blood flow distribution, or
      flush solution distribution. We conclude that in anesthetized pigs there is no
      evidence that routine repositioning protocols improve blood flow distribution,
      shunting, or dependent edema.

PMID- 8656635
TI  - Differential effect of growth factors on intestinal wall components.
AB  - Both the mucosal and muscle layers respond to surgical manipulation of the small
      intestine. Various growth factors influence the mucosal response but less is
      known about changes in the muscle layers. Our aim was to evaluate the effect of
      epidermal growth factor (EGF) and octreotide (OCT) on changes in the intestinal
      wall induced by serosal patching. Twenty-four New Zealand white rabbits (3-4 kg)
      were studied. Group I (n=6) were unoperated controls. Group II (n=6) underwent
      creation of a 2 X 5-cm serosal patch in the ileum. Group III (n=6) and Group IV
      (n=6) received EGF (1.5 micrometer/kg/hr SQ) or OCT (1000 microgram/d SQ) after
      serosal patching. Wall composition, collagen content, and mucosal proliferation
      and enzyme activity of normal adjacent ileum were studied after 7 days. Serosal
      patching resulted in thickening of the mucosa and muscle layers (circular muscle:
      189 +/- 54 vs 86 +/- 33 microns longitudinal muscle: 105 +/- 17 vs 55 +/- 12
      microns P < 0.05) with increased proliferation and collagen content. EGF
      augmented the mucosal thickening (705 +/- 66 vs 573 +/- 94 microns, P < 0.05) and
      stimulated mucosal proliferation but inhibited the changes in muscle and collagen
      content. OCT inhibited the mucosal thickening and proliferation, but had less
      affect on the muscle. Disaccharidase activity was similar in all of the patched
      groups. We conclude the following. (1) Growth factors have differential effects
      on the intestinal wall components. (2) EGF stimulates the mucosa but has
      inhibitory effects on induced muscle changes. (3) Octreotide inhibits mucosal
      proliferation with less effect on muscle. (4) These observations have important
      implications for the therapeutic applications of these agents.

PMID- 8656636
TI  - Effect of endotoxemia on intestinal villus microcirculation in rats.
AB  - Intestinal mucosal hypoperfusion with subsequent ischemia during endotoxemia
      might cause a breakdown of the gut barrier with translocation of bacteria and
      their toxins into the systemic circulation, thus maintaining a "gut-derived"
      septic state. The aim of this study was to investigate the influence of endotoxin
      on the microcirculation of intestinal villi, which represent the most vulnerable
      part of the mucosa. The changes in blood flow and in the diameters of the central
      villus arterioles located in the distal ileum were monitored in control rats
      without lipopolysaccharide (LPS) exposure (n=7), and in rats receiving 1.5 mg/kg
      b.w. LPS (n=7) or 15 mg/kg b.w. LPS (n=7) over 60 min. The blood flow and the
      arteriolar diameters were determined using in vivo videomicroscopy at baseline,
      and 60 min and 120 min later. In control animals, no change in blood flow and
      arteriolar diameters were observed during the entire experiment. Administration
      of 1.5 mg/kg b.w. LPS reduced the blood flow to 69.5 +/- 9.0% of the baseline
      value at the end of the study period. This decrease in blood flow was associated
      with a decrease in the villus arteriolar diameters by 17.4 +/- 2.5% from the
      baseline values. In animals exposed to 15 mg/kg b.w. LPS, the decrease in villus
      blood flow at 60 min was 64.8 +/- 10.9% of baseline, and at 120 min 66.9 +/-
      12.6% of baseline. The diameters of the villus arterioles were reduced by 11.5 +/
      2.4% and 15.1 +/- 1.7%, respectively. In the control group and in the 1.5-mg/kg
      LPS group, the mean arterial blood pressure did not change during the entire
      study period. In the 15-mg/kg LPS group, the mean arterial pressure tended to
      decrease after 60 min. These data suggest a reduction of villus blood flow due to
      vasoconstriction in the central villus arterioles during normotensive endotoxmia,
      which might represent the mechanism for the mucosal ischemia observed in
      critically ill patients.

PMID- 8656637
TI  - Hepatotrophic effect of folinic acid in rats.
AB  - Hepatic ischemia hinders the proliferative response of hepatocytes, necessary to
      restore the liver/body ratio after liver resection/transplantation. Folinic acid
      administered during the ischemic period following 70% hepatectomy plus 15 min of
      normothermic liver ischemia has restored the regenerative response to the levels
      of normoperfused livers. This unexpected finding has guided us to design the
      present study in order to find out whether the folinic acid is an hepatotrophic
      substance or not. Sprague-Dawley rats submitted to partial (40 or 70%)
      hepatectomies were used. Saline (2 cc) or folinic acid (2.5 mg/kg) have been
      administered i.v. Forty-eight hours after hepatectomy the hepatocyte's DNA
      content has been assessed by means of a cytophotometric technique, and the
      percentage of regenerating hepatocytes (PRH) has been calculated. Folinic acid
      administration has significantly increased the PRH in both resting (5.1 vs 1.2)
      and regenerating livers (70% hepatectomy) (22.2 vs 41) when compared with
      nontreated groups. Folinic acid administration after liver ischemia plus
      hepatectomy has shown similar results, corroborating our previous study. Although
      its mechanisms of augmentation of liver regeneration remain unclear and further
      studies are required, folinic acid seems to be a promising therapeutic tool in
      liver surgery.

PMID- 8656638
TI  - Continuous measurement of porcine renal cortex microcirculation with enhanced
      thermal diffusion technology.
AB  - Continuous monitoring of renal cortical blood flow (RCBF) in the perioperative
      setting of aortic or renal vascular surgery could facilitate the early detection
      of vascular complications, possibly resulting in a reduction of postoperative
      renal failure. A new prototype system for measurement of parenchymous organ
      perfusion based on the principle of thermal diffusion ("TD"-Thermal Diffusion
      Electrode, Thermal Technologies Inc., Cambridge, MA, USA) was used for RCBF
      measurements in the outer cortex of the porcine kidney. We validated the
      sensitivity of the device to detect renal blood flow impairment, comparing TD
      flow data with renal artery blood flow values (RABF), measured by ultrasonic flow
      probes. The hypothesis was tested that acute disturbances of RCBF, induced by a
      variable degree of renal artery stenosis, can be immediately detected and
      continuously monitored by TD measurements in the porcine renal cortex. Mean
      baseline RCBF measured by TD electrodes was 68.1 +/- 25.0 ml/100 g/min. Mean
      baseline RABF was 102.1 +/- 26.6 ml/min. Controlled induction of a variable
      degree of renal arterial occlusion by implanted vascular balloon occluders was
      always followed by an immediate and proportional decline of RCBF, as measured by
      TD. Flow data obtained with both methods were significantly correlated by linear
      regression (r=.82, r2=.68; P < 0.0001). Dynamic changes of RABF in the time
      course of renal artery partial/total occlusion and arterial flow release could be
      continuously followed by detection of corresponding flow changes of RCBF. We
      conclude that the TD system investigated in the current study allows a continuous
      and sensitive determination of porcine renal cortex perfusion. A clinical
      evaluation of the method, e.g., in the perioperative setting of aortic or renal
      transplantation surgery, now appears to be justified.

PMID- 8656639
TI  - Effect of fentanyl citrate analgesia on glucose production following trauma in
      rats.
AB  - The postoperative hormonal milieu enhances glucose production. The objectives of
      this study were to determine whether fentanyl plus pentobarbital anesthesia
      reduced the excretion of stress hormones and whether this resulted in decreased
      glucose production following trauma. Male Sprague-Dawley rats were assigned into
      control and trauma. The trauma group was further subdivided into three groups
      according to the methods of anesthesia: T-1, pentobarbital (PB) alone; T-2,
      pentobarbital plus fentanyl (FE); and T-3, given PB during surgery and FE at the
      end of surgery. Glucose production was measured by a primed constant infusion of
      3-3H-glucose. Fentanyl plus pentobarbital anesthesia prevented an increase in
      corticosterone levels in the plasma compared with in T-1 and T-3, 0.5 hr after
      the surgery. Fentanyl plus pentobarbital, anesthesia caused reductions of insulin
      and glucagon levels in the plasma and a decrease in catecholamines excretion in
      the urine. Glucose production was lower with FE+PB anesthesia than with PB alone
      (PB: 4.6 +/- 0.1 mg/kg/min vs PB+FE: 3.6 +/- 0.2 mg/kg/min, P < 0.05). However,
      fentanyl given at the end of surgery did not alter hormonal milieu and glucose
      production compared with pentobarbital alone. Blocking afferent neural stimuli
      from the wound and injury during the surgery is one approach to prevent an
      enhancement of postoperative glucose production.

PMID- 8656640
TI  - Adhesion of activated platelets to venous endothelial cells is mediated via
      GPIIb/IIIa.
AB  - Normal circulating platelets do not adhere to intact, undisturbed endothelium.
      Studies have shown, however, that platelets will adhere to virally infected or
      thrombin-stimulated human umbilical vein endothelial cells. Using a novel
      platelet/endothelial cell adhesion assay we studied the interaction of thrombin
      activated platelets to human saphenous vein endothelial cells (HSVEC), and its
      mechanism(s). Biotinylated platelets were exposed to Hepes-Tyrode buffer, 10E5 or
      PAC-1 [monoclonal antibodies (Mabs) blocking GPIIb-IIIa], AK4 (Mab blocking P
      selectin, 6D1 (Mab blocking vWf binding to GPIb), RGDS (small peptide blocking
      the fibrinogen binding site), or EDTA (dissociates GPIIb-IIIa complex) and then
      activated with thrombin. The platelets were subsequently exposed to thrombin
      stimulated monolayer HSVEC. Phycoerythrin-streptavidin was added to the wells to
      fluorescently label the platelets, followed by formaldehyde fixation and washing
      to remove nonadherent platelets. Adhesion of platelets to HSVEC was assessed
      using a fluorescent multiwell plate reader. Antibodies which blocked the GPIIb
      IIIa receptor and agents which competitively bound the receptor all significantly
      inhibited activated platelet adhesion to the activated HSVEC. We have found that
      thrombin significantly increases platelet/HSVEC adhesion, and this event is
      mediated via the integrin GPIIb-IIIa (fibrinogen receptor). These GPIIb-IIIa
      receptor blocking Mabs and RGDS may be useful adjuncts for improving patency
      following angiographic intervention and/or vein grafting in patients with high
      risk of thrombosis. The assay we have developed is a valuable and relatively
      simple method for assessing platelet/endothelial cell adhesion and activation.

PMID- 8656641
TI  - Myocardial cell damage by fatty acid ethyl esters.
AB  - Fatty acid ethyl ester (FAEE), a myocardial metabolite of ethanol, causes
      mitochondrial dysfunction in vitro in rabbits. We investigated the effect of
      these esters on rat heart mitochondria in vitro and in vivo. In vitro studies
      were conducted to investigate the binding of ethyl oleate (FAEE) to mitochondria
      and their capacity to hydrolyze these FAEE. In vivo effects of ethyl esters were
      studied by the direct transfer of [3H]oleate into the myocardium. Mitochondria
      were prepared from the myocardium of injected rats, and the amount of [3H]oleate
      bound to them was determined. In another in vivo study, 50 microliters of 50
      microM cold oleic acid ethyl ester was injected into the rat myocardium and the
      histopathological changes induced by oleic acid ethyl ester were examined by
      light microscopy. Our results show that fatty acid ethyl ester can bind to
      myocardial mitochondria in vitro as well as in vivo and the mitochondria can
      hydrolyze FAEE to fatty acid, which is a known uncoupler of oxidative
      phosphorylation. Of the total ethyl [3H] oleate injected, 8 microM [3H]oleate and
      1 microM ethyl [3H]oleate was bound to the mitochondria. Significant myocardial
      cell damage was first observed on day 4 and markedly increased on day 30 after
      ethyl ester injection, with cells showing gross deformation and enlargement.
      However, no significant histopathological changes were observed in the myocardial
      tissue on day 2 after injection. Our results suggest that the FAEE may damage the
      myocardial cells as well as the mitochondria and may provide a metabolic link
      between ethanol abuse and myocardial dysfunction.

PMID- 8656642
TI  - Pharmacokinetics and pharmacodynamics of TP-9201, a gpIIbIIIa antagonist,
      administered in combination with recombinant tissue-type plasminogen activator,
      heparin, and aspirin in beagles.
AB  - The effect of heparin, aspirin, and recombinat tissue-type plasminogen activator
      (rt-PA) on TP-9201 pharmacokinetics and pharmacodynamics was investigated in
      beagles. Animals received TP-9201, an Arginine-Glycine-Aspartic acid (RGD)
      containing synthetic peptide glycoprotein (gp)IIbIIIa antagonist as a bolus of
      0.31 mg/kg, followed by a 4-h infusion of 0.5 mg/kg/h. rt-PA was administered as
      a modification of the weight-adjusted standard regimen. Heparin was administered
      as a bolus followed by an infusion producing a 1.5- to 2-fold increase in the
      activated prothromboplastin time (aPTT) above baseline values. Aspirin was
      administered orally, approximately 24 and 2 h before TP-9201. TP-9201 had a
      plasma clearance of 9.9 +/- 2 ml/min/kg and a volume of distribution that was
      larger than plasma volume. Administration of heparin and aspirin with TP-9201 did
      not affect the clearance of TP-9201, whereas rt-PA resulted in a faster clearance
      (p = 0.05). Whether the faster clearance is physiologic or a result of rt-PA
      interference in the TP-9201 assay is unclear. TP-9201 completely inhibited ADP
      mediated platelet aggregation. After discontinuation of TP-9201, recovery of
      platelet aggregation had a half life (t1/2) of 2-3 h and was complete < or = 24
      h. Coadministration of heparin did not interfere with TP-9201 pharmacodynamics,
      whereas aspirin and rt-PA slowed the recovery of platelet aggregation. The
      template bleeding time profile for the TP-9201-treated animals was similar to
      that of the aspirin-treated animals.

PMID- 8656643
TI  - Distribution of endothelin-1-receptor subtypes in rat portal vein.
AB  - Endothelin-1 (ET-1), a potent vasoactive peptide, was first isolated from
      cultured porcine endothelial cells. Subsequent studies revealed the existence of
      two additional related peptides, ET-2 and ET-3, and at least two distinct ET
      receptor subtypes, ETA (selective for ET-1) and ETB (nonselective for ET
      isopeptides). These isopeptides and receptors are widely distributed in many
      tissues and are involved in numerous biological responses. The aim of this study
      was to identify the eventual distribution of the two distinct endothelin-receptor
      subtypes in isolated endothelium-denuded rat portal vein rings (PVRs) and strips
      (PVSs). BQ-123 (0.6, 1, and 6 microM) and PD-145065 (0.06, 0.1, 0.6, and 6
      microM) were used to differentiate the subtypes because they are selective
      antagonists for ETA and nonselective antagonists for ETA-ETB receptors,
      respectively. To characterize the ET receptors further, sarafotoxin-S6c (a
      selective ETB-receptor agonist) and IRL-1038 (a selective ETB-receptor
      antagonist) were used. In PVRs, cumulative additions of ET-1 (0.1-100 nM) caused
      graded and slow contractions and potentiated spontaneous rhythmic contractions.
      The EC50 values and maximal response to 100 nM of ET-1 were 2.72 nM and 0.75 g,
      respectively (n = 7). PVSs showed ET-1 EC50 values very similar to those of PVRs,
      but Emax values to 100 nM of ET-1 were significantly lower (Emax = 0.33 g; n =
      7). Moreover, ET-1 clearly increased the amplitude and frequency of spontaneous
      contractions in both types of specimens, although these were greater in the PVSs.
      Thirty-minute incubation with the selective ETA-receptor antagonist BQ-123
      blunted ET-1-induced effects in PVS specimens but only weakly antagonized ET-1
      induced contractions in PVRs. In contrast, the nonselective ETA-ETB-receptor
      antagonist PD-145065 significantly shifted the ET-1 concentration-response curve
      to the right in PVRs and partially inhibited ET-1 effects in PVSs. Moreover,
      sarafotoxin-S6c (0.1-100 nM) contracted PVRs and PVSs in a similar manner to ET
      1; its effects were antagonized by IRL-1038 only at the PVR level. The
      differences observed in PVR and PVS specimens in response to agonists and
      antagonists of ET confirmed the great heterogeneity of endothelin-sarafotoxin
      receptors. In our experimental models, functionally ETB-like (or non-ETA)
      receptors seem mostly to mediate vasoconstriction.

PMID- 8656644
TI  - Comparative effects of type 1 angiotensin II-receptor blockade with angiotensin
      converting-enzyme inhibitor on left ventricular distensibility and collagen
      metabolism in spontaneously hypertensive rats.
AB  - We compared the cardiac effects of the selective angiotensin II type 1 (AT1)
      receptor blockade, FK-739, with an angiotensin-converting-enzyme (ACE) inhibitor,
      enalapril, on left ventricular (LV) distensibility and collagen metabolism in
      spontaneously hypertensive rats (SHRs). We treated 14-week-old SHRs with FK-739
      (30 mg/kg/day) or enalapril (10 mg/kg/day) for 6 weeks. Both FK-739 and enalapril
      induced a significant decrease in blood pressure (p < 0.001) and regression of LV
      hypertrophy (p < 0.001) compared with vehicle, with no differences between the
      treated groups. Furthermore, FK-739 caused a greater decrease in LV collagen
      content than did enalapril (FK-739-treated group, 3.06 +/- 0.11 mg/g; enalapril
      treated group, 3.47 +/- 0.05 mg/g; p = 0.015) with no change in collagen
      phenotypes. Hearts taken from rats treated with FK-739 also showed greater LV
      distensibility than those taken from enalapril-treated rats (FK-739-treated group
      vs. enalapril-treated group at > or = 15 mm Hg, p < 0.001). These results suggest
      that, compared with ACE inhibition, AT1-receptor blockade may have additional
      effects on LV distensibility and collagen metabolism in the regression of LV
      hypertrophy induced by pressure overload.

PMID- 8656645
TI  - Endothelin-1 partially inhibits ATP-sensitive K+ current in guinea pig
      ventricular cells.
AB  - To clarify the pathophysiological significance of endothelin (ET) in the ischemic
      myocardium, we examined the effect of endothelin-1 (ET-1) on the ATP-sensitive K+
      current (IK.ATP) and compared it with that of ET-3 in guinea pig ventricular
      cells using conventional microelectrode and patch clamp techniques. In isolated
      guinea pig papillary muscles, ET-1 (30 nM) markedly increased developed tension
      (DT), with little influence on action potential duration (APD), whereas ET-3 at
      the same concentration failed to affect DT or APD. Both nicorandil (1 mM) and
      cromakalim (30 microM) markedly shortened APD and decreased DT in papillary
      muscles. ET-1, but not ET-3, partially reversed the nicorandil-induced decreases
      in APD and DT in a concentration-dependent manner. ET-1 also attenuated the
      cromakalim-induced decreases in APD and DT. In single ventricular myocytes, both
      nicorandil and cromakalim increased a steady-state outward current, which was
      sensitive to 1 microM glibenclamide, suggesting that these drugs activate IK.ATP.
      ET-1 (30 nM) significantly inhibited the IK.ATP, whereas ET-3 failed to affect
      it. The ET-1 induced inhibition of IK.ATP was abolished by BQ-485 (100 nM), an
      ETA receptor-selective antagonist. Neither the protein kinase C (PKC) inhibitor
      staurosporine (20 nM) nor the calmodulin antagonist W-7 (50 microM) affected the
      inhibitory action of ET-1 on the nicorandil-induced IK.ATP. In pertussis toxin
      (PTX)-treated cells, the inhibitory action of ET-1 on IK.ATP was augmented rather
      than attenuated. These results suggest that ET-1 partially inhibits the IK.ATP
      through the activation of ETA receptors, although the precise intracellular
      mechanism remains to be clarified. Because activation of the ATP-sensitive K+
      channels is considered to protect the ischemic myocardium, the partial inhibition
      of IK.ATP by ET-1 may lead to the aggravation of myocardial injury, potentially
      due to an increase in transmembrane Ca2+ influx.

PMID- 8656646
TI  - Rate-dependent effects of detajmium and propafenone on ventricular conduction and
      refractoriness in isolated guinea pig hearts.
AB  - Detajmium (4--3'-diethylamino-2'-hydroxypropyl--ajmalin) is an Na(+)-channel
      blocking drug with an extremely long recovery from use-dependent sodium channel
      block. The aim of the present study was to investigate the rate-dependent effects
      of detajmium on the intraventricular conduction of isolated, spontaneously
      beating, guinea pig hearts in comparison with the effects of propafenone.
      Detajmium (0.3 microM) and propafenone (0.3 microM) caused comparable
      prolongations of the intraventricular conduction time during sinus rhythm. The
      time to steady state of the rate-dependent QRS prolongation during rapid
      ventricular pacing follows an exponential function of the beat number after an
      abrupt change of frequency and is characterized by a drug-specific time constant.
      This time constant was significantly longer for detajmium (tau = 265 +/- 165
      beats; mean +/- SEM; n = 6) than for propafenone (tau = 31 +/- 4 beats; n = 11; p
      < 0.01). In the presence of propafenone, QRS duration peaked initially before
      decreasing to a steady state. Detajmium, in contrast, progressively broadened the
      QRS complex. Both substances caused the greatest increase in the ventricular
      effective refractory period (V-ERP) when the number of conditioning stimuli
      (interstimulus interval, 120 ms) was in the range of the time constant. However,
      when the number of conditioning stimuli was further increased, the V-ERP for
      propafenone diminished progressively. In conclusion, propafenone displayed, in
      comparison with detajmium, only a transient rate-dependent effect on
      intraventricular conduction and V-ERP.

PMID- 8656647
TI  - Mechanism of the antiischemic effect of mibefradil, a selective T calcium channel
      blocker in dogs: comparison with amlodipine.
AB  - Calcium channel blockers are active in variant angina principally by preventing
      coronary vasospasm. However, a direct antiischemic effect may also occur. In open
      chest dogs, an attack of variant angina was mimicked by a 2-min critical coronary
      stenosis, and the following reversible myocardial ischemia was assessed by
      measuring the decrease of segmental shortening. We compared the antiischemic
      mechanism of mibefradil, a T and L calcium channel blocker, with that of
      amlodipine, a pure L channel blocker. Both drugs showed a similar relationship
      between the decrease of the rate-pressure product and the antiischemic effect,
      but only mibefradil reduced heart rate. Amlodipine and mibefradil at the highest
      doses tested (20 and 70 micrograms/kg/min, respectively) restored 68 +/- 8 and 76
      +/- 5% of segmental shortening in the ischemic area, respectively, as compared
      with preischemic values. Matching blood pressure (by intraaortic balloon) or
      heart rate (by atrial pacing) to predrug values showed that the antiischemic
      effect was mainly afterload-dependent for amlodipine and heart rate-dependent for
      mibefradil. We conclude that in variant angina, in addition to their
      antivasospastic effects, calcium channel blockers may be antiischemic by a direct
      myocardial effect associated with a decrease of the rate pressure product.
      Blockade of the T channel does not seem to participate in the direct antiischemic
      effect of mibefradil but could explain the decrease of heart rate.

PMID- 8656648
TI  - Enhanced antiproliferative effect of nitric oxide in cultured smooth muscle cells
      from diabetic rats.
AB  - We examined the influence of experimental diabetes on the proliferation of
      cultured vascular smooth muscle cells (VSMCs) in presence of a nitric oxide (NO)
      generating agent, sodium nitroprusside (SNP), and 8-bromo-cGMP. VSMC cultures
      were prepared from aortas of control and streptozotocin-diabetic rats. SNP
      induced a time- and dose-dependent inhibition of control and diabetic VSMC
      proliferation, consistent with the data on [3H]thymidine incorporation, cell
      counts, and index of culture mass. However, the responses to SNP were
      significantly enhanced in VSMCs from diabetic rats. SNP induced an increased dose
      dependent accumulation of intracellular cGMP in diabetic VSMCs. In contrast,
      growth-inhibitory responses to 8-bromo-cGMP were not significantly different
      between the two VSMC models. Moreover, basal cGMP content in VSMCs was lower in
      diabetic rats than in controls, a result that can explain the enhanced
      proliferation observed in VSMCs from diabetic rats. These results suggest an
      enhanced antiproliferative effect of NO in VSMCs from diabetic rats through
      increased cGMP production. Therefore, experimental diabetes may impair and up
      regulate soluble guanylate cyclase activity in VSMCs.

PMID- 8656649
TI  - Up-regulation of endothelin-B receptors in atherosclerotic human coronary
      arteries.
AB  - Both endothelin-A (ETA) and endothelin-B (ETB) receptors are known to be present
      in human coronary arteries. However, their absolute and relative amounts,
      functional roles, and the influence of pathology are uncertain. The goal of the
      present study was to characterize endothelin receptors mediating constriction in
      human coronary arteries and to assess the influence of cardiomyopathy (CMP) and
      coronary artery disease (CAD) on ET receptors in human tissue. For comparison,
      porcine coronary arteries were evaluated in parallel. Competition binding
      experiments using [125I]ET-1 and different selective and nonselective ETA- and
      ETB-receptor agonists or antagonists revealed similar relative densities
      (relative Bmax) of ETA and ETB receptors in coronary arteries from human
      cardiomyopathic hearts (83% ETA and 17% ETB; n = 5) and porcine hearts (78% ETA
      and 22% ETB; n = 5). In marked contrast, the relative Bmax of ETB receptors were
      significantly higher in coronary arteries from human atherosclerotic hearts (51%
      ETA and 49% ETB; n = 3). Total receptor density (Bmax; fmol/mg protein) was
      highest in porcine (385 +/- 29) arteries, followed by human CAD (253 +/- 41) and
      CMP (174 +/- 20) coronary arteries. The relative and absolute Bmax values for ETA
      and ETB receptors in coronary arteries from a donor heart were similar to those
      obtained in CMP hearts. There were no significant differences in affinity
      constants (KD) values for ET-1, ET-3, Sarafotoxin S6c (SRTX S6c), BQ-123, and
      bosentan (Ro 47-0203) between tissues. In human coronary arteries from CMP
      hearts, ET-induced constriction seemed to be solely mediated via ETA receptors.
      In contrast, in porcine coronary arteries 20% of the maximal effect mediated by
      ET-1 could be attributed to ETB receptors, in agreement with the binding data.
      The functional role of ETB receptors in CAD tissue could not be evaluated because
      of the occurrence of spontaneous phasic contractions. We conclude that ETB
      receptors are up-regulated in human atherosclerotic coronary arteries. Further
      studies are needed to determine the pathophysiological importance of these
      receptors.

PMID- 8656650
TI  - Further evidence of the presence of constitutive and inducible nitric oxide
      synthase isoforms in human platelets.
AB  - Previous studies have suggested the presence of nitric oxide synthase (NOS)
      enzyme in human platelets. We herein provide definitive evidence for the presence
      of both endothelial constitutive NOS (ecNOS) and inducible NOS (iNOS) isoforms
      and their mRNA in human platelets. Total RNA was isolated from human platelets,
      and reverse-transcription polymerase chain reaction (RT-PCR) demonstrated the
      expression of the ecNOS and iNOS isoforms in platelets. High-stringency Southern
      analysis confirmed the molecular authenticity of the RT-PCR products for each NOS
      isoform. Western analysis with mouse monoclonal antibody against human ecNOS
      consistently demonstrated a band with a molecular weight of 140-150 kDa. Western
      analysis with mouse monoclonal antibody against rat macrophage iNOS showed a
      single 200-kDa band in both resting and lipopolysaccharide (LPS)-plus interferon
      gamma (IFN-gamma)-stimulated platelets. Immunoprecipitation further confirmed the
      presence of the 200-kDa iNOS band. Expression of iNOS protein, measured with
      densitometry, was increased in LPS- and IFN-gamma-stimulated platelets (p < 0.01
      vs. resting platelets). Thus, human platelets possess both ecNOS and iNOS
      isoforms and their mRNA, and iNOS exhibits molecular weight and kinetic
      characteristics distinct from those of ecNOS.

PMID- 8656651
TI  - Comparison of direct negative chronotropic and positive inotropic effects of
      sematilide to those of E-4031 and MS-551 and the reverse frequency-dependent
      prolongation of cardiac refractoriness of sematilide.
AB  - Direct cardiac effects of sematilide, a new class III antiarrhythmic drug, were
      compared with those of E-4031 and MS-551 in canine isolated blood-perfused heart
      preparations. Doses of sematilide, E-4031, and MS-551 causing a 10% decrease in
      the spontaneous sinoatrial beating rate were 58 +/- 15, 9 +/- 5, and 84 +/- 10
      micrograms (n = 5); those causing a 10% increase in developed tension of the
      papillary muscle were 485 +/- 49, 17 +/- 2, and 267 +/- 50 micrograms (n = 6);
      and those causing a 10% prolongation of effective refractory period (ERP) of the
      atrioventricular node were 68 +/- 10, 11 +/- 2, and 53 +/- 15 micrograms (n = 5),
      respectively. There were few effects on atrio-His or His-ventricular intervals.
      Also, in in situ open-chest dog hearts, the percent increases in ERP of the
      atrioventricular conduction system caused by 1 mg/kg of sematilide were 21 +/- 3,
      16 +/- 2 and 9 +/- 1% at cycle lengths of 800, 600, and 400 ms, respectively (p <
      0.01; n = 8). These results indicate that (a) sematilide, as well as E-4031 and
      MS-551, has direct negative chronotropic and positive inotropic effects and
      prolongs cardiac refractoriness without affecting conduction velocities; (b)
      quantitatively, the cardiac effects of sematilide were almost identical to those
      of MS-551 and five to ten times less potent than those of E-4031; (c) and
      prolongation of ERP of the atrioventricular conduction system by sematilide
      occurred in a reverse frequency-dependent manner.

PMID- 8656652
TI  - Contractile responses to various stimuli in isolated resistance vessels from
      simultaneously hypertensive and streptozotocin-diabetic rats.
AB  - Diabetes mellitus and hypertension are common chronic diseases that frequently
      occur simultaneously. The induction of streptozotocin (STZ) diabetes mellitus in
      spontaneously hypertensive rats (SHR) offers the opportunity to investigate the
      influence of both entities in a reproducible manner. We investigated the effects
      of various vasoconstrictors on isolated small arteries from the mesenteric
      vascular bed of normotensive rats (Wistar-Kyoto rats, WKY) and SHR with chronic
      (8 weeks), STZ-induced diabetes mellitus. No consistent changes in hemodynamic
      parameters of the (STZ-) normotensive and (STZ-) hypertensive rats were noted.
      The K(+)-normalization procedure yields the individual optimal lumen diameter,
      which was the same for the arteries of the four groups of rats. The passive wall
      tension resulting from this normalization procedure was higher only in
      preparations from the control hypertensive group as compared with those from the
      control normotensive rats. Morphological investigations showed that small
      arteries from control SHR had an increased tunica media thickness as compared
      with those of control WKY; the STZ-WKY had an increased tunica media thickness as
      compared with preparations from control WKY. The vasoconstriction caused by alpha
      1-adrenoceptor stimulation [norepinephrine (NE), methoxamine] and serotonin is
      unchanged in chronic experimental diabetes. The diabetic state reduced the
      sensitivity [-log EC50(M)] for the concentration-response curves (CRC) of calcium
      chloride. The CRC of potassium chloride indicated the same sensitivities, but
      maximal active wall tensions of vessels from STZ-SHR were reduced as compared
      with those from STZ-WKY. The well-known enhancement of the effects of various
      contractile stimuli caused by hypertension could not be demonstrated for the
      isolated small arteries used in the present study, although a nonsignificant
      tendency was observed. However, the STZ-diabetic state did not cause important
      additional pharmacodynamic changes, despite the morphological alterations in
      those vessels.

PMID- 8656653
TI  - Protective effect of beraprost sodium, a stable prostacyclin analogue, in
      development of monocrotaline-induced pulmonary hypertension.
AB  - Experimental pulmonary hypertension (PH) was induced by a single injection of
      monocrotaline (MCT), a pyrrolizidine alkaloid extracted from Crotalaria
      spectabilis. The effect of beraprost sodium, a stable prostacyclin analogue, on
      the development of MCT-induced PH in rats was studied. Chronic administration of
      beraprost sodium at a dose of 30 micrograms/kg/day initiated on the same day as
      MCT injection decreased the degree of PH determined by weight ratio of right
      ventricular free wall to that of left ventricle plus septum depending on the
      duration of administration. Although the injection of prostaglandin E1 (PGE1) at
      a dose of 200 micrograms/kg/day initiated 1 week after MCT injection did not
      decrease the degree of PH significantly, beraprost sodium administration at doses
      of 30 and 100 micrograms/kg/day decreased the degree of PH significantly. The
      cytoprotective effect of beraprost sodium against endothelial cell (EC) damage is
      believed to be involved in inhibiting development of PH in MCT-injected rats. The
      amounts of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and
      tumor necrosis factor (TNF) produced by alveolar macrophages decreased in
      accordance with the inhibiting effect of beraprost sodium on development of PH,
      indicating that beraprost sodium inhibited the development of PH in MCT-injected
      rats not only through its effect of vasodilation and anti-platelet aggregation in
      pulmonary circulation but also through its antiinflammatory effects.

PMID- 8656654
TI  - beta-Adrenergic relaxation in mesenteric resistance arteries of spontaneously
      hypertensive and Wistar-Kyoto rats: the role of precontraction and intracellular
      Ca2+.
AB  - An attenuated beta-adrenergic vasodilation of small arteries may help explain the
      increased peripheral resistance in hypertension. To investigate this, we compared
      the isoprenaline-induced relaxation of mesenteric resistance arteries of
      spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using a small
      vessel myograph. The arteries had similar diameters, but the contractile force
      induced by cumulative addition of K+ (10-130 mM) was 1.3-fold higher for the SHR.
      The beta-adrenoceptor-mediated relaxation of arteries, precontracted with 40 mM
      K+, was significantly less in SHR (41 +/- 3%, n = 11) than in WKY (56 +/- 3%, n =
      15, p = 0.003), and the pD2 value for isoprenaline was significantly lower in SHR
      (7.13 +/- 0.09 vs. 7.41 +/- 0.07, p = 0.02). In contrast, when precontracted with
      phenylephrine (PE, alpha 1-adrenoceptor agonist, 3-10 microM), isoprenaline
      relaxation was almost complete in both SHR and WKY, and the pD2 value for
      isoprenaline did not differ between strains. Forskolin induced complete
      relaxation of both precontractions. Because the beta-adrenergic relaxation of the
      mesenteric resistance arteries was attenuated only after K(+)-precontraction, we
      conclude that alterations in this precontracting mechanism in SHR rather than a
      defect in the beta-adrenoceptor system may provide an explanation for the
      decreased relaxation in these vessels. Intracellular Ca2+ measurements and a
      review of the literature support this conclusion.

PMID- 8656655
TI  - Vascular smooth muscle relaxation by alpha-adrenoceptor blocking action of
      dobutamine in isolated rabbit aorta.
AB  - We investigated the mechanism of vascular relaxation produced by dobutamine, a
      positive inotropic agent with beta 1-adrenergic action. Dobutamine concentration
      dependently (10 nM-10 microM) relaxed ring segments of rabbit aorta partially
      precontracted with 1 microM phenylephrine (PE) but did not relax those
      precontracted with 40 mM K+ or 5 microM prostaglandin F2 alpha (PGF2 alpha). The
      relaxation was not completely inhibited by pretreatment with 10 microM
      propranolol. Dobutamine did not significantly increase tissue cyclic AMP levels
      concomitantly with relaxation as does isoproterenol (ISO) in rabbit aorta.
      Dobutamine produced a parallel rightward shift in concentration-response curves
      to PE. The Schild plot analysis resulted in a linear regression of a slope of
      1.077 +/- 0.077, which was not significantly different from unity. The pA2 value
      of dobutamine as compared with PE in rabbit aorta was 6.81 +/- 0.03. Dobutamine
      causes arterial dilatation mediated not only through a beta-adrenergic action but
      also through an alpha-adrenergic blocking action in rabbit aorta.

PMID- 8656656
TI  - Acute presynaptic inhibition by doxorubicin of negative chrono- and inotropic
      responses to parasympathetic nerve stimulation in isolated, blood-perfused dog
      atrium.
AB  - The clinical use of doxorubicin, an anthracycline antineoplastic agent, is
      limited by its cardiotoxicity. Although several previous reports have shown
      neurotoxic effects of doxorubicin, there is little information about the acute
      effects of doxorubicin on the autonomic nerve functions in the heart.
      Accordingly, to evaluate the effects of doxorubicin on the cardiac responses to
      autonomic nerve activation, we studied the effects of doxorubicin on the negative
      chrono- and inotropic responses to intracardiac parasympathetic nerve stimulation
      and acetylcholine (ACh), and the positive chrono- and inotropic responses to
      norepinephrine (NE) in the isolated, blood-perfused dog atrium. Doxorubicin (0.01
      3 mumol), injected into the sinus node artery of the isolated atrium, induced
      negative inotropic effects dose dependently and weak negative chronotropic
      effects. Doxorubicin inhibited the negative chrono- and inotropic responses to
      parasympathetic nerve stimulation dose dependently. However, doxorubicin affected
      neither the negative chrono- and inotropic responses to ACh nor the positive
      chrono- and inotropic responses to NE. These results indicate that doxorubicin
      interacts with neither muscarinic receptors nor beta-adrenoceptors and suggest
      that doxorubicin inhibits the negative cardiac responses to parasympathetic nerve
      activation due to the inhibition of ACh release from nerve varicosities in the
      heart.

PMID- 8656657
TI  - Mechanisms of negative inotropic effects of class Ic antiarrhythmic agents:
      comparative study of the effects of flecainide and pilsicainide on intracellular
      calcium handling in dog ventricular myocardium.
AB  - We studied the subcellular mechanisms responsible for the negative inotropic
      effects of the two Ic drugs flecainide and pilsicainide. Aequorin luminescence
      (Ca2+i) and isometric tension were recorded simultaneously in isolated trabeculae
      from the dog ventricle. In isolated myocytes from the same ventricle, the slow
      inward current (ICa) was recorded. Both flecainide and pilsicainide decreased
      peak Ca2+i, peak tension, and peak ICa concentration dependently. Each effect
      with flecainide was more marked than that with pilsicainide; however, Ca2+i and
      ICa paralleled each other in changes in tension, and the tension-Ca2+i-ICa
      relationship showed the same curve for each drug. We conclude that the difference
      in negative inotropic effects of these class Ic drugs are primarily related to
      their effects on L-type Ca2+ channels and the subsequent decreases in the amount
      of Ca2+ released from the sarcoplasmic reticulum (SR) during each cardiac cycle.
      Therefore, their negative inotropic effects may not be directly correlated with
      the essential mechanisms responsible for their antiarrhythmic action.

PMID- 8656658
TI  - Effect of propionyl-L-carnitine on the mechanics of right and left papillary
      muscles from volume-overloaded rat hearts.
AB  - Propionyl-L-carnitine (PLC) was shown to improve global cardiac function in
      pressure overload hypertrophy by acting directly on muscle mechanics. We
      investigated whether PLC can effectively ameliorate papillary muscle mechanics in
      a volume overload (VO) model. We induced VO by constructing an aortocaval
      anastomosis in adult Wistar rats. Three experimental groups were studied: sham
      operated controls and untreated and PLC-treated VO animals. Isometric function of
      right and left papillary muscle was studied 16-18 weeks later. PLC was
      administered in the drinking water at the dose of 180 mg/kg for the last 2 weeks
      before experiment. One-way analysis of variance (ANOVA) showed that in right
      papillary muscles from the untreated VO group the time course of the isometric
      contraction was significantly prolonged [time-to-peak tension (TPT, ms +/- SEM)
      from 126 +/- 4.9 to 156 +/- 7.1; time from peak tension to 30% relaxation (TRel)
      from 133 +/- 11.9 to 196 +/- 13.9; n = 11 and 8, respectively], and peak rates of
      contraction and relaxation normalized over developed tension were significantly
      decreased in comparison with sham [from (s-1 +/- SEM) 12.9 +/- 0.5 to 10.8 +/-
      0.6, and from 7.2 +/- 0.6 to 5.2 +/- 0.4, respectively]. These parameters in the
      PLC VO group did not differ from sham (TPT, 140 +/- 5.7; TRel, 158 +/- 14.4;
      +dF/df/DT, 12.2 +/- 0.6; -dF/df/DT, 6.5 +/- 0.5; n = 8). Function of left
      papillary muscle was not modified by either VO or PLC treatment. Total carnitine
      levels in either ventricle free walls were unchanged by VO. PLC significantly
      increased total carnitine content of left ventricle free wall (from 5.4 +/- 0.28
      to 7.0 +/- 0.50). The contraction changes observed in the right papillary muscle
      are likely to depend on the pressure overload occurring in the right chamber;
      moreover, they are unrelated to tissue carnitine depletion. PLC improved the
      altered right papillary muscle mechanics without exerting any apparent effect on
      the functionally normal left papillary muscle. PLC activity is independent of
      carnitine stores, but may presumably be ascribed to its anaplerotic properties.

PMID- 8656659
TI  - Inhibitory effect of an angiotensin II type 1 receptor antagonist on growth of
      vascular smooth muscle cells from spontaneously hypertensive rats.
AB  - To investigate the role of endogenous angiotensin II (Ang II) in the growth of
      vascular smooth muscle cells (VSMC), we examined the effect of the novel
      nonpeptide Ang II type 1 (AT1) receptor antagonist CV-11974 on basal and
      stimulated-growth of VSMC from normotensive Wistar-Kyoto rats (WKY) and
      spontaneously hypertensive rats (SHR). CV-11974 inhibited basal DNA synthesis by
      VSMC from SHR, but not from WKY, in the absence of serum. In the presence of 10%
      calf serum, DNA synthesis was significantly higher in VSMC from SHR than in cells
      from WKY, and the inhibitory effect of CV-11974 was attenuated. Ang II dose
      dependently stimulated DNA synthesis by VSMC from both rat strains, and this
      effect was abolished by CV-11974. CV-11974 slightly but significantly suppressed
      proliferation of VSMC from both rat strains. CV-11974 competitively inhibited the
      specific binding of 125I-labeled Ang II to VSMC from both rat strains. The
      angiotensin-converting enzyme inhibitor (ACEI) delapril also reduced basal DNA
      synthesis by VSMC from SHR, but did not affect proliferation of VSMC from either
      rat strain. These findings suggest that VSMC from SHR may synthesize Ang II which
      promotes their basal growth in an autocrine/paracrine manner through the AT1
      receptor, and that this system may be associated with the exaggerated growth of
      VSMC from SHR.

PMID- 8656660
TI  - Influence of angiotensin-converting enzyme inhibition by fosinopril on myocardial
      perfusion in streptozotocin-diabetic rats.
AB  - We examined the influence of the new angiotensin-converting enzyme inhibitor
      (ACEI) fosinopril on function and perfusion of the diabetic rat heart.
      Streptozotocin-diabetic rats (60 mg/kg body weight) were treated with fosinopril
      (10 mg/kg body weight/day) for 4 months. Cardiac performance was analyzed in the
      isolated heart perfused at constant volume. Epicardial perfusion was determined
      by measuring epicardial fluorescence changes after injection of FITC-dextrane (3
      kDa) as described previously. As compared with controls, fosinopril prevented or
      diminished the increase in end-diastolic pressure (EDP), coronary perfusion
      pressure (CPP), and vascular resistance in diabetes. The intravascular volume
      strongly reduced in diabetes was increased, and the epicardial perfusion rate was
      accelerated in hearts of diabetic rats treated with fosinopril. The vascular
      exchange diminished in hearts of untreated diabetic rats was enhanced, and the
      transcapillary permeability was slightly accelerated at low flow rates. These
      data indicate that treatment of streptozotocin-diabetic rats with fosinopril
      prevents severe disturbances of coronary autoregulation and at least partly the
      impairment of cardiac perfusion generally observed in diabetic rats. Together
      with previously published morphological data demonstrating an inhibition of
      interstitial and perivascular fibrosis in hearts of diabetic rats with
      fosinopril, our observations suggest that ACE inhibition by fosinopril is
      cardioprotective in diabetes.

PMID- 8656661
TI  - Effect of hydrochlorothiazide on the pharmacokinetics of enalapril in
      hypertensive patients with varying renal function.
AB  - An open, randomised, cross-over study was performed to investigate the
      pharmacokinetics of enalaprilat, administered as 20 mg enalapril both as
      monotherapy and in combination with hydrochlorothiazide (HCTZ 12.5 mg). Three
      groups of 6 hypertensive patients were enrolled [untreated diastolic blood
      pressure (DBP) 90-115 mm Hg]; normal renal function [glomerular filtration rate
      (GFR) > 81 ml min-1 1.73 m-2], mild renal impairment (GFR 51-80 ml min-1 1.73 m
      2), and moderate renal impairment (GFR 31-50 ml min-1 1.73 m-2). The
      pharmacokinetics of enalaprilat and enalaprilat plus HCTZ correlated predictably
      with renal impairment with increased plasma concentrations and decreased urinary
      elimination at lower values of GFR. The coadministration of HCTZ had no
      significant effect on the pharmacokinetics of enalaprilat in any group. We
      conclude that although the pharmacokinetics of both enalaprilat and HCTZ are
      related to renal function, HCTZ has no significant effect on the pharmacokinetics
      of enalaprilat and that dosage adjustment for both regimens should be based on
      renal function.

PMID- 8656662
TI  - Effect of feeding psyllium and cholestyramine in combination on low density
      lipoprotein metabolism and fecal bile acid excretion in hamsters with dietary
      induced hypercholesterolemia.
AB  - We wished to determine the effectiveness of submaximal doses of cholestyramine
      and psyllium given in combination in reversing dietary-induced
      hypercholesterolemia in Golden Syrian hamsters, and to investigate the mechanism
      or mechanisms of action through which these agents together decrease plasma low
      density lipoprotein cholesterol (LDL-C) levels in this model. For 30 days, male
      hamsters were fed a cholesterol-rich cereal-based diet containing either a
      submaximal dose of cholestyramine (1% wt/wt) alone or in combination with
      psyllium (either 2 or 4%), or a high dose of cholestyramine (3%) alone. Although
      the greatest cholesterol-reducing action was achieved with 3% resin alone, in the
      animals fed one third as much cholestyramine combined with psyllium (4%) LDL-C
      production decreased from 288 +/- 15 to 187 +/- 17 micrograms/h per 100 g body
      weight, the suppression of LDL-receptor activity was almost fully reversed,
      plasma LDL-C levels were reduced from 90 +/- 8 to 41 +/- 5 mg/dl, and hepatic
      cholesterol content decreased from 17.1 +/- 1.9 to 2.4 +/- 0.1 mg/g. In the group
      that received 1% resin alone, the plasma LDL-C and hepatic cholesterol levels
      were 60 +/- 3 mg/dl and 7.2 +/- 0.6 mg/g, respectively. As compared with animals
      that received 1% resin alone, those fed both agents manifested higher rates of
      fecal bile acid excretion and lower levels of intestinal cholesterol absorption.
      A significant cholesterol-lowering benefit can be derived from using these
      nonsystemic agents in combination at lower, more tolerable doses.

PMID- 8656663
TI  - Inhaled nitric oxide in cardiac failure: vascular versus ventricular effects.
AB  - Inhaled nitric oxide (INO) is a powerful and selective pulmonary vasodilator in
      pulmonary hypertension, including that related to cardiac disease. Recently, NO
      was shown to have a direct negative inotropic action on the myocardium, but
      whether INO can impair left ventricular (LV) function is not known. We
      administered INO during right heart catheterisation in 10 subjects with LV
      failure and secondary pulmonary hypertension. INO was delivered for 10 min at
      concentrations of 10, 20, and 40 ppm in spontaneous respiration. Average age was
      49.9 years (range 19-59 years), and mean LV ejection fraction EF (LVEF) was 19.9%
      (range 15-27%). INO produced an average decrease in pulmonary vascular resistance
      (PVR) of 40% as compared with baseline (p < 0.0001) with no significant change in
      systemic vascular resistance (SVR). There was no significant difference in the
      haemodynamic response to the three doses of INO. The large decrease in PVR was
      due mainly to an increase in pulmonary capillary wedge pressure (PCWP). Cardiac
      index (CI) rose in 7 patients and was unchanged in 2. One patient had a marked
      increase in PAWP and a marked decrease in CI during administration of INO, which
      rapidly reversed after discontinuation of INO. This study demonstrates that the
      administration of INO to patients with impaired cardiac reserve may result in
      marked increase in ventricular preload with little benefit to pulmonary
      pressures. In view of the known in vitro effects of NO and the marked
      haemodynamic changes demonstrated in response to INO in this study, caution
      should be exercised when using INO in this population.

PMID- 8656664
TI  - Myocardial adenylyl cyclase type V and VI mRNA: differential regulation with age.
AB  - Myocardial beta-adrenergic signal transduction diminishes with age. This decrease
      is not due to a decrease in the number of beta-adrenoceptors, but may be a result
      of an impaired capacity to activate adenylyl cyclase (AC). Forskolin-stimulated
      AC activity is diminished, and the number of forskolin binding sites is
      decreased, suggesting that the decrease in signal transduction with age is a
      result of fewer AC catalytic units. To investigate whether the decrease in AC
      with age is associated with diminished AC mRNA, we assessed AC type V and type VI
      mRNA in ventricles from 6-, 11-, and 24-month-old F-344 rats. The predominant
      mRNA species, type V, increased by 45% between 6 and 11 months of age but
      decreased to just below the 6-month level by age 24 months. In contrast, type VI
      mRNA decreased by 44% between 6 and 11 months of age and then increased to the 6
      month level at age 24 months. The changes in type V and type VI mRNA did not
      parallel the decreases in the AC activity or forskolin binding sites with
      senescence. These data indicate that the steady-state levels of type V and VI AC
      mRNA are not reliable predictors of the efficacy of forskolin stimulation of AC
      activity at different ages.

PMID- 8656665
TI  - Vascular endothelial growth factor augments muscle blood flow and function in a
      rabbit model of chronic hindlimb ischemia.
AB  - Animal studies have shown that angiogenic factors can increase vascularity and
      improve blood pressure (BP) in an ischemic limb. Whether changes in these
      parameters are indicators of significant improvement in muscle function has not
      been demonstrated. In a rabbit model of hind limb ischemia, we measured blood
      flow in the extensor digitorum longus muscle (EDL) both at rest and during
      electrical stimulation. Ablation of the femoral artery caused significant
      reductions in resting and stimulated EDL blood flow. The chronic reduction in
      perfusion caused impairment of muscle function (p < 0.01). At 28 days after a
      single administration of vascular endothelial growth factor (VEGF), stimulated
      muscle blood flow (3 mg/kg intravenously, i.v.) and muscle function [1 mg
      intrarterially (i.a.) or 3 mg/kg i.v.] were significantly improved as compared
      with that of vehicle-treated controls. Simultaneous measurement of the
      hemodynamic responses in the contralateral limb and in the kidneys confirmed that
      the effects of VEGF were confined to the ischemic limb. The data agree with
      findings that angiogenic factors increase perfusion through angiogenesis. We
      hypothesized that neovascularization allows work-associated muscle hyperemia,
      resulting in a significant improvement in muscle function. Similar clinical
      improvements in muscle function would signify a substantial advance in the
      treatment of peripheral vascular disease.

PMID- 8656666
TI  - Effects of angiotensin-converting enzyme inhibition versus beta-adrenergic
      blockade on aortic stiffness in essential hypertension.
AB  - We assessed the effects of 6 months of treatment with an angiotensin-converting
      enzyme (ACE) inhibitor (cilazapril) or a beta 1-adrenergic blocker (atenolol) on
      aortic stiffness in essential hypertension. Forty patients (16 women) aged 47 +/-
      9 years (mean +/- SD) with baseline systolic and diastolic blood pressures of 162
      +/- 15 and 105 +/- 5 mm Hg, respectively, were entered into a double-blind,
      parallel-group study with cilazapril, 5 mg once daily, or atenolol, 100 mg once
      daily. The treatment period was preceded by a 4-week placebo washout phase.
      Aortic elastic modulus (Ep) was determined by cine magnetic resonance imaging
      (MRI) and indirect brachial artery blood pressure measurements prior to and after
      3 weeks and 6 months of therapy. The reductions in systolic and diastolic blood
      pressures from baseline to 6 months averaged -17 +/- 13 and -10 +/- 6 mm Hg,
      respectively, with cilazapril and -23 +/- 16 and -14 +/- 6 mm Hg with atenolol.
      Concomitantly, Ep of the ascending aorta decreased with cilazapril from a median
      of 2,234 10(3)dyn/cm2 (interquartile range, 866-3,740) to 868 10(3)dyn/cm2 (515
      1,486) and with atenolol from a median of 1,611 10(3)dyn/cm2 (895-2,790) to 1,054
      10(3)dyn/cm2 (616-1,860). In repeated-measurements analysis of variance, the
      change in Ep with time was statistically significant (p < 0.001) but the group x
      time interaction was not. We conclude that 6 months of treatment with either
      cilazapril or atenolol reduces the stiffness of the ascending aorta in essential
      hypertension. No statistically significant differences between the effects of the
      two drugs were observed. The mechanisms and clinical significance of improved
      aortic distensibility with antihypertensive therapy deserve further study.

PMID- 8656667
TI  - The molecular biology of chronic myeloid leukaemia.
AB  - Chronic myeloid leukaemia (CML) is characterized cytogenetically by a
      t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL
      gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase
      activity and transforming abilities. The t(9;22) was suggested to be associated
      with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the
      genes directly affected by the translocation, ABL and BCR, were shown not to be
      imprinted. For most diagnostic and research purposes the BCR-ABL gene can be
      efficiently identified by reverse-transcription and polymerase chain reaction
      (RT/PCR) amplification of its fusion transcripts, which can be quantified by
      competitive PCR and similar assays for assessment of residual disease in the
      follow-up of therapy. In the great majority of CML patients the BCR-ABL
      transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only
      detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2
      or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always
      'functional', since extremely low levels of BCR-ABL transcripts can be found in
      leucocytes from normal individuals and, conversely, it appears that no BCR-ABL
      transcription can be detected in a proportion of Ph-positive haematopoietic
      progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR
      hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR
      fusion protein has yet been identified in CML patients. The blast crisis of CML
      has been variably associated with abnormalities of proto-oncogenes, such as RAS
      and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with
      the generation of chimeric transcription factors, as in the AML1-EVI1 gene
      fusion. It is likely, therefore, that multiple and alternative molecular defects,
      as opposed to a single universal mechanism, underlie the acute transformation of
      the disease.

PMID- 8656668
TI  - Human recombinant interferon-inducible protein-10 inhibits the proliferation of
      normal and acute myelogenous leukemia progenitors.
AB  - Recombinant human interferon-inducible protein-10 (rIP-10) has been recently
      identified, purified and shown to suppress the multiplication of normal marrow
      early hemopoietic progenitors. In the present study we investigated the effect of
      rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor
      populations. We first studied hematologically normal bone marrow using the delta
      culture assay, in which marrow low-density cells were incubated in liquid culture
      with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1
      week, to allow the differentiation of mature progenitors, and thereafter cultured
      in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin
      (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal
      marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh
      normal marrow cells were cultured in methylcellulose without preincubation in
      liquid culture, rIP-10 did not affect the growth of colony-forming cells. In
      contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an
      increment in colony numbers was observed that was eliminated by rIP-10. Similar
      experiments performed with low-density, non-adherent, T cell-depleted AML marrow
      cells, obtained from 12 untreated adult AML patients, revealed qualitatively
      similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML
      delta assay but did not affect the growth of rGM-CSF-responsive AML colony
      forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL
      was added to rGM-CSF during plating in an effort to recruit additional AML
      progenitor populations, there was an increment in leukemic blast colony numbers
      that was eliminated by rIP-10. As observed with normal progenitors, the effect of
      rIP-10 on these AML progenitors was concentration-dependent, statistically
      significant and reversible with a rIP-10-neutralizing antiserum. To delineate the
      mechanism of action of rIP-10 we used the thymidine suicide assay and found that
      rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing
      DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably
      immature) AML progenitor populations by reducing the fraction of cells undergoing
      DNA synthesis. Additional studies are needed to further elucidate the mechanism
      of this inhibition and to determine the potential clinical benefits of rIP-10 in
      future therapies for AML.

PMID- 8656669
TI  - A phase II study of VP-16, intermediate-dose Ara-C and carboplatin (VAC) in
      advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia.
AB  - Thirty-one patients with either advanced AML (18) or blastic CML (13) were
      treated with an intensive timed sequential combination of VP-16 (100 mg/m2/day
      i.v., days 1-3 and 8-10), intermediate-dose Ara-C (500 mg/m2 i.v. over 1 h q 12
      h, days 1-3 and 8-10) and carboplatin (150 mg/m2/day i.v. continuous infusion,
      days 1-3 and 8-10). CR rates were 9/18 (50%) for patients with AML and 9/13 (69%)
      for those with blastic CML, for an overall CR rate of 58%. Among patients with
      AML, CR rates for specific subgroups were: primary resistant disease 2/6;
      resistant relapse 1/5; second relapse 6/7. Ten patients were refractory to VAC
      and three (10%) died of complications during marrow hypoplasia. Median overall
      survival was 7 months, and median DFS of the 18 responders 4 months. The major
      toxicity was myelosuppression and infection. The VAC regimen has significant
      activity and acceptable toxicity in myelogenous leukemias. The very high response
      rate observed in blastic CML warrants further testing of carboplatin-based
      regimens in this poor-risk form of leukemia.

PMID- 8656670
TI  - Differential expression of B29 (CD79b) and mb-1 (CD79a) proteins in acute
      lymphoblastic leukaemia.
AB  - CD79 is a heterodimeric molecule comprising two polypeptide chains, B29 (CD79b)
      and mb-1 (CD79a). It is physically linked in the surface of B cells to membrane
      immunoglobulin, forming the B cell antigen receptor complex. Expression of the mb
      1 (CD79a) chain has been studied in leukaemias and shown to be present in most B
      lineage acute lymphoblastic leukaemias (ALL). In contrast, little is known about
      the expression of B29 (CD79b) in this condition. Two monoclonal antibodies (MoAb)
      were used in this study by immunocytochemistry and flow cytometry: HM57, against
      an intracellular epitope of the mb-1(CD79a) chain, and SN8, reacting with an
      extracellular epitope of B29 (CD79b). Our aim was to investigate the expression
      of B29 (CD79b) in the various immunological subtypes of B lineage ALL and compare
      its cytoplasmic and membrane expression. Seventy-nine cases were studied,
      including 13 chronic myeloid leukaemia in B lymphoid blast crisis (CML-BC) and 66
      ALL, subclassified as early B (two), common (28), pre-B (23), mature (five) and
      biphenotypic with B lymphoid commitment (eight). Most cases expressed mb-1
      (CD79a) in the cytoplasm. B29 (CD79b) was expressed in the cytoplasm in 65%
      (15/23) of pre-B-ALL and in 14% (4/28) common-ALL but it was detected in the cell
      membrane in only three cases of mature B-ALL, being negative in all other B
      lineage subtypes ALL. Three of the biphenotypic leukaemias coexpressed
      cytoplasmic B29 (CD79b) and mu-chain. This was also seen in two cases of CML-BC,
      while four cases expressed only cytoplasmic B29 (CD79b) without mu-chain. Our
      results suggest that during B cell differentiation, B29 (CD79b) is expressed
      later than mb-1 (CD79a) in the cytoplasm and parallels the cytoplasmic expression
      of mu-chain. B29 (CD79b) is present in the membrane at a later stage compared to
      its cytoplasmic expression and found in mature B blasts (B-ALL) that express
      membrane Ig as it is in normal and leukaemic B lymphocytes.

PMID- 8656671
TI  - MLL tandem duplication and multiple splicing in adult acute myeloid leukemia with
      normal karyotype.
AB  - Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene
      through a reciprocal chromosomal translocation is found in 5% of adult acute
      myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25
      different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse
      the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These
      leukemias have poor prognosis and frequently have a monocytic, lymphoid or
      biphenotypic (myeloid and lymphoid) antigen expression in blast cells.
      Approximately 20-30% of patients diagnosed as having adult de novo, AML have
      normal chromosomes by metaphase analysis and the majority of these patients have
      good prognosis. With the use of reverse transcriptase-polymerase chain reaction
      (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such
      patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the
      MLL gene. These seven patients showed a median survival of 2.7 months, compared
      to a 6.8 months median survival for all other patients in the study. If confirmed
      on a large series of patients, our findings may help differentiate AML with
      normal karyotype and poor prognosis from those with normal karyotype and a more
      favorable prognosis.

PMID- 8656672
TI  - Differential expression of the ufo/axl oncogene in human leukemia-lymphoma cell
      lines.
AB  - The ufo protein (also termed axl) is a member of a new family of receptor
      tyrosine kinases and is encoded by a transforming gene that was initially
      isolated from primary human myeloid leukemia cells by DNA-mediated transformation
      of NIH/3T3 cells. The ligand, Gas6, a protein S-related molecule lacking any
      known function yet, has recently been identified. We report the expression
      pattern of ufo mRNA in a panel of 76 human continuous leukemia-lymphoma cell
      lines. The gene was not expressed in cell lines derived from lymphoid
      malignancies (n=28), but transcription was seen in 3/11 myeloid, 0/6 monocytic,
      9/13 erythroid and 11/18 megakaryocytic cell lines. Several cell lines were
      treated with phorbol ester leading to significant upregulation of the ufo message
      in constitutively positive cells. An apparent ufo mRNA overexpression was not
      found in any of the positive leukemia cell lines, but was identified in the drug
      resistant subclones of the cervix carcinoma cell line HeLa. Southern blot
      analysis of restriction enzyme-digested genomic DNA did not provide evidence for
      gene amplification, but the HeLa subclones showed banding patterns suggestive of
      gene rearrangement. Two main ufo mRNA bands of 3.2 and 5.0 kb were identified; no
      differences in the half-lives (t1/2 = 2.5 h) of these two mRNA species could be
      identified. In summary, ufo, representing a novel type of receptor tyrosine
      kinase, is expressed solely in myeloid and erythro-megakaryocytic leukemias but
      not in lymphoid malignancies. These and previous data suggest an involvement of
      the ufo receptor tyrosine kinase in normal and malignant myelopoiesis; however,
      its exact role, if any, and mode of operation in leukemogenesis remains to be
      determined.

PMID- 8656673
TI  - Increased Evi-1 expression is frequently observed in blastic crisis of chronic
      myelocytic leukemia.
AB  - Evi-1 is a transforming gene originally identified in a common integration site
      of murine leukemia retrovirus and mapped in human chromosome 3q26. It is not
      normally expressed in either human or murine hematopoietic cells, but is
      overexpressed in retrovirus-induced murine myeloid leukemias as well as human
      myeloid leukemias with 3q26 abnormalities, and thus thought to be responsible for
      both human and murine leukemogenesis. In this study, possible involvement of the
      Evi-1 gene in human leukemias was evaluated by Northern blot analysis in a total
      of 73 patients with various types of leukemias. We found that increased
      expression of the Evi-1 gene was most frequently observed in patients with CML in
      blastic crisis. It was found in 10 of 14 (71.0%) samples from CML in blastic
      crisis, three of 15 (20.0%) from acute myelocytic leukemia, three of 11 (27.3%)
      from MDS-derived leukemia, and one of 11 (9.1%) from acute lymphoblastic
      leukemia. Among 18 patients showing increased Evi-1 expression, none of 17
      informative patients showed cytogenetic abnormalities involving 3q26. In
      addition, Southern blot analysis revealed neither amplification nor
      rearrangements of the Evi-1 gene in 11 Evi-1-positive patients whose DNA samples
      were available. Our results suggest that increased expression of the Evi-1 gene
      may play an important role in development of human leukemias, especially in
      progression from chronic phase to blastic crisis of CML even without 3q26
      abnormalities.

PMID- 8656675
TI  - Characterization of murine stromal cell clones established from bone marrow and
      spleen.
AB  - Stromal cell lines were established by irradiating adherent layers of bone marrow
      and spleen cells in Dexter-type long-term culture with X-rays. Some of these cell
      lines support myelopoiesis and/or B lymphopoiesis in vitro. Furthermore, the
      characteristics of these stromal cell lines were studied. Cytokine activity was
      detected in the conditioned media from all hematopoietic-supportive and non
      supportive stromal cells. Quantitative reverse transcriptase-polymerase chain
      reaction analysis revealed that the mRNAs of macrophage colony-stimulating factor
      and stem cell factor, but not that of Interleukin-3, were detectable in all the
      hematopoietic-supportive and non-supportive stromal cell lines. The transcripts
      of granulocyte colony-stimulating factor, interleukin-6, interleukin-7, and
      leukemia inhibitory factor were expressed in a wide variety of cell lines. Most
      stromal cell lines synthesized mRNA of c-mpl, the ligand of which stimulates
      megakaryopoiesis and thrombopoiesis. These observations indicate that the pattern
      of mRNA expression of cytokines is not correlated with the hematopoietic
      supportive ability of stromal cell lines. There was a significant difference in
      the efficiency of adhesion of lineage marker-negative bone marrow cells to
      fibroblasts and stromal cell lines. This appears to be correlated with the
      hematopoietic-supportive ability of the stromal cell lines.

PMID- 8656674
TI  - Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: chronic
      myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic
      leukemia.
AB  - Chronic myelogenous leukemia (CML) can sometimes present in lymphoid blast phase
      (L-BP), and can be difficult to distinguish from Philadelphia chromosome-positive
      (Ph+) acute lymphoblastic leukemia (ALL). Some have suggested that the
      determination of cell lineages involved by the Ph chromosome may be used for
      distinguishing CML presenting in L-BP (presumably multilineage disease) from Ph+
      ALL (presumably lymphoid-restricted), although others have suggested the term
      'stem cell ALL' for the multilineage process. Because it has been difficult to
      perform lineage studies of the Ph chromosome, we investigated the use of
      fluorescence in situ hybridization (FISH) with probes for BCR (on chromosome 22)
      and ABL (on chromosome 9) to study lineage involvement in Ph+ lymphoblastic
      malignancies. We analyzed routine blood and marrow specimens from eight patients
      who presented with Ph+ lymphoblastic leukemia and found that FISH recognized the
      9;22 translocation, distinguished between the two common molecular variants, and
      readily identified multilineage vs lymphoblast-restricted disease. In our series,
      four patients had multilineage and four had lymphoblast-restricted disease.
      Multilineage disease was associated with morphologic features of CML at diagnosis
      and/or reversion to chronic phase CML after treatment leading us to consider it
      as CML presenting in L-BP. Patients with lymphoid-restricted disease lacked such
      findings. The survival of three of our four patients with multilineage disease
      was prolonged, at 25, 28+, and 126+ months, and when data from our entire series
      are added to those of 18 previously reported cases that were studied for lineage
      involvement (reviewed in Leukemia 1993; 7: 147), the difference in overall
      survival between patients with multilineage and lymphoblast-restricted disease is
      significant (median overall survival of 47 months vs 8 months, respectively;
      P=0.013, log rank). Our findings illustrate that FISH analysis can be used to
      recognize lineage involvement in patients presenting with Ph+ lymphoblastic
      malignancies, and they provide further support to the notion that multilineage
      and lymphoblast-restricted disease are distinct clinically as well as
      biologically.

PMID- 8656676
TI  - Long-term survival and proliferation of precursor-B acute lymphoblastic leukemia
      cells on human bone marrow stroma.
AB  - Leukemic cells frequently persist in the bone marrow of patients treated for
      acute lymphoblastic leukemia (ALL), and may regrow to produce relapse. We have
      used a long-term co-culture system to analyze the interaction of ALL blasts with
      components of the marrow microenvironment. Blast cells from 10 cases of precursor
      B ALL were cultured on allogeneic human bone marrow stromal layers at 37 degrees
      C in microtiter wells, and replated when stroma showed evidence of deterioration.
      Leukemic cells from seven of 10 cases showed evidence of survival and
      proliferation beyond 30 days in culture, while in three cases there was a
      progressive decline in the number of viable leukemic cells by 7-21 days. Two
      cases continued to proliferate for 149 to 332+ days, while five underwent
      senescence after 34-52 days. In the two cases with long-term proliferation, the
      leukemic identity of the cells was confirmed by immunophenotyping, cytogenetics,
      and demonstration of clonal immunoglobulin gene rearrangements. Evidence of
      selection of leukemic subclones was seen in two cases, with immumophenotypic
      evidence of loss of CD10 and CD34 antigens, and acquisition of CD20 and surface
      mu chain. The leukemic cells in these cases grew either in clumps attached to the
      surface of the stroma, or as'cobblestone areas' beneath the stromal cells.
      Survival and growth of two evaluable cases was dependent on the continuing
      presence of stromal cells in the culture system. In one case, direct contact with
      stroma was shown to be necessary to main- tain viability, while blast cells from
      the other case survived equally well when separated from the stroma by a 0.4
      micron pore size microporous membrane. These results indicate that leu- kemic
      cells from the majority of cases of precursor-B ALL are able to persist and
      undergo proliferation in vitro in the presence of normal marrow stroma. This
      process appears dependent on either direct cell-cell contact, or on diffusible
      factors derived from the stroma. The availability of ALL cells capable of
      indefinite proliferation under these conditions will allow further analysis of
      the mechanisms mediating leukemic cell proliferation.

PMID- 8656677
TI  - Role of serine and ICE-like proteases in induction of apoptosis by etoposide in
      human leukemia HL-60 cells.
AB  - This study was undertaken to examine the role of proteases in etoposide-induced
      apoptosis of human leukemia HL-60 cells. We found the potent activity to produce
      internucleosomal DNA fragmentation in a 150 000 g supernatant of cell lysate
      which was prepared from etoposide-treated HL-60 cells undergoing apoptosis. This
      nuclear-DNA fragmenting activity could be detected when the supernatant was
      incubated with isolated nuclei under Mg2+-dependent conditions. On the other
      hand, we could not detect such activity in the supernatant of cell lysate from
      non-treated HL-60 cells. Treatment of the supernatant with a serine protease
      inhibitor, N-tosyl-L-phenylala-nylchloromethyl ketone (TPCK), abolished the DNA
      fragmenting activity. An inhibitor of interleukin 1-beta-converting enzyme (ICE),
      Z-Val-Ala-Asp-fluoromethyl ketone (VAD-FMK), had no effect on this DNA
      fragmenting activity in vitro. However, when the cells were incubated with
      etoposide in the presence of VAD-FMK, the formation of TPCK-sensitive DNA
      fragmenting activity was blocked. Our data indicate that serine and ICE-like
      proteases may be involved in etoposide-induced apoptosis at the different stages,
      and especially a serine protease may be closely associated with the final step
      for induction of internucleosomal DNA fragmentation during apoptosis in HL-60
      cells.

PMID- 8656678
TI  - Pharmacokinetics and efficacy of low-dose all-trans retinoic acid in the
      treatment of acute promyelocytic leukemia.
AB  - A clinical trial was conducted in order to evaluate the therapeutic effect and
      side-effects of low-dose ATRA in the treatment of acute promyelocytic leukemia
      (APL). We compared the pharmacokinetic features in normal individuals with single
      oral ATRA at 15 mg/m2 and 45 mg/m2, respectively. The results showed that maximal
      plasma concentration (Cpmax) with oral 15 mg/m2 ATRA was high enough (10(-6) M)
      to induce APL cell differentiation. Based on these results, 27 cases of de novo
      APL patients were treated with continuous oral ATRA at the dose of 15-20
      mg/m2/day and 24/26 evaluable cases (92%) achieved clinical CR after 13 to 67
      days of ATRA treatment. No patient experienced RAS and DIC. The Cpmax with a
      single dose of ATRA on day 1 of treatment and immediately at CR obtained with
      continuous ATRA in three cases demonstrated similar values in one patient and an
      approximately two-fold decrease in two patients. More importantly, compared with
      a relatively well-matched historic group of 20 APL patients treated with high
      dose ATRA, our results suggest that low-dose ATRA is as effective as high-dose in
      treating APL patients and may provide advantages through decreased
      hyperleukocytosis and other side-effects.

PMID- 8656679
TI  - The CD30 ligand and CD40 ligand regulate CD54 surface expression and release of
      its soluble form by cultured Hodgkin and Reed-Sternberg cells.
AB  - The membrane-bound proteins CD30 ligand (CD30L), CD40L and 4-1BBL are members of
      the tumor necrosis factor (TNF) superfamily. They are expressed mainly by
      activated T cells. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells,
      regarded as the malignant components of Hodgkin's disease (HD), display high
      levels of the counter-receptors for these ligands, ie CD30, CD40 and 4-1BB. CD30L
      and CD40L are known to share some biological activities that can be linked to the
      unbalanced secretion of cytokines seen in HD. In addition, cell contact-dependent
      molecules such as adhesion or activation antigens are critically involved in T
      cell/H-RS cell interactions. Primary and cultured H-RS cells frequently
      overexpress intercellular adhesion molecule-1 (ICAM-1/CD54), BB-1 (B7-1/CD80) and
      B70/B7-2 (CD86). Here we show that CD30L and CD40L, but not 4-1BBL upregulate
      CD54 expression by cultured H-RS cells on the mRNA and protein level, as a result
      of transcriptional gene activation. Furthermore, enhanced CD54 surface expression
      by these cells is accompanied by increased shedding of surface-bound CD54, as
      evidenced by high levels of the 82 kDa soluble (s) CD54 form detectable in
      culture supernatants after specific stimulation. Addition of CD30L in combination
      with CD40L to cultured H-RS cells additively enhanced CD54 surface expression and
      its shedding. These results may give a plausible explanation why sCD54 serum
      levels are increased in patients with HD.

PMID- 8656681
TI  - Mutation of the ras genes is a rare genetic event in the histologic
      transformation of follicular lymphoma.
AB  - The role of ras gene mutations in the progression of follicular lymphoma has been
      ascertained by SSCP-PCR and sequencing. A total of 40 transformed lymphomas were
      studied, 16 of which had a matched preceding low-grade biopsy. Only one
      transformed lymphoma was found to have a missense mutation at codon 12 of N-ras,
      resulting in an amino acid change of glycine to serine. We conclude that mutation
      within the ras gene family is a rare event in the transformation of follicular
      lymphoma.

PMID- 8656680
TI  - Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone
      (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low
      Grade Lymphoma Study Group.
AB  - The current study was initiated to compare the anti-lymphoma activity and side
      effects of prednimustine/mitoxantrone (PmM) vs cyclophosphamide, vincristine,
      prednisone (COP) in patients with advanced low-grade non-Hodgkin's lymphomas in
      way of a prospective randomized multicenter trial. Two hundred and forty-six
      patients with stage III or IV centroblastic-centrocytic (CB-CC (Kiel
      classification)) or follicle center lymphoma (FCL (REAL classification)) and
      centrocytic (CC) or mantle-cell-lymphoma (MCL) were randomized for therapy with
      either PmM or COP and are fully evaluable for response and toxicity. PmM
      consisted of prednimustine 100 mg/m2/day on days 1-5 and mitoxantrone 8 mg/m2
      /day days 1 and 2, while COP comprised cyclophosphamide 400 mg/m2/day on days 1
      5, vincristine 1.4 mg/m2/day on day 1 and prednisone 100 mg/m2/day on days 1-5.
      Both regimens were repeated for a total of six cycles followed by an additional
      two courses for consolidation in responding cases and a subsequent second
      randomization for interferon alpha maintenance vs observation only. Overall
      response rates were comparable with 83% complete and partial remissions after COP
      and 84% remissions after PmM. PmM revealed a significantly higher rate of
      complete remissions (36 vs 18%, P < 0.006), the majority being achieved after
      four courses. The more rapid and possibly also more effective reduction of the
      lymphoma cell mass by PmM resulted in a tendency to a longer event-free interval
      for patients achieving remissions after PmM as compared to COP with estimated
      median event-free intervals of 31 vs 14 months, respectively (P=0.04). Separate
      analysis of lymphoma subtypes showed a tendency to a lower rate of complete
      remission in CC or MCL as compared to CB-CC or FCL (16 vs 30%, P=0.12, NS) while
      overall response rates were in a similar range (81 vs 85%). In both subtypes, PmM
      induced a higher rate of complete remission while overall response rates were
      comparable after PmM or COP. Treatment associated side-effects comprised
      predominantly myelosuppression and granulocytopenia in particular which was more
      frequently observed after PmM than COP (43 vs 31 %, P < 0.0001). This difference
      was clinically irrelevant, however, since serious infectious complications were
      encountered in less than 3% of cycles after both regimens. COP therapy was
      associated with a significantly higher incidence and degree of hair loss and
      complete alopecia (31 vs 2%) as well as of peripheral neurotoxicity (23 vs 2%).
      These data show that both PmM and COP reveal a high anti-lymphoma activity in
      patients with advanced stage non-Hodgkin's lymphoma. PmM appears advantageous
      with a higher rate of complete remissions and a better tolerability with regard
      to secondary side-effects. A longer follow-up is needed to assess the long-term
      effects of initial treatment on disease-free and overall survival and the impact
      on additional maintenance therapy with interferon alpha.

PMID- 8656682
TI  - Small B cell NHL and their leukemic counterpart: differences in subtyping and
      assessment of leukemic spread.
AB  - Three subtypes of small lymphocytic lymphoma were studied, namely B cell chronic
      lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL) and follicle center
      lymphoma (FCL). Agreement between tissue diagnosis, based on the proposal for a
      revised European-American classification of lymphoid neoplasms from the
      International Lymphoma Study Group, and the cytomorphological diagnosis on
      peripheral blood and/or bone marrow smears, using the proposals for the
      classification of chronic (mature) B and T lymphoid leukemias of the French
      American-British Cooperative Group, was studied. Full agreement was found in 90%
      of the CLL and 82% of the FCL cases. In MCL cases, agreement was 65% including
      all cases classified as intermediate/mantle zone lymphoma according to FAB
      criteria. The incidence of bone marrow involvement detection in trephines
      compared to smears was equal in CLL (both 100%) and slightly higher in MCL (56 vs
      48.5%); in FCL, however, trephine biopsies provided more reliable material (71 vs
      35%).

PMID- 8656683
TI  - Increased frequency of HLA-DPB1*0301 in Hodgkin's disease suggests that
      susceptibility is HVR-sequence and subtype-associated.
AB  - Hodgkin's disease (HD) is a complex lymphoma-like disease which occurs as four
      main subtypes, nodular sclerosing (NS), mixed cellularity (MC), lymphocyte
      predominant (LP) and lymphocyte depleted (LD). Suggestions from epidemiological
      studies that HD may represent an unusual response to infection imply that the
      lack of previous response could be due to genetic factors. Following recent
      reports suggesting that there is an increased frequency of HLA-DPB1*0301 in
      Hodgkins disease, we have studied DPB1 in two series of patients using molecular
      typing methods. One series is a retrospective group of 118 patients over the age
      of 15 years from a single centre, and the other is a multi-centre prospective
      group of 45 patients between the age of 16 and 24 years. In both series, the
      percentage of HD patients with DPB1*0301 is greater than in the controls,
      confirming that this seems to be an HD-susceptibility allele. However, extension
      of the analysis in relation to HD subtype shows that the increase in *0301 is
      present in nodular sclerosing (NS), mixed cellularity (MC) and lymphocyte
      predominant patients (LP) HD patients, but preliminary evidence suggests an
      increase in *0401, and possibly *0501 in MC- and LP-HD. The DPB1 hypervariable
      region (HVR) amino-acid motif Asp55, Glu56 (*0301-like, HVR-C) is increased in NS
      compared with non-NS (ie MC+LP), whereas the frequency of Ala55, Ala56 (*0401
      like) is increased in non-NS compared with NS. Conversely, Asp84,
      Glu85Ala86(*0301-like, HVR-F) motif is more frequent in NS than non-NS patients,
      but there is no increase in Gly84, Gly855, Pro86 (*0401-like). These findings
      suggest that genetic susceptibility in HD may reside at the level of HVR-encoded
      DPB1 peptide-binding residues, rather than with a specific allele, and that this
      may in some way influence the HD subtype.

PMID- 8656684
TI  - G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation
      of resistant or relapsing acute leukemias.
AB  - Peripheral blood progenitor cells (PBPC) were mobilized by G-CSF in normal HLA
      identical siblings and used for allogeneic transplantation in eight patients with
      refractory or relapsed acute leukemias. G-CSF administration was well tolerated
      and no significant side-effects were registered. The number of circulating WBC
      peaked at day 5 after G-CSF (range: 22.6-74.6 x 10(9)/l) with a median of 65
      CD34+ cells/microl (38-155). As a consequence of leukaphereses, platelets
      progressively decreased, reaching the nadir after the last procedure (84-205 x
      10(9)/l). A mean of two aphereses (1-3) were performed between day +4 and +7
      during which 10 liters of blood were processed each time by a cell separator.
      Conditioning regimens were: fractionated total body irradiation (FTBI) plus
      either HDAra-C (2 g/m2 x 2/day for 6 days) (n=5) or melphalan (110 mg/m2) (n= 1)
      and busulfan (4 mg/kg/day for 4 days) and melphalan (110 mg/m2) in two patients
      relapsed after a previous FTBI-based allogeneic or autologous BMT. At
      transplantation, a median of 6.9 x 10(6) CD34+ cells/kg (4.2-16.5) and 279 x
      10(6) CD3+ cells/kg (161-786) were infused. Engraftment of both neutrophils (> or
      v=1.5 x 10(9)/l) and platelets (> or v=20 x 10(9)/l) was observed in all patients
      after a median time of 18 days (range: 11-20 and 10-26, respectively). The
      evaluation of engraftment after transplantation was accomplished by PCR analysis
      of four hypervariable genomic regions (VNTR) (ApoB, ApoC2, YNZ-22, and MCT 118)
      which allowed to demonstrate the condition of donor chimaera in all patients
      after transplantation. As far as the clinical outcome, two patients died of
      interstitial pneumonitis at day +243 and +69 and two patients died at day +62 and
      +152 of pulmonary aspergillosis. Four patients remain alive in remission between
      day +88 and +287 with grade 0-l GVHD. Allogeneic PBPC transplantation is
      associated with a complete hematologic recovery and despite the infusion of a
      large amount of mature CD3+ lymphocytes, apparently acute GVHD is not worse than
      expected after transplantation of bone marrow progenitors.

PMID- 8656685
TI  - Establishment and characterization of three myeloma cell lines that demonstrate
      variable cytokine responses and abilities to produce autocrine interleukin-6.
AB  - A consensus regarding myeloma cell growth factor responsiveness and ability to
      produce autocrine interleukin (IL)-6 has not yet been obtained. In this study, we
      have established three new human myeloma cell lines (DP-6, KAS-6/1 and KP-6) from
      patients with aggressive disease. Extensive characterization of these cell lines
      revealed considerable heterogeneity at several levels. Growth factor
      responsiveness was initially addressed. Although the potent myeloma cell growth
      factor, IL-6, induced the proliferation and allowed for the expansion of all
      three cell lines, a panel of other cytokines elicited heterogeneous responses in
      each cell line. IL-3, IL-10, IL-11, insulin-like growth factor-I and tumor
      necrosis factor-alpha also stimulated DNA synthesis in all three cell lines;
      however, the magnitude of the response was generally lower than that observed in
      cultures containing IL-6. Transforming growth factor-beta, by contrast, uniformly
      inhibited the growth of all three cell lines. IL-1alpha and IL-1beta induced the
      proliferation of the DP-6 cells, but had minimal effects on the KAS-6/1 and KP-6
      cells. Interferon (IFN)-alpha stimulated DNA synthesis in the KAS-6/1 cells, but
      inhibited the proliferation of the DP-6 and KP-6 cells. By comparison, IFN-gamma
      induced the growth of the KAS-6/1 and DP-6 cells, but inhibited the KP-6 cells.
      The gp130-associated cytokines, IL-11, leukemia inhibitory factor and oncostatin
      M, stimulated the growth of the KAS-6/1 cells, but had minimal effects on the DP
      6 and KP-6 cells. The cell lines were also analyzed for IL-6 expression. RT-PCR
      analysis demonstrated that all three cell lines expressed IL-6 mRNA. However,
      when culture supernatants were tested using a sensitive IL-6 ELISA or IL-6
      bioassay only the DP-6 and KP-6 cells were shown to be secreting biologically
      active IL-6. In summary, although all three of these cell lines were established
      from myeloma patients, the heterogeneity observed between these cell lines was
      considerable and may reflect, as well as provide tools to study, the
      heterogeneity observed in clinical disease.

PMID- 8656686
TI  - Consensus protocol for the flow cytometric immunophenotyping of hematopoietic
      malignancies. Working Group on Flow Cytometry and Image Analysis.
AB  - Flow cytometry has become the preferred method for the lineage assignment and
      maturational analysis of malignant cells in acute leukemias and lymphomas.
      Multiparametric immunophenotyping allows the detection of aberrant antigen
      coexpression and the analysis of heterogeneity and clonality of malignant cells
      in leukemias and lymphomas. The complexity of multiparameter analysis techniques
      and the multitude of available monoclonal antibodies demand a standardization of
      protocols for the use of flow cytometry in clinical laboratories in order to
      achieve interlaboratory reproducibility. Therefore, the Working Group on Flow
      Cytometry and Image Analysis has started an initiative in order to establish a
      consensus protocol on the current methods of the phenotyping of hematological
      neoplasias as a basis for quality assurance and support for upcoming technologies
      such as quantitative analysis of antigen densities and automated knowledge-based
      analysis software. In addition to general recommendations on assay procedures and
      quality control specific recommendations are given for the selection of two-color
      reagent panels and data interpretation in an attempt to define a basis for cross
      evaluation against the different currently established laboratory protocols.

PMID- 8656687
TI  - Monitoring of residual disease in chronic myelogenous leukemia: methodological
      approaches and clinical aspects.

PMID- 8656688
TI  - Intercellular adhesion molecules (ICAMs) 2 and 3 are frequently expressed in B
      cell chronic lymphocytic leukemia.
AB  - Using different monoclonal antibodies (moAbs) from the 5th International Workshop
      on Leukocyte Differentiation Antigens we studied the expression of intercellular
      adhesion molecules (ICAMs) 2 and 3 on a homogeneous group of 23 B cell chronic
      lymphocytic leukemia (CLL) patients. Our results show that either ICAM-2 or ICAM
      3 are constitutively expressed on CD5+ B-CLL cells. Owing to the role of ICAM
      molecules in governing the migration and traffic of lymphocytes to lymph nodes,
      our findings need to be validated in a more consistent patient series to
      understand clinico-prognostic implications of such an expression.

PMID- 8656690
TI  - A patient with ammonia-producing multiple myeloma showing hyperammonemic
      encephalopathy.

PMID- 8656689
TI  - A T cell lymphoblastic lymphoma patient with two malignant cell populations
      carrying different 9p deletions including the p16INK4 and p15INK4B genes:
      Clinical response to interferon-alpha therapy in one of the subclones.

PMID- 8656691
TI  - Measurement of minimal residual disease in acute leukemia.

PMID- 8656692
TI  - Late relapse after autologous BMT.

PMID- 8656693
TI  - Acute undifferentiated leukemia with an unusual CD7+ CD56+ CD33+ immunophenotype
      of NK progenitors.

PMID- 8656694
TI  - Clinical relevance of drug resistance genes in malignant disease.
AB  - Drug resistance is a major reason for the failure of anticancer chemotherapy.
      Multidrug resistance has been recognized as an important type of resistance and
      can be due to various mechanisms. Here we review the published data on the
      presence and clinical significance of these mechanisms in solid tumors and
      hematological malignancies. We also refer to new treatment strategies resulting
      from the knowledge of the various mechanisms of drug resistance present in
      malignant diseases.

PMID- 8656695
TI  - Association of bcl-2, bax, bcl-xL and interleukin-1 beta-converting enzyme
      expression with initial response to chemotherapy in acute myeloid leukemia.
AB  - Bcl-2 expression is able to confer drug resistance to chemotherapy-induced
      programmed cell death. Bax, a partner protein of bcl-2 with extensive aminoacid
      homology, is a promoter of apoptosis. Apparently the equilibrium of bcl-2 and bax
      hetero- and homodimers is important for the susceptibility of cells for stimuli
      inducing apoptosis. In this study we determined the role of bcl-2 to bax
      expression ratio, bcl-xL and ICE expression level for predicting clinical
      response to chemotherapy in acute myelold leukemia (AML). Bone marrow samples
      from 14 patients with AML were examined using an immunophosphatase staining
      method. Initial bone marrow blast portion was over 80% in all cases. Clinical
      response was defined by bone marrow aspiration 4 weeks after treatment
      initiation. There was a significant correlation between bcl-2 to bax expression
      ratio and clinical response (P < 0.005). No patients with a bcl-2/bax ratio >1.0
      achieved complete remission after induction therapy. No significant correlation
      between bcl-2- and p-glycoprotein-expression was observed in this group.
      Conversely a high expression of ICE indicated a good clinical response (P <
      0.01), whereas expression of bcl-xL had no influence on therapeutic success in
      this group.

PMID- 8656696
TI  - P53 and induction of apoptosis as a target for anticancer therapy.
AB  - p53 is the most frequently mutated gone in human cancer cells. Its wild-type gone
      encodes for a protein with pivotal functions: (i) interaction with key players in
      the cell cycle leading to cell cycle arrest; (ii) induction of programmed call
      death, or apoptosis. P53 may be seen as another member of the family of proteins
      involved in resistance to anticancer therapy, since mutations/deletions involving
      the p53 gene lead frequently to resistance of radiation/cytotoxic drug treatment.
      Consequently, patients with p53-mutated tumors may harbor a worse prognosis. On
      the other hand, reintroducing wild-type P53 may lead to an adequate function of
      the cellular cell cycle and/or apoptosis program, thus enabling efficient anti
      cancer therapy even in the presence of mutated P53. Two options are being
      discussed: (i) gene therapy approaches; (ii) modulating mutated P53 with yet
      unknown molecules.

PMID- 8656698
TI  - MDR1 reversal: criteria for clinical trials designed to overcome the multidrug
      resistance phenotype.
AB  - Multidrug resistance (MDR) is a widely studied mechanism of cellular resistance
      to structurally unrelated cytotoxic agents. The MDR phenotype is related to the
      overexpression of the MDR1 gene product, P-glycoprotein (P-gp), a transmembrane
      drug efflux pump. The capacity to compete with the cytotoxic drug for the active
      outward transport process, thus inhibiting the activity of the P-gp pump, has
      been demonstrated for numerous non-cytotoxic compounds, termed MDR modulators.
      The possibility of modulating the activity of the P-gp pump has initiated
      numerous clinical trials, using a wide range of chemosensitizers. This article
      reviews these substances, discusses problems that may arise in connection with
      the concurrent administration of P-gp modulators and chemotherapeutic agents and
      provides guidelines for the design of future clinical trials. Furthermore, now
      data are presented concerning the potential of idarubicin to overcome the MDR
      phenotype.

PMID- 8656697
TI  - P-glycoprotein expression in patients with acute leukemia-clinical relevance.
AB  - P-glycoprotein (P-gp) is a crucial factor in the development of chemotherapy
      resistance in malignant disorders. Between 1989 and 1995, P-gp expression was
      studied in bone marrow blast cells of 322 (239 AML; 83 ALL) acute leukemia
      patients. 166 AML patients with the AML-6 protocol (EORTC), containing
      daunorubicin, vincristine and conventional-dose cytarabine (ara-C), and 63 AML
      patients treated with intermediate-does Ara-C plus amsacrine. Further 71 ALL
      patients were treated according to a German standard polychemotherapy protocol
      (BMFT04/1989). P-gp was determined by using monoclonal antibodies C219 and 4E3,
      and the cutoff point for P-gp overexpression was set at >/= 10%. A significant (P
      < 0.06) difference in P-gp overexpression was demonstrated between AML (21.6%)
      and ALL (10.2%) patients at primary diagnosis and between primary diagnosis and
      relapse/refractoriness in AML (21.6%; 51.0%) and ALL (10.2%; 27.2%) patients.
      According to FAB classification P-gp overexpression was detected in AML patients
      significantly (P < 0.05) more frequently in classes M4, M5a and M5b and less
      frequently in M3, as compared to other types. For AML patients with P-gp
      overexpression at primary diagnosis or early relapse/refractoriness, the
      predictive value for nonresponse to the AML-6 protocol was 91 and 95%,
      respectively, while late-relapsed AML patients with P-gp overexpression had a
      significantly (P < 0.05) lower predictive value of 73% for nonresponse.
      Additionally, in refractory and late-relapsed P-gp--overexpressing AML patients
      treated with intermediate-dose ara-C plus amsacrine the predictive values for
      nonresponse were 44 and 39%, respectively, significantly (P < 0.05) lower as
      compared to AML-6 protocol-treated refractory or late-relapsed AML patients. In P
      gp-overexpressing treated ALL patients the predictive values of 50 and 55% for
      non-response were calculated at primary diagnosis and late relapse, respectively.
      We conclude that P-gp overexpression is a common phenomenon in AML patients at
      primary diagnosis or relapse, has an inverse influence on AML-6 treatment outcome
      and should be taken into consideration in the development of new therapy
      strategies.

PMID- 8656699
TI  - MDR1, MRP, topoisomerase IIalpha/beta, and cyclin A gene expression in acute and
      chronic leukemias.
AB  - Gene expression was analyzed by cDNA-PCR at the mRNA level in bone marrow samples
      (>80% blasts) from ALL (28 primary, 22 first relapses, 10 recurrent relapses),
      from AML (14 primary, 23 relapses), In peripheral blood lymphocytes from CLL
      (five untreated, 10 treated), in one CML in blast crisis in the course of the
      disease (four samples), and in bone marrow samples from healthy donors (12
      specimens). We found low mean MDR1 expression in primary ALL, first relapses of
      ALL, and primary AML. Significantly higher mean relative MDR1 expression levels
      were seen in recurrent relapses of ALL, and in the group of relapsed state AML.
      MDR1 expression measured intermediate in bone marrow samples from healthy donors.
      The CLL lymphocytes showed generally relatively high MDR1 expression levels. MRP
      gene expression measured very similar in primary ALL, first relapses of ALL,
      primary AML, and normal bone marrow. Significantly increased MRP mRNA levels were
      observed in the groups of recurrent ALL and relapsed state AML. CLL lymphocytes
      also showed high MRP expression levels. A combined increase of MDRI (about 20
      fold) and MRP (about four-fold) was monitored in samples obtained from the CML in
      blast crisis after chemotherapy. While no significant differences of the mean
      topoisomerase IIbeta mRNA levels were found throughout, a significantly decreased
      topoisomerase IIalpha gene expression was measured in first and recurrent
      relapses of ALL. In CLL lymphocytes either the expression of the topoisomerase
      IIalpha gene was not detectable by cDNA-PCR, or it measured very low.
      Topoisomerase IIalpha gene expression was correlated to cyclin A gene expression
      in the samples of acute leukemias, Indicating the link of topoisomerase IIalpha
      expression to the proliferative activity of these leukemic blast cells. Our
      results point to a potentially multifactorial emergence of multidrug resistance
      in particular states and types of leukemias.

PMID- 8656700
TI  - Topoisomerase II activities in AML blasts and their correlation with cellular
      sensitivity to anthracyclines and epipodophyllotoxines.
AB  - We have developed a method to quantify topoisomerase (topo) II activities in
      partially purified nuclear extracts from human leukemia cells. By virtue of their
      different pH optima in the reaction buffer, two different topo II activities were
      found with activity optima at pH 7.9 and at pH 8.9 under high stringency
      conditions. The activities could be identified as topo II beta activity (pH 7.9)
      and topo II alpha activity (pH 8.9) by their different sensitivities to topo II
      alpha inhibitors, dephosphorylation experiments and immunoprecipitation with
      polyclonal antibodies. Seventy-two bone marrow or blood samples from patients
      with acute myeloid leukemias have been examined and their in vitro sensitivities
      to anthracyclines and epipodophyllotoxines correlated to the activities of topo
      II alpha and topo II beta. Although the topo II alpha activity could be directly
      inhibited by incubation of the cells with the mentioned drugs, no correlation
      between the topo II alpha activity and the sensitivity of the cells could be
      found. In contrast, the topo II beta activity which was not substantially
      inhibited by the drugs inversely correlated with the sensitivity of the cells.
      These findings were statistically significant for idarubicin (P=0.017) and
      daunorubicin (P=0.006). Vice versa, resistant cells (IC90 > median) had a higher
      topo II beta activity. Clinical relevance might be indicated by the finding that
      cells from patients that relapsed after initial treatment with anthracyclin
      containing regiments had a significantly higher topo II alpha/beta activity ratio
      (P=0.0276). Obviously, the sensitivity of AML cells is substantially influenced
      by the activity of the resistant topo II (topo II beta) which gives evidence that
      the remaining topo II activity after treatment helps the cell to survive the DNA
      repair phase.

PMID- 8656701
TI  - More individual markers are necessary for patients with acute myeloid leukemia
      (AML). Does cytomorphology or cytogenetics define the biological entity?
AB  - The biology of AML is reflected through several prognostic factors. Until now
      there has been no general agreement about these factors. In most studies therapy
      is not stratified according to risk factors with the exception of age. Since 1976
      the FAB classification has been the basis for the diagnosis in AML. But only for
      the AML M3 is this important for the choice of treatment. Therefore, it is
      unclear if the FAB classification is the best way to describe the individual
      biology in AML. We are able to verify that significant differences in remission
      rates and event-tree survival are much better reflected by the cytogenetic
      results. With data from the AML cooperative group on one hand and in a kind of
      meta-analysis with cytogenetic date from different studies on the other hand, we
      are able to conclude that cytogenetics are much more feasible to describe the
      biological entity in AML patients. Further studies should focus more on this
      individual prognostic factor.

PMID- 8656702
TI  - Dr. William J. Mayo and the masters of surgery.

PMID- 8656703
TI  - Ultrasound cardioscopy: embarking on a new journey.
AB  - OBJECTIVE: To present the results of investigation of a new application of
      invasive ultrasonography-ultrasound cardioscopy, a procedure in which a self
      contained ultrasound device is capable not only of producing an under-blood field
      of view but also of delivering diagnostic and therapeutic tools. DESIGN: Twenty
      adult mongrel dogs were studied with the ultrasound cardioscopy device during
      experimental catheter ablation procedures. MATERIAL AND METHODS: A rigid
      prototype probe, 34 cm long and 8 mm in diameter with a 7-MHz side-viewing
      transducer at the tip and an 8-F diameter tool delivery port, was introduced
      through the right external jugular vein into the right heart chambers. Remote and
      device-directed ablation procedures were monitored. Subsequently, the canine
      hearts were excised and examined. RESULTS: The self-contained cardioscopy device
      with a contained ablation catheter could both direct and visualize a specified
      ablation injury. Under-blood observation of the details of the ablation procedure
      was possible. Although a learning curve existed for appropriate manipulation of
      the device, inspection of the excised hearts showed that the size of the injury
      was accurately predicted with use of ultrasound cardioscopy. CONCLUSION:
      Ultrasound cardioscopy is a promising means of performing precise under-blood
      diagnostic and therapeutic maneuvers.

PMID- 8656704
TI  - Epithelioid sarcoma: a clinicopathologic review of 55 cases.
AB  - OBJECTIVE: To identify any clinical and pathologic features of treatment
      modalities that are predictive of outcome in patients with epithelioid sarcoma, a
      rare slow-growing soft tissue tumor most commonly occurring in the distal
      extremities of young adults. DESIGN: We reviewed the institutional files for
      cases of epithelioid sarcoma for the period 1956 to 1991 and analyzed the effect
      of various factors on survival. MATERIAL AND METHODS: Fifty-five cases of
      epithelioid sarcoma were found, and the relevant clinical, pathologic, treatment,
      follow-up, and outcome features were assessed. RESULTS: All tumors were treated
      initially by operative resection. The recurrence rate progressively decreased
      with increasing aggressiveness of the initial operation; however, no difference
      was noted in metastatic rate. Overall, the recurrence rate was 38% and the
      metastatic rate was 47%. At the end of a mean follow-up of 102 months, 69% of
      patients had no evidence of disease, 27% had died of the disease, and 4% were
      alive with disease. Increasing tumor size, necrosis of more than 30%, and
      vascular invasion correlated significantly with a worse prognosis. CONCLUSION:
      Epithelioid sarcoma should be considered a malignant neoplasm with a significant
      potential for aggressive behavior, and close follow-up of affected patients
      should be maintained for many years. Initial treatment should be aggressive in an
      attempt to prevent recurrence.

PMID- 8656705
TI  - Detection of hyperdiploid malignant cells in pleural effusions with chromosome
      specific probes and fluorescence in situ hybridization.
AB  - OBJECTIVE: To compare the efficacy of fluorescence in situ hybridization (FISH)
      by using chromosome-specific probes with standard cytology and cytogenetics for
      detection of hyperdiploid malignant cells in pleural effusions. MATERIAL AND
      METHODS: A blind study was done on 26 pleural effusions from 25 patients who had
      undergone thoracentesis (14 with and 11 without a malignant condition). Cytology,
      cytogenetics, and FISH with probes specific for chromosomes 7, 8, 12, 18, X, and
      Y were done on each pleural effusion. For FISH studies, malignant specimens were
      defined as having 8% or more of cells with hyperdiploidy. RESULTS: Results of
      cytology and FISH were both normal in each of the 11 patients with benign pleural
      effusions. Cytogenetic studies were successful in six of these patients: five
      were chromosomally normal, but one male patient had an abnormal clone that lacked
      a Y chromosome. Among the 14 patients with malignant pleural effusions, cytology
      and FISH were abnormal in 8 and 6, respectively. Cytogenetic studies were
      successful in 11 of these patients, and an abnormal clone was found in 5.
      CONCLUSION: FISH can detect hyperdiploid malignant cells in pleural effusions and
      can be useful in the work-up of patients suspected of having malignant pleural
      effusions.

PMID- 8656706
TI  - Gonadotroph adenoma of the pituitary gland: a clinicopathologic analysis of 100
      cases.
AB  - OBJECTIVE: To determine the clinical and pathologic features in a large cohort of
      randomly selected patients with gonadotroph pituitary adenomas. DESIGN: We
      retrospectively reviewed clinical, surgical, and pathologic findings in 100
      patients (79 men and 21 women, 30 to 82 years old) with this tumor. RESULTS:
      Diagnosis of a pituitary tumor was prompted by visual loss (43%), symptoms of
      hypopituitarism (22%), headache (8%), or a combination of these findings (10%);
      17% of the patients were asymptomatic. Visual field defects were present in 68%
      of the study group, and complete or partial anterior pituitary failure was
      present in 77%. Serum prolactin concentrations were increased (maximum, 110
      ng/mL) in 33% of patients. Hypersecretion of follicle-stimulating hormone (FSH)
      and luteinizing hormone (LH) was documented in 11 and 5 patients, respectively.
      The serum level of alpha-subunit was increased in 1 of 29 patients in whom it was
      measured. All patients had pituitary macroadenomas, only 21% of which were
      grossly invasive. The surgical approach was transsphenoidal in all but two
      patients, who underwent transfrontal craniotomy; gross total tumor resection was
      achieved in 90%. By definition, all tumors had at least 10% immunoreactivity for
      LH, FSH, or both. All tumors were chromophobic. Ultrastructurally, the tumors
      were characterized as gonadotroph adenomas of "male" (45%) or "female" (9%) type
      as well as null-cell adenomas of the oncocytic (35%) or nononcocytic (11%) type.
      After a median follow-up of 4.3 years, 69% of the patients who had had visual
      field defects noted normalization or improvement. Persistent or clinically
      recurrent pituitary tumor tissue was present in 42%. A second pituitary surgical
      procedure was required in eight patients. CONCLUSION: Most patients with
      clinically evident gonadotroph pituitary tumors have loss of vision and
      hypopituitarism. Hypersecretion of FSH or LH is unusual, and no distinct hormone
      dependent clinical phenotype is present. Transsphenoidal surgical treatment
      generally yields normalization or improvement of visual field defects.

PMID- 8656707
TI  - James D. Watson and DNA.

PMID- 8656708
TI  - Treatment of early Parkinson's disease: are complicated strategies justified?
AB  - A variety of medical treatment strategies have been proposed as a means of
      slowing the progression of Parkinson's disease. This includes administration of
      selegiline (deprenyl) therapy, early use of bromocriptine or pergolide, and delay
      of levodopa therapy or restriction of the dose. There is no compelling evidence
      supporting the use of any of these treatment strategies for this purpose.
      Carbidopa-levodopa remains the most potent medication for symptomatic treatment
      of Parkinson's disease. Although starting levodopa therapy with the controlled
      release formulation is advocated, this does not appear to have any major
      advantages over standard carbidopa-levodopa. Further studies are needed to
      identify other means of halting the progression of Parkinson's disease.

PMID- 8656710
TI  - Myoclonus.
AB  - Myoclonus is defined as sudden, brief, shocklike, involuntary movements caused by
      muscular contractions or inhibitors. Myoclonic movements have now been recognized
      to have many possible variants and pathophysiologic features. Myoclonus may arise
      from several sites within the neuraxis, of which the cortex and brain stem
      reticular formation are the most common. An etiologic classification scheme and
      electrodiagnostic tests are useful for clinical purposes. Therapy is limited and
      usually involves symptomatic treatment with valproic acid or clonazepam. Careful
      attention to the basic characteristics of the movement appearance, the clinical
      circumstances in which the myoclonus occurs, and the results of the
      electrodiagnostic assessment techniques provide a basis for identifying the
      syndrome in which the myoclonus occurs.

PMID- 8656709
TI  - Cerebral ischemia in patients with hepatitis C virus infection and mixed
      cryoglobulinemia.
AB  - We describe two women (ages 35 and 36 years) with cerebral ischemia, hepatitis C
      virus, and mixed cryoglobulinemia. One patient (case 1) was in otherwise good
      health when left parietal cerebral infarction developed, and she was found to
      have narrowing of the supraclinoid internal carotid artery siphon, anterior
      cerebral artery A1, and middle cerebral artery M1 segments bilaterally.
      Subsequent evaluation revealed abnormal liver enzymes, mixed cryoglobulinemia
      (type III), hypocomplementemia, and a high positive test result for rheumatoid
      factor. In the other patient (case 2), cerebral ischemia and seizures developed
      in the setting of previously documented mixed cryoglobulinemia (type II),
      membranoproliferative glomerulonephritis, and hypocomplementemia. In this
      patient, a brain biopsy demonstrated cerebral infarction. Hepatitis C virus
      infection was confirmed in both patients by polymerase chain reaction detection
      of hepatitis C virus RNA. These two cases document the occurrence of cerebral
      ischemia in patients with hepatitis C virus infection and mixed cryoglobulinemia.
      Testing for hepatitis C virus and cryoglobulins should be considered in selected
      patients with cerebral ischemia of inobvious cause.

PMID- 8656711
TI  - Glaucoma: changing concepts and future directions.
AB  - Important concepts about glaucoma have evolved during the past few decades.
      Glaucoma is a family of diseases not defined by a specific intraocular pressure
      but rather as an optic neuropathy that can occur at any intraocular pressure
      depending on the optic nerve susceptibility of the individual person. Increased
      risk factors for idiopathic open-angle glaucoma include advancing age, black
      race, a family history of glaucoma, and increased intraocular pressure. The
      primary-care physician is in the prominent position of recognizing patients with
      increased risk factors or suspicious eye findings who should be referred to an
      ophthalmologist. Topically applied ophthalmic medications have systemic side
      effects that must be recognized and monitored by the primary-care physician. In
      the United States, glaucoma is usually treated with topically applied
      medications; laser or surgical therapy is done if medical treatment fails. The
      National Eye Institute is conducting multicenter studies to confirm whether this
      is still the most appropriate strategy for this common disease.

PMID- 8656712
TI  - Magnetic resonance imaging in epilepsy.
AB  - The magnetic resonance imaging (MRI) appearance of the various histologic
      substrates of epilepsy and the clinical role of MRI in symptomatic epilepsy are
      reviewed. MRI is used clinically to identify potential surgical candidates among
      patients with epilepsy, assist in surgical planning, and help to determine the
      prognosis of patients with epileptic seizures. MRI can clearly characterize the
      morphologic substrates that underlie the electroclinical abnormalities noted in
      patients with epilepsy. The histologic substrates of symptomatic epilepsy can be
      divided into five major categories: tumors, disorders of neuronal migration and
      cortical organization, vascular malformations, mesial temporal sclerosis, and
      neocortical sclerosis attributable to brain injury (trauma, infection,
      inflammation, or infarction). Because of its ability to disclose subtle
      alterations in cortical architecture or changes in signal intensity, MRI is the
      most sensitive and specific imaging technique for the noninvasive identification
      of each of these substrates. Introduction of MRI into clinical practice during
      the past 10 years has substantially changed the management of patients with
      epilepsy.

PMID- 8656713
TI  - 15-year-old boy with abdominal pain and hypertension.

PMID- 8656714
TI  - From Osler with love: the Mayo brothers' Cosmas and Damian print.

PMID- 8656715
TI  - Journeys inside the heart: fantastic voyages, but what will their impact be?

PMID- 8656716
TI  - Complications of cardiac catheterization versus coronary angiography.

PMID- 8656717
TI  - Has the prothrombin time stood the test of time?

PMID- 8656718
TI  - Variations by specialty in physician ratings of the appropriateness and necessity
      of indications for procedures.
AB  - The authors compare the appropriateness ratings and mutual influence of panelists
      from different specialties rating a comprehensive set of indications for six
      surgical procedures. Nine-member panels rated each procedure: abdominal aortic
      aneurysm surgery, carotid endarterectomy, cataract surgery, coronary angiography,
      and coronary artery bypass graft surgery/percutaneous transluminal coronary
      angioplasty (common panel). Panelists individually rated the appropriateness of
      indications at home and then discussed and re-rated the indications during a 2
      day meeting. Subsequently, they rated the necessity of those indications scored
      by the group as appropriate. There were 45 panelists, including specialists
      (either performers of the procedure or members of a related specialty) and
      primary care providers, all drawn from nominations by their respective specialty
      societies. Main outcome measures included: individual panelists' mean ratings
      over all indications, mean change and conformity scores between rounds of
      ratings, and the percentage of audited actual procedures rated appropriate or
      necessary. Performers had the highest mean ratings, followed by physicians in
      related specialties, trailed by primary care providers. One fifth of all actual
      procedures were for indications rated appropriate by performers and less than
      appropriate by primary care providers. At the panel meetings, primary care
      providers and related specialists showed no greater tendency to be influenced by
      other panelists than did performers. Multispecialty panels provide more divergent
      viewpoints than panels composed entirely of performers. This divergence means
      that fewer actual procedures are deemed performed for appropriate or necessary
      indications.

PMID- 8656719
TI  - Full-time employment and informal caregiving in the 1980s.
AB  - The study examines the extent to which the effect of full-time employment on
      informal caregiving has changed over time. Such a change could be expected
      because women, who constitute the majority of unpaid caregivers, have been
      increasing their commitment to career employment. Full-time market work by an
      increasing proportion of successive cohorts of women means that proportionally
      fewer will be available to provide the amount of assistance needed by persons
      with disabilities that require the constant presence of a caregiver. This study
      is based on the National Informal Caregiver Surveys that are linked to the
      National Long-Term Care Surveys of 1982 and 1989. To achieve comparability
      between the 1982 and 1989 data, the analysis is based on primary caregivers whose
      care-recipients were disabled in performing the activities of daily living
      (ADLs): 1,489 in 1982 and 597 in 1989. A simultaneous-equations model estimates
      the number of weekly hours of unpaid help and the probability of full-time work
      for pay. The principal finding is that, compared with nonemployment, full-time
      employment reduced caregiving by 25 hours a week in 1982 and by 22 hours a week
      in 1989, but the difference of 3 hours is not statistically significant. The
      proportion of primary caregivers engaged in market work full time increased from
      15.8%, in 1982 to 19.3% in 1989, but this difference is not statistically
      significant. These findings suggest that full-time employment reduces caregiving
      time substantially but that the effect of full-time employment on informal
      caregiving by primary caregivers of ADL-disabled elderly did not change during
      the 1980s. Primary caregivers with full-time jobs were more likely to assist
      individuals disabled in bathing and dressing, two activities that do not require
      the constant presence of a caregiver. The primary caregivers of individuals with
      more than two ADL disabilities frequently were the spouses of the care
      recipients, themselves elderly persons who were not expected to be engaged in
      market work. The data from the 1980s appear to be reassuring in the sense that
      full-time employment by primary caregivers of ADL-disabled elderly did not
      further reduce the amount of time that they devoted to caregiving. In 1989, only
      about one fifth of these caregivers were engaged in market work full time. But
      this proportion is likely to increase in the future. As these future increases
      materialize, proportionally fewer caregivers will be available to provide the
      amount of help needed by persons with ADL disabilities that require the constant
      presence of a caregiver.

PMID- 8656720
TI  - A measurement model of the Medical Outcomes Study 36-Item Short-Form Health
      Survey in a clinical sample of disadvantaged, older, black, and white men and
      women.
AB  - The authors assess the factorial validity of the Medical Outcomes Study 36-Item
      Short-Form Health Survey (SF-36) for use in a clinical sample of disadvantaged,
      older adults with significant comorbidities. Confirmatory factor analysis was
      performed using LISREL VIII on data obtained from baseline face-to-face
      interviews with a clinical sample of 1,051 patients who were at risk for acute
      deterioration of their clinical condition due either to their age alone (75 years
      or older), or to their age (50 to 74 years old) and major comorbid conditions. An
      acceptable eight-factor measurement model reflecting the original specification
      (ie, subscales) of the SF-36 was obtained (chi-square to degrees of freedom ratio
      = 2.14; root mean squared residual = .055; adjusted goodness of fit index = .90).
      That model, however, required relaxing the assumptions associated with seven
      correlated error terms. Moreover, an alternative nine-factor model that allowed
      the ?getting sick? and ?getting worse? items to form their own factor, labeled
      ?health optimism,? fit the data significantly better (8 degrees of freedom chi
      square improvement = 61; P< 0.0001). Although continued use of the SF-36 in
      older, disadvantaged, clinical samples is appropriate, further assessment of the
      underlying measurement model in other samples using confirmatory factor analytic
      techniques is needed to resolve the issue of correlated error structures and the
      existence of the health optimism factor.

PMID- 8656721
TI  - Multiyear diagnostic information from prior hospitalization as a risk-adjuster
      for capitation payments.
AB  - As part of a move toward a more market-oriented health-care system, major changes
      have been implemented in the Dutch social health insurance system. The competing
      sickness funds now receive risk-adjusted capitation payments, currently based on
      the age-sex distribution of the insurance portfolios. These very crude health
      indicators do not reflect expected costs accurately. The authors examine whether
      the incorporation of inpatient diagnostic information over a multiyear period can
      increase the accuracy of the capitation model. Using a panel data set (n
      approximately 50,000) comprising annual costs and diagnostic information for 5
      successive years, the authors compare demographic and diagnostic models in their
      ability to predict future health care costs. The predictive accuracy of an age
      sex-based capitation formula improves substantially when diagnostic information
      from an individual's prior hospitalizations is used as an additional risk
      adjuster. The longer the period over which diagnostic information is available,
      the better is the predictive accuracy. The expected loss in 1992 for insured
      persons with the highest costs in 1988 decreases from 88% (demographic model) to
      62% (1-year diagnostic model) and to 43% (3-year diagnostic model). The use of
      diagnostic information from prior hospitalizations is a promising option for
      improving the capitation formulae. The authors' results are relevant not only for
      situations where competing insurers are capitated, as in the Netherlands, but
      also when providers (United Kingdom) or health maintenance organizations (United
      States) are capitated.

PMID- 8656722
TI  - SF-20 score and item distributions in a human immunodeficiency virus-seropositive
      sample.
AB  - The question of whether the full range of possible health states is measured by
      the Medical Outcomes Study (MOS) 20-Item Short-Form Health Survey (SF-20) in
      human immunodeficiency virus (HIV)-seropositive individuals is examined in this
      article. Ninety-five HIV-seropositive men (37 with asymptomatic infection, 58
      with symptomatic infection) from two primary care practices were enrolled.
      Patients completed the SF-20 evaluating six dimensions of health status.
      Asymptomatic patients reveal substantial skew in score distributions for the
      dimensions of physical (-1.60), role (-1.19), and social (-1.13) functioning; no
      substantial skew is exhibited by symptomatic patients. Both subgroups reveal
      ceiling effects for physical, role, and social functioning, and pain dimensions;
      asymptomatic patients' ceiling effects are higher (physical functioning: 65%
      versus 31%; role functioning: 73% versus 41%; social functioning: 54% versus 43%;
      and pain: 41% versus 24%). Patients from both subgroups reveal floor effects for
      the role functioning dimension (asymptomatic patients, 22%; symptomatic patients,
      34%). When looking at items rather than scales, asymptomatic patients' item
      distributions for the physical, role, and social functioning, and pain dimensions
      reveal clustering toward positive health states in most items; distributions of
      symptomatic patients are similar. Because this HIV-seropositive sample exhibits
      substantial ceiling effects in four of six SF-20 dimensions, effects that
      particularly are notable for asymptomatic patients, these dimensions should be
      revised for use in HIV-seropositive individuals or a disease-specific quality of
      life instrument should be constructed.

PMID- 8656723
TI  - Record linkage strategies, outpatient procedures, and administrative data.
AB  - By understanding the range of approaches implicit in modern record linkage,
      epidemiologists and health services researchers can better decide its suitability
      for their needs. The authors discuss a small record linkage project, providing a
      sense of where mistakes were made. The research first uses existing
      identification numbers as a gold standard for linking hospital abstracts and
      physician claims to investigate whether or not coronary angiography was performed
      on a given individual. Even if identification numbers are not available, a
      successful linkage (with more than 95% of the cases matched) may be possible
      under some circumstances. The linkage process highlights problems with the
      consistent recording of coronary angiography in inpatient and outpatient hospital
      abstracts. Our approach should prove useful when the same procedure is recorded
      in more than one place on a single file and when validating a procedure (or other
      event) across files is important. Given the growing number of health care
      databases and ongoing changes in the delivery of care, record linkage often can
      provide quality control and expand research opportunities in a timely fashion.

PMID- 8656724
TI  - Individual choice in spending accounts. Can we rely on employees to choose well?
AB  - Flexible spending accounts (FSA) represent a current health care financing tool
      that may become an important component of incremental health care reform. Because
      FSAs require employees to make financial contributions based on anticipated
      health care needs, contribution decisions are likely to be subject to many of the
      errors made in other insurance decisions. The authors analyzed the benefits
      selections, benefits forms completion, and FSA contribution levels of
      approximately 9,500 employees of the University of Pennsylvania from 1987 to
      1992. Default and repeat choice trends characterize the completion of benefits
      forms and the reselection of health insurance options by employees. Despite the
      economic benefits of contributing to an FSA, only 14% of employees contributed in
      any one year and 73% never made a contribution. Multivariate models of these
      contributions fail to demonstrate the importance of what ought to be relevant
      influences in contribution decisions (for example, age, income, family status, or
      underlying health insurance). Whereas most FSA decisions are characterized by
      default contributions of $0, employees who contribute in one year are most likely
      to contribute exactly the same amount the next year, even when other
      circumstances change. The pervasiveness of these patterns raises concerns that
      health care reform plans that rely on financial incentives at the consumer level-
      for example, proposed medical saving accounts--will be inefficient.

PMID- 8656725
TI  - Physician practice style and rates of hospitalization for chronic medical
      conditions.
AB  - Hospitalization rates for chronic medical conditions vary across small areas and
      are associated inversely with community income. The authors studied whether
      variation in hospitalization rates can be attributed to differences in physician
      practice style. Using census and hospital discharge data, hospitalization rates
      were calculated for asthma, congestive heart failure, and diabetes in 40 medical
      service areas in California. The authors surveyed a random sample of 1,530
      emergency physicians, general internists, and family and general practitioners in
      these areas, and measured clinical admission threshold by asking physicians
      whether they would hospitalize patients presented in 15 vignettes of graded
      severity. The authors measured social admission predisposition by asking how
      physicians' admission decisions would be influenced by social characteristics
      that increase patients' vulnerability to illness, including homelessness and drug
      use; 1,090 physicians responded (71%). There was significant variation across
      areas in both the clinical (P < 0.0001) and social (P < 0.001) admission scores.
      Variation in hospitalization rates correlated with physicians' clinical (r = .34,
      P = 0.03) and social (r = .36, P = 0.02) admission scores. However, in a multiple
      linear regression analysis that included community sociodemographic factors,
      physician practice style was not associated significantly with hospitalization
      rates. Physician practice style varies across areas, but does not explain
      variation in admission rates for chronic medical conditions after adjusting for
      community sociodemographic factors. Using methods such as practice guidelines or
      utilization review to re-set physicians' threshold for admission may not be
      effective in reducing hospitalizations for chronic medical conditions.

PMID- 8656726
TI  - Clinical predictors of functioning in persons with acquired immunodeficiency
      syndrome.
AB  - To help clinicians better assess and treat functional disabilities in persons
      with acquired immunodeficiency syndrome (AIDS), the authors estimate empirical
      relations among biologic and physiologic variables, symptoms, and physical
      functioning in persons with AIDS. The sample of 305 persons with AIDS for this
      cross-sectional analysis came from three sites in Boston, Massachusetts: a
      hospital-based group practice, a human immunodeficiency virus clinic at a city
      hospital, and a staff-model health maintenance organization. Physical
      functioning, 10 AIDS-specific symptoms, and mental health were assessed by
      interview. Clinical diagnoses, comorbidities, health habits such as smoking,
      laboratory results, and selected medication use were assessed by chart review.
      Significant predictors of physical functioning P < 0.01, R2 = .58) in a
      multivariable regression model included energy/fatigue, neurologic symptoms,
      fever symptoms, a lower hemoglobin level, and current non-pneumonia bacterial
      infection. Ninety-six percent of the explained variance in physical functioning
      was accounted for by three symptom complexes: energy/fatigue, neurologic
      symptoms, and fever symptoms. Significant predictors of energy/fatigue in
      multivariable models included poorer mental health, lower white blood cell count,
      longer time since diagnosis, and weight loss (P < 0.01, R2 =.36). Significant
      predictors of neurologic symptoms included poorer mental health, weight loss, and
      no zidovudine use (P < 0.001, R2 = .30). Predictors of fever symptoms included
      poorer mental health, no zidovudine use, weight loss, and history of asthma or
      chronic obstructive pulmonary disease (P < 0.05, R2 = .25). In conclusion,
      symptom reports were strong predictors of physical functioning. Poorer mental
      health and weight loss were correlated consistently with worse symptoms, and not
      using zidovudine was correlated with worse neurologic and fever symptoms. These
      variables, and the others the authors identified, may represent mutable
      determinants of physical functioning in persons with AIDS, and potential targets
      for specific clinical interventions.

PMID- 8656727
TI  - Outpatient geriatric evaluation and management. Results of a randomized trial.
AB  - The effectiveness and efficiency of outpatient geriatric evaluation and
      management (GEM) was compared with usual outpatient primary care (UPC). One
      hundred sixty frail elderly outpatients were assigned randomly to GEM or UPC and
      assessed at baseline and at 8 months on measures of (1) health and functional
      status, (2) psychosocial well-being, (3) quality of health and social care, (4)
      use of inpatient and outpatient services, and (5) cost of care. The results
      indicate that GEM was significantly more effective than UPC in reducing
      mortality, increasing patient satisfaction, and improving the quality of health
      and social care. However, it was not effective in reducing health care use or the
      cost of care.

PMID- 8656728
TI  - [Estimation of costs attributable to nosocomial infection: prolongation of
      hospitalization and calculation of alternative costs].
AB  - BACKGROUND: Nosocomial infection represents a prolongation of hospital stay and
      an increase of costs. The aim of the study was to estimate attributable costs by
      means of two methods: calculation of costs resulting from an increase of hospital
      stay and calculation of costs attributed to services. METHODS: A matched case
      control study was carried out with a cohort population. An appropriate control
      was found for 63 patients with surgical site infection, for 30 patients with
      respiratory infection and for 55 with urinary infection. The estimation of costs
      attributable to services includes the case-control pairs with surgical site
      infection and was performed of the sum of costs of diagnostic and therapeutic
      services rendered in the care of the surgical site infection. RESULTS: The median
      of postoperative stay was 21 days for cases with surgical site infection vs 10
      days for controls (p < 0.001); the median length of stay was 21.5 days for cases
      with respiratory infection vs 11.5 days for controls (p < 0.01); and for urinary
      infection the median length of stay was 21 days for cases vs 15 days for controls
      (p < 0.01). The surgical site infection cost attributed to extra days was 310,310
      pesetas and the surgical site infection cost attributed to service cost was
      220,546 pesetas. CONCLUSIONS: Nosocomial infection produces a increase median
      hospital stay of 7-10 days. In absence of a precise accounting system, the
      prolongation of hospital stay was considered as the more objective date to
      estimate the costs.

PMID- 8656729
TI  - [Cost-effectiveness analysis of serum ferritin screening in periodic physical
      examinations of women at the fertile age].
AB  - BACKGROUND: Fertile-aged women are a population group at special risk for
      developing ferropenia. In the periodic health care examinations, hemogram, among
      other tests, are included to detect the most advanced state of iron deficity,
      ferropenic anemia. Likewise, preanemic ferropenia presents a certain morbidity.
      The aim of this study was to analyze the cost-effectiveness of screening serum
      ferritin determination in health care examinations of fertile-aged women.
      SUBJECTS AND METHODS: An observational transversal study was carried out in 322
      women in whom hemogram and serum ferritin were determined. The effects of serum
      ferritin determination were simulated in a hypothetical cohort of 20-year old
      women annually examined up to the age of 50 years (mean age of menopause).
      RESULTS: The prevalence of preanemic ferropenia (serum ferritin < or = ng/ml) was
      44.1% and that of ferropenic anemica (Hb < 120 g/l and serum ferritin < or = 25
      ng/ml) was 3.4%. Hemogram sensitivity for detection of ferropenia was 7.2% (3.6
      12.5). By means of the screening program with serum ferritin avoiding of one year
      with ferropenia costs 2,428 pesetas. Prolonging the program to longer than 35
      years largely increases the marginal cost. Cost-effectiveness analysis is
      specially sensitive to the cost of the diagnostic tests and disease prevalence.
      CONCLUSIONS: Ferropenia in fertile-aged women is a frequent disorder. Avoiding
      ferropenia by early diagnosis may be performed at a relatively low cost.

PMID- 8656731
TI  - [Historical perspective of renin-angiotensin system blocking in the treatment of
      arterial hypertension].

PMID- 8656730
TI  - [Current use of statistics in biomedical research: a comparison of general
      medicine journals].
AB  - BACKGROUND: The use of statistical techniques has become strongly consolidated in
      biomedical investigation. The present study analyzes the statistical repertoire
      of the original articles published in 1993 in four general medicine journals: Med
      Clin (Barc), Rev Clin Esp, Lancet and N Engl J Med. METHODS: A single reviewer
      examined 100 original articles from Med Clin (Barc), 42 from Rev Clin Esp, 105
      from Lancet and 116 from N Engl J Med, studying the use of 18 categories of
      statistical analysis and the statistical accessibility of the reader. The
      criteria for assigning techniques to a specific category were those described by
      Emerson and Colditz. The knowledge of bivariable techniques (standard reader) was
      established as the reference for the study of statistical access. Statistical use
      consisted in the tabulation of frequencies, graphic representations and chi
      square tests. RESULTS: The five most used categories were: Contingency tables, t
      and z tests, epidemiologic statistics, survival analysis (in both English
      journals) and analysis of variance (in both Spanish journals). The percentage of
      articles without statistics or with only descriptive statistics was 16% in Med
      Clin (Barc), 29% in Rev Clin Esp, 18% for in Lancet and 23% in the N Engl J Med.
      A reader familiarized with bivariable techniques has statistical access to 58%
      for the originals of Med Clin (Barc), 62% of Rev Clin Esp, 35% of the Lancet and
      42% of the N Engl J Med. CONCLUSIONS: In the four journals selected, the use of
      bivariable techniques is still frequent although the growing use of multivariant
      analysis is of note. The study of the current profile of the standard reader in
      Spain is the aim of priority.

PMID- 8656733
TI  - [Relations between hospital and primary care. Experience at an internal medicine
      service].

PMID- 8656732
TI  - [Chronic autoimmune hepatitis following cholestatic hepatitis caused by
      droxicam].
AB  - Droxicam in a nonsteroid antiinflammatory from the oxicam family which acts as a
      pro-drug, being transformed into pyroxicam after being hydrolized in the stomach
      and has induced several cases of cholestatic or mixed hepatitis. A clinical
      observation in which droxicam provoked initial cholestatic hepatitis which later
      developed into chronic autoimmune hepatitis is presented. It has been postulated
      that, after causing cholestatic hepatitis by hypersensitivity and within the
      context of a previous autoimmune entity such as vitiligo, this drug triggered a
      silent autoimmune liver disease which was demonstrated clinical, analytical and
      histopathological manifestations 18 months later and required permanent
      immunosuppressive treatment.

PMID- 8656734
TI  - [Human gene therapy: trends and current problems].

PMID- 8656735
TI  - [Detection and intervention in excessive alcohol consumption].

PMID- 8656736
TI  - [Emergency care or fast consultation: the need for a model of response to social
      demand].

PMID- 8656737
TI  - [Zolpidem dependence].

PMID- 8656738
TI  - [Heat stroke and arterial hypertension].

PMID- 8656739
TI  - [Magnetic resonance of the spinal cord: a densitometric analysis].
AB  - BACKGROUND: Images obtained by magnetic resonance can present changes in a
      variety of haematologic disorders. The vertebral magnetic resonance signal
      depends chiefly on the relationship between fatty and cellular components of the
      haemopoietic bone marrow. A quantitative analysis of signal can be performed
      either during the magnetic resonance examination or on the computer-stored
      images. In this work, a densitometric grey-scale method is presented allowing to
      analyze the signal intensity on printed magnetic resonance images for those cases
      in which the computer-stored information is lacking. PATIENTS AND METHODS: A
      comparative study between magnetic resonance signal and the result of the
      densitometric analysis was carried out in 29 patients with different haematologic
      disorders. In order to achieve a suitable standardization, an internal control in
      both measures was used, i.e., the magnetic resonance signal intensity and the
      grey intensity of an area of spinal cord, respectively, yielding two ratios:
      magnetic resonance ratio and grey ratio. RESULTS: The precision analysis of the
      densitometric method gave the following results: within-batch coefficient of
      variation was 1.78%, between-batch coefficient of variation was 1.94% and overall
      reproducibility 6.4%. The correlation between magnetic resonance ratio and grey
      ratio was very high, i.e., 0.98 (p < 0.001). Moreover, the regression line
      displayed on ideal location since it originated in the point 0 and showed a slope
      of 45 degrees. CONCLUSION: The densitometric method presented in this paper can
      be useful for the quantitative analysis of the magnetic resonance signal
      intensity generated by the haemopoietic bone marrow, for those cases in which the
      computer-stored information is lacking.

PMID- 8656740
TI  - [Tuberculosis in recent immigrants in Barcelona].
AB  - BACKGROUND: The aim of the present was to study the prevalence of infection and
      tuberculous disease as well as the fulfillment of secondary antituberculin
      chemoprophylaxis in immigrants according to their geographic origin. PATIENTS AND
      METHODS: A descriptive study was carried out of 1,489 immigrants under the age of
      35 years attended in the Tropical and Imported Disease Unit Drassanes in
      Barcelona, Spain from 1989 to 1994. RESULTS: The patients were from 79 countries,
      with 81.7% being males and 18.3% females (p < 0.001) of a mean age 26.1 +/- 5.7
      and 23.4 +/- 7.5 years, respectively. Forty-three percent of the cases presented
      Mantoux test response > or = 10 mm of induration. The highest percent of
      positivity was observed in patients from Subsaharian Africa (52%) followed by
      Eastern Europeans and Asians (44%), South and Central Americans (38%) and Middle
      East and Northern Africa (34%) (p < 0.001). Thirty-nine percent of the 359
      patients who initiated secondary antituberculin chemoprophylaxis completed the 6
      months of treatment with the highest fulfillment being found in Africans (49%)
      followed by Americans (42%) and Asians (39%). The lowest rate was observed in the
      Eastern Europeans (20%) (p < 0.001). Fifty-six percent of the patients abandoned
      secondary antituberculin prophylaxis within the first three months. Eighteen
      cases of active tuberculosis were diagnosed. CONCLUSIONS: The prevalence of
      tuberculous infection and disease is high immigrants in Barcelona, Spain. The
      fulfillment of chemoprophylaxis is low and abandoned early. These facts should be
      evaluated when designing prevention and control programs.

PMID- 8656742
TI  - [Pulmonary rehabilitation: a caprice or a need?].

PMID- 8656741
TI  - [Prevalence of obesity in the Valencia community].
AB  - BACKGROUND: This paper describes the ponderal distribution of a representative
      adult population sample of the Community of Valencia (CV) in Spain. Moreover it
      estimates the prevalence of obesity by sex, age groups and levels of education.
      SUBJECTS AND METHODS: Weight and height data obtained by direct measurement of
      1.787 participants in the Survey of Nutrition and Health of the CV in 1994 with a
      representative population sample of adults over the age of 14. Quetelet's index
      (QI) (QI - kg/m2) was used as ponderal indicator and established populations with
      Q1 > or = 30 as being obese. The prevalence of obesity was estimated by age
      groups, sex and level of education adjusted by the age structure of the same
      sample. RESULTS: The overall prevalence of obesity was 16.4%, 17.8% in women
      versus 14.7 in men. The obesity varied with age from 3.7% in the 15-24 age group
      to 32.4% in the 50-64 age group and 28.6% for the over 65 years age group.
      Obesity was more frequent in men under 34 years, and in women over 50 years of
      age. In reference to levels of education, a higher prevalence was observed in
      individuals with a lower education. CONCLUSIONS: The results of this study make
      it evident that the prevalence of obesity in the CV is more than in other
      autonomous Spanish communities. The frequency of obesity increased with age up to
      65 years, and was more prevalent in women and in individuals with lower levels of
      education.

PMID- 8656743
TI  - [German words misleadingly translated in medicine].

PMID- 8656744
TI  - [Pseudotumorous cardiac infiltration in a patient with acute monoblastic
      leukemia].
AB  - Although cardiac infiltration is common in advanced stage of acute leukaemia, it
      is not usually diagnosed at life and it is extremely rare for it to become
      pseudotumoral. A 25-years-old patient with an acute monoblastic leukaemia who had
      a leukaemic infiltration which affected the main part of the left ventricle at
      the time of diagnosis, is referred. The heart infiltration was detected by a two
      dimension echocardiography. In spite of a massive infiltration, heart failure was
      not present and the left ventricle's ejection fraction was 50%. Even though
      chemotherapy was administered, the patient died four days after diagnosis due to
      septic shock of respiratory origin. The most relevant autopsy finding was a
      widespread pseudotumoral infiltration of the left ventricle, the back side of the
      right ventricle and the interventricular wall. The pseudotumoral infiltration of
      the heart by acute leukaemia is uncommon and must be differentiated from
      granulocytic sarcoma. The usefulness of the different diagnostic procedures is
      discussed.

PMID- 8656745
TI  - [Urinary infections in patients with non-permanent bladder catheter (and II):
      diagnosis, treatment, prevention and research aspects].

PMID- 8656746
TI  - [Cardiac tamponade in acute pericarditis: is drainage with intrapericardial
      catheter indicated?].

PMID- 8656747
TI  - [Alcoholic intoxication caused by intravenous nitroglycerin: an underestimated
      risk?].

PMID- 8656748
TI  - [Hepatic hamartoma in an adult patient].

PMID- 8656749
TI  - [Psoas abscess as initial manifestation of appendiceal tumor].

PMID- 8656750
TI  - [Platelet antiaggregants: a study of their use in Catalonia].

PMID- 8656751
TI  - [Appearance of impotence in relation to the use of methotrexate].

PMID- 8656752
TI  - [Fixed combinations of antihypertensive drugs].

PMID- 8656753
TI  - [Susceptibility to measles, rubella and parotitis in young adults].
AB  - BACKGROUND: The aim of this study was to know the prevalence of antibodies
      against measles, rubella and parotiditis in young adults. METHODS: The study was
      carried out in health care students during the academic year of 1992-1993.
      Demographic and geographic variables were obtained as were vaccination and
      history of diseases. Antibodies against measles, rubella, and parotiditis were
      determined by ELISA techniques with commercial reagents. RESULTS: Three hundred
      and six individuals of 21.3 +/- 2.2 years (range 17-36 years) with 27.5% being
      males were studied. Past history of measles, rubella and parotiditis was reported
      in 43.5, 30.7 and 37.3%, respectively, with vaccination being 23.2, 43.8 and
      20.6%, respectively. The prevalence of antibodies was 93.1% (measles), 96.4%
      (rubella) and 92.1% (parotiditis). CONCLUSIONS: The prevalence of infection of
      measles, rubella and parotiditis in the young population studied is mainly due to
      infection by wild type virus. The foreseeable growth of susceptibility groups in
      this population which should be adequately evaluated by extensive
      seroepidemiologic questionnaires, favors the appearance of epidemic outbreaks.
      The use of the triple viral vaccine is suggested as an alternative to rubella
      vaccination in presumable susceptible young women.

PMID- 8656754
TI  - [Use of mortality probability models (MPM II) in the evaluation of the
      effectiveness of care of critically ill patients. European and North American
      Study of Severity Systems].
AB  - BACKGROUND: The performance of the Mortality Probability Models (MPM II) has been
      assessed in Intensive Care Units (ICUs) in Catalonia and the Balearic Islands.
      The MPM II system has been customized to that geographic area and quality
      performance has been evaluated in each ICU. METHODS: 1,270 adult critical
      patients, consecutively admitted in 16 ICUs from Catalonia and 1 from the
      Balearic Islands have been included. Probability of dying in the hospital has
      been calculated at admission in the ICU and at 24 hours using the models MPM II0
      and MPM II24. Goodness-of-fit of the MPM II system in the overall group of 17
      ICUs has been analyzed. Logistic regression has been used to customize the MPM II
      system to all the ICUs together. A Quality Performance Index (QPI) for each ICU
      has been obtained by dividing the number of the observed deaths by the number of
      deaths expected by the MPM II system. RESULTS: The overall QPI was 1.15 when
      using the MPM II0 and 1.17 when using the MPM II24. The QPI in the 17 ICUs ranged
      from 0.58 to 2.05. Three ICUs showed excess of mortality and 2 ICUs had less
      deaths than expected. The process of customization of MPM II to the 17 ICUs as a
      group improved the estimation of expected mortality. CONCLUSIONS: The use of
      severity indexes allows to compare the outcome of patients in the ICU and
      provides an indicator of quality of care. The excess of mortality observed in
      some ICU should produce a watchful follow-up of outcome. Risk factors for excess
      of mortality should be studied.

PMID- 8656756
TI  - [Childhood diseases in adults. A regression to the past?].

PMID- 8656755
TI  - [Geographic distribution of avoidable mortality in the community of Valencia
      (1975-1990)].
AB  - BACKGROUND: Avoidable mortality (AM) has been proposed as the indicator of the
      quality and the efficacy of health care services and a parameter useful to
      distribute health care resources. The aim of this study was to analyze the size
      and geographic variability of AM in the Community of Valencia, Spain (1975-1990).
      METHODS: The causes of AM were analyzed by the classification of Holland divided
      into indicators of medical care (IMC) and indicators on national health care
      policy (INHCP) in addition to the causes of the Charlton classification. Standard
      rates for Spain and the European Community, the rate of masculinity and
      contribution to total mortality were calculated. Geographic distribution by areas
      and provinces was analyzed by the rate of standardized mortality. RESULTS:
      According to the Holland classification AM was 30% of the deaths from 5 to 64
      years of age. Out of these cases, 18.5% corresponded to INHCP and 11.1% to IMC.
      According to the Charlton classification, this percentage was 3.6%. A
      considerable variation was observed among the 20 areas analyzed due to many
      causes. The geographic distribution by groups (IMC, INHCP and the Charlton
      classification) is quite homogeneous. The worse results corresponded to the city
      of Valencia and to the area 21 (area of the city of Alicante). CONCLUSIONS: A
      great variation was found in the results regarding geographic distribution for
      individual causes of death while the distribution was quite homogeneous for all
      of the groups of mortality with the worst results being observed in large urban
      centers.

PMID- 8656757
TI  - [The European plan of action concerning alcohol consumption: a look to the
      future].

PMID- 8656758
TI  - [Analysis of response to interferon alpha-2b and the significance of antinuclear
      antibodies in hairy cell leukemia].
AB  - Hairy cell leukemia is a uncommon B-cell chronic lymphoproliferative disease
      rarely associated with autoimmune phenomena. We present a positive CD 5 case with
      a positive antinuclear antibodies test in the absence of any relation to any
      other clinical autoimmune disease syndrome and we analyse the evolutive profile
      of serum concentration of several factors with prognostic significance, relating
      to the interferon alpha-2b treatment: C reactive protein, beta 2-microglobulin
      and erythropoietin presented at first very high basal levels that descended
      progressively until the last two normalized completely; the tumor necrosis factor
      alpha manifested stable with normal values during the whole study; the gamma
      interferon and interleukin-6 revealed a precocious increase at the start of the
      treatment later returning to their basal levels. These parameters may aid to
      assess the response to treatment in these patients.

PMID- 8656760
TI  - [Prolonged fever syndrome and hepatosplenomegaly in a 50-year-old man].

PMID- 8656759
TI  - [Atrial fibrillation due to non-valvular causes: indications for antithrombotic
      therapy].

PMID- 8656761
TI  - [Clinical analysis of 7 patients with cerebral venous thrombosis].

PMID- 8656762
TI  - [Nitric oxide and hepatopulmonary syndrome].

PMID- 8656763
TI  - [Use of bromocriptine in suppression of lactation].

PMID- 8656764
TI  - [Colocynth poisoning, a rare cause of acute diarrhea syndrome].

PMID- 8656765
TI  - [Toxic epidermal necrolysis in a patient treated with high doses of deflazacort].

PMID- 8656766
TI  - [Osteoarticular disorders in the elderly: an approach to their population
      impact].
AB  - BACKGROUND: Despite the high prevalence of the osteoarticular disorders in the
      elderly, there are few studied about its impact on the population. The aim of the
      study was to estimate the prevalence and related disability associated to the
      osteoarthritis and rheumatic disorders in people aged 65 or more. SUBJECTS AND
      METHODS: The information was obtained from the Barcelona 1986 Health Interview
      Survey, a cross-sectional study in a representative sample of the non
      institutionalized population aged 65 or more, resident in Barcelona. Information
      was collected about chronic conditions, perceived morbidity, perceived health
      status, use of health services and a specific questionnaire of functional
      capacity was administered. RESULTS: Fifty-one percent of the interviewed (660 of
      1,287) reported having osteoarthritis or rheumatism (31.4% of the males and 63.3%
      of the females; p < 0.05). The proportion increased with age in males (p < 0.05)
      but not in females. 82% of the elderly with osteoarthritis or rheumatism reported
      suffering pain for this condition, being very frequent and moderate/intense in
      23% of them. They also rated a worse perceived health, and reported having
      functional dependency and chronic limitation more frequently than elderly people
      without this condition. 54% of them were not taking any medical treatment and 40%
      of the osteoarthritics or rheumatics with very frequent and moderate/intense pain
      had not been visited by a physician because of their condition in the previous
      year. CONCLUSIONS: A high prevalence of osteoarthritis or rheumatism and an
      important impact on health status and health services utilization was observed in
      the elderly. Likewise, the results suggest that there is insufficient or
      inadequate coverage of health care needs for this condition.

PMID- 8656767
TI  - [The kinetic characteristics of the erythrocyte glutathione S-transferase system
      as a function of sex and the tobacco habit].
AB  - BACKGROUND: Erythrocytic glutathion S-transferase (GST) plays an important role
      as a protective mechanism against oxidative stress. The present study was
      conducted to evaluate the influence of both smoking habit and sex upon the
      kinetic characteristics of the enzyme. SUBJECTS AND METHODS: 176 healthy subjects
      (100 men and 76 women), smokers and nonsmokers, were included. Enzyme parameters
      were calculated in erythrocytic haemolysates using 1-chloro-2,4-dinitrobenzene
      (CDNB) and glutathion (GSH) as substrates. Haemoglobin (Hb) was removed by
      affinity chromatography. In samples coming from 51 men and 42 women the native
      haemolysate was subjected to thermal shock (52 degrees C) and the enzyme
      parameters were compared with those obtained in the non-denatured samples.
      RESULTS: In non-denatured samples, Km (mM) and Vmax (mumol/min/g Hb) values for
      CDNB were significantly higher (p < 0.001) in smokers than in non smokers,
      especially in women. Thus, respectively for Km and Vmax (mean +/- standard
      deviation): for men non smokers, 1.43 +/- 0.54, 1.63 +/- 0.42 and smokers, 1.74
      +/- 0.5, 1.8 +/- 0.69; for women, non smokers 1.42 +/- 0.56, 1.57 +/- 0.46 and
      smokers, 2.05 +/- 0.59, 2.51 +/- 0.6. Thermal denaturation diminished the enzyme
      activity in all cases and modified the Km values, these results were opposite to
      those obtained in the non-denatured samples. Thus, for Km and Vmax respectively:
      for men, smokers, 1.6 +/- 0.71 and 0.9 +/- 0.32 and non smokers, 1.4 +/- 0.66 and
      0.53 +/- 0.29; for women, non smokers, 2.00 +/- 0.58, 1.13 +/- 0.29 and smokers
      1.22 +/- 0.77, 0.52 +/- 0.23. The GSt content was similar in the four groups
      studied (3.75 +/- 1.15 mumol SH/g Hb). CONCLUSIONS: The greater thermolability of
      GST activity and the increase in the Km values observed in smokers, especially in
      women, should be considered as indicative of an increased risk for the
      erythrocytes against oxidative stress.

PMID- 8656768
TI  - [Statistics in the clinical research on drugs. A study of original articles
      emanating from Spanish centers].
AB  - BACKGROUND: The aim of this study was to evaluate statistical analysis reported
      in clinical investigation articles of Spanish drugs. METHODS: Original articles
      provided by Spanish centers and indexed in EMBASE in 1975, 1980, 1985 and 1990
      were studied. The type of statistics used, their description and different
      aspects of results presentation are reported. RESULTS: Two hundred eighty-eight
      articles were studied of which 73.3% used inferential statistics with 57.3%
      presenting an adequate description of the same. The most frequently used
      statistical tests were bivariant techniques, mainly the Student's t test (33.7%)
      and chi square test (28.8%). The complexity of the statistical tests increased
      progressively in the years reviewed being greater in the articles published in
      foreign journals. The results were presented adequately and in a comprehensive
      form in 40% of the cases. Confidence intervals were used in 22.2% in the
      presentation of the results. In 49.1% of the articles statistical significance
      favored the group receiving the therapy studied. Of the 46.6% which did not
      present differences only 9.3% the statistical power was calculated. CONCLUSIONS:
      Although an improvement was observed in the years evaluated, the articles on
      clinical drug investigation carried out in Spanish centers still present
      insufficient information on statistical methodology, particularly in those
      published in Spanish journals.

PMID- 8656770
TI  - [Apoptosis and autoimmune diseases].

PMID- 8656769
TI  - [Why I do not grease up my axles...].

PMID- 8656772
TI  - [The current status of methods for evaluating body composition: their
      description, reproducibility, accuracy, scope of application, safety, cost and
      future prospects].

PMID- 8656771
TI  - [Disseminated Kaposi's sarcoma with hepatosplenic involvement in AIDS].
AB  - Kaposi sarcoma (KS) is the most frequent neoplasm found in AIDS patients. The
      disease is often disseminated and preferentially involves the skin and the
      lymphatic and digestive systems. Hepatosplenic involvement which is considered as
      a frequent autopsy finding is rarely diagnosed at life. A 27-year-old male HIV
      positive patient with severe immunosuppression who developed a rapidly
      progressive laterocervical cutaneous KS confirmed by pathologic study is
      presented. Abdominal echography and thoracoabdominal CT scand demonstrated
      lesions highly suggestive of pulmonary, lymph node, hepatic, splenic and rectal
      involvement by KS. The administration of 2 chemotherapy cycles produced
      subjective improvement and remission of the cutaneous lesions. Severe pulmonary
      superinfection led to death. An autopsy study was not performed. Hepatosplenic
      involvement by KS, diagnosed while the patient is alive is rare. The imaging
      techniques are useful to diagnose with high probability visceral involvement of
      KS. Systemic searching for visceral involvement in KS patients would lead to a
      marked increase in the cases such as that herein described with evident
      therapeutic and prognostic implications.

PMID- 8656773
TI  - ["Expert" general internists and physician specialists: a response to Lissen's
      article].

PMID- 8656774
TI  - ["Expert" general internists and physician specialists: a response to Lissen's
      article].

PMID- 8656775
TI  - [Phase IV of epidemiological studies: conceptual and methodological criticisms].

PMID- 8656776
TI  - [Severe hyponatremia and hypopotassemia induced by the consumption of Equisetum
      telmateia].

PMID- 8656777
TI  - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of
      human immunodeficiency virus type 1 (HIV-1) infections: strategies to overcome
      drug resistance development.

PMID- 8656778
TI  - ADP receptors on platelets and ADP-selective antiaggregating agents.

PMID- 8656779
TI  - Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2):
      rationale for selective inhibition and progress to date.
AB  - While a great deal has been discovered concerning the potential physiological and
      pathological role of prostanoids, much is left to be determined. The widespread
      distribution of both COX-1 and COX-2 coupled with the capacity of most vascular
      beds, smooth muscle, as well as leukocytes to respond to prostanoids make drawing
      generalities difficult. The problems with the majority of currently used NSAIDs
      are clear and ulcerogenic liability is of obvious concern. Interestingly enough,
      the mechanism of that damage is still the subject of controversy as illustrated
      by the recent review and hypothesis of Somasundaram et al. In this treatise, the
      suggestion is made that the initial gastric damage is the result of uncoupling of
      oxidative phosphorylation which is independent but simultaneous with COX
      inhibition. At least two currently marketed NSAIDs have improved G.I. liability
      (nabumetone and etodolac) with efficacy equivalent to other more ulcerogenic
      NSAIDs. These drugs appear to have achieved that by a mechanism distinct from
      selective inhibition of COX-2. Whether or not selective COX-2 inhibitors will
      demonstrate an improved profile over these compounds remains to be shown.
      Unfortunately, clinical experience with nimsulide and CGP 28238 suggest that
      NSAID-like toxicity may still be an issue. The promise of selective COX-2
      inhibitors remains largely untested. It is with great interest and expectation
      that the clinical evaluation of the more selective compounds of different
      structural types is awaited.

PMID- 8656781
TI  - [The good death and health care: a regulated euthanasia is better than the secret
      one].

PMID- 8656780
TI  - Antimitotic natural products and their interactions with tubulin.

PMID- 8656782
TI  - [Do not abolish forensic psychiatry but change the legislation].

PMID- 8656783
TI  - [Obesity in plain language--a wrongly nourished nation].

PMID- 8656784
TI  - [What happens when illegal refugees need emergency care?].

PMID- 8656785
TI  - [Criminality does not depend on mental health status].

PMID- 8656786
TI  - [What does certification mean?].

PMID- 8656787
TI  - [Advanced word processing programs allow spread of viruses].

PMID- 8656788
TI  - [The breast cancer unit has a problem].

PMID- 8656789
TI  - [General vaccination against hepatitis B is not justified].

PMID- 8656790
TI  - [Hepatitis B is an occupational risk for health personnel. Preventive vaccination
      is recommended].

PMID- 8656791
TI  - [Even children should be vaccinated against hepatitis B. Moderate additional
      costs results in great humanitarian benefits].

PMID- 8656792
TI  - [Knee arthroplasty. Nine out of ten patients experience relief from pain and
      improved quality of life].

PMID- 8656793
TI  - [A new model for a short-term course in pediatric psychiatry. Group work and
      private patient cases].

PMID- 8656794
TI  - [The physician as patient. A resource for better health care].

PMID- 8656795
TI  - [Intensive pain can be caused by Clostridia. Endoscopy is part of the cause of
      gangrene].

PMID- 8656797
TI  - [Nobody will be punished for one's own hereditary disposition. Genetic
      information should be protected by law].

PMID- 8656796
TI  - [Short time between diagnosis and start of therapy. Combination therapy of gas
      gangrene reduces mortality].

PMID- 8656798
TI  - [Too large supplies in medicine cabinets of the elderly. Prescription- and
      discount-systems should be revised].

PMID- 8656799
TI  - [Be familiar with a foreign body! A piece of wood and a piece of bark in the knee
      were not discovered].

PMID- 8656800
TI  - [WHO's World Health Report 1995: Z59.5 is the most frequent cause of death].

PMID- 8656801
TI  - [A new vaccine against the influenza epidemic of next autumn].

PMID- 8656802
TI  - [Angelman syndrome. A developmental disorder with important significance for
      understanding genetic imprinting].

PMID- 8656803
TI  - [Disclosure of X-ray results by the radiologist? Yes, say the patients. May be,
      say the physicians].
AB  - How radiologists should respond to patient's queries about x-ray results is
      discussed in this article outlining the views of Swedish patients, radiologists
      and clinicians. Most patient would like to be told the result at the x-ray
      department; but although radiologists are more inclined than clinicians to let
      the radiologist disclose the results, comparison of Swedish views on this issue
      with those outlined in an American report suggests both categories of Swedish
      physicians to be more reluctant than their American counterparts to allow the
      radiologist to disclose results.

PMID- 8656804
TI  - ["Plasticity" of the visual cortex. Nerve cells can offer substitution].

PMID- 8656805
TI  - [Is it possible to repair hearing? Promising development with cochlear implants].

PMID- 8656806
TI  - [Protein synthesis and hormones are necessary for the song memory of birds].

PMID- 8656807
TI  - [Intensifying the care of MS-patients].

PMID- 8656808
TI  - [Pdiatric endoscopy is both flexible and informative].

PMID- 8656809
TI  - [A snowball hitting the eye--is it dangerous? A small risk of visual loss].

PMID- 8656810
TI  - [One child out of a thousand is affected by autism. Sweden has leading position
      in pediatric neurology/psychiatry].

PMID- 8656811
TI  - [Managed care. A revolution in the USA].

PMID- 8656812
TI  - [New guidelines from the Medical Products Agency: the triple regime against
      Helicobacter pylori is necessary. Treat only if the ulcer is verified].

PMID- 8656813
TI  - [A Norwegian survey on priorities and resource allocation in medical research.
      Best cure for most].

PMID- 8656814
TI  - [A proposal on prioritization of medical research: support for medical research
      important for society].

PMID- 8656815
TI  - [Difficulties in facing cancer patients: learn of each others experiences to
      improve communication with the patient].

PMID- 8656816
TI  - [The government ordered wrong survey. Concentrate, instead, on how to avoid
      mistakes in health care].

PMID- 8656817
TI  - [Working in the EEC? Moving around is free--but certification is required].

PMID- 8656819
TI  - [How dumb can an authority be?].

PMID- 8656818
TI  - [Prescription rules for narcotics are too complicated].

PMID- 8656820
TI  - [The new prescription form does not function in everyday care].

PMID- 8656821
TI  - [Safety in Swedish health care--a function of the number of signatures!].

PMID- 8656822
TI  - [Good continuing education is more important than disadvantages of industrial
      sponsorship].

PMID- 8656823
TI  - [Wrong interpretation and wrong figures on adverse effects of Relifex].

PMID- 8656824
TI  - [Sepsis grading should be defined. Staging may result in better monitoring].

PMID- 8656825
TI  - [Prior to the new transplantation law more and more people are willing to become
      donors, but fewer organs are available].

PMID- 8656826
TI  - [A guideline program for physicians' leadership. The chief must have time for his
      task, recruitment must be stimulated].

PMID- 8656827
TI  - [Lars Jakt, anesthesiologist, Treliske Hospital, Truro, Cornwall: "nomadizing"
      physicians will probably remain in England].

PMID- 8656828
TI  - [Who is prescribing what and at what cost?].

PMID- 8656829
TI  - ["Prescription reform" increases demands on physicians' integrity. County council
      must finance continuing education].

PMID- 8656830
TI  - [The prescription registry must be used correctly: quality improvement--not a
      basis for sanctions].

PMID- 8656832
TI  - [A balanced debate on tacrine is necessary].

PMID- 8656831
TI  - [More accurate diagnosis could identify patients suitable for tacrine therapy].

PMID- 8656833
TI  - [Patients must have right to test available therapy].

PMID- 8656834
TI  - [Should ignorance be accepted?].

PMID- 8656835
TI  - "Forbidden fruit" is not seducing. Swedish narcotic restrictions should be
      retained.

PMID- 8656836
TI  - [Hepatitis B infections show a variety of clinical pictures. Variations in viral
      DNA is a possible explanation].

PMID- 8656837
TI  - [TENS is effective in painful menstruation].

PMID- 8656838
TI  - [Cholecystokinin receptors. A target for tomorrow's psychopharmaceuticals?].
AB  - The neuropeptide cholecystokinin (CCK) and its receptors are highly expressed in
      brain regions important for cognitive functions, emotions and the initiation of
      movements. Two high-affinity receptors exist for CCK, the A-and B-type. A number
      of ligands are developed for these receptors. Evidence for the involvement of CCK
      and its receptors in the pathofysiology of neuropsychiatric disorders is
      discussed. In addition, we discuss the possible use of CCK receptors ligands in
      the treatment of such disorders.

PMID- 8656839
TI  - [Ethics, insurance and genetic testing. Important public debate].

PMID- 8656840
TI  - [Children are bigger now than in the 50's. New reference curves for Swedish young
      children].

PMID- 8656841
TI  - [Growth of children as a health indicator. Growth curves used at the infant
      health centers are important as screening instrument].

PMID- 8656842
TI  - [Hospital-family practitioner in basic care. Who dares to test the model with a
      physician per patient?].

PMID- 8656843
TI  - [Ruptured aneurysm without abdominal symptoms. Unexpected fatal intraabdominal
      bleeding after a traffic accident].

PMID- 8656844
TI  - [Vaccination against whooping cough is beneficial for health economics. Results
      of a model analysis].

PMID- 8656846
TI  - [News on views of the research society: prioritization of resources for medical
      research].

PMID- 8656847
TI  - [Tough education awaits Swedish medical students in Budapest].

PMID- 8656845
TI  - [Depression caused by herpes simplex encephalitis. Atypical symptoms were
      misleading for diagnosis].

PMID- 8656848
TI  - [No to euthanasia--yes to palliative care! Physician-assisted suicide is
      unethical, too].

PMID- 8656849
TI  - [Great Britain and the "mad cow disease". No proof that BSE can be transmitted to
      man through beef].

PMID- 8656850
TI  - [A better life for physicians is desirable].

PMID- 8656851
TI  - [Even jaw-joint can be affected by rheumatoid arthritis].

PMID- 8656852
TI  - [Health care to illegal refugees].

PMID- 8656853
TI  - [Scientific documentation as support for IRV is not available].

PMID- 8656854
TI  - [The International Rotary Foundation is a great help in the eradication of
      poliomyelitis].

PMID- 8656855
TI  - [A national registry on diabetes--for what purpose?].

PMID- 8656856
TI  - [Theophylline in acute myocardial infarction with AV block?].

PMID- 8656857
TI  - [A national registry on diabetes--cooperation is necessary for quality].

PMID- 8656858
TI  - [Reduced protein intake is justified only in selected cases].

PMID- 8656859
TI  - [Coordinate drug insurance and Patient Insurance!].

PMID- 8656860
TI  - [Big congresses are valuable].

PMID- 8656861
TI  - [Watch for misuse of analgesics!].

PMID- 8656862
TI  - [Enterohemorrhagic Escherichia coli. A new contagious disease in Sweden].

PMID- 8656863
TI  - [Work-related voice problems. Teachers, social workers, lawyers and priests
      should receive preventive voice training].

PMID- 8656864
TI  - [Some glipses from the history of mammography: from radiography of preparations
      to general screening].

PMID- 8656865
TI  - [Pseudomembranous colitis in EHEC-infection (Enterohemorrhagic E. coli). Rapid
      improvement without antibiotics].

PMID- 8656866
TI  - [Subarachnoid hemorrhage: anamnesis is crucial for the diagnosis].

PMID- 8656867
TI  - [We should insist on mammographic mass screening. Its value for age groups 50-69
      is indisputable].

PMID- 8656868
TI  - [A study of smoking habits among pregnant women. Most pregnant smokers are in the
      lower social groups].

PMID- 8656869
TI  - [Disagreement among physicians about active euthanasia. 245 answers from a
      Swedish questionnaire reflect uncertainty].

PMID- 8656870
TI  - [Serial rapists. A heterogeneous group needs accurate classification].

PMID- 8656871
TI  - [Significant cost differences between different levels of care. Treatment of leg
      ulcers is more expensive than expected].

PMID- 8656872
TI  - [Hidden antagonism among supporters of projects which could be commercialized in
      the long run].

PMID- 8656873
TI  - [Small increase in the number of ST positions].

PMID- 8656874
TI  - [Respected research institutes in the USA receive support for alternative
      medicine. Self-hypnosis and laying-on-of-hands in heart surgery].

PMID- 8656875
TI  - [Cooperation and integrity. Analyse the relation to commercial interests!].

PMID- 8656876
TI  - [Is the drug industry going to pay our professional fight?].

PMID- 8656877
TI  - [Don't miss the possibility of depression among young people in crisis].

PMID- 8656878
TI  - [Depression caused by beta-blockers--an exception].

PMID- 8656879
TI  - [Leptin and obesity--an error].

PMID- 8656880
TI  - [The PCR technique for screening of viruses should be improved].

PMID- 8656881
TI  - [The practitioners' round has been a form of upgraded continuing education in
      Varberg for 39 years].

PMID- 8656882
TI  - [Considering alternative therapeutic forms is worthwhile].

PMID- 8656884
TI  - [Conflicts of interest in connection with physicians' statements].

PMID- 8656883
TI  - [Is mortality among healthy persons with lipid regulation decreasing in the long
      run?].

PMID- 8656885
TI  - [Persons with amalgam problems should be examined from different aspects].

PMID- 8656886
TI  - [Report patients to the home respiratory registry!].

PMID- 8656887
TI  - [Can lymphoma be cured by antibiotics?].

PMID- 8656888
TI  - [Laparoscopic colorectal surgery. High demands on methods, instruments and
      training].

PMID- 8656889
TI  - [Neonatal index better than Apgar].

PMID- 8656890
TI  - [Therapeutic strategy in vascular changes. New methods for a small group of
      patients difficult to treat].

PMID- 8656891
TI  - [Ascites--a diagnostic and therapeutic challenge].

PMID- 8656892
TI  - [A study of STD patients and their sexual behavior. Safer sex after interviews
      prior to journey abroad].

PMID- 8656893
TI  - [Unclear pathomechanism behind neck-shoulder pain. Problem with insurance claim].

PMID- 8656894
TI  - [Positive experience with a "triangular" revision. Three pediatric clinics
      inspected each other].

PMID- 8656896
TI  - [A seminar on autonomy and integrity in health care. Who decides the limits of
      medical self-determination?].

PMID- 8656895
TI  - [Reconsider management of Helicobacter pylori infections. Time to go over to the
      triple therapy].

PMID- 8656897
TI  - Pill scares and public responsibility.

PMID- 8656898
TI  - Defining ulcer depth in colitis.

PMID- 8656899
TI  - Diagnosis of closed wrist injuries.

PMID- 8656900
TI  - Peak-expiratory-flow meters and asthma self-management.

PMID- 8656901
TI  - Contraction-band necrosis: new use for an old friend.

PMID- 8656902
TI  - Allopurinol for prostatitis: where is the evidence?

PMID- 8656903
TI  - Gun deaths in schools, in the USA.

PMID- 8656904
TI  - Breast cancer and hormonal contraceptives: collaborative reanalysis of individual
      data on 53 297 women with breast cancer and 100 239 women without breast cancer
      from 54 epidemiological studies.
AB  - BACKGROUND The Collaborative Group on Hormonal Factors in Breast Cancer has
      brought together and reanalysed the worldwide epidemiological evidence on the
      relation between breast cancer risk and use of hormonal contraceptives. METHODS
      Individual data on 53 297 women with breast cancer and 100 239 women without
      breast cancer from 54 studies conducted in 25 countries were collected, checked,
      and analysed centrally. Estimates of the relative risk for breast cancer were
      obtained by a modification of the Mantel-Haenszel method. All analyses were
      stratified by study, age at diagnosis, parity, and, where appropriate, the age a
      woman was when her first child was born, and the age she was when her risk of
      conception ceased. FINDINGS The results provide strong evidence for two main
      conclusions. First, while women are taking combined oral contraceptives and in
      the 10 years after stopping there is a small increase in the relative risk of
      having breast cancer diagnosed (relative risk [95 percent CI] in current users
      1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23],
      2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there
      is no significant excess risk of having breast cancer diagnosed 10 or more years
      after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in
      women who had used combined oral contraceptives were less advanced clinically
      than those diagnosed in women who had never used these contraceptives for ever
      users compared with never-users, the relative risk for tumours that had spread
      beyond the breast compared with localised tumours was 0.88 (0.81-0.95; 2p=0.002).
      There was no pronounced variation in the results for recency of use between women
      with different background risks of breast cancer, including women from different
      countries and ethnic groups, women with different reproductive histories, and
      those with or without a family history of breast cancer. The studies included in
      this collaboration represent about 90 percent of the epidemiological information
      on the topic, and what is known about the other studies suggests that their
      omission has not materially affected the main conclusions. Other features of
      hormonal contraceptive use such as duration of use, age at first use, and the
      dose and type of hormone within the contraceptives had little additional effect
      on breast cancer risk, once recency of use had been taken into account. Women who
      began use before age 20 had higher relative risks of having breast cancer
      diagnosed while they were using combined oral contraceptives and in the 5 years
      after stopping than women who began use at older ages, but the higher relative
      risks apply at ages when breast cancer is rare and, for a given duration of use,
      earlier use does not result in more cancers being diagnosed than use beginning at
      older ages. Because breast cancer incidence rises steeply with age, the estimated
      excess number of cancers diagnosed in the period between starting use and 10
      years after stopping increases with age at last use: for example, among 10 000
      women from Europe or North America who used oral contraceptives from age 16 to
      19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess
      number of cancers diagnosed up to 10 years after stopping use is 0.5 (95 percent
      CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of
      use the difference between ever-users and never-users is not so much in the total
      number of cancers diagnosed, but in their clinical presentation, with the breast
      cancers diagnosed in ever-users being less advanced clinically than those
      diagnosed in never-users. The relation observed between breast cancer risk and
      hormone exposure is unusual, and it is not possible to infer from these data
      whether it is due to an earlier diagnosis of breast cancer in ever-users, the
      biological effects of hormonal contraceptives, or a combination of reasons...

PMID- 8656905
TI  - Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative
      Study Group.
AB  - BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300
      fold for monozygotic twins to 20-40-fold for biological first-degree relatives,
      suggesting a genetic influence. Yet if one identical twin has MS the other
      usually will not. One way of sorting out the contributions of genes and
      environment is to study half-sibs. METHODS In a Canadian population-based sample
      of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was
      reported by 939 index cases. By interview we elicited information on family
      structure and an illness in half-sibs and any full brothers or sisters. FINDINGS
      The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32
      percent compared with 3.46 percent for the 1395 full sibs of the same cases
      (p<0.001; likelihood ratio test). There were no significant differences in risk
      for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for
      those raised together versus those raised apart from the index case (1.17 percent
      vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the
      feasibility of using half-sib studies to throw light on the aetiology of complex
      disorders, our findings show that a shared environment does not account for
      familial risk in MS and that maternal effects (such as intrauterine and perinatal
      factors, breastfeeding, and genomic imprinting) have no demonstrable effect on
      familial risk. Halving the number of potentially contributory genes (by comparing
      full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an
      observation consistent with a polygenic hypothesis.

PMID- 8656906
TI  - Use of air enema radiography to assess depth of ulceration during acute attacks
      of ulcerative colitis.
AB  - BACKGROUND Acute colitis is usually assessed by means of plain abdominal
      radiographs, the diagnostic utility of which can be enhanced by barium enema.
      Colonoscopy can also be useful. The latter methods may be laborious and carry
      risk. We describe a radiographic technique using air as the contrast medium to
      show mucosal or deeper ulceration. METHODS Of 60 patients undergoing colectomy
      for acute ulcerative colitis, 35 had air enema radiography and 14 had plain films
      with sufficient amount of spontaneously occurring gas to allow visualisation of
      the mucosa, during the 10 days before surgery. The degree of inflammation on air
      enema films and the extent of histopathological ulceration in colectomy specimens
      were independently graded and compared with each other. Depth of ulceration was
      compared with clinical data including a preoperative risk stratification, the
      APACHE II score. FINDINGS The degree of inflammation on air enema radiography
      correlated significantly with depth of ulceration at histopathological
      examination (rs 0.61, p<0.001). Presence of mucosal changes had a close
      association with deep ulceration extending into the muscularis propria layer or
      beyond (p<0.001). Air enema radiography had a high sensitivity (0.91) for
      presence of and specificity (0.75) in the exclusion of deep ulceration, with
      positive and negative predictive values of 0.88 and 0.80. 42 of 49 patients were
      correctly classified as regards deep ulcers. The correlation between higher
      preoperative APACHE II scores and severity of histopathological colitis was weak
      (rs 0.30, p<0.05). INTERPRETATION Air enema radiography reliably assesses the
      presence of colonic ulceration in patients with an acute attack of ulcerative
      colitis. It is a first-line investigation to assess the presence of deeper
      ulceration in acute colitis.

PMID- 8656907
TI  - Chronic salicylate poisoning and severe malaria.
AB  - BACKGROUND Salicylates continue to be marketed and to be used in developing
      countries as over-the-counter (OTC) antipyretics in children, whereas in
      developed countries they are no longer used in children because of safety
      concerns. The presenting signs of salicylate poisoning, especially chronic
      (repeated administration of therapeutic or excessive doses for longer than 12 h),
      can include metabolic acidosis, hypoglycaemia, lethargy, and coma and fits. These
      signs are also common in severe malaria in African children. Admission of two
      probable cases of chronic salicylate poisoning prompted us to look for other
      cases among children presenting to our hospital in Kenya, apparently with severe
      malaria. METHODS All children admitted to Kilifi District Hospital between July
      and September, 1994, who had a positive blood film for Plasmodium falciparum, and
      one or more of coma, prostration, or respiratory distress were eligible. As well
      as routine tests for malaria and routine biochemistry, salicylate concentrations
      were measured. Management of children (aged 6 months to 10 years) in the
      community was assessed by a cross-sectional survey of 463 households and by
      interviews with mothers 2 days after they had bought OTC drugs for a child with
      fever. FINDINGS Data were available for 143 of 154 children with initial primary
      diagnoses of severe malaria. 129 (90 percent) had detectable (>l mg/dL)
      salicylate. Six of these had salicylate concentrations of 20 mg/dL or higher. All
      six had neurological impairment and metabolic acidosis and four were, or became,
      hypoglycaemic. OTC drugs were the first-line treatment in 188 (74 percent) of 254
      fever episodes during the 2 weeks before the cross-sectional survey. Of 250
      mothers who bought drugs for a febrile child, 236 (94 percent) bought a
      preparation containing salicylates and 50 (21 percent) gave a dose higher than
      the manufacturer's recommended maximum. INTERPRETATION These cases suggest that
      in some children salicylate poisoning may cause or contribute to the development
      of metabolic acidosis and hypoglycaemia, complications of severe malaria
      associated with high mortality.

PMID- 8656908
TI  - Falls and urinary incontinence in a 66-year-old woman.

PMID- 8656909
TI  - Current situation and control strategies for resurgence of diphtheria in newly
      independent states of the former Soviet Union.
AB  - Since 1990, an epidemic of diphtheria has spread throughout the newly independent
      states of the former Soviet Union, and by 1995 a total of 47 808 cases were
      reported. During the early stages of the epidemic, adequate control measures were
      not taken and vaccine was in short supply; possible contributing factors to the
      spread of the epidemic are the presence of highly susceptible child and adult
      populations, socioeconomic instability, population movement, and a deteriorating
      health infrastructure. Although WHO views the epidemic as an International public
      health emergency and, together with UNICEF and the International Red Cross, has
      formulated a strategy to combat the epidemic, the necessary funds have not been
      made fully available. Current vaccination recommendations also need to be
      reviewed to ensure that population immunity will be adequate to prevent any
      resurgence of diphtheria in Europe and North America.

PMID- 8656910
TI  - Screening colonoscopy: the cost of common sense.

PMID- 8656911
TI  - Why do mothers cradle babies on their left?
AB  - Many explanations have been put forward for the observed preference of mothers to
      cradle babies on the left side. These include handedness, the importance of the
      maternal heartbeat, left breast sensitivity, socio-psychological factors, and
      advantages in monitoring the infant. We propose that protection and facilitation
      of affective communication is at the core of cradling; and explore the relation
      between left-cradling and the role of the right hemisphere in early mother-infant
      interaction. Left-cradling not only directs maternal communication to the
      infant's right hemisphere but also facilitates affective feedback to the maternal
      right brain. The underlying neuro-linguistic mechanisms proposed in this article
      may be important in the early course of child language development and may also
      serve to illuminate our understanding of the evolution of human language.

PMID- 8656912
TI  - Isotretinoin for severe acne.

PMID- 8656913
TI  - Fighting obesity the Franco-British way.

PMID- 8656914
TI  - Favourable start for the NIH budget.

PMID- 8656915
TI  - Antagonism to calcium antagonists.

PMID- 8656916
TI  - Antagonism to calcium antagonists.

PMID- 8656917
TI  - Antagonism to calcium antagonists.

PMID- 8656918
TI  - Transmission of HIV-1 by human bite.

PMID- 8656919
TI  - Brucella melitensis--a sexually transmissible agent?

PMID- 8656920
TI  - Clot formation and gelatin-based plasma substitutes.

PMID- 8656921
TI  - Lens changes during rapid tightening of metabolic control in diabetes.

PMID- 8656922
TI  - Breastfeeding, dummy use, and adult intelligence.

PMID- 8656923
TI  - Breastfeeding, dummy use, and adult intelligence.

PMID- 8656924
TI  - Breastfeeding, dummy use, and adult intelligence.

PMID- 8656925
TI  - Tapeworm disease in vegetarians.

PMID- 8656926
TI  - An outbreak of visceral larva migrans due to Ascaris suum in Kyushu, Japan.

PMID- 8656927
TI  - Protein C in the treatment of coagulopathy in meningococcal disease.

PMID- 8656928
TI  - Health and moral responsibility.

PMID- 8656929
TI  - Health and moral responsibility.

PMID- 8656930
TI  - Health in Nepal.

PMID- 8656931
TI  - Commercialisation of disease management.

PMID- 8656932
TI  - From Erasmus to Socrates: should mobility move from students to teachers?

PMID- 8656933
TI  - An unusual mechanism of recumbent syncope.

PMID- 8656934
TI  - Fluoxetine and chronic fatigue syndrome.

PMID- 8656935
TI  - Fluoxetine and chronic fatigue syndrome.

PMID- 8656936
TI  - Fluoxetine and chronic fatigue syndrome.

PMID- 8656937
TI  - Epidemiological perspectives on alcohol and the law.

PMID- 8656938
TI  - Benign adipic aciduria.

PMID- 8656939
TI  - Sepsis associated with blood transfusion.

PMID- 8656941
TI  - Manganese toxicity and parenteral nutrition.

PMID- 8656940
TI  - Manganese toxicity and parenteral nutrition.

PMID- 8656942
TI  - Treating sick young infants in urban slum setting.

PMID- 8656943
TI  - Apolipoprotein E genotyping in Alzheimer's disease.

PMID- 8656944
TI  - Apolipoprotein E genotyping in Alzheimer's disease. The UK Alzheimer's Disease
      Genetic consortium.

PMID- 8656945
TI  - Apolipoprotein E genotyping in Alzheimer's disease.

PMID- 8656946
TI  - Cleaning as a cost-effective method of infection control.

PMID- 8656947
TI  - The history of laryngology in the United States.

PMID- 8656948
TI  - Advertisements in the Laryngoscope. The merits of cocaine--1896.

PMID- 8656949
TI  - Looking back at a century of cocaine--use and abuse.

PMID- 8656950
TI  - Bluestone et al.: Audiometry and tympanometry in relation to middle ear effusions
      in children. [Laryngoscope. 1973;83;594-604].

PMID- 8656951
TI  - Inverting papilloma presenting with meningitis.

PMID- 8656952
TI  - Quantitative criteria for predicting thyroplasty type I outcome.
AB  - The purpose of this study was to ascertain the relation between preoperative
      glottal gap and postoperative vocal function in thyroplasty type I. Twenty-two of
      64 patients who underwent thyroplasty type I between 1987 and 1994 were studied.
      In preoperative digitized laryngostroboscopic images, the glottal-gap, width
      (GGW), shape, and area were examined at the maximum closure of vibration and
      normalized by membranous vocal-fold length (MVFL). Postoperative vocal function
      analysis was performed with aerodynamic and acoustic measurements and compared
      with preoperative videostroboscopic images. In patients with preoperative
      posterior GGW of less than 10% of MVFL, postoperative vocal function was
      significantly better than in other patients. Although thyroplasty type I is an
      excellent medialization technique, it may need to be combined with a posterior
      closure procedure in patients with large posterior gaps.

PMID- 8656954
TI  - Edmund Prince Fowler Award Thesis. Evaluation of random skin flap survival in a
      porcine model.
AB  - The pathophysiology of random skin flap necrosis in the pig model was studied the
      effects of several drugs on skin flap survival were examined. The investigated
      drugs included acetylsalicylic acid (ASA), pentoxifylline (PTX), prostaglandin E2
      (PGE2), and an experimental 21-aminosteroid, U-74389G. Each drug altered
      different parameters known to be associated with tissue necrosis. Demonstrated
      mechanisms of skin flap failure included the alteration of erythrocyte
      flexibility and platelet function and the activation of neutrophils with
      resultant accumulation of damaging oxygen-free radicals. Random skin flap
      survival did not improve with ASA but did improve significantly with PTX, PGE2,
      and U-74389G. The results of this study underscore the importance of neutrophil
      mediated necrosis in the pathophysiology of skin flap failure. The data further
      demonstrate the need to develop drugs aimed at reversing or preventing the tissue
      damage from oxygen-free radicals in order to enhance the survival of random skin
      flaps.

PMID- 8656953
TI  - Growth rate characteristics of acoustic neuromas associated with
      neurofibromatosis type 2.
AB  - Neurofibromatosis type 2 (NF2) is a dominantly inherited disorder characterized
      by the occurrence of bilateral acoustic neuromas (ANs and other central nervous
      system tumors. Magnetic resonance images and audiologic data on 22 patients with
      NF2 who underwent multiple studies at the National Institutes of Health between
      1983 and 1993 were reviewed to determine the growth characteristics of ANs in
      these patients. The average growth rate of ANs in NF2 patients was 0.30 cm3 per
      year and was significantly higher in older patients (0.75 cm3 per year) than in
      younger ones (0.12 cm3 per year). Larger ANs were more commonly found in patients
      with concomitant spinal tumors or meningiomas. NF2 patients with spinal tumors
      but not meningiomas demonstrated faster growth rates than patients without
      additional tumor burden. The data from this study suggest that older patients or
      patients with associated spinal tumors have faster growing ANs and therefore
      should be followed closely and treated aggressively.

PMID- 8656955
TI  - Myology of the pharyngoesophageal segment: gross anatomic and histologic
      characteristics.
AB  - Although numerous studies have been performed on the function and dysfunction of
      the pharyngoesophageal segment, few studies have investigated features of the
      musculature in this area. Thus, the purpose of this study was to systematically
      exam. ine the structure (gross anatomy and histology) in this area and to relate
      these findings to the functions of the pharyngoesophageal segment. Twenty-one
      autopsy and surgery patients underwent careful measurement and observation of 1.
      the vertical (cephalad-caudad) height of the cricopharyngeus muscle (CP); 2. the
      presence or absence of Kilfian's dehiscence; and 3. the separation or blending of
      the CP with the upper esophageal circular muscles. Of the 21 subjects, muscle
      specimens were removed from 8 (4 autopsy, 4 surgical) to include a muscle strip
      from the upper esophageal circular muscles, CP, and inferior pharyngeal
      constrictor and submitted to a battery of histological and histochemical tests.
      Gross anatomic measurements of the vertical height of the CP were substantially
      longer than those reported elsewhere. Killian's dehiscence was shown to be
      present in fewer than one third of the specimens. Histology of these muscles also
      showed significant differences from the muscles discussed in other published
      reports, particularly when fresh and autopsy material were compared. These
      specialized muscles, therefore, require further detailed study.

PMID- 8656956
TI  - Avascular tympanojugular paraganglioma.
AB  - The avascular paraganglioma described in this article appears to be the second
      such tumor reported in the international literature and the first to be reported
      in the tympanojugular region. Despite a highly suggestive history and clinical
      appearance, the tumor showed no signs of vascularization on radiologic studies.
      The pathologic postoperative study confirmed the diagnosis of paraganglioma with
      extensive stromal fibrosclerosis and without the typical well-vascularized thin
      fibrous septa. In the authors' opinion, this observation is notable because of
      the difficulties encountered in the correct diagnostic interpretation of an
      avascular mass in the tympanojugular region. In such cases, the possibility of a
      paraganglioma should always be considered.

PMID- 8656957
TI  - General anesthesia with and without nitrous oxide (N2O) and the weight of middle
      ear effusion in children undergoing adenoidectomy and tympanostomy.
AB  - This study was designed to explore the effect of nitrous oxide (N2O) on the
      amount of middle ear effusion. Seventy-six children referred for adenoidectomy or
      tympanostomy tube placement were divided into two groups in the basis of the
      method of anesthesia. One group of 39 children was ventilated with a mixture of
      30% oxygen and 70% nitrous oxide, while the other group of 37 patients was
      ventilated with a mixture of oxygen and air. The amounts of middle ear effusion
      obtained in myringotomy were weighed and compared between these groups.
      Preoperative and perioperative tympanograms were performed. Ventilation with
      nitrous oxide caused a distinct rise in middle ear pressure. The amount of the
      middle ear effusion, however, remained the same in the two groups. It is
      concluded that the operating surgeon can rely on the myringotomy finding even
      when nitrous oxide anesthesia is used.

PMID- 8656958
TI  - Early otitis media and phonological development at age 2 years.
AB  - The effect of early otitis media on phonology and articulation in the presence of
      expressive language delay was investigated in 16 2-year-olds followed
      prospectively from birth. Eight of the children were designated otitis-positive
      and 8 were considered otitis-negative as determined by bilateral pneumatic
      otoscopy outcomes during year 1 of life. The groups differed significantly on
      measures of expressive, not receptive, language development. All members of the
      otitis-positive group were expressive language delayed. Phonological analyses
      were completed on spoken language samples elicited from each child at age 24
      months. Results showed similar developmental tendencies in speech sound
      acquisition between the groups, but the otitis-positive group had established
      significantly fewer initial consonant phones and produced them less accurately
      than the otitis-negative subject group. The otitis-positive group acquired
      significantly fewer consonants with back place of articulation. Similar
      phonological error patterns of deletion and phoneme class deficiency were used by
      the groups, but the otitis-positive group used the error patterns more
      frequently. Findings here lend support to the otitis media effect as one of
      interaction among risk factors.

PMID- 8656959
TI  - Age dependency of the composition of immunocompetent cells and the expression of
      adhesion molecules in rat laryngeal mucosa.
AB  - Clinical evidence shows that laryngeal infections in infants differ significantly
      from those in adults. Therefore, the composition of the mucosal immune system
      (granulocytes, macrophages, dendritic cells, natural killer cells, and T and B
      lymphocytes) and the epithelial expression of class II-MHC molecules and adhesion
      molecules ICAM-1, VCAM-1, and E-selectin were studied in the larynx of newborn, 5
      week-old, and 3-year-old rats. With the exception of macrophages, the
      immunocompetent cells began to immigrate into the laryngeal mucosa after birth,
      indicating that the laryngeal mucosa in newborn rats is immature. In contrast,
      ICAM-1 was already expressed. The number of immunocompetent cells and the
      expression of epithelial class II-MHC and ICAM-1 increased with age.
      Immunocompetent cells and epithelial class II-MHC and ICAM-1 expression were
      mainly detected in the subglottic region, but were almost absent in the vocal
      fold region.

PMID- 8656960
TI  - Prevalence and assessment of qualitative olfactory dysfunction in different age
      groups.
AB  - The prevalence of parosmia and phantosmia among 363 chemosensory and nasal/sinus
      patients was studied, as was the accuracy with which our clinical questionnaire
      could assess these dysfunctions. We then investigated whether patients with
      parosmia or phantosmia, matched for odor intensity, perform poorer on odor
      identification than do patients with no dysosmia. More than 40% of the study
      group evidenced either parosmia (18.7%) and/or phantosmia (25.6%), a finding that
      suggests that more attention should be paid by the medical practitioner in
      addressing qualitative olfactory dysfunction. Furthermore, it appears that
      assessment of these dysfunctions may aid in differential diagnosis, and that
      questionnaires can be used with reasonable validity irrespective of the patient's
      age. Finally, the results imply that parosmia may be reflected in a discrepancy
      between odor identification and detection.

PMID- 8656961
TI  - Characteristics of an in vivo canine model of phonation with a constant air
      pressure source.
AB  - Many previous studies of laryngeal biomechanics using in vivo models have
      employed a constant air How source. Several authors have recently suggested that
      the lung-thorax system functions as a constant pressure source during phonation.
      This study describes an in vivo canine system designed to maintain a constant
      peak subglottic pressure (Psub) using a pressure-controlling mechanism.
      Increasing levels of recurrent laryngeal nerve (RLN) stimulation resulted in a
      significant rise in resistance followed by a plateau. For a given Psub, flow
      decreased significantly and precipitously with increasing stimulation and then
      quickly plateaued. Vocal intensity increased with increasing RLN stimulation
      until a peak was reached. After this peak, intensity dropped until a plateau was
      reached, corresponding to the flow minimum. At a given Psub, increasing levels of
      RLN stimulation resulted in a normal distribution of vocal efficiencies.

PMID- 8656962
TI  - Intraoperative identification of laryngeal nerves with laryngeal
      electromyography.
AB  - The laryngeal nerves are at risk during thyroid surgery, and several techniques
      have been described for their intraoperative identification to minimize potential
      damage. Nerve protection is based on the electromyographic recording from the
      muscles innervated by the laryngeal nerves, and that electrical activity is
      picked up by various techniques. We evaluated an electrode attachment to the
      endotracheal tube that provides a stable method for continuous recording of the
      laryngeal electromyogram. In addition, we tested various modalities of electrical
      stimulation in the region where the nerves are located, identified the most
      reliable evoked electromyographic activity, and characterized the wave form and
      latency. The results, obtained in 28 patients scheduled for thyroid and
      parathyroid surgery, indicate that the technique of recording from electrodes
      attached to the endotracheal tube is safe and reliable. Insulated bipolar forceps
      or a monopolar electrode was used to deliver low-voltage pulses (1 to 3 V) at 1
      to 2 pulses/s generated by either battery-operated or optically isolated
      stimulators. The most unequivocal recordings were obtained with the monitoring
      equipment set to the nerve-conduction velocity modality, with the sweep set at 2
      msec/cm. The technique clearly differentiated the evoked electromyographic
      responses obtained from the superior or recurrent laryngeal nerve and was easily
      performed with no perioperative complications.

PMID- 8656963
TI  - Orbicularis oris muscle injury in brass players.
AB  - The embouchure of the brass player is critical to tone production and largely
      depends on the integrity of the orbicularis oris muscle. Injury to this muscle
      can cripple the professional musician by causing fatigue, pain, and tonal
      deterioration. Ten brass players presented with muscular defects in the
      orbicularis oris muscle. Examination identified areas of abnormality within the
      muscle and electromyography (EMG) ruled out a neurologic deficit. All patients
      underwent exploration under neuroleptic anesthesia, and 9 patients underwent
      repair. The technique is described. The repaired patients reported improvement
      after the operation and all resumed playing at their premorbid level. The 10th
      patient was found to have thinning of the entire orbicularis oris muscle
      (presumably congenital) and was not able to be repaired. There were no
      complications of the procedure and no recurrences.

PMID- 8656964
TI  - Extracorporeal electromagnetic shock-wave lithotripsy for salivary gland stones.
AB  - Sialoadenectomy for sialolithiasis is necessary when the stone cannot be removed
      through the salivary duct. In addition, extracorporeal. shock-wave lithotripsy
      has recently become available for this purpose. The safety and efficacy of this
      method was assessed in 52 outpatients bearing stones with an average diameter of
      6.76 mm in the submandibular or parotid gland. Anesthetics, sedatives, and
      analgesics were not required. Twenty-four of the 36 patients with submandibular
      gland calculi and all 16 with parotid sialolithiasis had complete stone
      disintegration or fragmentation of the calculi, with possible spontaneous
      clearance. Untoward effects were observed in 15 patients, namely localized skin
      petecchiae, transitory swelling of the gland, and self-limiting bleeding from the
      duct. No persistent damage of the salivary glands or adjacent structures was
      noted during a mean follow-up period of 10 months.

PMID- 8656966
TI  - Diltiazem does not protect the ear from noise-induced hearing loss in mongolian
      gerbils.
AB  - Recent data suggest that diltiazem reduces noise-induced hearing loss. Our study
      was designed to replicate and extend the results of Maurer et al. by using the
      gerbil as a model. In experiment A, subjects received diltiazem (30 mg/kg/day
      intraperitoneally) or saline for 3 days. After peripheral thresholds were
      measured, each subject was exposed to a 4-kHz tone (90-dB sound pressure level)
      for 20 minutes. Similar amounts of temporary threshold shifts (ITS) were measured
      in the saline and diltiazem groups. In experiment B, subjects were given saline
      or diltiazem (30 mg/kg/day intraperitoneally) for 3 days and then exposed to an
      octave band of noise centered at 4 kHz for 5 days, during which time the subjects
      continued to receive the drug or saline. The TTS and permanent threshold shifts
      were similar in the two groups. Measures of cochlear nonlinearities also showed
      no effect of diltiazem, suggesting that diltiazem does not protect the ear from
      the effects of noise.

PMID- 8656965
TI  - Predicting distant failure in nasopharyngeal cancer.
AB  - In a prospective study of 78 patients with nasopharyngeal cancer, we examined the
      prognostic significance of T stage, histology, parapharyngeal involvement, and
      lymph node dimensions, size, and level concerning distant metastasis. AU patients
      were treated with radical radiotherapy alone and completed 3 to 7 years of follow
      up. In univariate analysis of time to metastasis, there was a significant
      difference stratifying for T stage (T1 and 2 versus T3 and 4), node dimensions
      (less than 6 versus more than or equal to 6 cm), neck level (above versus below
      the thyroid notch), and parapharyngeal involvement, but not for bilaterality of
      lymphadenopathy. Histology was an important prognostic factor related to distant
      metastasis since none of the 24 World Health Organization class I cases showed
      distant metastasis versus 14 (26%) of 54 patients with World Health Organization
      class II/III carcinoma. A multivariate duration model of time to metastasis
      within the later histologic group suggested that lymph node dimensions, node
      level, and T stage were the most important factors related to distant metastases,
      with the hazard ratios being 3.98, 3.23, and 1.76, respectively. Multivariate
      analysis within the T3- to T4-stage group showed that node dimension was the only
      significant variable, with an associated hazard ratio of 4.09. Cases with upper
      neck lymphadenopathy and node dimensions of less than 6 cm had a distant
      metastasis rate of <5%. We conclude that adjuvant chemotherapy for nasopharyngeal
      cancer is justified in T3- and T4-staged cases with nonkeratinizing or
      undifferentiated histology and with lymph nodes larger than 6 cm and/or located
      below the thyroid notch.

PMID- 8656967
TI  - Association of mitochondrial DNA deletions and cochlear pathology: a molecular
      biologic tool.
AB  - The purpose of these experiments was to develop a method of isolation,
      amplification, and identification of cochlear mitochondrial DNA (mtDNA) from
      minute quantities of tissue. Additionally, studies were designed to detect mtDNA
      deletions (mtDNA del) from the cochlea that previously have been amplified from
      other organ systems and tissues. MtDNA del have been associated with many
      pathologies, including neurological disorders, sensorineural hearing loss,
      ischemia, cardiomyopathies, and aging. DNA was extracted from rat and human
      tissues, and polymerase chain reaction was used to amplify mtDNA sequences. A 360
      base pair (bp) cytochrome-b gene product and the highly conserved ND1-16S
      ribosomal ribonucleic acid regions found only in mtDNA were amplified from all
      tissues. Preliminary studies have identified a 4834 bp mtDNA del in aged rats and
      a corresponding 4977 bp mtDNA del in aged humans. Additionally, preliminary
      results in human archival temporal bone studies reveal the presence of the 4977
      bp mtDNA deletion in two out of three patients with presbycusis. The deletion was
      not evident in age-matched control patients without a history of presbycusis.
      This technique of mtDNA identification makes it possible to investigate specific
      mtDNA defects from a single cochlea, promoting the study of hereditary hearing
      loss and presbycusis at a molecular biologic level.

PMID- 8656968
TI  - Use of fibrin glue in parotidectomy closure.

PMID- 8656969
TI  - Laryngoscopic placement of laryngeal keels with percutaneous fixation.

PMID- 8656970
TI  - Minimally invasive laser surgery for the treatment of bilateral vocal cord
      paralysis.

PMID- 8656971
TI  - [Risk factors for the onset of ventricular tachycardia in patients with mitral
      valve prolapse].
AB  - Non-invasive diagnostic methods (history, ECG, phonocardiography, exercise
      testing, Holter monitoring and Doppler echocardiography) were done in 48 persons
      with mitral valve prolapse (MVP). The aim was to establish possible risk factors
      for occurrence of ventricular tachycardia (VT) in persons with MVP and to find a
      possible difference between these risk factors. The possible risk factors for VT
      are: syncope, negative T wave in the inferolateral ECG leads, longer duration of
      QT interval, ST devalvation and duration of the ST devalvation, reduction of
      oxygen consumption evaluated by exercise testing, left ventricular function
      impairment, polymorphic premature ventricular contractions (PVC's), paired PVC's,
      larger dimensions of left cardiac chambers, larger surface and thickness of
      anterior mitral leaflet, extent of mitral regurgitation and higher mitral valve
      prolapse score. In patients with sustained VT we found higher age, more frequent
      syncopal attacks, longer QTc interval, more frequent negative T wave in
      inferolateral ECG leads, deeper ST devalvations, lower oxygen consumption, more
      prominent left ventricular function impairment, more frequent polimorphic PVC's
      (more than 10/1000 ventricular complexes), paired PVC's and thicker anterior
      mitral leaflet than in patients with non-sustained VT. (For all these risk
      factors is p < 0.01). Non-invasive diagnostic methods could help to identify the
      patients with mitral valve prolapse at elevated risk for VT.

PMID- 8656972
TI  - [Changes in relevant attitudes of nurses after one year of working with Balint
      groups].
AB  - The present study was carried out in the Popovaca Psychiatric Hospital and the
      examinees were nurses (N = 44) allocated to educative work in Balint groups.
      Authors discuss if any change may occur in the attitude towards some relevant
      notions during the one-year educative work in Balint groups. A graphic form of
      semantic differential was used as the measuring instrument. The findings of this
      study suggest that during the educational process the attitude towards notions
      "education", "doctor" and "myself" becomes more negative. The attitude towards
      the notion "patient" remains unchanged.

PMID- 8656973
TI  - [Immunity against hepatitis A in younger age groups and the basis for an
      immunization program].
AB  - The naturally acquired immunity to hepatitis A virus (HAV) in a sample of 305
      children, aged up to 15 years, in the municipality of Ivanic-Grad amounted to
      18.7%. The study was conducted in September 1989. Of those 305 children, 16.8% of
      the boys and 20.7% of the girls were positive. No statistically significant
      difference was observed with regard to sex (p < 0.01) (chi 2 = 1.4). Of the
      children aged up to two years, 47.4% were exposed to the hepatitis A virus.
      Seropositive for anti-HAV were 8.3% in the group from 2-3 years of age, 6.4% in
      those aged from 4-5 years, 15.9% in the group from 6-7 years of age, 6.8% in
      those aged from 8-9 years, 20.0% in the group from 10-11 years of age, 27.8% in
      those aged from 12-13 years, and 29.0% in the group from 14-15 years of age. The
      spread of the infection by contact was predominant, reflecting the socioeconomic
      standards of the studied community (p < 0.01) (chi 2 = 29.5). A relatively high
      prevalence of hepatitis A infection compared to that of the developed countries,
      the first peak immunity rates in first-graders, a low number of cases among
      infants aged up to 5 years (approximately 6.0%), availability of commercial
      vaccine, speak in favour of including hepatitis A vaccination into the obligatory
      community-wide immunization program. It appears that the target age for HAV
      vaccination would be the age of five.

PMID- 8656974
TI  - [Radiographic pulmonary changes in children with tuberculosis].
AB  - Radiographs of the chest of 204 patients with recently diagnosed tuberculosis
      have been analyzed in terms of nature of changes, localization, age and
      interrelationship between these parameters. Patients have been treated for three
      years and a half. Their ages ranged from 0 to 14 years (SD 6.4 +/- 4.2 years).
      Lymphadenopathy was the commonest radiographic change accounting for 84.3% of all
      the patients (172 pts) and was more frequently encountered in the youngest age
      group from 0 to 4 years (p < .0001) and in the right hilomediastinal area (p <
      .0001). Parenchymal changes were seen in 125 (61.2%) patients, similarly, at an
      earlier age (p < .03), and more commonly on the right side. Other diseases such
      as atelectasis and miliary tuberculosis were less frequently encountered, except
      pleuritis which was found in 13 (6.3%) patients. The authors stress the
      importance of chest radiography in the diagnosis and follow-up of tuberculosis in
      young children.

PMID- 8656975
TI  - [Implantation of alloplastic surgical mesh in hernia repair. An anterior pre
      peritoneal approach].
AB  - Despite the fact that more than one century has passed from the first radically
      performed surgery of inguinal hernia by Bassini there is still an appreciable
      problem in repair of abdominal hernias. In reconstructive-plastic surgeries,
      without the application of prosthesis, recurrences amount to 10% in primary
      repairs, and up to 20% or more in repairing recurrences. Synthetic surgical
      meshes have been used in repair of hernias for over 4 decades. During that
      period, extensive experience has been gained in use of various kinds of
      nonabsorbent and absorbent synthetic meshes in either experimental animals or in
      clinical investigations. Following our experience with one hundred patients
      managed with dacron "Mersilene" mesh, throughout the period 1960-1974, we were
      very rigorous, i. e. we used synthetic meshes only in cases when defect could not
      be repaired by the tension-free living tissue from the surrounding area. Today,
      synthetic meshes are routinely used for almost all kinds of hernias and even in
      primary reconstruction of inguinal and femoral hernias without the plastic
      surgery of the surrounding tissue. During the past 20 years, Lichtenstein IL,
      Shulman AG, Parviz KA et al. from Los Angeles have been recommending "the tension
      free hernioplasty" for the repair of all kinds of primary and recurrent hernias
      with the results (infections, recurrences) being far more better than those
      achieved with the old classical operations. At present, the polypropylene
      "Marlex" mesh sewn with monofilamented polypropylene threads yields very good
      results and should be found in the hands of every surgeon practitioner.

PMID- 8656976
TI  - [Dynamic mutations--a newly detected category of mutations which is the basis for
      certain neurologic diseases].
AB  - This review offers some basic information on the discovery of a new type of
      mutations being the cause of some significant neurologic diseases: myotonic
      dystrophy, Huntington's disease, spinocerebellar ataxia type 1, spinobulbar
      pallido-louysian muscular atrophy, fragile X syndrome and some other, up to a
      total of ten entities. The basis of the so-called dynamic mutations is an
      abnormal multiplication of a trinucleotide producing sequences of several
      hundreds or even thousands of identical copies in the respective gene. The result
      is designated as expanded or amplified trinucleotide (or triplet) repeat. These
      sequences are not stable, but increase (or exceptionally decrease) in length
      during cell multiplication in successive generations. They segregate within
      families with the affected members, demonstrating a significant correlation
      between the length of the repeat sequence, the severity of the pathologic
      phenotype and an inverse correlation with the age at the clinical manifestation
      of the disease. Thus, at least, a formal explanation for the anticipation
      phenomenon of the age at which the disease is manifested within a family is
      offered. The importance of the discovery of dynamic mutations lies in the
      possibility for more precise and reliable genetic counselling. The discovery has
      opened a lot of new questions giving a new impetus for intensive research.

PMID- 8656977
TI  - [Modern information technology and the collection and exchange of biomedical and
      biochemical information].
AB  - Information technology as a new and powerful tool in the hands of scientists
      should provide efficient use of large amount of data. Every day scientific
      population put into circulation about 30000 printed pages containing different
      forms of information. Handling of such amount of written materials is "Sisyphean
      task" and now can be performed by computer which is powerful tool for accessing
      and analyzing large quantity of data. Many faculties, institutes and persons have
      access to networks but average user despite the power of the technology can often
      be frustrated by the simple questions: "What is my colleague's e-mail address?
      How can I most effectively find relevant information? How will I use e-mail,
      gopher or WWW? Who will help me learn more?" In the text I will try to give short
      answers on this and some other questions. I will also try to explain how we can
      use some new ways of communications, how to reach recent programs and information
      from wide areas of interest but specially from biochemistry and biomedicine.

PMID- 8656978
TI  - [The Zagreb Etruscan ceremonial fragment and an ancient Egyptian medical
      papyrus].
AB  - The Archeological museum in Zagreb treasures the linen strips of an Egyptian
      mummy with inscriptions in Etruscan, and an Egyptian medical papyrus. The
      Etruscan text has been deciphered, but only a small part has been translated.
      This religious-magical ceremonial might be in relation with theurgical measures
      for health protection, promotion and restitution. The medical text on the papyrus
      is a hieratic script dating back to Pharaonic New Kingdom, probably a fragment of
      a medicine book similar to the Ebers papyrus. This article provides its
      transcription and translation. Three recipes for a powder and ointments which
      were used in the local treatment of inflammed moist skin lesions are presented.

PMID- 8656980
TI  - [Microbiologic detection of pelvic actinomycosis].

PMID- 8656979
TI  - [Sibenik schoolchildren and the war (7 months later)].
AB  - We have conducted a study among 553 school children from the fifth and seventh
      classes of two primary schools; one, under the continuous Serbian bombardment,
      and another outside the activities of the enemy's cannons and artillery. The aim
      of the research, based on a questionnaire, was to discover how 11- and 13-year
      old school children have experienced alarms, rocket attacks at schools without
      shelters, what those children think about the war, who had started it and why,
      will the war come to finish soon, and what are they going to recall the longest
      from this brutal and dirty war.

PMID- 8656981
TI  - Fast spoiled gradient-recalled MR imaging of thoracic aortic dissection:
      preliminary clinical experience at 1.5 T.
AB  - The purpose of this study was to evaluate fast spoiled gradient-recalled (FSPGR)
      magnetic resonance (MR) imaging in the diagnosis of thoracic aortic dissection
      (TAD). Twenty-eight patients with suspected TAD underwent MR imaging with FSPGR
      and either cine or cardiac-gated spin-echo MR techniques. The average scanning
      time for the FSPGR images was approximately 1 min. Three readers interpreted the
      FSPGR images for the presence or absence of TAD. An ROC analysis was done. At a
      specificity of 90%, the sensitivity ranged from 52% to 90% for the three readers.
      Pulsatility artifacts and mural thrombus were causes of false-positive and false
      negative readings. The areas under the ROC curves (Az) ranged from 0.85 to 0.97
      for the three readers. There was a statistically significant difference in the Az
      values for two of the experienced readers (p = .02). The correct type of
      dissection was determined in only 65% of the true-positive diagnoses. FSPGR has a
      very limited role in screening and for rapid evaluation of the unstable patient.
      The results are reader dependent and susceptible to pulsatility artifacts.
      Determination of the type of dissection is limited. With a suspected thoracic
      aortic dissection, therefore, additional imaging sequences should be obtained to
      maximize accuracy.

PMID- 8656982
TI  - In vivo PO2 imaging in the porcine model with perfluorocarbon F-19 NMR at low
      field.
AB  - Quantitative pO2 imaging in vivo has been evaluated utilizing F-19 NMR in the
      porcine model at 0.14 T for the lungs, liver, and spleen following i.p.
      administration of the commercial perfluorotributylamine (FC-43)-based
      perfluorocarbon (PFC) emulsion, Oxypherol-ET. Calculated T1 maps obtained from a
      two spin-echo saturation recovery/inversion recovery (SR/IR) pulse protocol are
      converted into quantitative pO2 images through a temperature-dependent
      calibration curve relating longitudinal relaxation rate (1/T1) to pO2. The
      uncertainty in pO2 for a T1 measurement error of +/- 5% as encountered in
      establishing the calibration curves ranges from +/- 10 torr (+/- 40%) at 25 torr
      to +/- 16 torr (+/- 11%) at 150 torr for FC-43 (37 degrees C). However,
      additional uncertainties in T1 dependent upon the signal-to-noise ratio may be
      introduced through the SR/IR calculated T1 pulse protocol, which might severely
      degrade the pO2 accuracy. Correlation of the organ image calculated pO2 with
      directly measured pO2 in airway or blood pools in six pigs indicate that the PFC
      resident in lung is in near equilibrium with arterialized blood and not with
      airway pO2, suggesting a location distal to the alveolar epithelium. For the
      liver, the strongest correlation implying equilibrium was evident for venous
      blood (hepatic vein). For the spleen, arterial blood pO2 (aorta) was an
      unreliable predictor of pO2 for PFC resident in splenic tissue. The results have
      demonstrated the utility and defined the limiting aspects quantitative pO2
      imaging in vivo using F-19 MRI of sequestered PFC materials.

PMID- 8656983
TI  - Quantification of trabecular structure in the distal femur using magnetic
      resonance phase imaging.
AB  - A new approach for quantifying trabecular bone tissue using the phase images of a
      simple gradient-echo sequence is presented. The proposed method is based on the
      hypothesis that the differences in susceptibility between bone and bone marrow
      cause magnetic field (i.e., precession phase) variations between the image
      voxels. Phase images of the distal femur were obtained in vivo and characterised
      with the use of the phase variance. Computer simulations and experimental results
      indicate that the distribution of the phases varies with echo time and image
      resolution, as expected. Keeping these fixed, however, the phase variance is
      found to strongly reflect variations in trabecular structure.

PMID- 8656984
TI  - Noninvasive analysis of water movement in rat testis using deuterium magnetic
      resonance imaging.
AB  - To measure water movement in the testis without the effects from the blood-testis
      barrier, we performed in vivo deuterium magnetic resonance imaging (2H MRI) of
      rats administered with deuterated saline. Alcohol was injected into one testis of
      each animal and the other was administered with normal saline as a control.
      Dynamic 2H MRI was obtained at 2 T by FLASH pulse sequence (TR, 300 ms; TE, 10
      ms; alpha = 90 degrees) using a surface coil (3 cm in diameter). The variation in
      2H signal intensity between the two testes as a function of time after deuterated
      saline injection was examined every 1.1 min up to 20 min. The signal intensity in
      the testis receiving the alcohol treatment was lower than that in the normal
      control. Thus, deuterium MRI can be used to analyze functional disorders of the
      testis.

PMID- 8656985
TI  - A simple MR-compatible infusion pump.
AB  - A simple, mechanical infusion pump that employs a constant force,
      nonferromagnetic spring to squeeze a syringe is described. The contrast infusion
      rate is determined by the spring force, gadolinium solution viscosity, and the
      resistance of either a user-selected needle or a precision oriffice according to
      Poiseuille's Law or the Bernoulli effect. Its use in dynamic, gadolinium-enhanced
      3D MR angiography is described.

PMID- 8656986
TI  - Therapeutic efficacy of a case of pyruvate dehydrogenase complex deficiency
      monitored by localized proton magnetic resonance spectroscopy.
AB  - We experienced a case of pyruvate dehydrogenase deficiency observed by proton
      magnetic resonance spectroscopy (1H MRS). This case was diagnosed as West
      syndrome by characteristic convulsion and the periodic hypsarrhythmia pattern of
      EEG. At the age of 11 months, the first examination of 1H MRS revealed a high
      peak of lactate, and the high concentration of lactate and pyruvate was confirmed
      in sampled cerebrospinal fluid (CSF). Deficiency of pyruvate dehydrogenase
      complex was finally diagnosed by genetic examination. Dichloroacetate was
      administered to the patient as therapy. Decrease of lactate in the brain was
      found by 1H MRS. Lactate and pyruvate in the CSF was also decreased. In
      accordance with the suspension of dichloroacetate, increase of lactate in the
      brain was detected and the convulsions reappeared. After readministration of
      dichloroacetate, the patient was almost symptom free and lactate in the brain and
      CSF had decreased to the normal extent. We considered that 1H MRS provides useful
      information for screening metabolic disorders of infants and assessing the
      efficacy of therapy.

PMID- 8656987
TI  - Assessment of acute myocardial infarction in man with magnetic resonance imaging
      and the use of a new paramagnetic contrast agent gadolinium-BOPTA.
AB  - To assess the feasibility of and characterize the new paramagnetic contrast agent
      gadolinium-BOPTA/dimeglumine (Gd-BOPTA) to detect acute myocardial infarctions
      with MR imaging, 24 patients (53.3 +/- 8.3 yr) were examined 9.3 +/- 3.6 days
      after a first myocardial infarction. Short-axis T1-weighted and T2-weighted MR
      imaging was performed at three slice levels. T1-weighted images were obtained
      before, immediately after, 15, 30, and 45 min after injection. Patients received
      either 0.05 or 0.1 mmol/kg body weight Gd-BOPTA. Images were qualitatively and
      quantitatively analyzed. Two patients showed no signs of infarction on T2
      weighted images as opposed to contrast-enhanced T1-weighted images. Contrast-to
      noise ratio was not affected by the dosage level. Signal intensity (SI) of normal
      to infarcted myocardium was significantly improved by both dosages (p < .0005)
      but a dosage of 0.05 mmol/kg produced significantly higher SI inf/norm (1.42 +/-
      0.07 vs. 1.34 +/- 0.06, respectively, p = .015). SI of normal and infarcted
      myocardium enhanced immediately after administration of 0.05 mmol/kg (29.3 +/-
      5.1% and 53.8 +/- 9.6% respectively), which decreased thereafter to 5.3 +/- 4.8%
      and 40.2 +/- 8.5% respectively, at 45 min (p < .002 for normal myocardium). SI
      enhancement immediately after 0.1 mmol/kg Gd-BOPTA showed no decrease within the
      first 45 min. Gd-BOPTA enables the detection of myocardial infarction. Optimal
      infarct delineation is achieved from 15 to 45 min after administration of 0.05
      mmol/kg body weight Gd-BOPTA. Gd-BOPTA at 0.05 mmol/kg does improve image quality
      as measured by contrast-to-noise ratio and SI enhancement as compared to 0.10
      mmol/kg.

PMID- 8656988
TI  - Dynamic Gd-enhanced MR imaging of hepatic hemangioma: is high temporal resolution
      requisite for characterization?
AB  - We assessed the value of high temporal resolution in the dynamic characterization
      of hepatic hemangioma with use of magnetization-prepared gradient-echo (MP-GRE)
      imaging. Single-level inversion recovery incremental flip angle MP-GRE images
      were obtained in 26 patients with 34 hemangiomas before and at a repetition rate
      of 30 images/min after injection of Gd-DTPA without breath-holding. Enhancement
      patterns and temporal changes thereof were analyzed. Hemangiomas were categorized
      as small ( < 2.0 cm), medium (2.0-5.0 cm), and large ( > 5 cm) lesions. Classic
      early peripheral nodular enhancement (PNE) with progressive hyperintense fill-in
      was observed in 31 lesions (91%). Two of 10 small and 1 of 20 medium lesions
      showed complete fill-in within 10 s, and three small and one medium lesions
      within 45 s after the onset of PNE. In no cases of hemangioma was immediate
      homogenous hyperintensity observed without preceding PNE. In conclusion, temporal
      resolution of less than 10 s is a prerequisite for confident dynamic
      characterization of some hemangiomas, predominantly small hemangiomas.

PMID- 8656989
TI  - Superparamagnetic iron oxide (SPIO) as an oral contrast agent in gastrointestinal
      (GI) magnetic resonance imaging (MRI): comparison with state-of-the-art computed
      tomography (CT).
AB  - This study was conducted to compare the sensitivity and specificity of abdominal
      magnetic resonance imaging using oral superparamagnetic iron oxide with oral
      contrast-enhanced computed tomography in the detection of GI pathology. Overall
      sensitivity was calculated to be 83% for OECT compared to 67% by SPIO MRI.
      Specificity for OECT was 68% compared to 89% for SPIO MRI. The results from
      imaging with superparamagnetic iron oxide and imaging with oral contrast-enhanced
      computed tomography were in agreement in 14 subjects who had normal
      gastrointestinal tracts. In the remaining 16 patients, eight pathologic entities
      were detected by both modalities whereas 15 abnormalities were seen by only one
      modality. Superparamagnetic iron oxide magnetic resonance imaging was helpful in
      discriminating normal bowel from solid lesions and in detecting subtle
      gastrointestinal tract mass effect. In 30 consecutively studied patients
      suspected of having GI pathology, OECT was more sensitive than SPIO MRI in
      detecting abdominal pathology. Conversely, SPIO MRI was more specific than OECT.

PMID- 8656990
TI  - Monitoring of task performance during functional magnetic resonance imaging of
      sensorimotor cortex at 1.5 T.
AB  - Functional magnetic resonance imaging (fMRI) has found widespread clinical
      interest. Difficulties in clinical use of the fMRI technique arise, considering
      the lack of knowledge about activation task performance. This accounts especially
      for sensorimotor activation studies, in which performance of the sensorimotor
      activation task is-if at all-usually rated visually by subjective or
      semiquantitative methods (i.e., defining categories of performance such as
      neurological soft signs scales). Recently, instrumental methods for the
      measurement and analysis of motor performance have been developed.
      Pronation/supination (hand rotation) movement was shown to be an easily
      measurable and promising motor task. We have adapted a mechanic device
      (pronation/supination device, PSD) to monitor motor performance during the fMRI
      experiment. In a feasibility study, an investigation of fMRI activation strength
      dependence of sensorimotor cortices and supplementary motor area upon task
      frequency (25, 50, and 75 cycles/min) was carried out on 10 right-handed healthy
      volunteers. Furthermore, the authors report the observation of stimulus-induced
      activation changes in the cerebellum during pronation/supination movement.

PMID- 8656991
TI  - Neuroradiologic MR applications with multiparametric color composite display.
AB  - The purpose of this article is to demonstrate the application of a PC-based
      multiparameter full color composite display technique of MR images of 14 selected
      patients with neuropathology while assessing the ability of this technique to
      display clinically important neuroanatomic and neuropathologic tissues. Using a
      PC with a 386 microprocessor and full color 24-bit graphics display capabilities,
      custom and commercially available image-processing softwares were applied to
      spatially aligned multiparameter proton density, T1-weighted (with and/or without
      gadolinium-DTPA) and T2-weighted MR image sets obtained from 14 patients with
      known neuropathology to generate intensity-based color composites. Quantitative
      color channel applications were used to assess the ability of this technique to
      differentiate anatomically and pathologically confirmed tissue types into unique
      color regions within the full color spectrum display in each patient case. Based
      on the results of pathologic correlation and quantitative color imaging analysis,
      the application of full color composite generation techniques to multiple MR
      images of selected neuropathology cases represents a viable technique for
      displaying diagnostically relevant tissue contrast information in one color
      image. With this technique, it is possible to generate composites that
      simultaneously display uniquely color-coded neuroanatomic and neuropathologic
      tissue information within the context of partially natural-appearing images.

PMID- 8656992
TI  - Simulation of MRI cluster plots and application to neurological segmentation.
AB  - The advent of magnetic resonance imaging has provided new opportunities for
      volume measurement of tissues, with applications increasing dramatically in
      recent years. Cluster classification techniques have proved the most popular for
      volume measurement, yet little attention has been paid to how the choice of
      images for analysis affects the quality and ease of segmentation. To address this
      issue, we have developed a system to simulate MRI cluster plots using
      multicompartmental anthropomorphic software models of anatomy, and components for
      image contrast, signal-to-noise ratio, image nonuniformity, tissue heterogeneity,
      imager field strength, the partial volume effect, correlation between proton
      density, T1 and T2, and a variety of data preprocessing techniques. The effect of
      these components on tissue cluster size, shape, orientation, and separation is
      demonstrated. The simulation allows an informed choice of pulse sequence,
      acquisition parameters, and data preprocessing for cluster classification to be
      made as well as providing an aid to interpretation of acquired data cluster plots
      and a valuable educational tool. The system has been used to choose suitable
      images for neurological segmentation of grey matter, white matter, CSF, and
      multiple sclerosis lesions using spin-echo, inversion recovery, and gradient-echo
      pulse sequences. Constraints on image selection are discussed.

PMID- 8656993
TI  - Magnetic resonance imaging to study lesions of atherosclerosis in the
      hyperlipidemic rabbit aorta.
AB  - We have developed a high resolution magnetic resonance (MR) imaging technique to
      serially assess lesions of atherosclerosis in a rabbit model. A volume phased
      array coil was designed and used to image the abdominal aortas of six
      atherosclerotic rabbits and two age-, sex-, and weight-matched controls. Lesions
      of atherosclerosis were induced by a combination of repeat balloon injury and a
      hyperlipidemic diet. All animals were imaged on at least two occasions 9-16
      months after initiation of atherosclerosis. In addition, animals were imaged
      immediately after sacrifice. Anatomic dissection and histology were performed to
      verify the MR findings. The volume phased array coil improves the image signal-to
      noise ratio over existing extremity coils and resulted in higher resolution
      images of the abdominal aorta. Proton density-weighted images acquired with 2D/3D
      fast spin-echo are the most useful sequence to outline the vessel wall and to
      differentiate wall from lumen and background. Progressive wall thickening and
      lumen stenosis were observed in the serial images of the diseased rabbits. Wall
      thickness and lumen area derived noninvasively from the in vivo MR images
      correlate with postmortem MR images and sections of aorta examined by dissection
      microscopy and histology. Spin-echo and fast spin-echo imaging with a phased
      array body coil can be used to accurately assess plaque dimensions, and
      potentially can be used to image intraplaque features and to monitor lesion
      progression or regression. It should also be possible to adapt these techniques
      to assess human disease, especially for peripheral vascular problems.

PMID- 8656994
TI  - [Protection of workers' health against occupational psycho-social hazards-
      theoretical models].
AB  - Occupational Health Service are not yet equipped with tools which could permit
      them to include protection of workers' health against occupational psycho-social
      hazards into their prophylactic activities. The authors present a model of such a
      system, its objectives and conditions which should be satisfied in order to put
      the system into operation. The model discussed is somewhat an ideal solution
      which does not necessarily adhere to the reality but it sets tasks and identifies
      lines of activities to be carried out at the Department of Occupational
      Psychology, the Nofer Institute of Occupational Medicine, Lodz. These activities
      are aimed at monitoring and evaluating of health risk generated by psycho-social
      factors.

PMID- 8656995
TI  - [Analysis of work absenteeism due to illness in the provinces].
AB  - Sickness absenteeism in individual regions (voivodships) depends on various
      factors involved in temporary work disability, such as industrial advancement,
      industrial structure, socio-economic development, and recently also unemployment
      in individual regions as well as changes in the social insurance system.
      Certificates recording temporary work disability served as a reference material
      for the analysis. The material under study was derived from the nation-wide
      database covering a 15% random sample of those cards. Sickness absenteeism was
      expressed by the rate lost time which defined the percentage of work disability
      in days in relation to the product of calendar days and the mean number of the
      employed. In 1994 lost time rate in Poland accounted for 6.69 and it was very
      much diversified depending on individual regions. The lowest rates were
      registered in the region of Warsaw (3.17), Lomza (4.23), Suwalki (4.48), Koszalin
      (4.55) and Olsztyn (4.58), whereas the highest ones occurred in Sieradz (12.07),
      Nowy Sacz (11.10), Premysl (10.08), Tarnow (9.98) and Tarnobrzeg (9.89) regions.
      Over a twofold increase in sick absenteeism in comparison with 1990 was noted in
      Siedlce, Tarnobrzeg, Tarnow, Ostroleka, Sieradz and Zamosc regions. The Sieradz
      region shows the highest rate of sick absenteeism due to diseases of the
      musculoskeletal system (2.87), gynecological diseases and complications of
      pregnancy (1.52), the Nowy Sacz region due to diseases of the respiratory (1.82)
      and the circulatory (1.90) systems, and the Przemysl region due to neuroses,
      psychoses and other mental disorders (0.85). A considerable increase in sickness
      absenteeism in low industrialised regions (Siedlce, Ostroleka, Chelm, Zamosc and
      Sieradz) observed during the last five years applies mostly to chronic diseases
      and it related with the right to sickness benefits which discloses poor health of
      workers employed in agriculture. Industrial restructuring and establishment of
      small-scale enterprises have also contributed to essential changes in regional
      diversification of sickness absenteeism. These changes confirm the need verifying
      the discussed relationship through an in-depth study.

PMID- 8656997
TI  - [Test for the effects of mutagenic toxic fungal metabolites originating from
      municipal landfill sites].
AB  - The purpose of the study is to assess the mutagenic effect of mycotoxins produced
      by moulds growing on municipal landfill sites. Mutagenicity of toxic fungal
      metabolites was determined by the Salmonella plate incorporation assay with two
      strains of bacteria: TA98 and TA100, with and without metabolic activation. The
      results obtained indicate that there is a severe hazard caused by these
      mycotoxins detected main by TA98 with metabolic activation. The most mutagenic
      mixture of mycotoxins acting directly on both strains was produced by Aspergillus
      nidulans. The highest mutagenic effect detected by TA98 with metabolic activation
      was found in the mixture of mycotoxins produced by one of three isolated
      Aspergillus fumigatus varieties.

PMID- 8656996
TI  - [Allergic reaction to merthiolate (a disinfectant) based on material from the
      Occupational Medicine Institute in Lodz].
AB  - Incidence and causes of allergy to merthiolate (thimerosal) was studied in 685
      patients, examined in the Nofer Institute of Occupational Medicine, during the
      period from 1 September 1993 to 15 October 1995. Allergy to thimerosal was
      diagnosed in 39 persons (5.7%) including 25 (6.3%) females and 14 (4.9%) males.
      Health service workers predominated among those sensitized (13.8% of all medical
      personnel examined during that period). In 19 persons only allergy to mercury was
      observed. Among them 7 showed no skin changes, 6 manifested symptoms of hand
      dermatitis, in 4 patients atopic dermatitis and in 2 dermatitis diseminata were
      diagnosed. Two patients suffered from allergic rhinitis. It was found that the
      general vaccination of health service workers against viral hepatitis as well as
      immunotherapy with pollen preparations containing thimerosal (Catalet, Biomed,
      Poland) were the main causes of allergy to mertiolate. Allergy to thiosalicyclic
      acid was not observed and two persons reacted positively to mercuric chloride.

PMID- 8656998
TI  - [Evaluation of the irritative action of formaldehyde and glutaraldehyde
      aldehyde].
AB  - The irritative effect of formaldehyde and glutaraldehyde on the rabbit skin was
      determined under conditions of a single, closed exposure and under conditions of
      multiple, open exposure. It was revealed that the irritative effect was dependent
      on the concentration used, application mode and exposure duration. Under
      conditions of a single, 4 and 24-hour, closed exposure, threshold concentration
      which was inducing only slight inflammatory reaction of skin was equal to 2% of
      aqueous solution for both formaldehyde and glutaraldehyde. Under conditions of a
      10 open exposure, threshold concentration of irritative effect on the skin was
      determined as 5% aqueous solution for formaldehyde and 2.5% aqueous solution for
      glutaraldehyde. A single administration of 0.5% aqueous solution of formaldehyde
      and of 0.2% aqueous solution of glutaraldehyde into the rabbit's eye induced a
      slight and short lasting inflammatory reaction. These concentrations were
      recognised as threshold ones.

PMID- 8656999
TI  - [Exposure to dust mixtures containing free crystalline silica and mineral
      fibers].
AB  - Exposure to dust mixture containing at the same time respirable mineral fibres
      and free crystalline silica may occur in Poland in mines and in the Lower Silesia
      plants processing mineral raw materials as well as in all plants which use
      asbestos products and MMMF. Workposts where thermal insulation is exchange with
      possible phase transformations during operations under conditions of high
      temperature, expose particularly complex problems. In the work environment of
      this kind, dust concentration of free crystalline silica becomes important but
      not sufficient criterion for evaluating working conditions and it may be
      misleading. A range of studies indispensable for the proper evaluation of
      exposure to dust, covering together with measurement of dust and SiO2
      concentrations, determination of the mineral composition of dust, was developed.
      It was also found that the acceptable level of risk for neoplastic disease,
      namely 10(-3) can be attained in the work environment only if the concentration
      ranges from 0.05 to 0.1 f/cm3, that is equal to 20% of MAC value which is now
      binding in Poland. Cancer risk (lung cancer and mesothelioma jointly) during a 20
      year exposure to concentrations equal to present MAC values should be estimated
      as about 10(-2) what indicates that risk is too high and it is necessary to
      diminish MAC values for asbestos dust.

PMID- 8657001
TI  - [Effect of workplace modernization on decreasing energy expenditure of workers in
      a ceramic factors].
AB  - The main goal of the study was to prove the importance of technological
      improvements in decreasing workers' energy expenditure. The study covered seven
      workplaces in a ceramic factory producing tableware. The energy expenditure was
      analysed before and after technological improvements. The measurements were
      carried out by means of the indirect calorimetric method, using the Kofranyi
      Michaelis respiratory gas meter and the "Spirolyt" pulmonalizer during the basic
      work operations. The tabular method was applied for evaluating the energy
      expenditure during the auxiliary operations.

PMID- 8657000
TI  - [Liver angiosarcoma in a male exposed to vinyl chloride over 22 years].
AB  - The case liver sarcoma in a 47 year-old male worker exposed to vinyl chloride
      during 22 years is presented. During that period the patient inhaled about 0.8105
      kg of vinyl chloride. It is estimated that the asymptomatic phase of liver
      angiosarcoma lasted 21 years. The patient died 4 months after occurrence of
      clinical symptoms.

PMID- 8657002
TI  - [Evaluation of the usefulness of extrelut(R) columns obtained from MERCK for
      isolation of N-nitrosodimethylamine (NDMA) in the water phase].
AB  - The aim of the study was to evaluate the method of N-nitrosodimethylamine (NDMA)
      isolation from the water phase using Extrelut columns (Merck). Results were
      compared with data obtained from isolation of NDMA by classic distillation
      method. The estimation was carried out on fortificated water and blood samples.
      Extraction Extrelut columns are found very useful in isolation of NDMA both in
      water and blood samples. Their advantage over the method of water vapour
      distillation is also indicated.

PMID- 8657003
TI  - [The effect of painful dazzle on the perception process].
AB  - Perception is an active process of receiving, analysing and interpreting visual
      information coming for the environment. Particularly, in occupational activities
      which require great visual efficiency, obtaining of proper visual information,
      determined by a correct process of perception is extremely important. An optimal
      lightening of the workpost is one of the essential factors determining correct
      perception. However, various parameters of the luminous environment may have a
      negative effect on visual processes. Painful dazzle belongs to one of them. It is
      claimed by workers as the feeling of annoyance, lack of concentration and visual
      discomfort. The work presented proves a possible negative effect of painful
      dazzle on the perception process, and consequently on the occupational
      performance and even on workers health.

PMID- 8657004
TI  - [Use of computer base MEDIP in retrieving information on occupational medicine
      and hygiene].
AB  - In order to provide easier access to the world literature through scientific
      journals collected in the Library at the Nofer Institute of Occupational
      Medicine, the computed MEDIP database has been set up. It contains 18,000
      bibliographic documents in the areas of occupational medicine, toxicology and
      environmental hazards issued during the period 1990-1994. It is up-dated three
      times a year. It serves as the source of bibliographic data for researchers,
      industrial health services, sanitary and epidemiological services and all persons
      occupationally involved in issues pertaining to labour protection.

PMID- 8657005
TI  - [Occupational health services in Sweden. II. Internal control of the working
      environment].
AB  - The authors present the situation in the area of health care of workers in Sweden
      during the eighties which became a basis for developing an idea of internal
      controls (supervision of the working environment performed directly by an
      employer in his/her own enterprise). Employer's mandatory responsibilities,
      organization, performance and registration of internal controls as well as
      cooperation between the employer and employees under the system of internal
      control of the working environment are discussed.

PMID- 8657006
TI  - [MEDICHEM'95 Congress chemical industry as a global citizen--balancing risks and
      benefits, (19-22 September 1995) Cambridge, USA].

PMID- 8657007
TI  - [Exposure to asbestos and levels of selected tumor biomarkers].
AB  - Occupational exposure to asbestos, a recognised carcinogen, poses a risk for such
      diseases as asbestosis, lung cancer and mesothelioma. It is thought that asbestos
      fibres may damage microphages which undergo neoplastic transformation as well as
      fibroblast, while partial phagocytosis may generate free oxygenic radicals which
      induce cellular peroxidase and damage macromolecules. A search for cellular
      changes or changes in cellular metabolism products, present in biological fluids,
      in order to detect early stages of a neoplastic process is an important factor in
      the prophylaxis of workers exposed to asbestos. Neoplastic biomarkers such as
      tissue polypeptide antigen (TPA) or carcinoembryonic antigen (CEA) are now used
      for this purpose. The aim of the work was to identify workers exposed to asbestos
      in the population, especially high risk groups neoplastic diseases and to
      evaluate the usefulness of TPA and CEA determinations. The study covered a group
      of asbestos exposed workers (n = 4000 and the control group of workers (n = 135)
      nonexposed to any toxic factor at work. Age, exposure time, smoking habits and
      workpost characteristics were taken into consideration in the analysis of the
      results. It was revealed that in 38 persons exposed to asbestos, TPA values were
      above the concentration limit set on the basis of studies carried out in the
      control group, and elevated CEA values applied to 13 persons. Significant
      differences between groups under study were found in the proportion of
      pathological TPA values. Such a relationship was not observed in regard to CEA
      values. In the exposed group the results also indicated an evident effect of age
      and exposure time on the number of persons with TPA values above concentration
      limit. There is a growing tendency in those changes but only in regard to TPA
      values. The effect of smoking on the frequency of pathological TPA values was
      also clear-cut in workers exposed to asbestos. Taking into account three types of
      employment: blue collar workers, white collar workers and other personnel, the
      analysis indicated significant differences in TPA values between blue collar
      workers and other personnel; and between white collar workers and other
      personnel. This means a similar percentage of pathological TPA values in the
      group of blue collar and white collar workers. The study carried out allowed to
      identify persons exposed to asbestos who should be covered with targeted medical
      care. They also proved that TPA biomarker is better than CEA one for this kind of
      studies.

PMID- 8657008
TI  - [Evaluation of health risk in machine operators exposed to whole body vibration].
AB  - A total of 45 machine operators employed at the same power station were examined
      with special emphasis put on the musculoskeletal system. A group of 15 bulldozer
      operators, 19 engine operators and 11 tractor drives were exposed to the whole
      body vibration with average vertical equivalent acceleration ranging from 0.2 mg
      2 to 0.5 ms-2 r.m.s. The incidence of low back complaints over a period of 12
      months was similar to that observed in the occupational study groups. However,
      back pains combined with other health disorders were most common in bulldozer
      operators (80%) while the lowest percentage (36%) of such cases was observed
      among tractor drivers. The analysis of lifetime exposure to the whole body
      vibration in both groups showed that bulldozer operators worked only 5 years
      longer, on average, but they spent twice as many hours at work as tractor
      drivers. The study indicates that individual lifetime exposure to the whole-body
      vibration may play an important part in the evaluation of health effects.

PMID- 8657009
TI  - Vibrio trachuri sp. nov., a new species isolated from diseased Japanese horse
      mackerel.
AB  - A new species, Vibrio trachuri sp. nov., was isolated from the cultured Japanese
      horse mackerel (Trachurus japonicus). These Vibrio were Gram negative, motile
      rods and formed yellow colonies on BTB teepol and TCBS plate, turned TSI medium
      to yellow and was sensitive to 150 microM O/129 (2,4-diamino-6,7-diisopropyl
      pteridine phosphate) like Listonella anguillarum which has been described as
      Vibrio anguillarum. However, the results of VP test and decarboxylation of lysine
      or dihydrolation of arginine suggested that these Vibrio are rather closely
      related to V. parahaemolyticus. DNA similarity determined by the microplate
      hybridization technique revealed that these Vibrio are genetically quite distant
      from Listonella anguillarum or V. parahaemolyticus and rather close to V.
      harveyi, although there was no Vibrio species which had more than 70% similarity
      value. From these results we propose to nominate Vibrio trachuri sp. nov. for
      this new Vibrio species.

PMID- 8657010
TI  - Genetic identification of Staphylococcus aureus by polymerase chain reaction
      using single-base-pair mismatch in 16S ribosomal RNA gene.
AB  - Staphylococcus aureus is the most predominant and important pathogen in clinical
      microbiology. A DNA amplification assay using the polymerase chain reaction (PCR)
      was designed to identify S. aureus through a single-base-pair mismatch in the
      sequences of staphylococcal 16S ribosomal RNA (16S rRNA) genes. It was able to
      detect and identify S. aureus without requiring additional analytical techniques.
      Twenty-eight staphylococcal and non-staphylococcal strains were tested to verify
      the specificity of the assay, and only S. aureus strains gave a positive
      reaction. It may be possible to provide immediate and exact information for the
      identification of S. aureus.

PMID- 8657011
TI  - Major enteropathogenic bacteria isolated from diarrheal patients in Bolivia: A
      hospital-based study.
AB  - A total of 1,234 fecal samples from diarrhea cases were examined for etiological
      bacterial agents at medical facilities in La Paz and Sucre, Bolivia. Eighty
      strains of Shigella spp., 39 strains of Salmonella spp., 29 strains of Vibrio
      cholerae, and 222 strains of enteropathogenic Escherichia coli (139 EPEC, 55
      ETEC, 29 EIEC, and 1 EHEC) were isolated. With regard to the serovars of
      Shigella, S. flexneri 2a, 3a, and 1b were predominant. In the case of Salmonella,
      S. enteritidis was the most common, followed by S. typhi, S. poona, and S.
      paratyphi B. Out of 29 cholera strains, 25 belonged to biovar El Tor, serovar
      Ogawa while the remaining 4 were serovar Inaba. Among 55 strains of ETEC
      serotypes, 5 showed ST producers but none showed LT producers. Likewise, among 55
      strains of enterohemorrhagic serotypes, only one strain (O157:H7) produced
      verocytotoxin (VT 2). The results of drug sensitivity tests revealed the
      predominance of Shigella, EPEC, and ETEC strains resistant to aminobenzil
      penicillin (ABPC) and trimethoprim. Since diarrheal patients in Bolivia are
      treated mainly with ABPC or sulfamethoxazole/trimethoprim (SXT) and rarely with
      gentamicin, kanamycin, or other drugs, it is possible that ABPC- and SXT
      resistant strains will increase and persist in the near future.

PMID- 8657012
TI  - Sequence analysis of the Streptococcus mutans Ingbritt dexA gene encoding
      extracellular dextranase.
AB  - The complete nucleotide sequence (3,747 bp) of the dextranase gene (dexA) and
      flanking regions of the chromosome of Streptococcus mutans Ingbritt (serotype c)
      were determined. The open reading frame for dexA was 2,550 bp, ending with a stop
      codon TGA. A putative ribosome-binding site, promoter preceding the start codon,
      and potential stem-loop structure were identified. The presumed dextranase
      protein (DexA) consisting of 850 amino acids was estimated to have a molecular
      size of 94,536 Da and a pI of 4.79. The nucleotide sequence and the deduced amino
      acid sequences of S. mutans dexA exhibited homologies of 57.8% and 47.0%,
      respectively, to those of Streptococcus sobrinus dex. The homologous region of
      dex of S. sobrinus was in the N-terminal half. The C terminus of DexA consisted
      of a hexapeptide LPQTGD, followed by 7 charged amino acids, 21 amino acids with a
      strongly hydrophobic character, and a charged hexapeptide tail, which have been
      reported as a common structure of C termini of not only the surface-associated
      proteins of Gram-positive cocci but also the extracellular enzymes such as beta
      fructosidase of S. mutans and dextranase of S. sobrinus. The DexA protein had no
      significant homology with the glucosyltransferases, the glucan-binding protein,
      or the dextranase inhibitor of mutans streptococci.

PMID- 8657013
TI  - Specific deposition of passively transferred monoclonal antibodies against herpes
      simplex virus type 1 in rat brain infected with the virus.
AB  - The kinetics of human monoclonal antibody (anti-gB) to herpes simplex virus type
      1 (HSV-1) were investigated after intravenous injection of anti-gB into an HSV-1
      encephalitis animal model. Immunohistochemical study revealed specific deposition
      of passively transferred anti-gB in the hippocampus and thalamus of the infected
      rat brain, and it bound to the same neurons in which HSV-1 antigen was positively
      stained. To examine the macroscopic distribution of anti-gB in the infected
      brain, we undertook an 125I-labeled anti-gB injection study, and the same
      distribution of 125I-labeled anti-gB deposition was observed by brain
      semimicroautoradiography as in the immunohistochemical study. These results
      suggest that anti-gB easily permeates the capillary wall and is deposited in the
      inflammatory site where HSV-1-specific antigen is detectable. The use of
      radioisotope-labeled anti-gB injection and external brain imaging could lead to a
      noninvasive diagnostic tool for the early detection of HSV-1 antigen in cases of
      suspected HSV-1 encephalitis.

PMID- 8657015
TI  - Expression of 18.6/CD23 antigen on human lymphoid progenitor cell lines and
      phorbol 12-myristate 13-acetate (PMA)-induced microglia-shaped cells.
AB  - The nature of lymphoid progenitors and factor(s) determining commitment to either
      the T- or B-lymphocyte pathway are poorly understood in the human system. In this
      study, we generated a monoclonal antibody (MoAb), 18.6, that recognizes a cell
      surface antigen on a human lymphoid progenitor cell line (FL4.4). MoAb 18.6
      reacted with lymphoid progenitor lines, B lymphoid cell lines, and myelomonocytic
      cell lines. It did not react with any T cell or erythroid leukemic cell lines.
      Two color FACS analyses of normal lymphoid tissues showed that MoAb 18.6 reacted
      with a majority of CD20+ mature B cells and a minority of CD64+ monocytes.
      Molecules of 3 different sizes with MW of 34, 45, and 68 Kd were precipitated
      with MoAb 18.6 from the lymphoid progenitor cell line. The 18.6 antigen was not
      expressed on a fetal liver-derived lymphoid progenitor-like cell line, FL1.4,
      which has the capacity to differentiate into microglia-shaped cells upon PMA
      stimulation. Stimulation of FL1.4 cells with PMA induced expression of the 18.6
      antigen within 24 hr and the microglia-shaped cells stained positively with MoAb
      18.6. Finally, cloning of a cDNA that encoded the 18.6 antigen revealed that the
      18.6 antigen is identical to the CD23 antigen. Taken together, these data suggest
      that the 18.6/CD23 antigen is expressed on lymphoid precursors at a very early
      stage of differentiation.

PMID- 8657014
TI  - Gene expression of perforin and granzyme A in the liver in chronic hepatitis C:
      comparison with peripheral blood mononuclear cells.
AB  - Perforin and granzyme A are the major effectors of cytotoxic T cells in cell
      mediated cytotoxicity. However, there has been no report on these effectors in
      chronic viral hepatitis. In the present study, the expression of perforin and
      granzyme A mRNA was investigated by the reverse transcription polymerase chain
      reaction method using liver biopsy specimens and peripheral mononuclear cells
      (PBMC) from 21 patients with chronic hepatitis C and 5 control cases. Perforin
      mRNA was detected only in the liver of chronic hepatitis patients but not in the
      control livers. Conversely, perforin mRNA was not expressed in PBMC of the
      patients with chronic hepatitis (P < 0.01). Granzyme A mRNA was detected both in
      the liver and PBMC of all the cases including control cases. These results
      indicated that the perforin is an important effector molecule in the hepatocyte
      lysis in chronic viral hepatitis C.

PMID- 8657016
TI  - Flow cytometric analysis using lipophilic dye PKH-2 for adhesion of Vibrio
      cholerae to Intestine 407 cells.
AB  - A comparative study of indirect and direct flow cytometric analysis for adherence
      of Vibrio cholerae to Intestine 407 cells was performed. The direct flow
      cytometric analysis employed the lipophilic dye PKH-2. It was concluded that
      direct flow cytometry using the lipophilic dye PKH-2 is useful and convenient for
      analyzing bacterium-host cell interactions, since it does not require any
      specific antibody as the first antibody.

PMID- 8657017
TI  - Prevention of vascular graft infection by sisomicin incorporated into fibrin
      glue.
AB  - To examine the efficacy of sisomicin (SISO) incorporated into fibrin glue (FG)
      for the prevention of graft infection in animal models, the susceptibility to
      infection of Dacron grafts (control) and SISO-FG Dacron grafts following the
      inoculation of Staphylococcus aureus or S. epidermidis was compared. The results
      showed that SISO-FG Dacron grafts displayed resistance to graft infection.

PMID- 8657019
TI  - Growth and cytopathogenicity of herpes simplex virus in a macrophage cell line,
      RAW264: A good indicator of intraperitoneal pathogenicity.
AB  - Macrophages are known to play a critical role in host resistance to herpes
      simplex virus (HSV). In this study, we investigate the interaction between
      various HSV strains with different virulence and a murine macrophage cell line,
      RAW264. Highly attenuated strains replicated poorly in RAW264 cells and were
      cleared from the cultures. For the eleven viruses tested, there was good
      correlation between intraperitoneal pathogenicity for adult mice and replication
      in RAW264 cells. It was also shown that interferon alpha/beta was involved in
      restricted replication of some strains.

PMID- 8657018
TI  - Transfer of two Burkholderia and an Alcaligenes species to Ralstonia gen. Nov.:
      Proposal of Ralstonia pickettii (Ralston, Palleroni and Doudoroff 1973) comb.
      Nov., Ralstonia solanacearum (Smith 1896) comb. Nov. and Ralstonia eutropha
      (Davis 1969) comb. Nov.
AB  - Based on the results of phenotypic characterization, cellular lipid and fatty
      acid analysis, phylogenetic analysis of 16S rDNA nucleotide sequences and rNA-DNA
      hybrization, Burkholderia pickettii, Burkholderia solanacearum and Alcaligenes
      eutrophus are transferred to the new genus Ralstonia, and Ralstonia pickettii
      (Ralston, Palleroni and Doudoroff 1973) comb. nov., Ralstonia solanacearum (Smith
      1896) comb. nov., and R. eutropha (Davis 1969) comb. nov. are proposed. The type
      species of the new genus is R. pickettii. Type strain of R. pickettii is ATCC
      27511T, of R. solanacearum is ATCC 10696T, and of R. eutropha is ATCC 17697T.

PMID- 8657020
TI  - Genetic variation in VP7 gene of human rotavirus serotype 2 (G2 type) isolated in
      Japan, China, and Pakistan.
AB  - Sequence analysis of the gene encoding the major neutralization glycoprotein
      (VP7) was performed on sixteen human isolates of serotype 2 of rotavirus in
      Japan, China, and Pakistan and their genetic variations were examined.
      Comparative studies of their nucleotide and deduced amino acid sequences between
      the sixteen isolates and the HU5 strain revealed an overall homology of more than
      94%. A higher degree of homology in nucleotides was observed among the sixteen
      isolates than between HU5 and the isolates. A total of thirteen amino acid
      residues frequently converted to another amino acid. Out of the thirteen, five
      amino acid residues belonging to the major neutralizing epitope regions (C, E,
      and F in this communication) converted frequently. From the amino acid sequences
      three subtypes, subtype 1, subtype 2, and intermediate, were suggested to be
      classified as previously reported for serotype 1 (Xin et al, Virology, 1993, 197:
      813-816).

PMID- 8657022
TI  - Communication in hospitals: a quality management issue.

PMID- 8657021
TI  - No relationship between HTLV-1 infection and filariasis--Serological study on
      patients with filariasis in Recife, Brazil.
AB  - The seroprevalence of antibodies against human T-cell leukemia virus was
      determined by ELISA in 68 patients with filarial infestation living in an endemic
      area. The total seropositivity was 2.9% and the HTLV-1-positive cases were
      detected in 2 microfilaremic patients 12 and 40 years old. This value is very
      close to that obtained for healthy individuals in the same region and age groups.
      This result suggests that there is no relationship between filariasis and HTLV-1
      infection as previously proposed.

PMID- 8657024
TI  - Postsplenectomy overwhelming sepsis: reducing the risks.

PMID- 8657023
TI  - Prevention of postoperative venous thromboembolism.

PMID- 8657025
TI  - When medical research is beholden to politics.

PMID- 8657027
TI  - Hepatitis C virus infection in health care workers referred to a hepatitis
      clinic.
AB  - OBJECTIVES: To assess method of acquisition, presence of liver disease, potential
      infectivity and the effect on work practices in health care workers with
      hepatitis C virus (HCV) infection referred to a hepatitis clinic. PATIENTS AND
      METHODS: All 33 health care workers referred to a hepatitis clinic for management
      of HCV infection because of a positive test for HCV (enzyme-linked immunosorbent
      assay) between 1 January 1990 and 31 December 1994 (comprising six medical
      practitioners, 18 nurses, two scientists and seven others) were retrospectively
      assessed for most likely method of infection, alanine aminotransferase levels,
      results of liver biopsy and measurement of HCV-RNA. RESULTS: 30 health care
      workers (12 men and 18 women; age range, 27-68 years) had HCV infection confirmed
      on further testing. Only seven were believed to have acquired their infection
      occupationally (one with documented needlestick injury). Twenty-eight patients
      had elevated alanine aminotransferase levels and, of 23 patients who underwent
      liver biopsy, one had cirrhosis and 12 had chronic hepatitis and fibrosis. Of the
      24 health care workers with direct patient contact, four had retired, eight had
      stopped or modified their work practices and 12 continued to practise normally.
      CONCLUSIONS: Few health care workers with chronic HCV infection have acquired it
      occupationally. We recommend that guidelines be set up for institutional expert
      committees to advise health care workers with HCV infection about modifying their
      work practice.

PMID- 8657026
TI  - The incidence of deep venous thrombosis after laparoscopic cholecystectomy.
AB  - OBJECTIVE: To determine the incidence of deep venous thrombosis (DVT) after
      laparoscopic cholecystectomy. DESIGN: Prospective cross-sectional analysis, with
      a one-month follow-up, conducted in 1994. SETTING: University teaching hospital.
      SUBJECTS: 20 patients undergoing elective or urgent laparoscopic cholecystectomy,
      consecutively recruited. INTERVENTIONS: Patients received thromboprophylaxis
      according to the normal practice of the attending surgeon and underwent
      laparoscopic cholecystectomy. A venous duplex scan was performed before the
      operation and on Day 1, 7 and 30 after the operation. MAIN OUTCOME MEASURE: The
      presence of postoperative DVT. RESULTS: All patients were given graduated
      compression stockings to wear and 16 received electrical stimulation of the calf
      during the operation. Only 16 patients received pharmacological
      thromboprophylaxis before the operation, but all patients received this after the
      operation. The median duration of pneumoperitoneum was 80 minutes (40-160
      minutes). Eleven of 19 patients completing all the required scans developed
      venous thrombosis (incidence, 55%); in three the thromboses involved major axial
      veins. In one patient the Day 7 and Day 30 scans were not performed, but the Day
      1 scan was negative. Seven of the 11 thromboses were detected on the Day 1 scan.
      None of the DVTs were suspected clinically. CONCLUSIONS: This extremely high
      incidence of venous thrombosis correlates with the haemodynamic changes which
      occur in the venous system during pneumoperitoneum. Laparoscopic cholecystectomy
      should not be considered a procedure with a low risk of DVT, and further studies
      are needed to determine optimal DVT prophylaxis for laparoscopic surgery.

PMID- 8657028
TI  - Hospitalisation for adverse events related to drug therapy: incidence,
      avoidability and costs.
AB  - OBJECTIVES: To determine the incidence of hospital admissions for adverse events
      related to drug therapy, and to assess whether these drug-related admissions
      (DRAs) could have been reasonably prevented. SETTING: A tertiary teaching
      hospital. DESIGN AND PATIENTS: Prospective assessment of all admissions through
      the emergency department and resulting in a stay of more than 24 hours during 30
      consecutive days in November and December 1994 to determine if the admission was
      related to drug therapy. Cases of intentional overdose were excluded. MAIN
      OUTCOME MEASURES: The number, type, causality and avoidability of drug-related
      admissions. RESULTS: Of 965 admissions, 55 (5.7%) were assessed as being drug
      related. Drug-related admissions (DRAs) were designated possibly (38%), probably
      (46%) or definitely (16%) drug-related; caused by prescribing factors (26%),
      patient noncompliance (27%) and adverse drug reactions (47%); and classified as
      definitely (5.5%), possibly (60.0%) and not (34.5%) avoidable. The estimated
      annual cost to the hospital for all DRAs was $3,496,956 and for unavoidable DRAs
      was $1,629,494. CONCLUSION: The DRA rate we found lies around the middle of the
      range of other published rates. Few DRAs were judged definitely avoidable and
      over one-third were unavoidable. Nevertheless, the largest proportion were judged
      possibly avoidable. As the drugs identified in this study are clearly needed in
      the community, efforts to reduce DRAs must concentrate on education, counselling
      and monitoring of drug therapy.

PMID- 8657029
TI  - Communication breakdown: a preventable cause of acute renal failure in a newborn
      infant.
AB  - A three-week-old boy had life-threatening renal failure which was successfully
      treated by salbutamol and sodium bicarbonate infusion, rectal resonium and a left
      percutaneous nephrostomy. Ultrasonography of this child at 19 weeks' gestation
      had shown a treatable renal tract abnormality (bilateral hydronephrosis). No
      arrangements had been made for follow-up.

PMID- 8657030
TI  - Managing HIV. Part 6: People living with HIV. 6.1 Men and HIV.
AB  - The medical management of the HIV-infected man is covered throughout Managing
      HIV. Understanding the sexuality of men is a crucial factor in understanding the
      HIV pandemic.

PMID- 8657031
TI  - Managing HIV. Part 6: People living with HIV. 6.2 Women with HIV.
AB  - Gay men with HIV often belong to strong mutually supportive groups, but many
      women with HIV experience the disease in relative isolation. Informed primary
      care doctors can make a valuable difference to their management.

PMID- 8657032
TI  - Managing HIV. Part 6: People living with HIV. 6.3 Children with HIV.
AB  - Sometimes the diagnosis of HIV in a child is the first sign that other family
      members are affected by the virus. The immature immune system of children
      responds to HIV infection differently to that of adults. Disease progression is
      rapid in some, but most progress to AIDS at a similar or slower rate than do
      adults. A lack of developed immunity to various pathogens means that children are
      at special risk of opportunistic infection, demanding alert clinical management.

PMID- 8657033
TI  - 5. Update on lasers in dermatology.
AB  - A range of lasers with acceptably low rates of side effects is now available.
      Improved laser therapy has been made possible by combining wavelengths that are
      selectively absorbed by the target and pulses short enough to prevent heat
      transfer to surrounding tissue. Carbon dioxide (CO2) lasers are useful for
      treating disorders of skin surface texture and topography (wrinkles, scars, sun
      damage, benign skin appendages and rhinophyma). Vascular lasers, such as the
      flashlamp-pumped dye laser, are particularly effective for treating port-wine
      stains, haemangiomas, telangiectasia, rosacea and spider naevi. Q-switched
      lasers, which allow ultrashort high intensity pulses, are effective for treating
      most tattoos and some benign pigmented lesions.

PMID- 8657034
TI  - The ACT heroin trial proposal: an overview. Australian Capital Territory.

PMID- 8657035
TI  - "Acculturating" heroin use.

PMID- 8657036
TI  - The heroin trial we had to have.

PMID- 8657037
TI  - NHMRC recommendations on abstinence from alcohol in pregnancy. National Health
      and Medical Research Council.

PMID- 8657038
TI  - Analysis of 12 months of blood alcohol levels in patients in an urban emergency
      department.

PMID- 8657039
TI  - Deaths attributed to "ecstasy" overdose.

PMID- 8657040
TI  - Fatal outcome of interaction between warfarin and a non-steroidal anti
      inflammatory drug.

PMID- 8657041
TI  - Obstetric practice and indemnity insurance in Australia.

PMID- 8657042
TI  - Is there a medical litigation crisis?

PMID- 8657043
TI  - Rural practice: is the correct message getting through?

PMID- 8657044
TI  - The ecology of Legionella longbeachae in Australia.

PMID- 8657045
TI  - Legionella longbeachae in Western Australia: a 12-month retrospective review.

PMID- 8657046
TI  - Acetaminophen, NSAIDs and alcohol.

PMID- 8657047
TI  - Bicalutamide for prostate cancer.

PMID- 8657048
TI  - Simethicone for gastrointestinal gas.

PMID- 8657049
TI  - [Occurrence of TSH receptor antibodies and thyroid microsomal antibodies in
      Graves-Basedow disease].
AB  - Anti-TSH receptor antibody examination was performed in patients with Basedow
      Graves' disease (141 patient: 34 before treatment, 49 during medicamentous
      therapy, 55 in stable remission and 3 with spontaneous hypothyroidism). The
      following findings were found: anti-TSH receptor antibodies were positive in 87%
      of untreated patients; in patients with medicamentous therapy they are in
      correlation with the metabolic status of the patients; only in 2% of patients in
      remission findings were high; all of the three patients with spontaneous
      hypothyroidism have had high titer. Findings of the thyroid microsomal antibodies
      don't have such regularity: the results were high in 67% of untreated patients;
      were in correlation with functional status during therapy; highly present in
      remission (62%) and have high titers in spontaneous hypothyroidism. The gathered
      results confirm opinions that anti-TSH receptor antibodies are highly
      etiopathogenetically significant in autoimmune hypothyroidism, but underline that
      the finding of thyroid microsomal antibodies is not clear enough.

PMID- 8657050
TI  - [Maintenance therapy with low doses of clozapine in schizophrenia].
AB  - A sample of 27 schizophrenic outpatients, who were or had been in maintenance
      therapy with clozapine, were studied for the last 2 years, in an open clinical
      trial. Two groups were followed: group 1-with low maintenance doses of clozapine,
      and with a concomitant neuroleptic therapy, and group 2-where clozapine was
      switched to classical neuroleptics. Therapy strategies in group 1 have been
      significantly more effective than those in group 2.

PMID- 8657051
TI  - [Juvenile chronic arthritis in children].
AB  - Juvenile chronic arthritis is a descriptive term for a group of illnesses
      pertaining to children characterized by nonsuppurative inflammation of joints
      having a chronic course. The term is rather new and comes from a meeting of
      scientists of the European Society of Rheumatologists (EULAR) and the World
      Health Organization (WHO), 1977 in Oslo. The cause of illness is unknown. There
      are numerous theories about the role of viruses, bacteria and other noxae which
      most often could not be established. The prevalence of the disease is about 1%,
      but the incidence is unknown. The clinical picture of the juvenile arthritis is
      very variable. Depending on the way of onset three subtypes can be differed: 1.
      systemic; 2. polyarticular; 3. mono (oligo) articular. These subtypes show not
      only which the clinical symptoms at the beginning of the disease are, but also,
      to a certain extent, what the development, course and the prognosis of the
      disease will be like.

PMID- 8657052
TI  - [Correlation of postmortem coronarography and the macroscopic and microscopic
      determination of luminal narrowing of coronary arteries in ischemic heart
      disease].
AB  - In our work we used 30 consecutive abduction cases of individuals suffering from
      ischemic heart disease. Postmortal coronarography was performed in all and we
      examined the narrowness of artery lumen, its degree, existence and locality of
      the obturatory thrombus, artery domination, state of aortocoronary grafts and the
      existence of anastomoses. Coronary arteries were macroscopically examined by cuts
      on every 0.5 cm of the established aims, and then segments were examined
      microscopically. The gathered results were compared and the degree of agreement
      of the two methods was calculated. An agreement of 100% was established when
      determining artery domination and presence of obturatory thrombus, although the
      number of found thrombi was bigger when macroscopic/microscopic examination was
      done. The defined degree of artery lumen narrowness was identical in 75% of
      cases.

PMID- 8657053
TI  - [Prevention of thromboembolic disease in gynecologic surgery].
AB  - We presented two groups of patients gynecologically operated and examined in a
      five year period; the first group of 11536 patients was under thromboembolic
      protection, whereas the second group of 8532 patients was without thromboembolic
      protection. Protective measures concerning thromboembolic disease were carried
      out by applying elastic stockings 24 hours before operation and by early post
      operative getting up from bed. Low-molecular dextran was applied before operation
      as well as during the operation in the amount of 500-1000 ml. In risky patients
      with varicosities, recidive thrombophlebitis and cardiovascular diseases, we
      applied small doses of heparin subcutaneously two hours before the operation and
      after the operation every eight hours five days long. With such prevention of
      thromboembolic disease in gynecologic surgery, we achieved very favorable effects
      in reducing mortality to 0.05% concerning the operated, while it amounts to 0.3%
      in those who were without this kind of protection.

PMID- 8657054
TI  - [Multiple intracranial aneurysms and asymmetrical circle of Willis].
AB  - In a consecutive series of 268 patients harboring saccular aneurysms confirmed by
      digital subtraction angiography (DSA) all major blood vessels of the brain, 36
      patients (13.4%) with multiple aneurysms were identified. Majority of them
      (around 58%) were between 40 to 60 years of age, around 22% were below 40 years
      of age, but no was younger than 30 years of age. The asymmetric Willis circle was
      identified in 26 patients (74.2%) A hypoplastic A1 segment of the anterior
      cerebral artery was revealed in 10 patients; a combination of the hypoplastic A1
      segment and the fetal type of the posterior communicating artery with a
      hypoplastic P1 segment of the posterior cerebral artery were found in 9 cases,
      while 7 patients had only the fetal posterior communicating artery. A suggestion
      was put that the asymmetric circle of Willis, prenatal or acquired in postnatal
      life is inclined of developing aneurysm (multiple aneurysms) only if there exist
      a hemodynamic stress in postnatal life producing degenerative lesions of the
      circle of Willis at the site of the augmented hemodynamic vascular wave.

PMID- 8657055
TI  - [Undescended testes and paratesticular anomalies].
AB  - In the field of developmental paratesticular anomalies there are numerous
      questions without answers. The goal of this paper is to give some information on
      embryology of normal and disturbed development parallely, as well as to describe
      the occurrence of certain anomalies with a special review on anomalies of
      epididymis and deferent ductus considering their importance in urology. Results
      and statistical data from our work have been reported.

PMID- 8657056
TI  - [Parental behavior during the most common childhood diseases].
AB  - The paper analyzes certain aspects of parental behaviour in situations of the
      most frequent children's diseases: their reactions, habits and some medical
      knowledge concerning antipyretics and antibiotics. An anonymous self-report
      questionnaire was applied. Five questions assessed demographic and seven the
      studied characteristics. 160 parents from the city and surrounding villages
      participated during period May - June 1993 in the offices of The Children and
      Adolescent Health Service in Krusevac. Most parents follow up the state of their
      children and/or try to help on their own before visiting the doctor. Only a small
      percentage decide to apply antibiotics. Those from villages and those with lower
      education are more likely to panic. Parents have habits of keeping antipyretics,
      tea and alcohol in home pharmacies in high percentage. They usually buy drugs or
      keep them from the previous children's disease. About half of them follow the
      instructions of doctor at what time the drug is to be applied. The rest take the
      advice of pharmacists, or act according to previous experience or drug
      declaration. 53.8% think that raised temperature should be lowered immediately
      when higher than 37 degrees C. About half of them connect the meaning of
      antibiotics with infection, but only 17.8% specifically with bacterial
      infections. It can be concluded that a parent is still an unreliable partner of a
      doctor for his often medically unjustified behaviour. It is specially
      characteristic for parents with elementary or secondary education, those from
      villages and unemployed parents.

PMID- 8657057
TI  - [Clinical and epidemiologic aspects of paraneoplastic dermatoses in hospitalized
      patients treated at the Clinic for Dermatologic and Venereal Diseases in Novi Sad
      over a 10-year period (1980-1990)].
AB  - Authors report results of a retrospective investigation on frequency of
      paraneoplastic dermatoses, their clinical characteristics, time of onset and
      course regarding 10 - year material on hospitalized patients at the Clinic for
      Infectious and Dermatovenerous Diseases in Novi Sad. Out of 9086 hospitalized
      patients in 14 patients (0.16%) paraneoplastic dermatisis was diagnosed. Out of
      14 patients in 5 patients (35.71%) Herpes zoster was diagnosed; in 4 patients
      (28.57%) bullous dermatosis; in 2 patients (14.29%) paraneoplastic acrokeratosis;
      in 1 patient (7.14%) exudative multiform erythema in 1 patient (7.14%) erythema
      figuratum and in one more patient necrotic Herpes labialis was diagnosed.
      Concerning malignant neoplasms of internal organs together with paraneoplastic
      dermatosis in most cases (4 - 28.57%) chronic lymphocyte leucosis was found, and
      in remaining 10 (71.43%) carcinomas were diagnosed at different internal organs.
      In 7 cases (50%) malignancy proceeded paraneoplastic dermatosis, in 4 cases
      (28.57%) the malignancy was diagnosed at the same time as paraneoplastic
      dermatosis and in 3 cases (28.43%) malignancy was established after the onset of
      paraneoplastic dermatosis. Authors point to the fact that usual skin changes,
      characteristic for the dermatologic diseases mentioned, in cases when they are
      associated with visceral malignomas, are characterized by a more serious clinical
      picture, a longer course of the disease and resistance concerning usual therapy.

PMID- 8657058
TI  - [Effect of doxycycline in the treatment of progressive periodontal disease].
AB  - The aim of this paper was to establish effects of doxycycline on gingival
      inflammation and depth of periodontal sacculi in individuals with a form of
      paradontopathy in progress. The investigation was performed in two parallel
      groups of examinees from 38 to 56 years of age. The same kind of parodontal
      therapy was carried out in all patients and after that by a method of random
      sampling, where the examiner has not taken part, 30 patients were chosen and
      doxycycline was applied per os (200 mg on the first day and then 100 mg a day
      during a period of 13 days). Analyzing gathered results a significant decrease of
      gingival inflammation and of periodontal sacculi was established in persons
      treated with doxycycline. These results show that a 2 week application of
      doxycycline per os in combination with parodontal therapy is effective in
      treating paradontopathy in progress.

PMID- 8657059
TI  - [The role of the medical school in the health care system].

PMID- 8657060
TI  - [Perforation of the nasal septum due to sarcoidosis].
AB  - A female patient, 43 years old, with a combined pulmonary and extrapulmonary
      sarcoidosis of nose accompanied with a spontaneous perforation of septum is
      described. It has not been easy to make a diagnosis, and it was made on the basis
      of bronchobiopsy and pathohistologic analysis of nasal septum's mucus. It has
      finally been confirmed by ex invantibus therapy, for the patient reacted well to
      corticosteroids.

PMID- 8657062
TI  - [Morphologic characteristics of the vascular network in the striate area in
      humans].
AB  - The vascular network of the area striata consists of four vascular layers. The
      capillary network of the first vascular layer is completely filled only in some
      parts of the area striata. The capillary networks of second, third and fourth
      vascular layer have high density, although the capillary networks in border zones
      of each two adjacent cortical arteries have lower density. In the area striata
      the fountain-like arteries have been found, with some collateral branches
      dividing in fountain-like branches, too. In the brain of a 70 year old male we
      have found collateral branches initially twisted around its main trunk. The
      tangential sections of the area striata show the existence of vertically-oriented
      vascular units with centrally located venous vessel surrounded with one or two
      arterial rings.

PMID- 8657061
TI  - [Congenital methemoglobinemia].
AB  - This is a report on a case of inborn methemoglobinemia. The disease has been
      diagnosed in the first week of infant's life. At first it was assumed it was a
      case of inborn heart defect because of expressed generalized cyanosis, but very
      soon it was excluded. Values of methemoglobin were extremely high, so three days
      after birth hereditary methemoglobinemia was diagnosed. Our diagnosis was
      confirmed by disappearing of cyanosis after ascorbic acid was applied, by values
      of methemoglobin reductase of the infant and its father, anamnestic data
      revealing that mother had had temporary cyanosis during her infancy, and
      satisfactory clinical course of illness.

PMID- 8657063
TI  - [Bacterial study in patients with chronic disease of the palatine tonsils].
AB  - At the Otorhinolaryngology Clinic in Novi Sad, 58 patients, from 2 to 53 years of
      age, with chronic palatine tonsillitis were bacteriologically examined.
      Staphylococcus aureus was isolated in most patients and was detected in 21
      patients on the surface of the tonsil and in 25 patients at the place of a cut.
      Streptococcus pyogenes group A occurred only in 3 patients, group B in 1 patient
      which amounts to 5.17%, and 1.72%. The percentage of patients in whom rheumatism
      occurred was similar. The author points out the fact that there is a great
      disproportion between the number of patients who undergo surgery and number of
      complications at distant organs and appeals to reduction of indications for
      tonsillectomy to a reasonable level.

PMID- 8657064
TI  - [Chronic urticaria caused by penicillin. Results of monitoring cases of acute
      penicillin urticaria which developed into chronic urticaria].
AB  - Penicillin is known to cause allergic reactions with different clinical
      manifestations and possible immunologic mechanisms. The purpose of this study was
      to follow cases of established hypersensitivity to penicillin and its possible
      development into chronic urticaria. 35 patients with a clinical picture of acute
      urticaria and with or without angioedema were examined. Three kinds of tests to
      penicillin were performed: patch test, scarification test and PPL test.
      Hypersensitivity to penicillin was confirmed in 12 (34.27%) patients with
      positive PPL test. Seven (58.33%) out of these 12 developed the clinical picture
      of chronic urticaria. As food was assumed to be the hidden source of penicillin,
      eliminatory diet was included. In 4 (57.14%) patients there was a complete
      remission of the disease during the course of diet without milk and milk products
      (intradermal test to milk and specific IgE antibodies were negative). The
      gathered results show that acute urticaria caused by penicillin can get a chronic
      character. It is the consequence of prolonged penicillin's activity in some so
      called "hidden sources of penicillin".

PMID- 8657065
TI  - [Therapeutic modalities in upper gastrointestinal tract hemorrhage].
AB  - During the observed 5 year period 428 patients were hospitalized because of upper
      digestive tract hemorrhages. The commonest cause of hemorrhage was the peptic
      ulcer (46.5%). The bleeding duodenal ulcer occurs more often than the stomach
      ulcer (55.2% to 44.8%). These patients are usually of older age (more than 50% of
      men and 46% women in whom duodenal ulcer bleeding occurs are older than 60 years
      of age). In about half of ulcers (40%) acute bleeding occurs during the urgent
      endoscopic procedure. Oozing type of bleeding occurs most frequently (82.5%),
      while the most serious type of bleeding, aortic pulse, is much less frequent
      (7%). Fibrinous coagulum recidives in bleeding in about one fifth of cases.
      Active pulse bleeding is the cause of surgery in 66.7% as well as two thirds
      (75%) of recidivant bleedings. More than 80% of patients in whom gastroduodenal
      bleeding occurs are being conservatively treated and this percentage may be taken
      as an adequate choice of the therapy modality.

PMID- 8657066
TI  - [Subacute thyroiditis. A case report of an unusual etiology].
AB  - Occurrence of various forms of thyroiditis is getting higher in the last ten
      years. Subacute or granulomatous or thyroiditis de Quervain has, most certainly,
      the greatest practical and clinical importance. We present a case of subacute
      thyroiditis in a female patient 50 years of age in whom Q-fever was positively
      diagnosed. The disease had had a benign course nevertheless the cause and it
      passed without any consequences.

PMID- 8657067
TI  - [Lyme disease--neuroborreliosis].
AB  - Lyme disease is an infective disease caused by Borrelia burgdorferi transmitted
      by ticks of the Ixodes ricinus. The disease usually has three stages whereas the
      last, because of domination of neurologic symptomatology is called
      "neuroborreliosis". This is a case report of a female patient with
      neuroborreliosis in whom, due to lack of symptoms and signs which characterize
      the first stage of Lyme disease as well as lack of evidence about the tick,
      nobody assumed such an etiology. Lyme disease was not confirmed by serologic
      evaluation until the third stage of the disease occurred. This case points to the
      conclusion that by differential diagnosis of meningeal syndrome accompanied by
      maintenance and progredience of neurologic deficit and disorders in mental sphere
      one should think of the Lyme disease.

PMID- 8657068
TI  - [On the 185th anniversary of the birth of David Gruby (1810-1898)].
AB  - David Gruby, the founder of Medical Microbiology, is better known abroad than in
      his homeland. The Yugoslav public has no knowledge of him and only a small number
      of physicians have heard of David Gruby and his contribution to medicine. At the
      beginning of his career he was a passionate explorer and later a very well known
      practitioner. Although he had lived abroad during his active period of life, he
      had never denied his origin and considering his contribution to science, he and
      his work deserve to be known about more at least among physicians.

PMID- 8657069
TI  - [Laparoscopic versus classical gynecologic operations].

PMID- 8657070
TI  - [Zoo-anthroponoses in Vojvodina. IV. Epidemiologic characteristics of trichinosis
      in Vojvodina].
AB  - Epidemiological characteristics of trichinellosis in Vojvodina have been analyzed
      on the basis of registered cases of the disease, registration of epidemics and
      also epidemiological investigation of exposed persons. In the period 1984-1993,
      1802 diseased persons were registered, 958 male and 844 female. Death was
      registered in one case. Average morbidity was 8.9/10(5). Trichinellosis affects
      all age groups. At younger age the disease affects both sexes, but in the group
      over 20 years of age the disease is statistically more frequent in males. During
      the observed period 70 epidemics of trichinellosis were registered. The main
      source was the domestic swine. Epidemiologically the greatest risk were
      domestically produced sausages causing 80% of epidemics. Consequently the season
      for pork meat preparation is the most significant for trichinellosis. Analyzing
      the origin of affected meat it has been established that regions of Srem and
      South-West Backa are considered to be hyperendemic foci. 94.3% of epidemics were
      caused by affected meat from these regions.

PMID- 8657071
TI  - [Dynamic scintigraphy of gastric emptying in non-insulin dependent diabetics with
      autonomic neuropathy].
AB  - To ascertain whether gastric emptying of solids is affected by visceral autonomic
      neuropathy, 30 noninsulin-dependent diabetics (10 with autonomic neuropathy, 10
      with peripheral and 10 without neuropathy) and 10 control subjects were studied.
      Subjects were screened by clonidine test and two parasympathetic tests of
      cardiovascular reflexes to identify the presence of autonomic neuropathy. The
      peripheral neuropathy was diagnosed by classic neurological examination and EMG.
      Delayed gastric emptying was assessed by dynamic scintigraphy, using 99mTc
      labeled ham and eggs. The gastric emptying of solids was markedly delayed in
      diabetics, particularly in diabetics with poor metabolic control (p < 0.01) and
      those with autonomic and peripheral diabetic neuropathy (p < 0.05). The results
      of our study suggest that dynamic scintigraphy may be a more sensitive method
      than other tests for autonomic dysfunction of the gut in diabetics with the early
      manifestation of diabetic gastroparesis.

PMID- 8657072
TI  - [Morphologic characteristics of the vascular network in the gyrus rectus in
      humans].
AB  - The objective of this research was to assess morphological features of gyrus
      rectus frontal cortex vascular network, regarding its laminar and columnar
      organization. In all researches adult brains were used. Blood vessels were
      injected by mixture of india ink and gelatine. After the fixation and embedding
      in paraffin, parts of cortex have been cut in series, tangentionally and
      perpendicularely in respect to the surface. Strictly defined vascular layers of
      gyrus rectus vascular network were not found. All types of arteries were present
      in the vascular network but A3 and A4 arteries were dominant. In the gyrus rectus
      the fountain-like arteries were found with some branches divided in fountain-like
      branches, too. Boreder zones of lower vascular density were found between
      capillary network of the two adjacent cortical arteries. All types of veins were
      found in the cortex but they were smaller in calibre. Vertically oriented
      vascular units were also found in gyrus rectus.

PMID- 8657074
TI  - [Use of suture materials in gynecologic surgery].
AB  - This paper presents evolutionary development of suture materials in surgery from
      the "period of renaissance" to these days. Ideal suture materials in surgery
      should fulfil characteristic demands such as the four following: safety of knots,
      tension force, tissue reactions and wound safety. The table presents absorptive
      and nonabsorptive suture materials especially taking into consideration the
      application of the materials in contaminated-inflamed tissues. Recommendations in
      regard to choice of surgical suture materials are given considering gynecologic
      surgery.

PMID- 8657073
TI  - [The effect of blood from patients with idiopathic thrombocytopenia and
      thrombopoietin on the thrombocyte count in the blood of mice].
AB  - We examined effects of serum belonging to persons suffering from chronic
      autoimmune thrombocytopenia on the number of thrombocytes in the peripheral blood
      of mice. The serum, 0.2 ml, was given to groups of mice intravenously and then
      the number of thrombocytes was examined during 14 days. A significant decrease of
      thrombocytes was established in mice receivers during the period of 6 hours to 12
      days (it was maximal from the 4th to the 6th day). The same serum was given to
      two groups of mice and then one of them was also given thrombopoietin
      preparation. The number of thrombocytes was established 4 and 6 days later and in
      the group where only serum was given there was a significant decrease of
      thrombocytes. In the group where thrombopoietin was given apart from the serum,
      the number of thrombocytes remained normal. On the basis of these findings it has
      been suggested that, using such an experimental model, a biological in vivo test
      could be made to demonstrate antibodies in autoimmune thrombocytopenias and to
      establish that thrombopoietin could be a useful drug in cases of chronic
      autoimmune thrombocytopenia.

PMID- 8657075
TI  - [Determination of radiochemical purity of 99mTc(Sn)-methylene diphosphonate using
      gel chromatography].
AB  - The paper presents results of determining radiochemical purity of the osteopathic
      ligand 99mTc(Sn)-methylene diphosphonate (99mTc(Sn)-MDP). Application
      possibilities of gel chromatography on Sephadex G 25M were investigated depending
      on concentrations of reagents and composition of the eluence (Ph = 4-6.5).
      Concentrations of the ligand were 6.3 x 10(-3) and 6.3 x 10(-1) mol/dm3 Na3 -
      methylene diphosphonate and of the reductant 4.2 x 10(-1) and 4.2 x 10(-5)
      mol/dm3 SnCl2. The ratio ligand/reductant remained constant. It was concluded
      that under the given experimental conditions results of analyses depend solely on
      the composition of the eluence. The complex partially decomposes if pure saline
      is used as the eluence. The best results are obtained if the eluence contained
      both ligand and reductant. According to the obtained results it can be
      recommended to use eluence with the same concentration of the reagents (excluding
      technetium), as in the labelled complex. Under this condition Sephadex can be
      applied in determining radiochemical purity of 99mTc(Sn)-methylene diphosphonate.

PMID- 8657076
TI  - [Intrathecal synthesis of immunoglobulin G in patients of various ages with acute
      viral meningitis and meningoencephalitis].
AB  - Intrathecal antibody synthesis is a common local immunologic reaction in acute
      meningoencephalitis and encephalitis caused by Herpes group viruses, myxo and
      paramyxoviroses. The purpose of this study was to determine the quantity of de
      novo synthesized IgG during 24 hours in the liquor of patients of different ages
      suffering from acute viral meningitis and meningoencephalitis and to establish
      correlations between the dysfunction of blood-brain barrier and de novo IgG
      synthesis. We examined 73 patients of different ages divided into 5 groups
      according to their age. The state of blood-brain barrier was the most stable with
      high Qalb values of 225,596 for the youngest (from 2 to 6) and 193,190 for the
      somewhat older children (from 7 to 15). The most common damage of the blood-brain
      barrier was established in the oldest group of patients--over 40 years of age.
      The lowest intrathecal IgG production was established in the youngest group from
      2 to 6 (6.631 mg/24 hours), and the highest (64.61 mg/24 hours) at the beginning
      of the disease in the group from 16 to 25 years of age. We established a
      correlation between damages of blood-brain barrier and de novo synthesis of IgG,
      especially in the youngest patients in the first days of the disease as well as
      14 and more days later, when a low immunoglobulin production was established but
      a well preserved blood-brain barrier too. In the group of patients older than 40
      years of age such a correlation was not found which points to a tissue synthesis
      of antibodies in the central nervous system.

PMID- 8657078
TI  - [Cardiology update--I].

PMID- 8657077
TI  - ['95 pneumology update. Progress and prospects in pneumology. Paradigm of change-
      II].

PMID- 8657079
TI  - [Cardiology update--II].

PMID- 8657080
TI  - [Angiology update].

PMID- 8657081
TI  - [Nephrology update--I. Causes and possibilities of modifying the progression of
      chronic renal failure].

PMID- 8657082
TI  - [Nephrology update--II. Causes and possibilities for modifying the progression of
      chronic renal failure].

PMID- 8657083
TI  - [Clinical infectiology--I. Diagnosis, pathogen spectrum and resistance].

PMID- 8657084
TI  - [Endocrinology update--I].

PMID- 8657085
TI  - [Endocrinology update--II].

PMID- 8657086
TI  - [Rheumatology update--I. Summary of clinically significant current knowledge and
      outlook of possible relevant trends in etiopathogenic research, diagnostic
      methods and therapeutic possibilities].

PMID- 8657087
TI  - [Rheumatology update--II. Summary of clinically significant current knowledge and
      outlook of prospective relevant trends in etiopathogenic research, diagnostic
      methods and therapeutic possibilities].

PMID- 8657088
TI  - [Gastroenterology update].

PMID- 8657089
TI  - ['94 oncology update].

PMID- 8657091
TI  - [1995 gastroenterology update--II].

PMID- 8657090
TI  - [1995 gastroenterology update--I].

PMID- 8657092
TI  - ['94 pneumology update. Progress and prospects in pneumology. Paradigm of change-
      I].

PMID- 8657093
TI  - [Is the animal in hibernal sleep awake?].
AB  - It has been recognized for a long time that hibernation and slow wave sleep are
      homologous processes for energy conservation. Numerous EEG studies have
      demonstrated that during entrance into hibernation rapid eye movement sleep (REM)
      disappeared under cerebral temperature below 25 degrees C and that in deep
      hibernation, animals were preferentially in NREM sleep. Hibernation was thought
      to be an extension of NREM sleep. Nevertheless, other observations suggest that
      hibernation is not an homogeneous state. For example, in deep hibernation the
      activity of single thalamic units occurs with periods of activation and decline.
      High unit activity is associated with high electromyographic (EMG) activity,
      whereas low unit activity is associated with low EMG activity. To test the
      hypothesis that NREM sleep would have a restorative function, the EEG SWA
      activity (EEG delta power) was recorded during an arousal from hibernation and
      the following euthermic bout. Contrary to expectations, EEG SWA was maximal after
      an arousal and declined during the euthermic period. These findings suggest that
      a bout of hibernation is not NREM sleep, but would be the equivalent of a sleep
      debt.

PMID- 8657094
TI  - "High sleepability without sleepiness". The ability to fall asleep rapidly
      without other signs of sleepiness.
AB  - We find by the (polygraphic) multiple sleep latency test (MSLT) of daytime
      sleepiness that some normal, healthy subjects seem to be pathologically sleepy,
      but by equally discerning psychological tests of vigilance and sleepiness, this
      is not the case. They show no other symptoms of excessive daytime sleepiness, are
      good sleepers, and do not complain of daytime sleepiness. When they are given ad
      libitum sleep at night, the low MSLT scores persist; ie, when there is no
      underlying sleep debt. Such subjects are not unusual in the scientific
      literature, but unrecognised as such by many sleep researchers who maintain that
      they must be sleepy and "chronically sleep deprived'. We find that these "high
      sleepability no sleepiness' subjects can relax and "switch off' very efficiently,
      and if they wish, can simply go to sleep in the daytime, seemingly with little
      real need to sleep then.

PMID- 8657095
TI  - Development of circadian rhythmicity of temperature in full-term normal infants.
AB  - Twelve full-term infants (7 girls and 5 boys) with normal neurological,
      behavioral and somatic development were followed at regular intervals during the
      first 5 months of life to appreciate the development of circadian rectal
      temperature rhythmicity. Activity and temperature (oral at birth, rectal
      thereafter) were monitored for a minimum of 60 hours on seven separate occasions:
      at birth, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 16 weeks and 20 weeks of age.
      Activity was measured using an actigraph worn on the infant's wrist, and rectal
      temperature was measured using a rectal probe attached to a portable
      microprocessor (Vitalog TM). Data points were collected every 2 minutes. No fewer
      than ten infants were monitored at each session, and no infant missed more than
      one session. Missing recordings were due to equipment malfunctions, probe
      expulsions and minor health problems. Six infants out of 12 were successfully
      monitored at each of the first four sessions, from birth to 8 weeks of age
      inclusively, and two subjects were successfully monitored at all seven sessions.
      Periodic regression analysis was performed by least squares curve fit with
      secondary analysis of variance. Analysis of covariance was performed on repeated
      measures. There was no evidence of rectal temperature circadian rhythmicity at 3
      weeks. Two infants demonstrated a circadian rhythmicity at 6 weeks, and all
      infants had a circadian rhythmicity at 10 weeks post-natal age. At the time of
      the first observance of circadian rhythmicity of rectal temperature, the mean
      delta in temperature from peak to trough was 0.6 +/- 0.3 degrees C. This delta
      was greater at the 16th week, with a mean value of 1.2 +/- 0.3 degrees C. The
      trough was seen during the first part of the long nocturnal inactivity period.
      Circadian rhythmicity of rectal temperature was always observed in the studied
      subjects before the establishment of a consolidated, long daytime wake period.

PMID- 8657096
TI  - Insufficient sleep in the general population.
AB  - A questionnaire was sent out to a randomly selected, age (20-34, 35-49, and 50-64
      years) and sex stratified sample of 600 adult inhabitants in Uppsala County,
      Sweden. Overall response rate was 68%. The questionnaire comprised questions
      about sleep and sleep complaints. Subjects were also asked to rate the degree of
      a number of proposed causes and consequences of insufficient sleep, in accordance
      with how they had perceived them when they had experienced insufficient sleep.
      Results showed that twelve percent of the total sample fulfilled the criteria for
      persistent insufficient sleep (PIS), an operationally defined condition of
      considerable chronic sleep loss. One-half of these subjects also reported
      concomitant sleeping difficulties. In subjects with PIS without sleeping
      difficulties, the most conspicuous causes of insufficient sleep were work-related
      factors and simply too little time for sleep. As for the effects of insufficient
      sleep in subjects with PIS with concomitant sleep complaints, factors relating to
      somatic symptoms, dysphoric mood and impaired cognition were the most prominent,
      while dysphoric mood was most noticeable in subjects with PIS without sleep
      complaints.

PMID- 8657097
TI  - Homeostatic and circadian aspects of sleep regulation in young poor sleepers.
AB  - Poor sleepers are a valid model for studying sleep/wake regulation in insomnia.
      The respective influence of the homeostatic and circadian components of this
      regulation was studied using various protocols (habitual sleep, recovery after
      sleep deprivation, bedrest, sleep latency in MSLT and RTSW procedures, and
      circadian rhythms of body temperature and alertness during a 24-hour constant
      routine). Poor sleepers were compared to age matched good sleepers studied using
      similar procedures. The main results are reviewed. Our findings do not support a
      deficiency in the homeostatic component of sleep/wake regulation. An abnormality
      in the relationship between the sleep/wake cycle and temperature rhythm cannot be
      excluded, although most of our results are consistent with the hyperarousal
      hypothesis.

PMID- 8657098
TI  - Ultradian aspects of sleep in narcolepsy.
AB  - Following a baseline night recording, 9 narcoleptic subjects and 9 sex and age
      matched control subjects were maintained on 16 hours of diurnal sleep
      deprivation. Thereafter subjects were submitted to a 32 hour bed rest protocol in
      a sound-light attenuated room. The EEG was recorded and processed using a Fast
      Fourier Transform. Narcoleptic patients did not differ from control subjects in
      total sleep time over the whole time-span. An ultradian tendency to sleep seems
      to be predominant in narcoleptic patients and evidence of a strong basic rest
      activity cycle is shown. The coupling between the homeostatic process of sleep
      regulation and an ultradian drive to sleep would explain the peculiar 4 hour
      distribution pattern of SWA in narcoleptic patients.

PMID- 8657099
TI  - Use of modafinil in the treatment of narcolepsy: a long term follow-up study.
AB  - One hundred and forty patients (104 male and 36 female) aged 42.26 +/- 19.19
      (range = 8 to 79.5 years) with narcolepsy-cataplexy were given modafinil (200 to
      400 mg) at the Montpellier sleep disorders center from 1984 onwards. The follow
      up focused on the reduction of excessive daytime somnolence (EDS), side effects
      and duration of treatment. In order to determine if any clinical aspect of
      narcolepsy could be involved in modafinil discontinuation, patients were divided
      into two groups according to continued or interrupted treatment. When modafinil
      effect on EDS was evaluated according to a scale varying from 0 (no effect) to 3
      (excellent effect), 64.1% of the subjects, scored good or excellent. The mean
      duration of treatment was 22.05 months +/- 24.9, ranging from 1 to 114 months.
      Dependency signs were never observed.

PMID- 8657100
TI  - Detrimental influence of bright light exposure on alertness, performance, and
      mood in the early morning.
AB  - The aim of this study was to assess the effects of exposure for one night to
      moderate bright light (BL) on subjective and objective measures of alertness,
      performance, and mood. Eight subjects were exposed to either BL or dim light (DL)
      during one night. During the previous day, they were exposed to bright light in
      both experimental conditions. Nocturnal BL suppressed melatonin secretion and
      increased body temperature. The ability to stay awake during the night, as
      measured by the power density in the alpha band, was significantly improved by BL
      exposure. BL also improved subjective alertness and performance during the first
      part of the night. However, improvements in the last two variables were followed
      by marked disruption in early morning patterns, with deterioration of mood and
      motivation.

PMID- 8657101
TI  - A novel interferon regulatory factor family transcription factor,
      ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated
      genes.
AB  - We have isolated a novel cDNA clone encoding interferon (IFN) consensus sequence
      binding protein in adult T-cell leukemia cell line or activated T cells (ICSAT);
      this protein is the human homolog of the recently cloned Pip/LSIRF. ICSAT is
      structurally most closely related to the previously cloned ICSBP, a member of the
      IFN regulatory factor (IRF) family of proteins that binds to interferon consensus
      sequences (ICSs) found in many promoters of the IFN-regulated genes. Among T-cell
      lines investigated, ICSAT was abundantly expressed in human T-cell leukemia virus
      type 1 (HTLV-1)-infected T cells. When the HTLV-1 tax gene was expressed or
      phorbol myristake acetate-A23187 stimulation was used, ICSAT expression was
      induced in Jurkat cells which otherwise do not express ICSAT. When the binding of
      ICSAT to four different ICSs was tested, the relative differences in binding
      affinities for those ICSs were determined. To study the functional role of ICSAT,
      we performed cotransfection experiments with the human embryonal carcinoma cell
      line N-Tera2. ICSAT was demonstrated to possess repressive function over the gene
      activation induced by IFN stimulation or by IRF-1 cotransfection. Such repressive
      function is similar to that seen in IRF-2 or ICSBP. However, we have found that
      ICSAT has a different repressive effect from that of IRF-2 or ICSBP in some IFN
      responsive reporter constructs. These results suggest that a novel mechanism of
      gene regulation by "differential repression" is used by multiple members of
      repressor proteins with different repressive effects on the IFN-responsive genes.

PMID- 8657102
TI  - Mapping of the inducible IkappaB phosphorylation sites that signal its
      ubiquitination and degradation.
AB  - Extracellular stimuli that activate the transcription factor NF-kappaB cause
      rapid phosphorylation of the IkappaBalpha inhibitor, which retains NF-kappaB in
      the cytoplasm of nonstimulated cells. Phosphorylation of IkappaBalpha is followed
      by its rapid degradation, the inhibition of which prevents NF-kappaB activation.
      To determine the relationship between these events, we mapped the inducible
      phosphorylation sites of IkappaBalpha. We found that two residues, serines 32 and
      36, were phosphorylated in response to either tumor necrosis factor, interleukin
      1, or phorbol ester. Substitution of either serine blocks or slows down induction
      of IkappaBalpha degradation. Substitutions of the homologous sites in
      IkappaBbeta, serines 19 and 23, also prevent inducible IkappaBbeta degradation.
      We suggest that activation of a single IkappaB kinas e or closely related IkappaB
      kinases is the first cr itical step in NF-kappaB activation. Once phosphorylated,
      IkappaB is ubiquitinated. Unlike wild-type IkappaBalpha, the phosphorylation
      defective mutants do not undergo inducible polyubiquitination. As substitution of
      a conserved lysine residue slows down the ubiquitination and degradation of
      IkappaBalpha without affecting its phosphorylation, polyubiquitination is
      required for inducible IkappaB degradation.

PMID- 8657103
TI  - Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the
      linker region of Syk and is a substrate for Syk.
AB  - Antigen receptor ligation on lymphocytes activates protein tyrosine kinases and
      phospholipase C-gamma (PLC-gamma) isoforms. Glutathione S-transferase fusion
      proteins containing the C-terminal Src-homology 2 [SH2(C)] domain of PLC-gamma1
      bound to tyrosyl phosphorylated Syk. Syk isolated from antigen receptor-activated
      B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr
      783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on
      Tyr-771. The ability of Syk to phosphorylate PLC-gamma1 required antigen receptor
      ligation, while Lyn was constitutively active. An mCD8-Syk cDNA construct could
      be expressed as a tyrosyl-phosphorylated chimeric protein tyrosine kinase in COS
      cells, was recognized by PLC-gamma1 SH2(C) in vitro, and induced tyrosyl
      phosphorylation of endogenous PLC-gamma1 in vivo. Substitution of Tyr-525 and Tyr
      526 at the autophosphorylation site of Syk in mCD8-Syk substantially reduced the
      kinase activity and the binding of this variant chimera to PLC-gamma1 SH2(C) in
      vitro; it also failed to induce tyrosyl phosphorylation of PLC-gamma1 in vivo. In
      contrast, substitution of Tyr-348 and Tyr-352 in the linker region of Syk in mCD8
      Syk did not affect the kinase activity of this variant chimera but almost
      completely eliminated its binding to PLC-gamma1 SH(C) and completely eliminated
      its ability to induce tyrosyl phosphorylation of PLC-gamma1 in vivo. Thus, an
      optimal kinase activity of Syk and an interaction between the linker region of
      Syk with PLC-gamma1 are required for the tyrosyl phosphorylation of PLC-gamma1.

PMID- 8657104
TI  - Interaction of C/EBPbeta and v-Myb is required for synergistic activation of the
      mim-1 gene.
AB  - The retroviral oncogene v-myb encodes a transcription factor (v-Myb) which
      activates the myelomonocyte-specific mim-1 gene, a natural myb target gene, by
      cooperating with members of the C/EBP transcription factor family. The finding
      that v-Myb, together with C/EBP, is sufficient to activate the mim-1 gene in
      heterologous cell types has implicated Myb and C/EBP as a bipartite molecular
      switch, which regulates the expression of myelomonocyte-specific genes. To
      understand the relationship between v-Myb and C/EBP in more detail, we have
      examined the molecular basis of the activation of the mim-1 promoter by v-Myb and
      C/EBPbeta, a member of the C/EBP transcription factor family highly expressed in
      myelomonocytic cells. We have identified a composite Myb and C/EBP response
      element which mediates synergistic activation of the mim-1 promoter by both
      factors and consists of closely spaced Myb- and C/EBP-binding sites. In vitro and
      in vivo protein-binding studies indicate that v-Myb and C/EBPbeta interact with
      each other via their DNA-binding domains. We show that this interaction is
      essential for the synergistic activation of the mim-1 promoter by v-Myb and
      C/EBPbeta. Our work therefore identifies C/EBPbeta as an interaction partner of v
      Myb involved in myelomonocyte gene expression.

PMID- 8657105
TI  - Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell
      proliferation, migration, and adhesion.
AB  - cyr61 was first identified as a growth factor-inducible immediate-early gene in
      mouse fibroblasts. The encoded Cyr61 protein is a secreted, cystein-rich heparin
      binding protein that associates with the cell surface and the extracellular
      matrix, and in these aspects it resembles the Wnt-1 protein and a number of known
      growth factors. During embryogenesis, cyr61 is expressed most notably in
      mesenchymal cells that are differentiating into chondrocytes and in the vessel
      walls of the developing circulatory system. cyr61 is a member of an emerging gene
      family that encodes growth regulators, including the connective tissue growth
      factor and an avian proto-oncoprotein, Nov cyr61 also shares sequence
      similarities with two Drosophila genes, twisted gastrulation and short
      gastrulation, which interact with decapentaplegic to regulate dorsal-ventral
      patterning. In this report we describe the purification of the Cyr61 protein in a
      biologically active form, and we show that purified Cyr61 has the following
      activities: (i) it promotes the attachment and spreading of endothelial cells in
      a manner similar to that of fibronectin; (ii) it enhances the effects of basic
      fibroblast growth factor and platelet-derived growth factor on the rate of DNA
      synthesis of fibroblasts and vascular endothelial cells, although it has no
      detectable mitogenic activity by itself; and (iii) it acts as a chemotactic
      factor for fibroblasts. Taken together, these activities indicate that Cyr61 is
      likely to function as an extracellular matrix signaling molecule rather than as a
      classical growth factor and may regulate processes of cell proliferation,
      migration, adhesion, and differentiation during development.

PMID- 8657107
TI  - Constitutive expression of Bc1-3 in thymocytes increases the DNA binding of NF
      kappaB1 (p50) homodimers in vivo.
AB  - Previous studies have indicated that Bcl-3 interacts through its ankyrin repeats
      with the transcriptional factors NF-kappaB1 (p50) and NF-kappaB2 (p52), affecting
      their biological activities. To further investigate the role of Bcl-3 in vivo and
      its association with the NF-kappaB proteins, we have generated transgenic mice
      constitutively expressing Bcl-3 in thymocytes. The results indicate that Bcl-3 is
      associated with endogenous p50 and p52 in nuclear extracts from transgenic
      animals. Remarkably, constitutive expression of Bcl-3 in these cells augments the
      DNA binding activity of p52 homodimers. This effect could be reproduced in vitro
      and is blocked by anti-Bcl-3 antibodies. We have also shown that Bcl-3 is
      phosphorylated in thymocytes and that its dephosphorylation greatly decreases the
      effect on p50 homodimers.

PMID- 8657106
TI  - The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of
      differentiating neuroblastoma cells.
AB  - We are employing recent advances in the understanding of the cell cycle to study
      the inverse relationship between proliferation and neuronal differentiation.
      Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases,
      synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells
      and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The
      differentiated cells continue to express p21WAF1, even after removal of
      aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates
      with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of
      three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks
      expression of p21WAF1 and promotes programmed cell death. These data indicate
      that p21WAF1 expression is required for survival of these differentiating
      neuroblastoma cells. Thus, the problem of neuronal differentiation can now be
      understood in the context of negative regulators of the cell cycle.

PMID- 8657108
TI  - The t(12;21) translocation converts AML-1B from an activator to a repressor of
      transcription.
AB  - The t(12;21) translocation is present in up to 30% of childhood B-cell acute
      lymphoblastic and fuses a potential dimerization motif from the ets-related
      factor TEL to the N terminus of AML1. The t(12;21) translocation encodes a 93-kDa
      fusion protein that localizes to a high-salt- and detergent-resistant nuclear
      compartment. This protein binds the enhancer core motif, TGTGGT, and interacts
      with the AML-1-binding protein, core-binding factor beta. Although TEL/AML-1B
      retains the C-terminal domain of AML-1B that is required for transactivation of
      the T-cell receptor beta enhancer, it fails to activate transcription but rather
      inhibits the basal activity of this enhancer. TEL/AML-1B efficiently interferes
      with AML-1B dependent transactivation of the T-cell receptor beta enhancer, and
      coexpression of wild-type TEL does not reverse this inhibition. The N-terminal
      TEL helix-loop-helix domain is essential for TEL/AML-1B-mediated repression.
      Thus, the t(12;21) fusion protein dominantly interferes with AML-1B-dependent
      transcription, suggesting that the inhibition of expression of AML-1 genes is
      critical for B-cell leukemogenesis.

PMID- 8657109
TI  - Coordinating DNA replication to produce one copy of the genome requires genes
      that act in ubiquitin metabolism.
AB  - We have developed a genetic screen of the yeast Saccharomyces cerevisiae to
      identify genes that act to coordinate DNA replication so that each part of the
      genome is copied exactly once per cell cycle. A mutant was recovered in this
      screen that accumulates aberrantly high DNA contents but does not complete a
      second round of synthesis. The mutation principally responsible for this
      phenotype is in the DOA4 gene, which encodes a ubiquitin hydrolase, one of
      several yeast genes that encode enzymes that can remove the signalling
      polypeptide ubiquitin hydrolase, one of several yeast genes that encode enzymes
      that can remove the signaling polypeptide ubiquitin from its covalently linked
      conjugated forms. DOA4 is nonessential, and deleting this gene causes
      uncoordinated replication. Overreplication does not occur in cells with limiting
      amounts of Cdc7 protein kinase, suggesting that entry into S phase is required
      for this phenotype. The DNA formed in doa4 mutants is not highly unusual in the
      sense that mitotic recombination rates are normal, implying that a high level of
      repair is not induced. The temperature sensitivity of doa4 mutations is partially
      suppressed by extra copies of the polyubiquitin gene UB14, but overreplication
      still occurs in the presence of this suppressor. Mutations in DOA4 cause loss of
      the free ubiquitin pool in cells under heat stress conditions, and extra copies
      of UB14 restore this pool without restoring coordination of replication. We
      conclude that a ubiquitin-mediated signaling event directly involving the
      ubiquitin hydrolase encoded by DOA4 is needed in S. cerevisiae to prevent
      uncoordinated DNA replication.

PMID- 8657110
TI  - Functional domains of the transcription factor USF2: atypical nuclear
      localization signals and context-dependent transcriptional activation domains.
AB  - USF is a family of basic helix-loop transcriptional factors that recognizes DNA
      binding sites similar to those of the Myc oncoproteins. Here, various functional
      domains in the mouse USF2 protein were identified and characterized. Indirect
      immunofluorescence studies with transiently transfected cells revealed that both
      the basic region and the highly conserved USF-specific region (USR) are involved
      in the nuclear localization of USF2. Cotransfection assays with deletion mutants
      containing the DNA-binding domain of either USF2 or GAL4 identified two distinct
      transcriptional activation domains in USF2, the USR and the exon 5-encoded
      region. Activity of the exon 5 activation domain was detectable in both assay
      systems. Within USF2, however, its potency varied with the conformation induced
      by the surrounding regions, especially that encoded by alternatively spliced exon
      4. In contrast, the USR activated transcription only in its natural context
      upstream of the USF2 basic region and only with reporter constructs containing
      the adenovirus major late minimal promoter but not the E1b minimal promoter.
      However, insertion of an initiator element downstream of the TATA box rescued the
      activity of the USR on the E1b-driven reporters. The USR therefore represents a
      new type of activation domain whose function depends very strongly on the core
      promoter context.

PMID- 8657111
TI  - The LIM domain-containing Dbm1 GTPase-activating protein is required for normal
      cellular morphogenesis in Saccharomyces cerevisiae.
AB  - Normal cell growth in the yeast Saccharomyces cerevisiae involves the selection
      of genetically determined bud sites where most growth is localized. Previous
      studies have shown that BEM2, which encodes a GTPase-activating protein (GAP)
      that is specific for the Rho-type GTPase Rho1p in vitro, is required for proper
      bud site selection and bud emergence. We show here that DBM1, which encodes
      another putative Rho-type GAP with two tandemly arranged cysteine-rich LIM
      domains, also is needed for proper bud site selection, as haploid cells lacking
      Dbm1p bud predominantly in a bipolar, rather than the normal axial, manner.
      Furthermore, yeast cells lacking both Bem2p and Dbm1p are inviable. The nonaxial
      budding defect of dbm1 mutants can be rescued partially by overproduction of
      Bem3p and is exacerbated by its absence. Since Bem3p has previously been shown to
      function as a GAP for Cdc42p, and also less efficiently for Rho1p, our results
      suggest that Dbm1p, like Bem2p and Bem3p, may function in vivo as a GAP for
      Cdc42p and/or Rho1p. Both LIM domains of Dbm1p are essential for its normal
      function. Point mutations that alter single conserved cysteine residues within
      either LIM domain result in mutant forms of Dbm1p that can no longer function in
      bud site selection but instead are capable of rescuing the inviability of bem2
      mutants at 35 degrees C.

PMID- 8657112
TI  - Characterization of the intron-encoded U19 RNA, a new mammalian small nucleolar
      RNA that is not associated with fibrillarin.
AB  - We have characterized a new member (U19) of a group of mammalian small nuclear
      RNAs that are not precipitable with antibodies against fibrillarin, a conserved
      nucleolar protein associated with most of the small nucleolar RNAs characterized
      to date. Human U19 RNA is 200 nucleotides long and possesses 5'-monophosphate and
      3'-hydroxyl termini. It lacks functional boxes C and D, sequence motifs required
      for fibrillarin binding in many other snoRNAs. Human and mouse RNA are 86%
      homologous and can be folded into similar secondary structures, a finding
      supported by the results of nuclease probing of the RNA. In the human genome, U19
      RNA is encoded in the intron of an as yet not fully characterized gene and could
      be faithfully processed from a longer precursor RNA in HeLa cell extracts. During
      fractionation of HeLa cell nucleolar extracts on glycerol gradients, U19 RNA was
      associated with higher-order structures of approximately 65S, cosedimenting with
      complexes containing 7-2/MRP RNA, a conserved nucleolar RNA shown to be involved
      in 5.8S rRNA processing in yeast cells.

PMID- 8657114
TI  - Complexes from Trypanosoma brucei that exhibit deletion editing and other editing
      associated properties.
AB  - Transcripts from many mitochondrial genes in kinetoplastids undergo RNA editing,
      a posttranscriptional process which inserts and deletes uridines. By assaying for
      deletion editing in vitro, we found that the editing activity from Trypanosoma
      brucei mitochondrial lysates (S.D. Seiwert and K.D. Stuart), Science 266:114
      117,1994) sediments with a peak of approximately 20S. RNA helicase, terminal
      uridylyl transferase, RNA ligase, and adenylation activities, which may have a
      role in editing, cosediment in a broad distribution, with most of each activity
      at 35 to 40S. Most ATPase 6 (A6) guide RNA and unedited A6 mRNA sediments at 20
      to 30S, with some sedimenting further into the gradient, while most edited A6
      mRNA sediments at >35S. Several mitochondrial proteins which cross-link
      specifically with guide RNA upon UV treatment also sediment in glycerol
      gradients. Notably, a 65-kDa protein sediments primarily at approximately 20S, a
      90-kDa protein sediments at 35 to 40S, and a 25-kDa protein is present at <10S.
      Most ribonucleoprotein complexes that form with gRNA in vitro sediment at 10 to
      20S, except for one, which sediments at 30 to 45S. These results suggest that RNA
      editing takes place within a multicomponent complex. The potential functions of
      and relationships between the 20S and 35 to 40S complexes are discussed.

PMID- 8657115
TI  - Inhibition of alpha interferon but not gamma interferon signal transduction by
      phorbol esters is mediated by a tyrosine phosphatase.
AB  - Previous studies have indicated that the expression of viral oncoproteins, cell
      transformation, or phorbol ester treatment of cells can inhibit alpha/beta
      interferon (IFN-alpha/beta)-induced gene expression. The mechanisms by which
      these promoters of cell growth exert their inhibitory effects vary, but in most
      instances they involve a disruption of the IFN-alpha/beta-induced transcription
      complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa
      ISGF3gamma protein) does not bind to the interferon-stimulated response element
      (ISRE). In this report, we demonstrated that phorbol ester treatment of human
      peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B
      stimulated early response genes but by a mechanism which does not involve
      abrogation of the ISRE binding of ISGF3gamma. Phorbol ester treatment of
      monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the
      transcription factors Stat1alpha, Stat2, and Stat3 and of the tyrosine kinase
      Tyk2 but had no effect on IFN-gamma activation of Stat1alpha. IFNalpha-stimulated
      tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor
      were unaffected by phorbol 12-myristate 13-acetate (PMA). Moreover, PMA caused
      the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN.
      Pretreatment of cells with vanadate prevented the effects of PMA with regard to
      PMA-induced Tyk2 dephosphorylation. These observations suggest that PMA exerts
      its inhibitory effects by activation of a tyrosine phosphatase which selectively
      regulates Tyk2 but not Jak1 activity.

PMID- 8657113
TI  - Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II
      affects intrinsic protein stability.
AB  - The NF-kappaB/Rel transcription factors participate in the activation of immune
      system regulatory genes and viral early genes including the human
      immunodeficiency virus type 1 long terminal repeat. NF-kappaB/Rel proteins are
      coupled to inhibitory molecules, collectively termed IkappaB, which are
      responsible for cytoplasmic retention of NF-kappaB. Cell activation leads to the
      phosphorylation and degradation of IkappaBalpha, permitting NG-kappaB/Rel
      translocation to the nucleus and target gene activation. To further characterize
      the signaling events that contribute to IkappaBalpha phosphorylation, a kinase
      activity was isolated from Jurkat T cells that specifically interacted with
      IkappaBalpha in an affinity chromatography step and phosphorylated IkappaBalpha
      with high specificity in vitro. By using an in-gel kinase assay with recombinant
      IkappaBalpha as substrate, two forms of the kinase (43 and 38 kDa) were
      identified. Biochemical criteria and immunological cross-reactivity identified
      the kinase activity as the alpha catalytic subunit of casein kinase II (CKII).
      Deletion mutants of IkappaBalpha delta1 to delta4) localized phosphorylation to
      the C-terminal PEST domain of IkappaBalpha. Point mutation of residues T-291, S
      283, and T-299 dramatically reduced phosphorylation of IkappaBalpha by the kinase
      in vitro. NIH-3T3 cells that stably expressed wild-type IkappaBalpha (wtIkappaB),
      double-point-mutated IkappaBalpha (T291A, S283A), or triple-point-mutated
      IkappaBalpha (T291A, S283A, T299A) under the control of the tetracycline
      responsive promoter were generated. Constitutive phosphorylation of the triple
      point mutant was eliminated in vivo, although tumor necrosis factor-inducible
      IkappaBalpha degradation was unaffected. In cell lines and in transiently
      transfected cells, mutation of the CKII sites in IkappaBalpha resulted in a
      protein with increased intrinsic stability. Together with results demonstrating a
      role for N-terminal sites in inducer-mediated phosphorylation and degradation of
      IkappaBalpha, these studies indicate that CKII sites in the C-terminal PEST
      domain are important for constitutive phosphorylation and intrinsic stability of
      IkappaBalpha.

PMID- 8657116
TI  - Identification of two RNA-binding proteins in Balbiani ring premessenger
      ribonucleoprotein granules and presence of these proteins in specific subsets of
      heterogeneous nuclear ribonucleoprotein particles.
AB  - Balbiani ring (BR) granules are premessenger ribonucleoprotein particles (RNPs)
      generated in giant chromosomal puffs, the BRs, in the larval salivary glands of
      the dipteran chironomus tentans. Monoclonal antibodies were raised against
      nuclear proteins collected on a single-stranded-DNA-agarose affinity column, and
      two of them were used to identify RNA-binding proteins in BR granules. First, in
      Western blots (immunoblots), one of the antibodies recognized a 36-kDa protein
      and the other recognized a 45-KDa protein. Second, both antibodies bound to the
      BRs in immunocytological experiments. It was shown in cross-linking experiments
      that the two proteins are associated with heterogeneous nuclear RNP (hnRNP)
      complexes extracted from C. tentans nuclei. By immunoelectron microscopy of
      isolated and partly unfolded BR RNPs, it was specifically demonstrated that the
      BR granules contain the two proteins and, in addition, that both proteins are
      distributed frequently along the RNP fiber of the particles. Thus, the 36- and 45
      KDa proteins are likely to be abundant, RNA-binding proteins in the BR particles.
      To elucidate to what extent the two proteins are also present in other hnRNPs, we
      studied the binding of the antibodies to chromosomal puffs in general. It was
      observed that many puffs in addition to the BRs harbor the two proteins, but
      there are also puffs containing only one of the components, either the 36- or the
      45-kDa protein. We conclude that the two proteins are not randomly bound to all
      hnRNPs but that each of them seems to be linked to a specific subset of the
      particles.

PMID- 8657117
TI  - E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry.
AB  - The E2F transcription factor couples the coordinate expression of cell cycle
      proteins to their appropriate transition points. Its activity is controlled by
      the cell cycle regulators pRB, p107, and p130. These bind to E2F at defined but
      distinct stages of the cell cycle. Using specific antisera, we have identified
      the DP and E2F components of each of these species. Although present at very
      different levels, DP-1 and DP-2 are evenly distributed among each of these
      complexes. In contrast, the individual E2Fs have distinctly different binding
      profiles. Consistent with previous studies, E2F-1, E2F-2, and E2F-3 bind
      specifically to the retinoblastoma protein. In each case, their expression and
      DNA binding activity are restricted to post-G1/S fractions. Surprisingly, E2F-1
      and E2F-3 make unequal contributions to the pRB-associated and free E2F activity,
      suggesting that these proteins perform different cell cycle functions. Most
      significantly, this study showed E2F-4 accounts for the vast majority of the
      endogenous E2F activity. In arrested cells, E2F-4 is sequestered by the p130
      protein. However, as the cells pass the G1-to-S transition, the levels of pRB and
      p107 increase and E2F-4 now associates with both of these regulators. Despite
      this, a considerable amount of E2F-4 exists as free E2F. In G1 cells, this
      accounts for almost all of the free activity. Once the cells enter S phase, free
      E2F is composed of an equal mixture of E2F-4 and E2F-1.

PMID- 8657118
TI  - Functional interactions of phosphatidylinositol 3-kinase with GTPase-activating
      protein in 3T3-L1 adipocytes.
AB  - The role of phosphatidylinositol (PI) 3-kinase in specific aspects of insulin
      signaling was explored in 3T3-L1 adipocytes. Inhibition of PI 3-kinase activity
      by LY294002 or wortmannin significantly enhanced basal and insulin-stimulated
      GTPase-activating protein (GAP) activity in 3T3-L1 adipocytes. Furthermore,
      removal of the inhibitory influence of PI 3-kinase on GAP resulted in dose
      dependent decreases in the ability of insulin to stimulate p21ras. This effect
      was specific to adipocytes, as inhibition of PI 3-kinase did not influence GAP in
      either 3T3-L1 fibroblasts, Rat-1 fibroblasts, or CHO cells. Immunodepletion of
      either of the two subunits of the PI 3-kinase (p85 or p110) yielded similar
      activation of GAP, suggesting that catalytic activity of p110 plays an important
      role in controlling GAP activity in 3T3-L1 adipocytes. Inhibition of PI 3-kinase
      activity in 3T3-L1 adipocytes resulted in abrogation of insulin-stimulated
      glucose uptake and thymidine incorporation. In contrast, effects of insulin on
      glycogen synthase and mitogen-activated protein kinase activity were inhibited
      only at higher concentrations of LY294002. It appears that in adipocytes, P1 3
      kinase prevents activation of GAP. Inhibition of PI 3-kinase activity or
      immunodepletion of either one of its subunits results in activation of GAP and
      decreases in GTP loading of p21ras.

PMID- 8657119
TI  - Raf, but not MEK or ERK, is sufficient for differentiation of hippocampal
      neuronal cells.
AB  - To elucidate signal transduction pathways leading to neuronal differentiation, we
      have investigated a conditionally immortalized cell line from rat hippocampal
      neurons (H19-7) that express a temperature sensitive simian virus 40 large T
      antigen. Treatment of H19-7 cells with the differentiating agent basic fibroblast
      growth factor at 39 degrees C, the nonpermissive temperature for T function,
      resulted in the activation of c-Raf-1, MEK, and mitogen-activated protein (MAP)
      kinases (ERK1 and -2). To evaluate the role of Raf-1 in neuronal cell
      differentiation, we stably transfected H19-7 cells with v-raf or an oncogenic
      human Raf-1-estrogen receptor fusion gene (deltaRaf-1:ER). deltaRaf-1:ER
      transfectants in the presence of estradiol for 1 to 2 days expressed a
      differentiation phenotype only at the nonpermissive temperature. However,
      extended exposure of the deltaRaf-1:ER transfectants to estradiol or stable
      expression of the v-raf construct yielded cells that extended processes at the
      permissive as well as the nonpermissive temperature, suggesting that cells
      expressing the large T antigen are capable of responding to the Raf
      differentiation signal. deltaRaf-1:ER, MEK, and MAP kinase activities in the
      deltaRaf-1:ER cells were elevated constitutively for up to 36 h of estradiol
      treatment at the permissive temperature. At the nonpermissive temperature, MEK
      and ERKs were activated to a significantly lesser extent, suggesting that
      prolonged MAP kinase activation may not be sufficient for differentiation. To
      test this possibility, H19-7 cells were transfected or microinjected with
      constitutively activated MEK. The results indicate that prolonged activation of
      MEK or MAP kinases (ERK1 and -2) is not sufficient for differentiation of H19-7
      neuronal cells and raise the possibility that an alternative signaling pathway is
      required for differentiation of H19-7 cells by Raf.

PMID- 8657120
TI  - Conformational changes induced in the protein tyrosine kinase p72syk by tyrosine
      phosphorylation or by binding of phosphorylated immunoreceptor tyrosine-based
      activation motif peptides.
AB  - A critical event in signaling in immune cells is the interaction of Syk or ZAP-70
      protein tyrosine kinases with multisubunit receptors that contain an
      approximately 18-amino-acid domain called the immunoreceptor tyrosine-based
      activation motif (ITAM). Tyrosine-phosphorylated Syk from activated cells was in
      a conformation different from that in nonstimulated cells as demonstrated by
      changes in immunoreactivity. The addition of tyrosine-diphosphorylated ITAM
      peptides resulted in a similar conformational change in Syk from nonactivated
      cells. The peptides based on FcepsilonRIgamma were more active than those based
      on Fcepsilon RIbeta. In vitro autophosphorylation of Syk was dramatically
      enhanced by the addition of the diphosphorylated ITAM peptides. The
      conformational change and the enhanced autophosphorylation required the presence
      of both phosphorylated tyrosines on the same molecule. These conformational
      changes in Syk by tyrosine phosphorylation or binding to diphosphorylated ITAM
      could be critical for Syk activation and downstream propagation of intracellular
      signals.

PMID- 8657121
TI  - Stress-induced binding of the transcriptional factor CHOP to a novel DNA control
      element.
AB  - CHOP (GADD153) is a mammalian nuclear protein that dimerizes with members of the
      C/EBP family of transcriptional factors. Absent under normal conditions, CHOP is
      induced by the stress encountered during nutrient deprivation, the acute-phase
      response, and treatment of cells with certain toxins. The basic region of CHOP
      deviates considerably in sequence from that of other C/EBP proteins, and CHOP
      C/EBP heterodimers are incapable of binding to a common class of C/EBP sites.
      With respect to such sites, CHOP serves as an inhibitor of the activity of C/EBP
      proteins. However, recent studies indicate that certain functions of CHOP, such
      as the induction of growth arrest by overexpression of the wild-type protein and
      oncogenic transformation by the TLS-CHOP fusion protein, require an intact basic
      region, suggesting that DNA binding by CHOP may be implicated in these
      activities. In this study an in vitro PCR-based selection assay was used to
      identify sequences bound by CHOP-C/EBP dimers. These sequences were found to
      contain a unique core element PuPuPuTGCAAT(A/C)CCC. Competition in DNA-binding
      assays, DNase 1 footprint analysis, and methylation interference demonstrate that
      the binding is sequence specific. Deletions in the basic region of CHOP lead to a
      loss of DNA binding, suggesting that CHOP participates in this process. Stress
      induction in NIH 3T3 cells leads to the appearance of CHOP-containing DNA-binding
      activity. CHOP is found to contain a transcriptional activation domain which is
      inducible by cellular stress, lending further support to the notion that the
      protein can function as a positively acting transcription factor. We conclude
      that CHOP may serve a dual role both as an inhibitor of the ability of C/EBP
      proteins to activate some target genes and as a direct activator of others.

PMID- 8657122
TI  - Functional characterization of a non-AUUUA AU-rich element from the c-jun proto
      oncogene mRNA: evidence for a novel class of AU-rich elements.
AB  - AU-rich RNA-destabilizing elements (AREs) found in the 3' untranslated regions of
      many labile mRNAs encoding proto-oncoproteins and cytokines generally contain (i)
      one or more copies of the AUUUA pentanucleotide and (ii) a high content of
      uridylate and sometimes also adenylate residues. Recently, we have identified a
      potent ARE from the 3' untranslated region of c-jun proto-oncogene mRNA that does
      not contain the AUUUA motif. In an attempt to further our understanding of the
      general principles underlying mechanisms by which AREs direct rapid and selective
      mRNA degradation, in this study we have characterized the functionally important
      structural features and properties of this non-AUUUA ARE. Like AUUUA-containing
      AREs, this non-AUUUA ARE directs rapid shortening of the poly(A) tail as a
      necessary first step for mRNA degradation. It can be further dissected into three
      structurally and functionally distinct regions, designated domains I, II, and
      III. None of three domains alone is able to significantly destabilize the stable
      beta-globin mRNA. The two unlinked domains, I and III, together are necessary and
      sufficient for specifying the full destabilizing function of this non-AUUUA ARE.
      Domain II appears functionally dispensable but can partially substitute for
      domain I. Domain swaps made between the c-jun non-AUUUA and the c-fos AUUUA
      containing AREs reveal that the two AREs, while sharing no sequence homology,
      appear to contain sequence domains that are structurally distinct but
      functionally overlapping and exchangeable. These data support the idea that the
      ultimate destabilizing function of an individual ARE is determined by its own
      unique combination of structurally distinct and functionally interdependent
      domains. Our polysome profile studies show tha the destabilizing function of the
      c-jun non-AUUUA ARE does not require any active transit by ribosomes of the mRNA
      bearing it, further corroborating that the destabilizing function of AREs is not
      tightly coupled to ongoing translation by ribosomes. Moreover, unlike AUUUA
      containing AREs, the c-jun ARE is insensitive to blockage of its effects by
      addition of transcription inhibitors. Thus, our data provide further evidence for
      the existence of a novel class of ARE with unique properties.

PMID- 8657123
TI  - The cell cycle-coupled expression of topoisomerase IIalpha during S phase is
      regulated by mRNA stability and is disrupted by heat shock or ionizing radiation.
AB  - Topoisomerase II is a multifunctional protein required during DNA replication,
      chromosome disjunction at mitosis, and other DNA-related activities by virtue of
      its ability to alter DNA supercoiling. The enzyme is encoded by two similar but
      nonidentical genes: the topoisomerase IIalpha and IIbeta genes. In HeLa cells
      synchronized by mitotic shake-off, topoisomeraseII alpha mRNA levels were found
      to vary as a function of cell cycle position, being 15-fold higher in late S
      phase (14 to 18 h postmitosis) than during G1 phase. Also detected was a
      corresponding increase in topoisomerase IIalpha protein synthesis at 14 to 18 h
      postmitosis which resulted in significantly higher accumulation of the protein
      during S and G2 phases. Topoisomerase IIalpha expression was not dependent on DNA
      synthesis during S phase, which could be inhibited without effect on the timing
      or level of mRNA expression. Mechanistically, topoisomerase IIalpha expression
      appears to be coupled to cell cycle position mainly through associated changes in
      mRNA stability. When cells are in S phase and mRNA levels are maximal, the half
      life of topoisomerase IIalpha mRNA was determined to be approximately 30 min. A
      similar decrease in mRNA stability was also induced by two external factors known
      to delay cell cycle progression. Treatment of S-phase cells, at the time of
      maximum topoisomerase IIalpha mRNA stability, with either ionizing radiation (5
      Gy) or heat shock (45 degrees C for 15 min) caused the accumulated topoisomerase
      IIalpha mRNA to decay. This finding suggests a potential relationship between
      stress-induced decreases in topoisomerase IIalpha expression and cell cycle
      progression delays in late S/G2.

PMID- 8657124
TI  - Two chimeric receptors of epidermal growth factor receptor and c-Ros that differ
      in their transmembrane domains have opposite effects on cell growth.
AB  - Two chimeric receptors, ER1 and ER2, were constructed. ER1 contains the
      extracellular and transmembrane (TM) domains derived from epidermal growth factor
      receptor and the cytoplasmic domain from c-Ros; ER2 is identical to ER1 except
      that its TM domain is derived from c-Ros. Both chimeras can be activated by
      epidermal growth factor and are capable of activating or phosphorylating an array
      of cellular signaling proteins. Both chimeras promote colony formation in soft
      agar with about equal efficiency. Surprisingly, ER1 inhibits while ER2 stimulates
      cell growth on monolayer culture. Cell cycle analysis revealed that all phases,
      in particular the S and G2/M phases, of the cell cycle in ER1 cells were
      elongated whereas G1 phase of ER2 cells was shortened threefold. Comparison of
      signaling pathways mediated by the two chimeras revealed several differences.
      Several early signaling proteins are activated or phosphorylated to a higher
      extent in ER1 than in ER2 cells in response to epidermal growth factor. ER1 is
      less efficiently internalized and remains tyrosine phosphorylated for a longer
      time than ER2. However, phosphorylation of the 66-kDa She protein, activation of
      mitogen activated protein kinase, and induction of c-fos and c-jun occur either
      to a lesser extent or for a shorter time in ER1 cells. Cellular protein
      phosphorylation patterns are also different in ER1 and ER2 cells. In particular,
      a 190-kDa Shc-associated protein is tyrosine phosphorylated in ER2 but not in ER1
      cells. Our results indicate that the TM domains have a profound effect on the
      signal transduction and biological activity of those chimeric receptors. The
      results also imply that sustained stimulation of ER1 due to its retarded
      internalization apparently triggers an inhibitory response that dominantly
      counteracts the receptor-mediated mitogenic signals. These two chimeras,
      expressed at similar levels in the same cell type but having opposite effects on
      cell growth, provide an ideal system to study the mechanism by which a protein
      tyrosine kinase inhibits cell growth.

PMID- 8657125
TI  - Ku86 defines the genetic defect and restores X-ray resistance and V(D)J
      recombination to complementation group 5 hamster cell mutants.
AB  - X-ray-sensitive hamster cells in complementation groups 4, 5, 6, and 7 are
      impaired for both double-strand break repair and V(D)J recombination. Here we
      show that in two mutant cell lines (XR-V15B and XR-V9B) from group 5, the genetic
      defects are in the gene encoding the 86-kDa subunit of the Ku autoantigen, a
      nuclear protein that binds to the double-stranded DNA ends. These mutants express
      Ku86 mRNA containing deletions of 138 and 252 bp, respectively, and the encoded
      proteins contain internal, in-frame deletions of 46 and 84 amino acids. Two X-ray
      resistant revertants of XR-V15B expressed two Ku86 transcripts, one with and one
      without the deletion, suggesting that reversion occurred by activation of a
      silent wild-type allele. Transfection of full-length cDNA encoding hamster Ku86
      into XR-V15B cells resulted in a complete rescue of DNA-end-binding (DEB)
      activity and Ku70 levels, suggesting that Ku86 stabilizes the Ku70 polypeptide.
      In addition, cells expressing wild-type levels of DEB activity were fully rescued
      for X-ray resistance and V(D)J recombination, whereas cells expressing lower
      levels of DEB activity were only partially rescued. Thus, Ku is an essential
      component of the pathway(s) utilized for the resolution of DNA double-strand
      breaks induced by either X rays or V(D)J recombination, and mutations in the Ku86
      gene are responsible for the phenotype of group 5 cells.

PMID- 8657126
TI  - Cig2, a B-type cyclin, promotes the onset of S in Schizosaccharomyces pombe.
AB  - Cdc2, a catalytic subunit of cyclin-dependent kinases, is required for both the
      G1-to-S and G2-to-M transitions in the fission yeast Schizosaccharomyces pombe.
      Cdc13, a B-type cyclin, is required for the M-phase induction function of Cd2.
      Two additional B-type cyclins, Cig1 and Cig2, have been identified in S. pombe,
      but none of the B-type cyclins are individually required for the onset of S. We
      report that Cdc13 is important for DNA replication in a strain lacking Cig2.
      Unlike deltacdc13 cells, double-mutant deltacdc13 deltacig2 cells are defective
      in undergoing multiple rounds of DNA replication. The conclusion that Cig2
      promotes S is further supported by the finding that Cig2 protein and Cig2
      associated kinase activity appear soon after the completion of M and peak during
      S, as well as the observation that S is delayed in deltacig2 cells as they
      recover from a G1 arrest induced by nitrogen starvation. These studies indicate
      that Cig2 is the primary S-phase-promoting cyclin in S. pombe but that Cdc13 can
      effectively substitute for Cig2 in deltacig2 cells. These observations also
      suggest that the gradual increase in the activity of Cdc2-Cdc13 kinase can be
      sufficient for the correct temporal ordering of S and M phases in deltacig2
      cells.

PMID- 8657127
TI  - Role of polyadenylation in nucleocytoplasmic transport of mRNA.
AB  - To examine the role of polyadenylation in the nuclear export of mRNA, we have
      replaced the poly(A) signal in a Rev-responsive human immunodeficiency virus type
      1-based reporter gene with a cis-acting hammerhead ribozyme. Transcripts from
      this gene thus acquire a 3' terminus by cis-ribozyme cleavage rather than by
      polyadenylation. The nuclear and cytoplasmic distribution of transcripts was
      investigated using transient gene expression and quantitative RNase protection
      assays. In the absence of Rev, a basal level of polyadenylated unspliced mRNA
      transcribed from a poly(A) signal-containing control reporter gene was detected
      in the cytoplasm of transfected COS7 cells. However, cytoplasmic ribozyme-cleaved
      unspliced RNA was only barely detectable. The nuclear/cytoplasmic (n/c) ratio of
      polyadenylated RNAs was 3.8, while the n/c ratio for ribozyme cis-cleaved RNAs
      was 33. The cytoplasmic localization of the polyadenylated unspliced mRNA was
      enhanced about 10-fold in the presence of Rev and the Rev-responsive element. In
      marked contrast to this, ribozyme cleaved RNA accumulated almost exclusively (n/c
      ratio of 28) in the nucleus in the presence of Rev. Actinomycin D time course
      analysis suggested that the low levels of the cytoplasmic ribozyme-cleaved RNAs
      in both the presence and absence of Rev were due to serve export deficiency of
      ribozyme-cleaved RNA. Finally, by inserting a 90-nucleotide poly(A) stretch
      directly upstream of the ribozyme cassette, we have demonstrated that a long
      stretch of poly(A) near the 3' end of a ribozyme-cleaved transcript is not
      sufficient for directing mRNA export. Taken together, these results suggest that
      polyadenylation is required for the nucleocytoplasmic transport of mRNA and that
      Rev interaction with the Rev-responsive element cannot bypass this requirement.

PMID- 8657128
TI  - Protein polymorphism generated by differential RNA editing of a plant
      mitochondrial rps12 gene.
AB  - The rps12 gene transcripts encoding mitochondrial ribosomal protein S12 are
      partially edited in petunia mitochondria. Different petunia lines were found vary
      in the extent of rps12 transcript editing. To test whether multiple forms of
      RPS12 proteins are produced in petunia mitochondria as a result of partial
      editing, we probed mitochondrial proteins with specific antibodies against edited
      and unedited forms of a 13-amino-acid RPS12 peptide spanning two amino acids
      affected by RNA editing. Both antibodies reacted with mitochondrial proteins at
      the expected size for RPS12 proteins. The amounts of unedited RPS12 protein in
      different petunia lines correlate with the abundance of unedited transcripts in
      these plants. Unedited rps12 translation products are also detected in other
      plant species, indicating that polymorphism in mitochondrial rps12 expression is
      widespread. Moreover, we show that RPS12 proteins recognized by both edited
      specific and unedited-specific antibodies are present in a petunia mitochondrial
      ribosome fraction. These results demonstrate that partially edited transcripts
      can be translated and that the protein product can accumulate to detectable
      levels. Therefore, genes exhibiting incompletely edited transcripts can encode
      more than one gene product in plant mitochondria.

PMID- 8657129
TI  - Analysis of the ERK-stimulated ETS transcription factor ER81.
AB  - A plethora of extracellular signals leads to the stimulation of Ras, which
      triggers intracellular protein kinase cascades, resulting in activation of
      transcription factors and thus in enhanced gene activity. In this report, it is
      demonstrated that the ETS transcription factor ER81, which appears to be
      localized within the cell nucleus by virtue of its DNA binding domain, is
      transcriptionally activated by oncogenic Ras. Since this activation was dependent
      on the presence of Raf-1 and ERK-1, ER81 is a target of the Ras/Raf/MEK/ERK
      signaling cascade. Consistently, activated ERK-1 is capable to phosphorylate
      ER81. However, the carboxy-terminal region of ER81, which contains no potential
      ERK phosphorylation sites, is also transcriptionally activated by ERK-1,
      suggesting that an ERK-stimulated protein kinase phosphorylates and thus
      stimulates ER81 activity. Two acidic stretches of amino acids, which are
      conserved in the related PEA3 and ERM proteins, are localized within the amino
      and carboxy-terminal transactivation domains of ER81. In addition, an inhibitory
      domain may dampen the activation function of these two domains. In conclusion,
      ER81 is a target of Ras-dependent signaling cascades and may thus contribute to
      the nuclear response upon stimulation of cells and also to cellular
      transformation due to oncogenic Ras.

PMID- 8657130
TI  - Synthetic enhancement of a TFIIB defect by a mutation in SSU72, an essential
      yeast gene encoding a novel protein that affects transcription start site
      selection in vivo.
AB  - An ssu72 mutant of Saccharomyces cerevisiae was identified as an enhancer of a
      TFIIB defect (sua7-1) that confers both a cold-sensitive growth defect and a
      downstream shift in transcription start site selection. The ssu72-1 allele did
      not affect cold sensitivity but, in combination with sua7-1, created a heat
      sensitive phenotype. Moreover, start site selection at the ADH1 gene was
      dramatically shifted further downstream of the normal sites. Both of these
      effects could be rescued by either SUA7 or SSU72, thereby defining a functional
      relationship between the two genes. SSU72 is a single-copy, essential gene
      encoding a novel protein of 206 amino acids. The ssu72-1 allele is the result of
      a 30-bp duplication creating a sequence encoding a Cys-X2-Cys-X6-Cys-X2-Cys zinc
      binding motif near the N terminus of Ssu72p. Mutational analysis demonstrated
      that the N terminus of Ssu72p is essential for function and that cysteine
      residues in both the normal and mutant proteins are critical. We discuss the
      possibility that the potential zinc binding motif of Ssu72 facilitates assembly
      of the transcription preinitiation complex and that this effect is important for
      accurate start site selection in vivo.

PMID- 8657132
TI  - Functional interactions between the hBRM/hBRG1 transcriptional activators and the
      pRB family of proteins.
AB  - hBRG1 and hBRM are mammalian homologs of the SNF2/SW12 yeast transcriptional
      activator. These proteins exist in a large multisubunit complex that likely
      serves to remodel chromatin and, in so doing, facilitates the function of
      specific transcription factors. The retinoblastoma protein (pRB) inhibits cell
      cycle progression by repressing transcription of specific growth-related genes.
      Using the yeast two-hybrid system, we demonstrate that the members of the
      hBRG1/hBRM family of proteins interact with the pRB family of proteins, which
      includes pRB, p107, and p130. Interaction between the hBRG1/hBRM family with the
      pRB family likely influences cellular proliferation, as both hBRG1 and hBRM, but
      not mutants of these proteins unable to bind to pRB family members, inhibit the
      formation of drug-resistant colonies when transfected into the SW13 human
      adenocarcinoma cell line, which lacks endogenous hBRG1 or hBRM. Further, hBRM and
      two isoforms of hBRG1 induce the formation of flat, growth-arrested cells in a
      pRB family-dependent manner when introduced into SW13 cells. This flat-cell
      inducing activity is severely reduced by cotransfection of the wild-type E1A
      protein and variably reduced by the cotransfection of mutants of E1A that lack
      the ability to bind to some or all members of the pRB family.

PMID- 8657131
TI  - Distinct stages in adipogenesis revealed by retinoid inhibition of
      differentiation after induction of PPARgamma.
AB  - Retinoic acid (RA) inhibits adipocyte differentiation of 3T3-L1 preadipocytes but
      is effective only early in adipogenesis. RA prevented induction of the adipogenic
      factors PPARgamma and C/EBPalpha. Using receptor-specific ligands, we determined
      that the effects of RA were mediated by liganded RA receptors (RARs) rather than
      retinoid X receptors. Preadipocytes expressed primarily RARalpha and RARgamma;
      during adipocyte differentiation, RARalpha gene expression was nearly constant,
      whereas RARgamma1 mRNA and protein levels dramatically decreased. Ectopic
      expression of RARgamma1 extended the period of effectiveness of RA by 24 to 48h;
      RARalpha expression had a similar effect, suggesting functional redundancy of RAR
      subtypes. Remarkably, RA inhibited differentiation when added after PPARgamma1
      and PPARgamma2 proteins had already been expressed and resulted in the loss of
      PPARgamma proteins from cells. By 72 to 96 h after the induction of
      differentiation, RA failed to prevent differentiation of even ectopic-RAR
      expressing cells. Thus, the unresponsiveness of 3T3-L1 preadipocytes to RA after
      the induction of differentiation is initially due to the reduction in cellular
      RAR concentration rather than to the induction of PPARgamma. At later times cells
      continue along the differentiation pathway in a manner which is RA and RAR
      independent.

PMID- 8657133
TI  - A novel cis-acting element is essential for cytokine-mediated transcriptional
      induction of the serum amyloid A gene in nonhepatic cells.
AB  - Serum amyloid A (SAA) is a plasma protein which has been associated with several
      diseases, including amyloidosis, arthritis, and atherosclerosis, and its abnormal
      expression, particularly in nonhepatic cells, is implicated in the pathogenesis
      of these diseases. Transfection and DNA-binding studies were performed to
      investigate the mechanism controlling cytokine-induced, nonhepatic expression of
      the SAA gene. We have identified a novel promoter, located between positions -280
      and 224, that confers interleukin-6 (IL-6) inducibility to an SAA-chloramphenicol
      acetyltransferase reporter gene in both nonhepatic and hepatic cells. DNase I
      protection assays revealed, within this region, three homologous highly
      pyrimidine rich octanucleotide sequence motifs, termed SAA-activating sequences
      (SAS). Specific mutations within these three SAS motifs severely reduced IL-6
      mediated induction of the reporter gene in transfected nonhepatic cells but not
      in liver cells. A nuclear factor activated by IL-6 in both hepatic and nonhepatic
      cells efficiently interacts with the SAS. The induction kinetics and
      cycloheximide sensitivity of this SAS-binding factor (SAF) suggested that de novo
      synthesis of this factor itself or an activator protein is essential. Loss of DNA
      binding ability as a result of in vitro dephosphorylation, induction of SAA
      chloramphenicol acetyltransferase reporter gene activity in the presence of
      genistein, a protein kinase inhibitor, further indicate that a phosphorylation
      step is necessary for the activation of SAF. Our results suggest that SAF is a
      key regulator of cytokine-mediated SAA gene expression in some nonhepatic cells.

PMID- 8657134
TI  - Activation and association of Stat3 with Src in v-Src-transformed cell lines.
AB  - STAT proteins are a group of latent cytoplasmic transcription factors which
      function as signal transducers and activators of transcription. Stat1 and -2 were
      originally identified to function in interferon signaling, and Stat1 was also
      found to be activated by epidermal growth factor (EGF) and other cytokines. New
      members of the STAT gene family are identified. Among them, Stat3 has 52.5% amino
      acid sequence homology with Stat1 and is activated by platelet-derived growth
      factor (PDGF), colony-stimulating factor 1 (CSF-1), EGF, interleukin-6, and other
      cytokines. Treatment of cells with EGF activates Stat1 and Stat3, which become
      phosphorylated on tyrosine residues to form homo - or heterodimers and
      translocate into the nucleus, binding to the sis-inducible element (SIE) in the c
      fos promoter. Somatic cell genetic analyses demonstrated that Jaks, a family of
      nontransmembrane protein tyrosine kinases, are required for the activation of
      Stat1 and Stat2 in interferon-treated cells. However, little is known about the
      activation of Stat3 by growth factors. Here we report that in all v-Src
      transformed cell lines examined, Stat3 is constitutively activated to bind to DNA
      and the phosphorylation of tyrosine on Stat3 is enhanced by the induction of v
      Src expression. We also report that Src is shown to be associated with Stat3 in
      vivo, as well as in vitro, and phosphorylates Stat3 in vitro. Stat3 is also
      activated by CSF-1, possibly through CSF-1 receptor-c Src association in NIH 3T3
      cells overexpressing CSF-1 receptors. Together, the data suggest that Src is
      involved in activation of Stat3 in growth factor signal transduction.

PMID- 8657135
TI  - Casein kinase II increases the transcriptional activities of MRF4 and MyoD
      independently of their direct phosphorylation.
AB  - The myogenic regulatory factors (MRFs) are a subclass of a much larger group of
      basic helix-loop-helix transcription factors which includes members of the E
      protein such as E47, E2-2, and HEB. Although the MRFs are unique in their ability
      to confer a myogenic phenotype on nonmuscle cells, they require E protein
      partners to form a MRF-E protein heterodimer, which represents the functional
      myogenesis-inducing complex. The mechanisms controlling homodimer and heterodimer
      formation in vivo remain largely unknown, although it is likely that
      posttranslational modification of one or both basic helix-loop-helix partners is
      critical to this regulatory event. In this respect, MyoD and MRF4, both members
      of the MRF family, exist in vivo as phosphoproteins and contains multiple
      consensus phosphorylation sites, including sites for casein kinase II (CKII)
      phosphorylation. In this study, we demonstrate that overexpression of CKII
      increases the transcriptional activities of MRF4 and MyoD in vivo. Interestingly,
      mutation of the individual CKII sites within MRF4 and MyoF does not alter the
      ability of CKII to enhance MRF transcriptional activity, suggesting that the
      effect of CKII expression on the MRFs is indirect. Given that the MRFs require
      dimerization with E protein partners to activate muscle-specific transcription,
      the effects of CKII expression on E protein function also were examined. Our
      studies show that E47 serves as an in vitro substrate for CKII and that CKII
      phosphorylated E-47 proteins no longer bind to DNA. These observations were
      confirmed by in vivo experiments showing that overexpressing of CKII produces a
      dramatic reduction in E47 homodimer-directed transcription. We conclude from
      these studies that CKII may act as a positive regulator of myogenesis by
      preventing E protein homodimers from binding to muscle gene regulatory elements.

PMID- 8657136
TI  - A three-step pathway of transcription initiation leading to promoter clearance at
      an activation RNA polymerase II promoter.
AB  - The progress of transcription bubbles during inhibition in vitro was followed in
      order to learn how RNA polymerase II begins transcription at the activated
      adenovirus E4 promoter. The issues addressed include the multiple roles of ATP,
      the potential effect of polymerase C-terminal domain phosphorylation, and the
      ability of polymerase to clear the promoter for reinitiation. The results lead to
      a three-step model for the transition from closed complex to elongation complex,
      two steps of which use ATP independently. In the first step, studied previously,
      ATP is hydrolyzed to open the DNA strands over the start site. In a second step,
      apparently independent of ATP, transcription bubbles move into the initial
      transcribed region where RNA synthesis can stall. In the third step, transcripts
      can be made as polymerase is released from these stalled positions with the
      assistance of an ATP-dependent process, likely phosphorylation of the polymerase
      C-terminal domain. After this third step, the promoter becomes cleared, allowing
      for the reinitiation of transcription.

PMID- 8657137
TI  - Erythropoietin induces activation of Stat5 through association with specific
      tyrosines on the receptor that are not required for a mitogenic response.
AB  - The cytoplasmic domain of the erythropoietin receptor (EpoR) contains a membrane
      distal region that is dispensable for mitogenesis but is required for the
      recruitment and tyrosine phosphorylation of a variety of signaling proteins. The
      membrane-proximal region of 96 amino acids is necessary and sufficient for
      mitogenesis as well as Jak2 activation, induction of c-fos, c-myc, cis, the T
      cell receptor gamma locus (TCR-gamma), and c-pim-1. The studies presented here
      demonstrate that this region is also necessary and sufficient for the activation
      of Stat5A and Stat5B. The membrane-proximal domain contains a single tyrosine, Y
      343, which when mutated eliminates the ability of the receptor to couple Epo
      binding to the activation of Stat5. Furthermore, peptide competitions demonstrate
      that this site, when phosphorylated, can disrupt Stat5 DNA binding activity,
      consistent with a role of Y-343 as a site of recruitment to the receptor. Cells
      expressing the truncated, Y343F mutant (a mutant with a Y-to-F alteration at
      position 343) proliferate in response to Epo in a manner comparable to that of
      the controls. However, in these cells, Epo stimulation does not induce the
      appearance of transcripts for cis, TCR-gamma, or c-fos, suggesting a role for
      Stat5 in their regulation.

PMID- 8657138
TI  - Structural determinants within Pbx1 that mediate cooperative DNA binding with
      pentapeptide-containing Hox proteins: proposal for a model of a Pbx1-Hox-DNA
      complex.
AB  - Genetic studies have identified a family of divergent homeodomain proteins,
      including the human protooncoprotein Pbx1 and its drosophila homolog
      extradenticle (Exd), which function as cofactors with a subset of Hox and HOM-C
      proteins, and are essential for specific target gene expression. Pbx1/Exd binds
      DNA elements cooperatively with a large subset of Hox/HOM-C proteins containing a
      conserved pentapeptide motif, usually YPWMR, located just N terminally to their
      homeodomains. The pentapeptide is essential for cooperative DNA binding with
      Pbx1. In this study, we identify structural determinants of Pbx1 that are
      required for cooperative DNA binding with the pentapeptide-containing Hox protein
      HoxA5. We demonstrate that the homeodomain of Pbx1 contains a surface that binds
      the pentapeptide motif and that the Pbx1 homeodomain is sufficient for
      cooperative DNA binding with a Hox protein. A sequence immediately C terminal to
      the Pbx1 homeodomain, which is highly conserved in Pbx2 and Pbx3 and predicted to
      form an alpha-helix, enhances monomeric DNA binding by Pbx1 and also contributes
      to maximal cooperativity with Hox proteins. Binding studies with chimeric HoxA5
      Pbx1 fusion proteins suggest that the homeodomains of Pbx1 and HoxA5 are docked
      on the representative element, TTGATTGAT, in tandem, with Pbx1 recognizing the 5'
      TTGAT core motif and the Hox protein recognizing the 3' TGAT core. The proposed
      binding orientation permits Hox proteins to exhibit further binding specificity
      on the basis of the identity of the four residues 3' to their core binding motif.

PMID- 8657139
TI  - Transcriptional corepression in vitro: a Mot1p-associated form of TATA-binding
      protein is required for repression by Leu3p.
AB  - Signals from transcriptional activators to the general mRNA transcription
      apparatus are communicated by factors associated with RNA polymerase II or the
      TATA-binding protein (TBP). Currently, little is known about how gene-specific
      transcription repressors communicate with RNA polymerase II. We have analyzed the
      requirements for repression by the saccharomyces cerevisiae Leu3 protein (Leu3p)
      in a reconstituted transcription system. We have identified a complex form of TBP
      which is required for communication of the repressing signal. This TFIID-like
      complex contains a known TBP-associated protein, Mot1p, which has been implicated
      in the repression of a subset of yeast genes by genetic analysis. Leu3p-dependent
      repression can be reconstituted with purified Mot1p and recombinant TBP. In
      addition, a mutation in the Mot1 gene leads to partial derepression of the Leu3p
      dependent LEU2 promoter. These in vivo and in vitro observations define a role
      for Mot1p as a transcriptional corepressor.

PMID- 8657140
TI  - Analysis of muscle creatine kinase gene regulatory elements in skeletal and
      cardiac muscles of transgenic mice.
AB  - Regulatory regions of the mouse muscle creatine kinase (MCK) gene, previously
      discovered by analysis in cultured muscle cells, were analyzed in transgenic
      mice. The 206-bp MCK enhancer at nt-1256 was required for high-level expression
      of MCK-chloramphenicol acetyltransferase fusion genes in skeletal and cardiac
      muscle; however, unlike its behavior in cell culture, inclusion of the 1-kb
      region of DNA between the enhancer and the basal promoter produced a 100-fold
      increase in skeletal muscle activity. Analysis of enhancer control elements also
      indicated major differences between their properties in transgenic muscles and in
      cultured muscle cells. Transgenes in which the enhancer right E box or CArG
      element were mutated exhibited expression levels that were indistinguishable from
      the wild-type transgene. Mutation of three conserved E boxes in the MCK 1,256-bp
      5' region also had no effect on transgene expression in thigh skeletal muscle
      expression. All these mutations significantly reduced activity in cultured
      skeletal myocytes. However, the enhancer AT-rich element at nt - 1195 was
      critical for expression in transgenic skeletal muscle. Mutation of this site
      reduced skeletal muscle expression to the same level as transgenes lacking the
      206-bp enhancer, although mutation of the AT-rich site did not affect cardiac
      muscle expression. These results demonstrate clear differences between the
      activity of MCK regulatory regions in cultured muscles cells and in whole adult
      transgenic muscle. This suggests that there are alternative mechanism of
      regulating the MCK gene in skeletal and cardiac muscle under different
      physiological states.

PMID- 8657141
TI  - Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor
      E2F.
AB  - Within the region around 150 bp upstream of the initiation codon, which was
      previously shown to suffice for growth-regulated expression, the murine thymidine
      kinase gene carries a single binding site for transcription factor Sp1; about 10
      bp downstream of this site, there is a binding motif for transcription factor
      E2F. The latter protein appears to be responsible for growth regulation of the
      promoter. Mutational inactivation of either the Sp1 or the E2F site almost
      completely abolishes promoter activity, suggesting that the two transcription
      factors interact directly in delivering an activation signal to the basic
      transcription machinery. This was verified by demonstrating with the use of
      glutathione S-transferase fusion proteins that E2F and Sp1 bind to each other in
      vitro. For this interaction, the C-terminal part of Sp1 and the N terminus of
      E2F1, a domain also present in E2F2 and E2F3 but absent in E2F4 and E2F5, were
      essential. Accordingly, E2F1 to E2F3 but not E2F4 and E2F5 were found to bind sp1
      in vitro. Coimmunoprecipitation experiments showed that complexes exist in vivo,
      and it was estabilished that the distance between the binding sites for the two
      transcription factors was critical for optimal promoter activity. Finally, in
      vivo footprinting experiments indicated that both the sp1 and E2F binding sites
      are occupied throughout the cell cycle. Mutation of either binding motif
      abolished binding of both transcription factors in vivo, which may indicate
      cooperative binding of the two proteins to chromatin-organized DNA. Our data are
      in line with the hypothesis that E2F functions as a growth- and cell cycle
      regulated tethering factor between Sp1 and the basic transcription machinery.

PMID- 8657142
TI  - Cell cycle-regulated association of E2F1 and Sp1 is related to their functional
      interaction.
AB  - Because of the large number of growth-regulated genes containing binding sites
      for the transcription factors Sp1 and E2F and the reported ability of E2F to
      mediate cell cycle (growth) regulation, we studied interactions between E2F1 and
      Sp1. In transient transfection assays using Drosophila melanogaster SL2 cells,
      transfection with both Sp1 and E2F1 expression vectors resulted in greater than
      85-fold activation of transcription from a hamster dihydrofolate reductase
      reporter construct, whereas cotransfection with either the Sp1 or E2F1 expression
      vector resulted in 30- or <2-fold activation, respectively. Therefore, these
      transcription factors act synergistically in activation of dihydrofolate
      reductase transcription. Transient transfection studies demonstrated that E2F1
      could superactivate Sp1-dependent transcription in a promoter containing only Sp1
      sites and that Sp1 could superactivate transcription of promoters through E2F
      sites, further demonstrating that these physically associated in Drosophila cells
      transfected with Sp1 and E2F1 expression vectors and in human cells, with maximal
      interaction detected in mid- to late G1. Additionally, E2F1 and Sp1 interact in
      vitro through specific domains of each protein, and the physical interaction and
      functional synergism appear to require the same regions. Taken together, these
      data demonstrate that E2F1 and Sp1 both functionally and physically interact;
      therefore this interaction, Sp1 and E2F1 may regulate transcription of genes
      containing binding sites for either or both factors.

PMID- 8657143
TI  - The myeloid-cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel
      transcription factor.
AB  - The protein product of the c-fps/fes (c-fes) proto-oncogene has been implicated
      in the normal development of myeloid cells (macrophages and neutrophils). mRNA
      for c-fes has been detected exclusively in myeloid cells and vascular endothelial
      cells in adult mammals. Although a 13-kilobase-pair (kb) human c-fes transgene
      exhibits high levels of expression in mice, the sequences that confer myeloid
      cell-specific expression of the human c-fes gene have not been defined. Transient
      transfection experiments demonstrated that plasmids containing 446 bp of c-fes 5'
      flanking sequences linked to a luciferase reporter gene were active exclusively
      in myeloid cells. No other DNA element within the 13-kb human c-fes locus
      contained positive cis-acting elements, with the exception of a weakly active
      region within the 3'-flanking sequences. DNase I footprinting assays revealed
      four distinct sites that bind myeloid nuclear proteins (-408 to -386, -293 to 
      254, -76 to -65, and -34 to +3). However, the first two footprints resided in
      sequences that were largely dispensable for transient activity. Plasmids
      containing 151 bp of 5'-flanking sequences confer myeloid-cell-specific gene
      expression. Electrophoretic mobility shift analyses demonstrated that the 151-bp
      region contains nuclear protein binding sites for Sp1, PU.1, and/or Elf-1, and a
      novel factor. This unidentified factor binds immediately 3' of the PU.1/Elf-1
      sites and appears to be myeloid cell specific. Mutation of the PU.1/Elf-1 site or
      the 3' site (FP4-3') within the context of the c-fes promoter resulted in
      substantially reduced activity in transient transfections. Furthermore, transient
      cotransfection assay demonstrated that PU.1 (and not Elf-1) can transactivate the
      c-fes promoter in nonmyeloid cell lines. We conclude that the human c-fes gene
      contains a strong myeloid-cell-specific promoter that is regulated by Sp1, PU.1,
      and a novel transcription factor.

PMID- 8657145
TI  - Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box
      binding protein in erythroid cells and selected other cells.
AB  - CACCC boxes are among the critical sequences present in regulatory elements of
      genes expressed in erythroid cells, as well as in selected other cell types.
      While an erythroid cell-specific CACCC-box-binding protein, EKLF, has been shown
      to be required in vivo for proper expression of the adult beta-globin gene, it is
      dispensable for the regulation of several other globin and nonglobin erythroid
      cell-expressed genes. In the work described here, we searched for additional
      CACCC-box transcription factors that might be active in murine erythroid cells.
      We identified a major gel shift activity (termed BKLF), present in yolk sac and
      fetal liver erythroid cells, that could be distinguished from EKLF by specific
      antisera. Through relaxed-stringency hybridization, we obtained the cDNA encoding
      BKLF, a highly basic, novel zinc finger protein that is related to EKLF and other
      Kruppel-like members in its DNA-binding domain but unrelated elsewhere. BKLF,
      which is widely but not ubiquitously expressed in cell lines, is highly expressed
      in the midbrain region of embryonic mice and appears to correspond to the gel
      shift activity TEF-2, a transcriptional activator implicated in regulation of the
      simian virus 40 enhancer and other CACCC-box-containing regulatory elements.
      Because BKLF binds with high affinity and preferentially over Sp1 to many CACCC
      sequences of erythroid cell expressed genes, it is likely to participate in the
      control of many genes whose expression appears independent of the action of EKLF.

PMID- 8657144
TI  - Estrogen-induced apoptosis by inhibition of the erythroid transcription factor
      GATA-1.
AB  - Steroid hormones regulate diverse biological functions, including programmed cell
      death (apoptosis). Although steroid receptors have been studied extensively,
      relatively little is known regarding the cellular targets through which apoptosis
      is triggered. We show here that the ligand-activated estrogen receptor (ER)
      induces apoptosis in an erythroid cell line by binding to, and consequently
      inhibiting the activity of, GATA-1, an erythroid transcription factor essential
      for the survival and maturation of erythroid precursor cells. GATA-1 inhibition
      is reflected in the downregulation of presumptive GATA-1 target genes.
      Constitutive overexpression of a GATA-binding protein resistant to the effects of
      the ER partially rescues ER-induced apoptosis. Induction of apoptosis by a mutant
      ER defective in binding to the estrogen response element but active in GATA-1
      inhibition suggests that ER-mediated inhibition of GATA-1 is direct and does not
      require estrogen response element-dependent transcriptional activation. Thus, a
      lineage-restricted transcription factor, such as GATA-1, constitutes one cellular
      target through which steroid hormones may control apoptosis. As GATA-binding
      proteins are evolutionarily conserved, we speculate that members of the steroid
      receptor family may exert some of their diverse biological functions in different
      cellular contexts through interference with the function of GATA-binding
      proteins.

PMID- 8657146
TI  - cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS
      factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor
      nuclear translocator (Arnt).
AB  - We isolated mouse cDNA clones (Arnt2) that are highly similar to but distinct
      from the aryl hydrocarbon receptor (AhR) nuclear translocator (Arnt). The
      composite cDNA covered a 2,443-bp sequence consisting of a putative 2,136-bp open
      reading frame encoding a polypeptide of 712 amino acids. The predicted Arnt2
      polypeptide carries a characteristic basic helix-loop-helix (bHLH)/PAS motif in
      its N-terminal region with close similarity (81% identity) to that of mouse Arnt
      and has an overall sequence identity of 57% with Arnt. Biochemical properties and
      interaction of Arnt2 with other bHLH/PAS proteins were investigated by
      coimmunoprecipitation assays, gel mobility shift assays, and the yeast two-hybrid
      system. Arnt2 interacted with AhR and mouse Sim as efficiently as Arnt, and the
      Arnt2-AhR complex recognized and bound specifically the xenobiotic responsive
      element (XRE) sequence. Expression of Arnt2 successfully rescued XRE-driven
      reporter gene activity in the Arnt-defective c4 mutant of Hepa-1 cells. RNA blot
      analysis revealed that expression of Arnt2 mRNA was restricted to the brains and
      kidneys of adult mice, while Arnt mRNA was expressed ubiquitously. In addition,
      whole-mount in situ hybridization of 9.5-day mouse embryos showed that Arnt2 mRNA
      was expressed in the dorsal neural tube and branchial arch 1, while Arnt
      transcripts were detected broadly in various tissues of mesodermal and endodermal
      origins. These results suggest that Arnt2 may play different roles from Arnt both
      in adult mice and in developing embryos. Finally, sequence comparison of the
      currently known bHLH/PAS proteins indicates a division into two phylogenetic
      groups: the Arnt group, containing Arnt, Arnt2, and Per, and the AhR group,
      consisting of AhR, Sim, and Hif-1alpha.

PMID- 8657147
TI  - An activation domain of the helix-loop-helix transcription factor E2A shows cell
      type preference in vivo in microinjected zebra fish embryos.
AB  - The E2A protein is a mammalian transcription factor of the helix-loop-helix
      family which is implicated in cell-specific gene expression in several cell
      lineages. Mouse E2A contains two independent transcription activation domains,
      ADI and ADII; whereas ADI functions effectively in a variety of cultured cell
      lines, ADII shows preferential activity in pancreatic beta cells. To analyze this
      preferential activity in an in vivo setting, we adapted a system involving
      transient gene expression in microinjected zebra fish embryos. Fertilized one- to
      four-cell embryos were coinjected with an expression plasmid and a reporter
      plasmid. The expression plasmids used encode the yeast Gal4 DNA-binding domain
      (DBD) alone, or Gal4 DBD fused to ADI, ADII, or VP16. The reporter plasmid
      includes the luciferase gene linked to a promoter containing repeats of UASg, the
      Gal4-binding site. Embryo extracts prepared 24 h after injection showed
      significant luciferase activity in response to each of the three activation
      domains. To determine the cell types in which the activation domains were
      functioning, a reporter plasmid encoding beta-galactosidase and then in situ
      staining of whole embryos were used. Expression of ADI led to activation in all
      major groups of cell types of the embryo (skin, sclerotome, myotome, notochord,
      and nervous system). On the other hand, ADII led to negligible expression in the
      sclerotome, notochord, and nervous system and much more frequent expression in
      the myotome. Parallel experiments conducted with transfected mammalian cells have
      confirmed that ADII shows significant activity in myoblast cells but little or no
      activity in neuronal precursor cells, consistent with our observations in zebra
      fish. This transient-expression approach permits rapid in vivo analysis of the
      properties of transcription activation domains: the data show that ADII functions
      preferentially in cells of muscle lineage, consistent with the notion that
      certain activation domains contribute to selective gene activation in vivo.

PMID- 8657150
TI  - Role of negative regulation in promoter specificity of the homologous
      transcriptional activators Ace2p and Swi5p.
AB  - The Ace2p and Swi5p zinc finger proteins have nearly identical DNA-binding
      domains, yet in vivo they activate transcription of different genes, CTS1 and HO.
      We now demonstrate that Ace2p and Swi5p recognize sites in the CTS1 and HO
      promoters with the same affinities, raising the question of how promoter
      specificity is achieved by these proteins with similar DNA-binding domains. It
      has been previously shown that Swi5p binds to the HO promoter cooperatively with
      the Pho2p (Base2p/Grf10p) homeodomain protein, and we now show that Ace2p does
      not interact with Pho2p. Analysis of CTS1 promoter fragments inserted into a
      heterologous promoter identify a sequence 90 bp away from the Ace2p binding sites
      which is required to prevent activation by Swi5p through these binding sites.
      These results suggest that a regulatory protein bound to the CTS1 promoter is
      needed to prevent Swi5p from activating CT1S expression. A genetic screen was
      conducted to identify suppressor mutations which allow CTS1 expression in the
      absence of the Ace2p activator. The nce3 mutation suppresses the ace2 defect in
      CTS1 expression only if the strain contains a functional SWI5 gene, suggesting
      that NCE3 normally functions to prevent Swi5p from activating CTS1. The role of
      negative regulators such as NCE3, as well as the previously described SIN5 gene,
      in determining the promoter specificity of homologous activators is discussed.

PMID- 8657148
TI  - Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys
      802, a residue involved in the phosphate transfer reaction.
AB  - Wortmannin at nanomolar concentrations is a potent and specific inhibitor of
      phosphoinositide (PI) 3-kinase and has been used extensively to demonstrate the
      role of this enzyme in diverse signal transduction processes. At higher
      concentrations, wortmannin inhibits the ataxia telangiectasia gene (ATM)-related
      DNA-dependent protein kinase (DNA-PKcs). We report here the identification of the
      site of interaction of wortmannin on the catalytic subunit of PI 3-kinase,
      p110alpha. At physiological pH (6.5 to 8) wortmannin reacted specifically with
      p110alpha. Phosphatidylinositol-4,5-diphosphate, ATP, and ATP analogs [adenine
      and 5'-(4-fluorosulfonylbenzoyl)adenine] competed effectively with wortmannin,
      while substances containing nucleophilic amino acid side chain functions had no
      effect at the same concentrations. This suggests that the wortmannin target site
      is localized in proximity to the substrate-binding site and that residues
      involved in wortmannin binding have an increased nucleophilicity because of their
      protein environment. Proteolytic fragments of wortmannin-treated, recombinant
      p110alpha were mapped with anti-wortmannin and anti-p110alpha peptide antibodies,
      thus limiting the target site within a 10-kDa fragment, colocalizing with the ATP
      binding site. Site-directed mutagenesis of all candidate residues within this
      region showed that only the conservative Lys-802-to-Arg mutation abolished
      wortmannin binding. Inhibition of PI 3-kinase occurs, therefore, by the formation
      of an enamine following the attack of Lys-802 on the furan ring (at C-20) of
      wortmannin. The Lys-802-to-Arg mutant was also unable to bind FSBA and was
      catalytically inactive in lipid and protein kinase assays, indicating a crucial
      role for Lys-802 in the phosphotransfer reaction. In contrast, an Arg-916-to-Pro
      mutation abolished the catalytic activity whereas covalent wortmannin binding
      remained intact. Our results provide the basis for the design of novel and
      specific inhibitors of an enzyme family, including PI kinases and ATM-related
      genes, that play a central role in many physiological processes.

PMID- 8657149
TI  - Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA
      binding specificities across the Hox locus.
AB  - Pbx cofactors are implicated to play important roles in modulating the DNA
      binding properties of heterologous homeodomain proteins, including class I Hox
      proteins. To assess how Pbx proteins influence Hox DNA-binding specificity, we
      used a binding-site selection approach to determine high-affinity target sites
      recognized by various Pbx-Hox homeoprotein complexes. Pbx-Hox heterodimers
      preferred to bind a bipartite sequence 5'-ATGATTNATNN-3' consisting of two
      adjacent half sites in which the Pbx component of the heterodimer contacted the
      5' half (ATGAT) and the Hox component contacted the more variable 3' half
      (TNATNN). Binding sites matching the consensus were also obtained for Pbx1
      complexed with HoxA10, which lacks a hexapeptide but requires a conserved
      tryptophan-containing motif for cooperativity with Pbx. Interactions with Pbx
      were found to play an essential role in modulating Hox homeodomain amino-terminal
      arm contact with DNA in the core of the Hox half site such that heterodimers of
      different compositions could distinguish single nucleotide alterations in the Hox
      half site both in vitro and in cellular assays measuring transactivation. When
      complexed with Pbx, Hox proteins B1 through B9 and A10 showed stepwise
      differences in their preferences for nucleotides in the Hox half site core (TTAT
      to TGAT, 5' to 3') that correlated with the locations of their respective genes
      in the Hox cluster. These observations demonstrate previously undetected DNA
      binding specificity for the amino-terminal arm of the Hox homeodomain and suggest
      that different binding activities of Pbx-Hox complexes are at least part of the
      position-specific activities of the Hox genes.

PMID- 8657152
TI  - DOCK180, a major CRK-binding protein, alters cell morphology upon translocation
      to the cell membrane.
AB  - CRK belongs to a family of adaptor proteins that consist mostly of SH2 and SH3
      domains. Far Western blotting with CRK SH3 has demonstrated that it binds to 135-
      to 145-, 160-, and 180-kDa proteins. The 135- to 145-kDa protein is C3G, a CRK
      SH3-binding guanine nucleotide exchange protein. Here, we report on the molecular
      cloning of the 180-kDa protein, which is designated DOCK180 (180-kDa protein
      downstream of CRK). The isolated cDNA contains a 5,598-bp open reading frame
      encoding an 1,866-amino-acid protein. The deduced amino acid sequence did not
      reveal any significant homology to known proteins, except that an SH3 domain was
      identified at its amino terminus. To examine the function of DOCK180, a Ki-Ras
      farnesylation signal was fused to the carboxyl terminus of DOCK180, a strategy
      that has been employed successfully for activation of adaptor-binding proteins in
      vivo. Whereas wild-type DOCK180 accumulated diffusely in the cytoplasm and did
      not have any effect on cell morphology, farnesylated DOCK180 was localized on the
      cytoplasmic membrane and changed spindle 3T3 cells to flat, polygonal cells.
      These results suggest that DOCK180 is a new effector molecule which transduces
      signals from tyrosine kinases through the CRK adaptor protein.

PMID- 8657151
TI  - Platelet-derived growth factor induces phosphorylation of multiple JAK family
      kinases and STAT proteins.
AB  - Receptors for interferons and other cytokines signal through the action of
      associated protein tyrosine kinases of the JAK family and latent cytoplasmic
      transcription factors of the STAT family. Genetic and biochemical analysis of
      interferon signaling indicates that activation of STATs by interferons requires
      two distinct JAK family kinases. Loss of either of the required JAKs prevents
      activation of the other JAK and extinguishes STAT activation. These observations
      suggest that JAKs provide interferon receptors with a critical catalytic
      signaling function and that at least two JAKs must be incorporated into an active
      receptor complex. JAK and STAT proteins are also activated by ligands such as
      platelet-derived growth factor (PDGF), which act through receptors that possess
      intrinsic protein tyrosine kinase activity, raising questions about the role of
      JAKs in signal transduction by this class of receptors. Here, we show that all
      three of the ubiquitously expressed JAKs--JAK1, JAK2, and Tyk2--become
      phosphorylated on tyrosine in both mouse BALB/c 3T3 cells and human fibroblasts
      engineered to express the PDGF-beta receptor. All three proteins are also
      associated with the activated receptor. Through the use of cell lines each
      lacking an individual JAK, we find that in contrast to interferon signaling, PDGF
      induced JAK phosphorylation and activation of STAT1 and STAT3 is independent of
      the presence of any other single JAK but does require receptor tyrosine kinase
      activity. These results suggests that the mechanism of JAK activation and JAK
      function in signaling differs between receptor tyrosine kinases and interferon
      receptors.

PMID- 8657153
TI  - Transcriptional activation of RNA polymerase III-dependent genes by the human T
      cell leukemia virus type 1 tax protein.
AB  - The human T-cell leukemia virus-encoded tax protein is a potent activator of many
      viral and cellular genes transcribed by RNA polymerase II. We find that both
      chromatin and cell extracts derived from human T-cell leukemia virus type 1
      infected human T lymphocytes support higher levels of 5S rRNA and tRNA gene
      transcription than chromatin or extracts from uninfected T lymphocytes. The viral
      protein Tax was likely responsible for this higher level of class II gene
      transcription, as purified Tax was found to stimulate both genes when added to
      the uninfected cell extract or in reconstituted systems. Both limiting-component
      transcription assays and DNA binding assays identified the class III gene
      transcription factor TFIIIB as the principle target of Tax activity.
      Surprisingly, we find that Tax increases the effective concentration of active
      TFIIIB molecules. These data suggest that Tax stimulates RNA polymerase III
      dependent gene expression by accelerating the rate and/or extent of transcription
      initiation complex assembly.

PMID- 8657154
TI  - Analysis of wild-type and mutant p21WAF-1 gene activities.
AB  - The p21WAF-1 gene is positively regulated by the wild-type p53 protein. p21WAF-1
      has been shown to interact with several cyclin-dependent kinase complexes and
      block the activity of G1 cyclin-dependent kinases (cdks). Mutational analysis
      with the p21WAF-1 gene localized a site, at amino acid residues 21 and 24 in the
      amino terminus of the protein, for p21WAF-1 binding to cyclins D and E. This
      region of the protein is conserved (residues 21 to 26) in other p21WAF-1 family
      members, p27kip-1 and p57kip-2. The same p21WAF-121,24 mutant also fails to bind
      to cyclin D1-cdk 4 or cyclin E-cdk 2 complexes in vitro, suggesting that amino
      acid residues 21 and 24 are important for p21WAF-1-cdk-cyclin trimeric complex
      interactions. The p21WAF-1 wild-type protein will suppress tumor cell growth in
      culture while p21WAF-1 mutant proteins with defects in residues 21 and 24 fail to
      suppress tumor cell growth. The overexpression of cyclin D or E in these cells
      will partially overcome the growth suppression of wild-type p21WAF-1 protein in
      cells. These results provide evidence that p21WAF-1 acts through cyclin D1-cdk4
      and cyclin E-cdk2 complexes in vivo to induce the growth suppression. The p21WAF
      1 binding sites for cyclins (residues 21 to 26), cdk2 (residues 49 to 71), and
      proliferating-cell nuclear antigen (residues 124 to 164) have all been mapped to
      discrete sites on the protein.

PMID- 8657156
TI  - Topoisomerase I involvement in illegitimate recombination in Saccharomyces
      cerevisiae.
AB  - Chromosome aberrations may cause cancer and many heritable diseases.
      Topoisomerase I has been suspected of causing chromosome aberrations by mediating
      illegitimate recombination. The effects of deletion and of overexpression of the
      topoisomerase I gene on illegitimate recombination in the yeast Saccharomyces
      cerevisiae have been studied. Yeast transformations were carried out with DNA
      fragments that did not have any homology to the genomic DNA. The frequency of
      illegitimate integration was 6- to 12-fold increased in a strain overexpressing
      topoisomerase I compared with that in isogenic control strains. Hot spot
      sequences [(G/C)(A/T)T] for illegitimate integration target sites accounted for
      the majority of the additional events after overexpression of topoisomerase I.
      These hot spot sequences correspond to sequences previously identified in vitro
      as topoisomerase I preferred cleavage sequences in other organisms. Furthermore,
      such hot spot sequences were found in 44% of the integration events present in
      the TOP1 wild-type strain and at a significantly lower frequency in the top1delta
      strain. Our results provide in vivo evidence that a general eukaryotic
      topoisomerase I enzyme nicks DNA and ligates nonhomologous ends, leading to
      illegitimate recombination.

PMID- 8657155
TI  - Expression and activity of L-Myc in normal mouse development.
AB  - To determine the role of L-Myc in normal mammalian development and its functional
      relationship to other members of the Myc family, we determined the normal
      patterns of L-myc gene expression in the developing mouse by RNA in situ
      hybridization and assessed the phenotypic impact of L-Myc deficiency produced
      through standard gene targeting methodology. L-myc transcripts were detected in
      the developing kidney and lung as well as in both the proliferative and the
      differentiative zones of the brain and neural tube. Despite significant
      expression of L-myc in developing mouse tissue, homozygous null L-myc mice were
      found to be viable, reproductively competent, and represented in expected
      frequencies from heterozygous matings. A detailed histological survey of
      embryonic and adult tissues, characterization of an embryonic neuronal marker,
      and measurement of cellular proliferation in situ did not reveal any congenital
      abnormalities. The lack of an apparent phenotype associated with L-Myc deficiency
      indicates that L-Myc is dispensable for gross morphological development and
      argues against a unique role for L-Myc in early central nervous system
      development as had been previously suggested. Although overlapping expression
      patterns among myc family members raise the possibility of complementation of L
      Myc deficiency by other Myc oncoproteins, compensatory changes in the levels of c
      and/or N-myc transcripts were not detected in homozygous null L-myc mice.

PMID- 8657157
TI  - Distinct variant DNA-binding sites determine cell-specific autoregulated
      expression of the Drosophila POU domain transcription factor drifter in midline
      glia or trachea.
AB  - Transcriptional regulators utilizing the POU domain DNA-binding motif have been
      shown to form multi-protein complexes dependent on the POU domain itself and its
      flexible recognition of various octamer sequence elements. We have identified two
      variant POU domain recognition elements DFRE1 and DFRE2, which are found within a
      514-bp autoregulatory enhancer of the Drosophila melanogaster POU domain gene
      drifter (dfr). Both elements are capable of binding bacterially produced full
      length DFR protein with high affinity, although they differ in the 5'-to-3'
      orientation of POU-specific and POU homeodomain subelements. When placed in dfr
      loss-of-function genetic backgrounds, all expression of dfr-lacZ fusion genes
      under control of the autoregulatory enhancer is dependent on DFR activity levels.
      However, the complete enhancer sequence directs beta-galactosidase expression in
      only a subset of cells which normally express the endogenous DFR protein,
      including the middle pair of midline glias of the ventral nerve cord, the
      oenocyte clusters, and all tracheal cells. In addition, DFRE1 and DFRE2 exhibit
      separable tissue-specific functions when independently disrupted or deleted.
      Disruption of DFRE1 function specifically abolishes beta-galactosidase expression
      in the middle pair of midline glias. Deletion of DFRE causes a specific loss of
      tracheal expression, leaving oenocyte and midline glia expression intact. These
      results suggest that dfr cell-specific autoregulation is determined by the
      context of DFR POU domain binding within the enhancer, which is possibly mediated
      by the formation of recognition element-specific heteromultimeric complexes
      containing additional tissue-specific factors.

PMID- 8657158
TI  - TFIIB-directed transcriptional activation by the orphan nuclear receptor
      hepatocyte nuclear factor 4.
AB  - The orphan nuclear receptor hepatocyte nuclear factor 4 (HNF-4) is required for
      development and maintenance of the liver phenotype. HNF-4 activates several
      hepatocyte-specific genes, including the gene encoding apolipoprotein AI (apoAI),
      the major protein component of plasma high-density lipoprotein. The apoAI gene is
      activated by HNF-4 through a nuclear receptor binding element (site A) located in
      its liver-specific enhancer. To decipher the mechanism whereby HNF-4 enhances
      apoAI gene transcription, we have reconstituted its activity in a cell-free
      system. Functional HNF-4 was purified to homogeneity from a bacterial expression
      system. In in vitro transcription assays employing nuclear extract from HeLa
      cells, which do not contain HNF-4, recombinant HNF-4 stimulated transcription
      from basal promoters linked to site A. Activation by HNF-4 did not exhibit a
      ligand requirement, but phosphorylation of HNF-4 in the in vitro transcription
      system was observed. The activation function of HNF-4 was localized to a domain
      displaying strong homology to the conserved AF-2 region of nuclear receptors.
      Dissection of the transcription cycle revealed that HNF-4 activated transcription
      by facilitating assembly of a preinitiation complex intermediate consisting of
      TBP, the TATA box-binding protein component of TFIID and TFIID, via direct
      physical interactions with TFIIB. However, recruitment of TFIIB by HNF-4 was not
      sufficient for activation, since HNF-4 deletion derivatives lacking AF-2 bound
      TFIIB. On the basis of these results, HNF-4 appears to activate transcription at
      two distinct levels. The first step involves AF-2-independent recruitment of
      TFIIB to the promoter complex; the second step is AF-2 dependent and entails
      entry of preinitiation complex components acting downstream of TFIIB.

PMID- 8657159
TI  - Characterization of an essential Orc2p-associated factor that plays a role in DNA
      replication.
AB  - The Saccharomyces cerevisiae Orc2 protein is a subunit of the origin recognition
      complex, ORC, which binds in a sequence-specific manner to yeast origins of DNA
      replication. With screens for orc2-1 synthetic lethal mutations and Orc2p two
      hybrid interactors, a novel Orc2p-associated factor (Oaf1p) was identified. OAF1
      is essential, its gene product is localized to the nucleus, and an oaf1
      temperature-sensitive mutant arrests as large budded cells with a single nucleus.
      The mutant oaf1-2, isolated in the synthetic lethal screen, loses plasmids
      containing a single origin of DNA replication at a high rate, but it maintains
      plasmids carrying multiple potential origins of DNA replication. In addition, the
      OAF1 gene product tagged with the hemagglutinin antigen epitope binds to a DNA
      affinity column containing covalently linked tandem repeats of an essential
      origin element. These results suggest a role for OAFI in the initiation of DNA
      replication. Mutant alleles of cdc7 and cdc14 were also isolated in the orc2-1
      synthetic lethal screen. Cdc7p, like Oaf1p, also interacts with Orc2p in two
      hybrid assays.

PMID- 8657161
TI  - Recycling selectable markers in mouse embryonic stem cells.
AB  - As a result of gene targeting, selectable markers are usually permanently
      introduced into the mammalian genome. Multiple gene targeting events in the same
      cell line can therefore exhaust the pool of markers available and limit
      subsequent manipulations or genetic analysis. In this study, we describe the
      combined use of homologous and CRE-loxP-mediated recombination to generate mouse
      embryonic stem cell lines carrying up to four targeted mutations and devoid of
      exogenous selectable markers. A cassette that contains both positive and negative
      selectable markers flanked by loxP sites, rendering it excisable by the CRE
      protein, was constructed. Homologous recombination and positive selection were
      used to disrupt the Rep-3 locus, a gene homologous to members of the mutS family
      of DNA mismatch repair genes. CRE-loxP-mediated recombination and negative
      selection were then used to recover clones in which the cassette had been
      excised. The remaining allele of Rep-3 was then subjected to a second round of
      targeting and excision with the same construct to generate homozygous, marker
      free cell lines. Subsequently, both alleles of mMsh2, another mutS homolog, were
      disrupted in the same fashion to obtain cell lines homozygous for targeted
      mutations at both the Rep-3 and mMsh2 loci and devoid of selectable markers.
      Thus, embryonic stem cell lines obtained in this fashion are suitable for further
      manipulation and analysis involving the use of selectable markers.

PMID- 8657160
TI  - Protein kinase C-theta isoenzyme selective stimulation of the transcription
      factor complex AP-1 in T lymphocytes.
AB  - T-lymphocyte stimulation requires activation of several protein kinases,
      including the major phorbol ester receptor protein kinase C (PKC), ultimately
      leading to induction of lymphokines, such as interleukin-2 (IL-2). The revelant
      PKC isoforms which are involved in the activation cascades of nuclear
      transcription factors involved in IL-2 production have not yet been clearly
      defined. We have examined the potential role of two representative PKC isoforms
      in the induction of the IL-2 gene, i.e., PKC-alpha and PKC-theta, the latter
      being expressed predominantly in hematopoietic cell lines, particularly T cells.
      Similar to that of PKC-alpha, PKC-theta overexpression in murine EL4 thymoma
      cells caused a significant increase in phorbol 12-myristate 13-acetate (PMA)
      induced transcriptional activation of full-length IL-2-chloramphenicol
      acetyltransferase (CAT) and NF-AT-CAT but not of NF-IL2A-CAT or NF-kappaB
      promoter-CAT reporter gene constructs. Importantly, the critical AP-1 enhancer
      element was differentially modulated by these two distinct PKC isoenzymes, since
      only PKC-theta but not PKC-alpha overexpression resulted in an approximately 2.8
      fold increase in AP-1-collagenase promoter CAT expression in comparison with the
      vector control. Deletion of the AP-1 enhancer site in the collagenase promoter
      rendered it unresponsive to PKC-theta. Expression of a constitutively active
      mutant PKC-theta A148E (but not PKC-alpha A25E) was sufficient to induce
      activation of AP-1 transcription factor complex in the absence of PMA
      stimulation. Conversely, a catalytically inactive PKC-theta K409R (but not PKC
      alpha K368R) mutant abrogated endogenous PMA-mediated activation of AP-1
      transcriptional complex. Dominant negative mutant Ha-RasS17N completely inhibited
      the PKC-O A148E-induced signal, PKC-O. Expression of a constitutively active
      mutant PKC-O A148E (but not PKC-alpha A25E) was sufficient to induce activation
      of AP-1 transcription factor complex in the absence of PMA stimulation.
      Conversely, a catalytically inactive PKC-O K409R (but not PKC-alpha K368R) mutant
      abrogated endogenous PMA-mediated activation of AP-1 transcriptional complex.
      Dominant negative mutant Ha-enRasS17N completely inhibited in the PKC-O A148E
      induced signal, identifying PKC-theta as a specific constituent upstream of or
      parallel to Ras in the signaling cascade leading to AP transcriptional
      activation.

PMID- 8657164
TI  - Introduction: reconceptualizing the nature of children's conceptual structures
      and their development in middle childhood.

PMID- 8657165
TI  - Central spatial structures and their development.

PMID- 8657162
TI  - Genetic analysis of the bipolar pattern of bud site selection in the yeast
      Saccharomyces cerevisiae.
AB  - Previous analysis of the bipolar budding pattern of Saccharomyces cerevisiae has
      suggested that it depends on persistent positional signals that mark the region
      of the division site and the tip of the distal pole on a newborn daughter cell,
      as well as each previous division site on a mother cell. In an attempt to
      identify genes encoding components of these signals or proteins involved in
      positioning or responding to them, we identified 11 mutants with defects in
      bipolar but not in axial budding. Five mutants displaying a bipolar budding
      specific randomization of budding pattern had mutations in four previously known
      genes (BUD2, BUD5, SPA2, and BNI1) and one novel gene (BUD6), respectively. As
      Bud2p and Bud5p are known to be required for both the axial and bipolar budding
      patterns, the alleles identified here probably encode proteins that have lost
      their ability to interact with the bipolar positional signals but have retained
      their ability to interact with the distinct positional signal used in axial
      budding. The function of Spa2p is not known, but previous work has shown that its
      intracellular localization is similar to that postulated for the bipolar
      positional signals. BNI1 was originally identified on the basis of genetic
      interaction with CDC12, which encodes one of the neck-filament-associated septin
      proteins, suggesting that these proteins may be involved in positioning the
      bipolar signals. One mutant with a heterogeneous budding pattern defines a second
      novel gene (BUD7). Two mutants budding almost exclusively from the proximal pole
      carry mutations in a fourth novel gene (BUD9). A bud8 bud9 double mutant also
      buds almost exclusively from the proximal pole, suggesting that Bud9p is involved
      in positioning the proximal pole signal rather than being itself a component of
      this signal.

PMID- 8657166
TI  - Cross-cultural investigations.
AB  - In Piaget's system, the development of children's cognitive structures is seen as
      progressing through a universal sequence from sensorimotor, to concrete, to
      formal logical thought. The data that have been obtained on his measures are
      problematic in their support for this view, however, because they indicate that
      adults in traditional societies often fail his formal tasks. Piaget's (1972)
      interpretation of such findings was that they indicated a problem with his
      measures, not his theory - if appropriate measures were available, he believed
      that formal logical operations would be found in all cultures and social groups.
      Our own interpretation differs. While we acknowledge that adults in all cultures
      are capable of thinking in a fashion that is more sophisticated, subtle, and
      complex than that of young children, we see the highest forms of thought as being
      dependent on the mastery of systems that are cultural creations and not universal
      human attainments - and we see Piaget's system of formal operations as being just
      one example of the sort of system that can be created by a culture and passed on
      from one generation to the next. In a previous investigation, Fiati (1992)
      studied children who were growing up in isolated, agricultural villages in the
      Volta region of West Africa. In these communities, life was still a traditional
      one, and children's experiences with time, money, and mathematical computation
      were considerably different from those of children who were attending schools in
      the nearby towns. Under these conditions, Fiati found that village children's
      skill in using numbers or in thinking about quantitative variables did not
      develop to a very high level as compared to that of their peers in the towns or
      as compared to their own thinking about social issues. In the terms used in the
      present Monograph, it appeared as though children's central conceptual structures
      for number - in contrast to their central conceptual structures for narrative -
      did not advance much past the unidimensional level. Are unidimensional
      structures, at least, universal? Very probably the answer to this question is
      yes. Although systems for counting, for example, vary widely, no culture has yet
      been found in which counting does not play some role or where young children fail
      to pass Piaget's conservation of number test (Saxe, 1988). It seems highly
      likely, therefore, that a mental counting line of some sort is a universal
      construction. The situation in the domain of narrative is quite similar. Although
      folktales vary widely from one culture to the next, no culture has been reported
      in which folktales play no role whatever or where the story line of existing
      folktales does not have some form of intentional component (Propp, 1922/1968).
      The mental story line may thus be a universal construction as well. Finally, no
      culture has been reported in which some form of decorative art is not present or
      in which no technology exists for launching a projectile along a desired
      trajectory. If these activities require a mental reference line of some sort,
      then this would be a candidate for universal conceptual attainment as well. In
      the present series of studies, our investigations were confined to societies that
      are modern, highly literate, and schooled. Thus, our interest was in
      demonstrating a universal progression well beyond the unidimensional level, in
      the sorts of structure that are crucial to life in a modern industrial culture.
      In fact, this was what we found in each of our studies. On our tests of central
      conceptual structures, children progressed through the same stages and at the
      same rate. By contrast, on our tests of more specific understanding, especially
      on those dealing with issues on which different cultures place different
      emphasis, we found large and significant cross-national differences. From this we
      conclude that, if a culture values a particular task or set of tasks and invests
      a great deal of effort in teaching them, it is likely that the

PMID- 8657167
TI  - Modeling the dynamic interplay between general and specific change in children's
      conceptual understanding.
AB  - In introducing this chapter, I pointed out that traditional theories of learning
      and of cognitive development were in conflict with regard to the effects of
      specific learning. Developmental theorists saw general structures as influencing
      specific learning but not being affected by it, whereas learning theorists took
      the opposite view - that general structures (if they existed) were affected only
      by specific experiences. In the formulation of neo-Piagetian theory, both general
      and specific effects were acknowledged; however, general effects were assigned to
      mental capacity and specific ones to the child's schematic repertoire. Thus, the
      possibility of reciprocal influence did not emerge (or at least was not
      explored). In the present chapter, I have proposed the existence of such a
      reciprocal influence and explored its consequences. At a general level, the two
      consequences that follow are (1) that the overall pace of development is
      accelerated and (2) that the profile of development is evened out because
      benefits obtained from high-frequency learning experiences are passed on, via the
      mediation of the central conceptual structure, to low-frequency ones. These two
      effects were then advanced as one possible explanation for the difference in the
      data obtained between different cultures and different social classes. In the
      former case, the explanation utilized the notion that the benefits of high
      frequency learning could be passed on to low-frequency situations via the
      mediation of general structures; in the latter case, the explanation drew on the
      notion that experiential loops can accelerate or decelerate development by
      magnifying experiential differences that are relatively small but that prevail
      across most of the tasks that a child encounters. The last half of the present
      chapter was devoted to specifying the dynamics of this sort of interaction in
      mathematical terms. The data that were obtained in Chapters III and V were
      extremely regular and showed an even pattern of development across different
      tasks; hence, they could conceivably be modeled with single curves or even
      straight lines. The mathematical model chosen to fit these findings was much more
      complex, however. Each growth curve was generated by an expression that contained
      a dynamic tension between two opposing categories of effect: those whose tendency
      is to make different developmental pathways disperse (different growth rates and
      the effect of compounding) and those whose tendency is to hold development to a
      single course (the constraints imposed by a growing carrying capacity and the
      "binding together" or "squeezing" effect generated by the reciprocal feedback
      loop). The disadvantage of this sort of modeling is clearly its complexity. An
      equally clear advantage, however, is that it allows one to provide a unified
      explanation for a set of data that might otherwise seem quite disparate and to
      express relations in quantitative rather than merely qualitative terms. This, in
      turn, permits one to check the entire set of proposed relations for their
      consistency, and to explore the dynamic pattern of their interaction, by
      conducting "intellectual experiments" and checking them against common sense
      and/or existing data sets. In the present chapter, this approach has been used
      for the effects of social class and of culture. In principle, however, it could
      potentially be used equally to explore the effects of other variables, such as
      those that underlie intellectual retardation and/or "giftedness". At least for
      the moment, then, the mathematical modeling approach looks promising.

PMID- 8657163
TI  - A single telomerase RNA is sufficient for the synthesis of variable telomeric DNA
      repeats in ciliates of the genus Paramecium.
AB  - Paramecium telomeric DNA consists largely of a random distribution of TTGGGG and
      TTTGGG repeats. Given the precise nature of other ciliate telomerases, it has
      been postulated that there are two distinct types of the Paramecium enzyme, each
      synthesizing perfect telomeric repeats: one with a template RNA that specifies
      the addition of TTTGGG and the second dictating the synthesis of TTGGGG repeats.
      We have cloned and sequenced telomerase RNA genes from Paramecium tetraurelia, P.
      primaurelia, P. multimicronucleatum, and P. caudatum. Surprisingly, a single gene
      encodes telomerase RNA in all four species, although an apparently nontranscribed
      pseudogene is also present in the genome of P. primaurelia. The overall lengths
      of the telomerase RNAs range between 202 and 209 nucleotides, and they can be
      folded into a conserved secondary structure similar to that derived for other
      ciliate RNAs. All Paramecium telomerase RNAs examined include a template specific
      for the synthesis of TTGGGG telomeric repeats, which has not been
      posttranscriptionally edited to account for the conventional synthesis of TTTGGG
      repeats. On the basis of these results, possible mechanisms for the synthesis of
      variable telomeric repeats by Paramecium telomerase are discussed.

PMID- 8657168
TI  - Exploring the microstructure of children's central conceptual structures in the
      domain of number.

PMID- 8657169
TI  - Exploring the macrostructure of children's central conceptual structures in the
      domains of number and narrative.

PMID- 8657170
TI  - Evaluating the breadth and depth of training effects when central conceptual
      structures are taught.

PMID- 8657171
TI  - The 4th International Conference on Mechanisms of Antimutagenesis and
      Anticarcinogenesis. Banff, Canada, 4-9 September 1994.

PMID- 8657172
TI  - Antioxidant defences against reactive oxygen species causing genetic and other
      damage.

PMID- 8657173
TI  - Activity profiles of antimutagens: in vitro and in vivo data.
AB  - In this review, retinol, chlorophyllin, and N-acetylcysteine are examined and
      compared with regard to their antimutagenic activity against some promutagens and
      a group of direct-acting alkylating agents. The promutagens included aflatoxin
      B1, certain polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), and certain
      heterocyclic amines (e.g., food pyrolysates). Results of antimutagenicity testing
      selected from data surveyed in the published literature are displayed graphically
      as activity profiles of antimutagens showing both the doses tested and the extent
      of inhibition or enhancement of mutagenic activity. All three antimutagens are
      discussed in terms of their putative mechanisms of action in vitro and in vivo
      with emphasis on the xenobiotic metabolizing enzyme systems.

PMID- 8657174
TI  - Analysis of National Toxicology Program rodent bioassay data for anticarcinogenic
      effects.
AB  - We reanalyzed data from 218 two-year rodent carcinogenicity studies carried out
      by the National Toxicology Program (NTP). These data were originally collected
      for the purpose of identifying potential human carcinogens. However, the
      objective of our analysis was to investigate the frequency of possible
      anticarcinogenic effects in these data, since recurring cases of chemical
      associated tumor reductions have been noted in the course of these studies over
      time. Our analysis reveals that most (>90%) NTP-tested chemicals show at least
      one statistically significant (p<0.05) decrease in site-specific tumor incidence.
      Because of the large number of statistical comparisons made in a long-term
      bioassay, random variability can account for many of these tumor decreases.
      However, we found that certain tumors (predominantly those with a high
      spontaneous incidence) show chemically related decreases far more frequently than
      chance expectation. Many of these decreases, particularly those for pituitary and
      mammary gland tumors, adrenal pheochromocytoma and uterine polyps in rats and
      liver and lung tumors in mice, are associated with the reduced body weights
      frequently observed in the dosed groups. The chemically related decreased
      incidences of leukemia in rats appear to be related to spleen damage, i.e.,
      chemically related splenic toxicity is evident for most chemicals showing
      decreased incidences of leukemia. While random variability, associations with
      body weight and splenic toxicity can account for most of the decreased tumor
      incidences observed in NTP studies, there are other tumor decreases that could
      not be totally explained by these factors. Further investigations of possible
      mechanisms of action are underway. These data are relevant to the concept of
      chemoprevention as well as to the task of using long-term laboratory animal
      studies to predict enhanced human environmental-cancer risk for regulatory
      purposes.

PMID- 8657175
TI  - Natural antimutagenic agents.
AB  - Following a brief review of recent discoveries in the field of natural
      antimutagenic and tumor chemopreventive agents, contemporary findings in the
      author's laboratories employing the direct acting mutagen, ethyl
      methanesulfonate, in modified Ames tests and eukaryotic murine FM3A mammary tumor
      cells modified to be subject to thymidine-less death are described to illustrate
      the underlying principles. The EMS studies are illustrated with the isolation of
      the novel antimutagen, plicatin B, from the medicinal plants, Psoralea juncaea
      and P. plicata. The FM3A studies are carried out with extracts of Styrax
      asiatica, a plant previously studied extensively with the EMS system. The FM3A
      findings closely parallel the earlier work with EMS showing that the responsible
      agents, cinnamic acid, cinnamoyl ricinoleate and cinnamoyl cinnamate are
      effective both in prokaryotic and eukaryotic tests and that the new FM3A assay
      system has useful properties for screening and assay of novel antimutagenic
      agents.

PMID- 8657176
TI  - Radioprotective effects of antioxidative plant flavonoids in mice.
AB  - Radioprotective effects of tea infusions and plant flavonoids were investigated
      by using the micronucleus test for anticlastogenic activity and the
      thiobarbituric acid assay for antioxidative activity. A single gastric intubation
      of rooibos tea (Aspalathus linearis) infusion at 1 ml per mouse 2 h prior to gama
      ray irradiation (1.5 Gy) reduced the frequency of micronucleated reticulocytes
      (MNRETs). After the fractionation of rooibos tea infusion, the flavonoid fraction
      was found to be most anticlastogenic and antioxidative. From this fraction,
      luteolin was isolated as an effective component. Then, anticlastogenic effects of
      12 flavonoids containing luteolin and their antioxidative activities against
      lipid peroxidation by Fenton's reagent were examined. A good correlation
      (r=0.717) was observed between both activities. Luteolin showed the most
      effective potency. A gastric intubation of luteolin (10 micromoles/kg) 2 h prior
      to gamma-ray irradiation (6 Gy) suppressed lipid peroxidation in mouse bone
      marrow and spleen and a trend of protective effect of luteolin against the
      decrease of endogenous ascorbic acid in mouse bone marrow after gamma-ray
      irradiation (3 Gy) was observed. These results suggest that plant flavonoids,
      which show antioxidative potency in vitro, work as antioxidants in vivo and their
      radioprotective effects may be attributed to their scavenging potency towards
      free radicals such as hydroxyl radicals. Therefore, the flavonoids contained in
      tea, vegetables and fruits seem to be important as antioxidants in the human
      diet.

PMID- 8657177
TI  - Plant activation and its role in environmental mutagenesis and antimutagenesis.
AB  - This paper reviews the use of in vitro and in vivo antimutagenicity studies that
      determined the role of plant peroxidases in the activation of arylamine
      promutagens. New information presented here suggests a model in which tobacco
      cell peroxidases exuded into the culture medium undergo a maturation process
      affecting their capacity to activate arylamine promutagens. Tobacco cell
      peroxidases are present in medium recovered from stationary phase cells and are
      associated with a fraction that sediments at 12000 x g. These peroxidases have a
      greater capacity to activate arylamines than do peroxidases present in the
      supernatant fluid. These data suggest that the plant activation of arylamines
      into products that are mutagenic in Salmonella typhimurium may be intimately
      involved in the process of lignification.

PMID- 8657178
TI  - Suppressors of Escherichia coli mutT: antimutators for DNA replication errors.
AB  - Previous studies in our laboratory used a papillation assay to identify a set of
      mutations in the E. coli dnaE gene that confer increased accuracy of DNA
      replication (antimutators). These antimutators were isolated as suppressors of
      the hugh mutability of a mismatch-repair-defective mutL strain, in which the
      majority of mutations represent uncorrected replication errors (mainly A.T -->
      G.C and G.C --> A.T transitions). In the present study, we have sought
      suppressors of the high mutability of a mutT mutator strain. mutT strains produce
      a high frequency of A.T --> C.G transversions due to their lack of the mutT
      encoded 8-oxo-dGTPase, leading to a high frequency of A.(8-oxoG) mispairing
      errors. Following localized mutagenesis of the dnaE-dnaQ region of the
      chromosome, two strong suppressors of mutT mutability were obtained, both
      residing in the dnaE gene (dnaE940 and dnaE941). When subsequently tested in a
      mutL strain, these two alleles also proved antimutators in this background,
      dnaE941 being significantly stronger than the previously isolated antimutators.
      The results suggest that the DNA polymerase may use similar mechanisms to
      discriminate against A.(8-oxoG) transversion mispairs and A.C or T.G transition
      mispairs. The finding may also have significance for teh interpretation of the
      antimutator effect conferred by these dnaE alleles in a wild-type (mut+)
      background.

PMID- 8657179
TI  - Studies on the role of specific dietary fibres in protection against colorectal
      cancer.
AB  - Although dietary fibre is generally thought to protect against the development of
      colorectal cancer, some of the results of animal and epidemiological studies are
      equivocal. We believe that this may be because the term dietary fibre covers a
      range of complex materials and some may protect but others may not. Dietary fibre
      is mainly composed of plant cell walls which vary in composition and properties
      according cell type and plant species. In addition to polysaccharides, the walls
      of some plant cell types contain the hydrophobic polymers lignin or suberin. Two
      groups of mechanisms have been proposed for the way dietary fibres may protect
      against colorectal cancer: those in which the dietary fibre may act directly and
      those in which the dietary fibre may have an indirect effect as a consequence of
      it being degraded by colonic bacterial enzymes and the products fermented. Direct
      mechanisms include the adsorption of carcinogens onto undegraded dietary fibres
      which pass out of the intestinal tract in the faeces. we have shown that
      different types of plant cell walls adsorbed a range of carcinogens, including
      heterocyclic aromatic amines, to different extents. Cell walls that contained
      lignin or suberin adsorbed hydrophobic carcinogens particularly well.
      Furthermore, the presence of lignin, and probably suberin, in the walls makes
      them resistant to degradation in the colon. Wheat bran, which is a good source of
      dietary fibre, contains some cell types with lignified walls. We used Fischer-344
      rats to test the ability of wheat bran to protect against the formation of
      aberrant crypts (which are considered to be precursors to colon cancer) caused by
      the heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).
      Our results indicate that wheat bran protects and probably does so by a direct
      mechanism.

PMID- 8657180
TI  - Dietary fiber and the chemopreventive modelation of colon carcinogenesis.
AB  - Comparative international epidemiological data indicate that the difference
      between the highest and lowest colon cancer incidence is approximately 10-fold.
      This suggests that the dominant causes of colon cancer are environmental rather
      than genetic in origin, with the dominant environmental cause being the typical
      diet of Western industrialized countries. Many epidemiological and experimental
      studies have suggested an important role for dietary fiber in the prevention of
      colon cancer. Using the Fischer-344 rat as the experimental model, data clearly
      demonstrate a strong protective effect of a diet that is low in fat, high in
      fiber and high in calcium (low-risk diet). Such a diet prevents the development
      of both preneoplastic aberrant crypt foci (ACF) and colon tumors. Recent
      experiments have also demonstrated a direct relationship between a ras point
      mutation in ACF at different stages of rat colon carcinogenesis, and a ras point
      mutation that is subsequently present in colon tumors. Using wheat bran as the
      model dietary fiber source, its effects were compared to the effects of psyllium,
      phytic acid, vitamin E, beta-carotene, folic acid, alone or in combination, for
      their ability to prevent colon cancer in rats on high-risk Western-style diets.
      Our studies clearly demonstrated the ability of wheat bran to reduce ACF and
      colon tumors in rats that consumed high-fat, Western-style diets. Although phytic
      acid, which is a constituent of wheat bran, alone demonstrated strong cancer
      preventive potential, our experiments provided evidence for the cancer-preventive
      effect of the crude fiber fraction that is independent of the effect of phytic
      acid. The synergistic combination of wheat bran with the soluble fiber psyllium
      led to enhanced protection; while the combination of wheat bran with beta
      carotene showed only an additive effect. Beta-carotene appeared to show higher
      protection than wheat bran at an intake level that is nutritionally relevant to
      humans, suggesting the possibility of using beta-carotene to enhance the effects
      of dietary fiber in high-risk Western populations. Using ACF as an intermediate
      endpoint, it was also shown that vitamin E and beta-carotene appear to inhibit
      progression of ACF to colon cancer, while wheat bran and folic acid appeared to
      have weak cancer-preventive potential at this late stage of carcinogenesis. In
      conclusion, wheat bran alone, or in combination with psyllium, appears to have
      greater potential to inhibit earlier phases of carcinogenesis, while beta
      carotene and vitamin E may also inhibit later stages of carcinogenesis. Despite
      considerable epidemiological and experimental evidence that increasing the fiber
      and lowering the fat content of the Western diet could substantially reduce the
      risk of cancer and heart disease, the real challenge is to find effective ways to
      educate and motivate people to overcome their intrinsic cultural resistance to
      such changes in their eating habits.

PMID- 8657181
TI  - Antimutagenicity of yogurt.
AB  - Yogurt is milk fermented by a mixture of two bacteria: Lactobacillus delbrueckii
      ssp. bulgaricus and Streptococcus salivarius ssp. thermophilus. Epidemiological
      studies have correlated a reduced risk of colon cancer with yogurt consumption.
      Independent studies have established that yogurt and extracts thereof are
      antimutagenic. Although multiple explanations can account for yogurt's putative
      anticarcinogenicity, we are interested in testing the hypothesis that
      antimutagenic compounds produced during fermentation are responsible. We recently
      reported on the antimutagenicity of an acetone extract of yogurt against the
      experimental carcinogens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and
      3.2'dimethyl-4-aminobiphenyl (DMAB) (Mutation Res. (1995) 334, 213-224). We are
      now aware that palmitic acid is an active ingredient against MNNG.

PMID- 8657182
TI  - Microsatellite instability and mismatch repair defects in cancer.

PMID- 8657183
TI  - Fine structure mapping of DNA repair within a 100 kb genomic region in Chinese
      hamster ovary cells.
AB  - We have investigated at a high level of resolution the repair of cyclobutane
      pyrimidine dimers (CPD) in a large amplified genomic region in Chinese hamster
      ovary B11 cells. We found strand selective repair in DNA fragments within two
      active genes, DHFR and an unknown gene adjacent to DHFR. These genes generate
      divergent transcripts from the same promoter region; their transcribed strands
      were virtually free of CPD within 24 h after irradiation with 10 j/m2 of
      ultraviolet light (254nm), while their non-transcribed strands were poorly
      repaired. We also examined the repair of CPD in three DNA fragments within a 50
      kb region downstream of DHFR, in which two origins of replication flanking a
      matrix attachment site have been characterized from independently derived cell
      lines with amplified DHFR domains; repair of CPD in this non-transcribed region
      was similarly poor in both DNA strands. Transcription-coupled repair of CPD in
      the DHFR gene exhibited the same proficiency throughout the transcription unit:
      analysis of the efficiency of removal of CPD over time revealed no differences
      between repair in the 5' and the 3' ends of the DHFR gene. Implications for
      mechanisms of transcription-coupled repair are discussed.

PMID- 8657184
TI  - Analysis of the mammalian recombination protein complex RC-1.
AB  - Based on a novel cell-free assay for DNA recombination, we previously reported
      the purification and initial characterization of RC-1, a protein complex
      catalyzing the recombinational repair of deletions and gaps. RC-1 was isolated
      from calf thymus nuclear extracts and shown to copurify with several enzymatic
      activities, among them a DNA polymerase. Here, additional evidence is reported
      identifying the polymerase as DNA polymerase epsilon. Furthermore, a novel DNA
      structure-dependent endonuclease associated with RC-1 was observed, which
      recognizes and cleaves branched DNA substrates at specific sites. Implications of
      this endonuclease activity for the recombination reaction are discussed.

PMID- 8657185
TI  - Purine deoxynucleoside metabolism in human melanoma cells with a high spontaneous
      mutation rate.
AB  - A human melanoma cell line (MM96L) had a spontaneous mutation rate at the HGPRT
      locus of approx. 7 times normal. The cells had elevated dATP and dGTP pools,
      lacked purine nucleoside phosphorylase (PNP) and were sensitive to killing by
      deoxyadenosine, deoxyinosine and related purines but not to inosine or
      hypoxanthine. Four other melanoma cell lines exhibited a range of nucleoside
      sensitivities and dNTP pool sizes. Failure of intact MM96L cells to degrade
      exogenous deoxyadenosine and deoxyinosine to hypoxanthine was confirmed by NMR of
      culture medium. Normal melanocytes were PNP+ and were insensitive to
      deoxyinosine. Comparison of the metabolites of [14C]deoxyinosine from MM96L and a
      PNP+ cell line of similar doubling time (HeLa) showed that both cell types
      produced 14C-labelled guanine and adenine nucleotides, with [14C]dATP and
      [14C]dADP being found in MM96L. This indicates that human sAMP synthetase or a
      similar enzyme catalyses the conversion of dIMP to dAMP, the resultant elevation
      of dATP causing base misincorporation and a mutator phenotype.

PMID- 8657186
TI  - Protective effect of deoxyribonucleosides on UV-irradiated human peripheral blood
      T-lymphocytes: possibilities for the selective killing of either cycling or non
      cycling cells.
AB  - Non-cycling human T-lymphocytes from normal subjects show a 10-fold greater
      sensitivity than fibroblasts to UV-B (280-315 nm) irradiation from a Westinghouse
      FS20 lamp, but only a 2.7-fold greater sensitivity to UV-C (254 nm) irradiation.
      Hypersensitivity is associated with a deficiency in the rejoining of excision
      breaks. Non-cycling T-lymphocytes have extremely low deoxyribonucleotide pools.
      Addition to the medium of the four deoxyribonucleosides, each at a concentration
      of 10(-5) M, substantially increases survival and reduces the persistence of
      excision-related strand breaks following UV-B or UV-C irradiation (Yew and
      Johnson (1979) Biochim. Biophys. Acta 562, 240-241; Green et al. (1994) Mutation
      Res., 315, 25-32). UV-resistance of T-lymphocytes is also increased by
      stimulating the cells into cycle. The addition of deoxyribonucleosides does not
      further enhance survival of cycling cells and they do not reach the level of
      resistance achieved by non-cycling cells in the presence of deoxyribonucleosides.
      We suggest that two opposing effects are in operation. Cells out of cycle can
      show increased resistance to DNA damage in the absence of division but they also
      have reduced deoxyribonucleotide pools, which may limit DNA repair. With UV-B
      irradiation, the exceptionally low dNTP pools in non-cycling T-lymphocytes cause
      this second effect to predominate. In contrast, with ionising radiation, which
      forms highly cytotoxic double-strand breaks, non-cycling human T-lymphocytes are
      slightly more resistant than fibroblasts. Non-cycling cells such as T-lymphocytes
      should be especially sensitive to agents which produce a high proportion of read
      excisable damage, but should show normal resistance to agents which highly toxic
      lesions. It may be possible by choice of DNA damaging agent and manipulation of
      cellular deoxyribonucleotide pools, to choose regimes which will selectively kill
      either cycling or non-cycling cells and to improve the efficacy of standard
      therapeutic procedures. Conditions favouring selective killing of non-dividing T
      lymphocytes but sparing stem cells may be of value in bone marrow
      transplantation. Conditions favouring selective killing of dividing cancer cells
      but sparing non-dividing normal tissue may be of value in cancer therapy.

PMID- 8657187
TI  - Protection and repair of gamma-radiation-induced lesions in mice with DNA or
      deoxyribonucleoside treatments.
AB  - Mice can survive lethal doses of ionizing radiation if deoxyribonucleosides or
      'highly polymerized' salmon sperm DNA (Sigma) are administered 30 min to 24 h
      post-irradiation. DNA is more effective than deoxyribonucleosides in increasing
      the survival frequency. At supralethal exposures of gamma-irradiation,
      Deoxyribonucleosides and DNA are equally effective in reversing radiation damage
      which otherwise leads to chromosome breakage. The micronucleus frequencies in the
      polychromatic erythrocytes of bone marrow cells from DNA- or deoxyribonucleoside
      treated mice were near the unirradiated control values. This reduction in
      chromosome breakage was approximately 4-fold when compared with the irradiated,
      saline-treated control. 'Highly polymerized' DNA protects against mortality if
      administered 48 and 24 h prior to irradiation. This is somewhat comparable to the
      effectiveness of the growth factors Interleukin-1 alpha (IL-1 alpha) or tumor
      necrosis factor-alpha (TNFalpha) administered prior to irradiation. With survival
      as criterion, the sensitivity of 4 lines of mice to gamma-irradiation is BALB/c >
      C3H/OuJ > or = C3H/HeJ > C57B1/6.

PMID- 8657188
TI  - The beneficial effects of dietary restriction: reduced oxidative damage and
      enhanced apoptosis.
AB  - There is compelling evidence for the central role of oxidative damage in the
      aging process and for the participation of reactive oxygen species in tumor
      initiation and promotion. Caloric restriction (CR) or energy restriction retards
      age-associated increases in mitochondrial free-radical production and reduces the
      accumulation of oxidatively damaged cell components. CR has also been shown to
      slow down age-related declines in various repair capabilities, including some
      types of DNA repair. It is proposed that inhibitors of mitochondrial electron
      transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal,
      amiodarone, valinomycin, etc.), when used at extremely low doses, could mimic the
      effects of CR in model systems. The objective is to lower mitochondrial free
      radical production by decreasing the fraction of electron carriers in the reduced
      state. In addition to a variety of other effects, CR has been shown to increase
      the rate of apoptosis, particularly in preneoplastic cells, and in general, to
      promote elevated levels of free glucocorticoids (GCs). GCs are known to induce
      tissue-specific apoptosis and to upregulate gap-junction-mediated intercellular
      communication (GJIC). Tumor promoters like phorbol esters have the opposite
      effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme
      poly (ADP-ribose) polymerase (PARP) is thought to play a central role in
      apoptosis, in a manner that has been highly conserved in evolution. There is good
      evidence that the apoptosis-associated Ca/Mg-dependent DNA endonuclease is
      maintained in a latent form by being poly (ADP-ribosylated). Apoptosis would
      require the removal of this polymer from the endonuclease, and, most likely, its
      removal from topoisomerase II and histone H1 as well. The role of poly (ADP
      ribose) in apoptosis, carcinogenesis, and aging could be studied by the use of
      modulators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethanol,
      etc.), inhibitors of poly ADP-ribose) glycohydrolase activity (ethacridine, 43
      degrees C, etc.), and inhibitors of the PARP-specific protease (interleukin-1
      beta converting enzyme (ICE)-like protease). Also, it would be of interest to
      determine if CR can decrease the half-life of poly (ADP-ribose), upregulate GJIC,
      and modulate the activities of PARP, the glycohydrolase, and the PARP-specific
      protease, factors potentially important in these processes.

PMID- 8657189
TI  - DNA repair and cytokines in antimutagenesis and anticarcinogenesis.
AB  - UV is a complete carcinogen because it can induce skin cancer by sequential steps
      of initiation, promotion and progression. It produces the mutagenic DNA
      photoproducts that lead to activation of skin oncogenes, and also suppresses the
      cellular immune responses that are otherwise able to eliminate highly antigenic
      skin tumors. What is new is that these two steps are related because unrepaired
      DNA photoproducts cause the release of cytokines, producing a variety of response
      that contribute to tumor promotion, tumor progression, immunosuppression, and the
      induction of latent viruses. DNA repair enzymes are a key genoprotection
      mechanism not only by reversing DNA photoproducts, but also by blocking the
      carcinogenic cellular responses triggered by cytokines.

PMID- 8657190
TI  - Reversal of malignancy by the adenovirus E1a gene.
AB  - Tumor suppressor genes such as Rb and p53 usually kill tumor cells when
      overexpressed ectopically. This is a consequence of their normal cell cycle
      regulatory functions. By contrast, the E1a gene of adenovirus, a common cold
      virus, converts tumor cells into viable normal cells. This has advantages for
      investigation and control of cancer. In particular, E1a is a master programmer of
      the epithelial phenotype. This provides a new tool for understanding the
      molecular basis of the epithelial-mesenchymal transition, and how it goes awry in
      cancer cells. Furthermore, epithelial cells are sensitive to a form of apoptosis 
      'anoikis' - that is induced by detachment from extracellular matrix. This
      property confers strict anchorage-dependence. Transcriptional programming, by E1a
      or the formation of cell-cell junctional complexes, programs epithelial cells to
      be sensitive to anoikis.

PMID- 8657191
TI  - Retinoid receptors in human lung cancer and breast cancer.
AB  - Retinoids, the natural and synthetic vitamin A derivatives, are known to inhibit
      the proliferation of lung cancer and breast cancer cells and the growth of
      carcinogen-induced bronchogenic squamous cell carcinoma and mammary tumors, and
      have been used as chemoprevention agents against both types of cancer. However,
      clinical trials of retinoids in patients with advanced lung cancer and breast
      cancer have not been successful. In studying how retinoid sensitivity is lost in
      cancer cells, we have found that lack of the retinoic acid receptor beta (RAR
      beta) gene expression and its abnormal regulation by retinoic acid (RA) are
      common features in human lung cancer and breast cancer cells. The absence and
      abnormal RA regulation of RAR beta correlates with the loss of anti-proliferation
      effect of RA in hormone-independent breast cancer cells, and is due to different
      abnormalities found in cancer cells. Furthermore, expression of RAR beta gene in
      hormone-independent breast cancer cells restores their RA sensitivity. These data
      demonstrate that RAR beta can mediate the growth inhibitory effect of RA and
      suggest that the lack of RAR beta may contribute to retinoid resistance in
      certain cancer cells.

PMID- 8657192
TI  - Multiple mutations in human cancers.
AB  - Increasing evidence indicates that most human cancers contain multiple mutations.
      The exact number of mutations, their origin, and types remain to be determined.
      An over-riding question is whether the multiple mutations that accumulate in
      cancers is rate-limiting for the carcinogenic process. In this review we consider
      the argument that the large numbers of mutations routinely reported in human
      cancers cannot be accounted for by the rate of spontaneous mutation observed in
      normal human cells. We will analyze different mechanisms that might account for
      the accumulation of mutations in cancer cells. We conclude that cancer cells are
      genetically unstable; i.e., they exhibit a mutator phenotype. The recent reports
      of microsatellite instability in a variety of human cancers have provided the
      first strong evidence for the presence of a mutator phenotype in human cancers.
      However, we still lack information about the relationship between microsatellite
      instability and mutations that allow cancer cells to proliferate, invade, and
      metastasize.

PMID- 8657193
TI  - The 4th International Conference on Mechanisms of Antimutagenesis and
      Anticarcinogenesis: a summary.

PMID- 8657194
TI  - Somatic mutagenesis and antimutagenesis in aging research.
AB  - Somatic mutagenesis and antimutagenesis are reviewed from the point of view of a
      gerontologist. Aging can be defined as a set of phenotypes that have escaped the
      force of natural selection. In mammalian species, aberrations in proliferative
      homeostasis, including a variety of cancers, are conspicuous examples. The author
      argues that there is a strong coupling between intrinsic biological aging and the
      biology of neoplasia. Genomic instability is likely to be a dominant mechanism
      underlying such coupling. Ongoing experiments from his laboratory and those of
      collaborators are briefly reviewed. The approaches include: (1) the
      characterization of a striking progeroid mutation of man, the Werner syndrome,
      which exhibits a deletor mutator phenotype; (2) the comparative analysis of
      intragenic and chromosomal mutations in mammalian species of contrasting life
      span potentials; (3) attempts to synthesize antimutator strains of mice. An
      emerging generalization is that there is a significant degree of species
      specificity in the patterns of somatic mutation in aging mammals.

PMID- 8657195
TI  - Structural flexibility and functional versatility of cytochrome P450 and rapid
      evolution.
AB  - P450 represents a large group of heme-thiolate enzymes that exhibit remarkably
      diverse activities for the metabolism of numerous endogenous and exogenous
      chemicals. Recent site-directed mutagenesis studies indicate that a single
      mutation at any of the key residues can be enough to alter the substrate and/or
      product specificities in the P450 activities. Molecular modeling predicts that
      these key residues are located within the substrate heme pocket. Structural
      elements involved in diversifying P450 activity appear to correspond to the B'
      helix, the F helix and the F/G interhelical loop in the bacterial P450s.
      Structures represented by these regions are extremely variable despite the fact
      that the core of the P450 substrate pocket is well conserved. A mutation within
      these regions may result in a significant geometrical alteration of the pocket
      and lead to diversify the P450 activity. Phylogenetical analysis shows a
      relatively high rate of nonsynonymous substitution within these substrate binding
      regions. The functional versatility of P450 can thus be largely accounted for in
      terms of pocket change brought about by rapid mutations.

PMID- 8657196
TI  - The antievolutionary component of antimutagenesis and anticarcinogenesis: where
      do mutation rates come from and where are they going?

PMID- 8657197
TI  - Synergistic/comutagenic action in the Ames test as an indication of irrelevant
      positive findings.
AB  - A number of structurally very diverse compounds which cause weak positive effects
      in the Ames test by evident or suspect irrelevant mechanisms is discussed. As a
      unifying observation we describe synergistic effects in combination with known
      mutagens in the responsive strains and comutagenic effects in initially
      unresponsive strains. We argue that the compounds enhance the formation of
      spontaneous (or mutagen-induced) revertant colonies by test-specific mechanisms
      likely to be of no relevance to multicellular eukaryotic organisms rather than
      possessing intrinsic genotoxic (i.e. DNa-damaging) properties in the Ames test.

PMID- 8657198
TI  - Anti-mutagenic agents are also co-recombinogenic and can be converted into co
      mutagens.
AB  - In experiments using yeast without an external metabolic activation system, the
      hormones testosterone, beta-estradiol, and diethylstilbestrol were anti-mutagenic
      and co-recombinogenic. In the presence of Aroclor-induced rat liver S-9 plus
      cofactors (S9-mix) the same substances acted as co-mutagens and anti
      recombinogens. Since an external metabolic activation system was able to convert
      anti-mutagens into co-mutagens, we studied whether the different metabolism of
      yeast and mice would lead to different effects. In whole-animal experiments using
      the mouse spot test, anti-mutagenic effects of vanillin (Imanishi et al., 1990),
      phenobarbital (Shibuya and Murota, 1984), and tannic acid (Sasaki et al., 1990)
      have been observed. In our present experiments with yeast, tannic acid and
      phenobarbital showed anti-mutagenic effects also, whereas vanillin acted as a co
      mutagen. Thus, as in the case of the hormones, tannic acid and phenobarbital were
      anti-mutagenic and co-recombinogenic whereas vanillin was co-mutagenic as well as
      co-recombinogenic.

PMID- 8657199
TI  - Recombination-dependent mutation in non-dividing cells.
AB  - Over the past 6 years an unexpected way of making mutations in bacteria has
      challenged concepts of the genetic mechanisms behind evolution. Mechanistic
      studies of these so called 'adaptive' mutations are revealing a novel molecular
      mechanism involving DNA double-strand breaks, genetic recombination, probable DNA
      polymerase errors, and the possible suspension of mismatch repair during the
      reversion of a lac frameshift mutation in Escherichia coli. The molecular details
      of this process are altering our understanding of how mutations form in non
      dividing cells.

PMID- 8657200
TI  - Comments on the evidence in support of the epigenetic nature of radiogenic
      initiation.

PMID- 8657201
TI  - Is a mutagenic event involved in radiation induced malignant transformation?

PMID- 8657202
TI  - Selection of bacteriophage T4 antimutator DNA polymerases: a link between
      proofreading and sensitivity to phosphonoacetic acid.
AB  - During DNA replication, DNA polymerases alternate between DNA synthesis and
      proofreading the newly synthesized DNA. In order to understand the molecular
      details of how DNA polymerases determine the balance between polymerase and
      proofreading activities, it would be useful to have mutants which switch between
      the two activities either more or less frequently. Antimutator DNA polymerases
      switch more frequently and thus have more opportunity for proofreading. We have
      observed that mutant DNA polymerases which proofread less frequently have a
      mutator phenotype and are inhibited by the pyrophosphate analogue phosphonoacetic
      acid. Sensitivity to phosphonoacetic acid can be used to isolate second-site
      suppressor mutations. These suppressor mutations encode amino acid substitutions
      which produce antimutator DNA polymerases.

PMID- 8657203
TI  - Effects of phenethyl isothiocyanate on metabolism and on genotoxicity of
      dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo[4, 5-beta]pyridine
      (PhIP).
AB  - Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables,
      inhibited the genotoxic effects of N-nitrosodimethylamine (DMN) and of 2-amino-1
      methyl-6-phenylimidazo[4,5-beta]pyridine (PhIP) in differential DNA repair assays
      with E. coli K-12 strains in vitro and in animal mediated assays with mice. In
      Salmonella typhimurium, the mutagenic activities of DMN and PhIP measured after
      activation with S-9 homogenates from several organs of PEITC-treated mice were
      substantially lower than those obtained with homogenates of untreated animals as
      well. PEITC also reduced the formation of micronuclei by DMN in metabolically
      competent Hep-G-2 cells of human origin but was ineffective in combination with
      PhIP. Biochemical investigations showed that the prevention of genotoxic effects
      of DMN by PEITC results form an inhibition of its alpha-hydroxylation. The effect
      of oral administration of PEITC on the formation of DNA adducts of PhIP was
      examined in the colon and liver of mice. No inhibition of adduct formation was
      observed in these experiments. Biochemical experiments showed that PEITC reduces
      not only the metabolic activation of PhIP via 2-hydroxyamino PhIP but also
      inhibits a detoxification pathway (formation of 4-hydroxy PhIP). The present
      results can be taken as an indication that the anticarcinogenic activities of
      isothiocyanates towards nitrosamines are paralleled by antimutagenic effects, and
      that probably no such protective effects occur in combination with heterocyclic
      amines. Furthermore, our findings show that the effects of chemopreventive agents
      demonstrated in bacteria in vitro cannot always be extrapolated to reactions
      occurring in intact mammalian cells.

PMID- 8657204
TI  - A novel positive detection system of in vivo mutations in rpsL (strA) transgenic
      mice.
AB  - To positively detect the in vivo mutations accumulated in different mouse organs,
      we have developed a transgenic mouse system. This transgenic mouse carried an
      Escherichia coli (E. coli) plasmid pML4 as a shuttle vector that consisted of a
      replication origin (ori), the kanamycin-resistant gene (KanR) and the rpsL+ gene
      (strAS) derived from E. coli. These E. coli elements were expected to be inert in
      the transgenic mouse system; thus, neutral mutations would be accumulated on the
      shuttle plasmid in the transgenic mice. The shuttle plasmid vector was recovered
      from the mouse genomic DNA and introduced into kanamycin-sensitive (KmS) and
      streptomycin-resistant (SmR) E. coli cells by using electroporation. The original
      pML4 shuttle plasmid transformed the host E. coli to KmR and SmS, since both the
      KanR and rpsL genes exhibited dominant traits of KmR and SmS, respectively. On
      the other hand, when the retrieved pML4 shuttle plasmid carried a mutated rpsL
      gene, it could be positively detected as both KmR and SmR. Based on this
      principle, we were able to positively detect the in vivo mutations accumulated in
      the rpsL transgene of the shuttle vector pML4 integrated into the mouse genome.
      The total number of rescued shuttle plasmids were counted on the plates
      containing Km alone, while only mutants were detected on the plates containing
      both Km and Sm. We have so far established 22 independent transgenic mouse lines
      that carried up to approx. 750 copies of the shuttle plasmid pML4 in a haploid
      genome. By using high-copy-number transgenic mouse lines which carried 350 copies
      or more of the shuttle vector, we also developed a simple and proficient method
      for retrieving the shuttle plasmid from various tissues of the transgenic mice.
      The background mutant frequency was approx. 5 x 10(-5). In order to validate the
      applicability of the positive-detection transgenic system for the induced
      mutagenicity assay, methylnitrosourea (MNU) was administered to the transgenic
      mice, and an increase in the number of mutant frequencies was seen in all tested
      organs including spleen, liver and brain. The rpsL transgenic mouse system was
      therefore considered to provide a quick-and-easy risk assessment test for in vivo
      tissue-specific mutagenicity, using positive detection by streptomycin.

PMID- 8657205
TI  - Antimutagenicity of ellagic acid against aflatoxin B1 in the Salmonella
      microsuspension assay.
AB  - Ellagic acid (EA) is a phenolic compound with antimutagenic and anticarcinogenic
      properties. It occurs naturally in some foods such as strawberries, raspberries,
      grapes, black currants and walnuts. In the present study, we used the Salmonella
      microsuspension assay to examine the antimutagenicity of EA against the potent
      mutagen aflatoxin B1 (AFB1) using tester strains TA98 and TA100. Further, we used
      a two-stage incubation procedure that incorporates washing the bacterial cells
      free of the incubation mixture after the first incubation to investigate EA and
      AFB1 interaction. Three different concentrations of AFB1 (2.5, 5 and 10 ng/tube)
      were tested against five different concentrations of EA for TA98 and TA100. EA
      significantly inhibited mutagenicity of all doses of AFB1 in both tester strains
      with the addition of S9. EA alone was not mutagenic at the concentrations tested.
      The greatest inhibitory effect of EA on AFB1 mutagenicity occurred when EA and
      AFB1 were incubated together. Lower inhibition was apparent when the cells were
      first incubated with EA followed by a second incubation with AFB1, and also when
      the cells were first incubated with AFB1 followed by a second incubation with EA
      alone. The results of the sequential incubation studies support the hypothesis
      that one mechanism of inhibition could involve the formation of a chemical
      complex between EA and AFB1.

PMID- 8657206
TI  - Isolation of micronuclei: high yield by sucrose gradient versus maximum purity by
      cell sorting.
AB  - Micronuclei (MNC) of L929 cells were isolated 72 h after irradiation with 6 Gy
      for characterization of their DNA content, using gel electrophoresis. A novel
      method for isolation of MNC based on a sucrose gradient ultracentrifugation was
      developed. With this efficient method (80% recovery) more than 150 x 10(6) MNC
      per day could be isolated. The purity was > 99%. However, the low number of main
      nuclei in the MNC isolate ( < 1%) resulted in a contamination of MNC DNA with
      about 15% main nucleus DNA, due to the several times higher DNA content of main
      nuclei. Cell sorting was utilized to maximize the purity by choosing the
      recommended sorting mode for highest purity. Isolation of MNC with the cell
      sorter was successful (100% purity), but also time-consuming (1-2 x 10(6) MNC per
      working day could be isolated) and insufficient (10% recovery). Extraction of DNA
      of these isolated MNC resulted in less than 1 ng/day. Hence, at least 1 week of
      cell sorting would be necessary for one electrophoretic run. When employing the
      sucrose gradient method, 2000 times more DNA of MNC have been isolated. We
      therefore consider this method as the most efficient way for rapid and low cost
      isolation of large amounts of purified ( > 99%) MNC without the employment of
      sophisticated and expensive techniques (cell sorting) and the accompanied
      knowhow. In contrast, maximum purity but low yields of MNC can be obtained by
      cell sorting.

PMID- 8657207
TI  - Field bean protease inhibitor mitigates the sister-chromatid exchanges induced by
      bromoform and depresses the spontaneous sister-chromatid exchange frequency of
      human lymphocytes in vitro.
AB  - The mutagenicity of a trihalomethane-bromoform (CHBr3)-was assessed by the in
      vitro sister-chromatid exchange (SCE) assay using human peripheral blood
      lymphocytes. CHBr3 was found to induce SCEs significantly in a dose-dependent
      manner. When the cells were exposed to 600 ng CHBr3/ml of the medium, the
      SCE/cell mean reached a value as high as 18.78 +/- 0.17. Beyond this
      concentration. CHBr3 proved to be cytotoxic. A protease inhibitor (PI), purified
      appreciably by affinity chromatography from fieldbean (FB), was able to suppress
      significantly in a dose-dependent way the high SCE frequencies induced by this
      specific concentration of CHBr3 (600 ng/ml). Addition of 600 micrograms of
      FBPI/ml of the medium brought down the CHBr3-induced high SCEs to near (8.80 +/-
      0.15) base line or control value (8.45 +/- 0.21). A study of the effect of FBPI
      on the normal low SCE frequencies in these cells indicated that the FBPI has the
      intrinsic property to suppress in a dose-dependent manner these SCEs in the
      lymphocytes. This functional property of FBPI, which is related to its protease
      inhibitory activity and which is destroyed when it is inactivated by autoclaving,
      makes it an effective antimutagenic/chemopreventive agent.

PMID- 8657208
TI  - Anticlastogenic effects of galangin against mitomycin C-induced micronuclei in
      reticulocytes of mice.
AB  - We investigated the suppressive effect of galangin on the induction of
      micronucleated reticulocytes (MNRETs) by mitomycin C (MMC) in mouse peripheral
      blood. When galangin was given to mice 24 h before the intraperitoneal injection
      of MMC (1 mg/kg), a more marked decrease in the frequency of MNRETs was observed
      than in mice with simultaneous and post-treatment of galangin. On the other hand,
      when galangin was given to mice for 7 consecutive days before MMC injection,
      galangin showed potent anticlastogenic effects, even at the lowest dose level of
      0.1 mg/kg. Results from our in vivo studies indicate that galangin is capable of
      suppressing the clastogenic activity of the direct acting MMC. Together with our
      earlier observations, it appears that galangin is capable of protecting cells
      from the toxic effects of a variety of hazardous chemicals. Therefore, galangin
      may be an useful chemopreventive compound.

PMID- 8657209
TI  - Influence of DT diaphorase on quinone-mediated genotoxicity in human and fish
      cell lines.
AB  - The influence of the quinone-reducing enzyme, DT diaphorase [NAD(P)H: (quinone
      acceptor) oxidoreductase], on the genotoxicity of quinones was examined in two
      cell lines, namely a human hepatoma cell line, HepG2 and a brown bullhead
      fibroblast cell line, BB. The quinone-reductive characteristics of these two cell
      lines were examined using an acetylated cytochrome c reduction assay for
      enzymatic reductase activity. Subsequently, the influence of DT diaphorase on the
      genotoxicity of two model quinones, menadione (MND) and 9,10-phenanthrenequinone
      (PQ) was examined in an alkaline unwinding assay for DNA single-strand breaks.
      Results revealed that DT diaphorase was the predominant quinone reductase in
      cytosols of both cell lines, and that levels of specific DT diaphorase activity
      were generally equivalent in the two species. Despite these similarities, results
      revealed marked qualitative differences between the two species in terms of the
      influence of DT diaphorase on quinone-mediated genotoxicity. When pretreated with
      the DT diaphorase inhibitor, dicoumarol, HepG2 cells exhibited a marked
      exacerbation of genotoxicity in the presence of either MND or PQ, indicating
      protective influence of the enzyme. In contrast, quinone genotoxicity in BB cells
      was not affected by DT diaphorase inhibition, indicating the lack of a protective
      effect of DT diaphorase. This study illustrates the manner in which functionally
      analogous enzymes may have markedly distinct influences on xenobiotic toxicity in
      different cellular systems.

PMID- 8657210
TI  - A semi-automated, microplate version of the SOS Chromotest for the analysis of
      complex environmental extracts.
AB  - Environmental monitoring for genotoxicity requires that a large number of
      measurements be made across space and time. This requirement demands a rapid and
      efficient bioassay system. The SOS Chromotest is a rapid, efficient bacterial
      system for the detection of DNA damaging agents. Over 100 publications have
      described its use on a variety of samples. Relatively few studies have used the
      test to examine complex mixtures. Effective testing of complex samples poses a
      variety of problems. Although solutions have been proposed, few have validated
      the resulting protocol. In this work we present a semi-automated microplate
      version of the SOS Chromotest for the examination of complex mixtures.
      Experiments were conducted to determine the optimal cell concentration, exposure
      time, substrate conversion time and S9 enzyme concentration. The performance of
      the method was evaluated using 6 reference genotoxins and 3 complex mixtures. The
      complex mixtures examined are extracts of diesel particulate matter, urban dust
      and coal tar. The results obtained indicate that optimal responses often require
      fewer cells (approximately equal to 5-10 x 10(6) CFU/ml) and a longer exposure (3
      h) than that recommended in the original protocol. Interfering effects of colored
      and turbid samples are removed using centrifugation and initial optical density
      readings taken 60 min after cell resuspension and lysis. The performance of the
      established protocol was evaluated using mitomycin C and benzo[a]pyrene results
      for 207 microplates and solvent control results for 293 microplates. The results
      indicate that the established method is accurate, sensitive and precise.
      Coefficient of variation on mean SOSIP values for mitomycin C and benzo[a]pyrene
      are < 5%. Solvent control data indicate that the standard threshold for
      determination of a positive response (induction factor > 1.5) is excessively
      conservative. All liquid transfers were automated using the Biomek automated
      laboratory workstation. Automation permits a throughput of up to 72 samples per
      day and maintains excellent precision and accuracy.

PMID- 8657211
TI  - Thrombolytic therapy with streptokinase in acute ischemic stroke.
AB  - BACKGROUND: In patients with acute ischemic stroke, early treatment with
      thrombolytic agents is thought to permit reperfusion of ischemic neurons and to
      promote recovery of function. The Multicenter Acute Stroke Trial-Europe (MAST-E)
      was designed to assess the efficacy and safety of streptokinase in patients with
      acute ischemic stroke. METHODS: Patients with moderate-to-severe ischemia in the
      territory of the middle cerebral artery were randomly assigned to receive
      streptokinase (1.5 million units over a period of one hour) or placebo within six
      hours after the onset of stroke. The primary efficacy outcome was a binary
      criterion combining mortality and severe disability at six months, with severe
      disability defined as a score of 3 or higher on the Rankin scale. The primary
      safety outcomes were mortality at 10 days and cerebral hemorrhage. RESULTS: All
      randomized patients (156 in the streptokinase group and 154 in the placebo group)
      were evaluated at six months. The incidence of the primary efficacy outcome was
      similar in the two groups (124 patients in the streptokinase group and 126 in the
      placebo group died or had a Rankin score > or = 3). However, the mortality rate
      at 10 days was significantly higher in the streptokinase group than in the
      placebo group (34.0 percent vs. 18.2 percent, P = 0.002). The higher rate in the
      streptokinase group was mainly due to the hemorrhagic transformation of ischemic
      cerebral infarcts. At six months, more deaths had occurred in the streptokinase
      group than in the placebo group (73 vs. 59, P = 0.06). CONCLUSIONS: In patients
      with acute ischemic stroke, treatment with streptokinase resulted in an increase
      in mortality. The routine use of streptokinase cannot be recommended in acute
      ischemic stroke.

PMID- 8657212
TI  - Endometrial resection for the treatment of menorrhagia.
AB  - BACKGROUND: Endometrial resection is an alternative to hysterectomy in the
      treatment of women with menorrhagia, but it may not control the condition. We
      sought to evaluate the effectiveness of such resection. METHODS: We followed 525
      consecutive women (mean age at initial surgery, 42 years) for up to five years
      after endometrial resection. The women were examined 6 to 12 weeks after the
      operation and were then sent yearly questionnaires seeking information about
      their condition. The mean duration of follow-up was 31 months. Thirty-seven women
      (86 percent of the 43 women available for five years of follow-up) were followed
      for the entire period. RESULTS: Endometrial resection was completed successfully
      in 95 percent of the women, with operative complications in 6 percent. Forty
      eight women underwent subsequent resection. The yearly questionnaires indicated
      that 85 to 100 percent of the women (depending on the year of follow-up) had
      adequately controlled menorrhagia, 26 to 40 percent had amenorrhea, 71 to 80
      percent reported either a lessening of menstrual pain or no pain, and 79 to 87
      percent were satisfied with the results of their surgery. No further surgery was
      needed by 80 percent of the women, and only 9 percent underwent hysterectomy
      during the five years of follow-up, with 98 percent of those operations being
      performed in the first three postoperative years. CONCLUSIONS: Endometrial
      resection is an effective alternative to hysterectomy in women with menorrhagia.

PMID- 8657213
TI  - Placental blood as a source of hematopoietic stem cells for transplantation into
      unrelated recipients.
AB  - BACKGROUND: Transplantation of bone marrow from unrelated donors is limited by a
      lack of HLA-matched donors and the risk of graft-versus-host disease (GVHD).
      Placental blood from sibling donors can reconstitute hematopoiesis. We report
      preliminary results of transplantation using partially HLA-mismatched placental
      blood from unrelated donors. METHODS: Twenty-five consecutive patients, primarily
      children, with a variety of malignant and non-malignant conditions received
      placental blood from unrelated donors and were evaluated for hematologic and
      immunologic reconstitution and GVHD. HLA matching was performed before
      transplantation by serologic typing for class I HLA antigens and low-resolution
      molecular typing for class II HLA alleles. In donor-recipient pairs who differed
      by no more than one HLA antigen or allele, high-resolution class II HLA typing
      was done retrospectively. Fordonor-recipient pairs who were mismatched for two
      HLA antigens or alleles, high-resolution typing was used prospectively to select
      the best match for HLA-DRB1. RESULTS: Twenty-four of the 25 donor-recipient pairs
      were discordant for one to three HLA antigens. In 23 of the 25 transplant
      recipients, the infused hematopoletic stem cells engrafted. Acute grade III GVHD
      occurred in 2 of the 21 patients who could be evaluated, and 2 patients had
      chronic GVHD. In vitro proliferative responses of T cells and B cells to plant
      mitogens were detected 60 days after transplantation. With a median follow-up of
      12 1/2 months and a minimal follow-up of 100 days, the overall 100-day survival
      rate among these patients was 64 percent, and the overall event-free survival was
      48 percent. CONCLUSIONS: HLA-mismatched placental blood from unrelated donors is
      an alternative source of stem cells for hematopoietic reconstitution in children.

PMID- 8657214
TI  - Cord-blood transplantation from an unrelated donor in an adult with chronic
      myelogenous leukemia.

PMID- 8657215
TI  - Images in clinical medicine. Nutcracker phenomenon.

PMID- 8657216
TI  - Survival of Medicare patients after enrollment in hospice programs.
AB  - BACKGROUND: Each year more than 220,000 Medicare beneficiaries receive care from
      hospice programs designed to enhance the quality of the end of life. Enrollment
      requires certification by a physician that the patient has a life expectancy of
      less than six months. We examined how long before death patients enrolled in
      hospice programs. METHODS: Using 1990 Medicare claim data, we analyzed the
      characteristics and survival of 6451 hospice patients followed for a minimum of
      27 months with respect to mortality. RESULTS: The patients' mean age was 76.4
      years; 92.4 percent were white. Half the patients were women, and 80.2 percent
      had cancer of some type. The most common diagnoses were lung cancer (21.4
      percent), colorectal cancer (10.5 percent), and prostate cancer (7.4 percent).
      The median survival after enrollment was only 36 days, and 15.6 percent of the
      patients died within 7 days. At the other extreme, 14.9 percent of the patients
      lived longer than six months. Survival varied substantially according to
      diagnosis, even after adjustment for age and co-existing conditions. The
      unadjusted survival after enrollment was shortest for those with renal failure,
      those with leukemia or lymphoma, and those with liver or biliary cancer; it was
      longest for those with chronic lung disease, those with dementia, and those with
      breast cancer. Patients at for-profit, larger, outpatient, or newer hospices
      lived longer after enrollment than those in other types of hospice programs.
      CONCLUSIONS: Most patients who enter hospice care do so late in the course of
      their terminal illnesses. The timing of enrollment in hospice programs varies
      substantially with the characteristics of the patients and the hospices.

PMID- 8657217
TI  - Management of pulmonary disease in patients with cystic fibrosis.

PMID- 8657218
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 22-1996. Cerebral hemorrhage in a 69-year-old woman receiving
      warfarin.

PMID- 8657219
TI  - Alternatives to hysterectomy for menorrhagia.

PMID- 8657221
TI  - Caring at the end of our lives.

PMID- 8657220
TI  - Placental-blood banking--a new frontier in transfusion medicine.

PMID- 8657222
TI  - Ragweed immunotherapy in adult asthma.

PMID- 8657223
TI  - Ragweed immunotherapy in adult asthma.

PMID- 8657224
TI  - Ragweed immunotherapy in adult asthma.

PMID- 8657225
TI  - Ragweed immunotherapy in adult asthma.

PMID- 8657226
TI  - Ragweed immunotherapy in adult asthma.

PMID- 8657227
TI  - High-altitude pulmonary edema.

PMID- 8657228
TI  - High-altitude pulmonary edema.

PMID- 8657229
TI  - Positron-emission tomography and Alzheimer's disease.

PMID- 8657230
TI  - Campylobacter jejuni Infection and treatment for Guillain-Barre Syndrome.

PMID- 8657232
TI  - Costs of visits to emergency departments.

PMID- 8657231
TI  - Herpes simplex encephalitis.

PMID- 8657233
TI  - Costs of visits to emergency departments.

PMID- 8657234
TI  - Costs of visits to emergency departments.

PMID- 8657235
TI  - Costs of visits to emergency departments.

PMID- 8657236
TI  - College women and condom use, 1975-1995.

PMID- 8657237
TI  - Comparison of coronary bypass surgery with angioplasty in patients with
      multivessel disease.
AB  - BACKGROUND: Coronary-artery bypass grafting (CABG) and percutaneous transluminal
      coronary angioplasty (PTCA) are alternative methods of revascularization in
      patients with coronary artery disease. We tested the hypothesis that in selected
      patients with multivessel disease suitable for treatment with either procedure,
      an initial strategy of PTCA does not result in a poorer five-year clinical
      outcome than CABG. METHODS: Patients with multivessel disease were randomly
      assigned to an initial treatment strategy of CABG (n = 914) or PTCA (n = 915) and
      were followed for an average of 5.4 years. Analysis of outcome events was
      performed according to the intention to treat. RESULTS: The respective in
      hospital event rates for CABG and PTCA were 1.3 percent and 1.1 percent for
      mortality, 4.6 percent and 2.1 percent for Q-wave myocardial infarction (P <
      0.01), and 0.8 percent and 0.2 percent for stroke. The five-year survival rate
      was 89.3 percent for those assigned to CABG and 86.3 percent for those assigned
      to PTCA (P = 0.19; 95 percent confidence interval of the difference in survival, 
      0.2 percent to 6.0 percent). The respective five-year survival rates free from Q
      wave myocardial infarction were 80.4 percent and 78.7 percent. By five years
      after study entry, 8 percent of the patients assigned to CABG had undergone
      additional revascularization procedures, as compared with 54 percent of those
      assigned to PTCA; 69 percent of those assigned to PTCA did not subsequently
      undergo CABG. Among diabetic patients who were being treated with insulin or oral
      hypoglycemic agents at base line, a subgroup not specified by the protocol, five
      year survival was 80.6 percent for the CABG group as compared with 65.5 percent
      for the PTCA group (P = 0.003). CONCLUSIONS: As compared with CABG, an initial
      strategy of PTCA did not significantly compromise five-year survival in patients
      with multivessel disease, although subsequent revascularization was required more
      often with this strategy. For treated diabetics, five-year survival was
      significantly better after CABG than after PTCA.

PMID- 8657238
TI  - Outcome of pregnancy in women with moderate or severe renal insufficiency.
AB  - BACKGROUND: Pregnant women with mild preexisting renal disease have relatively
      few complications of pregnancy, but the risks of maternal and obstetrical
      complications in women with moderate or severe renal insufficiency remain
      uncertain. METHODS: We determined the frequency and types of maternal and
      obstetrical complications and the outcomes of pregnancy in 67 women with primary
      renal disease (82 pregnancies). All the women had initial serum creatinine
      concentrations of at least 1.4 mg per deciliter (124 mumol per liter) and
      gestations that continued beyond the first trimester. RESULTS: The mean (+/- SD)
      serum creatinine concentration increased from 1.9 +/- 0.8 mg per deciliter (168
      +/- 71 mumol per liter) in early pregnancy to 2.5 +/- 1.3 mg per deciliter (221
      +/- 115 mumol per liter) in the third trimester. The frequency of hypertension
      rose from 28 percent at base line to 48 percent in the third trimester, and that
      of high-grade proteinuria (urinary protein excretion, > 3000 mg per liter) from
      23 percent to 41 percent. For the 70 pregnancies (57 women) for which data were
      available during pregnancy and immediately post partum, pregnancy-related loss of
      maternal renal function occurred in 43 percent. Eight of these pregnancies (10
      percent of the total) were associated with rapid acceleration of maternal renal
      insufficiency. Obstetrical complications included a high rate of preterm delivery
      (59 percent) and growth retardation (37 percent). The infant survival rate was 93
      percent. CONCLUSIONS: Among pregnant women with moderate or severe renal
      insufficiency, the rates of complications due to worsening renal function,
      hypertension, and obstetrical complications are increased, but fetal survival is
      high.

PMID- 8657239
TI  - Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus
      related latent nuclear antigens before the development of Kaposi's sarcoma.
AB  - BACKGROUND: If Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of
      Kaposi's sarcoma, serologic evidence of infection should be present in patients
      before the disease develops. METHODS: Using an immunoblot assay for two latent
      nuclear antigens of KSHV, we tested serum samples from homosexual male patients
      with the acquired immunodeficiency syndrome (AIDS) with and without Kaposi's
      sarcoma (HIV-infected men with hemophilia), HIV-seronegative blood donors, and
      HIV-seronegative patients with high titers of antibodies against Epstein-Barr
      virus (EBV). Serial serum samples obtained from patients with Kaposi's sarcoma
      before the diagnosis of the disease were tested for evidence of seroconversion.
      RESULTS: Of 40 patients with Kaposi's sarcoma, 32 (80 percent) were positive for
      antibodies against KSHV antigens by the immunoblot assay, as compared with only 7
      of 40 homosexual men (18 percent) without Kaposi's sarcoma immediately before the
      onset of AIDS. Of 122 blood donors, 22 EBV-infected patients, and 20 HIV-infected
      men with hemophilia, none were seropositive. When studied by the immunoblot assay
      over a period of 13 to 103 months, 21 of the 40 patients with Kaposi's sarcoma
      (52 percent) seroconverted 6 to 75 months before the clinical appearance of
      Kaposi's sarcoma. The median duration of antibody seropositivity for KSHV-related
      latent nuclear antigens before the diagnosis of Kaposi's sarcoma was 33 months.
      CONCLUSIONS: In most patients with kaposi's sarcoma and AIDS, seroconversion to
      positivity for antibodies against KSHV-related nuclear antigens occurs before the
      clinical appearance of Kaposi's sarcoma. This supports the hypothesis that
      Kaposi's sarcoma results from infection with KSHV.

PMID- 8657240
TI  - The risk of stomach cancer in patients with gastric or duodenal ulcer disease.
AB  - BACKGROUND: Helicobacter pylori infection, now considered to be a cause of
      gastric cancer, is also strongly associated with gastric and duodenal ulcer
      disease. The discovery of these relations has brought the long-controversial
      connection between peptic ulcers and gastric cancer into focus. METHODS: We
      estimated the risk of stomach cancer in a large cohort of hospitalized patients
      with gastric or duodenal ulcers, as recorded in the Swedish Inpatient Register
      between 1965 and 1983. Altogether, 57,936 patients were followed through 1989,
      for an average of 9.1 years. The standardized incidence ratio--the ratio of the
      observed number of cancers to the number expected on the basis of the incidence
      in the Swedish population at large--was used as a measure of relative risk.
      RESULTS: After peaking in the first 3 years of follow-up, the standardized
      incidence ratio for gastric cancer among 29,287 patients with gastric ulcers
      leveled off at 1.8 (95 percent confidence interval, 1.6 to 2.0) and remained
      significantly increased throughout follow-up, which was as long as 24 years for
      some patients. Prepyloric ulcer, diagnosed in 8646 patients, was not associated
      with a significant excess risk (standardized incidence ratio, 1.2; 95 percent
      confidence interval, 0.8 to 1.6). In the cohort of patients with duodenal ulcers
      (24,456 patients), the incidence of gastric cancer was significantly lower than
      expected. After the second year of follow-up, the standardized incidence ratio
      was only 0.6 (95 percent confidence interval, 0.4 to 0.7) and remained stable
      thereafter. CONCLUSIONS: Gastric ulcer disease and gastric cancer have etiologic
      factors in common. A likely cause of both is atrophic gastritis induced by H.
      pylori. By contrast, there appear to be factors associated with duodenal ulcer
      disease that protect against gastric cancer.

PMID- 8657241
TI  - Images in clinical medicine. Helicobacter pylori in a gastric pit.

PMID- 8657242
TI  - Influence of cardiac-surgery performance reports on referral practices and access
      to care. A survey of cardiovascular specialists.
AB  - BACKGROUND: Reports on the comparative performance of physicians are becoming
      increasingly common. Little is known, however, about the credibility of these
      reports with target audiences or their influence on the delivery of medical
      services. METHODS: Since 1992, Pennsylvania has published the Consumer Guide to
      Coronary Artery Bypass Graft Surgery, which lists annual risk-adjusted mortality
      rates for all hospitals and surgeons providing such surgery in the state. In
      1995, we surveyed a randomly selected sample of 50 percent of Pennsylvania
      cardiologists and cardiac surgeons to find out whether they were aware of the
      guide and, if so, to determine their views on its usefulness, limitations, and
      influence on providers. RESULTS: Eighty-two percent of the cardiologists and all
      the cardiac surgeons were aware of the guide. Only 10 percent of these
      respondents reported that its mortality rates were "very important" in assessing
      the performance of a cardiothoracic surgeon. Less than 10 percent reported
      discussing the guide with more than 10 percent of their patients who were
      candidates for a coronary-artery bypass graft (CABG). Eighty-seven percent of the
      cardiologists reported that the guide had a minimal influence or none on their
      referral recommendations. For both groups, the most important limitations of the
      guide were the absence of indicators of quality other than mortality (cited by 78
      percent), inadequate risk adjustment (79 percent), and the unreliability of data
      provided by hospitals and surgeons (53 percent). Fifty-nine percent of the
      cardiologists reported increased difficulty in finding surgeons willing to
      perform CABG surgery in severely ill patients who required it, and 63 percent of
      the cardiac surgeons reported that they were less willing to operate on such
      patients. CONCLUSIONS: The Consumer Guide to Coronary Artery Bypass Graft Surgery
      has limited credibility among cardiovascular specialists. It has little influence
      on referral recommendations and may introduce a barrier to care for severely ill
      patients. If publicly released performance reports are intended to guide the
      choice of providers without impeding access to medical care, a collaborative
      process involving physicians may enhance the credibility and usefulness of the
      reports.

PMID- 8657243
TI  - Treatment of hypertension in pregnant women.

PMID- 8657244
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 23-1996. A 62-year-old woman with progressive dyspnea and diffuse
      reticulonodular pulmonary infiltrates.

PMID- 8657245
TI  - Myocardial revascularization--bypass surgery or angioplasty?

PMID- 8657246
TI  - Pregnancy and renal disease.

PMID- 8657247
TI  - Helicobacter pylori in the stomach--a paradox unmasked.

PMID- 8657248
TI  - Physical and emotional problems of elite female gymnasts.

PMID- 8657249
TI  - Transmission of hepatitis viruses by surgeons.

PMID- 8657250
TI  - Transmission of hepatitis viruses by surgeons.

PMID- 8657251
TI  - Transmission of hepatitis virus by surgeons.

PMID- 8657252
TI  - Transmission of hepatitis virus by surgeons.

PMID- 8657253
TI  - Transmission of hepatitis virus by surgeons.

PMID- 8657254
TI  - Transmission of hepatitis virus by surgeons.

PMID- 8657255
TI  - Electronic fetal monitoring in predicting cerebral palsy.

PMID- 8657256
TI  - Electronic fetal monitoring in predicting cerebral palsy.

PMID- 8657257
TI  - Electronic fetal monitoring in predicting cerebral palsy.

PMID- 8657258
TI  - Thrombophilia, homocystinuria, and mutation of the factor V gene.

PMID- 8657259
TI  - Thrombophilia, homocystinuria, and mutation of the factor V gene.

PMID- 8657260
TI  - Cisapride and fatal arrhythmia.

PMID- 8657261
TI  - A drumstick?

PMID- 8657262
TI  - A judgement fit for prime time.

PMID- 8657263
TI  - Problems of integrity are 'pervasive'.

PMID- 8657265
TI  - Activists seek retirement home for chimps.

PMID- 8657264
TI  - Clearing of researcher in 'Baltimore affair' boosts demand for reforms.

PMID- 8657266
TI  - BSE maternal transmission results may be released soon.

PMID- 8657267
TI  - Riddle of the tenth man.

PMID- 8657268
TI  - Riddle of the tenth man.

PMID- 8657269
TI  - The g factor.

PMID- 8657271
TI  - Hazards of the passive voice.

PMID- 8657270
TI  - Hazards of the passive voice.

PMID- 8657272
TI  - Between cows and monkeys.

PMID- 8657273
TI  - Taste transduction. A bitter-sweet beginning.

PMID- 8657274
TI  - Giant proteins with flour power.

PMID- 8657275
TI  - Fruit(less) flies provide a clue.

PMID- 8657276
TI  - BSE transmission to macaques.

PMID- 8657277
TI  - WW domains and retrovirus budding.

PMID- 8657278
TI  - Leptin activation in hypothalamus.

PMID- 8657279
TI  - Clonal selection and learning in the antibody system.
AB  - Each antibody-producing B cell makes antibodies of unique specificity, reflecting
      a series of ordered gene rearrangements which must be successfully performed if
      the cell is to survive. A second selection process occurs during immune responses
      in which a new antibody repertoire is generated through somatic hypermutation.
      Here only mutants binding antigen with high affinity survive to become memory
      cells. Cells expressing autoreactive receptors are counter-selected at both
      stages. This stringent positive and negative selection allows the generation and
      diversification of cells while rigorously controlling their specificity.

PMID- 8657280
TI  - Meiotic cell cycle requirement for a fly homologue of human Deleted in
      Azoospermia.
AB  - Infertility resulting from a severe defect in sperm production affects 2% of men
      worldwide. Of these men with azoospermia, the absence of sperm in semen, one in
      eight carry de novo deletions for a specific region of the Y chromosome. A
      candidate gene for the Y-chromosome azoospermia factor (AZF) has been identified
      and named Deleted in Azoospermia (DAZ). Here we describe the cloning and
      characterization of the Drosophila gene boule, which is a homologue of DAZ. The
      two genes encode closely related proteins that contain a predicted RNA-binding
      motif, and both loci are expressed exclusively in the testis. Loss of boule
      function results in azoospermia; meiotic divisions are blocked, although limited
      spermatid differentiation occurs. Histological examination of boule testes with
      cell-cycle markers indicates that the primary defect is at the meiotic G2/M
      transition. These results support the hypothesis that DAZ is the human AZF, and
      indicate that Boule and DAZ have an essential meiotic function in fly and human
      spermatogenesis.

PMID- 8657281
TI  - Functional receptor for GDNF encoded by the c-ret proto-oncogene.
AB  - Glial-cell-line-derived neutrophic factor (GDNF) promotes the survival and
      phenotype of central dopaminergic noradrenergic and motor neurons, as well as
      various subpopulations of peripheral sensory and sympathetic neurons. GDNF is
      structurally related to members of the transforming growth factor (TGF)-beta
      superfamily, several members of which have well-characterized receptor systems;
      however, GDNF receptors still remain undefined. Here we show that GDNF binds to,
      and induces tyrosine phosphorylation of, the product of the c-ret proto-oncogene,
      an orphan receptor tyrosine kinase, in a GDNF-responsive motor-neuron cell line.
      Ret protein could also bind GDNF and mediate survival and growth responses to
      GDNF upon transfection into naive fibroblasts. Moreover, high levels of c-ret
      mRNA expression were found in dopaminergic neurons of the adult substantia nigra,
      where exogenous GDNF protected Ret-positive neurons from 6-hydroxydopamine
      induced cell death. Thus the product of the c-ret proto-oncogene encodes a
      functional receptor for GDNF that may mediate its neurotrophic effects on motor
      and dopaminergic neurons.

PMID- 8657282
TI  - GDNF signalling through the Ret receptor tyrosine kinase.
AB  - Mutational analysis in humans and mice has demonstrated that the Ret, the product
      of the c-ret proto-oncogene, a member of the receptor tyrosine kinase (RTK)
      superfamily, is essential for development of the enteric nervous system and
      kidney. Despite the established role of Ret in mammalian embryogenesis, its
      cognate ligand(s) is currently unknown. Here we demonstrate, by using a Xenopus
      embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF), a
      distant member of the transforming growth factor (TGF)-beta superfamily, signals
      through the Ret RTK. Furthermore, using explant cultures from wild-type and Ret
      deficient mouse embryos, we show that normal c-ret function is necessary for GDNF
      signalling in the peripheral nervous system. Our data strongly suggest that Ret
      is a functional receptor for GDNF, and that GDNF, in addition to its potential
      role in the differentiation and survival of central nervous system neurons, has
      profound effects on kidney organogenesis and the development of the peripheral
      nervous system.

PMID- 8657283
TI  - Synaptic strengthening through activation of Ca2+-permeable AMPA receptors.
AB  - Postsynaptic Ca2+ elevation during synaptic transmission is an important trigger
      for short- and long-term changes in synaptic strength in the vertebrate central
      nervous system. The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate)
      receptors, a subfamily of glutamate receptors, mediate much of the excitatory
      synaptic transmission in the brain and spinal cord. It has been shown that a
      subtype of the AMPA receptor is Ca2+-permeable and is present in the
      subpopulations of neurons. When synaptically localized, these receptors should
      mediate postsynaptic Ca2+ influx, providing a trigger for changes in synaptic
      strength. Here we show that Ca2+-permeable AMPA receptors are synaptically
      localized on a subpopulation of dorsal horn neurons, and that they provide a
      synaptically gated route of Ca2+ entry, and that activation of these receptors
      strengthens synaptic transmission mediated by AMPA receptors. This pathway for
      postsynaptic Ca2+ influx may provide a new form of activity-dependent modulation
      of synaptic strength.

PMID- 8657284
TI  - Transduction of bitter and sweet taste by gustducin.
AB  - Several lines of evidence suggest that both sweet and bitter tastes are
      transduced via receptors coupled to heterotrimeric guanine-nucleotide-binding
      proteins (G proteins). Gustducin is a taste receptor cell (TRC)-specific G
      protein that is closely related to the transducins. Gustducin and rod transducin,
      which is also expressed in TRCs, have been proposed to couple bitter-responsive
      receptors to TRC-specific phosphodiesterases to regulate intracellular cyclic
      nucleotides. Here we investigate gustducin's role in taste transduction by
      generating and characterizing mice deficient in the gustducin alpha-subunit
      (alpha-gustducin). As predicted, the mutant mice showed reduced behavioural and
      electrophysiological responses to bitter compounds, whereas they were
      indistinguishable from wild-type controls in their responses to salty and sour
      stimuli. Unexpectedly, mutant mice also exhibited reduced behavioural and
      electrophysiological responses to sweet compounds. Our results suggest that
      gustducin is a principal mediator of both bitter and sweet signal transduction.

PMID- 8657285
TI  - Suppression of ceramide-mediated programmed cell death by sphingosine-1
      phosphate.
AB  - Ceramide is an important regulatory participant of programmed cell death
      (apoptosis) induced by tumour-necrosis factor (TNF)-alpha and Fas ligand, members
      of the TNF superfamily. Conversely, sphingosine and sphingosine-1-phosphate,
      which are metabolites of ceramide, induce mitogenesis and have been implicated as
      second messengers in cellular proliferation induced by platelet-derived growth
      factor and serum. Here we report that sphingosine-1-phosphate prevents the
      appearance of the key features of apoptosis, namely intranucleosomal DNA
      fragmentation and morphological changes, which result from increased
      concentrations of ceramide. Furthermore, inhibition of ceramide-mediated
      apoptosis by activation of protein kinase C results from stimulation of
      sphingosine kinase and the concomitant increase in intracellular sphingosine-1
      phosphate. Finally sphingosine-1-phosphate not only stimulates the extracellular
      signal-regulated kinase (ERK) pathway, it counteracts the ceramide-induced
      activation of stress-activated protein kinase (SAPK/JNK). Thus, the balance
      between the intracellular levels of ceramide and sphingosine-1-phosphate and
      their regulatory effects on different family members of mitogen-activated protein
      kinases determines the fate of the cell.

PMID- 8657288
TI  - A new view on polarization microscopy.

PMID- 8657286
TI  - A non-enzymatic p21 protein inhibitor of stress-activated protein kinases.
AB  - The stress-activated protein kinases (SAPKs), which are identical to the c-Jun
      amino-terminal kinases (JNKs), are activated in response to a variety of cellular
      stresses, including DNA damage, heat shock or tumour-necrosis factor-alpha. SAPK,
      a subfamily of the mitogen-activated protein (MAP) kinases, is a major protein
      kinase that phosphorylates c-Jun and other transcription factors. SAPK
      phosphorylation of transcription factors is important in stress-activated
      signalling cascades. Here we report that the protein p21 WAF1/CIP1/Sd:1, a DNA
      damage-inducible cell-cycle inhibitor, acts as an inhibitor of the SAPK group of
      mammalian MAP kinases. This highlights a new biochemical activity of p21, which
      may provide the first evidence for a non-enzymatic inhibitory protein for SAPK.
      We suggest that p21, by inhibiting SAPK, may participate in regulating signalling
      cascades that are activated by cellular stresses such as DNA damage.

PMID- 8657287
TI  - Reduction of transcription by homologue asynapsis in Drosophila imaginal discs.
AB  - The interactions between enhancers and promotor elements that control gene
      expression are generally considered to act in cis only, but genetic studies
      suggest that they can also function in trans between non-contiguous DNA
      molecules. Termed transvection, such trans interactions have been proposed to be
      responsible for several examples of intragenic complementation in Drosophila.
      Transvection is thought to depend on the physical proximity of sister
      chromosomes, because it is inhibited when chromosome rearrangements reduce the
      pairing of homologues. This led to the suggestion that transvection occurs when
      enhancer elements on one chromosome regulate expression on the other, with the
      pairing dependence resulting from a need for proximity between the two copies of
      the gene. Here we have analysed the levels of transcription from both alleles of
      the Drosophila Ultrabithorax (Ubx) gene, and report that the predictions of this
      simple model are not supported. Our findings indicate a more complex level of
      trans regulation that may have implications for the aetiology of genetic
      disorders that are influenced by chromosome rearrangements.

PMID- 8657289
TI  - Swifter, higher, stronger: pushing the envelope of performance.

PMID- 8657290
TI  - Science tracks down the training dangers.

PMID- 8657291
TI  - Could women take a lead over men in the long run?

PMID- 8657292
TI  - Performance-enhancers pose dilemma for rule-makers.

PMID- 8657293
TI  - Ownership of human genes.

PMID- 8657294
TI  - Ownership of human genes.

PMID- 8657295
TI  - Cost of living in domed cities.

PMID- 8657296
TI  - Less rosy view of science funding.

PMID- 8657297
TI  - A biological marker for dyslexia.

PMID- 8657298
TI  - Retinoblastoma protein. Another role rolls in.

PMID- 8657299
TI  - Neurotrophic factors. Crossing receptor boundaries.

PMID- 8657300
TI  - NO sexual behaviour in newts.

PMID- 8657301
TI  - Prion phylogeny revisited.

PMID- 8657302
TI  - Statistics suggest BSE now 'Europe-wide'.

PMID- 8657303
TI  - A possible high-temperature origin for the carbonates in the martian meteorite
      ALH84001.
AB  - The meteorite Allan Hills (ALH) 84001, commonly accepted to be of martian origin,
      is unique among known martian meteorites in containing abundant, zoned, pre
      terrestrial carbonate minerals. Previous studies of the oxygen isotope
      compositions of these minerals have suggested that they precipitated from a low
      temperature (0-80 degrees C) aqueous fluid in the martian crust--perhaps in a
      near-surface hydrothermal system. Here we report analyses of the major-element
      compositions of the carbonates, which provide an independent constraint on the
      composition and temperature of the fluid from which they formed. We argue that
      the most likely explanation for the observed compositions, and for the absence of
      co-existing hydrons minerals, is that the carbonates were formed by reactions
      between hot (> 650 degrees C), CO2-rich fluids and the ultramatic host rock
      during an impact event. Impact processes on the martian surface can produce both
      the hot, CO2-rich fluid (by volatilization of surface carbonates or other CO2
      sources) and--by brecciation--the condults through which it flowed. Impact
      metasomatism is also consistent with the observed oxygen isotope disequillbrium,
      sequence of mineral formation, and carbonate mineral zoning, reflecting carbonate
      formation during rapid cooling from high temperatures rather than prolonged
      exposure to low-temperature fluids.

PMID- 8657304
TI  - French action aims to quell BSE fears.

PMID- 8657305
TI  - Abnormal processing of visual motion in dyslexia revealed by functional brain
      imaging.
AB  - It is widely accepted that dyslexics have deficits in reading and phonological
      awareness, but there is increasing evidence that they also exhibit visual
      processing abnormalities that may be confined to particular portions of the
      visual system. In primate visual pathways, inputs from parvocellular or
      magnocellular layers of the lateral geniculate nucleus remain partly segregated
      in projections to extrastriate cortical areas specialized for processing colour
      and form versus motion. In studies of dyslexia, psychophysical and anatomical
      evidence indicate an anomaly in the magnocellular visual subsystem. To
      investigate the pathophysiology of dyslexia, we used functional magnetic
      resonance imaging (fMRI) to study visual motion processing in normal and dyslexic
      men. In all dyslexics, presentation of moving stimuli failed to produce the same
      task-related functional activation in area V5/MT (part of the magnocellular
      visual subsystem) observed in controls. In contrast, presentation of stationary
      patterns resulted in equivalent activations in V1/V2 and extrastriate cortex in
      both groups. Although previous studies have emphasized language deficits, our
      data reveal differences in the regional functional organization of the cortical
      visual system in dyslexia.

PMID- 8657306
TI  - Renal agenesis and the absence of enteric neurons in mice lacking GDNF.
AB  - Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor
      for dopaminergic neurons and motor neurons in culture. It also protects these
      neurons from degeneration in vitro, and improves symptoms like Parkinson's
      disease induced pharmacologically in rodents and monkeys. Thus GDNF might have
      beneficial effects in the treatment of Parkinson's disease and amyotrophic
      lateral sclerosis. To examine the physiological role of GDNF in the development
      of the mammalian nervous system, we have generated mice defective in GDNF
      expression by using homologous recombination in embryonic stem cells to delete
      each of its two coding exons. GDNF-null mice, regardless of their targeted
      mutation, display complete renal agencies owing to lack of induction of the
      ureteric bud, an early step in kidney development. These mice also have no
      enteric neurons, which probably explains the observed pyloric stenosis and
      dilation of their duodenum. However, ablation of the GDNF gene does not affect
      the differentiation and survival of dopaminergic neurons, at least during
      embryonic development.

PMID- 8657307
TI  - Defects in enteric innervation and kidney development in mice lacking GDNF.
AB  - Glial-lial-cell-line-derived neurotrophic factor (GDNF) has been isolated as
      neurotrophic factor for midbrain dopaminergic neurons. Because of its
      neurotrophic activity on a wide range of neuronal populations in vitro and in
      vivo, GDNF is being considered as a potential therapeutic agent for neuronal
      disorders. During mammalian development, it is expressed not only in the nervous
      system, but also very prominently in the metanephric kidney and the
      gastrointestinal tract, suggesting possible functions during organogenesis. We
      have investigated the role of GDNF during development by generating a null
      mutation in the murine GDNF locus, and found that mutant mice show kidney
      agenesis or dysgenesis and defective enteric innervation. We demonstrate that
      GDNF induces ureter bud formation and branching during metanephros development,
      and is essential for proper innervation of the gastrointestinal tract.

PMID- 8657308
TI  - Renal and neuronal abnormalities in mice lacking GDNF.
AB  - Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor
      for embryonic midbrain dopaminergic, spinal motor, cranial sensory, sympathetic,
      and hindbrain noradrenergic neurons, and is available to these cells in vivo. It
      is therefore considered a physiological trophic factor and a potential
      therapeutic agent for Parkinson's disease, amyotrophic lateral sclerosis, and
      Alzheimer's disease. Here we show that at postnatal day 0 (P0), GDNF-deficient
      mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but
      not in hindbrain noradrenergic or midbrain dopaminergic neurons. These mice
      completely lack the enteric nervous system (ENS), ureters and kidneys. Thus GDNF
      is important for the development and/or survival of enteric, sympathetic and
      sensory neurons and the renal system, but is not essential for catecholaminergic
      neurons in the central nervous system (CNS).

PMID- 8657310
TI  - Regulation by cAMP-dependent protein kinease of a G-protein-mediated
      phospholipase C.
AB  - The heterotrimeric G proteins mediate a variety of cellular processes by coupling
      transmembrane receptors to different effector molecules, including adenylyl
      cyclases and inositol-phospholipid-specific phospholipase C (PLC)1-3. Activation
      of adenylyl cyclases results in the production of cyclic AMP and activation of
      cAMP-dependent protein kinase (PKA). Phospholipase C catalyses the hydrolysis of
      phosphatidylinositol-4,5-bisphosphate (PtdInsP2) to generate diacylglycerol and
      inositol-1,4,5-triphosphate (InsP2), leading to the activation of protein kinase
      C (PKC) and the mobilization of intracellular calcium. The various PLC isoforms
      appear to be activated by different receptors, and in some cases by different G
      protein components. There are four well-characterized forms of PLC-beta and all
      of them are activated to various extents by the G alpha q family of G proteins.
      Specific activation of PLC isoforms beta 2 and beta 3 by G-protein beta gamma
      subunits has also been reported. Although it has been suggested that PLC activity
      might be modulated by the adenylyl cyclase pathway, no clear link has been
      established between the two pathways. Here we report that cAMP-dependent protein
      kinase specifically inhibits G beta gamma-activated PLC-beta 2 activity but not
      that of the G alpha-activated PLC isoforms, and that the effect of PKA is not
      mimicked by PKC isozymes. Furthermore, we show that PKA directly phosphorylates
      serine residues of the PLC-beta 2 protein both in vivo and in vitro. Our results
      provide an insight into the specificity and nature of the crosstalk between the
      two G-protein-coupled signal transduction pathways.

PMID- 8657309
TI  - Characterization of a multicomponent receptor for GDNF.
AB  - Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor
      for central and peripheral neurons, and is essential for the development of
      kidneys and the enteric nervous system. Despite the potential clinical and
      physiological importance of GDNF, its mechanism of action is unknown. Here we
      show that physiological responses to GDNF require the presence of a novel
      glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that
      is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We
      further demonstrate that GDNF promotes the formation of a physical complex
      between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing
      its tyrosine phosphorylation. These findings support the hypothesis that GDNF
      uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the
      ligand-binding and signalling components, respectively.

PMID- 8657311
TI  - Repression of RNA polymerase III transcription by the retinoblastoma protein.
AB  - Transcription by RNA polymerase (pol) III is under cell-cycle control, being
      higher in S and G2 than in G0 and early G1 phases. Many transformed cell types
      have elevated pol III activity, presumably to sustain sufficient protein
      synthesis for unrestrained growth. The retinoblastoma tumour-suppressor protein
      (Rb) restricts cellular proliferation, and is often found mutated in transformed
      cells. Here we demonstrate that Rb can repress the level of transcription from
      pol III templates both in vitro and vivo. Analysis of Rb-deficient SAOS2 cells
      and primary fibroblasts from Rb-/- mice demonstrates elevated levels of pol III
      activity in the absence of functional Rb protein. Rb-induced repression of pol
      III activity is alleviated by mutations in the Rb pocket domain that occur
      naturally in tumours, and by viral transforming proteins that bind and inactivate
      Rb. These results implicate repression of pol III transcription as a mechanism
      for Rb-induced growth arrest, and suggest that restraining protein biosynthesis
      may be important in the prevention of tumour development.

PMID- 8657312
TI  - A helical arch allowing single-stranded DNA to thread through T5 5'-exonuclease.
AB  - THE 5'-exonucleases are enzymes that are essential for DNA replication and
      repair. As well as their exonucleolytic action, removing nucleotides from the 5'
      end of nucleic acid molecules such as Okazaki fragments, many 5'-3'-exonucleases
      have been shown to possess endonucleolytic activities. T5 5'-3'-exonuclease
      shares many similarities with the amino terminal of eubacterial DNA polymerases,
      although, unlike eubacteria, phages such as T5, T4 and T7 express polymerase and
      5'-exonuclease proteins from separate genes. Here we report the 2.5-A crystal
      structure of the phage T5 5'-exonuclease, which reveals a helical arch for
      binding DNA. We propose a model consistent with a threading mechanism in which
      single-stranded DNA could slide through the arch, which is formed by two helices,
      one containing positively charged, and the other hydrophobic, residues. The
      active site is at the base of the arch, and contains two metal-binding sites.

PMID- 8657313
TI  - [Angina pectoris and myocardial infarct in infants].

PMID- 8657314
TI  - [Significance of pharmacoepidemiology for drug monitoring and quality of care:
      the pill].

PMID- 8657315
TI  - [Reperfusion therapy in acute heart infarct; things go better with 'Dotter'].

PMID- 8657316
TI  - [Inhalation therapy in young children with asthma].

PMID- 8657317
TI  - [Monoclonal antibodies for diagnosis and therapy in oncological patients].

PMID- 8657318
TI  - [Glucose intolerance in elderly persons in The Netherlands; the Twello Study].
AB  - OBJECTIVE: To determine the prevalence of grades of glucose intolerance in
      subjects over 64 years of age. DESIGN: Point prevalence study. SETTING: Twello, a
      rural village in the Netherlands. METHODS: Of a total of 696 persons aged over 64
      years recruited from a general practice, 460 subjects had an oral glucose
      tolerance test (OGTT) in 1985, 56 were known with non-insulin-dependent diabetes
      mellitus. Glucose estimations were done in capillary whole blood with a
      Glucometer. OGTT results were classified according to WHO 1985 recommended cut
      off points and combination rules. RESULTS: The prevalence of normal glucose
      tolerance was 42%, of impaired glucose tolerance 27% and of diabetes mellitus
      31%. The estimated prevalence in the source population were 45% (44.4-44.6), 28%
      (28.3-28.5) and 27% (95% CI: 27.1-27.2) respectively, adjusted for age and gender
      by standardization to the Dutch population of 1985. Re-evaluation of the earlier
      diagnoses of 'diabetes mellitus' according to the new WHO guidelines revealed
      that 55% of earlier diabetic with diet as the only therapy were no longer
      classified as diabetics. The prevalence of diabetes mellitus in persons over 64
      was 10% before the investigation took place, and 30% afterwards. CONCLUSIONS: Te
      prevalence of diabetes mellitus as well as of impaired glucose tolerance from the
      Twello study rank among the higher rates reported in Caucasian populations. Case
      finding of glucose intolerance in those at risk over 64 years of age is
      recommended.

PMID- 8657319
TI  - [Favorable long-term results of primary percutaneous transluminal coronary
      angioplasty in acute myocardial infarction compared to intravenous streptokinase
      treatment; a randomized study].
AB  - OBJECTIVE: To evaluate the treatment of patients with acute myocardial infarction
      with thrombolytic drugs or primary angioplasty in a randomized trial. DESIGN:
      Randomized trial. SETTING: Hospital De Weezenlanden, Zwolle, the Netherlands.
      METHODS: A total of 301 patients with acute myocardial infarction were included
      in the trial, of whom 152 patients were allocated to primary angioplasty and 149
      patients to intravenous streptokinase. The mean follow-up duration was 31 months
      (SD:9). Left ventricular function was assessed with a radionuclide technique
      before hospital discharge and at the end of the follow-up period. A cost analysis
      was performed based on the calculation of all medical costs. RESULTS: At the end
      of the follow-up period, 5% of the angioplasty patients had died from a cardiac
      cause compared with 11% of the patients randomized to intravenous streptokinase
      (p = 0.031). Death or non-fatal reinfarction occurred in 7% of angioplasty
      patients and in 28% of streptokinase patients (p < 0.001). There was a sustained
      beneficial effect of angioplasty in comparison with streptokinase on left
      ventricular function, 48 (SD12)% versus 43(SD13)% (p < 0.01). Most benefit was
      observed in patients with an anterior wall myocardial infarction. CONCLUSION:
      After an average of 31 months (SD:9) primary angioplasty in comparison with
      intravenous streptokinase resulted in a lower rate of cardiac death and
      reinfarction and a better left ventricular ejection fraction, without an increase
      in total costs.

PMID- 8657321
TI  - [Compositae dermatitis caused by contact allergy to sesquiterpene lactones].

PMID- 8657320
TI  - [Sleeping position and covering of infants in the fall of 1994].
AB  - OBJECTIVE: To determine whether the sleeping position and the use of duvets in
      infants in 1994 had changed in comparison with earlier years. DESIGN:
      Questionnaire survey. SETTING: Nationwide investigation in infant welfare
      centres. METHOD: 194 infant welfare centres participated in the investigation. In
      November a questionnaire was completed regarding 25 preferably consecutive
      infants younger than 10 months, featuring: age in completed months, sex, parity
      of the mother, birth weight and subsequently: the position in which the infant
      was laid to sleep, and its cover during the last night. RESULTS: The prone
      sleeping position decreased roughly from more than 55% in 1985-1987 to 24% in
      1988 and 9% in 1994. In these surveys prone sleeping was significantly associated
      with masculine gender, low birthweight and higher parity of the mother. These
      associations explain at least partly the increased risk of cot death in each of
      these three conditions. In the Netherlands in November 1994 duvets were still
      used (77%). CONCLUSION: A further reduction of the cot death incidence (in 1993
      0.30 per 1000 live births) may be expected from further implementation of
      preventive measures.

PMID- 8657322
TI  - [Rhesus blood group].

PMID- 8657323
TI  - [2 years further: a chafing WAO (Law for Work Disability Insurance)?].

PMID- 8657324
TI  - [Qualitative approach in medical research].

PMID- 8657325
TI  - [Pelvic pain caused by pregnancy].

PMID- 8657326
TI  - [An unusual complication of pneumococcal pneumonia: tamponade caused by purulent
      pericarditis].

PMID- 8657327
TI  - [The study of muscle strength in clinical practice].

PMID- 8657328
TI  - Immunohistochemical study of glutathione S-transferase-pi in meningiomas.
AB  - Immunostaining for glutathione S-transferase-pi was investigated in various
      subtypes of meningioma for the purpose of biological characterization. Specimens
      included five normal meninges and 25 meningiomas (10 meningothelial type, 6
      fibrous type, 5 transitional type, 3 microcystic type, and 1 secretory type). In
      the meningothelial type, most cells showed strongly positive staining. In the
      fibrous type, all cells were negative. In the transitional type, only the
      meningothelial components were positive. In the microcystic type, meningothelial
      cell clusters and arachnoid trabecular cells were positive. In the secretory
      type, the meningothelial components and the pseudopsammoma-body-producing cells
      were positive. These results suggest that the meningothelial type and the fibrous
      type have a different basis of development and biological features. The results
      also suggest that arachnoid trabecular cells and meningothelial cells share the
      same origin, and that the arachnoid trabecular cells serve as supportive cells
      and as cells which detoxify harmful substances in the subarachnoid space. The
      pseudopsammoma-body-producing cells in the secretory type represent the outcome
      of epithelial differentiation of meningothelial cells with their biological
      character being preserved.

PMID- 8657329
TI  - Mammosomatotroph adenoma cells secrete both growth hormone and prolactin.
AB  - Pituitary adenoma cells from a mammosomatotroph adenoma obtained from a 21-year
      old female presenting with acromegaly and amenorrhea were investigated by
      sandwich cell immunoblot assay, immunohistochemistry, and electron microscopy.
      The new, simple technique of sandwich cell immunoblot assay could detect two
      hormones secreted in the same one cell, and found that 89% of mammosomatotrophs
      secreted both growth hormone (GH) and prolactin (PRL). Immunohistochemistry
      showed that the tumor cells were positive for both GH and PRL. Electron
      microscopy showed cells contained granules ranging in size form 150 to 500 nm.
      This is the first demonstration of both GH and PRL in the same mammosomatotroph
      cell. Sandwich cell immunoblot assay can measure the amount of secreted hormone,
      allowing a new approach to the investigation of mammosomatotroph adenomas.

PMID- 8657330
TI  - Effects of cervical spinal cord stimulation on glucose consumption in patients
      with posttraumatic prolonged unconsciousness.
AB  - The effects of cervical spinal cord stimulation (CSCS) on glucose consumption
      were examined in two patients with prolonged disturbance of consciousness due to
      head injuries. Several clinical parameters, including glucose consumption using
      positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG),
      were compared before and after CSCS. After a 4-month period of stimulation, one
      patient (Case 1) regained consciousness and began to speak, but the other patient
      (Case 2) showed no improvement in consciousness level. Computed tomography and
      magnetic resonance imaging showed Case 1 had no abnormalities in the thalamus and
      brainstem and no diffuse brain atrophy. Case 2 had a low density area in the left
      thalamus and enlargement of the aqueduct with diffuse atrophy of the left
      cerebral hemisphere. Cerebral blood flow studies and electrophysiological
      examinations revealed no remarkable change after CSCS. The PET study showed an
      increase in FDG uptake in the hypothalamus and the thalamus in both patients, but
      an increase in FDG uptake in the left cingulate gyrus and left frontal lobe was
      observed only in Case 1. These observations suggest that activation of the
      ascending reticular activating system, hypothalamus, thalamus, cingulate gyrus,
      and frontal cortex, and the preservation of the fiber connections between the
      limbic system and the thalamus and hypothalamus are important for CSCS treatment
      to improve the level of consciousness.

PMID- 8657331
TI  - Cranioplasty with split-thickness calvarial bone.
AB  - Cranioplasty with autogenous split-thickness calvarial bone was performed in 10
      patients. Follow-up for a mean of 19 months (range 2-43 mos) showed satisfactory
      protection of the brain and cosmetic reconstruction. No serious complication was
      seen except in one patient with postoperative epidural abscess. Split-thickness
      calvarial bone graft is recommended in patients with previous infection or high
      risk of infection, in poorly vascularized recipient sites resulting from multiple
      operations or irradiation, and in younger patients aged more than 7 years.

PMID- 8657333
TI  - Cerebral gumma showing linear dural enhancement on magnetic resonance imaging-
      Case report.
AB  - A 51-year-old male presented with a rare cerebral gumma accompanied by abducens
      nerve paresis and cerebellar infarction. Magnetic resonance (MR) imaging
      demonstrated a homogeneous enhance mass lesion and adjacent linearly enhanced
      dura mater. Histological examination of the mass revealed a caseating granuloma.
      Serological studies were positive for active syphilis. Although linear dural
      enhancement adjacent to the mass lesion on MR imaging is characteristic of
      meningioma, this finding is also demonstrated in cerebral gumma. Therefore,
      cerebral gummas should also be included in the differential diagnosis.
      Immunological tests for syphilis (serum, cerebrospinal fluid) can confirm the
      diagnosis.

PMID- 8657332
TI  - Serial positron emission tomography imaging of changes in amino acid metabolism
      in low grade astrocytoma after radio- and chemotherapy-- Case report.
AB  - A 37-year-old male with mixed glioma was treated with combined radio- and
      chemotherapy. The amino acid metabolism of the tumor site and normal brain was
      followed by positron emission tomography using [11C]methionine ([11C]Met). The
      accumulation of [11C]Met in the tumor decreased during therapy and slightly
      increased 7 months after completion of the therapy, but then decreased markedly.
      However, computed tomography revealed no notable changes. The contralateral gray
      matter also showed a gradual decrease of [11C]Met accumulation. These findings
      indicate that reduction of amino acid metabolism in the tumor continues after
      radiochemotherapy although neuroimaging reveals no further morphological changes.
      Such therapy also has long-term effects on normal brain tissue.

PMID- 8657334
TI  - Eighth cranial nerve lipoma manifesting as intractable vertigo--Case report.
AB  - A 49-year-old female presented with an extremely rare lipoma of the
      cerebellopontine angle (CPA) manifesting as intractable vertigo and tinnitus.
      Subtotal removal of the lipoma was performed to debulk the tumor and decompress
      the cranial nerve VIII. Her complaints were resolved without new neurological
      deficit. We recommended surgery in patients with symptomatic CPA lipomas for
      diagnosis, debulking, and decompression of cranial nerves to relieve the
      symptoms.

PMID- 8657335
TI  - Dolichoectasia of the middle cerebral artery--Case report.
AB  - A 59-year-old female with a previous history of head injury presented with mild
      occipitalgia due to dolichoectasia of the middle cerebral artery (MCA). Initial
      examination by computed tomography and angiography using the usual projections
      suggested a terminal internal carotid artery saccular aneurysm. However,
      angiography by the reverse Waters view excluded a saccular aneurysm.
      Superselective angiography using a microcatheter revealed the complex tortuous
      course of the MCA due to dolichoectasia. She was discharged and has remained
      asymptomatic. Superselective angiography is extremely useful for the diagnosis of
      dolichoectasia localized in the MCA.

PMID- 8657336
TI  - Posterior cerebral artery aneurysm associated with unilateral internal carotid
      artery agenesis--Case report.
AB  - A 38-year-old housewife presented with a ruptured aneurysm associated with
      unilateral internal carotid artery agenesis. She had been in good health until
      May 31, 1994, when she was admitted to our facility immediately after sudden
      onset of headache and nausea. She was alert and exhibited no focal neurological
      deficit on admission. Cerebral angiography demonstrated an aneurysm arising from
      the junction of the horizontal segment of the right posterior cerebral artery and
      posterior communicating artery. The right internal carotid artery was totally
      absent. High resolution computed tomography demonstrated absence of the right
      carotid canal in the skull base. Neck clipping of the aneurysm was carried out
      through the right pterional approach on June 2. She returned home 52 days after
      the surgery with mild paresis of the left upper extremity and has since resumed
      household activities. Early surgery may be recommended in a patient with a
      ruptured aneurysm associated with agenesis of the internal carotid artery to
      prevent catastrophic rebleeding, if the initial insult is mild and subsequent
      vasospasm is unlikely to occur.

PMID- 8657337
TI  - Hypertrophic anterior falx artery associated with interhemispheric subdural
      empyema--Case report.
AB  - A 14-year-old boy presented with interhemispheric subdural empyema. Angiography
      demonstrated a hypertrophic anterior falx artery. He was treated with antibiotics
      and craniotomy to evacuate the lesion. The postoperative course was uneventful
      with no signs of neurological deficit. The abnormal artery was no longer
      visualized angiographically after the resolution of the empyema. Reactive
      appearance of the anterior falx artery is a pathognomonic sign of
      interhemispheric subdural empyema.

PMID- 8657338
TI  - [The effect of stereotaxic injuries on the medial temporal brain structures on
      memorization of successively or simultaneously presented material].
AB  - Effect of stereotaxic injuries to the medial temporal brain structures on
      memorization of material presented successively or simultaneously was studied.
      The study aimed at testing whether stereotaxic damage to the hippocampus and
      amygdala results in a memory deficit and whether functions subserved by those
      structures depend on type and organization of the memorized material. The results
      indicate that even small damage to the medial temporal lobe structures may result
      in a deficit in memorization ability. The greatest impairment was observed for
      successive presentation of nonverbal stimuli.

PMID- 8657339
TI  - [The acid-base balance of cerebrospinal fluid].
AB  - On the basis of literature the mechanisms of acid-base balance in cerebrospinal
      fluid (CSF) in physiological and pathological conditions were discussed. The
      author focused on acid-base balance in CSF in the course of meningitis and
      meningoencephalitis and the influence of its disorders in the pathogenesis of
      those illnesses of central nervous system.

PMID- 8657340
TI  - [The physiopathology of acute spinal cord injury and a hope for a successful
      treatment].
AB  - The acute phase of spinal cord injury includes primary and secondary pathological
      patterns. Primary patterns include the effects of contusion, laceration, stretch
      of neural tissue and direct vascular trauma. These changes are irreversible.
      Secondary patterns include posttraumatic ischemic changes, loss of energy
      metabolism, oedema, release of cytotoxic substances such as free radicals, and
      electrolyte changes such as an increase in intracellular calcium ions. These
      changes may be reversible. This determines treatment strategies. Free-radical
      scavengers, opioid receptor antagonists include TRH and its analogues, calcium
      channel blockers, volume expander, osmotic diuretics, hypothermia, antioxidants,
      cycloxygenase inhibitors, serotonin antagonists and NMDA receptor antagonists
      were tested in experimental models during the last 4 years. The successful
      treatment should break the feedback loops and trails of secondary injury cascade
      in many places so combined treatment connected with many elements and surgery
      decompression is necessary.

PMID- 8657341
TI  - [A case of giant hemangioma of the vertebral canal].
AB  - An 18-year-old girl with rarely occurring extensive vertebral canal haemangioma
      is described. The clinical onset of the disease was sudden, with weakness of
      lower extremities and girdle pains at the level of lower ribs. Despite several
      recurrences of the symptoms and permanent motor function deficit the patient was
      able after reparative operations, radiotherapy, rehabilitation treatment and
      pharmacological therapy to move around unaided using elbow crutches.

PMID- 8657342
TI  - [A case of incomplete cortical blindness].
AB  - A patient is reported with cortical blindness after craniocerebral injury in whom
      certain traces of visuals function were disclosed during treatment of
      Neurological Rehabilitation Hospital. The analysis of the observations is
      presented.

PMID- 8657343
TI  - [Neurology in Vilna in 1939-1945].

PMID- 8657344
TI  - [Report on the 11th Congress of European Committee for the treatment and research
      of multiple sclerosis, Jerusalem (Israel),Sept. 3-6, 1995].

PMID- 8657345
TI  - [Report on the 2nd International Conference on the surgery of acoustic nerve
      neuromas and from 2nd European Congress of the Society of cranial base surgery,
      Paris, April 22-26, 1995].

PMID- 8657346
TI  - [Report on the European course in neurosurgery, Ossiach-Klagenfurt, Austria,
      Sept. 9-15, 1995].

PMID- 8657347
TI  - [The application of immunoblotting micromethod for the detection of oligoclonal
      Igg in cerebrospinal fluid in multiple sclerosis].
AB  - The demonstration of the presence of intrathecal synthesis of immunoglobulins as
      oligoclonal band (OB) in cerebrospinal fluid (CSF) is considered to be important
      as an aid to multiple sclerosis diagnosis. We used the Phast System equipment for
      OB detection in the CSF. Separation was performed on polyacrylamide gels pI 3
      9.7. After separation proteins were visualised with silver staining according to
      manufacturer instruction or transferred electrophoretically on to nitro-cellulose
      membrane and developed by immunostaining technique. We also calculated indexes of
      intrathecal synthesis of IgG. We tested CSF of patients with clinically defined
      multiple sclerosis (n = 29) according to Poser criteria. In all cases IgG indexes
      were normal. OB were present in 83% with silver staining and in 93% when we used
      immunoblotting technique. CONCLUSIONS: 1. Detection of OB with Past System is
      easily performed in routine diagnostic process. 2. Immunoblotting technique
      increases sensitivity of detection of OB and needs small amounts of CSF. 3. The
      demonstration of OB in CSF is a method of choice in diagnostic process of
      inflammatory diseases of nervous system, especially in cases of MS.

PMID- 8657348
TI  - [Usefulness of EEG examination in the diagnosis of multiple sclerosis with
      particular reference to its prognostic importance in retrobulbar neuritis].
AB  - It is known from literature that 40-60% of eeg recordings from SM patients show
      changes. These changes are: slow generalised activity, focal changes, and sharp
      waves and spikes occurring in bursts. It is established that optic neuritis often
      precedes the occurrence of neurological focal changes in SM. The goal of this
      work was the analysis of eeg recordings from SM patients before and after
      treatment during disease exacerbation and from patients with optic neuritis
      without neurological changes. Eeg recordings in optic neuritis showed changes
      similar to those observed in SM. Follow-up studies proved that patients with
      changes in eeg during neuritis were at a risk group; absence of such changes does
      not exclude the possibility of SM. Patients after neuritis should periodically
      undergo neurological examination.

PMID- 8657349
TI  - [Blood-cerebrospinal fluid barrier in purulent cerebrospinal meningitis].
AB  - Our investigations concerned the blood-brain barrier (b.b.b.) in patients with
      acute bacterial purulent meningitis. For that purpose concentrations of proteins,
      which are synthesized beyond the central nervous system and in normal
      cerebrospinal fluid (CSF) exist only in slight amounts, were determined in CSF
      and in blood serum. Albumin was examined in the CSF of 59 patients and in the
      serum of 35 of them, transferrin of 40 and 32 patients, respectively. Etiological
      verification was obtained in 84.7% of patients. The control group consisted of 20
      persons. Quantitative analytical tests were carried out by means of
      immunochemical, turbidimetric methods. High levels of albumin and transferrin in
      CSF and low in serum of patients with meningitis were observed. The obtained
      results, confirmed by statistical analysis, demonstrate that in the acute phase
      of purulent meningitis b.b.b is impaired, what leads to the transfer of the
      proteins from the blood serum into the cerebrospinal fluid and that transferrins
      a better indicator of the damage to blood-brain barrier than albumin.

PMID- 8657350
TI  - [The effect of intravenous ascorbic acid on urinary 17-hydroxysteroid excretion
      at an early stage of cerebral stroke].
AB  - The main symptoms of stroke such as a displacement of intracranial structures,
      changes in spatial relations, secondary hemorrhagic and ischemic foci, oedema and
      metabolic disturbances are the cause of the disorders of hypothalamus-hypophysis
      system leading to increased secretion of corticosteroids including 17
      hydroxyketosteroids (17-OHKS). Steroidogenesis in inhibited by high
      concentrations of ascorbic acid. Intravenous injections of ascorbic acid 0.5 g
      were given to the patients with stroke and their urine was analysed daily to
      examine the secretion of 17-OHKS. A slight increase in 17-OHKS secretion was
      found on 1 and 2 days of the disease in patients suffering from TIA and a
      significant increase in 17-OHKS secretion was detected in patients with cerebral
      ischaemia (ischemic stroke) and cerebral hemorrhage and persisted for 3-4 days of
      the illness. One can presume that the disorders of hypothalamus-hypophysis
      adrenal system contributes much more to the decrease in 17 OHKS secretion on
      successive days of stroke than the administration of ascorbic acid.

PMID- 8657352
TI  - [Cyclophosphamide changes oligoclonal immunoglobulin G spectrum in cerebrospinal
      fluid in slowly progressing multiple sclerosis].
AB  - The effects of treatment with cyclophosphamide (CY) and prednisone on the
      spectrum of oligoclonal IgG (olgG) of the cerebrospinal fluid were studied in 33
      cases of slowly progressing multiple sclerosis. CY was administered intravenously
      in a total dose of 4 g during 10 days. This treatment was supplemented with
      prednisone 775 mg p.o. given during the following 25 days. The electrophoretic
      separation of proteins in non-concentrated CSF and in serum before and
      immediately after the treatment was done by Laemili's method with associated
      impregnation with silver salts. The analysis of these electrophorograms showed
      the presence of qualitative and quantitative changes of olgG spectrum.
      Quantitative changes found in 59% of the cases included more pronounced (8% of
      cases) appearance or attenuation (51% of cases) of individual bands. Qualitative
      changes in form of elimination of bands were noted in 29% of cases, and in 12% of
      cases new bands appeared. The authors conclude that, the results confirm a strong
      immunosupressive effect of CY on olgG in slowly progressing m.s.

PMID- 8657351
TI  - [The alpha-fetoprotein level analysis in open neural tube defects and chromosomal
      aberrations in the fetus].
AB  - During the last 12 years 4258 amniocenteses were performed between the 12th and
      20th week of gestation (including 323 early amniocenteses carried out before 15th
      week). In every case, cytogenetical examination was performed and concentration
      of AFP was determined. In cases with elevated AFP level electrophoresis of AchE
      izoenzymes was performed. The results of the tests enabled us to calculate
      laboratory standard values of AFP in the amniotic fluid for 12th to 20th weeks of
      gestation. In 22 of 44 pregnancies with Down's syndrome the value of AFP
      concentration was below the 25th percentile of the laboratory normal value. In 5
      of 10 pregnancies with Edward's syndrome AFP level exceeded significantly the
      75th percentile of the laboratory norm. In two cases it was due to coexisting
      spina bifida and in one case due to omphalocele. In 28 amniotic fluid samples AFP
      concentration exceeded normal level and electrophoresis of AchE revealed
      additional band. In 26 cases increased values of AFP were due to open neural tube
      defect in the fetus: 13 cases of anencephaly and 13 cases of spina bifida; in the
      remaining two other cases omphalocele was found.

PMID- 8657353
TI  - [The early results of surgical treatment of chronic subdural hematomas in
      computerized tomography imaging].
AB  - Since the introduction of computerized tomography (CT) it has been possible to
      trace the image of the brain after removal of subdural haematoma. Postoperative
      studies demonstrated often presence of residual haematoma. This raises the
      problem of establishing indication to reoperation, especially of patients with
      good clinical condition. The clinical condition and CT images before and after
      operation were assessed in 20 patients treated surgically for chronic subdural
      haematoma. A statistically significant correlation was found between the
      magnitude of the effect of the space occupying lesion in CT image and the
      severity of the clinical condition. A high-grade mass effect with major
      ventricular system shifting was more often connected with presence of partly
      haemolysed haematoma in CT. Subdural haematoma thickness exceeding 20 mm
      correlated with serious clinical condition of the patient, and increased the
      likelihood of hemiparesis persisting after the operation. Finding of residual
      haematoma in postoperative CT should not be an indication to reoperation, if not
      associated with high-grade mass effect and if the clinical condition is good. In
      our material out of 15 patients with good clinical condition postoperatively
      residual haematoma was detected by CT in 12 cases, but only one had to be
      reoperated because of persistent high-grade mass effect.

PMID- 8657354
TI  - [Cases of "delayed" subdural posttraumatic hygromas].
AB  - The authors present 6 cases of uni- or bilateral subdural hygromas that appeared
      a few weeks following severe head injury. Such hygromas were named by the authors
      as "delayed" ones. Surgical evacuation of hygroma resulted in patient's status
      improvement in all 6 cases, based on well-known theories of posttraumatic
      hygromas origin, the authors try to explain patomechanism of the "delayed"
      hygromas.

PMID- 8657355
TI  - [Meningiomas of sella turcica: some clinical aspects].
AB  - The authors present their own experience in the treatment of tuberculum sellae
      meningiomas. The presented series includes 14 patients operated on during past 7
      years. Visual loss was the first symptom in 78% of patients. The period between
      the onset of symptom and surgical treatment was long and in the majority of
      patients exceeded 2 years. Monocular blindness was found in 71% of cases prior to
      surgery. The authors present the results of surgical treatment with special
      attention directed to visual function after surgery. In conclusion, the authors
      stress the still unacceptably long period between the onset of symptoms and
      correct diagnosis. When the size of tumour exceeds 4 cm and compressing of
      adjacent important neurovascular structures is evident, possibilities of total
      removal are limited and the chance for visual improvement is low.

PMID- 8657356
TI  - Face and voice expression identification in patients with emotional and
      behavioural changes following ventral frontal lobe damage.
AB  - Impairments in the identification of facial and vocal emotional expression were
      demonstrated in a group of patients with ventral frontal lobe damage who had
      socially inappropriate behaviour. The expression identification impairments could
      occur independently of perceptual impairments in facial recognition, voice
      discrimination, or environmental sound recognition. The face and voice expression
      problems did not necessarily occur together in the same patients, providing an
      indication of separate processing. Poor performance on both expression tests was
      correlated with the degree of alteration of emotional experience reported by the
      patients. There was also a strong positive correlation between the degree of
      altered emotional experience and the severity of the behavioural problems (e.g.
      disinhibition) found in these patients. A comparison group of patients with brain
      damage outside the ventral frontal lobe region, without these behavioural
      problems, was unimpaired on the face expression identification test, was
      significantly less impaired at vocal expression identification and reported
      little subjective emotional change. The expression identification deficits in
      ventral frontal patients may contribute to the abnormal behaviour seen after
      frontal lesions, and have implications for rehabilitation.

PMID- 8657357
TI  - Response suppression, initiation and strategy use following frontal lobe lesions.
AB  - Ninety-one patients with cerebral lesions were tested on a task involving two
      conditions. In the first condition (response initiation) subjects were read a
      sentence from which the last word was omitted and were required to give a word
      which completed the sentence reasonably. In the second condition (response
      suppression) subjects were asked to produce a word unrelated to the sentence.
      Patients with frontal lobe involvement showed longer response latencies in the
      first condition and produced more words which were related to the sentence in the
      second, in comparison to patients with lesions elsewhere. Moreover, in the second
      condition patients with frontal lobe lesions produced fewer words which showed
      the use of a strategy during response preparation. Performance on the initiation
      and suppression conditions was unrelated at the group or single case level. The
      relationship between response initiation, suppression and strategy use are
      discussed.

PMID- 8657358
TI  - Stroop interference and disorders of selective attention.
AB  - Fourteen patients with right-hemisphere CVA and 8 patients with a left-hemisphere
      CVA were examined for selective attention deficits using a variant of the Stroop
      color-word task: the picture-word interference task. Experiments 1 and 2 first
      compared the performance of the two patient groups and a control group in three
      tasks of increasing difficulty: picture-word detection, word reading, and picture
      naming. The results showed that (a) the two patient groups were significantly
      slower than the control group, but did not differ from each other, and (b) the
      difference in mean RT between the two patient groups and the control group did
      not increase with task difficulty. In Experiment 3, the subjects were required to
      name pictures while ignoring accompanying distractors: nonletter symbols,
      unrelated words or semantically related words. In this task, the right hemisphere
      patients showed a much larger semantic interference effect than both the left
      hemisphere patients and the control group. It is argued that this finding most
      probably reflects problems in visual selective attention with the right
      hemisphere patients.

PMID- 8657359
TI  - Cerebral asymmetries in inspection time?
AB  - Recent studies have suggested that there are low-level processing asymmetries
      across the cerebral hemispheres, with a right visual field-left hemisphere
      advantage in tasks involving temporal resolution. In the present report, one such
      task, inspection time, was measured separately for each cerebral hemisphere in 10
      right-handed male subjects over 5 days. A number of methodological improvements
      were made on previous studies in which a general right visual field-left
      hemisphere advantage had been found relative to the left visual field-right
      hemisphere in inspection time performance. The present results suggest that there
      is no general left hemisphere advantage in inspection time, although there might
      be asymmetries in practice effects across the hemispheres. The findings also
      suggest the existence of individual differences in the extent and direction of
      hemispheric specialisation for this task (ranging from left hemisphere dominance
      to marked right hemisphere dominance for some subjects) even in right-handed
      subjects.

PMID- 8657360
TI  - Perception of apparent motion across the retinal midline following
      commissurotomy.
AB  - One subject (L.B.) with complete forebrain commissurotomy, another (D.K.) with
      posterior callosotomy, and 12 normal controls, were shown either single lights,
      simultaneous pairs, or successive pairs, presented either within the left or
      right visual fields or bilaterally. Regardless of location, all subjects scored
      at or near ceiling in discriminating: (1) simultaneous pairs from single lights,
      (2) successive pairs from single lights, (3) simultaneous pairs from successive
      pairs, and (4) leftward succession from rightward succession. However, with
      bilateral presentation, L.B. was often slow to respond to successive lights, and
      his accuracy in detecting bilateral succession deteriorated when successive
      presentations were intermixed with simultaneous pairs and single lights. These
      and other results suggest that three mechanisms may contribute to the
      discrimination of apparent motion: the detection of simultaneous events, a
      subcortically mediated switch in attention from first to second location, and
      cortical tracking between locations. Cortical tracking across the midline is
      incapacitated following complete forebrain commissurotomy.

PMID- 8657361
TI  - Systemic NMDA antagonist CGP-37849 produces non-specific impairment in a working
      memory task: the effect does not resemble those of AP5 and of lesions of the
      hippocampus or fornix.
AB  - The N-methyl-D-aspartate (NMDA) receptor antagonist CGP-37849 (D,L-(E)-2-amino-4
      methyl-5-phosphono-3-pentenoic acid), administered i.p. (2.0 and 4.0 mg/kg),
      impaired rats' performance in a delayed matching-to-sample working memory task.
      This task is sensitive to hippocampal/fornix lesions or intracerebroventricular
      (i.c.v.) administration of another NMDA antagonist, AP5 (2-amino-5-phosphono
      pentanoic acid) in a stimulus-specific manner: the highest impairment when simple
      stimuli are used repeatedly; moderate impairment when complex stimuli are used
      repeatedly; and no impairment when complex stimuli are used in a pseudo-trial
      unique fashion. The effect of CGP-37849, unlike those of surgical lesions and of
      AP5, was not stimulus-specific and therefore cannot be solely attributed to
      blockade of NMDA-dependent long-term potentiation (LTP) in the hippocampus. We
      infer that systemic administration of NMDA antagonists may affect a broad range
      of anatomical structures thereby interfering with other neural mechanisms of
      memory and motor performance.

PMID- 8657362
TI  - Are perception and memory for faces influenced by a specific age at onset factor
      in Parkinson's disease?
AB  - This study investigated the possibility that a specific age at onset factor in
      Parkinson's disease results in qualitative differences in cognitive functioning
      between early- and late-onset patients without dementia. Both early- and late
      onset patients performed more poorly than matched controls on face-matching,
      recognition memory for unfamiliar faces and famous face identification. When the
      performance of the early- and late-onset patients was contrasted, alongside that
      of controls, both Parkinson's disease and age were found to be factors that
      influenced cognitive ability. No interaction between these factors emerged. These
      results suggest that performance of early- and late-onset Parkinson's disease
      patients without dementia may be quantitatively different and lend no further
      support to the proposal that two separate disorders exist.

PMID- 8657363
TI  - Transient topographical amnesia and cingulate cortex damage: a case report.
AB  - Transient topographical amnesia (TTA) is the temporary inability to find one's
      way in familiar or unfamiliar surroundings due to the inability to use well known
      environmental landmarks for route finding. The syndrome has not been described as
      having any obvious aetiology and has been thought to be caused by a vascular
      deficit in right hemispheric structures which are crucial for topographic
      recognition, i.e. parietal association and parahippocampal cortex. The patient
      described in the present study complained of several critical episodes of TTA and
      tonic rigidity of the left limbs. Neuropsychological assessment was normal except
      for a deficit in spatial memory tasks. Magnetic resonance (MR) imaging of the
      brain showed an angioma at the border of areas 24d and 23 of the right cingulate
      cortex. Because area 23 is strategically located in a network that links the
      parietal associative (area 7a) and parahippocampal cortices, and because these
      cortical areas are involved in topographical orienting processes, we suggest that
      a transient functional inactivation of the network caused by epileptic discharges
      spreading from the damaged cingulate cortex towards the parahippocampal and
      parietal association cortex could account for the spatial disorder. Similar
      discharges spreading from area 24d towards the primary motor cortex and/or the
      spinal cord could account for the episodes of tonic rigidity of the left limbs.

PMID- 8657364
TI  - Resuscitation from out-of-hospital cardiac arrest: past, present and future.

PMID- 8657365
TI  - IGF-1 and IGFBP-3 screening for disorders of growth hormone secretion.
AB  - AIM: To assess the value of plasma assays of insulin like growth factor (IGF-1)
      and insulin like growth factor binding protein 3 (IGFBP-3) in the diagnosis of
      growth hormone disorders in children and adults. METHODS: Plasma IGF-1 and IGFBP
      3 were measured in 47 children referred for the assessment of short stature, 26
      adult subjects with hypopituitarism and in 10 adult subjects with acromegaly.
      Findings were compared with results obtained in 148 normal children and 124
      normal adult subjects who comprised the reference range. RESULTS: Levels of both
      growth factors and especially IGF-1 are highly age dependent in normal children
      and adults. Six of 47 short children had growth hormone deficiency and in these
      cases both IGF-1 and IGFBP-3 were close to the lower limit or below the normal
      reference range. In young children ( < 10 yr) IGFBP-3 was more informative than
      IGF-1, distinguishing normal short children from those with growth hormone
      deficiency. IGF-1 levels were raised in all 10 acromegalic adults, eight of whom
      had normal levels of IGFBP-3. Similarly growth hormone deficient adults were
      better identified (23 of 26 patients) by IGF-1 whereas IGFBP-3 was subnormal in
      only eight cases. CONCLUSIONS: Provided results are reviewed in relation to an
      age related normal reference range, both IGF-1 and IGFBP-3 are simple and
      convenient screening tests for assessing growth hormone deficiency in children.
      In adults plasma IGF-1 is the diagnostic test for a disorder of growth hormone
      excess. Low IGF-1 in an adult with a history of pituitary disease strongly
      suggests the presence of growth hormone deficiency.

PMID- 8657366
TI  - Waiting in the emergency department.
AB  - AIMS: To examine waiting times, reasons for waiting, and patient knowledge of
      those reasons, in the emergency department (ED). METHODS: Data were collected on
      patients presenting to the emergency department over 7 weeks. Those who waited
      more than 30 minutes in the waiting room or more than 2 hours in the total
      department were studied further. RESULTS: Thirty seven percent exceeded the times
      above (group A). Mean times for this group were 175 mins. Only 7% stayed in the
      waiting room more than 30 minutes. Delays were related to doctors (42%), waiting
      for tests and results (16%), prolonged treatment and assessment (12%), and other
      reasons (30%). Only 47% were clear about why they were waiting. CONCLUSIONS: Some
      extended waiting is appropriate. Unnecessary delays are common and can be avoided
      by attention to facilities, improving deployment of staff, and removal of
      bottlenecks in testing procedures. Waiting time in emergency departments will
      alter as observation wards and definitive treatments by emergency specialists
      increase. The public will need to be fully informed as these changes take place.

PMID- 8657367
TI  - Evaluation of alpha interferon for the treatment of chronic hepatitis B infection
      in Christchurch.
AB  - AIM: To evaluate alpha interferon for the treatment of chronic replicative
      hepatitis B infection in Christchurch patients. METHODS: Ten patients were
      divided into two groups depending upon whether their average pretreatment ALT
      levels were greater than twice the upper limit of normal (group 1, 6 subjects) or
      less than twice the upper limit of normal (group 2, 4 subjects). Interferon alpha
      2a (4.5 mega units) was administered three times a week for 24 weeks with the
      addition of a preceding priming course of prednisone in group 2. RESULTS: At 6
      months post treatment only one patient in group 1 had seroconverted (HBeAg to
      anti-HBe), however, the remaining five patients seroconverted from 18-32 months
      after therapy. This response was associated with normalisation of the
      transaminases and in 5/6 subjects a fall in the HBV DNA levels. In group 2 one
      subject seroconverted by 6 months despite a shortened course of Interferon. A
      delayed seroconversion (18 months) was observed in one patient and another had a
      partial response with the development of anti-HBe but associated with persistence
      of HBeAg. The remaining patient has not responded. CONCLUSIONS: Interferon alpha
      2a was effective in promoting a seroconversion HBeAg to anti-HBe in patients with
      chronic hepatitis B and transaminases elevated to twice the upper limit of
      normal, although in most cases this response was delayed. Larger studies will be
      required to determine the role of steroid priming in those with less active
      disease.

PMID- 8657368
TI  - One year of tuberculosis in Auckland.
AB  - AIM: To describe the recent epidemiology of tuberculosis in Auckland and the
      outcome of contact investigations. METHOD: Routine public health data were used
      to review the experience of tuberculosis (TB) in the Auckland region during a
      twelve month period in 1992-3. RESULTS: There were 152 cases, an age-standardised
      rate of 2.7 per 100,000 for Europeans, 37.8 for Maori, 70.9 for Pacific Island
      Polynesians and 131.3 for other ethnic groups. Fifty-two (35%) were born in New
      Zealand; 46 (31%) in Asia; 44 (30%) in the Pacific Islands. Forty-seven percent
      of foreign-born cases (28% of all cases) arrived in New Zealand in the 4 years
      preceding their notification. Forty-one per cent of cases appear not to have been
      diagnosed until 3 months or longer after the onset of their symptoms. Fifteen
      cases (including three sputum smear-positive cases) took 4 weeks or longer from
      diagnosis to be notified to the public health office. 12.5% of isolates were not
      notified. Two per cent of the 1079 contacts examined had tuberculosis.
      CONCLUSION: This review highlights the need for tuberculosis and the importance
      of timely comprehensive screening of immigrants from high incidence countries;
      reducing the interval between onset of symptoms and diagnosis; improving the
      notification rate of tuberculosis; and focusing contact investigation on those at
      highest risk.

PMID- 8657369
TI  - Chronic mesenteric ischaemia presenting as acute acalculous cholecystitis.

PMID- 8657370
TI  - The gatekeeper controversy: why it exists and how it can be resolved.

PMID- 8657371
TI  - New Zealand travellers overseas and schistosomiasis.

PMID- 8657372
TI  - Occupational back pain and ACC.

PMID- 8657373
TI  - Oral contraceptive pill method failures.

PMID- 8657375
TI  - HIV therapy--what's new?

PMID- 8657374
TI  - Immunisation: sacred cow or evidence based medicine?

PMID- 8657376
TI  - Unavailable doctors and death certificates.

PMID- 8657377
TI  - Chelation therapy statistics or common sense?

PMID- 8657378
TI  - Rates of sick building type symptoms in New Zealand offices.

PMID- 8657379
TI  - The Mental Health Act 1992.

PMID- 8657380
TI  - Managing acute low back pain.

PMID- 8657381
TI  - Infected surgeons.

PMID- 8657382
TI  - Trends and determinants of blood pressure in Auckland, New Zealand 1982-94.
AB  - AIM: To describe blood pressure trends in Auckland, New Zealand from 1982 to 1994
      and assess possible explanations for the trends. METHODS: Three cross sectional
      surveys of cardiovascular risk factors were undertaken in 1982, 1986-8 and 1993
      4, with a total of 3806 European men and women aged 35-64 years randomly selected
      from Auckland electoral rolls. RESULTS: Mean systolic blood pressure fell in
      males from 132.2 mmHg in 1982 to 126.3 mmHg in 1993-4, and in females from 125.9
      mmHg in 1982 to 121.7 mmHg in 1993-4. Both male and female diastolic mean blood
      pressure decreased more than 6 mmHg over the 12 years. The prevalence of
      antihypertensive drug use fell over the 12 year period. Regression analysis
      revealed a positive association between blood pressure and blood lipids. Body
      mass index (BMI) was also positively related to blood pressure while cigarette
      smoking was inversely related. However, concurrent trends in blood lipids, BMI
      and cigarette smoking could account for less than 6% of the average decline in
      systolic blood pressure over the 12 year period. CONCLUSION: There has been a
      substantial fall in mean blood pressure levels in Auckland adults aged 35-64
      years which appears to be due to a shift in the general population blood
      pressure. The reduction in blood pressure is not explained by changes in
      pharmaceutical interventions and only a small part of the decline can be
      explained by concurrent trends in cardiovascular risk factors.

PMID- 8657383
TI  - The microbiology of chronic otitis media with effusion in a group of Auckland
      children.
AB  - AIMS: To determine the microbiology of chronic otitis media with effusion in a
      group of Auckland children. To determine the antimicrobial sensitivities of
      isolated bacterial pathogens to commonly used antibiotics for this condition.
      METHODS: A descriptive study recruiting subjects from otherwise well children
      with chronic otitis media with effusion having insertion of ventilation tubes at
      Starship Children's Health, Auckland. Tympanocentesis was performed, the middle
      ear aspirate cultured and antimicrobial sensitivities obtained. RESULTS: Sixty
      seven children (11mo to 8yr) with chronic otitis media with effusion had
      tympanocentesis of 105 ears. 38/105 (36%) of the middle ear aspirate cultures
      were positive. Forty nine organisms were isolated with 10 ears having two or more
      different bacteria identified. Isolated were 17 Haemophilus influenzae (16
      nontype b and 1 type b), 13 Moraxella catarrhalis, nine Streptococcus pneumoniae
      and 10 'others'. All S pneumoniae(9/9), most H influenzae(14/17) and no M
      catarrhalis(0/13) were sensitive to amoxycillin. More than 80% of subjects had
      either a sterile effusion or an organism sensitive to amoxycillin or
      cotrimoxazole. CONCLUSIONS: Middle ear effusions were culture positive in a third
      of cases of chronic otitis media with effusion. The commonest organisms were H
      influenzae nontype b, M catarrhalis and S pneumoniae. This is similar to reports
      from other countries. Sensitivity data obtained supports the continued
      recommendation of amoxycillin or cotrimoxazole as first line therapy for the
      antimicrobial treatment of this condition.

PMID- 8657384
TI  - The development of independent practice associations and related groups in New
      Zealand.
AB  - AIMS: Independent practice associations (IPAs) have become an important feature
      of New Zealand's primary care system in the past two years and now represent
      nearly 60% of general practitioners. This survey was undertaken to document this
      important development. To determine the extent of the development of IPAs, their
      goals and barriers to achieving these goals, their policies, financing and
      contracting development. METHODS: Questionnaire sent to 42 IPAs and related
      groups in October 1994 with a supplementary questionnaire in April 1995. RESULTS:
      There were 34 responses, representing the views of 1263 general practitioners.
      Most important goals were "achieving better health outcomes for patients",
      "making better use of primary care resources" and "improving the health of the
      community you serve". Significant barriers to achieving these goals were "lack of
      time" and "lack of clear RHA policies". There was little support for financial
      risk sharing or for members personally retaining savings from budget holding.
      Although there had been significant progress with budget holding considerable
      frustration was expressed about contracting relationships with RHAs. CONCLUSION:
      The survey shows that general practitioners are seeing IPAs as ways of achieving
      professional goals, better quality health care and improving health status
      outcomes rather than as a means of personal gain. However, protecting and
      advancing the status of general practice was also important. IPAs expect to move
      progressively into both budget holding and managed care with the gradual
      assumption of secondary care services purchasing. This has important implications
      for the future of RHAs including the need for them to adopt a more strategic
      purchasing role.

PMID- 8657385
TI  - Survival from out of hospital cardiac arrest in Christchurch 1992-3.
AB  - AIMS: To review the rate of survival to hospital discharge of victims of out of
      hospital cardiac arrest in Christchurch 1992-3. METHODS: A written record was
      completed for all adult victims of cardiac arrest attended by the Canterbury
      Regional Ambulance Service for 1992-3. RESULTS: Seventy percent of the arrest
      rhythms were ventricular fibrillation or pulseless ventricular tachycardia.
      Eleven percent of the study population survived to hospital discharge. Sixteen
      percent of the patients presenting with a ventricular tachyarrhythmia survived to
      hospital discharge. CONCLUSIONS: Rates of survival to hospital discharge for out
      of hospital cardiac arrest in Christchurch compare favourably with published
      averages but are below rates considered the best achievable. Gains might be
      attained by improving rates of immediate call of emergency medical services and
      bystander cardiopulmonary resuscitation and by reducing time to defibrillation.

PMID- 8657386
TI  - A study of the lactational amenorrhoea method of family planning in New Zealand
      women.
AB  - AIM: To evaluate the acceptance and efficacy of the lactational amenorrhoea
      method of family planning in breastfeeding clients attending clinics of the NZ
      Association of Natural Family Planning. METHODS: Mothers who were fully
      breastfeeding their babies, were amenorrhoeic and were early postpartum were
      offered for the purpose of family planning either lactational amenorrhoea method
      or the usual fertility awareness charting method. The clients who chose
      lactational amenorrhoea method were contacted at monthly intervals to check if
      they continued to meet the lactational amenorrhoea method criteria of fully
      breastfeeding and amenorrhoea. The fertility awareness group followed the normal
      practice of clinic visits for instruction until they became autonomous users. The
      status of both groups were assessed at 6 months postpartum when lactational
      amenorrhoea method users were advised to adopt another family planning method.
      RESULTS: Of 149 breastfeeding clients, 110 met the lactational amenorrhoea method
      criteria. Seventy chose lactational amenorrhoea method, the majority (56.7%)
      because of its simplicity. Thirty (48.6%) of initial lactational amenorrhoea
      method users were able to use the method for the full 6 months postpartum period.
      None of the women conceived while using lactational amenorrhoea method.
      CONCLUSION: For mothers who choose to fully breastfeed and who maintain a state
      of amenorrhoea lactational amenorrhoea method is an effective means of avoiding
      pregnancy during the first 6 months postpartum.

PMID- 8657387
TI  - Hereditary persistence of fetal haemoglobin detected in a new diabetic following
      artefactual elevation of haemoglobin A1.

PMID- 8657388
TI  - Immunotactoid (fibrillary) glomerulopathy.

PMID- 8657389
TI  - Not perfectly formed.

PMID- 8657390
TI  - Chelation therapy.

PMID- 8657391
TI  - Childhood immunisation and diabetes mellitus.

PMID- 8657392
TI  - The effects of ageing.

PMID- 8657393
TI  - AIDS.

PMID- 8657394
TI  - Immunocompromised patients, herpes zoster and acyclovir.

PMID- 8657395
TI  - Practical aspects of hospital referrals, and general practitioner advice
      resulting from changes in the health services.

PMID- 8657396
TI  - A guest editorial: pregnancy in the twenty-first century: woman, nurturer,
      parent, judge.

PMID- 8657397
TI  - Clinical uses of antiestrogens.
AB  - An antiestrogen is a compound that blocks the action of estrogen. Most synthetic
      antiestrogens have agonistic or antagonistic activity depending on the tissue and
      the endogenous estrogen mileu. The triphenylethylene derivatives, clomiphene and
      tamoxifen, are the antiestrogens in greatest clinical use. Their biologic
      effects, clinical indications, and risks are reviewed. Novel antiestrogens which
      are beginning to be studied clinically include the benzothiophene derivative,
      raloxifene and the "pure" antiestrogens such as ICI 182,780. New clinical
      indications for existing compounds as well as the development of novel
      antiestrogens may lead to better treatment options for endocrine-dependent
      conditions.

PMID- 8657398
TI  - Race, perinatal outcome, and amniotic infection.
AB  - Racial differences in rates of amniotic infection were examined through a review
      of the literature. Following a computerized and manual search of the literature
      from 1966 to 1994, studies were selected that reported the prevalence by race of
      presumed markers of amniotic infection. These markers included: amniotic
      infection syndrome, histologic chorioamnionitis, clinical chorioamnionitis,
      premature rupture of the membranes, and early neonatal mortality from sepsis.
      With the exception of overall rates of histologic chorioamnionitis, black women
      showed higher rates of the all the conditions examined. Insofar as amniotic
      infection is a risk factor for poor perinatal outcomes, the finding of higher
      rates of markers of amniotic infection among black women suggests that such
      infections may contribute to racial disparities in perinatal outcome.

PMID- 8657400
TI  - Evidence that normal fetal growth can be noncontinuous.

PMID- 8657399
TI  - Genital fistulas secondary to diverticular disease of the colon: a review.
AB  - Genital fistulas that complicate diverticular disease of the sigmoid colon may no
      longer be considered esoteric, or even rare phenomena. The vast majority of such
      lesions present with a foul, often fecal, sometimes purulent and occasionally
      blood-tinged, vaginal discharge for which patients customarily first seek relief
      from their gynecologists. Despite this fact, the topic is not mentioned in a
      single American textbook of gynecology. It is the purpose of this report to
      review the pertinent literature and to include the authors' experience with 13
      additional cases in order to bring this topic to the attention of our gynecologic
      colleagues.

PMID- 8657401
TI  - Screening for cervical cancer.
AB  - It is well accepted that conscientious and widespread use of cervical cytology
      will significantly decrease the incidence and mortality rates of cervical cancer.
      The Papanicolaou smear for cervical cytology fulfills all the criteria for an
      ideal screening test. Not only is it cost effective, acceptable to most patients,
      and adaptable to widespread screening, it is sensitive enough to detect
      preinvasive disease resulting in decreased morbidity and mortality. Nevertheless,
      in developing countries cervical cancer still occurs at epidemic proportions,
      where an estimated 460,000 new cases per annum will be diagnosed, a significant
      proportion of which will be in advanced stages. First world notions pertaining to
      screening have proved unrealistic for the developing health care system of third
      world nations. This article provides an overview of screening for cervical cancer
      and considers cytological smearing, cervicography and direct visualization of the
      cervix, be it without or with the application of 4 percent acetic acid.

PMID- 8657402
TI  - Management of genital prolapse in neonates and young women.
AB  - The presence of genital prolapse in neonates and young women poses a challenging
      management problem to the gynecologist. Neonatal uterine prolapse is associated
      with congenital spinal defects, and successful correction has been achieved
      mainly with simple digital reduction or the use of a small pessary. Uterine
      prolapse can also occur in young or nulliparous woman who wish to preserve their
      fertility. Operations using sling, sacral cervicopexy, or transvaginal
      sacrospinal fixation techniques seem to provide excellent repair for these
      patients, including the possibility of childbearing. A review of the
      pathophysiology of genital prolapse in neonates and young women with emphasis on
      the surgical and nonsurgical options for management is presented.

PMID- 8657403
TI  - Dating of pregnancy by trimesters: a review and reappraisal.
AB  - Many patients and obstetricians divide the events of human pregnancy into three
      intervals traditionally termed "trimesters." This system presumably arose from an
      equal division of the "9 months of pregnancy" into 3-month intervals. There are
      several problems with this system that follows pregnancy by months or trimesters.
      First, the average human pregnancy lasting 280 days or 40 weeks is not evenly
      divisible by three, leaving one to wonder how long each trimester is. Second,
      conversion from "weeks pregnant" to "months pregnant" is often an estimate that
      can foster misunderstanding between the patient and her obstetrician. Last,
      following pregnancy by the Gregorian calendar does not reflect embryonic or fetal
      developmental milestones. We propose a revision of this system to one in which
      natural embryonic and fetal developmental landmarks are used instead of
      trimesters to define the progressive stages of pregnancy. These landmarks occur
      approximately at 5-week intervals allowing a more simple division of pregnancy
      into four 10-week quartiles, each with two 5-week intervals. This article reviews
      many of these important landmarks within this framework. This system emphasizes a
      developmentally based way of understanding the events of pregnancy for both the
      patient and the obstetrician.

PMID- 8657404
TI  - [Critical evaluation of factors influencing pancreatic cytoprotection].
AB  - The authors give a brief survey on adaptive pancreatic cytoprotection and
      vasoprotection in the framework of which noxious agents and factors of defensive
      mechanism are made known and critically evaluated. In development of acute
      pancreatitis intraacinar redistribution of lysosomal hydrolases, colocalization
      of digestive and lysosomal enzymes, escape of digestive and lysosomal enzymes
      from pancreatic ductal system into the interstitium, inflammatory modulators
      released from macrophages and evoking local inflammation, ischaemia, furthermore
      feedback regulation of pancreatic secretion can be regarded as motives. Factors
      of defensive mechanism include prostaglandins, nitric oxide and the unobstructed,
      juice flow which promote the repair of injured membranes in acinar and vascular
      endothelial cells, respectively. Their whole sum may be called adaptive
      pancreatic cyto- and vasoprotection or pancreatic "self-defence mechanism".

PMID- 8657405
TI  - [Blood circulation in retarded and normal offspring of hypertonic pregnant
      women].
AB  - Doppler velocimetry was carried out on 62 women with hypertensive disorders in
      pregnancy. From this group, 19 infants with intrauterine growth retardation
      (IUGR, defined as gestational age related birth weight of < 10.percentile) were
      born. The rest 43 were appropriate for gestational age (AGA, > 10. percentiled).
      Blood flow velocity studies were performed in maternal uterine vessels, and fetal
      umbilical, cerebral and renal arteries. Patients with IUGR exhibited a not always
      significant increase of indices in uterine, umbilical and renal arteries, and a
      non significant decrease in middle cerebral arteries. The difference was more
      marked when the ratio of cerebral/umbilical indices were calculated and compared.
      In this case the ratio of IUGR fetuses were half of the AGA, fetuses with
      significant differences. The value same reflective of IUGR were obtained in the
      ratio between arteria umbilicalis/middle cerebral artery indices. These ratios
      more clearly separate the IUGR from AGA fetuses, than any other indice of the
      investigated artery alone. There were in the study material one case of cerebral
      hemorrhage and one case of intrauterine death. Both belonged to the IUGR group.

PMID- 8657406
TI  - [Position taken by the profession of dermatology on the use of the solarium].
AB  - This article is to summarize the potential adverse effects of exposure to
      ultraviolet radiation from sunbeds and to provide recommendations from the
      British Photodermatology Group that, if followed, will minimize the risks of such
      effects. The recommendations in this document apply only to the use of sunbeds
      for cosmetic purposes.

PMID- 8657407
TI  - [Evaluation of iatrogenic accessory nerve injury in forensic medical practice].
AB  - The authors give a survey of the clinical and medical-legal characteristics of
      the accessory nerve injury. In the past two decades the conception of the
      successfulness of the surgical treatment of the accessory nerve injury became
      prevailing. About the medical-legal aspects of the iatrogenic injury of the nerve
      reported in connection of the reconstructive surgery chiefly also departments of
      neurosurgery, orthopedics and traumatology. In the case of the authors a 70 year
      old patient suffered 10 years ago a iatrogenic accessory nerve injury. The mild
      trapezius palsy recovered spontaneously practically with cosmetic disadvantage.
      In connection with the development of extreme dorso-lumbal scoliosis associated
      with torsion the trapezius atrophy worsened. Physical therapy was partly
      successful. But the patient became unfit for manual work. Their observations
      sustain the data of authors who established that in the case of accessory nerve
      injury not only the surgical but also conservative treatment is usually
      successful. In opposite to certain data of the literature the authors establish
      that the iatrogenic injuries of the accessory nerve may lead to significant
      lifelong disability. The diagnosis is not always made in time with consequent
      delay in repair. This may be regarded as an unfavorable issue during medical
      legal discussions. The authors recommend in interest to prevent nerve injury in
      the posterior triangle of the neck to perform operation in special department.

PMID- 8657408
TI  - [17 beta-hydroxysteroid dehydrogenase defect: female phenotype with 46,XY
      karyotype].
AB  - Deficiency of the 17 beta-hydroxysteroid dehydrogenase (17b-HSD-d) causes female
      external genital phenotype in spite of 46,XY karyotype and presence of testes due
      to disorder in biosynthesis of testosterone. However, marked somatic and genital
      virilization occurs during puberty. Clinical and laboratory investigation of
      three cases are presented with typical elevation of the precursor steroid
      androstenedione, and decrease of product steroid testosterone. All the three
      patients were reared as girls. During puberty orchidectomy was performed in two
      cases and vaginoplasty in one case. Estrogen replacement therapy contributed to
      development of female secondary sex characteristics.

PMID- 8657410
TI  - [Estimation of the prevalence of ischemic heart disease].

PMID- 8657409
TI  - [Health promotion in the past].

PMID- 8657411
TI  - [Liver transplantation--preparing patients, early postoperative care and
      occupational rehabilitation].
AB  - Authors summarize the results of liver transplantation first of all in the view
      of rehabilitation. Role of rehabilitation experts is discussed in the period
      before and after transplantation. The necessity of information for the patients
      is specially underlined already from the first raise of the possibility of liver
      transplantation. They express that after successful operation it is needed for
      the patients to return gradually to the used activities of everyday life. All the
      questions of immunosuppressive treatment, hygienic rules, physical activities,
      patient care at home and work place rehabilitation are discussed.

PMID- 8657412
TI  - [Serologic signs of Epstein Barr virus activity in acute viral hepatitis,
      symptomless HbsAg carriers as well as in alcoholic liver diseases].
AB  - The authors, based on their previous observations, analysed the serological
      incidence of the EBV infection in patients with viral hepatitis, HBsAg carriers
      and alcoholic liver diseases compared to control group. For the better
      statistical comparison they have selected the patients of 20-60 years of age and
      by using Khi-square probe, compared the incidence of IgM and IgG type antibodies
      against EBV in the samples. Significantly higher incidence (P < 0.05) of IgM
      antibodies were found in the samples of patients with alcoholic liver disease and
      of HBsAg carriers compared to the patients of viral hepatitis and control group.
      No similar distribution was observed related to the IgG type antibodies. Certain
      degree of "immunocompromised" condition is suspected in the cases of patients
      with HBsAg carrier state and with alcoholic liver disease known from the
      literature as the main reason behind the relatively more frequent Epstein-Barr
      virus infection.

PMID- 8657413
TI  - [Distribution and localization of nitric oxide containing neural elements in the
      digestive tract].
AB  - Nitric oxide free radical is a presumed neurotransmitter of the gastrointestinal
      tract. It can play an important role in the relaxation of the smooth muscles. We
      used nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)
      histochemistry and the localization and morphology of the NADPH-d positive neural
      elements of the different areas were compared in the cat. NADPH-d positive
      neurons could be found mainly in the myenteric plexus but some of them were
      located in the submucous plexus and in the inner circular muscle layer as well as
      around the blood vessels. The greatest number of the positive neuronal cell
      bodies could be seen in the myenteric plexuses of the sphincter regions. Stained
      nerve fibers were seen mainly in the inner circular muscle layer. These results
      suggest that the positive neurons of the sphincter regions can have an important
      role in the relaxation. NADPH-d positive neuronal elements of the submucous
      plexus were located around blood vessels and can regulate the blood flow and
      secretion of the glands or it is also possible that they belong to the sensory
      neurons.

PMID- 8657414
TI  - [Normal values of calcium and oxalate excretion in children].
AB  - Aim of the study was to establish normal values for calcium/creatinine (Ca/cr)
      and oxalate/creatinine (Ox/cr) ratio in infants and children. Urine probes of 416
      healthy children (25 infants aged 1-7 days and 391 children aged 1 month-14.5
      years) were analysed. Oxalate was measured by ion-chromatography. Urinary Ca2+/cr
      was normally distributed, Ox/cr had log-normal distribution. Ca/cr was the lowest
      in the first days of life, the highest between 7 month-1.5 years (mean +/- SD =
      0.39 +/- 0.28 mmol/mmol), a slight decrease could be observed until 14 years
      (0.34 +/- 0.18). The highest Ox/cr values were measured during the first month of
      life (geometric mean/range/ = 133 /61-280 mmol/mmol/), followed by gradual
      decrease until 14 years (25/6-73/). The measurement of Ca2+/cr and Ox/cr in first
      morning urine samples is suitable for screening of hypercalciuria and
      hyperoxaluria. The interpretation of the values requires age specific reference
      values. Both calcium and oxalate determinations should be the part of the
      evaluation of patients with hematuria, hypercalciuria or nephrolithiasis.

PMID- 8657415
TI  - [Simultaneous heart valve implantation and coronary bypass following kidney
      transplantation].
AB  - The authors report simultaneous aortic valve replacement and coronary artery
      bypass grafting surgery successfully performed in a patient with functioning
      transplanted kidney. The patient's cardiac status was classified as NYHA class
      III. The indication of the cardiac operation was a heavily calcified, stenotic
      and insufficient aortic valve and severe coronary artery disease. Renal function
      and blood biochemistry tests did not show significant changes in the
      postoperative period. The patient was discharged on the 15. postoperative day
      after an uneventful postoperative period. He remained asymptotic for two and a
      half years after operation. His cardiac status judged by postoperative treadmill
      stress was NYHA class I. The outcome of this case in accordance with results
      found in the literature further confirms that, if the clinical indications are
      appropriate, a kidney transplant patient can survive and benefit from cardiac
      surgery. To our knowledge our patient has been the only one who has survived
      aortic valve replacement and double coronary artery bypass grafting after kidney
      transplantation, and this is the first case that has ever been reported in
      Hungary.

PMID- 8657416
TI  - [The Urology Department of the Semmelweis Medical University is 75 years old].

PMID- 8657417
TI  - [Bernhard von Gudden (1834-1886), his life, work and tragic death].

PMID- 8657418
TI  - [Survival potentials of patients with papillary carcinoma of the thyroid gland in
      Hungary].
AB  - The typically benign, but occasionally rapid fatal clinical course of papillary
      thyroid cancer has raised the need for individual survival probability
      estimation, to tailor the treatment strategy exclusively to the given patient. A
      retrospective study was performed on 400 papillary thyroid cancer patients, with
      a mean follow-up time of 10.3 years, to establish a clinical database for uni-
      and multivariate analysis of the survival probability-related prognostic factors
      (Kaplan-Meier product limit method and Cox regression). For a more precise
      prognosis estimation, in the next step the most important clinical events were
      investigated and survival functions for each patient were calculated on the basis
      of a Markov renewal model. The basic concept of this approach is as follows: each
      patient has an individual disease course, which (besides the initial clinical
      categories) is affected by special events, e.g. internal covariates
      (local/regional/distant relapses), that a patient experiences throughout the
      course of the disease. On the supposition that these events and the cause
      specific death are influenced by the same biological process, the parameters of
      transient survival probability characterizing the speed of the course of the
      disease for each sequence of clinical events were determined. The individual
      survival curves for each patients were calculated by using the former parameters
      and the independent, significant clinical variables, summation of which resulted
      in an overall cause-specific survival function valid for the entire group. The
      patient's age, a distant metastasis at presentation, the extent of the surgical
      intervention, the primary tumour size, the dosage of the external irradiation and
      the degree of the TSH suppression proved to be statistically significant (in that
      sequence) and independent prognostic factors as concerns cause-specific survival
      in multivariate studies. During follow-up 14%, 14%, 9% and 12% of the patients
      underwent local/regional/distant relapses and thyroid cancer-related death.
      Through use of the above six independent clinical variables and the parameters
      relating to the interrelations of the four clinical events, mean cause-specific
      survival probabilities of 88%, 83% and 78% were determined at 10, 20 and 30
      years, respectively. The 30-year individual survival probability prediction for
      these study cases showed that no cancer-related death occurred > or = 92% (low
      risk group), while the tumour-related deaths were considerable (31%) < or = 78%
      (high-risk group), and there were only 6% deaths in the intermediate-risk group.
      The constructed survival function permits a prediction of the individual survival
      probability of extra-study cases under the given treatment conditions and within
      the given population, and thus affords a rationale for individualization of the
      treatment of papillary thyroid cancer patients.

PMID- 8657420
TI  - [Epidemiologic value of autopsy records (base on a number of actual cases].

PMID- 8657419
TI  - [Efficacy of combined oral hormone replacement therapy in postmenopausal
      symptoms].
AB  - The authors analyzed their observations with a fix combination of estrogen and
      progestogen pill-Kliogest. The protocol and treatment used in this study are
      reported. Treatment was the most effective in early postmenopausal complaints
      (flush), but was effective to prevent insomnia, neurotic complaints and urinary
      problems. The treatment was the less effective to treat pains in connection with
      osteoporosis. Endometrial atrophy was found by vaginal ultrasonography on the one
      year follow-up visit. There was no change in the labor parameters on the one year
      follow up visit. The most common side effects were metrorrhagia and breast
      tension. In the authors opinion combined per os hormonal replacement therapy
      treatment is an effective, simple and well tolerated method to treat some of the
      postmenopausal complaints.

PMID- 8657421
TI  - [46,XX karyotype males, based on a specific case].
AB  - Individuals with 46,XX karyotype and testicular tissue are known as XX males.
      They either have male phenotype or sexual ambiguity. SRY (testis determining
      factor) is present in 80% of the reported cases. In our patient the presence of
      SRY was verified by polymerase chain reaction, explaining the sex reversal.

PMID- 8657422
TI  - [Successful management of penetrating cardiac injuries].
AB  - Penetrating cardiac injuries lead to shock in a very short period of time because
      of bleeding and/or pericardiac tamponade. The prognosis is determined by the
      early diagnosis and operation. Sudden death occurs in 16-35% of these patients.
      Another one third of them expire during the transport to a hospital or during the
      preparation for the surgery. Based on 3 cases successfully treated, the authors
      emphasizes that because of the short time frame only basic examinations should be
      done without causing any delay in performing thoracotomy. As these patients are
      not candidate for further transport to another institute, personal and
      instrumental background should be organized in general surgical wards to treat
      penetrating thoracic and cardiac injuries. It is suggested to clarify the exact
      extension of the injury and to treat the possible complications in special
      cardiac surgical units after the life threatening situation is treated.

PMID- 8657423
TI  - [On Laszlo Benedek, with "provocative" intention].

PMID- 8657424
TI  - [60 years of the Radiotherapy Department of the Hungarian National Institute of
      Oncology].

PMID- 8657425
TI  - The burning mouth syndrome remains an enigma.

PMID- 8657426
TI  - Mechanisms of hyperalgesia and morphine tolerance: a current view of their
      possible interactions.
AB  - Over the last several years, compelling evidence has accumulated indicating that
      central hyperactive states resulting from neuronal plastic changes within the
      spinal cord play a critical role in hyperalgesia associated with nerve injury and
      inflammation. Such neuronal plastic changes may involve activation of central
      nervous system excitatory amino acid (EAA) receptors, subsequent intracellular
      cascades including protein kinase C translocation and activation as well as
      nitric oxide production, leading to the functional modulation of receptor-ion
      channel complexes. Similar EAA receptor-mediated cellular and intracellular
      mechanisms have now been implicated in the development of tolerance to the
      analgesic effects of morphine, and a site of action involved in both hyperalgesia
      and morphine tolerance is likely to be in the superficial laminae of the spinal
      cord dorsal horn. These observations suggest that hyperalgesia and morphine
      tolerance, two seemingly unrelated phenomena, may be interrelated by common
      neural substrates that interact at the level of EAA receptor activation and
      related intracellular events. This view is supported by recent observations
      showing that thermal hyperalgesia develops when animals are made tolerant to
      morphine antinociception and that both hyperalgesia and reduction of the
      antinociceptive effects of morphine occur as a consequence of peripheral nerve
      injury. The demonstration of interrelationships between neural mechanisms
      underlying hyperalgesia and morphine tolerance may lead to a better understanding
      of the neurobiology of these two phenomena in particular and pain in general.
      This knowledge may also provide a scientific basis for improved pain management
      with opiate analgesics.

PMID- 8657427
TI  - Electrical stimulation of precentral cortical area in the treatment of central
      pain: electrophysiological and PET study.
AB  - The clinical, electrophysiological and haemodynamic effects of precentral gyrus
      stimulation (PGS) as a treatment of refractory post-stroke pain were studied in 2
      patients. The first patient had a right hemibody pain secondary to a left
      parietal infarct sparing the thalamus, while the second patient had left lower
      limb pain developed after a right mesencephalic infarct. In both cases,
      spontaneous pain was associated with hyperpathia, allodynia and hypoaesthesia in
      the painful territory involving both lemniscal and extra-lemniscal sensory
      modalities in patient 1, extra-lemniscal sensory modality only in patient 2. Both
      patients were treated with electrical PGS by means of a 4-pole electrode, the
      central sulcus being per-operatively located using the phase-reversal of the N20
      wave of somatosensory evoked potentials. No sensory side effect, abnormal
      movement or epileptic seizure were observed during PGS. The analgesic effects
      were somatotopically distributed according to the localization of electrode on
      motor cortex. A satisfactory long-lasting pain control (60-70% on visual analog
      scale) as well as attenuation of nociceptive reflexes were obtained during PGS in
      the first patient. Pain relief was less marked and only transient (2 months) in
      patient 2, in spite of a similar operative procedure. In this patient, in whom
      PGS eventually evoked painful dysethesiae, no attenuation of nociceptive RIII
      reflex could be evidenced during PGS. Cerebral blood flow (CBF) was studied using
      emission tomography (PET) with O-labeled water. The sites of CBF increase during
      PGS were the same in both patients, namely the thalamus ipsilateral to PGS,
      cingulate gyrus, orbito-frontal cortex and brainstem. CBF increase in brainstem
      structures was greater and lasted longer in patient 1 while patient 2 showed a
      greater CBF increase in orbito-frontal and cingular regions. Our results suggest
      that PGS-induced analgesia is somatotopically mediated and does not require the
      integrity of somatosensory cortex and lemniscal system. PGS analgesic efficacy
      may be mainly related to increased synaptic activity in the thalamus and
      brainstem while changes in cingulate gyrus and orbito-frontal cortex may be
      rather related to attentional and/or emotional processes. The inhibitory control
      on pain would involve thalamic and/or brainstem relays on descending pathways
      down to the spinal cord segments, leading to a depression of nociceptive
      reflexes. Painful dysesthesiae during stimulation have to be distinguished from
      other innocuous sensory side effects, since they may compromise PGS efficacy.

PMID- 8657428
TI  - Characterization of supraspinal antinociceptive actions of opioid delta agonists
      in the rat.
AB  - Supraspinally mediated antinociception has been clearly established for agonists
      acting via both micro- and delta-opioid receptors. The present experiments were
      undertaken to further characterize the role of supraspinal opioid delta receptors
      in the mediation of antinociception in rats and to examine the possible role of
      putative delta1- and delta2-opioid receptors in the antinociceptive effect.
      Cannulae directed at the right lateral ventricle, the periaqueductal gray (PAG),
      or the medullary reticular formation (MRF) were implanted in adult male, Sprague
      Dawley rats for the microinjection of [D-Ala2,Glu4]deltorphin (delta2 agonist),
      [D-Pen2,D-Pen5]enkephalin (DPDPE, delta1 agonist), [D-Ser2,Leu5,Thr6]enkephalin
      (DSLET, mixed delta/micro agonist) or morphine (reference micro-opioid).
      Pretreatments (24 h prior to agonist microinjection) were made with the putative
      delta1 and delta2 antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) and [D
      Ala2,Cys4]deltorphin (Cys-DELT) and antinociception was measured in the 55
      degrees C hot plate (HP) and 52 degrees C and 55 degrees C (low and high
      intensity) warm-water tail-flick (TF) tests. Data were converted to percent
      maximal possible effect (%MPE). Intracerebroventricular (i.c.v.) administration
      of DPDPE produced less than a 50%MPE in the HP test whereas [d
      Ala2,Glu4]deltorphin produced Cys-DELT sensitive antinociception of up to 92%
      MPE. Neither i.c.v. agonist was effective in the TF assays, and both agonists
      were without effect in the PAG. [D-Ala2,Glu4]deltorphin microinjected into the
      MRF produced Cys-DELT sensitive antinociception of 60 and 47% MPE in the HP and
      low-intensity TF tests, respectively, but was not effective in the 55 degrees C
      TF test; DPDPE did not produce antinociception when microinjected at this site.
      Microinjection of DSLET in the MRF produced significant antinociception in all
      three assays. Morphine produced antinociception following i.c.v. administration
      or microinjection into the PAG in all tests. Microinjection of morphine into the
      MRF produced antinociception in the HP and 52 degrees C, but not 55 degrees C, TF
      tests. Morphine anticociception was not antagonized by either DALCE or Cys-DELT.
      These data demonstrate that supraspinal delta-opioid receptors can be activated
      to elicit antinociception in the rat and that opioid delta2 receptors predominate
      in this effect. Further, these effects may occur predominately via inhibition of
      supraspinally organized behavior without activation of descending systems such as
      those mediating the TF response in the rat.

PMID- 8657429
TI  - The orofacial formalin test in rats: effects of different formalin
      concentrations.
AB  - In this study of the orofacial formalin test in rats, the effects of different
      formalin concentrations (0.2%, 0.5%, 1.5%, 2.5%, 5% and 10%) on the behavioural
      nociceptive response (face rubbing) was investigated. The histological responses
      of the skin were also evaluated. Increasing the concentration of formalin caused
      a parallel aggravation of histological signs of tissue inflammation and injury.
      All concentrations provoked an early phase of nociceptive response, but its
      intensity was not concentration-dependent. The 2nd phase of response to formalin
      only occurred for concentrations of 1.5% and higher. A positive relationship
      between the formalin concentration and the amplitude of the rubbing activity
      measured between 12 and 45 min after injection could be observed until 2.5% but
      with the highest concentrations (5 and 10%), the amplitude of the response
      decreased. Our findings indicate that the orofacial formalin test should be
      carried out using concentration between 0.5 and 2.5%. This is essential to assess
      increase as well as decrease in pain intensity. Moreover, this will have the
      effect of minimizing the suffering of the experimental animal.

PMID- 8657430
TI  - Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviours
      in infant rats: sedation versus specific suppression of pain.
AB  - The behavioural response of infant rats to intraplantar injection of formalin
      consists of specific directed behaviours (limb flexion, shaking and licking the
      injected paw) and non-specific behaviours that are also induced by non
      nociceptive stimulation (squirming, hind limb kicks and whole body jerks), with
      specific indicators becoming more frequent as pups mature. The present study
      examined the effects of systemic morphine, pentobarbital and D-amphetamine on
      formalin-induced behaviours and behavioural state in rat pups from 1 to 20 days
      of age. Morphine (1 mg/kg) almost completely suppressed both specific and non
      specific indicators of pain, and produced mild sedation relative to handled
      control pups. Pentobarbital (10 mg/kg) produced a similar degree of sedation and
      suppression of non-specific measures as morphine, but only had weak effects on
      specific measures in pups less than 1 week old, and no effects thereafter.
      Suppression of both specific and non-specific pain measures after amphetamine (2
      mg/kg) emerged during the 2nd week of life and was not associated with sedation.
      Thus, morphine produced behavioural analgesia in infant rats in a model of injury
      induced inflammatory pain from the 1st postnatal day, when their neurological
      maturity is similar to a 25-week human fetus, and 1 week before antinociception
      is observed in thermal and pressure tests. The effects of morphine were
      qualitatively different from a sedative dose of pentobarbital. The data support
      the contention that opioids have specific analgesic effects in premature human
      neonates and underline the need for pain measures that discriminate between
      sedation and analgesia.

PMID- 8657431
TI  - Analgesic efficacy and safety of tramadol enantiomers in comparison with the
      racemate: a randomised, double-blind study with gynaecological patients using
      intravenous patient-controlled analgesia.
AB  - The opioid analgesic tramadol is a racemate and consists of 50% (+)- and 50% (-)
      enantiomer. This study investigated analgesic efficacy and safety of both
      enantiomers after intravenous (i.v.) injection in comparison with the racemate.
      Ninety-eight patients recovering from major gynaecological surgery under opioid
      free halothane anaesthesia were treated in a randomised, double-blind study with
      (+)-tramadol, (-)-tramadol or the racemate. Following an individualised i.v.
      loading dose up to a maximum of 200 mg, patient-controlled analgesia with demand
      doses of 20 mg was made available for 24 h. The primary criterion was of efficacy
      was the decrease of pain intensity on a 5-point verbal rating scale from severe
      or maximum pain to mild or no pain intensity on a 5-point verbal rating scale
      from severe or maximum pain to mild or no pain within the first hour after the
      loading dose. The secondary criterion was patient satisfaction with pain relief
      during the 24-h observation period stated in the final interview. Patients who
      terminated the study prematurely were evaluated as non-responders. Of patients
      treated with (+)-tramadol, tramadol racemate, and (-)-tramadol, 12%, 15%, and 53%
      of treated patients, respectively, terminated the study prematurely because of
      inefficacy. Of patients treated with (+)-tramadol, racemate or (-)-tramadol 67%,
      48% and 38%, respectively, were considered responders regarding the primary
      criterion of efficacy (P = 0.061), and 82%, 76%, or 41% with respect to the
      secondary criterion (P = 0.001). Assessment of laboratory screening, adverse
      events, vital signs and blood gas monitoring showed no serious drug-related
      events. Nausea and vomiting were the most frequently reported non-serious side
      effects and were most often seen with (+)-tramadol. Taking into account both
      efficacy and safety aspects, the racemate seems to be superior to either
      enantiomer alone.

PMID- 8657432
TI  - Differential right shifts in the dose-response curve for intrathecal morphine and
      sufentanil as a function of stimulus intensity.
AB  - To assess effects of stimulus intensity, dose-response curves in rats for radiant
      heat-evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.)
      injection of sufentanil and morphine, mu-opioid agonists differing in intrinsic
      activity, at Low, Medium, and High stimulus intensities. Baseline latencies
      observed at the 3 intensities were: low = +/- 0.3; medium = 8.9 +/- 0.2; high =
      5.7 +/- 0.1 sec. After i.t. administration of sufentanil or morphine, there was a
      right shift in the dose-response curves with morphine exhibiting a greater
      magnitude right shift than that of sufentanil. Dose ratios (ED 50 Medium/ED 50
      Low and ED 50 High/ED 50 Low) with 95% CI for sufentanil were, respectively, 2.5
      (2.2-2.9) and 7.7 (6.7-8.9), and the dose ratio for morphine (ED 50 Medium/ED 50
      Low) was 34 (28-41). At the highest intensity, due to a plateau in the morphine
      dose-response curve, ED 50 and dose ratio calculations could not be performed.
      The present study supports the pharmacological model of receptor occupancy, such
      that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser
      magnitude right shift than the lower efficacy agonist, morphine, while at the
      high stimulus intensity, morphine but not sufentanil, was a partial agonist.

PMID- 8657433
TI  - A pharmacokinetic approach to resolving spinal and systemic contributions to
      epidural alfentanil analgesia and side-effects.
AB  - A pilot study was conducted in 7 normal volunteers to demonstrate the feasibility
      of employing pharmacokinetic tailoring to achieve matching plasma opioid
      concentration-time curves after epidural (e.p.) and intravenous (i.v.) alfentanil
      administration. Each subject participated in 1 pretest and 2 test sessions. Our
      pain model was cutaneous electrical stimulation of the finger and toe, adjusted
      to produce a baseline pain report of 5 (strong pain on a 0-5 scale). On test day
      1, subjects received e.p. alfentanil (750 micrograms) and an i.v. saline
      infusion. Serial measurements of analgesia, end tidal CO2, pupil size, subjective
      side effects, and plasma alfentanil concentrations were conducted before and at
      various time intervals over a 4-h period after alfentanil administration. On test
      day 2, subjects received e.p. saline and a pharmacokinetically tailored i.v.
      infusion (using individual pharmacokinetics determined on the pretest day)
      designed to achieve a plasma concentration-time profile identical to that
      observed on the epidural day. The same battery of effect measurements was
      administered as on the 1st test day. Plasma alfentanil was measured to verify the
      accuracy of the tailored infusion. Plasma alfentanil concentration profiles were
      nearly identical on both test days. Peak plasma alfentanil concentrations were
      near the reported minimum effective analgesic concentration (MEAC). Overall,
      analgesia was slightly greater with e.p. administration. Onset of pain relief was
      rapid, and duration was approximately 1.5 h with e.p. and 1 h with i.v.
      alfentanil. There were no differences in pupil size, ETCO2, or subjective side
      effects between e.p. versus i.v. administration. We conclude that systemic
      redistribution from the epidural space appears to account for most, but not all,
      of the analgesia.

PMID- 8657434
TI  - Topical acetylsalicylic, salicylic acid and indomethacin suppress pain from
      experimental tissue acidosis in human skin.
AB  - Topically applied acetylsalicylic acid (ASA), salicylic acid (SA) and
      indomethacin were tested in an experimental pain model that provides direct
      nociceptor excitation through cutaneous tissue acidosis. In 30 volunteers,
      sustained burning pain was produced in the palmar forearm through a continuous
      intradermal pressure infusion of a phosphate-buffered isotonic solution (pH 5.2).
      In 5 different, double-blind, randomized cross-over studies with 6 volunteers
      each, the flow rate of the syringe pump was individually adjusted to result in
      constant pain ratings of around 20% (50% in study 4) on a visual analog scale
      (VAS). The painful skin area was then covered with either placebo or the drugs
      which had been dissolved in diethylether. In the first study on 6 volunteers, ASA
      (60 mg/ml) or lactose (placebo) in diethylether (10 ml) was applied, using both
      arms at 3-day intervals. Both treatments resulted in sudden and profound pain
      relief due to the cooling effect of the evaporating ether. With lactose, however,
      the mean pain rating was restored close to the baseline within 6-8 min while,
      with ASA, it remained significantly depressed for the rest of the observation
      period (another 20 min). This deep analgesia was not accompanied by a loss of
      tactile sensation. The further studies served to show that indomethacin (4.5
      mg/ml) and SA (60 mg/ml) were equally effective as ASA (each 92-96% pain
      reduction) and that the antinociceptive effects were due to local but not
      systemic actions, since ASA and SA dis not reach measurable plasma levels up to 3
      h after topical applications. With a higher flow rate of acid buffer producing
      more intense pain (VAS 50%). ASA and SA were still able to significantly reduce
      the ratings by 90% or 84%, respectively. On the other hand, by increasing the
      flow rate by a factor of 2 on average, during the period of fully developed drug
      effect it was possible to overcome the pain suppression, which suggests a
      competitive mechanism of (acetyl-) salicylic antinociception.

PMID- 8657435
TI  - Psychosocial factors discriminate multidimensional clinical groups of chronic low
      back pain patients.
AB  - Previous studies have empirically defined clinical subgroups of chronic low back
      pain (CLBP) patients, based on differing patterns of pain, disability and
      emotional distress. Because these identified groups generally are comparable in
      terms of physical and demographic variables, variation in functional status
      cannot be adequately explained by medical or social factors. In the present study
      we evaluated whether other psychosocial factors (stress, coping attempts, and
      satisfaction with social supports) might differentiate the observed groups. A
      discriminate function analysis indicated that ratings of life adversity, coping,
      and social support statistically differentiate clinical groups of CLBP patients.
      Patients categorized as chronic pain syndrome (i.e., high levels of pain,
      disability and depression) reported greater life adversity, more reliance on
      passive/avoidant coping strategies, and less satisfaction with social support
      networks. Patients categorized as having good pain control (i.e., low levels of
      pain, disability and depression) reported less life adversity, less reliance on
      passive/avoidant coping strategies, and more satisfaction with social support
      networks. Finally, a mixed picture of less life adversity, but more reliance on
      passive/avoidant coping strategies and more satisfactory social support networks
      was reported by patients categorized in the positive adaptation to pain group
      (i.e., high levels of pain, but relatively low levels of disability and
      depression). These findings suggest that psychosocial factors may be important
      and complex correlates of multidimensional clinical presentations of CLBP.
      Psychosocial factors may also offer an avenue for intervention across 3 key
      dimensions of CLBP.

PMID- 8657437
TI  - Fear of movement/(re)injury in chronic low back pain and its relation to
      behavioral performance.
AB  - Two studies are presented that investigated 'fear of movement/(re)injury' in
      chronic musculoskeletal pain and its relation to behavioral performance. The 1st
      study examines the relation among fear of movement/(re)injury (as measured with
      the Dutch version of the Tampa Scale for Kinesiophobia (TSK-DV)) (Kori et al.
      1990), biographical variables (age, pain duration, gender, use of supportive
      equipment, compensation status), pain-related variables (pain intensity, pain
      cognitions, pain coping) and affective distress (fear and depression) in a group
      of 103 chronic low back pain (CLBP) patients. In the 2nd study, motoric,
      psychophysiologic and self-report measures of fear are taken from 33 CLBP
      patients who are exposed to a single and relatively simple movement. Generally,
      findings demonstrated that the fear of movement/(re)injury is related to gender
      and compensation status, and more closely to measures of catastrophizing and
      depression, but in a much lesser degree to pain coping and pain intensity.
      Furthermore, subjects who report a high degree of fear of movement/(re)injury
      show more fear and escape/avoidance when exposed to a simple movement. The
      discussion focuses on the clinical relevance of the construct of fear of
      movement/(re)injury and research questions that remain to be answered.

PMID- 8657436
TI  - Intrathecal steroids to reduce pain after lumbar disc surgery: a double-blind,
      placebo-controlled prospective study.
AB  - This double-blind, placebo-controlled prospective study investigated whether
      corticosteroids (beta-methasone) influence residual radicular pain after lumbar
      disc surgery. The study population consisted of 26 patients undergoing surgery
      for a herniated lumbar disc at our University Neurosurgical Department. Thirteen
      patients received beta-methasone intrathecally prior to wound closure, and 13
      patients received normal saline. Main outcome measures were pain intensity graded
      on a 100-mm visual analogue pain scale (VAS) and consumption of non-steroidal
      anti-inflammatory agents (NSAIDs). Both patient groups had comparable presurgical
      findings and pain intensity level (55 mm and 54 mm, respectively, on a 100-mm
      VAS). After surgery, residual pain declined gradually in the placebo group (mean
      39, 29, 24, 20 mm on days 1-4; 10 mm on day 8) and abruptly in the corticosteroid
      group (mean 15, 15, 11, 8, mm on days 1-4; 5 mm on day 8). Analysis of variance
      (ANOVA) showed a highly significant influence of time (P < 0.001), a significant
      influence of steroid application (P = 0.014) and interaction between time and
      application of steroids (P = 0.042). Mean daily consumption of NSAIDs did not
      differ significantly in either group: 124 mg in the treatment vs. 150 mg in the
      placebo group (P > 0.25). At follow-up after 6 months, residual radicular pain
      was rated equally by both groups (4 mm in the treatment vs. 5 mm in the placebo
      group, P > 0.5). Intrathecal application of steroids provides short-lasting,
      significant pain reduction after lumbar disc surgery. Benefits of intrathecal
      steroids are probably outweighed by the risks associated with violation of the
      dural barrier.

PMID- 8657438
TI  - Cutaneous pretreatment with the capsaicin analog NE-21610 prevents the pain to a
      burn and subsequent hyperalgesia.
AB  - Cutaneous injection of the capsaicin analog NE-21610 (Procter and Gamble)
      produces analgesia to heat but not mechanical stimuli in humans. The present
      study examined whether pretreatment of the skin with NE-21610 prevents the
      development of hyperalgesia following heat injury. On the 1st day testing, 7
      volunteers received a 30-microl intradermal injection of vehicle to one volar
      forearm and 10 micrograms of NE-21610 to the other volar forearm. On the 2nd test
      day the subjects rated the intensity of pain to mechanical and heat stimuli
      before and after a burn (48 degrees C, 120 sec) to each injection site. At the
      vehicle site, the pain evoked by the burn was rated as moderate to strong. In
      addition, primary hyperalgesia to heat and mechanical stimuli, secondary
      hyperalgesia to mechanical stimuli, and flare were observed after the burn. In
      contrast, the pain evoked by the burn at the NE-21610-treated site was rated as
      weak, and primary hyperalgesia to heat and mechanical stimuli did not develop. In
      addition, the area of flare at the drug-tested site was smaller than that
      observed at the vehicle site, and no secondary hyperalgesia to mechanical stimuli
      was observed. These data suggest that pretreatment with the capsaicin analog NE
      21610 may attenuate the pain and hyperalgesia associated with injury.

PMID- 8657439
TI  - Effects of regional intravenous guanethidine in patients with neuralgia in the
      hand; a follow-up study over a decade.
AB  - A study on the effect of regional intravenous (i.v.) guanethidine blockade (RGB)
      was done over a 10 years period in patients with post-traumatic neuralgia. Seven
      patients, investigated with quantitative sensory testing (QST) before and after
      RGB between 1979 and 1982, were reinvestigated in the period 1990-1992. In
      addition to the RGB, 6 patients were subjected to a placebo procedure with
      tourniquet inflation and i.v. injection of saline at follow-up. All patients had
      ongoing pain and stimulus-induced pain (hyperalgesia) in one hand. The QST was
      done by an independent observer who was blind with regard to the different
      treatments. Three patients with long-lasting relief of ongoing pain and
      significant reduction of stimulus-induced pain after RGB, were classified as
      having sympathetically maintained pain (SMP) both at 1st examination and at
      follow-up 10 years later. In 2 patients, classified as having sympathetically
      independent pain (SIP), neither the ongoing pain nor the hyperalgesia improved at
      any occasion. Two patients, classified as SMP in 1979-1982, changed to SIP at
      follow-up. Placebo had no significant effect on the hyperalgesia to heat, cold or
      vibration in the 6 SMP/SIP patients tested. In conclusion, some patients with
      neuralgia, diagnosed 17-26 years ago, still had long-lasting pain relief from an
      i.v. RGB, whereas others consistently had no such effect. None obtained long
      lasting pain relief from placebo. This supports the notion that different
      pathophysiological mechanisms are involved in post-traumatic neuralgia.

PMID- 8657440
TI  - Comments on P.A.J. Borg and H.J. Krijnen.

PMID- 8657442
TI  - Pain in the brain and lower parts of the anatomy.

PMID- 8657441
TI  - Use of epidural somatostatin for postoperative analgesia is not justifiable.

PMID- 8657443
TI  - [Effect of lithium gamma-hydroxybutyrate on evoked potentials in the caudal
      trigeminal nucleus and somatosensory cortex in rats with trigeminal neuropathy].
AB  - Lithium gamma-hydroxybutyrate (20 mg/kg, i.e.) was studied for effects on the
      evoked potentials (EP) in the caudal trigeminal nucleus (CTN) and somatosensory
      cortex (SSC) in acute tests on rats with trigeminal neuropathy induced by
      incomplete compression of the infraorbital nerve. Before drug administration, EPs
      in CTN on the side of nerve compression were characterized by the increased
      amplitude of presynaptic R1N1 and late postsynaptic P3N3-P4N4 components and by
      the reduction in the early postsynaptic P2N2 component. In the contralateral CTN,
      EP had higher amplitudes. Spontaneous epileptoid activity was recorded in CTN in
      a third of the animals and in SSC in a half. These changes are regarded as a
      result of A-delta-C-afferent entry due to attenuation of afferentation along A
      beta fibers. After administration of the drug, there was suppression of EP in
      SSC, while in CTN there was a decrease in the amplitude of the EP presynaptic
      component with increases in the postsynaptic components. There was suppression of
      abnormally enhanced spontaneous activity in CT and SSC. The findings are under
      discussion in terms of the cortical action of the drug resulting in the
      suppression of the abnormally enhanced activity developed in the brain
      projectional regions in nerve compression lesion.

PMID- 8657444
TI  - [Change in prostaglandin levels and ATPase activity of cardiac membrane fractions
      during the formation of cerebral hematomas in animals with a hereditary
      predisposition to stroke].
AB  - The formation of subarachnoidal, intragastric, and intracerebral hepatomas
      provoked by stress in rats hereditarily predisposed to strokes was found to be
      accompanied by myocardial overstrain and changes in cardiac prostaglandin
      formations, as well as by a decrease in the activity of ion-transporting enzymes,
      such as Na, K- and Ca,Mg-ATPases in the plasma membranes, Ca-ATPase in the
      sarcoplasmic reticulum.

PMID- 8657445
TI  - [Effect of extreme conditions on succinate oxidation in rat brain mitochondria].
AB  - Emergencies which were different in origin, but identical in the magnitude of
      pathogenic action on the brain, such as 3.5-hour cerebral circulatory ischemia
      found 49-hour restriction stress, induced the the same brain mitochondrial
      responses in Wistar rats. Two types of responses in organelles were identified:
      (1) that wherein there were lower succinate oxidation rates than those in the
      control (sham = operated and intact animals) and diverted effects on succinate
      dehydrogenase activators; (2) that wherein there was accelerated succinate
      oxidation and persisted stimulating effects of enzyme activators. A relationship
      was shown between the type of responses and the degree of succinate dehydrogenase
      inhibition induced by emergencies.

PMID- 8657446
TI  - [Antidiabetogenic action of heparin during its oral administration].
AB  - Oral heparin given to rats was found to neutralize the hyperglycemic and
      hypoinsulinemic effects of diabetogenic factor and to produce a protective action
      by preventing the animals from the diabetogenic action of alloxan. The chronic
      oral heparin use alleviated the course of severe alloxan diabetes in rats, by
      contributing to the reduction of hyperglycemic levels, to the elevation of blood
      insulin concentrations, thus promoting their higher survival.

PMID- 8657447
TI  - [Effect of the histamine H2-receptor antagonist zantac on lipid peroxidation an
      antioxidant system in patients with gastroduodenal hemorrhage of ulcer etiology].
AB  - High lipid peroxidation rates and lower antioxidative protection were found in
      the serum of 64 patients with gastric (n = 20) and duodenal (n = 44) ulcers
      complicated by hemorrhage. The administration of zantac, a histamine H2-receptor
      blocker, considerably reduced lipid peroxidation and enhanced antioxidative
      activity, which positively affected the clinical course of diseases. The findings
      have led to the conclusion that zantac may have antioxidative properties.

PMID- 8657448
TI  - [Homeostasis disorders in orthotopic liver transplantation in an experiment].

PMID- 8657449
TI  - [Compensatory potential of the hematopoietic system under conditions of exposure
      of the body to gamma-irradiation at a dose of 0.9 Gy and prolonged emotional
      stress].
AB  - The compensatory capacities of the blood system were studied in rats and mice
      concurrently exposed to short-term gamma-radiation in the dose 0.9 Gy that could
      not cause radiation disease and to 18-day emotional stress. The compensatory
      capacities of the hemopoietic system were evaluated by the regenerative processes
      during additional gamma-radiation in a dose of 5 Gy after termination of stress
      exposure. Preradiation in a dose of 0.9 Gy was found to exert an inhibitory
      effect on the compensatory capacities of hematopoiesis in emotional stress.

PMID- 8657450
TI  - [Stress and arterial hypertension].

PMID- 8657451
TI  - [The bioregulatory system L-arginine--nitric oxide].

PMID- 8657453
TI  - [Activity of various enzymes of formed elements in the blood plasma during
      extracorporeal circulation].
AB  - The activity of the enzymes whose high activity is observed in blood cells, such
      as the glutathione metabolic enzymes glutathione reductase, glutathione-S
      transferase, glutathione peroxidase in erythrocytes and monoaminooxidase in the
      platelets, was examined at different perfusion stages in the plasma of 30
      patients undergone open heart surgery. The findings suggest that the enzymes
      release from the blood cells damaged during extracorporeal circulation into the
      plasma, which may be useful as a test for defining the degree of perfusion
      induced damage of blood cells.

PMID- 8657452
TI  - [Meningococcal infectious-toxic shock: pathogenetic features and biochemical
      signs].

PMID- 8657454
TI  - [Role of the hemostatic system in the mechanisms of development of high-altitude
      cerebral edema].

PMID- 8657455
TI  - [Effect of morphine derivatives on the function of glucocorticoid receptors in
      shock].
AB  - The effects of opiate receptor agonists and antagonists on the function of
      glucocorticoid receptors in the hepatic cytosol were examined in male Wistar rats
      weighing 180-240 g. With the Scatchard analysis, in vitro experiments by using
      labelled ligands revealed that the pure opiate agonist morphine in the wide range
      of concentrations (0,01-10,0 mM) failed to affect the function Type II
      glucocorticoid receptors, though inhibited the function of Type III
      glucocorticoid receptors in the dose-dependent manner. Buprenorphine and
      diprenorphine depressed the function of Types II and III glucocorticoid
      receptors. Buterphanol, an opiate receptor antagonist-agonist, like naltrexone,
      an opiate receptor antagonist, decreased the function of Type III glucocorticoid
      receptors, but modulated that of Type II glucocorticoid receptors by lowering the
      association constant of the ligand-Type II glucocorticoid receptor complex, but
      by enhancing the density of Type II glucocorticoid receptors. In vivo studies
      established that butorphanol dose-dependently increased the density of Type II
      glucocorticoid receptors in the hepatic cytosol and elevating blood pressure in
      rat traumatic shock. Whether glucocorticoid receptors involve in the mechanism of
      the antishock effect of morphine derivatives is discussed in the paper.

PMID- 8657456
TI  - Commentary: imaging and staging of Wilms' tumors: problems and controversies.

PMID- 8657457
TI  - Renal cell carcinoma in a patient with Beckwith-Wiedemann syndrome.
AB  - We report the case of a patient with Beckwith-Wiedemann syndrome (BWS) who
      developed renal cell carcinoma (RCC). At birth, this patient presented with
      macroglossia, diastasis recti, mild gigantism, hepatomegaly and hypoglycemia, and
      the diagnosis of BWS was made. At 22 months, an intrapelvic rhabdomyosarcoma was
      detected and resected. At 37 months, computed tomography (CT) demonstrated a
      small mass with high attenuation in the right kidney, which was surgically
      confirmed to be RCC.

PMID- 8657458
TI  - Cysts within septa: an ultrasound feature distinguishing neoplastic from non
      neoplastic renal lesions in children?
AB  - We present two cystic renal neoplasms observed by ultrasound scanning to have
      cysts within septa. We have looked at other neoplastic and non-neoplastic lesions
      in children and suggest that this feature may be helpful in the ultrasound
      differentiation of neoplastic from non-neoplastic cystic renal masses.

PMID- 8657459
TI  - Absence of a renal sinus echo complex in the ectopic kidney of a child: a normal
      finding.
AB  - The typical urographic and anatomic appearance of the extrarenal pelvicalyceal
      system of the normal ectopic kidney has been thoroughly described. We report the
      ultrasonographic correlate of this distinct configuration. The normal central
      renal sinus echo complex was absent in two thirds of the ectopic kidneys in this
      series. In the remaining one third, the sinus echo complex was eccentric.

PMID- 8657460
TI  - Evaluation of glomerular function in individual kidneys using dynamic magnetic
      resonance imaging.
AB  - We used the fast field-echo technique of magnetic resonance (MR) imaging with an
      intravenous bolus injection of paramagnetic contrast agent to evaluate glomerular
      function. The time-dependent curves of changes in signal intensity observed in
      the renal cortex and renal medulla brought about by the paramagnetic contrast
      agent allowed insight into excretory kinetics. The time at which the cortical and
      medullary curves cross, the cortico-medullary (C-M) junction time, was delayed
      with a decrease in glomerular function. The mean C-M junction time in both
      kidneys showed a significant inverse correlation with total creatinine clearance
      (Ccr), indicating the glomerular filtration rate. The C-M junction time in an
      individual kidney also showed an inverse correlation with individual Ccr in each
      kidney. Results suggest that dynamic MR imaging is a useful tool in evaluating
      renal morphology and in evaluating semiquantitatively the glomerular function of
      the kidneys, singly and together, in a manner analogous to radionuclide
      scintigraphy.

PMID- 8657461
TI  - Comparison of absorbed radiation doses in barium and air enema reduction of
      intussusception: a phantom study.
AB  - OBJECTIVE: We assessed the relative radiation load in patients undergoing
      hydrostatic and pneumatic reduction of childhood intussusception. MATERIALS AND
      METHODS: In a phantom study we simulated two situations occurring during
      reduction of intussusception. The absorbed radiation dose was measured at several
      positions in the phantom using either barium sulphate (BaSO4) or air in the
      simulated reduction, combined with either automatic exposure control (AEC) or
      constant exposure rate (CER) at fluoroscopy. From these values the mean absorbed
      dose was calculated for different depth compartments within the phantom. RESULTS:
      In the barium study the mean absorbed dose averaged over the total irradiated
      volume was 14-23 % lower when CER was used instead of AEC; in the air study the
      dose was 35-43 % lower when AEC was used instead of CER. The combination of air
      and AEC provided the lowest mean absorbed dose in the tissue. The barium enema
      created a low-radiation zone, which might be utilized for protecting radiation
      sensitive tissue. CONCLUSION: The use of BaSO4 or air in reduction of
      intussusception requires the proper combination with CER and AEC, respectively,
      to minimize the radiation load to the patient; the lowest radiation load is
      obtained by using air and AEC.

PMID- 8657462
TI  - Computed radiography in neonatal and pediatric intensive care units: a comparison
      of 2.5 K x 2 K soft-copy images vs digital hard-copy film.
AB  - OBJECTIVE: The goal of the study was to determine whether soft-copy images on
      high-resolution monitors (2.5 K x 2 K) are suitable for primary interpretation of
      images from pediatric and neonatal intensive care units. The hypotheses were that
      hard and soft images yield similar diagnostic information, and that both
      residents and faculty radiologists can use monitors effectively. Previous reports
      have produced conflicting results; the need for larger sample sizes has been
      emphasized. MATERIALS AND METHODS: One thousand one hundred and four images
      produced by computed radiography using the Kodak Ectascan Imagelink system were
      prospectively analyzed by two pediatric radiologists, one reading hard copy and
      the other soft copy of the same images. Bias was controlled by equal distribution
      of modalities between observers and by daily alternation of modality. Hard- and
      soft-copy observations of presence or absence of nine specific tubes and nine
      specific diagnostic findings were compared. Interobserver differences between
      pediatric radiologists and radiology residents were studied on additional images.
      The kappa statistic was used to evaluate the level of agreement for all
      observations. RESULTS: There was excellent agreement between hard and soft copy
      interpretation for each tube and diagnostic finding (kappa values 0.93-1.0) and
      excellent interobserver agreement between two pediatric radiologists (kappa
      values 0.84-1.0). The level of agreement between radiology residents and
      pediatric radiologist was excellent for the most objective findings. All results
      were statistically significant (p < 0.001). CONCLUSION: High resolution soft-copy
      images are suitable for primary interpretation in patients in pediatric and
      neonatal intensive care units.

PMID- 8657463
TI  - Hepatic spiral CT in children: scan delay time-enhancement analysis.
AB  - PURPOSE: To compare the effect of different time delays between contrast
      administration and the start of spiral CT scanning on hepatic enhancement in
      children. MATERIALS AND METHODS: Forty-five children (2-9 years old, mean 6
      years) with no evidence of hepatic disease were examined with spiral CT.
      Sequential spiral scans through the entire liver were performed following a
      uniphasic injection of nonionic contrast medium. In group 1 scanning started at
      80 % of the contrast injection time, in group 2 scanning started at 100 % of
      injection time, and in group 3 scanning started at 150 % of injection time. Mean
      hepatic, aortic, and inferior vena caval enhancement were determined using
      regions-of-interest measurements. RESULTS: Mean hepatic enhancement was 41.4,
      47.0, and 40.6 HU for the 80 %, 100 %, and 150 % injection times, respectively.
      Enhancement was significantly greater in the 100 % injection time group (p <
      0.05). A mean aortocaval difference of greater than 10 HU was present in all
      examinations. CONCLUSION: Our results suggest that delaying the initiation of
      spiral CT scanning until the completion of the contrast injection increases
      hepatic enhancement in children. These data should help to improve the quality of
      hepatic spiral CT in pediatric patients.

PMID- 8657465
TI  - Physiological bowlegs or infantile Blount's disease. Some new aspects on an old
      problem.
AB  - The differentiation between physiological bowlegs and infantile Blount's disease
      in patients aged 11-30 months is very difficult. Nevertheless, diagnosis is
      deemed important because treatment of infantile Blount's disease is recommended.
      Fourteen patients with severe bowing of the legs seen in our outpatient clinic
      were investigated retrospectively. We examined them and measured the tibiofemoral
      and metaphyseal/diaphyseal angles in radiographs taken at their first
      presentation. The finding that the tibiofemoral angle is not helpful in
      differential diagnosis could be confirmed but, contrary to reports by other
      authors, neither was the metaphyseal/diaphyseal angle. In view of the spontaneous
      recovery of all investigated patients, it must be doubted whether a diagnosis of
      infantile tibia vara can be made in early infancy, and whether infantile Blount's
      disease is a diagnosis in its own right.

PMID- 8657464
TI  - MR imaging of hepatic hemangiomas of infancy and changes seen with interferon
      alpha-2a treatment.
AB  - The purpose of this study was to describe the appearance on magnetic resonance
      (MR) imaging of hepatic hemangioma, and how the appearance changes in infants who
      have received interferon alpha-2a (IFN) treatment. We retrospectively studied 16
      MR examinations in seven infants (mean age 3.2 months; range 5 days to 13 months)
      who were symptomatic with hepatic hemangiomas. Five of these seven patients had
      MR examinations both before and after treatment with IFN. In six of the seven
      patients, the hepatic hemangiomas were multicentric; they were usually discrete,
      well-defined nodules, best seen on T2-weighted images as high intensity lesions.
      One patient had a large solitary heterogeneous lesion. They all exhibited fast
      flow (seen as flow voids on spin-echo images and high signal intensity structures
      on gradient-recalled echo images) and enlarged hepatic arteries and veins. There
      was enlargement of the proximal abdominal aorta with distal tapering. Treatment
      was followed by accelerated regression of the hemangiomas in size and number and
      variable shrinkage of the enlarged vessels. As the tumor nodules regressed, they
      were replaced by normal-appearing hepatic parenchyma; neither fat nor fibrosis
      was detected by MR imaging.

PMID- 8657466
TI  - Hypertrophic bursopathy of the subacromial-subdeltoid bursa in juvenile
      rheumatoid arthritis: sonographic appearance.
AB  - Hypertrophic bursopathy is a term used to describe the massive synovial
      proliferation occasionally seen in the bursae of patients with arthritis.
      Involvement of the subacromial-subdeltoid (SA-SD) bursa in adults in uncommon,
      and it is still rarer in children. It may simulate synovial proliferation or
      fluid within the adjacent shoulder joint. Sonography clearly shows the location
      and nature of the soft-tissue swelling. Two cases of this entity in children with
      juvenile rheumatoid arthritis are described, one with a uniquely severe
      sonographic picture.

PMID- 8657467
TI  - Factitious lambdoid perisutural sclerosis: does the "sticky suture" exist?
AB  - We report a patient with occipital flattening attributed to lambdoid synostosis
      on the basis of perisutural sclerosis. The lambdoid suture was patent at surgery
      and by histology. Specimen radiography showed no perisutural sclerosis. This case
      questions the validity of peri- sutural sclerosis as a radiographic indicator of
      impending lambdoid synostosis.

PMID- 8657468
TI  - A case of bronchial cast.
AB  - We report a case of bronchial cast in a boy 1 year and 5 months old. Bronchial
      casts often obstruct the main bronchi, causing dyspnea and hypoxia. The bronchial
      cast was studied pathologically, with findings of eosinophilia and neutrophilic
      infiltration; the cast seemed to involve an allergic reaction. Such casts can be
      removed during bronchoscopy, but we used aspiration.

PMID- 8657469
TI  - Ultrasound of the discharging umbilicus.
AB  - Ultrasound of a patent urachus has been well described. However, ultrasound of
      the other congenital abnormalities affecting the umbilicus has not. Two cases are
      described, one of a vitelline (omphalomesenteric) duct and one of an umbilical
      granuloma, in which the ultrasound findings guided the child's management,
      preventing a minilaparotomy.

PMID- 8657470
TI  - Extensive vascular calcification in a patient with perinatally acquired AIDS.
AB  - Extensive vascular calcification in an 8-year-old girl with perinatally acquired
      AIDS is reported. Complicating factors included cardiomyopathy, chronic lung
      disease, disseminated Mycobacterium avium complex (MAC), and wasting syndrome
      with total nutrition dependence. Plain abdominal films and CT of the abdomen
      immediately prior to her death revealed dense calcification of major vessels.
      Autopsy revealed calcification in the media of most major vessels typical of HIV
      arteriopathy. A review of the literature failed to reveal a description of
      similar vascular calcifications in pediatric AIDS.

PMID- 8657471
TI  - MR of right aortic arch.

PMID- 8657472
TI  - Magnetic resonance venography of congenital vascular malformations of the
      extremities.
AB  - Contrast angiography can demonstrate the vascular components of a vascular
      malformation, but can be technically challenging in small patients with complex
      venous anomalies. We reviewed the role of magnetic resonance venography (MRV) in
      the evaluation of children with predominantly low-flow, vascular malformations of
      the extremities. MRV (2D time-of-flight technique) and magnetic resonance (MR)
      imaging examinations were performed in ten young patients with congenital
      predominantly low-flow vascular malformations of the extremities. MR imaging was
      used to characterize and determine the extent of the malformations, and MRV to
      evaluate the deep and superficial venous channels. In all patients, MRV studies
      were reviewed in conjunction with contrast angiograms, considered the gold
      standard, to confirm the findings. All significant channel anomalies seen with
      contrast angiography were identified with MRV. In addition, MRV demonstrated some
      veins that were not intentionally opacified during contrast studies. MRV
      demonstrates both the superficial and deep conducting veins, whereas contrast
      angiography is a more directed study, evaluating only those channels
      intentionally opacified. Together, MR imaging and MRV data can non-invasively
      form the basis for determining the prognosis and choosing the individual
      treatment of congenital vascular malformations of the extremities.

PMID- 8657473
TI  - MR imaging in congenital lower limb deformities.
AB  - Treatment for children with congenital deformities of the lower extremities may
      vary, depending on the state of the unossified skeletal structures and
      surrounding soft tissues. The purpose of our study was to demonstrate the
      spectrum of the osteochondral and extrasosseous abnormalities as depicted with MR
      imaging. We retrospectively reviewed MR examinations of 13 limbs of ten children
      (aged 1 month-9 years, mean 2.1 years) with longitudinal and transverse
      deformities of the lower extremities. The lesions imaged were fibular hemimelia
      (n = 5), tibial hemimelia (n = 5), and congenital constriction bands (n = 3).
      Each examination was assessed for abnormalities in the osteocartilaginous and
      extraosseous (articular or periarticular components such as ligaments, tendons,
      and menisci; the muscles and the arteries) structures. Abnormalities were seen in
      all patients. Osteocartilaginous abnormalities in the patients with longitudinal
      deformities included abnormal distal femoral epiphyses, abnormal proximal tibial
      physes, hypertrophied and dislocated proximal fibular epiphyses, unsuspected
      fibular and tibial remnants, and absence or coalition of the tarsal bones. No
      osteocartilaginous abnormalities were seen in the patients with congenital
      constriction bands. Articular abnormalities about the knee in patients with
      either form of hemimelia included absent cruciate ligaments and menisci,
      dislocated or absent cartilaginous patellae, absent patellar tendons, and
      abnormal collateral ligaments. All but one limb imaged had absent or attenuated
      muscle groups. Of the nine MR arteriograms performed at the level of the knee,
      eight were abnormal. The normal popliteal trifurcation was absent or in an
      abnormal location. We conclude that MR imaging of children with congenital lower
      extremity deformities shows many osteochondral and extraosseous abnormalities
      that are not depicted by conventional radiography. This information can help to
      plan early surgical intervention and prosthetic rehabilitation.

PMID- 8657474
TI  - Imaging of biliary complications following paediatric liver transplantation.
AB  - Biliary complications (BC) are well recognised following paediatric liver
      transplantation. We reviewed retrospectively 169 consecutive liver transplants
      performed in 139 children. BC occurred in 36/169 grafts (21 %) in 35/139 patients
      (25 %). Biliary obstruction was present in 18/169 grafts (11 %), biliary leakage
      in 14/169 grafts (8 %) and a combination of obstruction and leakage was present
      in 4/169 (2 %) grafts. BC were as likely to present radiologically as they were
      with either clinical and/or biochemical abnormalities. Most BC (26/36, i. e. 72
      %) occurred in the first 2 weeks following transplantation. Ultrasound and
      cholangiography were the principle imaging modalities used for detection of these
      complications. False negative ultrasound examinations occurred in three patients
      with biliary obstruction and in three patients with biliary leakage. False
      negative cholangiograms occurred in two patients with biliary leakage. Ultrasound
      is important in the post-operative surveillance of paediatric liver transplants,
      with cholangiography having a complementary role in those with BC.

PMID- 8657475
TI  - Prenatal and neonatal sonographic imaging of a central diaphragmatic hernia.
AB  - A case of a central diaphragmatic hernia diagnosed prenatally is reported. The
      prenatal sonographic findings included central herniation of most of the liver
      into the chest and hydrops. The hernia was successfully repaired. However, the
      infant died secondary to respiratory distress syndrome.

PMID- 8657476
TI  - In utero appearance of a giant Meckel's diverticulum.
AB  - The authors present a case of a Meckel's diverticulum identified during a routine
      prenatal ultrasound examination as a complex mass, superior and posterior to the
      urinary bladder, that prompted meticulous postnatal evaluation. A 4.0-cm Meckel's
      diverticulum containing heterotopic gastric mucosa was excised before
      complications could arise. Meckel's diverticulum should be included in the
      differential of a complex intraabdominal mass of the fetus/neonate.

PMID- 8657477
TI  - Atypical pyloric stenosis in an infant with familial hyperlipidemia.
AB  - A 1-month-old infant presented with a typical pattern of pyloric stenosis but US
      revealed an intense hyperechogenicity of the thickened pyloric muscle.
      Cholecystitis and pancreatitis were also present in this child. Familial
      hyperchylomicronemia was detected. Surgery confirmed the fatty infiltration of
      the pyloric muscular layer, which was necrotic and inflammatory. Medical
      management with restriction of fat in the diet led to a complete recovery. This
      is an exceptional case of pyloric stenosis where the particular echographic
      appearance of the pyloric muscle led to successful to medical treatment.

PMID- 8657478
TI  - Multipolypoid intussusceptum: a distinctive appearance of ileoileocolic
      intussusception at the ileocecal valve.
AB  - Objective. To determine whether ileoileocolic intussusception can be diagnosed by
      a distinctive appearance during pneumatic reduction. Materials and methods. We
      reviewed the clinical, pathologic, and imaging findings of 11 patients with
      ileoileocolic intussusceptions seen in our hospital between January 1989 and July
      1994. The patients ranged in age from 4 months to 4 years and 2 months. We
      specifically evaluated the appearance of these intussusceptions on air enemas
      performed in nine of these patients. Another 22 air enemas of all patients with
      surgically proven ileocolic intussusception seen during the same time period were
      also reviewed for comparison. Results. In seven of the nine patients with
      ileoileocolic intussusception who had air enemas, the intussusceptum clearly had
      two or more separate polypoid components once it was reduced to the cecum. This
      distinctive appearance was not seen until the intussusceptum was tethered at the
      ileocecal valve. The intussusceptum was also reduced to the cecum in 19 patients
      from the control group with ileocolic intussusception. In contrast to the
      ileoileocolic intussusceptums, these intussusceptums were either smoothly
      marginated (16 patients) or slightly lobular (three patients). Conclusion. In
      most patients with ileoileocolic intussusception, the intussusceptum has two or
      more polypoid components at the level of the ileocecal valve which are easily
      distinguished from the smoothly marginated or slightly lobular intussusceptum
      seen with ileocolic intussusception.

PMID- 8657479
TI  - Perflubron as a gastrointestinal MR imaging contrast agent in the pediatric
      population.
AB  - OBJECTIVE: To evaluate the safety and efficacy of orally administered perflubron
      for bowel recognition on MR imaging in a pediatric population. MATERIALS AND
      METHODS: A multicenter trial evaluated 39 pediatric subjects before and after
      ingestion of perflubron with T1-, proton-density, and T2-weighted sequences
      through the abdomen and/or pelvis. Post-contrast images were compared with pre
      contrast images. Safety was evaluated through assessment of adverse events,
      clinical laboratory parameters, and vital signs. RESULTS: With regard to efficacy
      analysis, improvement in the percent of bowel darkened was observed for 85 % of
      the subjects on T1-weighted images and for 95 % of the subjects on proton-density
      and T2-weighted images. For images of the abdominal region, the percent of bowel
      darkened was improved for 90-92 % of the subjects across pulse sequences.
      Improvement rates for the images of the pelvic region ranged from 71 % to 100 %.
      For at least 75 % of the subjects, proton-density and T2-weighted images of the
      body and tail of the pancreas, left lobe of the liver, mesenteric fat, and
      pathological tissue were improved relative to predosing images. Twenty-three
      percent of the subjects experienced some adverse effects, most of which were
      minor and related to the digestive system. Clinical laboratory and vital sign
      evaluations revealed no trends associated with the administration of perflubron.
      CONCLUSION: Perflubron is a relatively safe and effective gastrointestinal MR
      contrast agent in the pediatric population.

PMID- 8657480
TI  - Burkitt's lymphoma of the skull base presenting as cavernous sinus syndrome in
      early childhood.
AB  - Primary non-Hodgkin's lymphoma of the skull base presenting with neuro
      ophthalmologic abnormalities or cavernous sinus involvement is very rare in
      children. We have found only 13 reported cases of cavernous sinus involvement by
      lymphoma [1]. We report the case of the youngest child diagnosed with Burkitt's
      lymphoma of the cavernous sinus and sphenoid sinus, whose first presentation was
      cavernous sinus syndrome with neuro-ophthalmologic findings.

PMID- 8657481
TI  - Precocious puberty with pituitary gland hyperplasia: two cases in one family.
AB  - Children with central precocious puberty have pituitary gland size comparable to
      that of pubertal children (pituitary gland height 6.1 +/- 1.1 mm). We present of
      two sisters with precocious puberty and a pituitary gland height of more than 1
      cm. On contrast enhanced MRI, there was homogeneous enhancement of the pituitary
      gland. There was no increase in pituitary gland size during the follow-up period
      (6 years and 2 years). These cases are reported for their rarity.

PMID- 8657482
TI  - The hourglass facial deformity as a consequence of orbital irradiation for
      bilateral retinoblastoma.
AB  - We report a case illustrating characteristic facial deformities following
      irradiation during infancy for bilateral retinoblastoma. CT and MR imaging
      revealed distinctive features of the resulting "hourglass facial deformity":
      hypotelorism, enophthalmos, depressed temporal bones, atrophy of the temporalis
      muscles, and a depressed nasion. This case also displayed premature metopic
      craniosynostosis and frontal sinus aplasia; these may be additional hallmarks of
      this deformity.

PMID- 8657483
TI  - Thyroid sonographic abnormalities in McCune-Albright syndrome.
AB  - McCune-Albright syndrome (MAS) is characterised by the clinical triad precocious
      puberty, polyostotic bone dysplasia and cafe-au-lait skin lesions. Some studies
      have shown the possibility of multiple endocrinological disorders in this
      condition, especially thyroid disorders. We report the case of three girls with
      MAS and a heteromultinodular thyroid at sonography, despite the fact that they
      were clinically and biologically euthyroid. This raises the question of the
      follow-up and treatment of these lesions.

PMID- 8657484
TI  - Tracheal growth in congenital tracheal stenosis.
AB  - Two cases of congenital tracheal stenosis were managed conservatively despite
      mild to moderate initial respiratory symptomatology in infancy. Serial CT
      examinations were performed on each child, with tracheal dimensions and cross
      sectional areas measured in the region of stenosis at each CT examination. The
      examinations document increases in tracheal cross-sectional area in the region of
      stenosis over time, confirming tracheal cartilage growth. We present these data
      to dispel the hypothesis that tracheal growth does not occur in complete-ring
      tracheal stenosis. The selection of cases for surgical repair must be considered
      with the knowledge that this anomaly does not carry an inevitably poor prognosis.

PMID- 8657485
TI  - Vertebra plana: benign or malignant lesion?
AB  - The case of a 9-year-old boy presenting with a vertebra plana at T7 is reported.
      The initial diagnosis, as suggested by clinical presentation, conventional
      radiographs and CT scans, was eosinophilic granuloma. Positive radionuclide bone
      scan led to biopsy of the posterior arch, which suggested giant cell tumour. MRI
      showed extraspinal tumour involvement. Vertebrectomy revealed osteosarcoma.

PMID- 8657486
TI  - [Once again about the early diagnosis of Hodgkin's disease].
AB  - We describe the initial presentation of Hodgkin's disease, which 40 years ago was
      generally not diagnosed until its advanced stages. The diagnosis is now being
      made earlier. The initial symptoms of Hodgkin's disease are described; this may
      facilitate earlier diagnosis.

PMID- 8657487
TI  - [Results of treatment for severe acquired aplastic anemia in children].
AB  - The authors evaluated results of treatment of 106 children with acquired aplastic
      anemia. The patients were divided into 3 groups depending on the severity of
      their disease. Thirty-nine patients were classified as very severe, 30 as severe
      and 37 as non-severe according to the modified Camitta criteria. Among them, 47
      children were treated with oxymetholone and prednisolone. In this group 32 died.
      Antilymphocyte globulin (ALG) was given to 48 patients and 20 received
      cyclosporin A (CsA). The results obtained by these two methods are nearly the
      same and 5 year survival was 61% and 59% respectively. Bone marrow was
      transplanted in only one child, who is still in complete remission. Statistical
      analysis showed a steady increase in incidence of aplastic anemia in the years
      1987-1989, which might coincide with the Czarnobyl explosion. However, further
      research is required to prove this point.

PMID- 8657489
TI  - [Analysis of brain tumors in children from the Rzeszow region].
AB  - The authors present an analysis of brain tumors diagnosed in the pediatric ward
      of the voivodship hospital in Rzeszow between 1988 and 1992. Age, sex and
      clinical manifestation leading to hospitalisation, localisation and
      histopathology of the tumors were assessed.

PMID- 8657488
TI  - [Fever in children with hematologic neoplastic diseases and implanted Broviac
      Hickman catheters].
AB  - A safe and effective method of venous access is important in the care and
      treatment of patients with malignancies. Thirty-seven Broviac-Hickman catheters
      were inserted in 32 children with haematological neoplastic disease. The mean
      indwelling time of the catheters was 7014 days. The catheters were used to
      administer chemotherapy and other drugs, blood products, and as well as to draw
      blood. Fever occurred 96 times. Forty-three percent of fever episodes were
      related to clinically documented infections and in 15% of cases, to catheter
      related bacteremia caused by Gram-positive and Gram-negative strains in
      equivalent proportions. Fever was observed with a two fold greater incidence in
      patients with severe granulocytopenia (< 0.5 G/l).

PMID- 8657490
TI  - [Thyroid neoplasms in children and adolescents--personal experience].
AB  - Between 1974-1992 we operated 12,344 patients at the Clinic of Surgery of the
      Institute of Endocrinology of the Lodz Medical Academy for various forms of
      goiter. Of these, 295 patients were between the ages of 9-18 years, including 268
      (90.8%) girls and 27 (9.2%) boys. Malignant thyroid neoplasm was diagnosed in 19
      of these children (6.4%). From among the 268 girls, malignant tumors were
      discovered in 15 (5.6%), while among the 27 boys, in 4 (14.8%). Ten of these
      neoplasms were carcinoma papillare, 9 carcinoma folliculare. All of the children
      are alive without signs of metastases or recurrence. None developed
      hypoparathyroidism, but one child presented unilateral paresis of the vocal
      chords.

PMID- 8657492
TI  - [Changes in the gastrointestinal system of children with inflammatory systemic
      connective tissue diseases].
AB  - Functional and morphological changes of the gastrointestinal system were assessed
      in patients suffering from juvenile chronic arthritis, juvenile systemic
      erythematosus and juvenile systemic scleroderma. The results of endoscopic
      investigation of the gastrointestinal tract showed inflammatory changes and
      cardiac and pylorus atony. Ultrasonography results suggested hepatic and
      pancreatic inflammatory changes, steatosis and/or amyloidosis. The above
      mentioned changes were confirmed by morphological investigation (biopsy and/or
      autopsy). The results of the capacity tests performed in JCA (systemic form)
      patients revealed an impairment of liver detoxication function, and pancreas and
      bowel functional capacity as well. Additionally, intolerance against lactose,
      casein and alpha- and beta-lactoglobulin was found in most of the patients. Some
      symptoms of malnutrition were observed in all of them. Such factors as underlying
      disease severity, adverse drug effects, environmental factors (infections,
      nutrition) were taken into consideration as probable causes of the
      gastrointestinal system damage.

PMID- 8657491
TI  - [Lesniowski-Crohn disease and ulcerative colitis in the pediatric clinic of
      rheumatology].
AB  - Some diagnostic problems concerning childhood ulcerative colitis and terminal
      ileitis are discussed. In a group of 10 patients referred to the pediatric clinic
      of rheumatology, systemic manifestations and arthritis causing diagnostic
      difficulties prevailed from the onset of the disease.

PMID- 8657493
TI  - [Use of intravenous megadoses of methylprednisolone for treatment of
      dermatomyositis in children].
AB  - Intravenous treatment with megadoses of glycocorticoids was used in 8 children
      with juvenile dermatomyositis (JDM). Methylprednisolone (Mp-Solu-Medrol) was
      administered in a dose of 20 mg/kg, not exceeding 1 g, in the form of drop
      infusion over a period of 1.5-2.5 hours. An initial 3-6 consecutive day course of
      intravenous pulse was followed by further treatment twice a week for 2 to 5
      weeks. A good response this therapy was observed in all of the children. However
      the best results were obtained in those patients who had not been treated
      previously and in when MP pulses were given soon from the onset of the disease
      (group I). MP pulse therapy administered in patients nonresponsive to
      conventional treatment (group II) did not prevent further relapses. When the
      treatment was introduced at the later, exacerbated stage of the disease, none of
      the patients entered into remission (group III). No side effects were observed
      during the pulse therapy. This study confirms the efficacy of MP pulse therapy in
      JDM, specially in the early severe stage of the disease.

PMID- 8657494
TI  - [Persistent pulmonary hypertension in newborns].
AB  - One of the most critical problems of neonatology persistent pulmonary
      hypertension in the newborn, is discussed. This syndrome is characterized by
      increased resistance in pulmonary vessels leading to hypertension in pulmonary
      arteries and a recurrence of R > L shunting at the ductus arteriosus and foramen
      ovale. This leads to deep hypoxia and hypoxemia. It is most important to rule out
      a congenital cyanotic heart defect in the differential diagnosis. The aim of the
      treatment is to establish normal ventilation and intrapulmonary shunting as well
      as to control the symptoms leading to pulmonary hypertension that persist over
      time. The goal preceding treatment should be to determine the initial cause of
      the persistent pulmonary hypertension.

PMID- 8657495
TI  - [A case of Wilm's tumor with full symptomatic WAGR syndrome].
AB  - The authors of this paper presented a case of a baby with full-symptomatic WAGR
      syndrome (Wilms tumor, aniridia, genital tract malformation and mental
      retardation) treated in the I Department of Pediatrics, Institute of Pediatrics,
      Medical Academy Poznan. The etiology of this syndrome was discussed (deletion of
      the 13th band of the 11th chromosome short arm). The reason for treatment failure
      was analysed.

PMID- 8657497
TI  - [Hypertrophic osteoarthropathy of cystic fibrosis].
AB  - A 17-year-old male patient with cystic fibrosis, advanced lung disease and finger
      clubbings presented symmetrical chronic arthritis of the knee and ankle joints of
      unknown origin. Hypertrophic osteoarthropathy diagnosed on the basis of the
      classic clinical features and anamnestic data was documented by the presence of
      periostosis of the tubular bones on radiographs. The considerably increased life
      expectancy of CF patients seems to mean the expansion of the list of diseases to
      be excluded when diagnosing JCA.

PMID- 8657496
TI  - [Congenital megaloblastic anemia in a 22-month-old boy].
AB  - A 22-month old boy with the congenital form of megaloblastic anaemia is
      presented. The child was admitted to hospital with moderate-to-severe
      hematological and neurological symptoms. Very low serum vitamin B12 concentration
      and normal gastric secretion were determined. A dramatic recovery after
      intramuscular injections with vitamin B12 was observed.

PMID- 8657498
TI  - [Specialist care of children with neoplastic diseases].

PMID- 8657499
TI  - [Diagnosis of nonepileptic fits and differentiation from epilepsy on the basis of
      interviews and clinical symptoms].

PMID- 8657500
TI  - [Brain injury in the premature infant--current concepts on prevention and
      treatment strategy].
AB  - The frequency of neurological abnormalities in premature newborns is about 20%.
      The probability of these deficiencies increases up to 45% in the group with
      abnormal sonographic evaluation. Particularly unfavourable prognosis is connected
      with grade III and IV intraventricular haemorrhages and periventricular
      leukomalacia. Current concepts on possible prevention strategies in this
      pathology are presented.

PMID- 8657501
TI  - [On carnitine requirements in full term and low birth weight neonates].
AB  - The concentration of total carnitine in the blood serum of 15 newborns between
      days 5-21 of life was determined. The concentration of carnitine in low-birth
      weight newborns is decreased in comparison with normal weight newborns; this
      deficiency may increase as a consequence of lack of carnitine provided with food
      or concomitant infection. The authors suggest that supplementation with carnitine
      be provided to this group of patients so as to prevent possible metabolic and
      clinical consequences.

PMID- 8657502
TI  - [The correlation between levels of IgE in cord blood in newborn infants and a
      family history of allergy].
AB  - The cord blood IgE level was assayed in 110 unselected newborn infants during the
      period from Jan. 15-March 24, 1993. Serum IgE levels ranged between 0.19-2.8
      IU/ml with a median value of 0.34 IU/ml. The group of newborn was subdivided into
      two groups based on family history of allergy: high risk and low risk. The
      geometric means, range and median values of cord blood IgE levels were calculated
      in each of these groups. The median value of the cord blood IgE level was
      significantly higher in the high risk group (0.40 IU/ml) than in the low risk
      group (0.34 IU/ml) (p < 0.005).

PMID- 8657503
TI  - [Effect of smoking in the families of newborn infants on levels of immunoglobulin
      E in cord blood].
AB  - The influence of active and passive parental cigarette smoking on cord blood IgE
      levels of their offspring was assessed. The geometric means of cord blood IgE
      levels in 110 of newborn infants of smoking and nonsmoking mothers were
      calculated in the entire analysed group and in families with a positive family
      history of atopy. The results were not statistically significant for the entire
      analysed group. The higher cord blood IgE concentrations in infants of nonsmoking
      mothers in the families with a positive family history of atopy were due to the
      influence of a genetic factor on IgE synthesis by the fetus.

PMID- 8657504
TI  - [Colonization with group B streptococci in neonates and premature infants from
      selected neonatal departments].
AB  - Group B streptococci are considered an important etiological agent of sepsis and
      meningitis in neonates and, particularly, in premature infants. There is a close
      correlation between colonization with these bacteria and the frequency of
      symptomatic infection. It is estimated that symptomatic infections occur in 1.0%
      of colonised neonates. The purpose of this work was to investigate the frequency
      of neonate colonization with group B streptococci for determination of the risk
      of symptomatic infection.

PMID- 8657505
TI  - [Septicemia in children treated with exchange transfusions because of hemolytic
      disease of the newborn].
AB  - Clinical signs and laboratory test results were analyzed in 70 neonates (42 boys
      and 28 girls) hospitalized because of neonatal haemolytic disease who were
      treated with exchange transfusion and later developed septicaemia. Serological Rh
      D incompatibility was diagnosed in 11 children, ABO incompatibility in 59. Signs
      of infection appeared between days 1 and 7 after transfusion. Pneumonic signs and
      diarrhoea dominated clinically in 45 newborns, skin abscesses were observed in
      10, osteomyelitis in 4. Septic shock occurred in 7. Gram-negative bacteria
      predominated (52.85%). A significant diagnostic value of the following was found
      (chi2): granulocytic band forms (expressed as percentages > or = 0.10, a
      neutrophil index > 0.2 and toxic granulations in neutrophils. These results were
      obtained in the early, asymptomatic stage of infection, i.e. before the exchange
      transfusion was performed. The importance of the presence of risk factors, not
      exchange transfusion per se, is stressed.

PMID- 8657507
TI  - [Thyroid gland function in neonates with transient hyperthyrotrophinemia from a
      region of slight iodine deficiency].
AB  - The aim of this study was to evaluate thyroid gland function in neonates and
      babies with transient hyperthyrotrophinemia during the first twelve months of
      life in an attempt to establish the causes of this condition in neonates born in
      a region of slight iodine deficiency. Thirty-eight newborns were screened.
      Clinical observations and measurements of serum T3, T4, TSH levels as well as
      urinary iodine were conducted for one year (at the age of 2 weeks, 3-4 months,
      and after one year of life). The screened children showed significantly higher
      values of T4 (p < 0.001) in comparison with the reference value in successive
      follow-up examinations. High T4 values may result from an increased TBG
      concentration in serum, and its level should be determined in the analysed
      material. Other hormonal values normalized after the second weak of life. Iodine
      deficiency was found in 80% of the children. Our assessments concerning the
      causes of transient hyperthyrotrophinemia conform with previous findings. It was
      established that the most common causes are iodine deficiency and maternal
      thyroid disease. None of the screened children had goitre somatic anomalies or
      delayed psychomotoric development did not appear more frequently than in the
      general pediatric population.

PMID- 8657506
TI  - [Evaluation of treatment results for anemia of prematurity treated with various
      doses of human recombinant erythropoietin].
AB  - We evaluated the results of administering recombinant human erythropoietin
      (rHuEPO) and iron in 19 randomly selected premature infants, who had no
      infections, did receive oxygen support or aminophylline. rHuEPO was administered
      intravenously from days to 37 (biweekly) in a dose of 100 U/kg (group I) or 400
      U/kg (group II). Also, infants in both groups were supplemented with 10
      mg/kg/week of iron intravenously. Seven of 19 infants did not receive either
      rHuEPO or iron (group III). Infants of all groups had similar birth weights,
      gestational age and hematocrit, RBC count as well as total and fetal hemoglobin
      concentrations in blood obtained within the first hour of life. However, infants
      treated with 400 U/kg of rHuEPO required a significantly (p < 0.04) lower volume
      of packed erythrocytes in comparison to untreated infants, both between days 7
      and 37 of life (18.6 ml vs 46.8 ml; p < 0.04) and between day 7 of life and the
      day of discharge (35.8 ml vs 94.2 ml; p < 0.04). No difference in neutrophil
      count, fetal hemoglobin concentration and no toxicity were observed in infants
      treated with rHuEPO in comparison to untreated prematures.

PMID- 8657508
TI  - [Congenital defects as a cause of infant mortality in Zielona Gora province in
      1987-1992].
AB  - A total of 1278 children with congenital defects born in Zielona Gora Province
      between 1987 and 1992 were studied. Of this group, 315 children (24,6%) died.
      Congenital defects were responsible for 38.1% of these deaths and were the main
      cause of late infant mortality. Congenital heart defects were the most frequent
      cause of death. Two hundred and ten (66%) of all of the deaths occurred in the
      neonatal period. Mortality from congenital defects among low birth weight
      neonates was twice the overall rate.

PMID- 8657509
TI  - [Immunization in preterm and term infants].

PMID- 8657510
TI  - [Hypothyroidism in three siblings].

PMID- 8657511
TI  - [Syndrome of congenital malformations and dysmorphic features in a newborn with
      partial trisomy 16q due to maternal translocation t(9;16)(p24;q13)].
AB  - A newborn with multiple congenital malformations and a pattern of dysmorphic
      features (microcephaly, uneven skull surface, exophthalmos, periorbital oedema,
      clefting of primary and secondary palates, camptodactylia of hands and feet,
      patent arterial duct, thoracic and spinal malformations, ambiguous external
      genitals) is described. Partial trisomy of chromosome 16q due to maternal
      reciprocal translocation t(9;16)(p24;q13) was detected. The risk for the next
      pregnancy was estimated to be low (below 2.6%).

PMID- 8657512
TI  - [Floating-Harbor syndrome in a girl with somatic asymmetry].
AB  - Floating-Harbor syndrome, a genetic disorder of unknown etiology, was diagnosed
      in a 9-year-old girl with delayed morphologic, bone and dental age, lateral
      asymmetry of the body, triangular face, hypotelorism, broad palpepral fissures,
      long eye-lashes, narrow jaw, retrogenia, a defect of phonemic audition and speech
      delay with poor articulation. Similarity between Floating-Harbor syndrome and
      Silver-Russel syndrome is discussed.

PMID- 8657513
TI  - [Specialist care in pediatric ophthalmology].

PMID- 8657514
TI  - [In memory of Doctor Hieronim Bartoszewski (1912-1993)].

PMID- 8657515
TI  - Markers for primary care: missed opportunities to immunize and screen for lead
      and tuberculosis by private physicians serving large numbers of inner-city
      Medicaid-eligible children.
AB  - OBJECTIVE: This study examines coverage levels for immunization, missed
      opportunities to immunize, and extent of lead and tuberculosis screening in inner
      city storefront physician offices and then relates child, visit, and physician
      characteristics to missed opportunities. METHODOLOGY: With the use of a nested
      sampling strategy, 232 charts were selected for review in 31 physicians' offices.
      Charts selected were for children 0 to 35 months of age who had three or more
      visits in more than 3 months. Physicians were selected from those in specific low
      income New York inner-city neighborhoods who submitted large volumes of Medicaid
      billing claims. Variables examined were missed opportunities to immunize,
      immunization coverage levels, lead, and tuberculosis screening. The outcome
      measure was missed opportunities to immunize. RESULTS: Only 26% of the children
      were up to date for their age for diphtheria, tetanus, pertussis (DTP), oral
      polio vaccine (OPV), and measles, mumps, rubella (MMR) compared with a city-wide
      coverage level of 49%. Children who were not up to date for immunization coverage
      were more likely not to be up to date for lead (RR = 1.24, CI 0.96 to 1.60) or
      tuberculosis (RR = 1.54, CI 1.14 to 2.08) screening. Physicians miss
      opportunities to immunize in 84% of the eligible visits. Opportunities to
      immunize are missed more frequently at sick care or follow-up visits (95% and 91%
      missed opportunities) than at well care visits (41% missed opportunities).
      CONCLUSIONS: The quality of pediatric primary care given by these inner-city
      storefront physicians is suboptimal. Sick and follow-up visits predominate; well
      care visits are infrequent. If care is to be improved, Medicaid reimbursement
      policies, which make delivery of well care unprofitable, will need to be changed.
      In addition, monitoring the quality of care will need to be more aggressive. In
      the near future children who receive Medicaid in New York will be in managed
      care. If reimbursement and monitoring policies that provide incentives for
      delivering pediatric primary care are to be in place, it will be the managed care
      plans that implement this.

PMID- 8657516
TI  - Prevention of traumatic deaths to children in the United States: how far have we
      come and where do we need to go?
AB  - OBJECTIVE: To describe the changes in injury mortality from 1978 to 1991 and
      determine the number of preventable deaths with currently available intervention
      strategies. METHODS: Comparison of injury mortality data for children and
      adolescents 0 to 19 years in 1978 and 1991. Review of the literature to determine
      the effectiveness of currently available prevention strategies and application of
      these to deaths in 1991. RESULTS: The injury death rate declined by 26% over the
      14-year period. Death rates of unintentional injuries decreased by 39%, with
      declines in all categories of unintentional injuries. Homicides increased by 67%
      and suicides by 17%; nearly all of this increase was in deaths from firearms. If
      currently available prevention strategies were fully used, 6640 deaths could have
      been prevented, a further 31% decrease. CONCLUSIONS: Although great studies have
      been made in preventing deaths from trauma, the application of currently
      available prevention strategies could save a large number of additional lives.
      However, the increasing problem of intentional injury will partly counterbalance
      the success in unintentional injury control.

PMID- 8657517
TI  - Progress toward integrating hepatitis B vaccine into routine infant immunization
      schedules in the United States, 1991 through 1994. Connecticut Hepatitis B
      Project Group.
AB  - OBJECTIVE: We assessed progress toward universal infant immunization against
      hepatitis B, which was first recommended in November 1991. METHODS: Multiple data
      sources were used to describe vaccination policies and trends in infant hepatitis
      B vaccine coverage. RESULTS: As of June 1993, 51% of the 63 local, state, and
      territorial immunization programs recommended hepatitis B vaccination of all
      newborns shortly after birth. The number of first dosages of hepatitis B vaccine
      administered to infants in public sector clinics increased rapidly from late 1992
      to 1993, and at the end of 1993 was approximately two thirds the number of first
      dosages of other infant antigens. In a nationwide survey of hospital nurseries
      47% offered hepatitis B vaccine to all newborns. Of 3982 sampled newborns in
      these hospitals, 36.2% had been vaccinated before discharge. In San Francisco and
      Connecticut, where public health officials encouraged hospitals to offer
      hepatitis B vaccination, first-dose coverage at discharge was 82.3% in 1994 and
      69.1% in 1993, respectively. Coverage was higher in healthier infants and lower
      in infants of older or better-educated mothers. Results from the National Health
      Interview Survey demonstrate that three-dose completion at 12 months of age
      increased form less than 1% of children born in 1989 to 40% of children born in
      the fourth quarter of 1992. Vaccination at birth increased from less than 1% of
      infants born in 1989 to 32% of infants born in the second half of 1993.
      CONCLUSIONS: Infant hepatitis B vaccination has expanded rapidly since national
      recommendations were made; however, universal coverage has not been achieved.

PMID- 8657518
TI  - Parent comprehension of polio vaccine information pamphlets.
AB  - BACKGROUND: Medical information pamphlets often are written using language that
      requires a reading level higher than parents of many pediatric patients have
      achieved. Anecdotal reports suggest that many parents may not readily understand
      the federally mandated Public Health Service vaccine information pamphlets
      prepared by the Centers for Disease Control and Prevention (CDC) in 1991. The
      level at which the pamphlets need to be written for low-reading-level parents is
      undetermined, as is whether parents reading at higher levels will accept low
      reading-level materials. METHODS: To determine whether a simple pamphlet prepared
      at a low reading level using qualitative and adult education techniques would be
      preferable to the available CDC polio vaccine information pamphlet, we conducted
      an integrated qualitative-quantitative study. We compared the parent reading time
      and comprehension of a simplified pamphlet (Louisiana State University, LSU)
      comprising 4 pages, 322 words, 7 instructional graphics, and a text requiring a
      6th grade reading ability with the equivalent 1991 CDC vaccine information
      pamphlet comprising 16 pages, 18,177 words, no graphics, and a text requiring a
      10th grade reading level. We measured the reading ability of 522 parents of
      pediatric patients from northwest Louisiana seen at public clinics (81%) and in a
      private office (19%). Of the entire group, 39% were white, 60% African-American,
      and 1% Hispanic; the mean age was 29 years; the mean highest grade completed was
      12th grade 3 months; and the reading level was less than 9th grade in 47% of
      parents and less than 7th grade in 20%. After parents were given one of the
      pamphlets to read, their reading time, comprehension, and attitude toward the
      pamphlet were measured. RESULTS: Mean comprehension was 15% lower for CDC than
      for LSU (56% vs 72% correct; P < .001) and reading time was three times longer
      for CDC than for LSU (13 minutes 47 seconds vs 4 minutes 20 seconds; P < .0001).
      These trends were significant for parents reading at all but the lowest levels.
      Mean comprehension and reading time did not differ among parents reading at the
      third grade level or less. However, mean comprehension was greater and reading
      time lower for LSU among parents at all reading abilities greater than the third
      grade. Parents in the private practice setting took the longest time to read the
      CDC (20 minutes 59 seconds vs 5 minutes 46 seconds, LSU), yet their comprehension
      on the LSU was significantly higher than on the CDC (94% vs 71%; P < .0001). Two
      focus groups of high-income parents were unanimous in preferring the LSU.
      CONCLUSIONS: A short, simply written pamphlet with instructional graphics was
      preferred by high- and low-income parents seen in private and public clinics. The
      sixth grade reading level appears to be too high for many parents in public
      clinics; new materials aimed at third to fourth grade levels may be required. The
      new 1994 CDC immunization materials, written at the eighth grade level, may still
      be inappropriately high. The American medical community should adopt available
      techniques for the development of more effective patient-parent education
      materials.

PMID- 8657519
TI  - Safety and pharmacokinetics of recombinant human superoxide dismutase
      administered intratracheally to premature neonates with respiratory distress
      syndrome.
AB  - OBJECTIVE: As a first step in the evaluation of recombinant human CuZn superoxide
      dismutase (rhSOD) in the prevention of neonatal lung injury, safety and
      pharmacokinetics of intratracheally (IT) administered rhSOD were studied.
      METHODS: Twenty-six preterm infants weighing 750 to 1250 g with respiratory
      distress syndrome were studied in three sequential groups (placebo, 0.5, and 5
      mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first
      surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate
      fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were
      performed over the 28-day study period. RESULTS: Serum SOD concentrations were
      similar at baseline for all three groups (geometric mean 0.2, upper-lower limit
      0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours
      (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to
      baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours
      (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to
      baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for
      all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL).
      There were no significant increases in the placebo group, but levels in the 0.5
      mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1,
      upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In
      the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric
      mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by
      day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric
      mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants
      (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased
      significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine)
      demonstrated that the enzyme still possessed significant activity. No adverse
      effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin
      concentrations, important acute lung injury markers, were significantly lower in
      the high-dose rhSOD group compared with the other groups. CONCLUSIONS: Data
      suggest that a single IT dose of rhSOD results in significant increases in both
      concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3
      days. The enzyme appears to be well tolerated, and TAF inflammatory markers are
      reduced after administration. This has important implications in rhSOD trials to
      prevent acute and chronic lung injury in preterm neonates.

PMID- 8657520
TI  - Cardiac effects of dexamethasone in very low birth weight infants.
AB  - OBJECTIVE: To characterize the cardiac effects of dexamethasone in very low birth
      weight infants. DESIGN: Prospective, randomized, placebo-controlled, double-blind
      trial. Enrolled subjects were randomized to receive either a 42-day tapering
      course of dexamethasone or a saline placebo. Echocardiographic measurements were
      obtained on days 0, 7, 14, 28, and 42. SUBJECTS: Thirteen infants received
      dexamethasone and 13 a saline placebo. The two groups were similar in birth
      weight, gestational age, age at enrollment, and sex/ race composition. RESULTS:
      Patients receiving dexamethasone had a significantly larger increase in septal
      thickness on days 7, 14, and 28 and left ventricle (LV) posterior wall thickness
      on day 14. A significantly lower left ventricular end-diastolic dimension in the
      dexamethasone group was initially noted on day 7 and persisted until day 42. With
      the reduced left ventricular end-diastolic dimension, no significant differences
      in LV mass were noted, despite the increased wall thickness. No differences in LV
      systolic function, as assessed by area shortening, were seen. Assessment of
      diastolic function showed a significant increase in the atrial portion of mitral
      inflow in dexamethasone patients on day 14, as well as a significant prolongation
      in isovolumic relaxation time on days 7, 14, and 28. CONCLUSIONS: Infants
      receiving dexamethasone developed evidence for impaired LV filling with a lager
      increase in wall thickness but no increase in LV mass, asymmetric septal
      hypertrophy, or augmented systolic function. This suggests that alterations in
      left ventricular filling play an important role in the development of hypertrophy
      seen with dexamethasone administration.

PMID- 8657521
TI  - Bilateral cystic periventricular leukomalacia in the premature infant: associated
      risk factors.
AB  - BACKGROUND: Bilateral cystic periventricular leukomalacia (PVL) is a major cause
      of neurodevelopmental delay in the premature infant. Thus, early identification
      of the preterm infant at highest risk for the subsequent development of this
      lesion is critical. OBJECTIVES: The three objectives of this case-control study
      were: (1) to determine the basic characteristics of cystic PVL, (2) to assess the
      relationship of perinatal clinical events and PVL, and (3) to ascertain the
      feasibility of identifying early those preterm infants at highest risk for the
      development of PVL. METHODS: The medical records and cranial ultrasound scans
      (HUSs) were reviewed for 632 infants weighing less than 1750 g who were admitted
      to the neonatal intensive care unit between January 1992 and December 1993. PVL
      developed in 14 infants of 1285 +/- 301 g birth weight (BW) and 29.4 +/- 1.5
      weeks' gestational age (GA); severe intraventricular hemorrhage (n = 21) and
      intraparenchymal echodensity (n = 12) developed in 33 infants of 904 +/- 248 g BW
      and 26.6 +/- 1.8 weeks' GA; and 585 infants of 1315 +/- 324 g BW and 29.7 +/- 2.4
      weeks' GA with normal HUS findings (n = 473) or grade I or II intraventricular
      hemorrhage (n = 112) served as a comparison group. RESULTS: Cystic PVL was
      observed in 14 (2.3%) of 632 infants weighing less than 1750 g, more
      specifically, in 3.2% of infants weighing less than 1500 g. Cysts were noted from
      the 7th to 14th days of life in 10 infants and from the 20th to 46th days of life
      in 4 infants. Ten (70%) of the infants had relatively benign clinical courses,
      and most cases were detected by routine HUS surveillance. Over hypotension in the
      immediate perinatal period was noted in 3 (21%) infants; late hypotension
      developed in 1 additional infant. Univariate analysis indicate that two clinical
      indicators, prolonged rupture of membranes (PROM) and chorioamnionitis, were
      significant predictors of PVL. For PROM, the odds ratio estimate and the 95%
      confidence limit are 6.59 and 1.96 to 22.10, with a sensitivity of 28.6% and
      positive predictive value of 11.5%. Similar values for chorioamnionitis are 6.77
      (1.77 to 25.93), with a sensitivity of 21.4% and positive predictive value of
      11.5%. CONCLUSIONS: (1) Most cases of symmetric cystic PVL occurred in infants
      with relatively benign clinical courses and were only detected by routine
      ultrasound screening. (2) Postnatal systemic hypotension seems to be an uncommon
      associated event. (3) Preterm infants born to mothers with PROM and/or
      chorioamnionitis seem to be at an increased risk for the development of PVL and
      should be carefully evaluated.

PMID- 8657522
TI  - Biliary atresia, cytomegalovirus, and age at referral.
AB  - OBJECTIVE: To determine the frequency with which patients with extrahepatic
      biliary atresia (EHBA) are infected with cytomegalovirus (CMV) and to ascertain
      the age at referral to a specialty center for surgical correction of EHBA.
      METHODS: The charts of all patients discharged from the Children's Hospital and
      Medical Center between July 1, 1989 and December 31, 1993 with a new diagnosis of
      EHBA were reviewed to determine the frequency with which EHBA was accompanied by
      CMV infection. Data analyzed included age at referral and sex of patients,
      histopathologic evidence of CMV infection and size of bile ducts in the resected
      liver, and serologic (IgM) or culture diagnosis of CMV infection. RESULTS: Twenty
      three patients with EHBA were evaluated at Children's Hospital and Medical Center
      in the study period. Twenty-one of the patients with EHBA were appropriately
      evaluated for infection with CMV and infection was documented in 5 (24%)
      patients. The median age of referral for all patients was 61 days (range 10 to
      124 days). Infected patients were referred later (82.4 +/- 28.7 days) than
      noninfected patients (48.8 +/- 21.8 days) (P = .01) and were more likely to be
      girls, bu the medians of the diameters of the bile ducts in the resected porta
      hepatis were similar. Viral inclusions were not identified in any of the liver
      specimens. CONCLUSIONS: CMV infection is present in an unexpectedly large
      proportion of patients with EHBA at the time of referral. The establishment of
      CMV infection in infants with cholestasis should not deter the search for EHBA.
      Physicians should strive to reduce the age of referral of patients with EHBA to
      pediatric surgical centers by evaluating infants who remained jaundiced at 4
      weeks of age.

PMID- 8657523
TI  - Normal birth weight intensive care unit survivors: outcome assessment.
AB  - RATIONALE/OBJECTIVE: Although the short- and long-term outcome of low birth
      weight neonatal intensive care unit (NICU) survivors has been extensively
      studied, much less information is available for normal birth weight (NBW) infants
      (greater than or equal to 2500 g) who require NICU care. METHODS: To address this
      issue, we retrospectively examined the neonatal hospitalizations and 6-month
      health status of 521 consecutive NBW admissions to a single NICU. Information on
      the neonatal hospitalization was obtained from a review of medical records.
      Postdischarge health status was collected by using telephone survey techniques.
      RESULTS: NBW infants comprised 88.1% of births in this hospital and 35.4% of NICU
      admissions during the study period. The in-hospital mortality rate for this group
      was 2%. The median length of stay was 7.7 days (range 1 to 110 days) with median
      hospital charges of $5222 (range $565 to $317,820). Only 59% of infants required
      active intensive care therapy; the remainder received only intensive monitoring.
      The need for intensive therapy on admission day along with the presence of
      prematurity and congenital anomalies were significant predictors of hospital
      charges (R2 = 0.31, P < .01). After initial discharge, 10.1% of these infants
      required rehospitalization in the first 6 to 8 months of life. The rate of
      readmission among infants with congenital anomalies was over 30%. In addition to
      its association with neonatal resource consumption, the presence of congenital
      anomalies along with low 5-minute Apgar scores was associated with higher
      postdischarge resource use, as measured by frequency of physician visits, need
      for special medical items, and rate of rehospitalization (P < .05). CONCLUSIONS:
      NBW infants represent a significant percentage of NICU admissions, but for many
      of these patients NICU admission could be avoided if alternative care settings
      that provided intensive monitoring were available. In addition, these infants
      also incur higher rates of postdischarge use of medical care.

PMID- 8657524
TI  - Phenylketonuria: plasma phenylalanine responses to different distributions of the
      daily phenylalanine allowance over the day.
AB  - OBJECTIVE: To achieve smooth control of plasma phenylalanine concentrations in
      phenylketonuric patients, it is advocated to divide the daily intake of natural
      protein and amino acid supplements equally over the meals. However, this may be
      quite an encumbrance for the patient. We, therefore, investigated whether a
      breakfast with an unequal daily distribution results in an undue rise in the
      plasma phenylalanine concentration. DESIGN: Plasma phenylalanine concentrations
      were measured in seven patients with phenylketonuria in response to three tests
      with breakfast and lunch, representing an equally or unequally divided daily
      distribution of the individually tailored phenylalanine intake. Breakfast
      contained 25%, 50%, or 75%, whereas lunch contained 30% or 10% of the individual
      daily phenylalanine allowance, respectively. RESULTS: Plasma phenylalanine
      concentrations showed postprandial increases of up to 26% above baseline.
      Generally, phenylalanine returned to baseline during the test and remained within
      the target range if baseline phenylalanine was within that range. Two patients
      having values in the upper target range showed a rise just above the target range
      for 60 minutes on an unequal daily distribution of phenylalanine. In another
      patient treated similarly, plasma phenylalanine did not return to baseline during
      the test. CONCLUSIONS: Unequal distributions of the daily phenylalanine allowance
      are justified, provided that the patient is in good clinical condition, adjusted
      to the diet adequately, and the daily allowance is not exceeded. At this time,
      however, we cannot recommend this unequal daily distribution for daily practice.

PMID- 8657525
TI  - Fetal alcohol syndrome--an ophthalmological and socioeducational prospective
      study.
AB  - BACKGROUND: The eye is a sensitive indicator of adverse effects of prenatal
      alcohol exposure. Anomalies of the eyes and their adnexa are known to be
      associated with the fetal alcohol syndrome (FAS), although long-term effects of
      these malformations are unknown. DESIGN: A prospective ophthalmologic follow-up
      (median, 11 years; range, 4 to 19 years) was performed in 25 children with FAS.
      Their social situation and educational status were also investigated. RESULTS:
      All but one of the children had ophthalmologic abnormalities. Fundus anomalies
      were observed in 23 children, of whom 19 had optic nerve hypoplasia. Thirteen
      children had concomitant strabismus. Microphthalmos, buphthalmos, phthisis,
      microcornea, coloboma of the iris and uvea, blepharoptosis, cataract, persistent
      hyperplastic primary vitreous, and nystagmus were observed in single cases. The
      dysmorphology of the eyes remained unchanged during the follow-up period. In 2
      children with severe mental retardation and, initially, very poor vision, the
      severe visual handicap persisted. Seventeen children had an initial visual
      activity > or = 20/70, which remained unchanged in 10 children and improved in 7
      children, despite the presence of optic nerve hypoplasia in 14 of the children.
      Ten mothers died, 8 of them because of alcohol-related diseases, and only 4 of
      the mothers were able to take care of their children. Sixteen children went to
      schools for the mentally retarded, and only 3 children had a normal school
      education without extra teaching assistance. CONCLUSIONS: In children with FAS,
      the major sequela, ie, brain, damage, remains despite extensive medical,
      educational, and social support. The presence of ophthalmic signs, which
      persisted but did not deteriorate during the follow-up period, strengthens the
      diagnosis of FAS, and the high frequency of ocular involvement indicates the
      importance of a complete ophthalmologic evaluation in children with FAS.

PMID- 8657526
TI  - Cocaine-exposed preterm neonates show behavioral and hormonal differences.
AB  - OBJECTIVE: Prematurity has been associated with prenatal cocaine exposure, but
      most studies on the behavioral effects of prenatal cocaine exposure have been
      restricted to full-term infant samples. The current study focused on behavioral
      and hormonal responses in preterm cocaine-exposed infants compared with a cohort
      of non-cocaine-exposed infants of similar gestational age. METHODOLOGY: A
      comparison between 30 cocaine-exposed and 30 non-cocaine-exposed preterm neonates
      suggested that the cocaine-exposed neonates were born to mothers who had higher
      parity and more obstetric complications. In addition, mothers of cocaine-exposed
      preterm neonates visited, touched, held, and fed their infants less frequently
      than mothers of nonexposed infants. RESULTS: The cocaine-exposed infants had
      smaller head circumferences at birth, spent more time in the neonatal intensive
      care unit, and had a greater incidence of periventricular-intraventricular
      hemorrhages. They also had inferior Brazelton cluster scores, including lower
      state regulation and range-of-state scores, and greater depression. During sleep
      wake behavior observations, they showed difficulty maintaining alert states and
      self-regulating their behavior, and they spent more time in indeterminate sleep
      and had decreased periods of quiet sleep and increased levels of agitated
      behavior, including tremulousness, mouthing, multiple limb movements, and
      clenched fists. Finally, higher urinary norepinephrine, dopamine, and cortisol
      levels and lower plasma insulin levels were noted in the cocaine-exposed preterm
      neonates. CONCLUSIONS: These findings highlight the need for follow-up
      assessments and early intervention.

PMID- 8657528
TI  - Cognitive functioning and brain magnetic resonance imaging in children with
      sickle Cell disease. Neuropsychology Committee of the Cooperative Study of Sickle
      Cell Disease.
AB  - OBJECTIVE: Brain magnetic resonance imaging (MRI) and neuropsychological
      evaluations were conducted to determine whether neuroradiographic evidence of
      infarct in children with sickle cell disease between ages 6 and 12 years would
      result in impairment in cognitive and academic functioning. METHOD AND DESIGN:
      Children enrolled in the Cooperative Study of Sickle Cell Disease were evaluated
      with brain MRI and neuropsychological evaluation. Completed studies were obtained
      for 194 children, 135 with HbSS. MRIs were categorized according to the presence
      of T2-weighted, high-intensity images suggestive of infarct and were further
      categorized on the basis of a clinical history of cerebrovascular accident (CVA).
      An abnormal MRI but no clinical history of CVA was classified as a silent
      infarct. Neuropsychological evaluations included assessment of both global
      intellectual functioning and specific academic and neuropsychological functions.
      RESULTS: Central nervous system (CNS) abnormalities were identified on MRI in
      17.9% of the children (22.2% of children homozygous for HbS), and a clinical
      history of CVA (N = 9, 4.6%) was identified in only children with HbSS disease.
      Subsequent analyses examined only children with HbSS. Children with a history of
      CVA performed significantly poorer than children with silent infarcts or no MRI
      abnormality on most neuropsychological evaluation measures. Children with silent
      infarcts on MRI performed significantly poorer than children with no MRI
      abnormality on tests of arithmetic, vocabulary, and visual motor speed and
      coordination. CONCLUSIONS: These results substantiate the importance of careful
      evaluation, educational planning, and medical intervention for CNS-related
      complications in children with sickle cell disease.

PMID- 8657527
TI  - Emotional problems during youth as predictors of stature during early adulthood:
      results from a prospective epidemiologic study.
AB  - OBJECTIVE: Adults with emotional disorders exhibit abnormalities in growth
      hormone secretion. If these abnormalities were to occur during childhood, they
      could affect growth. The purpose of this study was to examine the relationship
      between youth emotional disorders and stature in early adulthood. METHODS: Using
      data from a prospective epidemiologic study of youth psychopathologic status, we
      used linear regression to examine the prospective relationship between anxiety
      disorders (separation anxiety and over-anxious disorders) or major depressive
      disorder in youth and stature in early adulthood. RESULTS: Anxiety disorders
      during childhood prospectively predicted relatively short stature in early
      adulthood among females, accounting for more than 5% of the variance in adult
      height. However, these associations were not found among males. CONCLUSIONS:
      There may be an association between abnormalities in growth and emotional
      problems in youth. Further research should examine biological measures related to
      growth among youth with emotional disorders.

PMID- 8657529
TI  - Effect of removing Ascaris on the growth of Guatemalan schoolchildren.
AB  - OBJECTIVE: To determine whether successful deworming for 6 months in children
      with high levels of Ascaris improves physical growth. SUBJECTS: Two hundred
      twenty-eight children (mean age, 9.7 years) in a highland Indian town in
      Guatemala. DESIGN: Children were randomly assigned to receive albendazole or
      placebo at baseline and 12 weeks. Children and field workers were both blind to
      the group assignment. OUTCOME MEASURES: Children's heights, weights, and mid
      upper-arm circumferences were measured at baseline and 12 and 24 weeks. Fecal egg
      counts were taken at 0, 2, 12, 14, and 24 weeks to estimate the helminth burden
      (eggs per gram of feces [epg]). RESULTS: Baseline helminth prevalences were
      Ascaris, 91%, and Trichuris, 82%. Ascaris intensities were high: half of the
      children had moderate burdens (10 000 to 50 000 epg), and 25% had heavy burdens (
      > 50 000 epg). Trichuris burdens were light (72% < 1000 epg). The albendazole and
      placebo groups did not differ at baseline in epg, age, anthropometry, or
      socioeconomic status. The two rounds of treatment successfully reduced the
      Ascaris burdens but had less effect on Trichuris. At 6 months the treatment group
      showed a small gain in weight (0.18 kg) compared with the placebo group but no
      improvement in height or mid-upper-arm circumference. CONCLUSIONS: The successful
      removal of ascaris in a population of school-aged children with relatively high
      loads may have modest effects on weight gain. Ascaris is one of the most common
      infections in school-aged children, but its effect on the host may be less than
      that of other helminths.

PMID- 8657530
TI  - Observations on a recent increase in plagiocephaly without synostosis.
AB  - OBJECTIVE: To verify and determine the cause of an increase in the referral of
      infants with plagiocephaly without synostosis (PWS) to a single tertiary
      craniofacial center. DESIGN: A chart review was performed for 269 infants with a
      diagnosis of PWS who presented to a single tertiary craniofacial center between
      1979 and 1994. The pattern of referral for PWS was analyzed using both simple
      linear regression and time series regression analyses. In addition, the referral
      pattern for PWS was compared with that for infants seen at the same center who
      received a diagnosis of synostotic plagiocephaly. Changes in the distribution of
      several demographic, perinatal, and clinical variables during the study period
      were also assessed. Finally, in an effort to identify correlates of the risk of
      PWS developing, characteristics of patients who were Missouri residents and
      presented between 1992 and 1994 were evaluated and compared with those of the
      1993 Missouri live birth cohort. SETTING: The Cleft Palate and Craniofacial
      Deformities Institute, St Louis Children's Hospital, Washington University
      Medical Center. RESULTS: The average annual number of referrals to our center for
      PWS in the period 1992 to 1994 was more than sixfold greater than that for the
      preceding 13 years. There was a statistically significant increase in the annual
      number of referrals to our center during the 16-year study period. Moreover,
      there was evidence that the average annual increase in referrals was
      significantly greater during the last 3 years (1992 through 1994) of the study
      than in the first 13 years. This shift in the referral patterns is roughly
      contemporaneous with the American Academy of Pediatrics recommendations regarding
      infant sleep position. There was no evidence that either the mean number of
      referrals or the average annual increase in referrals for patients with
      synostosis changed during the study period. Among patients with PWS, the average
      age at presentation did not change during the study period. There were also no
      significant changes in the distribution of other demographic, perinatal, and
      clinical variables. When compared with the Missouri birth cohort, infants with
      PWS were significantly more likely to be boys and to have been delivered by
      forceps. There was also some evidence that patients with PWS were more likely to
      be born prematurely and to be products of multiple-gestation pregnancies. These
      associations were, however, of only borderline statistical significance.
      CONCLUSION: Referrals to our center for PWS increased markedly in 1992 relative
      to previous years. The temporal coincidence of this increase with the American
      Academy of Pediatrics recommendation to avoid the prone sleeping position, to
      reduce the risk of sudden infant death syndrome, suggests a possible causal
      relationship. If this association is causal, education regarding the need for
      head position rotation coupled with that for sudden infant death syndrome should
      obviate positional PWS.

PMID- 8657532
TI  - Fatal dog attacks, 1989-1994.
AB  - OBJECTIVES: To update data on fatal dog bites and see if past trends have
      continued. DESIGN: To merge data from vital records, the Humane Society of the
      United States, and searches of electronic news files. SETTING: United States.
      SUBJECTS: U.S. residents dying in the U.S. from 1989 through 1994 from dog bites.
      RESULTS: We identified 109 dog bite-related fatalities, of which 57% were less
      than 10 years of age. The death rate for neonates was two orders of magnitude
      higher than for adults and the rate for children one order of magnitude higher.
      Of classifiable deaths, 22% involved an unrestrained dog off the owner's
      property, 18% involved a restrained dog on the owner's property, and 59% involved
      an unrestrained dog on the owner's property. Eleven attacks involved a sleeping
      infant; 19 dogs involved in fatal attacks had a prior history of aggression; and
      19 of 20 classifiable deaths involved an unneutered dog. Pit bulls, the most
      commonly reported breed, were involved in 24 deaths; the next most commonly
      reported breeds were rottweilers (16) and German shepherds (10). CONCLUSIONS: The
      dog bite problem should be reconceptualized as a largely preventable epidemic.
      Breed-specific approaches to the control of dog bites do not address the issue
      that many breeds are involved in the problem and that most of the factors
      contributing to dog bites are related to the level of responsibility exercised by
      dog owners. To prevent dog bite-related deaths and injuries, we recommend public
      education about responsible dog ownership and dog bite prevention, stronger
      animal control laws, better resources for enforcement of these laws, and better
      reporting of bites. Anticipatory guidance by pediatric health care providers
      should address dog bite prevention.

PMID- 8657531
TI  - Combination therapy with stavudine and didanosine in children with advanced human
      immunodeficiency virus infection: pharmacokinetic properties, safety, and
      immunologic and virologic effects.
AB  - OBJECTIVES: To obtain preliminary information on the pharmacokinetic properties,
      tolerance, safety, and antiviral activity of combination therapy with stavudine
      and didanosine in children with advanced human immunodeficiency virus (HIV)
      infection. METHODS: Eight children (median age, 6.6 years; range, 2.8 to 12
      years) with advanced HIV disease (median CD4 + lymphocyte count at baseline, 42
      cells/ microL; range, 8 to 553 cells/microL) were treated with stavudine (2 mg/kg
      per day in two divided doses) and didanosine (180 mg/m2 per day in two divided
      doses) for 24 weeks. Seven children had histories of prior zidovudine therapy.
      All children had received stavudine alone for 19 to 33 months before the addition
      of didanosine to the treatment regimen. Children were assessed clinically and
      with laboratory studies at baseline, weekly through week 4 of combination
      therapy, and every 4 weeks thereafter. RESULTS: Analysis of stavudine and
      didanosine plasma half-life values, clearances, and area under the plasma
      concentration-versus-time curves revealed no obvious clinical pharmacokinetic
      interaction between the drugs through study week 12. Combination therapy was well
      tolerated, and there were no drug-associated clinical or laboratory adverse
      events. Signs and symptoms of peripheral neuropathy were not observed. All three
      children with baseline CD4 + lymphocyte counts greater than 50 cells/muL had
      greater than 20% increases in their counts within the first 12 weeks of therapy;
      CD4 + lymphocyte count increases were not observed in the other children. Plasma
      HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10
      to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks
      12 and 24, respectively. CONCLUSIONS: Combination therapy with stavudine and
      didanosine was well tolerated and safe in this small group of children with
      advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable
      effect of therapy on virus load. These findings should be confirmed, and the
      regimen's clinical efficacy should be examined, in controlled studies of HIV
      infected children with less-advanced disease.

PMID- 8657533
TI  - On listening to parents: the sudden infant death syndrome over 25 years.

PMID- 8657534
TI  - Ingredients of urban pediatric health care: fourth world pediatrics.

PMID- 8657535
TI  - Diagnosing psychosocial problems.

PMID- 8657536
TI  - Clinical and pathologic aspects of cardiomyopathy from ipecac administration in
      Munchausen's syndrome by proxy.

PMID- 8657537
TI  - Partial amputation of glans penis during Mogen clamp circumcision.

PMID- 8657538
TI  - Developing residents as teachers: process and content.

PMID- 8657539
TI  - Pool cue chalk: a source of environmental lead.
AB  - Lead compounds are used as coloring agents for numerous products. Two cases of
      children with elevated blood lead concentrations encountered by the authors
      suggested that pool cue chalk may serve as a source of environmental lead. The
      objective of this study was to determine lead content of various brands and
      colors of pool cue chalk. Atomic absorption analyses were conducted of 23
      different types of pool cue chalk for lead content. Three of 23 types of pool cue
      chalk contained more than 7000 ppm (mg/kg) lead: one manufacturer's green and
      tangerine chalk and another manufacturer's green chalk. It was concluded that
      some brands of pool cue chalk contain relatively large amounts of lead and could
      contribute to childhood lead poisoning.

PMID- 8657540
TI  - Long-term aspirin therapy for hepatopulmonary syndrome.

PMID- 8657541
TI  - Hypoglycemia and cortisol deficiency associated with low-dose corticosteroid
      therapy for asthma.

PMID- 8657542
TI  - Efficacy of low-dose dextromethorphan in the treatment of nonketotic
      hyperglycinemia.
AB  - Nonketotic hyperglycinemia (NKH) is an inborn error of glycine degradation
      causing muscular hypotonia, seizures, apnea, and lethargy; it has a poor
      prognosis. Accumulation of glycine in the brain is thought to cause excessive
      stimulation of the N-methyl-D-aspartate receptor. Dextromethorphan (DM), an N
      methyl-D-aspartate receptor antagonist, in doses of 5 to 35 mg/kg per day has
      been shown to have beneficial therapeutic effects in some patients with NKH. We
      report the case of a 1-year-old infant with NKH, seizure disorder, and
      psychomotor delay who was clinically seizure free during treatment with sodium
      benzoate, arginine, benzodiazepam, and phenobarbital. Although sodium benzoate
      normalized serum glycine levels (103 to 125 mumol/L), cerebrospinal fluid glycine
      levels remained elevated (42 to 47 mumol/L), with epileptiform activity on
      electroencephalography. The addition of low-dose DM (0.25 mg/kg per day) to the
      treatment led to improvement of electroencephalographic activity, resolution of
      nystagmus with increased eye contact, and modest progression of developmental
      milestones. These data suggest that DM at doses significantly lower than
      previously reported may be beneficial in some patients with NKH. Treatment with
      low-dose DM needs further evaluation.

PMID- 8657543
TI  - Policy on the development of immunization of tracking systems. American Academy
      of Pediatrics Committee on Practice and Ambulatory Medicine.

PMID- 8657544
TI  - Low-dose hepatitis B vaccine for adolescents.

PMID- 8657545
TI  - White blood cells and cerebrospinal fluid.

PMID- 8657546
TI  - Lumbar puncture in the evaluation for early neonatal sepsis.

PMID- 8657547
TI  - Lumbar puncture in the evaluation for early neonatal sepsis.

PMID- 8657548
TI  - Lead in breast milk.

PMID- 8657549
TI  - Varicella vaccination.

PMID- 8657550
TI  - Death and the internal milieu: Claude Bernard and the origins of experimental
      medicine.

PMID- 8657552
TI  - Immunity in natural history.

PMID- 8657551
TI  - Uncovering thymus function.

PMID- 8657553
TI  - Could atherosclerosis originate from defective smooth muscle cell death
      (apoptosis)?

PMID- 8657554
TI  - The controversy over the classification of Gilles de la Tourette's syndrome, 1800
      1995.

PMID- 8657555
TI  - The possible role of long-chain, omega-3 fatty acids in human brain phylogeny.
AB  - I propose that one of the key factors in human encephalization was increased HUFA
      intake, especially long-chain, omega-3 fatty acids from aquatic and terrestial
      meat source. This provided the needed neural membrane fluidity and
      transmitter/receptor functions for rapid acquisition of more advanced human
      traits and allowed the expansion of H. erectus into more northern climates. The
      human brain initially could build ecophenotypically, or adaptive/directed
      mutationally upon previously evolved mammalian sensor/motor structures, and could
      rapidly expand cognitive functions within a few million years; as more niches
      were invaded, more brain diversity was needed to guarantee reproductive success.
      The metabolically expensive and expanding brain was nutritionally and
      biochemically set, as it were, for rapid accommodation to tool making, rock
      throwing, culture language, electronics, and the eventual endless discussion and
      writings about the brain itself, the evolution of consciousness, and the mid-bran
      problem [107]. All of this fits, no matter which theory of human evolution one
      adheres to--i.e., out of Africa, multiregional, etc.--or even the precis fossil
      chronology [108]. This proposal, based as it is on known facts and certain
      assumptions appears logical, simple, and satisfying, but it may be wrong. Yet
      Charles Darwin himself would have approved, because as he so aptly said: false
      facts are highly injurious to the progress of science, for they often endure
      long; but false views, if supported by some evidence do little harm for everyone
      takes a salutory pleasure in providing their falseness; and when this is done our
      path toward error is closed and the road to truth is often opened. [109].

PMID- 8657557
TI  - Tsp49I (ACGT/), a thermostable neoschizomer of the Type II restriction
      endonuclease MaeII (A/CGT), discovered in isolates of the genus Thermus from the
      Azores, Iceland and New Zealand.
AB  - One hundred and forty eight isolates of the genus Thermus, from neutral and
      alkaline hot water springs on four continents, have been screened for the
      presence of restriction endonuclease activity. An isolate (SM49) from the island
      of Sao Miguel, in the Azores, showed a high level of restriction endonuclease
      activity when a cell-free extract was incubated with lambda phage DNA at 65
      degrees C. A Type II restriction endonuclease (Tsp49I) has been partially
      purified from this isolate and the recognition and cleavage site determined.
      Tsp49I recognizes the four base sequence ACGT, which is the same as the
      recognition sequence of the mesophilic Type II restriction endonuclease MaeII.
      However, unlike MaeII, which cleaves DNA between the first and second bass of the
      recognition sequence (A/CGT), Tsp49I hydrolyses the phosphodiester bond in both
      strands of the substrate after the last base of the recognition sequence 5'-ACGT/
      3', producing four base 3'-OH overhangs (sticky ends). The enzyme has a pH
      optimum of 9.0, requires 2 mM MgCl2 for maximum activity and retains full enzyme
      activity following incubation for 10 min at temperatures up to 8O degrees C. Two
      further examples of the same restriction endonuclease specificity as Tsp491 were
      detected in Thermus isolates from Iceland (TspIDSI) and New Zealand (TspWAM8AI).
      The three MaeII neoschizomers, Tsp49I, TspIDSI and TspWAM8AI, exhibit similar pH
      optima, heat stabilities and MgCl2 requirements, but differ in their requirements
      for NaCl and KCl.

PMID- 8657556
TI  - Compilation and analysis of viroid and viroid-like RNA sequences.
AB  - We have created a catalogue comprising all viroid and viroid-like RNA sequences
      which to our knowledge have been either published or were available from on-line
      sequence libraries as of October 1, 1995. In the development of this catalogue
      nomenclature ambiguities were removed, the likely ancestral sequence of most
      species was determined and the most stable secondary structures of these
      sequences were predicted using the MulFold package. Only viroids of PSTVd-type
      possessed a rod-like secondary structure, while most other viroids adopted
      branched secondary structures. Several viroids have predicted secondary
      structures that include either a Y or cruciform structure reminiscent of the tRNA
      like end of virus genomes at an extremity. However, it remains unknown whether or
      not these predicted structures are adopted in solution, and if they serve a
      particular function in vivo. Additional information such as the position of the
      self-catalytic domains are included in the catalogue. An analysis of the data
      compilated in the catalogue is included. The catalogue will be available on the
      world wide web (http://www.callistro.si.usherb.ca/jpperra), on computer disk and
      in printed form. It should provide an excellent reference point for further
      studies.

PMID- 8657558
TI  - Random-breakage mapping method applied to human DNA sequences.
AB  - The random-breakage mapping method [Game et al. (1990) Nucleic Acids Res., 18,
      4453-4461] was applied to DNA sequences in human fibroblasts. The methodology
      involves NotI restriction endonuclease digestion of DNA from irradiated calls,
      followed by pulsed-field gel electrophoresis, Southern blotting and hybridization
      with DNA probes recognizing the single copy sequences of interest. The Southern
      blots show a band for the unbroken restriction fragments and a smear below this
      band due to radiation induced random breaks. This smear pattern contains two
      discontinuities in intensity at positions that correspond to the distance of the
      hybridization site to each end of the restriction fragment. By analyzing the
      positions of those discontinuities we confirmed the previously mapped position of
      the probe DXS1327 within a NotI fragment on the X chromosome, thus demonstrating
      the validity of the technique. We were also able to position the probes D21S1 and
      D21S15 with respect to the ends of their corresponding NotI fragments on
      chromosome 21. A third chromosome 21 probe, D21S11, has previously been reported
      to be close to D21S1, although an uncertainty about a second possible location
      existed. Since both probes D21S1 and D21S11 hybridized to a single NotI fragment
      and yielded a similar smear pattern, this uncertainty is removed by the random
      breakage mapping method.

PMID- 8657559
TI  - The viral thymidine kinase gene as a tool for the study of mutagenesis in
      Trypanosoma brucei.
AB  - We have tested the use of thymidine kinase as a negative selection system for
      Trypanosoma brucei. To this end we have targeted a construct containing a Herpes
      simplex virus thymidine kinase (TK) gene into the ribosomal DNA array of
      procyclic T. brucei. This resulted in TK activity 30-50-fold above background and
      in susceptibility to the nucleoside analogues ganciclovir, ethyl-deoxyuridine and
      1-[2-deoxy,2-fluoro-8-D-arabinofuranosyl]-5-iodouracil, all of which have no
      effect on wild-type trypanosomes. TK+ trypanosomes, however, reverted to a
      ganciclovir resistant phenotype at a rate of 10(-6) per cell-generation. A
      similar reversion rate was observed using the Varicella-zoster virus TK gene.
      Loss of TK activity was not due to detectable DNA rearrangements or a decrease in
      TK mRNA. Sequence analysis of the revertant genes demonstrated, however, the
      occurrence of point mutations and frameshifts. One revertant line had a mutation
      in the thymidine binding site leading to the substitution of a conserved arginine
      by a glycine. Other mutations included single base insertion, single base
      deletion and the introduction of a premature termination codon by point mutation.

PMID- 8657560
TI  - Phosphorylation/dephosphorylation of the repressor MDBP-2-H1 selectively affects
      the level of transcription from a methylated promoter in vitro.
AB  - We have previously shown that in vivo estradiol-dependent dephosphorylation of
      MDBP-2-H1 (a member of the histone H1 family) correlates with the loss of in
      vitro preferential binding to methylated DNA. To study the effects of the
      phosphorylation/dephosphorylation of MDBP-2-H1 on the expression of the avian
      vitellogenin II gene, we optimised an in vitro transcription system using HeLa
      nuclear extracts. We show that in the absence of the phosphorylated form of MDBP
      2-H1 from rooster, methylation of the vitellogenin II promoter does not affect
      the transcription. Addition of purified MDBP-2-H1 from rooster to the in vitro
      transcription system inhibits transcription more efficiently from a methylated
      than an unmethylated DNA template. Dephosphorylation of rooster MDBP-2-H1 by
      phosphatase treatment or estradiol treatment of rooster lead to the loss of
      inhibitory activity of the protein when added to the in vitro transcription
      assays. These findings indicate that the phosphorylation of MDBP-2-H1 is
      essential for the repression of the transcription. Taken together these results
      establish the relationship between the dephosphorylation of MDBP-2-H1 caused by
      estradiol, the down regulation of its binding activity to methylated DNA and the
      derepression of vitellogenin II transcription.

PMID- 8657561
TI  - Identification and characterisation of two transcriptional repressor elements
      within the coding sequence of the Saccharomyces cerevisiae HXK2 gene.
AB  - A well-defined set of isogenic yeast strains has been constructed whereby each
      strain contains a different HXK2::lacZ gene fusion integrated at the URA3 locus.
      These HXK2::lacZ fusions differ in the amount of the HXK2 gene (encoding
      hexokinase 2 isoenzyme) that is fused to the lacZ reporter gene. Comparison of
      the beta-galactosidase activities of each strain during growth on glucose or
      ethanol revealed that some part of the coding region between +39 and +404 bp is
      involved in repressing gene expression in a carbon source dependent manner. A
      series of deletions of this HXK2 coding region were constructed and fused
      upstream of a minimal CYC1::lacZ promoter. beta-Galactosidase activities on
      glucose or ethanol growth yeast calls revealed that two different regulatory
      elements are present in this DNA region. Gel mobility shift analysis and in vitro
      DNase I footprinting have shown that proteins bind specifically to two downstream
      repressor sequences (DRS1 located from +140 to +163 and DRS2 located between +231
      and +251) that influence the rate of HXK2 transcription when ethanol is used as
      carbon source by Saccharomyces cerevisiae. We identified and partially purified a
      18 kDa protein that binds specifically to synthetic double-stranded
      oligonucleotides containing the (A/C)(A/G)GAAAT box sequence. Our data suggest
      that p18 synthesis is under the control of genes involved in glucose repression
      (MIG1 = CAT4) and glucose derepression (SNF1 = CAT1).

PMID- 8657563
TI  - Mutagenicity of a unique thymine-thymine dimer or thymine-thymine pyrimidine
      pyrimidone (6-4) photoproduct in mammalian cells.
AB  - The mutagenic properties of UV-induced photoproducts, both the cis-syn thymine
      thymine dimer (TT) and the thymine-thymine pyrimidine pyrimidone (6-4)
      photoproduct [T(6-4)T] were studied in mammalian cells using shuttle vectors. A
      shuttle vector able to replicate in both mammalian cells and bacteria was
      produced in its single-stranded DNA form. A unique photoproduct was inserted at a
      single restriction site and after recircularization of the single-stranded DNA
      vector, this latter was transfected into simian COS7 cells. After DNA replication
      the vector was extracted from cells and used to transform bacteria. Amplified DNA
      was finally analyzed without any selective screening, DNA from randomly picked
      bacterial colonies being directly sequenced. Our results show clearly that both
      lesions are mutagenic, but at different levels. Mutation frequencies of 2 and 60%
      respectively were observed with the TT dimer and the T(6-4)T. With the TT dimer
      the mutations were targeted on the 3'-T. With the T(6-4)T a large variety of
      mutations were observed. A majority of G-->T transversions were semi-targeted to
      the base before the 5'-T of the photoproduct. These kinds of mutations were not
      observed when the same plasmid was transfected directly into SOS-induced JM105
      bacteria or when the T(6-4)T oligonucleotide inserted in a different plasmid was
      replicated in SOS-induced SMH10 Escherichia coil bacteria. These semi-targeted
      mutations are therefore the specific result of bypass of the T(6-4)T lesion in
      COS7 cells by one of the eukaryotic DNA polymerases.

PMID- 8657562
TI  - In vitro and in vivo evidence that protein and U1 snRNP nuclear import in somatic
      cells differ in their requirement for GTP-hydrolysis, Ran/TC4 and RCC1.
AB  - GTP-hydrolysis, the small ras-related GTP-binding protein Ran and its cognate
      guanosine nucleotide exchange factor, the RCC1 gene product, have recently been
      identified as essential components of the protein nuclear import pathway. In this
      report we use three independent approaches to investigate the role of these
      components in U1 snRNP nuclear import in somatic cells. (i) Using a somatic cell
      based in vitro nuclear import system we show that U1 snRNP nuclear import, in
      marked contrast to protein transport, is not significantly inhibited by non
      hydrolyzable GTP-analogs and is therefore unlikely to require GTP-hydrolysis.
      (ii) Using the dominant negative Ran mutant RanQ69L, which is defective in GTP
      hydrolysis, we show that Ran-mediated GTP-hydrolysis is not essential for the
      nuclear import of U1 snRNP in microinjected cultured cells. (iii) Using a cell
      line expressing a thermolabile RCC1 gene product, we show that the nuclear
      accumulation of microinjected U1 snRNP is not significantly affected by RCC1
      depletion at the non-permissive temperature, indicating that RCC1 function is not
      essential for U-snRNP nuclear import. Based on these observations we conclude
      that protein and U-snRNP nuclear import in somatic cells differ in their
      requirements for GTP-hydrolysis, and Ran or RCC1 function. Based on these
      results, the substrates for nucleocytoplasmic exchange across the NPC can be
      divided into two classes, those absolutely requiring Ran, including protein
      import and mRNA export, and those for which Ran is not essential, including U
      snRNP nuclear import, together with tRNA and U1 snRNA nuclear export.

PMID- 8657564
TI  - Oligodeoxynucleoside phosphoramidates (P-NH2): synthesis and thermal stability of
      duplexes with DNA and RNA targets.
AB  - Syntheses of non ionic oligodeoxynucleoside phosphoramidates (P-NH2) and mixed
      phosphoramidate- phosphodiester oligomers were accomplished on automated solid
      supported DNA synthesizer using both H-phosphonate and phosphoramidite
      chemistries, in combination with t-butylphenoxyacetyl for N-protection of
      nucleoside bases, an oxalyl anchored solid support and a final treatment with
      methanolic ammonia. Thermal stabilities of the hybrids formed between these new
      analogues and their DNA and RNA complementary strands were determined and
      compared with those of the corresponding unmodified oligonucleotides, as well as
      of the phosphorothioate and methylphosphonate derivatives. Dodecathymidines
      containing P-NH2 links form less stable duplexes with DNA targets, d(C2A12C2)
      (deltaTm/modification -1.4 degrees C) and poly dA (deltaTm/modification -1.1
      degrees C) than the corresponding phosphodiester and methylphosphonate analogues,
      but the hybrids are slightly more stable than the one obtained with
      phosphorothioate derivative. The destabilization is more pronounced with poly rA
      as the target (deltaTm/modification -3 degrees C) and could be compared with that
      found with the dodecathymidine methylphosphonate. The modification is less
      destabilizing in an heteropolymer-RNA duplex (deltaTm/modification -2 degrees C).
      As expected, the P-NH2 modifications are highly resistant towards the action of
      various nucleases. It is also demonstrated that an all P-NH2 oligothymidine does
      not elicit Escherichia coli RNase H hydrolysis of the poly rA target but that the
      modification may be exploited in chimeric oligonucleotides combining P-NH2
      sections with a central phosphodiester section.

PMID- 8657565
TI  - The small subunit of the splicing factor U2AF is conserved in fission yeast.
AB  - The human splicing factor U2 auxiliary factor (hsU2AF) is comprised of two
      interacting subunits of 65 and 35 kDa. Previously we identified the
      Schizosaccharomyces pombe homolog, spU2AF59, of the human large subunit. We have
      screened a fission yeast cDNA library in search of proteins that interact with
      spU2AF59 using the yeast two-hybrid system and have identified a homolog of the
      hsU2AF35 subunit. The S. pombe U2AF small subunit is a single copy gene that
      encodes a protein which shares 55% amino acid identity and 17% similarity with
      the human small subunit. Unlike the human protein, the yeast protein lacks an
      arginine/serine-rich region. The predicted molecular mass of the spU2AF small
      subunit is 23 kDa. The region of spU2AF59 that interacts with spU2AF23 is similar
      to the region in which the human small and large subunits interact.

PMID- 8657566
TI  - The basic domain/leucine zipper protein hXBP-1 preferentially binds to and
      transactivates CRE-like sequences containing an ACGT core.
AB  - The transcription factor hXBP-1 belongs to the family of basic region/leucine
      zipper (bZIP) proteins and interacts with the cAMP responsive element (CRE) of
      the major histocompatibility complex (MHC) class II A alpha, DR alpha and DP beta
      genes. However, the developmental expression of hXBP-1 as revealed by in situ
      hybridization in mouse embryos, has suggested that it interacts with the promoter
      of additional genes. To identify other potential target genes of this factor, we
      performed binding site selection experiments with recombinant hXBP-1 protein. The
      results indicated that hXBP-1 binds preferably to the CRE-like element GAT
      GACGTG(T/G)NNN(A/T)T, wherein the core sequence ACGT is highly conserved, and
      that it also binds to some TPA response elements (TRE). hXBP-1 can transactivate
      multimers of the target sequences to which it binds in COS cells, and the level
      of transactivation directly correlates with the extent of binding as observed in
      gel retardation experiments. One target sequence that is strongly bound by hXBP-1
      is the 21 bp repeat in the HTLV-1 LTR, and we demonstrate here that hXBP-1 can
      transactivate the HTLV-1 LTR. Further, the transactivation domain of hXBP-1
      encompasses a large C-terminal region of the protein, containing domains rich in
      glutamine, serine and threonine, and proline and glutamine residues, as shown in
      transient transfection experiments using hXBP-1-GAL4 fusion proteins and a
      reporter gene under the control of GAL4-binding sites.

PMID- 8657567
TI  - Interaction of the IciA protein with AT-rich regions in plasmid replication
      origins.
AB  - A set of AT-rich repeats is a common motif in prokaryotic replication origins. We
      have screened for proteins binding to the AT-rich repeat region in plasmids F, R1
      and pSC101 using an electrophoretic mobility shift assay with PCR-amplified DNA
      fragments from the origins. The IciA protein, which is known to bind to the AT
      rich repeat region in the Escherichia coli origin of chromosome replication,
      oriC, was found to bind to the corresponding region from plasmids F (oriS) and
      R1, but not to pSC101. DNase I footprint analysis showed that IciA interacted
      with the AT-rich region in both F and R1. When the IciA gene was deleted, the
      copy number of plasmid F increased somewhat, whereas there was no major effect on
      the replication of pSC101 and R1, or on the E. coli chromosome.

PMID- 8657568
TI  - Structural and functional analysis of the human Y-box binding protein (YB-1) gene
      promoter.
AB  - We have isolated three overlapping genomic clones containing the 5'portion of the
      human YB-1 gene. These clones span approximately 25 kb of contiguous DNA
      containing 10 kb of 5' flanking sequence and 15 kb of the gene. The nucleotide
      sequence of the first exon and of 2000 upstream base pairs (bp) was determined.
      The first axon is unusually large and contains a 166 bp coding sequence and a 331
      bp untranslated region. CpG sequences cover the 5'-end of the YB-1 gene including
      its first axon and intron as well as the upstream regions. The GC content around
      the first exon is approximately 70% and a CpG-free region was located in the
      untranslated sequence. The segment preceding the major transcription initiation
      site does not contain a TATA box, CCAAT box and the binding sequence for known
      transcription factors. A transient expression assay using the chloramphenicol
      acetyltransferase (CAT) gene showed that the sequence from +24 to +281 was
      critical for CAT expression. Fluorescence in situ hybridization demonstrated the
      chromosomal locus of YB-1 gene on chromosome 1p34. Polymerase chain reaction
      analysis on other genomic phage DNAs showed that several clones were derived from
      pseudogenes.

PMID- 8657569
TI  - Kluyveromyces lactis killer system: analysis of cytoplasmic promoters of the
      linear plasmids.
AB  - All of the 14 genes encoded by the cytoplasmic linear killer plasmids of
      Kluyveromyces lactis are preceded by upstream conserved sequences (UCSs), cis
      acting elements involved in plasmid gene transcription. Using the bacterial
      glucose-dehydrogenase gene as a reporter, expression driven by seven cytoplasmic
      promoters was determined. The level of expression ranged from 0.5 to 6 nkat. The
      highest activity was displayed by UCS 6 of pGKL2 whereas the lowest level was
      obtained with UCS2 of pGKL2, all other values were in between. Sequences located
      5' upstream the UCSs do not influence expression. As exemplified for UCS5 and
      UCS10, deletion led to an almost complete loss of expression.

PMID- 8657570
TI  - DNA replication initiates non-randomly at multiple sites near the c-myc gene in
      HeLa cells.
AB  - The origin of replication of the c-myc gene in HeLa cells was previously
      identified at low resolution within 3.5 kb 5' to the P1 promoter, based on
      replication fork polarity and the location of DNA nascent strands. To define the
      initiation events in the c-myc origin at higher resolution the template bias of
      nascent DNAs in a 12 kb c-myc domain has been analyzed by hybridization to strand
      specific probes. Strong switches in the asymmetry of nascent strand template
      preference confirm that replication initiates non-randomly at multiple sites
      within 2.4 kb 5' to the c-myc P1 promoter, and at other sites over a region of 12
      kb or more. The strongest template biases occur in the 2.4 kb region 5' of the P1
      promoter, shown earlier to contain sequences which allow the autonomous
      semiconservative replication of c-myc plasmids. An asymmetric pyrimidine
      heptanucleotide consensus sequence has been identified which occurs 12 times in
      the c-myc origin zone, and whose polarity exactly correlates with the polarity of
      nascent strand synthesis.

PMID- 8657571
TI  - A nuclear matrix-specific factor that binds a specific segment of the negative
      regulatory element (NRE) of HIV-1 LTR and inhibits NF-kappa(B) activity.
AB  - The negative regulatory element (NRE) of human immunodeficiency virus type-1 (HIV
      1) long terminal repeat (LTR) is a defined region that has been reported to
      downregulate LTR-directed HIV gene expression. However, information on the
      precise role of this region in regulating HIV gone transcription is lacking. We
      have investigated the possibility that these NRE sequences regulate HIV
      transcription by a mechanism mediated through a nuclear matrix-specific DNA
      protein interaction. We find a nuclear matrix attachment region (MAR) present
      within the NRE of the HIV-1 LTR that recognizes a sequence-specific DNA-binding
      protein present in the nuclear matrix of HIV infected cells. Moreover, we also
      show that the purified DNA-binding nuclear matrix protein (NMP) specifically
      represses the DNA-binding activity of NF-kappaB. It is likely that the MAR and
      MAR-enriched specific DNA-binding NMP are brought into juxtaposition by the non
      chromatin scaffolding of the nucleus, thus influencing NF-kappaB (and other
      nuclear proteins) DNA-binding activity through protein-protein and protein-DNA
      interactions. Our date suggest that one possible role of the NRE could be to act
      as a matrix attachment site in the nuclear matrix, thus, allowing interaction
      with a sequence-specific trans-acting factor. The negative effect on NF-kappaB
      activity due to this MAR-NMP-specific interaction provides a mechanism by which
      the NRE downregulates HIV gene expression.

PMID- 8657572
TI  - Potent antisense oligonucleotides to the human multidrug resistance-1 mRNA are
      rationally selected by mapping RNA-accessible sites with oligonucleotide
      libraries.
AB  - Antisense oligonucleotides can vary significantly and unpredictably in their
      ability to inhibit protein synthesis. Libraries of chimeric oligonucleotides and
      RNase H were used to cleave and thereby locate sites on human multidrug
      resistance-1 RNA transcripts that are relatively accessible to oligonucleotide
      hybridization. In cell culture, antisense sequences designed to target these
      sites were significantly more active than oligonucleotides selected at random.
      This methodology should be generally useful for identification of potent
      antisense sequences. Correlation between oligonucleotide activity in the cell
      culture assay and in an in vitro RNase H assay supports the proposed role of the
      enzyme in the mechanism of antisense suppression in the cell.

PMID- 8657573
TI  - Fusion with an RNA binding domain to confer target RNA specificity to an RNase:
      design and engineering of Tat-RNase H that specifically recognizes and cleaves
      HIV-1 RNA in vitro.
AB  - A target RNA/DNA-specific nuclease could be constructed if a specific RNA/DNA
      binding domain allowing target RNA/DNA recognition was fused to a
      (deoxy)ribonucleolytic domain allowing target RNA/ DNA cleavage. The design and
      construction of such a chimeric enzyme could be of value for both basic research
      involving structure-function relationships and applied research requiring
      inactivation of harmful RNA/DNA molecules of cellular or pathogenic origin. The
      feasibility of this designer nuclease approach for inactivating specific RNA/DNA
      molecules was assessed using human immunodeficiency virus type-1 (HIV-1) RNA as a
      model. Trans-activator of transcription (Tat) protein is one of the key
      regulatory proteins encoded by HIV-1. It binds to the trans-activation-responsive
      (TAR) RNA element located within the 5' non-coding region of HIV-1 RNAs. The TAR
      RNA binding domain of this protein was fused to the ribonuclease (RNase) H domain
      of HIV-1 reverse transcriptase (RT). RNase H by itself lacks an RNA binding
      domain. The chimeric Tat-RNase H protein was shown to specifically recognize and
      cleave HIV-1 TAR RNA in vitro. Cleavage was abolished by mutations in the Tat
      binding region within the TAR RNA, indicating that it is specific to HIV-1 TAR
      RNA.

PMID- 8657574
TI  - Gene structure and characterization of the murine homologue of the B cell
      specific transcriptional coactivator OBF-1.
AB  - The B cell-specific activity of immunoglobulin (Ig) gene promoters is to a large
      extent mediated by the conserved octamer motif ATTTGCAT. This requires the DNA
      binding octamer factors Oct-1 and/or Oct-2, as well as an additional B cell
      restricted non-DNA binding cofactor. We recently cloned such a coactivator
      specific for Oct-1 or Oct-2 from human B cells and called it OBF-1. Here we
      report the isolation and characterization of the murine homologue. Full-length
      cDNA clones as well as genomic clones were isolated and the gene structure was
      determined. The deduced protein sequence shows that the mouse protein has an
      identical length, is likewise proline rich and shows 89% overall identity to the
      human protein. The OBF-1 gene is expressed in a very highly B cell-specific
      manner and is transcribed in cells representative of all stages of B cell
      differentiation, including the earliest ones. We show that OBF-1 interacts in the
      absence of DNA with the POU domain of Oct-1 or Oct-2 and also with the general
      transcription factors TBP and TFIIB. Furthermore, we demonstrate that although
      OBF-1 efficiently activates promoter octamer sites, it does not activate enhancer
      octamer sites.

PMID- 8657575
TI  - Substitution of basic amino acids in the basic region stabilizes DNA binding by
      E12 homodimers.
AB  - The E2A gene encodes two alternatively spliced products, E12 and E47. The two
      proteins differ in their basic helix-loop-helix motifs (bHLH), responsible for
      DNA binding and dimerization. Although both E12 and E47 can bind to DNA as
      heterodimers with tissue-specific bHLH proteins, E12 binds to DNA poorly as
      homodimers. An inhibitory domain in E12 has previously been found to prevent E12
      homodimers from binding to DNA. By measuring the dissociation rates using filter
      binding and electrophoretic mobility shift assays, we have shown here that the
      inhibitory domain interferes with DNA binding by destabilizing the DNA-protein
      complexes. Furthermore, we have demonstrated that substitution of basic amino
      acids (not other amino acids) in the DNA-binding domain of E12 can increase the
      intrinsic DNA-binding activity of E12 and stabilize the binding complexes, thus
      alleviating the repression from the inhibitory domain. This ability of basic
      amino acids to stabilize DNA-binding complexes may be of biological significance
      in the case of myogenic bHLH proteins, which all possess two more basic amino
      acids in their DNA binding domain than E12. To function as heterodimers with E12,
      the myogenic bHLH proteins may need stronger DNA binding domains.

PMID- 8657576
TI  - Transcriptional regulation of the MHC class I HLA-A11 promoter by the zinc finger
      protein ZFX.
AB  - Regulation of the human MHC class I HLA-A11 promoter is governed by a complex
      array of regulatory elements. One of these elements, shown here to be critical
      for the transcriptional activity of the promoter, was used to screen a lambda
      gt11 library and allowed the identification of a cDNA which coded for the zinc
      finger protein ZFX. ZFX was shown to bind the sequences AGGGCCCCA and AGGCCCCGA,
      located respectively at positions -271 to -263 and -242 to -234 of the HLA-A11
      promoter, with similar affinities through its three C-terminal zinc fingers.
      ZFX575, a short isoform of ZFX, activates transcription from the HLA-All promoter
      in a Leydig cell line.

PMID- 8657577
TI  - Initiator protein pi can bind independently to two domains of the gamma origin
      core of plasmid R6K: the direct repeats and the A+T-rich segment.
AB  - The pi protein of plasmid R6K functions in both replication and transcription. pi
      autoregulates its own synthesis and is required for replication of the RISK gamma
      origin. pi performs these functions by binding to specific DNA sites arranged as
      pairs of 6-10 bp inverted repeats (IRs) or as a cluster of seven tandem 22 bp
      direct repeats (DRs) which lack symmetry. The sites share the TGAGRG nucleotide
      motif (where R is A or G). The DRs and IRs flank the central A+T-rich segment of
      the gamma origin. In this work we carried out DNase I and hydroxyl radical
      protection experiments on various deletion derivatives of the gamma origin
      complexed with pi protein. These experiments revealed binding of pi to a novel
      site embedded within the A+T-rich segment. This interaction manifests primarily
      by the appearance of the enhanced scissions of DNA by DNase I and hydroxyl
      radicals. pi interaction with the A+T-rich site is independent of pi binding to
      the DRs and IRs. We propose that pi protein can recognize distinct families of
      DNA sequences in the gamma origin.

PMID- 8657578
TI  - Programmed DNA rearrangement from an intron during nuclear development in
      Tetrahymena thermophila: molecular analysis and identification of potential cis
      acting sequences.
AB  - During macronuclear development in the ciliate Tetrahymena thermophila, extensive
      rearrangement events occur as DNA deletions. We have studied a developmentally
      programmed deletion called mse2.9 that occurs within an intron in a gene in both
      genomic DNA and in an rDNA vector introduced into the cell by transformation.
      Extensive microheterogeneity at the deletion junctions has been found in
      caryonidal strains and in the rDNA in transformed cells. A transformation assay
      has been used to identify sequences required for proper processing of mse2.9.
      Models to explain deletion site selection as well as microheterogeneity at
      junction sites are presented.

PMID- 8657579
TI  - Apurinic/apyrimidinic (AP) endonuclease from Dictyostelium discoideum: cloning,
      nucleotide sequence and induction by sublethal levels of DNA damaging agents.
AB  - We have cloned an AP endonuclease gene (APEA) from Dictyostelium discoideum,
      along with 1.8 kb of the 5' flanking region. There are no introns. The sequence
      predicts a protein of 361 amino acids, showing high homology to the major
      human/Escherichia coli exonuclease III family of AP endonucleases. There is 47%
      identity and 64% similarity to the Ape endonuclease of human cells using the C
      terminal 257 amino acids of the Dictyostelium protein. The 104 amino acids on the
      N-terminus show only low homology with other AP endonucleases. Instead, this
      region shows high homology with the acid-rich regions of proteins associated with
      chromatin, such as nucleolins and HMG proteins. The gene is transcriptionally
      activated up to 7-fold after treatment of cells with sublethal levels of DNA
      damaging agents, including ultraviolet light, MNNG and bleomycin. Induction does
      not occur following blocking of replication fork polymerases with aphidicolin. It
      is not eliminated by treatment with kinase or phosphatase inhibitors. Four DNA
      damage-sensitive mutants all retained the DNA damage-induced up-regulation.

PMID- 8657581
TI  - Use of a pyrimidine nucleoside that functions as a bidentate hydrogen bond donor
      for the recognition of isolated or contiguous G-C base pairs by oligonucleotide
      directed triplex formation.
AB  - Synthesis of the nucleoside building block of the 6-keto derivative of 2'-deoxy-5
      methylcytidine (m5oxC) as an analog of an N3-protonated cytosine derivative is
      described. A series of 15mer oligonucleotides containing either four or six m5oxC
      residues has been prepared by chemical synthesis. Complexation of the 15 residue
      oligonucleotides with target 25mer duplexes results in DNA triplexes containing T
      A-T and m5oxC-G-C base triplets. When the m5oxC-G-C base triplets are present in
      sequence positions that alternate with TAT base triplets, DNA triplexes are
      formed with Tm values that are pH independent in the range 6.4-8.5. A 25mer DNA
      duplex containing a series of five contiguous G-C base pairs cannot be
      effectively targeted with either m5C or M5oxC in the third strand. In the former
      case charge-charge repulsion effects likely lead to destabilization of the
      complex, while in the latter case ineffective base stacking may be to blame.
      However, if the m5C and M5oxC residues are present in the third strand in
      alternate sequence positions, then DNA triplexes can be formed with contiguous G
      C targets even at pH 8.0.

PMID- 8657583
TI  - Improved cloning of antibody variable regions from hybridomas by an antisense
      directed RNase H digestion of the P3-X63-Ag8.653 derived pseudogene mRNA.

PMID- 8657580
TI  - The histone 3'-terminal stem-loop is necessary for translation in Chinese hamster
      ovary cells.
AB  - The metazoan cell cycle-regulated histone mRNAs are the only known cellular mRNAs
      that do not terminate in a poly(A) tall. Instead, mammalian histone mRNAs
      terminate in a highly conserved stem-loop structure which is required for 3'-end
      processing and regulates mRNA stability. The poly(A) tail not only regulates
      translational efficiency and mRNA stability but is required for the function of
      the cap in translation (m(7)GpppN). We show that the histone terminal stem-loop
      is functionally similar to a poly(A) tail in that it enhances translational
      efficiency and is co-dependent on a cap in order to establish an efficient level
      of translation. The histone stem-loop is sufficient and necessary to increase the
      translation of reporter mRNA in transfected Chinese hamster ovary cells but must
      be positioned at the 3'-terminus in order to function optimally. Mutations within
      the conserved stem or loop regions reduced its ability to facilitate translation.
      All histone mRNAs in higher plants are polyadenylated. The histone stem-loop did
      not function to influence translational efficiency or mRNA stability in plant
      protoplasts. These data demonstrate that the histone stem/loop directs efficient
      translation and that it is functionally analogous to a poly(A) tail.

PMID- 8657582
TI  - The transactivation potential of a c-Myc N-terminal region (residues 92-143) is
      regulated by growth factor/Ras signaling.
AB  - The colony stimulating factor-1 receptor (CSF-1R) affects mitogenic growth and
      gene expression in NIH 3T3 cells through signaling pathways that require the
      products of the c-ras and c-myc proto-oncogenes. In this work we tested the
      hypothesis that there is direct communication between the Ras and Myc pathways.
      In transient transfection assays Ras increased by 5-fold transcriptional
      transactivation by chimeric c-Myc-Gal4 proteins. A constitutive active form of
      the CSF-1R also stimulated this activity and co-expression of a dominant negative
      ras gene ablated receptor stimulation. Deletion analysis of the c-Myc N-terminal
      region demonstrated that amino acid residues between positions 92 and 143 are the
      targets for Ras action. Transactivation by chimeric Myc proteins that were stably
      expressed could be transiently enhanced by either CSF-1 or serum, with peak
      activity occurring 2 h after mitogen stimulation. The steady-state levels of the
      chimeric c-Myc transactivators were increased following stimulation with CSF-1 or
      serum, but this increase in steady-state protein level did not strictly correlate
      with the increase in transactivation activity. Thus, Ras signaling may directly
      affect the activity of the c-Myc N-terminal region.

PMID- 8657585
TI  - Reliability and variability of impedance measured by real-time telemetry.
AB  - With the aim to detect dysfunction of pacing leads, most present-day pacemakers
      measure pacing impedance by means of real-time telemetry. The recommended setting
      for impedance measurement is 5.0 V for pulse amplitude and 0.5 ms for pulse
      duration. Availability of reliable settings would facilitate impedance
      measurements during follow-up. The purpose of the present study was twofold: (1)
      to assess whether telemetrically measured impedance of the studied pacemaker is
      similar to impedance measured at implantation; and (2) to evaluate whether the
      pacemaker setting influences telemetrically measured impedance. Sixty-five
      consecutive patients receiving VVI(R) pacemakers were studied; in all patients,
      impedance measured at implantation by a pacing system analyzer was compared to
      measurements obtained telemetrically within 1 day after implantation. In 44 other
      patients, impedance was determined 3 months after implantation at 60 and 120 ppm
      (n = 44), twice at 60 ppm (n = 42), and 12 months after implantation at 60 ppm (n
      = 34). For each measurement, pulse amplitude was programmed to 0.8, 1.6, 2.5,
      5.0, and 8.0 V, and pulse duration to 0.05, 0.25, 0.50, and 1.00 ms. Impedance at
      implantation (606 +/- 113 ohms) did not differ from the data obtained with
      telemetry (629 +/- 113 ohms; P = NS). Different pacing rates, repeat
      measurements, and follow-up time failed to show any influence on impedance.
      Measurement tolerance was < 10% for 15 of 19 studied settings other than 5.0 V
      and 0.5 ms. CONCLUSION: The studied pacemakers provide reliable data for
      telemetrically measured impedance. Telemetrical impedance does not necessarily
      have to be measured at 5.0 V and 0.5 ms. These findings should be considered for
      measurement and interpretation of real-time telemetry impedance during follow-up.

PMID- 8657584
TI  - Mobitz type I atrioventricular block: an indication for permanent pacing?

PMID- 8657587
TI  - Reproducibility of electrophysiological measurements in cardiac transplant
      recipients.
AB  - The clinical usefulness of certain electrophysiological measurements,
      particularly those of sinus node function, is limited by variation in autonomic
      tone resulting in poor reproducibility. The denervated transplanted heart is not
      susceptible to direct autonomic control and, therefore, electrophysiological
      measurements may be more reproducible in this group. To our knowledge, this
      hypothesis has not previously been systematically evaluated. Ten adult recipients
      underwent serial electrophysiological studies between 10-18 days after cardiac
      transplantation. Five studies were performed at 2-hour intervals during a single
      day, between 9:00 a.m. and 5:00 p.m. Spontaneous cycle length (SCL) was recorded.
      Sinus node recovery time (SNRT), sinoatrial conduction time (SACT), and
      atrioventricular (AV) Wenckebach cycle length were measured using standard
      techniques. The effective refractory periods of the complete AV conducting system
      (AVERP), atrium (AERP), and ventricle (VERP) were measured. Corrected maximal
      SNRT was normal in all subjects. Mean coefficients of variation (Cv) for SCL,
      corrected maximal SNRT, and SACT were 2.8%, 7.4%, and 3.5%, respectively. AVERP
      was less than AERP in seven subjects, limiting further analysis. The mean Cv for
      AV Wenckebach cycle length was 2.1%. The mean coefficients of variation for AERP
      were 3.6% and 3.7%, and for VERP 3% and 3.3%, at 600- and 400-ms drive cycle
      lengths, respectively. Previous studies report much greater variation in
      innervated subjects particularly of indices of sinus node function. Thus, the
      reproducibility of electrophysiological measurements of sinus and AV node
      function in the transplanted heart is better than in normal subjects. This may
      have important implications for the reliability of electrophysiological testing
      in transplant recipients.

PMID- 8657588
TI  - Perforation of the right ventricle by transvenous defibrillator leads: prevention
      and treatment.
AB  - A series of 78 consecutive implants of the transvene PCD (Medtronic, Inc.)
      defibrillator system is presented and the occurrence of right ventricular
      perforation in 4 patients reported (5.2%). Diagnosis of perforation is made using
      four signs: (1) decrease in arterial blood pressure without any other
      explanation; (2) decrease in pulsatility of the cardiac silhouette as monitored
      by fluoroscopy; (3) increased size of the cardiac silhouette; and (4) abnormal
      position of the transvenous lead too far out toward the left ventricle along the
      pericardial outline. Perforation causes rapid and dramatic cardiac tamponade due
      to the large diameter and stiffness of the coil carrier lead. Immediate drainage
      of the hemopericardium must be carried out using the transxiphoid approach. The
      use of a thin blue-coded lead stylet (0.014-inch gauge) is recommended over the
      stiffer maroon-coded stylet. Since treatment must be carried out immediately, it
      is advised that a surgeon either perform, assist, or be immediately available
      whenever one of these systems is implanted.

PMID- 8657589
TI  - Demonstration of syncope in patients after pacemaker implantation: role of head
      up tilt test to distinguish neurocardiogenic vasodepressor syncope from pacemaker
      syndrome.
AB  - It is important to distinguish clinically neurocardiogenic syncope from pacemaker
      syndrome in patients after pacemaker implantation. We report two syncopal
      patients with AV sequential physiological pacemakers who displayed
      neurocardiogenic vasodepressor syncope (VDS) during head-up tilt (HUT) testing.
      Neurocardiogenic VDS, as a cause of syncope in patients following pacemaker
      implantation, might be involved in these patients as well as pacemaker syndrome.
      HUT is a useful diagnostic test in distinguishing neurocardiogenic VDS from
      pacemaker syndrome in patients with syncope following pacemaker implantation.
      Careful evaluations for diagnosis of pacemaker syndrome are needed in these
      patients.

PMID- 8657586
TI  - Transesophageal echocardiographic guidance of transseptal left heart
      catheterization during radiofrequency ablation of left-sided accessory pathways
      in humans.
AB  - Radiofrequency ablation (RFA) of left-sided accessory pathways can be achieved
      using catheters introduced by a retrograde or transseptal approach.
      Transesophageal echocardiography (TEE) has previously been demonstrated to be
      safe and efficacious in guiding transseptal puncture in patients during mitral
      valvuloplasty (MV). This study was undertaken to assess the feasibility, safety,
      and clinical utility of TEE during transseptal puncture and RFA of left-sided
      accessory pathways. METHODS: TEE was performed during transseptal puncture in 30
      patients (41 +/- 12 years, 19 females), 15 patients during attempted RFA of a
      left-sided accessory pathway and 15 patients during attempted balloon MV.
      RESULTS: There was no difference in age, sex distribution, or procedural
      complications when MV patients were compared to RFA patients. At baseline, left
      atrial dimension was increased and congestive heart failure was more common when
      MV patients were compared to RFA patients (P < 0.05) Adequate baseline two
      dimensional and Doppler TEE images were obtained in all patients. One patient
      sustained mild esophageal bleeding during the TEE. Positioning of the transseptal
      catheter in the fossa ovalis was facilitated and confirmed by TEE in 29 of 30
      cases. One case of cardiac perforation occurred and was associated with
      inadequate TEE localization of the fossa ovalis. Thrombus was detected on the
      transseptal catheter by TEE in two cases prior to systemic heparinization. In
      both cases, thrombus was removed without embolic event. CONCLUSIONS: TEE safely
      guides transseptal puncture in patients undergoing RFA of left-sided accessory
      pathways. TEE markers of the fossa ovalis facilitate puncture and may reduce the
      risk of cardiac perforation particularly in patients with a normal size left
      atrium. TEE may be especially valuable for identifying thrombus during
      transseptal puncture.

PMID- 8657590
TI  - Clinical application of a microcomputer system for analysis of monophasic action
      potentials.
AB  - Computerized analysis of monophasic action potentials (MAPs) has rarely been
      reported in clinical setting. We developed a computer system featuring on-line
      acquisition and user-monitored automatic measurement of multichannel MAPs with
      the capability of manual corrections. This system has been used in 34 patients in
      whom two-channel MAPs and 1-lead ECG were digitized during sinus rhythm, pacing,
      and programmed stimulation (PS). In total, 41, 413 MAPs in 212 data files were
      measured. The correct determination rate was 100% for MAP onset and plateau,
      99.78% (95.76% during PS) for MAP baseline, and 99.96% (54.29% during PS) for QRS
      onset. The comparison between the computerized and manual measurements in 292
      MAPs showed that the former highly agreed with the latter, with the limits of
      agreement, defined as mean difference +/- 2 SD, being from -4.8-4.9 ms for
      activation time and from -4.1-6.0 ms for MAP duration measurements. Using this
      system, two-channel MAPs of more than 300 consecutive beats can be measured in a
      few minutes, which made it possible to determine the steady state of MAP duration
      individually, and evaluate the MAP changes during intervention in detail. The
      clinical routine procedure for testing the effective refractory period and
      several new MAP parameters were also evaluated using this system. CONCLUSION: The
      MAP measurement using this computer system is reliable, rapid and accurate; it
      can therefore replace the manual method and provide more useful information for
      clinical research.

PMID- 8657591
TI  - Dependence of atrial sensing function on posture in a single-lead atrial
      triggered ventricular (VDD) pacemaker.
AB  - The influence of body posture on atrial sensing was examined in a single-lead VDD
      pacemaker in 16 patients. At implantation, a position was searched for the
      floating atrial bipolar sensor to obtain an adequate atrial signal amplitude.
      After 1-12 months the atrial signals were measured by programming the sensitivity
      in five postures: supine, sitting, and standing and lying on the right and left
      sides. The group mean amplitudes of the atrial signal were equal in all postures,
      and comparable to the supine value (1.01 +/- 0.51 mV). However, the values within
      each individual varied considerably according to position, by a range of 0.46 +/-
      0.41 mV on average. Testing only supine did not always predict decent sensing
      when upright, e.g., in 3 patients the atrial signal decreased more than 0.5 mV.
      In 24-hour ambulatory electrocardiography, with the sensitivity (0.15-0.30 mV)
      set to cover all postures, atrial beats were undersensed not at all in 4
      patients, < 0.01% in 6 patients, and < 0.1% in the remaining 6 patients. Thus,
      with a floating atrial electrode, sensitivity testing in various postures is
      advisable to ascertain proper sensing function.

PMID- 8657592
TI  - Time- versus frequency-domain analysis in predicting cycle length of inducible
      ventricular tachycardia after myocardial infarction.
AB  - To determine whether time- and frequency-domain analyses differ in their ability
      to predict sustained ventricular tachycardia (VT) induced by programmed
      ventricular stimulation, 60 consecutive patients with myocardial infarction and
      30 healthy control subjects were evaluated. Programmed ventricular stimulation
      using three extrastimuli and signal-averaged ECG recordings were performed in
      patients with myocardial infarction. Of the 60 patients, sustained monomorphic VT
      (SMVT) with cycle length (CL) > or = 250 ms (slow SMVT) was inducible in 9, and
      SMVT with CL < 250 ms (fast SMVT) was inducible in 9. The durations of the
      filtered QRS (f-QRS) at each high-pass filter (25, 40, and 80 Hz) and the low
      amplitude signal (LAS) at 25-Hz high-pass filtering were significantly longer in
      the slow SMVT group than in the fast SMVT, no VT, or normal control group. The
      root-mean-square voltages at 25-Hz and 80-Hz high-pass filters in the slow SMVT
      group were significantly lower than in the fast SMVT, no VT, or normal control
      group. There was no significant difference in time-domain variables among fast
      SMVT, no VT, and normal control groups. The CL of the induced sustained VT was
      significantly correlated with the durations of f-QRS and LAS. Concerning
      frequency-domain variables (area ratio and factor of normality), there was no
      significant difference between slow and fast SMVT groups. Both the slow and fast
      SMVT groups had a significantly higher area ratio and a significantly lower
      factor of normality than the group with no VT or the normal control subjects. In
      conclusion, there were significant correlations between time-domain variables and
      CL of SMVT, while there was no correlation when using frequency-domain
      parameters.

PMID- 8657593
TI  - Atrioventricular block occurring late after heart transplantation: presentation
      of three cases and literature review.
AB  - Sinus node dysfunction is a well-known occurrence following orthotopic heart
      transplantation, but atrioventricular block is rarely described. We compare the
      incidence and clinical presentation of atrioventricular block and sinus node
      dysfunction among the first 200 consecutive patients receiving heart
      transplantation at the University of Utah. Two of 200 patients (1%) required
      pacemaker implantation for symptomatic atrioventricular block compared to 13 of
      200 (6.5%) who required pacemaker for symptomatic sinus node dysfunction. Of the
      patients with atrioventricular block, one had intermittent Mobitz II second
      degree atrioventricular block and one had high grade atrioventricular block
      without ventricular escape. The most striking difference between the patients
      with atrioventricular block and those with sinus node dysfunction was the
      interval between transplantation and pacemaker implantation; time to pacemaker
      implantation in the atrioventricular block patients was 955 and 810 days compared
      to a median time of 26 days for sinus node dysfunction patients (P = 0.037). The
      patients requiring permanent pacemaker implantation were similar to those not
      requiring pacemaker implantation with respect to age, sex, ischemic time, and
      donor age. None of the patients requiring permanent pacemaker implantation was on
      amiodarone therapy within 2 months of transplant.

PMID- 8657594
TI  - Earlier activation of the distal than the proximal site of the coronary sinus may
      represent retrograde conduction through AV node: significance of recording of far
      distal coronary sinus.
AB  - During retrograde conduction through an accessory pathway (AP) or the
      atrioventricular (AV) node, earlier activation of the distal recording site than
      a more proximal site of the coronary sinus (CS) generally indicates retrograde
      conduction via a distally located AP. Thus, after successful ablation of a left
      sided AP, if the distal CS recording site is activated earlier than a more
      proximal site retrogradely, it is considered to suggest-in the absence of His
      bundle recording or more frequently in the setting of poor recording of the low
      septal right atrial electrogram-a conduction via a second AP (located more
      distally), and not conduction via the AV node. Yet, we hypothesized that
      retrograde conduction through the AV node may activate the far distal site of the
      CS (CSD) earlier than a more proximal site, as the anterior atrial wavefront,
      coming retrogradely from the AV node and traveling along the anterior mitral
      annulus, could reach the CSD earlier than a more proximal site. To test this we
      studied 18 patients with intact retrograde conduction via the AV node, but
      without evidence of an AP. The CSD was recorded by means of a quadripolar
      catheter (interelectrode distance of 2-5 mm); retrograde activation sequence at
      the distal (CSD1-2) versus proximal (CSD3-4) bipolar recording site was
      determined during ventricular stimulation. In 12 of 18 patients the CSD1-2
      recording site was activated 5-10 ms earlier than the CSD3-4 recording site, in 3
      of 18 patients the CSD1-2 site was activated 5 ms later than the CSD3-4 site; in
      the remaining 3 patients both recording sites were depolarized simultaneously.
      The results indicate that the CSD was often depolarized earlier than a more
      proximal site by impulses that conducted to the atria retrogradely via the AV
      node while the quadripolar recording catheter was placed at the CSD. This
      observation, although not well documented previously, suggests that the sequence
      of retrograde atrial activation in the CS should be studied carefully in
      consideration of the actual location of the mapping catheter in order to
      correctly diagnose the presence or absence of conduction via an AP.

PMID- 8657595
TI  - Correlation between time-domain measures of heart rate variability and
      scatterplots in postinfarction patients.
AB  - Heart rate variability (HRV) is usually measured in time or frequency domains.
      Beat-to-beat variability, which cannot be assessed by frequency-domain analysis,
      and can only be assessed globally by time-domain analysis, provides information
      concerning the nonlinear behavior of heart rate. This beat-to-beat variability
      can be displayed on scatterplots, where each RR interval is plotted against the
      preceding RR interval. However, the relationship between scatterplots and other
      measures of HRV is unknown. We studied the correlations between time-domain
      measures and scatterplot length, width, and area in 50 postinfarction patients.
      Scatterplot length and width were measured after printing. Scatterplot area was
      calculated from length and width, assimilating the plot to an ellipse. Long-term
      variability indexes (SDNN and SDANN) were strongly correlated with scatterplot
      length (r > 0.9, P < 0.0001), and short-term variability parameters (pNN50 and
      variability index) with scatterplot width (r > 0.9; P < 0.0001). Scatterplots
      are, therefore, a simple way of providing information concerning long- and short
      term HRV. Furthermore, measurement of scatterplot width at different given RR
      intervals could be an approach to the evaluation of short-term HRV for different
      heart rates. This could provide a simple way of assessing cardiac parasympathetic
      modulation at different heart rates.

PMID- 8657596
TI  - Control of rapid heart rate in patients with atrial fibrillation: drugs or
      ablation?

PMID- 8657597
TI  - Desktop publishing software.

PMID- 8657598
TI  - The human costs of over-regulation.

PMID- 8657599
TI  - Coexistent narrow and wide QRS complex tachycardia: an interesting duo.

PMID- 8657600
TI  - Spontaneous reversal of a cardiomyostimulator to asynchronous mode.
AB  - A patient who underwent dynamic cardiomyoplasty at our institute 10 months
      earlier was recently found to have asynchronous function of his
      cardiomyostimulator (model SP1005A, Medtronic, Inc.). This patient had been
      exposed to metal detection equipment 3 months earlier at an airport security
      gate, and this equipment was deemed responsible for this change in device
      programming. Despite the asynchronous function of the device, the patient did not
      suffer any functional impairment during this 3-month period. Moderate
      electromagnetic interference is capable of resetting the SP1005A
      cardiomyostimulator to the asynchronous mode of operation. Muscle stimulation,
      therefore, will not precisely occur during the systolic phase of the cardiac
      cycle and systolic augmentation may be lost. Despite asynchronous muscle
      stimulation, no impairment of this patient's functional Class was observed. This
      stability may be credited purely to the effect of the muscular wrap around the
      ventricles in which ventricular wall stress is decreased.

PMID- 8657601
TI  - Two cases of ventricular parasystole associated with ventricular tachycardia.
AB  - In two patients, ventricular parasystole (VP) was associated with ventricular
      tachycardia (VT), and in one patient, catheter ablation was successful. In
      patient 1, with dilated cardiomyopathy, VP led to VT, which converted to
      ventricular fibrillation. In patient 2, VP led to symptomatic nonsustained
      polymorphic VT. The origin of parasystolic focus was determined by endocardial
      mapping, and a radiofrequency current was delivered to patient 2. Both VP and VT
      disappeared immediately, and no recurrence has been observed during a follow-up
      of 8 months. Catheter ablation to the parasystolic focus was effective and a
      relationship between VP and VT was strongly suggested.

PMID- 8657602
TI  - Two hearts beating as one: radiofrequency ablation of the His bundle in a
      heterotopic heart transplant patient.
AB  - We describe a 54-year-old man with heterotopic heart transplantation, who had
      severe exertional angina and dyspnea related to native heart ischemic disease.
      Because of drug resistant atrial fibrillation and atrial flutter of the native
      heart with fast ventricular response (130 beats/min), right-sided radiofrequency
      ablation of the His bundle was undertaken, followed by permanent pacemaker
      linkage of donor and native hearts. The procedure was successful and uneventful.
      Remarkable relief of symptoms was achieved.

PMID- 8657603
TI  - Defibrillator twiddler's syndrome causing device failure in a subpectoral
      transvenous system.
AB  - Twiddler's syndrome is well described as a complication of cardiac pacing.
      Defibrillator twiddler's syndrome has been recently reported with abdominal
      implantations of epicardial and transvenous defibrillator systems. We report a
      case of a patient with a transvenous defibrillator system implanted with the
      pulse generator placed in the subpectoral plane. The patient developed twiddler's
      syndrome, which resulted in retraction of both leads. This caused inappropriate
      shocks due to sensing both the atrial and ventricular electrograms. While the
      subpectoral position leaves the generator deeper and more difficult for the
      patient to access, it may not lessen the chance of twiddler's syndrome. It is
      possible that the subpectoral position may actually predispose the patient to
      this malady.

PMID- 8657604
TI  - Pacemaker upgrade for recurrent pacemaker syndrome using a redundant
      contralateral electrode in a patient with bilateral venous stenoses.
AB  - Following His-bundle ablation and VVIR pacemaker implantation, severe pacemaker
      syndrome developed and was treated with DDDR pacing, in a 70-year-old woman. Due
      to bilateral subclavian vein stenoses, DDDR pacing could not be maintained and an
      unusual method of restoring atrioventricular synchrony is described using the
      contralateral redundant atrial electrode connected to the ipsilateral dual
      chamber pacemaker and ventricular electrode.

PMID- 8657605
TI  - Compatibility of implantable cardiac pacemakers with implantable cardioverter
      defibrillators (ICDs)

PMID- 8657606
TI  - Ethics of a randomized trial to compare VVI vs DDD pacing.

PMID- 8657607
TI  - STIMAREC report.

PMID- 8657608
TI  - [Problems with donor-recipient matching in kidney and bone marrow
      transplantation].
AB  - The main problem in matching donor-recipient pair in kidney transplantations is
      sensitization of dialysed patients. The patients with high percentage of
      cytotoxic antibodies to peripheral blood lymphocytes from a random panel, have a
      low chance of receiving a renal allograft. Negative results of the crossmatch
      between recipient serum and donor lymphocytes is decisive criterion for kidney
      transplantation. However not all antibodies are harmful for the graft. We present
      out methods of differentiating between auto- and alloantibodies and between IgM
      and IgG class of alloantibodies in sera of hypersensitized patients. The
      precision of identification of HLA matched donors is vital in bone marrow
      transplantations. The standard cytotoxicity tests cannot identify all HLA class
      II alleles and MLC testing is a long procedure. We present our observations from
      introducing the PCR Fingerprinting technique for a rapid identification of the
      class II compatible individual among potential donors bone marrow transplant.

PMID- 8657609
TI  - [Characteristics of cells in inflammation and neoplastic processes].

PMID- 8657610
TI  - [Cytokines in persons infected with HIV and patients with AIDS].
AB  - The cytokine system is affected by human immunodeficiency virus. The virus
      stimulates or inhibits the production of various cytokines. On the other hand,
      many cytokines may interfere with HIV replication. Interferons (mainly alpha- and
      beta-type) inhibit and tumor necrosis factors stimulate the virus replication in
      vitro. However, in vivo in HIV-infected patients it appears that IFN but not TNF
      is reliable progression marker of AIDS.

PMID- 8657611
TI  - [Immunologic function of the placenta and endothelium in virus infection; non
      specific immunity].
AB  - A placenta constitutes a specific immune system that can protect a fetus against
      viral infections. We examined TNF, IFN and IL-6 production in organ cultures of
      human placenta and amniotic membrane. VSV replication and the cytokine production
      (TNF, IFN, IL-6) by human umbilical cord vein organ cultures and isolated
      endothelial cells were compared. We suggest that the local production of
      cytokines is responsible for the antiviral activity of placenta and endothelium.

PMID- 8657612
TI  - [Initiation of DNA replication in Streptomyces; organizational comparison of the
      oriC region in prokaryotic organisms].
AB  - DnaA protein and its binding sequence (DnaA-box) are two elements essential for
      the initiation of chromosomal replication in Escherichia coli and other bacteria.
      Recently these two elements have been found to be conserved in four Gram-positive
      bacteria (Bacillus subtilis, Micrococcus luteus, Mycoplasma capricolum and
      Streptomyces lividans). The structures of eubacterial DnaA-box regions and their
      locations on the chromosome and than functional aspects od DnaA protein have been
      compared.

PMID- 8657613
TI  - [Importance of taxonomic and immunologic lipid markers of actinomycetes and
      similar bacteria].

PMID- 8657614
TI  - [Protective properties of antibodies raised against conjugates of endotoxin core
      oligosaccharides with proteins].
AB  - Endotoxins are responsible for initiation of septic shock which increases the
      number of fatalities in Gram-negative bacteremia among hospital patients. The
      mortality from septic shock is still high despite recent developments in
      antibiotic therapy. These substances are unable to decrease the level of free
      lipopolysaccharides in the bloodstream. Another approach to the treatment and
      prevention of septicaemia involves stimulation of an immune response against LPS.
      It was found that immunization with core structures of endotoxin conjugated with
      proteins protected animals against infections and endotoxic shock. Anticonjugate
      sera are of great interest because they are directed against common parts of LPS
      and therefore could have cross-reactive and cross-protective potencies towards
      many Gram-negative rods.

PMID- 8657615
TI  - [Studies on diversification and restriction of immune response against
      glycopeptide antigens].
AB  - The M and N human blood group antigens are complex glycopeptide determinants at
      the amino terminus of the red blood cell membrane glycoprotein, glycophorin A.
      The heavy and light chain variable region cDNA sequences were determined for
      eight murine monoclonal antibodies recognizing the M or N blood group
      determinants. Among anti-N, but not anti-M, hybridomas, apparent restriction was
      found: all four anti-N VH regions of the heavy chains were derived from the same
      family, VH2(Q52) and all used the same J4 gene segment. To determine whether the
      Fab fragments displayed on the bacteriophage surface retain the immunological
      characteristics of intact antibodies, Fab-phages were constructed from five
      murine monoclonal antibodies recognizing glycophorin A. In each case, the Fab
      phage had similar immunological characteristics as the respective antibodies.
      These results suggest that Fab-phages may be useful in studying the immune
      response to human glycosylation-dependent peptidic epitopes.

PMID- 8657616
TI  - [Biological role of HLA-C].
AB  - Human major histocompatibility complex class I molecules, HLA-A and -B, bind
      peptides derived from intracellular proteins, transport them to the cell surface
      and present them to T lymphocytes. Much less is known about the function of the
      third "classical" class I molecule, HLA-C. Recent data disclosing remarkable
      polymorphism of HLA-C, possible importance of this molecule for the recognition
      of target cells by nature killer cells, and capability to present viral antigens
      to the T lymphocytes are reviewed. Preliminary results from our laboratory on
      binding of synthesis peptides to HLA-Cw3+ cells are presented.

PMID- 8657617
TI  - [Fc gamma receptors. Properties and participation in IgG binding and other
      biological processes].
AB  - This review deals with the problem of transmission of the signal to cells via Fc
      gamma receptors. It was shown that in guinea pig macrophages changes in
      glycosylation of surface conjugates may affect the interaction by IgG
      immunoglobulins with the Fc gamma receptors. It also was found that binding of
      IgG caused an association of the Fc gamma receptors with the macrophage
      cytoskeleton. It was shown that the cytoskeleton was involved in induction of
      various biological functions in macrophages.

PMID- 8657618
TI  - [Regulation of interleukin 6 (IL-6) and TNF-alpha through lactoferrin in mice].
AB  - Lactoferrin, introduced intravenously, before i.v. injection of 50 micrograms of
      LPS, significantly lowered the serum activity of TNF-alpha. Moreover, lactoferrin
      induces by itself relatively high level of IL-6, peaking at 1 h following
      injection.

PMID- 8657619
TI  - [Use of anti-H-Y/Db transgenic mice in studies on T-lymphocyte development and
      mechanisms of leukemogenesis].
AB  - During the development of T cells in the thymus, the alpha beta T-cell receptor
      (TCR) mediated interactions of immature CD4+ CD8+ cells with thymic major
      histocompatibility complex (MHC) molecules in the absence of specific antigens
      are required for their survival and further maturation (positive selection)
      whereas interactions with MHC molecules presenting specific antigens result in
      their death by apoptosis (negative selection). Preliminary results suggest
      association of antigenic stimulation via TCR with leukemogenesis of TCR
      transgenic mice. TCR transgenic mice monitored over a period of 2 years revealed
      spontaneous leukemia development in mice of both sexes by the age of 8-12 months,
      with the surface expression of transgene and markers of T cell development
      pathway.

PMID- 8657620
TI  - [Role of intercellular interactions in tumor progression and metastasis].
AB  - Cell-cell and cell-substratum interactions are mediated by specific cell adhesion
      molecules. These cell adhesion molecules play a central role in normal tissue
      organization and cell migration, as well as in tumor growth and metastasis. There
      is growing evidence that carbohydrates profiles of tumor cells change during
      malignant progression. These cell-surface carbohydrates may play an important
      role in intercellular interactions, as a ligands for endogenous cellular lectins.

PMID- 8657621
TI  - [Antisense strategies in studies on the role of sugar chains in phenotype
      expression of neoplasms].

PMID- 8657622
TI  - [Strategies for studies on mechanism of action of antineoplastic agents].
AB  - A concise review of the progress in strategies of anticancer drug screening
      methods provides a background for showing the selected examples of the results
      from our studies in the field of experimental antitumor therapy. The
      antineoplastic activity of ifosfamide bromoanalogues is presented in comparison
      with clinically used cytostatic drugs from the same chemical group. The results
      obtained by combined chemo-immunotherapy with exploitation of mIL-2 gene
      transfected plasmacytoma cells (X-63-mIL-2) applied in tumor-bearing mice
      exemplifies one of the novel approaches in anticancer treatment.

PMID- 8657623
TI  - [Repertoire of rearranged immunoglobulin genes of human peripheral lymphocytes].
AB  - Immunoglobulin repertoire of normal adults is biased toward a small number of VH
      segments. One of these segments is VH4.21 overrepresented in autoimmune and
      neoplastic repertoire.

PMID- 8657625
TI  - [Pathogenesis of polyglobulia after kidney transplantation].

PMID- 8657624
TI  - [Immunologic aspects of bone marrow transplantation].

PMID- 8657626
TI  - [Role of nitric oxide in physiologic and pathologic function of the central
      nervous system].
AB  - Nitric oxide (NO) is implicated in a large number of physiological functions and
      also in pathologies in the brain. This article reviews recent advances in our
      understanding of the roles of NO in the central nervous system, as well as its
      implications for clinical medicine.

PMID- 8657627
TI  - [Pentoxifylline].
AB  - Pentoxifylline (PTX), methylxanthine derivative and phosphodiesterase inhibitor,
      has been in use for more than 20 years (with minimal side effects) for the potent
      hemorrheologic properties and was recently discovered to have influence on
      function of some immune cells and production of cytokines. Human and animal
      studies have shown that PTX therapy results in a variety of physiologic changes
      at the cellular level, which may be important in treating a diverse group of
      human afflictions. Immune modulation includes increased leukocyte deformability
      and chemotaxis, decreased endothelial leukocyte adhesion, decreased neutrophil
      degranulation and release of superoxides, decreased production of TNF-alpha and
      decreased NK cell activity. Potential medical uses of PTX are reviewed.

PMID- 8657629
TI  - [Calcitonin gene related peptide].
AB  - Paper presents a recent review on the function and practical importance of CGRP
      in both physiology and pathology of animals and humans. The special attention was
      paid on CGRP role in cardiovascular, endocrine and gastrointestinal systems and
      in neoplasms.

PMID- 8657628
TI  - [Cyclin dependent kinases. From molecular biology to pathology].
AB  - Cyclin-dependent kinases (cdks) is a family of serine-threonine kinases whose
      principal role is the promotion of the cell transition through the regulatory
      points of the cell cycle (G1 and G2/M). The best known human cdks are: cdk1-cdk7
      and p58-GTA. The latter one, contrarily to the other cdks, is supposed to act as
      a antiproliferative factor. Most cdks may be involved in the development of
      neoplastic disorders. This hypothesis is based on their biological features
      (interactions with viral oncoproteins), their hyperexpression in some
      malignancies and frequent deletions of cdk inhibitory genes in cancer cells.
      cdk5, which displays the maximal kinase activity in non-proliferating brain
      neurons may participate in the pathogeny of the Alzheimer's disease.

PMID- 8657630
TI  - [Importance of genetic factors in pathogenesis of subacute spongiform viral
      encephalitis].
AB  - Recently there has been achieved a substantial progress in research concerning
      pathogenesis of subacute spongiform viral encephalopathies. For this group of
      disorders, there has been found a common unconventional virus - proteinaceous
      infectious particle (PrP). There has been recognised a molecular mass,
      biochemical composition and physicochemical properties of this infectious form.
      Mutations of scrapie amyloid precursor gene discovered in Gerstmann-Straussler
      Scheinker syndrome (GSS) and familial cases of Creutzfeldt-Jakob disease (CJD)
      have been revealed. Nowadays examinations in the field of relationships between
      prion protein and mutations of scrapie precursor gene are continued.

PMID- 8657631
TI  - [Biological properties and clinical importance of interleukin 1].
AB  - The paper presents the molecular biology and biological activity of IL-1 alpha,
      IL-1 beta and IL-1 receptor antagonist. The role of IL-1 family in pathogenesis
      of a various disease including myeloid leukemias and other neoplastic diseases,
      diabetes mellitus, inflammatory diseases, sepsis syndrome and atherosclerosis is
      presented. Potential therapeutic value of IL-1 and IL-1 receptor antagonist is
      also discussed.

PMID- 8657632
TI  - [Biochemical aspects of cardiomyocyte damage during ischemia and reperfusion].
AB  - Universally accepted free radical damage cardiomyocytes hypothesis during
      ischemia and reperfusion, establish the pathway of reaction which destroys these
      cells. Free radicals may also break through antioxidative barrier of the cells.
      This process comprise also series of "paradoxal phenomena".

PMID- 8657633
TI  - [Polymorphonuclear leukocytes as a potential source of oxygen free radicals in
      myocardial infarction].
AB  - The review of literature on the role of free radicals derived from neutrophils in
      coronary heart disease is presented. Polymorphonuclear leukocytes are the main
      source of oxygen derived free radicals. They contribute significantly to the
      pathogenesis of postischemic dysfunction reperfused myocardium.

PMID- 8657634
TI  - [Possibilities and etiologic problems in prophylaxis of human virus infections].
AB  - There are areas of proved and successful prophylaxis of human's virus infections:
      vaccines, gammaglobulins and synthetic viral inactivators. In case of vaccine
      application the very important tasks concern situations of decreased
      immunological potency and viral latency. The progress and up to now achievements
      according to viral vaccines which may be used in immunocompromised people are
      presented in the paper, as well as the specificity of studies on vaccines against
      latent viral infections. Gammaglobulin preparations especially of commercial
      production, are characterized. Mechanism of their activity, different efficiency
      in viral infections and problems of safety, point on the important complementary
      role of gammaglobulin prophylactic application. Disinfecting agents grow in
      importance, so the main topic presented concerns the requirements, which must be
      fulfilled to achieve satisfactory results in preventing virus infections.

PMID- 8657635
TI  - [Human myoglobin (hMb) and its diagnostic value].
AB  - Composition, properties and occurrence of human myoglobin (hMb) were described.
      Methods for immunological assay of hMb were presented. Localization of antigenic
      determinants in myoglobin molecule was shown. Value of assay of hMb in serum and
      urine for early diagnosis of myocardial infarct and some other muscle diseases
      was discussed.

PMID- 8657636
TI  - [Lymph--biochemical composition, importance of its circulation in the physiology
      and pathology of the organism].
AB  - The lymph plasma contains various chemical constituents filtered out from the
      blood capillaries and metabolic or secretory products of tissue itself, and
      differs from tissue fluid. The various organs of the body contribute in very
      distinct manners to flow and composition of this main lymph. The paper presents
      review of the literature concerning the data on the role of lymph flow and lymph
      biochemistry.

PMID- 8657637
TI  - [Biological properties and therapeutic use of interleukin 2 (IL-2)].
AB  - A cytokine produced by the subpopulation of activated helper lymphocytes T has
      been called interleukin-2 (IL-2). The obtaining of recombinant cytokine has
      facilitated the study of its biological properties and its application in the
      treatment of certain neoplastic and infectious diseases. IL-2 affects the target
      cells by means of a receptor of great affinity consisting of three independent
      chains: alpha, beta, gamma. The cytokine is the most important growth factor of
      lymphocytes T, conditioning their clonal expansion. Antigen stimulation is the
      condition for the expression of IL-2 does not, however, affect resting
      lymphocytes T. The expression of the receptor for this cytokine on NK cells is,
      however, continuous in character but only a very small percentage of these cells
      has receptors of great affinity. IL-2 plays a great role in adoptive
      immunotherapy consisting in intravenous administration of cells with cytotoxic
      properties. Cells obtained from peripheral blood and grown in vitro are called
      LAK cells (lymphocyte activated killer cells), while cells obtained from
      neoplasms and grown in similar conditions are named TIL cells (tumor infiltrated
      lymphocytes). LAK and TIL cells reveal a similar antineoplastic activity in vivo.
      At present, however, recombinant IL-2 alone is used more often, either
      intravenously or subcutaneously. The cytokine is effective in the treatment of
      patients with disseminate cancer of the kidney and melanoma, and in adjuvant
      therapy of acute myeloid leukemia. Attempts have been made to apply it in the
      treatment of AIDS and leprosy. The toxic effect of IL-2 depends on the dose and
      the mode of administration. In the majority of patients parainfluenza symptoms
      appear. Most undesirable effects are connected with multisystemic syndrome of
      capillary vessels hyperpermeability leading to the increased fluid retention into
      extravascular spaces, oedema, hypotonia and oliguria.

PMID- 8657638
TI  - [Role of the autonomic nervous system (adrenergic, cholinergic and nonadrenergic,
      noncholinergic) in regulation of respiratory system function].
AB  - There is now recognized that the autonomic innervation of airways consists of
      classic adrenergic and cholinergic nerves as well as of a "third" - nonadrenergic
      noncholinergic (NANC) - nervous system. Taking into account its complex
      regulatory role can be crucial for better understanding of various phenomena
      attributable to bronchial asthma.

PMID- 8657639
TI  - [Steroid modulation of GABA(A) receptors].
AB  - It has been known for many years that steroids influence many processes by genome
      activation. In 40-th the fast (anesthetic)-effect of steroids on neuronal
      activity was discovered, and later the molecular mechanism of steroid action as
      modulators of GABA(A) receptors was documented. Such kind of influence of
      neuronal activity is characteristic for some glucocorticosteroids and some
      derivatives of androsterone and progesterone (for instance: THDOC, THP). The
      endogenous production of several steroids in the brain was proved. Recently
      modulatory effect (anti-anesthetic properties) of sulphate esters of pregnenolone
      (P) and dehydroepiandrosterone (DHEA) on GABAA receptors was discovered. The
      steroid influence on the neuronal activity is still poorly documented and
      requires further investigations.

PMID- 8657640
TI  - [CD23/sCD23--receptor/cytokine in IgE-dependent reactions].

PMID- 8657641
TI  - [Role of glyoxalases and methylglyoxal in cell proliferation and
      differentiation].
AB  - The glyoxalase system catalyses the conversion of methylglyoxal (and other 2
      ketoaldehydes) to D-lactic acid via the intermediate S-D-lactoylglutathione. It
      comprises two enzymes, glyoxalases I and glyoxalases II, and catalytic amount to
      reduced glutathione. Methylglyoxal inhibits cell growth, while the glyoxalase
      system by breaking down methylglyoxal may act as a promoter of cell growth.
      Inhibitors of glyoxalases may serve as possible therapeutic agents against cancer
      by virtue of their ability to elevate the level of methylglyoxal in the body.

PMID- 8657642
TI  - [Immuno-contraceptive vaccines].
AB  - Results of studies on birth control vaccines accomplished by many research groups
      within the WHO Special Programe of Research, Development and Research Training in
      Human Reproduction has been reviewed. The mostly investigated contraceptive
      vaccines contain human chorionic gonadotropin, and therefore structure,
      biological role and immunogenicity of the hormone were presented. Also, vaccines
      obtained on the basis of subunit beta of the human chorionic gonadotropin, its
      heterodimer with subunit beta of ovine lutropin or C-terminal peptide of beta
      subunit were described. Results of two phases of clinical trials with immuno
      contraceptive vaccines were presented. The use of contraceptive vaccines for
      treatment of some trophoblastic tumors and the idea of using contraceptive
      recombinant vaccines were also mentioned.

PMID- 8657643
TI  - [Mucosal immunity with implications for use in developing a new generation of
      vaccines].
AB  - The mucosal immune system is a very important component of the body's defence
      against pathogenic organisms, especially those responsible for enteric
      infections. On the basis of the concept of a common mucosal immune system, there
      is currently much interest in the possibility of developing oral vaccines against
      respiratory and urogenital tracts infections. There is also a great need to
      develop strategies for enhancing delivery of antigens to the mucosal immune
      system as well as to identify mucosa-active immunostimulating adjuvants.

PMID- 8657644
TI  - [Outline of immune deficiency pathogenesis in patients with chronic renal
      failure].
AB  - Up to day the pathogenesis of immune deficiency in chronic renal failure have not
      been clearly elucidated. There is no agreement where is situated the primary
      disturbance that makes that category of patients more susceptible to infections
      and neoplasms. The views presented in this paper seem to shift the balance toward
      multifactor theory. Possible influence of many biochemical abnormalities and
      effect of renal replacement therapies on main elements of immune system are
      discussed.

PMID- 8657645
TI  - [The importance of interleukin 6 (IL-6) in pathogenesis and diagnosis of renal
      glomerular diseases].
AB  - IL-6 synthesized by various types of cells and has multiple biological functions.
      In the kidney, IL-6 is synthesized by mesangial cells and acts as an autocrine
      growth factor. IL-6 was demonstrated in the glomerular mesangium and in the urine
      of patients with proliferative glomerulonephritis, suggesting that it has an
      important role in the pathogenesis of renal glomerular diseases.

PMID- 8657647
TI  - [Free radicals and their importance in medicine].
AB  - The work presents current views of free radicals and their role in medicine. In
      the first fact, the chemical nature of free radicals, their reactions in cells
      and its consequences are discussed. The second part deals with a role of free
      radicals in human pathology with a special stress put an arteriosclerotic
      process. In the third part, the defense mechanism against free radical action,
      particularly the importance of superoxide dismutase.

PMID- 8657646
TI  - [Function of endogenous opioid peptides and sex steroids at the level of the
      central nervous system].
AB  - Gonadal steroids and beta-endorphin (beta-EP) (and probably other - EOP
      endogenous opioid peptides) play a role of the pivotal hormones involved in
      integration of several neurophysiological mechanisms. The reproductive system
      could be disturbed at hypothalamic level by interference of beta-EP and GnRH
      secretion and/or at pituitary level with response of gonadotropes to GnRH.
      Gonadal steroids, through a feedback mechanism, may exert similar effect on
      hypothalamus and/or pituitary. The action of EOP on the hypothalamo-pituitary
      gonadal axis may be influenced by physiological and pathological changes in
      gonadal steroids during puberty, menstrual cycle in females, menopause, in case
      of idiopathic delayed puberty, in patients with gonadal dysgenesis or after
      castration. EOP seems to be "gonadostat" system that have a key role in the
      transmission of gonadal feedback signals to the brain.

PMID- 8657648
TI  - [Function of the autonomic nervous system in uremia].
AB  - Autonomic impairement is associated with poor prognosis in many diseases. The
      article (first of three parts) critically reviews arguments found in the
      literature showing autonomic dysfunction in chronic renal failure patients. The
      autonomic nervous system problems will become of great clinical relevance
      considering increasing number and age of uremic patients being dialysed
      worldwide.

PMID- 8657650
TI  - [Somatic gene therapy--is it safe?].

PMID- 8657649
TI  - [Role of hematopoietic factors in regulation of proliferation and function of
      phagocytes].
AB  - Hematopoietic growth factors belong to the family of glycoproteins responsible
      for regulation, differentiation and proliferation of myelopoietic cells. In this
      paper the role of these factors in regulation of the function of phagocytic cells
      (granulocyte, monocyte, macrophage) is discussed on the basis of literature data.

PMID- 8657651
TI  - [The Nobel Prize 1995 in medicine and physiology: embryogenesis and homeotic
      genes].

PMID- 8657652
TI  - [Repair of O6-methylguanine-DNA].

PMID- 8657653
TI  - [Oxidative damage repair of DNA in prokaryotes].

PMID- 8657654
TI  - [Structure and function of major tissue histocompatibility complex (MHC) class I
      antigens].

PMID- 8657655
TI  - [Changes in cell volume and modulation of their metabolism].

PMID- 8657656
TI  - [Phytochrome--structure and properties].

PMID- 8657657
TI  - [Reactive oxygen species and gene expression regulation].

PMID- 8657658
TI  - [Ethylene--its role in fruit ripening and senescence of blossoms. Biotechnologic
      aspects].

PMID- 8657659
TI  - [Biochemistry on the network].

PMID- 8657660
TI  - [Social relations of children in the primary school age group. A study with the
      SOBEKI method in 8- to 11-year-old primary school children].
AB  - From the beginning of their lifes children are involved in many different kinds
      of social relations, that influence the development of children's personality.
      With the "Soziales Beziehungsverfahren" (SOBEKI), a method for the clinical
      diagnostic of children is available, that allows of determining the social
      network of six- to twelve-year-olds as well as specific distributions of
      functions in the children's systems of relations and beyond, making conclusions
      about cohesion and hierarchical structures of children's networks in- and outside
      their families. In this article a study will be presented, in which the social
      relations of eight- to eleven-year-old primary school children were investigated
      with the SOBEKI.

PMID- 8657661
TI  - [First grade students in former East and West Berlin: socio-emotional adjustment
      and relation to attachment patterns of the children].
AB  - Adaptation to school of two samples of children (45 from East and 43 from West
      Berlin) grown up in two different political systems until the "Mauerfall" was
      studied over the first two school years using information from teachers in school
      and kindergarten, parents, and the children themselves. Cluster analysis revealed
      3 patterns of adaptation behavior: the first subgroup (61% of the sample) showed
      no problems at all, for a second subgroup (22%) teachers reported more adaptation
      difficulties, whereas the third subgroup (17%) was rated by their mothers as
      distractible, hard to motivate and less sociable. Sex differences turned out to
      be more significant than political-system differences. Adjustment patterns to
      school were also related to the child's quality of attachment, to the reported
      number of stressful life events happened to the family, as well as to mother's
      and teacher's existential anxiety.

PMID- 8657662
TI  - [Coping in the family context: active and avoidance strategies in adolescents
      from divorced families].
AB  - Studies on children's response to divorce have mainly emphasized negative
      psychological sequalae such as poor social adjustment and emotional disorders. In
      many studies children's coping strategies were important moderator variables. In
      a meta-analysis, Suls and Fletcher (1985) found better short-term outcomes
      related to avoidant coping. On the long run, however, active strategies were
      better off. To date, little is known about family climate influences on
      adolescents' coping. In the current study, 128 children (62 girls, 66 boys) from
      German middle class families were observed 6 months, 1, 2, and 7 years after the
      divorce of their parents. At the time of divorce their mean age was 14,8 years
      (SD = 2,5). The models presented in this article are based on 39 adolescents (17
      girls, 22 boys) for whom complete data were available. The study relates
      adolescents' coping strategies to measures of family functioning, as assessed
      through Family Environment Scale (Moos 1974). Coping strategies were assessed by
      Ways of Coping (Lazarus 1980), Impact of Event Scale (Horowitz 1979), and
      Stressverarbeitungs-Fragebogen (Janke 1985). Results, analyzed with LISREL
      models, indicate that supportive family climate, operationalized by openness and
      control, are good cumulative predictors for active coping. In a second model
      constraining family climates predicts avoidant coping in adolescents. Clinical
      implications are discussed.

PMID- 8657663
TI  - [Communication behavior between parents and their adolescent children and
      correlation with indicators of self concept].
AB  - Formats of communication within families are believed to be relevant contexts for
      children's development. Cultural values, norms, and interpretation patterns are
      transferred from parents to children within the family's specific communication
      framework. By the same token, skills to maintain the balance of living together
      or to realize one's own wishes are acquired within the scope of extant formats of
      exchange among family members. Puberty is a period, where a child strives for
      more autonomy and tends to dispute present parent-child relationships. The focus
      of the study is on links between formats of communication within the family and
      adolescents' estimations of the relationships with their parents and also
      adolescents' judgments about their self-esteem. 67 families with an adolescent
      child (between 11 and 12 years old at the beginning of data collection)
      participated in a longitudinal study, in which adolescents judged the quality of
      their relationship with parents as well as their self-esteem every six months
      over a period of three and a half years (8 waves). In addition, concrete
      communication behavior between parents and adolescents was observed and recorded
      during the first, fourth, sixth, and eight wave of data collection. Results point
      to considerable differences among adolescents' judgments concerning their quality
      of relationship with the parents and their self-esteem. Groups could be formed
      according to these differences. Data also show that adolescents show a high
      degree of constancy in their estimations over time. However, communication
      behaviors in parent-adolescent dyads showed divergent patterns of communication
      across the different groups on the one hand, and different degrees of variation
      of communication formats within groups over time on the other, dependent on
      whether adolescents belonged to the group of high quality relationship and self
      esteem (considerable variation over time) or to the group of low quality
      relationship and self-esteem (less variation over time). Results are discussed
      under the perspective of adolescents' different experiences in family
      communication, and implications of possible links between development of self
      esteem and adaptive or nonadaptive variations in family communication are
      considered.

PMID- 8657664
TI  - [Development, experience and relationship patterns: psychological health from the
      object attachment viewpoint].
AB  - In this article the author begins to integrate different theoretical perspectives
      in order to develop a more comprehensive model of normative and disordered
      pathways of development, in which genetic heritage, maturation, and individual
      differences in experience all play a role in the development of individual
      differences in adaptation. Specifically, differences in early attachment
      relationships are reconceptualized in terms of learned patterns of processing of
      cognitive and affective information and learned behavioral strategies for
      eliciting caregiving from attachment figures. In this model the basic nature of
      the mind is to be self-correcting so as to yield increasingly sophisticated and
      adaptive mental and behavioral patterns.

PMID- 8657665
TI  - [The value of child development psychological models for child and adolescent
      psychiatry].
AB  - The literature on personality research, developmental psychology and
      psychopathology has consistently revealed two types of personality. According to
      different theoretical and methodological approaches these types are considered as
      prototypes of a personality dimension, or as behavioral patterns in
      psychopathology. In the research on adult personality, they are known as
      extraversion and introversion. Child psychiatrists refer to these prototypes as
      externalizing and internalizing disorders. However, there are few empirical
      studies on the congruency between adult personality types and childhood
      disorders. Longitudinal studies from the USA and New Zealand give evidence that
      adult personality types can predict coping styles of school age children in
      stressful and challenging situations. Research on infant attachment to
      caregivers, revealing consistently different qualities of interaction patterns,
      may also be predictive for different coping styles in children of preschool age.
      Interdisciplinary discussions will focus on the question, whether early behavior
      patterns should be seen as predictors for adult traits (homotypic continuity) or
      as developmentally determined indicators for underlying functions (heterotypic
      continuity). Possibly, in early developmental stages behavior patterns have
      adaptive functions and in later stages become chronic strategies over time.
      Another topic concerns the relation between personality traits and pathologic
      behavior patterns and whether chronic strain may be influential.

PMID- 8657666
TI  - [Behavioral dimensions and behavior problems in 2 1/2-year-old children].
AB  - The present article gives a literature review on rating scales and psychometric
      instruments used for behavior rating in infants and toddlers. The results of
      gender specific factor analysis in a German normative sample of 2 1/2 year old
      children (N = 751) are compared to Achenbach's syndrome scales of the CBCL 2-3.
      In contrast to psychiatric diagnostic manuals (DSM-IV, ICD-10), which currently
      do not provide correct descriptions of the developmental psychopathology in this
      age group an empirically derived classification of age specific behavior is
      presented. Our own factor analysis replicated identically Achenbach's sleep
      problem-scale for this age group and came very next to Achenbach's syndrome
      scales. A comparison of the published international normative samples for the
      CBCL 2-3 shows, that the results in the Netherlands, in the United States and
      Canada are not statistically different from our German group. In the context of
      developmental psychopathology we prognose gender specific factor solutions
      derived from a normative sample and not from a clinical population. Psychometric
      data of these different versions are presented and discussed from a child
      psychiatrists view on developmental psychopathology.

PMID- 8657667
TI  - [Early attachment experiences and behavioral problems in young children in a
      social and cognitive test situation].
AB  - In this article, the influence of quality of attachment (Ainsworth Strange
      Situation at 21 months) and of the intensity of attachment insecurity on test
      performance and emotional state in the test situation (Bayley-test at 20 months)
      are analyzed. The quality of attachment of 75 infants was classified according to
      Crittenden's PAA (Preschool Assessment of Attachment) as: secure (B), insecure
      defended (A) and insecure-coercive (C). Alternately, the infants were classified
      according to their intensity of insecurity of attachment across subtypes of
      qualities (secure, insecure, highly insecure). Securely attached (B) infants had
      the best Bayley Mental scores, were socially open and bodily relaxed. The
      insecure-defended (A) infants had moderate test results, were moderately open and
      tense, whereas the insecure-coercive (C) infants showed not only the worst test
      results but were often withdrawn, fearful, tense, and poorly coordinated.
      Additional clinical signs of disorganization were spread unspecifically over all
      attachment groups particularly those of the insecure children. In the
      classification of children according to intensity of insecurity, these signs of
      disorganization accumulated particularly in the group of highly insecure infants.
      Children with highly insecure attachment who also exhibited unusual test
      situation behavior also had the lowest Bayley-test scores in the Mental Scale.
      These results are interpreted in the sense of balance between test engagement and
      emotional cost.

PMID- 8657668
TI  - [Munchhausen syndrome by proxy: a challenge for medicine].
AB  - In Munchhausen syndrome by proxy, a subject, usually a mother, pretends her child
      has a serious medical disorder. After simulating ficticious symptoms, or even
      producing clinical signs such as convulsions, fever, bleeding, vomiting, diarrhea
      or skin eruptions, the mother repeatedly takes her child to different hospitals
      for care. During hospitalization, the mother shows great concern for the child
      and is highly cooperative with the health care team. The consequences may be
      unwarrented, often invasive, investigations and therapy with a very high risk of
      morbidity and mortality. The underlying psychopathological structure is difficult
      to apprehend. Narcissic fragility and borderline personality are the must
      frequent, but passive-dependent hysteric personality or sadomasochist behavior
      can be found and depression is often associated. The main, if not the sole,
      benefit for the mother lies in the leading role she plays during the repeated
      hospitalizations in front of the admizing medical staff. Rare cases of adult
      adult Munchhausen syndrome by proxy have also been reported. Physicians should be
      aware of this syndrome in order to avoid unintentional participating in this
      morbid scenario by performing useless invasive examinations or by prescribing
      dangerous medication. Psychiatric treatment and sometimes legal action are
      required to avoid this particular kind of child abuse.

PMID- 8657669
TI  - [Renal scintigraphy: a major test for urologic diseases in children].
AB  - The number of asymptomatic uropathies detected by ultrasound has increased
      dramatically with antenatal diagnosis. Some of them only threaten the renal
      parenchyma and require surgery. Therefore, screening for patients at risk is a
      major challenge. During the initial evaluation and follow up of a dilated system,
      MAG3 scans evaluate and quantify the physiologic significance of a radiologically
      detected anatomic abnormality by measuring the relative renal function and wash
      out of the radiopharmaceutical. Moreover, DMSA scans show renal functional
      abnormalities due to pyelonephritis or dysplasia associated with vesicoureteral
      reflux or obstructive uropathy. With a low radiation burden, renal scintigraphy
      is now a major imaging modality for uropathies in pediatrics.

PMID- 8657670
TI  - [Advances in surgery for carotid stenosis. 900 operations (1983-1994)].
AB  - OBJECTIVES: To evaluate morbidity and mortality in carotid endarterectomy in a
      personal series. METHODS: Nine hundred endartectomies were performed from 1983 to
      1994. All patients had > 70% carotid narrowing. Five hundred five patients
      underwent without preoperative angiography. RESULTS: Outcome was analyzed for 3
      periods showing decreasing mortality from 4.56% in 1983-86 to 0.67% in 1990-1994.
      CONCLUSION: The reduction in morbidity and mortality resulted from the combined
      effects of pre-, per-, and post-operative care including noninvasive preoperative
      diagnosis of internal carotid artery stenosis using ultrasound duplex and surgery
      without previous angiography, delayed surgery in case of recent prolonged
      hemispheric deficit or of ischemic defect detected on computed tomography (CT) or
      magnetic resonance imaging (MRI), cerebral evaluation with CT-scan or MRI the day
      before operation, surgery under locoregional anesthesia, monitoring of arm
      arterial blood pressure during the first 24 hours following surgery.

PMID- 8657671
TI  - [Effects of digital rectal examination on serum prostate specific antigen].
AB  - OBJECTIVE: Prostate specific antigen (PSA) level is determined under precise
      conditions for the detection and follow-up of cancer of the prostate. The
      question is raised as to whether digital rectal examination has an effect on
      serum levels and whether an interval of time is required before PSA assay can
      give reliable results. METHODS: A prospective protocol was conducted for 6
      months. PSA was assayed in 56 patients hospitalized in an internal medicine ward
      whose clinical status justified digital rectal examination. Blood samples were
      taken 2 to 3 hours before the digital rectal examination, performed by the same
      physician in all cases, then 21 to 22 hours after the examination. RESULTS: After
      digital rectal examination, there was a nearly significant increase in PSA level
      (p = 0.06), an increase which was clinically unimportant (0.25 ng/ml). The levels
      before and after rectal examination were perfectly correlated and reproducible.
      These data confirmed those reported in the literature showing marginally
      significant increases of little or no clinical importance, usually within 2 hours
      of the examination. CONCLUSION: The interval of time between the two assays in
      our study indicates that in everyday clinical practice, for both inpatients and
      outpatients, digital rectal examination has no effect on prostate specific
      antigen and that subsequently there is no need to delay assay.

PMID- 8657672
TI  - [Dermatopolymyositis and primary biliary cirrhosis. A rare association].
AB  - We report a case of the uncommon association of dermatomyositis and primary
      biliary cirrhosis in a causasion male of 48-year-old. Diagnosis of dematomyositis
      was made because of muscle weakness, loss of weight, skin telangiectasia,
      elevated serum concentration of creatine kinase, polyphasic low amplitudes waves
      on electromyography and histologic confirmation on muscle biopsy. Diagnosis of
      primary biliary cirrhosis was made because of elevated values of alcaline
      phosphatase and gamma glutamyl transferase, elevated values of type II
      mitochondrial antibody and compatible histological lesions on liver biopsy. We
      found only ten case reports associating polymyositis and primary biliary
      cirrhosis. We hypothesize that hepatic and muscle mitochondrial dysfonction may
      be involved.

PMID- 8657673
TI  - [Munchhausen syndrome by proxy between two adults].
AB  - OBJECTIVES: Munchhausen syndrome by proxy has been well described in the case of
      a women producing or pretending symptoms in one of her children, leading that
      child to have numerous medical interventions. The case of two adults has been
      seldom described and the differences in the psychopathological features of the
      two situations are not well known. METHODS: We report our observation of a
      Munchhausen syndrome in a married couple where the wife injected tranquilizers to
      her husband, inducing repeated episodes of coma. Complex interactions between the
      pathological personalities of the husband and wife were present. Prominent
      features of the wife's personality included a narcissistic deficiency, poor
      defenses and signs of depression. DISCUSSION: Practioners should be aware of this
      peculiar pathology to avoid delayed diagnosis and its dramatic consequences.
      Appropriate medical, psychiatric, as well as legal measures must be taken.

PMID- 8657674
TI  - [Isolated invasive sphenoid aspergillosis].
AB  - Isolated aspergillosis of the sphenoid sinus is a difficult diagnosis because the
      often misleading clinical manifestations of this rare disease develop late. We
      report a case of invasive aspergillosis uniquely involving the sphenoid sinus
      revealed by clinical features suggesting pseudotumor of the pituitary in an
      immunocompetent man. A 71-year-old man presented sudden onset palsy of the
      abductor nerve of the left eye. Neuroimaging suggested a pseudotumor of the
      pituitary. Sphenoid sinusitis was discovered at surgery. The diagnosis of
      aspergillosis was provided by the histology examination of the sphenoid mucosa.
      Despite medical treatment with itraconazol alone then in combination with
      amphotericine B, the infectious process progressed to the pituitary, the
      cavernous sinus, the upper orbital fissue and the optic canal. Cure was finally
      achieved after a second surgical procedure to drain and aerate the sphenoid
      sinus. Aspergillosis of the sphenoid sinus is usually discovered due to
      neurological signs such as a cavernous sinus syndrome, pseudotumor of the
      pituitary or the orbit. Diagnosis is often made intraoperatively or at histology
      examination. Invasive forms almost always are seen in immunosuppressed subjects.
      In our case, the patient was immunocompetent and had no past history of
      sinusitis. The invasive sphenoid aspergillosis invaded bone tissue, the cavernous
      sinus and the meninges.

PMID- 8657675
TI  - [Mechanisms of atrial fibrillation. Recent progress and therapeutic
      implications].
AB  - Atrial fibrillation is usually due to multiple microreentry circuits. However, in
      some cases, the initial arrhythmia inducing the atrial fibrillation may be an
      abnormal automatism, or a macroreentry. The initial abnormalities may induce a
      desynchronization due to multiple macroreentry circuits. The main factors of
      atrial vulnerability are intraatrial conduction disturbances and changes in
      refractory periods. Critical mass and effects of autonomic nervous system may
      also play a role. Shortened refractory periods and decreased conduction velocity
      imply a short wavelength and an important arrhythmogenic risk. On the other hand,
      the longer the duration of atrial fibrillation, the more refractory periods will
      shorten and the more atrium will become vulnerable: atrial fibrillation tends to
      beget atrial fibrillation because of an electrophysiologic remodelage. In some
      cases atrial fibrillation, if its duration is long and if its rate is high, may
      be responsible for the development of a tachycardiomyopathy. The knowledge of
      atrial fibrillation mechanism may have interesting therapeutic implications such
      as resynchronization of the atria by stimulation or ablation, for example in the
      approaches comparable to the maze operation.

PMID- 8657677
TI  - [Cytomegalovirus colitis in acute renal failure].

PMID- 8657676
TI  - [Mixed cryoglobulinemia in hepatitis C virus infection].
AB  - Mixed cryoglobulinemia occurs in about half of all patients with chronic
      hepatitis C. Mixed cryoglobulinemia results from a lymphoproliferative disorder
      caused by polyclonal lymphocyte B proliferation (type III) or expansion of a B
      cell clone producing monoclonal Ig with anti-immunoglobulin activity (type II).
      Among the different viral infections studied to date (hepatitis A or B,
      cytomegalovirus, Epstein-Barr or herpes simplex virus) none except hepatitis C
      has been formally linked to cryoglobulinemia. The mechanisms involved with the
      hepatitis C virus and persistant cryoglobulinemia are unknown. Several studies
      have shown that the hepatitis C virus plays a distinct role in the pathogenesis
      of cryoglobulinemia. The high content of anti-HVC antibodies and viral RNA in the
      cryoprecipitates suggests that entire viral particles or encapsidized viral RNA
      may be involved. Viral variability over time and within the same individual might
      be responsible for repeated antigenic stimulation of the immune system leading to
      proliferation or expansion of the B-cell clone.

PMID- 8657678
TI  - [Streptococcus anginosus hepatic abscess].

PMID- 8657679
TI  - [Scorpion bites in southern France: experience at the poison-control centre of
      Marseilles].

PMID- 8657680
TI  - [Spontaneous and recent thrombosis of tetrafluoroethylene vascular prostheses
      secondary to progression of atherosclerosis of the lower limbs. 2 cases].

PMID- 8657681
TI  - [Dysfunction of implantable venous catheters inserted by the subclavian
      approach].

PMID- 8657682
TI  - [Features of clinical course of chronic nonspecific lung diseases in adolescents
      and youths in Uzbekistan].
AB  - 26985 and 459 young subjects of Uzbek nationality underwent preventive and
      inpatient examination to specify clinical characteristics of chronic nonspecific
      diseases of the lungs. These were characterized by slight subjective symptoms,
      poor informative value of general clinical tests, pronounced changes in lung
      ventilation, cytology of bronchoalveolar lavage, bronchologic and immunologic
      parameters. It is evident that Uzbek adolescents and youths suffering from
      chronic nonspecific pulmonary diseases develop homeostatic disorders. This
      contradicts the established views on young age as most favourable biologically
      and for maximal adaptation.

PMID- 8657684
TI  - [Tuberculosis in patients with HIV infections and AIDS].
AB  - As shown by tuberculosis screening in HIV-infected and AIDS subjects performed in
      the Moscow Anti-AIDS Center from 1989-1994, tuberculosis morbidity in the above
      subjects is 17.3 per 1,000. Mean age of the tuberculosis subjects was 34 years.
      Most of them were males with acute generalized pulmonary tuberculosis which
      coursed malignantly and resulted in deaths of progressive tuberculosis in 12 of
      18 patients within 15 months. Onset of tuberculosis in HIV-infected subjects is
      attributed to activation of endogenic infection in parallel with T4-lymphocyte
      depletion and deterioration of cellular immunity.

PMID- 8657685
TI  - [Treatment of patients with pulmonary tuberculosis and mental disorders].
AB  - In combined treatment of pulmonary tuberculosis and mental disease cessation of
      bacterial discharge was achieved in 79.5%, caverns closure in 73.8% of patients.
      The above percentage for chronic destructive tuberculosis reached 51 and 5.8%,
      respectively. However, positive results did not persist long

PMID- 8657683
TI  - [Characteristics of the course and treatment of pulmonary tuberculosis associated
      with nonspecific respiratory diseases in children].
AB  - Specific features of intrathoracic tuberculosis course, outcomes and treatment
      are outlined for 109 children. In 59 of them tuberculosis was associated with
      nonspecific respiratory diseases (NRD). 28.8%, 25.4%, 18.6, 27.2% of patients had
      cystic hypoplasia, chronic hypoplasia, recurrent pneumonia, recurrent bronchitis,
      respectively. Complicated course of tuberculosis occurred 2 times more frequently
      in its combination with NRD (71.2%). Destruction and discharge of bacteria were
      recorded in 49.2 and 47.5% of patients, respectively. Undulating running was 3.4
      and side effects 1.6 times more frequent. Tuberculous children with NRD need
      longer antituberculous therapy using wide-spectrum antibiotics, symptomatic and
      exercise treatment, massage, surgical intervention if necessary. Complete
      resolution of lung lesions in NRD children were seen 4.8 times less frequently.
      In case of late diagnosis 54% of them retained residual changes in the form of
      lung tissues fibrosis, calcified foci in the lungs and lymph nodes.

PMID- 8657686
TI  - [Organizational aspects of laboratory diagnosis of tuberculosis].

PMID- 8657687
TI  - [Significance of immunologic testing of patients in surgery of pulmonary
      tuberculosis].
AB  - Immunological testing of surgical patients with specific pulmonary tuberculosis
      revealed specific immunodeficiency in 68% of cases which appeared at higher risk
      of postoperative complications. A scheme of a simple immunological testing by 2
      reactions is provided.

PMID- 8657688
TI  - [Immune status of middle-aged and aged patients with tuberculosis].
AB  - After examination of 165 tuberculous patient of presenile and senile age, 150
      young patients, 65 healthy presenile and senile donors, 56 young healthy donors
      it was established that young and aged healthy donors differ by some parameters
      of T-cell immunity (inhibited blast-transformation response to PHA, reduced
      number of T-helpers, high suppressive activity of induced Con-A. Young
      tuberculous patients differ from their healthy counterparts by a variety of
      immunological parameters (low T-lymphocyte and helper count, poor blast
      transformation, increased number of T-suppressors and induced ConA suppression, B
      lymphocyte count and serum IgG level). Immunological reactivity is the least in
      aged tuberculous patients. Compared to aged healthy donors they have reduced
      number of T-lymphocytes, T-helpers, inhibited PHA response and IL-2 synthesis,
      greater count of T-suppressors, enhanced induced ConA suppression. B-cell
      immunity was similar in young and aged patients. Antituberculous immunity
      reactions were weaker than in young patients.

PMID- 8657689
TI  - [Bronchoscopic diagnosis of central peribronchial lung cancer in silicosis and
      silicotuberculosis].
AB  - Examination of 315 lung cancer patients with silicosis or silicotuberculosis gave
      grounds for recognition of 3 variants of bronchial stenosis. The efficacy of
      bronchoscopic techniques was related both to anatomic variant of the tumor and
      primary tumor position against the involved bronchus lumen. Central peribronchial
      cancer in silicosis and silicotuberculosis has specific features: combination of
      true tumor stenosis with false rigidity of the trachea and large bronchi,
      advanced scar anthracotic deformity of the bronchi and diffuse atrophy of
      bronchial mucosa, distinctive pattern of metastatic spreading.

PMID- 8657690
TI  - [Evaluation of clinical significance of tuberculin sensitization in patients with
      lung cancer].
AB  - Immunological and morphological findings were compared for 85 patients with lung
      cancer. Tuberculin sensitization was found to reflect the activity of antitumor
      immunity. The proportion humoral to cellular response to tuberculin and the
      intensity of these responses in lung cancer patients provide significant
      information on tumor histology and stage.

PMID- 8657691
TI  - [Economical aspects of diagnosis of tuberculosis in groups at risk based on
      questionnaire screening].
AB  - Social changes in Russia gave rise to appearance of new groups at risk to develop
      tuberculosis: refugees, homeless, migrants, etc. not covered by planned
      antituberculous measures. The design of a computer insurance policy base on
      regional population will promote quicker creation of risk groups, estimation of
      check-up frequency, saving of financial resources.

PMID- 8657692
TI  - [Eosinophilic pneumonia: course and prognosis].
AB  - Clinical manifestations of eosinophilic pneumonia (EP) are characterized basing
      on examination of 40 patients aged 19-65 years. The disease arose primarily due
      to chemicals, first of all, to medicinal agents. Eosinophils were found in
      peripheral blood, on cytogram of bronchoalveolar lavage, lung biopsies. The
      patients received corticosteroids, desensitization drugs, underwent
      plasmapheresis. All the patients responded, though 20 of the 30 evaluated
      patients developed later recurrences.

PMID- 8657693
TI  - [Oxidative metabolism changes in respiratory tract cells of guinea pigs during
      natural development of experimental tuberculosis and under specific
      chemotherapy].
AB  - 108 guinea pigs were infected with M-tuberculosis 2 weeks later 36 of them were
      put on treatment with rifampicin and isoniazid, the rest served as untreated
      control. The comparison was made of mixed population of all the cells isolated
      from bronchoalveolar lavage versus pure fraction of alveolar macrophages (AM) by
      spontaneous and BCG killed culture-stimulated NBT-test, activity of superoxide
      dismutase and catalase, levels of malonic dialdehyde. Estimations were conducted
      1 day, 1, 2 and 6 weeks after inoculation in untreated animals and after 1 months
      of treatment in treated animals. AM lost ability for stimulation to the end of 24
      h period since inoculation. 1-2 weeks later metabolic depression and complete
      areactivity occurred. Mixed population within postinoculation week 1 mobilized
      its defense potential. In extensive generalized tuberculosis all the cells of the
      respiratory tract worked for self-defense and lost protecting abilities. Specific
      chemotherapy reestablished functional status of both AM and cell population on
      the whole.

PMID- 8657694
TI  - [S and R forms of Mycobacterium tuberculosis as a problem of producing cloned and
      phenotypically competent strains].
AB  - The authors suggest that animals and humans carry M. tuberculosis in S form.
      These mycobacteria are virulent, do not form conglomerates and represent
      biologically most potent form. The state of R-form M. tuberculosis results from
      their culturing on artificial culture media which fail to secure compatible
      conditions for cells. M. tuberculosis S-form is convenient for microbiological
      and molecular-genetic research. The authors offer a method of biological
      production of single M. tuberculosis in S form.

PMID- 8657695
TI  - [Biological characteristics of mycobacterial agent in homeless patients with
      pulmonary tuberculosis].
AB  - 133 homeless subjects with pulmonary tuberculosis were examined microbiologically
      in Moscow Tuberculosis Hospital N 7 in 1993-1994. In most of the examinees the
      disease was advanced with destruction and intensive bacterial discharge (100
      10,000 microbes in the sample). New-onset cases discharged mycobacteria with
      multiple drug resistance. Acquired drug resistance was registered in 83.8% of
      previously treated patients, 73% of them had resistance to 2-6 drugs. Isoniazid-,
      rifampicin- and streptomycin- resistant were 48.6, 33.8 and 63.5% of the
      examinees, respectively.

PMID- 8657696
TI  - [Immunotropic activity of antimicrobial agents used in tuberculosis].
AB  - Mice with experimental tuberculosis were given isoniazid, rifampicin,
      erythromycin, cefotaxime, ofloxacin. Erythromycin, cefotaxime and ofloxacin
      enhanced macrophage activity if their course did not exceed 2-4 weeks. Isoniazid
      and rifampicin for a short time inhibited macrophage activity then stimulated it.
      These findings led the authors to the conclusion that erythromycin, cefotaxime
      and ofloxacin must be used only in short courses.

PMID- 8657698
TI  - [State of anti-infection defense in patients with chronic bronchitis].
AB  - Cellular and humoral antiinfection defense, frequency and severity of microbial
      infection were evaluated in patients with chronic nonobstructive and obstructive
      bronchitis. Systemic approach and analysis demonstrated that in chronic
      bronchitis there appeared shifts in cellular and humoral defense, functional
      dissociation of the above parameters, defects in intra- and intersystem
      compensation. Thus, in chronic bronchitis antiinfection defense needs
      immunocorrective therapy which is especially appropriate in bronchial obstruction
      and persistent infection of peripheral blood.

PMID- 8657697
TI  - [Tracheal suture with a monofilament thread in animal experiments].
AB  - Interrupted and continuous sutures were used in formation of tracheo-tracheal
      anastomosis in 13 guinea pigs. Insoluble prolene thread served as suturing
      material. Histologically, at the site of interrupted sutures there were
      structural changes of the tracheal wall in the form of lacunar dissolving of the
      cartilage and large granulomas of foreign bodies around the knot. Cartilaginous
      layer at the site of the continuous suture remained unchanged.

PMID- 8657699
TI  - [Methodical directions for grouping patients to be treated at tuberculosis
      hospitals].

PMID- 8657700
TI  - [Temporary occlusion of the bronchi in the treatment of complicated pulmonary
      tuberculosis].

PMID- 8657701
TI  - [A case of steroid tuberculosis in systemic scleroderma].

PMID- 8657702
TI  - [Current status of research on molecular genetics of mycobacteria].

PMID- 8657704
TI  - [Epidemiological situation of tuberculosis in Russian Federation and Moscow in
      1994].

PMID- 8657703
TI  - [Role of occupational factors in the incidence and course of respiratory system
      tuberculosis in fishery workers in the South Far East].
AB  - Tuberculosis morbidity among fishery workers in the South of Russian Far East
      remains high. Moreover, it is higher in fishermen working in the sea than in
      those who are engaged in fish-factories. This conclusion on fishing as a factor
      of tuberculosis risk was made basing on the results of 91 patients with
      tuberculosis of the respiratory organs. 65.9% of them were members of fishing
      ship's crew (group 1), 34.1% were workers of fish-factories (group 2). Pulmonary
      infiltrative tuberculosis running with exudation was typical for both groups, but
      group 1 subjects developed destruction of pulmonary tissue and discharged
      bacteria significantly more frequently. They had more compromised cellular
      immunity.

PMID- 8657705
TI  - Readmission of older heart failure patients.
AB  - The purpose of this article is to provide an overview of the literature on
      factors associated with hospital readmission of older heart failure patients.
      Important factors reported to be related to rehospitalization are
      sociodemographic and medical factors, premature discharge, failing support
      system, medication-related problems and noncompliance. To prevent readmission,
      interventions in the area of discharge planning, patient education and follow-up
      are recommended.

PMID- 8657706
TI  - Stress management for the cardiovascular patient: a look at current treatment and
      trends.
AB  - Recent research findings in psychoneurobiology are increasing our clinical
      knowledge of how emotions and mental stress impact the cardiovascular system.
      Clinical trial results strongly suggest that morbidity and mortality in cardiac
      patients can be improved when stress management is a part of a comprehensive
      treatment plan. This article discusses the state of stress management in current
      treatment and examines some of the newer interventions and techniques being used
      to address this risk factor. Recommendations for integration of stress reduction
      into cardiovascular treatment are outlined, with an emphasis on the role of the
      nurse.

PMID- 8657707
TI  - Women's compliance with cardiac rehabilitation programs.
AB  - As the incidence of cardiovascular disease in women increases, the process of
      cardiac rehabilitation in women is becoming increasingly important to nurses.
      Specifically, the issue of women's compliance with cardiac rehabilitation needs
      to be addressed by nurses. Most past and current research on cardiac
      rehabilitation and compliance with rehabilitation programs has been conducted on
      male subjects and cannot be accurately generalized to the female population. This
      article reviews current literature which addresses the issues of heart disease in
      women, cardiac rehabilitation and compliance in the general population, gender
      differences in cardiac rehabilitation, and compliance of women in cardiac
      rehabilitation.

PMID- 8657708
TI  - Management of venous thromboembolic (VTE) disease--Part II: Treatment.

PMID- 8657709
TI  - Cholesterol levels: coronary heart disease and mortality in men and women.

PMID- 8657710
TI  - Refusing to pay for health care: Part I (of III)--Evolution of the third-party
      payment system.

PMID- 8657711
TI  - Diagnosing ischemia from the bedside monitor.

PMID- 8657712
TI  - Pain management facilitates early postoperative recovery.

PMID- 8657713
TI  - Sleep disturbances post coronary artery bypass surgery.
AB  - The purpose of this study was to describe the nature and frequency of sleep
      pattern disturbances in patients post coronary artery bypass (CABG) surgery. An
      exploratory design using telephone interviews at one week, one month, three
      months and six months was used to describe the incidence and nature of sleep
      disturbances post CABG surgery. Forty-nine patients completed all four
      measurement times. More than half of the patients reported sleep disturbances at
      each measurement time. Sleep disturbances during the first month post CABG were
      reported to be the result of incisional pain, difficulty finding a comfortable
      position and nocturia. Although less frequent over time, these problems persisted
      for six months. The authors propose nursing interventions to improve sleep post
      CABG surgery. Implications for continuing research are discussed.

PMID- 8657714
TI  - Human polyoma virus infection of renal allografts: histopathologic diagnosis,
      clinical significance, and literature review.
AB  - Human polyoma virus infection was diagnosed by a needle biopsy of the allograft
      in two kidney transplant recipients. Viral infection was initially suggested by
      the occurrence of markedly enlarged tubular epithelial cells with nuclear atypia
      and chromatin basophilia. Confirmatory evidence was obtained by
      immunohistochemistry in both cases, and electron microscopy in one instance. Case
      1 presented as a refractory interstitial nephritis and underwent allograft
      nephrectomy. Case 2 showed viral infection concurrent with acute cellular
      rejection. The rejection initially responded to treatment, but recurred twice on
      subsequent followup. A review of the literature indicates that asymptomatic
      infection, ureteric stricture and hemorrhagic cystitis are other possible
      manifestations of polyoma virus in the human urogenital tract.

PMID- 8657715
TI  - A quantitative evaluation of mucosal eosinophils in the pediatric
      gastrointestinal tract.
AB  - Evaluation of the mucosal eosinophil content is important in the interpretation
      of endoscopic biopsies, as high eosinophil densities might reflect allergic
      gastrointestinal disease. Reference ranges gleaned from the literature have an
      upper limit of normal varying from 6 to 20 eosinophils per 400 x high power
      field. Preliminary data suggest a geographic variation with higher eosinophil
      counts in the southern United States. We examined intestinal tract mucosa from 44
      infants and children who died suddenly and unexpectedly in northeastern Texas.
      Subjects ranged in age from 3 wks to 17 yrs and were without known
      gastrointestinal disease. Using formalin-fixed, hematoxylin and eosin-stained 4
      microns sections, intramucosal eosinophils were counted in ten consecutive high
      power fields and the mean eosinophil count determined. Twenty-three subjects
      (52%) had counts of > 20 eosinophils/high power field from at least one site.
      There was no correlation with age, sex, season, or cause of death. In a subset of
      11 subjects, more extensive sampling showed the cecum and appendix to have the
      highest concentration of eosinophils and relatively low counts in the stomach and
      distal large intestine. These observations correlate with our impression that
      increased numbers of eosinophils, particularly in the proximal colon, are a
      common feature of otherwise unremarkable pediatric endoscopic biopsies. Efforts
      to distinguish the proportion of activated eosinophils in B5-fixed mucosal
      biopsies using the EG2 monoclonal antibody were unsuccessful, as this antibody
      does not appear specific for activation in B5-fixed tissue. Mucosal eosinophil
      counts should be interpreted with caution in geographic areas where a high
      background count is endemic.

PMID- 8657716
TI  - Hodgkin's disease in the Philippines.
AB  - Hodgkin's disease (HD) varies in prevalence, morphologic findings, and
      association with Epstein-Barr virus (EBV) in different parts of the world. HD in
      the Philippines and its relationship to EBV has not been studied. We reviewed all
      cases of HD in the Philippines for the years 1989 to 1994, diagnosed at three
      large hospitals in Manila and Cavite. During this study period, 68,121 surgical
      specimens were accessioned, of which there were 21 cases (0.03%) of HD. There
      were 11 males and nine females; sex was unknown in one case. The median age was
      22 yr (range, 11 to 64 yr). Thirteen cases occurred in patients less than 30 yr
      old, including six of 11 males and seven of nine females. The remaining cases
      were distributed among other age groups, with five cases in males occurring after
      the age of 50 yr. There were 10 cases of nodular sclerosis, nine cases of mixed
      cellularity, and two cases of nodular lymphocytic predominance. Nine cases were
      positive for EBV latent membrane protein: six of nine mixed cellularity and three
      of 10 nodular sclerosis. In situ hybridization confirmed the immunohistochemical
      results, and revealed EBV RNA predominantly in Reed-Sternberg and Hodgkin cells.
      A few small lymphocytes were also positive in many cases. These results suggest
      that HD is uncommon in the Philippines, similar to other Asian countries such as
      Japan. However, the age distribution and histologic subtypes of HD in the
      Philippines seem to be more similar to that of Western industrialized countries
      such as the United States. EBV was present in a subset of cases, most frequently
      in mixed cellularity.

PMID- 8657717
TI  - Cytometric measurement of cell proliferation in echo-guided biopsies from focal
      lesions of the liver.
AB  - Increased proliferative activity determined in surgical specimens of
      hepatocellular carcinoma (HCC) has been associated with tumor grade and patient
      survival. The measurement of cell proliferation in echo-guided biopsies of small
      focal liver lesions might provide useful information for the early recognition of
      malignancy and for predicting the aggressiveness of small HCCs. We assessed the
      diagnostic and prognostic value of cell proliferation in 91 echo-guided needle
      biopsies of focal liver lesions using the monoclonal antibody Ki-67, which
      detects a human nuclear antigen that is present in proliferating cells.
      Measurements were performed by image cytometry as the percentage of Ki-67
      positive hepatocytes nuclei over total hepatocyte nuclei in the biopsy. At the
      histological examination, 27 lesions were diagnosed as chronic hepatitis, 10 as
      cirrhosis, 11 as macroregenerative nodule, and 43 as HCC in cirrhotic liver.
      Although the highest Ki-67 values (> 20%) were found in less-differentiated HCCs,
      most well-differentiated HCCs and nine borderline nodules were completely devoid
      of Ki-67-positive hepatocytes. A sustained Ki-67 labeling (up to 16%) was found
      in hepatitis and cirrhosis, similar to that found in several malignant tumors. In
      the HCC subset, Ki-67 labeling was strongly correlated to the Edmondson-Steiner
      histological grade. However, survival analysis did not indicate a better outcome
      for those patients with low-proliferating tumors.

PMID- 8657718
TI  - Post-lung transplant biopsies: an 8-year Loyola experience.
AB  - A total of 125 transplant procedures involving the lung have been performed at
      Loyola University of Chicago in 120 patients. There were 67 single (40 right, 27
      left), 44 bilateral single, 2 double lung, and 12 heart-lungs (HL) transplant
      procedures. This paper summarizes the pathologic findings in 565 transbronchial,
      102 endobronchial, 20 open lung, and 92 endomyocardial biopsies and compares them
      with the recommendations in the published literature. The lung biopsies were
      evaluated according to the Working Formulation, Lung Rejection Study Group,
      International Society of Heart Transplantation. In transbronchial biopsies, all
      of which were from the transplanted lungs, the number of alveolated lung
      fragments ranged from 0 to 14 (mean, 5). Two hundred twelve biopsies showed no
      rejection, 113 had minimal rejection, 133 had mild rejection, 34 had moderate
      rejection, and 1 had severe acute rejection. Active airway damage (Grade B) was
      seen in 48 biopsies, which were graded from minimal to severe based on the amount
      of inflammation. Chronic rejection (Grade C) was diagnosed in 23, chronic
      vascular rejection (Grade D) in 8, and acute vasculitis (Grade E) in 9 biopsies.
      Routine trichrome and elastic van Gieson stains did not add to the diagnosis. All
      biopsies were routinely stained with immunoperoxidase for cytomegalovirus.
      Cytomegalovirus was diagnosed in 84 biopsies, 54 by both H&E and
      immunoperoxidase, 23 by immunoperoxidase alone, and 5 by H&E alone. The
      endobronchial biopsy of the anastomotic site had nonspecific inflammation in 46
      biopsies. Twenty-nine had infection with a specific organism, Aspergillus and
      Candida in each of 8 biopsies by Gomori's methenamine silver stain,
      cytomegalovirus in 7 (4 by H&E and immunoperoxidase; 3 by immunoperoxidase),
      bacteria in 4, and fungal hyphae in 2 biopsies. In the 12 patients with heart
      lung transplants, a total of 92 endomyocardial, 35 transbronchial, and 1
      endobronchial biopsies were obtained. Acute rejection was seen only in 2
      endomyocardial biopsies, whereas the transbronchial biopsy showed acute mild or
      moderate rejection in 10, chronic rejection in 1, and cytomegalovirus infection
      in six biopsies. We conclude that: (a) all biopsies with alveolated lung
      parenchyma can be evaluated for rejection and infection yielding clinically
      significant diagnoses; (b) sections from three levels stained by H&E are
      essential for evaluation; (c) routine Gomori's methenamine silver, elastic van
      Gieson, and trichrome stains are not required for transbronchial biopsy, however,
      routine Gomori's methenamine stain is recommended for all anastomotic site
      biopsies; (d) routine immunoperoxidase for cytomegalovirus is extremely helpful;
      (e) Grade B rejection should be further graded; and (f) endomyocardial biopsy
      played no significant role in the management of heart-lung recipients.

PMID- 8657719
TI  - The use of archival frozen tumor tissue imprint specimens for fluorescence in
      situ hybridization.
AB  - Fluorescence in situ hybridization for the detection of gene amplification or
      deletion has great promise as a method of providing diagnostic or prognostic
      information from tumor specimens. Fine needle aspiration samples or tumor tissue
      imprints are much easier to use and provide better results than paraffin
      sections, however, these materials are rarely archived and it may take many
      months to accumulate enough specimens for a study. Archival breast carcinoma
      tumor tissue samples, some stored frozen for several years, were used to prepare
      tumor tissue touch imprints on glass microscope slides. The imprints were
      subjected to fluorescence in situ hybridization analyses utilizing a biotin-dUTP
      labeled genomic DNA probe for the cyclin D1 gene (CCND1/PRAD1) and a digoxygenin
      labeled chromosome 11 alpha-satellite probe to control for chromosomal copy
      number. Amplification of CCND1 was easily detectable in frozen tissue imprints.
      The results indicate that both cytologic morphology and hybridization capacity
      are well preserved in archived frozen tissue and easily permit its use for in
      situ hybridization experiments. The ability to use stored frozen tumor tissue for
      molecular morphologic analysis should allow more rapid assessment of fluorescence
      in situ hybridization as a potential adjunct for tumor analysis by the surgical
      pathologist.

PMID- 8657720
TI  - Distribution of basement membrane components in normal adipose tissue and in
      benign and malignant tumors of lipomatous origin.
AB  - Normal adipose tissue as well as 13 benign and 17 malignant lipomatous tumors
      (lipomas, hibernomas, lipoblastomas, and liposarcomas) were immunohistochemically
      analyzed for their expression of the basement membrane components collagen IV,
      laminin, heparan sulfate proteoglycan, and fibronectin. Monovacuolar cells in
      normal white fat tissue and in lipomas generally exhibited a distinctive
      pericellular basement membrane composed of collagen IV and laminin, whereas
      heparan sulfate proteoglycan and fibronectin were almost completely missing. In
      brown fat tissue and hibernomas the characteristic multivacuolated cells differed
      from the monovacuolated white fat cells by the additional content of heparan
      sulfate proteoglycan and fibronectin and the more intensive staining for the
      other components tested. In contrast, multi-/monovacuolated cells in
      lipoblastomas exhibited no characteristic immunohistochemical feature because
      they reacted irregularly and only faintly for collagen IV, laminin, and heparan
      sulfate proteoglycan. Spindle cell areas in benign lipomatous tumors displayed
      more fibronectin than laminin and heparan sulfate proteoglycan indicating a
      "preadipose" fibroblast-like cellular differentiation. In liposarcomas, only well
      differentiated lipoma-like neoplasms revealed a basement membrane pattern
      resembling that of white fat tissue. Otherwise, in nonlipoma-like liposarcomas, a
      marked decrease particularly of collagen IV staining was evident. Poorly
      differentiated liposarcomas mostly failed to express any of the basement membrane
      components, but showed a relative increase of fibronectin. Our results provide
      evidence that the staining pattern of basement membrane components parallels the
      histogenetic derivation of benign lipomatous tumors from either brown or white
      adipose tissue and, additionally, may reflect such a derivation in liposarcomas.

PMID- 8657721
TI  - Langerhans cell histiocytosis of the thyroid: a series of seven cases and a
      review of the literature.
AB  - Langerhans cell histiocytosis is a rare disorder, with a few reports describing
      isolated thyroid gland involvement. We report seven cases, which included four
      females and three males ranging in age from 2 months to 55 years, with a median
      age of 37 years. Histologically, the cases demonstrated either diffuse or focal
      involvement of the thyroid gland by Langerhans cell histiocytes, characterized by
      bean-shaped, lobated, folded nuclei. In association with the histiocytic
      infiltrate, there was a prominent eosinophilic cellular component, as well as
      destruction of the thyroid follicles. All cases occurred in a background of
      lymphocytic thyroiditis. One case demonstrated adenomatoid nodules, whereas
      another had a microscopic papillary carcinoma. Immunohistochemical staining
      demonstrated positive reactivity with S-100 protein, lysozyme, and KP-1. Four
      patients with isolated thyroid disease, treated by surgical resection alone, are
      alive without systemic disease from 3 to 19 years after initial presentation. The
      three patients with systemic disease died within 1 year of the initial diagnosis
      with disease-related complications. Localized disease portends a favorable
      prognosis as compared to the thyroid involvement as part of systemic disease.

PMID- 8657722
TI  - Immunohistochemical detection of the type I interferon receptor in human fetal,
      adult, and neoplastic tissues.
AB  - We have used the monoclonal antibody IFNaR3 that recognizes the alpha subunit of
      the type I interferon (IFN) receptor to study the expression of this receptor in
      a large series of normal human adult and fetal tissues, as well as in a large
      number of tumors of diverse origin. Among fetal tissues (8-20 weeks) the type I
      IFN receptor was expressed in liver, striated muscle, epidermis, renal tubules,
      choroid plexus of the CNS, and epithelia of different origins (bronchial,
      gastrointestinal, and pancreatic). Adult tissues showed a similar pattern that
      includes epithelia from salivary ducts, genital tract, bladder, breast, as well
      as germinal centers of lymph nodes, tonsils, and spleen. The study of a large
      series of tumors revealed that the type I IFN receptor is expressed in most, but
      not all, melanomas, bladder, kidney, small bowel, lung, and breast
      adenocarcinomas. The majority of lymphomas, sarcomas, and endocrine tumors proved
      negative. These results support the concept that the type I IFN receptor is
      rather ubiquitously expressed in normal and malignant epithelial tissues. More
      interestingly, the expression of the type I IFN receptor was not detected in all
      tumors, raising the question of whether some cases may fail IFN alpha therapy due
      to the lack of receptor expression. This report demonstrates that the IFNaR3
      monoclonal antibody can be used for receptor detection in paraffin-embedded
      sections and it could represent a useful tool in the search for correlations
      between IFN alpha response and receptor expression in different diseases.

PMID- 8657723
TI  - Correspondence re: JA Emery, SS Spanier, G Kasnic Jr, NS Hardt. The synovial
      structure of breast-implant-associated bursae. Mod Pathol 7:728, 1994.

PMID- 8657724
TI  - Correspondence re: AS Jovanovic, CM McLachlin, WR Welch, CP Crum. Postmenopausal
      squamous atypia: a spectrum including "pseudo-koilocytosis." Mod Pathol 8:408,
      1995.

PMID- 8657725
TI  - Academic anatomic pathology--a perspective.

PMID- 8657726
TI  - c-myc amplification in hepatocellular carcinoma predicts unfavorable prognosis.
AB  - Structural alterations and amplifications of the c-myc oncogene have been
      implicated in the pathogenesis and progression of several human neoplastic
      diseases. To study the role of c-myc amplification in human hepatocellular
      carcinomas (HCC), we analyzed 20 HCC using differential polymerase chain reaction
      (PCR). DNA used for differential PCR was extracted from formalin-fixed, paraffin
      embedded tissue obtained by radiographically directed needle aspiration biopsy.
      Differential PCR reactions included sets of primers for c-myc and a control gene,
      dopamine D2 receptor (D2R), which yielded products of 150 bp and 110 bp,
      respectively. Evaluation of amplification was based on the relative concentration
      of c-myc and D2R PCR products. The c-myc amplification was detected in 10 of 20
      HCC. Cases with c-myc amplification tended to have higher histologic grade and
      were significantly (P = 0.05) associated with worse prognosis. Amplification was
      present in none of two Grade 1 tumors, seven of the fourteen Grade 2 tumors, and
      three of four Grade 3 tumors. The mean survival times (+/- SEM) for patients with
      and without c-myc amplification were 5.7 (+/- 1.8) and 13.8 (+/- 2.6) months,
      respectively. These results indicate that c-myc amplification in HCC can be
      evaluated by differential PCR of needle biopsy specimens, and is an unfavorable
      prognostic indicator.

PMID- 8657727
TI  - Determination of S-phase cells by in situ hybridization for histone H3 mRNA in
      hepatocellular carcinoma: correlation with histologic grade and other cell
      proliferative markers.
AB  - Cell proliferation has a crucial importance in biologic potentialities of tumor
      cells. Several methods to measure S-phase fraction in tumor samples have been
      developed, with considerable limitations in practical applications. Histones are
      nucleosomal proteins that are responsible for packaging chromosomal DNA into
      nucleosomes. The expression of histone genes is a fundamental step constituting
      the process of cell proliferation. Because histone H3 mRNA accumulates in the
      cytoplasm during S-phase, and then decreases as cells approach G2-phase,
      demonstration of histone H3 mRNA expression in a tumor cell population may
      represent responsible S-phase fraction. Thus, we have assessed S-phase fraction
      by nonisotopic in situ hybridization for histone H3 mRNA in paraffin sections of
      hepatocellular carcinomas (HCCs); then, we compared this with the histologic
      grades and other cell proliferative markers. In contrast to radioisotopic
      detection, signals were distinctly visualized, and quantitation of the stained
      cells was easily carried out. Histone H3 labeling index (LI) significantly
      correlated with other cell proliferative markers, including Ki-67 (MIB-1) and
      PCNA immunostainings, and mitotic index. In addition, a statistically significant
      correlation was seen between histone H3 LI and histologic grades of
      differentiation, i.e., histone H3 LI being higher in less-differentiated HCCs.
      Furthermore, histone H3 LI/Ki-67 LI ratio was significantly higher in the
      moderately and poorly differentiated subtypes (including one case of the
      undifferentiated subtype) than in well-differentiated HCCs. By using this
      nonisotopic in situ hybridization technique, it becomes possible to assess
      rapidly, retrospectively, safety, and easily a malignant potentiality of HCCs in
      paraffin-embedded tissues.

PMID- 8657728
TI  - Depopulation of highly excited singlet states of DNA model compounds: quantum
      yields of 193 and 245 nm photoproducts of pyrimidine monomers and dinucleoside
      monophosphates.
AB  - Formation of uracil and orotic acid photodimers, uridine and 5'-UMP
      photohydrates, TpT photodimers and (6-4)photoproducts, dCpT photohydrates and (6
      4)photoproducts and UpU, CpC and CpU photohydrates were studied in neutral
      deoxygenated aqueous solution at room temperature upon irradiation at either 193
      or 254 nm. The photoproducts were identified and quantified and the contribution
      from photoionization to substrate decomposition, using lambda irr = 193 nm, was
      separated. The ratio of the quantum yields of respective stable products, eta =
      phi 193/phi 254, is indicative of the yield of internal conversion from the
      second to the first excited singlet state, S2-->S1. For the observed photodimers
      eta decreases from 0.94 for uracil to 0.7 for TpT and further to 0.55 for orotic
      acid. For the (6-4)photoproducts of TpT and dCpT eta = 0.5-0.8 and for the
      photohydrates in the cases of UpU, CpC, CpU and dCpT eta ranges from 0.55 to 1.

PMID- 8657729
TI  - Intensity-dependent enzyme photosensitization using 532 nm nanosecond laser
      pulses.
AB  - The intensity dependence of the rose bengal (RB)-photosensitized inhibition of
      red blood cell acetylcholinesterase has been studied experimentally and the
      results compared to a quantitative excitation/deactivation model of RB
      photochemistry. Red blood cell membrane suspensions containing 5 microM RB were
      irradiated with 532 nm, 8 ns laser pulses with energies between 1 and 98.5 mJ. A
      constant dose (7 J) was delivered to all samples by varying the total number of
      pulses. At incident energies greater than approximately 4.5 mJ/pulse, the
      efficiency for photosensitized enzyme inhibition decreased as the energy/pulse
      increased. The generation of RB triplet state was monitored as a function of
      laser energy and the triplet-triplet absorption coefficient was determined to be
      1.9 x 10(4) M-1 cm-1 at 530 nm. The number of singlet oxygen molecules produced
      at each intensity was calculated from both the physico-mathematical model and
      from laser flash photolysis results. The results indicated that the
      photosensitized inhibition of acetylcholinesterase was exclusively mediated by
      singlet oxygen, even at the highest laser intensities employed.

PMID- 8657730
TI  - Phototoxicity of some bromine-substituted rhodamine dyes: synthesis,
      photophysical properties and application as photosensitizers.
AB  - The synthesis of some bromine-substituted rhodamine derivatives viz., 4,5
      dibromorhodamine methyl ester (dye 2) and 4,5-dibromorhodamine n-butyl ester (dye
      3) are reported. These dyes were synthesized to promote a more efficient cancer
      cell photosensitizer for potential use in in vitro bone marrow purging in
      preparation for autologous bone marrow transplantation. Spectroscopic and
      photophysical characterization of these dyes together with rhodamine 123 (dye 1)
      are reported in water, methanol, ethanol and also in a microheterogeneous system,
      sodium dodecyl sulfate. The possible mechanism of photosensitization is
      characterized in terms of singlet oxygen efficiency of these dyes. Singlet oxygen
      quantum yields for bromine-substituted dyes are in the range of 0.3-0.5 depending
      on the solvent. For dye 1 no singlet oxygen production is found. The photodynamic
      actions of these dyes in different cell lines are tested. It was found that dye 2
      and dye 3 are efficient photosensitizers and mediate eradication of K562, EM2,
      myeloid cell lines (CML) and the SMF-AI rhabdomyosarcoma line.

PMID- 8657731
TI  - Microenvironment effects on the excited state properties of psoralens: a clue to
      their photobiological activity.
AB  - The singlet and triplet excited state parameters (phi f, tau t and phi T) of
      psoralen (PSO) and derivatives 4,6,4'-trimethylangelicin (TMA) and 4,5',8
      trimethylpsoralen (TMP) show an extreme sensitivity to solvation in dioxane/water
      mixtures. These effects are attributed to the variation of the S1-->S0 internal
      conversion rate constant kic, which is the nonradiative deactivation path
      dominating their photophysical behavior. Depending on the compound, kic is very
      high, (approximately 1 x 10(10) s-1) in nonpolar solvents and then decreases to a
      low value (3 x 10(8) s-1), with increasing solvent polarity. This work shows that
      dioxane/water mixtures display the same solvent-induced changes in the electronic
      structure of psoralens during solvation as those induced by the biological
      microenvironment sensed by the drug's localization. This mixture matches the
      photophysical parameters of psoralens observed in protic and aprotic pure
      solvents, in micelles, in liposomes and in human serum low-density lipoproteins
      (LDL). They can be used to probe the solvating ability of the interaction site in
      macrocyclic hosts. A particular localization site, i.e. the more (TMA and TMP) or
      less (PSO) lipophilic sites found when in interaction with LDL, determines the
      amount of the triplet reactive state of psoralens and the molecular mechanism
      available for photoreaction: oxic (type I and type II) or anoxic (type III)
      pathways.

PMID- 8657732
TI  - Replication in UV-irradiated Caenorhabditis elegans embryos.
AB  - Replication continues in wild-type (but not rad mutant) Caenorhabditis elegans
      embryos even after exposure to massive fluences of UV radiation. It is of
      interest to elucidate the mechanism(s) for this "damage-resistant" DNA synthesis.
      In this study, DNA from unirradiated and UV-irradiated wild-type embryos was
      examined using the electron microscope. Large fluences of UV radiation (180 J m
      2) had little effect on either replication bubble size or distances between
      bubbles in wild-type embryos, indicating that the damage-resistant DNA synthesis
      was not grossly aberrant. Conversely, UV irradiation significantly decreased
      center-to-center distances between bubbles in excision-repair-deficient rad-3
      embryos. This suggests that the decreased DNA synthesis observed after UV
      irradiation in rad-3 embryos is due largely to blockage of elongation of DNA
      synthesis.

PMID- 8657733
TI  - Triplex-mediated, in vitro targeting of psoralen photoadducts within the genome
      of a transgenic mouse.
AB  - Light-activated psoralens can covalently modify DNA and are widely used to study
      nucleic acid secondary structure and mutagenesis. Sequence specificity can be
      added to the photoaddition reaction by attaching the psoralen to an
      oligonucleotide designed to recognize a double-stranded DNA binding site through
      formation of a triple helix. We have previously used this strategy to study
      targeted psoralen modification of a triplex binding site within the bacterial
      supF gene carried in viral genomes. In the present work we report the targeting
      of psoralen photoadducts in vitro to a specific site in the genome of a
      transgenic mouse. Both 10 base and 16 base oligonucleotide-psoralen conjugates
      were capable of sequence-specific modification of genomic mouse DNA, while a
      truncated 8 base conjugate was not. Light activation was necessary, and a dose
      dependence was demonstrated for target site modification and mutagenesis. The 10
      base conjugate rapidly found its target, with sequence-specific binding occurring
      after just 10 min incubation in the presence of mouse DNA. The ability to target
      psoralen photoadducts within mammalian genomes may prove useful in the study of
      chromatin structure and DNA repair. Moreover, this work may lead to potential in
      vivo applications of targeted psoralen modification.

PMID- 8657734
TI  - Fluorescence properties of isolated intact normal human corneas.
AB  - We have examined the fluorescence properties of excised intact normal human
      corneas from over a hundred donors, using synchronous excitation fluorescence
      spectroscopy. In some of the corneas from the donors, a fluorophore with an
      excitation band centered at 330 nm was observed. This fluorophore does not seem
      to correspond to the dityrosine moiety or to any photoproducts of tryptophan.
      Isolated corneas irradiated with light of 295 nm wavelength do not produce any
      fluorescent photoproducts, suggesting that the intact tissue has endogenous
      quenchers, radical scavengers and antioxidants that inhibit its photodamage. The
      non-tryptophan fluorophores that accumulate in some corneas thus appear to arise
      largely from the nonenzymatic glycosylation (glycation) of the constituent
      proteins as similar fluorophores are detected in the corneas of rats in which
      diabetes is induced.

PMID- 8657735
TI  - Structure-photodynamic activity relationships of a series of 4-substituted zinc
      phthalocyanines.
AB  - Radioiodinated zinc phthalocyanine including [125I]ZnPcI4 and differently
      sulfonated [65Zn]ZnPcS (ZnPcS4, ZnPcS3, ZnPcS2 and ZnPcS1.75, a mixture of
      adjacent di and 25% mono) were prepared in order to study cell uptake and release
      kinetics in EMT-6 cells. The same compounds were evaluated for their in vitro
      phototoxicity and the biological parameters were compared to partition
      coefficients to arrive at quantitative structure-activity relationships (QSAR).
      At 1 microM in 1% serum, at 37 degrees C, all dyes showed rapid cell uptake
      during the first hour followed by a slow accumulation phase. After 24 h, the
      highest cellular concentration was observed with the lipophilic ZnPcI4, followed
      by the amphiphilic ZnPcS2 and ZnPcS1.75. The hydrophilic ZnPcS4 and ZnPcS3 showed
      lower uptake. Dye release from dye-loaded cells during incubation in dye-free
      medium could reach up to 60% and was shown to depend mainly on the amount of drug
      incorporated rather than the type of compound. These results suggest that care
      should be taken in interpreting dye toxicity data, which involve in vitro cell
      manipulations in dye-free medium, particularly during in vitro-in vivo protocols.
      The EMT-6 cell survival after 1 h or 24 h incubation with 1 microM dye in 1%
      serum followed by exposure to red light was assessed by means of the colorimetric
      3-(4,5-dimethylthiazol-2-yl)-diphenyl-tetrazolium bromide (MTT) assay.
      Photocytotoxicities correlated inversely with the tendencies of the dyes to
      aggregate. Increased dye uptake by the cells also correlated with their
      activities, except for the lipophilic ZnPcI4, which showed the highest cell
      uptake but little phototoxicity. The QSAR between phototoxicity and the log of
      the partition coefficients (phosphate-buffered saline and n-octanol) gave a
      parabola with optimal partition values corresponding to the adjacent sulfonated
      ZnPcS2.

PMID- 8657736
TI  - Effect of photosensitizer delivery system and irradiation parameters on the
      efficiency of photodynamic therapy of B16 pigmented melanoma in mice.
AB  - Previous studies (Biolo et al., Photochem. Photobiol. 59, 362-365, 1994) showed
      that liposome-delivered Si(IV)-naphthalocyanine (SiNc) photosensitizes B16
      pigmented melanoma subcutaneously transplanted in C57 mice to the action of 776
      nm light. However, the efficacy of the phototreatment was limited by a lack of
      selectivity of tumor targeting by SiNc as well as by incomplete necrosis of the
      neoplastic mass. The present investigations show that the use of a different
      delivery system (Cremophor emulsion vs liposomes of
      dipalmitoylphosphatidylcholine) causes no significant increase in the selectivity
      of tumor targeting for three injected doses of SiNc (0.5, 1, 2 mg/kg). However,
      upon 776 nm light irradiation (300 mW/cm2; 520 J/cm2), the delay in the rate of
      tumor growth was maximal (7-8 days) for the highest naphthalocyanine dose. On the
      other hand, a remarkable improvement in the tumor response was obtained by
      inducing an intratumoral temperature increase to 44 degrees C immediately after
      PDT. The thermal effect appeared to be due to photoexcitation of melanin by 776
      nm light (550 mW/cm2; 520 J/cm2) and subsequent partial conversion of absorbed
      energy into heat.

PMID- 8657737
TI  - Benzophenothiazine and benzoporphyrin derivative combination phototherapy
      effectively eradicates large murine sarcomas.
AB  - The tumoricidal effects of photochemotherapy with two photosensitizers, 5
      ethylamino-9-diethylaminobenzo[a] phenothiazinium chloride (EtNBS) and
      benzoporphyrin derivative monoacid ring A (BPD-MA), were evaluated separately and
      in combination against the EMT-6 fibrosarcoma implanted subcutaneously in BALB/c
      mice. Animals carrying tumors 8-10 mm in diameter were divided into eight
      different groups (approximately 20/group) and subjected to various
      photoirradiation and drug conditions. The tumor response to photodynamic therapy
      (PDT) was measured as the mean tumor wet weight 2 weeks post-PDT. The combination
      treatment with 5.25 mg/kg EtNBS and 2.5 mg/kg BPD-MA followed by photoirradiation
      with 100 J/cm2 at 652 nm and then by 100 J/cm2 at 690 nm resulted in a 95%
      reduction in the average tumor weights compared to controls (no light, no drugs)
      with 76% of the mice being tumor free 2 weeks post-PDT. Because treatment with
      EtNBS or BPD-MA at twice the light dose and drug concentration resulted in either
      no significant reduction in tumor weights or increased the lethality of
      treatment, respectively, the data suggest that the enhanced PDT effect observed
      with the combination of drugs is synergistic rather than additive. Histology of
      tumors 24 h post-PDT with the combination of drugs showed nearly complete
      destruction of the tumor mass with little or no damage to the vasculature and no
      extravasation of red blood cells. There was no damage to the normal skin adjacent
      to the tumor. Fluorescence microscopy of EMT-6 cells incubated in vitro with the
      two photosensitizers revealed that they were localized to different intracellular
      compartments. The fluorescence pattern from frozen tumor tissue slices following
      the in vivo administration of the photosensitizers indicated a greater
      intracellular localization for EtNBS vs BPD-MA.

PMID- 8657738
TI  - The effect of purified extract of Fagopyrum esculentum (buckwheat) on protein
      kinases involved in signal transduction pathways.
AB  - The effect of a purified extract of the flowering herb of Fagopyrum esculentum
      (buckwheat) on various protein kinases involved in signal transduction was
      examined. We observed that buckwheat contains red fluorescent compounds having
      photosensitizing properties. Spectrophotometric analysis of the extract has
      indicated structural similarity to hypericin. Dose- and light-dependent
      inhibition of various protein kinases was observed. The purified buckwheat
      extract strongly inhibited two receptor-associated protein tyrosine kinases (EGF
      R and Ins-R) and a Ser/Thr kinase (PK-C) at an ng/ml concentration range.
      Selectivity was exhibited as a decreased sensitivity to cytosolic PTKs and
      protein kinase CK-2. The protein kinases are important components of the signal
      transduction pathway. Aberration of signal transduction is a hallmark of several
      proliferative diseases. Our results indicate that photosensitizing compounds in
      buckwheat are potential antiproliferative agents.

PMID- 8657740
TI  - Growth of cultured human bronchiogenic epithelioid CCD-14 Br cells and dermal
      fibroblasts, NB1 RGB treated with ginseng tetrapeptide and its isomer.
AB  - The configurations of the component amino acids in ginseng tetrapeptide 1
      isolated from Panax ginseng were determined by HPLC with an optical resolution
      column and the structure of 1 was established to be H-L-Val-gamma-D-Glu-D-Arg-
      Gly-OH. Synthesis of the ginseng tetrapeptide, 1, and of the configuration and
      conjugation isomers, H-L-Val-gamma-L-Glu-L-Arg-Gly-OH (2), H-L-Val-D-Glu- D-Arg
      Gly-OH (3), and H-L-Val-L-Glu-L-Arg-Gly-OH (4) was carried out by a solid-phase
      method using the Fmoc strategy. The effects of 1-4 on the proliferation of baby
      hamster kidney (BHK)-21 cells, normal female bronchiogenic epithelioid (CCD-14
      Br) cells, and normal human epidermal fibroblast (NB1 RGB) were examined. Only 1
      showed 32 and 23% enhancement of BHK-21 and human CCD-14 Br cells growth,
      respectively, at a concentration of 13.6 microM and 41% enhancement of NB1 RGB
      cells growth at a concentration of 32 microM under the conditions employed. It
      was shown that both the configuration of the component amino acids and the
      peptide conjugation at a gamma-position of D-Glu in 1 are important for
      proliferation of the cells. Compound 1 exerted a prominent effect on cell
      stimulation and growth rate without any morphological change and showed no
      cytotoxicity.

PMID- 8657739
TI  - The fungal teratogen secalonic acid D is an inhibitor of protein kinase C and of
      cyclic AMP-dependent protein kinase.
AB  - The teratogenic metabolite secalonic acid D deriving from the ergot-producing,
      rye-infecting ascomycete fungus Claviceps purpurea and from Penicillum oxalicum
      is an inhibitor of Ca2+- and phospholipid-dependent protein kinase C (PKC) and of
      the catalytic subunit of cyclic AMP-dependent protein kinase (cAK) (C50 values 15
      microM and 12 microM, respectively). Secalonic acid D also inhibits Ca2+
      calmodulin-dependent myosin light chain kinase (MLCK) and plant Ca2+-dependent
      protein kinase (CDPK). The inhibition of cAK by secalonic acid D is competitive
      with respect to both peptide substrate and ATP. However, secalonic acid D does
      not inhibit a high-affinity nucleotide-binding phosphatase from potato. A variety
      of other naturally-occurring teratogenic agents are not inhibitors of the protein
      kinases examined.

PMID- 8657741
TI  - Induction of morphological and functional differentiation of human promyelocytic
      leukemia cells (HL-60) by Tubeimoside 1.
AB  - Two functional parameters evaluated by nitroblue tetrazolium (NBT) dye reduction
      and zymosan particle phagocytosis and a morphological change assessed by the
      Wright-Giemsa stain of human promyelocytic leukemia cells (HL-60 cells) were used
      to determine the extent of HL-60 cell differentiation induced by tubeimoside 1.
      The results revealed that under the action of tubeimoside 1, HL-60 cells could be
      induced to differentiate to more mature cells with the functional characteristics
      of granulocytes. Therefore, tubeimoside 1 could be considered as a promising
      antileukemic agent for further animal trials.

PMID- 8657742
TI  - Mode of antibacterial action of totarol, a diterpene from Podocarpus nagi.
AB  - The antimicrobial mechanism of totarol was studied using Pseudomonas aeruginosa
      IFO 3080. This diterpene inhibited oxygen consumption and respiratory-driven
      proton translocation in whole cells, and oxidation of NADH in membrane
      preparation. NADH-cytochrome c reductase was inhibited by totarol while
      cytochrome c oxidase was not. NADH-DPIP reductase and NADH-CoQ reductase were
      also inhibited. The site of respiratory inhibition of totarol was thought to be
      near CoQ in the bacterial electron transport chain.

PMID- 8657743
TI  - Antiplasmodial activities and cytotoxic effects of aqueous extracts and
      sesquiterpene lactones from Neurolaena lobata.
AB  - Aqueous and lipophilic extracts of Neurolaena lobata (Asteraceae), obtained from
      Guatemala, were tested against Plasmodium falciparum in vitro. Moreover,
      sesquiterpene lactones, of the germacranolide and furanoheliangolide type,
      isolated from N. lobata, were shown to be active against P. falciparum in vitro.
      In addition to their antiplasmodial activity, their cytotoxic effects on human
      carcinoma cell lines were evaluated. Structure-activity relationships are
      discussed.

PMID- 8657744
TI  - Inhibitory effects of some steroidal saponins on human spermatozoa in vitro.
AB  - Twenty-nine C-27 steroidal saponins were tested for the inhibitory effects on
      human spermatozoa in vitro by means of a modified Sander-Cramer method. Twelve of
      them are responsible for this activity. The structure-activity relationship is
      discussed.

PMID- 8657746
TI  - Analgesic and antipyretic activities of an aqueous extract and of the flavone
      linarin of Buddleia cordata.
AB  - The dried aqueous extract of leaves of Buddleia cordata (loganiaceae) and its
      main flavonoid glycoside, linarin, have been evaluated for analgesic and
      antipyretic effects in mice and rats, respectively. Both the extract and linarin
      exerted significant and dose-dependent analgesic and antipyretic activities, the
      first being obtained against a chemical stimulus (writhing a test in mice) and
      the second being obtained by a pyretogenic stimulus (yeast-induced hyperthermia
      test). Furthermore, the response of the animals in the hot plate test was
      modified by linarin and an aqueous extract. These activities were similar to that
      showed by morphine sulfate (MS) and they were inhibited by naxolone pretreatment,
      a specific morphinic antagonist compound. These findings lead to the conclusion
      that the aqueous extract and linarin exert central analgesic properties. On the
      other hand, linarin was shown to be responsible for the antipyretic activity of
      this species.

PMID- 8657745
TI  - Antiplatelet and vasorelaxing actions of some aporphinoids.
AB  - A series of aporphines and oxoaporphines was tested for antiplatelet and
      vasorelaxing actions. (+)-N-Methylactinodaphnine, (-)-norannuradhapurine x HBr,
      xylopine, actinodaphnine, and N-methylnandigerine showed strong inhibition of
      adenosine 5'-diphosphate (ADP)-induced platelet aggregation. Boldine, (+)-N
      methylactinodaphnine, (-)-norannuradhapurine x HBr, xylopine, N
      acetyllaurolitsine, N-methyllaurotetanine, actinodaphnine, N-methylnandigerine, O
      methylbulbocapnine, and liriodenine showed strong inhibition of arachidonic acid
      (AA)-induced platelet aggregation. (+)-N-Methylactinodaphnine, fissoldine x
      HCIO4, (-)-norannuradhapurine x HBr, xlylopine, N-methyllaurotetanine,
      actinodaphnine, N-methylnandigerine, O-methylbulbocapnine, and liriodenine showed
      strong inhibiton of collagen-induced platelet aggregation. (-)-Norannuradhapurine
      x HBr, xylopine, N-methyllaurotetanine, and actinodaphnine showed strong
      inhibition of platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3
      phosphocholine)-induced platelet aggregation. (+)-N-Methylactinodaphnine,
      laurotetanine, N-methylactinodaphnine N-oxide, oxoglaucine, boldine, and
      actinodaphnine showed vasorelaxing action in rat thoracic aorta. The results are
      discussed on the basis of structure-activity relationships.

PMID- 8657747
TI  - Antinociceptive effect of smilaxin B administered intracerebroventricularly in
      the mouse.
AB  - We examined the antinociceptive effect of smilaxin B administered
      intracerebroventricularly (i.c.v.) in ICR mice. The tail-flick test was used as
      an analgesic assay. Smilaxin B showed a strong antinociceptive effect in a dose
      dependent manner. Sulfated cholecystokinin (CCK-8s, 0.5 ng), muscimol (50ng), or
      MK-801 [(+/-)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5, 10-imine
      maleate, 1 microgram] injected i.c.v. significantly reduced inhibition of the
      tail-flick response induced by smilaxin B administered i.c.v. However, naloxone
      (2 microgram), baclofen (10 ng), or CNQX (6-cyano-7- nitroquinoxaline-2,3-dione,
      0.5 microgram) injected i.c.v. did not affect inhibition of the tail-flick
      response induced by similaxin B administered i.c.v. The intrathecal (i.t.)
      injection of yohimbine (20 micrograms), but not methysergide (20 micrograms) and
      naloxone (2 microgram), significantly attenuated inhibition of the tail-flick
      response. induced by smilaxin B administered i.c.v. Our results suggest that
      GABAA or NMDA receptors but not opioid, GABAB, and non-NMDA receptors located at
      the supraspinal level may play important roles in the production of
      antinociception induced by smilaxin B administered supraspinally. Furthermore,
      smilaxin B administered supraspinally. may produce its antinociception by
      activating descending noradrenergic- but not opioidergic- and serotonergic
      neurons.

PMID- 8657749
TI  - Effect of crude fractions of psoralea corylifolia seed extract on bone
      calcification.
AB  - Non-polar crude fractions (Ho-0 and Ho-1) of an acetone extract of Psoralea
      corylifolia seeds were administrated orally to untreated and experimental
      rachitic rats. In the biological screening of the fractions, Ho-1, an elution
      with n-hexane-ethyl acetate by column chromatography over silica gel of the
      acetone extract, untreated rats showed a significant elevation of the serum
      inorganic phosphorus and revealed histomorphometrically a significant increase in
      bone calcification. When Ho-0, an elution with n-hexane, and Ho-1 were
      administrated to the rachitic rats fed with a vitamin D-free, low-phosphorus
      diet, they not only increased significantly the concentration of inorganic
      phosphorus in serum, but also significantly promoted bone calcification.
      Administration of 30 mg/kg of Ho-1 resulted in a marked decrease of osteoid
      volume and improvement of hyperosteoidosis in rachitic rats. These results
      suggested that Ho-0 and Ho-1 are useful as a remedy for bone fracture,
      osteomalacia, osteoporosis, and related conditions.

PMID- 8657750
TI  - Smooth muscle relaxing compounds from Dodonaea viscosa.
AB  - Bioassay-directed fractionation of the chloroform-methanol (1:1) extract of
      Dodonaea viscosa (L.) Jacq. (Sapindaceae) resulted in the isolation of four
      active spasmolytic principles: sakuranetin (1), 6-hydroxykaempferyl 3,7-dimethyl
      ether (2) hautrivaic acid (3), and ent-15, 16-epoxy-9 alpha H-labda-13(16)14
      diene-3 beta, 8 alpha-diol (4). All the isolated compounds elicited a
      concentration-dependent inhibition of the spontaneous and electrically-induced
      contractions of guinea-pig ileum. Sakuranetin and the ent-labdane inhibited ileum
      contractions evoked by acetylcholine (Ach), histamine, and barium chloride. In
      addition, both substances were capable of relaxing contractions of rat uterus
      induced by Ca2+ in K(+)-depolarizing solution, displacing to the right the
      concentration-response curves to Ca2+. These results suggest that sakuranetin and
      ent-15,16-epoxy-9 alpha H-labda-13(16)14-diene-3 beta, 8 alpha-diol produce an
      interference with calcium metabolism in smooth muscle cells. The spasmolytic
      activity exhibited by the active principles from D. viscosa, provides the
      pharmacological basis for the traditional use of the plant as an antispasmodic
      agent.

PMID- 8657748
TI  - Chemical and preliminary analgesic evaluation of geraniin and furosin isolated
      from Phyllanthus sellowianus.
AB  - The present study describes the occurrence of two ellagitannins in the ethanolic
      extract of the leaves and stems of Phyllanthus sellowianus (Euphorbiaceae). Their
      preliminary antinociceptive properties were also evaluated. The two ellagitannins
      were identified on the basis of 1H- and 13C-NMR spectra data and by mixed co-TLC
      and co-HPLC injection with an authentic sample of furosin and geraniin.
      Preliminary pharmacological analysis revealed that both furosin and geraniin (3
      to 30 mg/kg, i.p.), given 30 min before testing, exhibited significant and dose
      related antinociceptive properties against acetic acid-induced abdominal
      constrictions in mice. Geraniin and furosin were about six- to seven-fold more
      potent at the ID50 level (micromol/kg) as analgesics than aspirin and
      acetaminophen, respectively, although they were less efficacious when compared
      with the standard drugs. These data extend our previous studies and indicate that
      the two ellagitannins isolated from P.sellowianus, identified as furosin and
      geraniin are, at least in part, responsible for the antinociceptive actions
      reported previously for the hydroalcoholic extract of P.sellowianus and other
      plants belonging to the genus Phyllanthus.

PMID- 8657751
TI  - Two flavones from Artemisia giraldii and their antimicrobial activity.
AB  - Two new flavones, 4',6,7-trihydroxy-3',5'-dimethoxy-flavone (2) and 5',5-
      dihydroxy-3',4',8-trimethoxyflavone (3) were isolated from Artemisia giraldii and
      their structures were identified by spectroscopic methods. These two new flavones
      showed antibiotic activity against Staphylococcus aureus, Sarcina lutea,
      Escherichia coli, Pseudomonas aeruginosa, Proteus sp. Aspergillus flavus, and
      Trichoderma viride.

PMID- 8657752
TI  - Novel Saponins from Zizyphus spina-christi growing in Egypt.
AB  - From the butanol extract of the leaves of Zizyphus spina-christi (L.) Willd.
      (Rhamnaceae), four saponin glycosides were isolated: Christinin A (1), B (2), C
      (3), and D (4). Their structures were determined by chemical and spectroscopic
      evidence. Compound 1, was found to be 3-O-[alpha-L-fucopyranosyl (1 -> 2)-beta-D
      glucopyranosyl(1 ->3)-alpha-L-arabinopyranosyl]jujubogenin; the others are the
      new, 2 being 3-O-[alpha-D-fucopyranosyl(1 -> 2)-?beta-D- glucopyranosyl-4
      sulphate(1 ->3)?-alpha-L-arabinopyranosyl]jujubogenin, 3 being 3-O-beta
      glucopyranosyl(1 -> 2)-alpha-L-rhamnopyranosyl (1 -> 3)-alpha- L
      arabinopyranosyl]jujubogenin, and 4 being 3-O-[alpha-L-fucopyranosyl(1 -> 2) 
      ?beta-D-arabinopyranosyl(1 -> 3)-beta-D-glucopyranosyl(1 -> 3)?-alpha-L-
      arabinopyranosy]jujubogenin.

PMID- 8657753
TI  - Cytotoxicity and NMR spectral assignments of ergolide and bigelovin.
AB  - Two potent cytotoxic sesquiterpene lactones, ergolide (1) and bigelovin (2) were
      isolated from Inula hupehensis I. helianthus-aquatica and their structures and
      NMR data were assignment unambiguously by using a combination of one-and two
      dimensional NMR techniques and computer modeling calculations.

PMID- 8657754
TI  - Rapid analysis of small samples containing forskolin using monoclonal antibodies.
AB  - The effective range of the competitive ELISA test for detection of forskolin
      content in clonally propagated plant organs of Coleus forskohlii using monoclonal
      antibodies extends from 5ng to 5 micrograms. A correlation between the forskolin
      accumulation and the growth rate was investigated using the clonally propagated
      shoots. An increase of forskolin content was noted, beginning at week 6. Flowers,
      rachises, leaves, stems, tuberous roots, and roots were analyzed. Tuberous roots
      and the stem base contained higher amounts of forskolin than other organs. The
      forskolin content in the stem decreased gradually towards the top of the shoot.

PMID- 8657755
TI  - Reduction of ACh-induced contraction of rat isolated ileum by coptisine, (+)
      caffeoylmalic acid, Chelidonium majus, and Corydalis lutea extracts.
AB  - The crude extracts of Chelidonium majus and Corydalis lutea were examined for
      antispasmodic activity against acetylcholine (ACh)-induced contraction on
      isolated rat ileal smooth muscle. Further, coptisine and caffeolmalic acid as
      components of the alkaloid and the hydroxycinnamic acid ester fraction of both
      plants were similarly investigated. The ACh-induced contraction was found to be
      antagonized weakly by caffeolymalic acid (6.9%; 2.5 x 10(-5) g/ml/organ bath), C.
      majus extract (12.7%; 2.0 x 10(-4) g/ml), and a higher concentration of coptisine
      (16.5%; 1.0 x 10(-5) g/ml) whereas the antispasmodic activity of C.lutea extract
      reached 45% (2.0 x 10(-4) g/ml). Antagonism by papaverine as a positive control
      amounted to 83.2%.

PMID- 8657756
TI  - Indolopyridoquinazoline alkaloids with antiplatelet aggregation activity from
      Zanthoxylum integrifoliolum.
AB  - Bioassay-guided fractionation led to the isolation of three
      indolopyridoquinazoline alkaloids, 1-hydroxyrutaecarpine, rutaecarpine, and 1
      methoxyrutaecarpine as the active principles of antiplatelet aggregation in
      vitro, from the chloroform-soluble part of the fruit of Zanthoxylum
      integrifoliolum (Rutaceae). 1-Hydroxyrutaecarpine exhibited antiplatelet activity
      induced by AA and showed an IC50 value of ca. 1-2 micrograms/ml.

PMID- 8657757
TI  - Assays of the biological activities of two fatty acid derivatives formed in the
      edible mushrooms cantharellus cibarius and C. tubaeformis as a response to
      injury.
AB  - Cibaric acid (1) and 10-hydroxy-8-decenoic acid (2) are two fatty acid
      derivatives that are formed in the fruit bodies of Cantharellus cibarius
      (chanterelle) and C. tubaeformis as a response to injury. Unlike the potent
      defensive sesquiterpenes formed in injured fruit bodies of the pungent Lactarius
      species, compounds 1 and 2 only possess very weak antimicrobial and cytotoxic
      activity. Compound 2 was found to be a very weak direct-acting mutagen in the
      Ames test (<1 revertant/microgram and plate), while cibaric acid (1) was inactive
      in this assay. As 1 is destroyed during cooking, there are currently no reasons
      for suspecting that the consumption of C. cibarius poses a risk to consumers.

PMID- 8657758
TI  - Isolation of E-1-(4'-Hydroxyphenyl)-but-1-en-3-one from Scutellaria barbata.

PMID- 8657759
TI  - Plant metabolites active against Trypanosoma cruzi.
AB  - Parasitic diseases are widespread in less developed countries, and are a major
      cause of suffering and inability of the affected populations to improve their own
      living conditions. Among these diseases, American trypanosomiasis (Chagas'
      disease), due to the kinetoplastid protozoon Trypanosoma cruzi, is particularly
      relevant to Latin America. The natural products literature mentions a wide
      variety of isolated substances showing activity against this parasite. Although
      some of these compounds appear to be promising leads, their potential is
      presently limited by the need of high concentrations, unfavorable
      pharmacokinetics, and/or by their low solubility in blood. Their mechanisms of
      action are unknown in most cases, although some trends appear to be emerging.
      This review presents and discusses the data available until mid-1995.

PMID- 8657760
TI  - Does steroid medication reduce facial edema following face lift surgery? A
      prospective, randomized study of 30 consecutive patients.
AB  - A prospective, double-blinded study of 30 consecutive face lift patients was
      conducted to determine if the administration of corticosteroid medication would
      reduce postoperative facial edema. Half the patients received steroid medications
      in a random fashion. Three independent plastic surgeons who were blinded to the
      study rated facial swelling by comparing preoperative and postoperative
      photographs using a scale of 1 to 4. The data were tabulated and subjected to
      statistical analysis. There were no significant differences in facial swelling
      between the steroid-treated group and the untreated patients on any occasion.

PMID- 8657761
TI  - Repair of calvarial defects with flap tissue: role of bone morphogenetic proteins
      and competent responding tissues.
AB  - Bone morphogenetic proteins 2 through 8 have the ability to induce the in vivo
      transformation of extraskeletal mesenchymal tissue into bone. The aims of this
      investigation were to determine the optimal responding tissue and the specificity
      of the inductive effect of bone morphogenetic protein 3. The optimal responding
      tissue was found to be skeletal muscle. The specificity of this response to bone
      morphogenetic protein 3 was compared with that of recombinant human basic
      fibroblast growth factor, recombinant platelet-derived growth factor, and
      recombinant insulin-like growth factor. Bone morphogenetic protein 3 was the only
      factor that induced de novo bone formation. This ability to transform muscle into
      bone was tested in 7 x 7 mm irradiated skull defects in the rat. After 1500 rads
      of exposure, these defects showed no significant signs of healing by 8 months.
      When these defects were treated with the microvascular transfer of a
      nonirradiated muscle flap, they had 8 percent healing at 4 months and 37 percent
      healing by 8 months. Defects treated with 30 micrograms bone morphogenetic
      protein 3 (without the muscle flap) achieved 50 percent healing by 4 months and
      64 percent healing by 8 months. When the defects were treated with both the
      muscle flap and bone morphogenetic protein 3, there was 96 percent healing by 4
      months and 100 percent healing by 8 months (p < 0.015, compared with bone
      morphogenetic protein 3 alone at both time points). At 8 months, the transplanted
      muscle was entirely transformed into bone and healed the skull defect with newly
      generated bone indistinguishable from the surrounding calvarial tissue. These
      findings suggest a potential clinical utility of bone morphogenetic protein 3
      induced bone formation in skeletal reconstructions. Furthermore, they also show
      that there is a collaborative requirement for both the osteoinductive factor bone
      morphogenetic protein 3 and the presence of competent responsive cells in the
      well-perfused muscle.

PMID- 8657762
TI  - Lyophilized keratinocyte cell lysates contain multiple mitogenic activities and
      stimulate closure of meshed skin autograft-covered burn wounds with efficiency
      similar to that of fresh allogeneic keratinocyte cultures.
AB  - For several years, grafting with allogeneic keratinocyte cultures has been used
      successfully as a wound-healing therapy both by us and by many other groups.
      Since their postgrafting survival time is limited, the effect of these cultures
      is generally explained by the production of wound repair-stimulating factors that
      promote proliferation and migration of resident cells. In this study we show that
      lysates of cultured keratinocytes contain mitogenic activity for keratinocytes,
      endothelial cells, and fibroblasts. In addition, the lysates inhibit the
      contraction of collagen gels by human skin fibroblasts. On the basis of these
      observations and of in vivo data obtained by ourselves and others, we have
      evaluated the effect of total keratinocyte lysates on the healing of meshed skin
      autograft-covered burn wounds. Twenty burn wounds were tangentially excised and
      autografted with one to three meshed conventional skin transplants. An area
      treated with a gel containing lysated keratinocyte cultures was compared with an
      area treated with placebo-gel in terms of epithelialization on day 5. In six
      patients an additional fresh keratinocyte alloculture was applied as a positive
      control. Results indicate that the newly formed epithelium (difference between
      percentage of epithelialization on day 5 and on day 0) was 31.1 percent in the
      treated area compared with 16.5 percent in the placebo area. This result is
      comparable with the value obtained by treatment with fresh keratinocyte
      allocultures, namely, 33.8 percent. These figures show a twofold stimulation of
      epithelialization.

PMID- 8657763
TI  - Prevention of microvascular thrombosis with short-term infusion of human tissue
      type plasminogen activator.
AB  - A locally active thrombolytic agent, human tissue-type plasminogen activator (t
      PA), given over a finite time period (24 hours) by local infusion, maintains long
      term microvascular patency (7 days) in a proven thrombosis model using an
      arterial inversion graft in the rabbit model. Thirteen rabbits in the control
      group and 16 rabbits in the experimental group underwent an arterial inversion
      graft followed by continuous infusion (24 hours) with human tissue-type
      plasminogen activator (experimental) or normal saline (control). No significant
      clinical bleeding or alteration of coagulation parameters was noted in
      hematologic studies in both experimental and control groups. Scanning electron
      microscopy of the postoperative human tissue-type plasminogen activator-perfused
      arteries suggests an interaction of the human tissue-type plasminogen activator
      with specific platelet receptors in reversing microvascular thrombosis by
      decreasing or preventing further platelet aggregation and adhesion. Human tissue
      type plasminogen activator infused locally for a finite period (24 hours) allows
      adequate time for platelet metamorphosis to occur in converting a thrombogenic to
      a nonthrombogenic vessel surface. The clinical ramifications in preventing or
      reversing microvascular thrombosis in free-tissue transfers and replantation
      surgery are apparent. Further study in this area will enhance our understanding
      of the pathogenesis and prevention of microvascular thrombosis.

PMID- 8657764
TI  - The effects of radiation on neovascularization in a rat model.
AB  - It is thought that radiation treatment inhibits neovascularization of recipient
      and/or graft tissues, and this may account in part for abnormalities in wound
      healing associated with radiation therapy. We have examined this hypothesis using
      a model that measures the neovascularization of an implanted foreign material.
      Expanded polytetrafluoroethylene (PTFE) sheets were implanted adjacent to both
      superficial epigastric vascular pedicles of 63 rats distributed into 7 groups (n
      = 7) that differed with respect to dose and timing of irradiation. Zero to 10
      daily fractions of electron-beam radiation (300 cGy each) were delivered to the
      implant in the right groin, while the implant in the left groin served as a
      nonirradiated internal control. Unirradiated animals showed equal
      neovascularization of both implants. Rats that were irradiated twice (single
      fractions at 0 and 24 hours after implantation) did not show a significant
      decrease in the neovascularization of the irradiated implant compared with the
      contralateral control implant. In contrast, the implants that were irradiated
      three times (single fractions at 0, 24, and 48 hours after implantation)
      demonstrated significantly diminished ( > 25 percent, p < 0.05)
      neovascularization beyond day 7, whereas implants irradiated only at 48 hours
      after implantation did not. Interestingly, neovascularization of the implants
      irradiated with 10 fractions (3000 cGy) was not significantly decreased compared
      with irradiation with three fractions (900 cGy). Irradiation delivered before
      implantation (900 cGy) inhibited neovascularization significantly less than the
      same dose administered after implantation. The results of this study suggest that
      a subclinical cumulative dose of 900 cGy is the threshold for impaired tissue
      revascularization provided that treatment is delivered immediately after
      implantation over a 48-hour interval.

PMID- 8657765
TI  - The effect of ketorolac on microvascular thrombosis in an experimental rabbit
      model.
AB  - This study was undertaken to evaluate the effect of ketorolac (Toradol), a potent
      cyclooxygenase inhibitor used for postoperative pain, on microvascular thrombosis
      in an established thrombosis model. Bilateral 3-mm arterial inversion grafts (n =
      66) were constructed in the femoral arteries of New Zealand White rabbits. ALZET
      (ALZA Corporation, Palo Alto, Calif.) osmotic pumps were implanted in the
      external jugular veins for drug delivery. The blinded protocol called for the
      experimental animals to receive intravenous doses of ketorolac of 1.72 mg/kg per
      day (group 1) or 3.44 mg/kg per day (group 2), while control animals received
      equivalent volumes of saline. Patency was assessed at 7 days. Whereas 52 percent
      (13 of 25) of control vessels remained patent, 70 percent (14 of 20) and 86
      percent (18 of 21) of group 1 and group 2 vessels, respectively, were patent at 1
      week. This decrease in microvascular thrombosis with delivery of ketorolac was
      statistically significant (p = 0.0094). Ketorolac, at experimental doses
      approximating 9 and 18 mg IV q6h in a 70-kg man, demonstrated a statistically
      significant reduction in microvascular thrombosis. This study supports its use in
      clinical microvascular surgery.

PMID- 8657767
TI  - Method in the madness.

PMID- 8657766
TI  - The salvage of a degloved hand skin flap by arteriovenous shunting.
AB  - Nine cases of hand degloving injuries were treated successfully with
      arteriovenous shunting technique. Of these nine cases, four were degloved from
      the wrist level and one from the forearm, three were degloved at the palm and one
      at the dorsum of the hand. All injuries resulted in distally based skin flaps,
      which were either superficial to the palmar fascia or within the subcutaneous
      layer. Lack of active bleeding from the periphery of the avulsed flaps
      substantiated circulatory compromise before revascularization. Survival of the
      avulsed flaps was achieved by directing the proximal arterial flow into the
      venous channel within the avulsed skin flaps. The post-operative care and
      rehabilitation were straightforward, and functional results were satisfactory.

PMID- 8657768
TI  - Selling the TRAM.

PMID- 8657770
TI  - An introduction of the ultrasonic scalpel: utility in treatment of rhinophyma.

PMID- 8657769
TI  - The expanded forehead scalping flap: a new method of total nasal reconstruction.
AB  - The challenge of total nasal reconstruction is particularly formidable in the
      pediatric patient. Forehead skin is taut, and conventional methods of
      reconstruction, such as the midline forehead flap, provide a paucity of tissue in
      this age group. Tissue expansion is well-suited modification to overcome this
      limitation, but as applied to the midline forehead flap, it does not address the
      resulting vertical forehead scar. We present a new technique for total nasal
      reconstruction using an expanded, transversely oriented forehead scalping flap in
      a pediatric patient. This approach not only provides a generous amount of
      forehead skin but also limits donor-site morbidity and scarring by orienting
      incisions transversely at the hairline and within the scalp.

PMID- 8657771
TI  - A full nasal skin rotation flap for closure of soft-tissue defects in the lower
      one-third of the nose.
AB  - Large soft-tissue defects in the lower one-third of the nose challenge the
      reconstructive surgeon both technically and aesthetically. Many procedures have
      been described previously that close the wound with varying degrees of color and
      texture match. We present a modified nasal rotation flap that closes large soft
      tissue defects of the lower one-third of the nose in a single stage with minimal
      donor-site morbidity and a pleasing aesthetic result.

PMID- 8657772
TI  - Fascia lata suspension of malpositioned ears.
AB  - A new technique for the correction of malpositioned ears in congenital or
      acquired disorders is described. The use of a fascia lata strip makes a rigid
      fixation of the ear to the pericranium possible without total fixation of the ear
      in all directions. The configuration of the auricle is not altered, and the scars
      are inconspicuous.

PMID- 8657773
TI  - The role of bone centers in the pathogenesis of craniosynostosis: an embryologic
      approach using CT measurements in isolated craniosynostosis and Apert and Crouzon
      syndromes.
AB  - This paper describes the role of the displacement of bone centers, i.e., the
      tubers, in the pathogenesis of craniosynostosis. This displacement was studied in
      54 patients with isolated or syndromic craniosynostosis in the form of CT scans
      as well as in two dry neonate skulls with Apert syndrome. For comparison, 49
      fetal and 8 normal infant dry skulls were studied. Our investigation was
      restricted to the coronal and metopic sutures. The results showed a significantly
      more occipital localization of the frontal bone center and a more frontal
      localization of the parietal bone center at the side of a synostotic coronal
      suture in the isolated form as well as in Apert syndrome. In contrast, this was
      not the case in Crouzon syndrome, thus showing that these two syndromes have a
      different pathogenesis. For trigonocephaly, a more anteromedial localization of
      the frontal bone centers was found.

PMID- 8657774
TI  - A late follow-up of several severely wounded veterans of World War II.

PMID- 8657775
TI  - A simple self-retaining splint for conjunctival fornix reconstruction.

PMID- 8657776
TI  - A comparison of factors affecting aesthetic outcomes of TRAM flap breast
      reconstructions.

PMID- 8657777
TI  - Abdominal hernia after fasciotomy of the external oblique muscle for abdominal
      wall closure in TRAM surgery.

PMID- 8657778
TI  - Early free-flap debulking: avoiding the second donor site.

PMID- 8657779
TI  - High lateral tension abdominoplasty.

PMID- 8657780
TI  - Topical application of epidermal growth factor.

PMID- 8657781
TI  - Aerosolized silicone in a medical library.

PMID- 8657782
TI  - Positive cultures around breast prostheses.

PMID- 8657783
TI  - Two-stage abdominal wall reconstruction of sepsis-induced dehiscence.

PMID- 8657784
TI  - An easy maneuver to improve exposure in difficult end-to-side anastomoses.

PMID- 8657785
TI  - Craniofacial gliomas.
AB  - Ten patients with gliomas were treated between 1977 and 1993. Three of the
      lesions (30 percent) exhibited intracranial extension. Fifty percent (2 of 4) of
      the intranasal lesions exhibited intracranial extension. Effective removal of the
      lesion required manipulation of nasal bones in intranasal lesions and extranasal
      lesions with intranasal extension. Gliomas with an intracranial component were
      best addressed through a combined intracranial and extracranial approach.

PMID- 8657786
TI  - Complications of the pectoralis major myocutaneous flap in the oral cavity: a
      prospective evaluation of 220 cases.
AB  - A prospective study of 220 consecutive pectoralis major myocutaneous flaps used
      for oral cavity reconstruction from March of 1990 to February of 1991 showed that
      89 patients (40.5 percent) developed flap-related complications and 33 patients
      (15 percent) had complications unrelated to the flap; 92 patients (42 percent)
      had an uneventful recovery and there were 6 (2.7 percent) postoperative deaths.
      Sixty patients (27 percent) developed flap necrosis, of whom only 6 (2.7 percent)
      had total flap loss. Major partial loss occurred in 20 patients (9 percent) and
      minor flap loss occurred in 34 (15.5 percent). Flap necrosis was significantly
      lower in the purely myocutaneous flaps (p < 0.00000) vis-a-vis the bipedicled and
      osteocutaneous flaps. Fistula formation, wound infection, dehiscence at the flap
      margin, and postoperative hematomas occurred with comparable frequency in both
      groups. The female gender, primary tongue cancer, subtotal or total glossectomy,
      bipedicling of flaps, prior chemotherapy, and presence of systemic disease
      (diabetes) emerged as significant risk factors for flap necrosis on multivariate
      analysis (p < 0.005).

PMID- 8657787
TI  - The relative importance of septal and nasal valvular surgery in correcting airway
      obstruction in primary and secondary rhinoplasty.
AB  - Despite the apparent association of nasal airway obstruction with septal
      deviation and/or inferior turbinate hypertrophy, increasing clinical evidence
      suggests that incompetence of the internal or external nasal valves may also
      affect airflow. But how much? What is the relative importance of the valves and
      septum in causing nasal airway obstruction? One-hundred and sixty consecutive
      patients (88 primary rhinoplasty, 72 secondary rhinoplasty) without turbinate
      hypertrophy or septal perforation and operated on for correctable nasal airway
      obstruction were evaluated prospectively by anterior active mask rhinomanometry
      preoperatively and from 1 to 43 months (mean 8.4 months) postoperatively after 1%
      phenylephrine decongestion to eliminate mucosal factors. Patients were stratified
      according to the site(s) of preoperative obstruction at the internal valves, the
      external valves, the septum, or any combination of the three. Geometric mean
      nasal airflow was calculated from independent measurements of each nasal airway.
      Surgical treatment consisted of submucous septal resection, internal valvular
      reconstruction with dorsal or spreader grafts, and external valvular
      reconstruction with cartilage or bone grafts; inferior turbinectomy was not
      performed. All procedures were performed endonasally. In the entire 160 patient
      study group, septal and/or valvular surgery corrected the airway in 152 patients
      (95 percent); 8 patients had partial residual obstruction. Our data support the
      prior rhinologic data in showing only a modest (and statistically insignificant,
      p < 0.4, n = 25) improvement in (geometric) mean nasal airflow following septal
      surgery alone. However, external valvular reconstruction alone increased airflow
      2.6 times over preoperative values (n = 10). Internal valvular reconstruction
      alone by dorsal grafts (n = 17) or spreader grafts (n = 29) increased nasal
      airflow 2.0 times; spreader grafts and dorsal grafts were equally effective in
      supporting the internal valves. The largest improvement in postoperative airflow
      was seen in the patients with septal plus internal and external valvular
      incompetence (n = 21), in which flow increased 4.9 times over preoperative values
      (p < 0.0003). Patients in whom valvular incompetence alone was corrected
      experienced as much relative improvement as patients in whom valvular plus septal
      obstruction was corrected. Finally, valvular reconstruction in 54 secondary
      rhinoplasty patients who had previously undergone septoplasty corrected the
      airway obstruction in 49 patients (91 percent). Notably, 110 of 160 patients (69
      percent) had a lateralized preoperative obstruction; however, the septum was
      deviated toward the clinically obstructed side in only 51 of these patients (46
      percent); in the other 54 percent, the subjectively obstructed side was
      contralateral to the side toward which the septum was deviated. Nasal valvular
      function should be assessed in all preoperative rhinoplasty patients with airway
      obstruction; in many individuals, valvular effects may equal or surpass septal
      deviation as the primary cause of nasal airflow obstruction.

PMID- 8657788
TI  - Mechanical properties and microstructure of the superficial musculoaponeurotic
      system.
AB  - Because of the widespread reliance on SMAS tightening procedures in present-day
      face lift surgery, a study was undertaken to examine the physical properties and
      microscopic structure of both virginal (40 specimens) and reoperated (8
      specimens) SMAS tissue. The findings could be of practical value to the surgeon
      and are reported herewith: First, the SMAS is a composite fibrofatty layer
      comprising collagen and elastic fibers interspersed with fat cells. Second,
      microscopic appearance shows a considerable amount of elastic fibers in close
      relationship to the collagen fibers. Third, on scanning electron microscopy, the
      collagen fibers in the virginal SMAS show a convoluted appearance similar to that
      found in the dermis. In the reexcised SMAS tissue, there is some evidence of
      parallelization of the collagen fibers as seen in the stretched dermis. Fourth,
      mechanical testing (Instron), i.e., a series of loading/unloading tests at
      various rates and amplitudes, and stress relaxation tests were performed on
      samples of preauricular skin and SMAS. These indicated definite viscoelastic
      properties for both sets of specimens, with the tendency of an increased
      stiffness and a reduction in viscoelastic effects on repeated working of the
      samples. Overall, the mechanical behavior of both tissues was somewhat similar,
      the viscoelastic effects in SMAS being less pronounced. A nonlinear viscoelastic
      model is under development to represent the behavior of both tissues. The
      implications of these results may help to explain the slackening effect observed
      in some postoperative patients.

PMID- 8657789
TI  - Dynamic cranioplasty for brachycephaly.
AB  - In craniofacial surgery, the most common techniques for treatment of
      brachycephaly have been either to let the forehead float on the brain or to fix
      it in an advanced position. Since neither of these techniques renders acceptable
      results with enough consistency, we have developed a different way of addressing
      the problem. In principle, the design of the operation is to restrict upward and
      transverse growth of the cranium but to allow anterior and posterior expansion.
      This is accomplished by producing transverse tension across the skull and letting
      it expand anteriorly by means of a superiorly hinged fronto-orbital flap and
      posteriorly by an inferiorly based occipital flap. To prevent upward expansion at
      the squamosal sutures when still open, these junctions are bridged with
      miniplates. This surgical technique has brought definite improvement to the
      results even in some Apert syndrome children. During a 2-year period, we have
      treated 14 infants with this technique and followed 10 of them with
      roentgencephalometry, 3 for more than 1 year, and 4 for more than 6 months. The
      diagnoses were the following: nonsyndromal bicoronal synostosis (4), Apert (7),
      bicoronal synostosis with midline cleft, Saethre-Chotzen, and Antley-Bixler (1
      each). The mean age of surgery was 6.6 months (range 3 to 16 months). There were
      no major complications.

PMID- 8657790
TI  - Comparison of resource costs of free and conventional TRAM flap breast
      reconstruction.
AB  - Resource costs, which are the costs to the hospital of providing a service, were
      measured for 154 patients who underwent mastectomy and immediate breast
      reconstruction with TRAM flaps. Unilateral and bilateral reconstructions were
      evaluated separately. The resource costs required to perform mastectomy and
      reconstruction with free TRAM flaps were then compared with those required when
      conventional TRAM flaps were used. The mean total resource cost in the free TRAM
      group was slightly higher than in the conventional TRAM group, but the difference
      was small (4.1 percent) and not statistically significant (p = 0.290). The mean
      resource cost of performing bilateral mastectomy and reconstruction was higher
      than that of unilateral mastectomy and reconstruction, but the difference was
      only 5.0 percent (p = 0.046). This study shows that the cost to an institution of
      providing breast reconstruction with free TRAM flaps is not significantly higher
      than that of performing reconstruction with conventional TRAM flaps. Also, our
      findings show that the resource costs of performing bilateral mastectomy and
      reconstruction are not much higher than those of treating only one breast.

PMID- 8657791
TI  - Immunolocalization of keratan sulfate, chondroitin-4-sulfate, and chondroitin-6
      sulfate in periprosthetic breast capsules exhibiting synovial metaplasia.
AB  - The distribution of various proteoglycans and basement membrane components within
      10 breast capsules with synovial metaplasia was assessed immunohistochemically.
      Immunoreactive keratan sulfate and chondroitin-4-sulfate were present in many of
      the synovial metaplasia lining cells, suggesting active secretion of these
      proteoglycans into the intraprosthetic space. In contrast, chondroitin-6-sulfate
      was confined to the extracellular matrix of the underlying supporting fibrous
      capsule. Type IV collagen and laminin were not associated with the synovial
      metaplasia lining, thus confirming the absence of a basement membrane, as
      previously indicated by morphologic analysis. As with tendon reconstruction, the
      development and maintenance of a synovial metaplasia lining that secretes
      lubricating factors such as proteoglycans may be beneficial for decreased
      capsular contracture.

PMID- 8657792
TI  - The vascular anatomy of the tendinous intersections of the rectus abdominis
      muscle.
AB  - The purpose of this study was to define the arterial vascular anatomy of the
      tendinous intersections of the rectus abdominis muscle through anatomic
      dissection and perforator mapping. In 14 fresh cadavers, the deep inferior
      epigastric arteries were injected with blue latex. In 7 specimens (14 rectus
      abdominis muscles), dissection of each tendinous intersection was performed under
      loupe magnification. In the other 7 specimens (10 rectus abdominis muscles),
      perforator mapping was performed at each intersection relative to the rest of the
      rectus abdominis muscle. In 2 additional cadavers, radiographs were taken of
      barium-latex-injected specimens. We found that the vascular architecture of the
      intersections is characterized by transverse arcades arising from either the
      superior or inferior epigastric arteries, which send branches supplying muscle or
      the overlying skin. There is a higher number of perforators per square centimeter
      originating in the intersections than in the rest of the rectus abdominis muscle.
      To obtain optimal vascular supply, the design of transverse rectus abdominis
      flaps may be based on intersection location as well as paraumbilical location.

PMID- 8657793
TI  - Fat cylinder transplantation: an experimental comparative study of three
      different kinds of fat transplants.
AB  - In an experimental comparative study, fat cylinders harvested with a new
      instrument were compared with excised fat and aspirated fat. In 12 New Zealand
      White rabbits, fat grafts of about 1 ml were transplanted from the fat pad
      between the shoulders to the scalp and rear side of the ears by three different
      fat harvesting techniques. After 6 months, the change in the weight of each of
      the 36 specimens was measured. All specimens were freeze-cut after fixation and
      stained with Sudan IV, a fat-specific stain. They were examined under a light
      microscope and evaluated by computer-assisted image analysis. There was no
      statistical difference in the percentage change in weight between the excised fat
      and the fat cylinder groups (2 and 1 percent, respectively). For aspirated fat,
      however, the difference was significant (-59 percent). There also were
      significantly more surviving mature adipocytes in the fat cylinder group than in
      the aspirated fat group. We conclude that fat cylinders harvested with the new
      instrument are as good grafting material as excised fat, while aspirated fat in
      this study was clearly inferior for grafting.

PMID- 8657794
TI  - The inferiorly based rectus abdominis island flap for the treatment of complex
      hip wounds.
AB  - Complex wounds in the hip region often result from complications of orthopedic
      procedures performed in this region such as total hip arthroplasty, ORIF
      procedures, tumor ablation, and/or radiation therapy. Exposure of bone, joint
      capsule, prostheses, and other hardware often results with these wounds. Salvage
      of these exposed and/or infected essential elements and providing soft-tissue
      coverage are difficult and challenging problems for the orthopedic and plastic
      surgeon. To provide coverage for such situations, we have developed an aggressive
      strategy of thorough debridement, systemic antibiotics, and well-vascularized
      soft-tissue coverage utilizing an inferiorly based rectus abdominis island flap.
      This technique was utilized in five patients with all wounds and joints remaining
      stable at follow-up periods ranging from 2 to 7 years.

PMID- 8657795
TI  - [Introductory comment on the translation of Leo Kanner's article: "Follow-up
      study of eleven autistic children originally reported in 1943." Journal of Autism
      and Childhood Schizophrenia, 1971, 1-2, 119-145].

PMID- 8657796
TI  - [Follow-up study of eleven autistic children originally reported in 1943. 1971].
AB  - The destinies of the 11 children first reported in 1943 as suffering from
      autistic disturbances of affective contact are brought up to date. Their life
      histories are summarized succinctly in terms of developmental data, family
      constellations, clinical observations in the course of the years, the varieties
      of professional planning, and present status. Attention is called to the
      subsequent scientific studies of early infantile autism with ever-increasing
      facilities for research in nosology, biochemical and general systemic
      implication, and therapeutic amelioration. The need for continued follow-up
      studies of autistic children is emphasized.

PMID- 8657797
TI  - [Infantile autism in France in 1994].
AB  - The author tries, in is own, name to translate the French position on early child
      autism. This position can be expressed through a few acceptable points for the
      majority of French professionals, obviously without any idea of a consensus. The
      concept of a plurifactorial determinism and the psychopathological view of the
      disorder which is not thought of in France as susceptible to be reduced to a
      handicap of a primarily cognitive nature are therefore underlined. Thus the
      importance of a unified multidimensional therapeutic approach that considers the
      different consequences of the illness without forgetting its fundamentally
      interactive nature ("autistic-making process"). Today, the psychoanalytic
      approach tends to concentrate on the analysis of secondary factors of upholding
      and on the significance given in the after-thought by the autistic disorders
      within the family group. This opens the way to a collaboration between
      specialists of the different disciplines that are involved, including those who
      work in the field of neuroscience.

PMID- 8657798
TI  - [Theoretical perspectives on autism].
AB  - The French and American views of autism have often been seen as irreconcilable,
      the theoretical and inferential aspects of one conflicting with the empiricism
      and positivism of the other. Nevertheless, multiple lines of convergence tie
      together these two traditions, from the commitment to phenomenology embodied in
      the early work of Jean Itard and his American disciples, to the emphasis on
      developmental issues represented in French psychoanalytic approach and Kanner's
      reliance on Gesell's work. Several important differences remain, with an
      oftentimes sharp contrast between the predominantly psychogenic views in France
      and the predominantly neurobehavioral views in the United States. This divergence
      has important implications to research and services affecting individuals with
      autism. However, recent developments are bringing together these two viewpoints,
      with mutual benefits. There is a renewed commitment to cross cultural
      discussions, resulting in constructive reappraisal of concepts and research in
      both countries, and leading to the attention to important phenomena. The
      stimulation engendered by this dialogue is leading to new research.

PMID- 8657799
TI  - [Clinical guide scale for the developmental stages of treated autism].
AB  - An evolutionary diagram that takes into account the development of personality
      and its structuring or restructuring was developed thanks to a better
      understanding of autistic disorders from a psychodynamic point of view through
      long term psychoanalytic treatment of autistic children. This grid is organised
      around the major stages of the formation of the bodily ego which autistic
      children helped us understand better. The construction of space and the
      capacities of cognitive instrumentation are logically within this line of
      structuring. These major stages are defined: the first is the "successful"
      autistic state; the second is the stage where the primary skin is recovered
      (feeling of a circular envelope); the third is the symbiotic phase which includes
      vertical splitting then horizontal splitting of the image of the body; finally,
      the fourth is the phase of individuation/separation into a whole body. At each
      stage the following are assessed: state of the image of the body, of the gaze, of
      language, of writing, the autistic symptoms, emotional-relational manifestations,
      exploration of space and objects, recognition in time, the aggressive behaviours,
      reactivity to pain and to immune states (somatic and psychosomatic
      manifestations).

PMID- 8657800
TI  - [Early disturbances in parent-infant interactions and the construction of psychic
      life. The young child and his psychotic mother].
AB  - From their clinical experience with infants of psychotic mothers who present
      serious parental disorders, the authors wonder about the effects of early
      exposure of the child to maternal psychosis. The dynamic of development, within
      the frame of a major disturbance of mother-infant interactions is illustrated by
      the therapeutic follow-through treatment of a child and his family, from birth to
      the age of eight. This enables to formulate several hypotheses that aim to
      establish connections between interactive disfunctioning and characteristics of
      psychic life and the child's organisation mode on short and longer term.

PMID- 8657801
TI  - ["I non-exist". Paradoxes of death in adolescence].
AB  - This text presents, from the case study of the analytical treatment of a young
      girl after a very serious suicide attempt, a theoretical reflection on the
      question of death during adolescence and its place and function in the psyche.
      The hypothesis suggested is that resorting to the "idea of death" constitutes an
      attempt to neutralise the excitement created by the excess of representational
      activities. A parallel is suggested between the way death and pain are used as a
      protective shield.

PMID- 8657802
TI  - [Suicidal adolescents: psychotherapy and treatment interruption. Results of a
      controlled study].
AB  - Because of the scarcity of the research on the interruptions of treatment with
      adolescents and the clinical importance of suicide attempts in this population,
      the author studies the relation between these two variables. Using a group of
      nearly 300 adolescents, he statistically compares a certain number of socio
      demographic and clinical factors in adolescents who have committed suicide and
      those who haven't. If the global frequency of treatment interruption is
      comparable in both groups, a further analysis of the data shows the importance of
      a very intensive initial treatment program for the first group. Among the other
      results, like previous researches, this study points out a statistically
      significant relation between sexual violence and suicide attempts, as well as the
      frequency, also statistically higher in patients who have tried to commit suicide
      than in others, of a psychopathological diagnostic, in particular depression.

PMID- 8657803
TI  - [Reflections on transference, countertransference, session frequency and the
      analytic process].
AB  - It is suggested that there is a special correlation between the frequency of
      sessions in psychoanalytical treatment and the nature of the transferences which
      evolve and, at the same time, of the countertransference responses elicited in
      the therapist. This in turn has a crucial bearing on the characteristics of the
      psychoanalytical process which develops in the course of treatment. These
      interrelationships are explored with special reference to the treatment of
      children and adolescents. The author draws upon his experiences with high and low
      frequency treatments to make comparative assessments. On the basis of clinical
      examples from both analyses and psychotherapies, the effects of these various
      settings on the development and intensification of the transference are explored.
      Similarly, the repercussions on the countertransference are discussed. It is
      suggested that the density, i.e. the temporal proximity of sessions, provides the
      optimal conditions for the unfolding of the analytical material, the
      proliferation of fantasies and the emergence of transference derivatives. As for
      the therapist this setting provides the space that is necessary to gain the most
      thorough understanding of the patient's inner world, in particular his or her
      unconscious. Finally, the nature of the psychoanalytical process is discussed as
      well as the effects which different settings have on the development and quality
      of this process. It is suggested that different processes evolve in high
      frequency as against low frequency settings.

PMID- 8657804
TI  - [White walls for black holes: essay on graffiti psychopathology].
AB  - Through a clinical case, the authors propose a psychological approach of tagging.
      The phenomenon that started in Harlem's black ghettos at the end of seventies and
      appeared in France less than ten years after, does not seem to be a simple
      sociological one, but seems to take place within the psychic economy of certain
      adolescents as an attempt to operate the necessary identity work to become an
      adult. Tagging as well as wandering can be considered adolescents' acting out
      behaviors and show the externalization of the psychic processes, thus proving a
      basic insecurity in their psychic space, invaded by anaclitic depression.
      Graffing, on the other hand, bears a resemblance to strolling in a
      psychopathologic approach, and already shows an attempt to become a person, and a
      quest of the Other.

PMID- 8657805
TI  - [The adolescent's lexicon: study of lexical variations in normal adolescents
      depending upon the listener].
AB  - Clinicians and parents are familiar with the fact that adolescents have a special
      vocabulary, but very few studies have examined this. Linguists describe it as
      deeply metaphoric, creative and lively, thus showing that young people have a
      deep knowledge of language and truly experience pleasure using words. This
      contrasts with teachers' complaints about the little taste adolescents show for
      oral school activities and how poorly they express themselves. Some of them link
      this to the use of this polysemic and all purpose vocabulary. The context of
      locution is probably the explanation for these diverging opinions. Using this
      hypothesis, we have realised a quantitative study of the lexical variations
      depending on the person the adolescent is talking to in two groups (20 and 19
      subjects), from very different social and educational backgrounds. Each teen-ager
      had to perform the same linguistic task: the description of a photograph on two
      occasions, once with an adult examiner and once with a friend. We studied the
      lexical differences between the two narratives. When adolescents are together
      they use their particular vocabulary four times more than when with an adult. But
      this qualitative difference is not a quantitative one, such as the length of the
      narrative or the number and repetition of whole words, and isn't correlated with
      the lexical stock. The use of this vocabulary runs across gender and social class
      categories. It can equally be found in high performance and upper class students
      as well as in underprivileged youngsters of technical schooling. It is the only
      variable that does not change between the two high schools. Thus this special
      vocabulary would not be connected to the subject's lexical competence, nor to
      gender or social background. It is the psychological function of this language
      that seems to be prominent.

PMID- 8657806
TI  - [Day care treatment of a patient with Huntington chorea--a case report].

PMID- 8657807
TI  - [Psychiatric treatment in another specialty clinic?].

PMID- 8657808
TI  - [No contemporary psychiatric care without sectorization!].

PMID- 8657809
TI  - [Contemporary psychiatric care without sectorization?].

PMID- 8657811
TI  - [Hysteria, dissociation and conversion. A review of concepts, classification and
      diagnostic instruments].
AB  - Modern theories on hysteria are presented by describing the historical context of
      various scientific approach to hysterical phenomena as well as the concepts of
      dissociation and conversion which are closely linked. The subdivision of the
      classical hysterical neurosis into the dissociative disorders and the somatoform
      disorders within the diagnostic classifications of ICD-10 and DSM-III-R
      respectively DSM-IV is illustrated and discussed. These new theories have
      prompted the development of some instruments such as diagnostic interviews (SCID
      D) and self-measuring questionnaires (DES). The scientific value and importance
      of these instruments is discussed, especially with regard to further studies on
      dissociative disorders, particularly in the German-speaking countries.

PMID- 8657810
TI  - [2 class psychiatry].
AB  - Community care and sectorisation, specialisation and differentiation, integration
      of psychiatric and other medical services, crises intervention and emergency
      psychiatry--and patient's choice--are basic issues of the organisation of
      psychiatric services. They are discussed and evaluated in respect of the Region
      of Mannheim and the Mannheim Zentralinstitut fur Seelische Gesundheit.

PMID- 8657812
TI  - [The subjective experience in catatonia: systematic study of 24 catatonic
      patients].
AB  - Catatonic patients are often not able to communicate their subjective experiences
      behind their "fassade of immobility." Therefore was retrospectively (3 weeks
      later) investigated subjective experiences in 24 catatonic patients with a self
      assessment-scale especially for catatonia developed by us. Our results showed
      that catatonic patients subjectively experience less their altered movements but
      rather cognitive, i.e. ambivalence, or affective, i.e. intense emotions which
      couldn't be controlled, alterations. According to our results we were able to
      distinguish an emotive (intense anxiety) from a non-emotive, i.e. cognitive
      (predominating ambivalence), subtype in catatonia with regard to subjective
      experience.

PMID- 8657813
TI  - [Family management and psycho-education for prevention of schizophrenia
      recurrence in adolescent patients].
AB  - The rate of rehospitalisation of schizophrenic psychoses may attain 70% within 3
      years, for juvenile schizophrenics up to 80%. Psychoeducative counseling for the
      reduction of High Expressed Emotions (HEE) of the relatives of the patients shall
      be able to reduce the rate of rehospitalisation below 20%. But it seems, that HEE
      in relatives of young schizophrenics (ICD-9:295.x, DSM-III-R:295.xx) with short
      duration of illness is different from HEE in unselected samples of adult
      patients. Diagnostic, therapy and experiences in counseling 8 families with a
      schizophrenic child for a period of 3 years are described. HEE in relatives of
      young schizophrenics seems to be different to HEE in relatives of unselected
      samples. Finally changing and extension to the current forms of treatment for
      juvenile schizophrenics and there families will be discussed.

PMID- 8657814
TI  - [Vocational rehabilitation of psychiatric patients].
AB  - 135 former clients of the "Arbeitstrainingszentrum (ATZ)" in Upper Austria, a
      facility for vocational rehabilitation, participated in a comprehensive follow-up
      study 1 to 9 years (mean 3,8 years) after termination of the ATZ. 60% of them
      finished the ATZ regularly, meaning either that they completed the full training
      or that they left for another job. Occupational situation of the former clients
      at follow-up was as follows: 24% were competitively employed, 17% held a
      sheltered working place, 3% underwent training, 6% did not-economic work, 6%
      worked in a household. 13% were unemployed and in search for a job, 30% received
      a disability pension. 41% of all clients had held no job at all since termination
      of the ATZ.

PMID- 8657815
TI  - [Patient suicide in the psychiatric hospital: selected results of the Clinic
      Suicide Working Group Study I/II 1970-1992 of the "Suicidal Behavior and the
      Psychiatric Hospital" Study Group].
AB  - Data of the Baden-Wurttemberg and Bavarian inpatient suicide study (1970-1984)
      and (1985-1989) and (1990-1992) are presented comparing these different
      observation periods. The total group comprises 59% men and 41% women of 585
      suicides, 51% younger than 50 year (main group 21-30 years: 26%). An increase of
      suicides in the seventies and a plateau in the eighties is observed. 53% of the
      total group are schizophrenic and 26% depressive inpatients. There is a
      impressive shortening of the time period from index admission to suicide over the
      years: (1970-1984) 56% (1985-1989) 85% and (1990-1992) again 83% of the total
      group committed suicide during the first six month of inpatient treatment.
      Suicides of psychiatric inpatients seem to be a problem of acute psychiatry.

PMID- 8657816
TI  - [Euphoric effect of lidocaine].
AB  - A 42 year old drug addict reported on his experiences with intravenous
      application of scandicaine and lidocaine. Lidocaine led to short-lasting euphoria
      comparable with former cocaine-induced effects. Pharmacological hypothesis to
      explain these mental alterations are discussed.

PMID- 8657817
TI  - [Philippe Pinel and the legendary "unchaining" at the Paris Bicetre (1793) and
      Salpetriere (1795) Hospitals. II: Historical background, allegorical descriptions
      discipline generated myths].
AB  - Part I of this article has described Pinels carrier upto the 1790ies. This second
      part concentrates of the actual events and the general historical backgrounds of
      the so-called "chain liberation." This--in our opinion--cannot be regarded as one
      singular act, but as symbol for a complex and multistage process. The very common
      conception of a selective act of "chain liberation" is very simplified and
      influenced by the "myth of Pinel, " built by the 19th century psychiatrists and
      historians. Nevertheless: a scientifically sophisticated biography founded on
      archives material is yet expected.

PMID- 8657818
TI  - [Treatment of a borderline patient in a community psychiatry team center].

PMID- 8657819
TI  - [A case of "syphilitic neurasthenia". A new version of a nearly forgotten
      chameleon].

PMID- 8657821
TI  - Transforming psychological inquiry: clarifying and strengthening connections.

PMID- 8657820
TI  - [Treatment of depression with a neuro-thymoleptic combination in general
      practice].

PMID- 8657822
TI  - Jean-Paul Sartre's quest for immortality: The words (Les mots).

PMID- 8657823
TI  - A psychoanalytic study of Alexander the Great.
AB  - The purpose of this paper was to demonstrate how Freudian concepts such as the
      Oedipus complex, castration anxiety, fear of loss of love, the psychosexual
      stages of development, and the tripartite structure of personality can be used to
      understand the life and achievements of Alexander the Great. To accomplish this
      purpose, specific incidents, myths, and relationships in Alexander's life were
      analyzed from a Freudian psychoanalytic perspective. Green (1991), in his recent
      biography of Alexander, has questioned the merit of using Freudian concepts to
      understand Alexander's character. In fact, he stated specifically: If he
      (Alexander) had any kind of Oedipus complex it came in a poor second to the
      burning dynastic ambition which Olympias so sedulously fostered in him; those who
      insist on his psychological motivation would do better to take Adler as their
      mentor than Freud (p.56). Later, in the concluding section of his book, Green
      (1991, pp. 486-487) discounted Freudian interpretations of Alexander's distaste
      for sex, the rumors of his homosexual liaisons, his partiality for middle-aged or
      elderly ladies, and the systematic domination of his early years by Olympias as
      little more than the projected fears and desires of the interpreters. And again,
      an Adlerian power-complex paradigm was suggested as the preferable theoretical
      framework to use. Green's argument was based primarily on an exchange, reported
      originally by Plutarch, which took place between Alexander and Philip prior to
      Alexander's tutorship with Aristotle. Purportedly, Philip enjoined his son to
      study hard and pay close attention to all Aristotle said "so that you may not do
      a great many things of the sort that I am sorry I have done." At this point,
      Alexander "somewhat pertly" took Philip to task "because he was having children
      by other women besides his wife." Philip's reply was: "Well then, if you have
      many competitors for the kingdom, prove yourself honorable and good, so that you
      may obtain the kingdom not because of me, but because of yourself." Green
      interpreted this exchange as confirming that Alexander was more interested in his
      succession to the throne (power) than in any sexual relationships Philip might be
      having with any women other than Olympias. That is, Alexander's concern in this
      exchange was not about Philip's marital infidelity per se, but rather about the
      prospect of potential competitors (other children) for the throne. Significantly,
      by emphasizing the manifest content of the exchange, Green ignored a myriad of
      other possible fears and wishes on Alexander's part, including the fear of
      castration, the wish to have sex (like his father) with Olympias and other women,
      the wish to challenge his father's authority and superiority, the fear of loss of
      love, and the wish (given Philip's homosexual exploits with other boys) to have
      sex with Philip. Moreover, one could easily explain what Green has described as
      "the burning dynastic ambition which Olympias so sedulously fostered in him"
      (p.56), and Alexander's so called "power-complex" in terms which are perfectly
      consistent with drive/structure theory (e.g., see Freud, 1900/1953a and Freud,
      1914/1957, respectively). In other words, Green's arguments against the
      possibility of a Freudian solution to the puzzle of Alexander's character are
      less than compelling. By contrast, as demonstrated in this paper, a plethora of
      historical data exist to suggest that much of Alexander's personality structure
      and behavior can be explained by his unresolved Oedipus complex, the ambition and
      self-confidence instilled in him by Olympias, the anal-sadistic and narcissistic
      organization of his character, his unconscious wish to please his mother, and his
      being lapped (from birth) in the myth of the hero. Although it is risky, at best,
      to attempt to analyze an individual without the benefit of clinical data, and
      even more risky to base such an analysis on fragmentary and often contradictory
      data assimilated long

PMID- 8657824
TI  - The return of the projected: some thoughts on paranoia and a recent trend in
      horror films.
AB  - I have focused on two interrelated changes in horror films of the last twenty
      five years: a tendency for the "horror" to become internalized; and the use of
      what I call "bubbling flesh" to signify the internalized horror. Taking two films
      -the 1958 Fly and its 1986 remake--and treating them as (paranoid) fantasies, I
      have explored what I take to be the unconscious meanings of these changes.
      Although both films present oedipal as well as pre-oedipal conflicts, and
      although both employ paranoid mechanisms of negation and projection of an
      unacceptable wish, the earlier film also makes greater use of repression to keep
      the preoedipal wishes farther from consciousness. The earlier film is also more
      successful in its projection: In the later film the projective mechanisms fail
      and the projected returns to its original locus. The particular unacceptable wish
      that I see as being fundamental to these two films (and perhaps to all horror
      films) is a radically passive wish for merger with the mother--a merger wish so
      radical that it can be seen in terms of Gun-trip's "return to the womb" wishes,
      and so passive that it can be seen as a nearly pure form o Freud's death drive-
      the drive toward total quiescence and dissolution. I have associated the
      differences between the two films with changes in society in the past decades,
      and especially with changes in traditionally conceived gender roles and their
      associated senses of gender identity. Finally, I have suggested that we view
      these historical changes not as signs of societal regression but as the
      beginnings of the failure of one set of defense mechanisms that can possibly
      allow an opening to try out new strategies.

PMID- 8657825
TI  - Belle du Jour and Marnie.

PMID- 8657826
TI  - Crumb: whereof one should not speak.

PMID- 8657827
TI  - Disney's great escape.

PMID- 8657828
TI  - Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies
      with transdermal oestradiol therapy in menopausal depression.
AB  - In a double-blind, placebo-controlled study, the antidepressant and vigilance
      promoting properties of transdermal oestrogen in post-menopausal depression were
      investigated utilizing hormonal, syndromal and EEG mapping evaluations. Sixty
      nine menopausal women, aged 45-60 years without previous hormonal replacement
      therapy, diagnosed as major depression without psychotic or suicidal symptoms
      (DSM-III-R criteria), were randomly assigned to a 3-month treatment with
      transdermal oestradiol [Estraderm TTS (ETTS) 50 micrograms, applied twice weekly]
      or placebo. No other psychoactive medication was allowed. After removal of
      protocol violators, 32 patients were evaluable in each group, which did not
      differ in age, height or weight. As five patients discontinued prematurely in
      both groups and in one placebo patient a post-drug EEG could not be obtained, 27
      patients remained in the ETTS and 26 in the placebo group for efficacy analysis.
      While in the placebo group, oestradiol (E2) and follicle stimulating hormone
      (FSH) remained unchanged, E2 increased and FSH decreased significantly in the
      ETTS group. Syndromal evaluation showed a significant improvement in the
      Kupperman Index (KI) as well as Hamilton Depression Rating Scale (HAMD) in both
      groups, with no inter-group difference. However, EEG mapping demonstrated
      significant inter-drug differences in brain function, mostly over the left
      temporal region. While ETTS patients showed an increase of alpha and alpha
      adjacent theta activity and a decrease of beta activity, as well as an
      acceleration of the delta/theta centroid and a slowing of the alpha, beta and
      total power centroid, no changes occurred in the placebo-treated patients. These
      neurophysiological findings suggest improvement of vigilance by oestrogen,
      previously referred to as "mental tonic" effect. There were no changes, however,
      in the frontal alpha asymmetry index, reflecting left frontal hypo- and right
      frontal hyperactivation. Thus, this neurophysiological variable represents a
      state-independent marker for depression. The tolerability of ETTS was very good.

PMID- 8657829
TI  - Effects of morphiceptin in the medial preoptic area on male sexual behavior.
AB  - Morphiceptin, a selective mu opioid agonist, injected into the medial preoptic
      area (MPOA), delayed the onset of copulation in male rats, but did not affect
      genital reflexes, sexual motivation or general motor activity. In a dose
      dependent manner, morphiceptin (100 ng and 1000 ng) injected into the MPOA
      increased mount and intromission latencies. Similar injections of morphiceptin
      into the ventromedial hypothalamus had no effect on any parameter of copulation.
      The increase in copulatory latencies following the injection of the highest dose
      of morphiceptin was blocked by pretreatment with the opioid antagonist naloxone.
      In the X-maze task, morphiceptin had no effect on sexual motivation, as measured
      by the percentage of trials on which the male chose the female's chamber, but it
      increased the number of trials in which the subject did not select a chamber
      within 60 s and the latency to the female the first time he chose her chamber.
      Similar to the copulation task, the mount and intromission latencies were also
      increased in the X-maze, after the male reached the female. Morphiceptin in the
      MPOA had no effect on ex copula genital reflexes, tested in restrained supine
      males, or on motor activity, tested in a grid box. These results suggest that
      morphiceptin disrupts either the specific copulatory somatomotor pattern or a
      more general motivational component.

PMID- 8657830
TI  - Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu
      but not by kappa opioids.
AB  - The ability of mu and kappa opioids to alter the discriminative-stimulus and rate
      decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats
      trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8
      OH-DPAT from water using a two-lever food-reinforced drug discrimination
      procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488
      and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when
      tested up to doses that substantially reduced rates of responding. During
      antagonism tests, selected doses of the mu opioids, morphine and fentanyl,
      administered at various pretreatment times, attenuated the stimulus effects of
      both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and
      fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect
      curve that were partially surmountable and naltrexone-reversible. In contrast to
      the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed
      to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of
      dose or pretreatment time. The rate-decreasing effects of 8-OH-DPAT were not
      altered substantially by either the mu or kappa opioids examined. The present
      study demonstrates that the stimulus effects, but not the rate-decreasing
      effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas
      neither of these effects are changed by kappa opioids.

PMID- 8657831
TI  - Haloperidol differentially affects reinforcement and motivational processes in
      rats running an alley for intravenous heroin.
AB  - The role of drug-paired environmental stimuli in opiate self-administration was
      investigated by exposing animals to discrete cues that were predictive of the
      availability or unavailability of heroin reinforcement. Rats were trained to
      traverse a straight arm runway for a reinforcement consisting of a single 0.1
      mg/kg intravenous infusion of heroin delivered upon entrance to the goal box. On
      each trial, one of two discriminative olfactory stimuli (orange and almond) was
      used: one which signaled the availability of heroin in the goal box (S+), and one
      which signaled its absence (S-). The effect of dopamine (DA) receptor antagonism
      on reinforcement and motivational processes was investigated by pretreating
      subjects with 0.0, 0.15 or 0.30 mg/kg of the DA receptor antagonist drug,
      haloperidol. Haloperidol had no effect on operant runway performance (i.e. goal
      time) in any condition. However, 24 h later, on the first post-treatment trial,
      those haloperidol animals that received heroin in the goal box on the previous
      trial (i.e. the S+ condition) ran reliably more slowly than subjects that
      received vehicle on the previous S+ trial. These results suggest that haloperidol
      does not affect the motivational properties of stimuli which predict the
      availability of heroin, while it does diminish the reinforcing effects of
      actually receiving heroin.

PMID- 8657833
TI  - Euphorigenic doses of cocaine reduce [123I]beta-CIT SPECT measures of dopamine
      transporter availability in human cocaine addicts.
AB  - The in vivo potency of euphorigenic doses of intravenous cocaine for displacing
      [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding
      to striatal dopamine transporters (DAT) was assessed in human cocaine addicts
      using single photon emission computed tomography (SPECT). Cocaine-dependent
      subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under
      equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/-
      0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non
      specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a
      measure proportional to DAT binding potential. Regression analysis of the logit
      transformed data enabled reliable determination of the Hill coefficient (0.51)
      and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data
      suggest that cocaine produces behavioral effects in humans at measurable levels
      of DAT occupancy.

PMID- 8657832
TI  - Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors
      and place conditioning.
AB  - Dose-dependent effects of 7-OH-DPAT on several behaviors, including place
      preference, were assessed. Three 2-day conditioning trials were conducted. On 1
      day, animals received an injection of one of eight doses of 7-OH-DPAT (0-5 mg/kg)
      and were placed into a distinct compartment for 40 min. On the other day, animals
      received an injection of saline and were placed into a different compartment for
      40 min. Locomotion, sniffing, and yawning were measured following the first and
      last injection of 7-OH-DPAT. Place conditioning was assessed on the day following
      the last trial. 7-OH-DPAT produced a U-shaped dose-dependent change in locomotion
      and sniffing, and an inverted U-shaped dose-dependent change in yawning.
      Additionally, repeated administration of 0.1 mg/kg sensitized yawning, whereas 5
      mg/kg sensitized locomotion. None of the doses of 7-OH-DPAT produced conditioned
      place preference, however, there was a trend for conditioned place aversion at
      0.03 mg/kg. By contrast, LiCl (127 mg/kg) produced conditioned place aversion and
      amphetamine (1 mg/kg) produced conditioned place preference using the same
      conditioning parameters. A subsequent experiment in which the number of animals
      and conditioning trials were increased demonstrated that the 0.03 mg/kg dose of 7
      OH-DPAT produced conditioned place aversion. 7-OH-DPAT has a higher affinity for
      D3 receptors relative to D2 receptors. Therefore, it is suggested that
      intermediate doses (0.01-0.1 mg/kg) that increase yawning, and decrease
      locomotion and sniffing, may preferentially occupy D3 receptors. Furthermore, the
      results suggest that these putative D3-preferring doses have weak aversive
      effects.

PMID- 8657835
TI  - Anxiety: a potential predictor of vulnerability to the initiation of ethanol self
      administration in rats.
AB  - Anxiolytic effects of ethanol have been proposed to be important factors in the
      initiation of ethanol consumption. To examine this hypothesis, drug-naive Wistar
      rats were tested in the elevated plus-maze to determine their initial level of
      anxiety. Based on their response, we separated the animals into anxious and non
      anxious groups. After that, animals went through an oral ethanol self
      administration procedure. Rats that were initially classified as anxious showed a
      significantly (P < 0.01) higher intake and preference for ethanol during the
      initiation phase of the voluntary drinking procedure than non-anxious animals. In
      another experiment, intraperitoneal (IP) injections of ethanol (0.5-1.5 g/kg)
      produced dose-dependent anxiolytic effects in rats when tested in the elevated
      plus-maze procedure. Blood ethanol levels following IP injections during the plus
      maze test were similar to those reached during the oral ethanol self
      administration procedure, which shows that the rats indeed drank sufficient
      amounts of ethanol to experience its anxiolytic effects. These findings indicate
      that the basal level of anxiety plays an important role in vulnerability to
      alcohol drinking.

PMID- 8657834
TI  - Circadian variation in rat brain AP-1 DNA binding activity after cholinergic
      stimulation: modulation by lithium.
AB  - The potential influence of a circadian rhythm and its modulation by lithium on
      the stimulation of AP-1 DNA binding activity by the cholinergic agonist
      pilocarpine was investigated in rat cerebral cortex. Stimulation of AP-1 binding
      after pilocarpine (30 mg/kg) was evident within 1 h and was maximally stimulated
      by 200% at 2 h. Pilocarpine-stimulated AP-1 binding exhibited a circadian rhythm
      in AP-1 binding measured at 0800, 1200, and 1600 hours, 2 h after pilocarpine.
      Pilocarpine-stimulated AP-1 binding at 0800 hours was approximately twice the
      level measured at 1600 hours. After acute lithium treatment, pilocarpine
      administration induced generalized seizures after about 20 min and stimulated AP
      1 binding which increased continuously for 4.5 h, at which time the stimulation
      was 900% above control. A circadian variation was apparent in AP-1 binding
      stimulated by acute lithium plus pilocarpine, with stimulation at 0800 hours
      being 1.5 times that at 1600 hours. After chronic lithium and pilocarpine, which
      also produced seizures, there was no circadian variation in pilocarpine
      stimulated AP-1 binding. Thus pilocarpine-induced AP-1 binding in rat cerebral
      cortex was influenced by a circadian rhythm, but this was abolished by chronic
      lithium administration.

PMID- 8657836
TI  - Interaction of opioids with antidepressant-induced antinociception.
AB  - The antinociceptive activity of antidepressant drugs is poorly understood. In
      this study, using the acetic acid writhing test in mice, the antinociception
      produced by clomipramine (CLO), maprotiline (MAP), imipramine (IMI), and
      zimelidine (ZIM) was tested and correlated with opioid drugs. All the compounds
      displayed a significant dose-dependent antinociception, which was not antagonized
      by naloxone (NX) or naltrexone (NTX). The administration of morphine (M) plus
      CLO, MAP, IMI or ZIM resulted in a significant additive effect that was
      antagonized by 1 or 10 mg/kg NX or NTX, except in the case of IMI. This finding
      suggests that the additive effect seems to be partially due to activation of
      opioid receptors, except for the case of imipramine. However, aminophylline, a
      non-selective blocker of A1/A2 adenosine receptors, significantly antagonized the
      antinociceptive activity of CLO, IMI, MAP and ZIM, demonstrating an interaction
      at the level of adenosine receptors. This work suggests that the antinociceptive
      activity of antidepressants could be dependent on critical levels of free 5-HT
      and NE at receptor(s) site(s) in CNS and on their interaction with opioid and
      adenosine receptors.

PMID- 8657837
TI  - Do alpha-2 adrenoceptors modify coping strategies in rats?
AB  - Previous research has shown that resident rats treated with alpha 2 adrenoceptor
      blockers display a modified aggressive response towards intruding animals. In the
      present study we report data on the behavioral changes induced by alpha 2
      adrenoceptor blockers in intruder animals. In experiments 1 and 2 intruders
      smaller in body weight than the residents were treated with 0.0, 0.5, and 1.0
      mg/kg CH-38083 and idazoxan, respectively; in experiment 3 weight matched
      intruders were injected with 1 mg/kg CH-38083 or idazoxan. The treatment of
      smaller intruders did not change the behavior of residents. In contrast, weight
      matched intruders injected with alpha 2 adrenoceptor blockers elicited increased
      aggression in residents. Social behaviors, exploration and offensive aggression
      showed insignificant variation in intruders. Defensive behaviors, in contrast,
      showed major changes: in experiments 1 and 2 a dose-dependent decrease in
      immobility and a dose-dependent increase in defensive upright was noticed. In
      experiment 3, high scores of defensive upright were apparent, precluding
      detection of drug-induced changes. However, when the last 5 min of the encounter
      were analysed separately, results similar to the first two experiments were
      observed. Significant negative correlations were found between immobility and
      defensive upright scores. The results suggest that alpha 2 adrenoceptor blockers
      induce a shift from a passive (immobility) towards a more active (defensive
      upright) coping style. These and previous data show that alpha 2 adrenoceptor
      blockers, other than yohimbine, seem to exert a behavior-activating effect in
      rats.

PMID- 8657838
TI  - A double-blind, randomized, placebo-controlled, multi-center study of brofaromine
      in the treatment of post-traumatic stress disorder.
AB  - A large multi-center, double-blind, parallel trial to assess the efficacy of
      brofaromine in the treatment of post traumatic stress disorder (PTSD) failed to
      show a significant difference between the brofaromine and placebo treatment
      groups. The placebo response rate in this study was higher than that in
      previously published double-blind, placebo-controlled studies of PTSD.

PMID- 8657839
TI  - Nicotine self-administration in rats.
AB  - Considering the importance of self-administration models in determining
      mechanisms of drug maintained behavior, we attempted to replicate the findings of
      nicotine self-administration by Corrigall and Coen. Male, Sprague-Dawley rats,
      trained on food reinforcement, acquired relatively high and stable rates of self
      administration of IV nicotine bitartrate (0.03 mg/kg, free base). Extinction and
      reacquisition followed substituting saline and then nicotine, respectively.
      Responses, infusions and intake decreased at 0.003 mg/kg, while intake increased
      at 0.06 mg/kg. This model of nicotine self-administration provides a reliable
      alternative to experimenter-administration models for examining the effects of
      nicotine.

PMID- 8657841
TI  - Uses of dreams.

PMID- 8657840
TI  - The effects of scopolamine, lorazepam, and glycopyrrolate on classical
      conditioning of the human eyeblink response.
AB  - Human eyeblink conditioning, a relatively simple form of learning and memory, has
      previously been shown to be impaired by the central and peripheral
      anticholinergic scopolamine. The present study compared the behavioral effects of
      scopolamine with the benzodiazepine lorazepam and a peripherally active
      anticholinergic, glycopyrrolate. Thirty-six healthy normal volunteers (mean age:
      23.7 years) were studied with 12 assigned double-blind to each of three drug
      conditions (0.5 mg scopolamine IV, 2 mg lorazepam PO, or 0.2 mg glycopyrrolate
      IV). Subjects underwent classical conditioning of the eyeblink response in which
      the conditioned stimulus was an 80 dB binaural tone, and the unconditioned
      stimulus was a 2 psi airpuff to the right eye. Ten trials of unpaired stimulus
      presentations were followed by 60 paired trials and finally by an extinction
      period of five tone-alone presentations. An eyeblink response that occurred
      during the tone but before the airpuff was scored as a conditioned response (CR).
      Subjects treated with lorazepam (43% mean CRs) and scopolamine (51% mean CRs)
      exhibited a significantly lower asymptotic level of conditioning than those
      treated with glycopyrrolate (85% mean CRs; P < 0.01). However, during extinction,
      lorazepam-treated subjects (35% CRs) showed a lower overall level of responding
      to the tone than either scopolamine (60% CRs) or glycopyrrolate (62% CRs) treated
      subjects (P < 0.05). It seems unlikely that these differences could be accounted
      for by drug-induced alterations in motor responses because there were no
      significant differences between the three drug conditions in the frequency,
      latency, or amplitude of unconditioned responses to the airpuff. Overall, our
      data indicate that scopolamine and lorazepam impair eyeblink conditioning and
      suggest that some of the effects of benzodiazepines and anticholinergics on
      learning and memory can be differentiated using this paradigm.

PMID- 8657842
TI  - Porphyria: reexamination of psychiatric implications.
AB  - Acute intermittent porphyria mimics a variety of commonly occurring disorders and
      thus poses a diagnostic quagmire. Psychiatric manifestations include hysteria,
      anxiety, depression, phobias, psychosis, organic disorders, agitation, delirium,
      and altered consciousness ranging from somnolence to coma. Some patients develop
      psychosis similar to schizophrenia. Psychiatric hospitals have a disproportionate
      number of patients with this disorder as only difficult and resistant patients
      accumulate there. Presence of photosensitive porphyrins in the urine is
      diagnostic. When porphyrins are absent, excess of alpha aminolevulinic acid and
      porphobilinogen are present in the urine. The definitive test is to measure
      monopyrrole porphobilinogen deaminase in RBCs. This diagnosis should be
      entertained in the following situations: (a) unexplained leukocytosis; (b)
      unexplained neuropathy; (c) etiologically obscure neurosis or psychosis; (d)
      'idiopathic' seizure disorder; (e) unexplained abdominal pain; (f) conversion
      hysteria, and (g) susceptibility to stress. Porphyria is important in psychiatry
      as it may present with only psychiatric symptoms; it may masquerade as a
      psychosis and the patient may be treated as a schizophrenic person for years; the
      only manifestation may be histrionic personality disorder which may not receive
      much attention. Diagnosis is based on a high index of suspicion and appropriate
      investigation. Various psychotropic drugs exacerbate acute attacks. While it is
      important not to use the unsafe drugs in porphyric patients, it is also
      imperative to look for this diagnosis in cases where these drugs produce
      unprecedented drug reactions.

PMID- 8657843
TI  - Beyond the Hamilton depression scores in long-term treatment of manic-melancholic
      patients: prediction of recurrence of depression by quality of life measurements.
AB  - This study should be considered as a pilot study to investigate the applicability
      and validity of quality of life scales in manic-melancholic patients in long
      term, prophylactic treatment. The quality of life instruments included the
      SmithKline Beecham Quality of Life (SBQOL) scale, the PCASEE questionnaire (a
      modified paper-and-pencil version of the computerized SBQOL), the Psychological
      General Well-Being (PGWB) scale, and the Medical Outcomes Study (SF-36) scale.
      The patients (n = 23) fulfilled the DSM-IV criteria of bipolar or recurrent
      depressive disorders. They were investigated in a symptom-free period (HAM-D <
      14) and again 4 weeks later. The results showed that the quality of life scales
      had an adequate applicability and internal validity. Furthermore, at first visit
      a factor analysis identified two factors of which the quality of life scales
      loaded on the first factor (positive well-being) and the Hamilton scales loaded
      on the second factor (negative well-being). At the second visit, only one,
      general, factor emerged, because some of the patients had relapsed. Those
      patients with a relapse had low quality of life scores at the first visit
      indicating that the quality of life scales can predict recurrence of depression.

PMID- 8657844
TI  - The Massachusetts General Hospital (MGH) Hairpulling Scale: 1. development and
      factor analyses.
AB  - We developed the MGH Hairpulling Scale to provide a brief, self-report instrument
      for assessing repetitive hairpulling. Seven individual items, rated for severity
      from 0 to 4, assess urges to pull, actual pulling, perceived control, and
      associated distress. We administered the scale to 119 consecutive patients with
      chronic hairpulling. Statistical analyses indicate that the seven items form a
      homogenous scale for the measurement of severity in this disorder.

PMID- 8657845
TI  - The Massachusetts General Hospital (MGH) Hairpulling Scale: 2. reliability and
      validity.
AB  - Assessment of symptom severity and change in chronic hairpulling has been limited
      by the absence of a psychometrically validated clinical rating scale. The
      Massachusetts General Hospital Hairpulling Scale demonstrated test-retest
      reliability, convergent and divergent validity, and sensitivity to change in
      hairpulling symptoms.

PMID- 8657846
TI  - Body size perception and dissatisfaction in female subjects of different ages.
AB  - The relationships between age and both body size estimation and body
      dissatisfaction were assessed by Distorting Television Image Method (DTIM) and
      Body Cathexis Scale (BCS) in a sample of 96 female subjects of ages ranging from
      7 to 65 years. We found that there were no significant body distortion
      differences between different age ranges, although the most accurate perception
      seemed to occur during adolescence. As far as DTIM assessment of body
      dissatisfaction was concerned, adolescents showed no significantly greater
      aesthetic preoccupation than subjects of other age groups. On the other hand,
      using BCS, body dissatisfaction appeared to increase proportionally with age. The
      low, although significant, correlations between these two techniques of measuring
      body dissatisfaction suggest that, in addition to evaluating aesthetic features,
      BCS also assesses the degree of satisfaction with functional body aspects which
      are exposed to unavoidable decline with ageing.

PMID- 8657847
TI  - Defensiveness, cynical hostility and cardiovascular reactivity: a moderator
      analysis.
AB  - We examined the interaction of a defensive need for approval with cynical
      hostility, in the prediction of pressor and heart rate reactivity to a stressful
      mental arithmetic task. For both systolic blood pressure and heart rate, analyses
      revealed the predicted interaction between defensiveness and cynical hostility;
      subsequent analyses showed significant correlations of defensiveness with
      systolic blood pressure and heart rate reactivity only among the high cynical
      hostility subjects. These analyses support the theory and empirical findings
      linking the conflicting traits of cynical hostility and defensiveness to
      cardiovascular reactivity and, quite possibly, to stress-related coronary
      disease.

PMID- 8657848
TI  - Dimensions of anger and hostility in cardiac patients, hypertensive patients, and
      controls.
AB  - Anger and hostility have long been considered important factors in the etiology
      of essential hypertension (EH) and coronary heart disease (CHD). This case
      control study investigates the association of hostility, as measured by the Cook
      and Medley Hostility Scale (HO), and anger, as measured by the Multidimensional
      Anger Inventory (MAI), with CHD and EH in 80 CHD patients, 80 EH patients, and a
      control group of 80 healthy adults from Italy. Cases revealed significantly
      higher scores than controls in two subsets of HO and in two subscales of MAI.
      Some of these subscales appeared to be age-dependent. The results indicate that
      particular components of anger-hostility could be taken into consideration when
      studying psychological risk factors for CHD and EH.

PMID- 8657849
TI  - The use of presleep instructions and dreams in psychosomatic disorders.
AB  - Economic restrictions in health care delivery encourage the development and use
      of efficacious, inexpensive, and brief psychiatric interventions in the treatment
      of psychosomatic illness that can be employed by generalists as well as
      psychiatrists. This article reports on the successful new application of recently
      developed techniques in dream interpretation in three cases of varying
      psychosomatic symptomatology. The improvements noted suggest that this approach
      may provide a rapid, low-cost diagnostic and treatment method appropriate for a
      range of psychosomatic patients.

PMID- 8657850
TI  - Coping with fear of long-term complications in diabetes mellitus: a model
      clinical program.
AB  - Preliminary results are reported on the efficacy of a behaviorally oriented group
      therapy (n = 17) intended to improve coping with fear of long-term complications
      in patients with diabetes mellitus. Treatment consisted of exposure in
      imagination, relaxation training and analysis of dysfunctional health beliefs.
      Pre-, posttreatment and 3-month follow-up measure showed significant improvements
      regarding fear, acceptance of chronic disease and work. The usefulness of such a
      treatment program and the necessarity for further research is discussed.

PMID- 8657852
TI  - [Psychotherapeutic care and public health].
AB  - In 1992 the German Medical Association had passed a resolution in order to adapt
      the specialized training of physicians to future demands. This implied the
      introduction of the new special field of "psychotherapeutic medicine" and a
      redefinition of the special field of "psychiatry and psychotherapy". The
      expectable impacts of these innovations will be discussed regarding future
      perspectives of aims and structures of psychotherapeutic care as well as of
      interdisciplinary research and cooperation with other health-professionals,
      patients, and self-help-organisations. In particular, an argumentation is
      presented, how psychotherapy can be enabled to specific contributions to the
      promotion of the new public health-paradigm in Germany.

PMID- 8657851
TI  - [Quality of the therapeutic relationship: do common factors in psychotherapy
      correspond with common characteristics of psychotherapists? SPR Collaborative
      Research Network].
AB  - In view of the great diversity to be found among psychotherapists in many
      countries in terms of professional background, theoretical orientation, and other
      personal and demographic characteristics, it is surprising to find certain areas
      of great commonality. Among the most striking of these are therapists' reports of
      their ideals and perceptions concerning their manner of relating to their
      patients. A very large majority of nearly 2,400 therapists surveyed in an on
      going study of psychotherapeutic development wanted to and did see their behavior
      vis-a-vis patients as accepting, friendly, warm, tolerant, committed, and
      involved. These traits, which indicate a strong proclivity toward forming a
      positive therapeutic bond or alliance, also closely match qualities that
      therapists perceive in their own personal relationships. Discussion of these
      findings focuses on the possible sources and therapeutic consequences of this
      common pattern of interpersonal behavior.

PMID- 8657854
TI  - [Couple relationship dynamics in transition to parenthood].
AB  - In an prospective longitudinal study of family development, 39 healthy couples
      were examined by the Giessen-Test 1-3 months before and 1 month and 1 year after
      the birth of their first child. The self-assessment and the assessment of the
      other spouse were recorded from both partners. By this procedure information
      relating to intrapsychic and interpersonal dynamics of the couple was obtained.
      It was evident, that during the transition from the preto the postnatal period
      the assessments at the personal as well as at the couples' level remained very
      stable. Our sample showed considerable differences compared to a representative
      couple sample. These differences decreased by the time of the third survey one
      year after the birth of the child. Although pregnancy and the birth of the first
      child seem to cause specific, but transitory changes in the parents self-images
      and in the dynamics of their relationship, our results support the notion of a
      high stability during the transition to parenthood with regard to the self
      concepts of mother and father and especially to the structure of the parental
      dyad.

PMID- 8657853
TI  - [The dream as a relationship paradigm].
AB  - 279 dreams were drawn from a sample of 32 reports on psychoanalytic treatments of
      female patients diagnosed either as hysteric (H) or depressed (D). Depending on
      the gender of the analyst (female = w; male = m) four groups Dm, Dw, Hm, Hw were
      distinguished. Content analysis of the manifest dreams as to the occurrence of
      objects, emotions as well as characteristic object-emotion combinations yielded
      significant differences between groups. The results indicate that dreams can be
      viewed as relationship paradigms.

PMID- 8657855
TI  - [Effects of sexual abuse experiences on therapeutic outcome: study of eating
      disordered patients 2 years after inpatient psychotherapy].
AB  - The incidence of CSA in the general female population is supposed to range
      between 10 and 40 percent. There has not yet been done much research on how CSA
      victims differ in comparison to non-CSA patients in regard to psychotherapy
      outcome. This paper presents the results of a study concerning this problem. 670
      female patients suffering from anorexia or bulimia nervosa, who had undergone an
      inpatient treatment were asked to fill out a questionnaire on their body image
      two years later. Moreover the patients were asked if their symptomatology
      persisted, if they had been satisfied with the therapy, how often they were ill
      (and unable to work) before and after the therapy and if they attempted suicide
      before or after the therapy. The questionnaires of 393 patients could be
      evaluated. 21.1% (n = 83) of them had a history of CSA. There were only few
      statistically significant differences: 1. CSA patients more often improved their
      attitude towards their head and their genitals in comparison to non-CSA patients.
      2. They more often attempted suicide before therapy. 3. After the therapy only
      among the anorexic CSA patients suicidal attempts happened more often than among
      anorexics without CSA. These results suggest that CSA patients benefit from an
      inpatient therapy at least as well as non-CSA patients do. On the other hand
      further qualitative research is needed to understand more about the individual
      coping strategies of CSA victims.

PMID- 8657856
TI  - [Differential aspects of subjective burden of tinnitus aurium].
AB  - This study focuses on psychological variables, which could influence the
      subjectively perceived strain of tinnitus. They concern personality traits such
      as self-attentiveness, control beliefs and different dimensions of psychological
      health. Two groups of tinnitus patients were compared, one with low subjectively
      perceived strain (n = 20), the other with high subjectively perceived strain (n =
      30). Results reveal that people with high subjectively perceived strain do not
      only perceive their tinnitus more often, but they are more self-centered and
      report significantly more general somatic complaints than people with low
      subjectively perceived strain. They obviously pay more attention to themselves
      and as a consequence also to their tinnitus. However, we didn't find any
      relationship between control beliefs and subjectively perceived tinnitus strain.
      Furthermore, duration of the noises, their loudness, their localisation and the
      knowledge of the cause of tinnitus also seem to affect the perception of the
      noises.

PMID- 8657857
TI  - [Effects of relaxation therapy as group and individual treatment of chronic
      tinnitus].
AB  - 42 patients, suffering from chronic tinnitus, participated in our psychological
      orientated treatment consisting of relaxation therapy with autogenic training
      according to J. H. Schultz. The results of individual therapy are compared with
      group therapy. Using visual analogy scales the therapeutical efficiency can be
      tested. The individual estimated loudness and annoyance of tinnitus are
      registered as well as a general emotional status. The results show a positive
      short-time effect in most cases. A reduction of tinnitus loudness and annoyance
      after individual and group therapy is seen directly. A positive effect throughout
      the whole treatment is only found in individual therapy. Concerning the group
      therapy, many of our patients reported an increase of the pretherapeutical
      estimation of tinnitus loudness and -annoyance. We believe that the permanent
      confrontation with the tinnitus problem may advance the psychological conflict in
      many cases. Therefore psychological management of tinnitus should be concentrated
      on a temporary limited support aiming to the neglect of tinnitus sensation.

PMID- 8657858
TI  - [What is forensic psychotherapy?].

PMID- 8657859
TI  - [Psychotherapy as a career].
AB  - The author discusses the professional world and setting of a psychotherapist
      against the background of his subjective and personal experience manifested by
      typical polarities and fields of tension that exemplify in equal measure both the
      special features and the risks inherent in this "impossible vocation". The
      following problems and polarities are dealt with in detail: 1. Who chooses or is
      apt to become a psychotherapist? 2. Vocational training somewhere between method
      oriented meticulousness and innovative keenness to experiment. 3. Self-image-
      projected (foreign) image. 4. Own life--foreign life. 5. Innermost reality and
      individual difficulty in respect of external reality and social integration.

PMID- 8657860
TI  - [Psychotherapy in general practice of physicians and psychologists].
AB  - This study tries to reveal the epidemiology of outpatient psychotherapy in
      practices in a defined northern area of Germany (Schleswig-Holstein, 2.66 Mill.
      inhabitants) by a postal questioning of all medical (n = 242) and psychological
      (n = 45) psychotherapists registered. Psychotherapy was defined as enclosing at
      least 10 meetings. 54.7% of the questionnaires were returned to us. An analysis
      on this database showed that 8310 adult patients were psychotherapeutically
      treated within one year (0.3% of the population). On the base of different
      epidemiological studies the treatment prevalence widely differed from 3.9 to
      31.9%. The majority of diagnoses were reactive disorders or neuroses (52.8%) and
      psychosomatic disorders (24.3%). Patients out of middle and upper social classes,
      with higher educational levels, and from urban areas (> 100 000 inhabitants) were
      more likely to be treated than others. This trend was significantly more apparent
      in psychologists than in physicians.

PMID- 8657861
TI  - [Current status so far: psychotherapy in transition!].
AB  - In the context of the current discussion of the volume by Grawe, Donati and
      Bernauer "Psychotherapie im Wandel; Von der Konfession zur Profession" (1994) the
      main critical points are reviewed regarding essential-theoretical issues. The
      crucial points of the resulting criticism refer to the fact that metastudies are
      historical and culture bound, to etiological validity as well as to ethical
      political implications. One main statement designates the investigation by Grawe
      et al. as a conventional review that bases its conclusions on outcome-studies of
      psychotherapy that are to be considered outdated. Whether it is possible to
      decide which therapy is most effective is as doubtful as the necessity to
      contrast therapeutic orientations by discriminating valuation. The results of
      Grawe's therapy-outcome-analysis are put into a historical and cultural context.
      Thereby the findings are put into relation to particular periods and speech areas
      from which the included studies originate. In this context Grawe's volume appears
      not to be the Ultima ratio but is fruitful to initiate further research.

PMID- 8657862
TI  - The English debate on taxonomy and phylogeny, 1937-1940.
AB  - Between 1937 and 1940 the Taxonomic Principles Committee of the newly-founded
      Association for the Study of Systematics in Relation to General Biology (later
      the Systematics Association) attempted to define the relationship between
      evolution and taxonomy. The people who took part in the discussion were W.T.
      Caleman, C.R.P. Diver, J.S.L. Gilmour, J.S. Huxley, W.D. Lang, J.R. Norman, R.
      Melville, O.W. Richards, M.A. Smith, T.A. Sprague, H. Hamshaw Thomas, W.B.
      Turrill, B.P. Uvarov, A.F. Watkins, E.I. White, and A.J. Wilmott. Most of the
      botanists asserted that taxonomy was a practical matter to be kept distinct from
      phylogenetic speculation, and most of the zoologists insisted that taxonomists
      must strive to represent evolution if they wished to be scientific. The
      disagreement seemed to be hardening rather than approaching compromise when World
      War Two stopped the committee's work.

PMID- 8657863
TI  - [Darwinism, materialism and the revolution of 1848 in Germany. On the interaction
      of politics and science].
AB  - In recent years, the question of national styles in science has received
      increasing attention. The different forms of Darwinism that emerged in the
      nineteenth century provide an impressive example of the role of non-scientific
      factors in the development of scientific ideas. Although the reception of
      Darwinian theory has been acknowledged to differ according to distinct national
      traditions even in Darwin's time, there have been few systematic efforts to
      understand the underlying causal factors. Usually these explanations have
      conceived of the relationship of science to its social and political context as a
      distortion of science by ideology. In contrast to this picture, I attempt to
      demonstrate here how a scientific research program was situated in a concrete
      historical context. The German tradition of Darwinism in the nineteenth century
      will be described as a coalition of political liberalism, materialism, and
      morphology. Whereas the liberals used Darwinism to give their anti-religious and
      progressive program a naturalistic foundation, the morphologists appreciated that
      Darwinian theory allowed them to dispense with the idealistic origins of their
      research program, and the materialist were provided with a naturalistic
      explanation of the origin of organic form.

PMID- 8657864
TI  - Adam, Eve, and other ancestors: a story of human origins told by genes.

PMID- 8657865
TI  - The social and cultural history of medicine and health in Sweden.
AB  - The social and cultural history of medicine and health is a growing field of
      research in Sweden, stimulated by the present political, economic and social
      concern about health and health care. Since there have never been any chairs in
      the history of medicine within the medical faculty, the topic has mostly been
      approached by historians of science and ideas, social historians and
      anthropologists and sociologists interested in long-term developments. Psychiatry
      and psychiatric care is one of the most popular subjects. Other fields are
      professional history and social policy, cultural and local studies on different
      aspects, epidemics and public health and socio-demographic studies of mortality
      and morbidity. This report presents some major Swedish contributions and gives a
      short summary of some of the results. There has, during the recent years, been a
      trend towards interdisciplinary exchange, for instance through Swedish and
      Scandinavian networks, and towards an international orientation that has led to
      comparative studies and exchange of results, a trend that can also be observed in
      many other countries.

PMID- 8657866
TI  - The era of health care reform and the information superhighway. Implications for
      radiology.
AB  - Radiology is undergoing dramatic change, along with the rest of the health care
      system, in its mode of organization, financing, and delivery. Information
      technology is becoming central to health care delivery and will enable a higher
      degree of integration of imaging practice with the rest of the health care
      system. Radiology will need to address the requirements for achieving this
      integration to continue to be successful in the future.

PMID- 8657867
TI  - Image acquisition. Sites, technologies, and approaches.
AB  - This article examines the current and future methodologies for image capture.
      Data conversion devices and systems, radiographic techniques of ionizing and
      nonionizing radiation, passive imaging, and digital image data requirements are
      explored. The author also discusses the problem of how to connect acquisition
      devices to PACS.

PMID- 8657868
TI  - Imaging system architectures for picture archiving and communication systems.
AB  - Picture archiving and communications systems (PACS) provide for the
      intraelectronic management of acquired digital image examination. Mini-PACS are
      image-management systems focused on specific applications. Computer architecture
      to be applied to radiology applications includes pipelining to improve the speed
      of the central processing unit, client and server architecture for distributed
      radiology applications, and image file servers. Image-compression algorithms
      provide increased digital storage and increased image transmission speeds.
      Throughput rates can be improved by identifying the bottlenecks.

PMID- 8657869
TI  - Networks for electronic radiology.
AB  - Next-generation health care systems must successfully integrate hospital
      information, laboratory automation, and medical-image management to provide a
      seamless view of the complete medical record to the primary care physician across
      a distributed medical enterprise. Broadband networks are an important component
      of the systems required to achieve this goal. This article provides a brief
      tutorial on relevant network principles and products, a perspective on the
      evolution of the field, and a simple view of the network requirements posed by
      electronic radiology.

PMID- 8657870
TI  - Workstation design. Image manipulation, image set handling, and display issues.
AB  - The importance of this article is fourfold. First, the introduction of
      workstation technology and the types of image workstations provides readers with
      a better understanding of the state-of-the-art and availability of digital image
      display workstations in the market-place. Second, this article identifies primary
      processes related to image viewing in radiology daily operations. This is crucial
      because it illustrates the important concepts of the Folder Manger with image
      preprocessing, patient folder organization, and automatic image display
      sequencing. With these features incorporated in the workstation design, the
      number of steps required for a radiologist to interact with a workstation is
      minimized. Third, the discussions on how to present and manipulate images on the
      workstations suggest methods concerning the issue of displaying large volumes of
      image sets on a limited number of monitor screens. Lastly, examples of automatic
      image sequencing, high-resolution color monitors, and voice-based user interface
      illustrate current research topics in the future of digital workstation design.

PMID- 8657871
TI  - Three-dimensional imaging, surgical planning, and image-guided therapy.
AB  - Three-dimensional imaging is now widely available and used often to aid in the
      comprehension and application of volumetric data to diagnosis, planning, and
      therapy. CAS comprises visualization of complex anatomy, planning of
      interventions, image-based guidance for diagnosis and therapy, evaluation of
      results, and follow up. CAS-networked workstations have interactive pointing
      devices and specialized software that support simulation, navigation, and follow
      up functions. Volumetric and real time digital imaging are used to plan
      procedures, for intra-operative guidance, and to monitor progress. Monitoring
      with real time ultrasound, fluoroscopy, and MR imaging is performed to assess
      local effects of specific therapeutic modalities. Normative data bases,
      especially digital stereotactic atlases, allow incorporation of a priori anatomic
      knowledge in CAS. Computer-assisted planning and simulation of complex
      craniofacial surgery is feasible with commercially available software and
      hardware using CT scan and MR images. This can be performed by an operator with
      low-level computer skills on a graphics workstation. The outcome of computer
      simulated surgery can be validated quantitatively. Computer-simulated surgery
      does affect the choice of intervention for patients with complex craniofacial
      anomalies. Further evaluation of the process is needed to determine the influence
      of surgical simulation and planning on outcome.

PMID- 8657872
TI  - Image processing and computer-aided diagnosis.
AB  - The future of image processing and CAD in diagnostic radiology is more promising
      now than ever, with increasingly impressive results being reported from various
      observer performance studies in both mammography and chest radiography. Clinical
      trials in years to come will help optimize the accuracy of the programs and
      determine the actual contribution of CAD to the interpretation process.
      Radiologists using output from computer analyses of images, however, will still
      make the final decision regarding diagnosis and patient management. Nonetheless,
      studies have indicated that the computer output need not have greater overall
      accuracy than a given radiologist in order to improve his or her performance. A
      systematic and gradual introduction of CAD into radiology departments will be
      necessary so that radiologists can become familiar with the strengths and
      weaknesses of each CAD program, thereby avoiding either excessive reliance or a
      dismissive attitude toward the computer output. This should ensure the acceptance
      of CAD and optimal diagnostic performance by the radiologist. Thus, an
      appropriate role for each CAD program will be determined for each radiologist,
      according to his or her individual training and observational skills, reducing
      intraobserver variations and improving diagnostic performance.

PMID- 8657873
TI  - Reporting and communications.
AB  - The future of radiology reporting will be molded by the ever changing health care
      environment and developments in computer methods. Less reliance on transcription
      is certain. The challenges of producing faster and more useful reports should be
      rewarding in a positive sense. The next few years should include many computer
      approaches to help the radiologist to generate reports directly and to
      communicate them effectively.

PMID- 8657874
TI  - Decision aids in radiology.
AB  - Computer systems can help radiologists decide which tests to perform and which
      diagnoses to consider. Repositories of clinical data and general medical
      knowledge can provide information on demand for decision-making tasks; many of
      these information resources are available remotely via the Internet. Decision
      support systems can incorporate the techniques of artificial intelligence to
      apply their general knowledge to the features of a particular patient. Successful
      use of these technologies requires careful attention to design, implementation,
      and rigorous evaluation. Computer-based decision aids can improve the cost
      effectiveness and diagnostic accuracy of radiologic practice and are poised to
      play an important role in the future of radiology.

PMID- 8657875
TI  - Educational challenges.
AB  - Despite the efforts of some educators, computers and electronic networks have yet
      to achieve their proper role in education. Advances, such as more intuitive
      software, CD-ROM media, and networks, offer powerful new tools, but technology is
      only one facet of instructional design. Much like effective authors of print
      media, software designers must adhere to certain principles that seem to underpin
      all successful computer-assisted instruction.

PMID- 8657876
TI  - Teleradiology and telemedicine.
AB  - This article provides a historical perspective as well as an update on the
      current state of teleradiology and telemedicine in the United States. Technical
      implementation issues are discussed and enabling technologies are described.
      Considerations that impact network design are outlined including data
      transmission, data compression, applicable standards, and band-width
      requirements. Reimbursement, medicolegal, licensure, and regulatory issues
      related to the delivery of teleradiology and other telemedicine services are
      reviewed. Insight is provided into the role of teleradiology and telemedicine in
      a changing health care environment.

PMID- 8657877
TI  - Technology assessment methods for radiology systems.
AB  - This article discusses the strengths and weaknesses of technology assessment
      methods for the evaluation of novel and complex radiology systems, including
      picture archiving and communication systems (PACS), computed radiography (CR),
      teleradiology, and other new models for the delivery of radiology services. Using
      examples from PACS and CR, we review early economic assessments of PACS from the
      radiology department. We then broaden our perspective to discuss the analytic
      criteria that can be used to evaluate economic analyses of PACS as the health
      care delivery system shifts toward managed care. We close with a proposal for
      optimizing the integration of information technology into the clinical
      environment through ongoing target data collection during the implementation of
      new radiology systems.

PMID- 8657878
TI  - Radiology systems architecture.
AB  - This article focuses on the software requirements for enterprise integration in
      radiology. The needs of a future radiology systems architecture are examined,
      both at a concrete functional level and at an abstract system-properties level. A
      component-based approach to software development is described and is validated in
      the context of each of the abstract system requirements for future radiology
      computing environments.

PMID- 8657879
TI  - [Neuroradiologic findings in arterial cerebral ischemia].
AB  - New therapeutical approaches require neuroradiological description of cerebral
      infarcts under pathogenetical aspects. Knowledge of the pathophysiological
      concepts of arterial cerebral vessel disease is necessary. These concepts are
      described in the first part of this paper. The relation between neuropathologic
      and radiologic findings and the different patterns and pathomechanisms or
      cerebral infarction are reported. In the second part of this paper typical CT-
      and MRI-findings are described and the differential diagnosis of cerebral
      infarcts are discussed.

PMID- 8657880
TI  - [Noninvasive quantification of cerebral blood volume and blood flow with dynamic
      MR tomography. Studies of probands and patients with cerebrovascular
      insufficiency].
AB  - PURPOSE: A non-invasive MR-method for the quantification of regional cerebral
      blood flow (rCBF) and blood volume (rCBV) is used to examine healthy volunteers
      and patients with cerebrovascular disorders. MATERIALS AND METHODS: 20 healthy
      volunteers and 10 patients with severe cerebrovascular disorders were examined.
      MR imaging was performed on a 1.5 T imaging system. Before, during and following
      brief antecubital vein bolus injection of Gd-DTPA, a series of 32 rapid T2*
      weighted gradient echo images of two different slices ere simultaneously acquired
      in order to measure th concentration-time-curves in the brain tissue and the
      arterial input function in the brain feeding arteries. From these series of
      images the concentration-time-curves were computed. Principles of indicator
      dilution analysis were applied to compute rCBF and rCBV. The volunteers underwent
      one examination each. All patients underwent two examinations, one before and the
      second after azetazolamide stimulation. RESULTS: In volunteers the measured rCBF
      and rCBV values are in good agreement with data from positron emission tomography
      studies. In patients with cerebrovascular disorders in the asymptomatic
      hemisphere a mean increase of rCBF of 43,45 +/- 18.04% was observed after
      azetazolamide stimulation. In the affected areas of the symptomatic hemisphere in
      8 from 10 patients the acetazolamide test reveals a significantly reduced
      response to azetazolamide stimulation, indicating an exhausted cerebrovascular
      reserve capacity. CONCLUSION: Dynamic MR-Imaging can provide quantitative
      information about rCBF and rCBV. In patients with cerebrovascular disorders, this
      method can be applied to estimate the cerebrovascular reserve capacity.

PMID- 8657881
TI  - [Angiographic quantification of stenoses of the internal carotid artery].
AB  - BACKGROUND AND PURPOSE: The method of measuring cartid stenosis is under
      discussion since different methods of quantifying carotid stenosis were used in
      the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the
      European Carotid Stenosis Trial (ECST). METHODS: Angiograms from 80 patients (105
      cases of stenosis of the internal carotid artery), performed in a simultaneous
      biplanar manner, were retrospectively analyzed using the NASCET, the ECST method
      and a method based on measurement of the common carotid (CC) artery lumen
      diameter. Each linear measurement was converted into the ?squared? method
      (NASCET2, ECST2, CC2). The linear NASCET and ECST measurements of both views
      (stenosis 1, stenosis 2) were used to calculate the biplanar stenosis according
      to the formula: stenosis = stenosis 1 + stenosis 2 - stenosis 1 * stenosis 2, and
      termed ?local stenosis ECST-bi? and ?distal related stenosis NASCET-bi?
      Furthermore each stenosis was approximated by two neuroradiologists. RESULTS:
      Direct visualization proved agreement with measured local stenosis ECST-bi.
      Squared methods correlated exactly with linear measurements
      (Spearmancorrelation), thus providing no further data. Biplanar calculation
      caused considerable change in the order of the stenosis. The different results of
      the local stenosis ECST-bi and the distal related stenosis NASCET-bi are not
      contradictory, but complementary. CONCLUSIONS: Direct visualization should be
      replaced by measurement of the local stenosis ECST-bi. Biplanar calculation seems
      to give a better estimate of the degree of the stenosis, causing questions since
      the results of ECST and NASCET cannot be applied.

PMID- 8657882
TI  - [Correlation of preoperative neuroradiologic with postoperative histologic
      diagnosis in pathological intracranial processes].
AB  - PURPOSE: To determine the accuracy of preoperative neuroradiological diagnosis of
      pathological intracranial processes in a prospective study. MATERIALS AND
      METHODS: A team of three neuroradiologists determined the diagnosis in CT, MR and
      angiography prior to stereotactic biopsy or operative resection (173 patients).
      Only one diagnosis was allowed, except in those cases with two equally probable
      diagnosis (24 patients). In 106 patients a resection of a brain tumor, in 67
      cases a stereotactic biopsy was performed. According to the histological
      diagnosis the patients were subdivided into three groups: 1: complete agreement:
      the single diagnosis was correct. 2: conditional agreement: on of the 2
      differential diagnosis was correct. 3: no agreement RESULTS: In 131 cases (76%) a
      complete agreement, in 24 cases (14%) a conditional agreement and in 18 patients
      (10%) no agreement were found. Assuming only stereotactic procedures the
      neuroradiological diagnosis was correct in 44 cases (66%) and incorrect in 10
      cases (15%). In 13 patients (19%) one of the two differential diagnosis was
      correct. The specificity of the major tumors was calculated between 92% and 100%.
      The sensitivity for pituitary adenomas (n = 9) and neurinomas (n = 11) was 100%,
      the sensitivity for meningiomas (n = 32) was 94%. A sensitivity was calculated
      between 50% and 71% for astrocytomas (WHO I to WHO IV, n = 64) and metastases (n
      = 24). CONCLUSION: The accuracy was found to be higher than in the comparable
      retrospective studies.

PMID- 8657883
TI  - [Brain metastases of bronchial and breast carcinoma. Differences in metastatic
      behavior and prognosis].
AB  - Evaluation of 135 cases with brain metastases from non-small-cell lung cancer
      (group 1) compared with 51 cases from small-cell lung cancer (group 2) and 56
      cases from breast cancer (group 3) showed that the frequency of solitary
      metastases was significantly higher in group 1 and 3. However, in group 2 lesions
      without surrounding edema occurred more frequently. The rate of patients with
      extracerebral metastases was significantly higher in groups 2 and 3. The longest
      median interval between primary tumor and brain metastases was observed in breast
      cancer patients. The highest local remission rate was seen in small-cell lung
      cancer if patients who received whole-brain irradiation of 30 Gy alone were
      compared (63% vs 45% in group 1 and 52% in group 3). However, with regard to
      clinical course no significant differences were recorded. Survival of lung cancer
      cases was similar, whereas breast cancer cases survived significantly longer,
      both after radiotherapy alone and after surgery plus radiotherapy. This might be
      caused by differences in the natural course of the two diseases as well as
      adjuvant treatment modalities like hormone and chemotherapy. In conclusion,
      because long-term survivors were observed only in the breast cancer group, these
      patients probably have the highest chance of profiting from a locally aggressive
      treatment approach.

PMID- 8657884
TI  - [Magnetic resonance angiography of intracranial aneurysms after subarachnoid
      hemorrhage].
AB  - Magnetic resonance angiography is now commercially available for a variety of
      scanners and is being increasingly applied in the diagnosis of cerebrovascular
      disorders. Considering the clinical consequences, especially in intracranial
      aneurysms, studies to determine the sensitivity and specificity of the method are
      essential. Here we report our experience with a 3D-FISH time-of-flight magnetic
      resonance angiography protocol in 52 patients who have suffered an acute
      subarachnoid hemorrhage. In 26 of the 52 patients, conventional angiography
      identified 31 aneurysms (3-20 mm) that were confirmed during surgery or autopsy.
      Magnetic resonance angiography correctly identified 28 of the 31 aneurysms
      (sensitivity 90.3%) and missed one ruptured (3 mm) and two incidental aneurysms
      (3 mm) in patients with multiple aneurysms. The sensitivity for a ruptured
      aneurysm was 96%. The 26 patients who suffered subarachnoid hemorrhage without
      evidence of an intracranial aneurysm on repeated angiography served as a control
      group. Magnetic resonance angiography revealed no false-positive findings,
      resulting in a specificity of 100%. In correlation with the literature, we
      conclude that magnetic resonance angiography is not sensitive enough for the
      management of acute subarachnoid hemorrhage. However, the method provides
      important complementary information for definition of the bleeding site in
      patients with multiple aneurysms. In addition, the calculation of projections not
      possible with conventional angiography can aid surgical planning. Since only very
      small aneurysms were missed by magnetic resonance angiography, the sensitivity
      seems appropriate to screen asymptomatic patients who are at risk for
      intracranial aneurysms.

PMID- 8657885
TI  - [Titanium aneurysm clips and their advantages in diagnostic imaging].
AB  - Aneurysms clips made of a titanium alloy (TiAl6V4) were used in clinical practice
      for the first time. The design of the clips is identical to the routinely used
      Yasargil series. In 30 patients, 38 symptomatic and asymptomatic aneurysms were
      fixed with 45 clips. Metallurgical advantages of the new alloy are better
      biocompatibility, less magnetic susceptibility, and lower X-ray density. The
      postoperative imaging results are superior to the conventionally used alloys with
      respect to artifact reduction in computed tomography, angiography, and magnetic
      resonance imaging. With a follow-up period of 7 months, a statement on
      biocompatibility cannot yet be given.

PMID- 8657886
TI  - [Creutzfeldt-Jakob disease. What is the role of MR tomography?].
AB  - Creutzfeldt-Jakob disease (CJD) is a rare, but fatal and transmissible brain
      disease. The clinical diagnosis is based upon progressing dementia, myoclonic
      jerks and characteristic EEG changes, but it is difficult to diagnose and not
      only in the early phase of the disease. Cerebral biopsy is reserve for individual
      selected cases and contested because of the danger of contamination from
      instruments and potential transmission. We report three patients with
      histologically confirmed CJD and confirm that MRI is a valuable tool for the
      diagnosis of this disease.

PMID- 8657887
TI  - [Dopamine (D2) receptor SPECT with 123I-iodobenzamide (IBZM) in diagnosis of
      Parkinson syndrome].
AB  - For effective drug therapy of Parkinson's syndrome (PS), it is necessary to
      distinguish between idiopathic and secondary genesis and PS in neuronal systemic
      degeneration. [123I]Iodobenzamide ([123I] IBZM) is a radiolabelled benzamide and
      binds specifically to the cerebral dopamine receptor (D2) in the basal ganglia.
      The purpose of this study was to determine the value of the [123I]IBZM D2
      receptor SPECT in the differential diagnosis of PS. A total of 38 patients (20
      females, 18 males; age 61 +/- 13.3 years), with typical extrapyramidal symptoms
      were investigated. Twenty suffered from idiopathic and 11 from secondary PS.
      Seven patients in whom a neurological disease could be excluded, served as
      controls. SPECT data were acquired 90 min after i.v. injection of 185-200 MBq
      [123I]IBZM. After reconstruction with a Butterworth filter (cutoff frequency 0.5)
      and attenuation correction (coefficient 0.12 cm(-1)) we quantify the IBZM basal
      ganglia uptake as ratio to teh frontal D2-receptor-free cortex (BG/FC). The
      patients with idiopathic PS (IPS) and the controls revealed high and specific
      IBZM uptake in the basal ganglia compared to the adjacent frontal brain tissue
      (IPS: BG/FC = 1.44 +/- 0.10; controls: BG/FC = 1.48 +/- 0.10). A significant
      decreased striatal IBZM uptake is found in cases with secondary PS (BG/FC = 1.25
      +/- 0.10; p<0.0001, t-test compared to controls and IPS). The patient group with
      IPS can be subdivided into patients without L-dopatherapy (BG/FC = 1.49 +/-
      0.07), patients with longstanding L-dopa-therapy demonstrating significantly
      decreased striatal IBZM uptake (BG/FC = 1.31 +/- 0.04; p<0.0001, t-test compared
      to controls and other IPS), which correlates pathophysiological with a reduction
      of free D2 receptors, and patients with de novo PS showing a slight increased
      striatal IBZM uptake (BG/FC = 1.56 +/- 0.05), which represents D2-receptor
      stimulation. [123I]IBZM-SPECT is a sensitive and non-invasive test for striatal
      D2-receptor density and activity which permits relatively clear discrimination
      between idiopathic and secondary PS and yields important information for
      differential therapy.

PMID- 8657888
TI  - [Lumbar facet syndrome. Recommendation for staging before and after intra
      articular injection treatment].
AB  - INTRODUCTION: Lumbar facet joint syndrome is normally based on spondylarthrosis.
      One of the most common methods of treating it is intra-articular injection of
      local anaesthetics and cortisone. In this prospective study our goal was to have
      an objective grading scale to assess the severity of lumbar facet syndrome before
      and after injection. METHODS: Thirty-two patients were treated by CT-guided intra
      articular injections of 0.3 ml bupivacaine and 0.8 ml methylprednisolone. Five
      different parameters were scored in each patient: (1) finger-ground distance; (2)
      Schober index (10 cm distance along lumbar spine, difference in cm after flexion
      of lumbar spine); (3) rotation of lumbar spine; (4) lumbago; (5) pseudoradicular
      pain. The last two parameters were evaluated by a visual analog score (VAS) with
      zero for no pain and 10 for worst possible pain. Each parameter was evaluated
      with one, two or three points. After adding the points, we graded the severity of
      lumbar facet joint syndrome. RESULTS: Finger-ground distances improved
      statistically (P<0.05). Schober index and rotation of lumbar spine were not
      significant. VAS concerning lumbago and pseudoraducular pain were also
      statistically significant (P<0.001). Thirteen patients remained in the same
      grade, 18 patients improved by one grade and 1 patient by two grades. DISCUSSION:
      The grading system presented for assessing lumbar facet joint syndrome is a good
      parameter to evaluate the severity of the disease and follow-up after injection
      of local anaesthetics and cortisone. Although they showed no statistical
      significance, Schober index and rotation of lumbar spine are necessary to
      evaluate facet syndrome.

PMID- 8657889
TI  - [Anatomy and pathology of the parotid gland. COrrelation with magnetic resonance
      tomography].
AB  - Due to a very complex embryological development a variety of different tissues
      are mixed together within the parotid gland. Secondary degenerative metaplastic
      and regenerative alterations result in additional tissue variety. Epithelial
      cells of distinct differentiation, lymphatic tissue, partly within lymph nodes,
      partly in clusters, sebaceous tissue, fat and peripheral nervous tissue may be
      the origin of a pathological neoplastic or inflammatory intraparotid lesion. MRI
      is an optimal tool for the delineation of the anatomy of the parotid gland and of
      various intraparotid lesions and often permits differentiation among malignant
      and benign neoplastic and inflammatory lesions. The morphology of the different
      pathological lesions on MRI reflects the underlying histopathology. Due to great
      interindividual variations in the tissue characterization of a specific
      intraparotid lesion, great differences in MR morphology have to be expected.

PMID- 8657890
TI  - [100 years roentgen rays--a discovery conquers the medical world].
AB  - In the second half of the nineteenth century the prerequisites for research on
      the discharge of electricity in gases and the related phenomena were fulfilled.
      The first gas discharge tubes are associated with names like GeiBler, Hittorf,
      Crookes, Goldstein, Lenard and Hertz. These researchers studied the electrons
      escaping from the cathode, magnetic and electrical influence, chemical results,
      loss of energy and heating up of the anode. Lenard and Jackson were the first to
      describe phenomena outside the tube, but related the effects to electrons. It was
      W.C. Roentgen who discovered the ?unknown rays?; he systematically measured their
      penetrating properties and described them a short time thereafter. The scientific
      world was ready for this discovery, and the new of Roentgen's findings spread
      across the world in a matter of days, followed by intensive development of this
      innovation. The first and most important 35 years of development of the different
      types of X-rays tubes are described.

PMID- 8657891
TI  - [Osteopenia in childhood. Hereditary hyperphosphatasia].

PMID- 8657892
TI  - [Limits of rationality in health policy].

PMID- 8657893
TI  - [Invasion of the growth plate by bone tumors and osteomyelitis in childhood].

PMID- 8657894
TI  - Calcium pyrophosphate dihydrate crystal deposition disease revisited.

PMID- 8657895
TI  - MR imaging appearance of the uterus in postmenopausal women receiving tamoxifen
      therapy for breast cancer: histopathologic correlation.
AB  - PURPOSE: To describe the spin-echo and dynamic gadolinium-enhanced magnetic
      resonance (MR) imaging appearance of the uterus in women receiving tamoxifen.
      MATERIALS AND METHODS: Thirty-five postmenopausal women with breast carcinoma
      receiving tamoxifen therapy underwent pelvic MR imaging. T1-weighted, T2
      weighted, and dynamic gradient-echo T1-weighted sequences were used. Twenty-seven
      patients underwent uterine sampling within 3 months of MR imaging. RESULTS:
      Endometrial width on T2-weighted images ranged from 0.1 to 7.5 cm (mean
      thickness, 1.1 cm). Two uterine imaging patterns were noted. Patients with
      pattern 1 findings had homogeneous high signal intensity of the endometrium on T2
      weighted images (mean, 0.5 cm) and enhancement of the endometrial-myometrial
      interface and a signal void in the lumen on gadolinium-enhanced images (18
      patients). Patients with pattern 2 findings had heterogeneous endometrial signal
      intensity on T2-weighted images (mean, 1.8 cm) with enhancement of the
      endometrial-myometrial interface and latticelike enhancement traversing the
      endometrial canal on gadolinium-enhanced images (17 patients). Other imaging
      findings included subendometrial cysts, nabothian cysts, leiomyoma, and
      adenomyosis. Ten patients with pattern 1 findings had atrophic or proliferative
      endometria at histopathologic analysis; 12 of the 17 patients with pattern 2
      findings had polyps, one of which had a focus of endometrial carcinoma.
      CONCLUSION: MR imaging of the uterus showed two distinct patterns in women
      receiving tamoxifen therapy.

PMID- 8657896
TI  - A practical approach to minimally invasive breast biopsy.
AB  - With the development of stereotactic or ultrasound-guided, large-core
      percutaneous breast biopsy and the evolution of mammotomy, radiologists are now
      able to render definitive diagnoses of breast lesions. To ensure success,
      however, there must be a commitment at the outset to put into place the required
      personnel and equipment. The radiologists involved must conscientiously adhere to
      standardized technique and be willing to assume clinical responsibility,
      including comprehensive follow-up methods. With these commitments, radiologists
      can substantially increase their contribution to the care of patients with a
      breast abnormality.

PMID- 8657897
TI  - Interlobular vasculature in renal transplants: a power Doppler US study with MR
      correlation.
AB  - PURPOSE: To evaluate, with power Doppler (PD) ultrasound (US), the normal
      interlobular vasculature in patients who underwent renal transplantation and to
      assess if defects of the PD signal at the interlobular level correspond to
      cortical areas that lack blood perfusion at magnetic resonance (MR) imaging.
      MATERIALS AND METHODS: Thirty-two normal and 33 malfunctioning transplanted
      kidneys were studied with PD US (6.5 MHz). PD images of interlobular vessels were
      graded on a scale of normal (pattern I) and decreasing visualization. In kidneys
      with focal (pattern II) and diffuse (pattern III) absence of interlobular signal,
      correlative dynamic MR imaging was performed. RESULTS: Interlobular vessels were
      consistently depicted with PD US in the proximal cortex of normally functioning
      transplanted kidneys. Of kidneys with a pattern II appearance, five had no
      contrast material enhancement in the cortical sites in which the interlobular PD
      signal was detected and three were contrast enhanced but it was less intense than
      that in adjacent cortical sites with normal interlobular vasculature. All
      transplanted kidneys with a pattern III appearance had delayed contrast
      enhancement. CONCLUSIONS: Although PD US appears to depict the interlobular
      vasculature up to the renal capsule, care should be taken in the diagnosis of
      perfusion defects, since absence of detectable flow at the interlobular level
      does not always correspond to cortical areas that lack perfusion on MR images.

PMID- 8657898
TI  - High-dose administration of nonionic contrast media: a retrospective review.
AB  - PURPOSE: To assess the safety of high-dose nonionic contrast media (CM) during a
      single radiologic procedure. MATERIALS AND METHODS: From November 1991 to August
      1995, 255 high-dose angiographic procedures were performed in 228 patients with
      normal serum creatinine (SCr) levels (< or = 1.6 mg/dL [141 mumol/L]). All
      patients received 250-800 mL low-osmolarity CM (300 mg iodine per milliliter).
      Pre- and postprocedure SCr levels were assessed. Urine output was measured daily
      in the 75 patients who received more than 400 mL CM. With linear regression
      analysis, a dose-related elevation in SCr levels was calculated. RESULTS: No
      patient developed abnormal SCr levels (> 1.6 mg/dL [141 mumol/L]) as a result of
      the CM. Among the patients who received more than 400 mL, none developed oliguria
      over the first 36 hours. With follow-up up to 3 years, no patient experienced
      delayed clinical renal failure. In 11 (4.3%) patients, the SCr levels increased
      more than 25%, but all increases were within expected limits (chi 2 analysis).
      Linear regression analysis revealed a 0.015 mg/dL (1 mumol/L) increase in SCr
      levels per 100 mL CM. CONCLUSION: Intravenous administration of high-dose low
      osmolarity iodinated CM appears safe in patients without renal dysfunction or
      other underlying risk factors, in doses as large as 800 mL (300 mg iodine per
      milliliter).

PMID- 8657899
TI  - Graves ophthalmopathy: intracranial fat prolapse on CT images as an indicator of
      optic nerve compression.
AB  - PURPOSE: To determine the usefulness of a number of imaging features in the
      differentiation of patients with Graves ophthalmopathy who had optic neuropathy
      from those who did not. Intracranial herniation of orbital fat through the
      superior ophthalmic fissure and its clinical importance was also assessed.
      MATERIALS AND METHODS: The computed tomographic (CT) appearance of the orbital
      apex was examined in 50 patients without and in 50 patients with Graves
      ophthalmopathy. The clinical diagnosis of optic neuropathy was made by an
      ophthalmologist who was unaware of the imaging appearances and was based on
      clinical features and abnormalities of visual evoked potentials or changes at
      automated perimetry. RESULTS: Intracranial fat prolapse (P < .001) and optic
      nerve crowding (P < .05) were the only imaging features that were independently
      related to optic neuropathy. The presence of intracranial fat prolapse or optic
      nerve crowding on CT scans helped identify 16 of 17 patients with optic
      neuropathy. Sensitivity was 94%, specificity was 91%, positive predictive value
      was 69%, and negative predictive value was 98%. CONCLUSION: Intracranial fat
      prolapse correlates closely to the presence of optic neuropathy in Graves
      ophthalmopathy. This sign, in combination with optic nerve crowding, demonstrates
      a closer correlation to optic neuropathy than previously described imaging
      features.

PMID- 8657900
TI  - MR sialography. Work in progress.
AB  - PURPOSE: To develop a noninvasive method for demonstrating the main salivary
      gland duct systems. MATERIALS AND METHODS: The authors developed a magnetic
      resonance (MR) imaging protocol that uses a heavily T2-weighted (echo time, 750
      msec), fat-suppressed pulse sequence and rapid acquisition with relaxation
      enhancement. The technique was optimized to depict fluid within a two-dimensional
      thick slab. A preliminary evaluation was performed by examining the major
      salivary gland ducts in 10 asymptomatic volunteers and three symptomatic patients
      with known salivary duct abnormalities. RESULTS: The main parotid gland ducts
      were clearly demonstrated in all volunteers. The submandibular ducts were visible
      in all cases, although not always on projection images. In the three patients,
      the MR technique clearly demonstrated bilateral sialectasis, a calculus
      obstructing the left submandibular duct, and a fluid-filled ranula, respectively.
      CONCLUSION: Preliminary work indicates that this MR technique can successfully
      demonstrate both normal and abnormal parotid and submandibular gland duct systems
      and has several advantages over conventional x-ray sialography.

PMID- 8657901
TI  - Recurrence of head and neck cancer after surgery or irradiation: prospective
      comparison of 2-deoxy-2-[F-18]fluoro-D-glucose PET and MR imaging diagnoses.
AB  - PURPOSE: To evaluate the diagnostic accuracy of positron emission tomography
      (PET) with administration of 2-deoxy-2-[fluorine-18]fluoro-D-glucose (FDG)
      relative to that of magnetic resonance (MR) imaging and/or computed tomography
      (CT) in recurrent head and neck cancers. MATERIALS AND METHODS: Twelve adult
      patients (mean age, 63 years) with previously treated head and neck cancers and
      clinical suspicion of recurrence underwent FDG PET and MR imaging and/or CT. All
      images were blindly and independently interpreted without histopathologic
      findings (obtained within 1 week of imaging). The level of confidence in image
      interpretation was graded by using a five-point rating system (0 = definitely no
      recurrence to 4 = definite recurrence). RESULTS: Recurrence was confirmed in
      eight patients. With a rating of 4 as a positive finding, FDG PET yielded a
      sensitivity and specificity of 88% (seven of eight) and 100% (four of four),
      respectively; MR imaging and/or CT, 25% (two of eight) and 75% (three of four),
      respectively. Receiver-operating characteristic analysis showed significantly
      better diagnostic accuracy with FDG PET than with MR imaging and/or CT (area
      under curve = 0.96 vs 0.55, P < .03). CONCLUSION: These data indicate that PET
      metabolic imaging, as compared with anatomic methods, has improved diagnostic
      accuracy for recurrent head and neck cancer.

PMID- 8657902
TI  - Intervertebral disks on MR images: variation in signal intensity with the disk-to
      magnetic field orientation.
AB  - PURPOSE: To demonstrate and quantitate the magic angle effect in the
      intervertebral disk. MATERIALS AND METHODS: Magnetic resonance (MR) images of a
      lumbar intervertebral disk in a healthy volunteer were obtained with MR images
      with horizontal and vertical magnetic fields. Thin-section spin-echo images of an
      excised intervertebral disk were obtained with a horizontal field machine at
      orientations with respect to the main magnetic field between +90 degrees and -90
      degrees. T1 and T2 were measured independently in this disk at two orientations.
      RESULTS: Images of the in vivo disk demonstrated a variation in the signal
      intensity of the anulus fibrosus that was different for the two MR units. The
      images obtained in the excised intervertebral disk demonstrated a signal
      intensity variation with disk orientation that was most pronounced in the
      anterior portion of the anulus. Relaxation time measurements showed the signal
      intensity reduction to arise from a reduction in T2 with oblique orientations.
      CONCLUSION: The observed signal intensity variation with disk orientation arises
      from an anisotropy in T2 caused by the restriction of water associated with
      collagen in the anulus. The magic angle effect in intervertebral disks will be
      observed with vertical magnetic field MR imagers.

PMID- 8657903
TI  - Mapping of the cortical motor hand area with functional MR imaging and MR imaging
      guided laser-induced interstitial thermotherapy of brain tumors. Work in
      progress.
AB  - PURPOSE: To localize the cortical motor hand area with functional magnetic
      resonance (MR) imaging before and after MR imaging--guided laser-induced
      interstitial thermotherapy of tumors in the precentral brain region to control
      energy delivery and to improve safety. MATERIALS AND METHODS: Functional MR
      images were obtained in eight patients (five men, three women; aged 27-63 years)
      while they flexed their fingers. MR imaging--guided laser-induced interstitial
      thermotherapy was terminated when there was less than 8-12 mm between the border
      of the laser-induced lesion and the motor hand area anterior aspect. RESULTS:
      Seven patients had a statistically significant localized change in signal
      intensity in the central region of the contralateral hemisphere. This area was a
      spotlike circumscribed focus in three patients and scattered over a larger zone
      in four patients. Persistent deficits did not occur after thermotherapy in any
      patient. In three patients, onset of reversible perifocal edema in the motor hand
      area coincided with the development of hemiparesis, which completely resolved. No
      patient had activity within the tumor on functional MR images. CONCLUSION:
      Functional MR imaging findings can be used to prevent neurologic damage during MR
      imaging--guided laser-induced interstitial thermotherapy.

PMID- 8657904
TI  - The mechanisms of positional dysfunction of subclavian venous catheters.
AB  - PURPOSE: To determine the origin of subclavian vein catheter and lead
      dysfunction. MATERIALS AND METHODS: Cineradiography was performed on 10 patients
      with subclavian venous catheter dysfunction and three patients with pacemaker or
      defibrillator lead dysfunction. The leads and catheters were removed and replaced
      with use of a fluoroscopically guided technique; the needle entered the vein
      lateral to the first rib. Repeat cine examinations were performed following
      placement of new catheters. RESULTS: The cause of the dysfunction of all 10
      catheters was shown to be pinch by the subclavicular musculotendinous tissues as
      the catheter passed below the clavicle toward its entry into the vein. All three
      leads were entrapped in the subclavicular tissues and stretched during abduction.
      The abnormal motion and clinical problems were eliminated after replacement.
      CONCLUSION: Subclavian catheter and lead malfunction is not due to compression
      between the first rib and the clavicle. It is due to entrapment in the subclavius
      muscle-costoclavicular ligament complex, which binds or compresses the device
      during movements. These problems can be avoided by employing fluoroscopically
      guided puncture techniques that enter the vein lateral to the first rib.

PMID- 8657905
TI  - Renal artery stenosis: endovascular flow wire study for validation of Doppler US.
AB  - PURPOSE: To compare the accuracy of proximal and peripheral Doppler parameters
      for detection of renal artery stenosis (RAS). MATERIALS AND METHODS: The authors
      obtained absolute velocities and peripheral Doppler waveforms in 16 stenotic and
      14 normal renal arteries by using a 0.45-mm endovascular flow wire.
      Hemodynamically significant stenosis was established by measuring transstenotic
      invasive pressure gradients, with a 10 mm Hg or greater pressure drop indicating
      RAS. Accuracy of the Doppler parameters and of digital subtraction angiographic
      (DSA) results were compared by using receiver operating characteristic analysis.
      RESULTS: Measurements of absolute velocities at the site of the stenosis (maximal
      peak systolic velocity [PSVmax], PSV ratio, renal artery-to-aortic PVS ratio)
      showed high accuracy for diagnosis of RAS similar to that of DSA (areas under the
      ROC curve were 0.96, 0.97, 0.93, respectively). The distal intrarenal Doppler
      indexes (notably loss of early systolic peak, acceleration, acceleration time,
      pulsatility index, and resistive index) did not show statistically significant
      correlation with RAS. CONCLUSION: Doppler measurements in the main renal artery
      correlate well with RAS. The intrarenal Doppler spectrum, however, has no
      diagnostic value. The authors conclude that duplex Doppler US is not a suitable
      screening test for RAS.

PMID- 8657906
TI  - Pulmonary emboli from pulse-spray and mechanical thrombolysis: evaluation with an
      animal dialysis-graft model.
AB  - PURPOSE: To compare pulmonary emboli resulting from pulse-spray
      pharmacomechanical thrombolysis (PSPMT) and mechanical thrombolysis performed to
      declot dialysis-access grafts. MATERIALS AND METHODS: Polytetrafluoroethylene
      arteriovenous shunts were created in eight dogs and were deliberately clotted at
      monthly intervals. Animals were randomly assigned to treatment with pulse-spray
      urokinase thrombolysis or a low-speed rotational percutaneous thrombolytic
      device. Perfusion imaging, pulmonary-artery pressure measurements, and pulmonary
      arteriography were performed before and after each procedure. RESULTS: A total of
      22 procedures were performed (11 PSPMT and 11 mechanical thrombolysis).
      Declotting was successful in all procedures, with 100% 30-day patency. Segmental
      defects were seen on perfusion images after 10 (91%) of 11 PSPMT procedures and
      two (18%) of 11 mechanical thrombolysis procedures (P < .002). Transient
      increases in pulmonary-artery pressure occurred in the PSPMT group. Complete
      resolution of emboli and return to baseline pressures were seen in all cases,
      even after multiple (up to four) procedures in the same animal. There was no
      histologic evidence of pulmonary infarction in either group. CONCLUSION: The
      percutaneous thrombolytic device is effective for declotting dialysis grafts in
      dogs and results in statistically significantly fewer pulmonary emboli compared
      with PSPMT.

PMID- 8657908
TI  - Severe ascites: efficacy of the transjugular intrahepatic portosystemic shunt in
      treatment.
AB  - PURPOSE: To evaluate the transjugular intrahepatic portosystemic shunt (TIPS) as
      primary treatment in patients with cirrhosis and severe ascites. MATERIALS AND
      METHODS: A TIPS placement was attempted in 54 consecutive patients with
      intractable ascites. Clinical assessment findings, shunt patency, complications,
      and survival were analyzed. RESULTS: A TIPS was successfully placed in 50
      patients (93%). Follow-up for clinical effectiveness in 51 patients was a mean of
      285 days (range, 1-981 days). Forty patients (78%) gained clinical benefit from
      the shunt. Of these, 29 (57%) had a complete response (required no further
      paracentesis) and 11 patients (22%) had a partial response (required less
      frequent but additional paracentesis for control of ascites). The absence of
      preprocedure renal insufficiency (creatinine < 1.5 mg/dL [< 130 mumol/L]) was the
      only characteristic identified as an indicator of clinical success (P < .05).
      Eleven patients (22%) required shunt revision during follow-up to gain or prolong
      control of symptoms. Cumulative survival in the population evaluated for clinical
      efficacy was 53% at 6 months and 48% at 1 year. A complete response was the only
      variable that indicated increased survival (P < .05; R2 = 12%) with a 6-month
      survival rate of 76% and a 1-year rate of 71%. CONCLUSION: TIPS placement appears
      to be effective as a primary treatment of patients with cirrhosis and severe
      ascites.

PMID- 8657907
TI  - Quantitative cardiac perfusion: a noninvasive spin-labeling method that exploits
      coronary vessel geometry.
AB  - PURPOSE: To quantitate myocardial arterial perfusion with a noninvasive magnetic
      resonance (MR) imaging technique that exploits the geometry of coronary vessel
      anatomy. MATERIALS AND METHODS: MR imaging was performed with a spin-labeling
      method in six arrested rabbit hearts at 4.7 T. Selective inversion of
      magnetization in the short-axis imaging section along with all myocardium apical
      to that section produces signal enhancement from arterial perfusion. A linescan
      protocol was used for validation of flow enhancement. Flow was quantitated from
      two images and validated with spin-echo (SE) imaging. Regional perfusion defects
      were created by means of coronary artery ligation and delineated with gadolinium
      enhanced imaging. RESULTS: Linescan estimates of T1 obtained at physiologic flows
      agreed with model predictions. Flow-induced signal enhancement measured on SE
      images also agreed with expected values. Finally, perfusion abnormalities created
      by means of coronary artery ligation were detected. CONCLUSION: This spin
      labeling method provides quantitative estimates of myocardial arterial perfusion
      in this model and may hold promise for clinical applications.

PMID- 8657909
TI  - Iliofemoral venous stenoses: effectiveness of treatment with metallic
      endovascular stents.
AB  - PURPOSE: To assess effectiveness of metallic endovascular stents in treatment of
      venous stenoses and occlusions. MATERIALS AND METHODS: Stents were placed
      intravenously in 56 patients (59 stenoses or occlusions) over a 6-year period.
      Stent sites included the inferior vena cava (n = 10) and common iliac (n = 31),
      external iliac (n = 46), common femoral (n = 27), and superficial femoral veins
      (n = 4). Indications for stent placement included stenoses from pelvic malignancy
      and its treatment; trauma, surgery, or pregnancy; and idiopathic stenoses.
      Patients underwent anticoagulation therapy for 3-6 months after stent placement.
      Follow-up was performed with duplex ultrasound. RESULTS: With use of life-table
      analysis, overall primary and secondary 1-year patency rates were 50% and 81%,
      respectively. Primary and secondary 4-year patency rates were and 50% and 75%,
      respectively. Five patients died of primary disease progression within 6 months
      after stent placement. Major complications occurred in 6.8% of cases. One-year
      secondary patency rates were statistically significantly lower (P = .05) for
      patients with malignant disease, although primary patency rates were comparable.
      Overall sustained decrease in symptoms (P < .0001) was observed 1 year later.
      CONCLUSION: Endovascular stent placement is a nonsurgical alternative for
      reestablishment of venous flow and sustained relief of symptoms in patients with
      malignant or benign pelvic venous disease.

PMID- 8657910
TI  - Utilization of radiologic services in different payment systems and patient
      populations.
AB  - PURPOSE: To report population-based utilization rates and their variability
      across and within populations, geographic areas, and different payment systems
      for diagnostic radiology and radiation oncology procedures. MATERIALS AND
      METHODS: Aggregated claims data were obtained from four sources for up to nine
      radiologic modalities. The data cover Medicare, health maintenance organizations
      (HMOs), and conventional insurance. For some sources, the data were separated
      into four age groups. All radiologic services, including those provided by
      nonradiologists, were included. RESULTS: Average annual ambulatory diagnostic
      radiology utilization rates ranged from 570 procedures per 1,000 nonelderly
      persons in an HMO setting to 1,970 per 1,000 for Medicare enrollees. Radiation
      oncology utilization rate added 11 procedures per 1,000 to the HMO population
      rate and 260 per 1,000 to the Medicare population rate. In the Medicare data, the
      diagnostic radiology utilization rate in the 25th percentile state was 78% of the
      rate in the 75th percentile state. In a small sample of HMOs, the 25th percentile
      HMO rate was 45% of the 75th percentile HMO rate. CONCLUSION: Much variability
      exists in utilization rates. National or regional averages are not a good guide
      to the utilization rates in a specific patient population and should not be taken
      as norms. Only actual data from a patient population are likely to provide
      radiologists with fairly accurate predictions of their future utilization rates.

PMID- 8657911
TI  - Vascularity of the neonatal femoral head: in vivo demonstration with power
      Doppler US.
AB  - PURPOSE: To detect the intrinsic blood supply of the unossified neonatal femoral
      head in vivo by using power Doppler ultrasound (US) and to ascertain whether a
      reduction in blood flow could be demonstrated with hip abduction. MATERIALS AND
      METHODS: One hip of 13 neonates was examined with power Doppler sonography. After
      vessels within the femoral head were identified, the thigh was slowly abducted
      and the angle at which flow became undetectable was recorded. Spectral Doppler
      tracings were obtained in all subjects. RESULTS: Intrinsic blood flow of the
      femoral head was demonstrated in all subjects. Flow became undetectable during
      hip abduction in 11 of 13 neonates and reappeared during adduction. The angle at
      which flow became undetectable varied from 60 degrees to 85 degrees. Spectral
      Doppler signals demonstrated a mixed arterial and venous trace. CONCLUSION: Power
      Doppler US provides a simple real-time assessment of the femoral head blood
      supply. This may prove helpful in identifying neonates at risk of avascular
      necrosis, a complication of treatment of hip dysplasia with abduction hip
      restraints.

PMID- 8657912
TI  - Power Doppler sonography.

PMID- 8657913
TI  - Percutaneous biopsy for prognostic testing of neuroblastoma.
AB  - PURPOSE: To determine whether percutaneous biopsy can provide the diagnostic and
      prognostic information necessary to treat children with advanced neuroblastoma.
      MATERIALS AND METHODS: From 1991 through 1995, 21 percutaneous biopsies were
      performed in 20 children with advanced neuroblastoma by using 15- or 16-gauge
      core biopsy needles. An average of six samples were obtained. Since September
      1994, fresh tissue was sent to the reference laboratory, where touch preparations
      were prepared for N-myc evaluation. RESULTS: Histologic confirmation and
      prognostic information (Shimada classification) were obtained in all cases.
      Genetic prognostic information was obtained in 19 patients (95%), DNA index
      (ploidy) in 18 (90%), N-myc gene expression in 14 (70%), and cytogenetic analysis
      in 10 (50%). N-myc and ploidy determinations were successful in all five biopsy
      specimens obtained since September 1994. CONCLUSION: Percutaneous biopsy of
      advanced neuroblastoma is a feasible alternative to open biopsy.

PMID- 8657914
TI  - Air enema for reduction of intussusception in children: risk of bacteremia.
AB  - PURPOSE: To evaluate the incidence of bacteremia in children undergoing air enema
      for the diagnosis and reduction of intussusception. MATERIALS AND METHODS: Twenty
      seven children who underwent air enema for the diagnosis and treatment of
      intussusception were evaluated to identify the incidence of transient bacteremia
      and fever associated with the procedure. Blood cultures were obtained prior to
      the manipulation (point 0), immediately after completion of the procedure (point
      1), and 2 hours later (point 2). RESULTS: The results of six of 81 sets of blood
      cultures were positive for bacterial pathogens. Three of them that were obtained
      at point 0 and two at point 1 grew common skin contaminants. A sixth blood
      culture drawn at point 1 was positive for Staphylococcus aureus. No patient had
      more than one positive blood culture result, and all recovered without
      antimicrobial therapy. Five patients had temperature elevations to > or = 38
      degrees C following the enema. Only one of the patients was febrile at admission,
      and none had positive blood culture results. CONCLUSION: The risk of bacteremia
      from enteric pathogens following air enema for reduction of intussusception in
      children appears to be low.

PMID- 8657915
TI  - Neonates with congenital diaphragmatic hernia: radiographic findings during
      partial liquid ventilation.
AB  - PURPOSE: To determine the serial radiographic appearance of the lungs of neonates
      who underwent partial liquid ventilation with perflubron because of congenital
      diaphragmatic hernia (CDH) or primary pulmonary hypertension. MATERIALS AND
      METHODS: Bedside anteroposterior (AP) and lateral chest radiographs (n = 235)
      were scored for percentage of lung opacification by perflubron during partial
      liquid ventilation (PLV) and extracorporeal membrane oxygenation (ECMO). Five
      neonates participated in the study; four had CDH, and one had primary pulmonary
      hypertension. RESULTS: The lungs were opacified nearly completely after each dose
      of perflubron. The degree of opacification was the same on 117 of 169 (69%) AP
      radiographs and within one point on another 40 (24%). A gravity-dependent
      distribution was shown on 58 of 66 (88%) lateral radiographs. A minimal amount of
      perflubron remained in the lungs after 5.2 days. A hypoplastic bronchus and
      ipsilateral lung were manifest in all four of the patients with CDH after the
      airway and lung were filled with radiopaque perflubron. CONCLUSION: Lungs filled
      with perflubron were opacified to a similar degree in a gravity-dependent
      distribution. Evaporation of perflubron from the lungs of neonates is relatively
      rapid. The size of the ipsilateral bronchus and lung may be estimated by
      comparison of radiographs taken before and after the lungs were filled with
      perflubron.

PMID- 8657917
TI  - Acetabular labral tears: evaluation with MR arthrography.
AB  - PURPOSE: To determine the usefulness of magnetic resonance (MR) arthrography in
      the diagnosis of acetabular labral tears. MATERIALS AND METHODS: MR arthrography
      of the hip was performed in 10 patients who underwent subsequent surgical
      evaluation. Eight arthrograms were obtained with intraarticular administration of
      gadolinium solution and two with intraarticular administration of normal saline.
      T1-weighted spin-echo (intraarticular gadolinium) or T2-weighted gradient-echo
      (intraarticular normal saline) images were obtained in the axial, sagittal, and
      coronal planes with use of a surface coil. Criteria for labral tears included
      labral blunting, absence, displacement, intrasubstance contrast material, and
      contrast material at the acetabular-labral junction. Labra with enlargement,
      intrasubstance intermediate signal intensity, or irregular margins were
      interpreted as degenerative. RESULTS: Labral tears were diagnosed in eight hips.
      Tears included six labra with contrast material that tracked at the acetabular
      labral junction, one of which had associated intrasubstance extension. One tear
      was confined to the labral substance. The other tear exhibited absent labral
      tissue and an irregular remnant. One degenerative labrum and one normal labrum
      were identified. All MR arthrographic findings were confirmed at surgery.
      Extension of one anterosuperior tear into the posterosuperior labrum was not
      prospectively appreciated. CONCLUSION: In this preliminary study, MR arthrography
      appears to be a promising imaging modality for accurate diagnosis of acetabular
      labral tears.

PMID- 8657916
TI  - Lesions of the acetabular labrum: accuracy of MR imaging and MR arthrography in
      detection and staging.
AB  - PURPOSE: To determine the accuracy of magnetic resonance (MR) imaging and MR
      arthrography in the detection and staging of lesions of the acetabular labrum.
      MATERIALS AND METHODS: Fifty-seven hips of 56 patients with chronic hip pain and
      a strong clinical suspicion of labral lesions were examined with a three
      dimensional gradient-echo sequence in the coronal oblique and sagittal oblique
      projections before and after the intraarticular injection of gadopentetate
      dimeglumine. The labra were evaluated on the basis of morphology, signal
      intensity, the presence or absence of a tear, and their attachment to the
      acetabulum. Twenty-two of the hips underwent surgical intervention, and 35 hips
      were treated conservatively. RESULTS: Twenty of the 22 labra with surgical proof
      were staged accurately with MR arthrography. On the conventional MR images, only
      eight of the 22 labra were staged correctly. Whereas the sensitivity of MR
      arthrography was 90% and its accuracy was 91%, the sensitivity of MR imaging was
      30% and its accuracy was 36%, compared with surgical findings. CONCLUSION: MR
      arthrography enables accurate detection and staging of lesions of the acetabular
      labrum and appears to be indicated in the assessment of chronic hip pain in
      patients with a strong suspicion of labral lesions.

PMID- 8657918
TI  - Scapholunate ligament: normal MR appearance on three-dimensional gradient
      recalled-echo images.
AB  - PURPOSE: To evaluate the (a) capability of coronal three-dimensional (3D)
      gradient-recalled-echo (GRE) images in the demonstration of the volar, middle,
      and dorsal portions of the scapholunate ligament (SLL); (b) normal magnetic
      resonance (MR) appearance of these portions and of their attachment to the lunate
      and scaphoid; and (c) normal appearance of the ligament-cartilage interface for
      various portions of the SLL. MATERIALS AND METHODS: Coronal 3D GRE imaging was
      used to study the volar, middle, and dorsal portions of the SLL in 14 patients
      with an arthroscopically normal SLL and in five cadaveric wrists that had a
      normal SLL proved with dissection. RESULTS: The trapezoidal volar portion of the
      SLL was seen with inhomogeneous high intermediate signal intensity and attached
      directly to the lunate and scaphoid cortex. The triangular middle portion was
      seen with inhomogeneous intermediate signal intensity and in most cases attached
      to the hyaline cartilage of the lunate and scaphoid. The low-signal-intensity
      bandlike dorsal portion attached either to the cartilage, cartilage and cortex,
      or cortex alone of the lunate and scaphoid. CONCLUSION: The volar, middle, and
      dorsal portions of the SLL can be differentiated on the basis of MR appearance on
      3D GRE images. The various portions attach to cartilage and/or to cortex, and the
      appearance of the ligament-cartilage interface follows a specific pattern.

PMID- 8657919
TI  - Radiation protection of the hand in interventional radiology: should it fit like
      a glove?

PMID- 8657920
TI  - Benign versus malignant intraosseous lesions: discrimination by means of PET with
      2-[F-18]fluoro-2-deoxy-D-glucose.
AB  - PURPOSE: To assess the ability of positron emission tomography (PET) with 2
      [fluorine-18]fluoro-2-deoxy-D-glucose (FDG) to allow differentiation of benign
      from malignant intraosseous lesions. MATERIALS AND METHODS: Twenty patients with
      strictly intraosseous lesions (five benign and 15 malignant [three primary and 12
      metastatic]) were studied with FDG PET. The final diagnosis was confirmed with
      histopathologic examination in all patients. The uptake of FDG within each lesion
      was evaluated qualitatively as well as semiquantitatively by determination of the
      standardized uptake value (SUV). RESULTS: SUV assessment of FDG accumulation
      within osseous lesions was superior to subjective visual analysis for
      discriminating benign from malignant lesions. With use of a 2.0 cutoff value for
      SUV, 14 of 15 malignant lesions were categorized correctly versus 12 of 15
      correctly categorized by means of subjective image evaluation; four of five
      benign lesions were categorized correctly with both techniques. CONCLUSION: FDG
      PET can aid in differentiating benign from malignant strictly intraosseous
      lesions.

PMID- 8657922
TI  - Sarcoidlike reaction in patients with malignancy.
AB  - PURPOSE: To determine the radiologic features, pathogenesis, and prognostic
      importance of sarcoidlike reaction in patients with malignancy. MATERIALS AND
      METHODS: Radiographs and computed tomographic (CT) scans of the chests of 10
      patients with known malignancy and either concurrent or subsequent development of
      noncaseating granulomas (NCG) were reviewed and correlated with histopathologic
      reports and pertinent clinical data. RESULTS: Ten patients with malignancy were
      found to have either mediastinal or hilar lymph node enlargement (n = 4) or
      parenchymal lung disease (n = 6). The presumptive diagnosis was metastatic
      disease. In eight of 10 histopathologic specimens, no tumor was found, but
      innumerable NCGs were present. They were thought to be consistent with
      sarcoidlike reaction. In the other two specimens, only a small focus of tumor
      cells was found amidst innumerable NCGs. On CT scans of the chests, parenchymal
      lung disease took the form of either ground-glass attenuation (n = 1) or nodules
      following perivascular and peribronchial distributions (n = 5). CONCLUSION: Lymph
      node enlargement and parenchymal lung nodules may not indicate metastatic
      disease. Sampling of all abnormal areas may be helpful in staging the disease and
      in treating and determining the prognosis of patients. Likewise, the discovery of
      NCG does not necessarily indicate sarcoidosis and may represent sarcoidlike
      reaction.

PMID- 8657921
TI  - Indirect MR arthrography: optimization and clinical applications.
AB  - PURPOSE: To evaluate and optimize a method for producing magnetic resonance (MR)
      images similar to MR arthrograms of multiple synovial joints with intravenous
      gadopentetate dimeglumine injection. MATERIALS AND METHODS: The authors examined
      the effects of joint motion, dose of gadopentetate dimeglumine (0.1, 0.2, and 0.4
      mmol/kg), and fat saturation on the enhancement rate of the joint cavity and the
      degree of image contrast generated among articular structures on MR images in 14
      healthy volunteers. Shoulder, elbow, wrist, hip, knee, and ankle joints of 10
      volunteers were imaged with optimized parameters. Indirect MR arthrographic
      findings in 17 patients with joint disorders (eg, rotator-cuff tears, meniscal
      tears, and osteoarthritis) were compared with arthroscopic findings. RESULTS: Fat
      saturated images obtained after 10 minutes of exercise and administration of 0.1
      mmol/kg gadopentetate dimeglumine were similar to those obtained after
      intraarticular injection of contrast medium. Exercising the joint yielded the
      strongest joint-cavity enhancement. Increasing the dose of contrast medium in the
      unexercised joint did not statistically significantly improve the contrast-to
      noise ratio. Rotator cuff tears, meniscal tears, and cartilage defects were
      better delineated with this method than with unenhanced MR imaging and showed
      good correlation with arthroscopic results. CONCLUSION: Indirect MR arthrography
      of an exercised joint provides homogeneous enhancement and improved delineation
      of soft-tissue structures.

PMID- 8657923
TI  - Optic nerve dysfunction in thyroid eye disease: a clinician's perspective.

PMID- 8657924
TI  - Half-Fourier, three-dimensional technique for dynamic contrast-enhanced MR
      imaging of both breasts and axillae: initial characterization of breast lesions.
AB  - PURPOSE: To evaluate the ability of asymmetric half-Fourier three-dimensional
      (3D) magnetic resonance (MR) imaging to characterize signal intensity changes in
      breasts and axillae after contrast material injection and to compare the spatial
      resolution and measured signal intensity change of asymmetric and symmetric
      (keyhole) partial Fourier techniques. MATERIALS AND METHODS: Imaging was
      performed in 28 adult patients by collecting a single full-Fourier 3D data set
      with bolus injection of contrast material during the last 10 seconds followed by
      collection of six half-Fourier 3D data sets without interimage delays.
      Postcontrast keyhole and half-Fourier images were formed from the same full
      Fourier raw data set. RESULTS: The asymmetric half-Fourier 3D technique
      maintained the spatial resolution and lesion signal intensity of the full-Fourier
      image, whereas the 50% keyhole method degraded the spatial resolution by a factor
      of two and decreased the lesion signal intensity by 19% for a 2 x 2-pixel region
      of interest. Histopathologic correlation was attained in 32 lesions in 28
      patients. Sensitivity was 100% (five of five) and specificity was 89% (24 of 27).
      CONCLUSION: The asymmetric half-Fourier 3D MR imaging technique allows imaging of
      both breasts and axillae without loss of lesion contrast or temporal resolution
      and provides the maximum spatial resolution and lesion signal intensity
      attainable for the views sampled.

PMID- 8657925
TI  - Heel spur: radiation therapy for refractory pain--results with three treatment
      concepts.
AB  - PURPOSE: To evaluate radiation therapy (RT) to treat refractory pain in plantar
      heel spur. MATERIALS AND METHODS: From 1984 to 1994, 141 patients with refractory
      painful plantar heel spur (170 heels, because of bilateral disease) underwent RT.
      Quantitative criteria were used to evaluate heel pain and ankle function prior to
      RT, 6-12 weeks after RT, and at last follow-up (median, 4 years). Patients were
      divided into three treatment groups: group A (n = 72 heels [two courses, 1.0-Gy
      fractions, 12-Gy total RT dose]), group B1 (n = 50 heels [one course, 0.3-Gy
      fractions, 3-Gy total dose]), and group B2 (n = 48 heels [one course, 0.5-Gy
      fractions, 5-Gy total dose]). RESULTS: At last follow-up, complete pain relief
      was achieved in 48 (67%) of 72 group A heels and in 71 (72%) of 98 group B heels.
      Statistically significant (P < .05) differences between groups were found for
      insufficient pain relief (< 80%) in patients in whom the response time after RT
      was longer than 4 weeks or in whom pain recurred during follow-up. The best
      results were achieved with the 5-Gy total RT dose (P < .05). Prognostic factors
      for complete pain relief were acute pain and short duration of pain prior to RT.
      The prognostic factor for insufficient pain relief was total RT dose. CONCLUSION:
      Refractory heel pain is effectively treated with RT, which should be considered a
      primary treatment approach rather than a last resort.

PMID- 8657926
TI  - Gestational trophoblastic disease metastatic to the brain.
AB  - PURPOSE: To evaluate clinical characteristics, treatment technique, and results
      in patients with gestational trophoblastic disease metastatic to the brain.
      MATERIALS AND METHODS: From 1962 to 1994, 26 (4.1%) of 631 patients who underwent
      treatment for trophoblastic disease had or developed evidence of brain metastases
      (patients were aged 14-43 years). All patients received multiagent systemic
      chemotherapy and whole-brain irradiation. Total doses of radiation were 2,386
      4,000 cGy (200-300 cGy per fraction). No patient received intrathecal
      chemotherapy. Patients were divided into three groups: group A, symptomatic brain
      metastases at presentation; group B, asymptomatic or minimally symptomatic brain
      disease at presentation; and group C, development of brain metastases during
      systemic chemotherapy. RESULTS: The overall 5-year actuarial survival rate was
      51%. Multivariate analysis findings indicated that age, preceding pregnancy
      event, human chorionic gonadotropin level, World Health Organization score,
      performance of craniotomy, and number of brain metastases did not influence
      survival. The difference in the 5-year overall survival rates between groups A
      (39%) and B (100%) was significant (P = .03). CONCLUSION: Gestational
      trophoblastic disease metastatic to the brain is curable with systemic
      chemotherapy and whole-brain irradiation. The authors suggest treatment with
      steroids, chemotherapy (etoposide, high-dose methotrexate [1 g/m2], dactinomycin,
      cyclophosphamide, and vincristine sulfate), and concurrent whole-brain
      irradiation (3,000 cGy in 200-cGy fractions).

PMID- 8657927
TI  - Sonographic detection of femoral head vascularity in neonates.

PMID- 8657929
TI  - Science, not snake oil.

PMID- 8657928
TI  - Breast-conserving surgery for primary breast cancer: necessity for surgical clips
      to define the tumor bed for radiation planning.
AB  - Radiographs obtained at definitive and boost irradiation in 50 patients with
      stage I-II breast cancer were retrospectively examined. Tangent target fields
      planned on the basis of surgical clips placed at excision biopsy were evaluated
      with simulation radiographs. Four (8%) of 50 tangent target fields would have
      been inadequate without clips, and 23 (46%) of the boost targets would have been
      missed (12 [24%], totally; 11 (22%), marginally). Radiopaque surgical clips
      placed at excision biopsy help plan boost-irradiation target fields.

PMID- 8657930
TI  - Surgical malignancy rate in women who have undergone needle core biopsy.

PMID- 8657931
TI  - Use of pulsed Doppler US in healthy neonates and the potential for temperature
      elevation in the adjacent brain.

PMID- 8657932
TI  - Efficacy studies of low-field-strength MR imaging: feast or famine.

PMID- 8657933
TI  - Different terms for the same disease: intraductal mucin-producing tumor versus
      mucinous tumor of the pancreas.

PMID- 8657934
TI  - Hepatic artery resistance in portal vein thrombosis.

PMID- 8657935
TI  - Problems in the detection and characterization of small renal masses.

PMID- 8657936
TI  - Growth of renal masses.

PMID- 8657937
TI  - Definition of "equilibrium point".

PMID- 8657938
TI  - Virtual endoscopy: is it reality?

PMID- 8657939
TI  - Percutaneous transluminal angioplasty of the infrapopliteal vessels: the
      evidence.

PMID- 8657940
TI  - Infrapopliteal percutaneous transluminal angioplasty: what we know.
AB  - We believe that a substantial experience demonstrating the effectiveness and
      safety of infrapopliteal artery PTA has been accumulated. It is clear that the
      results of tibial PTA and femoropopliteal PTA are closely associated for most
      patients undergoing limb salvage procedures. Anatomic selection is most
      important; patients with focal disease and restorable runoff will generally
      benefit, and interventional radiologists should concentrate on treating this
      group of patients. PTA and surgery for limb salvage patients are indeed
      complementary procedures, and patients will benefit most by a methodical team
      approach to treatment. Problems with reporting of data in the literature have
      obscured the true effectiveness of distal PTA, with such deficiencies leading to
      both overestimation and underestimation of clinical utility. Nevertheless, the
      preponderance of evidence (as we see it) suggests a clinical effectiveness of
      about 80% at 2 years in appropriately selected patients. Like Dr. Fraser and his
      co-authors, we would welcome randomized trials of tibial PTA versus surgery, but
      even in the absence of these, the reporting of indications and results needs to
      be standardized: severity of symptoms at presentation and the extent of
      conservative treatments employed before intervention; life-table methodology on
      an intent-to-treat basis with clear delineation of end points; stratification by
      important variables such as lesion length, runoff status, extent of preexisting
      tissue loss, presence of diabetes and ESRD, and ideally, functional outcome and
      quality-of-life measures. Finally, we should learn from our surgical colleagues
      that close surveillance and early reintervention will probably increase the
      effectiveness of our percutaneous treatment methods.

PMID- 8657941
TI  - The future is separating us: disenrollment from professional societies as the
      result of financial pressure.

PMID- 8657942
TI  - Radiation-attenuating surgical gloves: effects of scatter and secondary electron
      production.
AB  - PURPOSE: To evaluate the effects of scatter and secondary electron production on
      the protection provided by flexible radiation-attenuating gloves. MATERIALS AND
      METHODS: Four sets of radiation-attenuating flexible gloves and one set of
      standard surgical gloves were tested for scattering characteristics and secondary
      electron production caused by the interactions of x rays inside the gloves. A
      thin-window ion chamber was used to measure the penetration of secondary
      electrons in polyethylene. A diagnostic-type chamber was used to measure forward
      scattered and backscattered x rays produced by the gloves. RESULTS: Forward
      scattered and backscattered x rays added an average of about 13% to the exposure
      of the hands. Secondary electrons increased the signal in the thin-window chamber
      by large factors but were weakly penetrating, and only a small fraction produced
      by x rays of 90 kVp and higher energies contributed to dose to basal cells.
      CONCLUSION: Forward-scattered and backscattered x rays reduce the effectiveness
      of radiation-attenuating gloves, and secondary electron dose to basal cells in
      the back of the hand can further reduce effectiveness.

PMID- 8657943
TI  - Future physician requirements: generalists and specialists--shortage or surplus.

PMID- 8657944
TI  - Colorectal polyp detection with CT colography: two- versus three-dimensional
      techniques. Work in progress.
AB  - PURPOSE: To compare detection of colorectal polyps with two-dimensional (2D)
      computed tomographic (CT) colography only, three-dimensional (3D) CT colography
      only, and a combination of 2D and 3D CT colography. MATERIALS AND METHODS: A
      total of 11 computer-simulated polyps (1-10 mm) were placed randomly in five
      identical CT data sets for images of a 72-year-old man's polyp-free, rectosigmoid
      colon. Fifteen CT colographic data sets were produced: five with 2D CT images
      only, five with 3D CT images only, and five with 2D and 3D CT images. Two
      radiologists randomly, blindly, and independently evaluated all 15 data sets to
      detect the simulated polyps. RESULTS: No polyps 2 mm or smaller were detected. No
      statistically significant differences in the detection of colorectal polyps were
      found between the three techniques. However, the combination of 2D and 3D CT
      colography resulted in polyp detection rates that were greater than or equal to
      those of 2D or 3D CT colography alone. Flat polyps were more difficult to detect
      than sessile polyps. Five false-positive findings occurred with 2D CT colography.
      CONCLUSION: A combined display of 2D and 3D CT images likely provides the
      greatest rate of detection of colorectal polyps.

PMID- 8657945
TI  - Power versus conventional color Doppler sonography: comparison in the depiction
      of vasculature in liver tumors.
AB  - PURPOSE: To compare power and conventional color Doppler sonography in the
      depiction of the intratumoral vasculature of hemangiomas, hepatocellular
      carcinomas (HCCs), and metastases of the liver. MATERIALS AND METHODS: Thirty-two
      patients with liver tumors (12 hemangiomas, 11 HCCs, and nine metastases) were
      prospectively evaluated with power and conventional color Doppler sonography by
      using a 2-4-MHz convex probe with 2-MHz Doppler frequency. Power Doppler
      sonography was performed with a 75%-88% gain. Conventional color Doppler
      sonography was performed with a 55%-75% gain and a pulse repetition frequency of
      700 Hz. Power Doppler signals and color Doppler signals interrogated in one plane
      were analyzed by two radiologists, who subjectively rated power Doppler
      sonography as superior, equal, or inferior to color Doppler sonography. RESULTS:
      Overall, power Doppler sonography was superior to color Doppler sonography in 18
      patients and equal in 14 (P < .01). In hemangiomas, power Doppler sonography was
      superior to color Doppler sonography in 10 patients and equal in two (P < .01).
      In HCCs, power Doppler sonography was superior to color Doppler sonography in
      four patients and equal in seven (P > .05). In metastases, power Doppler
      sonography was superior to color Doppler sonography in four patients and equal in
      five (P < .05). CONCLUSION: Power Doppler sonography is more sensitive than color
      Doppler sonography in the depiction of the vasculature of liver tumors,
      particularly in hemangiomas.

PMID- 8657946
TI  - Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA.
AB  - PURPOSE: To compare the usefulness of gadolinium ethoxybenzyl
      diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) and gadolinium
      diethylenetriaminepentaacetic acid (Gd-DTPA) in the diagnosis of focal liver
      lesions. MATERIALS AND METHODS: Thirty-one patients with focal liver lesions
      underwent T2- and T1-weighted spin-echo magnetic resonance (MR) imaging and fast
      low-angle shot two-dimensional MR imaging before, during, and after intravenous
      administration of three different doses of Gd-EOB-DTPA (12.5, 25, and 50 mumol
      per kilogram body weight). Gd-DTPA-enhanced imaging (dose, 0.1 mmol per kilogram
      body weight) was performed in the same patients within 1 week of Gd-EOB-DTPA
      imaging. RESULTS: During the perfusion phase (the 3 minutes after injection of
      contrast material), the dynamic enhancement characteristics seen after injection
      of 25 and 50 mumol of Gd-EOB-DTPA were similar to those seen with Gd-DTPA. At the
      lowest dose of Gd-EOB-DTPA (12.5 mumol), the dynamic enhancement characteristics
      were not comparable to those seen with Gd-DTPA. During the hepatobiliary phase
      (1.5 minutes to 4 hours after injection), Gd-EOB-DTPA-enhanced images yielded a
      dose-independent, statistically significant improvement in the detection rate of
      additional metastases, hepatocellular carcinomas, and hemangiomas compared with
      unenhanced and Gd-DTPA-enhanced images (P < .05). CONCLUSION: Gd-EOB-DTPA
      enhanced MR imaging enables improved detection of hepatic lesions over Gd-DTPA
      enhanced MR imaging while providing comparable differential diagnostic
      information.

PMID- 8657947
TI  - Hepatocellular carcinoma: MR imaging with mangafodipir trisodium (Mn-DPDP).
AB  - PURPOSE: To determine the efficacy of manganese (II) N,N'
      dipyridoxylethylenediamine-N,N'-diacetate 5,5'-bis(phosphate) (DPDP) at magnetic
      resonance (MR) imaging for evaluation of hepatocellular carcinoma (HCC).
      MATERIALS AND METHODS: MR imaging at 1.5 T was performed in 20 patients with 65
      HCC nodules. T1- and T2-weighted spin-echo and T1-weighted gradient-recalled-echo
      images were obtained before and after administration of 5 mumol/kg Mn-DPDP.
      Readers individually evaluated the pre- and postcontrast images for detection of
      tumor nodules, with subsequent consensus reading for interpretation
      discrepancies. Quantitative measurements of tumor-liver contrast-to-noise ratio
      (C/N) were also performed. Enhancement characteristics were correlated with
      histologic tumor differentiation. RESULTS: Precontrast images depicted 50 lesions
      in 17 patients, and postcontrast images depicted 49 lesions in 20 patients.
      Combination of pre- and postcontrast images enabled detection of 53 lesions in 20
      patients. Three lesions (three patients) were seen only on postcontrast images.
      Four lesions (three patients) were seen only on precontrast images. Reader
      evaluation of tumor conspicuity showed a significant preference for precontrast
      T2-weighted SE images (P < .01). Quantitative evaluation showed a significant
      increase in C/N on postcontrast T1-weighted images (P < .01). Well-differentiated
      lesions showed significantly greater enhancement than that of poorly
      differentiated lesions (P < .05). CONCLUSION: Mn-DPDP-enhanced MR imaging depicts
      HCC tumors not visualized with unenhanced studies. The degree of tumor
      enhancement correlates with histologic differentiation.

PMID- 8657948
TI  - Small hepatocellular carcinoma in patients with chronic liver damage: prospective
      comparison of detection with dynamic MR imaging and helical CT of the whole
      liver.
AB  - PURPOSE: To compare contrast material-enhanced dynamic magnetic resonance (MR)
      imaging with helical computed tomography (CT) for the detection of small
      hepatocellular carcinoma (HCC) in patients with chronic liver damage. MATERIALS
      AND METHODS: Fifty patients with chronic hepatitis or liver cirrhosis underwent
      dynamic contrast-enhanced fast low-angle shot MR imaging and multiple-phase
      helical CT. Arterial, portal-venous, and delayed-phase images were compared.
      Diagnostic ability with both techniques was evaluated by means of receiver
      operating characteristic (ROC) analysis; images in patients with (n = 27) and
      those without (n = 15) HCC in whom the same anatomic levels were available for
      both examinations were assessed. Seventy-two lesions were evaluated, and tumor
      diameter ranged from 0.5 to 3.0 cm (mean, 1.9 cm). RESULTS: ROC analysis showed
      that the arterial-phase images obtained with both techniques allowed better
      detection of HCC. Diagnostic ability was significantly better with arterial-phase
      MR imaging (mean area under the ROC curve [Az] = 0.96) than arterial-phase CT (Az
      = 0.87) or with images from any other phase (P < .05). For the delayed phase,
      diagnostic capability was significantly better with CT (Az = 0.84) than with MR
      imaging (Az = 0.77) (P < .05). CONCLUSION: Arterial-phase dynamic MR imaging is
      superior to helical CT for the detection of HCC in patients with chronic liver
      damage.

PMID- 8657949
TI  - Choledocholithiasis: comparison of MR cholangiography and endoscopic retrograde
      cholangiography.
AB  - PURPOSE: To prospectively compare magnetic resonance (MR) cholangiography with
      endoscopic retrograde cholangiography (ERC) in the diagnosis of
      choledocholithiasis. MATERIALS AND METHODS: Forty-seven patients with suspected
      choledocholithiasis underwent non-breath-hold, heavily T2-weighted, respiratory
      triggered turbo spin-echo MR cholangiography. They then underwent ERC within 5
      hours. The results of the two procedures were compared in 45 patients. RESULTS:
      The absence of ductal dilatation was shown in 16 patients at MR cholangiography
      and at ERC. MR cholangiography showed common duct dilatation in 28 of the 29
      patients with dilatation shown at ERC. MR cholangiography helped correctly
      identify 18 of the 19 patients with choledocholithiasis and 22 of the 26 patients
      without choledocholithiasis. Sensitivity with MR cholangiography was 95%,
      specificity was 85%, positive predictive value was 82%, and negative predictive
      value was 96%. Two of the false-positive findings were due to pneumobilia.
      CONCLUSION: Non-breath-hold MR cholangiography is as accurate for the evaluation
      of choledocholithiasis as ERC.

PMID- 8657950
TI  - Pancreas allograft rejection: correlation of transduodenal core biopsy with
      Doppler resistive index.
AB  - PURPOSE: To determine the usefulness of sonographically obtained resistive
      indexes (RIs) in the diagnosis of pancreas allograft rejection. MATERIALS AND
      METHODS: Findings were studied from 78 transduodenal pancreas allograft biopsies
      that were ultrasound-guided and cystoscopically directed. The 78 biopsies
      included 40 that were compared directly with baseline RI data. Biopsies were
      categorized by result and correlated with concurrent RIs (including 26 RIs
      obtained within 24 hours of biopsy) with the chi2 test for categoric variables
      and the Student t test for continuous variables. Sensitivity, specificity, and
      positive and negative predictive values were calculated with standardized
      formulas. RESULTS: The mean RIs between the no rejection, mild acute rejection,
      and moderate acute rejection groups were not statistically significantly
      different; however, the mean RI associated with chronic rejection was
      statistically significantly higher (P < .05) than that in the other groups. The
      sensitivity, specificity, and positive and negative predictive values of either
      an elevated RI (> 0.70) or greater than 10% increase in the RI above the baseline
      value in the diagnosis of acute rejection were approximately 50%. CONCLUSION:
      Neither the absolute level of the RI nor the relative increase was correlated
      with acute rejection proved at biopsy. Changes in RIs after pancreas
      transplantation were a poor indicator of acute rejection, but the absolute value
      of the RI was elevated in cases of chronic rejection.

PMID- 8657952
TI  - [Treatment for prevention of complications. The case of hypertension].
AB  - Nowadays treatment of risk factors seem to be most successful than treating
      illness itself or its complications. The importance of prospective international
      surveys in reducing complications has been underlined. From an epidemiological
      point of view, therapeutic strategies have proved to be more eficacious when
      applied to the whole hypertensive population than to selective high risk groups.
      Historically, tendency was aimed to lower diastolic blood pressure, classically a
      marker of essential hypertension. At present, trends seem to indicate that
      prognosis is more influenced by systolic hypertension, mainly in the aged. As
      aging progresses, diastolic pressure tends to decrease, arteries become rigid,
      cardiac output diminished and pulse wave velocity increases enhancing quick blood
      return to the heart at the end of systole. All these changes heighten blood
      pressure, overload the heart and diminish coronary flow. It has been recently
      reported that lowering diastolic blood pressure under 85-80 mmHg leads to
      coronary insufficiency or death. HOT study is under way in order to achieve the
      right criteria on this point. In our view, a key figure is not going to be the
      answer for everyone.

PMID- 8657951
TI  - Anatomy of the retroperitoneum: observations of the distribution of pathologic
      fluid collections.
AB  - PURPOSE: To correlate anatomic dissections with clinical observations regarding
      anatomic distribution of retroperitoneal fluid, and to document the existence of
      planes that lie between classically described retroperitoneal spaces. MATERIALS
      AND METHODS: Latex was injected in varying amounts into the pancreatic tail in
      three fresh cadavers to simulate peripancreatic fluid collections. Spiral
      computed tomography (CT) was performed of the abdomen and pelvis after each latex
      injection. Two cadavers were subsequently frozen and sectioned in axial planes;
      limited dissections were performed on these specimens. One was embalmed and
      underwent extensive anatomic dissection. Five embalmed, unprepared cadavers were
      also dissected to confirm observations made in the three prepared cadavers.
      RESULTS: Latex injected into the tail of the pancreas entered a retromesenteric
      plane that was posterior to the anterior pararenal space and anterior to the
      anterior renal fascia. The plane continued superiorly, extending to the diaphragm
      near the esophageal hiatus; inferiorly, extending to the pelvis along the
      anterolateral surface of the psoas muscle; and laterally, posterior to the
      descending colon and its mesentery. The plane also communicated with a retrorenal
      plane lying between the posterior renal fascia and the posterior pararenal space.
      CONCLUSION: Embryologic development of the dorsal mesenteries suggests the
      existence of retromesenteric planes, and clinical observations further support
      their existence. These findings may explain the observed distribution of
      retroperitoneal fluid collections from diaphragm to pelvis.

PMID- 8657953
TI  - [Kerion Celsi. A diagnostic problem? Experience with 6 cases].
AB  - We report six patients with Kerion Celsi due to Trichophyton verrucosum. Five of
      the patients were hospitalized with the diagnosis of Staphylococcal abscess. This
      confusion is due to that highly suppurative and inflammatory nature of the
      infection. Griseofulvin is the antimicrobial of choice for treatment, associated
      with imidazolics and corticosteroids to prevent alopecia. The authors suggest
      that an adequate use of simple microbiological diagnostic tests in the diagnosis
      of pyodermitis in rural children, may prevent unnecessary hospitalizations and
      permanent hair loss.

PMID- 8657954
TI  - [Extra meningeal cryptococcosis in a patient with AIDS].
AB  - We report a young homosexual male with AIDS that presented a systemic
      Cryptococcus neoformans infection. He had skin, lymph node and colonic
      involvement but the central nervous system was spared. Treatment was started with
      amphotericin B, achieving a good remission of skin lesions. However, malaise and
      digestive symptoms did not abate and the patient died.

PMID- 8657955
TI  - [A global agenda for bioethics: declaration of Ixtapa].

PMID- 8657956
TI  - [Functional adrenal hyperandrogenism: changing perspectives during its historical
      evolution].
AB  - The approach to adrenal hyperandrogenism, due to genetical or non-genetical
      enzymatic alterations, has changed dramatically during the last 50 years. To
      allow a better understanding of the subject, we focused it from a historical
      perspective, defining four stages analyzed in detail. Now there is consent on the
      existence of a functional adrenal hyperandrogenism, which has an important role
      in acne, hirsutism and menstrual disturbances.

PMID- 8657958
TI  - [Parkinson's disease secondary to flunarizine or other drugs].

PMID- 8657957
TI  - [The experience of 15 years in the accreditation of training centers for medical
      specialists].
AB  - The National Committee of the Association of Medical Schools for the
      Accreditation of Medical Centers to train specialists is active since 1979. At
      the present time, 1547 postgraduate medical students are engaged in training
      programs lasting 2 to 3 years. During the period in which the Committee has
      operated, 591 centers were assessed. Sixty percent were approved but the
      deficient academic or technical facilities for clinical practice or teaching
      motivated the rejection of 14%. During these years, several problems were
      detected such as the support given by the authorities of medical schools to
      accreditation, the instability and shortage of teaching faculty, the persistence
      of training programs in rejected centers, the excessive number of students for
      the capacity of the teaching center, the faulty integration between Medical
      Schools and the National Health Service and the increasing competition of
      scientific societies and private health institutions with medical schools in
      teaching activities. These issues must be appraised both at medical schools and
      the National Health Services.

PMID- 8657959
TI  - [How far should blood pressure be lowered in essential hypertension to optimize
      the results?].
AB  - Early studies of the seventies and eighties showed an inverse relationship
      between blood pressure reduction and incidence of complications and death.
      Afterwards, in the late eighties, some authors showed that reductions of
      diastolic blood pressure beyond 85 or 90 mm Hg increased coronary heart disease
      mortality (J shaped curve). Meta-analyses and recent epidemiological studies have
      shown that cardiovascular morbidity decreases along with reductions in diastolic
      blood pressure, if it is kept within normal limits (70-89 mm Hg). Cardiovascular
      mortality decreases significantly with blood pressure reductions of 7 to 8 mmHg.
      Some authors have suggested that diastolic blood pressure should be reduced to 85
      mmHg or less in individuals with several cardiovascular risk factors, to obtain a
      better risk reduction. This hypothesis waits for confirmation from follow-up
      studies.

PMID- 8657960
TI  - [50th anniversary of the great reform of Chilean medical education (1945)].
AB  - The author reminds the reform of medical education of 1945 in which he
      participated as a student. It was approved by the Decree #201 of april 2,
      introducing Chilean medicine into a new era of modernity. The reform was planned
      and conducted by professors Hernan Alessandri (1900-1980) and Alejandro Garreton
      (1900-1980) who proposed substantial modifications in the organization,
      methodology and contents of curricula. An active and formative medical teaching
      was imposed and scientific research was encouraged. The career lasted seven years
      and had 27 regular and five free courses. A Teaching Commission, with eleven
      professors and three students, was created to fulfill such reform during the
      deans-hips of Garreton and Alessandri. As a consequence of the reform, national
      medicine was modernized in the areas of public health and hospital assistance,
      since the number of professors, physicians and students increased in the new
      Faculties created in Valparaiso, Valdivia and Temuco. The teaching-assistance and
      basic-clinical relationships were consolidated, with the ensuing expansion of
      research and medical specialties. Bringing back this reform, we appraise its
      impact in the progress of Chilean medicine.

PMID- 8657961
TI  - [The effect of fluoxetine on insulin resistance in non diabetic obese patients].
AB  - Fluoxetine, a serotonin re-uptake inhibitor with antidepressive and appetite
      reduction effects, could improve insulin sensitivity. The aim of this work was to
      assess this effect of fluoxetine in obese subjects. We studied 12 subjects with a
      body mass index over 30, with a normal oral glucose tolerance test and not
      subjected to dietary restrictions. Insulin sensitivity using Bergman's minimal
      model, sex hormone binding globulin (SHBG) and insulin like growth factor binding
      protein 1 (BP 1) were evaluated before and after three weeks of treatment with 60
      mg OD of fluoxetine. During treatment, subjects lost a mean of 1.9 kg. When
      compared with basal values, insulin sensitivity index (S1) improved significantly
      at the end of treatment (1.71 +/- 0.44 and 2.72 +/- 0.63 respectively), SHBG
      increased (28.9 +/- 5.1 and 18.2 +/- 3.4 nM/ml respectively) and BP 1 did not
      change (2.8 +/- 0.9 and 1.5 +/- 0.3 ng/ml respectively). The changes in insulin
      sensitivity did not correlate with weight changes (r = 0.4 NS). Weight or insulin
      sensitivity changes did not correlate with initial degree of insulin resistance.
      We conclude that the improvement in insulin sensitivity elicited by Fluoxetine is
      not related to weight changes and may be useful in the treatment of insulin
      resistant obese subjects.

PMID- 8657962
TI  - [Decrease of labor absenteeism associated with hormone replacement therapy in
      postmenopausal women].
AB  - Absenteeism affects efficiency and costs of health care. Most of health workers
      are middle age women, whose climacteric symptoms may reduce their work capacity
      working at a public hospital in Santiago during 1992. Fifty-eight percent were
      postmenopausal and 34.8% of these were receiving hormone replacement therapy.
      Global absenteeism rate was 17.1 days/year. These figures were 14.8 days/year for
      premenopausal and 17.8 days/year for postmenopausal women (NS). Among the latter,
      those women receiving hormone replacement therapy had a significantly lower
      absenteeism rate (9.4 days/year compared to 20.4 days/year among those not
      receiving hormones). Osteoarticular diseases were responsible for 44.3% and
      psychiatric diseases for 18.1% of sick leaves. No differences in absenteeism were
      observed between different professional levels. We conclude that hormone
      replacement therapy is associated with a better working capacity in
      postmenopausal women.

PMID- 8657963
TI  - [Effect of a dry boldo extract on oro-cecal intestinal transit in healthy
      volunteers].
AB  - BACKGROUND: Boldo (Peumus boldus Molina) is a widely used medicinal plant.
      However, its physiological effects are not well known. Recent studies in animals
      showed that certain components of boldo relax smooth muscle and prolong
      intestinal transit. AIM: To assess the effects of a dry boldo extract on oro
      cecal transit time in normal humans. SUBJECTS AND METHODS: Twelve volunteers
      received 2.5 g of a dry boldo extract or a placebo (glucose) during two
      successive periods of four days. On the fourth day, 20 g of lactulose were
      administered and breath hydrogen was collected every 15 min. Oro cecal transit
      time was defined as the time in which breath hydrogen increased by 20 ppm over
      the fasting level. RESULTS: Oro cecal transit time was larger after dry boldo
      extract administration, compared to placebo (112.5 +/- 15.4 and 87 +/- 11.8 min
      respectively, paired t p < 0.05). CONCLUSIONS: Dry boldo extract prolongs oro
      cecal transit time, a possible explanation for its medicinal use.

PMID- 8657965
TI  - [Secondary inactive pulmonary tuberculosis and non specific bronchial
      reactivity].
AB  - Bronchial reactivity to methacholine was examined in three groups of smokers (N =
      93): subjects with secondary inactive pulmonary tuberculosis (TPI) 2 years after
      the beginning of treatment (N = 44); subjects with asymptomatic chronic
      bronchitis (N = 25) and healthy control (N = 24). Mean PC20FEV1 was 9.54 (SD
      6.05), 11.12 (SD 5.42) and 13.74 (SD 4.7) respectively (tuberculosis vs control,
      p < 0.02). According to the arbitrary criteria for bronchial asthma, nonspecific
      hyperreactivity was present in 50% of subjects with TPI, in 37.5% of bronchitic
      patients and in 16% of control subjects. No difference was found with regard to
      PC20FEV1, the chemotherapeutic regimen (9 or 12 months of therapy), results of
      tuberculin test (normo and hyperreactive) and X-ray findings determined before
      the onset of treatment. Mahalanobis statistical analysis with respect to smoking
      index, basal ventilatory function tests and nonspecific bronchial reactivity
      grouped together healthy volunteers and subjects with a history of pulmonary
      tuberculosis apart from the group with asymptomatic chronic bronchitis.

PMID- 8657964
TI  - [Prevention of surgical wound infections after appendectomy: intravenous versus
      rectal metronidazole].
AB  - AIM: To compare the efficacy of rectal and intravenous metronidazole in the
      prevention of anaerobic wound infections after appendicectomy. PATIENTS AND
      METHODS: One hundred patients subjected to appendicectomy were randomly assigned
      to receive, 2 hours before operation, gentamycin 80 mg i.v. and metronidazole 1 g
      i.v. or the same amount of gentamycin and 1 g of metronidazole as a suppository.
      Surgical wounds were observed for infections until the tenth day of the
      postoperative period. RESULTS: Seven of 45 patients receiving intravenous
      metronidazole and six of 44 receiving the drug as suppositories had wound
      infection. The frequency of infections was higher among patients with gangrenous
      or perforated appendices. They were detected at the fifth postoperative day in 8
      patients and the most frequently isolated bacteria were E coli and S aureus.
      CONCLUSIONS: Rectal metronidazole is equally effective than intravenous
      metronidazole in the prevention of would infections after appendicectomy.

PMID- 8657966
TI  - [Hepatopulmonary syndrome in decompensated cirrhotic patients].
AB  - Hypoxemia is common in cirrhotic patients and, when obvious pulmonary or cardiac
      causes are discarded, it is attributed to the so-called hepatopulmonary syndrome.
      The aim of this work was to assess the frequency of hypoxemia and orthodeoxia and
      its relationship with the degree of liver failure, in cirrhotic alcoholic
      patients. We studied 30 alcoholic cirrhotics. In all, arterial blood gases were
      measured in supine and standing positions, in 26 a chest X ray examination was
      done and in 20 a spirometry. Twelve patients had a subnormal PaO2 and this
      parameter fell more than 105 when assuming the standing position in one of these.
      The same reduction was observed in two subjects with normal supine PaO2. In the
      chest X ray examinations, pleural effusions were observed in five hypoxemic
      subjects and four with normal PaO2. Likewise minimal athelectasis was found in
      six and seven subjects and intestinal infiltrates in one of the two subjects. A
      significant association between hypoxemia and Pugh score was observed. Similarly,
      subjects with hypoxemia is frequent in alcoholic cirrhotic patients and, since it
      is not associated to obvious pulmonary causes, it may be attributed to the
      hepatopulmonary syndrome.

PMID- 8657967
TI  - [Fine needle aspiration biopsy of thyroid nodules. Analysis of results obtained
      using a new method with histological examination of the sample].
AB  - Fine needle aspiration biopsy (FNAB) is the most useful preoperative work up
      method for patients with nodular goiter. We analyze 173 patients that underwent
      FNAB and were subsequently operated. The sample with FNAB was processed both for
      cytological and histological study, using methods developed at the hospital. The
      preoperative diagnosis reached was compared with that obtained with the surgical
      piece. Results showed that the histological analysis of the FNAB sample improved
      the sensitivity of the method, when compared with the cytological study, from
      68.5% to 87.8% (p < 0.035) without modifying specificity (100% for both methods).
      It is concluded that FNAB with histological study of the sample has a high
      diagnostic yield and is exempt of complications.

PMID- 8657968
TI  - [Surgical treatment of intestinal complications of pelvic radiotherapy].
AB  - One hundred forty patients treated for intestinal complications of pelvic
      irradiation are presented. The most common clinical expression was radiation
      rectitis, complicated with rectovaginal fistulas in 58% of cases. These patients
      were subjected to Parks procedure for fistula repair with satisfactory results.
      Half the operated patients remained with an ostomy as a definitive sequel and
      overall perioperative mortality in these patients was 10%. Radiation enteritis
      has a high operative mortality due to delays in diagnosis and to severe septic
      complications. It must be suspected in irradiated patients presenting with
      chronic diarrhea and weight loss. Urological complications and involvement of
      several intestinal segments are bad prognostic factors. Resections and
      anastomoses with undamaged segments are the safest surgical procedures.
      Improvements of radiation techniques and the use of a reabsorbable mesh to seal
      the pelvis during radiation therapy are adequate preventive measures.

PMID- 8657969
TI  - [External quality control of the parasitological diagnosis of Cryptosporidium
      parvum].
AB  - Between 1991 and 1994, eight external quality assessments of Cryptosporidium
      parvum infection diagnosis were performed. Stool specimens were sent to 74
      laboratories, to be stained and examined. In 40 laboratories (54.1%), the
      diagnosis was correct in all evaluations, whereas in 34 (46%), the diagnosis
      disagreed with the parasitology reference laboratory in one occasion or more. The
      mean correlation of diagnoses with the reference laboratory was 88% (range 79
      96%). Ninety-three percent of negative samples and 87% of positive samples were
      correctly diagnosed. These figures are similar to those obtained abroad. These
      results lead to the development of a quality control network for the diagnosis of
      Cryptosporidium parvum infections along the country, aiming to improve its
      reliability.

PMID- 8657970
TI  - [What is your diagnosis? Fracture of the lateral process of the talus].

PMID- 8657971
TI  - [Ankle sprain--a harmless injury?].

PMID- 8657972
TI  - [The tragedy of early roentgen pioneers: chronic radiodermatitis].
AB  - The discovery of the X-rays in November 1895 confronted medicine with new and
      undreamed possibilities for diagnosis and therapy. It was welcomed by the
      professionals with enthusiasm, and soon X-rays were used all around the globe.
      Gradually, with increasingly powerful equipment, unfavorable side effects were
      observed. The radiologists themselves were especially concerned, because they
      were exposed to the rays for hours, and in the beginning without any protection.
      Their hands were not seldom developing a chronic dermatitis, eventually leading
      by way of neoplastic transformation to death. Although, as soon as in 1901, the
      crucial factors of radiation injury and the ways for an effective protection were
      known, hundreds of the often selfless pioneers of radiology had to die still in
      the sixties.

PMID- 8657973
TI  - [Socioeconomic advantages of laparoscopic cholecystectomy].
AB  - A cohort of 100 consecutive patients cholecystectomized by laparoscopy was
      compared retrospectively under diverse socio-economic viewpoints to a cohort of
      100 patients that underwent conventional cholecystectomy by means of the matched
      pair procedure. Laparoscopic cholecystectomy does not only combine enhanced
      comfort and less postoperative pain without loss of safety for the patient, but
      also offers objectively attainable socio-economic advantages in comparison to
      conventional, open cholecystectomy. Operation time was not prolonged in
      laparoscopic cholecystectomies. Patients stayed less long in the hospital and
      regained fitness for work earlier. The reduced time of inability to work could be
      lowered in the total cohort by 36% and was thus of great importance, particularly
      for working people. Costs saved by reduced time of hospitalization by
      laparoscopic cholecystectomy were balanced by higher additional costs of this
      procedure. Altogether, total costs for health insurance and other insurances
      induced by laparoscopic cholecystectomy were lower compared to those of
      conventional operation.

PMID- 8657974
TI  - [Cachexia, ascites and kidney failure].

PMID- 8657975
TI  - [Hypertension refractory to therapy].
AB  - A 41-year-old musician developed severe refractory hypertension 13 years after
      radiotherapy of the retroperitoneum because of a teratocarcinoma of the right
      testis. An angiography revealed severe stenoses of both renal arteries. After
      percutaneous transluminal angioplasty of both renal arteries, blood pressure
      valves returned to the normal range. Radiation-induced injury of arteries may
      provoke premature atherosclerosis, which cannot be differentiated morphologically
      from common atherosclerosis. Patients who develop severe hypertension some years
      after radiotherapy of the retroperitoneum should therefore be screened for the
      presence of renovascular hypertension.

PMID- 8657976
TI  - [A case from practice (345). 1. Suspicion of right-sided choroid melanoma--right
      sided ocular melanosis. 2. Suspicion of type II neurofibromatosis--status
      following surgery of right-sided acoustic neurinoma in 1992].

PMID- 8657977
TI  - [What is your diagnosis? Ebstein Anomaly with additionally hemodynamically
      relevant left-right shunt in type II atrial septal defect].

PMID- 8657978
TI  - [Bad news, discussion about prognosis, suffering and death].

PMID- 8657979
TI  - [Truth at the bedside in a historical overview].
AB  - To tell the truth and withhold information were old topics in the history of
      medicine, whereas the term 'informed consent' appeared first in 1957. The
      historical development manifests different standpoints and central dimensions in
      the perspective of medicine as well as of theology, philosophy, arts,
      jurisprudence and psychology and with regard to diagnosis, etiology, prognosis
      and therapy. Physicians and patients are parts of their society and culture and
      are therefore depending on the dominant types of communication and concepts of
      health, disease and death.

PMID- 8657980
TI  - [Truth disclosure in physicians' dialogue: compassionate lie or merciless
      statistics?].
AB  - Breaking bad news is one of the most important and most difficult tasks of a
      physician. The training for this dialogue should be intensified during the
      medical curriculum. Physicians of the town of Zurich in general inform their
      patients truthfully about the seriousnessy of their illness. The prognosis of a
      patient is revealed in a careful way with a wide range of options. In the
      northern countries of Europe the truth in medical diagnosis and prognosis is
      revealed in a straight way, whereas in the south and the southeast the truth is
      generally hidden from the patient. A few simple rules are given for the initial
      and the subsequent dialogues between the physician and a patient with an
      incurable disease.

PMID- 8657981
TI  - [Bad news and the successful life].
AB  - The following article analyses the context of time and structure for discussions
      about bad news. Patient and the physician live in different time frames:
      physician is in an ongoing hurry, meanwhile the patient is constantly waiting for
      something. The patient/physician relationship has to offer the patient the
      possibility to transform bad news successfully into the patient's life plan. This
      is possible only in an atmosphere of trust. Personal openness by the physician
      and helpful structures in a hospital are basic conditions for such a process. The
      process consumes time and energy of all people involved. To let things be as they
      are and to accept slowness as another option will bring new opportunities for
      patients and physicians to deal responsibly with bad news.

PMID- 8657982
TI  - [How much truth can the patient endure?].
AB  - Truth is not conceived by the doctor alone who then is expected to communicate it
      to an uninformed patient. Diagnostic and prognostic findings in each individual
      case are a result of an interactive process, where the patient as well as the
      doctor are participating. Adequate information of patients is inevitable, but in
      practice not yet quite satisfactory. Some proposals for improvement are made.

PMID- 8657983
TI  - [Nursing staff between physician and patient].
AB  - Departing from a report on today's understanding about nursing, the demanding
      duties nurses see themselves confronted with are featured in connection with the
      theme of this meeting. In a second part, difficulties in daily practise are
      treated. Furthermore, problematic aspects of collaboration within the nursing
      staff as well as between the disciplines burdening patients are covered. Possible
      improvements are proposed.

PMID- 8657984
TI  - [Truth at the bedside and physicians' legal responsibilities].
AB  - This contribution illustrates the problems of medical information on unfavorable
      diagnoses and prognoses form a legal view. The eminent significance of informed
      consent for the legitimation of medical action in German and Swiss law results in
      far-reaching duties of doctors to also inform in the cases; however, restrictions
      are accepted in the patient's predominant health interest. When a patient wishes
      information on the results and the prognosis, this is regularly to be fulfilled,
      even when further therapeutical measures are no longer the issue. The
      professional secrecy demands caution when relatives are concerned, as long as
      they are not legal representatives and competent for decision-making or as long
      as the (presumable) will of the patient consents to them being informed. As to
      the question of how the information is to be conveyed, one can only formulate
      general legal principles: unjustly leaving a patient ignorant may create a
      liability of the doctor, applies also to 'brutal information' which lacking the
      slightest bit of empathy.

PMID- 8657985
TI  - [Somatic gene therapy: perspectives in the use of hematopoietic stem cells].

PMID- 8657986
TI  - [Vigilance-decreasing effects of 2 plant-derived sedatives].
AB  - Previous studies on the efficacy of valerian extracts have given occasional hints
      of possible side effects involving impaired vigilance. Because of the currently
      insufficient knowledge about potential impairment of vigilance by plant-based
      sedatives, we have conducted a controlled study to assess the effects of two
      plant-based sleep remedies in comparison with flunitrazepam and placebo after
      single oral administration. Aim of the study was to derive recommendations
      concerning potential hazards in driving or operating machinery. Residual sedative
      effects (hangover) were examined in four groups of 20 healthy volunteers,
      receiving either tablets containing valerian and hops or syrup containing
      valerian only or flunitrazepam or placebo; furthermore, immediate sedative
      effects of the two plant preparations have been examined in comparison with
      placebo (three groups of twelve healthy volunteers). The tests included objective
      measurements of cognitive psychomotor performance as well as subjective
      questionnaires on well-being. Tolerability was assessed from spontaneous reports
      of side effects and a verbal inquiry at the end of the tests. We found that
      objectively measurable impairment of performance on the morning after medication
      occurred only in the flunitrazepam group, a finding which was even more
      pronounced in the subjective questionnaires. In addition, 50% of the volunteers
      in the flunitrazepam group reported mild side effects in the inquiry at the end
      of the tests, compared with only 10% from the other groups. The subjective
      perception of sleep quality was improved in all three medication groups, when
      compared to placebo. Examination of acute effects of the plant remedies 1 to 2
      hours after administration revealed no changes in the more important lead
      variables; however, a very slight impairment of vigilance after taking syrup was
      statistically significant as well as a retardation in the processing of complex
      information for the tablets. The subjective perception of effects was more
      pronounced (shaky legs, feeling less active). In conclusion, the residual
      sedative effects (hangover) observed in some earlier studies cannot be confirmed
      for the recommended doses of the two plant-based sleep remedies which we have
      examined with respect to vigilance and cognitive performance. On the contrary:
      our findings show improved subjective self-assessment (more alert, more active,
      feeling better). Hangover effects on the following morning need not be a cause
      for concern, which is of particular interest to car drivers; however, a slight
      impairment of performance during the first few hours after ingestion should be
      anticipated. Impairment of vigilance on the morning after ingestion of
      benzodiazepines, frequently reported and confirmed by our results, constitutes a
      potential hazard. In this situation, plant remedies such as those examined in
      this study should be considered as viable alternatives.

PMID- 8657987
TI  - [Latex allergy--not only a threatening danger to patients. A case report from an
      anesthesiological department].
AB  - A 31-old male nurse of anesthesiology was exposed to rubber gloves over a period
      of ten years. An atopic diathesis was known. From time to time he had episodes of
      pollinosis. Since nine months he had suffered from conjunctivitis, rhinitis and
      shortness of breath while wearing latex gloves. During a night shift ten minutes
      after consumption of tropical fruit (bananas, kiwi) he had to care for a patient
      in the emergency room. He wore rubber gloves and had to clean the emergency room.
      Initially, his palms and feet itched. Then he experienced angor and increased
      perspiration 90 seconds later he suffered severe dyspnea and dysesthesia in the
      lower extremities. Treatment with theophylline and beta sympathomimetics,
      steroids and antihistaminics was successful. This male nurse had a positive
      history for contact urticaria after exposition to rubber. He suffered a dramatic
      exacerbation when wearing latex gloves and inhaling latex-contaminated air after
      eating tropical fruits. Fruit could have been a potent booster. Hospital
      employees with a history of atopic disease should be screened for potential latex
      allergy before occupational exposure.

PMID- 8657988
TI  - [Acute cardiac insufficiency in interstitial pneumopathy].

PMID- 8657989
TI  - [Mydriasis, tachycardia].
AB  - We report a case of plant poisoning with atropa belladonna. A student took the
      berries because of the hallucinogen effects. In this case report we describe the
      symptoms and the therapy of poisoning with atropa belladonna. Another part
      informs about the historic and cultural importance of this nightshade. Since
      antiquity, the lethal as well as the hallucinogenic effects of poisoning with
      atropa belladonna are well known; therefore, they are an important part of orgies
      and rituals.

PMID- 8657991
TI  - [Immunostimulation: wishful thinking or reality?. Interview by Lydia Schaffner].

PMID- 8657990
TI  - [A case from practice (346). Wegener's disease with rhinitis,
      keratoconjunctivitis sicca, ethmoid sinusitis and early kidney involvement].

PMID- 8657992
TI  - [What is your diagnosis? Bodypacker].

PMID- 8657993
TI  - [Anti-synthetase syndrome: a special subgroup of idiopathic inflammatory
      myopathies. Apropos of 3 case reports].
AB  - Anti-synthetase antibodies are found in 20 to 25% of all idiopathic inflammatory
      myopathies and allow identification of a syndrome associating myositis with
      interstitial pulmonary disease (50 to 70%), polyarthritis, Raynaud's phenomenon
      and mechanic's hands. Anti-Jo-1 is the most common anti-synthetase antibody. If
      anti-Jo-1 is present, interstitial lung disease must be looked for, because this
      is the most important determinant of the outcome. Treatment with high doses of
      corticosteroids is required. Immunosuppressive drugs are added in resistant cases
      or as corticosteroid-sparing agents.

PMID- 8657994
TI  - [Rapid osteolysis of the hip and chondrocalcinosis].
AB  - Two old patients with a rapid destructive arthropathy of the hip with osteolysis
      of the femoral head are presented. X-Rays show chondrocalcinosis. The other
      common causes of destructive arthropathy have been dismissed. Although the exact
      mechanism of osteolysis remains unclear, chondrocalcinosis might be involved in
      the destructive process.

PMID- 8657995
TI  - [Chondrocalcinosis and Bartter syndrome].
AB  - A patient presenting with acute left-knee arthritis was diagnosed as having
      articular chondrocalcinosis. Routine laboratory tests motivated by a history of
      muscular cramps and weakness revealed hypokalemia and hypomagnesemia. Further
      investigations showed Bartter's syndrome. The characteristics of Bartter's
      syndrome and chondrocalcinosis and the relationship between the two diseases are
      developed.

PMID- 8657996
TI  - [Candida albicans spondylitis: successful treatment with fluconazole. 2 case
      reports].
AB  - Two patients suffering from candida albicans spondylitis in the lumbar spine are
      reported. Both had been operated on because of malignancy. One patient's clinical
      course was complicated by candida septicemia, and later on, serious candida
      endophthalmia developed. Conventional X-rays, combined with technetium
      scintigraphy, showed inflammatory destruction of the end plates of neighbouring
      vertebrae. Computerized tomography was done in the second patient, when an
      abscess was detected on both sides in the psoas muscle. Consecutively, operative
      removal and a spondylodesis were performed. Candida albicans could be isolated
      from removed discal material. Treatment by fluconazole for six months, in the
      first case in the beginning also by amphotericin B, lead to the healing of fungal
      spondylitis, accompanied by partial osseous consolidation.

PMID- 8657998
TI  - [Felty syndrome: a therapy-resistant variant of chronic rheumatoid arthritis? 2
      case reports and literature review].
AB  - Felty's syndrome is a rare but serious extra-articular manifestation of
      rheumatoid arthritis. Morbidity as well as mortality are increased on account of
      greater susceptibility to infectious agents. We report on two patients suffering
      from Felty's syndrome who were successfully treated by cyclophosphamide. A review
      of the literature with special regard to treatment of Felty's syndrome is given.

PMID- 8657997
TI  - [Prognosis of shoulder calcifications after irrigation treatment and roentgen
      findings. A prospective study and literature review].
AB  - In 106 shoulder joints of 94 patients suffering from calcifying shoulder
      (calcifying tendinitis), needling and lavage were performed. Patients were
      prospectively investigated before and after treatment to examine if location,
      size, number and density of calcium deposits would predict outcome after the
      above-mentioned lavage. Excellent and good results were seen for subacromial
      calcifications and those situated near the tuberculum majus. Density and number
      of calcifications were without discriminating value, whereas large calcium
      deposits (> 1,5 cm) and fairly small calcifications (< 1,0 cm) responded very
      well to conservative treatment as described above.

PMID- 8658000
TI  - [Basic principles of plastic and reconstructive surgery].

PMID- 8657999
TI  - [50th anniversary of the establishment of the Longeraie hospital and
      headquarters, 1946-1996. Historical note].

PMID- 8658001
TI  - [Thoracic outlet syndrome (TOS). Its limitations and indications for surgical
      treatment].

PMID- 8658003
TI  - [Rotator cuff rupture, traumatic or degenerative lesion].

PMID- 8658002
TI  - [Carpal tunnel syndrome].

PMID- 8658005
TI  - [Tendon pathology of the hand and wrist].

PMID- 8658006
TI  - [Reflex sympathetic algodystrophy].

PMID- 8658004
TI  - [Surgical treatment of articular arthritis of the thumb].

PMID- 8658007
TI  - [Principles of the treatment of metacarpal and phalangeal fractures].

PMID- 8658008
TI  - [Diagnosis of drug allergies].
AB  - A minority of adverse drug reactions only are true allergy. The pathophysiology
      of most reactions remains largely unknown. This explains why despite many
      research in this field, diagnostic tools available are still unsatisfactory.
      Careful medical history and clinical examination are still the standard approach.
      The goal of this article is to detail the diagnostic approach of drug allergies
      and to review critically a number of available in vivo and in vitro tests.

PMID- 8658009
TI  - [Importance of risk factors in drug allergies].

PMID- 8658010
TI  - [Contact allergies due to drugs].
AB  - Topically applied drugs which can cause contact dermatitis are numerous and
      diverse. The ingredients for vehicles, base components and additives, are as
      frequently the cause of drug eruptions as active ingredients. Patients with
      chronic leg ulcers are particularly exposed to the risk of developing allergic
      contact dermatitis. The diagnosis is based on the analysis of causative
      association between the localisation (often limited) of the lesions, the moment
      of their appearance and the application of a drug into the skin. Use tests and/or
      patch-tests are tools for determining the diagnosis. The exact knowledge of the
      offending ingredient, of its potential sources and the possibility of cross
      allergy are essential in order to prevent recurrence. Indeed, the causative
      treatment of drug contact dermatitis is based on the prescription and effective
      application of strict avoidance of the causative allergen, a procedure which
      necessitates special informative measures to both the patient and to his medical
      care environment.

PMID- 8658011
TI  - [Resisting AIDS?].

PMID- 8658012
TI  - Selenomethionine in the inhibition of a transplantable murine lymphoma:
      reflection on hepatic drug metabolizing enzymes.
AB  - This study attempts to determine whether selenomethionine treatment can improve
      the survival time of mice inoculated with Dalton's lymphoma (DL) and thereby to
      identify phase/phases of the neoplastic processes at which selenium exerts its
      maximal action as an anticancer agent. Accordingly, a maximum of 30.76 and 143%
      increase in survival was brought about by treatment of selenomethionine prior to
      lymphoma transplantation, in comparison to mice receiving selenomethione
      supplementation concurrently with inoculation of DL, and those tumor-bearing mice
      receiving no supplementation, respectively. Beneficiality of selenomethionine has
      also been studied by monitoring the continuous changes brought about by this
      compound on hepatic total cytochrome P-450 and b5 content, NADPH cytochrome c
      reductase, UDP glucuronyl transferase and glutathione S-transferase (GST)
      activities. These are important biotransformation enzymes and are altered
      significantly in neoplasia. The drastic increase in all the markers studied,
      excepting GST, was effectively counteracted by selenomethionine treatment (more
      before than concurrently), which sufficiently delayed and controlled the increase
      in those xenobiotic indices. The 112 and 78.78% induction in GST activity brought
      about by prior and concurrent treatment of selenomethionine, respectively,
      confirms the fact that inducers of GSTs are often antitumorigenic.

PMID- 8658013
TI  - Analytical and clinical evaluation of a procedure for measuring CA 15-3 in the
      IMx analyser.
AB  - CA 15-3 is the most widely used tumour marker in the follow-up of patients with
      breast cancer. Its postoperative blood level is closely related to the response
      to the treatment applied and to the evolution of the disease. In this study, we
      assessed both the clinical and analytical features of a new microparticle enzyme
      immunoassay for CA 15-3 quantification in the Abbott IMx system. In the precision
      study, the coefficients of variation within runs, between runs and between
      laboratories were 3.5, 5.1 and 6.5% or less, respectively. The analytical
      sensitivity of the assay was 0.11 U/ml. Linear regression analyses of the IMx CA
      15-3 assay with the Centocor and CIS CA 15-3 RIAs gave correlation coefficients
      of 0.88 and 0.95, respectively. The upper limit of the reference range, obtained
      from serum of healthy women, was 27.3 U/ml, while the ROC curve analysis for
      patients with active breast cancer compared to patients with no evidence of the
      disease gave an optimum cutoff of 33 U/ml (sensitivity 0.76 and specificity
      0.87). The overall agreement of the three methods was over 90%.

PMID- 8658014
TI  - Integrin signaling and matrix assembly.
AB  - Cell adhesion and migration are controlled by the level of alpha 5 beta 1
      integrin (fibronectin receptor) and by the amount of fibronectin matrix around
      the cell; adhesion is promoted at all levels of integrin expression and matrix
      assembly, whereas high levels of either or both curb cell migration. The alpha 5
      beta 1 integrin appears to be a growth-suppressing integrin, and it protects
      cells from apoptosis when growth factors are absent. In contrast, the alpha v
      beta 3 integrin (vitronectin receptor) cooperates with certain growth factors,
      potentiating their effect on cells. These effects of alpha 5 beta 1 and alpha v
      beta 3 depend on signaling pathways specific for these integrins; integrins have
      both common and specific pathways for signaling into the cell. Moreover,
      integrins require activation from the inside of the cell to be able to bind their
      ligand outside the cell. High alpha 5 beta 1 expression and abundant matrix
      formation also suppress tumorigenicity in vivo, whereas perturbing the function
      of alpha 5 beta 1 with peptides that block its ligand binding suppresses
      experimental metastasis. Effecting these changes in tumor cells by gene therapy
      or pharmacological approaches may provide useful new cancer therapies.

PMID- 8658015
TI  - Genetic clinical markers of human neuroblastoma with special reference to N-myc
      oncogene: amplified or not amplified?--An overview.
AB  - Neuroblastoma is the most common extracranial tumor in children, and
      cytogenetically, chromosome 1p deletions, extrachromosomal double minutes, and
      homogeneously staining regions (HSRs) are commonly observed in cell lines and in
      tumors in advanced stages. It is found that an HSR represents genomic
      amplification of N-myc, which plays a key role in determining the aggressiveness
      of neuroblastoma. However, stage IV neuroblastomas or cell lines which lack N-myc
      amplification are also progressive, and some of them show evidence of N-myc
      expression in terms of mRNA and/or N-Myc oncoprotein. It was recently shown that
      a small proximal locus mapped between 1p35-36.1 and 1p36.23 may function as a
      suppressor gene of N-myc amplification. In neuroblastoma, a pattern of diploidy
      is associated with rapid tumor growth and poor survival. Expression of bcl-2
      proto-oncogene is strongly associated with unfavorable histology, while
      expressions of Ha-ras and trk-A proto-oncogenes indicate a favorable prognosis.
      trk-A proto-oncogene encodes a receptor for nerve growth factor. Genetic
      characteristics of neuroblastomas found by urinary catecholamine mass screening
      are also discussed.

PMID- 8658016
TI  - Tumor ploidy as a risk factor for disease recurrence and short survival in
      surgically treated Dukes' B2 colon cancer patients.
AB  - The risk factors for colon cancer recurrence following a curative intent surgery
      include the tumor location and size, the presence of adhesions, perforation,
      bowel obstruction, depth of invasion, histological grade, percentage of S phase
      content and cell kinetic profile. The DNA content of tumor cells has recently
      been suggested as an additional prognostic factor. In this study we assessed the
      tumor ploidy as a prognostic factor for recurrence and survival in colon cancer
      patients. The DNA content of colon cancers in 20 Dukes' B2 patients followed up
      at our center, who relapsed either locally or systemically, following surgical
      treatment was measured by image analysis. The data were pair-matched for age,
      sex, tumor site and grade, and the period of follow-up with 20 Dukes' B2 patients
      who had no evidence of disease. Aneuploidy occurred in 16 (80%) patients with
      recurrence, whereas only in 8 (40%) in the control group. Nonaneuploid DNA
      content was found in 12 (60%) patients of the control group, but in only 4 (20%)
      patients with a relapse. Aneuploidy was associated with a significantly higher
      tumor recurrence rate (p = 0.024) and shorter overall survival (p < 0.002). Our
      data point to a possible indication of a systemic adjuvant chemotherapy in Dukes'
      B2 colon cancer patients who have aneuploid tumors on image analysis. This should
      be further investigated in a prospective controlled randomized study.

PMID- 8658017
TI  - Prognostic significance of SCC antigen in the serum of patients with head and
      neck cancer.
AB  - SCC antigen (Ag) is a tumor-associated Ag (TAA) obtained from squamous cell
      carcinoma of the uterine cervix. This study reports the evaluation of this TAA in
      patients with head and neck malignant diseases and its possible prognostic value.
      Serum samples from 28 patients with benign head and neck diseases from 399
      patients with cancer were obtained prior to treatment. SCC Ag serum levels were
      determined by radioimmunoassay using 2.5 ng/ml as the upper limit of normality.
      Elevated SCC Ag serum levels were found in 14% of 28 patients with benign
      diseases, in 29% of 217 patients with primary tumors, in 48% of 46 patients with
      recurrence (43% in locoregional, 64% in metastases) and in 4% of 136 patients
      with no evidence of disease. In patients with primary tumors, SCC Ag serum levels
      were related to nodal involvement and tumor location with significantly higher
      levels in node-positive patients (p = 0.001) and in tumors located in the
      nasopharynx and piriform sinus (p = 0.02). Presurgical SCC Ag serum levels in
      patients with primary tumors had prognostic value with shorter disease-free
      survival in those patients with abnormal values of this TAA (p < 0.001), in both,
      node-negative and node-positive patients (p < 0.01). Multivariate analyses showed
      that SCC Ag is a significant independent predictor of disease-free survival even
      when other prognostic factors are considered. In conclusion, pretreatment SCC Ag
      serum levels are an independent prognostic indicator in patients with head and
      neck malignancies.

PMID- 8658018
TI  - Soluble tumor necrosis factor receptors and CA 125 in serum as markers for
      epithelial ovarian cancer.
AB  - Increased serum levels of soluble tumor necrosis factor receptors (TNFRs) have
      been observed in patients with various types of malignancies. For the monitoring
      of ovarian cancer during treatment serum TNFRs have given information equivalent
      or better than that obtained by CA 125. In this study, we compared the diagnostic
      value of TNFRs and CA 125 in discriminating ovarian cancer from benign pelvic
      masses. Preoperative serum levels of p55 and p75, two distinct types of TNFRs,
      and that of CA 125 were determined by immunoassays in 45 patients with malignant
      and 27 patients with benign tumors operated consecutively. A group of 26 healthy
      women served as controls. For each of the three markers the group with ovarian
      cancer showed significantly higher values than the group with benign masses (p <
      0.01). The rate of marker elevation correlated with ovarian cancer staging. Using
      upper cutoff levels of 2.0 ng/ml (p55), 4.3 ng/ml (p75) and 20 U/ml (CA 125), the
      calculated sensitivities were 58% (p55), 16% (p75) and 82% (CA 125). The
      specificities were 89% (p55), 96% (p75) and 85% (CA 125), respectively. Adding
      p55 to CA 125 did not increase the diagnostic values compared to using the CA 125
      test alone. Our data confirm the superiority of serum CA 125 as a marker for
      discriminating ovarian cancer from benign pelvic masses. The p75 marker was found
      to be of no value, and for the detection of early stage ovarian cancer the
      sensitivity of p55 was too low to be of clinical importance.

PMID- 8658019
TI  - Tumor necrosis factor-alpha stimulates the production of squamous cell carcinoma
      antigen in normal squamous cells.
AB  - Squamous cell carcinoma (SCC) antigen, a tumor marker of squamous cell carcinoma,
      is also increased in several nonmalignant skin lesions, e.g. pemphigus. The aim
      of the present investigation was to determine if tumor necrosis factor-alpha (TNF
      alpha), one of the important environmental factors, stimulated the production of
      SCC antigen in the normal squamous cells. The exposure of normal human epidermal
      keratinocytes to TNF-alpha (100 IU/ml) for 72 h greatly increased the SCC antigen
      production. The stimulatory effect of TNF-alpha (1,000 IU/ml) on the production
      of SCC antigen was also observed in the normal squamous epithelium tissue. These
      results would be helpful for understanding the increase of SCC antigen in several
      nonmalignant skin disorders.

PMID- 8658020
TI  - Lipreading, reading and memory of hearing and hearing-impaired children.
AB  - The relationship between lipreading, reading and visual and sequential memory was
      investigated in hearing 10-year-olds and two groups of hearing-impaired 10-year
      olds, one educated through the medium of English and the other through British
      Sign Language. The scores and the pattern of correlations between the variables
      were hypothesized to be different in the three groups and this was found to be
      the case. In the case of the hearing, visual memory for complex shapes was
      significantly correlated with lipreading. For the oral deaf, reading ability was
      significantly correlated with lipreading, but for the bilingual deaf the
      correlation was not significant. The possible implications of these findings for
      the relationships between the cognitive processes involved in lipreading and for
      the education of the deaf are discussed.

PMID- 8658021
TI  - Averaging evoked potentials with an improved weighting algorithm.
AB  - The procedure of averaging generally applied for noise reduction of evoked
      potentials can probably be improved by weighting the sweeps in dependence on
      their noise energy, which fluctuates considerably. This article demonstrates that
      weighting factors must be free of the signal part in the sweeps if
      underestimation and distortion of the reconstructed evoked potential are to be
      avoided. This can be achieved by pairing the sweeps and weighting the sum of a
      pair by the reciprocal sample variance from its difference. In order to enhance
      precision in variance determination, pre-whitening the data has been suggested
      (Wernicke, 1992). In a feasibility study, this technique is compared with several
      other algorithms known from the literature.

PMID- 8658022
TI  - Speech recognition in noise. Development of a computerized test and preparation
      of test material.
AB  - In adaptable, Finnish language, "speech in noise" test was developed using a
      personal computer equipped with a sound card. each of the 1000 test items stored
      as a separate digitized wave form file on the hard disk of a personal computer
      consisted of disyllabic words on one stereo track and synchronized speech noise
      on the other. Because only a few randomly selected words are presented in this
      test for SRTN (speech recognition threshold in noise or S/N ratio corresponding
      to 50% recognition) the selection and equalization of test material is considered
      to be crucial to the achievement of reproducible results in short time.
      Equalization of the test items (word + noise) in accordance with degree of
      difficulty, by adapting the noise signal to the properties of the corresponding
      word, and selection of 510 of the initial 1,000 recordings with the smallest SDs
      are described. The effect of this procedure on the test-retest reliability of
      testing SRTN is evaluated. Despite contrary expectations, the procedure appears
      to have no effect on the reliability of the speech recognition threshold in noise
      (SD from 1.5 to 1.7 dB).

PMID- 8658023
TI  - Sound localization. The interaction of aging, hearing loss and hearing
      protection.
AB  - The effect of conventional ear plugs and ear muffs, and muffs with limited
      dichotic amplification on the ability to localize one-third octave noise bands
      was investigated under semi-reverberant listening conditions. Forty-eight normal
      hearing subjects, half over 40 years of age, and 23 subjects with bilateral
      sensorineural hearing loss participated. Sound localization was assessed using an
      array of six loudspeakers surrounding the subject at azimuth angles 60 degrees
      apart. One block of 120 forced-choice speaker identification trials was presented
      for each of 16 listening conditions defined by ear condition (unoccluded, E-A-R
      plug, E-A-R muff, and Bilsom 2392 muff), stimulus frequency (500 Hz and 4000 Hz),
      and background (quiet and continuous 65 dB SPL-white noise). Plugs and muffs,
      particularly active muffs, resulted in decrements in right/left judgments based
      on interaural intensity but not time-of-arrival differences. High-frequency
      front/back discrimination was affected more by muffs than by plugs. Error
      patterns for the conventional and active muffs were dissimilar. Aging resulted in
      a decrement in unoccluded front/back discrimination. Trends for the impaired
      subjects were the same as those for normal subjects at 500 Hz. Many could not
      hear 4000 Hz with conventional protectors. Their performance was no different
      from normal with the active muffs.

PMID- 8658025
TI  - Ketamine anaesthesia for electrocochleography in children. Are psychic side
      effects really rare?
AB  - Retrospectively, we have studied the occurrence of psychic side effects in 121
      children (median age 2.25 years) who have had ketamine anaesthesia for
      electrocochleography. For comparison, the same questionnaire was given to 66
      children who had had ketamine for the surgery of squints. Early signs of psychic
      disturbance ( < 3 days) were equally frequent in the two groups, whereas late ( >
      3 days) nightmare was most common in the patients undergoing cochleography (17%
      vs 5%). In several cases, signs of nightmare were reported by the parents to have
      lasted for months or even years. There was a significant (p = 0.00019)
      correlation between the occurrence of nightmare and the degree of hearing
      impairment. The frequency of late nightmare reported in the cochleography
      patients is unacceptably high, but as numerous possibilities of bias exist
      further investigations are necessary before conclusions can be safely drawn.

PMID- 8658024
TI  - Drilling in ear surgery. A comparison of pre- and postoperative bone-conduction
      thresholds in both the conventional and extended high-frequency ranges.
AB  - The pre- and postoperative bone-conduction thresholds for the frequencies 0.25
      through 16 kHz were compared in 46 ears in which a high-speed ear drill was used.
      In 15 of these, thresholds were also obtained in the contralateral ear. There was
      no statistically significant postoperative threshold change at any single
      frequency in either the operated or the contralateral ear. The mean threshold
      elevation of 1.4 dB for the ipsilateral extended high-frequency octave of 8-16
      kHz was marginally significant (p = 0.02), while this was not the case in the
      contralateral, unoperated ear. These findings are considered to be due to
      difficulties in placement of the cumbersome Pracitronic KH70 vibrator following
      bone removal ipsilaterally, with resultant defective transmission to the skull.

PMID- 8658026
TI  - Preferred test conditions for determining hearing thresholds for standardization.
      ISO/TC 43/WG 1 Threshold of hearing. International Organization for
      Standardization Technical Committee 43.

PMID- 8658027
TI  - Hearing protection in acute acoustic trauma in Finnish conscripts.
AB  - A prospective study was performed in all Finnish conscripts who were referred to
      the Central Military Hospital for acute acoustic trauma (AAT) in 1989-93. The
      study was designed to provide information on hearing protection at the time of
      AAT and also on the general habits of using hearing protection at shooting drills
      and combat training in the field. Altogether 449 conscripts with verified AAT
      were included. According to their statements, all conscripts always used hearing
      protectors at shooting drills on the range and 97% always or nearly always during
      combat training in the field. At the moment when AAT occurred, hearing protectors
      were not used in 83% of cases. Accidental shots or explosions (25.6%), unforeseen
      exposure to impulse noise, e.g. during combat training (17.5%), and loss of
      applied protectors (14.9%) were the most common reasons for absence of hearing
      protection. AATs can be avoided by improving instruction in handling firearms,
      planning combat training more carefully and making sure that application of
      earplugs is properly taught and mastered.

PMID- 8658028
TI  - Speech intelligibility index transfer functions and speech spectra for two
      Swedish speech recognition tests.
AB  - Speech spectra and Speech Intelligibility Index (SII) transfer functions are
      presented for the Swedish PB word material (SPB) and for a Swedish sentence
      material known as Hagerman's Sentences (HS). The transfer function were derived
      from the normative recognition scores in noise previously obtained from normal
      hearing subjects. The transfer function for HS is very similar to a transfer
      function for familiar English sentences. The function for SPB is more like
      functions of other monosyllabic word test materials. The slope of the HS transfer
      function is twice as steep as the slope of the SPB function. The long-term rms
      spectra of the speech materials and their associated noise signals are presented
      and recommended to facilitate accurate SII calculations with these speech tests.

PMID- 8658029
TI  - Transient evoked otoacoustic emissions as screening for hearing losses at the
      school for military training.
AB  - The present study was designed to investigate the applicability of transient
      evoked otoacoustic emissions (TEOAEs) as a method of screening for hearing losses
      among recruits attending obligatory military service. TEOAEs, tympanometry and
      puretone audiometry were recorded in 95 male recruits. Sixty-one recruits were
      tested after a 2-month period of gunfire exposure in order to document any
      permanent change in cochlear function. Screening by pure-tone audiometry showed
      an unexpectedly high prevalence of hearing losses > 20 dBHL, probably due to
      technical reasons. Thresholds were corrected using lower thresholds obtained at
      the end of service or by ENT specialists. The accuracy with which normal and
      impaired ears could be identified with TEOAEs analysed in frequency bands was
      determined by decision theory. Impairment was defined as mean hearing thresholds
      > or = 30 dBHL averaged from three neighbouring frequencies. Adequate accuracy
      was obtained in the middle frequencies. Further improvement of the technique is
      needed before it can be deemed suitable for detecting hearing losses at low and
      high frequencies. TEOAEs are quicker to measure and offer greater objectivity
      than pure-tone audiometry. A small decrease in TEOAE level was found after the
      training period. The TEOAEs were highly repeatable and had a higher sensitivity
      than pure-tone audiometry to detection of small changes in cochlear function
      under conditions normally found when testing recruits.

PMID- 8658030
TI  - Verification of decreased basal and stimulated serum pepsinogen-I levels is a
      useful non-invasive method for determining the success of eradication therapy for
      Helicobacter pylori.
AB  - BACKGROUND: We wanted to demonstrate the effect of Helicobacter pylori
      eradication on basal and stimulated pepsinogen-I levels in duodenal ulcer
      patients and to verify whether modification of such levels is a useful method for
      determining the success of eradication therapy. METHODS: Thirty-two patients (24
      men; mean age, 45 years) with active duodenal ulcer were studied. In all patients
      three biopsy specimens were taken from the duodenal bulb, gastric antrum, body
      and fundus for microbiologic and histologic examination. Triple therapy
      consisting of bismuth, metronidazole, and tetracycline was administered.
      Endoscopy was repeated 1 month after completing therapy, and biopsy specimens
      were again taken from the gastric antrum and body. Serum samples were taken at
      initial and repeat endoscopies, to measure basal and stimulated (120 min)
      pepsinogen-I levels after injection of pentagastrin. RESULTS: H. pylori was
      eradicated in 26 patients (81%). Significant histologic improvement, in both the
      antrum and body, was observed (p < 0.001). Basal pepsinogen-I levels (mean and
      95% confidence interval) at diagnosis and after eradication were 106 (92-119) and
      87 (74-100) ng/ml, respectively (P < 0.001). Similarly, stimulated pepsinogen-I
      levels (integrated values) decreased from 4790 (4199-5381) before therapy to 3970
      (3383-4557) ng/ml.min after eradication (P < 0.001). Pepsinogen I levels did not
      change in patients in whom H. pylori was not eradicated. The area under the
      receiver operating characteristic curve for decreased basal and stimulated
      pepsinogen-I levels was 0.77 (SE, 0.09) and 0.79 (SE, 0.1), respectively.
      CONCLUSION: H. pylori eradication in duodenal ulcer patients was associated with
      a significant decrease in basal and stimulated pepsinogen-I levels. Measurement
      of these levels could determine how successful response to therapy has been in
      both the eradication and resolution of associated gastritis. Other advantages of
      this procedure are that it has low cost and results are evident at an early
      stage.

PMID- 8658032
TI  - Gastric adaptation to aspirin and stress enhances gastric mucosal resistance
      against the damage by strong irritants.
AB  - BACKGROUND: Gastric mucosal adaptation to injury induced by repeated application
      of aspirin (ASA) or stress is a well-documented phenomenon, but it is known
      whether such adaptation affects the mucosal tolerance to other strong irritants.
      METHODS: In this study gastric adaptation was induced by repeated daily
      administration of acidified ASA for 4 consecutive days (Series A) or by 3.5H of
      water immersion and restraint stress (WRS) applied every other day for up to 8
      days (series B). When the adaptation to ASA or WRS was fully developed, rats of
      series A and B were challenged with strong irritants such as 100% ethanol, 200 mM
      acidified taurocholate (TC), or 25% NaCl for 1 h or with WRS for 3.5 h. RESULTS:
      ASA or WRS applied once produced numerous gastric lesions and deep histologic
      necrosis accompanied by a decrease in gastric blood flow. With repeated
      application of ASA or stress the mucosal adaptation to ASA and WRS developed; the
      area of gastric lesions was reduced by 86% and 56%, respectively, and this was
      accompanied by a marked decrease of superficial and deep necrosis, and increase
      in gastric blood flow (GBF) and the enhancement of mucosal regeneration. An
      increase in mucosal and luminal contents of epidermal growth factor (EGF) and in
      mucosal expression of EGF receptors was also observed in the mucosa adapted to
      ASA or stress. In rats adapted to ASA or stress and then challenged with 100%
      ethanol, 200 mm TC, 25% NaCl, stress or ASA, the areas of macroscopic gastric
      lesions and deep histologic necrosis were remarkable reduced as compared with
      those in non-adapted vehicle-treated rats. This was also accompanied by a
      significant decrease in (GBF), a marked increase of mucosal and luminal contents
      of EGF and expression of its receptors, and enhanced mucosal cell proliferation.
      CONCLUSIONS: Gastric adaptation to ASA or stress enhances mucosal resistance to
      the injury induced by strong irritants, and this appears to be mediated by
      mucosal regeneration, probably resulting from increased luminal and mucosal
      contents of EGF and excessive expression of its receptors.

PMID- 8658031
TI  - Effects of the anti-gastric secretory drugs IT-066 and omeprazole mitogenic
      activities in the gastric juice of the rat.
AB  - BACKGROUND: Salivary epidermal growth factor (EGF) retains its biologic function
      in gastric juice and may play a physiologic role. Little is know, however, about
      the existence of mitogens other than EGF and the constitutional alterations of
      these factors in gastric juice by anti-secretagogues. METHODS: The mitogenic
      activity was evaluated by measuring [3H]-thymidine incorporation, and the EGF
      contribution was determined by using a specific anti-rat EGF antibody. An H2
      receptor antagonist (IT-066) and a proton pump inhibitor (omeprazole) were used
      to determine whether these drugs alter the relative composition of active
      mitogens in gastric juice. RESULTS: Normal gastric juice significantly increased
      DNA synthesis. This activity was suppressed by antibody (87-88%). Both drugs
      increased EGF concentrations and activity dose-dependently IT-066 specifically
      increased total amount and activity of EGF. Approximately 50% of this activity
      was reduced by boiling or antibody. CONCLUSION: The major mitogenic activity of
      normal rat gastric juice depends on EGF, and antisecretory drugs enhance the
      mitogenic activity by preserving and including intraluminal mitogens than EGF.

PMID- 8658033
TI  - Non-steroidal anti-inflammatory drugs and ulcer complications: a risk factor
      analysis for clinical decision-making.
AB  - BACKGROUND: Use of non-steroidal anti-inflammatory drugs (NSAIDs) is recognized
      as an important cause of peptic ulcer complications. The aim of this nested case
      control study was to identify risk factors for NSAID-related ulcer complications.
      METHODS: Cases were consecutive NSAID users admitted with an ulcer complication
      (n = 118), and controls were a random sample of all NSAID users without ulcer
      complication identified by a pharmacoepidemiologic database (n = 540). RESULTS:
      Ninety-four of 118 cases were interviewed, and 324 of 540 controls answered the
      questionnaire. Analysis showed no difference between included and non-included
      subjects. Risk factors for patients at start of NSAID therapy were high age: 60
      75 years (odds ratio (OR), 3.5 (95% confidence interval (Cl), 1.8-7.1); > 75
      years (OR, 8.9 (4.3-18.3)); male sex (OR 1.7 (1.0-3.0)); ulcer history (OR 2.5
      (1.2-5.1)); steroid treatment (OR 2.0 (0.8-4.6)); smoking (OR 1.6 (0.9-2.7)); and
      alcohol use (OR 1.8 (0.9-3.6)). Risk factors for patients receiving NSAID therapy
      were high age, male sex, ulcer history, smoking and, furthermore, dyspepsia (OR
      2.0 (1.0-4.2)), especially NSAID-related dyspepsia (OR 8.7 (4.0-18.9)). Risk was
      lower for patients treated more than 3 months. CONCLUSION: Risk measured from
      this design can be shown to correlate strongly with the rate difference, a
      measure that is more clinically relevant than conventional relative risk
      estimates. Strong risk factors for NSAID-related ulcer complication are high age,
      male sex, ulcer history, and dyspepsia related to the NSAID therapy. Avoiding
      NSAID therapy in these high-risk patients, whenever possible, might prevent many
      adverse events.

PMID- 8658034
TI  - Is motility impaired in the entire upper gastrointestinal tract in patients with
      gastro-oesophageal reflux disease?
AB  - BACKGROUND: Although the pathogenesis of gastro-oesophageal reflux disease is
      multifactorial, abnormal function of the lower oesophageal sphincter has been
      established, and in some cases motility defects in the oesophageal body has been
      described. In some patients with gastro-oesophageal reflux disease delayed
      gastric emptying has also been observed. METHODS: Oesophageal and gastric motor
      function, as evaluated by use of scintigraphy and manometry, were studied
      concomitantly in 105 patients with chronic, gastro-oesophageal reflux disease
      before and after antireflux surgery. In a subgroup of these patients (n = 29)
      similar data were retrieved also at 2.7 years after antireflux surgery. RESULTS:
      Impaired oesophageal motor function expressed as delayed transit of a labelled
      bolus was closely associated with motor dysfunction also recorded in the stomach
      as determined by delayed emptying of labelled solid food items. A similar
      relationship was found when oesophageal motor dysfunction was characterized as
      the frequency of failed primary peristalses after water swallows during
      manometry. When the 105 patients were studied half a year after an antireflux
      operation, noncorrelation between oesophageal and gastric motor function could be
      recorded. CONCLUSIONS: These data further substantiate the view that gastro
      oesophageal reflux disease is associated with a disturbed motor function within
      the entire upper gastrointestinal tract.

PMID- 8658035
TI  - Gastric clearance of radiopaque markers in non-ulcer dyspepsia patients.
AB  - BACKGROUND: The use of radiopaque markers has been proposed as an easy, non
      invasive method for measuring gastric emptying. In this study we intended to
      evaluate the effectiveness of this test in determining the gastric motor function
      in patients with non-ulcer dyspepsia. METHODS: Simultaneous recording of
      scintigraphic solid gastric emptying and gastric clearance of radiopaque markers
      were conducted in 65 non-ulcer dyspepsia patients. RESULTS: Forty-two patients
      (64.4%) showed abnormal gastric clearance of radiopaque markers, and 38 patients
      (58.5%) showed delayed solid gastric emptying. There was no correlation between
      delayed solid gastric emptying and abnormal gastric clearance of radiopaque
      markers (p > 0.05). Although the frequency of abnormal gastric clearance of
      radiopaque markers was higher than that of delayed solid gastric emptying (64.6%
      versus 58.5%), it was not statistically significant. CONCLUSIONS: On the basis of
      the results of our study, gastric clearance of radiopaque markers may be used as
      an easy, non-invasive screening test for the purpose of detecting gastric motor
      dysfunction. However, this test is not superior to scintigraphic gastric emptying
      studies.

PMID- 8658036
TI  - The X-ray contrast medium iodixanol detects increased colonic permeability
      equally well as 51Cr-labeled ethylenediaminetetraacetic acid in experimental
      colitis of rats.
AB  - BACKGROUND: Non-ionic, water-soluble radiographic contrast media have been
      suggested as intestinal permeability probes. We studied the permeability of the
      isosmolar contrast medium iodixanol and 51Cr-labeled ethylenediaminetetraacetic
      acid (EDTA) from the non-perforated colon after induction of colonic
      inflammation. METHODS: Colonic inflammation and ulcerations were induced by
      luminal colonic instillation of trinitrobenzenesulfonic acid, dissolved in 40%
      ethanol. Controls received saline. Fourteen days later iodixanol, 320 mg I/ml,
      and 51Cr-EDTA were given as an enema. Urine was collected for the subsequent 6 h
      and subjected to high-performance liquid chromatography and gamma activity
      counting. RESULTS: Urinary recovery of iodixanol and 51Cr-EDTA increased
      gradually with severity of the colonic inflammation. The correlation between
      iodixanol and 51Cr-EDTA recovery was strong (corr.coeff = 0.97). CONCLUSIONS:
      Iodixanol shows as good properties as 51Cr-EDTA when used as intestinal
      permeability probe in the inflamed and ulcerated rat colon. Use of the radiopaque
      properties of iodixanol enable intestinal probe exposure registration by film or
      fluoroscopy.

PMID- 8658037
TI  - In vitro effects of ethanol on human gastric and pancreatic lipolytic
      activities/enzymes.
AB  - BACKGROUND: Ethanol ingestion may disturb fat digestion and absorption by
      affecting gastric, intestinal, hepatic, and pancreatic functions. Involved
      mechanisms are not well understood. We examined in vitro ethanol effects on
      gastric and pancreatic lipolytic activity. METHODS: Human gastric juice, pure
      gastric lipase, pancreatic lipase, colipase, carboxyl ester lipase, phospholipase
      A2, and duodenal contents were a) preincubated at 37 degrees C with ethanol (0
      30%) and then assayed under normal conditions (pH-stat titration), or b) assayed
      in the presence of various ethanol concentrations (0-30%). RESULTS: Ethanol
      reduced gastric and pancreatic lipolytic activities in a dose-dependent manner.
      The effect was more pronounced with alcohol present in the assay medium, with 5%
      ethanol reducing carboxyl ester lipase activity by 10%, gastric lipase activity
      by 20%, and pancreatic lipase activity by 46%. Colipase and phospholipase A2
      activities were only slightly affected by ethanol. CONCLUSIONS: Observed effects
      of ethanol on gastric and pancreatic lipase may be important when fat digestion
      is already impaired due to gastric, intestinal hepatic, and/or pancreatic
      diseases.

PMID- 8658038
TI  - Assessment of the diagnoses of Crohn's disease and ulcerative colitis in a Danish
      hospital information system.
AB  - BACKGROUND: Our aim was to estimate the completeness-that is, whether all
      patients were included in the system-and the validity-that is, whether the
      diagnostic criteria were fulfilled for the patients registered-of the diagnoses
      of Crohn's disease and ulcerative colitis in a Danish hospital system. METHODS:
      Information in a regional hospital system, in the County of North Jutland,
      Denmark, was compared with hospital records and information in a pathology
      system. RESULTS: The analysis of the completeness included 143 patients with
      Crohn's disease and 285 patients with ulcerative colitis. The completeness of the
      regional hospital system using the pathology system as a reference standard was
      94% for both diseases. The analysis of the validity included 281 patients
      registered as having Crohn's disease and 506 patients registered as having
      ulcerative colitis. The validity of the two diagnoses was 97% and 90%,
      respectively. CONCLUSIONS: The regional hospital system showed few
      misclassifications of the diagnoses of Crohn's disease and ulcerative colitis.
      Thus the nationwide hospital system (based on the regional hospital systems) may
      provide a unique study base for future research.

PMID- 8658039
TI  - Cholecystectomy as a risk factor for colorectal cancer: a meta-analysis.
AB  - BACKGROUND: It has been suggested that there is an increased risk of colorectal
      cancer after cholecystectomy due to increased levels of secondary bile acids.
      Some studies suggest the risk is higher for women and for the development of
      right-sided tumours. METHODS: A review of the literature yielded 95 relevant
      studies, of which 35 were suitable for a meta-analysis involving age- and sex
      matched controls. RESULTS: The pooled odds ratio for a positive association
      between cholecystectomy and colorectal cancer was 1.11 (95% confidence interval
      (CI), 1.02 to 1.21). For women the odds ratio was 1.14 (95 % CI, 10.01 to 1.28)
      and for right-sided cancer 1.86 (95% CI, 1.31 to 2.65). CONCLUSIONS: It is
      possible that this small observed association may be due to a publication bias
      for positive results or bias within the included studies. If it is indeed a real
      effect, the risk to an individual is very small.

PMID- 8658040
TI  - Plasminogen activators and plasminogen activator inhibitor in portal blood from
      patients with and without gastric malignancy.
AB  - BACKGROUND: Plasminogen activators (PA) may be released by the gut and eliminated
      by the liver. Patients with liver disorders or malignancy often have abnormal
      plasma levels of PAs. Some tumours may produce PAs. METHODS: In patients
      undergoing gastric surgery for malignant (n = 18) or benign (n = 21) disorders.,
      blood drawn from the portal vein and a peripheral vein was analysed for tissue
      type plasminogen activator antigen and activity (tPA: Ag, tPA: Act), single-chain
      urokinase-type plasminogen activator activity (scuPA: Act), and plasminogen
      activator inhibitor antigen and activity (PAI: Ag, PAI: Act). RESULTS AND
      CONCLUSIONS: In both groups tPA: Act and scuPA: Act levels were significantly
      higher in portal blood than in peripheral blood, but tPA: Ag and PAI: Act levels
      did not differ. PAI: Act levels were significantly lower in patients with
      malignant disease, but levels of the other markers did not differ in the two
      groups.

PMID- 8658041
TI  - A bacteriologic and scanning electron microscope study after implantation of
      foreign bodies in the biliary tract in rats.
AB  - BACKGROUND: Bacterial adherence to the stent surfaces, concomitant colonization,
      and possible stent blockage are the main complications after the use of biliary
      stents. The present study was assigned to investigate bacteriologic and
      morphologic changes in the biliary tract after the implantation of biliary drain
      materials. METHODS: Rubber and silicone pieces with a surface area of 1 cm2 were
      implanted into the biliary tract in rats after temporary obstruction of the
      common bile duct by the use of a mini-occluder. The animals were killed at 4, 8
      and 14 weeks, respectively, after implantation, and the implants were retrieved,
      cultured, and examined by scanning electron microscopy (SEM). Bacterial culture
      and SEM were also performed on tissue samples obtained from the mucosal surface
      of the biliary tract. RESULTS: Bacterial colonization and biofilm formation were
      found on the surfaces of the implanted materials and on the mucosal surface of
      the biliary tract in animals with implants but not on the biliary tract mucosa in
      rats without implants. CONCLUSION: Foreign bodies implanted in the biliary tract
      facilitate bacterial adherence not only to the surface of the implants but also
      to the mucosal surface in the biliary tract.

PMID- 8658042
TI  - Leukocyte and platelet depletion protects the liver from damage induced by
      cholestasis and ischemia-reperfusion in the dog.
AB  - BACKGROUND: Ischemia-reperfusion injury has been studied in various organs. The
      effects of leukocyte and platelet depletion on cholestasis and ischemia
      reperfusion-induced liver damage were evaluated in the dog liver. METHODS: The
      left hepatic duct was ligated for 4 weeks to create a cholestatic lobe. An
      ischemic condition was produced for 60 min by stopping the peristaltic pump
      supplying blood to the liver. The metabolism of substances modulated in the liver
      during cholestasis and I-R was assessed in non-treated and in leukocyte- and
      platelet-depleted animals. RESULTS: The extraction rate of insulin and
      indocyanine green decreased during cholestasis and ischemia-reperfusion.
      Cholestasis accelerated the release of thromboxane A2 but not prostaglandin I2
      after ischemia-reperfusion. Ischemia-reperfusion accelerated the release of
      prostaglandin I2 and thromboxane A2 from the liver. Further, ischemia-reperfusion
      increased the ratio of thromboxane A2 to prostaglandin I2. Cholestasis promoted
      an increase in the level. Ischemia-reperfusion caused an increase in the lipid
      peroxide level, and no change in the alpha-tocopherol level. Ischemia-reperfusion
      caused an increase in the lipid peroxide level, a decrease in the alpha
      tocopherol level, and no change in the glutathione level. Depletion of leukocytes
      and platelets reduced these changes during cholestasis and ischemia-reperfusion.
      CONCLUSIONS: Depletion of leukocytes and platelets thus appears to protect liver
      function from cholestasis and ischemia-reperfusion injury by reducing
      peroxidation of lipids composing the cell membrane and the rate of thromboxane A2
      prostaglandin I2, which predicts cellular damage, and by increasing the levels of
      alpha-tocopherol and glutathione, believed to be free radical scavengers.

PMID- 8658043
TI  - Expectant management of patients with gallbladder stones diagnosed at planned
      investigation. A prospective 5- to 7-year follow-up study of 153 patients.
AB  - BACKGROUND: Few studies have been done on the expectant management of patients
      with cholelithiasis diagnosed by planned investigation, and results are
      conflicting. METHODS: A prospective 6-year follow-up study of 153 patients with
      cholelithiasis diagnosed by oral cholecystography was carried out. RESULTS: An
      acute gallstone complication occurred during the follow-up period in 23 patients
      (15%)-that is, acute cholecystitis (n = 18), acute pancreatitis (n = 2), and
      jaundice (n = 3). The annual risk of developing an acute biliary complication was
      3.1%. A history of a gallstone complication predicted further gallstone
      complications during follow-up. The overall cholecystectomy rate was 20 % during
      the 1st year but fell to about 3% during the 5th year of follow-up. Young age and
      frequent attacks of biliary pain episodes predicted the need for gallstone
      surgery. CONCLUSIONS: Expectant management of patients with electively diagnosed
      cholelithiasis may be justified, especially in those with only occasional biliary
      symptoms and no history of gallstone complications.

PMID- 8658044
TI  - No effect of oxygen therapy on myocardial ischaemia during gastroscopy.
AB  - BACKGROUND: Myocardial ischaemia (defined as an ST-segment depression on ECG) may
      occur during upper gastrointestinal endoscopy, but the mechanism is still
      unknown. The aim of our study was to evaluate the effect of oxygen therapy and
      tachycardia on the occurrence of ST-segment depression during routine diagnostic
      esophagogastroduodenoscopy. METHODS: Eighty-nine consecutive patients were
      randomized to receive either oxygen (21/min by nasal prongs) or nothing during
      endoscopy, in which arterial oxygen saturation was measured by continuous pulse
      oximetry, and ECG was measured continuously with a Holter tape recorder. RESULTS:
      A total of 28 patients (12 receiving oxygen) developed ST-segment depression ( >
      0.1 mV) during endoscopy. In 22 patients (12 receiving oxygen) ST depression was
      related to tachycardia, and in 5 of these (none receiving oxygen) simultaneous
      episodic hypoxaemia was present during the event. Thus, in every case of ST
      depression related to episodic hypoxaemia there was simultaneous tachycardia. In
      six patients developing ST depression during endoscopy we did not find
      preendoscopy levels, and 63 patients (29 receiving oxygen) developed tachycardia
      during the procedure (rate > 100 min-1_. CONCLUSIONS: Oxygen therapy had no
      significant effect on the occurrence of ST-segment depression during upper
      gastrointestinal endoscopy. The results suggest that tachycardia is more
      important than hypoxaemia in the pathogenesis of ST depression during
      gastroscopy.

PMID- 8658045
TI  - Hepatotoxicity due to lysine salt of bendazac.
AB  - BACKGROUND: The lysine salt of bendazac is a non-steroidal anti-inflammatory
      agent, and it is marketed exclusively for the treatment of cataracts. We report
      two cases of possible hepatotoxicity due to the use of bendazac lysine. METHODS:
      Laboratory tests, serologic tests, abdominal sonography and scan were performed
      to study liver disease. RESULTS: Reversible increases of the hepatic enzymes were
      found in both cases. Anemia was also found in one of the cases (case 1).
      CONCLUSIONS: Abnormal liver test results could be related to a possible liver
      injury attributed to the use of bendazac lysine.

PMID- 8658046
TI  - The application of microridge analysis in the diagnosis of gastro-oesophageal
      reflux disease.
AB  - BACKGROUND: The percentage of epithelial surface area covered by microridges
      (%MR) seen during scanning electron microscopy of oesophageal biopsy specimens
      has previously been shown to correlate with symptomatic reflux disease, a result
      < or = 35% being abnormal. The aim of this study was to compare %MR with
      endoscopy, light microscopy, and pH monitoring results. METHODS: Sixty-seven
      patients with heartburn were divided into oesophagitis or none on the basis of
      endoscopy and light microscopy findings and into those with and without abnormal
      acid reflux on the basis of pH monitoring. RESULTS: The endoscopic and light
      microscopic oesophagitis groups had significantly greater degrees of acid reflux
      than those without oesophagitis (p < 0.05), even though neither the specific %MR
      nor the number of patients below the 35% cutoff showed any difference between
      those with and without endoscopic oesophagitis, light microscopic oesophagitis or
      those with normal and abnormal acid reflux on pH monitoring. CONCLUSION: Despite
      the significant relationship between endoscopic and light microscopic
      oesophagitis and abnormal pH monitoring microridge analysis did not correlate
      with any of these variables

PMID- 8658047
TI  - Co-stimulation and co-inhibition: equal partners in regulation.
AB  - Specific immune responses are controlled by two counterbalancing mechanisms-co
      stimulation and co-inhibition. Antigen receptors determine specificity, activate
      co-stimulation and/or co-inhibition, and interact with these co-stimulatory/co
      inhibitory mechanisms to dictate the direction of the immune response, either
      positive or negative. Co-stimulatory or co-inhibitory ligands interact with their
      specific receptors and may indicate the context in which antigen is perceived by
      lymphocytes. Ligation of antigen receptors may activate only co-stimulatory or co
      inhibitory mechanisms, and thus may influence secondarily the direction of the
      immune response. Furthermore, the activity of a given co-stimulator or co
      inhibitory receptor is modified depending on signalling via the antigen receptor.
      If neither co-stimulators nor co-inhibitors are present, lymphocytes, activated
      in response to antigen receptor signalling, produce low levels of effector
      elements and then revert to inactivity. Co-inhibitors are defective in autoimmune
      disease.

PMID- 8658048
TI  - Murine acariasis. II. Immunological dysfunction and evidence for chronic
      activation of Th-2 lymphocytes.
AB  - The authors describe the immunological profile of BALB/c mice with Mite
      Associated Ulcerative Dermatitis (MAUD)-like disease, due to Myocoptes musculinus
      (Koch 1844) infestation. The disease probably involves allergic mechanisms and is
      characterized by erythematous and pruritic skin lesions, widespread hair loss,
      lymphadenopathy, lymphocytopenia, granulocytosis and wasting. Affected
      individuals had much reduced numbers of pre-B and B cells in bone marrow and B
      cells in blood; decreased T-cell numbers in peripheral lymphoid organs and blood;
      hypergammaglobulinaemia with selective increases of IgG1, IgE and IgA, and
      depletion on IgM and IgG3, the same isotype distribution being detected in
      splenic plasmocytes; qualitative modifications of the serum antibody reactivity
      pattern; and increased production of IL-4 with decreased IL-2 production after in
      vitro polyclonal stimulation of T cells. Taken together, these results suggest
      that infestation by M. musculinus in BALB/c mice leads to a significant
      immunological disorder resulting in a T-helper-2 (Th-2) type response, with
      marked systemic consequences. This pathological condition may thus provide a
      useful model system for the immunobiological perturbation associated with chronic
      allergic disease.

PMID- 8658049
TI  - Indirect effects are independent of the way of tolerance induction.
AB  - Oral tolerance is a T-cell mediated phenomenon defined by a refractoriness to
      parenteral immunization with a protein that was first contacted by oral route.
      However, the authors have shown that the injection of a tolerated protein is not
      neutral for the immune system. In mice made tolerant to KLH by gavage, co
      immunization with KLH and DNP-Ova blocks anti-DNP antibody formation. Anti-DNP
      antibody formation resulting from immunization with DNP-Ova can also be blocked
      by co-immunization with a dietary protein (zein) or a self component
      (fibrinogen). The inhibitory effects resulting from immunization with a tolerated
      protein, designated indirect effects, do not affect the induction of oral
      tolerance to another protein. These results support the hypothesis that active
      mechanism are involved in the maintenance of tolerance.

PMID- 8658050
TI  - Heterogeneous expression of recombination activating genes and surface CD5 in
      CD3low CD4+ CD8+ thymocytes.
AB  - Clonal selection in the thymus occurs mostly in the CD4+ CD8+ (double positive;
      DP) stage. Within DP thymocytes, cells in the CD3low subset are believed to be
      involved in clonal selection, and this subset is generally considered as a
      homogeneous population. T-cell antigen-receptor (TCR) signals on DP thymocytes
      are known to (i) down-regulate recombination activating gene (RAG) expression;
      and (ii) up-regulate the expression of T-cell function-associated molecules,
      including the cell surface glycoprotein CD5. The present study examined the
      expression of RAG and CD5 molecules among the subpopulations of normal adult DP
      thymocytes. DP thymocytes were fractionated according to their cell surface
      expression levels of TCR-CD3 complex into CD3dim, CD3lo, CD3med, and CD3hi cells,
      since TCR expression is known to increase during thymocyte maturation. Down
      regulation of RAG mRNA was located between the CD3low and CD3med DP populations.
      However, within the DP CD3low subpopulation, we found that CD5 varies from low to
      high expression levels. Upon fractionation of DP CD3low thymocytes into CD5low
      and CD5high subsets, we were able to detect down-regulation of RAG transcripts
      within the CD3low subpopulation. Thus, by the criteria of CD5 surface expression
      and RAG mRNA expression levels, DP CD3low thymocytes can be considered a
      heterogeneous thymocyte subpopulation.

PMID- 8658051
TI  - Immunophenotyping of human bone marrow-derived macrophages.
AB  - In vitro cultured cells derived from human bone marrow stimulated with macrophage
      colony stimulating factor (M-CSF) or granulocyte-macrophage-colony stimulating
      factor (GM-CSF) were investigated for their immunophenotypic surface
      characteristics by flow cytometry. Approximately 80-90% of the cells showed
      morphological and histochemical features of macrophages and bore CD11a, CD11b,
      CD11c, CD14, CD29, CD32, CD33, CD44, CD45, CD54, CD64, CD71, HLA-DR antigen. The
      expression of CD4, CD25 and CD45RO were detected only in low density. Bone marrow
      derived macrophages were negative for CD8, CD45RA, CD16 and CD23. Functionally,
      macrophages were able to phagocytose opsonized Escherichia coli, but no oxidative
      bursts were induced either by fmlp or by opsonized bacteria. Cell surface
      phenotyping revealed a CD pattern very similar to monocyte-derived phagocytes,
      and was partially distinct from resident stromal macrophages.

PMID- 8658052
TI  - Fibronectin co-stimulates via the alpha 5 beta 1 receptor IL-2, IL-4 production
      by splenic, granuloma lymphocytes of Schistosoma mansoni infected mice.
AB  - In murine Schistosomiasis mansoni, soluble worm egg antigens (SEA) induce L3T4+ T
      helper cell-mediated chronic granulomatous inflammations around parasite eggs.
      Within the fully developed granuloma lymphocytes, macrophages, and eosinophils,
      fibroblasts are embedded in extracellular matrix (ECM) composed of fibronectin,
      laminin, glycosaminoglycans and collagens. The present study examined in vitro
      the putative co-stimulatory role of fibronectin (FN) in acute and chronic
      infection splenic and granuloma lymphocyte responses. Plate-bound FN enhanced the
      anti-CD3 MoAb stimulated normal and acute or chronic infection splenic
      lymphoproliferation by 20-32%. The co-stimulatory effect was evident in SEA
      stimulated acute but not chronic infection spleen cells. Proliferation of
      stimulated granuloma lymphocytes could not be up-regulated by immobilized FN.
      Plate-bound FN significantly enhanced IL-2 and IL-4 production by SEA-stimulated
      acute, but not chronic, infection granuloma lymphocytes. However, FN had no
      influence on the high level of IL-2, IL-4 production of anti-CD3 MoAb stimulated
      acute or chronic infection splenic or granuloma lymphocytes. Because in the
      antigen-stimulated acute infection spleen or granuloma cultures the co
      stimulatory effect by FN was abrogated by the tripeptide (RGD) arg-gly asp, and
      anti alpha 5 beta 1 antibody, enhancement is attributed to signalling via the
      alpha 5 beta 1 integrin receptor of lymphocytes.

PMID- 8658053
TI  - Activation of the protein kinase A increases the DNA-binding and transcriptional
      activity of c-Rel in T cells.
AB  - Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is known to have both negative
      and positive effects on the activation mechanisms of T lymphocytes. The authors
      have analysed the effect of increased cAMP on the activation of NF-kappa B
      transcription factor. This factor controls the expression of several genes (e.g.
      IL-2 and IL-2 receptor) involved in the activation and proliferation of T cells.
      The authors found that elevation of intracellular cAMP in Jurkat T leukaemia
      cells activated with phorbol ester (PDBu)/calcium ionophore (A23187) increased
      the DNA-binding of NF-kappa B as detected by the electrophoretic mobility shift
      assay (EMSA). Analysis of the subunit composition of the DNA-binding complex
      indicated that the amount of c-Rel was enhanced while RelA was decreased.
      Analysis of the effect of elevated cAMP on the degradation of I kappa B-alpha and
      I kappa B-beta did not reveal an essential change in degradation kinetics of
      these inhibitor proteins. The elevation of cAMP did not increase the synthesis of
      c-Rel, but it enhanced the nuclear localization of this protein. Transfection of
      Jurkat cells with a plasmid kB/TK10-CAT indicated that the increased DNA-binding
      of c-Rel containing complexes seen in EMSA was also functional. These data imply
      that the strong and long-lasting c-Rel nuclear localization and DNA-binding
      induced by protein kinase A is not due to increased c-Rel synthesis or enhanced
      degradation of the I kappa B inhibitors. Therefore, a direct phosphorylation of
      the c-Rel protein is the most plausible explanation for these observations. Taken
      together, these results suggest that cAMP is able to regulate the expression of
      NF-kappa B-dependent genes in T cells by modifying the composition and subunit
      activity of NF-kappa B.

PMID- 8658054
TI  - Activation of cloned human CD4+ Th1 and Th2 cells by blood dendritic cells.
AB  - Dendritic cells (DC) have been reported to be the most potent antigen-presenting
      cells (APC) for the activation of naive T cells and to be 10-100-fold more potent
      APC than monocytes (M phi) in the mixed lymphocyte reaction. In this study the
      authors compared human blood DC with M phi and B cells for their ability to
      activate cloned rye grass allergen Lol p I specific CD4+ Th1 and Th2 cells. In
      the presence of Lol p I, all three types of APC activated Th1 and Th2 cells to a
      similar extent, as shown by T-cell proliferation and interferon-gamma,
      interleukin-2 (IL-2) or IL-4 secretion. However, at low APC:T cell ratios, M phi
      were the most potent APC for both Th1 and Th2 cells followed in decreasing order
      by DC and B cells. This hierarchy was observed with APC preparations isolated by
      negative selection or highly purified by positive selection using fluorescent
      cell sorting for HLA-DR(high)-DC, CD14(pos)-M phi and CD19(pos)-B cells. The data
      demonstrate that, in contrast to what has been reported for naive T cells, human
      blood DC activate cloned memory Th1 and Th2 cells to a similar extent as M phi
      and B cells presumably because the requirements for activation of memory type T
      cells are less stringent than those for naive T cells.

PMID- 8658055
TI  - The effects of mitogens, IL-2 and anti-CD3 antibody on the T-cell receptor V beta
      repertoire.
AB  - Phytohaemagglutinin (PHA), Concanavalin A (Con A), interleukin-2 (IL-2), and
      monoclonal antibodies to CD3 (CD3MoAbs) are used for the assessment of the T-cell
      receptor (TCR) BV gene family expression in autoimmune disorders and multiple
      sclerosis, and to produce clones for assessment of cytokine profiles in
      progressive human immunodeficiency virus infection. The authors examined the
      effects of these stimulants on the TCR V beta repertoire of resting and blastic
      CD4+ and CD8+ normal human peripheral blood lymphocytes, using three-colour
      cytofluorometry and a panel of anti-TCR V beta monoclonal antibodies. IL-2 was
      associated with an increased percentage of blastic CD4+ cells expressing V beta
      5.1 (from median of 3.7% to 8.0%, P = 0.0002) and blastic CD8+ cells expressing V
      beta 5.3 (1.0 to 1.5%, P = 0.0039). CD3MoAb caused a slight increase in V beta
      6.7 + blastic CD4+ cells (4.5 to 6.9%, P = 0.0078). PHA did not alter the V beta
      repertoire of blastic cells. Con A caused skewing in CD8+ blastic cells, toward
      expression of V beta 5.2/5.3 (3.1 to 8.1%) and V beta 5.3 (0.8 to 4.8%) (P =
      0.0020). Thus, IL-2 stimulation causes slight alterations in the V beta
      repertoire that should be taken into account in certain research settings. Con A
      produced skewing in CD8+ blastic cells suggesting that, in the presence of CD8,
      either Con A binds selectively to certain V beta or the three-dimensional complex
      created by Con A's binding to other T-cell surface molecules induces preferential
      V beta 5 stimulation.

PMID- 8658056
TI  - Human T-cell epitopes on the Mycobacterium tuberculosis secreted protein MPT64.
AB  - Mycobacterium tuberculosis secretes a number of proteins into the extracellular
      environment, some of which are restricted to the M. tuberculosis complex. These
      proteins are targets for T- and B-cell immune responses in tuberculosis (TB)
      patients and their contacts. The authors have mapped the immunogenic regions of
      the MPT64 protein of M. tuberculosis using peripheral blood mononuclear cells
      (PBMC) from TB patients and a set of overlapping peptides encompassing the
      complete sequence of the protein. T-cell epitopes which induced proliferation or
      interferon-gamma (IFN-gamma) release were distributed over the full length of the
      protein. A C-terminal region of the protein, however, contains sequences
      recognized in the context of multiple HLA-DR phenotypes by more than 80% of the
      subjects tested. The nature of the T-cell response was further investigated by
      generating MPT64-specific T-cell lines. These lines also identified the T-cell
      epitopes in the C-terminal region of the protein. On stimulation with antigen the
      lines secreted IFN-gamma, but not interleukin 4 (IL-4). A minority of TB patients
      (6/32) mounted an antibody response to MPT64. Sera from half (3/6) of these
      identified two linear antibody binding sites. These results confirm the
      significance of this protein in the immune response to tuberculosis infection.

PMID- 8658057
TI  - Antibodies reactive to Trypanosoma cruzi epimastigotes or amastigotes express
      different idiotypic patterns if from patients with different clinical forms of
      Chagas' disease.
AB  - Antibodies (Abs) were purified from pooled sera of patients with either
      indeterminate (IND or I) or cardiac (CARD or C) Chagas' disease, on either
      epimastigote (EPI or E) or amastigote-enriched (AMAST or A) antigen (Ag) columns
      and their idiotypic (Id) expression examined. Anti-Id rabbit Abs were raised to
      the different preparations (E-IdI, E-IdC, A-IdI and A-IdC). Competitive ELISAs
      using anti-Ids were able to discriminate between IdI and IdC, disregarding Ag
      reactivity. E-IdI and A-IdI present different inhibitory abilities, as do E-IdC
      and A-IdC, but IdC always competes with IdI for anti-IdI comparably. In contrast,
      a 4-8-fold increase of IdI is required to compete in parallel with IdC for anti
      IdC. Therefore, Ids from IND patients share only low levels of the Ids that are
      most characteristic of CARD patients. While some CARD Abs also express Ids in
      common with IND patients, these studies reveal that CARD Abs express some Ids
      that are characteristic to only CARD patients, and these Ids are present on Abs
      purified with either EPI or AMAST.

PMID- 8658058
TI  - Serum level of interleukin-4 in patients with perennial allergic rhinitis during
      allergen-specific immunotherapy.
AB  - Interleukin-4 (IL-4) may play a central role in the IgE synthesis system, the
      development of Th-2-like cells, and co-ordination as well as the persistence of
      airway inflammatory process in allergic disorders. Therefore, IL-4 plays a key
      role in airway allergic disorders. This study aimed at investigating the serum
      concentrations of IL-4 in patients with perennial allergic rhinitis, with special
      reference to the possible changes and the clinical relevance following long-term
      immunotherapy. The study has demonstrated that the serum level of IL-4 in
      allergic rhinitis patients before immunotherapy is significantly higher than that
      in non-atopic individuals. However, the serum IL-4 level in allergic rhinitis
      patients did not decrease following anti-allergic medications but significantly
      decreased following immunotherapy. The percentage decrease in IL-4 was correlated
      significantly with the percentage decrease in specific IgE antibodies following
      long-term immunotherapy. Immunotherapy also significantly decreased specific IgE
      anti-bodies, but this reduction in specific IgE antibodies was not significantly
      correlated with the clinical improvement. In contrast, the percentage decrease in
      serum IL-4 was significantly correlated with the percentage decrease in
      symptomatic scores. The authors interpret these data to mean that immunotherapy
      alters T-cell cytokine profiles in the long-term, and a decline of IL-4 following
      immunotherapy could modulate not only production of specific IgE antibodies but
      also inflammatory cellular events, leading to symptomatic relief in allergic
      rhinitis.

PMID- 8658059
TI  - Down-regulation of anti-CD3 antibody-induced IL-4 production by bovine caseins
      hydrolysed with Lactobacillus GG-derived enzymes.
AB  - A prerequisite for systemic hyporesponsiveness to dietary antigens is their
      processing in the gut. This study investigated whether bovine caseins degraded by
      enzymes of an intestinal bacterial strain, Lactobacillus GG (ATCC 53103), could
      regulate the cytokine production by anti-CD3 antibody-induced peripheral blood
      mononuclear cells of 14 atopic patients, aged 5-29 (mean, 16) months. Purified
      casein up-regulated the interleukin-4 and interferon-gamma production, P = 0.008
      and P = 0.008, respectively. Conversely, Lactobacillus GG-degraded casein down
      regulated the interleukin-4 production, P = 0.003, with no effect on interferon
      gamma. These results indicate that intestinal bacteria may modify
      immunomodulatory properties of native food proteins and introduce a promising
      tool to provide protection from potentially harmful dietary antigens at a young
      age.

PMID- 8658060
TI  - Soluble CD4: a link between specific immune mechanisms and non-specific
      inflammatory responses?
AB  - The CD4 molecule is an important cell surface molecule expressed on many cell
      types including T-helper cells. CD4 can be shed from cells, and the truncated
      soluble form of CD4 (sCD4) has been found elevated in serum in several diseases.
      In this study the authors show that migration of polymorphonuclear neutrophils
      (PMN) is induced by sCD4. Histopathology of the site of injection of recombinant
      sCD4 in the skin shows local infiltration of PMN. In vitro, in Boyden chamber,
      sCD4 can rapidly give rise to a dose-dependent migration of PMN. The authors
      speculate that sCD4 can be another chemotactic factor and, as such, constitutes a
      link within the immune system between specific and non-specific elements of
      inflammation.

PMID- 8658061
TI  - Characterization of Haemophilus influenzae isolates from the respiratory tract of
      patients with primary antibody deficiencies: evidence for persistent
      colonizations.
AB  - A total of 117 consecutive patients with primary antibody deficiencies were
      followed for up to 5 years with regard to acute respiratory tract infections.
      Nontypeable Haemophilus influenzae (NTHI) was the sole pathogen in 61% (202/330)
      of the samples from which a potential pathogen was recovered. Common variable
      immunodeficiency (CVI) was the most prevalent condition (27/39 patients) in the
      group where H. influenzae was isolated. In patients where H. influenzae was not
      found only 9/78 patients had CVI. 49 of these 78 patients had isolated IgG3 or
      IgA deficiency. Both of these entities seemed to be associated with a lower
      prevalence of NTHI infections. 13 of 18 patients with at least 2 isolates of NTHI
      were colonized with the same strain from 3 to 43 months as shown by total genomic
      DNA-fingerprinting. Recurrent symptomatic infections occurred in these patients
      despite substitution therapy with gammaglobulins and repeated antibiotic
      treatments. All but 2 of the 224 H. influenzae isolates were beta-lactamase
      negative and sensitive to ampicillin. The use of 10 lipopolysaccharide-specific
      monoclonal antibodies in a whole cell ELISA showed that the LPS-epitopes on the
      224 H. influenzae isolates from the hypogammaglobulinemic group were very similar
      to 499 NTHI isolates from immunocompetent patients with respiratory infections.
      One may therefore conclude that i) patients with CVI, were prone to be
      permanently colonized with NTHI, and ii) the colonizing bacteria were ordinary
      strains showing the same LPS-phenotypes as those strains that cause acute
      respiratory tract infections in immunocompetent individuals.

PMID- 8658062
TI  - Prevalence of antibodies to herpes simplex virus types 1 and 2, Epstein-Barr
      virus and cytomegalovirus in teenage girls.
AB  - Seropositivity to herpes virus type 1 (HSV-1), herpes virus type 2 (HSV-2),
      cytomegalovirus (CMV) and Epstein-Barr virus (EBV) was estimated in a group of 98
      16-year-old Swedish girls. Antibodies to HSV-1 were seen in 41% of the girls and
      to HSV-2 in 1%, and antibodies to CMV in 45 and to EBV in 82%. In girls with
      coitus experience, there was significantly higher prevalence of HSV-1 and EBV
      antibodies, compared with girls with no sexual contact. The age of coitarche or
      number of coitus partners did not affect the rate of seropositivity. During 2
      years of follow-up, 13 girls seroconverted. All but one EBV-seroconverting girl,
      were sexually active, and no girl converted for more than one type of virus. We
      concluded that transmission of herpes viruses is common in adolescence, and
      sexuality, even with regard to its close association with kissing, is one
      important determinant.

PMID- 8658063
TI  - Efficacy of human leucocyte alpha-interferon treatment for chronic hepatitis C
      virus infection.
AB  - A total of 42 Swedish patients with biopsy-proven chronic hepatitis C virus (HCV)
      infection were treated with a natural human leucocyte alpha-interferon (HuIFN
      alpha-Le), Alfanative (BioNative AB, Umea, Sweden) in an open uncontrolled study.
      Two patients were withdrawn from treatment within 2 weeks due to non-compliance
      and were omitted from further analysis, and 40 patients (17 females), mean age 39
      years (range 24-71) completed the study. All patients were HCV RNA-positive in
      serum prior to treatment, with raised alanine aminotransferase (ALT) levels > 1.5
      times the upper normal limit known for more than 6 months. Interferon was given
      at a dose of 3 MU t.i.w. for an intended 24 weeks and follow-up was a further 24
      weeks after treatment. Biochemical non-responders were withdrawn from treatment
      within 12-16 weeks but continued follow-up. Overall 21/40 (52.5%) patients had a
      complete biochemical response with normal ALT levels at the end of treatment.
      Sustained response during follow-up was seen in 8 (20%) whereas 13 (32.5%) had a
      non-sustained response. At the end of treatment 23 (58%) patients had
      undetectable serum HCV RNA and 9 (23%) at follow-up. Patients with sustained, non
      sustained and non-response had a mean pretreatment HCV RNA level of 3.2 x 10(5),
      2.5 x 10(6) and 3.2 x 10(6) genomes/ml, respectively, differences that did not
      reach statistical significance. Of the patients 3, 9, 10 and 14 had genotype 1b,
      3a, 1a, and 2b, respectively, and 4 had mixed genotypes. Of the 23 patients with
      genotype 2b or 3a, 7 had a sustained response vs. none of the 13 patients with
      genotype 1a or 1b (p = 0.03). No patients with cirrhosis had a sustained response
      whereas 4/18 with chronic persistent and 4/18 with chronic active hepatitis had
      such a response.

PMID- 8658064
TI  - Combined alpha-interferon and ribavirin treatment in chronic hepatitis C: a pilot
      study.
AB  - 16 patients with chronic hepatitis C virus (HCV) infection were treated with a
      combination of interferon-alpha and ribavirin for 24 weeks in an open study. One
      patient declined further treatment due to depression after week 16 and did not
      complete further follow-up. A moderate decline was observed in hemoglobin and an
      increase in bilirubin level both reversible after discontinuing the treatment. 24
      weeks after treatment cessation 9/15 (60%) evaluable patients had complete
      clearance of HCV-RNA as measured with PCR. HCV genotype did not seem to be
      correlated with response, but patients with sustained response to treatment had a
      significantly reduced number of HCV RNA copies/ml serum at treatment start
      compared with the other patients. These findings support the promising results of
      this combination therapy noted in other pilot studies.

PMID- 8658065
TI  - Prevalence and determinants of anti-HCV seropositivity and of HCV genotype among
      intravenous drug users in Berlin.
AB  - A cross-sectional study was carried out to identify risk factors for
      seropositivity for antibodies against hepatitis C virus (HCV) and to assess to
      the distribution and determinants of HCV genotypes among intravenous drug users
      (IVDUs). The study population consisted of 405 IVDUs. Serum specimens were tested
      for seromarkers for HCV, for human immunodeficiency virus (HIV), for hepatitis B
      virus (HBV) and for syphilis. HCV RNA determination by polymerase chain reaction
      (PCR) and virus typing were performed in a subsample of anti-HCV-positive
      specimens (n=135). Of the IVDUs, 83% were anti-HCV-positive, 18% HIV-infected,
      and 58% HBV (anti-HBc)-positive. Longer duration of intravenous drug use, syringe
      sharing in prison, and higher number of IDVU sex partners were independent risk
      factors for anti-HCV positivity. GCV RNA was detected in 76% of anti-HCV-positive
      IVDUs. HCV genotypes 1 (49%) and 3 (44%) were most commonly found. All the type 3
      isolates were identified as subtype 3a, and 95% of the type 1 isolates as subtype
      1b. In logistic regression analysis, HCV type 3a viraemia was significantly
      associated with lack of HIV infection and a higher number of sex partners. The
      results indicate that preventive measures are needed to reduce syringe sharing
      among IVDUs in prisons. Sexual contacts with other IVDUs may play a role in the
      HCV epidemic among IVDUs. In Germany, HCV type 3a infection appears to be much
      more common among IVDUs than among other HCV risk groups such as transfusion
      recipients or haemophiliacs.

PMID- 8658066
TI  - Clinical and therapeutic features of childhood neurobrucellosis.
AB  - Brucellosis is a multisystem disease with diverse clinical presentations, and
      involvement of the nervous system is considered to be rare in childhood. Five
      children with meningitis (n=2), meningoencephalitis (n=1), meningomyelitis (n=1),
      or cerebellar ataxia (n=1) are described, all of whom had a history of exposure
      to a possible source of brucellosis. Examination of cerebrospinal fluid (CSF)
      revealed lymphocytic pleocytosis in 4 patients, high protein concentration in 5
      and low glucose concentration in 3. Reciprocal brucella agglutination titers were
      significantly elevated in serum (> or = 160) and in CSF (> or = 80) of all
      patients. Brucella melitensis was isolated from blood and CSF in one patient,
      from blood only in 2, and from bone marrow only in another one. All patients were
      treated successfully by a three-drug combination of streptomycin (4 patients) or
      doxycycline (one patient) with trimethoprim-sulfamethoxazole and rifampin, and in
      one patient dexamethasone was also added. In endemic areas, neurobrucellosis
      should be suspected in the evaluation of patients with unexplained neurologic
      symptoms.

PMID- 8658067
TI  - Coxiella burnetii infection in subjects with HIV infection and HIV infection in
      patients with Q fever.
AB  - The objective of the study was to determine whether HIV infection favors the
      acquisition of Coxiella burnetii infection or increases the frequency of
      symptomatic Coxiella infections. A total of 754 subjects were tested for Coxiella
      antibodies: 596 intravenous drug users (IVDUs) (306 HIV-infected IVDUs matched by
      aged and sex with 291 non-HIV-infected IVDUs), and 157 healthy puerperal women
      matched to the IVDU women. A total of 520 patients with Q fever were tested for
      HIV antibodies. The seroprevalence of Coxiella antibodies was similar in the 2
      groups of IVDUs (19.3% of HIV + IVDUs vs 22.9% of HIV - IVDUs). Likewise, there
      was no difference in the prevalence of Coxiella antibodies in the groups of IVDU
      women and healthy women. Of the 520 subjects with acute Q fever, diagnosed
      between 1987 and 1992, only 4 (0.77%) had HIV infection. The proportions of HIV
      infected subjects in the population of patients, with Q fever, of 20-39 years of
      age (the age of maximum incidence of both HIV and Coxiella infection in our
      region), coincided with the estimated proportions of HIV subjects in the
      respective general populations of the province. In conclusion, infection by
      Coxiella burnetii was not more frequent among HIV-infected subjects. It is not
      likely that Coxiella infection produces symptomatic infections more often in HIV
      infected subjects.

PMID- 8658068
TI  - Activation of phagocytes by Helicobacter pylori correlates with the clinical
      presentation of the gastric infection.
AB  - Only a minority of subjects with Helicobacter pylori infection develop clinical
      gastroduodenal disease. It is unclear whether host factors or bacterial virulence
      properties contribute to the pathogenic mechanisms. We have previously
      demonstrated a 25-35-kDa protein with phagocyte stimulatory activity in bacterial
      sonicates. Protein preparations were made from 15 H. neutrophil and monocyte
      chemotaxis and chemiluminescence was assessed with cells from healthy donors in
      comparison with N-f-methionyl-leucyl-phenylalanine and C5a anaphylatoxin. The
      potency of bacterial protein(s) for induction of monocyte chemiluminescence was
      significantly higher for strains from ulcer patients (1 +/- 1 microgram/ml
      induced > or = twofold increase of control response) and chronic active gastritis
      (1 +/- 1 microgram/ml) compared with superficial gastritis (> 1,000 microgram/ml,
      p<0.05). Neutrophil activation was also significantly more potent with strains
      from duodenal ulcer disease. The chemotactic activity of bacterial preparations
      was not significantly different between the groups. We conclude that bacterial
      strains with pronounced activation of phagocytes are associated with the presence
      of clinical ulcer disease, supporting the existence of ulcerogenic strains.

PMID- 8658069
TI  - Persistent reduction in lung function after Pneumocystis carinii pneumonia in
      AIDS patients.
AB  - By means of serial lung function tests we examined the changes in lung function
      and possible pulmonary long-term sequelae in AIDS patients with a primary episode
      of Pneumocystis carinii pneumonia (PCP). A total of 19 patients had lung function
      tests performed prospectively from the time of PCP diagnosis, at 7 days, 14 days,
      1, 2, 3, 4.5, 6 and 9 months after PCP. Forced vital capacity (FVC) and forced
      expiratory volume in 1 second (FEV1) were both reduced to a median of 61% of
      predicted at PCP diagnosis, and were normalized within 1 month and 1 week
      respectively. The median pulmonary diffusing capacity for carbon monoxide (DLCO)
      was severely reduced to 43% of predicted during the acute infection. Although
      DLCO improved significantly during the first 2 months, it remained reduced at a
      median DLCO of 64% of predicted 9 months after PCP. We conclude that despite a
      general improvement in lung function during the first 2 months following the PCP
      diagnosis, ther was a persistent reduction in DLCO up to 9 months following PCP.
      The pathological mechanisms causing this reduction remain to be established.

PMID- 8658070
TI  - Rapid simple and nested polymerase chain reaction for the diagnosis of
      Pneumocystis carinii pneumonia.
AB  - We have developed a rapid and easy extraction procedure for polymerase chain
      reaction (PCR) protocols. Using this simplified step, we evaluated the
      sensitivity and the specificity of a simple PCR using the primers of Wakefield et
      al, and of a nested PCR, using new internal primers selected by us, in a total of
      89 bronochoalveolar lavage (BAL) fluid samples from 43 immunosuppressed patients.
      In 13 patients, Pneumocystis carinii pneumonia (PCP) was diagnosed by
      immunofluorescent antibody (IFA) staining performed on BAL cells cytospun on
      microscope slides. In seven of these patients we attempted to estimate the post
      treatment persistence of P. carinii in BAL, by PCR. After a rapid 2-h extraction
      procedure, simple and nested PCR were positive in all cases of PCP. SImple and
      nested PCR both had a 100% sensitivity and a 98 and 84% specificity respectively,
      compared to IFA. After completion of treatment, BAL liquids from asymptomatic
      patients were no longer positive by both PCR techniques, whereas the BAL fluid of
      a patient who was still symptomatic was positive by simple and nested PCR. In
      follow-up BAL fluids of patients with proven PCP, persistence of P. carinii was
      detected for a longer period by nested PCR than by simple PCR. Simple PCR is a
      very rapid and sensitive assay for the diagnosis of PCP in BAL fluid and gives
      clear-cut results in the case of doubtful IFA staining results. Nested PCR seems
      to improve the sensitivity of the detection of P. carinii in BAL fluid, but the
      clinical relevance of a positive result remains to be investigated..

PMID- 8658071
TI  - Pneumocystis carinii in bronchoalveolar lavage and induced sputum: detection with
      a nested polymerase chain reaction.
AB  - To evaluate polymerase chain reaction (PCR) for detection of Pneumocystis
      carinii, 117 bronchoalveolar lavage (BAL) specimens, from HIV-infected patients
      undergoing a diagnostic bronchoscopy, were processed and a nested PCR, followed
      by Southern blot and hybridization with a P32-labelled probe was performed. The
      sensitivity and specificity were 85 and 100% 934/40 and 77/77) respectively. A
      non-radioactive labelling system BluGENE was evaluated on all specimens, and
      found to be as effective as P32-labelling. To increase the speed and convenience
      of detection, a dot blot system was tested, but sensitivity dropped markedly with
      this system. A further 33 patients had both induced sputum and bronchoalveolar
      lavage performed and the induced sputum was analysed using PCR and routine
      microbiological methods. The PCR sensitivity on induced sputum was equal to that
      of routine methods. At present the evaluated PCR cannot replace routine
      microbiological methods for detection of Pneumocystis carinii, on either BAL
      fluid or induced sputum.

PMID- 8658072
TI  - Phagocytosis and oxidative burst of blood phagocytes in chronic obstructive
      airway disease.
AB  - Acute diseases and chronic conditions might be associated with altered blood
      neutrophil functions. The aim of this study was to investigate teh effects of
      stable chronic obstructive pulmonary disease (COPD) and superimposed acute
      bacterial bronchopneumonia (ABP) on the phagocytosis and oxidative metabolism of
      blood phagocytes. The 129 participants were assigned to 6 groups: group 1,
      healthy controls; group 2, previously healthy controls with ABP; group 3,
      patients with stable COPD on inhaled corticosteroids (IC); group 4, individuals
      with stable COPD on IC and ABP; group 5, patients with stable COPD requiring oral
      corticosteroids (OC); group 6, individuals with COPD on OC and ABP. Phagocytosis
      and oxidative burst was measured. Both tests showed a significant difference
      between the groups without acute infection when compared to the patients with
      ABP. No differences were observed between patients with stable COPD without ABP
      (groups 3 and 5) and group 1. The number of phagocytized E. coli/cell was 9.1 +/-
      0.37, 7.9 +/- 0.27 and 8 .2 +/- 0.28 (groups 2, 4, and 6, respectively) reversed
      the observed changes. We conclude, that acute bacterial bronchopneumonia is
      associated with an impairment of phagocytosis and oxidative metabolism in blood.
      We suggest, that stable COPD has no influence on phagocytosis and oxidative
      burst.

PMID- 8658073
TI  - Interleukin-6, C-reactive protein, lactoferrin and white blood cell count in
      patients with S. aureus septicemia.
AB  - In a prospective study of 65 patients with S. aureus septicemia, the clinical
      value of measuring serum IL-6 and lactoferrin levels was assessed and compared
      with CRP levels and WBC count. 20/65 (31%) patients had a CRP value < or = 100
      mg/l on admission and 10 (50%) and 11 (55%) of these had serum levels of IL-6 >
      100 pg/ml or lactoferrin > 2.0 mg/l, respectively. 41/64 (64%) patients had a WBC
      count < or = 15.0 x 10(9)/l and the corresponding figures for increased IL-6 and
      lactoferrin values were 29 (71%) and 21 (51%) patients, respectively. The high
      concentrations of IL-6 and lactoferrin on admission decreased rapidly during the
      hospital stay, better reflecting the clinical course than CRP and WBC count.
      Patients with endocarditis showed higher IL-6 levels and body temperatures both
      on admission and during the first days of hospitalization compared with patients
      without endocarditis.

PMID- 8658074
TI  - High IL-6 serum levels are associated with septic shock and mortality in septic
      patients with severe leukopenia due to hematological malignancies.
AB  - The serum levels of immunoreactive interleukin-6 (IL-6) and tumor necrosis factor
      (TNF) were analyzed in 14 leukopenic patients with documented sepsis, at 60 min
      (T0), 24 h (T1), and one week (T3) after the onset of sepsis syndrome. Sera from
      10 leukopenic patients without sepsis (controls) were also tested. All septic
      patients had high IL-6 levels at T0. These levels persisted only in the seven
      patients who died of septic shock, presenting a 30-fold increase (p<0.001) as
      compared to the survivors and the controls. At T3, 7 survivors had recovered from
      sepsis and showed low IL-6 serum levels. The TNF serum concentration always <30
      pg/ml in both the subjects and in the controls. The C-reactive protein (CRP) and
      clinical parameters appeared to be less specifically associated with shock and
      mortality than IL-6.

PMID- 8658075
TI  - Effect of supplementation with an iron-fortified milk on incidence of diarrhea
      and respiratory infection in urban-resident infants.
AB  - To address the hypothesis that increased infectious morbidity is associated with
      iron supplementation, 783 randomly selected infants were provided with a powdered
      full fat cow's milk (non-fortified group) and 872 with a powdered acidified full
      fat cow's milk fortified with 15 mg of iron as ferrous sulfate (fortified group).
      All infants were followed from birth to 15 months of age with a monthly home
      visit by a nurse who recorded morbidity occurring during the previous 30 days. At
      9 months of age, 15% of infants in each cohort were receiving breast milk only;
      data for these infants were segregated to make the third group. Episodes (mean +/
      SD) of diarrhea/infant/year were 1.06 +/- 1.29, 1.14 +/- 1.37, and 0.82 +/- 1.04
      for the fortified, non-fortified and breast-fed groups, respectively; the
      fortified and non-fortified bottle-fed groups had a very similar incidence of
      respiratory illness; 2.66 +/- 2.07 and 2.74 +/- 2.24 episodes/infant/year,
      respectively. The incidence of respiratory illness for both bottle-fed groups was
      significantly higher than that for the breast-fed group (2.22 +/- 1.84
      respiratory episodes/infant/year). We conclude that for the infants the tested
      form of iron fortified milk, which is sufficient to lower iron deficiency anemia,
      does not result in an increased incidence of diarrhea or respiratory illness.

PMID- 8658076
TI  - Oral Candida albicans isolates with reduced susceptibility to fluconazole in
      Swedish HIV-infected patients.
AB  - A total of 62 patients with HIV-related conditions were examined for clinical and
      mycological oral findings. Cultures from 51 patients were positive for yeasts and
      included 49 Candida albicans and 8 non-albicans isolates. Of patients with
      positive culture, 35% had pseudomembranous thrush. In vitro susceptibility
      testing of 49 C. albicans isolates revealed that the minimal inhibitory
      concentration for 50% of the strains (MIC50) was 2.0 mg/l for fluconazole, and
      the MIC50 was < or = 0.125 mg/l for both ketoconazole and itraconazole.
      Fluconazole resistance (MIC > or = 32.0 mg/l) was found for 14% of the C.
      albicans isolates tested. Two C. albicans isolates showed cross-resistance to
      ketoconazole and itraconazole. Associations between reduced susceptibility to
      fluconazole and low CD4+ cell counts, the length of time since the first AIDS
      defining illness and the interval from the first fluconazole treatment,
      indirectly reflecting the total fluconazole exposure, were observed.

PMID- 8658077
TI  - Liver abscess: an unusual manifestation of pneumococcal infection.

PMID- 8658078
TI  - Atypical cellulitis due to group B streptococcus.
AB  - In a minority of late-onset Group B streptococcal (GBS) cases in neonates, facial
      or buccal cellulitis has been described. We report a case of sepsis with GBS, in
      which an atypical cellulitis in the inguinal area was seen as presenting symptom.

PMID- 8658079
TI  - Increased bactericidal activity as documented by serum bactericidal titers for a
      triple combination of cell wall active agents against gentamicin-resistant
      enterococci.
AB  - Infections caused by entercocci have become increasingly difficult to treat
      because these bacteria are becoming increasingly resistant to commonly used
      antibiotics such as ampicillin, gentamicin and vancomycin. A consensus for an
      optimal therapy of enterococcal infections caused by resistant isolates has not
      yet been determined. We present a patient with prolonged enterococcal sepsis in
      whom a combination of ampicillin, vancomycin and imipenem was ultimately
      successful in suppressing enterococcal bacteremia. The enhanced activity of this
      triple combination was documented by the results of serial serum bactericidal
      titers.

PMID- 8658080
TI  - Progressive intractable actinomycosis in patients with AIDS.
AB  - Two rare cases of progressive oropharyngeal actinomycosis, characterized by a
      subacute and invasive course despite seemingly appropriate antibiotic and
      surgical treatment, have been observed in patients with AIDS. A brief review of
      previously reported cases of actinomycosis in HIV-infected patients is presented.
      Clinical, diagnostic and therapeutic problems dealing with actinomycosis in the
      immunocompromised host are discussed.

PMID- 8658081
TI  - Yersinia enterolitica bacteremia with intracranial extension.
AB  - We report an unusual observation of Yersinia enterolitica (YE) bacteremia with
      subcutaneous with subcutaneous abscesses on the scalp and, by gradual extension,
      cerebritis in a diabetic patient. All clinical signs disappeared after surgical
      drainage of the abscesses and protracted antibiotherapy. The well-known affinity
      of YE for iron led us to demonstrate an unrecognized hemochromatosis.

PMID- 8658082
TI  - Tuberculous pericarditis in an HIV-infected patient.
AB  - Persons co-infected with mycobacterium tuberculosis (MTB) and HIV are at
      increased risk for developing active tuberculosis. While extrapulmonary
      tuberculosis is particularly common in patients with AIDS, tuberculous
      pericarditis is a very uncommon complication of AIDS in the United States. We
      present a case of tuberculosis involving the pericardium and review the current
      literature on this topic.

PMID- 8658083
TI  - Hepatobiliary tuberculosis presenting as a gall bladder tumor.
AB  - A 64-year-old married female was admitted with a presentation of anorexia, easy
      fatiguability, skin discoloration, tea-colored urine and weight loss of 1 month's
      duration. After a series of clinical and laboratory examinations including
      radiological image studies, a diagnosis of gall bladder tumor was presumed. A
      final diagnosis of tuberculosis of the liver and gall bladder was established by
      histopathological examination of tissue specimens obtained during exploratory
      laparotomy. Hepatobiliary tuberculosis presenting as a gall bladder tumor is rare
      and no pathognomonic diagnostic characteristics can be relied upon. It is
      necessary to confirm the diagnosis by histopathology, polymerase chain reaction
      (PCR), or microbiological studies on biopsy specimens in order to make possible
      appropriate, early therapy.

PMID- 8658084
TI  - Candida albicans meningitis in a 27 weeks premature infant treated with liposomal
      amphotericin-B (AmBisome)
AB  - We report a case of Candida albicans meningitis in a neonate born after 27 weeks
      of gestation. To the best of our knowledge this is the first report of a
      premature infant with Candida-meningitis treated with liposomal amphotericin B
      (AmBisome(R)). The patient did not respond well to conventional Amphotericin B,
      but was successfully cured with Ambisome(R). Liposomal amphotericin B was well
      tolerated and the baby recovered with a postinfectious hydrocephalus which
      necessitated a permanent ventriculo-peritoneal shunt. Six months after the
      infection the baby appears to have a near-normal cerebral development.

PMID- 8658085
TI  - Fluconazole failure in two cases of disseminated candidosis.
AB  - Amphotericin B has been the standard treatment of disseminated candidosis
      although the less toxic fluconazole tends to be used more frequently. In a recent
      report, no significant difference in the efficacy of candidaemia treatment was
      observed between fluconazole and amphotericin B. However, we report on 2 cases of
      invasive candidosis where fluconazole failed to eradicate Candida albicans
      although the isolates were susceptible to fluconazole in vitro. Pulsed-field gel
      electrophoresis was used to confirm the persistence of the same C. albicans
      strain after therapy failure in both patients.

PMID- 8658086
TI  - Short-term quinolones for successful eradication of multiply resistant Vibrio
      cholerae in adult patients.
AB  - There has been an increasing multiple drug resistance problem in Vibrio cholerae
      biotype Eltor, the causative agent of 7th pandemic. The aim of this study was to
      show in vitro and in vivo susceptibility and effectiveness of quinolones in the
      treatment of endemic cholera cases. Excellent results were obtained in 53
      bacteriologically confirmed cholera patients treated with short-term ofloxacin
      and ciprofloxacin. To our knowledge, there has been no previous report on this
      subject in the international medical literature. Our results show that quinolones
      can be an alternative drug for the treatment of multiply resistant V. cholerae
      infections.

PMID- 8658087
TI  - Infrequent finding of verotoxin-producing Escherichia coli in diarrheal stools in
      Belgrade, Serbia.
AB  - Out of 2,638 patients, with acute diarrhea, verotoxin-producing Escherichia coli
      (VTEC) was isolated from the stools of 8 (0.3%). There was no visible blood in
      their stools and none of them developed other syndromes associated with VTEC
      infection. None of the isolated VTEC agglutinated with O157 E. coli antiserum,
      while only 3 strains hybridized with the DNA probe CVD 419, designed to detect
      VTEC. The data obtained suggest that VTEC is not an important causative agent of
      acute diarrhea in Belgrade.

PMID- 8658088
TI  - [The Janus face of medicine].
AB  - Since antiquity medicine has repeatedly been accused of being noxious (or
      ineffective). Physicians have always admitted that their art-because of its
      efficacy-could be dangerous. Lack of success or unwanted effects stimulate
      research in quest of a better definition of efficacy and to improve safety. In
      practice, however, it is necessary to act here and now, by the available means,
      hopefully in line with Hippocrates' precaution, <<to help, or at least to do no
      harm>>.

PMID- 8658090
TI  - [Iatrogenic complications and quality improvement in everyday medical practice].
AB  - There is a relationship between iatrogenic complications of medical procedures
      and the quality of medical services. The risk of iatrogenic complications or
      diseases occurring is growing over time for several reasons: patients under
      medical care grow older and sicker, diagnostic and therapeutic procedures are
      expanding at a fast pace, and complexity and uncertainty in daily care tends to
      grow. This development will continue unless we actively start to prevent
      iatrogenic complications. The frequency of iatrogenic illness was found to be
      between 4 and 36% of all patients treated in a hospital setting. The wide span is
      a result of different definitions of what is an iatrogenic complication. When an
      iatrogenic illness occurs we are obliged to look for "errors in the system"in
      order to eliminate them. In a hospital and practice environment the respective
      methods are different. By eliminating unnecessary procedures the risk of possible
      damage is diminished. Necessary procedures must be performed at the most skilled
      level. We describe and discuss two cases of iatrogenic complications and the
      benefits and disadvantages of guidelines. The creation of guidelines should be
      placed on a rational and scientific basis.

PMID- 8658089
TI  - [Omit what is unnecessary--do not omit what is necessary].
AB  - "Omit what is unnecessary-do what is necessary" is a description of rational
      medicine. "Unnecessary" diagnostic procedures are not uncommon. Excessive
      laboratory testing and routine X-ray represent primarily financial burdens. The
      aim of diagnostic procedures is not to obtain absolute diagnostic certainty, but
      to minimize diagnostic uncertainty to a point where rational treatment can be
      offered. The number and type of diagnostic and therapeutic procedures correlate
      with the rate of iatrogenic damage. There are difficult situations, such as
      futile treatment in intensive care units, which are complex and must be solved in
      consensus with patients and/or their relatives. "Necessary"p6 diagnostic and
      therapeutic procedures are less numerous than unnecessary ones. In conclusion,
      rational medicine-which only does what is necessary and omits what is unnecessary
      is an ideal model with an optimum cost-benefit as well as risk-benefit ratio.

PMID- 8658091
TI  - [Parkinson syndrome: iatrogenic causes, iatrogenic treatment results].
AB  - Iatrogenically induced problems are well known in the treatment of Parkinson's
      disease. Too rapid introduction or changes in dosage of dopamine agonists and
      levodopa may lead to acute side effects. Wrong dosage of these drugs in the
      treatment of advanced Parkinson's disease can lead to severe dyskinesia. All
      other drugs used in the treatment of Parkinson's disease also have a side effect
      profile which must be known to the treating physician. In addition, iatrogenic
      problems may also be found in the general management of the patient and his
      family. It is also well known that a parkinsonian syndrome may be induced by
      several types of drugs.

PMID- 8658093
TI  - [Amalgam allergy and amalgam controversy].
AB  - Safety concerns regarding dental amalgam have been voiced ever since its
      introduction 150 years ago. As most people have amalgam fillings, the issue has
      received extensive coverage in the lay as well as the medical medical media. This
      has led to confusion about the terms amalgam allergy, mercury burden and
      intoxication, and amalgam disease, an understanding of which is crucial in
      consideration of this controversy. Allergy to amalgam is rare and should be
      investigated by a specialist, as diagnosis may result in a decision to remove
      dental amalgam. Dental amalgam is the most important source of mercury burden in
      the general population. Occupational exposure to mercury within established
      exposure limits reaches levels much higher without evidence of intoxication.
      However, mercury released from dental amalgam induces measurable organ effects.
      Amalgam disease has been introduced as a term to identify patients who typically
      ascribe a variety of symptoms to their amalgam fillings. Current literature lacks
      sound evidence of a role for amalgam in human disease other than allergy.

PMID- 8658092
TI  - [Side effects and consequences of frequently used antibiotics in clinical
      practice].
AB  - Oral antimicrobial substances belonging to the beta-lactams, quinolones,
      macrolides, tetracyclines and the trimethoprim-sulfamethoxazole combination are
      among the most prescribed classes of drugs in private practice. Knowledge of the
      potential side effects considered in the light of various patient-associated
      factors such as genetic makeup, renal and liver function, underlying diseases,
      drug allergies and coadministered drugs, is important in order to minimize the
      risk of adverse reactions. This article reviews important side effect patterns
      and focuses on more recent aspects of antibiotic-associated diarrhea and beta
      lactam allergy relevant to the practicing physician. Diarrhea occurring during
      antibiotic treatment raises the possibility of Clostridium-difficile-associated
      disease, which may evolve into life-threatening toxic megacolon. Mild cases with
      resolving symptoms after discontinuation of the antibiotic usually do not require
      further workup. More severe cases with watery diarrhea, abdominal pain,
      dehydration and electrolyte abnormalities warrant rapid diagnosis, cessation of
      antibiotic treatment and specific treatment including oral metronidazole. The use
      of oral vancomycin as a first line drug is discouraged because of the possibility
      of selecting vancomycin-resistant enterococci. Hypersensitivity reactions to beta
      lactams are the most important type of side effects which can often be prevented.
      Patients with a history of beta-lactam associated IgE-mediated hypersensitivity
      (hives, wheezing or hypotension) should undergo penicillin skin testing. The
      frequently observed maculopapular rash associated with aminopenicillins without
      hives is in most cases not caused by an IgE-mediated mechanism. Patients with
      previous life-threatening penicillin allergy such as anaphylaxis or Lyell's
      syndrome should not undergo skin testing. Currently available tests do not
      reliably predict cephalosporin hypersensitivity. More recent data suggest that
      crossreactivity between penicillins and cephalosporins is infrequent. It thus
      seems safe to administer a cephalosporin to a penicillin-allergic patient, though
      excluding patients with previous life-threatening penicillin reactions.

PMID- 8658094
TI  - Effect of postoperative intravenous loop diuretic on renal function after major
      surgery.
AB  - OBJECTIVE: To determine the effect on renal function of postoperative continuous,
      intravenous furosemide after major thoraco-abdominal or vascular surgery. DESIGN:
      Randomized, double-blind, placebo-controlled trial. SETTING: Intensive care unit
      of a referral hospital in Eastern Switzerland. METHODS: Furosemide (1 mg/h) or
      placebo was administered to 121 consecutive patients admitted to the intensive
      care unit after major abdominal, chest or vascular surgery and continued
      throughout the intensive care treatment period. Enrollment was performed during a
      6 months period. No patient was excluded. Renal function was determined serially
      by measuring creatinine clearances and plasma creatinine concentrations. RESULTS:
      Postoperatively, creatinine clearance decreased significantly to 83% (furosemide)
      and to 81% (placebo group) of the initial value (p = 0.004). This decrease was
      not affected significantly by furosemide. Retrospective subgroup analysis using
      stepwise regression also did not show any differences between the groups.
      Hypokalemia was detected in 36 (furosemide) versus 19% of the blood sample
      (placebo, p = 0.006). CONCLUSIONS: Low-dose intravenous furosemide appears to
      offer no advantage over placebo in an unselected group of patients with moderate
      postoperative renal impairment. As no patients with acute renal failure
      necessitating dialysis were observed during the study period, the effect of
      furosemide in more severe postoperative renal impairment and the effects of
      higher doses of loop diuretics remain to be investigated.

PMID- 8658095
TI  - [Syncope of unclear origin--role of 2 diagnostic tests with high specificity].
AB  - We report the diagnostic evaluation of an elderly woman admitted with recurrent
      syncopes induced by head rotation. A cardiac origin was exclude by Holter ECG,
      echocardiography and carotid sinus compression. Angiography showed unilateral
      vertebral artery hypoplasia, suggesting the possibility of hemodynamic
      vertebrobasilar insufficiency. This origin, however, could be ruled out by
      monitoring of blood flow velocities in both posterior cerebral arteries with
      transcranial Doppler, which showed no alteration during syncope induced by head
      rotation. Detailed analysis of the course of the syncope recorded on videotape
      suggested a psychogenic event. Furthermore, the syncopes could be prevented with
      a "protective" placebo despite head rotation, and induced by a "provocative"
      placebo without head rotation while EEG monitoring showed normal brain activity.
      This finding underscored the suggestion of a psychogenic cause.

PMID- 8658097
TI  - [The schizophrenia concept].

PMID- 8658096
TI  - [Heart surgery in acute heart infarct. Indications and results].
AB  - The therapy of acute myocardial infarction has made major advances in the last 10
      years. Cardiac surgeons have to adapt their strategies to the more aggressive
      management of acute myocardial infarction. Only in mechanical complications of
      acute myocardial infarction is cardiac surgery nowadays the therapy of choice. In
      cardiac rupture and ventricular septal defect, surgery is the only therapeutic
      option. In ischemic mitral regurgitation, cardiac surgery is required in the
      event of concomitant cardiogenic shock and pulmonary edema after intra-aortic
      balloon pump placement. Coronary artery bypass surgery my be indicated at low
      risk in patients with unstable angina pectoris when PTCA is not feasible or has
      failed, or in catheter emergencies.

PMID- 8658098
TI  - [100 years of conflict about schizophrenias].
AB  - A systematic concept of a homogeneous group of psychoses, which Eugen Bleuler
      subsequently termed "Schizophrenia", goes back to Emil Kraepelin initially, in
      fact it has not existed for more than 100 years. The dynamics inherent in its
      history show that it is advisable to make allowance for contemporary influences
      when arriving at conclusions on schizophrenia in our times. The article in
      question presents a brief review of the origins and the historic development of
      the concept of schizophrenia, and attempts to set the present-day "neo
      kraepelian" re-assessment of schizophrenic disorders in a modifying historic
      context.

PMID- 8658099
TI  - [The Bleuler tradition of the schizophrenia concept and Burgholzli as the site
      for psychotherapy of schizophrenic patients].
AB  - The author, who worked for many years with Manfred Bleuler, summarises the
      essence of Bleuler's theory of schizophrenia: that healthy and disturbed psychic
      processes occur simultaneously; an understanding of the complexity of the
      schizophrenic person; understanding the psychosis in relation to a persons life,
      which arises from a disposition that becomes manifest in the conflicts that life
      entails; the importance of psychotherapy and social care. The author shows how
      his own work contributed to this theory.

PMID- 8658100
TI  - [The ego/self experience of schizophrenic patients].
AB  - The self experience of schizophrenics (i.e. their ego-pathology) is
      conceptualized in a theoretical model of five basic dimensions of ego
      consciousness (identity, activity, demarcation, consistence/coherence, vitality).
      A systematic empirical study uses the Ego-pathology-Inventory (with 53 items,
      Interraterreliability Kappa 0.9, Retestreliability 0.65). The study population
      consists of 552 schizophrenics, 25 borderline personality disorders, 87
      depressive disorders. Ego-pathology clearly differs the three diagnostic groups.
      Confirmatory factorial analysis allows to accept the theoretical model. Various
      external measurements correlate with ego pathology. Three empirical syndromes
      resulted from statistical search for data-structures. A series of arguments for
      validation of the concept allow the conclusion the the proposed ego pathology
      concept is a viable approach for empirically studying the experimental core of
      the schizophrenias.

PMID- 8658101
TI  - [The effect of psychosocial factors in schizophrenia. Theoretical and practical
      therapeutic consequences].
AB  - The author first comments on the interaction of heredity and environmental
      factors and the need for an integrative psycho-social-biological model to
      understand all kinds of psychiatric disturbances. He then gives a selective
      presentation of research done in the last 20 to 30 years which clearly
      demonstrate the influence of psychosocial factors on schizophrenia. In the
      authors' multifactor scheme the above mentioned psycho-social-biological
      interactions in the premorbid, acute and chronic phases of the illness are shown.
      Based on the organisational integrating influences of the affects on the way of
      thinking according to the concept of "affect logic" he concludes that primarily
      emotional factors which secondarily influence the way of thinking play an
      important part in the development of schizophrenia. From this point of view
      schizophrenia could be classified as an "affective psychosis" sui generis (like
      mania and depression). Various consequences in the field of psychotherapy,
      sociotherapy and pharmacotherapy ensue.

PMID- 8658102
TI  - [Schizophrenia and substance dependence].
AB  - A review of epidemiological data regarding the prevalence of substance abuse in
      schizophrenia and vice versa points out differences which are hard to interpret,
      owing to inconsistent sampling procedures and to the application of different
      diagnostic criteria. Stimulant abuse in schizophrenics has apparently increased
      over the years, eventually alcoholic abuse, whereas no increase is evidenced for
      cannabis abuse. Patients with dual diagnosis have an increased risk for morbidity
      and mortality, for psychotic relapse and for social disintegration. No increased
      risk for schizophrenic psychosis is found for drug abusers. Possible explanations
      why schizophrenics could show an increased susceptibility to become substance
      abusers are discussed, and therapeutic recommendations added.

PMID- 8658104
TI  - [Recent developments in antipsychotic medication].
AB  - The development of new neuroleptics aims to reduce unwanted extrapyramidal motor
      side effects as well as the non-response rate, and to achieve a greater effect on
      negative symptoms. Preferential binding of neuroleptics to D2-receptors in the
      limbic system, as well as the combination of dopamine D2- and serotonin S2
      antagonism proved to be effective. A potent D2-S2-antagonism as was realized with
      positive results in risperidone serves as a model for a whole class of new
      neuroleptics.

PMID- 8658103
TI  - [Neurobiology of schizophrenia].
AB  - In this paper schizophrenia is taken to be a collection of diseases with similar
      pathological features, including the core Bleulerian symptoms. The aim is to see
      how far current research can specify the anatomical regions which are
      functionally defective in schizophrenia and what transmitter systems may be
      involved. It appears schizophrenic brains show a tendency toward fewer cells in
      the temporal region, including limbic system as well as the thalamus. Functional
      deficits are seen in the dorsolateral frontal cortex, as well as thalamus
      suggesting a cortical-thalamic-striatal pathway. It is clear that Dopamine
      disregulation in this pathway leads to psychotic symptoms but probably does not
      account for the ambivalence, affective blunting or asocial behavior. GABA lesions
      prenatally could lead to glutamate over activity with potential toxic
      consequences after puberty leading to a plausible hypothesis as to the central
      neurochemical defect in schizophrenia, this hypothesis is elaborated.

PMID- 8658105
TI  - [Processes of interpretation in psychiatry].
AB  - This article discusses whether the concept, which has been developed by the
      American philosopher Nelson Goodman in his book "Ways of Worldmaking", ist
      transferable to the field of psychiatry. After a brief review of Goodman's
      philosophical position the author tries to apply these ideas to methodology,
      diagnosis and therapy in psychiatry.

PMID- 8658106
TI  - Waking up.

PMID- 8658107
TI  - The changing quality of life.

PMID- 8658108
TI  - Wonderful town.

PMID- 8658109
TI  - Pushing the envelope for vaccines.

PMID- 8658110
TI  - Sunlight and skin cancer.

PMID- 8658111
TI  - The hidden world of surgery.

PMID- 8658112
TI  - AIDS and circumcision.

PMID- 8658113
TI  - AIDS and circumcision.

PMID- 8658114
TI  - Infections in splenectomised patients--how to prevent.

PMID- 8658115
TI  - Bacterial meningitis--the importance of cerebro-spinal fluid examination.
AB  - The role of lumbar puncture in bacterial meningitis has been debated in recent
      years, especially in the presence of worsening headache, alteration of conscious
      level, focal neurological signs, papilloedema or a haemorrhagic rash. However
      valuable bacteriological and epidemiological information will be lost if lumbar
      puncture is avoided, despite blood cultures being taken. This loss of information
      will be highlighted if pre-admission antibiotics are administered (this should
      now be standard practice).

PMID- 8658117
TI  - Overwhelming pneumoccoccal sepsis in two patients splenectomised more than ten
      years previously.
AB  - Asplenic individuals are known to be at a higher risk of developing serious and
      occasionally fatal sepsis. Prophylactic measures are generally recommended for
      the first few years post-splenectomy. We report two cases of severe Pneumococcal
      Sepsis occurring more than 10 years post-splenectomy leading to prolonged
      hospitalisation and long term morbidity and suggest that Prophylactic Penicillin
      should be taken life-long.

PMID- 8658116
TI  - Community-acquired toxigenic Clostridium difficile diarrhoea in the normoxaemic
      elderly who have received no antimicrobials: soft evidence for ischaemic colitis?
AB  - We report three examples of community-acquired toxigenic Clostridium difficile
      diarrhoea in elderly patients who had neither received antimicrobial therapy nor
      been institutionalised. These cases stimulated interest in the non-antimicrobial
      changes which might predispose the host to C. difficile-related disease and
      raised the spectre of bowel ischaemia as a possible aetiological factor.

PMID- 8658118
TI  - Miliary tuberculosis presenting as infection of a pacemaker pulse-generator
      pocket.
AB  - A seventy year old woman had a permanent VVI pacemaker inserted in 1983 for
      complete heart block and presented ten years later with purulent discharge from
      the generator pocket. During a prolonged pyrexial illness, she developed renal
      and respiratory failure and her illness was complicated by recurrent ventricular
      fibrillation. The patient died on her 31st hospital day. Subsequent histological
      and microbiological investigation revealed widespread miliary tuberculosis which
      included involvement of myocardial tissue, great vessels and the pacemaker
      pocket. To our knowledge, this is the first reported occurrence of miliary
      tuberculosis involving a permanent pacemaker system. Furthermore, the
      granulomatous myocarditis which occurred as part of the miliary picture is a rare
      occurrence and possibly explains the recurrent ventricular fibrillation.

PMID- 8658119
TI  - Selective IgA deficiency, hypothyroidism and congenital lymphoedema.
AB  - The occurrence of selective IgA deficiency and hypothyroidism with congenital
      lymphoedema has never previously been documented, although the association of
      hypogammaglobulinaemia with congenital lymphoedema has previously been reported
      and can result in recurrent respiratory infections. We report a 34 year old woman
      with congenital lymphoedema who was found to have symptomatic autoimmune
      hypothyroidism and asymptomatic selective IgA deficiency.

PMID- 8658120
TI  - Epidemic disease in Glasgow during the 19th century.
AB  - 19th.century Glasgow was an overcrowded city containing some of the worst housing
      conditions in the UK. Conditions were ripe for epidemics of infectious diseases
      and they came in waves causing high mortality particularly among the young.
      Diagnostic difficulties and ineffective therapy meant that little impact was made
      on these diseases during the first half of the period. Smallpox was the exception
      vaccination of children reduced the incidence and mortality early in the century
      but subsequent public complacency caused it to return within a few years. Measles
      and whooping cough surpassed smallpox as the major causes of infectious disease
      mortality as early as 1810. Epidemics were less common after the three-quarter
      century mark due to improved living conditions for the poor but also as a result
      of the assiduos application of Public Health principles.

PMID- 8658121
TI  - Evidence of continuing risk of HIV transmission among injecting drug users from
      Dundee.

PMID- 8658122
TI  - Reye's syndrome and the use of aspirin.

PMID- 8658123
TI  - Case histories--a new policy.

PMID- 8658124
TI  - Respect for the RAC.

PMID- 8658125
TI  - Benefit-cost analysis and the environment.

PMID- 8658126
TI  - Loco cow logo.

PMID- 8658127
TI  - IVF project stirs debate over how to preserve pandas.

PMID- 8658128
TI  - Gene linked to commonest cancer.

PMID- 8658129
TI  - Simple mice test antibody complexity.

PMID- 8658130
TI  - Did Neandertals lose an evolutionary "arms" race?

PMID- 8658131
TI  - Bacteria also vote.

PMID- 8658132
TI  - Molybdenum bolsters the bioinorganic brigade.

PMID- 8658133
TI  - Structural analysis of substrate binding by the molecular chaperone DnaK.
AB  - DnaK and other members of the 70-kilodalton heat-shock protein (hsp70) family
      promote protein folding, interaction, and translocation, both constitutively and
      in response to stress, by binding to unfolded polypeptide segments. These
      proteins have two functional units: a substrate-binding portion binds the
      polypeptide, and an adenosine triphosphatase portion facilitates substrate
      exchange. The crystal structure of a peptide complex with the substrate-binding
      unit of DnaK has now been determined at 2.0 angstroms resolution. The structure
      consists of a beta-sandwich subdomain followed by alpha-helical segments. The
      peptide is bound to DnaK in an extended conformation through a channel defined by
      loops from the beta sandwich. An alpha-helical domain stabilizes the complex, but
      does not contact the peptide directly. This domain is rotated in the molecules of
      a second crystal lattice, which suggests a model of conformation-dependent
      substrate binding that features a latch mechanism for maintaining long lifetime
      complexes.

PMID- 8658134
TI  - Crystal structure of DMSO reductase: redox-linked changes in molybdopterin
      coordination.
AB  - The molybdoenzyme dimethylsulfoxide (DMSO) reductase contributes to the release
      of dimethylsulfide, a compound that has been implicated in cloud nucleation and
      global climate regulation. The crystal structure of DMSO reductase from
      Rhodobacter sphaeroides reveals a monooxo molybdenum cofactor containing two
      molybdopterin guanine dinucleotides that asymmetrically coordinate the molybdenum
      through their dithiolene groups. One of the pterins exhibits different
      coordination modes to the molybdenum between the oxidized and reduced states,
      whereas the side chain oxygen of Ser147 coordinates the metal in both states. The
      change in pterin coordination between the Mo(VI) and Mo(IV) forms suggests a
      mechanism for substrate binding and reduction by this enzyme. Sequence
      comparisons of DMSO reductase with a family of bacterial oxotransferases
      containing molybdopterin guanine dinucleotide indicate a similar polypeptide fold
      and active site with two molybdopterins within this family.

PMID- 8658135
TI  - Sending and receiving the hedgehog signal: control by the Drosophila Gli protein
      Cubitus interruptus.
AB  - Drosophila limb development is organized by interactions between anterior and
      posterior compartment cells. Posterior cells continuously express and require
      engrailed (en) and secrete Hedgehog (Hh) protein. Anterior cells express the zinc
      finger protein Cubitus interruptus (Ci). It is now shown that anterior cells
      lacking ci express hh and adopt posterior properties without expressing en.
      Increased levels of Ci can induce the expression of the Hh target gene
      decapentaplegic (dpp) in a Hh-independent manner. Thus, expression of Ci in
      anterior cells controls limb development (i) by restricting hh secretion to
      posterior cells and (ii) by conferring competence to respond to Hh by mediating
      the transduction of this signal.

PMID- 8658136
TI  - Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium
      tuberculosis.
AB  - Mutations that eliminate KatG catalase-peroxidase activity prevent activation of
      isoniazid and are a major mechanism of resistance to this principal drug for the
      treatment of Mycobacterium tuberculosis infections. However, the loss of KatG
      activity in clinical isolates seemed paradoxical because KatG is considered an
      important factor for the survival of the organism. Expression of either KatG or
      the recently identified alkyl hydroperoxidase AhpC was sufficient to protect
      bacilli against the toxic effects of organic peroxides. To survive during
      infection, isoniazid-resistant KatG mutants have apparently compensated for the
      loss of KatG catalase-peroxidase activity by a second mutation, resulting in
      hyperexpression of AhpC.

PMID- 8658137
TI  - Arrested DNA replication in Xenopus and release by Escherichia coli mutagenesis
      proteins.
AB  - Xenopus oocytes and oocyte nuclear extracts repair ultraviolet photoproducts on
      double-stranded (ds) DNA and replicate single-stranded (ss) to ds DNA. M13 ss DNA
      molecules containing cyclobutane pyrimidine dimers were maintained but not
      replicated in Xenopus oocytes yet were replicated in progesterone-matured
      oocytes. The replication arrest functioned only in cis. The replication arrest
      was alleviated by injection into oocytes of messenger RNAs encoding the
      prokaryotic mutagenesis proteins UmuD'C or MucA'B. These results may help explain
      how cells stabilize repair or replication events on DNA with unrepairable
      lesions.

PMID- 8658138
TI  - Thymine-thymine dimer bypass by yeast DNA polymerase zeta.
AB  - The REV3 and REV7 genes of the yeast Saccharomyces cerevisiae are required for
      DNA damage-induced mutagenesis. The Rev3 and Rev7 proteins were shown to form a
      complex with DNA polymerase activity. This polymerase replicated past a thymine
      thymine cis-syn cyclobutane dimer, a lesion that normally severely inhibits
      replication, with an efficiency of approximately 10 percent. In contrast, bypass
      replication efficiency with yeast DNA polymerase alpha was no more than 1
      percent. The Rev3-Rev7 complex is the sixth eukaryotic DNA polymerase to be
      described, and is therefore called DNA polymerase zeta.

PMID- 8658139
TI  - A quasi-monoclonal mouse.
AB  - As a model for studying the generation of antibody diversity, a gene-targeted
      mouse was produced that is hemizygous for a rearranged V(D)J segment at the
      immunoglobulin (Ig) heavy chain locus, the other allele being nonfunctional. The
      mouse also has no functional kappa light chain allele. The heavy chain, when
      paired with any lambda light chain, is specific for the hapten (4-hydroxy-3
      nitrophenyl) acetyl (NP). The primary repertoire of this quasi-monoclonal mouse
      is monospecific, but somatic hypermutation and secondary rearrangements change
      the specificity of 20 percent of the antigen receptors on B cells. The serum
      concentrations of the Ig isotypes are similar to those in nontransgenic
      littermates, but less than half of the serum IgM binds to NP, and none of the
      other isotypes do. Thus, neither network interactions nor random activation of a
      small fraction of the B cell population can account for serum Ig concentrations.

PMID- 8658140
TI  - Identification of MAP kinase domains by redirecting stress signals into growth
      factor responses.
AB  - Mitogen-activated protein kinase (MAPK) cascades, termed MAPK modules, channel
      extracellular signals into specific cellular responses. Chimeric molecules were
      constructed between p38 and p44 MAPKs, which transduce stress and growth factor
      signals, respectively. A discrete region of 40 residues located in the amono
      terminal p38MAPK lobe directed the specificity of response to extracellular
      signals, whereas the p44MAPK chimera, expressed in vivo, redirected stress
      signals into early mitogenic responses, demonstrating the functional independence
      of these domains.

PMID- 8658141
TI  - Enzymatic synthesis of a quorum-sensing autoinducer through use of defined
      substrates.
AB  - Many bacteria, including several pathogens of plants and humans, use a pheromone
      called an autoinducer to regulate gene expression in a cell density-dependent
      manner. Agrobacterium autoinducer [AAI, N-(3-oxo-octanoyl)-L-homoserine lactone]
      of A. tumefaciens is synthesized by the Tral protein, which is encoded by the
      tumor-inducing plasmid. Purified hexahistidinyl-Tral (H6-Tral) used S
      adenosylmethionine to make the homoserine lactone moiety of AAI, but did not use
      related compounds. H6-Tral used 3-oxo-octanoyl-acyl carrier protein to make the 3
      oxo-octanoyl moiety of AAI, but did not use 3-oxo-octanoyl-coenzyme A. These
      results demonstrate the enzymatic synthesis of an autoinducer through the use of
      purified substrates.

PMID- 8658142
TI  - Site-directed hydroxyl radical probing of the rRNA neighborhood of ribosomal
      protein S5.
AB  - Cysteine residues were introduced into three different positions distributed on
      the surface of ribosomal protein S5, to serve as targets for derivatization with
      an Fe(II)-ethyl-enediaminetetraacetic acid linker. Hydroxyl radicals generated
      locally from the tethered Fe(II) in intermediate ribonucleoprotein particles or
      in 30S ribosomal subunits reconstituted from derivatized S5 caused cleavage of
      the RNA, resulting in characteristically different cleavage patterns for the
      three different tethering positions. These findings provide constraints for the
      three-dimensional folding of 16S ribosomal RNA (rRNA) and for the orientation of
      S5 in the 30S subunit, and they further suggest that antibiotic resistance and
      accuracy mutations in S5 may involve perturbation of 16S rRNA.

PMID- 8658143
TI  - Activation of Gal4p by galactose-dependent interaction of galactokinase and
      Gal80p.
AB  - Yeast galactokinase (Gal1p) is an enzyme and a regulator of transcription. In
      addition to phosphorylating galactose, Gal1p activates Gal4p, the activator of
      GAL genes, but the mechanism of this regulation has been unclear. Here,
      biochemical and genetic evidence is presented to show that Gal1p activates Gal4p
      by direct interaction with the Gal4p inhibitor Gal80p. Interaction requires
      galactose, adenosine triphosphate, and the regulatory function of Gal1p. These
      data indicate that Gal1p-Gal80p complex formation results in the inactivation of
      Gal80p, thereby transmitting the galactose signal to Gal4p.

PMID- 8658144
TI  - Optical imaging of functional organization in the monkey inferotemporal cortex.
AB  - To investigate the functional organization of object recognition, the technique
      of optical imaging was applied to the primate inferotemporal cortex, which is
      thought to be essential for object recognition. The features critical for the
      activation of single cells were first determined in unit recordings with
      electrodes. In the subsequent optical imaging, presentation of the critical
      features activated patchy regions around 0.5 millimeters in diameter, covering
      the site of the electrode penetration at which the critical feature had been
      determined. Because signals in optical imaging reflect average neuronal
      activities in the regions, the result directly indicates the regional clustering
      of cells responding to similar features.

PMID- 8658146
TI  - Is EIAV Tat protein a homeodomain?

PMID- 8658145
TI  - Human homolog of patched, a candidate gene for the basal cell nevus syndrome.
AB  - The basal cell nevus syndrome (BCNS) is characterized by developmental
      abnormalities and by the postnatal occurrence of cancers, especially basal cell
      carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS
      patients and a somatic mutation in a sporadic BCC were identified in a human
      homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a
      transmembrane protein that in Drosophila acts in opposition to the Hedgehog
      signaling protein, controlling cell fates, patterning, and growth in numerous
      tissues. The human PTC gene appears to be crucial for proper embryonic
      development and for tumor suppression.

PMID- 8658147
TI  - AIDS: a global response.

PMID- 8658148
TI  - Striving for creativity.

PMID- 8658149
TI  - The economics of contraceptives R&D.

PMID- 8658150
TI  - "Natural" cancer prevention.

PMID- 8658151
TI  - Imanishi-Kari ruling slams ORI.

PMID- 8658152
TI  - Phage transfer: a new player turns up in cholera infection.

PMID- 8658153
TI  - Divide and confer: how worm embryo cells specialize.

PMID- 8658154
TI  - The changing of the guard.

PMID- 8658155
TI  - The marketplace of HIV/AID$.

PMID- 8658156
TI  - Protease inhibitors: a tale of two companies.

PMID- 8658157
TI  - Eradicating HIV from a patient: not just a dream?

PMID- 8658158
TI  - HIV receptors and the pathogenesis of AIDS.

PMID- 8658159
TI  - HIV therapeutics.

PMID- 8658160
TI  - A perspective on AIDS vaccines.

PMID- 8658161
TI  - Tickling memory T cells.

PMID- 8658162
TI  - Image representations for visual learning.
AB  - Computer vision researchers are developing new approaches to object recognition
      and detection that are based almost directly on images and avoid the use of
      intermediate three-dimensional models. Many of these techniques depend on a
      representation of images that induce a linear vector space structure and in
      principle requires dense feature correspondence. This image representation allows
      the use of learning techniques for the analysis of images (for computer vision)
      as well as for the synthesis of images (for computer graphics).

PMID- 8658163
TI  - Lysogenic conversion by a filamentous phage encoding cholera toxin.
AB  - Vibrio cholerae, the causative agent of cholera, requires two coordinately
      regulated factors for full virulence: cholera toxin (CT), a potent enterotoxin,
      and toxin-coregulated pili (TCP), surface organelles required for intestinal
      colonization. The structural genes for CT are shown here to be encoded by a
      filamentous bacteriophage (designated CTXphi), which is related to coliphage M13.
      The CTXphi genome chromosomally integrated or replicated as a plasmid. CTXphi
      used TCP as its receptor and infected V. cholerae cells within the
      gastrointestinal tracts of mice more efficiently than under laboratory
      conditions. Thus, the emergence of toxigenic V. cholerae involves horizontal gene
      transfer that may depend on in vivo gene expression.

PMID- 8658164
TI  - Atmospheric, evolutionary, and spectral models of the brown dwarf Gliese 229 B.
AB  - Theoretical spectra and evolutionary models that span the giant planet-brown
      dwarf continuum have been computed based on the recent discovery of the brown
      dwarf Gliese 229 B. A flux enhancement in the 4- to 5-micrometer wavelength
      window is a universal feature from jovian planets to brown dwarfs. Model results
      confirm the existence of methane and water in the spectrum of Gliese 229 B and
      indicate that its mass is 30 to 55 jovian masses. Although these calculations
      focus on Gliese 229 B, they are also meant to guide future searches for
      extrasolar giant planets and brown dwarfs.

PMID- 8658165
TI  - Nuclear encoding of a chloroplast RNA polymerase sigma subunit in a red alga.
AB  - A chloroplast RNA polymerase sigma factor is encoded by a nuclear gene, sigA, in
      the red alga Cyanidium caldarium RK-1. The encoded protein functions as an RNA
      polymerase sigma factor in vitro and it is localized to the chloroplast in vivo.
      SigA shows high sequence similarity to the sigma factors of cyanobacteria, which
      is indicative of the ancestral endosymbiotic event and subsequent transfer of the
      sigA gene to the nuclear genome.

PMID- 8658166
TI  - Requirement for the adapter protein GRB2 in EGF receptor endocytosis.
AB  - Activated epidermal growth factor (EGF) receptors induce the formation of various
      complexes of intracellular signaling proteins that are mediated by SRC homology 2
      (SH2) and SH3 domains. The activated receptors are also rapidly internalized into
      the endocytotic compartment and degraded in lysosomes. EGF stimulation of canine
      epithelial cells induced a rapid and transient association of the SH3-SH2-SH3
      protein GRB2 with dynamin, a guanosine triphosphatase that regulates endocytosis.
      Disruption of GRB2 interactions by microinjection of a peptide corresponding to
      the GRB2 SH2 domain or its phosphopeptide ligand blocked EGF receptor
      endocytosis; other SH2 domains that bind EGF receptors or antibodies that
      neutralize RAS did not. Both activation and termination of EGF signaling appear
      to be regulated by the diverse interactions of GRB2.

PMID- 8658167
TI  - Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients
      as a result of CD28 costimulation.
AB  - Because stimulation of CD4+ lymphocytes leads to activation of human
      immunodeficiency virus-type 1 (HIV-1) replication, viral spread, and cell death,
      adoptive CD4+ T cell therapy has not been possible. When antigen and CD28
      receptors on cultured T cells were stimulated by monoclonal antibodies (mAbs) to
      CD3 and CD28 that had been immobilized, there was an increase in the number of
      polyclonal CD4+ T cells from HIV-infected donors. Activated cells predominantly
      secreted cytokines associated with T helper cell type 1 function. The HIV-1 viral
      load declined in the absence of antiretroviral agents. Moreover, CD28 stimulation
      of CD4+ T cells from uninfected donors rendered these cells highly resistant to
      HIV-1 infection. Immobilization of CD28 mAb was crucial to the development of HIV
      resistance, as cells stimulated with soluble CD28 mAb were highly susceptible to
      HIV infection. The CD28-mediated antiviral effect occurred early in the viral
      life cycle, before HIV-1 DNA integration. These data may facilitate immune
      reconstitution and gene therapy approaches in persons with HIV infection.

PMID- 8658168
TI  - Solution structure of a two-base DNA bulge complexed with an enediyne cleaving
      analog.
AB  - Nucleic acid bulges have been implicated in a number of biological processes and
      are specific cleavage targets for the enediyne antitumor antibiotic
      neocarzinostatin chromophore in a base-catalyzed, radical-mediated reaction. The
      solution structure of the complex between an analog of the bulge-specific
      cleaving species and an oligodeoxynucleotide containing a two-base bulge was
      elucidated by nuclear magnetic resonance. An unusual binding mode involves major
      groove recognition by the drug carbohydrate unit and tight fitting of the wedge
      shaped drug in the triangular prism pocket formed by the two looped-out bulge
      bases and the neighboring base pairs. The two drug rings mimic helical DNA bases,
      complementing the bent DNA structure. The putative abstracting drug radical is
      2.2 +/- 0.1 angstroms from the pro-S H5' of the target bulge nucleotide. This
      structure clarifies the mechanism of bulge recognition and cleavage by a drug and
      provides insight into the design of bulge-specific nucleic acid binding
      molecules.

PMID- 8658169
TI  - Induction of bystander T cell proliferation by viruses and type I interferon in
      vivo.
AB  - T cell proliferation in vivo is presumed to reflect a T cell receptor (TCR)
      mediated polyclonal response directed to various environmental antigens. However,
      the massive proliferation of T cells seen in viral infections is suggestive of a
      bystander reaction driven by cytokines instead of the TCR. In mice, T cell
      proliferation in viral infections preferentially affected the CD44hi subset of
      CD8+ cells and was mimicked by injection of polyinosinic-polycytidylic acid
      [poly(I:C)], an inducer of type I interferon (IFN I), and also by purified IFN I;
      such proliferation was not associated with up-regulation of CD69 or CD25
      expression, which implies that TCR signaling was not involved. IFN I [poly(I:C)]
      stimulated CD8+ cells survived for prolonged periods in vivo and displayed the
      same phenotype as did long-lived antigen-specific CD8+ cells. IFN I also
      potentiated the clonal expansion and survival of CD8+ cells responding to
      specific antigen. Production of IFN I may thus play an important role in the
      generation and maintenance of specific memory.

PMID- 8658170
TI  - Nonselective and G betagamma-insensitive weaver K+ channels.
AB  - Homozygous weaver mice are profoundly ataxic because of the loss of granule cell
      neurons during cerebellar development. This granule cell loss appears to be
      caused by a genetic defect in the pore region (Gly156-->Ser) of the
      heterotrimeric guanine nucleotide-binding protein (G protein)-gated inwardly
      rectifying potassium (K+) channel subunit (GIRK2). A related subunit, GIRK1,
      associates with GIRK2 to constitute a neuronal G protein-gated inward rectifier
      K+ channel. The weaver allele of the GIRK2 subunit (wvGIRK2) caused loss of K+
      selectivity when expressed either as wvGIRK2 homomultimers or as GIRK1-wvGIRK2
      heteromultimers. The mutation also let to loss of sensitivity to G protein
      betagamma dimers. Expression of wvGIRK2 subunits let to increased cell death,
      presumably as a result of basal nonselective channel opening.

PMID- 8658171
TI  - CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for
      macrophage-tropic HIV-1.
AB  - Human immunodeficiency virus-type 1 (HIV-1) entry requires fusion cofactors on
      the CD4+ target cell. Fusin, a heterotrimeric GTP-binding protein (G protein)
      coupled receptor, serves as a cofactor for T cell line-tropic isolates. The
      chemokines RANTES, MIP-1alpha, and MIP-1beta, which suppress infection by
      macrophage-tropic isolates, selectively inhibited cell fusion mediated by the
      corresponding envelope glycoproteins (Envs). Recombinant CC CKR5, a G protein
      coupled receptor for these chemokines, rendered CD4-expressing nonhuman cells
      fusion-competent preferentially with macrophage-tropic Envs. CC CKR5 messenger
      RNA was detected selectively in cell types susceptible to macrophage-tropic
      isolates. CC CKR5 is thus a fusion cofactor for macrophage-tropic HIV-1 strains.

PMID- 8658172
TI  - HIV-2 and natural protection against HIV-1 infection.

PMID- 8658173
TI  - Modeling HIV concentration during acute AIDS infection.

PMID- 8658174
TI  - Rate of killing of HIV-infected T cells and disease progression.

PMID- 8658175
TI  - T cell activation determined by T cell receptor number and tunable thresholds.
AB  - The requirements for T cell activation have been reported to vary widely
      depending on the state of the T cell, the type of antigen-presenting cell, and
      the nature of the T cell receptor (TCR) ligand. A unitary requirement for T cell
      responses was revealed by measurement of the number of triggered TCRs.
      Irrespective of the nature of the triggering ligand, T cells "counted" the number
      of triggered TCRs and responded when a threshold of approximately 8000 TCRs was
      reached. The capacity to reach the activation threshold was severely compromised
      by a reduction in the number of TCRs. Costimulatory signals lowered the
      activation threshold to approximately 1500 TCRs, thus making T cells more
      sensitive to antigenic stimulation.

PMID- 8658176
TI  - Mapping of catalytic residues in the RNA polymerase active center.
AB  - When the Mg2+ ion in the catalytic center of Escherichia coli RNA polymerase
      (RNAP) is replaced with Fe2+, hydroxyl radicals are generated. In the promoter
      complex, such radicals cleave template DNA near the transcription start site,
      whereas the beta' subunit is cleaved at a conserved motif NADFDGD (Asn-Ala-Asp
      Phe-Asp-Gly-Asp). Substitution of the three aspartate residues with alanine
      creates a dominant lethal mutation. The mutant RNAP is catalytically inactive but
      can bind promoters and form an open complex. The mutant fails to support Fe2+
      induced cleavage of DNA or protein. Thus, the NAD-FDGD motif is involved in
      chelation of the active center Mg2+.

PMID- 8658177
TI  - Prevention of islet allograft rejection with engineered myoblasts expressing FasL
      in mice.
AB  - Allogeneic transplantation of islets of Langerhans was facilitated by the
      cotransplantation of syngeneic myoblasts genetically engineered to express the
      Fas ligand (FasL). Composite grafting of allogeneic islets with syngeneic
      myoblasts expressing FasL protected the islet graft from immune rejection and
      maintained normoglycemia for more than 80 days in mice with streptozotocin
      induced diabetes. Graft survival was not prolonged with composite grafts of
      unmodified myoblasts or Fas-expressing myoblasts. Islet allografts transplanted
      separately from FasL-expressing myoblasts into the contralateral kidney were
      rejected, as were similarly transplanted third-party thyroid allografts. Thus,
      the FasL signal provided site- and immune-specific protection of islet
      allografts.

PMID- 8658178
TI  - Evidence for physical and functional association between EMB-5 and LIN-12 in
      Caenorhabditis elegans.
AB  - The Caenorhabditis elegans LIN-12 and GLP-1 proteins are members of the LIN
      12/Notch family of receptors for intercellular signals that specify cell fate.
      Evidence presented here suggests that the intracellular domains of LIN-12 and GLP
      1 interact with the C. elegans EMB-5 protein and that the emb-5 gene functions in
      the same pathway as the lin-12 and glp-1 genes. EMB-5 is similar in sequence to a
      yeast protein that controls chromatin structure. Hence, a direct consequence of
      LIN-12 or GLP-1 activation may be an alteration of chromatin structure that
      produces changes in transcriptional activity.

PMID- 8658179
TI  - Formation of a transition-state analog of the Ras GTPase reaction by Ras-GDP,
      tetrafluoroaluminate, and GTPase-activating proteins.
AB  - Unlike the alpha subunits of heterotrimeric guanosine triphosphate (GTP)-binding
      proteins, Ras-related GTP-binding proteins have hitherto been considered not to
      bind or become activated by tetrafluoroaluminate (AIF4-). However, the product of
      the proto-oncogene ras in its guanosine diphosphate (GDP)-bound form interacted
      with AIF4 - in the presence of stoichiometric amounts of either of the guanosine
      triphosphatase (GTPase)-activating proteins (GAPs) p120GAP and neurofibromin.
      Neither oncogenic Ras nor a GAP mutant without catalytic activity produced such a
      complex. Together with the finding that the Ras-binding domain of the protein
      kinase c-Raf, whose binding site on Ras overlaps that of the GAPs, did not induce
      formation of such a complex, this result suggests that GAP and neurofibromin
      stabilize the transition state of the GTPase reaction of Ras.

PMID- 8658180
TI  - Centric heterochromatin and the efficiency of achiasmate disjunction in
      Drosophila female meiosis.
AB  - The chromosomal requirements for achiasmate (nonexchange) homolog disjunction in
      Drosophila female meiosis I have been identified with the use of a series of
      molecularly defined minichromosome deletion derivatives. Efficient disjunction
      requires 1000 kilobases of overlap in the centric heterochromatin and is not
      affected by homologous euchromatin or overall size differences. Disjunction
      efficiency decreases linearly as heterochromatic overlap is reduced from 1000 to
      430 kilobases of overlap. Further observations, including rescue experiments with
      nod kinesin-like protein transgenes, demonstrate that heterochromatin does not
      act solely to promote chromosome movement or spindle attachment. Thus, it is
      proposed that centric heterochromatin contains multiple pairing elements that act
      additively to initiate or maintain the proper alignment of achiasmate chromosomes
      in meiosis I. How heterochromatin could act to promote chromosome pairing is
      discussed here.

PMID- 8658181
TI  - Battling heart disease.

PMID- 8658182
TI  - Battling heart disease.

PMID- 8658183
TI  - Release of RHD virus in Australia.

PMID- 8658184
TI  - Release of RHD virus in Australia.

PMID- 8658185
TI  - Auguste D. and Alzheimer's disease.

PMID- 8658186
TI  - Folding proteins caught in the act.

PMID- 8658187
TI  - AIDS research. Selling the immune system short.

PMID- 8658188
TI  - Muscling transplants into mice.

PMID- 8658189
TI  - Chromosome yield new clue to pairing in meiosis.

PMID- 8658190
TI  - Live long and prosper?

PMID- 8658191
TI  - Japan: feeling the strains of an aging population.

PMID- 8658192
TI  - New populations of old add to poor nations' burdens.

PMID- 8658193
TI  - For the cortex, neuron loss may be less than thought.

PMID- 8658194
TI  - Searching for drugs that combat Alzheimer's.

PMID- 8658195
TI  - Longevity, genes, and aging.
AB  - Until recently, biogerontology was a backwater of biology, but progress in the
      qualitative and quantitative genetic analysis of longevity has led to a
      revolution in aging research. This research has revealed that extended longevity
      is frequently associated with enhanced metabolic capacity and response to stress.
      Moreover, it suggests that there are multiple mechanisms of aging. Because of its
      complexity, the aging process takes us into the realm of integrative biology, and
      thus, biogerontology should prove instrumental in deciphering the functional and
      regulatory circuitry of the sequenced genome.

PMID- 8658197
TI  - Replicative senescence: implications for in vivo aging and tumor suppression.
AB  - Normal cells have limited proliferative potential in culture, a fact that has
      been the basis of their use as a model for replicative senescence for many years.
      Recent molecular analyses have identified numerous changes in gene expression
      that occur as cells become senescent, and the results indicate that multiple
      levels of control contribute to the irreversible growth arrest. These include
      repression of growth stimulatory genes, overexpression of growth inhibitory
      genes, and interference with downstream pathways. Studies with cell types other
      than fibroblasts will better define the role of cell senescence in the aging
      process and in tumorigenesis.

PMID- 8658196
TI  - Oxidative stress, caloric restriction, and aging.
AB  - Under normal physiological conditions, the use of oxygen by cells of aerobic
      organisms generates potentially deleterious reactive oxygen metabolites. A
      chronic state of oxidative stress exists in cells because of an imbalance between
      prooxidants and antioxidants. The amount of oxidative damage increases as an
      organism ages and is postulated to be a major causal factor of senescence.
      Support for this hypothesis includes the following observations: (i)
      Overexpression of antioxidative enzymes retards the age-related accrual of
      oxidative damage and extends the maximum life-span of transgenic Drosophila
      melanogaster. (ii) Variations in longevity among different species inversely
      correlate with the rates of mitochondrial generation of the superoxide anion
      radical (O2) and hydrogen peroxide. (iii) Restriction of caloric intake lowers
      steady-state levels of oxidative stress and damage, retards age-associated
      changes, and extends the maximum life-span in mammals.

PMID- 8658198
TI  - Menopause: the aging of multiple pacemakers.
AB  - Menopause signals the permanent end of menstrual cyclicity in a woman's life. Its
      impact reaches far beyond just the reproductive system. An understanding of the
      factors that interact and govern the process of aging in the reproductive system
      will help us to develop strategies for alleviating the negative aspects of
      menopause and may help us to better comprehend the process of biological aging.

PMID- 8658199
TI  - The aging immune system: primer and prospectus.
AB  - Changes in T lymphocyte populations underlie much of the age-related decline in
      the protective immune response. Aging leads to the replacement of virgin T cells
      by memory T cells and to the accumulation of cells with signal transduction
      defects. Studies of antibody gene assembly, accessory cell function, post-thymic
      T cell development, skewed selection of T cell receptor repertoire, and the
      clinical concomitants of immune senescence will shed new light on the causes and
      consequences of age-dependent immune failure.

PMID- 8658200
TI  - How T cells count.

PMID- 8658202
TI  - [Shoulder injuries and biological osteosynthesis procedures. 2nd Central European
      Accident Congress, 29 May-1 June 1996 in Davos/Switzerland].

PMID- 8658201
TI  - Mechanisms and evolution of aging.

PMID- 8658204
TI  - [Outcome evaluation after unstable injuries of the pelvic ring].
AB  - Open reduction followed by internal fixation is the method of choice after
      unstable pelvic ring fractures and gives better results than either conservative
      treatment or external fixation alone. Even after anatomic reconstruction of the
      pelvic ring, however, a high incidence of late sequelae is reported, especially
      after C-type fractures (translational instability). The purpose of the study
      reported in this paper was evaluation of a new scoring system for the rating of
      the long-term outcome after pelvic fractures. In all, 28 B-type fractures and 27
      C-type fractures (Tile) were subjected to surgical stabilization in 1985-1990
      (both external and internal stabilizations). These patients were followed up
      clinically and radiologically an average of 28 months after injury. The results
      were summarized in a new pelvic outcome score. The scoring included the
      radiological result (I = max. 3 points) and the clinical result with rating of
      function, neurological, urological and sexual deficits (II = max. 4 points). The
      "critical value" for the radiological evaluation was a 5-mm residual posterior
      displacement or a 15-mm anterior displacement in the pelvic ring defining a
      "poor" result (1 point). Social reintegration, an overall reflection of all
      accident-related sequelae, was rated independently (III = max. 3 points). I + II
      were summarized as "pelvic outcome," with 7 points rated as excellent, 6 points
      as good, 5 and 4 points as moderate, and 3 and 2 points as a poor result. Freedom
      from pain was achieved in 89% of the patients who had B-type injuries, and in 30%
      of those with C-type injuries. Neurological deficits were seen in 32% after B
      type (only sensory) and 70% after C-type fractures (33% motor nerve, 37%
      sensory). The maximum radiological rating was given to 86% of the patients after
      B-type and 27% after C-type injuries. The clinical rating was maximum (4 points)
      in 18% after B-type and 7% after C-type fractures, resulting in a good or
      excellent rating for "pelvic outcome" in 79% after B-type and only 27% after C
      type injuries. The maximum rating for social reintegration was given to 57% after
      B-type and 44% after C-type injuries. Even after anatomical reconstruction of the
      pelvic ring in C-type fractures (3 points) 20% of the patients were clinically
      rated as "poor" (1 point). The study showed that anatomic reconstruction of the
      pelvic ring is an important factor in a good or excellent clinical result, but
      even when this goal is met, other parameters (sacral fractures, SI dislocations,
      primary neurological/urological injuries) can lead to an unsatisfactory result.
      The new rating system is comprehensive and easy to apply and allows a clear
      differentiation of typical late sequelae after pelvic injuries; it will therefore
      be used for further long-term studies.

PMID- 8658203
TI  - [Current status of therapy of subtrochanteric femoral fractures].
AB  - Operative treatment of subtrochanteric femur fractures is demanding. The implants
      available follow different biomechanical and surgical principles. Extramedullary
      implants like the condylar blade plate and the dynamic condylar screw require
      subtle surgical and indirect reduction techniques. Intramedullary implants like
      intramedullary hip screws and interlocking nails are biomechanically
      advantageous. In contrast to the extramedullary implants these fixations can
      stand postoperative weight-bearing. The different operative techniques for the
      fixation of subtrochanteric fractures are presented and evaluated. Current trends
      in treatment rationales are outlined.

PMID- 8658205
TI  - [Arthrography of the wrist joint in acute trauma].
AB  - At least 20-25% of the patients with distal radius fractures show concomitant
      lesions of the intrinsic ligaments of the proximal carpal row and lesions of the
      triangular fibrocartilage complex. A high number of these lesions cause
      persistent pain and discomfort, even if there is a good radiological result.
      Wrist arthrography as a screening method can identify these lesions and help to
      select the patients in whom further diagnostic and therapeutic procedures
      (diagnostic arthroscopy, arthroscopical refixation of the discus or SL
      stabilization) should be performed. Wrist arthrography also allows cartilage
      lesions to be detected, as well as associated fractures or lesions of the
      capsular ligaments. The technique of wrist arthrography in the acute traumatized
      wrist, which is different from wrist arthrography in patients suffering from
      chronic post-traumatic pain, is described in this paper.

PMID- 8658206
TI  - [Quality of life after survival of severe trauma].
AB  - Quality of life (QoL) was analyzed in 73 patients with severe multiple trauma
      (PTS > or = 40 patients) between 1 and 13 years after injury. QoL was assessed by
      the Aachen Longtime Outcome Score (ALOS), the Spitzer Index (SI) and individual
      self-assessment. The patients were asked about further social, financial,
      psychological and physical items. According to the ALOS, 81% of the patients
      showed moderate, 14% severe and 5% no disability. In 66% of the patients a
      favorable Spitzerindex (8-10 points) was found. Only 14% had poor SI scores (0-4
      points). Also, two out of three patients regarded the current state of their
      health as "good" or "very good". Predominantly, handicaps resulted from permanent
      physical disability, in particular the lower extremities, whereas psychosocial
      and financial problems were reported infrequently. Besides injuries to the head
      or extremities, low QoL correlated with severity of injury and increasing age.
      Within the first 4 post-traumatic years SI and ALOS, as well as individual self
      assessment, improved with time after injury. The rate of patients who returned to
      work (69%) was similar to other multiple trauma series, including series with
      less severe injuries. The reasonable long-term outcome even after severe multiple
      trauma seems to justify the enormous staff and economic expense required to
      manage these patients. Further improvement in QoL may be achieved by professional
      psychological support and early fracture treatment.

PMID- 8658207
TI  - [Leg length inequality after childhood femoral fractures--permanent or temporary
      phenomenon?].
AB  - Leg length inequality is the most common complication reported after femoral
      shaft fractures in childhood. Most authors agree that significant overgrowth
      occurs in the first two years after injury and will not be further corrected. We
      reviewed 221 patients (166 boys, 44 girls) with a fracture of the femoral shaft.
      The mean age at the time of fracture was 6.5 years (range 11 months to 12 years);
      123 patients were treated conservatively, 96 by skin traction, 11 by skeletal
      traction, and 16 by immediate cast bracing. In 98 patients the fracture was
      stabilized by osteosynthesis. In 5 fractures located in the distal third of the
      femur we used crossed Kirschner wires. Fifty-nine patients were treated by
      intramedullary nailing, without problems regarding trochanteric apophyseal arrest
      or alteration in the collum angle. Thirty-four patients were treated by plate
      fixation, this being associated with high rates (9%) of implant-breakage. A total
      of 127 patients were interviewed and examined; they were skeletally mature at the
      time of reexamination. A leg-length discrepancy was found in 45 patients.
      Shortening from 10 to 30 mm (mean 14.3 mm) occurred in 7 patients; 38 patients
      had lengthening from 10 to 25 mm (mean 14.1 mm). Overgrowth significantly
      depended on the age at trauma (4-9 years; P = 0.04), number of repositions (2 or
      more; P = 0.0005) and degree of axial deviation (> 10 degrees; P = 0.04). Delayed
      surgical treatment (> 48 h; P = 0.0035), especially plate fixation (P = 0.0003)
      induced overgrowth as well. Forty-six patients had previously been reevaluated 12
      years before (1981). In 12 patients 13 years or older at the time of the first
      review, no change in leg-length difference occurred. At the first review 34
      patients were younger than 13 years. Eight of them had no leg-length discrepancy.
      In 16 patients the growth rate of the affected femur decreased, so that leg
      length discrepancy diminished after the 2-year period posttraumatically in a
      range from 5 to 15 mm. Overgrowth of the femur continued in 7 cases ranging from
      5 to 10 mm. No change occurred in 3 patients. Thus, there is a further change in
      length inequality more than 2 years post-traumatically.

PMID- 8658208
TI  - [Vacuum assisted wound closure after dermatofasciotomy of the lower extremity].
AB  - Between 1 January 1992 and 15 March 1994 25 patients with compartment syndromes
      of the lower limb were treated by the vacuum-sealing technique (VS). Ten out of
      25 patients had multiple injuries. Eight compartment syndromes were located in
      the thigh, 14 in the lower leg and 3 in the foot. The average time of VS was 12.7
      (4-31) days with 2.1 (1-8) changes per patient. The wounds were either closed by
      secondary suturing (n = 20) or by skin grafts after partial closure of the wounds
      by suturing (n = 5). One patient developed a superficial wound necrosis, which
      healed spontaneously without invasive surgical treatment. In 52 intraoperative
      swabs of the wound surface there was bacterial growth in five bacteriologic
      specimens, but there were no clinical signs of infection.

PMID- 8658209
TI  - [Blunt and penetrating abdominal trauma. Patient assessment algorithm and
      principles for management].

PMID- 8658210
TI  - [Traumatic hemipelvectomy. Experiences with 11 cases].
AB  - With further improvements of the prehospital rescue systems, an increasing number
      of patients with extreme injuries such as traumatic hemipelvectomy are admitted
      to trauma centers alive. The accepted definition of traumatic hemipelvectomy is:
      unstable ligamentous or osseous hemipelvic injury with rupture of the pelvic
      neurovascular bundle (open or closed integuments). A review of the literature up
      to 1995 yielded on 48 surving cases with such an injury. A review of 2002
      consecutive patients after pelvic fractures treated from 1972-1994 at the Medical
      School Hannover, resulted in the identification of 11 traumatic hemipelvectomies
      with four survivors. The purpose of the study was the analysis of the early
      clinical course of the patients after traumatic hemipelvectomy and the evaluation
      of the late outcome of the survivors. All accessible clinical and radiological
      data were reviewed for the preclinical and primary clinical treatment,
      concomitant injuries, cause of death and complications. The survivors are under
      continuous follow-up at our institution and were evaluated on average 5.5 years
      (range 2-7 years) after trauma. All patients were managed with early and
      aggressive shock therapy by an emergency physician, hemorrhage control with
      manual compression of the wound and a short transit time to a trauma center.
      Immediate surgical hemostasis was attempted in all cases. Despite this, four
      patients died within the first 4 h secondary to uncontrollable bleeding. Another
      three died between 2 days and 5 weeks after accident from complications of septic
      or hemorrhagic shock. In four patients a limb-saving procedure was attempted.
      Three of these died early, and in the remaining case secondary hemipelvectomy was
      necessary due to sepsis and paralyses. After primary surgical completion of the
      hemipelvectomy, three of four patients survived. The late result was good in two
      children and moderate in one adult (ambulatory and socially reintegrated). A bad
      result occurred in one male after secondary surgical completion of the
      hemipelvectomy (social deterioration and drug abuse). A strict protocol has to be
      set for the primary treatment of a traumatic hemipelvectomy. It includes
      immediate prehospital hemostasis by local pressure, advanced shock therapy and
      prompt transfer to a trauma center. In-hospital procedures include immediate
      surgical hemostasis and debridement. When the criteria or traumatic
      hemipelvectomy are fulfilled, surgical completion of the hemipelvectomy is
      mandatory. Limb-saving procedures endanger the patient's life. Early and frequent
      second-look operations minimize wound healing problems. Early psychological
      support for the patient and family is advantageous for personal well-being and
      social reintegration.

PMID- 8658211
TI  - Treatment of advanced breast cancer: How much chemotherapy is enough?

PMID- 8658212
TI  - Epidemiology of gastric cancer.
AB  - The incidence of gastric cancer varies widely by country and population, with
      higher rates among the lower socioeconomic groups. Although the most common cause
      of cancer death in the United States in 1930, its incidence has decreased
      dramatically during the past 60 years. Most populations show a 2-1 ratio for male
      to female gastric cancer cases, and a higher incidence rate among United States
      blacks than whites. Although rates have generally decreased, there has been a
      dramatic increase in the incidence of gastric cancer in the cardia. Diet has been
      the most studied risk factor for gastric cancer. Of particular interest have been
      N-nitroso compounds derived from the consumption of preserved, smoked, and cured
      foods. An inverse association with the consumption of fruits and vegetables has
      also been consistently demonstrated, though the specific nutrient(s) that this
      represents has been unclear, although ascorbate and beta-carotene have been
      intensively studied. Among nondietary factors, substantial evidence has
      accumulated for an increased risk with Helicobacter pylori infection. Other
      exposures which have been fairly consistently associated with gastric cancer
      include cigarette smoking, partial gastrectomy, radiation exposure, family
      history, pernicious anemia, blood group A, certain occupational exposures, and
      Epstein-Barr virus.

PMID- 8658213
TI  - Pathologic and phenotypic features of gastric cancer.
AB  - This article covers the basic pathologic features of gastric cancer. Gastric
      cancer is not a single entity but consists of several major tumor types. The risk
      factors for their development and their pathological features are discussed. The
      two major forms of gastric cancer, intestinal and diffuse, are described, as are
      the settings in which they arise. A number of prognostic factors exist for
      gastric cancer, including traditional pathologic variables such as histological
      staging grade and tumor type. Some more recent potential markers involve
      determinants of biologic behavior. The more frequently encountered types are
      covered, as well as their clinical implications. Finally, a scheme for
      standardized handling of gastric resection specimens is presented.

PMID- 8658214
TI  - Molecular biological observations in gastric cancer.
AB  - Alterations in the structure and function of oncogenes and tumor suppressor
      genes, as well as genetic instability at several other genetic foci may be
      responsible for stomach carcinogenesis. The particular combination of multiple
      gene changes found in gastric cancer differs depending on the two histological
      types, strongly indicating that different genetic pathways exist for well
      differentiated or intestinal type and poorly differentiated or diffuse type
      gastric cancers. In general, genetic instability, telomerase activity, CD44
      abnormal transcripts, and p53 mutation, all of which are common events of two
      types of gastric cancer, may be involved mainly in the early stage of stomach
      carcinogenesis, whereas activation of oncogenes and overexpression of the
      epidermal growth factor-related growth factor system may chiefly confer
      progression on gastric cancer. A new strategy of molecular diagnosis of
      gastrointestinal cancer, which has been implemented as a routine service in the
      Hiroshima University Clinical Laboratory, may provide new opportunities for early
      cancer diagnosis and more accurate evaluation of prognosis or grade of
      malignancy.

PMID- 8658215
TI  - Invasion and metastases in gastric cancer: in vitro and in vivo models with
      clinical correlations.
AB  - The major obstacle towards improved survival from gastric cancer is in the
      development of metastatic disease. Techniques in cellular and molecular biology
      have now advanced to the point to allow an examination of specific biomolecules
      in processes related to gastric cancer cell invasion through the basement
      membrane of blood vessels or lymphatics (eg, the first step in developing
      metastatic disease). Identification of such biomolecules in primary gastric
      cancer has been enhanced by the establishment of primary human gastric cancer
      cell lines. These cell lines, named SK-GT for Sloan-Kettering gastric tumor, have
      provided the basis for a detailed analysis of the invasive phenotype of gastric
      cancer cells and has resulted in the identification of potentially important
      prognostic biomarkers. These molecular studies have revealed that in gastric
      cancer cells there exists a series of integrated biomolecules that are intimately
      involved in processes related to tumor cell invasion. Included among these are
      proteins associated with attachment to the basement membrane (ie, laminin
      receptor) as well as with proteolysis of the basement membrane (ie, matrix
      metalloproteinase-2, MMP-2). These factors, as well as others, have been
      clinically evaluated for their prognostic significance in patients with resected,
      primary gastric cancer. These clinical studies indicate that overexpression of
      factors associated with the invasion of gastric cancer cells through the basement
      membrane, including E-cadherin, MMP-2, plasminogen activator inhibitor-1 (PAI-1),
      and tissue inhibitor metalloproteinase-2 (TIMP-2), can be predictive of tumor
      recurrence and overall survival in patients with this disease.

PMID- 8658216
TI  - Diagnosis and staging of gastric cancer.
AB  - The biphasic upper gastrointestinal examination using barium and gas distention
      of the stomach is approximately as accurate as endoscopy in the detection of
      gastric cancer. Endoscopy allows biopsy of suspicious lesions but is more
      invasive and costly. The barium examination can reliably differentiate gastric
      ulcers into three categories: benign, malignant, and equivocal. The radiographic
      findings in gastric carcinoma are described in detail. Staging of gastric cancer
      is limited by the inability of imaging techniques such as computed tomography
      (CT) or magnetic resonance imaging (MRI) to detect tumor in normal size lymph
      nodes. Determination of the presence or absence of local invasion is also
      difficult in many cases. CT and MRI are effective but imperfect tools for the
      detection of liver metastasis. Technique and pitfalls in the use of CT and MR in
      staging gastric carcinoma are emphasized.

PMID- 8658217
TI  - Endoscopic ultrasonography.
AB  - Optimal treatment of gastric carcinoma requires accurate staging as there are
      marked differences in the prognosis of early and advanced gastric cancer which
      influence the decision for surgical resection versus nonsurgical palliation.
      Endoscopic ultrasonography (EUS), by virtue of its considerable accuracy, has
      become the method of choice for regional staging of gastric cancer. EUS is unique
      in its ability to image the gastric wall as a 5-layer structure that correlates
      with actual histological layers. Thus, tumor depth can be imaged very precisely.
      Peritumor inflammation is the most common cause for overstaging by EUS;
      difficulty in determining tumor involvement of, but not through, the subserosa is
      another important reason for inaccurate staging. EUS is able also to detect small
      lymph nodes in the perigastric region. Although assessment of malignancy in nodes
      can be difficult, ultrasound-guided fine needle aspiration cytology appears to be
      an accurate method to determine lymph node status. Surgery remains the standard
      treatment for gastric cancer, but new methods of endoscopic resection combined
      with high-frequency ultrasound may hold promise for future treatment of early
      gastric cancer. In addition to current radial and sector scanning instruments,
      recently introduced high-frequency ultrasound probes enhance the diagnostic
      possibilities of this technology.

PMID- 8658218
TI  - Laparoscopy and laparoscopic ultrasound in the staging of gastric cancer.
AB  - As patients with gastric cancer are offered choices between surgical resection,
      investigational neoadjuvant chemotherapy, palliative chemotherapy, or symptomatic
      relief alone, the need for accurate preoperative staging becomes apparent.
      Laparoscopy has been suggested as an accurate staging modality in a variety of
      upper gastrointestinal malignancies. It allows for assessment of the stage of the
      primary tumor, identification of hepatic or regional nodal metastases, and the
      detection of small volume peritoneal disease unappreciated by other noninvasive
      staging modalities such as computerized tomography, magnetic resonance imaging or
      endoscopic ultrasound. This article reviews the current literature concerning
      laparoscopy and laparoscopic ultrasonography (LUS) in the staging of gastric
      cancer. The Memorial Hospital experience with 92 patients is described. In this
      group, metastatic disease unappreciated by conventional staging modalities was
      found in 31 cases. The preliminary experience with LUS suggests that its addition
      to standard laparoscopy increases the sensitivity and specificity of M1 screening
      as well as introducing T and N staging capabilities.

PMID- 8658219
TI  - Surgery for gastric cancer: the American view.
AB  - Gastric cancer has decreased significantly in incidence during the last half
      century in this country. Developments in surgery for gastric cancer have been
      slowed by the large percentage of patients presenting with advanced stages of the
      disease. In many ways, the combination and magnitude of these two characteristics
      pose a unique hurdle to progress in gastric cancer management in the United
      States. This review concentrates on current surgical issues, and offers a
      management approach that allows for continued progress in the pursuit of
      prolonging quality survival for patients with this disease.

PMID- 8658220
TI  - Surgical treatment for gastric cancer: the Japanese approach.
AB  - Present status of gastric cancer surgery in Japan and several new procedures are
      reviewed in this article. Japanese treatment results of this disease were
      significantly better than Western results even when stages were adjusted.
      Generally speaking, Japanese surgical procedures are more aggressive and
      meticulous compared with the Western approach, and these attitudes have produced
      the difference in survival. Particularly, systematic lymph node (LN) dissection
      is included as a standard procedure, and the adjacent organs are frequently
      resected when tumor invades them. The latest topics in surgery are the
      transdiaphragmatic approach for procedures in the mediastinum, para-aortic LN
      dissection, computer-assisted rational lymphadenectomy, LN imaging for complete
      dissection, removal of the peritoneum, and hyperthermo-chemotherapy for
      peritoneal carcinomatosis. Consideration of postoperative quality of life (QOL)
      is a new trend, and many interesting procedures have been proposed to maintain
      QOL, such as endoscopic mucosal resection and laparoscopic wedge resection for
      early cancer, pylorus-preserving gastric resection to reduce dumping syndrome,
      pancreas-preserving total gastrectomy to reduce fistula and postoperative
      diabetes.

PMID- 8658221
TI  - Adjuvant therapy of gastric cancer: the Japanese experience.
AB  - The 5-year survival rate of patients with advanced gastric cancer who undergo
      curative resection is gradually increasing and currently ranges between 67.1% to
      76.4% at the five major cancer centers in Japan. A belief that minimal residual
      disease has a high probability of being cured with adjuvant therapy prompted
      Japanese investigators to develop the D2 dissection with extended
      lymphadenectomy, more detailed pathologic staging, perioperative chemotherapy,
      and chemoimmunotherapy. This review focuses on comparative trials performed in
      Japan studying the use of adjuvant therapy with either chemotherapy alone or
      chemotherapy plus immunotherapy in the treatment of patients with curatively
      resected gastric carcinoma. Preoperative and intraperitoneal therapy also has
      been evaluated. At present, however, no chemotherapy has been shown to impact
      favorably on the survival of gastric cancer patients, whereas the biological
      response modifiers, PSK or OK-432, seem to add some benefit to chemotherapy in
      the adjuvant setting. Carefully designed randomized controlled trials with
      sufficient size which include a surgery-alone control arm are the only way to
      establish the efficacy of adjuvant therapy.

PMID- 8658222
TI  - Adjuvant and neoadjuvant therapy for gastric cancer.
AB  - In the United States and in Europe, curative resections are possible in only 50%
      to 60% of newly diagnosed gastric cancer patients chosen to undergo surgery. For
      patients with higher stage tumors (T3-N(any)M0, T34N(any)M0, stages II, IIIa or
      IIIb), even after resection of all gross disease with negative margins, the
      recurrence risk is high. In the absence of earlier diagnosis, there is a clear
      need to develop new innovative treatment strategies that will increase the
      potentially curative resection rate and decrease the risk of recurrence after
      operation. The major treatment strategy pursued during the last 20 to 30 years
      has been postoperative systemic therapy with or without associated regional
      radiation. In general, using the systemic treatment regimens available in the
      past, no major decrease in recurrence rate has been shown. The use of routine
      postoperative systemic chemotherapy remains unproven. Several new approaches are
      currently undergoing intense study, in addition to chemoradiation. One involves
      the use of preoperative (neoadjuvant) systemic chemotherapy. The goal of these
      treatment plans is to allow an early attack on systemic micrometastatic disease,
      and by downstaging the primary tumor to increase the percentage of patients able
      to undergo curative resection. Phase 11 studies performed to date indicate
      acceptable toxicity to multidrug regimens including cisplatin-fluorouracil,
      variants of the 5-fluorouracil, doxorubicin, high-dose methotrexate (FAMTX)
      regimen, or other cisplatin-containing combinations. No increase in operative
      morbidity or mortality has been found. Large-scale trials using neoadjuvant
      therapy are in the advanced planning stage. A second approach (used with or
      without neoadjuvant therapy) is treatment with intraperitoneal adjuvant
      chemotherapy given in the immediate postoperative period. This strategy is based
      on the failure pattern of resected gastric cancer with its high rate of
      peritoneal and hepatic metastasis. In addition to phase II trials, several small
      scale phase III studies have been completed. Although those which involve
      patients with known residual disease have, in general, been negative, studies in
      patients who were treated in the truly adjuvant setting (having undergone
      potentially curative resections with no residual disease) are more promising.
      Finally, chemoimmunotherapy has been extensively studied in trials in Japan and
      Korea. Thus, from the point of view of clinical practice, routine administration
      of intravenous postoperative chemotherapy has not yet shown clear evidence of
      benefit and the standard of care remains surgery alone. The most promising
      current approaches are neoadjuvant chemotherapy using newer combination regimens
      with or without postoperative intraperitoneal therapy, chemoimmunotherapy after
      surgery, and postoperative chemoradiation. National or international trials
      testing the hypothesis that these types of approaches are superior to expectant
      observation have a high priority. A large American intergroup trial is underway
      testing the concept of postoperative adjuvant chemoradiation. Additional trials
      involving preoperative and postoperative therapy are in the advanced planning
      stage.

PMID- 8658223
TI  - The role of radiation therapy in gastric cancer.
AB  - Radiation therapy has been used as an adjuvant, primary, and palliative treatment
      modality for gastric cancer. In the adjuvant setting, the role of postoperative
      radiation therapy plus chemotherapy is being examined in the phase III Intergroup
      trial 0116. Until the results of this trial are available, the standard treatment
      after a complete resection (with or without positive locoregional lymph nodes) is
      observation alone. In patients who are selected to receive adjuvant therapy,
      locoregional radiation to 45 Gy plus 5-fluorouracil (5-FU)-based chemotherapy is
      recommended. In patients with locally unresectable or residual disease,
      postoperative radiation therapy and 5-FU-based chemotherapy may decrease
      locoregional failure and improve survival. Intraoperative radiation therapy
      appears promising; however, it remains investigational. In the palliative
      setting, radiation therapy offers symptomatic relief in the majority of patients.

PMID- 8658225
TI  - Human rights and health within the dominant paradigm.

PMID- 8658226
TI  - A note on the relationship between ex ante and expected willingness to pay for
      health care.
AB  - It has been argued that the willingness to pay for health care services in
      contingent valuation studies should be assessed ex ante from an insurance
      perspective. It may however be easier to assess the willingness to pay among a
      group of patients in need of a specific treatment. This willingness to pay
      measure can be used to estimate the expected willingness to pay. This paper
      investigates the relationship between ex ante and expected willingness to pay. It
      is shown that expected willingness to pay is a lower bound for ex ante
      willingness to pay for a treatment that restores the individual to full health
      for an individual that is risk averse with respect to income. For a treatment
      that does not restore an individual to full health the expected willingness to
      pay is not necessarily a lower bound for the ex ante willingness to pay if the
      marginal utility of income increases with better health.

PMID- 8658227
TI  - Limitations of quantitative research in the study of structural adjustment.
AB  - Sociologists and, more recently, critical medical anthropologists have been
      arguing for a refocusing of the analysis of health and health care towards a
      perspective which considers the broader global political economy. In the context
      of the debt crisis and IMF/World Bank-inspired structural adjustment policies,
      the political economy theoretical perspective is becoming even more relevant in
      the analysis of health underdevelopment in many 'Third World' countries. This
      study focuses on the direct and indirect effects of the Jamaican debt crisis and
      structural adjustment programmes on health care services and health standards. In
      this paper it is argued that there are methodological problems using quantitative
      data when studying the effects of structural adjustment. In addition to providing
      a limited account of the effects, it is argued that the basic problem is a matter
      of the availability and reliability of the quantitative data in many 'Third
      World' countries. It is argued that some of these problems could be overcome by
      the application of qualitative micro-level analysis. This type of methodology is
      important to ascertain the effects of global processes at the grass roots level
      and to gain insights into what those working in the health sector are
      experiencing and what they perceive as the effects, if any, of structural
      adjustment policies. This has often been missing from the impersonal accounts
      offered by quantitative research on the subject to date.

PMID- 8658224
TI  - The treatment of advanced gastric cancer.
AB  - "Second generation" combination chemotherapy regimens were developed in the 1980s
      with high activity in locally advanced and metastatic disease. Among them were
      etoposide plus doxorubicin plus cisplatin (EAP), etoposide plus 5-fluorouracil
      plus leucovorin (ELF), continuous infusion of 5-fluorouracil plus cisplatin (FP)
      and high-dose methotrexate plus S-fluorouracil plus doxorubicin (FAMTX). In
      locally advanced disease a resectability rate of +/- 50% was reported with these
      protocols. FAMTX was felt to be superior to 5-fluorouracil, doxorubicin and
      mitomycin (FAM), which regimen had been considered "standard" treatment for many
      years. Randomized studies, however, did not reveal significant differences among
      various second generation regimens. Future studies should focus on innovative
      protocols in advanced disease, the role of neoadjuvant chemotherapy in clinically
      staged locally advanced disease, the role of local "consolidation treatment," ie,
      radiotherapy or intraperitoneal chemotherapy after primary chemotherapy plus
      resection, and preoperative and postoperative chemotherapy in operable disease.

PMID- 8658228
TI  - Cultural response to mental illness in Senegal: Reflections through patient
      companions--Part I. Methods and descriptive data.
AB  - Patient records from the Thiaroye mental hospital in Senegal were analyzed to see
      if the patterns of persons accompanying patients to the hospital could help
      portray the community's response to mental illness. A systematic sample of 935
      records of initial our-patient visits were examined. Patterns of patient
      companionship were found to strongly correlate with specific patient
      sociodemographic and clinical characteristics. Interpretation of these findings
      helped to clarify both prevailing attitudes toward the mentally ill and the
      social response and management of mental illness. This article presents the study
      setting, methods, patient sociodemographic and clinical characteristics, and
      characteristics of patient companions. The second article in this series examines
      the statistical associations of companion number, gender and kinship relationship
      with patient sociodemographic and clinical characteristics.

PMID- 8658230
TI  - Healing fictions': stories of choosing in the aftermath of the detection of fetal
      anomalies.
AB  - Between the cultural story of prenatal diagnosis emphasizing the expansion of
      choice and the countercultural story emphasizing the lack of choice are the
      individual stories of choosing told by expectant and new parents after learning
      of the existence of a fetal impairment. The results of a qualitative, descriptive
      study involving 40 interviews with 15 women and 12 of their partners suggest that
      they had often 'backed into', as opposed to having actively chosen or refused,
      prenatal testing. After learning of their babies' impairments, they constructed
      subtly different accounts of pregnancies continued or terminated that located the
      moral agency for effecting these pregnancy outcomes either in themselves or
      elsewhere. These emplotments of choice can be summarized as nature's choice,
      disowned choice, choice lost, close choice and choice found. The findings raise
      questions concerning which of these or other constructions of choice in the
      aftermath of positive fetal diagnosis are the most effective in promoting
      psychological recovery and optimum parent-infant interactions.

PMID- 8658229
TI  - Cultural response to mental illness in Senegal: reflections through patient
      companions--Part II. Statistical correlates.
AB  - Patient records from the Thiaroye Psychiatric Hospital in Senegal were studied to
      see if analysis of patterns of persons accompanying patients to the hospital
      could help to portray the community's response to mental illness. A systematic
      sample of 935 records of initial out-patients visits were examined. Patterns of
      patient companionship were found to strongly correlate with specific patient
      sociodemographic and clinical characteristics. Interpretation of these findings
      helped to clarify both prevailing attitudes toward the mentally ill and the
      social response and management of mental illness. The first article in this
      series presented the study setting, methods, sociodemographic and clinical
      characteristics of the patients, and characteristics of patient companions. The
      current article examines the statistical associations of companion number, gender
      and kinship relationship with patient sociodemographic and clinical
      characteristics.

PMID- 8658231
TI  - A cross-national study of quality of life factors associated with patterns of
      elderly disablement.
AB  - This study examines individual-level data of non-institutionalized elderly from
      Bahrain, Burma, DPR Korea, Egypt, Indonesia, Jordan, Sri Lanka, Thailand and
      Tunisia. The Grade of Membership multivariate procedure is used to determine
      profiles of disablement, based upon functional disability and depression items,
      and to examine socio-demographic and quality of life covariates associated with
      such profiles. The analysis yielded six profiles or types of disablement:
      functionally and emotionally healthy, functionally healthy with some depressive
      symptoms, some strength problems, severely depressed, mobility problems and
      functionally frail. The healthy profile had higher probabilities associated with
      males, whereas the very depressed, and those with physical strength limitations,
      and mobility problems were more likely to be female. There is a strong positive
      association between age and functional disabilities. The more depressed profiles,
      however, tended to be among the younger age categories, and the depressed had
      higher probabilities associated with being not married. The examination of
      quality of life covariates indicates that the functional and emotional
      limitations generally are correlated with a lower quality of life. The more
      functionally disabled and the depressed profiles had more negative self
      assessments of health and lower morale scores. The very depressed had less
      instrumental social support in terms of available kin. Also, the functionally and
      emotionally disabled profiles expressed less satisfaction of visits with family
      and friends. Country-specific patterns of elderly disablement indicate a possible
      disability transition such that as countries become more developed there may be
      an increase in the prevalence of disabled elderly. However, there are exceptions
      to this trend, and these may be due to both cultural factors and data
      limitations.

PMID- 8658232
TI  - The use of drug information sources by physicians: development of a data
      generating methodology.
AB  - The aim of this study was: (1) to develop and evaluate a methodology to determine
      hospital physician's use of personal drug information sources; (2) a preliminary
      insight into the use personal drug information sources. Written case simulations
      appeared to be the most appropriate method. To construct the written case
      simulations a step-wise procedure was developed. In the first stage 5 internists
      formulated 35 complex cases from their daily practice in which they consulted
      drug information sources; after an evaluation by experts 20 cases were left over.
      Next, using a written questionnaire, these 20 cases were evaluated in a random
      sample of 50 internists according to criteria concerning aspects of the process,
      the contents and the context. Finally, we analyzed these ratings using an
      elimination-by-aspects decision rule, with the dominant criterion 'need for
      consultation'. After this selection programme, two cases for each stage in the
      decision-making process of hospital physicians were selected which met the
      criteria. In general the colleague internist was the most frequently mentioned
      information source. Subspecialists and supporting specialists were considered
      less often and varied per stage in the decision-making process of physicians. The
      hospital pharmacist was hardly mentioned as a possible information source. The
      representatives of the pharmaceutical industry were not mentioned at all by the
      respondents.

PMID- 8658233
TI  - Medication decision-making and management: a client-centered model.
AB  - Although the traditional medical model dominates how 'provider-patient' roles are
      viewed, research has documented that client medication behavior strongly
      influences health outcomes, health care utilization, and ultimately health care
      costs. This paper explores the position that medication management outcomes can
      be improved by adopting more client-centered approaches. To examine the
      implications of a client-centered relationship this paper reviews research
      regarding client involvement in: (1) identifying treatment goals; (2) choosing
      from regimen options; (3) monitoring symptoms and evaluating regiments; and (4)
      self care with nonprescription pharmaceutical products. Based on this literature
      review, a collaborative client-centered model of medication consultation is
      examined, and implications for health care provider roles and public policy in
      pharmaceutical care are discussed.

PMID- 8658234
TI  - Areal and socioeconomic differentials in infant and child mortality in Cameroon.
AB  - Given its geographical, socio-economic, ethnic and cultural diversity, Cameroon
      offers an excellent setting for investigating the contribution of geographical
      and socioeconomic factors to mortality differences in infancy and childhood. Such
      research is crucial for designing appropriate health policies at the national and
      regional levels. Using data from a nationally representative sample of more than
      12,000 births, this study assesses infant and child mortality differences in
      Cameroon by residence area, mother's education, ethnicity, marital status and
      union type, religion and the interplay of those factors on differentials
      mortality. The most vulnerable groups of children in the country are: rural
      residents; residents of the East, North and South-West regions; Kaka-Baya and
      Fulbe-Fulani children; and children whose mothers have no education, are
      Traditionalists, are unmarried, or are in polygamous unions. Lack of maternal
      schooling alone explains all the excess childhood mortality of Fulbe-Fulani
      children, most of the excess mortality of children of the North and East regions,
      most of the excess mortality of the countryside vis-a-vis the metropolitan areas
      of Yaounde and Douala, and most of the excess mortality of children of
      Traditionalists. The robustness of the excess neonatal mortality of newborns in
      the East region probably reflects the higher prevalence of tetanus in that region
      compared to the rest of the country. The study also suggests that the
      place/region of residence in Cameroon is likely to be a proxy for inequalities in
      the provision of and/or use of health services.

PMID- 8658235
TI  - Innovations in acumoxa: acupuncture analgesia, scalp and ear acupuncture in the
      People's Republic of China.
AB  - This paper examines three 'innovations in acumoxa' (zhenjiu) that were
      promulgated by the Chinese government during the Maoist periods of the Great Leap
      Forward (1958-61) and the Cultural Revolution (1966-76): acupuncture analgesia
      (zhenjiu mazui), scalp acupuncture (touzhen) and ear acupuncture (erzhen). They
      all bear features of Chinese and Western medical practice, a characteristic which
      has been exploited in Chinese politics of health. On the one hand, the
      innovations have been promoted for the nationalistic reason in virtue of their
      being inherently Chinese. On the other hand, by equating Western medical practice
      with science, they signify modernity and progressiveness. In the late eighties,
      all still enjoyed official backing. Although they were no longer exclusively
      practised in government hospitals, they still stood for what they had originally
      been promulgated. Acupuncture analgesia, while no more practised in the clinic,
      is still the prototype of a Chinese scientific therapy, now subject to biomedical
      research in laboratories. Scalp acupuncture, which never became widely known as a
      modern Chinese-Western innovation, is still being practised exclusively by
      skilled doctors. Ear acupuncture is now practised also outside government
      institutions, for the same reasons of being easily applied, easily learnt and
      extremely economical as it had originally been promulgated. Paradoxically, ear
      acupuncture, the most popular of the three, was 'discovered' outside China, by a
      French doctor, and is founded on the principles of reflexology, a therapy that
      the biomedical establishment does not consider scientific.

PMID- 8658236
TI  - Importance of schistosomiasis in the Isoka district of Zambia: a prerequisite for
      its control using community participation.
AB  - The opinion has long been held that only by treating cases individually could
      diseases be controlled or eradicated. This view has been adopted from time
      immemorial and has failed miserably in, for instance, the control of
      schistosomiasis. This paper presents views of the head teachers on the prominence
      of schistosomiasis in the Isoka district, Zambia, as a step towards their
      involvement in a community mediated programme for the control of schistosomiasis.
      Information was sought on the importance of schistosomiasis in the district by
      means of two questionnaires, one distributed to head teachers, and the other to
      school children. Lack of clean water was considered to be the leading factor by
      71 (82.6%) teachers. Generally, schistosomiasis was not considered to be a
      prominent disease in the district. Nevertheless, teachers from highly infected
      areas ranked schistosomiasis as a health problem higher than those teachers from
      schools with lower prevalences (P = 0.002). The implications of these results to
      implementing a district wide schistosomiasis control programme covering both
      infected and uninfected areas are discussed.

PMID- 8658237
TI  - Acute respiratory infections--mothers' perceptions of etiology and treatment in
      south-western Nigeria.
AB  - The focus of this research was on what mothers do when their children suffer from
      ARI at household level in rural settlements in Oyo State, Nigeria. A total of 419
      mothers were interviewed. The study has combined three research methods, namely
      semi-structured questionnaire, in-depth interview and focus group discussion to
      get an insight into their perceptions in relation to cause and treatment of the
      disease. Most mothers regard ARI episodes as ordinary coughs and colds. They
      strongly believe that these are mostly caused by exposure to cold and perceive
      coldness of the body as a causal 'agent', whereas none of them mention viral or
      bacterial agents. The reported dominating practice of mothers was either the use
      of irritants to get rid of the cause of the disease ('coldness') through
      vomiting, by forcing the child to swallow bitter remedies such as cow urine, or
      to use a remedy with warming and soothing properties.'Robb', a methyl salicylate-
      probably the most popular Nigerian ointment-appeared to be the drug of choice to
      'warm the chest, both from outside and inside', either applied topically or
      dissolved in hot water to drink. The paper emphasizes the importance of
      behavioural and social science type studies to get closer to community
      perceptions of disease etiology and practices as a prerequisite for
      contextualized health education. The use of inappropriate administration of
      remedies should be discouraged. Marketing of medicinal drug products for
      inappropriate indications also needs to be controlled.

PMID- 8658238
TI  - Carbon monoxide suicide from car exhausts.
AB  - STUDY OBJECTIVE: the aim of the study was to analyse the victims and
      circumstances in carbon monoxide suicides from car exhausts in order to find
      strategies for mitigation of the suicide risk. DESIGN: necropsy, police and
      hospital records were scrutinized for 194 victims who committed suicide by carbon
      monoxide poisoning from car exhausts during a four-year period in Sweden. SETTING
      AND PARTICIPANTS: the State Institutes of Forensic Medicine in Umea and
      Stockholm. RESULTS: a higher incidence (24.2/million population) was seen in the
      rural region than in the urban region (14.9). Males dominated (88%), most of them
      middle aged. Most victims committed suicide in a car outdoors. A vacuum cleaner
      tube connected to the compartment was most commonly used. Severe disease, mostly
      psychiatric, was seen in 61% of the victims. Drugs were detected in 8% of the
      victims under psychiatric treatment. In 37%, earlier suicide behaviour was
      documented. Suicide notes were found in 40%. Blood alcohol was detected in 51% of
      the victims and other drugs in 7%. CONCLUSIONS: environmental changes may reduce
      the number of carbon monoxide suicide from car exhausts, e.g. introduction of a
      law requiring catalyst exhaust, of automatic idling stop, and of exhaust pipes
      incompatible with vacuum cleaner tubes. The importance of accurate treatment of
      psychiatric patients is stressed.

PMID- 8658239
TI  - Origins and working conditions of female sex workers in urban Thailand:
      consequences of social context for HIV transmission.
AB  - This paper examines the social origins and working conditions of selected female
      commercial sex workers in Thailand. Quantitative data gathered from 678
      commercial sex workers (CSWs) in low-price brothels, tea houses and other work
      sites in three urban centers were supplemented by focus group discussions and in
      depth interviews. The commercial sex establishments were selected from lists
      provided by local health officials. Social factors associated with entry into
      commercial sex work and condom use for sexual intercourse were investigated as
      they operate on contextual, intermediate and proximate levels. Women from the
      North region of Thailand predominated (68%) and they tended to be younger than
      the 27% from the Northeast. The majority of all women maintained financial ties
      to the home by sending income to parents, siblings and other relatives but this
      pattern is stronger among Northern women. Qualitative data suggest that women
      were systematically recruited into prostitution from villages in the North and
      their work enabled them to comply with traditional family support roles. Women
      from the Northeast revealed a more complex pattern of entry with intrafamily
      strife, divorce, efforts to find other employment, and entry into sex work at a
      later age than the women from the North. Northeastern women were more than twice
      as likely as Northern women to have had a husband as their first sex partner (55%
      vs 22%). The lives of CSWs were found to be tightly controlled by brothel owners
      and managers, although 8% were living with a husband or partner, and non
      commercial sexual relationships in the month prior to interview were reported by
      up to 23%. Data indicate need for even more intensive education on HIV
      transmission, especially with respect to risk of transmission in the absence of
      AIDS symptoms. Appearance and a trusting relationship were the common reasons
      given for not using condoms. With the most recent client, 92% reported use if the
      client was not known and 70% reported use if the client had visited the same CSW
      three or more times. Education on HIV must take these attitudes and motivations
      into account as well as sanctions for brothel owners who do not enforce condom
      use. The proportion of Thai men who visit brothels in addition to other sexual
      partners, high rates of HIV among CSWs, and inconsistent use of condoms create a
      complex web that accelerates the spread of the HIV epidemic in Thailand.

PMID- 8658240
TI  - Attitudes of pediatric nurses facing HIV risk.
AB  - The purpose of this study was to examine health related attitudes, including
      willingness to provide care, of health care professionals toward HIV-infected
      patients. To control for attitudes toward people who may have engaged in high
      risk behaviors for HIV infection, such as intravenous drug use or homosexual
      behavior, attitudes of pediatric nurses were studied since children with HIV
      almost never acquire the infection through these behaviors. The research
      population consisted of 517 pediatric nurses (46% response rate) from twenty
      states, the District of Columbia and Puerto Rico. The major findings were that
      those pediatric nurses with more experience caring for HIV-infected patients were
      more willing to care for these patients, and respondents reported more favorable
      attitudes after caring for people infected with HIV. Very few nurses would refuse
      to care for these children, although most acknowledged moderate fear of acquiring
      HIV from their patients. The level of experience caring for people with HIV was
      uncorrelated with reported likelihood of incidents of occupational HIV exposure
      risk. Greater occupational exposure risk was associated with less positive
      attitudes and less willingness to provide care. Implications of this study
      include that attitudes, including willingness to provide care, are more favorable
      with less suspected risk of infection and after more experience with such
      patients. In this study, where the sample of clients was adjusted to remove other
      biases, health caregivers were generally positive toward caring for HIV-infected
      patients.

PMID- 8658241
TI  - Radiologic and anatomic evaluation of the anterior sacral foramens and nerve
      grooves.
AB  - STUDY DESIGN: The present study evaluated the anterior sacral foramen using plain
      radiographs and projected the positions of S1-S3 anterior sacral foramen and
      corresponding nerve root groove on the posterior aspect of the sacrum.
      OBJECTIVES: To evaluate the plain radiographs of anteroposterior, inlet, and
      outlet views regarding the sacral foramen, and to determine quantitatively the
      location of the anterior sacral foramens on the posterior aspect of the sacrum.
      SUMMARY OF BACKGROUND DATA: Injury to the sacral nerve roots associated with
      posterior sacral screw placement remains a potential hazard. Few studies
      regarding the evaluation of the anterior sacral foramen and its projection on the
      posterior sacral surface are available. METHODS: Six bony pelves were harvested
      from preserved cadavers. The superior aspects of the sacral alae, the openings of
      the anterior and posterior foramens of S1-S2, were marked by outlining them with
      K-wires. Anteroposterior, inlet, and outlet plain radiographs were taken. The
      bony sacra were further disarticulated from the above six pelvic specimens. K
      wires were drilled through the sacra to project the dimensions of the anterior
      foramens and nerve grooves of S1-S3 onto the posterior sacral surface. The
      dimensions between the perimeter of the projection and the corresponding
      posterior foramen were measured. RESULTS: The plain radiographs show that the
      shape and relative position between the anterior and posterior foramens vary with
      different projections. It was believed that outlet projection is the best view of
      plain and radiographs in the evaluation of the sacral foramens and corresponding
      pedicles. The approximate boundaries of the anterior sacral foramens' projections
      were 6 mm superior, 10 mm lateral, 3 mm inferior, and 3 mm medial to the
      corresponding margins of the posterior foramens. CONCLUSIONS: The outlet
      projection is the most useful view in plain radiographs for the evaluation of
      sacral foramens and pedicles. Quantitative data of the anterior sacral foramen's
      anatomic position on the dorsal aspect of the sacrum may be helpful in the sacral
      pedicle screw placement.

PMID- 8658242
TI  - Ultrastructural changes in spinal nerve roots induced by autologous nucleus
      pulposus.
AB  - STUDY DESIGN: Ultrastructural changes were analyzed by transmission electron
      microscopy in nerve roots exposed to autologous nucleus pulposus experimentally.
      OBJECTIVES: To assess if ultrastructural changes were present in areas with no
      light microscopic changes in nerve roots exposed to autologous nucleus pulposus
      in a pig model. SUMMARY OF BACKGROUND DATA: Previous analyses have shown that
      there is focal nerve fiber damage in nerve roots exposed to autologous nucleus
      pulposus in the pig. These changes could not fully explain the reduction in nerve
      conduction velocity seen in the same nerve roots. In the present study, the parts
      of the nerve roots that did not display breakdown of axons or myelin sheaths at
      the light microscopic level were analyzed regarding ultrastructural changes.
      METHODS: In a previous study, nucleus pulposus was harvested from a lumbar disc
      and placed epidurally onto the cauda equina at the sacrococcygeal level in pigs.
      Retroperitoneal fat was used as control. After 1, 3, and 7 days, the nerve roots
      were excised and processed for light microscopy. Parts of the nerve roots that
      appeared normal at the light microscopic level were further processed for the
      present electron microscopic examination. RESULTS: Significant ultrastructural
      changes, such as expansion of the Schwann cell cytoplasm and intracellular edema
      with vesicular swelling of the Schmidt-Lanterman incisures, were observed in
      nerve fibers with normal axons. Although present after nucleus pulposus and
      control application, the changes were more pronounced after the application of
      nucleus pulposus. CONCLUSIONS: Epidural application of autologous nucleus
      pulposus without any pressure may induce not only nerve function impairment but
      also axonal injury and significant primary Schwann cell damage with vesicular
      swelling of Schmidt-Lanterman incisures. However, because axonal and Schwann cell
      changes affected only part of the nerve fibers, further causes of the impaired
      nerve conduction need to be determined.

PMID- 8658243
TI  - Transport properties of the human cartilage endplate in relation to its
      composition and calcification.
AB  - STUDY DESIGN: The transport properties of solutes of different sizes and
      conformations were studied in cartilage endplates. OBJECTIVES: The results were
      correlated with the composition of the cartilage matrix to determine if a
      relationship existed between this and the movement of molecules within it.
      SUMMARY OF BACKGROUND DATA: Solute transport through the hyaline cartilage
      endplate is important not only for the physiologic and metabolic processes of
      that tissue, but also for those of the adjacent intervertebral disc. Movement of
      solutes depends on solute size, shape or charges, and the composition of the
      matrix itself. Changes in composition of the cartilage endplate, such as those
      that occur in degeneration or scoliosis, may affect transport. METHODS: Partition
      and diffusion coefficients of solutes ranging in molecular weight from 115 to
      70,000 d have been measured on cores of cartilage endplate. Transport properties
      were assessed in relation to core composition. RESULTS: The shape and size of the
      solutes were found to affect their transport through cartilage matrix, with
      larger molecules being more highly excluded and diffusing more slowly. Long-chain
      polymers were able to penetrate the matrix less readily than the more globular
      molecules. The more hydrated the matrix, the higher the degree of penetration and
      the more easily solutes could move, in contrast to the inverse relationship
      between the other components of the matrix and solute transport. With increased
      proteoglycan, collagen, or calcification in the tissue, there was greater
      restriction of solute movement. CONCLUSIONS: The proteoglycans normally found in
      the endplate regulate movement of solutes into and out of the disc. It has been
      shown previously that removal of proteoglycans from the endplate accelerates the
      loss of proteoglycans from the nucleus. Hence, a major function of the cartilage
      endplate may be to prevent fragments of osmotically active proteoglycans from
      leaving the disc.

PMID- 8658244
TI  - The effect of substance P on proliferation and proteoglycan deposition of cells
      derived from rabbit intervertebral disc.
AB  - STUDY DESIGN: This study is an in vitro investigation of the effects of substance
      P on intervertebral disc cell metabolism. OBJECTIVES: To determine whether the
      neuropeptide, substance P, affects cells isolated from the intervertebral disc.
      SUMMARY OF THE BACKGROUND DATA: Nerve fibers containing substance P are present
      in the anulus fibrosus and may be released from the nerve terminals as in other
      tissues. Substance P is mitogenic for a variety of immune and connective tissue
      cells, and a fragment of the peptide affects the metabolism of articular
      chondrocytes. METHODS: Cells were isolated enzymically from the anulus fibrosus
      of intervertebral disc of 8-week-old rabbits. The effects of substance P and the
      C-terminal pentapeptide fragment SP7-11 on cell proliferation and proteoglycan
      deposition were determine by crystal violet and Alcian blue staining,
      respectively. RESULTS: Substance P ((10)-11-(10)-7 mol/l) had a small stimulatory
      effect on disc cell proliferation. Proteoglycan deposition in the cell layer
      increased concomitantly. A greater proliferative effect was observed with
      substance P fragment 7-11 or with the addition of the neutral endopeptidase
      inhibitor, phosphoramidon. CONCLUSIONS: Substance P has small mitogenic effects
      on rabbit intervertebral disc cells in vitro. Further investigation is required
      to establish whether this might have biologic relevance in relation to the
      maintenance or repair of the intervertebral disc.

PMID- 8658245
TI  - A biomechanical model of the lumbar spine during upright isometric flexion,
      extension, and lateral bending.
AB  - STUDY DESIGN: Task-specific and subject-specific lumbar trunk muscle function,
      muscle geometry, and vertebral density data were collected from 16 men. A
      biomechanical model was used to determine muscle strength and the compressive
      forces acting on the lumbar spine. OBJECTIVES: To develop an anatomic
      biomechanical model of the low back that could be used to derive task-specific
      muscle function parameters and to predict compressive forces acting on the low
      back. Several model-specific constraints were examined, including the notion of
      bilateral trunk muscle anatomic symmetry, the influence of muscle lines of
      action, and the use of density-derived vertebral strength for model validation.
      SUMMARY OF BACKGROUND DATA: Clinical and basic science investigators are
      currently using a battery of diverse biomechanical techniques to evaluate trunk
      muscle strength. Noteworthy is the large variability in muscle function
      parameters reported for different subjects and for different tasks. This
      information is used to calculate forces and moments acting on the low back, but
      limited data exist concerning the assessment of subject-specific, multiaxis,
      isometric trunk muscle functions. METHODS: A trunk dynamometer was used to
      measure maximum upright, isometric trunk moments in the sagittal (extension,
      flexion) and coronal (lateral flexion) planes. Task- and subject-specific trunk
      muscle strength or "gain" was determined from the measured trunk moments and
      magnetic resonance image-based muscle cross-sectional geometry. Model-predicted
      compressive forces obtained using muscle force and body force equilibrium
      equations were compared with density-derived estimates of compressive strength.
      RESULTS: Individual task-specific muscle gain values differed significantly
      between subjects and between each of the tasks they performed (extension >
      flexion > lateral flexion). Significant differences were found between left side
      and right side muscle areas, and the lines of action of the muscles deviated
      significantly from the vertical plane. Model-predicted lumbar compressive forces
      were 38% (lateral flexion) to 73% (extension) lower that the L3 vertebral
      compressive strength estimated from vertebral density. CONCLUSION: The present
      study suggests that biomechanical models of the low back should be based on task
      specific and subject-specific muscle function and precise geometry. Vertebral
      strength estimates based upon vertebral density appear to be useful for
      validation of model force predictions.

PMID- 8658246
TI  - Sustained loading generates stress concentrations in lumbar intervertebral discs.
AB  - STUDY DESIGN: Cadaveric motion segment experiment. Measurements on each specimen
      were compared before and after creep loading. OBJECTIVES: To show how sustained
      "creep" loading affects stress distributions inside intervertebral discs. SUMMARY
      OF BACKGROUND DATA: The central region of an intervertebral disc acts like a
      hydrostatic "cushion" between adjacent vertebrae. However, this property depends
      on the water content of the tissues and may be lost or diminished after creep.
      METHODS: Twenty-seven lumbar motion segments consisting of two vertebrae and the
      intervening disc and ligaments were loaded to simulate erect standing postures in
      life. The distribution of compressive stress in the disc matrix was measured by
      pulling a miniature pressure transducer through the disc in the midsagittal
      plane. Profiles of vertical and horizontal compressive stress were repeated after
      each specimen had been creep loaded in compression for 2-6 hours. RESULTS: Creep
      reduced the hydrostatic pressure in the nucleus by 13-36%. Compressive stresses
      in the anulus were little affected when the profiles were measured at 1 kN, but
      at 2 kN, localized peaks of compressive stress appeared (or grew in size) in the
      posterior anulus after creep. CONCLUSIONS: Increased loading of the apophysial
      joints causes an overall reduction in intradiscal stresses after creep. In
      addition, water loss from the nucleus causes a transfer of load from nucleus to
      anulus. Stress concentrations may lead to pain, structural disruption, and
      alterations in chondrocyte metabolism. Disc mechanics depend on loading history
      as well as applied load.

PMID- 8658247
TI  - Strength of fixation of anterior vertebral body screws.
AB  - STUDY DESIGN: The technique of hole preparation and the placement or orientation
      of anterior transvertebral screws in relation to the endplates were the subject
      of two experiments. OBJECTIVES: Experiment 1--to determine if anterior
      transvertebral body screws have higher pull-out strengths after unicortical
      predrilling compared with a bicortical predrilling; Experiment 2--to determine
      the effect of the screw's orientation in the vertebral body on its resistance to
      loosening. SUMMARY AND BACKGROUND DATA: There are a variety of surgical
      techniques for using anterior transvertebral screws in the vertebral body without
      any clear guidelines as to which techniques optimize the strength of fixation.
      METHODS: In experiment 1, 31 cadaveric vertebral bodies were tested for pull-out
      strength of transvertebral body screws placed after unicortical predrilling
      compared with bicortical predrilling. In experiment 2, 48 cadaveric vertebral
      bodies were tested with transvertebral screws inserted using four different screw
      orientations. RESULTS: There is no statistically significant difference in pull
      out strength of anterior transvertebral body screws inserted after unicortical
      compared with bicortical predrilling (Experiment 1). The resistance to loosening
      is greatest when transvertebral screws are oriented in the "superior oblique"
      position (Experiment 2). CONCLUSIONS: Experiment 1--preparation of the far cortex
      by predrilling is not necessary. Experiment 2--transvertebral screws should be
      obliquely oriented so that the forces applied to the screws are resisted by both
      of the endplates.

PMID- 8658248
TI  - The role of pediculolaminar fixation in compromised pedicle bone.
AB  - STUDY DESIGN: This in vitro study analyzed the effects of a supralaminar hook on
      pedicle screw fixation in compromised pedicle bone. OBJECTIVES: To determine the
      ability of pediculolaminar fixation to restore pedicle screw pull-out strength
      after stripping of senile pedicle bone. SUMMARY OF BACKGROUND DATA: Despite
      improvements in pedicle screw design, the bone-screw interface remains the
      "weakest link" in pedicle screw fixation. This interface is especially vulnerable
      in osteoporotic bone previously instrumented pedicles, and at the ends of long
      instrumentation constructs. METHODS: Side-to-side testing between a pedicle screw
      and a pedicle screw supplemented with a supralaminar hook (pediculolaminar
      fixation) was performed in human cadaveric lumbar vertebrae. Comparisons were
      made for intact and compromised pedicle bone. RESULTS: Pediculolaminar fixation
      restored 89% of intact pedicle screw pull-out strength whereas the pedicle screw
      alone restored only 19% of intact pull-out strength. The role of pediculolaminar
      fixation was greatest in weaker bone. Significant differences were noted in
      energy to failure and post-failure energy. In intact bone, the pediculolaminar
      construct did not increase pull-out strength or energy to failure, although it
      did have a greater post-failure energy. CONCLUSIONS: Pediculolaminar fixation can
      augment pedicle screw fixation in pedicle bone compromised by previous stripping
      or significant osteoporosis or both.

PMID- 8658250
TI  - Flexion failure of posterior cervical lateral mass screws. Influence of insertion
      technique and position.
AB  - STUDY DESIGN: The strength of posterior cervical lateral mass fixation was
      evaluated in a cadaver model for two techniques of screw insertion. OBJECTIVE: To
      compare the flexion failure strengths of posterior cervical plate fixation for
      two techniques of screw placement at the superior and inferior screw hole
      positions, and to evaluate the effect of bone mineral density on fixation
      strength. SUMMARY OF BACKGROUND DATA: Biomechanical analyses of various screw
      insertion techniques for posterior cervical lateral mass fixation have never
      evaluated the effect of screw position along the plate. METHODS: Individual C3-C6
      segments of 24 human cadaveric cervical spines were used. The spinous process and
      lamina were removed to simulate a postlaminectomy situation. Vertebral body bone
      mineral density for each specimen was determined by dual-energy radiograph
      absorption scanning. In each lateral mass, a bicortical 3.5-mm screw was placed
      using either the Magerl or Roy-Camille insertion technique through an end hole of
      a titanium bone plate. For "superior" screws, the plate was directed caudally;
      for "inferior" screws, the plate was directed cranially. Screw violation of the
      surrounding facet joint was noted. An increasing flexion moment was applied by
      loading the plate 4 cm from the screw head at a rate of 10 cm/min using a
      servohydraulic testing machine until screw failure. RESULTS: For the superior
      screw hole position, the Magerl screw sustained a significantly higher average
      moment to failure (190.2 Ncm) than the Roy-Camille screw (138.7 Ncm; P < 0.05).
      For the inferior screw hole position, there was no significant difference in
      flexion failure strength between the two techniques (Magerl screws, 287.7 Ncm;
      Roy-Camille screws, 308.2 Ncm). For each insertion technique, inferior screws
      were nearly twice as strong as superior screws (P < 0.01). Violation of the
      inferior articular process occurred with 53% of Roy-Camille screws and with none
      of the Magerl screws. Lateral mass fracture on screw insertion occurred with 6%
      of the Roy-Camille screws and with 7% of the Magerl screws. Significant
      correlation between screw path length and load to failure was found only at the
      superior screw hole position. Correlation with vertebral body bone mineral
      density was significant at both positions. CONCLUSIONS: The Magerl technique has
      advantages over the Roy-Camille technique for placing the end screws when
      performing posterior cervical lateral mass plate fixation, providing greater
      strength superiorly and not violating unfused facet joints inferiorly. Evaluation
      of bone mineral density by dual-energy radiographic absorption scanning is
      predictive of failure strength for both test modes.

PMID- 8658249
TI  - Tensile properties of nondegenerate human lumbar anulus fibrosus.
AB  - STUDY DESIGN: The in vitro tensile behavior of multiple-layer samples of anulus
      fibrosus were investigated from nondegenerate intervertebral discs. OBJECTIVES:
      To quantify the intrinsic tensile behavior of nondegenerate anulus fibrosus and
      the variations with position and age in the intervertebral disc. SUMMARY OF
      BACKGROUND DATA: Tension is an important loading mode in the anulus fibrosus. The
      tensile behavior of single- and multiple-layer samples of anulus fibrosus has
      been shown to vary with specimen orientation, position in the disc, and
      environmental conditions. Little is known of the changes in these site-specific
      tensile properties of the anulus with aging or degeneration of the intervertebral
      disc. METHODS: Multiple-layer specimens of anulus fibrosus were harvested with an
      orientation parallel to the circumference of the disc. Constant strain rate and
      uniaxial tensile tests were performed in 0.15 mol/l NaCl at slow strain rates to
      measure the intrinsic properties of the collagen-proteoglycan matrix of the
      anulus fibrosus. The tensile modulus, failure stress, failure strain, and strain
      energy density were determined. Statistical analyses were done to evaluate
      regional and age-related differences in these properties. RESULTS: Significant
      radial and circumferential variations in the intrinsic tensile properties of
      anular samples were detected. The anterior anulus fibrosus had larger values for
      tensile moduli and failure stresses than the posterolateral anulus. Also, the
      outer regions of the anulus had greater moduli and failure stresses and lower
      failure strains than the inner regions. Strain energy density did not vary
      significantly with region. Significant, but very weak, correlations were detected
      between tensile properties and age of the intervertebral disc. CONCLUSIONS: The
      observed variations in tensile behavior of multiple-layer anulus samples indicate
      that larger variations in tensile modulus and failure properties occur with
      radial position in the disc than from anterior to posterolateral regions. This
      pattern is likely related to site-specific variations in the tensile properties
      of the single-layer samples of anulus fibrosus lamellae and the organization of
      successive lamellae and their interactions. The results of the present study
      suggest that factors other than age, such as compositional and structural
      variations in the disc, are the most important determinants of tensile behavior
      of the anulus fibrosus.

PMID- 8658251
TI  - Restriction fragment length polymorphism of genes of the alpha 2(XI) collagen,
      bone morphogenetic protein-2, alkaline phosphatase, and tumor necrosis factor
      alpha among patients with ossification of posterior longitudinal ligament and
      controls from the Japanese population.
AB  - STUDY DESIGN: The present study analyzed the restriction fragment length
      polymorphism patterns of alpha 2(XI) collagen, bone morphogenetic protein-2,
      alkaline phosphatase, and tumor necrosis factor-alpha genes in patients with
      ossification of the posterior longitudinal ligament. This study investigates the
      genetic polymorphism of bone-induced factors in patients with ossification of the
      posterior longitudinal ligament and compares it with healthy control subjects.
      OBJECTIVES: To clarify the genetic markers linked to ossification of the
      posterior longitudinal ligament. SUMMARY OF BACKGROUND DATA: Ossification of the
      posterior longitudinal ligament is a genetic disease associated with abnormal
      calcium metabolism involving the posterior longitudinal ligament. Previous
      genetic studies have not identified the pathologic mechanism of ossification of
      the posterior longitudinal ligament. Histopathologic studies of ossification of
      the posterior longitudinal ligament and the animal model, the spinal hyperostotic
      mouse, have revealed an increase in Type XI collagen and bone morphogenetic
      protein-2 expression. METHODS: Eighteen Japanese patients with ossification of
      the posterior longitudinal ligament and 51 healthy, unrelated control subjects
      were investigated for the restriction fragment length polymorphism patterns of
      COL11A2, bone morphogenetic protein-2, alkaline phosphatase, and tumor necrosis
      factor-alpha, genes with various restriction endonucleases. RESULTS: The gene
      frequencies of COL11A2 obtained with BamHl (10.0 kb fragment) and HindIII (19.0
      kb fragment) observed in patients with ossification of the posterior longitudinal
      ligament were higher compared with control subjects (0.43 and 0.14,
      respectively). These differences were statistically significant (BamHl P = 0.018;
      Hindlll P = 0.046). Two new restriction fragment length polymorphism patterns
      were detected of the bone morphogenetic protein-2 gene with Mspl and Taql and one
      already known restriction fragment length polymorphism pattern of the tumor
      necrosis factor-alpha gene with Ncol. However, they were not significantly
      different from the control subjects. CONCLUSIONS: Seven restriction fragment
      length polymorphisms of COL11A2 gene were identified. Two of them (BamHl,
      10.0/10.0 kb genotype; HindIII, 19.0/19.0 kb genotype) were significantly
      different in patients with ossification of the posterior longitudinal ligament.

PMID- 8658252
TI  - A novel technique for laminoplasty augmentation of spinal canal area using
      titanium miniplate stabilization. A computerized morphometric analysis.
AB  - STUDY DESIGN: Titanium miniplates are used to secure the posterior elements in
      the open position after expansive open-door laminoplasty. Preoperative and
      postoperative spinal canal dimensions are measured to assess the effectiveness of
      this technique. OBJECTIVES: To develop a simple yet effective technique to
      stabilize the posterior elements after laminoplasty and to compare preoperative
      and postoperative spinal canal dimensions to accepted normal values. SUMMARY OF
      BACKGROUND DATA: Expansive open-door laminoplasty has been offered as a simple
      alternative to laminectomy, which has been associated with postoperative
      kyphosis. Although the technique of laminoplasty is effective, a simple and
      reliable method of holding the posterior elements open has not been described.
      METHODS: Ten myelopathic patients with multilevel cervical canal stenosis
      secondary to spondylosis or ossification of the posterior longitudinal ligament
      were treated with an expansive open-door laminoplasty. The posterior elements
      were stabilized in the open position with titanium miniplates. Computer-assisted
      morphometric analysis was performed on preoperative and postoperative computed
      tomography scans to obtain spinal canal dimensions. Plain radiographs were used
      to monitor construct integrity. RESULTS: The preoperative sagittal canal diameter
      was 8.2 +/- 0.96 mm, and the canal area was 180.6 +/- 33.7 mm2. These dimensions
      increased after surgery to 16.6 +/- 1.5 mm and 321.9 +/- 29.7 mm2, respectively.
      The titanium miniplate constructs did not fail during the follow-up period (mean,
      26.4 months), and the decompression was maintained. The single significant
      complication was transient C5 radiculopathy. CONCLUSIONS: Normal canal dimensions
      can be reestablished with open-door laminoplasty. Achieving and maintaining an
      increased sagittal canal diameter is probably the most important change in
      anatomic parameters to facilitate neurologic recovery. The use of titanium
      miniplates to stabilize the posterior elements after laminoplasty is a simple,
      durable, and effective technique to maintain the increased sagittal diameter of
      the spinal canal.

PMID- 8658253
TI  - Measurement of motor conduction in the thoracolumbar cord. A possible predictor
      of surgical outcome in cervical spondylotic myelopathy.
AB  - STUDY DESIGN: A prospective motor-evoked potential study with measurement of
      spinal cord motor conduction velocity in the thoracolumbar cord was performed
      before and after decompression surgery in 30 patients with cervical spondylotic
      myelopathy. OBJECTIVES: To evaluate the neurofunctional integrity of the spinal
      motor pathways in cervical spondylotic myelopathy in patients compared with age
      matched control subjects; to assess any changes after posterior surgical
      decompression; and to correlate such changes with functional outcomes so that the
      predictability of preoperative motor-evoked potentials could be determined.
      SUMMARY OF BACKGROUND DATA: Previous studies evaluating neurologic function and
      predictability of surgical results in cervical spondylotic myelopathy patients
      always depended on the morphologic changes of the cord and spinal structures. The
      recently developed motor-evoked potential study and noninvasive measurement of
      spinal cord motor conduction velocity may provided an objective method to
      evaluate physiologic motor function in cervical spondylotic myelopathy patients.
      METHODS: Spinal cord motor conduction velocity in the thoracolumbar cord was
      measured using percutaneous magnetic stimulation over the motor cortices and F
      wave studies in median and peroneal nerves. Motor function of cervical
      spondylotic myelopathy patients was graded according to evaluation of signs of
      cord involvement, ambulation, and degree of dependence in activities of daily
      living. Evaluation was performed at 6 months, 1 year, and 2 years after
      decompression surgery. RESULTS: Motor functional improvement accompanied by
      increased spinal cord motor conduction velocity occurred in Grade I patients with
      a mild neurologic dysfunction but not in Grade II or III patients with a moderate
      to serve neurologic deficit. Neurologic improvement does not appear to occur
      until 6 months after surgery. CONCLUSIONS: Measurement of spinal cord motor
      conduction velocity may provide an objective and quantitative approach to
      assessing the motor functional integrity of the spinal cord and serving as a
      predictor in evaluating surgical outcome in patients with cervical spondylotic
      myelopathy.

PMID- 8658254
TI  - Epidemiology of incident spinal fracture in a complete population.
AB  - STUDY DESIGN: Cross-section observational study of incident spinal fractures
      using an administrative data-base. OBJECTIVES: To identify and define all
      patients who have spinal fractures within a complete population. SUMMARY OF
      BACKGROUND DATA: The true incidence of spinal column and cord injury is not
      known. Previous studies have been institutional or practice based. Accurate
      information concerning the magnitude of the spinal injury population and their
      characteristics may provide more rational basis for public health decision making
      and resource allocation. METHODS: The study dates were April 1, 1981 to March 31,
      1984. Using the Manitoba Health Services Insurance Plan database, all patients
      with ICD-9-CM coding of 805.x and 806.x (spinal column fracture with and without
      spinal cord injury) were identified. Incidence rates, age and gender
      distribution, and ambulatory and hospital contracts were identified. Hospital
      discharge abstracts were used to classify mechanisms of injury, associated
      injuries, and length of stay. RESULT: The annual incidence rate of spinal
      fracture was 64 per 100,000. Two thousand sixty-three patients were identified,
      with 944 being admitted to the hospital. There were two peaks of incidence
      occurring in young men and elderly women. Of the hospitalized patients, 182 had
      cervical injury, 286 had thoracic fracture, and 403 had injury in the lumbosacral
      spine Associated injuries occurred in 38% of hospitalized patients. Length of
      stay was an average of 38.5 days. Overall mortality was 41%. Neurologic injury
      occurred in 122 patients. CONCLUSIONS: Ambulatory care of spine injuries is more
      common than hospital care. Two peaks of incidence occur-in young men and elderly
      women. Future decisions for research, public health policy, and resource
      allocation can be based on these data.

PMID- 8658255
TI  - Clinical characteristics of recurrent sciatica after lumbar discectomy.
AB  - STUDY DESIGN: A prospective and consecutive study with preoperative collection of
      data using a standard protocol for data processing. OBJECTIVES: The frequency of
      common symptoms and signs was determined in patients with recurrent disc
      herniation (n = 22), symptomatic postoperative epidural and periradicular
      fibrosis after a previous lumbar disc excision (n = 18) and compared with the
      same variables in primary disc herniation (n = 150). The ultimate diagnostic
      criterion was the finding at surgery. SUMMARY OF BACKGROUND DATA: Surgical
      treatment of recurrent sciatica after disc excision is rewarding in most cases of
      recurrent herniation but not in fibrosis and scarring. METHODS: Recorded were
      pain at rest, at night, and upon coughing. Three categories of analgesic use were
      collected: 1) none, 2) intermittent, and 3) regular. Walking capacity was
      determined as more than 5 km, 1-5 km, 0.5-1.0 km, or less than 0.5 km. the
      straight leg raising test was graded as positive 0 - 1.0 km, or less than 0.5 km.
      The straight leg raising test was graded as positive 0-30 degrees, positive 30-60
      degrees, positive more than 60 degrees, or negative. The results from a
      standardized neurologic examination were collected. RESULTS: Pain at rest and
      pain at night were equally common in all three patient groups, although pain upon
      coughing was more common in disc herniation (primary and recurrent) than in
      fibrosis, Severe reduction of walking capacity was reported more commonly by
      patients with dis herniation, whereas regular consumption of analgesics was
      reported most frequently by patients with fibrosis. CONCLUSION: The symptoms and
      signs profiles show differences that may be of interest in differential
      diagnostic considerations after previous lumbar disc surgery.

PMID- 8658256
TI  - Calcium pyrophosphate dihydrate crystal deposition disease as a cause of lumbar
      canal stenosis.
AB  - STUDY DESIGN: This study measured the incidence of calcium pyrophosphate
      dihydrate crystal deposition in specimens of ligamenta flava in consecutive
      patients undergoing decompressive laminectomy between 1984 and 1991. The results
      were compared to determine the difference between calcium pyrophosphate dihydrate
      negative patients with lumbar canal spinal stenosis. OBJECTIVES: The results were
      compared with cadaver specimens and literature values to determine if calcium
      pyrophosphate dihydrate crystal deposition disease contributes to the thickening
      of the ligamentum flavum and thereby contributes to spinal stenosis. SUMMARY OF
      BACKGROUND DATA: Calcium pyrophosphate dihydrate crystal deposition disease has
      been described in the axial skeleton. Hypertrophy of the ligamentum flavum has
      been suggested to contribute to stenosis. The association of calcium
      pyrophosphate dihydrate disease and hypertrophied ligamenta flava has not been
      fully defined nor linked to neurologic symptoms and signs. METHODS: The incidence
      of calcium pyrophosphate dihydrate crystal deposition in specimens of ligamenta
      flava obtained from four groups was measured: specimens obtained during surgery
      from 102 consecutive patients undergoing decompression laminectomy between 1984
      and 1991, 47 additional pathologic specimens of ligamentum flavum tested between
      1984 and 1991, 222 calcium pyrophosphate dihydrate-positive Pathology Department
      specimens collected between 1980 and 1991, and, as control specimens from 20
      cadavers. The associated patient histories were reviewed for the first two
      groups; no histories were available for the cadaver group. RESULTS: The incidence
      of calcium pyrophosphate dihydrate crystal deposition was 24.5% in the ligamentum
      flavum among the surgical patients, 31% among the Pathology Department specimens,
      33.8% among the calcium pyrophosphate dihydrate-positive Pathology Department
      specimens, and 5% among the cadavers. No associated medical conditions with
      calcium pyrophosphate dihydrate crystal deposition were found among the medical
      histories. Patients with the symptoms of spinal stenosis who were also calcium
      pyrophosphate dihydrate-negative patients with symptoms of less than 6 months'
      and less than 24 months' duration (P < 0.001). Except for time to presentation,
      calcium pyrophosphate dihydrate-negative patients had similar signs and symptoms
      of lumbar canal spinal stenosis. Having previous spine surgery did not produce a
      statistically significant risk of having calcium pyrophosphate dihydrate crystal
      deposition. No specific laboratory tests were found to be of predictive value.
      CONCLUSIONS: These findings suggest that calcium pyrophosphate dihydrate crystal
      deposition may indeed be associated with the thickening of the ligamentum flavum,
      if so, patients may benefit from medical treatment before undergoing surgical
      treatment of lumbar canal spinal stenosis.

PMID- 8658257
TI  - Spinal dural arteriovenous malformations. Intraoperative evoked potential
      evidence for pathophysiology. A case report.
AB  - STUDY DESIGN: This case report details intraoperative evoked potential changes
      during surgical removal of a T8 dural arteriovenous malformation. OBJECTIVES: The
      pattern of changes in somatosensory-evoked responses during surgical correction
      of spinal dural at arteriovenous malformation can illuminate the pathophysiologic
      process behind the clinical symptoms. SUMMARY OF BACKGROUND DATA: Arteriovenous
      malformation of the spinal dura can manifest with multiple symptoms, including
      progressive myelopathy and pain. The pathophysiologic process behind these
      symptoms could be either direct compression of the spinal cord by the
      arteriovenous malformation, ischemia resulting from the cord, or increased venous
      pressure. METHODS: To investigate these hypotheses further, the results of
      posterior tibial evoked potentials obtained during surgical removal of a T8 dural
      arteriovenous malformation were analyzed. RESULTS: At baseline, the cortical
      (P40) potential was markedly prolonged bilaterally. During surgery, just after
      the dura was opened, a marked increase was observed in the latencies of the P40
      and P60 components of the evoked response on the right, which began to resolve as
      soon as the arteriovenous malformation was occluded. Only minimal changes were
      seen on the left. CONCLUSIONS: These results are most consistent with the
      increased venous pressure hypothesis for the pathogenesis of neurologic symptoms
      in dural arteriovenous malformations.

PMID- 8658258
TI  - Osteochondroma of the upper cervical spine. A case report.
AB  - STUDY DESIGN: A report of a patient with osteochondroma of the upper cervical
      spine causing radiculopathy. OBJECTIVES: The surgical treatment of this patient
      involved the complete removal of tumor and compression of neural structures.
      SUMMARY OF BACKGROUND DATA: Osteochondromas affect mostly the long bones.
      Involvement of spine by solitary osteochondromas is rare condition. The present
      report represents a case of spinal osteochondroma causing neurologic symptoms.
      METHODS: Cervical osteochondromas, best evaluated with routine magnetic resonance
      imaging and noncontrast computed tomography scans, rarely contribute to cervical
      nerve root compression. RESULTS: The patient's symptoms gradually resolved after
      gross total tumor removal. CONCLUSIONS: Symptomatic spinal osteochondromas are
      rare occurrences in an individual surgeon's experience. Computed tomography or
      magnetic resonance imaging are the imaging procedures of choice. In the majority
      of patients with myelopathy or radiculopathy, surgery results in complete relief
      of symptoms as demonstrated in this case.

PMID- 8658259
TI  - Odontoid fracture and C1-C2 subluxation in psoriatic cervical
      spondyloarthropathy. A case report.
AB  - STUDY DESIGN: Case presentation and review of pertinent literature. OBJECTIVES:
      To present an unusual case and alert other physicians to possible missed
      diagnoses. SUMMARY OF BACKGROUND DATA: An unusual case is presented of a young
      man with server psoriatic spondyloarthropathy and fusion of C2-C7 (Type II
      cervical psoriatic ankylosing disease) who fell at home, sustaining an
      unrecognized fracture of the odontoid process leading to subluxation of C1-C2 and
      the transitory tetraplegia. The patient presented with torticollis, and the
      fracture was unrecognized for a long period of time. METHODS: Case presentation.
      RESULTS: This patient became independent in all activities of daily living after
      surgery and rehabilitation despite persistence of torticollis. CONCLUSIONS: A
      patient who presents clinically with traumatic torticollis after minor trauma and
      who also has psoriasis and ankylosis of the cervical spine should be suspected of
      having a fracture-subluxation until definitely proven otherwise. In the present
      case, the late diagnosis delayed surgical stabilization.

PMID- 8658260
TI  - Giant sacral schwannoma. A case report.
AB  - STUDY DESIGN: Case report. OBJECTIVES: To present a rare case of a previously
      operated giant schwannoma located in the sacrum, and to make some considerations
      regarding diagnostic modalities and treatment options. SUMMARY OF BACKGROUND
      DATA: Large sacral schwannomas with anterior cortex erosion and associated
      intrapelvic extension are uncommon. Only a few case reports and small series have
      been published. There is no established consensus regarding diagnostic
      modalities, necessity for histologic diagnosis before surgery, or best surgical
      option. METHODS: The patient presented with a 2-month history of right sciatica
      and severe low back pain. After a histopathologic diagnosis and a complete set of
      image studies, the resection of the tumoral mass was planned posteriorly.
      RESULTS: Seventeen months after tumor resection, the patient has a good clinical
      outcome, and there are no radiologic signs of instability or recurrence.
      CONCLUSIONS: Considering the experience of the few cases reported in the world
      literature, the management of this tumor appears to grant favorable results,
      recurrence being the most frequent complication.

PMID- 8658261
TI  - Studying low back pain (LBP)

PMID- 8658262
TI  - Marfan syndrome with back pain secondary to pedicular attenuation.

PMID- 8658263
TI  - Percutaneous intradiscal radio-frequency thermocoagulation.

PMID- 8658264
TI  - A randomized trial of exercise therapy in patients with acute low back pain-
      efficacy on sickness absence.

PMID- 8658265
TI  - [Possibilities of spiral-CT for diagnosis of focal liver lesions].

PMID- 8658266
TI  - [Possibilities for reducing radiation dosage in the heart catheterization
      laboratory].

PMID- 8658267
TI  - [Interesting differential diagnosis: pneumatosis cystoides intestinalis].

PMID- 8658268
TI  - [3-D multi-tissue reconstruction of petrous bone meningioma for preoperative
      craniotomy planning].

PMID- 8658269
TI  - [1995 literature review: diagnostic imaging of the liver].

PMID- 8658270
TI  - [Traumatic rupture of the greater pectoral muscle tendon].
AB  - The authors describe the case-history of a rare covered injury of the musculus
      pectoralis major, abruption of the attachment of its tendon on the humerus. In
      the world literature only three major groups were described, the majority of
      publications pertain only to individual observations. In the development of the
      injury always a very similar mechanism is involved, a considerable proportion are
      sports injuries. The injury is adequately defined from the diagnostic aspect, it
      may cause embarrassment because it is uncommon. As the loss of function is
      marked, surgical repair is considered the method of choice. The importance of
      early operation is emphasized. The described technique of reinsertion produced
      results satisfactory from the patient's point of view.

PMID- 8658271
TI  - [Desmoids: are there any new developments?].
AB  - In the submitted review of the literature the authors evaluate contemporary
      therapeutic possibilities of mesenterial desmoids. A more detailed pattern of
      cytotoxic and non-cytotoxic chemotherapy, actinotherapy and hormonal therapy is
      presented. Surgical resection is limited by the size of the tumour and above all
      by early detection before the size of 15 cm is reached. In larger tumours
      conservative treatment by a combination of non-cytotoxic and hormonal treatment
      is better. Actinotherapy of the intraabdominal region is not suitable. The
      percentage of relapses is high, a standard therapeutic procedure has not been
      elaborated so far. Despite rather surprising remissions of desmoids in individual
      cases the general results of different groups are not encouraging. In a case
      history the authors describe their experience with the treatment of a young
      female patient with a mesenterial desmoid which, however, was not successful.

PMID- 8658272
TI  - [Fluoroquinolones in antimicrobial therapy and prophylaxis in surgery].
AB  - The authors evaluate, based on laboratory and clinical experiments, the
      importance of quinolones in the antimicrobial prophylaxis and therapy in surgery.
      In the laboratory investigations they assessed the present state of resistance of
      some Gram-negative and Gram-positive bacteria to fluoroquinolones-pefloxacine,
      ofloxacine and ciprofloxacine. In the clinical part the authors made a
      comparative study of pefloxacine and a cephalosporin of the third generation,
      ceftazidime, in the treatment of nosocomial postoperative and posttraumatic
      inflammatory affestions of the lower airways in 20 patients in both groups. The
      patients were hospitalized at the intensive care unit in 1993-1994. The action of
      the two chemotherapeutic agents was comparable, in 18 patients of both groups the
      infections disappeared and regression of the inflammatory pulmonary affection was
      recorded.

PMID- 8658273
TI  - [Anatomic correction of transposition of the great arteries in the neonatal
      period].
AB  - In Cardiocentrum of the University Hospital in Prague-Motol in 1988-1994
      anatomical correction of transposition of the great arteries (arterial switch)
      was performed in 47 neonates aged 4 to 20 days. The aorta and pulmonary artery
      were transferred into the appropriate ventricle concurrently with reimplantation
      of the coronary arteries. The surgical technique was modified with regard to the
      anatomy of the coronary arteries and the presence of associated cardiac defects.
      Eleven of the 47 neonates (23%) died during the early postoperative period, one
      patient died two months after operation. Of the last 20 operated neonates only
      two died (10%) and both had an abnormal insertion of the coronary arteries.
      Thirty-five children are followed up for 2-45 months following anatomical
      correction. All are in a very good clinical condition without serious residual
      findings. The authors describe the protocol of the diagnostic and therapeutic
      procedure in transposition of the great arteries. They consider anatomical
      arterial correction in the neonatal period as the method of choice for this
      disease. The optimal age for anatomical correction in isolated transposition is
      between the 7th and 14th day and in transpositions with a major defect of the
      ventricular septum at the age of one month. The surgical results are steadily
      improving with accumulating experience. The medium-term results of anatomical
      correction of transposition of the great arteries are very favourable.

PMID- 8658274
TI  - [Treatment of cholecysto-choledocholithiasis in the present era of minimally
      invasive laparoscopic surgery].
AB  - The authors try to contribute to the solution of the problem of
      cholecystolithiasis associated with choledocholithiasis. Nowadays in the era when
      choledochilithiasis is treated by low-invasion methods the solution has a
      different character. The majority of gallstones is symptomatic, their
      verification and removal by the endoscopic route is not associated with major
      problems. Concrements not detected during the perioperative period and not
      detected by diagnostic methods may cause various postoperative difficulties. The
      authors' experience is based on 302 laparoscopic cholecystectomies performed in
      the course of 14 months. They made cholangiographic examinations in 54 of the
      operated patients. This number comprised 21 where the examination was made before
      the operation, 18 during the operation and in 5 it was made during the
      postoperative period. In 20 patients (37.03%) the cholangiographic finding was
      positive. Due to intensive collaboration with the endoscopic centre, when using
      the method of therapeutic splitting und per operative cholangiography in
      indicated cases, they were able to reduce the risk of missed concrements to
      0.33%.

PMID- 8658275
TI  - [Effects of the most frequently used solutions and ointments in routine surgical
      practice].
AB  - The authors tested the effect of local antiseptics commonly used at the Clinic of
      Plastic and Aesthetic Surgery in Brno on bacteria which most frequently infect
      extensive skin defects. The experiments were carried out in vitro and in vivo in
      a group of experimental animals. In vivo the effect on Staphylococcus aureus and
      Pseudomonas aeruginosa was investigated, in vitro also the effect on Proteus
      mirabilis. The authors found that 0.1% Persteril, Peru balsam, and Dermazine
      ung./Lek Co./exerted a very favourable effect on the tested microorganisms. A
      weaker effect was recorded after Vishnevsky balsam and 0.5% Rivanol. 0.5% gentian
      violet and 3% boricacid had no effect on P. aeruginosa, 0.05% permanganate and 2%
      Jodonal had no effect on staphylococci.

PMID- 8658276
TI  - [Video thoracoscopic splanchnicectomy in persistent epigastric pain].
AB  - For palliation of persisting pain caused by inoperable malignity in the
      epigastrium or chronic pancreatitis a number of surgical and non-surgical
      operations of the splanchnic nerves was elaborated. Abdominal and thoracic
      approaches are associated with technical difficulties and burden the patient;
      blocks by puncture are associated with risk. The optimal procedure appears to be
      videothoracoscopic left-sided splanchnicectomy, the authors performed this
      operation in nine patients (in seven on account of a malignant process, in two on
      account of chronic pancreatitis). In all immediate alleviation of pain occurred,
      in two later some pain reappeared. Based on the favourable experience, the
      authors recommend this minimal invasive procedure.

PMID- 8658277
TI  - [Ovarian teratoma (case report)].
AB  - Case-history of an accidentally detected teratoma, during X-ray examination
      because of back pain in a 44-year-old female patient. The teratoma contained a
      premolar and hair.

PMID- 8658278
TI  - [Anaphylactic reaction to protamine in cardiovascular surgery].
AB  - The authors describe a serious anaphylactic reaction after protamine
      administration and its successful control. In cardiovascular surgery protamine a
      basic peptide, is used as a matter of routine to eliminate the anticoagulation
      effect of heparin. The use of this drug is associated with a number of negative
      haemodynamic reactions, most of them not serious, the incidence of which varies
      from 0 to 100%. The incidence of serious reactions associated with a life
      threatening drop of the blood pressure is reported to be between 0.13% to 4%,
      depending whether a retrospective or prospective study is involved. The
      pathogenesis of this anaphylactic reaction is not quite clear. Prevention in
      patients with known risk factors is problematic. Treatment of the allergic
      reaction to protamine is still symptomatic. In the authors' patient the condition
      was coped with by administration of colloid solutions, adrenaline and solumedrol.

PMID- 8658279
TI  - [Venous aneurysms].
AB  - Venous aneurysms are a rare condition. It is an independent nosological unit
      which differs from varicosities by the following signs: it is not sex- or age
      linked, it is found also in children, it can affect any vein, it is found as a
      solitary lesion and is not associated with prolongation of the affected vein. The
      therapeutic approach is surgical extirpation. The most serious clinical
      manifestation can be pulmonary embolism. The author presents four of his own
      observations with localization on the external jugular vein, the v. cephalica
      antebrachii, the anterior tibial vein and v. dorsalis digiti manus.

PMID- 8658280
TI  - [Massive recurrent gastric hemorrhage caused by thrombosis of the splenic vein in
      chronic pancreatitis].

PMID- 8658281
TI  - [Prospective randomized comparison of the effects of pefloxacin and clindamycin
      with cefoxitin after hepatobiliary and pancreatic operations].
AB  - The authors present their experience from a prospective randomized study of
      therapeutic effects of a combination of pefloxacine (Abaktal) and klindamycin
      with cefoxitine in patients after hepatobiliary and pancreatic surgery. The
      therapeutic results in both investigated groups were evaluated in more than 95%
      patients as excellent, without statistically significant differences. The authors
      provided evidence of a comparable effectiveness of a combination of pefloxacine
      with klindamycin and the effectiveness of cefoxitine in patients after the above
      mentioned types of surgery, while treatment was cheaper when a combination of
      pefloxacine and klindamycin was used and moreover there was the possibility of
      oral administration of these preparations, as soon as the patients' condition
      made it possible.

PMID- 8658282
TI  - [Survival in patients after surgical closure of post-infarction rupture of the
      ventricular septum].
AB  - The authors discuss in the introduction hitherto reported data on the incidence
      and course of post-infarction ruptures of the interventricular septum and the
      results of conservative treatment. The high mortality rate after the conservative
      procedure led to attempts to resolve post-infarction ruptures of the
      interventricular septum surgically. The authors discuss in detail the indications
      for early and delayed operations has a decisive influence on the patients'
      survival. The authors had the opportunity to operate since 1978 till February
      1986 five patients with post-infarction perforation of the interventricular
      septum. Four of the patients were women, one was a man. The mean age of the
      operated patients was 61 years, the oldest patient was a 75-year-old man and the
      youngest a 46-year-old woman. During the last check-up in 1994 it was revealed
      that of five operated patients three had died. One of them three years after
      operation and two after seven years. One female patient survives for 13 years and
      one for 11 years. Both are in a satisfactory conditions.

PMID- 8658283
TI  - The Lichtenstein open "tension-free" mesh repair of inguinal hernias.
AB  - All standard methods of hernia repair involve suturing together tissues which are
      not normally in apposition. This violates the basic surgical principle that
      tissue must never be approximated under tension and thus accounts for an
      unacceptable number of failures. A total reinforcement of the inguinal floor with
      a sheet of suitable biomaterial and the employment of a "tension-free" technique
      is a more effective approach. Since June of 1984, 4,000 primary inguinal hernias
      have been repaired on an outpatient basis and under local anesthesia at the
      Lichtenstein Hernia Institute by the open "tension-free" technique using Marlex
      mesh. The patients were followed from one to 11 years (mean of 5 years) by
      physician examination. The follow-up rate was 87%. There were four recurrences.
      The causes of recurrence and how to avoid them are discussed herein. Three of the
      recurrences occurred at the public tubercle and were caused by placing the mesh
      in juxtaposition to the tubercle. This error has since been corrected by
      overlapping the mesh at the public bone. One recurrence was caused by disruption
      of the lower edge of the mesh from the shelving margin of Poupart's ligament. The
      error here was the utilization of a patch that was too narrow and therefore under
      tension. It became apparent that a wider patch, fixed in place with an
      appropriate degree of taxity, was required.

PMID- 8658284
TI  - [Removal of the kidney from a related transplant donor using subcostal
      lumbotomy].
AB  - Transplantation of the kidney from a live donor and transplantations to relatives
      account still for a not negligible percentage of all transplantations. Removal of
      the kidney from a healthy subject is a demanding and subtle operation. In recent
      years usually this procedure for transplantations to relatives is performed by
      subcostal lumbotomy. The authors analyze a group of eight patients, kidney
      donors, after operation. There were no serious surgical complications and
      therefore the authors will prefer this procedure also for future operations.

PMID- 8658286
TI  - Draft on organ transplants.

PMID- 8658285
TI  - [Reconstruction with intramedullary femoral nailing (a new implant made by Medin,
      A.S. for synthesis of concurrent fractures of the femoral shaft and neck-
      preliminary report)].
AB  - The authors discuss indications for the use of a femoral reconstruction nail
      synthesis of a diaphyseal fracture of the femur by an intramedullary nail with
      the necessity of concurrent treatment of cervical fracture or the necessity to
      safeguard by screws in the cervix a too short proximal fragment. The authors
      present short-term results obtained in a group of 13 clinical patients (followed
      up for 2-12 months, mean 6.6 months) who were operated using a Russel-Taylor
      reconstruction nail: 10 on account of a new fracture and the remaining three on
      account of complications of the original synthesis. The authors present the case
      histories of three patients. They also describe attempts to produce a
      reconstruction nail in the Czech Republic, the price of which would be accessible
      for our departments. They submit also one case-history of the first casualty
      treated using a Medin reconstruction nail.

PMID- 8658287
TI  - Adolescent tuberculosis.

PMID- 8658288
TI  - Compensation for disabilities.

PMID- 8658290
TI  - French nuclear testing and the prospects for 'global health'.

PMID- 8658289
TI  - The crisis in medicine -- a response.

PMID- 8658291
TI  - Assessment of alleged rape victims -- an unrewarding exercise.

PMID- 8658292
TI  - SASPREN -- a new development in family practice research in South Africa.
AB  - Research in the family practice setting can make unique contributions to our
      understanding of health, illness, and disease at the level of the individual
      patient as well as the population. In November 1990 a family practice research
      network (SASPREN) was established in South Africa. The network consists of
      sentinel practitioners who have volunteered to provide information on patients
      seen in their practices. This article describes the development of the network,
      focusing particularly on its accomplishments in the first 3 years. It is hoped
      that SASPREN will help overcome some of the obstacles to research encountered by
      family doctors and ultimately improve the care of patients in the community.

PMID- 8658293
TI  - The SASPREN primary care survey -- who consults the family doctor?
AB  - OBJECTIVE: To describe selected characteristics of patients consulting
      general/family practitioners in the Western Cape. DESIGN: A cross-sectional
      survey design was employed in which doctors completed a structured questionnaire
      during or immediately after each consultation. SETTING: Data were collected by
      family practitioners in private practice who were affiliated to the South African
      Sentinel Practitioner Research Network (SASPREN). PARTICIPANTS: All patients who
      had a face-to-face encounter with the doctor at his/her surgery. A total of 2 473
      such encounters was included. MAIN OUTCOME MEASURES: Age, sex, race, method of
      payment and smoking status. RESULTS: Females outnumbered males in all race groups
      except blacks, where they comprised 48% of patients. Most patients were under the
      age of 14 years (23.3%) or between 25 and 44 years (33.3%). However, after the
      demography of the catchment population was taken into account, the highest
      utilisation of general practitioner services was found to be at extremes of age.
      This utilisation pattern was demonstrated in both sexes and all races. In
      relation to their distribution in the population, whites and Indians are over
      represented in private practice while blacks and coloureds are under-represented.
      The bulk of patients (67%) pay for general practitioner services via some form of
      insurance (medical aid or benefit fund), but significant differences exist across
      race groups. In the case of blacks and Indians, the majority (72% and 64%
      respectively) of consultations are funded 'out of pocket'. An alarmingly high
      smoking prevalence was found in black and coloured men. In all race/sex groups
      smoking rates peak between 25 and 44 years. In this age group, 68.6% of black men
      and 73.3% of coloured men were current smokers. CONCLUSIONS: This study provides
      essential information on patients seen in family practice. Access to family
      doctor services in the Western Cape should be improved for blacks and coloureds.
      There is an urgent need for smoking cessation interventions in the region.

PMID- 8658294
TI  - National strategy for the prevention and management of transfusion-associated
      hepatitis.

PMID- 8658296
TI  - Is registrarship a different experience for women?
AB  - OBJECTIVE: To determine differences between male and female registrars in their
      subjective perceptions and experience of a paediatrics registrar training
      programme. DESIGN: Cross-sectional survey. SETTING: University-affiliated
      teaching hospitals. PARTICIPANTS: Thirty-nine paediatrics registrars. RESULTS: Of
      the 39 respondents, 18 (46%) were women. Men were older than women (30.4 v. 29.1
      years, P = 0.049). There were no gender differences in the number of hours worked
      per week (65.7 v. 67.8 hours, P = 0.384) or participation in the training
      programme. Success rates in postgraduate paediatrics examinations were also
      similar for the two groups (85% v. 76% P = 0.486). Male registrars were more
      likely to have 'moonlighted' (43% v. 6%, P = 0.011). Fifty-nine per cent of
      female registrars believed that they had been disadvantaged in their careers
      because of their gender, 28% felt that more was expected of a woman registrar and
      22% of the female trainees claimed to have been subjected to sexual harassment.
      The majority (82%) of women registrars contemplated taking time off from
      practising clinical paediatrics in the future (post-registrarship), mainly for
      child-bearing purposes. Female respondents criticised both the academic
      department and the hospital authorities for discriminatory practices, such as the
      awarding of home loans to men and women who were breadwinners only. The findings
      suggest that women registrars do feel disadvantaged and discriminated against,
      and highlight the need for flexible, creative programmes that recognise the needs
      and aspirations of female registrars and, indeed, all women in academic medicine.

PMID- 8658297
TI  - Limited private practice at academic hospitals -- an 'in-house' group practice.

PMID- 8658295
TI  - Is the use of recombinant human erythropoietin in anaemia of prematurity cost
      effective?
AB  - In a double-blind placebo-controlled study we showed a 3-fold decrease in blood
      transfusions (BTFs) given to preterm infants with anaemia of prematurity who
      received recombinant erythropoietin. However, only 50% of placebo recipients
      required a BTF. Data from the placebo group indicated that either mean daily
      weight gain < or = 7.5 g/day before study entry or haematocrit < or = 50% at
      birth was associated with BTFs (P < 0.001). We calculated that giving
      erythropoietin to patients in the treatment group with either of these variables
      prevented 24 of 28 BTFs and that it would cost R184 to prevent 1 BTF. The cost of
      each BTF was R187 (blood filtered to remove white cells and reduce
      cytomegalovirus transmission). Therefore, the costs of the two treatments were
      similar, but as the risk of transmitting infection is lower with erythropoietin,
      we recommend its use in selected preterm infants.

PMID- 8658298
TI  - Von Willebrand's disease in the Western Cape.
AB  - OBJECTIVE: To establish the prevalence of the various subtypes of Von
      Willebrand's disease (VWD) among patients with bleeding disorders in the Western
      Cape and to review appropriate treatment strategies. DESIGN: A systematic
      clinical and laboratory study. SETTING: Haemophilia clinics at two tertiary
      referral hospitals (Groote Schuur Hospital and Red Cross War Memorial Children's
      Hospital) in the Western Cape. PATIENTS: Twenty-two patients (14 females, 8
      males; ages 3 - 55 years) were studied. Those studied were selected for reasons
      of convenience, as they were compliant and regular attenders at the clinics. MAIN
      OUTCOME MEASURES: History of a bleeding tendency; bleeding time measurements;
      factor VIII assays, von Willebrand factor (VWF) antigen assays; ristocetin co
      factor assays and VWF multimer analysis. RESULTS: Fourteen patients had typical
      type I VWD; 2 had type II and 5 had type III variants, and there was 1
      unclassifiable variant. Analysis of local factor VIII concentrates showed the
      presence of high-molecular-weight VWF multimers. CONCLUSION: The results are
      similar to patterns reported elsewhere in the world. Locally produced factor VIII
      concentrates, unlike a number of commercially produced concentrates, contain
      sufficient multimers for use as appropriate replacement therapy.

PMID- 8658301
TI  - Tuberculosis control -- a new paradigm for South Africa.

PMID- 8658300
TI  - Growth hormone receptor deficiency (Laron syndrome) in black African siblings.
AB  - Non-Caucasians with growth hormone receptor (GHR) deficiency/Laron syndrome among
      the approximately 180 recognised cases are rare, and include a Japanese and 3
      African Americans. Black African siblings, a brother and a sister seen initially
      at 11 years 9 months and 5 years 6 months of age respectively were -7,4 and -8,0
      on the standard deviation score for height. They had characteristic features and
      biochemical findings including prominent forehead; depressed nasal bridge;
      central adiposity; high-pitched voices; micropenis; high GH levels and low levels
      of insulin-like growth factor (IGF)-I, IGF-II, insulin-like growth factor-binding
      protein 3 (IGFBP-3), and GH-binding protein (the solubilised extracellular domain
      of the GH cell surface receptor). Molecular genetic studies revealed a
      dinucleotide deletion in both siblings on exon 7 of the GHR gene, a mutation not
      found in any other GHR-deficient patient studied, including the North Americans
      of African origin. Since African Americans have a substantial admixture of
      Caucasian genes, it is of interest to document the presence of this condition in
      siblings from Africa.

PMID- 8658299
TI  - Management of premature rupture of the membranes after 34 weeks' gestation --
      early versus delayed induction of labour.
AB  - OBJECTIVE: To determine the optimal way to manage patients with premature rupture
      membranes after 34 weeks' gestation. DESIGN: A prospective, randomised controlled
      trial comparing immediate induction and delayed induction after 24 - 48 hours.
      SETTING: Tygerberg Hospital, Cape Town. PARTICIPANTS: Seventy consecutive
      patients with premature rupture of the membranes who presented at Tygerberg
      Hospital between July and October 1991. MAIN OUTCOME MEASURES: The two groups
      were compared with regard to infectious morbidity and antibiotic requirement in
      the mothers and babies, days spent in hospital, caesarean section rates, duration
      of labour and analgesic requirements. RESULTS: There was no difference between
      the two groups in terms of infectious morbidity in either the mothers or the
      babies, the duration of labour or the caesarean section rates. Nine patients
      (26%) in the delayed induction group required analgesic treatment during labour
      versus 18 patients (52%) in the group that was induced immediately (P = 0.049;
      odds ratio = 0.327; 95% confidence limits = 0.014 - 0.0998). In the delayed
      induction group, 74% of the patients went into spontaneous labour during the
      conservative management period. Patients in the active group (immediate
      induction) had a statistically significant better chance of being discharged
      within 48 hours of admission (P = 0.028; odds ratio = 3.34; 95% confidence limits
      = 1.12 -10.73). CONCLUSIONS: The management of patients with premature rupture of
      the membranes afer 34 weeks should be decided upon according to the level of
      antepartum and neonatal care which is available at the particular unit. Where
      there is adequate neonatal support and pressure on bed occupancy, immediate
      induction of labour should be considered, while peripheral units should consider
      conservative management before referral of patients.

PMID- 8658302
TI  - Regular reporting of tuberculosis in the SAMJ.

PMID- 8658303
TI  - Evaluation of the 'Japanese tool' for percutaneous vaccination with BCG in
      neonates.

PMID- 8658304
TI  - Pre-eclampsia and CVPs.

PMID- 8658305
TI  - Relative efficacy of hydrocortisone and methylprednisolone in acute severe
      asthma.

PMID- 8658307
TI  - Late stone-age coprolite reveals evidence of prehistoric parasitism.

PMID- 8658306
TI  - PAPNET automated screening.

PMID- 8658308
TI  - Identification and reporting of child sexual abuse -- a GP survey.

PMID- 8658309
TI  - Is your caesarean section necessary?

PMID- 8658310
TI  - The surgical cure of atrial flutter or fibrillation.

PMID- 8658311
TI  - Diet in ulcerative colitis -- is the jury still out?

PMID- 8658312
TI  - Breath testing for alcohol.

PMID- 8658313
TI  - Twin delivery after a caesarean section -- always a section?

PMID- 8658314
TI  - Increasing chloroquine resistance -- the Mpumalanga Lowveld story, 1990-1995.

PMID- 8658315
TI  - From a Bill to a Sir: Sir Raymond Hoffenberg. Interview by Ina van der Linde.

PMID- 8658316
TI  - Have we succeeded in reducing barriers to medical care for African and Hispanic
      Americans with disabilities?
AB  - There has been considerable progress in reducing barriers to care for African and
      Hispanics Americans. Yet current research indicates that overall African and
      Hispanic Americans are disproportionately encountering barriers to care.
      Unfortunately very little is known regarding the status of African and Hispanic
      Americans with disabilities. The purpose of this paper is to assess by using data
      from the 1987 National Medical Expenditure Survey (NMES), the degree of
      disability for African, Hispanic and Native Americans and the extent to which it
      is correlated with the use of services. The findings report that as in the case
      of other African and Hispanic Americans, African and Hispanic Americans with
      disabilities disproportionately encounter barriers to care. They are more likely
      than whites to lack insurance, a regular provider and less likely to see a doctor
      during the year. The implications of these findings for the care of persons with
      disabilities are discussed.

PMID- 8658317
TI  - Fewer black kidney donors: what's the problem?
AB  - This article describes a qualitative study which explored the factors that
      influence relatives' decisions about donating kidneys for transplantation within
      a specific minority culture, i.e., African-American, in the United States. The
      researchers interviewed caregiving relatives of End Stage Renal Disease patients
      to learn their ideas and feelings about donation and transplantation. Data
      analysis revealed six themes; each theme is presented with relevant social work
      activities.

PMID- 8658318
TI  - Exploring the relationship between purpose in life and African American
      adolescents' use of prenatal care services.
AB  - This article presents findings of a study that explored the relationship between
      purpose in life and African American adolescents' use of prenatal care services.
      The findings revealed no statistically significant relationship, thus suggesting
      that purpose in life may not be a crucial factor in determining whether African
      American adolescents use prenatal care services. The need to explore the
      influence of other variables on service use and the importance of considering
      such findings for appropriate health care and social work intervention are
      discussed.

PMID- 8658319
TI  - Perceived social support and adjustment to mastectomy in socioeconomically
      disadvantaged black women.
AB  - Breast cancer is the most common form of cancer among women and is the second
      leading cause of death of women in the United States. This study examined the
      relationship between perceptions of social support and adjustment to breast
      cancer for 100 socioeconomically disadvantaged black women and it explored the
      relationship between diverse demographic features as they influenced the breast
      cancer experience. Two groups of women were interviewed after their mastectomies:
      one group at three months and a second group at twelve months. Implications for
      social work intervention for socioeconomically disadvantaged women are explored.

PMID- 8658320
TI  - Development of a computer information management system.
AB  - The Department of Veterans Affairs, Social Work Service has designed, developed
      and implemented the Social Work Information Management System (SWIMS) which
      provides for both administrative and clinical reporting. The system is clinically
      based and includes an option for case recording. The social work staff, who will
      use the system, was integrally involved in all phases of planning. The processes
      of the design, development, testing and implementation are discussed.

PMID- 8658321
TI  - Computer integrated drug prevention: a new approach to teach lower socioeconomic
      5th and 6th grade Israeli children to say no to drugs.
AB  - Drug prevention education provides an important first line of defense against
      future drug use. Many drug prevention strategies have been developed which teach
      youngsters of all ages how to say no to drugs. Nevertheless, the problem of drug
      use and abuse continues to escalate, and younger children, particularly those
      undergoing harsh psychosocial stress (e.g., hunger, lack of housing, broken
      homes, family unemployment, etc.), are increasingly becoming a population at
      risk. In this paper, the authors describe an original drug prevention program
      that was developed in Israel aimed at teaching resiliency skills to 5th and 6th
      grade children growing up in a poverty stricken, urban community. The program,
      drawing on social learning theory, utilizes an attractive, cartoon illustrated,
      computer program combined with games, role-playing and group work techniques to
      prevent future drug use in preadolescent children.

PMID- 8658322
TI  - The influence of laparoscopy on lymphocyte subpopulations in the surgical
      patient.
AB  - BACKGROUND: Surgical stress is known to disturb the immune system so that the
      overall picture is one of generalized immunosuppression proportional to the
      degree of stress. It has been suggested that minimally invasive procedures, i.e.,
      laparoscopic cholecystectomy, should be accompanied by decreased surgical stress.
      METHODS: The present study utilized a panel of monoclonal antibodies to identify
      peripheral blood lymphocyte subpopulations in 11 patients scheduled for elective
      laparoscopic cholecystectomy. These were obtained immediately preoperatively, one
      day postoperatively, and one week postoperatively. RESULTS: The results
      demonstrated a significant (p < 0.05) decrease in T-helper to T-suppressor cell
      ratios the first day postoperatively compared to the preoperative ratios; the
      mean decrease was 13% below the preoperative ratios. There was no significant
      change in the ratios one week postoperatively. CONCLUSIONS: Even though
      laparoscopic cholecystectomy has been documented to have less disability and
      postoperative pain than open cholecystectomy, alterations in immune function,
      although attenuated, do persist.

PMID- 8658323
TI  - Gastrointestinal recovery following laparoscopic vs open colon surgery.
AB  - BACKGROUND: We prospectively studied the recovery of gastrointestinal motility in
      patients undergoing laparoscopic (LAP, n = 7) or open (OPEN, n = 7) colon
      resections. METHODS: At operation, bipolar recording electrodes were placed on
      the proximal and distal antrum, the proximal site of the colonic anastomosis, and
      the rectosigmoid for postoperative myoelectric recordings. RESULTS: Shorter
      postoperative hospitalization and earlier resumption of a regular diet of the LAP
      group just barely failed to achieve significant differences when compared with
      the OPEN group (p = 0.091, p = 0.050, respectively). There were no differences
      between groups for slow wave frequency, amplitude, or dysrhythmias in the antrum,
      nor for return of discrete (DERA) and continuous (CERA) electrical response
      activity in the colon. Percentage of slow waves with spike activity tended to
      increase with passage of time postoperatively in both groups. There was a
      significant difference between POD 3 and 7+ in the LAP group (p < 0.05). However,
      there were no significant differences in the percentage of slow waves with spike
      activities between groups on any postoperative day. CONCLUSIONS: The potential
      benefits of using a laparoscopic approach to colon resection are not clearly
      confirmed by these data. While such an approach may possibly result in shorter
      hospitalization, it appears to offer at best only modest increases in the
      rapidity of recovery of gastrointestinal function.

PMID- 8658324
TI  - Laparoscopic surgery in the rat. Beneficial effect on body weight and tumor take.
AB  - BACKGROUND: The ability of laparoscopic techniques to treat malignant disease is
      controversial. We developed a rat model to assess metabolic and oncological
      effects of laparoscopic surgery. METHODS: Experiment I. The postoperative body
      weight in 10 rats having laparoscopic bowel resection (group I), 10 rats having
      open bowel resection (group II) and 5 rats having anesthesia only (group III) was
      determined. Experiment II. Tumor take was scored in 11 rats having laparoscopic
      bowel resection (group IV), 11 rats having open bowel resection (group V), 6 rats
      having CO2 pneumoperitoneum without bowel resection (group VI) and 6 rats having
      anesthesia only (group VII). All rats had CC531 cancer cells injected
      intraperitoneally postoperatively. RESULTS: Experiment I. Body weight loss in
      group I compared to group II (p<0.036). Rats of group III lost no weight
      postoperatively. Experiment II. Tumor take was less in the subcutis (p=0.005),
      parietal peritoneum (p<0.001) and bowel anastomosis (p=0.021) in group IV
      compared to group V. Tumor take was significantly greater at all sites except for
      subcutis in group VI compared to VII (all p<0.022). CONCLUSIONS: Laparoscopic
      surgery is associated with less postoperative weight loss and less tumor take
      compared to open surgery. CO2 insufflation appears to increase tumor take.

PMID- 8658325
TI  - A randomized controlled trial of laparoscopic extraperitoneal hernia repair as a
      day surgical procedure.
AB  - BACKGROUND: A randomized controlled trial was conducted in a day surgery setting
      comparing a standardized variant of the Shouldice hernioplasty with
      extraperitoneal laparoscopic herniorrhaphy. METHODS: The laparoscopic repair was
      technically challenging, evidenced by conversion from extraperitoneal to
      transabdominal repairs in 6.25% of patients. It was free from the inherent
      dangers of intraperitoneal laparoscopy. Surgical morbidity was low and comparable
      to that for patients randomized to the open repair. RESULTS: Outcome following
      laparoscopic extraperitoneal herniorrhaphy varied depending on the parameter
      measured. It was comparable to the open repair with respect to postoperative
      activity levels and the number of days required for return to work but inferior
      to the open repair in terms of operation time and time to hospital discharge. The
      extraperitoneal approach was superior to the open repair with respect to
      postoperative pain levels and analgesic requirements. No attempt was made to
      compare recurrence rates due to the short follow-up period. CONCLUSIONS:
      Laparoscopic extraperitoneal herniorrhaphy should not supercede conventional
      hernia repair until subjected to further trials with the aid of larger study
      populations and greater technical expertise; the results of long-term recurrence
      rates are awaited.

PMID- 8658326
TI  - Tachocomb used in endoscopic surgery.
AB  - BACKGROUND: Diffuse bleeding from parenchymatous organs or bleeding of the lung
      both in conventional and endoscopic surgery has to this day been treated with the
      usual methods - coagulation, tamponade, or oversewing. METHODS: With the
      development by the pharmaceutical industry of a collagen fleece coated with
      fibrin glue (Tachocomb), an additional method of hemostasis became available.
      RESULTS: The positive results obtained with the fibrin-coated collagen fleece in
      conventional surgery encouraged us to employ it when performing endoscopic
      operations. Especially with laparoscopic cholecystectomies, but also in other
      endoscopic operations, the application of Tachocomb has proved very successful.
      Nevertheless, the method of applying Tachocomb was not adequate, and limited its
      use, which made it necessary for us to develop an application system for
      endoscopic use. CONCLUSIONS: The application system, which consists of a fan as
      the Tachocomb carrier and a mounting support, worked well during the first tests.
      In order to confirm this, clinical studies will now be carried out.

PMID- 8658327
TI  - The thoracoscope as diagnostic tool for solid mediastinal masses.
AB  - BACKGROUND: Despite the accuracy of percutaneous biopsy of mediastinal masses
      under CT scan or sonographic control, there is still a need for surgical biopsy
      because of difficult location or because of insufficiency of the percutaneous
      biopsy, especially for those tumors requiring an immunological classification.
      METHODS: The thoracoscopic approach to mediastinal masses is an alternative to
      the usual surgical biopsies performed through thoracotomy, sternotomy, or
      anterior mediastinotomy. The procedure is performed under general anesthesia and
      one-lung ventilation. RESULTS: In a series of 47 cases, a histological diagnosis
      was obtained in 44 cases (93.6%). There was one hemorrhagic complication
      requiring thoracotomy (2.1%). The mean postoperative duration of stay was 3.2
      days. CONCLUSIONS: Thoracoscopy is the method of choice in case of failure or
      contraindication of percutaneous biopsy. There is still a role for
      mediastinoscopy in treating paratracheal lymph nodes.

PMID- 8658328
TI  - Laparoscopic cholecystectomy in pregnancy. A safe option during the second
      trimester?
AB  - BACKGROUND: Laparoscopic cholecystectomy is now the standard treatment for
      symptomatic gallstones; while symptomatic gallstones during pregnancy are not
      frequent they are by no means rare. The role of laparoscopic cholecystectomy
      during pregnancy is controversial but initial reports suggest it is both safe and
      feasible. METHODS: During a consecutive series of 500 laparoscopic
      cholecystectomies, 3 patients have undergone laparoscopic cholecystectomy during
      pregnancy. The 3 patients were 16-27 weeks pregnant with an average age of 32
      years. The indication for laparoscopic cholecystectomy was severe pain in two
      patients and gallstone pancreatitis in one patient. Following standard obstetric
      anesthesia, laparoscopic cholecystectomy was performed. Open cannulation was used
      to establish peritoneal access, following which "standard," four-port
      laparoscopic cholecystectomy was performed without complication. The insufflation
      pressure used was 8-10 mmHg CO2 and a liver retractor was employed to facilitate
      access. RESULTS: In each case the postoperative recovery was rapid and uneventful
      for both mother and fetus. The patients were discharged on the first or second
      postoperative day. CONCLUSIONS: Laparoscopic cholecystectomy during the second
      trimester of pregnancy is both safe and feasible provided both suitable surgical
      and anesthetic expertise are available. Even up to the end of the second
      trimester there is sufficient access for the technique to be employed.

PMID- 8658329
TI  - Laparoscopic cholecystectomy during pregnancy. Review of anesthetic management,
      surgical considerations.
AB  - BACKGROUND: We present our experience with laparoscopic cholecystectomy in
      pregnant patients, with consideration of the physiological changes of pregnancy
      affecting anesthetic and surgical management. METHODS: We reviewed the medical
      records of all pregnant patients undergoing laparoscopic surgery at Brigham and
      Women's Hospital between January 1, 1991 and April 30, 1995. RESULTS:
      Laparoscopic cholecystectomy was performed without complication in ten patients
      (gestational age 9-30 weeks). Details of anesthetic and surgical management are
      described. The anesthetic and surgical implications of pregnancy-associated
      physiological changes in the gastrointestinal, respiratory, cardiovascular, and
      central nervous system are reviewed. CONCLUSIONS: With appropriate attention to
      the altered physiology of pregnancy, laparoscopic cholecystectomy can be
      performed safely and effectively during pregnancy.

PMID- 8658330
TI  - Laparoscopic cholecystectomy in the transplant population.
AB  - BACKGROUND: The results of laparoscopic cholecystectomy in a group of transplant
      recipients were reviewed to determine the safety and efficacy of the procedure in
      the setting of immunosuppression. METHODS: All solid-organ-transplant recipients
      who underwent laparoscopic cholecystectomy over a 3-year period were reviewed.
      Indication for operation, conversion to open procedure, length of stay, and
      complications were characterized. These results were compared to the registry
      data of all laparoscopic cholecystectomies performed at the same institution.
      RESULTS: There were 26 transplant patients who underwent laparoscopic
      cholecystectomy including renal, heart, double lung, and heart-lung recipients.
      The mean age was 47 years. Symptomatic cholelithiasis was the most common
      indication in 73% of patients followed by acute cholecystitis in 11%. Seven
      patients (27%) underwent conversion to an open procedure. Three patients (11.5%)
      experienced a minor complication in hospital. Median length of stay was 2.5 days.
      One patient died during a subsequent unrelated operation. These results compared
      favorably to the registry experience at the same institution where the mean age
      was 49 years, 24% of cases were performed for acute cholecystitis, there was a
      10% complication rate, median length of stay was 2 days, and 3 deaths occurred in
      hospital. The only statistically significant difference was a lower conversion
      rate (11% vs 27%) in the registry vs transplant group. CONCLUSIONS: This
      experience confirms that laparoscopic cholecystectomy is as safe in the
      transplant population as the general population. Despite a slightly higher
      conversion rate to an open procedure, the advantages of short hospital stay, low
      morbidity, and early return to preoperative routines remain equivalent.

PMID- 8658331
TI  - A cost comparison of disposable vs reusable instruments in laparoscopic
      cholecystectomy.
AB  - BACKGROUND: This paper compares the costs of disposable and reusable instruments
      in laparoscopic cholecystectomy. METHODS: The instrument set considered includes
      those instruments that are available in both a reusable and disposable form. A
      market study within the Belgian market was performed in order to compare purchase
      prices. In addition, costs of cleaning, sterilization, wrapping, maintenance,
      repair, and disposal of waste were calculated. The effects of reusables and
      disposables were examined by means of a literature overview. RESULTS: It was
      calculated that the instrument cost per procedure of a full disposable set is 7.4
      27.7 times higher than the cost per procedure with reusables. In comparison with
      disposables, modular systems ("semidisposable") and mixed use of disposables and
      reusables reduce costs, but still the cost per procedure remains higher than with
      reusables. A sensitivity analysis confirmed that these conclusions are robust to
      the model assumptions. In addition, the available evidence in the literature
      suggests that reusables do not compromise patient or staff safety. CONCLUSIONS:
      If reusables are used instead of disposables when performing a laparoscopic
      cholecystectomy, considerable savings can be achieved without compromising
      patient and staff safety.

PMID- 8658332
TI  - Laparoscopic treatment of known choledocholithiasis.
AB  - BACKGROUND: Occasionally patients present to the surgeon with known common duct
      stones. These will frequently have been detected by imaging modalities:
      ultrasound, computed tomography (CT) scans, transhepatic cholangiogram (THC) or
      IV cholangiography. Occasionally there are stones that had failed attempts at
      endoscopic retrieval (ERCP). METHODS: A retrospective analysis of a prospectively
      gathered database of 77 laparoscopic common bile duct explorations was done to
      assess the incidence, treatments and outcomes of patients who had known common
      duct stones (CDS) before surgery. RESULTS: Eighteen patients (23%) were
      identified as having a preoperative diagnosis of CDS. All underwent a
      laparoscopic common bile duct exploration. This exploration was successful in all
      cases. Outcomes were good with a 4% complication rate and one case of retained
      common duct stones (4%). CONCLUSIONS: Before laparoscopic cholecystectomy, known
      choledocholithiasis was considered a surgical disease except in cases of acute
      cholangitis or the very morbidly ill. The ability to perform cholecystectomy
      laparoscopically made many practitioners avoid open common duct exploration and,
      instead, rely on ERCP as primary treatment for known or suspected common duct
      stones. As techniques of laparoscopic common duct exploration improve, the
      ability to deal with common duct pathology surgically has increased, offering new
      options for treatment of this patient population. We present our experience with
      18 patients who presented with known choledocholithiasis and were treated
      laparoscopically with good results.

PMID- 8658333
TI  - Relation between postoperative infections and gallbladder bile leakage during
      laparoscopic cholecystectomies.
AB  - BACKGROUND: In 1,577 laparoscopic cholecystectomies, 111 due to acute and 1,466
      due to chronic cholecystitis, the incidence of intraoperative gallbladder rupture
      and its relationship with abdominal wound infections were evaluated. METHODS: A
      sampling test for binomial proportions and a binomial approximation test for
      discrete data were employed for statistical analysis. Gallbladder accidental
      opening took place in 250 (19%) out of the 1,466 chronic and in 44 (40%) out of
      the 111 acute cholecystitis, disclosing a statistically significant difference (p
      < 0.01). Postoperatively, there were 32 (2%) surgical wound infections, 17 (1.3%)
      in the absence of gallbladder injury and 15 (5%) when gallbladder injury was
      observed, likewise showing a statistically significant difference (p < 0.05).
      RESULTS: It should be pointed out that all 32 wound infections involved the
      umbilical incision, of which 3 with chronic suppuration required reintervention
      where remnants of stones were found in the parietal route. The seven with
      symptomatic abdominal fluid resolved without specific treatment. As regards the
      seven intraabdominal infections, two remitted with antibiotics and five required
      percutaneous drainage. There was no significant correlation between the presence
      of cavity fluid abdominal collections or infections and bile spillage.
      CONCLUSION: Gallbladder injury proved more frequent in laparoscopic
      cholecystectomies performed due to acute cholecystitis, while bile spillage
      increased the incidence of umbilical wound infection, particularly in the
      presence of remnants of stones, but there was no correlative increase in the
      incidence of intraabdominal collections or infections.

PMID- 8658334
TI  - Septic and other complications resulting from biliary stones placed in the
      abdominal cavity. Experimental study in rabbits.
AB  - BACKGROUND: The aim of this experimental study is to assess the consequences of
      biliary stones placed in the abdominal cavity of rabbits. METHODS: The animals
      were allocated to five groups. In group A a nonsterile gallstone was used. In
      group B animals with a nonsterile gallstone received preoperative
      chemoprophylaxis. In group C a sterile stone was placed in the abdomen. Group D
      served as control. In group E were animals with a nonsterile stone who had a
      prolonged follow-up period. Parameters studied postoperatively were temperature,
      white blood cell count, abscess formation, sepsis, peritonitis, adhesion
      formation, intestinal obstruction, and histological changes of the omentum
      enveloping the gallstones. RESULTS: There was no statistically significant
      difference among the five groups concerning morbidity, mortality, or histological
      findings. CONCLUSIONS: The prevalence of septic complications was higher among
      the four groups that received gallstones compared to the control group and thus
      an adverse effect of gallstone implantation can be suggested.

PMID- 8658335
TI  - Spermatic granuloma. An uncommon complication of the tension-free hernia repair.
AB  - A patient with a sperm granuloma following a tension-free hernia repair utilizing
      Marlex mesh 4 years prior to presentation is described. The mechanism of
      granuloma formation is believed to be secondary to vas deferens injury due to
      erosion by the cut edges of the mesh at the medial end of the slit used to
      recreate the internal inguinal ring. Spermatic granuloma has been rarely
      described in hernia surgery and requires a previous vas deferens injury. While
      the more common and clinically significant events of hernia recurrence and wound
      infection should be considered first, the occurrence of spermatic granuloma as a
      cause of postoperative pain or a mass should be included in the differential
      diagnosis.

PMID- 8658336
TI  - Laparoscopic resection of benign tumors of the posterior gastric wall.
AB  - Laparoscopic wedge excision of benign gastric tumors using stapling instruments
      alone is not feasible for distal lesions and some tumors arising from the
      posterior gastric wall. An alternative transgastric approach to distal posterior
      wall lesions utilizing an anterior gastrotomy for access has been successfully
      applied in two reported cases.

PMID- 8658337
TI  - Color Doppler ultrasound imaging of the eye and orbit.
AB  - Color Doppler imaging is a non-invasive ultrasound procedure which permits
      simultaneous gray scale imaging of structure and color-coded imaging of blood
      velocity. This improved technique allows the user to identify even very small
      blood vessels, such as those supplying the eye, from which measures of blood
      velocity and vascular resistance can be obtained. In the past five years, color
      Doppler imaging has found a number of applications in ophthalmology. A common
      examination procedure and expected normal values have been established, and the
      technique is becoming routinely employed to evaluate orbital vasculature in some
      medical centers. Color Doppler imaging has successfully demonstrated changes in
      orbital hemodynamics associated with a variety of pathological conditions,
      including central retinal artery and vein occlusions, cranial arteritis,
      nonarteritic ischemic optic neuropathy, and carotid disease. In addition, the
      method has been used to detect the vascularization of orbital and ocular tumors,
      as well as to investigate altered hemodynamics associated with diseases such as
      glaucoma and diabetic retinopathy.

PMID- 8658338
TI  - Spasm of the near reflex: a spectrum of anomalies.
AB  - Spasm of the near reflex has been characterized as the variable appearance of
      pseudomyopia, convergent strabismus and miosis. These characteristics may appear
      together or separately. In addition, abnormalities of accommodation may appear
      not only as pseudomyopia, but may also be manifest in cases with significant
      hypermetropia in which the patient is unable to relax accommodation even when
      plus lenses are used. The intent of this review is to identify the various
      clinical presentations of anomalies of the entire near reflex as well as the
      component parts. The relationship to functional and organic disorders are
      discussed as well as the related neuroanatomy. We suggest that one may more
      readily understand the clinical manifestations as a spectrum of anomalies of the
      near reflex rather than a multitude of disconnected entities.

PMID- 8658339
TI  - Harold Ridley and the invention of the intraocular lens.
AB  - On November 29, 1949, Harold Ridley implanted the first intraocular lens (IOL).
      This marked the beginning of a major change in the practice of ophthalmology and,
      for Ridley, the beginning of an era of inspiration, reward and challenge,
      unfortunately marred by the disdain and discourteous actions of many colleagues
      within the academic establishment in Europe and the United States. By the late
      1970s IOLs and implantation procedures had undergone many improvements, and
      Ridley's invention had become an accepted option for the optical correction of
      aphakia. Since that time Ridley has been accorded the recognition due him for his
      unique contribution to ophthalmology through the conferring of numerous awards
      and honors. This colorful biographical account is based on published history,
      statements from Ridley's colleagues, and recent interviews with Ridley himself.

PMID- 8658341
TI  - How to handle the pressure or too much of a good thing.
AB  - A 28-year-old non-obese woman with pseudotumor cerebri and minimal visual loss
      who underwent two optic nerve sheath decompression procedures. Different
      diagnosis and treatment options are discussed.

PMID- 8658340
TI  - Dermatologic diagnosis and treatment of itchy red eyelids.
AB  - Distinguishing the cause of itching, red eyelids is often difficult. Pruritic,
      inflamed eyelids can reflect various etiologies and are a common clinical
      presentation to the office of a dermatologist or ophthalmologist. In this
      article, five of the more common causes of eyelid dermatitis (atopic dermatitis,
      contact dermatitis, contact urticaria, rosacea, seborrhea, and psoriasis) are
      reviewed in detail, with particular emphasis on the ocular and periocular
      features. Clinical clues, historical features, and patch testing in cases of
      eczematous eyelid dermatitis aid in differential diagnosis. In addition,
      pathogenesis and treatment are reviewed.

PMID- 8658342
TI  - Negative MRI versus real disease.
AB  - A 76-year-old diabetic woman presented with progressive binocular vertical
      diplopia and right eye pain. Examination revealed a pupil-involving partial right
      third cranial nerve palsy, with development of anisocoria over the course of
      several hours. MRI of the brain showed no mass lesion. MRA, even with
      retrospective review of the images, failed to clearly identify a 1 cm right
      posterior communicating artery aneurysm detected by subsequent conventional
      cerebral angiography. While MRA has been reported to be highly sensitive in
      cerebral aneurysm detection at some centers, other investigators have indicated
      less favorable data. Standardized protocols for data acquisition and meticulous
      attention to proper post-processing and image interpretation are essential if MRA
      is to supplant invasive arteriography. Currently, conventional (x-ray)
      angiography remains the gold standard for aneurysm detection, while MRA possesses
      excellent potential in this regard.

PMID- 8658343
TI  - Cholesterol and cataracts.
AB  - Inherited defects in enzymes of cholesterol metabolism and use of drugs which
      inhibit lens cholesterol biosynthesis can be associated with cataracts in animals
      and man. The basis of this relationship apparently lies in the need of the lens
      to satisfy its sustained requirement for cholesterol by on-site synthesis, and
      impairing this synthesis can lead to alteration of lens membrane structure. Lens
      membrane contains the highest cholesterol content of any known membrane. The
      Smith-Lemli-Opitz syndrome, mevalonic aciduria, and cerebrotendinous
      xanthomatosis all involve mutations in enzymes of cholesterol metabolism, and
      affected patients can develop cataracts. Two established models of rodent
      cataracts are based on treatment with inhibitors of cholesterol biosynthesis. The
      long-term ocular safety of the very widely used vastatin class of
      hypocholesterolemic drugs is controversial. Some vastatins are potent inhibitors
      of cholesterol biosynthesis by animal lenses, can block cholesterol accumulation
      by these lenses and can produce cataracts in dogs. Whether these drugs inhibit
      cholesterol biosynthesis in human lenses at therapeutic doses is unknown. Results
      of clinical trials of 1-5 years duration in older patient populations indicate
      high ocular safety. However, considering the slow life-long growth of the lens
      and its continuing need for cholesterol, longterm safety of the vastatins should
      perhaps be viewed in units of 10 or 20 years, particularly with younger patients.

PMID- 8658344
TI  - Visual problems of the aging musician.
AB  - The presbyopic musician presents the ophthalmologist with an often demanding set
      of visual needs. Many modalities, some necessarily creative, are available to aid
      older musicians in their vision-dependent art.

PMID- 8658345
TI  - [Common basic knowledge. Interview by Klaus Reinhardt].

PMID- 8658346
TI  - [From the history of thrombosis prevention and treatment].
AB  - Rudolf Virchow described not only his famous triad in the 1840s but also the
      relationship between thrombosis and pulmonary embolism. Deep vein thrombosis
      (DVT) was recognized as postoperative complication from the 1890s. The preventive
      measures were directed against the factor blood stasis until heparin was applied
      clinically in the 1930s. The Swiss surgeon K. Lenggenhager was probably the first
      who recommended low dose heparin prophylaxis in 1940 on a rational experimental
      basis. Perhaps because his results were published only in German this application
      form became not popular before the great studies of Kakkar in the 70s took place.
      The introduction of low molecular weight heparins in the 80s simplifies
      prophylaxis and therapy of DVT again. The descriptions of deficiency of natural
      coagulation inhibitors start with antithrombin III in 1961. The recent discovery
      of the molecular basis of activated protein C resistance made history today.

PMID- 8658347
TI  - [Assessment of deep venous thrombosis].
AB  - Deep vein thrombosis (DVT) is a frequent disorder, which should not be missed
      diagnostically because of the associated morbidity and mortality due to pulmonary
      embolism and the postthrombotic syndrome. Clinical diagnosis is unreliable.
      Because of the possible risks a treatment by anticoagulation should not be
      undertaken without objective confirmation of DVT. Venography is generally
      considered as the gold standard for the diagnosis of DVT, but is invasive and
      associated with side effects. Noninvasive cw-Doppler ultrasound and the
      plethysmography are simple methods, but the accuracy is sufficient only for
      symptomatic proximal DVT and not for isolated DVT of the calf. In the past few
      years (color-coded) venous duplex imaging gained increasing importance. It is a
      noninvasive test with an accuracy comparable to that of venography. In addition
      to vascular changes perivascular structures can be investigated. B-mode
      compression sonography has a comparable accuracy for symptomatic proximal DVT.

PMID- 8658348
TI  - [Contribution of the hemostasis laboratory in the diagnosis of deep venous
      thrombosis].
AB  - Venography is still the gold standard for objective diagnosis of deep venous
      thrombosis (DVT). However, this investigation is costly and time-consuming,
      demands technical expertise and has potential side-effects. To reduce the number
      of phlebographies a simple, rapid and reliable screening test for exclusion of
      DVT would be greatly appreciated. In many studies markers of activated
      coagulation and fibrinolysis such as thrombin-antithrombin complex (TAT),
      prothrombin fragment 1 + 2 (F 1 + 2) and D-dimers, respectively, were
      investigated with respect to their potential use as screening tests. Especially D
      dimers as assessed by ELISA have turned out to have high sensitivity and negative
      predictive value for DVT and could therefore serve as screening test for
      exclusion of DVT. However, most of the easier, more rapid D-dimer Latex tests
      which would be better suited for emergency situations as well as the TAT- and F 1
      + 2-ELISA tests are according to most studies not sufficiently sensitive. In the
      present article the significance of the different activation markers in the
      diagnostic approach of DVT is discussed based on the literature.

PMID- 8658349
TI  - [Drug therapy of deep venous thrombosis].
AB  - The cornerstone of therapy of deep venous thrombosis (DVT) of the lower
      extremities is anticoagulation. Surgical thrombectomy and thrombolytic treatment
      are restricted to a small number of selected patients. Anticoagulation is started
      either with unfractionated heparin (continuous intravenous infusion or
      subcutaneous injection b.i.d.) with dose adjustments according to the partial
      thromboplastin time (PTT), or with subcutaneous injections of low-molecular
      weight heparin (LMWH) in one or two daily injections without laboratory
      monitoring. This initial treatment is rapidly followed and replaced by oral
      anticoagulants at an intensity corresponding to an International Normalized Ratio
      (I.N.R.) of 2-3 and for a duration of about 3 months after a first episode of
      proximal DVT. This duration should be modulated on an individual basis according
      to the risks of recurrent thromboembolism and hemorrhage.

PMID- 8658350
TI  - [Surgical treatment of deep venous thrombosis--indications, possibilities and
      limitations in venous thrombectomy].
AB  - Venous thrombectomy as a treatment of deep venous thrombosis is discussed
      extremely controversial. Occasionally, however, surgical technique, goal of the
      therapy, indications and limitations are not really known. Indication for
      surgical treatment is an extensive acute deep vein thrombosis with clinical
      symptoms of less than 7 days. Goal of the therapy is the preservation of valve
      function and prevention of a postphlebitic syndrome. Further indications are an
      embolizing venous thrombosis, a floating thrombus and an ischemic thrombosis. In
      these cases the single goal of the treatment is to reduce the individual risk of
      the patient. The best long term results can be achieved in young patients (below
      40 years of age) with no preexisting venous lesion and an acute iliofemoral
      thrombosis. Advantages, drawbacks and results of venous thrombectomy are
      discussed.

PMID- 8658351
TI  - [Sequelae of proximal venous stenosis].
AB  - We describe three typical consequences of chronic or subacute proximal vein
      obstruction: venous claudication, narrowing of the spinal canal by dilated veins
      that function as collaterals, and hypovolemia caused by trapping of blood in the
      periphery and slow return. Venous claudication is a well recognized clinical
      entity. We emphasize that the syndrome is often diagnosed in patients who do not
      remember acute thrombosis and that the signs on the skin of chronic venous
      insufficiency are typically absent in these patients. Venous drainage after
      proximal thrombosis often involves the veins of the spinal canal. Under the
      condition of sustained physical activity these veins become dilated and occupy
      space causing the syndrome of a narrow spinal canal. The clinical features differ
      from those encountered in other forms of a narrow spinal canal; the symptoms
      appear only after prolonged and strenuous exercise, do barely depend on the
      posture of the spine and do not disappear readily with cessation of the effort.
      In patients with bilateral pelvic vein occlusions we regularly found evidence for
      a shock-like syndrome that follows vigorous exercise. The patients experience
      sudden weakness and dizziness, with sweats, pallor and tachycardia and have to
      interrupt the effort to prevent collapse and fainting. The clinical features
      depend on the anatomical localisation of the obstruction as well as on the
      pathways of the collaterals. In patients with typical symptoms a venographic
      workup may be indicated to assess the possibility of recanalisation by
      endoluminal stenting. The presence of peripheral valve incompetence may be
      regarded as a contraindication to stenting since it may increase the volume
      overload and make the chronic venous insufficiency worse.

PMID- 8658352
TI  - [Color duplex ultrasonography in the diagnosis of deficient perforating veins in
      comparison to cw-Doppler ultrasonography and clinical examination].
AB  - The study was conducted to investigate the accuracy and agreement between
      clinical examination, cw-Doppler ultrasound and color-duplex sonography in
      diagnosing incompetent perforating veins. Nineteen patients with chronic venous
      insufficiency (CVI) were examined clinically, by hand-held cw-Doppler ultrasound
      in combination with tourniquet compression and color-coded duplex sonography CDS.
      The accuracy of the clinical examination and the diagnosis of ICPV by cw-Doppler
      were surprisingly low. The specificity was 15% and sensitivity 29%, when CDS was
      taken as gold standard. Furthermore the results show clearly that the application
      of a tourniquet cannot provide reliable results. It is concluded that in patients
      with CVI clinical and cw-Doppler examinations are not sufficient for an accurate
      diagnosis of incompetent perforating veins. Color-duplex provides a new
      noninvasive approach for accurate anatomical and functional diagnosis, which is
      of great importance prior to surgical interventions and/or sclerotherapy.

PMID- 8658353
TI  - [Ambulatory therapy in varicose veins].
AB  - The treatment of varicose veins comprises conservative and active options. Every
      patient with varices has to be informed on the conservative modalities and should
      apply them in daily life. Compression therapy, as the most important part of the
      conservative treatment, should be considered individually for any patient
      according to the varicose-type, the grade of chronic venous insufficiency and the
      compliance of the patient. Active treatment modalities are clearly indicated in
      varices with complications such as trophic skin changes, varicophlebitis or when
      varices cause pain. But the cosmetic problem should not be underestimated.
      Morphologic and hemodynamic information obtained by noninvasive duplex technique
      allows the individualization of the surgical strategy for each patient. Besides
      surgical techniques used being less and less traumatic (invagination stripping,
      stab evulsion phlebectomy), more and more interventions are realized under
      ambulatory conditions in local anesthesia, even crossectomy with partial
      stripping of truncal varices. More important and complex operations,
      interventions involving more than one saphenous vein or reinterventions in
      recurrent varices are still performed under hospital conditions. They require
      only a short hospitalization time (2 to 4 days). Considering this very favourable
      evolution in surgery with a net trend to ambulatory, thus more economic
      treatment, the indications for sclerotherapy--a traditionally ambulatory modality
      with high recurrence-rate--are limited to reticular varices and telangiectasies.

PMID- 8658354
TI  - [Treatment guidelines for venous leg ulcers: causal therapy initiation and local
      wound treatment].
AB  - Treatment of leg ulcers should consider two aspects, i.e. the exact underlying
      condition (main cause and contributing factors) and local conditions. Compression
      therapy remains the corner-stone of the therapeutic concept. A compression of 35
      mmHg at the distal calf improves insufficient venous function. A systolic ankle
      pressure of < or = 80% of blood pressure (ankle-arm-index < or = 0.8) requires
      reduction of compression therapy. At an ankle pressure below 80 mmHg compression
      should not be used. If superficial reflux is the major cause of chronic venous
      insufficiency, vein stripping should be considered. Contributing diseases like
      heart insufficiency, anemia or diabetes may require general medical care. Local
      contributing factors like reduced mobility of the ankle joint and lymphostasis
      may require physical therapy, and calcification of the wound bed should be
      excised. Local treatment considers ulcer bed and border. The ulcer bed needs
      debridement and moist wound care. Infection is treated with systemic antibiotics,
      according to the antibiogram. Tetanus immunization is required for all leg ulcer
      patients. Some centers report good results with endoscopic subfascial decision of
      perforator veins, paratibial fasciotomy and excision of fibrous tissue. Local
      application of recombined growth factors is currently under clinical evaluation.
      Adjuvant pharmacotherapy plays a minor role in the treatment of venous leg
      ulcers. An efficient treatment of the underlying cause combined with optimal
      wound care are the key to therapeutic success.

PMID- 8658355
TI  - Continuous volume computed tomography in pulmonary embolism: the answer, or just
      another test?

PMID- 8658356
TI  - Pleural non-Hodgkin's lymphoma arising in a patient with a chronic pyothorax.
AB  - A 69 year old man with a chronic left pyothorax was treated by decortication.
      Although the treatment rapidly improved respiratory function, histopathological
      examination revealed a diffuse large B cell non-Hodgkin's lymphoma. Subsequent
      bone marrow biopsy samples disclosed bone marrow involvement. It is possible that
      non-Hodgkin's lymphoma may develop from a chronic pyothorax.

PMID- 8658357
TI  - A malignant pleural effusion infected with Salmonella enteritidis.
AB  - A patient is described with a unilateral pleural effusion persistently infected
      with Salmonella enteritidis. The infection was eventually eradicated with
      ciprofloxacin. A computed tomographic scan and mediastinal lymph node biopsy
      demonstrated an underlying small cell bronchogenic carcinoma.

PMID- 8658358
TI  - Pleural effusion and toxocariasis.
AB  - The case history is described of a woman who presented with bilateral pleural
      effusions caused by Toxocara canis infestation. The condition responded rapidly
      to treatment.

PMID- 8658359
TI  - Commentary: pleural empyema and malignancy--another dimension.

PMID- 8658360
TI  - Myasthenia gravis presenting with stridor.
AB  - The case is described of a 72 year old woman who presented with a two year
      history of exertional stridor in whom the diagnosis of myasthenia gravis was
      delayed. Although an uncommon cause, myasthenia gravis should be included in the
      differential diagnosis of stridor.

PMID- 8658361
TI  - Salmeterol in smokers with COPD.

PMID- 8658362
TI  - Air pollution: brown skies research.
AB  - Direct information on the health effects of air pollution in humans relies mainly
      on chamber studies and epidemiological studies. Although chamber studies have
      limitations they allow the acute effects of individual pollutants to be studied
      in well characterised subjects under controlled conditions. Most chamber studies
      have shown relatively small falls in lung function and relatively small increases
      in bronchial reactivity at the concentrations of ozone, SO2, and NO2 that occur
      even during high pollution episodes in the UK. The possible exception is SO2
      where sensitive asthmatic patients may show a greater response at concentrations
      that are seen from time to time in certain areas and in proximity to power
      stations. There is no convincing evidence of potentiation between pollutants in
      chamber studies. Epidemiological studies are more difficult to carry out and
      require considerable epidemiological and statistical expertise to deal with the
      main problem-confounding by other factors. Although the health effects seen with
      current levels of pollution are small compared with those seen in the 1950s and
      close to the limits of detection, this should not be interpreted as being
      unimportant. A small effect may have large consequences when the population
      exposed is large (the whole population in this case). Recent data suggest that
      particles have more important health effects than the pollutant gases that have
      been studied. Much of this information comes from the USA though the findings are
      probably applicable in the UK. More information is needed on the size of the
      health effects that occur during the three types of air pollution episodes seen
      in this country and the relative contributions of particles, pollutant gases,
      pollen, and other factors such as temperature. Research into air pollution
      declined in the UK following the introduction of the Clean Air Acts; it is now
      increasing again following pressure from certain individuals and ginger groups,
      including the British Lung Foundation, and its potential importance is recognised
      by the Department of Health. This article has concentrated on the acute effects
      of air pollution episodes, though the long term effects of acute episodes of air
      pollution and chronic high levels of pollutants is equally, if not more,
      important. Roger Altounyan had severe chest-disease attributed to asthma and
      personal pollution (cigarette smoke). But did the smog episodes in Manchester in
      the 1950s or subsequent vehicle related pollution play a part and did they
      interact with the bronchial challenges he underwent over the years (estimated at
      3000)? Air pollution is a product of the way that society chooses to live.
      Obtaining an accurate picture of the extent to which current levels of air
      pollution cause acute and chronic effects on health is important if sensible
      choices are to be made by individuals and society about the processes
      contributing to air pollution. It is also important for patients with or at risk
      of developing cardiorespiratory disease.

PMID- 8658363
TI  - Role of spiral volumetric computed tomographic scanning in the assessment of
      patients with clinical suspicion of pulmonary embolism and an abnormal
      ventilation/perfusion lung scan.
AB  - BACKGROUND: A study was carried out to evaluate the potential place of spiral
      volumetric computed tomography (SVCT) in the diagnostic strategy for pulmonary
      embolism. METHODS: In a prospective study 249 patients with clinical suspicion of
      pulmonary embolism were evaluated with various imaging techniques. In all
      patients a ventilation/perfusion (V/Q) scan was performed. Seventy seven patients
      with an abnormal V/Q scan underwent SVCT. Pulmonary angiography was then
      performed in all 42 patients with a non-diagnostic V/Q scan and in three patients
      with a high probability V/Q scan without emboli on the SVCT scan. Patients with
      an abnormal perfusion scan also underwent ultrasonography of the legs for the
      detection of deep vein thrombosis. RESULTS: One hundred and seventy two patients
      (69%) had a normal V/Q scan. Forty two patients (17%) had a non-diagnostic V/Q
      scan, and in five of these patients pulmonary emboli were found both by SVCT and
      pulmonary angiography. In one patient, although SVCT showed no emboli, the
      angiogram was positive for pulmonary embolism. In one of the 42 patients the SVCT
      scan showed an embolus which was not confirmed by pulmonary angiography. The
      other 35 patients showed no sign of emboli. Thirty five patients (14%) had a high
      probability V/Q scan, and in 32 patients emboli were seen on SVCT images. Two
      patients had both a negative SVCT scan and a negative pulmonary angiogram. In one
      who had an inconclusive SVCT scan pulmonary angiography was positive. The
      sensitivity for pulmonary embolism was 95% and the specificity 97%; the positive
      and negative predicted values of SVCT were 97% and 97%, respectively.
      CONCLUSIONS: SVCT is a relatively noninvasive test for pulmonary embolism which
      is both sensitive and specific and which may serve as an alternative to
      ventilation scintigraphy and possibly to pulmonary angiography in the diagnostic
      strategy for pulmonary embolism.

PMID- 8658364
TI  - Compliance with treatment in adult patients with cystic fibrosis.
AB  - BACKGROUND: Patients with chronic disease comply with about 50% of their
      treatment. The complex and time consuming daily drug regimens needed in the care
      of adult patients with cystic fibrosis encourage non-compliance with prescribed
      treatments. Understanding the reasons for, and the extent of, non-compliance is
      essential for a realistic appraisal of the patient's condition and sensible
      planning of future treatment programmes. METHODS: Patients were invited to
      complete a questionnaire which asked about their compliance with daily treatment.
      The data were used to calculate a compliance score, the percentage of prescribed
      treatment taken, and to examine patient attitudes to each individual
      prescription. An assessment score derived from consultant, cystic fibrosis
      research fellow, specialist nurse, and physiotherapist ratings of patient
      compliance was compared with the compliance score. Both scores were correlated
      with patient characteristics and disease severity, and the compliance score was
      also correlated with the patient's knowledge of cystic fibrosis. RESULTS: More
      than half the patients claimed to take more than 80% of their treatments.
      Compliance with individual treatments varied according to their perceived
      unpleasantness and degree of infringement on daily activities. The most common
      reason given for omitting treatment was forgetfulness. Professional carers were
      poor judges of patient compliance. There was no correlation between compliance
      and patients' sociodemographic characteristics or their knowledge about cystic
      fibrosis. CONCLUSIONS: Non-compliance is universal and should be recognised as
      normal behaviour. There are no reliable criteria for predicting any patient's
      level of compliance. Treatment protocols should be planned around individual
      patient's requirements, modifying treatment ideals where necessary according to
      the exigency and pattern of that patient's lifestyle.

PMID- 8658365
TI  - Candidate gene loci in asthmatic and allergic inflammation.
AB  - New techniques for scanning the human genome promise great advances in tracking
      the origins of disorders caused by multiple genes. However, it is clear from the
      studies presented in this overview that we are far from understanding the genetic
      basis of asthma and atopy and their interaction with the environment. It is also
      clear that agreement must be reached on definition of the phenotype and methods
      of ascertainment in order to carry out large multicentre collaborative studies.
      Positive findings need to be validated in different populations selected for the
      presence of the disease and then confirmed in a random population where the
      prevalence of asthma and atopy will also be expected to be significant.

PMID- 8658366
TI  - Knowledge of adult patients with cystic fibrosis about their illness.
AB  - BACKGROUND: Adult patients need to understand their illness if the locus of
      control is to move from doctor to patient. Previous studies have shown important
      misconceptions and gaps in patients' knowledge about cystic fibrosis. METHODS:
      Patients were invited to complete a multiple choice questionnaire covering all
      major aspects of cystic fibrosis. The questionnaire score was compared with a
      predicted score derived from the consultant, cystic fibrosis fellow, nurse, and
      physiotherapist ratings of patient knowledge. Data were obtained to provide a
      comprehensive patient profile and disease severity score. Both scores were tested
      for any associations with patient characteristics. RESULTS: Although patients had
      good general knowledge about the aspects of cystic fibrosis that impacted most on
      their daily lives--that is, respiratory and gastrointestinal problems--important
      gaps and misconceptions in these areas were still present. Knowledge and
      understanding of genetic and reproductive issues and the less common
      complications of cystic fibrosis were only moderate. Older more severely affected
      patients, and those who had more contact with the hospital caring team, had
      better multiple choice questionnaire knowledge scores. Professional carers were
      poor judges of the knowledge of individual patients. CONCLUSIONS: Important gaps
      persist into adult life in the knowledge patients with cystic fibrosis have about
      their illness. Objective assessment of these deficits is required so that each
      patient can be counselled according to his or her needs.

PMID- 8658367
TI  - Determinants of health-related quality of life in patients with chronic
      obstructive pulmonary disease.
AB  - BACKGROUND: The consequences of chronic obstructive pulmonary disease (COPD) on
      daily life, encapsulated by the term "health-related quality of life" (HRQL), are
      important in determining appropriate home care. There is a need to understand the
      relative contribution of respiratory impairment, physical disability, coping,
      age, and socioeconomic variables on HRQL. METHODS: Patients with COPD were
      recruited on admission to a pulmonary rehabilitation centre. Respiratory
      impairment was assessed by lung function tests and physical disability was
      evaluated by a 12 minute walking test. HRQL was assessed by means of the St
      George's Respiratory Questionnaire (SGRQ) measuring "symptoms", "activity", and
      "impact". Because the SGRQ does not include a measure of "well being", this was
      taken from the medical psychological questionnaire for lung diseases. The COPD
      coping questionnaire and a questionnaire covering basic socioeconomic variables
      were also used. RESULTS: One hundred and twenty six patients of mean (SD) age 65
      (9) years and mean (SD) forced expiratory volume in one second (FEV1) 39 (9)%
      predicted were included. The scores on the SGRQ indicated severe impairment.
      Correlations were found between lung function parameters, 12 minute walking test,
      and the HRQL "activity" and "impact" components. Coping strategies were
      correlated with the "activity", "impact", and "well being" components. No
      correlations were found between age, socioeconomic variables, and HRQL. FEV1, 12
      minute walking test, and the coping strategies "avoidance" and "emotional
      reaction" were the best predictors of HRQL. CONCLUSION: In patients with COPD
      methods of improving physical performance and teaching adequate coping strategies
      should be considered in order to improve HRQL.

PMID- 8658368
TI  - Quality of life in patients with chronic obstructive pulmonary disease and severe
      hypoxaemia.
AB  - BACKGROUND: Patients with severe chronic obstructive pulmonary disease (COPD)
      have impairment in most areas of quality of life, but a relationship between
      impairment of the partial pressure of oxygen in arterial blood (PaO2) and quality
      of life has not been established. Previous studies used general health measures
      such as the Sickness Impact Profile (SIP). In this study a disease-specific
      health measure, the St George's Respiratory Questionnaire (SGRQ), was used to
      examine the relationship. METHODS: Forty one patients (20 men) of median age 71
      years (range 47-85) with COPD were assessed. Forced expiratory volume in one
      second (FEV1), PaO2 and partial pressure of carbon dioxide in the arterial blood
      (PaCO2) were measured, and the patients completed the SGRQ, SIP, and the Hospital
      Anxiety and Depression Scale (HAD). RESULTS: The mean (SD) values were: FEV1,
      0.83 (0.29) litres; PaO2, 7.49 (1.03) kPa; PaCO2, 6.30 (1.05) kPa; SGRQ total
      score, 55.3 (18.2); SIP total score 15.4 (9.2); anxiety score, 5.7 (4.3);
      depression score, 5.3 (3.4). PaO2 was significantly correlated with the SGRQ
      total scores but not with the SIP total score. The SGRQ total score also
      correlated with anxiety and depression. Multivariate analysis showed that
      depression score and PaO2 were both significant covariates of the SGRQ total
      score. CONCLUSIONS: These findings suggest that, in patients with severe COPD,
      quality of life is related to the severity of hypoxaemia, but this relationship
      is only detectable when using a disease-specific health measure.

PMID- 8658370
TI  - Evaluation of the beta 2 adrenoceptor agonist/antagonist activity of formoterol
      and salmeterol.
AB  - BACKGROUND: Salmeterol and formoterol have a lower intrinsic activity at beta 2
      receptors than isoprenaline in human bronchus in vitro. The aim of the present
      study was to evaluate in vivo the beta 2 agonist/antagonist activity of
      salmeterol and formoterol at rest with low endogenous adrenergic tone, on
      exercise with raised endogenous adrenergic tone, and in the presence of
      fenoterol, an exogenous full beta 2 receptor agonist. METHODS: Eight normal
      subjects were randomised to receive single doses of placebo, salmeterol 300
      micrograms, formoterol 72 micrograms, or propranolol 80 mg at weekly intervals.
      beta 2 adrenoceptor responses were evaluated at rest, at peak exercise, and after
      treatment with fenoterol 2.4 mg. RESULTS: At rest salmeterol and formoterol
      exhibited equivalent beta 2 agonist activity with regard to decrease in serum
      potassium levels and increase in finger tremor, with propranolol having no
      effect. Salmeterol and formoterol, like propranolol, potentiated the
      hyperkalaemic delta response to exercise compared with placebo, consistent with
      beta 2 antagonism: (mean difference and 95% confidence interval (CI) compared
      with placebo) salmeterol 0.20 (0.02 to 0.38) mmol/l, formoterol 0.17 (0.00 to
      0.34) mmol/l, propranolol 0.45 (0.08 to 0.82) mmol/l. Propranolol blunted the
      heart rate delta response to exercise, consistent with beta 1 blockade, whilst
      salmeterol and formoterol had no effect. Salmeterol and formoterol, like
      propranolol, attenuated the hypokalaemic, tremor, and heart rate delta responses
      to fenoterol compared with placebo, in keeping with beta 2 blockade: potassium,
      salmeterol 0.18 (0.0 to 0.36) mmol/l, formoterol 0.17 (-0.03 to 0.37) mmol/l,
      propranolol 0.80 (0.54 to 1.06) mmol/l; tremor, salmeterol -0.69 (-1.26 to -0.12)
      log units, formoterol -0.71 (-1.53 to 0.11) log units, propranolol -0.85 (-1.66
      to -0.04) log units; heart rate, salmeterol -6 (-13 to 1) beats/min, formoterol 
      10 (-19 to -1) beats/min, propranolol -18 (-29 to -7) beats/min. CONCLUSIONS: At
      rest with low endogenous adrenergic tone salmeterol and formoterol showed
      equivalent beta 2 mediated agonist activity in terms of serum potassium and
      finger tremor responses. In the presence of raised endogenous adrenergic tone at
      peak exercise and in the presence of fenoterol (an exogenous full beta 2 receptor
      agonist), salmeterol and formoterol, like propranolol, exhibited beta 2 receptor
      antagonism as evidenced by their attenuation of beta 2 receptor mediated
      responses. The degree of beta 2 blockade with formoterol and salmeterol was
      comparable but less than with propranolol. The relevance of these findings at
      extrapulmonary beta 2 receptors with regard to airway beta 2 responses remains
      unclear and warrants further investigation.

PMID- 8658369
TI  - Dose response study of ipratropium bromide aerosol on maximum exercise
      performance in stable patients with chronic obstructive pulmonary disease.
AB  - BACKGROUND: Although the bronchodilating effect of inhaled anticholinergics has
      been established in patients with chronic obstructive pulmonary disease (COPD),
      their effects on exercise capacity are still controversial. Previous studies have
      suggested that the standard dosage hardly affects exercise tolerance, whereas
      higher doses might elicit an improvement. The aim of the present study was to
      determine the dose of ipratropium bromide aerosol that improves exercise
      performance using progressive cycle ergometry in patients with stable COPD.
      METHODS: Twenty men with stable COPD of mean (SD) age 69.2 (4.6) years and forced
      expiratory volume in one second (FEV1) 1.00 (0.37) 1 were studied in a randomised
      double blind manner. Each patient received ipratropium bromide in doses of 240
      micrograms, 160 micrograms, 80 micrograms, 40 micrograms, and placebo from a
      metered dose inhaler (MDI) with an InspirEase spacer on five separate days.
      Spirometric parameters were assessed before and at 30, 60, 90, and 120 minutes
      after each inhalation, and pulse rate and blood pressure were also measured
      immediately before each spirometric measurement. Symptom limited progressive (20
      watts/min) cycle ergometer exercise tests were performed 90 minutes after each
      inhalation. RESULTS: Ipratropium bromide in doses of 160 micrograms and 240
      micrograms produced a greater increase in FEV1 than 40 micrograms or 80
      micrograms ipratropium bromide at all time points. Doses of 160 micrograms and
      240 micrograms ipratropium bromide also produced greater increases in maximal
      work load and maximal oxygen consumption than placebo, whereas 40 micrograms and
      80 micrograms ipratropium bromide did not. There was a weak correlation between
      the change in FEV1 and the change in maximal work load (r = 0.45). No differences
      were found in pulse rate or blood pressure between the treatment and placebo
      groups, and no side effects were noted throughout the study. CONCLUSIONS: A dose
      of at least four times the standard dose of ipratropium bromide from an MDI with
      a spacer device was necessary to improve maximal cycle exercise capacity in
      patients with stable COPD. Although the data from cycle ergometry cannot be
      directly applied to exercise performed during day to day activities, it is
      conceivable that the recommended doses of ipratropium bromide do not elicit the
      optimal clinical benefits.

PMID- 8658372
TI  - Effect of endobronchial aspirin challenge on inflammatory cells in bronchial
      biopsy samples from aspirin-sensitive asthmatic subjects.
AB  - BACKGROUND: The aspirin-induced bronchoconstriction in patients with aspirin
      sensitive asthma is caused by cysteinyl leukotriene release. The cellular source
      of the leukotrienes is unknown. The inflammatory cell infiltrate in bronchial
      biopsy samples from seven aspirin-sensitive asthmatic (ASA) subjects and eight
      non-ASA subjects before and after local challenge with lysine aspirin was
      therefore examined. METHODS: Using flexible bronchoscopy, airway mucosal biopsy
      samples were taken and lysine aspirin solution was placed directly onto a carina
      of the contralateral lung. Twenty minutes later a second series of biopsy samples
      was taken from the site of the local endobronchial lysine aspirin challenge. The
      biopsy samples were double immunostained with a rabbit polyclonal antibody to the
      enzyme 5-lipoxygenase and monoclonal antibodies to mast cells (AA1), neutrophils
      (NP57), macrophages (EBM11), T lymphocytes (anti-CD3), and total (BMK13) and
      activated eosinophils (EG2). RESULTS: A decrease in both absolute mast cell
      numbers staining with mast cell tryptase (AA1) and the percentage of mast cells
      co-immunostaining with 5-lipoxygenase was seen in the ASA patients after lysine
      aspirin challenge compared with the non-ASA control group. There was also an
      increase in the numbers of activated eosinophils (EG2) in the ASA subjects
      compared with the non-ASA group. No changes were observed in the total numbers of
      macrophages (EBM11), neutrophils (NP57), total eosinophils (BMK13), and T
      lymphocytes (anti-CD3) after challenge with lysine aspirin. CONCLUSIONS: The
      decrease in numbers of mast cells staining for tryptase and the increase in
      activated eosinophils after endobronchial challenge with lysine aspirin may
      represent degranulation of these cell types, and may be an early event associated
      with aspirin-sensitive reactions in ASA subjects.

PMID- 8658371
TI  - Usual dietary salt intake and asthma in children: a case-control study.
AB  - BACKGROUND: A decline in host resistance due to an alteration in diet--primarily
      of salt--was recently put forward as a possible explanation for rising rates of
      asthma. METHODS: A case-control study was conducted in participants in a
      prevalence survey which included 187 children with asthma (defined by prior
      diagnosis and/or a decline in forced expiratory volume in one second (FEV1) of >
      or = 10% after exercise) and 145 age and sex matched controls. Subjects were
      selected from 989 children aged 5-13 years attending 18 elementary schools on the
      island of Montreal. Usual dietary salt intake was estimated from a food frequency
      questionnaire administered to the mother, and a salt intake score was used to
      group the children into quartiles from I (lowest) to IV (highest salt intake).
      Bronchial hyperresponsiveness to methacholine was assessed by Yan's method. Cases
      and controls were combined in one group to examine the relationship of salt
      intake to bronchial hyperresponsiveness to methacholine. Methacholine
      responsiveness was expressed as a dose-response slope and ranks of dose-response
      slopes were used in the analysis. RESULTS: After accounting for important
      confounding variables, there was no association between asthma and salt intake,
      while methacholine dose-response slope ranks increased with increasing salt
      intake and methacholine responsiveness was greater in the highest quartile than
      in the lowest quartile of salt intake. The median dose-response slopes in % fall
      in FEV1 per mumol methacholine for quartiles I, II, III, and IV were 5.4, 5.9,
      7.7, and 8.7. CONCLUSIONS: No association was found between asthma or exercise
      induced bronchospasm and dietary salt intake. Bronchial hyperresponsiveness to
      methacholine did, however, appear to increase with greater salt intake, but the
      relevance of this association to asthma is unclear.

PMID- 8658373
TI  - Effect of inhaled thiorphan, a neutral endopeptidase inhibitor, on the
      bronchodilator response to inhaled atrial natriuretic peptide (ANP).
AB  - BACKGROUND: The hormone atrial natriuretic peptide (ANP) causes bronchodilation
      and partially protects against direct and indirect bronchial challenges. Both in
      vitro and in vivo studies have found that the protective effect of ANP against
      bronchoconstriction is enhanced by inhibition of the enzyme neutral endopeptidase
      (NEP). It was hypothesised that pretreatment with thiorphan, an NEP inhibitor,
      might enhance the bronchodilator response to inhaled ANP. METHODS: In a
      randomised double blind placebo controlled crossover study, six asthmatic
      patients (one woman) of mean (SD) age 47.3 (3.8) years and forced expiratory
      volume in one second (FEV1) 1.91 (0.42) 1, 55 (3.8)% predicted, were studied. All
      were shown at screening to have at least a 25% improvement in FEV1 to inhaled
      salbutamol. On five study visits the patients received either thiorphan 1 mg (in
      2 ml) followed by ANP 5 mg or placebo (saline), or placebo (saline) followed by
      ANP (5 mg), placebo or salbutamol 5 mg. Spirometric parameters were measured
      after each inhalation and thereafter for the next two hours. RESULTS: ANP alone
      caused a bronchodilator response up to 15 minutes when compared with placebo or
      thiorphan alone with a mean (SE) change in FEV1 of 16.8 (8.1)% and 16.1 (6.8)% at
      10 and 15 minutes from baseline, respectively. Prior inhalation of thiorphan
      prolonged the duration of the bronchodilator effect of ANP up to 60 minutes with
      a mean (SE) change in FEV1 of 23.1 (3.4)% at 60 minutes. There was no difference
      in the maximum degree of bronchodilation following the administration of ANP
      alone compared with the combination of thiorphan and ANP. The degree and duration
      of the bronchodilator response produced by ANP, or the combination of the NEP
      inhibitor and ANP, were less than that produced by salbutamol. CONCLUSIONS: These
      results confirm that, at least in part, the bronchodilator response to inhaled
      ANP is modulated by NEP. Analogues of ANP which are stable to NEP may have
      greater bronchodilator activity than ANP in the treatment of asthma.

PMID- 8658374
TI  - In vitro assessment of drug delivery through an endotracheal tube using a dry
      powder inhaler delivery system.
AB  - BACKGROUND: Jet nubulisers and metered dose inhalers are widely used to deliver
      aerosolised drugs to the lungs of intubated patients in adult intensive care
      units. Drug delivery using these systems has been shown to be inefficient and
      both forms of delivery have the potential to induce paradoxical
      bronchoconstriction in patients with reactive airways disease. METHODS:
      Experiments were carried out to determine whether it was possible to deliver drug
      from a dry powder delivery system through an endotracheal tube. A 200 micrograms
      budesonide Turbohaler was enclosed in a chamber which allowed it to be inserted
      into a ventilator circuit. Experiments were performed with a multistage liquid
      impinger in which drug was drawn through the Turbohaler and endotracheal tube at
      60 l/min providing an index of the maximum drug delivery achievable via this
      route. A second series of experiments was performed in which the Turbohaler was
      placed in a ventilator circuit using a Servo 900C volume cycled ventilator. Drug
      delivered from the Turbohaler during the inspiratory phase was collected on a
      filter placed between the end of a 9 mm endotracheal tube and a model lung. A
      tidal volume of 500 ml and inspiratory time of 0.5 seconds was used. Budesonide
      was assayed using an ultraviolet spectrophotometric assay. RESULTS: Thirty
      percent of the nominal dose passed through the endotracheal tube and was
      collected in the multistage liquid impinger. Mean drug delivery to the filter in
      the ventilator circuit was 20%. CONCLUSIONS: This in vitro study indicates that
      drugs from dry powder inhalers (in this case the Turbohaler) can be
      satisfactorily delivered through endotracheal tubes and that clinical evaluation
      of this technique is now indicated.

PMID- 8658375
TI  - Scottish national survey of tuberculosis notifications 1993 with special
      reference to the prevalence of HIV seropositivity.
AB  - BACKGROUND: The study sought to determine the contribution of HIV seropositivity
      to the arrest of decline in tuberculosis notifications in Scotland. METHODS:
      Survey forms relating to each tuberculosis notification in 1993 were completed by
      the notifying consultant. Voluntary anonymous HIV testing of tuberculosis cases
      aged under 65 was requested. Age, sex, ethnic status, country of birth,
      employment status, occupation, previous tuberculosis, contact status, risk
      factors for HIV infection, HIV serostatus of cases aged under 65, site,
      radiological extent, and bacteriological status of tuberculous disease were
      determined. RESULTS: Five hundred and seventy four cases of tuberculosis were
      originally notified, of which 77 (14%) subsequently proved to be non-tuberculous
      and were therefore denotified. Of the 497 cases 423 (85%) were white and 58 (12%)
      were from the Indian subcontinent. Eighty five per cent of patients from the
      Indian subcontinent were aged < 55 years whereas 64% of white patients were aged
      > 55 years. Pulmonary disease was found in 74%, non-pulmonary in 22%, and
      combined disease in 4% of patients. Of 242 HIV tests performed, three were
      positive and five other HIV positive patients were known, giving an HIV
      positivity rate of 1.6% of all tuberculosis notifications in 1993. Annual
      notification rates for Scotland were 9.7 per 10(5) before and 8.7 per 10(5) after
      exclusion of previously treated cases; rates were 8.4 per 10(5) for the white
      population and 179 per 10(5) for those from the Indian subcontinent. CONCLUSIONS:
      The study documents the distribution of tuberculous disease in Scotland by age,
      sex, site, and ethnic group for the first time. Notification practices, with
      respect to denotification, need to be improved. Infection with HIV is presently
      uncommon in cases of tuberculosis in Scotland but continued vigilance is
      essential.

PMID- 8658376
TI  - Peritoneal ventilation in rabbits: augmentation of gas exchange with cisapride.
AB  - BACKGROUND: Peritoneal ventilation has been shown to be effective in achieving
      extrapulmonary oxygenation and carbon dioxide elimination in an animal model of
      severe adult respiratory distress syndrome (ARDS). Cisapride is a "prokinetic"
      agent (increases gastric emptying), that may increase the splanchnic circulation
      and thus favourably affect gas exchange in peritoneal ventilation. METHODS: Using
      Doppler ultrasound the effect of cisapride on the portal venous circulation was
      examined in eight spontaneously breathing rabbits and the effect of cisapride on
      gas exchange in five rabbits spontaneously breathing room air was compared with
      that of a control group who did not receive cisapride. Its effect on gas exchange
      in five rabbits with ARDS being treated with mechanical lung and peritoneal
      ventilation was compared with that of a control group, and its effect on gas
      exchange in five rabbits with ARDS treated with conventional ventilation was also
      compared with that of a control group. RESULTS: Enteral administration of
      cisapride increased portal venous blood velocity, as measured
      ultrasonographically, by a mean of 188% one hour after receiving the drug. In
      rabbits with ARDS being treated with both peritoneal ventilation and mechanical
      ventilation to the lungs, those receiving cisapride had arterial oxygen tensions
      1.5-3 times that of controls. Cisapride had no effect on arterial blood gas
      tensions in rabbits who were spontaneously breathing room air, nor in rabbits
      with ARDS who received only conventional mechanical lung ventilation.
      CONCLUSIONS: Cisapride increases arterial oxygenation in rabbits with severe ARDS
      treated with peritoneal ventilation, probably due to its ability to increase
      splanchnic circulation. It should be considered as an adjuvant medication to
      peritoneal ventilation.

PMID- 8658377
TI  - Intrathoracic tuberculous lymphadenopathy: clinical and bronchoscopic features in
      17 adults without parenchymal lesions.
AB  - BACKGROUND: Whilst intrathoracic lymphadenitis is a characteristic sign of
      primary tuberculosis in children, its presence without parenchymal lesions in
      adults is unusual and makes the diagnosis using noninvasive techniques difficult.
      The diagnostic role of bronchoscopy in adults with intrathoracic tuberculous
      lymphadenitis is reported. METHODS: Seventeen patients with intrathoracic
      lymphadenopathy seen during 1993 who had all undergone bronchoscopy and had been
      found to have tuberculosis in the absence of any parenchymal lung lesions were
      evaluated retrospectively. RESULTS: Right paratracheal lymphadenopathy was
      observed on the plain chest radiograph in all the patients. Fifteen of the 17
      patients had an endobronchial abnormality and samples taken at bronchoscopy gave
      a definitive diagnosis in nine (53%) of the 17. Four patients had ulcerating
      endobronchial granuloma and all had biopsy samples positive for tuberculosis.
      Transbronchial or transcarinal needle aspiration samples were diagnostic in five
      of 11 patients (45%) subjected to the procedure. Peripheral lymph node biopsy
      diagnosed tuberculosis in two cases and in the remaining six patients the
      diagnosis wa achieved by mediastinoscopy or thoracotomy. CONCLUSIONS:
      Bronchoscopy has an important role in the diagnosis of intrathoracic tuberculous
      lymphadenopathy in adults and should be considered before other invasive
      procedures.

PMID- 8658378
TI  - Impairment of endothelium-dependent pulmonary vasodilation in patients with
      primary pulmonary hypertension.
AB  - BACKGROUND: Pulmonary vascular tone may be modulated by endothelium-derived
      vasoactive mediators. Endothelial dysfunction is thought to occur in primary
      pulmonary hypertension. The aim of this study was to evaluate the vascular
      responses of patients with severe primary pulmonary hypertension to endothelium
      dependent vasodilators (for example, substance P) and non-endothelium-dependent
      vaasodilators (for example, adenosine). METHODS: Six patients with primary
      pulmonary hypertension (mean (SE) systolic, diastolic, and pulmonary artery
      pressures 91.1 (7), 45.2 (3), and 62 (4.2) mm Hg, respectively, and baseline
      total pulmonary vascular resistance (TPVR) 1949 (164) dynes.s.cm-5) underwent
      sequential infusions of substance P (5-100 pmol/min) and adenosine (5-50
      micrograms/kg/min) in random order. Pulmonary and systemic haemodynamics were
      monitored by indwelling radial and pulmonary arterial catheters. RESULTS:
      Substance P caused a marked fall in systemic vascular resistance (SVR) but
      minimal pulmonary vasodilation (mean maximal percentage change from baseline in
      TPVR:SVR ratio 27.85 (6.5)%, p < 0.01). Adenosine caused TPVR to fall, but
      resulted in no change in SVR (mean maximum percentage change from baseline in
      TPVR:SVR ratio -9.85 (3.5)%, p < 0.05). CONCLUSION: Endothelium-dependent
      vasodilation is deficient in the pulmonary circulation of patients with primary
      pulmonary hypertension and may contribute to the abnormalities of pulmonary
      vascular tone and reactivity seen in that condition.

PMID- 8658379
TI  - Doppler assessment of pulmonary haemodynamics in chronic hypoxic lung disease.
AB  - Various methods of Doppler echocardiography are useful in the analysis of flow
      dynamics within the heart and the pulmonary circulation in patients with COPD. In
      addition, to distinguish patients with increased pulmonary artery pressures from
      those with normal pressures, Doppler techniques provide quantitative methods for
      estimating pulmonary artery pressures non-invasively. Doppler echocardiography
      can be performed repeatedly and can thus be used to assess serial changes in the
      clinical state of a patient or in the response to certain pharmaceutical
      interventions in the pulmonary vascular bed. The most useful and accurate method
      of estimating pulmonary artery pressures in patients with chronic hypoxic lung
      disease is the systolic trans-tricuspid gradient, calculated from tricuspid
      regurgitation detected by continuous wave Doppler echocardiography with
      estimation of the right ventricular pressure, followed by the acceleration time
      from pulmonary flow analysis using pulsed Doppler techniques. New contrast
      materials to enhance the continuous wave Doppler signal and transoesophageal
      echocardiography may provide even more satisfactory results in the future.

PMID- 8658380
TI  - Neurone-specific enolase levels in pleural effusions in patients with rheumatoid
      arthritis.
AB  - BACKGROUND: High pleural fluid levels of neurone-specific enolase (NSE) have been
      reported, not only in patients with small cell lung cancer but also in those with
      chronic inflammatory diseases. METHODS: NSE concentrations were determined in
      pleural fluid and serum from 342 patients with pleural effusions including 17
      with rheumatoid arthritis. RESULTS: The median NSE concentration in pleural fluid
      was higher in rheumatoid effusions than in any other condition studied. The
      median pleural fluid:serum NSE ratio was highest in patients with rheumatoid
      arthritis (11.6) and about unity in all other diseases including small cell lung
      cancer (0.9). In patients with rheumatoid arthritis pleural fluid concentrations
      of NSE correlated inversely with pleural fluid glucose concentrations and the pH
      of the pleural fluid. CONCLUSIONS: A high pleural fluid:serum NSE ratio was found
      consistently in pleural effusions from patients with rheumatoid disease.

PMID- 8658381
TI  - Epidemic outbreak of interstitial lung disease in aerographics textile workers-
      the "Ardystil syndrome": a first year follow up.
AB  - BACKGROUND: The longer term respiratory effects of massive inhalational exposure
      of textile printing sprayers to Acramin (the "Ardystil syndrome") are not well
      established. METHODS: A 12 month follow up of 27 heavily exposed textile sprayers
      was performed. RESULTS: Twenty one patients experienced cough, 18 dyspnoea, and
      17 nose bleeding at initial exposure, with histological evidence of organising
      pneumonia in 13 cases, radiological abnormalities detected by computed
      tomographic scanning in 20 cases, and diminution of diffusion capacity to below
      80% of predicted in seven cases. At one year after exposure symptoms persisted in
      15 cases, radiological alterations in six, and diffusion capacity was reduced in
      nine. CONCLUSIONS: Whilst most of our patients showed improvement at one year,
      evidence of persistent lung involvement was present in an appreciable minority of
      exposed cases.

PMID- 8658382
TI  - Exposure to crystalline silica and risk of lung cancer: the epidemiological
      evidence.

PMID- 8658383
TI  - Adolescent asthma. Introduction.

PMID- 8658384
TI  - Issues in adolescent asthma: what are the needs?
AB  - In the UK most children with asthma do not attend hospital clinics and continuity
      of care is provided by their general practitioner. However, those with severe
      asthma, most of whom will not grow out of their symptoms, need hospital-based
      care as well. As they progress through adolescence teenagers become increasingly
      uncomfortable in paediatric wards and outpatient clinics. They need clinics where
      they can meet the chest physician who will take on their care before they
      transfer to a clinic for adults (table 5). Adolescent asthmatic patients are a
      distinct group of patients with different treatment requirements from either
      paediatric or adult patients. It is important that physicians recognise
      adolescent needs and the importance of regular health checks, smoking, peer
      pressure, and the negotiation of treatment plans in this group of patients.

PMID- 8658385
TI  - Progression of allergy and asthma through childhood to adolescence.
AB  - The reduction in asthma symptoms and bronchial hyperresponsiveness in adolescence
      is not well understood. Nor can the differences in asthma prevalence and severity
      between the sexes, which reverse at puberty, be explained. It has been suggested
      that the improvement in asthma during adolescence may result from diminished
      clinical and immunological responsiveness directly related to hormonal changes
      and that the effect of age on the prevalence of asthma in each sex may relate to
      differences in hormonal status, potentially influencing airway size,
      inflammation, and smooth muscle and vascular functions. However, few
      comprehensive studies are available. In summary, all wheezing is not asthma. Non
      asthmatic wheezing illnesses may in part be attributable to anatomical
      abnormalities of the lung (transient early wheezing, premature birth). Little is
      known about the genetic and environmental determinants of childhood asthma, and
      factors related to the development of atopic sensitisation, such as exposure to
      allergens, infectious diseases, or tobacco smoke early in life, and dietary
      habits may be important, whereas the relevance of air pollution remains to be
      established. Unfortunately, we still do not know how to prevent the manifestation
      of childhood asthma.

PMID- 8658387
TI  - [Trauma epidemiology--a tool in trauma prevention].

PMID- 8658386
TI  - Prognostic factors for the outcome of childhood asthma in adolescence.
AB  - By the second decade of life asthma symptoms often abate and it may seem that
      patients with mild asthma have "outgrown" the disease. Unfortunately this is
      likely to be the exception rather than the rule. Although the severity of asthma
      symptoms fluctuates with time, the inherited tendency towards respiratory
      symptoms never disappears and many teenagers who seem to be free of symptoms do,
      in fact, have persistent asthma. During symptom-free periods subclinical, but
      nevertheless significant, airways obstruction and/or bronchial
      hyperresponsiveness may be present. It is not unusual for adults who have been
      asymptomatic for a number of years to redevelope asthma symptoms. Indeed, much of
      the so-called adult onset asthma has its roots in childhood. Levison concluded
      that, in these subjects, it is often not the asthma that is outgrown but the
      paediatrician. The more severe asthma is in childhood the more likely it is that
      the disease will persist in adulthood. A complete list of the characteristics of
      the disease in childhood, and the potential risk factors associated with an
      unfavourable prognosis, such as pulmonary function and bronchial responsiveness
      and markers of airway inflammation, is therefore needed. As properly matched and
      controlled prospective long term studies have not been published it has not been
      possible to evaluate the effects on prognosis of any single class of antiasthma
      agent. Such studies are needed to find out if it is possible to alter the natural
      history of the disease. In theory modern asthma treatments, because they are able
      to improve symptoms and underlying disease phenomena, are also beneficial in the
      long term prognosis of childhood asthma. The majority of patients with persistent
      asthma included in the currently available studies were not receiving adequate
      treatment. Since compliance with therapeutic regimens in asthma, especially in
      adolescence, is low, a monitoring system is needed to guarantee adequate follow
      up and treatment during and beyond puberty.

PMID- 8658388
TI  - [Abortion legislation and physician's role].

PMID- 8658389
TI  - [Acute respiratory distress syndrome--effective therapeutic methods, at last?].

PMID- 8658390
TI  - [Nitrogen oxide (nitrogen monoxide) administered via respirator. A new
      therapeutic alternative in acute respiratory failure and shock lung].
AB  - Adult respiratory distress syndrome (ARDS) still has a high rate of mortality. It
      is usually necessary to treat these patients with a respirator using a high
      inspiratory fraction of oxygen. The condition is often associated with pulmonary
      hypertension and increased pulmonary vascular resistance. Nitric oxide (NO) has
      been shown to be a potent endogenous vasodilator. It is a gas and can thus be
      delivered to the lungs of intubated patients by means of a respirator. Because of
      its very short halflife, the effect of inhaled nitric oxide is limited to the
      pulmonary vasculature and it has no systemic effects. The local vasodilatation
      caused by nitric oxide leads to improved oxygenation, primarily because of
      reduced intrapulmonary shunting of blood. From April 1993 to July 1995 we treated
      14 patients with severe ARDS with inhaled nitric oxide. All patients were
      critically ill, with a mean APACHE II score of 24.5. Oxygenation was increased in
      all patients after treatment with nitric oxide, but in spite of this eight
      patients (56%) died. There were no significant differences between survivors and
      non-survivors as regards age or severity of the disease.

PMID- 8658391
TI  - [Pneumoscrotum after air leak from tension pneumothorax].
AB  - Pneumoscrotum is a rare condition which may accompany retroperitoneal ruptures of
      air-filled gastrointestinal organs, endoscopic and surgical procedures and
      widespread subcutaneous emphysema. A case of pneumoscrotum as a complication to
      treatment of tension pneumothorax is reported, and the literature is reviewed.

PMID- 8658392
TI  - [The Ilizarov external fixator and method. Treatment of congenital and acquired
      deformities].
AB  - The Ilizarov method, with external fixation by means of rings, rods and wires,
      has been used at the Norwegian National Hospital, Orthopaedic Centre, since 1992.
      The method is unique in correcting multiplanar deformities in one surgical
      procedure. We have treated 70 patients with a wide variety of orthopaedic
      etiologies. Soft tissue and bone deformities in the lower extremity have been
      corrected separately or combined. The frequency of complications has been
      relatively high, but we still think that the Ilizarov method is useful to correct
      complex deformities in children and adults alike.

PMID- 8658393
TI  - [Neonatal alloimmune thrombocytopenia. Diagnosis and follow-up in pregnancy].
AB  - Neonatal alloimmune thrombocytopenia is present in every 2,000-3,000 pregnancy,
      that is in 20-30 pregnancies in Norway each year. Anti-HPA la antibodies are
      usually present in severe alloimmune thrombocytopenia in foetus and neonates.
      Pregnant women are not screened for the presence of anti-HPA la antibodies.
      Neonatal alloimmune thrombocytopenia can be suspected in newborn children who
      show signs or symptoms of thrombocytopenia. Laboratory investigation for neonatal
      alloimmune thrombocytopenia should be performed if the newborn child shows signs
      of bleeding, in women who have had multiple abortions and after stillbirth.
      Examples are presented from laboratory investigations in seven families with
      children who have thrombocytopenia.

PMID- 8658394
TI  - [Visual laser coagulation for benign prostatic hyperplasia. Preliminary
      experiences].
AB  - A total of 28 patients with symptomatic bladder outlet obstruction due to benign
      prostatic hyperplasia were treated by visual laser coagulation (VLAP) performed
      with the Myriadlase sidefiring neodymium: YAG laser fibre at 40 Watts power. The
      treatment was performed as an outpatient procedure using intraurethral gel
      anaesthesia and light intravenous sedation and analgesia. Prostatic volume was 32
      g (18-90 g), and 650 Joule per gram prostatic tissue (516-1000 J/g) was
      administered. The patients were evaluated at mean 9.2 weeks. The mean operative
      time was 34 minutes. The procedure was very gentle, all patients tolerated it
      well and there was no bleeding. Most patients experienced some dysuria for three
      to four weeks after the procedure, two had severe symptoms. Two patients remained
      in retention and required transurethral resection. The rest expressed subjective
      satisfaction with the results. Peak urinary flow increased from mean 9.0 ml/sec
      preoperatively to 15.4 ml/sec; a mean increase of 78%. One patient developed
      clinical urinary tract infection. There were no other complications of clinical
      significance.

PMID- 8658395
TI  - [Interruptions of physicians' work at hospitals. A threat to quality?].
AB  - When the working hours of junior doctors at a medical clinic were reduced from 44
      to 40.7 hours per week a questionnaire was distributed to the doctors themselves
      and to the different categories of nurses to find out how this change had
      affected the schedule for investigation and treatment of the patient, care of the
      patient, discharge from hospital, and collaboration with other health
      professionals. In the opinion of doctors and nurses alike, the reduced working
      hours had led to delays in investigation of patients, poorer care, problems in
      connection with discharge from hospital, and poorer collaboration with other
      professional groups. It could well be difficult to achieve normal working hours
      for junior doctors in hospitals with patients under continuous treatment without
      this having av decided negative effect on continuity of treatment.

PMID- 8658396
TI  - [Quality adjusted life years in assessment of preventive measures. Should blood
      donors be tested for HTLV-I/II infections?].
AB  - In planning preventive health measures, quality adjusted life-years (QALYs) are
      useful as a measure of benefit. As an example, the question of whether blood
      donors should be routinely tested for antibodies to the Human T-lymphotropic
      viruses I and II (HTLV I/II) is analysed. A mathematical model was set up to
      describe the consequences, in terms of lost life-years and years with disease due
      to transfusion-mediated infection (if testing is not performed) or years with
      reduced quality of life (in the case of testing). These future outcomes were
      discounted and converted to QALYs. The cost per QALY is about NOK 2.33 million
      when the prevalence is 1 per 50,000 blood donors, and is reduced to 190,000 per
      QALY when the prevalence is 10 per 50,000. Using QALYs in evaluation of
      preventive medicine can be complicated, and calls for cooperation between
      epidemiologists and health economists.

PMID- 8658398
TI  - [Why is genetic research beneficial and interesting?].

PMID- 8658397
TI  - [Insulin treatment is of value--also in type 2 diabetes].
AB  - Consensus has not been reached about the optimal treatment of type 2 diabetes,
      and several authors have questioned the use of insulin for this disorder. The
      reasons are that an association has been found between hyperinsulinaemia and
      cardiovascular disease in non-diabetic men, and the sparse evidence of a
      beneficial effect from tight glycaemic control in prevention of late
      complications in type 2 diabetes. We discuss the pathophysiology of
      atherosclerosis in type 2 diabetes, and review some of the recent literature. We
      find it likely that, in the metabolic cardiovascular syndrome found in many
      patients with type 2 diabetes, insulin resistance is more important than the
      accompanying hyperinsulinaemia. Furthermore, evidence is emerging of a strong
      association between hyperglycaemia and atherosclerotic vascular disease in
      patients with type 2 diabetes. We conclude that insulin treatment should be used
      in type 2 diabetic patients when the hyperglycaemia cannot be controlled by oral
      agents.

PMID- 8658399
TI  - [Increase and trends of efficiency at Norwegian hospitals].

PMID- 8658400
TI  - [Ambulatory surgery, preoperative anamnesis and clinical examination].

PMID- 8658401
TI  - [Folic acid deficiency, cancer and congenital abnormalities].

PMID- 8658402
TI  - [Winter depression--more than biology?].

PMID- 8658403
TI  - [The changing trauma pattern and treatment. Laparotomy in major abdominal
      injuries].

PMID- 8658404
TI  - [The Vacouver rules--common sense and civil manners].

PMID- 8658406
TI  - [Semper aliquid haeret].

PMID- 8658405
TI  - [Physical therapy without referral].

PMID- 8658407
TI  - [Obligations of employment agreements].

PMID- 8658408
TI  - [Conspicious consumption--a concept with Norwegian history].

PMID- 8658409
TI  - [Laparoscopic surgery in Norway. A 5-year retrospective study].

PMID- 8658410
TI  - [Pulmonary tuberculosis--a diagnostic challenge].

PMID- 8658411
TI  - [Simultaneous pulmonary tuberculosis and bronchial cancer. A diagnostic pitfall].
AB  - Simultaneous development of unsuspected primary cancer in close vicinity to an
      active tuberculous process of the lung can seriously complicate diagnosis. In
      most reported cases, a long interval had elapsed before carcinoma was suspected.
      Such a case is described. Initially a 72-year-old man with carvernous
      tuberculosis was successfully treated with adequate antituberculous drugs. After
      18 weeks of treatment, the patient's pulmonary parenchymal status showed no
      further improvement, and after 25 weeks the lung infiltration was seen to be
      slowly increasing. Thoracotomy performed after 40 weeks of treatment revealed
      inoperable squamous cell carcinoma and apparently healed tuberculosis.

PMID- 8658412
TI  - [Prognosis in primary tumors of the central nervous system. A patient material
      from the Norwegian Radium Hospital 1960-94].
AB  - We present the results of a retrospective survey of 1,218 patients treated at the
      Norwegian Radium Hospital during the years 1980-94 for primary tumours of the
      central nervous system. Median survival for patients with glioblastoma (n = 492)
      was 12 months, for patients with anaplastic astrocytoma (n = 83) 25 months,
      astrocytoma (n = 260) 95 months, oligodendroglioma (n = 85) 74 months, mixed
      glioma (n = 68) 65 months, and medulloblastoma (n = 53) 109 months. Median
      survival for patients with brain stem tumours (n = 37) was nine months, while 74%
      of patients with tumours in the pineal region (n = 38) survived for five years.
      The histology and localisation of the tumour, as well as age and functional
      status, are important prognostic factors for survival in patients with primary
      CNS tumours.

PMID- 8658413
TI  - [Glossopharyngeal neuralgia. Not just pain].
AB  - Glossopharyngeal neuralgia is a rare disease characterized by severe paroxysmal
      attacks of pain in the distribution of the 9th cranial nerve. The most important
      differential diagnosis is trigeminal neuralgia. Carbamazepin is the current drug
      of choice in therapy, but modern neurosurgical treatment will probably become
      more common in the future. Autonomic disturbances may occur during pain attacks
      in some patients. We describe a patient suffering from glossopharyngeal neuralgia
      with transitory unconsciousness due to cardiac asystole and arterial hypotension
      accompanying the attack of pain.

PMID- 8658414
TI  - [Bacterial endocarditis in premature children. A complication caused by central
      venous catheters].
AB  - During the last ten years, the literature has included an increasing number of
      reports of bacterial endocarditis in prematurely born neonates. We describe the
      cases of two prematurely born infants with structurally normal hearts who, when
      examined by echo cardiography, were shown to have intercardial vegetations. They
      were diagnosed as having infective endocarditis caused by coagulase negative
      staphylococci. Both infants had central venous lines and received total
      parenteral nutrition. Both infants were treated successfully with antibiotics.
      One of them died later of sudden infant death syndrome.

PMID- 8658415
TI  - [Prescription for diazepam 5 mg tablets in Vestfold 1989 and 1995].
AB  - During the last five years, the prescription of tranquillizers has been reduced
      by 26% in Vestfold County compared with 19% in the country as a whole. This is
      probably a result of two initiatives: a common strategy to reduce prescription in
      the county, and monitoring prescription rate of the individual general
      practitioners. We examined the prescription of diazepam 5 mg tablets and found a
      reduction of more than 30% from 1989 to 1995. The reduction was greatest among
      the younger age groups and decreased with increasing age. The most probable
      reason for this pattern is a more restrictive attitude among general
      practitioners towards using diazepam to treat the young and middle-aged. The
      results for 1995 show that women still receive about 60% more diazepam than men,
      and women aged 70-79 years receive 117% more than women aged 40-49 years.

PMID- 8658416
TI  - [Mobility and group discussions. Treatment of chronic muscle pain in women in
      general practice].
AB  - We describe the development of a programme based on group treatment for women
      suffering from chronic muscle pain, and the experience gained from it. Six such
      groups underwent 12 weeks of treatment consisting of specially adapted physical
      training twice weekly and a weekly discussion group in which a general
      practitioner and a physiotherapist took part. 60 of the 80 women who started the
      programme completed it. This assessment is based on in-training observations,
      interviews and a questionnaire. The participants maintain that they found the
      combination of physical and relaxation exercises, and the discussions, the social
      aspect and the mutual exchange of knowledge, beneficial. Their physical ability
      improved, they got more enjoyment from movement and achieved a greater sense of
      well-being. The extent of benefit experienced by the individual participant was
      dependent upon her feelings respected and appreciated, her sense of achievement
      and her ability to understand how various personal factors are related. The women
      underlined the benefit of a training programme based on mobility rather than
      stamina, and including discussion groups characterized by acceptance, a sense of
      belonging and co-operation. We believe that this approach can be further
      developed at general practitioner level, provided that the individual participant
      meets recognition and acceptance of her experiences, her feelings connected with
      physical activity and her background.

PMID- 8658417
TI  - [A small-group center. A model trial for activities of a center for rare diseases
      and syndromes at the National Hospital].
AB  - The Centre for Rare Disorders at the National Hospital is a trial project in
      connection with the Government's Plan of Action for the disabled. The intention
      is to establish nationwide facilities which in cooperation with local resources
      can provide both medical, pedagogical and social services for persons with rare
      disorders and their families. The work at the centre is based on a life span
      perspective and the goal is improved coping, independence and better quality of
      life. The centre gathers, adapts and spreads information on 15 rare disorders.
      Representatives from the user organisations ensure that the users have a strong
      influence on the management of the centre. It is hoped that systematic evaluation
      of the centre's activities will give an answer to the Government and to the host
      hospital as to whether the intentions and goals will be fulfilled or not during
      the project period.

PMID- 8658418
TI  - [High technology in a family perspective].
AB  - High technology medicine poses high demands for knowledge and technical
      competence. In addition, the hospital is expected to represent a model for total
      care where the "customers" also include family members, eg. parents and children.
      Both economic and human resources are needed in order to avoid negative after
      effects and complications for both patient and family. High technology medicine
      also raises difficult ethical questions: How much decision-making should be left
      to parents? These problems are illustrated by clinical examples, and hospital
      based ethical committees are suggested as a structure for the further efforts to
      improve ethical competency at the hospital and to find appropriate solutions for
      patients and their families in both the long and the short term.

PMID- 8658419
TI  - [Genetic screening activities. A political perspective].

PMID- 8658421
TI  - [Folate supplementation to pregnant and other women of childbearing age].

PMID- 8658420
TI  - [When your needs are most urgent, you will be denied help. Indistinct borderlines
      between advertisment, campaigns and information].

PMID- 8658422
TI  - [New antidepressive agents--expenses and incomes].

PMID- 8658423
TI  - [Falsely increased "long-term blood sugar"].

PMID- 8658424
TI  - [The national drug control agency approves of a humbug drug].

PMID- 8658425
TI  - [Treatment with anti-secretory agents for symptomatic relief].

PMID- 8658426
TI  - [Assessment at the Norwegian patient insurance authority].

PMID- 8658427
TI  - [Mydriasis and mydriatics].

PMID- 8658428
TI  - [Acute gastrointestinal hemorrhage. Is the available treatment satisfactory?].

PMID- 8658429
TI  - [Melatonin--myths and reality].

PMID- 8658430
TI  - [Increased plasma level of homocysteine as cardiovascular risk factor].

PMID- 8658431
TI  - [Homocysteine--an independent risk factor of premature vascular disease].

PMID- 8658432
TI  - [Patient characteristics and mortality in acute myocardial infarction].
AB  - Data on all patients with myocardial infarctions treated in the ten hospitals in
      Health region 1 in Norway were extensively analysed. Of the 487 patients with the
      diagnosis acute myocardial infarction, 429 (88%) had definite or suspected acute
      myocardial infarction; 440 (90%) were treated in an intensive care unit. Average
      age was 70 years, for men 68 years and for women 75 years, and 69% of the
      patients suffered their first acute myocardial infarction. Within six hours 59%
      of the patients were admitted to hospital and within 12 hours 76%. On admission,
      58% of the patients had an electrocardiogram showing ST elevation or bundle
      branch block. The remainder showed other findings, of which ST depression was the
      most frequent (23%). In-hospital mortality was 18% and of those discharged 10%
      died within six months. It is concluded that the true acute myocardial infarction
      population differs from the population of patients in clinical trials as follows:
      higher age, longer delay before admission to hospital, a different distribution
      of EGG findings, and higher mortality.

PMID- 8658433
TI  - [Use of thrombolytic agents and other drugs in acute myocardial infarction].
AB  - Data on all patients with acute myocardial infarction who were treated in the ten
      hospitals in Health region 1 in Norway were extensively analysed over a two month
      period. Of all the 487 patients 32% received thrombolytic treatment; i.e 36% of
      those with definite or suspected myocardial infarction on admission.
      Thrombolytics were withheld, mainly because only 58% of the patients showed ST
      elevation or bundle branch block on their ECG, and because of a long delay from
      onset of symptoms to admission to hospital. With increasing age use of
      thrombolytics decreased, and high age seemed to some degree to act as a
      contraindication. Relative contraindications such as history of stroke or peptic
      ulcer contributed modestly to the limited use of thrombolytics. Aspirin was used
      by 72% of the patients, and either aspirin or anticoagulants in 87%. At six month
      follow-up 50% used aspirin and 32% warfarin. Betablockers were given to 57% of
      the patients in hospital, but were not used to any extent in the acute phase of
      the disease; at six months the proportion of patients on betablockers was about
      the same. Oral nitrates were used more extensively than betablockers and there is
      a clear indication that angiotensin converting enzyme inhibitors are used
      increasingly for secondary prevention.

PMID- 8658434
TI  - [Hyperbaric oxygen therapy. Now an established treatment in Norway].
AB  - Hyperbaric oxygen therapy can be a life-saving form of treatment for certain
      acute medical conditions, e.g. cerebral gas embolism, clostridial infections, and
      smoke/carbon monoxide inhalation. It has long been used for treating
      decompression illness in divers. As from 1994 our hospital has been delegated the
      national responsibility for hyperbaric medicine in Norway. This paper describes
      the physiological basis, indications, and contraindications for hyperbaric oxygen
      treatment, and summarises hyperbaric oxygen treatment in Bergen over the last two
      years.

PMID- 8658435
TI  - [Transiliacal screw fixation of the sacrum in unstable pelvic ring fractures].
AB  - This article presents our experiences from fixation of the sacrum by transiliacal
      screw in 13 patients with unstable fractures of the pelvic ring. Early
      mobilization, with no secondary dislocation or postoperative complications, was
      achieved in all patients. Sagittal instability in unstable pelvic ring fractures
      must be acknowledged. The transiliac screw offers the possibility of early
      mobilization of patients with this fracture. The procedure is demanding and
      patients selected for this treatment should be referred to hospitals with
      experience in the treatment of pelvic fractures.

PMID- 8658436
TI  - [Diagnosis and treatment of gastrointestinal hemorrhage].
AB  - The handling of gastrointestinal bleeding was discussed at a national expert
      symposium in February 1995. Internists are in charge of therapeutic endoscopy of
      upper gastrointestinal bleeding at the majority of Norwegian hospitals, but close
      collaboration with the surgeon on call is vital. The need for intensive care and
      monitoring may have been underestimated, since decompensation of co-existing
      diseases is a more frequent cause of death than the haemorrhage itself.
      Endoscopic treatment is the primary choice in all parts of the gut where
      endoscopy is possible, but surgery must be considered for patients who rebleed.
      Injection of sclerosering agents is the most prevalent mode of treatment for
      oesophageal varices and ulcers, but thermal probes and rubber band ligation are
      probably equally effective in experienced hands. Major lower bowel haemorrhage
      can render colonoscopy impossible, and emergency resections may be warranted, but
      preferably after angiography or peroperative endoscopic localisation of the area
      of bleeding.

PMID- 8658437
TI  - [Administrative handling of gastrointestinal hemorrhage in Norway].
AB  - Rapid and adequate endoscopic treatment is a vital part of the initial handling
      of gastrointestinal haemorrhage. A national survey was carried out to study the
      logistics of the initial handling of these patients. Replies were received from
      97% of the hospitals, each of which received an average of 11 patients per month
      with haematemesis/melena or rectal bleeding. Patients with haematemesis or melena
      were admitted primarily to medical departments or intensive care units, while
      patients with haematochezia were admitted most often to the surgical department.
      47% of the hospitals performed emergency endoscopy as a routine on patients with
      red haematemesis, but even in this group of patients, endoscopy was postponed
      until the first working day in some instances, provided that the patient's
      condition was stable. The majority of emergency flexible endoscopies are
      performed by internists, but most hospitals describe close inter-departmental
      cooperation in the handling of these patients. The situation was deemed
      satisfactory at 91% of the hospitals.

PMID- 8658438
TI  - [Good quality in nursing home services? An analysis based on assessments by the
      head nurse].
AB  - Until quite recently few systematic studies have been carried out to determine
      quality in Norwegian nursing homes. Contrary to the negative pictures depicted in
      the media, 212 head nurses in a sample of 116 nursing homes assessed the overall
      quality as fairly good. However, the results show a clear potential for
      improvement at some nursing homes. About 3/5 of the residents have single rooms,
      and the results confirm that this fraction should be increased. In several
      nursing homes the normal every day life of non-demented residents is strained;
      one third of the head nurses characterize the social environment of this group as
      unsatisfactory. Many residents are in need of medical care and most head nurses
      are pleased with the medical service. However, too few hours and lack of
      continuity cause dissatisfaction at one out of ten units. The study demonstrates
      a need for more frankness and for possibilities for the residents to express
      their views about life in the nursing home.

PMID- 8658439
TI  - [Timolol eyedrops and sinusitis].

PMID- 8658440
TI  - [Immune reaction against silicone? Testing of a test].

PMID- 8658441
TI  - [Effect of physical therapy and chiropractic].

PMID- 8658442
TI  - [Physical therapy without physicians' referral].

PMID- 8658444
TI  - [Deficient competence at hospitals].

PMID- 8658443
TI  - [Leadership in hospitals].

PMID- 8658445
TI  - [Interruptions of physicians' work at hospitals].

PMID- 8658446
TI  - [Smoking in a different country].

PMID- 8658447
TI  - [No one can freely decide about life, neither about his own life nor about the
      lives of others. On conflict between patients' autonomy and the obligation to
      help].

PMID- 8658448
TI  - [Increased number of admitted students--decreased quality of education?].

PMID- 8658449
TI  - [Successful treatment of children with leukemia diagnosed 1966-72. A follow-up 23
      29 years after diagnosis].
AB  - Childhood leukemia was considered an incurable disease up to the beginning of the
      1970. However, before 1976 we discontinued therapy in remission in 13 (30%) of 43
      new cases of acute lymphocytic leukemia/acute undifferentiated leukemia diagnosed
      in the period June 1966-December 1972. One of the 13 cases relapsed after three
      years and the other after 14 years. Both were successfully retreated. One
      received intermediate dose metotrexate (0.5 g metotrexate/m2), the other high
      dose metotrexate (8 g metotrexate/m2) as consolidation. All 13 cases were healthy
      at the time of follow-up in the autumn of 1994. One testis had been removed in a
      case with initial testicular involvement and testicular relapse. No other
      definite late effects were diagnosed following treatment for childhood leukemia
      in the 13 cases. The article also contains information on health and
      socioeconomic status. The mean height of the six males was 183 cm, and of the
      seven females 170 cm. Nine of the 13 lived with a partner, one alone and three
      with parents.

PMID- 8658450
TI  - [Acute abdomen in pregnancy. Diagnosis of surgical causes].
AB  - The diagnostic work up of an acute abdomen may be more difficult in pregnant than
      in non-pregnant women due to the normal anatomical and physiological changes that
      occur during pregnancy. Delayed diagnoses and treatment may have more serious
      consequences for pregnant women than for other patients. We report the cases of
      two pregnant women, one with a volvulus of the small intestine and the other with
      a perforated appendix. We discuss important aspects of the diagnostic work up for
      acute abdomen with surgical etiology in pregnant women. If a surgical etiology is
      suspected in a pregnant women with acute abdominal pain, the patient should be
      examined and followed closely both by a surgeon and a gynaecologist until a final
      diagnosis is reached.

PMID- 8658451
TI  - [A two-year retrospective study of patients with acute myocardial infarction in a
      Norwegian county hospital].
AB  - The article describes a follow-up study extending over a period of two years
      (1992-93) of patients admitted with a diagnosis of acute myocardial infarction to
      a Norwegian district hospital. The mortality was 13.8%. In Norway, treatment of
      acute myocardial infarction is generally standardized, with only minor variations
      between hospitals. This follow-up illustrates that patients with uncomplicated
      acute myocardial infarction who do not require emergency surgical intervention
      can be safely treated in a district hospital.

PMID- 8658452
TI  - [Diverticulitis of the colon. Diagnosis and treatment illustrated by a patient
      material].
AB  - During the period 1985-92, 181 patients were treated at Aker Hospital for
      diverticulitis of the colon. 106 patients (59%) were treated conservatively, and
      75 (41%) were operated on for complications. The mortality among the patients
      treated conservatively was 4.7%. 47 patients underwent operation in the acute
      stage, most often for perforation or intestinal obstruction, and the most
      frequent operation was the Hartmann procedure. 28 patients had an elective
      operation, the most common indication being a fistula from the colon. In this
      group the operation was usually resection with anastomosis. After acute
      operation, 17 patients (36%) experienced surgical complications, and the
      mortality was 12.8% (six patients). After elective operation the morbidity was
      low (2/28), and the mortality was nil. Our preferred principle for acute surgery
      for diverticulitis is colonic resection. This eliminates the source of
      contamination, and allows debridation and cleansing of the peritoneum.

PMID- 8658453
TI  - [Ambulatory surgery. Patients and patient education].
AB  - This article reviews the concept of day surgery and shows how the treatment can
      be organized pre-, per- and post-operatively. It can be established in a hospital
      integrated unit, a unit separate from the hospital, but connected with it, or a
      satellite ambulatory facility. Because the patient spends only a short time in
      hospital it is necessary to have structured preparations before admission, for
      the benefit of both patient and staff. It should be easy to identify patients
      suitable for day surgery from the waiting lists, and preparations should be
      directed at treatment by day surgery right from the start. Rules must be worked
      out for selecting patients, as well as guidelines for information to patients. It
      is also necessary to plan the operation programme, and to agree how nurses and
      doctors should take care of the patient during the different steps of treatment.

PMID- 8658454
TI  - [Thromboembolic complications in ambulatory surgery. A retrospective study of
      1691 patients].
AB  - The risk of thromboembolic complications in outpatient surgery is regarded as
      being low. Thromboembolic prophylaxis is seldom administered as a routine. A
      retrospective study in our outpatient department, based upon patients readmitted
      for clinical thromboembolism, showed an incidence of deep vein thrombosis of
      0.05% (8/1 691) and of pulmonary embolism 0.0006% (1/1 691). None of the patients
      received prophylaxis for thrombosis, and all operations were performed under
      regional anaesthesia of the lower extremity. 50% of the operations were performed
      using a tourniquet. 2/3 of the patients were women and 2/3 were over the age of
      50. Operation time was usually 30-45 minutes. Our study indicates that patients
      undergoing knee arthroscopy, and operations for varicose veins and hallux valgus
      are at risk of thromboembolism. Prospective studies of these risk groups are
      necessary to figure out the need for thrombosis prophylaxis.

PMID- 8658455
TI  - [Health damages from passive smoking].
AB  - Environmental tobacco smoke is a complex mixture of many chemical substances. The
      term passive smoking is used when a person breathes in air contaminated by
      tobacco smoke. Active and passive smoking expose an individual to the same
      substances, but the relative concentrations of the various substances differ.
      Thus, under conditions where individuals are exposed to an amount of nicotine
      corresponding to their smoking 1/2 a cigarette, they will be exposed to an amount
      of nitrosodimethylamine corresponding to their smoking about five cigarettes.
      Exposure of children to environmental tobacco smoke is associated with increased
      risk of lower respiratory tract infections, middle ear infections and asthma.
      Accumulating evidence points to passive smoking as a risk factor for the sudden
      infant death syndrome. Long term exposure to environmental tobacco smoke
      increases risk of lung cancer and heart disease. It is estimated that in Norway,
      50 non-smokers die of lung cancer and 300-500 of heart disease annually, as a
      result of long term exposure to environmental tobacco smoke.

PMID- 8658456
TI  - [How does smoking affect blood pressure?].
AB  - It has been known for a long time that blood pressure and heart rate increase
      during smoking. These effects are associated specifically with nicotine. The rise
      in blood pressure is due both to an increase in cardiac output and in total
      peripheral vascular resistance. The rise in blood pressure occurs immediately,
      before any increase in circulating catecholamines. In hypertensives the blood
      pressure lowering effect of beta-blockers may be diminished by tobacco smoking
      whereas alpha-receptor blockers on the other hand seem to maintain their
      antihypertensive efficacy. It is a paradox that while smoking acutely increases
      blood pressure, some extensive epidemiological studies have shown a slightly
      lower blood pressure level among smokers than among non-smokers. Because blood
      pressure may rise after discontinuation of smoking, a smoking cessation programme
      should not postpone initiation of antihypertensive drug therapy in patients
      otherwise in need of such treatment.

PMID- 8658457
TI  - [Health hazards when using snuff].
AB  - Snuff taking produces a white to yellowish, wrinkled lesion of the oral mucosa at
      the site where the quid is placed. The lesion is reversible, and only rarely
      exhibits dysplasia. Gingival recession and loss of attachment may occur in
      conjunction with the mucosal lesion. The risk of oral cancer varies greatly among
      the different published studies, from a relative risk of 48 to no increase in
      risk at all. Case control studies have found no association between oral tobacco
      and bladder cancer, whereas cigarette smoking carries a relative risk of about
      two. There appears to be no evidence for an association between oral snuff and
      cancer in general when the analysis takes into account confounders such as
      occupation, smoking and alcohol. The epidemiological evidence for an association
      with cardiovascular disease is contradictory. Snuff may probably cause
      hypertension, and one large study has reported a relative risk of 2 for dying of
      ischaemic heart disease. Biochemical evidence disfavors the hypothesis that snuff
      is atherogenic. In conclusion, the health hazards of oral moist snuff seem
      modest, and very much smaller than those of cigarette smoking.

PMID- 8658458
TI  - [Smoking habits and use of snuff in Norway 1973-95. Has the declining trend
      levelled off?].
AB  - A number of studies indicate that the prevalence of smoking declined among young
      Norwegian adults during the 1960s and 1970s. The present paper shows, however,
      that this decreasing trend seemed to level out during the 1980s. Hence the total
      prevalence of smoking in Norway decreased by only two percent units from 1980 to
      1993, as compared with approximately 10% in many other European countries. Among
      persons aged 16-19 years an increased prevalence of smoking has been observed in
      most recent years. Consequently, in 1995 the smoking prevalences among young
      males and females were about the same as observed around 1980. These trends in
      smoking prevalence and use of snuff are discussed with particular reference to
      the lack of emphasis on preventive measures that has characterised the Norwegian
      tobacco policy during the last decades; especially that the funds allocated for
      tobacco-related health education and information were reduced by 90% during the
      1980s.

PMID- 8658459
TI  - [From experimentation to habitual smoking. A three-year follow-up study of
      smoking behavior of adolescents].
AB  - Newer studies indicate that the decline in adolescent smoking observed in Norway
      in recent years has levelled off and that, in some groups, smoking seems to be
      increasing. The number of adolescents who experiment with tobacco has remained
      fairly constant. In this article we present findings from a prospective cohort
      study on the development of regular smoking among adolescents 13 to 16 years of
      age. The study started in 1990 with a representative sample of 13 year old
      adolescents (N = 1,195) in the county of Hordaland, Norway. Data from follow-up
      studies conducted in 1991, 1992 and 1993 are included. The results indicate that
      more than 60% of the adolescents had tried to smoke by the age of 15. For about
      half of those who tried, the experimentation marks the beginning of a smoking
      career that develops from occasional to regular smoking. By the age of 16, 28% of
      the girls and 16% of the boys had become daily smokers. Smoking status at age 13
      is a strong predictor of regular smoking three years later. For this reason,
      early adolescence is a period of primary importance with respect to prevention of
      smoking.

PMID- 8658460
TI  - [A country with big economic, social and medical problems].

PMID- 8658461
TI  - [Jehovah's Witnesses--blood transfusion or not? Are physicians all-time losers?].

PMID- 8658462
TI  - [Postmenopausal hormone therapy and venous thrombosis].

PMID- 8658463
TI  - [Do we know enough about pulmonary sounds?].

PMID- 8658464
TI  - [Medical research and drug industry].

PMID- 8658465
TI  - [Centenary of medical radiology--development in Norway].

PMID- 8658466
TI  - [The anemic health institutions].

PMID- 8658467
TI  - [Working condition of physicians during their graduate education].

PMID- 8658468
TI  - [Snowboard injuries].

PMID- 8658469
TI  - [Is being good (enough) typical for Norwegians? Life expectancy as compared to
      other countries].

PMID- 8658470
TI  - [In this world anything is possible. Medical consequences of torture].

PMID- 8658471
TI  - [The elderly physicians].

PMID- 8658472
TI  - [Communication between cancer patients and their physicians. Knowledge and
      attitudes].

PMID- 8658473
TI  - [You have cancer. A qualitative study of women's immediate reactions to diagnosis
      of breast cancer].
AB  - 92 women, 70 years and younger, consecutively admitted to Rogaland Central
      Hospital with a new diagnosis of breast cancer were interviewed the day before
      surgery. The aim of the study was to explore the women's reactions to the
      diagnosis. During the interview the patients were asked to speak for five minutes
      about what they felt, thought and did after learning they had cancer. The
      narratives were taped and analysed. The reactions are grouped under the headings:
      mental preparation, problem focusing, emotional and bodily reactions, coping
      strategies and support. There was a wide range of reactions, probably because of
      differences in coping ability, social support and vulnerability. The patients'
      need for thorough information is pointed out.

PMID- 8658474
TI  - [Torture-related injuries--a medical challenge. Diagnosis and treatment of
      Falanga victims].
AB  - Torture victims are generally reluctant to present complaints linked to the
      torture. Many patients from refugee populations have experienced traumatic events
      such as war, violence and torture. Health professionals need to know more about
      the nature of these traumas, and how to diagnose the sequelae of torture. If they
      are to give torture victims adequate treatment they need to be familiar with the
      relevant diagnostic procedures, and how to treat health problems caused by
      systematic violence. A clinical case history is used to present the method of
      torture called Falanga, the beating of the soles of the feet. The case shows how
      the diagnosis and treatment of the physical injuries have a marked effect on the
      rehabilitation process. After receiving treatment for his foot injuries,
      patient's physical and mental health both improved dramatically, as did his
      psychosocial rehabilitation.

PMID- 8658475
TI  - [Pulmonary function in Norwegian farmers keeping domestic animals].
AB  - In a group of farmers keeping domestic animals, all pulmonary function tests,
      except for PEF, showed lower values than in a Norwegian reference population.
      Spirometric values for FVC, FEV1, and PEF were higher among pig farmers than
      among other farmers. Poultry farmers had lower values of PEF compared to other
      farmers. One third of all farmers had values of FEF25-75% that were depressed
      more than 20%, possibly indicating that the smaller, more peripheral airways more
      frequently are affected than the central airways. No single causal factor for the
      reduced lung function was found, but farmers that worked in newer cow-stables had
      a lower lung function than other farmers, especially if the houses were built in
      the interval 1975-84.

PMID- 8658477
TI  - [Chronic non-allergic rhinitis. Etiology, diagnosis and treatment].
AB  - Chronic rhinitis can be defined as an inflammation of the nasal mucosa lasting
      for more than three months. The condition may be due to allergy or infection, or
      to a number of non-allergic and non-infectious causes, such as trauma, hormonal
      imbalance, toxic influence or locally applied drugs. The etiology, diagnostic
      procedures and treatment of non-allergic chronic rhinitis are discussed.

PMID- 8658476
TI  - [Prion diseases. Review of the literature on the light of two case reports of
      Creutzfeldt-Jakob disease].
AB  - During the last ten years the diseases scrapie in sheep and bovine spongiform
      encephalopathy (or mad cow disease) in cattle have received increased attention.
      Through the 1960s it became apparent that scrapie in sheep and kuru and later
      Creutzfeldt-Jakob disease in man were infectious diseases. During the last decade
      the appearance of mad cow disease in Great Britain has increased the fear that
      humans can develop Creutzfeldt-Jakob disease through their food. A special
      characteristic of the infectious agent, the prion, is its lack of DNA. It has
      been shown that the prion most probably has a pure protein structure. The prion
      may exist in two slightly different structural patterns, one of which induces the
      various prion diseases in animals and man. In 1994 two men with Creutzfeldt-Jakob
      disease were diagnosed at Haukeland Hospital. Their symptoms and clinical data
      are presented, together with a review of the literature on prion diseases in
      animals and man.

PMID- 8658478
TI  - [Myxedema--an early model for hormone research].
AB  - Myxoedema, later known as hypothyroidism, was first described in England in 1873.
      During the following years it was thought that the disease was caused by a lesion
      in the nervous system. However, towards the end of the century it was established
      that the thyroid gland produced an essential substance later known as a hormone.
      An efficient treatment was introduced, consisting of different forms of tissue
      extracts. The thyroid gland and myxoedema became a model for the development of
      the concept of internal secretion. Norwegian physicians were well informed about
      the scientific advances and quickly accepted the new principles of treatment.
      This article describes the first Norwegian reference to the disease and its
      treatment.

PMID- 8658479
TI  - [The story of suffering. On the traces of narrative medicine].
AB  - In recognising the importance of narratives of illness we conducted a study on
      the ability of a specific method to elicit the patient's story. A Five Minute
      Speech Sample (FMSS) interview was applied to 92 patients with a recent diagnosis
      of breast cancer. According to Mishler, a complete narrative has six elements:
      abstract, orientation, complicating action, evaluation, result and coda, with
      complicating action and evaluation as the essential parts. Of the 92 patients, 50
      gave a narrative during the FMSS. One of the narratives is referred in detail.
      The article advocates giving renewed attention to patients' stories, because they
      bring the doctor closer to the patients' point of view. This is particularly
      important when dealing with chronic illness and crises.

PMID- 8658480
TI  - [Suicidal process and suicidal motives. Suicide illustrated by the art, life and
      illness of Vincent van Gogh].
AB  - A suicide will naturally be a shock to the surroundings, unexpected and brutal as
      it is. Suicide survivors will often emphasize the unexpected. Nevertheless a
      suicide must be regarded as the end result of a long process. In this paper the
      extremely well-documented case of Vincent van Gogh is used to study suicidal
      processes and suicidal motives. In van Gogh's case, an early childhood trauma
      initiated a life-long suicidal process. His difficulties as regards attachment to
      and separation from his parents continued throughout his life and his emotional
      instability, intensity and lowered tolerance to frustration seem to portray a
      borderline personality. Vincent van Gogh's chronic suicidal ideation and
      behaviour led to a series of crises throughout his life, escalating during the
      last 18 months before his suicide in 1890. It is possible to identify at least
      three prominent suicidal motives in van Gogh's case. The first is unbearable
      emotional pain related to personal experience of loss which reactivated the
      childhood trauma. The second is introverted murderous rage arising from conflicts
      with other persons. The third motive described is the need for a cathartic
      release of energy and emotion.

PMID- 8658482
TI  - [Olympic games 1994 and the Medical Department, Lillehammer county hospital].
AB  - Lillehammer is a town with almost 24,000 inhabitants. During the 16 days of the
      XVII Olympic Winter Games in February 1994, approximately 1.9 million spectators
      visited the area. The << extra >> population during that period, led to 50 people
      being admitted for treatment in the Medical Department at Lillehammer County
      Hospital, i.e. 2.6 per 100,000 spectators. The number of admissions of persons
      from the resident population was lower than during the same period in previous
      years.

PMID- 8658481
TI  - [Life expectancy in Norway--an international perspective].
AB  - Contrasts in life expectancy among countries are an important input for defining
      targets for the health service and for setting priorities for disease prevention
      and health promotion. In this article, the trend in life expectancy in Norway is
      compared with the trend in a selection of other OECD countries. Standardised
      measures of life expectancy were collected from WHO and OECD statistics. In 1960
      Norwegians ranged among the top three countries as regards life expectancy for
      both women and men. In 1990 Norwegians ranged tenth for women and ninth for men.
      Life expectancy was two years shorter for Norwegian than for Japanese women in
      1990, corresponding to a 20% surplus mortality throughout life. Similar
      differences were found for men. If Japanese age specific death rates are applied
      to the Norwegian population, this corresponds to a reduction of 9,600 deaths this
      year. The relatively unfavourable trend in life expectancy in Norway relative to
      other OECD countries raises concern, and should be considered when designing the
      future health policy.

PMID- 8658483
TI  - [Can vitamin E prevent development of coronary heart disease?].
AB  - Oxidation of low-density lipoprotein (LDL) probably plays an important part in
      atherosclerosis. Vitamin E (alpha-tocopherol) is a potent antioxidant carried in
      LDL. It increases the resistance of LDL to oxidation, thereby, among other
      things, inhibiting foam cell formation and proliferation of smooth muscle cells.
      Some animal experiments have indicated that vitamin E retards the development of
      atherosclerotic lesions. Observational studies (case-control and cohort) have
      shown that long-term treatment with vitamin E is associated with lower incidence
      of coronary heart disease in men and women alike. Randomisation to vitamin E in a
      large placebo controlled trial gave a nonsignificant reduction in mortality from
      ischemic heart disease. Although vitamin E seems to reduce the risk of coronary
      heart disease, randomised trials of adequate size are necessary in both secondary
      and primary prevention in order to test this. Such trials are in progress.

PMID- 8658484
TI  - [Medicine--sciency or intuition?].

PMID- 8658485
TI  - [Human failure--more frequent than expected?].

PMID- 8658486
TI  - [Multiple sclerosis, are we on the right track?].

PMID- 8658487
TI  - [Complications of acupuncture].

PMID- 8658488
TI  - [Health hazards of passive smoking].

PMID- 8658489
TI  - [Increased measures against smoking].

PMID- 8658491
TI  - [Quality assurance in surgery].

PMID- 8658490
TI  - [Occupational conditions for hospital-employed physicians during continuing
      education].

PMID- 8658492
TI  - [Infectious fluids in plastic bags].

PMID- 8658493
TI  - [The insurance authority should be privatized].

PMID- 8658494
TI  - [Viral hemorrhagic disease: an overview and personal data].
AB  - A review is given of current knowledge of taxonomy, clinical symptoms,
      pathogenesis and pathology, diagnosis, epizootiology and prevention of Viral
      Haemorrhagic Disease (VHD). We also report our own experiences with the
      (histo)pathology, laboratory diagnosis, and epizootiology of this disease. The
      frequency of other diagnoses in an eighteen months period.

PMID- 8658495
TI  - [Monitoring General Inspection Service for animal medications, meat and welfare].

PMID- 8658496
TI  - [Alopecia above the tail base in cats].

PMID- 8658497
TI  - [Contraceptive tablets for the cat].

PMID- 8658498
TI  - Vanadium-induced chemokine mRNA expression and pulmonary inflammation.
AB  - Occupational exposure to vanadium is common in petrochemical, mining, steel, and
      utilities industries and results in toxic effects largely confined to the
      respiratory system. Vanadium exposure has been associated with inflammatory
      changes in the upper and lower respiratory tracts in addition to changes in
      pulmonary function. We investigated the abilities of several vanadium compounds
      to increase mRNA levels for selected cytokines in bronchoalveolar lavage (BAL)
      cells and also to induce pulmonary inflammation. Rats (200-250 g) were
      intratracheally instilled with either sodium metavanadate (NaVO3), vanadyl
      sulfate (VOSO4), vanadium pentoxide (V2O5) at several concentrations, or vehicle
      alone. Pulmonary inflammation was assessed by cytologic analysis of cells
      recovered from the respiratory tract (1 hr to 10 days postexposure). All three
      vanadium compounds were capable of inducing pulmonary inflammation in a dose
      dependent manner. Neutrophil influx was greatest following exposure to VOSO4
      (peaked at approximately 40% of cell population) and lowest following exposure to
      V2O5 (peaked at approximately 20 %). Significant neutrophil influx was detected
      as early as 4 hr following the instillation of NaVO3 and VOSO4 but not until 24
      hr upon exposure to V2O5. The VOSO4-induced inflammatory response persisted
      longer (5 days) than that induced by NaVO3 and V2O5. Analysis of inflammatory
      cytokine mRNA expression closely followed these cytologic observations. Levels of
      mRNA for macrophage inflammatory protein-2 (MIP-2) and KC, considered the
      principal neutrophil chemotactic factors expressed in the rat, were rapidly
      induced as early as 1 hr following exposure, continued to be expressed throughout
      48 hr, and were low but detectable at 5 and 10 days. NaVO3 and VOSO4, both very
      soluble forms of vanadium, tended to induce pulmonary inflammation and
      inflammatory cytokine mRNA expression more rapidly and more intensely than the
      less soluble form, V2O5. Analysis of KC mRNA expression in BAL cells 24 hr after
      instillation of NaVO3 by PCR in situ hybridization confirmed the increase in KC
      mRNA levels and indicated that alveolar macrophages have the highest expression
      level observed. Vanadium content of lavage fluid, BAL cells, and lung indicated
      rapid clearance of the metal from the lung surface and substantial accumulation
      by BAL cells and lung tissue. The rapid expression of MIP-2 and KC mRNA in BAL
      cells prior to the observed neutrophilia implicate them as important in the
      initiation of inflammation.

PMID- 8658499
TI  - Vanadium affects macrophage interferon-gamma-binding and -inducible responses.
AB  - Mouse WEHI-3 cells were exposed overnight to vanadium [V; ammonium metavanadate
      (NH4VO3) or vanadium pentoxide (V2O5)] to determine whether documented V-induced
      immunomodulation might arise from altered macrophage (M phi) interactions with
      interferon-gamma (IFN gamma) or altered IFN gamma-inducible responses. Binding
      studies performed at 22 degrees C indicated that although NH4VO3-pretreated cells
      had approximately 48% fewer actively-binding Class I IFN gamma receptors, binding
      affinities were 1.5-fold greater than that of control cell receptors; Class II
      expression was unaffected but affinities were reduced 2-fold. Postbinding IFN
      gamma-receptor complex internalization was unaffected by V pretreatment.
      Spontaneous production of both hydrogen peroxide and superoxide anion was
      significantly increased by treatment with both V compounds. Total hydrogen
      peroxide and superoxide production was increased by stimulation of IFN gamma
      primed cells with zymosan, but relative increases in primed V-treated cells were
      lower than that in controls. Vanadium-treated cells also displayed decreased
      rates of IFN gamma-induced changes in [Ca2+]i levels secondary to increased
      resting [Ca2+]i levels. Although V-treated cells did not display significant
      increases in I-A expression after IFN gamma treatment, increased numbers of I-A+
      cells (irrespective of priming) and lower maximal antigen densities than observed
      on I-A+ control cells were evident. Results from this study show that V exposure
      may produce alterations in M phi-mediated functions, in part, by modifying cell
      interactions with IFN gamma and subsequent IFN gamma-dependent functional
      parameters.

PMID- 8658500
TI  - Mechanism of menadione-induced cytotoxicity in rat platelets.
AB  - The elevation of intracellular Ca2+ in various tissue through oxidative stress
      induced by menadione has been well documented. Increase of Ca2+ level in
      platelets results in aggregation of platelets. To test the hypothesis that
      menadione-induced Ca2+ elevations can play a role in platelet aggregation, we
      have studied the effect of menadione on aggregation of platelets isolated from
      female rats. Treatment with menadione to platelet-rich plasma (PRP), which proved
      to be an adequate system, appeared to induce dose-dependent platelet aggregations
      up to 60%, as determined by aggregometry. However, exposure of PRP to menadione
      led to slow reduction of platelet cell number coincident with a loss of
      viability, as measured by lactate dehydrogenase leakage, suggesting that
      menadione might induce cell lysis rather than aggregation of platelets. Light
      microscopy confirmed that menadione reduced the number of platelets and failed to
      show aggregates of platelets. To elucidate the mechanism of this cytotoxicity,
      menadione-induced oxygen consumption was studied in intact rat platelets.
      Incubation of platelets with menadione resulted in rapid dose-dependent increases
      of oxygen consumption, which were not inhibited by indomethacin and
      nordihydroguaiaretic acid, suggesting that menadione did not affect the
      cyclooxygenase and lipoxygenase pathways in platelets. Oxygen consumption, as
      well as cytotoxicity by menadione, was unaffected by addition of dicoumarol,
      which is a quinone reductase (QR) inhibitor. Consistent with these findings, no
      activity of QR was detected in any subcellular fractions of platelets. Oxygen
      consumption by several subcellular platelet fractions treated with menadione was
      examined in the presence of NADPH or NADH. Additions of NADPH or NADH to
      microsomal fractions or a 9000 g pellet (which contains plasma membranes) led to
      2-fold to 18-fold elevations in platelets may contribute to the oxidative damage
      associated with menadione-induced oxygen consumption, respectively. These results
      suggest that NADPH and/or NADH-dependent enzyme systems in menadione-induced
      cytotoxicity.

PMID- 8658501
TI  - Plasma and blood lead concentrations, lead absorption, and lead excretion in
      nonhuman primates.
AB  - In order to assess the comparability of lead disposition in the cynomolgus monkey
      to that in the human, we determined the relationships among blood lead
      concentration, plasma lead concentration, and lead excretion in monkeys. Six
      adult (3-5 kg) female cynomolgus monkeys (Macaca fascicularis) without previous
      experimental lead exposure were given single intravenous injections of from 750
      to 3300 micrograms lead as lead nitrate, labeled with 210Pb, per kilogram body
      weight. Four additional monkeys, fasted overnight, were administered single oral
      doses of either 750 or 1500 micrograms lead as lead nitrate, labeled with 210 Pb,
      per kilogram for the assessment of fractional absorption. Blood and plasma lead
      concentrations (10 monkeys) and urinary and fecal excretion of lead (2 monkeys)
      were followed up for up to 16 days after lead administration. Fractional
      absorption from an oral dose was 44% at the lower of the two doses and 22-28% at
      the higher dose. The relationship between plasma and blood lead concentrations
      was found to be similar to that in humans, with plasma lead concentration at most
      a few percent of total blood lead concentration at low concentrations.
      Partitioning of lead across the red cell membrane in the 2 monkeys given
      exceptionally high doses (3300 micrograms/kg) intravenously was distinctly lower
      than that in the 4 monkeys given lower intravenous doses. Urinary clearance of
      lead in these 2 monkeys was 19% of the estimated glomerular filtration rate,
      within the range of efficiencies reported for humans. Fecal clearance, however,
      was anomalous and appeared to be an artifact of the very high dose. Examination
      of published data for urinary and fecal lead excretion in three adult baboons
      showed that both functions in the baboons were quantitatively similar to those in
      humans. Urinary clearance in the baboons was 14-24% of the estimated glomerular
      filtration rate, and fecal clearance was 78-85% of the urinary clearance. We
      conclude that nonhuman and human primates are comparable with respect to the
      relationship of plasma lead concentration to blood lead concentration and the
      relative efficiency of lead excretion in urine and feces.

PMID- 8658502
TI  - Promotion of endometriosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats and
      mice: time-dose dependence and species comparison.
AB  - In the disease of endometriosis, endometrial tissue grows outside the uterus,
      usually in the peritoneal cavity. Rodent models of endometriosis allow a way to
      reproduce the disease, evaluate effects of chemicals, and study mechanisms.
      Twenty-one days prior to induction surgery which produces endometriosis, female
      Sprague-Dawley rats and B6C3F1 mice were pretreated with 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) at 0, 3 or 10 micrograms TCDD/kg. Animals were
      treated again at the time of surgery and at 3, 6, and 9 weeks following surgery.
      Evaluations were made at 3, 6, 9, and 12 weeks postsurgery. TCDD produced a dose
      dependent increase in endometriotic site diameter when all time points were
      pooled within each dose in rats and a dramatic increase in site diameter in mice
      at 9 and 12 weeks. In rats but not mice, ovarian weight was decreased at 9 and 12
      weeks, the occurrence of persistent vaginal estrus was increased at these times,
      and histological evaluation of the ovaries revealed ovulatory arrest at 12 weeks.
      In both species, thymic antrophy, indicating immune dysfunction, and hepatomegaly
      were observed as consequences of TCDD exposure. Body weight was reduced in rats
      but not in mice. Histological evaluations of endometriotic sites revealed
      fibrosis in control rats, necrotic and inflammatory changes in the sites from
      TCDD-treated rats, and predominantly fibrotic changes in sites from TCDD-treated
      mice. Differences observed between the rat and the mouse with respect to (a) the
      magnitude of the effect on endometrial site diameter (rats < mice), (b) measured
      effects on ovarian function (rats > mice) that may be based on the partial
      antiestrogenicity of TCDD, and (c) evidence that mice and rats differ in their
      immune response to TCDD suggest that the mechanisms mediating TCDD's action to
      promote endometriosis are complex and may be different in rats and mice. The
      mouse may be a better model for future studies necessary to elucidate these
      mechanisms.

PMID- 8658503
TI  - Liver injury and expression of cytochromes P450: evidence that regulation of
      CYP2A5 is different from that of other major xenobiotic metabolizing CYP enzymes.
AB  - The purpose of this study was to find out how liver injury caused by two well
      known hepatotoxins, chloroform and thioacetamide, alters the expression of
      hepatic xenobiotic metabolizing cytochrome P450 (CYP) enzymes of DBA/2N mice.
      Dose-dependent toxic effects of the two hepatotoxins were verified by
      histological examination. Along with the toxicity, intense staining of
      immunoreactive material was detected in the centrilobular zone, with anti-CYP2A5
      antibody in hepatic tissue. This apparent increase in the expression of Cyp2a-5
      was verified by Northern blot and Western blot analyses and by determining the
      enzymatic activity, coumarin 7-hydroxylase, in hepatic tissue. The results
      suggest that liver injury due to these hepatotoxins increases the expression of
      Cyp2a-5 and that the expression is pretranslationally regulated. The increased
      expression of Cyp2a-5 is in contrast with that of other xenobiotic metabolizing
      CYPs because a dose-[dose-dependent] dependent decrease of the total hepatic P450
      content and either a decrease or no change in the levels of CYP1A, 2B, 2C, 2E1,
      and 3A4 were observed. The results suggest that essential differences exist in
      the regulation of CYP2A5 and other major xenobiotic metabolizing CYP enzymes and
      that in a damaged liver CYP2A5 may be a major catalyst of xenobiotic metabolism.

PMID- 8658504
TI  - Lead differentially modifies cytokine production in vitro and in vivo.
AB  - An imbalance between helper T cell type 1 (Th1) and helper T cell type 2 (Th2)
      activation can result in immunodysregulations leading to impaired cell-mediated
      immunity with an increased incidence of infectious disease or cancer and/or
      aberrant humoral immunity that may culminate with an autoimmune disease. Mercury,
      a heavy-metal toxicant, is known to induce renal autoimmunity characterized by a
      predominant Th2 response. Lead, another metal toxicant, causes enhanced B cell
      activities and impairs host resistance to several bacterial and viral infections.
      In addition, Pb was reported to enhance Th2 proliferation and inhibit Th1
      proliferation. The differential effects of Pb on Th subset activation have been
      further investigated. In vitro IL-4 production by a Th2 clone was significantly
      increased by the addition of PbCl2, whereas IFN gamma production by a Th1 clone
      was decreased by the addition of PbCl2. When BALB/c mice were subcutaneously
      exposed to PbCl2, ex vivo Il-4 production by anti-CD3-stimulated splenic T cells
      was enhanced, but IFN gamma production was inhibited. Additionally, the plasma IL
      4 and IgE levels of Pb-exposed mice were increased, and the plasma IFN gamma
      levels were significantly lowered in the absence of any additional exogenous
      antigen. In vitro, ex vivo, and in vivo treatment with HgCl2 produced similar
      findings. This study is the first report of the preferential activation of a Th2
      response by Pb in vivo and suggests that PB, like Hg, may induce autoimmune
      responses by upsetting the balance between Th1- and Th2-like cells, which could
      enhance production of antibodies to self antigens.

PMID- 8658505
TI  - Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disposition following
      pulmonary, oral, dermal, and parenteral exposures to rats.
AB  - In evaluating human health risks posed by dioxins, it is necessary to accurately
      predict systematic dosimetry or the fate of these chemicals. Pharmacokinetic
      parameters pertaining to inhalation, ingestion, and dermal absorption may be
      estimated using animal models. The present study was designed to assess
      absorption, tissue distribution, and elimination of TCDD following intratracheal
      instillation (itr.), oral gavage (p.o.), or intravenous administration (i.v.) of
      1 nmol [3H]TCDD/kg to male rats; experimental conditions were chosen to permit
      comparison to a previous dermal disposition study (Banks and Birnbaum, Toxicol.
      Appl. Pharmacol. 107, 302-310, 1991). After treatment, rats were housed in
      individual metabolism cages for 3 days with daily excreta collection. Following
      termination, radioactivity was quantified in tissues and excreta. By 3 days
      postexposure, fecal excretion accounted for 22 (i.v.), 26 (itr.), and 32% (p.o.)
      of dose, while urinary excretion was only 2.2 (i.v.), 1.3 (itr), and 1.4% (p.o.).
      Pulmonary absorption was calculated as 95% of administered dose, while oral
      absorption was 88%. Dermal absorption of an equivalent administered dose was 40%
      (Banks and Birnbaum, 1991). For all exposure routes by 3 days, major tissue
      depots for absorbed dose were liver and fat. Distribution of absorbed dose was
      37% (i.v.) and 35% (itr.) to liver and 21% (i.v.) and 16% (itr.) to fat. Oral
      gavage-treated rats had similar dosimetry (28-30% absorbed dose) in both liver
      and fat. In contrast following dermal exposure, distribution to liver and fat was
      52 and 22%, respectively (Banks and Birnbaum, 1991). Results suggest that
      inhalation can be an important route for systemic absorption of dioxins.
      Moreover, all environmentally relevant routes of exposure (oral, dermal, and
      respiration) must be uniquely considered as important routes of systemic exposure
      for TCDD and related compounds.

PMID- 8658506
TI  - Specific antagonist of retinoid toxicity in mice.
AB  - AGN 193109 was recently identified as a potent retinoic acid receptor (RAR)
      antagonist in vitro. The purpose of the present study was to determine if AGN
      193109 functions as an RAR antagonist in vivo and thus could prevent and/or treat
      retinoid toxicity. Female hairless mice were treated topically for 5 consecutive
      days with the synthetic retinoic acid receptor agonist (E)-4-[2-(5,6,7,8-
      tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propen-1-yl]benzoic acid (TTNPB) alone
      or in the presence of a 1-, 4-, or 16-fold molar excess of AGN 193109. TTNPB
      caused skin flaking, skin abrasions, and splenomegaly, and these effects were
      blocked in a dose-dependent fashion by AGN 193109 cotreatment. In the same model,
      AGN 193109 also decreased topical irritation induced by the natural RAR agonist,
      all-trans-retinoic acid. To determine if topical AGN 193109 could block toxicity
      induced by an oral retinoid, mice were treated by gavage with TTNPB (0.75
      mumol/kg/day) and topically with 0, 0.3, or 1.2 mumol/kg/day of AGN 193109 for 4
      days. TTNPB treatment alone caused cutaneous irritation and weight loss, and
      these effects were inhibited by AGN 193109 cotreatment. To determine if AGN
      193109 could be used to treat preexisting retinoid toxicity, mice were pretreated
      topically on Days 1-2 with TTNPB (0.72 mumol/kg/day) and then treated topically
      on Days 3-5 with 0, 1.44, 7.2, or 36.0 mumol/kg of AGN 193109. TTNPB pretreatment
      caused precipitous weight loss and, in the absence of AGN 193109 intervention,
      60% mortality. AGN 193109 treatment at all dose levels significantly accelerated
      recovery of body weight and prevented death in TTNPB-intoxicated mice. These data
      demonstrate that AGN 193109 is a potent RAR antagonist and a potential antidote
      of retinoid intoxication in vivo. In addition to potential clinical applications
      in the prevention and treatment of retinoid toxicity, AGN 193109 should provide a
      powerful experimental tool for the elucidation of retinoid biology.

PMID- 8658508
TI  - Antidotal effect of dihydroxyacetone against cyanide toxicity in vivo.
AB  - Potassium cyanide (CN) intoxication in mice was found to be effectively
      antagonized by dihydroxyacetone (DHA), particularly if administered in
      combination with another CN antidote, sodium thiosulfate. Cyanide-induced
      convulsions were also prevented by DHA treatment, either alone or in combination
      with thiosulfate. Injection (i.p.) of DHA (2 g/kg) 2 min after or 10 min before
      CN (s.c.) increased LD50 values of CN(8.7 mg/kg) by factors of 2.1 and 3.0,
      respectively. Treatment with a combination of DHA and thiosulfate after CN
      increased the LD50 by a factor of 2.4. Pretreatment with a combination of DHA and
      thiosulfate (1 g/kg) increased the LD50 of CN to 83 mg/kg. Administration of
      alpha-ketoglutarate (2.0 g/kg), but not pyruvate, 2 min after CN increased the
      LD50 of CN by a factor of 1.6. Brain, heart and liver cytochrome oxidase
      activities were also measured following in vivo CN treatment with and without
      DHA. Pretreatment with DHA prevented the inhibition of cytochrome oxidase
      activity by CN and treatment with DHA after CN accelerated the recovery of
      cytochrome oxidase activity, especially in brain and heart homogenates. DHA is a
      physiological agent and, therefore, could prove to be a safe and effective
      antidote for CN, particularly in cases of fire smoke inhalation in which a
      combination of CN and carbon monoxide is present. In these cases the normally
      used antidote, sodium nitrite, to induce methemoglobin so as to trap the CN, is
      contraindicated because some of the oxygen-carrying capacity of the blood will
      have already been diminished by carbon monoxide.

PMID- 8658507
TI  - Time-dependent changes of inflammatory mediators in the lungs of humans exposed
      to 0.4 ppm ozone for 2 hr: a comparison of mediators found in bronchoalveolar
      lavage fluid 1 and 18 hr after exposure.
AB  - Acute exposure of humans to ozone results in reversible respiratory function
      decrements and cellular and biochemical changes leading to the production of
      substances which can mediate inflammation and acute lung injury. While pulmonary
      function decrements occur almost immediately after ozone exposure, it is not
      known how quickly the cellular and biochemical changes indicative of inflammation
      occur in humans. Increased bronchoalveolar lavage (BAL) fluid levels of
      neutrophils (PMNs) and prostaglandins (PGE2) have been reported in humans as
      early as 3 hr and as late as 18 hr after exposure. The purpose of this study was
      to determine whether a broad range of inflammatory mediators are elevated in BAl
      fluid within 1 hr of exposure. We exposed eight healthy volunteers twice: once to
      0.4 ppm ozone and once to filtered air. Each exposure lasted for 2 hr during
      which the subjects underwent intermittent heavy exercise (66 liters/min). BAL was
      performed 1 hr after the exposure. Ozone induced rapid increases in PMNs, total
      protein, LDH, alpha-1 antitrypsin, fibronectin, PGE2, thromboxane B2, C3a, tissue
      factor, and clotting factor VII. In addition, there was a decrease in the
      recovery of total cells and alveolar macrophages, and decreased ability of
      alveolar macrophages to phagocytize Candida albicans. A comparison of these
      changes with changes observed in an earlier study in which subjects underwent BAL
      18 hr after an identical exposure regimen indicates that IL-6 and PGE2 levels
      were higher 1 hr after exposure than 18 hr after exposure, fibronectin and tissue
      plasminogen activator levels were higher 18 hr after exposure, and that PMNs,
      protein, and C3a were present at essentially the same levels at both times. These
      results indicate that (i) several inflammatory mediators are already elevated 1
      hr after exposure; (ii) some mediators achieve their maximal levels in BAL fluid
      at different times following exposure. These data suggest that the inflammatory
      response is complex, depending on a cascade of timed events, and that depending
      on the mediator of interest one must choose an appropriate sampling time.

PMID- 8658509
TI  - Modeling the number and size of hepatic focal lesions following exposure to
      2,3,7,8-TCDD.
AB  - Data on the size and number of placental glutathione S-transferase-positive
      (PGST+) foci were collected from a two-stage hepatocarcinogenesis model in female
      Sprague-Dawley rats. the study consisted of multiple 2,3,7,8-tetrachlorodibenzo-p
      dioxin (TCDD)-exposed dose groups including both diethylnitrosomine (DEN)
      initiated and uninitiated animals. Groups were observed after 15 or 31 weeks of
      TCDD exposure. The parameters in the first half of a two-stage mathematical model
      of carcinogenesis were estimated from these data. If the model is valid, the
      results suggest that TCDD stimulates the production of PGST+ foci and promotes
      the growth of PGST+ foci. This finding suggests a complicated mechanism for TCDD
      induced production of Hepatic foci that we refer to as activation, labeling TCDD
      as an activator. The analysis also indicates that there is an interaction between
      DEN and TCDD which results in dose-related formation of initiated cells
      throughout the study period. Best-fitting curves (using maximum likelihood
      methods) for TCDD-induced activation and promotion reached saturation levels at
      low doses of TCDD. In summary, the model fit the data well, but leads to an
      interpretation of the data which either questions the validity of the model or
      implies that our understanding of the effects of TCDD and DEN is incomplete.

PMID- 8658510
TI  - Quantitative analysis of enzyme-altered liver foci in rats initiated with
      diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or
      1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin.
AB  - A quantitative method based upon a stochastic model was used to estimate rates of
      initiation (alteration to express the ATPase-deficient phenotype) and of clonal
      growth of altered cells in an initiation promotion experiment in the livers of
      female Wistar rats. Diethylnitrosamine (DEN) was used as the initiating agent
      followed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 1,2,3,4,6,7,8
      heptachlorodibenzo-p-dioxin (HCDD) as promoters. Two distinct versions of the
      stochastic model, called Model I and Model II, were fitted to the data. Model I
      made the assumption that, after the initial phase of acute initiation with DEN,
      background rates of initiation were equal in animals treated with DEN and
      controls that were not so treated. Model II, which fit the data substantially
      better than Model I, assumed that background rates of initiation were different
      in DEN-treated animals and animals not so treated, even after the acute phase of
      initiation was over. Both models indicate that the rates of cell division and
      apoptosis of altered cells are increased during TCDD treatment. In contrast, the
      rate of division remains more or less constant during treatment with HCDD, but
      the rate of apoptosis is decreased. The background rate of initiation during
      treatment with HCDD is equal to that in controls not administered promoters. With
      TCDD treatment, however, the rate of initiation estimated from the model is
      substantially increased over controls. The analysis also suggests that there is
      heterogeneity within foci of the rates of cell division, with cells on the
      surface of foci dividing faster than cells in the interior.

PMID- 8658511
TI  - Developmental exposure to lead interferes with glial and neuronal differential
      gene expression in the rat cerebellum.
AB  - Exposure to lead (Pb) has been shown to disrupt developmental processes in the
      brain and to result in impaired brain function. In these studies, we examined the
      role of differential gene expression as a possible target site which may
      partially mediate Pb's neurotoxicity. Animals were lactationally exposed to 0.2%
      lead acetate from birth to weaning. On postnatal days (PND) 3, 6, 9, 12, 15, 20,
      25, 30, 40, and 50, the cerebelli of control and Pb-exposed pups were examined,
      by Northern blot analysis for changes in the developmental profiles of
      neuronotypic and gliotypic markers: Growth-associated protein (GAP-43), myelin
      basic protein (MBP), and glial fibrillary acidic protein (GFAP), while actin was
      monitored as an indicator of generalized effects on developmental gene expression
      and exhibited no significant changes following Pb exposure. On PND 9, Pb exposure
      resulted in a significant stimulation in the expression of the neuronal GAP-43
      mRNA. Although Pb induced an early onset of MBP gene expression, the mRNA levels
      for both MBP and GFAP were decreased between PND 20 and 50, in Pb-exposed
      animals. These studies suggest that exposure to Pb may selectively interfere with
      critical developmental gene expression.

PMID- 8658513
TI  - A physiologically based model of chromium kinetics in the rat.
AB  - A physiologically based model of chromium kinetics in rats has been developed.
      The general structure of the model is similar to that of a model of lead kinetics
      in rats. Like lead chromium exchanges between plasma and the bone surfaces in
      contact with plasma, and also like lead, although with much lower efficiency, it
      can become incorporated into actively mineralizing bone. Both processes are
      included in the model. Parallel absorption and disposition schemes for
      chromium(VI) and chromium(III) are linked in the model by reduction processes
      occurring throughout the body, including the lung and gastrointestinal tract.
      Examination of a number of data sets from studies in which chromium salts were
      administered to rats intravenously, orally, or by intratracheal instillation
      established that intravenous administration, on the one hand, and oral or
      pulmonary administration, on the other hand, result in different disposition
      patterns. The model was calibrated based on published oral and intratracheal
      kinetic studies in rats given soluble chromium(III) and chromium(VI) salts. In
      the most complete of these studies, chromium concentrations were monitored in
      individual tissues for 42 days following intratracheal administration of a
      soluble chromium(VI) salt. Inclusion in the model of a urinary excretion delay
      was necessary in order to fit excretion data from two other intratracheal
      studies. Model predictions of blood chromium concentrations are compared with the
      results of a published kinetic study in which rats were administered a soluble
      chromium(VI) salt by inhalation.

PMID- 8658512
TI  - Diisopropylphosphorofluoridate-induced cholinergic hyperactivity and lipid
      peroxidation.
AB  - In the present study, the association between acetylcholine (ACh)-induced muscle
      necrosis and the appearance of lipid peroxidation products was investigated.
      Lipid peroxidation in this injury was quantified by the malondialdehyde
      thiobarbituric acid complex (TBA-MDA) using HPLC. To induce muscle necrosis, rats
      were treated with 1.0 or 2.0 mg/kg diisopropylphosphorofluoridate (DFP), an
      irreversible inhibitor of AChE that induced muscle fasciculations, and were
      euthanized 30-120 min after the DFP treatment. DFP caused a dose-dependent
      increase in AChE inhibition, muscle fasciculations, TBA-MDA formation, and muscle
      necrosis. Reduction of glutathione (GSH) by pretreatment with buthionine
      sulfoximine (BSO) potentiated the DFP-induced changes in TBA-MDA and caused an
      increase in the number of necrotic muscle fibers. Prevention of fasciculations by
      pretreatment with cholinergic antagonists such as atropine and d-tubocurarine,
      before DFP, inhibited the increase in lipid peroxidation, and significantly
      attenuated the muscle fiber necrosis. Without affecting muscle fasciculations,
      the antioxidant U-78517F prevented the increase in lipid peroxidation and reduced
      the number of muscle fibers that became necrotic. It is suggested that DFP
      induced AChE inhibition causes pronounced muscle hyperactivity as the initial
      step that triggers free radical-induced lipid peroxidation as the final common
      pathway to muscle injury.

PMID- 8658514
TI  - Distinct signal transduction pathways for activation of rabbit alveolar
      macrophages in vitro by cotton bract tannin.
AB  - These experiments were designed to study signal transduction pathways in alveolar
      macrophages stimulated by condensed tannin or zymosan. Condensed tannins, present
      in cotton mill dust, alter the host-defense function of alveolar macrophages and
      may contribute to the pathogenesis of byssinosis. We tried to determine the early
      steps in signal transduction mechanisms of cell activation by tannin. With the
      quantification of 51Cr release, we determined that tannin was cytotoxic for the
      cells after 30 min activation with 130 micrograms for 2 x 10(6) cells. 51Cr
      release was similar for control cells and zymosan- or 30 micrograms tannin
      activated cells. Using the luciferine luciferase reaction, we showed that tannin
      markedly depleted ATP cell content. In inositol-labeled cells, tannin increased
      inositolphosphate release in a dose-dependent manner. In lysoPAF-labeled cells,
      tannin induced synthesis of phosphatidic acid and diglycerides. In the presence
      of ethanol, the level of tannin-induced phosphatidic acid was slightly reduced,
      and phosphatidylethanol was synthesized. No phosphatidylethanol was found in
      alveolar macrophages stimulated by zymosan in the presence of ethanol. GF
      109203X, a specific inhibitor of protein kinase C decreased only tannin-induced
      phosphatidylethanol synthesis. In conclusion, tannin (at 30 or 130 micrograms/ml)
      activated an inositol phospholipase C in alveolar membranes. Phosphatidylcholine
      phospholipases C and D were found only at the higher concentration of tannin.

PMID- 8658515
TI  - Ricin depresses cardiac function in the rabbit heart.
AB  - Ricin, at toxic glycoprotein from the castor bean, causes myocardial hemorrhage
      and a decrease in blood pressure. We studied the effects of ricin on myocardial
      function in the isolated rabbit heart. Rabbits were given 0.22 micrograms/kg of
      ricin i.v. and 48 hr later, the heart was isolated and retrogradely perfused
      through the aorta with Tyrode's solution. A latex balloon was inserted into the
      left ventricle and isovolumic left ventricular function curves were generated.
      Left ventricular developed pressure (LVDP), heart rate, coronary artery flow,
      left ventricular end diastolic pressure, myocardial oxygen consumption, oxygen
      extraction (a - vO2), and contractility (+dp/dt) were measured over a range of
      left ventricular volumes. Dose-response curves to isoproterenol (10(-9)-10(-8) M)
      and phenylephrine (10(-9)-10(-6) M) were also obtained. Compared to the control
      group, ricin pretreatment markedly decreased ventricular compliance (p < 0.01),
      diminished maximum left ventricular developed pressure (p < 0.05), and reduced
      maximal +dp/dt (p < 0.05). Myocardial oxygen consumption, heart rate,
      electrocardiographic PR, QRS, and QT intervals were not different in control and
      ricin treatment groups. Ricin did not significantly alter the inotropic or
      chronotropic responses to isoproterenol and phenylephrine. The results from the
      binding studies showed that ricin neither reduced beta-adrenergic receptor
      numbers nor altered the dissociation constant. thus, ricin reduced both systolic
      (LVDP and +dp/dt) and diastolic (compliance) left ventricular functions, perhaps
      due to increased vascular permeability, without altering responses to the alpha-
      and beta-adrenoceptor agonists phenylephrine and isoproterenol.

PMID- 8658516
TI  - Evaluation of the subacute pulmonary and testicular inhalation toxicity of
      diborane in rats.
AB  - This study aimed to clarify the subacute pulmonary and testicular inhalation
      toxicity of diborane (B2H6, CAS: 19287-45-7) in rats. Male Wistar rats were
      exposed for 8 weeks to 0.11 or 0.96 ppm of diborane for 6 hr/day, 5 days/week.
      The control group was exposed to filtered air. Bronchoalveolar lavage fluid
      (BALF), hematological, biochemical, and histopathological examinations were
      conducted. Sperm counts and spermatic morphological changes were examined in
      epididymides, and histopathological examination was carries out in testes. BALF
      examinations revealed that the percentage of neutrophils increased in a dose
      dependent manner and that of macrophages decreased in rats exposed to 0.96 ppm.
      Quantities of total and individual phospholipids in BALF increased in rats
      exposed to 0.96 ppm. The proportion of phosphatidylglycerol plus sphingomyelin
      decreased, and phosphatidylethanolamine and phosphatidylinositol increased in
      rats exposed to 0.96 ppm. LDH increased in rats exposed to 0.96 ppm, and ALP
      showed a dose-dependent increase. In serum, alpha 1-antitrypsin and superoxide
      dismutase activities increased in rats exposed to 0.11 or 0.96 ppm. These changes
      showed dose-dependent effects on the lung in rats exposed to diborane, possibly
      indicating that the hyperenergia of type II cells with proliferation and/or
      hypertrophy without histopathological changes occurred even in rats exposed to
      0.11 ppm. Testicular examinations revealed no particular findings. The TLV-TWA of
      diborane (0.1 ppm) seems to be high and possibly unsafe, considering that the no
      observed-effect level over 8 weeks for rat lung was under 0.11 ppm.

PMID- 8658517
TI  - Interspecies scaling of clearance and volume of distribution for digoxin-specific
      Fab.
AB  - Digoxin-specific Fab are recognized to be effective in the treatment of acute
      cardiac glycoside poisoning but no pharmacokinetic studies have been performed in
      human volunteers. We thus propose an allometric approach among three mammalian
      species to predict Fab pharmacokinetic parameters in humans. Plasma disposition
      of digoxin-specific Fab was studied at a 20 mg/kg i.v. dose in mice, rats, and
      rabbits. Fab plasma concentration was determined by a sensitive and specific
      radioimmunoassay. Allometric equations showed that the pharmacokinetic parameters
      (distribution volumes (Vc (ml) = 0.084 W0.96; Vdss (ml) = 0.24 W0.96; Vd beta
      (ml) = 0.55 W0.96, r2 = 1), total body clearance (Cltot (ml/hr) = 0.61 W0.67, r2
      = 0.999), and terminal half-life (t 1/2 beta (hr) = 0.63 W0.29) correlated with
      body weight. The Fab plasma concentration-time data plotted as a complex Dedrick
      relationship were superimposable. Using these allometric techniques, Vdss, Vd
      beta, Cltot and t 1/2 beta were calculated as 10.75 liter, 24.64 liter, 17.9
      ml/min, and 16 hr, respectively, for a human subject of 70 kg body weight. These
      values are in accordance with those previously described in digoxin-Fab-treated
      patients (body weight = 61 +/- 3 kg, Vd beta = 24.9 +/- 3. 7 liter; Cltot = 20.8
      +/- 2.1 ml/min; t 1/2 beta = 14.3 +/- 1.8 hr). Results indicate that the primary
      Fab pharmacokinetic parameters can be reasonably estimated in man using
      pharmacokinetic data from three animal species.

PMID- 8658518
TI  - Ethanol consumption suppresses the IL2-induced proliferation of NK cells.
AB  - Ethanol (20% w/v) given to female, C57BL/6 mice in their drinking water
      suppresses natural killer (NK) and lymphokine activated killer cell cytolytic
      activity in mixed splenocytes and in splenocytes highly enriched for NK cells.
      The present study examined the effects of ethanol consumption on rIL2-induced
      proliferation of enriched NK cells. Mice were given 20% w/v ethanol in the
      drinking water for 2 weeks. Splenic NK cells were harvested and enriched up to
      88% based on surface expression of NK1.1. The enriched NK cells were cultured in
      the presence of 1000 IU/ml (20 pg/ml) murine recombinant interleukin 2 (rIL2).
      There were fewer cells (p < 0.02) from ethanol-consuming mice compared to cells
      from water-drinking control mice after incubation with IL2 at 2, 4, and 6 days of
      culture. Ethanol consumption was associated with significantly lower
      [3H]thymidine uptake (p < 0.05). Ethanol consumption did not affect apoptosis or
      intracellular levels of interferon-gamma, tumor necrosis factor-alpha, or
      granulocyte macrophage colony-stimulating factor in NK cells. Ethanol consumption
      did not affect the expression of c-myc mRNA in NK cells that were cultured for 10
      min or 4, 8, and 18 hr in rIL2. Suppression of IL2-induced NK cell proliferation
      is associated with ethanol consumption, and suppression is not due to altered IL2
      receptor expression, increased apoptosis, intracellular cytokine levels, or c-myc
      expression.

PMID- 8658519
TI  - Relative potencies of polychlorinated dibenzo-p-dioxins, dibenzofurans, and
      biphenyls derived from hepatic porphyrin accumulation in mice.
AB  - Hepatic porphyrin accumulation was studied after subchronic dosing of female
      B6C3F1 mice by gavage with single congeners of polychlorinated or polybrominated
      dibenzo-p-dioxins (PCDDs, PBDDs), polychlorinated dibenzofurans (PCDFs), and
      polychlorinated biphenyls (PCBs). Quantitative hepatic porphyrin profile analyses
      in selected samples showed uroporphyrin and heptacarboxylporphyrin as the main
      porphyrins detected. Dose-dependent increases in total hepatic porphyrins were
      found for all congeners tested. At lower dose levels, relative potencies, based
      on administered dose as well as target tissue dose, of PCDDs, PCDFs, and coplanar
      PCBs, using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a reference compound, were in
      the same range as those previously derived from the induction of hepatic CYP1A1
      and CYP1A2 enzyme activities. CYP1A2 has been reported to be involved in the
      oxidation of uroporphyringen III to uroporphyrin III. All these facts suggest the
      involvement of an aryl hydrocarbon receptor-medicated mechanism in hepatic
      porphyrin accumulation, possibly via CYP1A2. However, the relative potencies of
      the mono-ortho-substituted PCBs were higher for hepatic porphyrin accumulation
      than for hepatic CYP1A1 and CYP1A2 induction. In addition, hepatic porphyrin
      accumulation was the highest after exposure to mono-ortho-PCBs. Since mono-ortho-
      substituted PCBs induce the phenobarbital-inducible CYP2B isoforms of cytochrome
      P450, an additional induction of delta-aminolevulinic acid synthetase may also
      contribute to hepatic porphyrin accumulation following subchronic exposure to
      these particular congeners. Relative potencies derived from hepatic porphyrin
      accumulation after PCDD, PCDF, or coplanar PCB administration are a useful tool
      in risk assessment. However, the higher potencies of the mono-ortho-substituted
      PCBs have important implications for risk assessment of these compounds.

PMID- 8658520
TI  - Comparison of the effects of redox cycling and arylating quinones on
      hepatobiliary function and glutathione homeostasis in rat hepatocyte couplets.
AB  - Menadione (2-methyl-1,4-naphthoquinone, a redox cycling and arylating quinone; 5
      100 microM) inhibited the canalicular vacuolar accumulation (CVA) of a
      fluorescent bile acid, cholyl-lysyl-fluorescein (CLF), in rat hepatocyte
      couplets. This was associated with depletion of reduced glutathione and
      accumulation of oxidized glutathione, the latter indicating that the
      concentrations of menadione used were able to induce oxidative stress. There was
      no associated cytotoxicity as indicated by ATP content. Treatment of couplets
      with the redox cycling quinone 2,3-dimethoxy-1,4-naphthoquinone (up to 100
      microM) had relatively little effect on CVA, suggesting that the magnitude of
      reactive oxygen formation induced by this compound was insufficient to disrupt
      canalicular integrity. In comparison, the arylation of protein thiol groups by p
      benzoquinone (up to 100 microM) proved to be more potent in inhibiting
      canalicular vacuolar accumulation. The predominant mechanism of menadione-induced
      inhibition of couplet hepatobiliary function is therefore more likely to involve
      the arylation of critical thiol groups (such as those in the F-actin
      cytoskeleton) rather than their oxidation. The oxidative effects of menadione
      could, however, potentiate the deleterious effects induced by arylation, such as
      by reduced glutathione depletion.

PMID- 8658521
TI  - Relationship between parathion and paraoxon toxicokinetics, lung metabolic
      activity, and cholinesterase inhibition in guinea pig and rabbit lungs.
AB  - Kinetic parameters of parathion and paraoxon uptake were determined in isolated
      and perfused rabbit and guinea pig lungs. They were related to organophosphate
      induced lung cholinesterase inhibition. A single pass procedure was used to
      perfuse the lungs with an artificial medium perfusate containing paraoxon or
      parathion. The paraoxon and parathion concentrations were determined in the
      effluents collected at chosen intervals over an 18-min period beginning at the
      start of perfusion. Three inflowing concentrations (1 nmol/ml, 10 nmol/ml, and 20
      nmol/ml) were tested in guinea pig lungs and one (10 nmol/ml) in rabbit lungs.
      Cholinesterase activity was determined at time 0 and at the end of the
      experiment. The lungs abundantly extracted paraoxon and parathion over the
      perfusion period. The extraction ratio was consistently greater in guinea pig
      than in rabbit lungs. The uptake velocity varied biexponentially in time,
      suggesting the existence of two compartments. Initial uptake velocities (A, B)
      and slopes (alpha and beta) were calculated for both compartments. In guinea
      pigs, A, B and A + B increased proportionally to the supply rate of paraoxon and
      parathion while a and b remained constant. No significant difference was observed
      between parathion and paraoxon uptake kinetics. Parameter B was the only one to
      differ significantly between the two species (rabbits: 8.19 +/- 1.53 for
      parathion and 6.85 +/- 1.26 for paraoxon; guinea pigs: 12.75 +/- 0.88 for
      parathion and 15.02 +/- 3.84 for paraoxon). In the lungs of both species, there
      was a linear relation between y, the percentage of cholinesterase inhibition
      induced by either organophosphate, and X, the total amount of drug taken up by
      the lung tissue (in nmol/g/18 min). The following equations were obtained: y =
      0.128 x + 0.979 (R2 = 0.89, p < 0.001 for paraoxon); y = 0.120 x - 6.57 (R2 =
      0.82, p < 0.005 for parathion). No difference was observed between the two
      organophosphates. After treatment with the cytochrome P450 inhibitor piperonyl
      butoxide, the above relations ceased to apply, but this treatment did not
      influence the kinetics of paraoxon and parathion uptake. The IC50 value
      calculated for paraoxon, i.e., the paraoxon concentration required to produce 50%
      inhibition of lung cholinesterase activity, was similar for guinea pigs (2.22 10(
      7) +/- 0.22 M) and rabbits (2.36 10(-7) +/- 0.24 M). In conclusion, the
      biexponential evolution of the velocity of paraoxon and parathion uptake by the
      lungs thus demonstrates the presence of two pools. The lower extraction ratios
      calculated for rabbit lungs reflect the lower initial uptake velocity of the
      second compartment. In the range of concentrations investigated in guinea pigs,
      no saturable mechanism could be demonstrated for paraoxon and parathion.
      Cytochrome P450-related lung metabolic activity, through which parathion is
      converted to paraoxon, appears as a major step in parathion-induced lung
      cholinesterase inhibition, although it does not appear to affect parathion
      toxicokinetics.

PMID- 8658522
TI  - Elevated sphingoid bases and complex sphingolipid depletion as contributing
      factors in fumonisin-induced cytotoxicity.
AB  - Fumonisin B1 is an inhibitor of ceramide synthase, a key enzyme in de novo
      sphingolipid biosynthesis and reacylation of free sphingosine. The purpose of
      this study was to determine the contribution of increased intracellular free
      sphinganine and decreased complex sphingolipids on cell growth and cell death
      induced by fumonisin B1 in pig kidney LLC-PK1 cells. Fumonisin B1 caused an
      increase in intracellular free sphinganine which preceded depletion of complex
      sphingolipids, inhibition of cell growth, and cell death. The effects on cell
      growth and cell death were well correlated with the increase in free sphingoid
      bases and depletion of complex sphingolipids. Exogenously added sphinganine
      mimicked the effects of fumonisin, but beta-chloroalanine, an inhibitor of serine
      palmitoyltransferase which is the first enzyme in de novo sphingolipid
      biosynthesis, also inhibited cell growth and increased cell death. When added
      simultaneously, beta-chloroalanine reduced the fumonisin-induced sphinganine
      increase by approximately 90%; however, it exacerbated the decrease in more
      complex sphingolipids. The effects of fumonisin on cell growth and cell death
      were only partially prevented by beta-chloroalanine (approximately 50 to 60%).
      The results suggest that both the elevation of free sphingoid bases and the
      decrease in complex sphingolipids contribute to the decreased cell growth and
      cytolethality of fumonisin B1 in pig kidney LLC-PK1 cells.

PMID- 8658523
TI  - Rapid induction of hyperplasia in vitro in rat bladder explants by elevated
      sodium ion concentrations and alkaline pH.
AB  - The effects of alkaline pH and elevated sodium concentrations in culture medium
      on rat bladder explants for 1, 2, and 3 weeks were investigated by continuous
      BrdU labeling and histopathology. Increasing the sodium chloride concentration of
      normal medium by 50 or 100 mM caused slight urothelial hyperplasia with
      statistically significant increases in labeling in week 2 (50 mM) and at all time
      points with 100 mM NaCl. Cytotoxicity was seen in the high salt group. Increasing
      the pH from 7.2 to 7.8 and 8.2 also caused a slight hyperplastic response with
      significant increases in labeling and cytotoxicity at pH 8.2. However, bladder
      explants treated at pH 7.8 or 8.2 with excess sodium concentrations of 50 to 100
      mM had a more marked hyperplastic response with evidence of cytotoxicity as well.
      There were significant increases in the labeling index (6.4- to 15.0-fold
      relative to control) after 1 week, with the maximum response at 100 mM sodium/pH
      8.2. These results suggest that alkaline pH and elevated sodium concentration
      have a direct mitogenic effect on rat urothelial cells with some cytotoxicity
      induced regenerative cell proliferation as well. These in vitro results in an
      organ culture system are in agreement with in vivo studies that have shown an
      important role for elevated urinary cation concentrations and pH in the
      stimulation of DNA synthesis, induction of hyperplasia, and tumor promotion in
      rat bladder epithelium.

PMID- 8658524
TI  - Use of precision-cut liver slices to evaluate species differences in 2
      acetylaminofluorene-induced unscheduled DNA synthesis.
AB  - Precision-cut liver slices were prepared from male Sprague-Dawley rats
      (pretreated with or without Aroclor 1254), male Dunkin-Hartley guinea pigs, male
      cynomolgus monkeys, and humans. Liver slices were cultured for 24 hr using a
      dynamic organ culture system in medium containing [3H]thymidine and 2
      acetylaminofluorene (2-AAF), aflatoxin B1 (AFB1), or 6-aminochrysene (6-AC). The
      liver slices were then harvested and processed for autoradiographic evaluation of
      unscheduled DNA synthesis (UDS). All three genotoxins induced UDS in liver slices
      from untreated and Aroclor 1254-treated rats. In human liver slices 2-AAF
      produced a concentration-dependent induction of UDS and at the highest
      concentration examined 2-AAF also induced UDS in guinea pig liver slices.
      However, 2-AAF did not induce UDS in cynomolgus monkey liver slices, although
      both AFB1 and 6-AC induced UDS in liver slices from this species as well as from
      guinea pigs and humans. The inability of 2-AAF to induce UDS in cynomolgus monkey
      liver slices appears to be at least partially due to the absence of hepatic
      CYP1A2 in this species. Precision-cut liver slices appear to be a useful
      alternative to primary hepatocyte cultures for studies of xenobiotic-induced
      genotoxicity employing the UDS technique. As shown by this study they may also be
      employed to evaluate species differences in xenobiotic-induced genotoxicity.

PMID- 8658525
TI  - Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on insulin-induced
      responses in MCF-7 human breast cancer cells.
AB  - Insulin stimulated proliferation of MCF-7 human breast cancer cells in serum-free
      medium, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8
      tetrachlorodibenzofuran (TCDF) did not affect cell growth. In cells cotreated
      with insulin plus TCDD or TCDF, insulin-induced cell proliferation and
      [3H]thymidine incorporation were inhibited. In contrast, alpha-naphthoflavone, a
      partial aryl hydrocarbon (Ah) receptor antagonist, blocked the inhibitory effects
      of TCDD, suggesting that the Ah receptor was involved in TCDD-induced responses
      in MCF-7 cells. TCDD alone did not affect Kd and Bmax values for binding of
      [125I]insulin to the insulin receptor (IR); however, in MCF-7 cells cotreated
      with insulin plus TCDD, the insulin-induced Kd value for IR-ligand binding was
      decreased and the Bmax value was increased. TCDD induced IR mRNA levels and
      inhibited several other insulin-induced responses including c-fos protooncogene
      expression, phosphorylation of the insulin receptor, and a 185-kDa protein in MCF
      7 cells.

PMID- 8658526
TI  - Increased [3H]phorbol ester binding in rat cerebellar granule cells and
      inhibition of 45Ca2+ sequestration in rat cerebellum by polychlorinated diphenyl
      ether congeners and analogs: structure-activity relationships.
AB  - Our previous reports indicate that ortho-substituted non-coplanar polychlorinated
      biphenyl (PCB) congeners perturbed neuronal Ca2+-homeostasis in vitro, altered
      agonist-stimulated inositol phosphate accumulation, and caused protein kinase C
      (PKC) translocation. The structure-activity relationship (SAR) with 24 PCB
      congeners was consistent with a chlorination pattern that favored non-coplanarity
      while those with chlorination that favored coplanarity were less active. To test
      the hypothesis that coplanarity (or lack thereof) is a significant factor in the
      activity of PCBs, studies with related classes of chemicals such as the
      polychlorinated diphenyl ethers (PCDEs), in which coplanarity is more difficult
      to achieve regardless of degree and pattern of chlorination, were initiated. The
      selected PCDEs and their analogs are predicted to be active, since they are non
      coplanar in nature. The effects of these chemicals were studied using the same
      measures for which 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 45Ca2+
      sequestration as determined by 45Ca2+ uptake by microsomes and mitochondria
      isolated from adult rat cerebellum. All the PCDE congeners studied, increased
      [3H]PDBu binding in a concentration-dependent manner. The order of potency was
      2,4,4'-trichlorodiphenyl ether > 4,4'-dichlorodiphenyl ether > diphenyl ether,
      3,3',4,4'-tetrachlorodiphenyl ether and, 2,2',4,4',5- and 2,3',4,4',5
      pentachlorodiphenyl ethers. The structurally related diphenyl ether nitrofen and
      diphenyl ethanes o,p'-1,1,1-trichloro-2,2-bis[p-chlorophenyl]ethane (DDT) and
      p,p'-DDT increased [3H]PDBu binding to a similar extent (28-35% stimulation at
      100 microM). All PCDE congeners and their analogs inhibited 45Ca2+ sequestration
      by microsomes and mitochondria. Of all the chemicals, unchlorinated diphenyl
      ether was the least active. These results are in agreement with previous SAR
      findings in which non-coplanar PCBs are active and support our hypothesis that
      the extent of coplanarity determined by a pattern of chlorination on certain
      aromatic hydrocarbons can weaken their potency in vitro, although the extent of
      chlorination is also important.

PMID- 8658527
TI  - Chick embryos as an alternative experimental animal for cardiovascular
      investigations: stable recording of electrocardiogram of chick embryos in ovo on
      the 16th day of incubation.
AB  - Recording of electrocardiogram (ECG) tracings in developing chick embryos often
      fails because of spontaneous motion of the embryos in the egg shell. We attempted
      to record ECG of chick embryos in ovo. When we injected a mixture of 450 mg/ml
      urethane and 45 mg/ml alpha-chloralose into the air sac of fertile eggs at
      volumes of 0.1 to 0.3 ml, the spontaneous motor activity of chick embryos was
      decreased and stable ECG tracings could be obtained from at least 10 min after
      the injection. The P, QRS, and T waves were noted in the electrograms, and the QT
      interval was positively correlated to the RR interval. The heart rate (HR) could
      be analyzed for the RR interval in fertile eggs after the 8th day of incubation.
      The HR of the 16-day fertile embryos was linearly increased with incubation
      temperature in the range from 31 to 41 degrees C. Using this system, cardiac
      effects of some drugs were examined. Isoprenaline and acetylcholine increased and
      decreased the HR in a dose-dependent manner, respectively, and these effects were
      inhibited by respective antagonists, propranolol and atropine. These ECG
      responses of chick embryos were similar to those of mammals or humans. In
      conclusion, stable ECG tracings could be obtained from chick embryos anesthetized
      by urethane and alpha-chloralose in ovo and this method may be applicable for the
      investigation of the developing heart and the evaluation of cardiovascular drugs.

PMID- 8658528
TI  - Endogenous interleukin-1 alpha associated with skin irritation induced by
      tributyltin.
AB  - Tributyltin (TBT) salts are well-known skin irritants in both human and rodents.
      This study investigated the role of interleukin-1alpha (IL-1alpha) in the process
      in mice and in murine keratinocytes. The ears of Balb/c mice were painted with
      different amounts of TBT (67-536 nmol in acetone) or with acetone alone. Two
      hours later there was dose-related production of IL-1alpha along with ear
      swelling and accumulation of skin water, all of which were partially prevented by
      intraperitoneal injection of antibody against murine IL-1alpha. By reverse
      transcription-polymerase chain reaction we were able to show that the
      neutralizing antibody also partially prevented TBT-induced in vivo IL-6
      expression but no TBT-induced TNF-alpha expression, suggesting a paracrine effect
      of IL-1alpha on IL-6 production but not TNF-alpha expression and indicating that
      other inflammatory mediators are involved. TBT induced both intracellular
      production of IL-1alpha and its release into culture medium in a murine
      keratinocyte cell line (HEL30). IL-1alpha production was inhibited by addition of
      a neutralizing antibody against IL-1alpha, which suggests an autocrine effect of
      IL-1alpha on its own production. The intracellular production of IL-1alpha could
      he significantly inhibited by prior treatment with antioxidants, which strongly
      suggests a role for oxidative species in the mechanism of action of TBT in IL
      1alpha induction. The complex-1 inhibitor rotenone also significantly inhibits IL
      1alpha production. Since TBT causes disturbances in the respiratory chain in
      mitochondria, the mechanism of its action may be the production of reactive
      oxygen intermediates at the ubiquinone site, which activate transcription factors
      and promote IL-1alpha synthesis.

PMID- 8658529
TI  - Distribution and behavior of the Ah receptor in murine T lymphocytes.
AB  - Exposure of C57Bl/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes
      suppression of both cell-mediated and humoral immunity. Studies with mice
      congenic at the Ah locus have demonstrated that this suppression is mediated by
      the aryl hydrocarbon receptor (AhR). The Ah receptor is a ligand-dependent
      transcription factor that has been well-studied in hepatocytes; however, the
      mechanism of TCDD-mediated immunotoxicity remains unknown. Lack of mechanistic
      understanding is due, in part, to difficulty demonstrating a direct effect of
      TCDD on immune function in vitro. In this study, we have investigated the
      behavior of the murine AhR in T cells using isolated spleen T lymphocytes and T
      cell clones (10.5.17, F4, and F1.A.2) derived from Ah-responsive mouse strains.
      The presence of the AhR in whole cell extracts of resting and activated splenic
      lymphocytes and T cell clones was examined by Western blotting. Increased 7
      ethoxyresorufin-o-deethylase (EROD) activity was observed in T cell clones and
      spleen cells; however, the level of EROD induction by TCDD was approximately 100
      fold less than the level induced in hepa cells. The behavior of the murine T cell
      AhR was examined by assessing TCDD-induced nuclear translocation and DNA binding.
      The intracellular distribution of the AhR was studied by subcellular
      fractionation of both resting and activated T cells in the presence and absence
      of TCDD. DNA binding was measured using an electrophoretic mobility shift assay.
      The AhR was detected in all cell types examined, but the AhR translocated to the
      nucleus only in activated, TCDD-treated T cells. While AhR derived from TCDD
      treated wild-type hepa cells bound specifically to a DRE, no binding was detected
      when an identical amount of AhR obtained from activated T cells was used. Our
      inability to detect binding of the T cell nuclear AhR complex to a consensus
      response element, combined with the observation that it is difficult to reproduce
      the in vivo immunotoxic effects of TCDD in vitro, suggests that T cells may lack
      a factor(s) required for AhR binding to a DRE, or may contain a suppressor factor
      which inhibits AhR binding to DNA. Based on these data, TCDD appears to affect T
      cell function via an indirect mechanism.

PMID- 8658530
TI  - Mercury (Hg 2+) enhances the depressant effect of kainate on Ca-inactivated
      potassium current in telencephalic cells derived from chick embryos.
AB  - The effect of HgCl2 on kainate (KA)-induced depression of voltage-gated potassium
      (K+) current in chick embryo telencephalic cells was studied using conventional
      and nystatin-perforated whole-cell patch-clamp recordings, fluorescence imaging,
      and flow cytometry techniques. Hg2+ (1 microM) alone did not effect the 4
      aminopyridine-(4-AP)-sensitive transient K+ current in immature cells (Embryonic
      Day 5), but irreversibly potentiated the depressant effect of KA on this K+
      current. A 50% potentiation of KA-induced depression of the K+ current was
      produced by an application of 0.19 microM Hg2+. Application of ionomycin (5
      microM) or calcium ionophore A23187 (2 microM) suppressed the K+ current. To test
      the possibility that the 4-AP-sensitive transient K+ current is a Ca-inactivated
      current, the effect of intracellular Ca2+ concentration ([Ca2+]i) in the range of
      30 nM to 2 microM was determined. The amplitude of the K+ current was sensitive
      to [Ca2+]i with half-maximal inactivation at 370 nm at +60 mV. The concentration
      response curve of the K+ current inhibition by [Ca2+]i was shifted to lower
      [Ca2+]i and the slope of the curve was reduced in the presence of KA. Hg2+
      potentiated these effects of KA. The Ca-dependence of the K+ current was maximal
      at the 5th embryonic day, declined to the 9th embryonic day, and was absent at
      the 11th embryonic day. Application of Hg2+ (0.1-1 microM) had no effect on the
      basal [Ca2+]i of freshly dissociated cells (10th day in ovo) and cells in culture
      (the 4-day cultures from the telencephalon of 5-day-old embryos), but potentiated
      KA-induced increase of [Ca2+]i in a Ca-free-EGTA solution in a concentration
      dependent manner. Moreover 1 microM Hg2+ delayed and reduced the recovery to
      basal [Ca2+]i after washout of KA. Exposure to 5-30 microM H2+ caused an
      irreversible decline of membrane resistance, an increased cell size, and reduced
      cell granularity and complexity. Intracellular recording of spontaneous neuronal
      activity and immunocytochemical identification showed that the KA/Hg2+-sensitive
      Ca-inactivated K+ current exists in early differentiating telencephalic neurons.
      Because depression of the K+ current by KA and Hg2+ decreases the interspike
      interval and irreversibly perturbs the frequency code of information in the
      nervous system, the expression of this current during early neuroembryogenesis
      may be one of the reasons for the developmental toxicity of inorganic mercury.

PMID- 8658531
TI  - Developmental toxicity of inorganic arsenic in whole embryo: culture oxidation
      state, dose, time, and gestational age dependence.
AB  - Arsenic is a known teratogen and developmental toxicant in many animal models.
      The aim of the present study was to determine the influence of arsenic oxidation
      state, concentration, duration of exposure, and embryonic gestational age on
      arsenic-induced developmental toxicity. For these studies whole embryo culture
      was used since this experimental model allows an assessment of the direct effect
      of the toxicant on the embryo and precise control of the variables of interest.
      ICR and CD1 mouse embryos were prepared for whole embryo culture and exposed to
      concentrations of trivalent (1, 2, 5, 7.5, 10, 20, and 30 microM of sodium
      arsenite) and pentavalent arsenic (5, 10, 20, 50, and 100 microM of sodium
      arsenate) at different developmental stages (3, 4-6, 8-10, or 20-23 pairs of
      somites) and for different exposure periods (1, 4, 6, or 24 hr). Embryonic
      growth, development, malformation rates, and viability were evaluated. A
      comparison of the ED50s of the two oxidation states showed that arsenite was
      about three times more potent than arsenate with respect to both malformations
      and lethality. The pattern of malformations was similar for both arsenite and
      arsenate and involved nonclosure of the cranial neural tube, prosencephalic
      hypoplasia, dysmorphogenesis of the optic and otic anlagen, and pharyngeal arch
      defects. ICR conceptuses were more sensitive than CD1s with regard to
      perturbation in embryonic growth by both forms of arsenic. ICRs were also more
      sensitive to otic, pharyngeal arch, and somite dysmorphogenesis induced by
      arsenite. With increasing gestational age there was an increasing resistance to
      arsenic-induced effects. In comparison to the 4-6 somite stage, the ED50 for
      induction of dysmorphogenesis was increased about twice at the 8-10 somite and
      over three times in 20-23 somite stage embryos. Exposure to arsenite/arsenate for
      a 1-hr period was sufficient to induce maldevelopment. A 6-hr exposure induced
      prosencephalic, otic, and optic abnormal development at a rate similar to that
      produced by a 24-hr exposure. The malformation pattern produced by exposure to
      arsenite/arsenate in vitro closely corresponds to that produced by maternal
      administration at the same gestational stage. This indicates that the arsenic
      embryopathy may be the result of a direct impact of the agent on the conceptus.

PMID- 8658532
TI  - Characterization of chemical allergens as a function of divergent cytokine
      secretion profiles induced in mice.
AB  - Allergic contact dermatitis (contact sensitivity) may be caused by a wide variety
      of chemicals. In addition, some chemical allergens may also induce respiratory
      sensitization. It has been demonstrated previously that topical exposure of mice
      to chemical contact and respiratory sensitizers stimulates divergent immune
      responses consistent with the selective activation of T helper 1 (Th1)- and Th2
      type cells, respectively. Thus, exposure to trimellitic: anhydride (TMA) induces
      hapten-specific IgE antibody and a substantial increase in the total serum
      concentration of IgE. Conversely, oxazolone fails to provoke IgE production. In
      addition, lymph node cells (LNC) isolated following repeated topical exposure of
      mice to oxazolone or TMA display cytokine secretion profiles characteristic of
      Th1- and Th2-type cell stimulation. The purpose of the present investigations was
      to determine whether chemical allergens other than TMA and oxazolone, the
      respiratory allergen toluene diisocyanate (TDI) and the skin sensitizer
      dinitrofluorobenzene (DNFB), provoke differential cytokine expression. The
      production of the Th1-type product interferon gamma (IFN-gamma) and the Th2-type
      cytokines interleukins 4 and 10 (IL-4 and IL-10) by TDI- and DNFB-activated LNC
      has been measured. LNC derived from DNFB-exposed animals expressed substantial
      amounts of IFN-gamma, but only low levels of IL-10 and mitogen-inducible IL-4;
      exposure to TDI resulted in the converse profile of cytokine secretion. These
      data demonstrate that repeated topical administration of chemical allergen of
      different classes elicits in mice divergent cytokine secretion patterns
      consistent with the selective stimulation of distinct Th subsets. Analysis of
      such cytokine production profiles may permit in a single integrated assay the
      simultaneous identification and classification of chemical allergens.

PMID- 8658533
TI  - The peroxisome proliferations WY-14,643 and methylclofenapate induce hepatocyte
      ploidy alterations and ploidy-specific DNA synthesis in F344 rats.
AB  - WY-14,643 (WY) and methylclofenapate (MCP) are peroxisome proliferators (PP) and
      hepatocarcinogens in rats. MCP causes hepatic polyploidization and preferentially
      induces replicative DNA synthesis in binucleate tetraploid hepatocytes (2 X 2N)
      in young Alpk:AP rats. To compare the effect of WY and MCP on hepatocyte ploidy
      and ploidy-specific DNA synthesis, male F344 rats were fed WY (0.1% in diet) or
      gavaged with MCP (25 mg/kg/day in corn oil) for 2, 5, or 10 days. Four rats per
      treatment group (including corn oil and diet control groups) were euthanized and
      the livers perfused at each time point. To identify cells undergoing DNA
      synthesis, all animals received BrdU by continuous infusion for 2 or 5 days prior
      to euthanasia. Hepatocyte ploidy and DNA synthesis were determined using one- or
      two-parameter flow cytometry. Averages +/- SEM for adult male F344 rats as a
      percentage of total hepatocytes for each ploidy subclass are 2N = 3.4 +/- 0.7%,
      4N = 69.9 +/- 1.9%, 2 X 2N = 14.4 +/- 2.4%, 8N = 2.2 +/- 0.4%, and 2 X 4N = 9.6
      +/- 0.9%. Significant alterations were not induced in the proportions of 2 X 2N
      or 4N ploidy subclasses by WY or MCP at any time point. However, WY caused
      increases in 8N hepatocytes at 2, 5, and 10 days (2 days, 5.2% vs 2.2% for
      controls; 5 days, 7.0% vs 3.1% for controls; 10 days, 6.4% vs 3.6% for controls)
      as did MCP at 5 and 10 days (5 days, 6.3% vs 2.5% for controls; 10 days, 5.3% vs
      2.9% for controls). In addition, a majority of BrdU-containing hepatocytes were
      4N following 5 and 10 days of WY and MCP [34.3% (WY) and 16.8% (MCP) vs 1.8% and
      1.1% for controls, respectively, for 2 X 2N (5 days) as a percentage of total
      hepatocytes]. Hepatocytes with intermediary DNA content (between tetraploid and
      octaploid) from MCP- and WY-treated rats were predominantly mononuclear, the
      percentage of binucleate hepatocytes being similar to or less than the percentage
      of binucleate cells within the total tetraploid hepatocyte population. These data
      suggest that polyploidization is induced by PP and induction of S-phase by WY and
      MCP occurs primarily in 4N hepatocytes in mature F344 rats and not within 2 X 2N
      hepatocytes. Identification of a ploidy subpopulation at risk for tumor
      development in rodents is essential for clarifying the role of cell replication
      in risk assessment studies of PP.

PMID- 8658535
TI  - Pharmacological prevention of acute lead poisoning in Paramecium.
AB  - To understand how lead (Pb2+) and other metals and chelating agents effect living
      cells, behavioral experiments in the marine ciliate Paramecium calkinsi were
      carried out. The duration of Backward Swimming Behavior (BSB) of Paramecium was
      partially reduced when cells were exposed to 100 microM of Ni2+, CD2+ and Co2+.
      In contrast, Pb2+ increased Paramecium BSB in a dose-dependent manner. Thus, 1,
      10, 20, 50 and 100 microM of Pb2+ increased the duration of BSB by 20.4, 83.9,
      143.2, 163.2 and 185.2%, respectively. The naphthalenesulphonamide W-7, a calcium
      channel blocker in lower organisms, abolished the increase of Paramecium BSB
      initially produced by Pb2+. Paramecium, poisoned with 10 MicroM of Pb2+, were
      also treated with putative Pb2+ chelating agents, such as meso-2-3
      dimercaptosuccinic acid (DMSA), Ca-Na2-EDTA and ascorbic acid. These compounds
      inhibited the increase of the duration of BSB initially produced by Pb2+ in a
      dose-dependent manner. The potency of these antidotes in blocking the effects of
      Pb2+ was as follows: DMSA >> Ca-Na2-EDTA > ascorbic acid. These results provide
      evidence for a membrane-based mechanism of lead poisoning and support the use of
      DMSA as a lead antidote.

PMID- 8658534
TI  - Vomitoxin-mediated IL-2, IL-4, and IL-5 superinduction in murine CD4+ T cells
      stimulated with phorbol ester calcium ionophore: relation to kinetics of
      proliferation.
AB  - The effects of the trichothecene vomitoxin (VT) on the kinetics of cell
      proliferation and cytokine production were evaluated in murine CD4+ T cells. The
      CD4+ cultures were stimulated with phorbol 12-myristate 13-acetate (PMA) and
      ionomycin to activate protein kinase C and increase cytoplasmic free calcium,
      respectively, in a range of VT concentrations. Total and viable cell counts at 3,
      5, 7, 9, and 11 days revealed delayed or impaired cell proliferation in cultures
      containing between 50 and 100 ng/ml VT, with complete inhibition being observed
      at 250 and 500 ng/ml of VT. The VT concentration required to inhibit protein
      synthesis in a 3-day culture by 50% in this model was 40 ng/ml. When enzyme
      linked immunosorbent assay (ELISA) was used to quantitate cytokines, IL-2 levels
      in control cultures were highest at Day 1 and declined rapidly thereafter,
      whereas, in VT groups, IL-2 levels were highest at Day 3 and remained elevated up
      to 11 days. IL-2 levels were elevated by continuous exposure to 100-500 ng/ml of
      VT with more than 100-fold differences being observed between control and 250
      ng/ml VT from Days 5 to 11. When IL-2 levels were expressed on a per viable cell
      basis, increases were even more marked with as much as 6 log differences being
      observed between the treatments at 250-500 ng/ml VT and control cultures at Day
      7. Supernatant IL-4 and IL-5 levels were also elevated by 100 and 250 ng/ml VT in
      a dose- and time-dependent fashion compared to control cultures, whereas 500
      ng/ml VT was inhibitory. When relative IL mRNA abundance was analyzed during the
      first 3 days of culture by reverse transcriptase-polymerase chain reaction (RT
      PCR) in conjunction with Southern hybridization analysis, IL-2 mRNA levels in
      Days 1, 2 and 3 in cultures containing 100 and 250 ng/ml VT were greater than
      corresponding controls. IL-2 mRNA abundance in both control and VT-treated
      cultures was maximal at Day 1 and decreased rapidly thereafter in controls,
      whereas much slower rates of IL-2 disappearance were noted in 100 and 250 ng/ml
      of VT. IL-4 and IL-5 mRNA levels at VT doses of 50 and 100 ng/ml were also
      elevated compared to controls. Pulsed VT (8 to 48 hr) or cycloheximide (4 to 48
      hr) exposure of CD4+ cells enhanced supernatant levels of IL-2 but not IL-4 upon
      incubation for 24 hr in fresh medium. This effect was not persistent. Taken
      together, VT enhanced and/or delayed peak IL-2, IL-4, and IL-5 gene expression
      and secretion in CD4+ T cells stimulated with PMA and ionomycin. Remarkably,
      cytokine superinduction occurred simultaneously with partial or maximal
      inhibition of cell proliferation.

PMID- 8658537
TI  - Mechanism of prolongation of pentobarbital-induced sleeping time by empenthrin in
      mice.
AB  - The effect of empenthrin, a synthetic pyrethroid, on pentobarbital (PTB)-induced
      sleeping time was examined in mice and rats. In mice, pretreatment with
      empenthrin prolonged PTB-induced sleeping time in a dose-dependent manner. The
      maximum effect on PTB-sleeping time was noted when mice were pretreated orally
      with empenthrin 2-4 h before PTB injection. However, empenthrin did not change
      the sleeping time induced by diethyl ether which is hardly metabolized in liver.
      Empenthrin inhibited the clearance of serum PTB in mic, but did not change the
      PTB concentration in serum at which animals recovered from sleeping. To examine
      the effect of PTB on metabolic enzymes in mouse liver, PTB was incubated
      aerobically with a hepatic microsomal fraction in the presence of NADPH at 37
      degrees C. Empenthrin inhibited the vitro metabolism of PTB dose-dependently. In
      rats, empenthrin neither changed the PTB sleeping time, nor inhibited the
      clearance of serum PTB. No inhibitory effect of empenthrin was observed on the in
      vitro metabolism of PTB using rat hepatic microsomal fraction. These findings
      indicate that empenthrin prolongs PTB-sleeping time in mice through an inhibition
      of the PTB-metabolizing enzyme(s) in the liver , an effect that does not occur in
      rats. Also, there is a clear species-specificity in the inhibitory effect of
      empenthrin on the PTB-metabolizing enzyme(s).

PMID- 8658536
TI  - Comparison of protection by fructose against paracetamol injury with protection
      by glucose and fructose-1,6-diphosphate.
AB  - We have compared the protective effect of fructose in normal Ringer solution
      during the onset and progression of cell injury induced by paracetamol in rat
      liver slices with the protective effect of glucose and fructose-1,6-diphosphate.
      Liver slices obtained from phenobarbitone-induced and non-induced rats were used
      in a model in vitro system. Slices were exposed to 10 mM paracetamol for 120 min
      and then incubated without paracetamol in the presence or absence of protective
      agents for a further 240 min. Cell injury was quantified by measuring leakage of
      lactate dehydrogenase (LDH) and potassium (K+). Adenosinetriphosphate (ATP)
      levels were measured using the luciferin-luciferase bioluminescence assay.
      Addition of higher concentrations of glucose (10-50 mM) to Ringer solution were
      not found to result in protection at the end of incubation in paracetamol-treated
      slices obtained from phenobarbitone-induced rats. Neither did sucrose nor
      mannitol protect. However, exclusion of glucose from Ringer solution resulted in
      cell injury in paracetamol-treated slices obtained from non-induced rats.
      Methionine, a known antidote for paracetamol poisoning, failed to protect in this
      instances but fructose did protect. This suggests that the presence of a
      glycolytic substrate plays a crucial role in cell protection. Further evidence
      for this is the finding that iodoacetate, an inhibitor of glycolysis, not only
      increase cell injury in paracetamol-treated slices but also reverses fructose
      protection. Fructose-1,6-diphosphate was found to protect against the onset and
      progression of cell injury in paracetamol-treated slices obtained from
      phenobarbitone induced rats. This protective agent is found to maintain high ATP
      levels and cell viability in paracetamol-treated slices at a time when
      paracetamol-treated slices show a profound loss of ATP levels and a significant
      increase in cell injury as measured by leakage of LDH and K+.

PMID- 8658538
TI  - The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2
      dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in
      the rat.
AB  - The 3-hydroxypyridin-4-ones (HPs) are iron and aluminum chelators. Their ability
      to enter the brain had not previously been directly determined. To determine
      whether they cross the blood-brain barrier (BBB), three HPs possessing a wide
      range of lipophilicity were examined: 1-[ethan-1'ol]-2-methyl-HP (CP40), 1,2
      dimethyl-HP (CP20, L1, deferiprone), and 1,2-dimethyl-HP (CP94, EL1NEt). Their
      pharmacokinetics were determined in rats to establish dosing parameters for
      microdialysis studies of BBB permeation. Studies were then conducted with
      microdialysis probes in the blood, frontal cortex, and lateral ventricle to
      determine the rate and extent of HP BBB permeability. All three HPs were
      detectable in brain dialysate samples collected 0-7 min after HP injection,
      demonstrating rapid entry into the brain. The extent of unbound distribution (an
      indicator of the mechanism of BBB permeation) was 0.9 and 1.2 for the frontal
      cortex and lateral ventricle for CP20, and was 1.1 and 1.6 for CP94, suggesting
      diffusion across the BBB. The extent of unbound distribution of CP40 was 0.2 for
      both the frontal cortex and lateral ventricle, suggesting the presence of a
      transporter moving it out of brain extracellular fluid. Introduction of cyanide
      into the brain did not affect the brain to blood CP40 ratio, suggesting that the
      transporter is not energy-dependent. Both CP94 and CP40 caused death due to
      respiratory failure, whereas CP20 did not. The ability of less toxic bidentate HP
      chelators, such as CP20, to enter the brain may enable their use in the treatment
      of metal-induced diseases and iron-facilitated oxidative injury involving the
      central nervous system.

PMID- 8658539
TI  - Effect of pesticide mixtures on in vitro nervous cells: comparison with single
      pesticides.
AB  - The toxicity of dimethoate, azinphos-methyl, diazinon, pirimiphos methyl,
      organophosphorus insecticides, and benomyl (a benzimidazole fungicide) singly and
      in mixture was studied in a human neuroblastoma cell line, SH-SY5Y. The cells
      were incubated for 30 min and 4 h with pesticides at concentrations ranging from
      0.4 to 100 micrograms/ml, or with the same compounds mixed as follows: (a)
      dimethoate-diazinon-azinphos; (b) benomyl-pirimiphos; (c) all together.
      Pesticides in the mixtures were at the same concentration used when tested
      singly. Diazinon, azinphos-methyl and pirimiphos, but not dimethoate and benomyl,
      inhibited acetylcholine esterase (AchE) activity, whereas all the compounds
      inhibited protein synthesis in the following order: benomyl > azinphos > diazinon
      >> pirimiphos = dimethoate. The mixtures showed a toxicity on AchE activity at a
      maximum equal to that of the most active compound in the mixture. On the
      contrary, the mixture were more toxic than the single compounds on protein
      synthesis, and in certain cases potentiation occurred. Therefore, we can conclude
      that it is not feasible to predict the toxicity of pesticide mixtures on the
      basis of the results of the toxicity of single components.

PMID- 8658540
TI  - Species specificity of 2-aryl carbapenem-induced immune-mediated hemolytic anemia
      in primates.
AB  - L-695,256 is a novel 2-fluorenonyl carbapenem antibiotic with significant
      antimicrobial activity against strains of methicillin-resistant Staphylococci.
      This prototype compound was administered intravenously to rhesus monkeys (Macaca
      mulatta) at does of 50 or 200 mg/kg/day for 2 weeks to assess toxicity and found
      to induce a hemolytic anemia characterized by extravascular hemolysis and
      splenomegaly. A subsequent study in this species in which 100 mg/kg/day was
      administered i.v. for 4 weeks showed that all animals were direct antiglobulin
      test (Coombs' test) positive for IgG with 20-25% reductions in the erythron.
      Following 3 weeks of recovery, the erythron had returned to normal, although it
      took an additional 2 months for the Coombs' test to become negative. Challenge of
      these same animals with 0.5 million U/kg (300 mg/kg/day) of penicillin
      intravenously indicated no apparent cross-reactivity. Since attempts to establish
      a model for this immune-mediated hemolytic anemia with this drug in rats or mice
      were unsuccessful, a 2-week i.v. study in squirrel monkeys (Saimiri sciureus) was
      conducted at a dose of 200 mg/kg/day. All animals in this study remained Coombs'
      test negative with no changes in the erythron, suggesting an increased
      sensitivity to beta-lactam-induced anemia in rhesus monkeys compared to other
      species. Further support for this hypothesis was obtained using the cephalosporin
      antibiotic, cefotetan. This compound induced a high incidence of Coombs' test
      positive hemolytic anemia at clinically relevant doses in rhesus monkeys, despite
      a very low incidence of this adverse effect in patients with many years of
      clinical use. These data suggest that although rhesus monkeys respond in a
      qualitatively similar manner to humans with regard to high doses of beta-lactam
      antibiotics, their sensitivity may overestimate the risk of immune-mediated
      hemolytic anemia for clinical use.

PMID- 8658541
TI  - Bile is an important route of elimination of ingested aluminum by conscious male
      Sprague-Dawley rats.
AB  - We assessed the importance of bile as an excretory route for ingested aluminum
      (AI). Bile dusts in 30 male Sprague-Dawley rats were cannulated to allow both
      bile collection and reinfusion of bile acids. Five days after surgery, rats
      (average weight = 191 +/- 4 g) were given a single oral dose of aluminum (0, 0.2,
      0.4, or 0.8 mmol) as aluminum lactate in 1 ml of 16% citrate by gavage. Bile was
      collected 1-7 h after dosing from unanesthetized rats. Biliary aluminum secretion
      was highest during the first hour of bile collection. All rats dosed with
      aluminum secreted significantly greater amounts of aluminum in bile than control
      rats. However, biliary aluminum secretion did not vary among animals given the
      different aluminum doses suggesting that biliary secretion of aluminum was
      saturated at these doses. Rats dosed with 0.8 mmol A1 retained significantly
      greater amounts of aluminum in soft tissues than those given 0.2 or 0.4 mmol A1.
      This result suggests that physiological were unable to prevent tissue aluminum
      accumulation in the rats given the highest dose.

PMID- 8658542
TI  - Iron and manganese uptake by offspring of lactating mice fed a high aluminum
      diet.
AB  - High dietary A1 can result in lowered tissue Mn and Fe concentrations in weanling
      mice. Possible mechanisms underlying this effect of A1 (altered milk Fe and Mn
      content, altered absorption or retention of Fe and Mn) were investigated in this
      experiment. To determine if milk composition was changed, milk was analyzed for
      Fe and Mn at 0, 3, 7, and 12 days postnatal. To determine if A1 influenced
      absorption and/or retention of Fe and Mn, a single milk meal containing 54Mn and
      59Fe was administered by gavage to 12 day old pups and tissues were obtained 6
      and 24 h later. Pup body and tissue weights were not affected by the high A1
      diet. Milk from dams fed high A1 diets (1000 micrograms A1/g, n = 11, A11000) had
      similar Fe and Mn concentrations as milk from dams fed a control diet (7
      micrograms A1/g, n = 11), although A1 concentrations were higher. Absorption and
      tissue distribution of 54Mn and 59Fe, as determined at the 6 h timepoint, were
      unaffected by maternal diet group (control n = 16, AL1000 n = 10). However, total
      retention of both 54Mn and 59Fe was 8-10% lower in the AL1000 pups 24 h after
      gavage (P = 0.030 for Mn and 0.017 for Fe). These data suggest that high dietary
      A1 during development alters the ability of nursing mouse pups to retain absorbed
      Fe and Mn.

PMID- 8658543
TI  - Transgenic strains of the nematode C. elegans in biomonitoring and toxicology:
      effects of captan and related compounds on the stress response.
AB  - The fungicide, captan, induces a cellular stress response in the soil nematode
      Caenorhabditis elegans. Transgenic C, elegans, which produce beta-galactosidase
      as a surrogate stress protein, reveal that captan-induced stress is localized
      mainly to muscle cells of the pharynx. The stress response is elicited by captan
      concentrations above 5 ppm and occurs within five hours of the initial exposure
      to the fungicide. Higher concentrations of captan, up to the solubility limit,
      increase the intensity of the response. Adult nematodes are significantly more
      sensitive to captan than are larvae. Captan also inhibits feeding in C. elegans,
      and nematodes exposed to captan rapidly cease muscular contractions in the
      pharynx. Stress induction and feeding inhibition are also caused by the related
      fungicides, captafol and folpet, but not by the parent compounds, phthalimide and
      tetrahydrophthalimide. The inhibition of feeding caused by compounds which elicit
      the cellular stress response may be an important survival mechanism for C,
      elegans.

PMID- 8658545
TI  - Short-term crocidolite inhalation studies in mice: validation of an inhalation
      chamber.
AB  - A nose-only inhalation chamber is described: this chamber being computer
      automated has been particularly designed for mice on which it was validated using
      a crocidolite aerosol at a nominal concentration of 13.6 mg/m3, 6 h/day during 5
      days. A month later the mice showed typical inflammatory bronchoalveolar liquids
      with many polynucleated or activated macrophages and asbestos bodies. The burden
      of crocidolite fibers ranged from 345,000 to 1,300,000 fibers per mg of dried
      lung. This study demonstrates that during the month that followed a short-term
      mice exposure to crocidolite fibers, the inflammatory response was still
      persistent. These toxicological endpoints validate the nose-only inhalation
      chamber to be useful for common or transgenic mice.

PMID- 8658544
TI  - Systemic toxicity of a bitumen upgrading product in the rat following subchronic
      dermal exposure.
AB  - The subchronic toxicity following dermal exposure to a synthetic fuel, heavy gas
      oil No. 2 fraction of bitumen upgrading product (B-HGO II) was studied in the
      rat. B-HGO II was applied on the dorsal skin of rats at doses of 8, 20, 50 and
      125 mg/kg bw/day daily for 13 weeks. Control animals received normal saline and
      positive controls received a medium-boiling coal liquefaction product (CLP) at
      125 mg/kg bw/day. Both male and female rats in the treatment groups had reduced
      body weight gain, and males in the highest dose group were terminated in the 5th
      week due to overt toxicity. Increased liver weight relative to body weight was
      observed in males and females starting at 8 mg/kg. Increased relative heart and
      spleen weights were observed in males and females starting at the two
      intermediate doses (20, 50 mg/kg). Increased relative kidney weight was detected
      in males at 50 mg/kg and females at 125 mg/kg. Increased serum cholesterol was
      observed in both sexes starting at 50 mg/kg while elevated serum glucose was
      present in females starting at 8 mg/kg. Significant changes in AH, APDM and EROD
      activities were observed in treated rats of both sexes. Reduced red blood cell
      counts were detected in males starting at 8 mg/kg and females at 20 mg/kg.
      Microscopic examination of blood smears, spleen and hemosiderin accumulation
      patterns, as well as analysis of FEP and serum TIBC levels indicated that the
      cause of anemia was primarily intravascular hemolysis and secondarily iron
      deficiency. Marked thymic atrophy and thyroid abnormalities were the most
      prominent histological changes followed by changes in bone marrow (myelofibrosis)
      and liver. Both B-HGO II and CLP (positive control) caused kidney changes
      characterized by cytoplasmic inclusions and lesions in the tubular cells, which
      were observed in 50 mg/kg males but not in the females. B-HGO II was considered
      to be toxic at a subchronic dermal exposure level as low as 8 mg/kg/day.

PMID- 8658546
TI  - Heavy metal-specific inhibition of phagocytosis and different in vitro
      sensitivity of heterogeneous coelomocytes from Lumbricus terrestris
      (Oligochaeta).
AB  - Cell viability and phagocytic activity of coelomocytes from the gastrointestinal
      tract of Lumbricus terrestris were examined by flow cytometry after in vitro
      exposure to heavy metals. Control coelomocytes were incubated for 18 h at 15
      degrees C, 5% CO2, in Ca(++)-containing LBSS medium with 10(-4)-10(-9) M mercury
      chloride, methylmercury, cadmium chloride, zinc chloride, lead chloride or lead
      acetate. Heterogeneity of coelomocyte population was demonstrated by forward
      scatter (FSC) analysis and cytometric profile showing two different populations
      of type I/small (60%) and type-II/large (40%) cells. Exposure to either form of
      Hg, Cd and Zn was relatively highly toxic and affected both cell viability and
      phagocytosis, whereas Pb was relatively well tolerated by the coelomocytes. A
      fraction of cells within large coelomocyte population was exceptionally sensitive
      to the Hg-induced cytotoxicity, which did not affect, however, the relative
      phagocytic activity of the remaining cells. Overall, at least three different
      patterns of metal-specific toxicity, affecting both viability and phagocytic
      functions of earthworm coelomocytes, were confirmed in our in vitro studies.
      Further characterisation of both the target cells from heterogeneous coelomocyte
      population and the specific interaction of target cell-xenobiotic can possibly
      reduce biomonitoring problems in earthworm toxicology and immunotoxicology.

PMID- 8658547
TI  - Immune alterations in lead-exposed workers.
AB  - Peripheral blood lymphocytes, serum immunoglobulins (IgG, IgA and IgM), C3 and C4
      complement protein concentrations of 25 male lead-exposed workers from storage
      battery plants were examined and compared to 25 healthy male controls. Lead
      exposure was assessed using blood lead levels measured by atomic absorption
      spectrophotometry and zinc protoporphyrin (ZPP) levels assayed by
      hematofluorometry. The absolute number and the percentage of functionally
      different subsets of peripheral blood mononuclear lymphocytes, i.e. T, T
      suppressor, B and natural killer cells, were unchanged. However, T-helper
      lymphocytes were significantly lower in lead-exposed workers compared to healthy
      controls (P < 0.05). In addition, lead-exposed workers had a significant
      reduction in the IgG, IgM and C3, C4 complement levels (P < 0.05). These results
      suggest that human chronic exposure to lead may be detrimental to the immune
      system.

PMID- 8658548
TI  - Effect of Prograf (FK506) on spermatogenesis in rats.
AB  - Prograf (FK506) was given to male mature rats in a daily subcutaneous dose of 1
      or 3 mg/kg/day for 2 weeks to investigate its effect on spermatogenesis. Prograf
      dose-dependently sperm counts and motility, but did not affect testosterone level
      in the serum of rats. Histopathologically, there were no abnormal changes in the
      testis, seminal vesicle or prostate in any rats dosed with Prograf, but intra
      ductal eosinophilic globules, probably degeneration of the sperm cells, were
      observed in the epididymis of the 3 mg/kg/day group. Sperm counts and motility
      returned to the control levels after stopping of the drug. The results indicate
      that Prograf decreased sperm counts and motility through direct action on the
      sperm in the epididymis, but not the production of sperm in the testis.
      Cyclosporine A (CsA) was used as the reference drug in the present study. Thirty
      mg/kg/day of CsA also decreased sperm counts and motility, and stopping of the
      drug led to the recovery of these changes. The males dosed with Prograf for 2
      weeks were mated with non-dosed females to investigate its effect on the
      fertility potential of the males. Prograf did not affect copulation or fertility
      index, but a decrease in the number of live fetuses associated with implantation
      loss was observed in the 3 mg/kg/day group. The changes were considered to be due
      to the decrease of sperm counts and motility, although 1 mg/kg/day of Prograf, 5
      10 times the clinical dose, did not affect any fertility parameters including
      implantation index.

PMID- 8658549
TI  - Acetaminophen-arylated proteins are detected in hepatic subcellular fractions and
      numerous extra-hepatic tissues in CD-1 and C57B1/6J mice.
AB  - To identify acetaminophen (APAP)-bound proteins in addition to the major 44 and
      58 kDa APAP-binding proteins (Bartolone et al., 1992, Toxicol. Appl. Pharmacol.
      113. 19-9; Pumford et al., 1992, Biochem. Biophys. Res. Commun. 182, 1348-1355;
      Bulera et al., 1995, Toxicol, Appl. Pharmacol. 134, 313-320), we investigated
      subcellular localization of liver proteins and tissue distribution of proteins
      arylated by a hepatotoxic dose of APAP in CD-1 and C57B1/6J mice. Western blot
      analysis with affinity-purified, anti-APAP antibodies allowed the detection of
      covalently bound proteins in liver mitochondria, nuclei, membrane, cytosol, and
      microsomes. Enzyme market assays revealed that subcellular fractions were 90-98%
      pure. The lack of contamination from other isolated subcellular fractions
      indicates that covalently bound proteins were specific to the particular
      subcellular fraction. APAP-arylated proteins with molecular weights similar to
      those detected in the liver were found in cytosolic fractions from kidney, lung,
      pancreas, heart, skeletal muscle, and stomach. The presence of arylated proteins
      in extra-hepatic organs suggests that other organs may be susceptible to APAP
      toxicity and may contain critical protein targets that are important in APAP
      toxicity. In contrast, covalently bound proteins were not detected in cytosols
      isolated from spleen, small intestine, brain, and testis. The characterization of
      the APAP-arylated proteins identified in this study will aid in elucidating the
      mechanism of APAP-induced toxicity.

PMID- 8658550
TI  - The effects of some redox-active metals and reactive aldehydes on DNA-protein
      cross-links in vitro.
AB  - It has been suggested that the measurement of DNA-protein cross-links (DPCs) may
      be of value in the assessment of an individual's exposure to specific
      environmental insults. For a biomarker to be reliable, its results should be
      consistent and specific. In the present study, the precision and specificity of
      the K(+)-SDS precipitation assay as a measurement for DPCs was assessed. Chinese
      hamster ovary (CHO) and human fibroblast cells were exposed to a number of
      diverse oxidative insults, whose concentrations ranged from physiological to
      super-physiological levels. Only super-physiological concentrations of the
      insults induced the formation of DPCs. Formaldehyde, chromate, vanadate,
      acetaldehyde, and copper were found to be the greatest inducers of DPC formation
      followed by manganese and iron. DPC induction was consistently higher in the CHO
      cells than in human fibroblast cells. While the K(+)-SDS assay may be of value as
      an indicator of cumulative DNA damage, its value as a biomarker for specific
      environmental insults may be limited.

PMID- 8658551
TI  - Haloacetate-induced oxidative damage to DNA in the liver of male B6C3F1 mice.
AB  - Brominated and chlorinated haloacetates (HAs) are by-products of drinking water
      disinfection. Dichloroacetate (DCA) and trichloroacetate (TCA) are
      hepatocarcinogenic in rodents, but the brominated analogs have received little
      study. Prior work has indicated that acute doses of the brominated derivatives
      are more potent inducers of oxidative stress and increase the 8
      hydroxydeoxyguanosine (8-OH-dG) content of the nuclear DNA in the liver. Since,
      DCA and TCA are also known as weak peroxisome proliferators, the present study
      was intended to determine whether this activity might be exacerbated by
      peroxisomal proliferation. Classical responses to peroxisome proliferators,
      cyanide-insensitive acyl-CoA oxidase activity and increased 12-hydroxylation of
      lauric acid, were elevated in a dose-related manner in mice maintained on TCA and
      clofibric acid (positive control), but not with DCA, dibromoacetate (DBA) or
      bromochloroacetate (BCA). Administration of the HAs in drinking water to male
      B6C3F1 mice for periods from 3 to 10 weeks resulted in dose-related increases in
      8-OH-dG in nuclear DNA of the liver with DBA and BCA, but not with TCA or DCA.
      These findings indicate that oxidative damage induced by the haloacetates is, at
      least in part, independent of peroxisome proliferation. In addition, these data
      suggest that oxidative damage to DNA may play a more important role in the
      chronic toxicology of brominated compared to the chlorinated haloacetates.

PMID- 8658552
TI  - Reversal of acute theophylline toxicity by calcium channel blockers in dogs and
      rats.
AB  - Theophylline, widely used in the treatment of pulmonary diseases, has a narrow
      therapeutic index; the recommended plasma levels being 10-20 micrograms/ml in
      humans. The misuse or abuse of theophylline can cause life-threatening central
      nervous system and cardiovascular effects. Increased intracellular Ca2+ levels
      are thought to play an important role in theophylline toxicity and death. The
      objective of this study was to determine whether Ca2+ channel blockers, e.g.
      verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline
      treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with
      theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by
      administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0
      mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats
      were observed for toxic signs and survival over a period of 15 days. All three
      calcium channel blockers significantly reduced the theophylline-induced sudden
      death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor
      nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial
      necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented
      theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and
      sudden death. Our results support previously reported findings that calcium plays
      a major role in theophylline-induced toxicity and death.

PMID- 8658553
TI  - Comparative effects of the metabolic inhibitors 2,4-dinitrophenol and iodoacetate
      on mouse neuroblastoma cells in vitro.
AB  - The toxic effects of two metabolic inhibitors, dinitrophenol and iodoacetic acid,
      were compared. Mouse neuroblastoma cell cultures (Neuro-2a) were exposed to
      different concentrations of the toxic compounds for 24, 48 and 72 h to study
      basal toxicity effects (cell proliferation by quantification of total protein
      content (PR) and relative neutral red uptake (RNRU) by lysosomes). The following
      biochemical indicators assessed in the in vitro test system were: cytosolic
      phosphofructokinase (PFK) and enolase (ENL) activities in glycolysis;
      mitochondrial succinate dehydrogenase (SDH) activity in the citric acid cycle;
      lysosomal beta-galactosidase (GAL) activity; and neuronal acetylcholinesterase
      (AChE) activity. The effects of the two metabolic inhibitors on the various
      indicators differed. Iodoacetic acid was found to be far more toxic than
      dinitrophenol to neuroblastoma cell proliferation at 24 h exposure. Though 2,4
      dinitrophenol and iodoacetic acid both inhibited cell proliferation of the
      neuroblastoma cells, their effects on the other endpoints were opposite.
      Dinitrophenol was a general activator of the metabolism, particularly affecting
      lysosomal function. Iodoacetic acid did not significantly alter general
      metabolism, but considerably modified lysosomal function and AChE activity. The
      modification of lysosomal function of Neuro-2a cells by the two compounds was
      quite different: dinitrophenol increased RNRU and GAL activity, and iodoacetic
      acid decreased both parameters.

PMID- 8658554
TI  - Alterations of dendritic cells in the rat thymus without epithelial cell loss
      during cyclosporine treatment and recovery.
AB  - After cyclosporine treatment, dendritic cells disappear from the rat thymic
      medulla. The present study was undertaken to examine the ultrastructural
      alterations in the dendritic cell population during 14-day cyclosporine treatment
      and subsequent 6-week recovery. Four dendritic cell subtypes were defined
      ultrastructurally by a newly developed classification system. In addition, the
      potential effect of cyclosporine on six medullary epithelial cell subtypes was
      studied. During cyclosporine treatment, a prominent reduction of dendritic cells
      was seen at the ultrastructural level, whereas the total number of medullary
      epithelial cells remained largely unchanged. These findings were confirmed by
      immunohistochemistry. The number of mature dendritic cells declined later than
      the number of immature ones. A decrease in the antigen-processing capacity of
      remaining dendritic cells was suggested by the disappearance of Birbeck granules
      and the reduced number of tubulovesicular complexes. These findings support a
      disturbance of clonal deletion during cyclosporine treatment. The dendritic cell
      alterations appeared reversible 4 weeks after the restoration of the original
      architecture. During recovery, dendritic cells displaying lysosomal elements
      outnumbered those found in the normal uninvoluted thymus. This phenomenon
      probably reflects an enhanced turnover of cell organelles. No treatment-related
      effect on epithelial cell subtypes was seen.

PMID- 8658555
TI  - Role of Fas apoptosis and MHC genes in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
      induced immunotoxicity of T cells.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is well known for its immunotoxic
      effects particularly on the thymus as well as on T and B lymphocyte functions.
      Previous studies have suggested that TCDD may induce apoptosis in thymocytes
      although its demonstration in vivo has met with limited success. TCDD has also
      been shown to alter the major histocompatability complex- (MHC) encoded
      molecules, however, its role in immunotoxicity is not clear. In the current
      study, we investigated the role of Fas (CD95), an important molecule involved in
      the induction of apoptosis, on TCDD-mediated immunotoxicity using mice bearing
      homozygous lpr mutation which leads to failure of expression of Fas. When TCDD
      was administered orally at 0, 0.1, 1.0, or 5.0 micrograms/kg body weight for 11
      days, it was found to be less toxic to the thymocytes from C57BL/6 lpr/lpr mice
      (Ah-responsive, Fas-) when compared to C57BL/6 +/+ mice (Ah-responsive, Fas+).
      Similar results were obtained when peripheral T cell responsiveness to antigenic
      challenge with conalbumin was studied in these mice. When mice that differed only
      at the MHC were compared for immunotoxic effects of TCDD, it was noted that
      B10.D2 (Ah-responsive, H-2d) were more sensitive to TCDD-mediated thymic atrophy
      and peripheral T cell dysfunction when compared to B10 mice (Ah-responsive, H
      2b). In all TCDD-sensitive strains tested, the thymic atrophy was accompanied by
      a uniform depletion of all four subset of T cells (CD4+, CD4+CD8+, CD4-CD8-, and
      CD8+) and the percentage of these subsets was not altered. Furthermore, in these
      strains, TCDD suppressed the antigen-specific peripheral T cell responsiveness
      but not the responsiveness of naive resting T cells to polyclonal mitogens.
      Lastly, using cell-mixing experiments, it was demonstrated that TCDD directly
      affected the T cells responding to conalbumin but not the antigen presenting
      cells (APCs). Together, our studies demonstrate that although Ah locus plays the
      primary role, determining the toxicity of TCDD on the T cells, there are
      secondary factors such as expression of Fas or the MHC-phenotype which may play
      an important role in TCDD-mediated immunotoxicity. The role of Fas further
      suggests that TCDD may induce toxicity in T cells by triggering apoptosis.

PMID- 8658556
TI  - Nephrotoxicity of N-(3-bromophenyl)-2-hydroxysuccinimide: role of halogen groups
      in the nephrotoxic potential of N-(halophenyl) succinimides.
AB  - Among N-(halophenyl)succinimides. N-(3,5-dichlorophenyl)succinimide (NDPS) is a
      potent nephrotoxicant as well as an agricultural fungicide. Although two chloride
      groups on the phenyl ring are essential to induce optimal nephrotoxicity, the
      role of halogen groups in NDPS nephrotoxicity is not clear. In this study, N-(3
      bromophenyl)-2-hydroxysuccinimide (NBPHS) was prepared as a monohalophenyl
      derivative of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), an oxidative
      and nephrotoxicant metabolite of NDPS. The nephrotoxic potential of NBPHS was
      evaluated in vivo and in vitro to determine the role of halogen groups in N
      (halophenyl)succinimide nephrotoxicity. Male Fischer 344 rats (four/group) were
      administered a single intraperitoneal (i.p.) injection of NBPHS (0.1, 0.4 or 0.8
      mmol/kg) or vehicle (25% dimethyl sulfoxide in sesame oil) and renal function
      monitored for 48 h. Administration of NBPHS (0.8 mmol/kg) induced nephrotoxicity,
      while very mild changes or no changes in renal function were observed following
      administration of 0.4 mmol/kg or 0.1 mmol/kg of NBPHS, respectively.
      Nephrotoxicity induced by NBPHS (0.8 mmol/kg) was characterized by diuresis,
      transiently increased proteinuria, glucosuria and hematuria elevated kidney
      weight and reduced tetraethylammonium (TEA) uptake by renal cortical slices, and
      was not as marked as nephrotoxicity induced by NDHS (0.1 mmol/kg) or NDPS (0.4
      mmol/kg). In the in vitro studies the effects of NBPHS on organic ion
      accumulation, pyruvate-stimulated gluconeogenesis, and lactate dehydrogenase
      (LDH) release were measured using renal cortical slices. NBPHS decreased p
      aminohippurate (PAH) and TEA accumulation at NBPHS bath concentrations of 0.05 mM
      and 0.5 mM and 0.5 mM or greater, respectively. Renal gluconeogenesis was
      inhibited by NBPHS at 1 mM bath concentration, while LDH leakage was not
      increased at NBPHS bath concentrations up to 1 mM. The results demonstrate that
      NBPHS is a mild nephrotoxicant in vivo and in vitro, but does not have cytotoxic
      effects to renal tissues at the concentrations tested. From these results, it
      appears that halogen groups are essential to the nephrotoxic potential of N
      (halophenyl)-2-hydroxysuccinimides or N-(halophenyl)succinimides and play an
      important role in the mechanism of NDPS nephrotoxicity following NDHS formation.

PMID- 8658557
TI  - The antimalarials quinacrine and chloroquine induce weak lysosomal storage of
      sulphated glycosaminoglycans in cell culture and in vivo.
AB  - The antimalarial agents quinacrine and chloroquine are well known as potent
      inducers of lysosomal storage of polar lipids (lipidosis) in cell culture and in
      vivo. In previous experiments on cultured fibroblasts, chloroquine was shown to
      additionally cause weak lysosomal storage of sulphated glycosaminoglycans (GAGs)
      thus inducing mucopolysaccharidosis (MPS). In the present study, quinacrine was
      investigated for this ability, because we wished to know whether or not the
      acridine ring system in quinacrine would enhance the MPS-inducing potency as
      compared to chloroquine carrying an isoquinoline ring system. Tilorone (2,7-bis[2
      (diethylamino)ethoxy]fluoren-9-one) known as a potent inducer of MPS served as
      reference compound. The compounds were compared at a concentration (3 microM)
      which did not enhance the secretion of the lysosomal enzyme beta-hexosaminidase
      (E.C. 3.2.1.52), since this would be an indication of unspecific drug effects
      upon the endosomal/lysosomal compartments of the cell. Additionally the liver of
      quinacrine- and chloroquine-treated rats was examined with the question whether
      the lysosomal GAG storage induced by either drug in cell culture had an
      equivalent in intact organisms. Both, in cell culture and in vivo, quinacrine was
      found to be a more potent inducer of lysosomal GAG storage than was chloroquine.
      The results suggest that the acridine ring system favours this drug side effect
      as compared with the bicyclic isoquinoline ring system. On the other hand,
      quinacrine was significantly less potent than tilorone and the Symmetrically
      substituted acridine derivative 3,6-bis[2-(diethylamino)ethoxy]acridine
      investigated previously. This suggests that the asymmetric structure of the
      quinacrine molecule reduces the potency as compared to the symmetrically
      substituted bisbasic compounds with planary tricyclic ring systems such as
      tilorone and congeners.

PMID- 8658558
TI  - Formyl-methionyl-leucyl-phenylalanine and a calcium ionophore A23187 reverse the
      inhibition of phorbol myristate acetate-induced oxidative burst by linoleic and
      oleic acid anilides.
AB  - Linoleic and oleic acid anilides profoundly inhibited the production of reactive
      oxygen metabolites (ROM) in human polymorphonuclear leukocytes (PMNL) induced by
      a tumor promoter, phorbol myristate acetate (PMA). The addition of a Ca2+
      ionophore, A23187, or a chemotactic peptide, formyl-methionyl-leucyl
      phenylalanine (fMLP), readily reversed linoleic and oleic acid anilide-induced
      inhibiton of PMA-evoked respiratory burst in PMNL without affecting PMA-induced
      respiratory burst. fMLP or A23187 caused a marked increase in the production of
      ROM in PMNL that did not produce ROM after their co-exposure to PMA and cis-fatty
      acid anilides. This suggests a role for Ca2+ in this restoration of respiratory
      burst activity in PMNL. Oleic and linoleic acid anilides enhanced also
      respiratory burst in PMNL subsequent to their stimulation with fMLP.
      Interestingly, corresponding fatty acids, linoleic and oleic acid, also inhibited
      PMA-induced production of ROM in PMNL, but this inhibition was not reversed by
      A23187 or fMLP. These findings suggest that the aniline moiety of cis-fatty acids
      significantly modifies the effects of linoleic and oleic acids in the production
      of ROM in PMNL. Moreover, free intracellular Ca2+ may play a critical role in the
      activation of PMNL to produce ROM, and in the modulation of the effects of cis
      fatty acid anilides.

PMID- 8658559
TI  - Nephrotoxicity of 4-amino-2-chlorophenol and 2-amino-4-chlorophenol in the
      Fischer 344 rat.
AB  - Aminophenols and halogenated anilines induce nephrotoxicity and mild
      hepatotoxicity in rats. In this study, the in vivo and in vitro nephrotoxic
      potential of 4-amino-2-chlorophenol and 2-amino-4-chlorophenol, monochlorinated
      aminophenols and potential metabolites of 3-chloroaniline, was evaluated.
      Hepatotoxicity of both compounds was also examined in vivo. Male Fischer 344 rats
      (four/group) were administered 4-amino-2-chlorophenol hydrochloride (0.4, 0.8 or
      1.0 mmol/kg), 2-amino-4-chlorophenol hydrochloride (0.4, 0.8 or 1.2 mmol/kg) or
      vehicle intraperitoneally (i.p.) and renal and hepatic function monitored for 48
      h. Administration of 4-amino-2-chlorophenol (0.8 mmol/kg) induced nephrotoxicity,
      while only minor changes in kidney function were observed following
      administration of 0.4 mmol/kg of 4-amino-2-chlorophenol or 0.8 mmol/kg of 2-amino
      4-chlorophenol. Increasing the dose of 4-amino-2-chlorophenol to 1.0 mmol/kg or 2
      amino-4-chlorophenol to 1.2 mmol/kg resulted in lethality. Nephrotoxicity induced
      by 4-amino-2-chlorophenol was characterized by diuresis, increased proteinuria,
      glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and
      kidney weight, and marked proximal tubular damage, while 2-amino-4-chlorophenol
      induced milder effects on renal function and transient oliguria instead of
      diuresis. No hepatotoxicity was observed with either compound at any dose tested.
      In the in vitro studies, the direct effects of 4-amino-2-chlorophenol or 2-amino
      4-chlorophenol on organic ion accumulation, pyruvate-stimulated gluconeogenesis
      and lactate dehydrogenase (LDH) leakage were determined using renal cortical
      slices. 4-Amino-2-chlorophenol and 2-amino-4-chlorophenol were almost equally
      effective in inhibiting organic anion or cation uptake and gluconeogenesis or
      increasing LDH leakage, although small differences in the minimum effective
      concentrations were present (minimum effective concentration, 0.01-0.5 mM range).
      These results demonstrate that 4-amino-2-chlorophenol is a more potent
      nephrotoxicant than 2-amino-4-chlorophenol in vivo. The results also indicate
      that the addition of a chloride group to aminophenols enhances renal toxicity.

PMID- 8658560
TI  - Urine mutagenicity and biochemical effects of the drinking water mutagen, 3
      chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), following repeated oral
      administration to mice and rats.
AB  - Mutagenicity analysis of urine from rats treated by oral gavage with MX at a dose
      of 64 mg/kg for 14 days revealed that only 0.3% of the administered compound was
      excreted in a genotoxically active form. At lower doses, mutagenicity was not
      detectable. No evidence of micronucleus induction in peripheral blood
      erythrocytes was observed in mice treated similarly. These findings indicate that
      MX is extensively detoxified in vivo and is unlikely to cause genetic damage in
      systemic tissues except at relatively high doses where detoxification pathways
      become saturated. In a separate experiment, significant depressions were observed
      in D-glucaric acid and thioether excretion and in levels of several liver enzymes
      involved in xenobiotic metabolism. The mechanism for these metabolic alterations
      and their relevance to the in vivo metabolism of the compound require further
      investigation.

PMID- 8658561
TI  - Age dependence of the cardiac lesions induced by minoxidil in the rat.
AB  - To evaluate the age- and dose-dependence of the cardiotoxicity induced by
      minoxidil, histologic studies were made of the hearts of 3-, 6-, 15- and 24-month
      old Sprague Dawley rats treated with either 10, 50 or 250 mg/kg of the drug p.o.
      daily for two consecutive days. The 10 mg/kg dose of minoxidil induced myocyte
      necrosis in each of the 24-month-old rats but only in one other animal (6-month
      old). The 50 mg/kg dose produced necrosis in all the 15- and 24-month-old rats,
      but in only one of the other animals (6-month-old), while the 250 mg/kg dose
      induced necrosis in animals of all ages. Inflammation was present in all
      minoxidil-treated animals, but at each dose level it was most severe in the
      oldest rats. Interstitial hemorrhages were observed at all dose levels, but
      increased in frequency and severity with the dose of minoxidil, and at each dose
      level they were more severe in the oldest animals. Vascular lesions consisting of
      arteriolar damage and calcification were observed only in the 24-month-old
      animals. Thus, these data demonstrate that the cardiac lesions induced by
      minoxidil are more frequent and severe in older than in younger rats.

PMID- 8658562
TI  - Ortho-phenanthroline modulates enzymes of cellular energy metabolism.
AB  - The lipophilic iron chelator 1,10-phenanthroline has been used in mechanistic
      studies on intracellular oxidant damage because iron is assumed to play a role in
      the endogenous formation of highly reactive oxygen species. This study shows that
      1,10-phenanthroline has enzyme-modulatory properties in addition to its
      antioxidant activity. In rat hepatocytes, 1,10-phenanthroline caused inhibition
      of respiration and enhancement of cellular ATP content, pyruvate release and CO2
      formation from glycerol resulting from a modulatory action of 1,10-phenanthroline
      on various enzymes involved in cellular energy metabolism. In intact mitochondria
      and in submitochondrial particles, oxygen consumption, complex I activity, and
      ATPase degradation are inhibited by 1,10-phenanthroline. In submitochondrial
      particles, complex II activity can also be suppressed by 1,10-phenanthroline. The
      purified cytosolic enzymes lactate dehydrogenase and glycerol-3-phosphate
      dehydrogenase are inhibited while purified glyceraldehyde-3-phosphate
      dehydrogenase is activated by 1,10-phenanthroline. The results suggest that 1,10
      phenanthroline modulates various enzyme activities linked to cellular energy
      metabolism and that this property must be taken into account when using 1,10
      phenanthroline as a tool in experiments on oxidant effects in cells.

PMID- 8658563
TI  - Inhibition by lithium and rubidium of gentamicin-induced release of N-acetyl-beta
      D-glucosaminidase from perfused rat kidney.
AB  - N-acetyl-beta-D-glucosaminidase (NAG) is one of the sensitive hydrolytic
      lysosomal enzymes which is released after renal tubular damages. We studied
      gentamicin-induced nephrotoxicity by determining the NAG release in perfused rat
      kidney. 100 micrograms/ml of gentamicin caused a time-dependent increase in
      enzymuria, peaking at 90 min. At this time the released NAG is about sixfold more
      than the control. The effect of concurrent perfusion with 100 micrograms/ml
      gentamicin and with 0.5 mmol/l lithium chloride or 0.5 mmol/l rubidium chloride
      in the perfusion fluid was also studied by measuring NAG activity in the
      perfusate. Both cations decrease the gentamicin-induced NAG release. However, the
      inhibitory effect of lithium chloride may be due to interference of this ion with
      the polyphosphoinositide cycle in renal tubular lysosomal membranes. There is no
      obvious evidence for an inhibitory effect of rubidium chloride.

PMID- 8658565
TI  - [The reactivity characteristics of the organs of the oral cavity in an with
      different types of nervous systems].
AB  - Experiments were carried out on 120 albino rats, divided into "active" and
      "passive", depending on the type of their nervous system. The animals were
      exposed to complete fasting of up to 6 days, after which feeding was resumed for
      1 to 3 days. Oral mucosa, muscle tissue, and maxillofacial tissue were examined
      by histologic and histochemical methods. The adaptation reactions were the same
      in the active and passive animals, but the rates of their triggering and
      intensity differed. Adaptive processes rapidly triggered on in the active
      animals, but these animals were less resistant than the passive ones.

PMID- 8658564
TI  - Amiodarone-induced pulmonary fibrosis in Fischer 344 rats.
AB  - Amiodarone is a potent antiarrhythmic agent with a number of side-effects, the
      most serious being the development of pulmonary toxicity. The purpose of the
      study was to determine if a single intratracheal instillation of amiodarone would
      induce pulmonary fibrosis and associated functional changes in rats. Female
      Fischer 344 rats were given a single intratracheal instillation of 200
      microliters containing 1.25 mg amiodarone (n = 9) while the control group
      received an equivalent volume of sterile water (n = 8). After 6 weeks, pulmonary
      function tests, lung hydroxyproline measurements and lung histology were
      performed. The amiodarone-treated animals showed a significant reduction in the
      coefficient of diffusion (kCO) and a significant increase in lung hydroxyproline
      levels as compared to the control group. The treated group had abnormal histology
      including areas of septal thickening with cellular infiltration of the
      interstitial and alveolar spaces, whereas the control group had normal histology.
      These observations suggest that the intratracheal instillation route of
      amiodarone treatment produces a fibrotic response in rats that can be measured
      physiologically, biochemically and histologically. This model may aid in the
      elucidation of the mechanism of amiodarone-induced pulmonary toxicity
      (AIPT)./ABS.

PMID- 8658566
TI  - [The use of immunological indices for assessing the severity of the course of
      periodontitis and treatment efficacy].
AB  - The authors studied immunological status of patients with paradontosis. If
      included estimation of extended structure of lymphocytes and functional status of
      thymus. There was marked correlation between clinical of patients and
      immunological indices especially in severe form of paradontitis. As immunological
      preparation T-activin was used in injections and applications. Using of T-activin
      gave positive results in patient developed of paradontitis.

PMID- 8658567
TI  - [A mathematical analysis of the heart rhythm in assessing periodontal diseases in
      women].
AB  - Mathematical analysis of heart rhythm helps detect disorders in the adaptation
      and compensatory potential of the body patients with diseases of the periodontium
      which are associated with a high stress and overstrain leading to exhaustion of
      the regulatory mechanisms. This should be borne in mind when planning treatment
      of such patients.

PMID- 8658569
TI  - [The local activation of leukocytes and thrombocytes in periodontal diseases: the
      role of thrombocyte-activating factor].
AB  - Concentration of markers for platelet and leukocyte local activation including
      platelets factor four, beta-thromboglobulin, granulyte elastate and beta
      glucunidase was measured in gingival fluid from patients with gingivitis and
      periodontitis. It has been shown that there is a statistically significant
      increase in level of markers in these patients. The increase correlated with
      degree of periodontal injury. Radioimmune assay of concentrations of platelet
      activating factor (PAF) in gingival fluid and gingival tissue was performed. Its
      concentration also increased in gingivitis and periodontitis depending on
      intensity of the tissue injury. A close correlation between the PAF concentration
      has been revealed. It is likely that hypergeneration of PAF in the endothelium is
      a mechanism for the blood cell activation and accumulation in gingival tissue
      resulting in its failure due to secretion of different deleterious agents from
      the activated cells.

PMID- 8658568
TI  - [Antibacterial therapy in the combined treatment of periodontitis].
AB  - The sensitivities of clinical strains of obligate anaerobic bacteria, isolated
      from the periodontal pouches of patients with generalized periodontitis, to
      antibiotics, quinolone drugs, and metronidasole were studied. The minimal
      suppressing concentration (MSC90) of ciprofloxacin, norfloxacin, and antibiotics
      gramicidin C, eritromicin, lincomycin, levomicetin, and trichopol for sensitive
      strains of Porphyromonas, peptostreptococci, and fusobacteria ranged from 5 to 10
      mg/ml. Among the bacteria and actinomyces studied the highest percentage of
      resistant strains was noted for abactal and tarivid, and the minimal for
      gramicidin C and eritromicin. Actinomyces were little sensitive to quinolone
      derivatives.

PMID- 8658571
TI  - [The effect of Kislovodsk narzan mineral water on dental caries incidence and
      intensity and on periodontal status].
AB  - Effects of drinking Kislovodsk narzan water on the status of hard dental tissues
      and periodontium are assessed. A total of 540 residents of Kislovodsk of both
      sexes aged 20 to 59 were examined, 270 of these having contacts with narzan and
      drinking it for many years and 270 ones who had no contacts with this water and
      did not regularly drink it. A total of 150 intact human teeth were examined after
      being kept in tubes with narzan, normal saline, or 0.3 carbon dioxide for 30 days
      (the solutions in tubes were daily replaced). The results brought the authors to
      a conclusion that Kislovodsk narzan is a caries-static agent which, if indicated,
      may be effectively used for the treatment of periodontal inflammations.

PMID- 8658570
TI  - [The clinico-biochemical characteristics of periodontal diseases in subjects who
      are under conditions of constant, permanent stress].
AB  - A comparative study of prevalence of periodontal diseases in an indigenous
      Armenian population and a population of refugees in Armenia has been performed.
      The refugees population was considered a population of subjects under permanent
      stress conditions. It has been shown that in the refugees population there are
      higher prevalence of periodontal diseases, first of all periodontitis, and more
      marked heaviness of injures in periodontal tissues that those in the indigenous
      population. These changes were accompanied with elevated signs of disturbances of
      hemo-endothelial balance. In particular, there were profound alterations of
      normal ratio of 6-keto-PGF1a/NXB2 and increased level of markers for endothelial
      disorganization, thrombomodulin and von Willebrand factor, in the blood. It is
      that stress-induced disturbances of the hemo-endothelial balance among the
      refugees may contribute to developing periodontal diseases in this population.

PMID- 8658572
TI  - [The arterial pressure problem in dental practice].
AB  - High blood pressure (hypertension) is one the most frequent problems, especially
      for older patients in Europe. Often hypertension has no symptoms, therefore it is
      called a "Silent Killer". The morbidity and mortality is high among the
      population. This provides important significance for diagnosis and treatment of
      hypertension. In the USA and the Netherlands screening of blood pressure during
      dental check-ups was studied. It became well-known that blood pressure increases
      more in hypertensive patients than in controls. Before check-up increase is about
      8 mm Hg, but during treatment without a local anesthesia and during extraction
      under a local anesthesia there is a significant sudden increase. Therefore it is
      important to define patients physical status including blood pressure, in ASA
      risk score. This allows to take preventive measures during dental treatment in
      patients with a systolic blood pressure between 160 - 200 mm Hg and diastolic 95 
      115 mm Hg. A systolic blood pressure > 200 mm Hg and diastolic > 115 mm Hg is an
      absolute contraindication to dental procedure.

PMID- 8658573
TI  - [Ways to improve the quality of the dentist's work].

PMID- 8658574
TI  - [New endoprostheses for the condylar process of Russian manufacture].
AB  - Experience gained in repair of the mandibular condylar processes with titanium
      endoprostheses in 6 patients (8 endoprostheses) is presented. The defects were
      due to improperly healing fractures, ankylosis of the temporomandibular
      processes, and cancer. Two variants of endoprostheses differing by the fixing
      device are proposed. One variant is intended for replacement of defects of the
      condylar process only, the other permits the use of various titanium
      constructions to replace bone tissue defects in the branch, angle, and body of
      the jaw after its resection. Good immediate and late results (followed up for up
      to 14 months) demonstrate the efficacy of the proposed method.

PMID- 8658575
TI  - [The use of an analgin-novocaine-platyphylline mixture for arresting the pain
      attack and treating trigeminal neuralgia].

PMID- 8658576
TI  - [Combined plastic repair in head and neck tumors].
AB  - Combinations of arterialized flaps with other grafts have to be used for repair
      of extensive perforating defects caused by removal of local disseminated
      malignant tumors of the head and neck. A total of 635 plastic surgeries were
      carried out during the latest 15 years at Department for Tumors of the Upper
      Respiratory Tract, Cancer Research Center, Russian Academy of Medical Sciences.
      Of these, combined plasty was carried out in 79 cases; in 28 patients the tumor
      was localized in the median area of the face, in 37 in the lower part, and in 14
      on the neck. Primary combined plasty was carried out in 41 patients, delayed
      repair in 38. Musculocutaneous flaps were used in 42 cases, fatty-cutaneous ones
      in 37. A working schematic classification of variants of primary and delayed
      combined plasty in patients operated on for tumors of the head and neck has been
      developed.

PMID- 8658577
TI  - [The osteoplastic replacement of mandibular defects].
AB  - Remote (from 1 to 18 years) results of mandibular defect repair were followed up
      in 64 patients, to whom auto- and allografts and implants of glass ceramics were
      implanted. A relatively low incidence of complications in patients with glass
      ceramic implants demonstrates its advantages over other materials for plastic
      repair of mandibular defects.

PMID- 8658578
TI  - [The classification of combined deformities of the nose].
AB  - A classification of deformations of the nose is proposed. All deformations are
      classified into 5 degrees: I) deformations involving one compartment of the nose,
      II) two compartments, III) three compartments, IV and V) combined deformations
      involving more than 4 compartments. This classification helps the physician to be
      better oriented in the great variety of combined deformations of the nose and
      permits a more accurate planning of the steps of surgery. This classification is
      not a final or exhausting, it is merely an attempt to present a scheme of the
      great variety of combined deformations of the nose and attract the attention of
      specialists to development of better classifications needed by practical
      medicine.

PMID- 8658579
TI  - [Clinical picture and orthodontic treatment in a shortened interalveolar
      distance].
AB  - A total of 868 patients aged 25 to 68 with various types of occlusion and
      dentition defects were examined. 212 (24.4%) patients presented with a shortened
      interalveolar distance (height of occlusion). Abnormal abrasion of hard dental
      tissues, dentition defects in the lateral sections of dental arches, abnormal
      occlusion (deep or prognathic), reduced tolerance of periodontal tissues, and
      dysfunction of the masticatory muscles (bruxism) were found to be the
      pathogenetic factors leading to the development of this condition. Dysfunction of
      the masticatory muscles was detected in 41.5% of patients with shortened
      interalveolar distance and dysfunction of the temporomandibular joint in 9.9%;
      moreover, in many of them traumatic occlusion and disorders in the regional
      circulation in the periodontium of teeth exposed to overexercise were observed.
      Orthodontic treatment of patients with shortened interalveolar distance was
      carried out in two stages: the first stage consisted in functional and adaptation
      restructuring of the maxillodental system by repair of the height of occlusion
      and normalization of the mandibular position on a plastic cup which the patients
      wore for 3 months, and then the second stage ensued, at which they were fitted
      with dentures. Good results were attained in 95.7% patients.

PMID- 8658580
TI  - [Congenital developmental defects of the face and jaws in children (the
      statistical data for Moscow for 1979-1993)].
AB  - A stable increase in the rate of birth of children with congenital developmental
      defects in general and, specifically, with cleft lip and palate was observed in
      Moscow in 1979-1993. Regions of the city with stable high and low annual
      incidence of birth of children with maxillofacial clefts were distinguished.

PMID- 8658581
TI  - [The functional status of the periodontium during the treatment of tooth crowding
      by the edgewise technic].
AB  - The status of abutment tissues of permanent teeth was studied in patients with
      dense position of teeth, aged 13 to 18. Time course of periodontal changes at
      different stages of orthodontic treatment with permanent devices was followed up.

PMID- 8658582
TI  - [Estimating the cost of an arbitrary unit of labor intensity in dentistry].

PMID- 8658583
TI  - [Experience in organizing an office for emergency dental care based in a
      maxillofacial surgery department].

PMID- 8658584
TI  - [The prospects for the use of computers in dentistry].
AB  - A universal soft-art complex tentatively named Arm-Stomatolog, covering all
      sections of dentistry, has been developed. It is based on individual programs in
      dentistry, making use of high-level algorithmic languages fitted to modern
      operation systems and permitting block-to-block fitting of individual programs to
      unite them in a complex.

PMID- 8658585
TI  - [An experimental trial of a hydroxyapatite-based root paste].
AB  - Hydroxyapatite-based radicular paste was tried in 12 dogs with experimental
      chronic periodontitis. Hydroxyapatite, zinc-eugenol, and resorcin-formal pastes
      were compared. The periodontal status was assessed by morphometric methods.
      Hydroxyapatite-based radicular paste was found to be the most effective means of
      treating experimental chronic periodontitis. In control groups the therapeutic
      effect was either null or minimal.

PMID- 8658586
TI  - [The use of hydroxyapatite for the surgical preparation of the oral cavity for
      prosthesis].

PMID- 8658587
TI  - [The family dentist: the reality and the problems].

PMID- 8658588
TI  - [Introduction of subjectivity and objectivity in medicine: comments on the Viktor
      von Weizsacker's social medicine 1929-33].
AB  - It is well known that the principle of subjectivity played an important role in
      Viktor von Weizsacker's anthropological medicine. But it is less known that he
      tried to introduce subjectivity as well as objectivity as main principles into
      his social medicine since 1929. In Heidelberg he developed a so called social
      therapy for people suffering from traumatic neurosis. In the present study theory
      and praxis of Weizsacker's social medicine are described in detail.

PMID- 8658589
TI  - [Medicine and humanism: insights of the Nurnberg city physician Theodericus
      Ulsenius regarding Morbus Gallicus].
AB  - The Nuremberg physician and humanist Theodericus Ulsenius (c. 1460-1508) was the
      author of two works on the so-called Morbus Gallicus. In 1496 he published a
      Vaticinium in epidemicam scabiem, and he also wrote fifty aphorisms, entitled
      Cura mali francici. In this article I will characterize Ulsenius' ideas and
      compare these to the measures the Nuremberg town government took to diminish the
      dangerous effects of the epidemic. In the function of official town physician,
      Ulsenius was one of the chief advisers and executives of the Nuremberg health
      policy. As the 'Ratsverlasse' (records of the town-council meetings) give
      detailed information, the reactions of senate and physicians can be followed from
      day to day. The Vaticinium a poem of 100 hexameters was printed at the office of
      Hans Mair and presented as a pamphlet with a woodcut from the workshop of
      Albrecht Durer. The verses refer to a dream of the poet, in which the God Apollo
      addresses him and talks about the terrible disease. The origin and symptoms of
      the illness are discussed extensively, in accordance with the prevailing medico
      astrological conceptions. Nevertheless, the poem ist not a medical piece of work,
      but a literary-styled and humanistically appropriate description of the recent
      epidemic, meant for fellow members of the German respublica litteraria. Like most
      of Ulsenius' writings, the Cura mali francici only survived as a copy made by his
      colleague Hartmann Schedel. It seems that the author had different types of
      audience in mind. The aphorisms refer to the Aphorisms of his great example, the
      famous Ancient medical doctor Hippocrates of Kos. The addresses of the Cura are
      obviously medical professionals: the physician in the towns harassed by the
      Morbus Gallicus and especially the medical professors who hat to lecture on the
      new ailment.

PMID- 8658590
TI  - [The German addendum to Hildegard von Bingen's 'Liber simplicis medicinae' in
      Codex 6952 of the Bibliotheque Nationale in Paris (fol. 232v-238v)].
AB  - The article contains an analysis and edition of the German appendix to Hildegard
      of Bingen's 'Liber simplicis medicinae' ('LSM', also known as 'Physica') in Codex
      6952 of the Bibliotheque Nationale in Paris. Surprisingly, the German text is not
      based on the preceding Latin treatise, but on another unknown version of the
      'LSM' which is closer to the archetype. The appendix thus has to be regarded as a
      new manuscript find, which also contains material found only in Hildegard's
      'Liber compositae medicinae' ('LCM', also known as 'Causae et Curae'). This
      suggests that the translator had access to both texts, or that both once
      circulated as one treatise. In the reception of Hildegard's work, the 13-page
      German appendix is unique in that Hildegard's description of nature is
      transformed into three different types of medical writing: 1) a herbal, 2) a
      catalogue of diseases from head to toe and their remedies, and 3) a dietetic list
      of foodstuffs. To illustrate the technique applied by the compiler/translator,
      the edition of the Paris-appendix identifies all the quotes from the 'LSM' and
      'LCM' which have so far been uncovered.

PMID- 8658591
TI  - [Carl Gustav Jung: promotion records. Documents from the state archives of the
      Zurich canton].
AB  - Two documents dated 1902 show Eugen Bleuler as the supervisor of Carl Gustav
      Jung's thesis. In his expert opinion Bleuler declares himself convinced of the
      high scientific qualities of Jung.

PMID- 8658592
TI  - Presynaptic mechanisms of neurotransmission.

PMID- 8658593
TI  - Calcium-independent synaptic transmission: artifact or fact?
AB  - The release of neurotransmitters at classical chemical synapses occurs via Ca2+
      influx through voltage-dependent Ca2+ channels, which are opened following
      depolarization of presynaptic terminals. However, owing to a persistence or
      increase in the amount of transmitter released in preparations containing low
      concentrations of Ca2+, it has been proposed that transmitter release could also
      occur through a Ca(2+)-independent, carrier-mediated process. On the other hand,
      lowering extracellular [Ca2+] can actually promote Ca2+ influx through voltage
      activated Ca2+ channels via a modification of the surface potential of plasma
      membranes. Therefore, the proposed Ca(2+)-independent transmitter release could
      be re-accommodated within the framework of the Ca2+ hypothesis of synaptic
      transmission by taking into account the surface-charge effects.

PMID- 8658594
TI  - Metaplasticity: the plasticity of synaptic plasticity.
AB  - In this paper, we review experimental evidence for a novel form of persistent
      synaptic plasticity we call metaplasticity. Metaplasticity is induced by synaptic
      or cellular activity, but it is not necessarily expressed as a change in the
      efficacy of normal synaptic transmission. Instead, it is manifest as a change in
      the ability to induce subsequent synaptic plasticity, such as long-term
      potentiation or depression. Thus, metaplasticity is a higher-order form of
      synaptic plasticity. Metaplasticity might involve alterations in NMDA-receptor
      function in some cases, but there are many other candidate mechanisms. The
      induction of metaplasticity complicates the interpretation of many commonly
      studied aspects of synaptic plasticity, such as saturation and biochemical
      correlates.

PMID- 8658595
TI  - Integrator or coincidence detector? The role of the cortical neuron revisited.
AB  - Neurons can operate in two distinct ways, depending on the duration of the
      interval over which they effectively summate incoming synaptic potentials. If
      this interval is of the order of the mean interspike interval or longer, neurons
      act effectively as temporal integrators and transmit temporal patterns with only
      low reliability. If, by contrast, the integration interval is short compared to
      the interspike interval, neurons act essentially as coincidence detectors, relay
      preferentially synchronized input, and the temporal structure of their output is
      a direct function of the input pattern. Recently, interest in this distinction
      has been revived because experimental and theoretical results suggest that
      synchronous firing of neurons might play an important role for information
      processing in the cortex. Here, we argue that coincidence detection, rather than
      temporal integration, might be a prevalent operation mode of cortical neurons. We
      base our arguments on established biophysical properties of cortical neurons and
      on particular features of cortical dynamics.

PMID- 8658596
TI  - Directional motor control.

PMID- 8658597
TI  - Which GABAA-receptor subtypes really occur in the brain?
AB  - GABAA receptors are a heterogeneous family of ligand-gated ion channels
      responsible for mediating inhibitory neurotransmission in the CNS. Since the
      identification of mammalian cDNAs encoding 13 GABAA-receptor subunits, the
      composition of native receptor molecules and their localization in the brain has
      been an area of intense study. We conclude that the number of major subtypes is
      probably less than ten but their physiological roles have yet to be clearly
      defined and this represents the next step in GABAA-receptor research.

PMID- 8658598
TI  - The economics of neurite outgrowth--the addition of new membrane to growing
      axons.
AB  - Recent studies have shown that axonal growth is disrupted by treatments that
      block the synthesis of membrane components or their delivery by microtubule-based
      transport. This implies that a continuous supply of newly synthesized membrane
      components is necessary to sustain growth. In contrast, no clear consensus has
      yet been achieved about the site of insertion of new membrane components in the
      membrane of the growing axon, despite the application of new and refined
      biophysical and molecular techniques to the study of this issue. Until the site
      of insertion of new membrane components is resolved, little progress can be made
      in defining the feedback mechanisms by which the supply of new membrane
      components is co-ordinated with the demands of growth, particularly in cases
      where the dynamics of neurite growth change from minute to minute.

PMID- 8658599
TI  - Ca(2+)-activated K+ currents in neurones: types, physiological roles and
      modulation.
AB  - Action potentials in neurones are followed by a hyperpolarization, which can last
      up to several seconds. This hyperpolarization has several phases that are
      mediated by the activation of different types of Ca(2+)-activated K+ currents.
      Patch-clamp studies have revealed two families of Ca(2+)-activated K+ channels of
      small (SKCa) and high (BKCa) conductance. Activation of BKCa channels contributes
      to action-potential repolarization, while SKCa channels are thought to underlie
      the afterhyperpolarization (AHP). In addition, AHPs in neurones can be divided
      into two distinct types that are easily separated by kinetic and pharmacological
      criteria. It is now clear that only one type of AHP can be explained by
      activation of SKCa channels while a new type of Ca(2+)-activated K+ channel
      underlies the other. Modulation of this channel by a range of transmitters is a
      key determinant of the excitability of many neurones.

PMID- 8658600
TI  - Effect of HLA compatibility on kidney transplant survival in Asians.
      Collaborative Transplant Study.

PMID- 8658601
TI  - Twenty-year follow-up on the effect of HLA matching on kidney transplant survival
      and prediction of future twenty-year survival.
AB  - The difficulty in achieving long-term survival is demonstrated by the fact that
      an improvement of 30 percentage points in 1-year cadaver donor survival resulted
      in only a 10-percentage point improvement over 20 years. In early transplants
      from 1965 to 1974, the 20-year survival rate of HLA identical siblings was 46%,
      of parental donors 27%, and of cadaver donors 12%. More recent grafts, performed
      since 1987, had a projected survival of 57% for identical donors, 30% for
      parental donors, and 18% for cadaver donors. With respect to HLA matching for
      cadaver donor kidney transplants, a 0 AB-antigen mismatch produced higher graft
      survival than did mismatched transplants during the 20-year period from 1965 to
      1984. After the introduction of HLA Class II typing in 1980 and general
      improvements in typing for transplants performed after 1987, the 0 ABDR
      mismatched grafts have a projected 20-year survival of 40%. The projected
      survival rates for transplants with one or more mismatches fall progressively to
      13% for transplants that have 6 ABDR mismatches. Thus, the success due to HLA
      matching has improved ever since the introduction of cyclosporine because of the
      concurrent improvements in tissue typing for Class I and Class II specificities.

PMID- 8658602
TI  - Chronic rejection: pathogenesis and treatment.
AB  - Chronic rejection is a major cause of late graft loss, and pathogenesis of the
      chronic rejection is multifaceted. Further investigation of the pathogenesis is
      needed. Prevention and treatment include the reduction of risk factors and
      effective manipulation of factors involved in the pathogenesis.

PMID- 8658603
TI  - Influence of original disease on long-term outcome of cadaver kidney transplant.
      Collaborative Transplant Study.

PMID- 8658604
TI  - Induction of antigen-specific tolerance: antigen form and injection route.

PMID- 8658605
TI  - WOFIE hypothesis: some thoughts on an approach toward allograft tolerance.

PMID- 8658606
TI  - Experimental progress and clinical perspectives in xenotransplantation.

PMID- 8658607
TI  - Immunobiology of discordant xenograft rejection and potential therapeutic
      modalities.

PMID- 8658608
TI  - Outline and long-term prognosis in 15-deoxyspergualin-treated cases. Japan
      Collaborative Transplant Study Group of NKT-01.

PMID- 8658609
TI  - Posttransplant diabetes mellitus after renal transplantation in Korea.

PMID- 8658610
TI  - Hypertension in kidney transplant recipients.

PMID- 8658611
TI  - Malignancy in organ transplantation recipients.

PMID- 8658612
TI  - Hepatitis C in kidney transplant patients.

PMID- 8658613
TI  - Recurrent and de novo glomerulonephritis postrenal transplantation.
AB  - Important conceptual advances in recent years have been made in the area of
      posttransplant GN mainly in the de novo form rather than in recurrent
      posttransplant glomerulonephritis. Important patient subgroups have been
      identified for whom a significant risk exists. In particular, those carriers of
      hepatitis C virus may develop immune-complex renal disease leading to both MGN
      and MPGN. A de novo form of FSGN may occur in very long-term renal allograft
      patients. A case cited of an identical twin donor and her recipient developing
      glomerulosclerosis more than 10 years posttransplant represents an instance where
      the provocative hyperfiltration hypothesis was not relevant. The possibility that
      FK 506 may rescue cases of de novo posttransplant HUS11 is exciting and needs
      further elucidation. Finally, the serious lesions of CyA vasculopathy and those
      of chronic renal allograft rejection may be ameliorated as experience is gained
      with newer potent immunosuppressive drugs, such as FK 506 as the UNOS data
      suggest.

PMID- 8658614
TI  - Quality of life after renal transplantation.

PMID- 8658615
TI  - Renal transplantation in Korean children.

PMID- 8658617
TI  - Unlimited-term passive immunoprophylaxis after liver transplantation in HBsAg
      positive patients.

PMID- 8658616
TI  - Liver transplantation for primary liver cancer.

PMID- 8658619
TI  - Immunopathogenesis of GVHD.

PMID- 8658618
TI  - Newly developed preservation solution for the lung: 30-hour preservation with new
      ET-Kyoto solution.

PMID- 8658620
TI  - Graft-versus-host reactions: anti-leukemia effects of donor T cells.

PMID- 8658621
TI  - Status of organ transplantation in Indonesia.

PMID- 8658622
TI  - Current status of organ transplantation in Hong Kong.

PMID- 8658624
TI  - Current status of organ transplantation in Taiwan.

PMID- 8658623
TI  - Current status of organ transplantation in Japan.

PMID- 8658625
TI  - Current status of organ transplantation in India.

PMID- 8658626
TI  - Current status of organ transplantation in Saudi Arabia.

PMID- 8658628
TI  - Effects of misoprostol on renal function and plasma endothelin-1 levels during
      early postoperative stage of living donor renal transplant recipients.

PMID- 8658627
TI  - An open randomized parallel group study to compare Sandimmune Neoral with
      Sandimmune soft gelatin capsule in stable renal transplant patients.

PMID- 8658629
TI  - Reduction of ischemia-reperfusion injury by monoclonal antibody to intercellular
      adhesion molecule-1.

PMID- 8658630
TI  - Plasma endothelin levels in the early period after renal transplantation.

PMID- 8658631
TI  - Preexisting antibodies: the clinical relevance of auto-B-lymphocyte antibody and
      positive B-cell crossmatch.

PMID- 8658632
TI  - ABO mismatched living related donor liver transplantation.

PMID- 8658633
TI  - Donor-specific transfusion for kidney transplantation in the cyclosporine era.

PMID- 8658634
TI  - Microchimerism following small bowel allografts combined with donor-type bone
      marrow transplantation in rats.

PMID- 8658635
TI  - Immunologic and nonimmunologic contributors to glomerular segmental sclerosis in
      renal transplantation.

PMID- 8658636
TI  - Apoptosis in human kidney allografts.

PMID- 8658637
TI  - Effects of cyclosporine on expression of adhesion molecules on mesangial and
      endothelial cells.

PMID- 8658639
TI  - Donor-specific hyporesponsiveness is observed in renal transplant patients who
      successfully maintain their renal function more than 6 years.

PMID- 8658638
TI  - Daily serum interleukin-6 monitoring in multiple organ transplantation with or
      without liver allografts.

PMID- 8658641
TI  - Induction and analysis of lethal graft-versus-host disease in tolerant mice.

PMID- 8658642
TI  - T-cell restriction patterns in pig bone marrow chimera.

PMID- 8658640
TI  - Daily serum inflammatory cytokine (tumor necrosis factor-alpha, interleukin-6)
      monitoring in liver transplantation focusing on allograft rejection: a five-case
      report.

PMID- 8658643
TI  - Origin and function of microchimeric cells. I. Irradiation sensitivity.

PMID- 8658644
TI  - Changes in urinary interleukin-2 in kidney transplant recipients.

PMID- 8658645
TI  - Effects of interferon alpha/beta on cardiac allografts.

PMID- 8658646
TI  - Sequential changes of HLA-DR expression in renal allografts and their
      significance.

PMID- 8658647
TI  - Importance of HLA-DRB1 molecular matching between recipient and donor in
      cadaveric renal transplantation.

PMID- 8658648
TI  - HLA class II DNA typing using ocular tissue and its usefulness in corneal
      transplantation.

PMID- 8658649
TI  - Correlation between simplified immunocompetence assay and clinical graft states
      in kidney or liver transplant recipients.

PMID- 8658650
TI  - Effect of amino acid residue matching for HLA molecule in graft survival in renal
      transplantation.

PMID- 8658652
TI  - HLA compatibility can be predicted by matching only three residues with outward
      oriented sidechains.
AB  - A new method of residue matching based on three polymorphic upward-oriented amino
      acid residues on the alpha-helices of the HLA molecule is described. The
      projected 10-year graft outcome for 1232 transplants with none of these residues
      mismatched was 47%, essentially the same as for 0 BDR-mismatched kidneys. The
      projected impact of allocation to recipients in a local pool based on the three
      residues was a 5% improvement in overall graft survival at 10 years.

PMID- 8658653
TI  - Lymphocyte crossmatching in the sensitized patient.

PMID- 8658651
TI  - Microchimerism and graft acceptance: split tolerance in skin and cardiac
      transplantation with minor histocompatibility antigen H-Y differences.

PMID- 8658654
TI  - Is donor-specific blood transfusion effective for strong minor histocompatibility
      antigen barriers?

PMID- 8658656
TI  - HLA antigens in kidney allograft rejection.

PMID- 8658655
TI  - Serology versus polymerase chain reaction-sequence-specific primers in typing for
      HLA-DR in Pakistani populations.

PMID- 8658657
TI  - Hormonokinetics and histopathological evaluation of rabbit brain death model.

PMID- 8658658
TI  - Effects of hepatic denervation on ischemia-reperfusion injury in dogs.

PMID- 8658659
TI  - Assessment of microchimerism following rat liver transplantation.

PMID- 8658660
TI  - Whole organ vascularized thymus allografting effectively modulates cardiac
      rejection.

PMID- 8658661
TI  - Tolerance induction to cardiac allografts by sequential intrathymic inoculation
      of disparate alloantigens.

PMID- 8658662
TI  - Chimerism in survivors following allograft renal transplantation.

PMID- 8658663
TI  - Degree and sequential change of peripheral blood microchimerism in renal
      transplant recipients.

PMID- 8658664
TI  - Microchimerism and graft acceptance: V. Rat liver allograft acceptance.

PMID- 8658665
TI  - Microchimerism and graft acceptance: cardiac allografting with multiple minor
      histocompatibility antigen differences.

PMID- 8658666
TI  - Induction of MLR hyporesponsiveness after portal venous inoculation with donor
      splenocytes correlates with persistence of donor lymphocytes in host organs.

PMID- 8658667
TI  - Induction of warm ischemic tolerance following preconditioning of the small
      intestine.

PMID- 8658668
TI  - Withdrawal or reduction of steroids based on pharmacodynamics assessed by
      antilymphocyte action after renal transplantation.

PMID- 8658669
TI  - Cyclosporine-based immunotherapy for pediatric liver transplantation in Hong
      Kong.

PMID- 8658670
TI  - Diabetes mellitus after renal transplantation under FK 506 (tacrolimus) as
      primary immunosuppression.

PMID- 8658671
TI  - Factors affecting therapeutic effect of anti-CD3 and CD4 monoclonal antibody in
      acute renal allograft rejection.
AB  - Many factors can interfere with the therapeutic results for acute renal allograft
      rejection with anti-CD3 and CD4 MAbs. 1. When should we begin using MAbs and what
      about Scr levels while using MAbs? First-line treatment may be superior to rescue
      treatment; the earlier the better. 2. What is the level of blood concentration of
      CyA when rejection occurs? If the concentration of CyA is poor, the prognosis may
      be worse. 3. How do we maintain the dose of CyA during antirejection treatment
      with MAbs? Maintained use of CyA can play a coeffective role during antirejection
      treatment with MAbs. 4. What about the inhibiting degree of T-lymphocyte subsets
      after using MAbs? Whether CD3+ and CD4+/CD8+ decrease or not following the use of
      MAbs, the T-lymphocyte subsets may interfere significantly with the therapeutic
      results of MAbs. 5. The combined use of CD3 and CD4 MAbs seemed to get better
      results, especially for the intractable rejection cases. If we take care of the
      factors as referred to above, we may get a better therapeutic effect in reversing
      acute renal allograft rejection episodes with anti-CD3 and CD4 MAbs.

PMID- 8658672
TI  - Long-term beneficial effects of a nifedipine-supplemented immunosuppressive
      regimen in kidney transplantation.

PMID- 8658673
TI  - Effects of nicardipine on blood cyclosporine levels in renal transplant patients.

PMID- 8658674
TI  - Erythrocyte-to-plasma distribution ratio of cyclosporine: a useful indicator to
      predict cyclosporine pharmacokinetics and physiological changes during
      cyclosporine monitoring.

PMID- 8658675
TI  - To keep a stable therapeutic level of cyclosporine during the early
      posttransplant period is important in graft survival.

PMID- 8658676
TI  - Cyclosporine pharmacokinetics in stable renal transplant patients: effect of
      formulation Sandimmun versus Consupren versus Neoral.

PMID- 8658677
TI  - Influence of bioavailability on blood level of mizoribine in kidney transplant
      recipients.

PMID- 8658678
TI  - Cyclosporine pharmacokinetic profiles in stable renal allograft recipients
      converting from Sandimmun to Neoral.

PMID- 8658679
TI  - Sandimmun Neoral: Taiwanese experience in renal transplant patients with special
      reference to patients with existing liver disease.

PMID- 8658681
TI  - Safety, tolerability, and pharmacokinetics of Sandimmun Neoral: conversion study
      in stable renal transplant recipients.

PMID- 8658680
TI  - A randomized, controlled trial to assess the safety of switching stable renal
      transplant patients from Sandimmun to Sandimmun Neoral.

PMID- 8658682
TI  - Clinical study of sandimmun neoral in cadaveric renal transplantation.

PMID- 8658683
TI  - A comparative study of clinicopathologic characteristics of renal allografts
      under cyclosporine and FK506 immunosuppression.

PMID- 8658685
TI  - Improved cadaveric kidney graft survival with initiation of antilymphocyte
      globulin pretransplant in patients with a positive flow cytometry crossmatch.

PMID- 8658684
TI  - Immunosuppression for recipients of kidneys from non-heart-beating donors:
      comparison of triple therapy and OKT3 regimens.

PMID- 8658687
TI  - Increasing transplant cancer patient survival by conversion of immunosuppressive
      agents.

PMID- 8658686
TI  - Early steroid withdrawal after kidney transplantation.

PMID- 8658688
TI  - Evaluation of the new cyclosporine formulation, Consupren, in renal transplant
      patients.

PMID- 8658689
TI  - Long-term results of OKT3-treated renal transplant recipients.

PMID- 8658690
TI  - Addition of deoxyspergualin to standard triple immunosuppressive regimen in
      kidney transplantation.

PMID- 8658692
TI  - Experience with clinical use of Sandimmun Neoral in renal transplant patients.

PMID- 8658691
TI  - Long-term efficacy of OKT3 for steroid-resistant acute rejection in renal
      transplant patients.

PMID- 8658693
TI  - OKT3 rescue therapy for 63 refractory rejections in 405 renal allografts.

PMID- 8658694
TI  - Prevention of cyclosporine-induced nephrotoxicity by prazosin hydrochloride, an
      alpha-1-adrenoreceptor blocker.

PMID- 8658695
TI  - Blocking of ICAM-1 and LFA-1 in rat liver transplantation.

PMID- 8658696
TI  - Effect of pretreatment with fetal liver fragment transplantation on survival of
      rat liver allograft.

PMID- 8658697
TI  - Immunosuppressive effect of bactobolamine in rat liver allotransplantation.

PMID- 8658698
TI  - Difference in immunosuppressive effects of antibodies to ICAM-1 and LFA-1 between
      hepatic and cardiac allografts.

PMID- 8658699
TI  - Microchimerism and graft acceptance: cardiac allograft acceptance following
      antiadhesion molecules antibody therapy.

PMID- 8658700
TI  - L-arginine restores suppressed acetylcholine-induced endothelium-dependent
      vascular relaxation in cyclosporine A-treated rats.

PMID- 8658701
TI  - Long-term graft acceptance in allografted rats and dogs by treatment with a novel
      immunosuppressant, FTY720.

PMID- 8658702
TI  - Expression of proliferating cell nuclear antigen-positive cells during
      compensatory renal growth in cyclosporine-treated rats.

PMID- 8658703
TI  - Phenolic nortriterpene demethylzeylasteral: a new immunosuppressive component of
      Tripterygium Wilfordii Hook f.

PMID- 8658704
TI  - Cyclosporine and tacrolimus both suppress activation of Kupffer cells in vitro.

PMID- 8658705
TI  - Fas antigen expression and apoptosis induction of in vitro cultured hepatocytes
      with high concentrations of cyclosporine A.

PMID- 8658706
TI  - Effect of intraportal injection of hepatic nonparenchymal cells on tolerance
      induction to heart allografts in the rat.

PMID- 8658707
TI  - Topical immunosuppression in skin grafting with FK 506 ointment.

PMID- 8658708
TI  - Pharmacokinetic characteristics of two types of liposomal FK 506.

PMID- 8658709
TI  - Prolongation of canine renal allograft survival by a new potent immunosuppressive
      agent, bactobolamine.

PMID- 8658710
TI  - Suppressive effects of combination therapy with mizoribine and FK 506 on the
      development of accelerated coronary artery disease and myocardial rejection after
      heart transplantation.

PMID- 8658711
TI  - Prolongation of hamster-to-rat cardiac xenograft survival by hyperimmune blood
      transfusion without immunosuppression.

PMID- 8658712
TI  - Evaluation of 15-deoxyspergualin and cyclosporine in hamster-to-rat lung
      transplantation.

PMID- 8658713
TI  - Discordant effects of xenogeneic pig liver perfusion on function of sinusoidal
      endothelial cells and parenchymal cells.

PMID- 8658714
TI  - Xeno-tissue typing (Southern blot and xeno-MLR) in humans, monkeys, pigs, and
      beagles using HLA, SLA, C4A, and Bf cDNA probes.

PMID- 8658715
TI  - Transplantation of porcine fetal organs to discordant canine recipients.

PMID- 8658716
TI  - Effect of lipoprostaglandin E1 in concordant xenografts.

PMID- 8658717
TI  - Trial of xenogeneic fetal liver transplantation from pig to dog.

PMID- 8658718
TI  - Pancreatic xenotransplantation in rabbits.

PMID- 8658719
TI  - Which are the target vessels of xeno- and allo-lung rejection?--a primate single
      lung transplantation study.

PMID- 8658720
TI  - Pathologic examination of discordant lung xenotransplantation in the rat.

PMID- 8658721
TI  - Cholecystocholedochostomy for biliary tract anastomosis in hamster-to-rat liver
      xenotransplantation.

PMID- 8658722
TI  - Pig-to-rat xenotransplantation with mesh-reinforced polyvinyl alcohol bag:
      efficacy of agarose gel.

PMID- 8658723
TI  - Prolonged survival of xenogeneic fetal liver fragments with a microporous
      membrane in the omentum in rats.

PMID- 8658724
TI  - Effect of 15-deoxyspergualin in islet xenograft rejection.

PMID- 8658725
TI  - Long survival of xenografted bioartificial pancreas with a mesh-reinforced
      polyvinyl alcohol hydrogel bag employing a B-cell line (MIN6).

PMID- 8658726
TI  - Transplantation of xenogeneic hepatocytes: three-dimensionally cultured
      hepatocyte (spheroid) transplantation into the spleen.

PMID- 8658727
TI  - Administration of tacrolimus (FK506) in hamster-to-rat pancreas
      xenotransplantation.

PMID- 8658728
TI  - Pretreatment with splenectomy and FK506 in xeno-lung transplantation.

PMID- 8658729
TI  - Immunosuppressive effect of FK506 on orthotopic liver and small bowel
      xenotransplantation (xenoOLTx and SBTx).

PMID- 8658730
TI  - Possibility of gene transfer to the xenogeneic liver of guinea pig and pig using
      adenoviral vector.

PMID- 8658731
TI  - Clinical validity of Banff grading of chronic rejection in renal transplantation.

PMID- 8658732
TI  - Evaluation of serum immunological parameters in acute renal allograft rejection.

PMID- 8658733
TI  - Expression of cytokines, growth factors, and adhesion molecules in rejecting
      human renal allograft.

PMID- 8658734
TI  - Clinicopathological analysis of rejection episodes in ABO-incompatible kidney
      transplantation.

PMID- 8658735
TI  - Treatment of steroid resistant rejection following renal transplantation:
      benefits and risks of OKT3 therapy.

PMID- 8658736
TI  - Impact of early acute rejection on outcome of HLA-mismatched living related donor
      kidney transplants.

PMID- 8658737
TI  - Treatment of steroid resistant acute rejection after renal transplantation.

PMID- 8658738
TI  - Accelerated acute rejection in renal allograft.

PMID- 8658739
TI  - Risk factors for chronic rejection in renal allograft recipients.

PMID- 8658740
TI  - Hemodynamic study of renal transplant chronic rejection using power Doppler
      sonography.

PMID- 8658742
TI  - Expression of ATL-derived factor/human thioredoxin in rejected kidney grafts.

PMID- 8658741
TI  - Late onset acute rejection of renal allografts, an indicator of suboptimum
      cyclosporin dosage.

PMID- 8658743
TI  - Surgical complications in kidney transplantation: experience from 1200
      transplants performed over 20 years at six hospitals in central Japan.

PMID- 8658744
TI  - Percutaneous transluminal angioplasty for transplant renal artery stenosis.

PMID- 8658745
TI  - Transplant nephrectomy in 927 kidney transplantations.

PMID- 8658746
TI  - Urological complications in renal transplantation.

PMID- 8658747
TI  - Ocular complications in renal allograft recipients with special reference to
      steroid cataractogenic factor.

PMID- 8658749
TI  - Perforated gastrointestinal lymphomas in kidney transplant recipients.

PMID- 8658748
TI  - Hyperamylasemia in kidney transplant recipients.

PMID- 8658750
TI  - The mismatch of donor/recipient size influences development of proteinuria in
      allograft kidney transplants.

PMID- 8658752
TI  - Tertiary hyperparathyroidism after renal transplantation.

PMID- 8658751
TI  - Massive proteinuria after renal transplantation treated with LDL-apheresis.

PMID- 8658753
TI  - Hypertension following renal transplantation.

PMID- 8658755
TI  - Impact of donor hepatitis B antigenemia on renal allograft in hepatitis B
      recipients.

PMID- 8658754
TI  - Study of the efficacy and tolerability of oral terbinafine in the treatment of
      onychomycosis in renal transplant patients.

PMID- 8658756
TI  - Usefulness of measurement of serum viral DNA using dot-blot hybridization and
      polymerase chain reaction in renal transplant patients with hepatitis B-positive
      viral infection.

PMID- 8658757
TI  - Optimal immunosuppressive regimen for hepatitis B-positive kidney transplant
      recipients.

PMID- 8658758
TI  - Clinical implication of the presence of hepatitis C virus antibodies after kidney
      transplantation in Japan.

PMID- 8658759
TI  - Clinical outcome of anti-HCV(+) renal allograft recipients.

PMID- 8658760
TI  - Effect of interferon (IFN-alpha) for prevention of hepatitis C transmission from
      a seropositive donor to a seronegative recipient in renal transplantation.

PMID- 8658761
TI  - Immunocytochemical assay for cytomegalovirus detection in peripheral blood for
      renal transplant patients in clinical practice.

PMID- 8658762
TI  - Detection of cytomegalovirus infection in renal transplant recipients in Korea.

PMID- 8658763
TI  - Early diagnosis of CMV syndrome after kidney transplantation: comparison between
      CMV antigenemia and PCR assay.

PMID- 8658764
TI  - Varicella-zoster infection in cyclosporine A-treated renal transplant patients.

PMID- 8658765
TI  - Asymptomatic cytomegalovirus infection in renal transplants: treatment or no
      treatment.

PMID- 8658767
TI  - Kidney transplantation from hepatitis B surface antigen (HBsAg)-positive donors:
      changes of relative HBV genomic copy number after transplantation.

PMID- 8658766
TI  - Tuberculosis in renal allograft recipients.

PMID- 8658768
TI  - Clinical manifestations of tuberculosis in renal transplant patients.

PMID- 8658769
TI  - Effects of cytomegalovirus infection on renal function in kidney transplant
      recipients.

PMID- 8658770
TI  - Glomerular pathology of allograft kidneys in Hong Kong.

PMID- 8658771
TI  - Transplant glomerulopathy--a clinicopathological study.

PMID- 8658772
TI  - Rapidly progressive glomerulonephritis in a renal transplant with recurrent IgA
      nephropathy.

PMID- 8658773
TI  - Evaluation of renal allografts with duplex ultrasonography.

PMID- 8658774
TI  - Magnetic resonance angiography (MRA) in renal allografts: comparison with color
      Doppler echography.

PMID- 8658775
TI  - Transplantation of pediatric low-weight kidneys into adults from a non-heart
      beating donor.

PMID- 8658776
TI  - Correlation between proteinuria and prognosis of transplant IgA nephropathy.

PMID- 8658777
TI  - IgA nephropathy in renal transplant recipients: is it a significant cause of
      allograft failure?

PMID- 8658778
TI  - Renal transplantation in patients with IgA nephropathy.

PMID- 8658779
TI  - Erythropoietin, interleukin-3, interleukin-11, and GM-CSF in posttransplant
      erythrocytosis treated with enalapril.

PMID- 8658780
TI  - Clinical implication of hormone treatment in postmenopausal kidney transplants.

PMID- 8658781
TI  - Usefulness of machine perfusion preservation for non-heart-beating donors in
      kidney transplantation.

PMID- 8658782
TI  - Comparison of extravesical versus internal ureteroneocystostomy in renal
      transplants.

PMID- 8658783
TI  - Preventive effect of enalapril on erythrocytosis after renal transplantation.

PMID- 8658784
TI  - Effect of captopril in the treatment of erythrocytosis after renal
      transplantation.

PMID- 8658785
TI  - High incidence of osteonecrosis of femoral head in patients receiving more than 2
      g of intravenous methylprednisolone after renal transplantation.

PMID- 8658786
TI  - Changes of bone metabolism indices in patients receiving immunosuppressive
      therapy including low doses of steroids after renal transplantation.

PMID- 8658787
TI  - Multivariate analysis of factors affecting cadaver kidney allograft survival in
      the chronic stage.

PMID- 8658788
TI  - Clinical study and experience in cadaveric kidney transplantation for 15 years.

PMID- 8658789
TI  - Comparison of kidney graft survival in Asian and Caucasian patients transplanted
      in the United States.

PMID- 8658790
TI  - Factors influencing patient and graft survival in living related renal
      transplantation at a single centre.

PMID- 8658791
TI  - Availability of cryofiltration in renal transplantation.

PMID- 8658792
TI  - A 16-year experience with 1275 primary living donor kidney transplants:
      univariate and multivariate analysis of risk factors affecting graft survival.

PMID- 8658793
TI  - Effect of donor age on outcome of living related kidney transplantation.

PMID- 8658794
TI  - Influence of pregnancy on graft function after renal transplantation.

PMID- 8658795
TI  - Incidence of post kidney transplantation neoplasm in Thailand.

PMID- 8658796
TI  - A first report: living related kidney transplantation on a patient with Bartter's
      syndrome.

PMID- 8658797
TI  - Kidney transplantation from older ( > or = 55 years) donors: a risk factor for
      graft survival.

PMID- 8658798
TI  - Quadruple immunotherapy will promise excellent graft survival in cadaveric renal
      transplants using cardiac arrest donor grafts.

PMID- 8658799
TI  - Effects of deoxyspergualine on chronic transplant nephropathy.

PMID- 8658800
TI  - Percutaneous transluminal angioplasty for renovascular hypertension 9 years after
      hypoplastic kidney transplantation: report of a case.

PMID- 8658801
TI  - Diagnostic value of ratio of renal arterio-venous velocity for graft rejection in
      renal allografts.

PMID- 8658802
TI  - Hypertension in renal transplant recipients and its effect on long-term renal
      allograft survival.

PMID- 8658803
TI  - Causes of hospital admission following successful renal transplantation.

PMID- 8658804
TI  - Clinical and psychosocial consequences of renal transplantation in children.

PMID- 8658805
TI  - Unique triple malignancies following renal transplantation.

PMID- 8658807
TI  - Clinical evaluation of donor renal artery reconstruction in kidney
      transplantation.

PMID- 8658806
TI  - Alteration of erythrocyte sodium transport in renal transplant recipients.

PMID- 8658808
TI  - Living related donor kidney transplantation in patients with a positive flow
      cytometry crossmatch.

PMID- 8658809
TI  - Reconstruction of lower urinary tract in pediatric renal transplantation.

PMID- 8658810
TI  - Evaluation of cardiac function of renal transplant patients using stress and rest
      cardiac pool gated scintigraphy and myocardial scintigraphy with 99mTc-MIBI.

PMID- 8658811
TI  - Does atherosclerosis of the hypogastric artery in the recipient influence renal
      allograft function and blood pressure?

PMID- 8658812
TI  - Racial differences in long-term renal allograft outcome.

PMID- 8658814
TI  - Parathyroid function after kidney allografting.

PMID- 8658813
TI  - Application of corbrin capsule in human renal transplantation.

PMID- 8658815
TI  - Treatment of peripheral leukopenia after cadaveric kidney transplantation.

PMID- 8658816
TI  - Effect of hypertension, hyperlipidemia and cyclosporine A therapy on long-term
      renal allograft survival.

PMID- 8658818
TI  - Clinical evaluation of factor analysis by dynamic-SPECT for transplanted kidneys.

PMID- 8658817
TI  - Angiotensin converting enzyme inhibitor induced anemia in a kidney transplant
      recipient.

PMID- 8658819
TI  - Can successful renal transplantation resolve secondary hyper-parathyroidism?

PMID- 8658820
TI  - Clinical study of male sexual activity on chronic hemodialysis after renal
      transplantation.

PMID- 8658821
TI  - Study of renal retransplantation.

PMID- 8658822
TI  - De novo cancer in transplant recipients.

PMID- 8658823
TI  - Clinical outcome of HBsAg(+) renal allograft recipients.

PMID- 8658824
TI  - Patterns of bile salts and biliary lipids early after liver transplantation
      differentiate patients with unfavorable graft outcome.

PMID- 8658826
TI  - Liver transplantation from cadaveric and living donors.

PMID- 8658825
TI  - Risk factors for initial poor graft function and graft survival after initial
      poor graft function.

PMID- 8658827
TI  - Surgical techniques and results of hepatic vein reconstruction in 125 living
      related donor liver transplants.

PMID- 8658828
TI  - Donor characteristics for liver transplantation and risk factors for early poor
      graft function and survival.

PMID- 8658829
TI  - Liver transplantation for biliary atresia.

PMID- 8658830
TI  - Variation of the intrahepatic portal vein; angiographic demonstration and
      application in living-related hepatic transplantation.

PMID- 8658831
TI  - Variants of the bile ducts: clinical application in the potential donor of living
      related hepatic transplantation.

PMID- 8658832
TI  - Serum cholesterol level as an indicator of allograft liver function.

PMID- 8658833
TI  - Analysis of perioperative respiratory complications in 100 consecutive cases of
      pediatric living-related donor liver transplantation.

PMID- 8658834
TI  - Neurologic complications after orthotopic liver transplantation including central
      pontine myelinolysis.

PMID- 8658835
TI  - Reoperative procedures after orthotopic liver transplantation.

PMID- 8658836
TI  - Six cases of tracheobronchomalacia in perioperative pediatric living-related
      donor liver transplant recipients.

PMID- 8658837
TI  - Biliary complications in long-term recipients of reduced-size liver transplants.

PMID- 8658838
TI  - Orthotopic liver transplantation for primary hepatic cancer in rats.

PMID- 8658839
TI  - De novo hepatitis B virus infection after orthotopic liver transplantation.

PMID- 8658841
TI  - Histopathology of liver following transplantation: an experience in Taiwan.

PMID- 8658840
TI  - Hepatitis B immune globulin dose requirements following orthotopic liver
      transplantation for chronic hepatitis B cirrhosis.

PMID- 8658842
TI  - Liver transplantation for hepatocellular carcinoma: consideration from the
      findings on autopsy.
AB  - Extrahepatic spread of hepatocellular carcinoma was investigated in twenty
      autopsy cases with unresected hepatocellular carcinoma to define the appropriate
      patient selection criteria for liver transplantation. Diagnosis of extrahepatic
      spread of cancer by diagnostic imaging was not easy, and unsatisfactory prognosis
      after liver transplantation in patients with hepatocellular carcinoma might have
      been attributed to the high incidence of extrahepatic occult foci of cancer. All
      patients with multiple nodular, massive and diffuse tumor had extrahepatic spread
      of cancer. Only patients with a single nodular type tumor, no larger than 30 mm
      in diameter, had no extrahepatic metastasis, and these patients are the preferred
      candidates for liver transplantation.

PMID- 8658843
TI  - Respiratory management of orthotopic liver transplant patients.

PMID- 8658844
TI  - Early experience of liver transplantation at Seoul National University Hospital.

PMID- 8658845
TI  - Body temperature changes during orthotopic liver transplantation.

PMID- 8658846
TI  - Long-term immunoprophylaxis for hepatitis B virus reinfection after liver
      transplantation.

PMID- 8658847
TI  - Ursodeoxycholic acid therapy in recurrent or acquired genotype II hepatitis C
      virus infection after liver transplantation: a three-case report.

PMID- 8658848
TI  - Initiation of living-related liver donor transplantation in Taiwan.

PMID- 8658849
TI  - Liver transplantation for hepatocellular carcinoma.

PMID- 8658850
TI  - Successful treatment of invasive mucormycosis following liver transplantation.

PMID- 8658851
TI  - Changes in neuroimaging in Wilson's disease following orthotopic liver
      transplantation.

PMID- 8658852
TI  - Successful retransplantation for recurrent posttransplant hepatitis B virus
      infection in the primary allograft.

PMID- 8658853
TI  - Translocation of a liver transplantation program to southern Taiwan.

PMID- 8658854
TI  - Coagulopathy induced by overuse of heparin containing FLUH solution in orthotopic
      liver transplantation.

PMID- 8658855
TI  - Comparison of hemodynamic changes during orthotopic liver transplantation between
      total clamping and partial clamping of the inferior vena cava.

PMID- 8658856
TI  - Use of the laryngeal mask in off-floor anesthesia for hepatic angiography in
      pediatric liver transplant candidates.

PMID- 8658857
TI  - Lack of evidence for an effect of donor irradiation on liver allograft rejection.

PMID- 8658858
TI  - Reconstruction of the gastroduodenal artery in pancreatic transplantation.

PMID- 8658859
TI  - Enteric conversion of bladder-drained pancreas allograft.

PMID- 8658860
TI  - Neopterin changes after clinical heart transplantation.

PMID- 8658861
TI  - Clinical outcome of heart transplantation: experience at the National Taiwan
      University Hospital.

PMID- 8658862
TI  - Extracorporeal membrane oxygenation before and after heart transplantation.

PMID- 8658863
TI  - Bone loss after orthotopic liver transplantation: FK 506 versus cyclosporine.

PMID- 8658864
TI  - Comparison of the collection efficiency and characteristics of peripheral blood
      progenitor cells mobilized by G-CSF administration in the steady state versus
      postmyelosuppressive chemotherapy.

PMID- 8658865
TI  - Cytokine network in peripheral blood mononuclear cells after allogeneic bone
      marrow transplantation.

PMID- 8658866
TI  - Bone marrow transplantation in childhood acute lymphoblastic leukemia with
      closely matched family donors in Hong Kong.

PMID- 8658868
TI  - Dramatic change of soluble HLA class I band patterns after liver or bone marrow
      transplantation.

PMID- 8658867
TI  - CMV antigenemia assay using indirect ALP-immunostaining in bone marrow transplant
      recipients.

PMID- 8658869
TI  - Postreperfusion syndrome in swine liver transplantation: comparison between
      orthotopic liver transplantation and total hepatectomy with portacaval shunt
      using aortic graft.

PMID- 8658870
TI  - Detrimental effect of immediate portal hypertension in canine quarter orthotopic
      liver transplantation.

PMID- 8658871
TI  - Changes in plasma nitrite/nitrate level after orthotopic liver transplantation in
      pigs.

PMID- 8658872
TI  - Tracheal transplantation in dogs for future clinical application.

PMID- 8658873
TI  - Damage and repair of DNA after liver transplantation assessed by urinary thymine
      glycol output.

PMID- 8658874
TI  - Effects of neutrophil elastase inhibitor on reperfusion injury in the canine
      liver.

PMID- 8658875
TI  - Suppressive effects of serum from liver-transplanted rats against graft-versus
      host disease.

PMID- 8658876
TI  - Serum analysis using high performance liquid chromatography in porcine liver
      transplantation.

PMID- 8658878
TI  - Influence of portoarterial reflux on the development of hepatic arterial
      thrombosis in auxiliary partial liver transplantation in the rat.

PMID- 8658877
TI  - Analysis of prostanoid release from the liver graft following transplantation in
      pigs.

PMID- 8658879
TI  - Donor-derived cells in various tissues including brain of Balb/c CSD mice after
      fetal liver transplantation.

PMID- 8658880
TI  - Calcium mobilization in porcine orthotopic liver transplantation.

PMID- 8658881
TI  - Differences in cellular mechanisms in early and late immunological responses
      after liver transplantation in rats.

PMID- 8658882
TI  - Effects of hepatic arterialization (HA) in experimental liver transplantation in
      rats.

PMID- 8658883
TI  - Susceptibility of the liver in spontaneously hypertensive rats to hemorrhagic
      shock and suitability for donors.

PMID- 8658884
TI  - Study of liver function in a graft suffering from warm ischemia in porcine liver
      transplantation.

PMID- 8658885
TI  - Detection of nitrosylhemoglobin in liver allograft in rats by using near-infrared
      spectroscopy.

PMID- 8658887
TI  - Rapamycin in experimental liver transplantation in the rat.

PMID- 8658886
TI  - Dose dependent immunosuppressive effects of antibodies to ICAM-1 and LFA-1 on
      hepatic allografts.

PMID- 8658888
TI  - Split liver transplantation in pigs with reconstruction of the inferior vena
      cava.

PMID- 8658889
TI  - Octreotide effects on pancreatic graft pancreatitis in inbred pigs.

PMID- 8658891
TI  - New technique of orthotopic segmental pancreas transplantation with portal venous
      drainage established by interposing the splenic vessels.

PMID- 8658890
TI  - Effect of new thromboxane A2 synthesis inhibitor tetramethyl-pyrazine on
      pancreatic transplantation in diabetic rats.

PMID- 8658892
TI  - Protective effect of coenzyme Q10 against warm ischemia damage in rat pancreatic
      transplantation.

PMID- 8658894
TI  - Changes in spontaneous leukocyte blastogenesis during cardiac allograft rejection
      in rats.

PMID- 8658893
TI  - Anti-adhesion (anti-ICAM-1 and anti-LFA-1) therapy in a rat pancreas
      transplantation model.

PMID- 8658895
TI  - Tracheal allogenic immunoresponse is reduced by cryopreservation: canine
      experiment.

PMID- 8658896
TI  - An animal model of pulmonary infection after single lung transplantation.

PMID- 8658897
TI  - Ex vivo gene transfer to transplanted heart grafts using adenoviral vector.

PMID- 8658898
TI  - Effect of nitric oxide inhalation during harvesting of lung grafts in canine lung
      allotransplantation.

PMID- 8658899
TI  - Role of ICAM-1 in chronic rejection in the rat heart transplantation model.

PMID- 8658900
TI  - No coronary atherosclerotic changes were found after heart transplantation in
      tolerance-induced rats.

PMID- 8658901
TI  - Antigenicity of heart valves and vessels: a primate heart transplant study.

PMID- 8658902
TI  - Effects of a specific neutrophil elastase inhibitor (ONO-5046 Na) and neutrophil
      depletion using a G-1 column on lung reperfusion injury in dogs.

PMID- 8658903
TI  - Effect of recipient T cell subset depletion on graft coronary arteriosclerosis
      induction in the rat retransplant model.

PMID- 8658904
TI  - Maintenance of unresponsiveness by short-term pulse therapy with FK 506 in rat
      transplantation.

PMID- 8658905
TI  - Assessment of preserved lung function in an ex vivo rat model perfused with
      homologous blood.

PMID- 8658906
TI  - An arterial blood gas analysis in the canine bilateral sequential lung transplant
      model flushed with modified Euro-Collins solution.

PMID- 8658907
TI  - Bioelectrical tissue resistance in the heterotopic rat heart transplant model.

PMID- 8658908
TI  - Ultrastructural changes of the pulmonary vasculature in canine lungs preserved
      for 20 hours in newly developed solutions.

PMID- 8658909
TI  - Effect of luminal flush on mucosal injury during cold ischemia in the rat small
      bowel.

PMID- 8658910
TI  - Technical aspects of small bowel transplantation in the pig allograft model.

PMID- 8658911
TI  - Acetaminophen absorption test as a useful indicator of small intestinal rejection
      in rats.

PMID- 8658912
TI  - Donor pretreatment with deoxyspergualin on prevention of graft-vs-host reaction
      after small bowel transplantation.

PMID- 8658913
TI  - Unpurified islet cell transplantation in diabetic rats.

PMID- 8658914
TI  - Allogeneic islet transplantation without immunosuppression in swine leukocyte
      antigen (MHC)-matched miniature swine.

PMID- 8658915
TI  - Beneficial effects of intermittent additional islet cell transplantation.

PMID- 8658916
TI  - Conditions for the successful engraftment of hepatocyte progenitors injected into
      the spleen.

PMID- 8658917
TI  - Regenerative signals for heterotopic hepatocyte transplantation.

PMID- 8658918
TI  - Cotransplantation of microencapsulated hepatocytes and islets for acute hepatic
      failure in rats.

PMID- 8658919
TI  - Human allogenic airway epithelial cell line induces lymphocytes to secrete
      interleukin 10.

PMID- 8658920
TI  - Oxygenated diluted blood perfusion and microcirculation study in liver
      transplantation.

PMID- 8658921
TI  - Multiple organ harvesting from a single donor for transplantation: comparison
      study of the peritoneal cooling and the cardiopulmonary bypass method.

PMID- 8658922
TI  - Necessity of a recovery phase after in situ liver preparation to improve hepatic
      microcirculation prior to organ preservation.

PMID- 8658923
TI  - Proper donor management and multiorgan procurement: practical ways to cope with
      the organ shortage.

PMID- 8658924
TI  - New ET-Kyoto solution containing N-acetylcysteine, nitroglycerin, and dibutyryl
      cyclic AMP provides reliable 30-hour canine lung preservation.

PMID- 8658926
TI  - Possibility of pancreas transplantation from non-heart-beating cadaver donors.

PMID- 8658925
TI  - Prevention of reperfusion injury after rat pancreas preservation using rinse
      solution containing nafamostat mesilate.

PMID- 8658927
TI  - Utilization of warm ischemic livers from non-heart beating donors by portable
      cardiopulmonary bypass and heterotopic transplantation.

PMID- 8658928
TI  - Superiority of HTK solution to UW solution for tissue oxygenation in living
      related liver transplantation.

PMID- 8658929
TI  - Combined procurement of liver and pancreas does not influence early graft
      function and survival.

PMID- 8658930
TI  - Protective effects of MCI-186 on cold kidney preservation/reperfusion injury in
      the rat.

PMID- 8658931
TI  - Protection against hepatic ischemia/reperfusion injury by exogenous L-arginine.

PMID- 8658932
TI  - L-arginine can attenuate warm ischemic injury in the rat kidney and nitric oxide
      production in the preserved kidney.

PMID- 8658933
TI  - Optimal pH of University of Wisconsin solution and rinse solution for rat liver
      preservation.

PMID- 8658934
TI  - Effect of gammahydroxybutyrate on donor lung function after long-term hypothermic
      storage using low potassium University of Wisconsin solution.

PMID- 8658935
TI  - Impaired endothelial-dependent relaxation by acetylcholine after preservation of
      the human hepatic artery with UW solution.

PMID- 8658936
TI  - Endothelium-dependent relaxation of the canine pulmonary artery is preserved
      after prolonged preservation with University of Wisconsin solution.

PMID- 8658937
TI  - Prostanoid metabolism in porcine liver transplantation: influence of warm
      ischemia.

PMID- 8658938
TI  - FK506 reduces oxidative hepatic injury following cold ischemic preservation and
      transplantation.

PMID- 8658940
TI  - HTK solution is more effective than UW solution for cardiac preservation.

PMID- 8658939
TI  - Cytoprotective effect of nitric oxide on ischemia-reperfusion injury in rat
      kidneys.

PMID- 8658941
TI  - Activation of apoptosis during the reperfusion phase after rat liver ischemia.

PMID- 8658942
TI  - Effects of subzero nonfreezing storage on the preservation of myocardial energy
      and function.

PMID- 8658943
TI  - Minimal stimulation of endothelin-1 production within partial liver grafts due to
      physiological conditions during procurement from living related donors.

PMID- 8658945
TI  - Evaluation of plasma IL-8 (CINC) concentration during ischemia and after
      reperfusion in the small intestine.

PMID- 8658944
TI  - Effects of exsanguination before induction of ischemia on hepatic warm ischemia
      reperfusion injury in mice.

PMID- 8658946
TI  - Utilization of organ preservation machine as an ex vivo swine liver perfusion
      system with human whole blood at 37 degrees C.

PMID- 8658947
TI  - Effect of new ET-Kyoto solution on 17-hour lung preservation in isolated rat
      lungs.

PMID- 8658948
TI  - Effects of lipo-prostaglandin E1 on chemokine release in ischemia and reperfusion
      of the liver.

PMID- 8658950
TI  - Organ preserving effect of lidocaine administration in the model of orthotopic
      liver transplantation from non-heart-beating donors.

PMID- 8658949
TI  - Glutamine protects the morphological structure of small bowel grafts from cold
      preservation injury.

PMID- 8658951
TI  - Introduction of free donor cards in Japan.

PMID- 8658952
TI  - Attitudes and psychological characteristics of kidney donors toward organ
      donation.

PMID- 8658953
TI  - Quality of life in adult Japanese patients undergoing liver transplants overseas.

PMID- 8658954
TI  - Changes in the quality of life before and after renal transplantation and
      comparison of the quality of life between kidney transplant recipients, dialysis
      patients, and normal controls.

PMID- 8658955
TI  - Commercial living-nonrelated renal transplantation: observations on early
      complications.

PMID- 8658956
TI  - Post-renal transplant diabetes in Sri Lanka.

PMID- 8658957
TI  - Prolongation of survival of rat kidney allografts by transforming growth factor
      beta 2.

PMID- 8658958
TI  - Serum testosterone levels after renal transplantation.

PMID- 8658959
TI  - Platelet aggregation and peripheral serotonergic system in kidney transplant
      recipients treated with cyclosporine.

PMID- 8658960
TI  - Effect of hyperlipidemia and immunosuppressive drugs on cardiac allograft
      vascular disease in heterotopic rat cardiac transplantation.

PMID- 8658961
TI  - A bacteria-expressed mouse interleukin-1 receptor antagonist peptide protects
      alginate-poly-L-lysine-alginate microencapsulated rat islets against the
      suppressive effect of interleukin-1 beta in vitro.

PMID- 8658962
TI  - Expansion of a peripheral blood perforin+ CD8+ T-cell subset in long-term
      surviving lung transplanted patients.

PMID- 8658963
TI  - Orthotopic fetal bone allografts in primates: histologic outcome in three
      recipient baboons (Papio ursinus).

PMID- 8658965
TI  - Prevention of cyclosporine-induced nephrotoxicity by clenbuterol, a beta 2
      adrenoreceptor stimulant.

PMID- 8658964
TI  - Comparison of OKT3 and antithymocyte globulin as induction immunosuppressive
      agents in renal transplantation.

PMID- 8658966
TI  - A technique of urinary bladder transplantation in the rat.

PMID- 8658967
TI  - Synergistic effects of mycophenolate mofetil (MMF, RS-61443) and anti-LFA-1/ICAM
      1 monoclonal antibodies on the prolongation of heart allograft survival in rats.

PMID- 8658968
TI  - Evaluation of DNA injury in Langerhans' cells after warm ischemia of the pancreas
      in the rat.

PMID- 8658969
TI  - Miniature swine MHC class II heterodimers expressed through double-copy
      retroviral vectors.

PMID- 8658970
TI  - Effect of monoclonal antibody to VLA-4 on corneal allograft survival in mice.

PMID- 8658971
TI  - [Changes in the cytochemical and morphometric characteristics of the myocytes in
      the right heart of the rat in adrenal-regeneration hypertension].
AB  - A study was made on myocytes of the right atrium and the right ventricle of rats
      with experimental arterial hypertension due to adrenal regeneration. The nuclear
      DNA and the total protein in the cytoplasm were revealed using two consecutive
      tests: the Feulgen reaction and Napththol yellow S staining. A two-wavelength
      scanning cytophotometry was used for measuring DNA and protein contents. It has
      been ascertained that the polyploidy levels in the myocytes of the right atrium
      and the right ventricle, measured 6, 12 and 26 weeks after nephradrenalectomy by
      the Skelton technique, differ from the control level negligibly. A small increase
      in the share of tetraploid myocytes occurred in 12 weeks in the right atrium, and
      in 26 weeks in the right ventricle. The mean nuclear volume in atrial myocytes
      decreased gradually within 12 weeks, to increase afterwards but did not reach to
      control level in 26 weeks. The cytoplasm volume of atrial myocytes decreased in 6
      weeks, and then was seen to increase gradually approaching the norm within 26
      weeks. At the same time the mean cytoplasm volume of ventricular myocytes, which
      remained practically unchanged within 6 weeks, decreased within 12 weeks more
      than twice as compared to the control level, but in 26 weeks started to rise,
      although less quickly than the volume of atrial myocytes. The common protein
      content was seen to decrease 6 weeks after the operation both in atrial and
      ventricular myocytes, then gradually approached the control within 26 weeks,
      these changes in atrial myocytes being sharper than in ventricular myocytes.

PMID- 8658972
TI  - [A comparison of some methods for administering the Ca-dependent photoprotein
      obelin into the adipocytes of the brown fat in the rat].
AB  - An attempt was taken to incorporate Ca2(+)-dependent photoprotein obelin into
      young brown adipocytes using the three methods: 1) osmotic lysis of pinocytotic
      vesicles; 2) electroporation in a high electric field; 3) hypoosmotic shock. The
      young adipocytes were isolated from rat interscapular brown fat. The maximum
      incorporation of obelin into these cells was achieved using the hypoosmotic shock
      technique. A constant luminescence of intact cells loaded with obelin following
      hypoosmotic shock was observed in three independent experiments.

PMID- 8658973
TI  - [The relationship of the acid-base status of the blood to the electrophoretic
      mobility of the erythrocytes in liver pathology].
AB  - With cholestatic hepatite, the relationship between acid-alkaline condition of
      blood and electrophoretic mobility of erythrocytes was studied. It is shown that
      changes in parameters of the individual mobility distribution are translated into
      reality independently, and are directed to maintain the steadiness of the index
      middle level. Dependence of this sign on the pH value, hemoglobin content and
      bicarbonate-ion concentrating in blood, an on partial pressure of oxygen and
      carbonic gas was discovered. The intravenous infusion of patients with hemodese
      restored the middle level of cell electrophoretic mobility previously reduced due
      to liver pathology. Membrane mechanisms controlling stability of erythrocyte
      electrokinetic characteristics are discussed.

PMID- 8658975
TI  - [Single-stranded DNA breaks in the chromosomes of early mouse embryos].
AB  - The occurrence and distribution pattern of spontaneous single-strand breaks
      (nicks) and/or gaps of mouse chromosomal DNA were studied with the help of nick
      translation procedure omitting exogenous nucleases. The holoenzyme and a Klenow's
      fragment were used at a concentration of 0.I. U/20 microl of reaction mixture,
      resp. Bio-dUTP and streptavidin-alkaline phosphatase were used for labeling and
      detection. Chromosomes of postimplantation embryos and bone marrow were not
      stained. Chromosomes of all preimplantation stages of development were
      homogeneously stained with prominent dots of various size and intensities of
      grayish. DNA Pol I and the Klenow enzyme demonstrated a similar pattern of
      labelling. The centromeric heterochromatin was not labeled. The label was
      localized asymmetrically exclusive of NOR and telomeric regions.

PMID- 8658974
TI  - [The cytogenetic reaction of the lymphocytes to in-vitro irradiation in children
      born to patients after antitumor radio- and chemotherapy].
AB  - Stability of genome of children born to patients after antitumor radio- and
      chemotherapy was studied. For this aim the peripheral lymphocytes were irradiated
      in vitro at doses 0, 0.25, 0.50, 1.00, and 1.50 Gy of gamma-rays 137Cs, and
      induced chromosome aberrations on metaphases of cultivated lymphocytes were
      scored. The data obtained demonstrate an increased chromosomal radiosensitivity
      of patients' children as compared to the control children. A possible association
      between the chromosomal instability and the increased risk of cancer is
      discussed. The children prezygotically exposed to mutagenic factors are supposed
      to make a group of potentially increased risk of cancer.

PMID- 8658976
TI  - [An analysis of DNA reparative synthesis in the lymphocytes of bronchial asthma
      patients].
AB  - Spontaneous and UV-stimulated unschedule syntheses (US) of DNA in the peripheral
      blood lymphocytes and HLA antigens were investigated for asthmatic patients. The
      index of stimulation (IS) of DNA repair was determined as the ratio of the values
      of UV-stimulated US to spontaneous US. In the patients, a significant elevation
      of the intensity of spontaneous DNA US and the decrease in IS values were
      revealed as compared with the healthy controls. At the same time the intensity of
      UV-stimulated IS did not differ in patients and the control subjects. The values
      of IS appeared to be significantly higher in those patients who had the HLA-Al
      antigen in their phenotype compared to those who had not. Possible mechanisms for
      the alteration of the DNA repair capacity of lymphocytes and for the relationship
      between cytogenetic damages and immunogenetic features in asthmatic patients are
      discussed.

PMID- 8658977
TI  - [A quantitative evaluation of the glycogen content of the hepatocytes from
      different lobular ares of the normal human liver and in chronic hepatitides of
      different etiologies].
AB  - Investigation of glycogen function in hepatocytes of different liver lobule zones
      is particularly important in understanding glycogen metabolism in humans and
      animals in norm and pathology. The present study was done to investigate glycogen
      contents in hepatocytes of different lobule zones of human liver in norm, and in
      patients with chronic hepatitis of viral or alcohol etiology. Quantitative
      analysis of glycogen content in hepatocytes of portal and central lobule zones
      was conducted on slices of human liver (the material of series live punctional
      biopsies) stained using a quantitative variant of PAS-reaction (Kudryavtseva et
      al., 1970, 1974). The measurements were done by image analyzer <<Magiscan>>,
      which allows to make jointly cytophotometric analysis of substance in cells and
      definition of cell localization in tissue. The results showed clear differences
      of glycogen contents in different lobule zones in normal liver and in liver
      during chronic viral and alcohol hepatitis. Glycogen contents in hepatocytes of
      portal lobule zone were significantly higher than in the central lobule zone in
      patients with chronic viral hepatitis. Opposite data were obtained in patients
      with chronic alcohol hepatitis. Significantly higher glycogen contents were found
      in hepatocytes of the central liver lobule zone. Possible mechanisms of such a
      phenomenon are discussed . Thus, if glycogen contents in hepatocytes may be taken
      as an indicator of liver chronic damage degree (as has been shown elsewhere:
      Kudryavtseva, 1987; Kudryavtseva et al., 1988) the pattern of distribution of
      hepatocytes with different glycogen content in the liver lobule can be used as an
      indicator of etiology of chronic hepatitis. The obtained data seem to be
      important and actual, particularly for diagnostic of subclinical and symptomless
      forms of these diseases. Further investigation is required to find out reasons
      and mechanisms of this phenomenon.

PMID- 8658978
TI  - [The structure of the chromocenter in the oocytes, the initiation of homologous
      pairing and the regulation of the formation of crossing over in Drosophila].
AB  - The structure of chromocenter and pairing of homologs in Drosophila oocytes with
      different X-chromosome inversions (sc7, sc9, BM1, y4, sc4sc8), and acrocentric
      compound C(1)DX were studied. Disturbances of chromosome pairing in compound
      C(1)DX, inversion of heterozygotes and some homozygotes (BM1, sc4sc8) were
      observed. Besides, disturbances of precentromeric heterochromatin regions pairing
      and nonassociation of X-bivalents with chromocenter were observed. It turned out
      that inversion loops were formed only in chromocenter formation peculiarities. It
      is supposed that disturbance of homologous pairing in inversion homozygotes is
      associated with transference of sites initiating the homologous pairing. These
      sites are in pretelomeric and adjacent heterochromatin regions. Interchromosomal
      effects of chromosome aberrations on crossingover and, probably, modification of
      its frequency by other factors are associated with the state of precentrometic
      heterochromatin homologous pairing in chromocenter. The formation of crossover
      exchanges is completed with a total pairing in these chromosome regions and
      subsequently with reorganization of the meiotic chromosome structure.

PMID- 8658979
TI  - [An analysis of centriolar orientation in cultured ESK cells under the action of
      the calcium ionophor A23187].
AB  - Addition of 20 microM calcium ionophore A23187 to cultured PK (pig kidney embryo)
      cells gave an increase of Ca2+ in cytosol by more than 10 times. The maximum of
      [Ca2+] was achieved in 1-2 min after introduction of the drug. Later on [Ca2+]
      gradually decreased, and after 30 min of incubation with A23187 [Ca2+] was 3-5
      times above normal level. Immunofluorescent and electron microscope studies
      showed no alterations in the microtubule system of interphase cells after 1-30
      min treatment. The electro microscope study showed that-following 1.5 min
      introduction of the drug the random orientation of material and daughter
      centrioles changed: most of them settled down at an angle more, than 74 degrees
      to the substrate surface. After 3 min of A23187 treatment more than half of
      maternal centrioles were oriented perpendicular to the substrate surface. After 5
      min of A23187 treatment, the percentage of maternal centrioles with perpendicular
      orientation was the same and this orientation remained for 30 min. The percentage
      of perpendicular daughter centrioles decreased after 3 min of treatment, and
      after 30 min their orientation was random. We suggest that the perpendicular
      orientation of centrioles to the substrate surface is mediated through centrosome
      associated calcium-binding proteins.

PMID- 8658980
TI  - [An electron microscopic study of the natural death of cyst cells in
      Sarcosporidia. I. Ultrastructural changes in the cytoplasm of the cyst cells of
      Sarcocystis muris and S. bovifelis].
AB  - A complicated development of Sarcocystis muris and S.bovifelis, within tissue
      cysts (sarcocysts), was examined in terms of a phenomenon of programmed cell
      death well-known in Metazoa. It looks likely that this phenomenon of versatile
      significance in living organisms has not yet been followed in parasitic protozoa.
      This is the first attempt to find out a general picture of morphological changes,
      occurring in the course of natural death in parasitic protozoa. With electron
      microscope, a study was made of sarcocysts of S. bovifelis isolated from
      oesophagus muscles of a naturally infected cow. In 6-month old sarcocysts of S.
      muris, three morphofunctional cell types are commonly distinguished: little
      differentiated metrocytes, intermediate cells, and highly differentiated <<cyst
      merozoites>>, homologous to gamonts of other Sporozoa. Among numerous cyst cells,
      looking overtly normal, some <<abnormal>> cells tend to be encountered, which
      increase in number in 10 month old cysts, i.e. as sarcocysts are getting older.
      At least three stages of morphological degradation are to be distinguished in the
      cyst cells, with special attention being paid to changes in their cytoplasm. The
      first stage degradation involves ultrastructural changes in cell organelles,
      primarily in rough endoplasmic reticulum, whose membranes form vacuoles, with
      various kinds of membranous and non-membranous materials inside. At the second
      stage, apical organelles of cyst cells are involved: rhoptries are seen to lose
      their contrast, suggesting that their proteinaceous content may be discharged
      into the cell cytoplasm; eventually, membranes of rhoptries disappear. Micronemes
      seem to break into composing channels of endoplasmic reticulum. Ultimately, in
      the cells committed to death, the main body of cell organelles looks
      indecipherable, and the whole cells become filled with numerous vacuoles of
      different sizes and configuration. At the third statge of morphologoical
      degradation, cell trans

PMID- 8658981
TI  - [An electron microscopic study of the natural death of cyst cells in
      Sarcosporidia. II. Ultrastructural changes in the nuclei of cyst cells of
      Sarcocystis muris].
AB  - Nuclear changes in cyst cells, developing within 6 and 10 month old sarcocysts of
      Sarcocystis muris, were followed in terms of the programmed cell death
      phenomenon. This communication extends our previous studies in the cytoplasm of
      S. muris cyst cells (Radchenko et al., 1995) to include particular nuclear
      changes in different involve changes in nuclear configuration: the original
      spherical from is progressively substituted for irregular or lobulated shapes.
      This may suggest some corresponding changes in cytoskeleton, involved in
      formation and maintaining of some definite nuclear shape. In normal cyst cells,
      the nuclear chromatin appears as a filiform and reticulate structure with a few
      lumps made of granules and filaments. In the cyst stages subject to natural cell
      death, structural changes in nuclei involve disassembly of lumps into separate
      granules. Some spherical structures are seen outbudding from the nucleolus. These
      structures are presumably made of RNA-containing granules. The pattern of
      nucleolar segregation in S. muris cells resembles somewhat the changes in
      nucleoli reported for metazoan cells. However, the general picture of
      morphological evolution in the nuclei of S. muris cells, in the course of natural
      dying, differs from that in metazoan cell nuclei. No condensation of nuclear
      chromatin at the nuclear periphery, or blebbing of the nuclear and cytoplasmic
      membranes, so characteristic of the latter, was followed in the former. The
      peculiarities noticed in the sarcosporidia may reflect biological peculiarities
      of these specialized parasitic protozoa.

PMID- 8658982
TI  - "All change ...".

PMID- 8658984
TI  - Infective endocarditis due to Gemella morbillorum complicating hypertrophic
      obstructive cardiomyopathy.

PMID- 8658983
TI  - Malignant hyperpyrexia in an MDMA ("Ecstasy") abuser.

PMID- 8658985
TI  - Liposarcoma of the colon.

PMID- 8658987
TI  - Nephrobronchocutaneous fistula.

PMID- 8658986
TI  - Strangulation of the appendix in a femoral hernia sac.

PMID- 8658988
TI  - Coalition of the proximal row of the carpus.

PMID- 8658989
TI  - Guidelines for lumbar spine radiography in acute low back pain: effect of
      implementation in an accident and emergency department.
AB  - Guidelines for lumbar spine radiography were agreed by consultation between staff
      in the radiology, accident and emergency and neurosurgical departments of a large
      teaching hospital. Study of 322 consecutive patients over an eight month period
      showed that the proportion of patients referred for radiography was reduced from
      48.4% to 27.2% following introduction of the guidelines (p = 0.0002). Successful
      use of such guidelines requires cooperation between clinical and radiological
      staff and frequent review of performance.

PMID- 8658990
TI  - Prostaglandin E1 in the medical management of erectile dysfunction in a genito
      urinary medicine clinic.
AB  - Fifty consecutive patients with erectile failure who had previously proved
      refractory to papaverine and phentolamine intracavernosal therapy or were
      inappropriate candidates for such treatment were treated with intracavernosal
      prostaglandin E1. Forty patients (80%) achieved an erection sufficient for sexual
      intercourse and after a mean follow-up period of 5.9 months, 32 patients were
      continuing to use treatment successfully. The average dose was 14 micrograms
      (range 2.5 to 30 micrograms). There were no cases of priapism or cavernosal
      fibrosis and no systemic side effects. A low incidence (8%) of local discomfort
      was reported. We conclude that prostaglandin is a safe and effective vasoactive
      agent for the treatment of erectile failure in a genito-urinary outpatient
      clinic.

PMID- 8658991
TI  - Initial experience with a electronic CT image transfer system.
AB  - An electronic image transfer system for computed tomographic images links the CT
      scanner in Altnagelvin Hospital, Londonderry with the regional neuroradiology
      department in the Royal Victoria Hospital, Belfast. In the first 13 months of
      operation, scans of 100 patients were transferred; 49 scans were taken in acute
      neurosurgical emergencies, and 51 were non-acute sent for a specialist
      neuroradiological opinion. Potentially hazardous inter-hospital transfer was
      avoided in 21 cases of acute neurosurgical emergency, and more efficient and
      appropriate referral was achieved in the cases whose scans had been sent for sent
      for radiological second opinion. We believe that the system has substantially
      improved the diagnosis and management of patients with neurosurgical problems in
      both hospitals.

PMID- 8658992
TI  - Patients' perception of day case surgery.
AB  - A postal questionnaire was used to assess patient compliance with instructions,
      post-operative sequelae and general practitioner workload resulting from the day
      case unit of Daisy Hill Hospital, Newry. Compliance with instructions was good.
      There was little post-operative pain but there was a high incidence of other side
      effects. Few patients needed to see their general practitioner in the week
      following surgery.

PMID- 8658993
TI  - Acute appendicitis in young children in the Belfast urban area: 1985-1992.
AB  - Eighty-one cases of acute appendicitis in children aged less than six years were
      identified in the Belfast urban area between 1985 and 1992. Appendiceal
      perforation, found in 43%, was related to symptom duration but not to age at
      presentation. Prolongation of symptoms was related to parental delay in seeking
      medical advice (52% > 36 hours), delayed or inappropriate general practitioner
      referral to hospital (19%) and diagnostic delay following surgical consultation
      (12% > 12 hours). Diagnostic delay in hospital was usually the result of
      nonspecificity of symptoms and signs and was therefore largely unavoidable.
      Delayed referral from general practice did not contribute unnecessarily to
      appendiceal perforation, and given that an individual general practitioner will
      see a case of preschool appendicitis once in 30 years, diagnostic accuracy was
      remarkably high.

PMID- 8658994
TI  - Current ethical issues in organ transplantation.

PMID- 8658995
TI  - Adjuvant therapy for colorectal cancer--is there a place for a Northern Ireland
      study?
AB  - Survival from colorectal cancer has not improved over the last four decades
      despite advances in surgery and anaesthesia. The answer to the question whether
      adjuvant chemotherapy and radiotherapy will improve survival from the disease can
      only come from randomised, controlled trails. In the future, immunotherapy and
      gene therapy may be of benefit but these are still many years from the clinical
      arena. We believe that current evidence suggests that patients with Dukes B and C
      colorectal cancer should be entered into trials of adjuvant therapy. This
      evidence is reviewed below among with estimates of the impact that adjuvant
      therapy would have on the outcome from this disease in Northern Ireland.

PMID- 8658996
TI  - The legacies of Sir William Whitla.

PMID- 8658997
TI  - A corridor to the past.

PMID- 8658998
TI  - Uvulopalatopharyngoplasty for snoring: the Belfast experience.
AB  - We have studied thirteen patients to assess the efficacy of
      uvulopalatopharyngoplasty on snoring and on oxygen desaturation during sleep. Pre
      and post-operative overnight pulse oximetry studies were performed and the
      patients were divided into snorers and those with obstructive sleep apnoea on the
      basis of the preoperative test. Uvulopalatopharyngoplasty did not result in a
      significant change in the number of oxygen saturation dips in either snorers or
      those with the obstructive sleep apnoea syndrome. Subjectively, 85% (11/13) of
      patients reported good or excellent improvement in snoring following surgery.

PMID- 8659000
TI  - Clinical experience with inflatable and malleable penile implants in 104
      patients.
AB  - Penile prosthesis was implanted for erectile impotence of mainly organic origin
      in 104 patients. The AMS Dynaflex penile prosthesis was inserted in 39 cases, the
      AMS Malleable 600 prosthesis in 61 and the AMS Ultrex Plus prosthesis in 4. In 1
      patient receiving a malleable prosthesis both rods had to be removed owing to
      erosion into the urethra and reimplantation was performed at the same operation.
      Only 1 patient who underwent implantation of the Dynaflex device had mechanical
      failure that necessitated surgical revision. After implantation of the new
      prosthesis both patients had satisfactory intercourse. One Dynaflex penile
      prosthesis, implanted into a juvenile-onset diabetic, became infected and
      required removal. Another complication was secondary to spontaneous erosion
      (noninfected) in 1 patient with malleable prosthesis who suffered loss of only
      one rod and who is still satisfied with the result. The overall complication rate
      in our series has been approximately 4%. The rest of the patients report
      satisfaction with the ability to move the penis voluntarily permitting normal
      sexual activities as well as normal appearance in the flaccid position. According
      to our experience, careful preoperative assessment from the views of both patient
      and device selection along with patient education, and strictly obeying the rules
      of sterility during implantation and applying systemic and local antimicrobial
      prophylaxis are essential in obtaining a successful result in prosthesis
      implantation for the individual patient.

PMID- 8658999
TI  - "Sonic, tonic, clonic": three cases of video game epilepsy.

PMID- 8659001
TI  - Spontaneous hemorrhage of an adrenal cortical adenoma causing Cushing's syndrome.
AB  - We report the case of a spontaneously ruptured adrenal adenoma which caused
      Cushing's syndrome. The 34-year-old female patient had severe left-side back pain
      and anemia. Computerized tomography disclosed a retroperitoneal hemorrhage and a
      4-cm mass on the left which was considered to be an adrenal tumor. An operation
      was successfully performed, and the patient is well 12 months after surgery.

PMID- 8659002
TI  - Transplantation of a horseshoe kidney into 2 recipients.
AB  - We report the case of a transplantation of a horseshoe kidney to 2 recipients
      after isthmic section of the kidney. A review of the literature since 1975
      mentions only 14 cases of transplantation of a horseshoe kidney. In the absence
      of a significant urological clinical history of the donor, the presence of a
      horseshoe kidney, in the case of multiorgan harvesting, does not represent a
      contraindication for transplantation.

PMID- 8659003
TI  - Renal cell carcinoma in a transplanted kidney: successful organ-preserving
      procedure.
AB  - We report a case of a de novo renal cell carcinoma in a transplanted kidney,
      which was detected 3 years after the transplantation. The tumor was excised under
      hypothermia and perfusion. Immunosuppression was not stopped and the function
      remained excellent. Close-mesh follow-up of 45 months showed no evidence or
      recurrence or metastasis.

PMID- 8659004
TI  - Three-dimensional imaging using spiral computerized tomography prior to tumor
      enucleation in a patient with a solitary kidney.
AB  - The authors present a case of renal cell carcinoma in a man with a solitary
      kidney. Three-dimensional computerized tomography instead a selective renal
      angiography was used preoperatively as a noninvasive technique for visualization
      of the renal tumor and renal vascularization.

PMID- 8659005
TI  - Acute hemorrhagic cystitis by adenovirus type 11 with and without type 37 after
      kidney transplantation.
AB  - We report 2 kidney transplant patients with acute hemorrhagic cystitis.
      Adenovirus type 11 was isolated in the urine of both patients and in 1 patient
      adenovirus type 37 was also isolated. Each developed macrohematuria with urgency,
      micturition pain, elevated fever and functional deterioration of the transplanted
      kidney possibly due to acute rejection. These symptoms and laboratory data
      suggesting renal impairment persisted for approximately 4 weeks after therapy for
      acute rejection had been started without any specific additional treatment for
      adenovirus. Serum creatinine levels returned to slightly higher values than
      before this episode. Histological findings of biopsy specimens from the
      transplanted kidney in 1 patient indicated that renal impairment was attributable
      to acute rejection. According to the clinical results of our cases, there were no
      remarkable differences between adenovirus type 11 infection with or without type
      37 infection. Acute hemorrhagic cystitis caused by the adenovirus is an
      interesting complication after kidney transplantation, especially with regard to
      kidney impairment and treatment.

PMID- 8659006
TI  - Ureteral triplication, occasionally an isolated anomaly.
AB  - A case of isolated ureteral triplication is presented, the patient did not have
      any other urogenital anomaly. This presentation is rare and relevant literature
      is discussed.

PMID- 8659007
TI  - Postoperative spindle cell nodule of the bladder: a diagnostic problem.
AB  - A case of postoperative spindle cell nodule of the bladder is reported. Initial
      pathological analysis was interpreted as leiomyosarcoma for which the patient
      underwent radical cystectomy, but subsequent reviews were consistent with a
      postoperative spindle cell nodule. Recognition of this benign, yet rare lesion is
      of significant importance to urologists, pathologists, and to the patient who may
      undergo extensive surgical procedure unnecessarily.

PMID- 8659008
TI  - Detection of sex-determining region in a male with chromosomal abnormality
      (46,X+mar) and hypospadias.
AB  - A 1-year-old boy was referred to us because of abnormal external genitalia; that
      is, his penis was kinked toward the perineal region. We diagnosed hypospadias.
      Chromosomal examination was performed on a sample of peripheral blood, the
      karyotype was 46,X+mar. Detailed karyotypic analysis revealed that the short arm
      of the marker chromosome originated on the ninth chromosome, but we could not
      determine whether the long arm was part of the Y chromosome, even with the use of
      quinacrine mustard. The sex-determining region of the Y was detected using the
      polymerase chain reaction method, which suggested that the long arm of the marker
      chromosome was delivered from the short arm of the Y chromosome.

PMID- 8659010
TI  - Pathological changes of traumatic dislocated testis.
AB  - We present a 17-year-old patient with a right testicular dislocation. In this
      case, dislocated testis had been considered as hematoma and therefore remained
      untreated for 4 months. The patient underwent right orchiopexy 4 months after the
      injury. Intraoperative testicular biopsy revealed impaired spermatogenesis and
      existence of many alternative Sertoli cells, but no atrophy of seminiferous
      tubules. Six months after the operation, semen analysis of the patient revealed
      the deformity of most sperms. Eight months after the operation, rebiopsy of the
      right testis disclosed slight improvement in the spermatogenesis of the testis.
      Damage of the testis appears to be not severe in dislocation and may be recovered
      by repositioning.

PMID- 8659011
TI  - Laparoscopic bilateral ureterolysis in Ormond's disease.
AB  - We report a case of retroperitoneal fibrosis with dilation of the upper urinary
      tract on both sides and impaired renal function in a 66-year-old female. The
      patient was successfully treated by laparoscopic ureterolysis and
      intraperitonealization of both ureters with subsequent immunosuppressive
      medication. Due to intraoperative subcutaneous emphysema, surgical therapy had to
      be performed as a two-step procedure but postoperative morbidity was minimal with
      quick recovery. Laparoscopic ureterolysis is a reconstructive procedure and the
      ureters are accessible in full length either transperitoneally or
      retroperitoneally.

PMID- 8659009
TI  - Pseudoepitheliomatous, keratotic and micaceous balanitis. Case report and review
      of the literature.
AB  - A case of pseudoepitheliomatous, keratotic and micaceous balanitis (PEKMB) in a
      64-year old man is presented. The patient presented with the 2-year history of a
      slowly enlarging, hyperkeratotic plaque on his glans penis that was compatible
      with a clinical diagnosis of PEKMB. The lesion has been treated successfully with
      tropical 5-fluorouracil cream, with no evidence of recurrence at 2-year follow
      up. Histological examination revealed acanthosis, hyperkeratosis, and
      pseudoepitheliomatous hyperplasia with no cytological atypia. This rare penile
      condition was considered pseudomalignant, premalignant, or as a low-grade
      squamous malignancy. Apart from this patient we comprehensively review previously
      reported cases, and discuss a possible concept on etiology, diagnosis and
      treatment of this entity.

PMID- 8659012
TI  - Investigations on bone metabolism of urological tumors forming metastases.
AB  - Bone metastases of urological tumors occur in nearly 40% of all primary tumors of
      the prostate, the kidney and the bladder. The quality of metastases may be
      described as osteolytic, osteoplastic or mixed lesion. Whereas prostate cancers
      produce mainly osteoplastic lesions, renal cell carcinomas predominantly generate
      osteolytic lesions. In bladder cancer both forms of metastases occur in
      tantamount numbers. However, diagnostics still presents many difficulties, since
      it is not feasible to identify very small metastases until symptoms have
      manifested themselves. The purpose of our study was to evaluate measurement
      technique and classification of significant serum markers for monitoring the
      course of disease. Patients with primary urological tumors and metastases in the
      skeleton were investigated and compared with healthy volunteers.
      Osteodensitometry was used to confirm and to replace radiological diagnosis of
      bone metastases. Thus it was possible to locate the extent and obtain information
      on the maximum charge and the stability of metastases. Our examinations revealed
      that distinct serum markers describe the changes in bone evoked by metastases. In
      comparison with healthy volunteers, patients with osteoplastic lesions and
      osteolytic lesions showed increases in hydroxproline and pyridinium crosslinks
      (significance at least p < 0.005). Osteocalcin was elevated only in osteoplastic
      lesions versus healthy volunteers (p < 0.01). For diagnostics of osteoplastic and
      osteolytic metastases, either alkaline phosphatase or the skeleton-specific
      phosphatase (ostase) can be measured serologically. Both parameters showed
      significant elevation in the patient groups when set against the healthy controls
      (both p < 0.0001). Compared with lytic lesions osteoplastic carcinomas revealed
      significant increase of alkaline phosphatase (p < 0.0001) and osteocalcin (p <
      0.005). In examination of bone metabolism in patients with skeletal metastases
      the following parameters are of eminent interest: osteocalcin, hydroxyproline or
      pyridinium crosslinks, alkaline phosphatase or ostase. These serological
      parameters could be helpful even with regard to early diagnosis of bone
      metastases. Evaluation of measuring techniques suggests quantifying pyridinium
      crosslinks instead of hydroxyproline, because they may be assessed without taking
      the patient's diet into account. Determination of bone density may be helpful in
      diagnostics or control of therapy modalities.

PMID- 8659013
TI  - Biological properties of renal oncocytoma cells in culture.
AB  - This paper sought to determine biological properties of oncocytoma cells, both in
      vivo and in vitro, which may serve as useful diagnostic indicators. Cell lines
      were grown in short-term culture from two renal oncocytomas following enzymatic
      dissociation, characterised by immunohistochemistry and electron microscopy, and
      further studied for abnormal p53 or retinoblastoma genes. Cells in culture were
      shown to maintain the morphological attributes of the primary lesion, including
      the overproduction of mitochondria. Despite the absence of vimentin staining in
      the primary tumour, cells in culture were shown to express this intermediate
      filament. Immunohistochemistry for P53 protein demonstrated an overexpression in
      one of the tumours, suggesting that mutation had occurred. Restriction fragment
      length polymorphisms of the retinoblastoma and the p53 genes were not
      demonstrated. Mutation of the p53 gene does occur in oncocytomas. The maintenance
      of the phenotype of oncocytoma cells in culture suggests that in vitro studies
      may be useful in the identification of unique properties of the tumour.

PMID- 8659014
TI  - Transplantation in autosomal dominant polycystic kidney disease without
      nephrectomy.
AB  - Some transplantation centers still suggest nephrectomy in patients with autosomal
      dominant polycystic kidney disease (ADPKD) before kidney transplantation at least
      in selected cases. We wanted to learn whether prior nephrectomy is beneficial.
      The outcome of kidney transplantation in 47 consecutive ADPKD patients without
      prior nephrectomy was compared with that in matched controls with respect to
      complications of ADPKD. Although ADPKD patients were older than controls (mean,
      50.1 vs. 40.3 years), there was no statistically significant difference in 1- and
      5-year allograft survival between ADPKD patients and controls: 76.6 and 68.0%,
      respectively, in ADPKD patients, and 83.9 and 56.3% in controls. After a mean
      follow-up of 66.5 months 3 patients with ADPKD had cyst infections and were
      managed with antibiotics. Two patients had episodes of hematuria; neither
      required invasive therapy. There was no renal malignancy and clinical sign of
      urolithiasis in any patient. No posttransplantation nephrectomy was required.
      With only few indications remaining, there is no rationale for routine
      pretransplantation nephrectomy in patients with ADPKD.

PMID- 8659015
TI  - A comparative study between etiological factors of calcium oxalate monohydrate
      and calcium oxalate dihydrate urolithiasis.
AB  - A comparative study between different etiological factors of calcium oxalate
      monohydrate (COM) and calcium oxalate dihydrate (COD) is presented. The most
      frequent alteration in COD urolithiasis was associated with hypercalciuria,
      whereas in COM urolithiasis was associated with urinary pH. A comparison between
      COM and COD groups of stone formers that exhibited 1, 2 or 3 alterations was
      performed. Thus, in individuals with two simultaneous alterations, the
      association between altered urinary pH and hypomagnesiuria was the most frequent
      in the COM group, whereas the association between hypercalciuria and altered
      urinary pH was most frequent in the COD group. In individuals with three
      simultaneous alterations, the association between hypercalciuria,
      hyperphosphaturia and hyperuricuria was most frequent in both COM and COD stone
      formers.

PMID- 8659017
TI  - Increase in lectin binding sites on epithelial cells by chronic bladder infection
      in rats.
AB  - Using lectin histochemistry we assessed whether chronic bladder infection
      modifies carbohydrate residues of glycoconjugates on uroepithelial cells in rats.
      The bladder infection was produced by implanting a knotted silk thread with
      Escherichia coli into the bladder. One or 4 weeks after the implantation the
      bladder was excised, incubated with sixteen biotinylated lectins and stained. The
      bladder epithelia as a whole stained more strongly positive for eight lectins in
      the infected rats than in the control rats having a sterile silk thread in the
      bladder. In the infected rats, the superficial epithelial layer that stained
      negative for Arachis hypogaea (PNA) in the controls became strongly positive for
      PNA, whereas the middle and deep epithelial layers increased in staining for
      Canavalia ensiformis and six other lectins. These results indicate that chronic
      bladder infection increases carbohydrate residues on uroepithelial cells and may
      facilitate bacterial adherence to uroepithelial cells.

PMID- 8659016
TI  - Extracorporeal shock wave lithotripsy for renal stones in children.
AB  - The aim of our study is to determine the efficacy and safety of extracorporeal
      shock wave lithotripsy (ESWL) as a method of treatment of nephrolithiasis in
      childhood. Between 1986 and 1994, 50 children with renal calculi were treated by
      ESWL in our department. The age of the children ranged from 8 months to 14 years.
      Thirty-three of them were boys and 17 girls. The stone location was in the renal
      pelvis in 38 cases, in the upper renal calyx in 4 cases, in the lower calyx in 2,
      while 6 children had staghorn calculi. The stone size ranged between 3 and 39 mm.
      All treatments were performed with Dornier HM4 except 12 children, all older than
      10 years, who underwent ESWL with Dornier HM3. All ESWL procedures took place
      under general anesthesia or sedation with ketamine. The number of shock waves
      varied between 400 and 2,000 per treatment and the standard maximum generator
      voltage was 18 kV. The overall stone clearance rate at 1 month was 66%. Fourteen
      children with large residual fragments underwent a second ESWL procedure 3 months
      later. With a mean follow-up of 33 months, 41 children (82%) are stone-free. Ten
      children developed urinary tract infection and 5 Steinstrasse. Twelve children
      had a pre- and post-ESWL DMSA scan and no permanent impairment of renal function
      was observed. We conclude that ESWL is the treatment of choice for urinary tract
      lithiasis in childhood. It is a low-risk method, without serious complications,
      which yields as high a success rate in children as in adults. We believe that as
      the stone fragmentation and clearance is much higher in children that in adults,
      the method must be the initial approach and may be the monotherapy even in
      staghorn or complex stones.

PMID- 8659018
TI  - Evaluation of acute scrotal pain by color-coded duplex sonography.
AB  - In light of the high sensitivity of color-coded duplex sonography (CCDS), we
      analyzed a group of patients with acute scrotal pain to evaluate the use of CCDS
      in routine clinical examination. During March 1988 through April 1991, CCDS was
      used in 31 patients with acute scrotal pain before they underweight surgery in
      our department. In 15 patients, the structural and perfusion changes of the
      scrotal contents were such that a definitive diagnosis was possible. In the rest
      of the patients, the pathologic changes seen with CCDS were more complex, and the
      correct interpretation needed more expertise; this was especially true in
      patients with partial torsion, posttorsion status, and torsion of hydatids. CCDS
      with the simultaneous display of anatomic scrotal structures and blood flow over
      the entire scan field is an excellent method for evaluating patients with acute
      scrotal pain. However, apart from the classical case of no perfusion (as in
      testicular torsion) and increased perfusion (as in inflammation), more complex
      changes are more difficult to interpret. The correct diagnosis in the latter
      cases requires considerable experience and evaluation of all facts, including
      clinical history, results of palpation, and structural and perfusion changes of
      the scrotal contents.

PMID- 8659019
TI  - Physiology of the lower urinary tract.
AB  - This article presents the concepts that give meaning to the pressures observed in
      the various parts of the body occurring normally and abnormally in various
      conditions. Normal pressure relationships, holding urine, voiding, incontinence,
      and flatulence and defecation are discussed.

PMID- 8659020
TI  - Functional anatomy of the organs of micturition.
AB  - The anatomy of the organs of micturition has been the subject of study for nearly
      150 years. As a result of advances in techniques and methods of clinical and
      research investigation, studies over the past three decades have intensified and
      have been increasingly directed at the functional implications and significance
      of organ anatomy and structure. This has led to revision of many traditional
      ideas about micturition and the development of new viewpoints and modalities for
      study of its disorders. This article summarizes the evolution of our thinking and
      understanding of the functional anatomy of the bladder and urethra over the
      years, and suggests possible directions for continued clinical study and
      investigation.

PMID- 8659021
TI  - Smooth-muscle physiology.
AB  - In the last several years, significant advances have been made in the
      understanding of bladder smooth muscle physiology. This article provides a
      summary for the clinician of current knowledge about the detrusor smooth muscle
      cell structure, function, and the relationship of structure to function in terms
      of bladder storage and physical properties such as compliance. The integration of
      this basic science knowledge into clinical practice is illustrated in discussion
      of two common disorders: detrusor instability, and outflow obstruction.

PMID- 8659022
TI  - Neurophysiology of micturition and continence.
AB  - This article reviews the neuroanatomy, neurophysiology, and neuropharmacology
      involved in micturition and continence. Knowledge of these topics helps the
      clinician diagnose and treat voiding disorders that are caused by disease,
      trauma, drugs, and aging.

PMID- 8659023
TI  - Uroflowmetry.
AB  - Uroflowmetry is a widely used noninvasive screening modality for patients who
      present with symptoms of lower urinary dysfunction. However, it should be
      recognized that uroflowmetry represents the compound effect of bladder and
      urethral function because it may easily be misinterpreted. In elderly men with
      "prostatism", uroflowmetry is often sufficient to indicate treatment, while the
      value in women is less prominent. In pediatrics, more sophisticated urodynamic
      testing is crucial.

PMID- 8659024
TI  - Cystometry.
AB  - Cystometry provides crucial information on which therapy for voiding dysfunction
      is predicated. The technique of cystometry can be altered to address specific
      clinical questions; however, the goal of the study is to reproduce the clinical
      situation being investigated. Specific areas remain to be clarified, including
      the estimation and interpretation of compliance and the utility of standard
      versus natural filling methods.

PMID- 8659025
TI  - Leak-point pressures.
AB  - The pressure based management of patients with neurogenic vesical dysfunction has
      led to greatly improved outcomes with respect to upper and lower urinary tract
      complications. At the heart of this management is detrusor leak-point pressure
      testing that verifies that a low intravesical pressure is achieved and
      subsequently maintained. The abdominal (or Valsalva) leak-point pressure that
      quantifies the degree and type of urethral sphincter dysfunction, is an essential
      test in selecting the appropriate treatment for stress urinary incontinence. The
      authors discuss the history, importance, and application of these two very
      different tests.

PMID- 8659026
TI  - Micturitional urethral pressure profilometry.
AB  - The technique of micturitional urethral pressure profilometry using a trilumen
      catheter provides a method of assessing the dynamic behavior of the lower urinary
      tract during voiding. This method of evaluation is simple to perform, highly
      reproducible, accurate, and clinically useful not only in diagnosing the presence
      of outlet obstruction, but also in identifying its location and assessing its
      severity. The rationale for the use of this technique, the interpretation of the
      results, and various pressure profile configurations are discussed.

PMID- 8659027
TI  - Pressure-flow studies of micturition.
AB  - The purpose of pressure-flow studies is to identify and quantify the
      abnormalities of bladder function (bladder outlet obstruction) that underlie
      disorders of voiding already demonstrated in simpler ways. Techniques of
      measurement and data quality control are of primary importance. Different methods
      for analyzing bladder outlet obstruction in the male like the Abrams-Griffiths
      nomogram and the linPURR have different aims but give broadly consistent results.
      Methods for assessing detrusor contractility and obstruction in the female
      patient are briefly discussed.

PMID- 8659028
TI  - Electromyography of the perineal floor.
AB  - Electromyography is the study of minute potentials produced by the depolarization
      of the muscle membrane; they may be useful in the diagnosis of pelvic floor
      disorders. Either surface or needle electrodes may be used, depending on the type
      of information desired. Innervation deficits may be indicated by abnormal
      potentials observed in resting or active muscle. Electromyography is also useful
      in assessing coordination between bladder contraction and sphincter relaxation.

PMID- 8659029
TI  - Videourodynamic studies.
AB  - Videourodynamic evaluation that incorporates radiographic imaging with
      simultaneous measurement of bladder and urethral pressure is the most precise
      method available for diagnosing complex incontinence and voiding disorders. In
      addition, videourodynamics has been instrumental to the development of our
      present knowledge about urethral and bladder function including the concepts of
      detrusor and abdominal leak point pressures. Although these studies are more
      expensive and time consuming, the authors have found videourodynamic evaluation
      indispensable when the diagnosis remains in question after simple urodynamics and
      when the studies and clinical scenario do not agree.

PMID- 8659030
TI  - Bladder autoaugmentation.
AB  - Autoaugmentation has proved effective in many patients in lowering bladder
      pressures, increasing bladder capacity, and improving their related symptoms.
      Patients with sever bladder hyperreflexia, uncontrolled with medications, have
      also benefited greatly from autoaugmentation procedures. Only patients who failed
      conventional medical management have undergone autoaugmentation at the authors'
      institution.

PMID- 8659031
TI  - [Thyroid function in different clinical variants of glomerulonephritis in
      children].
AB  - The paper shows that children with glomerulonephritis develop autoimmune
      disorders and stable thyroid dysfunction. That's why it is valid to include
      thyroid function correcting drugs in the combined regimens. The drugs should be
      assigned with consideration of individual clinical syndromes of acute and
      clinical forms of chronic glomerulonephritis.

PMID- 8659032
TI  - [A familial form of nephrolithiasis in patients following kidney
      transplantation?].
AB  - Causes and mechanisms underlying nephrolithiasis after transplantation of the
      kidney differ much from known in other urological patients. We have found calculi
      in transplanted kidney in 5 of 939 surgical patients. Two cases of concrement
      formation in the transplant in the members of the same family aged 22 and 26
      years we report as interesting. Our experience and literature data suggested
      family nature of the concrements. One of the patients underwent pyelolithotomy,
      the other impulse lithotripsy. Both the transplants function normally 5 years
      after kidney transplantation.

PMID- 8659033
TI  - [The combined treatment of locally disseminated bladder cancer].
AB  - 39 untreated patients with local cancer of the bladder without distal metastases
      were included in the trial to assess efficacy of combined drug plus radiation
      treatment, its toxicity and chances to preserve the bladder. The examination
      comprised tumor biopsy, ultrasonography, computed tomography, excretory urography
      and routine laboratory tests. The patients received one or two courses of
      intraarterial chemotherapy, radiation (50 Gy) and two doses of cysplatinum in a
      dose 70 mg/m2 before and after radiation. A complete response was achieved in
      66.6%, partial in 12.8%, stabilization in 10.3% and progression in 10.3% of
      patients. One-year survival was reported in 89.7%, recurrence-free survival with
      functioning bladder being 66.7%. Side effects were mild and did not demand the
      treatment discontinuation.

PMID- 8659034
TI  - [The immunotherapy of bladder tumors and the immunoprophylaxis of disease
      recurrence].
AB  - Therapeutic and preventive effects have been analysed for 84 patients with
      superficial bladder cancer treated with BCG vaccine. The degree of cell
      infiltration of the tumor stroma served as a criterion of treatment efficacy and
      prognosis of recurrence. This degree diminished with augmentation of
      morphological changes this indicating depression of immunity while tumor
      formation and increased directly in BCG immunotherapy. In the absence of cell
      infiltration in response to immunotherapy recurrences become more likely.
      Preventive and therapeutic use of BCG vaccine in patients with surface tumors of
      the bladder reduced the number of recurrences 3.6-fold.

PMID- 8659035
TI  - [The long-term treatment of patients with benign prostatic hyperplasia using
      Proscar].
AB  - The drug proskar (finasterid) has been developed and synthetized in "Merck Sharp
      & Dohme" research laboratories and tried initially in healthy male volunteers.
      Proskar is highly active as a blocker of 5-alpha-reductase blocking conversion of
      testosteron in dehydrotestosteron (DHT). The assessment of proskar effect on the
      prostate has been performed in 2000 patients throughout the world, including
      Russia. Follow-up studies (up to 5 years) demonstrate that proskar in the dose 5
      mg/day produces a reduction in the levels of specific prostatic antigen, serum
      DHT and prostatic size, an increase in urination rate, life quality. In benign
      prostatic hyperplasia proskar realizes its effect in hormonal nature of the
      disease. The advantages are also safety and rare occurrence of side effects. The
      response became noticeable on the treatment month 6.

PMID- 8659036
TI  - [A method for urinary diversion in cystectomy for transitional-cell bladder
      cancer].
AB  - Modified cystectomy with formation of colonic urine reservoir and dry abdominal
      urostomy was performed in 12 patients with transitional cell carcinoma of the
      bladder T1-2NO-1M0. Four patients were previously treated surgically, received
      drugs or radiation. 8 patients were untreated. Early after surgery 1 patient died
      of hypostatic bronchopneumonia, 2 patients died 14-17 months after discharge from
      hospital of cardiovascular disorder, 4 patients were lost for follow-up, the rest
      5 patients are alive and socially fit. It is inferred that the above cystectomy
      is functionally and rehabilitatively appropriate for bladder cancer patients.
      Modification of some operative stages improves treatment outcomes.

PMID- 8659037
TI  - [Morphological factors in the prognosis of the treatment results in prostatic
      cancer].
AB  - Investigators from the Research Institute of Oncology and Radiology (Kyrgyzstan)
      from 1988 to 1994 have conducted a randomized trial entering 122 patients with
      prostatic cancer. 44 patients received radiation treatment (group 1), 43 patients
      in addition to radiation were given chemotherapy and estrogens (group 2), 35
      patients received drugs and estrogens (group 3). A complete response was
      registered in 80 (65.5%) patients. 84.2% and 69.8% of them survived 3 and 5
      years, respectively. Of 30 patients 24.5%) with partial response 3- and 5-year
      survival was recorded in 82.8 and 57.3%, respectively. Morphological examination
      of transrectal prostatic biopsies 3-72 months after the treatment stated the
      existence of tumor pathomorphosis and unchanged tumor in 111(29.7%) and 42(11.2%)
      samples. It was found that the above morphological changes had developed
      throughout 72 months. Their intensity was the greatest within the first after
      treatment year. Long-term outcomes proved better in those patients who had no
      residual tumor and in those who had tumor pathomorphosis during aftertreatment
      year 1.

PMID- 8659038
TI  - [The comparative efficacy of radiation and thermoradiation treatments in
      prostatic cancer].
AB  - Short- and long-term results of stage-III and -IV prostatic cancer treatment were
      compared in 147 patients without distant metastases. 38 patients were exposed to
      radiation, 109 patients underwent radiation treatment and local microwave
      hyperthermia. The response of the primary tumor was evaluated at palpation,
      ultrasonic investigation and computed tomography. Adjuvant local hyperthermia
      enhanced antitumor activity of the treatment raising the rate of a complete
      response from 69% on radiotherapy alone to 94% on thermoradiotherapy, 5-year
      survival in prostatic cancer stage III and IV increased also from 48 to 65%.

PMID- 8659040
TI  - [The late results of the combined hormonal chemoradiation treatment of prostatic
      cancer].
AB  - Combined treatment of 111 patients with prostatic cancer stage IV including 3
      components (hormones, drugs and radiation) proved superior by survival and
      tolerance over hormone therapy alone. Relevant dosages and regimens are detailed.

PMID- 8659039
TI  - [The immune homeostasis of patients with prostatic cancer on hormonal
      chemotherapy, radiation treatment and immunological action].
AB  - The trial covered 58 patients with prostatic cancer aged 50-79. Before treatment
      these patients exhibited weak proliferative response of T-cells to PHA, increased
      number of T-suppressors/killers, enhanced suppressive influence of regulatory
      cells. Hormone chemotherapy produced immunodepressive and immunomodulating
      effects (normalization of the count of T-suppressors/killers and their function).
      Subsequent radiotherapy on the prostatic region (total dose 60 Gy) worsened
      immunodepression. Efficacy of placental suspension and levamisol depends on the
      treatment stage at which the latter were used: during hormone chemotherapy the
      addition of the suspension and levamisol corrects its immunodepressive effects,
      in subsequent radiotherapy immunodeficiency greatly increased.

PMID- 8659041
TI  - [Bilateral pyeloureteral anastomosis in cervico-sphincteric ectopy of the ostia
      of both supernumerary ureters].
AB  - The paper reports a case of bilateral hydronephrosis diagnosed by ultrasound
      intrauterinely in a girl of 11 months of age. At the age of 5 months the child
      had attacks of pyelonephritis. Clinical examination has established: double
      kidney and ureters, cervico-sphincteric ectopy of the ostia in both accessory
      ureters, hydroureter of both accessory ureters, hydronephrosis of the upper
      kidneys. The patient underwent two-stage operation.

PMID- 8659042
TI  - [Raz's operation in the treatment of stress urinary incontinence in women].
AB  - Postoperative recurrences of enuresis range from 8 to 51%. One of the ways to
      correct this disorder is modification of transcutaneous urethrocervicopexy, Raz
      operation, in particular. Raz operation was performed in 53 females, of them in 5
      for recurrent enuresis. 4 patients underwent combined surgery: correction of
      anatomical defects of the bladder and urethra combined with Raz operation. Within
      3-year follow-up a response was achieved in 48 (91%) patients. Negative outcomes
      are explained in females with high motility of the fundus of the urinary bladder
      as the above surgical procedure does not strengthen the support apparatus of the
      bladder.

PMID- 8659044
TI  - [Low-intensity laser therapy in urology].

PMID- 8659043
TI  - [The effect of meteorological factors on the incidence of acute urinary
      retention].
AB  - The implication of meteorological factors in the incidence of acute urinary
      retention (AUR) were studied in prostatic adenoma patients. The trial was
      performed in the city of Perm (population 1.1 million) situated in the temperate
      zone with continental climate. The only center for emergency urological aid
      registered all AUR cases observed in the city throughout 1980-1990. All 1504
      episodes of AUR were recorded with reference to meteorological conditions on the
      day of admission (temperature, atmospheric pressure, etc.). The original data
      obtained after mathematical processing of the material indicate that AUR
      frequency goes up in day-to-day temperature fluctuations (5 degrees C and more),
      changes in atmospheric pressure (9 GPa and more) and in humidity (20% or more);
      in moderate and strong winds, cloudy wet weather, thunder storms. A complex of
      general and pharmacological measures is proposed to prevent AUR episodes in
      patients with prostatic adenoma.

PMID- 8659045
TI  - [Arterial hypertension in patients with terminal kidney failure: pathogenetic
      variants and treatment principles].

PMID- 8659046
TI  - [The use of high-intensity lasers in oncological urology].

PMID- 8659047
TI  - [Acute kidney failure from the nephrotoxic action of x-ray contrast media].
AB  - Causes and mechanisms involved in the onset of severe forms of acute renal
      insufficiency induced by highly osmotic ionic x-ray contrast media have been
      analyzed for 9 patients suffering from renal and other diseases. Risk factors and
      factors of principal importance in promotion of nephrotoxicity of contrast media
      are the following: preexisting renal dysfunction, cardiovascular insufficiency,
      hypovolemia, calcium and sodium dysbolism. Approaches to prevention of contrast
      media nephrotoxicity with employment of forced diuresis, vasodilators, calcium
      channels blockers are under consideration.

PMID- 8659048
TI  - [Alternative medicine--a true alternative or only another market?].

PMID- 8659049
TI  - [International developmental trends in life insurance medicine 1971-1995].
AB  - This retrospective of the eventful quarter of a century up to 1995 presents in
      brief sketches an international survey of developments with a bearing on
      insurance medicine. It identifies principle events in the field of clinical
      medicine that have had an effect on long-term prognoses and shows how they have
      been accounted for in the process of rating on the basis of insurance medicine
      prognoses. It highlights the main aspects of the scenarios from the 1970s down to
      the early years of the 1990s and illuminates in detail the developments in
      Germany. Finally, in the chapter "Life insurance medicine in the year 2000",
      there is a cautious "forecast on our own behalf", which names eleven points of
      development which contain possible messages for the future. In the final comment,
      the concern is expressed that life insurers and the insurance industry as a whole
      have not yet fully recognized the cost-benefit effect of insurance medical
      officers. A major role is played in this context by the increasingly important
      ethical guidelines.

PMID- 8659050
TI  - [Limits of intensive care medicine. Medical and legal aspects].
AB  - Modern intensive care can extend life. However, it may also extend the dying
      period. Because of this fact, doctors have been publicly accused of extending
      dying beyond human dignity, rather than accepting the end of life. In an attempt
      to regulate the abandonment, reduction or interruption of intensive care, the
      "Bundesarztekammer" has released new guidelines in 1993: measures which extend
      life - medicinal or apparative - may be interrupted if the delay of the patient's
      death results in an unreasonable extension of his suffering, and his terminal
      illness can not be influenced. Under these circumstances, a possible shortening
      of life may be accepted. A prescription of pain- and anxiety relieving drugs is
      both medically and legally accepted, even if it results in a shortening of life
      for a limited time. Today, an insufficient analgesia of seriously ill patients
      should be considered a treatment error.

PMID- 8659051
TI  - [Critical and heretical thoughts on the development of cardiology. Limits of
      mental and social compliance attitude of the population].
AB  - Medicine in total and cardiology seem to be in state of continuous development.
      However partially unproved theories and therapies at great cost of energy and
      money without scientific proof and cost benefit analysis for patients before
      uncritically and undisciplined thinking or by authorities who support status quo.
      Our basis of the described theories of arteriosclerosis and cholesterol the
      multiple uneffective studies with reduction in levels of plasmalipids must be
      provided. There is also a change of thinking in therapeutical doing in
      infarction, because conservative or invasive therapies do not change mortality
      rates. In Germany usual social benefits just as rehabilitation after infarction
      or cardiac surgery must be checked. The return of medicine to the possible and in
      useful means is the beginning for new theoretical development. Static behavior
      seems to be comfortable, but it stops the necessary changes for the future.

PMID- 8659052
TI  - [Homograft implantation in heart surgery].
AB  - In order to fulfill in the field of cardiothoracic surgery the obligations of
      patient-care and research in a university facility according to the international
      standard it is nowadays absolutely necessary to run a homograft bank.
      Implantation of an allograft is a preferable choice for a number of different
      operations, i.e. in aortic valve endocarditis, complex congenital heart disease,
      Ross' operation and others. Furthermore, in children, women of childbearing age
      and patients in whom anticoagulation is contraindicated, heart valve replacement
      with allografts has become routine. The most important advantages of allografts
      are the excellent hemodynamic qualities and the low risk endocarditis.
      Anticoagulation is not necessary, because there is no risk for thromboembolism or
      hemolysis. For the patients mentioned above, these factors are decisive for their
      quality of life and their prognosis. Because of the shortage of donor organs and
      the priority of heart transplantation over allograft harvesting, the use of
      allografts should be limited to the above mentioned indications, mechanical and
      bioprothetic valves and, just lately available, bioprothetic valves from
      autogenous pericardium are appropriate.

PMID- 8659053
TI  - [Prognosis of depression].
AB  - Contrary to classical psychopathological assessment of the phenomenology of
      depressive states, modern diagnosis tools like the DSM-III-R or DSM-IV rely upon
      the distinction between major depression, dysthymia and depressive symptoms
      during the course of other psychiatric diseases. Within each category, the degree
      of severity is determined and by using a multiaxial approach, different aspects
      of global social functioning, accompanying diseases, and characteristics of
      personality are assessed. Few long-term studies concerning outcome of the
      depressions exist. At least the following factors can be assumed to indicate a
      favorable outcome: minor extent of depressive symptoms at the beginning, no
      severe personality disorder, absence of psychotic symptoms, no alcohol dependency
      or major physical illness, reliable social background, intellectual functions not
      being impaired, and skillful choice of antidepressant drug therapy regimes.

PMID- 8659054
TI  - [Prognostic aspects of panic disorder].
AB  - Panic disorder is considered as a qualitatively distinct form among the anxiety
      disorders. Follow-up studies have demonstrated that the course of panic disorder
      may be chronic. Only one out of ten patients remains completely free of symptoms
      within an observational period of 3 to 7 years. The majority of patients suffer
      long-standing anxiety symptoms which do not significantly interfere with working
      performance or social relationships. Another ten percent of the patients are
      continuously impaired in everyday living by severe symptoms. Long duration and
      severe degree of symptoms at the initial assessment, as well as coexistent
      depression are associated with a poor outcome. There is evidence of an increased
      mortality in patients with panic disorder. Suicides are overrepresented among the
      causes of death. It is not clear whether this is due to the frequent comorbidity
      between panic disorder, major depression, and substance abuse.

PMID- 8659055
TI  - [Expert assessment of chronic fatigue syndrome].
AB  - The Chronic-Fatigue-Syndrome (CFS) has been first described in 1988 and has been
      also in Germany recently more frequently diagnosed. It is similar to a lot of
      other terms, especially to "neurasthenia", which has been introduced 1869 from
      Beard and is now again content of ICD-10. CFS is defined by primary and secondary
      criteria, which are however largely subjective. There are no objective signs. It
      is unknown if this syndrome represents a disease entity of its own. The
      explanation is either exclusive organic based on immunological and virological
      findings or exclusive psychogenic as a special form of anxiety psychosis.
      Possibly are both factors involved as part of "psycho-neuro-immunology". CFS is
      increased subject of medical certification. It has been tried to give a practical
      guidance to the assessment of CFS.

PMID- 8659056
TI  - [Chronic fatigue syndrome--also an insurance medicine problem].
AB  - Not everybody who is chronically tired has a chronic fatigue syndrome. The
      diagnosis of the chronic fatigue syndrome is still a problem, and is becoming a
      problem in health insurance medicine too. There is a lack of knowledge concerning
      the causes, the diagnosis and the therapy of the chronic fatigue syndrome. And
      there is still the question if the chronic fatigue syndrome is an entity of its
      own. For these reasons we should apply the few facts we really know about the
      chronic fatigue syndrome. This is the working case definition of Kaplan et al.
      from 1988. Otherwise there will be done hundreds of expensive laboratory tests,
      which are useless for the patient and very costly for the health insurance
      companies.

PMID- 8659057
TI  - [Amalgam--"etiology" of psychiatric disorders?].
AB  - In a liability lawsuit an expertise had to answer the question whether a mania in
      the course of an affective psychosis could have been caused by chronic mercury
      intoxication resulting from dental amalgam fillings. On the basis of current
      psychiatric and toxicological knowledge, such an association can be disproved.
      Mercury intake from amalgam fillings does not lead to toxic concentrations in
      organs or body fluids. Therefore physicians and dentists should avoid alarming
      patients and thus causing iatrogenic harm.

PMID- 8659058
TI  - [Use of quantum hemotherapy in the combined treatment of rhegmatogenous retinal
      detachment].
AB  - Results of treatment of 53 patients with detachment of the retina of various
      severity, with detachment on aphakic eyes of 6 of these, are analyzed. Various
      method of depressing the sclera with diathermo-, cryo-, or laser coagulation were
      used. Injection of sterile air into the anterior chamber directly before
      depressing the sclera was for the first time added to the complex of
      manipulations for the treatment of detachment of the retina in aphakic eyes; this
      measure helped attain a better contact of the detached retina with the underlying
      membranes. Ultraviolet irradiation of the blood after standard methods was used
      in 25 patients in the postoperative period. Complete adhesion of the retina was
      achieved in 46 patients (86 eyes), this number including all the patients with
      detachment of the retina on aphakic eyes. Ultraviolet irradiation of the blood
      was conductive to a sooner resolution of edema and of uveal and immunological
      symptoms, and improved the treatment efficacy in general.

PMID- 8659059
TI  - [A device for fixing wound edges of fibrous membranes of the eye during
      suturing].
AB  - A new instrument fixing the sutured tissue without compressing, deforming, or
      displacing it has been developed. The needle runs between special lugs of the
      instrument simultaneously fixing the sutured tissue to their surface. Use of this
      fixing device in microsurgical treatment of perforating wounds, keratoplasty, and
      cataract extraction yielded good functional results.

PMID- 8659061
TI  - [Methods of the study of basal lacrimal secretion].
AB  - The authors propose a nontraditional method for the study of basal lacrimal
      secretion, based on biometry of the height of the lacrimal flow meniscus during
      common biomicroscopy. The advantages of this method are shown: it is noninvasive,
      contact-free, available, and informative for assessing basal lacrimal secretion.
      The authors defined the normal value of lacrimal meniscus height in health and
      detected noticeable changes of basal secretion in secondary dry syndrome. Basal
      lacrimal secretion is suppressed in patients with pathologic changes of the
      anterior segment of the eye (relapsing erosions, pterygium, chronic
      conjunctivitis in contact correction, etc.). Prospects for practical use of the
      method are outlined.

PMID- 8659060
TI  - [Corneal astigmatism after refraction keratotomy].
AB  - Refraction keratotomy, by changing corneal refraction, may cause postoperative
      astigmatism, including its reverse form. The author suggests to assess
      astigmatism using astigmatic coefficient (K alpha), which is expressed as the
      cosine of the angle between the vertical and the direction of the stronger main
      meridian. Intra-and postoperative use of fibronectin solution is proposed to
      lower the K alpha and improve the efficacy of surgery.

PMID- 8659062
TI  - [Regularities of drug desorption from soft contact lenses. 2. In vitro study].
AB  - Radiometry of distribution of drugs introduced with soft contact lenses (with 40
      and 70% humor content and thickness of 0.2 and 0.7 mm) in the ocular cavity was
      carried out to compare this mode of drug administration with the traditional
      methods. The maximal concentrations of the drugs in the anterior chamber humor
      and in the vitreous body were attained by using saturated highly hydrophilic 0.7
      mm thick contact lenses. The drug content in the anterior chamber of the eye upon
      such a mode of administration was higher than after injection and much higher
      than after instillation.

PMID- 8659063
TI  - [Comprehensive electrophysiological study of the system of vision in children and
      adolescents with congenital myopia and diseases of the retina and optic nerve].
AB  - Visual evoked potentials were analyzed and general and local electroretinography
      carried out in 83 children and adolescents (145 eyes) aged 7 to 16 with different
      ocular diseases. The latencies of P100 component of evoked potentials reliably
      varied in different clinical groups. The role of electrophysiological studies in
      the differential diagnosis of pathological processes of different localization is
      shown, as is the role of time characteristics of evoked potentials in
      discrimination between the functional and organic disorders in the ocular system.

PMID- 8659064
TI  - [Morphological features of senile and secondary amyloidosis of the iris and
      sclera in patients with glaucoma].
AB  - Morphologic analysis of 173 biopsy specimens of the iris and sclera removed
      during antiglaucoma surgery in 115 patients with open-angle glaucoma revealed in
      44.4% cases extracellular depositions of amyloid, which aggravated the course of
      glaucomatous process and were pathogenetically significant. Amyloidosis was
      revealed in the sclera in 82% cases and in the iris in 70%. Amyloid was detected
      by Congo red staining with control in polarized light and by toluidine blue
      staining for chondroitin and dermatan sulfates. Vascular and muscular (involving
      the pupil muscles) forms of amyloidosis were detected in the iris, pericollagen
      and focal forms in the draining system and sclera. The authors discuss the
      contribution of amyloidosis to the pathogenesis of glaucoma. These findings
      confirm M.M. Krasnov's concept about glaucoma polymorphism.

PMID- 8659065
TI  - [Experimental and morphological results of implantation of carbon felt in plastic
      surgery of the locomotor stump and accessory system of the eye].
AB  - Carbon felt (carbotextime) was used to form a stump after enucleation and for
      plastic repair of the accessory system of the eye in 56 rabbits. Sixteen of these
      animals were controls in whom silicon implants were used. Comparative analysis of
      clinical follow-up of experimental animals showed good results of using carbon
      felt in plastic ophthalmic surgery. Use of silicon implants was associated with a
      more manifest inflammatory reaction, and there were cases of the implant
      migration and spontaneous rejection. No complications in early or late
      postoperative periods were observed in the experimental group. Results of
      morphologic studies of the tissues adjacent to the implant in various periods
      postoperation are presented in detail.

PMID- 8659066
TI  - [Effects of low-intensity infrared laser irradiation on the eye (an experimental
      study)].
AB  - Safe doses of low-intensive infrared laser (LIIL) exposure for the structures of
      the eye were searched for in rabbit experiments, and the potentials of such
      lasers in ophthalmology were assessed. Uzor, a therapeutic laser device with
      gamma = 0.89 mm, was employed. The doses varied from 0.0001 to 1.0 J/cm2, this
      corresponding to exposure duration of 0.3 to 45 min. Experiments were carried out
      on 20 animals. The right eyes were exposed, and the left ones were control. An
      increase of intraocular pressure was recorded at a dose of 0.1 J/cm2 (4.5 min)
      and higher; morphological study showed dilated, well-filled and newly formed
      vessels in the ciliary body and iris, as well as edema and destruction of the
      external layers of the retina. Exposure to a dose of 0.05 J/cm2 and lower did not
      lead to destruction of ocular structures and increase of intraocular pressure.
      The maximal LIIL dose causing no side effects for the organ of vision was
      established at 0.05 J/cm2, this corresponding to 2.5 min exposure.

PMID- 8659067
TI  - [Use of laser speckle in occupational eye diseases].
AB  - Forty-one diamond sorters aged 18 to 45 with occupational ophthalmopathy
      (asthenotopic complaints and accommodation disorders) were treated. In 35 female
      workers the vision acuity without correction was equal to 1.0, in 5 to 0.2-0.8
      because of slight myopia. He-Ne LG-52-2 laser specle was used in the treatment.
      The training was carried out using modified method of accommodation "swinging"
      after V.V. Volkov and L.N. Kolesnikova. The course of treatment lasted for 10
      days. The most appreciable shifts occurred in the nearest vision zone. The
      nearest point became closer to the eye by 0.55 +/- 0.02 diopters, the furthest
      became still further by 0.33 +/- 0.01 diopters. Relative accommodation reserve
      increased by 0.34 +/- 0.03 diopters. Asthenotopic complaints completely
      disappeared in 25 subjects and noticeably reduced in 4. Such exercises are
      recommended for subjects with asthenopia engaged in precision work.

PMID- 8659069
TI  - [Incidence of eye diseases in inhabitants of the Koryak Autonomous Territory].
AB  - This study was aimed at comprehensive examination of the visual status of
      residents of the Northern regions within the frames of investigations on the
      problem of vision deterioration in the residents of the North. The study covered
      seven regions of the Koryak Autonomous Territory. A total of 1067 patients were
      examined, 30% of these were children aged mostly from 6 to 12. About half the
      examinees were indigenous population of the North. On the whole, the results
      coincide with previous findings. At the same time, the incidence of myopia is
      somewhat higher than 10-15 years before. This increase is caused by two principal
      groups of factors: social and visual. The authors emphasize that the level of
      ophthalmologic care of the population in the Northern regions is to be improved
      and measures preventing diseases of the organ of vision be strictly adhered to.

PMID- 8659068
TI  - [Visual disability in children of Moscow: causes, structure and ways of
      prevention].

PMID- 8659070
TI  - [Treatment of primary open-angle glaucoma by the method of combined use of
      hyperbaric oxygenation and antioxidants].
AB  - Thirty-five patients (64 eyes) with primary open-angle glaucoma were treated by
      hyperbaric oxygenation combined with antioxidants. Repeated courses were
      administered during 5 years. Stabilization of the visual function was attained in
      80% patients. Follow-up of controls (34 patients-66 eyes) showed stabilization of
      the visual function in but 35% cases. The said treatment is possible both on an
      inpatient and outpatient basis.

PMID- 8659071
TI  - [Clinical and epidemiological aspects of diabetic retinopathy and its
      relationship with diabetic nephropathy].
AB  - Results of clinical and laboratory examinations of 161 diabetics are presented.
      The main factors or risk of nonproliferative diabetic retinopathy are the
      duration and degree of compensation of diabetes mellitus, development and stage
      of diabetic nephropathy, the latter factor replacing in experiments with
      simulation of diabetic retinopathy the level of arterial hypertension, and the
      blood serum content of high-density lipoprotein cholesterol and ratio of total
      cholesterol to high-density lipoprotein cholesterol. The factors of risk of
      proliferative diabetic retinopathy are duration and degree of compensation of
      diabetes mellitus, development and stage of diabetic retinopathy with this latter
      factor replacing in simulation of diabetic retinopathy the level of arterial
      hypertension, and the blood serum levels of triglycerides, low-density
      lipoprotein cholesterol, fibrinogen, soluble fibrin-monomer complexes, as well as
      fibrinolytic activity.

PMID- 8659072
TI  - [Immune and microcirculatory disorders in patients with diabetic retinopathy and
      their correction].
AB  - Secondary immunodeficiency after a relative hyposuppressor variant and
      microhemodynamic disorders whose severity augmented with the severity of ocular
      disease were detected in patients with diabetic retinopathy. The maximal shifts
      were observed in patients with proliferative diabetic retinopathy. The immune and
      microcirculatory shifts were closely related to each other. Addition of the drug
      antral to therapeutic complexes for patients with common diabetic retinopathy was
      conducive to rapid normalization of the immune status and microhemodynamics, thus
      improving the functional activity of the retina.

PMID- 8659073
TI  - [Viral hepatitis B as a factor in the etiology of cataracts in adults and
      children].
AB  - Vacuoles, aqueous fissures, crumb-like opacities, color iridescence, and
      thickening under the posterior capsule in the lens were found in 86% of 45
      patients with chronic active hepatitis B, mean age 33 +/- 2.5 years. Seven
      percent of patients developed posterior capsule cataracts. examinations of 42
      patients with cirrhosis of the liver caused by hepatitis B virus (mean age 39 +/-
      2 years) revealed changes in the lens in 100% and mature cataracts in 36% of the
      eyes. In 2 of the 4 healthy HBsAg carriers aged 31 to 35 initial changes in the
      lens and accumulation of antilenticular antibodies in the lacrimal fluid and
      serum. A reliable difference by all the tested parameters between the examinees
      and controls (HBsAg-negative age-matched blood donors, n = 20) confirms a
      relationship between hepatitis B infection and lenticular abnormalities in
      subjects of a productive age. Markers of hepatitis B virus (HBsAg, HBeAg, anti
      HBs, anti-HBe, anti-HBc) were found in the lenticular mass and blood sera of 11
      out of 14 children aged 1.5 to 4 operated on for congenital nonhereditary
      cataracts; in 4 of them viral replication still continued. HBV markers of chronic
      viral carriership or markers of potential contagiousness were found in the sera
      of their mothers (in 6 and 5 sera, respectively), this indicating a possible
      intrauterine infection of children. The findings evidence a possible etiological
      role of hepatitis B virus infection in the formation of congenital and early
      acquired cataracts.

PMID- 8659074
TI  - [Eye lesions in patients with pulmonary sarcoidosis].
AB  - Experience gained by ophthalmologists at Center for Sarcoidosis control is
      summarized. Sarcoidosis involvement of the eyes was revealed in 36% of patients
      with sarcoidosis of the respiratory organs. Uveitis and dry keratoconjunctivitis
      typical of sarcoidosis involvement of the eyes are described. A protocol of
      ophthalmologic examination of sarcoidosis patients to detect ocular diseases and
      monitor the treatment efficacy is offered. The knowledge of ocular symptoms in
      sarcoidosis patients by public health ophthalmologists will help diagnose the
      disease at the period when there are no apparent changes, the clinical signs are
      hardly discernible, and only the ophthalmological picture permits the physician
      suspect sarcoidosis and direct the patient to a tuberculosis center.

PMID- 8659076
TI  - [Toxic lesions of the optic nerve].

PMID- 8659075
TI  - [State of microcirculation in the bulbar conjunctiva in retinal thrombosis of
      patients with hypertension and diabetes mellitus].

PMID- 8659077
TI  - [Possibilities of magnetotherapy in stabilization of visual function in patients
      with glaucoma].
AB  - Courses of magnetotherapy (MT) using ATOS device with 33 mT magnetic field
      induction were administered to 31 patients (43 eyes) with primary open-angle
      glaucoma with compensated intraocular pressure. The operation mode was
      intermittent, with 1.0 to 1.5 Hz field rotation frequency by 6 radii. The
      procedure is administered to a patient in a sitting posture with magnetic
      inductor held before the eye. The duration of a session is 10 min, a course
      consists of 10 sessions. Untreated eyes (n = 15) of the same patients were
      examined for control. The patients were examined before and 4 to 5 months after
      MT course. Vision acuity improved by 0.16 diopters, on an average, in 29 eyes
      (96.7%) out of 30 with vision acuity below 1.0 before treatment.
      Visocontrastometry was carried out using Visokontrastometer-DT device with
      spatial frequency range from 0.4 to 19 cycle/degree (12 frequencies) and 125 x
      125 monitor. The orientation of lattices was horizontal and vertical. The
      contrasts ranged from 0.03 to 0.9 (12 levels). MT brought about an improvement of
      spatial contrast sensitivity by at least 7 values of 12 levels in 22 (84.6%) out
      of 26 eyes and was unchanged in 4 eyes. Visual field was examined using Humphry
      automated analyzer. A 120-point threshold test was used. After a course of MT,
      visual field deficit decreased by at least 10% in 31 (72%) out of 43 eyes,
      increased in 3, and was unchanged in 9 eyes; on an average, visual field deficit
      decreased by 22.4% vs. the initial value. After 4 to 5 months the changes in the
      vision acuity and visual field deficit were negligible. In controls these
      parameters did not appreciably change over the entire follow-up period.

PMID- 8659078
TI  - [A method of direct electrophoresis of the optic nerve in patients with far
      advanced glaucoma].
AB  - A new method for the treatment of diseases of the optic nerve and posterior
      segment of the eyeball is proposed: direct electrophoresis. Surgical treatment of
      85 patients with far-advanced glaucoma in combination with the said method helped
      attain a reliable improvement of the vision acuity, of the total visual field, of
      critical frequency of flashing fusion, and of the linear velocity of the blood
      flow in the ocular artery in the majority of patients. This method holds good
      promise in the treatment of partial atrophies of the optic nerve of different
      origin, including the descending ones, and of dystrophic conditions of the
      posterior segment of the eye.

PMID- 8659079
TI  - [Leptospirosis in slaughter cattle--serologic and bacterial study].
AB  - Antibodies to leptospiras were demonstrated in 91 cases (7.4%) out of 1,239
      animals examined by serological assays of blood sera of cattle slaughtered in
      slaughter-houses and coming from 21 farms of one district. The antibodies were
      detected in animals coming from eleven out of the farms investigated (52.4%). The
      most frequent reactions were proved with leptospiras of the serovar L.
      grippotyphosa (61.8%) and with leptospiras of the serological group Sejroe
      (18.9%), rarely with leptospiras of the serovar L. icterohaemorrhagiae or
      copenhageni (5.7%). Antibodies to leptospiras of other serovars (L. canicola, L.
      bulgarica and L. hardjo) were demonstrated only as coagglutionations with the
      above-mentioned leptospira serovars. We failed to demonstrate leptospiras in the
      animals examined by culture examinations as well as by bacterioscopy. The results
      of examinations have shown that the cattle on Czech farms is also exposed to
      infections by various serovars of leptospiras. The infections are not accompanied
      by manifest clinical symptoms in many cases nor do they cause significant
      elimination of leptospiras in urine in the serologically positive animals. On the
      Czech cattle farms the occurrence of antibodies to leptospiras of the serovar L.
      grippotyphosa is prevailing; this serovar seems not to be expressly pathogenic to
      cattle and does not cause the formation of anthropurgic foci. Reduction in the
      occurrence of antibodies to leptospiras of this type is possible to achieve by
      preventing the contact with natural foci of this type. Hence the prognosis of
      epizootologic situation in bovine leptospirosis in the conditions of this country
      is relatively favorable. But special attention should be paid to animals bought
      and imported from foreign countries. These animals could be a source of some
      highly pathogenic serovars of leptospiras to cattle.

PMID- 8659080
TI  - [The effect of Lactobacillus salivarius administration on coliform bacteria and
      enterococci in the crop and cecum of broiler chickens].
AB  - A rifampicin-resistant Lactobacillus salivarius 51R was isolated from chicken
      caeca and administered orally to newly hatched broiler chickens. The resistance
      to rifampicin enabled us to differentiate the administered organism from
      indigenous strains. First day after inoculation, L. salivarius 51R dominated
      among lactobacilli in the crop and caeca of inoculated chickens and its counts
      were slightly over 7 log c.f.u. per 1 g of digesta even after 10 days. L.
      salivarius significantly (P < 0.01) lowered counts of enterococci and coliforms
      in the crop during the whole experimental period (10 days). Effects of L.
      salivarius administration on caecal counts other than lactobacilli were generally
      small. The influence of Lactobacillus strain used to species composition of
      enterococci and coliforms were also observed. 105 strains of enterococci and 96
      strains of coliforms isolated from the crop and caeca of both control and
      experimental groups were characterized using identification sets and computer
      program. Regarding, enterococci, 63% was identified to the species level, 31% to
      the genus level, and 6% was not identified. Regarding coliforms, 48% was reported
      to the species level, 25% to the genus level, and 26% was not identified. The
      most prevalent species among the enterococci was E. faecalis and among the
      coliforms E. coli. 24 h after the administration of L. salivarius 51R there was
      significantly higher (P < 0.05) occurrence of E. faecalis (57% out of all
      enterococcal isolates) in experimental group than those in the control group (31%
      out of all enterococcal isolates). The perspectives in the control of pathogens
      in young chickens via probiotics was discussed.

PMID- 8659081
TI  - Characteristics of enterococci and staphylococci isolated from the crop and
      caecum of Japanese quails exposed to microgravity conditions.
AB  - Ten selected strains of enterococci and staphylococci were isolated from the crop
      and caecum of Japanese quails exposed to microgravity conditions. Isolates were
      allotted to the species Enterococcus gallinarum, Ent. avium, Ent. faecium,
      Staphylococcus gallinarum and Staph. aureus. Isolated strains were facultatively
      anaerobic, non-motile, Gram-positive cocci, occurring in pairs, short chains or
      irregular clusters. Isolates utilized most of the soluble sugars tested and
      produced bacteriocin-like substances. Enterococci and staphylococci were
      resistant to monensin (50 mg/l) and sensitive to tylosin and virginiamycin (10
      mg/l).

PMID- 8659082
TI  - Use of a polyurethane carrier for assessing the survival of helminth eggs in
      liquid biological sludges.
AB  - Soft expanded polyurethane (plastic foam) was used as an egg carrier. A carrier
      of helminth eggs and a method for their isolation were tested. They proved
      applicable to evaluation of the survival of helminth eggs in liquid biological
      substrates (sludges, liquid excrements). The inside of the carrier was inoculated
      with 1,000 +/- 50 Ascaris suum eggs. After 21 days of incubation in an aerated
      medium at room temperature, 660.7 (66.1%) eggs were isolated on the average (n =
      10, Tab. I). The carriers incubated in the medium at 4 degrees C yielded 716.2
      eggs (71.6%) on the average (Tab. II). The intactness of the carriers in helminth
      eggs was proved during 21 days of incubation in aerated medium when the detected
      mean percentage of embryonated eggs was 80.5% (Fab. I). From the carriers kept at
      4 degrees C for 21 days and subsequently incubated 76.6% of embryonated eggs were
      recovered on the average (Tab. II). Control showed 80.95% of embryonated eggs on
      the average, which is a statistically insignificant difference (P < 0.05). With
      the use of the carrier more than a 13-fold increase in the viable eggs was
      recorded, compared with a 5% yield obtained at a direct inoculation into liquid
      substrates. This method is rewarding for its optimization of experimental results
      and for reducing the number of eggs used in the experiments.

PMID- 8659084
TI  - [Cryptosporidia and other endoparasites in heifers imported into the Czech
      Republic].
AB  - Totally 887 heifers of Holstein-Friesian breed mostly in late pregnancy imported
      to the Czech Republic from France (597), Germany (89), Denmark (181) and Holland
      (20) were examined coprologically from September 1993 to March 1995 in the
      parasitological laboratory of the National Veterinary Institute (NVI). Prague.
      Feces were sampled individually, rectally, always on days 1-3 following
      importation from heifers housed in particular quarantine sheds. In compliance
      with presently valid veterinary regulations, all animals were examined for liver
      fluke disease (fascioliasis) and lungworm. Moreover, 634 heifers were submitted
      to qualitative coprological examination aimed at revealing the presence of cysts
      and oocysts of protozoa, eggs of taenias and nematodes of gastrointestinal tract.
      The method according to Pavlasek (1991), especially designed for proving oocysts
      of the genus Cryptosporidium, was applied in all fecal specimens delivered to the
      SVI from animals in quarantine (N = 887). From trematodes, 12 heifers imported
      from France were positive for eggs of Fasciola hepatica and in other two animals
      eggs of the genus Paramphistomum were found. None of the imported heifers showed
      lungworm disease. Summary of data on occurrence of endoparasites gained during
      qualitative examination of samples of feces taken from heifers imported from
      France, Germany and Denmark is presented in Tab. I. Parasitologically, 91.2 to
      100% of imported animals were positive. Taeniasis (the genus Moniezia) was
      detected in 2.8% of heifers imported from France and in 9.8% animals from
      Denmark. Protozoal parasites were found in 58.8% (Denmark) and 92.8% (Germany)
      heifers. Coccidial oocysts most frequently observed represented the genus Eimeria
      (E. bovis, E. auburnensis and E. zuernii). Gastrointestinal nematodes of nine
      genera were found in 72.5 to 80.8% of heifers. The most frequent findings were
      genera Ostertagia, Haemonchus and Trichostrongylus. Oocysts, morphologically
      identical with Cryptosporidium muris Tyzzer (1907), 1910, were detected in 4.5%
      of heifers imported into the Czech Republic from France and in 7.9% of those from
      Germany. In view of the fact the imported heifers were sampled always on days 1-3
      of their quarantine following their importation it is quite impossible,
      considering the development of the protozoon, they could become infected just in
      the territory of the Czech Republic. Therefore, with the highest probability, our
      findings of C. muris-like oocysts in heifers are of priority importance for
      France and Germany because in the literature these countries do not report cattle
      as a host of this protozoon. We have found out 57.9% out of 19 animals positive
      for C. muris on one farm of a private cattle keeper. On the basis of a long-term
      monitoring of three dairy cows and one bull, the duration of the patent period is
      longer than 18 months, while we do not know precise onset of shedding oocysts of
      the protozoon in these naturally infected animals. Furthermore, the paper
      discusses the need of future studies of C. muris from the point of view of
      spread, pathogenicity, specificity and host spectrum. The author proposes and
      recommends obligatory examinations of imported animals with special attention
      paid to presence of coccidia of the genus Cryptosporidium in order to maintain,
      with respect to their zoonotic character, these protozoal infections under proper
      control. At present the parasitological laboratory of the NVI in Prague has a
      bank of oocyst isolates of the C. muris type from cattle (Bos taurus), from
      desert hamsters (Phodopus roborovskii Satunin, 1903) and camels (Camelus
      bactrianus). Experimental infections is permanently kept in laboratory mice
      following successful transmission from desert hamsters.

PMID- 8659083
TI  - Comparison of mouse and chick embryo liver and hepatoma cell lines as model
      systems used for enzymological estimation of toxicity potentials of organic
      pollutants.
AB  - Cytochromes P450-dependent monooxygenase activities were determined and compared
      in mouse liver microsomes and in hepatoma cell homogenates after exposure to
      prototype inducers of individual P450 enzymes. In vivo inductions of levels of
      mouse hepatic monooxygenase activities have been found as effective biochemical
      markers of toxicity potentials of a series of classes of xenobiotics (CYP1A
      induction for toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, coplanar
      polychlorinated biphenyls, polycyclic aromatic hydrocarbons and related
      pollutants; CYP2E induction for dialkylnitrosamines and organic solvents, e.g.
      acetone and ethanol; CYP2B and CYP3A induction for phenobarbital- and
      dexamethasone-type of xenobiotics). A specific induction of CYP1A-dependent O
      dealkylase activities by TCDD was found in Hepa-1 and Hep G2 cell cultures, but
      no in vitro induction of other P450 enzymes was found after the treatment with
      phenobarbital, acetone or dexamethasone. Therefore, mouse liver is a suitable in
      vivo system for the testing of inducing effects of xenobiotics on all relevant
      P450 forms, while hepatoma cell cultures are usable only for the bioassay of TCDD
      like toxicity.

PMID- 8659085
TI  - [The effect of monensin on a rumen strain of Enterococcus faecium CCM 4231].
AB  - Monensin from three different manufacturing companies (Eli Lilly Co.,
      Indianapolis, USA; Pharmachim, Bulgaria; Spofa Prague, Czech Republic) were added
      to pure cultures of rumen strain Enterococcus faecium CCM 4231 at final
      concentrations 25 micrograms per ml and 50 microgram per ml. Enterococci
      represent a strong bacterial group colonizing the rumen regarding to lactic acid
      production. Ent. faecium CCM 4231 is own, lactic acid-producing isolate from the
      rumen content of calf with a broad antimicrobial activity (bacteriocin
      production). This strain was obtained in the microbial preparation Inhicol to
      protect enteritis in young ruminants, especially. The growth of CCm 4231 strain
      was inhibited at both concentrations (25 microgram/ml; 50 micrograms/ml) using
      all three monensins in comparison with controls (Figs. 1 and 2). The beginning of
      the growth inhibition was detected within 2 hours after ionophore addition.
      Monensin made in Bulgaria was the most effective of all when the three monensins
      were compared. No significant differences are found in the effect of monensins
      made in different production companies. Our results extend the knowledge about
      inhibition effect of monensin on Gram-positive bacteria, enterococci including.
      Moreover, the quality of monensins made by different companies is attested
      synchronous. In general, regarding the practical point of view, it is also
      contribution for the selection and application of the most suitable additives.

PMID- 8659086
TI  - [The effect of carbimazole on lactate dehydrogenase isoenzymes and thyroid
      hormone levels in sheep].
AB  - The oxidative processes in the organism are activated by hormones of the thyroid
      gland. The pyruvate-lactate component catalyzed by lactate dehydrogenase presents
      one of the important oxidic-reductive systems in the animal organism of
      biochemical importance (EC. 1.1.1.27). In certain cases of the thyroid gland
      disturbances antithyroid drugs, such as derivatives of thiouracil,
      mercaptoimidazole and some others may be used for the treatment of men and
      animals (Marchant et al., 1979; Negwer, 1987). In the present study, the activity
      changes of lactate dehydrogenase isoenzymes in the blood plasma of young rams and
      ewe hoggets in experiments with carbimasole [carbimasolum(1-carbaethoxy-3-methyl
      2-thioimidazolum) ] have been studied. The dose of carbimasole at the time of
      sampling (May, 1993) was 7O mg per animals and day. In May, no significant
      differences in T3 and T4 concentrations in the serum of experimental and control
      animals in males and females were found (Tab. 1). The T3 concentrations in the
      experimental group of young rams were 0.56 +/- 0.21 nmol/l (n = 3), in ewe
      hoggets 0.70 +/- 0.19 nmol/l (n = 6). The T4 concentrations in young rams were
      39.15 +/- 24.15 nmol/l (n = 3), in ewe hoggets 48.6 +/- 15.3 nmol/l (n = 6). Out
      of lactate dehydrogenase isoenzymes, only LD4 exhibited significant differences
      (P < 0.02) in the blood plasma of ewe hoggets (Tab. I). In the course of these
      months, no clinical signs of hypothyrosis were observed in experimental animals.

PMID- 8659087
TI  - [Thyroid and ovarian hormones in ewes treated with gestagens and PMSG in the
      spring season].
AB  - Recent experimental observations have shown that the thyroid gland plays a
      dominant part in the induction and maintenance of anoestrus in ewes. The
      mechanisms of the anoestrous effects of the thyroid gland are still unclear. On
      the basis of experiments, in which after thyroidectomy at the onset of sexual
      activity LH production was maintained also during the spring months,
      iodothyronines have been supposed to stimulate the inhibitory effects of
      oestrogens upon the neuroendocrine centres that generate pulsatile LH secretion
      (Moenter et al., 1991; Webster et al; 1991). However, in our previous work
      (Bekeova et al., 1995) we observed significant changes in iodothyronine levels,
      mainly T3, in ewes treated with FSH, LH-RH and oxytocin-based preparations in 24
      and 72 h after parturition in the spring. Having made the above observations we
      suppose seasonal anoestrus to result rather from changes in thyroid and ovarian
      hormone interactions or from a decrease in thyroid hormone levels that is induced
      by a temporary decrease in sexual hormones in this phase of the year. Within
      investigations into the effects of thyroid hormones and their interactions in
      spring this study focused on the response of the thyroid gland and ovaries in
      anoestrous ewes to chlorsuperlutin and PMSG treatment in the second half of May.
      Eighteen Slovak Merino ewes were divided into an experimental and a control group
      counting 15 and 3 animals, respectively. The experimental animals were each
      treated with 20 mg chlorsuperlutin (Agelin Spofa vaginal inserts) for 12 days. On
      day 12 the inserts were removed and each animal was given 500 IU PMSG. In the
      same time intervals the controls were treated with a placebo (sterile
      polyurethane, saline). Blood samples were obtained prior to swab insertion (day
      0) and in 4-day intervals under chlorsuperlutin treatment (days 4, 8 and 12). For
      the first 24 h after PMSG-treatment blood samples were taken in 2-hour intervals
      and then in 48 and 72 h. For radioimmunological determination of T4, T3, E2 and
      P4 levels the RIA-test-T4, RIA-test-T3, RIA-test-Estra and RIA-test-Prog
      commercial kits (manufacturer: URVJT Kosice, Slovak Republic) were used,
      respectively. When compared to the almost constant but significantly lower T4
      values in the controls (P < 0.05; P < 0.01; Tab. II, Fig. 1), a repeated massive
      release of T4 occurred in the experimental animals (Tab. I, Fig. 1). Its first
      peak observed 4 h after PMSG was significant in comparison both to Day 0 and the
      controls (P < 0.05 and P < 0.01, respectively). The same was true for the 2nd
      peak observed 20 h after PMSG-treatment (P < 0.001 and P < 0.01, respectively).
      The dynamics of T3 was similar in both groups. The transitory increase in T3
      levels observed in the controls (Tab. II, Fig. 2) on day 4 of chlorsuperlutin
      treatment was insignificant when compared to day 0. Both the decrease observed
      between day 8 and of chlorsuperlutin treatment and 20 h after PMSG gavage, and
      the increase between 24 and 72 h appeared to be insignificant. Comparison to day
      0 revealed increased T3 levels in the experimental group (Tab. I, Fig. 2) on days
      4 and 8 of chlorsuperlutin treatment, the levels of significance being P < 0.01
      and 0.05, respectively. Between 8 and 24 h after PMSG-gavage, in contrast to the
      controls, T3 levels in the experimental animals acquired the character of a
      slowly increasing rhythmic pulsation. At 72 h after PMSG a significant decrease
      occurred (P < 0.05). In the control animals (Tab. II, Fig. 3) E2 levels revealed
      interchanging episodes of insignificant increase and decrease beneath test
      sensitivity. In the experimental ewes (Tab. I, Fig. 3) a double-peaked elevation
      of E2 could be observed, the first (insignificant) peak occurring 18 and 20 h and
      the second (significant) one 48 and 72 h following PMSG treatment (P < 0.05 and
      0.01, respectively). The inter-group differences were significant at the level of
      P < 0.05 in each case.

PMID- 8659088
TI  - The effect of cadmium treatment on breeding hens and cocks and early viability of
      their chickens.
AB  - The effect of cadmium, with and without selenium, on breeding hens and cocks and
      their offspring up to 7 days of age was studied. In adult birds, the body weight,
      mortality rate, pathological changes and cadmium level were determined. In
      chicks, the mortality rate and level of cadmium were evaluated. Cadmium as
      cadmium chloride was orally administered to the hens at three dosages: 3 ppm, 20
      ppm and 30 ppm + 4 ppm of selenium. Cadmium levels in the muscles, liver and
      kidneys of laying hens analysed after 60 days and those of chicks after 30 and 60
      days of the experiment. Cd determinations were conducted by the method of
      electrothermic atomization, using an atomic absorption spectrophotometer. Body
      weight in laying hens was maintained at the control level, while in cocks it
      slightly increased in all experimental groups. In the adult birds, no mortality
      occurred while 0.25 - 1.11% mortality was observed in chicks. The results showed
      a variability in cadmium levels in hens, according to the dosage applied. These
      levels were high in the kidneys and liver, and lower in the muscles. A non
      significant increase of cadmium level was found in the liver and kidneys of
      chicks after the first month of application. The addition of selenium resulted in
      a reduction of cadmium level in the liver and kidneys of laying hens but not in
      the muscles. Gross pathological and histological changes in the kidneys and liver
      were observed in groups fed 20 ppm and 30 ppm of cadmium.

PMID- 8659089
TI  - [Combined parenteral and oral immunization against enterotoxigenic Escherichia
      coli diarrhea in weaned piglets].
AB  - Experiments were focused on diarrhea prevention in weaned piglets caused by
      enterotoxigenic strains of Escherichia coli (ETEC) with colonizing factor 8813.
      An immunization procedure consisted of intramuscular application of ETEC strain
      bacterin a day before weaning and a peroral administration of a live culture of
      nontoxic E. coli strain with the same colonizing factor on the day of weaning. In
      an experiment on the litter of 10 piglets (six were immunized, four were
      controls), their intestines were colonized by the nontoxic E. coli strain for 4-7
      days (Fig. 1). The challenge peroral infection by virulent ETEC strain
      demonstrated the protection of immunized piglets from the disease as well as from
      intestinal colonization by the administered ETEC strain. The same immunization
      procedure was tested on three pig farms with enzootic occurrence of diarrheas in
      weaned piglets. On these farms, besides ETEC strain with colonizing factor 8813
      (F18) ETEC strains with other colonizing factors (K88, F not specified) were
      found out in the weanlings - Tab. I. Immunization effect was evaluated according
      to the rate of mortality of immunized and nonimmunized piglets within a fortnight
      after weaning. Out of 222 immunized piglets on S farm (Tab. II), 25 piglets died
      (11.3%), out of 232 nonimmunized animals it was 39 that died (16.8%). As for T
      farm (Tab. III), 22 piglets (8.6%) died out of 255 immunized animals while 71 out
      of control 274 piglets died (25.7%). A total of 3,692 were immunized on V farm
      (Tab. IV). Ninety-four animals died among them (2.5%). Mortality rate in the
      control group of 6,301 animals was 523 piglets (8.3%).

PMID- 8659090
TI  - [Heavy metal poisoning in relation to glucose-6-phosphate dehydrogenase activity
      in sheep erythrocytes].
AB  - Peroxidative lesions of cells and production of free radicals from endo- and
      exogenous reasons, eg. due to air pollution, can result in severe lesions of
      cells and subsequent pathological processes (Rieger, 1992; Robbins and Cotran,
      1988). A pentose cycle plays an important role in the system of antioxidative
      protection: glucose-6-phosphate dehydrogenase (G-6-PD; EC 1.1.1.49) is its first
      enzyme. G-6-PD activity was evaluated in the erythrocytes of sheep kept in the
      region contaminated by heavy metals with mercury dominating among them, and in
      the same animals after administration of a feed mixture containing Hg, Pb Cd, Zn
      Cr, Cu, Fe and As (Fig. 1). Boehringer Mannheim test was used to determine the G
      6-PD activity. There was no significant differences in the enzyme activity in the
      sheep from a contaminated region and in the animals outside the air-pollution
      region (control animals) before the applications of heavy metals started. The
      average value of G-6-PD activity was 13.96 +/- 0.94 mU.10 (-9) Ec in control
      animals and 14.39 +/- 1.49 mU.10 (-9) Ec in the animals from a contaminated
      region. After eight-day applications of heavy metals the G-6-PD activity
      increased statistically significantly to 18.71 +/- 2.45 mU.10 (-9) Ec; P < 0.01,
      and to 23.55 +/- 1.87 mU 10 (-9) Ec after 16 days of application; P < 0.001 (Fig.
      2). An increase in G-6-PD activity after heavy metal applications is probably a
      compensation mechanism in the system of erythrocyte antioxidative protection due
      to higher peroxidation. The long term increased intake of heavy metals from
      polluted air did not lead to any rise of G-6-PD activity probably due to the
      lower dose of heavy metals and/or to adaptation of animal organisms to long run
      emission exposure. The results demonstrate that G-6-PD can be one of the
      biochemical indicators at organism load by heavy metals with mercury dominating
      among them.

PMID- 8659091
TI  - [The effect of supermethrin, an insecticide, on health status indicators in sheep
      during subchronic poisoning].
AB  - The effect of supermethrin on the overall health with respect to weight gains,
      diet intake, triad values (body temperature, pulse rate and breathing rate) and
      potential intoxication signs was investigated in sheep of the Slovak Mertino
      breed (age of 8 months, males and females) during 6-week feeding of the
      insecticide supermethrin (Research Institute of Chemical Technology, Bratislava).
      This insecticide supermethrin contains a cyanide group in its molecule and can be
      included in the group of type II pyrethroids. It is an analog of cypermethrin and
      it has a different proportion of cis- and trans-isomers. Supermethrin mixed with
      molasses feed M was administered daily at a dose of 50 mg/kg (about 1/70 of LD50)
      to five sheep of experimental group I, at a dose of 200 mg/kg (about 1/15 of
      LD50) to five sheep of experimental group II, and the dose increased from 200 mg
      to 300 mg/kg l.w. (about 1/20 of LD50) since the fourth week of trial. The main
      signs of its toxic action involved depressive effects on weight gains (Fig. 4)
      Over the whole period of trial, the live weight rose by 5.44 +/- 1.94 kg in
      control group, by 2.66 +/- 1.48 kg in experimental group I, which equates a
      significant decrease by 51.10% and only 0.34 +/- 0.95 kg in experimental group
      II, which equates a decrease in weight gains by up to 93.75% against the control.
      We do not believe that the growth depression can be related to diet intake. There
      were no larger differences in feed intake between the experimental groups and the
      control. The growth depression was caused by incessant diarrhea. The patho
      morphological examination did not reveal hyperemia and/or intestinal
      inflammation, the histological examination did not show any lesions of epithelium
      in the intestinal mucosa. An increase in supermethrin dose from 200 to 300 mg/kg
      l.w. resulted in signs coming from the CNS. Hypersensibility manifested by
      moderate unrest, head and neck shaking after auditory, and especially after touch
      stimuli was observed. This tremor was increasing to became spontaneous 3-4 days
      before trial termination. The above findings clearly suggest that supermethrin
      administration at lower doses has harmful effects primarily on the digestive
      tract, but at higher doses these effects are more intensive accompanied by the
      effects on the CNS. No negative effects on pulse rate (Fig. 1), breathing rate
      (Fig. 2) and internal body temperature (Fig. 3) were recorded.

PMID- 8659092
TI  - [Toxicologic evaluation of supermethrin, a pyrethroid insecticide, in rabbits and
      pheasants].
AB  - Basic information about a toxicologic hazard of the pyrethroid supermethrin
      (Research Institute of Chemical Technology, Bratislava) is presented in this
      paper for the conditions of acute intoxication in rabbits and pheasants and in
      the conditions of subacute intoxication in pheasants. The insecticide
      supermethrin under observation contains a cyanide groups in its molecule and can
      be included in the group of type II pyrethroids comprising among other substances
      also cypermethrin. Supermethrin is an analog of the latter and it has a different
      proportion of cis- and trans-isomers. At acute intoxication, supermethrin was
      applied to adult rabbits at doses of 2,000; 3,000; 4,000; 5,000 and 6,000 mg/kg
      and to adult pheasants at doses of 2,000; 4,000; 5,000 and 6,000 mg/kg live
      weight. Supermethrin dissolved in sunflower oil at a 1:2 ratio was administered
      in the above differentiated doses at single application by a peroral tube. Not
      even the highest supermethrin dose (6,000 mg/kg live weight) caused any clinical
      signs of intoxication in the birds. This fact suggests that its LD50 for rabbits
      and pheasants will apparently exceed the value of 6,000 mg/kg l.w. At subacute
      intoxication, supermethrin was applied as dissolved in sunflower oil (at a 1:2
      ratio) by per os tube at a dose of 500 mg/kg l.w. once a day within five days.
      The subacute doses of supermethrin did not induce, besides mild diarrhea at the
      end of the trial, any other clinical signs of intoxication in the pheasants. The
      negative effect of supermethrin (even though negligible) on the digestive tract
      of pheasants is in agreement with the results determined in sheep in the
      conditions of subchronic intoxication (Neuschl et al., 1995), Supermethrin
      administration in sheep resulted in permanent and intensive diarrheas. These
      findings clearly indicate that supermethrin administered at lower doses primarily
      affects the function of digestive tract. Tab. 1 shows the effect of supermethrin
      on the live weight of pheasants in the conditions of subacute intoxication. The
      negligible decrease in live weight recorded at the end of the trial was not due
      to supermethrin effects. It was also recorded in the control group. There were no
      significant differences between the control and experimental group. It was
      probably induced by the stress resulting from daily applications of the tested
      substance. In case the guidelines for its areal application (140 g/ha) are
      observed, it will not be toxic for rabbits and pheasants nor probably for hares
      and/or other gallinaceous birds. Supermethrin seems to be a little toxic
      substance according to WHO (1975) classification.

PMID- 8659093
TI  - Light and scanning electron microscopy of endometrium of ovariectomized cows
      treated with oestradiol.
AB  - Histomorphological and histochemical investigations showed that a single
      intramuscular dose of 3 mg or oral dose of 10 mg oestradiol were sufficient to
      induce physiological oestrogenization of endometrium in ovariectomized cows. The
      first signs of endometrial activation were observed already on post-treatment Day
      2. The resumption of secretory activity of surface epithelium cells and
      epithelial cells of proximal segments of uterine glands, active hyperaemia,
      slight oedema of lamina propria, and infiltration with cells responsible for non
      specific resistance of endometrium (lymphocytes, lymphoid cells, monocytes,
      macrophages, mast cells) were the typical signs of oestrogenic stimulation.
      Morphological and activation signs of the effects of oestradiol persisted up to
      post-treatment Day 9. High doses of oestradiol (10 mg intramuscularly or
      intravenously, 20 mg orally) induced non-physiological hyperoestrogenization of
      uterine mucosa.

PMID- 8659094
TI  - Mutagenicity of stable dust and drinking water on swine and cattle farms.
AB  - Single pilot examinations of mutagenicity of stable dust and drinking water were
      made on three swine farms (D., M., T.) and one cattle farm (N.) in the district
      of Hodonin in summer 1994. The mutagenicity was examined by the Ames test using
      the indicator strains Salmonella typhimurium TA 98 and TA 100 with (+S9) or
      without (-S9) metabolic activation. At the same time the contents of selected
      pesticides (PES) and polychlorinated biphenyls (PCB) in stable dust and drinking
      water and that of polycyclic aromatic hydrocarbons in stable dust were
      determined. Increased mutagenicity was demonstrated in drinking water (strain TA
      98 with metabolic activation; index Rt/Rk 3.6-7.7) and stable dust (strain TA 100
      with metabolic activation; index Rt/Rk 2.2) collected on the swine farm M. High
      contents of PAH (8.246 mg/kg) and PCB (0.263 mg/kg) were also found in the dust
      samples collected on this farm. Only drinking water showed mutagenic activity
      (strain TA 98 without metabolic activation; index Rt/Rk 2.6) on the swine farm D.
      On both the farms, the number of revertants was dose-dependent. Increased content
      of PAH (2.553 mg/kg) was also demonstrated on the dust samples collected on the
      farm D. No significant increase (twofold or higher when compared with negative
      controls) of mutagenic activity of stable dust or drinking water was demonstrable
      on the swine farm T. and the cattle farm N. Substances responsible for the
      mutagenicity of drinking water on the farms D. and M. have not yet been
      identified. Anyway, the increase of mutagenicity of stable dust and drinking
      water should be taken as a warning that mutagens that can jeopardise animal and
      human health have penetrated into the stable environment.

PMID- 8659095
TI  - [Embryotoxic effects of a combination of zearalenone and vomitoxin (4
      dioxynivalenole) on the chick embryo].
AB  - Mycotoxins zearalenone and vomitoxin (4-deoxynivalenol) are often joint
      contaminants of grains infested by micromycetes of the genus Fusarium. Toxic
      effects of both mycotoxins on experimental organisms and farm animals are well
      known, but we have not found any literary reference to toxic effects of the
      combination zearalenone and vomitoxin. Embryotoxic effects of zearalenone,
      vomitoxin and combinations of various doses of zearalenone with constant addition
      of vomitoxin were studied in a three-day chick embryo. The objective of the study
      was to determine the coaction of vomitoxin on zearalenone embryotoxicity.
      Thermostat-incubated fertile eggs of White Leghorn hens were candled after three
      day incubation, the shell above the embryo was removed, and within the
      embryotoxicity range zearalenone, vomitoxin and various doses of zearalenone with
      constant addition of 2 micrograms vomitoxin were applied to morphologically
      normal embryos. The groups of ten embryos were applied mycotoxins and their
      combinations in 10 microliters of their solutions to amnions using a special
      glass micropipette. Control group comprised twenty embryos which were applied 10
      microliters of solvents used, 1% NaHCO3 and 10% ethanol. The eggs were covered
      with glass plates and their incubation was going on until the eighth day of their
      development. The embryos that died during incubation were discarded. On the
      eighth day of development, surviving embryos were taken out from the eggs and
      malformations of head, orofacial region, body wall, limbs and heart were
      determined microscopically. Tab. I shows total numbers of dead and malformed
      embryos after application of the particular doses of zearalenone, vomitoxin,
      their combinations and control solvents. The embryotoxicity range started at a
      dose of 5 to 20 micrograms per embryo. Zearalanone did not have any teratogenic
      effects on chick embryos. Applications of high doses of zearalenone (100 and 30
      micrograms) instantly caused arrhythmia, atrio-ventricular dissociation or even
      heart stoppage. The beginning of the embryotoxicity range for vomitoxin was found
      to be within the narrow range of 1 to 3 micrograms per embryo. Among
      malformations, only a defect of the interventricular septum of the heart was
      found in 4% of the cases. The combined embryotoxic effects of zearalenone and
      vomitoxin were of additive, and mostly embryolethal nature. Among the
      malformations searched for, only 5% of the embryos exhibited a defect of the
      interventricular septum of the heart. Due to the good prediction fitness of chick
      embryo that has been proved by estimates of mycotoxin toxicity to mammals it is
      possible to suppose that toxic effects of the frequently occurring combinations
      of zearalenone and vomitoxin in fusarium-infected feeds will also be of additive
      nature for farm animals.

PMID- 8659096
TI  - Anatomical possibilities of access to and blockade of m. femoralis in the dog.
AB  - The anesthesia (blockade) of canine n. femoralis may be performed either from
      lumbar or inguinal region. The insensibility of skin in the medial part of the
      thigh, tibia and tarsus as well as the akinesia of m. quadriceps femoris are
      attained by the anesthesia. The blockade of n. femoralis from the lumbar region
      often attains n. obturatorius as well. If the blockade of n. femoralis and n.
      ischiadicus was performed at the same time, almost all muscles of the hind limb
      (except m. pectineus, m. gracilis, m. obturatoris internus and m. adductor) would
      be inactivated, which may considerably facilitate minor surgical and
      postoperative interventions on the canine hind leg. Access to femoral nerve from
      lumbar can be recommended because of better results and easier performance and
      after the application of anesthetic the effect is faster and more efficient. The
      signs of the obturator nerve blockade were obtain in some dogs especially in dogs
      with long legs.

PMID- 8659097
TI  - [The importance of flies (Diptera-Brachycera) in the dissemination of helminth
      eggs from sewage treatment plants].
AB  - Screenings were carried out in four mechanico-biological municipal wastewater
      treatment plants in two climatico-geographic regions of Slovakia (submontane
      region: Levoca, Poprad and Tatranska Lomnica, lowland region: Michalovce).
      Ovoscopical studies traced the occurrence of helminth eggs in stabilized sludges
      in sludge beds. The flies (Diptera-Brachycera) are considered as potential
      biological vectors of helminth eggs. The stabilized sludges in sludge beds showed
      the presence of a wide range of helminth eggs Ascaris sp. 0-184 spec. Hymenolepis
      sp. 0-5 spec. Toxocara sp. 0-17 spec. Taenia sp. 0-2 spec. Trichuris sp. 0-17
      spec. a Capillaria sp. 0-4 spec./100 g of sample dry matter. In the areas of four
      sewage treatment plants 461 fly specimens (358 females, 103 males) were captured,
      belonging to 31 species. On three specimens of Protophormia terraenovae
      ectoparasites (mites) were detected. No eggs were found on the body surface of
      the flies.

PMID- 8659098
TI  - Effect of fatty acid composition, cadmium and vitamin E intake on prooxidative
      antioxidative state of rat liver.
AB  - The effect of cadmium intake (100 micrograms/kg body weight/day as cadmium
      chloride over a period of three months) on the prooxidative-antioxidative state
      of liver was studied in 30 days old weaned male rats. Animals were fed a
      nutritionally balanced lacto-vegetable diet containing high-quality amino acid
      mixture (casein + gluten 1:1), lipids in form of either pork fat PF (% of
      polyunsaturated fatty acids PUFA = 11.9; unsaturation index UI = 72), margarine
      MA (% PUFA = 21.9; UI = 98), or soybean oil SO (% PUFA = 61.2; UI = 156) and
      vitamin E at amount of 60 mg/kg of food (groups PF, PF + Cd, MA, MA + Cd, SO, SO
      + Cd) or 600 mg (groups PF + Cd + E, MA + Cd + E, SO + Cd + E) in form of alpha
      tocopheryl acetate. The following parameters were measured: conjugated dienes of
      fatty acids (CD), activities of superoxide dismutase (SOD), catalase (CAT) (as
      relative generation of H2O2) and glutathione peroxidase (GSH-Px). A direct
      relation between lipoperoxidation values and unsaturation index of lipids was
      found both in spontaneous (PF, MA, SO-control) and cadmium-induced generation of
      free oxygen radicals. Cadmium intake resulted in a disbalance in prooxidative
      antioxidative processes which was manifested in a significant increase of CD in
      all fat sources (the degree of increase was directly proportional to UI and
      PUFA), in similar values of relative H2O2 generation and in a nonsignificant
      increase of GSH-Px in animals with most developed lipoperoxidation (SO). A
      tenfold increase in the administered dose of vitamin E restored a prooxidative
      antioxidative equilibrium disturbed by cadmium intake in the liver of rats fed
      the diet with animal fat (PF + Cd + E) and margarine (MA + Cd + E) (reduction of
      CD to the level of control groups, decrease of relative generation of H2O2
      significant in MA). In animals fed with soybean oil, a vitamin E-induced
      reduction of CD was significantly over the control level simultaneously with
      significant stimulation of GSH-Px activity. No changes in H2O2 generation
      together with CD levels and GSH-Px activity indicated that a synergic effect of
      several antioxidants is essential in the case of high lipoperoxidation. Presented
      results are important with respect to possible control or regulation of the
      equilibrium between prooxidative and antioxidative processes by nutrition.

PMID- 8659099
TI  - [Neurosurgical therapy of intervertebral disk disease in dogs].
AB  - Intervertebral disc degeneration and protrusion or extrusion of disc material
      into the vertebral canal cause focal compressive myelopathy and radiculopathy,
      the most common neurological syndrome in dogs. Clinical findings are variable
      depending on duration and location of the lesion, volume of the mass and dynamic
      considerations (peracute massive extrusion, chronic partial extrusion, chronic
      progressive extrusion). Aim of this article is to provide compendium of at-the
      present-time recommended methods of surgical treatment of intervertebral disc
      disease in the dog. In the case of compression of spinal cord is performed
      decompressive surgery (ventral cervical decompression, hemilaminectomy,
      minihemilaminectomy, dorsal laminectomy and foramenotomy). Fenestration is the
      only method of prophylaxis.

PMID- 8659100
TI  - Transforming activity of the E6 gene of HPV-11gt in NIH 3T3 and REF 52 cells:
      correlation with the level of E6 transcription.
AB  - Among human papillomavirus (HPV) types, clinical association with benign vs
      malignant lesions correlates with the ability of the corresponding oncogenes to
      transform cells in vitro. However, even though HPV-11 is considered a low-risk
      type, we have reported previously that the E5a oncogene of HPV-11gt is capable of
      transforming NIH 3T3 cells in culture. In this study, we found that HPV-11gt E5a
      and E6 oncogenes have the ability to transform NIH 3T3 and the rat embryo
      fibroblast line REF 52. Cells were transfected independently with expression
      plasmids containing the HPV-11gt E5a or E6 oncogenes or both plasmids
      simultaneously to examine potential interactions. Cells containing these plasmids
      were phenotypically transformed and had an accelerated doubling time, loss of
      contact inhibition of growth, and loss of anchorage dependence for cell division.
      Independent cell lines containing the HPV-11gt E6 gene exhibited variable levels
      of phenotypic transformation that correlated with the HPV-11gt E6 gene content.
      The degree of phenotypic transformation could be increased by elevating the level
      of transcription of the E6 gene, indicating that there is a dose response effect
      for transformation in this system. These results suggest that increased
      expression of E6 may be an important factor in malignant progression of naturally
      occurring tumors.

PMID- 8659101
TI  - Mutation of vaccinia virus gene G2R causes suppression of gene A18R ts mutants:
      implications for control of transcription.
AB  - This report provides genetic evidence that two vaccinia virus genes, A18R and
      G2R, both of which affect the fidelity of viral transcription in vivo, interact
      with each other or act on a common biochemical pathway. Previous experiments with
      the antipoxviral drug isatin-beta-thiosemicarbazone suggest that lethal mutation
      of gene G2R would compensate for mutations in gene A18R. We therefore tested the
      hypothesis that gene G2R is an extragenic suppressor of A18R mutations. First, we
      constructed a recombinant which contains both a G2R deletion mutation and an A18R
      temperature-sensitive mutation and found that this recombinant was viable.
      Second, we isolated both cold-sensitive and temperature-insensitive phenotypic
      revertants of A18R temperature-sensitive mutants and found in both cases that the
      revertants contained G2R mutations. In the case of the cold-sensitive revertants,
      we were able to prove that the cold-sensitive phenotype mapped to the G2R gene.
      Combined with the biochemical data on A18R and G2R, these results imply that the
      A18R and G2R genes interact with each other either directly or indirectly in a
      fashion which affects the fidelity of intermediate and late viral transcription.

PMID- 8659102
TI  - The "putative" leucine zipper region of murine leukemia virus transmembrane
      protein (P15e) is essential for viral infectivity.
AB  - In order to determine the role of the putative leucine zipper region of murine
      leukemia virus (MLV) transmembrane protein p15E, nine mutations in this region
      were introduced by site-directed mutagenesis. None of these mutations affected
      the expression or transport of the envelope protein or incorporation into
      virions. The mutants were analyzed for their ability to infect NIH3T3 cells and
      to induce cell fusion in a rat XC cell fusion assay. Mutations removing the
      charge of the hydrophilic residues reduced infectivity in NIH3T3 cells but had
      either no effect or a minor effect on envelope-induced XC cell fusion. Six
      mutations of hydrophobic residues of the putative leucine zipper region were
      constructed; four completely abolished the ability to infect NIH3T3 cells and
      these mutant envelopes were also unable to induce cell fusion in the XC cell
      fusion assay. These data demonstrate the absolute requirement for the putative
      leucine zipper region for both fusion and infection of MLV.

PMID- 8659103
TI  - Proteolytically active 2A proteinase of human rhinovirus 2 is toxic for
      Saccharomyces cerevisiae but does not cleave the homologues of eIF-4 gamma in
      vivo or in vitro.
AB  - During the replication of rhino- and enteroviruses, the translation initiation
      factor elF-4 gamma is specifically cleaved by the virally encoded 2 A proteinase.
      This cleavage has been proposed to lead to the inability of the host cell to
      translate its own capped mRNA and to stimulate internal initiation of protein
      synthesis from the viral mRNA. However, a direct causal relationship between
      these effects and 2A proteinase-mediated cleavage of elF-4 gamma has remained
      difficult to prove, mainly because of the toxicity of the 2A proteinase in
      mammalian expression systems. As an alternative approach, we placed the cDNA
      sequences for the human rhinovirus 2 2A proteinase and two mutants defective in
      proteolytic activity under the control of an inducible yeast Gal1-10 promoter and
      stably integrated them into the yeast genome. Induction of the wildtype enzyme
      led to changes in cellular morphology, an inhibition of cell division activity,
      and finally to cell death. As the yeast homologues of mammalian elF-4 gamma, p150
      and p130, were shown to be refractory to cleavage by human rhinovirus 2A
      proteinase both in vivo and in vitro and the rate of protein synthesis was
      unaffected, the toxicity of the 2A proteinase toward budding yeast must be due to
      its interaction with at least one other cellular protein essential for viability.

PMID- 8659104
TI  - Resistance to geminivirus infection by virus-induced expression of dianthin in
      transgenic plants.
AB  - Ribosome-inactivating proteins (RIPs) are naturally occurring plant toxins that
      exhibit antiviral activity against a diverse range of plant and animal viruses.
      Here, the action of dianthin, a potent RIP isolated from Dianthus caryophyllus,
      has been exploited to engineer resistance to a plant DNA virus, African cassava
      mosaic virus (ACMV), in transgenic Nicotiana benthamiana. To achieve this,
      dianthin has been expressed from the ACMV virion-sense promoter that is
      transactivated by the product of viral gene AC2. This avoids the need for
      constitutive expression of the RIP, facilitating the regeneration of
      phenotypically normal plants, and ensures transgene expression is localized to
      virus-infected cells. When challenged with ACMV, transgenic plants produce
      atypical necrotic lesions on inoculated leaves, indicative of dianthin
      expression, viral DNA accumulation is significantly reduced in these tissues, and
      plants exhibit attenuated systemic symptoms from which they recover. This
      phenotype holds for isolates of ACMV but not for other geminiviruses, suggesting
      that AC2 homologues from the latter are unable to efficiently transactivate the
      ACMV promoter.

PMID- 8659105
TI  - Construction, expression, and immunogenicity of chimeric HIV-1 virus-like
      particles.
AB  - The group-specific antigens Pr55gag of human immunodeficiency virus type-1 (HIV
      1) self-assemble into noninfectious virus-like particles (VLP) that are released
      from various eucaryotic cells by budding. Deletion analysis of Pr55gag mutants
      revealed three domains into which sequences of the third variable domain V3 or
      the CD4-binding domain of the gp120 external glycoprotein can be inserted without
      destroying the capacity of the chimeric proteins to assemble to VLP. Immunization
      of rabbits with different types of purified chimeric VLP without adjuvants raised
      a strong antibody response to the Pr55gag carrier component. The magnitude of the
      antibody response to the inserted gp 120 epitopes strictly depended on their
      position within the gag polyprotein. These antisera exhibited only weak
      neutralizing activity. However, BALB/c mice immunized by different routes with
      different types of chimeric Pr55gag/V3 VLP without adjuvants developed a strong
      MHC class I (Dd)-restricted, cytolytic CD8+ T-cell (CTL) reactivity against a
      known epitope within the V3 domain. When the recombinant antigen was emulsified
      in mineral oil (incomplete Freund's adjuvant) or adsorbed in aluminium hydroxide,
      its immunogenicity for CTL was drastically reduced or completely abrogated. The
      magnitude of the V3-specific CTL response was not influenced by the position of
      the V3 domain within the Pr55gag-carrier moiety; the flanking residues, hence,
      did not influence processing of the exogenous antigen for MHC class I-restricted
      peptide presentation. These results indicate ways for the rational design and
      optimal delivery of CTL-stimulating HIV candidate vaccines.

PMID- 8659106
TI  - The human immunodeficiency virus type 1 Vpu protein tethered to the CD4
      extracellular domain is localized to the plasma membrane and is biologically
      active in the secretory pathway of mammalian cells: implications for the
      mechanisms of Vpu function.
AB  - The HIV-1 Vpu protein induces the proteolysis of CD4 in the endoplasmic reticulum
      (ER) and enhances the release of virus particles from the plasma membrane. The
      two biological activities of HIV-1 Vpu appear to be reconstituted in distinct
      membrane compartments of the mammalian cell. We carried out experiments to
      understand the role of Vpu sequences in membrane trafficking of the Vpu protein
      and to gain insights into Vpu-mediated proteolytic reactions. To this end, we
      generated CD4/Vpu hybrid proteins and analyzed their biochemical and biological
      properties in HeLa cells. We show here that all hybrid proteins are delivered to
      the plasma membrane undergoing endo-H-resistant modifications in the Golgi
      complex. Importantly, a hybrid protein bearing the CD4 extracellular domain and
      full-length Vpu induced the degradation of HIV envelope glycoproteins bearing the
      transmembrane and cytoplasmic domains of CD4 (Vpu-responsive elements, VRE).
      Glycoproteins lacking the VRE are stable under these conditions. In addition, a
      hybrid protein having the extracellular-transmembrane domains of CD4 and the Vpu
      cytoplasmic domain was only partially active in inducing the degradation of Vpu
      sensitive proteins. These results suggest that the Vpu transmembrane domain is
      capable of regulating Vpu activity in the cell. Mutational studies have further
      demonstrated that casein kinase-2 phosphorylation is critically important in the
      degradation reaction, but does not regulate membrane trafficking of the CD4/Vpu
      hybrid proteins. We also show that the CD4 extracellular domain appended to the
      Vpu protein is protected from degradation while existing in a complex with Vpu
      sensitive ectodomains. Taken together, these studies have revealed that the Vpu
      protein does not possess sequences that have the ability to sequester CD4 in the
      intracellular compartments of mammalian cells and that the Vpu protein tethered
      to the CD4 extracellular domain was biologically active in inducing the
      degradation of VRE-bearing glycoproteins in the ER.

PMID- 8659108
TI  - cis-preferential stimulation of alfalfa mosaic virus RNA 3 accumulation by the
      viral coat protein.
AB  - RNA 3 of alfalfa mosaic virus (AIMV) encodes the movement protein P3 and the
      viral coat protein (CP) which is translated from the subgenomic RNA 4. RNA 3 is
      able to replicate in tobacco plants transformed with the AIMV replicase genes P1
      and P2 (P12 plants). Frameshifts or deletions in the P3 gene have little effect
      on RNA 3 accumulation in P12 protoplasts whereas such mutations in the CP gene
      result in a 100-fold reduction of plus-strand RNA 3 accumulation. When P12
      protoplasts were inoculated with a mixture of a RNA 3 mutant with a deletion in
      the P3 gene and a mutant with a deletion in the CP gene, CP expressed by the P3
      mutant was unable to upregulate plus-strand RNA accumulation of the CP mutant.
      However, when a wild-type CP gene and subgenomic promoter were inserted in a RNA
      3 mutant with a defective CP gene, the mutant accumulated at wild-type levels. It
      is concluded that the function of CP in plus-strand RNA 3 accumulation acts in
      cis and cannot be complemented in trans. In P12 plants, P3 and CP mutants were
      able to complement each other at low and variable levels. This complementation in
      plants appeared to be correlated with the occurrence of recombination to wild
      type RNA 3.

PMID- 8659107
TI  - The E3-11.6-kDa adenovirus death protein (ADP) is required for efficient cell
      death: characterization of cells infected with adp mutants.
AB  - We have reported that an 11,600-Da nuclear membrane glycoprotein named adenovirus
      death protein (ADP), encoded by the E3 region, is required for the efficient
      death (lysis) of adenovirus (Ad)-infected cells. We postulated that ADP mediates
      the release of virions from cells at the conclusion of replication. Here we
      provide further characterization of cells infected by adp+ and adp- Ads. Using
      virus mutants with deletions in the individual E3 genes, we show that only
      mutants that lack ADP have small plaques that are slow to develop. Mutants in the
      adp gene replicated as well as wild-type Ad, but the cells lysed much more
      slowly. Cell lysis and viability were determined by plaque size, cell morphology,
      trypan blue exclusion, the release of lactate dehydrogenase, and the MTT assay
      for mitochondrial activity. ADP is required for efficient lysis of human A549,
      KB, 293, and MCF-7 cells. A549 cells infected with adp+ Ads began to die at 2-3
      days postinfection and were dead by 6 days. With adp mutants, > 80% of cells
      remained viable for 5-6 days; when the medium was changed, > 80% of cells were
      viable after 7 days and 10-20% after 14 days. When the MTT assay was used, there
      was an increase in mitochondrial activity, suggesting that Ad infection
      stimulates respiratory metabolism. Nearly all nuclei from wild-type Adinfected
      cells lacked DAPI-stained DNA by 7 days, whereas with an adp mutant nearly all
      nuclei stained brightly after 15 days. Nuclei from adp mutant-infected cells were
      extremely swollen and full of virus, and appeared to have an intact nuclear
      membrane. Cells infected with wild-type Ad had many vacuoles and perhaps a
      disrupted nuclear membrane; they did not display features typical of apoptosis.

PMID- 8659109
TI  - Dynamic behavior of hepatitis C virus in chronically infected patients receiving
      liver graft from infected donors.
AB  - We studied the outcome of hepatitis C virus (HCV) infection in 14 patients with
      end-stage HCV-related liver disease who received HCV-positive liver allografts.
      Viral sequences specific for donor and recipient were established by direct
      sequencing of PCR products from the NS5 region and by single-strand conformation
      polymorphism. Within a few months after transplantation the donor strain took
      over the recipient strain in 8 patients while in 6 patients it was the recipient
      strain which ultimately prevailed. Donor and recipient were infected by identical
      genotypes in 6 donor/recipient pairs and by different genotypes in the remaining
      8 pairs. Subtype 1b and type 1 (1a + 1b) became the predominant strains in all
      recipient/donor pairs in which they were present. Patients retaining their own
      strain were found to have significantly more active liver disease than those
      infected by the donor strain. We show that HCV superinfection and overtake
      phenomena occur in humans and suggest that genotypes 1b and 1 (1a + 1b) may
      possess replicative advantages over other genotypes. Furthermore, we provide
      evidence of the existence of interference preventing simultaneous continuous
      infection even by the same genotype strains. The development of active liver
      disease associated with recipient strain infection and mild or no disease
      associated with infection from the donor suggests various pathogenic abilities of
      different HCV strains.

PMID- 8659110
TI  - Characterization of human papillomavirus-11 mRNAs expressed in the context of
      autonomously replicating viral genomes.
AB  - We have previously adapted an experimental system which supports autonomous
      replication of human papillomavirus-11 (HPV-11) genomic DNA in a human squamous
      carcinoma cell line (SCC-4) following electroporation of linearized viral DNA.
      This system allows evaluation of HPV-11 transcription in the context of
      replicating viral genomes. RNA was isolated from cells following transfection,
      and first-strand cDNA was produced by reverse transcription using HPV-11-specific
      primers. The cDNAs were amplified using the polymerase chain reaction, and
      resulting DNA products were cloned and sequenced. Transcripts were identified
      that utilize the same splice donor and acceptor sites as transcripts
      characterized previously from human lesions. Three previously unreported splice
      junctions that employ novel combinations of those splice sites were also
      identified. We also detected these newly identified transcripts in laryngeal
      papillomas. A modified version of the 5' rapid amplification of cDNA ends method
      was used to identify transcriptional start sites of several of the HPV-11
      transcripts. The family of mRNAs characterized in this replication system have
      the potential to encode all of the major HPV-11 E-region proteins described to
      date. The data support the utility of this system as an experimental model for
      examining mechanisms of viral replication and transcription.

PMID- 8659111
TI  - Unique genome arrangement of an ovine adenovirus: identification of new proteins
      and proteinase cleavage sites.
AB  - The completed sequence and genome organization of OAV287, a serologically
      distinct ovine adenovirus, is described. The genome of 29,544 bp has inverted
      terminal repeats that are only 46 bp in length. Many OAV genes are identified by
      their homology with other adenovirus (Ad) sequences but three groups of reading
      frames show little homology. One group at the left-hand end of the genome
      probably represents the E1A/E1B regions. Two others, on the complementary strand
      at the right-hand end of the genome, are tentatively proposed as the E4 and E3
      regions. They are separated by approximately 1 kb of A/T-rich sequence of unknown
      function with E3 being adjacent to the terminus. Structural proteins V and IX of
      human Ads are absent from the OAV genome but a new, processed, 28-kDa virion
      polypeptide is encoded on the strand complementary to the proposed E1A region.
      The coding sequences for two other structural proteins are unidentified. The OAV
      penton protein lacks the region containing an Arg/Gly/Asp sequence that, in human
      adenoviruses, is thought to interact with cellular integrins to facilitate virus
      entry. Analysis of proteins and peptides in purified OAV identified several
      cleavage sites utilized by the Ad proteinase. Some of these were previously
      identified in human Ad proteins, but new sites, some of which did not conform to
      the known specificity of the human Ad proteinase, were also identified. The data
      emphasize that this ovine virus differs significantly from other known human and
      animal adenoviruses.

PMID- 8659113
TI  - Construction and transfection of ovine adenovirus genomic clones to rescue
      modified viruses.
AB  - The genome of ovine adenovirus OAV287 has an arrangement which is unique among
      known adenoviruses. To facilitate further experimentation on the structure and
      function of this genome, plasmids containing a complete clone of the genome were
      constructed. The cloned viral genome was released from plasmids by restriction
      enzyme digestion as an intact linear molecule with authentic 5' termini.
      Transfection of the linear DNA into cells which supported replication produced
      infectious virus. Mutation of a unique SalI site at the right-hand end of the
      genome disrupted reading frames of unknown function without affecting virus
      rescue, identifying this region as nonessential for replication in vitro. A 20-bp
      oligonucleotide was also inserted into the short intergenic region between the
      pVIII and the fiber sequences, identifying a second site for gene insertion.
      These studies will facilitate the development of OAV as a gene transfer vector.

PMID- 8659112
TI  - Amino acid tandem repeats within a late viral gene define the central variable
      region of African swine fever virus.
AB  - The central variable region (CVR) of the African swine fever virus (ASFV) genome
      is contained within the 9-RL open reading frame (ORF). ORF 9-RL of the ASFV
      isolate Malawi Lil-20/1 predicts a protein of 614 amino acids with amino- and
      carboxy-terminal hydrophobic regions and a centrally located hydrophilic region.
      The CVR of the genome, located centrally within this ORF, is 372 bp and contains
      a 132-bp direct repeat. The translated CVR within ORF 9-RL contains 31 tandem
      tetramers, predominantly NADT, NANT, NVDT, and, in a few cases, CAST, GAST, or
      CADT. In vitro translation of 9-RL yielded a 94-kDa protein that was strongly
      reactive with convalescent pig serum while monospecific 9-RL antiserum identified
      a late viral protein of 94 kDa in ASFV-infected macrophages. The protein,
      detected by immunofluorescence staining with 9-RL antiserum, was distributed
      homogeneously throughout the cytoplasm of infected Vero cells. 9-RL protein size
      varied among different viral isolates and among cell-culture-adapted viruses.
      Protein size increased proportionately with the degree of cell culture adaptation
      and was directly correlated with the size of the CVR present within the ORF (300
      500 bp). Analysis of the number and composition of tandem tetramers present
      within the CVR of a given ASFV isolate may prove useful for identifying and/or
      grouping ASFV isolates.

PMID- 8659114
TI  - The E1 protein is mandatory for pore formation by Semliki Forest virus spikes.
AB  - Insect cells (Aedes albopictus, clone C6/36) were infected with various variants
      of Semliki Forest virus including the wild type using the SFV replicon system.
      The variants included deletion mutants lacking one of the structural proteins and
      a mutant with a point mutation in p62 (SQL). The latter mutation results in a
      failure to process p62 to E2 and E3. After infection of the cells with different
      variant viruses and subsequent expression of viral proteins in the host cell
      plasma membrane low pH-induced pore formation was detected by measuring the
      efflux of a radiolabeled compound. The results of these experiments clearly
      showed that the E1 protein is mandatory for the acid-induced pore formation. A
      participation of the 6K or C-protein could be excluded. Furthermore, results
      obtained with the SQL mutant suggest that dissociation of the E1/E2 heterodimer
      and subsequent homooligomerization of E1 are required for pore formation.

PMID- 8659115
TI  - Evidence for direct association of Vpr and matrix protein p17 within the HIV-1
      virion.
AB  - Vpr is one of the auxiliary proteins of HIV-1 and is selectively incorporated
      into the virion by a process involving the C-terminal p6 portion of the Gag
      precursor Pr55. Vpr and the matrix protein p17 are the components of the viral
      preintegration complex and appear to play important roles in the nuclear
      transport of proviral DNA in nondividing cells. In the present study, we have
      demonstrated by coimmunoprecipitation experiments that Vpr associates with matrix
      protein p17 but not with capsid protein p24 within the HIV-1 virion. Experiments
      employing the yeast two-hybrid GAL4 assay for protein-protein interactions also
      demonstrated a direct association between Vpr and the C-terminal region of matrix
      protein p17. Association of Vpr and the matrix protein p17 within the mature
      virion is consistent with their collaborative role in the nuclear transportation
      of the viral preintegration complex in nondividing cells such as macrophages.

PMID- 8659116
TI  - Gain of Sp1 sites and loss of repressor sequences associated with a young,
      transcriptionally active subset of HERV-H endogenous long terminal repeats.
AB  - HERV-H sequences comprise a large family of human endogenous retrovirus-like
      elements. Previous DNA sequence comparisons of HERV-H long terminal repeats
      (LTRs) have led to their classification into three subtypes, Types I, Ia, and II.
      Type Ia appears to have been generated by recombination between Type I and Type
      II LTRs. These subtypes differ in evolutionary age and transcriptional activity
      with Type Ia LTRs being younger in evolutionary terms and possessing stronger
      promoter function than the other two subtypes. In this study, possible mechanisms
      responsible for the functional difference between LTRs have been explored. Types
      I and II LTRs each contain different sets of repeated segments in their U3
      regions which are disrupted in Type Ia LTRs. Using reporter gene assays, we have
      shown that both types of repeated segments can suppress activity of the human
      beta-globin gene promoter when cloned at a distant site. Both sets of repeats
      also repress promoter activity of a Type Ia LTR when directly inserted within its
      U3 region. In addition, using deletion constructs, we have localized two positive
      regulatory segments within the Type Ia LTR, both of which contain a potential
      binding site for the transcription factor Sp1. Gel mobility shift assays
      demonstrated that fragments containing these sites do bind Sp1. Although Type I
      LTRs are generally similar to Type Ia LTRs in the regions surrounding the Sp1
      sites, there are sequence differences within the sites. Gel-shift analysis
      revealed no or much reduced Sp1 binding of Type I LTR fragments containing these
      sites. Thus, it appears that the loss of repeated suppresser elements and the
      acquisition of Sp1-binding sites have both contributed to the relatively strong
      transcriptional activity of the Type Ia LTRs.

PMID- 8659117
TI  - Immunization with VP2 is sufficient for protection against lethal challenge with
      African horsesickness virus Type 4.
AB  - Horses were immunized by inoculation with a vaccinia construct containing a full
      length cDNA corresponding to the L2 gene segment of African horsesickness virus
      type 4(AHSV-4). All immunized horses developed serum neutralizing antibodies
      prior to challenge with virulent AHSV-4. No ELISA-reactive antibodies were
      present prior to challenge. A group of four seronegative control horses died
      after developing clinical signs and lesions typical of the pulmonary form of
      African horsesickness while the immunized horses were clinically normal.
      Increases in serum neutralizing and ELISA-reactive antibody titers following
      challenge indicate that at least some replication of challenge virus occurred in
      immunized horses. These results demonstrate that AHSV VP2 alone is sufficient to
      induce a protective immune response in horses and indicate the usefulness of
      ELISA-reactive antibodies for differentiation of vaccinated and naturally exposed
      horses.

PMID- 8659118
TI  - Genetic identification of a new hantavirus causing severe pulmonary syndrome in
      Argentina.
AB  - A fatal case of serologically confirmed hantavirus pulmonary syndrome (HPS) was
      recently reported in southwestern Argentina. Nucleotide sequence analysis of PCR
      fragments from conserved regions of the S and M genomic segments of the virus,
      amplified from RNA extracted from autopsy lung and liver tissues, showed the
      virus (referred as Andes virus) to be novel. Comparisons between Andes virus
      genome sequences with the corresponding sequences of the more closely related
      hantaviruses revealed differences at the amino acid level from 13.6 to 23.9% for
      G2 protein regions and from 8.5 to 12.5% for the amino terminal region of the
      nucleocapsid protein. Phylogenetic analysis using the maximum parsimony and
      maximum likelihood methods showed that Andes virus maps within the clade
      containing the HPS-associated viruses from North America. Within this group,
      Andes virus represents a unique lineage. This is, to our knowledge, the first
      report on the genetic characterization of a hantavirus from South America.

PMID- 8659119
TI  - Expression of the major core structural protein (VP7) of bluetongue virus, by a
      recombinant capripox virus, provides partial protection of sheep against a
      virulent heterotypic bluetongue virus challenge.
AB  - A recombinant capripox virus was constructed containing a cDNA copy of genome
      segment 7 of bluetongue virus (BTV) serotype 1 from South Africa (BTV 1SA), which
      expressed high levels of the major BTV core protein VP7 in infected lamb testis
      (LT) cells. Sheep vaccinated with this recombinant virus developed antibodies to
      VP7 (detected by ELISA) but no neutralizing antibodies to either the homologous
      or heterologous BTV serotype, prior to challenge (BTV 1 or BTV 3, respectively).
      Following challenge with a virulent heterotypic strain of BTV (BTV3 SA), all of
      the animals developed clinical signs of disease, indicating that they were
      infected and that the challenge virus did replicate. While all of the control
      animals died, six of the eight animals that were vaccinated with the recombinant
      capripox virus expressing VP7 recovered fully. This is the first report of a
      significant level of cross serotype protection against the lethal effects of a
      challenge with virulent BTV, produced by vaccination with a single BTV core
      protein, which did not generate a neutralizing antibody response.

PMID- 8659120
TI  - Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a
      role in viral RNA replication.
AB  - Although many workers have investigated the maturation and processing of the
      flavivirus nonstructural glycoprotein NS1 in infected cells, these studies have
      provided little insight into a possible function for NS1. In this study we
      investigated the subcellular localization of NS1 both by immunofluorescence and
      cryo-immuno electron microscopy of infected Vero and C6/36 cells. NS1 was found
      to be tightly associated with intracellular membranes, in particular with vesicle
      packets and large cytoplasmic vacuoles. Surprisingly, NS1 did not associate with
      mature virus particles, a finding that is inconsistent with the postulated role
      for this protein in virion assembly and/or maturation. However, dual-labeling
      experiments did reveal in both the confocal immunofluorescence and cryo-immuno EM
      studies the colocalization of NS1 with the viral dsRNA replicative form.
      Furthermore, localization of the dsRNA to the vesicle packets and cytoplasmic
      vacuoles seen in infected Vero and C6/36 cells, respectively, suggests that these
      structures may comprise the flavivirus replication complex. These findings
      provide further insights into the maturation pathway of NS1 and suggest a
      possible role for this protein in viral RNA replication.

PMID- 8659122
TI  - The structure of a highly virulent Theiler's murine encephalomyelitis virus
      (GDVII) and implications for determinants of viral persistence.
AB  - GDVII is a highly virulent Theiler's murine encephalomyelitis virus (TMEV) which
      causes acute encephalitis in mice, while the BeAn and DA strains are the less
      virulent TMEV which cause chronic demyelinating disease in the central nervous
      system as a result of persistent infection. Purified GDVII virus isolated from
      infected BHK-21 cells was crystallized and its structure was determined to 3.5-A
      resolution by X-ray crystallography. In contrast to other TMEV structures, the
      VP1 C-terminus of GDVII virus has an ordered conformation that forms a hook over
      the VP3 knob near the threefold axis. Comparisons with the atomic structures of
      the less virulent BeAn and DA viruses revealed significant structural variations
      in a major site (cluster B) on the protruding surface loop puff B of VP2. Puff B
      is located near the VP3 GH loop region which is structurally analogous to the
      host receptor attachment site of the major serogroup of human rhinoviruses.
      Mutations at residue 1101 in VP1 and residue 2141 in VP2, which are also near the
      VP3 GH loop and adjacent to cluster B, were previously shown to influence
      persistence of DA virus. These observations indicate that the characteristic
      interaction with the host receptor through these sites may potentially alter TMEV
      persistence.

PMID- 8659121
TI  - Expression of the human MxA protein is associated with hyperphosphorylation of
      VSV P protein in human neural Cells.
AB  - Constitutive expression of the type I interferon-inducible human cytoplasmic MxA
      protein has been shown to interfere with primary transcription of vesicular
      stomatitis virus (VSV) in tissue culture cells. As phosphorylation of the VSV P
      protein has been linked to its ability to stimulate viral transcription, we
      analyzed the phosphorylation status of this protein in human brain cells (U-87)
      stably transfected with MxA. We observed a general increase in cellular kinase
      activity in the presence of MxA, affecting both cellular proteins and VSV P
      protein. Phosphorylation of the latter was up to threefold higher both in vivo
      and in vitro. In vitro phosphorylation of recombinant VSV P protein could be
      enhanced in MxA-negative cell extracts after exogenous addition of recombinant
      His-MxA. Biochemical evidence and phosphorylation of a mutant P protein lacking
      the recognized casein kinase II (CKII) sites suggested that hyperphosphorylation
      of VSV P protein was not due to a stimulation of CKII. We thus propose that
      expression of MxA in human brain cells is associated with the stimulation of a
      cellular kinase that is active in phosphorylating both cellular target proteins
      and VSV P protein.

PMID- 8659123
TI  - Characterization of the human cytomegalovirus UL105 gene and identification of
      the putative helicase protein.
AB  - We have characterized the transcription unit for the human cytomegalovirus UL105
      gene and identified its putative protein product. The UL105 gene product is
      proposed to mediate helicase activity in the assembled helicase-primase complex.
      The two other putative proteins in this complex are the gene products of UL102
      (primase-associated factor) and UL70 (primase). Using Northern blot analysis we
      have determined that the UL105 transcript is a 3.4-kb message that can be
      detected as early as 24 hr postinfection in the presence of phosphonoformic acid
      but not in the presence of cycloheximide. Subsequent primer-extension analysis
      showed a transcriptional start site upstream of a consensus TATA sequence and
      just downstream of a CCAAT box sequence motif. In addition, we have identified an
      infected cell protein with an approximate molecular weight (M(r)) of 110 kDa
      using anti-peptide antiserum. This same antiserum detected proteins of the same
      M(r) as those produced from two expression systems where the protein from the 981
      amino-acid UL105 open reading frame was overexpressed, suggesting that the ATG
      located at nt 151,850 of the genomic sequence is utilized in the context of the
      virus genome.

PMID- 8659124
TI  - Natural populations of woodchuck hepatitis virus contain variant precore and core
      sequences including a premature stop codon in the epsilon motif.
AB  - We have determined a consensus sequence and the type and the frequency of
      spontaneous sequence variations in the woodchuck hepatitis virus (WHV) precore
      gene and the 5' region of the core gene in 101 serum samples from 53 naturally
      WHV-infected woodchucks by polymerase chain reaction sequencing. Twenty of the 53
      woodchucks were found to have variant sequences. Ten patterns of variant
      sequences were identified in these 20 animals. WHV sequences from 4 woodchucks
      had 1 nucleotide change, 3 had 2 nucleotide changes and 3 had 3 nucleotide
      changes. The nucleotide changes were not randomly distributed, but were limited
      to only 8 sites. Four sites were in the epsilon motif of the precore gene and
      four were in the 5' region of the core gene. Sixteen of the 53 (30%) woodchucks
      had precore sequence variants. All altered sites were analogous to previously
      described mutations in hepatitis B virus. There was a nucleotide change at
      nucleotide 2016 in codon 29 of the precore region that produced a stop codon in 4
      animals. This site is analogous to a common hepatitis B virus e antigen mutation.
      The sequence from the initial blood samples from 3 of 4 animals with this stop
      codon producing variant appeared to be the consensus sequence; however, in later
      samples the variant occurred as a mixed infection with the consensus sequence.
      The mixed infections were chronic and the proportion of the variant sequence was
      maintained or increased in the course of infection. In the fourth animal only the
      variant was found and it persisted for over 14 months of infection. WHV appears
      to be a valuable model for the study of the structure and function of the
      hepadnavirus precore region.

PMID- 8659125
TI  - N-linked glycosylation of hepatitis B surface antigens is involved but not
      essential in the assembly of hepatitis delta virus.
AB  - Hepatitis delta virus (HDV) is a defective virus requiring the hepatitis B virus
      (HBV) to provide hepatitis B surface antigens as the envelope protein. The
      hepatitis B surface antigens are posttranslationally modified by N-linked
      glycosylation, and its significance in HDV assembly was investigated with a
      cotransfection system using human hepatoma cell line Huh-7. After the N-linked
      glycosylation of HBsAg was blocked by tunicamycin treatment, the packaging of HDV
      in the culture system could be suppressed to a level as low as 5-10% of the
      untreated control. The extent of inhibition correlated with the increased
      concentrations of tunicamycin. In contrast, the loss of HBsAg glycosylation did
      not affect the efficiency of assembly of HBV particles. When the N-linked
      glycosylation site of small HBsAg at amino acid 146 was mutated from asparagine
      to glutamine, the mutant HBsAg packaged only a modest amount of HDV particles.
      The quantity and kinetics of formation of HDV particles in culture system were
      reduced by the depletion of HBsAg glycosylation. Therefore HDV, similar to
      influenza and vesicular stomatitis viruses, depends on glycosylation of the
      envelope proteins as a signal for envelope protein maturation and for virion
      formation.

PMID- 8659126
TI  - Membrane association of influenza virus matrix protein does not require specific
      hydrophobic domains or the viral glycoproteins.
AB  - The matrix protein of influenza virus is a major structural component of the
      virion which is generally believed to bridge between the membrane envelope and
      the ribonucleocapsid core. To investigate the interaction of M1 with cellular
      membranes in the absence of other influenza proteins, we examined its
      distribution by subcellular fractionation after expression in HeLa cells.
      Approximately 81 to 88% of M1 protein, expressed without other viral proteins,
      was soluble, whereas the remaining 12 to 19% was tightly associated with
      membranes. Conditions known to release peripherally associated membrane proteins
      did not detach M1 proteins from isolated membranes, suggesting that the fraction
      of M1 bound to membranes behaves as an integral protein. Coexpression of M1 with
      hemagglutinin or neuraminidase did not alter the extent of membrane association
      of M1 protein, indicating that there is no strong interaction between M1 and the
      cytoplasmic tails of the viral glycoproteins. Additional attempts were made to
      identify membrane binding domains in M1 protein. Mutants constructed with
      mutations in the four hydrophobic regions thought to be responsible for membrane
      association still exhibited the same levels of membrane association as that
      observed with wild-type matrix protein. Therefore, specific hydrophobic domains
      are apparently not required for membrane binding.

PMID- 8659127
TI  - Retroviral infection of Syrian hamster BHK cells depends on age and
      susceptibility toward sialidase.
AB  - Infection with recombinant retroviruses is a standard method to efficiently
      manipulate murine or human cells genetically. Due to differences in glycosylation
      of the hamster homologue to the murine ecotropic receptor and the absence of an
      amphotropic receptor, murine retroviruses are unable to infect hamster cells.
      Here we describe an isolated cell clone of the Baby Hamster Kidney cell line, BHK
      21, that can be successfully infected with ecotropic murine retroviruses. This
      finding prompted us to investigate the possibility of changing the infectability
      of other cell strains by manipulating the receptors of these cell lines in vitro.
      We found that treatment of other BHK cell clones with sialidase from C.
      Perfringens makes these cell clones also permissive to murine ecotropic
      retroviruses. Long term cultivation of three tested cell clones increased this
      susceptibility. Although the resulting infectants show a higher rate of
      infectability, they still require the manipulation with sialidase for this
      superinfection to be efficient.

PMID- 8659128
TI  - The product of maize streak virus ORF V1 is associated with secondary
      plasmodesmata and is first detected with the onset of viral lesions.
AB  - We have used a polyclonal antiserum derived from a bacterially expressed viral
      fusion protein to investigate the expression and subcellular localisation of the
      maize streak virus V1 product (PV1). Western blot analysis of agroinfected tissue
      showed that PV1 was detectable from 10 days postinoculation, coinciding with the
      first appearance of chlorotic viral lesions. The viral protein was only
      detectable in cell wall fractions of plant protein extracts. PV1 migrated with an
      apparent size of 14 kDa on SDS-PAGE, larger than the 10.9 kDa predicted from the
      amino acid sequence and therefore suggestive of posttranslational modification.
      Immunogold labelling located PV1 to the cell walls within lesion tissue and
      demonstrated a close association between the viral protein and secondary
      plasmodesmata. These results are consistent with the V1 product of MSV playing a
      role in the cell-to-cell movement of the virus in infected plants.

PMID- 8659129
TI  - Overexpression of the herpes simplex virus type 1 tegument protein VP22 increases
      its incorporation into virus particles.
AB  - The tegument of herpes simplex virus type 1 (HSV-1) virus particles is a complex
      assemblage of virus proteins whose relative proportions within virions are
      essentially constant for a particular strain of virus. To examine the processes
      controlling incorporation into the tegument, we constructed a HSV-1 recombinant
      that expresses two copies of gene UL49, which encodes the major tegument protein
      VP22. One copy specifies the unmodified form of VP22 under the control of the
      native promoter while the second expresses an epitope-tagged version of the
      protein via the human cytomegalovirus immediate early promoter. In cells infected
      with the recombinant virus, the overall levels of VP22 synthesized were about
      fivefold higher than those for wild-type virus, due to the high levels of
      expression of tagged protein. Analysis of virus particles revealed that the
      amount of VP22 in the tegument was approximately two- to threefold higher in
      recombinant virions and L-particles than in particles produced by wild-type
      virus. These results provide the first evidence that, for certain proteins, the
      level of polypeptide synthesis can act as a controlling factor for the amount of
      protein incorporated into tegument.

PMID- 8659130
TI  - Host range restriction of parainfluenza virus growth occurs at the level of virus
      genome replication.
AB  - To illuminate the molecular basis for host range restriction of parainfluenza
      virus replication, we have examined the types of virus macromolecules produced
      during abortive infection of nonpermissive MDBK cells with human parainfluenza
      virus type 1 (hPIV1). While these cells do not support production of hPIV1 virus,
      they can be infected by hPIV1 as evidenced by accumulation of intracellular viral
      NP and HN proteins. HPIV1 is also able to drive transcription of a synthetic
      analog of Sendai virus (SV) genome RNA transfected into virus-infected MDBK
      cells. In contrast to transcription, hPIV1 genome replication does not occur in
      MDBK cells. Intracellular full-length genome RNA was detected only in trace
      amounts 2 days after infection, and was undetectable 4 days after infection. Full
      length antigenome (+) sense RNA was not detectable. Nucleocapsid complexes failed
      to accumulate in the cytoplasm of nonpermissive cells, and no detectable
      nucleocapsids were released into the medium as virus particles. The data indicate
      that defective vRNA synthesis and/or nucleocapsid formation is responsible for
      the inability of hPIV1 to grow in MDBK cells. Our data also show that hPIV1 is
      capable of providing all helper functions for packaging SV synthetic genome
      analogs into infectious particles, but these SV-specific RNAs encapsidated with
      hPIV1 proteins are in turn not replicated by SV proteins. These results suggest
      that functional protein-protein interactions between parainfluenza virus strains
      have more stringent requirements than do protein-RNA interactions.

PMID- 8659131
TI  - A conserved region of unknown function participates in the recognition of E2F
      family members by the adenovirus E4 ORF 6/7 protein.
AB  - E2F DNA-binding activity in vivo is due to heterodimer formation between members
      of the E2F and DP transcription factor families. The ability of these
      heterodimers to serve as transcriptional regulators is modulated by complex
      formation with additional proteins such as the products of the retinoblastoma
      gene and the adenovirus E4 ORF 6/7. Each of the E2F family members cloned to date
      contains a highly conserved region of unknown function, termed the marked box,
      which lies between their DNA binding and transactivation domains. Mutational
      analysis showed that the marked box contributed to the recognition of E2F family
      members by the E4 ORF 6/7 protein in vitro and in vivo.

PMID- 8659132
TI  - Protein-protein interactions between Epstein-Barr virus nuclear antigen-LP and
      cellular gene products: binding of 70-kilodalton heat shock proteins.
AB  - The EBNA-LP protein encoded by the open reading frame in the leader exons of the
      Epstein-Barr nuclear antigen messages is essential for efficient immortalization
      of B lymphocytes. Protein-protein interaction studies using affinity
      precipitation of proteins from [35S]methionine-labeled cell lysates and
      bacterially expressed maltose binding protein EBNA-LP fusions were performed. A
      cellular 68/72-kDa doublet protein was detected. This banding pattern was shown
      to be identical to that obtained in affinity precipitations with fusions of
      glutathione-S-transferase and Sp1 (a basal transcription factor). For both EBNA
      LP and Sp1 the specific interacting cellular proteins have been identified as
      heat shock proteins (HSP) 72/73. Affinity precipitation of HSP 72/73 with
      deletion mutants of EBNA-LP maps the interaction domain on EBNA-LP to exon Y2
      which is required for immortalization. Immunoprecipitation of EBNA-LP from EBV
      positive lymphoblastoid cell lines coprecipitated the HSP 72/73 proteins,
      indicating that the interaction occurs in vivo as well as in vitro. The
      association of HSPs with a widening range of nuclear proteins involved in gene
      expression and proliferation control now includes Sp1 and EBNA-LP and suggests
      that there is a central role for molecular chaperones in these processes.

PMID- 8659133
TI  - [The methodological aspects of military medical expertise].

PMID- 8659134
TI  - [The medical aspects of manpower recruitment for the Armed Forces].
AB  - The article examines the problems of draft procurement from the point of view of
      military medical expertise. Based upon concrete examples the authors show how the
      criteria of medical selection of call-up personnel depend upon the socio
      demographical situation of society, principles of Defense Policy and Force
      planning, health status of young generation. For the improvement of the draftees'
      health index and the quality of medical selection it is necessary to carry out
      definite sanitary and prophylactic measures among personnel of pre-conscription
      and call-up age, as well as assign qualified medical specialists to the staff of
      medical boards, who are good in the questions of military medical expertise. The
      authors provide one of the possible variants of changes in the medical draft
      selection procedure.

PMID- 8659135
TI  - [The influence of a district military medical commission on improving therapeutic
      and diagnostic work].

PMID- 8659136
TI  - [The determination of the cause-effect relationship in the loss of health and
      work capacity by former servicemen leaving military service].
AB  - A cause-and -effect criterion was applied to analyze the interconnection of
      disorders, diseases, wound, contusions and traumata with active duty status. On
      the basis of this analysis the authors come to a conclusion about the necessity
      to improve the relevant legislation. First of all it is the notion "duty status"
      that must be substituted by the notion "military service duty status". Taking
      into account the latter, it is necessary to establish within the terms of law a
      post of an official, a group of officials, or and organ that would have the
      rights to determine the circumstances of serviceman's incapacitation or
      invalidity and to draw up a relevant document for that matter. In the author's
      opinion the solution of these questions could considerably improve the socio
      legislative protection of servicemen.

PMID- 8659138
TI  - [The basic trends of military medical expertise in the Navy].

PMID- 8659139
TI  - [The medical examination of draftees and servicemen with surgical diseases].
AB  - The article analyzes a group of problems concerning the improvement of military
      medical expertise as a whole, as well as the methods for medical fitness
      estimate, incapacitation index of various surgical disorders of injury
      consequences. On the basis of his own experience the author gives methodic
      commendations to military medical boards for the improvement of their proceedings
      in most complicated cases.

PMID- 8659137
TI  - [Current problems in aviation medical expertise].

PMID- 8659141
TI  - [The reasons for erroneous drafting for military service based on health status].

PMID- 8659140
TI  - [The control checkup and medical examination of servicemen in the work practice
      of staff military medical commissions].

PMID- 8659142
TI  - [New approaches to the military medical expertise of servicemen with personality
      disorders].

PMID- 8659143
TI  - [Stages in the formation of military medical expertise for rocket forces and the
      ways for its improvement].

PMID- 8659144
TI  - [The diagnosis and treatment of postthrombotic disease].
AB  - A 10-year experience in the analysis of stationary examination and treatment of
      163 patients with post-thrombotic disease of lower extremities is given in this
      article. Surgical treatment was conducted in 102 cases, medical treatment was
      applied for 61 patients. There is a classification of diseases which defines
      medical tactics. On the basis of the data obtained during these studies the
      authors make a conclusion that in cases of varicose, indurative of indurative
      ulcerated forms of this disease surgical treatment is indicated in the accordance
      with the character of vein affection. Otherwise, it is more preferable to apply
      medical treatment in cases of eodemata.

PMID- 8659146
TI  - [Military medical expertise at its current stage].

PMID- 8659145
TI  - [Anesthesia by physiotherapy methods].

PMID- 8659148
TI  - [The radiation factors impacting on people in accidents at atomic power
      installations].

PMID- 8659147
TI  - [The clinico-epidemiological characteristics of burn trauma].
AB  - Analysis of medical and sociopsychological factors in 231 burn victims was
      provided during 4-year randomized study. Groups of burn-prone (working class
      males, alcohol abusers, burned drunk, violating safety measures, with concomitant
      somatic and brain disorders and maladjustment) and non-prone individuals were
      elucidated. Shifts in Spielberger's state and trait anxiety scores depend on the
      damage of their somatic and nervous "underground". Beck's depression and trait
      anxiety high scores in all subgroups were found.

PMID- 8659149
TI  - [131I as a factor in radiation exposure].

PMID- 8659150
TI  - [The emotional state of health in patients with pathology undergoing therapy].

PMID- 8659151
TI  - [The use of fiber bronchoscopy at a garrison hospital].

PMID- 8659152
TI  - [An acute pharmacological test in predicting the efficacy of hypotensive
      therapy].

PMID- 8659154
TI  - [Official statistical data].

PMID- 8659153
TI  - [The military medical aspects of HIV infection].

PMID- 8659155
TI  - [Methods for studying deviant personality behavior during the professional
      psychological selection of military specialists].

PMID- 8659156
TI  - [Basic stages in the development of Russian military medical expertise].

PMID- 8659157
TI  - [The training of specialists at the Military Medical Academy under the reform of
      the Armed Forces].

PMID- 8659158
TI  - [The work experience of the allergology office of a garrison hospital].

PMID- 8659159
TI  - [The pathogenesis of endotoxicosis in gunshot-wound peritonitis].

PMID- 8659161
TI  - [A new method for the surgical treatment of fractures of the mandibular condyle].
AB  - Four variants (modifications) of the method of surgical treatment of condylar
      process fracture, defended with the author certificate on invention, are
      described. Indications to application of each variant are determined, their
      detailed descriptions are given. One analyses 124 cases of using the method in
      clinic.

PMID- 8659160
TI  - [The surgical treatment of stomach cancer].
AB  - 1070 patients underwent radical operations for stomach carcinoma in the
      Vishnevsky Central Military Clinical Hospital for the period of time from 1969 to
      1993 (85.4% from the number of admitted patients in whom the cancer was revealed
      for the first time). Subtotal distal stomach resection was performed in 627
      (58.6%) patients, subtotal proximal resection--in 78 (7.3%), gastrectomy--in 365
      (34.1%), combined operations were conducted in 193 (18%) patients. After subtotal
      distal resection the complications developed in 12.6%; the lethality constituted
      5.4%. After subtotal proximal resection and gastrectomy with vertical anastomosis
      23.3% have died, with invagination anastomosis--9.7%. 5-year survival after
      radical operations in stomach carcinoma was documented in 38.9%, 10-year survival
      -in 28.6% of the patients.

PMID- 8659162
TI  - [The organizational bases for the building of a modern medical support system for
      the Armed Forces].
AB  - In the article the problems concerning characteristic features of the local wars
      and armed conflicts, organization bases of construction of The Army and Fleet
      medical support modern system are discussed. The organization of personnel
      medical security is considered depending on the duration, intensity and spatial
      scope of military conflict, peculiarities of group (forces) application and ways
      of military actions conduction. The distribution of federal troops sanitary
      losses during the war in Chechenskaya Republic is shown depending on the type,
      localization and degree of injuries gravity as well as volume of the wounded and
      invalids evacuation by air transport and work of military medical institutions.
      The following principles of construction of the Armed Forces medical support
      system are formulated: The system must be in compliance with troops goals,
      structure, strategy and tactics, its specificity; development of medical security
      forms and methods, their historicism; interdependency, completeness and integrity
      of the system's elements; territorial aspects of its construction and management
      optimization. Considering character of the goals being laid on the Mobile Forces
      the paramount importance is attached to the level of readiness of medical service
      and its formations and units to act in crisis situations.

PMID- 8659163
TI  - [Color duplex scanning of the vertebral arteries].

PMID- 8659164
TI  - [The Epidemiological Health Surveillance Center of the Ministry of Defense of the
      Russian Federation under the reform of the military medical service].

PMID- 8659165
TI  - [The neurological complications of diphtheria].

PMID- 8659166
TI  - [The efficacy of rehabilitation measures depending on the time that submarine
      personnel put in at a rest base].

PMID- 8659167
TI  - [An exceptional organizer of military medicine (on the 75th anniversary of the
      birth of I. A. Iurov)].

PMID- 8659168
TI  - [An outstanding Russian pharmacologist and toxicologist (on the centenary of the
      birth of N. V. Lazarev)].

PMID- 8659169
TI  - [A new impulse to developing technical equipment for the military medical
      service].

PMID- 8659170
TI  - [Immobilized preparations in virology and vaccinology].

PMID- 8659171
TI  - [Analysis of the primary structure of segments of the Karelian fever virus
      genome].
AB  - Primary structure of two parts of Karelian fever virus (KFV) genome (29-57 nt and
      10507-11591 nt) cloned in recombinant plasmids has been studied and compared with
      that of Sindbis (HRSP strain) and Ockelbo viruses. Fifty-four nucleotide
      substitutes were revealed in the sequenced parts of KFV genome including
      partially 5' and 3'-nontranslated sites ( a total of 1613 nucleotides, or
      approximately 13.8% of the genome length), in comparison with the Sindbis virus
      prototype HRSP strain, this being in good correlation with strain variability.
      Eighteen nucleotide substitutes (96.4% homology) were detected in the NSP1 gene
      site (60-557 nt) of KFV in comparison with Sindbis virus and only 5 substitutes
      (98.8% homology) vs. Ockelbo virus. These data on primary structure of KFV genome
      reliably and unambiguously indicate the appurtenance of this virus to Sindbis
      like viruses.

PMID- 8659172
TI  - [Quantitative determination of the infective activity of the human
      immunodeficiency virus by plaque formation using monolayer cultures].
AB  - A method for assessment of the infective activity of HIV using plaque formation
      method with human diploid cells (strains L-65, L-68, L-72) has been developed.
      This method is not inferior to plaque formation with poly-L-lysine in
      sensitivity, but superior to it in reproducibility of results and standardization
      of the test conditions. The method is fit for titration of HIV and virus
      neutralizing antibodies, as well as for assessment of the activity of anti-HIV
      preparations.

PMID- 8659173
TI  - [Analysis of the stability of some properties of tick-borne encephalitis virus
      (strain 205) upon passaging in mice].
AB  - Comparative analysis of the characteristics of tick-borne encephalitis (TBE)
      strain 205 used for the production of vaccine against TBE and of its variants
      obtained by passages in mouse brain showed the stability of such properties as
      infective activity, neurovirulence, sensitivity to physical (heating to 50 C) and
      chemical (sodium deoxycholate treatment) factors. At the same time increased
      neurovirulence of variants 205/M10 and 205/M20, which undergone through 10 and 20
      passages in white mouse brain, for low-sensitive Syrian hamsters was revealed.
      Use of a panel of 5 monoclonal antibodies to protein E and of 4 monoclonal
      antibodies to protein E and of 4 monoclonal antibodies to protein NS3 helped
      differentiate between not only strains 205 and Sofyin, but between variants of
      strain 205 as well.

PMID- 8659174
TI  - [Changes in biological and physico-chemical properties of avian influenza virus A
      hemagglutinin H2 during adaptation to a new host].
AB  - Avian influenza A virus with H2 hemagglutinin has been adapted to mice for the
      first time. Alterations in the hemagglutinin of adapted variants of the virus as
      a result of adaptation to a new host are described. Hemagglutinin of a highly
      virulent adapted variant differed from the parental avirulent strain by antigenic
      structure, electrophoretic mobility, and receptor activity during interactions
      with murine red cells.

PMID- 8659175
TI  - [Experimental study of the possibility of emergency prophylaxis of Bolivian
      hemorrhagic fever].
AB  - Describes changes in nonspecific immunity parameters (interferon, interleukin-1,
      tumor necrosis factor, and natural killers) in the course of experimental
      Bolivian fever (Machupo virus). Changes of these parameters were followed up
      after urgent prophylactic injections of Ridostin and specific gamma-globulin to
      infected animals. The possibility of treatment of experimental Machupo fever by
      intranasal administration of interferon inductor Ridostin has been demonstrated.

PMID- 8659176
TI  - [Optimization of preparation conditions of an inactivated hepatitis A vaccine and
      its characteristics].
AB  - Modernization of the protocol and optimization of the technology of preparation
      of inactivated hepatitis A vaccine helped prepare the experimental lots of
      inactivated vaccine meeting all the requirements to such preparations and the WHO
      recommendations.

PMID- 8659177
TI  - [Evaluation of reactivity and immunogenicity of a cultured concentrated
      inactivated vaccine against hepatitis A "Hep-A-In-Vak"].
AB  - Clinical trials of inactivated hepatitis A vaccine Hep-A-in-Vac demonstrated its
      specific safety and moderate reactogenicity, manifesting by short-term fibrillar
      twitching of musculus deltoideus at the site of injection. After a course of
      three immunizations 87.5% seronegative vaccines developed a high level of
      specific antibodies to hepatitis A virus with at least 100 reverse values of
      titers. In controls antibody titers remained seronegative in 90% cases. These
      data indicate evident immunologic activity of Hep-A-in-Vac vaccine.

PMID- 8659178
TI  - [Evaluation of the reactivity and antigenic activity of the live measles vaccine,
      Leningrad-16, in different regions].
AB  - The reactogenicity and antigenic activity of live measles vaccine prepared from
      strain Leningrad-16 were assessed for 4 territories, two of which were exposed to
      radiation contamination as a result of the Chernobyl accident. The study was
      carried out at the L. A. Tarasevich State Institute for Standardization and
      Control of Viral Preparations. The vaccine was weakly reactogenic in all the
      regions; no grave or uncommon reactions to its administration were observed.
      Serologic studies revealed a high antigenic activity of the vaccine. The level of
      seroconversion was estimated as 98.5%. The study failed to detect any appreciable
      effect of radiation contamination on the tolerance to vaccine or level of immune
      response.

PMID- 8659179
TI  - [Cross contamination of continuous cell cultures].
AB  - The possibility of air-droplet cell transmission during cell transfer was
      experimentally confirmed, this appearing to be the most probable route of cross
      contamination of cell cultures. The consequences of such contamination are
      assessed and measures reducing the risk of intercellular contamination proposed.

PMID- 8659180
TI  - [Morphological analysis of a cell system, infected with different strains of the
      human immunodeficiency virus].
AB  - Cell systems infected with 63 strains of types 1 and 2 HIV virus (HIV-1 and HIV
      2) were examined under electron microscope. HIV virions were most frequently
      detected near the cell membrane or budding from it. In the cytoplasm HIV occurred
      only in vacuole-like formations. Accumulations of mature virions were seen in the
      cell-to-cell space. Mature particles of HIV-1 and HIV-2 differed by their
      morphology from oncoviral C particles and were similar rater to the Visna/Medi
      type Lentiviruses. Morphological analysis of HIV strains isolated in Russia
      demonstrated their similarity to be foreign HIV strains.

PMID- 8659181
TI  - [Use of a latex-agglutination test for determining anti-measles antibody titer].
AB  - A new diagnostic agent for microtitration of antimeasles antibodies, making use
      of polyacrolein microspheres conjugated with purified measles virus has been
      developed. Parallel titration of blood sera of children and adults in latex
      agglutination test and in routine test (hemagglutination inhibition, passive
      hemagglutination, immunofluorescent tests) demonstrated a sufficient specificity
      of the new test, sensitivity compatible to that of hemagglutination inhibition,
      and correlation of the results of all tests.

PMID- 8659182
TI  - [The interferon system in acute tick-borne encephalitis and effect on the
      dynamics of clinical laboratory indicators using different methods of interferon
      therapy].
AB  - Study of the interferon system parameters, natural killer activity, and
      immunologic characteristics in patients with acute tick-borne encephalitis
      confirmed that addition of interferon preparations to combined therapy is
      pathogenetically justified. Reaferon was conducive to shortening of the manifest
      period of the disease and to alleviation of its symptoms, but it depressed its
      own interferonogenesis. Viferon had not only a positive impact on the time course
      of clinical parameters, but promoted a more active recovery of interferon
      production and immunologic parameters.

PMID- 8659183
TI  - [A method of testing alpha-acid labile interferon and prospects for using it in
      disorders of interferon status].
AB  - The authors discuss the possibility of using He-Ne laser for induction of alpha
      acid-labile interferon. Use of this laser represents an additional test for the
      detection of diseases involving a deficient induction of alpha-acid-labile
      interferon.

PMID- 8659184
TI  - [Changes in fecal bile acid excretion after proctocolectomy].
AB  - To study the effect of total colectomy for fecal bile acid excretion we examined
      groups of patients with ulcerative colitis and familial adenomatous polyposis
      coli 4,8 +/- 2.9 years after surgery. Patients after total colectomy showed a
      significant higher fecal bile acid excretion compared to healthy persons (mean +/
      SD: 190.8 +/- 195.2 mumol/d). The highest fecal output occurred in patients with
      permanent ileostomies (mean +/- SD: 7595.0 +/- 5651.4 mumol/d), it was
      significantly higher compared to patients with ileoanal pouch anastomosis (mean
      +/- SD: 2212.8 +/- 2132.8 mumol/d). The daily fecal output of patients with
      ileorectal anastomosis (mean +/- SD: 4331.8 +/- 6314.7 mumol/d) is between the
      results of both other groups without any significance. After total colectomy only
      primary bile acids were found in each group whereas healthy people had almost
      identically rates of primary and secondary bile acids in their stools.

PMID- 8659185
TI  - [The cytotoxic activity in intestinal lamina propria and peripheral blood in AIDS
      and Crohn disease].
AB  - In this study the cytotoxic activity of natural killer cells (NK) and lymphokine
      activated killer cells (LAK) in the peripheral blood was examined in ten patients
      with AIDS and in ten patients with Crohn's disease. The results were compared to
      the values of ten healthy patients. Cells of the lamina propria of the colon were
      isolated and cultivated to LAK-cells after the in vitro stimulation with
      interleukin-2 from patients belonging to these three groups. The highest NK
      activity of the monoclonal cells in the peripheral blood (PBMC) was found in the
      control group. In patients with AIDS and Crohn's disease the activity of the LAK
      cells of PBMC was significantly higher than the activity of the NK-cells. The
      PBMC activity of NK- and LAK-cells in the control group showed no important
      differences. The spontaneous cytotoxic activity of mononuclear lamina propria
      cells was very low or not verifiable. In lamina propria LAK-cells only a very low
      cytotoxic activity was found too. These results show that an in vitro stimulation
      of PBMC with interleukin-2 in patients with AIDS or Crohn's disease lead to a
      significant increase of the cytotoxic cell activity.

PMID- 8659187
TI  - [Primary sclerosing cholangitis: conventional and quantitative liver function
      tests during long-term therapy with ursodeoxycholic acid].
AB  - Primary sclerosing cholangitis, a chronic cholestatic liver disease, frequently
      leads to an impairment of liver function. In nine men and two women, aged 23 to
      57 years, we prospectively studied for three to six years the effect of treatment
      with ursodeoxycholic acid (UDCA) on liver function. 10 mg UDCA/kg bw
      significantly reduced serum activities of AP, gamma GT, AST and ALT for several
      years. After three years of treatment, however, serum concentration of bilirubin
      was higher than before therapy in eight out of eleven patients (1.8 +/- 0.8
      versus 0.9 +/- 0.1 mg/dl; p = 0.01). Likewise, serum concentration of bilirubin
      was higher in eight out of nine patients after four years of treatment (1.3 +/-
      0.3 versus 0.9 +/- 0.1 mg/dl; p = 0.03). In most cases, however, the increase was
      discrete. Parameters of synthetic liver function (coagulation, serum protein
      concentration, serum activity of cholinesterase) remained constant in the
      observation time. Quantitative liver function tests (galactose elimination
      capacity and indocyanine green half-life) also showed little variation in the
      observation time. We conclude that UDCA treatment significantly improves serum
      activities of liver enzymes for several years. Nevertheless, serum bilirubin
      concentration, believed to be of prognostic value in patients with PSC, seems to
      rise slowly over time. Serial determinations of galactose elimination capacity
      and indocyanine green halflife are not superior to conventional liver function
      tests in the timing of liver transplantation in the individual patient.

PMID- 8659186
TI  - Helicobacter pylori produces histamine and spermidine.
AB  - The mechanism by which Helicobacter pylori associates with the development of
      upper gastrointestinal diseases is still not well understood. Toxic metabolites
      of H. pylori are discussed as possible factors. We were interested to
      investigate, whether biogenic amines might be involved. Ten monocultures of H.
      pylori from the antrum of patients with H. pylori associated diseases were
      analyzed for the content of the biogenic amine histamine. The bacteria were
      isolated on Columbia blood agar with Skirrow's supplement in a microaerophilic
      environment. After three passages onto fresh agar plates the bacteria were
      harvested in their sonicated suspensions analyzed by reversed-phase high
      performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry
      (GC-MS). From the HPLC analysis, histamine was found in six cultures. Analysis
      with GC-MS, however, revealed the presence of histamine in all the cultures (0.1
      1.63 nmol histamine/10(8) bacteria). Additionally to histamine, all cultures were
      found to contain spermidine in concentrations of 0.010-7.912 nmol/10(8) bacteria.
      It is discussed that histamine produced by H. pylori may be involved in the
      pathogenesis of H. pylori associated gastrointestinal diseases.

PMID- 8659188
TI  - Complete reversal of FK 506 induced diabetes in a liver transplant recipient by
      change of immunosuppression to cyclosporine A.
AB  - We report the case of a 41-year old patient who underwent orthotopic liver
      transplantation because of decompensated liver cirrhosis due to chronic HCV
      infection. Severe acute allograft rejection was insufficiently controlled by
      cyclosporine A, steroids and a 6-day regimen of OKT 3 monoclonal antibody
      therapy. As a consequence immunosuppressive therapy was switched to FK 506 in a
      dose of 3 mg bid. The FK 506 concentration in whole blood consistently ranged
      between 5.1 and 7.8 ng/ml. Seven weeks after the onset of FK 506 therapy the
      patient developed severe diabetes mellitus with fasting blood glucose levels up
      to 640 mmol/l. The C-peptide was elevated reflecting a higher than normal insulin
      secretion. Intravenous insulin therapy with application of up to 85 units regular
      insulin per day was initiated. Because of the severe diabetes immunosuppression
      was changed back to cyclosporine A. After six weeks the patient did no longer
      require insulin and showed an entirely normal glucose tolerance test, C-peptide
      and Hb A1-level. This case shows that the diabetogenic side effect of FK 506 is
      more pronounced than that of cyclosporine A. We propose to change
      immunosuppressive therapy to cyclosporine A in cases of FK 506 induced severe
      diabetes mellitus, since long-term prognosis of many transplant recipients may
      depend on side effects of the immunosuppressive agents.

PMID- 8659189
TI  - [Inflammatory pseudotumor of the liver. Case report of a rare differential
      diagnosis of hepatocellular carcinoma].
AB  - A 46-year old man suffered from fever, sweating, vomiting, abdominal pains, and
      watery diarrhea during two weeks. The abdomen was tender on pressure. Laboratory
      findings revealed increased leucocytes to 18,500/microliters, increased
      thrombocytes to 513,000/microliters, an increased sedimentation rate of 105/129
      mm, CRP of 18.2 mg/dl and slightly elevated activities of the amino-transferases.
      Ultrasonography showed a tumor of the liver with a diameter of 10 cm and a
      echocomplex wheel-spoke structure. The tumor was confirmed by computed
      tomography, nuclear resonance tomography, angiography, and scintigraphy without
      signs of malignity. Fine needle biopsy was negative. Bisegment resection of the
      liver revealed a tumor of the liver with focal necrosis, with the histological
      aspect of fibrous tissue with lymphoid infiltration and multiple abscesses. The
      diagnosis was "inflammatory pseudotumor of the liver" (IPT). Postoperatively the
      follow-up half a year later was normal. The IPT ist an important differential
      diagnosis of the hepatocellular carcinoma. The review of 80 cases shows that
      operative resection of the tumor is the treatment of choice, because the benign
      diagnosis cannot maintained without doubts. But the pathognomonic trias of
      symptoms 1. Inflammatory signs, 2. solid tumor of the liver, 3. normal liver
      tissue allows to make this exceptional diagnosis. The question is whether the
      operation of the tumor can be avoided by conservative medical therapy.

PMID- 8659190
TI  - Transcription factors of T and B lymphocytes--basic research and clinical
      perspectives for gastroenterology.
AB  - Tissue specific regulation of gene expression by transcription factors is a
      fascinating new field in molecular immunology. This review summarizes data on
      specific regulation of promoters and enhancers by nuclear trans-acting factors in
      lymphocytes. The structural classes of transcription factors are described and
      basic methods for detection and analysis of transcription factors are detailed.
      Furthermore, the most important trans-acting factors of T and B lymphocytes (e.g.
      NF-kB, NF-AT and STAT families) and their functional importance are described.
      Several methods for specific down-regulation of transcription factors are shown
      that may be relevant to treatment of human disease. The data are discussed with
      regard to their potential clinical relevance for gastroenterology.

PMID- 8659191
TI  - [Value of antibiotic prophylaxis in acute necrotizing pancreatitis].

PMID- 8659192
TI  - [Endocrine tumors in transgenic mice].

PMID- 8659193
TI  - [Local drug administration systems, preclinical and clinical use: perspectives
      and limitations].
AB  - Platelet activation, inflammation, recoil, tissue hyperplasia and remodeling are
      pivotal pathophysiologic factors in acute myocardial ischemia and restenosis
      development after angioplasty. It has been suggested that short duration of
      effective drug levels and poor efficiency of systemic drug administration account
      for the failure of therapy in clinical trials. A rational effective therapy for
      angina and restenosis should therefore be locally administered at the site of
      vascular obliteration. Special local drug delivery devices could be used to
      administer sufficient drug amounts at the site that needs to be treated. Local
      drug delivery systems using modified balloon systems, stent systems or newly
      designed catheters have been developed. In experimental studies different effects
      can be demonstrated by using endoluminal and adventitial substance delivery.
      Endoluminal application usually resulted in < 1% effective drug delivery in the
      arterial wall and short lasting deposition. Adventitial deposition led to higher
      mural concentrations and the drug was detectable therefore up to 21 days. In
      media and adventitia the maximum is still comparable to the maximum obtained
      after systemic application. Experimental studies indicate positive therapeutic
      effects in restenosis models. Feasibility has been proven in clinical studies of
      unstable angina with anticoagulants or antithrombotics. Further preclinical and
      preliminary clinical studies are needed to clarify regional drug distribution,
      regional wash-out, adverse effects and evaluation of long-term therapeutic
      effects. Recent developments in catheter techniques might enable effective local
      drug application in angina and restenosis prophylaxis with a reduction in
      systemic adverse effects.

PMID- 8659194
TI  - [Levels and criteria for evaluation of primary preventive interventions and their
      relevance for the cholesterol problem].
AB  - Before medical interventions are implemented, they should be evaluated for their
      effectiveness, benefit and acceptability. The effectiveness of a measure does not
      guarantee its usefulness. And even the proof of a benefit, although an
      indespensable precondition, is not always sufficient for the intervention's
      acceptability. A decision about the latter can only be the result of a complex
      ethical discussion. Acceptability is the most important criterion and overrules
      effectiveness and benefit during evaluation of a treatment. More stringent
      criteria than those for the evaluation of therapeutic actions must be used for
      primary preventive interventions, because these relate to healthy people. When
      various criteria for the evaluation of extensive cholesterol prevention are used
      in light of the previously mentioned analytical levels, one must conclude that
      the particular intervention is not warranted.

PMID- 8659196
TI  - [Myocardial infarct with oral contraceptives: simultaneous thrombotic occlusion
      of the anterior interventricular ramus and the circumflex ramus].
AB  - A 28-year-old, previously healthy mother of one child, with cigarette smoking and
      oral contraceptive medication as only risk factors suffered an acute anterior
      myocardial infarction without prior anginal complaints. Angiographically there
      were thrombotic occlusions of the LAD after the first septal branch and also of
      the distal left circumflex coronary artery. Six days after catheter
      recanalisation of the LAD and i.e. infusion of urokinase, there were small
      residual thrombi in the otherwise perfectly normal LAD and in a diagonal branch
      whereas the circumflex coronary artery was completely normal. The left ventricle
      showed anteroseptal (but not inferior) akinesis. The case report supports the
      hypothesis that myocardial infarctions under oral contraceptive medication are a
      separate disease entity unrelated to coronary atherosclerosis and may be the
      consequence of a "coagulation accident".

PMID- 8659197
TI  - [Long-term follow-up after acute myocardial infarct cause by non-arteriosclerotic
      spontaneous coronary artery dissection].
AB  - Spontaneous coronary artery dissection is a rare cause of acute myocardial
      infarction, primarily in young women. The etiology of dissections is still under
      discussion. Possible factors are inflammation, changes of flow dynamics, and
      preexisting intima lesions. We report on two young women, 49 and 30 years of age,
      who suffered and acute anterior wall infarction. Coronary angiography confirmed
      diagnosis of spontaneous coronary artery dissection of the LAD in the acute an
      subacute phase of acute myocardial infarction. The patients suffered no further
      cardiac events at long-term follow-up of up to 9 years.

PMID- 8659195
TI  - [Hemodynamics in arterial hypertension treated with running endurance training or
      nifedipine therapy].
AB  - This is a report about the therapeutic behavior of blood pressure and heart rate
      in patients suffering from hypertension. Forty male patients with hypertension
      (age: 30-53 years) were treated either with running or swimming therapy according
      to the stamina principle or with nifedipine therapy (40-60 mg/d). Both groups
      were randomized. Peripheric hemodynamics were investigated by means of the Xenon
      133-muscle-clearance (M. tibialis anterior). The values of interest were half
      value time (T1/2) and the mean functional vessel diameter. Additionally total
      peripheric vascular resistance (TPR) and radiocardiographic cardiac output (CO)
      were measured. Significant decrease of systolic and diastolic blood pressure
      values at rest were obtained with the therapeutic regimens. CO increased and the
      TPR decreased. The decrease of blood pressure during physical therapy and with
      nifedipine therapy also is due to the enhanced microcirculation. Half-value time
      of muscle clearance (T1/2) and the mean functional vascular diameter were
      increased significantly.

PMID- 8659198
TI  - [Congenital coronary artery aneurysm: a rare cause of acute myocardial infarct].
AB  - An 18-year-old female presented with acute posterior wall infarction after
      exercise stress. Coronary angiography showed an aneurysm of the proximal right
      coronary artery partially occluded with thrombi, followed by a complete occlusion
      of the vessel. The left coronary artery was normal. Despite immediate
      intracoronary thrombolysis she developed a large posterior wall necrosis.
      Angiographic follow-up revealed worsening left ventricular function but not
      progression of the aneurysmatic ectasia. The diagnosis congenital coronary artery
      aneurysm was made since there was no evidence for an atherosclerotic, infectious
      or inflammatory vascular disease. The patient was treated conservatively and
      within 2 years of follow-up the clinical course was uneventful.

PMID- 8659199
TI  - [Are beta-blockers generally contraindicated in patients with peripheral arterial
      occlusive disease?].
AB  - Ninety patients with chronic ischemic heart disease and stage IIb peripheral
      arterial occlusive disease were investigated to determine the effect of
      celiprolol, atenolol and isosorbide dinitrate on peripheral arterial blood flow.
      Walking distance and the resistance index in the femoral artery were measured
      before and after 3 months medication and compared with the findings in controls
      (30 patients with chronic ischemic heart disease and stage IIb peripheral
      arterial occlusive disease) who received placebo. Patients with peripheral
      arterial occlusive disease who were treated with atenolol 50 mg/day demonstrated
      significant decreases in both pain-free and maximal walking distance. In
      contrast, the walking distances in those given celiprolol 200 mg/day and those
      who received isosorbide dinitrate 80 mg/day did not differ from the distances in
      control subjects. The Doppler flow through the femoral artery, as measured by
      color duplex sonography, showed a significant decrease in resistance index, both
      in patients given celiprolol and in those given isosorbide dinitrate. In patients
      treated with atenolol the resistance index rose significantly. The results of
      this study confirm that the beta-adrenoceptor blocker celiprolol exerts a
      supplementary vasodilatory action resembling that of nitrates and hence can be
      used in patients with chronic ischemic heart disease and impaired peripheral
      arterial perfusion.

PMID- 8659200
TI  - [Pseudoinfarct after placing an epicardial ICD patch electrode: differentiation
      with SPECT and PET technique].
AB  - A 64-year-old male who received an implantable cardioverter defibrillator with
      epicardial patch electrodes in 1990 was admitted to the emergency room because of
      recurrent defibrillator shocks. During the following diagnostic work-up a
      remarkable discrepancy between coronary angiography (no significant stenosis),
      201Thallium-SPECT imaging (antero-septal persistent defect) and PET imaging (no
      18FDG defect) was noticed. In order to assess the impact of the epicardial
      defibrillator patch electrodes on the imaging, we performed SPECT and PET
      measurements using a thorax phantom. We found that in 201Tl-SPECT an epicardial
      patch caused a significant (up to 20%) photon attenuation, which may lead to the
      phenomenon of "pseudoinfarction". On PET images epicardial patch electrodes
      failed to produce any significant attenuation artifacts suggestive of infarction.

PMID- 8659201
TI  - [Potential embolism sources in transesophageal echocardiography--prognostic value
      in patients with cerebral ischemia].
AB  - To determine whether potential sources of embolism such as atrial septal aneurysm
      (ASA), patent foramen ovale (PFO), mitral valve prolapse and atherosclerotic
      aortic debris can influence the outcome of patients after first cerebral ischemic
      event (CIE), 214 patients (124 stroke, 21 RIND, 69 TIA) were examined by
      transesophageal echocardiography (TEE) up to 3 weeks after CIE and followed up
      for 12 months. For risk estimation, the patients were subdivided into group I =
      without and group II = with potential sources of embolism. We additionally took
      into account cardiovascular diseases and atherosclerotic risk factors (group la +
      IIa without, Ib + IIb with). Recurrence occurred in 14 out of 214 patients
      (6.5%). Univariate analysis demonstrated that the presence of ASA, PFO and aortic
      debris as well as cardiovascular diseases and atherosclerotic risk factors was
      associated with a twofold to threefold higher incidence of recurrent events.
      While potential sources of embolism alone had no influence on the recurrence rate
      (group I:8/111 = 7.2% versus group II: 6/103 = 5.8%, n.s.), this was
      significantly different in relation to cardiovascular diseases and
      atherosclerotic risk factors (groups Ia + IIa: 0/66 = 0%, groups Ib + IIb: 14/148
      = 9.8%, p < 0.01). Our results show that potential sources of embolism do not
      appear to influence the recurrence rate in cardiac healthy subjects. In patients
      with cardiovascular diseases, however, potential sources of embolism are
      associated with a higher risk of recurrence, and should therefore be imaged by
      TEE.

PMID- 8659202
TI  - [Bilateral coronary fistula: a case report and review].
AB  - A case is presented of an atypical arteriovenous coronary artery fistula which
      occurred in a young man who was admitted to hospital with constant stress
      dependent dyspnea and a feeling of thoracic constriction. A continuous systolic
      diastolic murmur above the 5th intercostal space to the left of the sternum was
      present. By means of transoesophageal echocardiography and heart catheterization
      a rather atypical bilateral coronary fistula was found. A bilateral coronary
      fistula had been formed from RCA and RCX which drained via a common intramural
      cavity into the right ventricle. The fistula was operatively closed. Bilateral
      coronary artery fistula are rare, being found with a frequency of 0.002-0.013% in
      heart catheterization. In 36 reported instances of bilateral fistulae it has been
      noted that drainage into the pulmonary artery is more common than is the case
      with single coronary artery fistulae. The therapeutic considerations correspond
      with those for single fistulae.

PMID- 8659203
TI  - [Value of functional lymphoscintigraphy and indirect lymphangiography in lipedema
      syndrome].
AB  - Early terms of lymphostasis in lipedema can be detected with lymphoscintigraphy.
      A normal examination almost certainly excludes a lymphatic component. Indirect
      lymphography is only used to rule out morphological abnormalities of lymph
      vessels. If a lymphoscintigraphic study is normal indirect lymphography is not
      indicated.

PMID- 8659204
TI  - [Lymph drainage routes and variability in preoperative efferent lymph flow
      scintigraphy in malignant melanoma of the trunk].
AB  - Malignant melanoma of the skin has become a real problem due to the increasing
      number of cases. No other tumor is induced by long term UV-radiation of the skin.
      Excision of the primary tumor is the treatment of choice in this disease. Before
      excision of the tumor lymphoscintigraphy is the first choice in diagnosis to
      demonstrate the draining lymph vessels and lymph node groups of an malignant
      melanoma for later operation. This work current the status quo of
      lymphoscintigraphy in malignant melanoma of the trunk.

PMID- 8659206
TI  - [A case of secret self-mutilation--artificial hand edema by hand self
      constriction].
AB  - Edema caused by surreptitious self-mutilation leads to special diagnostic and
      therapeutic problems because the causal psychic illness is not immediately
      obvious or appears insignificant due to the diagnosis of edema and the frequent
      desire of the patients for invasive measures. The quickest clarification is
      achieved by contacting an experienced lymphologist, who can often classify the
      swelling as artificial edema at a glance. In order to avoid any secondary damage
      arising from the edema, it should be reduced as quickly as possible by referring
      the patient to a lymphological clinic for therapy. Thus, invasive diagnostics
      would certainly be avoided, and the patient's desire for invasive procedures
      circumvented by conservative therapy. A psychiatric/psychosomatic specialist must
      be consulted. Cooperation between patient, physicians in practice and hospital
      should be established as early as possible. In difficult cases, the patient
      should be referred to a psychiatric hospital. Even for the experienced
      lymphologist, cases in which Sudeck's disease in the congested extremity has to
      be taken into account and the compliance of the patient is restricted present
      particular problems.

PMID- 8659205
TI  - [Manual lymph drainage in new federal Germany].
AB  - Manual lymphatic drainage was virtually unknown in the former German Democratic
      Republic, and its method was deliberately not published for several reasons.
      However, patients with lymphedema heard of this therapy and some examples
      illustrate how patients benefitted from it. Soon lymphatic drainage was better
      known amongst therapists than doctors. Current efforts are underway to integrate
      this therapy into a coherent treatment plan. Lymphologically oriented hospitals,
      private care physicians, therapists and the German Society of Lymphology should
      cooperate closely cooperating to achieve this goal.

PMID- 8659207
TI  - [Anasarca caused by rheumatic carditis].
AB  - Report of a 55-year-old-male patient with most serious anasarca caused by
      insufficiency right heart. The reason of the heart failure was probably rheumatic
      carditis caused by streptococcal infections which followed recurrent erysipelas
      both legs with phleblymphedema. The necessity of consistent antibiotic treatment
      of the erysipelas, that's the only possibility to avoid more difficult secondary
      complications like this case of rheumatic carditis showed. The treatment of
      insufficiency heart was followed by physical decongestive therapy of the
      phleblymphedema of the legs. After a treatment period of 12 weeks a water loss of
      112 kg and reduction of abdominal circumference from 250 cm to 150 cm could be
      achieved.

PMID- 8659208
TI  - [Quality assurance in lymphology].
AB  - Quality assurance in the field of lymphology is both necessary and possible. This
      applies not only to practising lymphologists, but also to standardization of
      lymphological diagnosis, the application of lymphatic drainage and to its
      practitioners, lymphatic drainage therapists.

PMID- 8659209
TI  - [Effect of mood and analytic and intuitive judgement tendencies in the "false
      fame" effect].
AB  - In two experiments the process dissociation procedure (Jacoby, 1991) was used to
      examine the effects of mood on automatic and consciously controlled processes in
      a fame judgment task. Thirty nonfamous names were presented once in a study phase
      to the subjects. After a mood manipulation subjects performed a fame judgment
      task. The old nonfamous names were presented together with new nonfamous and
      famous names. Subjects got either the hint that names repeated from the study
      phase were all famous (inclusion test) or that they were all nonfamous (exclusion
      test). Results, especially the comparison of the inclusion and the exclusion
      test, indicated that subjects under negative mood based their judgments more on
      consciously controlled processes, i.e. recollection of names from the study
      phase. There was only a weak impact on good mood on controlled processes. In
      respect to automatic consequences of the study phase (familiarity of names) there
      was no difference between the three mood conditions.

PMID- 8659210
TI  - [Self concept and need for social approval in bulimia patients].
AB  - The present work concerns the relation between the need for social approval
      (assessed as social desirability) and bulimia with respect to gender-differences.
      Since bulimia is mainly a female issue, a relationship was predicted between the
      development of bulimia and the internalization of a socially desired feminine sex
      stereotype with respect to the self-concept. The need for approval was assessed
      for male subjects, female subjects not suffering from eating-disorders, and
      female bulimic subjects. The results show that bulimic women have significant
      higher self-ratings concerning the need for approval. Without neglecting
      multicausal explications, the results suggest that social desirability as an
      expression of social approval should receive more attention as a facilitating
      factor in the development of bulimia.

PMID- 8659211
TI  - [Determining the degree of stenosis of peripheral arteries. Hemodynamic and
      ultrasound principles].
AB  - With colour duplex sonography, the identification and quantification of arterial
      stenoses in peripheral arteries had become feasible in reasonable time. However,
      the haemodynamic considerations are more complicated in peripheral arteries than
      in carotid arteries. This is attributable to the much longer vessel length, the
      influences of peripheral resistance, the frequency of multiple stenoses and
      combinations of occlusion and stenosis with multiple collateral vessels.
      Different qualitative and quantitative approaches are used: b-mode sonography,
      spectral analysis, velocity measurements, continuity equation and estimation of
      systolic pressure gradients (Bernoulli equation). Although standardized criteria
      in the grading of stenoses are not commonly used, the peak velocity ratio (PVR as
      a ratio of intra-and prestenotic velocity) seems to be mathematically founded,
      usefully versatile and reliable.

PMID- 8659212
TI  - Do routinely registered preoperative data provide prognostic information on the
      short-term outcome of distal bypass surgery?
AB  - One hundred and thirty and patients were operated on with unilateral distal
      bypass procedures for critical ischemia. Fifty-one patients (39%) ended up with
      graft occlusion or required major amputation within six months after
      reconstruction. Two-year graft patency was 38%. These rather disappointing
      results may be partly ascribed to inadequate preoperative selection of patients.
      Logistic regression model was used to assess whether the independent variables
      age, gender, diabetes mellitus, smoking, ankle-brachial pressure index (ABI),
      type of graft, coronary heart disease (CHD), previous vascular operation and site
      of distal anastomosis were associated with the outcome amputation and graft
      occlusion six months after reconstruction. CHD, type of graft, ABI and the
      location of distal anastomosis were significantly associated with outcome. The
      odds for amputation or occlusion was 2.4 times higher in the CHD group, 4 times
      higher if the anastomosis was located to the peroneal artery and 2.6 times higher
      for synthetic grafts. The logistic regression model was statistical significant
      (p = 0.03). However, the model did not aid sufficiently in the prediction of
      outcome, since one third was erroneously classified as success or failure. Cox's
      proportional hazard regression was employed to estimate the influence of the
      independent variables on graft patency. Favorable patency was found for those
      with distal anastomosis located to the tibial arteries, the non-CHD group and for
      higher ABI values. There was a trend towards significance for better patency in
      the autogenous vein group (p = 0.06). Although combinations of risk factors
      usable for preoperative prediction of the likelihood of graft failure,
      appropriate selection models of patients suitable for distal bypass operation
      have to be improved, to minimize the number of failed procedures.

PMID- 8659213
TI  - Copper-induced low density lipoprotein oxidation is not a risk discriminator for
      intermittent claudication.
AB  - Oxidative modification of low density lipoprotein (LDL) is supposed to be
      important in atherogenesis. Recently it was shown that subjects with coronary
      atherosclerosis have an increased susceptibility of their LDL to copper-induced
      oxidation. We investigated if patients with intermittent claudication (IC) might
      have an increased susceptibility of LDL to copper-induced oxidation. Fifty-eight
      males were randomly selected from an epidemiological study of IC, 29 with IC and
      29 healthy controls matched for age, sex and smoking habits. All subjects
      performed a standard exercise test to confirm or exclude peripheral
      atherosclerosis. Claudicants had a lag phase of 99.7 +/- 14.8 minutes (mean +/-
      SD) and in healthy controls it was 104.6 +/- 12.9 minutes. The difference between
      the groups was not significant and neither was there any association between lag
      phase and degree of peripheral atherosclerosis in IC. Lag phase showed a positive
      and significant correlation to the plasma concentration of high density
      lipoprotein-2 (HDL2-) cholesterol. The correlation for the whole group was r =
      0.41, p < 0.01. We conclude that the susceptibility of LDL to copper-oxidation
      does not discriminate between claudicants and healthy controls. The results also
      suggest that high plasma concentrations of HDL2-cholesterol may have a protective
      effect on LDL against oxidation.

PMID- 8659214
TI  - Transcutaneous oxygen tension in patients with and without pericapillary fibrin
      cuffs in chronic venous insufficiency, porphyria cutanea tarda and non-venous leg
      ulcers.
AB  - To evaluate the influence of fibrin cuffs on the transcutaneous oxygen tension in
      patients with chronic venous insufficiency (CVI) we performed a prospective
      comparative study in an out-patient dermatological department of a district
      hospital in the Netherlands. 16 patients with CVI grade II or III, 6 patients
      with porphyria cutanea tarda (PCT) without any sign of CVI, 4 patients with
      clinical ecthyma type ulcers without CVI and 10 healthy volunteers were studied.
      Skin biopsies for fibrinogen staining, transcutaneous oxygen tension measurements
      (TcPO2) and light reflexion rheography (LRR) were performed. TcPO2 readings were
      significantly lower in patients with CVI compared to patients of the other
      groups. Fibrin cuffs were found in 8 out of 16 patients with CVI, all PCT
      patients and 3 out of 4 ecthyma-ulcer patients. On the basis of these results we
      conclude that the fibrin cuff alone does not act as a barrier for oxygen
      transport. Fibrin cuffs in CVI are not the cause of venous ulceration but only a
      part of the complicated mechanism of the altered microcirculation induced by
      reflux in the venous macrocirculation. Fibrin cuffs are not unique for CVI but an
      indication of a disturbed microcirculation.

PMID- 8659215
TI  - [Family practice diagnosis of patients with venous diseases in relation to
      severity, diagnosis and practice facilities. Results of the ASAM study "Physician
      status and factor evaluation study of ambulatory patient management"].
AB  - Although venous diseases are very common and represent frequent reasons for
      consultations in general practices, little is known about the actual ambulatory
      care for these patients. In a sentinel network consisting of general
      practitioners, 385 contacts with patients suffering from venous diseases (64%
      with varicose veins, 24% with phlebitis and 11% with ulcers) were documented. In
      9% of the cases, the functional disability was "severe". The diagnostic
      procedures included laboratory tests in 23%, ECG in 11%, Doppler sonography in 8%
      and X-ray or angiography in 5%. The frequency of these diagnostic procedures
      correlated significantly with the degree of severity. The probability of a
      Doppler sonography in practices with ultrasound equipment compared to practices
      without it, was-stratified for the degree of severity, the unequal distribution
      of diseases and the level of acquaintance with the patient-between 2.2 and 2.6 (p
      always < 0.05), the probability of laboratory tests between 2.4 and 2.6 (p always
      < 0.001). This significant dependence of diagnostic procedures from the available
      equipment calls for the introduction of diagnostic standards as measures of
      quality assurance even for so-called trivial diseases.

PMID- 8659216
TI  - [Stripping the Giacomini vein--pathophysiologic necessity or phlebosurgical
      games?].
AB  - The Giacomini vein is present in 2.5%-10% of all patients having a phlebography
      because of varicosis. In a patient analysis of the last 5 years 129 patients were
      detected with a Giacomini vein (2.5%) out of a total of 5132 patients with
      varicosis. This vein was found in a significantly higher number of patients with
      a combined insufficiency of the long and short saphenous vein (p = 0.0001). An
      analysis of the different insufficiency patterns showed a Giacomini vein in 80%
      of insufficiency of grade I of the long and short saphenous vein. Likewise, this
      vein could be detected in more than half of the cases with complete insufficiency
      of both venous trunks (51%) as well as in 55% of the patients with a short
      saphenous vein insufficiency of grade III and an incomplete insufficiency of the
      long saphenous vein. On the other hand, there was no connection between
      insufficiency of the long saphenous vein, incomplete insufficiency of the short
      saphenous vein and the presence of the Giacomini vein. From these results we draw
      the conclusion that the Giacomini vein is a pathophysiologic connection between
      the two providing areas and thus transfers the insufficiency from one vascular
      system to the other. It hereby enhances the combined varicosis of both trunks as
      well as the formation of relapses. Therefore the Giacomini vein should always be
      stripped or removed by exeresis.

PMID- 8659217
TI  - Intestinal ischemia following surgery for aorto-iliac disease. A review of 502
      consecutive aortic reconstructions.
AB  - A 7-year experience with 502 patients undergoing abdominal aortic reconstruction
      was reviewed to determine the incidence of intestinal ischemia and the clinical,
      anatomic and technical factors associated with this complication of aortic
      surgery. The other complications during the 30-day postoperative period were also
      collected. A total of 7 (1.4%) patients had intestinal infarction. Of these,
      colon necrosis occurred in 4, and 3 patients had necrosis in the superior
      mesenteric artery (SMA) territory. The occurrence of intestinal infarction after
      operation for ruptured aneurysm was 3.9% (4 patients) and for intact aneurysm
      1.3% (3 patients), respectively. None of the 174 patients operated on for
      aortoiliac occlusive disease developed intestinal infarction. The development of
      colon necrosis after operation for ruptured aneurysm was mostly in relation to
      shock and diminished tissue perfusion. Suprarenal aortic clamping with subsequent
      SMA embolization, prolonged aortic clamping time, and a sporadic thrombosis of
      the SMA were responsible for small bowel necrosis. In 4 of 7 patients (57%)
      intestinal infarction led to death. An overall 30-day mortality was 18% (91
      patients). Four per cent of these deaths were due to intestinal infarction.

PMID- 8659219
TI  - Management of venous leg ulcers.
AB  - In the management of leg ulcers two aspects should be considered, i.e. the exact
      underlying condition (main cause and contributing factors) and local conditions.
      Concomitant peripheral arterial occlusive disease must systematically be
      excluded. Effective compression therapy (35 mmHg pressure at the distal calf) is
      the corner-stone in treatment of venous leg ulcers. Superficial venous reflux can
      be the major cause of chronic venous insufficiency. Careful examination of reflux
      patterns helps to distinguish between indications for conservative treatment and
      indications suitable for surgical treatment. To what extent the stripping of
      varicose veins and/or endoscopic subfascial perforator vein discision really
      improves the outcome and prevents recurrence still remains to be shown in
      controlled trials. Local treatment considers ulcer wound bed and border. Modern
      synthetic wound dressings follow the concept of moist wound healing whilst local
      application of growth factors is currently under clinical evaluation. Management
      of eczema includes avoidance of potent or known allergens, patch tests in severe
      cases with suspicion of contact dermatitis and an adapted local therapy.

PMID- 8659218
TI  - Thromboprophylaxis with a low molecular weight heparin (tinzaparin) in emergency
      abdominal surgery. A double-blind multicenter trial.
AB  - In this prospective randomized double-blind study the thromboprophylactic effect
      of postoperative low molecular weight heparin (tinzaparin) was compared with
      placebo in 80 patients undergoing emergency abdominal surgery. The fibrinogen
      uptake test was used but because of withdrawal of the labelled fibrinogen from
      the market the calculated number of patients was not reached. However, this is
      one of the few studies in emergency abdominal surgery we thought it important to
      report. The frequency of deep vein thrombosis was reduced with prophylaxis from
      22% (95% conf. intervall 11-38%) to 8% (2-21%), a risk reduction of 65%, which is
      however not significant. Together with data from the few previously published
      studies it can be concluded that patients undergoing emergency abdominal surgery
      seem to benefit from prophylaxis, which should be instituted either before
      operation or at latest 24 hours after. The exact prophylactic relation between
      pre- and post-operative start would, however, require a separate, randomized
      study.

PMID- 8659220
TI  - [Heparin-associated type II thrombocytopenia as a cause of multiple
      thromboembolism complications].
AB  - 13 days after hysterectomy and subcutaneous treatment with unfractionated heparin
      (10000 IU daily) a 68 year old women developed a pulmonary embolism and deep vein
      thrombosis of the right leg. She thereupon received intravenous heparin (1000
      IU/h). Eight days later she developed acute ischaemia of both legs, and Doppler
      examination revealed acute Leriche's Syndrome with thrombosis of both iliac
      arteries. Platelet count fell from, initially 152 x 10(9)/I, to 44 x 10(9)/I.
      Although heparin-associated thrombocytopenia type II was suspected a confirmation
      by demonstrating a heparin dependent antibody with the heparin-induced platelet
      activation (HIPA)-test failed and therefore crossreactivity of low molecular
      heparins or heparinoids could not be assessed. After discontinuation of heparin
      and iliacal artery thrombectomy a combination therapy with aspirin plus
      ticlopidine (500 mg/d respectively) was started and continued until phenprocoumon
      could exert its full effect. No recurrent thromboembolic events occurred, the
      platelet counts normalized and the patient fully recovered.

PMID- 8659221
TI  - Untreated arteriovenous fistula after World War II trauma.
AB  - A 76-year-old-patient with severe congestive heart failure due to femoral
      arteriovenous fistula (AVF) after World War II trauma is presented. He was
      admitted to our clinic because of increasing dyspnea and vertigo during the last
      years. Moreover he suffered from chronic venous insufficiency on the lower limb
      distal of the fistula. History revealed a bullet trauma sustained 50 years ago in
      1945 while riding on a train that was taken under fire. In 1973 diagnosis of
      traumatic AVF was first established by arteriography but the patient did not
      undergo surgical repair. Actual diagnostic procedure included colour Doppler
      imaging, chest x-ray, and echocardiography. The patient refused invasive
      treatment, but drug therapy of congestive heart failure was accepted.

PMID- 8659222
TI  - [Leriche syndrome: treatment with local lysis and subsequent percutaneous
      transluminal angioplasty].
AB  - Two cases of Leriche's syndrome treated by local thrombolysis and subsequent
      percutaneous transluminal angioplasty with or without additional stent
      implantation are described. The fibrinolytic drugs were applied locally into the
      occlusions through a Mewissen Infusion Catheter and a Katzen Infusion Wire
      (initial 2.5 mg rt-PA as bolus followed by Urokinase (50000 IU/h) during 24 and
      48 hours respectively. Residual stenotic lesions and occlusions were successfully
      treated with PTA alone in case 1 and with PTA in combination with a stent
      implantation in case 2. In accordance with Bean et al. (1985) and Goffette et al.
      (1989) we recommend local lysis in combination with PTA with or without
      additional stent implantation as an alternative treatment to surgery or systemic
      lysis for the treatment of Leriche's syndrome.

PMID- 8659223
TI  - Mycotic aneurysm of the internal iliac artery caused by Klebsiella pneumoniae.
AB  - Mycotic aneurysms are rarely caused by Klebsiella species. We describe a male
      patient with diabetes mellitus and alcoholism who developed a mycotic aneurysm of
      the right internal iliac artery complicated by the formation of a false aneurysm.
      Klebsiella pneumoniae was cultured from arterial blood. An extra-anatomic bypass
      (left external iliac artery to right common femoral artery) was performed with a
      successful excision of the aneurysm.

PMID- 8659224
TI  - [Relevance of heparin-induced type II thrombocytopenia in surgery: report of 3
      cases].
AB  - Heparin-induced thrombocytopenia (HIT) is a frequent type of drug induced
      thrombocytopenia. The clinically benign type I has to be distinguished from the
      life threatening type II due to the risk of thromboembolic complications. Three
      cases of type II HIT with acute thrombosis of the pelvic and lower extremity
      arteries and successful surgical treatment are reported. The majority of cases of
      an imminent type II HIT can be recognized in time by monitoring platelet count.
      The laboratory tests relevant to diagnosis are discussed. An immediate stop of
      the heparin therapy represents the causal treatment of type II HIT. As an
      alternative, anticoagulants may be used.

PMID- 8659225
TI  - Thrombosis of the terminal aorta, deep vein thrombosis, recurrent fetal loss, and
      antiphospholipid antibodies. Case report.
AB  - The antiphospholipid syndrome (APS) consists clinically of both arterial and
      venous thrombosis, recurrent fetal loss and thrombocytopenia associated with
      antiphospholipid antibodies (aPL). Most of these patients were initially found to
      suffer from systemic lupus erythematosus (SLE). There is an increasing group of
      patients who exhibit antiphospholipid antibodies and thrombotic complications
      without clinical features of SLE or related autoimmune disease termed primary
      antiphospholipid syndrome (PAPS). The case of a 29-year-old woman with thrombosis
      of the terminal aorta and deep vein thrombosis, recurrent fetal loss,
      antiphospholipid antibodies and serological support for an underlying connective
      tissue disease, probably preclinical SLE is reported.

PMID- 8659226
TI  - Limited indication of gastrocystoplasty.
AB  - A 28-year-old woman presented a huge vesico-vagino-rectal fistula after
      radiotherapy applied because of a gynaecological tumour. Reconstruction consisted
      of a colostomy, closure of the rectal hole with a pedicled perineal skin graft, a
      bivalve opening of the bladder and, with the two halves coverage of the vaginal
      suture line, and augmentation gastrocystoplasty. The fistulas healed but the
      patient suffered from an intolerable burning sensation. That is, why the stomach
      wall was removed and ureteroileocutaneostomy was created. The colostomy was
      closed, and now the patient has a well-functioning urine stoma.

PMID- 8659227
TI  - Revision arthroplasty of the hip with extensive bone loss. Preliminary study.
AB  - In this preliminary study, authors describe their experiences with revision of
      the cup and with that of the femoral stem. Former has been performed by them
      since 1993 39 times on 37 patients, the latter 3 times on 3 patients. The method
      was successful in most of the cases; the anatomical integrity was preserved and
      stability was satisfactory.

PMID- 8659228
TI  - The use of epididymal fine-needle aspiration for the diagnosis of male genital
      tract obstruction.
AB  - Epididymal fine-needle aspirations (EFNA) were performed on 29 epididymides of 17
      infertile, azoospermic men in whom testicular cytology revealed adequate
      spermatogenesis. Sonograms confirmed the presence of all the excretory male
      organs. EFNA was performed to diagnose and locate the site of genital tract
      occlusion. The presence of cuboidal epithelial cells in the aspirate was the sole
      indication that epididymal content was aspirated. In 10 (34%) of the 29 aspirates
      there were only cuboidal epithelial cells and no spermatozoa, indicating proximal
      occlusion in the rete testis, in the canaliculi efferentes or in the most
      proximal segment of the epididymis itself. Occlusion in the distal segment of the
      epididymis or in the vas deferens was diagnosed in 13 epididymal aspirates (45%)
      which contained both cuboidal cells and spermatozoa. From 6 epididymides (21%) no
      conclusion could be reached because of failed aspirations. There are a variety of
      treatment modalities available for male genital tract obstruction, such as
      reconstructive surgery or assisted reproductive technology using sperm aspiration
      technique. The success rate of treatment is mainly dependent on the site of
      obstruction. Since vasography has its own limitations and hazards, diagnostic
      EFNA should be performed before treatment in men in whom genital obstruction is
      suspected.

PMID- 8659229
TI  - The results and failures of creating a pelvic reservoir in oncology (surgery,
      urology).
AB  - The results of abdominal and pelvic pouch operations are described in surgical
      and urological material. The lateral ileal pouch (Fonkalsrud) was used in 8
      patients with diffuse colonic polyposis and in 4 cases of colitis ulcerosa. The
      second step of this two-phase operation was completed in 7 patients. Five
      complications were observed. One patient died of faecal peritonitis. Some sort of
      pouch operation was carried out in 22 patients after radical cystectomy in
      urological practice. The indication was tumour of the urinary bladder in 18,
      tuberculosis in 2 and interstitial cystitis in 2 cases. The distribution of the
      different types of reconstructions was as follows: Kock's pouch in 11, Mainz
      pouch I in 5, and Mainz-pouch II in 6 patients. Early complications were observed
      in 3 cases with kock's reservoir, in 2 with Mainz I and in 2 with Mainz II
      intervention. Overnight incontinence appeared as a late complication in 30-60% of
      the cases. One of these patients died of a suture-line insufficiency after a
      Mainz-I substitution.

PMID- 8659230
TI  - Current thoughts on penile prosthetic surgery.
AB  - In this review the author discusses the indication and problematics of penis
      prosthesis calling the attention to the evaluation of postoperative
      complications. His investigations show that, in case of appropriate indication
      and selectively applied prosthesis implantation 90% of the patients are satisfied
      with the result.

PMID- 8659231
TI  - The role of excimer laser photorefractive keratectomy in treatment of residual
      myopia followed by radial keratotomy.
AB  - Authors report a case with photorefractive retreatment after previous radial
      keratotomy (RK) due to a -4.5 D refractive error. The indication of retreatment
      was a -2.75 D regression during the one-year follow-up time after RK. The
      photorefractive keratectomy (PRK) was performed with the Aesculap Meditec MEL 60
      excimer laser. During the 8-month follow-up time, in the retreated eye the
      uncorrected visual acuity was fully recovered, no regression was experienced. The
      excimer laser appears to be a good method to correct refractive errors, regressed
      or retained from previous refractive procedures due to the possibility of precise
      calibrating and the moderate ablation depth compared to the total thickness of
      the cornea.

PMID- 8659232
TI  - Dilation of strictures after esophageal resection and reconstruction.
AB  - Dilation has remained an indispensable method of therapy for postoperative
      esophageal stricture even nowadays. Dilation with proper equipment and
      instruments of esophageal stricture after resection is a safe procedure. It can
      be performed most effectively and with reduced danger by Savary-Gilliard
      instrument or balloon. If it is only scar and there is no relapse, dysphagia
      starts mostly within 2-3 months after the operation. In the case of local relapse
      the postoperation stenosis gives rise to dysphagia later. The possible presence
      of postoperative fistula does not contraindicate stricture dilation. In fact, the
      dilation of narrow anastomosis helps the closure of the fistula.

PMID- 8659233
TI  - Radial forearm flap in maxillo-facial surgery.
AB  - Thirty consecutive patients treated with a free radial forearm flap are reviewed.
      The flap was used in the reconstruction of intraoral defect in 24 patients and of
      extraoral defect in 6 patients. There were no total or partial flap failures.
      Donor site complication included a partial loss of skin graft in 4 and radial
      fracture occurred in 1 patient. The authors considered the application of the
      radial forearm flap a reliable method for resurfacing large skin defects of the
      face. However, according to their conviction the most important field of the
      forearm flap is its use in intraoral reconstruction after pull-through operation.
      Attention is drawn to the limitation of the use of osteocutaneous flap in the
      replacement of segmental mandibular defect.

PMID- 8659235
TI  - The outcome of pancreatic fistulas developed after surgery for pancreatic
      pseudocysts.
AB  - Pancreatic fistulas (PF) develop in about 20% of cases operated for pancreatic
      pseudocysts. The authors analyse 81 cases of postoperative PF. These were formed
      following 991 operations performed for pancreatic pseudocysts (PPCs) in 850
      patients from 1987 to 1992. It is concluded that the incidence of PF formation is
      significantly (P < 0.01) increased following interventions for acute-type
      pseudocysts and after external drainage. One-third of the fistulas closed
      spontaneously within 1-4 weeks, while another 1/3 persisted for 1-6 months before
      gradual closure. Closure of fistulas was facilitated by inhibition of pancreatic
      secretion with Somatostatin or endoscopic intervention (EST, endoprosthesis) in
      24% of all cases. Only 15% (14 cases), of the fistulas, i.e. 1% of total
      patients, required surgery. The procedure of choice in the 14 cases was
      exstirpation of fistulas alone (2 cases) or combined with necrectomy (10 cases),
      or with distal pancreatic resection (2 cases). In cases of drained pancreatic
      fistulas observation can be an appropriate treatment option, while long-standing
      fistulas producing large amounts require intervention.

PMID- 8659234
TI  - A new method to repair inguino-femoral hernias: laparoscopic hernioplasty.
AB  - The development of minimally invasive surgery has accepted the challenge by
      having tried to repair inguino-femoral hernias laparoscopically. The authors
      performed 65 laparoscopic hernioplasties in one year. "Transabdominal
      preperitoneal" technique was applied in 61 cases and "intraperitoneal onlay mesh"
      in 4 cases. Fifty-three patients were operated, 12 of them had bilateral hernias.
      Recurrent hernia was the indication in 22 patients (34%). The average operating
      time was 102 and 144 minutes in the unilateral and the bilateral cases,
      respectively. There was neither wound infection, nor general complication.
      Spontaneously dissolving seroma/haematoma of the spermatic cord was noticed
      (detected by ultrasound) in 5 patients (7.7%). The neuralgia caused by the
      irritation of the nerves of the region in 4 patients (6.1%) disappeared without
      sequels after treatment with vitamins B. The 2 early recurrences (3.2%) were
      considered to be caused by technical unexperience; the affected patients were
      treated successfully with the "intraperitoneal onlay mesh" technique. It is
      emphasized that laparoscopic hernioplasty has definite advantages, namely minimal
      postoperative pain, early mobilization, short hospital stay and early restoration
      of full physical activity (in 1 to 2 weeks). On the other hand, general
      anaesthesia and intraperitoneal invasion are required and the operation consumes
      much time and cost.

PMID- 8659237
TI  - Coronary artery bypass surgery on the beating heart.
AB  - Authors report their experiences with coronary artery bypass surgery without
      cardiopulmonary bypass. Between January 1993 and June 1995, 151 patients were
      operated upon by the same surgeon for ischaemic heart disease (IHD); 7 were of
      them without extracorporeal circulation (ECC). Patients were selected for the
      procedure on the following criteria: (1) symptomatic patient with proximally
      occluded, anteriorly located, major subepicardial artery(ies) unsuitable for, or
      after failed, PTCA; (2) presence of associated disease (like hypertension,
      diabetes mellitus, chronic obstructive pulmonary disease) enhancing a possible
      deleterious effect of cardiopulmonary bypass; (3) favourable response to beta
      blocking agent pretreatment without side effects. Seven patients' perioperative
      data (white cell count, platelet count, whole plasma protein level, chest
      drainage, CK-MB release--incidence of perioperative myocardial mess loss--and
      days spent in the intensive care unit /ICU/) are compared to the corresponding
      data of patients with comparable pathology operated on with ECC. No blood
      transfusion was required, nor perioperative myocardial necrosis occurred. The
      patients operated on without ECC spent only 24 hours in the ICU, and the clinical
      check-up after 1-24 months revealed conditions free from angina pectoris. The
      patient's quality of life improved.

PMID- 8659236
TI  - Anatomy of the chicken foot for the experimental investigation in flexor tendon
      surgery.
AB  - A chicken model for research in flexor tendon surgery is used despite the
      considerable differences between avian foot and human hand anatomy. In order to
      properly correlate and interpret the data collected from such experiments, a
      reexamination of chicken anatomy and terminology was undertaken. Thirty chicken
      feet were studied anatomically for tendon-tendon sheath structures including
      vascularization, flexor systems, and histologic specimens. The data collected
      show, besides striking similarities between human and avian anatomy, differences
      critical enough to warrant a reevaluation of previous descriptions of the avian
      structure.

PMID- 8659238
TI  - Thoracoscopic lung resection by the help of Nd:YAG laser.
AB  - The Swedish surgeon Jacobaeus was the first to use a lighted cystoscope for the
      lysis of pleural adhesions /5/. The same author reported, in 1921, five cases of
      intrathoracic malignancies diagnosed by thoracoscopy /6/. After the appearance of
      video-assisted cholecystectomy and abdominal surgery, video-assisted thoracic
      surgery (VATS) also occupied a major share in thoracic surgery. It was long ago
      that we introduced a thoracoscope (not the video-assisted type) for thoracic
      intervention. In 1988 we published 24 cases of thoracic sympathectomies in which
      we used the thoracoscope /16/.

PMID- 8659239
TI  - Cancer of the breast in young women.
AB  - Between 1966 and 1986, 126 women below the age of 35 years were treated for
      cancer of the breast. The course of the disease in this group was compared to
      that in patients aged between 35 and 55 years, and in those aged 55 years and
      over. The 5-year survival was 51.7% below 35, 63% between 35 and 55, and 73.5% in
      patients aged > or = 55 years. Negative or positive findings of axillary lymph
      nodes decisively affect the survival. The authors found no interpretation for the
      poor prognosis of breast cancer of young women.

PMID- 8659240
TI  - Disseminated Kaposi sarcoma in immunosuppressed patients.
AB  - Tumour incidence was examined in kidney-transplanted patients receiving
      immunosuppressive therapy. Eight hundred and fifty immunosuppressed patients
      (mean age: 34.5 years; mean follow-up time: 67 months; men/women = 3/2), were
      followed up. Two cases of disseminated visceral kaposi sarcoma (K.S.) are
      reported in detail. RESULTS: long-term immunosuppression significantly raises the
      risk of tumour development (30/850); one must reckon with the appearance of
      visceral K.S. (2/850), which is exceptionally rare in the general population.
      CONCLUSION: the classical lower extremity cutaneous manifestation is fairly
      benign, it appears later and responds to radiotherapy well. The visceral form
      appears early (in 3-6 months), it is aggressive, progressing quickly. Only early
      diagnosis followed by immediate reduction or discontinuation of
      immunosuppression, helps successful oncological treatment.

PMID- 8659243
TI  - Treatment for potency problems with Afrodor 2000.
AB  - The andrological role of the drug Afrodor 2000 (a special mixture of sedatives,
      aphrodisiacs and vitamin E) in patients with erectile dysfunction is discussed.
      In the conservative treatment of erectile dysfunction the aphrodisiacs and severe
      medicine mixtures are widely used. To our practice one of the most useful drugs
      is Afrodor 2000, mainly for the erectile dysfunction patients of psychological
      origin.

PMID- 8659241
TI  - Surgical relations of Crohn's disease and the frequency of recurrence.
AB  - There is no disease that would have as many and variable complications as Crohn's
      disease. One of the most common complications is bowel obstruction which can be
      caused by the angulation of the bowel or by inflammation, or by formation of
      granulation tissue (32.3%). Very common is the formation of fistulae amongst the
      bowels involved and other abdominal organs, and also entero-cutaneous fistulae
      occur frequently (11.3-14.4%). The frequency of complications is increasing with
      the duration of the illness. If they are life-threatening, only surgical
      treatment can help. Surgical treatment is also indicated when conservative
      treatment fails. The most commonly used surgical interventions are bowel
      resection and, recently, the plasty of stenotic areas. The operative mortality
      (3.7%) is influenced by the length of the disease and by the numbers of
      complications. Recurrence is very common in Crohn's disease (30.1-34.9%). The
      mortality rate of the second operation is 17.5%. The prognosis is usually poor
      because recurrence can occur years after the primary operation. In Hungary, the
      frequency of surgically treated patients with Crohn's disease is low, they count
      for 0.06% of all general surgical operations.

PMID- 8659242
TI  - Complicated marginal ulcers after surgery for duodenal ulcer.
AB  - During a period of 10 years, 10 cases of marginal ulcer (MU) after surgery for
      duodenal ulcer were evaluated retrospectively. The most common cause of MU was
      inadequate gastric resection plus incomplete vagotomy; the second common cause
      was incomplete vagotomy. In one case, the MU could be ascribed to malignant
      gastrinoma. In eight of the ten cases epigastric pain was a major symptom. MU was
      complicated with perforation, massive bleeding, gastrojejunocolic fistula and
      afferent loop obstruction in 2, 2, 2, and 1 cases, respectively. Gastroscopy was
      very useful for the diagnosis except in emergency cases. Hollander test was used
      in six of the 10 patients to evaluate if the vagotomy had been complete. The mean
      acid output by insulin induction was found 32 meq/h. As a surgical therapy, total
      gastrectomy (2 cases), truncal vagotomy (2 cases), truncal vagotomy plus 60%
      gastric resection or reresection and Roux Y gastrojejunostomy were performed.
      Postoperative complications (enterocutaneous fistula, intraabdominal abscess and
      delayed gastric emptying) occurred in 33 patients. One patient was lost after
      total gastrectomy in the malignant gastrinoma and gastrojejunocolic fistula case,
      due to sepsis. The patients were followed up for 4.4 years on the average. No
      recurrence was seen.

PMID- 8659244
TI  - Surgical challenges in cochlear implantation.
AB  - Surgical experience obtained on the basis of 47 cochlear implant patients is
      reported. Pitfalls of perioperative and postoperative period are discussed.

PMID- 8659245
TI  - Instituto Nacional de Cardiologia Ignacio Chavez.

PMID- 8659246
TI  - beta-Endorphin and propiomelanocortin-correlates peptides response in suspected
      and confirmed ischemic heart disease during exercise.
AB  - In this study, we investigated circulating beta-endorphin, ACTH and cortisol in
      subjects with suspected coronary artery disease (CAD) and in patients with CAD
      during stress testing. Group I: 18 subjects, all male (average age 48 +/- 9 yrs)
      with suspected (CAD) were enrolled. Group II: 35 patients, 30 males and 5 females
      (average age 54.3 +/- 7 yrs) with CAD, were enrolled. Ten patients had previous
      myocardial infarction. In all patients that underwent coronarography a stenosis >
      75% was found in at least one coronary artery. The stress test was performed with
      a cycloergometer, increasing work loads 25 watt every 2 min. All subjects and
      patients were in the recumbent position for at least 30 minutes prior to testing.
      During this period a 3-way catheter was placed in the antecubital vein and blood
      was drawn for Beta-endorphin, ACTH and cortisol; additional blood samples were
      drawn using a pre-chilled syringe at maximum effort and during the recovery
      period. RESULTS: group I: 9 of the subjects with suspected CAD had either ECG or
      clinical signs of ischemic during the stress test. In subjects with a negative
      test, the test was carried out for a longer period of time and at a higher work
      load. There was an increase in Beta-endorphin and ACTH at peak exercise and
      during recovery. Plasma cortisol increase during the period of recovery. Group
      II: 16 of the 35 patients with CAD exhibited ECG signs of induced myocardial
      ischemia; there was no difference in work loads in patients with positive or
      negative stress test. Exercise time was reduced in all patients and plasma Beta
      endorphin increased at peak exercise and recovery in patients with a negative
      stress test. In conclusion our study revealed a different response of Beta
      endorphin, ACTH and cortisol plasma levels in subjects with suspected CAD and in
      patients with CAD during exercise testing.

PMID- 8659247
TI  - Mortality trends in Belgium and The Netherlands. Closing the gap.
AB  - Mean life expectancy at birth (1967-1992) increased for both sexes combined with
      5.6 years in Belgium and 3.6 years in The Netherlands. Age adjusted mortality
      from all causes and cardiovascular diseases has been followed up from 1968
      onwards to 1989 in Belgium and The Netherlands and in Flanders and Wallonia from
      1971 to 1989 for each sex and two age classes, 45-74 y and 75-85 + y. Flanders
      and Wallonia were selected because of differences in mortality and life-style.
      Total mortality decreased faster in Belgium, especially in the period 1980-89,
      for almost all comparisons in each sex and age class and for most cardiovascular
      diseases. A comparison of mortality trends in the period 1980-89 among 35
      countries worldwide showed a better performance in Belgium than in The
      Netherlands for 10 different causes of death. The mortality gap between both
      countries is closing, especially between The Netherlands and Flanders. The
      decreasing slope in mortality from all causes is explained mostly by the change
      in cardiovascular mortality. Medical treatment and care, which are not better in
      Belgium, do not explain the differences in mortality trends Observed changes in
      life-style, including saturated and polyunsaturated fat intake, smoking habits
      and salt intake are consistent with the observed mortality changes.

PMID- 8659248
TI  - Early cranial neural crest migration in the direct-developing frog,
      Eleutherodactylus coqui.
AB  - Direct development is a common reproductive mode in living amphibians
      characterized by absence of the free-living, aquatic larval stage. In
      Eleutherodactylus, a species-rich genus of New World frogs, evolution of direct
      development from the ancestral biphasic ontogeny is correlated with a
      comprehensive modification in embryonic cranial patterning, including the loss of
      many larval-specific components and the precocious formation of many adult
      (postmetamorphic) structures. We use scanning electron microscopy (SEM) to
      examine the emergence and early migration of cranial neural crest cells in
      Eleutherodactylus coqui to begin to assess the possible role of the neural crest
      in mediating these evolutionary changes. As in metamorphosing frogs, cranial
      crest cells emerge prior to neural fold closure and assemble into three streams:
      rostral otic, and caudal otic. These streams contribute to the face and first
      visceral (mandibular) arch, to the second (hyoid) arch, and to posterior
      (branchial) arches, respectively. Rostrocaudal position, morphology, and/or
      migration patterns distinguish subpopulations of cells within the rostral stream
      and caudal otic stream. With the possible exception of the small size of the
      rostral otic caudal otic streams, evolution of direct development in E. coqui has
      not altered basic patterns of neural crest emergence or early migration as
      assessed by SEM. If observed evolutionary changes in embryonic cranial patterning
      are mediated by the neural crest, then they likely involve later aspects of crest
      migration or more subtle features related to pattern formation such as cell
      behavior and commitment, or gene expression.

PMID- 8659249
TI  - Spatial expression of two tadpole stage specific myosin heavy chains in Xenopus
      laevis.
AB  - Vertebrate skeletal muscles contain a family of myosin heavy chain (MyHC)
      proteins whose expression varies with clonal origin, developmental age, hormonal
      state, and innervation patterns. The number of MyHC genes and their regulation
      have been intensely studied in mammals and birds. However, Comparatively little
      is known about MyHC expression in other vertebrates. To understand better MyHC
      regulation in amphibians, I have examined the fiber type expression of two
      tadpole stage-specific MyHC transcripts in Xenopus laevis. cDNAs for these
      transcripts, called MyHC E3 and MyHC E19, were used to synthesize digoxigenin
      labeled antisense RNA probes. In situ hybridization of these probes revealed that
      MyHC E3 was expressed through the myotome but was most abundant in the core
      fibers of the axial muscles, which are larval type II. In contrast, E19 was
      expressed most abundantly in the small diameter peripheral fibers of the axial
      muscles, which are larval type I. Transcripts of both genes were detected
      exclusively in skeletal muscles neither heavy chain was expressed in cardiac
      muscle, smooth muscle, or lymph heart muscle. E3 expression was first detected at
      late gastrula in both segmented and unsegmented dorsal mesoderm. It remained
      abundant throughout premetamorphosis in myotomal muscle, and was also found in
      the levator hyoideus and mandibularis muscle of the head, and in abdominal wall
      muscles. In contrast, E19 was first detected at tailbud in the tail tip and its
      expression spread anteriorly among larval type I and type II fibers of the
      myotome and head muscles during the next few hours of development. The patterns
      of expression suggest that MyHC E3 is expressed predominately in larval type II
      fibers, and MyHC E19 is initially expressed predominately in larval type I fibers
      but as development proceeds is expressed in both type I and type II.

PMID- 8659250
TI  - Distribution pattern of F-actin, vimentin and alpha-tubulin in the bovine testis
      during postnatal development.
AB  - The distribution of F-actin, vimentin and alpha-tubulin was studied
      immunohistochemically in bovine seminiferous and straight testicular tubules,
      rete testis and intertubular tissue during postnatal development. Sites of
      antigenicity were detected by ABC immunoperoxidase technique and visualized by
      metal-enhanced deposition of diaminobenzidine. Within the seminiferous
      epithelium, F-actin appears at 20 weeks and is found in adult Sertoli cells as
      part of specialized cell contacts. In peritubular cells, F-actin increases
      gradually from 4 to 30 weeks when the adult concentration is achieved. After 20
      weeks, subepithelial fibroblasts of the mediastinum testis start to express F
      actin and at 52 weeks, a thick layer of positive myofibroblasts is seen beneath
      the epithelia of rete testis and straight testicular tubules. Testicular
      macrophages and light intercalated cells (LIC) are also characteristically
      decorated following F-actin immunoreaction. Vimentin is localized in perinuclear
      position in pre-Sertoli cells of 4-20 weeks and in adult Sertoli cells. During
      the period of transformation from pre-Sertoli to Sertoli cells, the perinuclear
      vimentin coat is absent. The epithelia of rete testis and straight tubules
      exhibit a strong vimentin immunoreaction in their basal parts. This specific
      pattern does not change from 4 weeks to adulthood. Alpha -tubulin is absent in 4
      week-old seminiferous tubules. At 8 weeks, the perinuclear area of pre-Sertoli
      cells reacts positive. The alpha-tubulin content increases in these cells
      continuously, and from 30 weeks on nearly the entire supranuclear cytoplasm of
      Sertoli cells is heavily decorated. The epithelial of rete and straight tubules
      display a growing number of alpha-tubulin-positive cells from 4 to 40 weeks. From
      then on, nearly all epithelial cells contain alpha-tubulin, particularly in a
      narrow zone beneath their lateral cell borders.

PMID- 8659252
TI  - Alcohol effects on paraventricular hypothalamic nucleus morphometry.
AB  - The morphometric effects of postnatal exposure to alcohol on the neurons of the
      paraventricular hypothalamic nucleus (PVN) have been studied in four different
      topographic subdivisions of the nucleus: rostral, intermediate medial,
      intermediate lateral and caudal. Male mice were exposed to alcohol during
      lactation and after weaning by addition of 20% of ethanol to the drinking water
      that was first ingested by the mother and thereafter by the experimental animals
      themselves. Animals were sacrificed at the 25th, 35th, 45th, 55th and 100th
      postnatal day. Nuclear sizes of the PVN neurons (Perimeter, area and maximum
      diameter) were determined in both control and experimental alcohol-treated
      groups. The shape of these neuronal nuclei was also determined and compared. PVN
      responds globally to alcohol exposure, showing a decrease in the neuronal nuclear
      sizes in the four studied PVN subdivisions of the alcohol-treated mice at the
      35th and 45th and 100th day. We suggest that these decreases could be related to
      changes in gonadal hormone levels induced by alcohol exposure and/or disturbances
      of brain neurotransmitter and neuropeptide metabolism caused by ethanol.

PMID- 8659251
TI  - Immunohistochemistry of secretory particles ('vesiculosomes') from the epithelium
      of bovine seminal vesicles and ampulla of the vas deferens.
AB  - Secretory particles, designated as 'vesiculosomes', were isolated and purified
      from bovine seminal vesicle fluid. The protein pattern was characterized using
      one- and two-dimensional gel electrophoresis. Native vesiculosome fractions were
      used for immunization of female New Zealand rabbits. The resulting vesiculosome
      antiserum was used for immunohistochemical studies, designed to obtain data on
      the intracellular formation, the localization and the potential release from
      secretory cells of the respective proteins present in these particles. The
      specificity and sensitivity of the antiserum was tested by Western blot analysis
      and by an ELISA system. Western blot analysis of isolated vesiculosomes separated
      on SDS-PAGE showed several heterogeneous immunoreactive bands in the range of 16
      kD and above 66 kD, indicating a polyvalent mixture of immunoglobulins.
      Immunohistochemical staining of different bovine tissues, nevertheless, revealed
      a strong reaction exclusively at the apical portion of secretory cells of the
      seminal vesicle and the ampulla of the vas deferens and of intraluminal
      secretion. The antiserum recognizes both secretory granules and plasma membrane
      proteins of seminal vesicle epithelium, supporting the concept of vesiculosomes
      to represent cytoplasmic particles formed from plasma membranes surrounding
      apical 'blebs' of the cells that are released physiologically during secretion.

PMID- 8659253
TI  - Corrosion cast demonstration of retinal vasculature of normal Wistar-Kyoto rats.
AB  - Plastic corrosion casts of the rat retinal vasculature were studied by scanning
      electron microscopy. This technique demonstrated the entire retinal vasculature
      of the rat. The retinal blood vessels supplying the rat's retina have a definite
      and fairly constant pattern. At the disk there are usually six main artery and
      vein branches that run symmetrically towards the periphery. Veins are wider and
      more tortuous. The characteristic arrangement of endothelial cell nuclear
      indentations clearly differentiates arteries from veins. Retinal arteries have
      side-arm and dichotomous branchings. The number of vessel branches is greater on
      the nasal side than on the temporal side of the retina. The vein-over-artery
      crossing phenomenon is more frequent than the artery-over-vein. Retinal
      capillaries appear tortuous and are arranged cylindrically in two layers. The
      superficial network of capillaries comes essentially from arterioles, while deep
      layer capillary networks are more regularly and densely arranged and are mainly
      connected with venules. The inner and the outer capillary networks have
      interconnections, vertical runs and short vascular bridges. Within the retina
      there are regional variations in capillary pattern and distribution. More
      regular, dense and rich capillary networks are observed in the peripheral area
      than at the posterior pole area. No arteriovenous shunts were seen. The study of
      such plastic casts makes possible a more accurate assessment of some aspects of
      vascular abnormalities. These findings will be helpful in further investigations
      of retinal vascular abnormalities.

PMID- 8659254
TI  - Effect of denervation on morphogenesis of the rat fungiform papilla.
AB  - In an attempt to elucidate the effects of denervation on development and
      maintenance of the structure of the fungiform papilla, unilateral neurectomy of
      the chorda tympani-lingual nerve of rats was performed at day 1 and at weeks 1,
      2, 3, 4, 7, and 10 after birth. Specimens were obtained at days 3, 7 and 10,
      weeks 2, 3, 4, 6, and 8, and months 3 and 4 after neurectomy for examination by
      light and scanning electron microscopy. At first, the fungiform papillae were
      atrophic, then progressed to forms resembling filiform papillae. When an immature
      fungiform papilla was denervated, it eventually changed to papilla identical to
      normal filiform papillae. The elicited changes differed according to the time of
      neurectomy; it was found that early neurectomy resulted in a more rapid and
      marked morphological change of the fungiform papillae. The filiform-like papillae
      derived from the fungiform ones showed various shapes, sizes, and orientations
      and were rarely present on the unoperated control side of the lingual dorsum.
      Sections of the filiform-like papillae revealed that they had no taste buds.
      These findings suggest: (1) Morphogenesis and structural maintenance of the
      fungiform papillae require the presence of the chorda tympani and/or lingual
      nerve. (2) Completion of differentiation and maturation differ in time among
      fungiform papillae. (3) Fungiform papillae may be transformed filiform papillae
      induced and maintained by a neurotrophic factor of factors coming from the chorda
      tympani and/or lingual nerve. (4) Fungiform papillae are rarely innervated
      contralaterally.

PMID- 8659256
TI  - Morphology and function of the cruciate ligaments in diapsids.
AB  - The extant diapsids (amniotes with two temporal fenestrate) consist of archosaurs
      (birds and crocodiles) and of lepidosaurs (sphenodon and squamates). The
      dichotomy of these two lineages occurred in the upper Permian. Originally, the
      intraarticular knee ligaments were three cruciates. The intermediate cruciate (a
      posterior one with guiding function) is present in all diapsids, whilst the
      medial one (an anterior with guiding function) is absent in birds. The lateral
      cruciate ligament is subdivided into a lateral anterior and a medial posterior
      shank. The posterior shank disappeared in birds and crocodiles. The anterior
      shank disposes of a guiding function in archosaurs, and is in the course of
      reduction in lepidosaurs. The reduction process has progressed least in
      sphenodons, whereas the lateral cruciate of chameleons is totally absent. The
      anterior cruciates of birds (the lateral one) and of chameleons (the medial one)
      are hence not homologous. The morphology and function of the cruciate ligaments
      can be related with gait evolution.

PMID- 8659255
TI  - Immunohistochemical correlates of peripheral gustatory sensitivity to sodium and
      amiloride.
AB  - In mammals, transduction of sodium stimuli occurs via amiloride-sensitive sodium
      channels. In rat, gustatory physiological sensitivity to sodium stimuli develops
      gradually during the early postnatal period. In addition, if pregnant rats are
      subjected to dietary sodium restriction during gestation, their offspring fail to
      develop normal gustatory physiological responses to sodium and sensitivity to
      amiloride. In the present study, we used polyclonal antibodies raised against
      amiloride-sensitive sodium channels to ascertain whether gustatory function is
      correlated with the immunological presence of the transduction apparatus for
      sodium stimuli in the taste buds of neonatal rats and adult offspring of sodium
      restricted dams. The results indicate that antiamiloride-sensitive sodium channel
      antisera bind cells within taste buds of neonatal and adult rats, regardless of
      maternal dietary condition. Therefore, despite the functional absence of taste
      system amiloride-sensitive sodium channels, the antigenic determinants of these
      channels are expressed. These data suggest that the onset of normal gustatory
      sodium sensitivity in neonatal normal rats results from the progressive
      activation of existing, quiescent channels. Furthermore, they rule out the
      possibility that the failure to synthesize channel protein underlies the lack of
      gustatory sodium and amiloride sensitivity in the offspring of sodium-restricted
      rats.

PMID- 8659257
TI  - Occipital emissary foramen in skulls from central Anatolia.
AB  - In this study, a total of 125 female and 175 male adult human skulls from Central
      Anatolia were examined. The incidence and localization of the rate occipital
      foramen found on the squama of occipital bone were investigated. This foramen has
      significant importance during suboccipital craniotomies since it transmits the
      occipital emissary vein. In the present study, the occipital foramen was found in
      8 (2.6%) skulls. Its location was closer to the foramen magnum but not to the
      external occipital protuberance.

PMID- 8659258
TI  - The geographic and temporal patterns of residency-trained family physicians:
      University of Washington Family Practice Residency Network.
AB  - BACKGROUND: There is a clear national mandate to increase the proportion of
      generalist physicians within the medical community and to increase their numbers
      within rural and underserved urban locations. Little is known, however, about the
      geographic and temporal career patterns of family physicians or about how these
      patterns differ by sex and graduation cohort. METHODS: Using information from a
      follow-up survey of the University of Washington Family Practice Residency
      Network, we analyzed the characteristics of 358 graduate physicians and their 493
      practices, including data on geographic practice locations. RESULTS: Two thirds
      of graduates began their practices in urban locations, and one third initially
      settled in rural communities. Female graduates were much less likely than their
      male peers to choose rural practice locations. Few physicians left practices
      after they had practiced in them for 5 or 6 years. The majority of graduates were
      still in the practice where they started as long as 18 years earlier.
      CONCLUSIONS: The most important career decision made by the graduate of a family
      medicine residency involves practice location. Because women are less likely to
      practice in rural areas, the increasing proportion of women graduating from
      family practice residencies might presage shortages of rural physicians in the
      future.

PMID- 8659259
TI  - A brief history of the American Board of Family Practice: the Second Annual
      Nicholas J. Pisacano, MD, Memorial Lecture.

PMID- 8659260
TI  - A diagnostic challenge: the child with fever, rash and arthritis.

PMID- 8659261
TI  - Exercise dependence in a pregnant runner.

PMID- 8659262
TI  - Mycobacterium haemophilum cellulitis and osteomyelitis in a man with AIDS.

PMID- 8659263
TI  - Treatment of AIDS and HIV-related conditions--1996.

PMID- 8659264
TI  - What do family medicine residency graduates do?

PMID- 8659265
TI  - Perinatal outcomes and family practice.

PMID- 8659266
TI  - Family medicine in Massachusetts.

PMID- 8659267
TI  - Use of mammography.

PMID- 8659268
TI  - Clinical and laboratory findings in acute appendicitis in the elderly.
AB  - BACKGROUND: Early diagnosis and surgery are important factors by which the
      morbidity and mortality of acute appendicitis in elderly patients can be lowered.
      This study was conducted to determine clinical and laboratory results that are
      commonly associated with acute appendicitis in elderly patients. METHODS: A
      retrospective chart review was conducted of patients aged 60 years or older who
      underwent appendectomy or laparotomy for suspected acute appendicitis during a 5
      year period in a metropolitan county. Acute appendicitis was confirmed by the
      pathology report. RESULTS: Elevated band cells and right lower quadrant pain were
      predictors of acute appendicitis in clinically suspected cases. Band cells
      greater than 6 percent had an excellent positive predictive value, as all
      patients with elevated band cells had acute appendicitis. With increasing white
      cell count and temperature, specificity increased, sensitivity decreased, and the
      positive predictive value remained high. CONCLUSIONS: It is essential to have a
      high degree of suspicion to recognize acute appendicitis in an afebrile elderly
      patient who has abdominal pain, a mildly elevated white cell count, and band
      cells in the upper limits of normal.

PMID- 8659269
TI  - The cost-effectiveness of interventions for preventing pressure ulcers.
AB  - BACKGROUND: While there is scientific evidence to support the efficacy of
      preventive interventions for pressure ulcers, few empirical data are available on
      their cost-effectiveness. The aim of this study was to determine the cost
      effectiveness of interventions to prevent pressure ulcers. METHODS: Cost of
      preventive interventions and days of ulcer-free survival were compared for two
      groups of patients. One group consisted of 250 patients from a geriatric unit of
      a British hospital (Norton sample). At the time of the study, no preventive
      measures were used. Data from the original report of the study were used to
      determine patients' attainment of one of three end points--ulcer formation,
      death, or discharge--from which a disease-free survival table was constructed.
      The second cohort of 420 patients consisted of residents of a long-term care
      facility in Iowa, where aggressive preventive measures were used (Iowa sample).
      Data were collected at the study onset and 3 months later. The types of
      preventive interventions used on each patient were assessed and their costs
      calculated. Cost of treatment for pressure ulcers was estimated from previous
      research performed at the Iowa facility. The cost-effectiveness of the preventive
      intervention was calculated by dividing the mean difference in cost between the
      two groups by mean difference in ulcer-free days. RESULTS: Survival analysis of
      days to ulcer development showed the Norton (no prevention) sample had a
      significantly shorter time to ulcer development than did Iowa sample (patients
      receiving preventive measures) (P < 0.0001). The mean cost for prevention and
      treatment of an ulcer was $167 +/- $307 for the Norton sample and $245 +/- $379
      for the Iowa sample. The mean number of ulcer-free days was 21.0 -/+ 17.4 for the
      Norton sample and 78.5 +/- 11.0 for the Iowa sample. The cost per day of ulcer
      free life gained was $1.36. CONCLUSION: The use of aggressive preventive measures
      in the long-term care setting is effective in reducing pressure ulcers and
      requires a relatively low level of institutional expenditures.

PMID- 8659271
TI  - Quality of the family physician component of AMA Masterfile.
AB  - BACKGROUND: This investigation was undertaken to gain insight into the validity
      of the American Medical Association (AMA) Masterfile data. METHODS: Allopathic
      family physicians were chosen as the study population Omissions were picked up
      from by comparing the AMA list with the 1990 Ohio Academy of Family Physicians
      Foundation-Ohio Department of Health (OAFPF-ODH) census. Verification of the 1990
      specialty and geographic location of allopathic family physicians not common to
      both files was achieved by sequentially (1) reviewing the AMA names against 1990
      deletions from the 1985 OAFPF-ODH census, (2) contacting physicians directly by
      telephone, (3) verifying 1990 physician status with county medical personnel, and
      (4) mailing a brief questionnaire to each physician whose 1990 status remained
      unverified. RESULTS: The status of specialty and geographic location in 1990 was
      verified in 91 percent of names not common to both lists. Incorrect omissions
      (undercounts) and incorrect inclusions (overcounts) offset each other for both
      lists. Two groups of family physicians contribute to counting biases: family
      physicians who fulfill short-term goals by part-time practice in several
      locations, and family physicians who restrict their practice to a limited medical
      content area. CONCLUSIONS: Because of nearly equal offsetting of overcounting
      (incorrect inclusions) and under counting (incorrect omissions), the 1990 Ohio
      family physician AMA Masterfile data is adequate for work-force projections and
      policy studies when the county data are aggregated at the state level. The
      overcounting and undercounting for smaller areas or categories must still be
      studied, however. Application of the AMA Masterfile data of other geographic
      areas requires a knowledge of the components of undercounts and overcounts of the
      population being studied.

PMID- 8659270
TI  - An educational needs assessment of rural family physicians.
AB  - BACKGROUND: A shortage of family physicians persists in rural and medically
      underserved areas of the United States. We explore the hypothesis that a
      definable set of educational needs should be addressed for rural family
      physicians, both during their formal education and as part of continuing
      education while in practice. METHODS: An educational needs assessment
      questionnaire was sent to 1096 family physicians who had finished residency and
      entered rural practice within the last 3 years. Six hundred twenty-seven (57.2
      percent) of the questionnaires were returned. The demographic characteristics of
      the respondent physicians and their assessment of the appropriateness and
      adequacy of their educational process in preparing them for rural practice were
      analyzed by looking at individual items and groups of items or subject areas.
      RESULTS: We were able to define successfully a group of items that were important
      components of rural practice but were not adequately addressed in training
      programs. Theses groups included counseling, pediatrics, obstetrics and
      gynecology, geriatrics, surgery and trauma, medical specialties, surgical
      specialties, community medicine and management, and a mixed factor that included
      rehabilitation, behavioral sciences, learning disabilities (in children), chronic
      childhood problems, and human growth. CONCLUSIONS: It is possible to define a
      group of educational areas not covered adequately by standard family practice
      curriculum that should be included in preparation for rural practice. If these
      areas were included in the education of rurally oriented family practice medical
      students and residents, these physicians would be more adequately prepared to
      meet the demands of rural practice. If preparation for rural practice is
      improved, rural communities might be more successful in recruiting and retaining
      well-trained family physicians.

PMID- 8659273
TI  - [The relationship of PSA to age and prostatic volume in patients with benign
      prostatic hypertrophy].
AB  - Prostate specific antigen (PSA) is the most useful market for the diagnosis,
      staging and monitoring of prostate cancer. However, the effect of benign prostate
      hyperplasia on PSA levels is less well known. It has been reported that 20-45% of
      all adult males with BPH have PSA values over the normal range. To study this
      confounding factor we have analyzed the likely relationships between monoclonal
      PSA, age and prostate size as determined by ultrasound, in our series of 163
      patients with BPH undergoing adenomectomy. Within the studied factors, the most
      conditioning parameter of PSA variability was prostate size. The correlation
      coefficient (r) was 0.61, with the determination coefficient (r2) being 0.037 (p
      < 0.001). Age correlation, although less important (r = 0.31), was statistically
      significant. Both variables were independent and resulted jointly in a
      correlation coefficient of 0.64. Also included is the mathematical formula used
      in our series to correlate PSA with age and prostate volume. Its application
      could mean an increased specificity of this tumoral marker.

PMID- 8659272
TI  - [New horizons of radical prostatectomy in the treatment of localized prostatic
      cancer].

PMID- 8659274
TI  - [The index of PSA age vs PSA density. 2 new instruments in the detection of
      prostatic carcinoma].
AB  - A prospective study was designed to get to know the reliability of PSA density
      and PSA age index as tools in the diagnostic approach for prostate carcinoma. It
      was noted that PSA age index is more susceptible than PSA density to diagnose
      prostate cancer. We noted also that up to 80% of patients with prostate cancer
      and intermediate PSA levels have PSA density < 0.15 and that, according to
      current protocols biopsy should not have been performed. It was concluded that
      the value of PSA age index is at least equal to PSA density, but it eradicates
      the subjectivity introduced by this data because of the need of measuring
      prostate volume. We believe that in the future it may be indicated to perform
      biopsies at PSA levels above 4 ng/ml, and it may be necessary to decrease PSa
      normal density levels down to 0.1 or less.

PMID- 8659276
TI  - [The evolution over time (1960-1990) of mortality and the ratio of males in
      bladder cancer in Spain].
AB  - A time series on the evolution of mortality and the masculinity attribute in
      vesical cancer in Spain (1960-1990) was prepared. The specific rates by age and
      sex by 100,000 inhabitants were calculated. To attain standardization the same
      study population was taken as the reference population. Overall mortality rates
      due to vesical cancer have increased progressively in a linearly ascending trend,
      though the slope in men is sharper that in women. The females cohort approaches
      that of males, but with a difference between them of 30 years. By age groups, the
      higher increase has occurred in those over 75-year old (113% men, 77% women). The
      masculinity attribute presents variations depending on the age group and decade
      considered (1.4-10.9). It is possible to establish three groups by masculinity
      attribute: 20-44 years (average 1.91), 45-69 years (average 7.8) and over 70
      years (average 6.3).

PMID- 8659275
TI  - [The diagnostic utility of PSA density].
AB  - Recently, the concept of PSA density has been introduced in order to increase the
      diagnosis sensitivity obtained with serum PSA dosing. The usefulness of this
      parameter has been assessed in 47 patients with benign prostate hyperplasia (BHP)
      and 26 patient with non-disseminated prostate adenocarcinoma. Using 0.15 as cut
      off value, below which were 97% of patients with uncomplicated BHP, we obtained a
      73% overall sensitivity. This sensitivity was stage related, reaching 100% in
      stage C patients. On the contrary, the test specificity was relatively low, since
      it considered patients with complicated HPB with urinary infection or with in
      dwelling vesical catheter, obtaining 41% false positives. These results suggest a
      special usefulness of this test for the correct diagnosis of those prostate cases
      with mild suspicion of cancer.

PMID- 8659277
TI  - [The surgical opportunity in metastatic lesions of renal-cell carcinoma after a
      response to adjuvant immunotherapy].
AB  - Surgical resection of primary lesions and single metastasis can be curative, but
      surgery, used as the only therapeutic option, is not unanimously accepted in
      patients with multiple metastasis and, apart from other considerations, there are
      no established clinical criteria to allow us to predict which patients will
      benefit from a metastectomy. This study evaluates four patients with advanced
      RCC. Three had multiple pulmonary metastasis at the time of diagnosis and one
      presented retroperitoneal mass at 36 months of follow-up. All patients were
      nephrectomized and received adjuvant immunotherapy with an association of IL-2
      and 2b alpha-IFN subcutaneously, obtaining partial response of the disease after
      two treatment courses. Later, the patients underwent debulking surgery. Two
      patients are still alive and have no evidence of disease progression at 28 months
      and 8 months of follow-up. This data and that contrasted with other authors,
      suggests that surgical management would be a reasonable option in patients who
      have partially responded to immunotherapy, even though the selection of both
      candidates and surgical strategy should be considered on an individual basis.

PMID- 8659278
TI  - [Extracorporeal shockwave lithotripsy in single kidneys. Our experience].
AB  - Forty patients with renal lithiasis in single kidney were treated with
      extracorporeal shock wave lithotrity in our unit. Nine patients required
      emergency urinary by-pass, because of original picture of obstructive anuria, and
      in another 21 cases a double-J catheterism was conducted as prophylaxis prior to
      lithotrity. Treatment was carried out with analgesia and ambulatory, except for
      10 patients with calculi of less than 10 mm where by-pass was not performed, and
      who were kept in preventive hospitalization for 24 hours. Average of sessions per
      patients was 1.59 (range 1-7). After 6 months follow-up there are 24 free renal
      units (60%), 12 (30%) with debris that can be expelled, failure in 4 (10%): 2
      with debris that can be expelled and 2 which were not fragmented. Renal function
      has not deteriorated during follow-up, except for 2 patients with obstructive
      uropathy, that subsequently normalized following resolution of the condition. No
      significant differences were found in the treatment of calculi of less than 10 mm
      with or without double-J. ESWL is considered to be the choice approach for
      lithiasis in patients with one single kidney, due to is efficacy and low
      morbidity, safety in the ambulatory environment, even for calculi of less than 10
      mm with no urinary by-pass.

PMID- 8659279
TI  - [Diagnostic and therapeutic retrograde ureterorenoscopy (URS)].
AB  - Presentation of results obtained in 50 procedures of retrograde ureterorenoscopy
      (URS), and discussion based on the literature and our results, on the current
      indications for URS with regard to extracorporeal lithofragmentation (ECL) for
      the treatment of pelvic ureteral lithiasis and the diagnosis and/or treatment of
      other conditions. Fifty URS were performed in 47 patients between February 1992
      and March 1994: 35 were conducted to treat ureteral lithiasis, achieving a 97%
      success rate and a mean post-surgery hospital stay of 48 hours; and for
      diagnostic and/or therapeutic reasons. There were no major complications, and a
      description is made of minors cases. We prefer to use URS in those cases of
      distal ureteral lithiasis, as compared to ECL, because of its level of efficacy
      (higher than or equal to ECL), low cost/benefit ratio, low morbidity and shorter
      hospital stay involved. The paper emphasizes the major diagnostic and
      therapeutical indications for URS, and finally, it is noted that URS can avoid
      undertaking other more aggressive urinary by-passes, since it allows to
      catheterize the ureters where a false intramural route is conducted.

PMID- 8659280
TI  - [The use of the IPSS questionnaire in surgical patients. International Prostatic
      Symptom Score].
AB  - Some feasibility problems were detected during the evaluation of the IPSS
      questionnaire in Spanish that might limit its application. Our initial experience
      with the IPSS in patients undergoing surgery had 3 aims: 1) assess if changes in
      format and wording will improve feasibility; 2) evaluate symptoms before and
      after surgery according to the patients' point of view and 3) determine possible
      predictive factors of bad outcome in patients undergoing surgery for BPH. 50
      patients were included and 35 completed symptom and urolow evaluation before and
      after the intervention. First objective: a modified format improved feasibility
      up to 92% (from 49% with the original format). Second objective: 7 patients had a
      poor symptomatic outcome (either worsened or had an unsignificant improvement),
      but only one of them had a low postoperative Qmax. Third objective: patients with
      preoperative urinary retention had a worse urodynamic outcome, but most improved
      in their symptoms. Worse symptomatic results occurred in: a) patients with a IPSS
      score smaller than 13 and b) patients undergoing transurethral incision of the
      prostate. The results are presented both in global (comparison of mean values)
      and in an individualized manner to call upon the pitfalls in their
      interpretation.

PMID- 8659281
TI  - [Bladder carcinosarcoma. A clinical case].
AB  - Presentation of a new case of vesical carcinosarcoma in a 49 year-old male
      patient. The tumour's pathoanatomical study showed an epithelial pattern of
      transitional and squamous cells and a sarcomatous pattern composed of
      rabdomiosarcoma, osteochondrosarcoma and pleomorphous indifferentiated sarcoma
      with giant multinuclear cells. Histogenesis, signs and symptoms, and treatment,
      as well as the need of performing an immunohistochemical study for its diagnosis
      are discussed.

PMID- 8659282
TI  - [Renal angiomyolipoma located intrasinusally. An anomalous location which poses
      diagnostic problems].
AB  - Presentation of one case of intrasinusale located renal angiomyolipoma. Given the
      location, the ECO as well as the IVU, arteriography and CAT presented diagnostic
      doubts. We believe this unusual presentation should be added to those
      circumstances where uncertainty of tumor diagnosis due to size, behaviour or
      clinical signs and symptoms, elicits a more aggressive attitude.

PMID- 8659285
TI  - [Cystic pyeloureteritis. A review of the literature in the period of 1946-1994
      and a report of a new case].
AB  - Presentation of a new case of unilateral cystic pyeloureteritis in a 46-year old
      female patient. The condition presented as a right renoureteral colic. A revision
      is made of the 69 national cases published on such an uncommon condition, of
      obscure etiologic, pathogenic and therapeutical features. The accent is placed on
      its most significant aspects, such as: difficulties of differential diagnosis
      with other repletion defect imagen in the excretory tract and their frequent
      association to other diseases.

PMID- 8659283
TI  - [Adrenal myelolipoma: apropos a case with urologic symptomatology. A review of
      the literature].
AB  - Presentation of a new case of Suprarenal Myelolipoma, its singularity being the
      urinary clinical presentation. Brief review of the literature, placing special
      emphasis on the Spanish references.

PMID- 8659284
TI  - [Obstructive uropathy secondary to genitourinary prolapse].
AB  - Genital prolapse is associated to a greater concurrence of repeat urinary
      infections, stress urinary incontinence, arterial hypertension and obstructive
      uropathy with a higher or lower degree of renal impairment. Incidence of uropathy
      in the genital prolapse setting ranges between 4 and 13%. This paper presents a
      female patient with renal insufficiency secondary to bilateral obstructive
      uropathy caused by a concomitant genital prolapse. A brief revision is made of
      the pathophysiological, diagnostic and therapeutic aspects in the literature. The
      need to perform both prone and standing urographic studies is emphasized; also a
      study of the renal function should be performed in these patients in order to
      establish the appropriate treatment and avoid major complications and renal
      function impairment.

PMID- 8659286
TI  - [Education andrology].

PMID- 8659287
TI  - [Urethral stenosis. Conceptual review and classification].
AB  - In an extensive review focused on male urethral stenosis, where more than 1,200
      publications relative to this problem were evaluated, we found a lack of
      conceptual precision when it comes to qualify the varied terminology used to
      define concepts such as normal urethra, urethral stenosis, relapsing urethral
      stenosis, spongiofibrosis and urethral callus. The lack of precision may be due
      to the fact that we surgeons are more interested in reporting our surgical
      successes than in semantic appraisals. No publications have either been commented
      with a global approach to the problem of the various and potential
      classifications of urethral stenosis in the various etiological, clinical,
      radiological, endoscopic, ultrasonic or therapeutic aspects. The current paper is
      an update of this old urological problem. The guidelines outlined below are
      neither entirely original, nor the only or even the most correct approach of all
      those that can be used to address this issue. They are simply the result of the
      cumulative surgical and medical experience as well as of the enthusiasm we feel
      toward this part of urology.

PMID- 8659288
TI  - [Prognosis significance of prostatic markers in patients with prostatic
      adenocarcinoma undergoing total hormonal blockade].
AB  - Evaluation of the prognostic value of prostatic markers with regard to disease
      progression after endocrine therapy in patients with prostate carcinoma. A total
      of 51 patients (21 stage C, 5 stage D1 and 25 stage D2). Endocrine therapy
      consisted in complete hormonal blockade with flutamide and an LH-RH analog depot
      (leuprolide). PSA-PAP levels were determined both pre-treatment and during follow
      up of patients using radioimmunometric techniques. Follow-up extended for 13 to
      62 months (mean 30 months). Death due to progression happened in 24 of 51
      patients. Previous PSA levels did not correlate to progression. Changes in PSA
      levels during treatment and time scope when they occurred were associated to
      subsequent evolution. Patients with PAP higher than 10 ng/ml at the beginning of
      therapy experienced higher progression rates (p < 0.05). Decrease of PSA levels
      by a percentage greater than 80% during the first quarter of treatment relative
      to initial figures was related to lower progression rates (p < 0.01). Maintenance
      of high levels in the first six months of treatment predicted a higher
      progression rate (p < 0.001). The study suggests a better prognosis for patients
      wit decreased serum PSA rates by a percentage of around 80% after one to three
      months treatment.

PMID- 8659289
TI  - [Infiltrating carcinoma of the bladder. Neo-adjuvant chemotherapy (2nd. part).
      Historic review and new treatment guidelines].
AB  - Analysis of 37 patients treated with neoadjuvant chemotherapy + radical
      cystectomy and bilateral lymphadenectomy. Follow-up of patients was until death
      and survival is between 43 and 68 months. There has been 26 deaths. Of these, 20
      occurred within 24 months of therapy and only 6 after a two-year period. Five did
      not undergo surgery due to accelerated tumour progression during cytostatics
      administration. In another 5 cases, the idea of removing the bladder was
      discarded after significant loco-regional progression had been confirmed by
      laparotomy. 54% had involved lymph nodes. Metastasis was found in 57.3% and local
      relapse in 17.3%. The pre- operative chemotherapy investigated has not
      contributed to prolong the disease-free interval in the group of patients
      studied. After extended follow-up, the chemotherapy-treated group fared worse as
      compared with cystectomy alone and irradiation therapy (4,500 and 2,000 Rads.)
      followed by cystectomy. Presently, no patient should be deprived of the most
      effective therapy available: Surgery. Surgery should be a key step for the
      treatment of vesical infiltrant cancer. There are no resistant subpopulations to
      this option. Another question is to argue what sort of surgery should be used:
      TUR, radical o partial cystectomy. The ?T? is useless to assess the efficacy of
      any therapeutical option adjuvant to surgery. Patients with pT2, pT3a tumours
      should be excluded from protocols designed to evaluate the performance of
      therapies added to surgery. All protocols investigating and adjuvant approach to
      radical cystectomy should include a control group with surgery alone.

PMID- 8659291
TI  - [Neuro-urologic impact of spinal cord untethering in patients with
      myelomeningocele and tethered cord].
AB  - Changes in bladder behaviour and neurological symptoms were evaluated in 47
      patients underwent untethered spinal cord because of tethered cord syndrome
      secondary to myeloneningocele closure. Patients were located in 3 categories (A <
      or = 5 years, B 6-10 years and C > 10 years) in relation to age of treatment.
      After untethering 77% improved neurologically and the best results were evident
      in children whose condition was repaired promptly (90%). Urodynamic studies were
      performed in 33 patients before and after surgery. Fifteen had hyperreflexic
      bladders, six low compliance and 12 hyperreflexia disappeared in 4 and sphinteric
      resistance increased in 2. In patients with tethered cord syndrome, untethering
      is recommended treatment in preventing further, sometimes rapid neurologic
      dysfunction and better results are got in childs whose condition is repaired at
      an early ages.

PMID- 8659290
TI  - [Feminization: a paradoxical effect of stimulation with hCG/hMG in the infertile
      male].
AB  - Male feminization is an uncommon and complex phenomenon which occurs as a
      consequence of an imbalance in the effective oestrogen/androgen relationship. One
      of the many approaches used in the treatment of idiopathic male infertility is
      hCG/hMG stimulation. This paper reports one case of an infertile male treated
      with hCG/hMG after surgical correction of a varicocele, which resulted in a
      feminization effect evidenced by gynaecomastia and severe spermatogenesis
      blockade. When therapy was discontinued the feminization disappeared, a rebound
      phenomenon with normalization of most of the seminal parameters being seen. No
      other fully documented cases were found in the literature. Finally, the
      pathoetiological mechanisms involved in the feminization are analyzed and a
      revision is made of the causes that may cause it.

PMID- 8659292
TI  - [Entero-vesical fistula in primary lymphoma of the small intestine].
AB  - The introduction of self-expandable urethral endoprotheses for the management of
      relapsing urethral stenosis has required the development of a minimally invasive
      therapeutical approach of widespread acceptance by the urological community. The
      reason for its success is the simplicity of implantation and the low rate of
      complications up to date. This paper reports on a patient carrying a ?Urolume?
      urethral endoprothesis for a relapsing bulbar urethral stenosis, which two years
      after implantation presents re-stenosis secondary to endoluminal inflammatory
      tissue growth. After two failure endoscopic resections, endoscopic removal of the
      prosthesis was required. Currently the patient carries a ?Urocoil? spiral
      endoprosthesis to avoid tissular reaction. The therapeutical aspects found in the
      literature are reviewed, emphasizing the need of follow-up to detect
      complications, to improve indications and to select those patients that may be
      candidates for this treatment.

PMID- 8659293
TI  - [Spontaneous bladder perforation secondary to bacterial cystitis. Cause of acute
      abdomen in diabetic elderly].
AB  - Presentation of two clinical cases of spontaneous vesical rupture secondary to
      bacterial cystitis in elderly patients. One corresponds to an intraperitoneal
      perforation while the second case was extraperitoneal. The patients were, in both
      cases, diabetic women admitted in emergency due to acute abdomen. We considered
      that although vesical perforation secondary to bacterial cystitis is a very
      uncommon process, it should be taken into account in the differential diagnosis
      of acute abdomen in predisposed patients (diabetic elderly patients with pyuria).
      In such instances, a retrograde cystography would provide the diagnosis. Although
      extraperitoneal vesical perforations can be resolved with a vesical catheter or
      cystostomy, extravasation of the infected urine may result in a perivesical
      abscess and septic shock. Early surgical management should be considered in these
      cases.

PMID- 8659294
TI  - [Perinephritic abscess as clinical presentation of pancreatitis].
AB  - Presentation of a female patient with pain in right hemiabdomen, suspected of
      perinephritic abscess. Emergency laboratory tests and X-rays evidenced presence
      of choledocholithiasis and acute pancreatic abscess which infiltrated cell and
      right perirenal space. The treatment established was surgical drainage of both
      the pancreatic cell and the retroperitoneal space. A good clinical history,
      differential diagnosis and immediate aggressive treatment facilitated a
      favourable evolution of such cases. The unusual perinephritic location of
      pancreatic abscesses is reported in the literature with a frequency of less than
      2%.

PMID- 8659295
TI  - [Obstruction of the urethral conduct following implantation of the endoprosthesis
      Urolume: therapeutic management].
AB  - The introduction of self-expandable urethral endoprostheses for the management of
      relapsing urethral stenosis has required the development of a minimally invasive
      therapeutical approach of widespread acceptance by the urological community. The
      reason for its success is the simplicity of implantation and the low rate of
      complications up to date. This paper reports on a patient carrying a ?Urolume?
      urethral endoprosthesis for a relapsing bulbar urethral stenosis, which two years
      after implantation presents re-stenosis secondary to endoluminal inflammatory
      tissue growth. After two failure endoscopic resections, endoscopic removal of the
      prosthesis was required. Currently the patient carries a ?Urocoil? spiral
      endoprosthesis to avoid tissular reaction. The therapeutical aspects found in the
      literature are reviewed, emphasizing the need of follow-up to detect
      complications, to improve indications and to select those patients that may be
      candidates for this treatment.

PMID- 8659296
TI  - [Asymptomatic bladder paraganglioma. Report of a case].
AB  - Paragangliomas are tumors which arise from collections of neuroepithelial cells
      (paraganglion system) scattered throughout the body and rarely in the urinary
      bladder. In this work, we described a case of bladder paraganglioma, not
      suspected in a 64-year-old male who showed occasional total hematuria as only
      symptom. Cystoscopically, it was diagnosed as a rounded, not papillary tumor, one
      centimeter in diameter on account of which it was subjected to TUR. Confirmed the
      diagnosis, a partial cystectomy and a limited regional lymphadenectomy were
      subsequently practised. Posterior evolution, after a year, was completely
      favourable. The main clinicopathologic characteristics of this entity are
      revised.

PMID- 8659297
TI  - [Myxoid neurofibroma of the renal sinus].
AB  - Presentation of one case of a 7.5 x 6 cm myxoid neurofibroma located in the left
      renal sinus, which is really exceptional. The finding in a 41-year-old,
      asymptomatic patient is casual and during a routine follow-up study with
      ultrasound for a Hodgkin lymphoma with a 9-year remission interval. Computerized
      axial tomography, intravenous urography and thin-needle puncture-aspiration
      cytology were performed to investigate its origin. Treatment is surgical and
      requires nephrectomy of the affected side.

PMID- 8659298
TI  - [Conceptual review of simple renal ectopy and suggestion of a unifying
      embryogenetic hypothesis].
AB  - Proposal for a conceptual review of the theories currently used to explain the
      pathogenesis of single kidney ectopia. The inner mechanisms which generate this
      frequent anomaly in the positioning and rotation of the kidneys are far from
      being understood. Based on a critical review of the literature and our own
      observational findings, we believe the single kidney ectopia is a time-dependent
      embryo-development change model which can be used as a ?chronopathy? paradigm.

PMID- 8659299
TI  - [Rapidly growing renal angiomyolipoma associated with pregnancy].

PMID- 8659300
TI  - [Retroperitoneal lymphadenectomy in the treatment of testicular cancer].

PMID- 8659301
TI  - [Stress urinary incontinence. Our experience with its treatment using the
      transvaginal colposuspension technique (Raz I and II)].
AB  - Presentation of our experience in the surgical treatment of urinary stress
      incontinence, with transvaginal colposuspension techniques, specifically those
      described by S. Raz and known as Raz I and Raz II. Over a 24-month period, 25
      transvaginal colposuspensions (22 Raz I and 3 Raz II) were performed. The results
      achieved were 21 patients (84%) have recovered, while 4 (16%) remain incontinent,
      3 of them referring improvement and 1 without improvement, after a follow-up of
      12 to 36 months. With regard to complications, there has been 5 cases (20%) of
      postoperative retention, one vesical perforation while passing the needles, and a
      vesicle perforation during vaginal dissection of the retropubic space.

PMID- 8659302
TI  - [Evolution of hypospadias surgery. Comparative study of the various techniques
      used for 20 years].
AB  - With the purpose of studying the long-term results of the different surgical
      techniques used for the treatment of hypospadias, we have examined 1186 patients
      treated in our centre over the last 20 years. To facilitate the comparative
      study, three well-defined periods have been established: 1974-1981 (165 pts.).
      Treatment was done in several operative times. Denis Browne and Mathieu's
      urethroplasties were the techniques more frequently used. Their long-term
      evolution show keratosis and hairiness of the neourethra, which in 17 patients
      required a new urethroplasty with vesicle mucosa, as the most serious
      complication. 1982-1986 (281 pts.). Restoration was done in one single operative
      time. Magpi, Mathieu and Duckett's techniques were the most frequently used
      during this period. 1987-1993 (624 pts.). An island flap is added as cutaneous
      plasty after urethroplasty has been performed. Fistulae were the most frequent
      complications in all the above time-periods (18, 10 and 7.3%, respectively),
      followed by stenosis (12, 6.5 and 4.4%) and megaurethra (6.8, 6.7 and 2.9%). The
      remarkable decrease both in number and seriousness of the complications is due to
      the island cutaneous flap, hormonal stimulation, use of slow reabsorption
      materials , silicone probes, silastic foam dressings, caudal anaesthetics and,
      above all, a better indication for the surgical technique in each case.

PMID- 8659303
TI  - [Role of autotransfusion of pre-stored blood in benign prostate hyperplasia. Our
      experience].
AB  - The essence of self-transfusion is the extraction of a patient's own blood for
      subsequent infusion to the same patient. The practice of this strategy has become
      particularly important from the moment the likelihood of AIDS virus transmission
      through transfusion with homologous blood products became known. This article
      presents our experience in both open and endoscopic BPH surgery over the period
      ranging from January 93 to December 94, and analyzes the health care and
      socioeconomic aspects of that experience.

PMID- 8659304
TI  - [Treatment of vesico-ureteral reflux in low compliance bladder].
AB  - Ten patients with noncompliant bladders and vesicoureteral reflux who did not
      respond to I.C. and anticholinergic therapy, underwent bladder augmentation and
      no effort was made to correct reflux surgically, because in these patients, in
      theory, reflux is secondary to bladder dysfunction. In 8 patients bladder
      augmentation was made with the intestine and in 2 with the ureter. All patients
      had a normal compliance after treatment and of the 10 patients with reflux (14
      renal units) it disappeared in 7 (11 renal units) and in the 90% of the patients
      with grades III and IV. In the 3 patients where reflux remained, in 2 it was a
      unilateral low grade reflux (II) and in 1, had improvement from grade IV to grade
      II. In these patients reflux only appearing when the bladder got too full, which
      under normal conditions patients do not get with the I.C. Our experience
      indicates the antireflux procedures are not routinely needed in this group of
      patients.

PMID- 8659306
TI  - [Epidemiology of urethral stenosis in the province of Alicante].
AB  - Urethral stenosis is the most frequently acquired disease of the male urethra.
      Currently there is a progressive increase of this condition's occurrence due to:
      improved living standard, increased number of permanent catheter bearers, surge
      of STDs incidence, and abuse of transurethral diagnostic or therapeutical
      instrumentation. However, and in spite of such increased incidence, the
      epidemiological features have been forgotten by most authors consulted who now
      focus more attention in the therapeutical aspects. This paper analyzes the most
      outstanding epidemiological aspects, in the province of Alicante, of 180 urethral
      stenosis corresponding to 175 males and 5 females, making some final
      considerations on the relevance of certain factors in the genesis of urethral
      stenosis: advanced age, depressed social class, active sexual life, STD history,
      urinary or genital infections.

PMID- 8659305
TI  - [Estimate of creatinine clearance with formulae: a valid option compared with
      conventional measurement?].
AB  - Determination of creatinine clearance is the most commonly used method to
      evaluate renal function, requiring collection of urine from a given period of
      time, usually 24 hours. Cockcroft and Gault developed a formula to estimate this
      parameter without urine samples, however some authors have shown the low
      reliability of this and similar nomograms. The present study is an attempt to
      evaluate the differences between the laboratory determination of this parameter
      and its evaluation using Cockcroft's equation. The study included 24 patients who
      had creatinine clearance determined through biochemical methods and with the
      formula proposed by Cockcroft. Mean clearance in the first instance was 81.4
      mL/min and 65.5 mL/min in the second one. The estimated mean difference in
      creatinine clearance obtained by both methods was 16.4 mL/min. A significant
      difference between clearance determinations was found using the above methods and
      therefore it is concluded that the values obtained with Cockcroft's formula are
      hardly reliable since the method tends to subestimate creatinine clearance. Also,
      two new formulas were developed which correlate better with the results obtained
      in our series. To conclude, we recommend that creatinine clearance should be
      measured at the laboratory using serum and 24-hour creatinine determination.

PMID- 8659307
TI  - [Focal infarction of the testis. Report of a case simulating a gonadal mass].
AB  - Series of comments on the clinical history of one patient diagnosed "a
      posteriori" with a focal infarction of the testis. The case was pre-operatively
      handled as a tumour, as a result of which the patient underwent radial
      orchiectomy. The only notable feature in the patient's background was a
      vasectomy, performed two years earlier. The rationale for this communication is
      the rarity of this entity and the differential diagnosis to be practised.
      Reference is made to some complementary diagnostic tests that may be requested.
      It includes a number of considerations on testis vascularization. After reviewing
      some studies contributed by the Spanish literature, several complications to be
      taken into consideration when performing a vasectomy are explained.

PMID- 8659308
TI  - [Carcinoma of the Bellini's collecting duct: report of 2 new cases].
AB  - Report on two new cases of Bellini's collector duct carcinoma (CTC), discussing
      the clinical, radiological and pathological aspects which differentiate this
      disorder from the clear cells carcinoma, and review of the related literature.

PMID- 8659309
TI  - [Bladder schistosomiasis: report of 2 new cases with different anatomoclinical
      features and review of the literature].
AB  - This paper reports two cases of vesical schistosomiasis in two black patients
      treated in this Service over the last three years. A description is made of the
      different anatomo-clinical presentations of these two cases, commenting on the
      characteristics of this disease, its pathogenesis, diagnosis and treatment, and
      stressing the slight increase in its frequency in our environment as a
      consequence of the increased migratory movements of people from endemic regions
      into our country.

PMID- 8659310
TI  - [Hemangioma of the adrenal gland].
AB  - Adrenal gland haemangioma is an uncommon tumour which finding usually occurs by
      chance. This paper presents one case of cavernous haemangioma in this location on
      which surgery was performed successfully. The basic aspects of the case are
      revised from a pathohistological and diagnostic point of view intended to attempt
      to suspect its presence preoperatively.

PMID- 8659311
TI  - [Effect of bombesin on cultured prostatic cells].
AB  - The detection of immunoreactivity to bombesin-like peptides in endocrine
      paracrine cells from normal and pathological prostates suggest they have a
      regulatory role over this structure. With the purpose of explaining the action of
      these peptides on the prostate tissue an analysis is made of the bombesin effect
      on single-layer cultures of normal (rat ventral prostate) and tumoral (PC-3 cell
      line) prostate tissue. After performing morphological studies through phase
      contrast microscopy, as well as using cell counts and immunohistochemical
      techniques (Ki-67) to study the influence of bombesin on cell proliferation, this
      has been shown to stimulate prostate cells proliferation "in vitro". This
      response was revealed with greater intensity at bombesin concentrations of 0.5
      nM/ml on the rat ventral prostate and bombesin 1 nM/ml on the PC-3 cell line. No
      morphological differences were observed between the controls and the bombesin
      containing microwells in the rat ventral prostate, but some greater size cell
      elements with irregular shape were seen in the PC-3 cultures, as well as an
      increased number of mitotic division shapes in the wells filled up with bombesin.

PMID- 8659312
TI  - Contraceptive use and reproductive history in women with cervical human
      papillomavirus infection.
AB  - The study was conducted to investigate whether cervical human papillomavirus
      infections (CHPI) are associated with contraceptive use and reproductive history.
      The contraceptive and reproductive histories in 972 women seeking contraceptive
      advice were noted and screening conducted for human papillomavirus infection. The
      interview included number of pregnancies and childbirths, legal and spontaneous
      abortions, and menstrual pattern. Information about current use of contraceptive
      methods, about casual sex, and history of combined oral contraceptive pill (OC)
      use was obtained. Women with a history of spontaneous abortion showed a
      significant correlation with CHPI, as did women who used high-dose OCs when
      compared with the remaining study population (odds ratio 3.0). There was no
      association between use of low-dose OCs and CHPI. In multifactorial analyses with
      adjustment for age, number of lifetime sexual partners, number of partners during
      the preceding six months and age at first intercourse, the significant
      correlation between use of high-dose OCs and CHPI remained (adjusted odds ratio
      2.8). The results indicate a relationship between female steroid hormones and the
      occurrence of CHPI. An association with high-dose OCs could not be excluded.

PMID- 8659313
TI  - Low-dose progestogen contraception and the nursing mother.
AB  - Breast feeding, though an important and efficient contraceptive method, suffers
      from one major limitation: the contraceptive protection it offers the nursing
      mother ends abruptly without giving any physical indication of the return of
      fertility. Barrier methods and progesterone-only hormonal contraceptives, either
      in the oral, implant or injectable form, appear to be the primary contraceptive
      alternative for the nursing mother today. They neither adversely affect
      lactation, nor does the minute quantity of progesterone (NET or LNG) transferred
      to the infant affect its growth and physical well-being. Puerperal insertion of
      IUD carries an inherent risk of pelvic inflammatory disease, high expulsion rates
      and menorrhagia, once menses resume. Combination contraceptives affect both the
      quality and quantity of breastmilk; hence they are not recommended. Sterilization
      is a permanent method and therefore useful only when the family has been
      completed.

PMID- 8659314
TI  - Effects of an implant of nomegestrol acetate, a 19-nor-progesterone derivative,
      on thyroid function.
AB  - This study was undertaken to assess tri-iodothyronine (T3), thyroxine (T4),
      thyroid stimulating hormone (TSH), T3 uptake, free T3 and free T4 in nomegestrol
      acetate implant (Uniplant) users. A total of eighteen volunteers of reproductive
      age who wanted to avoid conception were enrolled in the study. All subjects were
      investigated before starting treatment. Blood samples for hormonal analysis were
      taken prior to insertion of the implant. Thereafter, blood samples were drawn at
      3, 6, 12, 18 and 24 months of Uniplant use. All subjects had used non-hormonal
      contraceptives for at least 6 months prior to insertion of the implant. The
      results observed in this study showed that there was no significant difference in
      tri-iodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH)
      during two years of Uniplant use. No significant difference was found in free T3
      levels during two years of Uniplant use. A significant decrease was observed in
      T3 uptake (p < 0.05) in month 24 and in free T4 (p < 0.05) in month 3 of Uniplant
      use. All changes observed in this study were inconsistent and all levels were
      within the normal range.

PMID- 8659315
TI  - Comparison of the efficacy of intrauterine diclofenac and ibuprofen pellets as
      adjuvants to quinacrine nonsurgical female sterilization.
AB  - To investigate relative efficacy of intrauterine diclofenac and ibuprofen as
      adjuvants to intrauterine quinacrine for nonsurgical sterilization, a total of
      900 women were systematically allocated to 2 monthly insertions of pellets of
      diclofenac (75 mg) or ibuprofen (55.5 mg) as adjuvants to intrauterine quinacrine
      (216 mg) in a rural private practice in West Bengal, India. All women were
      prescribed oral contraceptives for three months from first insertion. In the
      middle of the study increased care was taken to insert pellets at the fundus.
      There was no statistically significant difference found in cumulative life-table
      pregnancy failure rates at 36 months for women receiving diclofenac (2.7 +/-
      0.82) or ibuprofen (3.4 +/- 0.89). Taking care to insert pellets at the fundus
      resulted in a decline of failures at 24 months from 4.4 +/- 0.92 to zero.
      Intrauterine administration of pellets of quinacrine (216 mg) plus diclofenac (75
      mg) or ibuprofen (55.5 mg) with 3 months' oral contraception provides acceptable
      efficacy if pellets are inserted to the fundus.

PMID- 8659316
TI  - Menstrual disorders and pelvic pain after sterilization.
AB  - Changes in menstrual cycle length, menstrual duration, number of pads,
      dysmenorrhea and non-cyclic pelvic pain were studied in 43 women following tubal
      sterilization with three different techniques. One group consisted of 17 women
      undergoing laparotomy by Pomeroy technique; the second group consisted of 11
      women undergoing laparoscopy by Fallope rings; and the third group consisted of
      15 women undergoing colpotomy by fimbriectomy. The differences before and after
      sterilization in cycle length were non-significant in all groups (p > 0.05).
      After sterilization, menstrual duration and number of pads were significantly
      increased in the laparotomy (p < 0.001) and laparoscopy (p < 0.01) groups but non
      significantly in the colpotomy group (p > 0.05). Comparison of these parameters
      between the groups did not show any significant differences (p > 0.05). After
      sterilization, increases in the severity of dysmenorrhea and non-cyclic pelvic
      pain were non-significant in all groups (p > 0.05). We concluded that there were
      no significant differences in menstrual disorders after sterilization among these
      three different techniques.

PMID- 8659318
TI  - Institutionalizing fertility management/human sexuality training in Colombian
      nursing schools.
AB  - While there is no universally applied definition of the terms,
      'institutionalization', 'capacity', 'capability' and 'commitment' have been
      suggested as subindicators of a self-sustained program. This paper describes
      efforts to measure these terms in the context of a fertility management/human
      sexuality (FM/HS) education program for student nurses in Colombia. Interviews
      with 19 school deans formed the basis of measuring progress towards
      institutionalization. All the deans supported the idea of having FM/HS
      instruction, although resource commitment to effectively carry out the
      instruction varied. Focus groups with professors from participating schools
      provided insights into the effect of the project on both the students and course
      teachers. Professors found that students who had taken the course were more
      effective FM/HS counselors in later practical courses. Responses from interviews
      with a random sample of students who had or had not attended the course were
      compared to assess the effect of the course on the nursing students. Although
      attitudes between the two groups did not differ significantly, knowledge levels
      about FM/HS were significantly higher among nursing students who had attended the
      course. In general, the results indicate that the participatory educational
      approach used in teaching the FM/HS topics was effective in sensitizing both
      students and teachers to this subject area.

PMID- 8659317
TI  - A framework for establishing integrated reproductive health training.
AB  - The challenge for the next decade will be to make quality family planning
      services accessible to all sexually active couples who want them. The key to
      fulfilling this goal is the need to rapidly increase the availability of quality
      voluntary family planning services globally. This paper presents a framework for
      integrated reproductive health training which provides a mechanism for ensuring a
      continuous sustainable supply of qualified trainers and service providers. The
      paper discusses the approach used by JHPIEGO, a Johns Hopkins University program
      for international education in reproductive health, to build up national training
      capacity through the development of integrated reproductive health training. This
      approach may be seen as a network of pathways linking the national system of
      higher education, the health care system, the political system and cultural norms
      to strengthen reproductive health policy, training and services. National
      integrated reproductive health training includes: updated national policies and
      service guidelines, pre-service training in health professional schools to
      prepare students to provide family planning services upon graduation; in-service
      training for practicing health professionals to improve family planning skills
      for immediate application on the job; and development of clinical training sites
      at service delivery points already providing family planning/reproductive health
      services.

PMID- 8659319
TI  - Family planning knowledge and practice among Nigerian women attending an
      antenatal clinic.
AB  - This study investigates family planning activity in 308 Nigerian women attending
      an antenatal clinic. Family planning awareness was present in 234 women (76%) and
      practice occurred in 168 (54.5%). Proposal to practice family planning occurred
      in 66 of 137 women who had never used contraception while 69 (22.4%) had no
      intention to practice family planning. The best-known type of contraception was
      the condom, 182 (59.1%); the most common used, the safe period (rhythm), 73 women
      (23.7%); while Billings' contraception was the most commonly proposed type, 72
      women (23.4%). Knowledge of the beneficial effects of the chosen method of
      contraception was claimed by 102 women (43.6%) while 33 (14.2%) conceded
      ignorance of this. Similarly, 81 women (34.6%) claimed to know the adverse
      effects of their chosen method of contraception, while 119 (50.9%) admitted
      ignorance of it. The most common source of information on contraception was the
      printed media, 112 (47.9%), while the least common was lecture/sex instruction,
      27 (11.5%). Lack of adequate information and ignorance are key factors militating
      against family planning practice in Nigeria. Family planning activity in Nigeria
      would be improved by wider dissemination of information on family planning
      through public lectures and the electronic media; training of family planning
      counselors to facilitate grass-roots coverage; universal entrenchment of family
      planning counseling into routine antenatal clinic activities; and integration of
      private medical centers into the national family planning service.

PMID- 8659321
TI  - Peter F.L. Boreham (1942-1995).

PMID- 8659320
TI  - Usefulness of a clinical scoring system to anticipate difficulty of Norplant
      removal.
AB  - OBJECTIVES: Removal of contraceptive implants (e.g. Norplant) is an issue
      affecting its worldwide acceptability. Reports of difficult, painful removals
      have resulted in lawsuits and reduced demand. To improve quality of care, we
      developed a scoring system to anticipate difficult removals. We report on the
      usefulness of such a system and present client perspectives about the removal
      experience. METHODS: A 9-point scoring system based on the visibility,
      arrangement, and position (VAP) of Norplant capsules was used to assess the
      anticipated difficulty of removal in 53 consecutive patients. The VAP score was
      then correlated with removal time and related parameters. RESULTS: Mean removal
      time was 14.74 min (range 4.75-47). In 20% of patients, the VAP score indicated a
      potentially difficult removal and the VAP score correlated significantly with
      removal time (r = 0.3, p = 0.05). Patients expected removal to be moderately
      difficult (mean visual analog score 4.7 out of a possible 10), but after removal
      they rated the actual removal experience as relatively easy (mean score 2.6/10).
      Before the removal, only 48% of patients said they would recommend Norplant to a
      friend but after removal, 70% said they would do so. CONCLUSIONS: A scoring
      system such as the VAP score can help identify potentially difficult removals so
      that an experienced remover can be present at the time of removal or an
      appropriate referral made. However, the VAP score cannot predict variables such
      as the density of the subcutaneous fibrous tissue "envelope". Although patient
      anxiety concerning removal may be high, the presence of a competent remover and
      an easy removal experience reduces this anxiety and encourages patients to be
      more positive about this method. The value of having properly trained, competent
      personnel available to perform removals cannot be over-emphasized.

PMID- 8659323
TI  - In vivo protective effect of the lectin from Canavalia brasiliensis on BALB/c
      mice infected by Leishmania amazonensis.
AB  - In vivo administration of Canavalia brasiliensis lectin (at the time of
      infection, or maintained throughout the infection) reduced the lesions of highly
      susceptible BALB/c mice infected by Leishmania amazonensis. At the doses used C.
      brasiliensis lectin (ConBr) does not interfere with penetration or fate of
      Leishmania in the macrophages in vitro. Since Interferon-gamma (IFN-gamma) is the
      major macrophage activating factor, and considered a critical element in the
      successful immune response against leishmaniasis, we explored its participation
      in this phenomenon. ConBr either in vivo or in vitro induced IFN-gamma production
      in normal or in leishmania-infected BALB/c mice. However we were unable to change
      the course of disease by in vivo IFN-gamma administration (although IFN-gamma
      preparations were effective in inducing a leishmanicidal effect in vitro on L.
      amazonensis-infected peritoneal macrophages). Additionally, IFN-gamma
      neutralization with anti-IFN-gamma monoclonal antibody did not alter the
      protection conferred by ConBr administration. These data show that lectin
      administration in vivo is protective in the otherwise unchecked L. amazonensis
      infection of BALB/c mice, and suggest that such effect is not mediated by IFN
      gamma.

PMID- 8659322
TI  - Serum antibodies to Trypanosoma cruzi antigens in Atacamenos patients from
      highland of northern Chile.
AB  - In the present work we have investigated the serum antibody spectrum to parasite
      antigens involved in human T. cruzi infection. Analysis was performed by
      conventional serology (IHA, IFAT and ELISA), complement-mediated lysis, anti-gal
      antibody assay and reactivity against recombinant and synthetic peptides and
      metacyclic antigens by immunowestern-blotting. All the sera showed a significant
      reactivity in IHA, IFAT and ELISA. We found that 84.2% of the sera showed lytic
      activity and thirty serum samples (78.9%) which showed a lytic activity higher
      than 50%, also showed anti-gal antibodies at serum dilutions higher than 1:1,600.
      Ninety-four percent of sera reacted with one or more of the recombinant DNA
      clones and 97.3% reacted with one or more of the synthetic peptides. A pool of
      serum samples with a lytic activity higher than 75% were able to produce 60% to
      78% inhibition of cell invasion. Thirty-six of the serum samples (94.7%) were
      able to react by immunowestern blotting with a T. cruzi metacyclic antigen with
      molecular size of 70 kDa. The results obtained give preliminary information about
      the humoral immune response and the possible role of antibodies in protection
      against T. cruzi infection of chronic patients from the highlands of Chile.

PMID- 8659325
TI  - A simple method for maintaining, detecting and recovering virulent Leishmania
      donovani in hamsters.
AB  - The ability of hamsters (Mesocricetus auratus) to retain amastigotes of
      Leishmania donovani at cutaneous sites was examined. Following intradermal
      inoculation of L. donovani stationary phase culture promastigotes in fore and
      hind footpads, nasal area and belly skin, cultures of aspirates taken fortnightly
      from these sites showed that amastigotes can survive in the skin for up to 10
      months without visceralizing. Hairless cutaneous sites were better at retaining
      L. donovani amastigotes than the hairy belly skin. L. donovani promastigotes
      cultivated from aspirates of sites of inoculation were highly virulent. The skin
      is suggested as one of the sites where viscerotropic L. donovani can remain
      cryptic for a long time before the infection either visceralizes or is aborted.
      Skins of hamsters when inoculated intradermally can serve as an easy site for
      maintaining, detecting and recovering virulent L. donovani without killing the
      hamster.

PMID- 8659324
TI  - Characterisation of cloned lines of Trypanosoma brucei expressing stable
      resistance to MelCy and suramin.
AB  - Two cloned drug-sensitive stocks of Trypanosoma brucei (STIB 247 and STIB 386)
      were each used to generate cloned lines expressing resistance to the
      melaminophenyl arsenical drug cymelarsan (247MelCyR and 386MelCyR) and to suramin
      (247SurR and 386SurR). The drug-resistance phenotypes were stable after passaging
      in mice in the absence of drug pressure and three of the lines were transmitted
      through tsetse flies with no alteration of drug-resistance. There was no evidence
      of cross-resistance between melCy and suramin in vivo. Twenty-four hour growth
      inhibition assays were conducted on bloodstream and procyclic forms in axenic in
      vitro cultures. Suramin-resistance was expressed in bloodstream forms but not in
      the procyclic stage, while the melCy-resistant lines expressed melCy-resistance
      in both stages. No cross-resistance between melCy and suramin was observed. Cross
      resistance between melCy and another arsenical drug, melB (melarsoprol), was
      observed in vivo, but to only a very limited extent in vitro. We propose that
      this difference between the in vivo and in vitro results for melB may indicate
      that an alteration in a surface adenosine transporter responsible for reduced
      melCy uptake was bypassed by melB over 24 hours in vitro.

PMID- 8659326
TI  - The effect of immune sera from hamsters immunized with sandfly gut and whole body
      extract antigens on the fecundity and mortality of Phlebotomus duboscqi (Diptera:
      Psychodidae).
AB  - Phlebotomus duboscqi were fed on hamsters previously immunized with different
      concentrations of homogenized crude sandfly gut antigen and supernatant obtained
      from whole body extract. The humoral response in the rodents was quantified at
      different times post-immunization by the enzyme-linked immunosorbent assay.
      Sandflies were fed on either immunized or saline control hamsters and the effect
      of the blood meals on sandfly feeding, survival and fecundity was investigated.
      The humoral response in immunized hamsters as measured by the presence of P.
      duboscqi-specific IgG antibodies was significantly greater (P < 0.05) as compared
      to the controls. This difference was noted in sera collected on 15 and 25 days
      post-immunization. Sandflies fed on immunized hamsters had a significantly higher
      mortality (P < 0.05) and decreased egg production (P < 0.05) than those fed on
      unimmunized control hamsters.

PMID- 8659327
TI  - Mefloquine insusceptibility of malaria in Thailand not promoted by nonregulated
      drug-use.
AB  - To determine whether the nonregulated use of antimalaria drugs on the Thai
      Cambodian border promoted the recent loss of mefloquine sensitivity by Plasmodium
      falciparum parasites, we identified the drugs consumed there by gem miners. Of
      those drug concoctions that were self-administered, five contained chloroquine,
      one contained primaquine and bactrim and two merely contained analgesics. Local
      nonregulated healers prescribed orally administered concoctions containing
      chloroquine, quinine, tetracycline or primaquine for patients suffering mild
      illness. They administered parenteral chloroquine for severely ill patients and
      quinine when malaria was life-threatening. Certain of these healers prescribed
      fansimef, but only infrequently and after 1990. Because gem miners appear not to
      have had informed access to mefloquine before 1990, we conclude that the loss of
      antimalaria efficacy of this drug on the Thai-Cambodian border during the late
      1980s was independent of its nonregulated use.

PMID- 8659329
TI  - [A new method of cancer treatment: the use of radiofrequencies in urological
      tumors].
AB  - This study reports our preliminary experience with interstitial radiofrequencies
      in the treatment of urological malignancies. Bipolar radiofrequency was
      interstitially delivered in four freshly removed human kidneys in an ex-vivo
      model. The kidney was perfused ex-vivo with 37 degrees C saline in order to mimic
      physiological conditions. Large reproducible and controlled lesions
      (hypereosinophilia and pyknosis) were observed in the parenchyma between the
      active needles. Further animal and human clinical studies are planned to precise
      the place of bipolar RF in the treatment or urological malignancies, and
      especially in kidney tumors.

PMID- 8659330
TI  - [High-grade intraepithelial prostatic neoplasms: diagnosis and association with
      prostate cancer].
AB  - Prostatic intraepithelial neoplasia (PIN) fulfils the majority of requirements
      for a premalignant change in the human prostate. Forty-eight patients were
      diagnosed to have high grade PIN on prostatic needle biopsy. During a follow-up
      period, 23 (47.9%) were found to have adenocarcinoma on subsequent biopsies. We
      compared the patients age, the digital examination, the transrectal ultrasound
      appearance (TRUS) and the serum PSA level between those in whom cancer was
      detected subsequently and those with PIN alone. There was a statistically
      significant difference in the transrectal ultrasound appearance (TRUS) and the
      serum PSA level between the two groups (p < 0.001, p < 0.016 respectively). In
      conclusion, patients with high grade PIN, elevated serum PSA with hypoechoic zone
      on TRUS should be rebiopsied 3 months after the initial diagnosis. If the results
      are negative, close follow-up is mandatory.

PMID- 8659328
TI  - Finasteride in the treatment of benign prostatic hyperplasia.
AB  - Finasteride is an enzyme inhibitor which blocks the conversion of testosterone by
      5 alpha-reductase to dihydrotestosterone, the active androgenic metabolite in the
      prostate. In a double-blind, placebo-controlled study, 707 patients with
      moderately symptomatic BPH were treated for 2 years. The study confirmed that
      treatment significantly improved symptoms, reduced prostate size and increased
      urine flow rate. Side effects were usually mild. The authors find that
      finasteride can reverse the natural progression of BPH.

PMID- 8659331
TI  - [Endoscopic extraperitoneal colposuspension].
AB  - The authors point out the advantages and the inconveniences of the different
      surgical procedures (conventional surgery, transperitoneal celioscopy and
      extraperitoneal endoscopy) performed in order to treat urinary stress
      incontinence. An original extraperitoneal endoscopic procedure, using a non
      resorbable mesh (polypropylene), is proposed. The technique is based on the
      principle of the open approach described by Burch. The short branches of an Y
      shaped mesh are sutured at the antero-lateral walls of the vagina. The basis of
      the Y is pulled out of the extraperitoneal space by using a grasper introduced
      through a short incision of the skin and the subcutaneous tissues, and
      perforating the aponeurosis of the rectus muscle. This technique provides the
      surgeon with an effective and strong tension on the mesh under endoscopic view
      control. The basis of the mesh is then fixed at the insertion of the rectus
      muscle on the pubic bone.

PMID- 8659333
TI  - [Treatment of hypospadias: 15-year experience].
AB  - Numerous hypospadias correction techniques were described in the literature. The
      technique varies according to the position of the meatus and the importance of
      the chordee. These new techniques and the care taken in the manipulation of the
      tissues tend to decrease complications like stenoses and fistulas, frequent in
      the long urethroplasty. The correction of hypospadias should conform to aesthetic
      and plastic surgery. More than 300 corrections were carried out in our service.
      Surgical technique varied in the long run. Currently, we choose as often as
      possible a correction in one time: release of the chordae and urethroplasty.
      Straightening of the penis is obtained on one hand by release of the cutaneous
      chordae and wide dissection of the hypoplastic urethral plate and one or more
      dorsal plications according to Nesbit are carried out if it proves necessary. In
      the distal, glandular and coronal forms, the correction is of type M.A.G.P.I.
      (meatal advancement, glanduloplasty). The complication rate is extremely low. The
      aesthetic and functional result is very satisfactory. In the proximal forms,
      Duckett technique is used only in the obligatory cases given the large number of
      complications. It is generally replaced by Onlay technique. The urethral plate is
      left in continuity and serves as support to the pedicled and vascularized flap.
      In the intermediate situations with a middle shaft hypospadias, Mathieu technique
      is again of application. The aesthetic and functional result of this type of
      surgery requires good knowledge and careful application of the technique adapted
      to each case.

PMID- 8659332
TI  - [Neoadjuvant hormone therapy with total radical prostatectomy: intermediate
      results].

PMID- 8659334
TI  - [Erectile dysfunction: the role of Rigiscan in the diagnosis].
AB  - OBJECTIVE: Nocturnal penile tumescence (NPT) was performed in all patients and
      was evaluated as normal or abnormal according to standardized general criteria.
      The results of NPT were then compared to penile duplex ultrasonography parameters
      peak systolic velocity (normal > 35 cm/sec) and diastolic velocity (normal < 5
      cm/sec), and to the flow rate needed to maintain erection (normal < 15 ml/min)
      with pharmaco-infusion cavernosometry. RESULTS: Of the 50 patients, 26 showed
      normal NPT where 25 patients (96%) had normal penile systolic velocity, 18
      patients (69%) had normal penile diastolic velocity, and 22 patients (85%) showed
      normal flow to maintain erection. On the other hand, 24 showed abnormal NPT,
      where 7 patients (29%) had abnormal penile blood flow velocity and 18 patients
      (75%) showed high flow rate to maintain erection. CONCLUSION: From this study, we
      can conclude that normal NPT appears to have a good correlation with normal
      systolic blood velocity and normal cavernosometry. However, this correlation is
      low when compared with diastolic blood velocity. On the other hand, a low
      correlation exists between abnormal NPT and abnormal systolic and diastolic blood
      flow or abnormal cavernosometry. According to this observation, we can presumed
      that NPT, penile duplex and infusion cavernosometry considering together should
      be performed in order to achieve a reasonably accurate diagnosis.

PMID- 8659335
TI  - [Complications of intravesical mitomycin chemotherapy, apropos of 2 clinical case
      reports].
AB  - Administration of intravesical chemotherapy by mitomycin C (MMC) is an adjuvant
      treatment of the recurrent superficial bladder cancer. Since use of MMC in 1967,
      many different toxicities were reported. Those are local toxicities. Systemic
      toxicity is rare. At the hand of 2 cases reports and recent literature, we
      discuss the possible complications of intravesical therapy with MMC.

PMID- 8659337
TI  - [Intra-cavernous collagen analysis in impotence].
AB  - The role of the different components of the corpus cavernosum is very important
      in the physiopathology of erectile dysfunction. The precise function of collagen
      fibers in erectile physiology is controversial. We measured the different types
      of collagen (I, III, IV) in the corpus cavernosum of 26 impotent and potent men
      using cell image analysis and immunohistochemistry. We found differences in the
      distribution of collagen I, III, IV in each pathological group (arterial, caverno
      venous, psychogenic). The augmentation of collagen I and the light diminution in
      collagen III makes the corpus cavernosum less compliant which translates
      clinically as an alteration in the filling of the vascular spaces and by
      dysfunction of the veno-occlusive mechanism. The diminution in collagen IV shows
      an alteration in the function of endothelial cells. The fact that in the
      psychogenic group we found also a diminution in collagen IV content, makes us
      infer that psychogenic impotence could be the first stage of an organic
      impotence.

PMID- 8659336
TI  - [Retroperitoneal seminoma. A case report and literature review].
AB  - The authors report the case of a man aged 28 showing symptoms which were
      diagnosed as a primitive retroperitoneal seminoma. On the basis of both this case
      and a literature review, they propose a line of conduct to be followed on
      diagnosis of a retroperitoneal germinal tumour without evident testicular lesion.

PMID- 8659338
TI  - Intersexuality in pigs: clinical, physiological and practical considerations.
AB  - Veterinary surgeons and practical pig farmers need to be aware of a condition
      that can have important deleterious consequences in a breeding herd. The animals
      in question have sometimes been referred to as hermaphrodites but would more
      correctly be termed intersexes. Whilst there is a complete spectrum of phenotypic
      sexual development within a population of such animals, the most common form is
      that of a putative female with a prominent up-turned vulva. Reflection of the
      vulval lips reveals a much-enlarged clitoris. There may be scrotal development,
      in conjunction with an enlarged penile and preputial sheath. Coarse hair and
      incipient tusk development may further indicate differing degrees of
      masculinization. Surgical exploration of intersex animals confirms a complete
      spectrum of gonadal types, ranging from 2 ovaries with a proportion of testicular
      tissue in one of them (i.e., an ovotestis) to 2, much-enlarged testicular-like
      structures with no detectable ovarian tissue. The gonads usually remain within
      the abdomen, but those with testicular tissue may descend to an inguinal or even
      scrotal location. The genital tract invariably comprises a bicornuate uterus, a
      partially vestigial Fallopian tube, and some development of one or both Wolffian
      ducts adjoining an ovotestis or testicular-like structure to form a convoluted
      epididymis. Spermatozoa are never present, either in abdominal or scrotal
      testicular tissue, nor are there any germ cells within the seminiferous tubules,
      only Sertoli-like cells. Due to the spectrum of gonadal types, sexual behaviour
      ranges from male-type aggressivity on the one hand to regular oestrous cycles on
      the other, with periods of standing oestrus during which intromission may be
      achieved. In animals with functional ovarian tissue in both gonads, foetal
      development has been observed, at least until days 25-30 of gestation. Almost all
      intersex pigs possess XX sex chromosomes and usually 36 autosomes; only a very
      small proportion are chimaeras or mosaics. Chromosome banding techniques have
      failed to demonstrate a portion of the Y chromosome translocated onto an X
      chromosome nor has molecular probing revealed the presence of the sex determining
      gene Sry or other classical Y-related DNA sequences, except in one instance.
      Breeding records suggest that the intersex condition results most frequently from
      the influence of an autosomal recessive gene carried by certain boars.
      Identification of such boars is therefore essential, as the incidence of
      intersexuality in their offspring may reach 4-5% or more. In terms of the pig
      industry, economic losses may result from: 1. Lack of fertility in intersex
      animals. 2. Aggressive behaviour in groups of growing/fattening pigs. 3. Boar
      taint in the carcase of animals possessing ovotestis. 4. Propagation of the
      deleterious condition, either by mating or more widely by artificial
      insemination.

PMID- 8659339
TI  - Effects of mild mitral valve insufficiency, sodium intake, and place of blood
      sampling on the renin-angiotensin system in dogs.
AB  - In 23 Cavalier King Charles Spaniels, 12 with mild mitral valve insufficiency
      (MVI) and 11 controls, the activity of the renin-angiotensin system (RAS) was
      assessed by measuring the plasma renin activity (PRA) and plasma aldosterone
      concentration (PAC) in 5 different settings. The dogs were sampled at the clinic
      before the trial and thereafter at home and at the clinic; during both a period
      on control diet and a period on low sodium diet. The dogs with mild MVI had the
      highest median PRA and PAC in all 5 settings. An analysis of variance accordingly
      showed that dogs with mild MVI had significantly higher PRA (p < 0.0001) and PAC
      (p = 0.03) than controls, and that the sodium intake and place of blood sampling
      did not significantly affect this finding. The sodium intake had highly
      significant effects on PRA and PAC, and the place of blood sampling had no
      significant effects on PRA and PAC. The activity of angiotensin-converting enzyme
      in serum was lower in dogs with mild MVI than in controls (p = 0.0002). The
      plasma levels of endothelin-1, atrial natriuretic peptide, and arginine
      vasopressin, 3 peptides of pathophysiologic importance in congestive heart
      failure, were not significantly changed by the disease. The early activation of
      the RAS in dogs with MVI suggests that the valvular disease process itself might
      be the cause of the activation, but confirmation of this requires further
      studies.

PMID- 8659341
TI  - Concentrations of progesterone during storage of whole blood from llama (Lama
      glama): effects of anticoagulants, storage time and temperature.

PMID- 8659340
TI  - Lactic acidosis in a Clumber spaniel.

PMID- 8659342
TI  - Prevalence of Listeria monocytogenes and other Listeria spp.in smoked and
      'gravad' fish.
AB  - Altogether 150 samples of vacuum-packed fish were examined for the presence of
      Listeria species. Listeria monocytogenes were isolated from 12 of 58 'gravad'
      fish samples, 3 of 26 cold-smoked and one of 66 hot-smoked fish samples. Ten of
      these 16 positive samples harboured more than 100 L. monocytogenes cfu/g. The
      highest level (132,000) was found in a sample of hot-smoked rainbow trout
      (Oncorhynchus mykiss). Serogroup 1/2 was most frequently found, followed by 4 and
      3. One sample of gravad rainbow trout harboured more than one serogroup of L.
      monocytogenes. L. innocua and L. seeligeri were isolated from 12 and 1 samples,
      respectively.

PMID- 8659343
TI  - Selenium and fertility in animals and man--a review.
AB  - To evaluate the information on selenium with relation to fertility in animals and
      man the available literature was reviewed. Selenium is incorporated in the sperm
      mitochondria capsule and may thus affect the behavior and function of the
      spermazoon. Se seems to be essential for normal spermatozoa development in both
      experimental animals and in livestock and probably also in humans. Regarding
      selenium and female fertility only sparse information exists. In experimental
      animals a low selenium level affects fertility in males, but little attention has
      been devoted to female reproductive performance, and the data are insufficient
      for conclusion. In livestock numerous investigations have been performed and the
      effects of selenium supplementation often in combination with other antioxidants
      have been evaluated, but no valid conclusion can be drawn. In general adequate
      nutritional supply will secure optimal reproduction in both males and females,
      while additional supplementation seems to have a negative effect. In humans
      contradictive information is found. Both low and high sperm selenium
      concentrations are reported to have a negative influence on the number of
      spermatozoa and on the motility. The optimal sperm selenium concentration waits
      to be defined. Some evidence indicates that a metabolic defect in a selenium
      incorporation into sperm cells may be associated with human infertility. No human
      data relating selenium to female infertility were found.

PMID- 8659344
TI  - A long term study of goats naturally infected with caprine arthritis-encephalitis
      virus.
AB  - The caprine arthritis-encephalitis virus (CAEV) is a big problem in dairy goat
      industry. Little is known about its characteristics in naturally infected goat
      herds. The aims of this study were: 1) to study how antibody expression, measured
      by agar gel immunodiffusion test (AGIDT), varied over time in naturally infected,
      seropositive goats, 2) to observe clinical signs in seropositive adult goats and
      3) to follow seroconversion and gamma globulin concentration in goat kids
      artificially reared on cow milk replacement product only, compared to kids reared
      on untreated goat milk. The antibody expression pattern to the viral proteins
      gp135 and p28 varied in the individual goat and intermittent negative reactions
      were seen in 19 adult animals followed for 30-91 weeks. Four seropositive goats
      developed clinical symptoms with difficulties to move. However, no correlation
      between clinical signs and antibody expression pattern was seen. During the first
      27 weeks of age no kid in the milk replacement reared group (N = 4)
      seroconverted, but 5 of the 7 kids fed goat milk occasionally showed a positive
      antibody reaction. The gamma globulin concentration was significantly higher in
      the goat milk fed group until the kids had become more than 19 weeks old. The
      results show that a great variation of the antibody pattern in individual goats
      occurs, and therefore the AGIDT is only reliable as a herd screening test.
      Frequent sampling is necessary to get reliable information about spreading of the
      CAEV in a naturally infected goat herd. Removing kids from their dams immediately
      after birth combined with segregation and artificial rearing protected them from
      CAEV infection. However their gamma globulin concentration was initially low.

PMID- 8659345
TI  - Bovine virus diarrhoea virus in semen from acutely infected bulls.
AB  - The risk of spreading bovine virus diarrhoea virus (BVDV) from acutely infected
      animals to susceptible animals was investigated. Ten bulls from a herd with no
      previous history of BVDV were used. The bulls were demonstrated free from BVDV
      and such antibodies. Six of the bulls were inoculated intravenously with
      cytopathogenic virus, and 4 bulls were used as controls. Semen samples were
      collected during a period of 66 days after inoculation. The samples were examined
      for BVDV, and spermatological parameters were registered. Testes and epididymides
      were examined histologically post mortem. All inoculated bulls exhibited elevated
      temperatures between days 4 and 8 after inoculation, and BVDV antibodies were
      found in all of them on day 22. The control animals remained antibody negative.
      Non-cytopathogenic BVDV was isolated from seminal plasma from 2 bulls on day 7
      after inoculation. Semen volume was significantly reduced from week 6 after
      inoculation. Percent abnormal sperm cells decreased in the same period. No
      significant differences were observed in sperm density or percentage of live
      spermatozoa. No pathological changes were found in the testes or epididymides.

PMID- 8659346
TI  - Welfare in Danish dairy herds 1. Disease management routines in 1983 and 1994.
AB  - This paper presents the first part of a questionnaire survey carried out in 2148
      Danish dairy herds during 1994, as well as results from a similar survey carried
      out in 1983. The welfare status in Danish dairy herds with respect to disease
      management routines currently applied is discussed. In detail this was: recording
      of mastitis incidents, use of veterinarian for milk fever cases, farmer's effort
      in reducing incidence of mastitis, milk fever, ketosis, calving problems, and
      lameness, as well as frequency of claw trimming, reasons for culling, and way of
      replacing cullings. Furthermore, trends during the 11 year period are discussed.
      The results show that the Danish dairy farmers in 1994 in general have a
      substantial knowledge of prevention and treatment of disease. However,
      adjustments in the following areas would be appropriate: 1) farmers should avoid
      making intravenous infusions, 2) they should be encouraged to use calving boxes
      for parturitions, 3) there should be more attention on claw health, and 4) to
      comply with the new Danish legislation, antibiotic dry cow treatment should only
      be carried out on the individual cow if pathogenic microorganisms have been
      isolated within 35 days prior to drying off.

PMID- 8659347
TI  - Welfare in Danish dairy herds 2. Housing systems and grazing procedures in 1983
      and 1994.
AB  - This paper presents the second part of a questionnaire survey carried out in 2148
      Danish dairy herds during 1994, as well as results from a similar survey carried
      out in 1983. The welfare status and trends during the 11 year period are
      discussed with respect to cattle housing systems and grazing procedures.
      Generally speaking, the results show that Danish dairy farmers in 1994 followed
      the common recommendations, i.e. 1) there are partitions between stalls in almost
      all tie stall houses, 2) feeding cubicles are seldom seen in cubicle houses, 3)
      bedding is provided for most cows, 4) saw dust as bedding for cows is not
      commonly used, and 5) the majority of cows and heifers are pastured during
      summer. However, adjustments in the following areas would be appropriate: 1) tie
      systems which restrict the cow's natural rising and lying should be phased out,
      and 2) loose housed heifers in boxes should have access to a bedded resting area.

PMID- 8659348
TI  - Welfare in Danish dairy herds 3. Health management and general routines in 1983
      and 1994.
AB  - This paper presents the third part of descriptive results of questionnaire
      surveys in 152 Danish dairy herds in 1983 and in 2148 dairy herds in 1994. Focus
      is on working routines related to health management and the close environment of
      the cows. The variables are grouped in 6 categories as man power, bedding, water
      supply, manure handling, health management routines, and the farmers' age and
      their opinion about health and welfare of the dairy cows. The results show that
      the husbands did the major parts of the job in the herds. Permanent laborers were
      mainly hired in cubicle and deep bed farms, while it was more common to hire a
      relief man (short term basis) in tie stall herds-i.e. in the generally smaller
      herds. The average time spent on milking and feeding per cow per day ranged from
      5.2 min in cubicle houses and 5.4 min in deep bed houses to 9.9 min in tie stall
      houses. The time per cow per day seemed to have been reduced by approximately 43%
      during the 11 year period. Straw was the primary choice of bedding, and the use
      varied much among the herds. In tie stall houses with open dung channel and
      concrete floor the daily average use of straw was 1.74 kg per cow. Only 37.0% of
      the farmers used bedding for the heifers. Water supply seemed to be well
      installed in all houses, and dung removal was highly automated. Apart from
      milking and feeding times the farmers looked after the cows on average twice a
      day. The farmers primarily looked for cows in heat, signs of disease, calving,
      and abnormal lying and raising patterns. At night 87.7% of tie stall farmers and
      80.8% of cubicle house farmers were likely to check the cows, particularly with
      respect to calving. In deep bed systems only 58.5% would check the cows at night.
      Contrary to this, farmers looked after pastured heifers less frequently. Farmers
      were generally concerned that the cows had a dry period. The average length
      stated was 6.6 weeks. Farmers were generally satisfied with the health and
      welfare of the cows. The answers also indicated that farmers differentiated
      between the 2 concepts, as the correlation between welfare and health was only r
      = 0.34 (p < 0.001).

PMID- 8659349
TI  - Granulosa-cumulus-corona expansion and aromatase localization in preovulatory
      follicles in superovulated heifers.
AB  - Granulosa-cumulus and cumulus-corona expansion as well as aromatase localization
      within ovarian follicles were monitored during the preovulatory period in
      superovulated cattle that were blood sampled every 2'nd h for LH analyses.
      Granulosa-cumulus as well as cumulus-corona expansion were studied by means of
      transmission electron microscopy and computerized image analysis. Localization of
      aromatase, an enzyme involved in estrogen synthesis, was determined
      immunocytochemically using anti-human placental aromatase cytochrome P-450
      antisera. Nuclear oocyte maturation was determined by aceto:orcein staining.
      Significant cell dissociation within the granulosa-cumulus stalk occurred before
      the breakdown of the germinal vesicle, i.e. the oocyte nucleus, during the period
      up to 5-7 h after the LH peak, i.e. the highest LH concentration during the
      surge. Significant increase in intercellular spacing between the cumulus-corona
      cells occurred at 13-15 and 19-21 h after the LH peak. Before the LH peak all
      layers of granulosa cells were immunocytochemically stained for aromatase. At 5-7
      h after the LH peak, however, only the granulosa cell layers located near the
      basal lamina were stained, and at all later intervals staining was absent. The
      granulosa cells of primary and secondary follicles, the interstitial gland cells,
      the theca interna cells and the oocytes in all follicles were
      immunocytochemically unstained.

PMID- 8659350
TI  - The relationship of thoracic lymphadenopathy to pulmonary interstitial disease in
      diffuse and limited systemic sclerosis: CT findings.
AB  - OBJECTIVE: Mediastinal lymphadenopathy is frequently associated with interstitial
      lung disease (ILD) in patients with systemic sclerosis (SSc). This study compared
      the extent of lymphadenopathy in diffuse and limited SSc with the presence and
      type of ILD found on CT scans. SUBJECTS AND METHODS: Seventy-three patients with
      diffuse and limited SSc underwent thoracic CT. The presence of lymphadenopathy
      was correlated with the frequency and type of ILD. RESULTS: Fifty-eight percent
      (18/31) of patients with diffuse cutaneous SSc and 40% (17/42) of patients with
      limited cutaneous SSc had lymphadenopathy. A significant relationship was found
      between lymphadenopathy and the presence of interstitial disease (p = .0002).
      Seventy-two percent (18/25) of patients with a ground-glass parenchymal pattern
      of interstitial disease and 74% (14/19) of patients with a honeycomb pattern had
      lymphadenopathy. CONCLUSION: Lymphadenopathy is prevalent in patients with SSc
      and ILD regardless of clinical subtype or interstitial pattern. Lymphadenopathy
      appears to increase as a function of the profusion rather than the morphology of
      ILD.

PMID- 8659351
TI  - Diagnostic accuracy and safety of CT-guided percutaneous needle aspiration biopsy
      of the lung: comparison of small and large pulmonary nodules.
AB  - OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy and
      safety of CT-guided percutaneous needle aspiration biopsy of pulmonary nodules
      less than or equal to 1.5 cm in diameter with those of nodules greater than 1.5
      cm in diameter. MATERIALS AND METHODS: We retrospectively reviewed a consecutive
      series of 97 patients who underwent CT-guided percutaneous needle aspiration
      biopsy of a lung nodule and then surgical resection (n = 95) or autopsy (n = 2).
      By examining CT images, we classified 27 nodules as small ( < or = 1.5 cm) and 70
      nodules as large ( > 1.5 cm). Diagnostic accuracy was calculated by comparing
      cytologic diagnoses based on biopsy with final diagnoses based on histologic
      findings from surgery or autopsy. Each case was reviewed for possible
      complications, including pneumothorax and chest tube placement. RESULTS: The
      diagnostic accuracy of CT-guided percutaneous needle aspiration biopsy of large
      nodules was 96%. The diagnostic accuracy for small nodules was 74%, a
      statistically significant difference (p < .05). The prevalences of pneumothorax
      in our population were nearly identical for small and large nodules (22 and 21%,
      respectively). The prevalence of chest tube placement in our population was
      approximately 2%. The prevalences of chest tube placement were 0% for small
      nodules and 3% for large nodules. CONCLUSION: CT-guided percutaneous needle
      aspiration biopsy is significantly less accurate for small pulmonary nodules than
      for large pulmonary nodules, but the complication rates for both are low.

PMID- 8659352
TI  - Detection of subtle interstitial abnormalities of the lungs on digitized chest
      radiographs: acceptable data compression ratios.
AB  - OBJECTIVE: To determine acceptable compression ratios for digital radiography, we
      evaluated the effect of data compression on the detection of subtle interstitial
      lung abnormalities using digitized chest radiographs. MATERIALS AND METHODS:
      Screen-film chest radiographs of 38 patients with subtle interstitial lung
      abnormalities and 40 patients with normal lung parenchyma were digitized (spatial
      resolution, 0.175 mm; 2000 x 2000 pixels; 10 bits per pixel) and compressed with
      the discrete cosine transform method at ratios of 10:1, 20:1, and 30:1. Five
      chest radiologists and five radiology residents examined the uncompressed and
      compressed digital images and rates the presence of interstitial lung
      abnormalities with a five-level scale of confidence. Results were analyzed by
      receiver operating characteristic methods. RESULTS: Overall, the interpretation
      of images with a compression ratio of 30:1 was significantly less accurate than
      that of uncompressed images (p < .05). For the five chest radiologists,
      interpretation of images with a compression ratio of 20:1 or 30:1 was
      significantly less accurate than that of uncompressed images (p < .05). However,
      for the five residents, no significant difference between interpretations of
      compressed and uncompressed images was noted (p > or = .05). CONCLUSION: These
      results suggest that a 10:1 data compression ratio does not influence the
      detection of subtle interstitial lung abnormalities. However, information that is
      lost with a 20:1 data compression ratio might be essential for interpretation by
      experienced chest radiologists.

PMID- 8659353
TI  - Lymphoma of bronchus-associated lymphoid tissue.

PMID- 8659354
TI  - Peripheral bronchopleural fistulas: CT imaging features.

PMID- 8659355
TI  - MR imaging of anterior cruciate ligament injury: independent value of primary and
      secondary signs.
AB  - OBJECTIVE: The purpose of this blinded study was to test the value of primary and
      secondary signs, independent of each other, for diagnosis of a tear of the
      anterior cruciate ligament (ACL) by means of MR imaging. MATERIALS AND METHODS:
      MR images of the knee in 74 patients who had the status of the ACL confirmed
      arthroscopically were blindly reviewed for status of the ACL three times: with
      primary signs masked, with secondary signs masked, and with no signs masked. On
      the basis of the observed signs at each session, the status of the ACL was
      predicted and the confidence in that prediction was noted. The MR imaging
      predictions were compared with the arthroscopic findings. The results were
      analyzed with receiver operating characteristic curves and stepwise discriminant
      analysis. RESULTS: We found no difference in diagnostic performance when only
      primary signs were used and when both primary and secondary signs were used. When
      using primary signs only, our observers performed significantly better than when
      using secondary signs alone. However, with secondary signs alone, our observers
      performed better than if left to chance for predicting ACL status. Of the
      secondary signs, our statistical analysis found bone contusion, anterior
      translation of the tibia, and an uncovered posterior horn of the lateral meniscus
      to be the most useful for diagnosis. CONCLUSION: Secondary signs do have value
      for deciding ACL status independent of primary signs. However, our observers
      performed much better when using primary signs instead of secondary signs. In the
      clinical setting, secondary signs do not help significantly in the diagnosis of
      ACL tears by means of MR imaging.

PMID- 8659357
TI  - Quantitative CT assessment of the lumbar spine and radius in patients with
      osteoporosis.
AB  - OBJECTIVE: We undertook this study to quantify the relationship between bone
      mineral assessments of the lumbar spine using quantitative CT (QCT) and of the
      radius using peripheral QCT (pQCT) and to test the sensitivity of both techniques
      in detecting changes in bone mass that are related to age and osteoporosis.
      SUBJECTS AND METHODS: Forty-two healthy premenopausal, 38 healthy postmenopausal,
      and 97 osteoporotic postmenopausal women were examined with pQCT of the distal
      radius and with QCT of the lumbar spine (L1-L4). The bone mineral density (BMD),
      bone mineral content (BMC), and a cross-sectional area of cortical bone were
      assessed at the distal radius. The BMD of trabecular and total bone and the BMC
      of total bone were assessed at the midvertebral bodies of the lumbar spine.
      RESULTS: In the healthy women, correlations of radial BMD with spinal trabecular
      and total BMD were modest (r = .39 and r = .49, respectively) but were higher for
      total BMC (r = .79). All correlations in osteoporotic women (r = .19 for
      trabecular BMD, r = .31 for total BMD, and r = .47 for total BMC) were lower than
      those in healthy women. For measurement of spinal bone mass in healthy women,
      trabecular BMD showed a higher correlation with age (r = .81) and a larger
      relative annual decrease (1.2%) than did total BMD (r = .75, .78%) or total BMC
      (r = .54, .55%). At the radius, the highest correlations with age were found for
      total BMC (r = .57, .53%), cortical area (r - .52, .67%), and cortical BMC (r =
      .48, .78%). Age-adjusted odds ratios for prevalent vertebral fractures were
      highest for total (4.5) and trabecular (4.4) spinal BMD. For radial measurements,
      odds ratios were highest for both total BMD (2.3) and cortical area (2.3).
      CONCLUSION: QCT of spinal trabecular bone showed the strongest capability for
      assessment of age-related bone loss and for discrimination of osteoporotic
      vertebral fractures. In comparison, pQCT of radial trabecular bone showed the
      weakest capability for these applications, and pQCT of radial cortical or total
      bone showed intermediate capability.

PMID- 8659356
TI  - Fat-suppressed three-dimensional spoiled gradient-echo MR imaging of hyaline
      cartilage defects in the knee: comparison with standard MR imaging and
      arthroscopy.
AB  - OBJECTIVE: The sensitivity of fat-suppressed three-dimensional spoiled gradient
      echo (SPGR) images was compared with that of standard MR images for detecting
      hyaline cartilage defects of the knee, using arthroscopy as the standard of
      reference. SUBJECTS AND METHODS: We assessed 114 consecutive patients for hyaline
      cartilage defects of the knee with both standard MR imaging sequences and a
      sagittal fat-suppressed three-dimensional SPGR sequence. Of these patients, 48
      with meniscal or ligament injury, or persistent symptoms, underwent subsequent
      arthroscopy. The standard MR images and SPGR images of these 48 patients were
      then retrospectively analyzed for articular defects in a blinded fashion by two
      independent observers. Sensitivity, specificity, and intraobserver and
      interobserver agreement were determined for the different imaging techniques.
      RESULTS: One fourth of the patients who went on to arthroscopy were shown to have
      isolated hyaline cartilage lesions that were clinically confused with meniscal
      tears and that were missed on the standard MR images. When looking at all
      surfaces combined for each reader, the SPGR imaging sequence had a significantly
      higher sensitivity than the standard MR imaging sequences for detecting hyaline
      cartilage defects (75-85% versus 29-38%, p < .001 for each comparison). When
      looking at individual surfaces for each reader, significant differences in
      sensitivity were shown for each surface except the trochlear and lateral tibial
      surfaces. We found no difference in specificity (97% versus 97%, p > .99). We
      also found that combined evaluation of standard MR and SPGR images gave no added
      diagnostic advantage (sensitivity, 86%; specificity, 97%; p > .42). Except for
      the lateral tibial surface, the study achieved excellent reproducibility among
      readings and between readers. CONCLUSION: Fat-suppressed three-dimensional SPGR
      imaging is more sensitive than standard MR imaging for the detection of hyaline
      cartilage defects of the knee.

PMID- 8659358
TI  - Evaluation of soft-tissue foreign bodies: comparing conventional plain film
      radiography, computed radiography printed on film, and computed radiography
      displayed on a computer workstation.
AB  - OBJECTIVE: The study was performed to evaluate detection of soft-tissue foreign
      bodies using conventional radiography (film-screen radiography), computed
      radiography printed on films (computed radiography-hard copy), and computed
      radiography displayed on a computer workstation (computed radiography-soft copy).
      SUBJECTS AND METHODS: Fifteen foreign bodies of different size, shape, and
      composition were implanted at different locations in a fresh cadaveric hand, and
      images were obtained using three radiographic techniques. Images were evaluated
      by four board-certified radiologists to ascertain the conspicuity of the foreign
      bodies with the different techniques. A subjective grade was assigned to each
      image in an attempt to identify the relative conspicuity of foreign bodies when
      imaged with the three techniques. RESULTS: Computed radiography-soft copy is the
      preferred imaging technique for the detection of wood and plastic foreign bodies
      in soft tissue regardless of the size of the wood or the plastic. No significant
      differences in conspicuity among the three techniques were demonstrated with
      glass foreign bodies. CONCLUSION: Detection of soft-tissue foreign bodies is best
      done using computed radiography-soft copy instead of film-screen radiography and
      computed radiography-hard copy imaging.

PMID- 8659359
TI  - Osteoid osteoma after a fracture of the distal radius.
AB  - We report a case of osteoid osteoma occurring at the site of a previous fracture
      of the radius treated by internal fixation with insertion of a rod. The fracture
      may have acted as a trigger for the formation of an osteoid osteoma.

PMID- 8659360
TI  - MR angiography of tibial runoff vessels: imaging with the head coil compared with
      conventional arteriography.
AB  - OBJECTIVE: We compared peripheral vascular MR angiography done with a standard
      transmit-receive head coil with conventional arteriography for identifying and
      evaluating runoff vessels below the knee. MATERIALS AND METHODS: We examined 55
      legs in 31 symptomatic patients with both conventional contrast angiography and
      gradient-echo two-dimensional time-of-flight MR angiography. Both legs of
      patients were placed in a standard transmit-receive head coil for MR angiography
      and were imaged simultaneously. For evaluation of stenoses, images of vessels
      were divided into 10 segments, and each segment was graded on a four-point scale.
      RESULTS: In the 393 native vascular segments evaluated, the sensitivity of MR
      angiography in identifying normal vessels was 95% and the specificity was 98%. In
      detecting segmental occlusion, MR angiography was 98% sensitive and 97% specific.
      Sensitivity and specificity for stenoses greater than 75% were 98% and 96%,
      respectively, and for stenoses greater than 50%, they were 98% and 95%,
      respectively. Interpretative discrepancies were found in 35 vessel segments in 18
      legs; none was of clinical relevance. Of all vessel segments shown as occluded by
      conventional angiography, 1% appeared patent on MR angiograms. No vessel segments
      shown as normal on MR angiograms were found to be occluded on conventional
      angiograms. CONCLUSION: When performed simultaneously on both legs of symptomatic
      patients, 2D time-of-flight MR angiography with a standard transmit-receive head
      coil provides a time-efficient and highly sensitive and specific means of
      evaluating below-knee runoff.

PMID- 8659361
TI  - Intravascular bullet localization by sonography.

PMID- 8659362
TI  - Quantitative blood flow measurements with cine phase-contrast MR imaging of
      subjects at rest and after exercise to assess peripheral vascular disease.
AB  - OBJECTIVE: The purpose of this study was to determine whether cine phase-contrast
      MR volume flow measurements can identify patients with peripheral vascular
      disease. SUBJECTS AND METHODS: We performed MR measurements of volume blood flow
      in the popliteal artery of subjects at rest and after 5 min of plantar flexion
      exercise in 10 volunteers (mean age, 28 years old), in five patients suspected of
      having peripheral vascular disease (mean age, 58 years old), and in five other
      volunteers of a similar age (mean age, 57 years old). RESULTS: Volume blood flow
      at rest was similar in volunteers and in patients. Four patients who had abnormal
      ankle-brachial indexes had lower flow increases after exercise (2.6-fold)
      compared with the five older normal volunteers (4.8-fold; p < .03, t test). These
      flow increases correlated well with ankle-brachial indexes: r = .97. The four
      patients with abnormal ankle-brachial indexes had monophasic resting waveforms,
      whereas all other subjects had triphasic waveforms. CONCLUSION: MR volume blood
      flow measurement may aid in evaluating peripheral vascular disease. Studies of
      larger patient groups will be necessary.

PMID- 8659363
TI  - Nonsurgical management of patients with blunt splenic injury: efficacy of
      transcatheter arterial embolization.
AB  - OBJECTIVE: We evaluated the efficacy of nonsurgical management of patients with
      blunt splenic injury using detailed angiographic examinations and transcatheter
      arterial embolization. SUBJECTS AND METHODS: We prospectively studied 228
      patients who had blunt abdominal injury and for whom CT was performed. When
      splenic injury was revealed by CT, angiography was performed in all patients
      except those requiring emergency surgery. Transcatheter arterial embolization was
      performed when patients had the following angiographic criteria: (1)
      extravasation of contrast material extending beyond or within the splenic
      parenchyma, (2) arterial disruption or major arteriovenous fistula, or (3) both.
      Splenic function was subsequently estimated by 99mTc-sulfur colloid scintigraphy
      and repeat angiography. RESULTS: Of 228 patients with blunt trauma, 31 patients
      had CT evidence of splenic injury. In three of these 31 patients, emergency
      laparotomy was performed before angiography because of an associated injury or
      unstable circulatory status. In 13 of the 28 remaining patients, transcatheter
      arterial embolization was not required as these patients did not meet the
      necessary criteria. They were treated with bed rest. Transcatheter arterial
      embolization was performed in the remaining 15 patients and was completely
      successful in 13. Because one of these 13 patients died of a brain contusion,
      follow-up angiography and scintigraphy were performed in the remaining 12
      patients and showed preservation of splenic function. Nonsurgical treatment of
      splenic injury with angiography was successful in 93% of patients. CONCLUSION:
      Our success rate for nonsurgical management of patients with blunt splenic injury
      should encourage more extensive evaluation and use of angiography for splenic
      injury and the subsequent management of splenic injury without surgery.

PMID- 8659364
TI  - MR-guided biopsy using ultrafast T1- and T2- weighted reordered turbo fast low
      angle shot sequences: feasibility and preliminary clinical applications.

PMID- 8659365
TI  - Evaluation of the mammographic abnormality.

PMID- 8659366
TI  - Mammographic features after conservation therapy for malignant breast disease:
      serial findings standardized by regression analysis.
AB  - OBJECTIVE: The purpose of this study was to determine the incidence and natural
      history of mammographic changes in patients within 5 years of conservation
      therapy for malignant breast disease. MATERIALS AND METHODS: We reviewed the
      records of 164 consecutive patients with a history of conservation therapy for
      malignant disease. We recorded mammographic changes related to treatment for each
      year after surgery. Linear regression analysis was applied to determine trends
      for progression, regression, or stability of findings. RESULTS: We evaluated 158
      patients with 162 lesions for which initial mammographic evaluation had occurred
      within 5 years of surgery. Of these 158 patients, 121 (77%) underwent serial
      studies. A total of 152 patients (96%) showed changes on mammograms that
      represented scarring, usually in multiple locations. Findings at initial
      evaluation included architectural distortion (n = 110; 82%), increased regional
      density or scarring (n = 106; 79%), skin thickening (n = 73; 54%), masses (n =
      16; 12%), and calcifications (n = 4; 3%). All findings except calcifications
      showed partial resolution over time, with architectural distortion showing the
      most significant resolution (p = .05). CONCLUSION: Mammographic features after
      conservation therapy for breast cancer are common at 1 year after treatment. With
      the exception of calcifications, we found that all changes showed decreased
      prominence during the next 5 years. Recognition of such trends during routine
      surveillance should facilitate the early identification of changes that represent
      recurrence or do novo malignancy.

PMID- 8659367
TI  - Evaluation of nonpalpable solid breast masses with stereotaxic large-needle core
      biopsy using a dedicated unit.
AB  - OBJECTIVE: In our institution for the past 4 years, stereotaxic core breast
      biopsy using a 14-gauge needle has been offered as an alternative to surgical
      excision. The purpose of this paper is to describe our protocol, results, and
      lessons learned from our experience. MATERIALS AND METHODS: From August 1991 to
      July 1995, 388 stereotaxic needle core biopsies of clinically occult,
      noncalcified, mammographically detected solid masses were performed. In this
      group, 103 patients underwent subsequent surgical excision. Another 169 have had
      follow-up examinations 1 year or more after their biopsies. RESULTS: Of the 61
      patients diagnosed with a malignant process on core biopsy, all had confirmation
      on subsequent surgical excision. Forty-one of the 42 core biopsies that showed a
      benign process were subsequently confirmed on surgical excision. One patient with
      atypical ductal hyperplasia on core biopsy had ductal carcinoma in situ on
      surgical excision. Patients with 169 benign masses on core biopsy have been
      followed for at least 1 year by mammography. Of these women, 110 have been
      followed for at least 2 years, and no malignant lesions have been found.
      CONCLUSION: Stereotaxic large-needle core biopsy appears to be an accurate
      alternative to surgical excision for evaluating a solid breast mass. However, the
      mammographic appearance, technical quality of the biopsy, and pathologic findings
      in each patient must be correlated to ensure the highest possible accuracy when
      using this technique.

PMID- 8659368
TI  - Sonographic location of the elusive breast lesion: a technical aid to stereotaxic
      large-needle core biopsy.

PMID- 8659369
TI  - Association of medullary carcinoma with reactive axillary adenopathy.

PMID- 8659370
TI  - Benign phyllodes tumor of the breast: MR imaging features.

PMID- 8659371
TI  - Proton MR spectroscopy of the brain: clinically useful information obtained in
      assessing CNS diseases in children.

PMID- 8659372
TI  - Single-voxel proton brain spectroscopy exam (PROBE/SV) in patients with primary
      brain tumors.
AB  - OBJECTIVE: The Single-Voxel Proton Brain Exam (PROBE/SV) is an automated MR
      spectroscopic technique. The purpose of this study was to investigate the use of
      PROBE/SV as a diagnostic tool in patients with primary brain tumors and to
      compare our findings with the known information obtained from conventional
      nonautomated MR spectroscopic techniques. SUBJECTS AND METHODS: We used PROBE/SV
      to image 10 normal adults and 46 patients with primary brain tumors: 29
      glioblastoma multiformes (GBMs), five anaplastic astrocytomas, and 12 low-grade
      astrocytomas. All studied were performed on a 1.5-T Signa unit. Average voxel
      sizes were 6-8 cm3. A corresponding point-resolved spectroscopy spectrum was
      obtained from normal-appearing brain parenchyma in each patient for comparison
      with the spectra from known areas of pathology. RESULTS: In patients with low
      grade gliomas (grades 1 and 2), we observed decreased N-acetylaspartate (12 of
      12) and slightly increased choline (11 of 12) when we compared these metabolites
      with those in the spectra of patients' normal brains. This comparison in patients
      with GBM yielded markedly decreased N-acetylaspartate (29 of 29) and prominently
      increased choline (27 of 29). In the short TE spectra, we frequently saw lipid
      signal in high-grade tumors, especially in GBMs (12 of 20). We identified lactate
      peaks in high-grade tumors (anaplastic astrocytoma and GBM, 29 of 34) and also in
      low-grade tumors (four of 12). The creatine signal in all gliomas was slightly
      less than that of healthy brain tissue. The lowest N-acetylaspartate, choline,
      and creatinine levels in conjunction with the highest lactate levels were usually
      found in necrotic portions of high-grade tumors. CONCLUSION: PROBE/SV is a
      simplified MR spectroscopy technique that reduces setup time and provides
      automatic on-line data processing and display. The voxel location can be selected
      to focus on the area of interest and to minimize voxel contamination from
      unwanted tissue. The results from our experimentation with PROBE/SV in patients
      with brain tumors generally concur with published reports of tumor spectra
      obtained by conventional MR spectroscopic techniques. The ease and accuracy of
      this new technique make it a useful clinical tool in differentiating human brain
      tumor grades.

PMID- 8659374
TI  - Arterial-phase three-dimensional contrast-enhanced MR angiography of the carotid
      arteries.
AB  - OBJECTIVE: The purpose of this study was to evaluate IV injection of a single
      dose of gadopentetate dimeglumine for three-dimensional (3D) arterial phase MR
      angiography of the carotid arteries. SUBJECTS AND METHODS: Nine adult patients
      were serially imaged after IV injection of a single-dose bolus of gadopentetate
      dimeglumine at 1.5 T with a coronal single-slice spoiled two-dimensional (2D)
      gradient-echo acquisition encompassing the common carotid arteries and internal
      jugular veins. Region-of-interest measurements for the nine patients generated a
      composite arteriovenous signal versus time profile. The time interval of maximum
      arteriovenous signal difference was subsequently matched to the center of K-space
      in a 3D spoiled gradient-echo coronal MR angiography sequence (field of view, 24
      or 26 cm; matrix size, 256 x 128; slice thickness, 3 mm; number of slices, 12;
      one excitation; bandwidth, 16 kHz; and scan time, 29 sec). This protocol allowed
      us to selectively enhance the arterial phase for carotid angiography. The
      protocol was then tested in 20 adult patients, after which we graded the degree
      of coincidental venous enhancement and the presence of artifacts. RESULTS: On the
      2D dynamic images, we identified a 10-sec window of selective arterial
      enhancement that began 20 sec after the start of the injection of the bolus of
      gadopentetate dimeglumine. With 3D MR angiography, we saw selective enhancement
      during the arterial phase of carotid MR angiography in nine of 20 patients. In
      seven of the remaining 11 patients, we saw the signal intensity of the arterial
      phase exceed a threshold greater than two standard deviations from venous signal.
      In the final four patients, we saw arterial signal equal to venous signal. We saw
      no ghosting artifact (from intravascular signal changing too rapidly during phase
      encoding) in any patient. CONCLUSION: By precisely timing the infusion of a
      single dose of gadopentetate dimeglumine, we were able to selectively enhance the
      arterial phase on 3D MR angiograms of the carotid arteries.

PMID- 8659373
TI  - The employment market for 1995 graduates of diagnostic radiology and radiation
      oncology training.
AB  - OBJECTIVE: Despite widespread concern that a major surplus of non-primary-care
      physicians is developing, little nonanecdotal information has been available.
      Therefore, we developed and applied a methodology for appraising the situation of
      new graduates. Graduates should be particularly vulnerable because, unlike
      seasoned physicians. they all must find employment. MATERIALS AND METHODS: In
      April-May 1995, and in a December follow-up, we surveyed diagnostic radiology and
      radiation oncology training program directors about the status of their 1995
      residency and fellowship graduates, their programs, and the employment market.
      More than 90% responded. We compared findings with similar 1994 surveys.
      Differences were assessed with t tests or multiple regression analyses, with a p
      value of less than or equal to .05 as the test of significance. RESULTS:
      Directors reported unemployment 6 months after graduation was 0.6% (+/- 0.3%) for
      diagnostic radiology fellows and less for others. They said approximately 90% of
      graduates had positions reasonably matching their training and personal
      employment goals. Reported unemployment rates and percentages of graduates in
      desired positions did not differ from 1994. However, training directors generally
      were more pessimistic in 1995, overwhelmingly reporting the employment market was
      more difficult than in recent years. Few statistically significant differences
      among subgroups--including diagnostic subspecialties--were found. Net planned
      changes in program size will generate reductions of at most a few percent in the
      annual number of graduates, and more than 98% of beginning year residency slots
      were filled. CONCLUSION: Unemployment was remarkably low. Also, surprisingly,
      even "soft" indicators such as undesired positions or difficulties during the
      process of employment search (i.e., in April-May) did not show deterioration.
      Projections of pending physician surpluses may be exaggerated. Given our
      findings, program directors' growing pessimism is puzzling. This pessimism has
      not called forth sizable cuts in program size and, if major surpluses are
      pending, neither reductions in program size nor failure to fill all available
      slots offer significant relief, at least to date. The employment market is about
      equally good (or equally difficult) across diagnostic subspecialties. The absence
      of regional differences indicates graduates are effectively reaching beyond the
      locality where they trained in their employment search.

PMID- 8659375
TI  - Clinical impact of contrast-enhanced MR imaging reports in patients with previous
      lumbar disk surgery.
AB  - OBJECTIVE: We wanted to assess the clinical impact of the reports of contrast
      enhanced MR imaging on the decision to repeat surgery and on the results of
      repeat surgery in patients with previous lumbar disk surgery. SUBJECTS AND
      METHODS: We interviewed 257 patients who had undergone lumbar disk surgery and
      who showed symptoms suggesting persistent or new disk herniation. We conducted
      our interviews 6-18 months after patients had undergone contrast-enhanced MR
      imaging. We then correlated patient outcome with original MR findings. RESULTS:
      Fifty-two patients underwent new surgical procedures after their MR examination.
      Findings of disk herniation on MR images were associated with a significantly
      greater frequency of repeat surgery. The size of main herniation seen on MR
      images was also a significant variable. Patients with Worker's Compensation
      Insurance files had significantly worse prognoses: Only two (8%) of 26 of these
      patients reported 50% improvement 1 year after repeat surgery. However, only 6
      (23%) of 26 non-Worker's Compensation patients reported 50% improvement 1 year
      after surgery. CONCLUSION: Despite its documented high anatomic accuracy, the
      clinical usefulness of enhanced MR imaging for patients with previous lumbar disk
      surgery needs further evaluation. In our series, findings of disk herniations on
      enhanced MR examinations were associated with a greater frequency of repeat
      surgery, but such surgery relieved symptoms in few patients. The influence of
      enhanced MR imaging on the decision for repeat surgery and on the type of surgery
      may be misleading. Selection criteria for repeat surgery need to be reassessed
      using rigorous outcome research protocols.

PMID- 8659376
TI  - MR imaging of the treated brachial plexus.

PMID- 8659377
TI  - Cerebral aneurysms associated with seizures but without clinical signs of
      rupture: seemingly distinctive MR imaging findings in two patients.

PMID- 8659378
TI  - Chest case of the day. Disseminated pulmonary blastomycosis.

PMID- 8659379
TI  - Chest case of the day. Rupture of a sinus of Valsalva aneurysm into the right
      ventricle.

PMID- 8659380
TI  - Chest case of the day. Tracheobronchomegaly--the Mounier-Kuhn syndrome.

PMID- 8659381
TI  - Chest case of the day. Malignant mesothelioma of the pleura presenting with
      spontaneous bilateral pneumothoraces.

PMID- 8659382
TI  - Gastrointestinal case of the day. Toxic megacolon with underlying ulcerative
      colitis.

PMID- 8659383
TI  - Gastrointestinal case of the day. Portal and mesenteric vein thrombosis.

PMID- 8659384
TI  - Gastrointestinal case of the day. Eosinophilic gastroenteritis.

PMID- 8659385
TI  - Gastrointestinal case of the day. Sarcoidosis with involvement of liver, spleen,
      abdominal and thoracic lymph nodes, and lungs.

PMID- 8659387
TI  - Genitourinary case of the day. Endometrioma.

PMID- 8659386
TI  - Genitourinary case of the day. Giant adrenal myelolipoma.

PMID- 8659388
TI  - Genitourinary case of the day. Peritoneal inclusion cyst in a patient with a
      history of prior pelvic surgery.

PMID- 8659389
TI  - Genitourinary case of the day. Urachal adenocarcinoma.

PMID- 8659390
TI  - Musculoskeletal case of the day. Congenital lipoatrophic diabetes.

PMID- 8659391
TI  - Musculoskeletal case of the day. Oncogenic osteomalacia.

PMID- 8659393
TI  - Musculoskeletal case of the day. Amyloid arthropathy.

PMID- 8659394
TI  - Neuroradiology case of the day. Meningioma.

PMID- 8659392
TI  - Musculoskeletal case of the day. Posttraumatic subchondral cyst.

PMID- 8659395
TI  - Neuroradiology case of the day. Myxopapillary ependymoma.

PMID- 8659396
TI  - Neuroradiology case of the day. Sagittal sinus thrombosis with hemorrhagic venous
      infarct.

PMID- 8659398
TI  - Pediatric case of the day. Biliary atresia and polysplenia syndrome.

PMID- 8659397
TI  - Neuroradiology case of the day. Multisystem atrophy.

PMID- 8659399
TI  - Leiomyosarcoma of the esophagus: radiographic findings in 10 patients.
AB  - OBJECTIVE: Leiomyosarcomas of the esophagus are rare malignant smooth-muscle
      tumors that have been described only anecdotally in the radiology literature. The
      objective of this study was to evaluate the clinical and radiographic findings of
      this unusual lesion. MATERIALS AND METHODS: A search of the radiology archives of
      the Armed Forces Institute of Pathology revealed 10 cases of esophageal
      leiomyosarcomas. Clinical and radiographic findings were reviewed
      retrospectively. RESULTS: All but one patient presented with dysphagia. The
      average duration of the dysphagia was 6.7 months, but five patients had dysphagia
      for 3 or fewer months. Frontal chest radiographs revealed a mediastinal mass in
      five patients. Barium studies revealed intramural lesions in six patients,
      intraluminal lesions in two, and infiltrative lesions in two. The intramural
      Lesions all had large exophytic components, and three contained ulceration or
      tracking. One of the intraluminal lesions appeared as a polypoid expansile mass
      and the other, as a smooth expansile sausage-shaped mass mimicking a
      fibrovascular polyp. CT revealed a mass involving the esophagus in five patients;
      three of these patients had heterogeneous lesions containing large exophytic
      components, central areas of low density, and extraluminal gas or contrast
      material within the tumor. In two patients, MR imaging revealed large masses that
      were isointense with skeletal muscle on T1-weighted images and hyperintense on T2
      weighted images. CONCLUSION: Our experience suggests that esophageal
      leiomyosarcomas have radiographic findings similar to those of leiomyosarcomas
      elsewhere in the gastrointestinal tract. Esophageal leiomyosarcomas have a better
      prognosis than squamous cell carcinomas and are often amenable to surgical cure.

PMID- 8659400
TI  - Pediatric case of the day. Hemolytic-uremic syndrome.

PMID- 8659401
TI  - Pediatric case of the day. Congenital absence of the pericardium.

PMID- 8659403
TI  - Low gallbladder ejection fraction following cholecystokinin cholescintigraphy.

PMID- 8659404
TI  - Treatment to minimize skin or subcutaneous injury if extravasation occurs.

PMID- 8659402
TI  - Pediatric case of the day. Diffuse lipoblastomatosis.

PMID- 8659406
TI  - Fistulography in a difficult case: using a new, practical, and inexpensive
      device.

PMID- 8659407
TI  - Ileal loop bypass: a historical encounter.

PMID- 8659405
TI  - Can gadolinium be safely given in renal failure?

PMID- 8659408
TI  - Unenhanced helical CT in patients with acute flank pain and renal infarction: the
      need for contrast material in selected cases.

PMID- 8659409
TI  - Prolonged supine positioning: a cause of ventricular enlargement with a
      functioning ventriculoperitoneal shunt.

PMID- 8659410
TI  - Ruptured aneurysm of the basilar artery simulating nonaneurysmal
      perimesencephalic subarachnoid hemorrhage.

PMID- 8659411
TI  - True breast hypoplasia in Poland's syndrome.

PMID- 8659412
TI  - Arterial encasement and cranial nerve displacement in a case of cholesterol
      granuloma of the petrous apex.

PMID- 8659413
TI  - Fibrous pseudotumor of the scrotum: MR imaging findings.

PMID- 8659414
TI  - Lymphoma of the appendix: sonographic findings.

PMID- 8659415
TI  - CT features of ulcerative colitis and Crohn's disease.

PMID- 8659416
TI  - Percutaneous management of enterocutaneous fistulas.
AB  - OBJECTIVE: Our objective was to evaluate retrospectively the results of
      percutaneous catheter management of enterocutaneous fistulas. SUBJECTS AND
      METHODS: From 1983 to 1995, 147 patients with enterocutaneous fistulas were
      referred to our department after at least 1 month of unsuccessful medical
      treatment. One hundred eleven of these patients (76%) had developed fistulas
      after surgery. Ninety-three of 147 patients (63%) had high-output fistulas, and
      54 (37%) had low-output fistulas. Patients underwent fluoroscopically guided
      catheterization of the fistulous tracts and cannulation of the enteric segments.
      Abscesses were drained either through the cutaneous orifice or under CT or
      sonographic control when no communication with the fistulous tract existed.
      RESULTS: We defined success as closure of the fistulous tract and the cutaneous
      orifice and definitive healing of abscesses. The overall closure rate was 81%.
      The respective clinical success rates for high-output fistulas and low-output
      fistulas were 90% with a mean duration of 32 days and 65% with a mean duration of
      45 days. CONCLUSION: Percutaneous management of enterocutaneous fistulas is a
      valuable therapeutic approach in patients not responding to medical treatment,
      particularly patients with high-output fistulas.

PMID- 8659418
TI  - Colorectal cancer: sonographic findings.

PMID- 8659417
TI  - Barium enema: detection of colonic lesions in a community population.
AB  - OBJECTIVE: The purposes of this study were to assess the prevalence of colonic
      lesions detected at barium enema in a community practice, to compare the findings
      at barium enema between patients who are asymptomatic and have no known risk
      factors for colorectal cancer (screening group) and patients who have symptoms of
      colonic disease or have known risk factors, and to determine if a questionnaire
      about symptoms and risk factors is an appropriate screening tool. SUBJECTS AND
      METHODS: A self-administered questionnaire about colorectal symptoms and risk
      factors was given to 1779 patients scheduled for barium enema examination. On the
      basis of their responses, patients were divided into three groups: screening
      group (asymptomatic, without risk factors), symptomatic, and asymptomatic with
      risk factors. Each patient underwent a fluoroscopic barium enema. We then
      compared the results (number, histologic type, size of lesion(s), location in the
      colon, and Patient's age) and risk factors among the three groups. RESULTS: At
      least one lesion within the colorectum was found in 166 (9%) of 1779 patients at
      combined proctosigmoidoscopy and barium enema. The prevalence of lesions in the
      111 patients with at least one lesion above the rectum at barium enema was 4% (32
      of 738) for the screening group, 8% (38 of 476) for asymptomatic patients with
      risk factors, and 7% (41 of 565) for symptomatic patients (p = .015 when
      comparing the prevalence in the screening group with the prevalences in the other
      two groups). Twenty-nine percent of all colonic lesions were found in the
      screening group. Among the asymptomatic patients, risk factors that included a
      history of colorectal polyps and advanced age were associated with a
      significantly higher prevalence of colonic polyps found at barium enema. In the
      symptomatic group, if patients with histories of polyps were excluded, we were
      unable to identify other risk factors that led to a significantly higher
      prevalence of polyps. CONCLUSION: Asymptomatic patients without known risk
      factors have a significantly lower prevalence of colonic polyps than either
      symptomatic patients or patients with risk factors alone. Despite this lower
      prevalence, 29% of all lesions in our series were in the screening group.
      Assessment of risk factors through a patient questionnaire was not helpful in
      identifying a group of patients with a higher prevalence of lesions--except for a
      history of polyps. Management decisions based on a patient questionnaire should
      be approached with caution. When low-risk patients are denied screening
      examinations, a significant number of lesions will be missed.

PMID- 8659420
TI  - Intrapancreatic lipoma: first case diagnosed with CT.

PMID- 8659419
TI  - A comparison of two injection protocols using helical and dynamic acquisitions in
      CT examinations of the pancreas.
AB  - OBJECTIVE: The patterns of pancreatic enhancement and their relation to various
      injection parameters remain largely unknown. The purpose of this study was
      twofold: to compare pancreatic enhancement obtained after high and low rates of
      i.v. injection of contrast medium and to compare image quality between helical
      and dynamic sequential CT examinations of the pancreas using optimized scanning
      parameters. SUBJECTS AND METHODS: One hundred patients were randomly allocated to
      undergo either a helical CT (HC) acquisition after contrast injection at 6 ml/sec
      or a dynamic sequential CT (DS) acquisition after contrast injection at 2 ml/sec.
      Both ionic and nonionic contrast material were used in each group. Pancreatic
      attenuation values were measured on each section in each patient and averaged for
      each group. Image quality and visualization of anatomic landmarks were scored by
      two independent reviewers who were blinded to the acquisition technique. RESULTS:
      Mean pancreatic enhancement was higher in the HC (61 +/- 17 H) than in the DS
      group (54 +/- 17 H) (p < .05). Peak pancreatic enhancement was similar in the HC
      (74 +/- 19 H) and DS (74 +/- 17 H) groups. In the HC group, the optimal
      pancreatic enhancement index was 47% versus 35% for the DS group. The time to
      peak enhancement was 39 sec in the HC group and 71 sec in the DS group. The
      optimal scanning interval was 13 sec in the HC group versus 21 sec in the DS
      group. Image quality was not significantly different between the protocols, but
      misregistration and motion artifacts were fewer on HC examinations. CONCLUSION:
      Overall pancreatic enhancement was higher in the HC group, but the faster rate of
      injection did not increase the peak pancreatic enhancement and decreased the
      optimal scanning interval (the interval of time during which pancreatic
      enhancement was greater than 60 H). Image quality was similar with both
      protocols.

PMID- 8659423
TI  - Right intrathoracic stomach secondary to congenital hiatal hernia and organoaxial
      torsion.

PMID- 8659422
TI  - The misty mesentery on CT: differential diagnosis.

PMID- 8659421
TI  - Helical CT of the abdomen: comparison of image quality between scan times of 0.75
      and 1 sec per revolution.

PMID- 8659424
TI  - The visible gallbladder: a plain film sign of pneumoperitoneum.

PMID- 8659425
TI  - Detecting hepatocellular carcinoma: value of unenhanced or arterial phase CT
      imaging or both used in conjunction with conventional portal venous phase
      contrast-enhanced CT imaging.
AB  - OBJECTIVE: Because rates of detection of hypervascular neoplasms by conventional
      dynamic incremental-bolus CT are lower than rates of detection of hypovascular
      tumors by CT and because both unenhanced CT imaging and arterial phase helical CT
      imaging may increase the detection of hypervascular tumors, such as
      hepatocellular carcinoma, we evaluated the value of unenhanced and arterial phase
      CT imaging used in conjunction with conventional portal venous phase CT imaging
      in patients with hepatocellular carcinoma. MATERIALS AND METHODS: Unenhanced and
      biphasic helical contrast-enhanced CT studies were performed on 81 patients with
      proven hepatocellular carcinoma. Arterial phase and portal venous phase images
      were obtained at 20-50 sec and at 60-100 sec, respectively. Three blinded readers
      evaluated portal venous phase images for the number of liver lesions. On separate
      dates, the readers compared the arterial phase images with the portal venous
      phase images and the unenhanced images with the portal venous phase images. The
      readers recorded the number of lesions that were seen on portal venous phase
      images and that were also detected on unenhanced or arterial phase images as well
      as the number of additional lesions seen on unenhanced or arterial phase images.
      Consensus readings of unenhanced, arterial phase, and portal venous phase images
      were obtained in the 42 patients who had definitive surgery or follow-up CT
      scans, documenting the total tumor burden in this patient subgroup. RESULTS: The
      readers identified 286-310 lesions on portal venous phase images. On unenhanced
      images, the readers identified 223-244 of the lesions seen on portal venous phase
      images and an additional 45-55 lesions that were not seen on portal venous phase
      images. Arterial phase imaging revealed 245-269 of the lesions seen on portal
      venous phase images and an additional 89-111 lesions that were not seen on portal
      venous images. The diagnosis of tumor was possible only on unenhanced images in
      two (3%) of 81 patients and only on arterial phase images in seven patients (9%).
      In the subset of 42 patients with proof of tumor burden, 157 proven lesions were
      found. Consensus readings identified 127 (81%) of these lesions on portal venous
      phase images, 98 (62%) of these lesions on unenhanced images, and 120 (76%) of
      these lesions on arterial phase images. Of the 30 lesions not seen on portal
      venous phase images, nine were seen on both unenhanced and arterial phase images,
      three were seen on unenhanced images only, and 18 were seen on arterial phase
      images only. CONCLUSION: In patients with known or suspected hepatocellular
      carcinoma, the use of unenhanced or arterial phase images or both in addition to
      conventional portal venous phase images resulted in more tumors being detected.
      The combination of arterial phase and portal venous phase images revealed
      significantly more hepatocellular carcinoma lesions than did the combination of
      unenhanced and portal venous phase images.

PMID- 8659426
TI  - Assessment of a technology that permits individualized scan delays on helical
      hepatic CT: a technique to improve efficiency in use of contrast material.
AB  - OBJECTIVE: We performed this study to assess the usefulness of a computer
      automated scan technology (CAST) for individualizing scan delay during helical CT
      to improve the efficiency of hepatic enhancement. SUBJECTS AND METHODS: We
      prospectively evaluated 183 patients who were randomized into five groups.
      Control patients received 100 or 150 ml of contrast material (320 mg I/ml) with a
      60-sec delay between contrast injection at 3 ml/sec and scanning. CAST patients
      received 100, 125, or 150 ml. In our latter groups we used an hepatic enhancement
      threshold of 50 H over baseline to determine the optimum delay between contrast
      injection and scanning. For the intergroup comparisons, we measured the liver on
      baseline and enhanced helical CT scans at the upper, mid, and lower levels of the
      liver. RESULTS: The mean enhancement in patients who received 150 ml of contrast
      material was 70.7 +/- 19.4 H for the control group and 81.0 +/- 17.5 H for the
      CAST group (p < .05). Hepatic enhancement above 50 H was achieved in 84% of the
      control subjects compared with 100% of CAST subjects; more than 60 H hepatic
      enhancement was achieved in 73% of control subjects and in 89% of CAST subjects.
      The use of CAST software with 125-ml contrast doses provided enhancement
      equivalent to that of control subjects who received 150 ml of contrast material
      (mean enhancement in CAST subjects, 70.3 +/- 15.4 H). Enhancement above 50 H was
      reached in 98% of CAST and 84% of control patients. With 100 ml of contrast
      material, 24% of patients failed to initiate CAST, resulting in enhancement
      similar to control patients (CAST, 54.2 +/- 11.4 H; controls, 56.9 +/- 15.2 H).
      CONCLUSION: Using a contrast dose of 150 ml, CAST provided significantly
      increased hepatic enhancement than that achieved in control subjects with less
      variability. For equivalent hepatic enhancement, contrast doses could be
      decreased by 25 ml using CAST technology because it provides individualized scan
      delays.

PMID- 8659427
TI  - Extrahepatic portal vein stenosis in recipients of living-donor allografts:
      Doppler sonography.
AB  - OBJECTIVE: The aim of this study was to describe the appearances obtained and the
      pitfalls involved with the use of Doppler sonography for detecting portal vein
      stenoses after surgery in 198 recipients of pediatric reduced-size transplants.
      SUBJECTS AND METHODS: We analyzed sonographic and Doppler studies after surgery
      for 167 children (average, 2.5 years old) who were recipients of 198 left lobe or
      left lateral segment liver segments (79 living-donor allografts and 119 cadaveric
      grafts). Sonographic and Doppler studies were performed either on the basis of
      clinical evidence of portal hypertension or as part of a screening protocol.
      Demographic and surgical data were compared with the incidence of portal vein
      structure. We calculated pressure gradients from Doppler jet velocities and
      compared them with gradients measured manometrically from direct portography in
      12 patients. Imaging criteria that indicated portal vein stenoses were (1) a
      visualized portal vein diameter of 2.5 mm or less, (2) an acceleration of flow at
      the stricture or a poststenotic jet of portal vein flow revealed by Doppler
      imaging, or (3) both. Stenoses meeting these criteria were verified by surgical
      or angiographic identification. RESULTS: Seventeen (22%) portal vein stenoses
      were detected in recipients of the 79 living-donor liver transplants, whereas
      three (3%) were detected in recipients of the 119 cadaveric grafts (p < .005).
      The use of cryopreserved venous extension grafts was the most significant
      parameter of correlation (p < .025). Doppler sonography predicted the stenoses in
      all cases, although it overestimated the pressure gradients in all but one of the
      verified cases. Intrahepatic portal vein flow was frequently normal in the
      presence of significant extrahepatic portal vein stenosis. CONCLUSION: Diagnosis
      of portal vein stenosis in recipients of living-donor allografts requires real
      time visualization of the entire length of the portal vein, combined with
      spectral and color Doppler investigations of the portal and splenic veins and a
      search for collateral vessels. Visualization of each component alone may be
      insufficient. In our study, when care was taken to follow this procedure,
      sonography accurately showed all angiographically verified portal vein stenoses,
      although pressure gradients frequently were inaccurate. A protocol for periodic
      follow-up with real-time and Doppler sonography is crucial for pediatric patients
      to permit early identification of portal vein stenoses.

PMID- 8659428
TI  - Fat-fluid level in hepatic hydatid cyst: a new sign of rupture into the biliary
      tree?

PMID- 8659429
TI  - Mirizzi syndrome associated with gallbladder cancer and biliary-enteric fistulas.

PMID- 8659430
TI  - Periportal low attenuation due to hepatic necrosis in a patient after liver
      transplant.

PMID- 8659431
TI  - University and college programs for personnel in deafness.

PMID- 8659432
TI  - Programs for deaf-blind children and adults.

PMID- 8659433
TI  - Programs and services for the deaf. Supportive and rehabilitative programs.

PMID- 8659434
TI  - How some schools for deaf and hard of hearing children are meeting the challenges
      of instructional technology.

PMID- 8659435
TI  - Instructional technology in schools educating deaf and hard of hearing children:
      a national survey.
AB  - A survey on the availability of technology for instructional use was conducted by
      means of a mail questionnaire sent to schools that participate in the Annual
      Survey of Deaf and Hard of Hearing Children and Youth. Responses from 546 schools
      indicated that computers and printers are now commonplace, but inventories remain
      low for a sizable minority (42%) of schools. Center schools reported larger
      inventories of computers, printers, closed-caption decoders, and VCRs than were
      reported by local schools, but inventories of newer technologies such as CD-ROMs,
      videodiscs, and computer projection systems were low among both types of schools.
      The top needs indicated by schools were more equipment; more software,
      videocassettes, and other supporting materials; more teacher training; and more
      time for teachers to devote to instructional technology.

PMID- 8659436
TI  - Educational programs for deaf students.

PMID- 8659437
TI  - Atypical squamous cells of undetermined significance. Is help on the way?

PMID- 8659438
TI  - Assessing the quality of sputum specimens submitted for mycobacterial culture.
      Old lessons, new lessons, and the future.

PMID- 8659439
TI  - Recommendations for the reporting of resected prostate carcinomas. Association of
      Directors of Anatomic and Surgical Pathology.

PMID- 8659440
TI  - STAT testing? A guideline for meeting clinician turnaround time requirements.
      Practice parameter.
AB  - This practice parameter, developed by the Practice Parameters and Outcomes
      Measurement Committee of the American Society of Clinical Pathologists (ASCP), is
      a guideline for the development of reasonable stat lists. Stat testing lists vary
      according to practice setting. Furthermore, although stat lists exist,
      extenuating clinical circumstances may warrant performing a test stat that is
      otherwise considered routine. Successful development of a stat testing list
      requires organizations to take an interdisciplinary approach, focusing on
      clinical and operational considerations of both the care provider and the
      clinical laboratory.

PMID- 8659441
TI  - Laboratory turnaround time.

PMID- 8659442
TI  - The continuing evolution of the nation's blood supply system.
AB  - The nation's blood supply system has undergone major change during the last
      decade. As a result, the blood supply is extremely safe. To accomplish this, the
      centers that supply most of nation's blood have made extensive changes in their
      regulatory affairs and quality assurance programs, personnel, or organizational
      structure, process control systems, computer and data management systems, and
      overall philosophy. The emphasis on a medical and patient focused organizational
      culture has been replaced by a more manufacturing and business culture. Research
      in transfusion medicine and related fields is bringing potential new transfusion
      therapies and blood components closer to reality. The blood system and the
      organizations and people who compose it must continue to evolve in ways to
      implement these new therapies.

PMID- 8659443
TI  - The effect of number of histogram events on reproducibility and variation of flow
      cytometric proliferation measurement.
AB  - Sources of variation in synthesis phase fraction (SPF) calculation were studied,
      and the number of histogram events was found to be an important quality control
      consideration. Six cell cycle models (CCMs) for histograms composed of 1,000 to
      20,000 events were compared. All CCMs were cytometer based, or available in
      Multicycle (MC) software. The experiment consisted of five consecutive
      acquisitions, on the same day, of the same propidium iodide (PI) stained sample
      of T24 human cell line, at each of nine "landmarks" between 1,000 and 20,000
      events. The authors found (1) all CCMs evaluated required > or = 5,000 events for
      accurate, reproducible SPF; and (2) in the 5,000-20,000 event range the MC models
      provided the most accurate, reproducible SPF values. Therefore, histogram
      dependent curve fitting models may enhance clinical applications of FCM
      proliferation measurements. The authors conclude that histogram rejection
      criteria for S-phase analysis should be established, and that two-color
      multiparametric DNA analysis "live" gating with tissue specific markers may
      assure acquisition of sufficient events for accurate SPF.

PMID- 8659444
TI  - Quantitative immunohistochemistry of factor VIII-related antigen in breast
      carcinoma: a comparison of computer-assisted image analysis with established
      counting methods.
AB  - Microvessel density in the area of the most intense neovascularization in
      invasive breast carcinoma is reported to be an independent prognostic factor. The
      established method of enumeration of microvessel density is to count the vessels
      using an ocular raster (counted microvessel density [CMVD]). The vessels were
      detected by staining endothelial cells using Factor VIII-related antigen. The aim
      of the study was to compare the CMVD results with the percentage of factor VIII
      related antigen-stained area using computer-assisted image analysis. A true color
      red-green-blue (RGB) image analyzer based on a morphologically reduced
      instruction set computer processor was used to evaluate the area of stained
      endothelial cells. Sixty invasive breast carcinomas were included in the
      analysis. There was no significant correlation between the CMVD and the
      percentage of factor VIII-related antigen-stained area (Spearman correlation
      coefficient = 0.24, confidence interval = 0.02-0.46). Although high CMVD was
      significantly correlated with poorer recurrence free survival (P = .024),
      percentage of factor VIII-related antigen-stained area showed no prognostic
      value. Counted microvessel density and percentage of factor VIII-related antigen
      stained area showed a highly significant correlation with vessel invasion (P =
      .0001 and P = .02, respectively). There was no correlation between CMVD and
      percentage of factor VIII-related antigen-stained area with other prognostic
      factors. In contrast to the CMVD within malignant tissue, the percentage of
      factor VIII-related antigen-stained area is not suitable as an indicator of
      prognosis in breast cancer patients.

PMID- 8659445
TI  - PAPNET-directed rescreening of cervicovaginal smears: a study of 101 cases of
      atypical squamous cells of undetermined significance.
AB  - Many women having cervicovaginal smears interpreted as atypical squamous cells of
      undetermined significance (ASCUS) ultimately prove to harbor squamous
      intraepithelial lesions (SIL). The question is whether rare cells diagnostic of
      SIL are present in so-called "atypical" smears, but simply go undetected. To test
      whether the PAPNET Cytological Screening System, an automated system, can detect
      the (assumed) presence of such cells, six reviewers independently evaluated
      PAPNET video images generated for 101 cases conventionally diagnosed as ASCUS.
      Using PAPNET-identified microscopic coordinates, selected cases were then
      manually reviewed and reclassified according to consensus opinion. Overall, 35
      cases were reclassified as SIL (22 low grade; 13 high grade). Histologic
      correlations showed 37 of the 101 cases conventionally interpreted as ASCUS
      carried tissue diagnoses of SIL, (28 low grade; 8 high grade, 1 ungraded). Using
      PAPNET, 24 of the 37 (65%) corresponding smears were reclassified as SIL (15 low
      grades; 9 high grade).

PMID- 8659446
TI  - Malignant meningioma: a clinicopathologic study of 23 patients including MIB1 and
      p53 immunohistochemistry.
AB  - Malignant meningiomas are rarely encountered neoplasms. Few studies have examined
      MIB1 (marker of cell proliferation) or p53 (tumor suppressor gene)
      immunoreactivity in these tumors. This study retrospectively examines 23
      malignant meningiomas (defined by the presence of either unequivocal brain
      invasion or metastasis) including MIB1 and p53 immunohistochemistry. The patients
      included 13 women and 10 men who ranged in age from 22 to 82 years (mean 63
      years). Initial clinical presentation included weakness or numbness in 10
      patients, visual signs or symptoms in 7 patients, and headaches in 6 patients.
      Histologically, nuclear pleomorphism was present in 23 of 23 tumors, disorganized
      architecture in 22 of 22, necrosis in 20 of 23, prominent nucleoli in 17 of 23,
      and hypervascularity in 4 of 23. One to 18 mitotic figures per 10 high power
      fields (HPF) (mean 6.1) were observed. Metastases were present in six patients
      (bone: 3 patients; lung: 2 patients; skin: 2 patients; kidney: 1 patient; and
      liver: 1 patient). MIB1 indices (positive tumor cells per 1,000 tumor cells
      evaluated x 100) in 20 tumors ranged from 1.3 to 24.2 (mean 11.7). p53 nuclear
      staining was observed in only 2 of 20 tumors. Follow-up information was available
      in 21 patients: 6 died of tumor (mean 27 months); 9 are alive with residual tumor
      (mean 35 months); 5 are alive with no evidence of tumor (mean 12 months); and 1
      died 13 days postoperatively. There was no obvious correlation of the MIB1 index
      and tumor behavior. The majority of malignant meningiomas are characterized by
      nuclear pleomorphism, architectural disorganization, necrosis, prominent
      nucleoli, and increased mitoses. MIB1 labeling in most malignant meningiomas was
      high, consistent with the generally rapid growth of these tumors. Only a rare
      malignant meningioma demonstrated p53 alteration by immunostaining.

PMID- 8659447
TI  - Microglandular carcinoma of the pancreas: immunohistochemical and ultrastructural
      study of an unusual variant of pancreatic carcinoma that may closely resemble a
      neuroendocrine neoplasm.
AB  - Two cases are described of an unusual form of primary adenocarcinoma of the
      pancreas characterized histologically by their striking resemblance with a
      neuroendocrine neoplasm. The tumors were composed of a population of relatively
      small, uniform cells arranged in sheets admixed with small microglandular
      structures resulting in a cribriform pattern of growth. The tumor cells displayed
      scant cytoplasm with indistinct cell borders and round to oval nuclei with
      irregular clumping of chromatin and small, inconspicuous nucleoli.
      Immunohistochemical studies in both cases showed positivity of the neoplastic
      cells with CAM 5.2 antibodies and negative staining with a battery of
      neuroendocrine-related markers including chromogranin, NSE and synaptophysin, as
      well as with a variety of peptide hormones including insulin, glucagon,
      vasoactive intestinal polypeptide, gastrin and serotonin. Ultrastructural
      examination revealed a cohesive population of cells forming abortive glandular
      lumens lined by imperfectly formed microvilli and showing well-developed
      junctional complexes. No dense core neurosecretory granules or zymogen granules
      could be identified in any of the cells, supporting a ductal type of
      differentiation for these tumors. The main importance of recognizing this rare
      variant of pancreatic adenocarcinoma lies in avoiding misdiagnosis with other
      primary and metastatic neuroendocrine neoplasms of this organ.
      Immunohistochemical and ultrastructural examination will be of value in such
      cases for differential diagnosis.

PMID- 8659448
TI  - Chronic active Epstein-Barr virus infection with giant coronary aneurysms.
AB  - Chronic active Epstein-Barr virus infection (CAEBV) is a nonfamilial syndrome
      that shows a specific immunodeficiency for the Epstein-Barr virus (EBV).
      Prolonged fever, hepatosplenomegaly, lymphadenopathy, and liver dysfunction were
      seen in CAEBV, but cardiac complications are rare. An autopsy case of CAEBV with
      giant coronary aneurysms and aortic aneurysms is reported. The patient was a 5
      year-old Japanese girl. At autopsy, the heart weighed 110 g, and bilateral
      coronary aneurysms were found. Microscopic studies revealed lymphoid vasculitis
      of coronary arteries, coronary venules, and aortic arteries.
      Immunohistochemically, infiltrating small lymphocytes were positive for CD3,
      CD45RO(UCHL-1), CD43(DF-T1). The presence of EBV in most of these T lymphocytes
      was proven by in situ hybridization using an EBV-encoded RNA-1 (EBER1) probe. To
      the best of the author's knowledge, pathology of aneurysms caused by lymphoid
      vasculitis in CAEBV has not been reported until now.

PMID- 8659449
TI  - bc1-1 rearrangement and cyclin D1 protein expression in multiple lymphomatous
      polyposis.
AB  - Multiple lymphomatous polyposis (MLP), characterized by multiple polyps involving
      long segments of the gastrointestinal (GI) tract, is believed to represent GI
      involvement by mantle cell lymphoma (MCL), primarily based on its histologic and
      immunophenotypic similarities with MCL. However, rearrangement of the bcl-1
      locus, the molecular lesion characteristic of MCL, has not been investigated in
      this group of patients. The authors evaluated the morphologic, immunophenotypic,
      and molecular features of 18 cases of MLP and 8 B-cell lymphomas involving the GI
      tract (including 6 MALT lymphomas). All MLP cases presented with GI disease, and
      were histologically similar to MCL. DNA extracted from formalin-fixed, paraffin
      embedded tissue was analyzed for evidence of bcl-1 rearrangement by PCR, using
      chromosome 11 specific and consensus JH primers. Amplifiable DNA was obtained in
      24 of 26 cases (16 of 18 MLP cases and 8 of 8 controls). bcl-1 rearrangement was
      detected in 6 of 16 cases (38%), subsequently confirmed by sequencing of the
      breakpoint region, and in 0 of 8 controls. Immunostaining for cyclin D1 was
      positive in 14 of 18 MLPs, including the 6 bcl-1 rearranged cases and negative in
      6 of 6 evaluable controls. The detection of bcl-1 rearrangement and cyclin D1
      expression in cases of MLP supports the view that MLP represents primary MCL, of
      the GI tract. These techniques may also be helpful in differentiating MLP from
      other GI lymphomas, particularly low grade lymphomas of MALT, when only small
      routinely fixed endoscopic biopsies are available.

PMID- 8659450
TI  - Immunophenotypic analysis of hematologic malignancy by laser scanning cytometry.
AB  - The authors tested a newly-developed computerized laser scanning cytometer (LSC)
      as a means of performing immunophenotypic analysis of hematologic specimens
      within their community hospital. Results were compared on a case-by-case basis
      with parallel flow cytometric and immunohistochemical data. A total of 71
      specimens analyzed include 22 excised lymph nodes or other tissue biopsies, 18
      peripheral bloods, 17 bone marrow aspirates, 7 body fluids, and 7 fine-needle
      aspiration biopsies of lymphoid tissue. The LSC proved to be a useful instrument
      capable of generating simultaneous two-color immunofluorescent data directly
      analogous to that obtained via conventional flow cytometry. However, laser
      scanning cytometric analysis provides advantages over flow cytometric analysis,
      because the LSC measures cells on a slide rather than in a fluid stream.
      Specifically, cells can be microscopically examined at any time--before, during,
      or after automated immunofluorescent analysis. In addition, specimen preparation
      techniques are less restricted and more cost efficient. Lastly, even extremely
      small and/or hypocellular specimens (such as body fluids and fine-needle
      aspiration biopsies) can be successfully analyzed.

PMID- 8659451
TI  - Reverse transcriptase-polymerase chain reaction for bcr/abl fusion in chronic
      myelogenous leukemia.
AB  - Reverse transcriptase-polymerase chain reaction (RT-PCR) has shown promise as a
      means of detecting low levels of cells bearing the Philadelphia chromosome (Ph1)
      and for detecting cytogenetically inapparent ("masked") Ph1 in patients with
      chronic myelogenous leukemia (CML). For detection by karyotyping, dividing cells
      must be used, precluding use of peripheral blood samples in cases with low
      peripheral blood blast counts. Reverse transcriptase-polymerase chain reaction
      was performed in 83 bone marrow and 30 peripheral blood samples from patients
      with CML to compare results with karyotyping and to evaluate utility of this test
      on peripheral blood samples. Using isolated total cellular RNA and a single
      primer pair, cDNA was transcribed, amplified, electrophoresed, and probed for
      bcr/abl fusion involving M-bcr exons 2 and 3 of the bcr gene. Fifty-three samples
      were from untreated or conventionally treated patients (pre-BMT), and 60 were
      from patients who had undergone bone marrow transplantation (post-BMT). Fifty of
      53 pre-BMT samples were positive by RT-PCR. Two samples, negative by RT-PCR, had
      complex translocations, t(9;16;22) and t(4;14;22). One case was indeterminate by
      RT-PCR, but positive on retesting. Forty-five of 53 had Ph1 by karyotyping; 8
      were negative, including 5 peripheral blood samples, 2 bone marrow samples with
      "masked" Ph1, and 1 bone marrow sample with poor growth. Thirty-five of 60 post
      BMT samples were positive by RT-PCR. Fourteen of 60 post-BMT samples had Ph1 by
      karyotyping. Of the RT-PCR+/Ph1- cases, most showed a weak but definite band by
      RT-PCR, suggesting a low level of the bcr/abl fusion gene. Nineteen patients had
      concurrent peripheral blood and bone marrow samples analyzed by RT-PCR and
      karyotyping. Of 16 patients with satisfactory RNA extraction, 15 had concordant
      results by RT-PCR. Five patients had adequate metaphase cells for karyotypic
      analysis. All had Ph1 in bone marrow, but were negative in peripheral blood. Our
      results indicate that RT-PCR for detection of bcr/abl fusion is more sensitive
      than karyotyping in pre- and post-BMT samples. Furthermore, RT-PCR can be
      successfully performed on peripheral blood, yielding excellent correlation with
      bone marrow samples.

PMID- 8659452
TI  - Myeloid antigen, CD13, CD14, and/or CD33 expression is restricted to certain
      lymphoid neoplasms.
AB  - The authors examined the expression of myeloid antigens (MyAg): CD11b, CD13,
      CD14, CD15, and CD33 in 249 adults with lymphoid neoplasms using flow cytometric
      analysis. In this study, acute leukemia that was myeloperoxidase negative by
      light microscopy and had at least one lymphoid antigen was defined as acute
      lymphoblastic leukemia (ALL). The patients were classified as follows: 6 with
      unclassified ALL, 35 early B precursor ALL, 32 T-ALL, 25 B-cell chronic
      lymphocytic leukemia (B-CLL) and its variants, 24 B-cell non-Hodgkin's lymphoma
      (B-NHL), 7 plasma cell disorders, 8 T-CLL, 2 adult T-cell leukemia, and 10 T-NHL.
      CD11b and CD15 were present in a wide range of lymphoid disorders irrespective of
      B/T lineage and maturity. Unclassified ALL and phenotypically immature ALL
      frequently expressed CD13 and CD33, and occasionally expressed CD14. Among early
      B precursor ALL, CD13, and/or CD33 were significantly associated with the
      presence of stem cell marker CD34 and the chromosomal abnormality t(9;22). In
      addition, ALL with deletion of chromosome 7 commonly expressed CD13 and CD33.
      Taken together, CD13 and/or CD33 positive ALL may originate from a multipotential
      stem cell. Among mature neoplasms, CD14 was frequently, and CD13 and CD33 were
      occasionally expressed in B-cell, but not T-cell tumors. These results suggest
      that CD13, CD14, and CD33 are preferentially expressed in two types of lymphoid
      neoplasms, namely undifferentiated ALL and mature B-cell lymphoproliferative
      disorders.

PMID- 8659453
TI  - Quality evaluation of sputum specimens for mycobacterial culture.
AB  - The evaluation of sputum specimen quality before bacterial culture is an accepted
      practice. Traditionally, sputum received for mycobacterial culture has been
      processed regardless of specimen quality. In view of the increasing emphasis
      placed on the primary acid-fast smear, the effect of specimen quality and the
      contribution of the presence of neutrophils on subsequent smear and culture
      positivity for mycobacteria was assessed. A total of 873 sputa were evaluated and
      initially assigned a quality (Q) score of 1 (many squamous cells relative to
      neutrophils) to 3 (no squamous cells) based on criteria for specimen
      acceptability for routine bacterial culture. The percentage of specimens that
      were Q1, Q2, and Q3 were 46.8, 35.3, and 17.9, respectively. Most of the
      specimens received were Q1, and these specimens demonstrated the highest number
      of positive smears and cultures compared to Q2 or Q3 specimens. Thus, routine
      bacterial culture criteria were not helpful in assessing specimen quality for
      mycobacterial culture. The contribution of the presence of neutrophils to smear
      and culture positivity was assessed. A total of 724 sputa were evaluated for
      cellular composition: 665 (91.9%) specimens contained neutrophils, and 59 (8.1 %)
      did not contain neutrophils. A total of 51 (7.0%) primary smears and 121 (16.7%)
      cultures were positive for mycobacteria; 92.2% of the positive smears; and 90.1 %
      of the positive cultures were from specimens that contained neutrophils. Thus,
      screening sputum specimens for the presence of neutrophils provides an effective
      method to evaluate the acceptability of sputum for mycobacterial smear and
      culture, especially from patients in respiratory isolation.

PMID- 8659454
TI  - Clinical evaluation of the BacT/Alert and isolator aerobic blood culture systems.
AB  - The BacT/Alert (BTA) (Organon Teknika, Durham, NC) and Isolator 10 (ISO) (Wampole
      Laboratories, Cranbury, NJ) blood culture systems were evaluated for their
      ability to detect aerobic and facultatively anaerobic microorganisms in blood of
      adult patients. For each culture 8 mL of blood was inoculated into both the
      aerobic standard BTA bottle and the ISO tube. Of 7,259 paired culture sets, 1,168
      organisms were recovered, and 667 (57.1%) of these were considered clinically
      significant. This represented 540 clinically significant positive cultures from
      266 patients. Of the significant isolates, 410 were recovered by both systems,
      108 by BTA only and 149 by ISO only (P <.025). Overall, the BTA detected 77.7% of
      the significant isolates, whereas ISO detected 83.8%. The ISO recovered
      significantly more isolates of Staphylococcus aureus (P = .0001), coagulase
      negative Staphylococcus spp (P <.01), and non-Enterobacteriaceae gram-negative
      rod species (P <.0025), whereas the BTA detected significantly more isolates of
      Streptococcus spp (P <.0025). Growth of S aureus (P <.0025), Enterococcus spp (P
      <.0025), and Streptococcus spp (P <.0075) was detected earlier by the BTA when
      laboratory coverage was available during the first shift only (7:30 AM to 4:00
      PM), and additionally of Enterobacteriaceae (P <.0005) and other gram-negative
      rod species (P <.0001) if coverage was extended to 12:00 AM. Yeasts were detected
      more rapidly by the ISO (P <.0025). The ISO contamination rate (5.9%) was six
      times that of the BTA. Taking into account its ability to rapidly detect most
      organisms, its automated and thus labor-saving features, and the minimal
      contamination rate associated with its use, the BTA appears to be a reliable
      alternative to the ISO as a blood culturing system, although improvement in
      detection of staphylococci and non-Enterobacteriaceae gram-negative rods would be
      desirable.

PMID- 8659455
TI  - Estimation of the lower limits of manual and automated platelet counting.
AB  - Most evaluators of automated or manual methods for platelet counting focus on
      characteristics such as imprecision, linearity, and carry over. The limits of the
      analytical procedure are usually not assessed. The limits of the different
      techniques are neither discussed in the literature nor do manufacturers of
      analytical systems supply these data. A new procedure is presented to assess the
      performance of the manual as well as the automated platelet count. This procedure
      allows, with defined statistical confidence (eg, 95%), the determination of (1)
      the limit of platelet detection (LD) at which signals of platelets can be
      discriminated from the system noise; (2) the lower limit of quantification (LLQ),
      at which a certain imprecision is not surpassed; and (3) the power of definition
      (PD) that defines the number of values that can be discriminated in a certain
      interval. For each value, the PD allows calculation of the two adjacent (lower
      and higher) values that are significantly (P > or = 0.95) different. For the
      manual count, LD was found to be 1.6 x 10(9) plt/L and the LLQ 6.9 x 10(9) plt/L.
      For the automated count with the Technicon H1, LD was 4.3 x 10(9) plt/L and LLQ
      13.8 x 10(9) plt/L (CVmax = 15%). The PD in the range 20 to 100 x 10(9) plt/L is
      8 for the automated and 7 for the manual count.

PMID- 8659456
TI  - Lupus anticoagulants: first French interlaboratory Etalonorme survey.
AB  - In 1994, the, French National Quality Control Group for Hematology, Etalonorme,
      conducted a large-scale interlaboratory survey concerning the detection of lupus
      anticoagulants (LA) involving all the 4,500 French laboratories. Each laboratory
      received the same batch of a lyophilized citrated plasma (94B3) prepared from a
      patient with LA that had been confirmed by all the techniques used in the
      intralaboratory study. In the interlaboratory survey, the screening test was
      activated partial thromboplastin time (APTT); mean APTT calculated from the
      results reported by 4,029 labs was prolonged (clotting ratio = 1.44) with a large
      dispersion (coefficients of variation = 18.8%). APTT of the mixture 94B3 + normal
      plasma were performed by 2,698 laboratories. No correction of APTT was obtained
      (R = 1.36, Rosner index = 24) with a wide variation between reagents (17 < Rosner
      index < 39). Only 15% of the participants performed confirmatory tests; dilute
      tissue thromboplastin inhibition test (TTI) performed by 509 laboratories gave
      75% positive results. Tests with an increased amount of phospholipids (Staclot LA
      and Staclot PNP from Diagnostica Stago), used by 116 and 72 laboratories, gave
      88% and 61% positive results, respectively. A total of 1,862 laboratories made
      the diagnosis of LA. The majority of those who failed in diagnosing LA used an
      APTT reagent largely used in France, containing kaolin. This survey allowed
      Etalonorme to inform French biologists and draft an educational program for the
      biologic detection of LA and the identification of its mechanism of action.

PMID- 8659458
TI  - The role of the transfusion medicine consultant.
AB  - Over the last 15 years, the field that was once known as blood banking has
      evolved into the discipline of transfusion medicine. Because of AIDS and a
      greater appreciation of other transfusion-transmitted diseases, attitudes toward
      transfusion therapy have changed significantly. Advances in the understanding of
      the pathophysiology of anemia and thrombocytopenia, as well as new tools for
      transfusion support have created new roles for the transfusion medicine
      physician. The transfusion medicine consultant has the opportunity to influence
      and improve transfusion safety, and contribute positively to cost containment by
      providing expertise as an educator, auditor of blood component usage, and
      providing leadership or oversight of therapeutic modalities (such as autologous
      transfusion, intraoperative red cell salvage, and therapeutic apheresis).

PMID- 8659457
TI  - Prothrombin time: one tube or two.
AB  - This study compares the prothrombin times (PTs) and calculated international
      normalized ratios (INRs) from first and second evacuation blood tubes to
      determine the clinical importance of using a second tube specimen for protime
      coagulation studies. The National Committee for Clinical Laboratory Standards
      (NCCLS) currently recommends that all coagulation studies be done on a second or
      later drawn blood tube. For patients on long-term anticoagulation therapy, this
      often requires that first blood tubes be drawn and discarded at each prothrombin
      evaluation. In this prospective study, a first and second evacuation blood tube
      was drawn from 343 outpatients who had a physician-ordered prothrombin time test
      performed. There was no statistically significant difference in the paired PT or
      calculated INR from any of the first and second tubes. The average difference in
      the INR from tube 1 to tube 2 was 2% (standard deviation [SD] 1.1%). In this
      sample of outpatients, the use of a second tube for PT testing was not clinically
      justified.

PMID- 8659459
TI  - Reporting of breast carcinoma.

PMID- 8659460
TI  - Breast carcinoma lumpectomy.

PMID- 8659461
TI  - bc1-1 gene rearrangements in paraffin-embedded tissues.

PMID- 8659463
TI  - Comment on the Roth/Rinchuse responses.

PMID- 8659462
TI  - Comment on electrothermal debonding.

PMID- 8659464
TI  - The Rinchuse/Roth group debate.

PMID- 8659465
TI  - Cause and effect: as applied to the growth of the jaw.

PMID- 8659466
TI  - Orthodontic management of patients with hematologic malignancies.
AB  - More than 50% of pediatric malignancies are leukemias or lymphomas. Oral changes
      associated with these conditions include: gingival oozing, petechiae, hematomas,
      ulcerations, gingival pain, gingival hypertrophy, mucosal pallor, pharyngitis,
      and lymphadenopathy. Current medical management for patients with hematologic
      malignancies includes chemotherapy, radiation, surgery, bone marrow
      transplantation or a combination of these modalities. Nearly 60% of patients
      diagnosed today with malignancy will be long-term survivors. Patients undergoing
      orthodontic treatment when a diagnosis of malignancy is made are best served by
      expedient removal of orthodontic appliances and delivery of retainers. After a
      patient has completed all cancer therapy and has at least a 2-year event-free
      survival, orthodontic treatment can be restarted.

PMID- 8659467
TI  - Evaluation of cervical spine abnormalities on cephalometric radiographs.
AB  - Cephalometric radiographs, a key element of orthodontic diagnosis, contain useful
      information related to the cervical spine often neglected by orthodontists and
      medical specialists. This article reviews cervical spine anatomy in a manner that
      will enable the clinician to trace the cervical spine accurately and detect
      cervical spine abnormalities. Examples of syndromic, nonsyndromic, and idiopathic
      anomalies of the cervical spine are presented and their significance discussed.
      Cephalometric radiographs can be used by clinicians as a potential resource for
      screening for pathologic abnormalities of the cervical spine and potentially
      averting some pathologic complications.

PMID- 8659468
TI  - Differential scanning calorimetry (DSC) analyses of superelastic and
      nonsuperelastic nickel-titanium orthodontic wires.
AB  - The purpose of this study was to determine the transformation temperatures for
      the austenitic, martensitic, and rhombohedral (R) structure phases in
      representative as-received commercial nitinol (NiTi) orthodontic wire alloys, to
      reconcile discrepancies among recent publications. Specimens were examined by
      differential scanning calorimetry (DSC) over a temperature range from
      approximately -170 degrees C to 100 degrees C, with a scanning rate of 10 degrees
      C per minute. Two different pathways, with the intermediate R structure either
      absent or present, were observed for the transformation from martensitic to
      austenitic NiTi, whereas the reverse transformation from austenitic to
      martensitic NiTi always included the R structure. The enthalpy (delta H) for the
      transformation from martensite to austenite ranged from 0.3 to 3.5 calories per
      gram. The lowest delta H value for the nonsuperelastic Nitinol wire is consistent
      with a largely work-hardened, stable, martensitic microstructure in this product.
      The DSC results indicate that the transformation processes are broadly similar in
      superelastic, body-temperature shape-memory, and nonsuperelastic NiTi wires.
      Differences in bending properties for the NiTi orthodontic wires at room
      temperature and 37 degrees C are due to the relative proportions of the
      metallurgical phases in the microstructures.

PMID- 8659469
TI  - Computer experiments using a two-dimensional model of tooth support.
AB  - The purpose of this investigation was to study the factors that may affect the
      position of the center of resistance and center of rotation. A two-dimensional
      computer model of the periodontal ligament was developed. The model permitted the
      simulation of an isotropic (responding in the same manner regardless of the
      direction of the applied force) and nonisotropic periodontal ligament and allowed
      changes in root shape and in position and direction of force application. The
      center of resistance was found to depend on the distribution of root surface
      area. For a model of the upper central incisor, it was located at 42% of the root
      length measured from the alveolar crest. The presence of anisotropy in the
      periodontal ligament significantly affected the position of the center of
      resistance, which was in this case also affected by the direction of the applied
      force. Forces passing through the center of resistance produced translation of
      the modeled tooth in a direction not necessarily the same as the direction of the
      applied force. Tipping forces produced much larger stresses than forces causing
      translation. Simulation of periodontal involvement resulting in loss of
      attachment increased the stresses exerted on the periodontal ligament. The model
      permitted easy assessment of various factors that may influence the position of
      the center of resistance of teeth and revealed a potentially large variability in
      the position of the center of resistance and center of rotation, caused by
      variation of the properties of the periodontal ligament.

PMID- 8659470
TI  - The effects of antirat nasal septum cartilage antisera on facial growth in the
      rat.
AB  - Antirat nasal septum cartilage antisera (RNS-IgG) produced in rabbits by
      injection of crude antigens derived from rat nasal septum cartilage was cytotoxic
      for rat chondrocytes in vitro. The effect of this antisera on rat facial growth
      was tested by injecting three groups of growing rats at 4-day intervals from
      birth to 30 days. The treatment group (n = 19) received injections of RNS-IgG,
      one control group (n = 11) received injections of the IgG fraction of preimmune
      rabbit sera (PI-IgG) and a second control group (n = 16) received injections of
      normal saline. All animals were killed at the conclusion of the experiment, and
      lateral and dorsoventral cephalometric radiographs were taken. Statistical
      difference between treatment and control groups were found for 15 cephalometric
      measurements. Specifically, snout length (as measured from the intersphenoidal
      synchondrosis to the upper incisors (is-i) was reduced in animals treated with
      RNS-IgG compared with both PI-IgG and saline injected controls (p < 0.06, p <
      0.005, respectively). In addition, premaxillary length, premaxillary
      displacement, and bimaxillary width were significantly reduced (p < 0.05) in RNS
      IgG treated animals compared with saline injected controls. Bimolar width was
      reduced (p < 0.05) between RNS-IgG and PI-IgG groups. These results demonstrate
      that injection of antinasal septum antisera reduces midfacial dimensions in
      experimental rats and that nonimmune rabbit antisera may have an effect on the
      growth process. In summary, the results of this pilot study suggest the
      possibility for using more specific antinasal cartilage antibodies to effect dose
      dependent, tissue specific, modulation of facial growth.

PMID- 8659471
TI  - Maxillary and cranial base changes during treatment with functional appliances.
AB  - The purpose of this prospective study was to investigate the maxillary and the
      cranial base changes after treatment with the Harvold activator and the Frankel
      function regulator appliances. Forty-two children, who are 10 to 13 years old,
      with Class II, Division 1 malocclusions were matched in triads according to age
      and sex and randomly assigned to either the control, Harvold activator, or
      Frankel function regulator group. Lateral cephalometric radiographs were taken at
      the start of the study and 18 months later. Both appliances reduced the overjet
      by tipping the maxillary incisors palatally and, as a consequence, the length of
      the maxillary arch was reduced. The appliances had no effect on either the
      horizontal or vertical position of the maxillary molars. Small, but statistically
      significant, changes in the cranial base angle in the Frankel function regulator
      group were attributed to relatively large changes at basion in several children,
      influencing the results because of the small size of the sample. The appliances
      had no effect on the position of the maxilla.

PMID- 8659472
TI  - Associations among upper airway structure, body position, and obesity in skeletal
      Class I male patients with obstructive sleep apnea.
AB  - Interactions between upper airway structure and posture in relation to obesity
      were studied in a sample of 61 adult Class I skeletal type male patients with
      obstructive sleep apnea (OSA) and 10 homologous control subjects. A pair of
      upright and supine lateral cephalometric films were taken for each subject. A
      Pearson correlation analysis identified significant r values for several
      demographic variables in patients with OSA such as apnea and hypopnea index,
      percentage of predicted neck circumference, minimum arterial oxygen saturation,
      and body mass index (BMI). The difference between cephalometric variables
      identified in upright and supine subjects was calculated. When patients with OSA
      changed their posture from upright to supine, significant correlations were
      observed between the cranial base to upper cervical column angle and the
      hypopharynx cross-sectional area and BMI. Moreover, the mandibular plane angle
      and the sella-nasion plane was significantly correlated with BMI. This occurred
      along with a significant positive correlation between the sella-nasion plane
      angle and BMI and a significant inverse correlation between the mandibular plane
      angle in reference to the absolute vertical and horizontal planes, with BMI after
      the positional change. Such correlations were not observed in control subjects.
      No correlations were observed between the variables related to the position of
      the hyoid bone with BMI in either patients with OSA or control subjects after the
      change in posture. On the basis of these findings, we propose that when patients
      with OSA change their body position from upright to supine (1) the patient's neck
      is more extended, and (2) the hyoid bone moves more anterosuperiorly in
      conjunction with an upward and forward rotation of the mandible. This change in
      craniofacial structure may be a compensatory geometrical change in the upper
      airway to secure its patency.

PMID- 8659473
TI  - Achieving improved visualization of the temporomandibular joint condyle and fossa
      in the sagittal cephalogram and a pilot study of their relationships in habitual
      occlusion.
AB  - Improved glenoid fossa and condyle visualization is achieved by adapting the
      Denar TMJ Orthoceph Slimline Cassette (Denar Corp., Anaheim, Calif.) to sagittal
      cephalometry. This cassette contains rare-earth intensifying screens to enhance
      the temporomandibular joint region. A plastic template of circles of varying
      diameters is positioned so that the appropriate circle size is tangent to the
      superior, anterior, and posterior borders of the glenoid fossa seen on the
      resultant radiograph. The planar geometric center of the glenoid fossa is then
      identified coincident with the center of the template circle. The condyle planar
      geometric center is similarly identified. The relationships of these centers with
      respect to each other is described by using a rectangular coordinate system with
      the origin at the glenoid fossa geometric center. The condyle center is further
      described as being in any one of four quadrant locations or concentric with the
      glenoid fossa geometric center. This method was then applied to 38 patients who
      were free of temporomandibular joint symptoms in a pilot study relating the
      condyle quadrant location with the dentition in habitual occlusion. Findings
      revealed 89% of the condyles were in any one of the four possible quadrants.
      Fifty-three percent of the condyles were located in a downward and forward
      position (quadrant IV). Eleven percent of the condyle geometric centers were
      concentric with the glenoid fossa geometric center.

PMID- 8659474
TI  - The incidence of bacteremia after orthodontic banding.
AB  - This investigation assessed the incidence of bacteremia after orthodontic
      banding. Thirty adult volunteers with good oral health, who were not at risk from
      bacterial endocarditis, were included in this study. An orthodontic band was
      placed on a first molar of each subject. Venous blood samples were taken before,
      and 1 to 2 minutes after the molar band was fitted. Microbiologic tests performed
      on the blood samples revealed a comparatively low incidence of bacteremia (10%)
      after orthodontic banding.

PMID- 8659475
TI  - Identification of condylar anatomy affects the evaluation of mandibular growth:
      guidelines for accurate reporting and research.
AB  - Mandibular length is measured on cephalographs to depict changes during growth
      and after orthodontic treatment, and is often defined between condylion (Co, most
      posterior superior point on the condylar outline) and pogonion (Pog, most
      anterior point on the chin). The aim of this study was to assess the accuracy of
      identifying condylar anatomy, thus the validity of using Co-Pog to evaluate
      mandibular growth. The sample included 34 children from a prospective study on
      the early treatment of distoclusions. Two lateral head films were taken of each
      child, the first with the mouth closed (MC), the second with the mouth open (MO).
      Three examiners, two orthodontists (U.H. and K.H.) and a dental radiologist
      (R.B.), rated the condyle as identifiable, nonidentifiable, and interpreted. The
      rating was applied to the left (L) and right (R) condyles, or to only one outline
      (O) when the R and L structures appeared superimposed and were not distinguished
      separately. Besides Co-Pog, the orthodontists traced sella-nasion (SN) and
      incisor tip-menton (I-Me) to evaluate variability in measurements that do not
      include Co. One operator (J.G.) measured all distances. Agreement among the three
      examiners was best in rating the MO radiographs (50%): 4.1% identifiable, 5.9%
      nonidentifiable or interpreted; in the MC films, they agreed in 32.3% of the
      cases, but only one of the ratings was identifiable (2.9%). The highest agreement
      was in identifying the left condyle on the MO film (35.3%). Intraclass
      correlation coefficients for CO-Pog ranged from r = 0.73 (L side) to r = 0.92 (O)
      for one orthodontist, and for the other from r = 0.76 (O) to r = 0.85 (L). Both
      orthodontists had high correlations for SN and I-Me between MC and MO (0.94 < r <
      0.98). The variability between examiners in recognizing condylar anatomy,
      particularly on radiographs taken with the mouth closed, suggests that the
      identification of condylar anatomy must be rated in studies of mandibular growth.
      Researchers measuring mandibular length in investigations of mandibular growth
      after orthodontic therapy should differentiate between cases where the condyle is
      readily identified, and those where condylar anatomy is interpreted.

PMID- 8659476
TI  - Presurgical satisfaction with facial appearance in orthognathic surgery patients.
AB  - Orthognathic surgery and orthodontic therapy are most often performed to improve
      the patient's appearance. However, not all patients are satisfied with the result
      though the procedure may be considered successful by the orthodontist and the
      maxillofacial surgeon. It has been suggested that the patient's satisfaction with
      his or her facial appearance before the surgery can predict later satisfaction
      with orthognathic procedures. The present study examined the role of several
      potential predictor variables in satisfaction with facial appearance before
      orthognathic treatment. The variables, identified in previous research, included
      severity of facial disharmony, self-concept, psychological distress, gender, age,
      and socioeconomic status. Questionnaires were gathered from 54 patients in 10
      orthodontic practices in Connecticut and New York. Contrary to expectations,
      gender, age and socioeconomic status failed to predict patients' presurgical
      satisfaction with appearance. Self-concept, psychological distress, and
      orthodontists' ratings of total facial appearance (from a lateral view) were
      bivariate predictors of satisfaction. When all variables were analyzed with a
      multiple regression analysis, however, only self-concept emerged as a significant
      independent predictor of satisfaction with appearance. This accounted for 15% of
      the variance in satisfaction. Orthodontists' ratings of facial views, considered
      here objective measures of disharmony, were predictive neither of satisfaction
      with appearance nor of self-concept. It is suggested that self-concept may be a
      predictor of postsurgical as well as presurgical satisfaction with appearance and
      that self-concept itself may be unaffected by severity of facial disharmony, at
      least in young adults. Orthodontists may need to pay special attention to those
      patients with poor self-concept, because these patients may be more likely to
      report unsatisfactory surgical outcomes.

PMID- 8659477
TI  - Imaging on a budget.

PMID- 8659478
TI  - Office policies and benefits update. Part II.

PMID- 8659479
TI  - Controversy of oral contraceptives and risk of rheumatoid arthritis: meta
      analysis of conflicting studies and review of conflicting meta-analyses with
      special emphasis on analysis of heterogeneity.
AB  - The authors analyze the heterogeneity present in the combined results of past
      observational studies that investigated the association between oral
      contraceptive use and rheumatoid arthritis. The authors also evaluate
      discrepancies among meta-analyses that focus on the same relation. Of the 15
      initially reviewed studies, 10 were selected for this meta-analysis, which also
      includes a qualitative summary of study characteristics and a critical appraisal
      of study quality. The authors used the direct method to combine the study results
      when there was no evidence of heterogeneity and the DerSimonian-Laird method when
      heterogeneity was present. Using a meta-regression to assess the sources of
      heterogeneity, the authors weighted summary estimates by sample size and
      undertook a sensitivity analysis. There was a strong indication of heterogeneity
      when combining all studies (x2 = 29.34, p = 0.00060) with the source of controls
      explaining most of the heterogeneity. The most important factor in explaining the
      differences among the overall summary estimates given by the meta-analyses is
      that different effect estimates had been selected for the same studies. There is
      no conclusive evidence of a protective effect of oral contraceptives on the risk
      of developing rheumatoid arthritis. Consensus is needed on how meta-analyses of
      observational studies should be conducted.

PMID- 8659480
TI  - Survey inference for subpopulations.
AB  - One frequently analyzes a subset of the data collected in a survey when interest
      focuses on individuals in a certain subpopulation of the sampled population.
      Although it may seem natural to eliminate from the data set all data from
      individuals outside the subpopulation before analysis, this procedure may yield
      incorrect standard errors and confidence intervals. The authors give two examples
      of this using data from the 1987 National Health Interview Survey and the 1986
      National Mortality Followback Survey. The correct method of analysis is
      described, as well as a simple condition that, when satisfied, ensures that the
      elimination approach yields identical answers to the correct method.

PMID- 8659481
TI  - Age, sex, and the familial risk of rheumatoid arthritis.
AB  - The familial aggregation of rheumatoid arthritis was examined to determine
      factors modifying the risk of rheumatoid arthritis in first degree relatives of
      165 cases ascertained from January 1, 1987, through March 31, 1987, using the
      Saint Margaret Memorial Hospital Rheumatoid Arthritis Registry, Pittsburgh,
      Pennsylvania, without regard to previous information concerning the occurrence of
      rheumatoid arthritis among their family members. The reported affection status of
      first degree relatives, verified through a structured clinical evaluation,
      revealed a false-positive reporting rate for family members of 61%. In contrast,
      there were no false-negative cases detected. There were no differences in average
      family size or total number of years at risk between 135 simplex and 30 multiplex
      families; however, aggregation analysis revealed that only 18 of 30 confirmed
      multiplex families had significant excess risk of rheumatoid arthritis.
      Significant differences were found when probands from multiplex families were
      compared with those from simplex families with regard to female to male ratio for
      probands (1:1 in multiplex families vs. 3:1 in simplex families) and average age
      of onset for probands (41 years in multiplex families vs. 48 years in simplex
      families). The familial risk for rheumatoid arthritis was similar in parents
      (4.2%) and siblings (4.6%) and lowest for children (0.7%) of probands. The
      authors assert that the affection status of first degree relatives of patients
      with rheumatoid arthritis is often falsely reported as positive. The familiality
      of rheumatoid arthritis may be more accurately related to the sex and age at
      onset of the affected family member.

PMID- 8659482
TI  - Randomized controlled trial of a low animal protein, high fiber diet in the
      prevention of recurrent calcium oxalate kidney stones.
AB  - Low protein diets are commonly prescribed for patients with idiopathic calcium
      nephrolithiasis, who account for > 80% of new diagnoses of kidney stones. This
      dietary advice is supported by metabolic studies and epidemiologic observational
      studies but has not been evaluated in a controlled trial. Using 1983-1985 data
      from three Northern California Kaiser Permanente Medical Centers, the authors
      randomly assigned 99 persons who had calcium oxalate stones for the first time to
      a low animal protein, high fiber diet that contained approximately 56-64 g daily
      of protein, 75 mg daily of purine (primarily from animal protein and legumes),
      one-fourth cup of wheat bran supplement, and fruits and vegetables. Intervention
      subjects were also instructed to drink six to eight glasses of liquid daily and
      to maintain adequate calcium intake from dairy products or calcium supplements.
      Control subjects were instructed only on fluid intake and adequate calcium
      intake. Both groups were followed regularly for up to 4.5 years with food
      frequency questionnaires, serum and urine chemistry analysis, and abdominal
      radiography; and they were urged to comply with dietary instructions. In the
      intervention group of 50 subjects, stones recurred in 12 (7.1 per 100 person
      years) compared with two (1.2 per 100 person-years) in the control group; both
      groups received a mean of 3.4 person-years of follow-up (p = 0.006). After
      adjustment for possible confounding effects of age, sex, education, and baseline
      protein and fluid intake, the relative risk of a recurrent stone in the
      intervention group was 5.6 (95% confidence interval 1.2-26.1) compared with the
      control group. The authors conclude that advice to follow a low animal protein,
      high fiber, high fluid diet has no advantage over advice to increase fluid intake
      alone.

PMID- 8659483
TI  - Plasma ferritin, iron intake, and the risk of colorectal polyps.
AB  - High iron exposure has been associated with colorectal neoplasia in several
      studies. The authors investigated plasma ferritin, an indicator of iron stores,
      and iron intake as risk factors for adenomatous polyps, intermediate markers for
      colorectal cancer. During 1991-1993, they collected fasting blood samples from
      and administered questionnaires to men and women 50-75 years old who visited free
      sigmoidoscopy clinics at a health maintenance organization. Data from 965
      subjects (467 cases, 498 controls) were analyzed. Compared with those who had low
      normal plasma ferritin concentrations (73-141 micrograms/liter), those with
      elevated concentrations ( > 289 micrograms/liter) had a multivariate-adjusted
      odds ratio of 1.5 (95% confidence interval (CI) 1.0-2.3) after excluding subjects
      with possible non-iron-related elevations in ferritin. Compared with subjects
      consuming an adequate amount of iron (11.6-13.6 mg/day), multivariate-adjusted
      odds ratios were 1.6 (95% CI 1.1-2.4) for < 11.6 mg/day and 1.4 (95% CI 0.9-2.0)
      for > 27.3 mg/day. These results provide further support for a weak positive
      association between iron exposure and colorectal polyps.

PMID- 8659484
TI  - Physical activity in relation to colon cancer in middle-aged men and women.
AB  - A population-based case-control study was conducted to assess the relation
      between physical activity and colon cancer among men and women aged 30-62 years.
      Cases were 251 men and 193 women diagnosed with colon cancer in 1985-1989 in
      three countries in the Seattle metropolitan area who were identified from the
      Seattle-Puget Sound Surveillance, Epidemiology, and End Results registry.
      Controls were 233 men 194 women identified by random digit telephone dialing who
      were selected by stratified random sampling to approximate the age, sex, and
      county distribution of cases. Physical activity was assessed by questions on
      frequency and duration of types of recreational and occupational activities
      during the 10-year period ending 2 years before diagnosis. Each activity was
      classified as low intensity (< 4.5 METs ) or moderate to high intensity (> or =
      4.5 METs). For men and women combined, moderate or high intensity recreational
      activity was associated with a decreased risk of colon cancer (relative risk (RR)
      for two or more times per week vs. none = 0.70, 95% confidence interval (CI) 0.49
      1.00). This relation was stronger for men than women. Occupational activity was
      not associated with colon cancer, except among men younger than 55 (RR for > or =
      14.5 hours per week of moderate activity vs. none = 0.29, 95% CI 0.12-0.69).
      Among men and women combined, total moderate or high intensity activity
      (occupational plus recreational) was marginally related to colon cancer (RR for >
      or = 5 hours per week vs. none = 0.78, 95% CI 0.55-1.10). These results were
      adjusted for age (and sex in the combined sex analyses) and were not confounded
      by body mass index, dietary factors, or other measured health behaviors. The
      results of this study provide modest support to the growing number of studies
      showing that recreational and/or occupational physical activity is associated
      with a reduced risk of colon cancer.

PMID- 8659485
TI  - Correlation between systolic blood pressure and physical development in
      adolescence.
AB  - Although the close relation between blood pressure and physical development in
      adolescence has been established in cross-sectional and comparative cross
      sectional studies, the entire trend of systolic blood pressure (SBP) during
      adolescence has not been elucidated in conjunction with physical development in a
      longitudinal study. Blood pressure (mmHg), body weight (kg), and body height (m)
      were measured annually for 418 subjects in Hiroshima and Nagasaki, Japan, from
      age 10 (1955 or 1956) through 18 years (1963 or 1964). The Gompertz growth model
      was used to determine the velocity of weight increase (VEL) during that age
      period. The relations between SBP from age 10 to 18 and VEL, weight, height, body
      mass index (BMI; weight/height2, kg/m2), and the age at which the measurements
      were made were investigated individually using random-coefficient growth-curve
      analysis. The SBP trend for the 10- to 18-year age period could be shown by the
      following prediction equations: for the 163 Hiroshima males, SBP = 82.38 + 0.89
      VEL at age 1.15 years prior to the current examination (VEL (age - 1.15)) + 1.40
      BMI; for the 57 Nagasaki males, SBP = 92.70 + 1.07 VEL (age - 1.15) + 0.79 BMI;
      for the 148 Hiroshima females, SBP = 104.88 + 1.63 VEL (age - 1.15) + 0.05 BMI;
      for the 50 Nagasaki females, SBP = 113.62 + 1.67 VEL (age - 1.15) - 0.59 BMI. VEL
      1.15 years prior to the current examination was significantly and positively
      related to SBP in each city by sex group (p < 0.01), and current BMI was
      significantly related to SBP for males in Hiroshima (p < 0.01) and nearly so in
      Nagasaki (p = 0.06), but not for females in either city (p = 0.84 and 0.13,
      respectively). Because the plot of VEL was a convex curve, SBP peaked
      approximately 1-2 years after the peak in VEL and then decreased in both sexes.
      The entire SBP trend during adolescence can be expressed as an equation of VEL
      and BMI in males and of VEL in females. SBP does not increase linearly with age.

PMID- 8659486
TI  - Serum transferrin saturation, stroke incidence, and mortality in women and men.
      The NHANES I Epidemiologic Followup Study. National Health and Nutrition
      Examination Survey.
AB  - Several studies have examined relatively large body iron stores and the risk of
      coronary heart disease with conflicting results. No reports of studies that
      associated body iron stores with stroke were found. To test the hypothesis that
      relatively high transferrin saturation is associated with increased stroke
      incidence and mortality in women and men, data from a follow-up study of a
      national cohort were examined. A total of 5,033 women and men aged 45-74 years
      from the First National Health and Nutrition Examination Survey Epidemiologic
      Followup Study who were free of stroke at baseline were followed an average of 12
      years. Transferrin saturation (serum iron concentration divided by total iron
      binding capacity) was used as a measure of the amount of circulating iron
      available to tissues. In white women aged 45-74, after adjusting for age or for
      age and other risk variables, the authors observed a significant U-shaped
      association of transferrin saturation with risk of incident stroke (> 44% vs. 30
      36%, relative risk = 1.96, 95% confidence interval 1.15-3.36; < 20% vs. 30-36%,
      relative risk = 1.80, 95% confidence interval 1.20-2.71). However, no significant
      associations were found in white men aged 45-74 after adjusting for other risk
      variables. Similar findings were observed for stroke mortality in whites, but no
      significant associations were seen in blacks. The significantly increased risk of
      stroke that was seen at both high and low levels of transferrin saturation in
      white women should be confirmed in other cohorts of women and men.

PMID- 8659487
TI  - Transmission of Mycobacterium tuberculosis from tuberculosis patients with HIV
      infection or AIDS.
AB  - Contacts exposed to tuberculosis patients with acquired immunodeficiency syndrome
      (AIDS) or human immunodeficiency virus (HIV) infection were compared with
      contacts of HIV-negative patients for evidence of Mycobacterium tuberculosis
      transmission, based on a review of records of tuberculin skin tests administered
      during routine health department follow-up investigations in Miami/Dade County,
      Florida, from 1985 through 1989. After an adjusted analysis designed to balance
      background prevalence, tuberculin positivity was 42.0% in 2,158 contacts of HIV
      negative patients compared with 28.6% and 31.3% in 363 contacts of HIV-infected
      patients and 732 contacts of AIDS patients, respectively. Similar results were
      observed in a subset of 5- to 14-year-old contacts of United States-born black or
      white tuberculosis patients chosen to minimize the possibility of false-negative
      tuberculin tests in contacts due to undiagnosed HIV infection. Analysis of
      contacts as sets showed a more than expected number of sets with none or all
      contacts infected, but this did not differ by HIV/AIDS group. In this study,
      tuberculosis patients with AIDS or HIV infection were less infectious to their
      contacts and, in this community, exposed fewer contacts than HIV-negative
      tuberculosis patients.

PMID- 8659488
TI  - Assessment of surveillance for meningococcal disease in New York State, 1991.
AB  - Prevention of meningococcal disease relies in part on the prompt treatment of
      household and other close contacts of cases. New York State requires that all
      meningococcal disease cases be reported within 24 hours of diagnosis to ensure
      that chemoprophylaxis is given to all exposed persons. The authors used a capture
      recapture method to assess completeness of reporting of meningococcal disease in
      1991 by comparing persons reported to the Department of Health surveillance
      system with patients listed in the New York State computerized hospital discharge
      data set who had a discharge diagnosis of meningococcal disease. Medical records
      of persons identified from the discharge data set were reviewed to verify the
      diagnosis of meningococcal disease, and timeliness of reporting was assessed by
      reviewing surveillance case reports. In 1991, 110 cases of meningococcal disease
      were reported to the Department of Health and 197 patients were identified from
      hospital discharge data, of which charts were reviewed for 179 (91%). Of the
      charts reviewed, 116 (65%) had confirmed or probable meningococcal disease, and
      57 (32%) did not have the disease. Completeness of reporting to the notifiable
      disease surveillance system was estimated to be 93%, and 78% were reported within
      2 days of diagnosis. Errors of physicians and medical records departments
      contributed to the misclassification of medical records. The authors conclude
      that notifiable disease surveillance for meningococcal disease is relatively
      complete, but there is a delay in reporting some cases. Frequent errors may make
      invalidated hospital discharge data unsuitable for communicable disease
      surveillance.

PMID- 8659489
TI  - Estimability and interpretation of vaccine efficacy using frailty mixing models.
AB  - The authors consider estimability and interpretation of vaccine efficacy based on
      time to event data, allowing that some of the population might have a very low
      probability of acquiring disease, and the rest have partial, possibly
      continuously distributed, susceptibility. The efficacy parameters of interest in
      the frailty mixing model include the fraction highly unlikely to acquire the
      infection or disease due to the vaccine, the degree of partial protection in
      those still susceptible, and the average protection or summary measure of
      efficacy under heterogeneity. The efficacy estimates can still be usefully
      interpreted when the heterogeneity results from heterogeneity in contact
      patterns, contact rates, or infectiousness of the contacts, as long as these are
      equal in the vaccinated and unvaccinated groups. A likelihood-based method allows
      estimation of the efficacy parameters of interest from grouped time to event
      data. Simulated vaccine studies assuming different levels and distributions of
      efficacy demonstrate that ignoring heterogeneity in susceptibility or exposure to
      infection generally results in underestimation of vaccine efficacy as well as
      incorrect interpretation of the estimates. The approach is also applicable to
      other covariates affecting susceptibility or exposure to infection in infectious
      diseases. Exploitation of the dependent happening structure of infectious
      diseases to obtain a shape for the baseline hazard may help identifiability. The
      authors recommend fitting several models to time to event data in vaccine
      studies.

PMID- 8659490
TI  - Tracking strategies involving fourteen sources for locating a transient study
      sample: parents of sudden infant death syndrome infants and control infants.
AB  - Strategies involving 14 sources were used to locate 230 parents of sudden infant
      death syndrome infants who died in Southern California between 1989 and 1992 and
      255 parents of healthy, living infants matched by birth hospital, birth date,
      race and sex. The sample consisted of adults of reproductive age residing in
      Southern California. After an event of sudden infant death, many parents moved
      without a forwarding address; only their names, last known address, and the
      infant's race, birth date, and sex were available. There was no access to birth
      certificates, obstetric or pediatric medical records, parents' Social Security
      numbers, or parents' birth dates. The most successful tracking sources for case
      parents were the Department of Motor Vehicles, postal service, reverse directory
      and neighbors, private investigator, and California Medicaid services. For
      control parents, the post office, Department of Motor Vehicles, and Folks Finders
      proved the most helpful. Using a combination of the 14 sources achieved an
      adequate sample size.

PMID- 8659491
TI  - Diabetic nephropathy in type II diabetes.
AB  - The incidence of end-stage renal failure in patients with type II diabetes has
      dramatically increased in recent years, both in the United States and, with some
      delay, in some European countries. These epidemiologic observations have
      thoroughly dispelled the mistaken belief that renal prognosis was benign in type
      II diabetes. Recent interest has focused on the early stages of nephropathy in
      type II diabetes. With respect to renal hemodynamics, renal morphology, and
      progression of established diabetic nephropathy, there are no substantial
      differences between types I and type II diabetes. There is good evidence that
      preventive measures are effective, ie, glycemic control, blood pressure control,
      protein restriction, and discontinuation of smoking. The high prevalence of the
      disease (which in principle is preventable) calls for intense efforts to (1)
      educate the medical community, (2) substantially improve patient education and
      medical care, and (3) intensify research in this field.

PMID- 8659492
TI  - Changes in renal function in primary hypothyroidism.
AB  - Renal function impairment and electrolyte disorders in hypothyroidism are
      frequently subtle and rarely observed in clinical practice. To assess the extent
      of these defects, serum concentration of electrolytes and glomerular filtration
      rate were estimated before and after thyroid replacement therapy in 41 patients
      with primary hypothyroidism. All patients had decreased glomerular filtration
      rates and 22 patients had increased serum creatinine levels. Although a
      relationship between creatinine clearance and serum thyrothropin-stimulating
      hormone was not found, a weak correlation between age and serum creatinine
      concentration was observed. Hyponatremia was documented in 45% of 22 patients
      with elevated serum creatinine but in only 21% of 19 patients with normal
      creatinine. All these defects were corrected by treatment with thyroid hormone.
      We conclude that creatinine clearance was slightly decreased in all patients with
      hypothyroidism, this decrease being more noticeable in elderly patients. The
      greater the impairment in renal function, the more common was the occurrence of
      hyponatremia.

PMID- 8659493
TI  - In hereditary nephritis angiotensin-converting enzyme inhibition decreases
      proteinuria and may slow the rate of progression.
AB  - The hereditary nephritides are often progressive, resulting in kidney failure and
      the need for renal replacement therapy. There is no currently known beneficial
      treatment for these disorders. We observed three patients with hereditary
      glomerulonephritis with plasma creatinine concentrations ranging from 1.7 to 2.0
      mg/dL who were treated with angiotensin-converting enzyme inhibitors (ACEIs) for
      3.5 to 6 years. Angiotensin-converting enzyme inhibitor therapy was accompanied
      by a decrease in the mean arterial pressure (MAP) from 115 +/- 10 mm Hg to 93 +/-
      2 mm Hg (+/- SD), a decrease in the mean urinary protein/creatinine ratio from
      2,910 +/- 1,720 mg/g to 391 +/- 355 mg/g, and stabilization of the decline of
      creatinine clearance with time in two of the three patients. Based on this
      apparent benefit of ACEIs in hereditary nephritis, we suggest that a prospective
      controlled trial of ACEIs should be undertaken among a large group of such
      patients. Pending the results of such a study, ACEIs should be considered for the
      treatment of patients with proteinuric and progressive hereditary nephritis.

PMID- 8659495
TI  - Effects of steroids on the progression of renal failure in chronic interstitial
      renal fibrosis: a pilot study in Chinese herbs nephropathy.
AB  - Chinese herbs nephropathy is characterized by an extensive interstitial fibrosis
      and by a rapid evolution to end-stage renal failure. We thus decided to try
      steroid therapy (prednisolone 1 mg/kg for 1 month, tapered off 0.1 mg/kg every 2
      weeks) in cases with moderate renal failure and evidence of deterioration in
      renal function. Our steroid group (SG) consisted of 12 female patients with
      biopsy-proven renal fibrosis who were followed for at least 12 months after the
      initiation of steroids. Plasma creatinine level (Pcreat) ranged from 1.8 to 3.9
      mg/dL (mean +/- SEM, 2.8 +/- 0.2 mg/dL) when steroids were initiated at t = 0.
      Renal failure was in progression since Pcreat was 2.1 +/- 0.1 mg/dL (P = 0.022) 3
      months before t = 0. Our control group (CG; N = 23) was selected retrospectively
      from among the 81 patients in the Belgian Register of Chinese Herbs Nephropathy.
      Compared with the CG, renal function was better preserved in the SG (Pcreat; mean
      +/- SEM): SG v CG, 2.9 +/- 0.3 mg/dL v 5.3 +/- 0.5 mg/dL at 6 months (P = 0.0024)
      and 4.0 +/- 0.7 mg/dL v 7.1 +/- 0.5 mg/dL at 1 year (P = 0.001). The slope of the
      reciprocal serum creatinine concentration was similar in both groups before t = 0
      (-0.0463 mg/dL/mo in the SG v -0.0438 mg/dL/mo in the CG; P = 0.83), but it
      became less steep after initiation of steroid therapy (between 0 and 6 months, 
      0.000742 mg/dL/mo in the SG v -0.0284 mg/dL/mo in the CG; P < 0.001). Finally,
      only two of the 12 patients in the SG required dialysis at 1 year compared with
      16 of the 23 patients in the CG (P = 0.0045). We conclude that steroid therapy
      slows the progression of renal failure in a disease characterized by an
      interstitial fibrosis that progresses quickly despite the fact that the insulting
      agent has been withdrawn. This supports the hypothesis that renal interstitial
      fibrosis may be an immune-mediated process.

PMID- 8659494
TI  - Gallium 67 scintigraphy as a predictor of renal prognosis in primary
      immunoglobulin A nephropathy.
AB  - From October 1987 to September 1989, 29 patients with newly diagnosed
      immunoglobulin A nephropathy underwent renal gallium 67 scintigraphy. The
      radioisotope uptake ratio between left kidney and soft tissue was measured 48
      hours after bolus injection of gallium 67. In 25 patients the ratio ranged from
      1.30 to 3.56 (mean, 1.95 +/- 0.47). Ratios were not obtained in four patients
      because strong gastrointestinal isotope excretion. Plots of reciprocal serum
      creatinine concentration against time and Kaplan-Meier plots of renal survival
      were used to assess the predictive value of the test in 20 patients for whom long
      term follow-up data were available. The radioisotope uptake ratio was negatively
      correlated with the slope of reciprocal serum creatinine against time (r = -0.64,
      P < 0.01). When the 20 patients were divided into two groups according to
      radioisotope uptake ratio (group A, ratio > 1.95, nine patients; group B, ratio <
      1.95, 11 patients), life table analysis of renal survival showed group B to have
      a better prognosis than group A (P < 0.05). The results indicate that increased
      renal gallium uptake is predictive of a poor prognosis in patients with
      immunoglobulin A nephropathy.

PMID- 8659496
TI  - Thin-section computed tomography scans detect medullary cysts in patients
      believed to have juvenile nephronophthisis.
AB  - Juvenile nephronophthisis (NPH) and medullary cystic kidney disease are an
      important cause of chronic renal failure in children and young adults. Medullary
      cysts are regarded as the hallmark of this condition. The diagnostic techniques
      that were used previously were not conclusive in most cases to demonstrate
      medullary cysts. We studied the role of thin-section (1.5-mm) computed tomography
      (CT) scan as an optimal imaging diagnostic technique. Three children who were
      admitted to our hospital consecutive with a clinical diagnosis of NPH were
      included. We found that the thin-section CT scan demonstrates the medullary cysts
      in all patients. We recommend CT scan as the investigation of choice in patients
      with clinical features suggestive of nephronophthisis-cystic renal medulla
      complex.

PMID- 8659497
TI  - Insurance for autosomal dominant polycystic kidney disease patients prior to end
      stage renal disease.
AB  - There recently has been substantial dialogue about access to health insurance for
      Americans. This discussion has highlighted the issues of pre-existing diseases
      and portability as barriers to adequate health insurance coverage. For these
      reasons we decided to investigate the issues relating to health insurance and
      life insurance coverage experienced by patients with autosomal dominant
      polycystic kidney disease (ADPKD). A questionnaire-based study was conducted. Two
      hundred thirty-eight of 354 subjects responded. There was no significant
      difference in gender, age, number of children, or level of renal function between
      responders and nonresponders. Twenty-eight of the 238 respondents had eight-stage
      renal disease and were eligible for Medicare; these patients were not used in the
      analyses relating to health insurance, but were used in the analyses relating to
      life insurance. Although 87% of the ADPKD patients were concerned about the
      availability of health insurance, 88% were currently insured. Eight-three percent
      of subjects with health insurance obtained it through their own or their spouse's
      employer. Of those individuals with employer-based health insurance who were
      aware of their ADPKD, only 25% informed their employer and 35% informed their
      insurer at the start of coverage. Fifty-seven percent of those with employer
      based health insurance had this availability determine their job choice and 37%
      stayed in the job because of health insurance. Thirty percent of the subjects had
      previously been denied health insurance. Although subjects were less concerned
      about life insurance, many of the same types of issues and factors were present.
      Thus, the current lack of universal health care in this country creates anxiety
      and difficulties for patients with ADPKD. The effect of a pre-existing condition
      and the lack of portability resulted in denials, work choice limitation, and
      unwillingness to share health information for this patient population with a
      hereditary, systemic disease.

PMID- 8659498
TI  - Laparoscopy for adult polycystic kidney disease: a promising alternative.
AB  - The purpose of this study was to evaluate the efficacy of laparoscopy in managing
      patients with abdominal symptoms from autosomal dominant polycystic kidney
      disease (ADPKD). From April 1993 to July 1995, four patients with ADPKD underwent
      seven laparoscopic procedures: five cyst decortications were performed in two
      patients using a laparoscopic ultrasound unit and two laparoscopic nephrectomies
      were performed in two patients with end-stage renal failure. The mean operative
      time was 207 minutes for laparoscopic cyst decortication and 272 minutes for
      laparoscopic nephrectomy. The two nephrectomy specimens were 2,200 g and 1,750 g,
      respectively. The mean intraoperative blood loss was 85 mL. The patients resumed
      their oral intake within 10 hours after laparoscopic cyst decortication and
      within 16 hours after laparoscopic nephrectomy. The mean amount of parenteral
      analgesics required postoperatively was 12 mg morphine sulfate for cyst
      decortication and 30 mg morphine sulfate for nephrectomy. The mean hospital stay
      was 3 days for cyst decortication and 3.5 days for nephrectomy. The patients
      returned to their usual activities after an average of 2 weeks. Based on pain
      analog scales, all the patients have shown marked reduction in their symptoms
      (average, 90%) during an average follow-up period of 6.6 months. Laparoscopic
      cyst decortication and nephrectomy are effective minimally invasive treatment
      options for patients with adult polycystic kidney disease who are experiencing
      abdominal symptoms due to marked renal enlargement. We believe that by using a
      laparoscopic ultrasound unit, most renal cysts may be safely removed, and if need
      be, even "giant" kidneys can be removed laparoscopically. To the best of our
      knowledge, the two nephrectomy specimens in this study represent the largest
      kidneys removed laparoscopically to date and the first laparoscopic nephrectomies
      in ADPKD patients.

PMID- 8659499
TI  - Intravenous iron supplementation for the treatment of the anemia of moderate to
      severe chronic renal failure patients not receiving dialysis.
AB  - Iron deficiency may develop in hemodialysis patients, especially when
      erythropoietin is given. The role of iron deficiency in the anemia of predialysis
      chronic renal failure (CRF), however, is much less clear. We have intravenously
      (IV) administered iron as ferric saccharate in a total dose of 200 mg elemental
      iron monthly for 5 months to 33 CRF patients who remained anemic despite oral
      iron supplementation and who had no laboratory signs of iron overload. None was
      receiving erythropoietin therapy. In 22 of the patients there was an increase in
      the hematocrit values by the end of the study. These patients were considered
      responders to intravenous iron (IV Fe) therapy. In 11 patients the iron
      administration was not associated with improvement of the anemia (nonresponders).
      Before onset of the IV Fe therapy there were no differences between the
      responders and nonresponders with regard to degree of anemia, serum ferritin,
      iron saturation, renal function, or blood pressure. One additional patient was
      excluded from the study because of a mild reaction during an IV test dose before
      the study. No worsening of kidney function and no other side effects were noted.
      In four patients (three responders and one nonresponder) the control of blood
      pressure necessitated antihypertensive drug therapy adjustment. In conclusion, IV
      Fe supplementation in two thirds of anemic CRF patients not receiving dialysis
      resulted in a significant improvement of the anemia, thus avoiding the necessity
      of erythropoietin or blood administration. This could be achieved by increasing
      the plasma ferritin levels to 200 to 400 microns/L and/or increasing the iron
      saturation to 25% to 35%. Intravenous ferric saccharate appears to be a safe and
      effective method of administering iron for the correction of anemia in CRF
      patients not receiving dialysis.

PMID- 8659500
TI  - Alterations in soluble intercellular adhesion molecule-1 and vascular cell
      adhesion molecule-1 in hemodialysis patients.
AB  - Hemodialysis (HD) patients can develop acute reactions during treatment as well
      as increased long-term susceptibility to infections and malignancies.
      Abnormalities in leukocyte adhesion may contribute to these processes. Recently,
      serum levels of soluble adhesion molecules have been detected in circulating
      blood of normal subjects and in patients with chronic renal failure. We studied
      the effects of a single dialysis session with new cuprophane membrane on the
      soluble (s) form of intracellular adhesion molecule-1 (ICAM-1) and vascular cell
      adhesion molecule-1 (VCAM-1), two adhesion molecules with a variety of
      immunologic roles. Significant elevations in both sICAM-1 (523 +/- 61 v 304 +/-
      45 [SEM] ng/mL, P < 0.05) and sVCAM-1 (2,055 +/- 270 v 1,189 +/- 149 ng/mL, P <
      0.05) were observed in HD patients at baseline compared with controls. Both sICAM
      1 and sVCAM-1 levels decreased after a 3-hour HD session (P < 0.001). Early in
      HD, sICAM-1 levels, though lower than predialysis, were elevated in the exit line
      of the dialyzer compared with entrance (339 +/- 64 v 259 +/- 53 ng/mL, P <
      0.001), whereas sVCAM-1 was decreased on the exit line compared with entrance
      (639 +/- 90 v 932 +/- 92 ng/mL, P < 0.001). Because ICAM-1 and VCAM-1 are
      important for many leukocyte functions, alterations in serum levels of sICAM-1
      and sVCAM-1 may play a role in the immunologic consequences of uremia and HD
      treatment.

PMID- 8659501
TI  - Effect of hemodialysis on leukocyte adhesion receptor expression.
AB  - Hemodialysis with complement-activating membranes such as cuprophane is known to
      transiently activate leukocytes, leading to increased cellular adhesiveness,
      pulmonary leukostasis, and reduced functional capacity of monocytes and
      neutrophils. Clinically, this repetitive cell activation may contribute to the
      increased morbidity and mortality associated with chronic hemodialysis. To
      examine the effect of cuprophane hemodialysis on expression of cell-surface
      proteins involved in leukocyte adhesiveness, we monitored CD11b, CD18, CD14,
      CD54, and plasma-soluble CD54 in 10 patients during hemodialysis with cuprophan
      dialyzers. To test the effect of local blood recirculation, in two patients,
      arterial supply to the dialyzer was accessed from the peripheral arteriovenous
      fistula and was returned via an indwelling central venous catheter. In an attempt
      to examine the possible role of membrane-induced complement activation, the
      results were compared with those seen after incubation with C5a in vitro.
      Finally, the leukocyte responses to C5a and lipopolysaccharide were measured
      before and after hemodialysis. Leukocyte expression of CD11b and CD18 increased
      and CD14 decreased with hemodialysis, while CD54 remained unaltered. Plasma CD54
      was markedly elevated before and remained unchanged during hemodialysis. Data
      obtained with C5a activation in vitro revealed identical changes in CD11b
      expression as that seen with hemodialysis, suggesting the role of membrane
      induced complement activation. Preliminary data obtained using remote arterial
      and venous access sites showed only a slight increase in CD11b expression in the
      arterial blood, suggesting that the apparent systemic activation seen with
      arteriovenous access may be due to recirculation and local activation within the
      blood access. Finally, dialysis procedure did not impair lipopolysaccharide- or
      C5a-mediated upregulation of CD11b expression.

PMID- 8659502
TI  - Postdialysis urea rebound: determinants and influence on dialysis delivery in
      chronic hemodialysis patients.
AB  - We measured postdialysis urea rebound (PDUR) 30 minutes after dialysis in 92
      chronic hemodialysis patients. The impact of PDUR on the estimation of dialysis
      delivery assessed by urea reduction ratio and Kt/V was evaluated. Total
      recirculation, access plus cardiopulmonary, was measured at the end of dialysis
      with the two-needle low blood flow method. The mean age of the 92 patients (49
      men and 43 women) was 59.6 +/- 1.4 years. Thirty-eight patients had been
      receiving erythropoietin therapy for more than 3 months. Fifteen patients had
      central venovenous access and 77 had peripheral arteriovenous access. Sixty-five
      patients were dialyzed using hemophan membranes and 27 were dialyzed using
      polyacrylonitrile membranes. The mean blood flow rate was 240 +/- 28 mL/min and
      the mean length of the hemodialysis sessions was 3.6 +/- 0.1 hours. Kt/V was
      calculated with Daugirdas' second-generation formula. The mean PDUR was 16.6% +/-
      0.8% (range, 2% to 44%) (n = 92), and significantly decreased the mean urea
      reduction ratio from 61.7% +/- 0.8% to 55.5% +/- 0.9%, the mean Kt/V from 1.14 +/
      0.03 to 0.97 +/- 0.02, and the mean protein catabolic rate from 1.06 +/- 0.04 to
      0.98 +/- 0.02 (P = 0.0001). The effective Kt/V at 30 minutes postdialysis was
      well predicted by using a recently proposed equation: eKt/V30 = Kt/Vsp - (0.6 x
      Kt/Vsp/t) + 0.03, with a mean value corresponding also to 0.97 +/- 0.02. However,
      this estimation was less predictive in patients with very high PDUR. Moreover,
      PDUR showed only a weak negative correlation with dialysis session length (r = 
      0.28) and predialysis patient weight (r = -0.29), and showed no correlation with
      predialysis serum urea level or with blood flow rate. However, dialysis
      efficiency, as assessed by K/V, presented a correlation of 0.54 with both PDUR
      and the difference in Kt/V when using urea immediately postdialysis and at 30
      minutes. The mean total recirculation was 7.4% +/- 0.6% (n = 86). Postdialysis
      urea rebound, calculated between 30 or 120 seconds and 30 minutes after dialysis
      to deduce the influence of recirculations, was reduced but remained important
      with a mean of 11.8% +/- 0.7%. Thus, total recirculation contributed to nearly
      30% of PDUR. The 24 patients with PDUR > or = 20% were compared with the 68
      patients with PDUR lower than 20%: women and patients with higher K/V and higher
      total recirculation presented greater PDUR. Because of relatively few predictive
      factors for PDUR, its potential considerable impact on dialysis delivery
      estimation, and the influence of recirculations on the total PDUR amount, total
      recirculation and PDUR should be determined on an individual basis in chronic
      hemodialysis patients. The equation proposed to estimate effective Kt/V at 30
      minutes is accurate in most patients with PDUR lower than 30% and is a simple
      alternative.

PMID- 8659503
TI  - Hemolytic reactions mechanically induced by kinked hemodialysis lines.
AB  - Ten hemolytic reactions occurred in our outpatient hemodialysis unit over a 12
      month period (December 1989 to December 1990). Eight patients were hospitalized
      and one died. All patients developed severe abdominal or back pain an average of
      2.5 hours into a 4-hour hemodialysis session using a bleach/formaldehyde
      reprocessed hollow-fiber cupraphan dialyzer (average reuse, three times) with
      blood flow rates of 375 mL/min. All had visible hemolysis in a spun hematocrit,
      seven had a significant decrease in hematocrit, and six developed pancreatitis.
      Hemolysis was further confirmed by a decrease in haptoglobin in all patients and
      an increase in lactic dehydrogenase in all but the last case. Investigation of
      each episode failed to find an abnormality in dialysate temperature or tonicity;
      dialysate or water levels of copper, zinc, nitrates, chloramine, or formaldehyde;
      or blood pump or venous alarm. Hemolytic reactions continued despite changing to
      15-gauge needles, removing bleach from the reuse procedure, or stopping reuse.
      During the eighth episode, a kink was noted in the arterial blood line. Two
      subsequent hemolytic reactions occurred, and in each kinks were found in the
      arterial blood line, either in the excess tubing between the blood pump and drip
      chamber or in the predialyzer. No further hemolytic reactions occurred after
      changing to a new arterial blood line without redundant tubing and securing all
      lines. Hemolytic reactions occurring during hemodialysis have many etiologies,
      including mechanical trauma, which we report may result from kinking of dialyzer
      lines. With new blood lines on the market, attention to this aspect of dialysis
      is mandatory.

PMID- 8659504
TI  - Alport's syndrome in monozygotic twins.
AB  - Identical twins presented at the same time with renal failure. They also recalled
      a simultaneous history of "nephritis" as early as the age of 6 years. Renal
      biopsies revealed variably thickened glomerular basement membranes with the
      lamellation and splitting characteristic of Alport's syndrome. Bilateral
      sensorineural deafness was demonstrated in both twins on audiometric testing. A
      positive family history in the mother and one elder sister confirmed the
      diagnosis of Alport's syndrome. This is the first reported case of Alport's
      syndrome occurring in monozygotic twins.

PMID- 8659505
TI  - Rolaids-yogurt syndrome: a 1990s version of milk-alkali syndrome.
AB  - Milk-alkali syndrome is characterized by progressive hypercalcemia, systemic
      alkalosis, and renal insufficiency. After calcium carbonate is ingested with
      diary products, hypercalcemia and alkalosis may develop in susceptible persons,
      particularly those with underlying renal insufficiency. We describe a young woman
      who neither drank milk nor had peptic ulcer disease, yet who ingested enough
      calcium carbonate to require admission to an intensive care unit for acute renal
      failure. Chronically bulimic, she was taking Rolaids (Warner-Lambert Co, Morris
      Plains, NJ), which contained calcium carbonate, and was eating yogurt daily to
      prevent osteoporosis. We discuss the characteristics and complex metabolic
      interactions of the milk-alkali syndrome, a critical but generally reversible
      electrolyte disorder. Early recognition of coincident hypercalcemia and alkalosis
      and prompt cessation of calcium carbonate ingestion are essential for successful
      recovery. Finally, we suggest that nephrologists should discourage patients with
      renal insufficiency and chronic vomiting from consuming calcium-containing
      antacids and excessive dietary calcium.

PMID- 8659506
TI  - Predominant tubulointerstitial lupus nephritis.
AB  - Predominant tubulointerstitial lupus nephritis is rare. Only eight cases have
      been described in the literature. We report the case of a 59-year-old man with
      systemic lupus erythematosus who presented with acute renal failure. On renal
      biopsy, he was found to have chronic tubulointerstitial nephritis with a
      mononuclear infiltrate. The immunofluorescence showed immune deposits in the
      tubular basement membranes, interstitium, and glomerular capsule. The glomeruli
      were minimally involved. He was initially treated with high-dose corticosteroids
      and supported with hemodialysis. Renal function improved and dialysis was
      discontinued after three treatments. The corticosteroid dosage was gradually
      tapered. Renal function after 72 months of follow-up has remained stable (serum
      creatinine, approximately 1.9 mg/dL) and except for one relapse, there has been
      no clinical or serologic evidence of lupus activity. Furthermore, 24-hour urinary
      protein excretion has remained within the normal range.

PMID- 8659507
TI  - Membranous glomerulonephritis associated with inflammatory demyelinating
      peripheral neuropathies.
AB  - A 55-year-old man with chronic inflammatory demyelinating polyradiculoneuropathy
      developed the nephrotic syndrome. Renal biopsy showed stage I membranous
      glomerulonephritis. Review of the literature revealed the association of these
      two rare syndromes, considered to be due to immunologic dysfunction, in two other
      cases, as well as several cases of the acute form of demyelinating peripheral
      polyradiculoneuropathy. The nephrotic syndrome appears to be persistent in the
      chronic form of the peripheral neuropathy but reversible in its acute form
      following immunosuppressive therapy. The possibility of a common
      immunopathogenesis in the association of membranous glomerulonephritis and
      inflammatory demyelinating peripheral neuropathies deserves further scrutiny.

PMID- 8659508
TI  - Acute renal failure secondary to solid tumor renal metastases: case report and
      review of the literature.
AB  - Renal metastases from solid tumors to both kidneys rarely result in acute renal
      failure (ARF). We present a case of squamous cell pulmonary carcinoma responsible
      for ARF due to (1) extensive (50% to 75%) bilateral parenchymal infiltration and
      replacement accompanied by tissue destruction, (2) widespread vascular invasion
      and thrombosis resulting in ischemia, and (3) histological evidence for foci of
      distal intratubular obstruction and pyelonephritis. Five additional cases,
      including one pulmonary cancer, causing ARF from extensive tissue replacement and
      destruction are reviewed. In a separate case, ARF resulted from lymphatic
      metastases rather than from parenchymal destruction or obstruction. Common
      findings in all six reported cases include bilaterally enlarged kidneys and
      progressive oligoanuria despite correction of prerenal or postrenal conditions.
      In our patient and in one other prior reported case, extrarenal obstruction was
      not considered important because invasive therapeutic procedures were
      unsuccessful in reversing ARF. In one case, irradiation of kidney tumor resulted
      in reversal of ARF. These cases emphasize the rare potential for solid tumors to
      metastasize to both kidneys and result in irreversible oligoanuric ARF. A high
      level of suspicion is required, and an early diagnosis may result in reversible
      ARF if the tumor is amenable to chemotherapy or irradiation.

PMID- 8659509
TI  - Hypertension, proteinuria, and hypocomplementemia in a multigravida.

PMID- 8659510
TI  - Health care in Sweden: "the devil's in the details".

PMID- 8659511
TI  - Huntington disease--another chapter rewritten.
AB  - To those of us who began life when humans had 48 chromosomes and who began
      working in genetics when the (by then 46) chromosomes had no bands and chromosome
      4 could not reliably be distinguished from chromosome 5, the mere ability to
      diagnose and correlate the clinical phenotypes of genetic disorders with their
      molecular genotypes is a source of continuing astonishment and pleasure. Indeed,
      molecular genetic analysis of neurogenetic disorders such as Huntington disease
      (HD) has provided a steady stream of challenges and surprises to all who believe
      the genetic principles that they were taught about these disorders. The paper by
      Rubinsztein et al. in this issue of the journal highlights yet another surprise,
      which was adumbrated even in the initial paper announcing the discovery of the HD
      gene: incomplete penetrance of HD gene mutations.

PMID- 8659512
TI  - Evidence against an X-linked visual loss susceptibility locus in Leber hereditary
      optic neuropathy.
AB  - Pedigree analysis of British families with Leber hereditary optic neuropathy
      (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with
      an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60%
      of affected females will show marked skewing of X inactivation. Linkage analysis
      in British and Italian families with genetically proven LHON has excluded the
      presence of such a VLSL over 169 cM of the X chromosome both when all families
      were analyzed together and when only families with the bp 11778 mutation were
      studied. Further, there was no excess skewing of X inactivation in affected
      females. There was no evidence for close linkage to three markers in the
      pseudoautosomal region of the sex chromosomes. The mechanism of incomplete
      penetrance and male predominance in LHON remains unclear.

PMID- 8659513
TI  - Segregation distortion of the CTG repeats at the myotonic dystrophy locus.
AB  - Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused
      by a CTG-repeat expansion, with affected individuals having > or = 50 repeats of
      this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely
      affected individuals die early in life; the milder form of this disease reduces
      reproductive ability. Alleles in the normal range of CTG repeats are not as
      unstable as the (CTG)(> or = 50) alleles. In the DM families, anticipation and
      parental bias of allelic expansions have been noted. However, data on mechanism
      of maintenance of DM in populations are conflicting. We present a maximum
      likelihood model for examining segregation distortion of CTG-repeat alleles in
      normal families. Analyzing 726 meiotic events in 95 nuclear families from the
      CEPH panel pedigrees, we find evidence of preferential transmission of larger
      alleles (of size < or = 29 repeats) from females (the probability of transmission
      of larger alleles is .565 +/- 0.03, different from .5 at P approximately equal
      .028). There is no evidence of segregation distortion during male meiosis. We
      propose a hypothesis that preferential transmission of larger CTG-repeat alleles
      during female meiosis can compensate for mutational contraction of repeats within
      the normal allelic size range, and reduced viability and fertility of affected
      individuals. Thus, the pool of premutant alleles at the DM locus can be
      maintained in populations, which can subsequently mutate to the full mutation
      status to give rise to DM.

PMID- 8659515
TI  - The proteolipid protein gene: double, double, ... and trouble.

PMID- 8659514
TI  - A familial factor independent of CAG repeat length influences age at onset of
      Machado-Joseph disease.
AB  - Machado-Joseph disease (MJD) is a late-onset, progressive, neurodegenerative
      disorder caused by the expansion of an unstable trinucleotide (CAG) repeat
      sequence in a novel gene (MJD1) on chromosome 14. Previous studies showed that
      age at onset is negatively correlated with the number of CAG repeat units, but
      only part of the variation in onset age is explained by CAG repeat length. Ages
      at onset and CAG repeat lengths of 136 MJD patients from 23 kindreds of
      Portuguese descent were analyzed, to determine whether familial factors
      independent of CAG repeat length modulate age at onset of MJD. Correlation among
      sibs for onset age adjusted for CAG repeat length was .43, which indicates that
      an environmental or genetic factor common to sibs influences onset age. Positive
      correlations were also observed for avuncular (r = .22) and first-cousin pairs (r
      = .28), which supports the hypothesis that a genetic factor is influencing age at
      onset. Commingling analysis of onset ages adjusted for CAG repeat length
      identified three distributions in this population of affected individuals.
      Further studies of a much larger sample are needed to determine whether these
      distributions represent the influence of a genetic or environmental factor.

PMID- 8659517
TI  - A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q.
AB  - Dyskinesias are hyperkinetic and involuntary movements that may result from any
      of a number of different genetic, infectious, and drug-induced causes. Some of
      the hereditary dyskinetic syndromes are characterized by paroxysmal onset of the
      abnormal movements. The classification of the familial paroxysmal dyskinesias
      (FPD) recognizes several distinct, although overlapping, phenotypes. Different
      forms of the disorder include attacks that are (1) induced by sudden movement
      (kinesiogenic); (2) spontaneous (non-kinesiogenic); and (3) induced by prolonged
      periods of exertion. Linkage analysis was pursued in a family segregating an
      autosomal dominant allele for non-kinesiogenic FPD. The disease allele was mapped
      to a locus on chromosome 2q31-36 (LOD score 4.64, theta = 0). Identification of
      distinct genetic loci for the paroxysmal dyskinesias will lead to a new genetic
      classification and to better understanding of these disorders.

PMID- 8659516
TI  - Chronic hepatitis B carriers with null genotypes of glutathione S-transferase M1
      and T1 polymorphisms who are exposed to aflatoxin are at increased risk of
      hepatocellular carcinoma.
AB  - This study was carried out to elucidate the effect of glutathione S-transferase
      (GST) Ml and Tl polymorphisms on the aflatoxin-related hepatocarcinogenesis among
      chronic carriers of hepatitis B surface antigen (HBsAg). A total of 32 newly
      diagnosed hepatocellular carcinoma (HCC) cases and 73 age-matched controls
      selected from a cohort of 4,841 chronic HBsAg carriers who had been followed for
      5 years were studied. The level of aflatoxin B1 (AFB1)-albumin adducts in their
      serum samples collected at the recruitment was examined by competitive enzyme
      linked immunosorbance assay, and genotypes of GST M1 and T1 were determined by
      PCR. There was a dose-response relationship between serum level of AFB1-albumin
      adducts and risk of HCC. The biological gradients between serum AFB1-albumin
      adducts level and HCC risk were observed among chronic HBsAg carriers who had
      null genotypes of GST M1 and/or T1 but not among those who had non-null
      genotypes. The multivariate-adjusted odds ratios of developing HCC for those who
      had low and high serum levels of AFB1-albumin adducts compared with those who had
      a undetectable adduct level as the referent (odds ratio = 1.0) were 4.1 and 12.4,
      respectively, for HBsAg carriers with null GST M1 genotype (P < .01, on the basis
      of the significance test for trend); 0.7 and 1.4 for those with non-null GST Ml
      genotype (P = .98); 1.8 and 10.2 for those with null GST T1 genotype (P < .05);
      and 1.3 and 0.8 for those with non-null GST T1 genotype (P = .93). The
      interaction between serum AFB1-albumin adduct level and polymorphisms of GST M1
      and T1 was at marginal statistical significance levels (.05 < P < .10).

PMID- 8659518
TI  - Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q.
AB  - Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of
      involuntary movements that last up to several hours and occur at rest both
      spontaneously and following caffeine or alcohol consumption. We analyzed a Polish
      American kindred with autosomal dominant PDC and identified tight linkage between
      the disorder and microsatellite markers on chromosome 2q (maximum two-point LOD
      score 4.77; recombination fraction 0). Our results clearly establish the
      existence of a locus for autosomal dominant PDC on distal chromosome 2q. The fact
      that three other paroxysmal neurological disorders (periodic ataxia with myokymia
      and hypo- and hyperkalemic periodic paralysis) are due to mutation in ion-channel
      genes raises the possibility that PDC is also due to an ion-channel gene
      mutation. It is noteworthy that a cluster of sodium-channel genes is located on
      distal chromosome 2q, near the PDC locus. Identifying the PDC locus on chromosome
      2q will facilitate discovery of the PDC gene and enable investigators to
      determine whether PDC is genetically homogeneous and whether other paroxysmal
      movement disorders are also genetically linked to the PDC locus.

PMID- 8659519
TI  - Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and
      vision, is assigned to chromosome region 11q12-13.
AB  - Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder
      characterized by severe juvenile-onset osteoporosis and congenital or juvenile
      onset blindness. The pathogenic mechanism is not known. Clinical, biochemical,
      and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis
      rather than a disorder of matrix structure. Consequently, identification of the
      OPS gene and its protein product could provide insights regarding common
      osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a
      first step toward determining the cause of OPS, we utilized a combination of
      traditional linkage analysis and homozygosity mapping to assign the OPS locus to
      chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples
      (seven affected individuals) from three different consanguineous kindreds.
      Studies in 10 additional families narrowed the candidate region, supported locus
      homogeneity, and did not detect founder effects. The OPS locus maps to a 13-cM
      interval between D11S1298 and D11S971 and most likely lies in a 3-cM region
      between GSTP1 and D11S1296. At present, no strong candidate genes colocalize with
      OPS.

PMID- 8659520
TI  - A recombination outside the BB deletion refines the location of the X linked
      retinitis pigmentosa locus RP3.
AB  - Genetic loci for X-linked retinitis pigmentosa (XLRP) have been mapped between
      Xp11.22 and Xp22.13 (RP2, RP3, RP6, and RP15). The RP3 gene, which is responsible
      for the predominant form of XLRP in most Caucasian populations, has been
      localized to Xp21.1 by linkage analysis and the map positions of chromosomal
      deletions associated with the disease. Previous linkage studies have suggested
      that RP3 is flanked by the markers DXS1110 (distal) and OTC (proximal). Patient
      BB was thought to have RP because of a lesion at the RP3 locus, in addition to
      chronic granulomatous disease, Duchenne muscular dystrophy (DMD), mild mental
      retardation, and the McLeod phenotype. This patient carried a deletion extending
      approximately 3 Mb from DMD in Xp21.3 to Xp21.1, with the proximal breakpoint
      located approximately 40 kb centromeric to DXS1110. The RP3 gene, therefore, is
      believed to reside between DXS1110 and the proximal breakpoint of the BB
      deletion. In order to refine the location of RP3 and to ascertain patients with
      RP3, we have been analyzing several XLRP families for linkage to Xp markers.
      Linkage analysis in an American family of 27 individuals demonstrates segregation
      of XLRP with markers in Xp21.1, consistent with the RP3 subtype. One affected
      mate shows a recombination event proximal to DXS1110. Additional markers within
      the DXS1110-OTC interval show that the crossover is between two novel polymorphic
      markers, DXS8349 and M6, both of which are present in BB DNA and lie centromeric
      to the proximal breakpoint. This recombination places the XLRP mutation in this
      family outside the BB deletion and redefines the location of RP3.

PMID- 8659521
TI  - Genotyping of PCR-based polymorphisms and linkage-disequilibrium analysis at the
      NF1 locus.
AB  - Six polymorphisms across the NF1 gene have been adapted for genotyping through
      application of PCR-based assays. Three exon-based polymorphisms--at positions
      702, 2034, and 10647 in the NF1 cDNA--were genotyped by mutagenically separated
      PCR (MS-PCR). A fourth polymorphism, DV1.9, is an L1 insertion element in intron
      30, and the other two polymorphisms, GXAlu and EVI-20, are short tandem repeats
      in intron 27b. All the polymorphisms were evaluated in a cohort of 110 CEPH
      individuals who previously had been analyzed by use of eight RFLPs at the NF1
      locus. Pairwise linkage-disequilibrium analyses with the six PCR-based
      polymorphisms and their flanking markers demonstrated disequilibrium between all
      tested loci. Genotypes of the four diallelic polymorphisms (702, 2034, 10647, and
      DV1.9) were also evaluated in cohorts from the CEPH, African, and Japanese
      populations. The CEPH and Japanese cohorts showed similar heterozygosities and
      linkage-disequilibrium coefficients. The African cohort showed a higher degree of
      heterozygosity and lower linkage-disequilibrium values, compared with the CEPH
      and Japanese cohorts.

PMID- 8659522
TI  - Phenotypic characterization of individuals with 30-40 CAG repeats in the
      Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently
      normal elderly individuals with 36-39 repeats.
AB  - Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease
      (HD). In the diagnostic setting it is necessary to define the limits of the CAG
      size ranges on normal and HD-associated chromosomes. Most large analyses that
      defined the limits of the normal and pathological size ranges employed PCR
      assays, which included the CAG repeats and a CCG repeat tract that was thought to
      be invariant. Many of these experiments found an overlap between the normal and
      disease size ranges. Subsequent findings that the CCG repeats vary by 8
      trinucleotide lengths suggested that the limits of the normal and disease size
      ranges should be reevaluated with assays that exclude the CCG polymorphism. Since
      patients with between 30 and 40 repeats are rare, a consortium was assembled to
      collect such individuals. All 178 samples were reanalyzed in Cambridge by using
      assays specific for the CAG repeats. We have optimized methods for reliable
      sizing of CAG repeats and show cases that demonstrate the dangers of using PCR
      assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36
      repeats, which confirms that this allele is associated with disease. Individuals
      without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78,
      79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years),
      and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an
      exceptional case from this series will be presented: a 95-year-old man with 39
      repeats who did not have classical features of HD. The apparently healthy
      survival into old age of some individuals with 36-39 repeats suggests that the HD
      mutation may not always be fully penetrant.

PMID- 8659523
TI  - Evidence for structural heterogeneity from molecular cytogenetic analysis of
      dicentric Robertsonian translocations.
AB  - Most Robertsonian translocations are dicentric, suggesting that the location of
      chromosomal breaks leading to their formation occur in the acrocentric short arm.
      Previous cytogenetic and molecular cytogenetic studies have shown that few
      Robertsonian translocations retain ribosomal genes or beta-satellite DNA.
      Breakpoints in satellite III DNA, specifically between two chromosome 14-specific
      subfamilies, pTRS-47 and pTRS-63, have been indicated for most of the dicentric
      14q21q and 13q14q translocations that have been studied. We have analyzed the
      structure of 36 dicentric translocations, using several repetitive DNA probes
      that localize to the acrocentric short arm. The majority of the translocations
      retained satellite III DNA, while others proved variable in structure. Of 10
      14q21q translocations analyzed, satellite III DNA was undetected in 1; 6 retained
      one satellite III DNA subfamily, pTRS-47; and 3 appeared to contain two 14
      specific satellite III DNA sub-families, pTRS-47 and pTRS-63. In 10/11
      translocations involving chromosome 15, the presence of satellite III DNA was
      observed. Our results show that various regions of the acrocentric short arm,
      and, particularly, satellite III DNA sequences, are involved in the formation of
      Robertsonian translocations.

PMID- 8659524
TI  - Association between nondisjunction and maternal age in meiosis-II human oocytes.
AB  - The relationship between advanced maternal age and increased risk of trisomic
      offspring is well known clinically but not clearly understood at the level of the
      oocyte. A total of 383 oocytes that failed fertilization from 107 patients
      undergoing in vitro fertilization were analyzed by FISH using X-, 18-, and 13/21
      chromosome probes simultaneously. The corresponding polar bodies were also
      analyzed in 188 of these oocytes. The chromosomes in the oocyte and first polar
      body complement each other and provide an internal control to differentiate
      between aneuploidy and technical errors. Two mechanisms of nondisjunction were
      determined. First, nondisjunction of bivalent chromosomes resulting in two
      univalents going to the same pole and, second, nondisjunction by premature
      chromatid separation (predivision) of univalent chromosomes producing either a
      balanced (2 + 2) or unbalanced (3 + 1) distribution of chromatids into the first
      polar body and M-II oocytes. Balanced predivision of chromatids, previously
      proposed as a major mechanism of aneuploidy, was found to increase significantly
      with time in culture (P < .005), which suggests that this phenomenon should be
      interpreted carefully. Unbalanced predivision and classical nondisjunction were
      unaffected by oocyte aging. In comparing oocytes from women <35 years of age with
      oocytes from women > or = 40 years of age, a significant increase (P < .001) in
      nondisjunction of full dyads was found in the oocytes with analyzable polar
      bodies and no FISH errors. Premature predivision of chromatids was also found to
      cause nondisjunction, but it did not increase with maternal age.

PMID- 8659525
TI  - Paleolithic and neolithic lineages in the European mitochondrial gene pool.
AB  - Phylogenetic and diversity analysis of the mtDNA control region sequence
      variation of 821 individuals from Europe and the Middle East distinguishes five
      major lineage groups with different internal diversities and divergence times.
      Consideration of the diversities and geographic distribution of these groups
      within Europe and the Middle East leads to the conclusion that ancestors of the
      great majority of modern, extant lineages entered Europe during the Upper
      Paleolithic. A further set of lineages arrived from the Middle East much later,
      and their age and geographic distribution within Europe correlates well with
      archaeological evidence for two culturally and geographically distinct Neolithic
      colonization events that are associated with the spread of agriculture. It
      follows from this interpretation that the major extant lineages throughout Europe
      predate the Neolithic expansion and that the spread of agriculture was a
      substantially indigenous development accompanied by only a relatively minor
      component of contemporary Middle Eastern agriculturalists. There is no evidence
      of any surviving Neanderthal lineages among modern Europeans.

PMID- 8659526
TI  - mtDNA variation indicates Mongolia may have been the source for the founding
      population for the New World.
AB  - mtDNA RFLP variation was analyzed in 42 Mongolians from Ulan Bator. All four
      founding lineage types (A [4.76%], B [2.38%], C [11.9%], and D [19.04%])
      identified by Torroni and colleagues were detected. Seven of the nine founding
      lineage types proposed by Bailliet and colleagues and Merriwether and Ferrell
      were detected (A2 [4.76%], B [2.38%], C1 [11.9%], D1 [7.14%], D2 [11.9%], X6
      [16.7%], and X7 [9.5%]). Sixty-four percent of these 42 individuals had
      "Amerindian founding lineage" haplotypes. A survey of 24 restriction sites
      yielded 16 polymorphic sites and 21 different haplotypes. The presence of all
      four of the founding lineages identified by the Torroni group (and seven of
      Merriwether and Ferrell's nine founding lineages), combined with Mongolia's
      location with respect to the Bering Strait, indicates that Mongolia is a
      potential location for the origin of the founders of the New World. Since lineage
      B, which is widely distributed in the New World, is absent in Siberia, we
      conclude that Mongolia or a geographic location common to both contemporary
      Mongolians and American aboriginals is the more likely origin of the founders of
      the New World.

PMID- 8659527
TI  - mtDNA variation in the Yanomami: evidence for additional New World founding
      lineages.
AB  - Native Americans have been classified into four founding haplogroups with as many
      as seven founding lineages based on mtDNA RFLPs and DNA sequence data. mtDNA
      analysis was completed for 83 Yanomami from eight villages in the Surucucu and
      Catrimani Plateau regions of Roraima in northwestern Brazil. Samples were typed
      for 15 polymorphic mtDNA sites (14 RFLP sites and 1 deletion site), and a subset
      was sequenced for both hypervariable regions of the mitochondrial D-loop.
      Substantial mitochondrial diversity was detected among the Yanomami, five of
      seven accepted founding haplotypes and three others were observed. Of the 83
      samples, 4 (4.8%) were lineage B1, 1 (1.2%) was lineage B2, 31 (37.4%) were
      lineage C1, 29 (34.9%) were lineage C2, 2 (2.4%) were lineage D1, 6 (7.2%) were
      lineage D2, 7 (8.4%) were a haplotype we designated "X6," and 3 (3.6%) were a
      haplotype we designated "X7." Sequence analysis found 43 haplotypes in 50
      samples. B2, X6, and X7 are previously unrecognized mitochondrial founding
      lineage types of Native Americans. The widespread distribution of these
      haplotypes in the New World and Asia provides support for declaring these
      lineages to be New World founding types.

PMID- 8659528
TI  - Analysis of the contribution of HLA genes to genetic predisposition in
      inflammatory bowel disease.
AB  - Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel
      diseases (IBDs) of unknown etiology. First-degree relatives of IBD patients have
      a 10-fold increase in risk of developing the same disease, and distinct
      associations between specific HLA types and both CD and UC have been reported. We
      have evaluated the contribution of genes at the HLA locus to susceptibility in
      IBD by linkage analysis of highly informative microsatellite polymorphisms in 43
      families with multiple affected cases. No evidence for linkage of HLA to IBD was
      obtained under any of the four models tested. Analysis of HLA haplotype sharing
      in affected relatives indicated that the relative risk to a sibling conferred by
      the HLA locus was 1.11 in UC and 0.75 in CD, with upper (95%) confidence limits
      of 2.41 and 1.37, respectively. This suggests that other genetic or environmental
      factors are responsible for most of the familial aggregation in IBD.

PMID- 8659529
TI  - Identification of a novel transcript disrupted by a balanced translocation
      associated with DiGeorge syndrome.
AB  - Most cases of DiGeorge syndrome (DGS) and related abnormalities are associated
      with deletions within 22q11. Shortest region of deletion overlap (SRO) mapping
      previously identified a critical region (the DGCR) of 500 kb, which was presumed
      to contain a gene or genes of major effect in the haploinsufficiency syndromes.
      The DGCR also contains sequences disrupted by a balanced translocation that is
      associated with DGS--the ADU breakpoint. We have cloned sequences at the
      breakpoint and screened for novel genes in its vicinity. A series of
      alternatively spliced transcripts expressed during human and murine
      embryogenesis, but with no obvious protein encoding potential, were identified.
      The gene encoding these RNAs has been named DGCR5 and it is disrupted by the
      patient ADU breakpoint. DGCR5 is distinct from the DGCR3 open reading frame (ORF)
      previously shown to be interrupted by the ADU translocation, although DGCR3 is
      embedded within a DGCR5 intron and in the same (predicted) transcriptional
      orientation. No mutations of DGCR5 have yet been detected. By analogy to other
      loci encoding conserved, nontranslated RNAs, it is possible that DGCR5 originates
      from a cis-acting transcriptional control element in the vicinity of the ADU/VDU
      breakpoint. Disruption of such an element would result in altered transcription
      of neighboring genes secondary to a position effect, a hypothesis in keeping with
      recent refinement of the SRO placing the ADU breakpoint outside the DGCR.

PMID- 8659532
TI  - On the formation of nucleosomes within the FMR1 trinucleotide repeat.

PMID- 8659531
TI  - Detection of the mtDNA 14484 mutation on an African-specific haplotype:
      implications about its role in causing Leber hereditary optic neuropathy.

PMID- 8659530
TI  - Cystic fibrosis carrier population screening in the primary care setting.
AB  - To determine the receptivity of prenatal care providers and their patients to
      carrier testing for cystic fibrosis (CF), we offered free carrier screening,
      followed by genetic counseling of carriers, to all prenatal care providers in
      Rochester, NY, for all their female patients of reproductive age, pregnant or
      not. Of 124 prenatal care providers, only 37 elected to participate, but many of
      these offered screening only to pregnant women. The acceptance rate among
      pregnant women was approximately 57%. The most common reasons for accepting
      screening were to obtain reassurance (50.7%) and to avoid having a child with CF
      (27.8 %). The most common reasons for declining screening were not intending to
      terminate a pregnancy for CF (32.4%) and believing that the chance of having a CF
      child was very low (32.2%). Compared with decliners, acceptors were more likely
      to have no children, regarded having a child with CF as more serious, believed
      themselves more susceptible to having such a child, knew more about CF, would be
      more likely to terminate a pregnancy if the fetus were shown to have CF, and more
      strongly supported offering CF screening to women of reproductive age. Of 4,879
      women on whom results were obtained, 124 were found to be carriers. Of these 124
      carriers, the partners of 106 were tested. Of the five at-risk couples, four
      requested prenatal diagnosis and one requested neonatal diagnosis. No woman found
      to be a carrier whose partner tested negative requested prenatal diagnosis.
      Except for the imperfect knowledge of those testing negative, none of the adverse
      outcomes predicted for CF carrier testing in the general population were observed
      in this study.

PMID- 8659533
TI  - Lack of ancient Polynesian-Amerindian contact.

PMID- 8659534
TI  - Misclassification and linkage of hereditary sensory and autonomic neuropathy type
      1 as Charcot-Marie-Tooth disease, type 2B.

PMID- 8659535
TI  - Elevated total plasma homocysteine and 677C-->T mutation of the 5,10
      methylenetetrahydrofolate reductase gene in thrombotic vascular disease.

PMID- 8659536
TI  - Evidence for genetic anticipation in non-Mendelian diseases.

PMID- 8659537
TI  - When does maternal age-dependent trisomy 21 arise relative to meiosis?

PMID- 8659538
TI  - A rational approach to cystic fibrosis mutation analysis in Hispanics: reply to
      Arzimanoglou et al.

PMID- 8659539
TI  - DNA fingerprinting loci do show population differences: comments on Budowle et
      al.

PMID- 8659540
TI  - A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by
      comparative multiplex PCR.
AB  - Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder caused
      by abnormalities in the proteolipid protein (PLP) gene, which is essential for
      oligodendrocyte differentiation and CNS myelin formation. Although linkage
      analysis has shown the homogeneity at the PLP locus in patients with PMD, exonic
      mutations in the PLP gene have been identified in only 10%-25% of all cases,
      which suggests the presence of other genetic aberrations, including gene
      duplication. In this study, we examined five families with PMD not carrying
      exonic mutations in PLP gene, using comparative multiplex PCR (CM-PCR) as a
      semiquantitative assay of gene dosage. PLP gene duplications were identified in
      four families by CM-PCR and confirmed in three families by densitometric RFLP
      analysis. Because a homologous myelin protein gene, PMP22, is duplicated in the
      majority of patients with Charcot-Marie-Tooth 1A, PLP gene overdosage may be a
      important genetic abnormality in PMD and affect myelin formation.

PMID- 8659541
TI  - Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation
      screening.
AB  - We have examined the distal half of the ataxia-telangiectasia (A-T) gene
      transcript for truncation mutations in 48 A-T affecteds. We found 21 mutations; 4
      of the mutations were seen in more than one individual. Genotyping of the
      individuals sharing mutations, by using nearby microsatellite markers,
      established that three of the four groups shared common haplotypes, indicating
      that these were probably founder effects, not public mutations. The one public
      mutation was found in two American families, one of Ashkenazi Jewish background
      and the other not. Most truncations deleted the PI3-kinase domain, although some
      exceptions to this were found in patients with typical A-T phenotypes. All
      patients not previously known to be consanguineous were found to be compound
      heterozygotes when mutations could be identified--that is, normal and abnormal
      protein segments were seen on SDS-PAGE gels. All 48 patients gave RT-PCR
      products, indicating the presence of relatively stable mRNAs despite their
      mutations. These results suggest that few public mutations or hot spots can be
      expected in the A-T gene and that epidemiological studies of A-T carrier status
      and associated health risks will have to be designed around populations with
      frequent founder-effect mutations, despite the obvious limitations of this
      approach.

PMID- 8659543
TI  - The Val192Leu mutation in the alpha-subunit of beta-hexosaminidase A is not
      associated with the B1-variant form of Tay-Sachs disease.
AB  - Substitution mutations adversely affecting the alpha-subunit of beta
      hexosaminidase A (alphabeta) (EC 3.2.1.52) result in Tay-Sachs disease. The
      majority affect the initial folding of the pro-alpha chain in the endoplasmic
      reticulum, resulting in its retention and degradation. A much less common
      occurrence is a mutation that specifically affects an "active-site" residue
      necessary for substrate binding and/or catalysis. In this case, hexosaminidase A
      is present in the lysosome, but it lacks all alpha-specific activity. This
      biochemical phenotype is referred to as the "B1-variant form" of Tay-Sachs
      disease. Kinetic analysis of suspected B1-variant mutations is complex because
      hexosaminidase A is heterodimeric and both subunits possess similar active sites.
      In this report, we examine a previously identified B1-variant mutation, alpha
      Val192Leu. Chinese hamster ovary cells were permanently cotransfected with an
      alpha-cDNA-construct encoding the substitution and a mutant beta-cDNA (beta
      Arg211Lys), encoding a beta-subunit that is inactive but normal in all other
      respects. We were surprised to find that the Val192Leu substitution, produced a
      pro-alpha chain that did not form alpha-beta dimers and was not transported to
      the lysosome. Finally, we reexamined the hexosaminidase activity and protein
      levels in the fibroblasts from the original patient. These data were also not
      consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease
      previously reported to be present. Thus, we conclude that the Val192Leu
      substitution does not specifically affect the alpha-active site.

PMID- 8659542
TI  - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in
      allergic bronchopulmonary aspergillosis.
AB  - The etiology of allergic bronchopulmonary aspergillosis (ABPA) is not well
      understood. A clinical phenotype resembling the pulmonary disease seen in cystic
      fibrosis (CF) patients can occur in some individuals with ABPA. Reports of
      familial occurrence of ABPA and increased incidence in CF patients suggest a
      possible genetic basis for the disease. To test this possibility, the entire
      coding region of the cystic fibrosis transmembrane regulator (CFTR) gene was
      analyzed in 11 individuals who met strict criteria for the diagnosis of ABPA and
      had normal sweat electrolytes (< or = 40 mmol/liter). One patient carried two CF
      mutations (deltaF508/R347H), and five were found to carry one CF mutation (four
      deltaF508; one R117H). The frequency of the deltaF508 mutation in patients with
      ABPA was significantly higher than in 53 Caucasian patients with chronic
      bronchitis (P < .0003) and the general population (P < .003). These results
      suggest that CFTR plays an etiologic role in a subset of ABPA patients.

PMID- 8659544
TI  - Glycogenosis type VII (Tarui disease) in a Swedish family: two novel mutations in
      muscle phosphofructokinase gene (PFK-M) resulting in intron retentions.
AB  - Phosphofructokinase (PFK) plays a major role in glycolysis. Human PFK is composed
      of three isoenzyme subunits (muscle [Ml, liver [L], and platelet [P]), which are
      encoded by different genes. Deficiency of muscle isoenzyme (PFK-M), glycogenosis
      type VII (Tarui disease), is an autosomal recessive disorder characterized by an
      exertional myopathy and hemolytic syndrome. Several disease-causing mutations
      have been identified in the PFK-M gene in Japanese, Ashkenazi Jewish, Italian,
      French Canadian, and Swiss patients. We describe the genetic defect in a Swedish
      family with affected individuals in two generations. The patients are compound
      heterozygotes: two different mutations result in retention of intron 13 or intron
      16 sequences into mRNA. A G1127A transition destroys the 5' donor site of intron
      13, resulting in a 155-nt retention of the intronic sequence. An a-to-g base
      change in intron 16 creates a new acceptor splice site, resulting in a 63-nt
      retention of intronic sequence. Both mutations are predicted to result in
      premature termination of translation. Some of the transcripts generated from the
      intron 16 mutated allele also contain intron 10 sequence unspliced.

PMID- 8659546
TI  - How many breaks do we need to CATCH on 22q11?

PMID- 8659545
TI  - Cloning of the cDNA for a human homologue of the Drosophila white gene and
      mapping to chromosome 21q22.3.
AB  - In an effort to contribute to the transcript map of human chromosome 21 and the
      understanding of the pathophysiology of trisomy 21, we have used exon trapping to
      identify fragments of chromosome 21 genes. Two trapped exons, from pools of
      chromosome 21-specific cosmids, showed homology to the Drosophila white (w) gene.
      We subsequently cloned the corresponding cDNA for a human homologue of the
      Drosophila w gene (hW) from human retina and fetal brain cDNA libraries. The gene
      belongs to the ATP-binding cassette transporter gene family and is homologous to
      Drosophila w (and to w genes from other species) and to a lesser extent to
      Drosophila brown (bw) and scarlet (st) genes that are all involved in the
      transport of eye pigment precursor molecules. A DNA polymorphism with 62%
      heterozygosity due to variation of a poly (T) region in the 3' UTR of the hW has
      been identified and used for the incorporation of this gene to the genetic map of
      chromosome 21. The hW is located at 21q22.3 between DNA markers D21S212 and
      D21S49 in a P1 clone that also contains marker BCEI. The gene is expressed at
      various levels in many human tissues. The contributions of this gene to the Down
      syndrome phenotypes, to human eye color, and to the resulting phenotypes of null
      or missense mutations are presently unknown.

PMID- 8659547
TI  - Analyses of loss-of-function mutations of the MITF gene suggest that
      haploinsufficiency is a cause of Waardenburg syndrome type 2A.
AB  - Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder
      characterized by a pigmentation anomaly and hearing impairment due to lack of
      melanocyte. Previous work has linked a subset of families with WS2 (WS2A) to the
      MITF gene that encodes a transcription factor with a basic-helix-loop-helix
      leucine zipper (bHLH-Zip) motif and that is involved in melanocyte
      differentiation. Several splice-site and missense mutations have been reported in
      individuals affected with WS2A. In this report, we have identified two novel
      point mutations in the MITF gene in affected individuals from two different
      families with WS2A. The two mutations (C760--> T and C895--> T) create stop
      codons in exons 7 and 8, respectively. Corresponding mutant alleles predict the
      truncated proteins lacking HLH-Zip or Zip structure. To understand how these
      mutations cause WS2 in heterozygotes, we generated mutant MITF cDNAs and used
      them for DNA-binding and luciferase reporter assays. The mutated MITF proteins
      lose the DNA-binding activity and fail to transactivate the promoter of
      tyrosinase, a melanocyte-specific enzyme. However, these mutated proteins do not
      appear to interfere with the activity of wild-type MITF protein in these assays,
      indicating that they do not show a dominant-negative effect. These findings
      suggest that the phenotypes of the two families with WS2A in the present study
      are caused by loss-of-function mutations in one of the two alleles of the MITF
      gene, resulting in haploinsufficiency of the MITF protein, the protein necessary
      for normal development of melanocytes.

PMID- 8659550
TI  - The Southern Society for Clinical Investigation at 50: the end of the beginning.

PMID- 8659548
TI  - Phenylalanine hydroxylase gene mutations in the United States: report from the
      Maternal PKU Collaborative Study.
AB  - The major cause of hyperphenylalaninemia is mutations in the gene encoding
      phenylalanine hydroxylase (PAH). The known mutations have been identified
      primarily in European patients. The purpose of this study was to determine the
      spectrum of mutations responsible for PAH deficiency in the United States. One
      hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were
      subjects for clinical and molecular investigations. PAH gene mutations associated
      with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on
      279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The
      spectrum is composed of 71 different mutations, including 47 missense mutations,
      11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen
      previously unreported mutations were identified. Among the novel mutations, five
      were found in patients with MHP, and the remainder were found in patients with
      PKU. The most common mutations were R408W, IVS12nt1g-->a, and Y414C, accounting
      for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen
      mutations had relative frequencies of 1%-5%, and 55 mutations each had
      frequencies < or = 1%. The mutational spectrum corresponded to that observed for
      the European ancestry of the U.S. population. To evaluate the extent of allelic
      variation at the PAH locus within the United States in comparison with other
      populations, we used allele frequencies to calculate the homozygosity for 11
      populations where >90% ascertainment of mutations has been obtained. The United
      States was shown to contain one of the most heterogeneous populations, with
      homozygosity values similar to Sicily and ethnically mixed sample populations in
      Europe. The extent of allelic heterogeneity must be a major determining factor in
      the choice of mutation-detection methodology for molecular diagnosis in PAH
      deficiency.

PMID- 8659549
TI  - Identification and expression of eight novel mutations among non-Jewish patients
      with Canavan disease.
AB  - Canavan disease is inherited as an autosomal recessive trait that is caused by
      the deficiency of aspartoacylase (ASPA). The majority of patients with Canavan
      disease are from an Ashkenazi Jewish background. Mutations in ASPA that lead to
      loss of enzymatic activity have been identified, and E285A and Y231X are the two
      predominant mutations that account for 97% of the mutant chromosomes in Ashkenazi
      Jewish patients. The current study was aimed at finding the molecular basis of
      Canavan disease in 25 independent patients of non-Jewish background. Eight novel
      and three previously characterized mutations accounted for 80% (40/50) of mutant
      chromosomes. The A305E missense mutation accounted for 48% (24/50) of mutant
      chromosomes in patients of western European descent, while the two predominant
      Jewish mutations each accounted for a single mutant chromosome. The eight novel
      mutations identified included 1- and 4-bp deletions (32 deltaT and 876 deltaAGAA,
      respectively) and I16T, G27R, D114E, G123E, C152Y, and R168C missense mutations.
      The homozygous 32 deltaT deletion was identified in the only known patient of
      African-American origin with Canavan disease. The heterozygosity for 876
      deltaAGAA mutation was identified in three independent patients from England. Six
      single-base changes leading to missense mutations were identified in patients
      from Turkey (D114E, R168C), The Netherlands (I16T), Germany (G27R), Ireland
      (C152Y), and Canada (G123E). A PCR-based protocol is described that was used to
      introduce mutations in wild-type cDNA. In vitro expression of mutant cDNA clones
      demonstrated that all of these mutations led to a deficiency of ASPA and should
      therefore result in Canavan disease.

PMID- 8659552
TI  - SSCI Founders Medal recipients' address.

PMID- 8659551
TI  - Presentation of the Southern Society for Clinical Investigation Founders Medal to
      Dr. Neil Kurtzman.

PMID- 8659553
TI  - Clinical correlates of an elevated diffusing capacity for carbon monoxide
      corrected for alveolar volume.
AB  - The diffusing capacity for carbon monoxide is partially dependent on lung volume
      at which it is measured. As a consequence, the diffusing capacity for carbon
      monoxide is often indexed to the simultaneously measured lung volume (VA), giving
      rise to the term DL/VA. This reflects the diffusing capacity of carbon monoxide
      per unit area of lung parenchyma. The authors investigated the pulmonary function
      of 18 patients who had an elevated DL/VA in order to identify factors that could
      account for this abnormality. Sixteen of the 18 had a reduction in vital
      capacity. The vital capacity was reduced because of obesity, pleural disease, and
      diaphragmatic dysfunction. Eight of nine patients with a body mass index > 30
      kg/m2 had a reduction in vital capacity. On the basis of these findings, we
      believe that an elevated DL/VA should alert the physician to the possibility of
      1) an increase in pulmonary capillary blood volume (Vc) (obesity, polycythemia,
      negative pleural pressure), and 2) reduced VA that does not directly affect the
      pulmonary capillary bed (pleural disease, neuromuscular disease).

PMID- 8659554
TI  - Comprehensive long-term management program for asthma: effect on outcomes in
      adult African-Americans.
AB  - To determine if a comprehensive long-term management program, emphasizing inhaled
      corticosteroids and patient education, would improve outcomes in adult African
      American asthmatics a nonrandomized control trial with a 2-year intervention was
      performed in a university-based clinic. Inclusion criteria consisted of (> or =
      5) emergency department (ED) visits or hospitalizations (> or = 2) during the
      previous 2 years. Intervention patients were volunteers; a comparable control
      group was identified via chart review at hospitals within the same area and time
      period as the intervention patients. Individualized doses of beclomethasone with
      a spacer, inhaled albuterol "as needed," and crisis prednisone were the primary
      therapies. Environmental control, peak flow monitoring, and a partnership with
      the patient were emphasized. Detailed patient education was an integral part of
      management. Control patients received usual care from local physicians. ED visits
      and hospitalizations for 2 years before and 2 years during the intervention
      period were compared. Quality of life (QOL) measurements were made at baseline
      and every 6 months in the intervention group. Study group (n = 21) had a
      significant reduction in ED visits (2.3 +/- 0.2 pre-intervention versus 0.6 +/-
      0.2 post-intervention; P = 0.0001). Control group (n = 18) did not have a
      significant change in ED visits during the 2-year post-intervention period (2.6
      +/- 0.2 pre-intervention versus 2.0 +/- 0.2 post-intervention; P = 0.11). Both
      groups had significant reductions in hospitalizations, but the study group had a
      greater reduction. Sixty-two percent of study patients had complete elimination
      of ED visits and hospitalizations, whereas no control patients had total
      elimination of the need for institutional acute care. QOL in the study patients
      revealed significant improvements for most parameters. A comprehensive long-term
      management program emphasizing inhaled corticosteroids combined with other state
      of-the-art management, including intensive patient education, improves outcomes
      in adult African-American asthmatics.

PMID- 8659555
TI  - Nocturnal monitoring of growth hormone, insulin, C-peptide, and glucose in
      patients with acromegaly.
AB  - Circulating growth hormone, insulin, C-peptide, and glucose levels were compared
      during the sleep state in adults with acromegaly and healthy control subjects.
      Growth hormone secretion was episodic in both groups, with the sleep-related
      growth hormone peak noticeably absent in the acromegalic subjects. The mean
      nocturnal plasma insulin concentration was greater in the acromegalics. There was
      no significant difference in the C-peptide between the two groups. Insulin and
      glucose levels did not show an early morning rise in either acromegalics or
      healthy subjects. The authors conclude that there is a marked difference in the
      circulating levels of growth hormone and insulin between the acromegalic and the
      healthy groups during the sleep state, and there is no sleep-related nocturnal
      growth hormone peak in the acromegalic subjects. The hyperinsulinism of patients
      with acromegaly cannot be attributed to excess secretion of insulin.

PMID- 8659556
TI  - Milrinone: basic and clinical pharmacology and acute and chronic management.
AB  - Milrinone (Inocor-Sanofi-Winthrop) represents a second generation
      phosphodiesterase inhibitor currently approved for intravenous administration in
      the treatment of decompensated congestive heart failure. By inhibiting Type III
      phosphodiesterase, milrinone increases intracellular cyclic adenosine
      monophosphate. This results in a positive inotropic effect on the heart and
      vasodilatation in the periphery. The hemodynamic consequences of this action
      produce left ventricular afterload reduction, with an increase in cardiac output
      and a reduction in total peripheral resistance. Unlike the sympathomimetic
      amines, milrinone produces no tolerance and possesses the distinct advantage of
      directly decreasing pulmonary vascular resistance. Short-term intermittent
      infusion by peripheral administration, continuous infusion, long-term therapy,
      and intermittent outpatient therapy was demonstrated to be safe, efficacious, and
      cost effective. It is hypothesized that intravenous milrinone, by producing
      biventricular afterload reduction, offers an efficacious, cost-effective tool for
      the treatment of decompensated heart failure.

PMID- 8659557
TI  - Reversal of liver failure in sickle cell vaso-occlusive crisis.
AB  - A severe but unusual complication of sickle cell vaso-occlusive crisis is acute
      liver failure related to intrahepatic cholestasis. The outcome is usually fatal
      in adults. A case of reversible acute liver failure in a patient with s/beta+
      thalassemia is reported. The patient was admitted to the intensive care unit
      because of major organ failure related to vascular occlusion phenomena. After
      blood-plasma transfusion and supportive therapy for acute liver failure, complete
      recovery was noted. A liver biopsy performed at the stage of recovery was
      compatible with intrahepatic cholestasis and sickling. Even though patients with
      s/beta+ thalassemia usually manifest milder symptoms, they rarely develop major
      organ failure such as acute liver failure.

PMID- 8659558
TI  - Primary hyperthyroidism and associated hyperparathyroidism in a patient with
      myotonic dystrophy: Steinert with hyperthyroidism and hyperparathyroidism.
AB  - A patient with myotonic dystrophy and associated primary hyperthyroidism and
      hyperparathyroidism is described; this association has not been reported
      previously, to the authors' knowledge. The patient also suffered from
      hypergonadotropic hypogonadism and hyperinsulinism with insulin resistance. The
      etiology of hyperthyroidism and hyperparathyroidism is not clear. At surgery, a
      parathyroid adenoma was extirpated, and a subtotal thyroidectomy was performed.
      Postoperative course was unremarkable, with consistently normal serum calcium
      levels but persistently elevated serum parathyroid hormone concentrations. The
      possibility that the patient had a residual hyperparathyroidism could not be
      eliminated. Thyroid function was normal. After surgery, the patient reported
      subjective improvement in his muscle strength. The authors conclude that both
      diseases-- hyperthyroidism and hyperparathyroidism--exert a negative effect on
      the myotonic dystrophy and that an early recognition of these two diseases is
      crucial for the favorable evolution of the patient.

PMID- 8659560
TI  - Home HIV test gets nod.

PMID- 8659559
TI  - IM injection volume limit.

PMID- 8659561
TI  - The five phases of behavioral change.

PMID- 8659562
TI  - Using high-dose fentanyl patches.

PMID- 8659563
TI  - Motivating staff: the pain-free week.

PMID- 8659564
TI  - No need to fear analgesia.

PMID- 8659565
TI  - Drugs and the elderly: do you know the risks?

PMID- 8659566
TI  - Cultural dimensions in home health nursing.

PMID- 8659567
TI  - Clinical snapshot: pleural effusion.

PMID- 8659568
TI  - Identifying chronic peripheral arterial disease.

PMID- 8659569
TI  - PCLNs: who are they? How can they help you?

PMID- 8659570
TI  - Emergency! Heat stroke.

PMID- 8659571
TI  - Tools of the heart.

PMID- 8659572
TI  - A new class of anti-HIV drugs debuts.

PMID- 8659573
TI  - How to write a winning proposal.

PMID- 8659574
TI  - When an organ donor names the recipient.

PMID- 8659575
TI  - Eroding care, cuts in RN staff anger AJN readers.

PMID- 8659577
TI  - Ten nurses define heroism: 'valor above and beyond the call of duty'.

PMID- 8659576
TI  - Speaking out with one strong voice.

PMID- 8659578
TI  - Gretchen's crisis.

PMID- 8659580
TI  - No one knows the preferred management for choroidal melanoma.

PMID- 8659579
TI  - Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis
      Vitrectomy Study.
AB  - PURPOSE: To determine the microbiologic spectrum and antibiotic susceptibilities
      of infecting organisms in postoperative endophthalmitis and to evaluate the
      effects of operative factors on the microbiologic spectrum. METHODS: Patients
      with bacterial endophthalmitis presenting within six weeks of cataract extraction
      or secondary intraocular lens implantation (IOL) were evaluated. Cultures and
      Gram stains were performed on intraocular specimens and susceptibility tests on
      the isolates. RESULTS: Confirmed microbiologic growth was demonstrated from
      intraocular specimens from 291 of 420 patients (69.3%). Gram-positive bacteria
      were isolated from 274 patients (94.2%) with confirmed growth and gram-negative
      bacteria from 19 (6.5%). Two hundred twenty-six of the 323 isolates obtained
      (70.0%) were gram-positive, coagulase-negative micrococci, 32 (9.9%)
      Staphylococcus aureus, 29 (9.0%) Streptococcus species, seven (2.2%) Enterococcus
      species, ten (3.1%) miscellaneous gram-positive species, and 19 (5.9%) gram
      negative species. All gram-positive isolates tested were susceptible to
      vancomycin. Seventeen gram-negative isolates (89%) were susceptible to both
      amikacin and ceftazidime and two (11%) were resistant to both. Anterior chamber
      or secondary IOL implantations were associated with higher rates of infection
      with gram-positives other than coagulase-negative micrococci than were posterior
      chamber IOL implantations (P = .022) or primary cataract extractions (P = .024).
      CONCLUSIONS: Gram-positive, coagulase-negative micrococci predominated in this
      series. Vancomycin was active against all gram-positive isolates tested. Amikacin
      and ceftazidime showed equivalent activity against gram-negative isolates.
      Secondary or anterior chamber lens implantations were associated with a possible
      spectrum shift toward gram-positive organisms other than the coagulase-negative
      micrococci.

PMID- 8659581
TI  - Double-armed McCannell suture for repair of traumatic iridodialysis.
AB  - PURPOSE: To repair iridodialysis in a traumatized eye with minimal surgical
      manipulation. METHODS: We examined a patient with traumatic iridodialysis. The
      separated iris obstructed the visual axis and was cosmetically disfiguring.
      RESULTS: At surgery we secured the iridodialysis to the anterior chamber angle by
      using a new technique with double-armed McCannell suture. CONCLUSION: Compared
      with other procedures, this technique is simple and provides the least amount of
      ocular manipulation for iridodialysis repair.

PMID- 8659582
TI  - Drug-induced transient myopia and angle-closure glaucoma associated with
      supraciliary choroidal effusion.
AB  - PURPOSE: We investigated the mechanism of drug-induced transient myopia, anterior
      chamber shallowing, and secondary angle-closure glaucoma in a young woman.
      METHODS: Ultrasound biomicroscopy was performed and the effects of cycloplegic
      eyedrops and unilateral laser iridotomy were evaluated. RESULTS: Cycloplegic
      eyedrops and unilateral laser iridotomy had no effect. Ultrasound biomicroscopy
      identified the presence of a supraciliary choroidal effusion that caused forward
      displacement of the lens-iris diaphragm, resulting in increased myopia, anterior
      chamber shallowing, and angle-closure glaucoma. Discontinuance of trimethoprim
      and sulfamethoxazole combination led to the complete resolution of the condition.
      CONCLUSIONS: Idiosyncratic drug reactions may produce a supraciliary choroidal
      effusion, resulting in myopia and secondary angle-closure glaucoma from the
      induced forward shift in the position of the crystalline lens and ciliary body.

PMID- 8659583
TI  - Ultrasound Biomicroscopy of shallow anterior chamber in Vogt-Koyanagi-Harada
      syndrome.
AB  - PURPOSE: We studied a case of Vogt-Koyanagi-Harada syndrome in a patient with a
      shallow anterior chamber. METHODS: High-resolution, anterior segment ultrasound
      biomicroscopy was performed to analyze the mechanism of a shallow anterior
      chamber. RESULTS: Ultrasound biomicroscopy disclosed a slit-like narrow angle and
      circumferential supraciliary fluid. The ciliary body was rotated anteriorly, and
      the iris showed anterior bowing consistent with pupillary block. With systemic
      corticosteroid treatment, the supraciliary fluid disappeared, and the ciliary
      body reverted to its normal position. CONCLUSION: Ultrasound biomicroscopy was
      useful in diagnosis and evaluation of the response to corticosteroid treatment in
      a patient with Vogt-Koyanagi-Harada syndrome accompanied by shallow anterior
      chamber.

PMID- 8659584
TI  - Acute posterior multifocal placoid pigment epitheliopathy after acute group A
      streptococcal infection.
AB  - PURPOSE: We studied a case of acute posterior multifocal placoid pigment
      epitheliopathy in a 40-year-old man who had had an acute febrile illness.
      METHODS: The medical record was reviewed for clinical manifestations, course of
      disease, and laboratory findings, including results of fluorescein and
      indocyanine green angiography. RESULTS: The patient had the typical clinical
      course of acute posterior multifocal placoid pigment epitheliopathy with
      spontaneous resolution of posterior pole lesions and improvement in visual acuity
      from 20/60 to 20/20. The laboratory evaluation was remarkable for a rise in the
      anti-DNAse B antibody titer between initial and convalescent-phase serum samples,
      providing evidence of recent group A streptococcal infection. CONCLUSION:
      Although acute posterior multifocal placoid pigment epitheliopathy is often
      attributed to a postviral condition, this syndrome may also develop after an
      acute group A streptococcal infection.

PMID- 8659585
TI  - Retinal hemorrhages from septic emboli in a patient with a ventricular false
      chorda.
AB  - PURPOSE: To demonstrate ophthalmic findings of bacterial endocarditis in a
      patient with a cardiac structural anomaly and to illustrate the potential
      usefulness of transesophageal echocardiography in the examination of such
      patients. METHODS: We examined a patient with bacteremia who had white-centered
      retinal hemorrhages. Complete clinical, laboratory, and echocardiographic
      evaluations were performed. RESULTS: Streptococcal bacteremia was proven and, by
      using transesophageal echocardiography, a ventricular false chorda was
      demonstrated. CONCLUSIONS: Patients with white-centered retinal hemorrhages
      should undergo thorough systemic examinations. In this unusual case of such
      hemorrhages caused by bacteremia in a patient with a ventricular false chorda,
      modern, high-resolution transesophageal echocardiography played an important role
      in confirming the diagnosis.

PMID- 8659586
TI  - Fusarium endophthalmitis in an intravenous drug abuser.
AB  - PURPOSE: We studied a case in which a patient had unilateral retinal infiltrates
      and a retinal vasculopathy resembling frosted branch angiitis. He later admitted
      to injecting cocaine intravenously. METHODS: The patient underwent a pars plana
      vitrectomy and received intravitreal and intravenous amphotericin B. RESULTS: The
      vitreous fluid grew Fusarium dimerium. There was rapid response to the treatment
      and full recovery of vision. CONCLUSION: Fusarium species should be considered as
      a potential pathogen in intravenous drug abusers with endogenous endophthalmitis
      and in patients with unilateral frosted branch angiitis.

PMID- 8659587
TI  - Treatment of clinically resistant cytomegalovirus retinitis with combined
      intravitreal injections of ganciclovir and foscarnet.
AB  - PURPOSE: To determine the efficacy of combined ganciclovir and foscarnet
      intravitreal injections in controlling clinically resistant cytomegalovirus
      retinitis in a 37-year-old man with the acquired immunodeficiency syndrome who
      refused systemic therapy. METHODS: The patient refused systemic therapy and was
      treated with intravitreal injections of ganciclovir and foscarnet, which were
      then combined when the retinitis became resistant to either drug alone. RESULTS:
      The retinitis was initially controlled with bilateral intravitreal ganciclovir
      injections. After reactivation of retinitis in the left eye, intravitreal
      foscarnet was effective until recurrent retinitis threatened the center of the
      fovea. The retinitis continued to progress until combined intravitreal injections
      of ganciclovir and foscarnet were administered. CONCLUSIONS: Combined
      intravitreal injections of ganciclovir and foscarnet may be effective in treating
      cytomegalovirus retinitis when the infection is clinically resistant to either
      intravitreal drug alone. Intravitreal injections can be effective in controlling
      cytomegalovirus retinitis in patients who are intolerant of or refuse systemic
      therapy.

PMID- 8659588
TI  - Obesity as a cause of mechanical entropion.
AB  - PURPOSE: Although lower eyelid entropion can result from many conditions, obesity
      is not a generally recognized factor. We treated a case of recurrent severe
      entropion that was a result of morbid obesity in a patient with de Morsier's
      syndrome. METHODS: The patient underwent surgery on both lower eyelids. RESULTS:
      The entropion was corrected by advancing the lower eyelid retractors and
      debulking the subcutaneous tissue in the lower eyelids. CONCLUSIONS: Mechanical
      entropion can occur as a rare complication of morbid obesity and may respond to
      surgical procedures that address its cause.

PMID- 8659589
TI  - Cancer-associated retinopathy with presumed vasculitis.
AB  - PURPOSE: To treat a 63-year-old woman who experienced fairly rapid vision loss in
      association with small-cell carcinoma of the lung. METHODS: She underwent a full
      ophthalmologic examination, including fluorescein angiography and an immunologic
      study by Western blot analysis. RESULTS: Fluorescein angiography demonstrated
      diffuse staining of the retinal vessels. She had 62-kd antiretinal antibody in
      her serum. Cancer-associated retinopathy was diagnosed. CONCLUSION: The staining
      seen on the angiogram appears to indicate vasculitis, which would cause the
      characteristic attenuation of retinal vessels in this disease.

PMID- 8659590
TI  - Visual loss as the manifesting symptom of ventriculoperitoneal shunt malfunction.
AB  - PURPOSE: To treat a 30-year-old man with a ventriculoperitoneal shunt who had
      progressive visual loss. METHODS: The patient underwent computed tomographic and
      magnetic resonance imaging scans and ocular examination. RESULTS: He was
      diagnosed with ventriculoperitoneal shunt failure despite the lack of
      ventriculomegaly on computed tomographic scan of the head and the lack of
      papilledema. The patient eventually underwent ventriculoperitoneal shunt
      revision, but visual function did not improve. CONCLUSIONS: Loss of visual acuity
      or visual field, or both, may be the initial and only symptom of
      ventriculoperitoneal shunt malfunction. Shunt failure may occur without other
      features of increased intracranial pressure or ventriculomegaly on neuroimaging
      studies.

PMID- 8659591
TI  - Severe sudden visual loss caused by pseudotumor cerebri and lumboperitoneal shunt
      failure.
AB  - PURPOSE: Severe vistral acuity loss associated with pseudotumor cerebri is
      usually caused by chronic optic disk edema or a retinal abnormality. METHODS: We
      treated a women, with known pseudotumor cerebri treated with a lumboperitoneal
      shunt, who developed acute pallied optic disk swelling and visual acuity of R.E.:
      no light perception and L.E.: 20/70 in association with lumboperitoneal shunt
      failure. There were no contributory retinal lesions. RESULTS: The patient
      underwent optic nerve sheath fenestration and lumboperitoneal shunt revision.
      Visual acuity improved to 20/20 in both eyes. The papilledema resolved.
      CONCLUSION: The severe sudden visual loss was attributed to axoplasmic stasis and
      optic nerve ischemia associated with a sudden rise in intracranial pressure.

PMID- 8659592
TI  - Posterior segment neovascularization associated with optic nerve aplasia.
AB  - PURPOSE: To report the presence of posterior segment neovascularization in eyes
      with optic nerve aplasia. METHODS: Three eyes in two patients with clinical optic
      nerve aplasia were studied. RESULTS: Examination disclosed posterior segment
      neovascularization in one eye and progressive posterior segment
      neovascularization in two eyes. CONCLUSIONS: Posterior segment neovascularization
      may occur in association with optic nerve aplasia. Retinal ischemia or
      retinochoroidal anatomic disorganization, or both, may provide the stimulus for
      neovascularization in such eyes.

PMID- 8659593
TI  - Retinal arterial occlusions in young adults.

PMID- 8659594
TI  - Retinal arterial occlusions in young adults.

PMID- 8659595
TI  - Astigmatic keratotomy combined with myopic keratomileusis in situ for compound
      myopic astigmatism.
AB  - PURPOSE: Myopic keratomileusis in situ by an automated microkeratome corrects
      myopia but not astigmatism, which is traditionally corrected by astigmatic
      keratotomy months after keratomileusis. We developed a technique for
      simultaneously correcting astigmatism and severe myopia, and examined its
      effectiveness in a retrospective case-control study. METHODS: Thirty-four eyes
      (23 patients) underwent myopic keratomileusis in situ combined with one or two
      arcuate keratotomy incisions performed after the refractive cut, in the bed of
      the primary keratectomy flap. The myopic keratomileusis control group consisted
      of 34 matched eyes (30 patients) undergoing keratomileusis without astigmatic
      keratotomy. The astigmatic control group consisted of 117 unmatched eyes (85
      patients) undergoing astigmatic keratotomy combined with radial keratotomy.
      RESULTS: Mean refractive astigmatism in the study group decreased from 2.4
      diopters (range, 1.0 to 4.0 diopters) preoperatively to 1.7 diopters (range, 1.0
      to 4.0 diopters) at three months postoperatively, and increased by 0.4 diopter in
      the myopic keratomileusis control group at three months postoperatively (P <
      .005). Eighteen of 27 eyes in the study group showed decreased refractive
      astigmatism compared with ten of 34 eyes in the myopic keratomileusis control
      group (P < .0001). Combining astigmatic keratotomy with myopic keratomileusis
      produced 0.2 +/- 0.9 diopter less astigmatic correction than that expected from
      the astigmatic control group. One of 27 eyes lost two or more lines of best
      spectacle-corrected visual acuity at the three-month postoperative visit. No eye
      lost two or more lines of best spectacle-corrected visual acuity at postoperative
      month 6. CONCLUSION: Eyes with substantial preoperative refractive astigmatism
      that undergo myopic keratomileusis in situ may benefit from simultaneous
      astigmatic keratotomy to reduce residual post-operative refractive astigmatism.

PMID- 8659596
TI  - Videokeratoscopy of recipient peripheral corneas in combined penetrating
      keratoplasty, cataract extraction, and lens implantation.
AB  - PURPOSE: We performed a prospective clinical trial to evaluate computerized
      videokeratoscopic analysis of the peripheral recipient cornea in intraocular lens
      power calculations for triple procedures: penetrating keratoplasty, cataract
      extraction, and intraocular lens insertion. METHODS: Patients with Fuchs'
      dystrophy underwent consecutive triple procedures. Surgery was performed in 16
      eyes by a single surgeon (O.N.S.) using a single technique. If videokeratoscopic
      analysis disclosed dioptric powers greater than 40 diopters in the circumference
      of the corneal map, the surgeon's average postoperative central corneal power of
      46 diopters was used with the regression formula. If dioptric powers less than 40
      diopters were detected in the circumference of the corneal map, 45 diopters was
      used to avoid postoperative hyperopic shifts and to decrease deviation from
      intended refractive error. Refraction and videokeratoscopic analysis were
      performed six months after suture removal (18 to 24 months postoperatively).
      RESULTS: Analysis of covariance demonstrated that preoperative peripheral
      videokeratoscopic data of the recipient cornea correlated (P = .0001) with
      postoperative central corneal power, whereas preoperative central corneal power
      of the recipient cornea did not correlate (P = .35). Deviation from intended
      refraction (range, -2.54 to +1.22 diopters) was within 2 diopters in 14 eyes
      (88%) and within 3 diopters in all eyes. No patients had anisometropia greater
      than 3 diopters. CONCLUSION: Preoperative data from computerized
      videokeratoscopic analysis of the recipient peripheral cornea correlated with
      postoperative central corneal power, and improved postoperative refractive
      outcomes compared with previously reported results of triple procedures.

PMID- 8659597
TI  - Surgical reconstruction of the ocular surface in advanced ocular cicatricial
      pemphigoid and Stevens-Johnson syndrome.
AB  - PURPOSE: Ocular cicatricial pemphigoid and Stevens-Johnson syndrome often cause
      ocular damage and blindness not amenable to surgical correction. We present a new
      surgical technique for reconstructing affected eyes. METHODS: Fourteen eyes of 11
      patients with cicatricial keratoconjunctivitis (seven patients with cicatricial
      pemphigoid and four with Stevens-Johnson syndrome; average age +/- S.D., 55.5 +/-
      25.4 years) were treated with a combination of allograft limbal transplantation,
      amniotic membrane transplantation, and tarsorrhaphy, followed every 15 minutes by
      artificial tears derived from the patient's blood serum. Eight eyes required
      concomitant penetrating or lamellar keratoplasty because of corneal opacity.
      RESULTS: With a mean follow-up of 143 days (range, 10 to 608 days), we achieved
      successful ocular surface reconstruction in 12 eyes, with minimal recurrence of
      symblepharon. Failure occurred in two eyes (one each in 9- and 10-year-old boys)
      that developed corneal infiltration and vascularization. CONCLUSIONS: A
      combination of allograft limbal transplantation, amniotic membrane
      transplantation, and tarsorrhaphy, followed by the use of serum-derived tears,
      can reconstruct the ocular surface in most cases. Although in this study the
      follow-up period was short and relatively few patients were studied, this
      approach appears to offer an alternative to keratoprosthesis for treating severe
      cicatricial keratoconjunctivitis with dry eye.

PMID- 8659598
TI  - Increase in iris-lens contact after laser iridotomy for pupillary block angle
      closure.
AB  - PURPOSE: To quantitate changes in anterior ocular segment anatomy after laser
      iridotomy for pupillary block angle closure. METHODS: We prospectively performed
      ultrasound biomicroscopy and A-scan biometry in 13 eyes of 13 consecutive
      untreated patients with relative pupillary block and appositional angle closure,
      without peripheral anterior synechiae on indentation gonioscopy. A radial,
      perpendicular image in the horizontal temporal meridian was obtained with
      ultrasound biomicroscopy before and one week after laser iridotomy in each eye.
      RESULTS: Mean age of the 13 patients was 69.3 +/- 1.8 (S.E.) years, mean
      refractive error was +1.37 +/- 0.39 diopters, and mean axial length was 22.54 +/-
      0.20 mm. In 13 eyes, before and after laser iridotomy measurements of angle
      opening distance (0.11 +/- 0.02 vs. 0.18 +/- 0.02 mm) (P = .0004; paired t test),
      angle aperture (8.3 +/- 1.3 vs 18.6 +/- 2.8 degrees) (P = .0003) and iris-lens
      contact distance (0.58 +/- 0.06 vs 1.18 +/- 0.14 mm) (P = .0003) were greater
      postoperatively, but anterior chamber depth was unchanged (P = .7). CONCLUSIONS:
      Flattening of the iris after laser iridotomy for pupillary block causes an
      increase in iris-lens contact. The change in angle configuration after iridotomy
      results more from an alteration in aqueous pressure gradients across the iris
      rather than from posterior lens movement.

PMID- 8659599
TI  - Indocyanine green angiographic findings in Vogt-Koyanagi-Harada disease.
AB  - PURPOSE: To report the indocyanine green angiographic findings associated with
      Vogt-Koyanagi-Harada disease and compare them with fluorescein angiographic
      findings and monochromatic scanning laser images. METHODS: In a prospective
      study, indocyanine green angiography, by scanning laser ophthalmoscopy or
      infrared fundus photography, was performed in ten consecutive patients (20 eyes)
      with Vogt-Koyanagi-Harada disease during the acute stage before and recovery
      stage after corticosteroid treatment. Findings were compared with fluorescein
      angiographic features and monochromatic scanning laser imaging. RESULTS: During
      the acute stage of the disease, indocyanine green angiography disclosed a dark
      background in the early phase and multiple, non-uniform hypofluorescent lesions
      in the midphases. Lesions were more numerous and extensive than areas either of
      serous retinal detachment on monochromatic scanning laser imaging or of punctate
      hyperfluorescence on fluorescein angiography. During the recovery stage, the
      abnormal dark background on indocyanine green angiography at initial examination
      resolved, with choroidal vessels visible in all cases, but nonuniform
      hypofluorescent lesions persisted in most eyes. Fluorescein angiography disclosed
      hypofluorescent patchy areas, and confocal infrared laser imaging showed some
      bright reflective lesions in three patients with especially severe clinical
      symptoms. On final examination after an average of 17.7 months, both
      angiographies still disclosed abnormal findings in these three patients.
      CONCLUSIONS: Indocyanine green angiographic findings suggest that choroidal
      inflammation may cause a transient choroidal circulatory disturbance during the
      acute stage of Vogt-Koyanagi-Harada disease. In more severe cases, this
      dysfunction may secondarily damage the retinal pigment epithelium.

PMID- 8659600
TI  - Ultrastructural features of tissue removed during idiopathic macular hole
      surgery.
AB  - PURPOSE: To compare the ultrastructural features of excised tissue removed during
      surgery for idiopathic macular holes with the preoperative stage of the macular
      hole. METHODS: Twelve consecutive patients with a unilateral idiopathic macular
      hole underwent vitrectomy with surgical removal of the internal limiting membrane
      of the retina and epiretinal tissue overlying and surrounding the hole. The
      excised specimens were evaluated with transmission electron microscopy, and
      findings were compared with the preoperative stage of the macular hole according
      to the classification of Gass. RESULTS: Surgery was performed on 12 eyes of 12
      patients with stage 2, 3, or 4 macular holes. Internal limiting membrane was
      present in 11 of 12 specimens. Tissue from one of two eyes with stage 2 holes
      showed cellular elements enmeshed in cortical vitreous. Tissue from four of seven
      eyes with stage 3 holes and three of three eyes with stage 4 holes had cellular
      proliferation on the internal limiting membrane. Cells with myofibroblastic
      differentiation were present in five of the eight cellular proliferations.
      CONCLUSION: Our results support the clinical stages of idiopathic macular holes
      described by Gass. Idiopathic macular holes appear to form from contraction of
      the prefoveal vitreous, and the hole enlarges because of contraction of
      myofibroblasts on the inner surface of the internal limiting membrane. On the
      basis of the mechanical mechanisms of idiopathic macular hole formation, removal
      of the internal limiting membrane and adherent epiretinal tissue surrounding and
      overlying the macular hole is a reasonable surgical approach to close idiopathic
      macular holes.

PMID- 8659601
TI  - Progressive subretinal fibrosis and blindness in patients with multifocal
      granulomatous chorioretinitis.
AB  - PURPOSE: To describe the clinical and histopathologic findings in four eyes of
      three patients who became blind because of multifocal choroiditis and massive
      subretinal fibrosis. METHODS: Clinicopathologic correlative study. RESULTS:
      During a period of several years, three healthy elderly patients developed severe
      visual loss only partly explained by multifocal chorioretinitis and massive
      subretinal fibrosis. Histopathologic examination of four eyes from these patients
      disclosed widespread destruction of the outer retina and retinal pigment
      epithelium, massive areas of subretinal fibrous tissue proliferation,
      granulomatous inflammation centered around degenerated and fragmented Bruch's
      membrane, and chronic uveitis. No infectious organisms were identified by special
      stains or electron microscopy in one eye. CONCLUSIONS: Clinical and
      histopathologic findings in these three patients were consistent with an
      autoimmune disease process directed at the retina, retinal pigment epithelium,
      inner choroid, or all three. Cellular injury in this location can result in
      massive subretinal fibrosis. Subretinal fibroplasia, however, is probably a
      nonspecific reparative response to injury. The pathogenesis of this blinding
      disorder in elderly patients may be similar to the less severe disease usually
      occurring in younger patients with multifocal choroiditis, panuveitis, and
      punctate inner choroiditis.

PMID- 8659602
TI  - Ocular iontophoretic supplementation of intravenous foscarnet therapy.
AB  - PURPOSE: Reactivation of cytomegalovirus retinopathy during intravenous antiviral
      therapy is usually treated with higher doses of drug. We sought to determine
      whether ocular iontophoresis increases the intravitreal foscarnet concentration
      attained by intravenous injection. METHODS: We injected foscarnet (120 mg/kg or
      180 mg/kg) intravenously into 24 rabbits and determined the time of maximal
      concentrations in serum and vitreous humor. We injected the same doses into 24
      additional rabbits and administered ocular foscarnet iontophoresis one hour
      later. Vitreous humor concentrations were assayed at one, four, eight, 24, 60,
      and 120 hours after iontophoresis and compared with those from injection alone.
      RESULTS: Maximum serum and vitreous humor concentrations were achieved one hour
      after each intravenous dose. Maximum vitreous humor concentrations were achieved
      four hours after 120 mg/kg intravenous doses plus iontophoresis and eight hours
      after 180-mg/kg intravenous doses plus iontophoresis. Vitreous humor levels were
      significantly higher in eyes receiving intravenous foscarnet (120 mg/kg, P <
      .0001; 180 mg/kg, P < .0001) plus ocular Foscarnet iontophoresis than in those
      receiving intravenous foscarnet alone. Vitreous humor foscarnet levels in eyes
      receiving 120 mg/kg intravenously did not differ significantly from those in the
      group receiving 180 mg/kg intravenously (P < .1). The intravenous dose did not
      significantly affect vitreous humor levels after iontophoresis (P < .1). Vitreous
      concentrations fell below therapeutic levels (25 microM) in all eyes 60 hours
      after intravenous foscarnet and ocular foscarnet iontophoresis. CONCLUSIONS:
      Ocular iontophoresis significantly increased intravitreous foscarnet
      concentrations above those attained by intravenous injection alone and may be an
      effective alternative to increasing the intravenous drug dose in patients with
      reactivated cytomegalovirus retinopathy.

PMID- 8659603
TI  - Correlation between intraocular pressure and CD4+ T-lymphocyte counts in patients
      with human immunodeficiency virus with and without cytomegalovirus retinitis.
AB  - PURPOSE: To determine the intraocular pressure in patients with human
      immunodeficiency virus (HIV) with and without cytomegalovirus retinitis, and to
      correlate intraocular pressure with CD4+ T-lymphocyte count and the presence,
      extent, and activity of cytomegalovirus retinitis. METHODS: Intraocular pressure
      was measured with calibrated Goldmann applanation tonometers in two groups of
      patients. Group A included 84 patients with HIV (120 eyes) with cytomegalovirus
      retinitis, and Group B included 110 patients with HIV (183 eyes) without
      cytomegalovirus retinitis. Thirty-three patients without HIV (66 eyes) were
      included as a control group. Step-wise regression analysis of intraocular
      pressure included correlation with cytomegalovirus retinitis (presence, extent,
      and activity), CD4+ T-lymphocyte count, age, and gender. RESULTS: The mean
      intraocular pressure was 9.8 mm Hg in Group A, 12.6 mm Hg in Group B, and 16.1 mm
      Hg in the control group. All three groups were statistically different from each
      other when intraocular pressure was compared (P < .0001). Step-wise regression
      showed that low CD4+ T-lymphocyte count (r2 = .20; P < .0001) and extent of
      cytomegalovirus retinitis (r2 = .08; P = .007) both correlated to low intraocular
      pressure. CONCLUSION: Intraocular pressure is lower than normal in patients with
      HIV. Decreased CD4+ T-lymphocyte count is the major association with low
      intraocular pressure (20% of the effect); extent of cytomegalovirus retinitis
      accounts for 8% of the effect. Knowledge of the normal range of intraocular
      pressure in patients with HIV will be important to the understanding and
      treatment of glaucoma and other disorders or treatments affecting intraocular
      pressure.

PMID- 8659604
TI  - Visual-spatial deficits expalin visual symptoms in Alzheimer's disease.
AB  - PURPOSE: To determine whether the visual symptoms of patients with Alzheimer's
      disease are related to visual-spatial dysfunction. METHODS: We administered a
      test battery modified from existing neuropsychometric materials that taxed visual
      spatial skills, form identification, color vision, and visual memory. We tested
      14 patients with Alzheimer's disease who had visual symptoms prominent enough to
      prompt ophthalmologic consultation, 11 patients with Alzheimer's disease who
      lacked such visual symptoms, and a control group of 53 subjects without
      Alzheimer's disease. The groups with Alzheimer's disease were matched for
      Wechsler Adult Intelligence Scale-Revised scores. RESULTS: Patients with
      Alzheimer's disease who had prominent visual symptoms differed significantly from
      those without prominent visual symptoms only in their relatively poor visual
      spatial test scores. CONCLUSIONS: Visual symptoms in Alzheimer's disease are
      related primarily to visual-spatial deficits. These findings are consistent with
      previous evidence that patients with Alzheimer's disease who have prominent
      visual symptoms have accentuated histologic and metabolic abnormalities in the
      parieto-occipital regions known to process visual-spatial information. The
      findings support the view that pathways mediating visual-spatial and form
      identification are at least partially segregated in the brain, and emphasize that
      tests used to screen visually symptomatic patients with Alzheimer's disease will
      be more effective if they prominently assess visual-spatial skills.

PMID- 8659605
TI  - The danger of reducing reimbursement for psychiatric disorders in late life.

PMID- 8659606
TI  - Neuroimaging X. Functional MRI studies of language by sex.

PMID- 8659607
TI  - The Internet and the future of psychiatry.
AB  - OBJECTIVE: The Internet is a rapidly growing communications resource that is
      beginning to have an impact on medicine, and it is anticipated that the Internet
      will soon have a major effect on psychiatry. It is essential for psychiatrists to
      have a conceptual framework for understanding the many aspects of the Internet.
      METHOD: Using a four-layer model, the authors describe the components of the
      Internet and how these work together to establish communication. They discuss
      some of the practical implications of the model, potential future applications of
      the Internet, and some of the challenges its use will create. RESULTS: In the
      Internet model described, the bottom three layers involve hardware and modes of
      information transmission; the fourth layer is human interaction. The Internet has
      great potential in psychiatric education, clinical care, research, and
      administration, but major adjustments in individual and organizational
      expectations and responses will be needed. These changes relate to the speed,
      dispersion, volume, privacy, and permanence of communication. CONCLUSIONS: The
      growth of the Internet and related information technologies is inevitable and has
      diverse technical and social implications. As psychiatrists, we must remain
      effective communicators of information and adjust to a changing world with new
      roles and skills that will permit us to best serve our professional mission.

PMID- 8659608
TI  - Treatment costs and use of community mental health services for schizophrenia by
      age cohorts.
AB  - OBJECTIVE: Research on schizophrenia has tended to ignore patterns and costs of
      mental health service use in late life. The present study examined the types of
      mental health services used and their costs for several age-defined cohorts in a
      large community mental health system. METHOD: The data covered all users of the
      mental health system included in the San Diego county billing information system
      in fiscal years 1986 and 1990. Community mental health service use and codes were
      modeled as a function of patient demographic characteristics, diagnosis, and age.
      The patients were grouped into the following age categories: 18-29, 30-44, 45-54,
      55-64, 65-74, and > or = 75 years of age. RESULTS: The total costs for
      schizophrenia were higher than those for other psychiatric disorders, and they
      were also age dependent. In both fiscal years, the costs of schizophrenia were
      higher for the youngest and oldest cohorts than for the patients in the 30-65
      year range. CONCLUSIONS: The economic burden of late-life schizophrenia to the
      public mental health system is at least as high as that of schizophrenia in
      younger adults.

PMID- 8659609
TI  - Disability in geriatric depression.
AB  - OBJECTIVE: The authors' purpose was to identify the relationship of disability to
      clinical measures that are part of a comprehensive psychiatric examination of
      depressed elderly patients. METHOD: The disability of 75 elderly inpatients and
      outpatients with major depression whose cognitive function ranged from normality
      to mild dementia was assessed with the Philadelphia Multilevel Assessment
      Instrument. Age at onset of depression, chronicity of depression, severity of
      depression, cognitive impairment, medical burden, social support and living
      environment were assessed with standardized instruments. RESULTS: Impairment in
      instrumental activities of daily living was significantly associated with
      advanced age, severity of depression, and medical burden. The relationship of
      depressive symptoms to impairment in instrumental activities of daily living was
      not influenced by age or medical burden. Anxiety and depressive ideation as well
      as retardation and weight loss were significantly associated with impairment in
      instrumental activities of daily living. Interviewer-rated global disability was
      associated with advanced age at onset of depression, medical burden, and overall
      cognitive impairment. Specifically, a disturbance in initiation and perseveration
      was significantly related to global disability. CONCLUSIONS: Impairment in
      instrumental activities of daily living appears to be a relatively independent
      dimension of health status that is related to depressive symptoms, particularly
      anxiety and depressive ideation as well as retardation and weight loss. Global
      disability may be associated with impairment in initiation and perseveration and
      with late onset of depression. These findings provide a basis for studies
      investigating whether psychotherapy aimed at depressive ideation and
      rehabilitation efforts focused on instrumental activities of daily living can
      improve the outcome of geriatric depression.

PMID- 8659610
TI  - Hypothalamic-pituitary-adrenocortical activity and response to cognitive behavior
      therapy in unmedicated, hospitalized depressed patients.
AB  - OBJECTIVE: Surprisingly little research supports the hypothesis that depressions
      characterized by objective measures of neurobiological dysregulation respond
      poorly to psychotherapy. Moreover, relevant studies testing this hypothesis have
      been compromised by low rates of neurobiological abnormality in outpatient
      samples. The authors therefore investigated response to cognitive behavior
      therapy in relation to pretreatment measures of hypothalamic-pituitary
      adrenocortical (HPA) activity in hospitalized, yet unmedicated, patients. METHOD:
      The subjects were 29 unmedicated, hospitalized patients with major depression
      (DSM-III-R and Schedule for Affective Disorders and Schizophrenia/Research
      Diagnostic Criteria), nonpsychotic/nonbipolar subtype. After a 7- to 14-day
      evaluation, urinary free cortisol levels and dexamethasone suppression tests
      (DSTs) were obtained. Patients were treated for an average of 3 weeks with
      intensive individual cognitive behavior therapy. Response was assessed in
      relation to clinical severity of illness and pretreatment HPA parameters.
      RESULTS: Response to inpatient cognitive behavior therapy was inversely
      associated with pretreatment urinary free cortisol concentrations, although not
      strongly correlated with DST results. Overall, 12 (92%) of 13 cortisol
      suppressors on the DST who had normal urinary free cortisol concentrations
      responded to treatment, compared with only seven (44%) of the 16 patients
      characterized by nonsuppression of cortisol and/or elevated urinary free cortisol
      excretion. The relation between response to cognitive behavior therapy and HPA
      activity was not explained by clinical measures of symptom severity. CONCLUSIONS:
      Results are consistent with the hypothesis that patients with increased HPA
      function are less responsive to psychotherapy and, hence, might require somatic
      interventions. It is proposed that the negative impact of hypercortisolism on
      neurocognitive function mediates this relationship.

PMID- 8659611
TI  - Depression spectrum disease, I: The role of gene-environment interaction.
AB  - OBJECTIVE: This study used an adoption study design to separate genetic from
      environmental factors in the etiology of depression spectrum disease, a type of
      major depression characterized by families in which male relatives are alcoholic
      and females are depressed. The genetic etiology hypothesis of depression spectrum
      disease proposes that an alcoholic genetic diathesis predisposes to depression in
      females but alcoholism, not depression, in males. METHOD: The study examined 197
      adult offspring (95 male and 102 female) of alcoholic biological parents and used
      logistic regression models to determine the contribution to major depression in
      male and female adoptees that could be explained by the genetic alcoholic
      diathesis combined with an environmental factor that was characterized by
      psychiatrically or behaviorally disturbed adoptive parents. RESULTS: Major
      depression in females was predicted by an alcoholic diathesis only when combined
      with the disturbed adoptive parent variable. The same regression model failed to
      predict depression in males. Other possible environmental confounding factors
      contributing to an increased chance of depression were found in females: fetal
      alcohol exposure, age at the time of adoption, and a family with an adopted
      sibling who had a psychiatric problem. These variables did not diminish the
      significance of the prediction of depression with the alcohol genetic diathesis
      and disturbed parent model. CONCLUSIONS: The results show that a genetic factor
      is present for which alcoholism is at least a marker, and which exerts its effect
      in women as a gene-environment interaction leading to major depression. This
      finding suggests that an important etiologic factor in depression spectrum
      disease is gene-environment interaction.

PMID- 8659612
TI  - Understanding the comorbidity between early-onset dysthymia and cluster B
      personality disorders: a family study.
AB  - OBJECTIVE: A number of studies have documented significant comorbidity between
      dysthymia and axis II personality disorders, particularly those grouped in
      cluster B. However, the nature of this comorbidity is poorly understood. The
      purpose of this investigation was to use the family study method to test five
      competing models of the comorbidity between early-onset dysthymia and cluster B
      personality disorders. METHOD: Proband groups consisted of subjects with early
      onset dysthymia and a co-occurring cluster B personality disorder (N = 28),
      subjects with early-onset dysthymia without a cluster B personality disorder (N =
      69), and a comparison group of subjects who had never been psychiatrically ill (N
      = 45). The groups were compared on rates of dysthymia with a cluster B
      personality disorder, dysthymia without a cluster B personality disorder, and
      cluster B personality disorders without dysthymia in their first-degree relatives
      (N = 675). RESULTS: The relatives of both subgroups of dysthymic probands
      exhibited higher rates of dysthymia with a cluster B personality disorder,
      dysthymia without a cluster B personality disorder, and cluster B personality
      disorders without dysthymia than the relatives of the never ill probands. In
      addition, the relatives of probands with comorbid dysthymia exhibited higher
      rates of cluster B personality disorders without dysthymia than the relatives of
      probands with noncomorbid dysthymia. CONCLUSIONS: This pattern of results is
      consistent with the notion that dysthymia and cluster B personality disorders co
      occur because of shared etiological factors. This was the only one of five models
      of the comorbidity between dysthymia and cluster B personality disorders that was
      supported by the family data.

PMID- 8659614
TI  - Conduct disorder, substance use disorders, and coexisting conduct and substance
      use disorders in adolescent inpatients.
AB  - OBJECTIVE: The authors examined the association between conduct disorder and
      substance use disorders in adolescent inpatients. METHOD: Structured diagnostic
      interviews were given to 165 adolescent inpatients to assess the presence of DSM
      III-R axis I disorders and personality disorders from axis II. Patients with
      conduct disorder (N = 25), substance use disorders (N = 24), and coexisting
      conduct and substance use disorders (N = 54) were compared to determine whether
      additional axis I and axis II disorders presented at significantly different
      rates. RESULTS: The groups with conduct disorder and coexisting conduct and
      substance use disorders had a higher proportion of male subjects than the group
      with substance use disorders alone. Patients with conduct disorder had an earlier
      age at first psychiatric contact and were diagnosed significantly more often with
      attention deficit hyperactivity disorder than the other two groups. Borderline
      personality disorder was diagnosed more frequently in the patients with substance
      use and coexisting conduct and substance use disorders than in the patients with
      conduct disorder. These differential co-occurrence patterns were observed for
      both male and female subjects. CONCLUSIONS: Conduct disorder and substance use
      disorders have high comorbidity rates with other psychiatric disorders in
      adolescent inpatients. The additional psychiatric comparison group (patients with
      coexisting conduct and substance use disorders) allowed for finer distinctions
      regarding psychiatric comorbidity. The validity of subtyping conduct disorder on
      the basis of the presence of a coexisting substance use disorder is suggested;
      conduct disorder patients without a coexisting substance use disorder are more
      likely to have attention deficit hyperactivity disorder.

PMID- 8659613
TI  - Childhood antecedents of adolescent personality disorders.
AB  - OBJECTIVE: The purpose of this study was to investigate the childhood antecedents
      of personality disorders that are diagnosed in adolescence. METHOD: A randomly
      selected community sample of 641 youths was assessed initially in childhood and
      followed longitudinally over 10 years. Childhood behavior ratings were based on
      maternal report; diagnoses of adolescent personality disorders were based on data
      obtained from both maternal and youth informants. Four composite measures of
      childhood behavior problems were used: conduct problems, depressive symptoms,
      anxiety/fear, and immaturity. Adolescent personality disorders were considered
      present only if the disorders persisted over a 2-year period. For all analyses,
      personality disorders were grouped into the three clusters (A, B, and C) of DSM
      III-R. RESULTS: Logistic regression analyses indicated that all four of the
      putative childhood antecedents were associated with greater odds of an adolescent
      personality disorder 10 years later. Childhood conduct problems remained an
      independent predictor of personality disorders in all three clusters, even when
      other childhood problems were included in the same regression model.
      Additionally, depressive symptoms emerged as an independent predictor of cluster
      A personality disorders in boys, while immaturity was an independent predictor of
      cluster B personality disorders in girls. No moderating effects of age at time of
      childhood assessment were found. CONCLUSIONS: These results support the view that
      personality disorders can be traced to childhood emotional and behavioral
      disturbances and suggest that these problems have both general and specific
      relationships to adolescent personality functioning.

PMID- 8659615
TI  - Psychiatric profile and sociodemographic characteristics of adults who report
      physically abusing or neglecting children.
AB  - OBJECTIVE: In this study the authors measured the number of adults in three U.S.
      communities who reported abusing and neglecting children in their lifetime and
      assessed the relative impact of sociodemographic characteristics and lifetime
      diagnosis of mental disorders on both child abuse and child neglect. METHOD: A
      total of 9,841 respondents, identified through a household sampling procedure for
      the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area
      study, were included in the analysis. Self-reported lifetime histories of abuse
      and neglect of children were measured in the antisocial personality module of the
      NIMH Diagnostic Interview Schedule. RESULTS: In the study sample, 147 adults
      (1.49%) stated that they had abused children, and 140 adults (1.42%) stated that
      they had neglected children. A total of 58.5% of those who reported abuse of
      children, and 69.3% of those who reported having neglected a child, had a
      lifetime diagnosis of a mental disorder. Increased odds of reports of both abuse
      and neglect were associated with having a greater number of children in the
      household. Low socioeconomic status was a risk factor for neglecting, but not
      abusing, children. In multivariate analyses, a lifetime history of alcohol
      disorder was associated with abuse and neglect, affective disorders with abuse,
      and anxiety disorders with neglecting children. CONCLUSIONS: In light of the
      associations between mental disorders and mistreatment of children, public health
      policies designed to prevent child abuse and neglect might be enhanced by an
      increased focus on interventions targeted at individuals with mental disorders.

PMID- 8659616
TI  - Basal cortisol, dexamethasone suppression of cortisol, and MHPG in adolescents
      after the 1988 earthquake in Armenia.
AB  - OBJECTIVE: This study evaluated basal salivary cortisol, 3-methoxy-4
      hydroxyphenylglycol (MHPG), and cortisol suppression following dexamethasone
      administration in adolescents exposed to two levels of earthquake-related trauma.
      METHOD: Five years after the 1988 earthquake, saliva samples were obtained from
      37 adolescents from two cities in Armenia at different distances from the
      epicenter. Baseline saliva samples were obtained at 8:00 a.m., 4:00 p.m., and
      11:00 p.m., following which 0.5 mg of dexamethasone was administered. Nine and 17
      hours later, saliva samples were again obtained. Subjects were evaluated for
      posttraumatic stress and depressive reactions through use of self-report
      instruments. RESULTS: Significantly lower mean baseline 8:00 a.m. cortisol levels
      and greater day 24:00 p.m. cortisol suppression following dexamethasone were
      observed in the more symptomatic adolescents living in the city closer to the
      epicenter. Of the three symptom categories of posttraumatic stress disorder
      (PTSD), only intrusion (category B) symptoms were significantly correlated with
      basal morning cortisol levels and percent suppression by dexamethasone. The more
      highly exposed adolescents also exhibited a more rapid decline in MHPG levels
      over the course of day 1. CONCLUSIONS: The findings indicate that chronic
      posttraumatic stress reactions among adolescents exposed to catastrophic disaster
      are associated with hypothalamic-pituitary-adrenal (HPA) axis alterations. The
      findings are congruent with those previously described in adults with chronic
      PTSD. Persistent intrusion (category B) symptoms may constitute continued
      episodes of distress and evoke repeated physiological stress responses, which,
      over time, alter HPA axis function. The MHPG findings suggest that there may be
      diurnal changes associated with severity of posttraumatic stress symptoms.

PMID- 8659617
TI  - Dissociation in aging Holocaust survivors.
AB  - OBJECTIVE: This study explored relationships among dissociation, trauma, and
      posttraumatic stress disorder (PTSD) in elderly Holocaust survivors with and
      without PTSD and in a demographically comparable group of nontraumatized
      subjects. METHOD: Holocaust survivors with PTSD (N = 35) and without PTSD (N =
      25) who had been recruited from the community and a comparison group (N = 16)
      were studied. Dissociation was evaluated with the Dissociative Experiences Scale.
      Past cumulative trauma and recent stress were evaluated with the Antonovsky Life
      Crises Scale and the Elderly Care Research Center Recent Life Events Scale,
      respectively. PTSD symptoms were assessed with the Clinician-Administered PTSD
      Scale. RESULTS: The Holocaust survivors with PTSD showed significantly higher
      levels of current dissociative experiences than did the other groups. However,
      the extent of dissociation was substantially less than that which has been
      observed in other trauma survivors with PTSD. Dissociative Experiences Scale
      scores were significantly associated with PTSD symptom severity, but the relation
      between Dissociative Experiences Scale scores and exposure to trauma was not
      significant. CONCLUSIONS: Possible explanations for this finding include the age
      of the survivors, the length of time since the traumatic event, and possible
      unique features of the Holocaust survivor population. Nevertheless, the findings
      call into question the current notion that PTSD and dissociative experiences
      represent the same phenomenon. The findings suggest that the relationships among
      dissociation, trauma, and PTSD can be further clarified by longitudinal studies
      of trauma survivors.

PMID- 8659618
TI  - Sleep impairment and daytime sleepiness in later life.

PMID- 8659619
TI  - Vincenzo Chiarugi, 1759-1820.

PMID- 8659620
TI  - Four-year outcome for cognitive behavioral treatment of residual symptoms in
      major depression.
AB  - OBJECTIVE: The authors' goal was to determine whether cognitive behavioral
      treatment of residual symptoms of depression might have a significant effect on
      relapse rate. METHOD: In an earlier study, 40 patients with primary major
      depressive disorder who had been successfully treated with antidepressant drugs
      were randomly assigned to either cognitive behavioral treatment of residual
      symptoms or standard clinical management. In both types of treatment,
      antidepressant drugs were gradually tapered and discontinued. In this study, a 4
      year follow-up assessment was performed. RESULTS: Cognitive behavioral treatment
      resulted in a substantially lower relapse rate (35%) than did clinical management
      (70%). CONCLUSIONS: Cognitive behavioral treatment of residual symptoms reduces
      the risk of relapse in depressed patients, probably by affecting the progression
      of residual symptoms to prodromes of relapse.

PMID- 8659621
TI  - High levels of dopamine D2 receptor occupancy with low-dose haloperidol
      treatment: a PET study.
AB  - OBJECTIVE: The purpose of this study was to determine the dopamine D2 receptor
      occupancy induced by low-dose haloperidol treatment in a prospective trial.
      METHOD: Seven patients with schizophrenia were treated with 2 mg/day of
      haloperidol for 2 weeks, and D2 receptor occupancy was measured by
      [11C]raclopride and positron emission tomography. RESULTS: The patients showed
      high levels of D2 occupancy (53%-74%); five of them showed substantial clinical
      improvement, and none showed important side effects. CONCLUSIONS: The findings
      demonstrate that low doses of haloperidol induce D2 receptor occupancies that are
      in the putative therapeutic range. In combination with recent empirical trials,
      these findings should encourage clinicians to initiate treatment of psychotic
      episodes with low (2-4 mg haloperidol equivalent) doses of typical neuroleptics,
      particularly for first-episode patients.

PMID- 8659622
TI  - Time required for initial improvement during clozapine treatment of refractory
      schizophrenia.
AB  - OBJECTIVE: To characterize better the length of time required for the onset of
      improvement during clozapine treatment for refractory schizophrenia, the author
      reanalyzed data from a naturalistic outcome study. METHOD: Medical records of 100
      adults sequentially treated with clozapine in a state hospital were reviewed
      through 18 months. A priori criteria were used to categorize change in a measure
      of global social functioning. RESULTS: Of 73 patients who met the criteria for at
      least some improvement during clozapine treatment, 55 demonstrated initial
      improvement within 6 months, and the remainder demonstrated improvement by month
      11. Response at 3 months was significantly correlated with outcome at 18 months.
      CONCLUSIONS: Gross social improvement as measured in this study is likely to lag
      behind more sensitive indicators of clinical response. This study supports the
      notion that initial response to clozapine occurs within the first few months of
      treatment.

PMID- 8659623
TI  - Disproportionate lethality in psychiatric patients with concurrent alcohol and
      cocaine abuse.
AB  - OBJECTIVE: The aim of this study was to examine the association between active,
      concomitant cocaine and alcohol abuse and the prevalence and severity of current
      suicidal and homicidal behavior among hospitalized psychiatric patients. METHOD:
      Three groups of patients--with cocaine and alcohol abuse (N = 38), alcohol abuse
      only (N = 38), and cocaine abuse only (N = 25)--consecutively admitted to a
      psychiatric and substance abuse dual-diagnosis unit were comparatively examined
      for the presence of current suicidal and homicidal behavior. RESULTS AND
      CONCLUSIONS: Logistic regression analysis revealed that the alcohol and cocaine
      abuse group had a higher likelihood of associated current homicidal behavior than
      the alcohol-only and the cocaine-only groups.

PMID- 8659624
TI  - Liability to alprazolam abuse in daughters of alcoholics.
AB  - OBJECTIVE: The purpose of this study was to determine mood changes in women with
      a parental history of alcohol dependence (daughters of alcoholics) after
      challenge does of alprazolam and placebo in comparison with responses in women
      without a history of parental alcohol dependence. METHOD: Visual analog scales
      that assess liability to benzodiazepine abuse were administered to 12 adult
      daughters of alcoholics and 11 comparison subjects after alprazolam challenge.
      RESULTS: The daughters of alcoholics had greater pleasant mood responses after a
      single dose of alprazolam than did the comparison subjects despite having similar
      plasma alprazolam levels. CONCLUSIONS: The findings of this study suggest that
      the mood-enhancing effects of alprazolam are greater in daughters of alcoholics
      than in subjects without a history of parental alcohol dependence.

PMID- 8659625
TI  - Cocaine-induced tics in untreated Tourette's syndrome.

PMID- 8659626
TI  - Delirium associated with a combination of sertraline, haloperidol, and
      benztropine.

PMID- 8659627
TI  - Sexism and heterosexism in the diagnostic interview for borderline patients?

PMID- 8659628
TI  - Ascertaining accurate blood pressure.

PMID- 8659629
TI  - Multimodal treatment for attention deficit hyperactivity disorder?

PMID- 8659630
TI  - Is family conflict denial relevant to prognosis for major depression?

PMID- 8659631
TI  - Patient evaluation through live video transmission.

PMID- 8659632
TI  - Festschrift in honor of John C. Nemiah, M.D.

PMID- 8659633
TI  - Treating the traumatic memories of patients with dissociative identity disorder.
AB  - OBJECTIVE: The author uses clinical experience informed by research findings to
      suggest approaches to the treatment of the traumatic memories of patients with
      dissociative identity disorder. METHOD: Recent findings in the treatment of
      patients with this disorder and current considerations with regard to memories of
      childhood trauma are used to develop recommended approaches. RESULTS: Treatment
      of traumatic memories appears crucial in the recovery of patients with
      dissociative identity disorder, even though the reported memories may not be
      historically accurate. Criteria are available for determining whether a patient
      with the disorder is able to undertake such efforts, and methods such as
      fractionated abreaction have been developed to make the process less unsettling.
      CONCLUSIONS: Despite the difficulties posed by the vulnerability of patients with
      dissociative identity disorder to decompensation when working with traumatic
      material and the vicissitudes of autobiographical memory, modern therapeutic
      approaches allow the processing of such patients' traumatic material in a manner
      that reduces the likelihood of disruptive events and the misuse of recovered
      material.

PMID- 8659634
TI  - Onset conditions for psychological and psychosomatic symptoms during
      psychotherapy: a new theory based on a unique data set.
AB  - OBJECTIVE: The author's goal was to evaluate theories of the conditions that
      exist before onset of psychological and somatic symptoms by assessing these
      preconditions clinically and quantitatively. METHOD: He assembled a set of texts
      from the cases of seven patients who had recurrent psychological or somatic
      symptoms and examined the segments of texts that came before the symptoms
      occurred; he then compared these segments with segments of text that occurred
      before control points in the same case. The recurrent psychological symptoms were
      momentary forgetting, shifts in level of depression, and phobic behavior; the
      recurrent somatic symptoms were stomach ulcer pains, migraine headaches, absence
      epilepsy (petit mal) episodes, and premature ventricular contractions of the
      heart. RESULTS: 1)Independent ratings of presymptom segments compared with
      precontrol segments revealed some significant differences in all seven cases. 2)
      Some variables that distinguished the presymptom from the precontrol segments
      occurred in all of the cases. In rank order of their effect size across cases,
      these variables were hopelessness, lack of control, anxiety, feeling blocked,
      helplessness, concern about "supplies," depression, and hostility toward the
      therapist. For example, hopelessness was significant in seven of the seven cases.
      CONCLUSIONS: For the first time, segments of texts of psychotherapy sessions that
      occurred before recurrent symptoms have been assembled and analyzed. These brief
      segments before recurrent symptoms showed more of certain qualities than did
      segments before control points where no symptoms appeared. On the basis of these
      results the author constructed a new symptom-context theory of symptom formation
      and compared this new theory with five classical theories of symptom formation,
      drawing implications for research and for treatment techniques.

PMID- 8659635
TI  - The panic-agoraphobic syndrome: a paradigm of the anxiety group of disorders and
      its implications for psychiatric practice and theory.

PMID- 8659636
TI  - Factors in the etiology and pathogenesis of panic disorder: revisiting the
      attachment-separation paradigm.

PMID- 8659637
TI  - Alexithymia: past and present.

PMID- 8659638
TI  - Natural history of male psychological health, XIII: Who develops high blood
      pressure and who responds to treatment.
AB  - OBJECTIVE: This study was an effort to clarify both the psychological
      contributions to and the long-term consequences of uncomplicated essential
      hypertension. METHOD: The subjects were 193 healthy college students selected as
      sophomores and prospectively followed for over 50 years. Independent assessments
      of physical and mental health were made. RESULTS: Although objective indices of
      psychopathology predicted both physical morbidity and mortality, they did not
      predict hypertension. When pyknic somatotype, college diastolic blood pressure,
      and well-integrated personality in college were controlled, no other preadult
      variable predicted hypertension. As expected, heart disease, obesity, and alcohol
      abuse were each correlated with hypertension. After roughly 20 years, 14 of the
      41 men with treated hypertension were in stable remission, and 13 men had
      developed cardiac complications. No differences between these groups could be
      discerned. CONCLUSIONS: Over time, hypertension appeared to be more a product of
      biological than of psychosomatic variables. Good psychological health did not
      diminish the risk of hypertension.

PMID- 8659639
TI  - Medical education: a commentary on historical and contemporary issues.

PMID- 8659640
TI  - Erotic obsession: relationship to hypoactive sexual desire disorder and
      paraphilia.

PMID- 8659641
TI  - Hypnotizability and traumatic experience: a diathesis-stress model of
      dissociative symptomatology.
AB  - OBJECTIVE: The authors propose a diathesis-stress model to describe how
      pathological dissociation may arise from an interaction between innate
      hypnotizability and traumatic experience. METHOD: To support the proposition that
      pathological dissociation may reflect autohypnotic process, the authors highlight
      clinical and research data indicating parallels between controlled hypnotic
      dissociative states and uncontrolled pathological dissociative symptoms and
      summarize evidence of hypnotizability in persons with psychiatric disorders that
      manifest these symptoms. The authors present this evidence by examining
      dissociative symptomatology in four psychological domains: perception, behavior
      and will, affect, and memory and identity. In addition, modern cognitive and
      neuropsychological models of dissociation are briefly reviewed. RESULTS: Several
      lines of evidence converge in support of the role of autohypnosis in pathological
      dissociation. There is considerable evidence that controlled formal hypnosis can
      produce a variety of dissociations of awareness and control that resemble many of
      the symptoms in uncontrolled pathological dissociative conditions; and it is
      possible to discern in dissociative pathology the features of absorption,
      dissociation, and suggestibility/automaticity that characterize formal hypnotic
      states. There is also accumulating evidence of high levels of hypnotic capacity
      in all groups with dissociative symptomatology that have been systematically
      assessed. In addition, the widespread and successful therapeutic use of hypnosis
      in the treatment of many dissociative symptoms and conditions (and the potential
      for hypnosis to induce dissociative symptomatology) also supports the assumption
      that hypnosis and pathological dissociation share an underlying process.
      CONCLUSIONS: High hypnotizability may be a diathesis for pathological
      dissociative states, particularly under conditions of acute traumatic stress.

PMID- 8659643
TI  - Psychotherapy, revelation, science, and deep thinking.
AB  - Psychodynamic psychotherapy has evolved in the 30 years since John Nemiah was the
      author's mentor in the endeavor. It has always occupied an epistemologic position
      somewhere between the scientific standard of physics and the postmodern or
      poststructuralist view that the search for truth using language is totally
      futile. However, the awkward niche that psychotherapeutic practice occupies is
      closer to literary imagination than "hard science." The use of such imagination
      was presented 25 years ago by John Nemiah in his paper on "Deep Thinking." The
      poet's "revelation ... not discovered by the rational intellect alone" often
      imparts in psychotherapeutic practice a compelling urgency toward a previously
      unrealized choice. Such vision is, however, always located at the periphery of
      acceptable scientific theory. Psychotherapists persist, often with doubts,
      because their place is reflective of humanity's awkwardness. Evolution and
      civilization mutually enfold the human ability to resonate to the anguish of
      others as well. A species altruism directed toward repair of human problems is
      coupled with the skills of affectively linked "deep thinking." There is a
      continuing marginalization of such efforts, which now need to be cared for
      deeply.

PMID- 8659642
TI  - Dissociation: the clinical realities.
AB  - An attempt was made by the authors of DSM-III to restrict its focus to the
      experimental, the observable, and the measurable. The intention was to free the
      nosology from the influence of unproven theories, and the philosophy was driven
      largely by the importance of research being able to identify diagnostic
      categories to facilitate the study of homogeneous groups. So it is of interest
      that the authors accepted dissociation-an ambiguous event linked to an explicit
      theoretical concept that had been introduced by Janet-as the basis for
      classification of clinical presentations that were formerly included under the
      rubric of hysteria, a similarly unclear category. Since DSM-III, there have been
      an increasing number of reports of dissociative experiences and dissociative
      identity disorder (formerly known as multiple personality disorder), but neither
      of these clinical presentations seems able to withstand the concern that it is
      dramatically influenced by environmental cues, e.g., the expectations of the
      therapist. Thus, a restricted phenomenological perspective does not fully
      appreciate the distorting potential of suggestibility and imagination on the
      nature of the emerging clinical picture. These factors might well have
      contributed to and laid the conceptual groundwork for the growth in the number of
      reports of dissociation.

PMID- 8659645
TI  - Dissociation, somatization, and affect dysregulation: the complexity of
      adaptation of trauma.
AB  - OBJECTIVE: A century of clinical research has noted a range of trauma-related
      psychological problems that are not captured in the DSM-IV framework of
      posttraumatic stress disorder (PTSD). This study investigated the relationships
      between exposure to extreme stress, the emergence of PTSD, and symptoms
      traditionally associated with "hysteria," which can be understood as problems
      with stimulus discrimination, self-regulation, and cognitive integration of
      experience. METHOD: The DSM-IV field trial for PTSD studied 395 traumatized
      treatment-seeking subjects and 125 non-treatment-seeking subjects who had also
      been exposed to traumatic experiences. Data on age at onset, the nature of the
      trauma, PTSD, dissociation, somatization, and affect dysregulation were
      collected. RESULTS: PTSD, dissociation, somatization, and affect dysregulation
      were highly interrelated. The subjects meeting the criteria for lifetime (but not
      current) PTSD scored significantly lower on these disorders than those with
      current PTSD, but significantly higher than those who never had PTSD. Subjects
      who developed PTSD after interpersonal trauma as adults had significantly fewer
      symptoms than those with childhood trauma, but significantly more than victims of
      disasters. CONCLUSIONS: PTSD, dissociation, somatization, and affect
      dysregulation represent a spectrum of adaptations to trauma. They often occur
      together, but traumatized individuals may suffer from various combinations of
      symptoms over time. In treating these patients, it is critical to attend to the
      relative contributions of loss of stimulus discrimination, self-regulation, and
      cognitive integration of experience to overall impairment and provide systematic
      treatment that addresses both unbidden intrusive recollections and these other
      symptoms associated with having been overwhelmed by exposure to traumatic
      experiences.

PMID- 8659644
TI  - Neural mechanisms in dissociative amnesia for childhood abuse: relevance to the
      current controversy surrounding the "false memory syndrome".
AB  - OBJECTIVE: There is considerable controversy about delayed recall of childhood
      abuse. Some authors have claimed that there is a "false memory syndrome," in
      which therapists suggest to patients events that never actually occurred. These
      authors point to findings that suggest that memory traces are susceptible to
      modification. The purpose of this paper is to review the literature on the
      potential vulnerability of memory traces to modification and on the effects of
      stress on the neurobiology of memory. METHOD: The authors review findings on
      mechanisms involved in normal memory function, effects of stress on memory in
      normal persons, children's memory of stressful events, and alterations of memory
      function in psychiatric disorders. The effects of stress on specific brain
      regions and brain chemistry are also examined. RESULTS: Neuropeptides and
      neurotransmitters released during stress can modulate memory function, acting at
      the level of the hippocampus, amygdala, and other brain regions involved in
      memory. Such release may interfere with the laying down of memory traces for
      incidents of childhood abuse. Also, childhood abuse may result in long-term
      alterations in the function of these neuromodulators. CONCLUSIONS: John Nemiah
      pointed out several years ago that alterations in memory in the form of
      dissociative amnesia are an important part of exposure to traumatic stressors,
      such as childhood abuse. The studies reviewed here show that extreme stress has
      long-term effects on memory. These findings may provide a model for understanding
      the mechanisms involved in dissociative amnesia, as well as a rationale for
      phenomena such as delayed recall of childhood abuse.

PMID- 8659646
TI  - Characteristics of emergency services personnel related to peritraumatic
      dissociation during critical incident exposure.
AB  - OBJECTIVE: The aim of this study was to identify characteristics of emergency
      services personnel related to acute dissociative responses at the time of
      critical incident exposure, a phenomenon designated "peritraumatic dissociation."
      METHOD: The authors studied 157 rescue workers who responded to the Nimitz
      Freeway collapse during the 1989 Loma Prieta earthquake in the San Francisco Bay
      Area as well as 201 rescue workers who were not involved in that disaster.
      Demographics, level of critical incident exposure, perceived threat at the time
      of exposure, personality attributes (assessed by the Hogan Personality
      Inventory), coping strategies (assessed by the Ways of Coping Questionnaire), and
      locus of control were related to subjects' scores on the Peritraumatic
      Dissociative Experiences Questionnaire. RESULTS: According to univariate tests,
      the subjects with clinically meaningful levels of peritraumatic dissociation were
      younger; reported greater exposure to critical incident stress; felt greater
      perceived threat; had lower scores on the adjustment, identify, ambition, and
      prudence scales of the Hogan Personality Inventory; had higher scores on measures
      of coping by means of escape-avoidance, self-control, and active problem solving;
      and had greater externality in locus of control. Linear modeling with multiple
      logistic regression analyses indicated that greater feelings of perceived threat,
      coping by means of escape-avoidance, and coping by means of self-control were
      associated with a greater likelihood of being in the peritraumatic dissociation
      group, above and beyond age and exposure to stress. CONCLUSIONS: Rescue workers
      who are shy, inhibited, uncertain about their identity, or reluctant to take
      leadership roles, who have global cognitive styles, who believe their fate is
      determined by factors beyond their control, and who cope with critical incident
      trauma by emotional suppression and wishful thinking are at higher risk for acute
      dissociative responses to trauma and subsequent posttraumatic stress disorder.

PMID- 8659647
TI  - Intrauterine infection and why preterm prevention programs have failed.

PMID- 8659648
TI  - Family planning, sexually transmitted diseases, and the prevention of AIDS-
      divided we fail?

PMID- 8659649
TI  - The dominant role of driver behavior in traffic safety.

PMID- 8659650
TI  - Directive counseling on long-acting contraception.
AB  - National rates of unintended births are a major public health concern. The
      availability of highly effective long-acting contraceptives has prompted some
      public officials to promote the coercive use of these methods to reduce such
      problems as intergenerational poverty and child abuse. Broad-brush public
      policies that require long-term contraceptive use are unethical. However,
      persuasion to use these methods can be appropriate. One place for exerting
      ethically justified influence is in family planning counseling. The dominant
      nondirective counseling model, which excludes the possibility of vigorous
      persuasion, is overly rigid. Family planning professionals should develop
      practice protocols that permit and guide the exercise of directive counseling to
      use long-acting contraception.

PMID- 8659651
TI  - Reducing alcohol-impaired driving in Massachusetts: the Saving Lives Program.
AB  - OBJECTIVES: The purpose of this study ws to assess whether a community program
      begun in March 1988 that organized multiple city departments and private citizens
      could reduce alcohol-impaired driving, related driving risks, and traffic deaths
      and injuries. METHODS: Trends in fatal crashes and injuries per 100 crashes were
      compared in Saving Lives Program cities and the rest of Massachusetts from March
      1984 through February 1993. In annual roadside surveys conducted at randomly
      selected locations, safety belt use among occupants of 54577 vehicles and travel
      speeds of 118442 vehicles were observed. Four statewide telephone surveys (n =
      15188) monitored self-reported driving after drinking. RESULTS: In program cities
      relative to the rest of Massachusetts during the 5 program years in comparison
      with the previous 5 years, fatal crashes declined 25%, from 178 to 120, and fatal
      crashes involving alcohol decreased 42%, from 69 to 36. Visible injuries per 100
      crashes declined 5%, from 21.1 to 16.6. The proportions of vehicles observed
      speeding and teenagers who drove after drinking were cut in half. CONCLUSIONS:
      Interventions organized by multiple city departments and private citizens can
      reduce driving after drinking, related driving risks, and traffic deaths and
      injuries.

PMID- 8659652
TI  - Age-related changes in total and high-density-lipoprotein cholesterol in elderly
      Dutch men.
AB  - OBJECTIVES: This study investigated changes in total and high-density-lipoprotein
      cholesterol (HDL) concentrations with age and time in elderly men. METHODS: A
      cohort of men born between 1900 and 1920 from the Dutch town of Zutphen was
      examined in 1977 and 1978 (n = 571), 1985 (n = 885), 1990 (n = 555), and 1993 (n
      = 345). Linear regression analysis and random-effects models were used to assess
      cross-sectional and longitudinal age- and time-related changes in cholesterol
      concentrations. RESULTS: In both cross-sectional and longitudinal analyses, total
      cholesterol decreased by 0.04 mmol/L a year with age. The longitudinal change was
      observed in the entire population as well as in men who participated in all four
      examinations (n = 135) and in a subgroup of men who were free of common chronic
      diseases, were not on cholesterol-lowering medication or a prescribed diet, and
      rated themselves as being "healthy" (n = 64). HDL cholesterol did not change
      significantly with age neither on a cross-sectional nor on a longitudinal basis.
      CONCLUSIONS: Among elderly men, total cholesterol diminishes with age both on a
      cross-sectional and on a longitudinal basis; HDL cholesterol does not vary with
      age in any way.

PMID- 8659653
TI  - Aiding troubled employees: the prevalence, cost, and characteristics of employee
      assistance programs in the United States.
AB  - OBJECTIVES: Employee assistance programs (EAPs) are job-based programs designed
      to identify and assist troubled employees. This study determines the prevalence,
      cost, and characteristics of these programs in the United States by worksite
      size, industry, and census region. METHODS: A stratified national probability
      sample of more than 6400 private, nonagricultural US worksites with 50 or more
      full-time employees was contacted with a computer-assisted telephone interviewing
      protocol. More than 3200 worksites responded and were eligible, with a response
      rate of 90%. RESULTS: Approximately 33% of all private, nonagricultural worksites
      with 50 or more full-time employees currently offer EAP services to their
      employees, an 8.9% increase over 1985. These programs are more likely to be found
      in larger worksites and in the communications/utilities/transportation
      industries. The most popular model is an external provider, and the median annual
      cost per eligible employee for internal and external programs was $21.83 and
      $18.09, respectively. CONCLUSIONS: EAPs are becoming a more prevalent point of
      access to health care for workers with personal problems such as substance abuse,
      family problems, or emotional distress.

PMID- 8659654
TI  - The cost of prematurity: a case-control study of twins vs singletons.
AB  - OBJECTIVES: This study evaluated the extent to which morbidity and costs at birth
      were associated with plurality, gestational age, and birth-weight with a sample
      of twins from a large urban hospital. METHODS: Each twin infant was matched to
      two singleton infants (control [ctrl]-singletons) for payor status and race, and
      to one singleton infant (gestation [ga]-singleton) for payor status, race, and
      gestational age; after exclusion of infants who were transferred, the study
      population included 111 twins, 242 ctrl-singletons, and 106 ga-singletons. Data
      were stratified by five gestational categories and compared across study groups.
      Outcomes included birthweight, neonatal diagnoses, infant length of stay, infant
      costs per day, and total infant and total birth costs. RESULTS: Total birth costs
      ranged from $280,146 at 25 to 27 weeks to $9,803 at 39 to 42 weeks, decreasing
      with advancing gestation to means of $88,891 (twins), $43,041 (ga-singletons),
      and $9,326 (ctrl-singletons). Twins did not differ from either group of
      singletons in prematurity-related diagnoses, length of stay, or costs until after
      34 weeks' gestation. CONCLUSIONS: In this sample, prematurity, not plurality, was
      the predominant cost factor at birth. Compared with singletons, twins experienced
      increased morbidity and associated costs after 38 weeks' gestation.

PMID- 8659655
TI  - Prenatal hospitalization and compliance with guidelines for prenatal care.
AB  - OBJECTIVES: This study examined the relationship between compliance with the US
      Public Health Service guidelines for prenatal care and the rate of prenatal
      hospitalization. METHODS: For all women admitted to a Boston referral center
      during January and February 1993 with a pregnancy of at least 18 weeks gestation
      (n = 1400), a proportional hazards model was used to examine factors associated
      with prenatal hospitalization. RESULTS: Prenatal hospitalization occurred during
      248 (17.7%) pregnancies. The median length of stay for all prenatal admissions
      was 4 days; the medial total charge was $5667. Prior medical and obstetrical
      problems were strongly associated with prenatal hospitalization. After adjustment
      for age, race, and medical and obstetrical complications, women who received less
      than 70% of the prenatal care recommended were significantly more likely to be
      hospitalized (relative risk [RR] = 2.14, 95% confidence interval [CI] 1.50,
      3.06). CONCLUSIONS: Prenatal hospitalization is a common, costly complication of
      pregnancy. Because of its association with compliance with the Public Health
      Service guidelines for the content of prenatal care, prenatal hospitalization may
      be a sentinel indicator of inadequate prenatal care amenable to intervention.

PMID- 8659656
TI  - Pregnancy outcomes of US-born and foreign-born Japanese Americans.
AB  - OBJECTIVES: This study investigated the birth outcomes of Japanese Americans,
      focusing on the role of the mother's place of birth. METHODS: Single live births
      to US-resident Japanese American mothers (n = 37,941) were selected from the 1983
      through 1987 US linked live birth-infant death files. RESULTS: US-born mothers
      were more likely than foreign-born mothers to be less than 18 years old and not
      married, to start prenatal care early, and to more adequately use prenatal care.
      Infants of foreign-born Japanese Americans had a slightly lower risk of low
      birthweight.No significant differences were found between nativity groups for
      very low birthweight or neonatal, postneonatal, and infant mortality. The
      mortality rates of infants of US-born (6.2) and foreign-born (5.4) Japanese
      American women were below the US Year 2000 objective but still exceeded Japan's
      1990 rate (4.6). However, low-birthweight percentages of the US-born group (5.7%)
      and the foreign-born group (5.0%) were similar to that of Japan (5.5%).
      CONCLUSIONS: The infants of foreign-born Japanese-American women exhibited
      modestly better low-birthweight percentages than those of US-born Japanese
      Americans. This finding supports theories of the healthy immigrant.

PMID- 8659657
TI  - The risk of prematurity and small-for-gestational-age birth in Mexico City: the
      effects of working conditions and antenatal leave.
AB  - OBJECTIVES: This study examined the effect of working conditions, occupational
      stress, and antenatal leave on risk of small-for-gestational age and premature
      births in Mexico City. METHODS: Over a 3-month period, 2663 (96.2%) of 2767 women
      who gave birth at three major hospitals and worked at least 3 months during
      pregnancy were interviewed shortly after delivery. After the exclusion of
      multiple gestations and birth defects, 261 (10.0%) small-for-gestational-age and
      288 (11.0%) preterm births were identified. RESULTS: For small-for-gestational
      age births, working more than 50 hours a week (odds ratio [OR] = 1.59), standing
      more than 7 hours a day (OR = 1.40), and no antenatal leave (OR = 1.55) were
      associated with an increased risk. Women with no antenatal leave were also much
      more likely to give birth prematurely (OR = 3.04). CONCLUSIONS: In this study,
      arduous working conditions and lack of antenatal leave benefits were found to
      increase the risk of poor birth outcome in Mexican women. Enforcement of existing
      antenatal leave laws and provision of comparable benefits for the uninsured may
      reduce the incidence of small-for-gestational-age births and prematurity.

PMID- 8659658
TI  - The association between cesarean delivery and breast-feeding outcomes among
      Mexican women.
AB  - OBJECTIVES: This study examined the impact of cesarean section delivery on the
      initiation and duration of breast-feeding in the 1987 Mexican Demographic and
      Health Survey. METHODS: The subsample (n = 2517) was restricted to women whose
      delivery of their last-born children (aged 5 years and younger) was attended by a
      physician. Multivariate logistic regression was used to examine the association
      between cesarean section and likelihood of either not initiating breast-feeding
      or doing so for less than 1 month. Among women who breast-fed for 1 month or
      more, multivariate survival analysis was used to examine the relationship between
      cesarean section and breast-feeding duration. RESULTS: Cesarean section was a
      risk factor for not initiating breast-feeding (odds ratio [OR] = 0.64, 95%
      confidence interval [CI] = 0.50, 0.82) and for breast feeding for less than 1
      month (OR = 0.58, 95% CI = 0.37, 0.91) but was unrelated to breast-feeding
      duration among women who breast-fed for 1 month or more (OR = 0.97, 95% CI =
      0.86, 1.11). CONCLUSIONS: It is desirable to provide additional breast-feeding
      support during the early postpartum period to women who deliver via cesarean
      sections.

PMID- 8659659
TI  - Adverse pregnancy outcomes: differences between US- and foreign-born women in
      major US racial and ethnic groups.
AB  - OBJECTIVES: This study examined whether there were significant differentials
      between US-born and foreign-born women in risks of infant mortality, low
      birthweight, and preterm birth and whether these differentials, if they existed,
      varied across major US racial/ethnic groups. METHODS: Multivariate logistic
      regression was applied to national linked birth/infant death records for 1985
      through 1987 to estimate overall and ethnic-specific maternal nativity effects on
      pregnancy outcomes. RESULTS: Substantial maternal nativity differences in risks
      of infant mortality and low birthweight were found, with the magnitude of the
      nativity effect varying significantly across racial/ethnic groups. Overall,
      foreign-born status was associated with 7% and 20% lower risks of low birthweight
      and infant mortality, respectively. However, the reduced risk of adverse
      pregnancy outcome associated with immigrant status tended to be substantially
      larger for Blacks, Cubans, Mexicans, and Chinese than for other ethnic groups.
      CONCLUSIONS: Maternal nativity status, along with ethnicity, may serve as an
      important axis of differentiation in birth outcome studies. Further research
      needs to be conducted to assess the effects of behavioral, cultural, and
      psychosocial factors in explaining the nativity differentials observed here.

PMID- 8659660
TI  - Vaginal douching and reduced fertility.
AB  - OBJECTIVES: This study investigated douching and reduced fertility. METHODS: The
      monthly probability of conception for douchers and nondouchers was compared in a
      sample of 840 married, parous women in King County, Washington. Data on the
      number of months required to conceive were analyzed. RESULTS: In comparison with
      nondouchers, women who douched were 30% less likely to become pregnant each month
      they attempted pregnancy. This relationship remained after adjustment for
      covariates, and it could not be explained by women douching for medical reasons.
      The reduction was not related to the type of douching preparation used. Young
      women who douched had significantly greater reductions in monthly fertility than
      older women (50% reduction for women 18 to 24 years old, 29% reduction for women
      25 to 29 years old, and 6% reduction for women 30 to 39 years old). CONCLUSIONS:
      Douching was associated with reduced fertility. Further research is needed to
      determine whether the relationship is casual and, if so, to what extent it is
      mediated by pelvic infection. In the meantime, women should be informed that
      douching may have adverse effects.

PMID- 8659661
TI  - What proportion of multiple births are due to ovulation induction? A register
      based study in Italy.
AB  - OBJECTIVES: This study evaluated the increase in risk of multiple births
      associated with ovulation induction and calculated the proportion of multiple
      births attributable to this treatment. METHODS: Cases were 350 multiple births
      and controls were 737 single births enrolled from April 1993 to March 1994 in the
      Mercurio Project, an investigation of reproductive outcomes in Italy. RESULTS:
      Ovulation induction was used in 45 case births (12.9%) and 24 control births
      (3.3%); the adjusted odds ratio was 4.1 (95% confidence interval [CI] = 2.4,
      6.9). The odds ratio for triplet or higher order births was 72.2 (95% CI = 25.7,
      202.8). When unlike-sexed multiple births were considered, the odds ratio
      increased for twin births, but not for triplet or higher births. The highest odds
      ratios were found when ovulation induction was used with assisted reproduction.
      The proportion of multiple births attributable to ovulation induction was 9.7%
      overall, 5.4% for twin births, and 69.8% for triplet or higher births.
      CONCLUSIONS: Ovulation induction increases the risk of multiple births and has
      been responsible for the rise in the rate of triplet or higher order births in
      Italy in the last decade. Its indiscriminate and improper use should be avoided.

PMID- 8659662
TI  - Risk factors for hazardous substance releases that result in injuries and
      evacuations: data from 9 states.
AB  - This study was undertaken to determine risk factors associated with hazardous
      substance releases (at fixed facilities or during transport) that have public
      health consequences. Data from nine states with surveillance systems for such
      releases and their consequences were analyzed. Risk factors were determined for
      releases resulting in (1) injuries or (2) evacuations. Both outcomes were more
      likely to occur as a result of facility releases (odds ratio [OR] = 1.89, 95%
      confidence interval [CI] = 1.44, 2.47, for injuries; OR = 3.29, 95% CI = 2.28,
      4.74, for evacuations). Releases of ammonia, chlorine, and acids resulted in
      injuries and evacuations more frequently than releases of other substances.

PMID- 8659663
TI  - Risk factors for self-reported uterine fibroids: a case-control study.
AB  - To identify risk factors for uterine fibroids, a case-control design used to
      analyze data from control subjects enrolled in the Cancer and Steroid Hormone
      Study. Case patients were 201 women who reported a history of uterine fibroids,
      and control subjects were 1503 women without fibroids, individually matched by
      age to case patients. Reporting of fibroids was more frequent among premenopausal
      women, women who had frequent Papanicolaou (Pap) smears, women who used oral
      contraceptives and had infrequent Pap smears, and women with higher education.
      Reporting of fibroids was less frequent among women with a lower body mass index
      who were current or long-time smokers.

PMID- 8659664
TI  - Liability for managed care decisions: the Employee Retirement Income Security Act
      (ERISA) and the uneven playing field.
AB  - As managed care organizations expand their programs of quality assurance and
      physician evaluation, more medical malpractice lawsuits may be brought against
      managed care organizations on the ground that, like hospitals, they are legally
      responsible for negligent corporate acts that injure patients. However, the
      federal Employee Retirement Income Security Act (ERISA) shields managed care
      organizations from liability when they are part of an employee group health plan
      governed by ERISA. Unlike patients with other types of insurance, patients in
      ERISA health plans do not have a malpractice remedy for a managed care
      organization's negligence. A few federal appeals courts recently recognized that
      ERISA plans can be vicariously liable for their physicians' medical malpractice,
      but only if the physician is the plan's employee or agent. Yet ERISA still
      prohibits negligence claims against ERISA health plans for injuries resulting
      from denial of plan benefits, failure to use qualified physicians, utilization
      review, or improper plan administration. Current managed care operations do not
      neatly distinguish between administering benefits and controlling quality of
      care. Neither should the law. ERISA should be amended to provide employees with
      the same remedies that patients in non-ERISA plans enjoy.

PMID- 8659665
TI  - Prematurity as a public health problem: US policy from the 1920s to the 1960s.
AB  - During the 1920s and 1930s, a number of physicians created model premature infant
      stations in select hospitals, arguing that medicine could successfully treat
      premature infants, most of whom could be expected to live normal lives. Most
      hospitals and doctors, however, remained indifferent to the special medical needs
      of premature infants. Subsequently, public health officials, beginning in
      Chicago, took up the cause of the medical management of newborn premature
      infants, defining the problem and finding the resources for a community-wide
      solution. The latter included multiple, high-quality premature nurseries, infant
      transport, regionalization, and public financing. The "Chicago model" was adapted
      by many state and municipal departments of health, particularly after World War
      II, to create community-based programs, the largest of which was in New York
      City. As premature infant care became of greater interest to pediatricians and
      hospitals, in part because of the success achieved by public health officials,
      the earlier, prominent role of the latter was increasingly diminished and
      historically forgotten.

PMID- 8659666
TI  - De Madres a Madres: an access model for primary care.

PMID- 8659667
TI  - Improving access to prenatal care in Vermont.

PMID- 8659668
TI  - Decreasing premature Norplant removals among low-income recipients.

PMID- 8659669
TI  - Florida goes statewide with alcohol health warning signs.

PMID- 8659670
TI  - Local research and legal advocacy for the medically indigent in Orange County,
      California.

PMID- 8659671
TI  - A prison release program for HIV-positive women: linking them to health services
      and community follow-up.

PMID- 8659672
TI  - DDE and insufficient breast milk.

PMID- 8659673
TI  - Native Hawaiian mortality, 1980 and 1990.

PMID- 8659674
TI  - The need for adolescent health education and training among health professionals.

PMID- 8659675
TI  - The CDC's proposed revision of polio immunization policy: is it wise?

PMID- 8659676
TI  - Reduce drunk driving for everyone's sake.

PMID- 8659677
TI  - Estimating the prevalence of women with breast implants.

PMID- 8659678
TI  - Nonfatal injuries among US children.

PMID- 8659679
TI  - Evidence that cytochrome P-4502E1 contributes to ethanol elimination at low
      doses: effects of diallyl sulfide and 4-methyl pyrazole on ethanol elimination in
      the perfused rat liver.
AB  - The roles of cytochrome P-4502E1 and alcohol dehydrogenase (ADH) on ethanol
      (EtOH) hepatic elimination was examined in the perfused rat liver. EtOH
      concentration-time curves of outflow after instantaneous administration (0.46 mg)
      through the portal vein with or without perfusion of diallyl sulfide (DAS), a
      selective cytochrome P-450E1 inhibitor, and/or 4-methyl pyrazole (4-MP), a
      classical ADH inhibitor, were analyzed by the statistical moment analysis and the
      compartment dispersion model. Recovery ratios obtained by moment analysis
      significantly changed with perfusion of inhibitors (p < 0.01). Values of the
      hepatic volume of distribution and the relative dispersion were significantly
      higher by the perfusion of DAS and 4-MP (p < 0.01). In the two-compartment
      dispersion model, the partition ratio (K') and the first-order elimination
      constant (K0) were decreased significantly by DAS (p < 0.05). By the addition of
      4-MP, the blood volume of distribution (VB) and the backward partition rate
      constant (k21) were increased significantly (p < 0.05). K sigma values were
      decreased significantly to 0 (p < 0.001). The decrease of elimination rates by
      DAS and/or 4-MP shows the inhibition of metabolic pathways. The change of V beta
      and k21 caused by DAS and 4-MP indicates that EtOH taken into hepatic tissues was
      not metabolized and flowed out into the perfusates. Inhibition rates calculated
      from the efficiency number with addition of DAS and DAS + 4-MP were 40.7 and
      99.3%. Therefore, cytochrome P-4502E1 and ADH accounted for 40 and 60% of the
      hepatic EtOH elimination at low doses.

PMID- 8659680
TI  - Effect of the cytochrome P-450IIE1 genotype on ethanol elimination rate in
      alcoholics and control subjects.
AB  - We studied an influence of genetic polymorphisms in the cytochrome P-450IIE1
      (CYP2E1) gene on ethanol elimination rate in alcoholic patients and healthy
      subjects. The CYP2E1 genotype was determined by polymerase chain reaction
      restriction fragment length polymorphism method for 124 alcoholics and 54 healthy
      subjects. There was no significant difference in the gene frequency of CYP2E1
      between alcoholics and healthy control subjects. Blood ethanol concentrations in
      the 65 alcoholics on admission ranged from 0.32 to 4.22 mg/ml. In the patients
      with the c1/c2 genotype, the elimination rate was significantly correlated with
      blood ethanol concentration. In each of the three genotypes of CYP2E1, the
      patients were divided into three groups based on ethanol concentrations. The
      average of the ethanol elimination rate in the patients with c1/c2 having blood
      ethanol levels of > or = 2.5 mg/ml was significantly higher than the rates in the
      two other groups of c1/c2. When blood ethanol levels were > or = 2.5 mg/ml, the
      elimination rate in the patients with c1/c2 was significantly higher than that in
      those with c1/c1. Regardless of the CYP2E1 genotype, the elimination rate in the
      alcoholics was higher than that in the control subjects when blood ethanol levels
      were < 1.0 mg/ml. These results suggest the possibility that the c2 allele of
      CYP2E1 Influences the rate of ethanol elimination at high ethanol levels. The
      rate of ethanol elimination was independent of liver disorder judged by serum
      total bilirubin values.

PMID- 8659681
TI  - Problems in pharmacokinetic analysis of alcohol disposition: a trial of the
      Bayesian least-squares method.
AB  - The technical problems of the pharmacokinetic analysis of alcohol disposition
      were studied using the Michaelis-Menten elimination kinetic model. This model was
      defined by two forms of equations: differential and integrated, with the latter
      being derived by integration of the differential equation. We compared the
      parameter values, estimated by one-line curve-fitting, using these two equation
      forms. We concluded that, for the kinetic analysis of alcohol disposition, curve
      fitting with the differential equation was superior to that with the integrated
      equation. We also studied the methodological problems involved in one-line
      fitting. The ordinary least-squares (OLS) method was compared with the Bayesian
      least-squares (BLS) method. Correlation between the Vmax and beta (ethanol
      elimination rate) values, and between the Vmax and K(m) values was seen when the
      parameter values were estimated by the OLS method. These results suggested that
      one-line fitting by the OLS method was not adequate for Michaelis-Menten-type
      elimination kinetic analysis. BLS analysis resulted in no correlation between the
      estimated parameter values that did not change with the level of the dose. The
      BLS method seemed to be more useful than the OLS method for the estimation of
      individual pharmacokinetic parameter values.

PMID- 8659682
TI  - Metabolism of acetaldehyde to acetate by rat hepatic P-450s: presence of
      different metabolic pathway from acetaldehyde dehydrogenase system.
AB  - NADPH-dependent activity of acetaldehyde oxidation was investigated in microsomes
      by assaying [14C]acetic acid produced from [14C]acetaldehyde with ion-exchange
      column. Rat hepatic microsomes exhibited acetaldehyde oxidation activity in the
      presence of NADPH. This activity was induced 2-fold by the treatment of rats with
      ethanol. We designated this NADPH-dependent oxidation system as microsomal
      acetaldehyde-oxidizing system (MAOS), to distinguish from the NAD-dependent
      acetaldehyde oxidation system by acetaldehyde in mitochondria and cytsol. We
      further investigated essential enzymes contributing to MAOS activity.
      Acetaldehyde oxidation activity was investigated in eight forms of purified P-450
      in a reconstituted system. Cytochrome P-450 (CYP) 2E1 had the highest oxidation
      activity and CYP1A2 and CYP4A2 had the next highest activity. Other forms had low
      activity. To assess the contribution of these forms to MAOS activity, immunoblot
      was done. CYP2E1 was induced 2-fold by ethanol treatment, but CYP1A2 and CYP4A2
      were not reflecting the MAOS activity increased by ethanol treatment. These
      results suggest that CYP2E1 is the essential enzyme in the MAOS of rats.

PMID- 8659683
TI  - Acetaminophen metabolism in patients with different cytochrome P-4502E1
      genotypes.
AB  - Cytochrome P-450 (CYP) 2E1 is the major ethanol-oxidizing enzyme of the
      nonalcohol dehydrogenase metabolic pathway in the liver. Recently, the presence
      of genetic polymorphisms of this enzyme was confirmed. In this study, to clarify
      the influence of CYP2E1 genotype on alcohol metabolism, we analyzed acetaminophen
      metabolism in subjects with different CYP2E1 genotypes. In normal subjects, a
      half-life of acetaminophen from blood was the longest in type A (c1/c1) and was
      the shortest in type C (c2/c2). The elimination rate in type C was more than
      twice that of type A and type B (c1/c2). In type A, both half-life and
      elimination rate of acetaminophen were not different between patients with
      noncirrhotic alcoholic liver disease within 1 week after abstinence and in normal
      subjects. In one patient with minimal change, there were no differences in both
      half-life and elimination rate within 1 and 6 weeks after abstinence. On the
      other hand, in type B, half-life was shorter and the elimination rate was greater
      in alcoholic noncirrhotic patients within 1 week after abstinence than in
      alcoholic patients with type A and in normal subjects with type B. In type B,
      half-lives were shorter, and the elimination rates were greater in patients with
      alcoholic liver disease within 1 week after abstinence than 4 to 6 weeks after
      abstinence. These results suggest the possibility that alcohol metabolism in
      individuals with the c2 gene may be greater than those with the c1 gene, and that
      the induction of CYP2E1 by ethanol in type B may occur more markedly than that in
      type A, although the sample number is too small to obtain final conclusions.

PMID- 8659684
TI  - Association of restriction fragment-length polymorphisms in the alcohol
      dehydrogenase 2 gene with alcoholic brain atrophy.
AB  - Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. To
      investigate whether genetic polymorphism of alcohol-metabolizing enzymes
      [including alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)] was
      related to alcoholic brain atrophy, we determined restriction fragment-length
      polymorphisms of the ADH2 and ALDH2 genes in 77 male alcoholics. Computed
      tomography was used to determine the severity of brain atrophy. Digestion with
      MaeIII and MboII after polymerase chain reaction amplification showed that the
      ADH2(1) gene frequency was significantly higher in patients with brain atrophy
      than in those without brain atrophy (chi 2 = 9.274, p < 0.01), whereas no
      significant association was observed between brain atrophy and the ALDH2 gene
      Multivariate analysis (including age, total alcohol intake, liver cirrhosis, and
      ADH2 genotype) showed that the ADH2(1)/ADH2(1) genotype was associated with
      alcoholic brain atrophy. These findings suggest that the ADH2(1) allele may be
      associated with alcoholic brain atrophy.

PMID- 8659685
TI  - Analysis of CA repeats in first intron of class I ADH gene in Long-Evans Cinnamon
      rats developing fatal intoxication after ethanol intake.
AB  - The Long-Evans Cinnamon (LEC) rat is a mutant strain established from Long-Evans
      rats that displays spontaneous hepatitis and liver cancer. We previously
      demonstrated that LEC rats died of acute ethanol intoxication after being fed a
      liquid diet containing 5% ethanol. Furthermore, we found that both alcohol
      dehydrogenase (ADH) and aldehyde dehydrogenase activities were remarkably
      suppressed in the liver of LEC rat, compared with Wistar rats. In the present
      study, we further investigated ethanol metabolism in the non-ADH pathway and what
      caused the decrease of liver ADH activity in LEC rats. Blood ethanol
      concentration 5 hr after intraperitoneal administration of ethanol in LEC rats
      was higher than in the Wistar rats, indicating that ethanol oxidation was
      impaired in LEC rats. The expression of liver cytochrome P-450IIE1 in the LEC rat
      was as much as that in Wistar rats. Regarding decreased ADH activity in the liver
      of LEC rats, we examined an alternating purine-pyrimidine (CA) repeat-length
      polymorphism in the first intron of a class I ADH gene that would play a role in
      altering ADH activity. A polymerase chain reaction method was used to amplify the
      CA repeat in the first intron of this class I ADH gene, a nine CA repeat
      insertion and a point mutation were detected in LEC rats. These results suggest
      that this alternating sequence would modify transcription of the class I ADH gene
      in LEC rats. Thus, LEC rats have abnormal ethanol metabolism in the ADH pathway.

PMID- 8659686
TI  - Effects of cimetidine on blood ethanol levels after alcohol ingestion and genetic
      polymorphisms of sigma-alcohol dehydrogenase in Japanese.
AB  - Administration of cimetidine, an H2-receptor antagonist increases blood alcohol
      concentrations. This has been attributed to decreased gastric first-pass
      metabolism of ethanol caused by cimetidine's inhibitory effect on gastric alcohol
      dehydrogenase (sigma-ADH) activity. Molecular studies on sigma-ADH showed that a
      point mutation might occur at position 287 (G --> T) of the sigma-ADH gene in
      Japanese deficient type of sigma-ADH activity. To clarify the relationship
      between first-pass metabolism of ethanol and polymorphism of sigma-ADH, we
      analyzed the nucleotide sequence at positions 287 and 294 of sigma-ADH in 11
      individuals who were administered ethanol orally before and after treatment with
      cimetidine. Higher blood ethanol levels after cimetidine administration were
      found in 4 of 11 cases (group A), whereas high blood ethanol levels were observed
      in 7 of 11 cases (B group), irrespective of cimetidine administration. Genetic
      polymorphisms at position 287 and 294 were not observed in all subjects. Even in
      59 Japanese men with various alcoholic liver diseases, no polymorphisms at
      position 287 were observed by restriction-length polymorphisms with Avail
      digestion after polymerase chain reaction.

PMID- 8659688
TI  - Evaluation of ethanol on gastric epithelial restoration in vitro.
AB  - Ethanol exerts damaging effects on gastric mucosa and delays ulcer healing. To
      investigate the effect of ethanol on the wound repairing process, we used a wound
      repair model using primary cultured gastric mucosal cells. A confluent monolayer
      gastric mucosal cell sheet consisting mainly of mucous cells was wounded to make
      a cell-free area of constant size. Cell-free area was restored with time after
      wounding and monitored every 12 hr using a computer image analyzer to observe
      epithelial cell restoration quantitatively in the presence and absence of ethanol
      (2.0%). It was found that, although the control wound was completely repaired in
      36 to 48 hr, the group treated with 2.0% ethanol showed a significant delay of
      repair. In the control, 5-bromodeoxyuridine-positive cells appeared around the
      wound in 24 to 36 hr. In contrast, the group treated with 2.0% ethanol showed no
      5-bromodeoxyuridine-positive cells during the experiment. In conclusion, 2.0%
      ethanol retarded the repair of gastric mucosal restoration by inhibiting the
      initial gastric cell migration, followed by inhibition of proliferation of cells.

PMID- 8659687
TI  - Changes in GABAA receptor function and cross-tolerance to ethanol in diazepam
      dependent rats.
AB  - Changes in gamma-aminobutyric acidA (GABAA) receptor function and their relation
      to cross-tolerance to ethanol (EtOH) were studied in diazepam (DZP)-dependent
      rats. Physical dependence on DZP was induced in male Fischer rats by using the
      drug-admixed food method. The 38Cl- influx into cerebral cortical
      synaptoneurosomes induced by 10 microM GABA in DZP-withdrawn rats was
      significantly increased, compared with control and DZP-tolerant rats. Although
      enhancement of GABA-dependent 38Cl- influx by the addition of EtOH and
      flunitrazepam (FZ) was recognized in the control, there was no such effect of
      EtOH or FZ in the DZP-tolerant animals. On the other hand, GABA-dependent 38Cl-
      influx was enhanced by FZ in the withdrawn group. The addition of picrotoxin and
      bicuculline inhibited GABA-dependent 38Cl- influx in each group. The stimulatory
      effect of FZ on GABA-dependent 38Cl- influx was inhibited by the addition of Ro
      15-1788 in the control group. However, such an inhibitory effect was not observed
      in the withdrawn group. The antagonistic effect of Ro 15-4513 on EtOH stimulation
      of GABA-dependent 38Cl- influx observed in the control was not recognized in the
      withdrawn group. In a [3H]FZ assay of binding to benzodiazepine (BZ) receptors,
      Bmax values were significantly increased in DZP-withdrawn animals, but decreased
      in the DZP-tolerant group, compared with the control. When [3H]muscimol binding
      was examined, the Kd of high-affinity sites of the GABAA receptor in withdrawn
      rats was significantly lower than in the control. In low-affinity binding sites,
      the values of Kd and Bmax were significantly decreased, compared with those in
      the control. The present study indicates that GABAergic transmission involving
      the regulation of GABA-dependent chloride channels is altered in DZP-dependent
      rats. Alterations of the GABAA/BZ/chloride channel complex function may be
      related to the cross-tolerance between BZ and EtOH.

PMID- 8659689
TI  - Effect of vitamin E deficiency on inhibition of liver regeneration by long-term
      administration of alcohol.
AB  - The effects of vitamin E (VE) deficiency on liver regeneration suppressed by long
      term administration of alcohol were studied. Male rats were divided into two
      groups: the alcohol group and the control group. In addition, each group was
      subdivided into two groups according to the presence or not of VE. Altogether,
      four groups were provided: a group maintained on the VE-deficient alcohol diet
      (group EA), a group maintained on the VE-deficient control diet (group EC), a
      group maintained on the ordinary alcohol diet (group A), and a group maintained
      on the ordinary control diet (group C). After pair-feeding for 6 weeks, partial
      hepatectomy was performed to determine the omithine decarboxylase (ODC) activity,
      polyamine levels, lipid peroxide levels, and DNA synthesis, DNA synthesis at 24
      hr after partial hepatectomy was suppressed significantly in the alcohol
      administration group, regardless of the presence or not of VE DNA synthesis at 48
      hr after partial hepatectomy tended to show low values in group EA, compared with
      group A. As for the hepatic ODC activity, group EA showed the lowest value at 4
      hr after partial hepatectomy. Of polyamines, the putrescine level in group EA at
      4 hr after partial hepatectomy was significantly low, compared with the other
      three groups. The levels of spermidine and spermine decreased by long-term
      administration of alcohol, but the effect of VE deficiency was not found. The
      lipid peroxide level increased significantly in the VE-deficient diet
      administration group, but the effect of alcohol administration was not found.
      These results suggested that the decrease in putrescine after ODC suppression by
      VE deficiency in addition to the decrease in spermidine and spermine caused by
      long-term alcohol administration were concerned with suppression of DNA synthesis
      later.

PMID- 8659691
TI  - Abnormality in membrane fatty acid compositions of cells measured on erythrocyte
      in alcoholic liver disease.
AB  - It has been proven that the fatty acids of esterified phospholipids in the cell
      membrane play an important role in membrane fluidity. Our previous in vitro
      experiment indicated that the impairment of erythrocyte membrane fluidity might
      be largely because of the change in fatty acids. The aim of this study is to
      clarify changes of cell membrane fatty acids in more detail in relation to
      various stages and pathology of alcoholic liver disease. For the analysis,
      erythrocyte membranes were exploited on the assumption that their fatty acid
      compositions may be similar to those of other organs. In alcoholic liver disease,
      unsaturated fatty acids in the erythrocyte membrane decreased and saturated fatty
      acids increased. Consequently, the unsaturated fatty acid/saturated fatty acid
      ratio decreased significantly. When fractions of saturated fatty acids were
      studied, myristic acid (C14:0) increased markedly in the alcoholic group, and the
      increase was striking particularly in the cases of alcoholic hepatitis
      concurrently with hemolysis. Palmitic acid (C16:0) also tended to increase in the
      alcoholic liver disease group. A longer chain saturated fatty acid, stearic acid
      (C18:0), showed a moderate but significant increase in the alcoholic fatty liver
      and hepatic fibrosis group, but it decreased significantly in the alcoholic liver
      cirrhosis, as with the finding in viral liver cirrhosis. As with unsaturated
      fatty acids, linoleic acid (C18:2), arachidonic acid (C20:4), and eicosapentanoic
      acid (C20:5) decreased significantly. The arachidonic acid/linoleic acid ratio,
      which indicates microsomal elongation activity of liver cells, was found to be
      broadly distributed. No significant change was found in each group of alcoholic
      liver disease. However, the cases showing a decrease in this ratio had severe
      hepatic dysfunction concurrently. Thrombogenic Index, serving as an indicator for
      fatty acids in food, and that is concerned with formation of thrombus, was
      studied, using fatty acid fractions of the erythrocyte membrane. The index was
      significantly increased in alcoholic liver disease. It was suggested that the
      chronic alcohol intake and the resultant liver diseases might enhance the
      abnormality of the membrane fatty acid composition. These changes may affect cell
      membrane fluidity and eventually metabolic functions of the cell.

PMID- 8659690
TI  - Identification of cholesta-3,5-dien-7-one by gas chromatography-mass spectrometry
      in the erythrocyte membrane of alcoholic patients.
AB  - Lipids and oxidized lipids were analyzed by gas chromatography-mass spectrometry
      in the erythrocyte membranes of alcoholic and control subjects. Cholesta-3,5-dien
      7-one and cholesta-trienes were detected in alcoholic samples examined, but not
      in significant amounts in controls. Levels of polyunsaturated fatty acids
      (arachidonic acid, 20:4; docosahexaenoic acid, 22:6; and docosatetraenoic acid,
      22:4) in alcoholic samples declined significantly, whereas cholesta-3,5-dien-7
      one levels increased. A high level of total bilirubin was observed in most
      patients. A possible mechanism of the accumulation of cholesta-3,5-dien-7-one in
      the erythrocyte membrane of alcoholics is discussed.

PMID- 8659692
TI  - Effects of long-term alcohol intake on ADP ribosylation in rat liver plasma
      membranes.
AB  - Mono-ADP-ribosylation, In which the ADP-ribosyl moiety is transferred from NAD to
      an acceptor protein, is one of the important posttranslational modifications of
      cellular proteins. Because mounting evidence suggests significant biological
      roles of this reaction in transmembrane signal transduction and other cell
      metabolic reactions, we assessed how long-term alcohol intake alters toxin
      catalyzed- and endogenous mono-ADP-ribosylation in the liver of a rat model. We
      first found that thiol-preactivated cholera toxin-catalyzed ADP-ribosylation of
      the alpha-subunit of the stimulatory GTP-binding protein was enhanced after long
      term alcohol intake. Unexpectedly, but interestingly, this enhancement was not
      accompanied by a concomitant increase of cholera toxin-catalyzed stimulation of
      the adenylate cyclase activity. We also found that long-term alcohol intake
      remarkably enhanced endogenous mono-ADP-ribosylation of a 58 kDa protein in
      plasma membranes. Thus, long-term alcohol intake stimulated endogenous, as well
      as, toxin-catalyzed mono-ADP-ribosylations. Characterization of the 58 kDa
      protein may uncover pathophysiological roles of this interesting phenomenon in
      alcohol-induced liver damage.

PMID- 8659693
TI  - Detection of activity in the conditioned medium of ethanol-treated HepG2 cells
      which stimulates collagen synthesis in IMR-90 cells.
AB  - Hepatic fibrosis often occurs in alcoholic liver diseases without accompanying
      tissue necrosis or inflammation. However, the precise mechanism of this fibrosis
      has not been fully clarified. In the present study, using the hepatoblastoma cell
      line HepG2 as a model for hepatocytes, we identified a factor that stimulates
      collagen synthesis of fibroblasts in a conditioned medium of HepG2 cells after
      treatment with ethanol. Type 1 procollagen peptide (PIC) in a culture of human
      fibroblast IMR-90 markedly increased after incubation with the conditioned medium
      of ethanol-treated HepG2 cells. The stimulating activity on the production of PIC
      by IMR-90 remained after the dialysis and evaporation of the conditioned medium
      of HepG2 cells, indicating this factor was not as volatile from low molecular
      substances such as acetaldehyde, acetate, or lactate. The activity of this factor
      diminished with heat or trypsin treatment. A gel chromatographic analysis
      disclosed that the molecular weight of this factor was approximately 8000 Da.
      These results suggest that a polypeptide factor secreted from HepG2 cells by
      treatment with ethanol stimulates collagen synthesis of fibroblasts.

PMID- 8659694
TI  - Effect of chronic ethanol feeding on Kupffer cell-mediated antitumor cell
      activity.
AB  - We have previously reported that the Kupffer cell has antitumor activity through
      mitochondrial damage to tumor cells by nitric oxide production. In this study,
      the effect of chronic ethanol feeding on antihepatoma cell activity of the
      Kupffer cell was examined in rats. Male rats of the Wistar strain were fed
      ethanol chronically for 8 weeks by liquid diets. Kupffer cells were isolated from
      the control rat or the ethanol-fed rat, and cocultured with AH 70 cells, a rat
      hepatoma cell line. Fluorescence of rhodamine 123 or propidium iodide was
      observed as indicators of the mitochondrial damage or cell membrane injury,
      respectively, by a laser scanning confocal microscopy. Mitochondrial damage of AH
      70 cells as indicated by reduction of rhodamine 123 fluorescence was smaller by
      the coculture with Kupffer cell from the ethanol rat than that from the control.
      Cell membrane barrier dysfunction of AH 70 cell was less frequently observed with
      the Kupffer cell from ethanol-fed rats. A metabolite of nitric oxide (nitrite and
      nitrate) was less in the cultured medium with the ethanol Kupffer cell than with
      the control Kupffer cell. Ca2+ mobilization, which induces inducible nitric oxide
      synthase and observed by the fluorescence of fluo-3, in Kupffer cells cocultured
      with AH 70 cells was suppressed in ethanol-fed rats. These result suggests that
      chronic ethanol feeding suppresses antitumor cell activity of Kupffer cell
      through the impairment of Ca2+ mobilization and nitric oxide production.

PMID- 8659695
TI  - Effect of chronic ethanol feeding on nitric oxide synthesis by rat Kupffer cells.
AB  - Kupffer cells contribute to the important role of the liver defense mechanism
      through nitric oxide (NO) production. In this study, the effect of chronic
      ethanol administration on the ability of Kupffer cells to synthesize and release
      NO was investigated after stimulation with lipopolysaccharide (LPS). Male Wistar
      rats were chronically fed ethanol for 8 weeks according to the method described
      by DeCarli and Lieber et al. (J Nutr.91:331-336, 1967). Kupffer cells were
      isolated and cultured with LPS (1 micrograms/ml) for 24 hr. The levels of nitrite
      and nitrate, metabolites of NO, were determined in the culture medium, NO
      synthase (NOS) activity in Kupffer cells was determined by the method that
      measures conversion of [14C]arginine into [14C]citrulline. In control rats, a
      significant increase of nitrite and nitrate levels in culture medium was observed
      after LPS treatment. The magnitude of this increase was significantly smaller in
      chronic ethanol-fed rats. When the activity of NOS was determined, inducible NOS
      (iNOS) activity was higher than that of constitutive NOS, and LPS administration
      produced a significant elevation of iNOS activity in both control and chronic
      ethanol-fed rats. However, the elevation of iNOS activity by LPS stimulation was
      diminished by chronic ethanol administration. Distribution of iNOS in Kupffer
      cells as determined by an immunofluorescence method using a laser scanning
      confocal image system showed a lower expression of iNOS in chronic ethanol-fed
      rats even in the presence of LPS. These results demonstrate that the excessive
      production of NO by increased iNOS activity in Kupffer cells is diminished by
      chronic ethanol administration.

PMID- 8659696
TI  - Hepatic saturation mechanism of ethanol: application of mathematical models to
      ethanol outflow profiles in the perfused rat liver.
AB  - The saturation mechanism of hepatic ethanol (EtOH) elimination was studied in the
      perfused rat liver. EtOH outflow profiles after the instantaneous administration
      of 3 (mg/ml) x 0.4(ml), 12 x 0.1, 24 x 0.1, and 3 x 0.1 mg (as a dose
      concentration x a volume) through the portal vein were analyzed by the
      statistical moment analysis and mathematical models (i.e., dispersion models).
      Results for 3 x 0.1 and 12 x 0.1 mg doses by moment analysis were similar. This
      demonstrated that the elimination exhibits linear kinetics. Recovery ratio and
      hepatic volume of distribution for 3 x 0.4 and 24 x 0.1 mg were larger than those
      for 3 x 0.1 and 12 x 0.1 mg doses and were similar. Kinetics after administration
      of 3 x 0.4 and 24 x 0.1 mg may be nonlinear. A difference in the relative
      dispersion (CV2) obtained by moment analysis between 3 x 0.4 and 24 x 0.1 mg
      doses indicated different properties of the nonlinear elimination kinetics. There
      were no differences in all the parameters in the one-compartment dispersion model
      between 3 x 0.4 and 24 x 0.1 mg doses. In the two-compartment dispersion model,
      there were differences in the blood volume (VB) and the forward partition rate
      constant (k12) between 3 x 0.4 and 24 x 0.1 mg (p < 0.05), whereas the
      elimination rate constant (k sigma) and the dispersion number values for these
      doses were similar. These findings demonstrated that there is difference in the
      no-equilibrium process between 3 x 0.4 and 24 x 0.1 mg doses. Therefore, we
      suggest that the continuous EtOH input into the liver causes the saturation of
      enzyme pathways and the change of the nonequilibrium process.

PMID- 8659697
TI  - Role of albumin and high-density lipoprotein as endotoxin-binding proteins in
      rats with acute and chronic alcohol loading.
AB  - In the present study, the role of albumin and high-density lipoprotein (HDL) as
      endotoxin (Et)-binding proteins in chronically alcohol-fed rats was studied. In
      acute ethanol-loaded rats, the Et clearance in the blood was slightly prolonged,
      and the amount of albumin and HDL- bound Et in the blood was markedly increased.
      In chronic ethanol-loaded rats, the Et clearance was significantly faster than
      that in the control, and HDL-bound Et was increased. In the chronic ethanol-fed
      rats with an additional 5 g/kg body weight of ethanol load, the Et clearance was
      much prolonged, and blood tumor necrosis factor and ALT was elevated, when HDL
      bound Et was not further increased. Et-binding capacity of total proteins,
      albumin, and HDL in the hepatocyte culture medium were increased when the Kupffer
      cells were preincubated in the medium containing ethanol, and the resultant
      culture supernatant was added to the hepatocyte culture system. In the culture
      experiment in the chronic ethanol-loaded rats, such increases were not observed.
      These results suggest that the increase in Et-binding capacity of HDL and albumin
      may serve as a protective mechanism against Et in chronic ethanol-loaded rats. An
      addition of high-dose ethanol to these rats may lead to impaired Et binding and
      inactivation, which may finally result in increased endotoxicity.

PMID- 8659699
TI  - Usefulness of technetium-99m-galactosyl human serum albumin liver scintigraphy
      for assessment of severity of alcoholic hepatitis.
AB  - We performed a liver scintigraphy using technetium-99m diethylene
      triaminepentaacetic acid-galactosyl human serum albumin (99mTc-GSA), which images
      the functional liver mass through its binding to the specific receptor
      asialoglycoprotein receptor in patients with severe alcoholic hepatitis. Receptor
      index (LHL 15) was significantly lower in patients with alcoholic hepatitis,
      compared with controls with normal liver. Difference in the isotope uptake
      patterns between liver and heart varied according to the severity of liver
      disease, and made it possible to categorize 5 grades. Grading score could
      discriminate between the eventual outcome of the patients. Furthermore, single
      photon emission computed tomography showed the variable uptake patterns in the
      hepatic lobule, wherein there were no evident findings in macroscopic view at
      autopsy. The results of this study show the usefulness of 99mTc-GSA scintigraphy
      in the evaluation and prognosis of alcoholic hepatitis.

PMID- 8659698
TI  - Ethanol-induced oxidative stress in the liver.
AB  - Oxygen stress is well recognized to be a key step in the pathogenesis of ethanol
      associated liver injury. Ethanol administration induces an increase in lipid
      peroxidation either by enhancing the production of oxygen-reactive species and/or
      by decreasing the level of endogenous antioxidants. Numerous experimental studies
      have emphasized the role of the ethanol-inducible cytochrome P-450 in the
      microsomes, as well as the molybdo-flavoenzymes xanthine oxidase in the cytosol.
      This review shows the putative role of ethanol-induced disturbances in iron
      metabolism in relation to iron as a prooxidant factor. Ethanol administration
      also affects the mitochondrial free radical generation. Although many previous
      studies suggest a role for active oxygens in ethanol-induced mitochondrial
      dysfunction in hepatocytes, the detailed mechanism of ethanol-induced oxidative
      stress on mitochondria remains to be clarified further. Studies of our laboratory
      using a confocal laser scanning microscopic system strongly suggest that active
      oxidants produced during ethanol metabolism modulate mitochondrial energy
      synthesis in isolated and cultured hepatocytes. In addition, our investigations
      implicate endogenous glutathione-glutathione peroxidase system and catalase as
      important antioxidants and cytoprotective machinery in the hepatocyte
      mitochondria exposed to ethanol. The fluorographic investigations using the
      confocal laser scanning microscopy may be useful to extend our knowledge and
      provide a new view about ethanol-associated oxidative stress and metabolic
      changes in hepatocytes.

PMID- 8659700
TI  - Roles of alcohol, hepatitis virus infection, and gender in the development of
      hepatocellular carcinoma in patients with liver cirrhosis.
AB  - To assess the interaction of alcohol, hepatitis C virus (HCV), and hepatitis B
      virus (HBV) infection in hepatocarcinogenesis, we prospectively observed 449
      patients with liver cirrhosis (LC) who presented to our outpatient clinics in 1
      month; 164 patients with habitual drinking [alcoholic liver-liver cirrhosis (AL
      LC)] who had taken > 72 g alcohol/day (HCV-positive 81 cases: HCV + AL; HCV
      negative 83 cases: AL); 176 patients with HCV infection, but without alcohol
      intake: 34 patients with HBV infection: 6 patients with HCV and HBV coinfection;
      and 82 patients with liver diseases from other etiologies, such as primary
      biliary cirrhosis. In the HCV group, the cumulative occurrence rate of
      hepatocellular carcinoma (HCC) was 9%, 18%, and 23% in the first, second, and
      third years, respectively. In the HCV + AL group, that was 13%, 17%, and 28%,
      respectively. There was no difference in the HCC occurrence rate between the two
      groups. In the AL group, the cumulative HCC occurrence rate was only 1% during
      the observation period of 3 years. The occurrence rate was significantly lower in
      the AL group, compared with the HCV and the HCV + AL groups. In the HBV group,
      the cumulative occurrence rate of HCC during the observation period of 3 years
      was 17%, which was similar to that of the HBV + AL group, 14%. We also examined
      some other variables that might be related to the development of HCC. The
      cumulative occurrence rate of HCC in male patients was 31%, whereas that was 18%
      in female patients. In the HCV group, there was a significant increase of HCC
      occurrence rate in male patients. In contrast, no difference was observed in the
      HCC occurrence rate between male and female patients in the HBV group. The
      present study suggests that alcohol alone may not be an independent risk factor
      for HCC, nor does it accelerate HCC development in LC patients with HCV and HBV
      infection during the prospective observation of 3 years.

PMID- 8659701
TI  - Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular
      carcinoma--its relationship to alcohol drinking and the age of transfusion.
AB  - Alcohol drinking has been reported to be an important factor that modulates the
      development and prognosis of chronic hepatitis B; however, little is known about
      an interrelationship between alcohol intake and the progression of chronic
      hepatitis C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We
      attempted to clarify this interrelationship in patients with hepatitis C and
      history of blood transfusion. Thirty LC and 85 HCC patients were enrolled. In
      patients with LC, no significant correlation was observed between the amount of
      alcohol intake and the period from transfusion to diagnosis. The period from
      transfusion to diagnosis in HCC patients with alcohol intake > or = 46 g/day and
      < 46 g/day were 26 +/- 6 and 31 +/- 9 years, respectively, resulting in a
      significant difference (p < 0.05). The period from transfusion to diagnosis of LC
      and/or HCC showed significant negative correlation with the age of transfusion (r
      = 0.82, Y = -0.67X + 48.0, p < 0.01; r = 0.76, Y = -0.70X + 54.1, p < 0.001,
      respectively). This correlation was also observed in patients with HCC,
      regardless of the amount of alcohol intake. In conclusion, these data suggest
      that alcohol drinking might be an important factor that promotes an occurrence of
      HCC in patients with hepatitis C, and that hepatitis C virus infection in the
      elderly promotes development of liver disease via LC to HCC.

PMID- 8659702
TI  - Evaluation of the acrosome in oligozoospermic patients by simplified triple stain
      technique.
AB  - The human acrosome, especially the acrosome reaction, is an important parameter
      for evaluation of sperm function. By histochemical staining, the acrosome is
      visualized at the light microscopic level. However, a high number of cells are
      lost due to the multiple centrifugation steps that are required for preparation
      of spermatozoa. In the present study, semen samples from oligozoospermic patients
      were stained by an improved method. Compared to the conventional triple-stain
      technique, optimal staining of the acrosome and a lower number of cells lost
      during sperm preparation were observed (P<0.025). Differences in the percentage
      of live acrosome-reacted spermatozoa were not statistically significant.

PMID- 8659703
TI  - Serum alpha-immunoreactive inhibin in males with renal failure, under
      haemodialysis and after successful renal transplantation.
AB  - Serum alpha-immunoreactive inhibin was evaluated in 16 male renal transplant
      recipients with stabilized renal function of mean age 38.5 +/- 10.7 years and was
      compared to that in sex- and age-matched 17 haemodialyzed patients; 10 patients
      with chronic renal failure and 26 healthy normal men (controls). Serum LH, FSH,
      prolactin and testosterone were also measured simultaneously, in the same
      samples. In renal transplant recipients, inhibin was found significantly higher
      than that in controls (P<0.001), 25% however of the values were in the normal
      range. In contrast, all haemodialyzed patients showed highly elevated inhibin
      values of inhibin were also highly elevated compared to those in normals. A
      negative correlation was noticed between inhibin and FSH only in controls (r(s) =
      -0.610, P<0.005). In renal transplant recipients, inhibin showed a strong
      correlation with serum creatinine (sCr) (r(s) = 0.710, P<0.008), while in the
      case of graft rejection the rise of sCr was immediately followed by a parallel
      increase of inhibin. In conclusion, the highly elevated inhibin in uraemic men
      not improved by haemodialysis and persistent after successful renal
      transplantation, might be implicated in the pronounced hypergonadotropic
      hypogonadism of haemodialyzed patients and the remaining dysfunction of
      hypothalamic-pituitary-testicular axis in renal transplant recipients.

PMID- 8659704
TI  - Response of testicular macrophages to EDS-induced Leydig cell death.
AB  - The response of testicular macrophages to massive Leydig cell death was studied
      by the administration of the specific Leydig cell cytotoxic ethylene dimethane
      sulphonate (EDS) to sham-operated (SO), short-term (STHX), and long-term (LTHX)
      hypophysectomized rats. EDS-killed Leydig cells showed the morphological features
      of the programmed cell death or apoptosis. A 2-fold increase in the number of
      macrophages was found on days 1-2 after treatment in both SO and STHX rats, and
      dead Leydig cells were completely eliminated by day 3 after treatment. Otherwise,
      in LTHX rats, there was a delay in the increase in the number of macrophages, and
      EDS-killed Leydig cells remained in the testicular interstitium for several days.
      These results indicate that the phagocytic capacity of the macrophage population
      was diminished in hypophysectomized rats, and particularly after long-term
      hypophysectomy.

PMID- 8659705
TI  - Acute lymphoblastic leukaemia in rats induces pathomorphological changes in germ
      cells.
AB  - Concern about the reproductive potential of long-term survivors of acute
      lymphoblastic leukaemia (ALL) prompted an investigation into the impact of the
      disease on spermatogenic cells. Using rats as a model, histological,
      immunocytochemical and electron microscopic analysis was applied to investigate
      changes in the seminiferous epithelium. In rats transplanted with leukaemic cells
      at early puberty, degenerate primary spermatocytes and spermatids were prevalent
      within stage VIII tubules. Electron microscopically, step 8 spermatids showed
      acrosomal abnormalities and nuclear contour distortion. In the distorted step 9
      spermatids, the microtubules of the manchette were abnormally oriented or
      deficient. Antitubulin antibody staining was reduced in elongating spermatids in
      the group transplanted with leukaemic cells at early puberty but was not observed
      in the older leukaemic group. Step 13 spermatids showed extracted chromatin and
      degenerate step 19 spermatids were occasionally found. Similar but less severe
      changes were seen in the group of rats transplanted with leukaemic cells at late
      puberty. We conclude that germinal cell damage induced by ALL is dependent on the
      developmental maturity of the seminiferous epithelium. The present findings are
      of particular importance when interpreting the impact of anticancer
      chemotherapeutics on germinal cells in patients with ALL.

PMID- 8659706
TI  - Chromatin condensation in cat spermatozoa during epididymal transit as studied by
      aniline blue and acridine orange staining.
AB  - Chromatin stability and DNA-resistance to acidic denaturation was evaluated by
      acidic aniline blue and acridine orange staining of cat sperm from different
      regions of the epididymis. The results were related to conventional sperm
      parameters. The percentage of aniline blue-stained spermatozoa (persisting
      histones) decreased significantly from the caput to the cauda region (31.8% and
      7.8%, respectively; P<0.0001). The percentage of stained heads of cauda sperm was
      much lower in populations of morphologically normal forms than in those with
      abnormal forms (4.1% and 13.8%, respectively, P<0.0001). Among spermatozoa with
      abnormalities, the percentage of stained heads was significantly higher in cells
      with head abnormalities than in sperm with only tail abnormalities (87.1% and
      10.3%, respectively; P>0.0001). With acridine orange fluorescence staining, 86.5%
      of cauda epididymal region (51.1%) to the cauda epididymal region (86.5%). The
      percentage of cauda epididymal sperm with normal condensed chromatin was neither
      linked to testicular sperm count, motility nor to age of the cats. The parameter
      of chromatin condensation and stability can be a valuable index of sperm quality,
      reflecting the possible disorders of spermatogenesis and epididymal sperm
      maturation, frequently observed in feline species.

PMID- 8659707
TI  - The effect of the antisperm auto-antibody-bound sperm on in vitro fertilization
      outcome.
AB  - To evaluate the effects of antisperm auto-antibody-bound sperm on the outcome of
      in vitro fertilization-embryo transfer (IVF-ET), 160 infertile couples undergoing
      treatment by in vitro fertilization were recruited in this study. In the study
      group (11 couples, 15 cycles), the male partners were positive for antisperm
      autoantibodies determined by immunobead test (IBT). In the control group (149
      couples, 152 cycles), the men had no such antibodies. The percentages of
      fertilization rate, cleavage rate and pregnancy rate of the study group and
      control group wer 75.0 +/- 5.2% vs. 69.3 +/- 2.4%; 82.8% +/- 3.7% and 6.7% +/-
      11.8%, respectively. There were no significant differences in in vitro region,
      type and/or percentage of sperm-bound antibodies also had no effect on the in
      vitro fertilization outcome. In conclusion, in vitro fertilization-embryo
      transfer is not significantly affected by antisperm autoantibody-bound sperm
      determined by immunobead test.

PMID- 8659708
TI  - Effect of intratesticular administration of oxytocin on testicular
      steroidogenesis in immature rats.
AB  - The possible physiological role of testicular oxytocin in testicular
      steroidogenesis was studied in immature rats. In 5-, 9-, and 25-day-old animals
      one of the testes was injected with 20, 50, and 200 ng of oxytocin, respectively,
      then the contralateral gonad was removed. Rats were killed 1 h, 1 day, or 7 days
      post-surgery. In each age group studied intratesticular injection of oxytocin
      resulted in a significant increase in basal testosterone secretion in vitro
      and/or serum testosterone concentration. Data indicate that in immature rats
      oxytocin of testicular origin might act as a local stimulator of steroidogenesis.

PMID- 8659709
TI  - The effects of pentoxifylline on the generation of reactive oxygen species and
      lipid peroxidation in human spermatozoa.
AB  - The aims of this study were to compare the in vitro effects of 3.6 mM and 7.2 mM
      pentoxifylline on the ability of spermatozoa to generate reactive oxygen species
      (ROS) and on lipid peroxidation (LPO). Semen samples were obtained from 10
      asthenozoospermic men who had been previously identified as producing ROS after
      addition of Phorbol 12-myristate 13-acetate (PMA) during the screening of
      patients attending with male factor infertility. Spermatozoa were prepared by a
      swim-up technique from unprocessed semen and divided into 3 aliquots. To the
      control aliquot [A] an equal volume of BWW medium was added. To aliquots B and C
      an equal volume of BWW medium containing pentoxifylline was added to obtain final
      concentrations of 3.6 and 7.2 mM, respectively. ROS production was measured from
      peak luminescence (mV 10(-7) sperm) using a lucigenin chemiluminescent probe. LPO
      was also measured in the medium surrounding the spermatozoa after 30 min exposure
      to pentoxifylline using the thiobarbituric acid (TBA) assay for malondialdehyde
      (MDA). The reduction in ROS production was significantly greater in the samples
      exposed to 7.2 mM pentoxifylline as compared with the control and 3.6 mM
      pentoxifylline samples. There was no significant difference in peak luminescence
      between control and 3.6 mM pentoxifylline specimens. Both concentrations of
      pentoxifylline caused comparable reductions in MDA concentration in the medium (P
      < 0.05) surrounding the spermatozoa compared with control after 30 min exposure.
      Extracellular ROS generation may damage surrounding healthy spermatozoa. These
      findings suggest that higher concentrations of pentoxifylline are protective
      against ROS release in susceptible spermatozoa and may also reduce collateral
      LPO.

PMID- 8659710
TI  - Acrosome content release in streptolysin O permeabilized mouse spermatozoa.
AB  - Sperm cell plasma membrane and the outer acrosomal membrane fuse profusely during
      the acrosome reaction. The process is triggered by extracellular signals that
      elicit several intracellular events leading ultimately to membrane fusion. We
      have developed a streptolysin O permeabilizing protocol that selectively affects
      the spermatozoon plasma membrane without causing a significant loss of the
      acrosomal content. Most of the acrosomal acid phosphatase remained sperm
      associated even after a 20 min incubation at 37 degrees C. However, the presence
      of 100 microM Ca2+ in the incubation buffer stimulates the release of the enzyme.
      The reaction was followed biochemically, measuring the acid phosphatase activity
      released to the medium and morphologically by the binding of fluorescein
      isothiocynate-conjugated peanut agglutinin and by electron microscopy. The
      results show that the streptolysin O permeabilized spermatozoon is a promising
      model for studying the complex set of events mediating and regulating the
      acrosome reaction.

PMID- 8659711
TI  - Fixation of testicular tissue for immunohistochemical and ultrastructural
      examination.
AB  - The fixation of testicular tissue with glutardialdehyde destroys the antigenicity
      of cell epitopes in many cases. To obtain both, morphological and
      immunohistochemical examination, a fixation which could preserve the antigenicity
      and condition of the testicular structure was sought. The solution obtained was a
      mixture of 3.7% formalin with 0.2% glutardialdehyde and 0.05% saponin in a
      phosphate buffer of pH 7.4. Blocks of human tests were immersed in this fixative,
      embedded in Epon 812 or paraffin for conventional light and electron microscopy
      and immunohistochemical staining. The immunohistochemical examination was focused
      on the lamina propria of the human seminiferous tubules. Good preservation of the
      structure was observed both in light and electron microscopy. Cytological details
      were seen by light microscopy, especially the recognition of single tumour cells.
      Electron microscopically, all cells of the seminiferous tubules and the lamina
      propria showed a well-preserved internal structure. At the same time the
      peritubular cells of the lamina propria exhibited a well-expressed vimentin and
      desmin immunoreactivity, thus providing evidence that the corresponding epitopes
      retain their antigenicity under these fixation conditions. The applied fixation
      procedure provides comparable results in preservation of the structure to
      glutardialdehyde but does not destroy the antigenicity of epitopes.

PMID- 8659712
TI  - Separation of sperm cells by sedimentation technique is not suitable for in vitro
      fertilization purposes.
AB  - Two methods of sperm preparation for in vitro fertilization were compared: the
      swim-up technique vs. the migration-sedimentation technique. The study comprised
      fresh semen samples obtained from 25 couples treated in the In Vitro
      Fertilization Unit. Oocytes aspirated in a single cycle were divided into two
      groups, each inseminated by sperm prepared by one of these techniques. Motility,
      degree of motility, and normal morphology were improved by both methods. The
      improvement was greater when the migration-sedimentation technique was applied.
      However, fertilization rate was significantly higher after the swim-up technique.
      In order to clarify this contradiction, an additional group of 26 semen samples
      was divided and then prepared by the swim-up or migration-sedimentation
      techniques. Sperm quality was examined up to 72 h after separation. Compared with
      the swim-up technique, sperm characteristics were better after separation by the
      migration-sedimentation technique. However, this difference abated after 24 h.
      The better results of the swim-up technique in the "survival experiment' may
      explain its improved performance in in vitro fertilization, despite lower
      separation capacity. Thus, the migration-sedimentation technique is not
      recommended for sperm preparation in in vitro fertilization.

PMID- 8659713
TI  - Disintegration of human spermatozoal membranes in seminal plasma decreases the
      binding capacity of integrins.
AB  - The in vitro binding capacity of spermatozoal integrins to matrix components
      after disintegration of sperm membranes was evaluated. The percentage of
      spermatozoa with functionally-relevant integrins was determined before and after
      devitalization of spermatozoa, which were resuspended in seminal plasma or in
      culture medium. The devitalization was performed by cryoshock or by incubation of
      spermatozoa with triton X-100 in a concentration ranging from 0.01 to 1.0%. The
      spermatozoal integrins were detected by the binding of anti-integrin antibodies
      and flow cytometry and the functional activity was monitored by the binding of
      the spermatozoa to the matrix components in a cell attachment assay. The seminal
      plasma decreased the binding of anti-integrin antibodies to the spermatozoal
      surface and the binding of spermatozoa to ligands and matrix components.
      respectively. In contrast, the expression of fibronectin and laminin on
      spermatozoa was increased. Not all spermatozoa, which expressed integrins on
      their surface bound to the ligands in the cell attachment assay. These results
      suggest that the detectable integrins only partially exert functional relevance.
      It can be concluded that the spermatozoa with fragile plasma membranes are more
      prone to functional inactivation of their integrins by the seminal plasma.

PMID- 8659714
TI  - Lipid peroxidation and morphology of rat testis in magnesium deficiency.
AB  - Male Wistar rats were fed diets with different Mg content, ranging from 70 to 850
      ppm Mg, for 30 days. After 0, 10, 20 and 30 days, some of the rats were
      sacrificed for measuring weight, lipid peroxidation, Fe, vitamin E, Na+, K+, Mg2+
      and Ca2+ content of testes. After 30 days, the morphology of the testes was
      investigated by electron microscopy. Mg deficiency induced an increase in weight,
      Na+, Ca2+ and Fe content and a reduction of K+ and Mg2+ content. Vitamin E
      content was reduced and the content of malondialdehyde as an indicator of lipid
      peroxidation was increased. Mg deficiency induced morphological alterations in up
      to 40% of the spermatids in the 70 ppm Mg group, which consisted: 1) in injured
      stretching of spermatids; 2) in an irregular arrangement of coarse fibres with
      missing microtubulus complex (axoneme) and microtubulus sheath; 3) in the
      development of up to 4 bundles of outer fibrils in one spermatid. The increase of
      Fe content, lipid peroxidation and the onset of morphological alterations
      occurred already at a mild degree of Mg deficiency.

PMID- 8659715
TI  - Selective isolation of acrosome-reacted human spermatozoa with progressive
      motility by using cell affinity chromatography on concanavalin A Sepharose.
AB  - In order to ensure fertility, mammalian spermatozoa have to undergo acrosome
      reaction, the most obvious morphological change during this being the exposure of
      the inner acrosomal membrane. In the present study, the acrosome-reacted human
      spermatozoa were successfully separated without loss of viability by using cell
      affinity chromatography on Concanavalin A (Con A) Sepharose. Con A demonstrated
      affinity for both the intact and the acrosome-reacted spermatozoa regardless of
      their viability; the latter, however, gave higher affinity than the former
      against Con A. Prior to the column chromatography, the immotile spermatozoa and
      the seminal plasma were excluded by means of a modified swim-down procedure and
      the resulting spermatozoa were subsequently immobilized by slow rate cooling in
      ice-cold water. Cell affinity chromatography was performed at 4 degrees C. To
      prevent mechanical trapping of the spermatozoa among the packed gel beads, the
      column was interconnected with a reservoir, the vertical drive of which was
      allowed to lose the gel bed and thereby release the trapped spermatozoa. Stepwise
      competitive elution with 5.0 microM mannose and 25% heat-inactivated human serum
      was capable of separating the intact spermatozoa and the acrosome-reacted
      spermatozoa from each other. The acrosome reaction rate of sperm fraction which
      was adsorbed to Con A Sepharose and eluted with 25% serum was found to be 83 +/-
      2.3%, and motility and viability of these fractions were measured to be 80 +/-
      6.3% and 83 +/- 7.6%, respectively (n = 8, mean +/- SD). The status of the
      acrosome in a final preparation (motility 92%, acrosome reaction rate 88%) was
      observed by scanning electron microscopy, and 81% spermatozoa lost their acrosome
      cap.

PMID- 8659716
TI  - Improved gastric tonometry for monitoring tissue perfusion: the canary sings
      louder.

PMID- 8659717
TI  - Equivalent outcomes during postoperative patient-controlled intravenous analgesia
      with lidocaine plus morphine versus morphine alone.
AB  - To evaluate a possible opioid-sparing effect of intravenous lidocaine we
      conducted a randomized, double-blind clinical trial. Patients undergoing
      intraabdominal surgery under general anesthesia were treated with patient
      controlled analgesia (PCA) in three groups: Group 1 (n = 100; morphine 1 mg/mL),
      Group 2 (n = 44; morphine 1 mg/mL plus lidocaine 10 mg/mL), and Group 3 (n = 51;
      morphine 1 mg/mL plus lidocaine 20 mg/mL). Pain was evaluated using a 0-10 visual
      analog scale in the postanesthesia care unit (PACU) during deep inhalation at 15
      and 30 min, and at 1, 2, and 4 h after arrival in the PACU, and continued after
      PACU discharge every 4 h for 36 h. Patients whose pain was more than 4/10 in the
      PACU received 2.5 mliters of the respective solutions every 7 min until pain was
      less than 4/10; then PCA was started. The number of bolus and cumulative drug
      doses during the study were recorded. Along with pain intensity, we assessed
      vital signs and side effects. Time to acceptance of oral liquids was also
      determined. Adding lidocaine 10 or 20 mg/mL to PCA morphine 1 mg/mL for acute
      pain treatment after abdominal surgery yielded no differences in opioid use, pain
      levels, or side effects.

PMID- 8659718
TI  - The effects of intrathecally administered FK480, a cholecystokinin-A receptor
      antagonist, and YM022, a cholecystokinin-B receptor antagonist, on the formalin
      test in the rat.
AB  - Cholecystokinin (CCK) is located in the brain and the spinal cord, and CCK
      antagonist is reported to enhance the analgesic effect of morphine. It has been
      suggested that, during inflammation, the level of endogenous opioid peptides
      increases in the spinal cord. Intrathecally administered CCK antagonist may have
      some analgesic effect during inflammation via the activated spinal opioid system.
      To gain a better understanding of the roles of CCK-A and CCK-B receptors in
      spinal nociceptive transmission during inflammation, this study evaluated the
      effects of intrathecally administered FK480 (a CCK-A receptor antagonist) and
      YM022 (a CCK-B receptor antagonist). Inflammation was induced by paw formalin
      injection (formalin test) in rats. The subcutaneous injection of formalin into
      the hind paw evoked biphasic flinching (Phase 1, 0-9 min; Phase 2, 10-60 min) of
      the injected paw. Drugs were administered intrathecally 10 min before
      (pretreatment) or 7 min after (posttreatment) the formalin injection. Neither
      pretreatment nor posttreatment with FK480 has any effect on the formalin test.
      Pretreatment, but not posttreatment, with YM022 depressed the Phase 1 and Phase 2
      flinching behavior in a dose-dependent manner, and this YM022 effect was
      stereospecific and was not antagonized by naloxone. These data indicate that a
      CCK-B receptor antagonist, but not a CCK-A receptor antagonist, produces an
      antinociceptive effect in the rat formalin test. This effect of a CCK-B receptor
      antagonist was not mediated by the spinal opioid receptor activation.

PMID- 8659719
TI  - Twenty-four of twenty-seven studies show a greater incidence of emesis associated
      with nitrous oxide than with alternative anesthetics.
AB  - All obtainable investigations that have compared the incidence of vomiting in
      groups of patients who received nitrous oxide (N2O) and in patients who received
      anesthetics or analgesics without N2O were examined for a single, dichotomous
      variable: whether patients who received N2O experienced an absolutely higher
      incidence, as distinct from a statistically significantly higher incidence, of
      vomiting. The null hypothesis is that N2O has no effect on emesis, such that an
      increased incidence of vomiting should occur in about half of the studies
      examined. However, patients receiving N2O experienced an absolutely higher
      incidence of emesis in 24 of 27 investigations. The two-tailed probability that
      this result occurred by chance is < 0.00005. It follows that N2O increases the
      incidence of emesis compared to alternative anesthetics.

PMID- 8659720
TI  - Combination of ondansetron and droperidol in the prophylaxis of postoperative
      nausea and vomiting.
AB  - The aim of this study was to compare the efficacy and safety of ondansetron plus
      droperidol with each drug alone or placebo in the prevention of postoperative
      nausea and vomiting (PONV). One hundred females, aged 18-65 yr, ASA physical
      status I-II, undergoing general anesthesia for elective abdominal surgery were
      included in a prospective, double-blind, placebo-controlled, randomized study. A
      standardized anesthetic technique and postoperative analgesia (ketorolac plus
      patient-controlled analgesia [PCA] with morphine) were used in all patients.
      Patients were randomly assigned to receive placebo (Group 1, n = 25), droperidol
      2.5 mg with induction of anesthesia and 1.25 mg 12 h later (Group 2, n = 25),
      ondansetron 4 mg with induction (Group 3, n = 25), and ondansetron plus
      droperidol at the same doses as Groups 3 and 2, respectively (Group 4, n = 25). A
      complete response, defined as no PONV in 48 h, occurred in 28% of patients in
      Group 1, 60% in Group 2 (P < 0.05 vs Group 1), 56% in Group 3 (P < 0.05 vs Group
      1), and 92% in Group 4 (P < 0.01 vs Groups 1, 2, and 3). Sedation was
      significantly greater with droperidol (Groups 2 and 4) for 12 h postoperatively.
      In conclusion, the combination of ondansetron plus droperidol was more effective
      than each antiemetic alone or placebo in the prevention of PONV in women
      undergoing elective abdominal surgery.

PMID- 8659721
TI  - Computed tomographic analysis of airway dimensions after carotid endarterectomy.
AB  - Airway obstruction is a rare but serious postoperative complication of carotid
      endarterectomy. We prospectively studied airway dimensions between the hyoid bone
      and cricoid cartilage in patients undergoing carotid endarterectomy using
      preoperative and postoperative computed tomographic (CT) scans of the neck. CT
      scans showed soft tissue swelling in all 19 patients. Five patients with clinical
      evidence of airway obstruction and a hematoma present on CT scan were intubated
      postoperatively. The three-dimensional reconstruction of the neck from the CT
      scans showed a reduction in the volume of the airway in all patients. This
      reduction was greater in the intubated (62% +/- 9%) compared to the nonintubated
      (32% +/- 7%) patients (P < 0.01). The anterior-posterior and transverse diameters
      of the airway were reduced, while retropharyngeal edema was increased after
      carotid endarterectomy. This change was greater for the upper airway at the level
      of the hyoid compared to the arytenoids and cricoid, and was significantly
      greater in the intubated than the nonintubated patients. Tracheal deviation was
      greater in the intubated than in the nonintubated patients. These results
      demonstrate significant soft tissue edema of the neck after carotid
      endarterectomy that reduces airway volume and can result in airway obstruction.

PMID- 8659722
TI  - Preoperative fasting time: is the traditional policy changing? Results of a
      national survey.
AB  - Several papers in the 1980s questioned the wisdom of withholding clear liquids
      for more than 3 h before elective surgery. Furthermore, recent papers have
      suggested relaxing the current NPO after midnight (Latin: Nulla per os; or
      "nothing by mouth") practice in children and adults. To see whether the policy
      and practice regarding NPO status before elective surgery have changed in the
      United States, we performed a national survey. In November 1992, 300
      questionnaires were mailed to the chairpersons of 114 university anesthesiology
      programs and the medical directors of 186 randomly selected, free-standing
      ambulatory surgery centers. Seventeen simple questions were asked regarding their
      NPO policy and practice guidelines before elective operations. Replies were
      tabulated, and the data were descriptively analyzed via frequency distribution.
      We received 191 replies, 85 from the university programs and 106 from the free
      standing units (75% and 57% response rates, respectively) from all six time zones
      of the United States. Fifty-seven percent of the responders stated that they had
      revised their NPO policy during the last 3 yr, whereas 39% reported that they had
      not changed their NPO policy. One hundred percent of the respondents who allowed
      clear liquids considered water to be acceptable for adults, whereas 94%
      considered water acceptable in the pediatric population. Eighty-one percent of
      the responders denied the use of routine prophylaxis for acid aspiration. None of
      the responders reported an adverse outcome which could be attributable to the
      recent change in the NPO guidelines. On a related question, 16% of all the
      respondents stated that they would cancel the operation if a patient arrived for
      an elective outpatient surgical procedure after consuming coffee with cream 2 h
      before operation. In conclusion, our survey revealed that 69% of
      anesthesiologists in the United States have either changed their NPO policy or
      are flexible in their practice in allowing clear liquids before elective
      operation in children and 41% have done so for adult patients. The most
      frequently allowed clear liquids in the adult and pediatric population were water
      and apple juice. None of the respondents reported any medical adverse event
      associated with the institution of a flexible NPO policy.

PMID- 8659723
TI  - A cost comparison of allogeneic and preoperatively or intraoperatively donated
      autologous blood.
AB  - We determined the cost of allogeneic packed red blood cells and autologous whole
      blood donated either preoperatively or in the operating room during hemodilution.
      Direct and indirect cost estimates were based on patients requiring simple
      transfusion and included procurement and preparation of the blood including
      testing performed, materials and time used, waste, and materials for
      administration. Data were derived from prospective blood bank time studies,
      material invoice records, and retrospective review of anesthesia times. Viral
      infection and transfusion reaction costs were accepted from previously published
      sources. Direct cost of purchasing and indirect costs of preparation resulted in
      an overall cost of $107.26 for the first unit of allogeneic packed red blood
      cells transfused. A second unit was slightly less costly ($100.89), as no type
      and screen was required and the same delivery set and filter can be used. The
      total cost of acquisition, processing, and transfusion of 1 U of preoperatively
      donated autologous blood was $97.83. The total cost of a 2-U transfusion of
      autologous whole blood donated in the operating room during acute normovolemic
      hemodilution was $83.10. These data suggest that autologous predonation of whole
      blood is somewhat less expensive than allogeneic packed red blood cells, and that
      hemodilution may be a cost effective alternative to autologous predonation in
      selected patients.

PMID- 8659724
TI  - The effect of laparoscopic cholecystectomy on cardiovascular function and
      pulmonary gas exchange.
AB  - Hemodynamic changes, pulmonary CO2 elimination (VECO2) and gas exchange were
      evaluated during laparoscopic cholecystectomy. An algorithm to calculate inspired
      ventilation (VI) needed to maintain constant PaCO2 was also developed. In 12 ASA
      physical status I patients undergoing laparoscopic cholecystectomy, heart rate
      (HR), mean arterial pressure (MAP), cardiac index (CI), and systemic vascular
      resistance index (SVRI) were measured by the analysis of a radial artery pressure
      profile before, during, and after CO2 insufflation. Alveolar-arterial oxygen
      pressure gradient (P(A-a)O2), physiological and alveolar ventilatory dead space
      fractions (VDphys/VT; VDalv/VT), and PaCO2 were measured as well. VECO2 was
      assessed every minute in the patients maintained in the head-up position. HR did
      not significantly change during pneumoperitoneum, whereas MAP showed a transient
      increase (24.9%; P < 0.05) after CO2 insufflation. CI remained stable during
      pneumoperitoneum, but increased (25.0%; P < 0.05) after deflation. As a
      consequence, SVRI transiently increased after CO2 insufflation and decreased by
      15.8% (P < 0.05) 5 min after deflation. P(A-a)O2 increased slightly (P < 0.05)
      with increased anesthesia time. VDphys/VT and VDalv/VT did not change after
      pneumoperitoneum onset, but VDalv/VT decreased after CO2 deflation (13.4%; P <
      0.05). VECO2 increased (decreased) after a monoexponential time course during
      (after) CO2 insufflation in 8 of 12 patients. The mean time constants (t) of the
      monoexponential functions were 26.3 and 15.4 min during and after
      pneumoperitoneum. A monoexponential time course was shown also by PaCO2 during
      CO2 insufflation (tau = 27.8 min). Finally, the VI needed to maintain PaCO2 at a
      selected value could be calculated by the following algorithm: VI = [0.448.(1-e(
      t/tau) + 2.52].(VA.PaCO2.713)-1, where VA corresponds to alveolar ventilation and
      t must be chosen according to the pneumoperitoneum phase. We conclude that CO2
      insufflation in the abdominal cavity does not induce significant changes in
      cardiopulmonary function in ASA physical status I patients. The algorithm
      proposed seems to be a useful tool for the anesthesiologists to maintain constant
      PaCO2 during all surgical procedures.

PMID- 8659725
TI  - Opioid neurotoxicity: neuropathologic effects in rats of different fentanyl
      congeners and the effects of hexamethonium-induced normotension.
AB  - We tested the hypotheses that convulsant doses of opioids would produce limbic
      system damage exacerbated by hexamethonium. Ventilated paralyzed rats received
      intravenous (IV) isovolumic infusion of fentanyl loading dose (LD) 1000
      micrograms/kg, maintenance dose (MD) 40 micrograms.kg-1.min-1 (n = 10),
      sufentanil LD 400 micrograms/kg, MD 13.3 micrograms.kg-1.min-1 (n = 10),
      alfentanil LD 1500 micrograms/kg, MD 150 micrograms.kg-1.min-1 (n = 10), or 0.9%
      saline control LD 4 mliter/kg, MD 4 mliter.kg-1.h-1 (n = 10), with O2/N2 30%/70%
      during opioid infusion and O2/N2O in controls during saline infusion.
      Hexamethonium (LD 20 mg/kg, MD 40-120 mg.kg-1.h-1) was given IV during opioid
      infusion to half of the rats. Cerebral perfusion-fixation with formalin was
      performed 24 h later, followed by histopathologic assessment. None of the control
      rats showed any histologic abnormalities. Overall summed neuropathologic severity
      was worse in opioid treated groups (P = 0.01). Lesions occurred primarily in
      cortical regions and limbic system structures. When arterial blood pressure was
      controlled to a lower level with hexamethonium (147 vs 100 mm Hg), rats had less
      severe lesions (P = 0.02). These data indicate that fentanyl, sufentanil, and
      alfentanil all can produce histopathologic evidence of brain injury in rats
      mitigated by hexamethonium.

PMID- 8659726
TI  - Halothane resistance in Drosophila melanogaster: development of a model and gene
      localization techniques.
AB  - Studying genetically altered animals that are resistant to inhaled anesthetics
      may ultimately lead to an understanding of anesthetics' mechanism(s) of action.
      We studied the genetics of halothane resistance in a strain of Drosophila
      melanogaster that showed substantially increased resistance to halothane
      anesthesia. We developed a test method that allowed us to repeatedly observe
      several samples of flies exposed to the same concentration of halothane, and we
      measured halothane resistance. The 50% effective dose (ED50) of 91R flies (our
      resistant population) was greater than the ED50 of Canton-S (our control strain)
      by 69% in females and by 48% in males. By assessing the contributions of the
      three major chromosomes of Drosophila to resistance, this study found that the X
      and third chromosomes of 91R have no effect on resistance, while the second
      chromosome has a major impact. Resistance within the second chromosome was
      further localized by testing marked recombinant chromosomes. The central region
      of 91R's second chromosome, bounded by the genes for black thoracic color and
      cinnabar eye color, determined most if not all of the increase in resistance. We
      were not able to further localize resistance within this segment of the second
      chromosome (containing about 8% of the total genetic map distance). An autosomal
      dominant gene for halothane resistance in 91R was localized to a small region of
      the second chromosome.

PMID- 8659727
TI  - Propofol and ethanol produce additive hypnotic and anesthetic effects in the
      mouse.
AB  - The sedative and anesthetic effects of ethanol and propofol when these drugs are
      coadministered are not known. Accordingly, we investigated the nature of the
      pharmacological interaction between ethanol and propofol during hypnosis and
      anesthesia in the mouse. Propofol, ethanol, and mixtures of the two were
      administered through the tail vein in male CD-1 mice (n = 162). The loss of
      righting response occurring 10 s after injection and persisting at least 10 s
      thereafter was defined as hypnosis, and lack of a motor response to tail clamping
      60 s after injection was defined as anesthesia. The 50% effective dose (ED50)
      values for the hypnotic and anesthetic actions of the drugs were determined with
      quantal dose-response curves, using probit analysis. The pharmacological
      interactions were identified by the locations of ED50 values on their
      corresponding hypnosis and anesthesia isoboles. For each drug alone, the hypnotic
      and anesthetic ED50 values with 0.95 confidence intervals were 16.70 (11.98,
      23.20) mg/kg and 25.02 (20.27, 31.29) mg/kg for propofol and 0.88 (0.81, 0.95)
      g/kg and 1.80 (1.45, 2.23) g/kg for ethanol, respectively. For the drugs in
      combination, the ED50 values for hypnosis with 0.95 confidence intervals were
      6.98 (6.50, 7.49) mg/kg propofol with 0.61 (0.57, 0.66) g/kg ethanol, and for
      anesthesia were 10.55 (9.76, 11.42) mg/kg propofol with 0.93 (0.86, 1.05) g/kg
      ethanol, respectively. When plotted isobolographically, we found these
      combinations to be behaviorally additive both for hypnosis and anesthesia.
      Although a finding of synergism would have excluded the possibility of an
      identical mechanism of action for the drugs, elucidation of the molecular basis
      of the additivity must await further studies.

PMID- 8659728
TI  - Direct relaxant effects of intravenous anesthetics on airway smooth muscle.
AB  - Ketamine, at concentrations achieved with the usual clinical doses, has a direct
      relaxant effect on airway smooth muscle (ASM). This study investigates the dose
      dependent direct relaxation effects of midazolam and propofol on both proximal
      and distal ASM compared with ketamine. The proximal and distal airways were
      dissected from eight mongrel dogs and cut into 2-mm rings. The rings were
      attached to pressure transducers and equilibrated in a Krebs-Ringer bicarbonate
      bath kept at 37 degrees C, pH 7.4, CO2 37 mm Hg, and PaO2 > 100 mm Hg. Optimal
      length was determined, a dose-response curve to acetylcholine was established,
      and the 50% effective dose (ED50) of acetylcholine was calculated. Ketamine,
      midazolam, or propofol were given in random order to each ring preconstricted
      with ED50 of acetylcholine in cumulative log incremental doses from 10(-6) to 10(
      4) M. Relaxation response was the tension during anesthetic equilibrium,
      expressed as a percentage of the tension from ED50 of acetylcholine. The drug
      vehicles were tested for their effects on the ASM. No bronchorelaxation was seen
      with any of the intravenous anesthetics at 10(-6) M. Ketamine 10(-5) M produced
      at 17.9% +/- 2.1% relaxation in the distal ASM but had no effect on the proximal
      ASM. Neither propofol nor midazolam affected the ASM at 10(-5) M. The distal ASM
      was significantly (P < 0.005) more sensitive to 10(-4) M of all three drugs
      compared with the proximal ASM. In the proximal ASM, 10(-4) M of ketamine,
      midazolam and propofol reduced ASM tension by 14.9% +/- 4.4%, 19.0% +/-8.8%, and
      14.7% +/- 5.5%, respectively, versus 36.4% +/- 3.2%, 58.6% +/- 6.1%, and 64.4% +/
      9.0% in the distal ASM. The drug vehicles had no effect on the ASM. We conclude
      that ketamine, midazolam, and propofol have direct relaxant effects on ASM. All
      three intravenous anesthetics have a greater direct relaxant effect on distal ASM
      than on proximal ASM. Only ketamine showed significant direct bronchorelaxing
      effects at concentrations that are likely to be achieved with the usual clinical
      dosing patterns.

PMID- 8659729
TI  - Large-dose propofol alone in adult epileptic patients: electrocorticographic
      results.
AB  - The primary objective of this study was to evaluate the electrophysiologic
      effects of large-dose propofol, used as the sole anesthetic in patients with
      epilepsy. Nine patients with medically intractable complex partial epilepsy
      undergoing a three-stage approach to the surgical management of epilepsy were
      recruited. State I involved placement of the intracranial electrode array, while
      Stage II consisted of extraoperative localization of the seizure focus. The
      patients were studied during induction of anesthesia for Stage III (removal of
      electrodes and resection of seizure focus). Unpremedicated patients were induced
      with a propofol infusion (0.5 mg.kg-1.min-1) until one of the following occurred:
      1) electrical seizure activity, 2) burst suppression, or 3) total dose of 10
      mg/mg. Electrocorticography (ECoG) was recorded continuously during this period.
      Two patients were excluded from the study after experiencing delayed awakening
      after the Stage I procedure. Both had received propofol along with other
      anesthetics. No ECoG evidence of seizure activity was detected in the seven
      patients completing the study. Burst suppression was attained in six patients
      using a mean dose of 5.7 mg/kg +/- 2.6. We conclude that large dose propofol
      alone does not trigger electrical epileptiform activity on the ECoG of seizure
      patients.

PMID- 8659730
TI  - Overcoming obstruction during bronchoscope-guided intubation of the trachea with
      the double setup endotracheal tube.

PMID- 8659731
TI  - Anterior spinal artery syndrome after left celiac plexus block.

PMID- 8659732
TI  - Tranexamic acid reduces transfusions and mediastinal drainage in repeat cardiac
      surgery.
AB  - The administration of tranexamic acid (TA) prior to cardiopulmonary bypass (CPB)
      has been associated with reduced bleeding during and after cardiac surgery. In a
      prospective, randomized, controlled, double-blind clinical trial, adult patients
      undergoing repeat open heart surgery received TA (n = 17) or an equal volume of
      saline placebo (n = 13). In the TA group, a 20-mg/kg intravenous (IV) initial
      dose of TA at akin incision was followed by an infusion of 2 mg.kg-1.h-1, which
      continued for the duration of the surgical procedure. Identical transfusion
      guidelines were followed in both groups. Routine coagulation tests, D-dimer
      levels, mediastinal tube drainage, and transfusion requirements were compared.
      Cumulative postoperative mediastinal tube drainage measured at 24 h was 649 +/-
      391 mliter (mean +/- SD) in the TA group compared with 923 +/- 496 mliter in the
      placebo group (P < 0.01). Forty-eight-and 72-h mediastinal tube drainage were
      also significantly less in the TA group (P < 0.01). Seven of 17 TA patients
      received to transfusion of allogeneic blood products compared with 1 of 13
      placebo patients (P = 0.047). The incidence and volumes of platelet and fresh
      frozen plasma transfusion in the TA group were not significantly different in
      comparison with the placebo group. The perioperative increase in D-dimer levels
      (post-CPB minus pre-CPB) in the placebo group (median difference = 675 ng/mliter,
      range 125-1648) was significantly more than in the TA group (median difference =
      182 ng/mliter, range -426-1950; P = 0.003). Sternal closure occurred in 41 +/- 21
      min in the TA group and 61 +/- 49 min in the placebo group (P = 0.14), and the
      subjective bleeding score was less in the TA group than in the placebo group
      (2.38 +/- 0.78 vs 3.08 +/- 1.04; P = 0.045). The data from the current study
      support the prophylactic use of TA in patients undergoing repeat cardiac surgery.
      TA administered prior to CPB reduced the incidence of allogeneic transfusions and
      postoperative mediastinal tube drainage, and improved the subjective assessment
      of post-CPB hemostasis in a group of patients at moderately high risk for
      perioperative bleeding.

PMID- 8659733
TI  - Neuroma of the superficial branch of the radial nerve after intravenous
      cannulation.

PMID- 8659734
TI  - Transient compartment syndrome of the forearm after attempted radial artery
      cannulation.
AB  - Radial artery cannulation for continuous intraoperative monitoring of arterial
      blood pressure is considered a safe procedure. One complication of arterial
      cannulation is hematoma formation at the time of insertion or removal of the
      catheter. Bleeding is usually self-limited or will stop with compression without
      significant sequelae, even in the anticoagulated patient. We describe a case of
      hematoma with a transient compartment syndrome of the forearm after attempts to
      cannulate the radial artery for intraoperative monitoring purposes.

PMID- 8659735
TI  - Gastropleural fistula: an unusual cause of intractable postoperative nausea and
      vomiting.
AB  - Gastropleural fistula is an uncommon finding (1). Gastropleural fistulae have
      been reported after pulmonary resection (1), perforated paraesophageal hernia
      (2), perforated malignant gastric ulcer at the fundus, and gastric bypass
      operation for morbid obesity. We present a case of gastropleural fistula that
      resulted acutely from intractable postoperative nausea and vomiting after
      ambulatory knee arthroscopic surgery under general anesthesia.

PMID- 8659736
TI  - Prolonged sevoflurane inhalation was not nephrotoxic in two patients with
      refractory status asthmaticus.

PMID- 8659738
TI  - Failure of ventilation in an infant due to increased resistance of a disposable
      heat and moisture exchanger.

PMID- 8659737
TI  - Reversal of a paradoxical reaction to midazolam with flumazenil.

PMID- 8659740
TI  - Flexible coordination allows more cases.

PMID- 8659739
TI  - Extraperitoneal carbon dioxide insufflation.

PMID- 8659741
TI  - Improved outcome with chronic subcutaneous infusion of odansetron for intractable
      nausea and vomiting.

PMID- 8659742
TI  - Anesthesia, blood loss, and coagulopathy during transurethral resection of the
      prostate.

PMID- 8659744
TI  - Blindness after hysteroscopic surgery.

PMID- 8659743
TI  - Combined use of spinal anesthesia and midazolam sedation increases the risk of
      hypoxemia.

PMID- 8659745
TI  - Unusual cause for a circle system leak.

PMID- 8659746
TI  - Retrieval of catheter using guide wire.

PMID- 8659747
TI  - Off-label use of ketorolac.

PMID- 8659748
TI  - Prevention of aspiration during Combitube insertion.

PMID- 8659749
TI  - Spinal anesthesia and midazolam hypnotic requirements.

PMID- 8659750
TI  - Choice of inspiratory vapor concentrations in comparative studies of inhaled
      anesthetic induction in children.

PMID- 8659751
TI  - Factors contributing to regional wall motion abnormalities during
      electroconvulsive therapy.

PMID- 8659752
TI  - Smith-Lemli-Opitz syndrome and malignant hyperthermia.

PMID- 8659753
TI  - Can succinylcholine antagonize mivacurium-induced neuromuscular block?

PMID- 8659754
TI  - The Bezold-Jarisch reflex.

PMID- 8659755
TI  - Simple modification of a medium concentration (Hudson type) oxygen mask improves
      patient comfort and respiratory monitoring with capnography.

PMID- 8659756
TI  - Limiting movement during retrobulbar block.

PMID- 8659757
TI  - Pain on injection of rocuronium bromide.

PMID- 8659758
TI  - Cost-effective modeling.

PMID- 8659759
TI  - Single versus multiple sites and mechanisms of inhaled anesthetics.

PMID- 8659760
TI  - Glyburide, a KATP channel antagonist, attenuates the cardioprotective effects of
      isoflurane in stunned myocardium.
AB  - This investigation examined the role of myocardial adenosine triphosphate
      regulated potassium (KATP) channels in isoflurane-induced enhancement of
      myocardial function after reversible tissue injury produced by a 15-min left
      anterior descending coronary artery occlusion (LAD) and reperfusion. Dogs (n =
      14) were chronically instrumented for measurement of left ventricular (LV) and
      aortic blood pressure, cardiac output, coronary blood flow velocity, and
      subendocardial segment length. Regional myocardial contractility was evaluated
      with preload recruitable work area (PRWA). Isovolumic relaxation was assessed
      with a time constant (tau). Hemodynamic variables and LV function were measured
      in the conscious state, during 2% isoflurane anesthesia for 45 min before and
      during a 15-min LAD occlusion, and at several intervals after reperfusion in dogs
      pretreated with glyburide (0.3 mg/kg, intravenously) or drug vehicle. LAD
      occlusion caused regional dyskinesia and increases in tau. Vehicle-pretreated
      dogs demonstrated full recovery of segment shortening by 5 h postreperfusion and
      recovery of PRWA and tau by 30 min postreperfusion. In contrast, dogs pretreated
      with glyburide demonstrated sustained systolic and diastolic dysfunction. Segment
      shortening recovered to only 70% +/- 5%, PRWA remained depressed at 48% +/- 10%
      and tau was prolonged to 116% +/- 5% of control values at 5 h postreperfusion.
      The results indicate that isoflurane enhances recovery of myocardial contractile
      function by 5 h postreperfusion, in comparison to previous findings in conscious
      dogs. These effects are partially blocked by glyburide pretreatment, indicating
      that KATP channel activation by isoflurance may mediate these cardioprotective
      effects.

PMID- 8659762
TI  - Does nitrous oxide cause vomiting?

PMID- 8659761
TI  - Renal function during cardiopulmonary bypass: influence of the calcium entry
      blocker felodipine.
AB  - Glomerular filtration and tubular activity are decreased during hypothermic
      cardiopulmonary bypass (CPB). The role of vasoconstriction to explain these
      changes is not known. The calcium entry blocking drug felodipine dilates
      constricted arterioles and reduces renal vascular resistance during noncardiac
      surgery. The present study was initiated to evaluate the effects of felodipine on
      renal perfusion and function during hypothermic, low pressure CPB. Twenty-two
      male patients (aged 61.7 +/- 2.3 y) were included in a prospective, randomized,
      controlled study. Renal blood flow was measured with thermodilution technique;
      renal extraction of 51Cr-EDTA and p-aminohippurate (PAH) were used to evaluate
      glomerular and tubular function. Systemic blood flow during hypothermic CPB was
      varied experimentally between 1.45 and 2.2 L.min-1.m-2. Felodipine reduced
      systemic vascular resistance but did not reduce the total renal vascular
      resistance during CPB. On the contrary, renal vascular resistance was increased
      at low CPB flow rates. The extraction of PAH (signifying tubular activity) was
      higher during felodipine infusion (0.74 +/- 0.04 vs 0.64 +/- 0.03 during low CPB
      flow, and 0.64 +/- 0.03 vs 0.57 +/- 0.05 during high CPB flow), whereas 51Cr-EDTA
      extraction was not influenced. The mechanism of enhanced PAH extraction may
      involve reduced regional vasoconstriction in PAH-extracting areas.

PMID- 8659763
TI  - The effects of triiodothyronine on hemodynamic status and cardiac function in
      potential heart donors.
AB  - Brain death is associated with altered cardiac function and low concentrations of
      circulating triiodothryronine (T3). However, the effects of T3 administration on
      hemodynamic status and cardiac function in potential heart donors remain
      controversial. Thirty-seven brain-dead patients were randomly and blindly
      allocated to receive an intravenous bolus of either 0.2 microgram/kg T3 (n = 19)
      or saline placebo (n = 18). Measurements included conventional hemodynamic and
      echocardiographic variables of cardiac volume conditions and systolic function of
      the left ventricle (fractional area change [FAC], velocity of myocardial fiber
      shortening) using a transesophageal probe, arterial and mixed venous blood gas
      parameters, and serum thyroid hormone concentrations. The mean concentration of
      T3 was 1.86 +/- 1.55 pmol/L, and only six patients (16%) had normal values of T3
      in control conditions. There was no significant correlation between T3
      concentration and FAC (R = 0.17, not significant). All patients receiving T3 had
      normalized serum T3 concentration (7.55 +/- 2.56 pmol/L) in contrast to patients
      receiving saline (1.48 +/- 1.26 pmol/L). No significant differences in
      hemodynamic and echocardiographic parameters were observed between the placebo
      and T3 groups. Indeed, FAC remained unchanged after T3 (44% +/- 17% vs 46% +/-
      22%) or placebo (47% +/- 18% vs 50% +/- 14%) administration. In 20 patients with
      impaired left ventricular function (FAC < 50%), FAC remained unchanged after T3
      (n = 10; 34% +/- 12% vs 30% +/- 10%) or placebo (n = 10; 38% +/- 12% vs 35% +/-
      13%) administration. In 17 patients in whom organ harvesting was delayed,
      transesophageal echocardiography was performed 6 h later and no significant
      changes in FAC were noted in the T3 group (n = 8; 49% +/- 17% vs 44% +/- 17%) and
      the placebo group (n = 9; 51% +/- 18% vs 47% +/- 18%). In conclusion, T3
      administration did not improve hemodynamic status and myocardial function in
      brain-dead patients, suggesting that the euthyroid sick syndrome is not the main
      determinant of myocardial dysfunction in these patients.

PMID- 8659764
TI  - Positioning the pacing esophageal stethoscope for transesophageal atrial pacing
      without P-wave recording: implications for transesophageal ventricular pacing.
AB  - This study determined guidelines for positioning a new pacing esophageal
      stethoscope (PES) used for transesophageal atrial pacing (TEAP) without having to
      record esophageal P waves. In 44 patients with heights ranging from 142 cm (4'8")
      to 193 cm (6'4"), the PES was inserted to a depth of insertion (DOI) of 43 cm. As
      the PES was withdrawn, TEAP thresholds were determined at every DOI in 1-cm
      intervals between 43 and 25 cm DOI inclusive. TEAP was accomplished in all 44
      patients. The minimum TEAP threshold (mean +/- SD 10.8 +/- 4.0 mA) was < or = 17
      mA in 43 of 44 patients (98%). Except for one patient, TEAP could be accomplished
      over a 9- to 19-cm (mean +/- SD, 13.7 +/- 2.8 cm) wide range of DOI.
      Unintentional transesophageal ventricular pacing (TEVP) occurred in 15 of 44
      (34%) of patients. TEVP occurred over a 1- to 7-cm (mean +/- SD, 3.7 +/- 1.7 cm)
      wide range of DOI; the minimum TEVP threshold averaged 30.4 +/- 6.4 mA. TEAP was
      consistently accomplished at DOIs more proximal than where TEVP could occur and
      with lower currents than that required for TEVP. An insertion depth, in
      centimeters, equal to half of the patient's height, in inches, produced
      successful TEAP in all 44 patients; the minimum TEAP threshold occurred on
      average at a DOI 2.6 cm more proximal. Asynchronous TEVP can be avoided by using
      lower currents at shallow DOIs.

PMID- 8659765
TI  - Desflurane attenuates the somatosympathetic reflex in rats.
AB  - Arterial blood pressure and heart rate changes after afferent somatic sensory
      nerve stimulation are termed the "somatosympathetic reflex" (SSR). Inhibition of
      the SSR may partially represent an antinociceptive action. This investigation
      examined the actions of the volatile anesthetic, desflurane, on the SSR evoked by
      peripheral nerve stimulation. Rats anesthetized with alpha-chloralose (50 mg/kg)
      and urethane (500 mg/kg) were mechanically ventilated and cannulated with
      arterial and venous catheters for monitoring arterial pressure and for fluid
      administration, respectively. The sciatic (n = 7) or tibial (n = 6) nerves were
      isolated and stimulated at one, two, and four times the voltage threshold
      required to elicit a change in systemic hemodynamics. These cardiovascular
      responses were recorded before, during, and after varying concentrations of
      desflurane, 1.8% (0.25 minimum alveolar anesthetic concentration [MAC]), 3.6%
      (0.5 MAC), 7.2% (1.0 MAC), and 10.8% (1.5 MAC). Desflurane decreased arterial
      pressure at 1.0 and 1.5 MAC and heart rate (at more than 0.5 MAC) compared to
      baseline levels. Tibial nerve stimulation decreased mean arterial pressure (MAP)
      with no consistent changes in heart rate. Desflurane significantly attenuated
      this depressor response to tibial nerve stimulation (MAP decrease: control; -20
      +/- 2 mm Hg versus 1.0 MAC desflurane; -6 +/- 4 mm Hg). The increases in MAP
      after sciatic nerve stimulation were also significantly inhibited by increasing
      concentrations of desflurane. At more than 0.5 MAC desflurane, the pressor
      response to sciatic nerve stimulation was significantly converted to a depressor
      response in four of seven rats (MAP: control; increase 24 +/- 2 mm Hg versus 1.0
      MAC desflurane; decrease -2 +/- 4 mm Hg). Sciatic nerve stimulation also elicited
      increases in heart rate which were significantly attenuated by desflurane
      (control; 37 +/- 6 bpm versus 1.5 MAC desflurane; 0 +/- 2 bpm). These findings
      demonstrate that desflurane produces dose-dependent cardiovascular depression in
      rats and, despite previous reports of sympathoexcitation, desflurane
      significantly attenuated both excitatory and inhibitory types of SSR. The results
      of this study also support a potential antinociceptive action for this
      anesthetic.

PMID- 8659766
TI  - A new method for continuous intramucosal PCO2 measurement in the gastrointestinal
      tract.
AB  - Gastric tonometry has been introduced for the early detection of impaired
      splanchnic perfusion by determination of the intramucosal PCO2. However, due to
      methodological problems, i.e., instability of CO2 in water, to assess the exact
      intramucosal PCO2 with the nasogastric tonometer is unreliable. The present in
      vitro and in vivo study examines a new fiberoptic PCO2 sensor for the continuous
      determination of the intramucosal PCO2 and compares these data with that of
      conventional tonometry. In an in vitro experiment the fiberoptic PCO2 sensor was
      used to determine the PCO2 of water and humidified air with predefined CO2
      values. In both media, predefined CO2 values (35, 42, 49 mm Hg) could be assessed
      exactly after 9 min of equilibration with a maximum deviation less than 3.5%. In
      contrast, the values obtained by conventional tonometry showed larger
      differences. In in vivo experiments on six pigs PCO2 differences were induced by
      ventilatory changes to validate the fiberoptic PCO2 sensor. Under anesthesia a
      laparotomy was performed, the ileum punctured, and the fiberoptic PCO2 sensor
      introduced into the ileal lumen. Arterial PCO2 (PaCO2), mesenteric venous PCO2
      (PmvCO2), and intramucosal PCO2, (PiCO2) were determined during normoventilation,
      hypoventilation, and hyperventilation. During hypoventilation the PiCO2 increased
      from 53.8 +/- 2.0 mm Hg (PaCO2 = 39.8 +/- 1.4 mm Hg, PmvCO2 = 48.7 +/- 2.7 mm Hg)
      to 66.5 +/- 4.9 mm Hg (PaCO2 = 52.7 +/- 3.1 mm Hg, PmvCO2 = 62.4 +/- 5.7 mm Hg).
      With hyperventilation the PiCO2 decreased to 46.8 +/- 2.5 mm Hg (PaCO2 = 29.8 +/-
      1.8 mm Hg, PmvCO2 = 41.8 +/- 2.7 mm Hg). The coefficient of correlation (r2)
      between PiCO2 and PaCO2 was 0.82, and between PiCO2 and PmvCO2 0.94. The
      fiberoptic PCO2 sensor can determine PiCO2 in a precise and reliable manner, and
      can continuously record fast intraluminar changes of CO2 in the ileum that were
      caused by ventilatory changes. The fiberoptic PCO2 sensor is the only method that
      reliably monitors PiCO2 in the gastrointestinal tract. By the direct measurement
      of PCO2 the methodological problems associated with the conventional nasogastric
      tonometry are abolished.

PMID- 8659767
TI  - Epinephrine dysrhythmogenicity is not enhanced by subtoxic bupivacaine in dogs.
AB  - Since bupivacaine and epinephrine may both precipitate dysrhythmias, circulating
      bupivacaine during regional anesthesia could potentiate dysrhythmogenic effects
      of epinephrine. We therefore examined whether bupivacaine alters the
      dysrhythmogenicity of subsequent administration of epinephrine in conscious,
      healthy dogs and in anesthetized dogs with myocardial infarction. Forty-one
      conscious dogs received 10 micrograms.kg-1.min-1 epinephrine. Seventeen animals
      responded with ventricular tachycardia (VT) within 3 min. After 3 h, these
      responders randomly received 1 or 2 mg/kg bupivacaine or saline over 5 min,
      followed by 10 micrograms.kg-1.min-1 epinephrine. In the bupivacaine groups,
      epinephrine caused fewer prodysrhythmic effects than without bupivacaine. VT
      appeared in fewer dogs and at a later time, and there were more sinoatrial beats
      and less ectopies. Epinephrine shortened QT less after bupivacaine than in
      control animals. One day after experimental myocardial infarction, six additional
      halothane-anesthetized dogs received 4 micrograms.kg-1.min-1 epinephrine until VT
      appeared. After 45 min, 1 mg/kg bupivacaine was injected over 5 min, again
      followed by 4 micrograms.kg-1.min-1 epinephrine. In these dogs, the
      prodysrhythmic response to epinephrine was also mitigated by preceding
      bupivacaine. Bupivacaine antagonizes epinephrine dysrhythmogenicity in conscious
      dogs susceptible to VT and in anesthetized dogs with spontaneous postinfarct
      dysrhythmias. There is no evidence that systemic subtoxic bupivacaine
      administration enhances the dysrhythmogenicity of subsequent epinephrine.

PMID- 8659768
TI  - The direct effects of enflurane on coronary blood flow, myocardial oxygen
      consumption, and myocardial segmental shortening in in situ canine hearts.
AB  - This study evaluated changes in coronary blood flow (CBF), myocardial oxygen
      consumption (MVo2), and myocardial segmental shortening (SS) during intracoronary
      administrations of enflurane in in situ canine hearts. The left anterior
      descending coronary artery (LAD) of 11 anesthetized and mechanically ventilated
      dogs was perfused at constant perfusion pressure (80 mm Hg) with enflurane-free
      blood or with blood equilibrated in an extracorporeal oxygenator with enflurane
      (1.1%, 2.2%, 4.4%). CBF (measured with a Doppler flow transducer) was multiplied
      by the local arteriovenous (A-V) O2 difference to calculate MVo2. SS was measured
      with ultrasonic crystals. Myocardial lactate uptake was assessed. Peak CBF
      responses during enflurane were compared with those during maximum coronary
      vasodilation with adenosine. Enflurane caused concentration-dependent increases
      in CBF, and decreases in MVo2 and SS. The greatest increase in CBF during
      enflurane (4.4%) was similar to that achievable with adenosine. Myocardial
      lactate uptake was not affected by enflurane. In conclusion, enflurane has a
      direct coronary vasodilating effect. The potency of this effect is underscored by
      the ability of enflurane to cause marked increases in CBF, while appreciably
      reducing myocardial O2 demand. Since the enflurane-induced reduction in
      myocardial contractility was not due to ischemia, it likely reflected a direct
      negative inotropic effect. When the direct effects of enflurane are compared with
      those of equianesthetic concentrations of halothane and isoflurane previously
      shown in the same model, enflurane has a coronary vasodilating effect similar to
      that of halothane but less than that of isoflurane, and it has a negative
      inotropic effect greater than that of both isoflurane and halothane.

PMID- 8659769
TI  - Nonstereospecific actions of ketamine isomers on the force of contraction,
      spontaneous beating rate, and Ca2+ current in the guinea pig heart.
AB  - Ketamine possesses stereospecific actions of anesthesia with the S(+)-isomer
      being three to four times as potent an anesthetic as the R(-)-isomer. We
      investigated the mechanical and electrophysiologic effects of ketamine isomers in
      guinea pig cardiac preparations. Both isomers decreased the contractile force of
      electrically driven papillary muscles and the spontaneously beating rate of the
      right atria in a concentration-dependent manner. There were no significant
      differences between the S(+)- and R(-)-isomers for these measured variables.
      Consistent with the results from mechanical experiments, electrophysiologic
      experiments using whole cell voltage clamp techniques revealed that both isomers
      suppressed identically the transsarcolemmal Ca2+ current (ICa), which plays a
      role in the generation of the force of contraction and the spontaneous firing of
      sinoatrial node cells. In conclusion, the optical isomers of ketamine have
      equipotent cardiodepressant effects in the guinea pig. Inasmuch as the S(+)
      isomer is the more potent anesthetic, it could offer significant clinical
      advantage over the R(-)-isomer or the racemate, in terms of impairment of cardiac
      functions, if the present results could be extrapolated to the clinical setting.

PMID- 8659770
TI  - Patient-controlled epidural analgesia after thoracotomy: a comparison of
      meperidine with and without bupivacaine.
AB  - The purpose of this study was to compare meperidine to meperidine with
      bupivacaine when used for patient-controlled epidural analgesia (PCEA) after
      thoracotomy. For 3 days after thoracotomy patients received thoracic PCEA with
      meperidine 0.1% plain or with added bupivacaine 0.1% or 0.01%. No background
      infusion was used. All patients received indomethacin postoperatively for the
      duration of the study. Patients were assessed with respect to meperidine
      consumption, analgesia, and side effects. Sixty-six patients participated.
      Patients in all three groups obtained effective analgesia with median meperidine
      consumption of 5-6 mg/h. There were no significant differences between groups in
      meperidine consumption or pain scores at rest or with coughing. The addition of
      bupivacaine 0.1% reduced the incidence of pruritus (P = 0.036), but 5 of 23
      patients in this group were with-drawn from the study because of significant
      hypotension, oliguria, and/or motor or sensory block (P = 0.006). We conclude
      that the addition of bupivacaine 0.1% or 0.01% to thoracic PCEA meperidine 0.1%
      does not affect meperidine requirements or analgesia after thoracotomy. The
      addition of bupivacaine 0.1% may reduce pruritus, but is associated with signs of
      excessive sensory, motor, or autonomic blockade in a significant number of
      patients.

PMID- 8659771
TI  - Intravenous tramadol versus epidural morphine for postthoracotomy pain relief: a
      placebo-controlled double-blind trial.
AB  - Tramadol, an analgesic deriving only part of its effect via opioid agonist
      activity, might provide postoperative pain relief with minimal risk of
      respiratory depression. We, therefore, evaluated it for the control of
      postthoracotomy pain. In this randomized, double-blind study, a single
      intravenous (IV) bolus dose of 150 mg tramadol (Group T) was compared to epidural
      morphine administered as an initial 2-mg bolus and subsequent continuous infusion
      at a rate of 0.2 mg/h (Group M). Patients in each group could receive morphine IV
      from a patient-controlled analgesia (PCA) device. Pain scores, morphine
      consumption, arterial blood gases, and vital capacity values were recorded at
      regular intervals postoperatively until 8:00 AM on the first postoperative day.
      Both groups obtained adequate pain relief, and there were no between-group
      differences in pain scores or PCA morphine consumption. Pao2 was significantly
      higher in Group T at 2 h and Paco2 significantly higher in Group M at 4 h
      postoperatively. There were no other significant respiratory differences. We
      conclude that a single dose of 150 mg tramadol given at the end of surgery
      provided postoperative analgesia equivalent to that provided by this dosage
      regimen of epidural morphine for the initial postoperative period.

PMID- 8659772
TI  - Sustained-release ibuprofen as an adjunct to morphine patient-controlled
      analgesia.
AB  - Previous studies have demonstrated reduced postoperative morphine requirements
      and/or improved pain relief when nonsteroidal antiinflammatory drugs are
      administered in conjunction with patient-controlled analgesia (PCA). This double
      blind study aimed to determine whether these effects could be obtained with a
      sustained-release ibuprofen formulation (Brufen Retard) given preoperatively,
      obviating the need for oral administration during the early postoperative period.
      We aimed also to determine whether the anticipated reduction in morphine
      requirements was associated with reduced opioid side effects. One hundred fifteen
      patients scheduled for lower abdominal gynecological surgery were randomly
      assigned to receive either sustained-release ibuprofen, 2 x 800 mg (n = 57), or
      placebo (n = 58) preoperatively and again 24 h after the first dose. Arterial
      oxyhemoglobin saturation (Spo2) was monitored preoperatively and for 24 h
      postoperatively. Patients were assessed every 4 h up to 24 h postoperatively.
      Those receiving ibuprofen reported significantly less pain at rest (P = 0.023)
      and less pain on movement, although the latter was not statistically significant
      (P = 0.051). Patients' opinions of the efficacy of their pain-relieving
      medication (P < 0.001) and quality of sleep (P = 0.036) favored ibuprofen.
      Morphine consumption was slightly but not significantly lower in the ibuprofen
      group (32 vs 38 mg/24 h, P = 0.096). Spo2 (P = 0.54), level of consciousness (P =
      0.65), and number of antiemetic administrations (P = 0.15) did not differ
      significantly between groups. These results demonstrate improved efficacy with no
      increase in side effects when sustained-release ibuprofen is used as an adjunct
      to morphine PCA.

PMID- 8659773
TI  - Hemodynamic responses to an epinephrine test dose in adults during epidural or
      combined epidural-general anesthesia.
AB  - The efficacy of an epinephrine test dose during epidural and combined epidural
      general anesthesia is unknown. Thirty-two patients were randomized to receive 2%
      lidocaine at either a high (25 mL) or low (12 mL) thoracic level of epidural
      anesthesia followed by general anesthesia with 1 minimum alveolar anesthetic
      concentration nitrous oxide and isoflurane. A 15-micrograms epinephrine test dose
      was intravenously administered prior to placement of the lumbar epidural
      catheter, 20 min after initiation of epidural anesthesia, and after 10 min of
      stable end-tidal concentrations of general anesthesia. Only high thoracic levels
      (T-5) of epidural anesthesia reduced the peak systolic blood pressure response to
      epinephrine (34 +/- 17 vs 18 +/- 11 mm Hg, control versus epidural stage; P <
      0.05) and reduced the peak heart rate response when combined with general
      anesthesia (31 +/- 11 vs 15 +/- 8 bpm; P < 0.05). Incidences of identification of
      intravascular injection from hemodynamic responses were similarly reduced for
      systolic blood pressure (100% vs 44%) and heart rate (100% vs 38%). The standard
      15-micrograms epinephrine test dose is unaffected by low thoracic levels of
      epidural anesthesia, but may have decreased sensitivity for detection of
      intravascular injection during high thoracic levels of epidural anesthesia,
      especially during general anesthesia.

PMID- 8659774
TI  - Planning the future of anesthesiology.

PMID- 8659775
TI  - More on the changing indications for transfusion of blood and blood components
      during anesthesia.

PMID- 8659776
TI  - Reduction of postburn hyperalgesia after local injection of ketorolac in healthy
      volunteers.
AB  - BACKGROUND: Nonsteroidal antiinflammatory drugs may be particularly effective
      against prostaglandin-mediated, post-injury hyperalgesia and related inflammatory
      pain. However, their usefulness may be limited by their systemic side effects.
      The current study determined if local effectiveness can be achieved by low-dose
      intradermal nonsteroidal antiinflamatory drug administration. METHODS: Ten
      healthy volunteers were asked to make magnitude estimations of the pain induced
      by a contact thermal stimulator at 1 degree C increments between 43 and 51
      degrees C at three 1 x 1 cm study sites on each forearm during three study
      phases:(1) baseline; (2) after pretreatment with 10 microl 0.9% saline (n=1 site
      on each forearm), 0.3 mg ketorolac (n=1 on each forearm), or nothing (n=1 on each
      forearm); and (3) after "injury" by a mild burn at the ketorolac- and saline
      treated sites on one arm or by injection of 10 nmol bradykinin at all three sites
      on the other arm. The effects of pretreatment on the pain induced by thermal
      testing were assessed using repeated-measures analysis of variance. RESULTS:
      Pretreatment with ketorolac had a selective effect on the postburn injury
      hyperalgesia, reducing the increase in pain intensity (P<0.05) but not the
      decline in pain threshold. It had no effect on the responses to thermal stimuli
      before injury or on the pain of burning, which were similar at ketorolac- and
      saline-treated sites. The effect of pretreatment with ketorolac on bradykinin
      induced hyperalgesia was not achieved after bradykinin injection at sites
      pretreated with saline as well as ketorolac.

PMID- 8659777
TI  - Semilinear canonical correlation applied to the measurement of the
      electroencephalographic effects of midazolam and flumazenil reversal.
AB  - BACKGROUND: The electroencephalographic (EEG) effect of benzodiazepines, and
      midazolam in particular, has been described using simple measures such as total
      power in the beta band, waves.s(-1) in the beta band and total power from
      aperiodic analysis. All these parameters failed to consistently describe the EEG
      effect of midazolam in a study in which large doses of midazolam were infused,
      and the effect subsequently reversed with flumazenil. Using a technique called
      semilinear correlation it is possible to extract a parameter from the EEG that is
      statistically optimally correlated with the apparent concentration of the
      benzodiazepine in the effect site. This method has been used to develop new
      univariate measures of the effects of opioids on the EEG but has not previously
      been applied to the EEG effects of benzodiazepines. METHODS: Data from ten
      subjects who received an infusion of midazolam were analyzed. The data were
      divided into "learning" and "test" sets. The learning set consisted of ten
      studies in which the volunteers received an infusion of 2.5 mg.min(-1) midazolam.
      Semilinear canonical correlation was used to extract an univariate descriptor of
      the EEG effect by weighting the different frequency bands of the EEG power
      spectrum. The test set comprised the same subjects on subsequent visits, in which
      the subjects received a continuous infusion of midazolam to maintain 20% or 80%
      of the peak drug effect for 3h. Twenty minutes after start of the midazolam
      infusion, the patient received an infusion of flumazenil to acutely reverse the
      benzodiazepine drug effect. The weights obtained from the learning set were
      tested prospectively in the test set, based on the coefficient of multiple
      determination, R(2), obtained by fitting the EEG effect to a sigmoid Emax model.
      RESULTS: The canonical univariate parameter of benzodiazepine drug effect on the
      EEG, when applied to the test set receiving the midazolam infusion with
      flumazenil reversal, yielded a median R(2) of 0.78. The median R(2) of six
      commonly used empirical EEG measures of drug effect ranged from 0.18 to 0.55.
      CONCLUSIONS: The canonical univariate parameter for benzodiazepine drug effect on
      the EEG correlates more accurately and consistently with the predicted EEG
      effects of midazolam and its reversal than previously reported EEG measures of
      benzodiazepine effect.

PMID- 8659778
TI  - Pharmacodynamics and pharmacokinetics of cisatracurium in geriatric surgical
      patients.
AB  - BACKGROUND: Cisatracurium, one of ten stereoisomers that comprise atracurium, is
      more potent than atracurium and has less propensity to release histamine. This
      study compares the pharmacokinetics and pharmacodynamics of cisatracurium in
      elderly and young patients. METHODS: Twelve elderly (aged 65-82 yr) and 12
      younger patients (aged 30-49 yr) were anesthetized with nitrous oxide, fentanyl,
      and isoflurane (0.7%, end-tidal). The mechanomyographic response to train-of-four
      stimulation was assessed every 15 s after the administration of cisatracurium
      (0.1 mg/kg). Arterial samples were obtained over 6 h. Plasma cisatracurium
      concentration versus time data were fit to compartmental models. Pharmacokinetic
      parameters were determined assuming that elimination occurred from the central
      compartment only. This provides accurate clearance and half-life estimates but
      underestimates V(ss) (reported herein as V(ss). The pharmacodynamic response was
      described by the neuromuscular blocking profile. RESULTS: Onset to 90% paralysis
      (mean +/- SD) was delayed in the elderly (3.4 +/- 1.0 vs. 2.5 +/- 0.6 min).
      Recovery profiles were the same for both groups. Elimination half-life was
      minimally prolonged in the elderly (25.5 +/- 3.7 vs. 21.5 +/- 2.4 min). The Vss
      was larger in the elderly (126 +/- 16 vs. 108 +/- 13 ml/kg), although the
      clearances were the same for the two groups (5.0 +/- 0.9 vs. 4.6 +/- 0.8 ml.kg(
      1).min(-1). CONCLUSIONS: There are minor differences in the pharmacokinetics of
      cisatracurium between elderly and young patients. These differences are not
      associated with changes in recovery profile after a single bolus dose, although
      the mean time to onset was approximately 1 min longer in elderly patients.

PMID- 8659779
TI  - Pharmacokinetics of propofol after a single dose in children aged 1-3 years with
      minor burns. Comparison of three data analysis approaches.
AB  - BACKGROUND: No complete pharmacokinetic profile of propofol is yet available in
      children younger than 3 yr, whereas clinical studies have demonstrated that both
      induction and maintenance doses of propofol are increased with respect to body
      weight in this age group compared to older children and adults. This study was
      therefore undertaken to determine the pharmacokinetics of propofol after
      administration of a single dose in aged children 1-3 yr requiring anesthesia for
      dressing change. METHODS: This study was performed in 12 children admitted to the
      burn unit and in whom burn surface area was less than or equal to 12% of total
      body surface area. Exclusion criteria were: unstable hemodynamic condition,
      inappropriate fluid loading, associated pulmonary injury, or burn injury older
      than 2 days. Propofol (4 mg.kg(-1))plus fentanyl (2.5 microg.kg(-1)) was
      administered while the children were bathed and the burn area cleaned during
      which the children breathed spontaneously a mixture of oxygen and nitrous oxide
      (50:50). Venous blood samples of 300 microl were obtained at 5, 15, 30, 60, 90,
      and 120 min, and 3, 4, 8, and 12 thereafter injection; an earlier sample was
      obtained from 8 of 12 children. The blood concentration curves obtained for
      individual children were analyzed by three different methods: noncompartmental
      analysis, mixed effects population model, and standard two-stage analysis.
      RESULTS: Using noncompartmental analysis, total clearance of propofol (+/-SD) was
      0.053+/-0.013l.kg(-1).min(-1), volume of distribution at steady state9.5 +/-
      3.7l.kg(-1),and residence time 188 +/- 85 min. Propofol pharmacokinetics were
      best described by a weight-proportional three-compartmental model in both
      population and two-stage analysis. Estimated and derived pharmacokinetic
      parameters were similar using these two pharmacokinetic approaches. Results of
      population versus two-stage analysis are as follow: systemic clearance 0.049
      versus 0.048 l.kg(-).min(-1), volume of central compartment 1.03 versus 0.95
      l.kg(-1), volume of steady state 8.09 versus 8.17 l.kg(-1). CONCLUSIONS: The
      volume of the central compartment and the systemic clearance were both greater
      than all values reported in older children and adults. This is consistent with
      the increased propofol requirements for both induction and maintenance of
      anesthesia in children 1-3 yr. (Key words: Anesthesia: pediatric.
      Pharmacokinetics: propofol.)

PMID- 8659780
TI  - Intravenous lidocaine and bupivacaine dose-dependently attenuate bronchial
      hyperreactivity in awake volunteers.
AB  - BACKGROUND: In standard textbooks, intravenous lidocaine is recommended for
      intubation of patients with bronchial hyperreactivity. However, whether and to
      what extent intravenous local anesthetics attenuate bronchial hyperreactivity in
      humans is unknown. Accordingly, nine awake volunteers with known bronchial
      hyperreactivity were subjected to an inhalational challenge with acetylcholine
      before and during intravenous infusion of lidocaine, bupivacaine, or placebo in a
      randomized, double-blinded fashion. METHODS: Baseline acetylcholine threshold
      concentrations were determined 3-5 days before initiation of the investigation.
      The response to the acetylcholine challenge was defined as hyperreactive, if
      forced expiratory volume in 1 s decreased by at least 20%. In addition, the
      acetylcholine threshold for a 100% increase in airway resistance was obtained by
      body plethysmography. On seven different days, the acetylcholine challenge was
      repeated at the end of a 30-min intravenous infusion period of three doses of
      lidocaine (1, 3, and 6 mg.min(-1)) or bupivacaine (0.25, 0.75, and 1.5 mg.min(
      1)), during saline placebo infusion, respectively. Acetylcholine-threshold
      concentrations were presented with the respective plasma concentrations of the
      local anesthetic. RESULTS: The infusion of lidocaine and bupivacaine resulted in
      plasma concentrations (means +/- SD) of 0.29 +/- 0.11, 1.14 +/- 0.39, and 2.02 +/
      0.5 microg.ml(-1) for lidocaine and 0.11 +/- 0.04, 0.31 +/- 0.09, and 0.80 +/-
      0.18 microg.ml(-1) for bupivacaine, respectively. Compared to baseline, the
      acetylcholine threshold for a 20% decrease of forced expiratory volume in 1 s as
      well as the threshold for a 100% increase in total airway resistance increased
      significantly with increasing plasma concentrations of both local anesthetics.
      Compared to placebo, acetylcholine threshold was almost quadrupled for lidocaine
      and tripled for bupivacaine with the highest plasma concentration of each local
      anesthetic. CONCLUSIONS: In awake humans, intravenous lidocaine and bupivacaine
      both dose-dependently attenuated the hyperreactive response to a nonspecific
      inhalational challenge with acetylcholine.

PMID- 8659781
TI  - Effect of epidural analgesia on fundal dominance during spontaneous active-phase
      nulliparous labor.
AB  - BACKGROUND: The purpose of this investigation was to determine if epidural
      analgesia, established during active phase labor, results in elimination or
      reversal of fundal dominance (lower uterine segment pressure equal to or greater
      than fundal pressure). METHODS: Upper and lower uterine segment intrauterine
      pressures were prospectively evaluated for 50 min before and 50 min after
      epidural analgesia using 0.25% bupivacaine in 11 nulliparous women in spontaneous
      active labor. A total of 958 contractions were evaluated. RESULTS: No significant
      differences were found in the number of contractions in the interval before
      epidural analgesia compared to after epidural analgesia. Significantly greater
      pressure readings were recorded in the upper segment than in the lower segment
      (consistent with fundal dominance) both before and after epidural analgesia
      (P<0.01). In addition, fundal dominance increased after epidural analgesia when
      compared to the preanalgesia period (P<0.01). CONCLUSIONS: Fundal dominance is
      present both before and after active phase epidural analgesia and is increased
      during the immediate 50-min postanalgesia period.

PMID- 8659782
TI  - Beat-to-beat augmentation of left ventricular function by intraaortic
      counterpulsation.
AB  - BACKGROUND: Measuring the effects of intraaortic balloon counterpulsation (IABP)
      in single cardiac beats may permit an improved understanding of the physiologic
      mechanisms by which IABP improves the circulation. The objective of the study was
      to use trans- esophageal echocardiography in combination with hemodynamic
      measurements to test the hypothesis that IABP improves global left ventricular
      systolic function selectively in the IABP-augmented cardiac beats by acutely
      decreasing left ventricular afterload. METHODS: Twenty-seven studies in which the
      IABP-to-R wave trigger ratio was serially changed from 1:1, 1:2, 1:4, 0:1 (IABP
      off) and back to 1:1 were performed in 20 anesthetized cardiac surgical patients
      during IABP support. Left ventricular short-axis end-diastolic cross-sectional
      area, end-systolic area, mean end-systolic wall thickness, and ejection time were
      measured by transesophageal echocardiography at the midpapillary muscle level.
      Aortic pressure was measured simultaneously from the central lumen of the
      intraaortic balloon catheter. These measurements were used to calculate the
      fractional area change, end-systolic meridional wall stress, and heart rate
      corrected velocity of circumferential fiber shortening. The echocardiographic and
      hemodynamic parameters of left ventricular preload, afterload, and systolic
      function immediately after balloon deflation (IABP-augmented cardiac beats) were
      compared to the parameters measured during nonaugmented cardiac beats to
      determine the beat-to-beat effects of IABP on left ventricular function. RESULTS:
      IABP-augmented cardiac beats had a decreased systolic arterial pressure and end
      systolic meridional wall stress and increased diastolic blood pressure,
      fractional area change, and velocity of circumferential fiber shortening compared
      to nonaugmented cardiac beats. IABP did not cause significant beat-to-beat
      changes in heart rate, pulmonary artery diastolic pressure, or central venous
      pressure. The improvement in left ventricular systolic function associated with
      IABP-augmented cardiac beats correlated with the decrease in end-systolic
      meridional wall stress for that cardiac beat. CONCLUSIONS: Beat-to-beat
      echocardiographic and hemodynamic measurements performed in anesthetized cardiac
      surgical patients during IABP support demonstrated improved left ventricular
      systolic function and decreased left ventricular systolic wall stress in the
      cardiac beats immediately after balloon deflation. The relationship between left
      ventricular systolic function and left ventricular systolic wall stress during
      IABP support suggests that afterload reduction was an important mechanism by
      which IABP instantaneously improved circulatory function in anesthetized cardiac
      surgical patients.

PMID- 8659783
TI  - Preservation of the ration of cerebral blood flow/metabolic rate for oxygen
      during prolonged anesthesia with isoflurane, sevoflurane, and halothane in
      humans.
AB  - BACKGROUND: In several animal studies, an increase in cerebral blood flow (CBF)
      produced by volatile anesthetics has been reported to resolve over time during
      prolonged anesthesia. It is important to investigate whether this time-dependent
      change of CBF takes place in humans, especially in clinical situations where
      surgery is ongoing under anesthesia. In this study, to evaluate the effect of
      prolonged exposure to volatile anesthetics (isoflurane, sevoflurane, and
      halothane), the CBF equivalent (CBF divided by cerebral metabolic rate for oxygen
      (CMRO2) was determined every 20 min during anesthesia lasting more than 4h in
      patients. METHODS: Twenty-four surgical patients were assigned to three groups at
      random to receive isoflurane, sevoflurane, or halothane (8 patients each). End
      tidal concentration of the selected volatile anesthetic was maintained at 0.5 and
      1.0 MAC before surgery and then 1.5 MAC for the 3 h of surgical procedure.
      Normothermia and normocapnia were maintained. Mean arterial blood pressure was
      kept above 60 mmHg, using phenylephrine infusion, if necessary. CBF equivalent
      was calculated every 20 min as the reciprocal of arterial-jugular venous oxygen
      content difference. RESULTS: CBF equivalent at 0.5 MAC of isoflurane, halothane,
      and sevoflurane was 21 +/- 4, 20 +/- 3, and 21 +/- 5 ml blood/ml oxygen,
      respectively. All three examined volatile anesthetics significantly (P<0.01)
      increased CBF equivalent in a dose-dependent manner (0.5, 1.0, 1.5 MAC). AT 1.5
      MAC, the increase of CBF equivalent with all anesthetics was maintained increased
      with minimal fluctuation for 3 h. The mean value of CBF equivalent at 1.5 MAC in
      the isoflurane group (45 +/- 8) was significantly (P<0.01) greater than those in
      the halothane (32 +/- 8) and sevoflurane (31 +/- 8) groups. Electroencephalogram
      was found to be relatively unchanged during observation periods at 1.5 MAC.
      CONCLUSIONS: These results demonstrate that CBF/CMRO2 ratio is markedly increased
      above normal and maintained during prolonged inhalation of volatile anesthetics
      in humans. It is impossible to determine whether these data indicate a stable CBF
      or whether CBF and CMRO2 are changing in parallel during the observation period.
      The unchanging electroencephalographic pattern suggests that the former
      possibility is more likely and that the increase of CBF produced by volatile
      anesthetics is maintained over time without decay, which has been reported in
      several animal studies. It also is suggested that isoflurane possesses greater
      capability to maintain global CBF relative to CMRO(2) than does halothane or
      sevoflurane. time.)

PMID- 8659784
TI  - Mivacurium when preceded by pancuronium becomes a long-acting muscle relaxant.
AB  - BACKGROUND: To ensure rapid recovery of neuromuscular block, it might be useful
      to administer a short-acting relaxant after a long-acting one. Therefore, the
      interaction between pancuronium and mivacurium was investigated when mivacurium
      was administered during the recovery from pancuronium block. METHODS: After
      written informed consent, 41 adult patients were studied during
      propofol/alfentanil/nitrous oxide/oxygen anesthesia. Neuromuscular function was
      monitored using an electromyographic (EMG) method. AFter a stable EMG calibration
      response, cumulative doses of pancuronium were given to establish a 95%
      neuromuscular block. In the control group, and ED95 dose of 100 microg/kg
      mivacurium was administered instead of pancuronium. When the EMG response after
      pancuronium or mivacurium had recovered to 25% of the baseline, a single
      randomized intravenous bolus dose of 10 or 70 microg/kg mivacurium was given.
      Thereafter, spontaneous recovery of the neuromuscular function was recorded.
      RESULTS: The time from pancuronium until T1 25% EMG recovery was 38 +/- 12 min
      (mean +/- SD). The respective times after 10 or 70 microg/kg mivacurium were 28
      +/- 8 and 54 +/- 7 min in the pancuronium group or 3 +/- 1 (n=3) and 10 +/- 4 min
      in the mivacurium group (P=0.0001). Times to 95% EMG recovery after 10 or 70
      microgm/kg mivacurium were 77 +/- 14 and 97 +/- 16 min in the pancuronium group
      and 11 +/- 3 and 20 +/- 7 min in the mivacurium group, respectively (P<0.0001).
      Recovery indexes after 10 or 70 microg/kg mivacurium group, respectively
      (P<0.0001). Recovery indexes after 10 or 70 microg/kg mivacurium wre 26 +/- 4 and
      22 +/- 6 min in the pancuronium group or 7 +/- 3 (n=3) and 5+/- 2 min in the
      mivacurium group, respectively (P<0.0001). Times from the administration of 10 or
      70 microg/kg mivacurium until train-of-four ration 0.7 were 94 +/- 16 and 111 +/-
      14 min in the pancuronium group and 12 +/- 4 and 22 +/- 8 min in the mivacurium
      group, respectively (P<0.0001). CONCLUSIONS: After pancuronium, mivacurium is not
      a short acting neuromusclar blocking agent.

PMID- 8659785
TI  - Compound A concentrations during sevoflurane anesthesia in children.
AB  - BACKGROUND: Sevoflurane is a new inhalation agent that should be useful for
      pediatric anesthesia. Sevoflurane undergoes degradation in the presence of carbon
      dioxide absorbents; however, quantification of the major degradation product
      (compound A) has not been evaluated during pediatric anesthesia. This study
      evaluates sevoflurane degradation compound concentrations during sevoflurane
      anesthesia using a 2-1 fresh gas flow and a circle system with carbon dioxide
      absorber in children with normal renal and hepatic function. METHODS: The
      concentrations of compound A were evaluated during sevoflurane anesthesia in
      children using fresh soda lime as the carbon dioxide absorbent. Nineteen patients
      aged 3 months-7 yr were anesthetized with sevoflurane (2.8% mean end-tidal
      concentration) using a total fresh gas flow of 21 in a circle absorption system.
      Inspiratory and expiratory limb circuit gas samples were obtained at hourly
      intervals, and the samples were analyzed using a gas chromatography-flame
      ionization detection technique. Carbon dioxide absorbent temperatures were
      measured in the soda lime during anesthesia for hepatic and renal function
      studies. Venous blood samples were obtained before anesthesia, at the end of
      anesthesia, and 2h after anesthesia for plasma inorganic fluoride ion
      concentration. RESULTS: The maximum inspiratory concentration of compound A was
      5.4 +/- 4.4 ppm (mean +/- SD), and the corresponding expiratory concentration was
      3.7 +/- 2.7 ppm (mean +/- SD). The maximum inspiratory compound A concentration
      in any patient was 15 ppm. Mean concentrations of compound A peaked at intubation
      and remained stable, declining slightly after 120 min of anesthesia. The duration
      of anesthesia was 240 +/- 139 min (mean +/-SD). Maximum soda lime temperature
      ranged between 23.1 degrees C and 40.9 degrees C. There was a positive
      correlation between maximum absorbent temperature and maximum compound A
      concentration (r2 = 0.58), as well as between the child's body surface area and
      maximum compound A concentration (r2 = 0.59). Peak plasma inorganic fluoride ion
      concentration was 21.5 +/- 6.1 microgmol/1. There were no clinically significant
      changes in hepatic or renal function studies performed 24 h postanesthesia.
      CONCLUSIONS: Sevoflurane anesthesia of 4 h in normal children using a 2-1 flow
      circle system produced concentrations of compound A of 15 ppm or less. There was
      no evidence of abnormality of renal or hepatic function up to 24 h after
      anesthesia; however, larger studies will be required to confirm the absence of
      organ toxicity.

PMID- 8659786
TI  - Preemptive analgesic effects of steroid anesthesia with alphaxalone in the rat
      formalin test. Evidence for differential GABA(A) Receptor modulation in
      persistent nociception.
AB  - BACKGROUND: The role of preemptive treatment with volatile and intravenous
      anesthetics has been examined in previous studies using the rat formalin test.
      Evidence describing analgesic properties of the gamma-amino butyric acid-ergic
      (GABAergic) steroid anesthetics, such as alphaxalone, suggest that they may
      suppress the development of central sensitization to pain. This study examined
      the preemptive effects of phaxalone in comparison with other GABAergic
      anesthetics, propofol and pentobarbital. METHODS: The pain behavior of rats was
      evaluated (using the previously validated weighted scores method of behavioral
      rating) 15-60 min after subcutaneous hind paw injection of 50 microg 1.5%
      formalin. In each trial, anesthetics and their respective vehicles were
      administered by tail-vein injection either 0.5-10 min before or 5 min after,
      formalin injection. When analgesic effects were observed with any of these
      agents, further studies were conducted with a GABA(A) receptor antagonist in an
      attempt to confirm a specific receptor-mediated action of the agent. RESULTS:
      Alphaxalone pretreatment produced transient analgesia in the early part of phase
      2, which was not observed in rats posttreated with alphaxalone. The analgesic
      effect of alphaxalone was antagonized by picrotoxin, as well. Neither
      pentobarbital nor propofol showed any analgesic effects at the doses used in our
      study. CONCLUSIONS: Whereas alphaxalone was shown to produce preemptive analgesia
      through its action at the GABA(A) receptor, pentobarbital and propofol, which
      also are known to act at this site, showed no analgesic effects. The diversity of
      receptor subtypes and functional complexity of GABA(A) receptors is such that
      steroid anesthetics may have effects that are different from other GABAergic
      agents. Further research into the role of progesterone metabolites and steroid
      anesthetics in the prevention of central sensitization may have clinical
      implications for the treatment of acute or chronic pain.

PMID- 8659787
TI  - Dual actions of halothane on intracellular calcium stores of vascular smooth
      muscle.
AB  - BACKGROUND: Halothane has been reported to affect the integrity of intracellular
      Ca2+ stores in a number of tissues including vascular smooth muscle. However, the
      actions of halothane on intracellular Ca2+ stores are not yet fully understood.
      METHODS: Employing the isometric tension recording method, the action of
      halothane in isolated endothelium-denuded rat mesenteric arteries under either
      intact or beta-escinmembrane-permeabilized conditions was investigated. RESULTS:
      Halothane (0.125-5%) produced concentration-dependent contractions in Ca2+ free
      solution in both intact and membrane-permeabilized muscle strips. Ryanodine
      treatment or repetitive application of phenylephrine eliminated both caffeine-and
      halothane-induced contractions in the Ca2+ free solution. When either halothane
      and caffeine, caffeine and halothane, phenylephrine and halothane, or inositol
      1,4,5-triphosphate and halothane were applied consecutively in the Ca2+ free
      solution in either intact or membrane-permeabilized muscle strips, the
      contraction induced by application of the second agent of the pair was inhibited
      compared to application of that agent alone. However, when procaine was applied
      before and during application of the first agent, the contraction induced by the
      first agent was inhibited and the contraction induced by the second agent was
      restored. Heparin inhibited the inositol 1,4,5-triphosphate-mediated contraction,
      but not contractions induced by halothane or caffeine. Halothane (0.125-5%),
      applied during Ca2+ loading, produced concentration-dependent inhibition of the
      caffeine contraction (used to estimate the amount of Ca2+ in the store) in both
      intact and membrane-permeabilized muscle strips. In contrast, halothane applied
      with procaine during Ca2+ loading produced concentration-dependent enhancement of
      the caffeine contraction. This enhancement was observed only in the intact but
      not in the membrane-permeabilized condition. CONCLUSIONS: Halothane has two
      distinct actions on the intracellular Ca2+ stores of vascular smooth muscle, a
      Ca2+ releasing action and a stimulating action on Ca2+ uptake. Halothane releases
      Ca2+ from the stores that are sensitive to both caffeine/ryanodine and
      phenylephrine/inositol 1,4,5-triphosphate through a procaine-sensitive mechanism.
      The observed inhibitory effect on Ca2+ uptake is probably caused by the Ca2+
      uptake after blockade of Ca2+ release may be membrane-mediated.

PMID- 8659788
TI  - Effects of thiopental on regional blood flows in the rat.
AB  - BACKGROUND: The goal of this investigation was to characterize the effects of
      thiopental on cardia output and regional blood flows in the rat. Blood flows
      influence thiopental pharmacokinetics. Acquisition of these data may ultimately
      permit evaluation of the contribution of thiopental-induced alterations in
      regional blood flows to the disposition and hypnotic effect of this drug.
      METHODS: Chronically instrumented unrestrained Wistar rats (n=20) aged 3-4 months
      received either a dose of thiopental sufficient to induce a brief period of
      unconsciousness (20 mg.kg(-1)) or a larger dose achieving electroencephalographic
      burst suppression (45 mg.kg(-1)). Cardiac output and blood flows to 14 tissues
      were determined at 4 times in each rat for a period of 420 min using injections
      of radioactive microspheres (expressed as mean +/- SD). Mean arterial pressure,
      heart rate, and blood gas tensions were determined at all measurement times.
      Arterial plasma concentrations were sampled at postinfusion times. RESULTS: No
      important changes in systemic cardiovascular measurements were detected after the
      smaller dose of thiopental. One minute after the larger dose, cardiac output
      decreased from baseline (123 +/- 14 to 84 +/- ml.min (-1), P< 0.01), flow to
      muscle and fat decreased, and muscle and fat resistance increased. At 5 min,
      compared to baseline, no difference in cardiac output was detected (123 +/- vs.
      119 +/- ml.min (-1)), intestinal flows increased and intestinal resistances
      decreased. Cardiac output was again depressed at 30, 90, and 180 min. Brain blood
      flow decreased 25 +/- 19 % (P< 0.01) from baseline for the duration of the study.
      CONCLUSIONS: Thiopental acutely decreases cardiac output, and blood flows to
      muscle and fat tissue. The temporary return of cardiac output to baseline may be
      related to intestinal vasodilation. These blood flow alterations may influence
      the pharmacokinetics of thiopental.

PMID- 8659789
TI  - Divergence of intracranial and central venous pressures in lightly anesthetized,
      tracheally intubated dogs that move in response to a noxious stimulus.
AB  - BACKGROUND: Intracranial pressure (ICP) may increase in tracheally intubated
      subjects during periods of movement (e.g, "bucking" and coughing). Recent
      research has suggested that factors other than passive congestion of the cerebral
      vessels, resulting from increases in central venous pressure, may contribute to
      the ICP response. The current study evaluated this issue in a canine model of
      intracranial hypertension and additionally evaluated the relationship between ICP
      and static increases in superior vena caval pressure. METHODS: Six dogs were
      lightly anesthetized with 0.65% end-expired halothane in oxygen and nitrogen, and
      ventilation was mechanically controlled. Intracranial pressure was increased to a
      stable baseline of 15-20 mmHg using a subarachnoid infusion of warm 0.9% saline
      solution. The following variables were quantified before, and for 6 min after,
      initiating a 1-min noxious stimulus to the trachea and skin: ICP, central venous
      pressure, electromyograms (masseter, deltoid, and intercostal muscles),
      intrathoracic pressure, and cerebral perfusion pressure (defined as mean arterial
      pressure -- ICP). Later, the protocol was repeated in the presence of
      neuromuscular block with pancuronium. Finally, in the same dogs, occlusion of the
      superior vena cava at its junction with the right atrium was used to increase
      superior vena caval pressure in 5-mmHg increments, from 5 to 30 mmHG, so that the
      resulting increases in ICP could be quantified. RESULTS: In unparalyzed dogs
      whose heads were maintained at the level of the right atrium, there was a 22-mmHg
      increase in ICP at 1 min after initiating the noxious stimulus (P<0.05). The ICP
      increase was related to electromyogram activation and a 6-mmHg increase in
      central venous pressure; however, it was not associated with significant
      increases in intrathoracic pressure or cerebral perfusion pressure. Treatment
      with pancuronium abolished the electromyographic, ICP, and central venous
      pressure responses to noxious stimulus. When superior vena caval pressure was
      statically manipulated, the resulting ICP increase was only one half the
      magnitude of the superior vena caval pressure increase. After elevating the head
      14 cm, the ratio of ICP to superior vena pressure increases was reduced to one
      third. CONCLUSIONS: If these results apply to humans, it was concluded that
      increases in ICP that accompany movement in tracheally intubated patients may
      arise from two complementary factors: (1) cerebrovascular dilation that
      correlates with electromyographic activity and is mediated by ascending neural
      pathways that transmit proprioreceptive information, and (2) passive venous
      congestion that results from any increase in central venous pressure. The
      influence of the latter factor can be reduced by elevating the head. (Key words:
      Blood pressure, venous pressure; mean arterial pressure. Muscle: afferent
      activity; electromyograms, skeletal. Neuromuscular relaxants: pancuronium.)

PMID- 8659790
TI  - Influence of polyethylene glycol superoxide dismutase/catalase on altered opioid
      induced pial artery dilation after brain injury.
AB  - BACKGROUND: The current study was designed to investigate the influence of
      pretreatment with the oxygen radical scavengers polyethylene glycol superoxide
      dismutase and catalase (SODCAT) on altered opioid-induced pial artery dilation
      after fluid percussion brain injury (FPI) in the newborn pig. It has been
      observed previously that brain injury produces pial artery vasoconstriction in
      the piglet associated with elevated cerebrospinal fluid opioid levels.
      Furthermore, opioid-induced vasodilation and cyclic guanosine monophosphate
      production are attenuated following brain injury. Finally, oxygen free radicals
      have been implicated in the pathogenesis of brain injury. METHODS: Anesthetized
      piglets equipped with a closed cranial window were connected to a percussion
      device consisting of a saline-filled cylindrical reservoir with a metal pendulum.
      Fluid percussion brain injury of moderate severity (1.9-2.3 atm) was produced by
      allowing the pendulum to strike a piston on the cylinder. Superoxide dismutase
      inhibited nitroblue tetrazolium reduction was determined as an index of
      superoxide generation. RESULTS: Superoxide dismutase- inhibited tetrazolium was
      increased markedly after FPI and these increases were blunted by SODCAT (1,000
      U/kg and 10,000 U/kg, respectively) treatment 30 min before FPI (1 +/- 1 vs. 14
      +/- 2 vs. 1 +/- 1 pmol/mm(2) for control, FPI, and FPI pretreated with SODCAT,
      respectively). Methionine enkephalin, an endogenous mu opioid agonist, produced
      vasodilation that was attenuated by FPI and partially restored by SODCAT
      pretreatment (17 +/- 1, 8 +/- 1, and 14 +/- 1% for methionine enkephalin 10(-6)m
      during control conditions, after FPI and after FPI pretreated with SODCAT,
      respectively). Methionine enkephalin-induced dilation was associated with
      increased cerebrospinal fluid cycle guanosine monophosphate and these biochemical
      changes were likewise blunted by FPI and partially restored by SODCAT (342 +/- 12
      and 640 +/- 13 vs. 267 +/- 6 and 321 +/- 17 vs. 301 +/- 9 and 504 +/- 43 fmol/ml
      for resting conditions and 10 (-6)M methionine enkephalin during control, after
      FPI, and after FPI pretreated with SODCAT, respectively). Leucine enkephalin, an
      endogenous delta agonist, induced pial dilation and associated changes
      incerebrospinal fluid cyclic guanosine monophosphate, which were similarly
      altered by FPI and partially restored by SODCAT. Dynorphin, an endogenous kappa
      agonist, which has been shown to revert from a dilator to a constrictor after
      FPI, was restored to a vasodilator by SODCAT (18 +/- 1, -11 +/- 4, and 17 +/-5%
      for dynorphin 10(-6)m during control conditions, after FPI, and after FPI
      pretreated with SODCAT, respectively). Dynorphin-induced vasodilation was
      associated with a large increase in cerebrospinal fluid cyclic guanosine
      monophosphate, which was blunted by FPI and partially restored by SODCAT.
      CONCLUSIONS: These data show that superoxide anion is produced after brain injury
      and that opioid-induced vasodilation and cyclic guanosine monophosphate
      production are partially restored after brain injury in the presence of SODCAT.
      (Key words: Brain injury: newborn. Circulation: cerebral. Free radicals: oxygen.
      Gases: nitric oxide. Nucleotides cyclic.

PMID- 8659791
TI  - Propofol inhibits cardiac L-type calcium current in guinea pig ventricular
      myocytes.
AB  - BACKGROUND: Propofol may exert negative inotropic and chronotropic actions in the
      heart. Single-channel studies show that propofol affects the kinetics of opening
      and closing of cardiac L-type calcium channels (ICa(L)) without altering channel
      conductance. The aim of this study was to investigate the mechanisms of
      depressant effects of propofol on cardiac whole-cell ICa(L). METHODS: Single
      ventricular myocytes were freshly dissciated from guinea pig hearts using
      enzymatic isolation. One-suction electrode voltage-clamp technique (whole-cell
      mode) was used. LCa(L) was separated from other contaminated ionic currents.
      Propofol was applied in the commercial 10% Intralipid emulsion formula (Zeneca,
      UK). RESULTS: In isolated cardiomyocytes, propofol significantly inhibited whole
      cell ICa(L) in a concentration-dependent manner (K D = 52.0 microM; Hill
      coefficient = 1.3). The solvent (Intralipid) did not affect ICa(L). Propofol
      decreased ICa(L) at all potentials tested along the voltage axis and reduced the
      slope conductance. The threshold potential for activation and the peak potential
      of the current-voltage relationship were not changed by propofol. The steady
      state activation curves overlapped in the absence and the presence of 56 microM
      propofol. In contrast, the steady-state inactivation curve was shifted in the
      hyperpolarizing direction. The time course of the recovery from inactivation was
      delayed by 56 microM propofol. The blocking action on ICa(L) of propofol shows
      marked resting block and use-dependent block. Propofol caused more pronounced
      inhibition at a higher stimulation frequency. The effect of propofol on the
      inactivation process was even more clear on ICa(L). CONCLUSIONS: The authors
      conclude tha propofol, at supratherapeutic concentrations, inhibits cardiac
      ICa(L). This inhibition is mainly due to a shift of inactivation curve and a
      reduction in slope conductance.

PMID- 8659792
TI  - Spinal antinociceptive action of an N-Type voltage-dependent calcium channel
      blocker and the synergistic interaction with morphine.
AB  - BACKGROUND: Four different voltage-dependent calcium channels (L-, N-, T-, and P
      types) are distinguished in the central nervous system. Both L- and N-type
      calcium channels have been implicated in the release of neurotransmitters from
      sensory neurons in the spinal cord. It has been demonstrated that intrathecal L
      type calcium channel blockers, which alone do not exhibit any antinociceptive
      effects, potentiate the antinociceptive effect of intrathecal morphine. The
      current study was designed to investigate the antinociceptive effects of the
      intrathecally administered N-type calcium channel blocker, omega-conotoxin GVIA
      (omega-CgTx). The interaction between morphine and omega-CgTx at the level of the
      spinal cord also was examined. METHODS: In male Sprague-Dawley rats, lumbar
      intrathecal catheters were chronically implanted. Tail flick and mechanical paw
      pressure tests were used to assess thermal and mechanical nociceptive thresholds,
      respectively. Morphine, omega-CgTx, or a combination of morphine and omega-CgTx
      was administered intrathecally, and the nociceptive thresholds were determined.
      Isobolographic analyses were used to define the nature of the functional
      interactions between morphine and omega-CgTx. RESULTS: Intrathecal omega-CgTx
      produced antinociception in a dose- and time-dependent manner. Isobolographic
      analyses revealed that intrathecal omega-CgTx and morphine interacted
      synergistically in both nociceptive tests. CONCLUSIONS: This study indicates the
      importance of the N-type calcium channel in the spinal cord on nociception and
      suggests the functional interaction between the N-type calcium channel blocker
      and opioid at the level of the spinal cord.

PMID- 8659793
TI  - Insulin treatment of corticosteroid-associated hyperglycemia and its effect on
      outcome after forebrain ischemia in rats.
AB  - BACKGROUND: Recent studies have reported that dexamethasone worsens neuronal
      injury after brain ischemia. This effect is assumed to be secondary to drug
      induced hyperglycemia. The current study used a rat model to test the hypotheses
      that insulin treatment of dexamethasone-induced hyperglycemia would result in a
      postischemic neurologic outcome that is: (1) better than that of hyperglycemic,
      dexamethasone-treated subjects; and (2) better than, or equal to, that of saline
      treated control subjects. METHODS: Twenty-four halothane-anesthetized (1.0%
      inspired) rats were randomly assigned to one of three treatment groups (N = 8 in
      each group): (1) normoglycemic, placebo-treated rats (group P) received an
      intravenous saline infusion; (2) hyperglycemic, dexamethasone-treated rats (group
      D) received 2 mg/kg intraperitoneal dexamethasone at days, 1 day, and h before
      ischemia plus an intravenous saline infusion; and (3) normoglycemic,
      dexamethasone- and insulin-treated rats (group DI) received the same treatment as
      group D, plus an intravenous insulin infusion shortly before ischemia. Blood
      gases and acid-base status were maintained within normal physiologic ranges.
      Pericranial and rectal temperatures were maintained at normothermia. Forebrain
      ischemia of 10 min duration was produced using an established model. Neurologic
      function was assessed by a blinded observer at 24 and 48 h postischemia. Brain
      histopathology was assessed at the time of ischemia-related death or after the
      examination at 48 h. All 24 rats were included in the analysis of neurologic
      function; however, only 21 rats that survived for > or = 24h post-ischemia were
      included in the histologic analysis. RESULTS: Rats were well matched for systemic
      physiologic variables, with the exception of glucose concentrations. Plasma
      glucose concentration immediately before ischemia was as follows: group P = 129
      +/- 8 mg/dl (mean +/- SD), group D= 344 +/- 29 mg/dl, and group DI = 123 +/- 17
      mg/dl. At 48h postischemia, groups P and DI were minimally injured and had
      similar functional scores. In contrast, all group D rats died of cerebral
      ischemia. Histologic injury was significantly worse in group D than in either
      group P or DI, but did not differ significantly between groups P and DI. When all
      groups were combined, there was a significant correlation between neurologic
      function and total histopathology score ranks. CONCLUSIONS: In the current study,
      dexamethasone administration before brain ischemia resulted in a worsening of
      postischemic outcome that was relate to drug-induced hyperglycemia. Restoration
      of normoglycemia, using insulin, resulted in a functional outcome similar to that
      in group P, and an attenuation of dexamethasone-associated histologic injury.

PMID- 8659794
TI  - Activation of endogenous protein kinase C by halothane in synaptosomes.
AB  - BACKGROUND: Protein kinase C is a signal transducing enzyme that is an important
      regulator of multiple physiologic processes and a potential molecular target for
      general anesthetic actions. However, the results of previous studies of the
      effects of general anesthetics on protein kinase C activation in vitro have been
      inconsistent. METHODS: The effects of halothane on endogenous brain protein
      kinase C activation were analyzed in isolated rat cerebrocortical nerve terminals
      (synaptosomes) and in synaptic membranes. Protein kinase C activation was
      monitored by the phosphorylation of MARCKS, a specific endogenous substrate.
      RESULTS: Halothane stimulated basal Ca2+ dependent phosphorylation of MARCKS (Mr
      = 83,000) in lysed synaptic membranes (2.1-fold; P< 0.01) and in intact
      synaptosomes (1.4-fold; P< 0.01). The EC50 for stimulation of MARCKS
      phosphorylation by halothene in synaptic membranes was 1.8 vol%. A selective
      peptide protein kinase C inhibitor, but not a protein phosphatase inhibitor
      (okadaic acid) or a peptide inhibitor of Ca2+/calmodulin-dependent protein kinase
      II, another Ca2+/-dependent signal transducing enzyme, blocked halothane
      stimulated MARCKS phosphorylation in synaptic membranes. Halothane did not affect
      the phosphorylation of synapsin 1, a synaptic vesicle-associated protein
      substrate for Ca2+/calmodulin-dependent protein kinase II and AMP-dependent
      protein kinase, in synaptic membranes or intact synaptosomes subjected to KC1
      evoked depolarization. However, halothane stimulated synapsin 1 phosphorylation
      evoked by ionomycin (a Ca2+ ionophore that permeabilizes membranes to Ca2+) in
      intact synaptosomes. CONCLUSIONS: Halothane acutely stimulated basal protein
      kinase C activity in synaptosomes when assayed with endogenous nerve terminal
      substrates, lipids, and protein kinase C. This effect appeared to be selective
      for protein kinases C, because two other structurally similar second messenger
      regulated protein kinases were not affected. Direct determinations of anesthetic
      effects on endogenous protein kinase C activation, translocation, and/or down
      regulation are necessary to determine the ultimate effect of anesthetics on the
      protein kinase C signaling pathway in intact cells.

PMID- 8659795
TI  - Anesthetic and nonanesthetic halogenated volatile compounds have dissimilar
      activities on nicotinic acetylcholine receptor desensitization kinetics.
AB  - BACKGROUND: The Meyer-Overton rule predicts that an anesthetic's potency will
      correlate with its oil solubility. A group of halogenated volatile compounds that
      disobey this rule has been characterized. These compounds do not induce
      anesthesia in rats at partial pressures exceeding those predicted by the Meyer
      Overton rule to be anesthetic. The observation that potentiation of GABA(A)
      receptor responses by anesthetic and nonanesthetic halogenated volatile compounds
      correlates with their abilities to induce general anesthesia suggests that this
      receptor is involved in the mechanism of general anesthesia. However, the GABA(A)
      receptor is only one member of a superfamily of structurally similar ligand-gated
      ion channels. This study compares the actions of both anesthetic and
      nonanesthetic halogenated volatile compounds on another member of this super
      family of receptors, the nicotinic acetylcholine receptor (nAcChoR). METHODS: The
      actions of both anesthetic and nonanesthetic compounds on desensitization
      kinetics were characterized from the time-dependent binding of the fluorescent
      acetylcholine analogue, Dns-C6-Cho, to the nAcChoR. RESULTS: At concentrations
      predicted by the Meyer-Overton rule to be equianesthetic, the anesthetics
      isoflurane and enflurane were significantly more effective than the
      nonanesthetics 1,2-dichlorohexafluorocyclobutane and 2, 3
      dichlorooctafluorobutane in enhancing the fraction of receptors preexisting in
      the slow desensitized state and increasing the apparent rates of agonist-induced
      fast and slow desensitization. CONCLUSIONS: The potencies with which anesthetic
      and nonanesthetic compounds enhance desensitization kinetics in the nAcChoR
      parallel their in vivo anesthetic potencies. These results support the use of
      desensitization of the nAcChoR as a mechanistic model for studies of general
      anesthesia and suggest that an insensitivity to nonanesthetic compounds may be a
      feature common to members of the superfamily of ligand-gated ion channels.

PMID- 8659796
TI  - Clonidine modulation of hemodynamic and catecholamine responses associated with
      hypoxia or hypercapnia in dogs.
AB  - BACKGROUND: Hypoxia or hypercapnia elicits cardiovascular responses associated
      with increased plasma catecholamine concentrations, whereas clonidine, an
      alpha(2)- adrenergic agonist, decreases plasma catecholamine concentrations. The
      authors examined whether systemic clonidine administration would alter the
      hemodynamic and catecholamine responses to hypoxia or hypercapnia in anesthetized
      dogs. METHODS: Pentobarbital-anesthetized dogs whose lungs were mechanically
      ventilated were instrumented for measurement of mean arterial pressure, heart
      rate, mean pulmonary artery pressure, right atrial pressure, cardiac output, left
      ventricular end-diastolic pressure, and the peak of first derivative of left
      ventricular pressure. The dogs were randomly assigned to receive an intravenous
      bolus injection of 10 microg/kg clonidine followed by continous infusion at a
      rate of 1 microg. kg (-1). min (-1)(clonidine-10 group, n = 7), an intravenous
      bolus injection of microg/kg clonidine followed by continuous infusion at a rate
      of 0.5 micro.kg(-).min(-1)(clonidine-5 group, n = 7), or an equivalent volume of
      0.9% saline (control group = 7). Each dog underwent random challenges of hypoxia
      (PaO2 30, 40, and 50 mmHg) and hypercapnia (PaCO2 60, 80, and 120 mmHg).
      Measurements of hemodynamic and plasma norepinephrine and epinephrine
      concentrations were made after the loading dose of clonidine and the first and
      the second exposure of hypoxia or hypercapnia. RESULTS: Although significant
      increases from prehypoxic values in mean arterial pressure (39 +/- 10 mmHg) and
      plasma norepinephrine (291 +/- 66 pg/ml) and epinephrine (45 +/- 22 pg/ml)
      concentrations were noted during hypoxia of PaO2 30, mmHg in the control group
      (P<0.05), such changes were absent in both clonidine groups. During hypercapnia
      of PaCo2 120 mmHg, changes from prehypercapnic values in mean arterial pressure,
      mean pulmonary artery pressure, the peak of first derivative of left ventricular
      pressure, and plasma norepinephrine and epinephrine concentrations in the
      clonidine-10 and clonidine-5 groups were significantly less than those in the
      control group. Plasma clonidine concentrations in the clonidine-10 and clonidine
      5 groups were 16.8 +/- 1.7 and 8.9 =/- 1.0, 42.5 =/- 2.9 and 21.5 +/- 1.5, and
      51.1 +/- 3.2 and 26.7 +/- 1.0 ng/ml after the loading dose of clonidine and the
      first and the second exposure of hypoxia or hypercapnia, respectively.
      CONCLUSIONS: Systemic clonidine administration alter the hemodynamic changes
      associated with hypoxia or hypercapnia and suppresses plasma catecholamine
      responses in anesthetized dogs when a larger dose of clonidine is administered.
      catecholamines: epinephrine; norepinephrine.)

PMID- 8659797
TI  - Laryngeal mask airway and the ASA difficult airway algorithm.

PMID- 8659798
TI  - Resident workforce in a time of U.S. health-care system transition.

PMID- 8659799
TI  - Anesthesia and perioperative medicine: a department of anesthesiology changes its
      name.

PMID- 8659800
TI  - Temperature dependence of the potency of volatile general anesthetics:
      implications for in vitro experiments.
AB  - BACKGROUND: When performing experiments at room temperature with volatile general
      anesthetics and in vitro mammalian preparations (such as isolated neurons), the
      question arises as to which concentrations of anesthetics are "clinically
      relevant." Different choices can lead to different interpretations of the
      anesthetic sensitivities of putative target sites. METHODS: Published data on the
      temperature dependence of minimum alveolar concentration were analyzed. RESULTS:
      Although gas-phase potencies of volatile anesthetics increase markedly with
      decreasing temperature, the corresponding aqueous-phase potencies are relatively
      constant. Changes in minimum alveolar concentration with temperature can be
      accounted for, on physical grounds, in terms of the temperature dependencies of
      anesthetics binding to their central nervous system target sites. CONCLUSION:
      When performing room-temperature in vitro experiments on simple mammalian
      preparations with a volatile anesthetic, the aqueous-phase (but not the gas-
      phase) minimum alveolar concentration calculated at normal body temperature is,
      to a first approximation, the appropriate choice for a clinically relevant
      anesthetic concentration. Recommended aqueous-phase minimum alveolar
      concentration values (in MM) for desflurane, enflurane, halothane, isoflurane,
      and sevoflurane have have been calculated.

PMID- 8659801
TI  - Fatal paradoxical cerebral embolization during bilateral knee arthroplasty.

PMID- 8659802
TI  - Univent tube provides a new technique for jet ventilation.

PMID- 8659803
TI  - Rhabdomyolysis and myonecrosis in a patient in the lateral decubitus position.

PMID- 8659804
TI  - Rebound hypertension and withdrawal associated with discontinuation of an
      infusion of epidural clonidine.

PMID- 8659805
TI  - Practice Guidelines for blood component therapy: A report by the American Society
      of Anesthesiologists Task Force on Blood Component Therapy.
AB  - In 1994, the American Society of Anesthesiologists established the Task Force on
      Blood Component Therapy to develop evidence-based indications for transfusing red
      blood cells, platelets, fresh-frozen plasma, and cryoprecipitate in perioperative
      and peripartum settings. The guidelines were developed according to an explicit
      methodology. The principal conclusions of the task force are that red blood cell
      transfusions should not be dictated by a single hemoglobin "trigger" but instead
      should be based on the patient's risks of developing complications of inadequate
      oxygenation. Red blood cell transfusion is rarely indicated when the hemoglobin
      concentration is greater than 10 g/dL and is almost always indicated when it is
      less than 6 g/dL. The indications for autologous transfusion may be more liberal
      than for allogeneic (homologous) transfusion. The risks of bleeding in surgical
      and obstetric patients are determined by the extent and type of surgery, the
      ability to control bleeding, the actual and anticipated rate of bleeding and the
      consequences of uncontrolled bleeding. Prophylactic platelet transfusion is
      ineffective when thrombocytopenia is due to increased platelet destruction.
      Surgical and obstetric patients with microvascular bleeding usually require
      platelet transfusion if the platelet count is less than 50 times 10(9)/l and
      rarely therapy if it is greater than 100 times 10(9)/l. Fresh-frozen plasma is
      indicated for urgent reversal of warfarin therapy, correction of known
      coagulation factor deficiencies for which specific concentrates are unavailable,
      and correction of microvascular bleeding when prothrombin and partial
      thromboplastin times are >1.5 times normal. It is contraindicated for
      augmentation of plasma volume or albumin concentration. Cryoprecipitate should be
      considered for patients with von Willebrand's disease unresponsive to
      desmopressin, bleeding patients with von Willebrand's disease, and bleeding
      patients with fibrinogen levels below 80-100 mg/dL. The task force recommends
      careful adherence to proper indications for blood component therapy to reduce the
      risks of transfusion. (Key words:Practice guide-lines: anemia: blood component
      therapy; coagulopathy; cryoprecipitate; fresh-frozen plasma; red blood cells;
      transfusion.)

PMID- 8659806
TI  - Neurolytic celiac plexus block should include contrast media.

PMID- 8659807
TI  - Effective topical anesthesia for awake tracheal intubation.

PMID- 8659808
TI  - Reconciling differences between in vitro and in vivo effects of propofol.

PMID- 8659809
TI  - Anesthetic gas-scavenging in the laboratory.

PMID- 8659810
TI  - Efficacy and safety of cricoid pressure needs scientific validation.

PMID- 8659811
TI  - Computerized approach to processing the American Board of Anesthesiology training
      report.

PMID- 8659812
TI  - Basic behavioral science research for mental health. Family processes and social
      networks. Basic Behavioral Science Task Force of the National Advisory Mental
      Health Council.

PMID- 8659813
TI  - Basic anatomical and physiological data for use in radiological protection: the
      skeleton. A report of a Task Group of Committee 2 of the International Commission
      on Radiological Protection.

PMID- 8659814
TI  - 3rd International Conference on Sodium-Calcium Exchange. Woods Hole,
      Massachusetts, April 23-26, 1995. Proceedings.

PMID- 8659815
TI  - Molecular biological studies of the cardiac sodium-calcium exchanger.
AB  - The intron-exon organization of the entire human Na-Ca-exchanger gene NCX1 and of
      the central part of the related gene NCX2 has been determined. The NCX1 gene is
      at least 75 kb long and consists of at least 12 exons, the two largest (the 2nd
      and the 12th) coding for the N-terminal half of the exchanger sequence and for
      the last three C-terminal transmembrane domains. They also code for the 3.3-kb 3'
      untranslated region and account for more than 90% of the length of the mature
      mRNA. The remainder of the NCX1 (NCX2) gene, coding for a putative cytoplasmic
      regulatory domain, is split into 9 (7) small exons. In spite of the limited (65%)
      average homology of the two cDNAs, analogous exons are readily identified within
      this portion of the two genes based on their high (80-95%) pairwise homology and
      similar patterns of differential splicing in brain. Human YAC clones have been
      identified in the CEPH library, which contain the entire NCX1/2 and NCKX1
      (retinal rod exchanger) genes, and are used for chromosomal localization of the
      three genes. A distant homolog of the mammalian NCX genes has been identified in
      the C. elegans EST database and has been completely sequenced. It encodes a 20%
      shorter protein, which has an average 55% homology to human NCX1, and lacks most
      of the region that is known to be encoded by multiple differentially spliced
      exons in vertebrates. Comparison of available data on the gene structure of the
      NCX homologs in various species suggests that this protein has emerged in the
      primitive nervous system and has been subsequently adapted to other cellular
      environments by the use of novel domains, encoded in additional exons.

PMID- 8659816
TI  - Expression of Na(+)-Ca2+ exchanger with modified C-terminal hydrophobic domains
      and enhanced activity.
AB  - A 6-Kb canine cDNA fragment complementary to the 5' region of the 7-Kb mRNA
      encoding the cardiac Na+-Ca2+ exchanger was expressed in human kidney 293 cells.
      The mRNA products were reverse transcribed and amplified by PCR. The determined
      DNA sequence of the amplified DNA fragments revealed the presence of an intron
      that was alternatively spliced. The partial exon sequence, located at the 3' end
      of the 6-Kb cDNA, was alternatively connected to bases 3198, 2821, 2620 and 1844
      in four types of splicing products identified. In the largest product the
      adjoining exon was located after the putative stop codon of the regular sequence.
      In a second and third type of shortened transcripts, a hydrophobic sequence
      encoded by the spliced-in exon was linked with the 4th or the 5th extracellular
      loops, and could possibly replace transmembrane segments 9 or 11. In the fourth
      type of spliced transcript the in-frame exon sequence introduced one Leu followed
      by a stop codon in the large hydrophilic loop. Measurements of Ca2+ uptake in 293
      cells expressing the modified exchanger indicated a higher activity in comparison
      with 293 cells expressing the 3.7-Kb cDNA, in which this alternative splicing
      does not occur. Deletion mutagenesis of the C-terminal region encoded by the
      spliced-in exon was performed to investigate its role in the enhancement of the
      transport activity.

PMID- 8659817
TI  - Identification and antisense inhibition of Na-Ca exchange in renal epithelial
      cells.
AB  - In summary, DCT cells express multiple isoforms of the Na-Ca exchanger and
      exhibit functional exchange, and antisense oligonucleotides to a downstream
      region of the exchanger transcript inhibit activity. These experiments provide
      direct evidence for Na-Ca exchange in DCT cells mediated by NACA2, NACA3, or
      NACA6.

PMID- 8659818
TI  - Effects of NCX1 antisense oligodeoxynucleotides on cardiac myocytes and primary
      neurons in culture.

PMID- 8659819
TI  - Initial characterization of the feline sodium-calcium exchanger gene.

PMID- 8659820
TI  - Cloning of the mouse cardiac Na(+)-Ca2+ exchanger and functional expression in
      Xenopus oocytes.

PMID- 8659821
TI  - Identification of a novel alternatively spliced isoform of the Na(+)-Ca2+
      exchanger (NACA8) in heart.

PMID- 8659822
TI  - Presence of NACA3 and NACA7 exchanger isoforms in insulin-producing cells.

PMID- 8659823
TI  - The cardiac Na-Ca exchanger in giant membrane patches.

PMID- 8659824
TI  - Multiple functional states of the cardiac Na(+)-Ca2+ exchanger. Whole-cell,
      native-excised, and cloned-excised properties.

PMID- 8659826
TI  - Cardiac Na-Ca exchange and pH.

PMID- 8659825
TI  - Mechanism of XIP in cardiac sarcolemmal vesicles.

PMID- 8659827
TI  - In squid axons phosphoarginine plays a key role in modulating Na-Ca exchange
      fluxes at micromolar [Ca2+]i.

PMID- 8659828
TI  - Molecular regulation of the Na(+)-Ca2+ exchanger.

PMID- 8659829
TI  - A nerve cytosolic factor is required for MgATP stimulation of a Na+ gradient
      dependent Ca2+ uptake in plasma membrane vesicles from squid optic nerve.

PMID- 8659830
TI  - Kinetics and mechanism: modulation of ion transport in the cardiac sarcolemma
      sodium-calcium exchanger by protons, monovalent, ions, and temperature.

PMID- 8659831
TI  - Voltage dependence of Na-Ca exchange in barnacle muscle cells. I. Na-Na exchange
      activated by alpha-chymotrypsin.

PMID- 8659832
TI  - Phosphorylation and modulation of the Na(+)-Ca2+ exchanger in vascular smooth
      muscle cells.

PMID- 8659833
TI  - Regulation of expression of sodium-calcium exchanger and plasma membrane calcium
      ATPase by protein kinases, glucocorticoids, and growth factors.

PMID- 8659834
TI  - Enzyme kinetics. Thermodynamic constraints on assignment of rate coefficients to
      kinetic models.

PMID- 8659835
TI  - Effects of external monovalent cations on Na(+)-Ca2+ exchange in cultured rat
      glial cells.

PMID- 8659836
TI  - ATP stimulation of a Na+ gradient-dependent Ca2+ uptake in cardiac sarcolemmal
      vesicles.

PMID- 8659837
TI  - Modifications of XIP, the autoinhibitory region of the Na-Ca exchanger, alter its
      ability to inhibit the Na-Ca exchanger in bovine sarcolemmal vesicles.

PMID- 8659838
TI  - Use of cysteine replacements and chemical modification to alter XIP, the
      autoinhibitory region of the Na-Ca exchanger. Inhibition of the activated plasma
      membrane Ca pump.

PMID- 8659839
TI  - Effects of Phe-Met-Arg-Phe-NH2 (FMRFa)-related peptides on Na-Ca exchange and
      ionic fluxes in rat pancreatic B cells.

PMID- 8659841
TI  - Kinetics of Na-Ca exchange current after a Ca2+ concentration jump.

PMID- 8659840
TI  - The structural basis of Na(+)-Ca2+ exchange activity.

PMID- 8659842
TI  - Calcemic hormones regulate the level of sodium-calcium exchange protein in
      osteoblastic cells.

PMID- 8659843
TI  - A novel approach for imaging the influx of Ca2+, Na+, and K+ in the same cell at
      subcellular resolution. Ion microscopy imaging of stable tracer isotopes.

PMID- 8659844
TI  - The Na(+)-Ca2+ exchanger in rat brain synaptosomes. Kinetics and regulation.

PMID- 8659845
TI  - Localization of the Na(+)-Ca2+ exchanger in vascular smooth muscle, and in
      neurons and astrocytes.

PMID- 8659846
TI  - Regulation of the bovine retinal rod Na-Ca+K exchanger.

PMID- 8659847
TI  - Turnover rate and number of Na(+)-Ca2+, K+ exchange sites in retinal
      photoreceptors.

PMID- 8659848
TI  - Na-Ca exchange in Ca2+ signaling and neurohormone secretion. Secretory vesicle
      contributions in adrenal chromaffin cells.

PMID- 8659849
TI  - Na(+)-Ca2+ exchange in anoxic/ischemic injury of CNS myelinated axons.

PMID- 8659850
TI  - A new splicing variant in the frog heart sarcolemmal Na-Ca exchanger creates a
      putative ATP-binding site.

PMID- 8659851
TI  - The sodium-calcium exchanger and glutamate-induced calcium loads in aged
      hippocampal neurons in vitro.

PMID- 8659852
TI  - Release of catecholamines and enkephalin peptides induced by reversal of the
      Na(+)-Ca2+ exchanger in chromaffin cells.

PMID- 8659853
TI  - Agents that promote protein phosphorylation increase catecholamine secretion and
      inhibit the activity of the Na(+)-Ca2+ exchanger in bovine chromaffin cells.

PMID- 8659854
TI  - What mechanisms are involved in Ca2+ homeostasis in hair cells?

PMID- 8659855
TI  - Immunohistochemical localization of the cardiac sodium-calcium exchange protein
      in the inner ear.

PMID- 8659856
TI  - Reversed mode Na(+)-Ca2+ exchange activated by ciguatoxin (CTX-1b) enhances
      acetylcholine release from Torpedo cholinergic synaptosomes.

PMID- 8659857
TI  - Calcium in the cardiac diadic cleft. Implications for sodium-calcium exchange.

PMID- 8659858
TI  - Action potential duration modulates calcium influx, Na(+)-Ca2+ exchange, and
      intracellular calcium release in rat ventricular myocytes.
AB  - The experimental work summarized in this paper and described in more detail in
      our previous publication demonstrates a very important functional role for Na(+)
      Ca2+ exchange in intracellular Ca2+ homeostasis in ventricular myocytes from rat
      hearts. Ca2+ homeostasis in mammalian cardiac myocytes can be considered to be
      the result of four interactive processes: (i) Ca2+ influx through L-type Ca2+
      channels, (ii) Ca2+ release from the SR and its subsequent re-uptake, (iii)
      intracellular Ca/+ buffering, and (iv) Ca2+ extrusion across the sarcolemma. Our
      results demonstrate a number of interesting features of these processes. (1) When
      the action potential voltage-clamp technique is used to identify the size and
      time-course of Ca2+ fluxes during the action potential, both the peak current and
      the associated influx of Ca2+ are relatively large as was previously demonstrated
      by Isenberg and his colleagues. (2) Nevertheless, this source of Ca2+ is unable,
      by itself, to produce a significant twitch, which is consistent with previous
      data from rat ventricle. (3) This Ca2+ influx, however, does represent the
      trigger for SR Ca2+ release. (4) The Na(+)-Ca2+ exchanger on the SR is able, on
      average, to extrude all the Ca2+ which enters through L-type Ca2+ channels,
      although it provides relatively little Ca2+, i.e., during the course of the
      normal action potential there is no significant reverse Na(+)-Ca2+ exchange
      activity, at least under our experimental conditions. Our results also suggest
      that although the L-type Ca2+ current cannot by itself trigger and control
      contraction its amplitude, frequency, and time-course can alter the rate and the
      extent of Ca2+ release from the SR. Recently, detailed mathematical formulations
      and a direct demonstration of some of these phenomena have been published. Stern
      and Stern and Lakatta predicted more than three years ago that the concentration
      and the time-course of change in concentration of Ca2+ very near the release
      sites of the SR may be critical determinants of the overall release process.
      Within the past year Wier and his colleagues and also Lederer et al. have
      combined electrophysiological measurements with recordings of localized
      intracellular Ca2+ (made using a confocal microscope) and have shown that rapid,
      and relatively large, but very localized changes in intracellular Ca2+ due to
      Ca2+ influx through L-type Ca2+ channels are responsible for triggering, and to
      some extent, controlling the release of Ca2+ from the SR. However, it has also
      been shown that this release depends importantly on the loading or priming state
      of the SR. Perhaps not surprisingly, the massive release of Ca2+ from the SR can,
      itself, alter the pattern of subsequent SR release events (cf. Ref. 46) and the
      time-course of Ca2+ influx through the L-type Ca2+ channels. Thus, although our
      relatively crude measurements have clearly demonstrated the relationship between
      L-type Ca2+ channel activity and Na+-Ca2+ exchanger function during a normal
      cardiac action potential in rat ventricle, they fall far short of any delineation
      of the functional roles of either of these processes in overall Ca2+ homeostasis.
      This additional information can, in principle, be obtained from studies in which
      cellular microanatomy can be visualized dynamically in conjunction with localized
      changes in intracellular Ca2+ as well as Ca2+ of L-type Ca2+ channels, SR
      release, and cell shortening.

PMID- 8659860
TI  - The roles of the sodium and calcium current in triggering calcium release from
      the sarcoplasmic reticulum.

PMID- 8659859
TI  - Na-Ca exchange and Ca fluxes during contraction and relaxation in mammalian
      ventricular muscle.
AB  - There are four cellular Ca transport systems which compete to remove Ca from the
      myoplasm in mammalian ventricular myocytes. These are 1) the SR Ca-ATPase, 2) the
      sarcolemmal Na-Ca exchange, 3) the sarcolemmal Ca-ATPase and 4) the mitochondrial
      Ca uniporter. Using multiple experimental approaches we have evaluated the
      dynamic interaction of these systems during the normal cardiac contraction
      relaxation cycle. The SR Ca-ATPase and Na-Ca exchange are clearly the most
      important, quantitatively; however, the relative roles vary in a species
      dependent manner. In particular, the SR is much more strongly dominant in rat
      ventricular myocytes, where approximately 92% of Ca removal is via SR Ca-ATPase
      and only 7% via Na-Ca exchange during a twitch. In other species (rabbit, ferret,
      cat, and guinea pig) the balance is more in the range of 70% SR CA-ATPase and 25
      30% Na-Ca exchange. Ferret ventricular myocytes also exhibit an unusually strong
      sarcolemmal Ca-ATPase. During the steady state the same amount of Ca must leave
      the cell as enters over a cardiac cycle. This implies that 25-30% of the Ca
      required to activate contraction must enter the cell, and experiments demonstrate
      that this amount of Ca may be supplied by the L-type Ca current.

PMID- 8659861
TI  - Evidence that reverse Na-Ca exchange can trigger SR calcium release.
AB  - Several results suggest that the Na-Ca exchange can function as a trigger
      promoting SR Ca release and ensuing contractions. First, if the Ca current was
      the sole trigger for contraction we would expect the relationship between
      triggered contractions and voltage to be similar to the relationship between Ca
      current and contraction. When Na is present in the pipette this is not observed.
      Between -40 and +10 mV the relationships between contractions and voltage and
      current and voltage are similar. At potentials positive to 10 mV the Ca current
      declines as expected but contractions either decline much more slowly or continue
      to increase depending upon the concentration of intracellular Na. In addition, we
      have observed that contractions can be activated when Ca current is largely or
      completely blocked. Since these contractions are sensitive to the presence of
      ryanodine and thapsigargin they appear to be triggered by Na-Ca exchange. Also,
      contractions that are activated in the presence of nifedipine are sensitive to
      the Na-Ca exchange inhibitor XIP. Finally, rapid removal of extracellular Na
      apparently stimulates enough reverse exchange triggering of SR Ca release without
      affecting the SR content. It is clear that the shape of the shortening voltage
      relationship depends upon the concentration of dialyzing Na. This is likely to
      occur for two reasons. Either the shape of the shortening voltage relationship
      depends upon the extent to which Na-Ca exchange contributes a trigger for SR Ca
      release or alternatively the shape of the shortening voltage relationship depends
      upon SR Ca content. The latter is known to depend upon the Na concentration. In
      addition it is now established that the gain of SR Ca release is influenced by SR
      content. However, we studied triggered contractions in the absence of a Na
      gradient when the only available trigger is the Ca current. We measured triggered
      contractions over a range of voltages between -30 and +60 mV. Between each
      measurement we reestablished the Na gradient and activated a series of
      conditioning pulses to standardize the SR Ca content. Just before a test pulse we
      removed extracellular Na and activated either 3 or 6 pulses to produce two
      different SR Ca loads (in the absence of a Na gradient entering Ca cannot be
      extruded and therefore changes the SR Ca content). Regardless of the number of
      prepulses in the absence of a Na gradient the shortening voltage relationship was
      similar and bell shaped. From this we conclude that the shape of the relationship
      between shortening and voltage does not depend upon SR Ca content. Therefore, we
      conclude that the asymmetry in the shortening voltage relationship that depends
      upon intracellular Na is due to a contribution of reverse Na-Ca exchange. It is
      too early to say what the physiological significance (if any) of triggering by
      reverse exchange actually is. However, it does seem likely that it might provide
      a powerful inotropic mechanism. For example intracellular Na might be expected to
      change with heart rate and to be elevated at higher heart rates. Presumably this
      increased intracellular Na would tend to favor triggering by reverse exchange and
      would therefore enhance contractility at a time when it would be most required.

PMID- 8659862
TI  - Alternative splicing of the Na(+)-Ca2+ exchanger gene, NCX1.
AB  - We describe an analysis of the NCX1 gene and show that various tissues express
      different alternatively spliced forms of the gene. Alternative splicing has been
      confirmed by the genomic analysis of the Na(+)-Ca2+ exchanger gene. We also
      describe the Drosophila Na(+)-Ca2+ exchanger as having many of the same
      structural characteristics of the mammalian exchangers and this locus as possibly
      undergoing alternative splicing in the same region that has been described in the
      NCX1 gene. The general structure of the exchangers is similar to that of the
      alpha-subunit of the (Na(+)+ K+)-A Pase. Finally, sequence comparison of the
      various molecules demonstrates that structural characteristics of these molecules
      are more strongly conserved than the primary sequence of these products.

PMID- 8659863
TI  - Regulation of sodium-calcium exchange in intact myocytes by ATP and calcium.
AB  - Regulation of Na-Ca exchange activity by ATP and by intracellular Ca (Cai) has
      been studied in suspensions of intact Na-loaded adult rat cardiac myocytes using
      45Ca uptake and exchange of 22Na. ATP depletion of Na-loaded myocytes results in
      a strong inhibition of the Na-Ca exchanger, manifested as a strong inhibition of
      intracellular Na-dependent Ca uptake. Ca uptake by Na-loaded cells in the course
      of ATP depletion can be very heterogeneous because of the heterogeneity amongst
      cells of the extent of ATP depletion. This can result in a false measure of the
      dependence of exchanger activity on cell ATP content. Under conditions intended
      to maximize the uniformity of cell ATP content amongst cells we found a half
      maximal rate of Ca uptake with a cell ATP content of 1.96 nmol/mg, about 10% of
      the normal cell ATP level. The results suggest that ATP depletion after ischemia
      plus reperfusion is unlikely to limit the rate of Ca uptake by Na-Ca exchange in
      the whole heart if at least one quarter of the ATP is restored. Ca addition to
      myocytes loaded with Na in the absence of Ca results in a strong activation of
      the Na-Ca exchanger at an intracellular site, manifested as a large activation of
      Na-Na exchange activity. A similar activation of the exchanger is observed in
      cells with a normal level of intracellular Na, suspended in a medium containing
      physiological levels of Ca, when the cells are stimulated to beat by application
      of an electric field. This suggests that regulation of the exchanger by Cai is
      important physiologically, in the regulation of excitation-contraction coupling.
      Cells depleted of ATP show not only a strongly inhibited rate of Na-Ca exchange
      and Na-Na exchange, but also a strongly reduced degree of activation by Cai, even
      in ATP-depleted cells with no acidosis. This could result from the combined
      effect of ATP loss and an elevated intracellular Mg concentration on Ca binding
      affinity at the regulatory site.

PMID- 8659864
TI  - Functional roles of sodium-calcium exchange in normal and abnormal cardiac
      rhythm.

PMID- 8659865
TI  - The exchanger and cardiac hypertrophy.

PMID- 8659866
TI  - Na-Ca exchange in circulating blood cells.
AB  - The experiments with peripheral lymphocytes raise two provocative questions: is
      SDCI composed of Ca influx via both a Ca channel and Na-Ca exchanger?, and what
      is the role of Na-Ca exchange in lymphocytes? In regard to the first issue, the
      potential for this dual Ca influx pathway exists, inasmuch as both Ca store
      depletion (by exposure of cells to EGTA) and TG-treatment initiated Ca influx
      that was enhanced following reversal of the Na gradient. These data could be
      interpreted to suggest a role for Ca influx via the exchanger during lymphocyte
      activation. However, our ability to demonstrate Na-Ca exchange activity was
      facilitated by the removal of Ca sequestering or extrusion mechanisms, including
      SERCA Ca pumps and forward mode Na-Ca exchange. Thus, it seems likely that under
      physiological conditions the primary function of the exchanger is to mediate Ca
      efflux. In this regard, it might play a role in lymphocyte activation by limiting
      net Ca entry during the sustained phase of Ca mobilization. Since sustained Ca
      entry is critical for Ca-dependent processes including interleukin-2 production,
      exchange activity would be an important modulator of this process. Changes in
      membrane potential, intracellular [Na] and cytosolic pH could therefore regulate
      Cai through its effects on Na-Ca exchange activity. Future challenges include
      defining the role of the Na-Ca exchange in Cai homeostasis and characterizing its
      function in lymphocyte populations.

PMID- 8659867
TI  - Effects of external Mg2+ on the Na-Ca exchange current in guinea pig cardiac
      myocytes.

PMID- 8659868
TI  - Ca2+ influx via Na-Ca exchange and ICa can both trigger transient contractions in
      cat ventricular myocytes.

PMID- 8659869
TI  - Demonstration of an inward Na(+)-Ca2+ exchange current in adult human atrial
      myocytes.

PMID- 8659870
TI  - Intracellular pH is insensitive to changes in intracellular calcium concentration
      in isolated rat ventricular myocytes.

PMID- 8659871
TI  - Immunolocalization of the Na(+)-Ca2+ exchanger in cardiac myocytes.

PMID- 8659872
TI  - Sodium-calcium exchange expression in ischemic rabbit hearts.

PMID- 8659873
TI  - Ontogeny and hormonal regulation of cardiac Na(+)-Ca2+ exchanger expression in
      rabbits.

PMID- 8659874
TI  - Functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in the
      failing human heart.

PMID- 8659875
TI  - Role of the cardiac sarcolemmal Na(+)-Ca2+ exchanger in end-stage human heart
      failure.

PMID- 8659876
TI  - Lanthanum provides cardioprotection by modulating Na(+)-Ca2+ exchange.

PMID- 8659877
TI  - Sodium-calcium balance in coronary angiography. Experimental experience with
      isotonic iodixanol.

PMID- 8659878
TI  - Properties of the Na(+)-Ca2+ antiport of heart mitochondria.

PMID- 8659879
TI  - Na-Ca exchange studies in sarcolemmal skeletal muscle.

PMID- 8659880
TI  - Lorin J. Mullins, professor of biophysics. A life dedicated to the study of the
      interaction of ions with excitable membranes.

PMID- 8659882
TI  - The molecular biology of the Na(+)-Ca2+ exchanger and its functional roles in
      heart, smooth muscle cells, neurons, glia, lymphocytes, and nonexcitable cells.

PMID- 8659881
TI  - The kidney sodium-calcium exchanger.

PMID- 8659883
TI  - Sodium-calcium exchange and calcium homeostasis in transfected Chinese hamster
      ovary cells.
AB  - Our experiments with transfected cells provide new insights into the role of Na
      Ca exchange activity in Ca homeostasis and emphasize the role of local
      interactions in determining exchanger function. Thus, the effects of ATP
      depletion and cytochalasin D highlight the influence of the actin cytoskeleton in
      regulating exchange activity. Cytoskeletal interactions could provide a mechanism
      for modulating exchange activity by mechanical stretch and might constitute a
      novel feedback mechanism for regulating contractile activity in the heart. The
      effects of Na on Ca entry during SDCI in the transfected cells suggest that local
      gradients of [Ca]i are important determinants of exchanger function. The surface
      distribution of exchanger proteins in relation to that of Ca channels therefore
      represents another area in which interactions with the cytoskeleton may be a
      central element in understanding the physiological function(s) of the exchange
      activity. At present, it seems likely that the exchanger's central hydrophilic
      domain mediates the connection between the exchanger and the cytoskeleton. This
      provides a rationale for understanding the importance of tissue-specific
      alterations in the exchanger's hydrophilic domain, which appear to have little
      affect on the kinetic behavior of the exchanger. Future work in our laboratory
      will be directed toward clarifying the role of cytoskeletal interactions in
      exchanger function.

PMID- 8659884
TI  - Mutagenesis studies of the cardiac Na(+)-Ca2+ exchanger.

PMID- 8659885
TI  - Antisense oligodeoxynucleotides directed against the Na-Ca exchanger mRNA.
      Promising tools for studies on the cellular and molecular level.

PMID- 8659886
TI  - Coordination of glycolysis and TCA cycle reaction networks. Citrate-glucose
      cometabolism eliminates acids and reveals potential metabolic engineering
      strategies.

PMID- 8659887
TI  - cis-regulatory elements of the peroxidase gene in Arabidopsis thaliana involved
      in root-specific expression and responsiveness to high-salt stress.
AB  - The pattern of organ-specific expression of Arabidopsis thaliana peroxidase was
      similar to that in horseradish. Tobacco plants transformed with the gus gene
      fused to the -580 bp deletion (Ea-580) of A. thaliana exhibited high GUS
      expression in roots. Gel retardation and footprinting analyses showed that at
      least three domains of fragment between -172 and -1 bp have cis-acting element
      activities. Several physiological functions for plant peroxidases have been
      suggested; for example, a metabolic adaptation to salinity in the environment can
      be induced by certain specific elements of the peroxidase gene. The prxEa
      promoter fragments (Ea-580 and Ea-390) show multiple cis-acting elements in the
      control of expression in high-salt stress. These data suggest that the DNA
      binding factor may be involved in the regulation of gene expression in specific
      organ and salt stress.

PMID- 8659888
TI  - The efficient production of human epidermal growth factor by Bacillus brevis.
AB  - A system has been developed for the efficient production of heterologous proteins
      using Bacillus brevis as a host that secretes large amounts of cell wall protein
      into the medium. The promoter region and signal peptide-encoding region of the
      cell wall protein gene were used to construct an expression-secretion vector.
      Bacterial proteins such as amylases can be produced in large amounts by this
      system (1 g/l or more), but mammalian proteins such as human alpha-amylase are
      produced at a low level (one or two orders of magnitude less than for bacterial
      proteins). The highly efficient secretion of human epidermal growth factor (h
      EGF, more than 1 g/l) was obtained with B. brevis HPD31 as the host and plasmid
      pHY481, derived from B. brevis 481, as the vector. Recombinant hEGF was purified
      easily from the culture supernatant by two steps. Purified hEGF had the identical
      NH2-terminal amino acid sequence and COOH-terminal amino acid sequence with those
      of the authentic hEGF, and it was fully active in biological assays. This
      recombinant hEGF has been shown to be successful for biological wool harvesting
      (CSIRO, Australia). These results, in combination with previous results, indicate
      that foreign proteins of diverse origins can be produced efficiently as
      functional proteins in B. brevis.

PMID- 8659889
TI  - Production of a malaria transmission-blocking protein from recombinant yeast.

PMID- 8659891
TI  - Production of antibody fragments in Escherichia coli.

PMID- 8659890
TI  - Characteristics of poly(3-hydroxybutyric acid) synthesis by recombinant
      Escherichia coli.

PMID- 8659892
TI  - Environmental dependence and behavior changes of a recombinant Escherichia coli.

PMID- 8659894
TI  - Characterization of a Streptomyces rochei endoglucanase.

PMID- 8659893
TI  - Metabolic engineering of cephalosporin biosynthesis in Streptomyces clavuligerus.
AB  - The biosynthesis of beta-lactams is one of the most thoroughly studied antibiotic
      pathways.  The availability of the characteristics and the time profiles of
      activities of enzymes involved in the biosynthesis allows one to critically
      evaluate the potential rate-limiting steps in its production.  Our approach to
      understanding the control of beta-lactam biosynthesis has been pursued using a
      two-stage strategy: (1) to predict the rate-limiting steps using a kinetic model
      and (2) to relax the rate-limiting steps by engineering the biosynthetic pathway
      or by altering the kinetic parameters of the predicted key rate-limiting enzyme. 
      Kinetic analysis of the pathway dynamics of cephamycin C production in
      Streptomyces clavuligerus was performed using data obtained from wild type. 
      Sensitivity analysis revealed that the availability of precursor alpha
      aminoadipic acid and activity of ACV synthetase were the potential rate-limiting
      steps.  Relaxation of the precursor limitation was accomplished by integration of
      an additional copy of the gene encoding lysine-epsilon-aminotransferase (lat)
      into the chromosome.  The recombinant strain showed an increased level of
      cephamycin C production as expected.  The intracellular levels of different
      intermediates in the pathway in batch cultures were analyzed.

PMID- 8659896
TI  - Transport mutants and transport genes of Corynebacterium glutamicum.

PMID- 8659895
TI  - Optimization of recombinant gene expression in Escherichia coli.
AB  - The major targets for improvement of recombinant expression efficiency in
      Escherichia coli are gene dosage, transcription and, to some extent, translation.
      In order to evaluate the relative importance of these factors, the kinetics of
      specific mRNA compared to product formation was studied for different widely used
      expression systems, producing recombinant human superoxide dismutase. For a
      system employing phage T7 RNA polymerase, where a high level of recombinant
      protein expression puts a high metabolic burden on the cells, it was shown that
      transcription is not the limiting factor. To improve the translation rate of a
      common vector based on the tac promoter, the Shine-Dalgarno (SD) sequence was
      mutated towards stronger homology to the anti-SD sequence of the E. coli 16S
      rRNA.  A 12.2-fold increase in protein yield was accompanied by a 4.3-fold
      increase in specific mRNA, indicating that transcription of the recombinant gene
      is coupled to translation.  As this coupling amplifies the detrimental effect of
      a low-efficiency ribosomal binding site, much attention should be paid to
      translation initiation when optimizing a recombinant protein production system.
      Finally, reasons for the high expression level before induction are discussed,
      and first results towards reducing it are presented.

PMID- 8659897
TI  - A URA3-promoter deletion in a pYES vector increases the expression level of a
      fungal lipase in Saccharomyces cerevisiae.
AB  - A simple deletion of the URA3 promoter from a Saccharomyces cerevisiae expression
      plasmid was performed. The promoter-deleted plasmid is shown to have an increased
      expression level of a fungal lipase gene. The deletion probably causes a poor
      expression of the URA3 selection marker, probably resulting in a higher copy
      number per cell of the plasmid. This higher copy number can increase the
      transcript level per cell and there by the expression level. In the case of the
      fungal lipase gene, the expression level with defined inoculum is increased at
      least three times. The principle is most likely similar to the LEU2d plasmids
      described previously. A part of the 2-micron origin of the pYES type plasmid was
      also deleted by the URA3 promoter deletion without affecting transformation
      frequency. The URA3 promoter can easily be deleted from most pYES type plasmids
      by the described method.

PMID- 8659898
TI  - Maltodextrin phosphorylase from Escherichia coli: production and application for
      the synthesis of alpha-glucose-1-phosphate.

PMID- 8659899
TI  - Protein engineering of a cephalosporin C acylase from Pseudomonas strain N176.

PMID- 8659900
TI  - Identification and characterization of cellulose-binding domains in xylanase A of
      Clostridium stercorarium.
AB  - The xynA gene encoding a major xylanase of Clostridium stercorarium F-9 was
      sequenced. The structural gene consists of an open reading frame of 1533 bp
      encoding a protein of 511 amino acids with an M(r) of 56,519. XynA consists of a
      catalytic domain belonging to family G at the NH2-terminus and two direct repeats
      of about 90 amino acids with a short spacing at the COOH-terminus. The repeated
      sequences, CBDI and CBDII, were not homologous with amino acid sequences of the
      CBDs classified into families I to V. Nevertheless, XynA showed an affinity for
      insoluble cellulose such as Avicel. Binding of XynA to Avicel was strongly
      dependent on the concentration of the incubation buffer and was inhibited by
      Triton X-100. XynA bound to Avicel (2.4 nmol/g-cellulose) and acid-swollen
      cellulose (180 nmol/g-cellulose), suggesting that this enzyme has higher affinity
      for amorphous cellulose than for crystalline cellulose. Functions of CBDI and
      CBDII were investigated by constructing the mutant enzymes and evaluating the
      cellulose-binding ability of each of them. XynA4 lacking CBDI and XynA5 lacking
      CBDII bound to Avicel to a lesser extent than the parental enzyme XynA; but
      XynA6, devoid of both CBDs, did not bind at all, indicating that CBDI and CBDII
      each functioned independently as CBD in XynA and their binding capacity was
      additive. Although the Ruminococcus albus endoglucanase EgIV that was joined to
      CBDs of XynA acquired cellulose-binding ability, the substrate specificity of
      EgIV was not altered in the presence or absence of CBDs.

PMID- 8659901
TI  - Construction of L-lysine-, L-threonine-, and L-isoleucine-overproducing strains
      of Corynebacterium glutamicum.
AB  - The gram-negative bacterium Corynebacterium glutamicum is used for the industrial
      production of amino acids, for example, of L-glutamate and L-lysine. By cloning
      and expressing the various genes of the L-lysine pathway in C. glutamicum, we
      would demonstrate that an increase of the flux of L-aspartate semialdehyde to L
      lysine could be obtained in strains with increased dihydrodipicolinate synthase
      activity. Recently we detected that in C. glutamicum two pathways exist for
      synthesis of D,L-diaminopimelate and L-lysine. Mutants defective in one pathway
      are still able to synthesize enough L-lysine for growth, but the L-lysine
      secretion is reduced to 50 to 70%. Using NMR spectroscopy, we could calculate how
      much of the L-lysine secreted into the medium is synthesized via either one or
      the other pathway. Amplification of the feedback inhibition insensitive
      homoserine dehydrogenase and homoserine kinase in a high L-lysine-overproducing
      strain enabled channeling of the carbon flow from the intermediate aspartate
      semialdehyde towards homoserine, resulting in a high accumulation of L-threonine.
      For a further flux from L-threonine to L-isoleucine, the allosteric control of
      threonine dehydratase was eliminated.

PMID- 8659902
TI  - Protein expression in the stressed Vibrio strains.
AB  - In a conjunction process using Escherichia coli SM10 (pLOF) KmR APR as donor and
      Vibrio S141 SmR as recipient, several mutants were constructed: Vibrio PH 101, V.
      PH 106, and V. PH 109 with lowered ability to synthesize poly-beta
      hydroxybutyrate. The survival and metabolic activities of parent and mutant
      strains were estimated when they were subjected to stress conditions (starvation
      of carbon and energy sources and/or cadmium treatment). Using two-dimensional
      electrophoresis, the synthesis of stress proteins was demonstrated. Vibrio
      cultures consecutively exposed to CdCl2 and then to starvation or vice versa
      responded similarly metabolically. These results show increased proteosynthetic
      activity of the stressed Vibrio cells, indicating that the primary cadmium
      treatment induced the expression and synthesis of the protective proteins,
      enabling the cells to cope with the secondary stress.

PMID- 8659903
TI  - Expression and purification of bovine trophoblast protein-1 (bTP-1) in
      Escherichia coli.

PMID- 8659904
TI  - Model-based monitoring and control of a monoclonal antibody production process.
AB  - A structured mathematical model describing the dynamics of hybridoma growth and
      monoclonal antibody (mAb) production in suspension cultures is presented. The
      model fits well to experimental data obtained from batch, fed-batch, and
      continuous cultures with hybridoma cells. Applications of the model for process
      control are demonstrated. 1. An extended Kalman filter (EKF) was designed to
      estimate the state of the process. The oxygen consumption rate of the cell
      culture is monitored on-line and is used as the only measurement information for
      the EKF. This EKF is able to provide good estimates for living and dead cell
      densities and the medium composition. 2. The mathematical model can be applied
      for the optimization of fed-batch cultures.

PMID- 8659905
TI  - Redox balances in recombinant Saccharomyces cerevisiae.

PMID- 8659906
TI  - Use of a modified tryptophanase promoter to direct high-level expression of
      foreign proteins in E. coli.
AB  - We have modified the tryptophanase promoter (PtnaA) for use as a temperature
      independent promoter for the production of recombinant proteins. Although any
      protein will have a temperature range in which its expression is optimal, we find
      the tryptophanase promoter functions at all physiologically relevant temperatures
      (20 degrees C to 42 degrees C). Induction at temperatures below 37 degrees C
      avoids eliciting the heat-shock response and may favor the production of protein
      in the soluble state. A short segment of the E. coli tnaA promoter containing the
      catabolite gene activator protein (CAP) binding site but no tryptophan-responsive
      elements was used to direct synthesis of various proteins. Conditions for high
      cell density fermentation and induction control were developed. Expression was
      induced by depletion of glucose and was maximal when an alternative nonrepressing
      carbon source was supplied. Expression of certain proteins was tightly
      controlled; however, pre-induction expression was observed with other reporter
      genes. The tnaC leader portion of the tnaA promoter was found to reduce pre
      induction expression in the presence of glucose, although maximal expression was
      observed only in the absence of this region. The effect of temperature on
      expression of several recombinant proteins was investigated. Although some
      proteins were produced only in inclusion bodies as insoluble material, the
      production of one protein in soluble form was clearly temperature dependent.

PMID- 8659907
TI  - Stability of plasmid pHV1431 in free and immobilized cell cultures. Effect of
      temperature.
AB  - The segregational and structural stability of pHV1431 has been examined in
      Bacillus subtilis grown at 30 and 37 degrees C in continuous cultures without
      selection pressure. Immediately after appearance of plasmid-free cells in the
      reactor, a competition was observed between bacteria that favored plasmid-free
      cells because of the faster growth. A stronger instability was found at 30
      degrees C compared to that at 37 degrees C. At 30 degrees C after 50 hours of
      culture, 2% of the cells carried the plasmid, whereas at 37 degrees C this
      percentage was reached after 130 hours. In both cases, no structural instability
      was observed. To improve the stability, the recombinant Bacillus subtilis
      (pHV1431) was immobilized in kappa-carrageenan gel beads. In comparison to free
      cell systems, a higher cell concentration was obtained. Moreover, the plasmid was
      maintained stable for longer periods; after 150 hours of culture 40% of cells in
      the reactor still carried the plasmid at both temperatures.

PMID- 8659908
TI  - Kinetics studies for the optimization of recombinant protein formation.

PMID- 8659909
TI  - Mathematical modeling of proteinase A overproduction by Saccharomyces cerevisiae.
AB  - A simple, structured model was developed to describe the growth and product
      formation behavior of two recombinant strains of Saccharomyces cerevisiae (JG176
      and JG180), both overproducing extracellular proteinase A. The model parameters
      were estimated to data from continuous fermentations obtained at steady-state
      conditions. Model predictions show good agreement with experimental data obtained
      by batch fermentations. The two concerned organisms are distinguished from each
      other by the type of promoter on the plasmids controlling the proteinase A
      expression. The proteinase A transcription is controlled by the natural
      proteinase A promoter in JG176 and by a tpi promoter in JG180. By means of
      experiments and simulations, the extracellular product formation from the two
      strains with different promoter systems was compared in batch and continuous
      fermentations. The results showed that the proteinase A formation kinetic from
      JG176 was a combination of growth and nongrowth associated (production in the
      stationary growth phase), whereas the proteinase A formation from JG180 was truly
      growth associated (production in the exponential growth phase). In both batch and
      continuous cultivations JG176 gave the highest product concentrations and
      volumetric productivities.

PMID- 8659910
TI  - Foam fractionation of proteins: modeling of a semi-batch operation.

PMID- 8659911
TI  - Bioprocessing with genetically modified and other organisms: case studies in
      processing constraints.
AB  - Whereas the gene stability related considerations are important in bioprocessing
      with recombinant cultures, bioreactor design and scale-up require attention to
      the often reduced shear tolerance of the genetically altered biocatalysts
      relative to the corresponding wild strains. In addition, the peculiarities of
      expression of the rDNA product impact the downstream recovery methods. As a
      consequence, a bioprocessing scheme and the process machinery designed for a
      naturally occurring organism may need significant modifications for use with a
      genetically modified variety of the same organism. The case studies described
      highlight some of the processing constraints and consideration of general
      relevance.

PMID- 8659912
TI  - Metabolic engineering of animal cells.
AB  - Substrate-limited fed-batch cultures were used to study growth and overflow
      metabolism in hybridoma and insect cells. In hybridoma cells a glucose-limited
      fed-batch culture decreased lactate formation but increased glutamine consumption
      and ammonium formation. Glutamine limitation decreased ammonium and alanine
      formation but did not enhance glucose consumption. Instead lactate formation was
      reduced, indicating that glucose was used more efficiently. The formation of
      lactate, alanine, and ammonium was negligible in a dual substrate-limited fed
      batch culture. The efficiency of the energy metabolism increased, as judged by
      the increase in the cellular yield coefficient for glucose of 100% and for
      glutamine of 150% and by the change in the metabolic ratios lac/glc, ala/gln, and
      NHx/gln, in the combined fed-batch culture. Insect cell metabolism was studied in
      Spodoptera frugiperda (Sf-9) cells. A stringent relation between glucose excess
      and alanine formation was found. In contrast, glucose limitation induced ammonium
      formation, while, at the same time, alanine formation was completely suppressed.
      Simultaneous glucose and glutamine limitation suppressed both alanine and
      ammonium formation. Alanine formation appears as wasteful as lactate formation
      because the growth rate of insect cells in substrate-limited cultures was the
      same as in batch cultures with substrate excess. In batch and fed-batch cultures
      of both cell lines, mu reaches it maximum early during growth and decreases
      thereafter so that no exponential growth occurs. The growth rate limiting factor
      for hybridoma cells was found to be a component of serum, because intermittent
      serum additions to batch cultures resulted in a high and constant growth rate.
      Insulin was identified as the main cause, inasmuch as intermittent insulin
      additions gave the same result as serum.

PMID- 8659913
TI  - Stabilization of recombinantly expressed proteins.

PMID- 8659914
TI  - Protein purification in preparative scale of mammalian cell culture-derived
      products. Strategies for extra high purity.

PMID- 8659915
TI  - Implementation in an expert system of a selection rationale for purification
      processes for recombinant proteins.
AB  - This work presents the development of an expert system for selecting the best
      sequence of operations for the downstream processing of proteins.  The core of
      the discussion is how the rationale for the selection of a sequence of processes
      for purification was developed.  It consists of a system that compares extensive
      data on the product to be purified and on the main contaminant proteins found in
      the expression system to be used (e.g. E. coli).  Definitions of parameters that
      translate (i) the rules employed in separations and (ii) the selection between
      high-resolution purification operations (chromatography) using the databases of
      properties of proteins in a rational quantitative manner to guide the selection
      are described.  After each separation step, there is a reduction in the amount of
      contaminant proteins. The amount of each "contaminant" eliminated is determined
      using an algorithm developed for this purpose, based on simplified
      interpretations of chromatograms, that indicates the new concentrations after
      each step.  The number of steps must be sufficient to achieve a defined level of
      purity.  The comparison of the concentration of the product after the separation
      with the defined level of purity indicates whether an additional step is
      necessary.

PMID- 8659916
TI  - Interactions of HIV-1 proteins with human T-cell cyclophilin A.

PMID- 8659917
TI  - The use of antibodies for characterization and quantification of a recombinant
      protein.
AB  - In this study, we characterized proteinase A secreted by recombinant
      Saccharomyces cerevisiae bearing a multicopy plasmid containing the encoding gene
      (PEP4). Polyclonal and monoclonal antibodies were raised to study the product
      heterogeneity. Characterization of proteinase A was performed by
      immunoelectrophoresis and immunoblotting techniques. None of the monoclonal
      antibodies raised against proteinase A was found to react with the glycosyl side
      chains; thus cross-reaction with other glycosylated proteins (e.g.
      carboxypeptidase Y) was very low. This study allowed us to develop an ELISA
      method for the quantification of proteinase A in culture supernatants as well as
      the evaluation of monoclonal antibodies for their use in immunoaffinity
      chromatography.

PMID- 8659918
TI  - Influence of a global deregulation of the heat-shock response on the expression
      of heterologous proteins in Escherichia coli.

PMID- 8659919
TI  - Chaperone-like effect during in vitro refolding of insulin-like growth factor I
      using a solubilizing fusion partner.
AB  - A fusion partner, ZZ, derived from staphylococcal protein A, has earlier been
      shown facilitate the in vitro folding of human insulin-like growth factor I (IGF
      I). Although no solubilizing agents were used, there was no problem with
      precipitation, even at relatively high protein concentrations.  We have here
      investigated this phenomenon further by characterizing the in vitro refolding of
      IGF-I fused to one or two solubilizing Z domains.  The comparison also included
      IGF-I without a solubilizing fusion partner.  Solubility studies of the reduced
      proteins were performed, in addition to an evaluation of the aggregation
      occurring during the refolding process. Fusion to one or two Z domains increased
      the solubility of reduced IGF-I more than 100-fold.  In addition, the Z or ZZ
      fusion partners decreased aggregation of the IGF-I moieties during the
      renaturation.  The fusion partner has an effect resembling that of a cis-acting
      chaperone during in vitro refolding and may be an alternative to overcome the
      problems of insolubility and aggregation.

PMID- 8659920
TI  - Improving protein refolding yields by minimizing aggregation.

PMID- 8659921
TI  - RNA libraries and RNA recognition.
AB  - Random RNA libraries, consisting of > 10(13) unique sequences, contain molecules
      capable of specifically binding small molecule and protein ligands by noncovalent
      interaction. Successive steps of affinity purification and amplification allow
      the propagation and eventual isolation of specific binding molecules, called
      aptamers. Although protein- and small-molecule-binding aptamers have been
      characterized previously, selection of RNA aptamers capable of binding nucleic
      acids has previously yielded only molecules capable of Watson-Crick base pairing
      to the nucleic acid ligand used for selection. On the other hand, it is known
      from studies on catalytic and other RNAs that both inter- and intramolecular RNA
      RNA interaction can occur by non-Watson-Crick means. We have therefore
      incorporated a strategy to obviate the possibility of Watson-Crick interaction
      into a selection scheme for the isolation of RNA-recognizing aptamers. The
      aptamers so isolated do not show extensive Watson-Crick complementarity with the
      RNA ligand used for the selection, thereby validating the selection strategy.
      Curiously, all of the aptamers characterized contain several oligo-G stretches
      bounded by U residues. This sequence motif, which occurs as DNA in telomeres
      (chromosome ends) may therefore be a general RNA-RNA interaction motif. An
      additional sequence motif is apparently superimposed on this background
      structure.

PMID- 8659922
TI  - The use of recombinant DNA technology in the design of a highly specific heroin
      sensor.

PMID- 8659923
TI  - T-cell-targeted immunofusion proteins from E. coli.
AB  - Antibodies and antibody domains are ideal agents for targeting the surface of
      cells, and fusion proteins between cell-targeting domains and cytotoxic proteins
      may be particularly effective therapeutic reagents. We constructed a family of
      immunofusion proteins linking the humanized Fab, F(ab')2, or single-chain
      antibody form of the H65 antibody (which recognizes the CD5 antigen on the
      surface of human T cells) with the plant ribosome-inactivating protein gelonin.
      To maximize the product yield and simplify the production process, each fusion
      protein was linked to a bacterial signal sequence for expression in E. coli as a
      secreted protein. More than 30 fusion genes were assembled with antibody domains
      and gelonin in various physical orientations. Each immunofusion accumulated in
      the bacterial culture supernatant in a properly folded, active form. Bacteria
      transformed with each fusion gene were then grown in a fermentor, and product was
      recovered from the cell-free fermentation broth by column chromatography. All of
      the immunofusion proteins were purified by a single process and each was tested
      for cytotoxicity toward antigen-positive human cells. A compact cGMP fermentation
      area was built to manufacture these fusion proteins. Our integrated approach to
      microbial protein production, including molecular genetics, bacterial
      fermentation, and initial isolation, is described in detail.

PMID- 8659924
TI  - Molecular cloning of a lytic beta-1,3-glucanase gene from Oerskovia
      xanthineolytica LLG109. A beta-1,3-glucanase able to selectively permeabilize the
      yeast cell wall.
AB  - Molecular cloning of the beta gIII gene encoding for an endo-beta-1,3-glucanase
      (beta gl II) from Oerskovia xanthineolytica LLG109, a yeast-lytic gram-positive
      bacterium, has been conducted in order to elucidate its primary sequence and
      subsequently express it into B. subtilis. This endo-beta-1,3-glucanase exhibits
      low yeast-lytic activity toward viable S. cerevisiae cells, and it has shown
      ability to selectively permeabilize the yeast cell wall and release intracellular
      proteins produced by yeast. Highly degenerate oligonucleotides have been used to
      PCR-amplify a region of the beta-1,3-glucanase II encoding gene from O.
      xanthineolytica LLG109. The amplified fragment has been cloned and sequenced. The
      deduced amino acid sequence contains regions identical to the amino acid
      sequences previously determined by direct sequencing of the purified enzyme from
      O. xanthineolytica LLG109. By using the 180-bp PCR product as a homologous probe,
      we have been able to isolate four positive clones harboring plasmids pPF1A,
      pPF1B, pPF8A, and pPF9A, respectively, from a partial genomic library from O.
      xanthineolytica LLG109. All four plasmids contained a 2.7-kb BamHI insert that
      hybridized to the PCR probe under high stringency conditions. The 2.7-kb fragment
      seemed to be identical in all four cases regarding preliminary partial
      restriction mapping analysis done on the four plasmids. The 1.5-kb BamHI/KpnI
      restriction fragment from pPF8A and pPF9A hybridizing with the 180-bp PCR probe
      is presently being sequenced. The cloning of the lytic beta-1,3-glucanase from O.
      xanthineolytica LLG109 expands the number of yeast lytic beta-glucanases so far
      cloned. The availability of the nucleotide sequences of such a family of genes
      will allow further understanding of the role and mode of action of these enzymes
      in yeast cell wall degradation. In addition, a more extensive study on the
      structure and functional relationships of these enzymes will allow us to engineer
      "tailor-made" lytic beta-1,3-glucanases for use in new and improved large-scale
      selective cell permeabilization (SCP) and selective protein recovery (SPR) from
      yeast cells, not only from S. cerevisiae but also from alternative yeast
      expression systems such as Hansenula polymorpha, Pichia pastoris, and others,
      which are becoming of increasing importance in biotechnology.

PMID- 8659925
TI  - Diversified shunt to the production of different proportions of secondary
      metabolites (polyketides and terpenes) induced by varying immobilization
      constraints on Gibberella fujikuroi.

PMID- 8659927
TI  - The argU gene product enhances expression of the recombinant human alpha 2
      interferon in Escherichia coli.

PMID- 8659926
TI  - Gene transfer and amplification in CHO cells. Efficient methods for maximizing
      specific productivity and assessment of genetic consequences.

PMID- 8659928
TI  - Rate limitations in posttranslational processing by the mammary gland of
      transgenic animals.
AB  - Our studies in transgenic animal bioreactors sought to determine the rate
      limitations in posttranslational processing of recombinant human protein C (rhPC)
      made in mammary gland of mice and pigs. Human protein C (hPC) is a complex plasma
      protein containing nine gamma-carboxylated glutamic acid (gla) residues that bind
      calcium at about 1 to 3 mM. Gamma carboxylation is a vitamin K-dependent
      posttranslational modification. The effect of rhPC synthesis rate on the extent
      of gamma-carboxylation of glutamic acid was studied. We have perturbed the
      biosynthesis of rhPC by using two different transgenes to direct mammary gland
      specific expression. Promoter elements of the murine whey acid protein (mWAP)
      gene were used to drive the expression of hPC-cDNA and hPC-genomic transgenes.
      Transgenic mice with hPC-cDNA and hPC-genomic sequences gave expression levels of
      11 +/- 4 micrograms rhPC/ml of milk and 895 +/- 21 micrograms rhPC/ml of milk,
      respectively. Transgenic pigs with hPC-cDNA and hPC-genomic sequences gave
      expression levels of 100 to 500 micrograms rhPC/ml of milk and 800 to 2000
      micrograms rhPC/ml of milk, respectively. A monoclonal antibody (7D7B10-mAb) that
      binds an epitope in the gla domain of hPC in the absence of calcium was used to
      study the conformational behavior of immunopurified rhPC. Immunopurified rhPC
      from lower expressing mice and pigs gave a calcium-dependent binding inhibition
      by 7D7B10-mAb similar to that of hPC. Immunopurified rhPC from higher expressing
      mice and pigs gave a less calcium-dependent response. This study suggests that a
      rate limitation in gamma-carboxylation by the mammary gland occurs at expression
      levels about > 20 micrograms/ml in mice and > 500 micrograms/ml in pigs.

PMID- 8659929
TI  - Construction of gene expression system in cultured tobacco cells.
AB  - To construct a gene expression system in cultured tobacco cells, useful
      regulatory elements of plant genes were studied. The promoter of the horseradish
      peroxidase gene, prxC2, showed high activity in tobacco cells, and it contained
      enhancer sequences and a cis element for wound induction. The heat shock promoter
      of the HSP18.2 gene from A. thaliana had strong activity of transcription when
      the incubation temperature of tobacco cells was shifted from 25 degrees C to 37
      degrees C. These elements could be good candidates for foreign gene expression in
      tobacco cells.

PMID- 8659931
TI  - Vascular effects of sustained-release fibroblast growth factors.
AB  - Since the half-life of most angiogenic growth factors is several hours or less,
      sustained-release delivery would be optimal for their future clinical use. Two
      fibroblast growth factors, basic fibroblast growth factor (bFGF) and endothelial
      cell growth factor (ECGF), were delivered in two sustained-released modalities
      (poloxamer 407 and a gelatin sponge [Gelfoam]) to attempt to increase soft tissue
      vascularity. In vitro bioactivity of ECGF-poloxamer formulations was also tested
      on endothelial cell cultures. Among vascular-compromised skin flaps in rabbits,
      ECGF-poloxamer (N = 26), bFGF-poloxamer (N = 5), ECGF-poloxamer (N = 9,
      irradiated), and bFGF-Gelfoam flaps (N = 22) did not demonstrate significant
      differences in viability and vascularity compared to controls (p > .05).
      Irradiation had a detrimental effect on both flap vascularity and viability (p =
      .02). Future efforts for sustained delivery of angiogenic proteins are critical
      in order to make them clinically useful in wound healing.

PMID- 8659930
TI  - Relative prognostic importance of histologic invasion of the laryngeal framework
      by hypopharyngeal cancer.
AB  - This study assessed the relative prognostic importance of histologic invasion of
      the laryngeal framework by hypopharyngeal cancer. The laryngeal specimens and
      medical records of 55 patients found to have primary hypopharyngeal cancer
      between 1962 and 1988 were reviewed. Full 3-year follow-up information was
      obtained for 51 patients. The overall 3-year survival rate was 43% A(22/51). The
      3-year survival rate was 55% (17/31) without histologic invasion versus 25%
      (5/20) with invasion (p < .05). To assess how invasion affected survival rates in
      conjunction with clinical predictors, we divided the cohort into two groups (mild
      versus severe illness) based on the presence or absence of anemia and
      comorbidity. Only in the group with mild illness did histologic invasion provide
      additional prognostic information. These results demonstrate that the inclusion
      of clinical variables in predictions of prognosis can strikingly alter the
      prognostic importance of invasion of the laryngeal framework.

PMID- 8659932
TI  - Learning disabilities and central auditory dysfunction.
AB  - Hearing loss, whether peripheral or central, compounds the communication and
      educational problems of the learning disabled student. A central auditory
      processing disorder uniquely interferes with both the input and integration of
      verbal information, further resulting in a potentially permanent cognitive
      dysfunction during the developmental period of acquisition of language.
      Illustrative cases are presented that indicate the panorama of cognitive
      dysfunction associated with the learning disabled status. Methods of evaluation
      and identification and diagnostic criteria are correlated with auditory, visual,
      and academic performance. Comments regarding clinical awareness, prompt
      recognition, and ensuing individualized remediation are submitted.

PMID- 8659933
TI  - Effects of two breath-holding maneuvers on oropharyngeal swallow.
AB  - This study quantified the effects of the supraglottic maneuver (SGM) and super
      supraglottic maneuver (SSGM) on laryngeal and pharyngeal movements before and
      during swallow. Simultaneous videofluoroscopic and videoendoscopic examinations
      of oropharyngeal swallowing were performed in eight healthy volunteers with and
      without maneuvers. Data analysis compared 1) temporal relationships of
      oropharyngeal events, 2) airway conditions at the time of selected oropharyngeal
      events, and 3) biomechanical computer analysis of swallowing events. Using these
      maneuvers, normal subjects produced earlier cricopharyngeal opening, prolonged
      pharyngeal swallow, some degree of laryngeal valving before swallow, and change
      in extent of vertical laryngeal position before swallow. These changes are more
      successful and maintained longer with the SSGM than the SGM. We concluded that
      breath-holding maneuvers alter not only airway conditions before swallow but also
      both the temporal relationships and biomechanical events during oropharyngeal
      swallow.

PMID- 8659935
TI  - Effects of platelet activating factor on mucociliary clearance of the eustachian
      tube.
AB  - The effects of platelet activating factor (PAF) on mucociliary clearance of the
      eustachian tube were investigated both in vitro and in vivo. Normal ciliated
      epithelium was obtained from the eustachian tube of guinea pigs and incubated
      with PAF at concentrations ranging from 10(-10) to 10(-6) mol/L. Ciliary activity
      was observed under an inverted microscope and quantified photoelectrically. The
      PAF dose-dependently inhibited ciliary activity. One milliliter each of 10(-5)
      mol/LPAF, 10(-5) mol/L prostaglandin E2 (PGE2), 10(-5) mol/LPAF and PGE2, or the
      control solution (0.1 v/v% methanol-phosphate-buffered saline) was directly
      injected into the tympanic bullae of anesthetized chinchillas. The middle ear was
      examined by otomicroscopy, tympanometry, and auditory brain stem response in
      relation to time. The PAF delayed middle ear clearance, and the PGE2 augmented
      its delay. These findings suggest that PAF inhibits mucociliary clearance of the
      eustachian tube from the middle ear, and that PGE2 plays an important role in the
      augmentation of inflammatory disorders.

PMID- 8659934
TI  - Ontogenetic expression of spot 35 protein (calbindin-D28k) in human olfactory
      receptor neurons and its decrease in Alzheimer's disease patients.
AB  - Expression of a calcium-binding protein, spot 35 protein (S-35, calbindin-D28k),
      was investigated immunohistochemically in the human olfactory mucosa of patients
      who ranged in age from 16 weeks of fetal development to 98 years old, including
      some with Alzheimer's disease (AD). S-35 immunoreactivity was observed clearly in
      olfactory receptor neurons (ORNs) and olfactory nerve bundles that were
      identified previously with antibodies to olfactory marker protein (OMP) and
      neuron-specific enolase (NSE). Throughout all ages, the mean number of ORNs
      immunoreactive for OMP did not change significantly, whereas the mean number of
      NSE- and S-35-immunoreactive ORNs declined markedly in the postnatal infant,
      young, and old patients when compared with that of the prenatal fetuses. S-35
      immunoreactive ORNs decreased significantly in AD patients when compared with AD
      control patients. These results indicate that ORNs in humans express S-35 and
      that there is an age-related trend in the expression of S-35. Furthermore, the
      marked decrease of S-35 expression in ORNs of AD patients suggests that cell
      excitability associated with calcium ions and cell protective function against
      overload of intracellular calcium ions decline in these patients.

PMID- 8659936
TI  - Lack of effect of hot, humid air on response to nasal challenge with histamine.
AB  - We have previously shown that whole body exposure of human subjects to
      environmental conditions of 37 degrees C and 90% relative humidity (RH) prior to
      and during nasal challenge with antigen decreases the early response. In this
      study, we evaluated 1) whether the decreased responses observed resulted from
      decreased end organ sensitivity to histamine and 2) whether the effect of hot,
      humid air persisted after the subject exited the hot, humid environment. Ten
      asymptomatic seasonal allergic subjects and 11 nonallergic subjects were
      randomized to environmental chamber conditions of either 20 degrees C, 30% RH or
      37 degrees C, 90% RH for 1 hour prior to and during performance of a nasal
      challenge with histamine. Twenty-two hours after exiting the environmental
      chamber, the allergic subjects were challenged with antigen. During both chamber
      conditions, histamine challenge was associated with a significant increase in all
      measured parameters compared to sham challenge, except for the sensations of
      pruritus and congestion. The response to histamine challenge was not different
      under the two experimental conditions or between allergic and nonallergic
      subjects. Following both exposure conditions, allergen challenge was associated
      with an increase in all measured parameters compared to sham challenge, with no
      significant difference between the two conditions. Exposure to 37 degrees C, 90%
      RH minimally affects the response to nasal challenge with histamine, and thus,
      the previously reported decreases in the early nasal response to antigen may
      primarily result from reduction in mast cell activation. The effect on antigen
      does not persist 22 hours after exposure.

PMID- 8659937
TI  - Bifid epiglottis.
AB  - The true bifid epiglottis is a rare congenital anomaly typically discovered
      during the evaluation of stridor in an infant or newborn. While it is not
      classified as a specific syndrome, there are frequent associations of other
      congenital anomalies with the bifid epiglottis. These include midline defects
      (such as microphallus, hypospadius, imperforate anus, and midline laryngeal
      cleft), endocrine disorders (including congenital hypopituitarism), and central
      nervous system neoplasms, including hypothalamic hamartoblastoma. The
      embryogenesis and options for surgical management of this anomaly are reviewed,
      and one case is presented in detail.

PMID- 8659938
TI  - Delayed and progressive hearing loss after microvascular decompression of cranial
      nerves.
AB  - An unusual case of unilateral delayed and progressive hearing loss following a
      microvascular decompression operation on cranial nerves V, VII, and VIII on the
      left side is reported. Preoperative and postoperative audiologic evaluation
      revealed a mild high-frequency hearing loss for both ears, normal thresholds for
      the acoustic middle ear reflex response, and normal brain stem auditory evoked
      potentials. Three years after this microvascular decompression procedure, the
      patient noticed slowly decreasing hearing in her left ear, and subsequent serial
      audiograms revealed a progressive sensorineural hearing loss and a decrease in
      her speech discrimination score. Brain stem auditory evoked potentials showed
      progressive changes. Because of the patient's increasing symptoms of vertigo and
      tinnitus in the left ear, reexploration of the eighth cranial nerve was performed
      5 1/2 years after the initial procedure. This second operation revealed reactive
      tissue around the eighth cranial nerve that was atrophic and yellow. We interpret
      the delayed and progressive hearing loss to be a result of reactive scar tissue
      and progressive atrophy of the auditory nerve.

PMID- 8659939
TI  - Hemangiopericytoma of the masticator space.
AB  - Hemangiopericytomas are rare tumors of the head and neck. The benign presentation
      of this tumor belies its high local recurrence rate, local aggressiveness, and
      malignant potential. In view of these characteristics, workup to provide a
      diagnosis preoperatively is of significant importance. Diagnostic imaging is
      helpful in planning operative management, detecting metastases, and narrowing the
      list of differential diagnoses. However, because of the variety and lack of
      specificity of radiologic findings, it is generally difficult to provide a
      diagnosis. A history of a painless, slowly growing, otherwise asymptomatic mass,
      together with the radiologic findings of a vascular neoplasm, should enhance the
      suspicion of an HPC as a diagnosis. Hemangiopericytoma should be included in the
      differential diagnosis of any vascular soft tissue lesion presenting in the head
      and neck, and plans for surgical intervention should include the possibility of
      aggressive, wide local resection in order to adequately treat such a lesion
      should it be encountered.

PMID- 8659940
TI  - Orofacial granulomatosis and Crohn's disease.
AB  - Orofacial granulomatosis is a clinical entity of either unknown or specific
      causation. Specific causes include sarcoidosis, chronic infective granulomas, and
      Crohn's disease. The remainder of cases are idiopathic, but the clinical
      presentations of orofacial swellings and intraoral mucosal lesions are similar.
      So, too, are the histopathologic findings of noncaseating granulomas, edema, and
      chronic lymphoproliferative infiltrate. Crohn's disease is not responsible for
      all forms of orofacial granulomatosis, but the orofacial manifestations of the
      disease may herald its diagnosis.

PMID- 8659941
TI  - Vocal fold paralysis following the anterior approach to the cervical spine.
AB  - The anterior cervical approach is commonly used for access to the cervical spine.
      Vocal fold paralysis (VFP), a complication of this approach, is underrepresented
      in the literature. A review of the database of the Vanderbilt Voice Center
      revealed 289 patients with VFP, including 16 patients who developed paralysis as
      a result of an anterior cervical approach. The paralysis was on the right side in
      all but 1 patient. Compared to patients who developed VFP after thyroidectomy and
      carotid endarterectomy, patients with VFP after an anterior cervical approach
      have a higher incidence of aspiration and dysphagia, suggesting the presence of
      trauma to the superior laryngeal and pharyngeal branches as well as the recurrent
      branch of the vagus nerve. Two patients had partial return and 1 patient had
      complete return of vocal fold movement within 10 months. Of the remaining 13
      patients, 8 underwent vocal fold medialization with improvement of symptoms. Two
      patients are 6 and 7 months postinjury and await vocal fold medialization. Two
      patients are 27 months and 45 months postinjury and are considering vocal fold
      medialization. The remaining patient was lost to follow-up. An anatomic-geometric
      analysis of the right and left recurrent laryngeal nerves was performed by using
      measurements obtained from computed tomography scans of 8 patients with
      idiopathic unilateral VFP, as well as experience gained through surgical and
      cadaveric dissections. We conclude 1) the anterior cervical approach may place
      multiple branches of the vagus nerve at risk; 2) because of anatomic-geometric
      factors, the right-sided anterior cervical approach may carry a greater risk to
      the ipsilateral recurrent laryngeal nerve than does the left; and 3) an
      understanding of the anatomy and geometry presented herein allows relatively safe
      exposure from either side of the neck.

PMID- 8659942
TI  - Supraglottic and pharyngeal sensory abnormalities in stroke patients with
      dysphagia.
AB  - Dysphagia and aspiration are two devastating sequelae of stroke, accounting for
      nearly 40,000 deaths from aspiration pneumonia each year in the United States.
      While motor deficits in the larynx and pharynx are thought responsible for
      dysphagia and aspiration in stroke patients, no prior study has evaluated whether
      these patients also have sensory deficits. The aim of this study was to evaluate
      the sensory capacity of the laryngopharynx (LP) in supratentorial or brain stem
      stroke patients who presented with dysphagia. Fifteen stroke patients (mean age,
      66.7 +/- 13.8 [SD] years) were prospectively evaluated by means of our previously
      described method whereby air pulse stimuli were delivered via a flexible
      fiberoptic telescope to the mucosa innervated by the superior laryngeal nerve.
      There were 15 age-matched controls. No LP sensory deficits were found in any of
      the age-matched controls. In all stroke patients studied, either unilateral (n =
      9) or bilateral (n = 6) sensory deficits were identified. Deficits were defined
      as either a moderate impairment in sensory discrimination thresholds (3.5 to 6.0
      mm Hg) or a severe sensory impairment (> 6.0 mm Hg). These sensory discrimination
      thresholds were significantly greater than in age-matched controls (7.05 +/- 0.17
      mm Hg for the supratentorial group and 6.05 +/- 1.22 mm Hg for the infratentorial
      group versus 2.61 +/- 0.69 mm Hg for the controls). Among patients with
      unilateral deficits, sensory thresholds were moderately to severely elevated in
      all 9 cases on the affected side compared with the unaffected side (p < .01,
      Fisher's exact test). Moreover, the sensory thresholds of the unaffected side
      were not significantly different from those of age-matched controls (2.51 +/-
      0.25 mm Hg versus 2.61 +/- 0.69 mm Hg, respectively). All 6 patients with
      bilateral deficits had severe impairments. The results of an outcome assessment
      in 13 of 15 patients revealed that 2 out of 5 patients with moderate LP sensory
      impairment and 5 out of 8 with severe impairment developed aspiration. Our
      results show for the first time that stroke patients with dysphagia have
      significant sensory deficits in the LP and that these impairments are likely to
      contribute to the development of aspiration.

PMID- 8659943
TI  - Pathophysiology of reactive airway disease and sinusitis.
AB  - The association between asthma and sinusitis was recognized more than a century
      ago. Since 1980, several studies have documented that severe asthma improved
      after coexisting sinusitis was effectively treated either medically or
      surgically. Because the mechanism relating sinusitis to asthma is not known,
      several theories have been proposed: 1) aspiration of infected sinus secretions
      into the lungs during sleep, 2) enhanced vagal stimulation in the infected sinus
      producing direct bronchospasm, 3) bronchospasm from excessive airway drying from
      mouth breathing, 4) production of bacterial toxins that induce partial beta
      blockade, and 5) production in the infected sinus of cytokines and
      bronchoconstrictive mediators. There are data to support each of these
      hypotheses, and any or all of them may be operative. In view of recent
      demonstrations of activated lymphocytes and eosinophils in asthmatic airways, it
      is intriguing that biopsies of chronic hypertrophic sinusitis have revealed
      increased numbers of eosinophils and increased levels of granulocyte-macrophage
      colony stimulating factor, interleukin-3, and interleukin-5 compared to control
      tissue. These findings suggest that sinusitis might induce asthma by stimulating
      eosinophil production and activation and thereby supplying peptidoleukotrienes
      (LTC4 and LTD4) and other asthmagenic eosinophil products.

PMID- 8659944
TI  - Obagi's modified trichloroacetic acid (TCA)-controlled variable-depth peel: a
      study of clinical signs correlating with histological findings.
AB  - Currently, no documentation correlates histological changes with clinical signs
      of depth of the trichloroacetic acid peel. Obagi identified clinical signs of
      depth of injury following topical trichloroacetic acid application, employing
      prepeel conditioning and a method for slowing trichloroacetic acid action. A
      three-part study of 20 patients was undertaken to determine whether Obagi's
      visual and palpatory signs of depth correlated histologically with depth of peel.
      Also analyzed were physiological mechanisms associated with these signs. Patients
      were pretreated and biopsy specimens were harvested before and after modified
      trichloroacetic acid peeling. The results largely confirmed the validity of
      Obagi's observations regarding the method of trichloroacetic acid peel described.
      These clinical signs are verified by histology and correlated with some findings
      by electron microscopy. Differentiation of papillary from upper reticular dermal
      penetration is particularly useful. Physiological explanations for the phenomena
      observed are proposed. The specificity and safety of peels may be improved with
      these criteria.

PMID- 8659945
TI  - The surgically delayed unipedicled TRAM flap for breast reconstruction.
AB  - Surgical delay is one method of enhancing the vascularity of the lower abdominal
      transverse rectus abdominis musculocutaneous (TRAM) flap. The outcome of 7
      patients who underwent surgical delay (by ligating both superficial and deep
      inferior epigastric vessels bilaterally) a week prior to definitive TRAM flap
      elevation is described. Three patients were smokers, 3 were obese, and 1 was an
      asthmatic on medication. A satisfactory aesthetic result was achieved in all
      patients and the complications that occurred were minor. Two patients developed
      minor skin necrosis due to inadequate trimming of zone 4 on the contralateral
      side to the pedicle and there were 3 cases of fat necrosis, which occurred below
      Scarpa's fascia. Surgical delay is a useful technique of breast reconstruction.
      It allows the flap to be centered safely in the lower abdomen. In the high-risk
      patient, delay may prevent the need for microsurgery or the sacrifice of both
      recti.

PMID- 8659946
TI  - Unexpected vascular compromise in transverse rectus abdominis musculocutaneous
      (TRAM) flap reconstruction: a report of two patients.
AB  - Although the vascular anatomy of the transverse rectus abdominis musculocutaneous
      flap has been well described, poor flap perfusion can lead to partial or total
      flap ischemia. To minimize the potential for flap loss, criteria have been
      developed to identify those patients who are deemed to be high risk. Some of
      these high-risk patients include smokers and those with previous abdominal
      surgery, obesity, and/or poor medical health. Despite our diligence in patient
      and operative selection, 2 patients with no preexisting risk factors have
      recently had venous congestion of their transverse rectus abdominis
      musculocutaneous flap, necessitating a delayed procedure. The cases are presented
      here and the potential etiology for this venous congestion explored.

PMID- 8659947
TI  - Mastectomy specimen weight and skin dimensions as an adjunct in breast
      reconstruction.
AB  - In performing breast reconstruction with autogenous tissue, it has become useful
      to have accurate documentation of the weight and skin dimensions of the resected
      specimen. This enables the plastic surgeon to reconstruct a more natural and
      aesthetic breast. Oftentimes this information is not available and requires, at
      best, an estimate based on the size and shape of the remaining contralateral
      breast. To help take the guesswork out of an already artistic endeavor, this
      important information can make a substantial difference in the results obtained.

PMID- 8659948
TI  - The effects of scalp expansion on the cranial bone: a clinical, histological, and
      instrumental study.
AB  - The effects of chronic compression of the cranial bone due to progressive
      expansion of the scalp have been investigated. Ten patients were studied, 6
      adults and 4 children, who were treated for congenital (microtia) or acquired
      (burns or traumatic) deformities by chronic expansion over a 2-month period. All
      underwent computed tomography scans of the expansion site prior to introduction
      of the expansion device, immediately before removal, and at 9 months after the
      operation. A case of postburn alopecia was lost to the study, because the
      patient, who had ultimated scalp expansion, did not return for flap advancement.
      Instead, she came back 3 months later, without the expander, which had been
      removed at another institution following an automobile accident. In this case,
      because of slower healing, we performed computed tomography scans 18 months
      postoperation. During the second procedure (expander removal and flap
      transposition), bone samples for histological examination were collected directly
      underneath and along the perimeter of the expanders. Macroscopically, the bone
      appeared thinned and had a reduced convexity. This reaction, although temporary,
      appeared more intense in the children and in the posttraumatic cases.
      Histological examination showed osteoclastic activation, bony hypotrophy, and
      reaction (deposition of osteoid matrix) under the device, with consequent bone
      resorption and remodeling. A marked hyperplasia with a hyperostotic reaction was
      observed around the expanders. At 9 months postoperation, in most cases, a
      complete normalization was confirmed by computed tomography scans. Expansion of
      target (fontanellar and sagittal) areas of the skull in children, as well as
      previous trauma to both scalp and skull should be taken into consideration as a
      risk factor. Further investigations are suggested.

PMID- 8659949
TI  - The surgical management of cranio-orbital neurofibromatosis.
AB  - Experience with the surgical management of cranio-orbital neurofibromatosis in 14
      patients is reported (age range, 6-40 years). The skeletal abnormality of the
      orbit that occurs in a small proportion (less than 1%) of patients with
      neurofibromatosis is, in essence, the absence of the membranous portions of the
      sphenoid and the adjacent bone forming the boundaries between the cranium and the
      orbit. The goal of surgery is tumor resection and reconstruction of the posterior
      bony defect by bone graft. Two additional procedures are also described that
      better enhance aesthetically-the mask lift and facial tissue expansion.

PMID- 8659950
TI  - Zone of injury: a valid concept in microvascular reconstruction of the
      traumatized lower limb?
AB  - Microvascular reconstruction at the lower extremity for complex composite wounds
      has traditionally been predicated upon performance of the microanastamosis beyond
      the so-called "zone of injury." Failure to do so was believed to account for
      increased rates of vessel thrombosis and transplant loss. Extensive vessel
      dissection and vein grafts were often employed in efforts to avoid the zone of
      injury. To further analyze the validity of this concept, we conducted a
      prospective evaluation of all patients undergoing microvascular reconstruction of
      composite lower limb wounds during a 5-month period at Los Angeles County Medical
      Center. There were 28 patients in this cohort. Twenty-six (93%) were judged
      Gustilo IIIB or worse preoperatively. Distance from the microanastamosis to the
      proximal bony osteotomy (zone of injury) averaged 45.7 mm. In no case was a vein
      graft required. All transplants healed uneventfully without any loss. A
      reassessment of the concept of zone of injury is urged with analysis of the
      quality of the recipient vessels and not their location being clinically
      important.

PMID- 8659951
TI  - Microvascular transplantation in the salvage of lower extremity trauma in the
      elderly.
AB  - Successful salvage of Gustilo IIIB tibial fractures with microvascular
      transplantation has been documented in the young. Similar results from the
      application of these techniques to the elderly has not been demonstrated. An 8
      year review located 12 patients 60 years or older who underwent soft tissue
      reconstruction of IIIB tibial fractures with microvascular transplants. Ten
      patients were available for long-term follow-up (average 43 months). To date, 80%
      remain ambulating with no secondary amputations or late infections reported.

PMID- 8659952
TI  - Pit viper bites: rational management in locales in which copperheads and
      cottonmouths predominate.
AB  - The management of pitviper bites remains controversial. In order to better assess
      the efficacy of different treatment modalities, charts of 107 patients
      hospitalized for pitviper bites at University of North Carolina Hospitals between
      1952 and 1992 were retrospectively reviewed. The series included 68 copperhead
      bites (64%), 8 cottonmouth bites (7%), 3 rattlesnake bites (3%), and 28 bites
      (26%) in which the snake could not be identified. First aid measures taken prior
      to hospitalization included cryotherapy (21%), incision and suction (22%), tight
      or loose tourniquets (32%), and moist heat (2%). After hospitalization, 29
      patients (27%) underwent wound excision and 4 patients (4%) required fasciotomy.
      Antivenin was administered to 34 patients (32%) and 9 patients (26%) developed
      serum sickness. No patients died as a result of a bite injury and 84 patients
      (79%) recovered uneventfully. Complications of the injuries included
      coagulopathies (4%), infections (13%), tissue loss (12%), and permanent physical
      deformities (8%). No first aid measure significantly affected the outcome,
      although there was a trend toward increased complication rates in bites with
      moderate (grade II) or greater envenomation if cryotherapy or tourniquets were
      utilized. Wound excision after hospitalization was associated with a decreased
      complication rate in these significantly envenomated bites. Antivenin utilization
      did not improve outcome and there was a significantly higher incidence of tissue
      loss associated with its use. Therefore, no first aid measures are recommended
      for pitviper bites due to copperheads and cottonmouths except immobilization and
      elevation. Excision is efficacious for patients seen within 1 to 2 hours of bite
      injury. The risk of complications and questionable efficacy of antivenin outweigh
      any potential benefit for these patients. Data from the current series were
      insufficient to make definitive recommendations regarding rattlesnake bites.

PMID- 8659953
TI  - Single-portal endoscopic carpal tunnel release: agee carpal tunnel release
      system.
AB  - This single-group prospective cohort study was conducted to define the efficacy
      and safety of single-portal endoscopic carpal tunnel release using the redesigned
      carpal tunnel release system (3M Healthcare, St Paul, MN). Eighty-six procedures
      in 69 patients were evaluated by objective motor/sensory testing and clinical
      outcome questionnaire at 10 days, and 6 and 10 weeks postoperatively. All cases
      were performed by the same surgeon using a similar local anesthetic technique.
      The subjective symptoms of carpal tunnel syndrome, including paresthesia,
      numbness, and pain, demonstrated substantial improvement by 10 days
      postoperatively, and less than 2% of the subjects remained symptomatic by 10
      weeks. The percentage of patients with normal, static, two-point discrimination
      in the median nerve distribution, demonstrated significant improvement by 6 weeks
      postoperatively. Preoperative grip and three-point pinch strength were regained
      by 6 weeks postoperatively, while lateral pinch demonstrated substantial
      improvement in the same time period. Workers' compensation cases required a
      significantly longer time to return to work (mean, 40.8 days) than nonworkers'
      compensation cases (mean, 22.2 days). No difference, however, was demonstrated
      between workers' compensation and nonworkers' compensation cases with respect to
      the time of return to activities of daily living (mean, 13.5 days). There were no
      major neurovascular injuries incurred during the performance of the study. The
      most important complications included one mild reflex sympathetic dystrophy,
      three transient digital neuropraxias, and one superficial wound infection. In
      conclusion, the performance of single-portal endoscopic carpal tunnel release
      using the redesigned Agee carpal tunnel release system is both a safe and
      efficacious procedure.

PMID- 8659954
TI  - Hand sensibility measures used by therapists.
AB  - Sensory evaluations are frequently used to assess patients with functional loss
      resulting from nerve injury. The results of these tests are routinely utilized by
      hand surgeons as an indication for conservative management or surgical
      intervention in the evaluation of surgical outcome and in the determination of
      disability ratings. Reports in the literature regarding specific tests for
      sensibility show variation in their application. The purpose of this study was to
      evaluate which tests are used to evaluate hand sensibility and the techniques of
      application currently used by hand therapists. Two hundred members of the
      American Society of Hand Therapists were randomly selected and a survey was sent
      to these members. The results of this study identify the need to develop
      standardized protocols for sensory evaluations and the need for therapists to
      follow the standardized methods for administration of moving and static two-point
      discrimination, and Semmes-Weinstein monofilaments, if comparisons of results
      between centers are to be meaningful.

PMID- 8659955
TI  - The effects of irradiation dose on the stiffness of cartilage grafts.
AB  - Various centers report irradiated cartilage graft absorption rates that differ
      quite widely. We postulated that a major factor governing this phenomenon might
      be irradiation dose. Irradiation produces collagen cross-binding and increased
      resistance to absorption of such material when implanted. Since cross-binding
      produces stiffening of collagen, cartilage grafts were exposed to increasing
      doses of irradiation and their elastic modulus was measured. The postulate was
      that increasing radiation doses will produce grafts of increasing stiffness.
      Sternal cartilage, harvested from horses, was cut into blocks of a standard size
      and irradiated to 4, 6, 8, and 10 megarads. The elastic modulus of each specimen
      and matched control were measured on an Instron flexural testing machine (Instron
      Corp, Canton, MA). Irradiation at all four doses reduced the elastic modulus of
      the cartilage grafts, with the lowest dose producing a reduction of 50% and the
      highest dose one of 90%. High-dose irradiation appears to lessen greatly the
      stiffness of cartilage grafts and may be responsible for increasing absorption of
      grafts in centers in which high doses are used.

PMID- 8659956
TI  - Hyperbaric oxygen and cyclosporine as a combined treatment regimen to prevent
      skin allograft rejection in immunohistoincompatible mice.
AB  - Several previous studies reported various immunosuppressive effects of hyperbaric
      oxygen on nonspecific and specific cell-mediated reactions. A highly immunogenic
      skin allograft mouse model was used to evaluate the clinical relevance of the
      previously described immunosuppressive effects of hyperbaric oxygen. A 1.5 x 2.0
      cm full-thickness skin allograft was cross-grafted between paired
      immunohistoincompatible mouse strains (N = 40, C57BL/6 and BALB/c female mice)
      that were randomly assigned to four groups receiving (1) no treatment (controls),
      (2) cyclosporine 1 mg per kilogram intraperitoneally daily, (3) cyclosporine plus
      a low-dose hyperbaric oxygen treatment (two treatments per day, once a week), and
      (4) cyclosporine plus a high-dose hyperbaric oxygen treatment (two treatments per
      day, three times a week) following surgery (N = 32). Allograft samples were taken
      from each group at day 9 after cross-grafting (N = 8). Skin allograft rejection
      was significantly delayed in all treatment groups compared to controls. No
      difference was found between animals who received cyclosporine only and the
      combined treatment regimen including low-dose hyperbaric oxygen. High-dose
      hyperbaric oxygen treatment in combination with cyclosporine substantially
      prolonged skin allograft survival compared to other treatments. These findings
      were histologically confirmed. We conclude that hyperbaric oxygen treatment as an
      adjunct to standard immunosuppressive therapy may only be advantageous if
      frequently applied.

PMID- 8659957
TI  - Late Clostridium perfringens breast implant infection after dental treatment.
AB  - Late infection is rare after breast augmentation. Pathogenesis is usually implant
      seeding caused by bacteremia as a consequence of antecedent distant infections or
      medical/dental procedures. Reported is the first case of late implant infection,
      after extensive dental treatment, caused by Clostridium perfringens, an anaerobic
      pathogen commonly present in the human gastrointestinal tract. Prompt diagnosis
      and early antibiotic treatment of all bacterial infections, and serious
      consideration of antibiotic prophylaxis for all bacteremia-producing procedures,
      is essential for breast implant patients.

PMID- 8659958
TI  - Sharing the radial forearm flap in reconstruction of two separate defects in the
      same patient.
AB  - The radial forearm flap is used extensively to cover defects for which a thin
      skin flap is needed. It can be used either as a pedicle or a free flap in various
      designs. In this case report, a new application of this flap is presented in
      which two flaps were created out of a single radial forearm flap to cover two
      separate defects. One of the flaps was a distally based reverse island flap. We
      used this flap to cover a defect developed by releasing a burn contracture on the
      flexor surface of the thumb. The other flap consisted of the proximal portion of
      the forearm flap and was transferred to the neck region as a free flap to cover a
      defect resulting from the release of a burn contracture. The radial artery allows
      sharing the fasciocutaneous unit of the forearm into two different flaps and
      transferring them to separate areas. Thus, donor site morbidity is reduced when
      there is more than one defect to be reconstructed.

PMID- 8659959
TI  - Vaginal reconstruction with free jejunal flap.
AB  - Congenital absence of a vagina is a rare but outstanding anomaly of plastic
      surgery. Although many methods are described for reconstruction of vaginal
      agenesis, there is not a method yet to be approved as a perfect solution to this
      problem. With the aim of solving the problems faced with conventional methods,
      free jejunal transplantation was planned to construct a neovagina. For this
      method, we isolated a 15-cm jejunal segment, with its pedicle, transferred it to
      the preprepared vaginal pouch, and anastomosed the donor vessels of the mesentery
      to the inferior epigastric vessels. In the postoperative sixth month, problems of
      intercourse or the need to use any lubricator or stent were still not experienced
      and reported. In this paper, we judge and compare our approach by reviewing
      others.

PMID- 8659960
TI  - Fibro-osseous pseudotumor of the distal phalanx.
AB  - Recurrent soft-tissue digital masses with osseous components frequently result in
      diagnostic and treatment dilemmas. We discuss a case of a recurrent fibro-osseous
      pseudotumor of the digit, review specific diagnostic and histological features,
      and recommend treatment.

PMID- 8659961
TI  - Bacille Calmette-Guerin (BCG)-itis of the hand: a potential hazard for health
      workers.
AB  - The bacille Calmette-Guerin vaccine has been used widely for several decades in
      tuberculosis prophylaxis. More recently, it has been used therapeutically in the
      management of neoplastic diseases such as malignant melanoma and urinary bladder
      tumors. Complications of the b. Calmette-Guerin vaccine and therapy are widely
      reported in the literature. However, its potential hazard to health workers is
      not well described. We present a case of b. Calmette-Guerinitis on the extensor
      surface of the left ring finger of a surgical resident following an accidental
      prick with a contaminated syringe while installing intravesical b. Calmette
      Guerin to a patient being treated for a bladder tumor. A brief review of
      tuberculous hand infection is presented together with its recommended treatment.
      A review of the various usages of b. Calmette-Guerin is also presented, stressing
      the various reported complications.

PMID- 8659962
TI  - Histoplasma capsulatum necrotizing myofascitis of the upper extremity.
AB  - Necrotizing myofascial fungal infections of the upper extremity is a rare event
      even in immunocompromised hosts. We report the course of a renal transplant
      patient who developed extensive necrotizing myofascial infection of an upper
      extremity secondary to Histoplasma capsulatum. Initial, functional, upper limb
      salvage was achieved after aggressive surgical debridement and high doses of
      amphotericin B. The patient ultimately succumbed to systemic fungal sepsis. The
      etiology and treatment of these infections are discussed.

PMID- 8659963
TI  - Patently unethical.

PMID- 8659964
TI  - Antipersonnel mines: the global epidemic.

PMID- 8659966
TI  - A nurse-led preadmission clinic for elective ENT surgery: the first 8 months.
AB  - A nurse-led preadmission clinic was set up in the Department of Otolaryngology of
      The Royal Berkshire Hospital, Reading, for patients undergoing elective ENT
      surgery. The progress of the clinic has been monitored during its first 8 months
      of service. A two-part study was undertaken: (a) A prospective study of the
      process from the time an admission appointment was sent until completion of
      surgery and, (b) a retrospective review of the case notes to study the quality of
      clerking and note keeping and the pattern of requests for investigations made by
      the nurses. In all, 514 patients were invited to attend the preadmission clinic
      before operation. Of these patients, 454 attended the clinic for preadmission
      clerking, 440 (96.9%) of whom underwent their operation without complication. All
      clerking notes were well kept, but a number of unnecessary investigations were
      requested. It is concluded that a nurse-led preadmission clinic is effective in
      the management of elective ENT operating lists. It assists in improving the
      quality of an SHO's training by reducing time spent on service commitments,
      thereby increasing the potential training time. More guidance to nurses on the
      use of preoperative investigations is needed.

PMID- 8659965
TI  - Assessment of peritonism in appendicitis.
AB  - The aim of this study was to evaluate the accuracy of different methods of
      demonstrating right iliac fossa peritonism in appendicitis. The methods used were
      cat's eye symptom (pain on going over a bump in the road), cough sign, right
      iliac fossa tenderness, percussion tenderness, rebound tenderness and guarding. A
      series of 100 consecutive patients with a median age of 25 years (range 4-81
      years), presenting with right iliac fossa pain were studied prospectively; the
      male:female ratio was 39:61. In all, 58 patients underwent operation, 44 had
      appendicitis confirmed on histology. Fourteen patients had a normal appendix
      removed; 11 were women aged between 16 and 45 years. Cat's eye symptom and cough
      sign were sensitive indicators of appendicitis (sensitivity 0.80 and 0.82,
      respectively), but were not specific (specificity 0.52 and 0.50, respectively)
      and therefore inaccurate (accuracy 64%). Percussion tenderness was less sensitive
      (sensitivity 0.57) but more specific (specificity 0.86). Rebound tenderness
      proved to be sensitive (sensitivity 0.82), specific (specificity 0.89) and
      accurate (accuracy 86%). Thus, rebound tenderness had a positive predictive value
      of 86% compared with 56% and 57% for cough sign and cat's eye symptom,
      respectively. In the difficult diagnostic group of young women, the positive
      predictive value of rebound tenderness was 88% compared with 58% and 56% for
      cat's eye symptom and cough sign. Appendicitis remains a difficult diagnosis,
      particularly in young women. Rebound tenderness still has an important role to
      play in clinical assessment.

PMID- 8659967
TI  - Subjective effects of double gloves on surgical performance.
AB  - This randomised trial compared single gloves with combinations of double gloves
      to determine the subjective effects on comfort, sensitivity and dexterity in 32
      surgeons. Glove perforation rates were also compared. Single gloves of the
      surgeon's normal size (method A) were used as control. Double gloves were worn in
      three different ways, selected randomly: normal gloves inside and gloves one-half
      size larger outside (method B); the larger gloves inside and the normal gloves
      outside (method C); and lastly, two pairs of gloves of normal size (method D).
      Double gloves by all three methods significantly protected against needle
      perforation of the inner gloves when compared with single gloves, but also
      significantly impaired comfort, sensitivity and dexterity. When the three types
      of double gloving were compared, there appeared to be advantages for method C for
      all modalities, but the differences did not reach statistical significance; also,
      more surgeons expressed a preference for method C. Perforation of the inner
      gloves was significantly less for double gloves than for single gloves. We
      conclude that double gloves often protect the surgeon against needle
      perforations, but are felt to impair comfort, sensitivity and dexterity.

PMID- 8659968
TI  - Four-year evaluation of a direct-access fibreoptic sigmoidoscopy service.
AB  - Over a 4-year period, a direct-access fibreoptic sigmoidoscopy service was
      evaluated prospectively. In all, 756 patients were referred (median age 58 years,
      range 18-91 years). The principal indications were rectal bleeding (45%) or
      change of bowel habit (28%); both features were present in 13%. Abnormalities
      were present in 68% of examinations. Major disease was identified in 22%
      (carcinoma 7.0%, adenoma 6.3%, inflammatory bowel disease 8.3%) and minor disease
      in 53% (haemorrhoids 36.8%, severe diverticular disease 10.9%, non-adenomatous
      polyp 3.4%, perianal disease 1.4%). In patients under 40 years of age, major
      disease was rare (one carcinoma, three adenomas). Of the patients, 21% underwent
      barium enema for incomplete examination or suspected additional disease. No
      additional major disease was identified, but one carcinoma found in a patient
      with stricture. These data show that a direct-access fibreoptic sigmoidoscopy
      service produces a high diagnostic yield and may be of value to both patients and
      general practitioners in expediting a clinical colorectal service.

PMID- 8659969
TI  - A prospective study of six methods for detection of hepatic colorectal
      metastases.
AB  - Many techniques are available for the identification of patients with hepatic
      colorectal metastases. The accuracy and clinical relevance of transabdominal
      ultrasound (US), computed tomography (CT), static scintigraphy, dynamic
      scintigraphy (HPI), intraoperative ultrasound (IOUS) and manual palpation, in the
      detection of intrahepatic colorectal metastases were assessed in 73 consecutive
      patients presenting with colorectal carcinoma; 39 were male and 34 female with a
      mean age of 68 years (range 43-90 years). In 33 patients either intraoperative
      ultrasound or palpation were omitted owing to emergency presentation (n = 14) or
      subsequent non-operative management (n = 19). All six investigations were
      completed in 40 patients. Computed tomography and hepatic perfusion scintigraphy
      (HPI) were the most sensitive, detecting over 90% of lesions, the others
      identifying approximately 80% of lesions, Specificity in all methods, apart from
      dynamic scintigraphy, was over 80%. Contrast-enhanced CT would appear to remain
      the most accurate method available. However, if the prognostic ability of HPI is
      confirmed on subsequent follow-up, the accuracy of HPI will rise with time,
      whereas that of CT will fall. Intraoperative ultrasonography took time to perform
      and did not alter the management of any patient within the study. We suggest that
      its use is limited to those patients in whom resection is contemplated, where the
      vascular anatomical detail provided may be invaluable.

PMID- 8659970
TI  - Nerves that say NO: a new perspective on the human rectoanal inhibitory reflex.

PMID- 8659971
TI  - Impact of laparoscopic cholecystectomy on surgical training.
AB  - All cholecystectomies in a single health district were studied during a 5-year
      period spanning the introduction of laparoscopic cholecystectomy (LC). The number
      of LCs increased from 2 (1.3%) in year 3 to 86 (56%) in year 5. The number of
      operative cholangiograms and explorations of the common bile duct performed both
      fell substantially. The age distribution did not change significantly during the
      study period, but the percentage of females undergoing cholecystectomy increased.
      The percentage of trainee operations remained constant in those Firms performing
      only open cholecystectomy (OC), but fell from 67% to 9% in those adopting LC. An
      increase in annual cholecystectomy rate was seen with the laparoscopic surgeons,
      with a corresponding fall for those surgeons performing only OC. There was a
      threefold increase in the percentage of operations performed privately from years
      2 to 5, with 73% being laparoscopic in year 5. The consequences for training of
      the introduction of LC must be addressed.

PMID- 8659972
TI  - Failure of trochanteric osteotomy in total hip replacement: a comparison of two
      methods of reattachment.
AB  - A retrospective study was undertaken to assess the rate of trochanteric union
      after a primary Charnley total hip replacement. In one group the trochanter was
      reattached with Wrobleski spring wire, and in the second group with a Dall-Miles
      clamp. Non-union occurred in 29% of each group. The high rate of failure may have
      implications for morbidity and function. Alternative surgical approaches for
      total hip replacement should be considered.

PMID- 8659973
TI  - Videothoracoscopy in the treatment of early empyema: an initial experience.
AB  - Seventeen consecutive patients were referred for management of empyema between
      April 1991 and March 1992. Fourteen patients defined as having an 'early' empyema
      were initially treated by videothoracoscopy. The other three patients, defined as
      having a 'late' empyema proceeded directly to thoracotomy. Videothoracoscopy was
      successful in 10 out of the 14 patients. The mean postoperative stay was 7.8
      days. At a mean follow-up at 16.7 months, these patients were rendered apyrexial
      with full lung expansion and no residual pleural collection. The postoperative
      results were at least equivalent to other conventional forms of treatment without
      an undue level of complications. In this series, thoracoscopy was found to be
      successful when symptoms had been present up to 31 days before presentation at
      the first hospital, and the mean length of treatment before referral to Harefield
      was 47 days. It is now our policy to videothoracoscope all patients with empyema
      thoracis, regardless of the length of referral. It may circumvent the need for a
      thoracotomy, it does not add any increased risk of complications, and does not
      appreciably increase the length of hospital stay should thoracotomy ultimately be
      required.

PMID- 8659974
TI  - Surgical opportunities to explore the function of the human epididymis.
AB  - The animal epididymis was known to play an essential role in the acquisition of
      motility and fertilising capacity of testicular spermatozoa. Little was known
      about the function of the human epididymis and this paper describes studies
      arising from tissues obtained at the time of surgical procedures on the
      epididymis and vas deferens. Even though the human epididymis differs from that
      of other animals in fine structure and luminal contents, its function is similar
      in that spermatozoa gain motility and fertilising capacity during their passage
      through it. The poor fertilising capacity (24% of 76 cycles) and 2 (2.6%)
      conceptions with spermatozoa from an obstructed epididymis or vas deferens
      compared with a fertilisation rate of 88% (pregnancy in 37.5%) in men without
      obstruction is evidence of this. The defect in fertilising capacity may be
      overcome by using the technique of intracytoplasmic sperm injection, where
      fertilisation and embryo transfer occurred in 95% of the 38 couples with
      obstruction and 34% of the wives conceived.

PMID- 8659975
TI  - Management of intra-abdominal abscesses in Crohn's disease.
AB  - Over a 5-year period, 54 intra-abdominal abscesses were observed in 40 (20.8%) of
      192 patients with Crohn's disease. The median age was 39 years (range 17-76
      years); median interval from diagnosis, 7.5 years (range 0-24 years) and the
      median number of surgical operations was 2 (range 0-7). Forty abscesses (74.1%)
      were spontaneous and 14 (25.9%) were postoperative. Thirty abscesses were
      initially managed by laparotomy, 14 by percutaneous drainage, nine by incision
      and drainage and in one case the abscess drained spontaneously. Intra-abdominal
      abscesses were managed successfully by laparotomy in 23 (76.7%) of 30 patients,
      with a 93% success rate (13 of 14) for spontaneous abscesses managed by resection
      and primary anastomosis. Three of 8 (37.5%) spontaneous abscesses were managed
      successfully by percutaneous drainage, a temporising effect being achieved in a
      further two cases. There was no significant difference in sepsis score or
      duration of hospital stay for patients managed initially by laparotomy and those
      managed by drainage. However, patients with stricturing or fistulating Crohn's
      disease were much more likely to have initial management by laparotomy and in
      these patients surgical intervention was found to be an effective initial
      strategy.

PMID- 8659976
TI  - Comparative audit of blood transfusion during war and peace in Sarajevo.
AB  - A comparative study was made between 146 patients receiving blood transfusion at
      the State Hospital, Sarajevo, in a 3-month period of peace (group 1) and 250
      patients receiving transfusions in a 3-month period of war (group 2). In group 1,
      trauma accounted for only 7% of transfusions while it accounted for 99% in group
      2. The threshold for transfusion was increased in war and the mean pretransfusion
      haematocrit in group 2 was 21%, compared with 27% in group 1 (P < 0.001). Less
      blood was also transfused per patient in war with a mean transfusion volume of
      1.1 units in group 2 compared with 2.6 units in group 1 (P < 0.001). The reasons
      and justification for such a conservative transfusion practice in a besieged city
      are discussed.

PMID- 8659977
TI  - Randomised study of sterile versus non-sterile urethral catheterisation.
AB  - Indwelling urethral catheters are the most common cause of urinary tract
      infections (UTI), yet there is no direct evidence that technique of catheter
      insertion affects this. In a prospective study, 156 patients underwent
      preoperative urethral catheterisation, randomly allocated to 'sterile' or
      'clean/non-sterile' technique groups. There was no statistical difference between
      the two groups with respect to the incidence of UTI. There was a considerable
      cost difference between the two groups, the 'sterile' method being over twice as
      expensive as the 'clean' method. Strict sterility is not necessary in
      preoperative short-term urethral catheterisation and is more expensive and time
      consuming.

PMID- 8659978
TI  - Ultrasound-guided excision of impalpable mass breast lesion.

PMID- 8659979
TI  - Use of skin staples for securing the mesh in the Lichtenstein repair of inguinal
      hernia.

PMID- 8659980
TI  - Osteomyelitis of the symphysis pubis after inguinal hernia repair.

PMID- 8659981
TI  - One in the eye for an orthopaedic surgeon.
AB  - Despite many reports of injuries to surgeons during operative procedures, there
      is no record of an eye injury caused by a foreign body. Orthopaedic surgeons are
      particularly vulnerable to such injury. An instance in which a penetrating eye
      injury occurred while hammering a rasp into the femur during a hip replacement is
      described. There is a potential oblique trajectory for a foreign body to reach
      the eye from the operative field despite the use of a visor for eye protection.

PMID- 8659982
TI  - Survival after resection and duodenocolostomy for massive mesenteric infarction
      after aortic surgery.

PMID- 8659983
TI  - Can preoperative factors predict for residual malignancy after breast biopsy for
      invasive cancer?

PMID- 8659984
TI  - Improving exposure and safety at the saphenofemoral junction.

PMID- 8659985
TI  - Laparoscopic appendicectomy: a trainee's perspective.

PMID- 8659986
TI  - Clinical studies of human islet transplantation.

PMID- 8659987
TI  - Split loop colostomy: a modification.

PMID- 8659988
TI  - Acute appendicitis: does removal of a normal appendix matter, what is the value
      of diagnostic accuracy and is surgical delay important?

PMID- 8659989
TI  - Severe hyponatraemia in elderly patients: cause for concern.

PMID- 8659990
TI  - Use of hand-held Doppler to identify 'difficult' forearm veins for cannulation.

PMID- 8659991
TI  - A 5-year audit of outcome of apicectomies carried out in a district general
      hospital.

PMID- 8659992
TI  - An objective assessment of surgical training.
AB  - The aim of this study was to determine the feasibility of assessing surgical
      training from routine, prospectively collected data and to establish whether
      weighted workload assessed surgical training more objectively than caseload (case
      counting). The surgeons in this surgical unit prospectively documented details of
      all operations and endoscopic procedures (caseload) on a database. Over a six
      month period the workload was calculated by weighting the caseload using
      Intermediate Equivalent (IE) values. Some 1827 procedures were documented. The
      three consultants performed 796 (44 per cent) procedures, the senior registrar
      (SR) 137 (7.5 per cent), the registrar 241 (13 per cent) and the three senior
      house officers (SHO) 644 (35 per cent). The consultant was first assistant in 185
      (66 per cent) procedures performed by the SHOs, in 52 (61 per cent) by the
      registrar in 9 (13 per cent) by the SR. When assessed by caseload one SHO (as a
      representative example) performed 224 procedures compared to 137 by the SR. The
      IE workloads were 156 and 166 respectively. This better reflected the greater
      complexity of the operations performed by the SR. This study has shown that
      details of surgical training can be easily retrieved from existing administrative
      databases. This can be used to document the number and type of operations
      performed by a trainee and the degree of consultant supervision. The degree of
      surgical training is better assessed by weighted workload rather than caseload.

PMID- 8659993
TI  - A clinician friendly computerised head and neck oncology audit: the first year
      results.
AB  - Surgical audit is only as good as the information recorded and data entry is
      often onerous and the domain of the enthusiastic clinician or research follow. A
      head and neck oncology audit which incorporates a specific software program has
      been established in our department. The software interface increases the user
      friendliness of two conventional database systems, ACCESS and SUPERBASE and
      structures data input for the clinical situation. The program has been designed
      for ease of use by every clinician irrespective of their computer competence. The
      departmental prospective audit has been active since January 1993 and the
      essential details on new patient presentation, assessment, surgery and outcome
      for the first year are included in this article.

PMID- 8659994
TI  - Written discharge advice sheets reduce visits to the general practitioner.
AB  - A prospective audit of early post-operative morbidity in patients who would not
      normally receive routine outpatient review was undertaken. One-hundred-and forty
      seven (92 per cent) of 162 patients invited returned for assessment. Thirty-five
      patients (24 per cent) had complications. These were of a minor nature with
      infected wounds being most numerous. Much of this morbidity appeared avoidable if
      the patients had received appropriate advice whilst in hospital. Also noted was
      the surprising frequency with which patients required to consult their general
      practitioner (GP) for guidance regarding an otherwise uncomplicated
      convalescence. Written advice sheets for the patients were drawn up and the study
      repeated. One-hundred-and-fifty (93 per cent) of 162 patients attended including
      11 (7.3 per cent) who did not receive an advice sheet. Twenty-five (16.7 per
      cent) had complications. Although the overall complication rate was not
      significantly different there were significantly fewer wound infections in the
      second group (6 (4 per cent) versus 15 (10 per cent); p < 0.05). The number of GP
      visits was also reduced (24 (16.3 per cent) versus 13 (8.7 per cent); p < 0.05).
      Written post-operative advice sheets should be given to all patients following
      minor surgery.

PMID- 8659995
TI  - A five consultant orthopaedic rota, to allow a consultant led trauma service.

PMID- 8659996
TI  - Endovascular grafting for abdominal aortic aneurysms.
AB  - The feasibility of minimally invasive treatment of abdominal aortic and other
      arterial aneurysms by introduction under X-ray control of an endovascular graft
      via the femoral artery is proven. Until the safety and efficacy of these
      techniques is established, their introduction into clinical practice needs to be
      monitored. This paper reports recommendations agreed jointly by the Vascular
      Surgical Society of Great Britain and Ireland and the British Society of
      Interventional Radiologists for assessment of endovascular grafting techniques.

PMID- 8659997
TI  - Teaching the craft of operative surgery.
AB  - (a) Recent changes in practice and organisation of surgery make it even more
      important than formerly to focus attention on the acquisition of operative
      skills. Once the elements of good operative technique are inculcated, the
      trainees need practice to establish and refine the natural skill patterns that
      convert competence into mastery. As opportunities to acquire practical operative
      experience diminish in Britain, we should encourage our future surgeons to spend
      a period in less affluent countries where there is a heavy workload of
      predominantly open surgery. At present such periods are too often dismissed as
      'experience, not training'. (b) Apprenticeship remains the essential element for
      acquiring the craft skills. Apprenticeship does not imply merely allowing
      trainees to watch and assist. They must also perform under supervision while
      being assisted by the master. (c) Craft workshops are valuable adjuncts for
      formal instruction and 'hands on' experience as a preliminary to continued
      practice of the skills. They allow the principles of good surgery to be formally
      stated and reinforced. (d) We do not yet have objective tests of operative skill
      and should not judge trainees at an early stage, except in their adherence to
      accepted precepts and by their results. (e) Those of us who are privileged to
      train the next generation of surgeons should critically assess the standards of
      our own technique, not just in relation to our surgical success but also to the
      standards we are passing on to our successors.

PMID- 8659998
TI  - The surgical specialist in Europe at the threshold of the century.

PMID- 8659999
TI  - Transplant surgeons in training: the present and their future?
AB  - Little is known of the numbers of serious trainees in transplantation surgery and
      their career aspirations. A national audit has been performed in 1992 and 1994.
      Eighteen registrar (R) and 18 senior registrar (SR) trainees were identified in
      1992 and 9 R and 16 SR in 1994. Mean age for R was 32 and SR 36 years. All bar
      one respondent had been awarded or were pursuing a transplant related thesis.
      Training received in 1994 was 43 per cent renal only and 57 per cent liver and
      renal. Only 2/36 in 1992 and 0/25 in 1994 wished to pursue a career in pure
      transplantation. In 1994 from a score of zero to 10, a career in liver and renal
      transplantation without general surgery scored, R n = 9, mean 4.3; SR n = 14,
      mean 2.4. Pure renal transplantation and vascular access without general surgery,
      R mean 1.4; SR mean 1.4. Transplantation surgery (multi-organ or renal only) and
      general surgery (eg, hepatobiliary or vascular) R mean 8, SR mean 8.
      Transplantation surgery in isolation was not considered to be fulfilling as a
      career and was considered to be making poor use of the considerable level of
      general surgical skills learnt. There appears to be a growing gap between the
      aspirations of transplant surgeons in training and the type of consultant post
      increasingly being offered. This problem has significant implications for future
      manpower planning as up to 40 per cent of trainees are being lost from the field.

PMID- 8660000
TI  - German data on the HUMVWA31 locus.
AB  - A population study was carried out on Caucasians from Dusseldorf using the short
      tandem repeat (STR) system HumVWA (von Willebrand factor; locus 12p12-12pter;
      intron A). After amplification, electrophoresis and silver staining 9 alleles
      could be detected in the sample of 304 unrelated individuals. No deviations from
      the Hardy-Weinberg equilibrium could be observed. The results were compared with
      other population studies.

PMID- 8660001
TI  - [Distribution of the Rhesus haplotype frequencies in the Dusseldorf
      administrative center (North Rhine-Westphalia)].
AB  - The Rhesus haplotype frequencies and their regional distribution have been
      studied in the administrative area of Dusseldorf, North Rhine-Westphalia. The
      area studied is characterised by a heterogeneous distribution of the haplotypes
      without clinical trends and by missing Hardy-Weinberg conditions.

PMID- 8660002
TI  - Distribution of apolipoprotein E genotypes in Asian Indians, Hungarians, and
      Papua New Guineans.
AB  - We report here the distribution of apo E genotypes and allele frequencies in
      Asian Indians, Hungarians, and Papua New Guineans using the DNA based analysis.
      Frequency of the apo E4 allele was thrice as high in Papua New Guineans as
      compared to the Caucasians. The rare apo E2 allele was also present in higher
      frequency in the Papuas as compared to other populations.

PMID- 8660003
TI  - Haematological traits, religion and rural/urban residence among the Lepchas of
      Kalimpong subdivision, Darjeeling district, West Bengal (India).
AB  - As a part of an ongoing multidisciplinary biomedical research programme,
      initiated by the Indian Statistical Institute in early 1976, entitled "Human
      Adaptability Programme", the present study was undertaken among the Lepchas of
      Kalimpong subdivision, Darjeeling district, West Bengal (India) to enquire at a
      micro-level into the possible relationship between the major sociocultural
      factors, viz. religious practices and rural/urban residence, on the one hand, and
      haematological traits such as haemoglobin level, haematocrit and anaemia, on the
      other. The results show that while effects of religious practices do not seem to
      exist on the haematological traits considered, significant effects of rural/urban
      residence do.

PMID- 8660004
TI  - [Approaches to risk analysis of infant mortality in the 19th century in 2
      adjacent South Germany rural communities].
AB  - High infant mortality, regional differences, and the remaining likewise
      differences over a long time period were already known in the last century.
      Multifactorial models were discussed to explain this phenomenon and great
      importance was given to social factors in these societies. We analysed two
      populations from the same region in South Germany with a high infant mortality in
      the 19th century. The environment (e.g. climate, rural regions) was similar, the
      two villages had small differences in population size. Since the end of the 16th
      century the two villages have belonged to different denominations, one village is
      catholic, the other protestant, and there are no marriages between them (until
      today). All data we analysed, came from parochial registers. The results show
      that in all decades of the last century the infant mortality was higher in the
      catholic population (about 450) than in the protestant population (ca. 350). We
      can find these differences on the microlevel, too. The comparison of families
      (marriages concluded 1840-1849 and 1850-1859) show the same effect. The analysis
      of the influences on the number of children per family and the age of the mother
      at birth of their children to infant mortality confirm the hypothesis that social
      factors, strongly influenced by the denomination, are the main factors to explain
      the differences.

PMID- 8660005
TI  - [Tooth eruption in Jena children in the first phase of mixed dentition].
AB  - Based on the process of tooth eruption in children of Jena during the first
      period of erupting permanent teeth secular changes of the dentition were
      investigated and the topicality of the current tables for dental age were
      checked. Mean age of eruption was computed for the individual types of teeth and
      for each sex in Jena's children and curves for eruption were constructed. On this
      basis population-specific standards for the dental age were calculated and the
      children were subdivided into "late, normal or early teether". By comparing the
      methods for age estimation using the number of teeth or the roentgenological
      method from Demirjian et al. (1973) it could be shown, that both methods lead to
      comparable results in the first period of permanent teeth eruption.

PMID- 8660006
TI  - VNTR locus D1S80: allele frequencies and genotype distribution in the region of
      Dusseldorf.
AB  - Hypervariable loci within the human genome are useful tools in several
      disciplines: for example in forensic medicine (paternity testing and forensic
      identification). One of these genetical markers is located at chromosome 1 and is
      called D1S80 (MCT118). The genotype distribution and the allele frequency of the
      VNTR locus D1S80 have been studied in a population of 378 unrelated Germans
      living at Dusseldorf. The determination of genotypes has been carried out by
      using the polymerase chain reaction and subsequent analysis of the amplified
      products by polyacrylamide electrophoresis followed by silver staining. The data
      demonstrate that the locus is highly polymorphic with an observed heterozygosity
      of 75.66%. The frequency distribution found does not meet Hardy-Weinberg
      expectations. We think that this is not astonishing because we found only 80 of
      the possible 231 phenotypes (alleles 16-34, 36-37, without anodal and cathodal
      variants). So before using the D1S80 data in forensic analyses and paternity
      tests a larger data base has to be established. The data of the Dusseldorf sample
      are compared with data of studies on other populations.

PMID- 8660007
TI  - Living with chronic illness.

PMID- 8660008
TI  - Creating health with chronic illness.
AB  - Within the current context of health care, health promotion for individuals with
      chronic illness often reflects the priorities of disease-specific preventive care
      needs and related physical, social, emotional, and spiritual well-being. This
      article reports a phenomenological study of how older people with chronic illness
      experience health and health promotion and illuminates a different perspective of
      health resources and strategies. The findings have profound implications for
      nursing practice and theory, suggesting the need for restructuring work
      assignments and refocusing nursing care more clearly away from the medical model.

PMID- 8660009
TI  - The psychiatric model: a critical analysis of its undermining effects on nursing
      in chronic mental illness.
AB  - Nursing has incorporated many aspects of the medical model in forming nursing
      practice. I argue that this conception has not resulted in an effective approach
      for patients with mental illness, especially those with chronic mental illness.
      In attempting to formulate practice, nurses are impeded by the constraints of
      this almost universally accepted model, perhaps in ways that have evaded
      conscious awareness. Patients, also, must try to live their lives within limited
      options imposed by professional people who supposedly have their best interest at
      heart. This article identifies the assumptions of the psychiatric medical model
      and shows how using this narrow, received format is inconsistent with nursing
      practice. The author delineates the process of her awakening to its undermining
      effect on her relationships with patients and offers suggestions for more
      appropriate practice in chronic mental illness.

PMID- 8660011
TI  - Testing an uncertainty model for women with multiple sclerosis.
AB  - This study sought to explain adaptation to the uncertainty of multiple sclerosis
      (MS) in women. A casual model, developed from the literature and from interviews
      with four women with MS, was tested on a sample of 90 women with MS. Successful
      adaptation was measured by self-esteem and mastery. The model accounted for 26%
      of the variance in mastery, with an empirical model accounting for a higher
      degree of variance (41%). Findings suggest that the negative impact of
      uncertainty in women with MS is significantly reduced by their spiritual and
      social relationships.

PMID- 8660010
TI  - Specter of the crone: the experience of vertebral fracture.
AB  - This study sought to document the experience of women who suffer postmenopausal
      vertebral fractures. As the women described it, the essential structure of the
      experience of postmenopausal spinal fractures was an abrupt descent into disease,
      disability, and deformity. Each informant described significant challenges to her
      ability to continue to function as a whole, independent person. Constant pain,
      loss of independent function, changes in physical appearance, feelings of
      isolation, a sense of vulnerability, and an uncertain future were the hallmarks
      of the experience. This study identified specific areas of concern and suggests
      new focuses for nursing intervention with women with spinal fractures. An
      intervention program that incorporates education, programs to regain or maintain
      function, pain management, techniques to reduce stress and isolation, and
      promotion of self-care ability has the potential to enhance the quality of life
      for women with postmenopausal spinal fractures.

PMID- 8660012
TI  - Womanspirit: a journey into healing through art in breast cancer.
AB  - In the sphere of chronic illness, where cure is no longer an expected outcome,
      the need to understand women's healing is paramount to the caring role of nurses.
      A collective of women survivors of breast cancer provided the data for this
      feminist esthetic cooperative inquiry. Esthetic representations of the experience
      of living through breast cancer were powerfully illustrated by these women
      coresearchers over a 6-month period. Using the method of feminist process,
      authentic collaboration, shared meaning, and the power of collectivity emerged.
      Womanspirit, the unifying essence underlying personal and collective knowledge,
      is presented. Allowing the meaning of experience to become visible through art in
      a collective is advocated.

PMID- 8660013
TI  - Struggling to gain meaning: living with the uncertainty of breast cancer.
AB  - Uncertainty is a common experience for women living with breast cancer,
      particularly when treatment cannot assure disease cure. The study described in
      this article sought to provide insight into uncertainty experiences for women
      living with breast cancer. Hermeneutic phenomenology and photographic
      hermeneutics were used to describe and interpret uncertainty for nine women
      between 2 and 6 years posttreatment for breast cancer. Data were collected using
      interviews and interpretations of photographs. Five themes of uncertainty among
      women were uncovered. Major study findings included support for a
      reconceptualization of Mishel's Uncertainty in Illness Theory and the explication
      of growth-producing aspects of uncertainty.

PMID- 8660014
TI  - Functional performance in people with chronic obstructive pulmonary disease: a
      qualitative analysis.
AB  - The variation of functional performance seen in people with chronic obstructive
      pulmonary disease (COPD) is perplexing. Some patients appear to do well in their
      day-to-day activities, while others, with the same apparent disease severity,
      have difficulty. This naturalistic inquiry sought to describe functional
      performance from the perspective of 12 people with COPD. Thematic analysis was
      used to identify activities in which these men and women were engaged and the way
      they perceived activities, symptoms, and treatments within the context of their
      daily lives. Decisions to perform activities were influenced by a sense of
      deriving satisfaction, weighed against the discomfort that might occur. Intruders
      and enablers influenced activity performance. The results of this study provide a
      useful framework for assessing functional performance and developing
      interventions that are sensitive to patient values and expectations and that have
      a greater likelihood of improving life quality.

PMID- 8660015
TI  - Ensuring the readability of patient education materials is one way to demonstrate
      perioperative nurses' value.

PMID- 8660016
TI  - Tuberculosis makes a comeback.
AB  - Tuberculosis (TB) has plagued mankind for many centuries. In the past, the number
      of people affected with this potentially deadly disease declined, but there has
      been a recent dramatic increase in TB incidence. This increase is attributed
      largely to people who are coinfected with TB and HIV and to the development of
      resistant strains of Mycobacterium tuberculosis during the last decade. The US
      social infrastructure also has contributed to a rapid rise in TB cases due to
      adverse socioeconomic factors and an increase in the number of immigrants and
      people infected with HIV. This article gives a historical overview of TB;
      discusses its diagnosis, transmission and prevention modalities; and provides a
      case study about a TB-infected patient who required emergent surgical
      intervention.

PMID- 8660017
TI  - Hyperthermic intraoperative intraperitoneal chemotherapy safety considerations.
AB  - Perioperative staff members encounter many occupational exposure hazards in the
      workplace. Cytotoxic agent exposure is a relatively new hazard that perioperative
      staff members are experiencing as more surgeons use hyperthermic intraoperative
      intraperitoneal chemotherapy (HIIC) to treat patients with abdominopelvic cavity
      malignancies. Routes of exposure include inhalation, ingestion, injection, and
      skin contact. The National Cancer Institute, the Occupational Safety and Health
      Administration, and the Joint Commission on Accreditation of Healthcare
      Organizations provide guidelines for the safe administration and handling of
      cytotoxic agents. Institutions in which cytotoxic agents are administered should
      use these guidelines to develop policies, procedures, and educational programs to
      protect surgical patients and perioperative staff members.

PMID- 8660018
TI  - Multiple subpial transection for Landau-Kleffner syndrome.
AB  - Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia caused by a
      lesion in the speech centers of the cerebral cortex during a critical period of
      childhood development. Characteristics of LKS include language deterioration,
      seizure disorders, and severe electroencephalogram abnormalities. Multiple
      subpial transection (MST) is a surgical procedure that eliminates seizure
      activity in the cerebral cortex while preserving the child's normal cortical
      functions of speech, movement, primary sensation, and memory. This article
      presents a summary of clinical studies on LKS and discusses the diagnosis of LKS,
      traditional medical treatments, patient selection for MST procedures, and
      perioperative care of children undergoing MST procedures.

PMID- 8660019
TI  - AORN sales professional course.
AB  - The sales professional course "Introduction to the Operating Room" offered by the
      AORN Center for Nursing Practice, Health Policy, and Research is an introductory
      program in OR etiquette. Its purpose is to provide sales professionals a working
      knowledge of OR protocol for them to function appropriately in OR settings. Sales
      professionals who have completed this course establish mutually beneficial
      perioperative partnerships with OR personnel. Sales professionals' effectiveness
      is strengthened as a result of their newly acquired knowledge of OR protocol, and
      patient safety is protected. An AORN Certificate of Recognition is awarded on
      completion of the course.

PMID- 8660020
TI  - Effect of music on ambulatory surgery patients' preoperative anxiety.
AB  - The authors investigated music as a method to reduce ambulatory surgery patients'
      preoperative anxiety. They assigned 42 patients to either an experimental or a
      control group and compared the patients' vital signs and self-reports of anxiety,
      which were measured using the state portion of the State-Trait Anxiety Inventory.
      The study results indicate that music can be more beneficial than preoperative
      instruction alone in reducing ambulatory surgery patients' anxiety. Patients who
      listened to their choice of music before surgery in addition to receiving
      preoperative instruction had significantly lower heart rates than patients in the
      control group who received only preoperative instruction. Differences in
      experimental and control group patients' blood pressure measurements and
      respiratory rates approached significance. The authors suggest that perioperative
      nurses offer music as a viable option to reduce anxiety in ambulatory surgery
      patients who believe music is a method of relaxation.

PMID- 8660021
TI  - The impact of parental presence on parental anxiety and satisfaction.
AB  - Researchers used an experimental research design to vary the amount of parental
      presence during their children's anesthesia induction and recovery and measured
      the effect of parental presence on parental anxiety and satisfaction with care.
      The State-Trait Anxiety Inventory was used to assess parental anxiety. The
      researchers measured parents' blood pressures and pulse rates as a second measure
      of anxiety. They found no significant differences in parental anxiety between
      study groups (i.e., the parents attending during their children's anesthesia
      induction and recovery, the parents not attending) but observed significant
      differences between mothers and fathers. Overall satisfaction scores were high,
      with little variability and no significant differences between study groups.
      Parents and physicians and nursing staff members supported the practice of
      parental presence during children's anesthesia induction and immediate
      postoperative recovery period.

PMID- 8660022
TI  - Hand signals in surgery.

PMID- 8660023
TI  - AORN's lobbyist stresses the importance of knowledge, perseverance, and timing.

PMID- 8660024
TI  - Nurses on Presidential Advisory Council on HIV/AIDS.

PMID- 8660025
TI  - Legislative restraints to nursing practice.

PMID- 8660026
TI  - RN first assistants. RN First Assistant Specialty Assembly 1995-1996 Governing
      Council.

PMID- 8660027
TI  - Normovolemic hemodilution in an adolescent having a spinal fusion for scoliosis.

PMID- 8660028
TI  - Recommended practices for safe care through identification of potential hazards
      in the surgical environment. Association of Operating Room Nurses.

PMID- 8660029
TI  - Rostromedial hypothalamic monoamine changes in response to intravenous infusions
      of insulin and glucose in freely feeding obese Zucker rats: a microdialysis
      study.
AB  - We have shown previously that intravenous infusions of insulin, known to induce
      glucoprivic hunger, and of insulin combined with glucose, known to induce
      satiety, produce in the VMH and PVN of Wistar rats monoaminergic changes that
      differ from those related to spontaneously occurring hunger and satiety, while
      the genetically obese Zucker rat is totally resistant to the behavioural effects
      of insulin and insulin + glucose infusions. In the present study, the impact of
      these infusions on VMH and PVN monoamines in obese Zucker rats was assessed using
      microdialysis. Monaminergic changes (increase in DOPAC and 5-HIAA and decrease in
      DA and 5-HT) were quite similar in obese rats to those we found in normal rats
      when insulin was infused. In contrast, changes in 5-HT or DA in response to
      insulin and glucose were quite different in the Zucker rat. Monoaminergic changes
      related to meals were more dramatic in the Zucker rat and so were able to reverse
      the background changes produced by the insulin infusion. These data confirm the
      idea that the effect on monoamines of spontaneously occurring hunger and satiety
      is different from the effect on monoamines by insulin and glucose-induced hunger
      and satiety. The results show disturbances of the obese Zucker rat related both
      to insulin and to hypothalamic monoamines that may be involved in the hyperphagia
      and obesity of this model.

PMID- 8660030
TI  - Micro- and macroanalyses of patterns within a meal in anorexia and bulimia
      nervosa.
AB  - Hospitalized women with anorexia nervosa and/or bulimia nervosa and dietarily
      restrained and unrestrained, clinically normal women were provided with a multi
      item breakfast meal. Eating patterns and hunger and satiety ratings were
      assessed. Subjects were offered three foods which varied in fat and carbohydrate
      contents. Anorectic-restrictors differed most from the control subjects: they had
      a longer meal duration, a slower overall rate of eating, more frequent pauses
      during the meal, and more short bouts of eating. They also displayed abnormal
      ratings of hunger and satiety: they were generally less hungry, had less urge to
      eat, and were more full than controls of bulimics. Both anorectic and bulimic
      patients showed more variability in total energy intake than did the controls.
      Patients usually displayed one of two patterns - either severe restriction or
      overeating. Abnormal hunger and satiety patterns indicating confusion typified
      the responses of bulimics; additionally, they showed more urge to eat in the post
      meal period than did the controls. A higher proportion of fat in the initial part
      of the breakfast was related to a larger meal size for the bulimics. It is
      suggested that these techniques may be useful in evaluating the outcome of
      treatment for eating disorder patients.

PMID- 8660031
TI  - Gender differences in the reasons given for meal termination.
AB  - Male and female undergraduate students (n = 387) were asked to complete the
      statement "I usually stop eating when" on a written survey which listed four of
      five alternative responses and an open, write-in, alternative. Half of the
      questionnaires listed the alternative, "I feel full"; the other half omitted this
      alternative. While the fullness option was the most popular response overall, men
      and women exhibited differing patterns in responses, particularly if fullness was
      not included as an option. The second most popular response for men was "the food
      is all gone", indicating an importance of external factors in controlling the
      amount of food eaten. In women, however, the second most popular response was
      "the food stops tasting good", indicating an importance of hedonic factors in
      meal termination. These results suggest that gender may be a critical variable in
      studies of food intake, and specifically in the study of satiety mechanisms.

PMID- 8660032
TI  - The nature of the ponderostat: Hervey's hypothesis revived.
AB  - In 1969, Hervey hypothesized the long-term stability of body weight is actually
      mediated through the regulation of blood steroid concentration. We suggest that
      glucocorticoids are the regulated variable the concentrations of which entails
      bodyweight stability. A descriptive model of this regulation is proposed. Because
      steroids are soluble in lipids, it follows that their concentrations in the body
      depend in part of the volume of lipids stored. Low fat stores increase the
      glucocorticoid concentration in the blood, and conversely high fat stores lower
      the glucocorticoid concentration. Body weight could thus be the end product of
      the glucocorticoid levels. The set-point for body weight would be adjusted by
      intracerebral CRH.

PMID- 8660033
TI  - Effect of exercise and dietary restraint on energy intake of reduced-obese women.
AB  - Self-selected food intake of 15 reduced-obese women living in a metabolic ward
      was studied for 14 consecutive days to determine the effect of exercise and other
      metabolic and behavioral variables on energy intake. A choice of prepared food
      items were offered at breakfast, lunch and dinner, and a variety of additional
      food items were available continuously 24 h/day. Subjects performed either
      moderate intensity aerobic exercise (A-EX) (n = 8) expending 354 +/- 76
      kcal/session or low intensity resistance weight training (R-EX)(n =7) expending
      96 +/- kcal/session, 5 days/week. Mean energy intakes (kcal/day, +/- SEM) of the
      exercise groups were similar: 1867 +/- 275 for A-EX, 1889 +/- 294 for R-EX. Mean
      energy intakes of individuals ranged from 49 to 157% of the predetermined level
      required for weight maintenance. Resting metabolic rate per kg 0.75 and the
      Eating Inventory hunger score contributed significantly to the between subject
      variance in energy intake, whereas exercise energy expenditure did not.
      Regardless of exercise, eight women consistently restricted their energy intake
      (undereaters), and seven other consumed excess energy (overeaters). Overeaters
      were distinguished by higher Eating Inventory disinhibition (P = 0.023) and
      hunger (p = 0.004) scores. The overeaters' diet had a higher fat content 34 +/-
      1% (p = 0.007). Also, overeaters took a larger percentage of their daily energy,
      than that of undereaters, 27 +/- 1 energy intake in the evening, 13 +/- 2%,
      compared to undereaters, 7 +/- 1% (p = 0.005). We conclude that the Eating
      Inventory is useful for identifying reduced-obese women at risk of overeating,
      and these individuals may benefit from dietary counseling aimed at reducing fat
      intake and evening snacking.

PMID- 8660034
TI  - Effects of high- and low-energy meals on hunger, physiological processes and
      reactions to emotional stress.
AB  - The effects of a reduced energy content of two meals on hunger motivation,
      physiological variables and reactions to emotional stress were investigated.
      Healthy normal-weight male students received breakfast and lunch in the
      laboratory. Half of the subjects (n = 28) received meals with normal energy
      content (1700 kcal), and half received meals with reduced energy content (260
      kcal). Psychological and physiological variables were obtained for 8 h from
      morning to afternoon, including during a period of emotional stress in the
      afternoon. Psychophysical state was altered by the reduction of energy in food
      (e.g. increased subjective motivation to eat, decreased systolic blood pressure).
      Noise decrease feelings of relaxation in subjects who had received low-energy
      meals, but not in subjects who had received high-energy meals. This enhanced
      emotional reactivity after low-energy intake is interpreted as a biologically
      meaningful consequence of the heightened hunger motivation. Furthermore,
      subjective hunger motivation was potentiated by stress when energy intake in the
      preceding hours was low. The latter result may be due to increased emotional
      reactions and/or an augmentation of deprivation-induced physiological changes by
      noise-induced emotional stress.

PMID- 8660035
TI  - Reasons for rejection of food items in Swedish families with children aged 2-17.
AB  - The aims of the study were to investigate family members' reasons for rejection
      of foods served in the family, the reasons for not serving specific foods,
      children's reasons for liking/disliking foods and the use of parental mealtime
      practices to encourage child eating. Also, the relationships between
      child/parental neophobia and (1) the reasons for not serving specific foods and
      (2) the use of mealtime practices were studied. A group of randomly selected
      families (n = 370) with children aged 2-17 years from two Swedish towns
      (stratified, 185 from each) were invited and 57 participated. The results are
      based on an ad hoc food-frequency questionnaire, a mealtime-practices
      questionnaire, the Food and Neophobia Scale (Pliner & Hobden, 1992), parental
      ratings of child food neophobia and on a child interview. The main reason for
      family members rejecting the foods and the main reason for children's dislikes
      was "distaste". The most frequent reason for children's likings was "good taste".
      The most frequent reasons for not serving the specific foods were "distaste", the
      "food did not occur to me", "seasonal/availability" and "habit". The mothers'
      total Food Neophobia score was significantly correlated with "did not occur to
      me". Parental ratings of child food neophobia were significantly correlated with
      mealtime-practice factors "postpone meals" and "child decides portion".

PMID- 8660036
TI  - Jenner, romanticism, and research.

PMID- 8660038
TI  - Benign partial epilepsy in infancy.
AB  - The aim was to examine the occurrence of benign partial epilepsy in infancy
      (BPEI). BPEI was defined as epilepsies with complex partial seizures (CPS) or
      secondary generalised seizures (SGS), or both, compatible with the following
      characteristics: normal development before and after onset, no underlying
      disorders, normal interictal electroencephalograms (EEGs), and good response to
      treatment. All 75 patients who developed epilepsy within the first 2 years of age
      between 1987 and 1993 were evaluated: 22 patients fulfilled the definition
      completely; eight had CPS only, four SGS only, and 10 had both CPS and SGS; 17
      had clusters of seizures. Eight patients had a positive family history. The
      average age of onset of seizures was 5.9 months. Interictal EEGs were all normal.
      Response to treatment was excellent and the average period of seizure persistence
      was 3.0 months. All had normal psychomotor development. Patients with BPEI were
      more common in this study than previously reported.

PMID- 8660037
TI  - Long term outcome of prophylaxis for febrile convulsions.
AB  - A cohort of 289 children with febrile convulsions who had been randomised in
      early childhood to either intermittent prophylaxis (diazepam at fever) or no
      prophylaxis (diazepam at seizures) was followed up 12 years later. The study
      focused on the occurrence of epilepsy and on neurological, motor, intellectual,
      cognitive, and scholastic achievements in the cohort. At follow up the two groups
      were of almost identical age (14.0 v 14.1 years), body weight (58.2 v 57.2 kg),
      height (168.2 v 167.7 cm), and head circumference (55.9 v 56.2 cm). The
      occurrence of epilepsy (0.7% v 0.8%), neurological examination, fine and gross
      motor development on the Stott motor test, intellectual performance on the
      Wechsler intelligence scale for children verbal IQ (105 v 105), performance IQ
      (114 v 111), and full scale IQ (110 v 108), cognitive abilities on a
      neuropsychological test battery, including short and long term, auditory and
      visual memory, visuomotor tempo, computer reaction time, reading test, and
      scholastic achievement were also very similar. Children with simple and complex
      febrile convulsions had the same benign outcome. The long term prognosis in terms
      of subsequent epilepsy, neurological, motor, intellectual, cognitive, and
      scholastic ability was not influenced by the type of treatment applied in early
      childhood. Preventing new febrile convulsions appears no better in the long run
      than abbreviating them.

PMID- 8660039
TI  - Autoimmune hepatitis.

PMID- 8660040
TI  - Investigating inflammatory bowel disease--white cell scanning, radiology, and
      colonoscopy.
AB  - OBJECTIVE: To evaluate different methods of examination of the bowel in suspected
      inflammatory bowel disease. DESIGN: Prospective investigation of all children
      over a three year period with suspected inflammatory bowel disease. A technetium
      99m-HMPAO labelled white cell scan (Tc-WCS), barium follow through examination
      (Ba-FT), and colonoscopy plus biopsy were undertaken. SETTING: Great Ormond
      Street Hospital for Children, London. SUBJECTS: 39 children (20 male and 19
      female), median age 12.1 years (range 3.9-15.1 years). MAIN OUTCOME MEASURES:
      There was total agreement in 21/39 cases, positive in 16, and negative in five.
      Of 31 histologically proved cases, positive results were obtained in 28 Tc-WCSs
      (sensitivity 90%), 10 of 24 Ba-FTs (sensitivity 42%), and 27 colonoscopies
      (sensitivity 87%). CONCLUSION: The Tc-WCS is sensitive, specific, and non
      invasive and should be a first line investigation. Ba-FT with a high radiation
      burden and relatively low sensitivity requires its role to be redefined.
      Colonoscopy, with endoscopic biopsy, has a high pick-up rate where facilities and
      expertise exist.

PMID- 8660041
TI  - The role of Epstein-Barr virus in Hodgkin's disease from different geographical
      areas.
AB  - Recent studies have suggested that Epstein-Barr virus (EBV) may play a role in
      the aetiology of Hodgkin's disease. To determine the role of EBV in childhood
      Hodgkin's disease in different geographical areas, immunohistochemical staining
      and in situ hybridisation were used to analyse latent membrane protein 1 (LMP 1)
      and small nuclear non-transcribed RNAs (EBER-1) respectively. Testing for EBV
      within the Reed-Sternberg and Hodgkin's cells was carried out in childhood
      Hodgkin's disease from 10 different countries. The proportion of LMP 1 positive
      cases varied significantly, being 50% of cases from the United Kingdom (38/75),
      South Africa (9/18), Egypt (7/14), and Jordan (8/16), 60% from the United Arab
      Emirates (6/10), 70% from Australia (11/16), 81% from Costa Rica (34/42), 88%
      from Iran (7/8), 90% from Greece (20/22), and 100% of the 56 cases from Kenya. A
      sensitive polymerase chain reaction based EBV strain typing technique was
      established using archival tissues. EBV strain type 1 was shown to be predominant
      in childhood Hodgkin's disease from the United Kingdom, South Africa, Australia,
      and Greece. Type 2 was predominant in Egypt. EBV strain types 1 and 2 were both
      detected in some cases of childhood Hodgkin's disease in the United Kingdom,
      Costa Rica, and Kenya. The high incidence of EBV and the presence especially in
      developing countries of dual infection with both strain types 1 and 2 may reflect
      socioeconomic conditions leading to malnutrition induced immunological
      impairment. The possibility of HIV infection also needs to be explored.

PMID- 8660042
TI  - Long term survival in Indian childhood cirrhosis treated with D-penicillamine.
AB  - Indian childhood cirrhosis (ICC) is an almost uniformly fatal disease whose
      outcome may be modified with penicillamine if given at a sufficiently early
      stage. Twenty nine children with ICC seen in Pune, India, in 1980-7, who had
      survived at least five years from onset of penicillamine treatment, were reviewed
      aged 6.3 to 13 years. They were assessed clinically, biochemically,
      histologically, and by duplex Doppler ultrasound examination. None had symptoms
      suggestive of liver disease. There were no toxic effects of penicillamine other
      than asymptomatic proteinuria. Hepatosplenomegaly reduced significantly and liver
      function tests returned to normal in all. In four children, significant
      hepatosplenomegaly was associated with an abnormal duplex Doppler hepatic vein
      flow pattern and micronodular cirrhosis on biopsy. Clinical findings, growth and
      development, and ultrasound examination were normal in the remainder. Review of
      serial liver biopsy specimens showed a sequence of recovery from ICC through
      inactive micronodular cirrhosis to virtually normal histological appearances. The
      four children who still have micronodular cirrhosis beyond four years from onset
      remain on penicillamine treatment. In the others penicillamine was stopped after
      1-7 (mean 3.5) years without relapse, strong evidence that ICC is not due to an
      inborn error of copper metabolism.

PMID- 8660043
TI  - Haemoglobin and ferritin concentrations in infants at 8 months of age.
AB  - AIM: To identify the optimum age to screen for iron deficiency, the normal
      distribution of haemoglobin and ferritin in a representative population sample
      was investigated. METHODS: Normal values for haemoglobin and ferritin were
      measured from heel prick capillary samples obtained from a representative cohort
      of 1175 infants at 8 months old who were randomly selected from children taking
      part in the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). RESULTS:
      Haemoglobin was normally distributed: mean (SD) 117 (11) milligrams, 95%
      confidence interval (CI) 116 to 118, and range 72-153 milligrams. Ferritin was
      log normally distributed: geometric mean 38.5 micrograms/l, 95% CI 37.0 to 39.9,
      range 7.1-224 micrograms/l. The 5th centile for haemoglobin was 97 milligrams and
      for ferritin 16.9 micrograms/l. No correlation was found between haemoglobin and
      ferritin. Multiple regression analysis showed ferritin concentrations to be
      positively related to birth weight (p < 0.0001) and the sex of the child (girls
      with higher concentrations) (p < 0.0001) but negatively with the child's weight
      at 8 months (p < 0.0001). Haemoglobin concentrations were positively related to
      the child's weight at 8 months (p = 0.04). Neither haemoglobin nor ferritin
      concentrations were related to social class as measured by maternal education
      level. CONCLUSION: These data define the normal range for haemoglobin and
      ferritin in capillary samples in the UK population, and suggest that anaemia is
      common in infancy. Using current recommendations, 23% of infants would be
      identified as anaemic. For British infants at 8 months of age, a more
      representative 'cut off' for anaemia would be haemoglobin concentration < 97
      milligrams and for iron deficiency ferritin < 16 micrograms/l.

PMID- 8660044
TI  - Recombinant human growth hormone treatment in infants with chronic renal failure.
AB  - Poor growth is a particular problem for children with congenital renal disease. A
      one year trial of the use of recombinant human growth hormone (rhGH) in eight
      infants and young children with chronic renal failure is reported here. At entry
      bone age was less than 2 years, mean (range) chronological age 1.9 (1.3-2.7)
      years, and glomerular filtration rate (GFR) was 17 (9-42) ml/min/1.73 m2. Height
      standard deviation score (SDS) was -3.3 (-4.6 to -2.0) and height velocity SDS
      was -1.3 (-3.1 to 0.7). One child was withdrawn when he received a renal
      transplant after 9.5 months. Two children required dialysis, but remained in the
      trial. Treatment with rhGH resulted in an increase in height SDS to -2.2 (-4.2 to
      -0.9), p = 0.0002, and height velocity SDS to 1.1 (-0.7 to 2.6), p = 0.006. There
      was no change in GFR and no serious adverse events. There was no effect on plasma
      lipids, calcium, phosphate, intact parathyroid hormone, or glucose. Alkaline
      phosphatase rose significantly. Thus rhGH improved growth in eight infants with
      chronic renal failure, with four children entering the normal range.

PMID- 8660046
TI  - Paediatricians' knowledge of cardiac arrest guidelines.
AB  - A telephone questionnaire was undertaken on middle grade trainee paediatricians
      to test their knowledge of European Resuscitation Council guidelines. Fifty seven
      responded of whom only 15 (26%) offered a correct sequence of management for
      asystole and eight (14%) failed to identify adrenaline in their management. For
      ventricular fibrillation only 18/57 (32%) identified a correct sequence and very
      poor specific knowledge was identified. Paediatricians will under perform in the
      event of cardiac arrest in children without improved training in resuscitation.

PMID- 8660045
TI  - Effects on growth of single short courses of fluoroquinolones.
AB  - The aim of the study was to document the effects of short courses of
      fluoroquinolones given during an outbreak of multidrug resistant typhoid fever in
      southern Viet Nam on the growth of children over a period of two years. In a
      prospective cohort study, 326 Vietnamese children aged between 1 and 14 years
      were followed up for two years after receiving either ciprofloxacin (70 mg/kg
      given over 7 d) (n = 173) or ofloxacin (45-50 mg/kg given over 3-5 d) (n = 153)
      for suspected typhoid fever. Growth velocity and weight for height were compared
      with an age matched control group of children from the same locality (n = 223)
      who had not contracted typhoid or received any fluoroquinolones. In the ofloxacin
      and ciprofloxacin treated patients there was no evidence of acute joint toxicity,
      nor of any joint symptoms attributable to either of the fluoroquinolones. There
      was no difference in expected weight for height measurements between the three
      groups of children over the two year period. During the first year, height
      velocity in ciprofloxacin treated children was greater than in either ofloxacin
      treated children or untreated controls. Height velocity in the latter two groups
      was not significantly different. After two years height velocity was similar in
      the three groups. The results support the use of short course fluoroquinolone
      treatment in childhood typhoid, especially when caused by strains resistant to
      other antibiotics.

PMID- 8660047
TI  - Hirschprung's disease.
AB  - Current evidence on the pathogenesis of Hirschprung's disease, then, favours the
      'abnormal microenvironment' hypothesis wherein the developing and migrating
      normal neural crest cells confront a segmentally abnormal and hostile
      microenvironment in the colon. This hypothesis would account both for the
      congenital absence of ganglion cells in the wall of colon and also for the range
      of enteric neuronal abnormalities encountered including neuronal dysplasia,
      hypoganglionosis, and zonal aganglionosis. The abnormal constitution of the
      mesenchymal and basement membrane extracellular matrix in the affected segment of
      colon is presumably genetically determined and further understanding of the
      pathogenesis of this disorder will emerge as molecular geneticists characterise
      the specific genes and gene products associated with Hirschprung's disease.
      Advances in this field should permit gene probes to be developed to facilitate
      prenatal and postnatal diagnosis.

PMID- 8660048
TI  - Deprivation and bronchiolitis.
AB  - OBJECTIVE: To test the hypothesis that socioeconomic deprivation is associated
      with an increased risk of admission with clinically suspected bronchiolitis.
      DESIGN: Case-control study. SETTING: Children under 1 year living in Sheffield in
      1989-90. SUBJECTS: 307 children resident in Sheffield admitted to Sheffield
      hospitals with clinically suspected bronchiolitis between 1 October 1989 and 28
      February 1990. METHODS: Children admitted with clinically suspected bronchiolitis
      were ascertained from laboratory records of nasopharyngeal aspirates cultured for
      respiratory syncytial virus. Case notes were examined to determine whether these
      children had required medical intervention and postcode of residence was
      recorded. Controls were selected from the Sheffield child development study
      (SCDS) data. Postcodes were converted to electoral wards which were assigned
      Townsend deprivation index scores. Electoral wards were then categorised by
      Townsend score into five levels of deprivation. Data on family smoking for cases
      and controls were extracted from the SCDS. RESULTS: Of the 307 children admitted
      with suspected bronchiolitis during the study period, 127 required one or more
      medical intervention. The risk of admission with clinically suspected
      bronchiolitis and with bronchiolitis requiring medical intervention rose with
      increasing level of deprivation score of electoral ward of residence. Children
      living in electoral wards in the two more deprived groups were more than 1.5
      times as likely to be admitted (odds ratio (OR) 1.67, 95% confidence interval
      (CI) 1.25 to 2.24) or admitted requiring a medical intervention (OR 1.74, 95% CI
      1.16 to 2.62) than children living in other parts of the city. Similar results
      were obtained after exclusion of children living in homes classified as smoky by
      the health visitor. CONCLUSION: Residence in an area of social and material
      deprivation increases the risk of admission with bronchiolitis even after taking
      account of parental smoking and when only more severe cases were considered.

PMID- 8660049
TI  - Estimation of the age of bruising.
AB  - Paediatricians are often requested to give an opinion on the age of a non
      accidental bruise. In forensic textbooks, the colour changes which a bruise
      undergoes with time are not based on research in children. The purpose of this
      study was to document the sequence of colour changes in photographs taken
      following accidental bruising in children. Fifty accidental bruises of known age
      in 23 children were photographed by a medical photographer using the same
      equipment throughout. The photographs were reviewed by a single observer, blind
      to the true age of the injury, who described the colours present in the bruise.
      Red colouration was seen in 15 out of 37 bruises which were less than one week
      old. Yellow colouration was seen in 10 out of 42 bruises over one day old. Aging
      of bruises from photographs was much less precise than textbooks imply.

PMID- 8660050
TI  - Is permanent congenital facial palsy caused by birth trauma?
AB  - OBJECTIVE: To study the relation between traumatic birth and the development of
      permanent facial palsy in the newborn. DESIGN: Retrospective case control study
      of children with 'congenital' facial palsy. SETTING: Two tertiary referral
      centres for patients with facial palsy. SUBJECTS: 61 children with established
      facial palsy. MAIN OUTCOME MEASURES: Odds ratios of recognised factors for birth
      injury: maternal primiparity, high birth weight, and the use of obstetric forceps
      at delivery. RESULTS: 13.2% of those studied had forceps assisted delivery
      compared to 10.2% in the normal population (odds ratio 1.34; 95% confidence
      intervals 0.61 to 2.97) 39.6% were born to primiparae compared to a national rate
      of 36.7% (1.13; 0.65 to 1.96) and only 18.9% weighed more than 3500 g at birth
      (0.37; 0.19 to 0.74). CONCLUSIONS: There is no association between the
      development of permanent 'congenital' facial palsy and recognised risk factors
      for birth injury. These data suggest an intrauterine rather than a traumatic
      aetiology.

PMID- 8660051
TI  - Clinical and molecular cytogenetic (FISH) diagnosis of Williams syndrome.
AB  - Sixteen children and adolescents with a firm clinical diagnosis of Williams
      syndrome were investigated with the chromosome fluorescence in situ hybridisation
      (FISH) technique employing the elastin gene probe. In each case there was a
      fluorescent signal on one chromosome 7 homologue only, indicating elastin gene
      deletion. No deletion was demonstrated in another child in whom an earlier
      diagnosis of Williams syndrome was judged doubtful at review. Firm clinical
      diagnosis correlates with elastin gene deletion in 16/16 cases of Williams
      syndrome and detection of such hemizygosity by FISH constitutes a useful
      confirmatory diagnostic test.

PMID- 8660052
TI  - Chromosome 22q11 microdeletions in tetralogy of Fallot.
AB  - Chromosome 22q11 fluorescence in situ hybridisation (FISH) studies were performed
      on 33 consecutive individuals attending a paediatric cardiology clinic with
      tetralogy of Fallot. Seven children had 22q11 microdeletions but only four had
      other clinical features associated with the newly recognised chromosome 22
      deletion syndrome (CATCH 22). Chromosome 22q11 FISH studies should therefore be
      performed on all patients with tetralogy of Fallot.

PMID- 8660053
TI  - Thalidomide treatment of mucosal ulcerations in HIV infection.
AB  - Pain relief and resolution of oral and perianal ulceration after treatment with
      thalidomide in a 14 year old girl with vertically acquired HIV infection is
      reported.

PMID- 8660054
TI  - Steroids for intubated croup masking airway haemangioma.
AB  - Recently, the beneficial role of steroids for acute laryngotracheobronchitis has
      been more clearly defined for both intubated and unintubated patients. However,
      corticosteroids also improve the clinical signs of airway haemangiomata. Two
      patients are described who illustrate how this can be a source of diagnostic
      confusion.

PMID- 8660055
TI  - Continuing medical education for paediatricians.

PMID- 8660056
TI  - Out-of-home day care and health.
AB  - Evidence from randomised trials indicates that out-of-home day care has important
      effects in domains that are integral to the health of mothers and children. The
      evidence that day care results in cognitive gains is compelling. These effects
      and the long term effects in reducing crime and violence should suffice to put
      the question of day care provision high on the paediatric agenda. However, some
      important questions remain to be answered. Evidence from a randomised trial
      suggests that the effect of infant day care on infectious disease morbidity is
      not as great as would be expected on the basis of results from observational
      studies. However, the trial in question had some important methodological
      weaknesses. No trials to date have examined the effect of day care on otitis
      media. Data from observational studies on the effect of day care on injury
      occurrence are confliciting. Finally, studies in the US point to an important
      effect of out-of-home day care on maternal employment. The effect of day care on
      maternal employment and income inequality in Britain has yet to be examined.

PMID- 8660057
TI  - Uses and abuses of pulse oximetry.

PMID- 8660058
TI  - Aetiology of bilateral sensorineural hearing impairment in children: a 10 year
      study.
AB  - The study was carried out on children born over a 10 year period from 1981 to
      1990 in a defined area known as Greater Manchester and referred to the Centre for
      Audiology or the Manchester Royal Infirmary for specialist audiological
      assessment. The children were investigated for possible congenital or
      intrauterine infection. Perinatal assessment was carried out in conjunction with
      paediatricians for adverse aetiological factors. Full medical histories were
      obtained with detailed family history relevant to hearing impairment and any
      associated condition or syndrome. Parents and siblings were examined and hearing
      assessed. A total of 339 cases was studied. Children with positive family history
      of deafness in parents or siblings, or both, constituted 23.3% of the cases
      (genetic group). Other aetiological groups showed the following distribution:
      cause unknown 33.9%; perinatal group 12.8%; congenital infections 8.2%; bacterial
      meningitis 6.5%; chromosomal anomalies 5.3%; syndromal group 5.3%; and
      miscellaneous group 4.7%. The high incidence of genetic causes indicates that
      steps should be taken to facilitate genetic counselling and conceivably to reduce
      the numbers affected.

PMID- 8660059
TI  - Nutritional management of cystic fibrosis.
AB  - Nutritional support is an integral part of the management of cystic fibrosis
      patients. It is arguably best provided by a qualified dietitian and nutritional
      care sister working in conjunction with the rest of the cystic fibrosis team. The
      patient's nutritional needs should be assessed, regularly reviewed, and
      nutritional treatment tailored to meet the changing clinical and psychosocial
      needs of the patient. Nutritional intervention is not without complications, and
      in particular attention to normal feeding behaviour and vigilance when
      instituting supplementary nutrition may prevent many feeding difficulties.

PMID- 8660060
TI  - Do children with hepatic cirrhosis complicating cystic fibrosis receive too much
      pancreatic enzyme?

PMID- 8660061
TI  - Fragile X syndrome.

PMID- 8660062
TI  - Monoclonal IgA gammopathy in a well infant.

PMID- 8660063
TI  - Long term follow up to determine the prognostic value of imaging after urinary
      tract infections.

PMID- 8660064
TI  - Long term follow up to determine the prognostic value of imaging after urinary
      tract infections.

PMID- 8660065
TI  - Non-accidental fracture occurring in hospital.

PMID- 8660066
TI  - Are cyclospora an important cause of diarrhoea in Bangladesh?

PMID- 8660067
TI  - Aspirin treatment and increased generation of cysteinyl leukotrienes in Kawasaki
      disease.

PMID- 8660068
TI  - Osteogenesis imperfecta, non-accidental injury, and temporary brittle bone
      disease.

PMID- 8660069
TI  - Recruiting patients to clinical trials: lessons from studies of growth hormone
      treatment in renal failure.

PMID- 8660070
TI  - Treatment related deaths during induction and in first remission in acute
      lymphoblastic leukaemia: MRC UKALL X.
AB  - The benefits of achieving a long term event free survival of 60-70% by using
      increasingly intense treatment regimens must be weighed against the increased
      risk of treatment toxicity. From 1985 to 1990, 1612 children with childhood acute
      lymphoblastic leukaemia (ALL) in the UK were treated on MRC UKALL X with
      intensive induction therapy, central nervous system directed therapy (cranial
      irradiation and intrathecal methotrexate), and continuing treatment for two
      years. There was a randomisation to receive blocks of additional intensification
      treatment at five weeks, 20 weeks, not at all, or both. The five year disease
      free survival was 71% for children randomised to two blocks of intensification, a
      14% improvement on children randomised to no intensification treatment. Treatment
      related mortality in this national multicentre study has been analysed for
      induction and first remission (including those after intensification treatment).
      There were 38 induction deaths, 2.3% and 53 deaths in first remission, 3.3%
      (including those from a second malignancy). Thirty one (84%) of the induction
      deaths followed an infection: bacterial in 22 and fungal in nine. Thirty seven
      infective remission deaths occurred: bacterial in 11, viral in 16, fungal in
      seven, and three caused by Pneumocystis carinii pneumonia. Ten of these deaths
      followed a block of intensification treatment. The majority of noninfective
      remission deaths followed the development of a second tumour. Risk analysis for
      an induction death showed girls and children with Down's syndrome to be at
      greater risk. For deaths in first remission analysis showed an increased risk for
      bone marrow transplant (BMT) patients and children with Down's syndrome. There
      was no effect of age and leucocyte count for either group. Most significantly
      when BMT patients were excluded from the analysis, intensification treatment did
      not increase the risk of remission death.

PMID- 8660071
TI  - Longitudinal study of free running exercise challenge: reproducibility.
AB  - The reproducibility of free running exercise challenge has been examined in an
      unselected population of 8-10 year olds. Using a standardised protocol, monthly
      exercise tests were performed on 143 children over one year. A positive test was
      defined using both a 15% and 20% fall in peak expiratory flow after exercise. The
      mean (95% confidence interval, CI) population frequency for a positive test at
      15% fall was 14.9% (6.5 to 23.3) and coefficient of variation 24.6%. For a 20%
      fall, the mean (95% CI) population frequency was 7.9% (2.9 to 12.9) and
      coefficient of variation 27.8%. Seventy two (50.3%) of the children gave at least
      one positive response at 15% fall. Exercise testing is not reproducible in the
      community setting and should not be used as a screening test. Exercise data from
      epidemiological studies of asthma should be interpreted with caution.

PMID- 8660072
TI  - The effect of a child's disability on mother's mental health.
AB  - The prevalence of maternal depression was investigated in the mothers of 96
      children: 30 premature infants at risk for the development of cerebral palsy; 35
      premature infants considered not to be at risk for the development of cerebral
      palsy; and 31 healthy fullterm infants. There were equally high levels of
      depression in all three groups of mothers, regardless of birth status, prediction
      of disability, or presence of actual disability, throughout the first year of the
      children's lives. Depressed mothers were, however, found to have significantly
      more psychosocial stress. An early physiotherapy intervention had no effect on
      the prevalence of depression in mothers whose children were at risk for the
      development of cerebral palsy.

PMID- 8660073
TI  - Patient characteristics affecting attendance at general outpatient clinics.
AB  - A study was carried out to identify the characteristics of children who do not
      attend appointments at general outpatient clinics. Over six months, 359 children
      who had an appointment at a general clinic were studied using a questionnaire
      given to parents (74% response rate) and by inspection of case notes. Based on
      their first appointment in the study period, children were divided into
      'attenders' (n = 262) and 'non-attenders' (n = 97) for analysis. Non-attenders
      were significantly more likely to have one or more of the following
      characteristics: lower social class, poorer housing, unmarried parent(s) (56% v
      33%), longer journey to clinic (35 v 27.6 minutes), more appointments per year
      (4.2 v 3.3), poorer past attendance record, and received their appointment by
      post (76% v 44%). Surprisingly parents of non-attenders rated their children to
      have a significantly more severe illness than those who attended. These results
      suggest that attendance is primarily determined by social and logistical factors
      as well as appointment details, rather than illness severity.

PMID- 8660074
TI  - Undetectable IgE responses after respiratory syncytial virus infection.
AB  - Sequential nasopharyngeal secretions were collected from 81 infants from one day
      to three months after admission to hospital with respiratory syncytial virus
      (RSV) infection. Samples from 21 infants were assayed for anti-RSV IgE in an
      antigen capture ELISA assay. No IgE antibodies were detected although an assay of
      IgA antibodies carried out in parallel by a similar technique detected IgA
      antibodies in the secretions of all patients tested. Neither prior absorption of
      IgA or IgG, concentration of the secretions by freeze drying, nor enzyme
      amplification of the assay revealed any virus specific IgE. Using an antibody
      capture ELISA with a sensitivity of 0.85 IU/ml, IgE could be detected in
      sequential secretions of only one of the 81 RSV infected infants studied. Further
      testing of the secretions from 12 of these patients and those of a further 15
      using an enzyme amplified assay with a sensitivity of 0.1 IU/ml revealed no
      further positives. Low concentrations of IgE were found in the sera of the
      majority of infants with RSV infection but they did not differ from those of
      virus negative children of a similar age collected between RSV epidemics. No rise
      in mean serum IgE concentrations between acute and convalescent samples was
      observed. No virus specific IgE was detected in the sera of any infant using the
      enzyme amplified antigen capture ELISA.

PMID- 8660075
TI  - Prevalence and severity of asthma, rhinitis, and eczema in Singapore
      schoolchildren.
AB  - This study was part of an international effort to evaluate the epidemiology of
      asthma and allergic diseases around the world. The aim was to assess the
      prevalence and severity of these disorders in Singapore schoolchildren. The
      international study of asthma and allergies in childhood (ISAAC) written
      questionnaire was administered to 6238 schoolchildren. The respondents were
      parents of a 6-7 year cohort (n = 2030), and schoolchildren aged 12-15 years (n =
      4208). The overall cumulative and 12 month prevalence of wheezing were 22% and
      12%, respectively. The prevalence of doctor diagnosed asthma was 20%. Rhinitis
      was reported by 44% and chronic rashes by 12%. Multiple logistic regression
      analysis showed that a higher prevalence of wheezing and rhinitis was associated
      with males, and subjects of higher socioeconomic status (based on type of housing
      and total family income). More severe asthma related symptoms were present in
      Malays and Indians than in the Chinese. Allergic disorders are common in
      Singapore and prevalence is comparable to some populations in the West.
      Demographic and socioeconomic factors appear to influence the prevalence and
      severity of these disorders.

PMID- 8660076
TI  - Calprotectin as a marker of inflammation in cystic fibrosis.
AB  - Calprotectin is an abundant neutrophil cytosolic protein released during
      neutrophil activation or death. The use of plasma calprotectin concentration as a
      marker of pulmonary inflammation was tested in 31 children with cystic fibrosis,
      none of whom was acutely unwell or pyrexic. Twenty three were receiving
      antibiotics, 21 had positive sputum cultures, but none of the traditional tests
      clearly diagnosed ongoing infection. Plasma calprotectin was significantly higher
      in the cystic fibrosis group than in matched controls. Sixteen children with
      cystic fibrosis had values above the control range (320-1570 micrograms/l). Their
      chest radiograph Northern score, an index of accumulated pulmonary involvement,
      and their plasma copper, an index of acute phase response, both correlated with
      plasma calprotectin. Plasma gamma-glutamyltransferase also correlated weakly with
      plasma calprotectin: thus, hepatic pathology may be a confounding variable.
      However, the data still suggested that plasma calprotectin is a better index of
      inflammation than the traditional indices in general use.

PMID- 8660077
TI  - Transmission of tuberculosis to contacts of sputum positive adults in Malawi.
AB  - Over a period of one year from June 1993 to May 1994, 282 children under 6 years
      old who were household contacts of sputum positive adults with tuberculosis were
      evaluated in a screening clinic. Of these, 180 (63.8%) had evidence of
      tuberculosis, a much higher transmission rate than reported elsewhere. HIV
      seropositivity was 77.4% in the adult index cases and 18% in the contact
      children. No increased infectivity to household contacts was detected in HIV
      seropositive index adults compared with those who were seronegative. Child
      tuberculosis contact tracing is essential in these families, where transmission
      of disease is higher than reported elsewhere, and attention to the health needs
      of the children may be diminished by the high morbidity and mortality among adult
      family members.

PMID- 8660078
TI  - Does BCG vaccine prevent tuberculous meningitis?
AB  - The reported efficacy of BCG vaccine in preventing pulmonary tuberculosis varies
      from 0-80%; however, its efficacy in preventing tuberculous meningitis ranges
      from 52%-84%. A case-control study was conducted to assess the efficacy of BCG in
      preventing tuberculous meningitis in children. New cases of tuberculous
      meningitis, confirmed bacteriologically, were registered as cases. Controls were
      children suffering from febrile convulsions attending the same hospital. A total
      of 107 cases and 321 controls, block matched for age, were registered.
      Vaccination status was determined from the history reported by the mother and by
      BCG scar reading. Data regarding socioeconomic status, crowding, and nutritional
      status were collected. Using multiple logistic regression analysis the odds ratio
      obtained for the presence of BCG scar was 0.23 (95% confidence interval (CI) 0.14
      to 0.37) and the protective efficacy of BCG vaccine in preventing tuberculous
      meningitis in children was found to be 77% (95% CI 71 to 83%).

PMID- 8660079
TI  - Why are brain tumours still being missed?
AB  - The prediagnosis period of 74 children with primary brain tumours was assessed to
      examine their presentation and reasons for any delay in diagnosis. Medical case
      notes were reviewed and parents were interviewed and asked to complete
      psychological questionnaires. Mean (SD) duration of clinical history was 20.0
      (29.1) weeks. Most common symptoms were vomiting (65%) and headache (64%). Only
      34% of headaches were always associated with vomiting and only 28% occurred
      'early morning'. Changes in the child's personality (47%) were also common. The
      average number of consultations before diagnosis was 4.6. Migraine was diagnosed
      in 24% of children and a psychological aetiology in 15%. One quarter of the
      children had altered levels of consciousness on arrival at the unit. Results
      indicate that delay in diagnosis still occurs, despite strong parental concern.
      The nonspecificity of symptoms and a high incidence of psychological symptoms may
      confound the clinical picture and are considered along with other possible
      contributory factors.

PMID- 8660080
TI  - Lymphoblastoid interferon alfa treatment in chronic hepatitis C.
AB  - Interferon is becoming the standard treatment in adults for chronic hepatitis C.
      Twenty one children with histologically proved chronic hepatitis C (10 boys,
      range 2.5-13 years), who were otherwise healthy, were enrolled in a randomised
      controlled study to test their response to interferon alfa. Eleven children were
      treated with lymphoblastoid interferon alfa (3 million units/m2) for 12 months;
      10 children received no treatment. All had raised transaminases and positive
      antihepatitis C virus (HCV) antibodies and HCV-RNA. Alanine aminotransferase
      (ALT) serum levels became normal in five (45%) treated patients after a mean of
      three weeks (range 1-6 weeks) and no relapse had occurred by the end of follow up
      (30th month). Only one (10%) untreated patient had normal ALT serum levels from
      the 11th until the 30th month. Disappearance of serum HCV-RNA, persisting
      throughout the follow up period, was observed in the six children (five treated)
      whose ALT became normal. Biopsy specimens in treated patients showed a
      significant improvement in Knodell's score (median (SD) basal 9.0 (2.2); final
      2.0 (0.4)). Interferon treatment was well tolerated in all. This study confirms
      the efficacy of interferon in children with chronic hepatitis C, not only by
      restoring normal ALT serum levels, but also viral clearance and histological
      amelioration of liver inflammation. Contrary to reports in adults no biochemical
      and virological relapses occurred in responder children.

PMID- 8660081
TI  - Low dose colestipol in adolescents with familial hypercholesterolaemia.
AB  - The effects of orange flavoured colestipol granules, 10 g/day, in 37 boys and 29
      girls aged 10-16 years with familial hypercholesterolaemia were examined first in
      an eight week double blind, placebo controlled protocol, then in open treatment
      for 44-52 weeks. All patients were on a low fat diet. Low density lipoprotein
      cholesterol levels were reduced by 19.5% by colestipol v 1.0% by placebo. Levels
      of serum folate, vitamin E, and carotenoids were reduced in the colestipol group,
      but not the vitamin E/cholesterol and carotenoid/cholesterol ratios or serum
      concentrations of vitamins A and D. After one year of colestipol, two thirds of
      the participants remained in the study, of whom half took > or = 80% of the
      prescribed dose. Those who took > or = 80% of the dose had a greater decrease in
      serum 25-hydroxyvitamin D levels than those who took < 80%. No adverse effects on
      weight gain or linear growth velocity were observed. Although low dose colestipol
      effectively reduces low density lipoprotein cholesterol levels, only a minority
      of adolescents adhered to the new formulation for one year. Folate and possibly
      vitamin D supplementation is recommended.

PMID- 8660082
TI  - Role of the pulsed dye laser in the management of ulcerated capillary
      haemangiomas.
AB  - A complication of capillary haemangiomas is ulceration, which may arise after
      trauma and/or infection. Until recently, conservative management was the rule.
      However, the recent advent of the pulsed dye laser has revolutionised the
      treatment of vascular birthmarks and provided a new tool for the management of
      capillary haemangiomas. Thirteen cases of ulcerated capillary haemangiomas
      referred to our department were reviewed; five were treated conservatively and
      eight were treated with the laser. Those treated with the laser had all failed
      conservative management and healed completely within one to four weeks.
      Remarkably rapid alleviation of pain was achieved. For those haemangiomas around
      the mouth and perineum, laser treatment enabled early restoration of normal
      feeding, micturition, and defaecation. It is therefore recommended that if
      ulcerated capillary haemangiomas do not improve after a short period of optimal
      conservative treatment, laser treatment should be considered.

PMID- 8660083
TI  - Comparing efficacy and tolerability of ibuprofen and paracetamol in fever.
AB  - The purpose of this study was to compare antipyretic activity and evaluate
      tolerability of ibuprofen and paracetamol suspension in the treatment of febrile
      children. It was designed as a double blind, parallel group, multiple dose study
      comparing ibuprofen (20 mg/kg/24 hours) with paracetamol (50 mg/kg/24 hours)
      given at six hourly intervals for a maximum of 12 doses. Children on paediatric
      wards between the ages of 0.2 and 12 years, with fever as defined by an axillary
      temperature > or = 37.5 degrees C, were included. The main outcome measures were:
      change in axillary temperature; palatability of medication; changes in
      irritability and clinical condition; overall efficacy at the end of treatment;
      and number and nature of adverse events. The mean temperature change from
      baseline at four hours was -1.8 degrees C and -1.6 degrees C in ibuprofen and
      paracetamol groups respectively. In both groups: median palatability score was
      'no reaction'; median irritability score at end point was 'not irritable'; median
      score for change in clinical condition was 'improved'; and median score for
      overall efficacy was 'good effect'. The proportion of patients experiencing
      adverse events was similar in both groups, the majority of events having doubtful
      or no relationship to therapy and being mild in severity. In conclusion,
      ibuprofen suspension was as effective and well tolerated as paracetamol in
      treatment of fever in young children.

PMID- 8660084
TI  - Haemorrhagic shock encephalopathy syndrome presenting with myoglobinuria.
AB  - An infant with haemorrhagic shock encephalopathy syndrome (HSES) who in addition
      presented with hyperpyrexia and myoglobinuria is reported. As rhabdomyolysis is a
      feature of heat stroke and malignant hyperthermia, the association of HSES with
      myoglobinuria supports the hypothesis that HSES may be a form of hypermetabolic
      state triggered by hyperthermia.

PMID- 8660085
TI  - High incidence of urinary tract infection in patients with coeliac disease.
AB  - The concomitant occurrence of urinary tract infection (UTI) and coeliac disease
      was studied retrospectively among children with coeliac disease. There was a
      significantly higher risk of first time UTI in children with coeliac disease than
      in an unselected population of children. In the majority of cases UTI was
      associated with untreated, active coeliac disease.

PMID- 8660086
TI  - Improving awareness of ethical issues.

PMID- 8660087
TI  - Smoking and other health related behaviour in the social and environmental
      context.
AB  - It seems clear that parental smoking is harmful, although the magnitude of its
      effect may be smaller than sometimes suggested. However, smoking and other
      behaviours detrimental to health must be seen within a social and historical
      context. Individuals are not 'free choosing actors' and their behaviour is
      determined, at least in part, by their social and environmental circumstances.
      Smoking might better be regarded as a 'proximal' cause. 'Proximal' causes such as
      infectious or toxic agents are themselves subject to 'causes of causes' which are
      the determinants of exposure to these agents. Smoking may act as the 'proximal'
      cause, directly harming the fetus, but is itself caused by factors in the social
      and environmental circumstances. The complexity of the relationship between
      social and environmental circumstances, health related behaviours, and adverse
      outcomes cannot be resolved by the search for single causative agents. As Rutter
      points out, in order to begin to understand causal complexity 'it is necessary to
      examine distal causal relationships in the form of chains and of linked sequences
      involving several different, relatively short-term effects or operations' (p 2).
      Health promotion programmes sensitive to social context avoid 'victim blaming'
      and acknowledge that it is not enough to exhort mothers to 'stop smoking before
      and during pregnancy because this will harm your baby' (p 99). Mothers know that
      smoking can harm themselves and their babies and the vast majority want to give
      up. Their choice is limited by their social circumstances, and failure to
      recognise this has ensured the failure of health promotion initiatives aimed at
      smoking reduction during pregnancy. There are limitations in the techniques
      available to control for confounding in multivariate analysis and results must be
      interpreted with caution. Misinterpretation can lead to overemphasis of the role
      of single factors, diverting attention from complex pathways. While health
      related behaviours may be a 'proximal' cause of ill health, there is a duty on
      researchers, health promoters, and health policy makers to take account of the
      complex causal pathways in which these 'proximal' causes lie.

PMID- 8660088
TI  - Making reading easier.

PMID- 8660089
TI  - Screening for growth: towards 2000.

PMID- 8660090
TI  - Transient gluten intolerance.

PMID- 8660091
TI  - Acyclovir in chickenpox.

PMID- 8660092
TI  - Expulsion of ventriculoperitoneal shunt tubing.

PMID- 8660093
TI  - Infant length measurements.

PMID- 8660094
TI  - Toledo type brachyolmia.

PMID- 8660095
TI  - Pulmonary embolism in parenteral nutrition.

PMID- 8660096
TI  - Human herpesvirus-6 infections.
AB  - HHV-6 is ubiquitous in the community, appears to be acquired early in life, and
      has been proved to cause the clinical syndrome of exanthem subitum, and rarely to
      cause encephalitis. Like other herpesviruses, HHV-6 is capable of establishing
      latent infection and reactivating under a variety of stimuli. Improved diagnostic
      techniques have led to increased recognition of HHV-6 in the presence of many
      diseases, but much of the evidence for an aetiological role is inconclusive.
      There is accruing evidence for possible pathological roles in the
      immunocompromised host, but the evidence is less convincing for the range of
      associations otherwise listed for the normal host at the present time.

PMID- 8660098
TI  - Problems with pain--is the messenger to blame?

PMID- 8660097
TI  - Methotrexate and liver toxicity: role of surveillance liver biopsy. Conflict
      between guidelines for rheumatologists and dermatologists.

PMID- 8660100
TI  - The diagnostic challenge of acute polyarthritis.

PMID- 8660099
TI  - Pathophysiology of joint pain.

PMID- 8660102
TI  - Signalling through neutrophil Fc gamma RIII, Fc gamma RII, and CD59 is not
      impaired in active rheumatoid arthritis.
AB  - OBJECTIVE: To compare neutrophil Fc receptor (Fc gamma R) and CD59 signalling
      responses in normal healthy subjects and patients with active rheumatoid
      arthritis (RA). METHODS: Intracellular free calcium concentrations were measured
      in neutrophils loaded with the fluorescent calcium indicator fura-2, using a
      spectrofluorimeter. RESULTS: Basal intracellular calcium ion concentrations were
      similar in both groups when no primary antibody, CD59, or CD32 (Fc gamma RIII)
      antibody was added. When CD16 (Fc gamma RIII) antibody was added, there was a
      significantly greater basal calcium concentration in the patient group compared
      with the control group. Transient cytosolic calcium ion fluxes were observed
      after binding Fc gamma RII, Fc gamma RIII, or CD59 with specific monoclonal
      antibodies and cross linking with the F(ab)2 fragment of sheep antimouse IgG.
      Peak concentrations of intracellular free calcium, [Ca2+]i, after cross linking
      each of the three receptors, were comparable between normal healthy donors and
      patients with RA. The lag period between addition of cross linking antibodies and
      the increase in calcium was also similar between normal individuals and patients.
      CONCLUSION: Contrary to previous reports, these results demonstrate that Ca2+
      signalling responses of cross linked Fc receptors in blood neutrophils from
      patients with RA are identical to those in neutrophils of normal subjects.
      Signalling responses of cross linked CD59 are also unaltered.

PMID- 8660101
TI  - Changes in (markers of) bone metabolism during high dose corticosteroid pulse
      treatment in patients with rheumatoid arthritis.
AB  - OBJECTIVE: To examine the effect of high dose corticosteroid pulse treatment
      (three times 200 mg dexamethasone intravenously in eight days) on calcium and
      bone metabolism in 17 consecutive patients with active rheumatoid arthritis (RA).
      METHODS: Bone formation was quantified by measurement of serum alkaline
      phosphatase, osteocalcin, and carboxyterminal propeptide of type I procollagen
      (pro-I-CPP) concentrations. Bone resorption was measured by urinary excretion of
      calcium, hydroxyproline, (free and total) deoxypyridinoline (Dpyr), (free and
      total) pyridinoline (Pyr), and serum concentrations of the carboxyterminal cross
      linked telopeptide of type I collagen (I-CTP). Disease activity of RA was
      measured by erythrocyte sedimentation rate, C reactive protein, and Ritchie and
      Thompson joint scores. RESULTS: Disease activity was initially high, and
      decreased during corticosteroid pulse treatment and the following five weeks.
      Osteocalcin, alkaline phosphatase, and pro-I-CPP concentrations were initially
      within normal limits, while I-CTP, Dpyr, and Pyr were increased. Osteocalcin and
      pro-I-CPP concentrations decreased (p < 0.01) during corticosteroid pulse
      treatment, but rapidly returned to baseline after the treatment. No changes were
      observed in alkaline phosphatase and urinary excretion of calcium and
      hydroxyproline. Bone resorption measured by serum I-CTP and urinary excretion of
      Pyr and Dpyr was unchanged or decreased (p < 0.05-0.01), depending on the time of
      measurement and the parameter measured. CONCLUSIONS: In these patients with
      active RA, bone resorption was increased, while bone formation was within normal
      limits. During high dose corticosteroid pulse treatment, bone formation was only
      transiently decreased, while markers of bone resorption were unchanged or
      decreased. Because corticosteroid pulse treatment has only a short term negative
      effect on bone formation, and because it probably reduces bone resorption, at
      least partly as a result of the decreased disease activity, the effect of
      corticosteroid pulse treatment on bone may be assumed to be relatively mild.

PMID- 8660104
TI  - Intravital microscopy and capillaroscopically guided nail fold biopsy in
      scleroderma.
AB  - OBJECTIVES: To describe the frequency, extent, and nature of microvascular
      lesions in patients with scleroderma by means of capillaroscopy and
      capillaroscopically guided nail fold biopsy, and to determine the diagnostic
      value of the two methods and the pathophysiological significance of the lesions
      described. METHODS: A cohort study was made of 24 consecutive patients with
      scleroderma and 10 healthy controls, using standardised clinical, serological,
      capillaroscopic, and histological (nail fold biopsy) techniques. RESULTS: All
      patients with scleroderma had distinct lesions of the microvascular system.
      Capillaroscopy revealed more than 90% of the patients to have the typical
      scleroderma pattern. Histologically, these changes most frequently consisted of
      splitting of the basal lamina, broadening of the perivascular connective tissue,
      perivascular round cell infiltrations, and immunoglobulin deposits (each in 60
      75% of the patients). Electron microscopy was the most sensitive method of
      histological examination, detecting abnormalities in 87.5% of patients; with
      light microscopy and immunohistochemical techniques, abnormalities were revealed
      less frequently (83.3% and 75%, respectively). In contrast, normal findings were
      observed in most of the healthy controls: capillaroscopy = 90%; histology = 80%.
      CONCLUSIONS: Microvascular lesions are a predominant feature in scleroderma and
      seem to have a central pathogenetic role in the disease. Capillaroscopy is able
      to identify this microangiopathy noninvasively, and capillaroscopically guided
      nail fold biopsy can detect the frequency and nature of the underlying
      ultrastructural changes. This may therefore be a useful tool in describing the
      pathogenetic role of the microvascular system in scleroderma.

PMID- 8660103
TI  - Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced
      expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis.
AB  - OBJECTIVES: To identify genes that are involved in the development and
      progression of rheumatoid arthritis (RA). METHODS: We used a multiple gene
      analysis system and a set of available genes participating in processes such as
      proliferation, differentiation, tumour progression, and metastasis, to identify
      their RA related expression. Synovial tissues from 22 patients with RA were
      evaluated in comparison with those from six patients with osteoarthritis and two
      patients with non-inflamed joints as controls, using northern blot and reverse
      transcriptase polymerase chain reaction experiments. RESULTS: Our data confirm
      the role of c-fos and c-jun as constitutive signal transmitters in solid RA
      tissues, thus demonstrating the potential of the approach. Activation of both
      genes persisted through multiple passages of the cells in tissue cultures derived
      from the synovial lining of RA tissues. There was an increased expression of ets
      2 in 30% of RA samples and an up to 30-fold decreased expression of the potential
      metastasis suppressor gene nm23-H1 in 90% of RA tissues, compared with control
      tissues. CONCLUSIONS: The data presented show for the first time a significant
      decrease of nm23-H1 expression in RA, which is possibly involved in local
      invasiveness, and a strong activation of the ets-2 nuclear oncogene in about one
      third of RA tissues, which may also be part of a pathway leading to advanced
      disease stages. The constitutive expression of c-fos and c-jun in RA tissue most
      probably results from a continuing inflammatory stimulus. These findings with
      cell cultures suggest an intrinsic activation mechanism of these early response
      genes in RA.

PMID- 8660106
TI  - Association of two loci on chromosome 2q with nodal osteoarthritis.
AB  - OBJECTIVE: To search for genetic association between microsatellite marker loci
      and sibling pairs with nodal osteoarthritis (NOA). METHODS: Using the affected
      sibling pair method of analysis, genomic DNA from 66 sib pairs with NOA was
      analysed for association with highly polymorphic microsatellite marker loci. The
      microsatellite markers were amplified using polymerase chain reaction and typed
      on polyacrylamide gels. RESULTS: A significant association (p < 0.05) was
      identified between NOA and two loci on the short arm of chromosome 2 (2q 23-35).
      Candidate genes for osteoarthritis in this region include: fibronectin, a
      glycoprotein present in the extracellular matrix of normal cartilage; the alpha 2
      chain of collagen type V, a major constituent of bone; and the interleukin-8
      receptor, important in the regulation of neutrophil activation and chemotaxis.
      CONCLUSIONS: The chromosomal region 2q 23-35 requires further detailed study in
      NOA. Confirmation of these findings in large independent data sets and further
      analysis of candidate genes in this region will be important in unravelling the
      molecular basis for this common disease.

PMID- 8660105
TI  - B cell clonality in gastric lymphoid tissues of patients with Sjogren's syndrome.
AB  - OBJECTIVE: To determine the prevalence of mucosa associated lymphoid tissue
      (MALT) in the stomach and of a possible antigen driven proliferation, in patients
      with Sjogren's syndrome (SS). METHODS: Twenty one patients with primary SS and 80
      dyspeptic controls underwent upper endoscopy. Lymphoid tissue and Helicobacter
      pylori were assessed by histopathological analysis. Epstein-Barr virus (EBV) or
      human herpes virus-6 (HHV-6) genome were studied by polymerase chain reaction
      (PCR) DNA amplification. Two PCR VDJ procedures were used to detect
      immunoglobulin heavy chain (IgH) gene rearrangement. RESULTS: Organised MALT was
      found in 33.3% of the patients, compared with 21.5% of the controls (NS). H
      pylori infection was seen in 71% of patients and 63% of controls. Genomic EBV or
      HHV-6 was found in a minor portion of SS gastric tissues. B cell expansion was
      detected in nine of the 21 patients. Infectious agents in the stomach might have
      contributed to B cell clonality only in 55.5% of the cases. No strict
      relationship was found between lymphoid follicles and clonality. CONCLUSION:
      Lymphoid accumulation in the gastric mucosa is common in Sjogren's syndrome, but
      full evidence for an antigen driven B cell expansion could not be demonstrated.
      Only a portion of those with clonal B cell expansion had evidence of an
      infectious agent. Other unknown infectious agents or factors related to the
      underlying disease (autoantigen) and its tissue environment may have a further
      role as possible causes of B clonal expansion in the gastric mucosa.

PMID- 8660107
TI  - Interobserver reliability in measuring flexion, internal rotation, and external
      rotation of the hip using a plurimeter.
AB  - OBJECTIVE: To determine reliability of the measurement of hip movements (flexion,
      internal rotation, and external rotation) between medical practitioners. METHODS:
      Six clinicians carried out measurements of hip movements on each of six patients
      with osteoarthritis of one hip, using a specifically designed plurimeter.
      RESULTS: There was no evidence of any systematic difference between medical
      practitioners in the measurement of hip flexion, internal rotation, or external
      rotation. The degree of agreement was greatest for hip flexion. CONCLUSIONS: This
      study has shown that measurement of range of movement at the hip is repeatable
      between practitioners using a simple plurimeter and may represent an examination
      that is suitable for monitoring progress and treatment.

PMID- 8660108
TI  - Concentrations of pyridinoline and deoxypyridinoline in joint tissues from
      patients with osteoarthritis or rheumatoid arthritis.
AB  - OBJECTIVE: To assess the usefulness of pyridinoline (Pyr) and deoxypyridinoline
      (Dpyr), intermolecular crosslinks of collagen, as markers in the evaluation of
      arthritis, by studying their distribution in tissues from knee joints. METHODS:
      Joint tissues (cartilage, bone, synovium) were obtained during operation from 10
      patients with osteoarthritis (OA) and 10 patients with rheumatoid arthritis (RA).
      Synovium was also obtained from 10 non-arthritic (NA) subjects. Hydroxyproline
      was measured in hydrolysed tissue samples and converted to an equivalent collagen
      content. The amounts of Pyr and Dpyr crosslinks measured in the hydrolysed
      samples using a fluorescence technique were expressed as mumol/mol of collagen.
      RESULTS: Pyr and Dpyr were distributed in all three tissues, but in different
      amounts. The ratio of the contents of Pyr and (Pyr:Dpyr) was 50:1 in cartilage,
      3:1 in bone, and 25:1 in synovium. OA cartilage had a greater Dpyr content than
      the RA cartilage, but there was no other significant difference in the contents
      of Pyr and Dpyr and the ratio Pyr:Dpyr in the joint tissues from patients with OA
      or RA. In synovium, there was no significant difference between the contents of
      Pyr and Dpyr and the Pyr:Dpyr ratio among OA, RA, and NA tissues. CONCLUSION:
      Both Pyr and Dpyr were located in cartilage, bone, and synovium. A significant
      amount of Pyr and Dpyr in these joint tissues, especially in synovium, may
      contribute to the urinary excretion of those crosslinks that is observed in
      arthritis.

PMID- 8660110
TI  - Bone mineral density and bone turnover in spinal osteoarthritis.

PMID- 8660109
TI  - Low dose desensitisation does not reduce the toxicity of sulphasalazine in
      rheumatoid arthritis.
AB  - OBJECTIVE: To examine the proposal that pretreatment low dose desensitisation may
      reduce the incidence of toxicity of sulphasalazine in the treatment of rheumatoid
      arthritis (RA). METHODS: A double blind, placebo controlled trial was performed
      with 422 patients satisfying the American College of Rheumatology criteria for RA
      who required sulphasalazine treatment because of increased disease activity.
      Patients received either sulphasalazine desensitisation, or placebo, for three
      weeks before commencement of sulphasalazine treatment. The frequency and nature
      of adverse effects and changes in clinical and laboratory parameters of disease
      activity were measured after three and six months. RESULTS: Improvement in the
      efficacy of sulphalasazine (measured by clinical and laboratory parameters) was
      significant and similar in magnitude in both groups. There was no significant
      difference between actively and placebo desensitised patients as regards the
      incidence or profile of adverse effects (toxicity). CONCLUSION: Pretreatment low
      dose desensitisation is unhelpful in reducing the toxicity associated with
      sulphasalazine treatment of RA.

PMID- 8660111
TI  - Effect of isradipine on endothelin-1 plasma concentrations in patients with
      Raynaud's phenomenon.

PMID- 8660112
TI  - Survival after aortic dissection in giant cell arteritis.

PMID- 8660113
TI  - Antibodies to collagens in sera from patients receiving bovine cartilage graft.

PMID- 8660114
TI  - [Conception and development of a universal scheme for sewage treatment in
      antibiotic production].

PMID- 8660115
TI  - [Cyclosporin A and the permeability of the cytoplasmic membrane in Aspergillus
      niger].
AB  - Cyclosporine A was shown to impair selective permeability of cytoplasmic
      membranes in Aspergillus niger thus inducing leakage of low molecular components
      of the intracellular fond from the cells. In this respect lyposomal cyclosporine
      had a more pronounced action than the free form. Cyclosporine was compared with
      amphotericin B and the latter in the free and lyposomal forms demonstrated a
      higher effect on the cell membranes of Asp. niger. In combination with
      amphotericin B cyclosporine markedly stimulated the effect of amphotericin B on
      permeability of the cell membranes.

PMID- 8660116
TI  - [Action of para-aminobenzoic acid and its combination with acyclovir in herpetic
      infection].
AB  - The effect of para-amino benzoic acid (PABA) on the virus of Herpes simplex (VHS
      1, strain L2) was studied and it was shown to be active in vitro and in vivo. The
      action of PABA was virucidal in the culture of the cell-free virus-containing
      material. It lowered the death rate of the laboratory mice with experimental
      herpetic encephalitis (intraperitoneal contamination) at the average by 40 per
      cent and increased the mean life-span of the animals significantly decreasing the
      virus titre in the mouse brain. PABA was not toxic with respect to the Vero cells
      thus not preventing the virus-induced cytopathic effect in the cultures. However,
      PABA showed high ability to potentiate the antiherpetic action of acyclovir
      (Zovirax, acycloguanosine) in the infected cultures when acyclovir was used in
      inactive concentrations.

PMID- 8660117
TI  - [Induction of antibiotic production in inactive cultures of actinomycetes.
      Monensin production by a mutant strain 2608 EB-1].
AB  - An actinomycete strain designated as 2608 was isolated from a soil sample. When
      cultivated on various solid and liquid media, the strain was inactive. The strain
      exposure to ethidium bromide resulted in formation of a mutant producing an
      antibiotic active against some gram-positive bacteria. The property of the
      antibiotic production proved to be stable. The antibiotic was identified by IR,
      NMR and mass spectroscopy as monensin. Strain 2608 producing monensin differs
      from the described monensin-producing culture Streptomyces cinnamonensis ATCC
      15413 and is a new culture producing monensin.

PMID- 8660119
TI  - [Microtest-system for detection of urinary tract infections].
AB  - A rapid physico-chemical method for detection of clinically significant
      bacteriuria is described. The method is based on turbidimetric detection of the
      bacterial growth after 6-hour incubation of the urine specimens in the wells of
      the microtest system which is a polysterol plate used in immunological studies
      with 96 wells (8 x 12 cm) of the volume of 0.2 ml each containing a dry medium.

PMID- 8660118
TI  - [Effect of drugs of various groups on the course of experimental local pyo
      inflammatory processes].
AB  - To develop new approaches to providing higher efficacy of antibacterial therapy
      of purulent infection, experiments on 104 rats were performed. A decrease in the
      inflammation was shown in a series of the experiments with the dermonecrotic test
      using mono- and mixed cultures of Staphylococcus aureuo, Pseudomonas aeruginosa
      and Escherichia coli at the background of the animal treatment with anapriline
      and heparin. The effect of mezatone and dicinone was the opposite one. The drugs
      had different effects on the host response to the introduction of microorganisms
      of various species as mono- and mixed cultures. The experiments on a group of
      animals with wound infection not subjected to the preliminary alteration of the
      tissues demonstrated that the treatment with gentamicin and anapriline
      combinations was more efficient than the gentamicin monotherapy. The use of
      anapriline improved the antibiotic pharmacokinetics, had a favourable effect on
      the wound reparation, promoted a decrease in the count of viable microbes in the
      wound secretion and increased the antibiotic concentration gradient.

PMID- 8660121
TI  - [Overcoming tumor multiple drug resistance. MDR modulators].

PMID- 8660120
TI  - [Pharmacokinetics of fluoroquinolones in patients with renal insufficiency].

PMID- 8660123
TI  - Mapping mental illness. A new era.

PMID- 8660122
TI  - [Chelating and oxidizing properties of tetracycline metabolites forming during
      its peroxidase or photoinduced oxidation].
AB  - Tetracycline metabolites forming on the antibiotic exposure to visible light or
      peroxidase as well as tetracycline as such showed the ability to bind iron
      cations. When the metabolites bound the cations of iron protoxide, they catalyzed
      its oxidation. Chelating agents such as o-phenanthroline and EDTA arrested the
      ions of iron protoxide and iron oxide in the respective iron/tetracycline
      complexes at a much lower rate than that with the use of the native tetracycline.
      This means that the affinity of the metabolites with the above mentioned iron
      ions was much higher than that of the native tetracycline. When the metabolites
      and tetracycline bound iron protoxide, they catalyzed its oxidation to the oxide.
      Tetracycline and its metabolites were shown as well to have the property of
      reversible regeneration of iron oxide to the protoxide.

PMID- 8660124
TI  - Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative
      neuroimaging.
AB  - BACKGROUND: Prior neuroimaging studies have not consistently demonstrated a
      structural or functional abnormality of the caudate nucleus in patients with
      obsessive-compulsive disorder (OCD). However, there is theoretical support for
      some associated dysfunction of the caudate nucleus. METHODS: We examined volumes
      of the caudate nucleus and putamen with magnetic resonance imaging in 24 patients
      with adult-onset OCD and 21 control subjects, group-matched on age, race,
      education, and sex. Patients were relatively free from tics. To evaluate function
      (metabolism or blood flow) of the caudate nucleus, we performed a quantitative
      review, including a meta-analysis, of normalized data from functional
      neuroimaging studies that compared patients who had OCD with normal control
      subjects. RESULTS: All structural basal ganglia measures failed to exhibit
      differences between patients with OCD and matched normal control subjects.
      Patients did not demonstrate evidence of ventricular enlargement. Quantitative
      meta-analysis of the functional neuroimaging literature did not demonstrate a
      consistent abnormality of the caudate nucleus. CONCLUSIONS: We did not observe
      evidence of a structural abnormality of the caudate nucleus in patients with OCD.
      Prior reports of a structural aberration of the caudate nucleus were mixed. We
      also did not find strong support for relative caudate metabolic or perfusion
      dysfunction in the literature, although increased function in the frontal
      cerebral cortex was identified. The heterogeneous nature of this disorder may
      account for inconsistencies between studies. For example, ventricular enlargement
      or reduced caudate volume or blood flow might be evident in patients with soft
      neurological signs (eg, tics), while patients in the current study were
      relatively free from tics. Although theories of OCD suggest a dysfunction of the
      caudate nucleus, the structural and functional neuroimaging literature has not
      consistently verified this.

PMID- 8660125
TI  - Sex differences in human brain morphometry and metabolism: an in vivo
      quantitative magnetic resonance imaging and positron emission tomography study on
      the effect of aging.
AB  - BACKGROUND: There are significant age and sex effects in cognitive ability and
      brain disease. However, sex differences in aging of human brain areas associated
      with nonreproductive behavior have not been extensively studied. We hypothesized
      that there would be significant sex differences in aging of brain areas that
      subserve speech, visuospatial, and memory function. METHODS: We investigated sex
      differences in the effect of aging on human brain morphometry by means of
      volumetric magnetic resonance imaging and on regional cerebral metabolism for
      glucose by positron emission tomography. In the magnetic resonance imaging study,
      we examined 69 healthy right-handed subjects (34 women and 35 men), divided into
      young (age range, 20 to 35 years) and old (60 to 85 years) groups. In the
      positron emission tomography study, we investigated 120 healthy right-handed
      subjects (65 women and 55 men) aged 21 to 91 years. RESULTS: In the magnetic
      resonance imaging study, age-related volume loss was significantly greater in men
      than women in whole brain and frontal and temporal lobes, whereas it was greater
      in women than men in hippocampus and parietal lobes. In the positron emission
      tomography study, significant sex differences existed in the effect of age on
      regional brain metabolism, and asymmetry of metabolism, in the temporal and
      parietal lobes, Broca's area, thalamus, and hippocampus. CONCLUSIONS: We found
      significant sex differences in aging of brain areas that are essential to higher
      cognitive functioning. Thus, our findings may explain some of the age-sex
      differences in human cognition and response to brain injury and disease.

PMID- 8660126
TI  - Functional magnetic resonance imaging of symptom provocation in obsessive
      compulsive disorder.
AB  - BACKGROUND: The new technique of functional magnetic resonance imaging was used
      to investigate the mediating neuroanatomy of obsessive-compulsive disorder
      symptoms. METHODS: Ten patients with obsessive-compulsive disorder and 5 normal
      subjects were studied via functional magnetic resonance imaging during control
      and provoked conditions. Data analysis entailed parametric and nonparametric
      statistical mapping. RESULTS: Statistical maps (nonparametric; P < 10(-3)) showed
      activation for 70% or more of patients with obsessive-compulsive disorder in
      medial orbitofrontal, lateral frontal, anterior temporal, anterior cingulate, and
      insular cortex, as well as caudate, lenticulate, and amygdala. No normal subjects
      exhibited activation in any brain region. CONCLUSIONS: Results of functional
      magnetic resonance imaging were consistent with past studies of obsessive
      compulsive disorder that used other functional neuroimaging modalities. However,
      paralimbic and limbic activations were more prominent in the present study.

PMID- 8660127
TI  - Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity
      disorder.
AB  - BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention
      deficit hyperactivity disorder (ADHD) have been limited by small samples or
      measurement of single brain regions. Since the neuropsychological deficits in
      ADHD implicate a network linking basal ganglia and frontal regions, 12
      subcortical and cortical regions and their symmetries were measured to determine
      if these structures best distinguished ADHD. METHODS: Anatomic brain MRIs for 57
      boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained
      using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the
      cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus,
      temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left
      asymmetries were examined along with midsagittal area measures of the cerebellum
      and corpus callosum. Interrater reliabilities were .82 or greater for all MRI
      measures. RESULTS: Subjects with ADHD had a 4.7% smaller total cerebral volume (P
      = .02). Analysis of covariance for total cerebral volume demonstrated a
      significant loss of normal right > left asymmetry in the caudate (P = .006),
      smaller right globus pallidus (P = .005), smaller right anterior frontal region
      (P = .02), smaller cerebellum (P = .05), and reversal of normal lateral
      ventricular asymmetry (P = .03) in the ADHD group. The normal age-related
      decrease in caudate volume was not seen, and increases in lateral ventricular
      volumes were significantly diminished in ADHD. CONCLUSION: This first
      comprehensive morphometric analysis is consistent with hypothesized dysfunction
      of right-sided prefrontal-striatal systems in ADHD.

PMID- 8660128
TI  - Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia.
AB  - BACKGROUND: Early-onset schizophrenia (first psychotic symptoms by age 12 years)
      has been the subject of a small number of studies, and its biological continuity
      with later-onset disorder has not been established. In this study quantitative
      anatomic brain magnetic resonance images of children and adolescents with early
      onset schizophrenia were compared with those of matched controls. Brain
      abnormalities in childhood-onset schizophrenia were examined in relation to those
      reported for later-onset schizophrenics. METHODS: Anatomic brain magnetic
      resonance imaging scans were obtained for 21 patients (mean +/- SD age, 14.6 +/-
      2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males,
      eight females) and 33 age-, sex-, height-, and weight-matched normal controls.
      Quantitative measurements were obtained for the cerebrum, anterior frontal
      region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus.
      RESULTS: Total cerebral volume and midsagittal thalamic area were smaller in the
      patients (analysis of variance, P = .002, and analysis of covariance, P = .03,
      respectively); the caudate, putamen, and globus pallidus were larger in the
      patients (analysis of covariance, P = .05, P = .007, and P < .001, respectively);
      and the lateral ventricles tended to be larger in the patients (analysis of
      covariance, P = .06). Globus pallidus enlargement correlated with neuroleptic
      exposure and with age of onset of psychosis. The magnitude of abnormalities
      compared with controls was similar to that reported in adult studies, although
      there was a trend toward relatively smaller cerebral volumes for the childhood
      onset group compared with controls. CONCLUSION: Brain anatomic abnormalities in
      childhood-onset schizophrenia are similar to those reported for adult
      populations, indicating overall continuity between these rare childhood cases and
      the adult schizophrenia populations.

PMID- 8660129
TI  - Cerebral structural abnormalities in obsessive-compulsive disorder. A
      quantitative morphometric magnetic resonance imaging study.
AB  - BACKGROUND: A previous pilot study of only posterior brain regions found lower
      white-matter volume in patients with obsessive-compulsive disorder than in normal
      control subjects. We used new cohorts of patients and matched normal control
      subjects to study whole-brain volume differences between these groups with
      magnetic resonance imaging-based morphometry. METHODS: Ten female patients with
      obsessive-compulsive disorder and 10 female control subjects, matched for
      handedness, age, weight, education, and verbal IQ, underwent magnetic resonance
      imaging with a 3-dimensional volumetric protocol. Scans were blindly normalized
      and segmented by means of well-characterized semiautomated intensity contour
      mapping and differential intensity contour algorithms. Brain structures
      investigated included the cerebral hemispheres, cerebral cortex, diencephalon,
      caudate, putamen, globus pallidus, hippocampus amygdala, third and fourth
      ventricles, corpus callosum, operculum, cerebellum, and brain stem. Anterior to
      posterior neocortical regions, including precallosum, anterior pericallosum,
      posterior pericallosum, and retrocallosum, with adjacent white matter were also
      measured. Volumes found different between groups were correlated with Yale-Brown
      Obsessive Compulsive Scale score and Rey-Osterieth Complex Figure Test measures.
      RESULTS: Confirming results of our earlier pilot study and expanding the findings
      to the whole brain, patients with obsessive-compulsive disorder had significantly
      less total white matter but, in addition, significantly greater total cortex and
      opercular volumes. Severity of obsessive-compulsive disorder and nonverbal
      immediate memory correlated with opercular volume. CONCLUSIONS: Replication of
      volumetric white-matter differences suggests a widely distributed structural
      brain abnormality in obsessive-compulsive disorder. Whereas determining the
      etiogenesis may require research at a microscopic level, understanding its
      functional significance can be further explored via functional neuroimaging and
      neuropsychological studies.

PMID- 8660130
TI  - Auditory attentional deficits in patients with schizophrenia. A positron emission
      tomography study.
AB  - BACKGROUND: Patients with schizophrenia have frequently been found to perform
      poorly on tasks requiring selective attention, defined as the ability to focus
      attention on relevant information while simultaneously ignoring irrelevant
      stimuli. This study explores the brain mechanisms mediating attentional
      processing in patients with schizophrenia by measuring their regional cerebral
      blood flow (rCBF) with positron emission tomography using [15O] water as they
      performed tasks that differed systematically in attentional demand. METHODS: Ten
      schizophrenic patients (either neurolepticnaive or withdrawn from medication)
      (patient group) and 10 normal volunteers (control group) performed auditory
      target detection tasks. Different types of auditory stimuli (environmental
      sounds, meaningless speech sounds, and words) were presented either binaurally
      (ie, same sounds in both ears) or dichotically (simultaneous and different sounds
      in the 2 ears). In dichotic conditions, subjects were instructed to focus on
      either their left or right ear. RESULTS: Initial subtraction-based image analyses
      sought significant rCBF changes anywhere in the brain. Patients consistently had
      less significant activation than controls in right superotemporal gyrus (STG).
      Follow-up analyses used regions of interest traced on individual magnetic
      resonance images to precisely measure rCBF in STG. Unlike controls, patients had
      higher rCBF in the left STG during all activation conditions. CONCLUSIONS: The
      abnormal task-related rCBF asymmetry in STG of schizophrenic patients may
      indicate an isolated temporal lobe deficit, but it may also indicate abnormality
      in the thalamocortical circuitry mediating selective attention and/or in the
      brain systems that integrate auditory processing in the 2 hemispheres.

PMID- 8660131
TI  - Brain glucose metabolism during non-rapid eye movement sleep in major depression.
      A positron emission tomography study.
AB  - BACKGROUND: Depression is characterized by several sleep-related abnormalities
      shortly before and after sleep onset, such as prolonged sleep latency, loss of
      stage 3-4 sleep, reduced rapid eye movement (REM) latency, increased nocturnal
      core body temperature, and abnormal hormone secretion patterns. Sleep deprivation
      is associated with a temporary improvement in depression. We hypothesized that
      depressed patients may be "overaroused" and that absolute cerebral glucose
      metabolism would be elevated during the first nocturnal non-REM sleep period in
      depressed patients compared with normal controls. In addition, since
      hypofrontality (greater metabolic activity in occipital compared with frontal
      cortical activity) has been reported in waking positron emission tomographic
      studies of depressed patients compared with controls, we predicted significant
      hypofrontality in depressed patients during the first non-REM period. METHODS:
      Positron emission tomography with fludeoxy-glucose F 18 was used to compare 10
      unmedicated men with unipolar depression with 12 normal men during the first non
      REM sleep period at normal bedtime. RESULTS: Whole-brain absolute metabolic rate
      during non-REM sleep was significantly elevated (+47%) in patients compared with
      controls. Mean absolute cerebral glucose metabolic rate was also higher in every
      area of the brain in patients compared with normal controls. The greatest
      significant mean increases were in the posterior cingulate and amygdala (+44%),
      hippocampus (+37% to +43%), occipital and temporal cortex (+33% to +34%), and
      pons (+33%). Relative metabolic rates in specific neroanatomical areas, however,
      varied considerably both within the patient group and between patients and
      controls. Patients showed significant hypofrontality, particularly in the medio
      orbital frontal cortex, compared with controls. Patients also showed significant
      reductions of relative metabolic rate in the anterior cingulate, caudate, and
      medial thalamus compared with controls. CONCLUSIONS: These findings provide
      further support for the hyperarousal hypothesis of some types of major depressive
      disorder. Abnormal patterns of cerebral metabolism during non-REM sleep in
      depressed patients confirmed earlier waking findings of decreased relative
      frontal and abnormal limbic metabolic activity and striatal metabolism in
      association with posterior cortical increases.

PMID- 8660132
TI  - Retinoid dysregulation may result in abnormal expression of glutamic acid
      decarboxylase in schizophrenia.

PMID- 8660133
TI  - Venlafaxine in obsessive-compulsive disorder.

PMID- 8660134
TI  - Characterization of the effects of an airborne mixture of chemicals on the
      respiratory tract and smoothing polynomial spline analysis of the data.
AB  - We expanded a previously published (Vijayaraghavan et al. 1994) computerized
      system to analyze the breathing pattern of unanesthetized mice in order better to
      recognize and quantify the effects of an airborne mixture of chemicals at three
      different levels of the respiratory tract. The airborne chemical mixture used was
      a machining fluid. Such fluids are widely used in industry and a large number of
      workers are exposed to these airborne mixtures. We found this mixture to be
      capable of inducing three types of effects on the respiratory tract: sensory
      irritation of the upper respiratory tract (S), airflow limitation along the
      conducting airways (A) and pulmonary irritation (P). Depending upon the exposure
      concentration, mainly S or P effects were obtained but an A effect was also
      identified. The three types of effects occurred at various times during the
      exposures and, furthermore, within a group of exposed animals some exhibited one
      type of effect while others exhibited another type. In order to analyze such
      complex data sets, two statistical methods for smoothing polynomial splines were
      utilized: the maximum likelihood (ML) method and generalized cross validation
      (GCV) method. The results indicated the previous methods used to characterize a
      single effect of airborne chemicals can now be extended to evaluate mixtures
      likely to induce multiple types of effects. However, statistical analysis
      methods, either the ML or GCV methods, or other appropriate methods are needed to
      evaluate the responses obtained due to the complex effects that a mixture can
      induce in comparison to single chemicals.

PMID- 8660135
TI  - Regional differences in expression of osteonectin mRNA after administration of
      cadmium to rats.
AB  - Osteonectin gene expression in relation to metallothionein mRNA expression was
      investigated in various tissues from Cd-treated rats. After a single 50
      micromol/kg subcutaneous injection of CdCl2, Cd predominantly accumulated in the
      liver and metallothionein gene expression significantly increased concomitantly
      with Cd accumulation, but no alteration of osteonectin gene expression was
      observed. In the kidney and lung, both metallothionein and osteonectin mRNA
      increased significantly but the elevation of metallothionein mRNA levels (1 h
      after Cd administration) preceded that of osteonectin (3 h after administration).
      A significant elevation of osteonectin mRNA levels was also observed in the
      testis after 3 h, but that of metallothionein mRNA occurred after 6 h. Not only
      accumulation of Cd but also increments in both osteonectin and metallothionein
      mRNA were minimal in the brain, but a significant increase in gene expression was
      observed after 1 h for osteonectin and after 3 h for metallothionein. Since,
      except in the testis, metallothionein gene expression preceded osteonectin gene
      expression, the induced metallothionein might transpose Cd and thereby affect its
      levels immediately, thus reducing the levels of Cd available for accumulation in
      other tissues. Hence, the osteonectin-Cd interaction might be secondary to the
      metallothionein-Cd interaction. However, the fact that osteonectin mRNA was
      predominantly induced by Cd administration in the target tissues of Cd toxicity,
      such as the lung, kidney and testis, suggests the possible involvement of
      osteonectin in Cd intoxication/detoxication mechanisms.

PMID- 8660137
TI  - Evidence for renal ischaemia as a cause of mercuric chloride nephrotoxicity.
AB  - The present study was undertaken to investigate if the source of oxidative stress
      and the renal injury produced by mercuric chloride could be renal ischaemia.
      Verapamil Vp was used because it was described that calcium channel blockers
      protect cells from nephrotoxicants and from ischaemia. Vp (75 micrograms/kg,
      i.v.; 30 min before HgCl2 injection) prevented mercuric chloride renal injury
      observed 1 h post-HgCl2 injection as measured by clearance techniques. Vp also
      prevented the diminution of non-protein-sulfhydryls (NPSH) and the increased
      lipid peroxidation (LPO) induced by HgCl2 in renal tissue. Hg2+ toxicokinetic
      alterations were not observed in Vp plus HgCl2 treated rats, nor was Vp ability
      found as a free radical scavenger in renal tissue homogenates. The results
      described in this study give some evidence for the role of renal ischaemia in the
      production of oxidative stress, generating LPO and functional and morphological
      renal injury described in mercuric chloride treated rats.

PMID- 8660136
TI  - Placental and lactational transfer of lead in rats: a study on the lactational
      process and effects on offspring.
AB  - The effects of placental and lactational exposure to lead (Pb) were studied in
      suckling rats after long-term exposure of their dams to Pb in drinking water.
      Dams were given 12 mM Pb-acetate in the drinking water 8 weeks prior to mating
      and during gestation. One group of dams was also continuously exposed during
      lactation until day 15. Neonates from Pb-treated dams were cross-fostered at
      birth to control dams treated with Na-acetate (12 mM) in the drinking water. In
      the same way, neonates from dams receiving control water were in the same way
      cross-fostered to Pb-exposed dams. All animals were killed at day 15 of
      lactation, when measurements were performed. Continuous Pb exposure during
      gestation and lactation resulted in milk Pb levels approximately 2.5 times higher
      than the blood Pb levels. When Pb exposure was terminated at parturition the milk
      Pb levels were at a level similar to those of blood Pb at day 15 of lactation,
      and only 10% of the milk levels found after continuous Pb exposure. Exposure to
      Pb via placenta and milk in offspring from dams exposed continuously resulted in
      more than 6 times higher blood and brain Pb levels than in offspring exposed only
      via the placenta. Exposure only via milk in offspring from dams exposed to Pb
      until parturition resulted in higher blood Pb levels than in offspring exposed to
      Pb only via the placenta. This indicates that the lactational transfer after
      current or recent exposure of Pb in dams is considerably higher than placental
      transfer. Offspring in all the exposed groups had decreased ALAD activity in the
      blood. An exponential relationship between blood Pb levels and ALAD activity was
      demonstrated in the offspring. Due to the exponential decrease in ALAD activity
      at increasing blood Pb levels, ALAD is particularly sensitive in reflecting
      differences in Pb exposure within the lowest range of blood Pb levels. There was
      a slight effect on weight gain in the offspring. However, there was no effect on
      milk quality, as measure by milk lipid, protein and calcium concentrations, nor
      on milk production assessed by the mammary gland RNA and DNA content. This
      indicates that the effect on weight gain was a direct effect of Pb in the
      offspring.

PMID- 8660138
TI  - Neurobehavioral development of CD-1 mice after combined gestational and postnatal
      exposure to ozone.
AB  - Outbred CD-1 mice were exposed continuously to ozone (O3, 0.6 ppm) from 6 days
      prior to the formation of breeding pairs to the time of weaning of the offspring
      on postnatal day 22 (PND 22) or to PND 26. One half of the mice in each of eight
      O3 and eight control litters were subjected on PND 24 to a 20-min open-field test
      after IP treatment by either saline or scopolamine (2 mg/kg). The remaining mice
      (those exposed until PND 26) were subjected on PNDs 28-31 to a conditioned place
      preference (CPP) test, using a short schedule with a single IP injection on PND
      29 of either d-amphetamine (3.3 mg/kg) or saline. Subsequently, the saline mice
      of the open-field experiment were used on PND 59 for an activity test in one of
      the CPP apparatus compartments after IP treatment by either d-amphetamine (same
      dose) or saline. In addition, the saline mice of the CPP experiment underwent a
      multi-trial, step-through passive avoidance (PA) acquisition test on PND 59 or
      60, followed 24 h later by a single-trial retention test. In the absence of
      effects on reproductive performance (proportion of successful pregnancies, litter
      size, offspring viability, and sex ratio), O3 offspring showed a long-lasting
      reduction in body weight without modification of sex differences. Ozone effects
      on neurobehavioral development were not large and quite selective, including:
      attenuation of the sex differences in several responses (rearing and sniffing in
      the open-field, activity in the final CPP test session); a change in response
      choices in the final CPP test, in the absence of a main effect on conditioning; a
      reduction of grooming in the activity test on PND 29; and impairment of PA
      acquisition limited to the initial period of training.

PMID- 8660139
TI  - In vitro influences of alcohols on mouse synaptosomes, and structure-activity
      relationships.
AB  - Little information is available on the structure-central nervous system membrane
      toxicity relationship of alcohols. The purpose of the present study was to study
      in vitro influence of alcohols (n = 20) on the activity of the toxic indicator
      Na+/K(+)-adenosine triphosphatase (Na+/K(+)-ATPase) and acetylcholinesterase
      (AchE), and membrane fluidity in mouse brain synaptosomes, in terms of the
      structure-activity relationship. The potency of inhibition for the enzymes (IC50)
      and the potency of increasing membrane fluidity (IC12.5) were determined
      experimentally, and n-octanol/water partition coefficient (P) and the steric
      constant Taft Es are cited from the literature. Regression analysis revealed that
      log 1/IC50 for Na+/K(+)-ATPase is a function of log P and Taft Es. The situation
      was true for AchE activity. The results indicate that the hydrophobicity
      expressed as log P and the steric effect of the alcohols play an important role
      in inhibiting both enzyme activities. A linear relationship between log 1/IC12.5
      for membrane fluidity and log P is shown, indicating a significant effect of the
      alcohols on membrane fluidity. Based on these results, it is suggested that the
      alcohols inhibit the Na+/K(+)-ATPase and AchE activity through a direct action on
      the enzymes and/or through changing the membrane fluidity.

PMID- 8660141
TI  - Investigation of potential oncogenetic effects of beta-cyclodextrin in the rat
      and mouse.
AB  - The results of oncogenicity studies of beta-cyclodextrin in inbred Fischer 344
      rats and CD-1 outbred mice are presented. Chronic feeding of beta-cyclodextrin to
      Fischer 344 rats and CD-1 mice did not cause any treatment related carcinogenic
      effects. The only toxic effect was seen in mice as macroscopic distension of the
      large intestine with soft or fluid contents, histologically associated with the
      mucosa covered by mucous secretion containing exfoliated cells, and mucosal
      flattening and intestinal gland atrophy. Despite these observations, no
      differences between control and treated groups were observed concerning
      mortality, clinical observations or body weight and food consumption.

PMID- 8660140
TI  - Effect of bolesatine on phospholipid/calcium dependent protein kinase in Vero
      cells and in rat thymus.
AB  - Bolesatine, a glycoprotein from Boletus satanas Lenz, has previously been shown
      to be mitogenic to rat and human lymphocytes at very low concentrations, whereas
      higher concentrations inhibit protein synthesis in vitro and in several in vivo
      systems. The mechanism whereby this mitogenic activity occurs was previously
      unknown. To elucidate this mechanism, the effects of bolesatine have been studied
      in a cell-free system, VERO cells, and in vivo in rat thymus. In a cell-free
      system, bolesatine appears to be a direct effector of PKC. The activation is
      concentration dependent for 1-10 ng/ml. At the same time, VERO cells
      significantly proliferate when incubated with the bolesatine (3, 5 and 10 ng/ml),
      since the DNA synthesis increases by 27, 48, and 59%, for respectively, 3, 5 and
      10 ng/ml compared with control. Moreover, Bolesatine (5 and 10 ng/ml) induces
      InsP3 release in a concentration-dependent manner (114 and 142%) as compared to
      control. In vivo, 24 h after oral administration of bolesatine to rates (20, 100
      and 200 microg/kg), PKC activity is significantly increased in thymus. THe most
      effective doses (100 and 200 microg/kg) give 590-620% increase in cytosolic PKC
      activity and 85-91% increase in total PKC activity as compared to control. This
      PKC activation by bolesatine in rat thymus is directly linked to the mitogenic
      activity observed in vivo. Bolesatine is thus capable of activating the PKC
      directly and/or indirectly (via InsP3 release) during its mitogenic processes.

PMID- 8660142
TI  - Chloropropionic acid-induced alterations in glucose metabolic status: possible
      relevance to cerebellar granule cell necrosis.
AB  - We have examined the effect of L- and D-2-chloropropionic acid (L-CPA and D-CPA)
      on the concentrations of pyruvate, lactate, glucose and beta-hydroxybutyrate in
      the blood at various times after doses which produce cerebellar granule cell
      necrosis. Blood pyruvate and lactate concentrations were reduced in these animals
      4 h after dosing and remained below those of controls for up to 48 h. No changes
      were seen in concentrations of plasma glucose of beta-hydroxybutyrate at any time
      point. Similarly, no changes in cerebellar glucose, pyruvate or lactate were seen
      24 h after 750 mg/kg L-CPA. Oxidation of [14C] pyruvate or [14C] glucose to
      [14CO2] by cerebellar slices from control rats was not altered by the presence of
      L- or D-CPA (1-10 mM for 2 h). Nor were these parameters affected in cerebellar
      slices from rats killed 24 h after a dose of 750 mg/kg L-CPA. We conclude that
      the activation of the pyruvate dehydrogenase complex is unlikely to be a critical
      factor in the selective toxicity of CPA to the cerebellum.

PMID- 8660143
TI  - Detection of the organophosphorus nerve agent sarin by a competitive inhibition
      enzyme immunoassay.
AB  - Two artificial antigens, NalphaNepsilon-di(O,O-diisopropyl) phosphoryl L-lysine
      (DIP)- bovine serum albumin (BSA) conjugate (DIP-BSA) and DIP-KLH (keyhole limpet
      hemocyanin), were synthesized. Antibodies against sarin (O-isopropyl
      methylphosphonofluoridate) were obtained after immunization of rabbits with DIP
      KLH conjugate. A competitive inhibition enzyme immunoassay (CIEIA) was developed
      to detect the organophosphorus nerve agent sarin. The antibody solutions could be
      inhibited by sarin as low as 10(-6) mol/l, and the standard curve was linear over
      3 orders of magnitude. The coefficients of intraassay and interassay variation of
      this method were 5.4-6.2% (n = 11) and 8.0-9.5% (n = 6) at a sarin concentration
      range of 10(-3)-10(-6) mol/l, respectively. The recovery of sarin in water
      samples at the concentration of 5 x 10(-5) mol/l was in the range of 96.8-102.5%.
      The specificity of the antiserum was assessed by comparing the inhibition induced
      by sarin with soman, Vx, isopropyl alcohol and isopropyl methyl phosphonic acid.
      The results showed that less than 5 mmol/l soman, 2 mmol/l Vx, 16 mmol/l
      isopropyl alcohol and 8 mmol/l isopropyl methyl phosphonic acid did not influence
      the determination of sarin in water samples.

PMID- 8660144
TI  - Prediction of the percutaneous penetration and metabolism of dodecyl
      decaethoxylate in rats using in vitro models.
AB  - Percutaneous absorption of a lipophilic surfactant, dodecyl decaethoxylate, can
      be predicted using in vitro models. In vivo, dermal penetration of dodecyl
      decaethoxylate was found to be 22.9% in 48 h. All of the absorbed dodecyl
      decaethoxylate in the rat was metabolised and excreted in expired air as carbon
      dioxide, or in the urine and faeces. Using rat skin mounted in the unoccluded
      flow-through diffusion cell with MEM as receptor fluid, in vivo absorption was
      predicted by the percentage of the applied dose recovered in the stratum corneum,
      epidermis, dermis and receptor fluid at 24 h (25%). Conversely, the penetration
      of dodecyl decaethoxylate was over-predicted in the unoccluded static diffusion
      cell using aqueous ethanol (50% v/v) as the receptor fluid where 49.4% recovered
      in the receptor fluid at 24 h. In vitro models may be used to predict
      percutaneous absorption and reduce animal use, provided a suitable receptor fluid
      is used in which the penetrant is soluble. Dermal metabolism of dodecyl
      decaethoxylate was low and not considered to influence dermal absorption.

PMID- 8660146
TI  - Epilepsy.

PMID- 8660145
TI  - Role of cytochrome P450 in hepatotoxicity induced by di- and tributyltin
      compounds in mice.
AB  - The role of cytochrome P450 in the induction of hepatotoxicity by butyltin
      compounds such as tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC)
      was investigated in vivo. The pretreatment of mice with SKF-525A, which decreased
      hepatic levels of cytochrome P450, suppressed TBTC-induced hepatotoxicity, as
      estimated by serum ornithine carbamyl transferase activity, whereas pretreatment
      with phenobarbital (PB), which increased the levels of cytochrome P450, enhanced
      the hepatotoxicity of TBTC. In the case of DBTC, PB pretreatment enhanced
      hepatotoxicity, while SKF-525A had no effect. Under these experimental conditions
      only PB pretreatment was found to increase hepatic levels of tin in mice treated
      with TBTC. These results suggest that hepatic metabolism of butyltin compounds by
      cytochrome P450 is more closely related to the induction of hepatotoxicity by
      TBTC than by DBTC. The active tin compounds formed during hepatic metabolism,
      which are responsible for induction of hepatotoxicity, will be discussed.

PMID- 8660147
TI  - Vigabatrin and carbamazepine monotherapy for newly diagnosed epilepsy.

PMID- 8660148
TI  - Motor changes in presymptomatic Huntington disease gene carriers.
AB  - OBJECTIVE: To determine whether changes in motor function and reaction time are
      present in presymptomatic individuals carrying the Huntington disease (HD)
      allele. DESIGN: A case-control, double-blind study comparing asymptomatic at-risk
      subjects, with or without the HD allele, and subjects clinically determined to
      have early manifest HD. SETTING: The Department of Medical and Molecular Genetics
      at Indiana University School of Medicine, Indianapolis. PARTICIPANTS: We studied
      383 patients at risk for HD. Each subject was asymptomatic by self-report.
      MEASURES: Genotype for the HD allele was determined by polymerase chain reaction
      testing. A battery of 8 physiological tests measuring speed of movement and
      reaction time was performed with a computer-driven system. RESULTS: Following
      neurologic examination, 17 of the 120 gene carriers (GCs) had symptoms sufficient
      for a clinical diagnosis of manifest HD. The remaining 103 GCs were designated
      presymptomatic GCs. When the non-GCs were compared with the presymptomatic GCs (1
      way analysis of covariance and the Fisher protected t test), results on 3 of the
      8 physiological tests--movement time, movement time with decision, and auditory
      reaction time--were different. Additionally, the number of trinucleotide (CAG)
      repeats significantly correlated with test performance for movement time with
      decision and visual reaction time with decision when both the entire group of GCs
      and the presymptomatic GCs alone were considered. CONCLUSION: These results
      suggest that subtle subclinical changes in motor function are present in
      presymptomatic individuals who have inherited the HD allele.

PMID- 8660149
TI  - Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or
      CAG repeat length in Huntington's disease.
AB  - OBJECTIVES: To investigate the hypothesis that psychiatric disturbances in
      Huntington's disease are related to degree of cognitive or motor compromise and
      to determine correlations between CAG repeat length within the gene for
      Huntington's disease and disease severity. DESIGN: Consecutive series of patients
      with Huntington's disease. SETTING: Neurological specialty hospital. PATIENTS:
      Seventeen men and 12 women from 24 families. MAIN OUTCOME MEASURES: The Hamilton
      Psychiatric and Anxiety Rating Scales and Brief Psychiatric Rating Scale were
      used to assess psychiatric disturbances; Folstein's Quantified Neurological
      Examination to evaluate motor status; and the Mini-Mental State Examination,
      Raven Progressive Matrices), Phonemic Verbal Fluency Test, Short Tale Test,
      Visual Search Test, and Benton's Visual Orientation Line Test to evaluate
      cognitive function. The length of the CAG repeat sequence in the Huntington's
      gene was determined by quantitative polymerase chain reaction. RESULTS: Cognitive
      test scores correlated significantly with each other; of these, results of the
      Visual Search and Short Tale tests correlated significantly with the Folstein's
      Quantified Neurological Examination score (P = .05 and P = .03, respectively).
      Results of the Folstein's Quantified Neurological Examination also correlated
      with the illness duration and the length of the CAG repeat. Although psychiatric
      scores correlated significantly among themselves (P < .01), neither cognitive
      compromise, motor deterioration, nor CAG length were related to the extent of
      psychiatric compromise. Patients who were depressed when they were examined
      tended to have a history of psychiatric disorders. CONCLUSIONS: The lack of
      correlation between disease severity and psychiatric disturbances indicates that
      psychiatric disorders progress nonlinearly, possibly because of differential
      degeneration of the striatal-cortical circuits; the possibility that psychiatric
      disorders are prevalent in certain families with a member who has Huntington's
      disease is being further investigated. The lack of correlation between CAG length
      and cognitive and psychiatric variables needs further investigation.

PMID- 8660150
TI  - Neurological signs, aging, and the neurodegenerative syndromes.
AB  - OBJECTIVES: To identify the prevalence of neurological signs said to be
      associated with "normal" aging in subjects 75 years and older. To examine the
      association of these signs with age, stroke, the neurodegenerative diagnoses
      (dementia, cognitive impairment, gait ataxia, gait slowing, and parkinsonism),
      and systemic diseases. DESIGN: Subjects participated in a standardized clinical
      history, examination, neurological evaluation, and neuropsychological assessment
      battery. A linear regression model that allowed the simultaneous consideration of
      multiple parameters was used to assess the independent contribution of age and
      disease to the presence of the signs. Correlations between the signs and age in
      the subgroup free of neurological diagnoses were performed. SETTING: Community
      based study in Sydney, Australia. PARTICIPANTS: A random sample of 647 community
      dwelling subjects older than 75 years. MAIN OUTCOME MEASURES: Standardized
      neurological examination in 537 subjects. RESULTS: With the exception of impaired
      vibration sense (beta = .009, P < .01), loss of upward gaze (beta = .005, P <
      .01), and bradykinesia (beta = .005, P < .01), all signs were associated with the
      neurodegenerative syndromes and stroke. Analysis of the subgroup free of
      neurological diagnoses confirmed these findings. Apart from impaired vibration
      sense of the thumbs (r = 0.22, P < .01) and gait instability (r = 0.20, P < .05),
      no significant associations with age were identified. CONCLUSION: It is not aging
      to which many neurological signs should be attributed, but rather to the
      neurodegenerative syndromes that accompany aging.

PMID- 8660151
TI  - An increased frequency of patent foramen ovale in patients with transient global
      amnesia. Analysis of 53 consecutive patients.
AB  - OBJECTIVE: Alerted by the number of patients with transient global amnesia (TGA)
      in whom Valsalvalike activities immediately preceded the onset of TGA, we have
      investigated the frequency of patent foramen ovale (PFO) as the prerequisite for
      paradoxical embolism. DESIGN: Case series with comparison to a control group.
      SETTING: Hospitalized and ambulatory patients at the neurological departments of
      the Alfried Krupp Hospital, Essen, Germany, and the Rheinisch-Westfalische
      Technische Hochschule, Aachen, Germany. PATIENTS: Fifty-three consecutive
      patients with TGA were evaluated by the 2 centers between 1988 and 1995. RESULTS:
      Using contrast transcranial Doppler sonography we have observed a PFO in 55% of
      the patients with TGA, compared with 27% of a control group of 100 patients. This
      difference was statistically significant (P < .01). Twenty-five patients with TGA
      (47%), 15 of them with a proven PFO, reported a precipitating activity, such as
      the lifting of heavy weights, immediately before the TGA occurred. CONCLUSIONS:
      In addition to other pathological mechanisms, paradoxical embolism with
      temporobasal ischemia could possibly play a role in the clinical syndrome of TGA.
      This hypothesis could explain the frequent observation of preceding Valsalvalike
      activities in patients with TGA.

PMID- 8660152
TI  - School problems in Tourette's syndrome.
AB  - BACKGROUND: A retrospective study of 138 children with Tourette's syndrome for
      associated school problems revealed that at the time of initial evaluation, 64
      subjects (46%) experienced a school-related problem. OBJECTIVE: To survey a
      childhood population with Tourette's syndrome to explore the contributions of
      neurobehavioral concomitants to academic difficulties. RESULTS: A diagnosis of a
      specific learning disorder had previously been made in 30 (22%) of 138 children.
      Among the 108 without a diagnosis of learning disorder, 36 (33%) experienced
      school difficulties defined as grade retention (16 [15%]) and/or special
      education placement (41 [38%]). Regression analysis of subjects without a
      diagnosis of learning disability revealed that the presence of attention-deficit
      hyperactivity disorder served as a significant predictor of school problems.
      CONCLUSIONS: Tics represented the primary reason for referral, but did not emerge
      as a significant predictor of academic problems. Rather, school-related
      difficulties appeared to be strongly associated with comorbid attention-deficit
      hyperactivity disorder.

PMID- 8660153
TI  - Detection of nontraumatic comatose patients with no benefit of intensive care
      treatment by recording of sensory evoked potentials.
AB  - OBJECTIVES: To determine the predictive ability of sensory evoked potential
      recordings in nontraumatic comatose patients. To evaluate the hypothesis that
      patients with bilateral absent cortical responses ultimately die despite long
      term intensive care treatment. DESIGN: Prospective cohort study. SETTING: Medical
      intensive care unit (ICU) of a university hospital. PATIENTS: Four hundred forty
      one adult nontraumatic comatose patients (unarousable unresponsiveness to
      external stimulation, Glasgow Coma Score < or = 7) from various causes. Six
      hundred seventy-six sensory evoked potential measurements were performed within 7
      days after onset of coma. MAIN OUTCOME MEASURES: Death or survival to hospital
      discharge. RESULTS: Eighty-six patients (20%) had a bilateral loss of the
      cortical evoked potential N20 peak. Despite long-term intensive care treatment,
      all died without awakening from coma (mortality rate, 100%; 95% confidence
      interval, 96-100). The mean stay at the ICU after evoked potential measurement
      until death was 8.1 days (697 patient days). The overall cost of ICU management
      for these 86 patients accounted for approximately $1,324,300. In the remaining
      355 comatose patients with preserved cortical N20 peak, 148 (42%) survived and
      207 (58%) died. In this latter group of patients, cervicomedullary N13 to
      cortical N20 conduction time was prolonged in nonsurvivors (mean +/- SD, 6.7 +/-
      1.3 milliseconds) compared with that in survivors (mean +/- SD, 6.4 +/- 1.2
      milliseconds, P < .05) and healthy controls (mean +/- SD, 5.5 +/- 0.4
      milliseconds, P < .05). Although this difference is statistically significant, a
      preserved N20 peak is not useful to discriminate whether the individual patient
      will survive (N13-N20 conduction time of > 7 milliseconds had a positive
      predictive value of correct prediction of death of 0.67). CONCLUSIONS: Recording
      of sensory evoked potentials identifies a subgroup of adult nontraumatic comatose
      patients with a mortality rate of 100% in our sample. In these patients, advanced
      intensive care treatment should be withdrawn to provide limited ICU resources for
      patients with higher probability of favorable outcome. We emphasize that these
      results are not applicable to comatose patients following closed head trauma and
      particularly not to children.

PMID- 8660154
TI  - Evaluation of the autonomic cardiovascular response in Arnold-Chiari deformities
      and cough syncope syndrome.
AB  - OBJECTIVE: To study the autonomic control of heart rate in patients with Arnold
      Chiari deformity types I and II who exhibit the signs and symptoms of cough
      syncope syndrome. DESIGN: Prospective, clinical descriptive study. SETTING:
      University clinical research center. PATIENTS: Nine patients with Arnold-Chiari
      deformity and cough syncope syndrome. INTERVENTIONS: None. MAIN OUTCOME MEASURES:
      Changes in heart rate, blood pressure, and electrocardiograms for power spectral
      analysis of heart rate variability were studied in the supine and standing
      positions, preoperatively (n = 9) and postoperatively (n = 5). RESULTS:
      Preoperatively, 8 (89%) of 9 patients increased their heart rate after postural
      change from supine to standing (mean +/- SD delta = 13 +/- 13 beats per minute
      [bpm]). Postoperatively, 4 (80%) of the 5 patients exhibited a greater increase
      in standing heart rate (mean delta = 19 +/- 16 bpm) compared with preoperative
      values. Changes in systolic, diastolic, and mean blood pressure with postural
      change were variable. Preoperatively, all patients exhibited abnormal control of
      heart rate in response to postural change. Three patients (33%) showed an
      abnormal decrease in low-frequency heart rate power (mean delta = -27 +/- 35
      bpm2); the remaining 6 (67%) demonstrated an abnormal increase in high-frequency
      heart rate power (mean delta = 25 +/- 41 bpm2). All patients were clinically
      asymptomatic at 2 months after surgery. A normal spectral response to postural
      change was demonstrated in heart rate power in all 5 patients who were
      reevaluated postoperatively, with an increase in low-frequency power (mean delta
      = 33 +/- 21 bpm2) and a decrease in high-frequency power (mean delta = -21 +/- 23
      bpm2). CONCLUSIONS: Patients with cervicomedullary anatomic abnormalities caused
      by Arnold-Chiari deformities may exhibit abnormal autonomic control of heart
      rate, and the autonomic control of their heart rate returns to a normal pattern
      after surgical palliation in conjunction with resolution of clinical symptoms.

PMID- 8660155
TI  - A comparison of alternative methods of screening for dementia in clinical
      settings.
AB  - OBJECTIVE: To compare 3 approaches to screening for dementia: cognitive testing,
      informant report, and neurovisual assessment in a clinical environment. SETTING:
      A university hospital in Geneva, Switzerland. PATIENTS: Subjects were 76 patients
      admitted to the Geriatric Hospital or outpatients assessed at the Memory Clinic
      of the Hospitals of the University of Geneva School of Medicine in Geneva,
      Switzerland. Thirty-three met criteria for dementia and 11 for depression based
      on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition,
      Revised. MAIN OUTCOME MEASURES: Performance in French-language versions of the
      Mini-Mental State Examination, the Informant Questionnaire on Cognitive Decline
      in the Elderly, and the Clinical Antisaccadic Eye Movement Test. RESULTS: All
      tests significantly discriminated cases of dementia from noncases. The receiver
      operator characteristic analysis demonstrated that the Mini-Mental State
      Examination and the Informant Questionnaire on Cognitive Decline in the Elderly
      were more efficient screening measures for dementia than the Antisaccadic Eye
      Movement Test in this setting. Unlike the Mini-Mental State Examination, the
      Informant Questionnaire on Cognitive Decline in the Elderly was unrelated to
      patients' educational attainment or premorbid intelligence. The previously
      reported strong relationship between the Mini-Mental State Examination and the
      Antisaccadic Eye Movement Test was not replicated in these patients. CONCLUSIONS:
      Both cognitive testing and informant report are efficient methods of screening
      for dementia in clinical settings. Factors such as sensorimotor disability or
      informant availability may dictate the viability of each approach in individual
      application. The performance of the Antisaccadic Eye Movement Test precludes
      recommending its use as a screen for dementia without further research into its
      performance.

PMID- 8660156
TI  - Frequency of dementia in Parkinson disease.
AB  - OBJECTIVE: To investigate the frequency of dementia in patients with Parkinson
      disease (PD). DESIGN: Community-based prevalence study. SETTING: The study
      population comprised 220,858 inhabitants from the Rogaland County, Norway.
      PARTICIPANTS: Almost 400 participants were examined by a neurologist, and 245
      were given the diagnosis of PD and included in the study. MEASUREMENTS: Mental
      functioning was rated with the Mini-Mental State Examination; Gottfries, Brane,
      and Steen scale; and the intellectual subscale of the Unified Parkinson's Disease
      Rating Scale. Criteria from the Diagnostic and Statistical Manual of Mental
      Disorders, Third Edition, Revised, were applied during a semistructured interview
      to determine the diagnosis of dementia. RESULTS: Dementia was found in 67
      patients (27.7%). Patients with dementia were older at the time of the study and
      at onset of PD and had had PD longer than the patients without dementia. Major
      depression was more common among patients with dementia (23%) than among patients
      without dementia (2.3%) (chi 2 , P < .001), and patients with dementia were more
      often institutionalized than those without dementia (62% vs 6%, respectively, chi
      2 , P < .001). Atypical neurologic features for idiopathic PD (ie, early
      occurrence of autonomic failure, symmetrical disease presentation, and only
      moderate response to a dopamine agonist) were associated with more severe
      dementia of a higher frequency rate and with lower scores on cognitive rating
      scales. CONCLUSION: Approximately one quarter of the patients with PD had
      dementia with the motor manifestations of PD. Dementia was associated with
      depression, institutionalization, older age at onset of PD, and atypical
      neurologic features.

PMID- 8660157
TI  - Characteristics of the dysarthria of multiple system atrophy.
AB  - OBJECTIVE: To characterize the dysarthria in patients with multiple system
      atrophy (MSA). DESIGN: Motor speech examinations, consisting of oral motor, oral
      agility, and perceptual speech analysis, were performed on 46 patients with MSA.
      SETTING: University department of neurology referral center. RESULTS: All
      patients had dysarthria with combinations of hypokinesia, ataxia, or spasticity.
      Thirty-two patients had all 3 components, 13 had 2 components, and 1 had only 1
      component. In most patients the hypokinetic components were the most severe.
      Hypokinetic components predominated in 22 patients (48%), whereas ataxic
      components predominated in 16 (35%), and spastic components in 5 (11%). In 1
      patient (2%) the hypokinetic and spastic components were equal and greater than
      the ataxic components, and in 1 patient (2%) the hypokinetic and ataxic
      components were equal and greater than the spastic components. One patient (2%)
      had only ataxic dysarthria. The predominant type of dysarthria corresponded well
      to the subtype of MSA. CONCLUSIONS: The finding of a mixed dysarthria with
      combinations of hypokinetic, ataxic, and spastic components is consistent with
      both the overall clinical and the neuropathologic changes in MSA. Motor speech
      examination can provide helpful information in evaluating patients who might have
      MSA.

PMID- 8660159
TI  - Twelfth-nerve palsy. Analysis of 100 cases.
AB  - OBJECTIVE: To describe the causes and characteristics of hypoglossal nerve palsy.
      DESIGN: A review of 26 years of personal experience in a large public hospital.
      RESULTS: Twelfth-nerve palsies usually appear as signs rather than symptoms.
      Tumors, predominantly malignant, produced nearly half of the palsies (49 cases),
      while gunshot wounds made trauma (12) the second most common cause. Stroke (6),
      hysteria (6), multiple sclerosis (6), surgery (5), Guillain-Barre neuropathy (4),
      and infection (4) together accounted for about one third of the patients.
      CONCLUSION: Twelfth-nerve palsy proved to be an ominous sign, with only 15% of
      patients experiencing complete or nearly complete recovery.

PMID- 8660158
TI  - Regional brain tissue composition in children with hydrocephalus. Relationships
      with cognitive development.
AB  - OBJECTIVE: To determine whether children with shunted hydrocephalus show
      variations in regional brain tissue composition that relate to cognitive
      functions. DESIGN: Nonequivalent control group. PATIENTS AND METHODS: Magnetic
      resonance imaging (MRI) and cognitive skills assessments were obtained on 28
      children, 6 to 9 years of age, with shunted hydrocephalus and 13 normal control
      subjects comparable in age, gender, ethnicity, and socioeconomic status. Three
      consecutive MRI slices below the vertex were segmented using a fuzzy clustering
      algorithm to separate pixels into gray matter, white matter, and cerebrospinal
      fluid (CSF) in quadrants representing left and right anterior and posterior brain
      regions. The cognitive skills assessments included the Wechsler Intelligence
      Scale for Children-Revised verbal and performance IQ scores, neuropsychological
      composites of language and visuospatial skills, a measure of visuomotor
      dexterity, and 2 measures of problem-solving abilities. The MRI data were
      analyzed in a group x tissue x hemisphere x region analysis of variance. Spearman
      rho correlations were computed within the hydrocephalus group between the MRI and
      cognitive measures. RESULTS: Children with hydrocephalus showed reductions in
      overall gray matter percentages and corresponding increased CSF percentages that
      were more pronounced in posterior than anterior regions of both hemispheres.
      White matter percentages were reduced in children with hydrocephalus only in the
      left posterior quadrant. Correlations of posterior, but not anterior, CSF and
      gray matter percentages were significant with verbal and performance IQ scores
      and language, visuospatial, and visuomotor dexterity skills, but not with problem
      solving abilities. Children with hydrocephalus who had proportionately greater
      posterior than anterior CSF percentages had significantly poorer visuomotor
      dexterity and visuospatial skills than did hydrocephalic children with
      proportionate CSF percentages. CONCLUSION: Regional variations in brain tissue
      composition in children with shunted hydrocephalus correlate with a variety of
      cognitive and visuomotor functions.

PMID- 8660160
TI  - Gilles de la Tourette and the discovery of Tourette syndrome. Includes a
      translation of his 1884 article.
AB  - In 1885, Gilles de la Tourette described 9 patients who suffered from a disorder
      characterized by involuntary movements, echolalia, echopraxia, coprolalia, and
      strange, uncontrollable sounds. In his article, Gilles de la Tourette presented
      some earlier descriptions of this disorder. To appreciate what first led Gilles
      de la Tourette to Tourette syndrome, however, it is necessary to turn to an
      article that he published a year earlier. In his 1884 article, Gilles de la
      Tourette cited several movement disorders that he thought were similar to each
      other, yet different from true chorea. After describing these disorders, namely,
      "jumping" of Maine, latah of Malaysia, and miryachit of Siberia, he briefly
      mentioned a boy in Charcot's ward in Paris, France, who seemed to exhibit the
      same condition. In an addendum, he then said that other cases were now surfacing
      in Paris and that he would write an additional article describing these
      individuals. To achieve a more thorough understanding of the events that led
      Gilles de la Tourette to his 1885 description of the disorder that now bears his
      name, we herein present an English-language translation of his 1884 article along
      with a commentary.

PMID- 8660161
TI  - Assessment of cytomegalovirus retinitis. Clinical evaluation vs centralized
      grading of fundus photographs. Studies of Ocular Complications of AIDS Research
      Group, AIDS Clinical Trials Group.
AB  - BACKGROUND: In the Foscarnet-Ganciclovir Cytomegalovirus (CMV) Retinitis Trial,
      time to first progression of newly diagnosed CMV retinitis was similar in the 2
      treatment groups but was shorter when assessed by grading of fundus photographs
      at a central reading center than when assessed at the participating clinical
      centers. This report describes the extent and causes of this disagreement and
      considers the implications of the findings for clinical practice and future
      research. METHODS: Clinical findings and photographic gradings were compared for
      extent and activity of retinitis at baseline and during follow-up. In selected
      cases of disagreement, the photographs and summaries of gradings and clinical
      findings were reviewed concurrently to determine the cause of disagreement.
      RESULTS: Movement of the border of retinitis was observed sooner and activity of
      the border was considered to have increased more often at the reading center than
      at the clinical centers. Disagreements on time to first progression were more
      frequent when degree of border movement was small (odds ratios [ORs] for several
      comparisons ranged from 1.7 to 5.2), when border activity was judged to have
      decreased or remained the same since the preceding visit (OR, 2.0-193), and when
      retinitis at baseline did not involve zone 1 (the area within 1 disc diameter of
      the disc or within 2 disc diameters of the center of the macula [OR, 1.4-3.6]).
      There were 2 important causes of disagreement between clinical center and reading
      center. First, difficulty was encountered clinically in recognizing retinitis
      border movement in the absence of an obvious increase in border activity. Second,
      the reading center used a threshold for border movement small enough to be
      crossed by an initial expansion of retinitis borders occurring within 2 to 5
      weeks of enrollment in some patients who were responding favorably to treatment
      (in that retinitis was becoming inactive and showed no further progression for
      many weeks). CONCLUSIONS: Comparisons of photographs from the current visit with
      those from several previous visits may increase clinicians' abilities to detect
      progression promptly. The use of additional outcome measures by reading centers,
      such as border movement of 1500 microns or more and change in area of retina
      involved by retinitis, may provide more accurate and useful comparisons of
      treatments. In making such comparisons, centralized photographic grading has the
      advantages of greater reproducibility and lesser risk of observer bias.

PMID- 8660162
TI  - Special issue: AIDS and the eye.

PMID- 8660163
TI  - Cytomegalovirus retinitis and viral resistance. Prevalence of resistance at
      diagnosis, 1994. Cytomegalovirus Retinitis and Viral Resistance Study Group.
AB  - OBJECTIVE: To determine the prevalence of cytomegalovirus (CMV) isolates
      resistant to ganciclovir sodium or foscarnet sodium at the time of diagnosis of
      CMV retinitis, prior to the initiation of therapy. DESIGN: Prospective
      epidemiologic study. SETTING: An acquired immunodeficiency syndrome ophthalmology
      clinic. PATIENTS: Patients with acquired immunodeficiency syndrome and newly
      diagnosed CMV retinitis. INTERVENTION: Culturing blood and urine samples for CMV
      and testing of all positive isolates for sensitivity to ganciclovir and
      foscarnet. MAIN OUTCOME MEASURE: Prevalence of the following: blood culture
      isolates resistant to ganciclovir (inhibitory concentration 50% [IC50] > 5.5
      mumol/L) or foscarnet (IC50 > 400 mumol/L) and urine culture isolates resistant
      to ganciclovir or foscarnet. RESULTS: Forty-nine patients were enrolled during a
      13-month period. Forty-four patients had blood culture samples that could be
      evaluated; of these, 66% were positive (59% of patients). Thirty-four patients
      had urine cultures that were evaluable; of these, 82% were positive (57% of
      patients). Overall, 78% of patients had either a urine or blood culture sample
      positive for CMV. No blood culture isolates were resistant to ganciclovir, and
      only 1 urine culture isolate (2% of patients) was resistant to ganciclovir. Three
      percent of blood culture isolates and 4% of urine culture isolates (2% and 2% of
      patients, respectively) were resistant to foscarnet. Overall, 4% of patients had
      either a blood or urine culture isolate resistant to foscarnet. CONCLUSION:
      Resistance to ganciclovir or foscarnet at the time of diagnosis of CMV retinitis
      is uncommon.

PMID- 8660164
TI  - Use of the ganciclovir implant in the treatment of recurrent cytomegalovirus
      retinitis.
AB  - OBJECTIVE: To evaluate the efficacy of the ganciclovir implant in the treatment
      of recurrent cytomegalovirus (CMV) retinitis. METHODS: Patients with acquired
      immunodeficiency syndrome and recurrent CMV retinitis were evaluated for entry
      into the study. A ganciclovir implant was inserted in 91 eyes of 70 patients
      between October 1992 and October 1995. The efficacy of the implant and visual
      results were retrospectively reviewed. RESULTS: Fifty-three (76%) of 70 eyes had
      inactive CMV retinitis 1 month postoperatively (positive initial response).
      Twenty-one eyes of 19 patients had less than 1 month of follow-up. Nineteen (36%)
      of 53 eyes developed recurrent CMV retinitis. The median time to recurrence for
      those patients with a positive initial response was 7 months. Forty-eight (84%)
      of 57 patients with follow-up longer than 1 month after implant insertion in the
      first eye received systemic anti-CMV medication during the study. The cumulative
      risk for developing a retinal detachment was 23% at 6 months following implant
      insertion. Other complications included vitreous hemorrhage, hyphema, and
      suprachoroidal implantation of the device. CONCLUSION: The ganciclovir implant is
      effective as an adjunct to continued systemic therapy in those patients with
      recurrent CMV retinitis.

PMID- 8660165
TI  - Occurrence of cytomegalovirus retinitis after human immunodeficiency virus
      immunosuppression.
AB  - OBJECTIVE: To estimate the incidence and prevalence of cytomegalovirus retinitis
      (CMV-R) in late-stage human immunodeficiency virus type 1 disease. DESIGN: Cohort
      study. SETTING: The Multicenter AIDS Cohort Study, an ongoing 10-year study of
      human immunodeficiency virus type 1-infected homosexual men with semiannual
      visits and CD4+ cell testing. STUDY PARTICIPANTS: Three hundred sixty-seven human
      immunodeficiency virus type 1-infected men from the Multicenter AIDS Cohort Study
      who were receiving zidovudine and Pneumocystis carinii prophylaxis and who had
      CD4+ cell counts fall below 0.10 x 10(9)/L (100/microL). MAIN OUTCOME MEASURES:
      Kaplan-Meier-type estimates for various longitudinal quantifications of incidence
      and prevalence of CMV-R were obtained. RESULTS: Among these 367 individuals,
      cytomegalovirus disease developed in 103, of whom 73 (71%) had ocular
      complications. At 4 years after the first CD4 cell count ( < 0.10 x 10(9)/L), the
      probability for these subjects to have (1) remained living without CMV-R was 11%,
      (2) died without experiencing CMV-R was 66%, (3) experienced CMV-R and be living
      was 6%, and (4) experienced CMV-R and died was 18%. During these 4 years, there
      was a 25% chance for the development of CMV-R and, on average, 0.211 person-years
      of CMV-R morbidity. Among those subjects in whom CMV-R developed, about 19% did
      have CMV-R before a CD4+ cell count of less than 0.05 x 10(9)/L ( < 50/microL)
      was observed, and 81% had CMV-R after the CD4+ cell count reached this threshold.
      CONCLUSION: These estimates may be relevant to current clinical practice and help
      in allocating resources and planning for treatment and prophylaxis against
      cytomegalovirus disease.

PMID- 8660166
TI  - Effectiveness of entoptic perimetry for locating peripheral scotomas caused by
      cytomegalovirus retinitis.
AB  - OBJECTIVE: To determine the the effectiveness of random particle motion,
      presented on a computer monitor, as a noninvasive test for detecting
      cytomegalovirus retinitis. DESIGN: A prospective masked study in which patients
      were asked to trace out any disturbances on a transparency placed over a computer
      monitor that displayed continuous random particle motion, while the patient
      fixated on a central spot (entoptic perimetry). SETTING: The Acquired
      Immunodeficiency Syndrome Ocular Research Unit at the University of California,
      San Diego, in La Jolla. PATIENTS: Twenty-two men with cytomegalovirus retinitis
      who were positive for human immunodeficiency virus, 11 men without
      cytomegalovirus retinitis who were positive for human immunodeficiency virus, and
      eight men who were negative for human immunodeficiency virus. INTERVENTION: None.
      MEASUREMENTS: Sensitivities and specificities were used to compare the results of
      entoptic perimetry with fundus photographs. RESULTS: Entoptic perimetry
      demonstrated a 95% sensitivity and a 95% specificity in detection of
      cytomegalovirus retinitis. CONCLUSION: Entoptic perimetry may be an effective and
      inexpensive screening test for cytomegalovirus retinitis in hospitals and
      community clinics.

PMID- 8660167
TI  - Acquired immunodeficiency syndrome--associated herpes simplex virus retinitis.
      Clinical description and use of a polymerase chain reaction--based assay as a
      diagnostic tool.
AB  - OBJECTIVES: To describe 2 patients with acquired immunodeficiency syndrome who
      experienced a rapidly progressive, bilateral retinitis due to herpes simplex
      virus (HSV) (1 case due to HSV type 1 [HSV-1] and 1 case due to HSV type 2 [HSV
      2] and to present a novel diagnostic polymerase chain reaction (PCR)-based assay.
      METHODS: The presentation, clinical course, and diagnostic PCR-based assay used
      to make the diagnosis of HSV retinitis in 2 patients with acquired
      immunodeficiency syndrome are described. RESULTS: Both patients experienced a
      rapidly progressive, bilateral retinal necrosis associated with intraretinal
      hemorrhages and a diffuse vasculitis. The PCR-based assays demonstrated HSV DNA
      in the vitreous specimens from the 2 patients. Restriction analysis on the
      amplified DNA showed HSV-1 in 1 patient and HSV-2 in the second patient. The
      diagnosis was supported in both patients by the occurrence of a herpes simplex
      like encephalitis, and in 1 patient by a positive vitreous culture. The HSV-1
      associated vasculitis affected primarily the retinal arterioles, with marked
      capillary dropout and occlusion of larger arcade vessels. In contrast, the HSV-2
      associated vasculitis affected the retinal veins more than the arterioles, and
      was associated with an exudative retinal detachment. CONCLUSIONS: To our
      knowledge, these are the first 2 patients with acquired immunodeficiency syndrome
      in whom HSV has been implicated as the sole cause of a rapidly progressing,
      necrotizing retinitis. Combined PCR and restriction analysis of vitreous samples
      from such patients is a useful and highly specific means of diagnosing HSV-1 and
      HSV-2 retinitis.

PMID- 8660168
TI  - Measuring visual function and quality of life in patients with cytomegalovirus
      retinitis. Development of a questionnaire. Studies of Ocular Complication of AIDS
      Research Group.
AB  - OBJECTIVE: To develop and test a brief questionnaire designed to assess visual
      symptoms, visual function in daily activities, and impact of treatment
      administration in patients with cytomegalovirus retinitis related to acquired
      immunodeficiency syndrome. DESIGN: Observational cross-sectional study. Patients
      were recruited in June and July 1992. SETTING: Seven university-based sites
      participating in the Studies of Ocular Complications of AIDS. PATIENTS: Twenty
      six subjects enrolled in a randomized trial that compared foscarnet and
      ganciclovir for the treatment of cytomegalovirus retinitis. MAIN OUTCOME MEASURES
      AND ANALYSIS: Distributions of scores, reliability, and validity of newly
      developed scales to assess visual function, visual symptoms, and global vision.
      Spearman rank correlations with 95% confidence intervals were used to test
      hypothesized relationships between scale scores, visual acuity, visual field, and
      findings from visual examination. RESULTS: The final 18-item self-administered
      questionnaire required 5 minutes to complete. The new scales had high internal
      consistency (Cronbach alpha = .81 to .94). As hypothesized, patient-reported
      vision scores decreased with greater abnormalities found on ophthalmologic
      examination. Visual symptoms were most strongly related to findings in the worse
      eye. Visual function and global vision scores were moderately correlated with
      findings from visual testing and examination, and less strongly related to
      general health perceptions. Patients reported considerable impairment: 42%
      reported blurred vision; 40%, difficulty reading; 44%, difficulty driving; and
      40%, that treatment interfered with social activities; 50% reported substantial
      trouble with their vision. CONCLUSIONS: The brief questionnaire developed to
      assess patient-reported visual function in cytomegalovirus retinitis appears
      reliable and valid as a measure of performance of vision-related activities,
      visual symptoms, and the impact of treatment administration. Further research is
      needed to test its utility as an outcome measure in longitudinal studies of
      cytomegalovirus retinitis.

PMID- 8660169
TI  - Clinical vs photographic assessment of treatment of cytomegalovirus retinitis.
      Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial Report 8. Studies of Ocular
      Complications of AIDS Research Group, AIDS Clinical Trials Group.
AB  - OBJECTIVE: To illustrate 2 common problems encountered in evaluating the response
      of cytomegalovirus retinitis to antiviral treatment and to consider their
      clinical importance. METHODS: Four illustrative cases were selected from 76 cases
      reviewed during a study that compared clinical evaluation and centralized grading
      of fundus photographs in the assessment of cytomegalovirus retinitis. RESULTS:
      These cases illustrate 2 problems noted during the review: (1) that progression
      of retinitis may be difficult to recognize clinically in the absence of an
      obvious increase in retinitis border activity and (2) that movement of retinitis
      borders by 750 microns or more (the principal criterion used to define retinitis
      progression) during the initial 4 weeks of treatment does not necessarily
      represent an unfavorable response to treatment. CONCLUSIONS: Ophthalmologists who
      participate in the management of cytomegalovirus retinitis should be aware of the
      subtlety of retinitis activity that sometimes accompanies progression in patients
      undergoing treatment with currently approved agents. Side-by-side comparison of
      good-quality photographs from the current visit (as soon as they are available)
      with photographs from previous visits, using adequate illumination and
      magnification, may be helpful in detecting progression promptly. When applying
      the results of clinical trials to clinical practice, clinicians should not equate
      retinitis border movement of 750 microns or more during the first 4 weeks of
      treatment with treatment failure.

PMID- 8660171
TI  - General principles for AIDS research.

PMID- 8660170
TI  - Maintenance of replicative intermediates in ganciclovir-treated human
      cytomegalovirus-infected retinal glia.
AB  - OBJECTIVES: To characterize the molecular structure of the human cytomegalovirus
      (HCMV) DNA maintained in cultures of human retinal glia following ganciclovir
      treatment and to determine the biological activity of the DNA. METHODS: Cultures
      of human retinal glia were established, infected with HCMV, treated with
      ganciclovir, and embedded in agarose, and the viral DNA was analyzed by field
      inversion gel electrophoresis. RESULTS: The HCMV DNA was found to persist in
      cultures of infected, ganciclovir-treated retinal glial cells in the form of
      replicative intermediates. After removal of ganciclovir, processed forms of DNA
      in the 500-to 1000-kilobase range were found as well as 230-kb unit length
      genome. Infectious virus was recovered after termination of ganciclovir
      treatment. CONCLUSION: The data are consistent with the concept that
      ganciclovir's virostatic nature permits maintenance of HCMV DNA in retinal glia
      in a biologically active form that is capable of replication after removal of the
      drug.

PMID- 8660172
TI  - Acquired immunodeficiency syndrome and the eye--1996.

PMID- 8660173
TI  - Magnifying lenses for use when operating. 1897.

PMID- 8660174
TI  - Cytomegalovirus keratitis in acquired immunodeficiency syndrome.
AB  - A man with acquired immunodeficiency syndrome developed a generalized rash and
      bilateral dendritic epithelial keratitis without retinitis. Cytologic examination
      of superficial corneal scrapings showed many megalosyncytial giant cells that
      were highly characteristic of cytomegalovirus (CMV) infection. Viral cultures
      yielded CMV from 2 separate specimens obtained by corneal epithelial debridement
      from both eyes. The slightly elevated, opaque, branching, nonulcerative
      epitheliopathy recurred after corneal scrapings and persisted despite oral and
      topical antiviral therapy. Stromal keratouveitis subsequently developed. This
      case report confirms that CMV can produce corneal involvement and suggests that
      CMV keratitis may be an emergent complication of acquired immunodeficiency
      syndrome.

PMID- 8660175
TI  - Bilateral endogenous Fusarium endophthalmitis associated with acquired
      immunodeficiency syndrome.
AB  - A 51-year-old man with acquired immunodeficiency syndrome and cytomegalovirus
      retinitis had bilateral endogenous fungal endophthalmitis. Cultures yielded
      Fusarium species. Histopathologic examination showed a severe necrotizing acute
      and granulomatous reaction, with numerous fungal elements in the retina and uveal
      tract. Fungal elements were seen in the lens, sclera, and emissarial vessels.
      Angiopathic infiltration by fungus and widespread thrombosis produced retinal and
      choroidal infarction. In some areas, fungal infection coexisted with
      cytomegalovirus retinitis. The bilateral distribution suggests hematogenous
      seeding of the eyes. The eye findings were the first clinically apparent
      manifestations of fungal disease in this patient.

PMID- 8660176
TI  - Anterior-segment ultrasound biomicroscopy in a patient with AIDS and bilateral
      angle-closure glaucoma secondary to uveal effusions.

PMID- 8660177
TI  - Endogenous bacterial endophthalmitis as a complication of intravenous therapy for
      cytomegalovirus retinopathy.

PMID- 8660178
TI  - Metastatic choroidal abscess in the acquired immunodeficiency syndrome.

PMID- 8660179
TI  - Long-term, successful maintenance of bilateral cytomegalovirus retinitis using
      exclusively local therapy.

PMID- 8660180
TI  - Cataract extraction after silicone oil repair of retinal detachments due to
      necrotizing retinitis.
AB  - Cataract is common after silicone oil repair of retinal detachment due to
      necrotizing retinitis in acquired immunodeficiency syndrome. Surgical management
      has not been reported. Twenty-two eyes of 19 patients were reviewed. The majority
      underwent phacoemulsification with a posterior chamber convexoplano implant
      without iridotomy Complications included capsular fibrosis and hyphema.
      Unpredictable refractions in the first 16 eyes prompted refinement of lens
      calculations and resulted in a reduction in refractive errors. A 3-step
      modification of intraocular lens calculations is recommended: (1) use of specific
      sound velocities to calculate axial length; (2) use of convexoplano lenses; and
      (3) addition of a constant to the lens power to compensate for the refractive
      index of silicone oil. Good surgical technique and accurate lens calculations
      should improve management of cataracts that arise after retinal detachment repair
      with silicone oil in patients with acquired immunodeficiency syndrome.

PMID- 8660181
TI  - Serous retinal detachments in a patient with clinically resistant cytomegalovirus
      retinitis.

PMID- 8660182
TI  - Increased prevalence of HIV-related retinal microangiopathy syndrome in patients
      with hepatitis C.

PMID- 8660183
TI  - Attitudes of veterinarians to undergraduate education in genetics and the use of
      genetics veterinary occupations.
AB  - A questionnaire regarding attitudes to undergraduate education in genetics and
      the subsequent use of that education was sent to 1000 veterinarians registered in
      New South Wales. Three hundred replies to the questionnaire were received and
      analysed. No significant difference in the perceived adequacy of courses at the
      four universities involved in teaching veterinary science was observed. Opinions
      on adequacy of education in genetics were not affected by age, sex or years since
      graduation. The major reason cited for lack of adequacy was that undergraduate
      genetics courses were not practical. Only 17 respondents stated that they were
      never approached for information on genetics or animal breeding, while 76 were
      approached more than 20 times annually for information. Eighty-three respondents
      claimed to deal with more than 20 cases annually that required some knowledge of
      genetics. The results of the questionnaire highlight the importance of genetics
      instruction in undergraduate veterinary education. The questionnaire responses
      also provide insight into how working veterinarians consider that courses in
      genetics could be improved.

PMID- 8660184
TI  - Diagnostic ultrasound in veterinary practice: How safe is it?
AB  - This paper provides information on the safety of ultrasonic diagnostic procedures
      as currently used in veterinary practice. The known mechanisms of action are
      described and selected literature on biological effects of ultrasound is
      reviewed. Current international consensus is presented on the safety of medical
      ultrasound with respect to thermal effects. To date, there is no independently
      verified clinical evidence that the level of exposure delivered to the tissues
      during scanned grey-scale ('B-mode') imaging has any adverse effects. Lung
      haemorrhage has been observed in animal experiments using diagnostic exposures,
      but the effects have not been reported in the foetus. Equipment that uses pulsed
      Doppler transmits higher acoustic outputs in a stationary beam, and can produce
      temperature increases that may have significant biological consequences. When
      considering sonographic and pulsed Doppler examinations of the prenatal animal,
      the safety margins are small and the operator should be aware of the acoustic
      output of the equipment, the exposure time, and the sensitivity of target
      tissues.

PMID- 8660185
TI  - Aggregate testing for the evaluation of Johne's disease herd status.
AB  - This paper examines methods for evaluating herd Johne's disease status that could
      be used in a survey of the cattle industry. Emphasis is placed on aggregate
      testing, a process whereby a random sample of cattle from a herd is assessed
      using an imperfect test, such as an ELISA for detecting antibody in serum.
      Important aggregate test parameters discussed include: sample size, herd-level
      sensitivity, herd-level specificity, the number of reactors used for declaring a
      positive herd result, and the expected within-herd prevalence of disease.
      Aggregate testing may be useful for several livestock diseases. However, problems
      arise when it is applied to Johne's disease because of the poor sensitivity of
      the available diagnostic tests, the low within herd prevalence of infection, and
      clustering of false positives within a herd.

PMID- 8660186
TI  - Enterohaemorrhagic Escherichia coli: a new problem, an old group of organisms.
AB  - All mammals are colonised by Escherichia coli generally at birth and these
      organisms become part of their intestinal flora for the rest of their lives. New
      types are acquired generally by an oral route. Some E coli are pathogenic and
      some may have a far more enhanced ability to colonise the human intestine than
      most others. Recently enterohaemorrhagic E coli have emerged. They can cause a
      number of intestinal illnesses in humans including bloody diarrhoea and
      haemolytic uraemic syndrome. These organisms produce a number of virulence
      factors particularly the Shiga-like toxins (verotoxins). The intestines of
      animals may be the reservoir of these organisms for human infection, and cattle
      particularly have been shown to harbour them. Food, especially undercooked meat
      products, have been associated with a number of outbreaks throughout the world.
      While a certain serotype O157.H7 has been associated with many outbreaks
      throughout the world, other serotypes, particularly O111.H-, have also been
      reported. This latter serotype appears to be more common in Australia.

PMID- 8660187
TI  - An outbreak of haemorrhagic septicaemia associated with Pasteurella multocida
      subsp gallicida in large pig herd.

PMID- 8660188
TI  - Edwardsiella tarda septicaemia in rainbow trout (Oncorhynchus mykiss).

PMID- 8660189
TI  - A survey of diets offered to dogs in metropolitan Perth, Western Australia.

PMID- 8660190
TI  - Pox in ostrich chicks.

PMID- 8660191
TI  - A simplified fluorescence inhibition test for the serotype determination of
      Australian bluetongue viruses.

PMID- 8660192
TI  - The duration of anthelmintic effects of moxidectin and ivermectin in grazing
      sheep.

PMID- 8660193
TI  - A trial comparing the virulence of some South African and Australian bluetongue
      viruses.

PMID- 8660194
TI  - Treatment of gastrointestinal tract impaction of a 2-year-old Asian elephant
      (Elephas maximus).

PMID- 8660195
TI  - The efficacy of diazinon impregnated ear tags against buffalo fly and resulting
      weight gains and diazinon residues in meat and milk.
AB  - Ear tags impregnated with 20% diazinon were evaluated for their efficacy against
      the buffalo fly (Haematobia irritans exigua) on beef cattle in southern
      Queensland. Buffalo fly numbers and weight changes were recorded and diazinon
      residues in tissues of beef cattle and milk from lactating dairy cattle were
      assayed at different time intervals after tagging. In 2-efficacy trials conducted
      over 19 and 20 weeks, the mean numbers of buffalo fly on cattle each fitted with
      ear tags were 1 to 9 and 0 to 16, respectively, in trials 1 and 2, compared with
      44 to 345 and 26 to 306 per head on untreated herds, respectively, despite
      regular spraying of the untreated herd in trial 1 with cypermethrin to reduce fly
      burdens. Percentage buffalo fly control was 96.7 to 99.5% and 89.3 to 100% in the
      2 trials. Cattle fitted with ear tags gained an average of 94 kg body weight
      after 5 months compared with 61 kg in the untreated herd, a net increase of 60%
      in treated animals compared with 28% in the untreated herd. Mean diazinon residue
      concentrations in the fat of perianal tissue biopsies were 0.02 to 0.03 mg/kg 1
      to 8 weeks after tagging. Mean diazinon residue concentrations in the butterfat
      of milk from lactating dairy cattle were 0.01 to 0.04 mg/kg after tagging.

PMID- 8660196
TI  - Echocardiographic evaluation of the effects of medetomidine and xylazine in dogs.
AB  - The echocardiographic effects of medetomidine and xylazine were evaluated in 6
      healthy dogs. Values for echocardiographic variables were significantly different
      from pre-treatment values after administration of both drugs. The effects of
      medetomidine were similar to that of xylazine. Because of their cardiac
      depressant effects, both drugs should be used with care in sick dogs.

PMID- 8660197
TI  - Effects of posture and accumulated airway secretions on tracheal mucociliary
      transport in the horse.
AB  - Tracheal mucociliary clearance was determined in horses by measuring the rostrad
      transport of the radiopharmaceutical 99mtechnetium-sulphur colloid following
      deposition on the tracheal epithelium by intratracheal injection. The effects of
      head position (head elevated to normal standing position vs head lowered) and of
      accumulated purulent secretions on tracheal mucociliary clearance were evaluated
      for the first time in the horse. In normal horses tracheal mucociliary clearance
      was greatly accelerated by lowering the head so that the cranial trachea was
      lower than the caudal trachea. Horses confined with their heads elevated for 24
      hours developed an accumulation of purulent airway secretions (and associated
      increased numbers of bacteria) in the lower respiratory tract and showed a
      decrease in tracheal mucociliary clearance when compared with their previously
      measured rate when the lower airway contained only normal secretions. These
      findings have implications for management practices where horses are prevented
      from lowering their heads, such as transportation and cross-tying, which may
      therefore contribute to lower respiratory tract disease in horses.

PMID- 8660198
TI  - Black soil blindness: a new mycotoxicosis of cattle grazing Corallocytostroma
      infected Mitchell grass (Astrebla spp).
AB  - A new, fatal mycotoxicosis of cattle has been recognised in north-western
      Australia. A feeding trial confirmed the toxicity of a previously unknown species
      of Corallocytostroma that grows on Mitchell grass (Astrebla spp). The disease has
      been colloquially named 'black soil blindness' because its most prominent
      features are its confinement to pastures on black soil, and blindness and death
      of affected animals. Over 500 cattle have died and considerable subclinical
      disease in present. Above average wet season rainfall and extended growing
      seasons may explain the emergence of the fungus. The disease is important because
      cattle production in large areas of Australia utilise Mitchell grass pastures.

PMID- 8660199
TI  - Glomerulopathy in dogs with congenital portosystemic shunts.
AB  - Kidney specimens from 12 dogs with congenital portosystemic shunts were examined
      histologically. Glomerulopathy of variable severity was present in the kidney
      sections of all 12. Marked irregular thickening of the glomerular capillary wall
      was the most prominent pathological change, the renal interstitium being largely
      unaffected. The severity of lesions was not correlated with the age of dogs at
      the time of necropsy. An immunoperoxidase technique failed to demonstrate
      significant IgA or IgG deposition in affected glomeruli. Proteinuria was
      generally mild or absent despite significant glomerular lesions, except in dogs
      with concurrent urinary tract infection.

PMID- 8660200
TI  - Use of enzyme-linked immunoassays for antibody to types C and D botulinum toxins
      for investigations of botulism in cattle.
AB  - The development of specific enzyme-linked immunosorbent assays (ELISA) for
      antibody to types C and D Clostridium botulinum toxins for investigation of
      botulism in cattle is described. Partially purified type C and D toxins were used
      as antigens to develop these ELISAs. Specificity of the ELISAs was evaluated on
      sera from 333 adult beef and dairy cattle from areas with no history or evidence
      of botulism in animals or water birds. The test was also evaluated on sera from
      41 herds that included herds vaccinated against botulism, confirmed botulism
      cases and herds from areas where the disease is considered endemic. The ELISAs
      detected the presence of antibody to botulinum toxins in samples from vaccinated
      cattle and both convalescent and clinically normal animals from unvaccinated
      herds with outbreaks of botulism. Antibody was also found in unvaccinated animals
      from herds in which there had been no diagnosed botulism cases in areas where
      botulism was considered endemic. Sera from some unvaccinated cattle with high
      ELISA reactivity was shown to be protective for mice in botulinum toxin
      neutralisation tests. The use of these tests in investigations of botulism in
      cattle is discussed.

PMID- 8660201
TI  - Use of tilmicosin in a severe outbreak of respiratory disease in weaned beef
      calves.
AB  - Severe respiratory disease, associated with seroconversion to bovine respiratory
      syncitial virus (BRSV), caused the death of two cattle and necessitated
      antibiotic treatment of 70 calves (rectal temperature of 39.6 degrees C or
      greater) from a group of 96 (73%) during an 8-day period. Tilmicosin injection
      resulted in a reduction in median rectal temperature from 40.3 degrees C to 39.2
      degrees C and 39.0 degrees C for the first and second days after treatment. The
      rectal temperature was 39.5 degrees C or lower in 72% (48 of 67) and 96% (64 of
      67) of cattle 1 and 2 days after tilmicosin treatment, respectively. Ten cattle
      were re-treated with tilmicosin 6 to 16 days after the first treatment. Our study
      demonstrated that bovine respiratory syncytial virus infection could cause severe
      respiratory disease in a beef herd that had no previous history of BRSV-related
      disease. Secondary bacterial invasion after BRSV infection was controlled
      effectively by tilmicosin treatment but repeat antibiotic treatments were
      occasionally necessary due to bacterial re-infection of the respiratory tract.

PMID- 8660202
TI  - Inherited disorders: the comparative picture.
AB  - When confronted with a novel familial disorder, veterinarians should consult
      McKusick's catalogue of inherited disorders in humans, called Mendelian
      Inheritance in Man (MIM), or its online version (OMIM), to see whether a similar
      disorder has been reported in humans. They should also consult the other readily
      available sources of comparative information on mice and domesticated species.
      Increasingly, such consultations can be conducted on the Internet via the World
      Wide Web. If it is thought that an animal disorder is homologous with a human
      disorder, publications describing the animal disorder should include the MIM
      number(s) for that disorder. Future research can then test the hypothesis of
      homology, until a consensus is reached.

PMID- 8660203
TI  - The potential of pasture to supply the nutritional requirements of grazing
      horses.

PMID- 8660204
TI  - Macrozamia toxicosis in a dog.
AB  - A case of Macrozamia riedlei seed poisoning is described in a young Dachshund.
      Vomiting and depression commenced within 6 h of ingestion; other signs that
      developed included severe hepatopathy, jaundice, abdominal pain that was
      unresponsive to analgesics, severe gastro-intestinal haemorrhage and
      thrombocytopenia as well as crystalluria and marrow dyserythropoiesis. The dog
      was euthanased 6 days after ingestion of the seeds.

PMID- 8660205
TI  - Surgical management of osteomyelitis of the sustentaculum tali in a horse.

PMID- 8660206
TI  - Genotypes of Leptospira isolated from Queensland cattle.

PMID- 8660207
TI  - Serological diagnosis of botulism in dairy cattle.

PMID- 8660208
TI  - The prevalence of Dirofilaria immitis in dogs in Sydney.
AB  - Four hundred and four dogs from 9 pounds in Sydney were examined for circulating
      microfilariae and antigens of Dirofilaria immitis. One hundred of these were also
      examined post mortem for adult heartworms. The prevalence of infection in the 404
      dogs as shown by serology was 11.4%, and 5.9% had circulating microfilariae of D
      immitis. Adult heartworms were present in 15 of 100 dogs. Dipetalonema reconditum
      microfilariae were present in 3.7% of dogs. Dirofilariosis is still a common and
      important parasite of dogs in the Sydney region and chemoprophylaxis is
      recommended.

PMID- 8660209
TI  - The occurrence of schistosomus reflexus in bovine dystocia.
AB  - The occurrence of schistosomus reflexus as a cause of bovine dystocia in south
      western Victoria is described. Examination of records made by 21 veterinarians
      during a 20-year period (1966 to 1985) showed that of 6901 cases of bovine
      dystocia attended, 90 (1.3%) were caused by schistosomus reflexus. Most cases
      (56.7%) were treated by embryotomy, 25.6% by caesarean section and 3.3% by simple
      traction. Treatment of the remaining 14.4% of cases was not completed and was
      considered hopeless, mainly because of the emphysematous condition of the foetus
      and the toxic condition of the cow, which gave a poor prognosis. Some of these
      hopeless cases were sent to slaughter, but most were euthanased by the attending
      veterinarian. Sixty-nine (76.7%) of the patients were cows and 21 (23.3%) were
      heifers. Seventy-two (80%) were dairy breeds and 18 (20%) were beef breeds.
      Jersey was the main dairy breed (63.8%) and Hereford the dominant beef breed.

PMID- 8660210
TI  - Effects of ingesta on systemic availability of phenobarbitone in dogs.

PMID- 8660211
TI  - Isolation of Leptospira interrogans serovar grippotyphosa from a heifer in New
      South Wales.

PMID- 8660212
TI  - Blindness in South Australian kangaroos.

PMID- 8660213
TI  - Spread of epizootic haematopoietic necrosis virus (EHNV) in redfin perch (Perca
      fluviatilis) in southern Australia.

PMID- 8660214
TI  - An unusual congenital cardiac anomaly in a Dexter calf.

PMID- 8660215
TI  - Bacillus larvae carrier status of swarms and feral colonies of honeybees (Apis
      mellifera) in Australia.

PMID- 8660216
TI  - Inclusion not exclusion.

PMID- 8660217
TI  - Eastern barred bandicoot recovery: the role of the veterinarian in the management
      of endangered species.
AB  - The eastern barred bandicoot, Perameles gunnii, formerly widespread on the
      volcanic plains of western Victoria, has been reduced to a single, rapidly
      declining, remnant population at Hamilton. Recovery of this critically endangered
      species has included local management, in an attempt to stabilise the wild
      population, captive breeding and reintroduction to selected sites. Veterinary
      advice and assistance have been an integral part of the investigation, planning
      and implementation phases of the program. The development of appropriate,
      standardised techniques has enabled successful treatment of problems in the
      captive colony. Husbandry, including the hand-rearing of pouch young has been
      refined. Parasitism, identified as a contributor to poor health or death, has
      been investigated. Experimental development of techniques for the attachment of
      radio-transmitters to bandicoots has enabled improved field research to take
      place. Fox predation, a major limiting factor in the recovery program, has been
      studied in detail, in order to refine control protocols.

PMID- 8660218
TI  - Efficacy of an ivermectin and pyrantel pamoate combination against adult
      hookworm, Ancylostoma braziliense, in dogs.
AB  - A chewable tablet incorporating ivermectin and pyrantel was tested in 12 Beagle
      dogs for efficacy against the adult hookworm, Ancylostoma braziliense. The dogs
      were administered infective larvae of A braziliense orally. Twenty-one days after
      infection the dogs were weighed and allocated randomly to receive either an oral
      treatment with ivermectin and pyrantel in a beef-based chewable tablet or no
      treatment. The chewable tablet was a commercially available product, which was
      made to deliver ivermectin at 6 micrograms/kg and pyrantel at 5.0 mg/kg to each
      dog. Seven days after treatment the dogs were euthanased, necropsied, and
      examined for adult hookworms. At necropsy, no adult A braziliense was observed in
      any of the 6 treated dogs and all 6 dogs that had been left untreated were
      infected with adult A braziliense (range, 48 to 161). It was concluded that this
      combination product is 100% efficacious against adult A braziliense.

PMID- 8660219
TI  - Tail docking in dogs: a sample of attitudes of veterinarians and dog breeders in
      Queensland.
AB  - One hundred veterinarians and 100 breeders of traditionally docked dogs from
      Queensland were surveyed by telephone to determine their attitudes towards tail
      docking. Eighty-four percent of the breeders surveyed were in favour of docking,
      whereas 83% of veterinarians were opposed to the practice. Most pups were docked
      between 1 and 3 days of age. All veterinarians surgically amputated the tail,
      whereas 16% of breeders applied rubber bands to the tail. Seventy-six percent of
      the veterinarians, but only 18% of the breeders believed that docking caused
      significant to severe pain. No veterinarians, but 25% of the dog breeders
      believed that docking was painless. Although recent changes to the Queensland
      Canine Control Council's rulings allow dogs with intact tails to be shown in
      traditionally docked classes, the requirement of breed standard was cited as the
      major reason for tail docking by both breeders and veterinarians.

PMID- 8660220
TI  - Simulation of the economic impact of proliferative enteritis on pig production in
      Australia.
AB  - The economic impact of proliferative enteritis (PE) on an 'average' pig farm was
      calculated using the AUSPIG decision support system. Inputs were modelled on
      actual cases of PE, in which affected herds suffered from depressed growth rate,
      decreased feed efficiency and stock losses. The costs associated with non
      haemorrhagic PE and proliferative haemorrhagic enteropathy ranged from $15/sow/yr
      to $141/sow/yr, respectively, depending on the clinical severity of the disease,
      incidence of infection and the type of medication strategy used to treat and
      control the disease.

PMID- 8660221
TI  - Serological characterisation of Haemophilus parasuis isolates from Australian
      pigs.
AB  - A total of 31 isolates of Haemophilus parasuis obtained from Australian pigs were
      serotyped by the Kielstein-Rapp-Gabrielson scheme. The isolates were assigned to
      serovar 1 (1 isolate), serovar 2 (1 isolate), serovar 4 (4 isolates), serovar 5
      (7 isolates), serovar 9 (2 isolates), serovar 10/7 (4 isolates), serovar 12 (1
      isolate) and serovar 13 (6 isolates). The remaining 5 isolates could not be
      assigned to a serovar. Two different serovars (5 and 13) were detected in one
      herd. The only 2 isolates obtained from clinically normal pigs (from the same
      herd) were serovar 9. The common serovars were isolated from pigs with pneumonia
      as well as from pigs with conditions of the Glasser's disease type. The
      serological heterogeneity amongst Australian isolates of H parasuis has important
      implications for the use of vaccines to control Glasser's disease.

PMID- 8660222
TI  - Animal health monitoring and surveillance in Switzerland.
AB  - Switzerland has traditionally used a passive disease reporting system for all
      notifiable diseases. This type of system is not suitable for the documentation of
      very low prevalences (freedom from disease), sub-clinical cases and non
      notifiable diseases. In order to meet the high international standards for animal
      health surveillance and to fulfil the general need for sound animal health data,
      Switzerland has evaluated the feasibility of modern monitoring and surveillance
      concepts. In general, the principle of active surveillance has been acquired and
      is now being applied whenever possible. In this paper, several examples of Swiss
      surveillance systems are presented and discussed. They include systematic testing
      of random population samples, carcase screening at abattoirs and sentinel herd
      monitoring.

PMID- 8660224
TI  - The present state of national animal welfare policy.
AB  - Animal welfare is expected to increase in importance as a political and marketing
      issue. There is a vigorous debate about what, besides the absence of physical
      pain, is necessary for acceptable animal welfare. This paper focuses on the
      present state of animal welfare policy at the national level.

PMID- 8660223
TI  - Calving rates in a tropical beef herd after treatment with a synthetic
      progestagen, norgestomet, or a prostaglandin analogue, cloprostenol.
AB  - Maiden heifers and lactating cows of known ovarian status and of several breeds
      were treated with a synthetic prostaglandin, cloprostenol, or a synthetic
      progestagen, norgestomet, at the start of an artificial insemination (AI)
      program. Animals in the cloprostenol treatment received 2 injections 10 days
      apart. Over the next 26 days those animals that showed oestrous behaviour were
      inseminated. Synchronisation rates and calving rates to insemination over the
      first 7 days were calculated. Those in the norgestomet treatment received an
      implant of norgestomet plus an injection of norgestomet and oestradiol valerate.
      The implant was removed 10 days later and the animals were given an injection of
      pregnant mare serum gonadotrophin (PMSG). They were inseminated at 48 h (maiden
      heifers) or 56 h (lactating cows) after implant removal. Calving rates to fixed
      time insemination were recorded. After completion of the AI program the animals
      in both treatments were joined with bulls. Overall calving rates (AI plus bulls)
      were calculated. By day 7 of the program, 82% of the maiden heifers and 76% of
      the lactating cows in the cloprostenol treatment had been detected in oestrus. By
      day 21 the respective figures were 99% and 81%. Norgestomet treatment had an
      immediate and a prolonged effect on ovarian activity in those females classified
      as having inactive ovaries at the start of the AI program. Calving rates of those
      females to fixed-time AI and overall were similar to those of the females with
      active ovaries in both treatments. Their calving rates to fixed-time
      insemination, and overall calving rates for the lactating females, were
      significantly higher than the corresponding values of their contemporaries
      treated with cloprostenol and inseminated on observed oestrus over 7 days. For
      those females classified as having active ovaries at the start of the AI program,
      calving rates to first insemination and overall were similar for both treatments.
      Overall calving rates of lactating cows of each breed were, with one exception,
      higher in the norgestomet treatment than in the cloprostenol treatment. Although
      norgestomet treatment was more expensive than cloprostenol treatment, the
      advantage in calf crop resulted in an overall monetary advantage to the
      norgestomet treatment.

PMID- 8660225
TI  - Combination chemotherapy of canine and feline cryptococcosis using subcutaneously
      administered amphotericin B.
AB  - Six cases (3 cats, 3 dogs) of cryptococcosis were cured using combination
      chemotherapy that included amphotericin B. We developed a simple, practical and
      inexpensive method of administering amphotericin B as a subcutaneous infusion
      during the treatment of these patients. For this, the calculated dose of
      amphotericin B (0.5 to 0.8 mg/kg) was added to 400 mL, for cats, or to 500 mL,
      for dogs, of 0.45% saline containing 2.5% dextrose. These amounts were given
      subcutaneously 2 or 3 times weekly over several months, to a total cumulative
      dose of 8 to 26 mg/kg body weight. Subcutaneous infusions were generally well
      tolerated by the animals, although concentrations of amphotericin B in excess of
      20 mg/L resulted in local irritation. This protocol enabled the administration of
      larger, and thus more effective, quantities of amphotericin B without producing
      marked azotaemia.

PMID- 8660226
TI  - Efficacy of intra-muscular analgesics for acute pain in sheep.
AB  - The analgesic action of intramuscularly injected buprenorphine, methadone,
      flunixin meglumine and xylazine was examined in sheep, using algesimetry based on
      a leg withdrawal response to an electrical stimulus. No analgesic response was
      detected for buprenorphine, methadone or flunixin meglumine. Only the alpha 2
      adrenoceptor agonist, xylazine, produced an analgesic response. The current
      required to elicit a response increased by 170% (4.5 +/- 0.43 mA to 12.23 +/-
      1.14 mA; mean +/- SE) after a dose of 0.05 mg/kg xylazine; by 180% (4.73 +/- 0.3
      mA to 13.28 +/- 2.35 mA) after 0.1 mg/kg and by 510% (4.52 +/- 0.29 mA to 27.63
      +/- 3.89 mA) after 0.2 mg/kg. Intramuscular xylazine appears to be an effective
      analgesic agent for acute pain in the sheep and further investigation into ideal
      administration regimens and dosage may provide more detailed information on
      relationships between dose, analgesic and sedative effects. The findings also
      suggest that some common analgesic agents, and opioids in particular, may be
      ineffective for the management of acute pain in sheep and that any analgesic
      should be administered only on the basis of its proven efficacy in that species.

PMID- 8660227
TI  - Adverse drug reactions: report of the Australian Veterinary Association Adverse
      Drug Reaction Subcommittee, 1994.
AB  - Seventy-seven reports of suspected adverse drug reactions (ADRs) were received by
      the Adverse Drug Reaction Subcommittee (ADRSc) of the Australian Veterinary
      Association from April 1993 to December 1994 inclusive. The number of reports
      received/number of animals involved per species were: dogs (32/44), cats (18/31),
      horses (17/48), and cattle (10/21). Of these, 49 (64%) were classified as
      definite ADRs and 9 (12%) as probable ADRs. In 11 (14%) reports an ADR could not
      be substantiated or there was insufficient information available to make a
      decision. Eight reports were not classified because the manufacturer and the
      ADRSc disagreed as to the appropriate classification. Sixteen reports involved
      apparent hypersensitivity reactions, which resulted in death on 6 occasions. Six
      reports were associated with 'off label' use and 1 report with use of an expired
      product. Of the definite, probable and unclassified reports of suspect ADRs, the
      most frequent types of drugs involved were antimicrobial drugs (13 reports),
      anthelmintics (13), insecticides (11), vaccines (10), nonsteroidal anti
      inflammatory preparations (5), chondroprotective agents (4),anaesthetic/sedative
      agents (4) and vitamin preparations (2). Single reports concerning definite,
      probable or unclassified ADRs to a vasodilator, a corticosteroid, a local
      anaesthetic and a disinfectant were received.

PMID- 8660228
TI  - Equine neonatal septicaemia: 24 cases.
AB  - Equine neonatal septicaemia was confirmed in 24 foals hospitalised at the Rural
      Veterinary Centre between 1989 and 1992 with suspected septicaemia. Septicaemia
      was confirmed by culture of bacteria from blood of live foals and tissues
      obtained at necropsy of foals that died or were euthanased. Pathogenic bacteria
      isolated were predominantly Enterobacteriaceae (including Escherichia coli and
      Salmonella serovars) and Actinobacillus equuli. Clinical manifestations of
      septicaemia included signs of depression, dehydration, abnormalities in body
      temperature and manifestations of localised infection including diarrhoea,
      pneumonia, and septic arthritis. Most common haematological abnormalities were
      neutropenia and increase of circulating band neutrophils. Survival rate of foals
      with confirmed septicaemia was 70.8%. Survival was found to be less likely in the
      presence of pneumonia, severe signs of depression, marked haematological changes
      or septic arthritis at the time of admission. Seven foals were confirmed to have
      septic arthritis without concurrent septicaemia. Of these, 4 had multiple joint
      involvement. Bacteria isolated from infected joints were predominantly Salmonella
      serovars. Four foals with septic arthritis failed to survive, due to multiple
      joint infection, which was unresponsive to treatment. The clinical and
      haematological abnormalities present in foals with confirmed septicaemia and
      septic arthritis were consistent with those observed in other studies. The
      bacterial isolates from foals with confirmed septicaemia were similar to those
      isolated in other studies. In contrast, the bacteria isolated from foals with
      septic arthritis without concurrent septicaemia were different from other
      studies.

PMID- 8660229
TI  - The effects of lactation on the fertility of dairy cows.
AB  - Lactation has been negatively associated with fertility because pregnancy rates
      in maiden heifers exceed those obtained after first or subsequent calvings. The
      extent of this difference is less in pasture-fed dairy cows ( < 10%) than in
      American Holsteins ( > 20%) fed grain and conserved forages. The latter cows have
      pregnancy rates to first insemination and oestrus detection rates of only 40 to
      45%. This suggests that the subsequent fertility of inherently fertile Holstein
      heifers may be severely compromised by high levels of milk production.
      International comparisons show that pasture-fed dairy cows may experience
      extended periods of anovulatory anoestrum but have normal fertility (60%
      pregnancy rate to first insemination) once cycling. The high-producing American
      Holstein may ovulate within 4 weeks postpartum but is more likely to continue
      ovulating without being detected in oestrus. Both situations are associated with
      negative energy balances (NEB) during early lactation. The severity and duration
      of this NEB may vary with body condition at calving, age or parity, ration
      formulation, production level and environmental factors. Relative daily milk
      yield is not an absolute indicator of NEB, because some lower producing cows
      within a herd have lower feed intakes and more severe energy deficits. NEB is not
      simple to measure; nonetheless, it is correlated with genetic improvement for
      milk yield. A positive energy balance, greater weight gain and higher body
      condition score have all been shown to be positively correlated with plasma
      progesterone concentrations in early lactation. No studies have investigated the
      possibility that the rapid increase in metabolic rate at this time may also alter
      steroid concentrations with consequent effects on oestrous behaviour and
      fertility. Studies to more precisely define the effects of increasing milk yields
      in early lactation, especially in Holsteins, may need to be completed in
      Australia and New Zealand. Oestrus detection rates and pregnancy rates for
      American Holsteins of less than 50% are accepted widely in the USA. Such low
      detection rates confound studies on fertility. The objective should be to
      increase these 2 rates to at least 80% and 60% respectively. This may involve the
      use of controlled breeding, especially if oestrous behaviour is less overt in
      high-producing Holstein cows.

PMID- 8660230
TI  - Inflammatory mediators in equine synovial fluid.
AB  - Enzyme immunoassay for prostaglandin E2 (PGE2), and radioimmunoassays for
      prostaglandin F2 alpha (PGF2 alpha), 6-keto-PGF1 alpha, and leukotriene B4 (LTB4)
      were performed on synovial fluid from normal middle carpal joints of 10 horses,
      and from 30 middle carpal or antebrachiocarpal joints of horses affected by
      degenerative joint disease and chip fractures to compare the concentrations of
      inflammatory mediators. Significantly greater concentrations of PGE2 were
      detected in fluid from affected than from control joints, but there were no
      significant differences in the mean concentrations of PGF2 alpha, 6-keto-PGF1
      alpha, and LTB4.

PMID- 8660231
TI  - Estimating deaths in breeder-age female cattle in the Kimberley region of Western
      Australia.

PMID- 8660232
TI  - Traumatic rupture of the urinary bladder in a horse.

PMID- 8660233
TI  - Hydrocele formation after castration in 3 geldings.

PMID- 8660234
TI  - Gonadotrophin secretion in ewes with bilateral gonadal hypoplasia.

PMID- 8660235
TI  - Zinc sulphate, diazinon and dam water.

PMID- 8660236
TI  - Scrapie: the risk of its introduction and effects on trade.
AB  - New Zealand and Australia are fortunate in that they are among the few sheep
      rearing countries free from scrapie, despite cases in imported sheep in the
      1950s. The importance of sheep rearing in the Australasian economies, and the
      difficulties involved in importing sheep without risking the introduction of
      scrapie, has meant that there have been very few importations of new blood lines
      in the last 40 years, and those that have been imported have been through
      stringent programs designed to ensure freedom from scrapie. While scrapie can be
      a cause of significant wastage in some sheep rearing situations, its major threat
      to Australasia is probably to the developing biopharmaceutical industries which,
      since the emergence of bovine spongiform encephalopathy, have benefitted from an
      international demand for products guaranteed to be derived from livestock free
      from the transmissible spongiform encephalopathies. This paper outlines one
      method which has been used to assess the risk of introducing scrapie as the
      result of importation of sheep and discusses the difficulty in ascertaining what
      constitutes an acceptable risk.

PMID- 8660237
TI  - Characterisation of haemolytic RTX toxins produced by Australian isolates of
      Actinobacillus pleuropneumoniae.
AB  - The haemolytic RTX toxins of 27 isolates of Actinobacillus pleuropneumoniae,
      representing all serovars that have been isolated in Australia, were
      characterised. The quantity of protein secreted by these isolates into the media
      was not significantly different between serovars, but haemolytic activity was
      detected only in the unconcentrated supernatants from cultures of serovar 1 and 5
      isolates. Haemolytic activity in supernatants of serovar 2, 3 and 7 isolates was
      detected only after the supernatants were concentrated. On Southern hybridisation
      blots, genomic DNA of serovar 1 and 5 isolates contained regions that were
      similar to the cloned structural genes for ApxI (apxIA) and for ApxII (apxIIA).
      In contrast, genomic DNA of serovar 2, 3 and 7 isolates only contained regions
      similar to, if not identical with, the cloned apxIIA gene. The haemolytic
      activity of the culture supernatant depends on the type or composition of media
      and adaptability of the bacteria to in-vitro cultivation. Low passage cultures of
      A pleuropneumoniae, which were characterised by waxy colonies, produced
      significantly weaker haemolytic activity than A pleuropneumoniae after several
      passages in vitro.

PMID- 8660238
TI  - The detection of lice (Bovicola ovis) in mobs of sheep: a comparison of fleece
      parting, the lamp test and the table locks test.
AB  - Knowledge of the presence or absence of lice in a flock of sheep enables wool
      growers to make informed decisions as to the need for insecticidal treatments.
      However, with inapparent infestations, traditional methods of detection are not
      sufficiently sensitive and, as a consequence, flocks may be left untreated.
      Conversely, the routine application of insecticide to sheep with no sign of
      infestation is an unnecessary cost. The sensitivity of 3 procedures for detecting
      lice was evaluated in 68 mobs of sheep from 50 farms. In 24 mobs of sheep known
      to be lightly infested, lice were detected in 17% (71%) [corrected] by either
      parting the fleece of 10 sheep or by the lamp test in which 8g samples of shorn
      wool from 30 randomly selected fleeces were placed under lamps for 10 min to
      repel the lice. Twenty of 23 mobs (87%) were found to be infested by the table
      locks test in which a 30 g sample of locks wool was dissolved in 10% sodium
      hydroxide and the filtered residue examined with x 40 magnification. A screening
      test, in which either fleeces on 5 sheep were examined by fleece parting or lice
      were repelled from 30 shorn fleeces for 5 minutes, detected about 60% of lightly
      infested mobs. When this was followed by the table locks test 91% of lightly
      infested mobs were detected. Conducting any one of the tests on more than one
      mob, and in large mobs testing more frequently, increases the sensitivity of
      detection of lice within the whole flock.

PMID- 8660239
TI  - The dispersal of Culicoides brevitarsis in eastern New South Wales and
      associations with the occurrences of arbovirus infections in cattle.
AB  - Distributions of the vector Culicoides brevitarsis Kieffer (Diptera:
      Ceratopogonidae) (determined from light trap data) and 2 arboviruses (determined
      from seroconversions in sentinel cattle) were studied in eastern New South Wales
      in 1993-94. C brevitarsis was recorded progressively from endemic areas on the
      north coast, to Nowra on the south coast, and westward to Scone, in the Hunter
      Valley. C brevitarsis also survived through winter at Paterson, in the Hunter
      Valley. Its apparently focal reappearance in this marginal area had no obvious
      effect on the broad pattern of its progression or the dispersal of Akabane and
      bluetongue viruses. These viruses were first recorded from foci near Coffs
      Harbour, on the mid-north coast. Their first occurrences at different locations
      were associated with those of C brevitarsis, but not with each other. The viruses
      were found only within the recorded limits of the vector's distribution. Delays
      between the initial occurrence of C brevitarsis and first evidence of virus
      transmissions at locations ranged from 2 to 7 months. The delays decreased away
      from the points of focus and were negatively associated with the time of initial
      occurrence of the vector. Seroconversions to the viruses were related to the
      presence of C brevitarsis. However, the densities of C brevitarsis had no
      apparent effect on the initial numbers of cattle seroconverting to either virus.
      The results support the conclusion that the progressions of C brevitarsis and
      Akabane and bluetongue viruses were the result of gradual movements by the
      vector.

PMID- 8660240
TI  - Importance of Staphylococcus hyicus ssp hyicus as a cause of arthritis in pigs up
      to 12 weeks of age.
AB  - Lame pigs, up to 12 weeks of age, were necropsied to establish a diagnosis. Of
      175 pigs examined, 165 were confirmed to have arthritis by histopathological
      examination of joint tissues. Lesions were most common in the elbow and tarsal
      joints and least common in the joints of the feet. Typically, there was severe
      fibrinopurulent inflammation of synovial membranes regardless of the bacteria
      isolated. A bacterial aetiology was found in 114 (69%) of the 165 pigs. In
      arthritic pigs in which an aetiology was established the causative agents were
      Staphylococcus hyicus ssp hyicus (24.6%), Streptococcus equisimilis (26.3%),
      Actinomyces pyogenes (13.2%), Staphylococcus aureus (7.9%) and Haemophilus
      parasuis (7.9%). While gender did not affect the prevalence of arthritis, there
      was an age influence, most of the pigs culled for arthritis being under 6 weeks
      of age.

PMID- 8660241
TI  - Transgenic animals: how they are made and their role in animal production and
      research.

PMID- 8660242
TI  - Serum copper concentrations and clinical signs in red deer (Cervus elaphus)
      during drought in central Victoria.

PMID- 8660243
TI  - Reducing the effects of clover disease by strategic grazing of pastures.

PMID- 8660244
TI  - Antibiotic resistant phage types of Salmonella typhimurium in dairy cattle.

PMID- 8660245
TI  - Validation of a commercial human fibronectin assay for use in dogs and cats.

PMID- 8660246
TI  - Ischemic preconditioning: a brief review.

PMID- 8660247
TI  - Comparison of a new intravenous echo contrast agent (BY 963) with Albunex for
      opacification of left ventricular cavity.
AB  - Transpulmonary echo contrast agents improve the evaluation of left ventricular
      function by two-dimensional echocardiography due to a better endocardial border
      delineation. To compare the contrast effect in the right and left ventricular
      cavities, a new transpulmonary echocontrast agent, BY 963 and Albunex were
      intravenously administered to five non-anaesthetized dogs. The right and left
      ventricular echocardiographic image intensities were quantitatively measured at
      60 cardiac cycles using a commercially available ultrasound system. BY 963 and
      Albunex were intravenously administered at three doses: 0.01 ml/Kg, 0.05 ml/Kg
      and 0.1 ml/Kg. The area under the curve (AUC, intensity units x heart cycles) and
      peak intensity (Peak I, intensity units) were estimated for the right (RV) and
      left ventricular (LV) cavities at the mid ventricular level using acoustic
      intensitometry. BY 963 injection produced the following values: At the dose of
      0.01, 0.05 and 0.1 ml/Kg the AUC amounted to 702 +/- 449, 877 +/- 470 and 890 +/-
      320 intensity units x heart cycles in RV and to 542 +/- 406, 806 +/- 557 and 721
      +/- 392 in LV (LV/RV ratios: 77%, 92% and 81%). Peak I was at the doses 0.01,
      0.05 and 0.1 ml/Kg 29 +/- 4.7, 33 +/- 5.2 and 35 +/- 3.2 intensity units in RV
      and 18 +/- 5.9, 21 +/- 6.2 and 20 +/- 3.3 in LV (LV/RV ratios: 62%, 64% and 57%).
      Albunex also produced right and left heart opacification values: at the doses
      0.01, 0.05 and 0.1 ml/Kg the AUC amounted to 416 +/- 231, 493 +/- 231 and 674 +/-
      390 in RV and to 71 +/- 71, 158 +/- 102 and 277 +/- 120 in LV (LV/RV ratios: 17%,
      34% and 41%). Peak I was at the doses of 0.01, 0.05 and 0.1 ml/Kg 19 +/- 5.2, 23
      +/- 5.4 and 29 +/- 4.1 in RV and 8 +/- 4.8, 13 +/- 4.7 and 17 +/- 3.2 in LV
      (LV/RV ratios: 42%, 57% and 59%). Intravenous injection of BY 963 leads to
      complete opacification of the left ventricular cavity and to high AUC values and
      peak intensity values at all three dosages. The loss of contrast effect from the
      right to the left ventricular cavity was very low: the LV/RV ratio of BY 963 was
      higher than that of Albunex. The new transpulmonary echo contrast agent BY 963
      promises to be an excellent echo contrast agent for the noninvasive assessment of
      left ventricular function.

PMID- 8660248
TI  - Three questions about preconditioning.

PMID- 8660249
TI  - Preconditioning-induced protection against post-ischemic contractile dysfunction:
      inhibitory effect of tissue washout.

PMID- 8660250
TI  - Adenosine and bradykinin: are they independent triggers of preconditioning?

PMID- 8660251
TI  - Activation of ecto-5'-nucleotidase and cardioprotection by ischemic
      preconditioning.

PMID- 8660252
TI  - Endothelial cells, nitric oxide and ischaemic preconditioning.

PMID- 8660253
TI  - Criteria for a mediator or effector of myocardial preconditioning: do KATP
      channels meet the requirements?

PMID- 8660254
TI  - Preconditioning: markers vs. epiphenomena.

PMID- 8660255
TI  - Limitation of infarct size by myocardial ischemic preconditioning.

PMID- 8660256
TI  - Role of protein kinase C in ischemic preconditioning: in search of the "pure and
      simple truth".

PMID- 8660257
TI  - Cardioprotection by organs in stress or distress.

PMID- 8660258
TI  - An alternative perspective on ischemic preconditioning derived from mathematical
      modeling.

PMID- 8660259
TI  - Preconditioning--a reappraisal of protection.

PMID- 8660260
TI  - Ischemic preconditioning and myocardial hibernation: is there a common mechanism?

PMID- 8660261
TI  - Delayed myocardial protection following ischaemic preconditioning.

PMID- 8660262
TI  - The early and late phases of preconditioning against myocardial stunning and the
      essential role of oxyradicals in the late phase: an overview.

PMID- 8660264
TI  - The ability of heat stress and metabolic preconditioning to protect primary rat
      cardiac myocytes.
AB  - Primary rat cardiocytes were subjected to either thermal "preconditioning" for 30
      min at 43 degrees C or 20 min metabolic "preconditioning" (10 mM deoxyglucose, 20
      mM lactate, pH 6.5). Eighteen hours later cells were analysed either for hsp 70i
      expression or subjected to a subsequent lethal heat stress or simulated ischaemia
      (10 mM deoxyglucose, 20 mM lactate, 0.75 mM sodium dithionite, 12 mM potassium
      chloride, pH 6.5) for 2 hours and assessed for survival by trypan blue exclusion.
      Hsp 70i was induced over 100 fold by thermal "preconditioning" and 30 fold by
      metabolic "preconditioning" (p < 0.001, p < 0.05), hsp 90 was induced 2.71 fold
      and 2.24 fold (p < 0.001, p < 0.001) by thermal and metabolic "preconditioning"
      respectively, while hsp 60 was no induced by either treatment. Preconditioned
      cultures had improved survival against subsequent lethal heat stress or simulated
      ischaemia: Thermal "preconditioning" reduced death from 69.22% to 52.46% upon
      subsequent "lethal" heat stress and from 49.13% to 36.66% upon subsequent
      "lethal" simulated ischaemia. Metabolic "preconditioning" reduced cell death from
      51.29% to 33.8% against subsequent "lethal" heat stress, and from 69.09% to
      55.61% upon subsequent "lethal" simulated ischaemia. A second marker of cell
      death, the release of lactate dehydrogenase activity into the culture media, was
      reduced to 65% and 60% of control values for thermally preconditioned cells
      subjected to "lethal" heat or "lethal" simulated ischaemia respectively.
      Metabolically "preconditioned" cells demonstrated lactate dehydrogenase activity
      of 59% and 51% that of control values, when subjected to "lethal" heat or
      "lethal" simulated "ischaemia" respectively.

PMID- 8660263
TI  - Substrate effects on sarcolemmal permeability in the normoxic and hypoxic
      perfused rat heart.
AB  - OBJECTIVES: Based on the hypothesis that provision of glucose is good and fatty
      acids are bad for the ischaemic myocardium, the aims of this study were to
      determine i) the effects of different substrates on sarcolemmal permeability
      during normoxia, low-flow hypoxia (HLF) and reperfusion, ii) whether increased
      membrane permeability is associated with ultrastructural damage and increased
      influx of Ca2+ into cells and iii) whether changes in membrane permeability
      correlate with myocardial function and high energy phosphate metabolism. METHODS:
      The isolated rat heart subjected to HLF was used as model of global ischaemia,
      and sarcolemmal permeability assessed by release of LDH from and influx of
      lanthanum and Ca2+ into myocardial tissue. Myocyte structural injury was also
      evaluated quantitatively, and mechanical activity was monitored throughout the
      experimental protocol. RESULTS: Regardless of the substrate used, HLF caused a 80
      90% and 20-40% reduction in myocardial oxygen uptake and coronary flow rate,
      respectively. Palmitate (0.5 mM conjugated to 0.1 mM albumin) or substrate-free
      perfusion caused ultrastructural damage and loss of normal sarcolemmal integrity
      during both normoxia and HLF. Although reperfusion reversed injury in some cells,
      in general, myocytes exhibited myofibrillar contracture, while membrane integrity
      recovered to some extent, as indicated by reduced lanthanum influx. Intracellular
      Ca2+ increased significantly upon reperfusion. Mechanical function as well as
      tissue high energy phosphates were significantly depressed during both HLF and
      reperfusion. Glucose, on the other hand, protected against ischaemia-induced
      structural damage and loss of sarcolemmal integrity. Reperfusion in these
      experiments resulted in almost complete recovery of normal morphology,
      ultrastructure and sarcolemmal integrity, while intracellular Ca2+ remained
      unchanged. Mechanical function and tissue high energy phosphates were
      significantly higher in glucose-perfused hearts than in palmitate-perfused or
      substrate-free hearts. Glucose was also able to attenuate the harmful effects of
      palmitate on myocardial ultrastructure, membrane integrity, mechanical function,
      energy metabolism and prevented Ca2+ overloading during reperfusion. CONCLUSION:
      The results provide new evidence for the protective role of glucose during
      myocardial ischaemia and reperfusion. Although the exact mechanism of the
      beneficial actions of glucose remains to be established, the results suggest that
      glycolytic flux and thus glycolytically derived ATP protect against ischaemic
      damage via preservation of membrane integrity.

PMID- 8660265
TI  - Ischemic preconditioning, remembrances of things past and future.

PMID- 8660266
TI  - Influence of endothelin 1 on human atrial myocardium--myocardial function and
      subcellular pathways.
AB  - The influence of endothelin 1 on isometrically contracting human atrial muscle
      strip preparations was investigated under physiological conditions (37 degrees C,
      1 Hz, Ca2+ 2.5 mM). Endothelin dose-dependently increased isometric tension from
      3 x 10(-10) M to 1 x 10(-7) M. At 1 x 10(-7) M the inotropic effect of endothelin
      was maximum with isometric tension being increased by 32 +/- 6% (n = 11, p <
      0.05). At 1 x 10(-7) M endothelin the positive inotropic effect was preceded by a
      transient negative inotropic effect with a decline in tension by -5 +/- 1% (n =
      11, p < 0.05). Endothelin prolonged time from peak tension to 50% relaxation
      (RT50) by 29 +/- 5%. With BQ123 a competitive antagonist of the ETA receptor
      positive inotropic effect and the prolongation of relaxation was significantly
      reduced and initial negative a inotropic effect was abolished, indicating a ETA
      receptor mediated effect. Preincubation with phorbolmyristateacetate (10(-5) M)
      to downregulate proteinkinase C (PKC) eliminated the positive inotropic effect of
      endothelin. Similarly, N-5,5-dimethylamiloride (10(-5) M) which inhibits Na+/H(+)
      exchanger activity, abolished the positive inotropic effect of ET. However, with
      either PMA or DMA the initial transient negative inotropic effect was still
      present (-13 +/- 7%, n = 9, p < 0.05 and -3 +/- 1%, n = 6, p < 0.05).
      Furthermore, both substances did not abolish the prolongation of twitch time
      parameters observed under endothelin. After preincubation with PMA, endothelin
      prolonged RT50 by 18 +/- 6% and with DMA by 11 +/- 2%. Using the photoprotein
      aequorin as an indicator for intracellular calcium concentrations showed that the
      positive inotropic effect was mainly mediated by an increase of systolic
      intracellular calcium concentrations. Thus, the present data indicate that the
      positive inotropic effect of endothelin in human atrial myocardium results from
      activation of PKC with a subsequent activation of the Na+/H(+)-exchanger.
      However, the initial negative inotropic effects as well as the prolongation of
      relaxation seem to result from a different intracellular mechanism of endothelin.

PMID- 8660267
TI  - Time to dP/dtmax, a preload-independent index of contractility: open-chest dog
      study.
AB  - A mathematical model of left ventricular pressure (LVP) during isovolumic
      contraction in the time domain shows the following predictions: 1) td, the time
      from onset of contraction to dP/dtmax and (dP/dt)/P, reflect only the time
      dependent aspects of contraction, and are independent of preload; 2) dP/dtmax
      depends on both preload and the time-dependent aspects of contraction. To test
      preload independence we reduced filling volume (FV) by the method of ventricular
      volume clamps with a remote-controlled mitral valve in 7 anesthetized open-chest
      dogs. A decrease in FV of 80 +/- 15% produced a 29 +/- 12% (p < 0.001) decrease
      in LVP, 34 +/- 13% (p < 0.001) decrease in dP/dtmax, 13 +/- 4% (p < 0.001)
      decrease in t-dP/dtneg, and no change in td (-3 +/- 5%, NS). The heart rate (HR)
      dependence on td was assessed in other 5 anesthetized open-chest dogs. HR was
      changed with atrial pacing (50-240 bpm). td was linearly and inversely related to
      HR in each dog, and at each HR: dobutamine lowered and propranolol elevated this
      relation when compared to control (p < .001, both). Since dP/dtmax occurs usually
      before the opening of the aortic valve, td is, thus, also afterload-independent.
      Conclusion. This study supports the theoretical predictions that td is
      independent of preload and that it can serve, at any given HR, as a reliable
      index of contractility, provided that dP/dtmax occurs before the opening of the
      aortic valve.

PMID- 8660269
TI  - Chronic exogenous hyperinsulinaemia does not modify the acute inhibitory effect
      of insulin on the secretion of very-low-density lipoprotein triacylglycerol and
      apolipoprotein B in primary cultures of rat hepatocytes.
AB  - Male Wistar rats were fitted with subcutaneous osmotic mini-pumps that delivered
      insulin at a constant rate of 0.20 i.u./h for 7 days. This treatment raised the
      plasma insulin concentration from 31 +/- 4 to 201 +/- 64 micro-i.u./ml.
      Hepatocytes prepared from the hyperinsulinaemic animals secreted very-low-density
      lipoprotein (VLDL) triacylglycerol (TAG) at a higher rate (172 +/- 21 microgram
      per 24 h per mg cell protein) than did those from sham-operated controls (109 +/-
      12 microgram per 24 h per mg) (P<0.05). However, chronic exogenous
      hyperinsulinaemia had no stimulatory effect on the secretion of VLDL
      apolipoprotein B (apoB) in derived hepatocytes compared with those from the sham
      operated controls (2.32 +/- 0.38 compared with 3.09 +/- 0.40 microgram per 24 h
      per mg). Hepatocytes from the hyperinsulinaemic rats thus secreted larger VLDL
      particles as evidenced by the increased TAG:apoB ratio (78.4 +/- 13.1 compared
      with 38.4 +/- 7.6; P<0.05). In hepatocytes from the hyperinsulinaemic rats a
      larger proportion of the newly synthesized TAG was secreted as VLDL. Hepatocytes
      from the hyperinsulinaemic and the sham-operated control animals were equally
      sensitive to the inhibitory effect of insulin added in vitro on the secretion of
      VLDL TAG. Insulin added in vitro to the culture medium of hepatocytes from
      hyperinsulinaemic animals significantly decreased the TAG:apoB ratio of the
      secreted VLDL. This change did not occur in hepatocytes from sham-operated rats.
      These results suggest that, in vivo, chronic hyperinsulinaemia is not in itself
      sufficient to desensitize the liver to the acute inhibitory effect of insulin on
      the secretion of VLDL.

PMID- 8660268
TI  - Role of insulin in hepatic fatty acid partitioning: emerging concepts.

PMID- 8660270
TI  - Kinetic modelling of the nitric oxide gradient generated in vitro by adherent
      cells expressing inducible nitric oxide synthase.
AB  - Inducible nitric oxide (NO) synthase produces a long-lasting NO flux which can
      exert cytotoxic effects on target cells. A prerequisite for the understanding of
      the molecular basis of NO action is quantitative data on the availability of this
      small neutral radical molecule at both the spatial and temporal levels. The
      limits of NO availability depend on the respective rates of NO production,
      diffusion and autoxidation by molecular oxygen. Kinetic modeling of these
      processes has been performed for a widely used experimental system consisting of
      a monolayer of adherent cells cultured in vitro for hours in unstirred culture
      medium. It appears that: (i) the maximal NO concentration in the culture is in
      the immediate vicinity of the monolayer, where target cells will sediment; (ii)
      the steady-state NO concentration in this area is lower than 4 to 5 microM; and
      (iii) measurements of nitrite/nitrate or citrulline accumulation in the bulk cell
      medium culture during a given time period significantly underestimate (by a
      factor of up to 3 to 4) the true rate of NO synthesis at the level of the
      producer cell. This rate can be, nevertheless, easily estimated from the rate of
      production of the stable NO synthase products.

PMID- 8660271
TI  - Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade
      and cardiac hypertrophy.
AB  - Phenylephrine and noradrenaline (alpha-adrenergic agonism) or isoprenaline (beta
      adrenergic agonism) stimulated protein synthesis rates, increased the activity of
      the atrial natriuretic factor gene promoter and activated mitogen-activated
      protein kinase (MAPK). The EC50 for MAPK activation by noradrenaline was 2-4
      microM and that for isoprenaline was 0.2-0.3 microM. Maximal activation of MAPK
      by isoprenaline was inhibited by the beta-adrenergic antagonist, propranolol,
      whereas the activation by noradrenaline was inhibited by the alpha1-adrenergic
      antagonist, prazosin. FPLC on a Mono-Q column separated two peaks of MAPK
      (p42MAPK and p44MAPK) and two peaks of MAPK-activating activity (MEK) activated
      by isoprenaline or noradrenaline. Prolonged phorbol ester exposure partially down
      regulated the activation of MAPK by noradrenaline but not by isoprenaline. This
      implies a role for protein kinase C in MAPK activation by noradrenaline but not
      isoprenaline. A role for cyclic AMP in activation of the MAPK pathway was
      eliminated when other agonists that elevate cyclic AMP in the cardiac myocyte did
      not activate MAPK. In contrast, MAPK was activated by exposure to ionomycin, Bay
      K8644 or thapsigargin that elevate intracellular Ca2+. Furthermore, depletion of
      extracellular Ca2+ concentrations with bis-(o-aminophenoxy)ethane-NNN'N'-tetra
      acetic acid (BAPTA) or blocking of the L-type Ca2+ channel with nifepidine or
      verapamil inhibited the response to isoprenaline without inhibiting the responses
      to noradrenaline. We conclude that alpha- and beta-adrenergic agonists can
      activate the MEK/MAPK pathway in the heart by different signalling pathways.
      Elevation of intracellular Ca2+ rather than cyclic AMP appears important in the
      activation of MAPK by isoprenaline in the cardiac myocyte.

PMID- 8660272
TI  - Differential effects of G-protein activators on 5-hydroxytryptamine and platelet
      derived growth factor release from streptolysin-O-permeabilized human platelets.
AB  - In this paper we have used streptolysin O (SLO)-permeabilized human platelets to
      examine the G-protein(s) that control Ca2+-independent secretion from alpha and
      dense-core granules. As shown for electropermeabilized platelets, Ca2+ alone
      stimulated a concentration-dependent increase in 5-hydroxytryptamine (5-HT)
      (dense-core-granule marker) and platelet-derived growth factor (PDGF) (alpha
      granule marker) release from the SLO-permeabilized cells. The EC50 values of Ca2+
      dependent 5-HT and PDGF release were 5 microM and 10 microM respectively.
      Guanosine 5'-[gamma-thio]triphosphate (GTP[S]) (100 microM) stimulated Ca2+
      independent release from both alpha and dense-core granules. In contrast, AlF4-
      had no effect on Ca2+-independent release from either alpha or dense-core
      granules. Neither GTP[S] nor AlF4- appeared to have a significant effect on Ca2+
      dependent release from alpha and dense-core granules. GTP[S] can activate both
      heterotrimeric and low-molecular-mass G-proteins, whereas AlF4- activates only
      heterotrimeric G-proteins. Our results, therefore suggest that secretion in the
      human platelet is regulated by a small G-protein. Both GTP[S]- and Ca2+-dependent
      secretion were effected by extending the time between permeabilization with SLO
      and stimulation of secretion. GTP[S]-stimulated secretion from alpha and dense
      core granules decreased rapidly after permeabilization. In contrast, Ca2+
      dependent 5-HT and PDGF release ran down at a much lower rate. These observations
      indicate that GTP[S] and Ca2+ act through parallel pathways to stimulate
      secretion from SLO-permeabilized platelets.

PMID- 8660273
TI  - Phosphatidic acid mobilized by phospholipase D is involved in the phorbol 12
      myristate 13-acetate-induced G2 delay of A431 cells.
AB  - This study was aimed at gaining an understanding of metabolic events responsible
      for the inhibition of cells in G2 phase, a known physiological restriction site
      in the cell cycle of multicellular organisms. In an earlier study, phosphatidic
      acid was proposed as an inhibitory mediator in the epidermal growth factor (EGF)
      induced inhibition of A431 cells in G2 phase via the phospholipase C pathway
      [Kaszkin, Richards and Kinzel (1992) Cancer Res. 52, 5627-5634]. We show here
      that the phorbol ester phorbol 12-myristate 13-acetate (PMA) induces a reversible
      inhibition of the G2/M transition in A431 cells under conditions of phospholipase
      D-catalysed phosphatidic acid formation. Such PMA-induced inhibition in G2 phase
      is largely attenuated in the presence of 1-propanol (but not of 2-propanol). In
      this case the amount of phosphatidic acid is reduced to almost control levels,
      and instead phosphatidylpropanol is formed. In the case of EGF-induced activation
      of a phospholipase D the amount of phosphatidic acid is only slightly decreased
      in the presence of a primary alcohol. Under these conditions the EGF-induced G2
      delay was not affected. The correlation between the formation of phosphatidic
      acid and the G2 delay induced by PMA, as well as by an exogenous bacterial
      phospholipase D (from Streptomyces chromofuscus), could be supported by using
      synchronized cells in order to increase the population of cells in G2 phase. This
      study indicates that the formation of substantial amounts of phosphatidic acid
      immediately before entry into mitosis seems to be important for establishing a
      delay in the cell cycle at the G2/M border by exogenous ligands.

PMID- 8660274
TI  - Evidence that the specificity of iron incorporation into homopolymers of human
      ferritin L- and H-chains is conferred by the nucleation and ferroxidase centres.
AB  - Mammalian ferritins are iron-storage proteins made of 24 subunits of two types:
      the H- and L-chains. L-chains, in contrast with H-chains, lack detectable
      ferroxidase activity. When ferritins were subjected to iron loading in vitro with
      increments near the saturation limit of 4000 Fe atoms per molecule, the
      homopolymers of human H-chains formed insoluble aggregates, caused by non
      specific iron hydrolysis, whereas the homopolymers of L-chains remained soluble
      and incorporated most of the available iron. To analyse the molecular reasons for
      the difference, Glu-57 and Glu-60, which are conserved and exposed on the cavity
      of L-chains, were substituted with His, as in H-chains. The double substitution
      made the L-homopolymers as sensitive as the H-homopolymers to the iron-induced
      aggregation, whereas the opposite substitution in the H-chain increased
      homopolymer resistance to the aggregation only marginally. Millimolar
      concentrations of citrate and phosphate increased iron incorporation in H
      homopolymers by reducing non-specific iron hydrolysis, but inhibited that in L
      homopolymers by sequestering available iron. The data indicate that the specific
      iron incorporation into L-homopolymers is mainly due to the iron-nucleation
      capacity of Glu-57, Glu-60 and other carboxyl groups exposed on the cavity; in
      contrast, the specificity of iron incorporation into H-homopolymers is related to
      its ferroxidase activity, which determines rapid Fe(III) accumulation inside the
      cavity. The finding that ferroxidase centres are essential for the incorporation
      of iron in the presence of likely candidates of cellular iron transport, such as
      phosphate and citrate, confirms their importance in ferritin function in vivo.

PMID- 8660275
TI  - A novel tool for the investigation of glutamate release from rat cerebrocortical
      synaptosomes: the toxin Tx3-3 from the venom of the spider Phoneutria
      nigriventer.
AB  - The present experiments investigated the effect of some of the toxic components
      present in the venom of the spider Phoneutria nigriventer on the release of
      neurotransmitter. The toxic fraction, Phoneutria nigriventer toxin-3 (PhTx3),
      abolished Ca2+-dependent glutamate release, but did not alter Ca2+-independent
      secretion of glutamate when rat brain cortical synaptosomes were depolarized with
      33 mM KCl. This effect was most likely due to interference with the entry of
      calcium through voltage-gated calcium channels, because PhTx3 reduced by 50% the
      increase in intrasynaptosomal free calcium induced by membrane depolarization,
      and did not affect the release of glutamate evoked by a calcium ionophore
      (ionomycin). A polypeptide (Tx3-3) present in the PhTx3 fraction reproduced the
      effects of the PhTx3 fraction on transmitter release and intrasynaptosomal free
      calcium in the low nanomolar range. We compared the alterations produced by the
      Tx3-3 with the actions of toxins known to block calcium channels coupled to
      exocytosis: the results indicated that the Tx3-3 inhibition of glutamate release
      and intrasynaptosomal calcium resemble that observed with omega-conotoxin MVIIC.
      We suggest that the Tx3-3 is a calcium-channel antagonist that blocked glutamate
      exocytosis.

PMID- 8660276
TI  - Characterization of Saccharomyces cerevisiae deficient in expression of
      phospholipase D.
AB  - A gene encoding phospholipase D (PLD) in Saccharomyces cerevisiae was identified.
      The 195 kDa product of PLD1 has 24% overall sequence identity with a plant PLD.
      Expression of yeast PLD activity was eliminated by one-step gene disruption.
      Yeast haploids lacking PLD activity were deficient in growth on non-fermentable
      carbon sources. Diploids lacking expression of PLD1 were unable to sporulate.

PMID- 8660277
TI  - Enzymic sulphation of dopa and tyrosine isomers by HepG2 human hepatoma cells:
      stereoselectivity and stimulation by Mn2+.
AB  - HepG2 human hepatoma cells, labelled with [35S]sulphate in media containing L-3,4
      dihydroxyphenylalanine (L-dopa), (D-dopa), DL-m-tyrosine or D-p-tyrosine, were
      found to produce the [35S]sulphated forms of these compounds. Addition to the
      labelling media of m-hydroxybenzylhydrazine, an aromatic amino acid decarboxylase
      inhibitor, greatly enhanced the production of L-dopa O-[35S]sulphate and DL-m
      tyrosine O-[35S]sulphate, with a concomitant decrease in the formation of
      dopamine O-[35S]sulphate and m-tyramine O-[35S]sulphate. With 3'-phosphoadenosine
      5'-phospho[35S]sulphate as the sulphate donor., HepG2-cell cytosol was shown to
      contain enzymic activity catalysing the sulphation of L-dopa, D-dopa, L-m
      tyrosine, D-m-tyrosine, L-p-tyrosine and D-p-tyrosine. The pH optimum of the
      enzyme, designated dopa/tyrosine sulphotransferase, was determined to be 8.75
      with D-m-tyrosine as the substrate. The enzyme exhibited stereoselectivity for
      the D-form of dopa or tyrosine isomers. Addition of 10mM MnCl2 to the reaction
      mixture resulted in a remarkable stimulation of dopa/tyrosine sulphotransferase
      activity, being as high as 267.8 times with D-p-tyrosine as the substrate.
      Quantitative assays revealed L-dopa, D-dopa and D-m-tyrosine to be better
      substrates than L-p-tyrosine. When the HepG2-cell cytosol was subjected to DEAE
      Bio-Gel and hydroxyapatite column chromatography, dopa/tyrosine sulphotransferase
      was co-eluted with the thermolabile 'M-form' phenol sulphotransferase.
      Furthermore dopa/tyrosine sulphotransferase displayed properties similar to that
      of the M-form phenol sulphotransferase with respect to thermostability and
      sensitivity to 2,6-dichloro-4-nitrophenol. Whether the M-form phenol
      sulphotransferase is truly (solely) responsible for the dopa/tyrosine
      sulphotransferase activity present in HepG2 cells remains to be clarified.

PMID- 8660278
TI  - Modulation of collagen gel contraction by decorin.
AB  - The small dermatan sulphate protein decorin interacts via its core protein with
      fibrillar collagens, and its glycosaminoglycan chains were proposed to be capable
      of self-association. It was therefore of interest to study the role of decorin in
      the contraction of cell-populated collagen lattices. Stable transfection of
      dihydrofolate reductase-deficient CHO cells with decorin cDNA resulted in
      impaired collagen lattice contraction. Using normal human skin fibroblasts in
      serum-free cultures, inclusion of 0.3 microM decorin in the culture medium also
      led to a delayed collagen gel contraction. Protein-free dermatan sulphate and the
      dermatan sulphate-degrading enzyme chondroitin ABC lyase were ineffective.
      Potential interactions between dermatan sulphate chains were studied by gel
      filtration. A shift in the elution position of [35S]sulphate-labelled decorin
      derived glycosaminoglycans by unlabelled decorin could be observed only when the
      chains were prepared by trypsin. Chains liberated by beta-elimination or by
      cathepsin C were eluted at identical positions in the presence or absence of
      decorin. It is therefore unlikely, that the effect of decorin on collagen-gel
      retraction is brought about solely by glycosaminoglycan-glycosaminoglycan
      interactions.

PMID- 8660279
TI  - Comparison of the effects of perchlorate and Bay K 8644 on the dynamics of
      cytoplasmic Ca2+ concentration and insulin secretion in mouse beta-cells.
AB  - Non-inbred ob/ob mice were used to study the dynamics of cytoplasmic Ca2+
      concentration ([Ca2+]i) in isolated pancreatic beta-cells using microfluorimetry
      with fura 2/AM as probe, and the dynamics of insulin secretion in isolated
      pancreatic islets. D-Glucose (20 mM) caused a transient peak increase in [CA2+]i
      which changed to either an oscillating or a flat, elevated phase. The lag-time
      before the first peak increase in [Ca2+]i was markedly shortened by 12 mM ClO4-
      and the glucose-stimulated level of [Ca2+]i after the first peak was clearly
      elevated by the anion. ClO4- did not change the basal [Ca2+]i at 3 mM glucose.
      Extracellular Ca2+ deficiency abolished the effect of high glucose and ClO4- on
      [Ca2+]i. This suggests that ClO4- acts as an amplifier of transmembrane Ca2+
      inflow. The L-type Ca2+ channel agonist, Bay K 8644 (0.01-1.0 microM), strictly
      reproduced all the effects of perchlorate on the glucose-stimulated beta-cell
      [Ca2+]i. Both phases of insulin release (20 mM glucose) were markedly enhanced by
      ClO4- (12 mM) or Bay K 8644 (1.0 microM). The lag-time for glucose-stimulated
      insulin release was shortened by both agents. Taken together, these data
      strengthen the idea that perchlorate amplifies the glucose-stimulation of [Ca2+]i
      and insulin release by directly modifying the function of the L-type Ca2+
      channel. This effect can induce both a more prompt onset of and an amplified
      level of beta-cell secretory activity.

PMID- 8660280
TI  - Inhibition of the cerebellar inositol 1,4,5-trisphosphate-sensitive Ca2+ channel
      by ethanol and other aliphatic alcohols.
AB  - The effects of ethanol and other aliphatic alcohols on the endoplasmic reticulum
      Ca2+ pump and the inositol 1,4,5-trisphosphate (InsP3)-sensitive Ca2+ channel
      were studied in pig cerebellar microsomes. Methanol, ethanol and propanol all
      stimulated ATP-dependent Ca2+ uptake, whereas butanol inhibited this process.
      Ethanol inhibited InsP3-induced Ca2+ release [half-maximal inhibition at 3.5%,
      v/v (600 mM)]. However, ethanol affected only the amount of InsP3-releasable
      Ca2+, without affecting the concentration of InsP3 required to induce half
      maximal release. Other alcohols of longer chain length were more potent than
      ethanol at inhibiting InsP3-induced Ca2+ release, but none of the alcohols tested
      affected [3H]InsP3 binding to its receptor. Using stopped-flow techniques,
      measurements of the rate of InsP3-induced Ca2+ release in the preparation of pig
      cerebellar microsomes used in this study showed the kinetics to be monophasic,
      with a rate constant of 0.93s-1 at 20 microM InsP3. This rate constant was
      dependent upon InsP3 concentration, decreasing to 0.38s-1 at 0.25 microM InsP3.
      Ethanol was shown to reduce the fractional amount of InsP3-induced Ca2+ release
      without significantly affecting the rate constant for this process.

PMID- 8660281
TI  - The role of protein kinase C in carbachol-induced and of cAMP-dependent protein
      kinase in isoproterenol-induced secretion in primary cultured guinea pig parotid
      acinar cells.
AB  - Stimulation of secretion by muscarinic agonists in guinea pig parotid or
      pancreatic acini is accompanied by a translocation of protein kinase C (PKC) from
      the cytosol to the particulate fraction [Machado-De Domenech and Soling (1987)
      Biochem. J. 242, 749-754] and by a PKC-mediated phosphorylation of the ribosomal
      protein S6 [Padel and Soling (1985) Eur. J. Biochem. 151, 1-10]. In order to
      decide whether PKC is directly involved in the secretory process, the effect of
      down regulation of PKC by phorbol 12-myristate 13-acetate (PMA) was studied in
      primary cultured guinea pig parotid acinar cells. These cells secrete in response
      to carbachol and isoproterenol. Only the carbachol response is associated with an
      increase in cytosolic calcium. Carbachol plus isoproterenol lead to an over
      additive stimulation of secretion, an effect which depends completely on the
      presence of external calcium. Down regulation of PKC by about 90% did not
      significantly affect carbachol-induced exocytosis, whereas isoproterenol
      stimulated secretion was almost doubled. The secretory response to permeable cAMP
      analogues was also enhanced in PKC-down-regulated acini, indicating a post
      receptor effect. The increased response to isoproterenol was also observed in the
      absence of external calcium. The isoproterenol effect was significantly inhibited
      by the relatively specific cAMP-dependent protein kinase inhibitor H-89, which
      had only a minor effect on carbachol-induced exocytosis. Although down regulation
      of total PKC by up to 90% did not significantly affect the secretory response to
      carbachol, RO 31-8220, a relatively specific inhibitor of PKC, abolished
      carbachol-induced secretion in normal as well as in PMA-down-regulated cells.
      This indicates that a PKC isoform resistant to down regulation by PMA is involved
      in carbachol- but not in cAMP-mediated secretion.

PMID- 8660282
TI  - Intracellular calcium stores and inositol 1,4,5-trisphosphate receptor in rat
      liver cells.
AB  - The D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor was localized by
      immunofluorescence experiments in situ in liver cryosections. Two anti
      Ins(1,4,5)P3 receptor antibodies (against the 14 C-terminal residues of the type
      1 receptor or against the entire cerebellar receptor) weakly decorated the whole
      cytoplasm, and a more intense labelling was observed at the periphery of the
      hepatocytes, particularly beneath the canalicular and the sinusoidal domains of
      the plasma membrane (PM). Antibodies against calreticulin, the Ca2+ pump
      (SERCA2b) or endoplasmic reticulum (ER) membranes homogeneously labelled the
      cytoplasm and the subplasmalemmal area. These data indicate that the ER can be
      divided into at least two specialized subregions: one is located throughout most
      of the cytoplasm and contains markers of the rough ER (RER), calreticulin,
      SERCA2b and a low density of Ins(1,4,5)P3 receptor, and the other is confined to
      the periphery of the cells and contains calreticulin, Ca2+ pump, RER markers and
      a high density of Ins(1,4,5)P3 receptor. A membrane fraction enriched in
      Ins(1,4,5)P3 receptor and in markers of the PM was immuno-adsorbed with the
      antibody against the C-terminal end of the Ins(1,4,5)P3 receptor and pelleted
      with Sepharose protein A. The immuno-isolated material was enriched in
      Ins(1,4,5)P3 receptor, but none of the markers of the ER or of the PM could be
      detected. This suggests that the Ins(1,4,5)P3 receptor is localized on discrete
      domains of the ER membrane beneath the canalicular and the sinusoidal membranes,
      where it was found at higher densities than the other markers.

PMID- 8660283
TI  - Soluble N-ethylmaleimide-sensitive-factor attachment protein and N-ethylmaleimide
      insensitive factors are required for Ca2+-stimulated exocytosis of insulin.
AB  - Ca2+ stimulates exocytosis in permeabilized insulin-secreting cells. To
      investigate the putative cytosolic components involved in the Ca2+ response, HIT
      T15 cells (a pancreatic B-cell line) were permeabilized with streptolysin-O, a
      procedure that allows rapid exchange of soluble components including
      macromolecules. We found that in this cell preparation the secretory response to
      Ca2+ but not to guanosine 5'-[gamma-thio]triphosphate was lost as a function of
      time and could be restored by rat brain cytosol in a concentration-dependent
      manner. Reconstitutive activity of rat brain cytosol was found in a high
      molecular-mass heat-labile partially N-ethylmaleimide(NEM)-sensitive fraction.
      The NEM-sensitive factor (NSF) and the soluble NSF attachment protein (alpha
      SNAP) were found to be expressed in HIT-T15 cells and largely lost (about 30%
      remaining) from porated cells. Recombinant alpha-SNAP partially reconstituted the
      Ca2+ response when added to the permeabilized cells. Moreover, alpha-SNAP
      restored the effect of NEM-treated cytosol to the level observed for untreated
      cytosol. In contrast, NSF was ineffective when preincubated alone or with NEM
      treated cytosol. Our results indicate that both alpha-SNAP and NEM-insensitive
      cytosolic factors are involved in Ca2+-mediated exocytosis from endocrine HIT-T15
      cells.

PMID- 8660284
TI  - The 90 kDa heat-shock protein (hsp90) modulates the binding of the oestrogen
      receptor to its cognate DNA.
AB  - The role of heat-shock protein 90 (hsp90) in the regulation of the oestrogen
      receptor (ER) function is less well understood than for other steroid-hormone
      receptors because hsp90 is not involved in the stabilization or induction of a
      high-affinity ligand-binding state of ER nor in the inhibition of receptor
      dimerization. Electrophoretic mobility-shift assays, using purified ER and hsp90,
      were employed to investigate directly the effect of hsp90 on the ability of ER to
      bind to the oestrogen-response element (ERE) from the vitellogenin A2 gene.
      Contrary to models in which hsp90 binds to and passively inactivates steroid
      hormone receptors, our studies show that the binding of ER to ERE is inversely
      dependent on the relative concentration of hsp90. Exposure of purified ER-hsp90
      complexes to ERE led to the dissociation of hsp90 and concomitant specific
      binding of ER to ERE. We demonstrate that the amount of ER-ERE complex decreased
      with increasing concentrations of hsp90. Furthermore hsp90 dissociated preformed
      high-affinity ER-ERE complexes. Kinetic dissociation experiments indicate the
      hsp90 acts in a dynamic and specific process rather than by simple trapping of ER
      owing to its inherent off-rate. The receptor released from the ERE-bound state by
      hsp90 was recovered associated with hsp90 and was able to rebind to ERE. These
      results indicate that hsp90 does not suppress ER function merely by steric
      hindrance. On the basis of these results and others, we propose that, in vivo,
      hsp90 may play a dual role in ER function: (i) at a physiological temperature,
      hsp90 stabilizes an active form of the receptor in accordance with its general
      molecular chaperone role; (ii) at elevated temperatures or under other
      environmental stress, the increased cellular concentration of hsp90 negatively
      interferes with ER-dependent transcription, in accordance with the inhibition of
      gene transcription attributed to hsp90 after heat shock.

PMID- 8660285
TI  - Retinoic acid modulation of glutathione and cysteine metabolism in chondrocytes.
AB  - The major objective of this investigation was to determine the thiol status of
      chondrocytes and to relate changes in the level of glutathione and cysteine to
      maturation of the cells as they undergo terminal differentiation. Chondrocytes
      were isolated from the cephalic portion of chick embryo sterna and treated with
      all-trans retinoic acid for one week. We found that the addition of 100 nM
      retinoic acid to the cultures decreased the intracellular levels of glutathione
      and cysteine from 6.1 to 1.6 and 0.07 to 0.01 nmol/microgram DNA respectively;
      retinoic acid also caused a decrease in the extracellular concentration of
      cysteine. The decrease in chondrocyte thiols was dose and time dependent. To
      characterize other antioxidant systems of the sternal cell culture, the
      activities of catalase, glutathione reductase and superoxide dismutase were
      determined. Activities of all of those enzymes were high in the retinoic acid
      treated cells; the conditioned medium also contained these enzymes and the
      cytosolic isoenzyme of superoxide dismutase. We probed the specificity of the
      thiol response by using immature caudal chondrocytes. Unlike the cephalic cells,
      retinoic acid did not change intracellular glutathione and extracellular cysteine
      levels, although the retinoid caused a reduction in the intracellular cysteine
      concentration. Finally, we explored the effect of medium components on
      chondrocyte thiol status. We noted that while ascorbate alone did not change cell
      thiol levels, it did cause a 4-fold decrease in the extracellular cysteine
      concentration. When retinoic acid and ascorbic acid were both present in the
      medium, there was a marked decrease in the level of glutathione. In contrast, the
      phosphate concentration of the culture medium served as a powerful modulator of
      both glutathione and cysteine. Results of the study clearly showed that there is
      a profound decrease in intracellular levels of both cysteine and glutathione and
      that thiol levels are responsive to ascorbic acid and the medium phosphate
      concentration. These findings point to a critical role for thiols in modulating
      events linked to chondrocyte maturation and cartilage matrix synthesis and
      mineralization.

PMID- 8660286
TI  - Inositol phosphates in the duckweed Spirodela polyrhiza L.
AB  - We have undertaken an analysis of the inositol phosphates of Spirodela polyrhiza
      at a developmental stage when massive accumulation of InsP6 indicates that a
      large net synthesis is occurring. We have identified Ins3P, Ins(1,4)P2,
      Ins(3,4)P2 and possibly Ins(4,6)P2, Ins(3,4,6)P3, Ins(3,4,5,6)P4, Ins
      (1,3,4,5,6)P5, D- and/or L-Ins(1,2,4,5,6)P5 and InsP6 and revealed the likely
      presence of a second InsP3 with chromatographic properties similar to
      Ins(1,4,5)P3. The higher inositol phosphates identified show no obvious direct
      link to pathways of metabolism of second messengers purported to operate in
      higher plants, nor do they resemble the immediate products of plant phytase
      action on InsP6.

PMID- 8660287
TI  - Metabolic evidence for the order of addition of individual phosphate esters in
      the myo-inositol moiety of inositol hexakisphosphate in the duckweed Spirodela
      polyrhiza L.
AB  - The aquatic monocotyledonous plant Spirodela polyrhiza was labelled with [33P]Pi
      for short periods under non-equilibrium conditions. An InsP6 fraction was
      obtained and dissected by using enantiospecific (enzymic) and non-enantiospecific
      (chemical) means to determine the relative labelling of individual phosphate
      substituents on the inositol ring of InsP6. Phosphates in positions D-1, -2, -3, 
      4, -5 and -6 contained approx. 21%, 32-39%, 9-10%, 14-16%, 19-23% and 16-18% of
      the label respectively. We conclude from the foregoing, together with identities
      [described in the preceding paper, Brearley and Hanke (1996) Biochem. J. 314, 215
      225] of inositol phosphates found in this plant at a developmental stage
      associated with massive accumulation of InsP6, that synthesis of InsP6 from myo
      inositol proceeds according to the sequence Ins3P-->Ins(3,4)P2-->Ins(3,4,6)P3-
      >Ins(3,4,5,6)P4-->Ins(1,3,4,5,6 ) P5-->InsP6 in Spirodela polyrhiza. These
      results represent the first description of the synthetic sequence to InsP6 in the
      plant kingdom and the only comprehensive description of endogenous inositol
      phosphates in any plant tissue. The sequence described differs from that reported
      in the slime mould Dictyostelium discoideum.

PMID- 8660288
TI  - Hepatocyte growth factor and transforming growth factor beta regulate 6
      phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression in rat
      hepatocyte primary cultures.
AB  - Hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta) are
      believed to be of major importance for hepatic regeneration after liver damage.
      We have studied the effect of these growth factors on fructose 2,6-bisphosphate
      (Fru-2,6-P2) levels and the expression of 6-phosphofructo-2-kinase/fructose-2,6
      bisphosphatase (6PF2K/Fru-2,6-BPase) in rat hepatocyte primary cultures. Our
      results demonstrate that HGF activates the expression of the 6PF2K/Fru-2,6-BPase
      gene by increasing the levels of its mRNA. As a consequence of this activation,
      the amount of 6PF2K/Fru-2,6-BPase protein and 6-phosphofructo-2-kinase activity
      increased, which was reflected by a rise in Fru-2,6-P2 levels. In contrast, TGF
      beta decreased the levels of 6PF2K/Fru-2,6-BPase mRNA, which led to a decrease in
      the amount of 6PF2K/Fru-2,6-BPase protein and Fru-2,6-P2. The different actions
      of HGF and TGF-beta on 6PF2K/Fru-2,6-BPase gene expression are concomitant with
      their effect on cell proliferation. Here we show that, in the absence of
      hormones, primary cultures of hepatocytes express the F-type isoenzyme. In
      addition, HGF increases the expression of this isoenzyme, and dexamethasone
      activates the L-type isoform. HGF and TGF-beta were able to inhibit this
      activation.

PMID- 8660289
TI  - Molecular cloning and functional identification of a plant ornithine
      decarboxylase cDNA.
AB  - A cDNA for a plant ornithine decarboxylase (ODC), a key enzyme in putrescine and
      polyamine biosynthesis, has been isolated from root cultures of the solanaceous
      plant Datura stramonium. Reverse transcription-PCR employing degenerate
      oligonucleotide primers representing conserved motifs from other eukaryotic ODCs
      was used to isolate the cDNA. The longest open reading frame potentially encodes
      a peptide of 431 amino acids and exhibits similarity to other eukaryotic ODCs,
      prokaryotic and eukaryotic arginine decarboxylases (ADCs), prokaryotic meso
      diaminopimelate decarboxylases and the product of the tabA gene of Pseudomonas
      syringae cv. tabaci. Residues involved at the active site of the mouse ODC are
      conserved in the plant enzyme. The plant ODC does not possess the C-terminal
      extension found in the mammalian enzyme, implicated in rapid turnover of the
      protein, suggesting that the plant ODC may have a longer half-life. Expression of
      the plant ODC in Escherichia coli and demonstration of ODC activity confirmed
      that the cDNA encodes an active ODC enzyme. This is the first description of the
      primary structure of a eukaryotic ODC isolated from an organism where the
      alternative ADC routine to putrescine is present.

PMID- 8660290
TI  - All-trans-retinoyl beta-glucuronide: new procedure for chemical synthesis and its
      metabolism in vitamin A-deficient rats.
AB  - All-trans-retinoyl beta-glucuronide (RAG) was chemically synthesized in high
      yields (up to 79%) by a new procedure involving the reaction of the
      tetrabutylammonium salt of glucuronic acid with all-trans-retinoic acid (RA) via
      the imidazole or triazole derivative. When RAG was fed orally to vitamin A
      deficient rats, RA was identified as the major metabolite in the serum within
      hours of administration of RAG. Very little or no RAG was detected in the serum.
      Thus RAG, which was not appreciably hydrolysed to RA in vitamin A-sufficient rats
      [Barua and Olson (1987) Biochem. J. 263, 403-409], was rapidly converted into RA
      in vitamin A-deficient rats.

PMID- 8660291
TI  - Fatty acid binding and conformational stability of mutants of human muscle fatty
      acid-binding protein.
AB  - Human muscle fatty acid-binding protein (M-FABP) is a 15 kDa cytosolic protein
      which may be involved in fatty acid transfer and modulation of non-esterified
      fatty acid concentration in heart, skeletal muscle, kidney and many other
      tissues. Crystallographic studies have suggested the importance of the amino
      acids Thr-40, Arg-106, Arg-126 and Tyr-128 for the hydrogen bonding network of
      the fatty acid carboxylate group. Two phenylalanines at 16 and 57 are positioned
      to interact with the acyl chain of the fatty acid. We prepared 13 mutant proteins
      by site-directed mutagenesis and tested them for fatty acid binding and
      stability. Substitution of amino acids Phe-16, Arg-106 or Arg-126 created
      proteins which showed a large decrease in or complete loss of oleic acid binding.
      Substitution of Phe-57 by Ser or Val and of Tyr-128 by Phe had no great effect.
      The stability of the mutant proteins was tested by denaturation studies on the
      basis of fatty acid binding or tryptophan fluorescence and compared with that of
      the wild-type M-FABP. There was no direct relationship between fatty acid-binding
      activity and stability. Less stable mutants (F57S and Y128F) did not show a
      marked change in fatty acid-binding activity. Substitution of Arg-126 by Gln or
      Arg-106 by Thr eliminated binding activity, but the former mutant protein showed
      wild-type stability, in contrast to the latter. The results are in agreement with
      crystallographic data.

PMID- 8660292
TI  - Postnatal selective suppression of lipoprotein lipase gene expression in brown
      adipose tissue (relative to the expression of the gene for the uncoupling
      protein) is not due to adrenergic insensitivity: a possible specific inhibitory
      effect of colostrum.
AB  - The levels of mRNA coding for the uncoupling protein (UCP) and for lipoprotein
      lipase (LPL) were monitored in the brown adipose tissue of newborn rat pups. At 5
      h after birth, the mRNA levels of UCP and LPL were high in pups exposed singly to
      28 degrees C and low in pups kept singly at thermoneutrality (36 degrees C); in
      pups staying with the dam, the UCP mRNA levels were intermediate. However, the
      LPL mRNA levels were lower in pups staying with the dam than in pups at 36
      degrees C, implying that factors additional to environmental temperature
      influenced LPL gene expression. Injection of noradrenaline into pups at
      thermoneutrality (36 degrees C) led to increases in UCP and LPL gene expression,
      but noradrenaline injections had no further effect in cold-exposed pups. The
      adrenergic effects were mediated via beta-adrenergic receptors. The cold-induced
      increases in both UCP and LPL gene expression were abolished by the beta
      adrenergic antagonist propranolol. Thus differences in adrenergic responsiveness
      could not explain the differential expression of the UCP and LPL genes observed
      in pups staying with the dam. The presence of a physiological suppressor was
      examined by feeding single pups at 28 degrees C with different foods: nothing,
      water, Intralipid, cow's milk, rat milk and rat colostrum. None of these agents
      led to suppression of UCP gene expression, but colostrum led to a selective
      suppression of LPL gene expression. It was concluded that the genes for UCP and
      LPL were responsive to adrenergic stimuli immediately after birth, and it is
      suggested that a component of rat colostrum can selectively suppress LPL gene
      expression.

PMID- 8660293
TI  - Emulsification and lipolysis of triacylglycerols are altered by viscous soluble
      dietary fibres in acidic gastric medium in vitro.
AB  - This in vitro study was designed to test the hypothesis that soluble dietary
      fibres can alter the process of intragastric lipid emulsification and possibly
      subsequent triacylglycerol lipolysis. Three guar gums, two pectins and gum arabic
      were dissolved in acidic gastric medium in the concentration range 0.3-2.0%
      (w/v). Viscosities of fibre solutions were measured and apparent viscosities
      varied over a wide range (0.7-77 mPa/s). Emulsification of a lipid mixture
      (triolein/phosphatidylcholine/cholesterol) was performed under mild conditions in
      the presence of increasing concentrations of soluble fibres. The amount of
      emulsified lipid was not affected whereas the size of the emulsified droplets was
      increased by raising the concentration of viscous fibres only. The droplet size
      (r=0.75, P=0.006) and overall droplet surface area (r=-0.69, P=0.009) were
      strongly correlated with the medium viscosity in the range 0-20 mPa/s. The
      addition of solutions of viscous fibres to a preformed standard emulsion did not
      change the initial velocity of human gastric lipase reaction. Conversely, when
      emulsions prepared in the presence of fibres (i.e. with different droplet sizes)
      were incubated with excess gastric enzyme for 2 h, the high-viscosity guar gum
      significantly reduced the extent of triacylglycerol lipolysis, as compared with
      control and low- or medium-viscosity fibres. In conclusion, the data obtained
      show that reducing emulsification of dietary lipids in the mildly acid medium
      found in the stomach is a mechanism by which soluble viscous fibres can alter
      lipid assimilation.

PMID- 8660294
TI  - A cleavage-site-directed inhibitor of interleukin-1 beta-converting enzyme-like
      proteases inhibits apoptosis in primary cultures of rat hepatocytes.
AB  - Apoptosis induced in primary hepatocytes by transforming growth factor beta1 and
      staurosporine produced chromatin condensation, DNA cleavage is detected by in
      situ end-labelling, field inversion and conventional gel electrophoresis, and
      cell detachment. These effects were abolished by benzyloxycarbonyl
      valinylalanylaspartylfluoromethyl ketone, a cleavage-site-directed inhibitor of
      interleukin-1beta-converting enzyme-like proteases, and this finding suggests
      that these enzymes are involved in liver apoptosis.

PMID- 8660295
TI  - Resistance of lipoprotein(a) to lipid peroxidation induced by oxygenated free
      radicals produced by gamma radiolysis: a comparison with low-density lipoprotein.
AB  - Lipid peroxidation of lipoprotein(a) [Lp(a)] by defined oxygen-centred free
      radicals (O2-/OH, O2-, O2-/HO2) produced by gamma radiolysis was compared with
      that of paired samples of low-density lipoprotein (LDL). Lp(a) appeared to be
      more resistant to oxidation than LDL, as indicated by the kinetic study of four
      markers of lipid peroxidation; decrease in vitamin E, formation of conjugated
      dienes and aldehydic products, and modification of electrophoretic mobility. In
      contrast, similar kinetics of lipid peroxidation were obtained for LDL and Lp(a
      ), which is the lipoparticle issued following the reductive cleavage of
      apolipoprotein(a) from Lp(a), thus suggesting that the greater resistance of
      Lp(a) to lipid peroxidation was due to the presence of apolipoprotein(a). Lipid
      peroxidation of Lp(a) and LDL induced by peroxyl radicals, which were produced by
      an azo compound [2,2'-azobis-(2-amidinopropane)dihydrochloride], confirmed both
      the resistance of Lp(a) to lipid peroxidation and the propensity of Lp(a-) to
      exhibit a greater susceptibility to oxidation than intact Lp(a). Our findings
      also indicated that the high content of apolipoprotein(a) in N-acetylneuraminic
      acid residues was only partly responsible for the resistance of Lp(a) to
      oxidation.

PMID- 8660296
TI  - High-density lipoprotein 3 physicochemical modifications induced by interaction
      with human polymorphonuclear leucocytes affect their ability to remove
      cholesterol from cells.
AB  - 1. We have recently reported that a short incubation (60 min) in vitro of high
      density lipoprotein (HDL) 3 with human polymorphonuclear leucocytes (PMNs) leads
      to a proteolytic cleavage of apolipoprotein (apo) AII and to a change in the
      distribution of apo AI isoforms [Cogny, Paul, Atger, Soni and Moatti (1994) Eur.
      J. Biochem. 222, 965-973]. Since PMNs have been observed to be present in the
      earliest atherosclerotic lesions for a number of days, we investigated the HDL3
      physiochemical modifications induced by in vitro interaction for a long period of
      time (24 h) with PMNs and the consequences of the changes on the ability of HDL3
      to remove cholesterol from cells. 2. The stimulated PMN modification of HDL3 over
      24 h resulted in a partial loss of protein with no variation in lipid molar ratio
      and a loss of 50% of HDL alpha-tocopherol content. The decrease in total protein
      was due first to a complete degradation of apo AII, and secondly to a partial
      loss of apo AI. The apo AI remaining on the particles was in part hydrolysed and
      the apo AI-1 isoform was completely shifted to the apo AI-2 isoform. These apo
      changes were accompanied by a displacement of the native HDL3 apparent size
      toward predominantly larger particles. 3. The ability of PMN-modified HDL3 to
      remove 3H-labelled free cholesterol from cells was measured in two cell lines:
      Fu5AH rat hepatoma cells and J774 mouse macrophages. HDL3 which had only a
      limited contact with PMNs (60 min) showed only a small non-significant reduction
      in the efficiency of cholesterol efflux. On the other hand, compared with native
      HDL3, HDL3 modified by PMNs for 24 h had a markedly reduced ability to remove
      cholesterol from cells, regardless of the type of cell. 4. The results suggest
      that PMN-modified HDL3, if occurring in vivo, could contribute to acceleration of
      the atherogenic process by decreasing the cholesterol efflux from cells.

PMID- 8660297
TI  - Single-strand-DNA-binding factors specifically recognize the pyrimidine element
      in the chick alpha2(I) collagen gene promoter.
AB  - A pyrimidine element with mirror repeats centered at position -192 bp of the
      chick alpha2(I) collagen promoter interacts with sequence-specific DNA-binding
      factors. These factors bind to only the pyrimidine strand of this region and have
      no affinity for the complementary purine strand. Binding activity is also seen
      with the double-stranded form of this element, but with less affinity than to the
      single-stranded pyrimidine species. Southwestern blot analyses have shown that
      proteins of 80 and 134 kDa in chick embryo fibroblast nuclear-extracts bind to
      the pyrimidine strand, whereas only a 134 kDa DNA-binding protein was found in
      chondrocyte nuclear extracts. The binding mechanism of these nuclear proteins
      with single-stranded DNA might be based on a non-B-DNA conformation of the
      pyrimidine element. The position of this binding site in the promoter region, its
      potential for adopting an unusual secondary structure and the presence of the 80
      kDa binding factor in chick embryo fibroblasts, but not in chondrocytes, suggest
      a possible role for this factor in the expression of the alpha2(I) collagen gene.

PMID- 8660298
TI  - Anionic phospholipids bind to L-selectin (but not E-selectin) at a site distinct
      from the carbohydrate-binding site.
AB  - It is known that L-selectin binds to glycoconjugates containing the
      tetrasaccharide sialyl Lewis X in a Ca2+-dependent manner. In addition, a number
      of other acidic oligosaccharides (for example heparin or chondroitin sulphate) or
      glycolipids (for example sulphatides) bind to L-selectin independent of cations.
      In this paper we have established that L-selectin binds to charged phospholipids,
      such as cardiolipin and phosphatidylserine, but not to neutral phospholipids such
      as phosphatidylcholine. No interaction between E-selectin and any phospholipid
      was observed. The interaction between L-selectin cardiolipin was inhibited by
      dextran sulphate, fucoidan, mannose 6-phosphate and monoclonal antibodies
      previously reported to block the interaction between L-selectin and its natural
      ligands. Analysis of the amino acid sequence of the selectins indicated that L
      selectin, but no E-selectin, contains a sequence homologous to the putative
      cardiolipin-binding epitope found in plasma glycoprotein beta2I. Glycoprotein
      beta2I and a peptide corresponding to the putative cardiolipin-binding epitope in
      beta2I inhibited the binding of L-selectin to cardiolipin or fucoidin. Based on
      the binding characteristics, sequence analysis and structural modelling of L
      selectin, we suggest that the amino acid sequence KKNKED (residues 84-89) is a
      novel site for the binding of acidic species to L-selectin. This motif is
      localized close to the putative carbohydrate-binding domain of L-selectin and may
      be a second site within the lectin domain for the interaction of leucocyte L
      selectin with its natural endothelial ligands.

PMID- 8660299
TI  - Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in
      human melanocytes.
AB  - To understand the signalling mechanisms involved in the dual stimulatory effects
      of endothelin-1 (ET-1) on DNA synthesis and melanization in cultured human
      melanocytes, we analysed the biological profile of ET-1 receptor and determined
      the effects of ET-1 on the protein kinase C, cyclic AMP system and mitogen
      activated protein kinase (MAP kinase) in comparison with their relevant
      stimulants. The photoaffinity labelling of ET-1 receptors with Denny-Jaff
      reagents revealed an ET-1 receptor with a molecular mass of 51 kDa in human
      melanocytes. The ET(A) receptor subtype-sensitive antagonist BQ123(50 nM) or
      pertussis toxin (100 ng/ml) significantly suppressed the ET-1-induced
      intracellular calcium mobilization, indicating the presence of pertussis toxin
      sensitive G-protein-coupled ET(A) receptors. An assay of protein kinase C
      activity revealed that 10nM ET-1 translocated cytosolic protein kinase C to
      membrane-bound protein kinase C within 5 min of the start of incubation. In
      contrast, receptor-mediated melanocyte activation by ET-1 was accompanied by an
      elevated level of cyclic AMP (4-fold over control) after 10-60 min of incubation,
      whereas 60 min of incubation of human melanocytes with c-Kit or c-Met ligands
      such as stem cell factor (10 nM) or basic fibroblast growth factor (10 nM) did
      not elevate the cyclic AMP level. We have also demonstrated that a specific
      tyrosine kinase inhibitor, tyrphostin B-42 (10 microM), inhibited the ET-1
      induced growth stimulation, suggesting the involvement of the tyrosine kinase
      pathway in growth stimulation. Consistently, an assay of MAP kinase revealed that
      ET-1 caused a 10-fold activation of MAP kinase after 5 min of incubation with
      human melanocytes in a similar way to tyrosine kinase ligands such as stem cell
      factor and hepatocyte growth factor. Further, the DNA synthesis stimulated by the
      c-Kit ligand stem cell factor at a concentration of 1 nM was synergistically
      enhanced by 5 nM ET-1. These results suggest that ET-induced dual cellular events
      in human melanocytes are closely associated with cross-talk between the protein
      kinase C and A and tyrosine kinase pathways.

PMID- 8660300
TI  - Identification of a nuclear-specific cyclophilin which interacts with the
      proteinase inhibitor eglin c.
AB  - We have identified a novel human cyclophilin (hCyP-60) which interacts with the
      proteinase inhibitor eglin c using the yeast two-hybrid system. A cDNA isolated
      from a Raji B lymphocyte library reveals a domain showing sequence similarity to
      known cyclophilins flanked by unique N- and C-terminal residues. In addition,
      hCyP-60 contains a tyrosine residue (Tyr 389) instead of a tryptophan residue
      found in most eukaryotic cyclophilins at a position important for cyclosporin
      binding. Northern and Western analysis reveal widespread expression with
      considerable tissue-specific variation. Specifically, the highest levels of mRNA
      are detected in the thymus, pancreas, testis, and K-562 cell line, while the most
      protein is detected in the kidney. Immunohistochemistry indicates a nuclear
      specific localization both in transfected cells and tissue sections. hCyP-60's
      specific subcellular localization and conserved amino acid sequence suggest that
      it may play a specific role in the nucleus.

PMID- 8660301
TI  - Overproduction, purification and characterization of M.EcoHK31I, a bacterial
      methyltransferase with two polypeptides.
AB  - The two overlapping genes coding for EcoHK31I methyltransferase have previously
      been cloned, sequenced and expressed [Lee, Kam and Shaw (1995) Nucleic Acids Res.
      23, 103-108]. Here we describe protocols developed to purify polypeptides alpha
      and beta together or separately, to apparent homogeneity by various
      chromatographic media. M.EcoHK31I is a heterodimer with a native molecular mass
      of 61 kDa. Its specific activity towards non-methylated lambda DNA was 3.0 x
      10(5) units per mg of protein. The respective denatured molecular masses of
      polypeptides alpha and beta were 38 and 23 kDa, and their pI values were 8.7 and
      6.8. Initial rate kinetic parameters of the native enzyme were 2.0 nM, 0.58
      microM and 3 min-1 for KmDNA, KmAdoMet and kcat. respectively, where AdoMet
      stands for S-adenosyl-L-methionine. Fully active enzyme was reconstituted by co
      purifying the two separately synthesized polypeptides, and activity assays
      confirmed our previous finding that two polypeptides were needed to methylate
      substrate DNA.

PMID- 8660302
TI  - Collagen type IX from human cartilage: a structural profile of intermolecular
      cross-linking sites.
AB  - Type IX collagen, a quantitatively minor collagenous component of cartilage, is
      known to be associated with and covalently cross-linked to type II collagen
      fibrils in chick and bovine cartilage. Type IX collagen molecules have also been
      shown to form covalent cross-links with each other in bovine cartilage. In the
      present study we demonstrate by structural analysis and location of cross-linking
      sites that, in human cartilage, type IX collagen is covalently cross-linked to
      type II collagen and to other molecules of type IX collagen. We also present
      evidence that, if the proteoglycan form of type IX collagen is present in human
      cartilage, it can only be a minor component of the matrix, similar to findings
      with bovine cartilage.

PMID- 8660303
TI  - Lysosomal alpha-glucosidase: cell-specific processing and altered maturation in
      HT-29 colon cancer cells.
AB  - We have previously described the abnormal localization of resident Golgi proteins
      and O-glycans in the rough endoplasmic reticulum of mucin-secreting HT-29 M6
      colon cancer cells, suggesting altered protein trafficking in these cells [Egea,
      Franci, Gambus, Lesuffleur, Zweibaum and Real (1993) J. Cell Sci. 105, 819-830].
      In the present work, we have chosen lysosomal alpha-glucosidase as a reporter to
      examine the intracellular traffic of glycoproteins in M6 cells. We have compared
      the synthesis and processing of alpha-glucosidase in mucin-secreting M6 cells and
      in Caco-2 colon cancer cells, the latter resembling normal absorptive intestinal
      epithelium. Our results show that alpha-glucosidase processing and secretion is
      markedly delayed in M6 cells as compared to Caco-2 cells or normal fibroblasts,
      and this delay is caused by an accumulation of alpha-glucosidase precursor form
      in the trans-Golgi network. Furthermore, treatment in Caco-2 cells with brefeldin
      A led to changes in alpha-glucosidase maturation similar to those observed in
      untreated M6 cells. To determine whether altered processing occurs in other
      cultured cells, a panel of cancer cell lines and cultures from normal exocrine
      pancreas were examined. In pancreas-derived cultures, alpha-glucosidase showed a
      processing pattern different from that described until now. Only HT-29 cells and
      HT-29-derived subpopulations displayed a defect in alpha-glucosidase maturation.
      In conclusion, alpha-glucosidase processing is more diverse than has previously
      been described; this finding may have tissue-specific functional implications.

PMID- 8660304
TI  - Purification and characterization of oil-bodies (oleosomes) and oil-body boundary
      proteins (oleosins) from the developing cotyledons of sunflower (Helianthus
      annuus L.)
AB  - Oil-bodies, from the immature cotyledons of sunflower (Helianthus annuus L.),
      were difficult to purify to homogeneity using conventional techniques. The major
      protein contaminants were albumin and globulin storage proteins. A protocol has
      been developed, therefore, based upon the stringent washing of the oil-body
      fraction in 9 M urea, which effectively removed almost all the contaminating
      protein as judged by SDS/PAGE. The urea-washed oil-bodies were enriched in two
      major proteins of M(r) 19000 and 20000. These proteins were oleosins as
      demonstrated by their amino acid compositions and the sequence analysis of
      peptides produced by CNBr cleavage. Far-UV CD spectra of the oleosins in
      trifluoroethanol, trifluoroethanol/water mixtures and as mixed micelles in SDS,
      were typical of alpha-helical proteins with alpha-helical contents of some 55%.
      The phospholipid content of the urea-washed preparations was less than 0.1% of
      that required to form a half-unit membrane surrounding the oil-body. The oil-body
      surface therefore appears to be an unusual and novel structure, covered largely
      by an oleosin protein coat or pellicle rather than a conventional fluid membrane,
      half-unit or otherwise.

PMID- 8660305
TI  - Glucose stimulates voltage- and calcium-dependent inositol trisphosphate
      production and intracellular calcium mobilization in insulin-secreting beta TC3
      cells.
AB  - The cellular processes leading to a rise in the intracellular free Ca2+
      concentration ([Ca2+]i) after glucose stimulation and K+ depolarization were
      investigated in insulin-secreting beta TC-3 cells. Stimulation with 11.2mM
      glucose causes inositol 1,4,5-trisphosphate production and release of Ca2+ from
      intracellular stores. A strong correlation was observed between the changes in
      Ins(1,4,5)P3 concentration and the rise in [Ca2+]i, consistent with the former
      compound being responsible for release of Ca2+ from intracellular stores. The
      increase in Ins(1,4,5)P3 production was reduced by 68 +/- 4% when [Ca2+]i was
      kept low on glucose stimulation by loading cells with the Ca2+ chelator 1,2-bis(2
      aminophenoxy)ethane-NNN'N'-tetra-acetic acid (BAPTA). The Ins(1,4,5)P3 production
      was prevented in cells hyperpolarized with diazoxide, an opener of ATP-sensitive
      K+-channels, consistent with the membrane potential controlling the rate of
      Ins(1,4,5)P3 synthesis. Depolarizing K+ concentrations evoked changes in [Ca2+]i
      and Ins(1,4,5)P3 production in both the presence and the absence of extracellular
      Ca2+, and from the relation between the extracellular K+ concentration and
      membrane potential we found a half-maximal Ins(1,4,5)P3 production by a 28mV
      depolarization from a resting potential of -56mV and by a rise in [Ca2+]i of
      390nM. We conclude that stimulation-induced changes in membrane potential and
      [Ca2+]i are important in controlling Ins(1,4,5)P3 production in beta TC-3 cells
      and that glucose-stimulated Ca2+ mobilization from intracellular stores is due to
      voltage-dependent Ins(1,45)P3 production and depends on the concurrent increase
      in [Ca2+]i.

PMID- 8660306
TI  - Extracellular calcium concentration controls the frequency of intracellular
      calcium spiking independently of inositol 1,4,5-trisphosphate production in HeLa
      cells.
AB  - Stimulation of single HeLa cells with histamine evoked repetitive increases of
      the intracellular calcium ion concentration (Ca2+ spikes). The frequency of Ca2+
      spiking increased as the extracellular hormone concentration was elevated. In
      addition, the frequency of Ca2+ spiking could be accelerated by increasing the
      extracellular Ca2+ concentration ([Ca2+]0) in the presence of a constant hormone
      concentration. The range of [Ca2+]0 over which the spiking frequency could be
      titrated was nominally-zero to 10mM, being half-maximally effective at approx. 1
      and 2.5mM for 37 and 22 degrees C respectively. The effect of [Ca2+]0 on inositol
      phosphates production was also examined. Changes of [Ca2+]0 over a range which
      had been found to affect the frequency of Ca2+ spiking did not have any effect on
      the rate of myo-inositol 1,4,5-trisphosphate (InsP3) production, although an
      increase in inositol phosphates production was observed as [Ca2+]0 was increased
      from zero to values giving less than half-maximal Ca2+ spike frequency. These
      data suggest that at low Ca2+ spike frequency, Ca2+-stimulated activation of
      phospholipase C may contribute to Ca2+ spiking in HeLa cells, but under some
      conditions the availability of Ca2+ to the intracellular stores, rather than
      changes in the rate of InsP3 production, determines the Ca2+ spike frequency.

PMID- 8660307
TI  - Rhodamine 123 efflux transporter in Haloferax volcanii is induced when cultured
      under 'metabolic stress' by amino acids: the efflux system resembles that in a
      doxorubicin-resistant mutant.
AB  - In this paper, we report that an archaebacterium, Haloferax volcanii, cultured in
      medium containing a large excess of amino acids showed very low levels of
      rhodamine 123 (RH123), which is a potent substrate for P-glycoprotein and the
      bacterial multidrug efflux transporter. This low level involved the active efflux
      of RH123 from the cells. The level of intracellular RH123 was increased and the
      efflux inhibited by the Ca2+-channel antagonist verapamil and also by various
      anti-cancer drugs. The efflux transporter was suggested to be ATP-driven. We have
      previously selected a mutant of H. volcanii with resistance to doxorubicin, by
      repeatedly culturing cells in 1.5 microM doxorubicin [Miyauchi, Komatsubara and
      Kamo (1992) Biochim. Biophys. Acta 1110, 144-150]. The acquisition of resistance
      to doxorubicin involves the active expulsion of lipophilic drugs such as RH123
      and doxorubicin. It is notable that the drug spectrum and ATP-dependency of the
      amino acid-induced efflux transporter resemble those of the efflux transporter
      induced by doxorubicin.

PMID- 8660308
TI  - Co-purification from Escherichia coli of a plant beta-glucosidase-glutathione S
      transferase fusion protein and the bacterial chaperonin GroEL.
AB  - The coding sequence of the mature cyanogenic beta-D-glucosidase (beta-D-glucoside
      glucohydrolase, EC 3.2.1.21) (linamarase) of Manihot esculenta Crantz (cassava)
      was cloned into the vector pGEX-2T and expressed in Escherichia coli. The
      bacterial chaperonin GroEL [Braig, Otwinowski, Hedge, Boisvert, Joachimiak,
      Horwich and Sigler (1994) Nature (London) 371, 578-586] was found to be tightly
      associated with the fusion protein and co-purified with it. In the presence of
      excess MgATP, release and folding of the fusion beta-glucosidase were
      demonstrated by a fast increase in both linamarase and p-nitrophenyl-beta-D
      glucopyranosidase activity at a low protein concentration. A slow endogenous
      folding process was also detected by activity measurements. Michaelis constants
      (Km) and the ratio between the maximal velocities and efficiency constants
      (Vmax., Vmax./Km) for the hydrolysis of the natural substrate, linamarin, and p
      nitrophenyl beta-D-glucopyranoside (PNP-Glc) by the recombinant protein were
      found to be almost identical with those of the native glycosylated plant enzyme
      [Keresztessy, Kiss and Hughes (1994) Arch. Biochem. Biophys. 314, 142-152].
      Molecular dissociation constants for the free enzyme (pK(E)1, pK(E)2) obtained
      with linamarin and PNP-Glc, and the enzyme substrate complexes (pK(ES)1, pK(ES)2)
      were also in accordance with that of the original protein. The reactive substrate
      analogue N-bromoacetyl beta-D-glucosylamine inactivated the fusion enzyme
      according to pseudo-first-order kinetics with first-order rate constant (k1=0.007
      min-1) and apparent inhibition constants (k1=20 mM) comparable with those of the
      plant protein [Keresztessy, Kiss and Hughes (1994) Arch. Biochem. Biophys. 315,
      323-330]. In comparison with the native glycosylated plant protein, the
      recombinant protein was, however, found to be extremely sensitive to proteolysis
      and misfolding.

PMID- 8660309
TI  - Effects of nucleotide substitutions within the T-loop of precursor tRNAs on
      interaction with ATP/CTP:tRNA nucleotidyltransferases from Escherichia coli and
      yeast.
AB  - Recognition of tRNA and tRNA-like substrates by the enzyme ATP/CTP:tRNA
      nucleotidyltransferase requires chemically intact nucleotides within the T-loop,
      especially at positions 57 and 58, which are invariant purines among naturally
      occurring tRNAs. To test the effects of base substitutions at these positions,
      which are distant from the site of catalysis, we synthesized mutant tRNA(Glu)
      molecules. These in vitro-synthesized RNAs also contained an extra 33 bases at
      the 5' end and lacked post-transcriptionally modified bases. The precursor tRNAs
      were used as substrates for nucleotidyltransferases from Escherichia coli and
      yeast. Substitution of cytidines at either position 57 or 58 had dramatic
      inhibitory effects on recognition by both enzymes, including raising the apparent
      Km and lowering the apparent Vmax.; substitution of an adenosine at position 57
      or a uridine at position 58 inhibited the reaction only slightly by comparison.
      Our results demonstrate that the identities of nucleotides at positions 57 and 58
      are relevant to recognition by nucleotidyltransferase, and that a purine is
      required at position 57. The extra bases at the 5' end and the lack of post
      transcriptionally modified bases did not substantially inhibit interaction with
      the enzyme, as judged by the wild-type precursor tRNA(Glu) acting as an effective
      substrate for both enzymes in the presence of equal concentrations of appropriate
      tRNA substrates isolated from E. coli.

PMID- 8660310
TI  - Identification of the domains of neuronal nitric oxide synthase by limited
      proteolysis.
AB  - Nitric oxide synthase (EC 1.14.13.39) binds arginine and NADPH as substrates, and
      FAD, FMN, tetrahydrobiopterin, haem and calmodulin as cofactors. The protein
      consists of a central calmodulin-binding sequence flanked on the N-terminal side
      by a haem-binding region, analogous to cytochrome P-450, and on the C-terminal
      side by a region homologous with NADPH:cytochrome P-450 reductase. The structure
      of recombinant rat brain nitric oxide synthase was analysed by limited
      proteolyis. The products were identified by using antibodies to defined
      sequences, and by N-terminal sequencing. Low concentrations of trypsin produced
      three fragments, similar to those in a previous report [Sheta, McMillan and
      Masters (1994) J. Biol. Chem. 269, 15147-15153]: that of Mr approx. 135000 (N
      terminus Gly-221) resulted from loss of the N-terminal extension (residues 1-220)
      unique to neuronal nitric oxide synthase. The fragments of Mr 90000 (haem region)
      and 80000 (reductase region, N-terminus Ala-728) were produced by cleavage within
      the calmodulin-binding region. With more extensive trypsin treatment, these
      species were shown to be transient, and three smaller, highly stable fragments of
      Mr 14000 (N-terminus Leu-744 within the calmodulin region), 60000 (N-terminus Gly
      221) and 63000 (N-terminus Lys-856 within the FMN domain) were formed. The
      species of Mr approx. 60000 represents a domain retaining haem and nitroarginine
      binding. The two species of Mr 63000 and 14000 remain associated as a complex.
      This complex retains cytochrome c reductase activity, and thus is the complete
      reductase region, yet cleaved at Lys-856. This cleavage occurs within a sequence
      insertion relative to the FMN domain present in inducible nitric oxide synthase.
      Prolonged proteolysis treatment led to the production of a protein of Mr approx.
      53000 (N-terminus Ala-953), corresponding to a cleavage between the FMN and FAD
      domains. The major products after chymotryptic digestion were similar to those
      with trypsin, although the pathway of intermediates differed. The haem domain was
      smaller, starting at residue 275, yet still retained the arginine binding site.
      These data have allowed us to identify stable domains representing both the
      arginine/haem-binding and the reductase regions.

PMID- 8660311
TI  - Expression in Escherichia coli and characterization of a reconstituted
      recombinant 7Fe ferredoxin from Desulfovibrio africanus.
AB  - Desulfovibrio africanus ferredoxin III is a monomeric protein (molecular mass of
      6585 Da) that contains one [3Fe-4S]1+/0 and one [4Fe-4S]2+/1+ cluster when
      isolated aerobically. The amino acid sequence consists of 61 amino acids,
      including seven cysteine residues that are all involved in co-ordination to the
      clusters. In order to isolate larger quantities of D. africanus ferredoxin III,
      we have overexpressed it in Escherichia coli by constructing a synthetic gene
      based on the amino acid sequence of the native protein. The recombinant
      ferredoxin was expressed in E. coli as an apoprotein. We have reconstituted the
      holoprotein by incubating the apoprotein with excess iron and sulphide in the
      presence of a reducing agent. The reconstituted recombinant ferredoxin appeared
      to have a lower stability than that of wild-type D. africanus ferredoxin III. We
      have shown by low-temperature magnetic circular dichroism and EPR spectroscopy
      that the recombinant ferredoxin contains a [3Fe-4S]1+/0 and a [4Fe-4S]2+/1+
      cluster similar to those found in native D. africanus ferredoxin III. These
      results indicate that the two clusters have been correctly inserted into the
      recombinant ferredoxin.

PMID- 8660312
TI  - Optical spectroscopic and reverse-phase HPLC analyses of Hg(II) binding to
      phytochelatins.
AB  - Optical spectroscopy and reverse-phase HPLC were used to investigate the binding
      of Hg(II) to plant metal-binding peptides (phytochelatins) with the structure
      (gammaGlu-Cys)2Gly, (gammaGlu-Cys)3Gly and (gammaGlu-Cys)4Gly. Glutathione
      mediated transfer of Hg(II) into phytochelatins and the transfer of the metal ion
      from one phytochelatin to another was also studied using reverse-phase HPLC. The
      saturation of Hg(II)-induced bands in the UV/visible and CD spectra of (gammaGlu
      Cys)2Gly suggested the formation of a single Hg(II)-binding species of this
      peptide with a stoichiometry of one metal ion per peptide molecule. The
      separation of apo-(gammaGlu-Cys)2Gly from its Hg(II) derivative on a C18 reverse
      phase column also indicated the same metal-binding stoichiometry. The UV/visible
      spectra of both (gammaGlu-Cys)3Gly and (gammaGlu-Cys)4Gly at pH 7.4 showed
      distinct shoulders in the ligand-to-metal charge-transfer region at 280-290 mm.
      Two distinct Hg(II)-binding species, occurring at metal-binding stoichiometries
      of around 1.25 and 2.0 Hg(II) ions per peptide molecule, were observed for
      (gammaGlu-Cys)3Gly. These species exhibited specific spectral features in the
      charge-transfer region and were separable by HPLC. Similarly, two main Hg(II)
      binding species of (gammaGlu-Cys)4Gly were observed by UV/visible and CD
      spectroscopy at metal-binding stoichiometries of around 1.25 and 2.5
      respectively. Only a single peak of Hg(II)-(gammaGlu-Cys)4Gly complexes was
      resolved under the conditions used for HPLC. The overall Hg(II)-binding
      stoichiometries of phytochelatins were similar at pH 2.0 and at pH 7.4,
      indicating that pH did not influence the final Hg(II)-binding capacity of these
      peptides. The reverse-phase HPLC assays indicated a rapid transfer of Hg(II) from
      glutathione to phytochelatins. These assays also demonstrated a facile transfer
      of the metal ion from shorter- to longer-chain phytochelatins. The strength of
      Hg(II) binding to glutathione and phytochelatins followed the order: gammaGlu-Cys
      Gly<(gammaGlu-Cys)2Gly<(gammaGlu-Cy s)3Gly<(gamma Glu-Cys)4Gly.

PMID- 8660313
TI  - Aplysia limacina myoglobin cDNA cloning: an alternative mechanism of oxygen
      stabilization as studied by active-site mutagenesis.
AB  - The isolation and cloning of the cDNA coding for myoglobin (Mb) from the mollusc
      Aplysia limacina is reported here. Five amino acid differences from the
      previously published protein sequence have been found in positions 22, 26, 27, 77
      and 80 by back transplanting the cDNA; some of these may be relevant for overall
      structure stabilization in this Mb. High-level expression of the holoprotein in
      Escherichia coli has been achieved in the presence of the haem precursor delta
      aminolevulinic acid, underlying the importance of tuning haem and apoprotein
      biosynthesis to achieve high-level expression of haemproteins in bacteria. The
      recombinant protein is identical to the protein purified from the mollusc buccal
      muscle. Native A. limacina Mb has an oxygen dissociation rate constant of 70 s(
      1) [as compared with the value of 15 s(-1) for sperm whale Mb, which displays
      His(E7) and Thr(E10)] (amino acid positions are referred to within the eight
      helices A-H of the globin fold). In order to understand the mechanism of oxygen
      stabilization in A. limacina Mb, we have prepared and investigated three active
      site mutants: two single mutants in which Val(E7) and Arg(E10) have been replaced
      by His and Thr, respectively, and a double mutant carrying both mutations. When
      Arg(E10) is substituted with Thr, the oxygen dissociation rate constant is
      increased from 70 s(-1) to more than 700 s(-1), in complete agreement with the
      previously proposed role of the former residue in ligand stabilization. In the
      His(E7)-containing single and double mutants, both displaying high oxygen
      dissociation rates, the stabilization of bound oxygen by the distal His is
      insufficient to slow down the ligand dissociation rate constant to the value of
      sperm whale Mb. These results essentially prove the hypothesis that in A.
      limacina Mb a mechanism of oxygen stabilization involving Arg(E10), and thus
      different from that mediated by His(E7), has evolved.

PMID- 8660314
TI  - Temporal patterns of changes in ATP/ADP ratio, glucose 6-phosphate and
      cytoplasmic free Ca2+ in glucose-stimulated pancreatic beta-cells.
AB  - Closure of ATP-sensitive K+ (K(ATP)) channels is part of the stimulus-secretion
      coupling mechanism in the pancreatic beta-cell, leading to membrane
      depolarization and influx of Ca2+ through voltage-sensitive L-type Ca2+ channels.
      The elevated ATP/ADP ratio seen in the presence of high levels of glucose has
      been postulated to mediate the glucose-induced closure of the K(ATP) channels and
      rise in cytoplasmic free Ca2+ concentration ([Ca2+]i), or alternatively to be a
      consequence of activation of mitochondrial dehydrogenases by the increase in
      [Ca2+]i. To distinguish between these two possibilities, the time course of the
      change in the ATP/ADP ratio was determined in comparison with that of [Ca2+]i. We
      here show that a severalfold rise in the ATP/ADP ratio occurs rapidly on
      stimulation of suspensions of mouse pancreatic beta-cells with glucose. The
      change in the ATP/ADP ratio is an early event that begins within 20-40 s and
      precedes the rise in [Ca2+]i. The temporal relationship indicates that the
      adenine nucleotide changes cannot be a consequence of the [Ca2+]i changes and may
      indeed be the connecting link between glucose metabolism and [Ca2+]i changes.
      When the cells were sequentially treated with high glucose concentration,
      clonidine and finally high extracellular Ca2+ concentration to induce
      synchronized oscillations in [Ca2+]i in the cell suspension, corresponding
      oscillations in the ATP/ADP ratio were observed. Glucose 6-phosphate levels
      oscillated out of phase with the ATP/ADP ratio. These results support the
      hypothesis that the Ca2+ oscillations previously observed in glucose-stimulated
      single islets or beta-cells may reflect oscillations in the ATP/ADP ratio that
      accompany oscillatory glycolysis.

PMID- 8660315
TI  - Control of 6-(D-threo-1',2'-dihydroxypropyl) pterin (dictyopterin) synthesis
      during aggregation of Dictyostelium discoideum. Involvement of the G-protein
      linked signalling pathway in the regulation of GTP cyclohydrolase I activity.
AB  - 6-(D-threo-1',2'-Dihydroxypropylpterin (dictyopterin) has been identified in
      extracts of growing Dictyostelium dicoideum cells [Klein, Thiery and Tatischeff
      (1990) Eur. J. Biochem. 187, 665-669]. We demonstrate that it originates from GTP
      by de novo biosynthesis and that the first committed step is catalysed by GTP
      cyclohydrolase I, yielding dihydroneopterin triphosphate [neopterin is 6-(D
      erythro-1',2',3'-trihydroxypropyl) pterin]. The GTP cyclohydrolase I activity is
      found in the cytosolic fraction and in a membrane-associated form. The level of a
      0.9 kb mRNA coding for GTP cyclohydrolase I decreases to about 10% of its initial
      value within 2 h after Dictyostelium cells start development induced by
      starvation. In the cytosolic fraction, the specific activities of GTP
      cyclohydrolase I, as well as the concentrations of (6R/S)-5,6,7,8
      tetrahydrodictyopterin (H4dictyopterin), follow this decline of the mRNA level.
      In the particulate fraction, however, the specific activities of GTP
      cyclohydrolase I and, in consequence, H4dictyopterin synthesis, transiently
      increase and reach a maximum after 4-5 h of development. The time-course of
      H4dictyopterin concentrations in the starvation medium closely correlates with
      its production in the membrane fraction. The activity of membrane-associated GTP
      cyclohydrolase I can be increased by pre-incubation of the cell lysate with
      guanosine 5'-[gamma-thio]triphosphate and Mg2+. This GTP analogue does not serve
      as a substrate and has no direct effect on the enzyme activity, indicating that a
      G-protein-linked signalling pathway is involved in the regulation of GTP
      cyclohydrolase I activity and thus in H4dictyopterin production during early
      development of D. discoideum.

PMID- 8660316
TI  - Bradykinin increases ceramide and sphingosine content in human fibroblasts:
      possible involvement of glycosphingolipids.
AB  - Sphingolipid-derived products are recognized as second messengers able to mediate
      the action of extracellular signals such as cytokines and growth factors. In the
      present study it is shown that also bradykinin (BK), a pro-inflammatory peptide
      acting through G-protein-coupled receptors, is able to activate sphingolipid
      metabolism. Fibroblast treatment with the peptide provokes a rapid and
      significant increase in ceramide followed by a transient rise in sphingosine
      content. Sphingomyelin does not appear to be the source of ceramide since BK was
      unable to decrease the [3H]sphingomyelin pool and no increase in neutral or
      acidic sphingomyelinase activities could be detected after treatment with the
      peptide. The observation that the labeled glycosphingolipid pool is decreased
      upon BK stimulation would rather suggest that the peptide increases ceramide
      cellular content by rapidly mobilizing neutral glycolipids. Even though the
      physiological relevance of ceramide and sphingosine increase induced by BK is not
      known, it is noteworthy that glycosphingolipids may participate in this lipid
      signalling pathway.

PMID- 8660317
TI  - Inactive zymogen and highly active proteolytically processed membrane-bound forms
      of the transglutaminase 1 enzyme in human epidermal keratinocytes.
AB  - The transglutaminase 1 enzyme is important for the formation of a cornified cell
      envelope in terminally differentiating keratinocytes. We show here that it is
      present in low levels in proliferating foreskin or cultured epidermal cells as an
      inactive zymogen full length form of 106 kDa, of which >95% is attached to
      membranes. In terminally differentiating keratinocytes, there is a > or = 100
      fold induction of mRNA and protein. In addition to some cytosolic protein, most
      of the newly expressed protein is attached to membranes, of which about half
      exist in the zymogen form. Other protein consists of a 67/33/10 kDa complex
      formed by proteolytic processing at specific sites, and is anchored by way of the
      10 kDa fragment. This processed form is very highly active and thus accounts for
      almost all transglutaminase 1 activity in keratinocytes.

PMID- 8660318
TI  - Dietary cholesterol induces transient changes in plasma nitrate levels in rabbits
      that are correlated to microcirculatory changes.
AB  - Dietary treatment of rabbits with 1% cholesterol resulted in a transient rise in
      their plasma nitrate levels. After 3 weeks of treatment the nitrate levels were
      about 50% higher than those of the controls (p<0.005). After 10 weeks of
      treatment the nitrate levels were similar to those at the start of the study. In
      accordance with previous work (Xiu et al., J. Clin. Invest., 1994, 93, 2732
      2737), the cholesterol treatment let to a decreased blood flow velocity in
      arterioli of the third order in the conjunctiva, and a decreased diameter of
      these arterioli. There was a significant correlation between plasma nitrate
      levels and the two microcirculatory variables (p<0.0001). Nitrate is the major
      metabolic end product of nitric oxide (NO), and plasma nitrate levels may be used
      as an index of the endogenous formation of NO. The present results suggest that
      dietary cholesterol induces a transient increase in the synthesis of NO. Such an
      increased synthesis may compensate for part of a cholesterol-induced degradation
      of NO.

PMID- 8660319
TI  - PACAP stimulates transcription of c-Fos and c-Jun and activates the AP-1
      transcription factor in rat pancreatic carcinoma cells.
AB  - Pituitary Adenylate Cyclase Activating Peptide (PACAP) strongly induces
      proliferation of the rat pancreatic carcinoma cell line AR4-2J via interaction
      with the G-protein coupled type 1 PACAP/VIP (PVI) receptor. RT-PCR analysis
      revealed that this mitogenic effect of PACAP is preceded by a rapid and transient
      increase of transcription of the protooncogene c-fos and to a lesser extent of c
      jun. Transcriptional activation is abolished by a specific PACAP antagonist and
      by inhibitors of PKC and PKA. In parallel to c-fos/c-jun induction, PACAP rapidly
      activates the heterodimeric transcription factor AP-1, as shown by
      electrophoretic mobility shift assay. These findings demonstrate that signal
      transduction of a growth-stimulating G-protein-coupled receptor involves the c
      fos/c-jun/AP-1 cascade, a pathway mainly linked to classical growth factor
      receptor tyrosine kinases.

PMID- 8660320
TI  - Purification and characterization of a glutathione dependent dehydroascorbate
      reductase from human erythrocytes.
AB  - A GSH-dependent dehydroascorbate reductase (EC 1.8.5.1) was purified to
      homogeneity from human erythrocytes. The enzyme was a monomer of 32 kDa and was
      purified 133-fold from a crude DEAE-Sepharose fraction with a 25% yield. The
      reduced protein had a pI of 5.1 as judged by isoelectric focusing. Kinetic
      analysis gave a Kcat of 316 min-1, a Km of 0.21 mM for DHA with a Kcat/Km of 2.47
      x 10(4) M-1 sec-1, and a Km of 3.5 mM for GSH with a Kcat/Km of 1.51 x 10(3) M-1
      sec-1. This is the second DHA reductase (after thioltransferase) isolated from
      human erythrocytes, but unlike thioltransferase, it has no thiol-disulfide oxido
      reductase activity.

PMID- 8660321
TI  - The clonal progression in the neoplastic process of nasopharyngeal carcinoma.
AB  - The clonality of a total of 70 human nasopharyngeal carcinomas (NPC) was analyzed
      using the structure of the terminal fragment of episomal Epstein-Barr virus
      (EBV). Thirty female samples heterozygous for the BstXI polymorphism of the
      phosphoglycerokinase (PGK) gene were analyzed using polymerase chain reaction
      (PCR) amplification of X-chromosome linked PGK gene for restriction fragment
      length polymorphism (RFLP). All NPC samples analyzed were shown to be monoclonal,
      with two exceptions that were polyclonal. Clonal determination was also performed
      for non-cancerous cell populations: normal, and simple hyperplastic, grade I
      (mild) and grade II-III (severe) atypical hyperplastic epithelia. It was found
      that the normal and simple hyperplastic and 3 grade I (mild) atypical
      hyperplastic epithelia were polyclonal, whereas the grade II-III (severe)
      atypical hyperplastic samples were monoclonal. The analysis of the clonality of
      various stages in the neoplastic process suggested that NPC might originate from
      several cells, after clonal selection; finally a large majority of NPC has been
      demonstrated to be monoclonal, also indicating that the alteration of clonal
      nature might have occurred at a very early stage.

PMID- 8660322
TI  - Transgenic yeast expressing human cytochrome P450s can serve as a tool in studies
      of the mechanisms of their induction by various effectors.
AB  - Transgenic Saccharomyces cerevisiae yeast strains were constructed which express
      CYP2D6 and CYP3A4 genes under control of an artificial promoter. When added to
      the growth medium, sparteine, a substrate for CYP2D6, was shown to increase the
      content of this cytochrome P450 isoform in yeast cells. No such increase was
      observed when a proteinase-deficient yeast mutant was used as a parent strain.
      Nifedipine, a substrate for CYP3A4, failed to affect the level of CYP3A4
      expression even in wild yeast cells. These results suggest that expression of
      CYP2D6 in human liver can at least partially be controlled post-transcriptionally
      by its inductors while for CYP3A4 such a mechanism is hardly possible.

PMID- 8660323
TI  - Purification of the growth hormone releasing hormone receptor with a C-terminal,
      biotinylated affinity ligand.
AB  - The receptor for growth hormone-releasing hormone (GHRH) has been purified from
      bovine pituitary tissue and HEK293 cells transfected with human or porcine
      receptor using a retrievable biotinylated GHRH analog. Custom synthesized [His1,
      Nle27, Biotin-Lys41]-human GHRH-(1-41)-NH2 (GHRHb) bound to pituitary membranes
      with affinity comparable to human GHRH. GHRHb which has the biotinyl group on the
      C-terminus of the peptide allowed simultaneous binding to both the receptor and
      streptavidin agarose. This analog was used directly in the purification of the
      receptor from pituitary tissue or was modified by incorporation of the
      photoaffinity group ANBNOS (GHRHlambdab), radioiodinated and used to demonstrate
      purification of the GHRH receptor from transfected HEK293 cell membranes.
      Membranes were prepared and prebound with the respective ligand followed by CHAPS
      solubilization and application of the solubilized complex to a streptavidin
      agarose column. Analysis of eluates from the pituitary tissue purification by
      silver stained SDS PAGE or of autoradiographs of gels from HEK293 eluates
      revealed specific bands of 52 and 55 kDa, respectively. The higher size of the
      latter band is expected for the ligand-crosslinked receptor. Both bands displayed
      similar mobility shifts of 10 kDa upon treatment with N-glycosidase, a method
      previously used to characterize this receptor. A 45 kDa band corresponding to the
      size of the Gs alpha subunit was also detected in eluates of the silver stained
      gels, suggesting that the GHRH receptor was retrieved as a heterotrimeric
      complex. Fold purification and yield for this procedure were estimated to be
      greater than 50,000 and 2.6-9%, respectively.

PMID- 8660324
TI  - p66Shc isoform down-regulated and not required for HER-2/neu signaling pathway in
      human breast cancer cell lines with HER-2/neu overexpression.
AB  - The HER2/neu protooncogene encodes a transmembrane receptor tyrosine kinase of
      Mr185 kDa (called p185) which is structurally and functionally homologous to the
      epidermal growth factor receptor. Shc proteins are important downstream signal
      transducers of receptor tyrosine kinases. We reported here a novel finding that
      p66Sch was absent or nearly absent in p185-overexpressing breast cancer cells.
      This inverse correlation of p185 overexpression and p66Shc expression is probably
      specific to breast cancer cells because this phenomenon was not observed in p185
      overexpressing human ovarian, lung, or oral cancer cells, or mouse fibroblast
      cells. In contrast, the p52Shc and p46Shc isoforms were expressed at similar
      levels in both p185-overexpressing and p185 basal level breast cancer cell lines.
      Furthermore, tyrosine phosphorylation of p52Shc and p46Shc and subsequent
      formation of Shc/Grb2 complex were detected in breast cancer cells in which the
      p185 tyrosine kinase is activated, indicating that p66Shc is not required for
      mediating the HER-2/neu signaling pathway in breast cancer cells.

PMID- 8660325
TI  - Location of the non-heme iron center on the alpha subunit of photoreactive
      nitrile hydratase from Rhodococcus sp. N-771.
AB  - Nitrile hydratase (NHase) from Rhodococcus sp. N-771, which possesses a non-heme
      iron center binding nitric oxide (NO), is activated by light irradiation. To
      localize the iron center in the protein, we quantified Fe atoms and performed
      FTIR measurements of the isolated alpha and beta subunits. The native NHase and
      the isolated alpha subunit contained about 1.0 and 0.8 mol Fe per mol protein,
      respectively, whereas the beta subunit contained only a trace of Fe. An NO
      stretching band was observed at 1852 cm-1 in the FTIR spectrum of the alpha
      subunit, but not in that of the beta subunit. Upon light irradiation of the alpha
      subunit, the affinity of the Fe atom decreased and the NO band disappeared from
      the FTIR spectrum. These observations indicate that the non-heme iron center,
      which is responsible for the photoreaction, is present in the alpha subunit.

PMID- 8660326
TI  - The Ca++/calmodulin-dependent protein kinase II inhibitors KN62 and KN93, and
      their inactive analogues KN04 and KN92, inhibit nicotinic activation of tyrosine
      hydroxylase in bovine chromaffin cells.
AB  - The possible role of Ca++/calmodulin-dependent protein kinase II (CAM-K-II) in
      the nicotinic activation of tyrosine hydroxylase in intact cultured bovine
      adrenal chromaffin cells has been investigated. Over the concentration range 3-30
      microM, KN62, a specific CAM-K-II inhibitor, inhibited basal tyrosine hydroxylase
      activity and the activity stimulated by nicotine or K+ depolarisation. KN04, a
      structural analogue of KN62 which does not inhibit CAM-K-II, produced an
      identical concentration-dependent inhibition of basal and nicotine-stimulated
      tyrosine hydroxylase activity. Another CAM-K-II inhibitor, KN93, also inhibited
      nicotine and K+ stimulation of tyrosine hydroxylase activity; however, an
      inactive analogue of KN93, KN92, mimicked these effect. The results suggest that
      the inhibition of nicotine- and K+-stimulated tyrosine hydroxylase activity by
      KN62 and KN93 is not due to their ability to inhibit CAM-K-II.

PMID- 8660327
TI  - Abnormal behavior and neurotransmissions of tenascin gene knockout mouse.
AB  - To examine the role of tenascin (TN) in vivo, we have produced mice in which the
      TN gene is inactivated. In behavioral studies, TN-knockout mice showed abnormal
      behavior such as hyperlocomotion and poor swimming ability. Biochemical analysis
      revealed that serotonin (5-HT) and dopamine (DA) transmission was decreased in
      the cerebral cortex, the hippocampus, or the striatum of TN-knockout mouse brain.
      The intraperitoneal administration of the DA receptor agonist, LY171555 (0.5
      mg/kg, BW), inhibited the hyperlocomotion, and swimming behavior was transiently
      improved by the treatment with the 5-HT receptor agonist, 1-(4-iodo-2,5
      dimethoxyphenyl)-2-aminopropane hydrochloride. These findings suggest that TN may
      play an important role in neurotransmissions related to behavior.

PMID- 8660328
TI  - cDNA cloning of a novel CYP3A from rat brain.
AB  - One full length cDNA clone, designated 3aH15, was isolated from a control male
      rat brain cDNA library. 3aH15 encoded a protein composed of 503 amino acid
      residues. The deduced amino acid sequence of 3aH15 was 92% identical to Cyp3a-13
      and had a 68.4% to 76.5% homology with the other reported CYP3A sequences. Clone
      3aH15 was thus named CYP3A9. No significant induction of the CYP3A9 expression in
      rat brain by dexamethasone was observed by Northern blot analysis. CYP3A9 cDNA
      was expressed in E. coli and the expressed P450 3A9 is active in the
      demethylation of erythromycin as well as benzphetamine.

PMID- 8660329
TI  - Nitric oxide donor SNAP induces apoptosis in smooth muscle cells through cGMP
      independent mechanism.
AB  - Recent evidence suggests that nitric oxide (NO) may function as a second
      messenger in the intracellular signal transduction pathways. We explored the
      possibility that NO was involved in the signal for triggering apoptosis in smooth
      muscle cells (SMCs). Chemical NO donors induced SMCs apoptosis in a concentration
      and time-dependent manner. The membrane-permeable cGMP analogue, dibutyryl-cGMP,
      did not induce SMCs apoptosis, and the highly selective inhibitor of cGMP
      dependent protein kinase, KT5823, was unable to inhibit the induction of NO
      induced SMCs apoptosis. Inhibitor of ADP-ribosyltransferase slightly attenuated
      the induction of SMCs apoptosis by S-nitroso-N-acetyl penicillamine (SNAP). The
      inhibitor of Na+-H+ antiporter, amiloride, completely inhibited the induction of
      SMCs apoptosis by SNAP. These results demonstrate for the first time that NO can
      induce apoptosis in SMCs, suggesting that NO acts as a mediator in the
      development of atherosclerosis lesion via alterations in the number of SMCs. In
      addition, the results suggest that NO exert these effects through a pathway that
      does not involve guanylate cyclase and cGMP-dependent protein kinase.

PMID- 8660330
TI  - Evaluation and optimization of different cationic liposome formulations for in
      vivo gene transfer.
AB  - Five commonly used cationic liposome formulations were tested for their ability
      to deliver DNA to established subcutaneous human tumor xenografts in SCID mice.
      Liposomes were complexed with a mammalian expression plasmid containing the
      bacterial beta-galactosidase gene and delivered to tumors by direct injection.
      The optimal lipid to DNA ratios in vivo were markedly different than those
      observed in vitro for each liposome formulation. Tumor size at the time of
      inoculation also effected transfection efficiency significantly. Of the five
      liposome formulations tested, DC-Cholesterol was found to be superior to all
      others in vivo. Even under optimal conditions however, the efficiency of in vivo
      transfection was low in our system (approximately 0.3%). Implications of these
      results for in vivo gene therapy of tumors are discussed.

PMID- 8660331
TI  - Ascertaining the number of essential thiol groups for the folding of creatine
      kinase.
AB  - Although the unfolding and refolding of proteins have been extensively studied in
      the literature, relatively few attempts have been made to see how many residues
      of the total residues of a certain amino acid in an enzyme can be modified
      without seriously affecting its folding. Based on a statistical analysis of the
      quantitative relationship between the extent of modification of protein
      functional groups and the decrease in their biological activity, a method
      proposed by Tsou (Sci. Sin. 1962, 11, 1535-1558) is widely used to determine the
      number of residues essential for the catalytic activity of modified proteins. In
      the present paper, Tsou's method is applied to determine the number of cystein
      residues essential for the folding of creatine kinase. The thiol groups of the
      cysteine residues in fully unfolded creatine kinase were modified by 2
      chloromercuri-4-nitrophenol (MNP). The relationship between the number of MNP
      groups introduced and the recovery of activity after refolding was determined.
      Quantitative treatment of the data by Tsou's plot shows that among the cystein
      residue modified in each subunit of creatine kinase, only three are essential for
      its folding.

PMID- 8660332
TI  - Stimulating effect of 6R-tetrahydrobiopterin on Ca2+ channels in neurons of rat
      dorsal motor nucleus of the vagus.
AB  - We have recently found that 6R-tetrahydrobiopterin (6R-BH4), a natural cofactor
      for aromatic L-amino acid hydroxylases and nitric oxide synthase, enhances
      dopamine release. Here, using a slice patch method, we examined the effect of 6R
      BH4 on Ca2+ channels in neurons of rat dorsal motor nucleus of the vagus, where
      dopaminergic neurons are densely located. 6R-BH4 enhanced N-type Ca2+ channel
      currents, whereas 6S-BH4, a diastereoisomer of 6R-BH4, had little effect. Neither
      sodium nitroprusside, a nitric oxide generator, nor L-DOPA, a product of tyrosine
      hydroxylation, mimicked the effect of 6R-BH4. These findings suggest that 6R-BH4
      enhances N-type Ca2+ channel currents in stereospecifically and independently of
      its cofactor activities as observed in its dopamine releasing action, and raise
      possibility that 6R-BH4 enhances dopamine release by activating Ca2+ channels.

PMID- 8660333
TI  - Characterization of bacterial cell membrane attachment sites of plasmid R6K.
AB  - In vitro binding studies revealed that plasmid R6K could attach to both inner and
      outer membrane fractions of its host cell, Escherichia coli. Derivatives of R6K
      carrying one or two of its three origins of replication could not bind stably to
      the same membrane fractions in the presence of salt. However, the derivative,
      pRK35, carrying the intact three origins of replication could bind stably to
      membrane fractions from its host in the presence or absence of salt. These
      observations suggest that the three origins of DNA replication must be contiguous
      for stable binding of the plasmid to the cell membrane. The results of binding
      experiments showed that plasmid R6K bound competitively with pRK35 as well as the
      heterologous plasmid, pl524.

PMID- 8660334
TI  - Modulation of adhesion-dependent cAMP signaling by echistatin and alendronate.
AB  - We measured intracellular cAMP levels in cells during attachment and spreading on
      different extracellular matrix (ECM) proteins. Increases in cAMP were observed
      within minutes when cells attached to fibronectin, vitronectin, and a synthetic
      RGD-containing fibronectin peptide (Petite 2000), but not when they adhered to
      another integrin alpha nu beta 3 ligand, echistatin. Because echistatin also
      inhibits bone resorption, we measured the effects of adding another osteoporosis
      inhibitor, alendronate, in this system. Alendronate inhibited the cAMP increase
      induced by ligands that primarily utilize integrin alpha nu beta 3 (vitronectin,
      Peptite 2000), but not by fibronectin which can also use integrin alpha 5 beta 1.
      These results show that cell adhesion to ECM can increase intracellular cAPM
      levels and raise the possibility that inhibitors of osteoporosis may act, in
      part, by preventing activation of this pathway by integrins.

PMID- 8660335
TI  - Vascular endothelial growth factor is induced by long-term high glucose
      concentration and up-regulated by acute glucose deprivation in cultured bovine
      retinal pigmented epithelial cells.
AB  - Vascular endothelial growth factor (VEGF) is closely correlated to diabetic
      retinopathy. Its basal production in three types of cultured retinal cells
      (endothelial cells, pericytes and retinal pigment epithelial cells; RPE) was
      examined. RPE production of VEGF was markedly higher than the rest of the cells.
      VEGF production in RPE was significantly elevated by 10-day, but not by 1- or 3
      day exposure to 16.5 mM glucose compared to a 5.5 mM glucose group. Transient
      deterioration of diabetic retinopathy is frequently observed during rapid
      correction of glycemic control. To determine whether VEGF is up-regulated
      following a sharp drop in the glucose concentration or not, we examined the
      changes in VEGF production in RPE before and after a sudden drop in the glucose
      concentration. VEGF production was significantly increased by a glucose
      concentration decrease from 5.5 to 0.5 mM, but not by a decrease from 33 or 16.5
      to 5.5 mM. These findings suggest that up-regulation of VEGF may contribute to
      the development of diabetic retinopathy and its worsening by hypoglycemia.

PMID- 8660336
TI  - Cloning and expression of a rat brain basic helix-loop-helix factor.
AB  - We cloned two rat cDNAs of brain basic helix-loop-helix factor 1 (BHF1). These
      have an identical coding region, contain 357 amino acids and exhibit 94.6%
      identity to MATH-2/NEX1 in the basic helix-loop-helix region. BHF1mRNAs are
      dominantly expressed in the brain particularly in the cerebellum, in the adult
      bovine, rat and mouse. Two shorter BHF1mRNAs (1.6 kb and 1.8 kb) were also
      detected in the mouse embryo, and these decreased in the developmental process.
      These results suggest that BHF1 may play important roles in cerebellum-specific
      functions and development of neurons.

PMID- 8660337
TI  - Adrenocorticotropin induces calcium oscillations in adrenal fasciculata cells:
      single cell imaging.
AB  - With fluorescence microscopic imaging, we have demonstrated that the Ca2+
      signaling occurred in individual Calcium Green-1 loaded bovine adrenal
      fasciculata cells upon stimulation with adrenocorticotropin (ACTH) at
      physiological concentration of 0.1-100 pM. We observed three patterns of Ca2+
      signaling which were Ca2+ oscillations (33%), step-like increase in Ca2+
      concentration (10%), and Ca2+ oscillations superimposed on step-like increase in
      Ca2+ (57%). The oscillation in intracellular Ca2+ concentration occurred with a
      frequency around 0.04 Hz. When Ca2+ signaling upon ACTH stimulation was inhibited
      by the treatment with EGTA, the corticoid production was considerably suppressed.
      The results suggest that the Ca2+ signaling is a probable candidate of the second
      messenger for ACTH-induced steroid hormone synthesis in zona fasciculata cells.

PMID- 8660338
TI  - Structural heterogeneity of phospholipase D in 10 dicots.
AB  - The occurrence of multiple forms of phospholipase D (EC 3.1.4.4) was investigated
      in different tissues of castor bean (Ricinus communis) and in other plant
      species. Phospholipase D variants were resolved by nondenaturing and isoelectric
      focusing polyacrylamide gel electrophoresis and detected by immunoblotting using
      anti-phospholipase D antibodies and by enzyme activity assay. Three phospholipase
      D variants were produced differentially in the roots, endosperm, cotyledons, and
      hypocotyl of 5-day postgermination seedlings of castor bean. Furthermore,
      different patterns of phospholipase D variants were found in the different
      regions of hypocotyl (elongated and hook). Multiple phospholipase D forms were
      found in florets of cauliflower and broccoli, leaves of cabbage, celery, tomato,
      and potato, and alfalfa sprouts, suggesting that structural heterogeneity of
      phospholipase D occurs widely in plants.

PMID- 8660340
TI  - Dehydrogenase binding to the 3'-untranslated region of GLUT1 mRNA.
AB  - Employing RNA gel mobility shift assays we detected specific binding events
      between several dehydrogenases and various regions of the GLUT1 mRNA 3'
      untranslated region. In particular, the enzymes glyceraldehyde 3-phosphate
      dehydrogenase (G3PDH), lactate dehydrogenase (LDH), and glucose 6-phosphate
      dehydrogenase (G6PDH) bound to the GLUT1 3'-UTR while isocitrate dehydrogenase
      (IDH) and glutamate dehydrogenase (GluDH) did not. Comparison of shifts obtained
      with purified dehydrogenases to those obtained using authentic cell extracts
      indicate that G3PDH and G6PDH may play a role in the intact cell.

PMID- 8660339
TI  - Visualisation of nitric oxide generated by activated murine macrophages.
AB  - We have visualised the release and approximate diffusion profile of nitric oxide
      (NO) from activated murine macrophages using a high transmission microscope
      coupled to a high sensitivity photon counting camera. The images generated by NO
      were cell-associated and spread over an area of approximately 175 micrometers
      from the activated macrophage. The signals obtained were dependent on the
      presence of exogenous L-arginine in the medium and followed a time course similar
      to that previously described for the generation of NO by the inducible form of NO
      synthase. The light signal was attenuated by the inhibitor of NO synthase, N
      omega-nitro-L-arginine methyl ester. Studies using superoxide-deficient
      macrophages further confirmed that the signals detected were generated by NO
      rather than reactive oxygen intermediates.

PMID- 8660341
TI  - Interaction of S100a0 protein with the actin capping protein, CapZ:
      characterization of a putative S100a0 binding site in CapZ alpha-subunit.
AB  - S100a0, a Ca2+-binding protein expressed predominantly in cardiac and skeletal
      muscle tissues, was demonstrated by chemical cross-linking to interact in a Ca2+ 
      dependent manner with the actin capping protein CapZ. TRTK-12, a peptide
      contained within the COOH-terminal region of CapZalpha, inhibited S100a0: CapZ
      interaction in a dose-dependent manner. TRTK-12 was shown by cross-linking to
      bind S100a0 in the presence of Ca2+, and by fluorescence spectrophotometry to
      interact in a saturable manner with the anionic phospholipid and a regulator of
      CapZ activity, phosphatidylinositol 4-monophosphate; but not with the neutral
      phospholipid, phosphatidylcholine. These data suggest S100a0 and
      polyphosphoinositides bind to the same COOH-terminal region of CapZalpha, thus
      potentially modulating CapZ activity.

PMID- 8660342
TI  - Evidence for a K+ channel requirement in spreading of rat basophilic leukemia
      cells on fibronectin-coated surfaces.
AB  - We investigated the ionic requirements for the early events of cell-extracellular
      matrix interactions leading to cell spreading. We found that potassium ions were
      required specifically in several cell types. Adhesion to fibronectin- (FN) coated
      surfaces was independent of K+ in the medium. In contrast, cells that adhered to
      FN in the absence of K+ failed to spread. This requirement for K+ occurred only
      during a discrete time frame: in the first 15 minutes following adhesion.
      Moreover, we identified a specific trans-membrane flux of the radioactive K+
      analog 86Rb+, the kinetics of which correlated with this requirement. Both this
      ion flux and cell spreading were blocked by the K+ -channel inhibitors
      tetraethylammonium (TEA) and 4-aminopyridine (4-AP). Our results suggest that
      this K+ ion flux and the channels that regulate it are important in regulating
      the initial responses to adhesion that lead to spreading.

PMID- 8660343
TI  - The house dust mite allergen Der p1 catalytically inactivates alpha 1-antitrypsin
      by specific reactive centre loop cleavage: a mechanism that promotes airway
      inflammation and asthma.
AB  - Der p1, a cysteine proteinase derived from the house dust mite (HDM)
      Dermatophagoides pteronyssinus, is a major component of the allergic immune
      response in HDM atopic individuals. Recent evidence suggests that cysteine
      proteinase activity is important in the disease process as it increases the
      permeability of the allergen in the respiratory tract and disrupts the regulation
      of IgE synthesis. Der p1 is found in high concentrations in the faecal pellets of
      mites which are aerosolised and inhaled via the respiratory tract. The serine
      proteinase inhibitor, alpha 1-antitrypsin, protects the lower respiratory tract
      against damage by proteinases released in the lung during inflammation. Der p1
      catalytically inactivates alpha 1-antitrypsin by a thiol-dependent mechanism
      involving specific cleavage of the reactive centre loop and we propose that this
      mechanism may be important in the pathogenesis of asthma.

PMID- 8660344
TI  - Endothelin stimulates sis-inducing factor-like DNA binding activity in CHO-K1
      cells expressing ETA receptors.
AB  - ET-1, a member of the family of peptides known as endothelins, binds to a G
      protein-coupled receptor, ET(A), and stimulates a variety of cellular responses,
      including contraction, growth, and mitogenesis. ET-1 stimulation of a chinese
      hamster ovary cell line stably transfected with the ET(A) receptor (CHO/ET(A))
      induced formation of SIF (sis-inducing factor), a key component of the STAT
      (Signal Transducers and Activators of Transcription) pathway, in a concentration
      dependent manner. SIF induction was blocked by a specific inhibitor of ET(A),
      BQ610, and by genistein, a tyrosine kinase inhibitor. This report demonstrates
      that ET-1 stimulates the STAT pathway of signal transduction through a G-protein
      coupled receptor, ET(A), in this stably transfected cell line.

PMID- 8660345
TI  - Keratin 8 phosphorylation in vitro by cAMP-dependent protein kinase occurs within
      the amino- and carboxyl-terminal end domains.
AB  - We reported earlier that phosphorylation in vitro of keratin filaments
      reconstituted from rat type I keratin 18 and type II keratin 8 by cAPM-dependent
      protein kinase induces disassembly of the keratin filament structure. Keratin 8
      rather than keratin 18 was the major target of the kinase. We have now identified
      the sites on rat keratin 8 for cAMP-dependent protein kinase. Sequential analysis
      of the purified phosphoropeptides, together with the known primary sequence,
      revealed that four major sites, Ser-12, Ser-23, Ser-36, and Ser-50, and three
      minor sites, Ser-8, Ser-33, Ser-42, are located in the amino-terminal head
      domain, while three minor sites, Ser-416, Ser-423 and Ser-425 locate in the
      carboxyl-terminal tail domain.

PMID- 8660346
TI  - The phosphatase inhibitor calyculin antagonizes the rapid initiation of apoptosis
      by photodynamic therapy.
AB  - DNA fragmentation and internucleosomal cleavage were rapidly initiated after
      lysosomal photodamage to murine leukemia cells, with apoptotic chromatin and DNA
      'ladders' detected within 30 min after irradiation. Apoptosis was inhibited by
      concurrent exposure of cells to a 10 nM concentration of the serine-threonine
      phosphatase inhibitor calyculin A and promoted by a serine/threonine kinase
      inhibitor. These results indicate that a late stage in apoptosis requires
      serine/threonine dephosphorylation.

PMID- 8660347
TI  - Titration of recombinant aequorin with calcium chloride.
AB  - The photoprotein aequorin emits light in the presence of a trace of Ca2+. The
      primary structure of the protein indicates the presence of three Ca2+-binding
      sites, whereas the luminometric titration of heterogeneous natural aequorin with
      Ca2+ has shown that the light emission takes place by the binding of two Ca2+
      ions. In the case of recombinant aequorin, which is more suitable for
      quantitative studies, the titration with Ca2+ monitored by a Ca2+-sensitive
      electrode revealed that the photoprotein can bind more than two, most likely
      three, Ca2+ ions, and the luminometric titration conclusively showed that the
      luminescence is triggered by the first two Ca2+ ions bound. The affinity of
      recombinant aequorin for the first two Ca2+ ions, which are essential for light
      emission, was about 20 times stronger than that for the third Ca2+ ion, which is
      unrelated to light emission.

PMID- 8660348
TI  - 17 beta-Estradiol and smooth muscle cell proliferation in aortic cells of male
      and female rats.
AB  - The low incidence of cardiovascular disease in women before menopause or during
      hormone replacement therapy suggests a protective effect of estrogens. The
      mechanism(s) are uncertain but may involve effects on lipids, coagulation and the
      endothelium. Vascular smooth muscle cell (VSMC) proliferation also contributes to
      atherosclerosis. Hence, we investigated whether 17 beta-estradiol (E2) inhibits
      VSMC proliferation. VSMC of 6 female and 6 male Wistar Kyoto rats (WKY; age 10-12
      weeks) were incubated for 24 h with E2 and/or fetal calf serum (FCS). E2 (10(-9)
      10(-5) M) alone reduced [3H]thymidine uptake at 10(-5) (n=8, p<0.05 vs control)
      in female cells only. In female and male VSMC, FCS (1%) increased [3H]thymidine
      uptake (4.5-fold, p<0.05 vs. control). When given simultaneously, E2 did not
      prevent this effect of FCS (1%). However, when cells were preincubated for 24 h
      with E2 and then stimulated with FCS, [3H]thymidine uptake was reduced by E2 at
      10(-5) M in female VSMC (n=7, p<0.05 vs FCS alone), while in male VSMC this
      effect was minimal (n.s.): Both female and male VSMC expressed estrogen receptors
      as demonstrated by RT-PCR. Pretreatment of female VSMC cells with the E2 receptor
      antagonist tamoxifen prevented the antiproliferative effects exerted by E2. In
      aortic VSMC of female rats, E2 moderately inhibited proliferation on its own and
      during stimulation with FCS, while this effect was small in VSM of male rats. The
      expression of the E2 receptor in female and male VSMC and the effects of
      tamoxifen suggest that this effect is mediated by E2 receptors.

PMID- 8660349
TI  - Efficient gene transfer into mammalian cells with cholesteryl-spermidine.
AB  - The naturally occurring polyamine spermidine was covalently conjugated with
      cholesterol, resulting in a novel cationic compound that mediates efficient gene
      transfer into mammalian cells. Using reporter plasmids coding for firefly
      luciferase and beta-galactosidase, a simple procedure was developed allowing
      highly reproducible and efficient transient and stable transfection of HuH-7
      cells. Transfection efficiency could be further increased when a fusogenic
      peptide derived from the influenza virus hemagglutinin HA2 aminoterminal sequence
      was included in the cholesteryl-spermidine-DNA complex. Cholesteryl-spermidine
      (Transfectall) represents a novel cationic compound for efficient transfection of
      cultured cells in vitro and has the potential to be used for gene transfer in
      vivo.

PMID- 8660350
TI  - Galanin increases cytoplasmic calcium in insulin-producing RINm5F cells by
      activating phospholipase C.
AB  - We showed previously that the neuropeptide, galanin, transiently and promptly
      increases the cytoplasmic concentration of Ca2+, [Ca2+]i, in insulin producing
      clonal RINm5F cells prior to a reduction in [Ca2+]i. We found that galanin (100
      nM) transiently increased the [Ca2+]i in the presence of 15 mM glyceraldehyde and
      3.3 mM glucose. This effect was abolished by both the inhibitor of the microsomal
      Ca2+ ATPase, thapsigargin, which depletes the intracellular Ca2+ stores, and the
      specific inhibitor of phospholipase C, U73122. In contrast, the blocker of L-type
      Ca2+ release, ryanodine, did not affect galanin-induced increase in [Ca2+]i.
      Thus, galanin induces a rapid mobilization of Ca2+ from intracellular Ca2+ stores
      in insulin producing RINm5F cells by an effect mediated by activated
      phospholipase C.

PMID- 8660351
TI  - Signaling mechanism of PMA-induced differentiation of K562 cells.
AB  - We have studied the signaling pathways responsible for the monocytic and/or
      megakaryocytic differentiation of K562 cells. The results demonstrated that
      although the mitogen-activated protein kinase (MAPK) was activated during the
      phorbol myristate acetate (PMA)-induced monocytic and/or megakaryocytic
      differentiation of K562 cells, the overexpression of Ha-ras which can activate
      the MAPK did not induce the monocytic and/or megakaryocytic differentiation of
      K562 cells. Instead PMA-induced megakaryocytic differentiation of K562 cells was
      inhibited by the pretreatment of pyrrolidine dithiocarbamate, a specific nuclear
      factor kappaB (NF-kappaB) inhibitor. Taken together, these results suggest that
      the activation of NF-kappaB rather than that of MAPK might be involved in the PMA
      induced megakaryocytic differentiation of K562 cells.

PMID- 8660352
TI  - C-type natriuretic peptide as an autocrine/paracrine regulator of osteoblast.
      Evidence for possible presence of bone natriuretic peptide system.
AB  - C-type natriuretic peptide (CNP) is a local regulator in the brain and vascular
      wall. We present data to demonstrate the production and action of CNP in the
      osteoblast. CNP increased cGMP production, far more potently than atrial
      natriuretic peptide (ANP) in an osteoblastic cell line, MC3T3-E1. Since ANP and
      CNP are the ligands for two particulate guanylate cyclases, guanylate cyclase-A
      (GC-A) and guanylate cyclase-B (GC-B), respectively, these results reveal the
      expression of GC-B in MC3T3-E1. In addition, CNP mRNA and CNP-like
      immunoreactivity were detected in cell extracts from MC3T3-E1 and its culture
      medium, respectively. Both CNP and 8-bromo cGMP dose-dependently decreased
      [3H]thymidine uptake, without affecting alkaline phosphatase activity. These
      results indicate that CNP is a novel autocrine/paracrine regulator of osteoblast
      and suggest the presence of "bone natriuretic peptide system."

PMID- 8660353
TI  - Purification of Escherichia coli chromosomal segments without cloning.
AB  - Pairs of genomic insertions made with elements carrying any one of several
      frequently used rare restriction sites allow physical purification of insertion
      delimited genes. However, native rare restriction sites can, either by causing
      (i) fragmentation of targeted intervals or (ii) generation of additional
      fragments that overlap electrophoretically with targeted ones, place severe
      limitations on this approach. We present a series of Escherichia coli mini-Tn10
      insertions containing the rare-cutting polylinker 2 (RCP2) of rare restriction
      sites, which includes the 18-base-pair I-SceI site (absent from native E. coli
      sequences). Pulsed-field gel purification from RCP2 double insertion mutants of
      both an I-SceI fragment from strain K-12 (containing approximately 90-95 min) and
      an allelic I-SceI fragment from a pathogenic strain is demonstrated. The complete
      series of RCP2 insertions, containing different antibiotic resistances at
      intervals of approximately 35 kb in prototype K-12 strain MG1655, allows rapid
      purification of the genes from any E. coli chromosomal interval as an isolated I
      SceI fragment.

PMID- 8660355
TI  - Replacement of the sole histidinyl residue in OmpF porin from E. coli by
      threonine (H21T) does not affect channel structure and function.
AB  - The sole histidine residue in OmpF porin was replaced by threonine using site
      directed mutagenesis. This exchange affected neither channel properties nor
      channel structure, as determined by X-ray analysis to 3.2 A. Conductance and
      critical voltage (Vc) were observed in the pH range 4.3-9.4, with results
      indistinguishable from those observed in the wild-type protein. The validity of
      these observations is supported by the independence of the methods used, and by
      the fact that mutants in residues located in the channel constriction yielded
      significantly different values from wild-type protein. The binding of a
      glycolipid molecule might be affected.

PMID- 8660356
TI  - Regulation of expression of the steroidogenic acute regulatory (StAR) protein by
      ACTH in bovine adrenal fasciculata cells.
AB  - Immunocytochemical studies and immunoblotting analysis demonstrated that there
      exists the StAR protein in bovine adrenal fasciculata cells, and ACTH activated
      expression of the StAR protein. Then roles of intracellular signal transduction
      systems in the regulation of expression of the StAR protein were studied. The
      addition of Bt2cAMP and forskolin, or phorbol ester plus calcium ionophore 23187
      activated expression of the StAR protein as well as cortisol production,
      suggesting that cyclic AMP- or protein kinase C-dependent process plays a crucial
      role in the regulation of expression of the StAR protein. Activating effects of
      ACTH which activates cyclic AMP formation on the StAR protein and cortisol
      production were inhibited by pretreatment with calphostin C which is a protein
      kinase C inhibitor, suggesting that ACTH enhances expression of the StAR protein
      possibly via both of two signal transduction systems such as cyclic AMP- and
      protein kinase C-dependent processes.

PMID- 8660354
TI  - Modulation of ICAM-1 levels on U-937 cells and mouse macrophages by interleukin-1
      beta and dexamethasone.
AB  - Differentiation of U-937 cells with phorbol ester (10 nM) induced a time
      dependent (24 h or 48 h) increase of adhesion molecules and lipocortin 1
      expression on the cell surface. Stimulation with interleukin-1 beta for a further
      16 h increased the levels of intercellular adhesion molecule-1, and this effect
      was inhibited by co-incubation with 0.1-1 microM dexamethasone. The effect of the
      glucocorticoid was not modified by addition of a specific anti-lipocortin 1
      monoclonal antibody (mAb 1A, 5 micrograms/ml). This opposite modulatory role of
      interleukin-1 and dexamethasone on intercellular adhesion molecule-1 expression
      was also, for the first time, observed in vivo using mouse peritoneal
      macrophages: a four-fold increase in intercellular adhesion molecule-1 expression
      was measured after local administration of the cytokine (5 micrograms/kg) and
      this effect was greatly inhibited (> 70%) by co-injection with 1 microgram
      dexamethasone. In conclusion, modulation of intercellular adhesion molecule-1
      expression by glucocorticoids is an effect independent endogenous lipocortin 1,
      and it is an in vivo feature of these potent anti-inflammatory drugs.

PMID- 8660357
TI  - Multiple structural domains within I kappa B alpha are required for its inducible
      degradation by both cytokines and phosphatase inhibitors.
AB  - Activation of the transcription factor NF-kappa B by various cellular stimuli
      involves phosphorylation and subsequent degradation of its inhibitor I kappa B
      alpha. Both the cytokine tumor necrosis factor alpha (TNF-alpha) and the
      phosphatase inhibitor calyculin A have been shown to induce rapid phosphorylation
      and degradation of I kappa B alpha. In the present study, we demonstrate that TNF
      alpha and calyculin A stimulate similar although not identical pattern of I kappa
      B alpha phosphorylation, as demonstrated by phosphopeptide mapping.
      Interestingly, phosphorylation of I kappa B alpha induced by both inducers
      involves serine-32 and serine-36 of I kappa B alpha. Furthermore, TNF-alpha- and
      calyculin A-induced degradation of I kappa B alpha appears to require the same
      structural domains within I kappa B alpha. In addition to the N-terminal
      phosphorylation sites and the C-terminal sequences, each of the five ankyrin-like
      repeats of I kappa B alpha is critically required for the inducible degradation
      of this NF-kappa B inhibitor. Together, these studies suggest that degradation of
      I kappa B alpha by both cytokines and phosphatase inhibitors is regulated by site
      specific phosphorylation and requires multiple structural domains.

PMID- 8660358
TI  - Role of bilirubin as an antioxidant in an ischemia-reperfusion of rat liver and
      induction of heme oxygenase.
AB  - The anti-oxidative effect of bilirubin was investigated in an ischemia
      reperfusion model of rat liver. The rat portal vessel and liver artery were
      ligated with a vascular clip, and after reperfusion the urine was collected at
      intervals. The amount of biopyrrins, the oxidative metabolites of bilirubin, in
      rat urine reached a maximum 4 hours after reperfusion. Biotripyrrin-a and -b
      which are biopyrrins isolated from human urine were included in urinary bilirubin
      oxidative metabolites of rats after reperfusion. The hepatic mRNA level of heme
      oxygenase-1 (HO-1), the rate limiting enzyme of bilirubin biosynthesis, reached a
      maximum after 4 hours. Furthermore, the hepatic activity of HO began to rise 4
      hours after treatment and remained high until 24 hours posttreatment. These
      findings suggest that bilirubin acts as a physiological antioxidant in vivo in
      ischemia-reperfusion and that bilirubin biosynthesis is evoked by oxidative
      stress.

PMID- 8660359
TI  - In vivo experimental studies on the role of free radicals in photodynamic
      therapy. II. Photodynamic effect on free radical concentration in mice tumors
      measured by ESR spectroscopy.
AB  - Changes in free radical concentrations of solid tumors of mice after photodynamic
      treatment using Photofrin II sensitizer has been measured by ESR spectroscopy.
      Decrease in the free radical concentrations by 46% in S180 and by 35% in P388
      tumors induced photodynamically was found. As expected, the effect was
      proportional to the steady state concentrations of the free radicals in the
      malignant cells of mice prior to photodynamic treatment if comparing either
      different types of tumors or data referring to various stages of the development
      of identical types of tumors. Results support the contribution of the
      interactions between triplet excited sensitizer molecules and native free
      radicals to photodynamic effects as assumed earlier.

PMID- 8660360
TI  - Regulation of growth, PSA/PAP and androgen receptor expression by 1 alpha,25
      dihydroxyvitamin D3 in the androgen-dependent LNCaP cells.
AB  - The involvement of vitamin D in prostate carcinogenesis was investigated using
      the human prostatic LNCaP cells. Incubation of the LNCaP with 100 nM 1 alpha,25
      dihydroxyvitamin D3 for 2 days resulted in a 30-40% suppression of cell growth,
      which was accompanied by a greater than 70% down-regulated expression of the
      proliferating cell nuclear antigen (PCNA). The intracellular and secreted forms
      of PSA showed a 2-fold increase following a 48 h culture in the presence of
      vitamin D3. The vitamin D3-elicited PSA increases were preceded by an induction
      of androgen receptor (AR) expression, as measured by Western blot analysis and by
      binding assays using [3H]R1881 as the ligand. These results are consistent with
      the hypothesis that the growth inhibitory effects of vitamin D3 is partially
      mediated through its ability to modulate PCNA expression. Moreover, vitamin D3
      may effect increases in PSA expression indirectly by up-regulating androgen
      receptors.

PMID- 8660361
TI  - Exercise induces the translocation of GLUT4 to transverse tubules from an
      intracellular pool in rat skeletal muscle.
AB  - Exercise stimulates glucose transport in skeletal muscle by increasing the number
      of GLUT4 glucose transporters at the cell surface. The effect of exercise on
      GLUT4 content in transverse tubules, which are deep extensions of the plasma
      membrane involved in myofiber contraction, has never been studied. In the present
      study, we have investigated whether acute exercise induces translocation of GLUT4
      to the transverse tubules. Plasma membranes and transverse tubules were isolated
      from control and exercised rats by a newly developed membrane fractionation
      procedure. As expected, acute exercise increased GLUT4 content in plasma
      membranes (95%; p < 0.01). Importantly, exercise also significantly increased
      GLUT4 content in a transverse tubule-enriched fraction (60%; p < 0.05).
      Furthermore, acute exercise was found to decrease GLUT4 content in an
      intracellular membrane fraction (-40%; p < 0.001). In conclusion, this study
      demonstrates that GLUT4 is translocated not only to the plasma membranes but also
      to the transverse tubules in acutely exercised muscles. The results also indicate
      that GLUT4 is recruited from a novel intracellular membrane fraction.

PMID- 8660362
TI  - Covalent association of protein disulfide isomerase with recombinant human
      interleukin 2 in vitro.
AB  - Protein disulfide isomerase has broad specificity in the catalysis of the
      formation and rearrangement of native disulfide bonds in proteins. This enzyme
      has two independent thioredoxin-like active sites (-CGHC-) and a peptide binding
      site. However, the mechanisms involving the catalytic processes are not clearly
      understood. It was reported that the enzyme associates with scrambled pancreatic
      ribonuclease A in vitro, and with misfolded human lysozyme in vivo. In the
      present study, recombinant human interleukin 2 has been chosen to probe the
      reaction intermediate in the reaction with the enzyme. We have identified and
      characterized a covalent associate formed in vitro by SDS-PAGE and Western blot
      analysis. This associate has a molecular weight of 71-72 kDa, the approximate sum
      of the molecular weights of the enzyme and the substrate. Western blot analysis
      confirmed that it formed via an intermolecular disulfide bond. Upon treatment
      with 2-mercaptoethanol, this bond was cleaved.

PMID- 8660363
TI  - A 11.5-kb 5'-terminal cDNA sequence of chicken breast muscle connectin/titin
      reveals its Z line binding region.
AB  - A partial 5'-region cDNA (11.5 kb) of chicken breast muscle connectin/titin
      encoding 3752 amino acids was sequenced. The predicted amino acid sequence
      contains 31 immunoglobulin C2 motifs and 10 interdomains. The sequence suggests a
      skeletal muscle type of connectin isoforms. Immunoelectron microscopic studies
      using antisera raised against several products of the cDNA fragments expressed in
      E. coli revealed that a region of some 800 amino acids from the N terminus of
      connectin is involved in its binding to the Z line in a sarcomere.

PMID- 8660364
TI  - Amyloid beta protein and its 3-kDa fragment are present in the axoplasm fraction
      of the white matter in human brain.
AB  - Production of the soluble amyloid beta-protein (A beta) precedes abnormal
      accumulation of A beta amyloid in the brains of subjects with Alzheimer's
      disease. To determine the cellular source and generating mechanisms of soluble A
      beta in the human brain, we separated an axoplasm fraction from the cerebral
      white matter and analyzed it. The axoplasm fraction contained secretory isoforms
      of beta-amyloid precursor protein (APP) and 11.5 kDa A beta-bearing carboxyl
      terminal fragments (CTFs) of APP. Furthermore, soluble 4 kDa A beta and 3 kDa
      fragments of A beta (p3) were obtained from the axoplasm fraction. These results
      suggest that amyloidogenic 4 kDa A beta is intracellularly produced in cerebral
      neurons and carried through the axons in human brain.

PMID- 8660365
TI  - Protein tyrosine kinase inhibitors promote amylase secretion and inhibit
      ornithine decarboxylase induction in sialagogue-stimulated rat parotid explants.
AB  - Three sialagogues, isoproterenol (IPR), carbachol, and methoxamine, caused
      induction of ornithine decarboxylase (ODC) in cultured rat parotid explants. All
      the protein tyrosine kinase inhibitors tested suppressed this ODC induction but
      enhanced sialagogue-dependent amylase secretion. Sodium orthovanadate showed the
      reverse effects as the kinase inhibitors. Immunoblot analysis with anti
      phosphotyrosine antibody revealed that herbimycin A depresses IPR-stimulated
      tyrosine phosphorylation of parotid proteins. Herbimycin A did not affect the IPR
      or dibutyryl cAMP-induced surge of the parotid cAMP level but inhibited these
      agonist-dependent ODC inductions. These results suggest that sialagogue-induced
      ODC induction and amylase secretion are mediated by different signal transduction
      pathways and that protein tyrosine kinase participates in IPR-dependent ODC
      induction and amylase secretion in the process subsequent to the cAMP surge.

PMID- 8660366
TI  - Effects of transition metals on the expression of the erythropoietin gene:
      further evidence that the oxygen sensor is a heme protein.
AB  - Both in vivo and in Hep3B cells, expression of the erythropoietin gene is induced
      by hypoxia as well as by certain transition metals (cobalt and nickel) and by
      iron chelation. When Hep3B cells were incubated in an iron deficient medium, Epo
      mRNA expression was enhanced 4-fold compared to Hep3B cells in iron enriched
      medium. The increased Epo expression in iron deficient medium was abolished when
      Fe2-transferrin complex was added. Epo induction by cobalt was also affected by
      iron concentration. In iron enriched medium, erythropoietin expression in Hep3B
      cells was maximally induced at CoCl2 concentrations between 100 to 200 microM. In
      contrast, in iron poor medium, a high level of induction was obtained at a CoCl2
      concentration of only 50 microM, indicating competition between iron and cobalt.
      Under hyperbaric oxygen, cobalt induction of erythropoietin mRNA was modestly
      suppressed while nickel induction was markedly enhanced. These observations
      support the proposal that the oxygen sensor is a heme protein in which cobalt and
      nickel can substitute for iron in the porphyrin ring.

PMID- 8660367
TI  - Nongenomic effects of aldosterone on intracellular pH in vascular smooth muscle
      cells.
AB  - The aim of the present study was to investigate rapid effects of aldosterone and
      other steroids on intracellular pH of vascular smooth muscle cells and to compare
      these effects with those of peptide hormones. After addition of 100 nmol/L
      aldosterone, initial acidification is followed by significant alkalinisation
      occurring within two minutes, while 1 mumol/L hydrocortison does not affect
      intracellular pH. The initial response to 100 nmol/L angiotensin II is similar;
      however, subsequent alkalinization is not seen for this agonist. PDGF induces an
      initial acidification followed by a minor recovery so that cells remain acidified
      for eight minutes. Both pH recovery after angiotensin II and alkalinization after
      aldosterone were blocked in sodium-free medium. These results demonstrate rapid
      effects of aldosterone on intracellular pH in vascular smooth muscle cells, which
      include final alkalinization not seen after angiotensin II or PDGF.

PMID- 8660368
TI  - Evidence for an alpha helical T cell epitope in the C-terminus of the main birch
      pollen allergen Bet V 1.
AB  - Secondary structure prediction of the main birch pollen allergen Bet v 1 was
      found to be in good agreement with the secondary structural elements found by
      analysing the Bet v 1 circular dichroism data. According to both experiment and
      prediction, 32% of 160 amino acids participate in alpha helices, 21% in beta
      sheets, 24% in turns, and 23% in other structural motifs. The peptide
      LRAVESYLLAHS which represents one of the major T cell epitopes on Bet v 1 was
      shown to have a high propensity to form an alpha helix. Time-resolved
      fluorescence anisotropy measurements of the allergen revealed an overall
      rotational correlation time of 7.35 ns, which corresponds to a hydrodynamic
      molecular radius of 19.2 A. This refers to a monomeric Bet v 1 molecule in
      solution, which is also reflected in the narrow band width of the 1H-NMR
      spectrum. The results presented here are in good agreement with the recently
      solved NMR structure of Amb t 5: both allergens are monomers in solution with an
      extended C-terminal alpha helix containing a major T cell epitope.

PMID- 8660369
TI  - The basic fibroblast growth factor (FGF-2) antisense RNA (GFG) is translated into
      a MutT-related protein in vivo.
AB  - The basic fibroblast growth factor (FGF-2) gene is transcribed bidirectionally to
      yield multiple sense (coding) transcripts and a unique 1.5 kb antisense
      transcript which may regulate sense RNA stability. The antisense RNA also
      contains a long open reading frame that predicts a hypothetical protein with
      homology to the prokaryotic MutT antimutator proteins. However, translation of
      this protein has not previously been demonstrated. We employed antibodies against
      the conserved MutT-domain of the deduced human FGF-2 antisense protein (GFG) to
      demonstrate expression of an immunoreactive 24 kDa protein in liver extracts from
      Xenopus laevis, and two proteins of 28 and 35 kDa in rat liver. In rats, GFG
      protein expression detected by western blot was tissue-specific and correlated
      with the level of FGF-2 antisense mRNA expression. These findings demonstrate
      that, in addition to its possible RNA regulatory function, the FGF-2 antisense
      transcript is translated into a conserved MutT-related protein.

PMID- 8660371
TI  - Increased intestinal Bak expression results in apoptosis.
AB  - Cells in the human intestinal epithelium have a life-span of around 5 days before
      being lost by apoptosis at the luminal surface. We examined changes in expression
      of the Bcl-2 gene family which may be responsible for epithelial cell loss. In
      the normal and neoplastic colon, mucosal expression of immunoreactive Bak co
      localized with sites of epithelial cell apoptosis. Inducing apoptosis in the
      human colon cancer cell line HT29 and the rat normal small intestinal cell line
      IEC 18 in culture was accompanied by increased Bak expression without consistent
      changes in expression of other Bcl-2 homologous proteins. Bak appears to be the
      endogenous Bcl-2 family member best correlated with intestinal cell apoptosis.

PMID- 8660370
TI  - Functional expression of thyrotropin receptor in differentiated 3T3-L1 cells: a
      possible model cell line of extrathyroidal expression of thyrotropin receptor.
AB  - Thyrotropin receptor (TSHR) in extrathyroidal tissue, especially fat tissue, is
      supposed to have important roles in the development of extrathyroidal
      manifestations of Graves' disease. However, the molecular mechanism of TSHR
      expression is not known. Expression of TSHR mRNA and TSH-dependent cAMP
      production were observed in differentiated but not in undifferentiated 3T3-L1
      cells. Maximal expression was obtained when the cells were differentiated in the
      presence of insulin, dexamethasone, and isobutylmethylxanthine (IBMX).
      Dexamethasone and IBMX were indispensable for the first three days. On the other
      hand, after day 4, insulin was indispensable for the expression of TSHR. 3T3-L1
      cell is the first non-thyroidal cell line reported that expresses TSHR and whose
      expression can be induced. 3T3-L1 cell can be a good model to investigate the
      mechanism of expression of TSHR and extrathyroidal manifestations of Graves'
      disease.

PMID- 8660372
TI  - Electroporation of small RNAs into plant protoplasts: mitochondrial uptake of
      transfer RNAs.
AB  - To study tRNA import into plant mitochondria, we have set up a system to follow
      the fate in vivo of tRNA transcripts introduced into plant protoplasts by
      electroporation. Conditions were optimized for maximum tRNA uptake into potato
      protoplasts. We have shown that in vitro synthesized tRNA transcripts are poor
      substrates due to rapid degradation leading to low efficiencies of transfer and
      short life in protoplasts. Labelled natural tRNAs were more efficiently
      electroporated into protoplasts and they remained stable during protoplast
      culture. We have observed import into mitochondria of total and purified
      cytosolic tRNAs in protoplasts but the process was not specific for the tRNA
      species which are normally imported.

PMID- 8660373
TI  - Characterization of additional host restriction-modification systems in the
      unicellular cyanobacterium Cyanothece sp.
AB  - In order to develop a gene transfer system for the unicellular diazotrophic
      cyanobacterium Cyanothece sp. strain BH68K, this organism has been further
      investigated for the presence of additional host restriction-modification enzymes
      other than Csp68KI, previously reported for Cyanothece sp. Analysis of cell
      extracts by phosphocellulose and Mono Q fast protein liquid chromatography (FPLC)
      has led to the identification of three new restriction endonucleases. These
      enzymes have been designated Csp68KII, Csp68KIII, and Csp68KVI. Csp68KII is an
      isoschizomer of AsuII and restricts DNA at the recognition sequence 5'-TT/CGAA
      3'. Cleavage occurred between thymine and cytosine producing 2 bp 5' overhang
      ends. The third restriction endonuclease, Csp68KIII, is an isoschizomer of AvaIII
      and restricts DNA at the recognition sequence 5'-ATGCA/T-3'. Cleavage occurred
      between the 3' adenosine and thymine nucleotides producing 4 bp 3' overhang ends.
      The fourth enzyme identified, Csp68KVI, recognizes CGCG and cleaves this sequence
      between the internal guanine and cytosine nucleotides producing blunt ends.

PMID- 8660374
TI  - Skeletal muscle of patients with Duchenne's muscular dystrophy: evidence of a
      mitochondrial proteolytic factor responsible for calmitine deficiency.
AB  - We studied the effect of mitochondrial extracts of skeletal muscle obtained from
      patients with Duchenne's muscular dystrophy (DMD) on calmitine of the
      mitochondrial matrix isolated from skeletal muscle of control mice. Our results
      in vitro clearly show that calmitine of the mitochondrial matrix of control
      muscle was degraded in the presence of mitochondrial extracts of muscle from DMD
      patients. The diseased muscle apparently contains an abnormal calmitine-specific
      proteolytic factor responsible for the calmitine deficiency previously observed
      in this tissue. As calmitine binds calcium and probably plays a role in
      regulating the balance of bound and free calcium within mitochondria, a calmitine
      deficiency could result in an overload of mitochondrial free calcium. Certain
      enzymes involved in ATP synthesis would be inhibited, resulting in the muscular
      degeneration characteristic of this myopathy. Our results suggest the cause of
      mitochondrial calcium overload and the events leading to muscular degeneration in
      this disease model. Abnormal protease activity could be the factor triggering all
      of these processes in the DMD patient. These findings suggest that it may now
      feasible to search for an efficient pharmacologic treatment for DMD.

PMID- 8660375
TI  - Heparin-binding EGF-like growth factor is an autocrine growth factor for rat
      gastric epithelial cells.
AB  - We examined the biological action and expression of heparin-binding EGF-like
      growth factor (HB-EGF) in a rat gastric mucosal cell line, RGM1. HB-EGF
      stimulated DNA synthesis of RGM1 cells in a dose-dependent manner. Mitogenic
      effect of HB-EGF was as potent as that of other known mitogens for gastric
      epithelial cells, such as hepatocyte growth factor (HGF) and transforming growth
      factor (TGF)-alpha. Northern blot analysis showed that RGM1 cells as well as rat
      gastric mucosal tissue expressed a 2.5-kilobase transcript of HB-EGF. Not only HB
      EGF and TGF-alpha but also HGF caused a rapid induction of HB-EGF mRNA in the
      cells. Treatment with heparitinase which destroys heparan sulfate proteoglycan
      (HSPG) or with chlorate which inhibits sulfation of HSPG diminished [3H]thymidine
      incorporation of RGM1 cells in serum-free medium. In addition, a synthetic
      peptide corresponding to the heparin-binding domain of HB-EGF inhibits the DNA
      synthesis of RGM1 cells in serum-free medium in a dose-dependent manner. These
      results suggest that HB-EGF is an autocrine and paracrine growth factor for
      gastric epithelial cells and may play significant roles in mucosal repair of the
      stomach in cooperation with other growth factors.

PMID- 8660376
TI  - Inactivation of cholesteryl ester transfer protein by cysteine modification.
AB  - The present studies examine the effects of various cysteine-modifying reagents on
      human recombinant cholesteryl ester transfer protein (CETP) activity.
      Dithiothreitol or other reducing agents had no effect on CETP transfer activity.
      Alkylating agents, including iodoacetamide and N-ethyl maleimide, also did not
      affect transfer activity. However, incubation of CETP with hydrophobic thiol
      modifying reagents such as p-chloromercuriphenylsulfonic acid (IC50 = 0.02
      microM), 4,4'-dithiodipyridine (IC50 = 0.5 microM), or 4,4'-dithiobis (phenyl
      azide) (IC50 = 0.5 microM) resulted in complete, time-dependent inactivation of
      both the cholesteryl ester and triglyceride transfer activities. Inactivation
      could be prevented by including dithiothreitol in the incubation. Long chain
      fatty acyl coenzyme A compounds were also found to be effective CETP inhibitors.
      The extent of inhibition was time-dependent, and proportional to the chain length
      of the fatty acyl portion of the molecule. These results suggest that CETP
      contains an essential free cysteine that resides in a hydrophobic environment
      within the protein.

PMID- 8660377
TI  - Tissue specific expression of testis angiotensin converting enzyme is not
      determined by the -32 nonconsensus TATA motif.
AB  - Testis ACE is an isozyme of angiotensin-converting enzyme (ACE) made by male germ
      cells. These cells recognize a small intragenic promoter which contains a
      positive regulatory element, TCTTAT, at position -32. A probe containing this
      element was gel shifted to an identical location by rat testis and rat liver
      nuclear extracts; formation of the complex was blocked by anti-TATA binding
      protein antibody. Recombinant TATA binding protein recognized the testis ACE
      TCTTAT motif as well as a probe containing the consensus TATA motif. Mice
      transgenic for testis ACE promoter constructs containing either the wild type
      testis ACE motif or a consensus TATA sequence expressed a reporter gene at high
      levels only within the testis. These data suggest that the testis ACE motif
      TCTTAT is a non-consensus TATA, but is not responsible for the highly restricted
      pattern of testis ACE gene expression.

PMID- 8660378
TI  - Nucleotide sequence, chromosomal assignment and mRNA expression of mouse hypoxia
      inducible factor-1 alpha.
AB  - The heterodimeric hypoxia-inducible transcription factor HIF-1 is involved in the
      oxygen-regulated transcription of several genes including erythropoietin. Cloning
      and sequencing of the alpha-subunit of mouse HIF-1 cDNA revealed a 90% overall
      homology to human HIF-l alpha but lack of any similarity in the 5' untranslated
      region and translational start site. Mouse HIF-1 alpha is encoded by an
      evolutionary conserved single-copy gene located on chromosome 12. We found a
      widespread constitutive expression of mouse HIf-1 alpha mRNA which was
      particularly high in lung and kidney. Despite a strong erythropoietin induction,
      HIF-1 alpha mRNA concentrations were not upregulated in hypoxic mouse tissues.

PMID- 8660379
TI  - Platelet-derived growth factor B-chain homodimer suppressing a convulsion of
      epilepsy model mouse El.
AB  - El mouse is a mutant which has epileptic convulsions after tossing-up
      stimulations and has a hippocampal dysfunction. Platelet-derived growth factor B
      chain homodimer has been reported to be a trophic factor of hippocampal neurons.
      We found that a recombinant PDGF-BB suppressed the convulsions of El mice in a
      dose-dependent manner. Furthermore, thrombin-treated mice manifested no
      convulsions, but thrombin receptor activating peptide-treated ones had
      convulsions. These findings suggest that an abnormality in PDGF-BB release may
      make El mice susceptible to tonic-clonic convulsions.

PMID- 8660380
TI  - An upstream positive regulatory element in human GM-CSF promoter is recognized by
      NF-kappa B/Rel family members.
AB  - To further extend the previous analysis of cis-acting elements and cognate trans
      acting factors that contribute to GM-CSF transcriptional regulations, we have
      examined a promoter region between -1742 and -2010. DNase I footprinting assays
      showed four protected sequences named A, B, C and D. DNA transfections in the T
      lymphoid Mo cell line, which constitutively expresses GM-CSF, indicated that the
      A element, located between -2002 and -1984, has a positive role on transcription.
      Further characterization by electrophoretic mobility shift assays in the presence
      of different competitor oligonucleotides showed that this element binds a factor
      of the NF-kappa B/Rel family.

PMID- 8660381
TI  - Different heat-shock proteins are constitutively overexpressed in cadmium and
      pentachlorophenol adapted Euglena gracilis cells.
AB  - To determine whether cellular resistance to a given stressor is related to
      induction of specific stress-proteins, responses of two adapted Euglena gracilis
      cell lines, one adapted to cadmium, the other adapted to pentachlorophenol, were
      analyzed. Our experiments showed that two sets of heat-shock proteins (hsps) were
      constitutively overexpressed in each cell line: while hsp90, hsp70, hsp55, and
      hsp40 were induced in cadmium-resistant cells, only hsp40 was induced in
      pentachlorophenol-adapted cells.

PMID- 8660382
TI  - Enzymatic pattern of aldehyde metabolism during HL-60 cell differentiation.
AB  - A number of metabolic changes, including modification of different enzyme
      activities, are linked to the acquisition of differentiated phenotype in HL-60
      cells. Enzymes metabolizing aldehydes contribute to maintaining the intracellular
      steady-state concentration of aldehydes derived from lipid peroxidation. 4
      Hydroxynonenal is one of the most important aldehydes produced by this process,
      and it is able to inhibit proliferation and induce differentiation of HL-60 human
      leukemic cells. We have now demonstrated that, after induction of HL-60 cell
      differentiation by 4-hydroxynonenal or DMSO, glutathione transferase activity
      increases in parallel to the degree of differentiation induction. Moreover, in 4
      hydroxynonenal- or DMSO-treated cells, the concentration of reduced glutathione
      decreases five days after treatment. The rise of glutathione transferase
      activity, as well as the decrease of reduced glutathione, are possibly linked to
      the increase of detoxification capability of differentiated cells.

PMID- 8660383
TI  - Differential regulation of insulin-stimulated tyrosine phosphorylation of IRS-1
      and SHC by Wortmannin in intact cells.
AB  - Wortmannin is an inhibitor of phosphatidylinositol (PI) 3'-kinase, a cellular
      kinase activated by docking to phosphotyrosyl residues of insulin receptor
      substrate-1 (IRS-1) that can also phosphorylate serine residues on IRS-1 in
      vitro. After treatment of hepatoma cells with 100 nM wortmannin, the tyrosine
      phosphorylation of IRS-1 in response to insulin was increased by 38.3 +/- 3.3%
      while its phosphoserine/threonine content was reduced by 19%. Treatment with 1
      microM wortmannin further increased IRS-1 tyrosine phosphorylation to 180% of
      control, while under these conditions, tyrosine phosphorylation of the IR
      substrate p52 Shc was reduced to less than 50% of control. Thus, alteration of
      the serine phosphorylation of IR substrates by a wortmannin-sensitive kinase may
      regulate post-insulin receptor signaling pathways by differential modulation of
      their insulin-stimulated tyrosine phosphorylation.

PMID- 8660384
TI  - Carbon centered radicals reduce the density of L-type calcium channels in rat
      cardiac membranes.
AB  - The carbon centered radicals generated by preincubation of cumene hydroperoxide
      with rat cardiac membranes dose dependently reduced the Bmax of [3H]nitrendipine
      binding, while KD was unchanged. The reduction induced by cumene hydroperoxide
      was prevented by 2,6-di-t-butlyl-4-methyl-phenol. The generation of OH did not
      influence the [3H]nitrendipine binding; also other oxidative agents (H2O2 and
      HClO4) did not modify this binding. Therefore the reduction in [3H]nitrendipine
      binding sites is not attributable to generic oxidative stress but to the
      formation of carbon centered radicals.

PMID- 8660385
TI  - Extended substrate specificity of serum amine oxidase: possible involvement in
      protein posttranslational modification.
AB  - The capacity of bovine serum amineoxidase (SAO) to oxidize free amino groups of
      nonconventional substrates, such as polylysine (up to 50 kDa) and some proteins
      as lysozyme and ribonuclease A, is described. The oxidation was quantified from
      the amount of H2O2 and NH3 enzymatically produced by SAO. Kinetic analysis
      indicated a stereospecific preference for L-configuration. Maximal oxidation rate
      was obtained with poly-L-lysine (9.6 kDa). After 10 h of incubation at 37 degrees
      C, the poly-L-lysine was partially oxidized generating 1.5 moles of H2O2 by one
      mole of polylysine. Denatured SAO presented very low oxidation rates with the
      mentioned substrates.

PMID- 8660386
TI  - Influence of various domains of protein kinase C epsilon on its PMA-induced
      translocation from the Golgi to the plasma membrane.
AB  - Subcellular redistribution (translocation) was initiated by treatment of NIH 3T3
      cells overexpressing different epitope-tagged fragments of PKC epsilon with PMA,
      and was analyzed by immunocytochemistry. The PMA-induced translocation of holo
      PKC epsilon, as well as fragments epsilon 2 (zinc finger domain + pseudosubstrate
      domain) and epsilon 7 (zinc finger domain + hinge region) from the Golgi to the
      plasma membrane was rapid (<10 min), while translocation of fragment epsilon 3
      (zinc finger domain) was much slower (30-60 min). These results, combined with
      results of studies carried out at 20 degrees C to inhibit exocytotic vesicle
      traffic, indicated that PMA-induced translocation from the Golgi to the plasma
      membrane may proceed by two distinct mechanisms: a rapid, vesicle independent
      process noted with holo PKC epsilon (which requires the presence of the
      pseudosubstrate and/or hinge regions), and a slow, vesicle-dependent pathway
      observed with the zinc finger fragment.

PMID- 8660387
TI  - Oxidative stress: the paradox of aerobic life.
AB  - The paradox of aerobic life, or the 'Oxygen Paradox', is that higher eukaryotic
      aerobic organisms cannot exist without oxygen, yet oxygen is inherently dangerous
      to their existence. This 'dark side' of oxygen relates directly to the fact that
      each oxygen atom has one unpaired electron in its outer valence shell, and
      molecular oxygen has two unpaired electrons. Thus atomic oxygen is a free radical
      and molecular oxygen is a (free) bi-radical. Concerted tetravalent reduction of
      oxygen by the mitochondrial electron-transport chain, to produce water, is
      considered to be a relatively safe process; however, the univalent reduction of
      oxygen generates reactive intermediates. The reductive environment of the
      cellular milieu provides ample opportunities for oxygen to undergo unscheduled
      univalent reduction. Thus the superoxide anion radical, hydrogen peroxide and the
      extremely reactive hydroxyl radical are common products of life in an aerobic
      environment, and these agents appear to be responsible for oxygen toxicity. To
      survive in such an unfriendly oxygen environment, living organisms generate--or
      garner from their surroundings--a variety of water- and lipid-soluble antioxidant
      compounds. Additionally, a series of antioxidant enzymes, whose role is to
      intercept and inactivate reactive oxygen intermediates, is synthesized by all
      known aerobic organisms. Although extremely important, the antioxidant enzymes
      and compounds are not completely effective in preventing oxidative damage. To
      deal with the damage that does still occur, a series of damage removal/repair
      enzymes, for proteins, lipids and DNA, is synthesized. Finally, since oxidative
      stress levels may vary from time to time, organisms are able to adapt to such
      fluctuating stresses by inducing the synthesis of antioxidant enzymes and damage
      removal/repair enzymes. In a perfect world the story would end here;
      unfortunately, biology is seldom so precise. The reality appears to be that,
      despite the valiant antioxidant and repair mechanisms described above, oxidative
      damage remains an inescapable outcome of aerobic existence. In recent years
      oxidative stress has been implicated in a wide variety of degenerative processes,
      diseases and syndromes, including the following: mutagenesis, cell transformation
      and cancer; atherosclerosis, arteriosclerosis, heart attacks, strokes and
      ischaemia/reperfusion injury; chronic inflammatory diseases, such as rheumatoid
      arthritis, lupus erythematosus and psoriatic arthritis; acute inflammatory
      problems, such as wound healing; photo-oxidative stresses to the eye, such as
      cataract; central-nervous-system disorders, such as certain forms of familial
      amyotrophic lateral sclerosis, certain glutathione peroxidase-linked adolescent
      seizures, Parkinson's disease and Alzheimer's dementia; and a wide variety of age
      related disorders, perhaps even including factors underlying the aging process
      itself. Some of these oxidation-linked diseases or disorders can be exacerbated,
      perhaps even initiated, by numerous environmental pro-oxidants and/or pro-oxidant
      drugs and foods. Alternatively, compounds found in certain foods may be able to
      significantly bolster biological resistance against oxidants. Currently, great
      interest centres on the possible protective value of a wide variety of plant
      derived antioxidant compounds, particularly those from fruits and vegetables.

PMID- 8660388
TI  - Plant polyphenols: free radical scavengers or chain-breaking antioxidants?
AB  - There is increasing interest in the biological effects of tea- and wine-derived
      polyphenols and many studies in vitro and in vivo are demonstrating their
      antioxidant properties. Tea is a major source of dietary polyphenols and an even
      richer source of the flavanols, the catechins and catechin/gallate esters.
      Although there are limited studies on the bioavailability of the polyphenols, the
      absorption of flavanols in humans has been shown. The studies described in this
      chapter discuss the relative antioxidant potentials of the polyphenolic
      flavonoids in vitro against radicals generated in the aqueous phase in comparison
      with their relative effectiveness as antioxidants against propagating lipid
      peroxyl radicals, and how their activity influences that of alpha-tocopherol in
      low-density lipoproteins exposed to oxidative stress.

PMID- 8660389
TI  - Plant carotenoids and related molecules: important dietary antioxidants.
AB  - The antioxidant effects of dietary carotenoids such as beta-carotene have been
      well documented in various systems in vitro, using either organic solvents or
      membrane systems. However, the biologically relevant studies of the effects of
      beta-carotene on low-density lipoprotein (LDL) oxidation are still controversial,
      as are those studies using LDL from individuals supplemented with large amounts
      of beta-carotene. These findings do not agree with the epidemiological evidence
      which suggests that individuals who consume fruits and vegetables rich in
      carotenoids, or who have relatively high serum carotenoid levels, are at a lower
      risk of developing coronary heart disease. What is apparent is that studies that
      have looked at antioxidant protection in the whole organism have demonstrated a
      decrease in markers of lipid peroxidation after beta-carotene supplementation.
      Maybe those studies trying to pin-point the antioxidant site of carotenoids in
      vivo have been looking at the wrong tissue.

PMID- 8660390
TI  - Therapeutic iron chelators and their potential side-effects.
AB  - A number of iron-chelating agents are currently being considered as orally active
      alternatives to desferrioxamine (DFO), the therapeutic agent for the treatment of
      body iron overload that is available at present. These include bidentate
      hydroxypyridinones (HPO), tridentate desferrithiocin (DFT) analogues and
      hexadentate aminocarboxylate (HBED) chelators. All chelating agents have the
      potential to induce toxic effects when iron homoeostasis is affected within the
      body. This can arise when the absorption, distribution and utilization of iron is
      affected. Alternatively, chelating agents can induce toxicity by directly
      interfering with iron-dependent metalloenzymes located within the body. These
      effects are, however, mainly localized to non-haem enzymes such as ribonucleotide
      reductase and lipoxygenase. The resultant iron complexes also have the ability to
      induce toxicity. Depending on the coordination geometry and donor atoms
      associated with the metal centre, redox cycling of the iron centre with the
      corresponding generation of free radicals can result.

PMID- 8660392
TI  - Biological and biochemical effects of air pollutants: synergistic effects of
      sulphite.
AB  - Air pollution has become a major public and political concern since the beginning
      of industrialization, particularly motor exhaust over the past three decades.
      Epidemiological studies, together with clinical trials and experiments in
      exposition chambers (including biochemical model reactions), have contributed to
      our knowledge of potential dangers and increased our understanding of the
      corresponding mechanisms and dose-response effects. Comparison of the threatening
      reports that appear almost daily in the press with the digest of over 800
      scientific publications allows the statement that the impact of ozone and nitric
      oxide on the health and performance of plants and animals is widely overestimated
      and appears to be used as a political instrument. In contrast, the combination of
      SO2 with soot and asbestos particles may represent an underestimated toxic
      potential. In this communication, we shall concentrate on basic redox mechanisms
      involving SO2 and important target molecules, as well as looking at the
      cooperative effects of sulphite and soot particles.

PMID- 8660391
TI  - Oxidative damage by ozone and nitrogen dioxide: synergistic toxicity in vivo but
      no evidence of synergistic oxidative damage in an extracellular fluid.
AB  - Inhalation of ozone (O3) and/or nitrogen dioxide (.NO2) is associated with the
      development of inflammation in the respiratory tract and various alterations in
      pulmonary functions. Respiratory tract lining fluids (RTLFs) represent the first
      biological fluids coming into contact with these inhaled toxicants. Using plasma
      as a surrogate for RTLFs, we have previously shown that O3 [Cross, Motchnik,
      Bruener, Jones, Kaur, Ames and Halliwell (1992) FEBS Lett. 298, 269-272] and .NO2
      [Halliwell, Hu, Louie, Duvall, Tarkington, Motchnik and Cross (1992) FEBS Lett.
      313, 62-66] are both capable of depleting antioxidants and damaging proteins and
      lipids. O3 particularly damages proteins, whereas .NO2 induces the peroxidation
      of lipids and nitrates aromatic amino acids. It has been reported that O3 and
      .NO2 cause synergistic toxicity in rodents [Gielzleichter, Witschi and Last
      (1992) Tox. Appl. Pharmacol. 116, 1-9]. In the present chapter, we review
      evidence showing that combined exposure of these two oxidant gases to human
      plasma fails to exert synergistic oxidative damage to plasma constituents, and in
      fact, O3 and .NO2 antagonize each other's actions. We conclude that the
      potentiating effect of these two gases on morbidity and mortality in rodents
      represents a complex interactive biological effect rather than a simple
      synergistic oxidative effect in extracellular fluids.

PMID- 8660393
TI  - Myeloperoxidase as a generator of drug free radicals.
AB  - Reactive metabolites are believed to be responsible for many types of toxicity,
      including idiosyncratic drug reactions. Bone marrow is a frequent target of
      idiosyncratic reactions, and, since these reactions have characteristics that
      suggest involvement of the immune system, the formation of reactive metabolites
      by leucocytes could also play a role in the aetiology of idiosyncratic drug
      reactions. The major oxidation system in neutrophils and monocytes is a
      combination of NADPH oxidase and myeloperoxidase. This system oxidizes primary
      arylamines, such as sulphonamides, to reactive metabolites and these drugs are
      also associated with a high incidence of agranulocytosis, generalized
      idiosyncratic reactions and/ or drug-induced lupus. Clozapine is oxidized by this
      system to a relatively stable nitrenium ion; clozapine is also associated with a
      high incidence of agranulocytosis. Arylamines that have an oxygen or nitrogen in
      the para position, such as amodiaquine, vesnarinone and 5-aminosalicylic acid,
      are oxidized to quinone-like reactive intermediates. Aminopyrine is oxidized to a
      very reactive dication. Such reactive metabolites could also inhibit neutrophil
      function and mediate some of the therapeutic effects of these drugs: for example,
      the use of dapsone for dermatitis herpetiformis and the use of 5-aminosalicylic
      acid for inflammatory bowel disease.

PMID- 8660394
TI  - Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and
      quinones: the kinetic basis for hypoxia-selective, bioreductive drugs.
AB  - Drugs based on nitroarene, aromatic N-oxide or quinone structures are frequently
      reduced by cellular reductases to toxic products. Reduction often involves free
      radicals as intermediates which react rapidly with oxygen to form superoxide
      radicals, inhibiting drug reduction. The elevation of cellular oxidative stress
      accompanying oxygen inhibition of reduction is generally less damaging than drug
      reduction to toxic products, so the drugs offer selective toxicity to hypoxic
      cells. Since such cells are resistant to radiotherapy, these bioreductive drugs
      offer potential in tumour therapy. The basis for the selectivity of action
      entails kinetic competition involving the contesting reaction pathways. The
      reduction potential of the drug, radical pKa and nature of radical/radical decay
      kinetics all influence drug activity and selectivity, including the range of
      oxygen tensions over which the drug offers selective toxicity. These properties
      may be quantified using generation of radicals by pulse radiolysis, presenting a
      physicochemical basis for rational drug design.

PMID- 8660395
TI  - Side-effects of drugs used in the treatment of rheumatoid arthritis.
AB  - A number of anti-inflammatory and other drugs used in the treatment of rheumatoid
      arthritis have been screened for their ability to cause oxidative damage to
      lipids and proteins in vitro. Although many drugs exhibited an antioxidant
      profile, a few drugs tested were pro-oxidant, increasing peroxidation of
      arachidonic acid by mixtures of haem proteins and H2O2. This system may be an
      appropriate model to use in the inflammatory situation, since microbleeding to
      release haemoglobin occurs in the inflamed rheumatoid joint, where H2O2 is
      produced by invading neutrophils. The damaging effects of the pro-oxidant drugs
      phenylbutazone, meclofenamic acid and flufenamic acid were investigated in some
      detail using this system. Arachidonic acid peroxidation was accentuated in a dose
      dependent manner and in the presence of haem proteins and H2O2, phenylbutazone
      also causes inactivation of alpha 1-antiproteinase, a major serine proteinase
      inhibitor in biological fluids. The above drugs may interact with ferryl
      haemoglobin, produced by the reaction of H2O2 with haemoglobin, to generate drug
      derived radicals causing oxidative damage in these systems. If such reactions
      occur in vivo, they could contribute to the side-effects induced by these drugs
      on administration to certain rheumatoid arthritis patients.

PMID- 8660396
TI  - Tamoxifen as an antioxidant and cardioprotectant.
AB  - Tamoxifen is widely used in the treatment of breast cancer and has been proposed
      as a prophylactic agent in this disease. Tamoxifen is an effective antioxidant
      and protects membranes and low-density lipoprotein (LDL) particles against
      oxidative damage. This antioxidant action is shared by endogenous and synthetic
      oestrogens. The ability of tamoxifen to protect LDL particles against the
      oxidative damage implicated in atherosclerosis may be an important factor in the
      reported cardioprotective action of tamoxifen in women being treated for breast
      cancer. In addition, tamoxifen has been found to act in a similar manner to
      oestrogens to lower plasma cholesterol levels. The cardioprotective action of
      tamoxifen may be a key factor in predicting the likely risk/benefit ratio for
      prophylactic tamoxifen treatment in otherwise healthy women, who have been
      calculated to be genetically predisposed to developing breast cancer. In the
      future, predisposition to breast cancer may be determined by genetic screening.

PMID- 8660397
TI  - Antioxidant agents in raw materials and processed foods.
AB  - Many food raw materials contain natural antioxidants which exert control of
      oxidative processes in the living cells. Among antioxidative agents are found
      enzymes such as superoxide dismutase, glutathione peroxidase and glucose oxidase
      catalase. Among naturally occurring non-enzymic antioxidants are carotenoids,
      especially astaxanthin (e.g. in fish), tocopherols in oils and other phenolic
      compounds in plant material. Enzymic antioxidants are mostly inactivated in food
      processing but the non-enzymic ones can be active also in heat-treated food and
      might also be active after consumption of the food, as is claimed with beta
      carotene, and vitamins A and E. Vitamin C is a generally reducing substance which
      acts synergistically with other antioxidants. Processing of food can result in
      the formation of antioxidative compounds, e.g. by protein hydrolysis, Maillard
      reaction and fermentation by lactic acid bacteria. Curing of meat yields
      nitrosylhaem pigments which can act as radical scavengers and protect both the
      meat pigment and the lipids from oxidation. Two or more antioxidants together can
      act synergistically, i.e. affect lipid oxidation to a higher extent than the sum
      of the contributions from each single antioxidant.

PMID- 8660398
TI  - Antioxidants in food packaging: a risk factor?
AB  - It is current practice to test all new additives for packaging polymers for
      toxicity before permitting them to be used in food contact applications. However,
      many antioxidants and stabilizers act sacrificially and are converted to
      oxidation products in the process of preventing polymer degradation. In most
      cases, little is known about the toxicity of antioxidant transformation products,
      and in some cases there is reason to suspect that they may be more toxic than the
      chemicals from which they are derived. Two possible solutions are presently
      showing promise. The first is to chemically react the antioxidant or stabilizer
      with the polymer, either at the polymer synthesis stage or preferably during
      processing, so that neither the antioxidant nor its transformation products can
      be leached into food. The second is to use a biological antioxidant (e.g. alpha
      tocopherol) whose oxidation chemistry and toxicology are known.

PMID- 8660399
TI  - Free radicals and food irradiation.
AB  - Ionizing radiation can be used to control insect and microbial infestation of
      foodstuffs, inhibit sprouting, delay ripening and reduce the dangers from food
      poisoning bacteria. Irradiation produces free radicals, most of which decay
      rapidly, although some are more persistent. These latter radicals can be detected
      and characterized by electron spin resonance (ESR). In bone and other calcified
      tissues, the radiation-induced radicals are distinguishable from naturally
      occurring radicals, and their stability makes them ideal for radiation dosimetry.
      The radicals induced in plant material, such as seeds and dried spices, are
      generally indistinguishable from the endogenous radicals and decay over a period
      of days or weeks. However, in many of these materials, a radiation-specific
      radical can be detected at low concentration, thereby permitting identification
      of irradiated samples, although precluding accurate dosimetry. ESR, although not
      universally applicable, currently provides the most specific method for the
      detection of irradiated food.

PMID- 8660400
TI  - Atherogenic and anti-atherogenic factors in the human diet.
AB  - New atherosclerosis causative factors and preventive modalities have been
      identified. Atherogenic factors include lipid oxidation products, such as
      cholesterol oxidation products, malonaldehyde and other aldehydes; trans-fatty
      acids; some saturated fatty acids (lauric, myristic and possibly palmitic acids);
      and myristic acid plus cholesterol. Lipid oxidation products are well suited to
      induce arterial damage, based on their known cytotoxic effects; evidence also
      indicates the possibility of plaque promotion and stimulation of thrombogenesis.
      Anti-atherogenic factors include antioxidants, fish oils and other
      polyunsaturates (if protected from oxidation), fibre and trace minerals such as
      copper, manganese, selenium and zinc. Iron is unique, being considered as both a
      potential promoter of atherosclerosis (component of ferritin, conceivably
      inducing lipid oxidation) and a possible anti-atherogenic component (of
      antioxidant enzyme catalase). It is apparent that an entire new series of
      research challenges has been uncovered.

PMID- 8660401
TI  - Nitric oxide and reactive oxygen species in vascular injury.
AB  - Nitric oxide (.NO), a free radical species produced by several mammalian cell
      types, plays a role in regulation of vascular, neurological and immunological
      signal transduction and function. The role of .NO in cytotoxic events is
      acquiring increased significance. The high rate of production and broad
      distribution of sites of production of .NO, combined with its facile direct and
      indirect reactions with metalloproteins, thiols and various oxygen radical
      species, assures that .NO will play a central role in regulating vascular,
      physiological and cellular homoeostasis, as well as critical intravascular free
      radical and oxidant reactions. At the same time, there are contradictions as to
      whether .NO mediates or limits free-radical-mediated tissue injury, and
      uncertainty regarding its mechanisms of action. .NO has been portrayed as a
      pathogenic mediator during ischaemia-reperfusion, and inflammatory and septic
      tissue injury. In contrast, cell-, metal- and oxidant-induced lipoprotein
      oxidation events, as well as hepatic, cerebrovascular, pulmonary and myocardial
      inflammatory and ischaemia-reperfusion injury studies, show convincingly that
      stimulation of endogenous .NO production or exogenous administration of .NO
      donating molecules can serve a protective role by inhibition of often oxidant
      related mechanisms. The final outcome of toxic versus tissue-protective reactions
      of .NO will depend on several factors, including sites and relative
      concentrations of individual reactive species and their diffusion distances. The
      following sections address these issues and conclude with a proposal as to how
      .NO serves as a central regulator of oxidant reactions and diverse free radical
      related disease processes.

PMID- 8660402
TI  - Ultraviolet radiation and free radical damage to skin.
AB  - Solar UVB (290-320 nm) and particularly UVA (320-380 nm) radiations have a
      capacity to generate reactive chemical species, including free radicals, in
      cells. These intermediates have been shown to be involved in various biological
      effects in cultured human skin cells (e.g. cell death) and skin (e.g. erythema).
      Endogenous glutathione is a critical molecule in protection against the cytotoxic
      effects of both wavelength ranges. Although there is evidence from cellular
      studies for the involvement of an oxidative component of UVC/UVB radiations in
      activation of several genes, the doses used are generally extremely cytotoxic and
      could cause aberrant signalling. Genes activated by sublethal doses of UVA
      radiations (e.g. haem oxygenase 1 and the CL100 phosphatase) are clearly redox
      regulated. The strong induction of haem oxygenase 1 in human fibroblasts has been
      implicated in an adaptive response to oxidative membrane damage that involves
      increased synthesis of the iron storage protein, ferritin.

PMID- 8660403
TI  - Thiyl radicals in biological systems: significant or trivial?
AB  - Thiyl radicals are formed from one-electron oxidation of thiols. Thiyl radicals
      participate in a number of reactions including electron transfer, hydrogen
      abstraction and addition reactions with several biological constituents and
      xenobiotics. Thiyl radicals can be detected by optical spectroscopy or by
      electron spin resonance (ESR) spectroscopy. Thiyl radicals appear to play a role
      in the nitrosylation of thiols and protein thiols. The exact mechanism of thiol
      induced enhancement of oxidative modification of low-density lipoprotein remains
      questionable. The proposed role of thiyl radicals in lipid peroxidation needs to
      be re-examined. It has been proposed that thiyl radicals are detoxified by
      superoxide dismutase in mammalian cells and by a thiol-specific enzyme in
      bacterial systems. We propose that thiols or protein thiols act as potent
      antioxidants in radical-induced damage via formation of thiyl radicals.

PMID- 8660404
TI  - The chemistry of lipid alkoxyl radicals and their role in metal-amplified lipid
      peroxidation.
AB  - Reaction of polyunsaturated fatty acid hydroperoxides with metal complexes
      generates lipid alkoxyl radicals and metal-oxo complexes. Lipid alkoxyl radicals
      are presumed to be the species responsible for metal-amplified lipid peroxidation
      because of the chemical analogy of simple organic alkoxyl radicals to the
      hydroxyl radical. However, polyunsaturated fatty acid alkoxyl radicals exhibit a
      rich and diverse chemistry that is dominated by intramolecular cyclization to
      epoxyallylic radicals. Studies described herein demonstrate that the equilibrium
      between cyclization and ring-opening of epoxyallylic radicals lies overwhelmingly
      toward cyclization. Thus lipid alkoxyl radicals have a steady-state concentration
      that is so low that their contribution to metal-amplified lipid peroxidation is
      insignificant. In fact, the species responsible for metal amplification of lipid
      peroxidation appears to be the epoxyperoxyl radical formed by coupling the
      epoxyallylic radical to molecular oxygen.

PMID- 8660405
TI  - How to characterize an antioxidant: an update.
AB  - The term antioxidant is widely used but rarely defined. One suggested definition
      is that an antioxidant is 'a substance that, when present at low concentrations
      compared with those of an oxidizable substrate, significantly delays or prevents
      oxidation of that substrate'. Many substances have been suggested to act as
      antioxidants in vivo, but few have been proved to do so. This chapter addresses
      the criteria necessary to evaluate a proposed antioxidant activity. Simple
      methods for assessing the possibility of physiologically feasible scavenging of
      important biological oxygen-derived species (superoxide, hydrogen peroxide,
      hydroxyl radical, hypochlorous acid, haem-associated ferryl species, radicals
      derived from activated phagocytes and peroxyl radicals, both lipid-soluble and
      water-soluble) are presented. Methods that may be used to gain evidence that a
      compound actually does function as an antioxidant in vivo are discussed.

PMID- 8660406
TI  - Amphotericin B kills unicellular leishmanias by forming aqueous pores permeable
      to small cations and anions.
AB  - The polyene antibiotic amphotericin B (AmB) is known to form two types of ionic
      channels across sterol-containing liposomes, depending on its concentration and
      time after mixing (Cohen, 1992). In the present study, it is shown that AmB only
      kills unicellular Leishmania promastigotes (LPs) when aqueous pores permeable to
      small cations and anions are formed. Changes of membrane potential across
      ergosterol-containing liposomes and LPs were followed by fluorescence changes of
      3,3' dipropylthiadicarbocyanine (DiSC3(5)). In KCl-loaded liposomes suspended in
      an iso-osmotic sucrose solution, low AmB concentrations (</=0.1 microM) induced a
      polarization potential, indicating K+ leakage, but no movement of cations and
      anions was allowed until AmB concentrations greater than 0.1 microM were added.
      In agreement with these data, it was found that AmB altered the negative membrane
      potential held across LPs in a manner consistent with the differential
      cation/anion selectivity exhibited by the channels formed in liposomes. Thus, LPs
      suspended in an iso-osmotic sucrose solution did not exhibit any AmB-induced
      membrane depolarization effect brought about by efflux of anions until 0.1 microM
      or higher AmB concentrations were added. By contrast, LPs suspended in an iso
      osmotic NaCl solution and exposed to 0.05 microM AmB exhibited a nearly total
      collapse of the negative membrane potential, indicating Na+ entry into the cells.
      The concentration dependence of the AmB-induced permeability to different salts
      was also measured across vesicles derived from the plasma membrane of leishmanias
      (LMVs), by using a rapid mixing technique. At concentrations above 0.1 microM,
      AmB induced the formation of aqueous pores across LMVs with a positive
      cooperativity, yielding Hill coefficients between 2 to 3. Measured anion
      selectivity across such aqueous pores followed the sequence: SCN > NO3 > Cl > I >
      Br > acetate (SO2-4 being impermeable). Cell killing by AmB was followed by
      fluorescence changes of the DNA-binding compound ethidium bromide (EB). At low
      concentrations (</=0.1 microM), AmB was found to be nonlethal against LPs but,
      above this concentration, leishmanias were rapidly killed. The rate and extent of
      such an effect were found to be dependent on the type of cation and anion present
      in the external aqueous solution. For both NH+4 and Na+ salts, the measured rank
      order of AmB cell killing followed the same sequence that was determined for AmB
      induced salt permeation across LMVs. Further, replacement of either extracellular
      Na+ by choline or Cl- by SO2-4, or its partial substitution by sucrose, in iso
      osmotic conditions, led to a complete inhibition of the killing effect exerted by
      otherwise lethal AmB concentrations. Finally, it was shown that
      tetraethylammonium (TEA+), an organic cation that is known to block AmB-induced
      salt permeation across LMVs was able to retard the time lag observed for EB
      incorporation across LPs, indicating that this parameter can be taken to
      represent the time taken for salt accumulation inside the parasites. The present
      results thus indicate clearly that low AmB concentrations (</=0.1 microM) were
      able to form across LPs, cation channels that collapsed the parasite membrane
      potential but are not lytic. At high concentrations (>/=0.1 microM), a salt
      influx via the aqueous pores formed by the antibiotic was followed by osmotic
      changes leading to cell lysis. This last stage is supported by electron
      microscopy observations of the changes of parasite morphology immediately upon
      addition of AmB, which indicated that the typical elongated promastigote cell
      forms became rounded and the flagella swells and round up. The present work is
      the first demonstration of the in vitro sensitivity of Leishmania promastigotes
      to osmotic lysis by AmB.

PMID- 8660407
TI  - Calcium-dependent modulation of the agonist affinity of the mammalian olfactory
      cyclic nucleotide-gated channel by calmodulin and a novel endogenous factor.
AB  - The calcium-dependent modulation of the affinity of the cyclic nucleotide-gated
      (CNG) channels for adenosine 3',5'-cyclic monophosphate (cAMP) was studied in
      enzymatically dissociated rat olfactory receptor neurons, by recording
      macroscopic cAMP-activated currents from inside-out patches excised from their
      dendritic knobs. Upon intracellular addition of 0.2 mM Ca2+ (0.2 Ca) the
      concentration of cAMP required for the activation of half-maximal current (EC50)
      was reversibly increased from 3 microM to about 30 microM. This Ca2+-induced
      affinity shift was insensitive to the calmodulin antagonist, mastoparan, was
      abolished irreversibly by a 2-min exposure to 3 mm Mg2+ + 2 mm EGTA (Mg + EGTA),
      and was not restored by the application of calmodulin (CAM). Addition of CAM plus
      0.2 mM Ca2+ (0.2 Ca + CAM), further reversibly shifted the cAMP affinity from 30
      microM to about 200 microM. This affinity shift was not affected by Mg + EGTA
      exposure, but was reversed by mastoparan. Thus, the former Ca2+-only effect must
      be mediated by an unknown endogenous factor, distinct from CAM. Removal of this
      factor also increased the affinity of the channel for CAM. The affinity shift
      induced by Ca2+-only was maintained in the presence of the nonhydrolyzable cAMP
      analogue, 8-bromo-cAMP and the phosphatase inhibitor, microcystin-LR, ruling out
      modulation by phosphodiesterases or phosphatases. Our results indicate that the
      olfactory CNG channels are modulated by an as yet unidentified factor distinct
      from CAM.

PMID- 8660408
TI  - Cultured giant fiber lobe of squid expresses three distinct potassium channel
      activities in selective combinations.
AB  - Neurons from the giant fiber lobe (GFL) of squid Loligo bleekeri were dissociated
      and cultured. The ionic currents were recorded using whole-cell patch clamp
      methods. The sodium current and the noninactivating potassium current like those
      elicited by the giant axon were among the currents expressed in axonal bulbs and
      bulblike structures upon dissociation. Meanwhile axonless cell bodies did not
      elicit such currents. Axonless cell bodies and some bulblike structures elicited
      two kinds of inactivating potassium currents, the slow- and the fast-inactivating
      current, which differed in their inactivation kinetics and pharmacology. Within
      24 hr of plating, the current composition remained the same. While the
      noninactivating current was not sensitive to 4-aminopyridine, the two
      inactivating currents were sensitive, the slow-inactivating current being more
      sensitive. Selective combinations of the sodium current and the three potassium
      currents expressed in different structures of the acutely dissociated GFL could
      have resulted from cellular control of synthesis and transportation of the
      channel proteins to the somatic and the axonal membrane. The sodium current and
      the noninactivating potassium current could be recorded from some axonless cell
      bodies maintained in culture for over three days, indicating that the separation
      of the giant axon from its somata could result in the transportation of the
      channels normally expressed on the giant axon membrane to the somatic membrane.

PMID- 8660410
TI  - Two novel toxins from the venom of the scorpion Pandinus imperator show that the
      N-terminal amino acid sequence is important for their affinities towards Shaker B
      K+ channels.
AB  - Two novel peptides were purified from the venom of the scorpion Pandinus
      imperator, and were named Pi2 and Pi3. Their complete primary structures were
      determined and their blocking effects on Shaker B K+ channels were studied. Both
      peptides contain 35 amino acids residues, compacted by three disulfide bridges,
      and reversibly block the Shaker B K+ channels. They have only one amino acid
      changed in their sequence, at position 7 (a proline for a glutamic acid). Whereas
      peptide Pi2, containing the Pro7, binds the Shaker B K+ channels with a Kd of 8.2
      nm, peptide Pi3 containing the Glu7 residue has a much lower affinity of 140 nm.
      Both peptides are capable of displacing the binding of 125I-noxiustoxin to brain
      synaptosome membranes. Since these two novel peptides are about 50% identical to
      noxiustoxin, the present results support previous data published by our group
      showing that the amino-terminal region of noxiustoxin, and also the amino
      terminal sequence of the newly purified homologues: Pi2, and Pi3, are important
      for the recognition of potassium channels.

PMID- 8660409
TI  - Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel
      alpha-subunits expressed in tsA201 cells.
AB  - We have expressed recombinant alpha-subunits of hH1 (human heart subtype 1),
      rSkM1 (rat skeletal muscle subtype 1) and hSkM1 (human skeletal muscle) sodium
      channels in human embryonic kidney cell line, namely the tsA201 cells and
      compared the effects of ATX II on these sodium channel subtypes. ATX II slows the
      inactivation phase of hH1 with little or no effect on activation. At intermediate
      concentrations of ATX II the time course of inactivation is biexponential due to
      the mixture of free (fast component, taufasth) and toxin-bound (slow component,
      tauslowh) channels. The relative amplitude of tauslowh allows an estimate of the
      IC50 values approximately 11 nM. The slowing of inactivation in the presence of
      ATX II is consistent with destabilization of the inactivated state by toxin
      binding. Further evidence for this conclusion is: (i) The voltage-dependence of
      the current decay time constants (tauh) is lost or possibly reversed (time
      constants plateau or increase at more positive voltages in contrast to these of
      untreated channels). (ii) The single channel mean open times are increased by a
      factor of two in the presence of ATX II. (iii) The recovery from inactivation is
      faster in the presence of ATX II. Similar effects of ATX II on rSkM1 channel
      behavior occur, but only at higher concentrations of toxin (IC50 = 51 nM). The
      slowing of inactivation on hSkM1 is comparable to the one seen with rSkM1. A
      residual or window current appears in the presence of ATX II that is similar to
      that observed in channels containing mutations associated with some of the
      familial periodic paralyses.

PMID- 8660411
TI  - Uptake of L-leucine by trout red blood cells and peripheral lymphocytes.
AB  - The uptake of l-leucine by trout red blood cells and peripheral lymphocytes has
      been analyzed. The present study shows two functionally different Na+-independent
      systems for apolar branched-chain amino acids. They are designated as L systems
      because they share some properties with the mammalian L system. The carrier
      present in red blood cells has low Km values, is trans-stimulable and not
      stereospecific for leucine uptake; on the other hand, the system present in
      lymphocytes is stereospecific for leucine uptake and trans-inhibitable. Both
      carriers are pH sensitive in a similar fashion at low pHs, but there are
      important differences at higher pH values (above neutrality). These properties
      are compared with these of the asc systems previously reported in these cells.

PMID- 8660412
TI  - Mechanisms of K+ channel regulation.

PMID- 8660413
TI  - Architecture of the neuronal nicotinic acetylcholine receptor ion channel at the
      binding site of bis-ammonium blockers.
AB  - Structure-activity relationships of 56 pentamethylenbis-ammonium compounds, the
      blockers of the neuronal nicotinic acetylcholine receptor (nAChR) ion channel,
      have been studied to estimate the cross-sectional dimensions of the channel pore.
      The cat superior cervical sympathetic ganglion in situ and isolated guinea pig
      ileum were used to evaluate the potency of the compounds to block ganglionic
      transmission. Minimum-energy conformations of each compound were calculated by
      the molecular mechanics method. A topographic model of the binding site of the
      blockers was proposed. It incorporates two narrowings, a large and a small one.
      The small narrowing is located between the large one and the cytoplasmic end of
      the pore. The cross-sectional dimensions of the large and small narrowings
      estimated from the dimensions of the blockers are 6.1 x 8.3 A and 5.5 x 6.4 A,
      respectively, the distance between the narrowings along the pore being
      approximately 7 A. Most potent blockers would occlude the pore via binding to the
      channel at the levels of both narrowings. Less potent blockers are either too
      large or too small to bind to both narrowings simultaneously: large blockers
      would occlude the pore at the level of large narrowing, while small blockers
      would pass the large narrowing and occlude the pore at the level of small
      narrowing only. A comparison of the topographic model with a molecular five-helix
      bundle model of nAChR pore predicts Serine and Threonine rings to be the most
      probable candidates for the large and small narrowings, respectively.

PMID- 8660414
TI  - The permeation of ammonium through a voltage-independent K+ channel in the plasma
      membrane of rye roots.
AB  - Nitrogen is available to the plant in the form of NH+4 in the soil solution. Here
      it is shown that a voltage-independent K+ channel in the plasma membrane of rye
      (Secale cereale L.) roots is permeable to NH+4. The channel was studied following
      its incorporation into planar 1-palmitoyl-2-oleoyl phosphatidyl ethanolamine
      bilayers. The unitary conductance of the channel was greater when assayed in the
      presence of 100 mM NH4Cl than 100 mM KCl. However, the probability of finding the
      channel open (Po) was lower in the presence of 100 mm NH4Cl (Po = 0.63) than in
      100 mM KCl (Po = 0.8), suggesting that Po can be regulated by the (permeant) ions
      present in solution. When assayed in equimolar concentrations of NH4Cl (cis) and
      KCl (trans), the zero-current (reversal) potential for the channel (Erev)
      exhibited a complex concentration dependence. At low cation concentrations, the
      apparent permeability of NH+4 relative to K+ (PNH4/PK) was greater than 1.0.
      However, as the cation concentration was increased, PNH4/PK initially decreased
      to a minimum of 0.95 at 3 mM before increasing again to a maximum of 1.89 at 300
      mM. At cation concentrations above 300 mM, PNH4/PK decreased slightly. This
      implies that the pore of the channel can be occupied by more than one cation
      simultaneously. Ammonium permeation through the pore was simulated using a model
      which is composed of three energy barriers and two energy wells (the ion-binding
      sites). The model (3B2S) allowed for single-file permeation, double cation
      occupancy, ion-ion repulsion within the pore and surface potential effects.
      Results indicated that energy peaks and energy wells were situated asymmetrically
      within the electrical distance of the pore, that cations repel each other within
      the pore and that the vestibules to the pore contain negligible surface charge.
      The energy profile obtained for NH+4 is compared with ones obtained for K+ and
      Na+. This information allows the fluxes through the K+ channel of the three major
      monovalent cations present in the soil solution to be predicted.

PMID- 8660422
TI  - The "Phoca standard": an external molecular reference for calibrating recent
      evolutionary divergences.
AB  - Comparison of the complete mitochondrial DNA (mtDNA) of the high-Arctic ringed
      seal (Phoca hispida) and the sub-Arctic harbour (P. vitulina) and grey
      (Halichoerus grypus) seals shows that they are genetically equidistant from one
      another. We relate the evolutionary divergence of the three species to expanding
      glaciation in the Arctic Basin and establish, in conjunction with mtDNA data, a
      standard reference for calibration of recent divergence events among mammalian
      taxa. In the present study, we apply the "Phoca standard" to the dating of
      divergences within the hominid phylogenetic tree. After determining the relative
      rates of substitution over all mitochondrial protein-coding genes in the
      different evolutionary lineages, we estimate that humans and chimpanzees diverged
      from each other 6.1 Mya (95% confidence limits: 5.2-6.9 Mya). The corresponding
      lower-limit divergence between common chimpanzee, Pan troglodytes, and pygmy
      chimpanzee, P. paniscus, occurred 3 (2.4-3.6) Mya, and the primary split within
      the P. troglodytes complex 1.6 (1.3-2.0) Mya. The analyses suggest that the split
      between Gorilla and Pan/Homo occurred 8.4 (7.3-9.4) Mya. They also suggest that
      Pongo (orangutan) and the lineage leading to gorillas, chimpanzees, and humans
      diverged 18.1 (16.5-19.6) Mya. The present analysis is independent of the hominid
      paleontological record and inferential morphological interpretations and thus is
      a novel approach to the lower-limit dating of recent divergences.

PMID- 8660423
TI  - Gene duplication and recombination in the evolution of mammalian Fc receptors.
AB  - The immunoglobulin-related chains of cell-surface receptors for the Fc region of
      immunoglobulins (FcepsilonRIalpha, FcgammaRI, FcgammaRII, and FcgammaRIIIalpha)
      are encoded by members of a gene family. Phylogenetic analysis of representative
      members of this family from mammals revealed that FcgammaRIIIalpha genes of
      human, mouse, and rat are not orthologous to one another in the region of the
      gene encoding the immunoglobulin C2-set domains. In phylogenetic trees of this
      region, FcgammaRIIIalpha and FcgammaRII clustered together. However, in trees
      based on both coding and noncoding regions 5' and 3' to the C2 domains,
      FcgammaRIIIalpha genes of human, mouse, and rat clustered together. This pattern
      of relationship is most easily explained as a result of two independent
      recombinational events occurring in the mouse and rat after these two species
      diverged, in each of which the exons encoding the C2 domains were donated to an
      FcgammaRIIIalpha gene by an FcgammaRII gene.

PMID- 8660424
TI  - Identification of putative nonautonomous transposable elements associated with
      several transposon families in Caenorhabditis elegans.
AB  - Putative nonautonomous transposable elements related to the autonomous
      transposons Tc1, Tc2, Tc5, and mariner were identified in the C. elegans database
      by computational analysis. These elements are found throughout the C. elegans
      genome and are defined by terminal inverted repeats with regions of sequence
      similarity, or identity, to the autonomous transposons. Similarity between loci
      containing related nonautonomous elements ends at, or near, the boundaries of the
      terminal inverted repeats. In most cases the terminal inverted repeats of the
      putative nonautonomous transposable elements are flanked by potential target-site
      duplications consistent with the associated autonomous elements. The
      nonautonomous elements identified vary considerably in size (from 100 bp to 1.5
      kb in length) and copy number in the available database and are localized to
      introns and flanking regions of a wide variety of C. elegans genes.

PMID- 8660425
TI  - Transposable elements behavior following viral genomic stress in Drosophila
      melanogaster inbred line.
AB  - To analyze the behavior of endogenous transposable elements under genomic stress,
      a Drosophila melanogaster inbred line was submitted to three kinds of viral
      perturbations. First, a retroviral plasmid containing the avian Rous Associated
      Virus type 2 (RAV-2) previously deleted for the viral envelope coding gene (env)
      was introduced by P element transformation into the Drosophila genome. An
      insertion of this avian retroviral sequence was detected by in situ hybridization
      in site 53C on polytene chromosome arm 2R. Second, Drosophila embryos were
      injected with RAV-2 particles produced by cell culture after transfection with
      the retroviral plasmid. Third, the Drosophila melanogaster inbred line was stably
      infected by the sigma native virus. It appears that neither the offspring of the
      flies in which the viral DNA was found integrated nor those from the infected
      sigma flies showed copia or mdg1 element mobilization. Injection of the avian RAV
      2 particles led, however, to the observation of somatic transpositions of mdg1
      element on the 2L chromosome, the copia element insertion pattern remaining
      stable. Thus, endogenous transposable elements show more instability in sublines
      injected with exogenous viral particles than in a transgenic subline containing a
      foreign viral insert, all transposable elements not being equally sensitive to
      such genomic stress.

PMID- 8660426
TI  - Selection on the codon bias of Chlamydomonas reinhardtii chloroplast genes and
      the plant psbA gene.
AB  - Plant chloroplast genes have a codon use that reflects the genome compositional
      bias of a high A+T content with the single exception of the highly translated
      psbA gene which codes for the photosystem II D1 protein. The codon usage of plant
      psbA corresponds more closely to the limited tRNA population of the chloroplast
      and is very similar to the codon use observed in the chloroplast genes of the
      green alga Chlamydomonas reinhardtii. This pattern of codon use may be an
      adaptation for increased translation efficiency. A correspondence between codon
      use of plant psbA and Chlamydomonas chloroplast genes and the tRNAs coded by the
      chloroplast genome, however, is not observed in all synonymous codon groups. It
      is shown here that the degree of correspondence between codon use and tRNA
      population in different synonymous groups is correlated with the second codon
      position composition. Synonymous groups with an A or T at the second codon
      position have a high representation of codons for which a complementary tRNA is
      coded by the chloroplast genome. Those with a G or C at the second position have
      an increased representation of codons that bind a chloroplast tRNA by wobble. It
      is proposed that the difference between synonymous groups in terms of codon
      adaptation to the tRNA population in plant psbA and Chlamydomonas chloroplast
      genes may be the result of differences in second position composition.

PMID- 8660428
TI  - A fitness principle for pre-Darwinian evolution based on selection of the least
      action path.

PMID- 8660427
TI  - On transition bias in mitochondrial genes of pocket gophers.
AB  - The relative contribution of mutation and purifying selection to transition bias
      has not been quantitatively assessed in mitochondrial protein genes. The observed
      transition/transversion (s/v) ratio is (micros Ps)/(microv Pv), where micros and
      microv denote mutation rate of transitions and transversions, respectively, and
      Ps and Pv denote fixation probabilities of transitions and transversions,
      respectively. Because selection against synonymous transitions can be assumed to
      be roughly equal to that against synonymous transversions, Ps/Pv approximately 1
      at fourfold degenerate sites, so that the s/v ratio at fourfold degenerate sites
      is approximately micros/microv, which is a measure of mutational contribution to
      transition bias. Similarly, the s/v ratio at nondegenerate sites is also an
      estimate of micros/microv if we assume that selection against nonsynonymous
      transitions is roughly equal to that against nonsynonymous transversions. In two
      mitochondrial genes, cytochrome oxidase subunit I (COI) and cytochrome b (cyt-b)
      in pocket gophers, the s/v ratio is about two at nondegenerate and fourfold
      degenerate sites for both the COI and the cyt-b genes. This implies that mutation
      contribution to transition bias is relatively small. In contrast, the s/v ratio
      is much greater at twofold degenerate sites, being 48 for COI and 40 for cyt-b.
      Given that the micros/microv ratio is about 2, the Ps/Pv ratio at twofold
      degenerate sites must be on the order of 20 or greater. This suggests a great
      effect of purifying selection on transition bias in mitochondrial protein genes
      because transitions are synonymous and transversions are nonsynonymous at twofold
      degenerate sites in mammalian mitochondrial genes. We also found that
      nonsynonymous mutations at twofold degenerate sites are more neutral than
      nonsynonymous mutations at nondegenerate sites, and that the COI gene is subject
      to stronger purifying selection than is the cyt-b gene. A model is presented to
      integrate the effect of purifying selection, codon bias, DNA repair and GC
      content on s/v ratio of protein-coding genes.

PMID- 8660430
TI  - What can 18S rDNA do for bivalve phylogeny?
AB  - Molecular characteristics, especially 18S rDNA sequences, may be of great value
      for the study of bivalve evolution and its numerous morphological convergencies
      once the reliability of these data can be evaluated. The analysis of 11 published
      complete molluscan sequences and two new ones, Arca noae and Atrina pectinata,
      reveals considerable differences in relative substitution rates. The gastropod
      and eulamellibranch species have the fastest and Atrina species have the slowest
      rates. Two methods are used to assess the information contents of the dataset in
      addition to bootstrap analysis, spectral analysis, and the "pattern of resolved
      nodes" technique. Tree reconstructions by parsimony, neighbor-joining, and
      maximum-likelihood differ in regard to the position of the eulamellibranch family
      Mactridae and of Crassostrea. Although there is a signal for the monophyly of
      Bivalvia, Mactridae cluster with Gastropoda in most runs, rendering Bivalvia
      diphyletic. The position of Crassostrea was extremely variable, probably due to
      the high substitution rate of this species. Atrina roots deeper than Arca in all
      trees, although a corresponding signal in spectral analysis is absent.
      Phylogenetic signals among the three pectinid species are low but sufficient to
      resolve the branching pattern. The tree inferred from the 18S rDNA and from
      morphological data has Bivalvia monophyletic with a basal polytomy of Mactridae,
      Crassostrea, and the remaining Pteriomorphia, where Arca branches off before
      Atrina and the Pectinidae. Argopecten is sister group to the other two pectinids;
      18S sequence data will have great impact on our understanding of bivalve
      phylogeny, but only when more sequences of similar substitution rates are
      available.

PMID- 8660429
TI  - The evolution of the RNase P- and RNase MRP-associated RNAs: phylogenetic
      analysis and nucleotide substitution rate.
AB  - We report a detailed evolutionary study of the RNase P- and RNase MRP- associated
      RNAs. The analyses were performed on all the available complete sequences of
      RNase MRP (vertebrates, yeast, plant), nuclear RNase P (vertebrates, yeast), and
      mitochondrial RNase P (yeast) RNAs. For the first time the phylogenetic distance
      between these sequences and the nucleotide substitution rates have been
      quantitatively measured.The analyses were performed by considering the optimal
      multiple alignments obtained mostly by maximizing similarity between primary
      sequences. RNase P RNA and MRP RNA display evolutionary dynamics following the
      molecular clock. Both have similar rates and evolve about one order of magnitude
      faster than the corresponding small rRNA sequences which have been, so far, the
      most common gene markers used for phylogeny. However, small rRNAs evolve too
      slowly to solve close phylogenetic relationships such as those between mammals.
      The quicker rate of RNase P and MRP RNA allowed us to assess phylogenetic
      relationships between mammals and other vertebrate species and yeast strains. The
      phylogenetic data obtained with yeasts perfectly agree with those obtained by
      functional assays, thus demonstrating the potential offered by this approach for
      laboratory experiments.

PMID- 8660431
TI  - Geosiphon pyriforme, a fungus forming endocytobiosis with Nostoc (cyanobacteria),
      is an ancestral member of the Glomales: evidence by SSU rRNA analysis.
AB  - Geosiphon pyriforme inhabiting the surface of humid soils represents the only
      known example of endocytobiosis between a fungus (Zygomycotina; macrosymbiont)
      and cyanobacteria (Nostoc; endosymbiont). In order to elucidate the taxonomical
      and evolutionary relationship of Geosiphon pyriforme to fungi forming arbuscular
      mycorrhiza (AM fungi), the small-subunit (SSU) ribosomal RNA genes of Geosiphon
      pyriforme and Glomus versiforme (Glomales; a typical AM fungus) were analyzed and
      aligned with SSU rRNA sequences of several Basidiomycetes, Ascomycetes,
      Chytridiomycetes, and Zygomycetes, together with all AM-fungal (Glomales)
      sequences published yet. The distinct group of the order Glomales, which includes
      Geosiphon, does not form a clade with any other group of Zygomycetes. Within the
      Glomales, two main lineages exist. One includes the families Gigasporaceae and
      Acaulosporaceae; the other one is represented by the genus Glomus, the members of
      which are very divergent. Glomus etunicatum and Geosiphon pyriforme both form
      independent lineages ancestral to the Glomales. The data provided by the present
      paper confirm clearly that Geosiphon represents a fungus belonging to the
      Glomales. The question remains still open as to whether or not Geosiphon is to be
      placed within or outside the genus Glomus, since this genus is probably
      polyphyletic and not well defined yet. Geosiphon shows the ability of a Glomus
      like fungus to form a "primitive" symbiosis with a unicellular photoautotrophic
      organism, in this case a cyanobacterium, leading to the conclusion that a
      hypothetical association of a Glomus-like fungus with a green alga as a step
      during the evolution of the land plants appears probable.

PMID- 8660432
TI  - Fast analysis of genomic homologies: primate immunodeficiency virus.
AB  - We have recently published a new probabilistic algorithm which performs genomic
      comparisons on a huge scale. In the present paper it was applied to
      immunodeficiency viral sequences extracted from international gene databanks.
      During global sequence analysis of human (HIV1 and HIV2) and simian viruses by
      means of dot-matrix representation, series of homology were obtained which
      permitted the definition of families of viruses overlapping the species
      divisions. Sequences of interest were characterized to the lexical base sentence
      through successive zoomings. Strain-to-strain comparison confirmed subfamily
      classifications and led, for example, to the identification of divergent LTR
      sequences. By way of example, we described the application of the algorithm to
      the ANT70C and MVP5180 HIV1-O viruses, for which the observed differences were
      shown to correspond to a deletion in the U3 region, situated between the LEF and
      NF-kappaB sites. It was of interest to consider these data in a tentative
      phylogenetic interpretation.

PMID- 8660433
TI  - The molecular evolution of vertebrate growth hormones: a pattern of near-stasis
      interrupted by sustained bursts of rapid change.
AB  - It has been demonstrated previously that in mammals the evolution of pituitary
      growth hormone shows an unusual pattern, with an underlying slow rate and at
      least two sustained bursts of rapid evolution (in the artiodactyls and primates),
      during which the rate increased at least 25-fold. It is demonstrated here that a
      similar pattern applies for growth hormone evolution throughout the vertebrates,
      with a basal rate similar to that seen in mammals, but bursts of rapid evolution
      in the amphibia and the elasmobranchs, and several bursts in the teleosts. The
      placental growth-hormone-like proteins of primates show a similar pattern. It is
      argued that the bursts of evolution seen for growth hormone are a consequence of
      selection and that this may reflect changes in the functions of the hormone
      additional to its basic growth-promoting actions.

PMID- 8660434
TI  - Caenorhabditis globin genes: rapid intronic divergence contrasts with
      conservation of silent exonic sites.
AB  - Globin genes from the Caenorhabditis species briggsae and remanei were identified
      and compared with a previously described C. elegans globin gene. The encoded
      globins share between 86% and 93% amino acid identity, with most of the changes
      in or just before the putative B helix. C. remanei was found to have two globin
      alleles, Crg1-1 and Crg1-2. The coding sequence for each is interrupted by a
      single intron in the same position. The exons of the two genes are only 1%
      divergent at the nucleotide level and encode identical polypeptides. In contrast,
      intron sequence divergence is 16% and numerous insertions and deletions have
      significantly altered the size and content of both introns. Genetic crosses show
      that Crg1-1 and Crg1-2 segregate as alleles. Homozygous lines for each allele
      were constructed and northern analysis confirmed the expression of both alleles.
      These data reveal an unusual situation wherein two alleles encoding identical
      proteins have diverged much more rapidly in their introns than the silent sites
      of their coding sequences, suggesting multiple gene conversion events.

PMID- 8660435
TI  - Human lipoprotein lipase last exon is not translated, in contrast to lower
      vertebrates.
AB  - We have sequenced the first fish (zebrafish, Brachydanio rerio) lipoprotein
      lipase (LPL) cDNA clone. Similarities were found in mammalian LPL cDNA, but the
      codon spanning the last two exons (which is thus split by the last intron) is AGA
      (Arg) as opposed to TGA in mammals. Exon 10 is thus partially translated. These
      results were confirmed with rainbow trout (Oncorhynchus mykiss). We also
      investigated whether mammal TGA coded for selenocystein (SeCys), the 21st amino
      acid, but found that this was not the case: TGA does not encode SeCys but is a
      stop codon. It thus appears that the sense codon AGA (fish) has been transformed
      into a stop codon TGA (human) during the course of evolution. It remains to be
      determined if the "loss" of the C-terminal end of mammalian LPL protein has
      conferred an advantage in terms of LPL activity or, on the contrary, a
      disadvantage (e.g., susceptibility to diabetes or atherosclerosis).

PMID- 8660436
TI  - Phylogenetic analysis of DNA length mutations in a repetitive region of the
      Hawaiian Drosophila yolk protein gene Yp2.
AB  - Nucleotide sequence analysis has demonstrated that interspecific size variation
      in the YP2 yolk protein among Hawaiian Drosophila is due to in-frame insertions
      and deletions in two repetitive segments of the coding region of the Yp2 gene.
      Sequence comparisons of the complex repetitive region close to the 5' end of this
      gene across 34 endemic Hawaiian taxa revealed five length morphs, spanning a
      length difference of 21 nucleotides (nt). A phylogenetic character reconstruction
      of the length mutations on an independently derived molecular phylogeny showed
      clade-specific length variants arising from six ancient events: two identical
      insertions of 6 nt, and four deletions, one of 6 nt, one of 12 nt, and two
      identical but independent deletions of 15 nt. These mutations can be attributed
      to replication slippage with nontandem trinucleotide repeats playing a major role
      in the slipped-strand mispairing. Geographic analysis suggests that the 15 nt
      deletion which distinguishes the planitibia subgroup from the cyrtoloma subgroup
      occurred on Oahu about 3 million years ago. The homoplasies observed caution
      against relying too heavily on nucleotide insertions/deletions for phylogenetic
      inference. In contrast to the extensive repeat polymorphisms within other
      Drosophila and the human species, the more complex 5' Yp2 repetitive region
      analyzed here appears to lack polymorphism among Hawaiian Drosophila, perhaps due
      to founder effects, low population sizes, and hitchhiking effects of selection on
      the immediately adjacent 5' region.

PMID- 8660438
TI  - Tandemly repeated satellite DNA of Dolichopoda schiavazzii: a test for models on
      the evolution of highly repetitive DNA.
AB  - Three specific satellite DNA families can be detected in the genome of the cave
      cricket Dolichopoda schiavazzii. The pDoP102 and the pDsPv400 families are
      species specific for D. schiavazzii; the pDoP500 family is probably present in
      all Dolichopoda species. The three satellite DNA families were characterized from
      individuals of three isolated populations of D. schiavazzii with respect to
      nucleotide sequence, sequence complexity, sequence variability, and copy number.
      This unique data set on satellite DNAs of D. schiavazzii seems to allow one to
      test the significance of theoretical approaches to the mode of evolution of
      noncoding, tandemly arranged satellite DNA. At least for satellite DNAs of D.
      schiavazzii two clear trends were observed: (1) sequence variability increases
      with copy number and (2) the repeat length decreases with copy number. The first
      trend is in good agreement with the theory but the second is not. Thus, a
      revision of the models is proposed.

PMID- 8660437
TI  - Sequence simplicity and evolution of the 3' untranslated region of the histone
      H1o gene.
AB  - The H10 gene has a long 3' untranslated region (3'UTR) of 1,125 nucleotides in
      the rat and 1,310 in humans. Analysis of the sequences shows that they have
      features of simple DNA that suggest involvement of replication slippage in their
      evolution. These features include the length imbalance between the rat and human
      sequences; the abundance of single-base repeats, two-base runs and other simple
      motifs clustered along the sequence; and the presence of single-base repeat
      length polymorphisms in the rat and mouse sequences. Pairwise comparisons show
      numerous short insertions/deletions, often flanked by direct repeats. In
      addition, a proportion of short insertions/deletions results from length
      differences in conserved single-base repeats. Quantification of the sequence
      simplicity shows that simple sequences have been more actively incorporated in
      the human lineage than in the rodent lineage. The combination of
      insertions/deletions and nucleotide substitutions along the sequence gives rise
      to three main regions of homology: a highly variable central region flanked by
      more conserved regions nearest the coding region and the polyA addition site.

PMID- 8660439
TI  - Sequence variations in the large-subunit ribosomal RNA gene of Ammonia
      (Foraminifera, Protozoa) and their evolutionary implications.
AB  - An unusually high divergence was observed in the ribosomal RNA genes of a free
      living population of foraminifera belonging to the genus Ammonia. The sequences
      of a large-subunit (LSU) rDNA expansion segment D1 and flanking regions were
      obtained from 20 specimens named Ammonia sp. 1 and Ammonia sp. 2. The sequence
      divergence between the two species averages 14%. Within each species it ranges
      from 0.2% to 7.1% in Ammonia sp. 1 and from 0.7% to 2.3% in Ammonia sp. 2. We did
      not find two specimens having identical sequences. Moreover, in opposition to the
      generally accepted view, rDNA sequence variations were also found within a single
      individual. The variations among several rDNA copies in a single specimen of
      Ammonia may reach up to 4.9%. Most of the observed variations result from
      multiplication of CA or TA serial repeats occurring in two particularly variable
      regions. For single base changes, C-T transitions are most frequently observed.
      We discuss the evolution of expansion segments and their use for phylogenetic
      studies.

PMID- 8660440
TI  - Mammalian evolution and the interphotoreceptor retinoid binding protein (IRBP)
      gene: convincing evidence for several superordinal clades.
AB  - Phylogenetic relationships of 25 mammalian species representing 17 of the 18
      eutherian orders were examined using DNA sequences from a 1.2-kb region of the 5'
      end of exon 1 of the single-copy nuclear gene known as interphotoreceptor
      retinoid binding protein (IRBP). A wide variety of methods of analysis of the DNA
      sequence, and of the translated products, all supported a five-order clade
      consisting of elephant shrew (Macroscelidea)/aardvark (Tubulidentata)/and the
      paenungulates (hyracoids, sirenians, and elephants), with bootstrap support in
      all cases of 100%. The Paenungulata was also strongly supported by these IRBP
      data. In the majority of analyses this monophyletic five-order grouping was the
      first branch off the tree after the Edentata. These results are highly congruent
      with two other recent sources of molecular data. Another superordinal grouping,
      with similar 100% bootstrap support in all of the same wide-ranging types of
      analyses, was Artiodactyla/Cetacea. Other superordinal affinities, suggested by
      the analyses, but with less convincing support, included a
      Perissodactyla/Artiodactyla/Cetacea clade, an Insectivora/Chiroptera clade, and
      Glires (an association of rodents and lagomorphs).

PMID- 8660441
TI  - A possible relationship between VSP mismatch repair and gene expression level.

PMID- 8660442
TI  - Fatal Salmonella typhimurium infection of a vascular graft in an infant.
AB  - A case of Salmonella typhimurium endocarditis of a Blalock-Taussig shunt in an
      infant is described for its rarity. Wider appreciation of such infections is
      warranted.

PMID- 8660443
TI  - Clinicopathologic characteristics of hypertrophic cardiomyopathy detected during
      mass screening for heart disease.
AB  - Between 1981 and 1992 a total of 10 patients with hypertrophic cardiomyopathy
      (HCM) were detected by mass screening for heart disease in Tokyo's Adachi Ward.
      Four were first grade elementary school children and six were first grade junior
      high school adolescents. Two-dimensional echocardiography at the initial
      evaluation revealed asymmetric septal hypertrophy in four patients, diffuse
      hypertrophy of the left ventricle in five, and poor left ventricular
      contractility with wall thinning in one (dilated phase). Three of the five
      patients with diffuse hypertrophy progressed to asymmetric septal hypertrophy
      during the average 4-year follow-up period. The degree of septal thickness and
      the left ventricular wall thickness index were significantly less than in those
      of young adult controls (12 +/- 3 versus 21 +/- 9 mm, p < 0.05; and 22 +/- 4
      versus 28 +/- 16 mm, p < 0.05, respectively). Right ventricular endomyocardial
      biopsy specimens obtained from 9 of the 10 patients showed features typical of
      HCM (e.g., myocyte hypertrophy with myofibril disarray) in five patients and
      atypical features (mainly interstitial fibrosis with perivascular cell
      infiltration) in another four. One patient with dilated phase disease died of
      congestive heart failure 6 months after the initial evaluation. These results
      indicate that HCM detected during mass screening is a mild form of the disease
      and may have atypical pathologic features, such as interstitial fibrosis and
      perivascular cell infiltration, mimicking the sequela of chronic myocarditis.

PMID- 8660444
TI  - Exercise-induced hypertension after corrective surgery for coarctation of the
      aorta.
AB  - The purpose of this investigation was to study exercise-induced hypertension
      after surgical repair of coarctation of the aorta (CoA). Groups of 27 patients
      with CoA and 27 healthy control subjects, 6-21 years old, were exercised to
      exhaustion using the Bruce protocol. Fourteen patients had undergone surgery
      during the first year of life (group A), and 13 patients had been operated on
      later (group B). The pulse rate and systolic blood pressures (BP) in the arm and
      leg were measured before, during, and after exercise to evaluate changes in the
      BP and the arm/leg BP gradient with exercise. The systolic BP was significantly
      higher in the patients than in the controls at all stages of the exercise test (p
      < 0.01), as was the arm/leg BP gradient both before and after exercise (p <
      0.01); the latter increased significantly with exercise in the patient group (p <
      0.05). We found hypertension to be a more common and severe problem in group B
      patients, who had higher blood pressures than their controls at rest and during
      exercise (p < 0.05). Exercise-induced hypertension was also more common in group
      B (23%) than in group A (7%). We conclude that exercise-induced hypertension and
      recoarctation are problems in postoperative CoA patients. Moreover, exercise
      induced hypertension is more common in patients with CoA operated on after the
      first year of life.

PMID- 8660445
TI  - Echocardiography for the diagnosis of congenital cardiac anomalies with multiple
      lesions.
AB  - The purpose of this study was to determine the sensitivity and specificity of
      echocardiography for the diagnosis of congenital cardiac abnormalities with
      multiple lesions. The study was carried out on 80 patients (ages 1 day to 14
      years). After clinical evaluation all patients were studied by echocardiography.
      Cardiac catheterization and angiocardiography were performed, and
      echocardiographic findings were compared with those obtained by cardiac
      catheterization. The sensitivity and specificity of echocardiographic diagnosis
      were determined based on the false-negative and false-positive results. Of the 80
      patients, 19 had double-outlet right ventricle, 17 transposition of the great
      arteries, 10 common atrium, 9 atrioventricular septal defect, 7 single ventricle,
      7 corrected transposition, 6 tricuspid atresia, 3 Ebstein's anomaly, and 2 cor
      triatriatum. All of these entities were visualized correctly by echocardiography
      (sensitivity 100%, specificity 100%). There were also 12 instances of atrial
      isomerism with one false-negative diagnosis, 6 pulmonary atresia with two false
      negative diagnoses, and 5 total anomalous pulmonary venous connections with one
      false-negative diagnosis. The total number of individual cardiac lesions was 291.
      Nineteen false-negative and four false-positive echocardiographic diagnoses were
      obtained (sensitivity 93%, specificity 99%). It is concluded that double-outlet
      right ventricle, transposition of the great arteries, atrioventricular septal
      defect, single ventricle, corrected transposition, and tricuspid atresia can be
      accurately diagnosed by echocardiography. However, the role of echocardiography
      is limited for evaluation of right ventricular outflow tract and small patent
      ductus arteriosus, especially when associated with pulmonary hypertension.

PMID- 8660446
TI  - Pathologic lung function in children and adolescents with congenital heart
      defects.
AB  - Lung function tests (i.e., spirometry, flow volume, and body plethysmography)
      were performed in 213 patients (age 6-21 years, mean 11.3 years) with
      hemodynamically significant congenital heart defects: atrial septal defect,
      ventricular septal defect (VSD), tetralogy of Fallot, aortic stenosis and
      coarctation of the aorta. We measured lung vital capacity, total lung capacity
      (TLC), residual volume (RV), the percentage ratio of the latter two measurements
      (%RV/TLC), maximal expiratory flow rates at 25% and 50% of vital capacity, and
      specific airway conductance. Pulmonary restriction dominated in patients with
      tetralogy of Fallot; pulmonary hyperinflation was more frequent in patients with
      VSD and coarctation of the aorta; and obstruction of the airways was observed
      most frequently in patients with tetralogy of Fallot. In conclusion, we found a
      range of pathologic lung function parameters in patients with hemodynamically
      significant congenital heart defects.

PMID- 8660447
TI  - Anomalous origin of coronary artery in association with aorticopulmonary window.
AB  - Aorticopulmonary window associated with anomalous origin of coronary arteries is
      rare; only 12 cases have been reported previously. Origin of coronary arteries
      from the communicating bridge is rare, having occurred in only five of these
      cases. We describe two additional cases of this entity, in one of which the right
      coronary artery arose from the window proper. We also review the previously
      reported cases.

PMID- 8660448
TI  - Partial anomalous left pulmonary artery: new evidence on the development of the
      pulmonary artery sling.
AB  - Clinical and angiographic data of a child with a unique form of partial anomalous
      left pulmonary artery are reported. Because the anomalous pulmonary artery does
      not run posterior to the trachea, this malformation is not associated with airway
      obstruction, as are all other forms of anomalous left pulmonary artery described
      to date. This case strengthens our understanding of the development of the
      pulmonary artery sling.

PMID- 8660449
TI  - Truncus arteriosus communis associated with mitral valve and left ventricular
      hypoplasia without ventricular septal defect: unique combination.
AB  - A unique case of truncus arteriosus communis associated with mitral valve and
      left ventricular hypoplasia, but without ventricular septal defect (VSD), is
      described. The embryology of this anatomy is considered. The neonatal
      hemodynamics and the clinical implications of this rare combination of defects
      are discussed.

PMID- 8660450
TI  - Congenital malformations of the tricuspid valve in siblings.
AB  - The occurrence of familial heart disease in association with tricuspid atresia is
      rare. The first reported instance of tricuspid atresia and Ebstein's anomaly in
      siblings is presented. The presence of these two distinct pathologic variants of
      tricuspid valve malformations in siblings suggests that these malformations
      result from a common abnormality occurring during the development of the inlet
      portion of the right ventricle.

PMID- 8660451
TI  - Building a pediatric cardiac catheterization laboratory and conference room:
      design considerations and filmless imaging.
AB  - Building or upgrading a dedicated pediatric cardiac catheterization laboratory is
      an expensive and elaborate undertaking complicated by long-standing biases based
      on adult laboratory requirements. Optimal design for the needs of pediatric
      cardiologists and their patients has never been published. This communication
      discusses these design issues in the context of pediatric needs and offers
      potential solutions. It also attempts to educate the reader on the basics of
      digital imaging and its advantages over cine film technology; and it explains how
      to achieve optimal filmless data acquisition and subsequent display for pediatric
      cardiac management.

PMID- 8660452
TI  - Pulmonary cavernous hemangiomatosis treated with interferon alfa-2a.
AB  - Pulmonary hemangiomatosis is a rare, usually fatal disorder characterized by
      diffuse proliferation of blood vessels within the thorax. We describe a 7-year
      old boy with cavernous-type pulmonary hemangiomatosis successfully treated with
      interferon alfa-2a. He presented with respiratory distress and hemoptysis that
      were alleviated during a 2-year follow-up period.

PMID- 8660453
TI  - Iatrogenic neonatal hypertrophic cardiomyopathy.
AB  - Transient hypertrophic cardiomyopathy is a rare sequela of both glucocorticoid
      and insulin excess. We report two ELBW infants who developed hypertrophic
      cardiomyopathy as an iatrogenic complication of the concurrent therapeutic
      administration of a glucocorticoid and insulin. In both cases the hypertrophic
      cardiomyopathy resolved completely on cessation of therapy. We advise caution
      when using this therapeutic combination and stress the need for regular
      echocardiography.

PMID- 8660454
TI  - Thromboembolic pulmonary hypertension due to disseminated fibromuscular
      dysplasia.
AB  - We present two patients with thromboembolic pulmonary hypertension associated
      with unusual complications probably caused by disseminated fibromuscular
      dysplasia (FMD) or FMD-like vascular lesions. Intimal fibroplasia, which is
      typical of the vascular lesions associated with FMD, was observed in both
      patients. The presence of such intimal lesions suggests that there was a systemic
      factor that caused the formation of recurrent thrombi in the systemic vessels in
      these patients. These cases are the first ones reported in which an association
      between FMD and pulmonary hypertension has been observed. The pathogenesis of the
      thrombi in our patients was thought to be recurrent pulmonary thromboembolisms
      resulting from FMD.

PMID- 8660455
TI  - Percutaneous transluminal balloon angioplasty of abdominal aortic coarctation in
      an infant.
AB  - Abdominal aortic coarctation is rare in children. We report successful
      percutaneous transluminal balloon angioplasty of an abdominal aortic coarctation
      in an infant who presented with heart failure.

PMID- 8660456
TI  - Static balloon dilatation of the atrial septum.

PMID- 8660457
TI  - Differential intrachromosomal hyper-recombination phenotype of spt4 and spt6
      mutants of S. cerevisiae.
AB  - In order to test whether mutations affecting transcription also affect DNA
      recombination, we have determined the influence of a number of snf/swi and
      spt/sin transcriptional regulatory mutations on the recombination of a DNA
      inverted repeat. Among the nine different mutations analyzed, we found that spt4
      and spt6 confer a significant hyper-recombination phenotype. Both mutations
      produced increases in the frequencies of reciprocal exchange/gene conversion and
      deletion events ranging from 1- to 15-fold above the wild-type levels, as
      determined in six direct repeat systems and one inverted repeat. The frequency of
      mitotic recombination between homologs, determined at one chromosomal locus, was
      not affected. We discuss the intrachromosomal hyper-recombination phenotype of
      spt4 an spt6 on the basis of the possible functions of SPT4 and SPT6 on
      transcriptional regulation and on chromatin structure.

PMID- 8660458
TI  - GNP1, the high-affinity glutamine permease of S. cerevisiae.
AB  - Glutamine uptake in S. cerevisiae is mediated by at least three transporters:
      high- and low-affinity glutamine permeases and the general amino-acid permease.
      We have isolated the gene encoding the high-affinity glutamine permease and named
      it GNP1. The amino-acid sequence of GNP1, and its hydropathy profile of 12
      transmembrane domains, closely resemble those of known amino-acid permeases. The
      Km of GNP1 for glutamine uptake was determined to be 0.59 mM. Cells lacking GNP1
      exhibit reduced levels of glutamine transport, and are resistant to a toxic
      analog of glutamine, L-glutamic acid gamma-monohydroxamate. Unlike other amino
      acid permeases, whose expression is nitrogen-source limited, GNP1 is expressed on
      both rich and poor nitrogen sources.

PMID- 8660459
TI  - Amphimeric mitochondrial genomes of petite mutants of yeast. I. Flip-flop
      amphimers make up the mitochondrial genomes of "palindromic" petite mutants of
      yeast.
AB  - The mitochondrial (mt) genomes of three spontaneous cytoplasmic "palindromic"
      petite mutants of yeast were studied by restriction-enzyme analysis. These mt
      genomes were shown to be made up of an amplified "master basic unit" consisting
      of two inverted segments (a and A) and of two different unique segments (d and t)
      separating them. The basic unit was called "amphimeric", this term having been
      first proposed for certain lambda-phage mutants. We propose that in the mt
      genomes of the petite mutants studied, the four possible variants of the
      amphimeric basic unit form two - "flip" and "flop" - tetra-amphimeric repeat
      units datA-datA-DaTA-DaTA and DatA-DatA-daTA-daTA, respectively. These repeat
      units make two types of "amphimeric" mt genomes which exist in equal proportions
      in the cell. In each mt genome, the duplicated segment regularly alternates in
      its direct and inverted orientation (a...A...a...A...), whereas the unique
      segments are arranged twice in tandem fashion and twice in inverted fashion
      (d...d...D...D...d...d...andt...t...T...T...t...t...). The only difference
      between flip and flop amphimeric mt petite genomes is the different relative
      orientation of the unique segments in the mono-amphimers. In the mono-amphimers
      of flip mt genomes, both unique segments are arranged in the same direction
      (d...t and D...T), whereas in the mono-amphimers of flop mt genomes, both unique
      segments are arranged in opposite directions (D...t and d...T). Control
      experiments on one spontaneous petite mutant (which was an ancestor of the
      mutants studied here) and on three independent, previously investigated, EtBr
      induced mutants showed that all of them were, in fact, organized in the same way.
      Analysing our experimental data and the results published by others, we conclude
      that amphimeric organization is a general feature of mt petite genomes of yeast
      previously called "palindromic" or "rearranged".

PMID- 8660460
TI  - Amphimeric mitochondrial genomes of petite mutants of yeast. II. A model for the
      amplification of amphimeric mitochondrial petite DNA.
AB  - A model for the recombination-directed replication and amplification of the mtDNA
      of amphimeric petite mutants of S. cerevisiae is proposed. Replication of an
      amphimeric master basic unit datA would be initiated in the inverted components a
      and A. The initiation of replication should be associated with the amphimeric
      structure of the master basic unit itself, but could be promoted by the presence
      of ori sequences or of sequences facilitating the initiation of replication in
      the inverted duplications. The amplification unit of amphimeric genomes is
      considered to be the double-stranded circular hetero-diamphimer datA-DaTA.
      Amplification of both diamphimeric strands involves an invasion of the 3' ends of
      the newly synthesized strands into symmetrical homologous duplex DNA regions
      promoting the continuation of replication, and leads to the accumulation of two
      ("flip" and "flop") types of multi-amphimers. We consider that this mode of
      amplification represents a modified rolling-circle mechanism. By analogy, we
      propose to call our model of amplification the "rocking-circle model". This model
      is likely to apply to other genomes organized as amphimeric structures.

PMID- 8660461
TI  - Isolation and molecular analysis of the gene for cytochrome c1 from Kluyveromyces
      lactis.
AB  - By ethyl methanesulphonate mutagenesis of the yeast Kluyveromyces lactis we have
      isolated five nuclear mutants that were unable to grow on non-fermentable carbon
      sources. The mutations were found to belong to three complementation groups.
      After functional complementation of the mutation in one of these mutants we have
      cloned the structural gene for cytochrome c1, named KlCYT1. This gene has been
      assigned to chromosome VI and its nucleotide sequence exhibited 74.3% identity to
      the homologous gene of S. cerevisiae.

PMID- 8660462
TI  - Comparison of three 3' non-coding regions in Schizosaccharomyces pombe expression
      vectors: efficiencies of transcription termination and mRNA 3'-end formation.
AB  - Analysis of an established Schizosaccharomyces pombe episomal shuttle vector
      suggested that inefficient transcription termination was deleterious to plasmid
      function. We undertook a study to determine if transcription in the presence and
      absence of 3'-processing within a vector could affect the ability of the plasmid
      to transform, transcribe and translate the RNA produced. This report provides an
      analysis of the effects that three S. pombe 3' non-coding regions have on the
      transformation and expression efficiencies of a fission yeast plasmid vector. The
      3' regions from adh1, act1 and ura4 were tested for their ability to terminate
      and process adh1 promoter-driven transcription of a lacZ reporter gene.
      Differences between the 3'-processing sequences were observed, with transcription
      termination mediated by the ura4 3' region being more efficient than termination
      by the 3' regions of adh1 and act1. We show that plasmids containing inefficient
      transcription termination signals result in readthrough transcription and reduced
      transformation efficiencies. In addition, the readthrough transcripts containing
      3' non-coding regions show impaired translation efficiencies. We describe an S.
      pombe vector (pURAS) with a high transformation efficiency that directs the
      production of highly translatable, discrete-sized transcripts.

PMID- 8660463
TI  - Highly efficient homologous integration via tandem exo-beta-1, 3-glucanase genes
      in the common mushroom, Agaricus bisporus.
AB  - Homologous integration was studied in the common mushroom, Agaricus bisporus,
      using a plasmid (pHAG3-1) carrying the hygromycin-resistance gene and a 3.2-kb
      genomic fragment from A. bisporus. Homologous integration was found in 30-60% of
      the transformants obtained with pHAG3-1 linearized at three different positions
      within the homologous sequence, generating either blunt, 5'- or 3'-protruding
      ends. The genomic fragment was found to contain two homologous open reading
      frames in tandem, which showed 60% similarity to exo-beta-1,3-glucanases from
      Saccharomyces cerevisiae and Candida albicans. The level of the corresponding
      mRNA is low in the vegetative mycelium and relatively high in fruiting bodies. In
      the vegetative mycelium of a transformant with tandemly integrated pHAG3-1
      plasmids at the homologous position, exoglucanase mRNA was strongly increased
      without any apparent effect on growth rate or morphology.

PMID- 8660464
TI  - DNA polymorphism among Fusarium oxysporum f.sp. elaeidis populations from oil
      palm, using a repeated and dispersed sequence "Palm".
AB  - A worldwide collection, of 76 F. oxysporum f.sp. elaeidis isolates (Foe), and of
      21 F. oxysporum isolates from the soil of several palm grove was analysed by
      RFLP. As a probe, we used a random DNA fragment (probe 46) from a genomic library
      of a Foe isolate. This probe contains two different types of sequence, one being
      repeated and dispersed in the genome "Palm", the other being a single-copy
      sequence. All F. oxysporum isolates from the palm-grove soils were non-pathogenic
      to oil palm. They all had a simple restriction pattern with one band homologous
      to the single-copy sequence of probe 46. All Foe isolates were pathogenic to oil
      palm and they all had complex patterns due to hybridization with "Palm". This
      repetitive sequence reveals that Foe isolates are distinct from the other F.
      oxysporum palm-grove soils isolates. The sequence can reliably discriminate
      pathogenic from non-pathogenic oil palm isolates. Based on DNA fingerprint
      similarities, Foe populations were divided into ten groups consisting of isolates
      with the same geographic origin. Isolates from Brazil and Ecuador were an
      exception to that rule as they had the same restriction pattern as a few isolates
      from the Ivory Coast, suggesting they may originated from Africa.

PMID- 8660465
TI  - Mitochondrial RNA editing is sequence specific and independent of transcript
      abundance in Sorghum bicolor.
AB  - The DNA sequence which encodes the amino-terminal extension to the conserved core
      of the atp6-1 gene found in line IS1112C is absent from Tx398. Sequences further
      upstream are present in Tx398, but at a different genomic location. The atp6-2
      genes are present in similar copy numbers in IS1112C and A3Tx398, a near-isogenic
      line carrying the IS1112C cytoplasm in a Tx398 background. However, transcript
      abundance of atp6-2 in these lines is about ten-times higher than that of atp6-1.
      RNA editing of atp6-1 transcripts is identical to that of atp6-2 and therefore
      sequence specific. A single non-silent editing site in the unique atp6-1 pre
      piece sequence may indicate mitochondrial-guided RNA editing. While in Petunia
      the abundance and RNA editing of a transcript are correlated, we show here that
      RNA editing is independent of transcript abundance and is sequence specific in
      Sorghum.

PMID- 8660466
TI  - Rap1p is a negative regulator of the RAP1 gene.
AB  - The promoter of the RAP1 gene contains four potential binding sites for Rap1p,
      located between the UAS and the RNA initiation site. We have confirmed that three
      of these sites are recognised by Rap1p in vitro. Different combinations of the
      three sites were then mutated to abolish Rap1p binding, and the effect of these
      mutations on promoter activity was determined. When all three Rap1p sites were
      mutated, the activity of the promoter increased by about 130%, indicating that at
      least one of the sites is a negative element. Analysis of promoters with
      different combinations of the mutant sites revealed that the 5'-most site (A) is
      the principal target for repression. To test the involvement of Rap1p in
      controlling RAP1 expression, we have measured transcription of the chromosomal
      RAP1 gene in a RAP1 wild-type strain and two strains containing rap1ts mutations.
      At a semi-permissive temperature, the RAP1 promoter was more active in the rap1ts
      strains than in the RAP1 wild-type strain, suggesting that expression of the
      chromosomal RAP1 gene is greater when the activity of Rap1p in the cell is
      compromised. The activities of the wild-type promoter, and the promoter with
      mutations in the three Rap1p-binding sites, were compared in sir1, sir2, sir3 and
      sir4 mutant strains. In each case, the mutated promoter was significantly more
      active than the wild-type promoter, implying that the repression mechanism is not
      dependent on any one of the SIR gene products.

PMID- 8660468
TI  - Characterization of the Saccharomyces cerevisiae RTA1 gene involved in 7
      aminocholesterol resistance.
AB  - 7-aminocholesterol has been described as being a strong inhibitor of yeast and of
      Gram+-bacteria proliferation. In order to determine the precise molecular target
      of the toxicity of this compound, we searched for yeast resistance linked to gene
      over-expression. We named the new yeast gene that was isolated RTA1 (EMBL
      X84736). This gene led to strong resistance to the inhibitor. Gene sequencing
      revealed that RTA1 is adjacent to the NAB1 gene which is orientated in an
      opposite direction and localized on chromosome VII. The RTA1 gene, which encodes
      a putative protein with seven potential membrane-spanning segments, was shown to
      be a non-essential gene in yeast.

PMID- 8660467
TI  - Characterization of the Saccharomyces cerevisiae FMS1 gene related to Candida
      albicans corticosteroid-binding protein 1.
AB  - In order to investigate ergosterol metabolism in S. cerevisiae we studied the CM8
      mutant strain defective in the regulation of this pathway. A genomic multicopy
      library was screened to reverse the CM8 phenotype. This allowed us to
      characterize a new gene, FMS1, which relieves mutant phenotype by extragenic
      functional complementation. FMS1 may encode a 508 amino-acid protein. The
      predicted protein shares 35% identity with Cbp1p, a Candida albicans
      corticosteroid binding-protein. Fms1p also shows a weaker homology with monoamine
      oxidases. The construction of a FMS1 null-allele yeast strain demonstrated that
      this gene is not essential for yeast in normal usual laboratory culture
      conditions. The existence of a gene related to CBP1 of C. albicans in S.
      cerevisiae strongly suggests a possible function of steroid-binding proteins in
      yeast general physiology rather than in a process related to pathogenicity.

PMID- 8660470
TI  - Occurrence of nuclear-encoded tRNAIle in mitochondria of the liverwort Marchantia
      polymorpha.
AB  - Although 29 tRNA genes have been deduced from the complete nucleotide sequence of
      the mitochondrial genome from the liverwort Marchantia polymorpha, a tRNAIle gene
      decoding AUU and AUC codons is conspicuously absent. In order to address the
      question of the possible involvement of nuclear-encoded tRNA, we isolated and
      identified three variant copies of the nuclear-encoded tRNAIle(AAU) gene from the
      liverwort. Northern analysis showed the presence of nuclear-encoded tRNAIle both
      in the mitochondrion and the cytosol, while both chloroplast DNA-encoded tRNAIle
      and nuclear-encoded tRNATyr were absent in liverwort mitochondria. These results
      unequivocally establish that import of nuclear tRNAIle into mitochondria indeed
      occurs in one of the most primitive plants, M. polymorpha.

PMID- 8660469
TI  - Identification of a new antifungal target site through a dual biochemical and
      molecular-genetics approach.
AB  - The target site of the antifungal compound LY214352 [8-chloro-4-(2-chloro-4
      fluorophenoxy) quinoline] has been identified through a dual biochemical and
      molecular-genetics approach. In the molecular-genetics approach, a cosmid library
      was prepared from an Aspergillus nidulans mutant that was resistant to LY214352
      because of a dominant mutation in a single gene. A single cosmid (6A6-6) that
      could transform an LY214352-sensitive strain of A. nidulans to LY214352
      resistance was isolated from the library by sib-selection. Restriction fragments
      from cosmid 6A6-6 containing the functional resistance gene were identified by
      transformation, and sequenced. The LY214352-resistance gene coded for a protein
      of 520 amino acids that had a 34% identity and a 57% similarity in a 333 amino
      acid overlap to E. coli dihydroorotate dehydrogenase (DHO-DH). The results of a
      series of biochemical mechanism-of-action studies initiated simultaneously with
      molecular-genetic experiments also suggested that DHO-DH was the target of
      LY214352. Assays measuring the inhibition of DHO-DH activity by LY214352 in a
      wild-type strain (I50=40 ng/ml) and a highly resistant mutant (I50>100
      microgram/ml) conclusively demonstrated that DHO-DH is the target site of
      LY214352 in A. nidulans. Several mutations in the DHO-DH (pyrE) gene that
      resulted in resistance to LY214352 were identified.

PMID- 8660495
TI  - Correction for amino acid loss during acid hydrolysis of a purified protein.
AB  - Hydrolyzing a protein in acid for a single hydrolysis interval, normally 24 h,
      will lead to inaccurate estimates of the amino acid composition of that protein
      due to an effect of the time of hydrolysis on peptide bond cleavage and amino
      acid degradation. The simultaneous yield and decay of amino acids during the
      hydrolysis of a protein can be described by a compartmental model with parameters
      for the hydrolysis and loss rates specific to each amino acid in a protein. The
      amino acid composition of the protein prior to hydrolysis can be determined by
      nonlinear regression of data derived from multiple hydrolysis intervals. In the
      present study egg-white lysozyme was hydrolyzed in 6 M HCl using 18 hydrolysis
      intervals (range, 2-141 h) using the conventional duplicate hydrolyses/interval
      system. Hydrolysis and loss rates were determined for each amino acid. Increasing
      the number of hydrolysis intervals prior to the maximum point on the hydrolysis
      curve, and including an hydrolysis interval greater than 100 h increased the
      accuracy with which the hydrolysis and loss rates were estimated. Most of the
      amino acids underwent some degree of loss during hydrolysis. Of particular note
      was the loss rate for cysteic acid, which was greater than that found for serine
      which is commonly regarded as an acid-labile amino acid. The determined amino
      acid composition of the protein, based on the nonlinear regression of the data
      from four different series of hydrolysis intervals, was compared with the known
      amino acid composition (sequencing). Using the routine duplicate sampling system,
      a nonlinear regression including 10 hydrolysis intervals (2, 6, 10, 14, 18, 22,
      26, 30, 60, and 141 h) resulted in a mean amino acid recovery of 100% (range, 94
      110%) and provided an acceptable compromise between accuracy and the cost of
      analysis.

PMID- 8660494
TI  - Micropreparative gel electrophoresis of low-molecular-weight peptides:
      purification of highly insoluble amyloid peptide fragments.
AB  - We have used the continuous-elution micropreparative gel electrophoresis device
      described by Baumann and Lauraeus (Anal. Biochem. 214, 142-148, 1993) to purify
      low-molecular-weight peptide fragments from in-gel digested standard proteins as
      well as highly in-soluble amyloid peptides. Alzheimer's amyloid beta-peptide,
      gelsolin-derived amyloid peptide of the Finnish type, and a novel amyloid of the
      British type were purified from either homogenized brain or kidney tissue
      material to a high degree of purity in a single run. Using the high resolving
      capacity of the Tris-Tricine-SDS buffer system of Schaegger and von Jagow (Anal.
      Biochem. 166, 368-379, 1978) we were able to isolate two synthetic peptides with
      M(r)4329 and 3284, differing only by 1045 in mass. The total peptide recovery, as
      determined by amino acid sequence analysis and scanning densitometry, ranged
      between 60 and 80%. In order to demonstrate the utility of this technique we
      subjected some of the purified peptides to direct N-terminal amino acid sequence
      analysis, mass spectrometry, microbore high-performance liquid chromatography,
      and immunochemical studies. Our results show that micropreparative gel
      electrophoresis is an effective tool for the isolation of not only larger
      polypeptides but also small peptide fragments in a form suitable for further
      biological use.

PMID- 8660496
TI  - An amperometric new methylene blue N-mediating sensor for hydrogen peroxide based
      on regenerated silk fibroin as an immobilization matrix for peroxidase.
AB  - A simple and effective procedure was described for the immobilization of
      peroxidase in regenerated silk fibroin membrane prepared from waste silk. The
      membranes of regenerated silk fibroin with or without peroxidase, before or after
      the ethanol treatment, were characterized by ir spectra. An amperometric H202
      sensor, based on the immobilized peroxidase in regenerated silk fibroin membrane,
      in the use of new methylene blue N as an electron transfer mediator, was
      fabricated. The characteristics of the sensor with respect to linearity, response
      time, effect of pH and temperature, stability, and reproducibility were
      investigated. Dependences of Michaelis-Menten constant KMapp on the concentration
      of the mediator, and the applied potential were also studied and the results were
      presented. The sensor was highly sensitive to H2O2 with a detection limit of 1.0
      x 10(-7)M and with response time of less than 40 s.

PMID- 8660497
TI  - Inhibition assay for the binding of biotinylated von Willebrand factor to
      platelet-bound microtiter wells in the presence of ristocetin or botrocetin.
AB  - We developed a solid-phase inhibition assay for the binding of biotinylated von
      Willebrand factor (vWF) to platelet glycoprotein (GP)Ib based on an enzyme-linked
      immunosorbent assay (ELISA) with platelet-bound microtiter wells. Washed
      platelets were immobilized onto the microplates via the anti-GPIIb/IIIa
      monoclonal antibody (mAb) VNR-5. In the presence of an antibiotic ristocetin (1
      mg/ml, final) or the snake venom botrocetin (2 micrograms/ml, final),
      biotinylated vWF bound to the affixed platelets with half-maximal binding
      occurring at a vWF concentration of approximately 2 micrograms/ml. Several
      specific inhibitors of the binding of vWF to GPIb abolished the interaction of
      biotinylated vWF with GPIb in a dose-dependent fashion, with comparable protein
      concentrations to those seen in the liquid-phase inhibition assay using 125I-vWF.
      These inhibitors included mAb against vWF (NMC-4), mAb against GPIb (AP-1), and
      two vWF fragments containing vWF's putative GPIb-binding domain, namely a 39/34
      kDa dispase-digested vWF fragment and a recombinant vWF fragment. Thus, this new
      assay is a convenient alternative to the conventional inhibition assay using 125I
      vWF.

PMID- 8660498
TI  - Detection of multiple antigens on western blots.
AB  - An immunoblotting method is described that permits sequential detection of
      multiple antigens on a single protein blot without stripping off prior
      antibodies. The procedure utilizes horseradish peroxidase (HRPase)-based
      detection with a chemiluminescent substrate. After detection by enhanced
      chemiluminescence (ECL) with exposure to X-ray film, the antigen-antibody
      complexes on the blot are reacted with a chromogenic substrate (either 3.3'
      diaminobenzidine [DAB] or SG [Vector Labs, Inc.]) which renders the antigen
      antibody-HRPase complexes unreactive in subsequent reprobings of the same
      membrane with additional antibodies using the same detection method. Because no
      stripping is involved, immobilized proteins are not lost from the membrane, thus
      allowing for multiple sequential reprobings of the same membrane with different
      primary antibodies (> or = 12) and retention of strong signal intensities for all
      antibody probings. A variation of the method (the "rainbow Western") is described
      in which four different HRPase-colorimetric substrates that produce black, brown,
      red, and green colors are employed sequentially for detection and simultaneous
      display of four different antigens on the same blot. Both techniques could be
      particularly valuable for analysis of cellular populations that are difficult to
      isolate in large numbers or of clinical specimens where the amounts of protein
      samples that can be obtained are limiting or only available on a one-time basis.

PMID- 8660500
TI  - Synthesis of Peroxynitrite in a Two-Phase System Using Isoamyl Nitrite and
      Hydrogen Peroxide
AB  - A new method for the preparation of high concentrations of peroxynitrite (up to 1
      M) is described. The synthesis uses a two-phase system and involves a
      displacement reaction by the hydroperoxide anion (in the aqueous phase) on
      isoamyl nitrite (in the organic phase). The product peroxynitrite remains in the
      aqueous phase, whereas isoamyl alcohol forms a new organic phase along with the
      unreacted isoamyl nitrite. The aqueous phase contains some 0.15 M isoamyl alcohol
      and the unreacted hydrogen peroxide, but no isoamyl nitrite. Removal of isoamyl
      alcohol or traces of isoamyl nitrite is accomplished by washing the aqueous phase
      with dichloromethane, chloroform, or hexane. A near total removal of hydrogen
      peroxide is then achieved by passing the solutions through a short column of
      manganese dioxide. The peroxynitrite in these postprocessed solutions has a broad
      absorption spectrum with a maximum around 302 nm, follows a characteristic first
      order decomposition at pH 7.2 and 25&deg;C (k = 0.34 &plusmn; 0.1 s-1), and
      reacts with organic compounds to give either nitrated or one-electron transfer
      products. When stored frozen at -20&deg;C, these peroxynitrite solutions
      decompose at a rate of about 1.7% per day and should be used within 2-4 weeks.
      For short-term storage of about 1 week or less, these solutions can be stored at
      refrigerator temperatures (approximately5&deg;C) where peroxynitrite has a half
      life of about 7 days.

PMID- 8660499
TI  - An alternative quantitative polymerase chain reaction method.
AB  - The exponential nature of the polymerase chain reaction (PCR) makes quantitation
      of amplified products possible only if the efficiency of the enzymatic steps is
      estimated or cast off. To obtain a relative quantitative measurement of the
      reverse transcription (RT)-PCR products, a series of seven progressive dilutions
      achieved by mixing RNA solutions of two different samples to be compared was
      prepared in a constant final volume. An aliquot of each dilution mix was
      submitted to a standard RT-PCR. This range of concentrations allowed the
      elimination of the tube-to-tube efficiency variations. Indeed, after gel
      densitometric analysis of the amplified products, the alignment of the seven
      measurements along a regression line demonstrated that the PCR efficiencies in
      all tubes was equal allowing a direct comparison between the two samples. To
      illustrate this method, the renal erythropoietin (EPO) expression level was
      compared in anemic and control rats. Reverse transcription was performed using
      specific primers for EPO and GAPDH genes. The EPO mRNA expression was also
      checked by Northern blotting. Quantitative PCR indicated that anemic rats
      produced 19 times more EPO mRNA than did control rats. The results from Northern
      blotting matched with those of PCR. This simple new method does not provide
      absolute amounts of nucleic acid but relative ones, and it works with any set of
      primers. It could be used alternatively to methods such as competitive RT-PCR.

PMID- 8660501
TI  - Senescent fibroblasts as feeder cells for lymphoid cell cloning.
AB  - Senescent primary human skin fibroblasts were used as feeder layers for cloning
      lymphoid cells by limiting dilution. B-cells including mouse hybridoma cells,
      human multiple myeloma cells C1R and DIG, as well as an immortalized T-cell line
      (Jurkat cells) were cloned using this approach. From heterogenous populations,
      homogeneous (clonal) populations were obtained and further analyzed. The major
      advantages of senescent fibroblasts as feeder cells are (i) the need to establish
      primary cultures from experimental animals for preparing feeder cells is
      obviated; (ii) the risk of contamination with infectious agents is diminished;
      (iii) primary skin fibroblasts are easily maintained in culture, can be kept at
      confluence for extended periods of time, and do not undergo spontaneous
      transformation; and (iv) lymphoid cells are readily separated from fibroblast
      monolayers. The use of senescent fibroblasts overcomes limitations inherent with
      primary mouse cell cultures and irradiated cells commonly used as feeder cells in
      cloning techniques.

PMID- 8660502
TI  - Inhibition by L-ascorbic acid and other antioxidants of the 2.2'-azino-bis(3
      ethylbenzthiazoline-6-sulfonic acid) oxidation catalyzed by peroxidase: a new
      approach for determining total antioxidant status of foods.
AB  - The accumulation of 2.2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS)
      radical catalyzed by peroxidase can be inhibited by the presence of L-ascorbic
      acid in the reaction medium, this inhibition delaying the accumulation of the
      ABTS radical and giving rise to a lag time. A kinetic approach to explain this
      lag time is presented, which also makes it possible to determine the amount of L
      ascorbic acid in the reaction medium. The stoichiometry of the system was
      determined as 1 mol of L-ascorbic reducing 2 mol of ABTS radicals. L-Ascorbic
      acid is not the only compound to have this ability, since other antioxidant
      compounds also react with the ABTS radical. We studied the ABTS/H2O2/horseradish
      peroxidase system in the presence of L-ascorbic acid and other antioxidant
      compounds. The influence of such factors as pH, enzyme concentration, and L
      ascorbic acid concentration was studied. A good correlation between the lag time
      and the L-ascorbic acid present in the medium was observed, and under optimal
      conditions, the method could determine as little as 0.65 nmol of L-ascorbic acid.
      Based on our findings, we propose a method to measure the total antioxidant
      activity of different compounds related to L-ascorbic acid and apply this method
      to determining the total antioxidant activity present in fruit juices.

PMID- 8660503
TI  - Detection of methylglyoxal as a degradation product of DNA and nucleic acid
      components treated with strong acid.
AB  - The 1,2-diaminobenzene derivation assay for methylglyoxal in biological systems
      involves the use of perchloric acid, both as a deproteinizing agent and to
      prevent the spontaneous formation of methylglyoxal from glycolytic pathway
      intermediates. However, while using a modification of the standard literature
      assay to measure methylglyoxal in Chinese hamster ovary cells, we found that
      oxidation of nucleic acids and related compounds by perchloric or trichloroacetic
      acid results in the formation of methylglyoxal. Compounds containing 2
      deoxyribose gave higher levels of methylglyoxal than those containing ribose;
      purine nucleotides and deoxynucleotides gave more methylglyoxal than did the
      pyrimidines. Nucleic acids were the most susceptible to degradation, with 12-fold
      more methylglyoxal being formed from DNA than RNA. Oxidation of nucleic acids
      increased with higher temperatures and with decreasing nucleic acid fragment
      size. Another product of nucleic acid oxidation was 2,3-butanedione, the 1,2
      diaminobenzene derivative of which is sometimes used as an internal standard
      during methylglyoxal measurement. Unless accounted for during the assay
      procedure, the generation of methylglyoxal and 2,3-butanedione due to the
      oxidation of nucleic acids may lead to substantial errors in the determination of
      methylglyoxal concentrations in biological systems.

PMID- 8660504
TI  - Measurement of intracellular calcium in cell populations loaded with aequorin:
      neurokinin-1 responses in U373MG cells.
AB  - Changes in intracellular calcium concentration are important in mediating a wide
      variety of physiological responses. Recently there has been renewed interest in
      the use of aequorin, a protein from jellyfish that emits light when calcium is
      bound, to measure calcium levels in cells. We have loaded populations of cells
      from the human glioma line, U373MG, with aequorin. Lysis of aequorin-loaded but
      not control cells with detergent resulted in a luminescence signal that was
      dependent on extracellular calcium. Aequorin-loaded cells responded to substance
      P, histamine, or the calcium ionophore, ionomycin, with an increase in
      luminescence. Signals in response to detergent, ionomycin, or substance P could
      be detected up to 48 h after cells were loaded with aequorin. Other neurokinin-1
      agonists but not agonists at neurokinin-2 or neurokinin-3 receptors produced
      luminescence signals. Neurokinin-1 antagonists inhibited the substance P-induced
      signal. The aequorin-loading procedure worked well with U373MG cells but not with
      AR42J, CHO, IMR-90, or WI-38 cells.

PMID- 8660505
TI  - Interpretation of deviations from pseudo-first-order kinetic behavior in the
      characterization of ligand binding by biosensor technology.
AB  - Macromolecular interactions observed using surface plasmon resonance technology
      (BIAcore, Pharmacia) often display kinetic behavior which deviates from the
      pseudo-first-order time dependence that has been predicted for 1:1 interactions
      of ligand and ligate. In the present study we reviewed the majors reasons for
      such deviations, and present results which suggest that the most common source of
      deviations from the pseudo-first-order kinetic approximation of BIAcore kinetic
      data is likely to be heterogeneity of the immobilized ligand sites. A simplified
      analysis of the adsorption stage of BIAcore data is presented in terms of the net
      observed pseudo-first-order rate constant, kobs, rather than in terms of the
      association and dissociation rate constants, ka and kd. The analysis is then
      extended to the determination of the dissociation equilibrium constant for the
      interaction of ligand and ligate in the solution phase from sensorgrams
      reflecting competition between soluble and immobilized forms of ligand for
      ligate.

PMID- 8660506
TI  - Pronase-based assay method for O6-methylguanine-DNA methyltransferase.
AB  - A new, simple, and rapid assay method for O6-methylguanine-DNA methyltransferase
      (MGMT) has been developed. When [methyl-3H] DNA radiolabeled with N-[methyl-3H]-N
      nitrosourea was incubated together with tissue homogenate, [methyl-3H] group was
      transferred to the enzyme, forming S-[methyl-3H]cysteine. In contrast to the
      previous methods which determined the amount of [methyl-3H] group removed from
      [methyl-3H] DNA, the present method measured the amount of [methyl-3H]
      transferred to the enzyme. This has been done by hydrolyzing the radiolabeled
      enzyme with pronase which is a proteolytic enzyme with a broad substrate
      specificity. On pronase digestion, [methyl-3H]-labeled enzyme becomes soluble in
      trichloroacetic acid. The method is very simple and rapid, and the only expensive
      equipment required is a scintillation counter which is a relatively routine piece
      of equipment at present. More than a dozen samples can be processed within 4-5 h
      without any difficulty. This new method has been employed in the studies on organ
      distribution of MGMT of rat and mouse.

PMID- 8660508
TI  - A microassay for measuring glycogen in 96-well-cultured cells.
AB  - This study describes a rapid, sensitive, and automated spectrophotometric
      enzymatic microassay that measures the intracellular glycogen of primary cultured
      hepatocytes and other cultured cells in 96-well plates and can be adapted for
      other samples that are transferred to these plates. The procedure involves in
      situ disruption of cells, followed by hydrolysis of glycogen into glucosyl units
      by fungal glucoamylase (exo-1.4-alpha-glucosidase, EC 3.2.1.3), and glucose
      determination with the glucose oxidase colorimetric method. The color intensity
      can be measured in conventional ELISA readers, and the data can be fed to an on
      line computer for rapid processing. The advantages of this method are its
      simplicity and automation, the reduction in sample handling, and the small number
      of cells required compared to other conventional methods.

PMID- 8660507
TI  - Chemiluminescent immunoperoxidase assay for the dot blot hybridization detection
      of Parvovirus B19 DNA using a low light imaging device.
AB  - A new synthesized stable trifluoro-substituted acridan (2',3',6'-trifluorophenyl
      10-methylacridan-9-carboxylate known as Lumigen PS-3) has been applied as
      chemiluminescent substrate of the horseradish peroxidase (HRP) enzyme (neutral
      isoenzyme C) in a dot blot hybridization assay for the detection of B19
      Parvovirus DNA. The dot blot hybridization assay uses digoxigenin-labeled DNA
      probes which are immunoenzymatically revealed by anti-digoxigenin Fab fragments
      conjugated with HRP. The results obtained using PS-3 reagent or the luminol-based
      enhanced chemiluminescence detection system (ECL Amersham and Renaissance DuPont
      NEN kits) were compared. A high-performance, low-intensity-light imaging
      luminograph apparatus to collect light emission was used. The detection systems
      using the different chemiluminescent substrates gave sensitive and reproducible
      results for calibration graphs, with high precision (relative standard deviation
      5-18%). With the chemiluminescent assay it was possible to detect 0.5, 1, or 2 pg
      of target homologous DNA, using PS-3, ECL, or Renaissance (RE) reagents,
      respectively, while colorimetry had a detection limit of 5 pg. When clinical
      samples were analyzed the positive reference sera and the PCR-positive products
      gave light emissions with values higher than background at 2 sigma level, while
      the negative samples gave a signal comparable to the background noise for all
      chemiluminescent reagents. The PS-3 reagent detected one more dilution (1/256)
      than ECL and RE (1/128) of positive reference sera.

PMID- 8660509
TI  - Linearization of the Bradford protein assay increases its sensitivity:
      theoretical and experimental studies.
AB  - Determination of microgram quantities of protein in the Bradford Coomassie
      brilliant blue assay is accomplished by measurement of absorbance at 590 nm.
      However, as intrinsic nonlinearity compromises the sensitivity and accuracy of
      this method. It is shown that under standard assay conditions, the ratio of the
      absorbances, 590 nm over 450 nm, is strictly linear with protein concentration.
      This simple procedure increases the accuracy and improves the sensitivity of the
      assay about 10-fold, permitting quantitation down to 50 ng of bovine serum
      albumin. Furthermore, protein assay in presence of up to 35-fold weight excess of
      sodium dodecyl sulfate (detergent) over bovine serum albumin (protein) can be
      performed. A linear equation that perfectly fits the experimental data is
      provided on the basis of mass action and Beer's law.

PMID- 8660510
TI  - Quantitation of 1-stearoyl-2-arachidonoyl-sn-3-glycerol in human basophils via
      gas chromatography-negative ion chemical ionization mass spectrometry.
AB  - Investigation of the role of diacylglycerol molecular species in signal
      transduction in human basophils has been impeded by the lack of an assay method
      with adequate sensitivity and selectivity. Conversion of 1-stearoyl-2
      arachidonoyl-sn-3-glycerol to the pentafluorobenzoyl ester conveys electron
      capture properties to the diacylglycerol. The electron-capture derivative of the
      diacylglycerol is amenable to gas chromatographic analysis and undergoes limited
      fragmentation under negative ion mass spectrometric conditions with generation of
      an intense molecular anion at m/z 838. Monitoring m/z 838 for detection of 1
      stearoyl-2-arachidonoyl-sn-3-glycerol and m/z 841 for detection of 1
      trideuterostearoyl-3-arachidonoyl-sn-2-glycerol employed as the internal standard
      provides the analytical basis for GC-MS quantitation of the endogenous
      diacylglycerol in human basophils. The assay displays excellent reproducibility
      over a wide range of concentrations with variations < or = 10%. The GC-MS assay
      is highly selective and exquisitely sensitive with a detection limit of < or =
      0.20 pg (approximately 30 fmol) for endogenous 1-stearoyl-2-arachidonoyl-sn-3
      glycerol per injection. Approximately 400 fmol of the diacylglycerol were
      extracted from 10(5) stimulated human basophils.

PMID- 8660511
TI  - A chemiluminescence-based method for the detection and quantification of antigen
      antibody interactions on the surface of eukaryotic cells.
AB  - Enhanced chemiluminescence was applied to detect the binding of monoclonal
      antibodies to surface antigens on intact cells. The fast and simple assay is
      performed in the microtiter scale and thus allows for the simultaneous processing
      of a large number of samples with a sensitivity comparable to conventionally used
      techniques such as cytometry or Western blot analysis. In two model experiments,
      we demonstrate (a) the detection of a heterologously expressed cytokine receptor
      subunit on the surface of suspension cells and (b) the screening of hybridoma
      clones for the production of antibodies specifically recognizing surface antigens
      on a tumor cell line. Moreover, the assay is shown to be suitable for the
      determination of antibody affinities and of antibody binding sites per cell.

PMID- 8660512
TI  - Neutral carrier-based "Ca(2+)-selective" microelectrodes for the measurement of
      tetraphenylphosphonium.
AB  - Ca(2+)-selective microelectrodes with Simon's neutral carrier ETH 1001 are
      commercially available and have been widely used for the measurement of both
      extra- and intracellular calcium. The electrodes demonstrate high selectivity
      against other cations such as magnesium, sodium, and potassium. We report,
      however, that the ETH 1001-based microelectrode is a superior
      tetraphenylphosphonium (TPP+)-sensitive electrode. The electrode exhibits a
      Nernstian response for [Ca2+] > 10(-5) M but for [TTP+] > 10(-7) M. Using two
      different methods, we found that log kTTPCa (selectivity coefficient for TPP+
      with respect to Ca2+) is in the range of -3.0 to -5.3. We argue that the ETH 1001
      microelectrode can be used as a commercially available TPP+ electrode. We
      illustrate this application by making membrane potential recordings in respiring
      mitochondria. The results are identical to those obtained using conventional ion
      exchange TPP+ electrodes.

PMID- 8660513
TI  - Nitrate analysis in biological fluids by gas chromatography-nitrogen-phosphorous
      detection.
AB  - Nitrate analysis in body fluids is an important part of the study of nitric oxide
      metabolism. A sensitive, simple procedure for nitrate analysis was developed by
      producing nitrobenzene from the nitrate in the samples and benzene. The
      nitrobenzene produced was measured on a gas chromatograph (GC) equipped with a
      nitrogen-phosphorous detector. Cl-, which interfered with the derivitization
      procedure, was removed as silver chloride after precipitation with silver
      lactate. Rat urine samples were also analyzed after elution through a C18 reverse
      phase sample preparation column to remove organic molecules that competed with
      benzene for the nitrate in the sample. A benzene derivative, 2-nitro-1,3
      dimethylbenzene (2-nitro-m-xylene), was chosen as an internal standard for GC
      analysis. Recovery of nitrate was 67 +/- 2% in serum and 87 +/- 8% in urine.
      Sensitivity of the procedure was 1 microM. This procedure offers improvements in
      sensitivity, simplicity, and consistency over previously published procedures and
      makes possible the measurement of nitrate and determination of isotopic ratios by
      GC-MS on the same sample.

PMID- 8660514
TI  - Measurement of P-glycoprotein expression in multidrug-resistant human
      neuroblastoma cell lines using self-competitive binding assay.
AB  - To date, all reported measurements of multidrug resistance have been
      semiquantitative. The purpose of the present study is to establish and validate
      the self-competitive binding assay technique utilizing monoclonal antibody for
      quantitative estimation of multidrug resistance in tumor cells. This technique is
      used for P-glycoprotein concentration measurement in BE(2)-C human neuroblastoma
      cell line and its sublines with primary resistance to colchicine and actinomycin
      D. Monoclonal antibody MRK-16 was used in this study. It was labeled with iodine
      125 (125I) to trace the concentration of antibody-antigen complexes. The binding
      data were obtained by varying the concentration of the unlabeled antibody. The
      results were fitted to a model equation to estimate the number of binding sites
      and antibody-antigen dissociation constant. The P-glycoprotein concentration was
      significantly higher in the resistant sublines than in the sensitive line. The
      highest levels were achieved in actinomycin D-resistant cells: 2.1 x 10(6)
      binding sites/cell versus 5.4 x 10(4) binding sites/cell in the sensitive cells.
      The consistency of the results was verified by repeating the study three times
      for each cell line. The binding assay results were confirmed by Western blot
      experiments performed on the same cell lines.

PMID- 8660515
TI  - Enzyme-triggered formation of electrochemiluminescent ruthenium complexes.
AB  - A sensitive enzyme assay is described using substrates derivatized with metal
      binding ligands. Enzymes catalyzed changes in the abilities of substrates to bind
      to the nonelectrochemiluminescent complex ruthenium (II) bis(bipyridyl),
      Ru(bpy)2(2+), to form electrochemiluminescent mixed-ligand complexes. A highly
      electrochemiluminescent complex was formed between Ru(bpy)2(2+) and picolinic
      acid (1) but not picolinic acid ethyl ester (4), permitting the detection of 4
      hydrolysis by pig liver esterase (PLE). Electrochemiluminescence (ECL)
      differences between Ru(bpy)2(2+) mixtures of 1 and 4 were detected to a lower
      concentration limit of 65pM. Under the conditions used in actual enzyme assays,
      it was possible to detect 4.4 pM PLE and the hydrolysis of 1.3 microM 4. In a
      second assay, leucine aminopeptidase (LAP) hydrolyzed 8-(L)-leucylaminoquinoline
      (9) to leucine and aminoquinoline (10). A mixed-ligand complex formed between (9)
      and Ru(bpy)2 (2+) was substantially more electrochemiluminescent than a complex
      of Ru(bpy)2(2+) and 10. ECL differences between Ru(bpy)2(2+) mixtures of 9 and 10
      were detectable to 65 nM. Under actual enzyme assay conditions, 375 pM LAP could
      be detected as well as the hydrolysis of 1.3 microM 9.

PMID- 8660517
TI  - Calibrating gelatin zymograms with human gelatinase standards.
AB  - We describe the use of gelatinase standards from human capillary whole blood for
      calibrating gelatin zymograms. Capillary blood was obtained by fingerstick
      puncture and prepared in nonreducing Laemmli SDS-PAGE sample buffer without
      heating. Gelatin zymography revealed that whole blood (0.25- 1 microliter)
      contained substantial fibroblast-derived (72-kDa) and neutrophil-derived (92-,
      130-, and 225-kDa) gelatinases which could be used for calibration purposes.
      Calibration was linear under different electrophoretic conditions using 6.5-10%
      polyacrylamide gels containing 1-2 mg/ml gelatin (correlation range, r = 0.990
      0.998; perfect correlation, r = 1.000). The use of the standards for
      characterizing gelatinases from arthritic joint fluid is demonstrated. The
      standards are easily obtained and well characterized, and should facilitate
      interlaboratory comparison and standardization.

PMID- 8660516
TI  - Identification of zinc finger mRNAs using domain-specific differential display.
AB  - An oligonucleotide primer specific for a conserved amino acid region of the
      Cys2/His2 zinc finger proteins was used in conjunction with mRNA differential
      display to amplify related mRNAs from a human ovarian cancer cell line. Six of
      the 12 cDNAs analyzed from the differential display polyacrylamide gel exhibited
      zinc finger homology at the nucleotide and predicted amino acid sequence level.
      None of these cDNA fragments, however, shared complete homology with genes
      encoding any known zinc finger proteins. All 6 cDNA fragments with zinc finger
      homology had a poly-A tail and 3 of these fragments contained a putative
      polyadenylation signal. Northern blot analysis was performed using radiolabeled
      probes prepared from the 12 cDNA fragments. Two of the 6 cDNA fragments with zinc
      finger homology hybridized to 3.6- and 6.0-kb mRNAs. In addition, 2 of the
      fragments which did not contain significant homology to zinc finger or any other
      known sequences hybridized to 4.1- and 5.8-kb mRNAs. These results suggest that
      domain-specific differential display may be a useful approach for the
      identification of novel gene family members as well as for the analysis of
      changes in gene expression of family members between related cell lines or tissue
      samples.

PMID- 8660518
TI  - Chloramphenicol resistance interferes with purification of histidine-tagged
      fusion proteins from recombinant Escherichia coli.

PMID- 8660519
TI  - Detection of modified amino acids in lantibiotic peptide mutacin II by chemical
      derivation and electrospray ionization-mass spectroscopic analysis.

PMID- 8660521
TI  - Urea reduces the aggregation of membrane proteins on sodium dodecyl sulfate
      polyacrylamide gel electrophoresis.

PMID- 8660520
TI  - A solid-phase enzyme-linked assay for ceramide glycanase using GM1 and a novel
      beta-galactosidase inhibitor.

PMID- 8660522
TI  - Electroblotting of proteins to Teflon tape and membranes for N- and C-terminal
      sequence analysis.

PMID- 8660523
TI  - A semiautomated method for the assay of cyclic adenosine 5'-monophosphate
      phosphodiesterase.

PMID- 8660524
TI  - Preparation of pyridylaminated O-linked sugar chains from glycoproteins blotted
      on a polyvinylidene difluoride membrane and application to human granulocyte
      colony-stimulating factor.

PMID- 8660525
TI  - T7 vectors with modified T7lac promoter for expression of proteins in Escherichia
      coli.

PMID- 8660526
TI  - Nonradioactive single-strand conformation polymorphism analysis with application
      for mutation detection in a mixed population of cells.

PMID- 8660528
TI  - Total in Vitro Synthesis of Plasmid DNA Facilitates Site-Directed Mutagenesis

PMID- 8660527
TI  - Potential sources of discrepancies between living tissue near infrared
      spectroscopy algorithms.

PMID- 8660529
TI  - Determination of Synephrine Enantiomers in Food and Conjugated Synephrine in
      Urine by High-Performance Liquid Chromatography with Electrochemical Detection

PMID- 8660530
TI  - Theory and practice of gel electrophoresis of interacting macromolecules.

PMID- 8660531
TI  - Iodixanol (Optiprep), an improved density gradient medium for the iso-osmotic
      isolation of rat liver peroxisomes.
AB  - The suitability of Iodixanol {5,5'-[(2-hydroxy-1, 3-propanediyl)
      bis(acetylamino)] bis-[N,N'-bis(2, 3-dihydroxypreopyl-2,4,6-triiodo-1,3
      benzenecarboxamide)]}, a nonionic iodinated compound with a molecular weight of
      1550, for the isolation of peroxisomes from rat liver was investigated.
      Centrifugation of light mitochondrial fractions in 20 to 40% (w/v) Iodixanol
      gradients, made iso-osmotic by the addition of sucrose, resulted in an excellent
      separation of peroxisomes from the remaining organelles, which were not able to
      enter the gradient. Peroxisomes banded around 30% (w/v) Iodixanol (d
      approximately 1.175) and, as revealed by marker enzyme analysis, were enriched 35
      to 40-fold. Morphological examination of the peroxisomal fractions confirmed the
      near absence of other organelles and revealed structurally well-preserved
      peroxisomes. Free cores, also present in the starting fractions, migrated to
      higher densities and were trapped on a cushion. No interference of Iodixanol with
      marker enzyme determinations was observed, except for the UV-metric determination
      of urate oxidase and for the analysis of protein.

PMID- 8660532
TI  - Electrophoretic separation of betaA4 peptides (1-40) and (1-42).
AB  - Different sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
      systems designed for the separation of peptides were compared for their
      usefulness in separating synthetic beta-amyloid peptides betaA4 (1-40) and betaA4
      (1-42). Clear resolution was achieved by addition of 8 M urea to the separation
      gel and use of a multiphasic buffer system employing bicine and sulfate as
      trailing and leading ions, respectively (bicine/Tris/urea gels). Under these
      conditions, the longer peptide migrated faster than the one ending at amino acid
      40. The usefulness of this SDS-PAGE system for the analysis of betaA4-related
      peptides generated during cellular metabolism was demonstrated by
      immunoprecipitation and electrophoretic separation of radiolabeled peptides
      secreted by cells transfected with amyloid precursor protein cDNAs.

PMID- 8660533
TI  - High-performance liquid chromatographic resolution of NADP+ after induction of
      fluorescence and its application to assay for an NADPH-dependent enzyme:
      application to the determination of glutathione reductase activity in plant leaf
      extracts.
AB  - A method is described for the determination of glutathione reductase activity
      (GR; EC 1.6.4.2) in plant extracts utilizing HPLC quantitation of NADP+ following
      the reduction of glutathione disulfides. After protein incubation, fluorescence
      of NADP+ was induced under strongly basic conditions, and the product was
      directly resolved from the reaction medium by isocratic reversed-phase elution on
      a silica-coated alumina support which took 2 min. The mobile phase was
      acetonitrile-water (50:50) delivered at a flow rate of 1.5 ml/min. The adduct
      (stable for at least 7 days) was detected fluorometrically and quantitated by
      direct integration of peak area.

PMID- 8660534
TI  - Calcium content and respiratory control index of isolated skeletal muscle
      mitochondria: effects of different isolation media.
AB  - Calcium (Ca) content measured with graphite furnace atomic absorption
      spectrometry and polarographical measurement of respiratory control index (RCI)
      were performed on isolated skeletal muscle mitochondria. Four different isolation
      media were used in order to develop a method for isolating physiologically intact
      mitochondria in small samples with an endogenous Ca content as close as possible
      to in vivo conditions. With ruthenium red in the isolation medium, the mean Ca
      content decreased fourfold to 19.3 +/- 6.8 nmol/mg protein and RCI increased
      about 25% to 6.9 +/- 1.1 compared with a standard medium. With EGTA or EGTA plus
      ruthenium red, the mean Ca content decreased further to 5.8 +/- 1.0 and 5.1 +/-
      0.9 nmol/mg protein and the mean RCI values increased to 8. 4 +/- 1.2 and 8.8 +/-
      1.3, respectively. Isolated mitochondria from human muscle samples using EGTA and
      ruthenium red in the isolation medium had mean Ca values of 11.0 +/- 0.9 nmol/mg
      protein and mean RCI values of 12.2 +/- 1.6. The data indicate that the Ca
      concentration in the skeletal muscle mitochondria is inversely proportional to
      RCI, and the mitochondrial functional property is significantly improved upon
      lowering the intramitochondrial Ca accumulation by the incorporation of a
      chelating agent (EGTA) and a potent Ca antagonist, ruthenium red, in the
      isolation media.

PMID- 8660535
TI  - Screening of protein tyrosine kinases activated during neural induction in
      Xenopus.
AB  - We have screened Xenopus animal cap ectodermal cells during neural induction for
      protein kinases (PK) and protein tyrosine kinases (PTKs) after their renaturation
      in gels containing the polydispersed substrate poly(Glu, Tyr). Following
      guanidine hydrochloride denaturation, renaturation, and phosphorylation with
      [gamma-32P]ATP, kinase activity was detected by autoradiography. Incubation of
      gels in hot alkali after glutaraldehyde crosslinking completely eliminated the
      activity of non-PTK enzymes. This method is very sensitive and can be applied to
      development biology for the detection of PTKs in very small samples such as
      ectoderm explants dissected from animal caps in amphibian embryos. A large number
      of PTKs were visualized in uninduced and induced ectodermal cells. This procedure
      should be useful for investigating the role of PTKs in intracellular signaling
      during neural induction.

PMID- 8660536
TI  - Analysis of hemoglobin adducts of benzene oxide by gas chromatography-mass
      spectrometry.
AB  - A method is reported for measuring cysteinyl adducts of the benzene metabolite
      benzene oxide (BO) with hemoglobin (Hb) in blood from humans or rodents exposed
      to benzene. After reacting the purified, dried protein with trifluoroacetic
      anhydride and methanesulfonic acid, the resulting phenyltrifluorothioacetate is
      extracted, washed, and detected by GC-MS in the negative-ion chemical ionization
      mode. The analysis of Hb adducts of BO from rats dosed with 50-400 mg/kg
      [13C6]benzene via this method resulted in values which were generally consistent,
      though slightly lower, than those obtained using an established method. However,
      while 3 weeks were required to process the samples by the former method, only 2
      days were needed with the new procedure. This new method should, therefore, prove
      to be reliable and convenient for the rapid quantitation of cysteine-bound Hb
      adducts of BO.

PMID- 8660537
TI  - Identification of monohydroxy fatty acids by electrospray mass spectrometry and
      tandem mass spectrometry.
AB  - Negative-ion electrospray mass spectrometry (ESI-MS) and tandem mass spectrometry
      (ESI-MS/MS) were used to characterize saturated and unsaturated monohydroxy fatty
      acids and fatty acid metabolites formed following incubation with soybean
      lipoxygenase. Ions corresponding to [M-H]- of eicosanoids were readily observed
      using ESI-MS, but double bond migration precluded the use of MS to localize
      double bonds or the position of hydroxyl moieties; however, by following MS
      analysis with negative-ion ESI-MS/MS of precursor ions, the position of
      oxygenation could be determined for picogram quantities of underivatized
      monohydroxy fatty acids. Loss of 46 mass units from the precursor ion of
      saturated monohydroxy compounds was explained in some cases by resonance
      stabilization of enolate ions, but this product ion was found in spectra of
      compounds where resonance was not possible. Spectra of deuterated analogs
      supported charge-driven vinylic processes as the most common mechanism of
      fragmentation. The utility of low-collision-energy ESI-MS/MS to examine
      biological samples was shown by examining the products formed by the metabolism
      of linoleic (18:2omega6) and arachidonic (20:4omega6) acids by soybean
      lipoxygenase using aerobic and anaerobic incubation conditions that generated
      increasingly complex mixes of metabolites.

PMID- 8660538
TI  - Two applications using N,N'-diethyldithiocarbamate as a stain for copper in
      native polyacrylamide gels of superoxide dismutase.
AB  - N,N'-Diethyldithiocarbamate has been shown to be an analytical stain for copper
      in native polyacrylamide gels of the copper-zinc superoxide dismutase from
      purified preparations as well as from crude red cell extracts, i.e., lysates from
      which hemoglobin has been removed (Jewett, S. L., and Rocklin, A. M. (1994) Anal.
      Biochem. 217, 236-240). Applying this methodology, it was found that the relative
      amounts of copper-containing forms of copper-zinc superoxide dismutase (EC
      1.15.1.1) from bovine red cell extracts did not change significantly with either
      the age or with hydrogen peroxide treatment of the red cells. Furthermore, no
      significant changes were seen in the specific activity of the dismutase in either
      type of experiment. These observations for both types of experiments are contrary
      to what was expected from similar studies reported in the literature. However,
      discrepancies may be accounted for by hemoglobin interference in indirect
      dismutase assays of the previous work. In the case of the peroxide treatment of
      red cells, however, there is an additional factor in that the dismutase is
      protected from peroxide-mediated changes in copper content and heterogeneity by
      the hemoglobin present. This protection was demonstrated in in vitro experiments
      using only a 24-fold excess of hemoglobin over the dismutase.

PMID- 8660540
TI  - Interference in protein assays of biological specimens by vanadyl compounds.
AB  - Vanadyl ribonucleoside and orthovanadate are commonly employed as inhibitors of
      ribonuclease and protein phosphatase activities, respectively, in a variety of
      tissue preparations. We have observed that the presence of these agents in the
      tissue samples interferes in the measurement of their protein content using the
      Coomassie dye binding procedure. We have demonstrated that this interference in
      the protein assay can be overcome by including H2O2 at a final concentration of
      0.1% in the protein assay medium prior to the addition of the dye reagent. This
      results in accurate measurements of the protein content in the tissue preparation
      containing vanadyl ribonucleoside or orthovanadate.

PMID- 8660539
TI  - A cell-free, nonisotopic, high-throughput assay for inhibitors of type-I
      interleukin-1 receptor.
AB  - A cell-free, nonisotopic assay has been developed to discover molecules that
      compete with the natural ligands for binding to the active site of the Type-I
      interleukin-1 receptor. The key reagents are the interleukin-1 receptor
      antagonist, a recombinant soluble form of the receptor (sIL-1R), and a specific
      anti-sIL-1R nonneutralizing monoclonal antibody (MAb79). With these molecules a
      sensitive assay has been developed using a reversed format: the ligand is
      immobilized and the receptor is in solution. The ligand-bound receptor is
      detected using MAb79 and an enzyme-linked secondary antibody. Since no cells or
      cell membranes are used, the assay is very robust, with no interference from
      membrane-perturbing agents and high resistance to the organic solvents normally
      used to resuspend compounds of chemical libraries. The microplate format and
      colorimetric detection have allowed the complete automation of the immobilized
      ligand IL-1 receptor binding assay, which has been used for high-throughput
      screening of synthetic compounds and natural products.

PMID- 8660541
TI  - Perfusion chromatography on reversed-phase column allows fast analysis of human
      globin chains.
AB  - Human globin chain analysis provides important information on the genetics and
      molecular pathophysiology of hemoglobinopathies. We propose using perfusion
      chromatography on the reversed-phase stationary phase to perform these studies.
      The technique, herein described, involves a high-velocity flow of the mobile
      phase through a porous chromatographic stationary phase made of microspheres of
      poly(styrene-divinylbenzene) having throughpores of 6000-8000 A diameter with
      short diffusive pores of 500-1000 A diameter connected to them. The composition
      of fetal hemoglobin (Ggamma:Agamma ratio) is determined, using this method, as an
      order of magnitude faster than with conventional HPLC. Elution is performed by
      developing a linear gradient of acetonitrile at a flow rate of 3 ml/min (or
      more), easily obtained on any HPLC machine. Analyses may be done on samples
      containing as low as 3.0% Hb F. Results are similar to those obtained with the
      reference HPLC technique, which uses a C4 column. In addition, reversed-phase
      perfusion chromatography, using a shallow curvilinear gradient, may help in the
      characterization of Hb variants. This technique allowed us to discriminate
      several alpha and beta chain mutants from variants that have closely similar
      patterns of electrophoretic mobilities.

PMID- 8660543
TI  - A continuous fluorometric assay for pectin methylesterase.
AB  - A continuous, fluorometric assay for pectin methylesterase (PME) activity is
      described. In this assay, methanol produced by PME hydrolysis of pectin methyl
      esters is oxidized to formaldehyde by alcohol oxidase, and the formaldehyde is
      continuously reacted with 4-amino-3-penten-2-one to create a stable, fluorescent
      product. The increase in fluorescence intensity is linearly proportional to PME
      activity. The assay can be used in crude plant or fungal extracts with relatively
      little interference with chemicals or buffers commonly used in PME purification.
      The fluorescence assay has a useful pH range, from pH 5.0 to 6.5, which overlaps
      pH optima for many bacterial and fungal PMEs, but which limits its usefulness in
      assaying plant PMEs with alkaline pH optima. Nevertheless, the method is valuable
      for rapid assay of plant PMEs during their purification or for comparison of
      plant tissue PME activities.

PMID- 8660542
TI  - Generation and structural characterization of a range of unmodified chondroitin
      sulfate oligosaccharide fragments.
AB  - Chondroitin sulfate C has been used to demonstrate an approach of generating a
      range of unmodified glycosaminoglycan oligosaccharide fragments. This involves
      cleavage by oxymercuration treatment of the nonreducing terminal 4,5-unsaturated
      uronic acid (DeltaUA) residues from the fragments produced by enzymatic digestion
      of chondroitin sulfate with chondroitinase ABC. Carrying out the reaction on the
      unfractionated digestion mixture produces a range of mono- to tridecasaccharides,
      the compositions of which were established by liquid secondary ion mass
      spectrometry (LSIMS) and their chromatographic patterns compared with
      oligosaccharides in the untreated digest. Ten of the main sequences, tri- to
      octasaccharides, isolated by HPLC from the treated and untreated digests were
      fully characterized by a combination of LSIMS and 1H NMR. Of these, 6 are
      homologs of the series with structures DeltaUA1-[3GalNAc(6S)beta1- 4GlcAbeta1]n
      3Gal-NAc(6S) and [GalNAc(6S)beta1-4GlcAbeta1]n- 3GalNAc(6S), where n = 1-3. The
      other 4 sequences, DeltaUA1-[3Gal-NAc(6S)beta1-4GlcAbeta1]n-3GalNAc(4S) and
      [GalNAc(6S)beta1-4GlcAbeta1]n-3GalNAc(4S), where n = 1 and 2, contain the
      alternative 4-sulfated GalNAc at the reducing terminal. These results establish
      that oligosaccharides generated by oxymercuration treatment retain their
      integrity and only lack the terminal DeltaUA residue.

PMID- 8660544
TI  - Cloning differentially expressed genes by linker capture subtraction.
AB  - We have developed a simple and effective method, designated linker capture
      subtraction (LCS), for cloning differentially expressed genes between two cell
      types or between cells treated in two different ways. In the first step of the
      method, two mRNA populations are converted to double-stranded cDNAs, fragmented,
      and ligated to linkers for PCR amplification. In the second step, the linkered
      DNA (tester) from one mRNA population is hybridized to an excess of the
      unlinkered DNA (driver) from the other mRNA population, followed by incubation
      with mung bean nuclease which digests single-stranded DNA specifically. This
      leaves only tester-tester homohybrids to be amplified by PCR in the following
      step, so as to achieve an enrichment of tester-specific sequences. The amplified
      PCR products are then used as tester for another round of subtraction. The
      process of subtraction is carried out three times, and the final PCR products are
      inserted into a vector for clonal analysis. We have used the strategy to begin to
      clone and identify the genes expressed differentially between the human prostate
      cancer cell lines LNCaP and PC-3, which have different tumorigenic and metastatic
      potentials. We demonstrated strong enrichment of target sequences. We also report
      the identities of two of the genes expressed differentially in these cell lines.
      One is prostate-specific antigen (PSA) which is known to be expressed in LNCaP
      but not in PC-3. The other is vimentin, the differential expression of which has
      not been reported previously in these prostate cancer cells.

PMID- 8660545
TI  - Binding of biotinylated DNA to streptavidin-coated polystyrene latex: effects of
      chain length and particle size.
AB  - The binding of 5'-end biotinylated DNA, ranging in size from 100 to 5000 base
      pairs, was studied using streptavidin-coated polystyrene latex particles with
      diameters between 0.944 and 0.090 micron. The experimental binding constants and
      forward rate constants of this solid-phase reaction were determined to be several
      orders of magnitude lower than values for the biotin-streptavidin interaction in
      solution as expected and were shown to depend on the size of both ligand and
      substrate. An observed inflection in the binding constant of the biotinylated DNA
      appeared around 1000 base pairs, possibly indicating different surface
      orientations of the macroligand above and below this critical size. This effect
      was more pronounced for the smaller latex particles used in this study and
      highlighted possible differences in the surface arrangement of streptavidin on
      the differently sized particles. Diffusion limitation to the binding reaction was
      found to be significant in all cases. In this present work, an exponential
      relationship was established between the experimental binding constant and the
      number of base pairs in the biotinylated DNA. This relationship possibly provides
      a means to predict capacity and binding speed in cases where adsorption,
      purification, and release of larger DNA chains are required.

PMID- 8660546
TI  - Comparison of reflectance and transmission densitometry, using document and laser
      scanners, for quantitation of stained Western blots.
AB  - The quantitation of stained Western blots by reflectance and transmission
      scanning was explored using a blot of monoclonal immunoglobulin G probed with
      anti-mouse antibody. The so-called "scanned absorbance" output from a document
      scanner was found to be directly proportional to the fraction of light absorbed
      rather than obeying the logarithmic relationship expected for true
      spectrophotometric absorbance. This explains observations in the literature of a
      strongly curved relation between loading and "absorbance." Laser transmission
      densitometry of a blot immersed in a clarifying solvent mixture showed that peak
      area was linearly related to loading over a wide range. In reflectance mode the
      document scanner also gave equally linear quantitation of dry blots, providing
      that a logarithmic correction curve was applied during scanning. It was found
      advantageous to interpose a red acetate filter sheet between the blot and the
      scanning table to aid detection of weakly stained bands. The document scanner
      gave less satisfactory results when used in transmission mode on a clarified blot
      because weak bands were poorly quantitated.

PMID- 8660547
TI  - Development of a scintillation proximity assay for human cytomegalovirus protease
      using 33phosphorous.
AB  - A scintillation proximity assay (SPA) using 33phosphorous is described for human
      cytomegalovirus (HCMV) UL80 protease. This is the first demonstration that
      33phosphorous is compatible with the SPA system. The peptide substrate used in
      the assay contains an HCMV protease cleavage site and is biotinylated at its
      amino terminus. The peptide also contains a site for protein kinase A, enabling
      radiolabeling at its carboxy terminus with [gamma-33P]ATP. Peptide is incubated
      with protease, followed by binding to streptavidin-coated SPA beads via biotin.
      Cleavage of the peptide by the protease results in a decrease in the radioactive
      signal, which is prevented by the presence of a protease inhibitor. This
      methodology is applicable to other proteases whose cleavage site is known.

PMID- 8660548
TI  - Proteolytic mapping of the thymidine/thymidylate binding site of herpes simplex
      virus type 1 thymidine kinase: a general photoaffinity labeling method for
      identifying active-site peptides.
AB  - The herpes simplex virus type 1 thymidine kinase (HSV-1 TK) is an important
      pharmacological target of antiviral nucleoside drugs and it uniquely possesses
      both a thymidine kinase and a thymidylate kinase activity. The structural
      relationship between these two activities is addressed in this study using a
      combination of active-site directed photoaffinity analogs, proteases, and tricine
      SDS-polyacrylamide gel electrophoresis. For analysis of the thymidylate binding
      site, the thymidylate analog [32P]5-azido-dUMP was specifically photocrosslinked
      to the active site of HSV-1 TK. Because the amino acid sequence of HSV-1 TK is
      known, endoprotease Lys-C, V8 protease, trypsin, or chymotrypsin was used to
      generate a proteolytic map of photoincorporated peptides by separation on high
      resolution tricine-SDS-polyacrylamide gels. Analysis of the resulting peptides
      indicated that the photoprobe was localized to one region comprising amino acids
      Ile112-Tyr132. Photolabeling of this region indicates that the thymine base of
      thymidine and TMP bind at one shared site in HSV-1 TK. In addition, the results
      reported in this study demonstrate that photolabeling with azidonucleotides can
      be used to identify photolabeled peptides by proteolytic mapping. This technique
      bypasses the problems of peptide purification and sequencing and yields rapid
      results when the primary amino acid structure of the protein of interest is
      known.

PMID- 8660550
TI  - An improved method for polymerase chain reaction using whole yeast cells.

PMID- 8660549
TI  - S-nitrosation of serum albumin: spectrophotometric determination of its
      nitrosation by simple S-nitrosothiols.
AB  - The transfer of nitroso groups from S-nitroso-L-cysteine (1) and six other simple
      S-nitrosothiols to Cys 34 of bovine serum albumin (2) has been followed using
      Ellman's reagent, 5,5'-dithio-bis (2-nitrobenzoate) (3), to detect the resulting
      thiols. The described method utilizes the low reactivity of (3) with (2) and the
      high extinction coefficient of 2-nitro-5-thiobenzoate produced upon its reaction
      with thiols to follow the transfer of nitroso moieties at low concentrations
      where other procedures are not feasible. A second-order rate constant of 6400 M-1
      s-1 obtained for the reaction of (2) with S-nitrosomercaptoethylamine is
      approximately 10 times faster than that for its reaction with (1), approximately
      40 times faster than that for its reaction with S-nitrosoglutathione, and
      consistent with Cys 34 being located in a narrow crevice in close proximity to an
      anionic charge.

PMID- 8660551
TI  - Effect of polybrene on the N-terminal sequencing of peptides bound to
      polyvinylidene difluoride membranes.

PMID- 8660552
TI  - A competitive single-step reverse transcriptase-polymerase chain reaction assay
      for quantification of heme oxygenase 1.

PMID- 8660553
TI  - Helix-coil transitions in DNA using a pH variation method: case of a melting
      paradox as a function of ionic strength.

PMID- 8660554
TI  - Subtractive cDNA cloning from limited amounts of biological material.

PMID- 8660555
TI  - Processed pseudogenes interfere with reverse transcriptase-polymerase chain
      reaction controls.

PMID- 8660556
TI  - An S1 nuclease mapping method for detection of low abundance transcripts.

PMID- 8660557
TI  - Vectors for expression of protein-A-tagged proteins in vertebrate cells.

PMID- 8660558
TI  - Measurement and Manipulation of Intracellular Ions, Volume 27, Methods in
      Neurosciences. Edited by Jacob Kraicer and S. Jeffrey Dixon

PMID- 8660559
TI  - Methods in Enzymology, Volume 253, Adhesion of Microbial Pathogens. Edited by Ron
      J. Doyle and Itzhak Ofek

PMID- 8660560
TI  - Methods in Enzymology, Volume 254, Oncogene Techniques. Edited by Peter K. Vogt
      and Inder M. Verma

PMID- 8660561
TI  - A highly selective assay for neutral endopeptidase based on the cleavage of a
      fluorogenic substrate related to Leu-enkephalin.
AB  - An intramolecularly quenched fluorogenic peptide structurally related to Leu
      enkephalin, containing o-aminobenzoyl (Abz) and ethylenediamine 2,4-dinitrophenyl
      (EDDnp) groups at amino- and carboxyl-terminal amino acid residues, Abz-Gly-Gly-D
      Phe-Leu-Arg-Arg-Val-EDDnp (Abz-GGDFLRRV-EDDnp), was selectively hydrolyzed at the
      Arg-Val bond by neutral endopeptidase (NEP, enkephalinase, neprilysin, EC
      3.4.24.11) with kinetic parameters (Km = 3 microM, kcat = 127 min-1 and
      kcatsolidusKm = 42 min-1 microM-1) similar to those of the Leu-enkephalin. The
      specificity of the NEP assay was demonstrated by incubating Abz-GGDFLRRV-EDDnp
      with a kidney homogenate or with crude membrane preparations of brain and lung:
      more than 95% of all products released were the complementary fragments Abz
      GGDFLRR and V-EDDnp which were totally inhibited by 1 microM thiorphan, a highly
      specific NEP inhibitor. The blocked amino- and carboxyl-terminal amino acids
      protected this substrate against the action of aminopeptidases as well as of
      carboxypeptidases. Furthermore, D-Phe amino acid also ensured a very good
      protection of Abz-GGDFLRRV-EDDnp against the action of other tissue
      endopeptidases distinct from NEP. A continuous fluorometric assay for only 5 min
      was sufficient to quantify the NEP activity with a minimum sensitivity of 5 ng of
      purified enzyme or the equivalent enzymatic activity in crude tissue
      preparations. Therefore, amounts as little as 0.5 ng of enzyme could be
      quantified employing longer times of incubation.

PMID- 8660562
TI  - Analysis of ligase chain reaction products via matrix-assisted laser
      desorption/ionization time-of-flight-mass spectrometry.
AB  - A rapid and accurate detection of ligation products generated in ligase chain
      reactions (LCR) by using matrix-assisted laser desorption/ionization time-of
      flight-mass spectrometry (MALDI-TOF-MS) is reported. LCR with Pfu DNA ligase was
      performed with a wild-type template and a template carrying a single point
      mutation within the Escherichia coli lacI gene as a model system. Starting from
      about 1 fmol of template DNA the ligation product generated in the positive
      reactions was analyzed with HPLC and MALDI-TOF-MS, whereby the need of proper
      sample purification prior to mass spectrometric analysis was demonstrated. A
      purification procedure with a high potential for automation using streptavidin
      coated magnetic particles and ultrafiltration was introduced. Plasmid DNA and
      short single-stranded oligonucleotides have been used as template. A point
      mutation could be discriminated from the wild-type template due to the absence or
      presence of ligation product. This approach allows the rapid-specific detection
      of template DNA in femtomole amounts and moreover can distinguish between
      sequence variations in DNA molecules down to point mutations without the need for
      labeling, gel electrophoresis, membrane transfer, or hybridization procedures.

PMID- 8660563
TI  - A newly developed procedure for monitoring of extracellular proteins using a push
      pull microdialysis.
AB  - A microdialysis technique combined with a push-pull pump was applied for
      monitoring protein dynamics in the liver. A newly developed probe has a 0.34 x 10
      mm (membrane thickness, 0.05 mm) dialysis membrane of polysulfon and can allow
      the passage of molecules of up to approximately a few hundred kilodaltons in
      molecular weight. The probe was inserted in the liver of a rat under
      pentobarbital anesthesia. Perfusion medium (phosphate-buffered saline) was pumped
      through the microdialysis probe and collected every 15 min. Effect of ischemic
      treatment of the protein constitution and the activity of lactate dehydrogenase
      (LDH) in dialysate were determined to confirm the accuracy of the present
      technique. The protein constitute in preischemic dialysate differed from those
      obtained in the serum and hepatic homogenate, showing that the dialysate
      reflected extracellular protein. LDH activity was high immediately after
      insertion of the probe, decreased constantly, and then reached a plateau of a
      relatively low level. When transit ischemic treatment (for 15 min) was performed
      by ligation of both hepatic artery and portal vein, LDH activity increased
      significantly, which continued for over 5 h. The concentration of albumin in the
      dialysate increased immediately after the ischemia. Such changes in LDH activity
      and albumin concentration reflected ischemic change, and the newly developed
      technique may be useful for the monitoring of extracellular dynamics of proteins
      with molecular weight less than 200 kDa.

PMID- 8660564
TI  - An assay for lectin activity using microtiter plate with chemically immobilized
      carbohydrates.
AB  - A simple microtiter plate assay for lectins or carbohydrate-binding proteins was
      developed. The method utilizes carbohydrates immobilized in the wells of the
      microtiter plate containing primary amino groups on their surface. After
      incubation of the lectins, bound proteins are measured by the protein assay using
      the colloidal gold solution. When the binding of Ricinus communis agglutinin,
      concanavalin A, and wheat germ agglutinin was measured using the microtiter plate
      wells coated with lactose, mannose, or N-acetylglucosamine, binding of the
      lectins according to their known specificity was observed. Inhibition experiments
      with various carbohydrates also demonstrated that the specificity of lectins for
      different carbohydrates could be determined quantitatively. Since there is no
      need for modification of the lectins, such as biotinylation or conjugation with
      marker enzymes, the carbohydrate-binding ability of intact proteins can be easily
      determined by this method. When gel filtration fractions from the extract of the
      marine invertebrate Cucumaria echinata were subjected to this assay, different
      carbohydrate-binding activities were observed with different elution profiles,
      suggesting that this assay could also be widely applicable for the simultaneous
      detection of lectins from various sources.

PMID- 8660565
TI  - 5-Nitrosothio-2-nitrobenzoate: a reagent for the nitrosation of thiol groups in
      proteins.
AB  - The S-nitroso derivative of 5-thio-2-nitrobenzoate was synthesized from 5,5'
      dithiobis(2-nitrobenzoic acid) and partially characterized. Although relatively
      unstable, it is easy to prepare and reacts very rapidly with thiols and thiol
      groups of proteins to give corresponding S-nitrosothiols and 5-thio-2
      nitrobenzoate dianion. The latter's easy spectrophotometric detection makes such
      reactions easy to follow and to quantitate.

PMID- 8660566
TI  - Detection of protein kinase activities toward oligopeptides in sodium dodecyl
      sulfate-polyacrylamide gel.
AB  - In the previous paper, we reported a sensitive method for detection of protein
      kinase activities in gels after SDS-polyacrylamide gel electrophoresis
      (Kameshita, I., and Fujisawa, H. (1989) Anal. Biochem. 183, 139-143). This method
      is useful for the detection of various protein kinase activities toward protein
      substrates included in gels, but inapplicable to oligopeptide substrates because
      most of the oligopeptides eluted from the gel matrix during electrophoresis. The
      present study describes a new procedure for the detection of protein kinase
      activities toward synthetic oligopeptides in the gel. The oligopeptides which
      were linked to amino acid polymers such as poly-L-lysine through their amino
      terminal cysteinyl residue by a heterobifunctional reagent were efficiently
      retained in the gel matrix and served as substrates for the protein kinases. As
      little as 2.5 pg of the catalytic subunit of cAMP-dependent protein kinase was
      detected by this in-gel assay method using a synthetic peptide as a substrate.
      This technique can be used for selective and sensitive detection of various
      protein kinases in crude tissue extracts.

PMID- 8660567
TI  - A quantitative method of determining initial amounts of DNA by polymerase chain
      reaction cycle titration using digital imaging and a novel DNA stain.
AB  - A new nonradioactive method is described for quantitative determination of small
      amounts of DNA by PCR, examplified with mitochondrial DNA. The method represents
      a combination of serial dilution PCR and kinetic PCR and avoids the use of
      radioactivity by applying the fluorescent dye SYBR Green I, allowing
      visualization of PCR amplified bands on agarose gels in a broad exponential range
      of PCR cycles. After recording agarose gel images with a video camera in a
      computer, the band intensities are processed with the NIH image program and
      analyzed by a new graphical method. This nonradioactive method allows calculation
      of small original amounts of specific DNA in samples at high accuracy.

PMID- 8660568
TI  - Activity and molecular weight of protein tyrosine phosphatases in cell lysates
      determined by renaturation after gel electrophoresis.
AB  - A procedure for renaturing and detecting the activity of protein tyrosine
      phosphatases (PTPases) after sodium dodecyl sulfate (SDS)-gel electrophoresis
      with greatly improved sensitivity and resolution is described. Epidermal growth
      factor receptor-kinase, c-src kinase, and focal adhesion kinase were
      phosphorylated on tyrosine with 32PO4 and incorporated into gels prior to
      electrophoresis. These proteins are dephosphorylated when cellular proteins are
      electrophoresed and the separated PTPases are renatured in the gel by removing
      SDS with extensive washing. With whole cell lysates, at least eight separate
      bands of decreased radioactivity corresponding to PTPase activity with molecular
      weights between 110 and 34 kDa are seen in autoradiographs of the dried gels.
      PTPases detected are similar with different cell types and with the three 32P
      labeled protein substrates, although they are different in cytosolic and membrane
      associated fractions. A PTPase detected above 200 kDa in wheat germ agglutinin
      eluates from solubilized cells suggests that some receptor PTPases can be
      renatured. While microgram levels of recombinant PTP-1C are required for
      detection, nanogram levels of recombinant PTP-1B are easily detected. Assaying
      the activity of renatured PTPases after they have been separated by molecular
      weight in SDS gel electrophoresis provides a simple and rapid means of
      determining the activity of individual PTPases in cell fractions.

PMID- 8660569
TI  - Synthetic peptide substrates for a conductimetric assay of Pseudomonas aeruginosa
      elastase.
AB  - Pseudomonas aeruginosa is a zinc metalloprotease which may be involved in many
      infection processes, especially in the lung. In order to evaluate the production
      of the enzyme in culture supernatants, we developed an assay using peptide
      derivatives; the conductimetric method was used for monitoring the enzymatic
      activities. Tetrapeptide derivatives were enzymatically synthesized by coupling Z
      Ala2 and X-AlaR using either thermolysin or P. aeruginosa elastase itself. In
      these substrates, X could be phenylalanine, tyrosine, or leucine and C-protection
      was performed by either an amide (NH2) or a methyl (OMe) group. Z-Ala2-Phe-AlaNH2
      was found to be the best substrate, giving a catalytic ratio kcat/KM of 8600 mM
      1.s-1. The evaluation of the alkaline protease activity with this substrate
      showed that the catalytic ratio is 1000-fold lower. The sensitivity of the
      conductimetric method was also demonstrated with as little as 1 nM elastase (0.13
      microgram), being easily and accurately detected (SD, 3.8% for 10 measurements).
      Furthermore, the enzymatic activity was measured in a culture supernatant from a
      clinical strain.

PMID- 8660570
TI  - A colorimetric assay for estimation of polyethylene glycol and polyethylene
      glycolated protein using ammonium ferrothiocyanate.
AB  - A colorimetric method for quantitative assay of polyethylene glycol (PEG)
      described here is based on partitioning of a chromophore present in ammonium
      ferrothiocyanate reagent from an aqueous to a chloroform phase in the presence of
      PEG. The method is simple, reproducible, and can detect PEG in amounts as low as
      5 microg. It gives a linear response over a range of 5-100 microg. The absence of
      any interference by proteins makes the assay equally suitable for the estimation
      of PEG in PEG-protein conjugates. The method was employed to monitor the
      separation profile of a mixture of free and PEG-5000 coupled to bovine serum
      albumin during purification through a gel filtration column. In this report we
      have also demonstrated for the first time an assay method which permits a
      critical evaluation of pharmacokinetic properties of any PEG-protein conjugate
      under in vivo conditions.

PMID- 8660571
TI  - Further observations on the measurement of fatty acid incorporation by
      erythrocyte ghosts to quantify unbound palmitate concentration in albumin
      palmitate mixtures.
AB  - Advantage has been taken of the extensive and reversible incorporation of long
      chain fatty acids by erythrocyte ghosts to characterize the interaction of
      tritium-labeled palmitic acid with human serum albumin (pH 7.4, 37 degrees C). A
      stoichiometric binding constant for 1:1 complex formation (K1) of 4.6 (+/-0.3) x
      10(8) M-1 was obtained from experiments in which erythrocyte ghosts were the
      source of fatty acid. An essentially identical estimate of 4.1 (+/-0.7) x 10(8) M
      1 was obtained from a second series of experiments in which the [3H]palmitate was
      included with the albumin in the aqueous phase. The magnitude of the present K1
      estimate, which is three- to fivefold larger than most recently reported values,
      reflects binding measurements restricted to a very limited range of unbound
      palmitate concentration (-0.2 nM) to ensure that the ligand is essentially
      monomeric. This use of erythrocyte ghosts to quantify the palmitate-albumin
      interaction has reinforced the basic tenets of a published procedure [I. N.
      Bojesen, and E. Bojesen (1992) J. Lipid Res. 33, 1327-1334], the major virtue of
      which is its ability to provide a direct measure of the equilibrium concentration
      of unbound fatty acid in albumin-palmitate mixtures.

PMID- 8660572
TI  - Synthetic depsipeptide substrates for the assay of human hepatitis C virus
      protease.
AB  - Hepatitis C virus (HCV) is the major etiological agent of both parenterally
      transmitted and sporadic non-A, non-B hepatitis. The disease is a major health
      problem with an estimated 50 million people infected worldwide, a high percentage
      of whom become chronically infected and are at high risk for liver cirrhosis. The
      serine protease contained within the N-terminal region of the nonstructural
      protein 3 (NS3 protease) of HCV is considered a promising target for the
      development of an antiviral therapy. A prime requisite to study in detail the
      biochemistry of the protease as well as develop inhibitors is the availability of
      a fast and sensitive in vitro assay of enzyme activity. However, due to their low
      kcat/Km values, synthetic peptide substrates based on the natural cleavage sites
      appear unsuitable for this purpose. We show here that appropriate substrates can
      be obtained by substituting the scissile amide bond with an ester linkage. The
      resulting depsipeptides show >100-fold improvement in kcat/Km values, up to
      13,000 M-1 s-1, enabling detection of activity with subnanomolar NS3
      concentrations. The ester substrates are obtained in high yield entirely by solid
      phase synthesis using commercially available materials, without the need for any
      preassembled building blocks.(c) 1996 Academic Press, Inc.

PMID- 8660573
TI  - Electrophoretic mobility shift assay identifies vitamin D binding protein (Gc
      globulin) in human, rat, and mouse sera.
AB  - Serum vitamin D binding protein (DBP, also known as Gc-globulin) is a
      multifunctional protein capable of binding both vitamin D metabolites and actin.
      DBP can be visualized when analyzed by polyacrylamide gel electrophoresis
      followed by staining. Confirmation of its identity had previously required
      immunoprecipitation with specific anti-DBP antisera or occupancy of the protein
      with radioactive vitamin D sterols. We present studies showing that preincubation
      of G-actin with mammalian sera produced a discernible DBP protein band shift on
      native gel electrophoresis. Addition of DNaseI, a 33-kDa intracellular protein
      with an avid actin-binding site, to the incubations resulted in a supershift of
      DBP-actin complexes to an even more cathodal region of the gels. Following
      incubations with human, rat, and murine sera the same actin shift occurred as did
      the actin plus DNaseI supershift. The migrations of each complex were correlated
      with purified DBP migrations under identical conditions. It was confirmed that
      the supershifted bands contained DBP by Western blotting and detection of DBP by
      binding of 25-OH[3H]D3. After intravenous G-actin injections into living mice, a
      serum DBP-actin complex could be detected on native gels as the uncomplexed DBP
      band decreased in intensity. This simple, direct-staining technique appears to be
      suitable for identifying DBP/Gc phenotypes in human populations as well as for
      semiquantitatively monitoring the plasma actin-scavenger system in vivo in animal
      models or in human diseases.

PMID- 8660574
TI  - Oriented binding of a lipid-anchored cell adhesion protein onto a biosensor
      surface using hydrophobic immobilization and photoactive crosslinking.
AB  - The carboxymethyl-dextran surface of a biosensor instrument was modified to
      couple, in an active state, the lipid-anchored contact site A (csA) glycoprotein,
      a homophilic adhesion molecule of aggregating cells of Dictyostelium discoideum.
      The carboxy groups were modified by heptyl residues for hydrophobic binding of
      the molecule with its lipid anchor to the dextran matrix. Alternatively, the
      protein was fixed in a similar orientation by covalent linkage through a
      perfluorophenylazide-derived hydrophobic crosslinker. Titration of the bound csA
      molecules with antibodies that recognize either the native or the denatured
      glycoprotein verified that the csA molecules were coupled in a native state to
      the sensor surface. Interaction of the immobilized csA protein with csA in
      solution established that the bound molecules are capable of taking part in
      homophilic interactions.

PMID- 8660575
TI  - Program DYNAFIT for the analysis of enzyme kinetic data: application to HIV
      proteinase.
AB  - A computer program with the code name DYNAFIT was developed for fitting either
      the initial velocities or the time course of enzyme reactions to an arbitrary
      molecular mechanism represented symbolically by a set of chemical equations.
      Seven numerical tests and five graphical tests are applied to judge the goodness
      of fit. Experimental data on the inhibition of the dissociative dimeric
      proteinase from HIV were used in four test examples. A set of initial velocities
      was analyzed to see if a tight-binding inhibitor could bind to the HIV proteinase
      monomer. Three different sets of progress curves were analyzed (i) to determine
      the kinetic properties of an irreversible inhibitor, (ii) to investigate the
      dissociation and denaturation mechanism for the protease dimer, and (iii) to
      investigate the inhibition mechanism for a transient inhibitor. The program is
      available by anonymous ftp via uwmml.pharmacy.wisc.edu and on the World Wide Web
      via http://uwmml.pharmacy.wisc.edu.

PMID- 8660576
TI  - Spectroscopic determination of cytochrome c oxidase content in tissues containing
      myoglobin or hemoglobin.
AB  - A simple spectroscopic method for determining the cytochrome c oxidase,
      cytochrome a, a3, content in tissue and mitochondria samples independent of
      myoglobin or blood contamination is described. Using tissue homogenates
      solubilized in Triton X-100, this assay relies on the selective reduction of
      mitochondrial cytochromes by the action of potassium cyanide. Monitoring the
      optical absorbance of these samples at 605 nm provided a quantitative
      determination of cytochrome c oxidase content in the presence of myoglobin or
      blood. The cytochrome c oxidase content of porcine heart mitochondria and whole
      tissue was determined to be 0.85 nmol/mg protein and 30.5 nmol/g wet wt,
      respectively.

PMID- 8660577
TI  - Filamentous phage display of oligopeptide libraries.

PMID- 8660578
TI  - Entrapment by immobilized metal ion affinity chromatography of assembled yeast
      mitochondrial ATP synthase containing individual subunits tagged with
      hexahistidine.
AB  - We demonstrate the use of immobilized metal ion affinity chromatography for
      isolating the constituent subunits of assembled mitochondrial ATP synthase
      (mtATPase) wherein a single subunit of the complex has been modified to contain
      hexahistidine. Genes encoding subunit d or OSCP of mtATPase from Saccharomyces
      cerevisiae were modified each to encode a polypeptide having a C-terminal
      addition of six consecutive histidines. Expression of plasmid-borne modified
      genes, in host yeast cells lacking a functional copy of the relevant endogenous
      gene, generated functional mtATPase complexes as judged by growth of rescued
      cells on the nonfermentable substrate ethanol. Significantly, the oligomycin
      sensitive ATP hydrolase activity in mitochondria from cells expressing tagged
      subunits was similar to that of cells expressing unmodified subunits, indicating
      that there had been no impairment of the functional integrity of mtATPase.
      Mitochondrial lysates were prepared from each strain and subjected to
      chromatography under nondenaturing conditions on a resin containing immobilized
      Ni2+. It is likely that the mtATPase complexes adsorbed by immobilized metal ion
      affinity chromatography are fully assembled because their subunit composition
      closely matches that of a preparation of assembled mtATPase conventionally
      isolated from mitochondrial lysates by ammonium sulfate precipitation and
      purification by sucrose gradient centrifugation. Furthermore, assembled mtATPase
      containing a tagged subunit could be adsorbed, albeit at lower yield, when the
      relevant modified gene was expressed in wild-type host cells. The general
      application of this novel isolation procedure greatly simplifies and reduces the
      number of steps required for the isolation of assembled multi-subunit complexes.
      Moreover, the approach may be used for studying subunit-subunit interactions
      within the mtATPase complex.

PMID- 8660579
TI  - Sequencing oligonucleotides by exonuclease digestion and delayed extraction
      matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
AB  - A protocol was developed for sequencing oligonucleotides by matrix-assisted laser
      desorption ionization time-of-flight (MALDI-TOF) mass spectrometry.
      Oligonucleotides were partially hydrolyzed in separate time-course digestions
      with 3' --> 5' and 5' --> 3' acting phosphodiesterases in a MALDI-compatible
      buffer or in the MALDI matrix itself. The partial digests were analyzed by MALDI
      TOF mass spectrometry employing an instrument equipped with delayed ion
      extraction and the sequence was inferred from the mass differences between
      adjacent peaks. Resolution, mass accuracy, and sensitivity were considerably
      enhanced with delayed extraction, in comparison with the standard MALDI
      technique. Much longer lengths of DNA can be unambiguously sequenced with delayed
      extraction MALDI compared with standard MALDI-MS.

PMID- 8660580
TI  - Assay for in vivo yeast invertase activity using NaF.
AB  - The methods used for invertase activity determination are based on the
      measurement of glucose or reducing sugars produced by the enzymatic hydrolysis of
      sucrose into glucose and fructose. When whole yeast cells are used in these
      assays, the monosaccharides formed by the action of the periplasmic enzyme can be
      taken up and metabolized, leading to errors on the enzyme activity determination.
      This study reports a method for a more accurate invertase activity measurement by
      blocking the glycolytic pathway. In this method the cells were preincubated with
      50 mM sodium fluoride, and inhibitor of enolase. This in vivo measurement of the
      enzyme activity, under initial rate conditions, was performed using cell
      concentrations up to 64 mg cell/ml. The results obtained showed that this method
      is particularly useful for cells with low invertase activity.

PMID- 8660581
TI  - Sensitive method for the determination of pulmonary surfactant
      phospholipid/sphingomyelin ratio in human amniotic fluids for the diagnosis of
      respiratory distress syndrome by thin-layer chromatography-immunostaining.
AB  - By TLC-immunostaining with the monoclonal antibody VJ-41, which preferentially
      reacted with sphingomyelin (Sm) and disaturated fatty acid-containing
      phosphatidyl choline (DSPC), Sm and surfactant phospholipid dipalmitoyl PC were
      only detected in the lipid extracts from human amniotic fluid. The method was
      useful in the selective and simultaneous determination of surfactant phospholipid
      and Sm concentrations in the amniotic fluids to determine the level of maturity
      of the lungs of the fetus. By measuring the density of spots visualized by TLC
      immunostaining, we detected Sm at a sensitivity two times higher than that for
      dipalmitoyl PC using the antibody. More than 50 ng of dipalmitoyl PC and Sm was
      detected on the same TLC plate and the standard curves were linear up to 1
      microgram of phospholipids. The method was applied to determine the surfactant
      phospholipid/Sm ratio in 20 microliter of the amniotic fluids obtained at
      delivery, and the amniotic fluids from the women who delivered a baby suffering
      from respiratory distress syndrome (RDS) were easily discriminated from the
      normal amniotic fluids. In an analysis of 200 microliter of amniotic fluids from
      4 RDS cases and 16 normal baby cases, the mean DSPC/Sm ratios were 0.97 +/- 0.53
      and 5.75 +/- 1.29, respectively.

PMID- 8660582
TI  - Simultaneous determination of adenosine, inosine, hypoxanthine, xanthine, and
      uric acid in microdialysis samples using microbore column high-performance liquid
      chromatography with a diode array detector.
AB  - In the myocardial interstitial space, adenosine and its metabolites are important
      markers of ischemia, regulators of blood flow, and may produce cardioprotection
      against ischemia. A fast and sensitive method to assess the concentrations of
      adenosine and its metabolites is necessary to determine their involvement in
      mediating these effects. A method for the simultaneous determination of
      adenosine, inosine, hypoxanthine, xanthine, and uric acid in the interstitial
      fluid of the canine myocardium was developed using microdialysis, microbore
      column high-performance liquid chromatography, and a photo diode array detector
      (DAD). The microdialysis samples were injected directly onto a microbore C18
      reverse-phase column without any prior sample preparation. Use of a DAD in this
      method provided many advantages. First, a DAD allowed the simultaneous detection
      of UV absorbance at multiple wavelengths, allowing the detection of each compound
      at their maximal UV absorbance. Further, the full UV absorption spectrum was
      recorded for each detected peak, confirming peak purity and identity. Using a
      microbore HPLC column and detection of UV absorbance at the maximal absorbance
      for each compound improve the sensitivity for all compounds. The detection limit
      of these compounds is 50 fmol (signal-to-noise ratio, S/N = 3). This method is
      useful in analyzing the temporal effect of a prolonged period of myocardial
      ischemia and reperfusion upon interstitial adenosine, inosine, hypoxanthine,
      xanthine, and uric acid concentrations in an in vivo canine model.

PMID- 8660583
TI  - High-performance liquid chromatographic determination of anandamide amidase
      activity in rat brain microsomes.
AB  - A rapid, sensitive, and reliable method for measuring anandamide amidase activity
      in rat brain microsomes by reversed-phase high-performance liquid chromatography
      (RP-HPLC) and its applications are described. Enzymatic activity was assayed by
      the determination of the rates of hydrolysis of anandamide or its analogs at 37
      degrees C. The reaction products were separated using an ODS guard column eluted
      with aqueous phosphoric acid-acetonitrile and quantitated with uv detection at
      204 nm and an external standard method. Baseline separation of the acid products
      from their substrates was completed in less than 2 min. The detection limits were
      1.4 pmol for arachidonic acid and 0.22 pmol for anandamide at a signal to noise
      ratio of 4:1. The stability of anandamide in the acidic mobile phase was tested,
      and no significant decomposition was observed up to 1 h. The method was
      successfully applied to the examination of substrate specificity as well as for
      testing the ability of amidase inhibitors to block its hydrolysis. Kinetic
      constants obtained for (S)-methanandamide were an apparent Km of 8.6 +/- 1.3
      microM and a Vmax of 362 +/- 16 pmol/min/mg of protein. A highly potent
      inhibitor, palmitylsulfonyl fluoride (PSF), was found to have an IC50 of 50 nM.
      PSF is 210 times as potent as phenylmethylsulfonyl fluoride. The method offers
      several advantages over existing methodology using radioisotopes or a solvent
      extraction procedure.

PMID- 8660584
TI  - Spectrophotometric assay for processes involving changes in hydrogen ion
      concentration in aqueous solution.
AB  - A strategy for the design of simple colorimetric assays to follow any process
      that involves the net generation or consumption of hydrogen ions in aqueous
      solutions over the pH range of 3-10 is described. This procedure relies upon the
      measurement of the change in absorption when a weakly or moderately buffered
      solution of a pH indicator is subjected to a small change in pH. Buffers and
      indicators are chosen with closely matching pKa values. The versatility of this
      type of assay technique is illustrated using three examples.

PMID- 8660585
TI  - Upside-down stopped-flow electrofractionation of complex protein mixtures.
AB  - The excellent resolution of SDS-PAGE in protein analysis stimulated the creation
      of various preparative devices. The main approach used in these devices is the
      construction of a elution chamber in the lower end of the polyacrylamide gel
      cylinder or plate. Although this continuous lower buffer flow
      electrofractionation system serves as an acceptable preparative electrophoresis,
      some limitations to this approach exist. There is strong dilution of protein
      zones by the eluting buffer, which drastically restricts the sensitivity of the
      determination of minor proteins, and the restricted current flow caused by
      electric resistance arising from the column holder prevents application to
      purification of complex protein mixtures. To overcome these problems, the upside
      down stopped-flow electrofractionation system (UDSFE) was designed. The necessary
      quantity of fraction is drawn with a pipet in a small volume from just above the
      gel cylinder. This invention improves the possibility of electrofractionation of
      deluted complex protein mixtures. The efficiency of this technique is
      demonstrated by purification a protein kinase from rat liver. The method has also
      been successfully used for purification of error-correcting 3'-5' exonuclease.

PMID- 8660586
TI  - Classification of sugar chains of glycoproteins by analyzing reducing end
      oligosaccharides obtained by partial acid hydrolysis.
AB  - Sugar chain types were classified on the basis of reducing end di- and
      trisaccharide structures. Sugar chains liberated from glycoproteins by the
      hydrazinolysis-N-acetylation method were pyridylaminated, and pyridylamino (PA-)
      sugar chains were purified by HPLC. The PA-sugar chains thus purified were
      partially hydrolyzed with 1 M trifluoroacetic acid. The acid hydrolysis
      conditions were investigated with the object of obtaining PA-di- and
      trisaccharides with high yields for different types of PA-sugar chains. The acid
      hydrolysates were separated by size-fractionation HPLC into PA-mono-, PA-di-, and
      PA-trisaccharides, and each fraction was analyzed by reversed-phase HPLC. The
      structures were then identified by comparing the HPLC elution positions with
      those of authentic PA-oligosaccharides derived from N-linked sugar chains and 12
      types of O-linked sugar chains.

PMID- 8660587
TI  - Ultramicro-analysis by use of light-scanning photoacoustic densitometry for
      electrophoresed protein in human hair.
AB  - A technique was developed for the ultramicro-analysis of proteins electrophoresed
      by Laemmli's method using a light-scanning photoacoustic densitometer. After
      electrophoresis, the proteins were blotted on a nitrocellulose membrane filter
      and colored by the avidin-biotin complex method. This filter was then measured
      using a photoacoustic densitometer. The optimal blotting time was 150 min. The
      relative standard deviation of four measurements was 3.89% for 200 ng bovine
      serum albumin (BSA). The limits of detection were 2.3, 0.69, 4.4, and 2.9 ng (S/N
      = 3) for BSA, ovalbumin, carbonic anhydrase, and alpha-Lactoalbum respectively.
      Proteins eluted from hair by various harmful agents, such as a surfactant and UV
      irradiation, were analyzed by the present method. Using 2-mercaptoethanol, the
      molecular weights of proteins in hair were in the range of 14,000-64,000. Maximal
      elution of protein was obtained at pH 8. More protein was eluted under alkaline
      conditions than under acidic conditions. A protein of Mr 68,000 was eluted from
      hair by oxidative treatment with either UV irradiation or sodium bromate.

PMID- 8660588
TI  - Coupled enzymatic assay for estimation of branched-chain L-amino acid
      aminotransferase activity with 2-Oxo acid substrates.
AB  - A convenient continuous spectrophotometric assay for estimation of branched-chain
      L-amino acid aminotransferase activity was established: Branched-chain 2-oxo acid
      dependent transamination of L-glutamate was coupled-via 2-oxoglutarate-to L
      aspartate aminotransferase plus L-malate dehydrogenase or to L-alanine
      aminotransferase plus L-lactate dehydrogenase as indicator systems. The rate of
      transamination can be monitored specifically by measuring the decrease in NADH
      absorbance at 334 nm over time. The method was applied, e.g., for evaluation of
      some kinetic properties of the rat heart (iso)enzyme.

PMID- 8660589
TI  - Assay for tyrosine hydroxylation activity of tyrosinase from betalain-forming
      plants and cell cultures.
AB  - In our studies on tyrosinase-catalyzed tyrosine hydroxylation, possibly involved
      in betalain biosynthesis, we have evaluated different assays for the detection
      and quantification of the enzymatic product Dopa with respect to sensitivity,
      simplicity, and suitability for automatization. A tyrosinase assay including
      reversed-phase high-performance liquid chromatography with isocratic elution and
      fluorescence detection has been developed (native fluorescence of Dopa;
      excitation at 281 nm, emission at 314 nm). This improved assay was sensitive
      (detection limit: 2 pmol Dopa) and showed a wide linear range of Dopa detection
      (10 pmol-20 nmol Dopa). The method proved to be suitable for high-performance
      liquid chromatography with an autosampler and has been applied for measuring
      tyrosinase activity of cell cultures and different tissues of Portulaca
      grandiflora.

PMID- 8660590
TI  - Real-time monitoring of reduced beta-adrenergic response in fibroblasts from
      patients with pseudohypoparathyroidism.
AB  - The activation of cell-surface receptors usually produces a transient increase of
      the extracellular acidification rate in culture cells that can be detected with a
      biosensor-based instrument. We describe here the application of this method in
      monitoring hormonal response of Galphas-deficient fibroblasts from patients with
      pseudohypoparathyroidism type Ia (PHP-Ia). We found that following exposure to
      isoproterenol, the mean acidification response of fibroblasts from four PHP-Ia
      patients was only 18% of the response in normal cells. In contrast, these two
      groups of fibroblasts had similar levels of response to insulin and dibutyryl
      cAMP. This is the first reported experimental evidence correlating reduced
      Galphas activity with diminished cellular responsiveness to hormones in cultured
      living cells. Our results also indicate that this approach will be useful for
      rapid screening of other metabolic diseases caused by abnormal cellular
      signaling.

PMID- 8660591
TI  - On-the-probe sample cleanup strategies for glycoprotein-released carbohydrates
      prior to matrix-assisted laser desorption-ionization time-of-flight mass
      spectrometry.
AB  - On-the-probe sample cleanup strategies were developed for matrix-assisted laser
      desorption-ionization (MALDI) time-of-flight mass spectrometry to improve the
      mass spectral characteristics of glycoprotein-released carbohydrate samples,
      including those fractionated by high pH anion exchange (HPAE) chromatography or
      treated with glycosidases. Small in situ amounts of chromatographic media are
      codeposited with matrix onto a probe containing a carbohydrate sample to minimize
      interferences from cations, anions, and/or detergents introduced from the sample
      and/or matrix. On-the-probe sample cleanup is fast (a few minutes) and operates
      best on picomole quantities of analyte in sample volumes less than 5 microliter
      containing nanomole quantities or less of impurities. This in situ cleanup
      dramatically increases the mass spectral signal-to-background, improves mass
      accuracies, better equalizes the sensitivities for diverse carbohydrate
      structures, and has the potential to remove contaminants that bypassed previous
      purification schemes. Direct MALDI mass profiling of digest aliquots containing
      low picomole amounts of carbohydrate structures either enzymatically released
      from a glycoprotein or sequentially degraded with multiple glycosidases was
      performed using only microscale digest conditions with reduced buffer amounts and
      on-the-probe sample cleanup to minimize the digest impurities. Membrane
      microdialysis was compared to on-the-probe sample cleanup and found to more
      completely remove the nano- to micromole amounts of anions (and cations) in HPAE
      fractions in one step as opposed to multiple on-the-probe steps.

PMID- 8660592
TI  - Resolution of all four transferrin isoforms produced during the iron binding
      process using multizone electrophoresis.

PMID- 8660593
TI  - In situ microassay of ornithine decarboxylase.

PMID- 8660595
TI  - An alternative to digoxigenin-labeled primers for manual nonradioactive
      sequencing allows reading of more than 700 bases.

PMID- 8660594
TI  - Phosphoamino acid analysis by semidry electrophoresis on cellulose thin-layer
      plates using the Pharmacia/LKB Multiphor or Atto flatbed apparatus.

PMID- 8660597
TI  - Antibody Applications: Essential Techniques. By P. J. Delves. Wiley, New York,
      1996. $23.95.

PMID- 8660596
TI  - Quantification of hydrophobic insoluble peptide-protein interaction using peptide
      resin adduct.

PMID- 8660599
TI  - Evaluation of phenotypic alteration by microcell-mediated chromosome transfer.

PMID- 8660598
TI  - Methods in Enzymology, Volume 263, Plasma Lipoproteins, Part C, Quantitation.
      Edited by William A. Bradley, Sandra H. Gianturco, and Jere P. Segrest. Academic
      Press, San Diego, 1995. 373 pp., $80.00.

PMID- 8660600
TI  - Analysis of carotenoids and carotenol fatty acid esters by matrix-assisted laser
      desorption ionization (MALDI) and MALDI-post-source-decay mass spectrometry.
AB  - Matrix-assisted laser desorption ionization (MALDI) time-of-flight mass
      spectrometry and MALDI post-source-decay (PSD) fragment ion mass analysis were
      employed to examine various model carotenoids and some of their fatty acid
      esters. It was demonstrated that the use of MALDI helps overcome problems
      resulting from the inherent thermal instability and lack of solubility which
      render this group of compounds rather difficult for conventional ionization
      techniques. Detection limits were in the subpicomolar range. Rather abundant
      metastable fragmentation occurred under conditions of prompt extraction, but was
      significantly restricted under conditions of delayed extraction (DE). In DE the
      quasimolecular ion signals (mainly as odd electron radical ions) became the base
      peak even in spectra of the most delicate fatty acid esters. PSD fragment ion
      patterns were similar to those recorded under linked B/E scanning in conventional
      fast atom bombardment-MS and contained information on structural end group
      substituents such as hydroxyl, epoxide, or carbonyl functions and on the extent
      of double bond conjugations. The mono- and bis-fatty acid esters fragmented
      mainly by simple fatty acid cleavage but also furnished some of the end group
      specific fragments.

PMID- 8660601
TI  - Quantitation of the putative neurotransmitter agmatine as the
      hexafluoroacetylacetonate derivative by stable isotope dilution gas
      chromatography and negative-ion chemical ionization mass spectrometry.
AB  - A method is described for detection and quantitation of agmatine [4
      (aminobutyl)guanidine] by gas chromatography/negative-ion chemical
      ionization/mass spectrometry after derivatization with hexafluoroacetylacetone.
      The lower limit of detection of the derivative was about 25 fmol on-column. For
      quantitative studies of agmatine content in biological samples, a procedure
      utilizing an internal standard ([15N4]agmatine prepared from [15N4]arginine) and
      an extraction step had a lower limit of detection of about 15 pmol for total
      sample content. Agmatine content was measured in rat tissue samples and
      normalized to protein content. Kidney and spleen samples exhibited the greatest
      content of agmatine per unit protein mass but agmatine was also detected in
      pancreatic islets and brain regions (cerebellum and cerebral cortex). On the
      basis of these measurements, it is estimated that the pancreatic islet
      intracellular agmatine concentration may exceed 1 microM. The sensitive and
      highly specific means of detection and quantitation provided by mass spectrometry
      may be useful in investigating the physiological role of agmatine in mammalian
      systems.

PMID- 8660602
TI  - Analysis of hemoglobin derivatives by capillary isoelectric focusing and its
      application in the antidotal research of cyanide poisoning.
AB  - Cyanide toxicity can be reduced by the use of methemoglobin (MetHb) formers, and
      antidotal dosage is based on the extent of MetHb formation. Hemoglobin and
      ferrihemoglobin (MetHb, hemimethemoglobins alpha3+beta2+ and alpha2+beta3+,
      tetracyanmethemoglobin, and dicyanmethemoglobin) concentrations in human, pig,
      and mouse blood were determined after separation by isoelectric focusing with an
      octyl-bonded capillary. The predominant species formed in blood when MetHb
      formers, such as potassium ferricyanide, hydroxylamine, sodium nitrite, and 4
      dimethylaminophenol (DMAP), added at molar ratios ranging from 1:10 to 1:1 to
      hemoglobin, are the valency hybrid intermediates alpha3+beta2+ and alpha2+beta3+.
      In the detoxication of cyanide with methemoglobin, an intermediate
      dicyanhemimethemoglobin was demonstrated to be the predominant species in the
      formation of tetracyanmethemoglobin. Complex mixtures of hemoglobin derivatives
      were observed with DMAP at 1:1 or greater molar ratio to hemoglobin. Comparison
      of the MetHb values obtained with a hemoxometer indicated that the valency
      hybrids were measured as MetHb and the values of oxidized hemoglobin were
      overestimated. In cyanide poisoning, incorrect dosages of MetHb formers could be
      calculated, and misinterpretation of MetHb data would result from methods that
      fail to discriminate among the various species of MetHb.

PMID- 8660603
TI  - The catalysis of redox cycling by pyrroloquinoline quinone (PQQ), PQQ
      derivatives, and isomers and the specificity of inhibitors.
AB  - Pyrroloquinoline quinone (PQQ) is a widely distributed redox-active cofactor and
      essential nutrient. For its detection in protein-free ultrafiltrates or
      dialysates, a highly sensitive amplification assay was developed on the basis of
      PQQ's ability to catalyze redox cycling at pH 10 in the presence of excess
      glycine, oxygen, and nitro blue tetrazolium. Herein, we examine the propensities
      of PQQ, PQQ triester, and its various isomers, and certain PQQ triester
      derivatives, to catalyze glycine-fueled redox cycling and show that PQQ is the
      most capable of catalyzing redox cycling. Furthermore, PQQ has a unique pattern
      of inhibition induced by a series of PQQ antagonists of different potencies. The
      data indicate that putative PQQ from a biological sample, separated by HPLC and
      detected by the glycine-fueled redox-cycling assay, can be further identified as
      PQQ based on the profile of inhibition it displays with the antagonists such as
      those employed in this study. The methodology presented here should facilitate
      the specific detection of PQQ in biological samples.

PMID- 8660604
TI  - Convenient colorimetric and fluorometric assays for S-nitrosothiols.
AB  - S-nitrosothiols have been shown to affect a number of physiological functions.
      Several techniques have been used to detect these species in biological systems,
      primarily by methods utilizing chemiluminescence. Since the apparatus required
      for measurement of chemiluminescence are not readily available in most
      laboratories, methods employing more conventional techniques such as uv-vis and
      fluorescence spectroscopy may be of greater use. Herein, we report the
      development of colorimetric and fluorometric methods for the reliable
      quantitation of S-nitrosothiols. Solutions containing sulfanilamide/N-(1
      naphthyl)- ethylenediamine dihydrochloride or 2,2'-azinobis (3
      ethylbenzthiazoline-6-sulfonic acid), when exposed to S-nitrosoglutathione
      (GSNO), S-nitrosocysteine, or S-nitrosoacteylpenicillamine, resulted in no
      absorbance changes in the range of 400-800 nm. Exposure to HgCl2 or Cu(acetate)2
      resulted in release of nitric oxide (NO) from the S-nitrosothiols. The liberated
      NO reacted subsequently with oxygen and formed a chemical species which reacted
      with either analysis solution, resulting in an increase in absorption between 400
      and 800 nm. A plot of RSNO versus absorbance was linear for both mercury(II) and
      copper(II) ions where the slope in the presence of mercury ion was significantly
      greater than that for copper ion. The sensitivity was as low as 5 microM RSNO
      using HgCl2. The fluorometric method using 2, 3-diaminonaphthalene as the
      scavenger of the NOsolidusO2 products gave a sensitivity of 50 nM for GSNO. In
      addition, S-nitrosylated proteins were quantitated using the fluorometric
      technique. These methods provide accurate determination of low concentrations of
      S-nitrosothiols, utilizing conventional spectroscopic techniques available in
      most laboratories.

PMID- 8660605
TI  - Measurement of the protein tyrosine kinase activity of c-src using time-resolved
      fluorometry of europium chelates.
AB  - A nonradioactive, sensitive assay method to evaluate the activity of protein
      tyrosine kinases is described. This method utilizes europium chelate-labeled anti
      phosphotyrosine antibodies to detect phosphate transfer to a polymeric substrate
      coated onto microtiter plate wells. The amount of phosphorylation is then
      detected using time-resolved, dissociation-enhanced fluorescence. Recombinant c
      src was used to demonstrate that substrate phosphorylation was dependent on
      incubation time, enzyme concentration, and the amount of substrate used to coat
      the microtiter plate wells. A series of proprietary c-src inhibitors was
      evaluated in competition assays, and demonstrated a rank order of potency which
      was identical to that determined by other assay methods. Substrate
      phosphorylation was also demonstrated to be dependent on the concentration of ATP
      present during the kinase reaction. Because the kinase assay can be performed
      with different ATP concentrations (unlike with assays utilizing radioactive ATP
      analogs), the assay described can be used to distinguish compounds that compete
      for the ATP or substrate binding sites of the kinase.

PMID- 8660606
TI  - Energy transfer primers with 5- or 6-carboxyrhodamine-6G as acceptor
      chromophores.
AB  - Energy-transfer (ET) fluorescent primers for DNA sequencing and multiplex genetic
      analysis (Ju, J., Ruan, C., Fuller, C. W., Glazer, A. N., and Mathies, R. A.
      (1995) Proc. Natl. Acad. Sci. USA 92, 4347-4351) are named according to the
      convention D-N-A, where D is the donor, N is the number of bases between the
      donor and the acceptor, and A is the acceptor. Thus, a primer that carries 6
      carboxyfluorescein (FAM) at the 5'-end and 6-carboxy-4', 5'-dichloro-2',7'
      dimethoxyfluorescein (JOE) attached to a modified thymidine 10 bases away is
      designated F10J. We describe here new ET primers, with 5- or 6-carboxyrhodamine
      6G (G5 or G6) as acceptors (with FAM as the donor) in place of JOE, with improved
      match in the electrophoretic mobilities of the DNA fragments extended from the ET
      dye-labeled primers, and less overlap in the fluorescence emission of the various
      labeled DNA fragments. This reduced spectral overlap is most likely due to the
      narrower emission from G5 or G6 in F10G compared to that from JOE in F10J. With
      single-stranded M13mp18 DNA as the template, a typical run with F10G6 and three
      other ET primers on a capillary sequencer provided DNA sequences with 99%
      accuracy in the first 620 bases.

PMID- 8660607
TI  - Method for determination of free intracellular and extracellular methylglyoxal in
      animal cells grown in culture.
AB  - Methylglyoxal is present at low levels in most cells as a by-product of
      glycolysis and a product of lipid and amino acid catabolism. The most widely
      accepted method for measurement of methylglyoxal involves the derivatization of
      methylglyoxal with 1,2-diaminobenzene derivatives, such as o-phenylenediamine,
      followed by quantification of the resulting quinoxaline with high-performance
      liquid chromatography (HPLC). Here we describe the modification of this procedure
      for the measurement of free intra- and extracellular methylglyoxal in animal
      cells grown in culture. Cell harvest and sample volume measurement techniques
      were developed. Solid-phase extraction prior to methylglyoxal derivatization
      reduced interferences unique to cell culture, such as the phenol red indicator
      dye used in most cell culture media, and extended the useful life of the HPLC
      column. In addition, this extraction step significantly lessened the interference
      represented by oxidative degradation of nucleic acids to methylglyoxal by
      perchloric acid under assay conditions. The concentration of free intracellular
      methylglyoxal in Chinese hamster ovary (CHO) cells grown in culture ranged from
      0.7 +/- 0.3 microM (mean +/- 2 standard deviations; n = 4) to 1.2 +/- 0.3 microM
      (mean +/- 2 standard deviations; n = 7). The concentration of free extracellular
      methylglyoxal in the growth medium was 0.07 +/- 0.02 microM (mean +/- 2 standard
      deviations; n = 4), severalfold less than that found inside the cell. A possible
      explanation for the difference between measured free intracellular and
      extracellular methylglyoxal levels is that the assay for free intracellular
      methylglyoxal also measures some reversibly bound methylglyoxal.

PMID- 8660608
TI  - A combined high-performance liquid chromatographic-microbiological assay for
      serum folic acid.
AB  - An assay of folic acid in human serum is described involving HPLC fractionation
      of deproteinized serum prior to Lactobacillus casei assay. High specific activity
      [3H]folic acid is added as internal standard to 1 ml serum prior to
      deproteinization with perchlorate and an aliquot is applied to a C18 reverse
      phase HPLC column. The folic acid fraction was assayed by L. casei microtiter
      plate assay. Intra- and interassay variations (CV) were 5.5 and 7.5% respectively
      for sera (n = 10) spiked with folic acid. The percentage recovery for folic acid
      additions of 10 and 20 ng/liter were 105.2 and 103.7%, respectively. The lower
      limit of detection was 1 ng folic acid/ml serum. Folates other than folic acid
      and 5-methyltetrahydrofolate were not detected. The assay permitted serial
      measurements to be made of folates in serum following an oral dose.

PMID- 8660609
TI  - An E-selectin binding assay based on a polyacrylamide-type glycoconjugate.
AB  - Here we show that biotinylated polyacrylamide-type glycoconjugates which contain
      sialyl Lewis X (sLex-polymer) or sialyl Lewis A (sLea-polymer) are ligands for E
      selectin. sLea-polymer bound E-selectin with higher affinity than sLex-polymer.
      Based on this property we used the sLea-polymer to establish a sensitive cell
      free binding assay for the characterization of E-selectin antagonists. The assay
      involves complexation of the biotinylated sLea-polymer with streptavidin
      peroxidase. This complex is incubated with E-selectin mouse Ckappa fusion protein
      immobilized onto microtiter plates. Bound complex is detected by the peroxidase
      reaction. sLea-polymer bound in a Ca2+-dependent manner consistent with the
      function of E-selectin as a C-type lectin. Control glycoconjugates with sialic
      acid (alpha-Neu5Ac), Lewis A (Lea), or beta-D-glucose residues instead of sLea
      failed to interact with the E-selectin. Neutralizing anti-E-selectin antibodies
      blocked completely binding to E-selectin. This demonstrates specificity of the
      assay system. sLex blocked binding of the sLea-polymer to E-selectin by 50% at a
      concentration of 550 microM (IC50). The assay was used to characterize sLea
      polymers with differing sLea content as multivalent inhibitors of E-selectin
      binding. The inhibitory activity of these polymeric forms of sLea increased with
      their sLea content up to IC50s in the low micromolar range. The binding assay
      described is sensitive, rapid, and simple and of low variability. Therefore it
      should be advantageous for the identification and characterization of novel E
      selectin antagonists.

PMID- 8660610
TI  - Circular dichroism assay for decarboxylation of optically pure amino acids:
      application to ornithine decarboxylase.
AB  - A circular dichroism (CD) assay for decarboxylation of optically pure amino acids
      is described. The viability of this assay is demonstrated using the Trypanosoma
      brucei ornithine decarboxylase (ODC)-catalyzed reaction of L-ornithine to
      putrescine and CO2. The results from the CD assay (kcat of 7.5 +/- 0.7 s-1 and Km
      230 +/- 60 microM) were identical to the results obtained from the commercially
      available dye-linked assay which couples CO2 production with NADH oxidation (kcat
      of 7.3 +/- 0.5 s-1 and Km 320 +/- 30 microM). The CD assay has advantages over
      the currently used 14CO2 and dye-linked assays since it can be continuously
      monitored and does not contain additional enzymes. The CD assay will enable the
      determination of the effects of pH, ionic strength, and D2O on catalysis by ODC.
      Furthermore, the availability of cuvets with pathlengths from 0.01 to 100 mm
      provides an effective range for the CD assay from 10 microM to 2.5 M L-ornithine
      concentration for this assay. This technique should be generally applicable for
      steady-state analysis of other decarboxylases but is not easily amenable to the
      analysis of crude enzyme preparations.

PMID- 8660611
TI  - Nondestructive detection of neutral glycosphingolipids with lipophilic anionic
      fluorochromes and their employment for preparative high-performance thin-layer
      chromatography.
AB  - In this study a simple and effective procedure for the isolation of individual
      neutral glycosphingolipids (GSLs) by preparative thin-layer chromatography is
      described. The method is based on nondestructive visualization of neutral GSLs on
      silica gel precoated thin-layer chromatography plates with anionic lipophilic
      fluorochromes. After thin-layer chromatography, individual neutral GSLs were
      detected by spraying the plate with fluorochrome solution followed by exposure to
      ultraviolet light. GSL containing silica gel was scraped off and extracted with
      chloroform:methanol:water (30:60:8, by vol). Neutral GSLs were freed from
      contaminating anionic fluorochrome by DEAE-Sepharose anion-exchange
      chromatography. Finally, a stepwise chloroform:methanol gradient chromatography
      on a small silica gel K60 column was employed to remove non-GSL impurities. Of
      nine different anionic fluorochromes tested, 2-(N-methylanilino)-naphthalene-6
      sulfonic acid was found to be the most suitable for preparative purposes. The
      method was proved with reference GSL mixtures containing glucosyl-, galactosyl-,
      lactosyl-, globotriaosyl-, and neolactotetraosylceramides, each substituted with
      C24- and C16-fatty acids, resulting in isolation of individual GSL fractions. The
      technique was applied for the purification of neutral GSLs from mouse kidney and
      human granulocytes carrying Lewisx-epitopes. In summary, the method described
      offers an easy to handle and successful preparative thin-layer chromatography
      strategy to obtain pure neutral GSLs in microgram and milligram quantities.

PMID- 8660612
TI  - A time-saving biological test to evaluate phagosome-lysosome fusion in cells.

PMID- 8660613
TI  - Engineering DNA and protein chimeras utilizing coding sequences of restriction
      sites.

PMID- 8660614
TI  - A homogeneous time-resolved fluoroimmunoassay for haptens utilizing liposomes.

PMID- 8660615
TI  - Preparation of solutions of dissolved hydrogen and oxygen gases using an
      anaerobic chamber.

PMID- 8660616
TI  - The accessibility of the prosthetic group biotin during monomeric avidin affinity
      chromatography.

PMID- 8660618
TI  - Enzyme-linked immunosorbent assay by image analysis using a charge-coupled device
      array detector.
AB  - This paper describes a fluorescence enzyme-linked immunosorbent assay (ELISA) for
      the quantification of (+/-)-2-(2, 4-dichlorophen-oxy)propionic methyl ester
      (dichlorprop methyl ester). Antibodies for dichlorprop methyl ester were produced
      by immunizing rabbits with a conjugate of dichlorprop methyl ester with bovine
      serum albumin. Data acquisition on microtiter wells is performed by a
      spectrofluorometer through a fiber optic and by a charge-coupled device camera. A
      correlation was obtained between the image analysis data on ELISA and the data
      acquired by the spectrofluorometer. The results demonstrate that the fluorescence
      image analysis performed by the charge-coupled device detector is applicable to
      ELISA, and the analysis time, sensitivity, and precision of the ELISA procedure
      are compared to conventional fluorescence ELISA performed by the
      spectrofluorometer. The ELISA procedure was selective for structurally similar
      compounds or usually found in formulation pesticides. Concentrations for 50%
      displacement curves were dichlorprop, 83.59 microg/ml, and 2,4,5-T, 388.23
      microg/ml; triclopyr, ioxynil, bentazone, and MCPA had no response.

PMID- 8660619
TI  - Analysis of ascorbate in plant tissues by high-performance capillary zone
      electrophoresis.
AB  - We describe here a simple and rapid capillary electrophoresis method for the
      determination of ascorbic acid (L-AA) and isoascorbic acid (D-AA) in vegetative
      tissues. For optimal yields and stabilization, samples are extracted with cold 3%
      metaphosphoric acid. Hydrophobic contaminants are then removed by passage through
      a C18 solid-phase extraction cartridge. The analysis itself is performed on a
      fused silica capillary with 200 mM borate, pH 9, as the carrier electrolyte,
      using on-line diode array detection over the range 190-350 nm. Quantitation was
      performed at 260 nm, the uv-absorption maximum for ascorbate at this pH. This
      method has a minimum detection limit of 84 fmol/injection and linearity of
      detector response was observed up to at least 12 pmol/injection. We also describe
      the influence of electrolyte concentration, pH, and the presence of detergent on
      separations of L-AA, D-AA, and L-galacturonic acid-1,4-lactone. The protocol has
      been demonstrated to be suitable for the analysis of L-AA in Arabidopsis,
      parsley, and mushroom. The method has superior resolution to comparable HPLC
      separations, a comparable analysis time, but lower sensitivity because of the
      concentration limitations of the detection system.

PMID- 8660620
TI  - A scintillation proximity assay for UDP-GalNAc:polypeptide, N
      acetylgalactosaminyltransferase.
AB  - A rapid and simple method for quantitating the reaction product of UDP
      GalNAc:polypeptide, N-acetylgalactosaminyltransferase (GalNAc-transferase) by
      scintillation proximity assay (SPA) was developed. The assay quantitates the
      radioactivity incorporated from 3H-labeled UDP-GalNAc into a biotin-labeled
      acceptor peptide, as measured after adsorption of the acceptor peptide to avidin
      coated SPA beads. The acceptor peptide, PPASTSAPG (Elhammer et al. (1993) J.
      Biol. Chem. 268, 10029-10038) was conjugated to biotin using a di-beta-alanine
      spacer arm. The conjugated peptide reacted readily with the enzyme and it had an
      apparent Km comparable to that of the parent peptide. Using a reaction mixture
      consisting of 4 mg of SPA beads, 17 microM acceptor, 0.5 microM nucleotide sugar,
      and 7.5 U/ml enzyme, the time dependence of product formation obeyed Michaelis
      Menten-type kinetics throughout the full course of the reaction-until exhaustion
      of the donor substrate-and the beginning portion of the reaction was sufficiently
      linear for calculating accurate initial rates. Analysis of the time dependency
      yielded an apparent Km of 0.38 +/- 0.12 microM for UDP-GalNAc. The assay is
      conveniently carried out in 96-well microtiter plates; it is ideally suited for
      assaying large numbers of samples and for screening large collections of
      chemicals for competitive inhibitors.

PMID- 8660622
TI  - Mass spectrometric characterization of sequence-specific complexes of DNA and
      transcription factor PU.1 DNA binding domain.
AB  - Electrospray ionization mass spectrometry (ESI-MS) has been used to study the
      noncovalent interaction of the 13.5-kDa DNA binding domain of PU.1 (PU.1-DBD)
      with specific double-stranded DNA (dsDNA) target molecules. Mixtures of PU.1-DBD
      protein and wild-type target DNA sequence yielded ESI-MS spectra showing only
      protein-dsDNA complex ions of 1:1 stoichiometry and free dsDNA. When PU.1-DBD
      protein, wild type target DNA, and a mutant target DNA lacking the consensus
      sequence were mixed, only the 1:1 complex with the wild-type DNA was observed,
      consistent with gel electrophoresis mobility shift assay results, demonstrating
      the observation of sequence-specific protein-dsDNA complexes using ESI-MS.

PMID- 8660621
TI  - Monitoring cleavage of fusion proteins by matrix-assisted laser desorption
      ionization/mass spectrometry: recombinant HIV-1IIIB p26.
AB  - Matrix-associated laser desorption ionization/mass spectrometry (MALDI/MS) has
      been used to examine whole bacteria for the presence of a recombinant HIV p26
      fusion protein. MALDI/MS, combined with affinity-purification techniques, is also
      shown to be very useful in monitoring the enzymatic cleavage of both affinity
      bound fusion protein and fusion protein in solution. The combination of mass
      resolution, sensitivity, and speed of analysis makes MALDI/MS an attractive
      alternative to SDS-PAGE.

PMID- 8660623
TI  - Luminometric measurement of subnanomole amounts of key metabolites in extracts
      from isolated heart muscle cells.
AB  - In principle, luminometry allows very sensitive metabolite measurements as shown
      with standards in aqueous solutions (e.g., buffers). However, components of
      complex biological samples may largely interfere with luminometric reactions. We
      now describe a procedure by which subnanomole amounts of intermediary metabolites
      (malate, glucose 6-phosphate) can be measured by luminometry in extracts from
      isolated mammalian cells, namely rat heart muscle cells. Basically, measurements
      occur in two steps: (i) Enzymatically catalyzed reactions involving the
      metabolite to be measured lead to the stoichiometric production of NAD(P)H; (ii)
      the oxidation of this NAD(P)H in a luciferase/reductase system results in light
      production which is proportional to the original concentration of the metabolite.
      The reaction scheme is thus as follows: (1) Metabolite (malate, glucose 6
      phosphate) + NAD(P)+ --> X + NAD(P)H + H+; (2) NAD(P)H + O2 + RCOH --> NAD(P)+ +
      RCOOH + H2O + hnu. The cardiomyocytes used are previously subjected to an
      ethanolic extraction in which the cellular NAD(P)H is destroyed by acidification.
      Subsequent evaporation of the extracts allows to neutralize and to concentrate
      the samples. This contributes, along with other experimental maneuvers, to
      increasing the sensitivity of the method. With this procedure, we were able to
      detect amounts of approximately 70 pmol of malate and approximately 90 pmol of
      glucose 6-phosphate in cardiomyocyte samples. In addition, the calculated
      cellular concentrations of malate and glucose 6-phosphate (101.1 +/- 4.5, and
      202.8 +/- 26.1 microM, respectively, in the absence of exogenous substrate)
      correspond to values previously reported for heart tissue. In principle, the
      procedure described could be applied to the measurement of any ethanol
      extractable metabolite that can be converted in reactions involving NAD(P)+.

PMID- 8660624
TI  - Optimizing enzymatic cycling assays: spectrophotometric determination of low
      levels of pyruvate and L-lactate.
AB  - A kinetic analysis of enzymatic cycling systems covering the whole course of the
      reaction, i.e., the transient phase and the steady state, is presented. The cost
      of enzymatic cycling assays is minimalized by using equations to calculate the
      smallest amount of enzymes which should be used to obtain a given rate constant
      of the cycle. The model chemical system chosen for illustration purposes involved
      the determination of pyruvate and/or L-lactate via the coupling of L-lactate
      dehydrogenase and L-lactate oxidase cycling and NADH mediation. The method is
      simple although thorough and can be applied to any technique that uses enzymatic
      cycling.

PMID- 8660625
TI  - Double strand breaks induced by low doses of gamma rays or heavy ions:
      quantitation in nonradioactive human DNA.
AB  - We have developed a method of quantitating low frequencies (0-30 sites/10(9) base
      pairs) of double strand breaks in approximately 1 microgram of nonradioactive
      human DNA. Unirradiated or irradiated DNA is digested with the restriction
      endonuclease NotI, producing cleavage fragments that include a major group
      centered at approximately 1.2-1.3 Mbp. The DNA molecules are separated as a
      function of size by transverse alternating field electrophoresis. The frequency
      of double strand breaks is computed directly from the decrease in number average
      molecular length induced in the 1.2- to 1. 3-Mbp cleavage fragment group by 137Cs
      gamma or Fe26+ (1.1 GeV/nucleon) irradiation vs the corresponding unirradiated
      DNA samples. The double strand break frequency can be quantitated easily in the
      dose range of 0-10 cGy of gamma rays. The frequency of breaks per unit dose
      calculated for gamma irradiation of DNA in human cells (approximately 4.6 double
      strand breaks/10(9) bp/Gy) is within the range of values obtained by others (2-8
      sites/10(9) bp/Gy) who used methods requiring higher doses.

PMID- 8660626
TI  - Detection of single-base mutations by a competitive mobility shift assay.
AB  - We have developed an assay for the rapid screening of point mutations in specific
      genes. Our assay is based upon competitive hybridization of differentially
      labeled wild-type and mutant oligonucleotide probes to a PCR-generated DNA
      template and a subsequent analysis of the mobility of the probe-template hybrids.
      The assay is referred to as a competitive mobility shift assay. Generation of a
      hybridization stringency gradient allows perfect-matched hybrids to be formed to
      a greater extent at a slightly higher stringency than the corresponding
      mismatched hybrids. The stringency gradient is achieved by carrying out the
      hybridizations at a steadily decreasing temperature (from 95 to 20 degrees C) in
      a thermal cycler. This step allows the assay to be competitive while avoiding the
      need to establish precise hybridization conditions for each gene-specific probe,
      a major disadvantage associated with reverse oligonucleotide hybridization. The
      assay is rapid and sensitive and can selectively detect mutant DNA in the
      presence of a large (up to one million-fold) excess of wild-type DNA.

PMID- 8660627
TI  - The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power":
      the FRAP assay.
AB  - A simple, automated test measuring the ferric reducing ability of plasma, the
      FRAP assay, is presented as a novel method for assessing "antioxidant power."
      Ferric to ferrous ion reduction at low pH causes a colored ferrous
      tripyridyltriazine complex to form. FRAP values are obtained by comparing the
      absorbance change at 593 nm in test reaction mixtures with those containing
      ferrous ions in known concentration. Absorbance changes are linear over a wide
      concentration range with antioxidant mixtures, including plasma, and with
      solutions containing one antioxidant in purified form. There is no apparent
      interaction between antioxidants. Measured stoichiometric factors of Trolox,
      alpha-tocopherol, ascorbic acid, and uric acid are all 2.0; that of bilirubin is
      4.0. Activity of albumin is very low. Within- and between-run CVs are <1.0 and
      <3.0%, respectively, at 100-1000 micromol/liter. FRAP values of fresh plasma of
      healthy Chinese adults: 612-1634 micromol/liter (mean, 1017; SD, 206; n = 141).
      The FRAP assay is inexpensive, reagents are simple to prepare, results are highly
      reproducible, and the procedure is straightforward and speedy. The FRAP assay
      offers a putative index of antioxidant, or reducing, potential of biological
      fluids within the technological reach of every laboratory and researcher
      interested in oxidative stress and its effects.

PMID- 8660628
TI  - Mass spectrometric methods for determination of [13C]Leucine enrichment in human
      muscle protein.
AB  - Two modified GC-based isotope ratio MS (IRMS) techniques, for measurement of
      [13C]leucine enrichment in muscle protein, were compared with a conventional dual
      inlet technique. Of these three, two involved HPLC purification of leucine and
      liberation of carbon dioxide (CO2) using the ninhydrin reaction. In the
      conventional technique the CO2 was introduced into the MS by a dual inlet system
      following cryogenic concentration. In the second method (ninhydrin/GC/IRMS) the
      CO2 was purified by on-line GC. In the third technique, GC/combustion/IRMS,
      derivatized amino acids are separated by GC and analyzed after combustion. A
      primed continuous infusion of L-[1-13C]leucine was given intravenously to human
      subjects and needle quadriceps muscle biopsies were taken to measure [13C]leucine
      enrichment in muscle protein. All three methods demonstrated excellent
      correlation (r > 0. 999). Differences in the measurement of [13C]leucine
      enrichment in muscle protein were <6%. The ninhydrin techniques require microgram
      quantities of leucine, with the conventional technique requiring twice the amount
      as the ninhydrin/GC/IRMS method. The GC/combustion/IRMS technique requires only
      nanogram quantities of leucine with similar precision enabling measurement of
      synthesis rates of individual proteins from biopsy samples. We have measured the
      isotopic enrichment of myosin heavy chain and mixed muscle protein in human
      subjects using the GC/combustion/IRMS technique.

PMID- 8660629
TI  - Microdetermination of proteins by resonance light scattering spectroscopy with
      bromophenol blue.
AB  - Reaction of bromophenol blue with proteins results in an enhanced resonance light
      scattering at 334 nm. Based on this, a new quantitative determination method for
      proteins in the aqueous solution is established. This assay is characterized by
      high sensitivity (0.34-18.7 microg/ml), short reaction time (>2 min), and
      simplicity (a one-step assay). Due to protein-to-protein variability, this method
      gave results higher than that of the bromocresol green assay in detection of
      human serum albumin.

PMID- 8660630
TI  - The use of high-performance anion-exchange chromatography and matrix-assisted
      laser desorption/ionization time-of-flight mass spectrometry to monitor and
      identify oligosaccharide degradation.
AB  - High-performance anion-exchange chromatography (HPAEC) with pulsed-amperometric
      detection was used to monitor the consistency of the oligosaccharides released
      from several partially purified preparations of a tissue-type plasminogen
      activator mutant (TNK-tPA). Differences in the oligosaccharide map were observed,
      primarily in the neutral carbohydrate region of the separation. Subsequent
      investigations using matrix-assisted laser desorption ionization time-of-flight
      mass spectrometry (MALDI/TOF/MS) identified the neutral oligosaccharides to be
      primarily asialo-diantennary complex-type glycans with 2, 1, or 0 galactose
      residues. Additional asialo-triantennary and asialo-tetrantennary structures were
      also observed with varying amounts of galactose. Hydrolysis of the chromogenic
      substrate 4-methyl umbelliferyl-beta-galactoside confirmed that host-cell
      lysosomal beta-galactosidase is present at the first step in the purification
      process and is the cause of the observed glycan degradation. Subsequent steps in
      the purification process quantitatively remove this enzyme. Comparison of HPAEC
      and MALDI/TOF/MS analysis of time-course samples revealed quite similar rates of
      degradation and demonstrates the quantitative utility of these methods. HPAEC did
      not reveal significant changes in the sialylated structures as evidenced by
      nearly identical profiles for the sialic acid-containing structures.

PMID- 8660632
TI  - Inverse polymerase chain reaction for cloning complete human immunoglobulin
      variable regions and leaders conserving the original sequence.

PMID- 8660633
TI  - Immunoreplica from the gel surface: rapid and sensitive blot plus intact gel.

PMID- 8660631
TI  - Synthesis of aryl azide derivatives of UDP-GlcNAc and UDP-GalNAc and their use
      for the affinity labeling of glycosyltransferases and the UDP-HexNAc
      pyrophosphorylase.
AB  - The chemical synthesis and utilization of two photoaffinity analogs, 125I-labeled
      5-[3-(p-azidosalicylamido)-1-propenyl]-UDP-GlcNAc and -UDP-GalNAc, is described.
      Starting with either UDP-GlcNAc or UDP-GalNAc, the synthesis involved the
      preparation of the 5-mercuri-UDP-HexNAc and then attachment of an allylamine to
      the 5 position to give 5-(3-amino)allyl-UDP-HexNAc. This was followed by
      acylation with N-hydroxysuccinimide p-aminosalicylic acid to form the final
      product, i.e., 5-[3-(p-azidosalicylamido)-1-propenyl]-UDP-GlcNAc or UDP-GalNAc.
      These products could then be iodinated with chloramine T to give the 125I
      derivatives. Both the UDP-GlcNAc and the UDP-GalNAc derivatives reacted in a
      concentration-dependent manner with a highly purified UDP-HexNAc
      pyrophosphorylase, and both specifically labeled the subunit(s) of this protein.
      The labeling of the protein by the UDP-GlcNAc derivative was inhibited in dose
      dependent fashion by either unlabeled UDP-GlcNAc or unlabeled UDP-GalNAc.
      Likewise, labeling with the UDP-GalNAc probe was blocked by either UDP-GlcNAc or
      UDP-GalNAc. The UDP-GlcNAc probe also specifically labeled a partially purified
      preparation of GlcNAc transferase I.

PMID- 8660634
TI  - Rapid screening and mapping of conformational epitopes expressed in the secretion
      expression system Pichia pastoris.

PMID- 8660635
TI  - Development of a nonradioactive ribonuclease H assay.

PMID- 8660636
TI  - Filipin as a fluorescent probe of lipoprotein-derived sterols on thin-layer
      chromatograms.

PMID- 8660637
TI  - Spin-column chromatography for DNA purification.

PMID- 8660650
TI  - Decomposition of S-nitrosoglutathione in the presence of copper ions and
      glutathione.
AB  - The decomposition of S-nitrosoglutathione (GSNO) in the presence of Cu2+ and
      glutathione (GSH) was studied by stopped-flow/rapid-scan spectroscopy. Reduction
      of Cu2+ by GSH and subsequent formation of a GS-*Cu+ complex occurred within 200
      ms, with the amount of complex formed depending on the GSH-to-Cu2+ ratio. The
      rate of GSNO decomposition at a fixed concentration of Cu2+ increased linearly
      with the concentration of GSH at low GSH-to-Cu2+ ratios (< or = 0.2), but sharply
      declined at higher ratios. The same pattern was observed for the rate of NO.
      release, measured with an NO.-sensitive electrode. GSNO decomposition and NO.
      release in the presence of GSH and/or Cu2+ were completely inhibited by the Cu+
      chelator neocuproine, but unaffected by the Cu2+ chelator cuprizone. Ascorbate
      and cysteine, which will reduce Cu2+ but have little or no affinity for Cu+, also
      stimulated GSNO decomposition in the presence of Cu2+, but did not inhibit it at
      higher concentrations. It is concluded that the homolytic cleavage of GSNO is
      efficiently catalyzed by Cu+ and that the GS-*Cu+ complex is catalytically
      inactive. By determining the anaerobic GSNO decomposition rates in the presence
      of varying concentrations of Cu+ a value of 4 x 10(3)M(-1) x s(-1) was derived
      for the apparent Cu+-GSNO association rate constant.

PMID- 8660651
TI  - Proteins and their amino acid compositions: uniqueness, variability, and
      applications.
AB  - Amino acid compositions (AAC) of proteins were analyzed in terms of their
      uniqueness and variability. Using several measures of convergence between the
      AACs of randomly chosen proteins versus those stored in protein data banks, it
      was established that certain families of proteins have unique AACs despite the
      mutations of their sequences which were imposed in the process of evolution. AACs
      may be used to establish the identities of many proteins which were sorted
      through various chromatographic media prior to their fractionation on two
      dimensional (2D) gels. Subfractionations of proteins markedly enhance the chances
      for proper identification of low-abundant proteins which rest inaccessible if the
      total protein extract of an organ is analyzed on 2D gels. Although the amino acid
      composition versus protein identity (AAC-PI) method allows identification with
      high confidence of unique proteins resolved on monodimensional SDS-PAGE (1D) gels
      and arrays of protein isoforms resolved on two-dimensional (2D) gels, selective
      immunoblotting is still a more robust method. Thus, in principle, the AAC-PI
      method may allow limiting the number of "unknown" spots on 2D gels which could be
      further investigated by microsequencing and/or mass spectroscopy. However, to
      resolve certain ambiguities inherently linked with protein identities derived
      only from their AACs, the AAC-PI method must be sometimes aided by
      microsequencing and immunoblotting, especially in the construction of high
      resolution 2D maps of proteins. A suite of algorithms which form the AAC-PI
      method are described in detail.

PMID- 8660652
TI  - Purification and enzymatic characterization of recombinant prohormone convertase
      2: stabilization of activity by 21 kDa 7B2.
AB  - Although previous efforts to produce significant quantities of purified
      prohormone convertase 2 from either recombinant or natural sources have been
      unsuccessful, our recent finding that the neuroendocrine polypeptide 7B2 is
      necessary for the biosynthesis of enzymatically active prohormone convertase 2
      (PC2) has enabled us to obtain active recombinant enzyme from the conditioned
      medium of PC2-producing CHO cells supertransfected with cDNA coding for 21 kDa
      7B2. The recombinant enzyme was purified to apparent homogeneity, with a 40%
      recovery, in milligram quantities. Two protein bands of Mrs 71 and 75 kDa were
      observed after SDS-PAGE followed by either Coomassie staining or Western blotting
      with PC2 antiserum. Spontaneous conversion of the 71- and 75-kDa species to the
      66-kDa form occurred during incubation at pH 5.0; the degree of conversion
      correlated with a dramatic increase in activity. Kms of 124 and 131 microM and
      Kcats of 0.49 and 0.81 s(-1) were obtained for the substrates Cbz-Arg-Ser-Lys-Arg
      AMC and Pyr-Arg-Thr-Lys-Arg-AMC, respectively. The pH optimum was 5.0, and the
      enzyme was inhibited by h7B2(155-185') p-CMS, and EDTA but not by other
      inhibitors tested. Interestingly, 21 kDa 7B2 was observed to copurify with the
      enzyme in a molar ratio of about 1:100 (7B2:PC2). Prior addition of recombinant
      21 kDa 7B2 to activated 66 kDa PC2 provided significant protection against
      thermal denaturation. When coassociated 7B2 was mostly removed from activated PC2
      through gel filtration, subsequent addition of recombinant 7B2 exerted a
      significant stabilizing effect on enzyme activity. Millimolar Ca2+ and pHs
      between 5 and 6 were required to observe this effect. Since these conditions
      resemble those thought to occur within secretory granules, and since 21 kDa 7B2
      represents a stored secretory granule protein, our data suggest a physiological
      role for 21 kDa 7B2 in the stabilization of PC2 activity.

PMID- 8660653
TI  - Molecular analysis of the Drosophila catalase gene.
AB  - The main objective of this study was to isolate and characterize the catalase
      gene and accompanying cis-regulatory regions in Drosophila melanogaster. Genomic
      clones were obtained on the basis of cross-hybridization to catalase cDNA and a 7
      kb SalI-KpnI fragment encompassing the catalase gene was introduced into
      Drosophila by P element-mediated transformation. A single transgene, when placed
      in a catalase null background, was sufficient to restore resistance to H2O2 as
      well as reduce susceptibility to early death. DNA sequence of the catalase gene
      domain was obtained. This included 1365 bp of sequence upstream of the
      transcription initiation site and 1423 bp downstream of the termination codon.
      The Drosophila catalase gene is composed of 3 exons, encoding 19, 307, and 180
      amino acids, which are separated by 3520- and 96-bp introns. Sequence analysis of
      the promoter domain is presented, revealing multiple sequence similarities
      between catalase and Cu,Zn superoxide dismutase promoter domains. Developmental
      RNA get analysis shows that peaks of catalase mRNA accumulation correspond
      roughly with major peaks of ecdysone titer during third instar and pupal stages.
      Candidate ecdysone response element sequences are noted downstream of the
      catalase polyadenylation site.

PMID- 8660654
TI  - Ubiquitous expression and cell cycle regulation of the protein kinase PIM-1.
AB  - The murine pim-1 gene, isolated as a locus frequently activated by proviral
      integration in T cell lymphomas, encodes a protein serine kinase. Although
      genetic evidence suggests a crucial role for this protooncogene in cell growth
      and transformation, very little is known about its protein product. The murine
      pim-1 mRNA provides alternate translational starts at a CUG codon +87-89 and an
      AUG codon at +339-341, in the same open reading frame (ORF), resulting in 44-kDa
      (397 amino acids) and 34-kDa (313 amino acids) isoforms. In this report, we
      demonstrate that the human PIM-1 mRNA is translated only from the single
      initiation methionine codon at +339-341 under cell-free conditions.
      Immunoblotting analyses of several human solid tumor cell lines, with highly
      specific antisera reveal two ubiquitously expressed isoforms (35 and 34 kDa). The
      estimated half-life of these proteins is shorter in the normal peripheral blood
      leukocytes (<5 min) than in the chronic myelogenous leukemia cells K562 (<20
      min). Immunoblotting analyses of centrifugally elutriated fractions of the
      chronic myelogenous leukemia BV173 cells demonstrate that the levels of PIM-1
      increase during the progression from early to late GI, remain high at the G1/S
      boundary and G2 phases of the cell cycle. The results presented here suggest a
      ubiquitous role for PIM-1 in progression through cell cycle.

PMID- 8660655
TI  - Detection of free radical metabolite formation using in vivo EPR spectroscopy:
      evidence of rat hemoglobin thiyl radical formation following administration of
      phenylhydrazine.
AB  - The spin-trapping technique in conjunction with a low-frequency electron
      paramagnetic (or spin) resonance (EPR or ESR) spectrometer was used to detect the
      hemoglobin thiyl free radical in living rats using a whole body resonator. The
      hemoglobin thiyl free radical was formed following the intragastric
      administration of phenylhydrazine at the LD50 dose of 188 mg/kg. The hemoglobin
      thiyl free radical was then trapped by preinjected 5,5-dimethyl-1-pyrroline N
      oxide (DMPO), which formed the DMPO/hemoglobin thiyl-free radical adduct in the
      blood. The time course of the in vivo formation and disappearance of the spin
      adduct was followed. The DMPO/hemoglobin thiyl free radical was detected in blood
      samples using 9.5 GHz (X-band) and 1.1 GHz (L-band) EPR at room temperature and
      77 K. Pretreatment of rats with ascorbate and diethylmaleate (DEM) decreased the
      signal intensity of the DMPO/hemoglobin thiyl free radical spin adduct. The
      incubation of ascorbate or DEM at 37 degrees C with rat blood containing
      preformed DMPO/hemoglobin thiyl radical adduct showed that there was no effect of
      DEM on the free radical concentration, while ascorbate reduced the radical
      adduct. This study provided direct evidence of the formation of the
      DMPO/hemoglobin thiyl free radical in vivo and enabled us to study this formation
      in living animals free of any artifacts that can occur when using ex vivo
      methods.

PMID- 8660656
TI  - Transcriptional regulation of the TATA-less NADPH cytochrome P-450 oxidoreductase
      gene.
AB  - Multiple cis-acting DNA sequences regulating expression of the rat liver NADPH
      cytochrome P-450 oxidoreductase gene have been identified in transient
      transfection assays using promoter deletion constructs linked to the
      chloramphenicol acetyl transferase gene. The TATA-less promoter possesses nine GC
      boxes which contain the consensus sequence for the transcription factor Sp1.
      While loss of the seven distal GC-boxes had minimal effect on transcriptional
      activity, deletion of the next 35 bp, from -206 to -172, resulted in
      approximately 90% loss of promoter activity. Contained within this region is an
      Sp1 binding site indicating that either (1) this particular consensus sequence
      was essential for transcription, (2) the two proximal GC boxes act in concert, or
      (3) a yet unidentified regulatory element resides within this 35-bp stretch. In
      addition, transfection experiments demonstrated that two separate distal regions
      (-622 to -1167 and -1500 to -2300) contain negative regulatory elements which
      down-regulate gene transcription in a position-independent manner. Mobility-shift
      analyses and DNase footprinting identified sequences in the proximal region of
      the promoter that bound proteins present in nuclear extracts. Four protected
      segments were observed within the first 100 bp upstream of the transcription
      start site; these include (1) the region encompassing the transcription start
      site (-7 to +4), (2) the region normally occupied by a TATA-box (-38 to -18), (3)
      the bases from -78 to -60 which contain the regulatory element CACC, and (4)
      bases -105 to -92 which include an Sp1 binding site. Hence, regulation of the
      NADPH-cytochrome P-450 oxidoreductase gene is controlled by both positive and
      negative regulatory elements, and, of the nine Sp1 consensus sites, the two
      proximal sites are sufficient to support basal transcription.

PMID- 8660657
TI  - Superoxide dismutase activity in the giant hemoglobin of the earthworm, Lumbricus
      terrestris.
AB  - The giant hemoglobin, which occurs in free solution in the blood of earthworms,
      contains copper and zinc and exhibits superoxide dismutase activity as assessed
      by competition assays using cytochrome c or nitroblue tetrazolium. On a molar
      basis, the activity of this hemoglobin was approximately 10% that of the
      mammalian copper, zinc superoxide dismutase. The dodecamer, which contains the
      globin chains but lacks the linker subunits, had very little activity when
      compared to the complete native molecule. This suggests that the superoxide
      dismutase activity resides in one of the linker subunits. This is the first
      report of a superoxide dismutase bound to a respiratory pigment.

PMID- 8660658
TI  - Isolation and sequencing of the rat Coq7 gene and the mapping of mouse Coq7 to
      chromosome 7.
AB  - We recently identified the Saccharomyces cerevisiae COQ7 gene and showed that its
      product affects one or more monoxygenase steps in the synthesis of ubiquinone.
      Other investigators have independently isolated the yeast COQ7 gene as CAT5 and
      identified it as a gene necessary for the derepression of gluconeogenic enzymes
      in yeast. In the present study, a homolog of the yeast COQ7 (CAT5) gene was
      isolated from a rat testis cDNA library by functional complementation of a coq7
      deletion mutant of S. cerevisiae. The resulting cDNA clones contained a 0.8-kb
      insert with an open reading frame encoding a 183-amino-acid polypeptide. The rat
      Coq7 amino acid sequence is 49% identical to that of yeast Coq7p and 58%
      identical to a C. elegans homolog over a 152-aa region. Sequence homology
      searches fail to identify any other significant homologies. The Coq7 gene was
      mapped to mouse chromosome 7, 7.6 +/- 3.6 cM proximal to the marker D7Mit7, by
      linkage analysis of an interspecific backcross. This region of chromosome 7
      containing Coq7 is part of a linkage group conserved between mouse chromosome 7
      and human chromosome 11p15.

PMID- 8660659
TI  - The glucocorticoid attenuated response genes GARG-16, GARG-39, and GARG-49/IRG2
      encode inducible proteins containing multiple tetratricopeptide repeat domains.
AB  - In a search for glucocorticoid attenuated response genes (GARGs) induced by
      lipopolysaccharide (LPS) in murine Swiss 3T3 cells, we cloned 12 GARG cDNAs (J.
      B. Smith and H. R. Herschman, 1995, J. Biol. Chem. 270, 16756-16765). Analysis of
      complete cDNA sequences indicates that three of these genes encode members of a
      highly conserved family of proteins containing multiple tetratricopeptide repeat
      (TPR) domains. GARG-16 is a homologue of the interferon-induced human IFI-56K
      gene. GARG-39 is a homologue of the interferon-induced human ISG-54K and hamster
      CL-54K genes. The predicted GARG-49/IRG2 protein is 60-75 amino acids shorter
      than other known members of this gene family, and its carboxyl-terminal half is
      relatively divergent. Homologues of GARG-49/IRG2 in other species have not been
      reported. The predicted GARG-16 and GARG-39 proteins, and their homologues,
      contain 10 TPR domains. GARG-49/IRG2 shares the first 6 domains and part of the
      7th, but lacks domains 8,9, and 10. Message levels of GARG-16, GARG-39, and GARG
      49/IRG2 are increased by LPS stimulation in Swiss 3T3 cells and in peritoneal
      macrophages. Unlike many primary response genes, these three genes are not
      induced by serum stimulation in Swiss 3T3 cells. All three are induced in the RAW
      264.7 macrophage cell line by LPS, by interferons-alpha/beta, and by interferon
      gamma. Despite these similarities, quantitative differences in their responses to
      different stimuli indicate that GARG-16, GARG-39, and GARG-49/IRG2 are regulated
      independently. We speculate that the proteins encoded by these LPS- and
      interferon-inducible genes may participate in multicomponent assemblies via their
      TPR domains.

PMID- 8660660
TI  - Relative activities of retrovirally expressed murine prostaglandin synthase-1 and
      -2 depend on source of arachidonic acid.
AB  - We have developed derivatives of mouse embryonic fibroblasts (10T1/2) and Chinese
      hamster ovary (AS52) cells that stably express high levels of murine
      prostaglandin synthase-1 or -2 (PGHS-1 or -2). The cDNAs were transferred using
      retroviral vectors and the resulting G418-resistant clones were analyzed for
      prostaglandin E2 (PGE2) production. Specific expression was confirmed by Western
      and Northern analyses. Enzyme activities, protein, and message levels peaked 1
      (10T1/2) or 2 (AS52) days after seeding but decreased as cells became density
      arrested. Upon subculturing, enzyme activities returned to their initial high
      levels. With 10 microM exogenous arachidonic acid (AA) as the substrate, PGHS-1
      activities were approximately 3- to 5-fold higher than PGHS-2 activities.
      Conversely, when exogenous AA was left out of the medium and only endogenous AA
      was available as substrate, enzyme activities were lower; but PGHS-2 activities
      were 5-fold (10T1/2) or 1.5-fold (AS52) higher than PGHS-1 activities. Following
      phorbol ester treatment to stimulate endogenous AA release, PGHS-2 activities
      increased over time and by 6 hours, were 4-fold (10T1/2) or 2-fold (AS52) higher
      than PGHS-1 activities. However, when calcium ionophore A23187 was used to
      stimulate endogenous AA release, maximum PGHS activities occurred within 30 min
      of treatment; PGHS-1 activities were equal to (10T1/2) or 2-fold higher (AS52)
      than PGHS-2 activities. Because these cell lines allow us to measure specific
      PGHS activity in intact cells, we were able to demonstrate that the relative
      activities of the two PGHS isozymes depend on the source of AA (exogenous versus
      endogenous) or biochemical stimulus used to mobilize endogenous AA (A23187 versus
      phorbol ester). These data suggest that PGHS-1 and PGHS-2 preferentially utilize
      different pools of AA and may be modulated through different stimulus-initiated
      pathways.

PMID- 8660661
TI  - ATP hydrolysis is not required for the dissociation of a substance P.BiP complex.
AB  - BiP is a member of the hsp70 family of proteins that is present in the
      endoplasmic reticulum where it functions as a molecular chaperone. Rapid
      quantitative assays have been used to study the effect of mutating BiP residue
      229, located in the ATP binding site, from threonine to glycine. Although binding
      of ATP to the mutant BiP was not affected, the mutant protein possessed 10-20% of
      the wild-type BiP ATPase activity. Binding to a model peptide substrate,
      substance P (Brot et al. (1994) Proc. Natl. Acad. Sci. USA 91, 12120-12124), was
      twofold higher with mutant BiP at 4 degrees C than with wild-type BiP, and was
      ATP dependent. Under these conditions the substance P that was bound to mutant
      BiP, but not the wild-type, could be released by higher levels of ATP (5-10
      microM), and the ratio of substance P released to ATP hydrolyzed was greater than
      10. These results suggest that stoichiometric ATP hydrolysis is not required for
      release of a chaperone from its substrate.

PMID- 8660663
TI  - Characterization and site-directed mutagenesis of aspen lignin-specific O
      methyltransferase expressed in Escherichia coli.
AB  - Aspen lignin-specific caffeic acid/5-hydroxyferulic acid 3/5-O-methyltransferase
      (EC 1.2.1.68) was expressed in an active form in Escherichia coli using pET-23
      vector. Two steps were used to purify (Phenyl Sepharose and S
      adenosylhomocysteine-agarose chromatographies) enzyme to homogeneity. O-Methyl
      transferase has a subunit of 40 kDa and native gradient gel electrophoresis
      indicated the active form is a dimer. Substrate specificity was investigated
      using over 20 phenolic compounds, which defined the nature of the substrate
      binding site and required substrate characteristics such as a hydroxyl group para
      to the side chain. Enzyme accommodates large substrates well if the side chain
      contains the trans-double bond found in lignin precursors. Kinetically S-adenosyl
      L-methionine must bind before phenolic substrate; however, S-adenosyl-L
      homocysteine and phenolic substrate or product can form stable complexes
      complicating the kinetic mechanism. The role of thiol side chain(s) in the
      catalytic mechanism was investigated since the enzyme is inhibited by p
      chloromercuribenzoate. Of nine cysteine residues in the enzyme's sequence, only
      cysteine residues at positions 276 and 283 are invariant among higher plant O
      methyltransferases of this class. These residues were replaced by serine and
      alanine, singly and in combination, using site-directed mutagenesis. All
      combinations of cysteine replacements at positions 276 and 283 yielded enzyme
      virtually as active as wild-type and all were still sensitive to thiol
      inhibition. We concluded that thiol(s) were not important in the catalytic
      mechanism of this class of O-methyltransferases and sensitivity to the large
      thiol inhibitor was probably due to reaction of cysteine thiol(s) near the
      surface which sterically hindered the active site.

PMID- 8660662
TI  - Regulation of prostaglandin endoperoxide H synthase-2 expression by 2,3,7,8,
      tetrachlorodibenzo-p-dioxin.
AB  - We have examined the molecular mechanisms for 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD)-stimulated prostaglandin synthesis in Mardin Darvey canine kidney cells
      (MDCK). TCDD stimulates prostaglandin synthesis in these cells, at least in part,
      by elevating prostaglandin endoperoxide H2 synthase-2 (PGHS-2) levels. TCDD
      stimulated transcription of the PGHS-2 gene was maximal (6-fold) within 2 h and
      resulted in a 100-fold increase in PGHS-2 mRNA and a 25-fold increase in PGHS-2
      protein levels by 4 h. Transient transfection experiments using luciferase
      reporter plasmids demonstrated that control element(s) responsible for TCDD
      activation of the murine PGHS-2 promoter in MDCK cells are located in the first
      965 nucleotides upstream from the PGHS-2 transcriptional initiation site. A
      canonical xenobiotic response element, similar to those that control
      transcription of other well-known TCDD-sensitive genes, is present at position 
      157, but does not appear to be sufficient for halogenated aromatic hydrocarbon
      (HAH) activation of the PGHS-2 promoter. TCDD failed to stimulate transcription
      from the PGHS-2 promoter when reporter plasmids were transfected into Hepa 1c1c7
      cells, a line which contains the functional aryl hydrocarbon receptor. It seems
      likely that inappropriate expression of PGHS-2 may contribute to the toxic
      effects of TCDD and other HAHs. In particular, PGHS-2 expression may affect those
      toxic reactions that involve inappropriate cellular growth, such as dermal
      hyperplasia and tumor formation. It is also likely that elevated synthesis of
      prostaglandins, which are potent regulators of immune function, could play a role
      in the immunotoxicity associated with HAH exposure.

PMID- 8660664
TI  - Protein inhibitor of mitochondrial ATP synthase: relationship of inhibitor
      structure to pH-dependent regulation.
AB  - In the absence of an electrochemical proton gradient, the F1 moiety of the
      mitochondrial ATP synthase catalyzes the hydrolysis of ATP. This reaction is
      inhibited by a natural protein inhibitor, in a process characterized by an
      increase in ATPase inhibition as pH is decreased from 8.0 to 6.0. In order to
      gain greater insight into the molecular and chemical events underlying this
      regulatory process, the relationships among pH, helicity of the inhibitor
      protein, and its capacity to inhibit F1-ATPase activity were examined. First,
      peptides corresponding to four regions of the 82-amino-acid inhibitor protein
      were chemically synthesized and assessed for both retention of secondary
      structure, and capacity to inhibit F1-ATPase activity. These studies showed that
      a region of only 24-amino-acid residues, from Phe 22 through Len 45, accounts for
      the inhibitory capacity of the inhibitor protein, and that retention of native
      helical structure in this region is not essential for inhibition. Second, three
      mutants (33P34, 39P40, and 43P44) of the intact inhibitor protein were prepared
      in which a proline residue was inserted within the inhibitory region to disrupt
      native helical structure. The secondary structures and inhibitory capacities of
      these mutants were analyzed as a function of pH. These studies revealed that,
      despite the initial loss of helical structure within the inhibitory region due to
      proline insertion, a further loss of helical structure is required to modulate
      inhibitory activity. These results suggest that a loss of helical structure
      outside the inhibitory region correlates with an increase in inhibitory capacity.
      Finally, two separate mutants (H48A and H55A) were prepared in which a conserved
      histidine residue in the wild-type inhibitor protein was replaced with an
      alanine. The secondary structures and inhibitory capacities of these mutants were
      also investigated as a function of pH. Results indicated that, although histidine
      residues do not directly affect the inhibitory capacity of the protein, they are
      important for maintaining the inhibitor protein in an inactive form at high pH.
      Furthermore, these results show that loss in helical structure, although
      correlated with an increase in inhibitory capacity, is not essential for this
      function. These novel experiments are consistent with a model in which the
      inhibitor protein is envisioned as consisting of two regions, an inhibitory
      region and a regulatory region. It is suggested that reduction of pH allows for
      the protonation of a histidine residue blocking the interaction between the two
      regions, thus activating the inhibitory response. The pH reduction also
      correlates with a partial unfolding of the protein that may either cause or
      result from the loss of interaction between the two helices. This unfolding may
      be necessary for further optimization of inhibitor function.

PMID- 8660665
TI  - Metabolites of all-trans-retinol in day 10 conceptuses of vitamin A-deficient
      rats.
AB  - It has been previously demonstrated that vitamin A-deficient rats supplemented
      with retinoic acid cannot complete gestation. Resorption of fetuses invariably
      occurs in these animals beginning Day 15 of gestation. Retinol must be
      administered on or before Day 10 of gestation in order to prevent this
      phenomenon. The administration of as little as 2 micrograms on Day 10 is
      sufficient to allow continuation of gestation through parturition. This study
      examines the metabolites of all-trans-retinol in the conceptuses of vitamin A
      deficient, retinoic acid-supported pregnant animals at Day 10 of gestation. The
      retinoids recovered in this study could be identified as all-trans-retinol,
      retinyl palmitate, and other retinyl esters. Virtually no radiolabeled retinoic
      acid was found in the conceptuses of these animals over the 12-h period examined.
      This may suggest that retinoic acid that may be required by the fetus can arise
      directly from maternal sources. Additionally, the isolation of an early
      appearing, very polar metabolite of retinol is reported. This aqueous-soluble
      compound accounts for more than 20% of the radioactivity recovered at 1 h post
      dose. The amount of this compound increases through 6 h post-dose. This
      metabolite is not found in urine from the same animals and is not likely to be an
      excretion product.

PMID- 8660666
TI  - Interaction of sheep liver apo-serine hydroxymethyltransferase with pyridoxal-5'
      phosphate: a physicochemical, kinetic, and thermodynamic study.
AB  - Sheep liver serine hydroxymethyltransferase (EC 2.1.2.1) is a homotetramer of Mr
      213,000 requiring pyridoxal-5'-phosphate (PLP) as cofactor. Removal of PLP from
      the holoenzyme converted the enzyme to the apo form which, in addition to being
      inactive, was devoid of the characteristic absorption spectrum. Upon the addition
      of PLP to the apoenzyme, complete activity was restored and the visible
      absorption spectrum with a maximum at 425 nm was regained. The interaction of PLP
      with the apoenzyme revealed two phases of reaction with pseudo-first-order rate
      constants of 20 +/- 5 s(-1) and 12.2 +/- 2.0 x 10(-3) s(-1), respectively.
      However, addition of PLP to the apoenzyme did not cause gross conformational
      changes as evidenced by circular dichroic and fluorescence spectroscopy. Although
      conformationally apoenzyme and holoenzyme were indistinguishable, they had
      distinct apparent melting temperatures of 51 +/- 2 and 58 +/- 2 degrees C,
      respectively, and the reconstituted holoenzyme was thermally as stable as the
      native holoenzyme. These results suggested that there was no apparent difference
      in the secondary structure of holoenzyme, apoenzyme, and reconstituted
      holoenzyme. However, sedimentation analysis of the apoenzyme revealed the
      presence of two peaks of S20,w values of 8.7 +/- 0.5 and 5.7 +/- 0.3 S,
      respectively. A similar pattern was observed when the apoenzyme was
      chromatographed on a calibrated Sephadex G-150 column. The first peak
      corresponded to the tetrameric form (Mr 200,000 +/- 15,000) while the second peak
      had a Mr of 130,000 +/- 10,000. Reconstitution experiments revealed that only the
      tetrameric form of the apoenzyme could be converted into an active holoenzyme
      while the dimeric form could not be reconstituted into an active enzyme. These
      results demonstrate that PLP plays an important role in maintaining the
      structural integrity of the enzyme by preventing the dissociation of the enzyme
      into subunits, in addition to its function in catalysis.

PMID- 8660667
TI  - Functional group characterization of homoserine kinase from Escherichia coli.
AB  - Homoserine kinase (EC 2.7.1.39), a key enzyme in the aspartate pathway of amino
      acid biosynthesis in Escherichia coli, catalyzes the phosphorylation of L
      homoserine to form L-homoserine phosphate. The ThrB gene coding for this enzyme
      has been cloned, and the enzyme has been overexpressed and purified to
      homogeneity with a simplified purification scheme. An examination of the pH
      dependence of the V/K profile for L-homoserine shows that the enzyme loses
      activity upon protonation of a single functional group and upon de-protonation of
      a second functional group, with both groups appearing to be of the cationic acid
      type. Incubation of the enzyme with diethylpyrocarbonate leads to the complete
      loss of enzyme activity. Spectral and chemical characterization of the
      derivatized enzyme has shown that this activity loss is caused by the
      modification of a histidine residue. Treatment of the enzyme with pyridoxal-5'
      phosphate also results in enzyme inactivation. The spectra evidence for the
      formation of a Schiff base, and the complete protection afforded by substrates
      and inhibitors, indicate that homoserine kinase also contains a lysine that is
      essential for catalytic activity.

PMID- 8660668
TI  - A comparison of the renal and hepatic microsomal glucose-6-phosphatase enzymes.
AB  - The liver glucose-6-phosphatase enzyme has been extensively characterized and
      relatively little is known about the renal microsomal glucose-6-phosphatase
      enzyme. The reason for lack of study of the renal glucose-6-phosphatase enzyme is
      that it has been assumed to be the same as the liver enzyme. Immunoblotting with
      antibodies raised against the liver enzyme revealed differences in apparent
      molecular weight and antigenicity between the liver and kidney glucose-6
      phosphatase enzyme proteins. Characterization of the activity of the renal
      glucose-6-phosphatase enzyme also showed that it is regulated differently to the
      liver enzyme in some metabolic states. This implies that the renal and liver
      glucose-6-phosphatase enzymes may have different roles.

PMID- 8660669
TI  - Fluorescence polarization study on the dynamics and location of peroxidized
      fluorescent phospholipids in liposomes.
AB  - Motional properties of fluorescent substances produced by lipid peroxidation by a
      time-resolved fluorescence polarization technique were studied. When liposomes
      containing phosphatidylethanolamine (PE) and linoleic hydrocarbon chain were
      incubated at 37 degrees C, fluorophores absorbing maximally at 360 nm and
      emitting near 430 nm were produced. Their fluorescence anisotropy decay measured
      at 23 degrees C was fitted well with a sum of a fast relaxation and a time
      independent residual term. With the increase of oxidation degree, the time
      constant of the relaxation term increased. This may be explained by alteration in
      the membrane structure or by modification of the fluorescent products themselves.
      Information on the location of the fluorescent products was obtained when their
      motional property was compared with those of various extrinsic probes that were
      incorporated at different positions of the lipid bilayer. It was found that the
      motional property of the fluorescent oxidation products is similar to that of 1
      (4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene, a rod-shaped hydrophobic
      probe with a charged terminal. Other probes sensing the polar region or the
      hydrophobic region of the membrane were characterized by a lower order parameter.
      It is suggested that the fluorescent oxidation products have a polar moiety
      located at the membrane surface and attached to the amino group of PE while the
      tail part being buried in the hydrophobic region of the membrane. This picture is
      supported by fluorescence quenching experiments with the aqueous quencher Co2+.
      On the other hand, fluorophores produced by the reaction of malondialdehyde and
      PE suggested to have a chemical structure in which the angle between the
      absorption and emission dipole moments is very large. On the basis of these
      observations, the production pathway of fluorophores in oxidized membranes is
      discussed.

PMID- 8660670
TI  - The interaction of Q analogs, particularly hydroxydecyl benzoquinone (idebenone),
      with the respiratory complexes of heart mitochondria.
AB  - We have studied the interaction of idebenone (2,3-dimethoxy-5-methy-6-(10
      hydroxy)decyl-1,4-benzoquinone) with the energy-conserving complexes of the
      respiratory chain in beef heart mitochondria and compared its energetic
      efficiency with that of other analogs of coenzyme Q. Idebenone is a very
      effective substrate for succinate:Q reductase and ubiquinol:cytochrome c
      reductase, but it is clearly a poor substrate for NADH:Q reductase (complex I).
      Indeed, idebenone is a strong inhibitor of both the redox and proton pumping
      activity of complex I, showing effects in part similar to those of coenzyme Q-2.
      However, the mechanism of idebenone interaction with complex I may be different
      from that of Q-2 because of its different sensitivity to inhibitors. The possible
      relevance of the present findings to the therapeutic use of idebenone is
      discussed.

PMID- 8660671
TI  - Extracellular iron (II) can protect cells from hydrogen peroxide.
AB  - We hypothesized that exposure of cells to H2O2 plus Fe2+ would increase formation
      of cell-derived lipid peroxides that would inactivate prostaglandin H synthase,
      resulting in decreased prostaglandin synthesis. Therefore, we treated human
      endothelial cells with 0-100 microM H2O2 followed immediately by addition of 0
      200 microM Fe2+. After oxidant exposure, cells were stimulated with 20 microM
      arachidonic acid to induce prostaglandin I2 (PGI2) synthesis. Adding 100 microM
      H2O2 prior to arachidonic acid decreased PGI2 synthesis more than 80%. However,
      to our surprise, the addition of Fe2+, in increasing amounts, progressively
      protected PGI2 synthesis against the harmful effects of H2O2. A ratio of one part
      H2O2 to two parts Fe2+ offered almost complete protection, whereas Fe3+ did not
      protect PGI2 synthesis from H2O2. We found that 100 microM H2O2 was not
      cytolytic; however, 250 microM H2O2 was cytolytic; Fe2+ protected against this
      cytotoxicity. In addition, extracellular Fe2+ prevented the rise in intracellular
      calcium caused by H2O2 and extracellular Fe2+ preserved intracellular glutathione
      in H2O2-exposed cells. Electron paramagnetic resonance spin trapping demonstrated
      that extracellular Fe2+ generated the hydroxyl free radical, HO. outside the
      cell. We speculate that extracellular Fe2+ protects the intracellular space from
      H2O2 by initiating the Fenton reaction outside the cell. This reductive cleavage
      of H2O2 generates HO. in the extracellular space, where much of the HO. will
      react with noncellular components, thereby protecting the cell interior.

PMID- 8660673
TI  - Light-induced charge separation between plastocyanin and the iron-sulfur clusters
      FA and FB in the complex of plastocyanin and photosystem I.
AB  - The light-induced electron transfer in a crosslinked complex between plastocyanin
      and photosystem I from spinach was studied by EPR at low temperature. Electron
      donation from reduced plastocyanin to P700+ was observed under illumination above
      a temperature of about 160 K, resulting in a second charge separation and an
      electron transfer from rereduced P700 to the terminal electron acceptors FA/FB.
      The charge-separated state Pc oxP700+ [FA/FB](2-) was found to be stable at 15 K.
      Implications of these results for the kinetic constants of the donation reaction
      and the backtransfer of electrons from reduced acceptors as well as for the
      structural models of the terminal acceptors are discussed.

PMID- 8660672
TI  - Vitamin B6 deficiency accelerates metabolic turnover of cystathionase in rat
      liver.
AB  - Although most of cystathionase was found to exist as an inactive apoenzyme in the
      liver of vitamin B6-deficient rats, the concentrations of the immunoreactive
      enzyme protein were virtually the same for control and vitamin B6-deficient
      livers. Under vitamin B6 deficiency, however, the rate of synthesis of
      cystathionase, measured by incorporation of labeled amino acid into the
      immunoprecipitated enzyme, was increased severalfold due to an increased level of
      cystathionase mRNA. Western blot analysis of lysosomal proteins showed that the
      amount of cystathionase in the lysosomes from the liver of vitamin B6-deficient
      rats was also increased severalfold. This observation suggests that lysosomes
      specifically recognize the apocystathionase for sequestration in preference to
      the holoenzyme. The present study provides the molecular basis for dual roles of
      vitamin B6 in controlling the metabolic turnover of cystathionase; it regulates
      synthesis of the enzyme by modulating the expression of cystathionase gene, and
      it regulates degradation of the enzyme by different susceptibilities of apo- and
      holoenzymes to lysosomal proteolysis.

PMID- 8660674
TI  - Prostaglandin synthase 2 expression in epidermal growth factor-dependent
      proliferation of mouse keratinocytes.
AB  - BALB/c mouse keratinocytes (BALB/MK) are nontumorigenic epithelial cells which
      are dependent on mouse epidermal growth factor (EGF) for maintaining
      proliferation in culture. In BALB/MK the oxygenation of both arachidonic acid and
      linoleic acid was dependent on EGF. EGF stimulated the formation of prostaglandin
      E2 and prostaglandin F2 alpha from arachidonic acid and 9- and 13
      hydroxyoctadecadienoic acid (HODE) from linoleic acid. Analysis of the linoleic
      acid metabolites determined the ratio of 9-HODE to 13-HODE was approximately 6 to
      4, and the 9-HODE was the (R) enantiomer, consistent with metabolism by
      prostaglandin G/H synthase (PGHS). The formation of these linoleic acid
      metabolites was sensitive to indomethacin, a PGHS inhibitor. EGF induced the
      expression of PGHS-2 mRNA after 30 min, which peaked after 1 h, and remained
      expressed for at least 24 h after the addition of EGF. A less significant
      increase in the expression of PGHS-1 mRNA occurred 4 h after EGF stimulation.
      Immunoblot analysis did not detect expression of PGHS-1 protein. However, PGHS-2
      protein expression was increased 2 h after EGF exposure and was dependent on EGF.
      PGHS-2 protein was not transiently expressed as reported with other cell types,
      but was continually expressed in proliferating cells maintained with EGF at a
      subconfluent density. Indomethacin significantly attenuated EGF-dependent
      mitogenesis and cell proliferation. These results suggest that PGHS-2 activity
      contributes to the proliferative response of BALB/MK to EGF.

PMID- 8660675
TI  - Fatty acid amide biosynthesis: a possible new role for peptidylglycine alpha
      amidating enzyme and acyl-coenzyme A: glycine N-acyltransferase.
AB  - Fatty acid primary amides have recently been recognized as mammalian hormones
      [Cravatt et al. (1995) Science 268, 1506-1509]. The route to their biosynthesis
      is unknown. Many mammalian peptide hormones also possess a C-terminal alpha-amide
      moiety that arises from the posttranslational oxidative cleavage of a C-terminal
      glycine-extended precursor. The enzyme that catalyzes this reaction is
      peptidylglycine alpha-amidating enzyme, which is known to preferentially amidate
      peptide substrates containing a penultimate, hydrophobic amino acid [Tamburini et
      al. (1990) Int. J. Pept. Protein Res. 35, 153-156]. We show that N
      myristoylglycine is a substrate for peptidylglycine alpha-amidating enzyme with a
      (V/K)app that is 55 +/- 4% of the value measured for D-Tyr-Val-Gly. N-Fatty
      acylglycines are enzymatically produced in mammals from fatty acyl-coenzyme A
      (CoAs) and glycine by acyl-CoA:glycine N-acyltransferase. The sequential actions
      of acyl-CoA:glycine N-acyltransferase and peptidyl-glycine alpha-amidating enzyme
      would lead to the biosynthesis of fatty acid amides.

PMID- 8660676
TI  - Purification and characterization of protein phosphatase 2C in rat parotid acinar
      cells: two forms of Mg(2+)-activated histone phosphatase and phosphorylation by
      cAMP-dependent protein kinase.
AB  - Two forms of Mg(2+)-activated histone phosphatase activities were partially
      purified from rat parotid acinar cells using Mono Q and gel filtration
      chromatography. Both enzymes activities were dependent on the presence of Mg2+,
      showing little activity in the presence of EDTA. The activities fractionated on
      the Mono Q column into two peaks: the first was a minor peak of histone
      phosphatase activity; the second was a major peak. These two peaks eluted at
      distinct positions on the gel filtration column. The molecular masses of the two
      peak fractions corresponded to 46 and 55 kDa, respectively on SDS-gels. The first
      46-kDa peak immunoreacted with anti-PP2Calpha phosphatase antibody and like
      PP2Calpha phosphatase could be phosphorylated by cAMP-dependent protein kinase.
      The second 55-kDa peak showed neither reactivity with anti-PP2Calpha phosphatase
      antibody nor phosphorylability by cAMP-dependent protein kinase, but retained a
      Mg2+ or Mn2+ dependence for its histone phosphatase activity. Ca2+ showed a
      strong inhibition on this activity. On the basis of these observations, we have
      identified the first peak enzyme as PP2Calpha phosphatase and the second peak as
      a novel PP2C-like phosphatase.

PMID- 8660677
TI  - The effects of nitric oxide on electron transport complexes.
AB  - The effect of nitric oxide on mitochondrial electron transfer complexes was
      studied by comparing the activities of nitric oxide-treated and untreated,
      deoxygenated samples of purified beef heart succinate-cytochrome c reductase,
      succinate-ubiquinone reductase, and ubiquinol-cytochrome c reductase. More than
      90% of succinate-cytochrome c reductase activity is lost during nitric oxide
      treatment. The activity of the succinate-ubiquinone reductase component of
      succinate-cytochrome c reductase decreases 95%, while the ubiquinol-cytochrome c
      reductase component is unaffected by nitric oxide. This inactivation is due
      primarily to the destruction of iron-sulfur clusters from succinate-ubiquinone
      reductase. When purified beef heart succinate-ubiquinone reductase was treated
      with nitric oxide, virtually all activity was irreversibly lost. The electron
      paramagnetic resonance (EPR) spectra of the treated complex showed typical iron
      nitric oxide complex signals, confirming that inactivation is due to destruction
      of the iron-sulfur clusters. Similar results were obtained with purified
      Escherichia coli succinate-ubiquinone reductase. Pure beef heart ubiquinol
      cytochrome c reductase treated with nitric oxide loses 40% of its initial
      activity, but regains most of it (90-100 % after 24 h of incubation at 0 degrees
      C in the absence of nitric oxide. This suggests that ubiquinol-cytochrome c
      reductase is protected from nitric oxide when complexed with succinate-ubiquinone
      reductase or that when split from succinate-ubiquinone reductase, ubiquinol
      cytochrome c reductase undergoes a conformational change which allows access of
      nitric oxide to the Rieske iron-sulfur center. Such access is not possible when
      ubiquinol-cytochrome c reductase is complexed with succinate-ubiquinone
      reductase. The loss of ubiquinol-cytochrome c reductase activity correlates with
      a decrease in the Rieske protein EPR signal intensity without formation of any
      new EPR signal. The Rieske iron-sulfur cluster signal is recovered after 24 h
      incubation in the absence of nitric oxide.

PMID- 8660678
TI  - Kinetics of the slow pH-mediated transition of polyphenol oxidase.
AB  - Catecholase activity of latent polyphenol oxidase from broad bean leaves showed a
      hysteresis phenomenon above pH 4, whereas a steady-state rate was reached
      immediately when pH values were lower, thus suggesting that slow pH-induced
      conformational changes in the protein occur during the assay. When the enzyme was
      activated by sodium dodecyl sulfate, the lag period completely disappeared. This
      transition was reversible, since a burst was observed when the enzyme was
      preincubated at acid pH, before being returned to its previous experimental
      conditions. The pK for the isomerization process (pK(H) = 4.6) was estimated by
      preincubating the enzyme at different pH values and analyzing the product
      accumulation curves. Negative kinetic cooperativity was evident over a pH range
      in which the isomerization reaction was significant when the steady state was
      measured as a function of different substrate concentrations.

PMID- 8660679
TI  - Determination of the core sequence of an antagonist of selectin-dependent
      leukocyte adhesion and correlation of its structure with molecular modeling
      studies.
AB  - The sequence 36-50 from the lectin domain of human P-selectin has been previously
      identified as a weak inhibitor of selectin-dependent leukocyte adhesion. A series
      of C- and N-terminally truncated peptides was synthesized to determine the limits
      of the active core region within the parent sequence. Deletions from both the N-
      and C-termini gave significant increases in inhibitory activity and identified 41
      50 or 36-49 as minimum active sequences, but surprisingly not the common 41-49
      peptide. All peptides tested showed parallel inhibition of both P- and E-selectin
      dependent adhesion. A molecular model of the lectin domain was constructed using
      homology modeling. Examination of this model suggests one hypothesis to explain
      the increase in activity on deletion of Asp36.

PMID- 8660680
TI  - 1,4-Benzoquinone reductase from basidiomycete Phanerochaete chrysosporium:
      spectral and kinetic analysis.
AB  - The reaction mechanism of a 1,4-benzoquinone reductase from the wood-rotting
      basidiomycete Phanerochaete chrysosporium was investigated. The native, oxidized,
      FMN-containing enzyme was reduced quantitatively by NADH and the resulting
      reduced enzyme was reoxidized in the presence of one equivalent of 2,6-di-methoxy
      1,4-benzoquinone (DMBQ). The stoichiometry of NADH oxidation versus DMBQ
      reduction is 1:1. The enzyme catalyzes the reduction of quinones to hydroquinones
      by a ping-pong steady-state mechanism. However, inhibition is observed at low
      NADH concentrations. Quinone products derived from the autooxidation of the
      unstable compounds 1,2,4-trihydroxybenzene and 5-chloro-2,3,4-trihydroxybenzene
      also appear to be substrates for the quinone reductase. The enzyme reduces the
      one-electron acceptors ferricyanide and ferricytochrome c (Cc3+) with rates of
      58.4 and 0.08%, respectively, compared to DMBQ. The stoichiometry of NADH
      oxidation versus ferricyanide reduction is 1:2. In the presence of quinones the
      rates of Cc3+ and ferricyanide reduction are increased, owing to the nonenzymatic
      reduction of these acceptors by enzyme-generated hydroquinone products. Dicumarol
      and Cibacron blue are competitive inhibitors with respect to NADH, with Ki values
      of 2.1 and 0.30 microM, respectively. Reconstitution of the apoprotein with FMN
      yields a fully active enzyme at an FMN-to-protein ratio of 2:1, suggesting that
      the flavin content of the enzyme is two molecules of FMN per dimer.

PMID- 8660681
TI  - Functional muscarinic receptors in cultured skeletal muscle.
AB  - We studied the influence of muscarinic and nicotinic stimulation on both
      phosphoinositide metabolism and intracellular calcium levels in rat skeletal
      muscle primary cultures. Both nicotine and muscarine induced an increase in
      cytosolic calcium measured by fluo 3 fluorescence in confocal microscopy. The
      mass of inositol (1,4,5)trisphosphate measured by radioreceptor assay rose 2- to
      3.5-fold upon carbachol, nicotine, or muscarine stimulation. The muscarine effect
      was mimicked by oxotremorine-M; pirenzepine prevented the muscarine-induced
      inositol (1,4,5)trisphosphate increase, whereas 4-diphenylacetoxy-N-methyl
      piperidine methiodide was ineffective. A relatively small (40 fmol/mg protein)
      high-affinity 3-quinuclidinylbenzilate binding to rat myotube microsomes was
      consistent with the muscarinic effect found. On the other hand, the effect of
      nicotine on the mass of inositol (1,4,5)trisphosphate was totally suppressed in
      sodium-free medium. Expression of Ml muscarinic receptors coupled to
      phospholipase C and to internal calcium stores in cultured skeletal muscle is
      proposed; nicotinic receptors could be acting via ion fluxes and membrane
      depolarization.

PMID- 8660682
TI  - Inhibition of the reconstituted mitochondrial oxoglutarate carrier by arginine
      specific reagents.
AB  - The effect of arginine-specific reagents on the function of the purified and
      reconstituted oxoglutarate carrier protein of the inner mitochondrial membrane
      has been investigated. The alpha-dicarbonyl reagents 2,3-butanedione, 2,3
      pentanedione, 2,3- and 3,4-hexanedione, 1-phenyl-1,2-propanedione, phenylglyoxal,
      and phenylglyoxal derivatives caused a concentration-dependent inhibition of
      oxoglutarate transport with an IC50 of 0.05 mM for 2,3-hexanedione, 0.08 mM for 4
      hydroxy-3-nitrophenylglyoxal, and 0.17 mM for 2,3-pentanedione. The inhibition
      increased with pH from 6.0 to 8.0, indicating that the pK of the reacting
      group(s) is rather high. Mersalyl and pyridoxal 5'-phosphate (or 4,4'
      dinitrostilbene-2,2'-disulfonate), which are known to react specifically and
      reversibly with cysteine residues and lysine residues, respectively, were unable
      to protect the oxoglutarate carrier against inhibition by alpha-dicarbonyl
      reagents. Other diketone compounds, which do not react with arginine residues,
      had no significant effect on the oxoglutarate transport activity. Oxoglutarate
      and L-malate effectively protected the oxoglutarate carrier against inactivation
      caused by arginine-specific reagents; other dicarboxylates, which are not
      substrates of the carrier, had no protective effect. A 50% substrate protection
      was observed at half-saturation of the external binding site. These results
      indicate that the arginine-specific reagents used in this investigation interact
      with the oxoglutarate carrier at the level of an arginine residue(s), which is
      essential for binding and/or translocation of substrates and which may be
      localized in, or near, the substrate-binding site.

PMID- 8660683
TI  - Characterization of an acyl-CoA-binding protein from Arabidopsis thaliana.
AB  - A cDNA clone was obtained from Arabidopsis thaliana that encodes a protein
      containing 92 amino acid residues with high sequence identity (57%) to bovine
      acyl-CoA-binding protein (ACBP). The coding sequence of this clone was expressed
      in Escherichia coli and the gene product (10.4 kDa) was purified. The recombinant
      A. thaliana ACBP (rAthACBP) was shown to bind acyl-CoA esters and protect acyl
      CoAs from degradation by microsomal acyl-hydrolases. Antibodies that were raised
      to rAthACBP recognized the native Arabidopsis ACBP and also cross-reacted with a
      number of other plant ACBPs, including rapeseed (Brassica napus) ACBP. The
      pattern of expression and level of the gene product were examined in various
      tissues of Arabidopsis and Brassica using Western blotting. A. thaliana tissues
      contained between 3 and 143 micrograms AthACBP g(-1) FW depending on the tissue
      (0.4 to 14 nmol g(-1) FW). Developing B. napus seeds underwent a 12-fold increase
      in ACBP levels during seed maturation (20 to 250 micrograms ACBP g(-1) FW); the
      highest concentration occurring near the peak of triacylglycerol accumulation (26
      nmol g(-1) FW.

PMID- 8660684
TI  - Antioxidants, tissue damage, and endurance in trained and untrained young male
      rats.
AB  - It is well known that physical training permits an animal to respond successfully
      to exercise loads of various types, intensities, and durations. Furthermore, the
      trained animal can sustain the activity for a long period before the fatigue
      becomes limiting. The effects of physical training on the antioxidant defenses of
      tissues and on their susceptibility to damage induced by exhaustive exercise have
      been investigated. Therefore, untrained rats were sacrificed either at rest or
      immediately after swimming to exhaustion. Rats trained to swim for 10 weeks were
      also sacrificed, 48 hr after the last exercise, either at rest or after
      exhaustive swimming. Homogenates of liver, heart, and muscle were used for
      biochemical determinations. Mitochondrial and sarcoplasmic (SR) or endoplasmic
      (ER) reticulum integrity was assessed with measurements of respiratory control
      index and latency of alkaline phosphatase activity. Lipid peroxidation was
      measured by determination of malondialdehyde and hydroperoxides. Additionally,
      the effect of training on the antioxidant protection systems of tissues was
      examined by determining the glutathione peroxidase and glutathione reductase
      activity and the overall antioxidant capacity. Mitochondrial, SR, and ER
      integrity and lipid peroxidation were similar in trained and untrained at rest
      animals, whereas the glutathione peroxidase and glutathione reductase activity
      and the overall antioxidant capacity of tissues were greater in trained animals.
      The exhaustive exercise gave rise to tissue damage irrespective of the trained
      state, as documented by similar loss of SR and ER integrity, and by increase in
      lipid peroxidation found in exhausted trained and untrained rats. Because
      exercise endurance capacity was greatly increased by training, our results
      suggest that free radical-induced damage in muscle could be one of the factors
      terminating muscle effort. In effect, the greater antioxidant level should allow
      trained muscle to withstand oxidative processes more effectively, thus
      lengthening the time required so that the cell function is sufficiently damaged
      as to make further exercise impossible.

PMID- 8660685
TI  - Interaction of ferric complexes with NADH-cytochrome b5 reductase and cytochrome
      b5: lipid peroxidation, H2O2 generation, and ferric reduction.
AB  - NADH is reactive in interacting with iron and liver microsomes to catalyze the
      formation of reactive oxygen species. NADH-dependent microsomal electron transfer
      involves the enzymes NADH-cytochrome b5 reductase and cytochrome b5. Experiments
      were carried out to evaluate the ability of reconstituted systems containing
      purified reductase in the absence or presence of b5 to reduce several ferric
      complexes, to generate H2O2, and to catalyze lipid peroxidation. The reductase
      directly reduced ferric-EDTA; addition of b5 inhibited this reduction probably
      due to competition for the reductase. Cytochrome b5 was required for reduction of
      low (5 microM) and high (50 microM) concentrations of ferric-histidine and ferric
      ammonium sulfate and low concentrations of ferric-ATP. The reductase could
      interact directly with high (50 microM) concentrations of ferric-ATP.
      Peroxidation of phospholipids extracted from liver microsomes by the reductase
      required b5. Molar ratios of b5 to reductase approximating those found in liver
      microsomes (e.g., 10) were effective in catalyzing lipid peroxidation and ferric
      reduction. The role of b5 in catalyzing lipid peroxidation appears to involve
      reduction of the ferric catalyst to help form an initiation complex and
      degradation of lipid hydroperoxides by the hemeprotein to catalyze propagation of
      the peroxidation cycle. In contrast to results with microsomes, lipid
      peroxidation by the complete reconstituted system was sensitive to super-oxide
      dismutase; this sensitivity was decreased if the reconstituted system was
      dialyzed overnight to form vesicular preparations, indicating that accessibility
      of enzymes to sites of peroxidation was important. High rates of H2O2 formation
      were observed in the presence of ferric-EDTA plus reductase; rates of H2O2
      formation with the other ferric complexes were low even in the presence of b5.
      These results indicate that the ability of NADH reductase and cytochrome b5 to
      interact with various ferric complexes depends on the nature of the chelating
      agent used to complex the iron and on the concentration of the iron.

PMID- 8660686
TI  - Involvement of synthesis and phosphorylation of nuclear protein factors that bind
      to the positive cis-acting element in the transcriptional activation of the
      CYP2B1/B2 gene by phenobarbitone in vivo.
AB  - The synthesis and phosphorylation of protein factor(s) that bind to the positive
      cis-acting element (-69 to -98 nt) of the CYP2B1/B2 gene have been examined in
      vivo in the rat. Treatment of rats with cycloheximide, a protein synthetic
      inhibitor, suppresses basal as well as phenobarbitone-induced levels of CYP2B1/B2
      mRNA and its run-on transcription. Under these conditions, complex formation of
      the nuclear extract with the positive element is also inhibited, as judged by gel
      shift assays. Treatment of rats with 2-aminopurine, a general protein kinase
      inhibitor, blocks the phenobarbitone-mediated increase in CYP2B1/B2 mRNA, cell
      free transcription of a minigene construct containing the positive element,
      pP450e179DNA, and binding of nuclear proteins to the positive element. Treatment
      of rats with okadaic acid, a protein phosphatase inhibitor, mimics the effects of
      phenobarbitone, but only partially. Thus, both phenobarbitone and okadaic acid
      individually enhance binding of the nuclear protein(s) to the positive element,
      cell-free transcription of the minigene construct, and phosphorylation of the
      approximately 26- and 94-kDa proteins binding to the positive element. But unlike
      phenobarbitone, okadaic acid is not an inducer of CYP2B1/B2 mRNA or its run-on
      transcription. Thus, phenobarbitone-responsive positive element interactions
      constitute only a minimal requirement, and okadaic acid is perhaps not able to
      bring about the total requirement for activation of CYP2B1/B2 gene transcription
      that should include interaction between the minimal promoter and further upstream
      elements. An intriguing feature is the antagonistic effect of okadaic acid on
      phenobarbitone-mediated effects on CYP21B1/B2 mRNA levels, cell-free and run-on
      transcription, and nuclear protein binding to the positive element. The reason
      for this antagonism is not clear. It is concluded that phenobarbitone treatment
      enhances in vivo the synthesis and phosphorylation of protein factors binding to
      the positive element and these constitute a minimal requirement for the
      transcriptional activation of the CYP2B1/B2 gene.

PMID- 8660687
TI  - Expression and distribution of meprin protease subunits in mouse intestine.
AB  - Meprins, zinc metalloendopeptidases of kidney and intestinal brush border
      membranes, are composed of differing ratios of alpha and beta subunits. Previous
      work indicated that the beta subunit was expressed in kidney and intestine of all
      mouse strains, but that the alpha subunit was only expressed in kidney of random
      bred and some inbred strains and not in mouse intestine. The work herein,
      however, reports that low levels of meprin alpha subunit mRNA and protein are
      detectable in mouse intestine and are present in increasing concentrations from
      the duodenum to the ileum. In ICR mice, the duodenum expressed less than 1% of
      the meprin alpha mRNA (micrograms/g tissue) relative to kidney, the ileum
      approximately 20%. The large intestine contained approximately 10% of the message
      found in kidney. An inbred mouse strain, C3H/He, found previously to contain only
      meprin beta subunits in kidney and intestine, displayed very low levels of meprin
      alpha mRNA (approximately 1% of that in ICR kidney) in both the kidney and
      intestine. Intestinal meprin beta mRNA in ICR and C3H/He mice, by contrast, was
      expressed at similar levels to that found in kidney, and for both strains there
      was an increase (two- to threefold) in the beta message in the ileum relative to
      duodenum or jejunum. In general, the pattern of the meprin alpha protein along
      the intestine was similar to that of alpha mRNA, and activity and response of
      intestinal meprin A to inhibitors were typical of the enzyme isolated from
      kidney. These data indicate that meprin alpha can be detected in mouse small and
      large intestine and that expression is not only tissue- and strain-specific but
      also longitudinally variable in intestine. The expression pattern for both a and
      beta subunits indicates an ileal function for the meprins.

PMID- 8660688
TI  - Purification and characterization of Ca(2+)-dependent phospholipases A2 from rat
      kidney.
AB  - Three phospholipase A2 (PLA2) activities were identified in rat kidney. In the
      particulate fraction a PLA2 activity was present which was cross-reactive with
      polyclonal antibodies against the 14-kDa group II PLA2. This PLA2 was partially
      solubilized and purified to near homogeneity. The amino acid sequence at the N
      terminus of the purified enzyme was identical to that of the 14-kDa rat group II
      PLA2 from rat liver mitochondria, platelet, and spleen. The cytosolic fraction of
      rat kidney contained at least two PLA2 activities which could be separated on a
      Mono Q column. Upon gel filtration the activity that eluted from the anion
      exchange column in the salt gradient behaved as a high molecular mass PLA2,
      exhibited a preference for arachidonic acid at the sn-2 position of
      glycerophospholipids, and was already optimally active at submillimolar Ca2+
      concentrations. The cytosolic PLA2 activity that did not bind to the anion
      exchange column was purified by gel filtration, immunoaffinity chromatography
      using immobilized polyclonal antibodies to group I PLA2, and C18 reversed-phase
      chromatography. Immunological properties and N-terminal sequence analysis
      identified this enzyme as rat group I PLA2. Rat glomerular mesangial cells
      contained only group II and high molecular mass PLA2 enzymes.

PMID- 8660689
TI  - Elevations of hepatic quinone reductase, glutathione, and alpha- and mu-class
      glutathione S-transferase isoforms in mice with chronic hepatitis: a compensatory
      response to injury.
AB  - Hepatic levels of GSH and Phase II detoxication enzymes were compared to
      biochemical and histological indices of hepatic damage in 4- to 76-week-old
      nontransgenic mice and their transgenic littermates that overexpress the
      hepatitis B virus large envelope protein. The mice were fed a low-sucrose AIN-76A
      diet ad libitum. Hepatic-specific activities of quinone reductase (QR) and
      glutathione S-transferase (GST) were increased 2- to 10-fold beginning at 12
      weeks of age in transgenic mice and correlated with increases in serum alanine
      aminotransferase (ALT) (r = 0.84 and 0.59, respectively). Quantitative
      histological analysis demonstrated that apoptosis was the predominant feature in
      4- to 12-week-old transgenic mice, whereas necrosis and inflammation predominated
      at later time points. Surprisingly, 3-fold elevations in ALT were observed
      beginning at 52 weeks of age in nontransgenic mice, and hepatic-specific
      activities of QR and GST were also modestly increased in elderly nontransgenic
      animals. In contrast to transgenic mice, apoptosis was not a prominent feature.
      The strongest histological correlates to ALT in 4- to 76-week-old nontransgenic
      mice were necrosis and inflammation (r > 0.96), which in turn may have been
      evoked by hepatic fat accumulation. Profiles of specific GST isoforms were
      quantitated chromatographically and identified by sequencing tryptic digests. The
      Ya1 subunit of alpha-class GST was markedly increased from undetectable levels in
      transgenic mice, while more modest increases were observed in nontransgenic mice
      more than 1 year old. Fivefold elevations of the Yb1 subunit, a constitutively
      expressed mu-class GST, were found in transgenic mice older than 4 weeks of age,
      while 2-fold increases were observed in nontransgenic animals that were more than
      1 year old. These studies demonstrate that selected increases in Phase II
      detoxication enzymes are a stereotyped response to chronic hepatitis that is
      strikingly reminiscent of the treatment of mice with anticarcinogenic enzyme
      inducers.

PMID- 8660690
TI  - Thiol modification and site directed mutagenesis of the flavin domain of spinach
      NADH:nitrate reductase.
AB  - Incubation of either Chlorella nitrate reductase or the recombinant flavin domain
      of spinach nitrate reductase with reagents specific for modification of cysteine
      residues, such as N-ethylmaleimide, resulted in a time-dependent inactivation of
      NADH:ferricyanide reductase activity which could be prevented by incubation in
      the presence of NADH. At 25 degrees C and employing a fixed enzyme:modifier
      ratio, the rate of inactivation for both the Chlorella and spinach enzymes
      followed the order p-chloromercuribenzoate > methyl methanethiosulfonate > 2-(4'
      maleimidylanilino)naphthalene-6-sulfonic acid > N-ethylmaleimide. For the spinach
      flavin domain, inactivation by methyl methanethiosulfonate or p
      chloromercuribenzoate was found to be concentration independent suggesting the
      absence of nonspecific modifications. Initial rate studies of the methyl
      methanethiosulfonate-modified flavin domain indicated a reduction in
      NADH:ferricyanide activity (Vmax) from 85 to 44 micromol NADH consumed/min/nmol
      FAD and an increase in the Km for NADH from 12 to 35 microM when compared to the
      native enzyme, confirming a role for cysteine residue(s) in maintaining
      diaphorase activity. Site-directed mutagenesis of the four individual cysteines
      (residues 17, 54, 62, and 240) in the recombinant spinach flavin domain resulted
      in mutant proteins with visible and CD spectra very similar to those of the wild
      type domain. Initial rate studies indicated that only substitutions of serine for
      cysteine 240 decreased diaphorase activity with maximal NADH:ferricyanide
      activity for the C240S mutant corresponding to 51 micromol NADH consumed/min/nmol
      FAD with a Km for NADH of 14 microM. Mutation of C240 to Ala or Gly resulted in
      greater loss of activity. The thermal stability of the four serine mutants was
      slightly decreased compared to the wild-type domain with the C62S mutant
      exhibiting the greatest instability. In contrast to the effects on diaphorase
      activity, square wave voltammetric studies indicated changes in the oxidation
      reduction midpoint potential for the FAD/FADH2 couple in the C54S (E0'= -197 mV),
      C62S (E0' = -226 mV), and C240S (E0' = -219 mV) mutants compared to the wild-type
      domain (E0' = -268 mV). These results indicate that of the four cysteine residues
      in the spinach nitrate reductase flavin domain, only C240 plays a role in
      maintaining diaphorase activity, while C54 has the greatest influence on flavin
      redox potential and that no correlation between changes in catalytic activity and
      flavin redox potential was observed.

PMID- 8660691
TI  - Cloning of a cDNA for short/branched chain acyl-Coenzyme A dehydrogenase from rat
      and characterization of its tissue expression and substrate specificity.
AB  - The acyl-CoA dehydrogenases are a family of related enzymes which catalyze the
      alpha,beta-dehydrogenation of acyl-CoA esters, transferring electrons to electron
      transferring flavoprotein. A cDNA for human short/branched chain acyl-CoA
      dehydrogenase has recently been cloned, and it has been suggested that this
      enzyme represents the human homolog for the previously reported 2-methyl branched
      chain acyl-CoA dehydrogenase purified from rat liver. We now report the cloning
      and expression of rat short/branched chain acyl-CoA dehydrogenase and
      characterization of its substrate specificity. The rat enzyme is more active
      toward longer carbon side chains than its human counterpart, while the human
      enzyme can utilize substrates with longer primary carbon chains. In addition,
      short/branched chain acyl-CoA dehydrogenase can utilize valproyl-CoA as a
      substrate. Northern blotting of mRNA shows ubiquitous tissue expression of both
      the rat and human enzyme. Further study of these enzymes will be helpful in
      understanding structure/function relationships in this gene family.

PMID- 8660692
TI  - Active-site topologies of human CYP2D6 and its aspartate-301 --> glutamate,
      asparagine, and glycine mutants.
AB  - Cytochrome P450 2D6 (CYP2D6) catalyzes the oxidation of substrates with a
      positively charged nitrogen atom 5-7 angstroms from the site of the oxidation.
      The active-site topology of CYP2D6 is examined here with phenyl-, 2-naphthyl-,
      and p-biphenyldiazene, which react with P450 enzymes to form sigma-bonded aryl
      iron (Fe-Ar) complexes. Ferricyanide-mediated migration of the aryl group from
      the iron to the porphyrin nitrogens produces the N-arylprotoporphyrin IX
      regioisomers (NB:NA:NC:ND, in which the aryl group is bound to the nitrogen of
      pyrrole rings B, A, C, and D, respectively) in the following ratios (zero means
      <5%): phenyl, 10:90:00:00; 2-naphthyl, 09:91:00:00; and p-biphenyl, 16:84:00:00.
      These results suggest that the CYP2D6 active site is open above pyrrole ring A
      and to a small extent above pyrrole ring B but is closed above pyrrole rings C
      and D. This geometry differs from those determined by the same method for P450s
      for which crystal structures are available. Replacement of Asp-301 by a Glu,
      which preserves the carboxylate side chain, causes no detectable change in the N
      aryl porphyrin regioisomer patterns and only minor changes in the catalytic
      activity. Replacement of Asp-301 by an Asn or Gly, which eliminates the
      negatively charged side chain, suppresses migration of the aryl groups to pyrrole
      ring B without impairing migration to pyrrole ring A and virtually abolishes
      catalytic activity. These results provide a refined model of the active site of
      CYP2D6. They confirm, furthermore, that the loss of activity observed when Asp
      301 is replaced by a neutral residue is due to loss of the charge-pairing
      interaction with the substrate positive charge and/or subtle structural effects
      in the vicinity of pyrrole ring B, but not to major structural reorganization of
      the active site.

PMID- 8660693
TI  - Inhibition of mitogen-activated protein kinase kinase blocks activation and
      redistribution of 5-lipoxygenase in HL-60 cells.
AB  - In Ca2+ ionophore-activated HL-60 granulocytes the mitogen-activated protein
      kinase kinase-1 inhibitor, PD098059, blocked translocation of 5-lipoxygenase from
      the cytosol to the nuclear membrane and the corresponding enzyme activation.
      PD098059 inhibited 5-HETE formation with an IC50 = 9.4 microM in cells stimulated
      with A23187 alone, and with an IC50 = 12 microM in cells stimulated with A23187
      plus 20 microM arachidonic acid. PD098059 inhibited translocation of 5
      lipoxygenase in a concentration-dependent manner with an IC50 approximately 10
      microM. At concentrations less than 100 microM PD098059 had no effect on purified
      recombinant 5-LO activity. Collectively, these data indicate that MAPKK-l
      participates in the molecular processes governing activation and translocation of
      5-lipoxygenase from the cytosol to the nuclear membrane.

PMID- 8660694
TI  - Effects of freezing, thawing, and storing human liver microsomes on cytochrome
      P450 activity.
AB  - The stability of cytochrome P450 enzymes, cytochrome b5, and NADPH-cytochrome c
      reductase was examined in (A) human liver samples frozen in liquid nitrogen and
      stored at -80 degrees C, (B) human liver microsomes suspended in 250 mM sucrose
      and stored at -80 degrees C, and (C) human liver microsomes subjected to as many
      as 10 cycles of thawing and freezing. In study A, microsomes from five human
      livers were prepared from fresh (unfrozen) tissue and from tissue that was stored
      frozen at -80 degrees C for 1, 2, 4, or 6 months. The apparent concentration of
      cytochromes P450 and b5 and the activity of NADPH-cytochrome c reductase
      decreased 20-40% as a result of freezing the liver, regardless of whether the
      liver was stored for 1 or 6 months. Similar decreases were observed in the
      activities of cytochrome P450 enzymes belonging to several gene families, namely
      CYP1A2 (7-ethoxyresorufin O-dealkylation and caffeine N3-demethylation), CYP2A6
      (coumarin 7-hydroxylation), CYP2C9 (tolbutamide methylhydroxylation), CYP2C19 (S
      mephenytoin 4'- hydroxylation), CYP2D6 (dextromethorphan O-de-methylation),
      CYP2E1 (chlorzoxazone 6-hydroxylation), CYP3A4solidus5 (testosterone 6beta
      hydroxylation), and CYP4A9solidus11 (lauric acid 12-hydroxylation). Freezing
      human liver did not convert cytochrome P450 to its inactive form, cytochrome
      P420, but it increased the contamination of liver microsomes with hemoglobin or
      other heme-containing proteins, which resulted in a uniform decrease in the
      specific activity of cytochromes P450 and b5 and in the specific activity of all
      P450 enzymes. In study B, the concentration of cytochromes P450 and b5, the
      activity of NADPH-cytochrome c reductase, and the activity of individual
      cytochrome P450 enzymes were determined in 10 samples of human liver microsomes
      stored at -80 degrees C for approximately 0, 1, or 2 years. The sample-to-sample
      variation in the concentration and activity of cytochrome P450, cytochrome b5,
      and NADPH-cytochrome c reductase was nominally affected by long-term storage of
      human liver microsomes at -80 degrees C, indicating there was no differential
      loss of cytochrome P450 activity, cytochrome b5 concentration, or NADPH
      cytochrome c reductase activity. In study C, microsomes from a pool of human
      livers were subjected to 1, 2, 3, 5, 7, or 10 cycles of freezing at -80 degrees C
      followed by thawing at room temperature. Freezing/thawing liver microsomes for up
      to 10 cycles did not convert cytochrome P450 to P420, nor did it cause
      significant loss of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or
      CYP4A9/11 activity. Overall, these results suggest that our current methods for
      storing and processing human liver are well suited to preserving microsomal P450
      enzyme activity.

PMID- 8660695
TI  - A role for threonine 302 in the mechanism-based inactivation of P450 2B4 by 2
      ethynylnaphthalene.
AB  - 2-Ethynylnaphthalene (2EN) is a mechanism-based inactivator of P450 2B4 that
      covalently modifies an amino acid in the peptide Glu273-Met314 with a 2
      naphthylacetyl group [Roberts et al. (1994) Biochemistry 33, 3766-3771].
      Truncated 2B4 lacking amino acids 2-27, 2B4 (Delta2-27), was expressed in
      Escherichia coli, purified, and found to catalyze the oxidation of 2EN to 2
      naphthylacetic acid (2NA). The metabolism of 2EN resulted in the inactivation and
      covalent modification of the protein moiety as we have previously reported with
      P450 2B4 purified from the livers of phenobarbital-induced rabbits. The rate
      constants of inactivation of the O-deethylation activity of 7-ethoxy-4
      trifluoromethylcoumarin (EFC) were 0.15 +/- 0.01 and 0.20 +/- 0.05 min-1 for the
      protein purified from rabbit liver and 2B4 (Delta2-27), respectively. A protein
      in which threonine 302 was replaced with alanine, P450 2B4 (Delta2-27, T302A),
      was inactivated by 2EN with a much slower rate constant (0.05 +/- 0.01 min-1) and
      formed 1.8-fold more 2NA as compared to P450 2B4 (Delta2-27) over a 10-min
      incubation. When the formation of 2NA was supported by cumene hydroperoxide, 2B4
      (Delta2-27, T302A) formed 30% less product than 2B4 (Delta2-27) over a 5-min
      incubation. After incubation with [3H]2EN and NADPH, P450 2B4 (Delta2-27) had
      significant radioactivity associated with the P450 in an NADPH-dependent manner
      when the incubation mixture was analyzed by SDS-PAGE followed by autoradiography
      and 10-fold more radioactivity associated with the P450 as compared to P450 2B4
      (Delta2-27, T302A) when analyzed by reverse-phase HPLC. Thus, threonine 302 is
      not required by 2B4 for oxidation of 2EN or EFC but appears to play an important
      role in the inactivation of P450 2B4 by 2EN and the covalent labeling of the P450
      protein by 2EN.

PMID- 8660696
TI  - The role of glycosylation in synthesis and secretion of beta-amyloid precursor
      protein by Chinese hamster ovary cells.
AB  - Alzheimer's disease is characterized by beta-amyloid deposition in the brain.
      This peptide is derived by proteolytic cleavage from beta-amyloid precursor
      protein (APP), a highly glycosylated membrane glycoprotein containing both N- and
      O-glycans. There are three major isoforms of APP, which are derived by
      alternative splicing and contain 695, 751, or 770 amino acids. Since
      glycosylation can affect many properties of glycoproteins, we studied the role of
      N- and O-glycosylation in the synthesis and secretion of APP. APP expression was
      examined in untransfected wild-type, Lec-8 mutant, and ldlD mutant Chinese
      hamster ovary (CHO) cells and in analogous clonal cell lines expressing either
      the transfected human wild-type 695-amino-acid form of APP (APP695-WT) or a form
      mutated to delete N-glycosylation sites (APP695-XX). These studies showed that
      maturation of APP in CHO cells is accompanied by the addition of multiple short O
      glycans with the following structures: Neu5Acalpha2-3Galbeta1-3GalNAc,
      Neu5Acalpha2-3Galbeta1-3[Neu5Acalpha2-6]GalNAc, and GalNAc. Using glycosylation
      defective mutant CHO cell lines and soluble inhibitors of glycosylation, we found
      that APP secretion was diminished when core N-glycosylation or N-glycan
      processing was blocked. Surprisingly, similar results were found when synthesis
      and secretion of either APP695-WT or APP695-XX were analyzed. These results
      indicate that defective N-glycosylation of other cellular proteins, but not of
      APP itself, affects the metabolism of APP. Interestingly, inhibition of O
      glycosylation did not affect the biosynthesis or secretion of APP. The results of
      these studies may shed some light on the role that protein glycosylation may play
      in the pathogenesis of Alzheimer's disease.

PMID- 8660697
TI  - Activation by acetaldehyde of the promoter of the mouse alpha2(I) collagen gene
      when transfected into rat activated stellate cells.
AB  - The effect of acetaldehyde in activating the mouse alpha2(I) collagen promoter in
      transiently transfected rat activated stellate cells and the possible mediating
      effect of transforming growth factor beta1 (TGFbeta1) on type I collagen gene
      expression were determined. Acetaldehyde and TGFbeta1, each had a similar effect
      in activating the wild-type promoter, but failed to activate the promoter with a 
      352 to -104 deletion, or the promoter containing a 3-bp substitution between -305
      and -303 in the putative nuclear factor I (NF-I) binding site. The effects of
      acetaldehyde and TGFbeta1 are therefore mediated by a similar factor or factors
      that bind to the NF-I consensus sequence within the region -352 to -104.
      Additional factors may also play a role in the effects of acetaldehyde and
      TGFbeta1, which have similar effects on the wild-type promoter, but become
      additive in activating the promoter with a more distal deletion containing a cis
      repressor element. Pretreatment of activated stellate cells with antibodies to
      TGFbeta1 suppressed the effect of acetaldehyde in increasing the alpha1(I)
      collagen message, indicating that TGFbeta1 mediates the effect of the
      acetaldehyde-induced increase in the expression of the alpha1(I) collagen gene
      which also contains NF-I binding sites.

PMID- 8660698
TI  - Regulation of intracellular magnesium in ascites cells: involvement of different
      regulatory pathways.
AB  - Extracellular ATP causes 40% stimulation of Mg2+ efflux from Ehrlich ascites
      tumor cells (EATC) incubated under 0-trans conditions. ATP also causes a
      threefold increase of arachidonic acid (AA) metabolite release from [3H]AA
      preloaded EATC, indicating that, under these experimental conditions, it induces
      phospholipase A2 (PLA2) activation. ATP-induced Mg2+ efflux can be prevented by
      cyclooxygenase inhibition with indomethacin or lysine acetylsalicylate, but not
      by 5-lipooxygenase inhibition with BWA4C. Mg2+ efflux is also directly stimulated
      by exogenous AA in a concentration-dependent manner. This phenomenon involves PKA
      as it is virtually abolished by the specific inhibitor 8-bromoadenosine-3',5'
      cyclic monophosphothioate. While stimulating Mg2+ efflux, exogenous AA also
      increases cAMP content of EATC and this effect can be prevented by cyclooxygenase
      inhibition. Measurements in mag-fura-2-loaded EATC reveal that stimulation of
      Mg2+ efflux does not correlate with significant fluctuations of [Mg2+]i. This
      suggests that Mg2+ efflux is compensated for by mobilization of bound Mg2+,
      leaving [Mg2+]i unaltered. Altogether these data indicate that Mg2+ efflux can be
      modulated by extracellular stimuli capable of activating PLA2. This modulation is
      triggered by cyclooxygenase products which, by activating adenylcyclase,
      determine an elevation of cAMP. This intracellular messenger upregulates Na
      dependent Mg2+ efflux.

PMID- 8660699
TI  - Effect of GLUT1 glucose transporter overexpression on the stimulation of glucose
      transport in response to inhibition of oxidative phosphorylation.
AB  - Glucose transport is markedly stimulated in response to inhibition of oxidative
      phosphorylation by cyanide or azide in Clone 9 cells, a rat liver cell line in
      which only the GLUT1 isoform of glucose transporters is expressed. Here, we
      examine the possibility that the stimulation of glucose transport by azide is
      similarly observed in cells exhibiting high basal rates of glucose transport. We
      stably transfected Clone 9 cells with an expression plasmid containing full
      length rat GLUT1 cDNA; nontransfected cells and cells transfected with plasmid
      alone served as controls. Two clones of cells transfected with the GLUT1-cDNA
      containing insert, labeled A and B, respectively, expressed 8- and 20-fold higher
      levels of GLUT1 mRNA, contained 11- and 23-fold higher levels of GLUT1, and
      manifested 11- and 17-fold higher rates of glucose transport in the basal state.
      Upon incubation with 5 mM azide for 2 h, the rate of glucose transport was
      markedly stimulated in both clones. Moreover, the transient fall in cell ATP
      content following exposure to azide did not correlate with the magnitude of the
      glucose transport response. We conclude that in GLUT1-overexpressing Clone 9
      cells (i) GLUT1 content and glucose transport parallel cellular GLUT1 mRNA
      content, suggesting no major translational or posttranslational control of GLUT1
      expression and function in the basal state, and (ii) the rate of glucose
      transport in cells overexpressing GLUT1 is markedly stimulated by exposure to
      azide. These results indicate that the stimulation of glucose transport in
      response to inhibition of oxidative phosphorylation is maintained in cells with
      very high basal rates of glucose transport.

PMID- 8660700
TI  - Maitotoxin induces calpain activation in SH-SY5Y neuroblastoma cells and
      cerebrocortical cultures.
AB  - Maitotoxin (MTX) is a highly potent marine toxin that activates both voltage
      sensitive and receptor-operated calcium channels in the plasma membrane. This
      results in calcium overload that rapidly leads to cell death. We now report that
      maitotoxin (0.1-1 nM) induces calpain activation in both SH-SY5Y neuroblastoma
      cells and fetal rat cerebrocortical cultures. MTX-induced calpain activation was
      confirmed by the presence of autolytic fragmentation of both subunits of calpain.
      Secondly, the formation of calpain-produced alpha-spectrin breakdown products
      (150 and 145 kDa) was observed. We were also able to detect intracellular
      hydrolysis of a peptide substrate (succinyl-Leu-Leu-Val-Tyr-7-amido-4
      methylcoumarin) by activated calpain in MTX-treated cells. Calpain inhibitors
      (calpain inhibitor I, MDL28170 and PD150606) inhibited spectrin breakdown and
      SLLVY-AMC hydrolysis in MTX-treated SY5Y cells. Our results suggest that (i)
      calpain is activated as a result of the maitotoxin-induced calcium influx; and
      (ii) coupling with the in situ calpain assays, maitotoxin would be a useful tool
      in investigating the physiologic and pathophysiologic roles of calpain in
      neuronal cells.

PMID- 8660701
TI  - A single mouse glutathione synthetase gene encodes six mRNAs with different 5'
      ends.
AB  - To understand more about the role of glutathione (GSH) in metabolism, we have
      cloned both cDNA and genomic sequences for mouse glutathione synthetase (GSH
      syn), the enzyme that catalyzes the last step in the synthesis of glutathione.
      The mouse cDNA contains an open reading frame (ORF) of 474 aa and shares 64 and
      95% deduced amino acid sequence identity with Xenopus cDNA and rat cDNA,
      respectively. The cDNA complements Schizosaccaromyces pombe strains deficient in
      GSH syn. The gene is a single-copy gene spanning approximately 30 kb and is
      composed of at least 15 exons. Steady-state RNA levels and enzyme activity levels
      are highest in kidney, about 3-fold lower in liver, and 8- to 10-fold lower in
      lung and brain. We have identified six different GSH syn RNAs: three, termed
      types A1, A2, and A3, have different 5' ends that localize to different sites in
      the gene, but appear to encode the same protein (474 aa). Types B, C1, and C2 all
      have unique 5' ends and type-specific ORFs, which are shorter than that for types
      A1, A2, and A3. In liver only type A1 GSH syn RNA is detectable, while in kidney
      90% of GSH syn RNA is type A1 and types B and C account for about 10%.

PMID- 8660702
TI  - Induction of a permeability transition in rat kidney mitochondria by
      pentachlorobutadienyl cysteine: a beta-lyase-independent process.
AB  - A Ca2+-dependent inner mitochondrial membrane permeability transition is induced
      by a number of agents, an effect which is thought to cause cytotoxicity. This
      transition involves formation of a pore allowing the passage of solutes of up to
      1500 Da; it is blocked by cyclosporine A and Ca2+ chelating agents. The
      mitochondrial nephrotoxicant S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine
      (PCBC) caused collapse of the mitochondrial membrane potential, Ca2+-independent
      oxidation of pyridine nucleotides and release of accumulated Ca2+ in isolated rat
      kidney mitochondria, three hallmarks of the permeability transition. These
      effects were blocked by cyclosporine A and by ethylene glycol bis(beta-aminoethyl
      ether) tetraacetic acid (EGTA). Furthermore, EGTA was capable of reversing the
      collapse of the membrane potential. These data indicate that PCBC induced an
      inner membrane permeability transition. Interestingly, addition of aminoxyacetic
      acid, a beta-lyase inhibitor, did not prevent the permeability transition, and a
      nonmetabolizable analog of PCBC, S-(1,2,3,4, 4-pentachlorobutadienyl)-L-alpha
      methyl cysteine, induced the permeability transition. Thus PCBC may act to induce
      the permeability transition through a mechanism that does not require metabolism
      by a beta-lyase. Since metabolism by a beta-lyase is required for PCBC toxicity,
      it is not clear that the permeability transition is involved in cysteine
      conjugate-mediated renal cell injury.

PMID- 8660703
TI  - Age-related decline of rat liver multicatalytic proteinase activity and
      protection from oxidative inactivation by heat-shock protein 90.
AB  - To test whether an observed age-related increase in the level of oxidized protein
      in rat liver is due to a decrease in the activity of the multicatalytic
      proteinase (MCP), this protease was isolated from liver of young (8-month-old)
      and old (24-month-old) male Fischer 344 rats. Three peptidase activities of the
      MCP were assayed using fluorogenic peptides: trypsin-like, chymotrypsin-like, and
      peptidylglutamyl-peptide hydrolase. Only peptidylglutamyl-peptide hydrolase
      activity declined with age, with protease from old animals exhibiting
      approximately 50% of the activity of that from young animals. Bidimensional gel
      electrophoresis and thermostability studies did not reveal age-related structural
      modifications of the MCP subunits. Peptidylglutamyl-peptide hydrolase activity
      and trypsin-like activity were sensitive to metal-catalyzed oxidation. In some
      preparations, a 95-kDa protein that has been identified as the heat shock protein
      90 copurified with the MCP. In the presence of HSP 90, trypsin-like activity is
      protected from oxidative inactivation and chymotrypsin-like activity is slightly
      activated. Peptidylglutamyl-peptide hydrolase activity remained sensitive to
      oxidation in protease isolated from young rats, but that from old rats was
      resistant to oxidative inactivation. Furthermore, addition of rat HSP 90 to rat
      liver MCP (purified from 8-month-old animals and free of contaminating HSP 90)
      was found to protect trypsin-like activity from oxidative inactivation.

PMID- 8660704
TI  - The effect of various nitric oxide-donor agents on hydrogen peroxide-mediated
      toxicity: a direct correlation between nitric oxide formation and protection.
AB  - The role that nitric oxide (NO) plays in various degenerative and disease states
      has remained a mystery since its discovery as a biological messenger, prompting
      the question, "NO, friend or foe?" Some reports have suggested that NO is
      cytotoxic, and yet others have shown that it possesses protective properties
      against reactive oxygen species (ROS). Many studies have used various NO donor
      complexes arriving at seemingly different conclusions. This report will address
      the effects of various NO donor compounds on ROS-mediated toxicity. Consistent
      with our previous study, the NO donor compound, DEA/NO ((C2H5)2N[N(O)NO]-Na+),
      afforded protection against hydrogen peroxide-mediated cytotoxicity in V79
      Chinese hamster lung fibroblasts at concentrations as low as 10 microM DEA/NO.
      Furthermore, a survey of other NO donor complexes revealed that some either
      protected or potentiated hydrogen peroxide-mediated cytotoxicity. 3
      Morpholinosynodiomine.HCl (SIN-1) and sodium nitroprusside (SNP) enhanced
      hydrogen peroxide-mediated cytotoxicity, while S-nitrosoglutathione (GSNO), and S
      nitroso-N-acetylpenicillamine (SNAP) afforded protection. Electrochemical
      detection of NO in cell culture medium revealed that neither 1000 microM SIN-1
      nor SNP yielded appreciable NO concentrations (<0.3 microM). In contrast, DEA/NO,
      SNAP, and GSNO yielded fluxes of NO >1.0 microM. Thus, a direct correlation
      between inhibition of hydrogen peroxide cytotoxicity and NO production was
      observed: agents that release NO during hydrogen peroxide treatment afford
      significant protection, whereas agents that do not release NO do not protect.
      Similar results were observed for NO donors studied when
      hypoxanthinesolidusxanthine oxidase was used as the source for ROS, although the
      S-nitrosothiol agents were much less protective. These results demonstrate that
      NO possesses properties which protect against ROS toxicity and demonstrate how
      the use of different NO donor compounds can lead to different conclusions about
      the role that NO can play in the cytotoxicity of ROS.

PMID- 8660705
TI  - Physical factors affecting the storage stability of freeze-dried interleukin-1
      receptor antagonist: glass transition and protein conformation.
AB  - The effects of glass transition of, and protein conformation in, the dried solid
      on the storage stability of freeze-dried recombinant human interleukin-1 receptor
      antagonist (rhIL-1ra) were examined. Glass transition is a temperature-dependent
      phenomenon. Amorphous materials become hard and brittle at temperatures below
      their characteristic glass transition temperatures (Tg) such that diffusion of
      molecules along the matrix is not sufficient to cause large-scale structural
      changes. To ascertain the importance of the glass transition in protein storage
      stability, we compared 10 different lyophilized rhIL-1ra formulations, with Tgs
      ranging from 20 to 56 degrees C, during several weeks of storage at temperatures
      above and below the samples' Tgs. Protein degradation, both deamidation and
      aggregation, was greatly accelerated at temperatures above Tg, but for some
      formulations also arose below Tg. Thus, storage of dried proteins below the Tg is
      necessary but not sufficient to ensure long-term stability. To examine the
      effects of protein structure in the dried solid, we prepared formulations with
      various sucrose concentrations, all of which had a Tg = 66 +/- 2.5 degrees C.
      With infrared spectroscopy, we determined that the protein lyophilized with </=1%
      sucrose was unfolded in the initial dried solid. In contrast, in those
      formulations with >/=5% sucrose, conformational change was inhibited during
      lyophilization. When stored at 50 degrees C, degradation of the freeze-dried
      protein varied inversely with sucrose concentration. These results indicate that
      structural changes arising during the lyophilization process led to damage during
      subsequent storage, even if the storage temperature was less than the Tg.
      Together the results of these studies document that to obtain optimum stability
      of dried rhIL-1ra it was necessary to inhibit conformational change during
      lyophilization and to store at temperatures below the Tg of the dried
      formulation.

PMID- 8660781
TI  - Constructing and Validating Motive Bridging Inferences
AB  - Understanding Jane left early for the birthday party, She spent an hour shopping
      at the mall requires detecting that the first statement motivates the second. The
      validation model states that before accepting this bridging inference, the reader
      validates it with reference to relevant knowledge. In particular, a mediating
      idea is first derived from the text outcome and its candidate motive. If the
      mediating idea is supported by general knowledge, then the inference has been
      validated. In tests of this anaylsis, experimental subjects read motive or
      control sequences and then answered questions probing the knowledge hypothesized
      to validate the motive inferences, such as Do birthday parties involve presents?
      Five experiments confirmed that understanding motive sequences facilitates
      validating knowledge. A control procedure also refuted a priming
      counterexplanation of these effects (Experiment 1). Validation processing
      obtained for motive-outcome statements separated by two to four sentences in
      coherent sequences (Experiments 2 to 4). Inferred and explicit validating
      knowledge had a similar representational status (Experiment 3). Whereas
      proofreading abolished the validation effect, a reading strategy promoting causal
      processing did not enhance it (Experiment 4). A delayed priming procedure
      indicated that validating knowledge is integrated with the text representation
      (Experiment 5). The implications of these findings for the constructionist and
      minimal inference analyses were explored. The validation effects were simulated
      using construction-integration model.

PMID- 8660706
TI  - The effect of the exogenous NADH dehydrogenase of heart mitochondria on the
      transmembranous proton movement.
AB  - Heart mitochondria can be made to oxidize extramitochondrial NADH via the
      exogenous NADH dehydrogenase. Oxidation of extramitochondrial NADH was found to
      be associated with the disappearance of H+ from the suspension medium. Our
      studies on the possible pathway through which H+ may disappear from the
      extramitochondrial space were focused on (i) an unspecific transmembranous H+
      leakage along the electrochemical H+ gradient following peroxidative membrane
      alteration, (ii) stimulation of a controlled H+ reconduction through the H+
      channel of the ATP synthase, and (iii) stimulation of the Na+/H+ counterporter by
      Ca2+ release. Our experiments revealed that none of these H+ pathways was
      involved in the observed alkalinization of the extramitochondrial space during
      respiration of external NADH. The latter effect was inhibited when oxidation of
      external NADH via the respiratory chain was blocked and could be turned into the
      opposite when artificial e- acceptors of the exogenous NADH dehydrogenase were
      used to reactivate NADH consumption. Stoichiometric analysis of H+ disappearance
      and O2 consumption revealed that reducing equivalents of external NADH were
      transferred to oxygen via cytochrome oxidase and H+ from the suspension was used
      to release water.

PMID- 8660782
TI  - The Slow Time-Course of Visual Attention
AB  - Visual attention is often conceived as a high-speed serial system moving rapidly
      from one object to another at rates of a few dozen milliseconds per item. We
      present four experiments demonstrating that this high-speed model is incorrect.
      Subjects identify two objects, presented at separate times. We measure how long
      the first object continues to interfere with accuracy on the second, and hence
      the time-course of the first object's attentional demand. We find interference
      for a half-second or more-roughly 10 times longer than might be predicted from
      conventional visual search paradigms. In further experiments, we show that the
      time-course of interference depends upon the number of attended objects, not the
      number or complexity of responses. Even objects which require no response, such
      as nontargets in visual search, can still produce long lasting interference on
      subsequent identification. We suggest that visual attention is not a high-speed
      switching mechanism, but instead a sustained state during which representations
      of relevant objects become available to guide behavior.

PMID- 8660783
TI  - Acknowledgment

PMID- 8660784
TI  - Analog Imagery in Mental Model Reasoning: Depictive Models
AB  - We investigated whether people can use analog imagery to model the behavior of a
      simple mechanical interaction. Subjects saw a static computer display of two
      touching gears that had different diameters. Their task was to determine whether
      marks on each gear would meet if the gears rotated inward. This task added a
      problem of coordination to the typical analog rotation task in that the gears had
      a physical interdependency; the angular velocity of one gear depended on the
      angular velocity of the other gear. In the first experiment, we found the linear
      relationship between response time and angular disparity that indicates analog
      imagery. In the second experiment, we found that people can also solve the
      problem through a non-analog, visual comparison. We also found that people of
      varying spatial ability could switch between analog and non-analog solutions if
      instructed to do so. In the third experiment, we examined whether the elicitation
      of physical knowledge would influence solution strategies. To do so, we
      manipulated the visual realism of the gear display. Subjects who saw the most
      realistic gears coordinated their transformations by using the surfaces of the
      gears, as though they were relying on the friction connecting the surfaces.
      Subjects who saw more schematic displays relied on analytic strategies, such as
      comparing the ratios made by the angles and/or diameters of the two gears. To
      explain the relationship between spatial and physical knowledge found in the
      experiments, we constructed a computer simulation of what we call depictive
      modeling. In a depictive model, general spatial knowledge and context-sensitive
      physical knowledge have the same ontology. This is different from prior
      simulations in which a non-analog representation would be needed to coordinate
      the analog behaviors of physical objects. In our simulation, the inference that
      coordinates the gear motions emerges from the analog rotations themselves. We
      suggest that mental depictions create a bridge between imagery and mental model
      research by positing the referent as the primary conceptual entity.

PMID- 8660785
TI  - Working memory: activation limitations on retrieval.
AB  - Two experiments which require subjects to hold a digit span while solving an
      equation and then recall the digit span are performed. The size of the memory
      span and the complexity of the equation are manipulated as well as whether the
      subject is required to substitute items from the digit span for constants in the
      equation. As either task (digit span recall or equation solving) gets more
      complex there are performance decrements (accuracy or latency) not only in that
      task but also in the other task. It is also shown that the majority of the errors
      are misretrievals. These results are consistent with the proposal that working
      memory load has its impact on retrieval from memory. These results are fit by the
      ACT-R theory (Anderson, 1993) which assumes that there is a limit on source
      activation and that this activation has to be divided between the two tasks. As
      either task increases in complexity there is less activation for retrieval of
      information from declarative memory. Subjects' misretrievals of associatively
      related information could be predicted by assuming a partial matching process in
      ACT-R.

PMID- 8660787
TI  - The Role of Information Reduction in Skill Acquisition
AB  - Theories of skill acquisition assume that the effects of practice on task
      performance are due to either qualitative changes in the task structure, an
      increased efficiency of performing individual task components, an increased
      efficiency of performing sequences of task components, or some combination of
      these mechanisms. We propose an extension to the existing theories by arguing
      that for many tasks, practice affects which information is processed. More
      specifically, we argue that people learn, over the course of practice, to
      separate task-relevant from task-redundant information, and to limit their
      processing to relevant aspects of the task. In three experiments, subjects
      verified alphabetic strings, such as M [4] R S T. Strings were correct if they
      followed the alphabet when the number of letters, given by the digit in
      parentheses, was skipped. Strings were constructed such that errors occurred only
      within the initial "letter-digit-letter" triplet. Analyses of subjects' RTs for
      strings of varying lengths demonstrated that: (a) subjects were able to
      distinguish relevant from redundant task information, and to limit their
      processing to the relevant information, (b) the ability to reduce the amount of
      information that is processed takes time and develops gradually over the course
      of practice, and (c) the mechanism underlying this ability appears to be largely
      stimulus-independent in the sense that structural components of a task are
      ignored, rather than specific task information. The findings and their
      implications for general theories of skill acquisition are discussed.

PMID- 8660786
TI  - Intelligence and the frontal lobe: the organization of goal-directed behavior.
AB  - Basic to the study of individual differences is the concept of 'general
      intelligence' or Spearman's g. In this article we suggest that g is largely a
      reflection of the control functions of the frontal lobe. A series of experiments
      investigates a phenomenon we call goal neglect: disregard of a task requirement
      event though it has been understood and remembered. Subjectively it is as though
      the neglected requirement "slips the subject's mind." Previously described in
      frontal patients, we show that goal neglect can also be seen in some members of
      the normal population. In line with conventional distinctions between controlled
      and automatic processing, eliciting conditions for goal neglect include novelty,
      weak error feedback, and multiple concurrent task requirements. Under these
      conditions neglect is linked closely to g and extremely common after frontal
      lesions. Following many other models, we suggest that behavior in any task is
      structured by a set of action constraints or requirements, derived in part from
      verbal instructions and specified at multiple levels of abstraction. A frontal
      process of constraint or requirement activation is fundamental to Spearman's g.

PMID- 8660791
TI  - First Louis Pasteur Conference on Infectious Diseases: Genetics of the
      Susceptibility to Infectious Diseases

PMID- 8660793
TI  - Tumors antigens encoded by oncogenes and the impact of oncogenes upon the immune
      responses.

PMID- 8660794
TI  - Requirement of cell interactions through adhesion molecules in the early phase of
      T cell development.
AB  - We investigated the role of adhesion molecules in T cell development. A large
      proportion of murine fetal thymus (FT) cells obtained at Day 13 of gestation,
      which are c-kit+, express the adhesion molecules Pgp-1, VLA-4, LFA-1, and ICAM-1
      on their surface at high levels. The expression profiles of these adhesion
      molecules resemble quite well those on c-kit+ cells in fetal liver (FL). The
      level of expression of these molecules on FT cells declines with the embryonal
      age and becomes mostly negative by birth except for LFA-1. In the case of LFA-1,
      a reincrease of expression levels is seen in newborn mice. The role of these
      adhesion molecules in T cell development was investigated by adding monoclonal
      antibodies (mAb) into the FT organ cultures, where T cell development from FT or
      FL progenitors was induced by coculturing these cells with a deoxyguanosine
      treated FT lobe. We found that anti-Pgp-1, anti-LFA-1, and anti-VLA-4 mAb
      severely inhibited the early phase of T cell development from FL progenitors. On
      the other hand, the suppressive effect of these mAb on the T cell development
      from FT progenitors was only slight, if any. These findings strongly suggest that
      interactions with elements in the thymic microenvironment through Pgp-1, LFA-1,
      and VLA-4 are indispensable for prethymic progenitors to develop into T cells.

PMID- 8660795
TI  - LPS does not directly induce STAT activity in mouse macrophages.
AB  - Induction of gene expression in cytokine-treated cells involves the protein
      tyrosine kinase-dependent activation of members of the STAT family of
      transcription factors. To determine if lipopolysaccharide (LPS) might activate
      one or more STAT factors, nuclear extracts from LPS-treated RAW264.7 macrophages
      were assayed for STAT-like DNA binding activity using oligonucleotides recognized
      by different members of this protein family. Within 30 min a single LPS-inducible
      DNA-protein complex was detected using three separate oligonucleotides. This
      activity was not reactive with anti-STAT antibodies and was subsequently
      identified as composed of the NF kappa B components NF kappa B1 and Rel-A. Thus,
      LPS does not directly stimulate STAT factors with known sequence-specific DNA
      binding activity.

PMID- 8660796
TI  - Soluble MHC II-peptide complexes induce antigen-specific apoptosis in T cells.
AB  - Soluble major histocompatibility (MHC) class II molecules in association with
      antigenic peptide recognize T cell receptors (TCRs) on CD4+ T cells. Such
      recognition of MHC II-peptide complexes by T cells in the absence of
      costimulatory signals is known to induce T cell nonresponsiveness. The present
      study describes that recognition of TCRs by MHC class II-peptide complexes
      induces antigen-specific apoptosis in a T cell clone independently of
      nonresponsiveness. Apoptosis was demonstrated in a murine T cell clone (4R3.9)
      restricted for IAk in association with a peptide analog of myelin basic protein
      [MBP(1-14)A4]. A dose- and time-dependent T cell death was observed upon
      incubation of 4R3.9 T cells with purified IAk-MBP(1-14)A4 complexes. The
      specificity of T cell apoptosis was shown by incubating 4R3.9 T cells with
      irrelevant IAs-MBP(90-101) complexes. The DNA fragmentation as a result of
      apoptosis was demonstrated by agarose gel electrophoresis and by pulsing T cells
      with BrdU followed by the detection of BrdU-labeled DNA fragments using an
      antibody enzyme-linked immunosorbent assay. The expression level of two
      regulatory intracellular proteins, bcl-2 and bax, involved in apoptosis showed a
      decrease in bcl-2 and an increase in bax with time. Finally, the nuclear
      shrinkage and chromatin condensation, typical hallmark of apoptosis, have been
      demonstrated by transmission electron microscopy of complex-treated T cells.
      Since the T cell clone (4R3.9) used in this study failed to show
      nonresponsiveness by IAk-MBP(1-14)A4 complexes, our results suggest that
      apoptosis induced by purified MHC class II-peptide complexes may involve distinct
      pathways rather than T cell nonresponsiveness. Such antigen-specific apoptosis
      may have significant clinical relevance in deleting autoreactive T cells in
      various autoimmune diseases.

PMID- 8660797
TI  - Evidence for endogenous C1q modulates TNF-alpha receptor synthesis and autocrine
      binding of TNF-alpha associated with lipid A activation of murine macrophages for
      nitric oxide production.
AB  - The role of endogenously synthesized complement subcomponent C1q on autocrine
      binding of tumor necrosis factors (TNF-alpha) and on TNF-alpha receptor (TNF-R)
      mRNA synthesis by mouse macrophages was investigated. Activation of C3H mouse
      peritoneal macrophages (C3H-PM phi) by Lipid A induced TNF-alpha and nitric oxide
      (NO) to kill tumor targets. Such activation also increased macrophage-endogenous
      C1q synthesis and secretion in a dose-dependent fashion. Antibody for C1q
      markedly inhibited C3H-PM phi NO production in response to Lipid A, but had no
      effect on TNF-alpha production. C3H-PM phi treated with C1q or Lipid A displayed
      increased TNF-R mRNA synthesis and in combination with Lipid A and anti-C1q
      antibody inhibited TNF-R and nitric oxide synthase (NOS) mRNA synthesis compared
      with Lipid A only, but had no effect on TNF mRNA synthesis. In vitro treatment of
      C3H-PM phi with C1q also increased TNF-alpha binding to their surfaces. Taken
      together, the data indicate that endogenously synthesized C1q is operative in
      promoting TNF-R mRNA synthesis and resultant autocrine binding of TNF-alpha for
      induction of NOS in the process of NO-mediated tumor cytotoxicity by Lipid A
      activated macrophages.

PMID- 8660798
TI  - Antigen-specific Il-4- and IL-10-secreting CD4+ lymphocytes increase in vivo
      susceptibility to Trypanosoma cruzi infection.
AB  - Control of macrophage parasiticidal function by treatment with recombinant
      cytokines or their neutralizing antibodies modifies the severity of experimental
      Trypanosoma cruzi infections. However, so far, no direct in vivo evidence has
      demonstrated changes in disease outcome after altering the initial ratios of
      parasite-specific IFN-gamma and IL-10/IL-4-secretor cells in secondary lymphoid
      organs. To this end, a population of predominantly CD4+ parasite-Ag-reactive, IL
      4- and IL-10-secreting T lymphocytes derived from T. cruzi-immunized mice was
      adoptively transferred to naive recipients. Compared with cell responses from
      normal mice, spleen cells of uninfected recipients proliferated significantly to
      T. cruzi Ag and produced much greater amounts of IL-4 and IL-10; lower IFN-gamma
      levels and increased IL-4/IL-10 levels were induced by Con A stimulation.
      Recipient mice challenged with T. cruzi presented overwhelming tissue and blood
      parasitemia and early death, contrasting with typically resistant controls.
      Uninfected recipients did not exhibit tissue damage following cell transfer. No
      disease exacerbation occurred in recipients of OVA-reactive CD4+, IL-4/IL-10
      secreting T lymphocytes stimulated with OVA at the start of infection. On Day 6
      postinfection, not only spleen cells but also LN cells from infected recipients
      showed decreased production of IFN-gamma and augmented secretion of IL-4/IL-10
      compared to cells from untransferred infected mice. The results indicate that an
      imbalance of Th cell populations leading to the predominance of secreted IL-4 and
      IL-10 at the start of infection and the concomitant down-regulation of IFN-gamma
      secretion reversed the host's resistance to T. cruzi. Moreover, transfer of anti
      T. cruzi Th2-type cells most likely favored the in vivo expansion of parasite
      specific host cells toward a Th2 phenotype.

PMID- 8660799
TI  - Mechanism of the development of autoimmune dacryodenitis in the mouse model for
      primary Sjogren's syndrome.
AB  - To elucidate the mechanism of development in autoimmune lacrimal gland disease,
      we analyzed different aspects of autoimmune dacryoadenitis in a newly established
      mouse model for primary Sjogren's syndrome, focusing on the local expressions of
      cytokine genes, and the repertoire of T cell receptor (TCR) V beta genes
      transcribed within the inflammatory infiltration in the lacrimal glands. We found
      that the vast majority of inflammatory infiltration into the lacrimal glands were
      CD4+ V beta 8+ T cells. We detected the up-regulation of local cytokine genes (IL
      1 beta, TNF-alpha, IL-2, IFN-gamma, IL-10, IL-12p40) in the lacrimal glands with
      very early inflammatory lesions by reverse transcriptase (RT)-PCR analysis. The
      predominant expression of the V beta 8 gene segment was detected from a very
      early stage, while extensive age-related diversity of TCR V beta gene usage was
      observed. Single-strand conformation polymorphism (SSCP) analysis demonstrated a
      distinct and a common binding pattern in the PCR product of the V beta 8 gene on
      the infiltrating cells during the course of the disease. These data suggest that
      in autoimmune dacryoadenitis of the mouse model for primary Sjogren's syndrome
      there may be a restricted usage of TCR V beta elements on a very early stage of
      the autoimmune lesion to recognize unknown self-antigen, and the autoreactive
      CD4+ T cells constitute a unique cytokine profile in the autoimmune lacrimal
      gland disease.

PMID- 8660800
TI  - Alterations in structure and cellular localization of molecular forms of DP
      IV/CD26 during T cell activation.
AB  - Dipeptidyl peptidase IV (DP IV, CD26), known as an activation marker of T
      lymphocytes, is a proline-specific protease thought to be involved in the
      regulation of the immune response. The physiological role of dipeptidyl peptidase
      IV in the immune system and the molecular events of lymphocyte activation
      mediated by this enzyme are only partly established. Former results suggested the
      occurrence of different molecular forms of DP IV in distinct human sources. As
      yet it has been unknown whether DP IV from human hematopoietic cells also appears
      in different forms and whether similar structural modifications are involved in
      functional processes of the regulation of the immune response. Here we describe
      that lymphocytic DP IV/CD26 occurs in various molecular forms and that some of
      them are associated with the activation process. In cell lysates of mitogen
      activated lymphocytes at least 5 enzymatically active DP IV forms and up to 11
      immunoreactive molecular forms of this enzyme with isoelectric points between pH
      3.5 and 5.9 were discernible. Corresponding analyses of soluble and membrane cell
      fractions of human lymphocytes showed significant differences in the staining
      pattern of molecular DP IV structures. After mitogenic stimulation a special
      molecular form of DP IV arises in the membrane, which was originated either from
      the soluble part of the cell (translocation) or represents a new synthesized
      form. Particularly, changes of molecular DP IV forms after mitogenic stimulation
      strongly suggest that special forms/epitopes of this enzyme are directly involved
      in the process of lymphocyte activation and growth. Importantly, different
      monoclonal DP IV antibodies partly define different molecular forms of DP IV.
      Moreover, the pattern of immunostaining and enzymatic staining (Gly-Pro-beta
      methoxynaphthylamide) also reveals drastic differences. These data strongly
      suggest a direct relationship between the expression/recognition of special DP IV
      epitopes and the contradictory functional effects of monoclonal DP IV antibodies
      found by us and other groups.

PMID- 8660801
TI  - Interleukin 4 (IL-4) blocks the IL-2-induced increased in natural killer activity
      and DNA synthesis of decidual CD16-CD56bright NK cells by inhibiting expression
      of the IL-2 receptor alpha, beta, and gamma.
AB  - The natural killer (NK) activity and DNA synthesis of decidual CD16-CD56bright NK
      cells were markedly elevated by treatment with interleukin 2 (IL-2). IL-4 did not
      affect NK activity or DNA synthesis of decidual CD16-CD56bright NK cells, but
      inhibited the IL-2-induced NK activity and DNA synthesis in a dose-dependent
      manner. Flow cytometry of decidual mononuclear cells cultured in IL-2 or IL-4 or
      both IL-2 and IL-4 demonstrated IL-4 inhibition of the expression of the IL-2
      receptor alpha (IL-2R alpha), IL-2R beta, and IL-2R gamma on decidual CD16
      CD56bright NK cells. This suggests that IL-4 blocks the IL-2-induced NK activity
      and DNA synthesis of decidual CD16-CD56bright NK cells by inhibiting the
      expression of IL-2R alpha, IL-2R beta, and IL-2R gamma.

PMID- 8660802
TI  - T cell receptor-independent apoptosis of thymocyte clones induced by a thymic
      epithelial cell line is mediated by steroids.
AB  - We have studied the mechanisms involved in TcR-independent apoptosis of radiation
      leukemia virus (RadLV)-transformed thymocyte clones induced by a thymic
      epithelial cell line (TEC). TEC induced apoptosis of an immature CD4+8+3+ (PD1.6)
      but not of a CD4-8-3- (B10) thymocyte clone. TEC-derived conditioned medium did
      not mimic the signal induced by TEC in PD1.6 cells. However, the TEC-resistant
      clone B10 apoptosed in response to TEC, provided that PD1.6 cells were also
      present in the culture. This effect on bystander cells suggests that a secreted
      factor was involved. The involvement of glucocorticoid hormones as potential
      mediators was addressed. PD1.6 cells apoptosed in response to dexamethasone or a
      cell-permeating analog of cAMP, while BIO cells were relatively resistant to
      dexamethasone. TcR cross-linking inhibited both TEC- and dexamethasone- but not
      cAMP-induced apoptosis. Aminoglutethimide and Ru38486 inhibited TEC-induced
      apoptosis of PD1.6 cells, whereas Ru28318 had a negligible effect. The results
      suggest that steroid hormones are involved in TcR-independent apoptosis of
      immature double-positive thymocyte clones induced by TEC.

PMID- 8660803
TI  - IFN-gamma-stimulated enhancement of MHC class II antigen expression by the human
      mast cell line HMC-1.
AB  - The expression of MHC class II molecules by human mast cells has been reported in
      immunohistochemical surveys of inflammatory conditions, such as in tuberculin
      hypersensitivity. While these data suggest that human mast cells may act as
      antigen-presenting cells under inflammatory conditions, the induction of class II
      antigens on human mast cells has not been examined. In this study, we determined
      the effects of the inflammatory cytokines IFN-gamma and IL-4 on the expression of
      class II antigens HLA-DR, -DP, and -DQ by the human mast cell line HMC-1. HMC-1
      cells were incubated with or without 1000 U/ml recombinant human IFN-gamma (rhIFN
      gamma) and IL-4 (rhIL-4) for 72 hr and analyzed for expression of MHC class II
      antigens by direct immunofluorescence and flow cytometry. HMC-1 cells expressed
      significant levels of HLA-DR and moderate levels of HLA-DP and -DQ at baseline
      and when cultured without exogenous cytokines. Stimulation by rhIFN-gamma for 72
      hr significantly increased the levels of HLA-DR and -DP expression but did not
      affect levels of HLA-DQ. Stimulation by rhIL-4 for 72 hr had minimal effect on
      expression of class II molecules, but induced a significant difference in levels
      of ICAM-1 (CD54) expression, indicating that this cytokine is involved instead in
      the control of certain accessory molecules. Our data showing constitutive
      expression of MHC class II molecules on HMC-1 cells and upregulation of that
      expression by rhIFN-gamma suggest that human mast cells function as antigen
      presenting cells at sites where inflammatory cytokines are present.

PMID- 8660804
TI  - Lymphocytes utilize CD11b/CD18 for adhesion to Candida albicans.
AB  - Large granular lymphocytes require adherence to hyphae of Candida albicans to
      inhibit growth of this fungus. This study was undertaken to identify the
      lymphocyte surface structures that mediate this adhesion. Monoclonal antibodies
      specific for epitopes of the alpha subunit (CD11b) and the beta 2 subunit (CD18)
      of Mac-1 eliminated lymphocyte adhesion to C. albicans hyphae. Significant
      inhibition of lymphocyte adhesion to C. albicans was also achieved with known
      protein ligands of Mac-1. These proteins included the extracellular matrix
      proteins vitronectin, laminin, and fibrinogen as well as two engineered peptides
      containing RGD (arginine-glycine-aspartic acid) sequences. Carbohydrates
      including N-acetyl-D-glucosamine which have been demonstrated to inhibit Mac-l
      mediated adhesion to whole yeast and yeast zymosan also blocked lymphocyte
      adhesion to hyphae. These results identify Mac-1 (CD11b/CD18) as the surface
      structure that mediates lymphocyte adhesion to C. albicans. A model is proposed
      for lymphocyte Mac-1 activation by microbial ligands.

PMID- 8660807
TI  - CD2 regulates T cell-dependent induction of monocyte IL-1 beta mRNA during anti
      CD3 mitogenesis.
AB  - The induction of monocyte IL-1 mRNA during T cell activation requires that
      monocytes receive contact-dependent signals from activated T cells. Furthermore,
      the ability of T cells to induce IL-1 beta mRNA is not constitutive but rather is
      rapidly acquired (< or = 30 min) following activation via mechanisms that do not
      require protein synthesis. The goal of these studies is to identify the T cell
      signal(s) that mediates the cell contact-dependent induction of monocyte IL-1
      beta mRNA. The induction of IL-1 beta mRNA during anti-CD3 mitogenesis was
      significantly inhibited by anti-CD2 mAb, whereas mAb against CD11a, CD18, CD69,
      or CD5 molecules had no effect. The inhibition of IL-1 beta mRNA induction by
      anti-CD2 mAb was restricted to only those mAb that block CD2/CD58(LFA-3)
      interactions. Furthermore, anti-CD2 blocked the induction of monocyte IL-1 beta
      mRNA by T cells that were preactivated using either immobilized anti-CD3 or anti
      T11(2) plus anti-T11(3) mAb, thereby indicating that the inhibition of IL-1 beta
      mRNA was not due to negative signaling effects exerted on the T cell by anti-CD2.
      Finally, although anti-CD69 mAb had no effect on IL-1 beta mRNA induction, it
      inhibited the generation of soluble IL-1 beta. The combination of anti-CD69 and
      anti-CD2 mAb exhibited greater inhibition of secreted IL-1 beta than either
      antibody alone. These results indicate that CD2 is required for T cell induction
      of IL-1 beta mRNA through interaction with LFA-3 on the monocyte and that the
      generation of soluble IL-1 beta is regulated by CD69.

PMID- 8660808
TI  - Impaired IgG production in the lungs of HIV-infected individuals.
AB  - Human immunodeficiency virus (HIV)-infected individuals are at risk for pulmonary
      infections with encapsulated bacterial pathogens. This could reflect impaired
      production of opsonizing antibodies in the lower respiratory tract. We examined
      antibody production in the alveolar space by measuring immunoglobulin
      concentrations in bronchoalveolar lavage (BAL) of HIV-infected patients and
      normal volunteers and by assessing the ability of alveolar macrophages (AM) to
      induce immunoglobulin production in normal peripheral blood mononuclear cells
      (PBMC). BAL from HIV-infected patients contained significantly less IgG than
      normal BAL. IgA and IgM concentrations were similar in both groups. Normal AM
      supported IgG and IgA production in PBMC. While HIV AM could induce IgA
      production in PBMC, in no instance did they induce IgG secretion. HIV AM produced
      significantly more transforming growth factor-beta (TGF-beta), a factor known to
      suppress IgG production, than normal AM. Finally, TGF-beta antibodies blocked the
      inhibitory effect of HIV AM on normal IgG secretion without affecting IgA
      secretion. These findings demonstrate impaired production of opsonizing IgG in
      the alveolar space of HIV-infected subjects and implicate excess TGF-beta
      production by AM as the cause of this impairment.

PMID- 8660809
TI  - Evidence for a role of phosphatidylinositol 3-kinase in IL-4-induced germline C
      epsilon transcription.
AB  - Association of interleukin-4 receptor (IL-4R) with phosphatidylinositol 3-kinase
      (PI3-kinase) has been demonstrated as the proximal event of IL-4 signaling. We
      investigated the role of this enzyme in the IL-4 signaling pathway in a human
      Burkitt lymphoma B cell line, DND39, that expresses germline C epsilon
      transcripts in response to IL-4. Stimulation of DND39 cells with IL-4 resulted in
      an accumulation of PI-3-monophosphate as well as a decrease of PI-4,5
      bisphosphate, which were abrogated by wortmannin, a potent inhibitor of PI3
      kinase. Activation of PI3-kinase was further confirmed by the finding that IL-4
      caused an increase in PI3-kinase activity coimmunoprecipitated with anti-IL-4R
      and with anti-JAK3 kinase antibodies. As a possible downstream event of PI3
      kinase activation, the translocation of a zeta isoform of protein kinase C (PKC)
      from the cytosol to the membrane fraction was observed after IL-4 stimulation,
      and wortmannin also suppressed this translocation. Moreover, IL-4-induced
      expression of germline C epsilon transcription was inhibited not only by
      wortmannin, but also by a PKC inhibitor, K252a. These results suggest that the
      signaling pathway involving PI3-kinase and PKC zeta plays an important role in
      induction of germline C epsilon transcription in DND39 cells by IL-4.

PMID- 8660810
TI  - An age-related decrease in rescue from T cell death following costimulation
      mediated by CD28.
AB  - We previously reported that T cell proliferation in response to a primary signal
      through the T cell receptor (TCR) and a costimulatory signal via the CD28
      molecule is impaired in healthy, aged mice. Here we extend these studies to
      examine factors which may be involved in this defect in T cells from aged mice.
      To determine if age-related changes in cytokine production might be responsible,
      splenic T cells from young (2-4 months) and aged (20-26 months) mice were
      stimulated with immobilized anti-CD3 epsilon and soluble anti-CD28 mAbs in the
      presence of exogenous IL-2, IL-4, IFN-gamma, IL-1 alpha, or IL-6. No improvement
      in the proliferative response of T cells from aged mice was found following the
      addition of any cytokine. In addition, the decreased proliferative response of T
      cells from aged mice was not caused by the enhanced production of IFN-gamma or
      other inhibitory factors. Interestingly, despite the age-related reduction in
      proliferation, no significant difference was found in the percentage of live
      cells entering the S, G2, or AM phase of the cell cycle in stimulated T cells
      from young and aged mice. Instead, anti-CD28-mediated costimulation was found to
      rescue T cells from young mice from anti-CD3epsilon-induced cell death, but did
      not rescue T cells from aged mice. This failure of T cells from aged mice to
      respond to costimulatory signals appears to contribute to the decreased
      proliferation observed from cultures containing these cells, and may be involved
      in many other age-related alterations in immunological responsiveness.

PMID- 8660811
TI  - Dual control of human interleukin-2 and interferon-gamma gene expression by
      histamine: activation and suppression.
AB  - Histamine is considered to be an activator of cells with suppressive capacity. In
      agreement with this concept, we show that histamine elicits a strong inhibition
      of the induced expression of interleukin-2 (IL-2) and interferon-gamma (IFN
      gamma) genes. However, our experiments reveal a novel property of histamine:
      early in the induction process, it strongly stimulates expression of these two
      genes in cultured human peripheral blood mononuclear cells (PBMC). The histamine
      mediated superinduction of IL-2 mRNA is seen also in a Th cell line, showing that
      such cells respond directly to histamine. In the course of mitogenic induction, a
      20-fold stimulation by histamine is converted into an equally strong inhibition.
      The response of a PBMC population to histamine thus undergoes a remarkable change
      following T cell activation. The dual effect of histamine can be blocked by the
      H2 histamine receptor antagonist cimetidine, while the early activation by
      histamine is mimicked by the H2 agonist impromidine, showing that both activation
      and inhibition of IL-2 and IFN-gamma gene expression by histamine are exerted via
      this receptor. These results support the concept that histamine, released during
      an immune response, exerts opposite regulatory effects by first activating cells
      able to express the IL-2 and IFN-gamma genes and only then suppressive cells that
      become responsive to histamine more slowly, but once activated shut off the
      expression of these genes.

PMID- 8660814
TI  - Vitamin D3-binding protein as a precursor for macrophage activating factor in the
      inflammation-primed macrophage activation cascade in rats.
AB  - When rat peritoneal nonadherent cells were treated with inflammatory lipid
      metabolites and cultured with adherent cells in 1% fetal calf serum (FCS)
      supplemented medium RPMI 1640 (FCS medium) for 3 hr, markedly enhanced phagocytic
      and superoxide generating capacities of macrophages were observed. Stepwise
      preparation of conditioned medium of lysophosphatidylcholine (lyso-Pc)-treated B
      cells and untreated T cells in FCS medium generated a potent macrophage
      activating factor whereas cultivation of lyso-Pc-treated B cells alone in a 1%
      adult rat serum supplemented medium efficiently generated the macrophage
      activating factor. Generation of macrophage activating factor requires a
      precursor protein, serum vitamin D3-binding protein (DBP), as well as
      participation of lymphocyte glycosidases. The lyso-Pc-inducible beta
      galactosidase of B lymphocytes and the Neu-1 sialidase of T lymphocytes modified
      bovine DBP (bDBP) to yield the macrophage activating factor, a protein with N
      acetylgalactosamine as the remaining sugar. In contrast, lyso-Pc-inducible beta
      galactosidase of B cells alone modified rat DBP (rDBP) to yield the macrophage
      activating factor, a protein with N-acetylgalactosamine as the remaining sugar.
      Thus, we conclude that bDBP carries a trisaccharide composed of N
      acetylgalactosamine, galactose, and sialic acid while rDBP carries a disaccharide
      composed of N-acetylgalactosamine and galactose.

PMID- 8660815
TI  - The anti-Dextran response of scid mice transgenic for the heavy chain of a
      Dextran specific IgM antibody.
AB  - Mice homozygous for the scid mutation bear a severe defect in their ability to
      rearrange V(D)J gene segments to yield active genes for immunoglobulin and T cell
      receptor molecules. In older animals few clones of B and T cells can arise at
      random, a phenomenon called leakyness of the scid mutation. We established scid
      mice carrying as a transgene the rearranged heavy chain of the IgM/lambda1
      antibody MOPC 104E with specificity for the alpha(1,3) glucosidic linkages in
      Dextran. Despite the scid defect one-third of these mice immunized with the
      thymus independent antigen Dextran at 2 weeks of age, and all of those immunized
      at 6 weeks responded with anti-Dextran antibodies bearing the lambda light chain.
      This indicates that despite the scid mutation these animals had at least once
      successfully rearranged their endogenous lambda1 light chain gene segments and
      harbor Dextran specific B cells. These mice thus provided for the first time the
      opportunity to study the immune response of B cells of a single specificity in an
      environment that should, as we shall argue, be devoid of regulatory B and T cells
      able to recognize the idiotype of the responding cells. One week after
      immunization the anti-Dextran response of 5- to 6-week-old mu-transgenic scid
      mice amounted to 30% of the response of mu-transgenic non-scid mice but in
      essence both responses followed the same kinetics, reaching antibody
      concentrations indistinguishable from each other 8 weeks after a single dose of
      Dextran. Furthermore, the ready response of young mu-transgenic scid mice to this
      antigen by employment of endogenously rearranged lambda1 light chains allowed
      experiments to be done to compare the frequency of lambda1 light chain
      rearrangements in mu-transgenic scid mice to that in mu-transgenic non-scid mice.
      This was done in limiting dilution assays counting B cell precursors responsive
      to mitogen and differentiating in vitro to produce antibodies toward Dextran.
      Specific precursors were reduced to about 1% in the spleen of mu-transgenic scid
      mice when compared to the spleen of mu-transgenic non-scid mice; those in the
      peritoneal cavity lymphocyte population were reduced to about 12%.

PMID- 8660816
TI  - Prostaglandin-E2 regulation of tumor necrosis factor receptor release in human
      monocytic THP-1 cells.
AB  - Recent in vitro studies indicate that tumor necrosis factor (TNF) production in
      human monocytic THP-1 cells is suppressed by action of arachidonic acid
      metabolite prostaglandin-E2 (PGE2). PGE2 stimulation of human monocytic cell line
      THP-1 demonstrates that PGE2 not only regulates TNF activity at production
      levels, but does so through the release of two soluble TNF receptors (BP-55, BP
      75) as well. PGE2 can thus exert a regulatory effect on TNF biologic activity by
      interfering with its ability to reach cell membrane receptors. THP-1 cells were
      activated with PGE2 for either 2- or 6-hr time periods, and the supernatants
      subsequently tested by ELISA to quantitate the levels of soluble receptor
      released. In addition, we examined mechanisms of receptor shedding by
      investigating the rate of membrane internalization and the role of serine
      proteases. PGE2-stimulated THP-1 cells showed soluble 55- and 75-kDa TNF receptor
      release levels which exceeded that of spontaneous release at both 2- and 6-hr
      activation periods. The numbers of both membrane TNF receptors were significantly
      upregulated as well in PGE2-activated cells, whereas the levels of 55- and 75-kDa
      TNF receptor mRNA levels remained unchanged. Thus, PGE2 induces TNF receptor
      release primarily at posttranscriptional levels. Inhibition of serine proteases
      with Pefabloc, a phenylmethylsulfonyl fluoride analog, resulted in the inhibition
      of both spontaneous and PGE2-stimulated release. Treatment of THP-1 cells with N
      ethylmaleimide and low-temperature incubation, both known to block membrane
      internalization, also blocked spontaneous and PGE2-induced release.
      Internalization and cleavage by protease are therefore critical factors in PGE2
      induced release of soluble TNF receptor shedding.

PMID- 8660817
TI  - A role for Th2 T-memory cells in early airway obstruction.
AB  - The role of T-cell memory in late-phase allergic lung inflammation is not well
      defined. To evaluate the role of systemic T-cell memory in allergic late-phase
      lung inflammation, BALB/c mice were injected intraperitoneally with ovalbumin
      (OVA) or ragweed (RW) allergens (Test I and Test II groups) or saline (control
      groups C I and C IV) and then challenged intratracheally with the allergen. Late
      phase allergic lung inflammation was defined by: (i) recruitment of eosinophils
      to airways, (ii) IL-5 mRNA upregulation in BAL fluid cells, and (iii) detection
      of a Th2 cell cytokine profile in BAL fluids. The number of eosinophils recruited
      in allergic mice following intratracheal challenge with allergen was at least 300
      fold higher P < or = 0.01) in mice with allergen-specific T-memory cells in BAL
      fluid (Test I and Test II) than in control mice without allergen-specific T
      memory cells (C I and C IV). Further, the number of eosinophils recruited in Test
      I and II correlated with the magnitude of in vitro T-cell memory responses (r =
      0.93, P < or = 0.04). Moreover, IL-5 mRNA upregulation in BAL cells and Th2
      cytokine production in BAL fluids were observed only in Test I and Test II, and
      not in any of the control groups. Further, results from pulmonary function tests
      performed on the same allergic animals indicated that only animals from Test I
      and Test II groups had impaired lung function after allergen challenge. Taken
      together, these data strongly suggest that allergen-specific Th2-type T-cell
      memory is required for the development of allergic asthma. That is, without T
      cell memory responses, no eosinophil recruitment and release of EPO (which is
      known to induce bronchoconstriction) occurred in the airways, and no Th2 cytokine
      profile was detected in the BAL fluid. Furthermore, if the Th2 cytokine profile
      was absent, then pulmonary functions remained normal.

PMID- 8660818
TI  - Activation of nonspecific cytotoxic cells with a multiple antigenic peptide:
      specificity and requirements for receptor crosslinkage.
AB  - Nonspecific cytotoxic cells (NCC) of teleost fish recognize a conserved antigenic
      determinant found on the protozoan Tetrahymena pyriformis and on many different
      tumor target cells. This determinant is located on a 46-kDa Tetrahymena protein
      referred to as natural killer target antigen (NKTag). The NKTag cognate sequence
      recognized by NCC is composed of seven to nine amino acids. In the present study,
      synthetic peptides of the cognate NKTag determinant were prepared as multiple
      antigenic peptides (MAP). Immobilized MAP activated NCC lysis of IM-9 target
      cells in the absence of antigen presenting cells or exogenous added cytokines.
      NCC binding to immobilized MAP produced two- to fivefold increased lysis of IM-9,
      U937, and HL-60 target cells compared to scrambled control MAP (composed of the
      same amino acids only in random sequence). NCC receptor crosslinkage was required
      for activation. Immobilized monomeric homologous cognate peptide did not activate
      increased NCC lysis of IM-9 target cells; however, NCC preincubated with soluble
      homologous monomer inhibited MAP activation of lysis. Ligand activation of NCC
      was antigen specific. Binding of the immobilized ligand with anti-MAP mab 22A12
      prior to addition of NCC blocked activation. Mab 22A12 also inhibited NCC lysis
      of IM-9 target cells. A possible mechanism of NCC activation was determined.
      Binding of NCC to immobilized MAP produced significantly increased membrane
      expression of a putative receptor as defined by mab 5C6 binding. These studies
      demonstrate that activation of NCC by a target cell antigenic determinant depends
      on crosslinkage of an NCC "receptor" by polymeric repetitive sequences, a soluble
      or fixed monomer cannot activate but can inhibit activation, and MAP binding
      initiates increased expression of a putative NCC receptor protein.

PMID- 8660819
TI  - Changes in superoxide anion production and phagocytosis by circulating
      neutrophils during tumor progression in a rat model.
AB  - The functional state of circulating neutrophils was monitored in a rat model of
      mesoblastic nephroma during tumor progression. Superoxide anion (O2.-) production
      in response to PMA and phagocytosis of yeast particles (Saccharomyces cerevisiae)
      were measured every second day after tumor cell implantation. Both phagocytosis
      and PMA-induced 02.- generation were found to be enhanced in the first period (on
      Days 6, 8, and 10), while they became significantly reduced in the advanced stage
      of cancer (on Days 12, 14, 16, and 18). The suppression of PMNL functions was
      accompanied with tumor progression and an increased number of neutrophils in the
      peripheral blood. Studies were also carried out on PMNLs isolated from normal
      rats and the cells were treated with plasma samples obtained from tumor-bearing
      animals at different stages of nephroma. Incubation of the normal cells with
      plasmas separated on the 2nd and 8th days of tumor growth influenced neither the
      02.- generation nor the phagocytosis. In contrast, plasma preparations obtained
      on the 14th day significantly inhibited both 02.- production and phagocytosis by
      normal neutrophils. The alterations in 02'- generation and phagocytosis by PMNLs
      were observed in close association with tumor growth, thus they could be
      considered as indicators of tumor progression. However, further studies are
      required to see whether the granulocyte dysfunctions observed in our animal model
      could provide additional prognostic information in the case of human malignancies
      as well as to clarify the origin of inhibitory factor(s) present in the blood of
      tumorous animals.

PMID- 8660820
TI  - Suppression of interleukin-1 and tumor necrosis factor-alpha production by
      acanthoic acid, (-)-pimara-9(11),15-dien-19-oic acid, and it antifibrotic effects
      in vivo.
AB  - Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are major
      proinflammatory cytokines inducing the synthesis and release of many inflammatory
      mediators. They are involved in immune regulation, autoimmune diseases, and
      inflammation. Acanthoic acid, (-)-pimara-9(11),15-dien-19-oic acid, is a
      pimaradiene diterpene isolated from the Korean medicinal plant, Acanthopanax
      koreanum. When human monocytes/macrophages stimulated with silica were treated
      with 0.1-10 microg/ml acanthoic acid, the production of IL-1 and TNF-alpha was
      inhibited up to 90%, but the production of interleukin-6 (IL-6) was not inhibited
      at all. At these concentrations, it had no cytotoxic effect on human
      monocytes/macrophages. It also suppressed the production of TNF-alpha by alveolar
      macrophages and lymphocytes stimulated with silica. In addition, acanthoic acid
      inhibited the release of superoxide anion and hydrogen peroxide from human
      monocytes/macrophages and neutrophils. To know the antifibrotic effects of
      acanthoic acid, its effects on fibroblast proliferation and collagen synthesis
      were tested. The proliferation of NIH3T3 cells was inhibited almost completely by
      the addition of the culture supernatants of human monocytes/macrophages treated
      with acanthoic acid, but not by the addition of acanthoic acid only. In vitro and
      in vivo treatment with acanthoic acid reduced collagen production by rat lung
      fibroblasts and lung tissue. Furthermore, acanthoic acid suppressed granuloma
      formation and fibrosis in the experimental silicosis. Acanthoic acid reduced
      serum GOT and GPT in the rats with cirrhosis induced by CCl4, and it was
      effective in reducing hepatic fibrosis and nodular formation. Taken together,
      these data indicate that acanthoic acid has a potent anti-inflammatory and
      antifibrosis effect by reducing IL-1 and TNF-alpha production.

PMID- 8660822
TI  - Retinoids as Ig Isotype-Switch Modulators
AB  - The role of retinoids was analyzed in directing isotype switching to IgA and IgG1
      (IgE) by LPS-stimulated murine &mu;(+)B-cells in the presence of two Th2-type
      cytokines, IL-4 and IL-5. All trans retinoic acid (RA) enhanced the production of
      IgA at high concentrations (10-100 nM) in the presence of IL-5. Addition of IL-4
      to the system modulated the IgA response in a dose-dependent manner. Namely, IL-4
      inhibited the response at concentrations higher than 250 usolidusml, but showed
      slight enhancement at lower concentrations (130 usolidusml). IL-4 alone, which is
      considered to be an IgE isotype-switch inducer, strongly enhanced the IgG1 and
      IgE responses. Addition of IL-5 to the system showed a synergistic effect which
      could be attenuated by addition of low concentrations of RA (about 1 nM). Thus,
      the presence of switch modulators such as IL-4 and IL-5, their concentration
      ratios, and concentrations of retinoids are crucial factors in initiating and
      directing isotype switching to IgA and IgG1 (IgE).

PMID- 8660821
TI  - Splenic CD4+ and CD8+ T cells from influenza immune mice concurrently produce in
      vitro IL2, IL4, and IFN-gamma.
AB  - The cytokine responses exerted by virus-primed spleen T cells upon in vitro
      restimulation were studied. Spleen cells obtained from mice injected
      intraperitoneally with A/PR8 (H1N1) influenza virus (PR8) were restimulated in
      vitro with UV-inactivated PR8 virus. The percentage of both CD4+ and CD8+ T cells
      producing IL2, IL4, or IFN-gamma was assayed at the single cell level by flow
      cytometric analysis of intracytoplasmic cytokine content. In parallel, the levels
      of the different cytokines in spleen cell culture supernatants were quantitated
      by enzyme linked immunosorbent assay. The results showed that in vitro virus
      restimulation of immune spleen cells induced the concurrent increase, in both
      CD4+ and CD8+ T cells, of the frequency of IL2-, IFN-gamma-, and IL4-producing
      cells. The frequency of IFN-gamma-producing T cells was found to be significantly
      higher in CD8+ T cells. Significant levels of the three cytokines were also
      detected in the culture supernatants. These data suggest that both CD4+ and CD8+
      T cells play an important role in cytokine response to virus infection and that
      the synthesis and secretion of antiviral and regulatory cytokines is not mutually
      exclusive either between or within the two T cell subsets. The results of the
      experiments also indicated that the virus restimulation did not induce a dominant
      type 1 or type 2 cytokine response.

PMID- 8660823
TI  - Extracellular matrix components of the mouse thymus microenvironment. V.
      Interferon-gamma modulates thymic epithelial cell/thymocyte interactions via
      extracellular matrix ligands and receptors.
AB  - Extracellular matrix (ECM) proteins influence cell migration and differentiation
      in a variety of cell systems. Within the thymus, the ECM distribution pattern is
      conserved among various mammalian species, but its physiological role is not
      completely understood. Interferon-gamma (IFN-gamma), a cytokine produced by
      thymocytes, is able to in vitro modulate ECM production by thymic epithelial
      cells (TEC) in a dose-dependent biphasic pattern. In the same model, we
      determined herein that the expression of VLA-5 and VLA-6 (fibronectin and laminin
      receptors, respectively) were upregulated by low doses of IFN-gamma, whereas high
      doses of the cytokine induced an opposite effect. In a second in vitro system, we
      evidenced that thymocyte adhesion to a TEC line was also modulated by IFN-gamma.
      Importantly, such effects were due to the biphasic modulation of ECM ligands and
      receptors since they could be specifically prevented by preincubating the TEC
      cultures with anti-ECM or anti-ECM receptor antibodies. Additionally, spontaneous
      thymocyte release from thymic nurse cells was similarly biphasically modulated by
      IFN-gamma. Our data provide support for the notion that thymocyte-derived
      products can play a role in the dialogue that exists in the thymus, involving
      differentiating thymocytes and microenvironmental cells. Moreover, we bring
      arguments indicating that one of the implicated mechanisms involved is the
      modulation of ECM ligands and receptors by the thymic epithelium.

PMID- 8660824
TI  - A kinase/phosphatase system involving the protooncogene Lck is necessary for
      inducible modulation of Sob 1 during T cell activation.
AB  - The phosphotyrosine containing protein Sob 1 regulates inducibility of a DNA
      binding complex (Band A) at the SRE of c-fos during T cell activation. In the
      present study, Sob 1 was regulated by activation of T cells through the T cell
      antigen receptor. Inhibition of protein tyrosine kinases (PTK) inactivated Sob 1
      function and allowed the Band A DNA-protein complex to form. Inhibition of
      protein tyrosine phosphatases (PTP) caused constitutive activation of Sob 1
      function and prevented induction of Band A at the SRE. Thus, Sob 1 is regulated
      by a constitutive PTP/PTK system. J.CaM 1 cells that lack a functional form of
      the PTK Lck are unable to induce Band A through the T cell antigen receptor.
      J.CaM 1 cells reconstituted with Lck seem to induce Band A normally. Thus,
      functional Lck is required for regulation of Sob 1.

PMID- 8660826
TI  - Cell cycle progression out of G1 sensitizes primary-cultured nontransformed T
      cells to TCR-mediated apoptosis.
AB  - Shortly after primary activation and IL-2-induced entry into cell cycle, splenic
      or lymph node T cells can be induced to undergo apoptosis by recrosslinking of
      the TCR complex using anti-TCR antibodies. We demonstrate here that primary
      activated T cells induced to undergo apoptosis by TCR recrosslinking during the
      G1 phase of the cell cycle did not arrest in the G1 phase of the cell cycle.
      Instead, the cells continued to progress through the cell cycle and underwent at
      least one mitosis before dying. Rapamycin, an inhibitor of IL-2-induced S phase
      entry, prevented this apoptotic death. Prevention of cell death correlated with
      delayed entry into S phase from G1 following TCR religation in the rapamycin
      treated cultures. Addition of rapamycin after cells had entered S phase or had
      already divided failed to prevent cell death. Treatment of activated T cells with
      dibutyryl cAMP or forskolin, which also block primary-activated T lymphocytes in
      G1, also inhibited TCR-induced cell death. In contrast, treatment of TCR
      religated cells with reagents that blocked cell cycle progression in S phase
      (aphidicolin, deferoxamine) after TCR religation failed to prevent apoptotic cell
      death. Activated T cells sorted for S + G2/M DNA content following Hoechst 33342
      staining were also found to be more sensitive to TCR-induced apoptosis than cells
      sorted for G1 DNA content. Rapamycin inhibited apoptosis in G1-sorted cells, but
      not in S + G2/M-sorted cells. Together, these results suggest that factors
      regulating cell cycle progression also control the induction of TCR-mediated
      apoptosis. Primary-activated T cells may become committed to programmed cell
      death only after progressing into S phase of the cell cycle.

PMID- 8660825
TI  - Iron regulates microglial cell-mediated secretory and effector functions.
AB  - Iron homeostasis and macrophage physiology are tightly intertwined. In the
      present study, we evaluated the influence of iron loading on the constitutive and
      interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS)-induced functional and
      secretory properties of microglial cells, using the in vitro established murine
      cell line BV-2. We demonstrate that iron augments the basal and IFN-gamma plus
      LPS-enhanced anti-Candida albicans activity exerted by BV-2 cells and that the
      phenomenon occurs with no enhancement of phagocytic activity. Furthermore, when
      the secretory properties of IFN-gamma plus LPS-treated BV-2 cells were assessed,
      we found that tumor necrosis factor remains unchanged while nitric oxide
      production is significantly reduced in iron-loaded cells. The addition of the
      iron chelator deferiprone (L1) reverts the effects of iron on BV-2 functional and
      secretory properties. These data suggest that iron differently affects secretory
      and effector functions of BV-2 microglial cells, thus implying that iron
      interferes with murine microglial cell physiology.

PMID- 8660827
TI  - Phospholipase A2 activity and calpactin I levels in rat lymphokine-activated
      killer cells: correlation with the cytotoxic activity.
AB  - In the present paper we have shown evidence for a significant increase of type II
      sPLA2 activity in A-LAK cells. The A-LAK-mediated cytotoxicity against YAC-1
      target cells was strongly inhibited by two inhibitors of sPLA2, p-BPB and
      mepacrine, suggesting the involvement of this enzyme in the lytic mechanism of A
      LAK. On the other hand, stimuli such as A23187 ionophore and TPA, which were able
      to induce in control cells an increased AA release, failed to cause this effect
      in IL-2-treated cells, suggesting that PLA2 was not active in these cells. Thus,
      we analyzed the levels of calpactin I, which is considered to be involved in the
      down-regulation of PLA2 activity. HrIL-2 treatment led to an increased expression
      of calpactin I at both the RNA and the protein level. A substantial portion of
      calpactin I was associated with the external surface of A-LAK and was able to
      exert a strong inhibitory effect on a purified porcine pancreatic PLA2 activity
      in vitro. Our results suggest that the role of calpactin I could be relevant to
      regulate PLA2 activity, and to protect the effector cells against a possible
      toxic effect which this enzyme could exert if present at high levels.

PMID- 8660828
TI  - T cells with two Tcrbeta chains and reactivity to both MHC/idiotypic peptide and
      superantigen.
AB  - It is thought that Tcrbeta genes are effectively allelically excluded, while
      Tcralpha genes are not. We report here that endogenous Tcrbeta genes are
      expressed on as much as 5-7% of CD4+ T cells in 8-week-old Tcralphabeta
      transgenic mice. In this model, the transgenic Tcr recognizes residues 91 - 101
      of a lambda2(315) Ig light chain, presented on the I-Ed class II molecule. From
      such mice, a CD4+ T cell clone was isolated which not only responded to
      lambda2(315), but also mobilized Ca2+ and proliferated in response to Mls-1a.
      (Inadvertently we found that the C3H/Tif substrain, in contrast to C3H/HeJ, is
      Mls-1a positive.) The clone expressed the transgenic Tcr (Valpha1 and Vbeta8.2),
      and in addition an endogenous Vbeta6 chain, conferring the Mls-1a reactivity. On
      the population level, 1-2% of Tcr-transgenic lymph node cells displayed Vbeta6,
      in addition to the transgenic beta-chain. Such dual Tcrbeta expressor cells could
      be preferentially expanded in vitro by first stimulating with DBA/2 spleen cells
      and then with lambda2(315)-pulsed BALB/c antigen-presenting cells. In addition to
      demonstrating that allelic exclusion of Tcrbeta-chain genes is substantial but
      not complete in this model, the data show that the double beta-chain expressors
      can have two different specificities, and be signaled through both receptors, by
      physiological ligands. However, such dual-Tcr T cells appear to have reduced
      sensitivity to ligands, due to their decreased expression of each receptor. This
      holds true for both early (Ca2+ mobilization) and late (proliferation) T cells
      activation parameters. Dual Tcr cells may have a role in the pathogenesis of
      autoimmune diseases: If naive T cells are first stimulated by (infectious)
      superantigen, they could later, as activated T cells, respond to self-peptide/MHC
      on costimulation-deficient cells and cause autoimmunity. As a corollary, dual Tcr
      Id-specific T cells could, once activated, directly regulate Id+ B cells.

PMID- 8660829
TI  - Anti-CD4 monoclonal antibodies suppress murine collagen-induced arthritis only at
      the time of primary immunisation.
AB  - We have examined the ability of a mixture of two anti-CD4 mAbs to protect against
      collagen-induced arthritis. Anti-CD4 mAbs, administered around the time of
      primary immunisation with type II collagen in adjuvant, reduced the subsequent
      incidence of arthritis from 67 to 16% (P < 0.01 by Fisher exact test). However,
      anti-CD4 treatment 3 weeks after the primary immunisation did not significantly
      affect the incidence of arthritis. This result extends earlier findings
      concerning the lack of efficacy of anti-CD4 treatment in established collagen
      induced arthritis. Next, the ability of anti-CD4 treatment to induce tolerance to
      bovine type II collagen (and hence protect against arthritis) was evaluated using
      a regime known to be capable of inducing tolerance to human gamma-globulin. Anti
      CD4 treatment completely failed to induce tolerance to type II collagen, as
      judged by levels of anti-collagen antibody, or protect against collagen-induced
      arthritis. These findings highlight the potential limitations of anti-CD4 mAb
      depleting treatment in immunotherapy.

PMID- 8660831
TI  - Regulation of HLA-DR and invariant chain expression by human peripheral blood
      mononuclear cells with lead, interferon-gamma, or interleukin-4.
AB  - It has been reported that the expression of major histocompatibility complex
      (MHC) class II can be regulated by lead (Pb) in murine cells. In both human and
      mouse, the expression of MHC class II and invariant chain (Ii) can be regulated
      by cytokines, including interferon-gamma (IFN-gamma) and interleukin-4 (IL-4).
      Herein we report that in humans, as with IL-4, Pb enhanced MHC class II antigen
      DR (HLA-DR) surface expression by monocytes and B cells; Ii surface expression by
      monocytes and B cells was not affected by Pb while it was enhanced by IL-4. IFN
      gamma increased HLA-DR and Ii surface expression by monocytes but it decreased
      HLA-DR and Ii surface expression by B cells. Total cellular HLA-DR expression by
      peripheral blood mononuclear cells (PBMC) was increased by Pb, IFN-gamma, or IL
      4. Total cellular Ii (p33 and p35) expression by PRMC was not affected by Pb or
      IFN-gamma while it was increased by IL-4. In PBMC, the steady-state mRNA levels
      of HLA-DR alpha and Ii were not affected by Pb; IFN-gamma increased HLA-DR alpha
      mRNA expression but not Ii; IL-4 increased both mRNA levels of HLA-DR alpha and
      Ii. Furthermore, Pb, IFN-gamma, or IL-4 significantly increased the total
      cellular level of HLA-DR:Ii complexes in PBMC while they had no effect on cell
      surface HLA-DR:Ii complex expression. Overall, these results suggest that, in
      vitro, Pb, IFN-gamma, and IL-4 differentially modulate HLA-DR and Ii expression
      by human PBMC.

PMID- 8660833
TI  - The role of apoptosis in antibody-dependent cell-mediated cytotoxicity against
      monolayers of human squamous cell carcinoma of the head and neck targets.
AB  - Antibody-dependent cellular cytotoxicity (ADCC) against squamous cell carcinoma
      of the head and neck (SCCHN) targets in the presence of human/mouse chimeric
      monoclonal antibodies (cMAbs), SF-25 and 323/A3, is mediated by natural killer
      (NK) cells. In 4-hr 51Cr-release assays with SSCHN targets in suspension, ADCC
      was always significantly better (P < 0.01) than that measured in parallel with
      the same target cells in monolayers. No differences were observed in the level of
      expression of the relevant antigens recognized by cMAbs on these targets. To
      better explain the difference, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl
      tetrazolium bromide (MTT) monolayer and [3H]thymidine-release assays were used.
      Cytostasis and cell death measured in monolayer MTT assays and DNA fragmentation
      measured in [3H]thymidine-release assays were significantly higher (P = 0.028)
      than cytotoxicity determined using 51Cr-labeled SCCHN monolayers. Cell death
      observed in monolayer MTT assays was blocked by pretreating SCCHN targets with
      cycloheximide or actinomycin-D or by paraformaldehyde fixation of effector cells.
      The presence of apoptotic cells in monolayers co-incubated with effector cells
      was demonstrated in situ by labeling fragmented ends of DNA with fluorescein
      conjugated dUTP and terminal deoxynucleotidyl transferase and also by flow
      cytometry of target cells obtained from such monolayers. Our results indicate
      that NK cells preferentially utilize membrane lysis (necrosis) in ADCC with tumor
      cell targets in single-cell suspensions. However, necrosis is not efficient in
      monolayers. In the presence of cMAbs, apoptosis is the primary mechanism of NK
      cell-mediated killing in monolayers of SCCHN targets, which were found to express
      receptors for tumor necrosis factor and fas ligand.

PMID- 8660832
TI  - Lysosome-associated membrane proteins h-LAMP1 (CD107a) and h-LAMP2 (CD107b) are
      activation-dependent cell surface glycoproteins in human peripheral blood
      mononuclear cells which mediate cell adhesion to vascular endothelium.
AB  - Lysosome-associated membrane proteins (LAMPs) are transmembrane lysosomal
      glycoproteins which are detectable at the cell surface of lymphocytes in patients
      with scleroderma and systemic lupus erythematosus. While these proteins have been
      shown to mediate adhesion of tumor cells to vascular endothelial selectins, the
      function of LAMPs expressed at the cell surface of peripheral blood lymphocytes
      has not been previously examined. In the present study, the role of lamp2
      (CD107b) in lymphocyte adhesion to vascular endothelium and the factors which
      influence in vitro cell surface expression of both lamp1 (CD107a) and lamp2
      (CD107b) are examined. Freshly isolated PBMCs and unstimulated PBMCs in the
      culture had low levels of cell surface lamp1 and lamp2 expression which were
      significantly increased following PHA stimulation (P < 0.0001). A dose-dependent
      response to PHA and the effect of varying concentrations of serum were defined.
      Kinetic analysis revealed that the majority of the increase in both lamp1 and
      lamp2 occurred within the first 2 hr of incubation and that a subset of PBMCs
      maintained expression for at least 96 hr. Incubation of cells with colchicine and
      cycloheximide modified the cell surface expression of these proteins.
      Interleukins 2, 4, 6, and 8 had only a modest effect on the degree of cell
      surface lamp1 and lamp2 expression, though they did significantly affect the
      distribution of expression among different subtypes of lymphoid cells. Under the
      conditions utilized in this study, cell surface LAMP expression was confined
      primarily to CD56+ cells and to CD3+ cells. Functional analysis utilizing a
      fluorescence-based adhesion assay revealed that cell surface lamp2 mediates
      adhesion of PBMCs to vascular endothelium, possibly by interacting with
      endothelial selectins. LAMPs likely contribute to the migration of activated
      leukocytes to sites of inflammation in vivo.

PMID- 8660834
TI  - Effects of a nonapeptide thymic hormone on intestinal intraepithelial lymphocytes
      in mice following administration of 5-fluorouracil.
AB  - A significant fraction of murine small intestinal intraepithelial lymphocytes (i
      IELs) mature in local sites outside the thymus. However, there is evidence
      suggesting that extrathymic differentiation of i-IELs is still influenced by the
      thymus or thymus-derived factors. Facteur thymique serique (FTS), a nonapeptide
      thymic hormone, is involved in several aspects of intra- and extrathymic T cell
      differentiation in vivo. In this study, we investigated the effects of FTS on the
      kinetics of i-IELs in mice following a single administration of 5-fluorouracil (5
      FU). FTS treatment significantly accelerated the recovery in cell number of i
      IELs after administration of 5-FU. Flow cytometric analysis revealed that this
      accelerated recovery was mainly due to a rapid increase in CD8 alpha alpha+ i
      IELs. Similar findings were also evident in adult thymectomized (ATX) mice,
      indicating that FTS treatment caused a rapid recovery of CD8 alpha alpha+ i-IELs
      following 5-FU administration in the absence of a functional thymus. Furthermore,
      expression levels of the mRNAs for interleukin-2, interferon-gamma, and
      transforming growth factor beta 1 in the i-IELs were augmented by FTS treatment.
      Notably, FTS treatment protected mice from 5-FU-induced lethal toxicity,
      accompanied with an inhibition of the translocation of Enterobacteriaceae. These
      results suggest that FTS has an important function in the extrathymic maturation
      and activation of i-IELs in the small intestine following 5-FU administration,
      which may contribute at least partly to the protection against 5-FU-induced
      lethal toxicity.

PMID- 8660836
TI  - Increased lung cell cytotoxic but not bactericidal or phagocytic activity in
      Mycobacterium avium complex-infected mice.
AB  - Following intranasal infection of mice with Mycobacterium avium complex (MAC)
      organisms, bacterial growth plateaued at the fourth week postinfection and then
      remained relatively constant thereafter. Inflammatory cell numbers in the lungs
      increased 10-fold by 4 weeks postinfection, and lung cell cytotoxicity and the
      production of NO, H202, and 02- by lung cell cultures had all increased
      significantly by this time and remained elevated throughout the 15-week
      experimental study. Although these parameters are generally associated with
      increased bactericidal activity, there appeared to be a defect in phagocytosis by
      lung cells, so that bactericidal activity could not be demonstrated in either in
      vitro or in vivo experiments. This study suggests that following intranasal
      infection with MAC, inflammatory cells are activated, sufficient to prevent
      further bacterial growth in vivo but not sufficient to clear the infection. We
      suggest that the deficiency may lie in the phagocytic activity of the cells.

PMID- 8660837
TI  - CD2 ligation abrogates antigen-independent apoptosis in B cells.
AB  - We have described recently the prevention of apoptosis by CD2-soluble CD48
      interaction on antigen B cell receptor occupancy. Here, we show that CD2 ligation
      is also able to interfere with B cell receptor-independent apoptosis pathways
      such as spontaneous death in spleen B cells or serum deprivation and hydrogen
      peroxide exposure in the BAL-17 cell line. In all cases, CD2 ligation induces a
      signal that prevents the downregulation of Bcl-2 expression. The specific CD2
      signal pathway involved in this phenomenon is still unknown. As reported, CD2 did
      not appear to induce Ca2+ mobilization, phosphatidylinositol turnover, or PKC
      translocation in B cells. Nevertheless, we show that CD2 receptor ligation is
      coupled to the tyrosine phosphorylation pathway in B cells. These observations
      indicate that CD2 is functionally able to trigger at least an early signal that
      could play a role in apoptosis blockage B cells in addition to the adhesion one.
      The results suggest the participation of cellular membrane receptors other that
      CD40 in apoptosis rescue, not only in the antigen-dependent but also in the
      antigen-independent phases of B cell lymphopoiesis.

PMID- 8660838
TI  - Functionally active T cell receptor/CD3 complexes are present at the surface of
      cloned cytotoxic T cells without fluorescence-immunological detectability.
AB  - The cytotoxic T cell clone 10BK.1 is activated in response to the ovalbumin
      peptide OVA257-264 in a major histocompatibility complex class I-restricted
      manner. Following activation 10BK.1 cells proliferate, secrete lymphokines, and
      kill syn- and allogeneic target cells. Using immunofluorescence analysis we
      detected CD8, LFA-1, and ICAM-1 on the surface of 10BK.1 cells, but no CD3 or T
      cell receptor (TCR). In contrast, the proliferative response of 10BK.1 cells to
      antigen was efficiently blocked by soluble antibodies directed at CD3 epsilon or
      TCR alpha beta, but not by antibodies directed at TCR gamma delta. In addition,
      lysis of target cells was blocked by F(ab')2 fragments of antibodies directed at
      CD3 epsilon, and 10BK.1 cells proliferate in response to immobilized anti-CD3
      epsilon or anti-TCR alpha beta antibodies. Furthermore, 10BK.1 cells lyse
      hybridoma cells that secrete antibodies directed at CD3 epsilon or TCR alpha
      beta, but not TCR gamma delta. These results demonstrate that functionally active
      molecules of the TCR/CD3 complex exist on the surface of 10BK.1 cells, obviously
      in low amounts, undetectable by immunofluorescence. In contrast, using
      permeabilized cells, we found high cytoplasmatic expression of TCR alpha beta,
      CD3 epsilon, and zeta-chain in 1OBK.1 cells, indicating that the low level of
      TCR/CD3 expression on the surface is not a consequence of a reduced synthesis of
      these molecules, but that the transport of these molecules to the surface is
      reduced. Our data demonstrate that the absence of TCR/CD3 complexes on the
      surface of cells, as detected by immunofluorescence, does not warrant the
      conclusion that these complexes are also functionally absent from the surface of
      these cells.

PMID- 8660839
TI  - Abnormal association between invariant chain and HLA class II alpha and beta
      chains in chronic lymphocytic leukemia.
AB  - We have previously shown that peripheral blood lymphocytes from patients with
      chronic lymphocytic leukemia (CLL) express increased amounts of the minor p35
      form of class II invariant chain (Ii) relative to the major p33 form. In this
      report we demonstrate in Western blots that in CLL lymphocytes, but not in normal
      or Epstein-Barr virus-transformed normal lymphocytes, p35 and p33 Ii form sodium
      dodecyl sulfate (SDS)-resistant complexes with class II alpha and beta chains and
      that these complexes form an abnormally large proportion of the total class II
      molecules. Others have shown that stable SDS-resistant alpha-beta complexes are
      only formed upon binding of exogenous antigenic peptides for presentation at the
      cell surface. Large amounts of p35 Ii remaining in the endoplasmic reticulum and
      capable of forming stable complexes with alpha and beta chains could compete with
      endogenous antigenic peptides for available class II peptide binding sites. The
      presentation of endogenous tumor antigens would thus be prevented, leading to the
      escape of the CLL clone from immunological surveillance.

PMID- 8660840
TI  - Can bone marrow-derived thymic stromal cells mediate the positive selection of
      class I-restricted T cells?
AB  - Positive selection of T lymphocytes expressing self. MHC-restricted T cell
      receptors is mediated by MHC molecules expressed on thymic stroma. Among the more
      controversial aspects of this process is the relative role of MHC molecules on
      epithelial versus bone marrow-derived stromal elements (BM-APC). For CD4+ T
      cells, the weight of evidence suggests that positive selection is driven solely
      by MHC class II molecules expressed on thymic epithelial cells. In contrast,
      recent experiments have been interpreted to show that CD8+ T cell development can
      be driven by MHC class I molecules expressed on BM-APCs as well as epithelial
      cells. To directly address this issue, we have examined the development of T
      cells expressing a transgenic, MHC class I-restricted TCR in mice deficient in
      the rearrangement of endogenous TCR genes. Since the transgenic TCR is the only
      TCR expressed, this system is extremely sensitive and specific for detecting even
      inefficient events in T cell development. Our experiments demonstrate that MHC
      class I expression exclusively on BM-APC is incapable of driving positive
      selection of CD8+ T cells. This finding, together with earlier experiments for
      MHC class II, suggests a qualitatively unique function of thymic epithelial cells
      in mediating positive selection.

PMID- 8660841
TI  - An improved circularly permuted interleukin 4-toxin is highly cytotoxic to human
      renal cell carcinoma cells. Introduction of gamma c chain in RCC cells does not
      improve sensitivity.
AB  - We have previously demonstrated that a chimeric protein composed of human IL-4
      and Pseudomonas exotoxin, termed IL4-PE4E, is cytotoxic to primary cells derived
      from human renal cell carcinoma (RCC). To improve the cytotoxicity of IL4-toxins
      such as IL4-PE4E and IL4-PE38KDEL to IL-4 receptor (IL-4R) positive tumor cells,
      a circularly permuted chimeric toxin was prepared by fusing a truncated PE gene
      encoding PE38KDEL 3' to a circularly permuted IL-4 mutant gene encoding IL4 amino
      acids 38-129, the linker GGNGG, and IL4 amino acids 1-37. The resulting chimeric
      protein, termed IL4(38-37)-PE38KDEL, was tested on five RCC cell lines and its
      cytotoxicity was compared to that of the native IL4-toxins IL4-PE4E and IL4
      PE38KDEL. IL4(38-37)-PE38KDEL was found to be 5 to 10 times more cytotoxic to all
      cell cultures tested compared to either native IL4-toxin. The cytotoxic activity
      of IL4(38-37)-PE38KDEL was competible by excess IL-4 and was confirmed by
      clonogenic assay. IL4(38-37)-PE38KDEL bound to IL-4R on RCC cells with 6- to 12
      fold higher affinity than IL4-PE38KDEL or IL4-PE4E. RCC tumor cells were found to
      lack the common gamma chain (gamma c) of the IL-4R reported to be present on
      immune cells. The stable transfection of RCC cells with the gamma c chain gene
      did not significantly change their sensitivity to IL4(38-37)-PE38KDEL. Taken
      together, our results indicate that the CPIL4-toxin IL4(38-37)-PE38KDEL is highly
      cytotoxic to human RCC cells due to increased binding affinity to IL-4R while it
      is not cytotoxic or slightly cytotoxic to T and B cells, monocytic cell lines,
      and fresh resting or activated bone marrow-derived cells. The gamma c does not
      seem to increase the internalization rate and/or processing of IL4-toxins in RCC
      cells. CPIL4-toxin may be a useful agent for the treatment of human RCC.

PMID- 8660842
TI  - Recombinant human macrophage-colony stimulating factor suppresses the mouse mixed
      lymphocyte reaction.
AB  - We examined the effect of recombinant human macrophage-colony stimulating factor
      (rhM-CSF) on mouse macrophage accessory functions in vitro. The addition of rhM
      CSF to an allogenic mixed lymphocyte culture (MLC) consisting of mouse spleen
      cells suppressed the proliferation of lymphocytes in a concentration-dependent
      manner. However, rhM-CSF did not suppress the mixed lymphocyte reaction (MLR) on
      the MLC that contained only purified T and dendritic cells. This suggested that
      the suppressive effect of rhM-CSF on the MLR occurs via spleen macrophages.
      Suppression of the MLR by rhM-CSF could not be neutralized by the addition of
      synthetic inhibitors of prostaglandin E2 (indomethacin) and nitric oxide (NG-mono
      methyl-L-arginine). An antibody specific to mouse interleukin-10 (IL-10), which
      can neutralize the inhibitory effect of recombinant IL-10 in vitro, did not
      prevent rhM-CSF-induced suppression of the MLR. Even higher concentrations of IL
      1 could not overcome the inhibitory effect of rhM-CSF. Moreover, culture
      supernatants of macrophages stimulated with rhM-CSF had a suppressive effect on
      the MLR. The concentrations of transforming growth factor beta (TGF-beta) and IL
      10 in the suppressive culture supernatants were lower than those in the
      supernatants of nonstimulated macrophages. The supernatants suppressed the
      proliferation of the LBRM 33 TG6 mouse T cell line, but it did not affect the
      proliferation of other cell lines (L1210, L5178Y-R, and MC/9). These results
      suggest that rhM-CSF modulates a macrophage accessory function by stimulating
      macrophages to secrete a suppressive factor that causes suppression of the T cell
      response in vitro.

PMID- 8660843
TI  - Prostaglandin E2 inhibits the nuclear transcription of the human interleukin 2,
      but not the Il-4, gene in human T cells by targeting transcription factors AP-1
      and NF-AT.
AB  - Prostaglandin E2 (PGE2) release from activated macrophages and/or stimulation of
      T cells is associated with cAMP formation and activation of protein kinase A
      (PKA). cAMP inhibits Th1- but not Th2-cytokine production and may influence the
      nature of the immune response to a given antigen. Using DNA transfection and
      electrophoretic mobility shift assays (EMSA), we have examined the mechanisms for
      the transcriptional regulation of human IL-2 and IL-4 genes by PGE2. Stimulation
      of Jurkat cells with ionomycin and PMA in the presence of PGE2 inhibited the IL-2
      but not the IL-4-promoter activity. In EMSAs, nuclear extracts from primary
      human T cells stimulated with ionomycin and phorbol esters in the presence of
      PGE2 demonstrated decreased binding at the AP-1 and NF-AT sites of the human IL-2
      promoter; binding to the OCT-1 and NF-kappa B sites was not affected. These
      results suggest that cAMP regulates IL-2 production in human T cells by a
      transcriptional mechanism which involves discrete transactivating pathways for IL
      2-promoter activation.

PMID- 8660844
TI  - Membrane form of TNF alpha induces both cell lysis and apoptosis in susceptible
      target cells.
AB  - Tumor necrosis factor alpha, in the secreted as well as membrane-associated (mTNF
      alpha) form, represents a cytotoxic effector mechanism of activated macrophages;
      in contrast, direct evidence of the mTNF alpha involvement in cytotoxic T
      lymphocyte (CTL)-mediated lysis has not yet been obtained. We observed that
      following activation with anti-CD3 monoclonal antibody (mAb), both cloned CTL and
      peritoneal exudate lymphocytes rapidly upregulated mTNF alpha; a similar effect
      was observed in the macrophage cell line J774 after stimulation with
      lipopolysaccharide endotoxin. Activated effector cells, which were fixed with
      paraformaldehyde before testing, exerted lytic activity against the TNF-sensitive
      WEHI 164 tumor cell line, but not against the TNF-resistant P-815 mastocytoma.
      This effect was completely inhibited in the presence of anti-mouse TNF alpha Ab.
      Moreover, both mTNF alpha-expressing macrophages and CTL induced nuclear DNA
      fragmentation in WEHI 164 cells, which was also blocked by anti-TNF alpha Ab and
      was accompanied by a morphologic degeneration characteristic of the apoptotic
      form of cell death. These data on the whole indicate a common mode of action for
      mTNF alpha expressed on different cell populations endowed with cytotoxic
      capability and also imply a role for this molecule in T-cell-mediated
      cytotoxicity.

PMID- 8660845
TI  - Antigen-driven peripheral immune tolerance: suppression of experimental
      autoimmmune encephalomyelitis and collagen-induced arthritis by aerosol
      administration of myelin basic protein or type II collagen.
AB  - Antigen-driven tolerance is an effective method of suppressing cell-mediated
      immune responses. We have previously demonstrated that exposure of gut-associated
      lymphoid tissue to myelin basic protein (MBP) via oral administration suppresses
      experimental autoimmune encephalomyelitis (EAE). To further study presentation of
      antigen to the immune system by mucosal surfaces as a method of antigen-driven
      tolerance, the effect of inhalation of MBP was investigated. MBP was given as an
      aerosol to Lewis rats on Days -10, -7, -5, and -3 prior to immunization with MBP
      in Freund's adjuvant and on Days 0, 2, and 4 following immunization.
      Aerosolization of MBP completely abrogated clinical EAE in 100% of treated rats.
      Central nervous system inflammation and delayed-type hypersensitivity and
      antibody responses to MBP were also significantly reduced in aerosol-treated
      animals. Aerosolization of histone, a basic protein of similar weight and charge
      as MBP, had no effect. Disease was also suppressed with one aerosol treatment on
      Day -3 or by administering MBP nasally. Aerosolization was more effective than
      oral administration of MBP over a wide dose range (0.005-5 mg). Splenic T cells
      isolated from animals postaerosolization adoptively transferred protection to
      naive animals immunized with MBP. Aerosolization of MBP to animals with relapsing
      EAE after recovery from the first attack decreased the severity of a subsequent
      attack. Aerosol and oral MBP were equally effective at suppressing the in vitro
      immune response as measured by proliferation and interferon-gamma production. We
      then tested aerosolization of a different autoantigen in a different disease
      model and found that aerosolization of type II collagen was effective in
      suppressing collagen-induced arthritis. Thus, aerosolization of an autoantigen is
      a potent method to downregulate an experimental T cell-mediated autoimmune
      disease and suggests that exposure of antigen to lung mucosal surfaces
      preferentially generates immunologic tolerance.

PMID- 8660846
TI  - Topographic distribution of CD18 integrin on human neutrophils as related to
      shape changes and movement induced by chemotactic peptide and phorbol esters.
AB  - The acquisition of high-affinity ligand binding may result from a topographical
      redistribution of beta2 integrins (CD11/CD18) in the plane of the membrane in
      response to agonist-induced neutrophil stimulation. We examined the topographical
      distribution of CD18 on human neutrophils in relation with shapes changes and
      movements induced by stimulation with 10(-8) M N-formylmethionyl-leucyl
      phenylalanine (fMLP) and 10(-7) M phorbol myristate acetate (PMA). To localize
      CD18, we used immunogold-labeling methods and backscattered electron images
      obtained with scanning electron microscopy. On unstimulated neutrophils, CD18
      integrin was randomly distributed on the nonvillous planar cell body. Stimulation
      of neutrophils with 10(-8) M fMLP and 10(-7) M PMA for 10 min induced distinctive
      shape changes, i.e., polar and nonpolar ruffled shapes, and upregulation of the
      surface membrane content of CD18. These changes were accompanied by a specific
      topographic distribution of CD18. fMLP-stimulated (10(-8) M) cells accumulated
      CD18 on the ruffled plasma membrane at the frontal pole of polar neutrophils. PMA
      stimulated (10(-7) M) cells displayed CD18 aggregates on all plasma membrane
      domains, mainly on ruffles of nonpolar ruffled neutrophils. We conclude that the
      motile neutrophil responses elicited by chemotactic peptide and phorbol ester are
      associated with distinct patterns of topographic distribution of CD18 integrin.
      These features of CD18 expression may influence adhesive interactions mediated by
      human neutrophils.

PMID- 8660847
TI  - Homotypic interactions mediated through LFA-1/ICAM-3 decrease the proliferative
      response of activated T cells.
AB  - T cell activation occurs when the T cell receptor (TCR) is engaged by an antigen
      MHC complex on the surface of an antigen-presenting cell (APC). Additional
      signals provided by accessory molecules serve to modulate this response.
      Independent of TCR engagement, treatment of T lymphocytes with a combination of
      phorbol ester and CD28 ligation will result in a proliferative response. This
      also induces homotypic adhesion mediated by LFA-l/ICAM interactions. We
      demonstrate that the prevention of homotypic interactions between T cells
      resulted in a two- to fivefold increase in the proliferative response. This
      occurred whether the homotypic interactions were prevented by blockade of LFA-1,
      by the use of plate immobilized antibodies against other cell surface molecules,
      or by culture at low cell density. We further demonstrate that the increased
      proliferation was a result of interference with a negative signal delivered to
      the T cell as a result of ICAM-3-mediated events. These data demonstrate LFA
      1/ICAM-3 interactions between T cells in turn regulate an LFA-1-independent
      pathway that results in homotypic adhesion and a downregulation of the
      proliferative response of activated T cells.

PMID- 8660848
TI  - Thymus ontogeny and the development of TCR alpha beta intestinal intraepithelial
      lymphocytes.
AB  - Murine T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes
      (IEL), which express the CD8 molecule as a homodimer (CD8 alpha alpha), can be
      divided into two subsets: those which are CD4+ (CD4+CD8+alpha alpha) and those
      which are CD4- (CD4-CD8+alpha alpha). Here, we demonstrate that most TCR alpha
      beta CD4+CD8+alpha alpha IEL and TCR alpha beta CD4-CD8+alpha alpha IEL subsets
      appear to be of thymus origin, as neonatal thymectomy of BALB/c mice on Day 3
      nearly eliminated both subsets. To further support this hypothesis, we
      demonstrate by grafting the thymus of CBF1 (BALB/c x C57BL/6) mice into nude mice
      that the thymus is capable of generating both TCR alpha beta CD4-CD8+alpha alpha
      IEL and TCR alpha beta CD4+CD8+alpha alpha IEL. However, which of the two TCR
      alpha beta IEL subsets is generated depends largely on the age of the thymus. The
      thymus from fetal up to 2 weeks of age generates predominantly TCR alpha beta CD4
      CD8+alpha alpha IEL, but very scant amounts CD4+CD8+alpha alpha IEL. In contrast,
      the thymus after 2 weeks of age generates very little TCR alpha beta CD4
      CD8+alpha alpha IEL, but generates an abundant amount of TCR alpha beta
      CD4+CD8+alpha alpha IEL. These results are consistent with the observation in
      euthymic mice that TCR alpha beta CD4-CD8+alpha alpha IEL precede the appearance
      of TCR alpha beta CD4+CD8+alpha alpha IEL by several weeks, thus further
      suggesting that the thymus is the major source of both TCR alpha beta IEL
      subsets.

PMID- 8660850
TI  - Cellular activation induced by BCG is a PTK-dependent event.
AB  - Mycobacterial antigens including BCG stimulate human peripheral blood mononuclear
      cells resulting in cellular proliferation and the release of inflammatory
      cytokines such as TNF-alpha. However, the signal transduction mechanisms
      responsible for the BCG-induced cell activation are not completely understood. In
      this study, we investigated the role of PTK as a signal transduction pathway in
      BCG-induced cell activation, with the use of two PTK inhibitors (genistein and
      tyrphostin). Our results indicated that genistein significantly inhibited BCG
      induced cell growth determined by thymidine uptake in a dose-dependent manner.
      BCG-induced TNF-alpha secretion was completely suppressed by genistein in a dose
      dependent manner, producing 92% inhibition at a concentration of 50 microM. In
      addition, strong inhibition (81%) of BCG-induced TNF-alpha secretion was observed
      with tyrphostin (30 microM), another specific protein tyrosine kinase with a
      different mechanism of action. These inhibitory effects were not attributed to an
      alteration in cell viability as judged by trypan blue staining, and were not due
      to LPS contamination. On the other hand, monoclonal antibodies directed against
      HLA-DR and DQ inhibited the BCG-induced secretion of TNF-alpha. Taken together,
      these findings suggest that PTK may play an essential role in BCG-induced
      cellular activation.

PMID- 8660849
TI  - The regulation of tumor necrosis factor-alpha production in murine mast cells:
      pentoxifylline or dexamethasone inhibits IgE-dependent production of TNF-alpha by
      distinct mechanisms.
AB  - Mast cells activated via high-affinity receptors for IgE can produce a variety of
      multifunctional cytokines, including TNF-alpha, which is thought to be involved
      in the pathophysiology of allergic diseases and other inflammatory disorders. We
      investigated the regulation of Fc Fc epsilon RI-dependent TNF-alpha production by
      mouse mast cells using dexamethasone and pentoxifylline, pharmacological agents
      which are known to suppress TNF-alpha production by macrophages. We now report
      that either dexamethasone or pentoxifylline can inhibit IgE-dependent mouse mast
      cell production of TNF-alpha; however, the major site of action of these agents
      was different. Pentoxifylline inhibited mast cell TNF-alpha gene transcription,
      while dexamethasone inhibited TNF-alpha production predominantly by a post
      transcriptional mechanism. These results demonstrate that the synthesis of mast
      cell TNF-alpha can be regulated pharmacologically at either the transcriptional
      or the translational level and that pentoxifylline and dexamethasone, two agents
      that are used to treat inflammatory disorders, can modulate mast cell TNF-alpha
      production at different points in the synthetic pathway of this cytokine.

PMID- 8660852
TI  - Extracellular Activities of Human Granzymes
AB  - Situated in secretory granules of cytotoxic cells, granzymes are essential for
      induction of target cell apoptosis with perforin. However, since cytotoxic cells
      constitutively secrete a portion of their synthesized granzymes, these proteases
      could mediate extracellular functions independently of their role in the lytic
      event. Thrombin has been shown to function as an activation molecule by cleaving
      its receptor. We hypothesize that granzymes may act similarly. In this report, we
      show that purified human granzyme A can induce human lung fibroblasts to produce
      IL6 and IL8. Cytokine induction is abrogated by treating the serine protease with
      the suicide serine protease inhibitor 3,4-dichloroisocoumarin. Other fibroblast
      lines as well as epithelial cells produced cytokines in response to granzyme A.
      Our data suggest that granzyme A can function as an activation molecule with
      potentially important immunoregulatory functions.

PMID- 8660851
TI  - IL-4 and IL-13 modulate IL-10 release in endotoxin-stimulated murine peritoneal
      mononuclear phagocytes.
AB  - Several recent reports presented conflicting data on the action of IL-4 and IL-13
      in regulating the release of proinflammatory cytokines by human monocytes. Here
      we show that the regulation of cytokine release by IL-4 and IL-13 could be either
      inhibitory or stimulatory in LPS-treated murine peritoneal macrophages. When
      macrophages were treated with IL-13 or IL-4, between 6 and 24 hr prior to
      endotoxin challenge, TNF alpha and IL-6 levels were significantly augmented. On
      the other hand, when the cells were cotreated with LPS plus IL-13 or IL-4, the
      release of TNF alpha and IL-6 was inhibited. These effects of IL-4 and IL-13 were
      associated with the modulation of IL-10; pretreatment resulted in a decrease,
      whereas cotreatment gave rise to a dramatic increase in IL-10 levels. The
      inhibitory effect of IL-4 and IL-13 on the release of TNF alpha was partially
      reversed by neutralizing anti-IL10 antibody, and the inhibition of IL-6 release
      was completely reversed by the antibody. These data suggest that the mechanism of
      action of IL-13 and IL-4 in modulating macrophage TNF alpha and IL-6 release
      partially involves IL-10.

PMID- 8660853
TI  - Focal adhesion kinase-related fakB is regulated by the integrin LFA-1 and
      interacts with the SH3 domain of phospholipase C gamma 1.
AB  - Signal transduction through integrin molecules expressed on platelets and
      nonlymphoid cells involves activation of the intracellular focal adhesion kinase
      ppI25FAK (FAK) to phosphorylate substrate proteins on tyrosine residues. Similar
      mechanisms are also functional in T-lymphocytes through the beta 1-integrin VLA
      4. A putative FAK-related phosphoprotein (fakB) was identified that is responsive
      to intracellular signals induced through ligation of antigen receptors on both T-
      and B-lymphocytes, and whose induced tyrosine phosphorylation is augmented by TCR
      costimulation through the adhesion/costimulatory receptors CD2 and CD4. In this
      report, fakB is shown to respond to extracellular signals through the beta 2
      integrin LFA-1 in the absence of primary signals through the TCR. Protein-protein
      complex formation was observed involving an association between fakB,
      phospholipase C gamma 1 (PLC gamma 1), and the tyrosine phosphoprotein pp35-36.
      Evidence is provided here that fakB interacts with PLC gamma 1 through its SH3
      domain. The association between fakB and PLC gamma 1 does not appear to require T
      cell activation, whereas the induced tyrosine phosphorylation of the protein
      complex components occurs following engagement of LFA-1. These data indicate that
      the beta2-integrin LFA-1 expressed on T-lymphocytes stimulates a novel, FAK
      related molecule that may function in the interplay between adhesion receptors
      and intracellular signaling enzymes responsible for downstream second messenger
      generation.

PMID- 8660858
TI  - Contribution of early-emigrating midbrain crest cells to the dental mesenchyme of
      mandibular molar teeth in rat embryos.
AB  - Teeth are formed by reciprocal interactions between the epithelium and mesenchyme
      in the first pharyngeal arch. Although the contribution of midbrain and hindbrain
      crest cells to the first pharyngeal arch has been previously examined in rodent
      embryos, no direct evidence exists that these cells are actually involved in the
      dental mesenchyme. In order to elucidate the contribution of the cranial neural
      crest cells in tooth formation, we first identified the emigration sites and
      stages providing the crest cells that migrate to the presumed tooth-forming
      region of the mandibular prominence. Focal labeling with DiI was performed at the
      midbrain and anterior hindbrain crests in rat embryos, and the labeled embryos
      were cultured for 30 or 60 hr. The resultant migration patterns indicated that
      posterior midbrain crest cells emigrating by the end of the 4-somite stage
      predominantly migrated to the region where tooth buds normally develop. Second,
      we established a new type of long-term culture system in which whole embryo
      culture is followed by a mandibular organ culture. Using this system, rat embryos
      were maintained from the early-somite stage and the molars in the explants were
      able to reach the bud stage within 8 days. Finally, to ascertain if posterior
      midbrain crest cells emigrating by the end of the 4-somite stage were involved in
      the dental mesenchyme, these cells were labeled with DiI and processed for the
      long-term culture. Labeled crest cells were clearly detectable in the dental
      mesenchyme. These findings indicate that the early-emigrating posterior midbrain
      crest cells contribute to mandibular molar tooth development in rat embryos.

PMID- 8660859
TI  - Development of the indirect flight muscle attachment sites in Drosophila: role of
      the PS integrins and the stripe gene.
AB  - Using markers that are expressed at muscle attachment sites, we have examined the
      early pupal development (first 36 hr) of Indirect Flight Muscle (IFM) attachments
      in the fruit fly Drosophila melanogaster. Expression of the Drosophila homologs
      of vertebrate integrins, the Position-Specific (PS) antigens, is known to
      differentially mark epidermal (PS1alpha) and muscle (PS2alpha) components of the
      developing IFM attachment sites. During myogenesis, PS2alpha is detected
      transiently in imaginal myoblasts that fuse with persistent larval muscles to
      give rise to the Dorsal Longitudinal Muscles (DLMs), but not in myoblasts that
      fuse de novo to give rise to the Dorso Ventral Muscles. The integrins are not
      expressed at attachment sites when the muscle fibers first make their appearance
      (12-20 hr). Following muscle-epidermal contact, PS1 and PS2 are detected at
      muscle attachment sites. PS1 expression is at the muscle ends and also in the
      long epidermal processes that connect the developing muscle fibers to their sites
      of attachment in the epidermis, while PS2 expression is restricted to the muscle
      ends. Epidermal cells that will contribute to the adult attachment sites are
      defined as early as the third larval instar. Both anterior and posterior sites of
      attachment of the IFMs are marked by the expression of reporter beta
      galactosidase activity in a P-element line B14.0, which is an insertion at the
      stripe locus. B14.0 (stripe) is seen in distinct domains in the wing and leg
      imaginal discs which give rise to the thoracic cuticle. The expression is
      maintained during pupal development. The B14.0 (stripe) expressing epidermal
      cells contact the developing muscle fibers, leading to the formation of the
      myotendon junction. We show that the dorsal and ventral attachment sites of one
      group of IFMs, the DVMs arise from two different imaginal discs (wing and leg,
      respectively), which may explain the differential effect of mutations such as
      bendless on these muscles. Attachment sites for the other group of IFMs, the
      DLMs, on the other hand, arise from one imaginal disc (wing). B14.0 (stripe)
      expression defines epidermal cells of the adult attachment sites and is likely to
      function during early events leading to the formation of muscle-epithelial
      contacts. The PS integrins are detected at later stages, suggesting a role in the
      stabilization and maturation of the muscle-epidermal contacts into myotendon
      junctions.

PMID- 8660860
TI  - Morphological and molecular characterization of retinoic acid-induced limb
      duplications in mice.
AB  - This study reports a morphological, skeletal, and molecular characterization of
      the supernumerary limbs induced by systemic administration of all-trans retinoic
      acid to egg-cylinder stage mouse embryos. As initially described by Rutledge et
      al. (Proc. Natl. Acad. Sci. USA 91, 5436, 1994), we have found that oral
      administration of all-trans retinoic acid (70 mg/kg body weight) at 5.5 days
      postcoitum induced the formation of supernumerary limbs. Most often, these arose
      as a pair of extra buds located caudally and ventrally to the normal (orthotopic)
      hindlimb buds without duplication of the lower body axis. The resulting one or
      two supernumerary hindlimbs were connected to an imperfectly mirror-image
      duplicated pelvic girdle. Variable truncations of the stylopodium and zeugopodium
      skeleton, as well as abnormal splitting of the distal skeleton, were frequently
      observed. The apical ectodermal ridge of the extra limb buds expressed expected
      growth factor genes. However, an ectopic anterior expression of Sonic hedgehog
      and Hoxd-13 was seen in the supernumerary buds, suggesting that these buds would
      incorporate potential polarizing cells of the hindlimb or genital field and
      generate an ectopic polarizing zone. This is consistent with the reverse
      orientation of most supernumerary limbs at later stages. Some of the buds did not
      express limb-specific markers and were thus expected to degenerate or form
      nonlimb structures, as observed in an adult specimen. Less frequently, extra limb
      buds with normal polarity were associated to a duplicated lower body axis.
      Retinoic acid also generated a novel type of duplication in which "twin"
      hindlimbs with two parallel apical ectodermal ridges and zones of polarizing
      activity arose on one side of the embryo.

PMID- 8660861
TI  - Fertilization in Drosophila melanogaster: centrosome inheritance and organization
      of the first mitotic spindle.
AB  - Microtubule, chromatin, centrosome, and nuclear envelope configurations during
      the first division of the Drosophila melanogaster zygote were analyzed in order
      to investigate the organization of the first cleavage spindle and the origin of
      the functional centrosome. After pronuclear apposition the parental complements
      congress at the equatorial plane of the metaphase spindle. The chromatids,
      however, seem to move to the poles in two separate groups in each half spindle,
      mingling together during telophase, before the formation of the daughter nuclei.
      The spatial separation of parental complements during the first mitosis is also
      supported by the behavior of the nuclear envelope of female and male pronuclei. A
      low frequency of polyspermy is also observed during fertilization in D.
      melanogaster.

PMID- 8660862
TI  - Multiple roles for dopamine in Drosophila development.
AB  - Manipulation of dopamine levels by inhibition of tyrosine hydroxylase activity
      was accomplished in Drosophila melanogaster larval instars by feeding enzyme
      inhibitors for a 24-hr period. Behavioral assays performed immediately after
      treatment demonstrated that larval phototaxis, salt aversion, and heptanol
      preference were unaffected by reduced levels of dopamine. Within a few hours of
      treatment, the larvae ceased exploratory behavior and were unresponsive to
      external stimuli; these larvae eventually died. This behavior is strikingly
      similar to that displayed by dopamine-deficient transgenic mice. Treated larvae
      placed immediately onto normal food (to replenish dopamine levels) showed
      significant developmental delays and decreased fertility as adults. The
      lethality, developmental retardation, and decrease in fertility were reversed by
      addition of L-DOPA to inhibitor-containing food, suggesting that these effects
      were due solely to inhibition of tyrosine hydroxylation. Depletion of dopamine in
      newly eclosed females resulted in abnormally developed ovaries. These results
      suggest that the enzymatic function of tyrosine hydroxylase is vital and that
      reduced levels of dopamine result in akinesia and lethality, developmental
      retardation, and decreased fertility.

PMID- 8660863
TI  - Muscle organizers in Drosophila: the role of persistent larval fibers in adult
      flight muscle development.
AB  - In many organisms muscle formation depends on specialized cells that prefigure
      the pattern of the musculature and serve as templates for myoblast organization
      and fusion. These include muscle pioneers in insects and muscle organizing cells
      in leech. In Drosophila, muscle founder cells have been proposed to play a
      similar role in organizing larval muscle development during embryogenesis. During
      metamorphosis in Drosophila, following histolysis of most of the larval
      musculature, there is a second round of myogenesis that gives rise to the adult
      muscles. It is not known whether muscle founder cells organize the development of
      these muscles. However, in the thorax specific larval muscle fibers do not
      histolyze at the onset of metamorphosis, but instead serve as templates for the
      formation of a subset of adult muscles, the dorsal longitudinal flight muscles
      (DLMs). Because these persistent larval muscle fibers appear to be functioning in
      many respects like muscle founder cells, we investigated whether they were
      necessary for DLM development by using a microbeam laser to ablate them singly
      and in combination. We found that, in the absence of the larval muscle fibers,
      DLMs nonetheless develop. Our results show that the persistent larval muscle
      fibers are not required to initiate myoblast fusion, to determine DLM identity,
      to locate the DLMs in the thorax, or to specify the total DLM fiber volume.
      However, they are required to regulate the number of DLM fibers generated. Thus,
      while the persistent larval muscle fibers are not obligatory for DLM fiber
      formation and differentiation, they are necessary to ensure the development of
      the correct number of fibers.

PMID- 8660864
TI  - Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian
      CNS stem cell.
AB  - There is increasing interest in the role of RNA-binding proteins during neural
      development. Drosophila Musashi is one of the neural RNA-binding proteins
      essential for neural development and required for asymmetric cell divisions in
      the Drosophila adult sensory organ development. Here, a novel mammalian neural
      RNA-binding protein, mouse-Musashi-1, was identified based on the homology to
      Drosophila Musashi and Xenopus NRP-1. In the developing CNS, mouse-Musashi-1
      protein was highly enriched in the CNS stem cell. Single-cell culture experiments
      indicated that mouse-Musashi-1 expression is associated with neural precursor
      cells that are capable of generating neurons and glia. In contrast, in fully
      differentiated neuronal and glial cells mouse-Musashi-1 expression is lost. This
      expression pattern of mouse-Musashi-1 is complementary to that of another
      mammalian neural RNA-binding protein, Hu (a mammalian homologue of a Drosophila
      neuronal RNA-binding protein Elav), that is expressed in postmitotic neurons
      within the CNS. In vitro studies indicated that mouse-Musashi-1 possesses binding
      preferences on poly(G) RNA homopolymer, whereas Hu is known to preferentially
      bind to short A/U-rich regions in RNA. Based on their differential expression
      patterns and distinct preferential target RNA sequences, we believe that the
      mouse-Musashi-1 and Hu proteins may play distinct roles in neurogenesis, either
      through sequential regulatory mechanisms or differential sorting of mRNA
      populations during asymmetric division of neural precursor cells.

PMID- 8660865
TI  - Repetitive calcium waves induced by fertilization in the nemertean worm
      Cerebratulus lacteus.
AB  - To analyze fertilization-induced calcium dynamics in a protostome worm,
      unfertilized oocytes of the nemertean Cerebratulus lacteus were co-injected with
      calcium green (CG) and rhodamine (Rh) dextrans for dual-channel confocal imaging
      of early development. Based on CG/Rh ratioed images collected every 800 msec,
      fertilization elicits a "cortical flash" of elevated free calcium that spreads
      rapidly around the oocyte without propagating as a point-source wave. A similar
      calcium transient occurs in unfertilized oocytes treated with KCl to depolarize
      the oolemma, and the fertilization-induced cortical flash is eliminated if cobalt
      is used to block calcium channels, collectively indicating that fertilization
      initially triggers an influx of calcium ions through voltage-gated calcium
      channels in the oolemma. However, within minutes after producing a cortical
      flash, C. lacteus oocytes begin to display a series of point-source, oscillating
      waves of elevated free calcium that are propagated at about 15 micron/sec. The
      first two calcium waves arise at the site of sperm fusion and typically fail to
      reach the antipode, but after sperm incorporation, the waves spread globally
      throughout the ooplasm and typically shift their origin to a pacemaker region in
      the vegetal cortex. About 10 oscillations with an average duration of 3.3 +/- 1.2
      min are generated for approximately 60-100 min postfertilization as meiotic
      maturation is completed, and such waves continue to occur in cobalt-containing
      seawater or calcium-free seawater. Thus, wavelike calcium oscillations induced by
      fertilization are apparently dependent upon internal calcium stores, which in
      turn may contain IP3-insensitive and/or IP3-sensitive receptors based on
      experiments using ryanodine, caged IP3, and heparin. Unfertilized oocytes also
      display repetitive calcium waves following intracytoplasmic injections of whole
      sperm, and such oscillations are eliminated if the sperm suspensions are boiled
      prior to injection, suggesting the possible presence of a heat-labile sperm
      component that can elicit wavelike oscillations during fertilization.

PMID- 8660866
TI  - Gain-of-function alleles of Bearded interfere with alternative cell fate
      decisions in Drosophila adult sensory organ development.
AB  - We have isolated a novel class of gain-of-function mutations at the Bearded (Brd)
      locus which specifically affect the development of adult sensory organs in
      Drosophila. These Brd alleles cause bristle multiplication and bristle loss
      phenotypes resembling those described for the neurogenic genes Notch (N) and
      Delta (Dl). We have found that supernumerary sensory organ precursor (SOP) cells
      develop in the proneural clusters of Brd mutant imaginal discs; like normal SOPs,
      these are dependent on the function of the proneural genes achaete and scute, and
      express elevated levels of ac protein. At cuticular positions exhibiting the Brd
      bristle loss phenotype, we have found that the progeny of the multiplied SOPs
      develop aberrantly, in that neurons and thecogen (sheath) cells appear but not
      trichogen (shaft) and tormogen (socket) cells. This appears to represent a
      transformation of the pIIa secondary precursor cell within the SOP lineage to a
      pIIb secondary precursor cell fate. These results suggest that Brd gain-of
      function alleles interfere with Notch pathway-dependent cell-cell interactions at
      two distinct stages of adult sensory organ development. We have also identified
      enhancers and suppressors of the Brd dominant phenotypes; these include both
      previously characterized mutations and alleles of apparently novel loci. Finally,
      we have found that Brd null mutants are viable and exhibit no mutant phenotypes,
      suggesting that Brd may be a component of an overlapping function.

PMID- 8660869
TI  - Multiple cis-acting elements act cooperatively in directing trochoblast-specific
      expression of the alpha-tubulin-4 gene in Patella embryos.
AB  - During early embryogenesis of the mollusc Patella vulgata the alpha-tubulin-4
      gene is specifically expressed in the differentiation process of a particular
      cell type, the trochoblasts. The 5' region of the gene has been analysed for
      elements that are required for the regulation of the cell-type-specific
      activation of the gene. In a functional assay, seven elements that play a role in
      the spatiotemporal activation of the gene were detected in the promoter sequence.
      They are not required all together at the same time. A core of two elements,
      together with two or three auxiliary elements, are sufficient in controlling
      trochoblast-specific expression of the gene in the Patella embryo. One of the
      core elements is always required, without it, the gene is not expressed at all.
      The other core element acts as a positive element in trochoblasts and as a
      negative element in non-trochoblasts and thus is involved in directing the cell
      type specificity of expression. The seven elements act cooperatively, and at
      least some of them can substitute for each other. Sequence comparison revealed
      that six of the seven fragments contain the sequence element GTTAA, including one
      of the core elements. Both core elements seem to play a crucial role in the
      expression of the alpha-tubulin-4 gene during the differentiation process of
      trochoblasts in the Patella embryo. A model for the regulation of the cell-type
      specificity of the gene during trochoblast differentiation is proposed.

PMID- 8660867
TI  - Sp4, a member of the Sp1-family of zinc finger transcription factors, is required
      for normal murine growth, viability, and male fertility.
AB  - We report the cloning, characterization, and targeting of an Sp1-related zinc
      finger transcription factor gene from the distal arm of mouse chromosome 12. This
      gene, previously identified in rats and humans and designated sp4, is homologous
      to the Drosophila buttonhead (btd) gene, which is expressed in the head region of
      developing flies. Similarly, in situ hybridizations show that sp4 is highly
      expressed in mouse embryos in the developing central nervous system (CNS).
      Expression of sp4 is seen as early as Day 9 of development, where transcripts are
      abundant in the posterior neuropore. Expression in later embryos is detected
      throughout the CNS as well as in other structures, including the nasal mucosa,
      the vomeronasal organ, the epithelium of the lung and intestinal tract, the
      testes, and the developing teeth. Northern blot analysis showed sp4 expression in
      the adult brain and other tissues. Gene targeting by homologous recombination was
      used to determine the role of sp4 during mouse development. Two-thirds of
      homozygous mutants die within the first few days after birth and those that
      survive are smaller than their wild-type littermates. While fertility of the
      female mutants appears normal, homozygous mutant males do not breed, despite
      having histologically intact testes containing mature sperm. sp4/sp4 mutant males
      fail to copulate, indicating that this gene is required for normal male
      reproductive behavior.

PMID- 8660870
TI  - Functional equivalence and rescue among group 11 Hox gene products in vertebral
      patterning.
AB  - Hoxa-11 and Hoxd-11 are paralogous genes required for proper development of the
      vertebral column, the limbs, and the urogenital system. To further explore the
      functional relationship between these genes, as well as the potential rescue of
      one function by the other, we have introduced a Hoxd-11-expressing transgene into
      Hoxa-11/Hoxd-11 mutant genetic backgrounds. A range of phenotypes was observed,
      with transgenic mice displaying as few as four lumbar vertebrae while double
      mutant mice had as many as eight. When transgenic, double homozygote mutant
      animals showed six lumbar vertebrae, instead of the eight usually observed. The
      phenotypic rescue of these genotypes shows that the Hoxa-11 and Hoxd-11 products
      are functionally equivalent and that extra doses of Hoxd-11 can rescue Hoxa-11
      loss of function.

PMID- 8660872
TI  - A switch in broad-complex zinc-finger isoform expression is regulated
      posttranscriptionally during the metamorphosis of Drosophila imaginal discs.
AB  - The Broad-Complex (BR-C) is a key member of the 20-hydroxyecdysone regulatory
      hierarchy that coordinates changes in gene expression during Drosophila
      metamorphosis. The family of transcription factors encoded by the BR-C share a
      common amino-terminal domain which is fused by alternative splicing to one of
      four pairs of C2H2 zinc-finger domains (Z1, Z2, Z3, and Z4). In this study, we
      examine the temporal expression of transcripts encoding each BR-C zinc-finger
      isoform-including the newly discovered fourth zinc-finger domain-during the
      metamorphosis of imaginal discs which form the integumental structures of the
      adult head and thorax. We find that all BR-C zinc-finger RNA isoforms are induced
      as a primary response to 20-hydroxyecdysone. However, induced BR-C RNA isoforms
      exhibit two divergent expression profiles. The Z2, Z3, and Z4 RNA isoforms
      accumulate to high levels at the beginning of the ecdysone response and abruptly
      disappear after several hours. In contrast, the Z1 RNA isoform continues to
      accumulate while the others decline, resulting in a switch in relative isoform
      levels. Using probes specific to different regions of the BR-C, we show that the
      switch in BR-C RNA isoform expression appears to be posttranscriptionally
      regulated, presumably by ecdysone-responsive factors. We propose that this switch
      results from a change in splice acceptor site choice. Finally, we present a model
      describing how this temporal switch in isoform expression could mediate changes
      in BR-C function, from transcriptional activation to repression and vice versa,
      that are critical for coordinate downstream target gene expression.

PMID- 8660873
TI  - Clustering and functional cooperation of Ng-CAM and axonin-1 in the substratum
      contact area of growth cones.
AB  - Growth cones and neurites of chicken dorsal root ganglia neurons cultured on
      laminin, Ng-CAM, or axonin-1 exhibit substratum-dependent morphology and growth
      patterns which are accompanied by distinctive distributions of axonin-1 and Ng
      CAM in the growth cone membrane. On either Ng-CAM or axonin-1 substratum, both Ng
      CAM and axonin-1 were depleted from some areas of the apical growth cone
      membrane. In contrast, on laminin, both axonin-1 and Ng-CAM remained randomly
      distributed. Removal of axonin-1 from growth cones resulted in a blockage of
      neurite outgrowth on both Ng-CAM and axonin-1 substrata, indicating that in these
      neurons axonin-1 cooperates with Ng-CAM in the activation of axon growth. Based
      on these results possible molecular models for cooperation between axonin-1 and
      Ng-CAM on the growth cone are discussed.

PMID- 8660874
TI  - Determination of neuroepithelial cell fate: induction of the oligodendrocyte
      lineage by ventral midline cells and sonic hedgehog.
AB  - Near the floor plate of the embryonic neural tube there is a group of
      neuroepithelial precursor cells that are specialized for production of the
      oligodendrocyte lineage. We performed experiments to test whether specification
      of these neuroepithelial oligodendrocyte precursors, like other ventral neural
      cell types, depends on signals from the notochord and/or floor plate. We analyzed
      heterozygous Danforth's short tail (Sd/+) mutant mice, which lack a notochord and
      floor plate in caudal regions of the neural tube, and found that oligodendrocyte
      precursors did not appear at the ventricular surface where there was no floor
      plate. Moreover, oligodendrocytes did not develop in explant cultures of Sd/+
      spinal cord in the absence of a floor plate. When a second notochord was grafted
      into an ectopic position dorsolateral to the endogenous notochord of a chicken
      embryo, an additional floor plate was induced along with an ectopic focus of
      oligodendrocyte precursors at the ventricular surface. Oligodendrocytes developed
      in explants of intermediate neural tube only when they were cocultured with
      fragments of notochord or in the presence of purified Sonic hedgehog (Shh)
      protein. Thus, signals from the notochord/floor plate, possibly involving Shh,
      are necessary and sufficient to induce the development of ventrally derived
      oligodendroglia. These signals appear to act by specifying the future fate(s) of
      neuroepithelial cells at the ventricular surface rather than by influencing the
      proliferation or differentiation of prespecified progenitor cells in the
      parenchyma of the cord.

PMID- 8660875
TI  - The origin of spinal cord oligodendrocytes is dependent on local influences from
      the notochord.
AB  - During spinal cord development, oligodendrocytes originate in a discrete region
      of the ventral ventricular zone. What regulates this initial localization of
      oligodendrocyte precursors is unclear. Using a combination of notochord
      transplantations in vivo and co-culture experiments, we demonstrate that the
      origin of chick spinal cord oligodendrocytes is dependent on local influences
      from the notochord. In stage 10-12 dorsal chick spinal cord, Mab O4+
      oligodendrocyte precursors were induced both in vivo by isochronic
      transplantation of an additional notochord adjacent to the dorsal neural tube and
      in vitro by co-culture of notochord and dorsal neural tube. Heterochronic
      transplantations demonstrated that the notochord was capable of inducing O4+
      cells in adjacent neural tube until stage 12 and that the competence of the
      dorsal neural tube to respond to this inductive signal declined after stage 10.
      During normal development the ventral neural tube is competent to develop
      oligodendrocytes independent of the notochord by stage 10. The induction of
      oligodendrocytes by the notochord may either reflect a direct interaction or be
      mediated through other ventrally located cells such as the floor plate. In the
      majority of experimental animals the appearance of ectopic oligodendrocyte
      precursors was correlated with local floor plate formation.

PMID- 8660876
TI  - Investigation of developing embryonic morphology using optical coherence
      tomography.
AB  - Improved imaging of morphological changes has the potential of offering new
      insight into the complex process of embryonic development. Optical coherence
      tomography (OCT) is a new imaging technique for performing in vivo cross
      sectional imaging of architectural morphology by measuring backscattered infrared
      light. This study investigates the application of OCT for imaging developing
      structure in Rana pipiens, Xenopus laevis, and Brachydanio rerio. Images are
      compared to conventional histological baselines. Cross-sectional imaging can be
      performed and structural morphology identified at greater imaging depths than
      possible with confocal and light microscopy. Repeated OCT imaging may be
      performed in vivo in order to track structural changes throughout development.

PMID- 8660877
TI  - The expression of Brachyury (T) during gastrulation in the marsupial frog
      Gastrotheca riobambae.
AB  - Gastrulation in the marsupial frog Gastrotheca riobambae has been analyzed by the
      distribution of the Brachyury (T) protein. Comparison with other amphibians
      provides mechanistic insights, since G. riobambae develops slowly and has the
      most divergent mode of amphibian gastrulation, producing an embryonic disk. The T
      pattern indicates that the prospective mesoderm is superficial, as in many
      amphibians. The dorsal blastopore lip could not be identified by the expression
      of T, or by morphological criteria, thus it is unknown whether Gastrotheca
      embryos have a dorsal organizer before or after blastopore closure. The
      circumblastoporal and notochordal expression of T, which are temporally
      contiguous in Xenopus, are separated in Gastrotheca, implying that distinct
      regulatory mechanisms may control the expression of T in its two domains. The
      separation of the T pattern also indicates that involution at the blastopore is
      separate from notochord formation. In addition, extension of the archenteron and
      notochord occurs after blastopore closure, suggesting that dorsal convergence and
      extension have been delayed until after blastopore closure. Therefore, dorsal
      convergence and extension need not be the cause of blastopore closure in
      Gastrotheca. The separation of gastrulation events in embryos that have not been
      experimentally manipulated, such as those of Gastrotheca, helps in understanding
      the distinct nature of gastrulation processes.

PMID- 8660878
TI  - Disperse versus compact elements for the regulation of runt stripes in
      Drosophila.
AB  - The segmented body pattern of the Drosophila embryo is established through a
      hierarchical network of interacting genes. At each successive step in this
      pathway, transcriptional regulation is used to convert coarse positional
      information into finer patterns of gene expression. Central to this process are
      the cis-regulatory regions that drive the dynamic spatial expression of the
      different segmentation genes. Here we describe the cis-regulatory region of the
      runt gene. As found for both other primary pair-rule genes, hairy and even
      skipped, there are stripe-specific elements which mediate the initial regulation
      of runt stripes by gap genes. We did not find autoregulatory elements as
      described for even-skipped and fushi tarazu. The regulation of runt by other pair
      rule genes is mediated by a large region, extending over 5 kb upstream and
      downstream of the transcription start site. This "disperse" element cannot be
      subdivided into functionally independent subelements or minimal elements. Such
      disperse elements mediating pair-rule gene interactions may have escaped
      detection in other segmentation genes and may involve molecular mechanisms
      different from those mediating regulation by gap genes.

PMID- 8660879
TI  - Conditioned medium from activated microglia promotes cholinergic differentiation
      in the basal forebrain in vitro.
AB  - In earlier studies we found that treatment with interferon-gamma (IFN-gamma)
      produced an 8- to 11-fold increase in choline acetyltransferase (ChAT) in
      cultured cells taken from Embryonic Day 16 (E16) septal nuclei with adjacent
      basal forebrain (SN/BF). Since younger cultures responded even more profoundly to
      IFN treatment, we have tested the possibility that the action of IFN (or its
      intermediate; see below) is to prompt the cholinergic differentiation of neuronal
      precursors. SN/BF cultures of various ages were labeled with a retrovirus
      engineered to express beta-galactosidase (Lac-Z), and ChAT-positive descendants
      of the retrovirally labeled precursors were counted. IFN-gamma treatment of
      cultures caused as much as an 8.8-fold increase in the proportion of ChAT
      positive cells present in Lac-Z-positive clones, suggesting that IFN promoted
      cholinergic differentiation in precursor populations. By contrast, bFGF increased
      clone size but did not change the proportion of ChAT-positive cells. NGF affected
      neither. Only ameboid microglia present in the cultures responded to IFN with
      characteristic nuclear translocation of the signal transducing molecule p91,
      suggesting that a microglial-derived molecule may mediate the action of IFN.
      Consistent with this hypothesis, conditioned media from cultures of enriched,
      activated microglia also increased ChAT activity in a dose-dependent fashion.
      Conditioned media from an unstimulated macrophage/monocyte cell line (RAW 264.7)
      also proved extremely efficacious in raising ChAT activity. In addition,
      conditioned media from both activated microglia and RAW 264.7 cells increased the
      proportion of ChAT-positive cells in retrovirally labeled clones to the same
      extent as IFN itself, suggesting the possibility that they contain the
      molecule(s) that mediates the action of IFN. Preliminary characterization of this
      molecule suggests that it is a very stable and large protein. Together these data
      suggest that a molecule promoting cholinergic differentiation is produced by
      activated microglia and other macrophage-like cells. The identity of this
      molecule and its precise role in normal development await its further
      purification.

PMID- 8660880
TI  - Role of notochord in specification of cardiac left-right orientation in zebrafish
      and Xenopus.
AB  - The left-right body axis is coordinately aligned with the orthogonal dorsoventral
      and anterioposterior body axes. The developmental mechanisms that regulate axis
      coordination are unknown. Here it is shown that the cardiac left-right
      orientation in zebrafish (Danio rerio) is randomized in notochord-defective no
      tail and floating head mutants. no tail (Brachyury) and floating head (Xnot)
      encode putative transcription factors that are expressed in the organizer and
      notochord, structures which regulate dorsoventral and anterioposterior
      development in vertebrate embryos. Results from dorsal tissue extirpation and
      cardiac primordia explantation indicate that cardiac left-right orientation is
      dependent on dorsoanterior structures including the notochord and is specified
      during neural fold stages in Xenopus laevis. Thus, the notochord coordinates the
      development of all three body axes in the vertebrate body plan.

PMID- 8660881
TI  - The wingless signaling pathway is directly involved in Drosophila heart
      development.
AB  - Heart development in both vertebrates and Drosophila is initiated by bilaterally
      symmetrical primordia that may be of equivalent embryological origin: the
      anterior lateral plate mesoderm in vertebrates and the dorsal-most mesoderm in
      arthropods. These mesodermal progenitors then merge into a heart tube at the
      ventral midline (vertebrates) or the dorsal midline (Drosophila). These
      observations suggest that there may be similarities between vertebrate and
      invertebrate heart development. The homeobox gene, tinman, is required for heart
      as well as visceral mesoderm formation in Drosophila, and at least one of several
      vertebrate genes with similarities in protein sequence and cardiac expression to
      tinman is crucial for heart development in vertebrates. Inductive signals are
      also required for Drosophila heart development: The secreted gene product of
      wingless (wg) is critical for heart development during a time period distinct
      from its function in segmentation and neurogenesis. Here, we show that wg is
      epistatic to hedgehog (hh), another secreted segmentation gene product, in its
      requirement for heart formation. We also provide evidence show that downstream of
      wg in the signal transduction cascade, dishevelled (dsh, a pioneer protein) and
      armadillo (arm, beta-catenin homolog) are mediating the cardiogenic Wg signal. In
      particular, overexpression of dsh can restore heart formation in the absence of
      wg function. We discuss the possibility that Wg signaling is part of a
      combinatorial mechanism to specify the cardiac mesoderm.

PMID- 8660882
TI  - Genetic analysis of the Drosophila beta3-tubulin gene demonstrates that the
      microtubule cytoskeleton in the cells of the visceral mesoderm is required for
      morphogenesis of the midgut endoderm.
AB  - We have investigated the cellular basis for lethality of mutant alleles of the
      Drosophila melanogaster beta3-tubulin gene, betaTub60D. Lethal beta3 mutations
      can be grouped into two classes: the most severe mutations (Class I alleles)
      cause death during the first larval instar, while weaker alleles (Class II) cause
      death in later larval stages or in early pupal development. Since beta3 is not
      expressed during larval development, lethality of the Class I mutations must
      reflect essential functions of beta3 in embryogenesis. Beta3-tubulin is
      zygotically expressed during midembryogenesis in the developing mesoderm, and the
      major site of beta3 accumulation is in the developing muscles during myogenesis.
      We show that the embryonic pattern of beta3 expression, including accumulation in
      the developing musculature, is conserved in other Drosophila species. However, we
      found that loss of beta3 function does not cause discernible defects in either
      the ultrastructure or function of the larval muscle. Thus beta3-tubulin is
      dispensable in its highest site of accumulation. Rather, the essential site of
      function of beta3 in embryos is in cells of the visceral mesoderm. Lethality of
      Class I alleles is caused by defects in midgut morphogenesis and failure of gut
      function. Although the folding pattern is irregular and the gut is smaller than
      normal, a complete folded gut forms in mutant larvae, and the visceral muscle
      functions normally to move food through the gut. However, mutant larvae cannot
      absorb nutrients across the gut wall. Thus loss of beta3 function in the mesoderm
      results in defects in the underlying endodermally derived layer of the gut. Our
      data provide an assay for cellular interactions between mesoderm and endodermal
      tissues and reveal a role for the microtubule cytoskeleton of the visceral
      mesodermal cells in differentiation of the endodermal cell layer of the larval
      gut.

PMID- 8660883
TI  - decapentaplegic overexpression affects Drosophila wing and leg imaginal disc
      development and wingless expression.
AB  - We have used the GAL4-UAS expression system to increase the level of expression
      of the Drosophila gene decapentaplegic (dpp) in a pattern approximating its
      normal pattern in leg and wing imaginal discs. Intermediate increases of dpp
      expression have little effect in wing discs but high levels of dpp overexpression
      lead to reduction of the scutellum and duplication of posterior wing structures.
      In leg discs intermediate increases cause supernumerary outgrowths of ventral leg
      structures in the anterior-ventral region. Greater increases of dpp expression
      cause the loss of ventral leg structures with the concomitant fusion of left and
      right dorsal forelegs. The defects observed in both legs and wings appear to
      arise through dose-dependent effects of dpp on wingless (wg) expression. A high
      level of dpp overexpression in the wing disc causes reduction of wg expression in
      the presumptive scutellar region, consistent with the subsequent reduction of the
      scutellum. An intermediate increase of dpp expression in leg discs induces the
      expansion of wg expression into the ventral outgrowths. At higher dpp expression
      levels, ventral wg expression in leg discs is eliminated, consistent with the
      loss of ventral leg cuticle. In the leg disc end knob and in the wing margin
      primordium, where wg and dpp cooperate in producing distal outgrowth, dpp
      overexpression has no detectable effect either on patterning or on wg expression.
      We propose that a critical role for dpp in other regions of the leg and wing
      discs is to reduce or block the expression of wg. This role of dpp is supported
      by the observation that ectopic wg expression is detected in imaginal discs where
      dpp signaling is compromised by lowering the activity of one of its receptors,
      tkv. This antagonism between dpp and wg expression may be critical to assigning
      only one disc region as the distal organizer.

PMID- 8660884
TI  - Extracellular cAMP depletion triggers stalk gene expression in Dictyostelium:
      disparities in developmental timing and dose dependency indicate that prespore
      induction and stalk repression by cAMP are mediated by separate signaling
      pathways.
AB  - During Dictyostelium development, amoebae differentiate into spores and stalk
      cells. Earlier studies showed that extracellular cAMP is essential for induction
      of prespore differentiation and that cAMP represses stalk gene expression in
      vitro. We show that the repressive pathway is operative in vivo, because
      activation of the stalk-specific promoter region of the ecmB gene is strongly
      enhanced by overexpression of a phosphodiesterase that depletes extracellular
      cAMP. To test whether a single cAMP transduction pathway controls the choice
      between prespore or stalk cell differentiation, we compared the timing and dose
      dependency of the effects of cAMP on both responses. Cells acquire competence for
      cAMP repression of ecmB promoter activity 4 hr later than for prespore gene
      induction. Half-maximal prespore induction requires 30 microM stable cAMP analog
      Sp-cAMPs, while ecmB induction is half-maximally repressed by 200 nM Sp-cAMPs,
      which is equivalent to about 3 to 13 nM cAMP. At concentrations exceeding 10
      microM, Sp-cAMPs stimulates ecmB expression from the intact promoter, but not
      from the stalk-specific subregion. These data suggest that distinct signaling
      pathways operating at different developmental stages control induction of
      prespore genes on one hand and repression of stalk genes on the other. Both stalk
      gene repression and prespore gene induction by Sp-cAMPs are antagonized by
      millimolar adenosine concentrations. However, an adenosine analog that is
      resistant to extracellular metabolism is active at 10 microM. Since adenosine
      inhibits cAMP binding to cAMP receptors, it may facilitate stalk gene expression
      by reducing the perceived cAMP concentration.

PMID- 8660885
TI  - Intraretinal grafting reveals growth requirements and guidance cues for optic
      axons in the developing avian retina.
AB  - To study environmental factors controlling the growth and navigation of optic
      axons in the eye, grafts of retinal, optic disc, optic tectum, and floor plate
      tissue were transplanted into organ-cultured embryonic chick or quail eyes. The
      growth of axons into and out of the graft was studied in cross sections of the
      cultured eyes and by DiI tracing in retinal whole mounts. Based on the location
      and trajectory of axons and based on the quantity of axons that entered and
      exited the grafts, several requirements for axonal navigation were established:
      (1) Axonal growth is restricted to an approximately 10-microm-thick layer at the
      vitreal surface of the retina. (2) The retinal neuroepithelium prior to
      axogenesis is nonpermissive for neurite outgrowth. This nonpermissive quality is
      transient and recedes peripherally as the differentiation of the retina
      progresses. (3) Embryonic axons are able to grow into neonatal and adult retinal
      grafts, demonstrating that older retina remains permissive for axonal growth. (4)
      The trajectory of axons into and from retinal grafts that had been rotated in
      their peripheral-central orientation showed that the retina has an inherent
      polarity that permits axon growth toward and away from the optic disc, but does
      not allow axon growth perpendicular to this direction. This centroperipheral cue
      operates locally rather than by long distance. (5) The optic disc provides an
      exit for the axons from the retina, but has no detectable neurotropic activity.
      Finally, optic axons from the host retina readily enter grafts of their target
      tissue, the optic tectum, but few axons are able to leave tectal transplants.

PMID- 8660886
TI  - External Mg2+ triggers oscillations and a subsequent sustained level of
      intracellular free Ca2+, correlated with changes in membrane conductance in the
      oocyte of the prawn Palaemon serratus.
AB  - We have provided evidence that external Mg2+ induces correlated changes in
      [Ca2+]i and membrane current or potential in prawn oocytes without any
      requirement of fertilization, using the fluorescent Ca2+ indicator Ca green
      dextran and voltage and current clamp methods. Replacement of Mg2+-free ASW with
      standard (40 mM Mg2+)ASW triggered a diphasic [Ca2+]i response consisting of an
      oscillation period followed by a second state of sustained [Ca2+]i level devoid
      of oscillation, lasting about 70 min and up to 3 hr, respectively. In contrast,
      oocytes maintained for a long time in Mg2+-free ASW showed no changes in [Ca2+]i
      which remained at a basal concentration of about 0.2 microM. The simultaneous
      records of [Ca2+]i and membrane or current changes showed that the oscillation
      period started with a first [Ca2+]i peak (about 1.7 microM) and was correlated
      with an initial transient membrane hyperpolarization or a transient initial
      outward current peak. The first [Ca2+]i peak was followed by a slow decrease in
      [Ca2+]i followed by a series of [Ca2+]i transients, concurrent with a slow
      depolarization of the membrane or a related inwardly directed current. The
      oscillation period ended with an oscillatory plateau of [Ca2+]i (about 0.6
      microM) lasting 49.6 +/- 4.5 min, the onset of which was concomitant with a final
      membrane hyperpolarization or a related final outward current. A continuous
      contact between external Mg2+ and the oocyte membrane was necessary to maintain
      the program of [Ca2+]i and membrane conductance changes. The sources of Ca2+
      mobilization are of internal origin for both the first peak and the subsequent
      series of [Ca2+]i oscillations, and are mainly of external origin for the
      oscillation plateau and for the second state of sustained [Ca2+]i level. The
      first and second step of the cortical reaction occurred during the oscillatory
      plateau and the second state of sustained [Ca2+]i level, respectively.

PMID- 8660887
TI  - Isolated maize zygotes mimic in vivo embryonic development and express
      microinjected genes when cultured in vitro.
AB  - We established conditions for the regeneration of natural maize zygotes isolated
      from pollinated plants with the goal of investigating the molecular control of
      early embryogenesis in higher plants. Viable zygotes were excised from embryo
      sacs by minimal enzymatic digestion and microdissection. Viable zygotes
      transferred to coculture with androgenic microspores from barley developed into
      embryo-like structures in 61% of the cases. No development was observed when
      zygotes were cultured in the presence of maize anthers undergoing androgenetic
      embryogenesis. Zygote-derived embryo-like structures regenerated into fertile
      plants through secondary embryogenesis when transferred to solid medium. The
      first zygotic division was asymmetrical and bipolar structures similar to
      pretransitional embryos observed in planta were later produced as observed using
      light and electron microscopy. Conditions for efficient microinjection of DNA
      into zygotes were established. Calcofluor and PATAG staining of zygotes showed
      that cell wall regeneration occurred as early as 20 min after enzymatic isolation
      and that after 2 hr, each zygote was bordered with cell wall material. Through
      quantitative microphotometry, DNA synthesis during the first cell cycle of the
      zygote was shown to occur between isolation and 12 hr of culture. Microinjection
      of two types of reporter genes (GUS gene and anthocyanin regulatory genes)
      demonstrates transient expression in plant zygotes. On average, 3.5% of
      microinjected zygotes showed transgenic expression. Reporter gene expression was
      observed in zygotes at different time points of their first cell cycle.

PMID- 8660889
TI  - Crumbs, a component of the apical membrane, is required for zonula adherens
      formation in primary epithelia of Drosophila.
AB  - The zonula adherens (ZA) is a cell-cell adherens junction that forms a belt in
      the apical most region of the lateral cell surface of many epithelia. It is
      composed of the cadherin-catenin complex and many associated proteins and is
      connected to a prominent belt of microfilaments. The ZA is believed to play an
      important role in the differentiation and behavior of epithelial tissues and thus
      contributes substantially to embryonic morphogenesis. In Drosophila embryos the
      ZA is formed during and shortly after gastrulation from adherens junction
      material that appears on the cell surface during cellularization. A ZA is present
      in a subset of epithelia in the Drosophila embryo called primary epithelia. A
      second specific marker for primary epithelia is the Crumbs protein, which in
      concert with the gene product of stardust is required to maintain epithelial
      polarity. This report shows that both genes are required for the reorganization
      of adherens junction material into the ZA. Using immunoelectron microscopy it is
      shown that Crumbs is not a component of the ZA but is distributed over the entire
      apical cell surface and concentrated in the immediate vicinity of the ZA. These
      results indicate a rather direct requirement of an apical activity for the
      organization of the lateral membrane domain in Drosophila primary epithelia. It
      is proposed that the marginal zone of the apical cell surface contains a crumbs-
      and stardust-dependent retention mechanism for adherens junction material that
      aids in the formation of the ZA.

PMID- 8660888
TI  - Characterization of changes in F-actin during maturation of starfish oocytes.
AB  - Major morphological and mechanical changes occur in the starfish oocyte during
      maturation. Measurements made by quantitative fluorescence microscopy of fixed
      specimens stained with saturating levels of rhodamine-phalloidin demonstrated
      that changes in the level of F-actin in intact oocytes, in the endoplasm, and in
      the cortex may contribute to these changes. The level of F-actin increased
      transiently after exposure of oocytes to the maturation inducing hormone, 1
      methyladenine (1-MA). This increase correlated with the formation of spikes on
      the cell surface. The level of F-actin decreased at the time of germinal vesicle
      breakdown (GVBD), which may account for the decrease in stiffness that occurs at
      this time. No increase in the level of F-actin was observed during formation of
      polar bodies, suggesting the existence of a secondary mechanism affecting oocyte
      stiffness. The changes in the amount of F-actin during oocyte maturation were
      largest in the cortex. The data also suggested that there are two distinct
      populations of cortical actin that are regulated both spatially and temporally;
      these are the F-actin in spikes and nonspike cortical F-actin. Changes in either
      or both of these populations of cortical actin were induced independently of GVBD
      by short exposures to 1-MA, induction of maturation with dithiothreitol, and
      pretreatment of immature oocytes with forskolin before adding 1-MA. Stabilization
      of F-actin by microinjection of phalloidin had no effect on GVBD. These results
      suggest that polymerization and depolymerization of actin during maturation are
      responsible for morphological and mechanical changes in the oocyte. In addition,
      the data suggest that the regulation of actin polymerization and depolymerization
      can be dissociated from GVBD.

PMID- 8660890
TI  - DNA sequences mediating the transcriptional response of the Mix.2 homeobox gene
      to mesoderm induction.
AB  - Peptide growth factors can initiate changes in cell fate in Xenopus ectodermal
      explants and induce the formation of mesoderm. Marker genes expressed in mesoderm
      allow the analysis of whether, or how much, induction has occurred, but do not
      tell us what molecules are involved in carrying out the response. In this report
      we describe the isolation of genomic and cDNA clones of Mix.2, a gene closely
      related to the Xenopus homeobox gene Mix.1, and demonstrate that the promoter of
      the Mix.2 gene is responsive to mesoderm induction signals when linked to a CAT
      reporter and microinjected into developing Xenopus embryos. Like the chromosomal
      Mix.1 gene, microinjected Mix.2 gene plasmids respond to activin in the presence
      of cycloheximide in animal cap assays and also respond to the embryonic inductive
      signal in Nieuwkoop recombinants. The injected promoter does not respond to TGF
      beta2 or FGF. Deletion analysis of the Mix.2 promoter demonstrated that sequences
      required for maximal transcriptional activity in response to mesoderm induction
      are scattered across a 290-bp region. This is the first report of a microinjected
      plasmid responding to immediate-early transcriptional activation in developing
      Xenopus embryos. This assay reduces the complexity of the cellular response to
      embryonic induction to the simple question of which molecules activate the Mix.2
      promoter and provides a sensitive and rapid test with which to pursue the answer.

PMID- 8660891
TI  - Targeted disruption of hoxc-4 causes esophageal defects and vertebral
      transformations.
AB  - Mice carrying a nonfunctional allele of hoxc-4 have been generated by gene
      targeting. The phenotype of mice homozygous for this mutation is strikingly
      different from those reported in mice lacking the paralogous genes hoxa-4, hoxb
      4, and hoxd-4. In contrast to the mutants of the paralogous family members, hoxc
      4 homozygotes do not manifest abnormalities in the cervical vertebrae, but
      instead show vertebral defects that extend from the second thoracic vertebra (t2)
      to t11. Therefore, defects do not correspond to the anterior limit of expression
      of hoxc-4, but rather begin within the region of strong hoxc-4 expression in the
      prevertebral anlagen (i.e., pv7-14). While hoxc-4 mutant homozygotes that reach
      adulthood are fertile and appear outwardly normal, most die before weaning age.
      The high lethality appears to result from partial or complete blockage of the
      lumen of the esophagus over a large portion of its length, as well as
      disorganization of the esophageal musculature. Although the Drosophila homolog of
      hoxc-4, Deformed, is autoregulated, mutation of the hoxc-4 gene does not affect
      transcription of its paralogous family members. However, in hoxc-4 mutant
      embryos, transcription of both the hoxc-5 and hoxc-6 genes is altered. Employment
      of cissolidustrans analysis showed that the hoxc-4 mutation acts in cis to affect
      the pattern of hoxc-5 expression. Therefore, this mutation is likely to cause a
      reduction of hoxc-5 function as well as complete loss of hoxc-4 function.

PMID- 8660892
TI  - Avian serum response factor expression restricted primarily to muscle cell
      lineages is required for alpha-actin gene transcription.
AB  - Serum response factor (SRF) gene expression in avian embryonic muscle lineages
      plays a central role in activating alpha-actin gene activity. In early stage HH 6
      avian embryos, SRF mRNA expression showed strong localization to the neural
      groove, primitive streak, lateral plate mesoderm, and Hensen's node, while
      distinct SRF expression was seen later in the neural folds and the somites by HH
      stage 8. SRF transcripts appeared in the precardiac splanchnic mesoderm in stage
      HH 9 embryos and was detected at higher levels in the myocardium, somites, and
      lateral mesoderm of HH 11 embryos. SRF antibody staining demonstrated significant
      SRF protein accumulation in the myocardium of the developing heart and the
      myotomal portion of somites. During primary myogenesis in culture, SRF
      transcripts and nuclear SRF protein content increased about 40-fold, as primary
      myoblasts withdrew from the cell cycle, reaching their highest levels prior to
      the upregulation of the skeletal alpha-actin gene. A dominant-negative SRF
      mutant, SRFpm1, which inhibited DNA binding, but not dimerization of monomeric
      SRF subunits, blocked transcriptional activation of a skeletal alpha-actin
      promoter-luciferase reporter gene during myogenesis. Transcriptional blockade was
      reversed by co-transfections of a wild-type SRF expression vector, but was not
      rescued by the expression of other myogenic factors, such as MyoD and Mef-2C.
      Thus, SRF displayed an embryonic expression pattern restricted primarily to
      striated muscle cell lineages, in which increased mass of nuclear SRF was
      obligatory for alpha-actin gene transcription.

PMID- 8660893
TI  - The fate diversity of mesodermal cells within the heart field during chicken
      early embryogenesis.
AB  - In gastrulation stage embryos of birds and mammals, the heart field is
      established as mesodermal crescents flanking the area rostrolateral to Hensen's
      node. Subsequent fusion of the bilateral heart primordia gives rise to a single
      tubular heart consisting of two epithelial layers: an outer myocardium and an
      inner endocardium. To date, it is uncertain whether these two distinct cell types
      of the heart arise from common or separate progenitor populations of mesodermal
      cells within the heart field. By retroviral single cell marking and tracking, we
      examined the diversity of cell populations present in the heart field of stage 4
      chicken embryos. Here we demonstrate that individual mesodermal cells in the
      heart field gave rise to a clone consisting only of one cell type, either
      endocardial or myocardial cells; i.e., 95.1% of the mesoderm-derived clones were
      localized in the myocardium, while 4.9% of them were found in endocardium. No
      clones containing both of these two cell types were detected. The results suggest
      that the heart field mesoderm at stage 4 consists of at least two distinct
      subpopulations, containing more premyocardial cells than preendocardial cells. If
      there exists a common precursor of both myocardial and endocardial cells, the
      lineage diversification must occur at or prior to the arrival of mesodermal cells
      to the heart field.

PMID- 8660894
TI  - A candidate gene for the amnionless gastrulation stage mouse mutation encodes a
      TRAF-related protein.
AB  - We report the identification of a new recessive prenatal lethal insertional
      mutation, amnionless (amn). amn mutant embryos first appear abnormal during the
      Early Streak stage, between E6.5 and E7.0, when they initiate mesoderm
      production. Subsequently, the amn mutants become developmentally arrested between
      the Mid and Late Streak stages of gastrulation and they die and are resorbed
      between E9.5 and E10.5. While extraembryonic structures, including the chorion,
      yolk sac blood islands, and allantois appear to develop normally, the small
      embryonic ectoderm remains undifferentiated and generates no amnion. In addition,
      the embryonic mesoderm that is produced does not become organized into node,
      notochord, and somites and there is no morphological evidence of neural
      induction. Interspecific backcross and fluorescence in situ hybridization
      analyses map the transgene insertion, and thus the amn mutation, to the distal
      region of mouse chromosome 12, which has synteny with human chromosome 14q32. A
      gene encoding a 7.5-kb transcript has been identified at a junction between the
      integrated transgene and host chromosome 12 sequences that meets three criteria
      expected of a candidate amn gene. This gene maps to the site of transgene
      insertion; it is transcribed during gastrulation, and its expression is disrupted
      in amn mutant embryos. Nucleotide sequencing studies show that the 567 amino acid
      protein encoded by the 7.5-kb transcript is a member of the newly defined family
      of putative signal transducing proteins, TRAFs, that associate with the
      cytoplasmic domains of members of the tumor necrosis factor (TNF) receptor
      superfamily. Thus, we have named the gene encoding the 7. 5-kb transcript
      TRAFamn. TRAFamn is identical to a recently reported protein (CD40bp, CAP-1,
      CRAF1, LAP1) that can bind the cytoplasmic domains of CD40 and the lymphotoxin
      beta receptor (LTbetaR), both of which are known members of the TNF receptor
      superfamily. The implications of these findings regarding a possible role for the
      TNF receptor superfamily during gastrulation are discussed.

PMID- 8660895
TI  - IGF-I and insulin in the acquisition of limb-forming ability by the embryonic
      lateral plate.
AB  - Acquisition of limb-forming ability by discrete regions of the lateral plate of
      the chick embryo is dependent on a medial-lateral inductive signaling cascade
      moving sequentially from the area of Hensen's node to the somitic mesoderm, the
      intermediate mesoderm, and then to the prospective limb-forming regions of the
      lateral plate. IGF-I and insulin are expressed by medial tissues as they are
      influencing the prospective limb-forming regions of the lateral plate. Here we
      report that IGF-I and insulin, but not FGF-2 or FGF-4, induce the formation of
      limb bud-like structures in vitro from prospective limb regions before they have
      acquired the ability to form limbs independent of medial tissues, and also induce
      the formation of limb bud-like structures from the prospective flank. The limb
      bud-like structures induced by IGF-I and insulin possess a thickened cap of
      ectoderm along their distal tips that resembles the apical ectodermal ridge (AER)
      and this thickened distal apical ectoderm expresses the AER-characteristic
      homeobox-containing gene Msx-2. Like in normal limb buds, a population of highly
      proliferating cells which express the homeobox-containing gene Msx-1 are
      localized in the mesoderm directly subjacent to the thickened AER-like structures
      induced by IGF-I and insulin. However, the limb bud-like structures induced by
      IGF-I and insulin do not express sonic hedgehog, which encodes a secreted
      signaling molecule that has been implicated in regulating the anteroposterior
      patterning of the developing limb bud. IGF-I- and insulin-treated prospective
      limb explants give rise to rudimentary limbs containing identifiable skeletal
      elements when grafted into the coelom or to somites of host embryos. Overall,
      these results suggest that IGF-I and insulin may be endogenous signals produced
      by medial tissues that are involved in conferring limb-forming ability to the
      lateral plate and may promote the initial outgrowth of limb buds and possibly
      induce the AER. However, other signals are necessary to promote the expression of
      genes such as sonic hedgehog that regulate the patterning of the developing limb.

PMID- 8660896
TI  - Increased expression of alphaq family G-proteins during oocyte maturation and
      early development of Xenopus laevis.
AB  - G-proteins of the alphaq family link extracellular stimulation of plasma membrane
      receptors to phospholipase C and consequently to intracellular Ca2+ release.
      Because they might function in initiating Ca2+ release at fertilization, we
      examined Galphaq family proteins in oocytes and eggs of Xenopus laevis. Three
      members of this protein family were identified by immunoblotting and antisense
      depletion. These proteins are barely detectable in the immature oocyte, but
      undergo a 6-fold increase in amount during oocyte maturation. This increase in
      Galphaq family protein expression correlates with the acquisition, during oocyte
      maturation, of the ability to release Ca2+ at fertilization (Schlichter and
      Elinson, 1981, Dev. Biol. 83, 33-41). In contrast, amounts of Galphas and
      Galphai3 are constant during maturation. We also examined the amounts of Galphaq,
      Galphas, and Galphai3 proteins during early development. While amounts of Galphas
      and Galphai3 show little or no change, Galphaq family protein expression
      increases 27-fold between the egg and neurula stages, suggesting that these
      proteins may be important in initiating Ca2+ release during early development.

PMID- 8660898
TI  - The dynamics of head activation changes during proportioning in Hydra oligactis
      with altered head-body ratios.
AB  - Normal hydra head-body proportions were altered by axially grafting a second head
      in place of the lower body column. The resulting animals had double the head
      tissue and one-quarter the normal body column. Changes in the head activation
      potential of tissue subjacent to both heads were monitored by assaying the
      ability of these animals to regenerate heads. The host head, the grafted head, or
      both heads were removed at varying times following graft construction and the
      animals were scored for head regeneration and/or the ability to express a head
      specific antigen recognized by monoclonal antibody, CP8. In the presence of the
      grafted head, tissue subjacent to the host head lost the ability to regenerate a
      head or express the head-specific antigen over a 48-hr period. In the presence of
      the host head, tissue subjacent to the grafted head regenerated heads at a very
      low frequency and lost the ability to express the head-specific antigen over the
      same 48-hr period. Following simultaneous removal of both heads, animals
      initially regenerated both heads for the first 48 hr after graft construction.
      Then, both head regeneration and expression of the head-specific antigen declined
      gradually over the next 3 days, though not to the very low levels observed when
      one head remained. These data, especially the loss of CP8 labeling, support the
      hypothesis that loss of regeneration ability was due to a loss of head activation
      potential in tissues subjacent to the heads. We propose that this reflected the
      attempt of grafted animals to compensate for the altered head-body proportions
      through reproportioning. In keeping with this hypothesis, feeding the grafted
      animals to stimulate growth of body column tissue and a shift toward more normal
      head-body proportions prior to decapitation resulted in animals which were
      capable of regenerating heads when decapitated. Several interpretations of the
      results based on the Gierer-Meinhardt reaction-diffusion model of pattern
      formation are discussed.

PMID- 8660897
TI  - GATA-6: a zinc finger transcription factor that is expressed in multiple cell
      lineages derived from lateral mesoderm.
AB  - Members of the GATA family of zinc finger transcription factors play important
      roles in the development of several mesodermally derived cell lineages. In the
      studies described in this report, we have isolated and functionally characterized
      the murine GATA-6 cDNA and protein and defined the temporal and spatial patterns
      of GATA-6 gene expression during mammalian development. The GATA-6 and -4
      proteins share high-level amino acid sequence identity over a proline-rich region
      at the amino terminus of the protein that is not conserved in other GATA family
      members. GATA-6 binds to a functionally important nuclear protein binding site
      within the cardiac-specific cardiac troponin C (cTnC) transcriptional enhancer.
      Moreover, the cTnC promoter enhancer can be transactivated by overexpression of
      GATA-6 in noncardiac muscle cells. During early murine embryonic development, the
      patterns of GATA-6 and -4 gene expression are similar, with expression of GATA-6
      restricted to the precardiac mesoderm, the embryonic heart tube, and the
      primitive gut. However, coincident with the onset of vasculogenesis and
      development of the respiratory and urogenital tracts, only the GATA-6 gene is
      expressed in arterial smooth muscle cells, the developing bronchi, and the
      urogenital ridge and bladder. These data are consistent with a model in which
      GATA-6 functions in concert with GATA-4 to direct tissue-specific gene expression
      during formation of the mammalian heart and gastrointestinal tract, but performs
      a unique function in programming lineage-restricted gene expression in the
      arterial system, the bladder, and the embryonic lung.

PMID- 8660899
TI  - Induction of embryonic vasculogenesis by bFGF and LIF in vitro and in vivo.
AB  - The de novo formation of blood vessels (vasculogenesis) is an integral part of
      embryogenesis. Elucidation of the role of cytokine cooperation in vasculogenesis
      may lead to a better understanding of organogenesis, blood vessel regulation
      during tumorigenesis, and tissue injury. We have used embryonic stem cells to
      derive an endothelial cell line, designated IEM, which expresses a range of
      endothelial markers, including Von Willibrand Factor VIII related antigen,
      vascular cell adhesion molecule, platelet-endothelial cell adhesion molecule
      (CD31), and receptors for acetylated low-density lipoprotein. More importantly,
      IEM cells can be induced upon exposure to combinations of basic fibroblast growth
      factor and leukemia inhibitory factor (LIF) to proliferate and undergo
      vasculogenesis in vitro, resulting in the formation of vascular tubes and
      microcapillary anastomoses. Moreover, exposure to both cytokines conditionally
      permits IEM cells to specifically chimerize microvascular endothelium in vivo
      following blastocyst injection. These results indicate that bFGF and LIF together
      contribute to the induction and support of embryonic vasculogenesis in an
      isolated endothelial cell line. Our results provide evidence that combined
      actions of bFGF/LIF may play a role in mechanisms controlling blood vessel
      development.

PMID- 8660902
TI  - FEATURES

PMID- 8660900
TI  - Regulated expression of homeobox genes Msx-1 and Msx-2 in mouse mammary gland
      development suggests a role in hormone action and epithelial-stromal
      interactions.
AB  - The murine homeobox genes Msx-1 and Msx-2 are related to the Drosophila msh gene
      and are expressed in a variety of tissues during mouse embryogenesis. We now
      report the developmentally regulated expression of Msx-1 and Msx-2 in the mouse
      mammary gland and show that their expression patterns point toward significant
      functional roles. Msx-1 and Msx-2 transcripts were present in glands of virgin
      mice and in glands of mice in early pregnancy, but transcripts decreased
      dramatically during late pregnancy. Low levels of Msx-1 transcripts were detected
      in glands from lactating animals and during the first days of involution, whereas
      Msx-2 expression was not detected during lactation or early involution.
      Expression of both genes increased gradually as involution progressed. Msx-2 but
      not Msx-1 expression was decreased following ovariectomy or following exposure to
      anti-estrogen implanted directly into the gland. Hormonal regulation of Msx-2
      expression was confirmed when transcripts returned to normal levels after
      estrogen was administered to ovariectomized animals. In situ molecular
      hybridization for Msx-1 showed transcripts localized to the mammary epithelium,
      whereas Msx-2 expression was confined to the periductal stroma. Mammary stroma
      from which mammary epithelium had been removed did not transcribe detectable
      amounts of Msx-2, showing that expression is regulated by contiguous mammary
      epithelium, and indicating a role for these homeobox genes in mesenchymal
      epithelial interactions during mammary development.

PMID- 8660901
TI  - Ingression during early gastrulation of fundulus.
AB  - This study demonstrates that involution does not occur during early gastrulation
      of Fundulus heteroclitus, prior to and during germ ring formation. This
      conclusion has been reached by following the motile behavior of large numbers of
      individual cells. Instead of involution, superficial deep cells of the marginal
      region of the blastoderm undergo ingression. They do not leave the surface as
      members of a flowing cohesive sheet, but sink beneath rather haphazardly as
      individuals. Indeed, during much of ingression, many marginal cells are so
      loosely arranged that they move about freely on the yolk syncytial layer. A small
      proportion of the cells initially at the blastoderm margin undergo ingression
      there, but most recede from the margin and ingress supramarginally one to three
      cell diameters from the margin. Cells that are initially supramarginal ingress
      mainly there, sometimes quite far from the margin. Only a small number moves to
      the margin and ingresses there. Interestingly, although most ingression takes
      place supramarginally, much occurs close to the margin-up to one to four cells
      away. Ingression begins immediately after the onset of epiboly and is most active
      before appearance of the germ ring; it ceases quite soon thereafter. It is also
      more active dorsally than ventrally, correlating with the earlier formation of
      the germ ring dorsally. Ingression constitutes the first invasive cellular
      activity of development. Significantly, it proceeds by blebbing locomotion, a
      noncontact inhibiting mode of cell movement. The possible broader import of these
      discoveries is given appropriate attention.

PMID- 8660908
TI  - Myocardial Infarction Is Coupled with the Activation of Cyclins and Cyclin
      Dependent Kinases in Myocytes
AB  - To determine whether the molecular components implicated in the regulation of the
      cell cycle are activated in myocytes after infarction, the expression of cyclins
      E, A, and B and the levels of their associated kinase activity were measured at 1
      and 7 days following surgery. The quantity of cdk2 and cdc2 and the level of
      their kinase activity were also determined. Myocardial infarction was
      characterized by an increase in cyclins E, A, and B and cdc2 proteins in the
      surviving myocytes at 1 and 7 days. Cyclin E, A, and B and cdk2 and cdc2 kinase
      activity also increased. The quantity of cyclins E and A and the level of cyclin
      E-associated kinase activity in myocytes after infarction were comparable with
      those measured in neonatal myocytes. Moreover, cdc2 protein and cdc2 kinase
      activity in myocytes reached levels after infarction which were similar to those
      in neonatal myocytes. Thus, myocytes react to myocardial infarction by activating
      cyclins and cyclin-dependent kinases which may be coupled with the regeneration
      of muscle mass and recovery of ventricular function.

PMID- 8660910
TI  - Sorting of messenger RNAs in the cytoplasm: mRNA localization and the
      cytoskeleton.

PMID- 8660911
TI  - c-Myc and Max interactions in quiescent and mitogen-stimulated primary
      hepatocytes.
AB  - The c-myc oncogene has been linked with cell proliferation, apoptosis, and
      differentiation, and when its expression is deregulated also with malignant
      transformation. In primary hepatocytes c-myc expression is constitutive and in
      part regulated by hepatocyte-specific growth factors (HGF, TGFalpha, and EGF) in
      a delayed early response manner. Max expression in these cells was found to be
      constitutive throughout the in vitro lifetime and mRNA transcript levels were
      increased at 12 h after induction with growth factors. Max was found to be
      associated in vivo with hepatocyte Myc species, with this association being
      independent of growth conditions and of the endogenous Myc or Max levels.
      Inhibition of endogenous hepatocyte Max levels via expression of an antisense max
      construct driven by the MMTV promoter did not affect the DNA synthetic response
      in the presence of dHGF (a variant of HGF). The unusually long half-life of the
      endogenous Myc species was found to be independent of their association with the
      widely accepted as "stable" partner, Max. We suggest that Myc and Max in
      hepatocytes are involved in the growth (proliferation, cell death) and
      differentiation program of these cells, acting independently or as a complex.

PMID- 8660912
TI  - Interactions of human skin fibroblasts with monomeric or fibrillar collagens
      induce different organization of the cytoskeleton.
AB  - Fibrillar collagens represent the most abundant extracellular matrix components
      surrounding fibroblasts. Although there is a large heterogeneity in the collagen
      composition and in the physiological functions of different tissues, interactions
      between cells and native collagens monomers are mediated by only two integrins,
      the alpha1beta1 and alpha2beta1 integrins. In tissue, fibroblasts are exposed to
      collagen polymers, supramolecular assemblies which might play a role on the
      availability of the cell-binding sites at the surface of the fibrils. We have
      addressed this issue by investigating the patterns of adhesion structures in
      normal human skin fibroblasts exposed to collagen monomers or polymers. Our
      results showed that cell morphology, cell adhesion pattern, actin organization,
      and distribution of integrin subunits, talin, vinculin, and phosphotyrosine
      containing proteins are dependent on the supramolecular organization of the
      collagens. In particular, compared to monomers, collagen polymers induced a
      looser organization of the actin network and a linear clustering of integrins,
      talin, vinculin, and phosphotyrosine-containing proteins. These results emphasize
      the role of the physical state of collagen on cellular interactions and underline
      the role of the extracellular matrix in the phenotypic modulation of fibroblasts.
      Furthermore, our studies suggest the existence of a local heterogeneity in the
      biological activity of collagen fibrils.

PMID- 8660914
TI  - SV40 large T antigen interferes with adult myosin heavy chain expression, but not
      with differentiation of human satellite cells.
AB  - The growth of muscle fibers during late development as well as in regeneration
      following muscle injury is the result of the proliferation and differentiation of
      satellite cells. However, all human cells, including satellite cells, show a
      limit in their proliferation. In order to define a cellular system with enhanced
      proliferative capacity, human satellite cells were transfected with a construct
      containing large T antigen from SV40 under the control of the human vimentin
      promoter. Vimentin is normally expressed during proliferation, and its expression
      is down-regulated as differentiation proceeds. In transfected cells, the
      construct is regulated like the endogenous vimentin gene. The effect of exogenous
      T antigen expression on both the proliferation and differentiation of human
      satellite cells was investigated. T antigen expression reduced the doubling time
      of human satellite cells from 36 to 20 h and increased the final proliferative
      capacity from 46 to 69 mean population doublings. When differentiation was
      triggered, although T antigen did not prevent the formation of myotubes, fusion
      was delayed. A similar delay was observed in the appearance of myogenin protein,
      one of the HLH regulatory factors, but not in the corresponding mRNA. Finally, T
      antigen has an effect on adult myosin isoform expression, since both adult slow
      and fast isoforms were only detected in myotubes negative for T antigen. These
      results led us to propose a model of the possible interactions between T antigen
      and muscle-specific factors.

PMID- 8660915
TI  - Histone H4 acetylation and replication timing in Chinese hamster chromosomes.
AB  - The distribution of acetylated isoforms of histone H4 along Chinese hamster
      chromosomes has been studied by immunostaining with antibodies recognizing H4
      acetylated at defined lysines in its N-terminal domain. The heterochromatic long
      arm of the X chromosome in both female (CHO) and male (DON) cell lines is
      underacetylated at three out of four lysines (5, 8, and 12). In contrast, the
      level of acetylation at lysine 16, which is the first to be acetylated in
      mammals, was similar in X chromosomes and autosomes. Labeling of the cells with
      bromodeoxyuridine (BrdU) to mark late-replicating chromosome domains, followed by
      double immunostaining with antibodies to BrdU and acetylated H4, showed a close,
      though not perfect, correlation between late replication and low levels of H4
      acetylation. The results show that levels of histone acetylation are associated
      with the replication timing of defined domains on both the X chromosome and
      autosomes, but the exceptions we observe suggest that this link is not absolute
      or essential.

PMID- 8660913
TI  - Functional reconstitution of oxidase activity in X-linked chronic granulomatous
      disease by retrovirus-mediated gene transfer.
AB  - The feasibility of correction of the disease phenotype by gene gene transfer was
      investigated in cells of four patients with X-linked chronic granulomatous
      disease. These patients carry point mutations of the gp91-phox gene, encoding for
      the large subunit of the catalytic core of the phagocytic cell NADPH oxidase. A
      retroviral vector expressing the gp91-phox protein was constructed and used to
      transduce lymphoblastoid cell lines established from the patients. Several
      transduced lymphoblastoid cell clones were investigated for mRNA and protein
      expression, and for functional reconstitution of oxidase activity. Although
      extensive quantitative variability was detected among different clones,
      functional reconstitution of O2- production was obtained in most cases, with
      oxidase function within the same range as in B cell lines derived from normal
      individuals. The same vector was also used for transduction of hematopoietic
      precursors from bone marrow or peripheral blood either with or without enrichment
      for CD34+ cells. A comprehensive analysis was performed on differentiated myeloid
      colonies, to evaluate the efficiency of transduction, the levels of gp91-phox
      expression, and the extent of functional reconstitution of oxidase activity. A
      high efficiency of transduction was obtained in most experiments, with 60-100% of
      colonies containing proviral DNA. Among the transduced colonies, an extensive
      variability in the levels of expression of the transduced gene and of functional
      restoration of NADPH oxidase activity was observed. These results represent a
      step toward the development of a gene therapy protocol for these patients.

PMID- 8660916
TI  - Regulation and activity of the retinoblastoma protein family in growth factor
      deprived and TGF(beta)-treated keratinocytes.
AB  - The retinoblastoma protein (pRB) and the pRB-related pocket proteins p130 and
      p107, when bound to DNA via the E2F family of transcription factors, suppress
      transcription and through this may mediate growth arrest. We show here that in
      HaCat cells arrested by treatment with TGFbeta the only pocket protein
      associating with DNA-bound E2F is pRB. This contrasts the situation in HaCat
      cells arrested via growth factor withdrawal, where we find that both pRB and p130
      can bind. The above implies that p130 participates in regulating E2F-dependent
      genes upon growth factor deprivation but not upon TGFbeta arrest. More
      importantly perhaps, in TGFbeta-arrested cells pRB alone in association with its
      partner E2Fs may be in charge and sufficient to control E2F-dependent gene
      transcription. Although p130 is not associated with a DNA-binding E2F complex in
      TGFbeta-treated cells, it is present in such cells in its underphosphorylated
      form. We provide evidence for a serum-induced process that may regulate p130 by a
      mechanism independent of p130 hyperphosphorylation.

PMID- 8660917
TI  - A protein kinase-dependent block to reinitiation of DNA replication in G2 phase
      in mammalian cells.
AB  - Eukaryotic cells normally replicate their DNA only once between mitoses. Unlike
      G1 nuclei, intact G2 nuclei do not replicate during incubation in Xenopus egg
      extract. However, artificial permeabilization of the nuclear membrane of G2
      nuclei allows induction of new initiations by Xenopus egg extract. This is
      consistent with the action of a replication licensing factor which is believed to
      enter the nucleus when the nuclear membrane breaks down at mitosis. Here, we show
      that G2 nuclei will initiate a new round of replication in the absence of nuclear
      membrane permeabilization, if they are preexposed to protein kinase inhibitors in
      vivo. Competence to rereplicate is generated within 30 min of drug treatment,
      well before the scheduled onset of mitosis. This demonstrates that a protein
      kinase-dependent mechanism is continually active in G2 phase to actively prevent
      regeneration of replication capacity in mammalian cells. Kinase inhibition in G2
      cells causes nuclear accumulation of replication protein A. Rereplication of
      kinase-inhibited G2 nuclei also depends on factors supplied by Xenopus egg
      extract, which are distinct from those required for replication licensing.

PMID- 8660918
TI  - Regulation of human (Caco-2) intestinal epithelial cell differentiation by
      extracellular matrix proteins.
AB  - Extracellular matrix regulation of intestinal epithelial differentiation may
      affect development, differentiation during migration to villus tips, healing,
      inflammatory bowel disease, and malignant transformation. Cell culture studies of
      intestinal epithelial biology may also depend on the matrix substrate used. We
      evaluated matrix effects on differentiation and proliferation in human intestinal
      Caco-2 epithelial cells, a model for intestinal epithelial differentiation.
      Proliferation, brush border enzyme specific activity, and spreading were compared
      in cells cultured on tissue culture plastic with interstitial collagen I and the
      basement membrane constituents collagen IV and laminin. Each matrix significantly
      increased alkaline phosphatase, dipeptidyl peptidase, lactase, sucrase
      isomaltase, and cell spreading in comparison to plastic. However, the basement
      membrane proteins collagen IV and laminin further promoted all four brush border
      enzymes but inhibited spreading compared to collagen I. Proliferation was most
      rapid on type I collagen and slowest on laminin and tissue culture plastic.
      Basement membrane matrix proteins may promote intestinal epithelial
      differentiation and inhibit proliferation compared with interstitial collagen I.

PMID- 8660919
TI  - AAMP, a newly identified protein, shares a common epitope with alpha-actinin and
      a fast skeletal muscle fiber protein.
AB  - AAMP (angio-associated migratory cell protein) shares a common epitope with alpha
      actinin and a fast-twitch skeletal muscle fiber protein. An antigenic peptide,
      P189, derived from the sequence of AAMP was synthesized. Polyclonal antibodies
      generated to P189 readily react with AAMP (52 kDa) in brain and activated T
      lymphocyte lysates, alpha-actinin (100 kDa) in all tissues tested, and a 23-kDa
      protein in skeletal muscle lysates. The antibody's reactivity for alpha-actinin
      can be competed with the purified protein. Activation of T lymphocytes does not
      alter the degree of alpha-actinin reactivity with anti-P189 as it does for AAMP's
      reactivity in these lysates. Competition studies with peptide variants show that
      six amino acid residues, ESESES, constitute a common epitope in all three
      proteins in human tissues. The antigenic determinant is continuous in AAMP but
      discontinuous (or assembled) in alpha-actinin. alpha-Actinin does not contain
      this epitope in its linear sequence so reactivity is attributed to an epitope
      formed by its secondary structure. Limited digestion of the reactive proteins
      with thermolysin destroys anti-P189's reactivity for alpha-actinin while
      reactivity for recombinant AAMP is retained. Specificity of anti-P189 for human
      skeletal muscle fast fibers seen on immunoperoxidase staining may be explained by
      anti-P189's reactivity with a 23-kDa protein found only in skeletal muscle
      lysates. Its pattern of reactivity is the same as that obtained using monoclonal
      anti-skeletal muscle myosin heavy chain in type II (fast-twitch) fibers.

PMID- 8660920
TI  - Changes in the cytoskeletal and nuclear matrix proteins in rat hepatocyte
      neoplastic nodules in their relation to the process of transformation.
AB  - In a previous paper (Barboro et al., 1993, Biophys. J. 65, 1690-1699) we have
      shown that cancer development in the resistant hepatocyte model of Solt and
      Farber is characterized by the progressive unfolding of the higher-order
      structure of chromatin. A possible functional role of decondensation phenomena in
      cell transformation cannot be ruled out. Genetic activation involves the
      relaxation of the superstructure of chromatin, which may be, at least in part,
      modulated by its interaction with the nuclear matrix. Moreover, recent
      observations suggest that gene expression can be stimulated by alterations in the
      organization of the cytoskeleton. Therefore, we have characterized the changes in
      composition that the nuclear matrix-intermediate filament complex undergoes
      during the evolution of rat hepatocyte nodules. Dramatic changes in the
      expression of both the nuclear matrix and intermediate filament proteins occur
      during transformation; they are, however, related in a different way to the
      stages of carcinogenesis. Several new nuclear matrix proteins appear in early
      nodules, isolated 9 weeks after initiation. The subsequent evolution of
      persistent nodules is also characterized by discrete changes in the composition.
      Thus, the new synthesis of nuclear matrix proteins reflects the emergence of
      successive cellular populations, in line with the recent finding that a subset of
      components of the nuclear matrix is cell type-specific. In contrast, intermediate
      filament proteins undergo continuing changes. A new keratin with apparent
      molecular weight of 39 kDa, analogous to human keratin 19, appears in early
      nodules, and its expression steadily increases up to the 32nd week from
      initiation; at the same time, the amount of the proteolytic fragments of keratins
      A and D increases sharply. These findings suggest that the inappropriate
      expression of keratin 19 may be involved in the epigenetic activation of new
      cellular programs, through the rearrangement of the cytoskeleton which in turn
      may perturb nuclear matrix function.

PMID- 8660921
TI  - The novel catenin p120cas binds classical cadherins and induces an unusual
      morphological phenotype in NIH3T3 fibroblasts.
AB  - p120cas (CAS) is a tyrosine kinase substrate whose phosphorylation has been
      implicated in cell transformation by Src and in ligand-induced signaling through
      the EGF, PDGF, and CSF-1 receptors. More recently, CAS has been shown to
      associate with E-cadherin and its cofactors (catenins), molecules that are
      involved in cell adhesion. Although both CAS and beta-catenin contain armadillo
      repeat domains (Arm domains), the amino acid identity between these proteins in
      this region is only 22%, and it is not yet clear whether CAS will emulate other
      catenins by associating with other members of the cadherin family. Here we report
      that in addition to binding E-cadherin, wild-type CAS associated with N-cadherin
      and P-cadherin. Transient transfection of cloned CAS isoforms into MDCK
      epithelial cells indicated that CAS1 and CAS2 isoforms are equally capable of
      binding to E-cadherin even though these cells preferentially express CAS2
      isoforms. In addition, CAS colocalized with N-cadherin in NIH3T3 cells and
      analysis of CAS mutants in vivo indicated that the CAS-N-cadherin interaction
      requires an intact CAS Arm domain. The data suggest that CAS-cadherin
      interactions in general are dictated by the conserved armadillo repeats and are
      not heavily influenced by sequences added outside the Arm domain by alternative
      splicing. Interestingly, overexpression of CAS in NIH3T3 cells induced a striking
      morphological phenotype characterized by the presence of long dendrite-like
      processes. This branching phenotype was specific for CAS, since (i)
      overexpression of the structurally similar beta-catenin had little effect on cell
      morphology, and (ii) the branching was abolished by deletions in the CAS Arm
      domain. Our data indicate that, like other catenins, CAS is a cofactor for
      multiple members of the cadherin family. However, the dramatically distinct
      phenotype exhibited by fibroblasts overexpressing CAS, versus beta-catenin,
      support recent data suggesting that these catenins have fundamentally different
      and possibly opposing roles in cadherin complexes.

PMID- 8660923
TI  - The subcellular distribution of eukaryotic translation initiation factor, eIF-5A,
      in cultured cells.
AB  - To gain insight into the role of the eukaryotic translation initiation factor,
      eIF-5A, we investigated the subcellular distribution of this protein in several
      cultured cell types and at different stages of the cell cycle using a highly
      potent monospecific polyclonal antibody to eIF-5A. Studies using indirect
      immunofluorescence and confocal microscopy in conjunction with subcellular
      fractionation demonstrate that eIF-5A is primarily localized in the cytoplasm of
      cells. This cytoplasmic location of eIF-5A is not significantly altered in
      different stages of the cell cycle and the subcellular distribution pattern of
      eIF-5A is not changed by viral oncogene transformation. Cell fractionation
      experiments identified two populations of eIF-5A in the cytoplasm, a soluble
      fraction and a fraction bound to internal membranes. By double immunofluorescence
      staining with an antibody against calnexin, a resident protein of the endoplasmic
      reticulum (ER), we demonstrate that the membrane-bound fraction of eIF-5A
      colocalizes with the ER and not with the cytoskeleton. Expression of Rev, a
      regulatory protein of human immunodeficiency virus type 1 (HIV-1), does not alter
      the subcellular distribution of endogenous eIF-5A in these cells. eIF-5A is
      detected in all tissues and cells examined including extracts prepared from
      Xenopus oocytes. Our results indicate that eIF-5A is a ubiquitous cytoplasmic
      protein and suggest that a site of eIF-5A function is likely to be in association
      with the ER.

PMID- 8660922
TI  - AP-2.2: a novel AP-2-related transcription factor induced by retinoic acid during
      differentiation of P19 embryonal carcinoma cells.
AB  - A 2.8-kb cDNA encoding a new transcription factor (AP-2.2) has been cloned from
      mouse P19 embryonal carcinoma cells, in which the corresponding mRNA begins to
      accumulate 30 min after retinoic acid (RA) addition. The predicted protein is 449
      amino acids long and exhibits approximately 65% overall identity with other AP-2
      related proteins (human AP-2, mouse AP-2alpha and beta). A 96-amino-acid-long
      sequence, which is almost fully conserved between all these proteins, corresponds
      to the previously characterized human AP-2 DNA binding domain. Expression of AP
      2.2 in Escherichia coli generated a protein that formed a specific complex with
      the AP-2 recognition site GCCN3GGC. AP-2.2 activated transcription from a
      reporter gene containing an AP-2 DNA binding site and acted synergistically with
      RARalpha to activate transcription from the CRABPII gene promoter.
      Transcriptional activation required the AP-2.2 amino-terminal region that
      contains a domain rich in proline and glutamine residues. The pattern of AP-2.2
      expression in adult tissues, which is distinct from that of AP-2alpha, is
      essentially restricted to male and female gonads, to most if not all the squamous
      epithelia, and to several exocrine glands.

PMID- 8660924
TI  - DNA digestion and chromatin condensation during nuclear death in Tetrahymena.
AB  - DNA fragmentation and nuclear condensation are key features in the regulated cell
      death of higher animal cells. Nuclear death also occurs as part of a
      developmentally programmed process during the sexual life cycle of the
      unicellular organism Tetrahymena. We examined the regulation of nuclear death and
      the relationship between DNA fragmentation and chromatin condensation in this
      model system. Nuclear death is accompanied by DNA digestion to low-molecular
      weight oligonucleosomal-length fragments, in agreement with a previous study,
      indicating an endonuclease-like activity typical of apoptosis in higher
      organisms. Actinomycin D and cycloheximide block DNA digestion as well as nuclear
      condensation suggesting that nuclear death is under genetic regulation. DNA
      digestion is completely blocked by aurin, a general nuclease inhibitor. In
      addition, when DNA fragmentation is blocked, nuclear condensation also fails to
      occur. Moreover, a kinetic analysis of DNA breakdown, using agarose gels, shows
      that some DNA digestion occurs before nuclear condensation has taken place. Thus
      the initiation of DNA digestion may provide conditions necessary for nuclear
      condensation. Temporary inhibition of nuclear death aborts the death program
      since after removal of inhibitors cells revert to a vegetative pathway without
      having eliminated the old or developed the new macronucleus. Zn2+ and EGTA, both
      of which inhibit apoptosis in some cell types, fail to prevent nuclear
      condensation or DNA digestion in Tetrahymena, suggesting a requirement here for
      an endonuclease which is Ca2+-independent and Zn2+-insensitive. With the TUNEL
      assay, DNA breakdown is detected exclusively in the condensed macronucleus (and
      occasional micronuclei identified as degenerating haploid products of meiosis),
      but not in precondensed macronuclei. These studies show that apoptotic-like DNA
      fragmentation occurs after condensation of the degenerating macronucleus.
      However, early DNA digestion may be critical for nuclear condensation and
      subsequent degeneration.

PMID- 8660925
TI  - Protein kinase C-delta associates with vimentin intermediate filaments in
      differentiated HL60 cells.
AB  - The subcellular localization of protein kinase C (PKC)-delta was determined in
      HL60 cells differentiated toward monocytes/macrophages by treatment with TPA. PKC
      delta was detected in the nucleus and cytoplasm of differentiated HL60 cells and,
      more specifically, associated with structures resembling intermediate filaments.
      Indirect immunostaining revealed that PKC-delta colocalized with vimentin in the
      cytosol and perinuclear region of these cells. Immunoprecipitation studies showed
      that PKC-delta was in an active (autophosphorylated) state in differentiated HL60
      cells and that vimentin immunoprecipitated from these cells was also
      phosphorylated. Treatment of HL60 cells with the PKC-specific inhibitor
      chelerythrine decreased the phosphorylation of vimentin. These data suggest that
      vimentin is a substrate for PKC-delta and that this PKC isoenzyme may play a
      specific role in the regulation of shape change and cell adhesion during HL60
      differentiation.

PMID- 8660926
TI  - Sequential expression of nucleoproteins during rat spermiogenesis.
AB  - Transition proteins and protamines are highly basic sperm-specific nuclear
      proteins that serve to compact the DNA during late spermiogenesis. To understand
      their sequential role in this function, transition protein 1 (TP1), transition
      protein 2 (TP2), and protamine 1 (P1) were assayed by polyacrylamide gel
      electrophoresis in pools of microdissected, staged seminiferous tubule segments
      in the rat. The results were compared with immunocytochemical analyses of squash
      preparations from accurately identified stages of the epithelial cycle. TP2 was
      the first to appear as a faint band at stages IX-XI, followed by high levels at
      stages XII-XIV of the cycle. TP1 showed a low expression at stage XII of the
      cycle and peaked at stages XIII-I, whereas protamine 1 first appeared at stage I
      of the cycle and remained high throughout the rest of spermiogenesis.
      Immunocytochemical analyses and Western blots largely confirmed these results:
      TP2 in steps 9-14, TP1 in steps 12-15, and P1 from late step 11 to step 19 of
      spermiogenesis. We propose that TP2 is the first nucleoprotein that replaces
      histones from the spermatid nucleus, and its appearance is associated with the
      onset of nuclear elongation. TP1 shows up along with the compaction of the
      chromatin. The two transition proteins seem to have distinct roles during
      transformation of the nuclei and compaction of spermatid DNA.

PMID- 8660927
TI  - Cytosolic and nuclear mitogen-activated protein kinases are regulated by distinct
      mechanisms.
AB  - We have investigated the regulation and localization of mitogen-activated protein
      kinase (MAPK) and mitogen-activated protein kinase kinase (MAPKK) in both
      cytosolic and nuclear fractions of glomerular mesangial cells. p42 MAPK was
      localized by both immunoblot and kinase activity in both cytosol and nucleus and
      was rapidly activated, in both fractions, by fetal bovine serum and TPA.
      Downregulation of protein kinase C (PKC) by TPA inhibited stimulation of
      cytosolic p42 MAPK, but unexpectedly had no effect on stimulated p42 MAPK in the
      nucleus. Next we studied the upstream kinase p45 MAPKK by indirect
      immunofluorescence microscopy, Western blot analysis, and kinase specific
      activity. Unlike MAPK, p45 MAPKK is almost exclusively cytosolic in resting cells
      and kinase activity stimulated by TPA is restricted to the cytosol.
      Interestingly, PKC downregulation for 24 h with TPA dramatically enhanced nuclear
      MAPKK as assessed by all three techniques. Cytosolic stimulated MAPKK was
      attenuated in PKC downregulation. Collectively these results show that in
      mesangial cells: (i) p42 MAPK and p45 MAPKK localize in both the cytosol and the
      nucleus, and (ii) PKC exerts a negative effect on nuclear MAPKK activity as
      documented by PKC downregulation, which augments p45 MAPPK nuclear mass and
      activity. These results indicate that the dual regulation of these two kinases is
      under differential control in the cytosol and the nucleus.

PMID- 8660928
TI  - Localization of nucleic acids in hepatocyte nucleoli of rats upon D-galactosamine
      induced block of transcription.
AB  - The precise localization of DNA and RNA within rat hepatocyte nucleoli during the
      process of D-galactosamine-induced nucleolar segregation has been studied by
      using sensitive methods for their detection: osmium-ammine staining and terminal
      deoxynucleotidyl transferase reaction for DNA, and immunoelectron microscopy with
      anti-RNA antibodies, RNase-gold, and autoradiography with tritiated orotic acid
      for RNA. The blocking of transcription was followed by the disappearance of
      intranucleolar condensed chromatin. Agglomerates of thin extended DNA filaments
      were found to change their location to the nucleolar periphery and to coalesce
      with each other. At the last stage of nucleolar segregation they were
      concentrated at the pole of the nucleolar fibrillar remnant while the rest of the
      nucleolus did not contain any DNA. No DNA was found in the dense fibrillar
      component of both intact and treated hepatocyte nucleoli. During the process of
      nucleolar segregation the bulk of the nucleolar RNA was found within the so
      called spherical bodies. This RNA appeared to be synthesized shortly before or
      even after drug administration. The results obtained are in agreement with the
      hypothesis that the fibrillar centers are the site of nucleolar transcription.
      They also show that uncompleted molecules of pre-rRNA whose synthesis has been
      blocked are segregated from the rest of nucleolar RNA species into the spherical
      bodies.

PMID- 8660929
TI  - Inhibition of the proliferative cycle and apoptotic events in WiDr cells after
      down-regulation of the calcium-binding protein calretinin using antisense
      oligodeoxynucleotides.
AB  - The colon adenocarcinoma cell line WiDr expresses the calcium-binding protein
      calretinin (CR). In order to deduce possible functions of calretinin in these
      cells we decreased its concentration by antisense techniques. Treatment of WiDr
      cells with phosphorothioate antisense oligodeoxynucleotides (AS-ODNs) led to a
      drop in calretinin expression, as evidenced by immunohistochemical staining of
      WiDr cells and Western blot analysis of cytosolic cell extracts. The morphology
      of these epithelial cells changed from polygonal to spherical and they formed
      dense cell clusters. Cells displaying morphological alterations typical for
      apoptotic cells were observed after incubation with AS-ODNs, as evidenced by
      phase-contrast and electron microscopy. The mitotic rate of AS-ODN-treated cells
      dropped significantly, as demonstrated by mitotic labeling and time-lapse
      microcinematography. Furthermore, an accumulation of cells in phase G1 and a
      reduction of [3H]thymidine-labeled cells was observed in antisense-treated cells.
      The basal level of [Ca2+]i was not influenced by the down-regulation of
      calretinin. WiDr cells incubated with the nonsense, reverse-sense, or with an
      oligodeoxynucleotide with a totally unrelated sequence did not show any
      significant differences when compared to control cells. We conclude that
      calretinin levels have an impact on the progression of the cell cycle of WiDr
      cells.

PMID- 8660930
TI  - Sertoli cell lines established from H-2Kb-tsA58 transgenic mice differentially
      regulate the expression of cell-specific genes.
AB  - Sertoli cell lines have been established from H-2K(b)-tsA58 transgenic mice
      carrying an inducible temperature-sensitive SV40 T antigen in their germline. All
      cell lines tested for expression of Sertoli cell products by reverse
      transcription-polymerase chain reaction were shown to express mRNAs for alpha
      inhibin, Steel factor, SGP-2, and transferrin as well as for androgen receptor
      and the orphan nuclear receptor SF-1. Selected cell lines were shown by
      immunocytochemistry to express the established Sertoli cell-specific pattern of
      cytoskeletal markers. The FSH receptor gene was also expressed, though
      downregulated by comparison with in vivo levels of expression. In some lines low
      expression of the luteinizing hormone receptor gene could also be detected. The
      gene for the transcription factor GATA-1, which is expressed specifically in
      Sertoli cells, was expressed only in a subset of the cell lines. Quantitative
      analysis of SGP-2 transcript levels by ribonuclease protection assays showed an
      increase at the nonpermissive temperature, whereas using a similar assay, Steel
      factor mRNA was shown to be expressed in amounts comparable to the in vivo
      situation only in two cell lines during permanent growth. In summary, cell lines
      that exhibit distinct Sertoli cell characteristics have been established, which
      may resemble different stages of phenotypic development.

PMID- 8660931
TI  - Interleukin 2 modulates intestinal epithelial cell function in vitro.
AB  - Although interleukin 2 (IL-2) has been presumed to have a highly circumscribed
      range of target cells limited largely to classic immune cell populations, the
      presence of functional IL-2 receptors in rat epithelial cell lines has recently
      been demonstrated. Limited information is available about the functional effects
      of IL-2 on intestinal epithelial cells. The effect of recombinant IL-2 on
      intestinal epithelial cell migration was assessed using a previously described in
      vitro model of epithelial restitution by quantitation of cells migrating into
      standard wounds established in confluent IEC-6 cell monolayers. Transforming
      growth factor beta content was assessed by Northern blot and bioassay. Exogenous
      IL-2 enhanced epithelial cell restitution in vitro on average 3.8-fold; this
      effect was independent of cell proliferation. Enhancement of restitution through
      IL-2 could be completely blocked through antibodies directed against TGFbeta1 and
      interleukin-2 receptor, indicating that stimulation of epithelial cell
      restitution is specifically enhanced by interleukin-2 and mediated through a
      TGFbeta-dependent pathway. In addition, increased expression of TGFbeta1 mRNA and
      increased levels of bioactive TGFbeta peptide in wounded monolayers treated with
      IL-2 compared to unwounded monolayers cultured in serum-deprived medium alone
      support the notion that enhancement of epithelial cell restitution in vitro is
      mediated through a TGFbeta-dependent pathway. These studies suggest that IL-2, a
      potent cytokine whose biological origin and targets have been presumed to be
      largely limited to lymphocyte and macrophage populations, may play a role in
      preserving the integrity of the intestinal epithelium following various forms of
      injuries.

PMID- 8660932
TI  - BCL-2 and MCL-1 expression in Chinese hamster ovary cells inhibits intracellular
      acidification and apoptosis induced by staurosporine.
AB  - Multiple physiological and pharmacological stimuli induce cells to die by
      apoptosis. In many cases, this apoptosis is inhibited by BCL-2, suggesting the
      involvement of a common regulatory pathway. One frequent characteristic of
      apoptosis is the digestion of DNA into oligonucleosome-length fragments.
      Intracellular acidification and increased intracellular calcium have been
      variously implicated in activating the endonuclease responsible for this DNA
      digestion. To explore the involvement of these potential signals in endonuclease
      activation, we have analyzed three Chinese hamster ovary cell lines: a parental
      line, one expressing a cDNA encoding BCL-2, and the third expressing the BCL-2
      family member MCL-1. Apoptosis was induced with the protein kinase inhibitor
      staurosporine and intracellular pH and calcium were measured by flow cytometry.
      We found that both MCL-1 and BCL-2 inhibited DNA digestion compared to the parent
      cell line, although BCL-2 was more potent in this regard. Concurrent with DNA
      digestion, we observed intracellular acidification; MCL-1 and BCL-2 inhibited
      intracellular acidification to an extent commensurate with their ability to
      inhibit DNA digestion. In contrast, staurosporine caused a dose-dependent
      increase in intracellular calcium in all three cell lines, demonstrating that
      intracellular free calcium levels did not correlate with the induction of
      apoptosis. These results suggest that BCL-2 and MCL-1 may regulate a pathway for
      intracellular pH homeostasis during apoptotic cell death.

PMID- 8660933
TI  - TNF-alpha inhibits anti-IgM-mediated apoptosis in Ramos cells.
AB  - We have examined the effects of tumor necrosis factor-alpha (TNF-alpha) as an
      inducer or modulator of necrosis and/or apoptosis in B cell lines. TNF-alpha does
      not induce either necrosis or apoptosis in EBV-positive or -negative cell lines,
      regardless of the culture conditions of the cells or the presence or absence of
      cytokines. By contrast anti-IgM induces apoptosis in two EBV-negative cell lines
      (Ramos and ST486) but not in EBV-positive cell lines. Since TNF receptor and CD40
      belong to the TNF receptor superfamily and anti-CD40 is a known inhibitor of
      apoptosis, we tested for TNF-alpha's effects on the inhibition of apoptosis
      induced by anti-IgM. Our results indicate that TNF-alpha inhibits apoptosis
      induced by anti-IgM in Ramos cells but not in ST486. The effects are dose and
      time dependent; the degree of apoptosis achieved and the selectivity of the
      effect among cell lines are strikingly similar for both TNF-alpha and anti-CD40.
      Furthermore when both agents are tested together no additivity in the inhibition
      is observed. The inhibition of apoptosis is a direct effect of TNF-alpha and not
      a permissive effect of another cytokine, since it is observed in defined medium.
      Although anti-IgM induces both TNF-alpha secretion and TNF receptors in Ramos
      cells, the concentration of secreted TNF-alpha is too low to affect apoptosis.
      Inhibition does not involve perturbation of the cell cycle distribution of Ramos
      cells. Furthermore rapid induction of c-fos and the decrease in c-myc observed
      after anti-IgM treatment are both unaltered by TNF-alpha. Our results suggest
      that TNF-alpha is an inhibitor of apoptosis in Ramos cells, that its overall
      pattern of inhibition is similar to that of anti-CD40, and that both agents act
      at some point distal to the alteration of c-fos and c-myc by anti-IgM.

PMID- 8660934
TI  - Localization of the N-terminus of SCP1 to the central element of the synaptonemal
      complex and evidence for direct interactions between the N-termini of SCP1
      molecules organized head-to-head.
AB  - The synaptonemal complex (SC) is a meiosis-specific, tripartite structure
      essential for synapsis of homologous chromosomes; it contains a central element
      positioned between two lateral elements and transversal filaments connecting the
      lateral elements. In mammals, a major constituent of the transversal filament is
      known: the SCP1 protein. It contains a long central coiled-coil motif and the
      molecules are probably organized as dimers, each forming a coiled-coil fiber. We
      have now developed a new sensitive procedure for immunoelectron microscopy of
      synaptonemal complex proteins and determined the exact localization of the two
      nonhelical ends of the SCP1 protein within the mouse synaptonemal complex. We
      found that the N-terminal end of the SCP1 protein is located within the central
      element of the synaptonemal complex, whereas the C-terminal end is close to or
      within the lateral element of the synaptonemal complex. This result supports the
      notion that SCP1 is an extended filamentous protein and that the two molecules of
      the putative SCP1 dimer are likely to have the same polarity. The observation
      that the N-termini are confined to the central element indicated that SCP1
      dimers, anchored in opposite lateral elements, could establish contact with each
      other in the central element via their N-termini. To test this possibility we
      used the yeast two-hybrid system and found that the N-terminal end of the SCP1
      protein indeed strongly interacted with itself, but not with other protein
      domains tested. We therefore suggest that a transversal filament consists of one
      or more pairs of SCP1 dimers, each pair being organized in a head-to-head
      arrangement with the C-termini anchored in the lateral elements and the two N
      termini being joined in the central element.

PMID- 8660935
TI  - Organization of SCP1 protein molecules within synaptonemal complexes of the rat.
AB  - SCP1, a major protein component of synaptonemal complexes (SCs), is probably a
      constituent of the transverse filaments (TFs). The protein consists of three
      domains: a short, proline-rich N-terminal part, a stretch of 700 amino acid
      residues capable of forming an amphipathic alpha-helix, and a C-terminal domain
      of 240 amino acid residues which is capable of binding to DNA. To analyze the
      orientation of SCP1 molecules within SCs, we elicited polyclonal antibodies
      against three non-overlapping fragments of SCP1, which comprise, respectively,
      the N-terminus, the C-terminus, and a fragment from the middle of the SCP1
      molecule. Using these antibodies, we performed immunoelectron microscopy on SCs
      in two types of preparations, namely, surface-spread spermatocytes and ultrathin
      sections of Lowicryl-embedded testicular tissue of the rat. For each of the three
      antibodies used, the distribution of immunogold label on surface-spread
      spermatocytes differed significantly from the distribution of label on sections.
      Masking of SCP1 epitopes within the lateral elements (LEs) and the central
      element (CE) of SCs in surface-spread preparations and the influence of the
      surface morphology of the spreads on the labeling pattern were considered as
      possible explanations for these differences. We therefore relied on the results
      from sections for the localization of epitopes. On the basis of the distributions
      of immunogold label in Lowicryl sections and the predicted secondary structure
      and dimensions of SCP1 molecules, we present the following model: the C-terminus
      of SCP1 molecules lies in the inner half of the LE, the molecules protrude from
      the LE through the central region into the CE, and end up with their N-terminus
      between the center of the CE and the opposite LE, so that the N-termini of SCP1
      molecules from opposite LEs overlap. The model has several implications for the
      assembly of SCs and the possible functions of SCP1.

PMID- 8660936
TI  - Embryonic Xenopus neurites integrate and respond to simultaneous electrical and
      adhesive guidance cues.
AB  - Nerve cells detect and respond to multiple extrinsic guidance cues during
      development and regeneration using a motile growth cone. Navigational decisions
      may be required of the growth cone when different guidance cues are encountered
      simultaneously. We have tested the relative potencies of two opposing cues by
      presenting Xenopus spinal cord nerve cells growing on a micropatterned laminin
      culture substratum with an orthogonal DC electric field. Substrata composed of
      repeating 25-micron laminin tracks and spaces failed to influence the position of
      neuritogenesis from nerve cell soma. Once established, however, growth cone
      movement was constrained by laminin tracks such that neurites of 65% of cells
      were aligned after 5 h in vitro. Two hours after the application of a 100-140
      mV/mm DC field the majority of cells remained aligned with the laminin tracks.
      Around 70% of Xenopus neurites normally orient cathodally on homogenous laminin
      substrata; therefore the galvanotropic response was impeded by prior exposure to
      a patterned laminin substrate. However, a proportion of aligned neurites did
      orient cathodally and evidence of a response to both directional cues was even
      found within the same cell. Video-enhanced contrast, differential interference
      contrast (VEC-DIC) microscopy was used to examine the detailed behavior of growth
      cones on micropatterned laminin substrata. The present study has demonstrated
      that growth cones can detect and integrate at least two morphogenetic guidance
      cues simultaneously. The strength of the galvanotropic response in Xenopus growth
      cones, however, was often insufficient to override established adhesive guidance
      in this model system.

PMID- 8660937
TI  - Macrophage-stimulating protein induces proliferation and migration of murine
      keratinocytes.
AB  - Macrophage stimulating protein (MSP) is a chemotactic factor for murine
      peritoneal macrophages. The receptor for human MSP was recently identified as the
      ron gene product, a transmembrane protein tyrosine kinase cloned from a human
      keratinocyte cDNA library. Here we report that MSP induced proliferation of
      murine primary keratinocytes and established keratinocyte cell lines in a
      concentration-dependent manner. The growth efficacy of MSP was comparable to that
      of epidermal growth factor and keratinocyte growth factor. In three of four cell
      lines tested in a chemotaxis chamber, MSP also stimulated migration of
      keratinocytes on a collagen type IV substratum. The action of MSP was mediated by
      specific binding of MSP to the STK gene product, a murine homologue of the RON
      MSP receptor. Binding of MSP to keratinocyte STK induced phosphorylation of the
      150 kDa STK beta chain. Herbimycin A, a protein tyrosine kinase inhibitor,
      blocked MSP-mediated phosphorylation of the STK receptor as well as proliferation
      of keratinocytes, suggesting the importance of tyrosine kinase activity for
      transduction of the message delivered by MSP. Previously, the only known target
      cell for MSP was the resident peritoneal macrophage. These studies establish the
      keratinocyte as a new target cell for MSP. The action of MSP on keratinocytes may
      have implications for tissue repair, wound healing, and tumor growth.

PMID- 8660938
TI  - Molecular interactions between human B-cell progenitors and the bone marrow
      microenvironment.
AB  - Apoptosis of normal and leukemic immature B-cells in vitro is suppressed when
      either cell type is grown in direct contact with a feeder layer of bone marrow
      derived stromal cells, including fibroblasts, macrophages, endothelial cells, and
      adipocytes. In this study, our objective was to identify a stromal cell type
      which is essential for lymphoblast survival and to characterize the molecules
      involved in lymphoblast adhesion to these cells. In experiments with B-lineage
      acute lymphoblastic leukemia (ALL) cells (n = 28) and purified CD19(+) cells from
      normal bone marrow (n = 6) we found that homogeneous populations of bone marrow
      fibroblasts could sustain survival of normal and leukemic immature B-cells as
      efficiently as composite bone marrow stromal layers. Electron microscopic studies
      showed that leukemic lymphoblasts associate with fibroblasts and with the
      extracellular matrix (ECM) primarily via their specialized cell surface
      structures. Immunogold labelingsoliduselectron microscopy analysis revealed that
      the areas of contact between lymphoblasts and fibroblasts contained beta1
      integrins (VLA-4 and VLA-5), fibronectin, vascular cell adhesion molecule (VCAM
      1), and a cartilage-link protein, CD44. Double immunogold labeling studies
      disclosed a direct in situ relationship between fibronectin and VLA-4, VLA-5, and
      CD44. We hypothesize that these molecular interactions either bring lymphoblasts
      into close physical proximity with other fibroblast-bound or ECM-bound survival
      factors or provide survival signals themselves.

PMID- 8660940
TI  - 1,25-Dihydroxyvitamin D3 and Transforming Growth Factor-beta Act Synergistically
      to Override Extinction of LiversolidusBonesolidusKidney Alkaline Phosphatase in
      Osteosarcoma Hybrid Cells
AB  - In this study, a somatic cell genetic approach was used to study the regulation
      of liversolidusbonesoliduskidney alkaline phosphatase (ALPL) gene expression in
      osteoblasts. ALPL plays an important role in skeletal mineralization and serves
      as a good index of bone formation. A series of intertypic hybrids constructed by
      fusion of the human osteosarcoma TE-85 with the mouse fibrosarcoma La-t-
      demonstrated a 10-fold reduction of ALPL steady-state mRNA and enzyme activity, a
      phenomenon termed extinction. Hybrid subclones which reexpressed ALPL contained
      reduced numbers of fibroblast chromosomes compared to earlier passages. This
      suggests that a trans-acting negative regulatory factor expressed from the
      fibroblast genome regulates ALPL expression. Two factors known to influence ALPL
      expression are 1,25-dihydroxyvitamin D3 (1,25D3) and transforming growth factor
      beta1 (TGFbeta1). 1,25D3 is involved in mobilizing bone calcium stores and
      TGFbeta1 plays a critical role in bone remodeling. The extinguished hybrids were
      exposed to 1,25D3, TGFbeta1, and a combination of these factors. For two hybrids,
      the combination induced reexpression of ALPL activity to levels comparable to the
      TE-85 parent, indicating a competition between the factors and the
      extinguisher(s). Neither factor alone could induce ALPL reexpression to the
      levels observed with the combination. In only one hybrid, the combination of
      factors synergistically increased ALPL expression. These data help define the cis
      sequence element(s) in the ALPL promoter which are involved in the negative
      regulation of this gene.

PMID- 8660939
TI  - The synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation might be
      explained by the differential activation of their intracellular signaling
      pathways.
AB  - As previous studies showed, PDGF-AA exerts a poor mitogenic effect on vascular
      smooth muscle cells. Simultaneous addition of insulin-like growth factor 1 (IGF
      1), itself also poorly mitogenic, led to a significant increase in [3H]thymidine
      incorporation into the cell DNA as well as a strong increase in cell number. To
      explain the synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation, we
      describe the effects of the two growth factors on distinct intracellular signals:
      on the activation of the signal proteins mitogen-activated protein kinase (MAPK)
      isoforms p42 and p44 and on the protein kinase C (PKC) isoforms alpha, delta, and
      epsilon, and on the induction of the transcription factor c-fos. PDGF-AA strongly
      activated the MAPK isoforms and PKC delta as well as the induction of c-fos. In
      contrast, IGF-1 exerted no effect on the signals induced by PDGF-AA, but strongly
      activated PKC epsilon isoform. Comparing this signal pattern to the one of the
      mitogenically potent PDGF isoform PDGF-BB, we found that PDGF-BB activated all of
      the signal proteins investigated.

PMID- 8660941
TI  - Cell adhesion via murine alpha4 human beta1 integrin chimera on transfected K562
      cells to endothelial cells.
AB  - To evaluate the property of binding activity of alpha4beta1 integrin in cell-cell
      interaction, we newly established a cell line, alpha4mK562, by transfecting cDNA
      of murine integrin alpha4 subunit into human erythroleukemic K562 cells.
      alpha4mK562 transfectant expressed both murine alpha4 and human beta1 subunit,
      which generated a functional heterodimer. alpha4mK562 cells more efficiently
      bound to murine endothelial cell lines and recombinant human TNFalpha (rhTNF)
      treated human umbilical vein endothelial cells (HUVEC) than the parental K562
      cells. These adhesion resulted from the interaction between alpha4beta1 and VCAM
      1. Interestingly, treatment with mAb against human beta1 (4B4 clone), which has
      been known as inhibitory mAb, enhanced binding of alpha4mK562 cells to rhTNF
      treated HUVEC but not to murine endothelial cells. This increase in binding
      induced by 4B4 mAb was completely inhibited by another mAb against human beta1
      (mAb13), but only partially by anti-alpha4 mAb (PSsolidus2). The increase in
      binding induced by 4B4 mAb was also abolished by metabolic inhibitors, indicating
      that the increased binding is energy dependent. These observations suggest that
      the binding of 4B4 mAb to the chimeric alpha4beta1 induces an unique outside-in
      signaling and enhances the specific binding of alpha4mK562 cells to rhTNF-treated
      HUVEC.

PMID- 8660942
TI  - Differentiation-associated antimicrobial functions in human colon adenocarcinoma
      cell lines.
AB  - We report that the enterocytic cells of the HT-29 glc-/+ cell subpopulation
      strongly expressed two antimicrobial enzymes: the lysozyme and alpha1
      antitrypsin. Moreover, we found that 20 to 30% of these cells expressed positive
      immunoreactivity using the mAbs directed against the gut porcine PR-39 and
      cecropin P1 antimicrobial peptides, but did not express immunreactivity against
      the human antimicrobial polymorphonucleated neutrophil-associated HNP 1-3
      defensin and the Xenopus skin magainin. The HT-29 glc-/+ cell subpopulation
      develops bacteriolytic activity against the enterovirulent diffusely adhering
      C1845 Escherichia coli characterized by dramatic alterations of the bacterial
      cell, suggesting lysis, and bacterial death. In contrast, no expression of
      immunoreactivity against the antimicrobial peptides and no C1845 bacterial
      alteration were found in the cultured human embryonic undifferentiated INT407
      cells and the colon adenocarcinoma T84 crypt cells. The development of the
      bacterial alteration and the expression of the antimicrobial components were
      examined as a function of the cell differentiation using the Caco-2 cell line
      which spontaneously differentiates in culture. We found that the bacterial
      alteration and the expression of the PR-39 immunoreactivity are differentiation
      associated events. Altogether, our results suggest that in the intestine the
      enterocytes could develop antimicrobial defenses participating in the protection
      of the gut epithelium against enterovirulent microorganisms.

PMID- 8660943
TI  - Receptor-mediated regulation of pulmonary surfactant secretion.
AB  - Surfactant protein A (SP-A) regulates surfactant secretion via an SP-A specific
      type II cell membrane receptor (SPAR). We report here that two anti-SPAR
      monoclonal antibodies can modulate the secretory inhibition caused by SP-A. A2C
      and A2R are rat monoclonal antibodies raised independently and recognize a 32-kDa
      protein on rat alveolar type II cell membranes. Immunocytochemical studies show
      that these antibodies bind to isolated type II cells. Scatchard analysis confirms
      that SP-A binds alveolar type II cells through a single affinity receptor and
      shows that A2C and A2R recognize that same receptor. Both antibodies inhibit the
      binding of 125I-SP-A to isolated type II cells. The functional activity of this
      32-kDa protein was studied by examining surfactant secretion in isolated type II
      cells. Surfactant phospholipid secretion was measured in cells that were exposed
      to various surfactant phospholipid secretagogues (ATP, dibutyryl cAMP,
      terbutaline, or ionomycin), +/-SP-A (100 ng/ml), +/-A2C or A2R. Both antibodies
      block the negative feedback loop by which SP-A inhibits surfactant secretion.
      This activity of A2C and A2R is dose-dependent and is independent of the
      secretagogue used. Thus, the 32-kDa type II cell membrane protein bound by A2C
      and A2R is the functional receptor on alveolar type II cell membranes and
      regulates type II cell surfactant secretion.

PMID- 8660944
TI  - NF-kappaB activation by triphenyltin triggers apoptosis in HL-60 cells.
AB  - Trisubstituted organotin pesticides are lethal for different cell types. In this
      study we investigated whether triphenyltin chloride (TPT) causes apoptosis in HL
      60 promyelocytic cells and, if so, by what mechanisms. We report that 5 microM
      TPT increased intracellular Ca2+ in HL-60 cells within seconds; concomitantly
      actin depolymerization was detected 30 s and 1 min after the treatment. This was
      followed 15 min later by NF-kappaB activation, and apoptotic bodies and DNA
      fragmentation were evident after 3 and 6 h, respectively. At these times TPT also
      induced the release of tumor necrosis factor-alpha (TNF-alpha). Prior treatment
      of the cells with a polyclonal antibody to human TNF-alpha abolished TPT-induced
      DNA fragmentation, which suggests that the ultimate effect of TPT may be mediated
      by TNF-alpha. Prior treatment of the cells with 100 microM pyrrolidine
      dithiocarbamate, an antioxidant and potent inhibitor of NF-kappaB activation,
      prevented actin depolymerization, NF-kappaB activation, and DNA fragmentation,
      although it did not affect TPT-induced Ca2+ mobilization. These findings suggest
      that TPT increases intracellular Ca2+, alters actin polymerization and the
      cytoskeleton, and induces NF-kappaB activation, TNF-alpha synthesis, DNA
      degradation, and apoptosis. Reactive oxygen species seem to be essential to NF
      kappaB activation, TNF-alpha synthesis, and the subsequent steps.

PMID- 8660945
TI  - Protection by ascorbate against apoptosis of thymocytes: implications of
      ascorbate-induced nonlethal oxidative stress and poly(ADP-ribosyl)ation.
AB  - Apoptosis can be triggered in thymocytes with stimuli (6alpha-methylprednisolone,
      thapsigargin, and etoposide) acting by different mechanisms. In each of these
      instances cell death is extensively prevented until 5 h of incubation when cells
      are preincubated with 250 microM ascorbic acid (AA) for 1 h, then washed, and
      incubated in fresh medium containing the above mentioned apoptotic stimuli. In
      addition, the degree of spontaneous apoptosis of untreated thymocytes is somewhat
      lower in the AA-preincubated cells. The protection against apoptosis does not
      seem to be dependent on the intracellular enrichment of AA, as measured at the
      end of the preincubation period. On the contrary, such a protection is strictly
      related to a partial loss of ascorbate in the medium (possibly due to its
      autooxidation), is catalase-inhibitable, and is reproduced by a preincubation of
      the cells with nontoxic concentrations of hydrogen peroxide. The AA-supplemented
      cells show a remarkable decrease in NAD+ levels and a significant increase of
      poly(ADP-ribose) polymerase (PARP) activity. Consistently with these results, the
      addition of PARP inhibitors, such as thymidine and 3-aminobenzamide, during the
      preincubation with AA, prevents NAD+ depletion and abolishes the protective
      effect of AA against apoptosis. The possibility is discussed that an early
      activation of PARP by stimuli which are nontoxic per se makes the cells able to
      withstand subsequent apoptotic stimuli which are otherwise lethal.

PMID- 8660946
TI  - Conditions favoring RNA polymerase I transcription in permeabilized cells.
AB  - RNA synthesis can be detected in nuclei using modified RNA precursors (Br-UTP)
      introduced in permeabilized cells. Surprisingly, RNA pol I transcripts are
      detected only after inhibition of RNA pol II or salt enhancement of RNA pol I
      activity. By modifying a previously reported protocol, we found that RNA pol I
      transcripts can be detected selectively or simultaneously with RNA pol II
      transcripts without any drug treatment. Removing glycerol from the
      permeabilization and transcription buffers and improving the permeabilization
      using Triton X-100 revealed RNA pol I transcription in two cell lines (mammalian
      and Xenopus) and in isolated mouse oocytes. The transcripts were most probably
      rRNA because they were detected in the nucleoli, digested by RNase, sensitive to
      actinomycin D, and resistant to alpha-amanitin. We found by microinjection of the
      Br-UTP precursors in living cells that low ionic strength allows the detection of
      RNA pol I transcription. Electron microscopy of mouse oocytes showed that the
      "looseness" of the nucleolar organization is associated with the detection of the
      RNA pol I transcription; this detection does not necessarily need nucleolar
      disorganization. The data obtained with both permeabilized cells and
      microinjections of RNA precursors in the absence of glycerol support the
      hypothesis that the degree of hydration of the cell plays a role in RNA pol I
      transcription.

PMID- 8660947
TI  - Roles of XPG and XPF/ERCC1 endonucleases in UV-induced immunostaining of PCNA in
      fibroblasts.
AB  - To investigate the relationship between proliferating cell nuclear antigen (PCNA)
      complex formation and dual incisions in the nucleotide excision repair (NER)
      process, xeroderma pigmentosum group G (XP-G), XP-F, and XP-G equivalent mouse UV
      sensitive mutant ERCC group 5 cells were utilized as a model in this study. These
      cells are deficient in endonucleases related to 3' (XP-G and ERCC group 5) or 5'
      (XP-F) incision of the DNA lesions in the NER process. PCNA complex formation was
      detected by an indirect immunofluorescence method after the cells were fixed in
      methanol. When Sps1 (XP-G) and XL216-7 (ERCC group 5) cells were UV irradiated,
      neither of them showed PCNA staining. In contrast, SFN4 (a human normal strain)
      and heterokaryons of Sps1 and XP96TO (XP-A) cells fused by polyethylene glycol
      treatment showed PCNA staining following UV irradiation. Furthermore, XLgfPAneo1
      cells, derived from XL216-7 cells transfected with a plasmid containing mouse
      ERCC5 (xpg) cDNA, also restored staining and UV sensitivity. On the other hand,
      we observed a very faint PCNA staining in XP2YO (XP-F) cells, expressing no
      detectable ERCC1 or XPF protein, after UV irradiation. X rays induced PCNA
      staining in all cell lines with a similar staining pattern, and radiosensitivity
      was exactly the same between XL216-7 and XLgfPAneo1 cells. These results may have
      implications for the NER process in vivo in that coordinately occurring dual
      incisions by XPG and XPF/ERCC1 proteins play an important role in inducing PCNA
      complex formation, but the step may not be required for PCNA-dependent repair of
      X-ray-induced DNA damage.

PMID- 8660948
TI  - Cross-resistance, cisplatin accumulation, and platinum-DNA adduct formation and
      removal in cisplatin-sensitive and -resistant human hepatoma cell lines.
AB  - The BEL7404 human hepatoma cell line was selected in vitro for primary cisplatin
      resistance. A panel of four cisplatin-resistant sublines were generated which
      exhibited resistance to cisplatin (up to 34-fold) but were not cross-resistant to
      adriamycin, taxol, etoposide, or mitomycin C. Further characterization of this
      panel of cell lines revealed that increased cisplatin resistance was associated
      with decreased cisplatin accumulation in the selected sublines (up to 14-fold)
      relative to the parental BEL7404 cell line. A significant reduction in platinum
      DNA adduct formation (9-fold) and ribosomal RNA gene-specific interstrand
      crosslink formation (12-fold) were also observed in the 7404-CP20 cell line. No
      differences in the rate of platinum efflux from the BEL7404 and 7404-CP20 cell
      lines were detected following a 4-h loading period, and total platinum-DNA adduct
      and gene-specific interstrand crosslink removal rates were similar in both cell
      lines. There were approximately 3-fold more total platinum-DNA adducts present in
      the BEL7404 cells relative to the 7404-CP20 cells at equitoxic concentrations of
      cisplatin, suggesting that DNA damage tolerance also contributes to the cisplatin
      resistance phenotype. Overall, these results indicate that decreased cisplatin
      accumulation is the major cisplatin resistance mechanism present in the in vitro
      selected cell lines. This model system of acquired cisplatin resistance may be
      valuable in determining the molecular basis for decreased cisplatin uptake and be
      useful for the study of potential resistance modulators.

PMID- 8660949
TI  - Keratocytes produce thrombospondin 1: evidence for cell phenotype-associated
      synthesis.
AB  - Immunochemical techniques were used to determine whether cells of the avascular
      corneal stroma (keratocytes) have the ability to synthesize thrombo- spondin 1
      (TSP1), a glycoprotein originally described in platelets and more recently
      implicated in regulating cell behavior (e.g., migration) during wound repair in
      vascular tissue. Immunoprecipitation experiments with metabolically labeled cells
      showed that bovine keratocytes in preconfluent cultures produced TSP1, but de
      novo TSP1 production could not be detected in confluent keratocyte cultures.
      Immunofluorescence studies of the preconfluent cells revealed that the keratocyte
      TSP1 was distributed in perinuclear granules and peripheral foci. TSP1 expression
      also was observed in keratocytes cultured in a collagen matrix model of stromal
      wound healing and, in this model, immunogold labeling revealed TSP1 foci on
      keratocyte surfaces adjacent to collagen fibers in the matrices. TSP1 expression
      was not observed in the syncytial keratocytes of normal bovine cornea. The
      results indicate that keratocytes have the ability to synthesize TSP1, and do so
      in vitro under conditions which simulate corneal stroma repair, but suggest that
      keratocytes in a syncytial arrangement (as in the normal cornea) do not make
      TSP1. TSP1 may play a role in corneal pathologies which induce keratocytes to
      change from a syncytial to a wound repair phenotype, such as mechanical damage to
      the stroma. Local production of TSP1 might provide an alternative source to
      platelet-derived TSP1 during nonvascularized stromal tissue repair.

PMID- 8660950
TI  - Target proteins for arginine-specific mono(ADP-ribosyl) transferase in membrane
      fractions from chick skeletal muscle cells.
AB  - In a previous study, we found that a specific inhibitor of cellular arginine
      specific mono(ADP-ribosyl) transferase, meta-iodobenzylguanidine (MIBG),
      reversibly inhibited both proliferation and differentiation of cultured embryonic
      chick primary muscle myoblasts. In addition, we observed that arginine-specific
      ADP-ribosyltransferase activity increased with muscle-cell differentiation in
      cultures. Therefore, muscle-cell cultures, especially the 96-h myotube cultures
      that contain the highest levels of ADP-ribosyltransferase, were used as a working
      system to determine the cellular protein substrates for arginine-specific ADP
      ribosyltransferase. When membrane fractions extracted from 96-h chick myotubes
      were incubated with [32P]NAD at 30 degrees C for 30 min, only a few proteins were
      labeled. The labeling of two proteins of 36 and 56 kDa was inhibited by the
      presence of an arginine-specific mono(ADP-ribosyl) transferase inhibitor, MIBG,
      and by novobiocin. To prove that these proteins are indeed the targets for
      arginine-specific mono(ADP-ribosyl)ation, active recombinant muscle ADP
      ribosyltransferase was incubated with membrane proteins under the same
      conditions. ADP-ribosylation of these two membrane proteins, as seen in the
      endogenous reactions, was also catalyzed by the added muscle transferase and was
      also inhibited by MIBG and novobiocin. By using antibody specific for desmin for
      immunoprecipitation and immunoblot analysis, we found that a 56-kDa protein
      associated with the membrane of myotubes is desmin. Our results showed that
      incorporation of isotope into this protein band from [32P]NAD is due to ADP
      ribosylation of desmin.

PMID- 8660951
TI  - Complementation of Ah receptor deficiency in hepatoma cells: negative feedback
      regulation and cell cycle control by the Ah receptor.
AB  - The Ah receptor (AhR) is a ligand-dependent transcription factor subunit that
      heterodimerizes with the AhR nuclear translocator (Arnt) and mediates the
      predominant biological effects of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD).
      TCDD activates target genes in xenobiotica metabolism in many cell lines and,
      more specifically, delays G1-S progression of 5L hepatoma cells. Here we describe
      transient and stable AhR-expression analysis in AhR-deficient subclones of the
      TCDD-sensitive 5L cells. We tested the integrity of the AhR-signaling system
      beyond the lack of the receptor in the variant subclone and analyzed the role of
      AhR in cell cycle regulation. Transiently expressed AhR has a high basal activity
      on promoters containing AhR-binding sites, so-called XREs, when transfected into
      receptor-deficient variant cells compared to wild-type cells. Single- and double
      hybrid analysis dissociates AhR ligand responsiveness, transactivation, and
      heterodimerization with Arnt from receptor binding to an XRE. Hybrid receptors
      also show the high basal activity in the absence of exogenous TCDD in AhR
      deficient variant cells, indicating that the endogenous AhR-activating signal
      acts directly on the receptor rather than XRE-dependent promoters or DNA binding
      of the receptor. Stable expression of AhR in variant cell clones by retroviral
      infection fully reconstitutes TCDD responsiveness, including target-gene
      induction and delay of cell cycle progression. These AhR-reconstituted cells,
      like AhR-containing wild-type cells, show low basal activity of the transiently
      expressed AhR hybrid. Thus, the increased basal activity in AhR-deficient cells
      suggests a negative feedback control of AhR activity. In vitro ligand-binding
      assays are compatible with the idea that the increased basal activity is due to
      the accumulation of an AhR-binding endogenous ligand. In conclusion, AhR is
      causally responsible for TCDD-dependent cell cycle regulation and feedback
      control of AhR activity.

PMID- 8660952
TI  - HPV immortalization of human oral epithelial cells: a model for carcinogenesis.
AB  - Human papillomavirus (HPV) has been implicated in the etiology of oral and
      cervical cancers. Normal oral epithelial cells at passage two were infected with
      recombinant retrovirus containing the E6/E7 open reading frames of HPV type 16.
      The G418-selected cells that were immortalized and express HPV 16 E6/E7 have been
      in culture for over 4 years and 350 passages. In contrast, the normal oral
      epithelial cells did not survive the culture environment beyond 7 to 9 passages.
      Fifteen clones were selected from the pooled population. By Northern blot
      analysis all clones demonstrated the presence of E6solidusE7 genes. Keratin
      expression of both normal and immortalized oral epithelial cells was studied in
      organotypic culture. Both cell types were positive with antibodies AE1, AE3, and
      34BE12. Both were focally positive with AE8, which stains for keratin 13
      (specific for oral and esophageal epithelial cells). The normal control cells
      were focally positive for filaggrin, while the HPV 16-immortalized cells (IHGK
      cells-immortalized human gingival keratinocytes) were negative. The IHGK cells
      were strongly positive with KS19.1, which stains the embryonal keratin K19, an
      indicator of premalignant or malignant changes, while the normal control cells
      were only lightly and focally positive. In conclusion, we present an oral
      epithelial cell line successfully immortalized with HPV E6/E7 which will
      facilitate further research on the involvement of HPV in oral carcinogenesis.

PMID- 8660953
TI  - Hypermethylated myoblasts specifically deficient in MyoD autoactivation as a
      consequence of instability of MyoD.
AB  - MyoD is one of a family of basic helix loop helix (bHLH) transcription factors
      acting as master switches of skeletal muscle differentiation. In addition to
      transcriptionally activating differentiation-specific genes, it autoactivates its
      own expression through a positive feedback loop. It was cloned following the
      observation that treatment with the DNA methylation inhibitor 5-azacytidine
      converts cultured fibroblasts into muscle, presumably through the activation of a
      transcriptionally silenced locus. In an attempt to experimentally recapitulate
      this phenomenon, I have stably transfected mouse C2C12 myoblasts with a
      selectable marker fused to the MyoD promoter/enhancer, treated the cells with
      methyldeoxycytidine triphosphate to promote genomic hypermethylation, and
      negatively selected for loss of activity from the MyoD promoter/enhancer. Several
      clones were recovered that had lost expression of MyoD and the ability to
      differentiate to myotubes, but could be reverted by treatment with 5-azacytidine.
      One clone ("C2G2") was studied in detail. C2G2 cells resume differentiation
      through the forced expression of exogenous MyoD, but paradoxically fail to
      autoactivate the endogenous MyoD, suggesting that they are deficient in the MyoD
      positive feedback circuit but otherwise competent in downstream events in
      myogenesis. The myogenic bHLH proteins in this clone exhibit nuclear instability.
      Both the nuclear stability of MyoD and resumption of the autoactivation circuit
      may be restored either through cell fusion with fibroblasts or by treatment of
      the cells with protease inhibitors. This suggests that the transcriptional
      silencing of a factor, not in itself necessary for muscle differentiation but
      governing the proteolytic stability of MyoD, is responsible for the decay of the
      autoactivation circuit in these cells. A theoretical analysis offers an
      explanation for how increased rates of MyoD turnover may result in the kinetic
      dissociation of autoactivation from the "cross-activation" of downstream genes
      and suggests a mechanism for the phenomenon of myogenic "memory."

PMID- 8660954
TI  - Poly(ADPribosyl)ation system in rat germinal cells at different stages of
      differentiation.
AB  - In order to study the possible functional relationship between poly(ADP
      ribosyl)ation and spermatogenesis, the three main germinal cell types have been
      isolated and characterized as haploid spermatids and diploid and tetraploid
      spermatocytes. Purified germinal cell populations and rats of different age were
      used for activity-, immuno-, and Northern blot experiments, to determine at which
      level poly(ADPR)polymerase (PARP) is regulated at various stages of
      spermatogenesis. Poly(ADPR)glycohydrolase (PARG) activity was also determined, as
      was the subcellular distribution of both PARP and PARG enzymes. The results show
      that the maximum of both PARP amount and PARP activity can be detected on
      tetraploid spermatocytes which undergo meiotic division, whereas PARG activity
      does not differ in germinal cells; the cytoplasmic form of this enzyme is
      prevalent in testis. Moreover, a difference in timing was observed in maximal
      level between PARP expression, determined on testis from 60-day-old rats, and
      PARP activity, detected on testis from 30-day-old animals. It seems that
      different mechanisms modulate the poly(ADPribosyl)ation system during
      spermatogenesis. Regulation of the poly(ADPribose) turnover, variations of PARP
      amount, as well as changes of PARP transcription level, seem to accompany
      germinal cell differentiation, possibly being implicated in DNA replication,
      repair, and transcription.

PMID- 8660955
TI  - Defective calcium influx in rat myelomonocytic leukemia cells which are resistant
      to differentiation-inducing effects of lipid A.
AB  - We compared the calcium mobilization in parent lipid A-sensitive leukemia cells
      (P2) and lipid A-resistant cells (LR) after treating them with lipid A in order
      to clarify the signal transduction involved in the differentiation induced by
      lipid A. Lipid A induced differentiation in P2 cells; however, LR cells were
      completely resistant to it. A dramatic elevation of intracellular free calcium
      ion concentration ([Ca2+]i) occurred in P2 cells, but only a slight elevation of
      [Ca2+]i in LR cells. Calcium ionophore in combination with lipid A induced
      differentiation in LR cells. An elevation of [Ca2+]i observed in P2 cells was
      abrogated by an addition of EGTA, which partially inhibited the differentiation
      of P2 cells stimulated by lipid A. Altogether, these data indicate that calcium
      influx is essential for the differentiation of P2 cells stimulated by lipid A and
      that defective calcium influx is responsible for the resistance to lipid A in LR
      cells.

PMID- 8660956
TI  - Identification and characterization of a unique chondrocyte gene involved in
      transition to hypertrophy.
AB  - The character of differentiating chondrocytes in growing long bones has been
      defined by altered expression of a limited number of genes. To expand this set we
      have applied differential display to identify genes expressed in either
      mineralizing or nonmineralizing chondrocytes. One such gene, Band 17, has the
      following characteristics: (1) Band 17 expression is predominantly found in
      cartilage destined for mineralization. Band 17 mRNA is undetectable in articular
      cartilage and undetectable or weak in all other tissues tested. (2) Band 17
      expression is spatially restricted to the lower proliferative/upper hypertrophic
      zone of chondrocytes in the growth plate of long bones and embryonic vertebrae.
      (3) Induction of a hypertrophic phenotype in progenitor sternal chondrocytes by
      treatment with ascorbate increases expression of Band 17. (4) Induction of
      hypertrophy in growth plate chondrocytes in short-term monolayer cultures
      correlates with a rapid but transient rise in Band 17 message. Our interpretation
      of these findings is that Band 17 expression is associated with the transition to
      hypertrophy, not maintenance of the hypertrophic phenotype. Molecular analysis of
      the 3' end of Band 17 cDNAs and genomic structure has shown that Band 17 is a
      single copy gene transcribed into four messages. Alternative splicing of these
      messages is predicted to result in two proteins that differ at the C-terminal by
      131 amino acids. The longer protein contains a C-terminal consensus sequence that
      potentially targets this protein to the lumen of the endoplasmic reticulum. There
      is a Band 17 homologue in humans, suggesting conservation of Band 17 function in
      mammals. In summary, the pattern of expression and the predicted primary
      structure identify Band 17 as unique among all previously known chondrocyte
      genes.

PMID- 8660957
TI  - Determination of the epitope of an inhibitory antibody to proliferating cell
      nuclear antigen.
AB  - Proliferating cell nuclear antigen (PCNA) is an essential component for the
      normal processive DNA synthesis by DNA polymerase delta and is also required for
      DNA excision repair. Human PCNA autoantisera has been shown to inhibit the
      function of PCNA in vitro, in contrast to induced antibodies. A monoclonal IgG2
      PCNA antibody, 74B1, that effectively inhibited DNA replication in vitro was
      identified. The inhibitory effect was dose dependent and using synthetic
      overlapping peptides of PCNA the 74B1 epitope was mapped to aa 121-135, a region
      of the PCNA protein containing the interdomain connector implicated in
      intermolecular interactions. Interestingly, a neighboring and partly overlapping
      peptide, aa 111-125, contains an immunodominant region recognized by a number of
      monoclonal PCNA antibodies with no inhibitory effect on DNA synthesis. The 74B1
      antibody is a potentially useful antibody in future studies of PCNA and its
      interaction in complexes associated with cell cycle progress, DNA replication,
      and DNA repair.

PMID- 8660958
TI  - Density-dependent inhibition of growth involves prevention of EGF receptor
      activation by E-cadherin-mediated cell-cell adhesion.
AB  - Normal human breast epithelial (HBE) cells grown at logarithmic phase and those
      at the plateau phase were starved of EGF for 3 days then stimulated with EGF. HBE
      cells which were growth arrested at low density responded to EGF to initiate DNA
      synthesis 20 h later, whereas cells growth arrested at saturated density lost
      their responsiveness to EGF. Although the responsiveness to EGF between the two
      cultures at different densities was distinct, neither the number nor the affinity
      of EGF receptor (EGFR) in the two cultures significantly differed. In addition,
      the EGFR mRNA level was not affected by an increase in the cell density. A
      significant difference between the two cultures was the responsiveness of EGFR to
      EGF. The intrinsic tyrosine kinase activity and dimerization of the EGFR in cells
      at low density were induced by EGF, whereas those in cells at saturated density
      were not. Immunostaining revealed that the EGFR was localized only in the
      boundary region where adjacent cells are in close contact at low density but in
      the entire surrounding region of each cell at saturated density. The distribution
      of EGFR overlapped the region where the cell-cell adhesion protein, E-cadherin,
      is distributed. The E-cadherin mRNA levels in the two cultures were comparable;
      however, nearly fivefold more E-cadherin protein accumulated in cells at
      saturated than at low density. Incubation of cells at saturated density with an
      antibody to E-cadherin followed by adding EGF resulted in the stimulation of DNA
      synthesis, which was preceded by autophosphorylation but not dimerization of the
      EGFR. The results suggested that density-dependent inhibition of growth is
      achieved through prevention of the EGFR activation by extensive cell-cell
      adhesion that is mediated by excess E-cadherin.

PMID- 8660959
TI  - 3-D coculture of hepatic sinusoidal cells with primary hepatocytes-design of an
      organotypical model.
AB  - Models for cocultures of parenchymal (PC) and nonparenchymal cells (NPC) of the
      liver relied on mixing the cells in a two-dimensional configuration or on
      establishing spheroidal aggregates. In vivo hepatic nonparenchymal cells, such as
      endothelial cells and Kupffer cells, are separated from parenchymal cells by
      extracellular matrix (ECM). Due to their location outside of the space of Disse
      they can form a barrier toward the sinusoid. Hepatocytes are attached to ECM of
      the space of Disse via two opposing sinusoidal surfaces. No three-dimensional
      coculture model reflecting this specific microenvironment of the liver cell
      plates in vivo has been available to date. We designed a three-dimensional model
      by positioning NPC on top of PC enclosed as a monolayer within a collagen
      sandwich. A gas-permeable membrane support can be used to allow the supply of
      oxygen to the resulting cell plate also from underneath the cell layers.
      Morphological analysis was performed by inverse and cross-sectional studies by
      light microscopy, scanning, and transmission electron microscopy of the coculture
      model. Cuboidal hepatocytes formed confluent layers below the NPC layer. They
      regularly expressed bile canaliculi at intercellular contact zones. Both
      sinusoidal surfaces expressed microprojections. Characteristic NPC including
      endothelial cells, Kupffer cells, and Ito cells completely covered the second
      matrix layer within a week. Kupffer cells were located on top of endothelial
      cells. Ito cells were intermingled and could be identified by their
      intracytoplasmic lipid droplets. LPS stimulation of cocultures resulted in a
      depression of albumin secretion. Phase I and phase II metabolites of the
      cytochrome P-450 1A1 substrate ethoxyresorufin were generated independently from
      the presence of cocultured NPC. This study describes the development of a novel
      three-dimensional coculture model, which intends to mimic more closely the
      microenvironment of the hepatic sinusoid by respecting the specific plate
      structure of the liver parenchyma. The model could serve as a complex tool to
      study potential collaborations between PC and NPC of the liver.

PMID- 8660960
TI  - Viscoelasticity in wild-type and vinculin-deficient (5.51) mouse F9 embryonic
      carcinoma cells examined by atomic force microscopy and rheology.
AB  - We have been studying mouse F9 embryonic carcinoma cells which contain no
      detectable vinculin protein (5.51 cells), and compared them with F9 wild-type
      cells. Employing atomic force microscopy, we probed the elastic properties of
      individual F9 wild-type and 5.51 cells by measuring the dynamic response of
      controlled loads of the cantilever tip. An elastic modulus (Young) of
      approximately 3.8 and approximately 2.5 kPa was calculated for wild-type and 5.51
      cells, respectively. Using disc rheometry, we detected a marked change in shear
      of a 1000g pellet of approximately 55 x 10(6) cells between wild-type and 5.51
      mutants. These differences are attributed to the loss of vinculin and altered
      cytoskeletal organization in these cells.

PMID- 8660962
TI  - A 4.5-megabase YAC contig and physical map over the hemochromatosis gene region.
AB  - We have constructed a yeast artificial chromosome (YAC) contig over the candidate
      hemochromatosis gene region. This contig comprises 16 YACs from the CEPH,
      Washington University, and ICI YAC libraries and covers 4.5 Mb at 6p21.3-6p22.
      The complete contig has been restriction mapped, enabling the precise
      relationship between the YACs to be determined and the mapping of a total of 12
      STSs. Nine of these are highly polymorphic STSs that are closely linked to
      hemochromatosis; this series includes D6S265 and D6S1260, which comprise the most
      proximal and distal markers linked to HC. This is the first YAC contig that spans
      the hemochromatosis candidate region, and it provides valuable resource material
      for the cloning of this and other genes in the region distal to the MHC class I
      complex.

PMID- 8660963
TI  - Incorporation of 35 novel gene transcripts into the physical and genetic map of
      human chromosome 13.
AB  - A panel of somatic cell hybrids carrying a defined set of rearrangements
      involving chromosome 13 has been used to assign 35 novel gene transcripts
      regionally. The positions of the chromosome 13 breakpoints in each somatic cell
      hybrid have previously been defined relative to the Genethon genetic linkage map.
      As a result, the position of each gene transcript has been determined relative to
      both the physical and the genetic linkage maps. Analysis of the distribution of
      these gene transcripts indicates a slight overrepresentation toward locations on
      the distal long arm of chromosome 13, with no localizations noted in the 13q22
      q31 region. Seven of these novel gene transcripts and the gene encoding small
      ribonucleoprotein U6 have been mapped to YACs known to contain Genethon
      microsatellite markers, thereby providing further sublocalization relative to the
      genetic map. The positioning the these gene transcripts within the genetic and
      physical maps provide candidate genes for disease loci that are being mapped to
      the same intervals on the chromosome.

PMID- 8660964
TI  - The mouse BP-1 gene: structure, chromosomal localization, and regulation of
      expression by type I interferons and interleukin-7.
AB  - The BP-1/6C3 antigen is a homodimeric, phosphorylated type II membrane integral
      glycoprotein expressed on immature B-lineage cells, bone marrow stromal cells,
      thymic cortical epithelial cells, endothelial cells, enterocytes, and renal
      proximal tubular cells. Biochemical and molecular analysis identified BP-1 as
      glutamyl aminopeptidase, an ectoenzyme that catalyzes the hydrolysis of acidic
      amino acid residues from the amino termini of regulatory peptides. We have
      isolated genomic clones that encode the BP-1 gene (gene symbol Enpep). The gene
      spans more than 110 kb and contains 20 exons. Except for the first and the last
      exons, it is composed of small exons ranging from 56 to 171 bp that are separated
      by introns ranging from less than 100 bp to approximately 10 kb. The zinc binding
      motif HEXXH and the glutamic acid residue 19 amino acids downstream, which also
      binds zinc, are encoded in exons 5 and 6. Primer extension analysis revealed a
      common major transcriptional start site in a pre-B cell line, in a bone marrow
      stromal cell line, and in kidney cells. The promoter region contains a TATA-like
      element and potential DNA-binding motifs for lymphocyte-specific transcription
      factors including Ikaros, BSAP, PU.1, and octamer binding proteins, as well as
      DNA binding motifs for several ubiquitous transcription factors. An interferon
      responsive element also located in the promoter region appeared to be functional,
      since type I interferons (IFN-alpha/IFN-beta) upregulated BP-1 expression in pre
      B cell lines. A 2.1-kb promoter fragment, when fused to a luciferase reporter
      gene, was able to drive luciferase expression in pre-B cells, which normally
      express BP-1, and the Ag8 cells, in which BP-1 expression is extinguished. The BP
      1/ Enpep gene was localized to a distal region of mouse chromosome 3 in a region
      homologous to human chromosome 4q25. Interestingly, while interleukin-7 (IL-7)
      induced both cell growth and increased BP-1 expression, IFN-alpha/IFN-beta
      upregulated BP-1 expression but inhibited IL-7 induced proliferation. This
      finding indicates that the upregulated BP-1 expression can be disassociated from
      the cell growth signal.

PMID- 8660965
TI  - Structure and organization of the human metaxin gene (MTX) and pseudogene.
AB  - Metaxin encodes a mitochondrial protein and is an essential nuclear gene in mice.
      The cDNA sequence and genomic organization of the human metaxin gene (MTX) have
      now been determined. MTX is 6 kb and consists of eight protein-encoding exons.
      The gene is contiguous to thrombospondin 3 (THBS3) and to the pseudogene for
      glucocerebrosidase (psGBA), but it transcribed in a direction opposite to the
      latter two genes. Thus, MTX and THBS3 share a common promoter region and are
      transcribed convergently, whereas MTX and psGBA are transcribed convergently and
      have closed apposed polyadenylation sites. Human metaxin contains 317 amino acids
      and is 91.5% identical to mouse metaxin. Metaxin is rich in leucine (14.2%) and
      in basic (12.9%) and acidic (12.0%) amino acids. The predicted protein lacks an
      amino-terminal signal sequence and N-glycosylation sites, but contains a putative
      transmembrane domain near its carboxy terminus. A DNA duplication has led to a
      direct repeat and the evolution of a pseudogene for GBA. A pseudogene for metaxin
      (psMTX) is also located within the 16 kb of DNA separating GBA from psGBA. The
      psMTX sequence is nearly identical to the 3' part of exon 2 through exon 8 of
      MTX, and both the intronic and the 3'-flanking sequences are highly conserved.
      Thus, there is a 278 amino acid open reading frame that is 97.8% identical to
      metaxin. However, psMTX lacks the first intron and promoter present in MTX, and
      at least in liver, the pseudogene is not expressed.

PMID- 8660966
TI  - A high-resolution whole genome radiation hybrid map of human chromosome 17q22
      q25.3 across the genes for GH and TK.
AB  - We have constructed a whole genome radiation hybrid (WG-RH) map across a region
      of human chromosome 17q, from growth hormone (GH) to thymidine kinase (TK). A
      panel of 128 WG-RH hybrid cell lines generated by X-irradiation and fusion has
      been tested for the retention of 39 sequence-tagged site (STS) markers by the
      polymerase chain reaction. This genome mapping technique has allowed the
      integration of existing VNTR and microsatellite markers with additional new
      markers and existing STS markers previously mapped to this region by other means.
      The WG-RH map includes eight expressed sequence tag (EST) and three anonymous
      markers developed for this study, together with 23 anonymous microsatellites and
      five existing ESTs. Analysis of these data resulted in a high-density
      comprehensive map across this region of the genome. A subset of these markers has
      been used to produce a framework map consisting of 20 loci ordered with odds
      greater than 1000:1. The markers are of sufficient density to build a YAC contig
      across this region based on marker content. We have developed sequence tags for
      both ends of a 2.1-Mb YAC and mapped these using the WG-RH panel, allowing a
      direct comparison of cRay6000 to physical distance.

PMID- 8660967
TI  - Recovery of probes linked to the jcpk locus on mouse chromosome 10 by the use of
      an improved representational difference analysis technique.
AB  - Representational difference analysis (RDA) is a subtractive hybridization
      technique by which the differences between two complex genomes can be isolated.
      An improved version of this technique was used to isolate DNA segments that map
      to a narrow genetic region adjacent to the jcpk locus on Chromosome 10 of the
      mouse. A mutation at this locus acts recessively and causes an early onset
      polycystic kidney disease. Genomic subtractions involving DNA from C57BL/6 (B6)
      and its partially congenic partner, B6-jcpk/jcpk, produced 39 restriction
      fragments (difference products), 25 of which were unique and represented
      differences in BglII sites between these two strains. Although none identified
      the jcpk locus itself, 7 of these were mapped to an interval between 3.4 and 6.5
      cM distal to the jcpk locus. Five of these 7 difference products were developed
      by subtracting B6-jcpk/jcpk from B6 DNA, but only 1 of the 5 was isolated using
      the original RDA technique. The other 4 were obtained by an improved technique
      that included size selection of difference products after the third round of
      subtractive hybridization and amplification. The remaining 2 of the mapped
      products resulted from the reciprocal subtraction experiment using the
      improvements. Thus, by this improved technique and two-way subtraction, we were
      able to add seven new markers to a relatively small genetic region on Chromosome
      10.

PMID- 8660968
TI  - A human gene (DDX10) encoding a putative DEAD-box RNA helicase at 11q22-q23.
AB  - A human gene encoding a putative RNA helicase, designated DDX10, was identified
      400 kb telomeric to the ataxia-telangiectasia gene at chromosome 11q22-q23. The
      predicted amino acid sequence shows very high similarity to a subgroup of DEAD
      box RNA helicases involved in ribosome biogenesis. This novel gene encodes a 3.2
      kb transcript in a variety of human tissues. A processed pseudogene of DDX10 was
      detected at chromosome 9q21-q22. We observed a rare trinucleotide repeat length
      polymorphism within the coding sequence of DDX10.

PMID- 8660969
TI  - Sequence, genomic structure, and chromosomal assignment of human DOC-2.
AB  - DOC-2 is a human gene originally identified as a 767-bp cDNA fragment isolated
      from normal ovarian epithelial cells by differential display against ovarian
      carcinoma cells. We have now determined the complete cDNA sequence of the 3.2-kb
      DOC-2 transcript and localized the gene to chromosome 5. A 12.5-kb genomic
      fragment at the 5'-end of DOC-2 has also been sequenced, revealing the intron
      exon structure of the first eight exons (788 bases) of the DOC-2 gene.
      Translation of the DOC-2 cDNA predicts a hydrophobic protein of 770 amino acid
      residues with a molecular weight of 82.5 kDa. Comparison of the DNA and amino
      acid sequences of DOC-2 to publicly accessible sequence databases revealed 83%
      identify to p96, a murine protein of similar size, thought to be a mitogen
      responsive phosphoprotein. In addition, about 45% identity was observed between
      the first 140 N-terminal residues of DOC-2 and the Caenorhabditas elegans M110.5
      and Drosophila melanogaster Dab genes.

PMID- 8660970
TI  - Homologies between human and marmoset (Callithrix jacchus) chromosomes revealed
      by comparative chromosome painting.
AB  - Regions of DNA homology between human and marmoset (Callithrix jacchus)
      chromosomes have been demonstrated using fluorescence in situ hybridization. All
      24 chromosome paints and two centromere repeat sequences from Homo sapiens (HSA)
      have been annealed to previously G-banded metaphase spreads of Callithrix
      jacchus. All human paint probes, except Y, successfully hybridized to marmoset
      chromosomes. Fifteen of them hybridized to one region only, seven to two regions,
      and paint 1 to three regions. Homologies proposed from previous banding
      comparisons have been confirmed for HSA 2, 4-6, 10-12, 18, 19, 21 and X and
      partially confirmed for HSA 1 and 3, but were not in agreement for HSA 14 and 17.
      Human centromere repeat sequences for X and 18 did not hybridize to marmoset
      chromosomes. Because, at present, there is the confusion situation of several
      different numbering systems for marmoset chromosomes, we propose a new simpler
      nomenclature based on descending order of chromosome size.

PMID- 8660972
TI  - Complete nucleotide sequences of the domestic cat (Felis catus) mitochondrial
      genome and a transposed mtDNA tandem repeat (Numt) in the nuclear genome.
AB  - The complete 17,009-bp mitochondrial genome of the domestic cat, Felis catus, has
      been sequenced and conforms largely to the typical organization of previously
      characterized mammalian mtDNAs. Codon usage and base composition also followed
      canonical vertebrate patterns, except for an unusual ATC (non-AUG) codon
      initiating the NADH dehydrogenase subunit 2 (ND2) gene. Two distinct repetitive
      motifs at opposite ends of the control region contribute to the relatively large
      size (1559 bp) of this carnivore mtDNA. Alignment of the feline mtDNA genome to a
      homologous 7946-bp nuclear mtDNA tandem repeat DNA sequence in the cat, Numt,
      indicates simple repeat motifs associated with insertion/deletion mutations.
      Overall DNA sequence divergence between Numt and cytoplasmic mtDNA sequence was
      only 5.1%. Substitutions predominate at the third codon position of homologous
      feline protein genes. Phylogenetic analysis of mitochondrial gene sequences
      confirms the recent transfer of the cytoplasmic mtDNA sequences to the domestic
      cat nucleus and recapitulates evolutionary relationships between mammal species.

PMID- 8660971
TI  - Characterization of a chromosome-specific chimpanzee alpha satellite subset:
      evolutionary relationship to subsets on human chromosomes.
AB  - Alpha satellite DNA is a tandemly repeated DNA family found at the centromeres of
      all primate chromosomes examined. The fundamental repeat units of alpha satellite
      DNA are diverged 169- and 172-bp monomers, often found to be organized in
      chromosome-specific higher-order repeat units. The chromosomes of human (Homo
      sapiens (HSA)), chimpanzee (Pan troglodytes (PTR) and Pan paniscus), and gorilla
      (Gorilla gorilla) share a remarkable similarity and synteny. It is of interest to
      ask if alpha satellite arrays at centromeres of homologous chromosomes between
      these species are closely related (evolving in an orthologous manner) or if the
      evolutionary processes that homogenize and spread these arrays within and between
      chromosomes result in nonorthologous evolution of arrays. By using PCR primers
      specific for human chromosome 17-specific alpha satellite DNA, we have amplified,
      cloned, and characterized a chromosome-specific subset from the PTR chimpanzee
      genome. Hybridization both on Southern blots and in situ as well as sequence
      analysis show that this subset is most closely related, as expected, to sequences
      on HSA 17. However, in situ hybridization reveals that this subset is not found
      on the homologous chromosome in chimpanzee (PTR 19), but instead on PTR 12, which
      is homologous to HSA 2p.

PMID- 8660974
TI  - A 9.75-Mb map across the centromere of human chromosome 10.
AB  - We present a yeast artificial chromosome (YAC) and pulsed-field gel
      electrophoresis (PFGE) map across the centromere of human chromosome 10 that
      links expressed sequences in 10p11 to expressed sequences in 10q11.2. This map is
      the first of its kind to link genes across a human centromere. It consists of a
      2.5-Mb YAC contig extending from 10p11 to our previously published 5.35-Mb PFGE
      map of the centromeric satellite arrays, and a 2.65-Mb YAC contig extending from
      these satellite arrays to 10q11.2. This map covers approximately 6.5-7% of the
      total DNA of chromosome 10. Two Genethon genetic markers, D10S578 and D10S604,
      are included. These markers are only 1 cM apart but are separated by a physical
      distance of more than 9.2 Mb, including the centromere. This gives a ratio of
      genetic to physical distance of 0.11 cM/Mb, 9-11 times lower than average
      estimates for the human genome and chromosome 10. Markers linked to the
      centromere include the duplicated zinc finger genes ZNF11A, ZNF33A, and ZNF37A
      (which map to 10p11) and ZNF11B, ZNF33B, and ZNF37B (which map to 10q11.2).
      Restriction mapping confirms that the genes on each arm lie in opposite
      orientation with respect to the centromere, consistent with the hypothesis that a
      pericentric inversion has occurred in this region during primate evolution.

PMID- 8660973
TI  - Zfp-37 is a member of the KRAB zinc finger gene family and is expressed in
      neurons of the developing and adult CNS.
AB  - The murine Zfp-37 gene encodes a protein with 12 zinc fingers at its C-terminus
      (Nelki et al., 1990, Nucleic Acids Res. 18: 3655; Burke and Wolgemuth, 1992,
      Nucleic Acids Res. 20: 2827-2834). Contrary to the published data, our Northern
      blot analysis demonstrates not only that the Zfp-37 gene is expressed as 2.3,
      2.6, and 4.2 kb mRNAs in testis, but also that there is a 3.7-kb message in the
      adult mouse brain. Using a partial cDNA as a probe, we have isolated a brain
      specific Zfp-37 cDNA clone of 3.3 kb, whose sequence was extended to full length
      using 5' end RACE. This revealed that the 3.7-kb mRNA is in fact a collection of
      transcripts with heterogenous 5' ends. Comparison of cDNA and genomic sequences
      shows that the Zfp-37 gene is spread over a region of approximately 20 kb and
      consists of six exons, the large 3' end exon containing the complete zinc finger
      domain, and 3' UTR. Our data show that the Zfp-37 gene utilizes different
      promoters, alternative splicing, and differential polyadenylation to generate the
      distinct transcripts of brain and testis. Several protein isoforms are encoded by
      these mRNAs, some of which contain a truncated form of a conserved domain
      (Kruppel-associated box) found in other zinc finger genes. In situ hybridization
      analysis of postnatal brain sections indicates that the Zfp-37 gene is expressed
      in all neurons of the central nervous system. Together, these results suggest
      that ZFP-37 is a transcriptional regulator predominantly present in postmitotic
      cells from two different lineages.

PMID- 8660975
TI  - Cloning, genomic organization, and chromosomal localization of human citrate
      transport protein to the DiGeorge/velocardiofacial syndrome minimal critical
      region.
AB  - DiGeorge syndrome (DGS) and velocardiofacial syndrome have been shown to be
      associated with microdeletions of chromosomal regions 22q11. More recently,
      patients with conotruncal anomaly face syndrome and some nonsyndromic patients
      with isolated forms of conotruncal cardiac defects have been found to have 22q11
      microdeletions as well. The commonly deleted region, called the DiGeorge
      chromosomal region (DGCR), spans approximately 1.2 Mb and is estimated to contain
      at least 30 genes. We report a computational approach for gene identification
      that makes use of large-scale sequencing of cosmids from a contig spanning the
      DGCR. Using this methodology, we have mapped the human homolog of a rodent
      citrate transport protein to the DGCR. We have isolated a partial cDNA containing
      the complete open reading frame and have determined the genomic structure by
      comparing the genomic sequence from the cosmid to the sequence of the cDNA clone.
      Whether the citrate transport protein can be implicated in the biological
      etiology of DGS or other 22q11 microdeletion syndromes remains to be defined.

PMID- 8660976
TI  - The genes encoding the eph-related receptor tyrosine kinase ligands LERK-1
      (EPLG1, Epl1), LERK-3 (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are clustered on
      human chromosome 1 and mouse chromosome 3.
AB  - Hek and elk are members of the eph-related family of receptor tyrosine kinases.
      Recently, we isolated five cDNAs encoding membrane-bound ligands to hek and elk.
      Because of the promiscuous nature of their binding, we have termed these proteins
      ligands of the eph-related kinases or LERKs. The LERKs can be divided into two
      subgroups by virtue of their sequence identity, binding properties, and mode of
      cell membrane attachment. For example, LERK-2 (EPLG2, Epl2) and LERK-5 (EPLG5,
      Epl5) are type 1 transmembrane proteins, while LERK-1 (EPLG1, Epl1), LERK-3
      (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are anchored to the membrane by glycosyl
      phosphatidylinositol (GPI) linkage. Using Southern hybridization analysis of
      human x rodent somatic cell hybrid DNAs, we have assigned the genes that encode
      the GPI-anchored LERKs (EPLG1, EPLG3, and EPLG4) to human chromosome 1.
      Fluorescence in situ hybridization to metaphase chromosome preparations using
      genomic clones from each locus refined this localization to chromosome 1, bands
      q21-q22. In addition, Southern blot analysis of DNA from interspecific backcross
      mice indicated that the mouse homologues Epl1, Epl3, and Epl4 map to a homologous
      region on mouse chromosome 3.

PMID- 8660977
TI  - Isolation, characterization, and mapping of two mouse mitochondrial voltage
      dependent anion channel isoforms.
AB  - Voltage-dependent anion channels (VDACs) are small pore-forming channels found in
      the mitochondrial outer membrane of all eukaryotes. VDACs conduct adenine
      nucleotides and are the binding sites for several cytosolic enzymes, including
      the isoforms of hexokinase and glycerol kinase. VDAC binding is developmentally
      and metabolically regulated and allows the kinases preferential access to
      mitochondrial ATP. Two human VDAC cDNAs have recently been identified, and a
      total of four VDAC loci have been mapped. Here, the isolation of two mouse VDAC
      cDNAs (VDAC5 and VDAC6) is described. By Northern analysis the two mouse VDAC
      isoforms show nearly identical expression patterns, with high levels of
      expression detected in heart, kidney, brain, and skeletal muscle and lesser
      levels of expression in all other tissues examined. The only exception is the
      lack of expression of VDAC5 in testes, whereas VDAC6 expression is highest in
      this tissue. VDAC6 appears to be encoded by more than one transcript. The mouse
      VDAC5 gene was mapped using an interspecies DNA mapping panel to the proximal
      region of chromosome 11, and the mouse VDAC6 gene was mapped using a panel to the
      proximal region of chromosome 14.

PMID- 8660978
TI  - Definition of the locus responsible for systemic carnitine deficiency within a
      1.6-cM region of mouse chromosome 11 by detailed linkage analysis.
AB  - Carnitine is an essential cofactor for oxidation of mitochondrial fatty acids.
      Carnitine deficiency results in failure of energy production by mitochondria and
      leads to metabolic encephalopathy, lipid-storage myopathy, and cardiomyopathy.
      The juvenile visceral steatosis (JVS) mouse, an animal model of systematic
      carnitine deficiency, inherits the JVS phenotype in autosomal recessive fashion,
      through a mutant allele mapped to mouse chromosome 11. As a step toward
      identifying the gene responsible for JVS by positional cloning, we attempted to
      refine the jvs locus in the mouse by detailed linkage analysis with 13
      microsatellite markers, using 190 backcross progeny. Among the 13 loci tested, 5
      (defined by markers D11Mit24, D11Mit111, D11Nds9, D11Mit86, and D11Mit23) showed
      no recombination, with a maximum lod score of 52.38. Our results implied that the
      jvs gene can be sought on mouse chromosome 11 within a genetic distance no
      greater than about 1.6 cM.

PMID- 8660979
TI  - Structure and organization of the human neuronatin gene.
AB  - Neuronatin is a brain-specific human gene that we recently isolated and observed
      to be selectively expressed during brain development. In this report, the genomic
      structure and organization of human neuronatin is described. The human gene spans
      3973 bases and contains three exons and two introns. Based on primer extension
      analysis, a single cap site is located 124 bases upstream from the methionine
      (ATG) initiation codon, in good context, GAACCATGG. The promoter contains a
      modified TATA box, CATAAA (-27), and a modified CAAT box, GGCGAAT (-59). The 5'
      flanking region contains putative transcription factor binding sites for SP-1, AP
      2 (two sites), delta-subunit, SRE-2, NF-A1, and ETS. In addition, a 21-base
      sequence highly homologous to the neural restrictive silence element that governs
      neuron-specific gene expression is observed at -421. Furthermore, SP-1 and AP-3
      binding sites are present in intron 1. All splice donor and acceptor sites
      conformed to the GT/AG rule. Exon 1 encodes 24 amino acids, exon 2 encodes 27
      amino acids, and exon 3 encodes 30 amino acids. At the 3'-end of the gene, the
      poly(A) signal, AATAAA, poly(A) site, and GT cluster are observed. The neuronatin
      gene is expressed as two mRNA species, alpha and beta, generated by alternative
      splicing. The alpha-form contains all three exons, whereas in the beta-form, the
      middle exon has been spliced out. The third nucleotide of all frequently used
      codons, except threonine, of neuronatin is either G or C, consistent with codon
      usage expected for Homo sapiens. This information about the structure of the
      human neuronatin gene will help in understanding the significance of this gene in
      brain development and human disease.

PMID- 8660980
TI  - The gene for human U2 snRNP auxiliary factor small 35-kDa subunit (U2AF1) maps to
      the progressive myoclonus epilepsy (EPM1) critical region on chromosome 21q22.3.
AB  - We used targeted exon trapping to clone portions of genes from human chromosome
      21q22.3. One trapped sequence showed complete homology with the cDNA of human
      U2AF35 (M96982; HGM-approved nomenclature U2AF1), which encodes for the small 35
      kDa subunit of the U2 snRNP auxiliary factor. Using the U2AF1 cDNA as a probe, we
      mapped this gene to cosmid Q15D2, a P1, and YAC 350F7 of the Chumakov et al.
      (Nature 359: 380, 1992) contig, close to the cystathionine-beta-synthase gene
      (CBS) on 21q22.3. This localization was confirmed by PCR using oligonucleotides
      from the 3' UTR and by FISH. As U2AF1 associates with a number of different
      factors during mRNA splicing, overexpression in trisomy 21 individuals could
      contribute to some Down syndrome phenotypes by interfering with the splicing
      process. Furthermore, because this gene maps in the critical region for the
      progressive myoclonus epilepsy I locus (EPM1), mutation analysis will be carried
      out in patients to evaluate the potential role of U2AF1 as a candidate for EPM1.

PMID- 8660981
TI  - GenomeInspector: basic software tools for analysis of spatial correlations
      between genomic structures within megabase sequences.
AB  - The speed of acquisition of genomic sequence data exceeds the evaluation of
      function of the sequences by a vast margin. Most software available for the
      prediction of individual features does not assess the correlation of different
      motifs (level 1 methods). Here, we present a second-level software package called
      GenomeInspector (GI) for further analysis of results obtained with level 1
      methods. Our approach does not require any a priori knowledge about motif
      organization and was designed as a modular package with a graphical user
      interface. Three examples for GI application are presented.

PMID- 8660982
TI  - Computer-assisted search for sites of nuclear matrix attachment.
AB  - This communication describes a useful approach for assessing the significance of
      the occurrence of multiple motifs within defined segments of the genome. Regions
      of potential biological importance are identified using various sequence motifs,
      and then the results are displayed as their cumulative statistically weighted
      distribution. We illustrate the utility of this strategy to the search for known
      nuclear matrix-associated regions by its application to the human beta-globin and
      other loci.

PMID- 8660983
TI  - Mapping of the gene for the p60 subunit of the human chromatin assembly factor
      (CAF1A) to the Down syndrome region of chromosome 21.
AB  - Exon trapping was used to clone portions of genes from the Down syndrome critical
      region (DSCR) of human chromosome 21. One trapped sequence showed complete
      homology with nucleotide sequence U20980 (GenBank), which corresponds to the gene
      for the p60 subunit of the human chromatin assembly factor-1 (CAF1A). We mapped
      this gene to human chromosome 21 by fluorescence in situ hybridization, by the
      use of somatic cell hybrids, and by hybridization to chromosome 21-specific YACs
      and cosmids. The CAF1A gene localizes to YACs 745H11 and 230E8 of the Chumakov et
      al. (1992, Nature 359: 380) YAC contig, within the DSCR on 21q22. This CAF1A,
      which belongs to the WD-motif family of genes and interacts with other
      polypeptide subunits to promote assembly of histones to replicating DNA, may
      contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.

PMID- 8660984
TI  - Mouse microsomal triglyceride transfer protein large subunit: cDNA cloning,
      tissue-specific expression and chromosomal localization.
AB  - Microsomal triglyceride transfer protein (MTP) catalyzes the transfer of
      triglyceride, cholesteryl ester, and phospholipid between membranes. It is
      essential for the secretion of apolipoprotein B from the cell. Mutations in MTP
      are a major cause of abetalipoproteinemia. The mouse is a popular animal model
      for lipoprotein metabolism. We have cloned and sequenced mouse MTP cDNA. The DNA
      deduced amino acid sequence indicates that mouse MTP contains 894 amino acids;
      the mouse protein shows 93, 86, and 83% sequence identity to the hamster, human,
      and bovine sequences, respectively. Northern blot analysis indicates that mouse
      MTP mRNA is expressed at high levels in the small intestine and at substantially
      lower levels in the liver and that it is not detectable in six other tissues
      examined. The mouse MTP gene has been localized to the distal region of
      chromosome 3 by Southern blots of interspecific backcross panels using progeny
      derived from matings of (C57BL/6J x SPRET/Ei)F1 x SPRET/Ei. Comparison of MTP
      sequences from human, bovine, hamster, and mouse indicates that the C-terminal
      region of MTP is better conserved than its N-terminal region.

PMID- 8660985
TI  - Genomic Organization of the ATM gene.
AB  - The ATM gene was recently identified and found to be responsible for the genetic
      disorder ataxiatelgiectasia. The major ATM transcript is 13 kb. Using long
      distance PCR, we determined the genomic structure of this gene and identified all
      of its exon-intron boundaries. The ATM gene spans approximately 150 kb of genomic
      DNA and consists of 66 exons. The initiation codon falls within exon 4. The last
      exon is 3.8 kb and contains the stop codon and a 3'-untranslated region of about
      3600 nucleotides.

PMID- 8660986
TI  - Visual demonstration of the organization of the human complement C4 and 21
      hydroxylase genes by high-resolution fluorescence in situ hybridization.
AB  - We analyzed the gene organization in the complement component C4 and 21
      hydroxylase (21OH) gene region of the human major histocompatibility complex
      using visual mapping of stretched DNA by multicolor fluorescence in situ
      hybridization (FISH). Normally, this region contains a duplicated 21OH-C4 gene
      cluster (21OHB-C4B-21OHA-C4A). Duplication and deletion of one or more copies of
      the 21OH-C4 gene unit are known to occur frequently. Biotin-labeled cDNA of the
      C4 gene and digoxigenin-labeled cDNA of the 21OH gene were hybridized to
      decondensed nuclei of peripheral blood lymphocytes obtained from individuals with
      various 21OH-C4 haplotypes. Hybridization signals of the C4 and 21OH probes were
      detected with fluorescein isothiocyanate (green) and rhodamine (red),
      respectively. Two linear green and red signal clusters were observed in each
      nucleus showing the normal haplotype. Gene duplication and deletion were
      visualized as addition and deletion of the signal cluster, respectively. The DNA
      types of the 21OH-C4 region determined by FISH were concordant with the results
      previously obtained by conventional molecular studies. Our high-resolution FISH
      technique is found to be useful for screening gene duplications and deletions.

PMID- 8660987
TI  - Chromosome mapping of human (ZNF179), mouse, and rat genes for brain finger
      protein (bfp), a member of the RING finger family.
AB  - The bfp, a member of the RING finger family, has been shown to be predominantly
      expressed in brain and up-regulated in neural differentiation of P19 embryonic
      carcinoma cells. Chromosome mapping of the bfp gene by fluorescence in situ
      hybridization reveals that human BFP (ZNF179) is located at 17p11.2, mouse Bfp at
      11B1.3, and rat BFP at 10q22. These results provide additional evidence that the
      mouse 11B region displays conserved linkage homology with the 17p11.2 region of
      the human genome and the 10q22 region of the rate genome.

PMID- 8660988
TI  - The TGF beta type II receptor, Tgfbr2, maps to distal mouse chromosome 9.

PMID- 8660989
TI  - The Bin1 Gene Localizes to Human Chromosome 2q14 by PCR Analysis of Somatic Cell
      Hybrids and Fluorescence in Situ Hybridization

PMID- 8660990
TI  - Assignment of the human FKBP12-rapamycin-associated protein (FRAP) gene to
      chromosome 1p36 by fluorescence in situ hybridization.

PMID- 8660991
TI  - The human phosphoribosylpyrophosphate synthetase-associated protein 39 gene
      (PRPSAP1) is located in the chromosome region 17q24-q25.

PMID- 8660992
TI  - Assignment of GUCIA2, the gene coding for the alpha 2 subunit of soluble guanylyl
      cyclase, to position 11q21-q22 on human chromosome 11.

PMID- 8660993
TI  - Human/mouse homology relationships.

PMID- 8660994
TI  - The organization and expression of the mdm2 gene.
AB  - The mdm2 gene encodes a zinc finger protein that negatively regulates p53
      function by binding and masking the p53 transcriptional activation domain. Two
      different promoters control expression of mdm2, one of which is also
      transactivated by p53. We cloned and characterized the mdm2 gene from a murine
      129 library. It contained at least 12 exons and spanned approximately 25 kb of
      DNA. Sequencing of the mdm2 gene revealed three nucleotide differences that
      resulted in amino acid substitutions in the previously published mdm2 sequence.
      Sequencing of normal BalbC/J DNA and the original cosmid clone isolated from the
      3T3DM cell line revealed that they are identical, suggesting that the published
      sequence is in error at these three positions. In addition, we analyzed the
      expression pattern of mdm2 and found ubiquitous low-level expression throughout
      embryo development and in adult tissues. Analysis of mRNA from numerous tissues
      for several mdm2 spliced variants that had been identified in the transformed
      3T3DM cell line revealed that these variants could not be detected in the
      developing embryo or in adult tissues.

PMID- 8660995
TI  - Linkage mapping in sheep and deer identifies a conserved pecora ruminant linkage
      group orthologous to two regions of HSA16 and a portion of HSA7Q.
AB  - Two orthologous linkage groups have been mapped in sheep and deer. Seven loci
      have been mapped in deer, and 12 in sheep. The sheep linkage group is assigned to
      ovine chromosome 24. The linkage groups consist of loci from the short arm of
      human chromosome 16, spanning the region containing the human Batten disease
      locus, and from human chromosome 7. One locus from the long arm of human
      chromosome 16 is also present, demonstrating a previously unknown rearrangement
      between human and ruminant chromosomes. There is no significant difference in
      marker order and distances between the two linkage groups, implying that this
      linkage pattern was present in the genome of the common ancestor of the pecora
      ruminants.

PMID- 8660996
TI  - A 900-kb cosmid contig and 10 new transcripts within the candidate region for
      myotubular myopathy (MTM1).
AB  - The X-linked myotubular myopathy locus (MTM1) has been assigned to the Xq28
      region by linkage analysis. By observation of an interstitial deletion in a
      female patient, the candidate region could be further reduced to a region of 600
      kb flanked by the markers DXS304 and DXS497. We describe here cosmid contigs
      covering a region of 900 kb, including the entire MTM1 candidate region. Cosmids
      from the region were used to construct an enriched cDNA library from this area.
      Filter grids carrying this library were then screened by hybridization with whole
      cosmid clones, with CpG island-containing fragments from linking clones located
      in the area, and with total exon trap products of cosmid clones from the
      candidate region. In this analysis, 10 new transcripts were identified and
      localized precisely within the map. Genes in this area are candidates for MTM1
      and a number of other diseases localized by genetic linkage studies to the
      chromosomal band Xq28.

PMID- 8660997
TI  - Structure and genomic organization of the human B1 receptor gene for kinins
      (BDKRB1).
AB  - Two subtypes of mammalian bradykinin receptors, B1 and B2 (BDKRB1 and BDKRB2),
      have been defined based on their pharmacological properties. The B1 type kinin
      receptors have weak affinity for intact BK or Lys-BK but strong affinity for
      kinin metabolites without the C-terminal arginine (e.g., des-Arg9-BK and Lys-des
      Arg9-BK, also called des-Arg10-kallidin), which are generated by kininase I. The
      B1 receptor expression is up-regulated following tissue injury and inflammation
      (hyperemia, exudation, hyperalgesia, etc.). In the present study, we have cloned
      and sequenced the gene encoding human B1 receptor from a human genomic library.
      The human B1 receptor gene contains three exons separated by two introns. The
      first and the second exon are noncoding, while the coding region and the 3'
      flanking region are located entirely on the third exon. The exon-intron
      arrangement of the human B1 receptor gene shows significant similarity with the
      genes encoding the B2 receptor subtype in human, mouse, and rat. Sequence
      analysis of the 5'-flanking region revealed the presence of a consensus TATA box
      and of numerous candidate transcription factor binding sequences. Primer
      extension experiments have shown the existence of multiple transcription
      initiation sites situated downstream and upstream from the consensus TATA box.
      Genomic Southern blot analysis indicated that the human B1 receptor is encoded by
      a single-copy gene.

PMID- 8660998
TI  - Gene structure, cDNA cloning, and expression of a mouse mercurial-insensitive
      water channel.
AB  - Three cDNAs encoding isoforms of a mercurial-insensitive water channel (mMIWC)
      were cloned from a mouse brain cDNA library. The predicted proteins had distinct
      N-terminal sequences and were 32.0 (mMIWC1), 34.3 (mMIWC2), and 37.8 (mMIWC3)
      kDa. Immunoblot analysis of mouse brain membranes with a C-terminus-derived
      polyclonal antibody was consistent with the predicted sizes. Expression in
      Xenopus oocytes indicated that each isoform functioned as a mercurial
      insensitive, water-selective channel. Northern blot analysis indicated a major
      transcript of 5.5 kb in brain > eye > lung approximately kidney, and a minor 1.7
      kb transcript in heart and muscle. Sequence comparison of mMIWC1 cDNA with a
      cloned 24-kb mouse genomic DNA indicated three introns (lengths 1.5, 0.5, and 4.0
      kb) separating four exons with boundaries at amino acids 127, 182, and 209;
      analysis of mMIWC2 and mMIWC3 sequences indicated an additional intron at
      nucleotide -34 upstream from the mMIWC1 translation initiation site. The mMIWC1
      promoter was identified and contained TATA, CAAT, GATA, and AP-2 elements; primer
      extension revealed mMIWC transcription initiation at 621 bp upstream from the
      mMIWC1 translational initiation site. Genomic Southern blot analysis revealed a
      single-copy mMIWC gene. These data indicate the presence of multiple mMIWC
      isoforms with distinct N-termini encoded by mRNAs produced by distinct
      transcriptional units and alternative splicing. The genomic cloning of mMIWC
      represents the first step in the construction of a targeting vector for mMIWC
      gene knockout.

PMID- 8660999
TI  - Assembly of high-resolution restriction maps based on multiple complete digests
      of a redundant set of overlapping clones.
AB  - An approach to restriction-site mapping and contig building that uses fragment
      size data from multiple complete digests of a set of clones that oversample a
      genomic region is presented. Maps containing both fragment-length data and clone
      end data are maintained for each restriction enzyme. Synchronization between the
      maps for the different enzymes is achieved by requiring the clone-end maps for
      all enzymes to be compatible. Basic concepts that underlie multiple-complete
      digest mapping--including the match/merge approach to map incorporation,
      extension vs assimilation, ambiguity, and clone-end compatibility--are presented.
      An initial application of multiple-complete-digest mapping to real data on a set
      of cosmid clones suggests that this mapping method has exceptional power to
      produce accurate maps that are well suited to the needs of large-scale DNA
      sequencing projects.

PMID- 8661000
TI  - Human phenol sulfotransferase STP2 gene: molecular cloning, structural
      characterization, and chromosomal localization.
AB  - Sulfonation is an important pathway in the biotransformation of many drugs,
      xenobiotics, neurotransmitters, and steroid hormones. The thermostable (TS) form
      of phenol sulfotransferase (PST) preferentially catalyzes the sulfonation of
      "simple" planar phenols, and levels of activity of TS PST in human tissues are
      controlled by inheritance. Two different human liver TS PST cDNAs have been
      cloned that encode proteins with amino acid sequences that are 96% identical. We
      have determined the structure and chromosomal localization of the gene for one of
      these two cDNAs, STP2, as a step toward understanding molecular genetic
      mechanisms involved in the regulation of this enzyme activity in humans. STP2
      spans approximately 5.1 kb and contains nine exons that range in length from 74
      to 347 bp. The locations of most STP2 exon-intron splice junctions are identical
      to those of a gene for the thermolabile form of PST in humans, STM; a rat PST
      gene; a human estrogen ST (EST) gene, STE; and a guinea pig EST gene. The two
      initial STP2 exons, IA and IB, were identified by performing 5'-rapid
      amplification of cDNA ends with human liver cDNA as template. Exons IA and IB are
      noncoding and represent two different human liver TS PST cDNA 5'-untranslated
      region sequences. The two apparent 5'-flanking regions of the STP2 gene, regions
      flanking exons IA and IB, contain no canonical TATA boxes, but do contain CCAAT
      elements. STP2 was localized to human chromosome 16 by performing the PCR with
      DNA from NIGMS human/rodent somatic cell hybrids as template. Structural
      characterization of STP2 will make it possible to begin to study molecular
      genetic mechanisms involved in the regulation of TS PST activity in human tissue.

PMID- 8661001
TI  - Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis
      locus (TSC1) candidate region on chromosome 9Q34.
AB  - In the search for candidate genes for the tuberous sclerosis (TSC1) disease locus
      on chromosome 9q34, we have isolated an overlapping series of 22 plasmid and
      phage cDNA clones covering nearly 7 kb and with an open reading frame of 5070 bp
      encoding a protein of 1690 amino acids. The putative protein product is a member
      of the kinesin superfamily and is homologous to the mouse KIF1A and the
      Caenorhabditas elegans unc-104 genes. Both KIF1A and unc-104 function in the
      anterograde axonal transport of synaptic vesicles. The human homolog is therefore
      termed H-ATSV (axonal transporter of synaptic vesicles, HGMW-approved
      nomenclature ATSV) Screening of DNA from 107 tuberous sclerosis patients and 80
      unaffected individuals with H-ATSV cDNA probes by pulsed-field gel
      electrophoresis/Southern blotting following digestion by rare-cutting methylation
      sensitive restriction enzymes showed variant banding patterns in three patients
      with tuberous sclerosis. However, further analysis indicated that these variant
      fragments represent a rare polymorphism probably associated with methylation of
      clustered restriction sites. There is no evidence to support H-ATSV as a
      candidate gene for TSC1.

PMID- 8661002
TI  - Toward a high-resolution Plasmodium falciparum linkage map: polymorphic markers
      from hundreds of simple sequence repeats.
AB  - A total of 507 simple sequence repeats (SSRs or "microsatellites") were
      identified from Plasmodium falciparum sequences in GenBank and from inserts in a
      genomic DNA library. Oligonucleotide primers from sequences that flank 224 of
      these SSRs were synthesized and used in PCR assays to test for simple sequence
      length polymorphisms (SSLPs). Of the 224 SSRs, 188 showed SSLPs among 12
      different P. falciparum lines; 116 of these SSLPs were assigned to chromosome
      linkage groups by physical mapping and by comparing their inheritance patterns
      against those of restriction fragment length polymorphism markers in a genetic
      cross (HB3xDd2). The predominant SSLPs in P. falciparum were found to contain
      [TA]n, [T]n, and [TAA]n, a feature that is reminiscent of plant genomes and is
      consistent with the proposed algal-like origin of malaria parasites. Since such
      SSLPs are abundant and readily isolated, they are a powerful resource for genetic
      analysis of P. falciparum.

PMID- 8661003
TI  - Mapping genomic library clones using oligonucleotide arrays.
AB  - We have developed a high-density DNA probe array and accompanying biochemical and
      informatic methods to order clones from genomic libraries. This approach involves
      a series of enzymatic steps for capturing a set of short dispersed sequence
      markers scattered throughout a high-molecular-weight DNA. By this process, all
      the ambiguous sequences lying adjacent to a given Type IIS restriction site are
      ligated between two DNA adapters. These markers, once amplified and labeled by
      PCR, can be hybridized and detected on a high-density oligonucleotide array
      bearing probes complementary to all possible markers. The array is synthesized
      using light-directed combinatorial chemistry. For each clone in a genomic
      library, a characteristic set of sequence markers can be determined. On the basis
      of the similarity between the marker sets for each pair of clones, their relative
      overlap can be measured. The library can be sequentially ordered into a contig
      map using this overlap information. This new methodology does not require gel
      based methods or prior sequence information and involves manipulations that
      should allow for easy adaptation to automated processing and data collection.

PMID- 8661004
TI  - Cloning of the canine GALC cDNA and identification of the mutation causing
      globoid cell leukodystrophy in West Highland White and Cairn terriers.
AB  - Globoid cell leukodystrophy, or Krabbe disease, is a severe, autosomal recessive
      disorder resulting from a deficiency of galactocerebrosidase (GALC) activity.
      GALC is responsible for the lysosomal catabolism of certain galactolipids,
      including galactosylceramide and psychosine. In addition to the human patients,
      there are several naturally occurring animal models for this disease, including
      the twitcher mouse, West Highland White terriers (WHWT), and Cairn terriers. All
      species have deficient GALC activity and have the characteristic pathological
      findings in the nervous system. We now describe the cloning of the canine GALC
      cDNA and the identification of the disease-causing mutation in both terrier
      breeds. The 2007-bp open reading frame is 88% identical to that in human, and the
      deduced amino acid sequence is about 90% identical. However, the 3'-untranslated
      region is about 1 kb shorter than that in the human. Two nucleotide changes were
      found in affected dogs, an A to C transversion at cDNA position 473 (Y158S) and a
      C to T transition at position 1915 (P639S). Expression studies in COS-1 cells
      demonstrated that the A to C change at 473 is the disease-causing mutation. A
      rapid test for the identification of the genotype at that position has been
      developed, and over 100 WHWT and Cairn terriers have been screened. This will
      allow breeders to mate their dogs selectively and will permit the establishment
      of a colony of dogs for use in therapy trials.

PMID- 8661005
TI  - Transcripts from a novel human KRAB zinc finger gene contain spliced Alu and
      endogenous retroviral segments.
AB  - During the course of an investigation into the potential effects of endogenous
      retroviruses on adjacent gene expression, we isolated two cDNA clones containing
      a small sequence segment belonging to the human endogenous retrovirus family,
      HERV-H. Characterization of the clones revealed that they represent transcripts
      from a novel KRAB zinc finger gene termed ZNF177. The two cDNA clones differ at
      their 5' termini and in the presence of a 559-bp internal exon. The clone
      containing this internal exon has six imperfect zinc finger motifs followed by
      seven perfect copies of the C2H2 type but has a frame shift between the KRAB
      domain and the downstream zinc finger region. The smaller clone lacks the six
      imperfect motifs and has an intact ORF. The 5' putative untranslated regions of
      both cDNAs contain an 86-bp HERV-H env segment and a segment of an Alu repeat,
      both in the antisense orientation, that have been incorporated by splicing. RT
      PCR experiments show evidence of alternative splicing but the majority of
      transcripts appear to contain the Alu and env segments. Genomic PCR and
      hybridization experiments suggest that a partial HERV-H element is integrated
      within the ZNF177 locus, which Southern analysis has shown to be a single-copy
      gene. Northern and RT-PCR analyses suggest that ZNF177 is transcribed at a low
      level in a variety of cell types.

PMID- 8661006
TI  - Structure of the human type IV collagen COL4A6 gene, which is mutated in Alport
      syndrome-associated leiomyomatosis.
AB  - Basement membrane (type IV) collagen, a subfamily of the collagen protein family,
      is encoded by six distinct genes in mammals. Three of those, COL4A3, COL4A4, and
      COL4A5, are linked with Alport syndrome (hereditary nephritis). Patients with
      leimoyomatosis associated with Alport syndrome have been shown to have deletions
      in the 5' end of the COL4A6 gene, in addition to having deletions in COL4A5 (Zhou
      et al., Science 261: 1167-1169, 1993). The human COL4A6 gene is reported to be
      425 kb as determined by mapping of overlapping YAC clones by probes for its 5'
      and 3' ends. In the present study we describe the complete exon/intron size
      pattern of the human COL4A6 gene. The 12 lambda phage clones characterized in the
      study spanned a total of 110 kb, including 85 kb of the actual gene and 25 kb of
      flanking sequences. The overlapping clones contained all 46 exons of the gene and
      all introns, except for intron 2. Since the total size of the exons and all
      introns except for intron 2 is about 85 kb, intron 2 must be about 340 kb. All
      exons of the gene were assigned to EcoRI restriction fragments to facilitate
      analysis of the gene in patients with leiomyomatosis associated with Alport
      syndrome. The exon size pattern of COL4A6 is highly homologous with that of the
      human and mouse COL4A2 genes, with 27 of the 46 exons of COL4A6 being identical
      in size between the genes.

PMID- 8661007
TI  - Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and
      exon to protein domain relationships.
AB  - We have isolated, sequenced, and characterized a human MN/CA9 gene. This gene is
      a novel member of the carbonic anhydrase (CA) family, which codes for widely
      distributed catalysts of the reversible conversion of carbon dioxide to carbonic
      acid. So far, MN/CA IX is the only tumor-associated CA isoenzyme. The entire
      genomic sequence of MN/CA9, including the 5'-flanking region, encompasses 10.9
      kb. The coding sequence is divided into 11 exons, whose organization and
      relationships to predicted protein domains suggest that the gene arose by exon
      shuffling. Exon 1 encodes a signal peptide and a proteoglycan-related region.
      Exons 2-8 code for a CA domain with a highly conserved active site. The
      exon/intron pattern of the CA coding region is similar but not identical to other
      described animal kingdom alpha-CA genes. Exons 10 and 11 encode a transmembrane
      anchor and an intracytoplasmic tail, respectively. We have also determined the
      transcription initiation and termination sites by RNase protection assay and
      analyzed the 3. 5-kb region upstream of the MN/CA9 gene. Sequence of the
      proximate 5' end of the flanking region shows extensive homology to the long
      terminal repeats of HERV-K endogenous retroviruses. The putative MN/CA9 promoter
      immediately preceding the transcription start site does not possess a TATA box,
      but contains consensus sequences for the AP1, AP2, p53, and Inr transcription
      factors. This study will allow further investigations of the molecular events
      regulating expression of MN/CA IX as well as elucidation of its biological
      function.

PMID- 8661008
TI  - A 2-megabase physical contig incorporating 43 DNA markers on the human X
      chromosome at p11.23-p11.22 from ZNF21 to DXS255.
AB  - A comprehensive physical contig of yeast artificial chromosomes (YACs) and cosmid
      clones between ZNF21 and DXS255 has been constructed, spanning 2 Mb within the
      region Xp11.23-p11.22. As a portion of the region was found to be particularly
      unstable in yeast, the integrity of the contig is dependent on additional
      information provided by the sequence-tagged site (STS) content of cosmid clones
      and DNA marker retention in conventional and radiation hybrids. The contig was
      formatted with 43 DNA markers, including 19 new STSs from YAC insert ends and an
      internal Alu-PCR product. The density of STSs across the contig ranges from one
      marker every 20 kb to one every 60 kb, with an average density of one marker
      every 50 kb. The relative order of previously known genes and expressed sequence
      tags in this region is predicted to be Xpter-ZNF21-DXS7465E (MG66)-DXS7927E
      (MG81)-WASP, DXS1011E, DXS7467E (MG21)-DXS- 7466E (MG44)-GATA1-DXS7469E (Xp664)
      TFE3-SYP (DXS1007E)-Xcen. This contig extends the coverage in Xp11 and provides a
      framework for the future identification and mapping of new genes, as well as the
      resources for developing DNA sequencing templates.

PMID- 8661009
TI  - The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene
      family.
AB  - A physiological role for paraoxonase (PON1) is still uncertain, but it catalyzes
      the hydrolysis of toxic organophosphates. Evidence that the human genome contains
      two PON1-like genes, designated PON2 and PON3, is presented here. Human PON1 and
      PON2 each have nine exons, and the exon/intron junctions occur at equivalent
      positions. PON1 and PON2 genes are both on chromosome 7 in human and on
      chromosome 6 in the mouse. Turkey and chicken, like most birds, lack paraoxonase
      activity and are very susceptible to organophosphates. However, they have a PON
      like gene with approximately 70% identity with human PON1, PON2, and PON3.
      Another unexpected finding is that the deduced amino acid sequences of PON2 in
      human, mouse, dog, turkey, and chicken and of human PON3 are all missing the
      amino acid residue 105, which is lysine in human PON1. The expanded number of PON
      genes will have important implications for future experiments designed to
      discover the individual functions, catalytic properties, and physiological roles
      of the paraoxonases.

PMID- 8661010
TI  - Genomic organization, promoter analysis, and chromosomal localization of the gene
      for the mouse glial high-affinity glutamate transporter Slc1a3.
AB  - The mouse gene encoding glial high-affinity, Na+-dependent glutamate transporter
      Slc1a3 (GluT-1/GLAST) was isolated, and its structural organization was
      characterized. The gene appeared to exist as a single copy in the mouse genome
      and comprised 10 exons spanning more than 56 kilobases. The transcription
      initiation sites were mapped to positions 503, which is the first transcriptional
      point (defined as +1), 128 (+376), and 64 (+440) basepairs upstream of the 3'-end
      of exon 1 by primer extension. The 5'-flanking region of the mouse GluT-1 gene
      had a typical CCAAT box and a GC box but lacked a TATA box. These features of the
      promoter region were characteristic of housekeeping genes. The fusion plasmids
      containing approximately 4 kb of the 5'-flanking region (-3830 to +450) and the
      firefly luciferase gene induced a significant luciferase activity when
      transfected into COS-1 cells. Distal deletion of the 5'-flanking region, leaving
      619 bp (-169 to +450), resulted in a marked decrease in luciferase activity in
      COS-1 cells, suggesting that a CCAAT box, which was positioned at -200, is
      necessary for the expression of this gene. In situ hybridization localized this
      gene to mouse chromosome 15A2. These structural features will lead to a better
      understanding of the regulatory mechanism of the expression of the GluT-1 gene by
      ischemia and will also provide a basis for future evolutionary comparisons with
      other neurotransmitter transporters.

PMID- 8661011
TI  - The mouse glutathione peroxidase Gpx2 gene maps to chromosome 12; its pseudogene
      Gpx2-ps maps to chromosome 7.
AB  - The GPX2 gene codes for GSHPx-GI, a glutathione peroxidase whose mRNA is readily
      detectable in the gastrointestinal tract. Although GPX2 is a single gene in
      humans, there are two genes in the mouse genome with homology to GPX2. By
      analyzing a panel of mouse interspecies DNA from the Jackson Laboratory's
      backcross resource, we have chromosomally mapped these two genes. One was mapped
      to the central region of mouse chromosome 12 between D12Mit4 and D12Mit5, near
      fos and Tgfb3. This region is homologous to human 14q24.1, where human GPX2 has
      been mapped, and most likely represents the functional mouse Gpx2 gene. The other
      Gpx2-like gene was mapped to mouse chromosome 7 between Pcsk3 and Hbb. We have
      isolated the latter gene from a P1 phage library. Its pseudogene nature is
      revealed by the sequence analysis: (a) it is intronless; (b) it has a single
      nucleotide deletion in the coding region; and (c) it has a poly(A) tail at its 3'
      untranslated region.

PMID- 8661012
TI  - The human intron-containing gene for glycogenin maps to chromosome 3, band q24.
AB  - Glycogenin is the autocatalytic, self-glucosylating primer for glycogen
      synthesis, providing the anchor on which the macromolecule is constructed. We
      have sequenced the cDNA coding for human muscle glycogenin and have deduced the
      corresponding amino acid sequence. By means of the polymerase chain reaction and
      fluorescence in situ hybridization, we have found the chromosomal location of the
      gene coding for glycogenin. This is localized to human chromosome 3, band q24.

PMID- 8661013
TI  - A gene for autosomal dominant congenital nystagmus localizes to 6p12.
AB  - Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular
      oscillations usually manifest during infancy. Vision is typically decreased due
      to slippage of images across the fovea. As such, visual acuity correlates with
      nystagmus intensity, which is the amplitude and frequency of eye movements at a
      given position of gaze. X-linked, autosomal dominant, and autosomal recessive
      pedigrees have been described, but no mapping studies have been published. We
      recently described a large pedigree with autosomal dominant congenital nystagmus.
      A genome-wide search resulted in six markers on 6p linked by two-point analysis
      at theta = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis
      localizes the gene for autosomal dominant congenital motor nystagmus to an 18-cM
      region between D6S271 and D6S455.

PMID- 8661014
TI  - Mapping of the ARIX homeodomain gene to mouse chromosome 7 and human chromosome
      11q13.
AB  - The recently described homeodomain protein ARIX is expressed specifically in
      noradrenergic cell types of the sympathetic nervous system, brain, and adrenal
      medulla. ARIX interacts with regulatory elements of the genes encoding the
      noradrenergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta
      hydroxylase, suggesting a role for ARIX in expression of the noradrenergic
      phenotype. In the study described here, the mouse and human ARIX genes are
      mapped. Using segregation analysis of two panels of mouse backcross DNA, mouse
      Arix was positioned approximately 50 cM distal to the centromere of chromosome 7,
      near Hbb. Human ARIX was positioned through analysis of somatic cell hybrids and
      fluorescence in situ hybridization of human metaphase chromosomes to chromosome
      11q13.3-q13.4. These map locations extend and further define regions of conserved
      synteny between mouse and human genomes and identify a new candidate gene for
      inherited developmental disorders linked to human 11q13.

PMID- 8661015
TI  - Chromosomal mapping of the human M6 genes.
AB  - M6 is a neuronal membrane glycoprotein that may have an important role in neural
      development. This molecule was initially defined by a monoclonal antibody that
      affected the survival of cultured cerebellar neurons and the outgrowth of
      neurites. The nature of the antigen was discovered by expression cDNA cloning
      using this monoclonal antibody. Two distinct murine M6 cDNAs (designated M6a and
      M6b) whose deduced amino acid sequences were remarkably similar to that of the
      myelin proteolipid protein were previously isolated. We have isolated partial
      human cDNA and genomic clones encoding M6a and M6b and have characterized them by
      restriction mapping, Southern hybridization with cDNA probes, and sequence
      analysis. We have localized these genes within the human genome by FISH
      (fluorescence in situ hybridization). The human M6a gene is located at 4q34, and
      the M6b gene is located at Xp22.2. A number of human neurological disorders have
      been mapped to the Xp22 region, including Aicardi syndrome (MIM 304050), Rett
      syndrome (MIM 312750), X-linked Charcot-Marie-Tooth neuropathy (MIM 302801), and
      X-linked mental retardation syndromes (MRX1, MIM 309530). This raises the
      possibility that a defect in the M6b gene is responsible for one of these
      neurological disorders.

PMID- 8661016
TI  - Localization of the human mitogen-induced GTP-binding protein gem to chromosome
      8q22.3.

PMID- 8661017
TI  - Localization of the ileal sodium-bile acid cotransporter gene (SLC10A2) to human
      chromosome 13q33.

PMID- 8661018
TI  - Chromosomal assignment of human DNA fingerprint sequences by simultaneous
      hybridization to arbitrarily primed PCR products from human/rodent monochromosome
      cell hybrids.
AB  - We have developed a technique for the simultaneous chromosomal assignment of
      multiple human DNA sequences from DNA fingerprints obtained by the arbitrarily
      primed polymerase chain reaction (AP-PCR). Radioactively labeled human AP-PCR
      products are hybridized to DNA fingerprints generated with the same arbitrary
      primer from human/rodent monochromosome cell hybrids after electroblotting to a
      nylon membrane. Human-specific hybridization bands in the human/rodent
      fingerprints unambiguously determine their chromosome of origin. We named this
      method simultaneous hybridization of arbitrarily primed PCR DNA fingerprinting
      products (SHARP). Using this approach, we determined the chromosomal origins of
      most major bands of human AP-PCR fingerprints obtained with two arbitrary
      primers. Altogether, the chromosomal localization of near 50 DNA fragments,
      comprehensive of all human chromosomes except chromosomes 21 and Y, was achieved
      in this simple manner. Chromosome assignment of fingerprint bands is essential
      for molecular karyotyping of cancer by AP-PCR DNA fingerprinting. The SHARP
      method provides a convenient and powerful tool for this purpose.

PMID- 8661019
TI  - Genomic organization of the human SCN5A gene encoding the cardiac sodium channel.
AB  - The voltage-gated cardiac sodium channel, SCN5A, is responsible for the initial
      upstroke of the action potential. Mutations in the human SCN5A gene cause
      susceptibility to cardiac arrhythmias and sudden death in the long QT syndrome
      (LQT). In this report we characterize the genomic structure of SCN5A. SCN5A
      consists of 28 exons spanning approximately 80 kb on chromosome 3p21. We describe
      the sequences of all intron/exon boundaries and a dinucleotide repeat
      polymorphism in intron 16. Oligonucleotide primers based on exon-flanking
      sequences amplify all SCN5A exons by PCR. This work establishes the complete
      genomic organization of SCN5A and will enable high-resolution analyses of this
      locus for mutations associated with LQT and other phenotypes for which SCN5A may
      be a candidate gene.

PMID- 8661020
TI  - Delineation of 7q11.2 deletions associated with Williams-Beuren syndrome and
      mapping of a repetitive sequence to within and to either side of the common
      deletion.
AB  - The majority of Williams-Beuren syndrome (WBS) patients have been shown to have a
      microdeletion within 7q11.2 including the elastin gene locus. The extent of these
      deletions has, however, not been well characterized. Thirty-five deletion
      patients were tested for all polymorphic markers in the 7q11.2 region bounding
      ELN to define the extent of deletions associated with WBS. With only one
      exception, ELN, D7S1870, and one copy of the D7S489 locus (D7S489U) were always
      included in the deletions. One patient showed lack of maternal inheritance at
      D7S1870 and not at ELN or D7S489U. A product corresponding to D7S489U was
      amplified from YAC 743G6 and from the P1 clone RMC07P008, thereby localizing both
      to within the common deletion. The boundary of the deleted region on the proximal
      (centromeric) side is D7S653 and on the distal side is D7S675, neither of which
      were ever included in the deletion. One locus, D7S489L, was variably deleted in
      patients, indicating a minimum of two common breakpoints on the proximal side. At
      least one additional repeat amplified by D7S489 (D7S489M) was localized to a YAC
      contig mapping distal to the common deletion. The D7S489 sequence is highly
      homologous to several cDNA clones in the GenBank database and contains an Alu
      sequence. It is possible that this andsolidusor other repetitive sequences in
      this region could play a role in the mechanism of deletion.

PMID- 8661021
TI  - The structural organization of the human skeletal muscle ryanodine receptor
      (RYR1) gene.
AB  - The RYR1 gene encoding the Ca2+ release channel of human skeletal muscle
      sarcoplasmic reticulum has been cloned and exon/intron boundaries have been
      determined, together with a minimum of 30 bp of intron sequence flanking each
      splice junction. The gene contains 106 exons, of which two are alternatively
      spliced. The length of the gene, determined by the alignment of 16 genomic phage
      clones, a cosmid clone, and several long polymerase chain reaction products, is
      approximately 160 kb. Exons range from 15 to 813 bp, while introns range from 85
      to about 16,000 bp. Analysis of the gene has confirmed published errors in the
      human RYR1 cDNA and confirmed the structure of two alternatively spliced exons.
      The numbering of the nucleotides comprising the RYR1 cDNA and the numbering of
      amino acids encoded by them were corrected to account for these earlier errors
      and omissions. Analysis of 2.4 kb of the 5' upstream sequence indicated the
      presence of a CCAAT box and several Sp1 binding sites between nucleotides -200
      and -60 bp, flanking the proposed transcription start site at -130 bp. Several
      other potential transcription factor binding sites were identified throughout the
      5' sequence. Knowledge of the structure of the RYR1 gene will provide an
      invaluable resource for the discovery of mutations in the gene that are causal of
      human malignant hyperthermia and central core disease.

PMID- 8661022
TI  - YAC/STS map across 12 Mb of Xq27 at 25-kb resolution, merging Xq26-qter.
AB  - A 12-Mb YAC contig has been assembled spanning the Xq27 cytogenetic band with 203
      YACs, 121 STSs, and >300 hybridization probes to a resolution of 25 kb. At its
      centromeric end, the contig is merged with a 9-Mb contig covering Xq26.1-q26.3 at
      a point 1 Mb telomeric to the factor IX gene; at its telomeric end, it is merged
      to 7.5 Mb of contigs from the IDS gene to the Xq28 telomere. Thus, the distal 29
      Mb of the Xq arm is available cloned in long-range contiguity. The physical map
      has been integrated with current genetic data by the localization of 18 markers
      that detect polymorphism. Apparent recombination levels reach >4.5 cM/Mb near the
      centromeric border of Xq27. The ratio of cM/Mb correspondingly delimits the
      location of several disease genes-including, for example, X-linked
      hypoparathyroidism in 3 Mb (6 cM) telomeric to Factor IX.

PMID- 8661023
TI  - YAC/STS map of 9 Mb of Xq26 at 100-kb resolution, localizing 6 ESTs, 6 genes, and
      32 genetic markers.
AB  - To facilitate functional analysis of the Xq26 region, the physical map has been
      extended across 9 Mb with 192 YACs and markers including 90 STSs (sequence-tagged
      sites) and 50 hybridization probes. Six genes and six ESTs are localized. In
      addition, 32 markers that detect polymorphism permit an integration of physical
      with genetic linkage data. The localizations of eight uncloned disease genes are
      thereby delimited on the physical map. The data also suggest a possible gradient
      of recombination across the cytogenetic band, with little or no recombination
      reported in the centromeric 3.5-4 Mb.

PMID- 8661024
TI  - The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and
      mutation analysis in human breast tumors.
AB  - The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor
      gene for human breast cancer. It has been shown to reduce the tumorigenicity of
      breast cancer cell lines in nude mice, and loss of expression of this gene has
      been shown in primary breast tumors. Furthermore, the human MDGI gene has been
      mapped to human chromosome 1p32-p35, a common region of deletion in sporadic
      breast tumors. We have determined the genomic structure of the human MDGI gene
      from a cosmid clone mapping to chromosome 1p32-p35 and have more finely mapped
      the MDGI gene relative to chromosome 1p microsatellite markers. The gene covers
      approximately 8 kb of genomic DNA and is divided into four exons. In an attempt
      to identify possible inactivating mutations in the MDGI gene in human breast
      cancer, we have sequenced all four exons and their surrounding splice junctions
      in 30 sporadic breast tumors. Ten of these tumors showed loss of heterozygosity
      (LOH) in the 1p32-p35 region, with 5 tumors showing LOH in the subregion
      containing the MDGI gene. No mutations were found in this analysis. A
      polymorphism was identified in exon 2 in the constitutional DNA of 1/30 cases in
      this study, which resulted in the conversion of a lysine to an arginine residue
      at codon 53. This variant was present in the constitutional DNA of a further 3/26
      women with sporadic breast cancer and 2/90 control individuals (P = 0.20).
      Despite experimental evidence that MDGI has tumor suppressor activity, our data
      suggest that mutations in the coding region are uncommon in human breast
      tumorigenesis.

PMID- 8661025
TI  - The human gene CGT encoding the UDP-galactose ceramide galactosyl transferase
      (cerebroside synthase): cloning, characterization, and assignment to human
      chromosome 4, band q26.
AB  - We have previously cloned the human UDP-galactose ceramide galactosyltransferase
      (CGT, E.C. 2.4.1.45) cDNA. Its open reading frame encodes the key enzyme in the
      biosynthesis of the glycosphingolipids, cerebrosides and sulfatides, essential
      constituents of the myelin membrane of the central nervous system (CNS) and PNS.
      Expression of the CGT gene and of the myelin-specific proteins in the terminal
      differentiated oligodendrocyte of CNS and in Schwann cells of PNS is cell
      specific and highly time-regulated. The CGT gene therefore is important in the
      differentiation program of the oligodendrocyte lineage. Here we report the
      structural organization and the chromosomal localization of the human CGT gene.
      The coding sequence is separated into five exons, which are distributed over >40
      kb. The CGT locus was mapped to the distal region of human chromosome 4, band
      q26. The organization of the CGT gene and of the UGT
      (uridylglucuronosyltransferases) gene family suggests a correlation to functional
      domains of the encoded proteins.

PMID- 8661026
TI  - The human serotonin N-acetyltransferase (EC 2.3.1.87) gene (AANAT): structure,
      chromosomal localization, and tissue expression.
AB  - Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT, HGMW
      approved symbol AANAT; EC 2.3.1.87) is the penultimate enzyme in melatonin
      synthesis and controls the night/day rhythm in melatonin production in the
      vertebrate pineal gland. We have found that the human AA-NAT gene spans
      approximately 2.5 kb, contains four exons, and is located at chromosome 17q25.
      The open reading frame encodes a 23.2-kDa protein that is approximately 80%
      identical to sheep and rat AA-NAT. The AA-NAT transcript (approximately 1 kb) is
      highly abundant in the pineal gland and is expressed at lower levels in the
      retina and in the Y79 retinoblastoma cell line. AA-NAT mRNA is also detectable at
      low levels in several brain regions and the pituitary gland, but not in several
      peripheral tissues examined. Brain and pituitary AA-NAT could modulate serotonin
      dependent aspects of human behavior and pituitary function.

PMID- 8661028
TI  - Gene assignment, expression, and homology of human tropomodulin.
AB  - Tropomodulin is a newly characterized pointed end capping protein for actin
      filaments. It binds specifically to the N terminus of tropomyosin and blocks the
      elongation and depolymerization of tropomyosin-coated actin filaments. A 1.9-kb
      human tropomodulin cDNA clone was used to map its gene by fluorescence in situ
      hybridization. The tropomodulin gene was assigned to human chromosome 9q22.2
      q22.3, a region that is also known to contain several other genes and disease
      loci and is proximal to the loci for gelsolin and alpha-fodrin. The gene for
      tropomodulin is expressed in major human tissues at different levels in the
      following order: heart and skeletal muscle much greater than that in brain, lung,
      and pancreas, which is greater than that in placenta, liver, and kidney. Human
      tropomodulin and a 64-kDa autoantigen in Graves disease (1D) are related:
      tropomodulin has 42 and 41% identity with the Graves protein in the N-terminal
      (69 residue) and C-terminal (194 residue) regions, respectively. The insertion of
      several homologous repeats in the midsection of the Graves protein, together with
      the extension of a proline-rich C terminus, accounts for the differences in
      length between the Graves protein (572 residues) and tropomodulin (359 residues).
      The significant sequence identity indicates that these two genes are evolved from
      a common ancestral gene.

PMID- 8661027
TI  - The complete sequence of the host cell factor 1 (HCFC1) gene and its promoter: a
      role for YY1 transcription factor in the regulation of its expression.
AB  - We report here the complete sequence of the Host Cell Factor (HCFC1) gene,
      including two kilobases of the 5'-flanking region and 5.9 kb of the first intron.
      The upstream and 5'-untranslated regions contain several putative transcriptional
      factor binding sites and a 17-nt-long repeated element (SiSa element) present in
      six regularly spaced copies, of which five are perfectly identical, while the
      sixth has a transition substitution (CT for TC) at nucleotides 13 and 14. Four
      copies are contained in the flanking region, the fifth is at the beginning of the
      mRNA (position +9), and the sixth is at position 195 of the mRNA. This 17-bp
      element contains at its 5' side an octamer sequence known to bind the Yin/Yang 1
      (YY1) transcription factor; another YY1 binding octamer is present at the end of
      the first intron. The promoter also contains several Sp1 binding sites, some of
      which are located very close to SiSa elements. We demonstrate that YY1 binds to
      the 5' half of the SiSa element, whose 3' region binds in gel shift experiments
      an additional, as yet unidentified nuclear factor. Therefore the YY1 binding site
      in HCFC1 overlaps the site of a second factor, as has been described in several
      YY1-site-containing promoters. This suggests that HCFC1 expression might be
      regulated by the reciprocal interaction of several transcription factors.

PMID- 8661029
TI  - A human chromosome 22 fosmid resource: mapping and analysis of 96 clones.
AB  - We have created a resource for chromosome 22 consisting of 96 unique, well
      characterized Fosmids. The Fosmid vector permits efficient cloning of DNA
      fragments averaging 40 kb in a single-copy vector based on the F factor of
      Escherichia coli. We have found that Fosmid clones from human chromosome 22 show
      remarkable stability and are useful for a wide variety of applications in genome
      analysis. These 96 clones have been localized by FISH, using high-resolution
      fluorescent banding and multicolor mapping techniques, and their position on the
      chromosome was correlated with their content of a number of common repeated
      sequence elements. We identified a subset of clones likely to contain genes by
      restriction analysis using the enzymes NotI, MluI, SacII, and BssHII. This
      collection of cytogenetically anchored clones, representing nearly 7% of the
      chromosome, is of immediate value for detecting chromosomal rearrangements, for
      use in gene isolation, and as a framework for physical mapping.

PMID- 8661030
TI  - Rapid detection of mitochondrial sequence polymorphisms using multiplex solid
      phase fluorescent minisequencing.
AB  - This work describes a novel method, multiplex solid-phase fluorescent
      minisequencing, for the simultaneous detection of several point mutations and/or
      small deletions and insertions. The method is applied to the analysis of
      mitochondrial DNA polymorphisms for the purposes of individual identification. A
      database of 152 British Caucasians and 103 British Afro-Caribbeans has been
      constructed, and the probability of a chance match between two unrelated
      individuals is calculated as 0.054 for Caucasians and 0.026 for Afro-Caribbeans.

PMID- 8661032
TI  - Physical mapping of the retinoblastoma interacting zinc finger gene RIZ to D1S228
      on chromosome 1p36.
AB  - The retinoblastoma interacting zinc finger gene RIZ is a member of the recently
      discovered PR domain family that includes the MDS1-EVI1 breakpoint gene involved
      in human leukemia. To help understand the role of RIZ in human diseases, we have
      determined the cytogenetic and physical localizations of the RIZ gene. Using
      fluorescence in situ hybridization, we determined that RIZ maps to 1p36. On the
      physical map, RIZ is adjacent to the polymorphic marker D1S228. We suggest that
      the RIZ gene may be a candidate target of 1p36 alterations that commonly occur in
      neuroendocrine, breast, liver, colon, and lymphoid tumors.

PMID- 8661031
TI  - Isolation of cDNA and genomic clones of a human Ras-related GTP-binding protein
      gene and its chromosomal localization to the long arm of chromosome 7, 7q36.
AB  - A Ras-related GTP-binding protein cDNA has been isolated from a human skin
      fibroblast cDNA library using a genomic subclone derived from a YAC clone as a
      probe. The polypeptide, consisting of 184 amino acids deduced from nucleotide
      sequences, contains five repeats of the Ras-related GTP-binding region and is
      highly homologous to the rat RHEB (Ras homologue enriched in brain) gene, which
      encodes a Ras-related growth factor- and synaptic activity-regulated protein,
      with 98.9% amino acid identity. Therefore, it is suggested to be a human
      homologue of the rat RHEB protein, and we have designated it human RHEB. Using
      fluorescence in situ hybridization, we concluded that this human RHEB gene was
      localized to band q36 on chromosome 7. Considering the chromosomal localization
      as well as the potential function of this protein, it will be very important to
      investigate whether it may play a role in the etiopathogenesis of
      holoprosencephaly type 3 or hereditary sacral agenesis, in which the disease
      susceptible locus is linked to the microsatellite marker, D7S22, in this
      chromosomal region, 7q36.

PMID- 8661033
TI  - Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM):
      reassignment to human chromosome 12q.
AB  - Phosphofructokinase (PFK) is a key rate-limiting enzyme in glycolysis and
      represents a major control point in the metabolism of glucose. There are at least
      three known isoforms of PFK in humans, referred to as the muscle, platelet, and
      liver forms, each of which is differentially expressed in various tissues. The
      gene for muscle phosphofructokinase, PFKM, is mutated in Tarui disease and
      conceivably contributes to non-insulin-dependent diabetes mellitus (NIDDM). Based
      on physical and genetic mapping, we have found that the gene for PFKM does not
      map to chromosome 1 as previously described, but instead maps to chromosome 12.
      PCR analysis with a somatic cell hybrid mapping panel using primers derived from
      intron 6 and exon 18 of the PFKM gene showed consistent amplification of cell
      lines containing chromosome 12 (concordance, 100%). Fluorescence in situ
      hybridization analysis with CEPH YAC 762G4, isolated with exon 18 primers,
      indicated that this clone maps to 12q13, centromeric to the diacylglycerol kinase
      gene (DAGK) at 12q13. 3. A highly informative genetic marker isolated from YAC
      762G4 was used to map PFKM genetically between the CHLC framework markers
      D12S1090 and D12S390. This placement for 762G4 was significantly proximal to the
      recently reported locus for a third gene for maturity onset diabetes of the young
      (MODY). The PFKM-associated microsatellite will be a valuable tool in the
      evaluation of PFKM in diabetic populations as well as in linkage analysis in
      families with Tarui disease.

PMID- 8661034
TI  - A 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region in
      17p11.2-p12.
AB  - Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1. 5-Mb tandem
      duplication in chromosome 17p11.2-p12, and hereditary neuropathy with liability
      to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus.
      Both diseases appear to result from an altered copy number of the peripheral
      myelin protein-22 gene, PMP22, which maps within the critical region. To identify
      additional genes and characterize chromosomal elements, a 1.5-Mb cosmid contig of
      the CMT1A duplication/HNPP deletion critical region was assembled using a yeast
      artificial chromosome (YAC)-based isolation and binning strategy. Whole YAC
      probes were used for screening a high-density arrayed chromosome 17-specific
      cosmid library. Selected cosmids were spotted on dot blots and assigned to bins
      defined by YACs. This binning of cosmids facilitated the subsequent fingerprint
      analysis. The 1.5-Mb region was covered by 137 cosmids with a minimum overlap set
      of 52 cosmids assigned to 17 bins and 9 contigs.

PMID- 8661035
TI  - Close linkage of the two keratin gene clusters in the human genome.
AB  - Mapping studies of functional keratin genes in the human genome have localized
      most of the acidic keratin genes to chromosome 17q12-q21 and the basic keratin
      genes to chromosome 12q11-q13. Within the acidic keratin locus two clusters were
      identified, one containing the genes for K15 and K19, the other the genes for
      K14, K16, and K17. The relative positions and the distance between the two
      clusters have not been determined previously. In this paper we describe our
      analysis of P1 clones containing multiple acidic keratin genes, which were
      studied using restriction analysis and Southern blot hybridization with PCR
      amplified probes specific for functional human keratin genes 15, 17, and 19. Our
      results show that the two clusters are very closely linked to each other, within
      a 55-kb region in the human genome. The genes are organized 5' to 3' in the
      following order: 5'-K19-K15-K17-K16-K14. Between K15 and K17 at least one
      additional, unidentified keratin gene is present.

PMID- 8661036
TI  - Structure of the mouse Saa4 gene and its linkage to the serum amyloid A gene
      family.
AB  - The serum amyloid A (SAA) proteins are a polymorphic family of apolipoproteins
      associated with high-density lipoproteins (HDL). Three distinct subfamilies have
      been identified: (i) a cytokine-induced acute phase subfamily that is hepatically
      produced and can become the major apolipoprotein on HDL (SAA1, SAA2); (ii) a
      peripherally produced acute phase SAA3 that is only a minor HDL apolipoprotein;
      and (iii) a constitutive subfamily (SAA4) that is a minor normal HDL
      apolipoprotein comprising more than 90% of the SAA during homeostasis. Here we
      define the structure of the Saa4 gene. Similar to other Saa family members, it
      has four exons and three introns. It is 4588 bp long from the transcription start
      site to the end of the 3'-untranslated region and is approximately 20% larger
      than other Saa genes. We have located Saa4 11 kb upstream from Saa3 and 5 kb
      downstream from Saa1, with the pseudogene approximately 1 kb from the 5' end of
      Saa4. Saa4 has the same orientation as most other Saa family members, with only
      Saa2 having an opposing orientation. These data promote our understanding of the
      evolution of the Saa family. They enhance our ability to develop the mouse as a
      transgenic and gene deletion model to advance the understanding of the function
      of these apolipoproteins.

PMID- 8661037
TI  - Identification of a testis-expressed creatine transporter gene at 16p11.2 and
      confirmation of the X-linked locus to Xq28.
AB  - Creatine and creatine phosphate act as a buffer system for the regeneration of
      ATP in tissues with fluctuating energy demands. Following reports of the cloning
      of a creatine transporter in rat, rabbit, and human, we cloned and sequenced a
      creatine transporter from a human intestinal cDNA library. PCR amplification of
      genomic DNAs from somatic cell hybrid panels localized two creatine transporter
      (CT) genes: CT1 to Xq26-q28 and CT2 to 16p11.2. Refinement of CT1 to Xq28 was
      confirmed by FISH. Identification of CT2 sequences in YACs and cosmid contigs
      that had been ordered on human chromosome 16 enabled its assignment to the
      proximal end of 16p11.2. Sequencing of the CT2 gene identified sequence
      differences between CT1 and CT2 transcripts that were utilized to determine that
      CT2 is expressed in testis only. CT2 is the most proximally identified gene on
      chromosome 16p to date. The existence of an autosomal, testis-specific form of
      the human creatine transporter gene suggests that creatine transporter activity
      is critical for normal function of spermatazoa following meiosis.

PMID- 8661038
TI  - Cloning a cDNA for carbonyl reductase (Cbr) from mouse cerebellum: murine genes
      that express cbr map to chromosomes 16 and 11.

PMID- 8661039
TI  - Assignment of the p60 subunit of chromatin assembly factor I to chromosome
      21q22.2.

PMID- 8661041
TI  - Localization of Staf50, a member of the Ring finger family, to 11p15 by
      fluorescence in situ hybridization.

PMID- 8661040
TI  - Assignment of a new TGF-beta superfamily member, human cartilage-derived
      morphogenetic protein-1, to chromosome 20q11.2.

PMID- 8661042
TI  - Assignment of the human weak inward rectifier K+ channel TWIK-1 gene to
      chromosome 1q42-q43.

PMID- 8661043
TI  - Characterization of a novel gene product (mammalian tolloid-like) with high
      sequence similarity to mammalian tolloid/bone morphogenetic protein-1.
AB  - Bone morphogenetic protein-1 (BMP-1), a metalloprotease isolated from osteogenic
      extracts of demineralized bone, is capable of cleaving the C-propeptides of
      procollagen types I, II, and III. A single mammalian gene produces alternatively
      spliced RNA transcripts for BMP-1 and for a second longer protein, designated
      mammalian tolloid (mTld) due to a domain structure identical to that of the
      Drosophila dorsal-ventral patterning gene product tolloid (Tld). Here we report
      the use of a cDNA library, prepared from BMP-1/mTld-null mouse embryos, to
      isolate cDNA clones for a novel mammalian protein with a domain structure
      identical to that of mTld. The new protein, designated mammalian tolloid-like
      (mTll), has 76% identity with mTld for amino acid residues in all domains
      downstream of, and including, the protease domain. In contrast, the N-terminal
      activation domains of the two proteins show little similarity. In situ
      hybridizations show the distribution of mTll RNA to overlap extensively that
      previously shown for the BMP-1 and mTld RNA forms. However, mTll shows additional
      strong expression in structures of the developing, neonatal, and adult brain in
      which expression of BMP-1 and mTld has not been observed. The murine mTll gene
      (Tll) is mapped to central chromosome 8, which is a different chromosomal
      location than that of the BMP-1/mTld gene. Loci for some developmental
      abnormalities map to the same general chromosomal location as Tll.

PMID- 8661044
TI  - Cloning and characterization of a putative human holocytochrome c-type synthetase
      gene (HCCS) isolated from the critical region for microphthalmia with linear skin
      defects (MLS).
AB  - Microphthalmia with linear skin defects syndrome (MLS) is an X-linked male-lethal
      disorder associated with X chromosomal rearrangements resulting in monosomy from
      Xpter to Xp22. Features include micro- phthalmia, sclerocornea, linear skin
      defects, and agenesis of the corpus callosum. Using a cross-species conservation
      strategy, an expressed sequence from the 450- to the 550-kb MLS critical region
      on Xp22 was identified by screening a human embryo cDNA library. Northern
      analysis revealed a transcript of approximately 2.6 kb in all tissues examined,
      with weaker expression of approximately 1.2- and approximately 5.2-kb
      transcripts. The strongest expression was observed in heart and skeletal muscle.
      Sequence analysis of a 3-kb cDNA contig revealed an 807-bp open reading frame
      encoding a putative 268-amino-acid protein. Comparison of the sequence with
      sequences in the databases revealed homology with holocytochrome c-type
      synthetases, which catalyze the covalent addition of a heme group onto c-type
      cytochromes in the mitochondria. The c-type cytochromes are required for proper
      functioning of the electron transport pathway. The human gene (HGMW-approved
      symbol HCCS) and the corresponding murine gene characterized in this paper are
      the first mammalian holocytochrome c-type synthetases to be described in the
      literature. Because of the lack of a neuromuscular phenotype in MLS, it is
      uncertain whether the deletion of a mitochondrial holocytochrome synthetase would
      contribute to the phenotype seen in MLS. The expression pattern of this gene and
      knowledge about the function of holocytochrome synthetases, however, suggest that
      it is a good candidate for X-linked encephalomyopathies typically associated with
      mitochondrial dysfunction.

PMID- 8661045
TI  - Molecular cloning and characterization of the human xanthine dehydrogenase gene
      (XDH).
AB  - Xanthine dehydrogenase (XDH, EC 1.1.1.204) is a rate-limiting enzyme in the
      oxidative metabolism of purines and is thought to play a key role in a variety of
      pathophysiologic processes including ischemiasolidusreperfusion injury, viral
      pneumonia, and renal failure. We herein report the isolation and characterization
      of the human XDH gene. The gene is composed of 36 exons and 35 introns and spans
      at least 60 kb. The exon sizes range from 53 to 279 bp, and the intron sizes
      range from 0.2 to over 8 kb. Using primer extension and RNase protection
      analyses, two transcriptional initiation sites were identified 59 and 82
      nucleotides upstream of the ATG start codon. One Goldberg-Hogness box (ATTTAT)
      like sequence was found 24 bp upstream from the second transcriptional initiation
      site, and two inverted CCAAT sequences were found 19 and 42 bp upstream from the
      second transcriptional initiation sites. A relative GC-enriched region was found
      between -55 and -121. Approximately 2 kb of the 5'-flanking region was sequenced,
      and a variety of putative regulatory elements were identified including
      CsolidusEBP binding sites, IL-6 and NF-kappaB sites, and potential TNF-RE, IFN
      gamma-RE, and IL-1-RE sites.

PMID- 8661046
TI  - Organization of the human gene for nucleobindin (NUC) and its chromosomal
      assignment to 19q13.2-q13.4.
AB  - Nucleobindin (Nuc) was first identified as a secreted protein of 55 kDa that
      promotes production of DNA-specific antibodies in lupus-prone MRL/lpr mice.
      Analysis of cDNA that encoded Nuc revealed that the protein is composed of a
      signal peptide, a DNA-binding site, two calcium-binding motifs (EF-hand motifs),
      and a leucine zipper. In the present study, we analyzed the organization of the
      human gene for Nuc (NUC). It consists of 13 exons that are distributed in a
      region of 32 kb. The functional motifs listed above are encoded in corresponding
      exons. NUC was expressed in all organs examined. Comparison of nucleotide
      sequences in the promoter regions between human and mouse NUC genes revealed
      several conserved sequences. Among them, two Sp1-binding sites and a CCAAT box
      are of particular interest. The promoter is of the TATA-less type, and
      transcription starts at multiple sites in both the human and the mouse genes.
      These features suggest that NUC might normally play a role as a housekeeping
      gene. NUC was located at human chromosome 19q13.2-q13.4.

PMID- 8661047
TI  - Construction of a radiation hybrid map of chromosome 9p.
AB  - A radiation hybrid panel has been constructed for chromosome 9 using the somatic
      cell hybrid GM10611 as the donor cell line fused to the hamster cell line A23.
      The hybrid GM10611 was characterized by fluorescence in situ hybridization and
      reverse painting onto spreads of normal human metaphase chromosomes; it contains
      human chromosome 9 as the only cytogenetically detectable human material. GM10611
      was irradiated with 6000 rads of X rays prior to fusion, a total of 93
      independent clones were selected, and frozen stocks and DNA were prepared from
      each clone. These clones were screened by PCR amplification with oligonucleotide
      primers for sequence-tagged sites specific for 50 single-copy loci mapping to the
      short arm of chromosome 9. The average retention frequency of these hybrids was
      approximately 23%. The markers were ordered into a framework map by analyzing
      coretention patterns, minimizing the number of obligatory chromosome breaks, and
      finally confirming the order by maximum likelihood methods. A framework map
      ordering 27 markers with odds greater than 1000:1 was constructed. A further 16
      markers that could not be uniquely placed on the map with the required support
      were positioned within a range of adjacent intervals.

PMID- 8661048
TI  - Construction of a mouse whole-genome radiation hybrid panel and application to
      MMU11.
AB  - Whole-genome radiation hybrids have been used to construct human genome maps that
      integrate different types of markers. To investigate this methodology in
      mammalian species other than humans, a panel of 164 mouse x hamster whole-genome
      radiation hybrids was constructed. This set of hybrids was used to produce a high
      resolution map of a region on MMU11 that included microsatellite markers and cDNA
      sequences. The mouse homologue of the human SRY-related gene SOX9 was mapped to
      an interval of approximately 1.1 cM flanked by the microsatellite markers
      D11Mit11 and D11Mit291. This interval includes the region containing the mouse
      Tail-short mutation, a possible homologue of the human syndrome campomelic
      dysplasia, which is caused by mutations in SOX9. Our results suggest that whole
      genome radiation hybrid technology will be a useful adjunct to mapping the
      genomes of nonhuman mammalian species.

PMID- 8661049
TI  - Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer
      disease gene.
AB  - Mutations in the gene STM2 result in autosomal dominant familial Alzheimer
      disease. To screen for mutations and to identify regulatory elements for this
      gene, the genomic DNA sequence and intron-exon structure were determined. Twelve
      exons including 10 coding exons were identified in a genomic region spanning
      23,737 bp. The first 2 exons encode the 5'-untranslated region. Expression
      analysis of STM2 indicates that two transcripts of 2.4 and 2.8 kb are found in
      skeletal muscle, pancreas, and heart. In addition, a splice variant of the 2.4-kb
      transcript was identified that is the result of the use of an alternative splice
      acceptor site located in exon 10. The use of this site results in a transcript
      lacking a single glutamate. The promotor for this gene and the alternatively
      spliced exons leading to the 2.8-kb form of the gene remain to be identified.
      Expression of STM2 was high in skeletal muscle and pancreas, with comparatively
      low levels observed in brain. This expression pattern is intriguing since in
      Alzheimer disease, pathology and degeneration are observed only in the central
      nervous system.

PMID- 8661050
TI  - The Sp4H deletion may contain a new locus essential for postimplantation
      development.
AB  - Sp4H is a semi-dominant mutation that maps to mouse chromosome 1. Heterozygous
      mice exhibit white spotting of the belly, whereas the fate of the homozygous
      embryos is unknown. We have previously shown that the entire coding region of the
      Pax3 gene is deleted in the Sp4H mutant. In this study, we have analyzed the fate
      of the Sp4H homozygous embryos. No Sp4H homozygotes were detected by Southern
      blot or PCR analysis in 82 E9-E13-day embryos. We have also documented a
      significant increase in the number of resorption sites in Sp4H heterozygous
      matings compared to control litters. Sections of the resorption sites (moles)
      suggest that postimplantation development is arrested prior to gastrulation. We
      have mapped the extent of the deletion to a maximum of 1.53 +/- 0.6 cM using
      markers flanking the Pax3 locus. Four anonymous markers, D1Mit215, D1Mit253,
      D1Mit332, and D1McG156, have been shown to be deleted in the Sp4H mutation.
      Further nondeleted markers have been used to extend the linkage map of this
      region. A total of 22 loci were analyzed in a Splotch intraspecific backcross.
      Using these data and deletion mapping data, we predict the following order of
      markers: (D1Mit46, Vil)-(D1Mit79)-(D1Mit132, D1McG153)-(D1Mit332)-(D1-McG156,
      D1Mit253, D1Mit215, Pax3)-(D1Mit134)-(D1Mit8, D1Mit9, D1Mit44, D1Ler3, D1Mit183)
      (D1Mit53, D1Mit82, D1Mit182)-(Bcl2). As the deletion is large enough to include
      other genes, and it seems that deletion of Pax3 is not likely to account for the
      early death of the embryos, we suggest that another developmentally important
      gene may be deleted in the Sp4H mouse mutant and that this may be responsible for
      the early death of the homozygous mutant embryos.

PMID- 8661051
TI  - Construction and characterization of a human bacterial artificial chromosome
      library.
AB  - We have constructed an arrayed human genomic BAC library with approximately 4x
      coverage that is represented by 96,000 BAC clones with average insert size of
      nearly 140 kb. A new BAC vector that allows color-based positive screening to
      identify transformants with inserts has increased BAC cloning efficiency. The
      library was gridded onto hybridization filters at high density for efficient
      identification of BAC clones by colony hybridization. The library was also
      formulated into characteristic DNA pools to allow for PCR screening of the
      library for STS content. We have characterized the library mainly by screening
      with more than 300 different landmarks that include cDNA, STSs, and cosmid
      clones. We describe methods for using BAC clones and discuss the implications for
      genome characterization, mapping, and sequencing.

PMID- 8661052
TI  - Localization and physical mapping of genes encoding the A+U-rich element RNA
      binding protein AUF1 to human chromosomes 4 and X.
AB  - Messenger RNAs encoding many oncoproteins and cytokines are relatively unstable.
      Their instability, which ensures appropriate levels and timing of expression, is
      controlled in part by proteins that bind to A+U-rich instability elements (AREs)
      present in the 3'-untranslated regions of the mRNAs. cDNAs encoding the AUF1
      family of ARE-binding proteins were cloned from human and murine cDNA libraries.
      In the present study monochromosomal somatic cell hybrids were used to localize
      two AUF1 loci to human chromosomes 4 and X. In situ hybridization analyses using
      P1 clones as probes identified the 4q21.1-q21.2 and Xq12 regions as the locations
      of the AUF1 genes.

PMID- 8661053
TI  - Assembly of a 1-Mb restriction-mapped cosmid contig spanning the candidate region
      for Finnish congenital nephrosis (NPHS1) in 19q13.1.
AB  - We describe the assembly of a 1-Mb cosmid contig and restriction map spanning the
      candidate region for Finnish congenital nephrosis (NPHS1) in 19q13.1. The map was
      constructed from 16 smaller contigs assembled by fingerprinting, a BAC and a PAC
      clone, and 42 previously unmapped cosmids. In most cases, single-step cosmid
      walks were sufficient to join two previously assembled contigs, and all but one
      gap was filled from this cosmid contig library. The remaining gap of about 19 kb
      was spanned with a single BAC and a single PAC clone. EcoRI mapping of a dense
      set of overlapping clones validated the assembly of the map and indicated a
      length of 1040 kb for the contig. This high-resolution clone map provides an
      ideal resource for gene identification through cDNA selection, exon trapping, and
      DNA sequencing.

PMID- 8661054
TI  - Plasmacytoma-associated neuronal glycoprotein, Pang, maps to mouse chromosome 6
      and human chromosome 3.
AB  - A new member of the immunoglobulin/fibronectin superfamily of adhesion molecules,
      Pang (plasmacytoma-associated neuronal glycoprotein), was recently isolated from
      a plasmacytoma. In previous studies, Pang was found to be normally expressed in
      the brain and ectopically activated by intracisternal A-type particle long
      terminal repeats in plasmacytomas. In this study, Pang was initially mapped to
      mouse Chr 6 by somatic cell hybrid analysis and further positioned on the
      chromosome between Wnt7a and Pcp1. Southern blot analysis of human-rodent somatic
      cell hybrids together with predictions from the mouse map location indicate that
      human PANG is located at 3p26.

PMID- 8661055
TI  - The human PECAM1 gene maps to 17q23.
AB  - We have determined the chromosomal and regional location of the gene encoding
      PECAM-1 (termed PECAM1 by GBD nomenclature) using a polymerase chain reaction
      (PCR)-based analysis of somatic cell hybrids. Analysis of a somatic cell hybrid
      chromosome panel established that the PECAM1 gene is on chromosome 17.
      Interestingly, several adhesion molecules expressed on platelets and endothelium
      also localize to chromosome 17: the GP1BA locus (glycoprotein (GP) Ibalpha) has
      been provisionally mapped to the region 17p12-pter, the ITGA2B (GPIIb) and the
      ITGB3 (GPIIIa) loci have been confirmed to the region 17q21.32; and the ICAM2
      locus has been provisionally mapped to the region 17q23-q25. To determine if the
      PECAM1 locus colocalizes with any of the loci for these adhesion molecules, PCR
      based analysis of a regional mapping panel for human chromosome 17 was conducted.
      We found that the PECAM1 locus is on the long arm of chromosome 17, in the region
      q23-qter. To confirm this observation and obtain a more precise localization of
      the PECAM1 locus, fluorescence in situ hybridization was conducted. Together our
      data allowed assignment of the PECAM1 locus to the region 17q23.

PMID- 8661056
TI  - The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy
      gene.
AB  - The mouse homologue of the polycystic kidney disease 1 gene (PKD1) was mapped to
      chromosome 17 using somatic cell hybrids, B x D recombinant inbred strains, and
      FISH. The gene is located within a previously defined conserved synteny group
      that includes the mouse homologue of tuberous sclerosis 2 (TSC2) and is linked to
      the alpha globin pseudogene Hba-ps4. Although the human genome contains multiple
      copies of genes related to PKD1, there is no evidence for more than one copy in
      the mouse genome. Like their human counterparts, the mouse Tsc2 and Pkd1 genes
      are arranged in a tail-to-tail orientation with a distance of only 63 bp between
      the polyadenylation signals of the two genes.

PMID- 8661058
TI  - The chromosomal mapping of four genes encoding winged helix proteins expressed
      early in mouse development.
AB  - Members of the winged helix family of transcription factors are required for the
      normal embryonic development of the mouse. Using the interspecific backcross
      panel from The Jackson Laboratory, we have determined the chromosomal locations
      of four genes that encode winged helix containing proteins. Mf1 was assigned to
      mouse Chromosome 8, Mf2 to Chromosome 4, Mf3 to Chromosome 9, and Mf4 to
      Chromosome 13. Since Mf3 is located in a region of Chromosome 9 containing many
      well-characterized mouse mutations such as short ear (se), ashen (ash), and
      dilute (d), we have analyzed deletion mutants to determine the location of Mf3
      more precisely.

PMID- 8661057
TI  - A YAC contig of the human CC chemokine genes clustered on chromosome 17q11.2.
AB  - CC chemokines are cytokines that attract and activate leukocytes. The human genes
      for the CC chemokines are clustered on chromosome 17. To elucidate the genomic
      organization of the CC chemokine genes, we constructed a YAC contig comprising 34
      clones. The contig was shown to contain all 10 CC chemokine genes reported so
      far, except for one gene whose nucleotide sequence is not available. The contig
      also contains 4 CC chemokine-like genes, which were deposited in GenBank as ESTs
      and are here referred to as NCC-1, NCC-2, NCC-3, and NCC-4. Within the contig,
      the CC chemokine genes were localized in two regions. In addition, the CC
      chemokine genes were more precisely mapped on chromosome 17q11.2 using a somatic
      cell hybrid cell DNA panel containing various portions of human chromosome 17.
      Interestingly, a reciprocal translocation t(Y;17) breakpoint, contained in the
      hybrid cell line Y1741, lay between the two chromosome 17 chemokine gene regions
      covered by our YAC contig. From these results, the order and the orientation of
      CC chemokine genes on chromosome 17 were determined as follows: centromere
      neurofibromatosis 1-(MCP-3, MCP-1, NCC-1, I-309)-Y1741 breakpoint-RANTES
      (LD78gamma, AT744.2, LD78beta)-(NCC-3, NCC-2, AT744.1, LD78alpha)-NCC-4-retinoic
      acid receptor alpha- telomere.

PMID- 8661059
TI  - Chromosomal assignment and imprinting tests for the mouse delta subunit of the
      cytosolic chaperonin containing TCP-1 (Cct4) gene to proximal chromosome 11.
AB  - The CCT (chaperonin containing TCP-1) complex functions as a molecular chaperone
      in the eukaryotic cytosol. This complex consists of several species of related
      polypeptides. The chromosomal localization of the mouse Cct4 gene encoding the
      delta subunit of CCT was assigned in this study to proximal chromosome 11 by
      genetic mapping. Restriction mapping analysis using YAC and pulse-field gel
      electrophoresis showed that Cct4 is located within a region about 300 kb from the
      imprinted gene U2af1-rs1. Expression of Cct4 was biallelic, and therefore Cct4 is
      not imprinted in neonatal mice. The localization of the human homologue of Cct4
      on chromosome 2 corresponds well with the fact that homologues of other genes in
      the proximal region of mouse chromosome 11 also map to the region of conserved
      synteny in human chromosome 2.

PMID- 8661060
TI  - Loss of heterozygosity of chromosome 10p in human gliomas.
AB  - Molecular loss of heterozygosity studies on human gliomas have shown several
      regions on chromosome 10 frequently deleted in higher grade tumors, suggesting
      that chromosome 10 may contain several tumor suppressor genes. We assessed loss
      of heterozygosity with microsatellite markers in 20 gliomas, consisting of
      various grades and containing two chromosome 10 copies. The locus that exhibited
      the most loss (69%) was the region bordered by D10S249 and D10S558 and inclusive
      of D10S594, with a linkage distance of 3 cM. This region was noted to be deleted
      in various grades of tumor, including low- and high-grade tumors. These results
      suggest that chromosome region 10p15 is involved in human gliomas of diverse
      grades and that this region may harbor genes important in the development of and
      progression to the malignant phenotype.

PMID- 8661061
TI  - Chromosomal localization of murine and human oligodendrocyte-specific protein
      genes.
AB  - Oligodendrocyte-specific protein (OSP) is a recently described protein present
      only in myelin of the central nervous system. Several inherited disorders of
      myelin are caused by mutations in myelin genes but the etiology of many remain
      unknown. We mapped the location of the mouse OSP gene to the proximal region of
      chromosome 3 using two sets of multilocus crosses and to human chromosome 3 using
      somatic cell hybrids. Fine mapping with fluorescence in situ hybridization placed
      the OSP gene at human chromosome 3q26.2-q26.3. To date, there are no known
      inherited neurological disorders that localize to these regions.

PMID- 8661062
TI  - Scn2b, a voltage-gated sodium channel beta2 gene on mouse chromosome 9.

PMID- 8661063
TI  - Phospholipid transfer protein maps to distal mouse chromosome 2.

PMID- 8661064
TI  - Assignment of the REST gene to 4q12 by fluorescence in situ hybridization.

PMID- 8661065
TI  - Assignment of the human amiloride-sensitive Na+ channel delta isoform to
      chromosome 1p36.3-p36.2.

PMID- 8661066
TI  - Assignment of human ADP ribosylation factor (ARF) genes ARF1 and ARF3 to
      chromosomes 1q42 and 12q13, respectively.

PMID- 8661068
TI  - Long-range physical map and deletion characterization of the 1100-kb NotI
      restriction fragment harboring the APC gene.

PMID- 8661067
TI  - Localization of the guanylyl cyclase C gene to mouse chromosome 6 and human
      chromosome 12p12.

PMID- 8661069
TI  - Chromosomal localization of cdx2, a murine homologue of the Drosophila gene
      caudal, to mouse chromosome 5.

PMID- 8661070
TI  - Ethical issues in international collaborative research on the human genome: the
      HGP and the HGDP.

PMID- 8661097
TI  - The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.
AB  - Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized
      by disproportionate dwarfism, polydactyly, and congenital heart disease. This
      rare disorder is found with increased frequency among the Old Order Amish
      community in Lancaster County, Pennsylvania. We have used linkage analysis to
      localize the gene responsible for the EVC phenotype in nine interrelated Amish
      pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now
      report the linkage for the Ellis-van Creveld syndrome gene to markers on the
      distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for
      marker HOX7, in a region proximal to the FGFR3 gene responsible for the
      achondroplasia phenotype.

PMID- 8661098
TI  - The human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of
      chromosome 8 involved in branchio-oto-renal syndrome.
AB  - To identify candidate genes for Branchio-oto-renal (BOR) syndrome, we have made
      use of a set of cosmids that map to 8q13.3, which has previously been shown to be
      involved in this syndrome. These cosmids were used as genomic clones in the
      attempts to isolate corresponding cDNAs using a modified hybrid selection
      technique. cDNAs from the region were identified and used to search for sequence
      similarity in human or other species. One cDNA clone was found to have 89%
      sequence similarity to the bovine B22 subunit of NADH-ubiquinone oxidoreductase,
      a mitochondrial protein in the respiratory electron transport chain. Given the
      history of other mitochondrial mutations being involved in hearing loss
      syndromes, this gene should be considered a strong candidate for involvement in
      BOR.

PMID- 8661099
TI  - Isolation and characterization of the human cardiac troponin I gene (TNNI3).
AB  - Troponin I (TnI) is a constituent protein of the troponin complex located on the
      thin filament of striated muscle that provides a calcium-sensitive switch for
      striated muscle contraction. Unlike other contractile proteins, the cardiac
      isoform of troponin I (TnIc) is expressed only in cardiac muscle and therefore
      offers a model for cardiac-specific expression. It is also subject to
      developmental regulation with increased expression occurring at the time of
      birth. Here we describe the isolation and characterization of the human TnIc gene
      (HGMW-approved symbol TNNI3) and its promoter. The gene comprises eight exons
      contained within 6.2 kb of genomic DNA. The proximal promoter and 1.1-kb 5'
      flanking region were sequenced, and several putative cis-acting elements that are
      conserved between the human and the mouse TnIc genes were identified. In
      addition, multiple copies of a 37-bp chromosome 19-specific mini-satellite
      sequence were identified within this region. Following transfection, 2300 bp of
      5' sequence is active in both cardiac myocytes and skeletal muscle cells but is
      inactive in fibroblasts, indicating that it can drive expression but is
      insufficient to confer cardiac specificity.

PMID- 8661101
TI  - A novel human CCAAT/enhancer binding protein gene, C/EBPepsilon, is expressed in
      cells of lymphoid and myeloid lineages and is localized on chromosome 14q11.2
      close to the T-cell receptor alpha/delta locus.
AB  - Members of the CsolidusEBP family of transcriptional factors have been implicated
      in the regulation of genes in a variety of tissues. We report here the isolation
      and characterization of the human C/EBPepsilon gene (CEBPE). By using low
      stringency hybridization conditions and probes derived from the C/EBPalpha and
      C/EBPdelta genes, we have isolated overlapping genomic clones that cover almost
      25 kb of the C/EBPepsilon gene locus and corresponding cDNA clones. DNA sequence
      analysis reveals that the gene encodes a protein highly homologous to rat CRP1.
      The gene was assigned to chromosome 14q11.2 by fluorescence in situ hybridization
      and was physically linked to the genetic marker D14S990. Based on linkage data
      derived from this marker, we positioned the CEBPE gene between the T-cell
      receptor alpha/delta locus and a cluster of four serine proteases expressed
      exclusively in hematopoietic cells. Expression of C/EBPepsilon was detected in
      Jurkat T-cell and in HL 60 promyelocytic cell lines. From a variety of normal
      human tissues studied, expression of mRNA was monitored only in peripheral blood
      mononuclear cells, tissues involved in the immune system, and ovaries. These data
      demonstrate that the C/EBPepsilon gene shows a restricted pattern of expression,
      has an intriguing chromosomal location, and suggest a possible role for the
      regulation of certain genes in cells of myeloid and lymphoid lineages.

PMID- 8661100
TI  - Genomic structure and chromosomal localization of the mouse CDEI-binding protein
      CDEBP (APLP2) gene and promoter sequences.
AB  - The genomic structure of the mouse gene encoding the CDEBP protein has been
      established. The protein was initially identified on the basis of its ability to
      bind the CDEI motif (GTCACATG). The same locus has been independently described
      under the name APLP2, on the basis of sequence similarities with the Amyloid
      Precursor Protein (APP). The exon-intron distribution of Cdebp appears strikingly
      similar to that of the App gene in the regions encoding the conserved domains,
      with a divergent structure in the other parts. The transcription start site has
      been localized, and sequences with promoter activity have been identified
      immediately upstream of it by their ability to direct the expression of a
      reporter luciferase gene in transfected cells. This region is devoid of either
      TATA or CAAT boxes. The gene has been mapped to mouse chromosome 9 by in situ
      hybridization on metaphase chromosomes.

PMID- 8661103
TI  - Physical mapping of chromosome 8p22 markers and their homozygous deletion in a
      metastatic prostate cancer.
AB  - Numerous studies have implicated the short arm of chromosome 8 as the site of one
      or more tumor suppressor genes inactivated in carcinogenesis of the prostate,
      colon, lung, and liver. Previously, we identified a homozygous deletion on
      chromosome 8p22 in a metastatic prostate cancer. To map this homozygous deletion
      physically, long-range restriction mapping was performed using yeast artificial
      chromosomes (YACs) spanning approximately 2 Mb of chromosome band 8p22. Subcloned
      genomic DNA and cDNA probes isolated by hybrid capture from these YACs were
      mapped in relation to one another, reinforcing map integrity. Mapped single-copy
      probes from the region were then applied to DNA isolated from a metastatic
      prostate cancer containing a chromosome 8p22 homozygous deletion and indicated
      that its deletion spans 730-970 kb. Candidate genes PRLTS (PDGF-receptor beta
      like tumor suppressor) and CTSB (cathepsin B) are located outside the region of
      homozygous deletion. Genethon marker D8S549 is located approximately at the
      center of this region of homozygous deletion. Two new microsatellite
      polymorphisms, D8S1991 and D8S1992, also located within the region of homozygous
      deletion on chromosome 8p22, are described. Physical mapping places cosmid CI8
      2644 telomeric to MSR (macrophage scavenger receptor), the reverse of a
      previously published map, altering the interpretation of published deletion
      studies. This work should prove helpful in the identification of candidate tumor
      suppressor genes in this region.

PMID- 8661102
TI  - Identification and chromosomal localization of Atm, the mouse homolog of the
      ataxia-telangiectasia gene.
AB  - Atm, the mouse homolog of the human ATM gene defective in ataxia-telangiectasia
      (A-T), has been identified. The entire coding sequence of the Atm transcript was
      cloned and found to contain an open reading frame encoding a protein of 3066
      amino acids with 84% overall identity and 91% similarity to the human ATM
      protein. Variable levels of expression of Atm were observed in different tissues.
      Fluorescence in situ hybridization and linkage analysis located the Atm gene on
      mouse chromosome 9, band 9C, in a region homologous to the ATM region on human
      chromosome 11q22-q23.

PMID- 8661105
TI  - Comparative mapping identifies the fusion point of an ancient mammalian X
      autosomal rearrangement.
AB  - Previous comparisons of gene location in the three major groups of mammals
      (eutherians, marsupials, and monotremes) have suggested that the long arm of the
      human X represents the ancestral mammalian X chromosome, whereas the short arm
      represents an autosomal region(s) recently added to the eutherian X chromosome.
      To identify the fusion point of this ancient X-autosome rearrangement, we have
      mapped four genes, three of which map near the centromere of the human Xp, in
      marsupials and in a monotreme. We found that ARAF1, ALAS2, and GATA1 are located
      on the X chromosome in marsupials, and ALAS2 and GATA1 are also located on the X
      in the platypus. This implies that the proximal short arm of the human X
      chromosome, including the centromere, was part of the ancestral mammalian X
      chromosome. The fusion point between the conserved region and the recently added
      regions therefore maps to human Xp11.23, although gene order on the human X
      indicates that there has been some rearrangement of this region.

PMID- 8661104
TI  - Structure and methylation-associated silencing of a gene within a homozygously
      deleted region of human chromosome band 8p22.
AB  - The structure and expression pattern of a human gene located within a
      homozygously deleted region of a metastatic prostate cancer have been
      characterized. Multiple cDNA fragments of this gene were isolated by hybrid
      capture with yeast artificial chromosome clones covering the deletion region.
      Eleven coding exons spanned 205-220 kb of the 730- to 970-kb deletion. The
      predicted amino acid sequence was 43% identical to that of an anonymous
      Caenorhabditis elegans gene and 20% identical to an accessory or regulatory
      subunit of the oligosaccharyltransferase enzyme complex in Saccharomyces
      cerevisiae. Hydrophobicity profiles of all three gene products were similar and
      showed four putative membrane-spanning domains in the molecules' C-terminal
      halves, suggesting a general conservation of function. The gene was expressed as
      an approximately 1.5-kb mRNA in most nonlymphoid human cells/tissues including
      prostate, lung, liver, and colon. Expression was detected in many epithelial
      tumor cell lines, but was undetectable by Northern blot or RT-PCR in 14 of 15
      colorectal, 1 of 8 lung, and 1 of 4 liver cancer cell lines. Lack of expression
      in tumor cell lines was highly correlated with hypermethylation of a CpG island
      located at the gene's 5' end. These findings form a basis for further work on
      this candidate tumor suppressor gene.

PMID- 8661106
TI  - Efficient construction of a physical map by fiber-FISH of the CLN5 region:
      refined assignment and long-range contig covering the critical region on 13q22.
AB  - The variant form of late infantile neuronal ceroid lipofuscinosis (vLINCL, locus
      definition CLN5) represents a progressive brain disease with autosomal recessive
      inheritance. We have previously assigned the CLN5 locus to chromosome 13q21.1-q32
      between markers D13S160 and D13S162 by linkage analysis in Finnish families. The
      information on ancient recombination events obtained from linkage disequilibrium
      provided an efficient tool for further refining the assignment of the CLN5 locus.
      Isolation of two novel (CA)n markers, COLAC1 and AC224, resulted in a dramatic
      restriction of the critical DNA region. We utilized the Fiber-FISH technique to
      orient and order the large DNA clones isolated by STSs and were able to eliminate
      almost totally the restriction digestion and PFGE step in the construction of the
      long-range DNA contig. Both linkage disequilibrium data and Fiber-FISH analyses
      assigned the CLN5 locus to a well-defined 200-kb region. Here we report a
      complete physical map of about 350 kb covering the critical chromosomal region of
      CLN5, which will facilitate the final isolation of the CLN5 gene.

PMID- 8661107
TI  - The construction of a yeast artificial chromosome (YAC) contig in the vicinity of
      the Usher syndrome type IIa (USH2A) gene in 1q41.
AB  - The gene for Usher syndrome type II (USH2A), an autosomal recessive syndromic
      deafness, has been mapped to a region of 1q41 flanked proximally by D1S217 and
      distally by D1S439. Using sequence-tagged sites (STSs) within the region, a total
      of 21 yeast artificial chromosome (YAC) clones were isolated and ordered into a
      single contig that spans approximately 11.0 Mb. The order of microsatellite and
      STS markers in this region was established as D1S505-D1S425-DXS217-D1S556-D1S237
      D1S4 74-EB1-EB2-KB6-AFM144XF2-KB1-K B4-D1S229-D1S490-D1S227-TGFbeta2-D1S439.
      Analysis of newly positioned polymorphic markers in recombinant individuals in
      two Usher syndrome type IIa families has enabled us to identify DXS474 and
      AFM144XF2 as two flanking markers for the Usher type IIa locus. The physical
      distance between the two markers is 1.0 Mb. This region is covered by eight YACs
      from the CEPH library: 945f7, 867g9, 762a6, 919h3, 794b8, 785h4, 848b9, and
      841g2. A long-range physical map of the Usher type IIa critical region, using
      MluI, BssHII, NotI, EagI, and SacII, has been developed.

PMID- 8661108
TI  - A 350-kb cosmid contig in 3p14.2 that crosses the t(3;8) hereditary renal cell
      carcinoma translocation breakpoint and 17 aphidicolin-induced FRA3B breakpoints.
AB  - The constitutive fragile site at human chromosomal band 3p14.2, FRA3B, has been
      described as the most active common fragile site in the human genome. FRA3B is
      cytologically indistinguishable from the chromosome 3 breakpoint observed in the
      hereditary renal cell carcinoma (hRCC) translocation t(3;8) (p14.2;q24.13).
      Previous work demonstrated that a 1330-kb YAC clone, YC850A6, spans both the
      t(3;8) translocation and FRA3B and also encompasses FRA3B-associated breakpoints
      induced in hamster-human hybrids. This YAC was used to construct a multi-hit
      cosmid library. Screening of this library resulted in a 350-kb cosmid contig that
      extends distally from the t(3;8) translocation breakpoint. Seventeen aphidicolin
      induced 3p14. 2 breakpoints derived from hamster-human hybrids were mapped within
      this cosmid contig. These breakpoints were found to localize as two distinct
      clusters, separated by 200 kb, which lie on either side of a region of frequent
      breakage within FRA3B as defined by FISH analysis using cosmids from the contigs.
      The most proximal of the breakpoint clusters lies approximately 100 kb distal to
      the hRCC t(3;8) breakpoint. The distribution of these breakpoints, together with
      the region of frequent chromosomal breakage mapped by FISH analysis, further
      confirms the position of FRA3B and helps to define the extent over which its
      fragility is exerted. These data indicate that FRA3B comprises several hundred
      kilobases of DNA sequence within 3p14.2. The 350-kb contig and the cosmid library
      constructed from YAC YC850A6 will be essential for further characterization of
      the region surrounding FRA3B and in experiments to determine the molecular basis
      of the fragility of FRA3B.

PMID- 8661109
TI  - Physical mapping and genomic structure of the human TNFR2 gene.
AB  - The tumor necrosis factor receptor 2 (TNFR2) gene localizes to 1p36. 2, a genomic
      region characteristically deleted in neuroblastomas and other malignancies. In
      addition, TNFR2 is the principal mediator of the effects of TNF on cellular
      immunity, and it may cooperate with TNFR1 in the killing of nonlymphoid cells.
      Therefore, we undertook an analysis of the genomic structure and precise physical
      mapping of this gene. The TNFR2 gene is contained on 10 exons that span 26 kb.
      Most of the functional domains of TNFR2 are encoded by separate exons, and each
      of the repeats of the extracellular cysteine-rich domain is interrupted by an
      intron. The genomic structure reveals a close relationship to TNFR1, another
      member of the TNFR superfamily. Based on electrophoretic analysis of yeast
      artificial chromosomes, TNFR2 maps within 400 kb of the genetic marker D1S434. In
      addition, we have identified a new polymorphic dinucleotide repeat within intron
      4 of TNFR2. The genetic sequence information and exon-intron boundaries we have
      determined will facilitate mutational analysis of this gene to determine its
      potential role in neuroblastoma, as well as in other cancers with characteristic
      deletions or rearrangements of 1p36.

PMID- 8661110
TI  - Paralogy mapping: identification of a region in the human MHC triplicated onto
      human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and
      NOTCH loci.
AB  - The human genome contains a group of gene families whose members map within the
      same regions of chromosomes 1, 6, and 9. The number of gene families involved and
      their pronounced clustering to the same areas of the genome indicate that their
      mapping relationship is nonrandom. By combining mapping data and sequence
      information for the gene families, we have determined that these sequences are
      part of a large region that spans several megabases. This region is present in
      three copies: on the long arm of human chromosome 1, the short arm of chromosome
      6, and the long arm of chromosome 9. We have characterized the phylogenesis of
      two of the gene families involved and propose an evolutionary route for the
      creation of the three regions. Our analysis led us to predict and demonstrate the
      presence of two loci, a PBX locus on chromosome 6 and a NOTCH locus on chromosome
      1. The discovery of this triplicated region increases our understanding of the
      evolution of the human genome and may have considerable practical implications
      for gene mapping prediction and novel approaches to isolating new gene family
      members and uncloned disease loci.

PMID- 8661111
TI  - Direct cloning of DNA sequences from the common fragile site region at chromosome
      band 3p14.2.
AB  - Despite several lines of evidence suggesting that common chromosomal fragile
      sites are biologically important as hot spots for recombination, their structure
      remains unknown. We showed previously that the plasmid pSV2neo preferentially
      integrates into bands containing fragile sites in cells transfected under
      conditions of fragile site induction. Here we report the isolation and
      characterization of the DNA sequences from two such independent integrations into
      3p14.2, a common fragile site (FRA3B). These FRA3B region sequences were shown to
      lie within a 1330-kb YAC, 850A6, approximately 350 kb telomeric of the breakpoint
      of t(3;8), a constitutional rearrangement. The two integration sites are 10 kb
      apart, but each integration is associated with a deletion. We have constructed a
      partial genomic contig of the integration sites and deleted regions spanning
      approximately 85 kb. Analysis of the DNA sequences immediately surrounding the
      plasmid integrations revealed no known coding sequences or repeat structures
      resembling the (CGG)n motif characteristic of the rare fragile sites. In
      addition, by Southern blotting analysis, none of the phage clones isolated from
      the FRA3B region were found to contain CGG repeats. Fluorescence in situ
      hybridization analysis of genomic clones from this contig to metaphase cells
      induced to express breaks demonstrated hybridization adjoining the chromosome
      breaks, and occasionally the hybridization signal spanned the break. The results
      imply that breakage occurs at variable positions within a large region (at least
      on the order of 85 kb). Together, these data suggest that the structure of FRA3B
      differs from that of rare fragile sites.

PMID- 8661112
TI  - Physical mapping of the bloom syndrome region by the identification of YAC and P1
      clones from human chromosome 15 band q26.1.
AB  - The gene for Bloom syndrome (BLM) has been mapped to human chromosome 15 band
      q26.1 by homozygosity mapping. Further refinement of the location of BLM has
      relied upon linkage-disequilibrium mapping and somatic intragenic recombination.
      In combination with these mapping approaches and to identify novel DNA markers
      and probes for the BLM candidate region, a contiguous representation of the 2-Mb
      region that contains the BLM gene was generated and is presented here. YAC and P1
      clones from the region have been identified and ordered by using previously
      available genetic markers in the region along with newly developed sequence
      tagged sites from radiation-reduced hybrids, polymorphic dinucleotide repeat
      loci, and end sequences of YACs and P1s. A long-range restriction map of the 2-Mb
      region that allowed estimation of the distance between polymorphic microsatellite
      loci is also reported. This map and the DNA markers derived from it were
      instrumental in the recent identification of the BLM gene.

PMID- 8661113
TI  - Genomic structure and chromosomal assignment of the mouse Ku70 gene.
AB  - DNA-dependent protein kinase (DNA-PK) consists of three polypeptide subunits:
      Ku70, Ku80, and the DNA-PK catalytic subunit (DNA-PKcs). Mammalian mutants
      deficient in either Ku80 or DNA-PKcs function have been shown to be lacking in
      DNA double-strand break repair and V(D)J recombination, respectively. The precise
      role of the Ku70 gene in this process has not yet been determined, in part
      because no cell lines, animals, or human diseases involved with deficiencies in
      this gene have yet been identified. Both the human and the mouse Ku70 cDNAs have
      been cloned, and the human gene has been mapped to chromosome 22q13. The original
      mouse cDNA clones, however, lacked a complete 5'-region, and none of the
      mammalian Ku70 genomic sequences have been characterized. This report contains an
      analysis of the 5'-region of the mouse cDNA sequence, a characterization of the
      mouse Ku70 genomic structure, and fluorescence in situ hybridization data that
      map the mouse gene to chromosome 15. The deduced amino acid sequence of the mouse
      gene consists of 608 amino acids compared to 609 for the human gene. The genomic
      sequence is 24 kb and consists of 13 exons, including an untranslated first exon.
      Sequences from the upstream region of exon 1 revealed four consensus GC box
      sequences and a strong transcription initiation site at a reasonable location.
      The assignment of the mouse Ku70 gene to chromosome 15 is consistent with the
      syntenic relationship of this gene in human (chromosome 22q13) and mouse and adds
      to the comparative mapping data for the genes involved in the SCID phenotype.

PMID- 8661115
TI  - Characterization of msim, a murine homologue of the Drosophila sim transcription
      factor.
AB  - Mutations in the Drosophila single-minded (sim) gene result in loss of precursor
      cells that give rise to midline cells of the embryonic central nervous system.
      During the course of an exon-trapping strategy aimed at identifying transcripts
      that contribute to the etiology and pathophysiology of Down syndrome, we
      identified a human exon from the Down syndrome critical region showing
      significant homology to the Drosophila sim gene. Using a cross-hybridization
      approach, we have isolated a murine homolog of the Drosophila sim gene, which we
      designated msim. Nucleotide and predicted amino acid sequence analyses of msim
      cDNA clones indicate that this gene encodes a member of the basic-helix-loop
      helix class of transcription factors. The murine and Drosophila proteins share
      88% residues within the basic-helix-loop-helix domain, with an overall homology
      of 92%. In addition, the N-terminal domain of MSIM contains two PAS dimerization
      motifs also featured in the Drosophila sim gene product, as well as a small
      number of other transcription factors. Northern blot analysis of adult murine
      tissues revealed that the msim gene produces a single mRNA species of
      approximately 4 kb expressed in a small number of tissues, with the highest
      levels in the kidneys and lower levels present in skeletal muscle, lung, testis,
      brain, and heart. In situ hybridization experiments demonstrate that msim is also
      expressed in early fetal development in the central nervous system and in
      cartilage primordia. The characteristics of the msim gene are consistent with its
      putative function as a transcriptional regulator.

PMID- 8661116
TI  - Characterization of the mouse cyclin D3 gene: exon/intron organization and
      promoter activity.
AB  - The three D-type cyclins have been shown to be differentially expressed in a
      number of cell types, suggesting that they play distinct roles in cell cycle
      regulation in particular cell lineages. We have determined the complete
      nucleotide sequence (-1681 to + 6582) of the mouse cyclin D3 gene, which encodes
      a G1 phase cyclin. The gene consists of five exons and four introns, varying in
      length from 422 to 2472 bp. Primer extension analysis revealed one major
      transcription initiation site at the position 107 bp 5' upstream of the
      translation start. The promoter region lacks both canonical "TATA" and "CAAT"
      boxes. It contains, however, multiple transcription factor recognition sites,
      including multiple "GC-rich" sequences to which Sp1 factor binds and sequences
      recognized by GATA, NF-kappaB, ATF, E2F, and TRE/AP1 transcription factors, E box
      binding myogenic factors, and the IL-6 induced-transcription factor, APRF.
      Promoter activity of the 1681-bp fragment upstream of the transcription
      initiation site was confirmed by linking it to a reporter gene and subjecting it
      to transient expression experiments in various cell types. Promoter activity was
      high in cell lines that expressed high levels of endogenous D3 mRNA, as indicated
      by Northern blot analyses, and was significantly reduced when the promoter was
      truncated to -122 bp. The characterization of the mouse cyclin D3 gene and
      insight into its promoter region will allow further studies defining the
      molecular events regulating the expression of this cyclin in proliferating and
      quiescent cells.

PMID- 8661114
TI  - The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic
      expression indicate a candidate gene for Down syndrome.
AB  - We have recently isolated a human homolog (hSIM) of the Drosophila single-minded
      (sim) gene from the Down syndrome critical region of chromosome 21 using the exon
      trapping method. The Drosophila sim gene encodes a transcription factor that
      regulates the development of the central nervous system midline cell lineage. To
      elucidate the structure of the mammalian SIM protein, we have isolated cDNA
      clones from a mouse embryo cDNA library. The cDNA clones encode a polypeptide of
      657 amino acids with a bHLH (basic-helix-loop-helix) domain, characteristic of a
      large family of transcription factors, and a PAS (Per-Arnt-Sim) domain in the
      amino-terminal half region. Both of these domains have striking sequence homology
      with human SIM and Drosophila SIM proteins. In contrast, the carboxy-terminal
      half of the mouse SIM protein consists of a proline-rich region with no sequence
      homology to the Drosophila SIM protein. A similar proline-rich domain is known
      for the activator domain of a number of transcription factors. Whole-mount embryo
      in situ hybridization experiments revealed that the SIM mRNA is expressed
      prominently in the diencephalon of mouse embryos at 8-9.5 days postcoitum. The
      structural characteristics of the mouse SIM protein and its expression in the
      diencephalon during embryogenesis strongly suggest that the newly isolated
      mammalian SIM homolog may play a critical role in the development of the
      mammalian central nervous system. We propose that the human SIM gene may be one
      of the pathogenic genes of Down syndrome.

PMID- 8661117
TI  - A cluster of transfer RNA genes (TRM1, TRR3, and TRAN) on the short arm of human
      chromosome 6.
AB  - We have isolated two lambda clones that contain three transfer RNA (tRNA) genes
      (TRM1, TRR3, and TRAN). Both clones map to the same region (6p21.2-p22.3) of the
      short arm of chromosome 6. One clone contains a methionine tRNA gene and also an
      arginine tRNA gene, the first such human gene to be described. The other clone
      contains an alanine tRNA gene, again the first such human gene to be reported,
      and it differs from the species of human alanine tRNA transcripts sequenced to
      date. These clones have been used to investigate the structure of this tRNA gene
      cluster. The results of both conventional and pulsed-field gel analysis suggest
      that the alanine tRNA gene is a member of a low-copy repeat series at this
      location. The other clone is not located within this domain and appears to be a
      unique segment of DNA. Nevertheless, we also show that at least half of the
      methionine tRNA genes are located on the short arm of this chromosome, and if
      these are also located at 6p21.2-p22.3, this would constitute another major tRNA
      locus in human.

PMID- 8661118
TI  - Characterization and genomic mapping of genes and pseudogenes of a new human
      protein tyrosine phosphatase.
AB  - Previously described protein tyrosine phosphatases (PTPs) are classified into
      three types according to their sequence homology and structural features. Here we
      describe the characterization of genes and pseudogenes of a member of a fourth
      type of PTP, designated protein tyrosine phosphatase 4A (PTP4A). The 167-amino
      acid human PTP4A bears the signature active site of all PTPs, but does not show
      any other sequence homology to any of the previously described PTPs. Two cDNAs
      encoding PTP4A that differed in their noncoding regions were isolated. Another
      cDNA that has a high level of sequence identity with these two cDNAs and a
      deletion in the coding region was also isolated. Northern analysis using a probe
      from a common 3'-untranslated region of the cDNAs recognized mRNAs of about 2 and
      4 kb. Both species of mRNA were seen in all human adult and fetal tissues tested.
      Fluorescence in situ hybridization mapping of the corresponding yeast artificial
      chromosome clones and sequence-tagged site analysis suggested that one of the
      PTP4A coding genes is located at 1p35 and the other is on chromosome 11. A
      processed pseudogene for PTP4A was found in the BRCA1 region of 17q21 and shares
      96% sequence identity to one of the PTP4A coding cDNAs. Our studies also suggest
      the existence of another processed pseudogene on chromosome 11.

PMID- 8661120
TI  - Tandem repeats 3' of the IGHA genes in the human immunoglobulin heavy chain gene
      cluster.
AB  - The human IGH constant region spans 350 kb and includes nine genes and two
      pseudogenes. All of the constant region gene cluster has been cloned except for
      sequences between the IGHD and IGHG3 genes, between the IGHA1 and IGHG2 genes,
      and the 3' region downstream of the IGHA2 gene. The regions 3' of the IGHA genes,
      which are not cloned, are of interest since transcriptional control elements were
      found downstream of the IGHA genes in the rat and the mouse IGH loci. In
      addition, by pulsed-field gel electrophoresis mapping, CpG islands were
      identified approximately 30 kb downstream of each IGHA gene, within the uncloned
      portion of the human IGH. These findings indicate that the regions 3' of the IGHA
      genes are candidate regions for additional transcriptional elements of the human
      IGH genes. In an effort to characterize these regions, we screened five different
      libraries and determined the regions 3' of the IGHA genes to be unclonable by
      standard cloning methods. Therefore, we applied the Inverse-PCR technique to
      amplify the sequences flanking the IGHA genes. We obtained 1418 bp of new
      sequence 3' of the IGHA1 gene. The new sequence included tandem repeats of 20 bp,
      which we propose is the cause of the unclonability of this region.

PMID- 8661119
TI  - The structure of the prostaglandin EP4 receptor gene and related pseudogenes.
AB  - The EP4 prostaglandin receptor (EP4R) is a member of the seven transmembrane
      receptor superfamily. We have obtained the human EP4 receptor gene sequence and
      determined its structure relative to EP4R cDNA synthesized from peripheral blood
      lymphocytes. The EP4R gene spans approximately 22 kb and consists of three exons
      separated by two introns. The first exon (530 bp) is noncoding. After an intron
      of 472 bp, the second exon contains a short (43 bp) 5' sequence before a 289
      amino-acid open reading frame (ORF). An 11.5-kb intron is found at the end of
      transmembrane 6, and the rest of the ORF is in exon 3. The gene structure is
      analogous to those of the thromboxane, PGI, and PGD receptors. The deduced
      initiation site does not contain a conventional TATA box but is 70% GC-rich and
      contains CCAAT boxes, SP1 and AP2 motifs, and motifs consistent with activation
      by proinflammatory cytokines. Southern blot analysis of human genomic DNA shows
      two genes with homology to the EP4R gene. Both appear to be pseudogenes with 70%
      amino acid identity to the EP4R up to the "ERY" sequence at the end of
      transmembrane 3, where an Alu-like repetitive sequence element was found. The ORF
      sequence is also interrupted by a stop codon. The pseudogenes differ in that one
      contains a second "repetitive element" (a line 1 repeat) in the 5' end of the
      ORF. Northern blot analysis of human mRNA using a pseudogene probe showed
      hybridization only to the EP4 receptor transcript. PCR also failed to detect
      expression of either pseudogene. This study defines the gene structure of EP4R
      and suggests the existence of two related pseudogenes.

PMID- 8661121
TI  - A yeast artificial chromosome contig and NotI restriction map that spans the
      tumor suppressor gene(s) locus, 11q22.2-q23.3.
AB  - Human chromosome 11q22-q23 is a pathologically important region in which a high
      level of loss of heterozygosity has been reported for breast, ovary, cervical,
      colon, and lung carcinomas, malignant melanomas, and hematologic malignancies.
      This strongly indicates that one or more tumor suppressor genes reside within the
      deleted region. In this report, we report the development of a contig map that
      covers most of the deleted regions found in these malignancies. The map comprises
      a contig of 66 overlapping yeast artificial chromosomes (YACs) and spans a region
      of 17 Mb from the PGR gene at 11q22.2 to the MLL gene at q23.3. In the process of
      screening the YACs, 50 new sequence-tagged site markers were developed from the
      termini of the YAC inserts. These markers were used for chromosome walking, and
      the data were then integrated into the contig map. NotI restriction mapping of
      these YACs revealed the presence of at least 26 NotI sites in the region. Using
      22 of them, a NotI restriction map of the region from PGR to D11S939 was
      developed. This YAC contig will provide efficient tools for identification of the
      putative tumor suppressor gene(s).

PMID- 8661122
TI  - Coamplification in tumors of KRAS2, type 2 inositol 1,4,5 triphosphate receptor
      gene, and a novel human gene, KRAG.
AB  - Analysis of a region of DNA, coamplified in tumors with KRAS2, resulted in the
      identification of the human homologue of the mouse KRAG gene. The gene was widely
      expressed in a range of cell lines, tumors, and normal tissue and demonstrated a
      high degree of alternate splicing. A human KRAG cDNA sequence, with a structure
      similar to that encoded by the amplified gene in mouse Y1 adrenal carcinoma
      cells, was isolated by RT-PCR. The predicted amino acid similarity between the
      two sequences was 91%, and hydrophobicity plots suggested a structure closely
      resembling that of transmembrane 4 superfamily members. Identification of a PCR
      based restriction fragment length polymorphism confirmed biallelic expression of
      KRAG but suggested allele-specific splicing differences in tumors. Northern
      analysis of mRNA derived from a range of tissues suggested high level expression
      in muscle and confirmed alternate splicing. To facilitate the analysis of exon
      junctions, a YAC clone encoding the genomic sequence was identified. This allowed
      the localization of KRAG to human chromosome 12p11.2. Isolation of one end of
      this nonchimeric clone demonstrated a perfect match with a 247-bp sequence within
      the 3' untranslated region of the type 2 1,4, 5-inositol triphosphate receptor
      gene. Multiplex PCR confirmed the inclusion of both genes in the KRAS2 amplicon
      in human malignancy, suggesting that either may contribute to the malignant
      phenotype.

PMID- 8661123
TI  - Molecular cloning, chromosomal mapping, and characterization of the mouse UDP
      galactose:ceramide galactosyltransferase gene.
AB  - UDP-galactose:ceramide galactosyltransferase (CGT) (EC 2.4.1.62) catalyzes the
      final step in the synthesis of galactocerebroside, a glycosphingolipid
      characteristically abundant in myelin. In this report, we describe the isolation
      of genomic clones spanning the mouse CGT gene. The mouse CGT gene consists of six
      exons that span a minimum of 70 kb of DNA and that encode a 541 amino acid
      translation product with extensive sequence similarity to the rat CGT enzyme and
      to UDP-glucuronosyltransferases (UGT). The 5'-untranslated region of the mouse
      CGT gene is encoded by a separate exon located approximately 25 kb upstream of
      the first protein-encoding exon. Furthermore, the genomic organization of the
      five coding region exons of the mouse CGT gene resembles that of the human UGT1
      and rat UGT2B1 genes. Finally, analysis of somatic cell hybrids by PCR and
      fluorescence in situ hybridization to metaphase chromosomes has localized the
      mouse CGT gene to chromosome 3, bands E3-F1.

PMID- 8661124
TI  - Molecular cloning and characterization of the mouse CGT gene encoding UDP
      galactose ceramide-galactosyltransferase (cerebroside synthetase).
AB  - UDP-galactose ceramide galactosyltransferase, CGT, EC 2.4.1.45, is the key enzyme
      in the biosynthesis of cerebrosides and sulfatides, which are the most abundant
      glycosphingolipids in the myelin of the central nervous system and the peripheral
      nervous system. The cell-specific and highly time-regulated expression of the CGT
      gene is thought to play an important role in oligodendrocyte and Schwann cell
      differentiation. Three genomic clones encoding the mouse CGT gene were isolated
      and characterized. The gene is distributed over >42 kb, and the coding sequence
      is distributed over five exons ranging from 77 to 822 bp. Putative transcription
      start sites were determined by primer extension experiments. The CGT gene locus
      is highly conserved during evolution.

PMID- 8661125
TI  - Locations of human and mouse genes encoding the RFX1 and RFX2 transcription
      factor proteins.
AB  - RFX transcription factors constitute a highly conserved family of site-specific
      DNA binding proteins involved in the expression of a variety of cellular and
      viral genes, including major histocompatibility complex class II genes and genes
      in human hepatitis B virus. Five members of the RFX gene family have been
      isolated from human and mouse, and all share a highly characteristic DNA binding
      domain that is distinct from other known DNA binding motifs. The human RFX1 and
      RFX2 genes have been assigned by in situ hybridization to chromosome 19p13.1 and
      19p13.3, respectively. In this paper, we present data that localize RFX1 and RFX2
      precisely within the detailed physical map of human chromosome 19 and genetic
      data that assign Rfx1 and Rfx2 to homologous regions of mouse chromosomes 8 and
      17, respectively. These data define the established relationships between these
      homologous mouse and human regions in further detail and provide new tools for
      linking cloned genes to phenotypes in both species.

PMID- 8661126
TI  - Construction of a normalized directionally cloned cDNA library from adult heart
      and analysis of 3040 clones by partial sequencing.
AB  - Large-scale sequencing of clones from cDNA libraries derived from specific
      tissues is a rapid and efficient way of discovering novel genes expressed in
      those tissues. However, because the heart is continually contracting and
      relaxing, it strongly expresses muscle-contractile genes and/or mitochondrial
      genes, a bias that reduces the efficiency of this method. To improve the
      efficiency of identifying novel genes expressed in the heart, we constructed a
      normalized directionally cloned cDNA library from adult heart and partially
      sequenced 3040 clones. Comparisons of these sequence data with known DNA
      sequences in the database revealed that 57.1% of the clones matched human genes
      already known, 23.4% were identical or almost identical to human expressed
      sequence tags (ESTs), 14.2% bore no significant homology to any sequences in the
      database, and 1.2% represented repetitive sequences. The remaining 4.1% showed
      some homology with known genes, and Northern blot analysis of several clones in
      this category revealed that most of them were expressed mainly in the heart and
      skeletal muscle. After redundancy was excluded, the 3040 clones accounted for
      1395 distinctive ESTs, 446 of which exhibited no match to any known sequence. Our
      results suggest that our normalized library is less redundant than standard
      libraries and is a useful resource for cataloging genes expressed in the heart.

PMID- 8661127
TI  - Genomic organization of the human ERM (ETV5) gene, a PEA3 group member of ETS
      transcription factors.
AB  - The ERM protein belongs to the family of Ets transcription factors. We show here
      that the human ERM gene is organized into 14 exons distributed along 65 kb of
      genomic DNA on chromosome 3. The two main functional domains of ERM, the acidic
      domain and the DNA-binding ETS domain, are overlapped by three different exons
      each. The 3'-untranslated region of ERM is 2.1 kb, whereas the 5'-untranslated
      region is about 0.3 kb; this allows the transcription of ERM transcripts of
      approximately 4 kb. The human ERM gene is localized to the q27-q29 region of
      chromosome 3.

PMID- 8661128
TI  - Gene structure and chromosome localization to 7q21.3 of the human rod
      photoreceptor transducin gamma-subunit gene (GNGT1).
AB  - The transducin gamma-subunit gene (GNGT1) encodes a member (gamma1) of the family
      of heterotrimeric G-protein gamma-subunits that is specific to rod
      photoreceptors. In this report we have determined the complete structure of the
      GNGT1 gene and have localized it to human chromosome 7q21.3 using somatic cell
      hybrid and yeast artificial chromosome analysis.

PMID- 8661129
TI  - A new region of conservation is defined between human and mouse X chromosomes.
AB  - Comparative mapping of the X chromosome in eutherian mammals has revealed
      distinct regions of conservation as well as evolutionary rearrangements between
      human and mouse. Recently, we and others mapped the murine homologue of CLCN4
      (Chloride channel 4) to band F4 of the X chromosome in Mus spretus but to
      chromosome 7 in laboratory strains. We now report the mapping of the murine
      homologues of APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism
      type I), two genes that are located on the human X chromosome at band p22. 3 and
      in close proximity to CLCN4. Interestingly, Oa1 and Apxl map to bands F2-F3 in
      both M. spretus and the laboratory strain C57BL/6J, defining a new rearrangement
      between human and mouse X chromosomes.

PMID- 8661130
TI  - Inactive allele-specific methylation and chromatin structure of the imprinted
      gene U2af1-rs1 on mouse chromosome 11.
AB  - The imprinted U2af1-rs1 gene that maps to mouse chromosome 11 is predominately
      expressed from the paternal allele. We examined the methylation of genomic
      sequences in and around the U2af1-rs1 locus to establish the extent of sequence
      modifications that accompanied the silencing of the maternal allele. The analysis
      of HapII or HhaI sites showed that the silent maternal allele was hypermethylated
      in a block of CpG sequences that covered more than 10 kb. By comparison, the
      expressed paternal allele was unmethylated from a CpG island upstream of the
      transcribed region through 2 kb. An analysis of DNaseI hypersensitivity of a
      putative promoter of U2af1-rs1 showed an open chromatin conformation only on the
      unmethylated, expressed paternal allele. These results suggest that allele
      specific hypermethylation covering the gene and its upstream CpG island plays a
      role in maternal allele repression of U2af1-rs1, which is reflected in altered
      chromatin conformation of DNaseI hypersensitive sites.

PMID- 8661131
TI  - Structure and sequence of human FGF8.
AB  - Recent evidence indicates that Fgf8 is expressed during vertebrate development in
      multiple locations involved in the patterning and outgrowth of important embryo
      structures. Cloning and analysis of the murine gene revealed at least eight
      potential protein isoforms that share a common carboxyl region, encoded by exons
      2 and 3, but possess different amino termini, generated by alternative splicing
      of RNA encoded by multiple 5' exons (exons 1A, 1B, 1C, and 1D). We now report the
      cloning and sequence of the human FGF8 gene. Human FGF-8 isoforms are identical
      to their murine counterparts in the common carboxyl region. Four of the human
      isoforms are identical to, or very similar to, the murine isoforms in the amino
      termini. However, four of the potential murine isoforms do not have corresponding
      human isoforms due to marked sequence divergence, leading to a blocked reading
      frame in exon 1B of FGF8. The lack of the four murine isoforms in humans raises
      the question of their function in murine development.

PMID- 8661132
TI  - Genomic structure of the human PAX2 gene.
AB  - PAX2 is one of nine PAX genes that have been described in vertebrates. Each PAX
      gene contains a conserved paired box domain that was first identified in
      Drosophila. PAX2 encodes a transcription factor that has a critical role in the
      development of the urogenital tract, the eyes, and the CNS. Recently, we reported
      a mutation of PAX2 in patients with optic nerve coloboma, vesicoureteric reflux,
      and renal anomalies. To facilitate further analysis of PAX2 mutations in human
      disease, we have now determined the complete structure of the human PAX2 gene.
      Five genomic lambda clones containing human PAX2 gene sequences were isolated.
      Sequencing and restriction mapping of these clones showed that human PAX2 was
      composed of 12 exons spanning approximately 70 kb. Two alternatively spliced
      exons and a dinuclotide repeat polymorphism were also determined in PAX2. These
      data will be useful in characterizing the role of PAX2 in human disease.

PMID- 8661134
TI  - Assignment of the human melanoma inhibitory activity gene (MIA) to 19q13.32
      q13.33 by fluorescence in situ hybridization (FISH).

PMID- 8661133
TI  - Chromosomal mapping of the human and mouse homologues of two new members of the
      AP-2 family of transcription factors.
AB  - The AP-2 transcription factor has been shown to play an important role in the
      development of tissues of ectodermal origin and has also been implicated in
      mammary oncogenesis. It has recently been found that AP-2 is encoded by a family
      of related genes, AP-2alpha, AP-2beta, and AP-2gamma. As a further step in
      understanding the role each of these genes has in development, we have used
      fluorescence in situ hybridization to map the chromosomal locations of the mouse
      and human homologues of the newly isolated AP-2beta and AP-2gamma genes. Tcfap2b
      and Tcfap2c map to mouse chromosomes 1A2-4 and 2H3-4, respectively, while TFAP2B
      and TFAP2C map to human chromosomes 6p12 and 20q13.2, the latter being a region
      that is frequently amplified in breast carcinoma.

PMID- 8661135
TI  - Assignment of the human PP5/TFPI-2 gene to 7q22 by FISH and PCR-based
      human/rodent cell hybrid mapping panel analysis.

PMID- 8661136
TI  - Polymorphism in and localization of the gene LCP2 (SLP-76) to chromosome 5q33.1
      qter.

PMID- 8661137
TI  - Chromosomal localization of the human natural killer cell class I receptor family
      genes to 19q13.4 by fluorescence in situ hybridization.

PMID- 8661141
TI  - Cloning, chromosomal localization, physical mapping, and genomic characterization
      of HKR3.
AB  - The Kruppel-type zinc finger proteins are members of a conserved family of
      transcription factors that are important in developmental regulation. Altered
      expression of several of these proteins has been implicated in human diseases,
      including cancer. We report the cloning, mapping, and characterization of the
      zinc finger gene Human Kruppel-Related 3 (HKR3). Genomic clones of HKR3 were
      isolated from a P1 library and localized to human chromosome subband 1p36.3 by
      human-rodent somatic cell hybrid mapping and fluorescence in situ hybridization.
      The gene was physically mapped to within 40 kb of D1S214 by YAC content and long
      range restriction mapping. HKR3 spans 9.5 kb of genomic DNA and is contained in
      11 exons. Sequencing defined each of the exon/intron splice site junctions and
      identified a CpG island in the 5' region of the gene. HKR3 is ubiquitously
      expressed in human tissues as at least two major transcripts, the shorter of
      which excludes a conserved finger-associated box and a putative acidic activation
      domain contained in the full-length transcript. HKR3 is a novel zinc finger gene
      that maps to a region of the genome commonly rearranged or deleted in human
      cancers.

PMID- 8661140
TI  - Regional localization of over 300 loci on human chromosome 22 using a somatic
      cell hybrid mapping panel.
AB  - A somatic cell hybrid panel, consisting of 25 cell lines, has been developed to
      localize loci subregionally on chromosome 22. Over 300 markers in the form of
      STSs or hybridization probes have been assigned to one of 24 unique regions or
      "bins" using this panel. This ordered collection of markers will aid in the
      assembly of physical maps and contigs of chromosome 22 and assist in positional
      cloning of disease loci mapped to chromosome 22.

PMID- 8661142
TI  - Rapid mapping of genomic P1 clones: the mouse L-isoaspartyl/D-aspartyl
      methyltransferase gene.
AB  - We report the mapping of the gene for the murine protein-L-isoaspartate (D
      aspartate) O-methyltransferase (EC 2.1.1. 77) from a 129 mouse strain. This gene
      encodes an enzyme present in all tissues that can catalyze the first step of a
      repair reaction in which age-damaged proteins containing abnormal l-isoaspartyl
      (or d-aspartyl) residues can be converted to forms containing normal l-aspartyl
      residues. We first mapped the restriction sites from a genomic P1 clone using a
      rapid method generally applicable to all bacteriophage P1 clones containing large
      DNA inserts. We show that a single pulsed-field electrophoresis blot can be used
      to map an entire 89-kb P1 clone insert for eight restriction endonucleases with
      an error of no more than 2% of the length of the fragment, or 1 kb at the middle
      of the insert. In this method, we combine complete restriction endonuclease
      digestion at rare sites within the P1 vector with partial restriction
      endonuclease digestion within the insert. After size separation by pulsed-field
      gel electrophoresis and blotting, the fragments are detected by Southern
      hybridization with probes to the vector. This method is potentially useful for
      restriction mapping other large DNA clones such as artificial chromosomes. We
      then determined the positions of the exons of the methyltransferase gene by
      restriction mapping of long PCR fragments. The previously unidentified exon 8,
      which encodes the -DEL C-terminus of the more acidic isozyme II, was sequenced
      and mapped 5. 3 kb from the end of exon 7.

PMID- 8661143
TI  - The structure and organization of the human follicle-stimulating hormone receptor
      (FSHR) gene.
AB  - The structure and organization of the human follicle-stimulating hormone receptor
      (FSHR) gene were determined by either screening a phage library of human genomic
      DNA or applying the long PCR technique to amplify different exon pairs with their
      corresponding introns. The FSHR gene spans a region of 54 kb and consists of 10
      exons and 9 introns. Most of the extracellular domain is encoded by 9 exons,
      ranging in length between 69 and 251 bp; the C-terminal part of the extracellular
      domain, the transmembrane domain, and the intracellular domain are encoded by the
      large exon 10 (1234 bp). Overall the gene encodes 695 amino acids. The structure
      of the human FSHR displays striking similarity to that of the previously
      characterized rat FSHR gene, with a high degree of conservation in exon sizes and
      exon/intron junctions.

PMID- 8661144
TI  - The ZNF75 zinc finger gene subfamily: isolation and mapping of the four members
      in humans and great apes.
AB  - We have previously reported (Villa et al. (1993), Genomics 18: 223) the
      characterization of the human ZNF75 gene located on Xq26, which has only limited
      homology (less than 65%) to other ZF genes in the databases. Here, we describe
      three human zinc finger genes with 86 to 95% homology to ZNF75 at the nucleotide
      level, which represent all the members of the human ZNF75 subfamily. One of
      these, ZNF75B, is a pseudogene mapped to chromosome 12q13. The other two, ZNF75A
      and ZNF75C, maintain an ORF in the sequenced region, and at least the latter is
      expressed in the U937 cell line. They were mapped to chromosomes 16 and 11,
      respectively. All these genes are conserved in chimpanzees, gorillas, and
      orangutans. The ZNF75B homologue is a pseudogene in all three great apes, and in
      chimpanzee it is located on chromosome 10 (phylogenetic XII), at p13
      (corresponding to the human 12q13). The chimpanzee homologue of ZNF75 is also
      located on the Xq26 chromosome, in the same region, as detected by in situ
      hybridization. As expected, nucleotide changes were clearly more abundant between
      human and orangutan than between human and chimpanzee or gorilla homologues.
      Members of the same class were more similar to each other than to the other
      homologues within the same species. This suggests that the duplication and/or
      retrotranscription events occurred in a common ancestor long before great ape
      speciation. This, together with the existence of at least two genes in cows and
      horses, suggests a relatively high conservation of this gene family.

PMID- 8661145
TI  - Cloning the cDNA of human PWP2, which encodes a protein with WD repeats and maps
      to 21q22.3.
AB  - We have used exon trapping to contribute to the development of the transcription
      map of chromosome 21q22.3 and to clone the genes responsible for disorders that
      map in the 21q22.3 region. Polypeptides deduced from three trapped sequences that
      map near PFKL showed homology to the yeast PWP2 gene. The full-length coding
      region of a human homologue of this yeast gene was subsequently cloned from human
      infant brain and fetal kidney cDNA libraries. The 919-codon open reading frame of
      human PWP2 belongs to the family of genes that contain tryptophan-aspartate (WD)
      repeats; other than its yeast counterpart, PWP2 is most closely homologous to the
      beta subunits of the trimeric G-protein family and may putatively be involved in
      signal transduction. Northern blot analysis revealed that the PWP2 gene is
      expressed in all fetal and adult human tissues examined (3.4 kb mRNA species).
      This single-copy gene maps approximately 200 kb proximal to PFKL in chromosome
      21q22.3 between markers EHOC-1 and D21S25.

PMID- 8661147
TI  - Cosmids map two incontinentia pigmenti type 1 (IP1) translocation breakpoints to
      a 180-kb region within a 1.2-Mb YAC contig.
AB  - Incontinentia pigmenti (IP) is an X-linked dominant disorder of neuroectodermal
      development. Based on the observation of six unrelated females with clinical
      features of nonfamilial IP with constitutional de novo reciprocal X;autosome
      translocations, a putative incontinentia pigmenti type 1 locus (IP1; MIM No.
      308300) was localized to region Xp11.21. Using available regional DNA markers, we
      constructed a yeast artificial chromosome (YAC) contig that contained 1.2 Mb of
      distal Xp11.21 and spanned two IP1 X-chromosomal breakpoints. This contig was
      used to generate a detailed molecular map of the region and identify three
      regional CpG islands. YAC-derived cosmids were used to clone and map the IP1
      breakpoints to a 180-kb interval that was flanked by DNA markers DXS705 and
      DXS741. The physical map and genomic clones should facilitate the isolation and
      characterization of transcripts associated with the IP1 translocation
      breakpoints.

PMID- 8661146
TI  - LAPTM5: a novel lysosomal-associated multispanning membrane protein
      preferentially expressed in hematopoietic cells.
AB  - While a large body of knowledge about cell membrane proteins exists, much less is
      known about the repertoire and function of integral membrane proteins of
      intracellular organelles. In looking for novel classes of genes that are
      functionally important to hematopoietic cells, we have cloned the cDNA for a gene
      preferentially expressed in adult hematopoietic tissues. During embryonic
      development the gene is expressed in both hematopoietic and nonhematopoietic
      tissues. In cell lines the gene is expressed specifically in hematopoietic
      lineages, whereas in normal adult tissues the mRNA is preferentially detected at
      high levels in lymphoid and myeloid tissues. The predicted protein is a
      pentaspanner with no homology to known genes and conserved across evolution.
      Immunocytological and cell fractionation studies with a specific antibody
      revealed a protein localizing in lysosomes. The gene, provisionally named LAPTM5,
      maps to chromosome 1p34. The expression pattern of the gene together with
      preliminary evidence that the protein interacts with ubiquitin indicates that the
      protein may have a special functional role during embryogenesis and in adult
      hematopoietic cells.

PMID- 8661149
TI  - A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere.
AB  - A contiguous physical map was constructed from the Harvey ras-1 (HRAS1) gene to
      the 11p telomere. The contig spans approximately 500 kb and is minimally composed
      of a telomere-containing YAC and P1 and cosmid clones. Included in the contig are
      11 sequence-tagged sites derived from P1 and cosmid ends. Three genes were placed
      on the contig in the following order: telomere-ribonuclease/angiogenin inhibitor
      (RNH)-Harvey ras-1 (HRAS1)-HRAS1-related complex (HRC). Two novel tetranucleotide
      repeats (heterozygosity of 66 and 68%) and a complex CA repeat (heterozygosity of
      78%) were isolated and characterized.

PMID- 8661148
TI  - Mouse autosomal homolog of DAZ, a candidate male sterility gene in humans, is
      expressed in male germ cells before and after puberty.
AB  - Deletion of the Azoospermia Factor (AZF) region of the human Y chromosome results
      in spermatogenic failure. While the identity of the critical missing gene has yet
      to be established, a strong candidate is the putative RNA-binding protein DAZ
      (Deleted in Azoospermia). Here we describe the mouse homolog of DAZ. Unlike human
      DAZ, which is Y-linked, in mouse the Dazh (DAZ homolog) gene maps to chromosome
      17. Nonetheless, the predicted amino acid sequences of the gene products are
      quite similar, especially in their RNP/RRM (putative RNA-binding) domains, and
      both genes are transcribed predominantly in testes; the mouse gene is transcribed
      at a lower level in ovaries. Dazh transcripts were not detected in testes of mice
      that lack germ cells. In testes of wildtype mice, Dazh transcription is
      detectable 1 day after birth (when the only germ cells are prospermatogonia),
      increases steadily as spermatogonial stem cells appear, plateaus as the first
      wave of spermatogenic cells enters meiosis (10 days after birth), and is
      sustained at this level thereafter. This unique pattern of expression suggests
      that Dazh participates in differentiation, proliferation, or maintenance of germ
      cell founder populations before, during, and after the pubertal onset of
      spermatogenesis. Such functions could readily account for the diverse
      spermatogenic defects observed in human males with AZF deletions.

PMID- 8661151
TI  - The active gene that encodes human high mobility group 1 protein (HMG1) contains
      introns and maps to chromosome 13.
AB  - The human genome contains a large number of sequences related to the cDNA for
      High Mobility Group 1 protein (HMG1), which so far has hampered the cloning and
      mapping of the active HMG1 gene. We show that the human HMG1 gene contains
      introns, while the HMG1-related sequences do not and most likely are
      retrotransposed pseudogenes. We identified eight YACs from the ICI and CEPH
      libraries that contain the human HMG1 gene. The HMG1 gene is similar in structure
      to the previously characterized murine homologue and maps to human chromosome 13
      band q12, as determined by in situ hybridization. The mouse Hmg1 gene maps to the
      telomeric region of murine Chromosome 5, which is syntenic to the human 13q12
      band.

PMID- 8661150
TI  - New variants of the human and rat nuclear hormone receptor, TR4: expression and
      chromosomal localization of the human gene.
AB  - TR4 is a new member of the nuclear hormone receptor family. This receptor is
      highly conserved in rat and human, but an in-frame insertion of 19 amino acid
      residues in the amino-terminal (A/B) region was found in the human homolog, which
      we refer to as hTR4alpha1. By reverse transcription-PCR (RT-PCR) we have
      identified a human TR4 mRNA (hTR4alpha2) that is analogous in size and sequence
      to the reported rat TR4. RT-PCR analysis using total RNA derived from various rat
      tissues revealed a new rat TR4 transcript, referred to as rTR4alpha1, which is
      homologous to hTR4alpha1 since it contains the extra 19 amino acids in the A/B
      region. The two rat transcripts showed a differential tissue distribution.
      Analysis of the exon-intron organization of the hTR4 A/B region showed that the
      19-amino-acid peptide insert in hTR4alpha1 was encoded by a separate exon,
      indicating that hTR4alpha1 and hTR4alpha2 transcripts were produced by the
      differential usage of the exon. RT-PCR analysis revealed that both hTR4alpha1 and
      hTR4alpha2 were detectable in brain, placenta, and ovary. In contrast, the human
      ovarian cancer cell line, PA1, failed to express hTR4alpha1. By fluorescence in
      situ hybridization, we have mapped the hTR4 gene to 3p25, a region deleted in
      some forms of cancer.

PMID- 8661152
TI  - Molecular cloning and chromosomal mapping of the mouse gene encoding cyclin
      dependent kinase 5 regulatory subunit p35.
AB  - A neural-specific activating subunit, p35, of cyclin-dependent kinase 5 (Cdk5)
      was recently reported to differ from other mammalian cyclins, suggesting a new
      type of regulatory subunit for Cdk activity. The mouse gene encoding p35, Cdk5r,
      was isolated from a mouse 129/SvJ genomic library, and the genomic structure of
      Cdk5r was characterized. The most notable features of Cdk5r are the absence of
      introns in the amino acid coding region and the high homology of amino acid
      sequence among species. The 5'-flanking region of Cdk5r contained no canonical
      TATA or CAAT box but had several putative promoter elements, including Sp1, AP2,
      MRE, and NGFIA. The mouse Cdk5r transcript was detected only in the brain by
      Northern blot analysis. Mouse Cdk5r was mapped to a position on mouse chromosome
      11.

PMID- 8661153
TI  - The gene encoding LERK-7 (EPLG7, Epl7), a ligand for the Eph-related receptor
      tyrosine kinases, maps to human chromosome 5 at band q21 and to mouse chromosome
      17.
AB  - The eph-related receptors are the largest subfamily of receptor tyrosine kinases.
      Recently, we and others have identified seven different, but related, cDNAs
      encoding membrane-bound ligands for this family of receptors. One member, LERK-7,
      is attached to the cell membrane via glycosyl-phosphatidylinositol linkage and
      has been found to be a ligand for the eph-family receptors hek, elk, eck, and
      rek. Using PCR-based screening of human x rodent somatic cell hybrid DNAs, we
      have assigned the gene that encodes LERK-7 (EPLG7) to human chromosome 5.
      Fluorescence in situ hybridization to metaphase chromosome preparations using a
      genomic clone from the locus refined this localization to chromosome 5, band q21.
      In addition, Southern blot analysis of DNAs from interspecific backcross mice
      indicated that the mouse homologue Epl7 maps to a homologous region on chromosome
      17.

PMID- 8661154
TI  - The MAS proto-oncogene is not imprinted in humans.
AB  - Recently it was shown that the murine Mas gene, which is located less than 300 kb
      from the imprinted Igf2r gene, is also imprinted in Day 11.5 embryos with
      expression exclusively from the paternal allele. We have assigned the human MAS
      gene to chromosomal bands 6q25.3-q26 in close proximity to the IGF2R gene. In
      contrast to its murine homologue, the human IGF2R gene is not imprinted. By
      making use of a novel intragenic polymorphism, we have studied the expression of
      the MAS gene in three heterozygous human fetuses. In all tissues examined,
      including tongue, biallelic expression of the MAS gene was observed. Hence both
      MAS and the neighboring IGF2R gene are not imprinted in humans.

PMID- 8661155
TI  - The genomic organization of a human creatine transporter (CRTR) gene located in
      Xq28.
AB  - During the course of a large-scale sequencing project in Xq28, a human creatine
      transporter (CRTR) gene was discovered. The gene is located approximately 36 kb
      centromeric to ALD. The gene contains 13 exons and spans about 8.5 kb of genomic
      DNA. Since the creatine transporter has a prominent function in muscular
      physiology, it is a candidate gene for Barth syndrome and infantile
      cardiomyopathy mapped to Xq28.

PMID- 8661157
TI  - Genetic localization of Cd63, a member of the transmembrane 4 superfamily,
      reveals two distinct loci in the mouse genome.
AB  - The membrane protein CD63, a molecular marker for early stages of melanoma
      progression, has been associated with platelet storage pool deficiency disorders
      (SPD). CD63 localizes to the membranes of platelets, lysosomes, and melanosomes,
      all of which are affected in a specific subgroup of SPD. The cDNA encoding CD63
      detects two closely related sequences that map to different regions of the mouse
      genome. One locus maps to mouse Chromosome (Chr) 10 in a region that shares
      linkage homology with the human chromosome encoding human CD63. The second locus
      maps to mouse Chr 18 in a region that bears no known human CD63-related genes. No
      SPD has been localized to these regions of either the mouse or the human
      chromosomes.

PMID- 8661156
TI  - Isolation and characterization of WNT8B, a novel human Wnt gene that maps to
      10q24.
AB  - Wnt genes encode intercellular signalling molecules that play important roles in
      key processes of embryonic development such as mesoderm induction, specification
      of the embryonic axis, and patterning of the central nervous system, spinal cord,
      and limb. Multiple such genes are known to exist in each of several species that
      have been investigated, and they have been classified into various groups and
      subgroups on the basis of high sequence homology and common expression patterns.
      The vertebrate Wnt8 subfamily includes genes from Xenopus, zebrafish, and
      chicken, but, to date, no mammalian homologues have been described. We now report
      cloning and characterization of a novel human member of this family that we have
      termed WNT8B on the basis of the very high sequence similarity of the inferred
      protein to those encoded by the Xenopus and zebrafish Wnt8b genes. PCR typing of
      a human monochromosomal hybrid cell panel mapped the gene to chromosome 10, and
      FISH mapping provided a subchromosomal location at 10q24. Northern blotting and
      RT-PCR assays indicated that the WNT8B gene is expressed in several human tissues
      during fetal and adult stages.

PMID- 8661159
TI  - Identification of human OGR1, a novel G protein-coupled receptor that maps to
      chromosome 14.
AB  - We describe the cloning of a novel G protein-coupled receptor, termed ovarian
      cancer G protein-coupled receptor 1 (OGR1), from an ovarian cancer cell line that
      maps to chromosome 14q31. The predicted open reading frame of OGR1 encodes a
      protein of 365 amino acids. OGR1 is expressed as a single 3.0-kb transcript in
      several tissues, including spleen, testis, small intestine, peripheral blood
      leukocytes, brain, heart, lung, placenta, and kidney, with no detectable OGR1
      expression in thymus, prostate, ovary, colon, liver, skeletal muscle, or
      pancreas. OGR1 shares strongest homology (49-54%) with the human orphan receptor
      GPR4. The structural features of OGR1 suggest that the ligand for OGR1 is likely
      to be a small peptide or a small bioactive molecule.

PMID- 8661158
TI  - cDNA cloning, tissue distribution, and chromosomal localization of
      myelodysplasia/myeloid leukemia factor 2 (MLF2).
AB  - A fusion gene between nucleophosmin (NPM) and myelodysplasia/myeloid leukemia
      factor 1 (MLF1) is formed by a recurrent t(3;5)(q25.1;q34) in myelodysplastic
      syndrome and acute myeloid leukemia. Here we report the identification of a novel
      gene, MLF2, which contains an open reading frame of 744 bp encoding a 248-amino
      acid protein highly related to the previously identified MLF1 protein (63%
      similarity, 40% identity). In contrast to the tissue-restricted expression
      pattern of MLF1, the MLF2 messenger RNA is expressed ubiquitously. The MLF2 gene
      locus was mapped by fluorescence in situ hybridization to human chromosome 12p13,
      a chromosomal region frequently involved in translocations and deletions in acute
      leukemias of lymphoid or myeloid lineage. In a physical map of chromosome 12,
      MLF2 was found to reside on the yeast artificial chromosome clone 765b9. Southern
      blotting analysis of malignant cell DNAs prepared from a series of acute
      lymphoblastic leukemia cases with translocations involving chromosome arm 12p, as
      well as a group of acute myeloid leukemias with various cytogenetic
      abnormalities, failed to reveal MLF2 gene rearrangements.

PMID- 8661162
TI  - Projections.

PMID- 8661160
TI  - Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to
      10q26.13-q26.3 by fluorescence in situ hybridization.

PMID- 8661164
TI  - Spectral analysis of heart rate variability in the ICU: a measure of autonomic
      function.
AB  - Beat-to-beat heart rate variability (HRV) is a measure of autonomic nervous
      system activity, which can be quantified using frequency domain analysis. Despite
      its potential utility, routine serial analysis of HRV in an ICU setting has
      rarely been attempted. We have developed an automated system for real-time
      spectral analysis of HRV and have utilized this system to study the effect of
      alterations in HRV on mortality in a surgical ICU population. HRV measurements
      were performed every 6 hr on all patients in the ICU. Total spectral power in the
      variability signal (TP, a measure of overall autonomic activity) and the ratio of
      high frequency to low frequency components (HF/LF ratio, a measure of
      parasympathetic/sympathetic balance) were calculated. Over a 6-month period 7994
      automated HRV measurements were made in 742 patients. Both low TP (low autonomic
      tone) and high HF/LF ratio (relative lack of sympathetic tone) were associated
      with increased mortality. A low HF/LF ratio (relatively high sympathetic tone)
      was associated with increased survival, especially in patients with low autonomic
      tone. We conclude that serial spectral analysis of HRV is practical in an ICU
      setting and that HRV parameters appear to be a clinically relevant indication of
      autonomic activity. Low sympathetic tone and vagal predominance are associated
      with increased mortality, while sympathetic predominance favors survival.
      Monitoring of HRV parameters has the potential to detect physiologic
      deterioration or response to therapy.

PMID- 8661163
TI  - Soluble ICAM-1 (sICAM-1) provokes PMN elastase release.
AB  - Elevated levels of soluble intercellular adhesion molecule-1 have been shown
      predictive of post-injury multiple organ failure. We hypothesized that sICAM-1
      augments distant organ injury via its affect on the PMN and; thus, have examined
      neutrophil elastase and superoxide production in response to sICAM-1. To obtain
      soluble ICAM-1, Chinese Hamster Ovarian (CHO) cells were transfected with human
      ICAM-1 (cDNA vector CD1.8), lysed and centrifuged at 150,000g for 1 hr;
      supernatant was passed over an ICAM-1 affinity gradient, eluted with 0.1 mM
      glycine x HCl, and concentrated using an Amicon Spin-X filter. PMNs were
      incubated for 1 hr with sICAM-1 at 37 degrees C. Quiescent and PMA-activated PMNs
      served as negative and positive controls respectively. Elastase activity was
      measured by the cleavage of methoxy-succinyl-alalyl-alalyl-prolyl-valyl-p
      nitroanilide. Superoxide production was determined by superoxide dismutase
      inhibitive ferricytochrome C reduction over a 5-60 min incubation. PMN incubation
      with sICAM-1 provoked marked increase in elastase release 10.43 +/- 2.90 (10(-6)
      U/hr) compared to control 1.64 +/- 0.57, and was equivalent to PMA-activated PMN
      elastase release 11.60 +/- 1.50 (10(-6) U/hr). In contrast, sICAM-1 alone did not
      promote spontaneous PMN superoxide production beyond buffer treated PMNs (0.25 +/
      0.09 nmole/2.5 x 10(5) PMN/min). In sum, sICAM-1 stimulates PMN elastase release
      in vitro. Clinically, this may represent a mechanism by which sICAM-1
      participates in the genesis of post-injury multiple organ failure.

PMID- 8661165
TI  - Vasomotor response to pentoxifylline mediates improved renal blood flow to
      bacteremia.
AB  - Bacteremia leads to rapid intrarenal vasoconstriction, mediated by endogenous
      vasoconstrictors such as TXA2 and endothelin. These changes occur before the
      onset of neutrophil adherence, platelet aggregation, or increases in
      proinflammatory cytokines. Pentoxifylline (PTX) increases red cell deformability,
      reduces neutrophil adhesion, abrogates rises in TNFalpha, and lessens the
      deleterious effects of other cytokines during prolonged sepsis. PTX also improves
      renal function in models of established sepsis, but the specific mechanisms of
      this effect are unclear. Because PTX is a relatively selective visceral
      vasodilator we sought to determine whether PTX improves renal microvascular
      hypoperfusion during bacteremia and whether the mechanism involves altered
      vascular reactivity. Rat hydronephrotic kidneys were studied by videomicroscopy.
      Interlobular (ILA) arteriolar diameter and flow, afferent (AFF) and efferent
      (EFF) arteriolar diameters, and cardiac output (CO) were measured at 15-min
      intervals for 120 min. PTX was infused alone or prior to a bolus injection of
      live Escherichia coli. The responses were compared to controls infused with
      equivalent volumes of normal saline alone. PTX led to improved renal blood flow
      and to pre- and postglomerular vasodilatation. This improvement remained
      significant compared to bacteremic animals throughout the period of observation.
      We conclude that PTX improves renal blood flow during bacteremia due to pre- and
      postglomerular vasodilation. These responses may be a consequence of increased
      intracellular cAMP and release of vasodilator prostanoids.

PMID- 8661166
TI  - NO prevents neutrophil-mediated pulmonary vasomotor dysfunction in acute lung
      injury.
AB  - The purpose of this study was to examine the effect of administration of inhaled
      nitric oxide (NO) on lung neutrophil accumulation and pulmonary vascular
      endothelial cell function in endotoxin-induced acute lung injury. Mechanically
      ventilated rats were studied 4 hr after endotoxin (0.5 mg/kg IP). Inhaled NO (20
      ppm) was administered for either the entire 4 hr after endotoxin (continuous
      group) or for only the first 2 of 4 hr after endotoxin (abbreviated group).
      Endothelial-dependent (acetylcholine, ACh) and -independent cGMP-mediated
      relaxation (nitroprusside, SNP) pulmonary vasorelaxation were studied in isolated
      pulmonary arterial rings. Lung neutrophil accumulation was determined by
      myeloperoxidase assay (MPO). Inhaled NO prevented endotoxin-induced lung
      neutrophil accumulation as well as pulmonary endothelial cell dysfunction.
      However, this protection required continuous administration of inhaled NO. We
      conclude that inhaled NO prevents neutrophil-mediated pulmonary vascular
      endothelial cell dysfunction in acute lung injury.

PMID- 8661167
TI  - Preconditioning with ischemia or adenosine protects skeletal muscle from ischemic
      tissue reperfusion injury.
AB  - Prolonged tissue ischemia and subsequent reperfusion results in significant
      tissue injury due to the ischemic-reperfusion (IR) syndrome. Ischemic
      preconditioning (IPC) or adenosine (ADO) pretreatment are known to protect IR
      injury in cardiac muscle. Our aim was to determine whether IPC or ADO
      pretreatment attenuates and protects against ischemic tissue reperfusion injury
      in skeletal muscle. Rats were anesthetized and global hindlimb ischemia was
      induced by 60 min of suprarenal aortic clamping followed by 30 min of reperfusion
      period. The degree of skeletal muscle dysfunction was determined by decreases in
      maximum contractile force, and adenosine triphosphate (ATP) and creatine
      phosphate (CP) levels of extensor digitorum longus (EDL) muscle. The distal
      tendon of the EDL was attached to a force transducer for maximum isometric force
      measurement. Samples were taken from the EDL for measurement of ATP and CP
      levels. The following were protective protocols prior to the IR challenge: (1)
      four consecutive 5-min periods of ischemia separated by 5-min reperfusion periods
      (PC/I) or (2) i.v. adenosine infusion (350 microg/kg/min x 10 min, PC/A). Our
      data suggest that pretreatment with brief periods of ischemia or systemic ADO
      infusion attenuates ischemic tissue reperfusion injury in skeletal muscle.
      [Table: see text]

PMID- 8661168
TI  - Myocardial glucose metabolism and ATP levels are decreased two days after global
      ischemia.
AB  - We hypothesized that following reversible myocardial ischemia recovery of glucose
      metabolism would be prolonged and would parallel recovery of high energy
      phosphate levels. Normothermic ischemia was achieved in dogs by aortic cross
      clamping for 20 min on cardiopulmonary bypass. Glucose uptake was determined by
      [18F]fluorodeoxyglucose uptake and positron emission tomography (PET) 1 week pre
      ischemia and at 2 and 7 days post-ischemia (n = 8). Oxygen consumption (MVO2) and
      glucose uptake were also measured by Fick. In a separate group of animals,
      adenosine triphosphate (ATP) and creatine phosphate (CP) levels were measured by
      left ventricular/septal biopsies at baseline, 2 days, and 7 days (n = 6). Glucose
      uptake, as measured by PET, was reduced to 15% of baseline at 2 days post
      ischemia and returned to normal by 7 days post-ischemia (P < 0.05). These results
      were confirmed by Fick measures of glucose uptake. ATP levels were reduced to 49%
      of pre-ischemic levels at 2 days and returned to baseline by 7 days (P < 0.05).
      CP and MVO2 levels were normal at 2 and 7 days following ischemia. We conclude
      that reduced glucose uptake in the presence of intact oxidative metabolism
      suggests that glucose is not the favored substrate for ATP production following
      ischemia.

PMID- 8661169
TI  - Thrombospondin-1 (TSP-1) promotes the invasive properties of human breast cancer.
AB  - TSP-1 is a matrix-bound adhesive glycoprotein, which plays a role in tumor cell
      proliferation and tumor angiogenesis. The purpose of this study was to
      investigate the effect of TSP-1 on breast tumor cell invasion. Tumor cell
      invasion assays were performed using a modified Boyden chamber apparatus with
      collagen-coated membranes. Four breast cell lines were studied in serum-free
      media: the malignant MDA-MB-231, SKBR-3, and MCF-7 cell lines, and the benign MCF
      10A cell line. Invasion was measured as the summation of the number of cells in
      five representative high power fields (400x) traversing the collagen barrier
      after a 3-hr incubation period. The effect of an anti-TSP-1 antibody (100
      microgram/ml) was also evaluated in the malignant cell lines. Statistical
      analysis was performed by ANOVA and Student's unpaired t test. TSP-1 promoted a
      dose-dependent increase in invasion as compared to buffer controls in all three
      malignant cell lines. TSP-1 (100 nM) promoted a greater than five-fold increase
      over controls in tumor cell invasion for MDA-MB-231, SKBR-3, and MCF-7 cell lines
      (P < 0.005). TSP-1 had no effect on the invasiveness of the benign cell type MCF
      10A. Anti-TSP-1 antibody inhibited TSP-1 promoted invasion in the MDA-MB-231,
      SKBR-3, and MCF-7 cell lines by 45, 48, and 39%, respectively (P = 0.003, 0.044,
      0.047). TSP-1 promotes tumor cell invasion of collagen by breast cancer cells.
      Therapy designed to inhibit TSP-1 may prevent invasion and metastasis in breast
      cancer.

PMID- 8661171
TI  - Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates
      tumorigenesis and experimental lung metastasis in vivo.
AB  - Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines
      and solid human tumors. The effect of tumor cell NO on tumor biology is poorly
      understood. The purpose of this study was to investigate the effect of NO
      production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and
      subcutaneous tumor growth and experimental pulmonary metastasis in vivo. EMT-6
      cells were incubated with endotoxin (LPS, 10 microgram/ml) and interferon-gamma
      (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega
      nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number
      were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN,
      in the presence or absence of L-NAME, washed and injected either subcutaneously
      in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c
      mice. Two weeks following tumor cell injection, tumor size and number of
      pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6
      cells and inhibited cell growth in vitro by 50%. L-NAME blocked LPS/IFN
      stimulation of NO production and restored cell growth to near control levels.
      When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two
      fold increase in subcutaneous tumor growth and experimental pulmonary metastases
      over control cells. L-NAME reduced tumor size and number of lung metastases to
      control levels, suggesting that tumor cell NO production was responsible for this
      effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells
      inhibits tumor cell growth in vitro, yet paradoxically augments tumor growth and
      metastasis in vivo.

PMID- 8661170
TI  - A novel endotoxin antagonist attenuates tumor necrosis factor-alpha secretion.
AB  - Twenty-seven amino acid peptides with sequences corresponding to a proposed
      endotoxin binding region of bactericidal permeability increasing protein (BPI):1)
      inhibit lipopolysaccharide induced macrophage tumor necrosis factor-alpha (TNF
      alpha) secretion, 2) have bactericidal activity against gram-negative bacteria,
      and 3) protect mice from a lethal lipopolysaccharide (LPS) challenge.
      Unfortunately, peptides have a short halflife in vivo. Therefore, we have
      chemically conjugated the BPI based peptide, BG38, to a larger carrier protein,
      keyhole limpet hemocyanin (KLH), and characterized its ability: 1) to inhibit LPS
      induced macrophage TNF-alpha secretion and 2) to decrease plasma endotoxin and
      TNF-alpha levels following an i.v. injection of E. coli 0111:B4 LPS. BG38-KLH
      inhibited cultured macrophage TNF-alpha secretion in response to LPS derived from
      four pathogenic strains of gram-negative bacteria in a dose dependent manner
      (>90% inhibition at 50 microgram/ml, P < 0.05 Student's t test). BG38-KLH also
      decreased serum endotoxin (>90%, P < 0.05 Student's t test) and peak TNF-alpha
      levels (>30% inhibition, P < 0.05 Student's t test) following E. coli LPS
      challenge in a murine gram-negative bacterial sepsis model. Novel endotoxin
      antagonists based upon a small domain of BPI represent promising reagents for the
      treatment of serious gram-negative bacterial infections.

PMID- 8661172
TI  - Prolactin: a novel and safe immunomodulating hormone for the treatment of
      immunodepression following severe hemorrhage.
AB  - Recent studies have shown that the anterior pituitary hormone prolactin, together
      with various cytokines, plays an important role in maintaining normal immune
      responses. Although there is evidence that prolactin may be a significant
      immunotropic hormone that can counteract the immunosuppressive effects of drugs
      such as cyclosporine, morphine, or glucocorticoids, it remains unknown whether
      prolactin administration has any salutary effects on the depressed immune
      responses following severe hemorrhage. To study this, mice were bled to and
      maintained at a mean arterial pressure of 35 mm Hg for 60 min, then adequately
      resuscitated and segregated into two groups. One group received saline-vehicle
      (hem-SS); animals in the other group were treated with prolactin (hem-PRL) (100
      micrograms per 25 g BW, subcutaneously) immediately before resuscitation. Two
      hours following saline or prolactin injection, splenocytes (SPL) were harvested
      and assessed for proliferative capacity (PC) and their ability to release IL-2
      and IL-3. Supernatant lymphokine levels were determined by bioassay. The
      proliferative capacity of the splenocytes, as well as their ability to release IL
      2 and IL-3, was significantly depressed in the vehicle-treated hemorrhaged
      animals, compared to shams. Treatment with prolactin restored the depressed
      splenocyte functions seen after severe hemorrhage. These results support the
      notion that the immunosuppression following hemorrhage and trauma may be mediated
      by hormones from the hypothalamic-pituitary-adrenal axis. Furthermore, our
      results suggest that the use of prolactin, which did not produce any adverse
      hemodynamic effects, represents a novel and safe immunomodulating hormone for the
      treatment of immunodepression following severe blood loss.

PMID- 8661173
TI  - Detection of intestinal bacterial translocation using PCR.
AB  - Microbial translocation has been suspected to be a major contributing factor in
      the development of sepsis of unknown origin and multiple organ failure syndrome,
      but there are currently no tests capable of detecting and quantitating
      translocation sequentially in humans. The purpose of this study was to develop a
      sensitive polymerase chain reaction (PCR) test to detect Escherichia coli (E.
      coli) DNA in the blood of animals after inducing bacterial translocation from the
      gut. DNA was extracted from blood and primers were used to amplify an 800-bp gene
      fragment of E. coli by 30-cycle PCR. Detection by southern blotting achieved a
      sensitivity of 10-100 organisms per 0.3 cc blood. Experimental groups included
      mice gavaged with 10(10) E. coli followed by 20% body surface area thermal
      injury, or no injury. Controls included burn only and no treatment groups. Blood
      was obtained by cardiac puncture 1 hr after burn. Cultures were done on blood
      samples from all groups. More animals in the burn/gavage group had positive
      bacterial cultures. All controls were culture negative. E. coli detection by PCR
      was 100% sensitive in culture positive animals with detection in the gavage/burn
      group higher than that in all other groups. PCR was negative for all mice without
      treatment. Several culture negative animals had detectable bacterial DNA by PCR.
      This highly sensitive and specific method can be used repeatedly to test the
      blood of patients for the presence of microbial DNA, which could be originating
      from the gut.

PMID- 8661174
TI  - Sex hormones affect the calcium signaling response of human arterial cells to
      LDL.
AB  - The present study was designed to examine the role of calcium-dependent signal
      transduction as a common link between the atherogenic effect of LDL and the
      mitigating influence of sex hormones in aortic endothelial (EC) and smooth muscle
      cells (SMC). Human aortic EC and SMC were pre-incubated for 48 hr in media
      containing no hormone, 17-beta-estradiol (20 ng/ml) or testosterone (300 ng/ml).
      Low density lipoprotein (N-LDL) or its minimally oxidized species (Ox-LDL) was
      added to the media at different concentrations (0, 2, 5, 10, 20, and 40
      micrograms protein/ml), and changes in cytosolic calcium [Ca+2]i were measured by
      spectrofluorometric analysis using a Fura 2-AM indicator. Cell viability was
      determined with a 51chromium release assay. In EC, exposure to N-LDL resulted in
      a weak and unsustained increase in [Ca+2]i, (max. 21.9 +/- 4.6%) while a more
      marked rise was seen in SMC (max. 79.1 +/- 11.5%; P < 0.005). There was an
      amplified response to the more atherogenic Ox-LDL in both EC (max. 130.9 +/-
      22.9%) and SMC (max. 240.5 +/- 14.2%; P < 0.0002). Estrogen was associated with a
      lower resting level of [Ca+2]i in both cell types, and resulted in a significant,
      dose-dependent inhibition of cytosolic calcium mobilization in SMC exposed to Ox
      LDL (P < 0.05). Alternatively, testosterone increased cytosolic calcium response
      in SMC exposed to either N-LDL (P < 0.05) or Ox-LDL (P < 0.05). Similar trends
      were seen in EC, but failed to reach statistical significance. These changes
      could not be attributed to cell toxicity. Sex hormones may modulate the
      atherogenic potential of LDL by influencing intracellular, calcium-dependent
      signaling mechanisms.

PMID- 8661175
TI  - Endotoxin activates T cell interferon-gamma secretion in the presence of
      endothelium.
AB  - T lymphocytes (T cells) and their secreted lymphokine interferon-gamma (IFN
      gamma) play important mediator roles in endotoxin-induced inflammation. We sought
      to explore the necessary conditions for and degree of LPS-induced T cell
      activation for IFN-gamma secretion in a human syngeneic microvascular endothelial
      T cell coculture system. Human peripheral blood T cells, with or without
      monocytes, were cocultured in the presence or absence of a syngeneic human
      adipose microvascular endothelial cell (HAMVEC) monolayer. Cocultures were
      stimulated with LPS (1 microgram/ml) and 3-day coculture supernatants assayed for
      IFN-gamma and IL-2 by ELISA. In the absence of HAMVEC, LPS-induced T cell
      activation for IFN-gamma secretion was only minimally demonstrated in the
      presence of monocytes. However, in the presence of HAMVEC, LPS activated T cells
      for IFN-gamma secretion in the absence of monocytes and markedly augmented the
      response in the presence of monocytes. A subset of donor cocultures showed no IFN
      gamma response to LPS. IL-2 was not secreted as part of the LPS-induced T cell
      activation response. Our data support a hypothesis that endothelium serves as an
      accessory cell for T cell IFN-gamma secretion in endotoxin-induced inflammation.
      T cell-endothelial interactions may play a crucial role in promoting T cell
      activation during LPS-induced inflammation.

PMID- 8661176
TI  - VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in
      porcine hearts.
AB  - Several recent studies have demonstrated the potential for improving myocardial
      perfusion by the continuous administration of angiogenic growth factors. Studies
      in our laboratory have shown that a single intraarterial or intravenous bolus of
      the endothelial cell specific mitogen vascular endothelial growth factor (VEGF)
      can significantly improve perfusion in a rabbit ischemic limb model. To test the
      efficacy of this therapeutic approach in chronic myocardial ischemia, 18
      Yorkshire pigs underwent a left thoracotomy followed by placement of an ameroid
      constrictor around the proximal circumflex coronary artery. Gradual occlusion of
      the artery (26 +/- 4 days) was accompanied by identifiable hypokinesis of the
      posterolateral wall of the left ventricle (2D echo). Thirty days postoperatively,
      rhVEGF(165) (2 mg; n = 8) or saline (n = 10) was administered directly into the
      left coronary ostium. Postadenosine myocardial perfusion studies using colored
      microspheres 30 days later demonstrated superior blood flow in the ischemic zone
      of the VEGF-treated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05)
      compared with those receiving saline injection. Four of eight VEGF-treated
      animals succumbed, however, to severe hypotension following VEGF administration.
      Therefore 500 micrograms of VEGF were administered intracoronary to five normal
      pigs. A significant drop in mean arterial pressure (-44.4 +/- 3.2%, P < 0.05 vs
      baseline) and peripheral resistance (-13.2 +/- 4.5%, P < 0.05 vs baseline) was
      accompanied by increased heart rate. IV administration of N(omega)-nitro-L
      arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We
      conclude that a single intracoronary bolus of VEGF is capable of significantly
      augmenting flow to collateral-dependent ischemic myocardium. The associated
      hypotension appears to be EDRF-mediated. Further studies are needed to define the
      best dose and route of administration of VEGF for the treatment of coronary
      insufficiency.

PMID- 8661177
TI  - Tolerance to cardiac allografts requires a time lag between intrathymic treatment
      and transplantation.
AB  - Permanent tolerance to an experimental heterotopic cardiac allograft can be
      achieved by pretreatment with antilymphocyte serum (ALS) and intrathymic
      inoculation of donor cells. Most successful experimental protocols have employed
      a time lag of 2 to 3 weeks between intrathymic pretreatment and transplantation,
      which makes this treatment strategy impractical for clinical heart
      transplantation. In these experiments we modified the standard protocol by giving
      ALS 24 hr prior to both intrathymic injection of donor cells and heterotopic
      transplantation. Seven Lewis rats had intraperitoneal injection of 1 ml of ALS
      and 24 hr later underwent intrathymic injection of 5 X 10(7) donor Lewis-Brown
      Norway (LBN) splenocytes and heterotopic cardiac transplantation using an LBN
      donor. Mean graft survival was 24.4 days, significantly longer than the 7.8-day
      graft survival observed in untreated Lewis recipients (n = 5) (P < 0.02).
      However, graft survival was not different from that observed in Lewis rats
      pretreated with ALS alone (n = 5) (25.8 days, P = NS). Permanent graft survival
      was produced in two rats receiving only A-LS and in one rat receiving both ALS
      and intrathymic inoculation. In these experiments it appears that prolongation of
      graft survival may have been due to the effect of A-LS alone. These results
      suggest that there is a critical time period between intrathymic inoculation and
      transplantation that is needed for permanent tolerance to be induced
      consistently. This may be due to the kinetics of the effects of ALS on
      alloreactive T-lymphocytes or to a time-dependent requirement for antigen
      processing in the thymus.

PMID- 8661178
TI  - Cardia allograft unresponsiveness using a posttransplant strategy :
      characterization of the graft infiltrate.
AB  - We evaluated a combined posttransplant strategy using antilymphocyte serum (ALS)
      at time of engraftment followed by low dose total lymphoid irradiation (TLI) and
      donor bone marrow cell (BMC) inoculation administered either intrathymically (IT)
      or intravenously (IV) in the vigorously rejecting strain combination DA into Lew
      recipients. Allograft survival was significantly prolonged with administration of
      ALS in combination with TLI and IT (105 +/- 28.6 days) or IV (106.8 +/- 28.6
      days) BMC compared to administration of ALS combined with either TLI (17.8 +/-
      0.4 days) or BMC (9.0 +/- 0.0 days), or TLI combined with BMC (1 1.5 +/- 0.5
      days) (P < 0.000 1, experimental vs control animals). There was no difference in
      survival between those animals who underwent IT or IV BMC inoculation. Third
      party (WF) BMC inoculation did not significantly prolong allograft survival (10.0
      +/- 1.0 days). A mild to moderate cellular infiltrate was present in allograft
      tissue after 100 days. To further characterize these cells, cytokine mRNA
      expression in allograft tissue (> 100 days posttransplant) was evaluated using
      nonisotopic in situ hybridization. A similar cytokine profile was demonstrated in
      allograft tissue compared to naive and isograft tissue, except for a slight
      increase in IL-2 (P < 0.02, control vs IV BMC; P = NS, other groups). In summary,
      unresponsiveness was induced in a high-responder strain combination using a
      combined posttransplant strategy of ALS, TLI, and donor antigen either IT or IV.
      The cytokine profile of the graft infiltrating cells was similar to that of
      normal tissue. Unresponsiveness may be the result of functional inactivation of
      these cells.

PMID- 8661179
TI  - Magnesium is essential in mechanisms of pulmonary vasomotor control.
AB  - Magnesium (Mg2+) is an important cofactor in many intracellular biochemical
      reactions; however, its role in the signal transduction pathways of pulmonary
      vascular smooth muscle is poorly defined. The purpose of this study was to
      examine the following mechanisms of pulmonary vascular smooth relaxation in the
      presence and in the absence of Mg2+: (1) Endothelium-dependent cGMP-mediated
      relaxation (response to acetylcholine, ACh), (2) Endothelium-independent cGMP
      mediated relaxation (response to sodium nitroprusside, SNP), and (3) beta2
      adrenergic cAMP-mediated relaxation (response to isoproterenol, ISO). Dose
      response curves were generated in isolated rat pulmonary artery rings
      preconstricted with phenylephrine. With Mg2+, ACh 10(-6) M produced complete ring
      relaxation but in the absence of Mg2+, only 66% relaxation was produced in
      response to ACh 10(-6) M (P < 0.05). On the other hand, endothelium-independent
      cGMP-mediated relaxation (response SNP) was not impaired without Mg2+. Beta2
      adrenergic cAMP-mediated relaxation was also impaired in the absence of Mg2+. In
      the presence of Mg2+, ISO 10(-6) M produced complete relaxation but without Mg2+,
      only 30% relaxation was produced (P < 0.05). We conclude that Mg2+ is essential
      for cGMP- and cAMP-mediated mechanisms of pulmonary vasorelaxation.
      Hypomagnesemia should be avoided to prevent pulmonary vasomotor dysfunction.

PMID- 8661180
TI  - Early gene response to hepatic ischemia reperfusion.
AB  - The purpose of this study was to define the differences in heat shock protein
      (hsp)70, albumin, alpha(-1)-acid glycoprotein (AGP), and CCAAT enhancer binding
      proteins (C/EBP) alpha and beta mRNA between hepatic ischemia and reperfusion,
      and to begin to explore C/EBP protein production. These genes have been found
      important in the hepatic response to lipopolysaccharide and inflammation. In two
      experiments, Sprague-Dawley rats underwent temporary occlusion of the median and
      left hepatic lobe vasculature. The first experiment included a single sham
      operated group and ligation of the right hepatic lobes during reperfusion. It
      compared 30 and 60 min ischemia to 2 h reperfusion. The second experiment
      included a sham-operated group for every time point, and the right hepatic lobes
      were not ligated during reperfusion; a 30-min ischemia group was compared to 2-,
      5-, and 24-h reperfusion groups. Total RNA from the ischemic lobes was analyzed
      by Northern hybridization for hsp70, albumin, AGP, and C/EBPalpha and beta.
      C/EBPalpha and beta proteins were compared by Western blotting. Differences in
      experimental design played an important role in interpretation of results. hsp70
      mRNA began to increase during ischemia. Albumin mRNA remained constant during
      ischemia and reperfusion. The ischemic hepatocyte nucleus is not quiescent and
      retains the ability to upregulate certain genes, e.g., hsp70. Changes in mRNA in
      response to hepatic ischemia/reperfusion occur rapidly. Hepatic
      ischemia/reperfusion does not recapitulate the classic acute phase response;
      albumin is not down regulated during reperfusion.

PMID- 8661181
TI  - Gastrin receptor expression during azaserine-induced rat pancreatic
      carcinogenesis.
AB  - The hormone gastrin is thought to stimulate the growth of certain pancreatic
      carcinoma cell lines. We have previously detected the presence of the gastrin
      receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas.
      We had not, however, previously demonstrated that gastrin receptor is expressed
      in pancreatic carcinomas developing in the rat in vivo. Therefore, in the present
      study, we examined rat pancreatic tissue at various stages in azaserine-induced
      pancreatic carcinogenesis for gastrin binding and for the presence of gastrin
      receptor mRNA to determine the temporal expression pattern of the gastrin
      receptor during the in vivo development of pancreatic cancer. Autoradiography of
      pancreatic tissue using (125)I-gastrin-17-I from all azaserine-treated and
      control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin
      binding. At 18 months of age, normal pancreas, azaserine-induced premalignant
      pancreatic nodules, and internodular pancreas demonstrated no specific gastrin
      binding. One of three azaserine-treated animals developed an area of pancreatic
      acinar cell carcinoma at 18 months of age which exhibited significant specific
      gastrin binding of 141.8 - 32.8 fmole/gm of tissue. Southern blot analysis of
      pancreatic RNA isolated from animals at 12 months of age revealed no gastrin
      receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in
      all azaserine-treated animals but absent in control animals. In summary, specific
      gastrin binding is present in in vivo azaserine-induced pancreatic acinar cell
      carcinoma but absent in normal pancreas and azaserine-induced premalignant
      pancreatic nodules. Gastrin receptor mRNA is first expressed in azaserine-treated
      rat pancreas at some point between 12 and 18 months of age. These results
      demonstrate that expression of gastrin receptor is altered in azaserine-treated
      rat pancreas and may play a role in the development of pancreatic cancer.

PMID- 8661182
TI  - Effect of endoluminal PTFE graft placement on cell proliferation, PDGF secretion,
      and intimal hyperplasia.
AB  - To determine the effects of intraluminal placement on peri-anastomotic intimal
      hyperplasia and platelet derived growth factor (PDGF) secretion in
      polytetrafluoroethylene (PTFE) grafts. Infrarenal aortic PTFE grafts were placed
      in 30 dogs as either interposition (n = 12) or intraluminal stented (n = 18)
      grafts. Grafts were explanted at 4 and 8 weeks. At each anastomosis, intima to
      media height ratios (IMHR) were calculated, and smooth muscle (Actin),
      proliferating (PCNA), and PDGF secreting cell content determined using cell
      specific immunohistochemical stains. At the proximal anastomosis, control and
      stented graft IMHRs were 1.01 +/- 0.16 vs 0.59 +/- 0.18 in 4-week and 1.42 +/-
      0.16 vs 0.50 +/- 0.14 in 8-week specimens. Similar IMHR values were present for
      the distal anastomosis. Peri-anastomotic PCNA cell counts were greater in control
      grafts at both 4 and 8 weeks. Stented grafts were associated with diminished IMHR
      and PCNA+ content at both 4 and 8 weeks (P < 0.05). PDGF+ content was similar
      among control and stented grafts at 4 weeks, while lower in stented grafts at 8
      weeks (P < 0.05). At the distal anastomosis, a correlation between PDGF secretion
      and Actin+ cell content was observed in control grafts at 4 (r = 0.74) and 8 (r =
      -0.56) weeks. Cell proliferation was associated with PDGF content in 4-week
      intraluminal and 8-week control grafts (P < 0.05). Changes in IMHR were not the
      result of differential PDGF secretion. Intraluminal location attenuates intimal
      hyperplasia in PTFE grafts. The reduced intimal hyperplasia and improved healing
      of endoluminal grafts could not be attributed to lower PDGF content alone.

PMID- 8661183
TI  - The temporal sequence of G-protein expression in intimal hyperplasia.
AB  - The universal response of a blood vessel to intimal injury is the development of
      intimal hyperplasia. The etiology of this lesion is not fully understood but is
      assumed to involve stimulation of receptors on smooth muscle cells with their
      subsequent proliferation. Many receptor-mediated processes are coupled to G
      proteins but little information exists regarding the expression of G-proteins
      during the development of intimal hyperplasia. This study examines the kinetics
      of G-protein expression in experimental vein grafts. Male New Zealand White
      rabbits had a right carotid interposition bypass graft using the ipsilateral
      external jugular vein. These were harvested on days 1, 3, 5, 7, 14, and 28
      postoperatively for histology (n = 3), for in vitro isometric tension studies of
      potassium chloride, serotonin, bradykinin, and histamine (n = 3), or for Western
      blot analysis (n = 3) of the G-protein subunits (alpha(i1), alpha(i2), alpha(i3),
      alpha(S) and beta). The results show that expression of alpha(i3) developed de
      novo, was detectable by day 1, and continued to increase through day 7,
      paralleling the development of intimal hyperplasia. The expression of alpha(S)
      (52 kDa) increased significantly by day 1 and also continued to increase until
      day 7. In contrast, expression for alpha(i2), alpha(S) (45 kDa) and beta subunits
      increased at a much slower rate from 1 to 7 days and remained constant
      thereafter. No alpha(i1) was detected. The contractile response to potassium
      chloride was significantly reduced (36% of the response in the jugular vein) over
      the first 7 days and increased to 196% of the jugular vein response at 14 and 28
      days. There was minimal response to serotonin, bradykinin, and histamine over the
      first 7 days. Contractile responses to serotonin increased while those to
      bradykinin and histamine decreased from 7 to 28 days. This study demonstrates
      that there are specific changes in alpha(i) and alpha(S) subunits within 24 hr of
      grafting and that increases in all G-proteins occur in a time dependent manner up
      to 7 days postoperatively. Microscopic development of intimal hyperplasia occurs
      from days 3 to 5 and increases rapidly between 7 and 14 days. Changes in the
      expression of G-proteins in the vein grafts, particularly the alpha(i3) subunit,
      parallel this formation of intimal hyperplasia. These alterations in G-protein
      expression do not appear to correlate with G-protein-mediated, contractile
      responses in the vein grafts.

PMID- 8661184
TI  - Intestinal intraepithelial lymphocytes: identification of an inhibitory
      subpopulation.
AB  - The intestinal intraepithelial lymphocytes (iIEL) may play a critical role in
      preventing overwhelming sensitization to foreign luminal antigens. The purpose of
      this experiment was to identify the subpopulation of the iIEL responsible for
      this inhibitory action. One-way mixed lymphocyte cultures (MLC) were performed
      with rat splenocytes [Brown Norway (BN) as responder; irradiated Lewis as
      stimulator]. BN iIEL (comprising 5% of cells per well) were added to assess
      inhibitory function. In the control group, irradiated BN splenocytes were added
      to maintain identical cell numbers. Proliferation assays were expressed as mean
      counts per minute (CPM) +/- SD. Subpopulations of the iIEL were created by
      biomagnetically extracting iIELs labeled with monoclonal antibodies. The addition
      of iIELs to the MLC resulted in a 59% reduction in proliferation (P < 0.05). When
      the CD45+ population was removed from the iIEL this inhibitory activity was lost.
      Removal of the CD8+ population, but not the CD4+ population, also caused a loss
      of inhibitory activity. Separate analysis of either CD8(alpha)(alpha)+ or
      CD8(alpha)(beta)+ subpopulations identified the CD8(alpha)(alpha)+ population as
      having the majority of the inhibitory effect. IN CONCLUSION: 1) The iIEL has an
      inhibitory action on proliferation. 2) The involved population is of lymphoid
      origin, as a loss of CD45+ cells resulted in a loss of inhibition. 3) Loss of
      CD8+ iIEL cells resulted in a loss of inhibition demonstrating that these cells
      are responsible for this action. This inhibitory activity appears to be
      restricted to the CD8(alpha)(alpha)+ subpopulation.

PMID- 8661186
TI  - Antisense suppresssion of protein kinase C-alpha and -delta in vascular smooth
      muscle.
AB  - Understanding and being able to manipulate intracellular signaling pathways which
      control VSMC gene expression and proliferation will be important in efforts to
      control neointimal hyperplastic vascular diseases. Activation of the protein
      kinase C (PKC) family of enzymes is a central event in growth factor-stimulated
      cells. PKC activation results in the activation of downstream protein kinases
      including mitogen activated protein kinase (MAPK). PKC isozymes alpha (alpha) and
      delta (delta) predominate in cultured rat aortic VSMC and both isozymes are
      completely downregulated upon prolonged (16-24 hr) stimulation with the PKC
      activator, phorbol 12,13 dibutyrate (PDBu). At these low levels of PKC, MAPK
      activation in response to PDBu is nearly abolished. To assess the role of
      specific PKC isozymes in regulating MAPK, isozyme-specific antisense
      oligodeoxynucleotides (ODNs) were used to inhibit reexpression of PKC in
      downregulated cells. ODNs were phosphorothioated to increase stability and
      contained C-5 propynyl modified pyrimidines which are reported to have increased
      binding affinity. ODNs were administered in low concentration (400 nM) with a
      cationic liposome carrier (Lipofectin; GibcoBRL). Optical imaging of cells
      treated with FITC-labeled ODNs confirmed that virtually all cells took up the
      ODNs within 2 hr. With this technique, PKCalpha-specific antisense ODNs
      selectively inhibited PKCalpha recovery compared to cells treated with an equal
      length nonsense ODN (76 +/- 3.9, P < 0.001), with no effect on recovery of
      PKCdelta. However, activation of MAPK by PDBu was not significantly inhibited in
      these PKCalpha downregulated cells. This suggests that only a small amount of the
      total PKCalpha is required for PDBu induced activation of MAPK and/or that
      PKCdelta can mediate the response. Manipulation of PKC isozymes using this model
      system should allow assessment of the roles of specific isozymes in controlling
      diverse downstream effectors and events related to VSMC growth and proliferation.

PMID- 8661185
TI  - Lazaroid therapy (methylaminochroman: U83836E) reduces vein graft intimal
      hyperplasia.
AB  - The development of intimal hyperplasia is now recognized as a major impediment to
      graft patency and recent studies suggest that the infiltration of
      polymorphonucleocytes and oxygen free radical mediated injury are involved in the
      early development of intimal hyperplasia. This study examines the effect of a
      methylaminochroman, U83836E (Upjohn Company), a second generation lazaroid, in
      controlling the development of intimal hyperplasia and its associated smooth
      muscle cell physiological responses in an experimental model of vein bypass
      grafting. Twenty New Zealand White rabbits had a right carotid interposition
      bypass graft using the ipsilateral external jugular vein. Ten animals received
      chronic oral therapy with U83836E (10 mg/kg/day; begun 5 days before surgery and
      continued until harvest) and 10 control animals received vehicle only. All
      animals were sacrificed on the 28th postoperative day. Vein grafts were harvested
      either for morphology/videomorphometry (n = 6 per group) or for in vitro
      isometric tension studies (n = 4; four 5-mm rings per graft). The incorporation
      of [3H]thymidine into the cellular DNA of serum-stimulated rabbit aortic smooth
      muscle cells (passage 6th to 9th) was also assessed in the presence of increasing
      concentrations of U83836E (10(-9) to 10(-4) M). Treatment with U83836E produced a
      41% decrease in overall mean intimal thickness in the U83836E-treated vein grafts
      compared to untreated vein grafts (P = 0.003). There were no differences in the
      medial thicknesses or luminal dimensions of the control and treated vein grafts.
      U83836E induced norepinephrine hypersensitivity in both jugular veins and vein
      grafts compared to controls. Other physiological contractile responses of the
      jugular veins and vein grafts were unaltered by U83836E. U83836E did not inhibit
      the in vitro [3H] thymidine incorporation in a dose-dependent manner until very
      high concentration when there was a significant and precipitous response with an
      IC(50) of 67 microM (114 microgram/ml) and a maximal inhibition of 97 +/- 2%
      (mean +/- SEM) at 80 microM (137 microgram/ml). Therapy with the
      methylaminochroman, U83836E, is beneficial in controlling the early development
      of intimal hyperplasia without significant changes in the physiological responses
      of the smooth muscle cells.

PMID- 8661187
TI  - Thalidomide inhibits TNF response and increases survival following endotoxin
      injection in rats.
AB  - Sepsis is a leading cause of death following major trauma and complicated
      abdominal surgery. Tumor necrosis factor-alpha (TNF) is believed to be a central
      mediator in the inflammatory response syndrome. Numerous methods of blunting the
      TNF response in sepsis have been attempted with suggestion of increased survival
      and decreased organ injury. Thalidomide, shown in vitro to selectively inhibit
      TNF production, has been used clinically in states of chronic TNF elevation with
      encouraging results. In this study, we examined the effect of thalidomide
      administration in a rat model of acute septic shock. Femoral artery cannulation
      was performed and baseline TNF measured. Dose response was determined by giving
      varying doses of thalidomide by gavage. Rats were injected intraarterially with
      endotoxin and serial samples drawn. TNF was measured by ELISA. For survival,
      thalidomide was given by gavage and endotoxin injected intraperitoneally. Serum
      TNF elevation occurred after endotoxin injection with peak levels at 90 min.
      Thalidomide treated rats had lower TNF levels at all time points (P = <0.01 at 90
      and 120 min), with the inhibition being dose dependent. Survival in treated rats
      exceeded that of untreated rats (53% vs 19%, P = <0.05) at 48 and 72 hr. In
      conclusion, we found that thalidomide administration leads to increased survival
      following acute endotoxemia, which may be due to the observed TNF inhibition.

PMID- 8661188
TI  - Effects of serosal-side acidosis on cell pH (pHi) and membrane electrical
      properties in gastric mucosa.
AB  - Acute gastric mucosal injury and bleeding occur in the settings of both
      respiratory acidosis or metabolic acidosis secondary to systemic sepsis or shock.
      Respiratory acidosis, however, is more predictably associated with acute injury
      than metabolic acidosis. We hypothesized that the gastric surface epithelial
      cells are more susceptible to acute increases in PCO2 than to acute decreases in
      HCO3-, even for the same level of extracellular acidification. To evaluate this
      hypothesis, we used intracellular microelectrodes to measure pHi, cell membrane
      potential (Vc), as well as ion conductances of the apical (Ga) and basolateral
      (Gb) membranes and the paracellular pathway (Gs) in gastric mucosal cells during
      acute changes in serosal PCO2 or HCO3-. Necturus antral mucosae were mounted in
      Ussing chambers, perfused on both sides by Ringer solution (40 mmHg PCO2, 18 mM
      HCO3-, pH 7.3). Measurements were performed before and during increases in PCO2
      (80 mmHg, pH 7.0) or decreases in HCO3- (7.2 mM, pH 6.8 or 2.4 mM, pH 6.4). Both
      forms of acidosis acidified pHi, depolarized membrane potentials, and decreased
      ion conductances across apical and basolateral membranes, but not the
      paracellular pathways. For the same level of extracellular acidification,
      increases in PCO2 were more effective than acute decreases in HCO3- in acidifying
      pHi and eliciting disturbances in voltage-generating and ion permeability
      properties of the cell membranes. These findings suggest that pH-buffering
      mechanisms in gastric surface cells respond less effectively to high PCO2 than
      low HCO3.

PMID- 8661189
TI  - The role of luminal nutrients in intestinal injury from mesenteric reperfusion
      and platelet-activating factor in the developing rat.
AB  - Necrotizing enterocolitis (NEC) develops primarily after the onset of enteral
      feeds in the premature infant. The purpose of this study was to evaluate the
      influence of intestinal luminal nutrients on histologic injury and the oxidant
      response in a rat model of NEC. On postnatal Days 10 and 35, Sprague-Dawley rats
      (total n = 81) underwent abdominal laparotomy. A control group received sham
      injury only. The ischemia groups received a single intraluminal injection of 0.25
      ml (Day 10) or 1.0 ml (Day 35) of lactose (8.6 g/dl), casein (2.2 g/dl), corn oil
      (4.4 g/dl), or infant formula (Similac; 20 g/dl). After injection of the nutrient
      solutions, ischemia groups underwent mesenteric occlusion for 1 hr and
      intraluminal injection of platelet-activating factor (50 microgram/kg).
      Necropsies were performed after 6 hr or at demise. Intestinal samples were taken
      for histology, total glutathione (GSH; an antioxidant), and conjugated dienes (a
      lipid peroxidation product). Histologic injury was scored from 0 (normal) to 5
      (transmural necrosis). Microscopic injury scores in the oil group were
      significantly higher than the casein group (P < 0.05) and trended toward being
      higher in the formula group (P = 0.085) at age 10 days. Total GSH activity was
      significantly higher in the sham groups than all ischemia groups on Day 10 (P <
      0.001) and than the corn oil group on Day 35 (P < 0.05). GSH activity did not
      differ among ischemia groups. Conjugated diene concentrations were significantly
      higher in the casein group than the lactose and sham groups at age 10 days (P <
      0.05) only. We conclude that intraluminal lipids may augment intestinal ischemic
      injury in the newborn (age 10 days) but not the weanling rat. While oxygen-free
      radicals were present during injury, lipid peroxidation from oxygen radicals was
      not responsible for this increase in histologic injury.

PMID- 8661190
TI  - Immediate burn wound excision restores antibody synthesis to bacterial antigen.
AB  - Although burn wound excision and grafting have been shown to improve patient
      survival, the effects on immune function, especially humoral immunity, are not
      completely understood. The purpose of this study was to investigate the effect of
      immediate and early wound excision on antibody synthesis and B-cell
      proliferation, specifically, antibody response to PGPS, a ubiquitous bacterial
      cell wall antigen. Thirty-six male BALB/c mice were divided into four groups.
      Sham mice received no burn, and remaining mice received a 30% body surface area
      full-thickness burn. Under general anesthesia, excision and grafting was
      performed either 6 or 72 hr after injury (BE&G6 and BE&G72 groups). A fourth
      control group received burn but did not undergo excision and grafting (Burn
      group). Splenocytes were isolated 8 days postburn and stimulated with 2.5
      microgram/ml lipopolysaccharide. Anti-PGPS IgM, total IgM, and total IgG levels
      were determined by ELISA. B-cell proliferation, measured by [3H]-thymidine
      uptake, was expressed as stimulation index. All B-cell functions were
      significantly suppressed by burn injury. Immediate excision and grafting (BE&G6)
      restored anti-PGPS IgM synthesis to normal, while nonspecific B-cell functions
      did not change significantly. Early excision and grafting (BE&G72), however,
      failed to significantly improve any B-cell functions. Immediate but not early
      BE&G restored antibody synthesis to the bacterial cell wall antigen (PGPS).
      Immediate BE&G may therefore lead to a decrease in bacterial infection after burn
      injury.

PMID- 8661191
TI  - Epidermal growth factor improves intestinal adaptation during somatostatin
      administration in vivo.
AB  - Somatostatin (SMS) is administered to patients with short bowel syndrome and
      enterocutaneous fistulae. Previous studies have shown detrimental effects of SMS
      on intestinal adaptation after bowel resection. We examined whether
      administration of epidermal growth factor (EGF) could reverse the deleterious
      effects of SMS seen after enterectomy. Sixty-four Sprague-Dawley rats underwent
      an 80% small bowel resection or transection as control. Rats received either SMS
      at 50 ng x kg(-1) x h(-1), EGF/Urogastrone at 1.5 microg x kg(1-) x h(-1), or
      both via subcutaneous miniosmotic pumps. Samples were obtained at 1 day and 1
      week after surgery for histologic examination, analysis of apical Na+/glucose
      cotransporter protein and mRNA expression, and analysis of basolateral Na+/K+
      ATPase protein and mRNA expression. Protein expression was analyzed by Western
      blotting whereas mRNA expression was compared by ribonuclease protection assay.
      Histologically, villus to crypt length after intestinal resection showed
      increased adaptation in EGF/SMS vs SMS treated animals in both jejunum and ileum.
      Analysis of mRNA and protein of epithelial transporters show early increases when
      EGF is administered with SMS vs SMS only. We conclude that combination therapy
      using EGF and SMS may be beneficial to intestinal adaptation after small bowel
      resection. Both histologic and molecular data suggest an enhanced absorptive
      potential and adaptation of the remaining intestine when EGF is administered.

PMID- 8661192
TI  - Beta3 integrin expression in melanoma predicts subsequent metastasis.
AB  - Previous studies have suggested that differential expression and/or activation of
      integrins facilitates metastatic progression in murine and human melanoma. While
      recent data show that the integrin alphavbeta3 is involved in tumor angiogenesis
      and that tumor growth may be abrogated by alphavbeta3 inhibitors in vitro, the
      clinical significance of beta3 integrin expression in human malignant melanoma is
      not known. To assess the prognostic value of beta3 integrin expression, we
      examined primary cutaneous melanomas from 160 patients followed for a mean of 98
      months or until death. We quantified the percentage of tumor area stained with
      beta3 integrin Ab CD-61 using an image analyzer. beta3 integrin expression was
      detected in 107/160 primary melanomas (69%). beta3-integrin-positive (beta3+)
      tumors were thicker (mean 2.98 +/- 0.3 mm) than beta3-integrin-negative (beta3-)
      melanomas (mean 1.64 +/- 0.2 mm) (P = 0.002). Patients with beta3+ melanomas were
      more likely to relapse (57/107, 53%) and to die from disease (45/107, 42%) than
      those with beta3- tumors (6/53, 11%; and 4/53, 8%, respectively) (P < 0.001).
      Overall survival was greater for beta3- than for beta3+ patients (mean 102 +/- 9
      vs 69 +/- 6 months) (P = 0.001). These data show that beta3 integrin expression
      in primary cutaneous melanoma predicts subsequent metastatic progression. Further
      study of beta3 integrins in the development of melanoma metastases may yield new
      therapeutic strategies, as well as prognostic information, for the treatment of
      this cancer.

PMID- 8661193
TI  - Tissue factor pathway inhibitor protects the ischemic spinal cord.
AB  - Tissue factor pathway inhibitor (TFPI) is a novel agent that binds to tissue
      factor/VIIa complex and factor-Xa, thereby reducing the effect of tissue factor
      (TF) on inflammation and the extrinsic pathway of coagulation. We hypothesize
      that systemic treatment with TFPI may limit ischemia-reperfusion (IR) injury. Our
      experiment was designed to evaluate the effects of TFPI on IR in the spinal cord.
      Twenty-three adult New Zealand white rabbits had snare occlusion devices placed
      circumferentially around the aorta and tunneled to a subcutaneous position. Forty
      eight hours later, in the fully awake state, the animals were treated with either
      TFPI (1 mg/kg bolus followed by a 1-hr infusion of 20 microgram/kg/min), or
      heparin (100 U/kg bolus) followed by a 1-hr infusion of 10 ml/kg/hr of PBS while
      controls received phosphate buffered saline (20 ml followed by a 1-hr infusion of
      10 ml/kg/hr). The infrarenal aorta was occluded for 21 min in all groups via the
      snare device. Animals were observed for 3 days and neurologic recovery was graded
      by the Tarlov criteria. Results were evaluated as percent of animals with
      hindlimb recovery (Tarlov 3 and 4). At 24 hr postocclusion, 88% of the TFPI
      treated animals had recovered neurologic function versus only 20% of heparin
      treated animals and 10% of the phosphate buffered saline group (P=0.031 and
      0.009, respectively). At 72 hr, 63% of the TFPI animals retained neurologic
      function versus 20% of heparin-treated animals and 10% of phosphate buffered
      saline-treated animals (P=0.032, TFPI versus phosphate buffered saline). The
      mechanism of action of TFPI is not completely understood, yet this drug may hold
      promise in the prevention of IR injury of the spinal cord.

PMID- 8661195
TI  - Effects of lipopolysaccharide on intestinal injury; potential role of nitric
      oxide and lipid peroxidation.
AB  - Nitric oxide can react with superoxide anion to form peroxynitrite. The resultant
      free radical can be rapidly protonated to yield even more toxic substances such
      as hydroxyl radical and nitric dioxide. The generation of either of these free
      radical species can promote lipid peroxidation and subsequent tissue injury if
      they are formed in excessive amounts. During sepsis, both nitric oxide synthesis
      and peroxynitrite production are substantially enhanced in a variety of tissues,
      effects which favor the development of lipid peroxidation. Consequently, this
      study was undertaken in conscious rats, to ascertain what effect
      lipopolysaccharide (LPS) has on inducible nitric oxide synthase expression in the
      small intestine and to determine whether this is associated with lipid
      peroxidation or morphologic injury. When examined by Western immunoblot analysis,
      significantly more inducible nitric oxide synthase immunoreactivity was detected
      in the ileum than in the jejunum 5 hr after treatment with intraperitoneal LPS (1
      and 20 mg/kg). Further, using the thiobarbituric acid assay as an index of lipid
      peroxidation, it was demonstrated that significantly more thiobarbituric acid
      reactive substances were present in the ileal mucosa than in the jejunal mucosa
      after LPS (20 mg/kg) administration. However, LPS (20 mg/kg) resulted in
      morphologic damage to both segments of the intestinal epithelium. These data
      indicate that the gut is a target during sepsis and that regional differences
      exist within the small bowel with respect to induction of nitric oxide synthase
      and lipid peroxidation following LPS treatment. Thus, while induction of nitric
      oxide synthase during endotoxic shock may still represent a mechanism of local
      intestinal damage, it is not necessarily associated with enhanced lipid
      peroxidation.

PMID- 8661196
TI  - A single endotoxin challenge induces delayed myocardial protection against
      infarcation.
AB  - Sublethal endotoxemia attenuates cardiac functional injury from global ischemia
      but it is unknown whether endotoxemia can protect myocardium against infarction.
      Furthermore, increases in myocardial catalase and heat shock protein (HSP)
      following endotoxemia have been associated with cardiac ischemic protection. We
      therefore hypothesized that a 72-hr pretreatment with endotoxin (ETX) would
      reduce myocardial tissue necrosis in association with augmented catalase activity
      and stress protein expression. Rabbits were treated with normal saline or
      lipopolysaccharide (Salmonella typhimurium) at 10, 5, and 1 microgram/kg doses.
      Three days after saline or ETX injection they were subjected to 45 min of
      coronary artery occlusion followed by 3 hr of reperfusion. Area of necrosis
      (tetrazolium staining) was normalized to anatomic risk zone size (Evans blue
      staining). Catalase activity was measured by a standard assay and HSP 72 was
      assessed by immunohistochemistry. During regional ischemia and reperfusion there
      were no differences in heart rate or mean arterial blood pressure between groups.
      ETX treated rabbits had the same risk zone size as controls. Infarct size was
      reduced in the ETX treated rabbits at the 10 and 5 microgram/kg doses compared
      with control rabbits (17.5 +/- 1.5% and 22.2 +/- 3.1% vs 45.3 +/- 2.5%; P < 0.05)
      but no protective effect was observed at the 1.0 micrograms/kg dose (38.0 +/-
      4.6%; P > 0.05 vs control). Catalase activity was not different between control
      and ETX (5 microgram/kg) treated groups (997.8 +/- 59.1 U/g vs 1099.6 +/- 69.3
      U/g myocardium; P > 0.05) but endotoxin induced expression of myocardial HSP 72.
      We conclude that a single challenge with endotoxin can induce delayed myocardial
      protection against infarction in vivo. This delayed cardioprotective response
      involves enhanced stress protein expression without changes in myocellular
      catalase activity.

PMID- 8661197
TI  - Compartmentation of endogenously synthesized amino acids in neonates.
AB  - The conversion of D-[U-13C]glucose to proline (Pro), aspartate (Asp), and
      cysteine (Cys) is limited in premature neonates, implying that these amino acids
      (AA) are conditionally essential. This study was performed to determine whether
      these findings resulted from an insufficient precursor dose or intracellular
      compartmentation of newly synthesized amino acids, rather than inadequate
      synthesis. In the first phase of this study, seven total parenteral nutrition
      fed, premature neonates received IV D-[U-13C]glucose at 5 mg/kg/min for 4 hr. In
      the second phase, a separate cohort of eight patients received an identical
      infusion. Blood was obtained before and at the end of the infusion. Isotopic
      enrichments of the free plasma AA and glucose were measured using gas
      chromatography/mass spectrometry in both studies. In phase 2, the isotopic
      enrichments of the AA bound to the hepatically synthesized proteins, fibrinogen
      and VLDL-apolipoprotein B-100 (apo B-100), were measured. In phase 1, despite a
      glucose precursor enrichment greater than 66%, Pro, Asp, and Cys remained the
      least enriched of all amino acids studied (P < 0.05). Asp, but not Pro,
      demonstrated very high enrichments in apo B-100 (P < 0.001), reflecting distinct
      intracellular compartmentation. We conclude that the limited conversion Of D-[U
      13C]glucose to Pro, Asp, and Cys did not result from low precursor glucose
      enrichment and that there is evidence of Asp compartmentation (intracellular) in
      premature neonates. However, the low Pro enrichment in the free plasma AA pool
      and the absence of intracellular Pro compartmentation suggest that Pro may be a
      conditionally essential AA for premature neonates.

PMID- 8661198
TI  - Measuring functional residual capacity in normal and oleic acid-injured lungs.
AB  - Functional residual capacity (FRC) is an important oxygen reserve that is often
      depleted in acute respiratory failure. Recent interest in the mechanisms of
      liquid ventilation and limited experience in measuring FRC in paralyzed,
      mechanically ventilated, normal and lung-injured animal models have mandated
      development of accurate laboratory techniques. Eight sheep, from 17 to 27 kg,
      were anesthetized and instrumented to provide a tracheostomy, a pulmonary artery
      catheter, and carotid arterial line. They were randomized to two groups, one of
      which received 0.07 ml/kg of intravenous oleic acid to induce lung injury. Gas
      ventilation of both groups was identical except for respiratory rate, which was
      adjusted to normalize PaCO2. FRC was measured in duplicate by both helium
      dilution (HD) and body plethysmography (BP). When measurements were completed,
      the animals were euthanized and their endotracheal tubes clamped at end
      expiration. The lungs were then removed and their water displacement (WD) FRC
      values were measured. FRC was the difference between WD and tissue weight
      assuming 1 ml = 1g. Pearson's correlation coefficient (R(2)) was calculated.
      During in vitro measurement of test lungs, HD had an R(2) value of 0.99 and BP
      had an R(2) value of 0.98. When compared to WD, in vivo measurement of FRC by HD
      had an R(2) value of 0.94 while the value for BP was 0.97. In conclusion, both HD
      and BP are accurate methods of determining FRC in an uninjured and injured lung
      model when compared to postmortem WD. Documenting changes in FRC will aid in
      elucidating the mechanisms of alternative ventilatory techniques.

PMID- 8661199
TI  - Discordant reprogramming of LPS-stimulated cytokine gene transcription and
      secretion by macrophages after LPS pretreatment.
AB  - Dysregulated macrophage (Mphi) cytokine release occurs during systemic
      inflammation and may predispose to organ failure. We showed that Mphis pretreated
      (PreRx) in vitro with low-dose LPSp are "reprogrammed" to release less TNF and
      more IL-1 in response to subsequent LPS activation (LPSa). The effects of this
      LPSp "reprogramming" on Mphi cytokine gene transcription were investigated in the
      present study. Murine peritoneal exudate Mphis were cultured in vitro 48 hr, then
      PreRx 24 hr +/- 100 ng/ml of LPSp. Cultures were stimulated with 0-1000 ng/ml
      LPSa and 6-hr supernatant TNF and IL-1 were measured using specific bioassays.
      Cytokine gene transcription was estimated 6 hr after LPSa using RT-PCR. PreRx
      with LPSp inhibited TNF and augmented IL-1 release by LPSa. PreRx with LPSp
      significantly inhibited cytokine gene transcription; however, messages for both
      TNF and IL-1 were detectable after high-dose LPSa. Despite LPSp inhibition of IL
      1 transcription by most LPSa concentrations, IL-1 protein was augmented by PreRx.
      High-dose LPSa can override LPSp reprogrammed inhibition of cytokine gene
      transcription, but altered TNF and IL-1 protein release after LPSp may be
      regulated posttranscriptionally.

PMID- 8661200
TI  - Endothelin-1 synthesis and receptor-mediated activity in porcine lymph vessels.
AB  - Endothelin-1 (ET-1) is a potent vasoconstrictor of blood vessels and interacts
      with nitric oxide (NO) to regulate vascular tone. We hypothesized that ET-1 may
      modulate lymph vessel tone via local synthesis, receptor-mediated
      vasoconstriction, and interaction with NO. Serial sections obtained from formalin
      fixed porcine mediastinal tissue, incubated with either ET-1 or von Willebrand
      factor antibody and stained with avidin-biotin complex and peroxidase,
      demonstrated ET-1 in lymphatic vascular endothelium. Isometric tension was
      recorded in vitro in fresh porcine tracheo-bronchial lymph vessel rings in
      response to the cumulative addition of ET-1 (10(-11) to 10(-6) M). ET-1 induced a
      tonic contraction with peak tension at 3 x 10(-7) M (mean tension 3731 +/- 306
      mg; 259 +/- 20 percent of response to 65 mM KCl). The addition of specific
      receptor antagonists (ET(A) (BQ-610), ET(B) (BQ-788), or both) blocked the
      contractile response seen in ET-1 stimulated controls (ET(A) + ET(B) > ET(A)>>
      ET(B). The response to ET-1 was increased by endothelial damage but was
      unaffected by the inhibition of NO synthesis by N (G)-monomethyl-L-arginine (L
      NMMA) Endothelial damage altered the ET-1 response in the presence of ET(B)
      antagonist but not ET(A) antagonist. ET-1 is a potent endothelium-derived
      vasoconstrictor of lymph vessels. Its effects are mediated through specific
      receptors, are not importantly modulated by NO, but may be modified by release of
      other endothelium-derived relaxing factors. We conclude that lymph vessel tone
      may be regulated by ET-1.

PMID- 8661201
TI  - Dichloroacetate enhanced myocardial functional recovery post-ischemia : ATP and
      NADH recovery.
AB  - This study was undertaken to determine the effect of dichloroacetate (DCA) on
      myocardial functional and metabolic recovery following global ischemia. Isolated
      rabbit hearts were subjected to 120 min of mildly hypothermic (34 degrees C),
      cardioplegic arrest with multidose, modified St. Thomas' cardioplegia. Hearts
      were reperfused with either physiologic salt solution (PSS) as controls, (CON, n
      = 10) or PSS containing DCA (DCA, n = 6) at a concentration of 1 mM. Functional
      and metabolic indices were determined at baseline and at 15, 30, and 45 min of
      reperfusion. In four DCA and four CON hearts, myocardial biopsies were taken at
      baseline, end-ischemia, 15 and 45 min for nucleotide levels. Functional recovery
      was significantly better in hearts reperfused with DCA as demonstrated by
      recovery of baseline developed pressure (DCA = 69 +/- 5%, CON = 45 +/- 9%) and
      dP/dt (DCA = 64% +/- 10% versus CON = 48% +/- 10%). Coronary blood flow was not
      different between groups either at baseline or during reperfusion, but myocardial
      oxygen consumption (MVO2) was increased in the DCA versus CON hearts (79% +/- 20%
      of baseline vs 50% +/- 18%). Recovery of myocardial adenylate energy status was
      improved in the DCA versus CON hearts (ATP recovered to 45% +/- 20% versus 8% +/-
      6% of baseline). Coronary sinus lactate concentration was decreased in DCA
      perfused hearts at 45 min of reperfusion. Percent of baseline NADH values was
      similar at 15 min of reperfusion, but at 45 min, DCA hearts showed a decrease in
      NADH levels, while CON hearts showed an increase (DCA = 48%; CON = 121%). The
      enhanced myocardial function and improved metabolic status noted with DCA may
      result from increased oxidative phosphorylation due to altered pyruvate
      dehydrogenase (PDH) activity.

PMID- 8661202
TI  - The use of objective structured clinical examination (OSCE) for evaluation and
      instruction in graduate medical education.
AB  - This study had two purposes: determining the reliability and validity of the
      Objective Structured Clinical Examination (OSCE) in assessing performance by
      trainees at all levels, including medical students and chief residents; and
      estimating the impact of providing OSCE participants with immediate feedback
      about their performance. A comprehensive 210-min OSCE was administered to 53
      surgical residents and 6 junior medical students. Faculty experts proctored all
      patient stations and provided immediate feedback to participants after the
      patient interaction segments (Part A). The participants then answered questions
      about the patients seen (Part B). The reliability of the OSCE was high (.91),
      identical to that of a previous resident OSCE with no feedback. The standard
      error of measurement for both parts was approximately 4%. At the 95% confidence
      interval, each participant's actual level of clinical performance (Part A) and
      clinical knowledge (Part B) could be estimated with an error of +/-8%.
      Participants showed significant differences in clinical performance (Part A, P <
      0.01) and knowledge (Part B, P < 0.01) by level of training. Most participants
      (74%) rated the OSCE as an above average or outstanding educational method. The
      OSCE is a valid and reliable test of residents' clinical skills. Feedback to
      participants during the OSCE was positively received and did not perturb test
      reliability.

PMID- 8661203
TI  - Transgenic animals demonstrate a role for the IL-1 receptor in regulating IL
      1beta gene expression at steady-state and during the systemic stress induced by
      acute pancreatitis.
AB  - Interleukin-1 (IL-1) gene expression is selectively induced in tissues involved
      in multisystem organ failure during acute pancreatitis, suggesting a role in the
      pathogenesis of distant organ dysfunction. This study was undertaken to
      investigate the mechanism of pancreatitis-induced end organ cytokine production
      and to better understand the processes by which IL-1 production is regulated.
      Seventy adult male transgenic mice in which the type 1 IL-1 receptor had been
      deleted by gene targeting in embryonic stem cells were utilized (homozygous -/-
      IL-1R knockout). Acute pancreatitis was induced by one of two methods: (A) IP
      injections of caerulein (50 microgram/kg/hr x 4) with animals sacrificed at 0,
      .5, 1, 2, 4, 6, and 8 hr; (B) 48-hr exposure to a choline deficient ethionine
      supplemented (CDE) diet with animals sacrificed at 0 and 72 hr. Knockout animals
      were compared to strain-specific control mice expressing the normal wild-type IL
      1 receptor gene in which pancreatitis was similarly induced. The severity of
      pancreatitis was stratified by serum amylase, lipase, and blind histologic
      grading. IL-1 mRNA production was determined within the pancreas, lungs, liver,
      and spleen by quantitative differential RT-PCR. Deletion of the IL-1R1 attenuated
      the severity of pancreatitis, reaching statistical significance in the less
      severe edematous model. There was little or no constitutive expression of IL-1
      mRNA within any of the tissues examined from wild-type animals; however, knockout
      animals showed elevated steady-state levels in each tissue. IL-1 mRNA became
      detectable in all tissues of wild-type animals shortly after either form of
      pancreatitis became apparent and increased significantly with worsening
      pancreatitis. Despite the attenuated pancreatitis, knockout animals produced
      significantly greater levels of IL-1 mRNA in each tissue, typically demonstrating
      a 30-50% increase over time matched IL-1 mRNA production in wild-type animals
      which was not pancreatitis model dependent. We conclude that genetic deletion of
      IL-1 receptors results in the overproduction of IL-1 mRNA in organs known to
      produce cytokines during pancreatitis even when the severity of pancreatitis is
      lessened. This suggests that a negative feedback loop exists between the IL-1
      receptor and IL-1 gene expression.

PMID- 8661204
TI  - Nitric oxide regulates wound healing.
AB  - Nitric oxide (NO) synthesis occurs during wound healing, but its role has not
      been defined. To study the effect of NO on wound repair, S-methyl isothiouronium
      (MITU, a competitive inhibitor of NO synthase) was administered at a dose of 10,
      50, and 100 mg/kg body weight/day, using intraperitoneally implanted miniosmotic
      pumps. Groups of 10 male Balb/C mice underwent a dorsal skin incision and
      polyvinyl alcohol sponges were inserted subcutaneously. The animals were
      sacrificed 10 days postwounding and wound breaking strength and hydroxyproline
      content of sponges, an index of reparative collagen deposition, were determined.
      Some sponges were used to harvest wound fluid and infiltrating cells, which were
      then incubated overnight with or without 1 mM MITU. Nitrite and nitrate, stable
      end products of NO, were measured in wound fluid and in wound cell culture
      supernatants. Continuous intraperitoneal infusion of MITU significantly decreased
      wound fluid nitrite/nitrate concentrations in a dose dependent manner (P < 0.01).
      Inhibition of wound NO synthesis by 100 mg MITU/kg/day was paralleled by lowered
      wound collagen accumulation (P < 0.01) and wound breaking strength (P < 0.01). In
      vitro NO synthesis by wound cells obtained from animals treated with 100 mg
      MITU/kg/day was not significantly different from controls (12.6 +/- 1.2 vs 10.7
      +/- 0.6 nmole NO2 + NO3/microgram DNA), reflecting the reversible inhibition of
      NO synthase by MITU. However, NO production was equally inhibited in wound
      infiltrating cells by the in vitro addition of MITU (83% vs 85%, respectively).
      These data suggest that nitric oxide synthesis is critical to wound collagen
      accumulation and acquisition of mechanical strength.

PMID- 8661205
TI  - Liver endothelial cell dysfunction occurs early following hemorrhagic shock and
      persists despite crystalloid resuscitation.
AB  - Although hepatocellular function is depressed early following hemorrhage, it
      remains unknown whether liver endothelial cell function is also compromised under
      such conditions. The aim of this study, however, was to determine if liver
      endothelial cell function is depressed during hemorrhage and persists following
      crystalloid resuscitation. To study this, rats underwent a 5-cm laparotomy (i.e.,
      trauma induced) and were bled to and maintained at a mean arterial pressure of 40
      mm Hg until 40% of maximal bleedout volume was returned in the form of Ringer's
      lactate. The animals were then resuscitated with 4 times the volume of maximal
      bleedout volume with Ringer's lactate. Arterial blood was taken before and during
      hemorrhage and after resuscitation. Plasma hyaluronic acid (HA) levels were
      determined using a Pharmacia assay kit. To determine whether the elevated HA is
      due to a decrease in its removal, HA clearance was assessed at 0 and 24 hr after
      resuscitation by injecting 30 microgram/100 g body wt HA intravenously. The
      results indicate that plasma HA levels increased significantly at the time of
      maximal bleedout, which persisted even 24 hr after the completion of
      resuscitation. Hyaluronic acid clearance decreased significantly at 0 and 24 hr
      after resuscitation, suggesting that the decreased HA clearance plays a major
      role in producing the elevated plasma HA levels. Since circulating HA is cleared
      exclusively by liver endothelial cells, these results, taken together, indicate
      that liver endothelial cell dysfunction (i.e., the increased plasma HA levels and
      decreased HA clearance) occurs early during hemorrhage (i.e., approximately 44
      min after the onset of the insult) and persists despite resuscitation. Thus, the
      depressed liver endothelial cell function may directly or indirectly contribute
      to hepatocellular dysfunction observed under such conditions.

PMID- 8661206
TI  - A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor
      necrosis factor.
AB  - Therapeutic successes following treatment of murine tumors with tumor necrosis
      factor-alpha (TNF) have not been easily applied to clinical oncology because the
      concentrations of TNF required in humans induces systemic toxicity. This has led
      us to identify mediators which could sensitize tumors to the effects of TNF,
      permitting administration of lower doses and possible realization of the
      therapeutic potential of this cytokine. Our study reports the ability of a novel
      cytokine, endothelial-monocyte-activating polypeptide II (EMAP II), to sensitize
      initially resistant murine and human tumors to TNF-induced regression employing a
      murine model. Recombinant (r) EMAP II was purified from Escherichia coli
      transformed with a plasmid expressing mature EMAP II. The B16 melanoma, raised in
      C57BL/6 mice, or a human fibrosarcoma (HT-1080), grown in immunocompromised mice,
      was injected intratumorally with either vehicle or rEMAP II/heat-treated EMAP II
      (50-100 micrograms) followed by systemic TNF/heat-treated TNF (5 micrograms) and
      assessed for tumor volume, hemorrhage, and histologic appearance. Both the B16
      melanoma and the HT-1080 human fibrosarcoma underwent thrombohemorrhagic and
      acute inflammatory changes concomitant with regression or significantly slowed
      growth after administration of intratumor EMAP II followed by systemic TNF.
      Omission or inactivation of either cytokine abrogated this effect. These results
      demonstrate that local treatment of certain tumors with EMAP II results in
      enhanced susceptibility to TNF-mediated induction of thrombohemorrhage and
      regression.

PMID- 8661207
TI  - Melatonin administration attenuates depressed immune functions trauma-hemorrhage.
AB  - The pineal hormone melatonin has been used in clinical trials in patients
      suffering from AIDS and also as an adjuvant for cancer therapy. Although
      melatonin has been reported to have beneficial effects in some animal models of
      immune dysfunction, it remains unknown whether this hormone has any salutary
      effects on immunity following soft-tissue trauma and/or major blood loss. To
      study this, soft-tissue trauma (2.5-cm midline laparotomy) and hemorrhagic shock
      (arterial BP 35 +/- 5 mm Hg) were induced in C3H/HeN mice. The mice were
      resuscitated after 90 min of hypotension with the shed blood and lactated
      Ringer's solution. Treatment with saline, vehicle, or melatonin (10 mg/kg BW)
      subcutaneously was administered in the evening of the day of surgery and again on
      the following evening. All animals were sacrificed at 48 hr following trauma
      hemorrhage and resuscitation to obtain plasma, splenocytes, as well as splenic
      and peritoneal macrophages (Mphi). The results indicate that melatonin
      administration after trauma-hemorrhage significantly improved the depressed
      immune functions, as evidenced by the restoration of Mphi IL-1 and IL-6 release,
      as well as significantly improved splenocyte IL-2 and IL-3 release and splenocyte
      proliferative capacity. No differences in circulating corticosterone levels
      between vehicle- and melatonin-treated animals were observed. This is the first
      study to show that melatonin, which is reported to be free of adverse side
      effects, can be considered a safe and effective therapeutic agent for restoring
      the depressed immunological function after soft-tissue trauma and hemorrhagic
      shock.

PMID- 8661208
TI  - Dietary modulation of amino acid transport in rat and human liver.
AB  - Specialized diets enriched in the amino acids glutamine and arginine have been
      shown to benefit surgical patients. In the liver, glutamine supports glutathione
      biosynthesis, arginine regulates nitric oxide synthesis, and both of these amino
      acids serve as precursors for ureagenesis, gluconeogenesis, and acute phase
      protein synthesis. The effects of a diet enriched with glutamine and arginine on
      hepatic plasma membrane transport activity have not been studied in humans. We
      hypothesized that feeding supradietary amounts of these nutrients would enhance
      the activities of the specific carriers which mediate their transmembrane
      transport in the liver. We fed surgical patients (n = 8) and rats (n = 6) one of
      three diets: a) a regular diet, b) an enteral liquid diet containing arginine and
      glutamine, or c) an enteral diet supplemented with pharmacologic amounts of
      glutamine and arginine. Diets were isocaloric and were administered for 3 days.
      Hepatic plasma membrane vesicles were prepared from rat liver and from human
      wedge biopsies obtained at laparotomy. The transport of glutamine and arginine by
      rat and human vesicles was assayed. Vesicle integrity and functionality were
      verified by osmolarity plots, enzyme marker enrichments, and time courses.
      Provision of both a standard enteral liquid diet and one enriched with glutamine
      and arginine increased the activities of Systems N (glutamine) and y+ (arginine)
      in rat and human liver compared to a control diet. The diet supplemented with
      glutamine and arginine was the most effective in increasing transport activity.
      We conclude that the liver responds to diets enriched with specific amino acids
      by increasing membrane transport activity. This adaptive response provides
      essential precursors for hepatocytes which may enhance hepatic synthetic
      functions during catabolic states. This study provides insights into the
      mechanisms by which enteral nutrition regulates nutrient transport at the
      cellular level and may provide a biochemical rationale for the use of formulas
      which are enriched with conditionally essential nutrients.

PMID- 8661209
TI  - Kinetics of decreased LPS-stimulated cytokine release by macrophages exposed to
      CO2.
AB  - The mechanisms responsible for the lack of inflammation after laparoscopic
      surgery remain unknown. Peritoneal macrophages (M phi) incubated in carbon
      dioxide (CO2) but not air or helium (He), had significant, reversible inhibition
      of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) and
      interleukin-1 (IL-1) release. In these experiments the kinetics of these C02
      induced alterations in cytokine secretion were examined. Murine peritoneal Mphi
      were stimulated with LPS for 4 hr and incubated in different test gases (95%
      air/5% CO2,80%CO2/20%O2,80% He/20% O2) for intervals between 0.25 and 4 hr. Time
      between gas incubation and LPS stimulation was varied to determine the
      persistence of CO2 inhibition. Parallel M phi groups received LPS stimulation 24
      hr later. Supernatant TNF and IL-1 were measured by bioassay and polymerase chain
      reaction was used to examine cytokine mRNA. Significant reversible inhibition of
      TNF and IL-1 was seen with CO2, but not He or air. Inhibition of IL-1 occurred 15
      min after CO2 exposure, was associated with decreased IL-1 mRNA, and was rapidly
      lost following incubation in the control atmosphere. TNF inhibition was seen
      despite normal levels of TNF message, required more than 30 min of CO2 exposure,
      and persisted after CO2 removal. CO2 produced profound, reversible, inhibition of
      LPS-stimulated cytokine release by peritoneal Mphi. The transient inability to
      secrete inflammatory cytokines after CO2 exposure may explain the lack of
      systemic inflammation after laparoscopic surgery with CO2.

PMID- 8661210
TI  - Trauma ultrasound workshop improves physician detection of peritoneal and
      pericardial fluid.
AB  - Hemoperitoneum represents a major indication for surgical intervention after
      trauma. To improve the ability of surgical residents and trauma physicians to
      detect intraperitoneal and pericardial fluid using ultrasound as a diagnostic
      modality, we conducted a focused trauma ultrasound workshop consisting of
      discussion of ultrasound physics, demonstration of instrumentation, review of
      pertinent literature, videotaped demonstration, and "hands-on" teaching of the
      skills utilizing live patient models. The ultrasound probes were placed in four
      standard locations--right and left upper quadrants, epigastrium, and Pouch of
      Douglas. Skills acquisition was tested by pre- and postworkshop performance on 12
      sonograms (3 for each location, 6 were positive for fluid). Thirty physicians (21
      residents and 9 staff: Group I) who attended the workshop were compared to 30
      matched controls (Group II). The results (means +/- SD) were as follows (R =
      number right, I = number of "indeterminate," W = number of wrong responses out of
      12, *P < 0.05 compared to Group II): [Table: see text] False positive (%) and
      false negative (%) decreased from 12.9 +/- 1.5 to 8.9 +/- 5.3 and 15.0 +/- 10.4
      to 5.0 +/- 5.2, respectively, in Group I but did not change in Group II.
      Postworkshop ability to detect fluid was significantly (P < 0.05) improved, with
      no major differences between residents and staff. Our data suggest that these
      workshops can significantly improve the skills of nonradiologists in sonographic
      identification of pericardial and intraperitoneal fluid and should therefore be
      considered an essential component of ultrasound training for trauma physicians.

PMID- 8661211
TI  - A [+18RGD] protamine variant for nontoxic and effective reversal of conventional
      heparin and low-molecular-weight heparin anticoagulation.
AB  - Protamine sulfate reversal of heparin anticoagulation causes adverse side
      effects. Additionally, protamine sulfate is relatively ineffective at reversing
      factor Xa inhibition caused by low-molecular weight heparin (LMWH, Enoxaparin).
      Previously, a +18 compound partially reversed heparin and LMWH with minimal
      toxicity. In the present study, a new +18 protamine-like variant, [+18RGD], with
      an added RGD sequence [acetyl-EA(R2A2R2A)4R2GRGDSPA-amide], was compared to a
      previously developed compound, [+18BE,Acetyl-EAA-(K2A2K2A)4K2-Amide] and standard
      protamine [Prot +21] regarding the reversal of conventional unfractionated
      heparin (Hep) and LMWH. These three agents were given at 1 mg per 100 IU activity
      of Hep or LMWH rapidly over 10 sec. Hemodynamic toxicity was based on maximum
      declines in blood pressure, heart rate, cardiac output, and oxygen consumption
      over the first 5 min after reversal (calculated as a total toxicity score, TTS).
      The more negative the TTS, the more toxic the agent. Degrees of toxicity (TTS) of
      [+18RGD], [+18BE],and[Prot +21] for reversal of Hep were -1.19, -2.00, and -7.32,
      respectively; and for reversal of LMWH they were -2.85, -3.98,and -6.17,
      respectively. These differences were significant for Hep (P < 0.01) and
      approached significance for LMWH (P = 0.07). Maximum hemodynamic perturbations
      paralleled the TTS pattern. [+18RGD] provided equal reversal efficacy to [Prot
      +21] for Hep, with a statistically significant (P < 0.05) lessening of platelet
      count declines (Plt 27, -46, and -55%, respectively). [+18RGD] improved reversal
      efficacy for LMWH, at 3, 10, and 30 min following its administration. At 3 min,
      antifactor Xa reversal was 72, 40, and 30%, respectively, for [+18RGD], [+18BE],
      and [Prot +21]; [+18RGD] effects were significantly better (P < 0.01). [+18RGD]
      reversed both Hep and LMWH anticoagulation with minimal toxicity. Such a compound
      should decrease clinical complications attending the use of standard protamine
      for reversal of conventional heparin or LMWH anticoagulation.

PMID- 8661212
TI  - Inhibition of phosphatidylinositol-3'-kinase prevents induction of endotoxin
      tolerance in vitro.
AB  - Previous studies have shown an increase in the expression of phosphatidylinositol
      3'-kinase (PI-3'-K) in macrophages from endotoxin tolerant (ET) rats. This
      implicates PI-3'-K cell signaling in attenuated macrophage responsiveness to
      lipopolysaccharide (LPS). These experiments examined the effects of selective
      pharmacologic inhibition of PI-3'-K in an in vitro model of ET. To induce ET, RAW
      264.7 macrophages cultured in RPMI 1640 with 10% fetal calf serum were initially
      exposed to 10 ng/ml LPS (E. coli 0111:B4) for 19 hr. Non-tolerant cells received
      an equal volume of phosphate buffered saline. Some cultures were also incubated
      with the specific PI-3'-K inhibitor wortmannin (10 nM) during this tolerizing
      period. Cells were then washed and re-challenged with 100 ng/ml LPS for 24 hr.
      Next, macrophage tumor necrosis factor-alpha (TNF-alpha) and nitrite production
      were measured as indicators of ET induction. Macrophage TNF-alpha production
      decreased significantly while nitrite production increased significantly
      following ET induction. Specific inhibition of PI-3'-K prevented this decrease in
      TNF-alpha and increase in nitrite production in ET macrophages. Production of
      each mediator returned to levels not different than in non-tolerant macrophages.
      In this in vitro model of macrophage ET, pharmacologic inhibition of the PI-3'-K
      signaling pathway prevented the induction of LPS tolerance as measured by the
      production of two inflammatory mediators.

PMID- 8661213
TI  - Glutamine suppresses PGE2 synthesis and breast cancer growth.
AB  - Reduced natural killer (NK) activity found in tumor-bearing hosts has been
      associated with high levels of prostaglandin E2 (PGE2) produced by monocytes in
      vitro. We have previously demonstrated a dependence of NK cell activity on
      glutamine (GLN) levels in vitro and in vivo. Further, glutathione (GSH) is
      antagonistic to PGE2 synthesis. We hypothesized that GLN, through increased GSH
      production, leads to decreased PGE2 synthesis and upregulation of NK cytotoxic
      activity. To test this, we examined the effects of oral GLN on GSH and PGE2
      concentrations, NK activity and tumor growth in a rat breast cancer model.
      Starting on the day of MTF-7 tumor implantation 18 Fisher 344 rats were pair-fed
      chow and gavaged with 1 g/kg/day GLN (n = 9) or an isonitrogenous amount of
      Freamine (FA) (n = 9). Seven weeks after tumor implantation rats were sacrificed.
      Tumors were measured, weighed, and processed for tumor morphometrics. Spleens
      were removed, lymphocytes isolated and assayed for NK activity. Blood GLN, GSH,
      and PGE2 concentrations were measured. Over the 7-week study period tumor growth
      was decreased by approximately 40% in the GLN-supplemented group. This decrease
      in growth was associated with a 2.5 fold greater NK activity in the GLN-fed rats
      vs FA-fed rats. This correlated with a 25% rise in GSH concentration and a
      proportional decrease in PGE2 synthesis. Decreased tumor volume in rats fed GLN
      was not associated with changes in morphometrics. Oral GLN supplementation
      enhances NK activity resulting in decreased tumor growth. The enhanced NK
      activity seen with oral GLN supplementation in the tumor-bearing host is
      associated with GSH mediated suppression of PGE2 synthesis.

PMID- 8661215
TI  - Indomethacin prevents elastase-induced abdominal aortic aneurysms in the rat.
AB  - Perfusion of the rat abdominal aorta with elastase induces abdominal aortic
      aneurysms (AAA), in which the development of aortic dilatation correlates with
      the influx of inflammatory cells, increased production of matrix
      metalloproteinases (MMPs), and destruction of medial elastin. We tested the
      hypothesis that indomethacin, an inhibitor of macrophage MMP expression, might
      attenuate aneurysmal degeneration in this model. Fourteen adult male Wistar rats
      underwent 2-hr aortic perfusion with elastase. Six animals received injections of
      saline and eight animals received 4 mg/kg/day indomethacin for 7 days. Pre
      perfusion, post-perfusion, and final aortic diameters (AD) were determined, and
      histology and substrate gel zymography were performed. Five out of six control
      animals developed AAA, while no aneurysms were observed in the indomethacin
      treated group (P < 0.01). Whereas AD increased 126 +/- 16% in control animals,
      the mean increase in the indomethacin-treated group was only 56 +/- 6% (P <
      0.001). Although animals in both groups demonstrated an inflammatory response
      dominated by macrophages, the marked destruction of medial elastin in the control
      group was not present in the treatment group. In addition, substrate zymography
      demonstrated decreased levels of MMP-9 in animals treated with indomethacin.
      Indomethacin inhibits aneurysm growth in this model, and the data suggest that it
      does so by decreasing macrophage expression of at least one elastolytic
      metalloproteinase, MMP-9.

PMID- 8661216
TI  - Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine
      pancreatic tumors.
AB  - Type-II diabetes is a risk factor for pancreatic cancer. In addition, diabetic
      patients present with more advanced tumors and have shortened survival compared
      to stage-matched counterparts. We hypothesize that the diabetic endocrine milieu,
      particularly elevated plasma insulin, favors pancreatic cancer growth. This study
      examines six human pancreatic cancer cell lines for the presence of insulin
      receptors and the influence of insulin on tumor proliferation. Classical
      competitive binding assays are performed using [125I insulin. Cell proliferation
      assays are conducted over 3 days on cultured cell lines (n = 6 replicates) with
      increasing concentrations of insulin. Insulin receptors are demonstrated on all
      six cell lines and dose dependent increases in cell proliferation (15-120% of
      control) are demonstrated in response to insulin. Patients with type-II diabetes
      hypersecrete insulin. The presence of high-affinity insulin receptors and dose
      dependent increases in pancreatic cancer cell proliferation with insulin supports
      the hypothesis that insulin may be an important tumor growth promoter in
      diabetes, particularly if paracrine mechanisms are involved. Additional study is
      required to determine whether other islet peptides altered in diabetes influence
      tumor growth and whether elevated plasma insulin favors pancreatic cancer
      induction.

PMID- 8661217
TI  - The beneficial effects of heat-shock for prolonged hypothermic storage.
AB  - Heat-shock has been reported to induce tolerance for subsequent ischemia. We
      wished to determine whether thermal stress is protective for hypothermic storage.
      Three groups of Sprague-Dawley rats were studied (n = 8 per group). Control
      animals received routine care (CONT) while anaesthetized rats were either warmed
      to 42 degrees C for 20 min (HEAT) or maintained at room temperature (SHAM).
      Twenty-four hours later, hearts were mounted on a Langendorff apparatus with an
      intraventricular balloon. Hearts were then flushed and stored in UW solution for
      8 hr at 0 degrees C and reperfused for 45 min. Data are reported as a percentage
      of the prestorage results or as the absolute value (mean +/- SD). Recovery of
      developed pressure was significantly greater (P < 0.05) in the heat-shocked
      animals (79.5 +/- 10.2%) than in the SHAM (63.6 +/- 17.2%) or CONT groups (59.0
      +/- 10.8%). Coronary flow was similarly enhanced (P < 0.05) in the HEAT group
      (86.8 +/- 5.5%) vs the CONT (77.0 +/- 12.3%) or SHAM hearts (74.5 +/- 10.2%).
      Diastolic compliance as assessed by evaluation of the end-diastolic pressure
      volume curves was reduced in all groups (P < 0.0001) but not different among
      groups. Cardiac creatine kinase release during reperfusion was greater in the
      CONT and SHAM groups (CONT: 726.9 +/- 297.8 IU/g; SHAM: 548.9 +/- 420.9 IU/g)
      than in the heat-shocked rodents (282.3 +/- 175.5 IU/g, P < 0.05 HEAT vs CONT).
      Cardiac biopsies were performed sequentially in separate animals (n = 6 per
      group). Tissue levels of ATP and total adenine nucleotides were greater in the
      heat-shocked or SHAM hearts following reperfusion compared with controls (P <
      0.05). Thermal stress provides additional protection for prolonged hypothermic
      storage.

PMID- 8661218
TI  - The time course of CTLAIg effect on cardiac allograft rejection.
AB  - T cell response to alloantigen is dependent not only on T cell receptor
      activation, but also upon co-stimulation through the CD28 receptor, as T cell
      receptor activation alone is insufficient for an optimal immune response. The
      CD28 receptor on helper T cells interacts with its ligand B7 on activated B
      cells/macrophages as the co-stimulus to support T cell activity. The natural
      ligand for CD28, B7 is expressed in both constituitive and inducible forms.
      Expression of the inducible form, B7.1 is the most co-stimulatory and may peak at
      48 hr following antigen presentation. CTLA4Ig (a soluble CD28 receptor analog)
      binds both B7's and inhibits CD28 activation. This experiment was undertaken to
      examine the optimal time course of CTLA4Ig effect at or following antigen
      presentation. In vivo studies used a rat MHC mismatch heterotopic cardiac
      allograft transplant model (Brown-Norway to Lewis). Controls received no
      immunotherapy. Experimental recipients received CTLA4Ig (0.05 mg i.p.) the day of
      transplant only or had CTLA4Ig x 7-21 days begun at Day 0, 3, or 5 following
      transplant. Rejection was defined as a lack of allograft contraction. Allograft
      survival was best when CTLA4Ig was present on Day 2. These findings demonstrate
      that CTLA4Ig was most effective 48 hr following antigen presentation, perhaps
      reflecting induction of tolerance at a time of maximal CTLA4Ig/B7.1 blockade.
      CTLA4Ig given later, at a time when the recognition/rejection process has already
      begun was not as effective indicating the lack of immunosuppressive function of
      CTLA4Ig itself and confirms CTLA4Ig's mechanism of co-stimulation blockade.

PMID- 8661219
TI  - Alpha-adrenergic preservation of myocardial pH during ischemia is PKC isoform
      dependent.
AB  - alpha-adrenergic stimulation of patients with ischemic heart disease should
      intuitively impose a destructive stress. However, therapeutic alpha1-adrenergic
      receptor mediated cardioadaptation prior to myocardial ischemia protects
      ventricular mechanical function, promotes electrophysiologic stability, and
      preserves myocyte viability. Prior to an anticipated cardiac ischemic insult,
      alpha1-adrenergic preconditioning attenuates ischemic myocardial acidosis by a
      protein kinase C-(PKC) dependent mechanism. The alpha1-adrenoceptor can directly
      stimulate calcium-independent nPKC isoforms via diacylglycerol (DAG) or
      indirectly stimulate calcium-dependent cPKC isoforms through the release of
      intracellular calcium via inositol triphosphate, (IP3). We hypothesized that
      alpha1-adrenergic limitation of ischemic acidosis is mediated by the family of
      calcium-dependent PKC isoforms. [31P]NMR spectra were obtained in isolated,
      buffer perfused rat hearts treated with alpha1-adrenergic stimulation
      [phenylephrine (PE) 50 microM, 2 min]; PKC blockade [chelerythrine chloride,
      (Chel) 20 microM]; or stearoyl-arachidonoyl glycerol (SAG, a DAG analogue, 100
      microM, 2 min) administered 10 min prior to ischemia. Control hearts were
      perfused under normoxic conditions for 20 min. All hearts were then subjected to
      global ischemia (20 min, 37.5 degrees C). Developed pressure (DP) and heart rate
      were recorded continuously. pHi was obtained from chemical shift of inorganic
      phosphate. Immunohistochemical staining was utilized to delineate the
      translocation and activation profiles of specific PKC profiles established with
      each stimulus. Pre-ischemic alpha1-adrenergic stimulation did attenuate the
      myocellular hydrogen ion accumulation during sustained normothermic ischemia
      (6.90 +/- 0.13 vs control 6.54 +/- 0.10; P < 0.05). General PKC inhibition
      abrogated this effect (end-ischemic pH 6.17 +/- 0.10; P < 0.05 vs control and
      PE). Ischemic acidosis was not attenuated following selective nPKC stimulation
      (SAG, 6.48 +/- 0.08; NS vs control). Myocellular immunohistochemical staining
      revealed translocation of the calcium-independent PKC-epsilon isoform in the
      calcium-dependent PKC (SAG) group, but not in response to alpha1-adrenergic
      stimulation. The results suggest that (1) alpha1-adrenoceptor stimulation limits
      ischemic acidosis, (2) alpha1-adrenergic stimulated attenuation of ischemic
      acidosis is PKC dependent, (3) direct nPKC stimulation with SAG does not limit
      ischemic acidosis, and (4) SAG stimulates nPKC-epsilon isoform activation where
      alpha1-adrenergic stimulation does not. We conclude that alpha1-adrenergic
      stimulation limits ischemic acidosis by a cPKC-dependent mechanism and that the
      mobilization of the IP3 arm by receptor stimuli suppresses PKC-epsilon thus
      permitting the limitation of ischemic acidosis.

PMID- 8661220
TI  - Nitric oxide reduces endothelial expression of intercellular adhesion molecule
      (ICAM)-1.
AB  - Nitric oxide (NO.) has proven effective in improving oxygenation and reducing
      pulmonary hypertension in the acute respiratory distress syndrome (ARDS), but the
      precise mechanism remains unclear. NO. has been shown to reduce leukocyte
      endothelial adhesion, attenuate neutrophil (PMN) sequestration, and protect
      endothelium from an inflammatory insult. Intercellular adhesion molecule (ICAM)-1
      is a pivotal regulator of PMN-endothelial adhesion and, thus, a critical mediator
      of PMN cytotoxicity. Consequently, we hypothesized that NO. suppresses ICAM-1
      expression on endothelium. Human umbilical vein endothelial cells (HUVEC) were
      cultured. The NO. donor 3-morpholinosidnonimine (SIN-1) (0.1-10 microM) was
      incubated with HUVEC for 4 hr. In separate experiments, HUVEC were incubated with
      bacterial lipopolysaccharide (LPS) (100 ng/ml) alone or following SIN-1
      pretreatment. ICAM-1 expression on HUVEC was measured by flow cytometric
      analysis. SIN-1 (1 and 10 microM) reduced the expression of ICAM-1 on resting
      HUVEC by 58 and 47%, respectively. LPS upregulated ICAM-1 expression; however,
      this was not affected by SIN-1 pretreatment. We conclude that NO. reduces
      constitutive endothelial expression of ICAM-1, but does not prevent LPS
      stimulated upregulation of ICAM-1 expression. Downregulation of ICAM-1 may be a
      mechanism whereby NO. protects resting endothelium (distant organ bed) from
      circulating primed or activated PMNs, but may not be as effective at a primary
      inflammatory site.

PMID- 8661221
TI  - Physiologic concentrations of TNFalpha and IL-1beta released from reperfused
      human intestine upregulate E-selectin and ICAM-1.
AB  - Intestinal ischemia-reperfusion (I/R) causes local and distant tissue injury via
      neutrophil (PMN) activation and adhesion. Endothelial cell adhesion molecules (E
      selectin, ICAM-1) mediate the adhesion and transmigration of PMN in the
      microcirculation. Expression of these receptors is influenced by cytokines. To
      determine the physiologic concentrations of two specific cytokines involved in
      I/R, tumor necrosis factor (TNF) and interleukin-1 (IL-1), human intestinal
      segments were exposed to 30 min of ischemia followed by reperfusion. Venous
      effluent samples were obtained; enzyme immunoassays measured maximum
      concentrations of TNF (30.5 +/ 1.0 pg/ml) and IL-1 (59.0 +/- 6.0 pg/ml). Cultured
      human endothelial cells were then exposed to physiologic concentrations of human
      recombinant TNF (10 pg/ml) and IL-1 (10 pg/ml), individually and in combination.
      Flow cytometric analysis of receptor expression demonstrated upregulation of E
      selectin as early as 2 hr (P < 0.05) with maximum effects at 4 hr. At 4 hr, E
      selectin expression (% shift from baseline) was greater with TNF and IL-1
      combined (50.9 +/- 2.9, P < 0.01) than with either cytokine alone (TNF 34.6 +/-
      4.0; IL-1 23.5 +/- 4.0, P < 0.01). ICAM-1 receptor expression began at 4 hr with
      maximum effects at 24 hr. ICAM-1 expression after TNF and IL-1 exposure (15.4 +/-
      1.3, P < 0.001) was also greater than TNF (10.9 +/- 0.3, P < 0.01) or IL-1 (3.1
      +/- 1.5) alone. TNF and IL-1 are present in venous effluent in concentrations
      capable of increasing PMN adhesion in the microcirculation. These findings
      support a role for these cytokines in local and distant organ injury from I/R.
      Since combined effects are greater than either cytokine alone, antagonism of both
      TNF and IL-1 may be required for a therapeutic benefit in clinical applications.

PMID- 8661222
TI  - Effects of CO2 pneumoperitoneum in pregnant ewes.
AB  - Laparoscopy has been considered a relative contraindication in pregnant patients
      because the CO2 pneumoperitoneum may cause maternal and/or fetal hypotension,
      acidosis, hypercarbia, hypoxia, changes in cardiac output, or uterine artery
      blood flow. These potential changes were studied in an established animal
      pregnancy model. Twelve gravid ewes (116-120 days gestation) underwent
      catheterization of maternal femoral artery and vein, fetal hindlimb artery and
      vein, insertion of a uterine artery flow probe, and pulmonary artery catheter.
      Six animals underwent creation of a CO2 pneumoperitoneum (10 mm Hg for 30 min; 15
      mm Hg for 30 min). Six control animals were studied without a pneumoperitoneum.
      The following parameters were recorded at baseline and at preset time points:
      cardiac output (CO), uterine blood flow (UtBF), amniotic cavity pressure (ACP),
      end-tidal CO, (Et CO2), maternal and fetal heart rate (HR), blood pressure (BP),
      and lactate, glucose, and arterial blood gasses. Percent change at each time
      point compared to baseline was determined for each variable. Statistical
      significance was determined by repeated measures analysis of variance. No changes
      were found between study and control animals in maternal BP; CO; lactate,
      glucose, oxygenation, or fetal HR; oxygenation, lactate, or glucose.
      Statistically significant differences (P < 0.01) between study and control
      animals were noted in ACP, Et CO2, MHR, UtBF, FBP, and Maternal/fetal pH, PCO2.
      All ewes delivered healthy lambs at full gestation. A CO2 pneumoperitoneum up to
      15 mm Hg pressure in gravid ewes causes increased intrauterine pressure,
      decreased UtBF, and induces maternal and fetal acidosis. Despite these
      intraoperative deleterious effects, long-term fetal well being was not effected.

PMID- 8661223
TI  - Epithelial-matrix interactions : laminin downregulates enterocyte EGF receptor
      and IGF-I receptor expression.
AB  - Intestinal crypt cells continuously proliferate to yield functional villus cells
      which terminally differentiate prior to sloughing into the intestinal lumen.
      Growth factors and extracellular matrix have been shown to regulate this process.
      To investigate how these effectors may interact, Epidermal Growth Factor (EGF)
      receptor and Insulin-like Growth Factor-I (IGF-I) receptor expression was
      evaluated in IEC-6 cells incubated on laminin or collagen I. EGF receptor and IGF
      I receptor expression were decreased in cells grown on laminin. The data suggest
      that the mechanism by which laminin inhibits enterocyte growth is downregulation
      of growth factor receptors for important enterocyte mitogens.

PMID- 8661224
TI  - Role of protein kinase C in attachment, spreading, and migration of human
      endothelial cells.
AB  - Attachment, spreading, and migration of vascular endothelial cells (EC) are
      necessary for angiogenesis, reendothelialization of an injured artery, or seeding
      of a prosthetic graft. However, little is known about the signaling pathways that
      mediate these effects. Protein kinase C (PKC) is a ubiquitous intracellular
      messenger which we have previously shown to be necessary for EC proliferation
      (Kent et al., 1995, Circ. Res. 77, 231-238). In this study, we investigate
      whether activation of PKC is necessary for EC attachment, spreading, and
      migration. Using human umbilical vein EC, we found that direct activation of PKC
      with the phorbol ester phorbol 12-myristate-13-acetate enhanced all three
      processes. Inhibition of PKC by the selective agent, chelerythrine, markedly
      diminished the ability of EC to attach, spread, and migrate. Depletion of
      intracellular PKC by downregulation (prolonged exposure of EC to phorbol ester)
      reduced EC attachment and migration; however, downregulation had no effect on
      endothelial spreading. PKC is a family of isotypes, each of which may control
      specific cellular functions. By Western blotting, we identified PKC alpha, beta,
      delta, epsilon, eta, theta, and zeta isotypes in human EC. Downregulation led to
      a significant reduction in the quantity of PKC alpha and epsilon. These data
      demonstrate that activation of PKC is both necessary and sufficient for
      attachment, spreading, and migration of human EC. An isotype of PKC that is
      susceptible to downregulation (either alpha and/or epsilon) is at least partially
      responsible for attachment and migration. Pharmacological activation of PKC may
      be used as a method to enhance reendothelialization.

PMID- 8661225
TI  - Inhibition of selectin- and integrin-mediated inflammatory response after burn
      injury.
AB  - Inflammation and microvascular injury in the areas adjacent to burn wounds
      produces extension of postburn tissue necrosis. Leukocytes are potent mediators
      of the local inflammatory response preceding tissue necrosis, and the selectin
      and integrin adhesion molecules have been implicated in leukocyte-mediated tissue
      destruction. We sought to examine the role of L-selectin (CD62-L) and CD18 in
      leukocyte accumulation and tissue necrosis following burn injury. New Zealand
      White rabbits (n = 36) were subjected to burn injury and were randomized to
      treatment with saline (control) or monoclonal antibodies to L-selectin or CD18.
      Animals given the anti-L-selectin antibody demonstrated reduced
      immunohistochemical evidence of leukocyte accumulation at 24 hr postinjury but
      did not show improved wound perfusion or reduced tissue necrosis. Animals in the
      anti-CD18 group showed significantly improved tissue survival and improved tissue
      perfusion but had grades of leukocyte accumulation similar to those in the
      control group. These observations suggest that leukocyte accumulation is
      partially L-selectin dependent and that leukocyte accumulation alone is not
      sufficient to cause changes in blood flow and tissue destruction, both of which
      appear to be largely CD18 mediated.

PMID- 8661226
TI  - Actin disruption inhibits bombesin stimulation of focal adhesion kinase
      (pp125FAK) in prostate carcinoma.
AB  - Jasplakinolide is a member of a new class of antitumor agents targeting the actin
      cytoskeleton with activity against prostate cancer. Focal adhesion kinase (FAK)
      is an actin-associated mediator of mitogenic peptides. We hypothesized that the
      neuropeptide bombesin would activate FAR in prostate carcinoma, and that
      disruption of the actin network would block FAK activation and inhibit cell
      growth. METHODS: PC-3 human prostate carcinoma cells were exposed to 50-200 nM
      jasplakinolide (Jas) or cytochalasin E (CyE) in cytotoxicity experiments. FAK
      phosphorylation was measured in cells stimulated with 0.01-10 nM bombesin;
      separate cells were pretreated 6 hr with 50-500 nM Jas or CyE. Cell lysates and
      anti-FAK immunoprecipitates were subjected to SDS-PAGE, Western blotting, and
      detection with anti-actin or anti-phosphotyrosine. Depolymerized G-actin was
      separated from total actin by ultracentrifugation. Cytoskeletal changes were
      confirmed by fluorescence microscopy. RESULTS: Jas (GI50 = 47 +/- 7 nM) and CyE
      (GI50 61 +/- 20 nM) potently inhibited PC-3 growth (P < 0.01 vs control).
      Bombesin rapidly stimulated tyrosine phosphorylation of FAK in a dose dependent
      manner. FAK phosphorylation was inhibited to near-basal levels (50% of bombesin
      stimulated) by 500 nM Jas (63%) and 500 nM CyE (61%). CONCLUSIONS: Bombesin
      stimulated FAK in prostate carcinoma cells. Jasplakinolide, which induced over
      polymerization of actin, and CyE, which depolymerizes actin, both inhibited
      bombesin-stimulated phosphorylation of FAK and inhibited PC-3 cell growth. Actin
      disrupting agents block FAK signal transduction, which may be critical to their
      antitumor activity in prostate carcinoma.

PMID- 8661227
TI  - Roles of gastrin and somatostatin in the regulation of gastric acid secretion in
      the fetal rabbit.
AB  - In adult gastric epithelium, gastrin and somatostatin regulate parietal cell acid
      secretion; however, their expression and function in the fetus are largely
      unknown. We defined the developmental expression of gastrin and somatostatin in
      the fetal rabbit stomach and determined their effects on fetal acid secretion. To
      define peptide expression, fetuses from 12 time-mated New Zealand white rabbit
      does were analyzed at successive ages during the third trimester (term is 31
      days). Peptides were extracted from fetal gastric tissue by boiling in water and
      then in acetic acid. Amidated gastrin and somatostatin levels were measured by
      radioimmunoassay using antisera 1296 for gastrin and 8402 for somatostatin. To
      determine the effects of gastrin and somatostatin, pentagastrin (64 microg/kg/hr)
      or octreotide (35 microg/kg/hr) were infused intravenously in conscious pregnant
      rabbits at 28 days of gestation for 3 hr. Fetuses (n = 45) were harvested and
      gastric acid was titrated with 0.02 N NaOH. Gastrin and somatostatin tissue
      content were 12 +/- 3 and 51 +/- 6 pmol/g at gestational day 20, respectively,
      and increased to 146 +/- 10 and 162 +/- 5 pmole/g by day 30 (P < 0.05). Between
      days 24 and 26, when gastric acid was first detectable, the molar ratio of
      somatostatin to gastrin decreased from 5.0 +/- 1.0 to 1.1 +/- 0.1 (P < 0.05).
      Fetal gastric acid content (micromole) was 28.5 +/- 1.7 in controls, 27.5 +/- 1.9
      with pentagastrin treatment, and 15.8 +/- 1.4 micromole with octreotide (P <
      0.05). In summary, 1) In fetal gastric tissue, gastrin increased 12-fold and
      somatostatin increased 3-fold between days 20 and 30 of gestation. 2) The
      decreased ratio of somatostatin to gastrin between days 24 and 26 of gestation
      coincides with the onset of fetal gastric acid secretion in the fetal rabbit. 3)
      Maternal administration of octreotide inhibited fetal gastric acid content;
      however, pentagastrin had no effect. We conclude that, in the fetal rabbit
      stomach, the relative expression of gastrin and somatostatin may regulate the
      onset of parietal cell acid secretion.

PMID- 8661228
TI  - Intrapancreatic interleukin-1beta gene expression by specific leukocyte
      populations during acute pancreatitis.
AB  - The importance of interleukin-1beta (IL-1beta) in the pathogenesis of acute
      pancreatitis has been demonstrated by dramatic attenuation of pancreatic
      destruction and significant increases in survival when its actions are inhibited.
      The pancreas has been shown to be a major producer of IL-1beta during
      pancreatitis but the cell(s) of origin remains unknown. Hypothesizing that
      infiltrating leukocytes contribute substantially, the intrapancreatic production
      of IL-1beta was examined after specific leukocyte populations were manipulated in
      vivo prior to the induction of pancreatitis. Sixty-four adult male Swiss mice
      were assigned to one of four groups 48 hr prior to induction of pancreatitis: (1)
      PMN depletion via anti-murine PMN antiserum. [PMN-d], (2) macrophage (Mphi)
      depletion via anti-macrophage antiserum [Mphi-d], (3) PMN and Mphi depletion
      [PMN+Mphi-d], and (4) Immunocompetent Pancreatitis. Edematous pancreatitis was
      induced in all experimental groups by caerulein (50 microg/kg/hr ip X 4). Animals
      were sacrificed 6 hr after induction of pancreatitis with severity determined by
      blind histologic grading and serum amylase, lipase, and interleukin-6 (IL-6)
      levels. Intrapancreatic IL-1beta production was determined by
      immunohistochemistry and semiquantitative differential RT-PCR. Pancreatitis
      developed in all animals receiving caerulein; however, leukocyte-depleted animals
      showed significantly attenuated levels of serum amylase, lipase, and IL-6, as
      well as lower histologic severity scores. Similarly, pancreatitis induction in
      immunocompetent mice showed pancreatic infiltration of IL-1beta-producing cells,
      whereas the leukocyte-depleted animals had significantly decreased numbers
      (PMN+Mphi-d < Mphi-d < PMN-d). IL-1beta mRNA was upregulated in all animals
      developing pancreatitis with significantly lower levels seen in the leukocyte
      depleted groups. We conclude that infiltrating leukocytes, both neutrophils and
      macrophages, are responsible for the majority of intrapancreatic IL-1beta
      production during acute pancreatitis. The elimination of leukocytes and their
      products, including IL-1beta, significantly decreases the severity of pancreatic
      destruction.

PMID- 8661229
TI  - Nitric oxide production during the hyperacute vascular rejection.
AB  - A complete understanding of the biological mechanisms that take part in the
      hyperacute vascular rejection is necessary to prevent its development. Nitric
      Oxide (NO) release by the graft could be one of those mechanisms as cytokine
      induction of NO synthase in reticuloendothelial cells produces NO with cytotoxic
      activity. We have performed 20 heterotopic pig-to-dog kidney xenotransplantations
      in order to determine if cytotoxic NO is released during the hyperacute
      rejection. Nitrites and cGMP levels were determined in plasma samples taken from
      the graft artery and vein until vessel thromboses. NO synthase activity was
      measured in pieces from renal artery and renal tissue. The results show that
      after discordant xenotransplantation, inducible NO synthase is activated in the
      transplanted organ, indicating that NO can mediate host tissue damage during the
      hyperacute rejection.

PMID- 8661230
TI  - Analysis of the hemodynamics of a bypass with adjunctive arterio-venous fistula
      using a direct electrical circuit model.
AB  - BACKGROUND: The purpose of this work was to study, in a theoretical electric
      model the effect that an adjunctive arterio-venous fistula (AVF) produces on the
      flow patterns of a distal infrapopliteal bypass. METHOD: A theoretical electric
      model that mimics a femoro-infrapopliteal bypass with an adjunctive AVF was
      designed. Based on Thevenin's Theorem, flows in different areas of the circuit
      (bypass, collaterals, AVF, segment of artery distal to bypass anastomosis,
      arteriolar system) were calculated at different resistance values for AVF,
      collaterals, and bypass. RESULTS: This model demonstrated the following: (1) An
      adjunctive AVF with large resistance (smaller vein diameter) maintains distal
      flow, as opposed to a low-resistance AVF (2) Good collateral flow, in addition to
      low-resistance AVF, can produce retrograde flow in the segment of the artery
      distal to the AVF. (3) True distal flow (arteriolar flow) in the presence of high
      collateral resistance can decrease with decreasing resistance of the AVF, but it
      will never become retrograde. CONCLUSION: The effect of an adjunctive AVF on the
      hemodynamics of a bypass and its distal runoff vessels depends on the resistance
      of the AVF and the collateral vessels. The presence of AVF always increases the
      bypass flow and in this respect it may promote graft patency. However, Bypass
      grafting in the face of a low collateral resistance is of dubious value and the
      addition of a fistula in this situation is detrimental.

PMID- 8661231
TI  - Effect of chronic oral pentoxifylline administration on murine erythrocyte
      deformability.
AB  - BACKGROUND: Pentoxifylline has been reported to increase radiation sensitivity in
      vivo. We sought to evaluate whether this effect is mediated by changes in murine
      erythrocyte flexibility. METHODS: Pentoxifylline was administered via liquid or
      solid diet to young adult male CF-1 mice for 1-6 weeks. After 1, 3, and 6 weeks
      of drug administration, plasma levels of pentoxifylline and major derivatives
      were measured and erythrocyte deformability was assessed by rheoscopy, a
      technique which permits direct measurement of individual cellular dimensions.
      RESULTS: Contrary to prior reports, we found no discernible effect of the drug on
      erythrocyte deformability. CONCLUSIONS: The beneficial effect of pentoxifylline
      administration on radiation sensitivity in tumor-bearing mice is mediated by
      other mechanisms.

PMID- 8661233
TI  - Calcium-induced inotropy is in part mediated by protein kinase C.
AB  - Protein kinase C (PKC) is an ubiquitous regulatory enzyme with dense myocardial
      distribution and activity; however, its physiologic relevance to myocardial
      function remains poorly understood. Although endogenous Ca2+ is a potent stimulus
      of PKC isoforms alpha and beta (cPKCs) it remains unknown whether exogenous Ca2+
      activates these PKC isoforms, and if so, whether PKC plays any role in Ca2+
      induced myocardial inotropy. To study this, ventricular sections from isolated
      rat hearts, with and without Ca2+-induced inotropy (CaCl2, 0.5 mM coronary
      concentration x 2 min), were probed for cPKC isoform translocation using
      immunofluorescence in order to determine if exogenous Ca2+ indeed activates
      cPKCs. We further examined the effects of exogenous Ca2+, with and without
      concurrent PKC inhibition (chelerythrine, 20 microM coronary concentration x 2
      min), on fundamental physiologic parameters of myocardial developed pressure
      (DP), dP/dt, and coronary flow (CF) in the isolated rat heart to determine if
      Ca2+-induced inotropy involves PKC. Results indicated that exogenous Ca2+ results
      in translocation of PKC a from the cytoplasm to the sarcolemma and intercalated
      discs, as well as the translocation of PKC beta from the perinuclear to the
      intranuclear compartment. This dose of exogenous Ca2+ resulted in myocardial
      inotropy as determined by DP, dP/dt, and CF. Furthermore, myocardial inotropy was
      attenuated with concurrent inhibition of PKC activity. These findings link the
      physiologic effects of exogenous Ca2+ to PKC, providing a better understanding of
      the physiologic mechanism of Ca2+-induced inotropy.

PMID- 8661234
TI  - The role of transient mucosal ischemia in acetic acid-induced colitis in the rat.
AB  - The importance of early microcirculatory changes in the rat colon after exposure
      to acetic acid was investigated. Administration of 4% acetic acid for 15 sec into
      an exteriorized colonic segment induced a marked, transient (starting 2 min after
      the challenge with acetic acid and persisting for 15 min) decrease in the colonic
      blood flow as estimated by a laser-Doppler flowmeter. Four days after acetic acid
      administration, a uniform colitis had developed in the exteriorized colonic
      segment with a total morphological score (TMS) of 15.1 +/- 0.8, myeloperoxidase
      activity (MPO) increased more than threefold, and plasma exudation into the
      colonic lumen increased sevenfold. Administration of hydrochloric acid (HCl) with
      the same pH as the acetic acid or sodium acetate (pH 7.0) did not affect colonic
      blood flow or produce colitis. Mechanical colonic ischemia, induced by a
      controlled increase in the intraluminal pressure, resulted in several
      pathological features of colitis with a TMS of 7.3 +/- 0.2, combined with a
      significant increase in MPO activity. The TMS and MPO were further increased when
      mechanical colonic ischemia was combined with HCl or sodium acetate. Pretreatment
      with SOD and catalase 5 or 15 min before acetic acid administration did not
      affect the transient ischemia immediately following acetic acid administration.
      However, it partially prevented the development of colitis. It is concluded that
      immediate transient ischemia accompanied by the generation of oxygen free
      radicals might be of importance in the pathogenesis of acetic acid-induced
      colitis in the rat.

PMID- 8661236
TI  - A new animal model of reversible acute pancreatitis.
AB  - Numerous animal models of acute pancreatitis are utilized to assess
      pathophysiologic events and to evaluate therapeutic options. However, none of the
      small animal models simulates reversible biliary pancreatitis with long-term
      follow-up (weeks). The present study was designed to create a reversible model of
      acute biliary pancreatitis in small experimental animals. Male Sprague-Dawley
      rats were subjected to laparotomy, and the common bile duct was dissected free at
      its junction to the duodenum. Experimental animals had a polypropylene tie
      occluder passed around the common bile duct and brought out through a separate
      stab wound in the abdominal wall. The duct was occluded for 24 hr; the blockage
      was then relieved and the tie withdrawn from the animal. Sham-operative animals
      had similar surgical procedures but without the occluder. Serum amylase values on
      Days 1 and 2 following surgery were significantly increased in the experimental
      group, but were not different from those of control animals on Day 3 or 4,
      suggesting reversibility of this biliary pancreatitis model. Likewise, serum
      bilirubin levels were increased in the experimental group on Days 1 and 2.
      Histologic analysis revealed edema, zymogen degranulation, inflammatory
      infiltration, vacuolization of acinar cells, and focal areas of fat and
      parenchymal necrosis in the experimental group. Only mild edema was observed in
      the sham-operative controls due to surgical manipulation. Pancreatic tissues
      obtained at 1 week postinduction of pancreatitis showed near total destruction of
      the architecture and dissolution of zymogen granules; in contrast, histology at
      the 3rd week showed almost normal-appearing pancreas with return of zymogen
      granules, suggesting recovery from the acute pancreatitis. This reproducible and
      reversible model of acute pancreatitis in the rat will provide for further
      studies in the pathogenesis of pancreatitis and its therapeutic interventions.

PMID- 8661235
TI  - Fluid resuscitation in a model of uncontrolled hemorrhage: too much too early, or
      too little too late?
AB  - Early fluid resuscitation in hypotensive trauma patients is controversial due to
      the risk of increasing blood loss and mortality. We determined the effects of
      infusion rate and time of resuscitation on blood loss and mortality and compared
      the outcome to nonresuscitated animals in severe, uncontrolled hemorrhagic shock
      in a rat model. In anesthetized rats, piercing of the infrarenal aorta with a 25
      G needle caused a fall of mean arterial pressure to <20 mm Hg and blood loss of
      about 20 ml/kg in 90% of the animals. Animals were assigned to the following
      treatment groups (n = 6): 60 ml/kg of lactated Ringer's solution (LR) infused at
      a rate of 1.5 ml/min and given at 2.5 min (Group I), 5 min (Group II), or 10 min
      (Group III) postinjury, or LR infused at a rate of 3.0 ml/min and given at 5 min
      (Group IV) or 10 min (Group V) postinjury. Another group (n = 9) was not
      resuscitated. The animals were followed for 3 hr. Total blood loss in Group I
      (30.5 +/- 2.6 ml/kg) was significantly (P < 0.05) higher when compared to
      nonresuscitated animals (22.1 +/- 0.8 ml/ kg) or Group III (22.7 +/- 1.0 ml/kg),
      and also significantly higher in Group IV (35.8 +/- 4.1 ml/kg) when compared to
      nonresuscitated animals or Group V (23.0 +/- 1.2 ml/kg). The mortality rate was
      7/9 in nonresuscitated animals and 5/6 in Group IV, both were significantly
      higher than in Groups II, III, and V (0 or 1/6) and markedly higher than in Group
      I (2/6). CONCLUSIONS: In this model of uncontrolled hemorrhage, initially
      uncorrected severe shock resulted in a high mortality rate. The risk of increased
      blood loss and mortality associated with early fluid resuscitation could be
      diminished by avoiding too fast of infusion rates early after the injury.

PMID- 8661237
TI  - Development of a reliable colorectal cancer liver metastasis model.
AB  - The liver is the most frequent and most fatal site of distant spread of
      colorectal cancer. Most current animal models of liver metastases utilize direct
      liver or intravascular injection (dissimilar to mechanisms of metastasis) or
      immunosuppression to establish metastases. AIM: The aim of this study was to
      develop a reliable rat model of liver metastases in immunocompetent hosts,
      whereby metastases spread hematogenously as in colorectal cancer. METHODS: WB
      2054 is a poorly differentiated colon adenocarcinoma induced by 1,2 DMH in a WF x
      BN F1 hybrid rat. WB-2054-M0, Ml, M2, M3, and M4 are successive metastatic
      variant cell lines obtained through serial application of the Fidler hypothesis.
      WF x BN F1 rats were inoculated intrasplenically with 1 x 10(6)(M0) or 5 x
      10(6)(M0-M4) cells; the spleen was left intact. Animals were evaluated 4 to 12
      weeks postinjection and, if no metastases were found, reexplored 1-2 weeks later.
      Animals with liver metastases were sacrificed, and full abdominal and thoracic
      zoopsy was performed. Livers were excised and serially sectioned, to determine
      size, number, and location of liver metastases, and studied histologically to
      confirm the nature of the metastases. RESULTS: 44% (4/9), 80% (8/10), 86%
      (65/76), 94% (34/36), and 100% (65/65) of animals inoculated with the M0, M1, M2,
      M3, and M4 cell lines, respectively, developed liver metastases. Metastases were
      uniformly spread throughout all lobes of the livers. CONCLUSION: We have
      developed an extremely hepatotrophic metastatic colorectal cancer cell line.
      Intrasplenic injection of WB-2054-M4 cells is a reliable model for producing
      colorectal cancer liver metastases without the need for immunosuppression and
      should prove valuable in colorectal liver metastasis experiments.

PMID- 8661238
TI  - Role of Kupffer cells in the induction of tolerance after liver transplantation.
AB  - The role of Kupffer cells (KC) in the induction of tolerance caused by
      preoperative donor-specific blood transfusion (DST) was investigated. DA rats
      (RT1a) were used as donors and Lewis rats (RT1(l)) as recipients. Recipients of
      an orthotopic liver transplantation (OLT) were divided into eight groups: Group
      1, only OLT was performed; Group 2, on Days 9 and 8 before OLT, gadolinium (Gd)
      was injected intravenously; Group 3, on Day 7 before OLT, donor blood was
      injected intravenously (ivDST); Group 4, DST was performed via the portal vein
      (ipvDST); Group 5, Gd was injected twice as described for Group 2 before ivDST;
      Group 6, Gd was injected as described for Group 2 before ipvDST; Group 7; ivDST
      was performed, and then on Days 3 and 2 before OLT, Gd was injected; Group 8,
      ipvDST was performed, and then Gd was injected as described for Group 7. The mean
      survival times (MSTs) were 11.6, 11.8, 52.7, 64.4, 27.7, 39.4, 49.4, and 64.2
      days in each group. That is, injection of Gd only or injection after DST had no
      effects for the survival days of recipients. There was no statistically
      significant difference between Group 6 and Groups 3 and 4, but the MST of Group 5
      was significantly shorter than those of Groups 3 and 4. Microscopic studies
      demonstrated marked portal and lobular infiltration and endothelialitis, as well
      as necrosis of the parenchyma and paucity of interlobular bile ducts in Groups 1,
      2, and 5. While in Groups 3, 4, and 6 these findings were considerably mild.
      These results suggested that KC participated in the induction of tolerance caused
      by DST and that portal venous injection of donor blood diminished the effects of
      Gd.

PMID- 8661239
TI  - Aerobic preservation of organs using a new perflubron/lecithin emulsion
      stabilized by molecular dowels.
AB  - The purpose of the study reported here was to explore a new strategy for the
      aerobic preservation of transplants using stable concentrated fluorocarbon
      emulsions as an oxygen delivery system. Fluorocarbons (FCs) are synthetic
      molecules, chemically and biologically inert, with a high oxygen-dissolving
      capacity. As they do not mix with water, it is necessary to emulsify them for
      intra-vascular use. Perfluorooctyl bromide (or perflubron) can be emulsifled with
      egg-yolk phospholipid (EYP), a nontoxic emulsifiant. The recent adjunction of
      amphiphilic fluorocarbon-hydrocarbon diblock molecules allows the obtaining of
      stable emulsions. By contrast with hemoglobin, fluorocarbons release oxygen
      following Henry's linear law rather than Barcroft's sigmoid curve. Release of
      oxygen by the FCs is only slightly influenced by temperature, which is an
      advantage for the preservation of organs. We tested a new 90% w/v fluorocarbon
      stem emulsion (perflubron/EYL/F6H10) diluted to 36% w/v with a hydroelectrolytic
      solution containing albumin, on four multiple organ blocks (MOBs; heart-lungs,
      liver, pancreas, kidneys, small intestine) of rats (EMOBs). Five control MOBs
      were perfused with a 50% v/v mixture of rat-blood and Krebs solution (KBMOBs).
      The lungs were ventilated with a FiO2 = 100%. In all cases the survival of the
      MOBs was greater than 210 min, with stable hemodynamics and preserved
      hydroelectrolytic and acid-base balances. The levels of lactate, amylase, and CK
      of the EMOBs were inferior (P < 0.05) to those of the KBMOBs between the first
      and the second hour. The diuresis of the EMOBs was higher (P < 0.05) than that of
      the KBMOBs (5.65 +/- 1.76 vs 1.21 +/- 0.28 mg/min). The production of bile, and
      the AST and ALT levels, were not significantly different. The PaO2 of the EMOBs
      was higher (P < 0.01) than for the KBMOBs. In normothermy, the maintenance of an
      aerobic metabolism using the FC emulsion caused less damage to the organs.
      Aerobic preservation of organs using FC emulsions therefore appears to be an
      attractive alternative to the presently used cold ischemia.

PMID- 8661240
TI  - Cholestatic liver injury down-regulates hepatic glutathione synthesis.
AB  - Hepatocellular injury caused by cholestasis may be caused in part by oxidant
      stress. The purpose of this study was to establish how acute cholestasis might
      alter hepatic glutathione homeostasis and to determine whether injured
      hepatocytes are capable of reverting to normal glutathione homeostatic
      mechanisms. Acute cholestasis was achieved by surgical ligation of the common
      bile duct in rats. Bile duct ligation induced a 3.7-fold increase in hepatic
      glutathione content over 4 days. This increase was not due to increased hepatic
      activity of gamma-glutamylcysteine synthetase (GCS); on the contrary, whole-liver
      GCS activity was substantially diminished in the bile duct-ligated liver to 34
      and 11% of normal after 4 and 7 days, respectively. To determine if hepatocytes
      removed from the cholestatic environment maintained these changes in glutathione
      homeostasis, hepatocytes were isolated from bile ductligated livers and
      established in primary culture. In cells isolated after 4 days of bile duct
      ligation, the elevated hepatocyte glutathione content decreased and the low GCS
      activity increased over 2 days in culture. More importantly, the ability of
      postcholestatic hepatocytes to substantially increase their glutathione synthetic
      capacity by increasing GCS activity in response to stress was preserved. This
      compensatory increase was due primarily to new protein synthesis. Together, these
      observations suggest that acute cholestasis impairs the ability of the liver to
      synthesize glutathione by down-regulating the key regulatory enzyme for its
      synthesis in response to acutely elevated glutathione levels and that the
      impaired glutathione synthetic capacity is corrected after cells are removed from
      the cholestatic environment.

PMID- 8661242
TI  - Saline wound irrigation reduces the postoperative infection rate in guinea pigs.
AB  - Wound irrigation with saline is widely used alone or together with systemic
      antibiotic prophylaxis to prevent postoperative wound infection. This study was
      aimed to investigate the effect of saline irrigation upon the bacterial load on
      wound surfaces and on the wound infection rate in an animal model. In 16 guinea
      pigs, two wounds were contaminated with Bacteroides fragilis and Escherichia
      coli. One wound was irrigated with saline, while the other received no
      prophylaxis. Quantitative wound cultures were performed before and after
      irrigation. The wound infection rate was determined at 10 days. Saline irrigation
      reduced the aerobic and anaerobic bacterial counts in wound margins. The
      infection rate was also reduced (15/16 nonirrigated vs 6/16 irrigated, P <
      0.001). High bacterial counts at the end of operation were associated with wound
      infection (P < 0.001). At skin closure, wounds which later became infected
      harbored fourfold more bacteria than noninfected wounds [8.7 (6.4- 1 1.0) vs 2.3
      (0.8-3.7) colony-forming units x 10(3) of E. coli/cm2; P < 0.005]. Saline wound
      irrigation diminishes infection rate in experimental animals by means of a
      significant reduction of the bacterial inoculum present at the time of skin
      closure.

PMID- 8661241
TI  - Factors influencing hepatocyte trafficking during allogeneic hepatocyte
      transplantation: improved liver sequestration with isolated perfusion.
AB  - Transplantation of normal or ex vivo modified hepatocytes holds promise in
      therapy of a variety of diseases. In order to investigate hepatocyte trafficking,
      and specifically to determine whether the route, method of delivery, or other
      host factors may affect hepatocyte sequestration in the liver, 51chromium- and
      111indium-labeled hepatocytes were transplanted into allogeneic hosts. Systemic
      injection of hepatocytes into the femoral vein resulted in sequestration mainly
      in the lungs (30 +/- 4%) whereas sequestration in the liver amounted to only 5 +/
      1%. Portal injection resulted in a dramatic increase in the liver sequestration
      (52 +/- 4%) and a reduction in the lung (2 +/- 1%, P < 0.05 vs systemic
      injection). Nevertheless, nearly half of portally injected hepatocytes came to
      rest in other organ sites. Partial hepatectomy prior to transplantation did not
      change the total hepatocyte sequestration in the liver or the organ specific
      activity. A remote site of inflammation, in the form of a turpentine abscess,
      also did not alter the pattern of hepatocyte trafficking. Isolated perfusion of
      the liver with labeled hepatocyte, however, significantly increased the
      sequestration of hepatocytes at this organ (control, 52 +/- 4%; isolated
      perfusion, 71 +/- 9%; P < 0.05). In the delivery of potentially toxic gene
      products for therapy, isolated perfusion of the target organ appears to provide
      the greatest likelihood of restricting expression of potentially toxic gene
      products to the target organ.

PMID- 8661243
TI  - Intestinal neuromuscular function after preservation and transplantation.
AB  - While it is well known that prolonged preservation of the intestinal graft causes
      severe mucosal damage after transplantation, little is known about the effect on
      neuromuscular function. The entire small intestine of adult hound dogs was
      flushed and preserved with cold lactated Ringer's solution and autotransplanted
      either immediately (n = 6) or after 24 hr (n = 6). Animals undergoing sham
      operation (n = 4) were used as a control. Fasting motility and the response of
      the intestinal smooth muscle and enteric nerves to bethanechol (100 microg/kg/0.5
      hr, iv) and cisapride (0.5 mg/kg, iv) were determined by a multiple strain gauge
      method on Postoperative Days 2,4,7,14,21, and 28. Compared to the control,
      immediately transplanted grafts and those preserved for 24 hr developed delayed
      reappearance of migrating myoelectric complexes (MMC), hypercontractile activity,
      and reduced response to bethanechol and cisapride administration. Animals in the
      preservation group developed more abnormal fasting motility after
      transplantation, but responses to bethanechol and cisapride stimulation were not
      markedly different from those of the immediate group. The reappearance of MMC
      occurred 3 weeks postoperatively in the preservation group compared to 2 days in
      the immediate group. The results of our study indicate that intestinal
      dysmotility is augmented in prolonged-preservation grafts compared to those with
      brief preservation. The dysmotility was transient and normalized 3 to 4 weeks
      after surgery. Preservation and reperfusion injury to the neuromuscular system of
      intestinal grafts are reversible and are attenuated by simple hypothermia.

PMID- 8661244
TI  - Ultrastructural changes in canine lung preserved in newly developed solutions.
AB  - The present study was undertaken to clarify the effect of differences in the
      ionic composition of a preservation solution by investigating ultrastructures of
      pulmonary endothelial cells and oxygenation ability of preserved lungs after
      reperfusion. The relation between the ultrastructural changes and the oxygenation
      ability was also examined. Canine lungs flushed with an extracellular-type (ET)
      Kyoto solution (group A, n = 6), with an intracellular-type-Kyoto solution and
      prostaglandin El (group B, n=6), or with Euro-Collins solution and prostaglandin
      E1 (group C, n=6) were stored at 4 degrees C for 20 hr. In transmission electron
      microscopic findings, the frequency of ultrastructural changes (protrusion of
      endothelial cells and cellular vacuolization) was significantly less in group A
      (23.3 +/- 9.1 and 13.3 +/- 5.2%, respectively) than in group B (64.4 +/- 6.1 and
      42.2 +/- 8.8%, respectively). In group A, PaO2 after 40, 70, and 130 min of
      reperfusion was uniformly excellent (289.4 +/- 5.7, 303.3 +/- 7.0, and 303.0 +/-
      19.6 mm Hg, respectively) and significantly higher than in groups B and C (202.6
      +/- 32.0 and 185.9 +/- 23.0 mm Hg, respectively) after 70 min and higher than in
      group C (155.7 +/- 36.3 mm Hg) after 130 min of reperfusion. A negative
      correlation was noted between the frequency of cellular vacuolization and the
      PaO2 after reperfusion. These results indicated that extracellular ion
      composition has significantly better effect on pulmonary vascular ultrastructures
      than intracellular ion composition. This may be a factor making ET-Kyoto solution
      superior to the other two solutions in oxygenation ability after reperfusion.
      When attempting to develop better lung preservation solution, the ability to
      preserve the ultrastructures of preserved lung may be an important consideration
      in the evaluation.

PMID- 8661245
TI  - Alterations in venous endothelial cell and smooth muscle cell relaxation induced
      by high glucose concentrations can be prevented by aminoguanidine.
AB  - High glucose concentrations lead to the formation of advanced glycosylation end
      products (AGE). Increased glucose concentrations are found during the systemic
      inflammatory response syndrome and during coronary artery bypass surgery. This
      study examines the pharmacological effect of AGE on venous endothelial-dependent
      and -independent relaxation and seeks to determine if aminoguanidine, a known AGE
      inhibitor, can prevent changes induced by the presence of high glucose
      concentrations. Standard isometric tension studies on rings from endothelialized
      and deendothelialized rabbit external jugular veins were performed after
      incubation for 6 hr in 5.5 mM glucose (control) or 44 mM glucose. The effects of
      preincubation with either indomethacin (10 microM) to inhibit cyclo-oxygenase
      activity or aminoguanidine (10 microM) to inhibit protein glycosylation were also
      studied. In the presence of 44 mM glucose, there was a significant reduction in
      acetylcholine (endothelial cell based)- and forskolin-induced (smooth muscle cell
      based) relaxation without associated alterations in serotonin-, calcium ionophore
      , and sodium nitroprusside-mediated relaxations. The alterations in acetylcholine
      mediated relaxation were inhibited by the addition of indomethacin; co-incubation
      with aminoguanidine prevented the decrease in acetylcholine-mediated and
      forskolin-mediated responses. This study shows that in vitro elevated glucose
      concentrations lead to a reduction in both endothelial cell and smooth muscle
      cell relaxation, which may be due to AGE-mediated generation of endothelial cell
      cyclo-oxygenase products and AGE-induced changes in cAMP-mediated relaxation.
      Therefore, AGE production in the vessel wall cells produces alterations in
      receptor-dependent and receptor-independent cyclo-oxygenase production and these
      changes result in altered endothelial- and nonendothelial-mediated relaxation.
      Alterations in the endothelial and smooth muscle cell responses can be inhibited
      by aminoguanidine, suggesting that means to reduce or prevent glycosylation are
      beneficial in ameliorating the acute changes induced by short-term exposure to
      elevated glucose concentrations.

PMID- 8661246
TI  - Age and stress history effects on spatial performance in a swim task in Fischer
      344 rats.
AB  - This study determined whether prior habituation to water immersion would
      ameliorate age-related deficits in learning and memory in a swim task. Aged (22
      months) and young adult (3 months) rats were immersed in water (30 degrees C) for
      15 min on each of 28 consecutive days before training in the swim task.
      Additional groups of age-matched animals served as handled controls. Training on
      a spatial discrimination version of the water task was conducted over 5 days with
      two trials per day (1-h intertrial interval). A probe trial was substituted for
      the last trial on the fifth day to assess the rats' use of spatial information.
      Three days later, rats received cue discrimination training to find a visible
      platform. In the spatial task, prior habituation to water immersion ameliorated
      deficits in acquisition within each day (i.e., at a 1-h intertrial interval) but
      not across days (at 24 h). The results obtained with the 24-h interval confirm
      the rapid forgetting characteristic of aged rats in many tasks. The stress
      habituation procedures reduced age-related deficits seen on the probe trial and
      on cue discrimination training. These findings indicate that several aspects of
      age-related impairments in the swim task, often attributed to primary age-related
      deficits in learning and memory processes per se, may instead be secondary to age
      related differences in stress responses to water immersion.

PMID- 8661247
TI  - Beta-amyloid accumulation correlates with cognitive dysfunction in the aged
      canine.
AB  - It is well known that beta-amyloid accumulates abnormally in Alzheimer's disease;
      however, beta-amyloid's relationship to cognitive dysfunction has not been
      clearly established and is often confounded by the presence of neurofibrillary
      tangles. We used canines to investigate the relationship between beta-amyloid
      accumulation and cognitive function in an animal model of aging lacking
      neurofibrillary tangles. The performance of 20 canines (11 purebred beagles and 9
      mongrels) on a battery of six cognitive tasks was measured. These tasks included
      Reward Approach and Object Approach learning, as well as Discrimination,
      Reversal, Object Recognition, and Spatial learning and memory. Aged canines were
      impaired on some tasks but not others. beta-Amyloid-immunopositive plaques were
      found in many of the older animals. Plaques were all of the diffuse subtype and
      many contained intact neurons detected with double-labeling for neurofilaments.
      No neurofibrillary tangles were detected. beta-Amyloid was also associated with
      the processes of many neurons and with blood vessels. Using computerized image
      analysis, we quantified the area occupied by beta-amyloid in entorhinal cortex,
      frontal cortex, and cerebellum. Controlling for age-related increases in beta
      amyloid, we observed that increased beta-amyloid deposition is strongly
      associated with deficits on Discrimination learning (r = .80), Reversal learning
      (r = .65), and Spatial learning (r = .54) but not the other tasks. There were a
      few differences between breeds which are discussed in the text. Overall, these
      data suggest that beta-amyloid deposition may be a contributing factor to age
      related cognitive dysfunction prior to the onset of neurofibrillary tangle
      formation.

PMID- 8661248
TI  - The involvement of Ca2+/calmodulin-dependent protein kinase in memory formation
      in day-old chicks.
AB  - Day-old chicks trained on a single trial passive avoidance learning task showed a
      significant increase, relative to untrained controls, in activity of the
      Ca2+/calmodulin-dependent protein kinase (CaMK) in the particulate fraction from
      tissues from the intermediate medial hyperstriatum ventrale region of the
      forebrain. The increased kinase activity was observed within 10 min following
      training and persisted for at least 70 min posttraining. Amnesia for the task was
      induced by micromolar concentrations of the specific CAMK II antagonist, KN-62,
      administered into the neostriatal/hyperstriatal region of the forebrain. The
      effect of KN-62 was lateralized. In the right hemisphere, KN-62 induced amnesia
      only when injected within 2. 5 min following training, with memory loss evident
      by 5 min posttraining. In contrast, in the left hemisphere amnesia was induced by
      KN-62 administered as late as 5 min posttraining, with onset of amnesia occurring
      after 10 min posttraining. The findings were interpreted within the context of a
      three-stage model of memory formation.

PMID- 8661249
TI  - Transient increase of AMPA and NMDA receptor binding in the barrel cortex of mice
      after tactile stimulation.
AB  - The effects of sensory stimulation and sensory conditioning upon [3H]MK-801 [(+)
      5-methyl-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-5, 10-imine] binding to N
      methyl- d-aspartate (NMDA) receptor sites and [3H]AMPA (alpha-amino-3-hydroxy-5
      methylisoxasole-4-propionic acid) binding to AMPA receptor sites were examined in
      the primary somatosensory (SI) cortex of mice. Following short-lasting unilateral
      tactile stimulation of a selected row of vibrissae, and tactile stimulation
      paired with noxious stimulus (the pairing procedure was found to alter cortical
      representation of vibrissae), in vitro receptor binding autoradiography was
      performed on the sections of the barrel cortex of mice. One hour after the end of
      tactile stimulation or training procedure there was an increase of [3H]MK-801 and
      [3H]AMPA binding in the corresponding row of barrels in layer IV of the SI cortex
      of adult mice. These effects disappeared 24 h after the end of each experimental
      procedure. The results suggest that both subtypes of glutamate receptors are
      regulated in an activity-dependent way and that sensory stimulation transiently
      modifies local cortical processing.

PMID- 8661250
TI  - Differential effects of anterior and posterior insular cortex lesions on the
      acquisition of conditioned taste aversion and spatial learning.
AB  - In this study, we evaluated the effects of NMDA-induced lesions in different
      sites of the insular cortex of the rat on the acquisition of conditioned taste
      aversion and spatial learning in the Morris water maze. The lesions were produced
      by bilateral microinjections of NMDA in the insular cortex at +3.7 mm (Anterior
      group), +1.7 mm (Central group), and -0.3 mm (Posterior group) anteroposterior
      from bregma. The results showed that the central and posterior, but not the
      anterior, lesions disrupted the acquisition of water maze learning as measured by
      the high latency to reach the target. In contrast, the conditioned taste aversion
      learning was disrupted by lesions in the central but not in the anterior or
      posterior insular cortex. These data confirm functional heterogeneity of the
      insular cortex and demonstrate that the more caudal parts are only necessary for
      acquisition of the water maze task, while the central insular cortex is crucial
      for the acquisition of both the conditioned taste aversion learning and the
      Morris water maze.

PMID- 8661251
TI  - A computational model of cholinergic disruption of septohippocampal activity in
      classical eyeblink conditioning.
AB  - A previous neurocomputational model of corticohippocampal interaction (Gluck &
      Myers, 1993) can provide a framework for examining the behavioral effects of
      septohippocampal modulation during classical conditioning. The model assumes that
      the hippocampal region is necessary for forming new stimulus representations
      during learning, but not for the formation of simple associations. This paper
      considers how septohippocampal interaction could affect this function. The septal
      nuclei provide several modulatory inputs to the hippocampus, including a
      cholinergic input which Hasselmo (1995) has suggested may function to regulate
      hippocampal dynamics on a continuum between two states: a storage state in which
      incoming information is encoded as an intermediate-term memory and a recall state
      when this information is reactivated. In this theory, anticholinergic drugs such
      as scopolamine should disrupt learning by selectively reducing the hippocampus's
      ability to store new information. An approximation of Hasselmo's idea can be
      implemented in the corticohippocampal model by a simple manipulation of
      hippocampal learning rate; this manipulation is formally equivalent to adjusting
      the amount of time the hippocampus spends in learning and recall states. With
      this manipulation, the model successfully accounts for the effects of scopolamine
      in retarding classical conditioning in humans (Solomon, Groccia-Ellison, Flynn,
      Mirak, Edwards, Dunehew, & Stanton, 1993) and animals (Solomon, Soloman, van der
      Schaaf, & Perry, 1983). The model further predicts that although cholinergic
      agonists (such as Tacrine) may improve learning in subjects with artificially
      depressed brain acetylcholine levels, there may be limited memory improvement in
      normal subjects from such cholinergic therapy. This is consistent with the
      general finding of a U-shaped dose response curve for cholinergic drugs in normal
      subjects: low to moderate doses may improve learning, but higher doses are
      ineffective or even degrade learning (e.g., Ennaceur & Meliani, 1992; Dumery,
      Derer, & Blozovski, 1988; etc.).

PMID- 8661252
TI  - Habituation and sensitization of the acoustic startle response in rats:
      amplitude, threshold, and latency measures.
AB  - The amplitude of the acoustic startle response habituates to repetitive
      stimulation. The input and output of the startle system were measured to
      determine if the decrease in startle amplitude during repetitive stimulation is
      due to an increase in the startle threshold. Two experimental approaches were
      used in 35 Sprague-Dawley rats to probe the relationship between the input (the
      sound pressure level of the stimulus) and the behavioral output (startle
      amplitude). The results show that the minimum threshold for a response does not
      change during habituation; rather, the slope of the dependence of startle
      amplitude on stimulus level decreases. Because habituation does not influence
      startle threshold we propose that the site for habituation is located in the
      neural circuitry downstream from the site for startle threshold. Besides
      amplitude and threshold, as an additional parameter we measured startle latency.
      In general, the latency of the acoustic startle response is negatively correlated
      with the response amplitude. This correlation has been repeatedly shown,
      therefore one would expect a latency increase during the amplitude decrease
      caused by habituation. However, the latency of the startle reaction also
      decreased during the course of repetitive stimulation. According to the dual
      process theory of habituation, a stimulus has both a response-decreasing, i. e.,
      habituating, as well as a response-increasing, i.e., sensitizing, influence on a
      behavior (Groves & Thompson, 1970). Our explanation of the present results is
      that startle amplitude is reduced following repetitive stimulation because it is
      mainly influenced by habituation; latency, however, is shortened because it is
      mainly influenced by sensitization.

PMID- 8661253
TI  - Amnesic effects of preacquisition, postacquisition, or preretrieval tetrodotoxin
      administration into the medial septal area on rat's passive avoidance
      memorization.
AB  - By means of local administration of tetrodotoxin (TTX) fully reversible
      functional inactivation of the medial septal area (MSA) of the rat was obtained
      in order to define the role of this structure in the retention of a conditioned
      passive avoidance response (PAR). In permanently cannulated animals, TTX (5 ng in
      0.5 microl saline) or saline (0.5 microl) was injected in the MSA. TTX or saline
      was administered to six different groups of rats, respectively 1 h before PAR
      acquisition, immediately after PAR acquisition, and 1 h before PAR retrieval,
      performed 48 h after the acquisition trial. It was shown that MSA preacquisition
      and preretrieval TTX injections were followed by significant PAR retention
      impairment, while postacquisition TTX administration had no effect on PAR
      retention. The results indicate a well-defined mnemonic role of MSA during the
      acquisition and retrieval periods but not during the consolidation of PAR engram.
      The experimental evidence is discussed in relation to other reports and to MSA
      connectivity with other subcortical structures.

PMID- 8661254
TI  - Reversible changes in hippocampal 3H-AMPA binding following inhibitory avoidance
      training in the rat.
AB  - We have recently shown that inhibitory avoidance training produces a rapid,
      selective, and learning-specific increase in the number of 3H-AMPA glutamate
      receptors in several subfields of the dorsal hippocampal formation in the rat. In
      the present study we investigated the posttraining temporal course of this
      enhancement by quantitative autoradiography of 3H-AMPA binding. Confirming
      previous results, rats submitted to a step-down inhibitory avoidance paradigm
      showed a marked increase (50-90%) in hippocampal 3H-AMPA binding that peaked 2 h
      posttraining. In CA3 and dentate gyrus this increase persisted for at least 48 h
      following training. In contrast, 24 h after training the binding of 3H-AMPA in
      the CA1 subfield did not differ significantly from naive control values. In all
      hippocampal regions studied, the binding of 3H-AMPA at 168 h posttraining reached
      control values. No changes were observed in the shocked or free exploration
      groups in comparison with naive controls. The results suggest that hippocampal
      AMPA receptors undergo rapid and reversible changes after inhibitory avoidance
      learning and give further support to the hypothesis that changes in hippocampal
      AMPA receptors participate in the synaptic plasticity mediating certain forms of
      learning and memory.

PMID- 8661257
TI  - Determination of the Bound Water Fraction in Cells and Protein Solutions Using
      17O-Water Multiple-Quantum Filtered Relaxation Analysis
AB  - Multiple-quantum filtering NMR sequences were used to study the multiexponential
      relaxation behavior of H217O in the presence of macromolecules. By this means,
      the fraction and the correlation time of water in slow motion, or "bound" water,
      were determined, as well as the relaxation time of bulk water in the extreme
      narrowing limit. Aqueous solutions of bovine serum albumin and intact human red
      blood cells were studied. The small fraction of bound water of less than 1%
      appeared to correspond to "strongly bound" water, whereas the behavior of bulk
      water was different from pure water and was interpreted as being due to weak (or
      transient) interactions with macromolecules. The experiments and the data
      analysis appeared to be reproducible, which suggests that diverse samples might
      be studied this way and thus help define the properties of water in these
      systems.

PMID- 8661255
TI  - Technical note on omega-conotoxin GVIA disrupts memory formation in the day-old
      chick.

PMID- 8661258
TI  - Measuring Nitrate in Plant Cells by in Vivo NMR Using Gd3+ as a Shift Reagent
AB  - NMR investigations of nitrate in plant cells and tissues have hitherto been
      limited by the indistinguishability of the signals from intracellular and
      extracellular nitrate. Gd3+ is shown to be an effective shift reagent for 14N and
      15N nitrate NMR signals, resolving the internal and external nitrate signals in
      plant tissues, including cell suspensions and root material. However, time-course
      experiments show that, while the use of Gd3+ allows nitrate levels to be
      monitored over extended periods, it also has adverse effects on growth and
      nitrate uptake. Accordingly, a number of chelated forms of gadolinium were
      investigated, and it is concluded that the NMR contrast agent Gd(DTPA-BMA) is
      likely to be a suitable shift reagent for physiologically relevant studies of
      nitrate transport in roots.

PMID- 8661259
TI  - Possible Systematic Errors in Single-Shot Measurements of the Trace of the
      Diffusion Tensor
AB  - There have been recent proposals of diffusion-weighting pulse sequences that
      purport to measure the trace of the diffusion tensor, or to weight an image by
      that rotationally invariant quantity. Here the effect of a time-dependent
      diffusion tensor on such sequences is investigated theoretically. It is found
      that the time dependence of the diffusion tensor both breaks the rotational
      invariance of the pulse sequence and affects the overall magnitude of the
      diffusion weighting. These deviations are calculated for two pulse sequences,
      with parameters relevant to experiments on brain tissue. The departure from
      rotational invariance is found to be surprisingly small: <1%, for reasonable
      parameters and approximately5% for the most extreme choice of parameters. The
      overall magnitude of the diffusion weighting, however, may be significantly
      altered; 10% is estimated for reasonable parameters. It is proposed that this
      effect should prove a sensitive probe of time dependence in the diffusion tensor.

PMID- 8661260
TI  - Spectral-Density Mapping of 13Calpha-1Halpha Vector Dynamics Using Dipolar
      Relaxation Rates Measured at Several Magnetic Fields
AB  - The spectral-density mapping of a 13Calpha-1Halpha vector of Leu10 in the 22
      residue peptide hormone motilin [P. Allard, J. Jarvet, A. Ehrenberg, and A.
      Graslund, J. Biomol. NMR 5, 133-146 (1995)] is extended in this paper to three
      polarizing fields 9.4, 11.7, and 14.1 T in order to improve the accuracy of the
      calculated spectral-density function J(omega) and to extend the sampling range up
      to 750 MHz. The problem with a usually large relative error in J(omegaH) is
      eliminated since the generally more precise J(omegaH - omegaC) and J(omegaH +
      omegaC) determined at other fields appear at nearly the same frequencies. The
      fitting of dynamic models to the points of spectral density was made with error
      weighting, and the influence of J(omegaH) was found to be negligible. Therefore,
      the high-frequency part of the spectral-density function is determined
      essentially without influence from the two transverse-type relaxation rates. In
      the case of a carbon-proton vector, the relaxation is mainly determined by
      dipolar interaction and is only weakly influenced by other relaxation mechanisms,
      which makes it particularly suitable for the spectral-density mapping technique.
      The measured relaxation rates in the time domain are transformed into the
      frequency domain by spectral-density mapping, and the slopes in different
      frequency regions are important parameters when comparing experimental data with
      theoretical models of motion. Using an adjustable internuclear distance reff,
      combined with the model-free approach, it is possible to obtain a reasonable fit
      to measured spectral-density points at J(0) and around J(omegaC). At the same
      time, however, the high-frequency slope of the spectral-density function defined
      by J(omegaH - omegaC) and J(omegaH + omegaC) could not be reproduced.

PMID- 8661261
TI  - Deuterium Quadrupole-Coupling and Chemical-Shielding Tensors in the Model
      Dipeptide Glycylglycine Monohydrochloride Monohydrate
AB  - The electric field gradient (EFG) and chemical-shift (CS) tensors for the amide,
      carboxylic acid, and amino deuteron sites in glycylglycine monohydrochloride
      monohydrate were measured. For each site, the EFG tensors are found to lie nearly
      along the deuteron bond. The magnitudes of the quadrupole-coupling constants
      agree well with previous empirical relationships to hydrogen-bond lengths. A new
      relationship is presented which correlates hydrogen-bonding geometries and EFG
      asymmetry parameters for N-D&middot;&middot;&middot; (hydrogen-bond acceptor)
      systems that suggests the importance of intermolecular geometry in determining
      these parameters. The measured amino and amide CS tensors are found to agree well
      with the few examples in the literature and agree qualitatively with those
      determined from ab initio calculations. The carboxylic acid deuteron CS tensor
      agrees well with empirical relationships to hydrogen-bond distance.

PMID- 8661262
TI  - Quantitative Determination of Cross-Relaxation Rates in NMR Using Selective
      Pulses to Inhibit Spin Diffusion
AB  - Overhauser effects and hence internuclear distances can be measured accurately
      with selective experiments designed to suppress spin diffusion. It is essential
      to consider effects of both transverse and longitudinal relaxation during
      selective radiofrequency pulses. Fitting procedures allow one to refine selected
      cross-relaxation rate constants, and hence determine internuclear distances with
      improved accuracy. For the sake of illustration, selected cross-relaxation rates
      are determined that correspond to short- and long-range distances involving two
      diastereotopic sugar protons in a double-stranded B-DNA dodecamer. Such distances
      are difficult to distinguish by traditional Overhauser methods because of spin
      diffusion effects.

PMID- 8661264
TI  - Nonuniform Phase-Encode Distributions for MRI Scan Time Reduction

PMID- 8661263
TI  - Self-Diffusion Maps from Wavelet De-Noised NMR Images
AB  - A wavelet transform was used to improve the signal-to-noise in NMR microimages of
      Phaseolus vulgaris cotyledonary tissues. Two cases were tested: a relatively
      clean image and, at longer TE, a relatively noisy image. Significant improvement
      in the image quality of both test cases was achieved, with the most dramatic
      improvement noted in the noisy image. The conditions were extended to include
      diffusion weighting with the aim of computing diffusion maps for the tissues.
      Again, the wavelet procedure was effective in improving the appearance of the
      (diffusion-weighted) images. Finally, diffusion maps from the raw and de-noised
      data were computed and compared. The de-noised images produced maps with better
      detail and more consistent features. It is concluded that wavelet de-noising is a
      very useful approach for enhancing the image quality of hard-to-image tissues.

PMID- 8661265
TI  - Spectral Editing and Water Suppression in Double-Quantum Experiments

PMID- 8661266
TI  - In Vitro and in Vivo Spectral-Editing Technique for the Detection of Ethanolamine

PMID- 8661269
TI  - Continuous probability distribution (CUPID) analysis of potentials for internal
      rotations.
AB  - The continuous probability distribution (CUPID) approach for analyzing the
      rotamer populations from NMR spin-spin couplings and nuclear Overhauser
      enhancements [Z. Dzakula, W.M. Westler, A.S. Edison, and J.L. Markley, J. Amer.
      Chem. Soc. 114, 6195 (1992)] can be expanded to allow computation of the
      rotational potential from the Fourier coefficients of the angular probability
      distribution. This approach provides a general solution to the nonnegativity
      problem, which appears when lack of data causes a serious truncation in the
      Fourier series that defines the probability distribution. In favorable cases,
      this approach also allows thermodynamic characterization of internal rotation.
      Use of this extension of the CUPID method is illustrated by the analysis of
      internal rotations in an amino acid, two peptides, and an oligosaccharide from
      published experimental data. Three strategies have been devised for dealing with
      cases where the experimental input data do not provide enough information for
      complete reconstruction of the potential: (1) two-dimensional grid search for the
      undetermined third-order Fourier coefficients of the potential, (2) transfer of
      these coefficients from related model compounds, and (3) restriction of the
      magnitudes of the Fourier coefficients as required by the assumption of fast
      exchange averaging of the input parameters. In addition, equations for
      translating uncertainties in experimental NMR input data into errors in
      calculated continuous probability distributions of rotamers are presented. The
      dependence of errors on various features of the distributions has been studied
      systematically from simulations. The results show that, typically, the confidence
      intervals are +/- 30-40 degrees for dihedral angles and +/- 0.2 for rotamer
      populations. For chi 1 rotamers of amino acids, the analysis is most sensitive to
      the uncertainties in C'-H beta couplings. A critical reexamination of the use of
      Gaussian functions to reconstruct a probability distribution is presented. In
      particular, the simplifying assumption of identical widths for all Gaussian
      probability peaks has been justified by showing that it does not lead to large
      errors in other CUPID parameters. finally, the angular dependencies of cross
      relaxation rates, their uncertainties, and the potential for their use in
      studying chi 1 internal rotations in amino acids are discussed.

PMID- 8661268
TI  - Ionic association and electron spin relaxation rates in aquo gadolinium (III)
      complexes.
AB  - The electron paramagnetic resonance linewidth of aquo gadolinium(III) ion changes
      with the counter-ion identity and concentration in aqueous solutions. The EPR
      linewidth of 2 mM gadolinium(III) chloride increases from 49.2 to 89.0 mT when
      carbonate ion is added and decreases to 17.3 mT when nitrite ion is added. These
      observations suggest association reactions between aquo gadolinium(III) ion and
      anions that change the electron spin relaxation rates of the aquo ion. The
      concentration dependence of the gadolinium(III) EPR linewidth is consistent with
      binding constants for nitrite and nitrate ion with the aquo gadolinium(III) ion
      of 37 +/- 6 and 2.3 +/- 0.3 L mol-1 respectively. The decreases in the EPR
      linewidth factors with these association reactions are difficult to understand
      unless the anion reactions increase the symmetry of the metal center. Although
      first-coordination reactions may not be ruled out, the decrease in EPR linewidth
      is more consistent with an outer-sphere association reaction that also reduces
      the coordination number of the metal center from 9 to 8.

PMID- 8661270
TI  - Simulation of Mn (II) EPR spectra using a full spin-Hamiltonian approach.
AB  - A full spin-Hamiltonian approach was used to calculate continuous-wave EPR
      spectra of Mn(II) complexes, and a comparison was made with spectra previously
      simulated by perturbation methods. Successful fits were performed using single
      values of the zero-field splitting parameter, D. The advantage of the new
      procedure is that it provides better fits where the magnetic field is not very
      large compared to zero-field splitting terms.

PMID- 8661271
TI  - Some practical aspects of double-resonance techniques in solution-state NMR
      studies of high-molecular-weight systems.
AB  - This paper addresses some of the practical issues associated with solution NMR
      investigations of high-molecular-weight ( > 20 kDa) biomolecules and their
      complexes. The experimental example of a high-molecular-weight system used here
      is a 52 kDa Fab/peptide complex. Theoretical as well as experimental aspects of
      solution NMR techniques employed to study such larger systems are discussed.
      Specific topics covered include hardware considerations, solvent suppression, and
      the relative efficiencies of various isotope-edited NMR techniques. Typical NOE
      methods used to derive structural information on these higher-molecular-weight
      systems and the scope of structural detail achievable are also examined.

PMID- 8661272
TI  - EPR linewidth (T2) method to measure oxygen permeability of phospholipid bilayers
      and its use to study the effect of low ethanol concentrations.
AB  - It is well known that continuous-wave EPR spectra of nitroxide probes (labels)
      introduced into phospholipid bilayers are sensitive to molecular oxygen. However,
      accurate determination of oxygen broadening from these experiments is complicated
      by the complex shapes of EPR spectra, which are strongly influenced by
      anisotropic restricted motion of the probe molecules. An accurate method is
      presented to extract the oxygen broadening from the spectra measured with and
      without oxygen and at the same temperature. The method is based on a fast
      convolution algorithm with Levenberg-Marquardt optimization. This method was
      previously applied to EPR oximetry with nitroxides exhibiting rotational motion
      in the fast limit. It is shown that for several membrane spin probes, the oxygen
      broadening can be described as homogeneous; thus, a one-linewidth-parameter
      fitting model is appropriate. The method is applied to measure permeability
      profiles of model membranes composed from 1,2-dimyristoyl-sn-glycero-3
      phosphocholine above and below the main phase transition. For both membrane
      phases, the broadening of doxyl- and sterol-type labels is found to be
      homogeneous, a finding consistent with the model of Heisenberg exchange between
      molecular oxygen and spin probes. As an example, the method is applied to study
      the ethanol effect on local oxygen permeability of a phospholipid bilayer. It is
      shown that ethanol concentrations as low as 1% (v/v) increase oxygen permeability
      of the bilayer. The effect is larger at the surface of the membrane than at its
      center, indicating that ethanol molecules interact primarily within the polar
      head region of the bilayer.

PMID- 8661273
TI  - Rotational motion of Ca-ATPase monitored by electron spin echoes.
AB  - Electron spin echoes are used to study the dynamics of different aggregational
      forms of spin-labeled Ca-ATPase in the sarcoplasmic reticulum membrane. The 2D
      ESE measurements are sensitive to motions on the microsecond time scale. The
      motional information is extracted from the variation of the echo decays across
      the CW-ESR absorption spectrum. The motional contribution to the decays is
      described by assuming that the Ca-ATPase molecule is perfectly oriented along the
      normal to the membrane surface and only undergoes rotational motion about its
      long axis. The echo-amplitude decays have been evaluated in the time domain by
      solving the Bloch equations for the stochastic spin Hamiltonian on making use of
      stochastic trajectories for the orientational behavior of the spin-labeled
      protein. This approach provides a useful insight into the information provided by
      the 2D-ESE measurements and affords a direct comparison of the results obtained
      with different experimental techniques. It is shown that the 2D-ESE technique
      monitors the orientational motions of dimers or larger aggregates of Ca-ATPase
      molecules whose rotational correlation times vary between 200 microseconds and 1
      ms for the temperature range between 37 and 4 degrees C.

PMID- 8661274
TI  - An Improved Homonuclear TOCSY Experiment with Minimal Water Saturation

PMID- 8661275
TI  - Lack of magnetization transfer from the ferritin molecule.

PMID- 8661276
TI  - Small Birdcage Resonators for High-Field NMR Microscopy

PMID- 8661277
TI  - NMR determination of crystal field parameters and electron-spin correlation times
      for the LnDOTP5- complexes.

PMID- 8661278
TI  - The application of "excitation sculpting" in the construction of selective one
      dimensional homonuclear coherence-transfer experiments.

PMID- 8661279
TI  - Excitation of Arbitrary Shapes in Nuclear Magnetic Resonance by a Random Walk in
      Discrete k Space

PMID- 8661280
TI  - NMR Spectroscopy and Imaging of Sodium in Ordered Environments. The Return of the
      Central Transition

PMID- 8661281
TI  - Use of selective C alpha pulses for improvement of HN(CA)CO-D and HN(COCA)NH-D
      experiments.

PMID- 8661282
TI  - Simultaneous 13C and 15N isotope editing of biomolecular complexes. Application
      to a mutant lac repressor headpiece DNA complex.

PMID- 8661283
TI  - Hyperpolarized 129Xe MR imaging of the oral cavity.

PMID- 8661284
TI  - Corrections and Additions

PMID- 8661285
TI  - Microstructural and physiological features of tissues elucidated by quantitative
      diffusion-tensor MRI.
AB  - Quantitative-diffusion-tensor MRI consists of deriving and displaying parameters
      that resemble histological or physiological stains, i.e., that characterize
      intrinsic features of tissue microstructure and microdynamics. Specifically,
      these parameters are objective, and insensitive to the choice of laboratory
      coordinate system. Here, these two properties are used to derive intravoxel
      measures of diffusion isotropy and the degree of diffusion anisotropy, as well as
      intervoxel measures of structural similarity, and fiber-tract organization from
      the effective diffusion tensor, D, which is estimated in each voxel. First, D is
      decomposed into its isotropic and anisotropic parts, [D] I and D - [D] I,
      respectively (where [D] = Trace(D)/3 is the mean diffusivity, and I is the
      identity tensor). Then, the tensor (dot) product operator is used to generate a
      family of new rotationally and translationally invariant quantities. Finally,
      maps of these quantitative parameters are produced from high-resolution diffusion
      tensor images (in which D is estimated in each voxel from a series of 2D-FT spin
      echo diffusion-weighted images) in living cat brain. Due to the high inherent
      sensitivity of these parameters to changes in tissue architecture (i.e.,
      macromolecular, cellular, tissue, and organ structure) and in its physiologic
      state, their potential applications include monitoring structural changes in
      development, aging, and disease.

PMID- 8661286
TI  - 17O NMR Studies of the Solvation State of cissolidustrans Isomers of Amides and
      Model Protected Peptides
AB  - 17O shielding constants have been utilized to investigate solvation differences
      of the cissolidustrans isomers of N-methylformamide (NMF), N-ethylformamide
      (NEF), and tert-butylformamide (TBF) in a variety of solvents with particular
      emphasis on aqueous solution. Comparisons are also made with protected peptides
      of the formulas CH3CO-YOH, CH3CO-Y-NHR (Y = Pro, Sar), and CH3CO-Y-Z-NHR (Y =
      Pro; Z = D-Ala) selectively enriched in 17O at the acetyl oxygen atom. Hydration
      at the amide oxygen induces large and specific modifications of the 17O shielding
      constants, which are practically the same for the cis and trans isomers of NMF,
      NEF, and the protected peptides. For tert-butylformamide, the strong deshielding
      of the trans isomer compared to that of the cis isomer may be attributed to an
      out-of-plane (torsion-angle) deformation of the amide bond andsolidusor a
      significant reduction of solvation of the trans isomer due to steric inhibition
      of the bulky tert-butyl group. Good linear correlation between delta(17O) of
      amides and delta(17O) of acetone was found for different solvents which have
      varying dielectric constants and solvation abilities. Sum-over-states
      calculations, within the solvaton model, underestimate effects of the dielectric
      constant of the medium on 17O shielding, while finite-perturbation-theory
      calculations give good agreement with the experiment.

PMID- 8661287
TI  - Maximizing signal-to-noise ratio in the presence of coil coupling.
AB  - Crosstalk due to coupling produces noise correlation between receiver coils. It
      has been stated that this correlation reduces the signal-to-noise ratio
      obtainable from combining signals from the coils. In this paper, it is shown that
      the effects of crosstalk on the signal-to-noise ratio may in theory be eliminated
      by properly combining signals. Equations are derived which show how the signals
      from two coils should be combined in the presence of crosstalk in order to obtain
      the same signal-to-noise ratio as in an ideal case of no crosstalk. The deviation
      from optimum signal-to-noise ratio due to imperfect circuits and amplifiers is
      discussed. An experimental technique for achieving the proper combination of
      signals is presented.

PMID- 8661288
TI  - Detection of Anisotropic Pulsating Flow and Its Velocity-Fluctuation Rate in
      Fertilized Bird Eggs by NMR Microimaging
AB  - Coherent and incoherent flows in fertilized quail and bantam eggs have been
      studied with the aid of NMR microimaging techniques in the course of incubation
      until the end of the sixth day. The methods employed were multiplane tagging NMR
      imaging and a NMR gradient-echo imaging pulse sequence supplemented by bipolar
      gradient pulses in the coherence-evolution interval. The latter technique is
      suited for recording of velocity maps as well as for localizing of regions with
      enhanced echo attenuation by incoherent motions. Slight coherent displacements in
      the middle of the upper part of the egg white were found after the fourth day of
      incubation with the aid of both pulse schemes. The maximum velocity was estimated
      to be 1 mmsoliduss. More pronounced effects revealed themselves in the
      examination of incoherent motions. After the same time of incubation and in a
      somewhat more restricted area of the upper part of the egg white, distinct
      motions could be localized consistently with either technique. It is shown that
      these motions are directed to and from the yolk. Furthermore, the analysis of the
      time fluctuations of the local signals with the aid of a Fourier transformation
      showed that the flow is largely of a pulsating nature. The pulsation frequency
      was found to be 0.4 Hz.

PMID- 8661289
TI  - Water self-diffusion measurements in excised rat lungs.
AB  - Water self diffusion in excised rat lungs has been measured using pulsed-field
      gradient (PFG) techniques. The apparent diffusion coefficient, Dapp, was measured
      from a plot of the magnetization M vs ga2 to be 4.0 x 10(-6) cm2/s in the limit
      of small gamma delta ga, where gamma is the gyromagnetic ratio, delta is the
      duration of the applied gradient pulses, and ga is the applied gradient strength.
      Dapp is independent of the diffusion time, t, for values of t between 18 and 106
      ms. For larger values of gamma delta ga, an additional smaller value of the slope
      of M vs ga2 was observed, indicating the existence of other, more slowly
      dephasing spins. Variation of t revealed that the relative magnetization
      associated with the more slowly dephasing spins decreases as t is increased. In
      addition, the relative magnetization of the slowly dephasing spins decreases as
      the temperature, T, of the excised rat lung is increased. Slow exchange from the
      compartment of the more rapidly to that of the more slowly dephasing spins may
      explain some of the observed dependence of the relative magnetizations on t and
      T. Measurements of water self diffusion in rat lung at various levels of water
      content indicate a correlation between T2 components and diffusion components. A
      new technique that combines the PFG with the Carr-Purcell-Meiboom-Gill technique
      is presented. The application of this technique to excised rat lung confirms the
      correlation between T2 and diffusion components.

PMID- 8661290
TI  - Chiral spin traps. The spin trapping chemistry of 5-methyl-5-phenylpyrroline-N
      oxide (MPPO).
AB  - The use of 5,5-dimethylpyrroline-N-oxide (DMPO) as a versatile spin trap was
      first published in this journal (E.G. Janzen and J.I.-P. Liu, J. Magn. Reson. 9,
      510-512 (1973). In this paper, the general use of an improved DMPO-type spin
      trap, namely 5-methyl-5-phenylpyrroline-N-oxide (MPPO), is proposed. MPPO is more
      stable than DMPO and has an excellent shelf life. Commonly known artifacts of
      DMPO are not present in MPPO. The EPR spectra of MPPO spin adducts have the same
      patterns as DMPO spin adducts which users have become familiar with. The
      lifetimes of spin adducts are longer for MPPO than for DMPO and the rate
      constants of spin trapping are similar. An interesting additional feature is
      associated with the detection of two spin-adduct spectra in some cases. The major
      component is assigned to the trans addition product (with respect to the phenyl
      group) in the case of carbon-centered radicals. The minor component is assigned
      to the cis adduct. In the superoxide/peroxyl radical adduct, however, the reverse
      appears to be the case. Only one EPR spectrum is detected in the hydroxyl radical
      adduct of MPPO.

PMID- 8661291
TI  - The spin dynamics of heteronuclear multiple-spin systems formulated in the
      extended strong-narrowing limit.
AB  - Employing the perturbation approach directly in the multiply rotating frame, the
      master equation governing the spin dynamics of scalar-coupled heteronuclear
      multiple-spin systems has been derived. The resulting equation for the spin
      density operator and the matrix form of the relaxation superoperator are
      relatively simple under the conditions of the "extended" strong-narrowing limit.
      The extended strong-narrowing limit, which requires that omega iI tau c << 1 and
      2 pi Jij tau c << 1 [where I represents one of the spin types in the
      heteronuclear spin system, omega Ii is the chemical-shift range of spin type I in
      radians per second, Jij is the coupling constant J between spin i and spin j
      (like or unlike) in hertz, and tau c is the correlation time in seconds per
      radian], can be applied to heteronuclear spin systems of both small molecules and
      biopolymers in high-resolution liquid NMR. This newly developed formalism is used
      to investigate the effect of transverse cross relaxation on the apparent coupling
      constants in a heteronuclear 1H-1H-13C three-spin system. The calculation shows
      that, despite the strong dipolar interaction between directly bonded 1H and 13C,
      this perturbation on the apparent couplings is trivial. This result is in
      contrast to the homonuclear proton spin system, where the scalar coupling
      constants between two protons are significantly modulated if one proton is
      strongly dipole coupled to another proton. The underlying physical reasons for
      the different behavior of heteronuclear and homonuclear systems are explained.

PMID- 8661293
TI  - Gaussian Spectral-Density Function for Protein Internal Motions

PMID- 8661292
TI  - Oxygen-centered spin adducts of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 2H
      imidazole 1-oxides.
AB  - The hydroxyl and some alkoxyl spin adducts of 5,5-dimethyl-1-pyrroline 1-oxide
      (DMPO) are difficult to assign due to the remarkable similarity of their EPR
      spectra. The utility of resolving superhyperfine (SHF) structure followed by
      computer simulations has been demonstrated to assist in the assignment of EPR
      spectra with close values of hyperfine splitting constants, e.g., DMPO/ .OH and
      DMPO/.OR. Here, .OR is the alkoxyl radical derived from thermal decomposition of
      2,2' -azobis (2-amidinopropane) hydrochloride (AAPH). In addition, two other spin
      traps, derivatives of 2H-imidazole 1-oxide, namely, 2,2,4-trimethyl-2H-imidazole
      1-oxide (TMIO) and 2,2-dimethyl-4-phenyl-2H-imidazole 1-oxide (DMPIO), have been
      used in a model study to develop a procedure for distinguishing between oxygen
      centered spin adducts. These results are compared with those for DMPO. TMIO and
      DMPIO spin traps provide more distinguishable individual spectra with .OH and
      AAPH-derived .OR radicals than the DMPO spin trap. The formation of
      DMPO/.OR(AAPH) and DMPIO/ .OR(AAPH) spin adducts was confirmed by mass
      spectrometry. The comparison of spin trapping by DMPO and 2H-imidazole 1-oxides
      using typical biological sources of other oxygen-centered radicals reveals
      application limits of these spin traps. For example, 2H-imidazole 1-oxides do not
      form superoxide spin adducts in the xanthine/xanthine oxidase system. Also, for
      the first time, experimental evidence is presented for SHF structure in spectra
      of TMIO and DMPIO spin adducts with .OH/.OD and .CH3/ .CD3 radical species.

PMID- 8661294
TI  - Simulations and demonstrations of localized tagging experiments.

PMID- 8661295
TI  - Simultaneous Multislice Rapid (SMR) FLASH MRI with Hard Pulse Excitation

PMID- 8661296
TI  - Multiple-pi-pulse sequences in biological solid-state NMR. Enhancement of
      sensitivity by permutation of the phases.

PMID- 8661298
TI  - Separation of NOEs from degenerate amide protons in 13C/15N-labeled proteins
      using a 3D 13C'-edited NOESY-H(N)CO experiment.

PMID- 8661297
TI  - Temporal dynamics of hyperpolarized 129Xe resonances in living rats.

PMID- 8661301
TI  - Analytical Solutions and Simulations for Spin-Echo Measurements of Diffusion of
      Spins in a Sphere with Surface and Bulk Relaxation
AB  - Nuclear spins (in molecules) are considered to be diffusing in a sphere in a
      linearly inhomogeneous magnetic field (field gradient) that is imposed during a
      spin-echo NMR experiment. Relaxation of magnetization both in the bulk medium and
      on the inner surface of the sphere is assumed to occur. Analytical solutions were
      obtained for the relevant modified diffusion (partial differential) equation by
      using separation of variables with a Green's function (propagator) and three
      different boundary conditions. Neuman [J. Chem. Phys. 60, 4508 (1974)] analyzed
      the same physical system, but with no relaxation, to obtain an expression that
      relates the NMR spin-echo signal intensity to the magnitude of the magnetic field
      gradient, the spin-echo time, and the intrinsic molecular diffusion coefficient.
      The present analysis was based on that originally used by Neuman and, like the
      latter, it employed the assumption of a Gaussian distribution of phases of the
      spin magnetizations. This assumption, while rendering a tractable solution,
      nevertheless limits its range of applicability; this aspect, and the convergence
      properties of the series solutions were investigated in conjunction with
      numerical simulations made with diffusion modeled as a three-dimensional random
      (Monte Carlo) walk. A novel prediction for spheres with finite surface relaxation
      and a given radius is the presence of two minima in a graph of the normalized
      spin-echo signal intensity versus the reciprocal of the diffusion coefficient.

PMID- 8661302
TI  - Proton detection of choline and lactate in EMT6 tumors by spin-echo-enhanced
      selective multiple-quantum-coherence transfer.
AB  - An extension of the Sel-MQC pulse sequence--SEE-SelMQC (spin-echo-enhanced
      selective multiple-quantum coherence transfer)--that completely suppresses lipid
      and water in tissues containing mobile lipid in a single scan and detects 1H
      resonances of multiple metabolites is described. As in the Sel-MQC lactate
      editing experiments [Q. He et al., J Magn. Reson. B 106,203 (1995)], SEE-SelMQC
      acquires lactate from its ZQ --> DQ coherence-transfer pathway; in addition, the
      method recovers signal from other metabolites by selective generation of
      additional spin echoes using extra frequency-selective pulses and gradients. This
      method introduces no loss of lactate signal intensity beyond the 50% that is lost
      through the multiple-quantum coherence-transfer process. The spatial
      distributions of choline and lactate with a phantom and in vivo, in
      subcutaneously implanted murine EMT6 tumors, have been simultaneously mapped.

PMID- 8661303
TI  - Cation-binding location and hydrogen-exchange sites for gramicidin in SDS
      micelles using NOESY NMR.
AB  - The site of monovalent cation binding and sites of hydrogen exchange between
      amide protons and water molecules in the gramicidin A and Phe-1 gramicidin A
      channels incorporated into SDS micelles have been determined using a NOESY NMR
      technique. The cation-binding pocket was found to involve residues 10-15 of the
      peptide.

PMID- 8661304
TI  - NMR spectral quantitation by principal-component analysis. II. Determination of
      frequency and phase shifts.
AB  - This paper extends the use of principal-component analysis in spectral
      quantification to the estimation of frequency and phase shifts in a single
      resonant peak across a series of spectra. The estimated parameters can be used to
      correct the spectra accordingly, resulting in more accurate peak-area estimation.
      Further, the removal of the variations in phase and frequency cause by
      instrumental and experimental fluctuations makes it possible to determine more
      accurately the remaining variations, which bear biological significance. The
      procedure is demonstrated on simulated data, a 3D chemical-shift-imaging dataset
      acquired from a cylinder of inorganic phosphate (Pi), and a set of 736 31P NMR in
      vivo spectra taken from a kinetic study of rate muscle energetics. In all cases,
      the procedure rapidly and automatically identifies the frequency and phase shifts
      present in the individual spectra. In the kinetic study, the procedure is used
      twice, first to adjust the phase and frequency of a reference peak
      (phosphocreatine) and then to determine the individual frequencies of the Pi peak
      in each of the spectra which further can be used for estimation of pH changes
      during the experiment.

PMID- 8661305
TI  - Two-Dimensional NMR Study of a Liquid-Crystal Solution under Magic-Angle
      Spinning. Conformation of Carboxylic Ionophore Lasalocid A Dissolved in a
      Lyotropic Liquid Crystal
AB  - The conformation of a carboxylic ionophore, lasalocid A, has been determined in a
      lyotropic liquid crystal by means of magic-angle spinning (MAS) and two
      dimensional NMR experiments. The information extracted from ROESY spectra
      measured under MAS was analyzed according to the distance-geometry algorithm. The
      liquid crystal used for the solvent is cesium perfluorooctanoate dissolved in
      D2O, and the resulting structure of lasalocid A is a cyclic one, indicating
      cation complexation within a hydrophobic region of the liquid crystal. In this
      way, the two-dimensional MAS NMR experiment is proved to be a useful technique in
      conformational studies of complex molecules dissolved in lyotropic liquid crystal
      which may be regarded as offering a membrane-like environment.

PMID- 8661306
TI  - Application of the Quadrupolar Carr-Purcell-Meiboom-Gill Pulse Train for
      Sensitivity Enhancement in Deuteron NMR of Liquid Crystals

PMID- 8661307
TI  - Effect of Cation Binding on the Proton Chemical Shifts and the Spin-Spin Coupling
      Constant of Citrate

PMID- 8661308
TI  - Fully 13C-Refocused Multidimensional 13C-Edited Pulse Schemes Using Broadband
      Shaped Inversion and Refocusing Pulses

PMID- 8661309
TI  - Verification of the projection resultant method for two-bond 13C- 13C coupling
      sign determinations in carbohydrates.

PMID- 8661310
TI  - Carbon-relayed correlation of intranucleotide sugar H1' and base H6/H8 protons in
      oligonucleotides at natural abundance.

PMID- 8661311
TI  - A potential involving multiple proton chemical-shift restraints for
      nonstereospecifically assigned methyl and methylene protons.

PMID- 8661312
TI  - Simple, distortion-free homonuclear spectra of peptides and nucleic acids in
      water using excitation sculpting.

PMID- 8661313
TI  - Fast magnetic-resonance temperature imaging.

PMID- 8661314
TI  - High-resolution solid-state NMR spectra of integral membrane proteins
      reconstituted into magnetically oriented phospholipid bilayers.

PMID- 8661316
TI  - Meetings Calendar

PMID- 8661315
TI  - Amino-acid-type identification for deuterated proteins with a beta-carbon-edited
      HNCOCACB experiment.

PMID- 8661328
TI  - Implications of arsenic genotoxicity for dose response of carcinogenic effects.
AB  - Epidemiological data relating arsenic ingestion and skin and internal cancers
      strongly suggest a sublinear or threshold relationship. Physiological saturation
      of methylation-based arsenic detoxification has been proposed as one explanation
      for a sublinear response. We have evaluated the molecular bases for sublinearity
      in light of new data and hypotheses regarding arsenic genotoxicity and chemical
      carcinogenesis. A review of the dose-response relationships observed in arsenic
      genotoxicity assays is presented. With the exception of sister chromatid
      exchanges, sublinear dose-response relationships for arsenic-induced chromosomal
      aberrations were observed repeatedly in different mammalian and human cell
      systems. Arsenic also enhanced the clastogenicity and mutagenicity of other DNA
      damaging agents with a sublinear dose response. Consistent with the dose response
      of arsenic-induced genetic alterations, arsenic also inhibited DNA ligases I and
      II, enzymes which play a role in DNA repair, with a sublinear dose response. In
      some cases, protective effects of relatively low exposures to arsenic have been
      observed, again consistent with sublinearity. We discuss recent theories on the
      mechanism of arsenic carcinogenicity and the potential implications for dose
      response modeling and risk assessment. Overall, based on available arsenic
      genotoxicity data, we conclude that it is likely that arsenic indirectly induces
      genetic damage with a sublinear dose response in humans, thus providing a
      biological basis for a sublinear dose-response relationship for human cancer.
      Furthermore, these results suggest that linear dose-response modeling from
      populations experiencing high arsenic exposures is likely to overpredict cancer
      risks at relatively low arsenic levels.

PMID- 8661329
TI  - Chemistry, toxicology, and human health risk of cyanide compounds in soils at
      former manufactured gas plant sites.
AB  - Cyanide-containing wastes are commonly found in soils at former manufactured gas
      plant (MGP) sites, also known as town gas sites. The complex forms of cyanide are
      responsible for the blue-stained soils and rocks found at these sites. Most
      concentrations of cyanide at MGP sites are below 2000 ppm, although
      concentrations greater than 20,000 ppm have been observed. An understanding of
      the chemistry of the MGP cyanide-containing compounds, their fate, and transport
      as well as their toxicology is critical to accurately assessing potential human
      health risks from these compounds. In this paper, the authors demonstrate that
      the most prevalent types of cyanide compounds found at former MGP sites are the
      relatively nontoxic iron-complexed forms, such as ferric ferrocyanide, rather
      than the highly toxic free cyanide forms. Moreover, the chemical conditions at
      most former MGP sites limit the extent to which free cyanide may be released into
      air and water from complex cyanides. Using a screening analysis, the authors
      estimate potential risks from a multiroute exposure to complex and free cyanides
      in soil, air, and groundwater at former MGP sites and demonstrate that such risks
      are likely to be insignificant. Unfortunately, the lack of readily available
      measurement techniques to characterize cyanides in soil can result in erroneous
      conclusions about potential risks from cyanide compounds in soils at former MGP
      sites, particularly if health-based soil criteria for free cyanide (e.g., the
      Massachusetts Department of Environmental Protection criterion for free cyanide
      is 100 ppm (MA. DEP, 1995)) are applied. The authors recommend development of
      routine methods for field sampling and laboratory testing techniques to
      demonstrate that cyanides in soil at former MGP sites are predominated by iron
      complexed species and that free cyanide is less than levels of concern.

PMID- 8661330
TI  - Measures of cell replication in risk/safety assessment of xenobiotic-induced,
      nongenotoxic carcinogenesis.
AB  - The phenomena associated with nongenotoxic carcinogenesis are multifaceted and
      complex. Nongenotoxic carcinogens stimulate cell replication in the presence or
      the absence of cytotoxicity. Cell proliferation is pivotal in the neoplastic
      process, but the extent of its contribution to the development of xenobiotic
      induced cancer remains an open question. The search for a better understanding of
      this process has generated considerable interest and effort, often with the
      objective of obtaining useful predictors of the tumourigenic potential of
      xenobiotics. Alterations in the natural balance of endogenous humoural agents
      that maintain replicative homeostasis results in proliferative stimulation (or
      inhibition) which may be transient or sustained. The bases for the molecular
      interaction of these mediators with cellular receptors, trans-cytoplasmic message
      conveyance, and subsequent nuclear responses leading to xenobiotic-induced
      mitosis are becoming better understood. Assessment of tissue replicative status
      has now become established and utilizes biochemical and histological methodology
      in a routine manner. The increasingly challenging international regulatory
      environment is demanding greater understanding of the mechanisms that underlie
      fundamental phenomena and the influences exerted by xenobiotics prior to their
      registration. While the precise mode of action of an individual xenobiotic may
      not be known, sound interpretation of toxicological data, including the
      contribution made by cell replication, creates greater confidence of its safety
      in the scientific, regulatory, and commercial communities. This article offers a
      view of cell proliferation from molecular interactions at the cellular level,
      through practical assessment of cell and tissue replicative status to its utility
      in contributing to the registration of new drugs and chemicals.

PMID- 8661331
TI  - Carcinogen classification systems: similarities and differences.
AB  - An overview of regulatory classification systems on carcinogens in the
      Organization for Economic Cooperation and Development (OECD) countries is
      presented based on a questionnaire study. Most OECD countries have implemented
      legislation including classification systems and lists of carcinogens. Basically,
      there are two types of classifications systems. The major difference between the
      two is that in one system carcinogens are classified according to the weight of
      evidence for carcinogenic effects in humans, whereas in the other carcinogens are
      allocated to various groups according to potency. Even if the classification
      systems may differ, the substances classified as carcinogens are to a large
      extent the same. Classification of carcinogens will in many countries require
      hazard labeling. This labeling, i.e., the limit for labeling of substances and
      preparations, and risk phrases show considerable similarities, but differ in
      certain aspects. Several countries have restrictions on sale and/or use of
      carcinogens. There is a trend toward introducing more mechanistic considerations
      in the classification of carcinogens.

PMID- 8661332
TI  - Estimating the probability of occurrence of tumor for a rare cancer with zero
      occurrence in a sample.
AB  - In many physical situations one needs to estimate the probability of occurrence
      of a rare event based on a random sample when the event has not occurred at all.
      For example, if the true lifetime incidence of a tumor at a particular tissue
      site is less than 1%, it is not uncommon to observe no tumors in a typical sample
      size of 50 animals. This paper explores the suitability of nonzero Bayesian
      estimation procedures to replace zero maximum likelihood estimates for tissue
      sites with nonzero background tumor incidences.

PMID- 8661333
TI  - The influence of petrochemicals and stress on the immune system of seabirds.
AB  - There is increasing attention directed to the role of environmental pollutants in
      altering immune function. Only with the identification of the responsible
      environmental toxicants, and an understanding of their mechanisms of action, can
      we hope to treat immunotoxic injuries. This situation is exemplified by the
      exposure of wild birds to oil spills, the subsequent potential for direct
      toxicity from the oil, and the secondary toxicity of stress-induced immune
      modulation. Immunosuppressive mechanisms related to oil ingestion and handling
      stress are implicated in the morbidity and mortality of seabirds during care and
      following reentry into the wild. This does suggest that improvements in the
      treatment of these affected animals will enhance their survival and well-being.
      However, a survey of the literature shows that the implementation of better
      techniques are hampered by inadequate information on the immunological
      consequences of oil contact with seabirds. Marine oil pollution is a constant
      occurrence and will continue as long as oil and oil products are important
      commodities transported by sea routes. Among the numerous negative consequences
      of oil pollution are its effects on marine wildlife. There is much evidence that
      oil spills are responsible for massive seabird deaths. However, the constant, low
      level releases of petrochemicals probably contribute to the harmful effects of
      oil pollution on seabird populations. In an attempt to rectify the damage
      inflicted on seabirds by accidental oil discharge, rehabilitation centers are
      established for the cleaning and care of affected wildlife. Unfortunately, there
      is evidence that the ingestion of oil by preening and the handling stress
      undergone by birds in these centers lowers their ability to survive and reproduce
      following release to their native habitats. Although the reasons for this are
      unclear, there is the suggestion that both oil and handling will induce
      immunosuppressive mechanisms that ultimately predispose birds to infections and
      immune-mediated diseases, as well as reproductive, behavioral, and other
      problems. Thus, there are questions concerning the effectiveness of intervention
      measures currently being used in the rehabilitation of seabirds.

PMID- 8661334
TI  - Determination of the intra- and interlaboratory reproducibility of the low volume
      eye test and its statistical relationship to the Draize eye test.
AB  - The reproducibility of toxicologic test methods, including alternative tests, is
      a key scientific and regulatory concern. In the present work, historic rabbit eye
      irritation data were used to determine the intra- and interlaboratory
      reproducibility of the low volume eye test (LVET). The standard Draize eye
      irritation test was used as the basis for comparison. The LVET and Draize tests
      had similar degrees of intra- and interlaboratory reproducibility as determined
      by examination of their coefficients of variation, although the variability in
      LVET results was directionally lower. Results from 70 parallel Draize and LVET
      tests indicated a strong positive association between results from the two tests,
      for corneal, iridial, conjunctival, and maximum average scores (MAS). Correlation
      coefficients were 0.60, 0.73, 0.69, and 0.73, respectively (P </= 0.0001). The
      linear relationship between LVET and Draize MAS values was examined by regression
      analysis and found to follow the relationship LVET MAS = 0.522 (Draize MAS).
      Thus, the LVET is at least as reproducible as the Draize test and gives responses
      that are (linearly) correlated to the Draize. The previous findings that the LVET
      is more predictive of human eye responses than the Draize test lends additional
      support for its use as a refined alternative to the Draize test.

PMID- 8661335
TI  - The timing of preclinical toxicological studies: pharmaceutical company
      approaches to toxicity testing in support of initial clinical investigations.
AB  - The completion of preclinical toxicity studies to support the first
      administration to humans is a time-critical step in the clinical development of
      medicines, and is complicated by differences in national regulatory requirements.
      A questionnaire-based study was carried out in 1994 to ascertain pharmaceutical
      companies' actual practices and views on an ideal approach to the timing of
      different types of nonclinical safety studies in relation to clinical
      investigation. Forty-one companies or their subsidiaries from Europe, Japan, and
      the United States responded by providing data. A range of preclinical packages
      were indicated as being used by companies prior to initiating Phase I clinical
      trials. The selection of studies tended to be based on the recommendations of the
      regulatory authority of the region in which the respondents were located.
      Differences were evident regarding the extent of genetic toxicity testing, the
      duration of repeat-dose toxicity studies, and the need for male fertility testing
      to support the first single administration of a compound to humans. In an ideal
      situation, the respondents would have preferred to conduct shorter duration
      repeat-dose toxicity studies prior to the first single administration to humans
      than was their actual practice in 1994. A harmonized guideline on the timing of
      toxicity studies in relation to clinical trials will allow better integration
      between clinical and nonclinical studies in an international development program.
      However, the diversity in the responses has demonstrated the need for flexibility
      in any future guideline.

PMID- 8661336
TI  - Copper regulatory level in drinking-water as proposed by Sidhu et al.

PMID- 8661337
TI  - Immunoquantitation and microsomal monooxygenase activities of hepatic cytochromes
      P4501A and P4502B and chlorinated hydrocarbon contaminant levels in polar bear
      (Ursus maritimus).
AB  - Contamination of the Arctic ecosystem by anthropogenic compounds has resulted in
      exposure of polar bear (Ursus maritimus) to lipophilic chlorinated hydrocarbon
      contaminants (CHCs) accumulated through the marine food web. Liver samples were
      collected from 16 adult male polar bears in the Canadian arctic and subjected to
      chemical analysis for CHCs and metabolites, determination of alkoxyresorufin O
      dealkylase activities, and immunoquantitation of cytochrome P450 (CYP) protein
      levels. We report on the relationships between the hepatic microsomal levels of
      immunoreactive CYP1A and CYP2B isozymes, catalytic activities, and hepatic CHC
      and metabolite concentrations in polar bear. We specifically explored the
      influence of several CHCs on the induction of hepatic CYP in polar bear and the
      potential use of immunoassay quantitation as a bioindicator of CHC exposure.
      Polychlorinated biphenyls (PCB) classed as CYP1A and mixed CYP1A/CYP2B inducers
      accounted for about 25% of the total PCB residues present (18,680 +/- 5053 ng/g
      lipid). CYP1A protein content correlated strongly with hepatic levels of PCBs,
      PCDDs (0.032 +/- 0.018 ng/g lipid, and PCDFs (0.011 +/- 0.007 ng/g lipid) and
      their corresponding toxic equivalents (TEQ, 0.377 +/- 0.182 ng/g lipid). Mono
      ortho-CB-156, CB-157, and CB-105 were the predominant TEQ contributors.
      Correlations between CYP2B protein content and CHC residue levels in polar bear
      liver suggested that ortho-chlorine-substituted PCBs and chlordanes were the
      major contributors to CYP2B induction. CYP1A and CYP2B contents were therefore
      good indicators of CHC exposure in polar bear liver. Ethoxyresorufin,
      pentoxyresorufin, and benzyloxyresorufin O-dealkylase activities increased with
      increasing CYP1A protein content up to protein levels of approximately 5 pmol/mg,
      suggesting that all three activities were primarily CYP1A-mediated. These results
      were substantiated by antibody inhibition experiments. In summary,
      immunoquantitated CYP1A and CYP2B isozymes are a more reliable measure of
      exposure to CHC inducers than alkoxyresorufin O-dealkylase activities in polar
      bear.

PMID- 8661338
TI  - Fate of germ cells in 2,5-hexanedione-induced testicular injury. I. Apoptosis is
      the mechanism of germ cell death.
AB  - 2,5-hexanedione (2,5-HD) is a Sertoli cell toxicant which causes germ cell loss
      and testicular atrophy in the rat. The mechanism of germ cell death over the
      course of 2,5-HD treatment is not known nor is the reason why residual germ cells
      do not repopulate the seminiferous epithelium following toxicant withdrawal. In
      the current study, the role of apoptosis in germ cell loss was studied. Male
      Fischer rats were treated for up to 5 weeks with 1% 2,5-HD in the drinking water
      and killed between 0 and 12 weeks after the start of toxicant exposure. Apoptosis
      was assessed in control and treated animals by (1) DNA fragmentation detected by
      gel electrophoresis, (2) cellular morphology on plastic sections, and (3) DNA
      fragmentation in situ by terminal deoxy-nucleotidyl transferase-mediated
      digoxigenin-UTP nick end label (TUNEL) staining of testis cross sections. All
      three indices demonstrated a substantial increase in apoptosis which peaked at 5
      weeks of 2,5-HD treatment. Morphological analysis determined that apoptosis
      occurred in germ cells of the seminiferous epithelium. DNA fragmentation
      determined by gel electrophoresis was barely detectable until 5-6 weeks of
      toxicant exposure. However, TUNEL staining of testis cross sections indicated
      that germ cell apoptosis increased after as early as 2 weeks of toxicant
      exposure, providing a highly sensitive biological marker of toxicant-induced
      testicular injury. These data also suggested a differential sensitivity of germ
      cells to toxicant exposure with spermatid apoptosis occurring first at 4-5 weeks
      of treatment followed by apoptosis of spermatocytes and spermatogonia between 6
      and 12 weeks. Together, these data demonstrate that apoptosis is the mechanism of
      germ cell loss in 2,5-HD-induced testicular injury.

PMID- 8661340
TI  - Tricyclic antidepressants inhibit human natural killer cells.
AB  - The commonly used antidepressants imipramine, amitriptyline, and nortriptyline
      were found to significantly inhibit human natural killer (NK) cell-mediated
      cytolysis in vitro and suppress the stimulation of NK cells by IFN-gamma. This is
      a previously unrecognized biologic property of these drugs with psychotropic
      activity. Tricyclic antidepressants did not decrease effector-target cell
      conjugation formation, nor did they induce target cell resistance to NK lysis,
      indicating that the drugs might interfere with the killing mechanism of the
      effector cells. Kinetic data reveal that the drug interference is related to an
      early postbinding event in the activation of NK cells. Results also showed that
      the inhibitory effect of tricyclic antidepressants on human NK cell activity
      occurred in parallel to an increase in intracellular cyclic GMP concentration.
      However, the attenuation in the cyclic GMP formation by methylene blue, a
      selective inhibitor of soluble guanylate cyclase, was not accompanied by a
      corresponding increase in NK cell cytolytic activity. It is suggested that the
      stimulation of cyclic GMP was not directly involved in the inhibitory effect of
      antidepressants on NK cells and perhaps was a secondary phenomenon. This immune
      cell modulatory property of tricyclic antidepressants seems to indirectly provide
      evidence for the concept that human brain neurons and NK cells might share
      regulatory system(s).

PMID- 8661341
TI  - Biotransformation of the MPTP analog trans-1-methyl-4-[4
      dimethylaminophenylethenyl]-1,2,3,6-tetra- hydropyridine to a fluorescent
      pyridinium metabolite by intact neuroblastoma cells.
AB  - The possibility of imaging monoamine oxidase (MAO) containing neurons through the
      MAO-mediated conversion of the nonfluorescent tetrahydropyridine compound trans-1
      methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydro pyridine (t-THP) to
      the corresponding fluorescent trans-1-methyl-4-[4
      dimethylaminophenylethenyl]pyridinium species (t-P+) was examined with the aid of
      human neuroblastoma cells (SH-SY5Y). Fluorescence microscopy and fluorescence
      measurements established the intracellular formation of a fluorescent species
      with maximal excitation/emission wavelengths of 485/620 and 530/620 nm
      corresponding to the fluorescence characteristics of synthetic t-P+. An
      independent assay confirmed the presence of both MAO-A and MAO-B in these cells.
      As expected, the development of the fluorescence was inhibited by both clorgyline
      (an MAO-A inhibitor) and deprenyl (an MAO-B inhibitor). Cytotoxic effects, as
      determined by trypan blue dye exclusion for viability and by the MTT [3-(4,5
      dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] assay for mitochondrial
      integrity, were not observed in cells incubated with concentrations of t-THP as
      high as 10(-3) M for 4 hr. The results from these studies with a neuronal cell
      line of human origin suggest: (1) that SH-SY5Y cells metabolize and, therefore,
      can be used for study of tetrahydropyridine compounds in vitro, and (2) that t
      THP may be a useful agent to monitor neurodegenerative processes in MAO-rich
      neurons, including the dopaminergic nigrostriatal neurons that are damaged by the
      parkinsonian-inducing tetrahydropyrridine MPTP. The potential advantage of using
      t-THP over related imaging techniques is the possibility of assessing neuronal
      function by an in vivo processing of the reporter molecule rather than by
      postmortem immunofluorescent or formaldehyde-based procedures.

PMID- 8661342
TI  - Sex differences in rat hepatic cytolethality of the protein kinase C inhibitor
      safingol: role of biotransformation.
AB  - Safingol [(2S,3S)-2-amino-1,3-octadecanediol], a sphingosine analog that inhibits
      protein kinase C, was developed to treat dermatoses and cancer. Preclinical
      toxicology studies performed to assess the effects of safingol showed that 6
      weeks of dermal application over 10% of body surface area caused dose-dependent
      increases in serum enzymes and hepatic histopathological changes associated with
      liver damage in female rats. Liver toxicity was not seen in male rats at the same
      doses. Plasma safingol concentrations were similar in male and female rats
      following topical exposure. The underlying mechanism(s) for the sex differences
      in toxicity in rats were examined using isolated hepatocytes. An in vitro model
      of male versus female differences in safingol.HCl-induced hepatotoxicity was
      established using a suspension/culture technique. Concentrations of safingol.HCl
      which produced cytolethality in 50% of the hepatocytes were 125 and 48 microM for
      male and female rat hepatocytes, respectively. Cytolethality was time-,
      concentration-, and cell number-dependent. Inhibition of cytochrome P450 in vitro
      with 1-phenylimidazole increased safingol.HCl-induced cytolethality in male but
      not female hepatocytes, suggesting that male rat hepatocytes have a cytochrome
      p450 isoenzyme which metabolizes safingol.HCl to an inactive metabolite thus
      reducing hepatotoxicity. Furthermore, in vivo pretreatment with the CYP4A
      inducing agent, clofibrate, protected both male and female hepatocytes from
      cytolethality. The results of this study indicate that the sex differences seen
      in hepatotoxicity could be due to differences in biotransformation such that
      female rat hepatocytes either lack or have a reduced constitutive level of a
      cytochrome P450 isoenzyme that metabolizes safingol to a nontoxic metabolite. In
      addition, safingol produced hepatocyte cell death without inflammation in vivo,
      and a "ladder-like" DNA fragmentation pattern in vitro, consistent with an
      apoptotic mechanism of cell death.

PMID- 8661343
TI  - Toxicity of ochratoxin A, its opened lactone form and several of its analogs:
      structure-activity relationships.
AB  - Ochratoxin A (OA); its three natural analogs, ochratoxin C (OC), B (OB), and
      alpha (Oalpha); and its six synthetic analogs, the epimere of OA (d-OA), the
      ethylamide of OA (OE-OA), decarboxylated OA (DC-OA), O-methylated OA (OM-OA),
      lactone-opened OA (OP-OA), and the methyl ester of Oalpha (M-Oalpha) were assayed
      for their toxicities in prokaryotic (Bacillus brevis) and eukaryotic (HeLa cell)
      systems and in animals (mouse and rat). The LC50S (mM) for HeLa cells, were 0.005
      (OA), 0.009 (OC), 0.163 (d-OA), 10.1 (OE-OA), 7.6 (DC-OA), 0.83 (OM-OA), 0.054
      (OB), and 0.56 Oalpha). The minimum inhibitory doses (nmol/disc) for the growth
      of B. brevis (pH 6.5) were 8.7 (OA), 2.0 (OC), 5.5 (d-OA), 1.1 (OE-OA), 54 (OB),
      390 (Oalpha), and 90 (M-Oalpha) while no inhibition of the bacterial growth was
      observed for OM-OA, DC-OA, and OP-OA at doses as high as 350 nmol/disc. The
      results indicate that the toxicities of OA were associated with its isocoumarin
      moiety but that neither the dissociation of the phenolic hydroxyl group nor the
      iron-chelating properties of OA were directly related to its toxicities. The
      lactone carbonyl group of OA, however, appears to be involved in OA toxicity as
      OP-OA is found in the bile of rats injected with OA and has similar toxicity to
      that of OA when administered intravenously to the rat. Overall, the structure
      activity studies suggest that the toxicity of OA is attributable to its
      isocoumarin moiety and that the lactone carbonyl group may be involved in its
      toxicity.

PMID- 8661344
TI  - Hepatic peroxisomal and drug metabolizing activity in CD-1 mice after oral
      treatment with a novel 5-lipoxygenase inhibitor.
AB  - The effects of zileuton, a 5-lipoxygenase inhibitor, on hepatic peroxisomal
      enzyme activity as well as hepatic drug metabolizing activity in male and female
      CD-1 mice were assessed after oral administration of the drug (50, 150, or 450
      mg/kg/day) for 14 days. The effects were compared to those in mice receiving
      clofibrate (CLOF;462 mg/kg/day, po) or sodium phenobarbital (PB; 50 mg/kg/day,
      po). Zileuton pretreatment caused hepatomegaly and elevated liver peroxisomal KCN
      insensitive palmitoyl CoA oxidase activity in a dose-dependent manner. However,
      these changes were marginal (< or = 121% increase), when compared to those
      elicited by CLOF (approximately 370% increase). In both sexes, zileuton
      pretreatment also caused a dose-dependent increase in the levels of liver
      microsomal cytochrome P450 2B and cytochrome P450 4A (CYP4A) proteins, and their
      associated monoxygenase activity. In the case of CYP4A, the induction of lauric
      acid 12-hydroxylase activity by zileuton was more pronounced in female (maximal
      851% increase) than in male mice (maximal 111% increase). Based on the dose
      normalized response observed in CD-1 mice, zileuton can be considered a
      relatively weak inducer of peroxisome enzyme activities (cf.CLOF) and a moderate
      inducer of cytochromes P450. Moreover, zileuton exhibits characteristics of both
      a PB- and a CLOF-type hepatic enzyme inducer, especially in the female mice.

PMID- 8661345
TI  - Paradoxical increase in peroxisomal cyanide-insensitive respiration following
      dietary exposure to WY-14,643 in the perfused liver.
AB  - WY-14,643, a lipid-lowering drug, increases basal rates of oxygen uptake in
      perfused livers. Because peroxisomes consume oxygen for H2O2 production and are
      induced by WY-14,643 treatment, it is possible that peroxisomal beta-oxidation
      can account for some of this increase in cellular respiration. Therefore,
      cyanide, an inhibitor of mitochondrial cytochrome oxidase, was infused into
      livers of WY-14,643-fed rats (0.1% WY-14,643 in laboratory rat chow for 1, 21,
      and 105 days) to assess peroxisomal cyanide-insensitive respiration. As expected,
      the addition of cyanide abolished oxygen uptake nearly completely; however, after
      approximately 20 min oxygen consumption unexpectedly returned to basal levels in
      105-day WY-14,643-treated animals but not in untreated controls. Urea synthesis,
      a process dependent upon ATP, was decreased and remained low during cyanide
      infusion in livers from both groups, indicating that mitochondria were not
      responsible for this unusual increase in oxygen uptake in the presence of
      cyanide. Methanol metabolism, which requires oxygen to form H2O2, was decreased
      from 37 +/- 5 to 6 +/- 1 micromol/g/hr in all groups treated with cyanide;
      however, it was increased significantly about 20 min later to 25 micromol/g/hr in
      livers from WY-14,643-treated rats, indicating that oxygen for peroxisomal H2O2
      production is involved in cellular respiration in the presence of cyanide.
      Fasting abolished the recovery of both oxygen uptake and methanol metabolism in
      WY-14,643-fed rats, suggesting that ATP for acyl CoA synthetase, an enzyme which
      metabolizes fatty acids to acyl CoA compounds, is provided by glycolysis. Indeed,
      oleate significantly increased methanol metabolism in fed control rats from 8 +/-
      4 to 26 +/- 3 micromol/g/hr in the presence of cyanide, indicating that fatty
      acid supply is necessary for peroxisomal respiration. Taken together, these
      experiments demonstrate that when mitochondrial respiration is inhibited, livers
      from rats fed WY-14,643 chronically have the unique ability of metabolizing fatty
      acids through the peroxisome using glycolytic ATP.

PMID- 8661347
TI  - Three-dimensional quantitative structure--activity relationships for androgen
      receptor ligands.
AB  - Comparative molecular field analysis (CoMFA), a three-dimensional quantitative
      structure-activity relationship (3D-QSAR) paradigm, was used to examine androgen
      receptor-binding affinities of a series of structurally diverse natural,
      synthetic, and environmental chemicals of interest. The CoMFA/3D-QSAR model
      successfully illustrates that the overall steric and electrostatic properties of
      structurally diverse ligands for the androgen receptor are necessary and
      sufficient to describe the binding affinity. The practical utility of models of
      this type is demonstrated using parent compounds in the training set and known as
      well as putative biological metabolites as test set molecules. The ability of the
      model to accurately predict binding affinity of test set molecules suggests that
      structure-based 3D-QSAR models may be used to supplement the process of hazard
      identification. The application of 3D-QSAR models within a toxicological
      framework is, at present, limited by the quantity and quality of biological data
      for relevant biomarkers of toxicity.

PMID- 8661346
TI  - In vivo modulation of 17 beta-estradiol-induced vitellogenin synthesis and
      estrogen receptor in rainbow trout (Oncorhynchus mykiss) liver cells by beta
      naphthoflavone.
AB  - Vitellogenesis or egg yolk production represents a key estrogen initiated process
      in oviparous vertebrates which is crucial for oocyte maturation. Previous in
      vitro studies have shown that cytochrome P4501A1 (CYP1A1)-inducing compounds such
      as beta-naphthoflavone (betaNF) modulate 17 beta-estradiol-induced vitellogenin
      (Vg) synthesis in primary cultures of juvenile rainbow trout liver cells. In this
      study, treatment of juvenile trout with 0.5 mg/kg 17 beta-estradiol plus either
      25 or 50 mg/kg betaNF confirmed in vivo that betaNF may depress Vg synthesis by
      the liver. Alternatively, trout treated with 0.5 mg/kg 17 beta-estradiol plus
      12.5 mg/kg betaNF or 5 mg/kg 17 beta-estradiol plus 12.5, 25, or 50 mg/kg betaNF
      showed a potentiation of Vg synthesis relative to estradiol-only injected fish.
      These results are significant as they suggest that changing plasma estrogen
      levels in sexually maturing trout will determine whether or not CYP1A1-inducing
      compounds may suppress, have no effect, or potentiate estrogen-induced liver Vg
      synthesis. Depressed Vg synthesis by trout injected with 0.5 mg/kg 17 beta
      estradiol plus 50 mg/kg of betaNF correlated with depressed estrogen-binding
      capacity of liver, as assessed by [3H]17 beta-estradiol binding to liver nuclear
      protein extracts. Using gel mobility shift assay, the decrease in estrogen
      responsiveness of liver was not attributed to depressed estrogen response element
      estrogen receptor binding. The fish liver vitellogenesis process offers a
      comparative model with which to further study the mechanism(s) of aryl
      hydrocarbon receptor-mediated antiestrogenicity and endocrine disruption.

PMID- 8661348
TI  - Chronic cadmium exposure-induced renal anemia in ovariectomized rats.
AB  - Cadmium (Cd) chloride was intravenously injected at doses of 0.05 and 0.5
      mg/kg/day in ovariectomized rats for 50 weeks, and the chronic Cd exposure
      induced nephrotoxicity and anemia were investigated. The rats treated with 0.05
      mg/kg Cd showed no apparent hematological, urinary, and histopathological
      abnormalities. In the 0.5-mg/kg group, renal tubular disorders became marked at
      16 weeks, and cortical fibrosis with glomerular dysfunction appeared at 50 weeks.
      Anemia occurred at 12 weeks in the 0.5-mg/kg group and became increasingly marked
      with time. The mean corpuscular volume (MCV) and mean corpuscular hemoglobin
      (MCH) were decreased at 12 and 25 weeks; however, the decreases of MCV and MCH
      disappeared at 50 weeks. A slight decrease in mean corpuscular hemoglobin
      concentration was noted at 50 weeks. The blood chemistry from the same group
      revealed a decrease in plasma iron levels and an increase in total iron binding
      capacity throughout the administration period. The erythropoietin (EPO) level was
      increased as the hemoglobin level decreased at 12 weeks, whereas the EPO level
      was not elevated even when the hemoglobin level was decreased at 50 weeks. These
      findings showed that renal anemia also occurred in addition to the iron
      deficiency anemia at 50 weeks.

PMID- 8661350
TI  - Methyl mercury pharmacokinetics in man: a reevaluation.
AB  - Data taken from Aberg et al. ((1969) Arch. Environ. Health 19, 478-484) and
      Miettinen et al. ((1971) Ann. Clin. Res. 3, 116-122) were analyzed by means of
      models that describe methyl mercury pharmacokinetics in man in terms of parent
      compound only (Model I) or in terms of parent compound plus metabolite, inorganic
      mercury (Model II). Fecal and urinary excretion of mercury are linear for both
      models. In Model I all excreted mercury arises from a common pool. This model
      successfully simulates the time profiles for body total mercury and fecal
      excretion but fails to explain the continuous increase in daily urinary mercury
      that occurs for several weeks following methyl mercury administration. In Model
      II fecal mercury arises from the methyl mercury compartment and urinary mercury
      from the inorganic mercury compartment. Simulations from this model are
      comparable to those from Model I for body total mercury and fecal excretion but
      are significantly more precise for urinary excretion. Model II also accounts for
      the observation (Miettinen et al., 1971) that blood mercury comprises a steadily
      declining proportion of body mercury burden for at least 91 days after methyl
      mercury dosing. Data simulated by means of Model II, using parameters estimated
      from Aberg's and Miettinen's data sets, predict methyl mercury half-lives of 51
      and 56 days, respectively. These values are comparable to the methyl mercury half
      life of 44 days reported by Smith et al. ((1994) Toxicol. Appl. Pharmacol. 128,
      251-256) and are approximately 70% of half-lives reported by Aberg and Miettinen.

PMID- 8661349
TI  - Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent enzyme
      activities by proinflammatory cytokines and possible role of nitric oxide in
      primary cultures of pig hepatocytes.
AB  - Proinflammatory cytokines play an important role in the depression of cytochrome
      P450 (CYP450)-dependent drug metabolism in mammals during inflammation and
      infection. Although much has been learned concerning the effects and mechanisms
      of cytokine-mediated suppression of CYP450, there is limited knowledge about how
      cytokines affect UDP glucuronosyl transferases (UDPGT). The aim of the present
      study was to investigate the effects and dose dependency of recombinant human
      proinflammatory cytokines on both CYP450- and UDPGT-dependent enzyme activities
      in primary cultures of pig hepatocytes. A possible role of nitric oxide in
      cytokine-induced suppression of enzyme activities was studied by incubating
      hepatocytes in the presence of N G-nitro-L-arginine (L-NAME), a competitive
      inhibitor of nitric oxide (NO) biosynthesis. Incubation of hepatocytes with
      interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), and tumor necrosis factor
      alpha (TNF-alpha) decreased both oxidation and glucuronidation activities dose
      dependently, in which the effects on glucuronidation activities were even more
      pronounced. IL-6 differed from IL-1alpha and TNF-alpha by inhibiting CYP450 and
      UDPFT more effectively after 24 hr of incubation, whereas the inhibition by IL
      1alpha and TNF-alpha was more pronounced after 12 hr. Only at a concentration of
      500 U/ml did interferon-gamma (IFN-ganna) inhibit CYP450 and UDPGT. The
      inhibition of CYP450 enzyme activities by cytokines was probably not due to the
      production of NO, because L-NAME totally blocked NO production but had no effect
      on the cytokine-induced suppression of CYP450 enzyme activities. However, there
      might be a role for NO in the decrease of glucuronidation by cytokines, as L-NAME
      slightly though significantly prevented the inhibition of glucuronidation.

PMID- 8661351
TI  - Predicting cancer risk from vinyl chloride exposure with a physiologically based
      pharmacokinetic model.
AB  - A physiologically based pharmacokinetic (PBPK) model capable of describing the
      metabolism of vinyl chloride (VC) in rats, mice, and humans has been developed
      and validated by comparison with experimental data from experiments not used in
      model development. This PBPK model has been used to predict measures of delivered
      dose (reactive VC metabolites produced in the livers of the affected species)
      hypothesized to be involved in the induction of liver angiosarcoma in rats, mice,
      and human populations exposed to VC. Measures of delivered dose in rats were fit
      to an empirical dose-response model (the linearized multistage model of Crump et
      al.) and used to make predictions of liver angiosarcoma incidence in mice and
      human populations exposed to VC. This procedure gave a good prediction of
      angiosarcoma incidence in mice. Predictions of angiosarcoma incidence in humans
      were more than two orders of magnitude lower than risk estimations which did not
      utilize pharmacokinetic data, but were still almost an order of magnitude higher
      than actually observed in exposed human populations.

PMID- 8661352
TI  - Isomer-specific acute toxicity and cell proliferation in livers of B6C3F1 mice
      exposed to dichlorobenzene.
AB  - The acute hepatotoxicity of isomers of dichlorobenzene (o-, m-, and p-DCB) was
      compared in livers of male B6C3F1 mice at different time points after a single
      intragastric administration. The highest doses of o-, m-, and p-DCB administered,
      300, 300, and 1800 mg/kg, respectively, are below the lethal range. Acute hepatic
      injury was assessed by serum alanine aminotransferase (ALT) activity and hepatic
      histology. Hepatocyte replication was estimated by means of immunohistochemical
      demonstration of BrdU-labeled cells. Both o-DCB and m-DCB at a dose of 300 mg/kg
      produced significant elevations of liver weight and ALT activity as well as
      extensive liver cell necrosis. In contrast, p-DCB at a highest dose of 1800 mg/kg
      induced slight hepatocyte injury. Dose-response studies indicated that the rank
      order for acute hepatotoxicity of the isomers was m-DCB > o-DCB > or = p-DCB.
      However, p-DCB induced hepatocyte cell proliferation in spite of the lack of
      manifest hepatotoxicity. In contrast, increases of cell proliferation due to o-
      or m-DCB exposure occurred only after dosages that caused hepatic injury. These
      data suggest the hepatocyte proliferation induced by o- or m-DCB is compensatory
      regeneration while that induced by p-DCB is a response to mitogenic stimulation.

PMID- 8661354
TI  - S-[(1 and 2)-phenyl-2-hydroxyethyl]-cysteine-induced cytotoxicity to rat renal
      proximal tubules.
AB  - S-[(1 and 2)-phenyl-2-hydroxyethyl]-glutathione is nephrotoxic in rats through
      its metabolic conversion to corresponding cysteine-S-conjugate, e.g., S-[(1 and
      2)-phenyl-2-hydroxyethyl]-cysteine (PHEC). The present study was carried out to
      determine the mechanism of PHEC-induced toxicity in isolated rat renal proximal
      tubules. PHEC decreased tubule viability in concentration (0-2 mM)- and time (0-3
      hr)-dependent manner, with initial decreases occurring 2 hr after exposure.
      Tubule basal and nystatin-stimulated oxygen consumption decreased before cell
      death following exposure to 0.5 and 1 mM PHEC. Assessment of direct mitochondrial
      function within the proximal tubules showed that respiration was reduced in the
      absence and presence of a phosphate acceptor using site II (succinate) and site I
      (malate/glutamate) respiratory substrates 30 and 45 min after exposure to 0.5 and
      1 mM PHEC. Exposure of proximal tubules to 1 mM PHEC caused a time-dependent
      decline of mitochondrial membrane potential (as measured by the uptake of the
      cationic fluorescent dye, rhodamine 123 by the proximal tubules) and depletion of
      ATP content with initial decrease occurring as early as 30 min after the
      exposure. Glutathione depletion and lipid peroxidation occurred within 90 min
      clearly preceding cell death after exposure to 0.5 and 1 mM PHEC. Pretreatment
      with 1 mM deferoxamine prevented PHEC-induced lipid peroxidation but did not
      prevent PHEC-induced cytotoxicity, whereas deferoxamine pretreatment prevented
      lipid peroxidation, mitochondrial dysfunction, and cytotoxicity after exposure to
      0.5 mM tertiary-butyl hydroperoxide, suggesting that iron-mediated lipid
      peroxidation does not contribute to PHEC-induced proximal tubule cell death.
      Pretreatment of renal proximal tubules with 10 mM fructose failed to prevent the
      change in mitochondrial membrane potential, the ATP depletion and cytotoxicity
      caused by 1 mM PHEC, indicating that the glycolytic pathway is not important in
      renal proximal tubule respiration and cell injury. Pretreatment of renal tubules
      with aminooxyacetic acid failed to prevent the mitochondrial dysfunction induced
      by 1 mM PHEC, indicating an absence of further metabolism of PHEC by a beta-lyase
      dependent pathway. It is therefore proposed that the alteration of mitochondrial
      functions and the consequent loss of cellular energy supplies can represent the
      mechanisms by which PHEC expressed its acute cytotoxicity.

PMID- 8661353
TI  - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elevates basal B-cell intracellular
      calcium concentration and suppresses surface Ig- but not CD40-induced antibody
      secretion.
AB  - Humoral immune responses to either T-independent or T-dependent antigens have
      previously been shown to be suppressed by the halogenated aromatic hydrocarbon
      environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through
      direct action on B-lymphocytes. To better understand the molecular nature of the
      TCDD-induced suppression of B-cell differentiation, we studied the effects of
      TCDD using in vitro models of T-independent (antibody directed against surface
      IgM) and T-dependent [activated T-helper (TH) cells bearing CD40 ligand] B-cell
      maturation. We report here that TCDD suppresses murine B-cell IgM secretion
      induced by either soluble or insolubilized anti-IgM plus lymphokines but does not
      affect IgM secretion stimulated by activated T(H)-cells and lymphokines. Because
      soluble or insolubilized anti-IgM but not fixed, activated TH-cells was found to
      trigger increases in intracellular ionized calcium in isolated B-cells, the
      effect of TCDD exposure on B-cell intracellular calcium concentration and
      mobilization was examined. In comparison to the endoplasmic reticulum calcium
      ATPase inhibitor thapsigargin, which induces an immediate rise in resting [Ca2+]i
      of up to four- to fivefold, TCDD treatment did not produce a rapid increase in
      [Ca2+]i but did result in an elevation of basal levels of nearly the same
      magnitude 18 hr postexposure. However, anti-IgM-induced calcium transients were
      similar in the presence or absence of TCDD. TCDD exposure also produced
      instability of the calcium concentration curve, with the observed elevation of
      basal intracellular calcium occurring after both in vitro and in vivo treatment
      paradigms. The immunomodulatory profiles of activity of TCDD and thapsigargin on
      the B-cell proliferative response to PMA plus ionomycin differ, suggesting that
      the kinetics of calcium release by these compounds dictates the overall effect on
      the responding B-cell. Taken together, the data indicate that TCDD elevates
      resting intracellular calcium levels in murine B-cells and may selectively
      inhibit calcium-dependent signaling pathways linked to surface Ig.

PMID- 8661355
TI  - Neonatal phenobarbital-induced persistent alterations in plasma testosterone
      profiles and testicular function.
AB  - Daily sc injections of phenobarbital at anticonvulsant therapeutic doses for the
      rat (40 mg/kg) for the first 7 days of life resulted in below normal levels of
      serum testosterone from around birth to before puberty, normal levels during
      puberty and above normal levels of the androgen after puberty and in adulthood.
      Cluster analysis of the plasma testosterone secretory profiles obtained at 15-min
      intervals from phenobarbital-treated rats at 65 and 165 days of age revealed a
      significant increase in both the peak amplitudes and their durations resulting in
      a 100% increase in the amount of hormone secreted during the peak periods. In
      general, most of the rats (control and experimental) secreted testosterone as two
      large peaks, each 3 to 4 hr in duration, during the 10-hr lights-on collection
      period. In addition to permanently disrupting the ultradian profiles of plasma
      testosterone, neonatal exposure to the barbiturate altered testicular
      responsiveness to steroidogenic regulatory agents. That is, neonatal exposure to
      phenobarbital enhanced the responsiveness to exogenous hCG as measured by an
      above-normal increase in testosterone concentration. Moreover, phenobarbital
      induced reductions in serum testosterone levels were delayed in adult rats
      neonatally exposed to the barbiturate. Whereas a single challenge dose of
      phenobarbital (1 or 10 mg/kg) reduced serum testosterone concentrations in
      control animals by almost 80% within 3 hr, a decline in serum androgen levels in
      the neonatally phenobarbital exposed males was not observed until 12 hr after the
      challenge dose. These results indicate that postpartum exposure to therapeutic
      levels of phenobarbital can permanently disrupt testosterone secretory profiles
      and alter pathways regulating testicular steroidogenesis.

PMID- 8661356
TI  - Comparison of cadmium uptakes from apical and basolateral membranes of LLC-PK1
      cells.
AB  - Cadmium (Cd) uptake from the apical and basolateral membranes was investigated in
      LLC-PK1 cells grown as a monolayer on a permeable membrane. The cells were
      incubated at 37 degrees C for 1 hr with 1 microM CdCl2 from either the apical or
      the basolateral side. The accumulation of Cd from the apical side was 23% higher
      than that from the basolateral side. However, the translocation of Cd from the
      apical to the basolateral side and vice versa were similar. Cytotoxicity, as
      evaluated by transepithelial electrical resistance (TER), was undetectable at 1
      microM Cd concentration. The preincubation of cells with carbonylcyanide p
      (trifluoromethoxy)-phenylhydrazone (a metabolic inhibitor) and ouabain (a Na+/K+ 
      ATPase inhibitor) or coincubation with Cd and 2,4-dinitrophenol (a metabolic
      inhibitor) decreased both the accumulation (16-24%) and the translocation of Cd
      (22-25%) from the apical side, but not from the basolateral side. Incubation of
      cells with 50 and 75 microM CdCl2 for 1 hr resulted in 52-112% higher
      accumulation and translocation of Cd from the basolateral than from the apical
      side. The TER decreased at high Cd concentrations, suggesting that Cd
      concentrations of 10 microM and higher were cytotoxic. It is concluded that
      uptake of Cd from both the apical and the basolateral membranes represents
      passive diffusion. Additionally, under nontoxic conditions, about 20% of the Cd
      taken up at the apical membrane reflects carrier-mediated transport involving
      sodium ion- and energy-dependent processes; this accounts for higher accumulation
      through the apical membrane.

PMID- 8661357
TI  - Metallothionein-I-transgenic mice are not protected from acute cadmium
      metallothionein-induced nephrotoxicity.
AB  - Mice pretreated with Zn have increased renal metallothionein (MT) levels and are
      protected from CdMT nephrotoxicity. To determine whether MT is important in this
      Zn-induced protection against CdMT-induced nephrotoxicity, MT-transgenic mice
      that have high levels of MT in their kidneys (10-fold over control mice) have
      been studied to determine whether they are resistant to CdMT-induced
      nephrotoxicity. Mice were injected with CdMT (0.1-0.6 mg Cd/kg, iv) and kidney
      injury was evaluated 24 hr later. CdMT produced renal toxicity in a dose
      dependent manner. At a nephrotoxic dose of CdMT (0.4 mg Cd/kg), urinary protein
      and glucose excretion were increased 30- and 60-fold, respectively, in control
      mice. However, similar increases in protein and glucose excretion were also
      observed in MT-transgenic mice. CdMT also induced a similar dose-dependent
      proximal tubular cell necrosis in both control and MT-transgenic mice in a dose
      dependent manner. Treatment of control mice with Zn (100 micromol/kg, sc x 2
      days) increased renal MT to levels similar to those of untreated MT-transgenic
      mice and protected against CdMT-induced renal injury. Furthermore, when Zn (25
      100 micromol/kg, sc) was given immediately before CdMT injection (i.e., without
      preinduction of MT), it was still effective in preventing CdMT nephrotoxicity. We
      conclude that Zn-induced protection against CdMT nephrotoxicity does not appear
      to be due to induction of renal MT.

PMID- 8661359
TI  - Announcements

PMID- 8661360
TI  - ACKNOWLEDGMENT

PMID- 8661358
TI  - Comparison of Ah receptor-mediated luciferase and ethoxyresorufin-O-deethylase
      induction in H4IIE cells: implications for their use as bioanalytical tools for
      the detection of polyhalogenated aromatic hydrocarbons.
AB  - A recombinant H4IIE rat hepatoma cell line (H4L1.1c4, H4IIE-luc), containing a
      luciferase reporter gene under control of dioxin-responsive enhancers, was
      examined for responsiveness to several polyhalogenated aromatic hydrocarbons
      (PHAHs). The recombinant cell system was compared with the widely used wild-type
      cell line (H4IIE-wt), which expresses Ah receptor-mediated cytochrome P450 1A
      induction. We also report an improved and down-scaled method for the H4IIE-wt
      bioassay which allows for the rapid screening of environmental samples for Ah
      active PhAHs. This method employs 96-well plates, a plate-reading
      spectrofluorometer, and a fluorescence-based protein assay that enables the
      simultaneous measurement of resorufin and protein. Both cell lines demonstrated a
      dose-dependent increase in Ah receptor-mediated response upon exposure to a
      number of known Ah receptor agonists, including Halowax 1014. H4IIE-luc cells
      were 3-fold more sensitive than H4IIE-wt cells to 2,3,7,8-tetrachlorodibenzo-p
      dioxin (TCDD). The detection limit and ED50 for EROD induction by TCDD were 0.6
      and 4.9 fmol/well (2,4 and 20 pM), respectively; for luciferase induction they
      were 0.2 and 1.4 fmol/well (0.8 and 5.6 pM). The detection limit for EROD
      induction in H4IIE-wt cells was a 50-fold improvement over that reported
      previously (Tillitt et al., Environ. Sci. Technol. 25, 87-92, 1991) and
      comparable to that of a chicken embryo primary hepatocyte bioassay (Kennedy et
      al., Anal. Biochem. 211, 102-112, 1993). The tested PHAHs exhibited a similar
      structure-activity relationship in H4IIE-luc as in H4IIE-wt cells. Binary
      mixtures of TCDD, PCB-126, and PCB-77 showed no departure from additivity in
      their combined responses when tested in H4IIE-wt cells. PCB-153 at the highest
      tested dose of 14 nmol/well (56 microM) significantly reduced the potency of TCDD
      and PCB-126 without affecting their efficacy in both H4IIE-wt and H4IIE-luc
      cells. These findings support the use of H4IIE-luc cells as an alternative
      bioanalytical tool to the wild-type cells for the detection of Ah agonists in
      environmental samples.

PMID- 8661362
TI  - Chemical Index for Volume 137

PMID- 8661364
TI  - Ninth Summer Institute in Environmental Health Sciences

PMID- 8661366
TI  - Third European Congress of Pharmaceutical Sciences

PMID- 8661365
TI  - IV International Dermatology Symposium Berlin: Sebaceous Gland and Its Disorders

PMID- 8661371
TI  - Chemical Index for Volume 138

PMID- 8661369
TI  - XIV International Symposium on Medicinal Chemistry

PMID- 8661368
TI  - Vomitoxin-Mediated IL-2, IL-4, and IL-5 Superinduction in Murine CD4+ T Cells
      Stimulated with Phorbol Ester and Calcium Ionophore: Relation to Kinetics of
      Proliferation
AB  - The effects of the trichothecene vomitoxin (VT) on the kinetics of cell
      proliferation and cytokine production were evaluated in murine CD4(+) T cells.
      The CD4(+) cultures were stimulated with phorbol 12-myristate 13-acetate (PMA)
      and ionomycin to activate protein kinase C and increase cytoplasmic free calcium,
      respectively, in a range of VT concentrations. Total and viable cell counts at 3,
      5, 7, 9, and 11 days revealed delayed or impaired cell proliferation in cultures
      containing between 50 and 100 ngsolidusml VT, with complete inhibition being
      observed at 250 and 500 ngsolidusml of VT. The VT concentration required to
      inhibit protein synthesis in a 3-day culture by 50% in this model was 40
      ngsolidusml. When enzyme-linked immunosorbent assay (ELISA) was used to
      quantitate cytokines, IL-2 levels in control cultures were highest at Day 1 and
      declined rapidly thereafter, whereas, in VT groups, IL-2 levels were highest at
      Day 3 and remained elevated up to 11 days. IL-2 levels were elevated by
      continuous exposure to 100-500 ngsolidusml of VT with more than 100-fold
      differences being observed between control and 250 ngsolidusml VT from Days 5 to
      11. When IL-2 levels were expressed on a per viable cell basis, increases were
      even more marked with as much as 6 log differences being observed between the
      treatments at 250-500 ngsolidusml VT and control cultures at Day 7. Supernatant
      IL-4 and IL-5 levels were also elevated by 100 and 250 ngsolidusml VT in a dose-
      and time-dependent fashion compared to control cultures, whereas 500 ngsolidusml
      VT was inhibitory. When relative IL mRNA abundance was analyzed during the first
      3 days of culture by reverse transcriptase-polymerase chain reaction (RT-PCR) in
      conjunction with Southern hybridization analysis, IL-2 mRNA levels in Days 1, 2
      and 3 in cultures containing 100 and 250 ngsolidusml VT were greater than
      corresponding controls. IL-2 mRNA abundance in both control and VT-treated
      cultures was maximal at Day 1 and decreased rapidly thereafter in controls,
      whereas much slower rates of IL-2 disappearance were noted in 100 and 250
      ngsolidusml of VT. IL-4 and IL-5 mRNA levels at VT doses of 50 and 100
      ngsolidusml were also elevated compared to controls. Pulsed VT (8 to 48 hr) or
      cycloheximide (4 to 48 hr) exposure of CD4(+) cells enhanced supernatant levels
      of IL-2 but not IL-4 upon incubation for 24 hr in fresh medium. This effect was
      not persistent. Taken together, VT enhanced andsolidusor delayed peak IL-2, IL-4,
      and IL-5 gene expression and secretion in CD4(+) T cells stimulated with PMA and
      ionomycin. Remarkably, cytokine superinduction occurred simultaneously with
      partial or maximal inhibition of cell proliferation.

PMID- 8661373
TI  - The Low pH-Dependent Entry of Avian Reovirus Is Accompanied by Two Specific
      Cleavages of the Major Outer Capsid Protein &mu;2C
AB  - Avian reoviruses are capable of inducing rapid and extensive syncytium formation,
      a process that occurs preferentially under conditions of neutral or alkaline pH.
      In order to ascertain whether the membrane fusion-inducing capability of avian
      reovirus confers a pH-independent entry mechanism on the virus, virus entry was
      investigated using internalization assays and several lysomotropic agents that
      inhibit endosomal acidification. The ability of avian reovirus to infect cells
      was severely restricted under all conditions that prevented endosomal
      acidification. The decreased infection efficiency in the presence of the
      lysomotropic agents correlated with an inhibition in the proteolytic processing
      of the major outer capsid protein &mu;2C. The importance, with respect to virus
      infection, of the low pH-dependent cleavage of the avian reovirus &mu;2C protein
      was confirmed by demonstrating that infectious subviral particles, generated by
      proteolytic processing in vitro, were capable of efficiently infecting cells in
      the presence of the lysomotropic agents. These results indicated that avian
      reovirus entry-specific membrane interactions are largely dependent on an
      endosome-mediated proteolytic processing of the virus particle, suggesting that
      the syncytium-inducing property of the sigma3 protein is not sufficient to
      promote virus uptake. Furthermore, avian reovirus internalization was associated
      with two distinct cleavages of the major outer capsid protein &mu;2C, unlike the
      entry-specific processing of the analagous mammalian reovirus major outer capsid
      protein &mu;1C. The &mu;2C cleavages occured sequentially and appeared to involve
      distinct cleavage specificities. Moreover, the second cleavage event was observed
      to be both virus strain- and cell type-independent, suggesting that the cleavage
      is both specific and biologically significant.

PMID- 8661377
TI  - A Feldmannia algal virus has two genome size-classes.
AB  - Persistent viruses occur intracellularly in brown algae, specifically the
      Ectocarpales, and as reported here in the genus Feldmannia. Feldmannia species
      are small (1 mm-several cm), filamentous forms with single-celled meiotic
      sporangia that normally produce haploid zoospores. In the isolate reported here,
      spores were not observed in the sporangia but rather numerous (approximately
      10(6) per cell) polyhedral viruses are formed in their place. Two dsDNA genome
      classes of 158 and 178 kbp, with two restriction site variants of each, are
      described. The individual abundance of each genome in viral preparations is
      affected by culture temperature. A cosmid library was used to generate circular
      restriction enzyme (BamHi, Noti, and Psti) site maps.

PMID- 8661376
TI  - A potential proline-rich motif upstream of the immunoreceptor tyrosine-based
      activation motif in bovine leukemia virus gp30, Epstein-Barr virus LMP2A,
      herpesvirus papio LMP2A, and African horsesickness virus VP7.

PMID- 8661378
TI  - Inhibition of feline immunodeficiency virus infection in vitro by envelope
      glycoprotein synthetic peptides.
AB  - Sixty-six 20- to 23-amino-acid synthetic peptides, partially overlapping by 10-12
      amino acids, spanning the entire sequence of the envelope SU and TM glycoproteins
      of the Petaluma isolate of FIV, have been used to investigate the Env domains
      involved in viral infection. Peptides 5 to 7, spanning amino acids 225E-P264
      located in a conserved region of the SU protein, and peptides 58 to 61, spanning
      amino acids 767N-P806 and encompassing hypervariable region 8 of TM protein,
      exhibited a remarkable and specific antiviral effect against the homologous and
      one heterologous isolate, as judged by inhibition of FIV-induced syncytium
      formation and p25 production in CrFK cells. Peptides 5 and 7, but not peptides 58
      and 59, also inhibited viral replication of a fresh FIV isolate on nontransformed
      lymphoid cells. By flow cytometry, peptides 5, 7, 58, and 59 were shown to bind
      the surface of FIV permissive cells. The antiviral activity of peptides 5 and 7,
      however, was time-dependent, as inhibition of FIV replication was seen when the
      peptides were administered before or within 3 hr after virus inoculation; in
      contrast, TM peptides 58 and 59 exerted a potent inhibitory effect when added up
      to 24 hr after virus inoculation. Circular dychroism analysis showed that peptide
      5 folds to a helical conformation in the presence of a hydrophobic environment.
      Although the basis for the antiviral action of the peptides is not understood,
      our data suggest that the inhibitory peptides may act by interacting with cell
      surface molecules involved in viral infection.

PMID- 8661379
TI  - Succession of mutations in the Sabin strain of type 3 poliovirus replicating in
      the central nervous system of monkeys.
AB  - Sabin strains of oral poliovirus vaccine (OPV) undergo limited genetic changes
      during replication in cell cultures, the gastrointestinal tract of vaccinees, and
      the central nervous system of monkeys. Some of these changes are associated with
      loss of attenuation markers. Here we report the dynamics of mutant accumulation
      in the Sabin strain of poliovirus type 3 inoculated intraspinally into monkeys.
      Thr --> lle reversion in amino acid 6 of VP1 (2493 C --> U) occurred within the
      first few days postinoculation (p.i.), but decreased on later days and completely
      disappeared by Day 17 p.i. 472 U --> C reversion in the 5'-untranslated region
      appeared to accumulate slower and by Day 17 completely substituted for the
      vaccine-type nucleotide at this site. These results indicate that experimental
      infection of the central nervous system of monkeys consists of early and late
      phases in which a different genetic constitution of the virus is favored. In
      several isolates one additional neurovirulent revertant was found: a Phe --> Ser
      at amino acid 91 of VP3 (2034 U --> C). Since this mutation was never detected in
      vaccine lots and is strongly selected against in cell cultures at temperatures
      below 38.5 degrees, it does not threaten the safety of OPV.

PMID- 8661380
TI  - Mutations within the primer binding site of the human immunodeficiency virus type
      1 define sequence requirements essential for reverse transcription.
AB  - The primer binding site (PBS) is involved in two stages during the reverse
      transcription of the retroviral RNA genome. In the early stage, the PBS provides
      complementary sequences through which tRNA(Lys,3) binds the viral RNA genome to
      initiate minus-strand DNA synthesis; in the later stages, complementarity between
      the plus- and minus-strand copies of the PBS is required to facilitate the second
      template transfer needed to complete reverse transcription. We previously
      constructed a mutant HIV-1 proviral genome, designated as pHXB2PBS(pheC + 5) (now
      referred to as pheC + 5), which was used to identify regions of the PBS involved
      in the initiation and second template transfer steps of reverse transcription. To
      further define the sequence requirements of the PBS for the initiation of reverse
      transcription, we have made single nucleotide substitutions within the first six
      nucleotides of the pheC + 5 PBS. Our results demonstrate that mutations within
      the first five nucleotides of the PBS which disrupt base paring with tRNA(Lys,3)
      PBS results in an noninfectious virus; a G-U base pair at position six of the
      tRNA(Lys,3)-PBS complex was tolerated. In contrast to the requirements for
      initiation, we found that complementary binding between only three base pairs of
      the plus- and minus-strand PBSs was required for the extension of plus-strand DNA
      during the second template transfer. Furthermore, regions of the minus-strand DNA
      of up to 24 nucleotides could be looped-out to facilitate the complementarity
      required for the completion of plus-strand DNA synthesis. Taken together, the
      results of our studies demonstrate that different features of the PBS with
      respect to RNA:RNA and DNA:DNA interactions are required for initiation of
      reverse transcription and the completion of plus-strand DNA synthesis,
      respectively.

PMID- 8661381
TI  - Glycoproteins gl and gE of feline herpesvirus-1 are virulence genes: safety and
      efficacy of a gl-gE deletion mutant in the natural host.
AB  - Feline rhinotracheitis virus (FRV) is an important upper respiratory tract
      pathogen of cats. FRV is a member of the subfamily Alphaherpesvirinae and is
      designated feline herpesvirus-1 (FHV-1). Besides upper respiratory clinical
      signs, FHV-1 may cause generalized infections in neonates or abortions in
      pregnant queens. Recently we described a recombinant FHV-1 strain with a deletion
      in the genes for glycoproteins gl and gE (FHB beta-galglgE delta) and reported
      that cats vaccinated subcutaneously with high doses of the recombinant FHV-1
      strain responded with only mild clinical signs and developed strong immunity
      against subsequent virulent virus challenge. Here we compare the intranasal and
      subcutaneous routes of administration of this strain and assess its ability to
      induce protective immunity and prevent virus shedding after challenge. Cats
      vaccinated subcutaneously or intranasally with high doses of the recombinant FHV
      1 strain responded with only mild clinical signs and developed strong immunity
      against subsequent virulent virus challenge. This was especially evident when the
      mutant vaccine was administered oronasally. In contrast, intranasal
      administration of two other FHV-1 isolates induced severe clinical signs in cats.
      We conclude from testing this FHV-1 mutant in the natural host that deletion of
      gE and a portion of gl genes strongly reduces viral virulence but that
      immunogenicity is maintained.

PMID- 8661382
TI  - CD40/CD40L interactions and cytokines regulate HIV replication in B cells in
      vitro.
AB  - Using our in vitro model of normal B cell infection, we investigated whether
      cellular interactions and/or cytokines directing the B cell response also
      regulate HIV replication. Phorbol esters and CD40 Ab plus IL4, added prior to
      infection, substantially increased subsequent viral replication. Postinfection,
      IL2 with or without IL4 and, to a lesser extent, CD40/CD40L interactions enhanced
      viral replication. In contrast, IL10 down-regulated HIV replication induced by
      cytokines, without affecting spontaneous or CD40 Ab-induced replication. Both
      enhancing and inhibitory effects of cytokines on viral replication were
      independent of their ability to modulate B cell proliferation. Thus, these two
      phenomena seem to be independently regulated in human B cells.

PMID- 8661384
TI  - Inhibition of human parainfluenza virus-3 replication by interferon and human
      MxA.
AB  - We have investigated the IFN-mediated inhibition of human parainfluenza virus-3
      (HPIV-3) replication in cultured human A549 cells. IFN-alpha inhibited the virus
      yield significantly with concomitant reduction of viral RNA accumulation by more
      than 90%. Further studies indicated that the inhibitory action of IFN was at the
      level of primary transcription of HPIV3 replication. Since the IFN-inducible
      protein, MxA, has been shown to inhibit virus replication in several RNA viruses,
      we examined the role of MxA in HPIV-3 replication using a stably transfected
      human glioblastoma cell line expressing MxA. In these cells HPIV-3 replication
      was decreased by more than 100-fold depending on the virus dosage used with
      concomitant inhibition of viral RNA synthesis by about 80%. However, the viral
      primary transcription was not affected in this MxA-producing cell line. In
      contrast, in the parental cell line IFN-mediated inhibition occurred at the
      primary transcription step of HPIV-3 replication. These data suggest that in
      addition to MxA, other IFN-inducible proteins are involved in the anti-HPIV-3
      effect of IFN in both the cell lines used.

PMID- 8661383
TI  - The effect of simian immunodeficiency virus infection in vitro and in vivo on the
      cytokine production of isolated microglia and peripheral macrophages from rhesus
      monkey.
AB  - Microglia are the major target for human immunodeficiency virus (HIV) infection
      within the central nervous system. Because only a few cells are productively
      infected, it has been suggested that an aberrant cytokine production by this cell
      population may be an indirect mechanism leading to the development of
      neurological disorders in HIV-infected patients. Therefore we decided to study
      the secretion pattern of several interleukins (IL) by microglial cells and
      peripheral blood macrophages isolated from uninfected and simian immunodeficiency
      virus (SIV)-infected Rhesus monkeys. We found that uninfected, unstimulated
      primate microglia produce more IL-6 and less TNF alpha than peripheral blood
      macrophages, but generate comparable levels of IL-1 beta and IL-8. After
      infection with SIV in vitro, synthesis of all cytokines tested is increased
      compared to uninfected cultures and to peripheral blood macrophages. Microglia
      isolated from infected animals produce more IL-8 and TNF alpha than the
      uninfected cultures and display a strongly increased capacity to secrete TNF
      alpha upon stimulation with lipopolysaccharide. In addition, production of IL-6
      by in vivo-infected microglia increases with time in culture to very high levels
      despite the fact that only a few cells contained replicating virus. These
      findings clearly show that the cytokine production of microglia is impaired after
      SIV infection both in vitro and in vivo and that a low level of viral replication
      is sufficient for these alterations to occur. In conclusion, the results of this
      study further support a possible role of cytokines in the pathogenesis of neuro
      AIDS.

PMID- 8661385
TI  - Structural limitations of the Ad5 E1A 12S nuclear localization signal.
AB  - The Ad5 E1A 12S gene encodes an oncoprotein with the ability to immortalize and
      cooperate with other viral or cellular oncoproteins to transform primary
      epithelial cells. The immortalizing function is dependent on the protein's
      efficient localization to the nucleus. A five amino acid nuclear localization
      signal (NLS), Lys-Arg-Pro-Arg-Pro, has been identified at the extreme COOH
      terminus. This signal is necessary but not sufficient for efficient nuclear
      localization. A mutational analysis has been undertaken to further characterize
      the 12S NLS. The individual amino acids of the signal appear to have varying
      functional relevance. The lysine residue (a.a. 239) and the first arginine
      residue (a.a. 240) are the most critical. Changing the second arginine (a.a. 242)
      to threonine or either proline (a.a. 241 or 243) to alanine marginally diminishes
      signal function. Replacing the 12S NLS with the SV40 large T antigen (LT) NLS
      does not measurably affect the protein's nuclear localization. Sequences directly
      upstream of the NLS have a significant role in the proper localization of the 12S
      protein as illustrated by inefficiently localized mutants that have deletions of
      these sequences. Analyses of these mutants using a monoclonal antibody that
      recognizes the COOH-terminal four amino acids of the NLS have revealed that their
      signals are probably masked. To further investigate the importance of protein
      context in signal function, several NLS insertion mutants were constructed. Two
      regions in the first exon with predicted high surface probabilities and no known
      functions were chosen as sites for NLS insertions. Neither a wild-type 12S- nor a
      SV40 LT-NLS was functional in any of the new locations, indicating that for 12S,
      positioning of the NLS in the protein is critical.

PMID- 8661386
TI  - Influenza B virus NB glycoprotein is a component of the virion.
AB  - The influenza B virus NB glycoprotein is abundantly expressed at the surface of
      virus-infected cells. NB spans the membrane once and has an 18 amino acid
      ectodomain, a 22 amino acid transmembrane domain, and a 60 amino acid cytoplasmic
      tail. The NB N-terminal ectodomain contains two asparagine residues that are
      modified by the addition of palmitic N-linked carbohydrate chains, which become
      further modified by the addition of polylactosaminoglycan. We have now shown that
      NB is also modified by addition of acid. To determine if NB is incorporated into
      virions, metabolic labeling, immunoblotting, and immunogold electron microscopy
      techniques were used. NB was identified in virions grown in MDCK cells or in
      embryonated chicken eggs in two forms: (a) NB modified by addition of
      polylactosaminoglycan (NBpl), and (b) a cleaved species (NBc) that has a smaller
      molecular weight than unglycosylated NB (NB12). Proteinase K digestion of
      purified virions converted NBpl to NBc. Examination of virions purified by
      isopycnic centrifugation by electronmicroscopy and immunogold staining, using an
      affinity-purified antibody raised to a peptide derived from the NB cytoplasmic
      tail, showed staining for NB in influenza B virions. Quantification of the amount
      of NB in purified virions using two unrelated biochemical methods indicated there
      are on average approximately 15-100 molecules of NB per virion. Although the
      number of NB molecules incorporated on average into an influenza B virus particle
      is small, this finding is reminiscent of the number of molecules (14-68 monomers)
      found on average of the M2 integral membrane protein of influenza A virus.

PMID- 8661388
TI  - Activation of oriLyt, the lytic origin of DNA replication of Epstein-Barr virus,
      by BZLF1.
AB  - oriLyt, the cis-acting element of the lytic origin of DNA replication of Epstein
      Barr virus, is activated by the viral transactivator BZLF1 which belongs to the
      extended bZIP class of transcription factors. Seven binding sites for BZLF1, so
      called ZRE sites, are located within oriLyt. By mutational analysis of individual
      ZRE sites, we found that lytic DNA replication is dependent on only four of these
      sites which colocate with the promoter of the BHLF1 gene. The remaining three ZRE
      sites distal to the BHLF1 promoter were dispensable for DNA replication and did
      not contribute to long-range transcriptional activation of this promoter by
      BZLF1. This finding indicated that a similar set of ZRE sites is involved in DNA
      replication and transcriptional activation. To determine the function of BZLF1 in
      DNA replication, BZLF1 mutants with successive deletions in the transactivation
      domain were analyzed in replication assays. Unexpectedly, most BZLF1 mutants
      which failed to support DNA replication were found to be equally defective in
      transcriptional activation. Therefore, similar trans-acting domains of BZLF1 are
      involved both in replication and in transcription.

PMID- 8661387
TI  - Conservation of a hairpin ribozyme sequence in HIV-1 is required for efficient
      viral replication.
AB  - We have previously described a hairpin ribozyme that targets a highly conserved
      sequence in the U5 region of HIV-1. To determine if escape mutations would
      compromise virus replication, we introduced critical mutations into the ribozyme
      target site of an infectious molecular clone of HIV-1MN. HIV-1 MNA has a
      substitution of A for G immediately 3' to the cleavage site and HIV-1 MNGC has
      two substitutions in the flanking sequences that are complementary to the
      ribozyme. In vitro studies confirmed that neither the MNA-nor the MNGC-mutated
      target sequence was cleaved by the ribozyme, and furthermore, the MNGC-mutated
      target sequence failed to bind the ribozyme. Compensatory GC substitutions in the
      substrate recognition domain of the ribozyme resulted in a switch of binding and
      cleavage specificity. Replication of both the MNA and MNGC mutant viruses was
      initially two to three logs lower than that of wild-type virus, but after 3
      weeks, virus production rose sharply in both cultures. Nucleotide sequence of RT
      PCR-amplified viral sequences obtained from virus produced at later time points
      revealed complete reversion of MNA or partial reversion of MNGC to wild-type
      genotypes. No additional mutations within the ribozyme target sequence were
      observed. These results indicate that mutations in this conserved ribozyme target
      sequence led to significant attenuation of HIV-1MN.

PMID- 8661389
TI  - Long-term protection against HIV-1 infection conferred by tat or rev antisense
      RNA was affected by the design of the retroviral vector.
AB  - We have constructed a series of retroviral vectors in which the expression of
      antisense RNA targeted at the full length coding sequence of HIV-1 tat or rev was
      driven by three different promoters and in the context of double-copy or single
      copy vectors. Jurkat cells transduced by these vectors were shown to express the
      expected tat or rev antisense RNA without alteration in cell proliferation or
      surface CD4 expression. After challenge with HIV, four patterns of protection
      were identified, with the degree of protection being determined primarily by the
      design of the expression system. In those patterns showing long-term complete
      protection, we could detect no HIV p24 in the culture supernatants or in the
      cells, and no HIV RNA or HIV proviral DNA (by PCR), during a 23-week follow-up.
      Experiments designed to rescue any live virus still formed in the culture after
      20 weeks' challenge demonstrated that, with some constructs, infectious virus
      could no longer be isolated, while with other constructs, only a low level of
      infectious virus was still being formed and providing a continuing virus
      challenge, although all other markers of infection remained undetectable. Our
      results demonstrated that antisense RNA expression driven by tRNA promoter in the
      context of a double-copy vector conferred better long-term protection against HIV
      infection compared to that driven by HIV LTR or MLV LTR promoters, and that the
      optimized vectors may be useful in developing a gene therapy against HIV-1
      infection and AIDS.

PMID- 8661390
TI  - Conservation of DNA sequence in the predicted major late promoter regions of
      selected mastadenoviruses.
AB  - The major late promoter (MLP) of the subgroup C human adenoviruses is a
      preeminent model for the study of the mechanisms of basal and activated
      transcription, both in vivo and in vitro. However, while the structure and
      function of the human virus MLP has been the subject of extensive investigation,
      the conservation of the various promoter elements among the adenoviruses from
      different species has not been examined. Conservation of specific elements would
      strongly suggest the importance and universality of their function. To address
      this issue, sequences were obtained from cloned DNAs of several representative
      Mastadenoviridae, mouse adenovirus type 1 (MAV-1), Tupaia adenovirus type 1 (TAV
      1), and two bovine adenoviruses of two distinct subgroups, BAV-3 and BAV-7. The
      results of the sequencing studies showed that the TATA box and an upstream
      inverted CAAT box are conserved in all species and that the binding site for
      transcription factor USF is present in all except MAV-1, in which a sequence
      similar to an Sp1-binding site is present at a similar position. The initiator
      element (INR) sequence is not well conserved, and only one or other of the two
      downstream activating elements, DE1 and DE2, is predicted to be present in the
      nonprimate virus MLP regions. Ribonuclease protection assays on RNA isolated from
      MAV-1-infected cells late in infection indicated that the predicted MLP is
      functional, and transcription initiation and splice donor sites were identified.
      The human virus MLP is embedded in the essential DNA polymerase sequence on the
      opposite DNA strand. The primary amino acid sequences of the C-terminal regions
      of the predicted DNA polymerases show strong conservation of sequence motifs
      observed in replicative polymerases ranging from prokaryotes to mammals, and
      additional regions of strong conservation among the adenovirus polymerases.
      Pairwise comparisons between the newly sequenced regions of the polymerases and
      previously published sequences show that BAV-7 is most dissimilar to all others,
      while TAV-1 has a greater similarity to the primate sequences than to the others.
      The sequence data from both strands were also used to construct phylogenetic
      trees, based on BAV-7 as the outgroup. The trees constructed from the two sets of
      sequences are broadly similar, showing close relationships between primate
      viruses, but differing in the order of divergence of TAV-1 and MAV-1 branches.

PMID- 8661391
TI  - Mechanisms of immunization with a replication-defective mutant of herpes simplex
      virus 1.
AB  - We have investigated the mechanisms by which subcutaneous immunization of mice
      with a replication-defective mutant of herpes simplex virus 1 protects against
      infection of the eye and latent infection of the trigeminal ganglion following
      corneal challenge. First, we have shown that immunization reduces the number of
      trigeminal ganglion neurons in challenged animals that express the latency
      associated transcript. This indicates that the reduction in the incidence of
      latent infection by challenge virus is likely due to immune mechanisms and not
      saturation of the potential sites of latent infection by the immunizing mutant
      virus itself. Second, the duration of protective immunity against acute
      infection, keratitis, and latent infection was similar in mice immunized with
      replication-defective or -competent virus; thus, the replication-defective mutant
      virus is able to induce durable immunity apparently without spread in the host.
      Third, although the mutant virus showed no evidence of replication in vivo, it
      was present in footpad tissue in an infectious form for several days. This
      surprising observation raises the possibility that continued infection events by
      input virus over an extended period of time may have a boosting effect on the
      developing immune response which could explain, at least in part, the capacity of
      these replication-defective mutant viruses to elicit a robust and durable
      immunity despite their inability to spread within the host.

PMID- 8661392
TI  - A comparison of the spread of Murray Valley encephalitis viruses of high or low
      neuroinvasiveness in the tissues of Swiss mice after peripheral inoculation.
AB  - A Murray Valley encephalitis virus (MVE) field isolate of high neuroinvasiveness
      (BH3479) and a neutralization escape variant of low neuroinvasiveness (BHv1)
      selected from BH3479 (which differ by a single amino acid at residue 277 in the
      envelope glycoprotein) were examined for their distribution in the tissues of
      weanling Swiss mice at various times after footpad inoculation. BH3479 was first
      detected in lymph nodes draining the inoculated limb at 24 hr postinoculation
      (pi) and was found in serum between 36 and 72 hr pi. BH3479 was first detected in
      the central nervous system (CNS) at 4 days pi and reached maximum CNS titers ( >
      10(9) PFU/g) between 6 and 9 days pi. All BH3479-infected mice developed
      encephalitis and died before 10 days pi. In contrast, BHv1 was not detected in
      lymph nodes draining the footpad at any time after inoculation; BHv1 was first
      detected in the serum between 60 and 72 hr pi-24 hr later, and at a 20-fold lower
      titer than for BH3479. BHv1 was first detected in the CNS at 7 days pi 3 days
      later and at a 300-fold lower titer than for BH3479. After 10 days pi, BHv1 could
      not be isolated from the CNS or from other host tissues. Most BHv1-infected mice
      experienced a subclinical infection; the mortality rate from BHv1 infection was
      less than 1%. Both viruses appeared to enter the CNS via the olfactory lobes.
      BH3479 spread throughout the CNS in a rostral to caudal direction over 3-4 days.
      In contrast, BHv1 infection in the CNS was restricted to the olfactory lobes and
      adjacent structures of the forebrain.

PMID- 8661393
TI  - Localization of the Us protein kinase of equine herpesvirus type 1 is affected by
      the cytoplasmic structures formed by the noval IR6 protein.
AB  - Previous work revealed that the Us (unique short) segment of equine herpesvirus
      type-1 (EHV-1), like that of other alphaherpesviruses, encodes a serine/threonine
      protein kinase (PK). Experiments were carried out to identify the PK encoded by
      the EHV-1 EUS2 gene (ORF 69) and to ascertain its time course of synthesis and
      cellular localization. Western blot and immunoprecipitation analyses of EHV-1
      infected cell extracts using a PK-specific polyclonal antibody generated against
      a bacterially expressed TrpE/PK fusion protein identified the Us PK as a 42- to
      45-kDa phosphoprotein. The PK protein is first synthesized at 3 hr postinfection,
      is produced throughout the infection cycle, and is incorporated into EHV-1
      virions. Interestingly, immunoprecipitation analyses revealed that the PK protein
      within the cytoplasm is associated with the 33-kDa IR6 novel protein of EHV-1, is
      expressed abundantly as an early protein, and is present in the large rod-like
      structures formed by the IR6 protein (ORF67 protein) within the cytoplasm of
      infected cells. Confocal microscopic examination of cells stained with
      fluorescein-labeled antibody clearly showed that the PK protein colocalized with
      the cytoplasmic IR6 rod-like structures and remained associated with these unique
      structures during infection. In contrast, in cells infected with the EHV-1 RacM
      strain in which the IR6 protein harbors four amino acid substitutions that
      prevent formation of the rod-like structures (Osterrieder et al., 1996, Virology
      217, 442-451), the PK protein localized predominantly to the nucleus. The
      possible significance of the association of the IR6 and PK proteins in EHV-1
      replication is discussed.

PMID- 8661394
TI  - Functional characterization of the V1V2 region of human immunodeficiency virus
      type 1.
AB  - The level of proviral DNA sequence variation in the V1V2 region was monitored
      over time in six HIV-1-infected individuals. Substitutional and length variation
      was observed, where the majority of length changes, ranging from 28 to 49 amino
      acids, was located within the V1 region. Evidence for convergent evolution in the
      V2 region was found. The functional significance of this variation was assessed
      by cloning the V1V2 sequences into an infectious molecular clone, HXB2. The
      majority of chimeras replicated, demonstrating that the sequences, though
      genetically distinct, were capable of conferring a viable phenotype. Chimeras
      expressing closely related sequences in a constant genetic background displayed
      different biological phenotypes, with respect to both cytopathicity and cell
      tropism. However, no association between primary V1V2 amino acid sequence and
      viability or cytopathicity of the chimeric virus was observed, suggesting that
      predictions of virus phenotype based on sequences alone may be incorrect. The
      effect of V1V2 variation on the overall gp 120 conformation was measured by
      expressing the gp 20 from a number of viable and nonviable clones. No differences
      were observed, suggesting that misfolding of the chimeric gp 120 protein was not
      an explanation for the nonviability of some virus clones. Several chimeras were
      noncytopathic and only able to replicate in PBMC cultures, demonstrating that the
      V1V2 region, independent of the V3 sequence, is capable of defining both tropism
      and cytopathicity.

PMID- 8661395
TI  - Chimeric viruses expressing primary envelope glycoproteins of human
      immunodeficiency virus type I show increased sensitivity to neutralization by
      human sera.
AB  - We constructed a number of HXB2 viruses chimeric for the gp 120 glycoprotein
      derived from a number of viable molecular clones obtained from a primary isolate.
      Comparative biological characterization of the parental primary viruses with the
      gp 120.HXB2 chimeras demonstrated identical patterns of cell tropism and
      cytopathicity. Furthermore, both parental and chimeric viruses were insensitive
      to neutralization by sCD4 and a panel of conformation-dependent monoclonal
      antibodies, demonstrating that transfer of the gp 120 protein alone was
      sufficient to confer a "neutralization-resistant" phenotype to the T-cell-adapted
      clone HXB2. We assessed the contribution of gp 120 epitopes to the neutralizing
      immune response by comparing the sensitivity of these viruses to neutralization
      by a panel of sera from HIV-infected individuals. Seven of eleven sera tested
      were able to neutralize HXB2 and two or more of the chimeric viruses; in
      contrast, only one serum neutralized more than one of the parental primary virus
      clones. The association of gp 120-gp41 envelope at the surface of infected PBMC
      cultures was measured in the presence or absence of soluble CD4. No differences
      in CD4-induced gp 120 dissociation were seen between the chimeric and parental
      virus-infected cultures. Since gp 120 conformation appeared the same between
      primary and chimeric viruses, we suggest that the ability of human sera to
      neutralize the chimeric viruses may be mediated by epitopes within gp41.

PMID- 8661396
TI  - Mutational analysis of HIV-1 gp160-mediated receptor interference: intracellular
      complex formation.
AB  - Formation of CD4-gp160 intracellular complexes represents an important mechanism
      leading to the induction of receptor interference. Previous studies have
      demonstrated that cells coexpressing gp160 and CD4 formed complexes of CD4 and
      gp160 which became blocked within the endoplasmic reticulum (ER), preventing CD4
      from reaching the cell surface. In this report we have investigated the domains
      and residues of CD4 and gp160 involved in intracellular interaction. Accordingly,
      we have introduced mutations in both CD4 and gp160 at sites previously shown to
      disrupt CD4-gp120 interactions at the cell surface. Using a T7-vaccinia virus
      transient expression system, we expressed these gp160 and CD4 mutants in HeLa
      cells and analyzed their effects on intracellular complex formation and CD4
      surface modulation. We observed that a number of gp160 mutants which failed to
      interact with CD4 at the cell surface also failed to bind and trap CD4 within the
      ER as expected. However, mutations at a critical residue, W427, did not abrogate
      intracellular CD4 binding. These gp160 mutants continued to interact with
      intracellular CD4 and inhibit CD4 transport to the cell surface, although gp120
      produced from these mutants did not bind CD4 at the cell surface as expected. A
      number CD4 mutants also continued to form intracellular complexes with gp160,
      resulting in the loss of CD4 surface expression. Again, these CD4 mutants did not
      bind to gp120 at the cell surface, consistent with earlier reports. These results
      demonstrate that intracellular interactions between gp160 and CD4 in the ER may
      utilize different contact sites compared to those used during CD4 and gp120
      binding at the cell surface. The data provide further evidence that the
      environment in which CD4 and the HIV-1 envelope glycoprotein interact can have a
      significant effect on their interaction.

PMID- 8661397
TI  - Membrane anchorage of gp160 is necessary and sufficient to prevent CD4 transport
      to the cell surface.
AB  - The HIV envelope glycoprotein gp160 plays a major role in the posttranslational
      down-regulation of its receptor, CD4. In this report we have analyzed the
      requirements of both CD4 and gp160 involved in transport block of the gp160-CD4
      complex causing the down-regulation of cell surface CD4. Using a transient
      expression system we observed that both soluble and membrane-bound CD4 were
      equally blocked by the wild-type gp160, indicating that neither the transmembrane
      domain nor the cytoplasmic tail of CD4 affected its interaction with gp160 or
      exocytic transport block of the complex. Similarly, deletions of the gp160
      cytoplasmic domain or mutation in the transmembrane domain had little effect on
      its transport, or its ability to down-regulate CD4 surface expression.
      Furthermore, substitution of the gp160 transmembrane domain and cytoplasmic tail
      with that of the influenza virus hemagglutinin or with a
      glycophosphatidylinositol moiety did not affect its ability to bind CD4 and block
      its transport. However, soluble envelope glycoprotein constructs (either gp120 or
      soluble gp160) were unable to block CD4 transport to the cell surface despite
      their binding to CD4 within the ER. Taken together these results demonstrate that
      neither the gp160 cytoplasmic tail nor the specific sequences of the
      transmembrane region of gp160 nor the membrane anchoring of CD4 were involved in
      ER retention of the CD4-gp160 complex and that anchoring of gp160 to the ER
      membrane was responsible for gp160-mediated cell surface down-regulation of CD4.

PMID- 8661398
TI  - Generation of defective interfering particles by two vaccine strains of measles
      virus.
AB  - A systematic study was made to measure the generation of defective interfering
      particles upon up to 13 serial passages of two measles vaccine strains, Edmonston
      and Edmonston-Zagreb, through either simian (Vero) or human (WI-38) cell lines.
      Results for the Vero cell passage were nearly identical for both viruses.
      Infectivity titers dropped by nearly 8 logs to undetectable levels at passage 4
      and cycled between maximum and minimum levels every 4 passages. Samples with the
      lowest infectivity titers produced the greatest reduction in titer of standard
      virus and contained an approximately 900-nucleotide subgenomic RNA for the
      Edmonston strain and two subgenomic RNAs of 4300 and 3000 nucleotides for the
      Edmonston-Zagreb vaccine strain. A defective interfering RNA-specific reverse
      transcription-polymerase chain reaction (RT-PCR) detected subgenomic RNAs at all
      passage levels. In contrast, samples obtained after passage of these viruses in
      WI-38 did not reduce the yield of standard virus and did not contain subgenomic
      RNAs in both Northern blot and RT-PCR assays. These results clearly show that
      cell type rather than virus strain affects defective interfering particle
      generation for measles virus.

PMID- 8661400
TI  - Neutralizing epitope on penetration protein of vaccinia virus.
AB  - The monoclonal antibody 2D5 neutralized vaccinia virus by preventing penetration
      of the virus and reacting with VP23-29K. The conformation of the VP23-29K was
      maintained by a disulfide bond(s), and the 2D5mAb reacted stronger with the
      nonreduced 23-kDa form than with the reduced 29-kDa form. We selected several
      escape mutants. Sequences of the A17L genes, which were thought to encode the
      VP23-29K, did not show cognate mutation. Genomic DNA of a 2D5mAb-resistant mutant
      (M4) was cleaved with HindIII, and all the fragments were introduced into
      parental IHD-J strain vaccinia virus by transfection. Only the L fragment
      produced a 2D5mAb-resistant virus. Dissection of the L fragment and subsequent
      transfection revealed that the L1R gene induced the 2D5mAb-resistant virus. The
      2D5mAb-resistant mutants showed a consensus G to A conversion at nucleotide 101
      of their LIRs which would replace asparatic acid 35 with asparagine. Ishibashi
      111 strain mousepox virus spontaneously resistant to 2D5mAb also had the same
      sequence at this region. Moreover, the VP23-29K was myristoylated as predicted by
      the L1R gene. The coding gene of the VP23-29K was L1R.

PMID- 8661399
TI  - Analysis of the intracellular transport properties of recombinant La Crosse virus
      glycoproteins.
AB  - The G1 and G2 glycoproteins of La Crosse virus, a member of the Bunyavirus genus
      of the Bunyaviridae, are encoded as a single open reading frame (ORF) in the
      viral middle-sized RNA segment. The primary product from this ORF is processed,
      either cotranslationally or shortly after translation, into the two glycoproteins
      and a nonstructural protein, NSm, of unknown function. We have expressed La
      Crosse glycoproteins using vaccinia vectors and studied their processing and
      localization. When expressed in the native G2-NSm-G1 configuration, both G1 and
      G2 targeted to the Golgi apparatus as shown by their colocalization with wheat
      germ agglutinin and acquired resistance to endoglycosidase H. When expressed
      independently, G2 was targeted to the Golgi apparatus but G1 was retained in the
      endoplasmic reticulum, indicating that a G1-G2 association is required for Golgi
      targeting of G1. In contrast to results with other members of the Bunyaviridae,
      we found that expression of G1 and G2 from separate vectors did not lead to the
      transport of the G1-G2 complex to the Golgi. However, disruption of the NSm
      region with a foreign sequence did not interfere with transport of the complex.
      When a portion of the beta-galactosidase gene was inserted in frame into NSm, the
      glycoproteins derived from this construct were processed and targeted properly
      and were capable of mediating cell-to-cell fusion.

PMID- 8661402
TI  - Nucleo-cytoplasmic redistribution of the HTLV-I Rex protein: alterations by
      coexpression of the HTLV-I p21x protein.
AB  - The function of the Rex protein of human T-cell leukemia virus type I (HTLV-I)
      has been demonstrated to be very similar to the Rev protein of human
      immunodeficiency virus type 1 (HIV-1). Both of these retroviral regulatory
      proteins rescue unspliced viral RNAs from the nuclei of infected cells. The Rev
      protein of HIV-1 has been reported to shuttle between the nucleus/nucleolus and
      the cytoplasm. Here, we have found that Rex also relocated out of the nucleus in
      the presence of actinomycin D. This effect was demonstrated in dose- and time
      course-dependent manners. In comparison with previous reports on HIV-1 Rev, these
      effects with Rex seemed to be similar, but less distinct, which may reflect
      precise differences in the subcellular localization and/or shuttling pathways of
      Rev and Rex. Interestingly, the endogenous truncated form of the Rex protein,
      p21x, significantly interfered with the intracellular translocation of Rex, when
      coexpressed in trans. As expression of p21x occurs in various HTLV-I-infected
      cells, p21x may play a role in the life-cycle of HTLV-I, through regulating the
      dynamic subcellular distribution of the viral trans-activator, Rex.

PMID- 8661403
TI  - Viral persistence in neurons alters synaptic plasticity and cognitive functions
      without destruction of brain cells.
AB  - Neurons have a restricted expression of MHC heavy chain molecules which prevents
      presentation of antigens of infecting viruses. As a result, such infected cells
      escape immune surveillance and allow the establishment of noncytolytic persistent
      infection. Here we show that a chronic noncytolytic viral infection both in vitro
      and in vivo selectively perturbed the expression of GAP-43, a protein that plays
      a central role in neuronal plasticity processes accompanying learning and memory.
      GAP-43 expression was greatly decreased in the hippocampus, an area of heightened
      viral replication, while synaptic density was preserved. Concurrently, the
      ability to learn tasks was significantly impaired in these persistently infected
      mice. Yet, infected neurons remained free from structural injury.

PMID- 8661404
TI  - Molecular interactions between the HSV-1 capsid proteins as measured by the yeast
      two-hybrid system.
AB  - HSV-1 B capsids are composed of seven major proteins, designated VP5, VP19C, 21,
      22a, VP23, VP24, and VP26. VP indicates that the capsid protein is also a
      component of the infectious virion. Capsid proteins 21, 22a, and VP24 are
      specified by a single open reading frame (UL26) that encodes 635 amino acids. An
      objective of the work in our laboratory is to identify and map interactions among
      and between capsid proteins. In the present studies we employed the yeast GAL4
      two-hybrid system developed by Fields and his colleagues (Nature 240, 245-246
      (1989)) for this purpose. DNA corresponding to the capsid open reading frames was
      derived as a PCR product and fused to sequences of the GAL4 activation and DNA
      binding domains. Using this system each of the capsid proteins has been tested
      for interactions with all of the other capsid proteins. Three interactions have
      been identified: a relatively strong self-interaction between 22a molecules
      (residues 307-635 of UL26), bimolecular interactions between 22a and VP5, and
      another between VP19C and VP23. The interactions were detected by the expression
      of beta-galactosidase enzyme activity, and yielded 289, 86, and 63 units of
      enzyme activity, respectively. For the 22a self-interaction, elimination of
      residues 611-635 resulted in an approximately twofold decrease in enzyme
      activity. The C-terminal 25 amino acids of 22a were also essential for the
      bimolecular interaction between 22a and VP5.

PMID- 8661405
TI  - Prolonged infection in rhesus macaques with simian immunodeficiency virus
      (SIVmac239) results in animal-specific and rarely tissue-specific selection of
      nef variants.
AB  - We analyzed the sequence of nef genes from different tissues of three rhesus
      macaques that had been infected with molecularly cloned SIVmac239 for 88 to 92
      weeks. Comparison of the predicted amino acid sequences revealed that each
      macaque had selected out specific amino acid substitutions and that most of this
      variation (70%) was confined to four regions, amino acids 39 to 75, 90 to 105,
      153 to 167, and 191 to 217, comprising 36% of the protein. The nef genes in these
      animals underwent extensive genetic variation with average nucleotide and amino
      acid substitution rates varying from 0.86 to 2.84% and 2.47 to 6.27%,
      respectively, although tissue-specific selection of nef variants occurred in only
      1 of 14 tissues examined in this study. Comparison of the rate of nucleotide and
      amino acid substitutions in the nef genes to those previously reported in the env
      in the central nervous system (CNS) and lymph node (LN) revealed that the
      predicted amino acid substitution rates for Nef were much higher than for the
      gp120 region of env in the CNS and LN tissues for one macaque. In the two other
      macaques, the predicted amino acid substitution rates were similar between these
      two proteins in LN tissues, but the amino acid substitution rates in Nef were
      significantly higher than in the gp120 from the CNS. Comparison of the nucleotide
      substitutions in the region of overlap between the env and the nef revealed that
      approximately 83% of the nucleotide substitutions in this area resulted in a Nef
      amino acid sequence change, 26% of the nucleotide substitutions resulted in a
      gp41 amino acid change, and 9.5% of nucleotide substitutions resulted in amino
      acid sequence changes in both proteins, suggesting a preference for the selection
      of amino acid substitutions in the Nef in these animals. Our results indicate
      that in animals infected with SIVmac239 for prolonged periods, variation in the
      nef occurs at rates similar to or exceeding that observed for the env gene.

PMID- 8661406
TI  - HIV-1 Gag protein associates with F-actin present in microfilaments.
AB  - Several studies have provided evidence that the cellular cytoskeleton may be
      involved in the assembly and budding of retroviruses. In fractionation studies of
      HIV-1-infected CEM cells, the majority of the unprocessed Gag polyprotein
      cofractionated with the cellular cytoskeleton. In vivo and in vitro analyses of
      this interaction indicated that the unprocessed Gag polyprotein is capable of
      association with polymerized actin (F-actin). Binding of Gag to F-actin may be
      involved in the assembly or budding of HIV-1.

PMID- 8661407
TI  - Replacement of the tyrosine residue that links a potyviral VPg to the viral RNA
      is lethal.
AB  - Mutants of tobacco vein mottling virus (TVMV) were constructed in which the
      tyrosine residue (Tyr1860) that links the VPg to the viral RNA was changed to
      phenylalanine or serine or was inverted in position with the adjacent glycine
      residue. In another mutant, the tyrosine residue nearest to Tyr1860 (Tyr1867) was
      changed to a phenylalanine residue. The resulting mutants were tested for their
      ability to infect Nicotiana tabacum plants or protoplasts. The Tyr1860 mutants
      did not accumulate to detectable levels in infected plants when tested by ELISA
      and Northern blot analysis. Moreover, the Tyr1860-associated mutants were not
      infectious in protoplasts, indicating that mutations involving the linking amino
      acid of the TVMV VPg abolished viral replication. In contrast to the Tyr1860
      mutants, transcripts from the mutation of Tyr1867 to a phenylalanine residue
      infected both protoplasts and plants. Analysis of progeny RNA from plants
      inoculated with the Tyr1867 mutant indicated that a reversion to wild type had
      occurred in systemically infected leaves.

PMID- 8661408
TI  - Analysis of cis-acting elements in the 5' leader sequence of alfalfa mosaic virus
      RNA 3.
AB  - The leader sequence of RNA 3 of the Leiden isolate of alfalfa mosaic virus strain
      425 consists of 345 nucleotides (nt) and contains four putative stem-loop
      structures each with a motif in the loop that resembles the internal control
      region 2 (ICR2) of tRNA genes. The sequence of the 5' terminal 112 nt of this
      leader contains one of these stem-loop structures and is sufficient for a reduced
      accumulation of RNA 3 in protoplasts and a delayed accumulation in plants (E. A.
      G. van der Vossen et al., Nucleic Acids Res. 21, 1361-1367 (1993). A number of
      mutations were made in this 112-nt leader sequence to investigate its role in RNA
      3 accumulation. Deletion of nucleotides 23-43, 44-90, or 55-112 and inversion or
      duplication of nucleotides 44-90 all abolished RNA 3 accumulation. Similarly, two
      base substitutions in the ICR2 motif (nucleotides 60-77) abolished RNA'3
      accumulation. Mutations in the stem sections of the putative stem-loop structure
      had various effects on RNA 3 accumulation and supported the notion that this
      structure is important for plus-strand promoter activity.

PMID- 8661409
TI  - Variability of herpes simplex virus 1 gL and anti-gL antibodies that inhibit cell
      fusion but not viral infectivity.
AB  - Herpes simplex virus type 1 gL lacks a transmembrane domain but stably associates
      with membranes through its oligomerization with the integral membrane
      glycoprotein designated gH. The gH-gL oligomers are essential for virion
      infectivity and virus-induced cell fusion. Monoclonal and polyclonal antibodies
      were raised against HSV-1(KOS) gL as probes for antigenic structure and
      functional protein domains. Antigenic determinants recognized by these antibodies
      were found to be present on gL expressed by many, but not all, strains of HSV-1
      and were not detected on gL expressed by HSV-2 strains. These antigenic
      determinants were localized to the C-terminal region of HSV-1 gL, where amino
      acid substitutions define at least two classes of HSV-1 gL and where the
      sequences of HSV-1 and HSV-2 gL diverge considerably. The antibodies were
      extremely effective at inhibiting virus-induced cell fusion, provided the virus
      strain expressed the relevant antigenic determinants, but failed to neutralize
      viral infectivity despite demonstrable binding to virions. These results define
      strain-dependent differences in the structure and antigenic conformation of HSV-1
      forms of gL and suggest that the roles of gL in cell fusion and viral entry are
      different.

PMID- 8661410
TI  - Antigenic variation of SIV: mutations in V4 alter the neutralization profile.
AB  - Antigenic variation is a characteristic feature of lentiviral infection. The
      SIV/macaque model of AIDS provides an ideal system in which to investigate the
      molecular basis of antigenic variation. The purpose of this study was to
      genetically map the nucleotide changes in env that alter the neutralization
      phenotype of SIV. Serum taken from an SIVmac239-infected macaque (2D) at 30 weeks
      postinoculation was found to neutralize the input virus (SIVmac239) and an
      isolate, P9, obtained at 10 weeks p.i., but did not neutralize two other
      isolates, P13 and P23, obtained at 20 and 52 weeks, respectively. Sequence
      analysis of these virus variants revealed clustered amino acid changes in V1 and
      single base pair changes in V2-V4 of P13 and P23. Infectious recombinant viruses
      in which the V1 and V1-V3 sequences of SIVmac239 were replaced with those of P13
      or P23 retained the neutralization profile of SIVmac239; both were neutralized by
      macaque 2D serum. Recombinants containing the entire surface glycoprotein (gp120)
      (V1-V5) and the 5' portion of gp41 of P13 and P23 and those containing gp120
      sequences from V4 through the 5' portion of the transmembrane glycoprotein (gp41)
      were not neutralized by 2D serum. Using a panel of monoclonal antibodies in
      radioimmunoprecipitation assays, P23 and recombinants containing V4 and V5 of P23
      were shown to be antigenically distinct from P13 and SIVmac239. The majority of
      the amino acid changes in the antigenically distinct viruses were clustered in V4
      (amino acids 413-418) and these changes created new potential N-linked
      glycosylation sites. This study demonstrates that a small number of specific
      amino acid changes (amino acids 412 to 418 in the env gene) in the V4 region of
      the SIV envelope glycoprotein can alter antibody recognition and neutralization
      and that these phenotypic changes may be associated with altered glycosylation of
      the envelope.

PMID- 8661411
TI  - Assembly and release of SIV env proteins with full-length or truncated
      cytoplasmic domains.
AB  - We have used recombinant vaccinia viruses expressing full-length or truncated gag
      or env genes of SIVmac239 to investigate the requirements for assembly of SIV
      proteins. We observed that assembly of virus-like particles (VLPs) was found to
      be 3- to 5-fold higher with full-length Env than with the truncated forms, or
      than VLPs containing only Gag proteins, in primary monkey cells or various human
      cell lines. When cells expressing Env proteins in the absence of Gag were
      examined by immunoelectron microscopy, clusters of Env protein and membrane
      vesicles containing Env proteins were observed at cell surfaces. A low level of
      vesicles was released from cells expressing full-length Env, but about a 10-fold
      higher level was released in cells expressing a truncated form of Env [Env733(t)]
      in which the cytoplasmic domain is only 17 amino acids in length. Another
      truncated protein, Env718(t), with a short cytoplasmic tail of 3 aa, was also
      incorporated into VLPs at a 10-fold higher level than the full-length Env protein
      and was more efficiently released in vesicles. The mature SU and TM proteins were
      predominantly incorporated into VLPs with full-length Env, but both cleaved and
      uncleaved precursor proteins were present in VLPs with truncated Env as well as
      in Env and Env(t) vesicles. A more prominent layer of spikes was seen by electron
      microscopy in VLPs with truncated Env than in VLPs containing full-length Env.
      These results indicate that truncated Env proteins have the ability to self
      associate on the cell surface and are assembled into a more closely packed array
      than full-length Env, which could explain the preferential incorporation of Env
      proteins with short cytoplasmic tails into virions.

PMID- 8661412
TI  - Genetic analysis of the bovine papillomavirus E2 transcriptional activation
      domain.
AB  - The bovine papillomavirus type 1 E2 transactivator has a large amino-terminal 215
      residue transcriptional activation domain (TAD) that is active in Saccharomyces
      cerevisiae and higher eukaryotic cells. Comparison to other transcriptional
      activators suggests that its functions may be mediated in part through two acidic
      regions, A1 and A2, in this domain. We have characterized the functional elements
      within the E2 TAD using LexA-E2 fusions and by screening randomly generated
      libraries of E2 mutations for transcriptional activation in yeast. The A1 region
      was highly sensitive to substitutions that reduce negative charge, although there
      was not a perfect correlation between overall charge and transcriptional
      activity. Mutations were isolated within a hydrophobic amino acid motif that
      overlaps the A2 region and resembles elements described in other viral and
      cellular transactivation domains. When fused to the LexA DNA binding domain, this
      hydrophobic motif within the acidic A2 region was unable to activate
      transcription in S. cerevisiae. Multiple highly defective mutations primarily
      altering hydrophobic amino acids were identified in the distal third of the E2
      TAD. The transcription phenotype of many of these E2 TAD mutations was similar in
      yeast and COS cells.

PMID- 8661413
TI  - The transactivation and DNA binding domains of the BPV-1 E2 protein have
      different roles in cooperative origin binding with the E1 protein.
AB  - The bovine papillomavirus E2 transactivator protein enhances the ability of the
      E1 protein to bind to the viral origin of replication which contains an E1
      binding site flanked by two E2 binding sites. To determine which regions and
      functions of the E2 protein are important for this cooperative interaction, a
      series of mutated E2 proteins were assayed for their ability to enhance E1 origin
      specific binding. Cooperative origin binding required at least one E2 DNA binding
      site, an intact functional E2 DNA binding domain, and an intact transactivation
      domain. The hinge region of the E2 proteins was dispensable for this activity. To
      further examine the role of the E2 C-terminal domain, a series of chimeric
      proteins were generated that substituted the yeast GAL4 DNA binding domain for
      the E2 DNA binding domain. These chimeric proteins were able to cooperatively
      bind to a hybrid origin that contained GAL4 binding sites in place of the E2
      binding sites. These studies indicate that the E2 transactivation domain is
      sufficient for interaction with the E1 protein and that the E2 DNA binding domain
      is required for interaction with origin DNA sequences.

PMID- 8661414
TI  - In vitro studies on the activation of the hepatitis C virus NS3 proteinase by the
      NS4A cofactor.
AB  - Proteolytic processing of the nonstructural proteins of the hepatitis C virus
      (HCV) is mediated by two viral proteinases: the NS2-3 proteinase cleaving at the
      NS2/3 junction and the NS3 serine-type proteinase responsible for processing at
      the NS3/4A, NS4A/B, NS4B/5A, and NS5A/B sites. Activity of the NS3 proteinase is
      modulated by NS4A. In the absence of this cofactor processing at the NS3
      dependent sites does not occur or, in the case of the NS5A/B junction, is poor
      but increased when NS4A is present. Although recent studies demonstrated that
      proteinase activation requires direct interaction between NS3 and NS4A, the
      mechanism by which NS4A exerts the activation function is not known. To further
      analyze the conditions of proteinase activation and to characterize the NS3
      sequences important for complex formation and activation we used an in vitro
      assay in which radiolabeled HCV substrates were mixed with NS3 proteinase and
      synthetic NS4A peptides. We found that microsomal membranes are not required for
      proteinase activation. However, they are important for efficient accessibility of
      the NS4A/B site but not the other trans-cleavage sites. Studies with NS3 deletion
      mutants identified a region between amino acids 15 and 22 which is essential for
      proteinase activation. Results obtained with several mutations introduced into
      this sequence show that a weak overall association between NS3 and NS4A is
      sufficient for proteinase activation and suggest that a beta-sheet at the NS3
      amino terminus plays an important role. Although not essential for proteinase
      activation the amino terminal 14 NS3 residues were found to have an auxiliary
      function probably by stabilizing the NS3/4A interaction. Finally, we could
      demonstrate intracellular, peptide-mediated modulation of proteinase activity
      providing the basis for the development of a novel therapeutic concept.

PMID- 8661415
TI  - Modulation of bacteriophage T4 capsid size.
AB  - Bacteriophage T4 capsid assembly requires the vertex protein (gp24). Mutations
      that bypass this requirement are found in gene 23, which produces the major
      capsid protein (gp23). The latter were used to study the role of gp24 in head
      length control. We found that gp24 is no longer present in the capsids of several
      gp24 bypass mutants. We measured the capsid lengths of several of these bypass
      mutants, because gp24 had been reported to be implicated in head length control.
      One bypass mutant (reported in 1977) produced 40-60% short headed ("petite")
      phage in the presence of wild-type amounts of gp24. The bypass mutations, when
      combined with amber mutations in gene 24, produced normal size heads in either
      suppressor or nonsuppressor host bacteria. When several known bypass mutations
      were back-crossed with wild-type phage, one-third of the byp/24wt mutants
      isolated produced large amounts of petite phage, indicating that the ability to
      produce petite phage is a general property of the bypass mutations. Sequencing
      several of these bypass mutants showed that those that produced petite phage
      contained at least one additional missense mutation in gene 23. This suggests
      that gp24 itself has no direct role in head length regulation, but that in the
      presence of bypass 24 mutations and certain easily acquired gene 23 mutations
      (called trb) the gp23-gp24 interactions can modulate head length.

PMID- 8661416
TI  - Expression of bovine interleukin-1 beta in a bovine herpesvirus-1 vector: in
      vitro analysis.
AB  - In order to evaluate whether bovine herpesvirus-1 (BHV-1) could be used as a live
      viral vector for the expression of cytokines, we constructed a recombinant BHV-1
      expressing bovine interleukin-1 beta (boIL-1 beta). The boIL-1 beta coding
      sequence, corresponding to the cleaved mature product, was fused with the BHV-1
      glycoprotein C (gC) signal peptide sequence; the resultant gC-boIL-1 beta fusion
      gene was recombined into the gC locus of the BHV-1 genome. Southern blot analysis
      confirmed the proper genomic configuration of the recombinant virus. Results from
      transcript analysis showed that boIL-1 beta was expressed in infected cells with
      kinetics similar to that of gC. Indirect immunofluorescence and
      immunoprecipitation assays showed that the recombinant protein was produced in
      both cell-associated and secreted forms. Western blot analysis detected a 19.3
      kDa protein. Further analysis, using an IL-1 beta bioassay demonstrated that both
      the cellular and secreted forms of recombinant boIL-1 beta possessed biological
      activity. The expression of the boIL-1 beta protein did not affect the in vitro
      growth efficiency of the virus, which exhibited similar growth kinetics to that
      of a simple gC deletion mutant. The results from this study demonstrate that BHV
      1 can be used to express a functional cytokine, thereby establishing the basis to
      further study recombinant BHV-1 expressing cytokines as an alternative means to
      attenuate the virus and also as a potential in situ cytokine delivery system to
      modulate immune responses against BHV-1 and other cattle pathogens.

PMID- 8661417
TI  - Palmitoylation of the murine leukemia virus envelope glycoprotein transmembrane
      subunits.
AB  - The envelope protein of Friend murine leukemia virus is modified by fatty
      acylation of the transmembrane (TM) protein subunit. The labeling by [3H]palmitic
      acid was found to be sensitive to treatment with the reducing reagents 2
      mercaptoethanol and hydroxylamine, indicating the presence of a thioester
      linkage. Pulse-chase experiments showed that the precursor protein can be labeled
      by [3H]palmitic acid prior to its cleavage into the surface and TM subunits. By
      using site-directed mutagenesis, we determined that palmitoylation occurs on a
      cysteine residue, Cys 606, located in the transmembrane domain. A thin-layer
      chromatography assay after acid hydrolysis showed that incorporated label
      comigrated with palmitic acid. When another cysteine residue was introduced into
      the cytoplasmic tail 22 amino acids from the transmembrane domain, no
      palmitoylation was observed to occur on this cysteine residue, demonstrating the
      importance of the position of the cysteine residue for palmitoylation. Sequence
      comparison revealed that most retrovirus envelope proteins have one or two
      conserved cysteine residues in their transmembrane domain. Mutations that change
      the palmitoylation state of the murine leukemia virus envelope protein did not
      affect its transport, processing, surface expression, or cell fusion activity.
      The palmitate-deficient viral envelope proteins were incorporated into virus
      particles, and replication of the virus in vitro was not affected significantly
      by the mutation of the palmitoylation site.

PMID- 8661418
TI  - Intracellular synthesis, processing, and transport of proteins encoded by ORFs 5
      to 7 of porcine reproductive and respiratory syndrome virus.
AB  - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), a small enveloped
      virus containing a positive-strand RNA genome, possesses at least three major
      structural proteins designated N, M, and E. The N protein is considered as the
      major component of the nucleocapsid, whereas M and E are membrane-associated.
      Previous studies using peptide-specific antibodies assigned these proteins to
      ORFs 7, 6, and 5, respectively. In the present report, monospecific antisera
      raised against Escherichia coli-expressed ORFs 5, 6, and 7 products were used to
      study the synthesis and processing of PRRSV structural proteins in the highly
      permissive MARC-145 cell line. Treatment of viral proteins with various
      glycosidases showed that only E was modified by N-linked glycans. Pulse-chase
      experiments revealed that intracellular transport of the major envelope
      glycoprotein was delayed in the premedial Golgi compartment. During the first 30
      min of chase, E undergoes a gradual downward shift of its apparent molecular
      weight, thought to result from trimming of the mannose-rich glycan structures.
      Once E is transported to the medial Golgi or proximal elements, some molecules
      undergo complete processing of all their high-mannose N-linked oligosaccharides
      to complex type, while in other molecules only a fraction of N-linked glycans are
      terminally glycosylated. These two differentially glycosylated forms of E were
      found to be incorporated into extracellular virions. In cells and virions, both M
      and E were shown to occur in heterodimeric complexes linked by disulfide bonds.
      The oligomerization process, as analyzed from pulse-chase experiments, showed
      that M and E are incorporated into M-E complexes with different kinetics and
      efficiencies, in a fashion similar to their counterparts in equine arteritis
      virus. Apparently, all steps of E protein N-glycans processing proceed after its
      association with M which occurs in the endoplasmic reticulum (ER). In the
      infected cells, E and M appear highly membrane-associated, while N is
      predominantly cytosolic.

PMID- 8661419
TI  - Interferon induction by HIV-1-infected cells: a possible role of sulfatides or
      related glycolipids.
AB  - We have investigated the mechanism of interferon (IFN) induction in peripheral
      blood mononuclear cells by HIV-1(IIIB)-infected H9 cells or by recombinant gp120.
      A monoclonal antibody specific for the galactosylsphingosinyl moiety in
      galactocerebrosides and sulfatides inhibited IFN induction in a dose-dependent
      manner. Furthermore, exogenous sulfatides inhibited with an ID50 of approximately
      1 microM, whereas galactocerebrosides were not inhibitory at 40 times higher
      concentrations. These studies suggest that sulfate containing galactolipids such
      as sulfatides on responder cells may be part of the gp120-membrane complex that
      initiates the induction of IFN. A partial homology of an epitope on the V3 loop
      of gp 120 with a previously suggested binding domain for sulfated glycoconjugates
      supports this conclusion.

PMID- 8661420
TI  - Ligation of double-stranded and single-stranded [oligo(dT)] DNA by vaccinia virus
      DNA ligase.
AB  - Vaccinia virus DNA ligase has been expressed in Escherichia coli, purified, and
      biochemically characterized. The enzyme ligates double-stranded (ds) DNA
      substrates with either cohesive or blunt-end termini and the latter reaction is
      stimulated by PEG. Vaccinia virus DNA ligase can also ligate oligo(dT) when
      annealed to either a poly(dA) or a poly(rA) backbone and, remarkably, free
      oligo(dT). This ligation of a single-stranded (ss) substrate is unique among
      eukaryotic DNA ligases. The enzyme requires high ATP concentrations with a Km for
      the overall ligation of a ssDNA substrate of 0.8 mM. The salt, divalent cation,
      temperature, and pH requirements of the enzyme for the optimal ligation of ss and
      ds substrate are described.

PMID- 8661421
TI  - Reexamination of the Sendai virus P protein domains required for RNA synthesis: a
      possible supplemental role for the P protein.
AB  - The Sendai virus P protein plays a central role in viral genome amplification and
      expression, forming complexes with the viral L protein to generate the polymerase
      (P-L) and unassembled N (P-N(o)). This latter complex prevents N from self
      assembling illegitimately, i.e., independently of the concurrent assembly of a
      nascent viral genome, and is thought to represent the functional form of N in
      nucleocapsid assembly. Based upon earlier functional studies using an in vitro
      transcription/ replication system in which the P, L, and N proteins were
      coexpressed, we identified two regions of the P protein required for RNA
      synthesis, namely, the C-terminal 40% of the protein, and a second, apparently
      redundant domain near the N-terminus (either amino acids 1-77 or 78-145). The
      lack of sequence conservation in this second region, apart from overall negative
      charge, was reminiscent of the acidic activation domains of cellular
      transcription factors. However, we recently mapped a chaperone domain at the N
      terminal of P (aa 33-41), which is required for stable complex formation with
      unassembled N(o) and, thus, for assembly and genome replication. In this present
      study we show that coexpression of N protein with P deletion mutants lacking this
      region (e.g., P delta 1-324) results in the sequestration of the mutant P by the
      illegitimately assembled form of N. As a consequence, P protein is unavailable
      for RNA synthesis from bona fide templates. We also find that in the absence of
      coexpressed N protein, the entire N-terminal 60% of the P protein is not required
      for mRNA synthesis. During these studies, a supplemental role for the P protein
      in viral RNA synthesis, independent of stable complex formation with L, was
      observed. This function involves, at least in part, the binding of additional
      copies of P to the N:RNA template.

PMID- 8661422
TI  - Poliovirus neurovirulence correlates with the presence of a cryptic AUG upstream
      of the initiator codon.
AB  - Poliovirus mutants with extended (> 150-nt) deletions in the 5'-untranslated
      region between the internal ribosome entry site and the initiator codon have been
      selected previously (Pilipenko et al., Cell 68, 119-131, 1992; Gmyl et al., J.
      Virol. 67, 6309-6316, 1993). These deletions were transferred into the genome of
      a mouse-pathogenic poliovirus strain and found to be strongly attenuating. The
      deletions can be considered as covering three structural elements, a stem-loop
      (domain E) with a conserved cryptic AUG and two spacers, upstream and downstream
      of it. In an attempt to identify putative essential determinants of
      neurovirulence in these individual structural elements, appropriate mutants were
      engineered. The results demonstrated that neither of the above elements is
      essential for neurovirulence. The results strongly suggested that the presence of
      a cryptic AUG in the oligopyrimidine/AUG tandem followed, at a sufficient
      distance, by the initiator codon was necessary to ensure the neurovirulent
      phenotype of our constructs. On the other hand, the attenuated phenotype appeared
      to correlate with the occurrence of the initiator AUG as a moiety of the
      oligopyrimidine/AUG tandem. Possible mechanisms underlying these effects are
      discussed. Identification of the cryptic AUG as an essential determinant for
      neurovirulence provides a rational basis for the design of genetically stable
      attenuated poliovirus variants.

PMID- 8661423
TI  - An early gene of the Chlorella virus PBCV-1 encodes a functional aspartate
      transcarbamylase.
AB  - PBCV-1 belongs to a family of large viruses that replicate in the exsymbiont
      green algae Chlorella strain NC64A. The viral, 330-kb DNA genome encodes a
      relatively large number of functionally active proteins including restriction and
      modification enzymes, DNA polymerase, glycosylation, and cell wall degrading
      enzymes. Sequencing of the viral DNA, now in progress, revealed many major open
      reading frames (ORF), which resemble known genes in sequence data bases and which
      have not previously been found in viral genomes. Here we report on the
      identification and characterization of one such gene, aspartate transcarbamylase
      (ATCase), an enzyme that catalyzes the committing step in the de novo
      biosynthetic pathway of pyrimidines. The cloned gene is highly homologous to a
      variety of plant ATCases and includes the typical ATCase catalytic motif. When
      cloned into the pGEX-2T expression vector, a fusion protein with ATCase activity
      could be demonstrated and distinguished from the host ATCase activity. The viral
      enzyme is expressed early and transiently in the infection. To our knowledge,
      this is the first virus known to encode and express its own de novo nucleotide
      precursors' synthetic enzymes.

PMID- 8661424
TI  - A Sendai virus vector leading to the efficient expression of mutant M proteins
      interfering with virus particle budding.
AB  - A Sendai virus expression vector in the form of a transcribing copy-back
      defective interfering RNA was constructed and shown to efficiently express a
      tagged matrix protein in the only context of a Sendai virus infection. In an
      attempt to identify relevant M protein domains involved in viral assembly and
      budding, a series of deletion mutants were tested for their ability to bind to
      cellular membrane fractions. The deletion of a region spanning amino acids 105
      137 significantly decreased this binding when the protein was expressed in a
      system driven by the T7 RNA polymerase away from any other viral proteins. Plus
      or minus charges were introduced in the hydrophobic portion of a predicted
      amphiphilic helix in this region, and M proteins with altered membrane binding
      properties were produced. The genes encoding these mutant M proteins were then
      inserted in the Sendai virus vector and shown to be expressed at levels similar
      to that of the endogenous wild-type M protein. The presence of a negative charge
      in the hydrophobic region of the putative amphiphilic helix prevented the
      incorporation of the mutant protein into virus particles and appeared to decrease
      the efficiency of virus particle budding. In contrast, the introduction of a
      positive charge appeared to increase the M mutant uptake into virions. The use a
      Sendai virus vector has therefore been shown instrumental in the identification
      of mutant M proteins interfering with the viral assembly-budding process.

PMID- 8661425
TI  - 293 cell lines that inducibly express high levels of adenovirus type 5 precursor
      terminal protein.
AB  - 293 cell lines that inducibly express high levels of adenovirus type 5 precursor
      terminal protein (pTP) under the control of a tetracycline-dependent promoter
      were constructed. To construct the cell lines expressing pTP, 293 cells were
      stably transfected with a plasmid encoding the tetracycline repressor/VP16
      transactivator protein (tTA) using selection with hygromycin. Cell lines that
      expressed high levels of tTA activity were then stably transfected with plasmids
      in which pTP expression is directed by the tTA-dependent promoter from either a
      cDNA or a modified genomic construct using selection with G418. Cell lines that
      expressed high, inducible levels of pTP efficiently complemented a temperature
      sensitive pTP mutant virus for growth and plaque formation at the nonpermissive
      temperature.

PMID- 8661426
TI  - Characterization of the heparin-mediated activation of PKR, the interferon
      inducible RNA-dependent protein kinase.
AB  - Heparin can substitute for double-stranded (ds) RNA in the autophosphorylation
      and activation of the interferon-inducible, RNA-dependent elF-2 alpha protein
      kinase (PKR). We have used heparin oligosaccharides of defined lengths to examine
      the heparin-mediated activation of human PKR. Heparin oligosaccharide with 8
      sugar residues was nearly as efficient as 16-residue heparin (Hep-16) in
      mediating the activation of PKR autophosphorylation, whereas 6-residue heparin
      was a poor activator. When examined in combination, Hep-16 and dsRNA did not act
      synergistically in activating PKR autophosphorylation. The RNA-binding activity
      of recombinant PKR, measured with adenovirus VA RNA, was competed by
      poly(rl):poly(rC) but not by Hep-16. When the catalytically inactive, histidine
      tagged mutant PKR protein [His-PKR(K296R)] was examined as a substrate for
      purified wild-type PKR, the intermolecular phosphorylation of His-PKR(K296R) was
      efficiently catalyzed by dsRNA-activated PKR but not by heparin-activated PKR.
      However, elF-2 alpha phosphorylation was catalyzed by both heparin-and dsRNA
      activated PKR. Preincubation of PKR with Hep-16 in the absence of ATP blocked
      subsequent autophosphorylation mediated either by Hep-16 or dsRNA, whereas
      preincubation with dsRNA either alone or in combination with Hep-16 did not
      impair subsequent autophosphorylation. Neither Hep-16 nor dsRNA caused a
      detectable degradation of PKR during preincubation or subsequent
      autophosphorylation of PKR. These results suggest that, while both dsRNA and
      heparin are capable of activating PKR autophosphorylation, the structural and
      functional basis of PKR activation differs for these two classes of polyanionic
      biomolecules.

PMID- 8661427
TI  - Variability and phylogeny of the L1 capsid protein gene of human papillomavirus
      type 5: contribution of clusters of nonsynonymous mutations and of a 30
      nucleotide duplication.
AB  - We analyzed the variability and established the phylogeny of the L1 capsid
      protein gene of 33 isolates of human papillomavirus type 5 (HPV5) obtained from
      epidermodysplasia verruciformis patients from different continents. By comparing
      the sequences of a 419-bp fragment with those published for two Japanese
      isolates, we found 12.9% variable nucleotide positions, defining 25 variants with
      mutation rates ranging from 0.2 to 8.8%. Such a high intratypic diversity is
      unusual among HPVs. Nine of the 139 encoded amino acids were variable and 12
      protein variants were identified. Fifteen of the 16 substitutions observed were
      clustered in two short regions. A 9-amino-acid insert, already reported for the
      Japanese HPV5b isolate, was found within one of the regions in five isolates. Our
      data support that the insert arose from the duplication of a 30-nucleotide
      sequence. Phylogenetic trees distributed the DNA variants into three subtypes (a
      to c) with a divergence higher than 4.5% and allowed the recognition of European
      and African lineages. By contrast with the trees based on the HPV5 E6 gene, HPV5a
      DNA variants and the HPV5b variants lacking the insert constituted a single group
      in the L1 amino acid tree, probably reflecting different levels of structural
      constraints for the HPV5 L1 and E6 proteins. In that respect, the short variable
      L1 sequences should represent less constrained regions.

PMID- 8661428
TI  - Organization of the 3'-terminal half of beet yellow stunt virus genome and
      implications for the evolution of closteroviruses.
AB  - The 3'-terminal half of the beet yellow stunt virus (BYSV) genome 10,545 nt, has
      been cloned and sequenced. The sequenced portion of the BYSV genome encompasses
      10 open reading frames (ORFs) and 241 nt of the 3' untranslated region. The
      sequence spans, in the 5' to 3' direction, the C-terminal region of the
      replication-associated polyprotein gene (ORF 1a) which includes the set of motifs
      typical of helicases (HEL), the entire 53-kDa polymerase (RdRp) gene (ORF 1b),
      and genes encoding 30-kDa (ORF 2), 6-kDa (ORF 3), 66-kDa (ORF 4), 61-kDa (ORF 5),
      25-kDa (ORF 6), 23.7-kDa (coat protein, CP) (ORF 7), 18-kDa (ORF 8), and 22-kDa
      (ORF 9) proteins. The double-stranded RNA "replicative form" of the BYSV was
      demonstrated to have a nontemplate G residue at the 3' terminus of the (+)
      strand. The RdRp of BYSV is presumably expressed via a +1 ribosomal frameshift.
      The five-gene module conserved among closteroviruses was identified in BYSV; it
      includes a gene array coding for a 6-kDa small hydrophobic protein, a 66-kDa
      homolog of the cellular HSP70 heat shock proteins, a 61-kDa protein, and a 25-kDa
      diverged copy of the CP followed by the CP gene itself. Phylogenetic analysis of
      the replication-associated HEL and RdRp domains as well as proteins from the five
      gene module demonstrated the closest relationship between BYSV and two other
      closteroviruses, beet yellows (BYV) and citrus tristeza (CTV) viruses. Like CTV,
      the BYSV genome contains a 30-kDa protein gene between the RdRp and the 6-kDa
      protein genes, and like BYV it has only two genes downstream of the CP gene. The
      organization of the BYSV genome appears to be intermediate between BYV and CTV,
      which suggests that these three viruses might represent three distinct but
      probably close stages in the closterovirus evolution.

PMID- 8661429
TI  - Nucleotide sequencing and generation of an infectious clone of adeno-associated
      virus 3.
AB  - We have determined the complete nucleotide sequences of adeno-associated virus 3
      (AAV-3) and generated an infectious clone. The single-stranded DNA genome of AAV
      3 is 4726 nucleotides in length. The positive strand contains two large open
      reading frames; the left open reading frame encodes the nonstructural proteins
      and the right open reading frame encodes the structural proteins. The coding
      regions are flanked by identical inverted terminal repeat sequences containing
      palindromes. AAV-3 has little homology with the autonomous parvoviruses or
      erythroviruses but has 82% overall sequence homology with AAV-2. At the amino
      acid level there was 88% homology with AAV-2 nonstructural (Rep) proteins and 87%
      homology with AAV-2 capsid proteins. In addition, AAV-3 differed importantly from
      AAV-2 in the lack of a typical promoter sequence (TATA box) at p40 and the
      presence of the consensus sequence for adenovirus-related transcription factor
      E4F binding within the upstream region of the p5 promoter. These results suggest
      that AAV-3 not only consists of serologically distinct structural proteins but
      that viral propagation also may be controlled by different gene regulatory
      elements at the transcription level. The infectious clone confirmed the sequence
      and may be useful for developing new vectors for gene therapy.

PMID- 8661430
TI  - Mapping nucleotides in the 126-kDa protein gene that control the differential
      symptoms induced by two strains of tobacco mosaic virus.
AB  - The differential symptom determinants of the Holmes' masked (M) and U1 strains of
      tobacco mosaic virus previously were mapped to the 5'-coterminal open reading
      frame (ORF) encoding the 126-kDa protein and the N-terminal two-thirds of the 183
      kDa protein. Both proteins influence viral RNA accumulation, but the function of,
      and impact on, symptom formation by large domains within the 126-kDa gene, which
      are not conserved with sequences in analogous ORFs from other related viruses,
      are unknown. In the current study, cDNA clones representing each strain (i.e.,
      MIC-TMV and U1-TMV) were mutated in these nonconserved domains to further define
      the nucleotides responsible for mosaic symptom induction on Nicotiana tabacum.
      Progeny virus of a mutant containing only eight nucleotide substitutions from the
      MIC-TMV sequence to the U1-TMV sequence within the 126-kDa protein ORF of MIC-TMV
      induced U1-TMV-like symptoms. Single or multiple substitutions among these eight
      nucleotides further defined residues critical for symptom modulation.
      Complementary substitutions in the MIC-TMV and U1-TMV sequences did not always
      yield progeny virus that induced complementary visual symptoms. Progeny of some
      mutants contained second-site spontaneous mutations at specific positions shown
      to influence symptom phenotype. For a subset of the stable site-directed mutants,
      there was no correlation between severity of systemic symptoms and chlorotic
      lesion size or virus accumulation in these chlorotic lesions on inoculated
      leaves.

PMID- 8661431
TI  - Evidence that the soluble factors secreted by activated immune cells suppress
      replication of human neurotropic JC virus DNA in glial cells.
AB  - Coordination of the immune response to viral infection and disease in the brain
      is believed to involve bidirectional interaction between the immune system and
      the central nervous system (CNS). Progressive multifocal leukoencephalopathy
      (PML) is a demyelinating disease of the CNS that generally affects patients
      exhibiting an immunocompromised condition due to various illnesses. The human
      polyomavirus, JCV, which infects greater than 70% of the adult population is the
      etiological agent of this disease. Infection with JCV occurs during childhood and
      the virus remains in the latent state with no apparent clinical signals. However,
      under immunocompromised conditions, the virus enters the lytic cycle, and upon
      cytolytic destruction of glial cells, causes PML. To understand the molecular
      mechanism underlying immune regulation of JCV replication, we have developed a
      cell culture system and have investigated the effect of soluble factors from T
      cell cultures on replication of JCV DNA in glial cells. Our data demonstrate that
      replication of JCV DNA in the presence of PMA-stimulated T-cell supernatant is
      substantially decreased in transfected glial cells. Heat-inactivation and size
      fractionation studies revealed participation of a heat labile factor(s) which
      loses its maximum activity at 60 degrees and ranges between 30 and 100 kDa in
      size. The unfractionated T-cell supernatant and the fraction enriched in 30- to
      100-kDa proteins reduced the level of viral DNA replication during the early
      phase of the lytic cycle. These observations suggest that regulatory factors
      which are secreted by immune cells may modulate the level of JCV DNA replication
      in glial cells. The importance of these observations in reactivation of JCV in
      immunocompromised individuals and development of PML is discussed.

PMID- 8661432
TI  - Both codon context and leader length contribute to efficient expression of two
      overlapping open reading frames of a cucumber necrosis virus bifunctional
      subgenomic mRNA.
AB  - The importance of codon context and leader length in the translational regulation
      of p20 and p21 from the bifunctional 0.9-kb subgenomic mRNA cucumber necrosis
      virus was investigated. Nucleotide substitutions introduced into the -3 and +4
      positions of the p21 AUG codon (where the A of the AUG is +1) verified that
      purines in these positions are favored and demonstrated the similar contribution
      of the -3 and +4 positions to the efficiency of initiation codon selection in
      plants. The effect of nucleotide substitutions in the +5 position, most clearly
      demonstrated when pyrimidines occupy the -3 and +4 positions, also provided
      direct insight into the influence of the +5 position in plants. The codon context
      of the upstream p21 initiation codon affected expression from the downstream p20
      AUG codon. In addition, an increase in the length of the subgenomic mRNA leader
      decreased expression from the downstream p20 initiation site. These latter
      observations are in accordance with the "Kozak rules" for accession of internal
      AUG codons by leaky ribosomal scanning and provide the first example of an effect
      of leader length on the efficiency of translation initiation in a plant (viral)
      mRNA.

PMID- 8661433
TI  - Lymphocytes are the major reservoir for foamy viruses in peripheral blood.
AB  - Simian and human foamy virus (FV) DNA can be readily detected in peripheral blood
      leukocytes. However, it is unknown which leukocyte populations harbor the virus
      in vivo. We, therefore, analyzed blood samples from nine African green monkeys,
      four chimpanzees, and two humans for the presence of foamy virus proviral DNA in
      different FACS-purified leukocyte populations, using a highly sensitive nested
      polymerase chain reaction (PCR). The CD8+ lymphocytes were PCR positive in all 15
      samples and the average viral burden was highest in this population. FV DNA was
      detected in 10 of 15 cell samples enriched for B lymphocytes, and 4 of 9 CD4+
      lymphocyte, 3 of 13 CD14+ monocyte, and 4 of 13 polymorphonuclear leukocyte
      samples. A highly sensitive reverse transcriptase PCR was performed to detect
      viral transcripts in peripheral blood leukocytes. All samples were negative. In
      conclusion, lymphocytes, and especially CD8+ T lymphocytes, were found to be a
      major target for foamy virus in the peripheral blood, but viral gene expression
      was not detected.

PMID- 8661434
TI  - Characterization of Nla protease from turnip mosaic potyvirus exhibiting a low
      temperature optimum catalytic activity.
AB  - Nuclear inclusion protein a (Nla) protease of turnip mosaic potyvirus is
      responsible for the processing of the viral polyprotein into functional proteins.
      The Nla protease was found to exhibit its optimum catalytic activity at
      approximately 15 degrees and a bell-shaped pH-dependent activity profile with a
      maximum at approximately pH 8.5. Kinetic studies showed that both Km and V(max)
      values were lower at 12 than at 25 degrees in all three different pH conditions,
      pH 7.0, 7.4, and 8.3, indicating that the higher activity at 12 degrees is due to
      the lower value of Km. Interestingly, the self-cleavage of the 27-kDa protease to
      generate the 25-kDa protease occurred more rapidly at 25 than at 12 degrees,
      implying that the C-terminal self-cleavage site may interfere with the binding of
      the peptide substrate to the active site of the protease. Mutations and deletions
      at the C-terminal cleavage site had no effect on the temperature dependence of
      the proteolytic activity, demonstrating that the C-terminal self-cleavage is not
      related to the low-temperature optimum catalytic activity. The fluorescence
      measurement of the Nla protease upon temperature variation revealed that the
      protease undergoes a large conformational change between 2 and 42 degrees and a
      drastic transition near 45 degrees, suggesting that the low-temperature optimum
      catalytic activity is due to the highly flexible structure of the Nla protease.

PMID- 8661435
TI  - Rotavirus stimulates IL-8 secretion from cultured epithelial cells.
AB  - Rotavirus is the most important cause of severe gastroenteritis in children
      worldwide. We have investigated cytokine responses to rotavirus infection of
      cultured intestinal epithelial cells. Interleukin 8 (IL-8) is a chemotactic and
      cell-activating cytokine that is synthesized by epithelial cells and induced in
      response to bacterial enteric pathogens. Rotavirus inoculation increased IL-8
      mRNA levels in cultured intestinal epithelial cells within 2 hr of infection. IL
      8 secretion increased 10(2)- to 10(3)-fold by 8 hr postinfection. Secretion of
      TNF alpha or IL-1 beta, cytokines which themselves increase IL-8 secretion, was
      not induced by rotavirus, nor was that of TNF alpha, IFN alpha, IFN gamma, or IL
      6. Neutralizing antibodies to TNF alpha or IL-1 alpha/beta did not affect the IL
      8 response. Secretion of IL-8 was dependent on an intact viral capsid, as single
      shell particles were inert. Neutralizing monoclonal antibodies (vp7-specific)
      that do not block cell attachment did block rotavirus stimulation of IL-8
      secretion, indicating that attachment to the cell surface is not a sufficient
      stimulus to induce IL-8. Genetically inactivated rotavirus was also effective for
      IL-8 induction, indicating that viral replication was not required. These data
      suggest that epithelial cytokine IL-8 may be an important mediator of the host
      response to viral gastroenteritis pathogens such as rotavirus.

PMID- 8661437
TI  - The 5' terminal sequence of alfalfa mosaic virus RNA 3 is dispensable for
      replication and contains a determinant for symptom formation.
AB  - Transgenic P12 tobacco plants, transformed with the replicase genes P1 and P2 of
      alfalfa mosaic virus (AIMV), can be infected with RNA 3 of the tripartitite AIMV
      genome or with a DNA copy of RNA 3 fused to the CaMV 35S promoter and nos
      terminator. The effect of various modifications on the infectivity of the
      35S/cDNA 3 construct to P12 plants was studied. When nonviral sequences ranging
      from 11 to 200 bp were inserted between the 35S promoter and cDNA 3, the
      infection became dependent on addition of coat protein (CP) to the inoculum.
      About 80% of the progeny RNAs resulting from these infections were full-length
      and had lost the nonviral sequence, whereas 20% were truncated by a deletion of
      the 5' terminal 79 nucleotides (nt). When the sequence corresponding to the 5'
      terminal 22 nt of RNA 3 was deleted from the 35S/cDNA 3 construct, the clone was
      as infectious as the wild type (wt), provided that CP was added to the inoculum,
      but only progeny RNA with a 5' terminal deletion of 79 nt was produced. The 5'
      truncated RNA 3 molecules induced necrotic ringspot-like symptoms on P12 tobacco
      plants, whereas wt RNA 3 did not induce detectable symptoms on these plants. It
      is proposed that in the infections with the modified 35S/cDNA 3 clones, CP is
      required in the inoculum to permit internal initiation of plus-strand RNA 3
      synthesis on 3'-extended or 3'-truncated minus-strand RNA templates. Evidence was
      obtained that minus-strand RNA 3 synthesized under the control of the 35S
      promoter was not infectious to P12 plants.

PMID- 8661436
TI  - Superinfection of HIV-2-preinfected macaques after rectal exposure to a primary
      isolate of SIVmac251.
AB  - To test the protection afforded by a weakly pathogenic HIV-2 isolate against the
      superinfection or development of SIV-induced disease, we intrarectally challenged
      six HIV-2-preinfected rhesus monkeys with a pathogenic isolate of SIVmac251. At
      the time of SIV challenge, none of these HIV-2-infected animals was positive for
      virus isolation, p27-Gag antigenemia, or HIV-2 provirus detection in PBMCs or
      peripheral lymph nodes. However, all monkeys exhibited anti-HIV-2 antibody titers
      ranging from 10(2) to 10(3). Neutralizing antibodies against the challenge SIV
      strain were also detected in two animals. After rectal exposure to SIVmac251,
      five of the six HIV-2-preinfected macaques were superinfected. SIVmac251 DNA
      sequences were detected repeatedly in the PBMCs of the five superinfected animals
      and the two controls, whereas no HIV-2 provirus was detected for 14 months
      postchallenge. The one monkey that resisted superinfection was negative for all
      SIV infection criteria. This monkey exhibited the highest anti-SIV ELISA and
      cross-neutralizing antibody titers on the day of SIV challenge. Preinfection with
      a weakly pathogenic HIV-2 ROD isolate protected one of six macaques from
      infection with the closely related pathogenic SIVmac251 isolate, but no
      protection from the progression of disease was evidenced in the other five.

PMID- 8661438
TI  - A dominant mutant form of the herpes simplex virus ICP8 protein decreases viral
      late gene transcription.
AB  - The herpes simplex virus (HSV) infected cell protein 8 (ICP8) is required for
      viral DNA replication and normal viral gene expression. Previous work in our
      laboratory has shown that ICP8 may play a role in stimulating late gene
      expression. In V2.6 cells which express the d105 mutant form of ICP8, synthesis
      of late proteins and accumulation of the late gC mRNA are reduced during HSV
      infection (Gao, M., and Knipe, D.M., J Virol. 65, 2666-2675, 1991). To determine
      if the negative effect of d105 ICP8 on the late gene expression was exerted at
      the transcriptional level, we measured the levels of mRNAs and transcription from
      three late genes, gC, UL47, and gD, in V2.6 cells and Vero cells infected with
      the HSV-1 wild-type virus. In infected V2.6 cells, the levels of late gC and UL47
      mRNA were 7- to 12-fold lower than those of infected Vero cells under conditions
      where the levels of viral DNA replication in these two cell types were similar.
      The transcription levels of these two late genes in infected V2.6 cells were
      reduced to similar extents (9- to 14-fold). The levels of accumulated mRNA and
      transcription of the early-late gD gene also showed parallel reductions in
      infected V2.6 cells (about 6-fold). In contrast, transcription of the beta pol
      gene was reduced only slightly (about 2-fold) by d105 ICP8. These results
      demonstrate that the d105 ICP8 inhibits expression of three viral late genes at
      the transcriptional level, and in general, the effect of d105 ICP8 on viral gene
      expression appears to correlate with the extent to which expression of the gene
      is stimulated by viral DNA synthesis.

PMID- 8661439
TI  - Terminal region sequence variations in variola virus DNA.
AB  - Genome DNA terminal region sequences were determined for a Brazilian alastrim
      variola minor virus strain Garcia-1966 that was associated with an 0.8% case
      fatality rate and African smallpox strains Congo-1970 and Somalia-1977 associated
      with variola major (9.6%) and minor (0.4%) mortality rates, respectively. A base
      sequence identity of > or = 98.8% was determined after aligning 30 kb of the left
      or right-end region sequences with cognate sequences previously determined for
      Asian variola major strains India-1967 (31% death rate) and Bangladesh-1975
      (18.5% death rate). The deduced amino acid sequences of putative proteins of > or
      = 65 amino acids also showed relatively high identity, although the Asian and
      African viruses were clearly more related to each other than to alastrim virus.
      Alastrim virus contained only 10 of 70 proteins that were 100% identical to
      homologs in Asian strains, and 7 alastrim-specific proteins were noted.

PMID- 8661440
TI  - Host cell effect upon glycosylation and antigenicity of human respiratory
      syncytial virus G glycoprotein.
AB  - Infection of different human epithelial cell lines with human respiratory
      syncytial virus (HRSV) revealed significant differences in the electrophoretic
      mobility of the viral attachment glycoprotein (G). Cell-type specific differences
      in G protein glycosylation were observed with certain lectins and sugar-specific
      reagents. Furthermore, substantial changes in the reactivity of the G
      glycoprotein with anti-G monoclonal antibodies were associated to the infected
      cell type. Strain-specific epitopes--present in a limited number of HRSV isolates
      of the same antigenic group--were particularly susceptible to cell-type-specific
      modifications of the mature G protein. Some of these epitopes, which were either
      exposed in the unglycosylated precursor or reproduced with synthetic peptides,
      were nonetheless masked in the mature G protein expressed in certain cell lines.
      Antigenic and electrophoretic mobility changes of the G glycoprotein were
      reverted in extracts of HEp-2 cells infected with HRSV grown in other cell types,
      indicating that phenotypic traits rather than selection of variants were
      associated to the above stated changes. These results highlight the importance of
      cell-type-specific modifications for HSRV G glycoprotein antigenicity and raise
      questions about the actual antigenic structure of this molecule when HRSV
      replicates in the respiratory tract.

PMID- 8661442
TI  - Genetic characterization and phylogeny of Sabia virus, an emergent pathogen in
      Brazil.
AB  - Sabia virus, one of five arenaviruses from South America known to cause
      hemorrhagic fever in humans, emerged in 1990 when it was isolated from a fatal
      case in Sao Paulo, Brazil. Subsequently, it has caused two laboratory-acquired
      infections. Its natural distribution and host are still unknown. Using viral RNA
      and multiple polymerase chain reaction products as templates, the nucleotide
      sequence of the small (S) RNA segment of Sabia virus, which codes for the
      nucleocapsid (N) and glycoprotein precursor, was determined. This virus shares an
      ambisense genome in common with other arenaviruses, although it has a unique
      predicted three stem--loop structure in the S RNA intergenic region. Phylogenetic
      analysis of a portion of the N gene sequence confirmed that Sabia virus is
      distinct from all other members of the Arenaviridae and shares a progenitor with
      Junin, Machupo, Tacaribe, and Guanarito viruses.

PMID- 8661441
TI  - The Tat and C2-V3 envelope genes in the molecular epidemiology of human
      immunodeficiency virus-1.
AB  - In this study HIV-1 proviral DNA sequences derived from 201 clones of the C2-V3
      env region and the first exon of tat were obtained from six HIV-1-infected
      heterosexual couples. These molecular data were used to confirm the
      epidemiological relationships. The ability of the molecular data to draw such
      conclusions was also tested. A bootstrap parsimony analysis of the C2-V3
      sequences showed one couple failed to cluster and only two couples clustered in
      more than 70% of the replicates. The rapid diversification of the C2-V3 region
      and the length of time that elapsed since the infection event may have limited
      the certainty of the conclusions that can be reached to infer epidemiological
      relatedness from this region. Using data from the tat region, all couples
      clustered, four of them in more than 80% of bootstrap replicates. A single clone
      from the tat region did not cluster with others from that patient or with those
      from that patient's partner, indicating that multiple clones are necessary to
      firmly establish phylogenetic linkage. Nevertheless, the tat region was much more
      useful in establishing epidemiological relationships among this group than the
      commonly used C2-V3.

PMID- 8661443
TI  - Syncytia formation induced by coronavirus infection is associated with
      fragmentation and rearrangement of the Golgi apparatus.
AB  - Coronavirus mouse hepatitis virus (MHV) possesses a membrane glycoprotein (M)
      which is targeted to the Golgi apparatus (GA). We used immunocytochemistry with
      an organelle-specific antiserum to investigate the morphologic changes of the GA
      during infection of L2 murine fibroblasts with MHV-A59. Twenty-four hours after
      infection the GA was fragmented and translocated in the center of syncytia, while
      the microtubular network was also rearranged displaying radiating elements toward
      the center of syncytia. Two fusion-defective mutants, which contain an identical
      amino acid substitution in the cleavage signal sequence of the spike glycoprotein
      (S), induced fragmentation of the GA. However, the GA migrated only partially to
      the centers of syncytia during infection with these mutants. Revertant viruses,
      in which the above mutation was corrected, had fusion properties and GA staining
      similar to wtMHV-A59. Experiments with brefeldin A (BFA), which induces
      redistribution of the GA into the rough endoplasmic reticulum (RER), revealed
      that an intact GA for a period of 4-16 hr postinfection, is required for
      coronavirus replication and syncytia formation. Thus, during MHV infection,
      syncytia formation is associated with fragmentation of the GA, followed by a
      previously undescribed phenomenon of migration of the organelle into the centers
      of syncytia. The fragmentation of the GA, however, may occur without the
      formation of syncytia. Therefore, two distinct mechanisms may be responsible for
      the fragmentation of the GA and its subsequent migration to the center of
      syncytia.

PMID- 8661444
TI  - Proteolytic activity of purified avian sarcoma and leukemia virus NC-PR protein
      expressed in Escherichia coli.
AB  - Processing of the internal structural and enzymatic proteins of retroviruses
      occurs during or shortly after budding and is accomplished by the viral protease
      (PR), which belongs to the large family of aspartic proteases. It is not known
      how the activity of PR is regulated so that proteolysis occurs at this time.
      Cellular aspartic proteases are synthesized as zymogens with short N-terminal
      extensions that are proteolytically removed to generate the free active enzyme.
      In the avian sarcoma and leukosis viruses (ASLV), PR is expressed as the carboxy
      terminal domain of the Gag polyprotein, which thus has a structure analogous to
      such a zymogen. We have investigated the enzymatic properties of ASLV PR when it
      is part of a longer protein, NC-PR, serving as a model for Gag. This protein
      represents about one-third of Gag and consists of the nucleocapsid (NC) domain
      fused to the N-terminus of PR. NC-PR and derivatives of NC-PR were expressed in
      bacterial cells and purified. In short-term assays, these fusion proteins lacked
      measurable protease activity toward an exogenous substrate prepared by in vitro
      translation. In contrast to PR, which is a homodimer, NC-PR migrated as a monomer
      both by glycerol gradient sedimentation and by gel filtration chromatography.
      Thus the NC domain appears to inhibit enzymatic activity by altering the
      dimerization potential of the PR domains. However, upon long incubations NC-PR
      was found to cleave itself to generate free and fully active PR, implying that
      dimerization was not prevented entirely. On the basis of these results, we
      hypothesize that the Gag protein in vivo is also incompletely active as a
      protease, because upstream portions of Gag interfere with proper interaction of
      the PR domains. The eventual dimerization, perhaps triggered by other events,
      then could lead to a cascade whereby PR is proteolytically freed from Gag and
      thereby gains enzymatic activity.

PMID- 8661446
TI  - SFV topoisomerase: sequence specificity in a genetically mapped interval.
AB  - Poxviral DNA topoisomerases are sequence-specific enzymes whose activities are
      thought to influence such diverse processes as transcription, DNA replication,
      and genetic recombination. To obtain further insights into the relatedness of
      these enzymes, and their influence on virus-mediated recombination, we have
      determined the target-specificity and other catalytic properties of the Shope
      fibroma virus (SFV) topoisomerase. SFV topoisomerase was expressed in Escherichia
      coli and purified as a glutathione S-transferase (GST) or (his)6-tagged fusion
      protein. The recombinant Leporipox-virus (SFV) enzyme displayed catalytic
      properties very similar to vaccinia topoisomerase. In particular SFV
      topoisomerase recognizes the same pentanucleotide motif [5'-(C/T)CCTT-3'] and
      promotes the same DNA relaxation, strand transfer, and strand cleavage reactions
      catalyzed by the Orthopoxviral (vaccinia) enzyme. The SFV enzyme can also
      efficiently cleave DNA 3' of the variant site 5'-CCCTG-3' in certain sequence
      contexts. These studies identified several sites where SFV topoisomerases
      interact with a recombinational substrate and permitted a comparison of
      recombination frequencies across intervals which did, or did not, span these
      sites. We failed to detect any effect of topoisomerase-recognition sites on
      recombination frequencies, except for a small (< 2-fold) stimulation seen when
      the substrates encoded a nearby poxviral promoter. This and other work shows that
      poxviral topoisomerases from several genera share common target specificities,
      but other enzymatic systems probably catalyze the high-frequency recombination
      seen in poxvirus-infected cells.

PMID- 8661445
TI  - Sequence analysis of a highly divergent HIV-1-related lentivirus isolated from a
      wild captured chimpanzee.
AB  - Two strains of simian immunodeficiency viruses (SIV) isolated from chimpanzees
      (SIVCPZ-GAB and SIVCPZ-GAB2) originating from Gabon have previously been
      genetically characterized and shown to belong phylogenetically to the same
      lineage as the human immunodeficiency virus type 1 (HIV-1). We describe the
      sequence analysis of a third HIV-1-related virus, SIVCPZ-ANT, isolated from a
      wild captured chimpanzee originating from Zaire. This virus displayed the same
      genetic organization as HIV-1 and was found to fall on the same lineage as HIV-1
      and SIVCPZ-GAB. Protein sequence identity with SIVCPZ-GAB ranged from 72% (Pol)
      to 48% (Env) for the structural proteins, while a particularly divergent Vpu was
      found (only 25% identity to SIVCPZ-GAB). The V3 regions of the SIVCPZ isolates
      were exceptionally conserved in contrast to the high divergence of V3 among HIV-1
      isolates. However, SIVCPZ-ANT did not show a greater degree of sequence
      similarity with SIVCPZ-GAB than with HIV-1 isolates and represents a quite
      divergent outgroup of the HIV-1 lineage. Our data suggest multiple introductions
      of HIV-1 in the human population and shed new light on the origin of the HIV-1
      pandemic.

PMID- 8661447
TI  - Identification of a variable region at the carboxy terminus of SV40 large T
      antigen.
AB  - The entire early regions of three human isolates of simian virus 40 (SV40), as
      well as two laboratory strains recovered from monkeys, were sequenced. The early
      coding region of each isolate contains a number of nucleotide differences when
      compared to the reference strain SV40-776. These differences result in some
      changes in the predicted amino acid sequence of the unique region of small t
      antigen and in the carboxy (C) terminus of large T-antigen. The amino acid
      sequence of the remainder of large T-antigen was absolutely conserved among all
      isolates. Thus, SV40 large T-antigen contains a variable domain at the C-terminal
      end of the molecule.

PMID- 8661448
TI  - Transactivation of the two promoters of SFV-3 by different mechanisms.
AB  - Simian foamy virus type 3 (SFV-3), a member of the spumavirus genus of
      retroviruses, has a complex genome organization and encodes two open reading
      frames (ORFs), in addition to the structural genes gag, pol, and env. ORF-1
      encodes a viral transcriptional transactivator designated Taf (transactivator of
      foamy viruses) which augments transcription from the viral long terminal repeat
      (LTR). It was recently shown that human foamy virus, as well as the simian
      viruses SFV-1 and SFV-3, contains a second internal transcriptional promoter in
      the transmembrane domain of the env gene; this promoter also is transactivated by
      Taf. Here we report the characterization of the internal promoter of SFV-3. The
      transcriptional start site of this promoter has been mapped in two different SFV
      3-infected cell lines to nt position 9761 in the proviral genome of SFV-3. All
      cis-regulatory elements required for transactivation by Taf are located between 
      202 and -32 (+1 representing the transcription initiation site in the internal
      promoter). Analysis of hybrid promoter constructs and deletion mutants in
      transient expression assays revealed that this region contains two elements which
      are independently responsive to Taf. In addition, we employed an in vivo DNA
      competition assay to determine whether the transactivation mechanisms of both SFV
      3 promoters are similar or different. The differences observed utilizing this
      competition assay suggest that Taf transactivates the internal promoter and the
      LTR through different cellular transcription factors.

PMID- 8661449
TI  - Isolation and characterization of Marek's disease virus (MDV) cDNAs from a MDV
      transformed lymphoblastoid cell line: identification of an open reading frame
      antisense to the MDV Eco-Q protein (Meq).
AB  - Two Marek's disease virus (MDV) cDNAs of 852 and 1168 bp, which map to the right
      end of the BamHI-I2 fragment of the MDV genome, were isolated from a cDNA library
      derived from the MDV transformed lymphoblastoid cell line MKT-1. These cDNAs
      hybridized to relatively abundant leftward mRNA transcripts in MKT-1 cells and
      cells lytically infected with MDV. The transcriptional initiation site for these
      transcripts was located in the adjacent BamHI-Q2 fragment, as determined by RNase
      protection and primer extension assays. A computer search for the presence of
      leftward open reading frames (ORFs) revealed two ORFs encoding 135- and 195-amino
      acid polypeptides. A polyclonal antibody raised against a protein sequence in the
      N-terminus of the latter ORF detected a 23-kDa protein in the nuclear fraction of
      MDV-transformed lymphoblastoid cells. Furthermore, this ORF was antisense to part
      of the MDV Eco-Q protein (Meq) sequence.

PMID- 8661450
TI  - Infection and cellular activation by human T-cell leukemia viruses, types I and
      II.
AB  - Resting peripheral blood mononuclear cells (PBMC) or purified T-cells can be
      induced to proliferate when cocultured in vitro with fixed HTLV-infected T-cells.
      This process of HTLV-dependent cellular activation and induction of proliferation
      has been considered distinctive because of an apparent independence from
      conventional T-cell costimulatory signals. We have examined several HTLV-infected
      cell lines and found that proliferation was readily induced in resting PBMC by T
      cells that were productively-infected with HTLV. However, equivalent HTLV
      productive infection in a B-cell line failed to induce proliferation in PBMC,
      suggesting that HTLV-dependent induction of proliferation in PBMC was, at least
      in part, dependent upon a T-cell-specific signal. Furthermore, the induction of
      proliferation in PBMC populations was found to overlap with, and actually
      require, transfer and establishment of HTLV infection within the T-cell
      compartment of the PBMC population. These findings suggest that virus-induced
      activation of target cells may be directly associated with transfer and spread of
      HTLV infection.

PMID- 8661452
TI  - DT-diaphorase induction by lead acetate in the liver of rats.

PMID- 8661453
TI  - High levels of HCB and DDE associated with reproductive failure in prairie
      falcons (Falco mexicanus) from California.

PMID- 8661454
TI  - Volatile N-nitrosamines in selected Italian cheeses.

PMID- 8661455
TI  - Organochlorine pesticide residues in human breast milk from tropical areas in
      Mexico.

PMID- 8661456
TI  - Loss of pirimicarb residues from contaminated fabrics.

PMID- 8661457
TI  - Assessment of biodegradability of organic acids by a defined microbial mixture.

PMID- 8661458
TI  - Variations of volatile chlorinated hydrocarbons in ambient air at industrial
      areas in Niigata.

PMID- 8661459
TI  - Delta-aminolevulinic acid dehydratase activity in weanling and adult rats exposed
      to lead acetate.

PMID- 8661460
TI  - Mutagenic activity (Ames test) of wood-preserving waste sludge applied to soil.

PMID- 8661461
TI  - Comparative toxicity in earthworms Eisenia fetida and Lumbricus terrestris
      exposed to cadmium nitrate using artificial soil and filter paper protocols.

PMID- 8661462
TI  - Toxicity of phenol and monochlorophenols to growth and metabolic activities of
      Pseudomonas.

PMID- 8661463
TI  - Quantitative structure-activity relationships and mixture toxicity studies of
      heterocyclic nitrogen compounds.

PMID- 8661464
TI  - Toxicity test of Nanji Island landfill (Seoul, Korea) leachate using Japanese
      Medaka (Oryzias latipes) embryo larval assay.

PMID- 8661465
TI  - Toxicity and accumulation of mercury in three species of crabs with different
      osmoregulatory capacities.

PMID- 8661466
TI  - Inhibitive effect of organotin compounds on the chlorophyll content of the green
      freshwater alga Scenedesmus quadricauda.

PMID- 8661467
TI  - Correlation between the in vitro cytotoxicity of inorganic metal compounds to
      cultured fathead minnow fish cells and the toxicity to Daphnia magna.

PMID- 8661468
TI  - Organochlorine compounds in three species of shellfish from Waikareao Estuary,
      Tauranga Harbour, New Zealand.

PMID- 8661469
TI  - Effects of vanadium on population growth and Na-K-ATPase activity of the brackish
      water hydroid Cordylophora caspia.

PMID- 8661470
TI  - Effects of cadmium and environmental pollution on metallothionein and cytochrome
      P450 in tilapia.

PMID- 8661471
TI  - Toxicity of fluoranthene to Daphnia magna, Hyalella azteca, Chironomus tentans,
      and Stylaria lacustris in water-only and whole sediment exposures.

PMID- 8661472
TI  - Accumulation of tetradifon in an algae (Nannochloris oculata) and the cladoceran,
      Daphnia magna.

PMID- 8661473
TI  - Bioaccumulation and lethal body burden of four triorganotin compounds.

PMID- 8661474
TI  - Distribution of oil and grease and petroleum hydrocarbons in the Straits of
      Johor, peninsular Malaysia.

PMID- 8661475
TI  - Grain size effect on trace metals distribution in sediments from two coastal
      areas of Chile.

PMID- 8661476
TI  - Correlation of ultrasound velocity in the tibial cortex, calcaneal
      ultrasonography, and bone mineral densitometry of the spine and femur.
AB  - We compared the attributes of tibial cortex speed of sound (SOS) measurements
      with the SOS and broadband ultrasound attenuation (BUA) of the calcaneus, and
      bone mineral densities of the lumbar spine and femoral neck in a patient
      crossover study. The three instruments used in the crossover study were the LUNAR
      DPX and AchillesTM, and a newly introduced device for measuring tibial cortical
      SOS, the SoundScanTM 2000. Ultrasound precision determinations on the two
      instruments were performed with the same group of 10 volunteers, and the bone
      densitometry precision was derived from 22 patients who were assessed twice in a
      single visit, with repositioning between spine and hip scans. There were 220
      female patients in the clinical study, 28 of whom had thoracic spine fractures,
      and all had measurements with the three instruments. Of the three instruments,
      the best precision, or lowest coefficient of variation and standardized
      coefficient of variation, was obtained with the SoundScanTM 2000; 0.20% and
      1.39%, respectively. The tibial SOS correlated more poorly with the lumbar spine
      and femoral neck bone mineral densities (BMDs) than the calcaneal parameters in
      220 patients. Tibial SOS measurements could not distinguish the group with spinal
      fracture from an age-matched control group to a P < 0.05 level, whereas the
      lumbar spine BMD and calcaneal BUA and stiffness showed a significant difference.
      We conclude that the SoundScanTM 2000 system measures propagation of sound in the
      tibial cortex with great precision, but its role in clinical practice is moot.
      Yet to be established by a long-term prospective study is its efficacy in
      predicting fracture risk and how well it reflects bone change in response to
      treatment of osteoporosis.

PMID- 8661477
TI  - Ultrasound velocity of the tibia in normal German women and hip fracture
      patients.
AB  - One of the latest developments in quantitative ultrasound (QUS) is the
      measurement of the speed of sound (SOS) of cortical bone of the midtibia. To
      determine the diagnostic validity of this method we measured 150 healthy women
      aged 22-94 years. Additionally, we report on first results of patients with hip
      fracture. Precision in vivo of the tibial QUS expressed as the percentage
      coefficient of variation (CV) was 0.39% for the first day and 0.45% after
      repositioning the second day (mean CV = 0.42%). No significant dependency of
      tibial SOS was found with weight, height, and body mass index in pre- and
      postmenopausal women. There was a significant decline of SOS with age in
      postmenopausal women (SOS = 4225 - 5.3 age, r = -0.46, P < 0. 001), whereas
      premenopausal women showed no decline (SOS = 3906 + 1. 3 age, r = 0.13, ns) Mean
      SOS values of premenopausal women were significantly higher than those of
      postmenopausal women (3960 +/- 78.7 m/second and 3898 +/- 120 m/second,
      respectively, P < 0.001). Postmenopausal women on estrogen substitution had
      significantly higher mean tibial SOS values than age-comparable postmenopausal
      women without estrogen substitution (3980 +/- 99 m/second and 3869 +/- 100
      m/second, respectively, P < 0.001). Significant difference between age-matched
      healthy women, n = 11, and hip fracture patients, n = 13, expressed as z-score of
      -1.4 SD was found. In conclusion, tibial QUS declines with age and detects higher
      values in premenopausal women and postmenopausal women on estrogen substitution
      and lower values in hip fracture patients. Further prospective studies are needed
      to clarify its role in fracture risk assessment.

PMID- 8661478
TI  - Gender and race differences in bone mass during infancy.
AB  - The purpose of this study was to determine whether race or gender differences in
      total body bone mineral content (BMC) are evident within the first 18 months of
      age. Total body bone mineral measurements were obtained on 64 healthy infants 1
      18 months of age. There were no significant differences in age, weight, or height
      between race and gender groups. Taking into account weight and age, both bone
      mineral density (BMD) and BMC were greater in male infants compared with female
      infants (both, P = 0.02) and BMD was slightly higher in black infants compared
      with white infants (P = 0.07).

PMID- 8661479
TI  - Quantitative computed tomography for measuring bone mineral density in athletes.
AB  - We studied the effect of different training patterns on vertebral trabecular and
      cortical bone mineral density (BMD) in male athletes using quantitative computed
      tomography. Vertebral trabecular (t) and cortical (c) BMDs of the first three
      lumbar vertebrae were measured using single energy quantitative computed
      tomography in 51 athletes including 10 weight lifters (mean age 20 years), 13
      soccer players (mean age 27 years), 28 wrestlers (mean age 17 years), and 45 age
      matched volunteers (mean age 21 years). Measured BMDs were correlated with age,
      body height and weight, training hours per week, sports years, and type of
      physical activity. Vertebral tBMDs were found to be 44%, 23%, and 24% higher in
      the weight lifters, soccer players, and wrestlers, respectively, compared with
      the volunteers. The corresponding cBMDs were 18%, 6%, and 11% higher than that of
      volunteers. There was significant correlation between the trabecular and cBMD,
      and height of the athletes, sports years, training hours per week, and physical
      activity. The most significant correlation with BMD was the type of physical
      activity. Both the height of the subjects and physical activity variables showed
      variations of 47% and 32% in trabecular and cBMD, respectively. According to the
      multiple analysis of variance (MANOVA) only the physical activity factor was
      effective, with a significance level of P < 0.01; the other factors and
      interactions were not effective (P > 0.05) on trabecular and cBMD. Different
      training patterns have a different anabolic effect on both trabecular and cBMDs
      of the vertebrae, and this effect is more pronounced on the trabecular
      compartment. Weight lifting showed the highest anabolic effect on both trabecular
      and cBMDs compared with soccer playing and wrestling. Of the independent
      variables, physical activity showed the highest anabolic effect on the vertebrae.
      These results may have implications for devising exercise strategies to reduce
      the possibility of fracture in old age.

PMID- 8661480
TI  - Local bone mineral density, muscle strength, and exercise in adolescent boys: a
      comparative study of two groups with different muscle strength and exercise
      levels.
AB  - The primary objective of the present study was to evaluate the impact of physical
      activity and muscle strength on bone mineral density (BMD) of the tuberositas
      tibiae in adolescent boys. Two groups with different exercise levels were
      compared. The high activity group consisted of 20 subjects (age 15.9 +/- 0.3)
      from a junior ice hockey team. The reference group consisted of 24 volunteers
      (age 15.9 +/- 0.3) not training for more than 3 hours per week. The groups were
      matched for age, weight, and pubertal stage. BMDs (g/cm2) of the tuberositas
      tibiae and proximal tibia were measured using dual energy X-ray absorptiometry.
      Quadriceps strength was significantly higher in the high activity group (P <
      0.01). Univariate correlations were measured between tuberositas tibiae BMD and
      pubertal stage, weight, height, BMI, fat mass, lean body mass, quadriceps
      strength, and hamstrings strength in the high activity group and the reference
      group, respectively. Quadriceps strength was estimated to be the best significant
      predictor of BMD of the tuberositas tibiae in the reference group. A multivariate
      analysis confirmed this result. In the high activity group, there was no
      significant predictor of BMD of the tuberositas tibiae. There was no significant
      difference in BMD at this site when comparing the two groups. However, five of
      the boys in the high activity group had a former history of Mb Osgood-Schlatter
      with a significantly lower BMD of the tuberositas tibiae than the rest of the
      boys in that group. After exclusion of these boys, the remaining 15 boys were
      matched against 20 boys from the reference group using the previous criteria.
      These 15 boys then showed a significantly higher BMD of the tuberositas tibiae (P
      < 0.05) but not of the proximal tibia than the 20 boys in the reference group. In
      conclusion, this study demonstrates site-specific increments of tuberositas
      tibiae BMD in adolescent ice hockey players unless they are affected by the
      negative effects on BMD by Mb Osgood-Schlatter. These increments seem primarily
      to be associated with forceful muscle contractions related to high quadriceps
      strength and not greater weight-bearing loading. Muscle strength seems to
      positively affect BMD of the tuberositas tibiae in adolescents, but only up to a
      certain level, above which additional muscle strength has no effect.

PMID- 8661481
TI  - Classification of osteoporosis in the elderly is dependent on site-specific
      analysis.
AB  - Vertebral osteoporosis accounts for over 500,000 spinal fractures annually, the
      majority of which occur in older women. Despite these statistics, data regarding
      the rate of spinal bone loss in this population are conflicting. Moreover, the
      site of skeletal evaluation may significantly alter classification of
      osteoporosis in this age group. To examine trabecular-rich spinal bone loss with
      a measurement less affected by age-related artifacts than the AP spine, we
      measured lateral lumbar spine bone density (BMD) using dual-energy X-ray
      absorptiometry in 120 healthy, ambulatory, community-dwelling women 65 years of
      age and older (mean 70 +/- 5 years, range 65-88). We also examined cortical-rich
      sites in the forearm and total body along with AP spine and femoral BMD to assess
      the impact of site specificity using the World Health Organization (WHO)
      classification of osteoporosis. Significant losses in BMD were observed at the
      lateral spine (-1.1%/year, P < 0.01), forearm (-0. 77%/year, P </= 0.01), total
      hip (-0.75%/year, P </= 0.01), femoral neck (-0.70%/year, P </= 0.05), and
      trochanter (-0.78%/year, P </= 0. 01), but not the AP spine. Using the WHO
      criteria, lateral spine BMD determinations classified 66% of women with
      osteoporosis in contrast to 29% using the AP projection. Osteoporosis was
      diagnosed in 55% of women using measurements of the femoral neck, 43% using the
      total radius, and 19% using the total body. We conclude that elderly women lose
      bone at trabecular- and cortical-rich sites (lateral spine and total radius,
      respectively) in addition to sustaining significant age-related bone loss at
      mixed cortical/trabecular sites such as the hip. Classification of osteoporosis
      in this age group more than doubles using lateral versus AP spinal projections,
      supporting the necessity of developing more uniform agreement on site-specific
      analyses.

PMID- 8661482
TI  - Bone mineral density in Chinese elderly women with hip fracture.
AB  - In order to examine the status of osteoporosis of the patients with hip fracture,
      we assessed the bone mineral density (BMD) of the contralateral hip of 81 elderly
      females with hip fracture and compared those with 77 normal Chinese women. The
      age of fracture subjects was 73.5 +/- 6.6 years (mean +/- SD), and 69.2 +/- 6.9
      years for the controls. All of these fractures were caused by minor trauma, such
      as falls from a standing position or slipping to the ground. The Norland 2600
      dual-photon absorptiometer (DPA) was used to evaluate the BMD in the femoral
      neck, trochanter, and Ward's triangle areas. The BMD for the fracture subjects
      was significantly lower than those of the controls. By linear regression, the
      probability of fracture increased exponentially with age and low BMD. The mean
      BMD for femoral neck of the fracture subjects versus controls was 0.556 versus
      0.624 g/cm2; for trochanter: 0.505 versus 0.566 g/cm2; for Ward's triangle: 0.432
      versus 0.485 g/cm2. Both negative predictive value (NPV) and positive predictive
      value (PPV) were acceptable at the prevalence of hip fracture of 5% or 20% and at
      a cutoff point of 0.65 g/cm2. These data revealed that the degree of relative
      osteoporosis in the patients with hip fractures was more severe than that of
      controls.

PMID- 8661483
TI  - Inhibition of parathyroid hormone-stimulated resorption in cultured fetal rat
      long bones by the main metabolites of ipriflavone.
AB  - Ipriflavone is an isoflavone derivative used in the prevention and treatment of
      postmenopausal and senile osteoporosis in humans. To assess the potential
      contribution of the main in vivo ipriflavone metabolites (M1, M2, M3, and M5) on
      the pharmacological properties of the drug, we investigated their effect on
      osteoclastic resorption induced by the well-known stimulator of bone resorption
      bovine parathyroid hormone fragment 1-34 (bPTH 1-34). The study was carried out
      using fetal rat long bones in stationary cultures. The amount of osteoclastic
      resorption was determined by assaying for 5 days the release from bones in the
      media of previously incorporated 45Ca. All metabolites were effective at
      inhibiting osteoclastic resorption. Maximal potency was shown by M3,
      characterized by a significant effect at 10 microM (P < 0.01) and by an IC50
      value of 17 microM. M2 was about threefold less potent than M3 (IC50 = 46
      microM). M1 and M5 were the least active compounds with an IC50 value of 117 and
      200 microM, respectively. The present evidence indicates that metabolites of
      ipriflavone, in particular M3 and M2, inhibit bPTH 1-34-induced bone resorption
      in fetal rat long bones. Accordingly, they may play an important role in the
      pharmacological effects of the drug.

PMID- 8661484
TI  - Bicarbonate dependence of ion current in damaged bone.
AB  - The aim of this work was to characterize the ion current that enters mouse
      metatarsal bones following damage to the cortex. We assessed both the spatial
      distribution of this current and its dependence on the presence of bicarbonate in
      the medium. We used a voltage-sensitive probe system vibrating in two dimensions
      and recorded the signal as function of the position of the probe with respect to
      the site of damage and of ion substitutions in the medium. When the cortex was
      damaged (50 microm cylindrical hole penetrating into the marrow cavity), we
      recorded a steady state net inward electrical current directed toward the site of
      damage. In nonbicarbonate media, the density of the current was maximal near the
      center of the hole and ranged from 6 to 18 microA/cm2. As the probe was moved off
      the center of the hole, measured current density decreased in a manner consistent
      with the hypothesis that the source of the inward current is localized to the
      hole. After changing bicarbonate concentration in the medium from 0 to 42 mM, the
      current density nearly doubled, then decayed back to its original level
      exponentially over 35 minutes. When the diaphysis of living bone was left intact
      the current density was close to background level either in the presence or
      absence of bicarbonate in the medium. Damaged dead bone did not drive any current
      higher than background level. We conclude that the vibrating probe technique is a
      powerful tool to characterize ion currents in injured bone, helping to understand
      the physiology of bone-plasma interface and the bone healing processes. The
      current density transiently doubled upon addition of bicarbonate, indicating that
      this ion may carry the electrical current in damaged bone, probably by pump-leak
      mechanisms operating at the bone-plasma interface.

PMID- 8661485
TI  - Retinoids modulate the effect of PTH and calcitriol on EGF receptor expression in
      UMR 106-01 cells.
AB  - Although osteoblast proliferation is a prominent feature of osteitis fibrosa,
      studies in vitro using osteoblast-like cells have shown that parathyroid hormone
      (PTH) impairs cell growth. Recent studies in our laboratory have shown that PTH
      increases epidermal growth factor (EGF) receptor expression in UMR 106-01
      osteoblast-like cells, and thus, osteoblast proliferation may occur as a result
      of an enhanced response of the osteoblast to EGF. In the present studies we
      investigated the effect of calcitriol and the influence of retinoids on the
      regulation of EGF receptors. Calcitriol increased 125I-EGF binding 2.5-3-fold
      after 72 hours of incubation and was maximal at a calcitriol dose of 100 nM.
      Scatchard analysis showed that this effect was due to increased receptor number.
      In contrast, all-trans retinoic acid or 9-cis retinoic acid alone, even at 10
      microM, caused less than a 50% increase in 125I-EGF binding. However, the effect
      of calcitriol was totally abolished in the presence of all-trans retinoic acid. 9
      cis retinoic acid was equivalent with all-trans retinoic acid in this regard. In
      the presence of either retinoid, the stimulatory effect of PTH was totally
      eliminated and EGF binding was actually decreased below control values.
      Additional studies revealed that retinoic acid decreased PTH-stimulated cAMP
      generation in a dose-dependent manner. These data are consistent with our
      previous studies which showed that the effect of PTH on the induction of EGF
      receptors was mediated by a cAMP-dependent mechanism. The inhibition of the
      calcitriol effect by retinoids is consistent with the requirement of the retinoid
      X-receptor (RXR) for binding of the vitamin D receptor (VDR) to its target
      sequences in DNA. These data indicate that EGF receptors in UMR 106-01 cells are
      up-regulated by PTH and calcitriol and that this process can be modulated by
      retinoids. Retinoids, therefore, may play a major role in the regulation of
      osteoblast function by PTH and calcitriol.

PMID- 8661487
TI  - Effect of bisphosphonates on the increase in bone resorption induced by a low
      calcium diet.
AB  - This study investigates whether bisphosphonate-treated rats are still able to
      adapt to low calcium supply through an increase in bone resorption assessed by
      measuring the urinary excretion of [3H]-tetracycline from chronically prelabeled
      rats. First it was shown that in this model, parathyroid hormone was responsible
      for the increase in bone resorption on the low calcium diet. In the second part,
      animals were treated with the three bisphosphonates-clodronate, alendronate, and
      ibandronate-given in two doses. Animals receiving a dose that already strongly
      inhibits bone resorption were still able to respond to a low calcium diet by
      increasing bone resorption, showing the potency of the latter as a stimulator of
      bone resorption. Higher doses were, however, able to blunt this response. As soon
      as the treatment was discontinued, this increase in bone resorption resumed with
      clodronate but not with alendronate or ibandronate.

PMID- 8661486
TI  - An ultrastructural and immunogold localization study of proteoglycans associated
      with the osteocytes of fetal bone in osteogenesis imperfecta.
AB  - Osteogenesis imperfecta (OI) is a rare, heterogeneous, inherited connective
      tissue disorder frequently caused by abnormalities of type I collagen. It is
      characterized by bone fragility, osteopenia, and progressive skeletal
      deformities. Electron microscopy of three OI type II fetal bone samples revealed
      numerous large osteocyte lacunae. In addition, there was a perilacunar osteoid
      like band of collagen surrounding the osteocytes, which was unmineralized and
      morphologically unusual. Furthermore, large osteocyte lacunae contained fine
      particles and filamentous material similar to the expected ultrastructural
      appearance of proteoglycans. More detailed examination was carried out using
      histochemical and immunogold localization of proteoglycans at light and
      ultrastructural levels. These tests and the use of electron probe X-ray
      microanalysis confirmed that the material in the osteocyte lacunae was
      proteoglycan. In contrast, in the age- and site-matched normal fetal bone, all
      the osteocyte lacunae appeared negative for proteoglycan. Proteoglycans are
      regarded as inhibitors of calcification. Our observation of substantial amounts
      of proteoglycan in abnormally enlarged osteocytic lacunae of some OI fetal bone
      suggests association with the abnormal bone of this particular subtype of OI type
      II.

PMID- 8661488
TI  - Regional analysis of bone mineral density in the distal femur and proximal tibia
      using peripheral quantitative computed tomography in the rat In vivo.
AB  - The use of peripheral quantitative computed tomography (pQCT) was investigated
      for the measurement of volumetric bone mineral density (BMD) in mg x cm-3. Two
      studies were undertaken. In the first study, the precision of pQCT in vivo and ex
      vivo was tested at 14 weeks postovariectomy (OVX). In the second study, the
      efficacy of a standard antiresorptive treatment, 17beta-estradiol (E2), was
      tested 6 weeks post-OVX. The precision for total (compact plus trabecular) BMD
      was 1.3-1.9%, and that for trabecular BMD was 2.4-2. 7%. There was excellent
      agreement between trabecular BMD measurements in vivo and ex vivo (r = 0.91).
      Significant reductions in trabecular BMD were observed in vivo at 14 and 6 weeks
      following ovariectomy in the femur, in each study. The loss of trabecular BMD
      depended on slice location, and varied from 0 to 22% at 6 weeks, and from 0 to
      26% at 14 weeks (P < 0.001, at the affected locations). The antiresorptive effect
      of treatment was demonstrated in the 6-week study: there was no significant
      difference in BMD between sham-operated and E2-treated OVX rats.

PMID- 8661490
TI  - Regulation of Ca2+-activated K+ channel from rabbit distal colon epithelium by
      phosphorylation and dephosphorylation.
AB  - The Ca2+-activated maxi K+ channel is predominant in the basolateral membrane of
      the surface cells in the distal colon. It may play a role in the regulation of
      the aldosterone-stimulated Na+ reabsorption from the intestinal lumen. Previous
      measurements of these basolateral K+ channels in planar lipid bilayers and in
      plasma membrane vesicles have shown a very high sensitivity to Ca2+ with a K0.5
      ranging from 20 nm to 300 nm, whereas other studies have a much lower sensitivity
      to Ca2+. To investigate whether this difference could be due to modulation by
      second messenger systems, the effect of phosphorylation and dephosphorylation was
      examined. After addition of phosphatase, the K+ channels lost their high
      sensitivity to Ca2+, yet they could still be activated by high concentrations of
      Ca2+ (10 micron). Furthermore, the high sensitivity to Ca2+ could be restored
      after phosphorylation catalyzed by a cAMP dependent protein kinase. There was no
      effect of addition of protein kinase C. In agreement with the involvement of
      enzymatic processes, lag periods of 30-120 sec for dephosphorylation and of 10
      280 sec for phosphorylation were observed. The phosphorylation state of the
      channel did not influence the single channel conductance. The results demonstrate
      that the high sensitivity to Ca2+ of the maxi K+ channel from rabbit distal colon
      is a property of the phosphorylated form of the channel protein, and that the
      difference in Ca2+ sensitivity between the dephosphorylated and phosphorylated
      forms of the channel protein is more than one order of magnitude. The variety in
      Ca2+ sensitivities for maxi K+ channels from tissue to tissue and from different
      studies on the same tissue could be due to modification by second messenger
      systems.

PMID- 8661489
TI  - Lack of conventional ATPase properties in CFTR chloride channel gating.
AB  - CFTR shares structural homology with the ABC transporter superfamily of proteins
      which hydrolyze ATP to effect the transport of compounds across cell membranes.
      Some superfamily members are characterized as P-type ATPases because ATP
      dependent transport is sensitive to the presence of vanadate. It has been widely
      postulated that CFTR hydrolyzes ATP to gate its chloride channel. However, direct
      evidence of CFTR hydrolytic activity in channel gating is lacking and existing
      circumstantial evidence is contradictory. Therefore, we evaluated CFTR chloride
      channel activity under conditions known to inhibit the activity of ATPases; i.e.,
      in the absence of divalent cations and in the presence of a variety of ATPase
      inhibitors. Removal of the cytosolic cofactor, Mg2+, reduced both the opening and
      closing rates of CFTR suggesting that Mg2+ plays a modulatory role in channel
      gating. However, channels continued to both open and close showing that Mg2+ is
      not an absolute requirement for channel activity. The nonselective P-type ATPase
      inhibitor, vanadate, did not alter the gating of CFTR when used at concentrations
      which completely inhibit the activity of other ABC transporters (1 mM). Higher
      concentrations of vanadate (10 mM) blocked the closing of CFTR, but did not
      affect the opening of the channel. As expected, more selective P-type (Sch28080,
      ouabain), V-type (bafilomycin A1, SCN-) and F-type (oligomycin) ATPase inhibitors
      did not affect either the opening or closing of CFTR. Thus, CFTR does not share a
      pharmacological inhibition profile with other ATPases and channel gating occurs
      in the apparent absence of hydrolysis, although with altered kinetics. Vanadate
      inhibition of channel closure might suggest that a hydrolytic step is involved
      although the requirement for a high concentration raises the possibility of
      previously uncharacterized effects of this compound. Most conservatively, the
      requirement for high concentrations of vanadate demonstrates that the binding
      site for this transition state analogue is considerably different than that of
      other ABC transporters.

PMID- 8661491
TI  - The Ach-evoked Ca2+-activated K+ current in mouse mandibular secretory cells.
      Single channel studies.
AB  - Although acetylcholine (ACh) is able to activate voltage- and Ca2+-sensitive K+
      (BK) channels in mouse mandibular secretory cells, our recent whole cell studies
      have suggested that these channels, like those in sheep parotid secretory cells,
      do not contribute appreciably to the conductance that carries the ACh-evoked
      whole cell K+ current. In the present study, we have used cell-attached patch
      clamp methods to identify and characterize the K+ channel type responsible for
      carrying the bulk of this current. When the cells were bathed in a NaCl-rich
      solution the predominant channel type activated by ACh (1 micromol/l or 50
      nmol/l) had a conductance only of 40 pS; it was not blocked by TEA but it was
      sensitive to quinine and it conducted Rb+ to an appreciable extent. BK channels,
      which could be seen in some but not all patches from resting cells, also showed
      increased activity when ACh was added to the bath, but they were much less
      conspicuous during ACh stimulation than the 40-pS channels. When the cells were
      bathed in a KCl-rich rather than a NaCl-rich solution, a small-conductance K+
      channel, sensitive to quinine but not to TEA, was still the most conspicuous
      channel to be activated by ACh although its conductance was reduced to 25 pS. Our
      studies confirm that the ACh-evoked whole-cell K+ current is not carried
      substantially by BK channels and show that it is carried by a small-conductance
      K+ channel with quite different properties.

PMID- 8661492
TI  - Diffusion through narrow pores: movement of ions, water and nonelectrolytes
      through track-etched PETP membranes.
AB  - The rates at which ions (86Rb+, [3H]-choline, 36Cl), 3H2O and nonelectrolytes
      ([14C]-urea, [14C]-glycerol, and [14C]-sugars) equilibrate across track-etched
      polyethyleneterephthalate (PETP) membranes (isotopic diffusion) have been
      measured by a 'static' and a 'dynamic' technique under conditions where no net
      flow takes place; the two techniques give essentially the same results. All
      tracers diffuse faster the longer the membranes are etched, consistent with an
      increase in pore size. Water and neutral solutes diffuse at rates that are
      relatively independent of ionic strength, pH or the presence of divalent cations.
      Diffusion of cations is decreased by high ionic strength, by reducing pH or by
      addition of divalent cations; diffusion of chloride is increased by these
      procedures. Treatment of the membrane with diazomethane to reduce the negative
      fixed charge decreases diffusion of cations and increases that of anions;
      diffusion of water and neutral solutes is unaffected by methylation except in the
      membranes with the narrowest pores (i.e., those etched for the shortest time), in
      which case diffusion is reduced. We conclude (1) that the special features of
      flow near a charged surface apply to ions but not to water or nonelectrolytes and
      (2) that calculation of absolute rates of diffusion leads to values for the radii
      of pores through track-etched PETP membranes that are in remarkably good
      agreement with measured values.

PMID- 8661493
TI  - Characterization of a phenylglyoxal-sensitive passive Ca2+ permeability in human
      erythrocytes.
AB  - In viable human erythrocytes, passive downhill entry of Ca2+ through the plasma
      membrane is opposed by an active extrusion Ca2+-pump mechanism which maintains a
      free [Ca2+]i approximately 10(-7) M. This passive Ca2+ permeability can be
      determined reliably in cells with a completely arrested Ca2+ pump, as can be
      achieved in cells which are both ATP-depleted and vanadate-treated. With this
      approach, whole-cell preparations from banked human erythrocytes exhibited
      passive net uptake of Ca2+ that has characteristics of a carrier-mediated process
      which could be shunted by the addition of the Ca2+ ionophore A23187. Passive Ca2+
      uptake was apparently independent of extracellular Na+, K+ or Cl- and was not
      responsive to a variety of Ca2+ channel entry blockers. However, in the presence
      of phenylglyoxal, a specific, covalent modifier of arginyl residues, the initial
      (0 to 60 min) rate of passive Ca2+ uptake was inhibited in a dose-dependent
      manner. This can be taken in support of a proteinaceous carrier-mediated passive
      Ca2+ entry mechanism that involves one or several functional arginyl residue(s)
      and may represent Ca2+ back-diffusion through the arrested Ca2+ translocation
      pump.

PMID- 8661494
TI  - Increased resistance to extracellular cation block by mutation of the pore domain
      of the Arabidopsis inward-rectifying K+ channel KAT1.
AB  - Inward-rectifying potassium channels in plant cells provide important mechanisms
      for low-affinity K+ uptake and membrane potential control in specific cell types,
      including guard cells, pulvinus cells, aleurone cells and root hair cells. K+
      channel blockers are potent tools for studying the physiological functions and
      structural properties of K+ channels. In the present study the structural and
      biophysical mechanisms of Cs+ and TEA+ block of a cloned Arabidopsis inward
      rectifying K+ channel (KAT1) were analyzed. Effects of the channel blockers Cs+
      and TEA+ were characterized both extracellularly and intracellularly. Both
      external Cs+ and TEA+ block KAT1 currents. A mutant of KAT1 ("m2KAT1"; H267T,
      E269V) was produced by site-directed mutagenesis of two amino acid residues in
      the C-terminal portion of the putative pore (P) domain. This mutant channel was
      blocked less by external Cs+ and TEA+ than the wild-type K+ channel. Internal
      TEA+ and Cs+ did not significantly block either m2KAT1 or KAT1 channels. Other
      properties, such as cation selectivity, voltage-dependence and proton activation
      did not show large changes between m2KAT1 and KAT1, demonstrating the specificity
      of the introduced mutations. These data suggest that the amino acid positions
      mutated in the inward-rectifying K+ channel, KAT1, are accessible to external
      blockers and may be located on the external side of the membrane, as has been
      suggested for outward-rectifying K+ channels.

PMID- 8661495
TI  - Role of translocases in the generation of phosphatidylserine asymmetry.

PMID- 8661496
TI  - Nickel block of a family of neuronal calcium channels: subtype- and subunit
      dependent action at multiple sites.
AB  - Nickel ions have been reported to exhibit differential effects on distinct
      subtypes of voltage-activated calcium channels. To more precisely determine the
      effects of nickel, we have investigated the action of nickel on four classes of
      cloned neuronal calcium channels (alpha1A, alpha1B, alpha1C, and alpha1E)
      transiently expressed in Xenopus oocytes. Nickel caused two major effects: (i)
      block detected as a reduction of the maximum slope conductance and (ii) a shift
      in the current-voltage relation towards more depolarized potentials which was
      paralleled by a decrease in the slope of the activation-curve. Block followed 1:1
      kinetics and was most pronounced for alpha1C, followed by alpha1E > alpha1A >
      alpha1B channels. In contrast, the change in activation-gating was most dramatic
      with alpha1E, with the remaining channel subtypes significantly less affected.
      The current-voltage shift was well described by a simple model in which nickel
      binding to a saturable site resulted in altered gating behavior. The affinity for
      both the blocking site and the putative gating site were reduced with increasing
      concentration of external permeant ion. Replacement of barium with calcium
      reduced both the degree of nickel block and the maximal effect on gating for
      alpha1A channels, but increased the nickel blocking affinity for alpha1E
      channels. The coexpression of Ca channel beta subunits was found to
      differentially influence nickel effects on alpha1A, as coexpression with beta2a
      or with beta4 resulted in larger current-voltage shifts than those observed in
      the presence of beta1b, while elimination of the beta subunit almost completely
      abolished the gating shifts. In contrast, block was similar for the three beta
      subunits tested, while complete removal of the beta subunit resulted in an
      increase in blocking affinity. Our data suggest that the effect of nickel on
      calcium channels is complex, cannot be described by a single site of action, and
      differs qualitatively and quantitatively among individual subtypes and subunit
      combinations.

PMID- 8661497
TI  - Regulation of cell volume by beta2-adrenergic stimulation in rat fetal distal
      lung epithelial cells.
AB  - Cell-volume changes induced by terbutaline (a specific beta2-agonist) were
      studied morphometrically in rat fetal distal lung epithelium (FDLE) cells. Cell
      volume changes qualitatively differed with the concentration of terbutaline.
      Terbutaline of 10(-10)-10(-8) M induced transient cell swelling. Terbutaline of
      10(-7) M induced transient cell swelling followed by slow cell shrinkage.
      Terbutaline of 10(-6)-10(-5) M induced rapid cell shrinkage followed by slow cell
      shrinkage. Terbutaline of 10(-3) M induced transient cell shrinkage; then cell
      volume oscillated during stimulation. Benzamil of 10(-6) M suppressed the cell
      swelling induced by 10(-10)-10(-8) M terbutaline and quinine of 10(-3) M
      inhibited the cell shrinkage induced by 10(-6)-10(-5) M terbutaline. These
      results suggest that cell swelling would be induced by NaCl influx and the cell
      shrinkage is by KCl efflux. Dibutyryl cyclic AMP (DBcAMP) also induced similar
      cell-volume changes over a wide range of concentrations (10(-9)-10(-3) M): a low
      concentration induced transient cell swelling; a high concentration, rapid and
      slow cell shrinkage. Forskolin (10(-4) M), like terbutaline (10(-5) M), induced
      rapid cell shrinkage followed by slow cell shrinkage, and this decrease in the
      cell volume was enhanced by the presence of benzamil. On the other hand, cell
      shrinkage was induced by ionomycin (even low concentration; 3 x 10(-10) M
      ionomycin), and after that cell volume remained at a plateau level. Removal of
      extracellular Ca2+ abolished the cell swelling caused by terbutaline of 10(-10)
      10(-8) M. With removal of extracellular Ca2+, the initial, rapid cell shrinkage
      induced by 10(-5) M terbutaline became transient, but we still detected slow cell
      shrinkage similar to that in the presence of extracellular Ca2+. Overall, at low
      concentrations (10(-10)-10(-8) M), terbutaline induced benzamil-sensitive cell
      swelling in FDLE cells, which was cAMP- and Ca2+-dependent; high concentrations
      (> or =10(-6)) induced quinine-sensitive rapid cell shrinkage, which was Ca2+
      dependent; high concentrations (> or = 10(-7)) induced slow cell shrinkage, which
      was cAMP-dependent. These findings suggest that terbutaline regulates cell volume
      in FDLE cells by cytosolic cAMP and Ca2+ through activation of Na+ and K+
      channels.

PMID- 8661498
TI  - Role of LTD4 in the regulatory volume decrease response in Ehrlich ascites tumor
      cells.
AB  - Stimulation with leukotriene D4 (LTD4) (3-100 nM) induces a transient increase in
      the free intracellular Ca2+ concentration ([Ca2+]i) in Ehrlich ascites tumor
      cells. The LTD4-induced increase in [Ca2+]i is, however, significantly reduced in
      Ca2+-free medium (2 mM EGTA), and under these conditions stimulation with a low
      LTD4 concentration (3 nM) does not result in any detectable increase in [Ca2+]i.
      Addition of LTD4 (3-100 nM) moreover accelerates the KCl loss seen during
      Regulatory Volume Decrease (RVD) in cells suspended in a hypotonic medium. The
      LTD4-induced (100 nM) acceleration of the RVD response is also seen in Ca2+-free
      medium and also at 3 nM LTD4, indicating that LTD4 can open K+- and Cl--channels
      without any detectable increase in [Ca2+]i. Buffering cellular Ca2+ with BAPTA
      almost completely blocks the LTD4-induced (100 nM) acceleration of the RVD
      response. Thus, the reduced [Ca2+]i level after BAPTA-loading or buffering of
      [Ca2+]i seems to inhibit the LTD4-induced stimulation of the RVD response even
      though the LTD4-induced cell shrinkage is not necessarily preceded by any
      detectable increase in [Ca2+]i. The LTD4 receptor antagonist L649, 923 (1 microM)
      completely blocks the LTD4-induced increase in [Ca2+]i and inhibits the RVD
      response as well as the LTD4-induced acceleration of the RVD response. When the
      LTD4 receptor is desensitized by preincubation with 100 nM LTD4, a subsequent RVD
      response is strongly inhibited. In conclusion, the present study supports the
      notion that LTD4 plays a role in the activation of the RVD response. LTD4 seems
      to activate K+ and Cl- channels via stimulation of a LTD4 receptor with no need
      for a detectable increase in [Ca2+]i.

PMID- 8661499
TI  - Single K+ channels in embryonic leech ganglion cells.
AB  - We investigated the properties of single K+ channels in the soma membrane of
      embryonic leech ganglion cells using the patch-clamp technique. We compared these
      K+ channels with the K+ channels found previously in Retzius neurons of the adult
      leech. In ganglion cells of 9- to 15-day-old embryos we characterized eight
      different types of K+ channels with mean conductances of 21, 55, 84, 111, 122,
      132, 149 and 223 pS. The 55 pS and 84 pS channels showed flickering and were
      active for less than 2 min after excising the patch. The 111 pS channel was an
      outward rectifier, and the open state probability (po) decreased in the inside
      out configuration when the Ca2+ concentration was raised from pCa 7 to pCa 3. The
      122 pS channel also showed outward rectification. This type of channel was
      activated after changing from the cell-attached to the inside-out configuration
      and it did not inactivate during more than 30 min. The po was Ca2+- and voltage
      insensitive. One hundred micron glibenclamide reversibly reduced po. The 132 pS
      channel was an outward rectifier and was Ca2+-insensitive. The 149 pS channel
      inactivated in the inside-out configuration. The 149- and the 223 pS channel
      showed inward rectification. The 111 pS channel had similar properties to the
      Ca2+-dependent K+ channel and the 122 pS channel resembled the ATP-inhibited K+
      channel found previously in Retzius neurons of the adult leech.

PMID- 8661500
TI  - Sarcoplasmic reticulum Ca2+ release in rat slow- and fast-twitch muscles.
AB  - The same isoform of ryanodine receptor (RYR1) is expressed in both fast and slow
      mammalian skeletal muscles. However, differences in contractile activation and
      calcium release kinetics in intact and skinned fibers have been reported. In this
      work, intracellular Ca2+ transients were measured in soleus and extensor
      digitorum longus (EDL) single muscle fibers using mag-fura-2 (KD for Ca2+ = 49
      microM) as Ca2+ fluorescent indicator. Fibers were voltage-clamped at Vh = -90 mV
      and sarcoplasmic reticulum calcium release was measured at the peak (a) and at
      the end (b) of 200 msec pulses at +10 mV. Values of a-b and b were assumed to
      correspond to Ca2+-gated and voltage-gated Ca2+ release, respectively. Ratios
      (b/a-b) in soleus and EDL fibers were 0.41 +/- 0.05 and 1.01 +/- 0.13 (n = 12),
      respectively. This result suggested that the proportion of dihydropyridine
      receptor (DHPR)-linked and unlinked RYRs is different in soleus and EDL muscle.
      The number of DHPR and RYR were determined by measuring high-affinity [3H]PN200
      110 and [3H]ryanodine binding in soleus and EDL rat muscle homogenates. The Bmax
      values corresponded to a PN200-110/ryanodine binding ratio of 0. 34 +/- 0.05 and
      0.92 +/- 0.11 for soleus and EDL muscles (n = 4-8), respectively. These data
      suggest that soleus muscle has a larger calcium-gated calcium release component
      and a larger proportion of DHPR-unlinked RYRs.

PMID- 8661501
TI  - A Ca2+-activated whole-cell Cl- conductance in human placental cytotrophoblast
      cells activated via a G protein.
AB  - Whole-cell patch clamp experiments were performed on cultured human
      cytotrophoblast cells incubated for 24-48 hr after their isolation from term
      placentas. Cl--selective currents were examined using K+-free solutions. Under
      nonstimulated conditions, most cells initially expressed only small background
      leak currents. However, inclusion of 0.2 mM GTPgammaS in the electrode solution
      caused activation of an outwardly rectifying conductance which showed marked time
      dependent activation at depolarized potentials above +20 mV. Stimulation of this
      conductance by GTPgammaS was found to be Ca2+-dependent since GTPgammaS failed to
      activate currents when included in a Ca2+-free electrode solution. In addition,
      similar currents could be activated by increasing the [Ca2+] of the pipette
      solution to 500 nM. The Ca2+-activated conductance was judged to be Cl-
      selective, since reversal potentials were predicted by Nernst equilibrium
      potentials for Cl-. This conductance could also be reversibly inhibited by
      addition of the anion channel blocker DIDS to the bath solution at a dose of 100
      microM. Preliminary experiments indicated the presence of a second whole-cell
      anion conductance in human cytotrophoblast cells, which may be activated by cell
      swelling. Possible roles for the Ca2+-activated Cl- conductance in human
      placental trophoblast are discussed.

PMID- 8661502
TI  - CFTR channels expressed in CHO cells do not have detectable ATP conductance.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP
      activated, ATP-dependent chloride channel which may have additional functions.
      Recent reports that CFTR mediates substantial electrodiffusion of ATP from
      epithelial cells have led to the proposal that CFTR regulates other ion channels
      through an autocrine mechanism involving ATP. The aim of this study was to
      determine the ATP conductance of wild-type CFTR channels stably expressed in
      Chinese hamster ovary cells using patch clamp techniques. In the cell-attached
      configuration with 100 mM Mg middle dot ATP or Tris middle dot ATP solution in
      the pipette and 140 mM NaCl in the bath, exposing cells to forskolin caused the
      activation of a low-conductance channel having kinetics resembling those of CFTR.
      Single channel currents were negative at the resting membrane potential (Vm),
      consistent with net diffusion of Cl from the cell into the pipette. The
      transitions decreased in amplitude, but did not reverse direction, as Vm was
      clamped at increasingly positive potentials to enhance the driving force for
      inward ATP flow (>+80 mV). In excised patches, single channel currents did not
      reverse under essentially biionic conditions (Clin/ATPout or ATPin/Clout),
      although PKA-activated currents were clearly visible in the same patches at
      voltages where they would be carried by chloride ions. Moreover, with NaCl
      solution in the bath and a mixture of ATP and Cl in the pipette, the single
      channel I/V curve reversed at the predicted equilibrium potential for chloride.
      CFTR channel currents disappeared when patches were exposed to symmetrical ATP
      solutions and were restored by reexposure to Cl solution. Finally, in the whole
      cell configuration with NaCl in the bath and 100 mM MgATP or TrisATP in the
      pipette, cAMP-stimulated cells had time-independent, outwardly rectifying
      currents consistent with CFTR selectivity for external Cl over internal ATP.
      Whole-cell currents reversed near Vm = -55 mV under these conditions, however the
      whole cell resistance measured at -100 mV was comparable to that of the gigaohm
      seal between the plasma membrane and glass pipette (7 Gomega). We conclude that
      CFTR does not mediate detectable electrodiffusion of ATP.

PMID- 8661503
TI  - K+ channels and the intracellular calcium signal in human melanoma cell
      proliferation.
AB  - K+ channels, membrane voltage, and intracellular free Ca2+ are involved in
      regulating proliferation in a human melanoma cell line (SK MEL 28). Using patch
      clamp techniques, we found an inwardly rectifying K+ channel and a calcium
      activated K+ channel. The inwardly rectifying K+ channel was calcium independent,
      insensitive to charybdotoxin, and carried the major part of the whole-cell
      current. The K+ channel blockers quinidine, tetraethylammonium chloride and Ba2+
      and elevated extracellular K+ caused a dose-dependent membrane depolarization.
      This depolarization was correlated to an inhibition of cell proliferation.
      Charybdotoxin affected neither membrane voltage nor proliferation. Basic
      fibroblast growth factor and fetal calf serum induced a transient peak in
      intracellular Ca2+ followed by a long-lasting Ca2+ influx. Depolarization by
      voltage clamp decreased and hyperpolarization increased intracellular Ca2+,
      illustrating a transmembrane flux of Ca2+ following its electrochemical gradient.
      We conclude that K+ channel blockers inhibit cell-cycle progression by membrane
      depolarization. This in turn reduces the driving force for the influx of Ca2+, a
      messenger in the mitogenic signal cascade of human melanoma cells.

PMID- 8661504
TI  - Mechanisms of active transport in the FOF1 ATP synthase.

PMID- 8661505
TI  - Multiple mechanosensitive ion channels from Escherichia coli, activated at
      different thresholds of applied pressure.
AB  - Mechanosensitive ion channels from Escherichia coli were studied in giant
      proteoliposomes reconstituted from an inner membrane fraction, or in giant round
      cells in which the outer membrane and the cell wall had been disrupted by a
      lysozyme-EDTA treatment and a mild osmotic shock. Patch-clamp experiments
      revealed the presence in these two preparations of an array of different
      conductances (100 to 2,300 pS in 0.1 M KCl) activated by stretch. The electrical
      activity induced by stretch in the native membrane was complex, due to the
      activation of several different conductances. In contrast, patches of
      proteoliposomes generally contained clusters of identical conductances, which
      differed from patch to patch. These experiments are consistent with the notion
      that these different conductances correspond to different proteins in the plasma
      membrane of E. coli, which segregate into clusters of identical channels on
      dilution involved in reconstitution in proteoliposomes. These conductances could
      be grouped into three subfamilies of poorly selective channels. In both
      preparations, the higher the conductance, the higher was the negative pressure
      needed for activation. We discuss the putative role of these channels as parts of
      a multicomponent osmoregulatory system.

PMID- 8661506
TI  - Activation of Cl- currents in cultured rat retinal pigment epithelial cells by
      intracellular applications of inositol-1,4,5-triphosphate: differences between
      rats with retinal dystrophy (RCS) and normal rats.
AB  - Using the whole-cell configuration of the patch-clamp technique, we studied the
      conditions necessary for the activation of Cl--currents in retinal pigment
      epithelial (RPE) cells from rats with retinal dystrophy (RCS) and nondystrophic
      control rats. In RPE cells from both rat strains, intracellular application of 10
      microM inositol-1, 4,5-triphosphate (IP3) via the patch pipette led to a
      sustained activation of voltage-dependent Cl- currents, blockable by 1 mm 4, 4'
      diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). IP3 activated Cl- currents
      in the presence of a high concentration of the calcium chelator BAPTA (10 mM) in
      the pipette solution, but failed to do so when extracellular calcium was removed.
      Intracellular application of 10(-5)M Ca2+ via the patch pipette also led to a
      transient activation of Cl- currents. When the cells were preincubated in a bath
      solution containing thapsigargin (1 microM) for 5 min before breaking into the
      whole-cell configuration, IP3 failed to activate voltage-dependent currents.
      Thus, IP3 led to release of Ca2+ from cytosolic calcium stores. This in turn
      activated an influx of extracellular calcium into the submembranal space by a
      mechanism as yet unknown, leading to an activation of calcium-dependent chloride
      currents. In RPE cells from RCS rats, which show an increased membrane
      conductance for calcium compared to normal rats, we observed an accelerated speed
      of Cl--current activation induced by IP3 which could be reduced by nifedipine (1
      microM). Thus, the increased membrane conductance to calcium in RPE cells from
      RCS rats changes the response of the cell to the second messenger IP3.

PMID- 8661509
TI  - Na+-independent lysine transport in human intestinal Caco-2 cells.
AB  - The nature of transepithelial and cellular transport of the dibasic amino acid
      lysine in human intestinal epithelial Caco-2 cells has been characterized.
      Intracellular accumulation of lysine across both the apical and basolateral
      membranes consists of a Na+-independent, membrane potential-sensitive uptake. Na+
      independent lysine uptake at the basolateral membrane exceeds that at the apical
      membrane. Lysine uptake consists of both saturable and nonsaturable components.
      Na+-independent lysine uptake at both membranes is inhibited by lysine, arginine,
      alanine, histidine, methionine, leucine, cystine, cysteine and homoserine. In
      contrast, proline and taurine are without inhibitory effects at both membranes.
      Fractional Na+-independent lysine efflux from preloaded epithelial layers is
      greater at the basolateral membrane and shows trans-stimulation across both
      epithelial borders by lysine, arginine, alanine, histidine, methionine, and
      leucine but not proline and taurine. Na+-independent lysine influx (10 micron) in
      the presence of 10 mm homoserine shows further concentration dependent inhibition
      by lysine. Taken together, these data are consistent with lysine transport being
      mediated by systems bo,+, y+ and a component of very low affinity (nonsaturable)
      at both membranes. The relative contribution to lysine uptake at each membrane
      surface (at 10 micron lysine), normalized to total apical uptake (100%), is
      apical bo,+ (47%), y+ (27%) and the nonsaturable component (26%), and basal bo,+
      (446%), y+ (276%) and the nonsaturable component (20%). Northern analysis shows
      hybridization of Caco-2 poly(A)+RNA with a human rBAT cDNA probe.

PMID- 8661508
TI  - A CNS catecholaminergic cell line expresses voltage-gated currents.
AB  - CATH.a is a central nervous system (CNS) catecholaminergic cell line derived from
      a transgenic mouse carrying the SV40 T antigen oncogene under the transcriptional
      control of regulatory elements from the rat tyrosine hydroxylase gene (Suri et
      al., 1993). CATH.a cells express several differentiated neuronal characteristics
      including medium and light chain neurofilament proteins, synaptophysin, tyrosine
      hydroxylase, and dopamine beta-hydroxylase; they synthesize dopamine and
      norepinephrine. Conversely, they do not express glial-specific fibrillary acidic
      protein. To establish definitively that CATH.a cells are of neuronal origin, we
      characterized the repertoire of voltage-gated inward currents expressed by CATH.a
      cells. Such inward currents are necessary for neuronal excitability. We report
      that all CATH.a cells possess a tetrodotoxin-sensitive sodium current (peak
      amplitude = 590 +/- 319 pA) and 68% possess a high voltage-activated calcium
      current (peak amplitude = 175 +/- 67 pA). Pharmacological analyses suggest that
      individual cells express varying levels of L- and N-type calcium current, but no
      P-type current. In addition, in 55% of the cells with a calcium current, about a
      half of this current is resistant to selective antagonists for L- and N-type
      currents, suggesting that another calcium current exists in these CATH.a cells
      which is not L-, N-, or P-type. The heterogeneous pattern of current detected
      persisted in several CATH. a subclones, suggesting that factors other than
      genetic variability influence current expression. The demonstration that CATH.a
      cells express these currents indicates that they have excitable membrane
      properties characteristic of neurons. Although many peripheral nervous system
      (PNS) cell lines exist, very few CNS cell lines with differentiated neuronal
      properties exist. Since the CATH.a cells can be grown continuously in large
      amounts, they may be useful for purifying, characterizing, and/or cloning various
      neuronal-specific molecules and thereby may add to our understanding of CNS
      catecholaminergic neurons.

PMID- 8661510
TI  - N-type inactivation in the mammalian Shaker K+ channel Kv1.4.
AB  - Mammalian voltage-gated K+ channels are oligomeric proteins, some of which may be
      composed in vivo of subunits derived from several similar genes. We have studied
      N-type inactivation in the rapidly inactivating Kv1.4 channel and, in specific,
      heteromultimers of this gene product with Kv1.5 noninactivating subunits.
      Heteromultimeric channels were analyzed for the stoichiometry of Kv1.4:Kv1.5
      subunits by observing shifts in the midpoints of steady-state availability from
      that of homomultimeric channels. This analysis was employed to examine
      inactivation of heteromultimeric channels expressed in Xenopus oocytes using two
      model systems: by expression of a Kv1. 4-Kv1.5 tandem fusion construct and by
      coexpression of native Kv1.4 and Kv1.5 channels across a wide relative
      concentration range of microinjected mRNA. Additionally, inactivation was
      examined in coexpression experiments of N-terminal deletion mutants of Kv1.4. We
      found that (i) a single inactivating subunit conferred inactivation in all hetero
      multimers studied; (ii) the rate of inactivation could not be distinguished in
      channels containing two inactivating subunits from those containing one
      inactivating subunit; and (iii) large deletions in the linker region between the
      N-terminal inactivation region and the first membrane-spanning domain had no
      effect on the rate of inactivation. These data confirm the importance of the
      proximal N-terminal region in the inactivation of mammalian Kv1.4 channels, and
      suggest that the inactivation particle remains in close proximity to the
      permeation pathway even when the channel is in the open state.

PMID- 8661511
TI  - Effect of adenosine on Na+ and Cl- currents in A6 monolayers. Receptor
      localization and messenger involvement.
AB  - The effect of adenosine regulation on sodium and chloride transport was examined
      in cultured A6 renal epithelial cells. Adenosine and its analogue N6
      cyclopentyladenosine (CPA) had different effects on short-circuit current (Isc)
      depending on the side of addition. Basolateral CPA addition induced an
      approximately threefold increase of the Isc that reached a maximum effect 20 min
      after addition and was completely inhibited by preincubation with either an A2
      selective antagonist, CSC, or the sodium channel blocker, amiloride. Apical CPA
      addition induced a biphasic Isc response characterized by a rapid fourfold
      transient increase over its baseline followed by a decline and a plateau phase
      that were amiloride insensitive. The A1 adenosine antagonist, CPX, completely
      prevented this response. This Isc response to apical CPA was also strongly
      reduced in Cl--free media and was significantly inhibited either by basolateral
      bumetanide or apical DPC preincubation. Only basolateral CPA addition was able to
      induce an increase in cAMP level. CPA, added to cells in suspension, caused a
      rapid rise in [Ca2+]i that was antagonized by CPX, not affected by CSC and
      prevented by thapsigargin preincubation. These data suggest that basolateral CPA
      regulates active sodium transport via A2 adenosine receptors stimulating
      adenylate cyclase while apical CPA regulates Cl- secretion via A1 receptor
      mediated changes in [Ca2+]i.

PMID- 8661512
TI  - Monitoring of the membrane potential in proteoliposomes with incorporated
      cytochrome-c oxidase using the fluorescent dye indocyanine.
AB  - A method has been developed to monitor changes of the membrane potential across
      vesicle membranes in real time. Using the potential-sensitive fluorescent dye
      indocyanine and on the basis of a water/lipid redistribution model, a calculation
      procedure has been introduced to estimate the membrane potential in vesicles with
      incorporated cytochrome-c oxidase. Physical parameters, such as vesicle size
      distribution and density of the lipid bilayer were estimated and used as
      calculation parameters. By extrapolation of the transient potential change to
      zero time, the initial rate of the potential change (dU/dt) could be calculated.
      It is also shown, that the initial potential change (dU/dt) may be used to study
      the proton/electron stoichiometry of cytochrome-c oxidase incorporated in the
      vesicles.

PMID- 8661513
TI  - Transient expression of Na+/H+ exchanger isoform NHE-2 in LLC-PK1 cells:
      inhibition of endogenous NHE-3 and regulation by hypertonicity.
AB  - Na+/H+ exchanger isoforms NHE-2 and NHE-3 demonstrate distinct tissue expression
      patterns in renal epithelial cells. NHE-2 is predominantly expressed in the inner
      medulla whereas NHE-3 is highly expressed in the proximal tubule cells. The
      purpose of the current experiments was to study the characteristics of NHE-2 upon
      its own expression in cultured proximal tubule cells, LLC-PK1. Toward this end,
      LLC-PK1 cells were subjected to six cycles of proton suicide. The mutant cells,
      when grown to confluence and assayed for Na+/H+ exchanger by 22Na+ influx, showed
      significant reduction in NHE activity as compared to the parent cells (10.4
      nmole/mg prot/4 min in parent cells vs. 1.8 in mutant cells, P < 0.001, n = 4).
      This remaining exchanger activity was mostly mediated via NHE-3 as shown by
      inhibition of the Na influx following PKC stimulation (65% with PMA vs. 100%
      without PMA. P < 0.05, n = 4). The mutant cells were transiently transfected with
      a pCMV/NHE-2 expression vector using calcium phosphate precipitation method.
      Northern blot analysis showed the expression of a 3.4 kb transcript only in the
      transfected cells. The expression peaked at 48 hr and diminished by 96 hr. The
      exchanger activity at 48 hr after transfection was mostly due to NHE-3 (as shown
      by inhibition in the presence of PMA) but was significantly lower than in sham
      transfected cells (1.2 nmoles/mg prot. in NHE-2-transfected and 2.1 in sham
      transfected, P < 0.05, n = 4). At 60 hr after transfection, the cells exhibited
      PMA-stimulated Na influx (>28%) indicating functional expression of NHE-2.
      Increasing the osmolality of the media to 510 mOsm/l stimulated the Na+/H+
      exchanger in NHE-2 transfected cells but inhibited the exchanger activity in sham
      transfected cells. In conclusion, NHE-2 appears as a 3.4 kb transcript in
      transfected LLC-PK1 cells and functional expression of NHE-2 is preceded by
      inhibition of endogenous NHE-3 activity. The NHE-2 is stimulated by
      hypertonicity, indicating a likely role for this isoform in cell volume
      regulation.

PMID- 8661514
TI  - Swelling and Ca2+-activated anion conductances in C127 epithelial cells
      expressing WT and delta F508-CFTR.
AB  - CFTR is a chloride channel that is required for fluid secretion and salt
      absorption in many exocrine epithelia. Mutations in CFTR cause cystic fibrosis.
      CFTR expression influences some ion channels, but the range of channels
      influenced, the mechanism of the interaction and the significance for cystic
      fibrosis are not known. Possible interactions between CFTR and other ion channels
      were studied in C127 mouse mammary epithelial cell lines stably transfected with
      CFTR, delta F508-CFTR, or vector. Cell lines were compared quantitatively using
      an 125I efflux assay and qualitatively using whole-cell patch-clamp recording. As
      expected, 125I efflux was significantly increased by forskolin only in the CFTR
      line, and forskolin-stimulated whole-cell currents were time- and voltage
      independent. All three lines responded to hypotonic challenge with large 125I
      efflux responses of equivalent magnitude, and whole-cell currents were outwardly
      rectified and inactivated at positive voltages. Unexpectedly, basal 125I efflux
      was significantly smaller in the delta F508-CFTR cell line than in either the
      CFTR or control cell lines (P < 0.0001), and the magnitude of the efflux response
      to ionomycin was largest in the vector cell line and smallest in the cell line
      expressing delta F508-CFTR (P < 0.01). Whole-cell responses to ionomycin had a
      linear instantaneous I-V relation and activated at depolarizing voltages.
      Forskolin responses showed simple summation with responses to ionomycin or
      hypotonic challenge. Thus, we found no evidence for interactions between CFTR and
      the channels responsible for swelling-mediated responses. Differences were found
      in basal and ionomycin-stimulated efflux, but these may arise from variations in
      the clonally selected cell lines that are unrelated to CFTR expression.

PMID- 8661515
TI  - Regulation of voltage-dependent sodium channels.

PMID- 8661516
TI  - Interaction of nisin with planar lipid bilayers monitored by fluorescence
      recovery after photobleaching.
AB  - Nisin, a prominent member of the lantibiotic family of antimicrobial agents, has
      wide application as a food preservative despite poor understanding of its mode of
      action. Fluorescence recovery after photobleaching has been used with planar
      lipid bilayers as a model membrane system to examine how nisin might interact
      with the surface of bacterial cells. Nisin associates with planar lipid bilayers
      in the absence of an applied membrane potential causing an array of effects
      consistent with adsorption of nisin onto the membrane surface which involves
      inhibition of the lateral diffusion and fluorescence of the lipid probe N-(7-
      1,2,3-benzoxadiazol-4-yl) phosphatidylethanolamine (NBD-PE) and a reduction of
      the capacitance of the bilayer. Nisin adsorption is dependent on phospholipid
      composition. In the presence of dioleoylphosphatidylcholine (PC): cardiolipin
      (CL) 4:1, the rate of lateral mobility of phospholipid is reduced to 61% of the
      control level which decreases to a value of 46% when CL is replaced by 1
      palmitoyl-2-oleoylphosphatidylserine (PS). These effects on bilayer parameters
      are transient, and with time the values return to near original levels. High
      electrical conductivity is observed on application of a voltage ramp suggesting
      that insertion into the membrane follows surface association. Results have been
      interpreted in terms of a model in which nisin initially binds to the surface of
      the membrane causing a modulation of bilayer properties.

PMID- 8661519
TI  - Effects of Diflubenzuron on Benthic Macroinvertebrates in Littoral Enclosures
AB  - Two applications of the insect growth regulator diflubenzuron were made to
      replicate littoral enclosures at nominal concentrations of 0.7, 2.5, 7.0, and 30
      &mgr;g/L. Assessment of the effects of this insecticide on benthic
      macroinvertebrate community structure was accomplished by measuring changes in
      abundance and taxonomic richness. Chironomidae and Ephemeroptera were the most
      sensitive groups sampled, with no observed effect concentrations of 2.5 and 0.7
      &mgr;g/L, respectively. No adverse effects were observed on Mollusca or
      Oligochaeta at any of the test concentrations. Taxonomic richness was noticably
      reduced at 7.0 and 30 &mgr;g/L on all post-application sampling dates, producing
      changes in community structure that persisted for >/=57 days.

PMID- 8661517
TI  - Heavy metal and selenium levels in Franklin's Gull (Larus pipixcan) parents and
      their eggs.
AB  - Lead, cadmium, mercury, chromium, selenium, and manganese concentrations were
      measured in the breast feathers of 25 pairs of Franklin's Gull (Larus Pipixcan)
      and in their eggs from a breeding colony at Agassiz National Wildlife Refuge in
      Northwestern Minnesota. Metal concentrations in eggs represent metals sequestered
      in the egg by females at the time of egg formation; while metal concentrations in
      parents represent concentrations of metals in blood supply at the time of feather
      formation. There were no significant sexual differences in metal concentrations
      in feathers, assuming the male to be larger of each pair, but there were
      significant differences between the concentrations of metals in parents and their
      eggs. Eggs had significantly higher concentrations of selenium and chromium, but
      significantly lower concentrations of all other metals than the feathers of their
      parents. There were few significant correlations among metal concentrations
      within the egg or within the feather of females, but there were correlations for
      the feathers of males. Lead and cadmium in feathers were positively correlated
      for both males and females. Chromium concentrations in eggs were generally higher
      than reported in the literature. The concentrations in eggs and the feathers of
      females were positively correlated for mercury, and negatively correlated for
      chromium and manganese.

PMID- 8661518
TI  - Free peripheral sulfhydryl groups, CD11/CD18 integrins, and calcium are required
      in the cadmium and nickel enhancement of human-polymorphonuclear leukocyte
      adherence.
AB  - Cadmium and nickel stimulate the early spontaneous adherence of peripheral human
      polymorphonuclear leukocytes (PMNs). Formyl-methionylleucylphenylalanine (fMLP)
      at 0.25 nM inhibited the PMN adherence but was stimulated at 10 or 100 nM.
      Cadmium or nickel, nullified the FMLP inhibitory effect, and enhanced the
      adherence. No clear additive effect was noticed for either metal with fMLP.
      Blockade of CD11/CD18 receptors abolished the adherence modulatory effect of both
      fMLP and metals. p-Chloromercuriphenyl sulfonate (PCMPS), at a concentration that
      blocks peripheral SH groups, did not affect spontaneous adherence, but completely
      prevented the adherence enhancement caused by cadmium or nickel. Removal of
      extracellular calcium diminished both the spontaneous and the metal-stimulated
      adherence. Ryanodine, at a concentration that persistently inactivates ryanodine
      sensitive intracellular channels, inhibited spontaneous PMN adherence, but had no
      effect on the cadmium or nickel induced adherence enhancement. Therefore, the
      results indicate that cadmium and nickel adherence stimulation depends on
      constitutive peripheral SH groups, CD11/CD18 integrins and extracellular calcium,
      but not on intracellular stored-calcium release through ryanodine-sensitive
      channels (RyRS). In contrast, spontaneous adherence greatly depends on the
      release of stored calcium through RyRs, and only slightly on extracellular
      calcium.

PMID- 8661520
TI  - Degradation of Fenamiphos Sulfoxide and Fenamiphos Sulfone in Soil with a History
      of Continuous Applications of Fenamiphos
AB  - Mineralization rates of fenamiphos sulfoxide (FSO), total-toxic-residue [TTR,
      FSO+fenamiphos sulfone (FSO2)] disappearance rates for FSO, disappearance rates
      of FSO2, and metabolites in surface and subsurface soil samples collected from a
      turfgrass site (fairway) were determined. This site had been treated with
      fenamiphos annually or biannually for 20 years, and enhanced degradation of
      fenamiphos TTR was observed. Both the mineralization of FSO and the disappearance
      of FSO TTR, as well as the disappearance of FSO2 in soil samples collected from
      the fairway were much more rapid than in soil samples collected from a nearby
      site (rough) that had no previous history of fenamiphos application. Both FSO and
      FSO2 were degraded more rapidly in surface soil samples than in subsurface
      samples. The degradation pathway of FSO in the fairway soil samples was different
      from the rough samples. Hydrolysis to FSO phenol (FSO-OH) was the initial route
      of degradation of FSO in the fairway samples, whereas hydrolysis to FSO-OH and
      oxidation to FSO2 were the initial routes of degradation in the rough samples.

PMID- 8661521
TI  - Trophic Transfer of a Sediment-Associated Organophosphate Pesticide from
      Meiobenthos to Bottom Feeding Fish
AB  - Experiments were conducted to examine the dynamics of a sediment-associated
      pesticide azinphosmethyl (APM) using a sublethal benthic based trophic transfer
      model (meiobenthic copepods to juvenile fish). Two predominant pathways for
      contaminant transfer during feeding, prey ingestion and sediment ingestion, were
      examined to determine their relative contributions to APM transfer and subsequent
      effects on fish brain AChE inhibition. Experiments were conducted in 1993 and in
      1994. Field collected benthic copepods were exposed to 14-C labeled APM, a potent
      acetylcholinesterase (AChE) inhibitor, in sediments for 96 h. APM burdens were
      measured in the copepods, and these contaminated copepods were fed to the
      juvenile fish predator Leiostomus xanthurus in uncomtaminated sediments. After
      gut clearance, fish were examined for brain AChE activity and APM residues in the
      liver, heart, gut, muscle, gill, and remains. Similar experiments were conducted
      in which meals of uncontaminated copepods were fed to spot in APM contaminated
      sediments, to determine the relative contribution of contaminated sediments to
      APM transfer. Copepods exposed to APM at a mean sediment concentration of 1223
      ng/g dry weight accumulated APM at the level of 2.5 &mgr;g/g dry tissue. Brain
      AChE activity was significantly depressed (23%) in the 1993 fish fed one meal of
      contaminated copepods, however there was no significant decline in AChE activity
      in the fish tested during 1994. APM accumulation in fish feeding in contaminated
      sediments was generally greater than in fish feeding on contaminated prey.
      Significant accumulation was found in bodily remains, gills, gut, and muscle in
      fish that fed in contaminated sediments. No significant APM accumulation was
      found in fish fed the contaminated copepods.

PMID- 8661522
TI  - Use of Biota-Sediment Accumulation Factors to Assess Similarity of Nonionic
      Organic Chemical Exposure to Benthically-Coupled Organisms of Differing Trophic
      Mode
AB  - The U.S. Environmental Protection Agency is in the process of developing Sediment
      Quality Criteria (SQC) to specify the acceptable degree of risk from sediment
      mediated chemical exposure for the protection of benthically-coupled organisms.
      In this study, potential differences in chemical exposure for benthic organisms
      of differing habitats or feeding types were evaluated through the use of Biota
      Sediment Accumulation Factors (BSAFs). It was hypothesized that If species of
      different habitats have similar exposures, then the BSAF values should not be
      different. The BSAFs are calculated using the concentrations of chemicals in an
      organism (&mgr;g/g lipid) divided by the concentrations of the same chemicals in
      sediment (&mgr;g/gOC). Data from both freshwater and saltwater studies that met
      specified criteria for data quality were obtained from published papers or
      reports. These included three laboratory and five field studies containing 27
      species and 4054 BSAF values. The BSAFs were intercompared for similarity of
      central tendency as grouped by chemical class (PCBs, PAHs, pesticides),
      individual species, and species grouped by habitat (infaunal deposit feeder,
      scavenger, filter feeder, and benthically-coupled fish). Plots of BSAFs grouped
      by class and KOW revealed that the BSAFs for the PAHs were uniformly lower (mean
      0.34) than the PCB (1.03) or pesticide (1.36) classes. For the PCBs, the BSAFs
      for all species exhibited a KOW dependency with decreased bioaccumulation evident
      above and below the range of 5.99-7.27 log10 KOW. In order to optimize the
      detection of species/habitat differences in the BSAFs, further analyses were
      segregated by chemical class and excluded PCB data outside the above KOW range.
      These analyses revealed similar BSAF values for various species both within and
      among habitat groups, and indicated that the sum total of exposures from all
      routes is similar across species. This similarity of chemical exposure across
      benthic species, and the similarity of sensitivities between benthic species and
      species used to derive WQC FCVs supports the applicability of SQC for all benthic
      organisms as a group.

PMID- 8661523
TI  - Determination of Aldehydes, Ketones, Esters, and Ethers in Air Using Porapak N
      and Charcoal
AB  - A method was developed to determine aldehydes, ketones, esters, and ethers in air
      which is simple, efficient, and sensitive. Analytes are trapped on a glass
      cartridge filled with 4 in of Porapak N followed by 1 in of charcoal. These are
      eluted with 1 ml of methanol, and the eluate is injected onto a gas chromatograph
      equipped with a photoionization detector (PID). Quantitation is performed by
      measuring the peak height or area of each analyte of interest and comparing it
      with a standard in methanol. These cartridges can be reused a number of times
      after reconditioning. This method is efficient since it lends itself to the use
      of an autosampler, which can inject large numbers of samples onto the gas
      chromatograph while it is unattended.The method detection limit was from 0.6 to
      16.5 &mgr;g/m3, which is comparable to other methods, and recoveries ranged from
      83 to 120%. The sensitivity from highest to lowest, with respect to class of
      compound, was determined to be aldehydes, ketones, esters, and ethers. Up to 150
      L of air can be passed onto the cartridge without any expected breakthrough of
      analytes, as opposed to only 10 to 30 L with 1 in of charcoal alone, which is
      normally the adsorbent of choice.

PMID- 8661524
TI  - Copper, Zinc, and Cadmium Concentrations in Peromyscus maniculatus Sampled Near
      an Abandoned Copper Mine
AB  - Concentrations of zinc, copper, and cadmium were determined in soil and liver,
      kidney, bone and stomach contents of deer mice (Peromyscus maniculatus) from two
      sites near an abandoned mine and one control site, on Vancouver Island, British
      Columbia, Canada. Soil concentrations of copper were significantly elevated at
      the mine and off site vs the reference site. In contrast, there was no difference
      in soil cadmium and zinc concentrations between the mine and reference site.
      Concentrations of copper, cadmium and zinc in livers of mice from the mine site
      were significantly elevated relative to the reference and off site locations.
      Cadmium kidney concentrations tended to be greater in mice from the mine versus
      the off site and reference site. No differences in bone cadmium, copper and zinc
      and, kidney copper and zinc concentrations were noted among mice from the three
      locations. Diet of mice from mine and off sites contained significantly greater
      copper concentrations than the reference population; no differences in cadmium or
      zinc diet concentrations in mice from the three sites were noted. Comparison of
      ratios of metal concentrations in diet:soil and concentrations in liver:soil
      suggest that for zinc and copper, soil and diet are of equal importance as a
      source of metal contamination to these mice. In contrast, cadmium diet:soil and
      cadmium liver:soil ratios were much greater than one indicative of
      bioconcentration of cadmium from soil to diet and from soil to liver. For
      assessing routes of metal exposure, in this case for deer mice inhabiting an
      abandoned mine site, for copper and zinc, soil will most likely be indicative of
      exposure conditions. In contrast, concentrations of cadmium in diet will be more
      representative of amounts that the animal is potentially ingesting. Of further
      importance is that relative to reference sites, mice inhabiting an abandoned
      copper mine site have significantly elevated tissue levels of copper. This is
      turn will provide a route of metal exposure to carnivorous birds such as owls and
      hawks. The toxicological significance of this exposure to birds of prey has yet
      to be assessed adequately.

PMID- 8661526
TI  - Polychlorinated Biphenyls, Dibenzo-p-dioxins, and Dibenzofurans in Harbor
      Porpoises (Phocoena phocoena) Stranded on the Dutch Coast Between 1990 and 1993
AB  - Congener-specific polychlorinated biphenyl (PCB) concentrations were determined
      in the blubber, kidney, and liver tissues of 22 harbor porpoises (Phocoena
      phocoena) stranded on the Dutch coast. For comparison, the PCB concentrations in
      blubber and liver samples of four porpoises from the vicinity of Greenland were
      investigated. In ten blubber samples, the non-ortho PCB concentrations were
      determined, while in four of these the levels of chlorinated dibenzo-p-dioxins
      (PCDDs) and dibenzofurans (PCDFs) were analyzed. It is shown that the PCB level
      increases with age in males, whereas in mature females the levels remain
      relatively constant. A comparison with earlier data indicates a slight decrease
      over the last 20 years in the PCB burden of porpoises living near the Dutch
      coast. The amount of the most prominent and persistent congener, PCB 153, can be
      related to the feeding pattern of male porpoises; it appears to be completely
      retained in this species. Bioaccumulation of non-ortho PCBs and PCDD/Fs does not
      take place. The overall toxicity, expressed as 2,3,7,8-tetrachlorodibenzo-p
      dioxin toxic equivalents (TEQ), is mostly covered by di-ortho and mono-ortho
      PCBs, depending on age and sex, whereas the contribution of the notorious toxic
      PCDDs and PCDFs to the overall TEQ is at most 0.5%.

PMID- 8661525
TI  - Changes in antioxidative activities induced by Fe (II) and Fe (III) in cultured
      Vero cells.
AB  - The toxicity of iron (II) and iron (III) chlorides was studied at different
      biochemical and cellular levels, including antioxidative and metabolic enzymes
      and two general indicators of cytotoxicity in Vero monkey kidney cells after 24-h
      exposure. Iron (II) was fourfold more toxic than Fe (III) in cell proliferation,
      with EC50 of 5.5 and 22 mM, respectively. Metabolic markers were far more
      sensitive than cytotoxicity assays at these concentrations. At the highest
      concentrations of toxicant tested [10 mM Fe(II) and 50 mM Fe(III)], both species
      produced nearly total inhibition of the relative uptake of neutral red (RNRU) and
      phosphofructokinase activity (PFK), and stimulated intracellular specific lactate
      dehydrogenase activity (LDH). Succinate dehydrogenase (SDH) and hexosaminidase
      (HEX) activities were reduced in dose-dependent manner, as was the antioxidative
      enzyme glucose-6-phosphate dehydrogenase (G-6-PDH) with both forms of iron.
      Glutathione reductase (GOR) and glutathione-S-transferase (GST) activities were
      stimulated by Fe (II) but were inhibited by the higher Fe (III) concentrations.
      In conclusion, the experimental model may be useful for the study of different
      metabolic effects induced by the two oxidation states of iron.

PMID- 8661527
TI  - Bioaccumulation of vanadium and other trace metals in livers of Alaskan cetaceans
      and pinnipeds.
AB  - Concentrations for 38 elements are routinely measured in the marine mammal liver
      tissues archived in the National Biomonitoring Specimen Bank (NBSB). Results show
      that hepatic concentrations of vanadium, selenium, silver, cadmium, and mercury
      are positively correlated with age for beluga whales (Delphinapterus leucas) and
      of vanadium, selenium, cadmium, and mercury with length for ringed seals (Phoca
      hispada). Many researchers have reported linear correlations of hepatic selenium,
      cadmium, and mercury with marine mammal age; however, there is only one other
      report of a linear correlation of hepatic vanadium with marine mammal age.
      Vanadium levels are at or below detection limits (< or = 0.01 micrograms/g) in
      liver tissues of U.S. east coast marine mammals from the NBSB but are present at
      levels ranging from 0.02 to 1.2 micrograms/g of wet weight in the tissues of
      Alaskan marine mammals. Although only three bearded seal (Eriganthus barbatus)
      and three bow-head whale (Balaena mysticetus) liver samples have been analyzed,
      hepatic vanadium levels also increased with animal size for these species. The
      presence of relatively high levels of vanadium in the livers of these Alaskan
      animals may reflect a unique dietary source of vanadium, a unique geochemical
      source of vanadium, or anthropogenic input to the Alaskan marine environment.

PMID- 8661529
TI  - Effects of Pulp and Paper Mill Effluent (BKME) on Physiology and Biochemistry of
      the Roach (Rutilus rutilus L.)
AB  - The effects of bleached kraft pulp and paper mill effluent (BKME) on the roach
      (Rutilus rutilus L.) were studied under experimental and natural field
      conditions. In the acute experiment (72 h exposure to the concentrated BKME), the
      roach suffered from a general stress syndrome, characterized by a significant
      increase of cortisol and blood glucose, as well as a significant decrease of
      leucocrit and total plasma protein. In three weeks' exposure in a polluted and an
      unpolluted lake and in fish caught from the same lakes, the more specific effects
      of BKME treatments appeared. During the three weeks' exposure, slight
      hyperglycaemia as well as a decrease in a transaminase activity (GPT) and
      increase in the plasma total protein concentration of the fish occurred in the
      polluted lake. Fish caught from the polluted lake exhibited lower values of
      haematocrit, transaminases (GOT and GPT), and calcium concentration plus a higher
      chloride concentration in the plasma than in the unpolluted lake. The
      differential leukocyte counts also showed slight differences: Fewer lymphocytes
      and more granulocytes were found in roach from polluted waters. The morphology of
      the red blood cells in the roach from polluted lakes had more elongate
      erythrocytes with a longer major axis and a shorter minor axis than in fish from
      the polluted lake. The possibilities of determining the origin of fish based on
      their erythrocyte morphology is discussed.

PMID- 8661530
TI  - Protein Profile Variation in Cultivated and Native Freshwater Microorganisms
      Exposed to Chemical Environmental Pollutants
AB  - Assimilation of 35S-precursors into microbial proteins was used to investigate
      toxicity and adaptational responses that occur in nutrient enriched and natural
      freshwater samples experimentally contaminated with benzene, toluene,
      trichloroethylene (TCE), or xylene. Experiments were conducted to analyze (1) the
      potential of using microbial community protein profiles for responsive
      identification of chemical pollutant exposure, (2) the inhibition of microbial
      productivity through reduction in rate of protein synthesis caused by specific
      chemical pollutants, and (3) whether selection of subpopulations in freshwater
      microbial communities challenged with chemical pollutants leads to adaptive
      strategies mediated by production of particular polypeptides. The results show
      that distinct banding patterns of polypeptides in the range of 30 to 100
      kilodaltons that were obtained following collective cultivation of freshwater
      microorganisms differ with each chemical pollutant. Protein yield and
      radioisotope incorporation were reduced within ten minutes of micro-bial exposure
      to chemical pollutants in the following order: xylene < toluene < benzene < TCE.
      Adaptation of the freshwater microbial community to chemical pollutants prior to
      radioisotope incorporation produced differences in polypeptide profiles, in the
      banding patterns of radioactive polypeptides, and in the rate of radioisotope
      incorporation. The rate of radioisotope incorporation by freshwater
      microorganisms pre-adapted to chemical pollutants was lowest with xylene (88.1%
      reduction), followed by TCE (84.0% reduction),toluene (67.3% reduction), and
      benzene (43.5% reduction). In long-term radioisotope incorporation experiments,
      protein yield and polypeptide radioactivity was higher in the presence of
      chemical pollutants than in uncontaminated control samples, suggesting increased
      metabolic productivity attributable to the chemical pollutants.

PMID- 8661528
TI  - Activities of liver and lung cytochrome P450-dependent monooxygenases and
      antioxidant enzymes in laboratory and wild Norway rats exposed to reference and
      contaminated soils.
AB  - Laboratory and wild Norway rats were exposed in the laboratory to an
      uncontaminated soil and to a soil from a site contaminated with petrochemical
      waste. Activities of microsomal lung and liver cytochrome P450-dependent
      monooxygenases, including 7-ethoxyresorufin O-deethylase (EROD), 7
      pentoxyresorufin O-depentylase (PROD) and 7-benzoxyresorufin O-debenzylase (BROD)
      were measured at selected times during the course of the study. The highest
      degree of induction of hepatic EROD (7-fold) was shown after 3 days of exposure
      to the contaminated soil. However, two months later, the EROD activity declined
      to fourfold increase over the control. The PROD and BROD activities displayed a
      similar time course of induction, but the degree of induction was lower. The
      induction of hepatic monooxygenase activities was observed in both laboratory and
      wild rats. Lung monooxygenase EROD was highly induced (up to 28-fold) after 3
      days of exposure, and the activity remained elevated throughout the two-month
      experiment. BROD and PROD activities were not induced. The activities of three
      antioxidant enzymes, namely superoxide dismutase, glutathione peroxidase (Se- and
      non-Se- dependent) and catalase also were measured in lung and liver cytosol, but
      no significant changes were observed after two months of exposure to contaminated
      soil.

PMID- 8661531
TI  - Protistan Bacterivory in an Oligomesotrophic Lake: Importance of Attached
      Ciliates and Flagellates
AB  - Seasonal and depth variations of the abundance, biomass, and bacterivory of
      protozoa (heterotrophic and mixotrophic flagellates and ciliates) were determined
      during thermal stratification in an oligomesotrophic lake (Lake Pavin, France).
      Maximal densities of heterotrophic flagellates (1.9x10(3) cells ml-1) and
      ciliates (6.1 cells ml-1) were found in the metalimnion. Pigmented flagellates
      dominated the flagellate biomass in the euphotic zone. Community composition of
      ciliated protists varied greatly with depth, and both the abundance and biomass
      of ciliates was dominated by oligotrichs. Heterotrophic flagellates dominated
      grazing, accounting for 84% of total protistan bacterivory. Maximal grazing
      impact of heterotrophic flagellates was 18.9x10(6) bacteria 1(-1)h-1. On average,
      62% of nonpigmented flagellates were found to ingest particles. Ciliates and
      mixotrophic flagellates averaged 13% and 3% of protistan bacterivory,
      respectively. Attached protozoa (ciliates and flagellates) were found to colonize
      the diatom Asterionella formosa. Attached bacterivores had higher ingestion rates
      than free bacterivorous protozoa and may account for 66% of total protozoa
      bacterivory. Our results indicated that even in low numbers, epibiotic protozoa
      may have a major grazing impact on free bacteria.

PMID- 8661532
TI  - Broad-Scale Approaches to the Determination of Soil Microbial Community
      Structure: Application of the Community DNA Hybridization Technique
AB  - Broad-scale approaches seek to integrate information on whole microbial
      communities. It is widely recognized that culture techniques are too selective
      and unrepresentative to allow a realistic assessment of the overall structure of
      microbial communities. Techniques based on fatty acid or metabolic profiles
      determine the phenotypic composition of the community. Complementary information
      about the genotypic structure of soil microbial communities necessitates analysis
      of community DNA. To determine broad-scale differences in soil microbial
      community structure (i.e., differences at the whole community level, rather than
      specific differences in species composition), we have applied a community
      hybridization technique to determine the similarity and relative diversity of two
      samples by cross hybridization. In previous studies this assay failed with whole
      soil community DNA. Usable hybridization signals were obtained using whole-soil
      DNA, in this study, by digesting the DNA with restriction enzymes before the
      labeling with a random-primer reaction. The community hybridization technique was
      tested using a graded series of microbial fractions, increasing in complexity,
      all isolated from the same soil sample. This demonstrated that single bacterial
      species and a mixture of cultivable bacteria were less complex and only 5%
      similar to whole-community DNA or bacteria directly extracted from the soil.
      Extracted bacterial and whole-community DNA were 75% similar to each other and
      equally complex. When DNA was extracted from four different agricultural soils,
      their similarities ranged from 35 to 75%. The potential usefulness of community
      hybridization applied to soil microbial communities is discussed.

PMID- 8661533
TI  - The Examination of Seliberia stellata Exopolymers Using Lectin Assays
AB  - Holdfast exopolymers of the dimorphic oligotrophic bacterium Seliberia stellata
      were examined using fluorescent lectins under light microscopy and colloidal gold
      lectins using transmission electron microscopy. Examination using fluorescent
      labeled lectins revealed that lectins specific for polysaccharides and
      monosaccharides such as glucose and/or mannose, galactose, N-acetylgalactosamine,
      and N-acetylglucosamine (and its dimer) adhered to holdfast structure. Colloidal
      gold-labeled lectin assays also suggested the presence of these sugars. Both the
      holdfast that mediates swarmer cell adhesion and the holdfast that facilitates
      rosette formation gave similar results, suggesting the structures may be the
      same. Another exopolymer produced later in the growth cycle was observed using
      transmission electron microscopy. It appeared as an amorphous glycocalyx-like
      material very different from holdfast exo-polymers. Retention of the gold lectin
      (Wheat Germ Agglutinin (WGA), suggested the presence of N-acetylglucosamine, but
      fluorescent analyses were unsuccessful. The data suggest that S. stellata
      produces at least two different exopolymers: (a) the exopolymer of the swarmer
      cell and rosette holdfast whose function is adhesion and whose composition is
      (but may not be limited to) polysaccharides and (b) a slime-like exopolymer whose
      composition and function remain unknown.

PMID- 8661534
TI  - A Mini-review of Microbial Consortia: Their Roles in Aquatic Production and
      Biogeochemical Cycling
AB  - Molecular oxygen (O2) is a potent inhibitor of key microbial processes, including
      photosynthesis, N2 fixation, denitrification, sulfate reduction, methanogenesis,
      iron, and metal reduction reactions. Prokaryote survival and proliferation in
      aquatic environments is often controlled by the ability to tolerate exposure to
      oxic conditions. Many prokaryotes do not have subcellular organelles for
      isolating O2-producing from O2-consuming processes and have developed consortial
      associations with other prokaryotes and eukaryotes that alleviate metabolic
      constraints of high O2. Nutrient transformations often rely on appropriate
      cellular and microenvironmental, or microzonal, redox conditions. The spatial and
      temporal requirements for microenvironmental overlap among microbial groups
      involved in nutrient transformations necessitates close proximity and diffusional
      exchange with other biogeochemically distinct, yet complementary, microbial
      groups. Microbial consortia exist at different levels of community and metabolic
      complexity, as shown for detrital, microbial mat, biofilm, and planktonic
      microalgal-bacterial assemblages. To assess the macroscale impacts of consortial
      interactions, studies should focus on the range of relevant temporal (minutes to
      hours) and spatial (microns to centimeters) scales controlling microbial
      production, nutrient exchange, and cycling. In this review, we discuss the
      utility and application of techniques suitable for determining microscale
      consortial activity, production, community composition, and interactions in the
      context of larger scale aquatic ecosystem structure and function.

PMID- 8661535
TI  - Bacterial Degradation of Low Concentrations of Phenanthrene and Inhibition by
      Naphthalene
AB  - Phenanthrene-degrading bacteria were isolated from enrichment cultures of soils
      contaminated with creosote and jet fuel. The isolates from the creosote
      enrichments were classified by fatty acid methyl ester profiles as Acidovorax
      delafieldii and Sphingomonas paucimobilis; the bacterium from the jet fuel
      contaminated soil was not identified and was designated strain JFD11. All three
      isolates used phenanthrene as a sole carbon and energy source, and two of the
      isolates used fluoranthene as a sole carbon and energy source. Anthracene and
      fluorene were cometabolized by all three strains, but pyrene was not transformed.
      Naphthalene inhibited all of the strains, and 28-h cultures of A. delafieldii
      were inhibited by naphthalene concentrations as low as 5 ppm. Short-term
      degradation experiments were undertaken with center-well flasks and
      concentrations of phenanthrene ranging from 1.2 to 12.0 &mgr;M. Since initial
      degradation rates were not a function of phenanthrene concentration, it was
      inferred that the half-saturation constants were less than the lowest
      phenanthrene concentration tested.

PMID- 8661536
TI  - Differential Metabolism of Dimethylsulfoniopropionate and Acrylate in Saline and
      Brackish Intertidal Sediments
AB  - In anoxic Spartina alterniflora-dominated sediments along a naturally occuring
      salinity gradient (the Cooper River estuary, South Carolina, U.S.A.),
      dimethylsulfoniopropionate (DMSP) was metabolized to dimethyl sulfide (DMS) and
      acrylate by sediment microbes. The rate of DMSP degradation and acrylate
      mineralization by sediment microbes was similar at all sites along this 25-km
      transect. However, sediments amended with acrylate (or DMSP) showed significantly
      higher rates of N2 fixation (measured as acetylene reduction activity) (ARA) in
      the saline sediments downstream than brackish sediments. These results are
      consistent with the fact that acrylate stimulated the rates of both
      denitrification and CO2 production in the saline sediments at the mouth of the
      river more than tenfold over rates in brackish sediments. Enrichment experiments
      indicate that microbes capable of using DMSP or acrylate were not present in
      upstream sediments despite the fact that microbial biomass, percent organic
      matter, and both glucose-stimulated ARA and denitrification were highest
      upstream. It appears that acrylate utilizing, N2 fixing, and denitrifying
      populations are insignificant in the lower salinity sediments of the estuary.
      These results may reflect the availability of DMSP, which averaged 10.3 nmol g
      wet wt-1 of saline sediments and levels less than our detection limit (1 &mgr;M)
      in brackish sediments.

PMID- 8661537
TI  - Relationship Between Abundance of N2-fixing Cyanobacteria and Environmental
      Features of Spanish Rice Fields
AB  - In order to estimate the potential utilization of N2-fixing (heterocystous)
      cyanobacteria as natural biofertilizers in the Valencian rice fields (Spain), the
      distribution and seasonal variation of these microorganisms in water and sediment
      samples were evaluated, and the relationships among cyanobacterial abundance and
      physical and chemical characteristics of soil and water were investigated. N2
      fixing cyanobacteria were present in all the samples analyzed (25 sampling points
      sampled three times per year during two years). The relative cyanobacterial
      abundance in soil and water followed contrasting patterns, maximum presence in
      soil coincided with minimum abundance in water. Correlation analysis showed that
      cyanobacterial abundance in the two phases (water and sediment) was influenced
      more by water than by soil properties. Salinity,mineralization variables, and
      soluble reactive phosphate (SRP) correlated positively with heterocystous
      cyanobacteria presence. Furthermore, dissolved inorganic nitrogen (DIN) and the
      ratio DIN:SRP correlated negatively with cyanobacterial abundance. However
      DIN:SRP ratio better described the cyanobacterial distribution, with a threshold
      effect: below the Redfield ratio value (7.2 in mass units) cyanobacterial
      abundance was clearly higher.

PMID- 8661538
TI  - The Effect of Temperature on Viability of Carbon- and Nitrogen-Starved
      Escherichia coli
AB  - Escherichia coli was grown in a defined medium at optimum temperature and then
      transferred to each of five different starvation regimes at 5&deg;C, 20&deg;C, or
      37&deg;C, for 1000 hours. Cells were maintained with growth-limiting amounts of
      carbon or nitrogen, or without either or both nutrients. Bacterial cell viability
      was assessed by dilution plating, the reduction of 2-(p-indophenyl)-3-(p
      nitrophenyl)-5-phenyl tetrazolium chloride (INT), direct viable counts (DVC), and
      microcolony development. The recoverability of cells on solid medium declined
      most rapidly, and to the greatest extent in most cases, in cultures maintained at
      37&deg;C. Only nitrogen-starved cells maintained at 5&deg;C became completely
      nonculturable. The reduction of INT consistently indicated higher numbers of
      viable cells compared to the other methods in all cultures. The viabilities of
      carbon- and nitrogen-limited cells, assessed by all methods, were similar to one
      another at each of the temperatures. Viability was lowest at 37&deg;C. Nutrient
      downshifted cells also followed a temperature-dependent pattern of survival with
      viability lowest at 37&deg;C. Morphological differences were noted at different
      temperatures but were most obvious for nitrogen-starved cells at 37&deg;C, which
      increased in length.

PMID- 8661540
TI  - A Comparison of the Survival of Intraperiplasmic and Attack Phase Bdellovibrios
      with Reduced Oxygen
AB  - The ability of intraperiplasmic and attack phase bdellovibrios to survive and/or
      grow under anoxic and microaerobic conditions was examined. Both halotolerant and
      nonhalotolerant bdellovibrio strains were examined. In all instances, the
      bdellovibrio strains were unable to grow under anoxic conditions, but were able
      to survive for periods of time in both the extracellular and intraperiplasmic
      forms. However, the intraperiplasmic organisms were observed to survive longer.
      Increased temperature hastened the loss of viability of both forms of the
      predatory bacteria in oxic and anoxic environments. Under microaerobic
      conditions, halotolerant bdellovibrios were observed to grow, although at a
      slightly reduced rate than in atmospheric oxygen, while two nonhalotolerant
      isolates survived but did not grow. The ability of attack phase bdellovibrios to
      survive in an anoxic environment for up to nine days and their growth or survival
      under microaerobic conditions greatly expands the possible ecological niches in
      which the predators may be active members of the microbial community.

PMID- 8661539
TI  - Exopolysaccharide Production and Attachment Strength of Bacteria and Diatoms on
      Substrates with Different Surface Tensions
AB  - Attachment strength and exopolysaccharide (EPS) production of Pseudomonas sp.
      (bacteria) and the diatom Amphora coffaeformis were studied on six different
      substrata with surface tensions between 19 and 64.5 mN m-1. Test panels of the
      materials were exposed to bacterial cultures between 3 and 120 hours, and to
      diatom cultures between 48 and 72 hours. Exopolysaccharide production by surface
      associated cells was measured using the phenol sulfuric acid method. Attachment
      studies were run by exposing test panels to laminar flow pressure using a radial
      flow chamber. Highest EPS production by bacteria and diatoms was recorded on
      substrata with surface tensions above 30 mN m-1. Lowest EPS production occurred
      on substrata between 20 and 25 mN m-1. Highest EPS production and strongest
      adhesion was found on polycarbonate (33.5 mN m-1). Both test organisms improved
      their attachment strength with exposure time on most materials. However, amounts
      of produced EPS and improvement of attachment indicated that mechanisms other
      than polysaccharide production are more important on substrata with low surface
      tensions (<25 mN m-1). Simply producing more polysaccharides is not sufficient to
      overcome weak attachment on materials with low surface tensions. For example,
      adhesion of Pseudomonas sp. and A. coffaeformis on
      polytetrafluorethylene/perfluor-copolymer (PFA; 22 mN m-1) and glass (64.5 mN m
      1) was equally strong although EPS production was much higher on glass than on
      PFA. This is somewhat surprising for A. coffaeformis because polysaccharide
      production has been considered the most important attachment mechanism of A.
      coffaeformis.

PMID- 8661541
TI  - Seasonal Denitrification in Flooded and Exposed Sediments from the Amazon
      Floodplain at Lago Camaleao
AB  - Denitrification processes were measured by the acetylene-blockage technique under
      changing flood conditions along the aquatic/terrestrial transition zone on the
      Amazon floodplain at Lago Camaleao, near Manaus, Brazil. In flooded sediments,
      denitrification was recorded after the amendment with NO3- (100 MUmol liter-1)
      throughout the whole study period from August 1992 to February 1993. It ranged
      from 192.3 to 640.7 MUmol N m-2 h-1 in the 0- to 5-cm sediment layer. Without
      substrate amendment, denitrification was detected only during low water in
      November and December 1992, when it occurred at a rate of up to 12.2 MUmol N m-2
      h-1. Higher rates of denitrification at an average rate of 73.3 MUmol N m-2 h-1
      were measured in sediments from the shallow lake basin that were exposed to air
      at low water. N2O evolution was never detected in flooded sediments, but in
      exposed sediments, it was detected at an average rate of 28.3 MUmol N m-2 h-1
      during the low-water period. The results indicate that under natural conditions
      there is denitrification and hence a loss in nitrogen from the Amazon floodplain
      to the atmosphere. Rates of denitrification in flooded sediments were one to two
      orders of magnitude smaller than in temperate regions. However, the nitrogen
      removal of exposed sediments exceeded that of undisturbed wetland soils of
      temperate regions, indicating a considerable impact of the flood pulse on the
      gaseous turnover of nitrogen in the Amazon floodplain.

PMID- 8661542
TI  - Genetic Nature, Stability, and Improved Virulence of Hybrids from Protoplast
      Fusion in Beauveria
AB  - Genetic improvement of two different strains of the entomopathogenic fungus
      Beauveria bassiana for more effective control of Ostrinia nubilalis and
      Leptinotarsa decemlineata was obtained by crosses with the insecticidal toxin
      producing strain Beauveria sulfurescens. Protoplast fusion between diauxotrophic
      mutants resulted in the recovery of some stable prototrophic fusion products. The
      low levels of virulence of the wild type strain B. bassiana 28 isolated
      originally from L. decemlineata were enhanced both on L. decemlineata and O.
      nubilalis for one of the hybrids obtained (FP 8) from the cross B. bassiana 28xB.
      sulfurescens 2. Fusion product 25 obtained from the cross between B. sulfurescens
      and the highly pathogenic strain B. bassiana 147 showed a three-day reduction in
      the LT50 towards O. nubilalis. Southern blot hybridization with nine probe-enzyme
      combinations were conducted on genomic DNAs from the original wild strains,
      parental mutant strains, and fusion products. Additive banding patterns or unique
      banding pattern of either parental strain was observed in five hybrids,
      indicating their status as recombinant and/or partially diploid. Combination of
      RFLP markers indicative of both parental genomes was never observed with fusion
      product FP 25. The stability of the virulence following passage through insect
      host and stability of molecular structure for the fusion products FP 8 and FP 25
      suggest that asexual genetic recombination by protoplast fusion may provide an
      attractive method for the genetic improvement of biocontrol efficiency in
      entomopathogenic fungi.

PMID- 8661543
TI  - Studies on the Aquatic Hyphomycetes of a Sulfur Spring in the Western Ghats,
      India
AB  - Studies on the occurrence of aquatic hyphomycetes were carried out in Panekal
      sulfur spring in the Western Ghats, India by incubation of leaf litter and
      analysis of natural foam and of induced foam. Sampling was done once every three
      months over a period of two years from September 1989 to June 1991. The
      temperature, pH, dissolved oxygen, and sulfide content of water were also
      measured. No fungi were observed within the spring, whereas 16 species belonging
      to 13 genera were isolated from two outflow sites of the stream. The percent
      frequency of Triscelophorus monosporus was high (24.0%). The temperature of water
      in the spring ranged between 30.0 and 38.5&deg;C and the sulfide content between
      3.2 and 4.3 mg 1(-1). Studies showed that sulfide water (4.0 mg 1(-1)) from the
      spring inhibited the growth of the colonies of Dactylella aquatica, Phalangispora
      constricta, Tetracladium setigerum, Vermispora cauveriana, and Wiesneriomyces
      laurinus. When the leaves colonized by aquatic hyphomycetes were incubated at
      different temperatures in sulfur-spring water and stream water separately,
      sporulation was not observed in any of the fungi at and above 35&deg;C except
      Phalangispora constricta, which could sporulate at 35&deg;C. At lower
      temperatures (15-30&deg;C) relatively fewer species were found to sporulate in
      sulfur-spring water than in stream water.

PMID- 8661544
TI  - Evaluation of Extracellular, High-affinity beta-N-acetylglucosaminidase
      Measurements from Freshwater Lakes: An Enzyme Assay to Estimate Protistan Grazing
      on Bacteria and Picocyanobacteria
AB  - Protistan community grazing rates upon both bacterioplankton and autotrophic
      picoplankton were estimated using fluorescently-labeled prey and by measurement
      of extracellular hydrolysis of 4-methylumbelliferyl (MUF) beta-N
      acetylglucosaminide in a eutrophic reservoir and an oligo-mesotrophic lake during
      phytoplankton blooms. In addition, enzyme methods were optimized in bacterivorous
      flagellate cultures by two enzyme assays, based on fluorometric detection of
      protistan digestive activity, which were compared and calibrated independently
      against flagellate bacterivory. Enzymatic hydrolyses of MUF beta-N,N',N''
      triacetylchitotriose and MUF beta-N-acetylglucosaminide were measured in cell
      free (sonicated) and whole-cell (unsonicated) samples. The hydrolysis of both
      substrates, using the whole-cell enzyme assay at in situ pH, was correlated
      significantly with total grazing rate of Bodo saltans. Thus the whole-cell enzyme
      assay with MUF beta-N-acetylglucosaminide was used for freshwater samples. High
      affinity (Km < 1 MUmol l-1) and low-affinity (Km > 100MUmol l-1) enzymes were
      distinguished kinetically in most samples from both systems studied. Activities
      (Vmax) of the high-affinity enzyme varied from 0.24 to 1.43 nmol l-1 h-1.
      Protistan community grazing on bacterioplankton was in the range of 0.15-1.36 MUg
      C l-1 h-1 both for lake and reservoir, the differences being observed in grazing
      on picocyanobacteria (lake, 0.03-0.22 MUg C l-1 h-1; reservoir, 0.35-1.56 MUg C l
      1 h-1). The enzyme activities were correlated significantly with the protistan
      grazing both on bacterioplakton (rs=0.62, P<0.001) and total procaryotic
      picoplankton (the sum of organic carbon grazed from bacteria and
      picocyanobacteria, rs=0.73, P<0.001) in the eutrophic reservoir. Weaker
      relationships (rs=0.42) with a lower slope were found for the oligo-mesotrophic
      lake. Ingestion rate studies are time-consuming and the digestive enzyme assay
      with MUF beta-N-acetylglucosaminide presents a rapid alternative for estimating
      total protistan prokaryotic picoplanktivory in freshwaters.

PMID- 8661545
TI  - MRI diagnosis and staging of rectal carcinoma.

PMID- 8661546
TI  - Endoscopic ultrasonographic staging of primary gastric lymphoma.

PMID- 8661547
TI  - Spread of gallbladder carcinoma: CT evaluation with pathologic correlation.
AB  - BACKGROUND: To assess the accuracy of computed tomographic (CT) imaging in the
      detection of spread and staging of gallbladder carcinoma. METHODS: CT findings of
      spread of gallbladder carcinoma in 59 Japanese patients who underwent radical
      surgery were correlated retrospectively with pathologic findings. RESULTS: The
      incidence of histologically proven nodal involvement was 54% (32 patients) and
      the most common spread of gallbladder carcinoma. The sensitivities in CT
      detection of N1 and N2 nodal involvement were 36% and 47%, respectively; positive
      predictive values were 94% and 92%, respectively. Direct extension to the liver,
      extrahepatic bile duct, and gastrointestinal tract or pancreas were
      histologically confirmed in 24, 18, and five patients. The sensitivities in the
      CT detection of direct spread to the liver of less than 2 cm, more than 2 cm, the
      extrahepatic bile duct, and the gastrointestinal tract or pancreas were 65%,
      100%, 50%, and 57%, respectively; positive predictive values were 77%, 100%, 90%,
      and 100%, respectively. The incidence of liver metastases and involvement of
      interaortocaval nodes were 7% and 16%, respectively. The sensitivities in CT
      detection of liver metastases and involvement of interaortocaval nodes were 75%
      and 21%, respectively; positive predictive values were 100% and 86%,
      respectively. CT could not detect direct spread to omentum and peritoneal
      seedings. CONCLUSION: For detecting the spread of gallbladder carcinoma, CT
      imaging has low to moderate sensitivity; however, CT imaging can help in
      determining resectability and in planning the treatment, especially in advanced
      stage gallbladder carcinoma, because of a high positive predictive value.

PMID- 8661548
TI  - Vascular involvement in pancreatic adenocarcinoma: reassessment by thin-section
      CT.
AB  - We defined computed tomographic (CT) criteria of vascular involvement by
      pancreatic carcinoma and used these criteria to assess vascular involvement in 56
      patients with pancreatic adenocarcinoma. CT of the pancreas was performed at 1.5
      mm section thickness and 5-mm section intervals during a bolus phase of
      intravenous contrast enhancement. The type of vascular involvement was correlated
      with surgical and pathologic findings. When there was fat-plane (type A) or
      normal pancreatic parenchyma (type B) separating the tumor from adjacent vessels,
      the tumor could be resected without venous resection in 21 of 22 patients (95%).
      When the tumor was inseparable from the vessels but the points of contact formed
      a convexity against the vessel (type C), CT was not reliable in predicting
      whether or not the tumor was fixed against the vessel. When the tumor was
      partially encircling (type D) the vessel, the tumor was fixed against the vessels
      in most cases. The resectable rate was 47%, but resection would also require
      venous resection. When the tumor was completely encircling (type E) or occluding
      (type F) the vessel, all tumors were not resectable with a negative margin. Thin
      section CT with bolus intravenous contrast enhancement improved the ability to
      assess vascular involvement in pancreatic adenocarcinoma.

PMID- 8661549
TI  - Pancreatic adenocarcinoma.

PMID- 8661551
TI  - Wedge-shaped intrahepatic cholangiocarcinoma: MRI-pathologic correlation.
AB  - On magnetic resonance imaging (MRI) studies, wedge-shaped areas of signal
      abnormality noted in association with liver lesions have been attributed to
      secondary phenomena and are said to be substantially larger than the actual
      tumor. We describe the MRI and pathological appearance of a wedge-shaped
      cholangiocarcinoma. In cases where therapy might be affected, biopsy of wedge
      shaped MRI abnormalities associated with hepatic malignancy should be considered
      for accurate tumor staging.

PMID- 8661552
TI  - Mucin-hypersecreting papillary cholangiocarcinoma presenting as abdominal wall
      abscess: CT and spiral CT cholangiography.
AB  - We describe CT findings of a case of mucin-hypersecreting papillary
      cholangiocarcinoma (MHPC), with extrahepatic bile leakage to the rectus abdominis
      muscle via the ligamentum teres hepatis forming an abdominal wall abscess.
      Endoscopic retrograde cholangiography was unsatisfactory. Spiral three
      dimensional CT cholangiography was helpful in assessing the resectability of MHPC
      by offering anatomic details of the uninvolved biliary tree.

PMID- 8661553
TI  - Jaundice due to afferent loop obstruction following hepatectomy for a hilar
      cholangiocarcinoma.
AB  - A case of jaundice due to obstruction of Roux en Y-limb following hepatectomy for
      a hilar cholangiocarcinoma is presented. Percutaneous transhepatic biliary
      drainage improved the jaundice but promoted disseminated intravascular
      coagulopathy. Our limited experience suggested that afferent loops should be
      drained directly to prevent reflux of enteric contents into the biliary system.

PMID- 8661554
TI  - Peribiliary cysts in cirrhotic liver: observation on computed tomography.
AB  - BACKGROUND: To analyze the frequency and number of suspected peribiliary cysts in
      cirrhotic liver on computed tomography (CT). METHODS: Three hundred forty-six
      cases with clinically diagnosed liver cirrhosis (LC) and 307 cases with
      clinically diagnosed non-LC were subjected to the study. The frequency and number
      of suspected peribiliary cysts on CT were compared between the two groups. The
      existence of peribiliary cysts was suggested when a cyst was observed around the
      second- to fourth-order branches of the intrahepatic portal vein. RESULTS:
      Peribiliary cysts were suggested on CT in 31 of 346 cirrhotic livers (9.0%) and
      10 of 307 noncirrhotic livers (3.3%). This difference in the frequency of
      peribiliary cysts was statistically significant (chi2, p < 0.01). Multiple
      peribiliary cysts were seen in 71% of cirrhotic patients with peribiliary cyst.
      The size of peribiliary cysts was smaller than 1.5 cm in diameter. CONCLUSION:
      Peribiliary cyst is radiologically observed more frequently in cirrhotic liver
      than in noncirrhotic liver and is occasionally multiple.

PMID- 8661555
TI  - Color doppler imaging of the gallbladder wall in acute cholecystitis: sonographic
      pathologic correlation.
AB  - BACKGROUND: The purpose of this study was to evaluate the usefulness of color
      Doppler imaging (CDI) in suspected cases of acute cholecystitis. METHODS: Twenty
      two patients suspected of having acute cholecystitis were prospectively evaluated
      over a 12-month period using gray-scale and color Doppler technique. Gallbladder
      wall thickness was greater than 2 mm in all patients included in the study.
      Pathologic correlation was obtained in 17 patients, with clinical or sonographic
      follow-up in five for a period of 6-/011001/months. CDI was considered positive
      only if the mid to fundal wall demonstrated flow. Sonographic Murphy's sign and
      laboratory values were recorded. RESULTS: Eight patients had acute cholecystitis.
      All had positive color Doppler flow. Wall thickness in these patients ranged
      between 4 and 10 mm. Three patients with necrotizing acute cholecystitis had no
      flow within 6-8-mm walls. Six patients with pathologically proven chronic
      cholecystitis had no evidence of increased flow within thickened walls. Five
      patients with presumed chronic cholecystitis (thickened wall without increased
      color flow) were treated medically, and their symptoms resolved. CDI was more
      sensitive in predicting acute cholecystitis than was the sonographic Murphy's
      sign and/or laboratory values. CONCLUSION: CDI demonstrates hyperemic changes in
      thickened gallbladder walls and is an important adjunct in the diagnosis of acute
      cholecystitis.

PMID- 8661556
TI  - CT of Hodgkin's lymphoma limited to the gallbladder.
AB  - A complex mass confined to the gallbladder found on CT is unusual, but nor rare,
      with causes including benign inflammatory disease, early primary carcinoma and
      metastases. Non-Hodgkin's lymphoma is rare and Hodgkin's disease, prior to the
      current case, unheard of involving just the gallbladder. Thus, this should be
      considered part of the differential diagnosis of a complex gallbladder mass.

PMID- 8661557
TI  - Duodenojejunal intussusception with biliary obstruction and atrophy of the
      pancreas.
AB  - Enteroenteric intussusceptions in adults are rare events caused by tumors in most
      cases. A case of duodenojejunal intussusception is presented which became
      manifest because of marked biliary obstruction and extensive pancreatic atrophy.
      As lead point, a large duodenal polypous hamartoma could be identified. The role
      of ultrasound and CT as diagnostic imaging of choice in this entity are
      discussed.

PMID- 8661558
TI  - Small bowel enteroclysis: pros.

PMID- 8661559
TI  - Small bowel enteroclysis: cons.

PMID- 8661561
TI  - Solitary malignant mesothelioma of the small intestine: radiological appearances.
AB  - Malignant peritoneal mesothelioma is virtually unknown to feature as a solitary
      lesion. A patient presented with abdominal pain, weight loss, and melena and
      underwent enteroclysis, computed tomography, and superior mesenteric
      arteriography. Sharp angulation, narrowing, and mucosal destruction in a jejunal
      segment, caused by an encapsulating infiltrative mesenteric mass, were shown. The
      diagnosis of a malignant peritoneal mesothelioma, localized to the small
      intestine, was made at histology.

PMID- 8661560
TI  - Current status of small bowel radiography.
AB  - BACKGROUND: In the past, small bowel examinations were usually ordered for the
      sake of "completeness." As a result, small bowel radiography was performed
      casually and without attention to detail. This review examines pertinent clinical
      issues and the recent contribution of small bowel radiography to the evaluation
      and management of the patient with suspected small bowel disease. Recommendations
      for the clinical utilization of small bowel radiography are discussed. METHODS:
      Analysis of pertinent citations addressing valid indications for, and technique
      of, small bowel radiography from 1980 to July 1995 through a computerized
      bibliographic search (Medline and Current Contents). RESULTS: Accepted clinical
      indications for small bowel radiography include (1) unexplained gastrointestinal
      bleeding, (2) possible small bowel tumor, (3) small bowel obstruction, (4) Crohn
      disease, and (5) malabsorption. The current literature reflects the limitations
      of the conventional small bowel follow-through, various modifications to improve
      its clinical yield, the important contribution of enteroclysis in the workup, and
      subsequent management of patients with possible small bowel disease. A
      controversy in the radiology literature exists as to whether to use the small
      bowel follow-through or enteroclysis as the primary method of examining the small
      bowel. CONCLUSION: The thoughtful selection of patients by clinicians for small
      bowel radiography is essential to make radiologic evaluation cost effective. The
      incidence of disease of the small intestine is low and is associated with
      nonspecific symptoms. Because of the inherent difficulty of visualizing numerous
      loops of an actively peristalsing bowel, a reliable imaging method is needed that
      not only detects small or early structural abnormality but also accurately
      documents normalcy. The yield of information provided by enteroclysis and its
      high negative predictive value suggests that it should be the primary method for
      small bowel examination. The "overhead"-based conventional small bowel follow
      through should be abandoned. The "fluoroscopy"-based small bowel follow-through
      augmented when necessary by the peroral pneumocolon or the gas-enhanced double
      contrast follow-through method is an acceptable alternative when enteroclysis is
      not possible.

PMID- 8661562
TI  - Restorative proctocolectomy: morphological and functional study with coronal CT.
AB  - BACKGROUND: Restorative proctocolectomy with ileal pouch has become the surgical
      treatment of choice for patients with ulcerative colitis (UC) and familial
      polyposis of the colon. Defecography is the radiological technique commonly
      employed to obtain detailed information on function and morphology of the ileal
      pouch; it allows the direct visualization of the ileal pouch and the anal canal,
      but it does not provide the visualization of the pelvis. METHODS: In all
      patients, computed tomography (CT) on coronal planes was performed to determine
      its possibilities as an alternative to defecography; 10 patients with UC
      submitted to restorative proctocolectomy and were examined. RESULTS: Coronal CT
      images provided a panoramic vision of the pelvis and demonstrated the morphology
      of the ileal pouch, the thickness of its walls, and its correlation with the
      surrounding tissues. Coronal CT also allowed the evaluation of the continence of
      ileo-anal and ileo-ileal anastomosis and the functional changes of the perineal
      muscles at rest and during squeezing. CONCLUSION: CT images acquired on coronal
      planes allows an easy and clear detection of the major postoperative
      complications, such as stenosis or dehiscences of the anastomosis, pelvic
      phlogosis, and fistulae.

PMID- 8661564
TI  - Renal cell carcinoma and tumor thrombus neovascularity: MR demonstration with
      pathologic correlation.
AB  - A case of renal granular cell carcinoma with inferior vena cava and right atrium
      involvement is presented. Spin-echo and single breath-hold gradient-recalled-echo
      magnetic resonance pulse sequences demonstrate a patchy flow signal within the
      cavoatrial thrombus. This pattern, in correlation with the histopathologic
      findings, represents tumoral neovascularity characteristic of renal carcinoma
      venous invasion, which was previously reported by angiography, computed
      tomography, and color Doppler duplex ultrasound.

PMID- 8661563
TI  - Retroperitoneal amyloidosis, factor IX and X deficiency,and gastrointestinal
      bleeding.
AB  - A patient with gastrointestinal bleeding due to amyloidosis-related factor X
      deficiency had extensive calcified retroperitoneal amyloid deposition that was
      visible on plain radiographs and then localized by computed tomography. The
      radiologic findings were important in arriving at the proper diagnosis despite
      negative biopsies.

PMID- 8661565
TI  - Testicular feminization: radiologic considerations in a unique form of
      cryptorchidism.
AB  - A case report of complete testicular feminization is presented. The medical and
      radiological characteristics of this condition which distinguish it from male
      cryptorchidism and other disorders of sexual differentiation are discussed. To
      our knowledge, only three previous case reports have been published in the
      radiology literature. Our report is the first to describe MRI findings.

PMID- 8661566
TI  - Bladder pheochromocytoma with ring calcification.
AB  - A case of a 19-year-old male with a paraganglioma (pheochromocytoma) arising in
      the prostate and involving the urinary bladder is presented. The radiological
      studies, including computed tomography, demonstrated ringlike calcification of
      the tumor, a rare finding that is highly suggestive of the diagnosis of
      pheochromocytoma. The tumor was excised and found to be malignant at surgery.

PMID- 8661569
TI  - Hepatic pseudolesion around the falciform ligament: prevalence on CT examination.
AB  - BACKGROUND: The purpose of this study was to determine the prevalence of hepatic
      pseudolesions seen around the falciform ligament on computed tomography (CT) of
      the abdomen obtained with intravenous administration of contrast material.
      METHODS: We first retrospectively reviewed the CT scans of six patients in whom
      hepatic pseudolesions were seen around the falciform ligament. The abdominal CT
      scans of 587 patients were then prospectively analyzed for the presence of
      hepatic pseudolesions around the falciform ligament to determine the prevalence
      of this finding on CT examinations. RESULTS: CT scans in the first six patients
      showed two types of hepatic pseudolesion around the falciform ligament. In three
      patients, hepatic pseudolesions were focal spared areas in fatty liver. In three
      patients, hepatic pseudolesions were developed in nonfatty liver. Prospectively,
      hepatic pseudolesions were found on five of 587 CT examinations (prevalence =
      1%). A single hepatic pseudolesion was found in segment 4 on two examinations.
      Two hepatic pseudolesions (one in segment 4 and one in segment 3) were found
      together on three CT examinations. CONCLUSION: Hepatic pseudolesions around the
      falciform ligament are seldom seen on CT scan. However, recognition of these
      pseudolesions is crucial because they may be interpreted as true tumors.

PMID- 8661570
TI  - Transjugular retrograde obliteration for gastric varices.
AB  - We evaluated the transjugular retrograde obliteration (TJO) in treatment of
      gastric varices with gastrorenal shunt. Twenty patients with posthepatitic
      cirrhosis were included in this study. A cobra-shaped 5 French occlusive balloon
      catheter was inserted into the gastric varices or gastrorenal shunt through the
      internal jugular vein. As the sclerosants, absolute ethanol and 5% ethanolamine
      oleate with iopamidol were injected into the varices to make thrombi. In all
      cases, gastric varices were obliterated successfully. Endoscopic examination 3
      months after treatment revealed the complete eradication of gastric varices in
      all cases. No major complications during or after therapy were observed. We think
      that TJO can be an effective method for the treatment of gastric varices with
      gastrorenal shunt.

PMID- 8661571
TI  - Pirenzepine versus scopolamine methyl bromide in double-contrast barium enema
      study of large bowel.
AB  - To evaluate the usefulness of pirenzepine for diagnostic double-contrast barium
      enema study of the large bowel, pirenzepine and scopolamine methyl bromide (SMB)
      were compared in a single, blind, randomized trial. Sixty consecutive patients
      were enrolled in the study. Quantitative analysis of bowel distention was done by
      measuring the maximum diameter of the transverse colon before and after drug
      administration. Four independent observers blindly evaluated distention and
      mucosal coating of the large bowel and global quality of the images. No
      differences were found in the diagnostic performance between the two drugs.
      However, pirenzepine induced a slight but significantly larger distention of the
      large bowel (68 +/- 12 vs. 65 +/- 8 mm, p = 0.02). Heart rate and rhythm during
      the study were recorded by ECG. SMB induced tachycardia in all patients (from 72
      +/- 15 to 98 +/- 24 beats/min, p < 0.01), whereas pirenzepine did not (from 76 +/
      13 to 78 +/- 20, p = NS). After SMB, one-patient exhibited faintness, and some
      patients complained of visual accommodation defects, dryness of the mouth, and
      dizziness. Pirenzepine had a diagnostic performance similar to SMB in avoiding
      adverse effects elicited by SMB.

PMID- 8661573
TI  - Computed tomographic appearance of sigmoid volvulus.
AB  - The computed tomographic (CT) appearance of two cases of sigmoid colon volvulus
      is described. Both underwent plain abdominal radiographs, contrast enema, and CT.
      The findings of sigmoid volvulus at CT were characteristic, having a whirl
      pattern of the dilated sigmoid loop around mesocolon and vessels and a bird-beak
      aspect of the afferent and efferent segments. CT may be valuable in a case of
      unusual clinical or plain film presentation as an alternative to contrast enema.

PMID- 8661572
TI  - Reduction of peristaltic artifacts on magnetic resonance imaging of the abdomen:
      a comparative evaluation of three drugs.
AB  - BACKGROUND: Peristaltic motion is an omnipresent source of degradation in
      abdominal magnetic resonance (MR) imaging by blurring images and producing ghost
      artifacts that can mask or mimic lesions. The objective of this study was to
      select an effective and easy-to-administer drug to provide consistent reduction
      of peristaltic motion artifacts on MR images. METHODS: One hundred forty-eight
      adult patients with MR examinations of the abdomen were enrolled in a
      prospective, single-blind comparative study. Four groups were defined: (a) no
      drug control group (n = 35), (b) 1 mg of intravenous (IV) glucagon (n = 19), (c)
      20 mg of IV butylscopolamine (n = 28), and (d) 20 mg of oral dicyclomine (n =
      66). All patients received high-density barium sulphate as a negative oral
      contrast medium. Quantitative image analysis was performed with operator-defined
      region-of-interest measurements of signal intensity. Gastrointestinal noise was
      measured outside the patient at the posterior part of the left hemiabdomen along
      the phase-encoding direction on a short inversion time inversion recovery (STIR)
      sequence. RESULTS: Treatment groups showed reduced gastrointestinal noise (p <
      0.01). When compared with the control group, IV butylscopolamine (p < 0.05) and
      oral dicyclomine (p < 0.05) significantly reduced gastrointestinal noise, whereas
      glucagon did not. CONCLUSION: Anticholinergic drugs significantly reduced the
      intensity of ghost artifacts on MR imaging of the abdomen. Twenty milligrams of
      oral dicyclomine is an effective and safe alternative to more expensive and
      parenterally administered drugs such as glucagon and butylscopolamine.

PMID- 8661576
TI  - Migratory surgical clip in the common bile duct: CT diagnosis.
AB  - There are only a few case reports in the literature describing the migration of
      metallic surgical clips into the common bile duct. Diagnosis of this
      postcholecystectomy complication is usually made during ERCP. We describe the
      identification on CT scan of a migratory surgical clip in the common bile duct in
      a patient with biliary colic.

PMID- 8661575
TI  - CT evaluation of the resectability of gastric cancer postchemotherapy.
AB  - BACKGROUND: To determine the accuracy of CT in the postchemotherapy assessment of
      resectability of gastric cancer. METHODS: Thirty patients deemed to have
      unresectable gastric cancer on CT were studied. This was verified at laparotomy
      in 10 of these patients. Following initial assessment, all received three to
      eight cycles of chemotherapy aiming for disease control and potential resection.
      Serial CT examinations, endoscopy, and biopsy were performed after the fourth,
      sixth, and eighth cycle of treatment. The primary tumor and lymph nodes seen on
      CT were compared with operative findings. RESULTS: After completion of
      chemotherapy, CT findings were correct in 23 patients. Fourteen of them had
      operable tumors and nine were inoperable. However, the CT findings were either
      equivocal or incorrect in the remaining seven patients. CONCLUSION: Chemotherapy
      is now able to downstage a previously inoperable gastric cancer, and CT is an
      accurate method in identifying those patients who can proceed to resection.

PMID- 8661578
TI  - Hyperattenuating insulinoma at unenhanced CT.
AB  - We report a case with insulinoma that showed higher attenuation than normal
      pancreatic parenchyma on precontrast CT. Pathology of the surgical specimen
      revealed the presence of psammoma bodies, which were responsible for
      hyperattenuation. It is worthwhile to obtain precontrast CT in patients suspected
      of having insulinoma.

PMID- 8661577
TI  - A new criterion in differentiation of pancreatitis and pancreatic carcinoma:
      artery-to-vein ratio using the superior mesenteric vessels.
AB  - Evaluation of infiltration of the superior mesenteric vein (SMV) and artery (SMA)
      fat planes has been considered in differentiating pancreatic carcinoma from
      pancreatitis. Some pancreatitis cases, however, can cause perivascular fat plane
      obliteration due to extension of the inflammatory process, mimicking appearances
      of carcinoma. This study investigated the diameters of SMV and SMA on CT scans,
      just caudal to the origin of SMA and portal confluens, in 68 pancreatitis and in
      48 pancreatic carcinoma patients. SMA-to-SMV diameters (A/V diameter) were
      compared and ratios were obtained. In conclusion, it appears that when the A/V
      ratio is over 1.0, a malignant condition can be suspected. This may be used as a
      secondary criterion in the differential diagnosis of pancreatitis and pancreatic
      carcinoma.

PMID- 8661579
TI  - Insulinoma: correlation of short-TI inversion-recovery (STIR) imaging and
      histopathologic findings.
AB  - We studied the value of short-TI inversion-recovery (STIR) imaging for the
      localization of pancreatic insulinoma. Four patients (three women and one man
      aged 35-65 years) with surgically proven insulinoma were included in this study.
      All patients were examined by MR imaging with spin echo (SE) and STIR sequences.
      The STIR images were compared with the histopathologic findings in each case. In
      two patients, the tumors were markedly hyperintense on STIR images, and a 5-mm
      insulinoma was depicted only by this imaging method in one of the two. In the
      other two patients, 10-mm insulinomas were only slightly hyperintense on STIR
      images. The latter tumors had a higher content of collagen fibers than the
      former, indicating that the amount of collagen influences the signal intensity of
      insulinoma. Despite some limitations, STIR imaging is a useful noninvasive method
      for the localization of pancreatic insulinoma.

PMID- 8661580
TI  - A new method for study of the rectum using transvaginal ultrasound with water
      enema.
AB  - BACKGROUND: To propose a new method for the ultrasound study of the rectum.
      METHODS: Twenty-one healthy female patients, 58-72 years old, were examined. To
      achieve optimal filling and distention of the rectum, the examination was
      performed with the patient in the right lateral decubitus position. After placing
      the probe into the vagina, 1000-1500 mL of water warmed to 35 degrees C was
      introduced into the rectum through a cannula. After the rectum was completely
      full, the cannula was extracted. Images were obtained before and after rectum
      distention on the transverse plane by using a 5.0-MHz convex radial endocavitary
      probe. RESULTS: Using water eliminated air and fecal artifacts, so rectal wall
      layers were reliably demonstrated, with the rectal ampulla well distended. In
      addition, the rectum in whole circumferential extension and the perirectum fat
      were clearly visualized. CONCLUSION: This new method is useful for study of the
      rectum.

PMID- 8661581
TI  - Value of endorectal coil versus body coil MRI for diagnosis of recurrent pelvic
      malignancies.
AB  - BACKGROUND: To compare endorectal coil magnetic resonance imaging (MRI) with body
      coil MRI in detecting local recurrence of gynecologic tumors and prostate and
      rectal cancers. METHODS: Forty-six patients with suspected recurrent pelvic
      malignancies (13 gynecologic, 15 prostatic, and 18 anorectal primaries) were
      enrolled in the study. Axial T1- and T2-weighted body coil images and T2- and
      contrast-enhanced T1-weighted axial endorectal coil images were obtained on a 1.5
      T system. Results of the MR examinations were compared with histological findings
      and follow-up examinations with respect to the diagnostic accuracy and diagnostic
      confidence for assessment or exclusion of local recurrence. RESULTS: Recurrent
      disease was histologically confirmed in eight patients with primary gynecologic
      malignancies, seven with suspected prostatic recurrence, and seven with suspected
      anorectal recurrence. Overall, accuracy of body coil MRI was 67% for gynecologic
      tumors, 36% for prostatic recurrences, and 59% for rectal recurrences. T2- and
      contrast-enhanced T1-weighted endorectal sequences yielded similar results, with
      an accuracy of 73% for depiction of gynecologic recurrence, 77% for prostatic
      recurrence, and 77% for rectal recurrence. The difference in accuracy between
      body coil and endorectal coil examinations was statistically significant (p < 0.
      05) only for prostatic cancer. Diagnostic confidence was, however, significantly
      improved (p < 0.05) in all tumors (T2-weighted endorectal coil examination was
      superior to T2-weighted body coil images in 71% of cases). CONCLUSION: Although
      the results of endorectal coil MRI are only slightly superior to those of body
      coil MRI for the detection of recurrent gynecologic and anorectal tumors,
      diagnosis can be made with greater diagnostic confidence in many cases. For
      detection of prostatic recurrence, endorectal MRI is highly recommended.

PMID- 8661582
TI  - CT and anal endosonography in the evaluation of electrically stimulated neoanal
      sphincter: a preliminary report.
AB  - We report a preliminary experience concerning the postoperative assessment of
      three patients who underwent gracilis neosphincter operation for severe fecal
      incontinence and were studied by computed tomography and anal endosonography soon
      after gracilis transposition and later after 6-8 weeks of neuromuscular training.
      Morphologic assessment was correlated with physiologic testing (manometry).
      Continence was satisfactorily improved in all patients. Both imaging techniques
      demonstrated the anatomy of the transposed muscle. Computed tomography also
      assessed lead placement onto the gracilis nerve root and the completeness of
      muscle transposition around the anal canal. Anal endosonography provided a more
      accurate assessment of the relation between the neosphincter and residual
      external sphincter.

PMID- 8661583
TI  - Complications of renal angiomyolipomas: CT evaluation.
AB  - Complications from angiomyolipomas are rare but often severe depending on the
      size and content of the angiomyolipoma. In this study, we describe 10 cases from
      63 patients with renal angiomyolipomas in whom computed tomography revealed the
      following complications: compression of pyelocalyceal system in three cases,
      intratumoral bleeding in two cases, rupture in four cases with subcapsular,
      perirenal, or pararenal hematoma and extensive intrarenal/parapelvic hematoma,
      cystic degeneration in one case.

PMID- 8661584
TI  - Arterial embolization to control renal hemorrhage in patients with percutaneous
      nephrostomy.
AB  - Two patients with renal hemorrhage treated by arterial embolization are reported.
      In one patient, one kidney was injured and the another had poor function. The
      other patient had one kidney. Although both patients had hematuria and underwent
      percutaneous nephrostomy, the bleeding location was not detected
      angiographically. Repeated embolization and irrigations through a nephrostomy
      catheter following each embolization arrested the bleeding.

PMID- 8661585
TI  - Serum prostate-specific antigen as a predictor of staging abdominal/pelvic
      computed tomography in newly diagnosed prostate cancer.
AB  - BACKGROUND: The standard staging evaluation for prostate cancer includes digital
      rectal examination, measurement of serum tumor markers, and radionuclide bone
      scan. In many institutions, abdominal/pelvic computed tomography (CT) scan or
      nuclear magnetic resonance imaging (MRI) is performed. We retrospectively
      reviewed 425 cases of newly diagnosed, untreated adenocarcinoma of the prostate
      to evaluate the ability of serum prostate-specific antigen (PSA) to predict
      results of staging abdominal pelvic CT. METHODS: The medical records of 425 newly
      diagnosed, untreated prostate cancer patients were reviewed. The following
      information was collected on a standard data form: age, clinical stage based on
      digital rectal exam, method of diagnosis, histological grade, serum PSA level,
      and results of abdominal pelvic CT including adenopathy and abnormalities of the
      upper urinary tract. The results of this review were tabulated and analyzed with
      regard to the ability of serum PSA level to predict positive results of abdominal
      pelvic CT. RESULTS: The mean PSA level of the study group was 22.1 ng/ml.
      Fourteen patients (3.6%) presented with a positive abdominal/pelvic CT (12 with
      adenopathy, one with a renal cell tumor, and one with an adrenal metastasis).
      Eleven of these (79%) had serum PSA levels of 30.0 ng/ml or greater, ranging from
      30.0 to 234 ng/ml. No patient with a positive study presented with a normal serum
      PSA level. Two patients with a positive study had a serum PSA level between 4.1
      and 10.0 ng/ml (0.6%), and one had a PSA level between 10.1 and 20 ng/ml (0.3%).
      CONCLUSION: We conclude that in asymptomatic patients with newly diagnosed,
      untreated prostate cancer and serum PSA levels of less than 20 ng/ml the
      likelihood of positive findings on abdominal/pelvic CT is extremely low (<1.0%).
      Abdominal/pelvic CT does not appear necessary in this setting. With 200,000 cases
      of newly diagnosed prostate cancer each year in the United States, elimination of
      staging abdominal/pelvic CT in these patients could reduce medical expenditures
      for prostate cancer management by $20-50 million per year.

PMID- 8661587
TI  - The query corner

PMID- 8661588
TI  - Abstracts of selected papers from the current literature

PMID- 8661586
TI  - Complications of inferior vena cava filters.

PMID- 8661592
TI  - Partial subfascial abdominoplasty.
AB  - An efficient liposuction is one performed behind and above the abdominal
      superficial fascia. It is followed first by a dissection at the deep side of this
      fascia, and then after a change of plane, at the supra-umbilical level to reach
      the pre-muscular fascia plane. Dissection is then adjusted according to the
      amount of excess skin. As the amount of tissue that needs to be vascularized by
      the subdermal arterial network is reduced, and as no major lymphatic trunk is
      cut, the partial subfascial abdominoplasty respects the anatomy of the region
      better. In our experience (65 cases since March 1989) this quick and reliable
      technique totally avoids the most frequent risk of abdominoplasty: seroma.

PMID- 8661591
TI  - Two methods of anesthesia for rhinoplasty in outpatient setting.
AB  - This retrospective study was designed with the aim to evaluate suitability of two
      methods of anesthesia: local anesthesia combined with sedation (midazolam +
      pethidine) or dissociative (midazolam + ketamine hydrochloride) anesthesia for
      performing rhinoplasties in an outpatient setting. During 1985-1994, we performed
      516 rhinoplasties in 464 patients. Sedation and local anesthesia was used in 263,
      and dissociative and local anesthesia in 253 procedures. Both methods were well
      tolerated by the patients, no serious anesthetic complications were seen, and the
      clinical problems in connection with anesthesia were acceptably low. The use of
      sedation technique and dissociative anesthesia in combination with local
      anesthesia have both proved to be safe and effective anesthetic methods for
      performing rhinoplasty.

PMID- 8661593
TI  - Subperiosteal transblepharoplasty forehead lift.
AB  - Contemporary options for correction of the aging upper one-third of the face
      include open techniques with a coronal or anterior hairline incision, endoscopic
      access to the forehead including muscle transection, brow lift through direct
      forehead skin excision and various forms of brow-pexies. Realizing the common
      need for aesthetic improvement in the upper eyelids and desiring minimal
      incisions for forehead rejuvenation, an approach through the blepharoplasty
      incision has been developed which addresses all of the components of the aging
      upper third of the face: A combined subperiosteal approach for forehead elevation
      and transection of corrugator and procerus muscles through the blepharoplasty
      incision is presented. The postoperative improvements in the position of the brow
      as well as improvement in the glabellar area rivals other approaches and allows
      simultaneous improvement in upper eyelid aesthetics.

PMID- 8661594
TI  - Endoscopy for regional lipectomy.
AB  - With the advances in endoscopic surgery, reconstructive surgeons search for
      applications in the field of soft tissue contouring. The improvements in
      endoscopic surgery in other fields are based on surgery within well-contained
      spaces that allow insufflation. However, minimally invasive surgery in the soft
      tissue planes has been limited by the relative inability to control separation of
      the tissue planes to allow a working space for instrumentation. This animal model
      shows the ability to open up and elevate any soft tissue space by means of
      external traction elevation and exact separation of tissue layers to allow
      endoscopic surgery without the need for insufflation. With the use of endoscopic
      equipment, the removal of fat from any area of the body becomes a much more
      precise art because of visualization and illumination and the ability to gain
      immediate hemostasis while exact contouring through removal of layers of fat can
      be achieved.

PMID- 8661595
TI  - An easy canthoplasty.
AB  - The round eye, which is a congenital feature or the result of a blepharoplasty,
      is a troubling condition for patients. Many techniques for changing the round eye
      into an almond-shaped eye have already been described. A simple technique that
      can be performed at the time of an eyelid plasty is presented here. Recent and
      long-lasting results are shown.

PMID- 8661596
TI  - All about nasal valve collapse.
AB  - For correcting collapsed alae, blunt dissection of the septal mucoperichondrium
      through the transfixion incision is extended on both sides up to the vault of the
      upper lateral cartilages, which are severed from their insertion. I remodel the
      lower lateral cartilage and secure the lateral crus together with the upper alar
      groove in a less concave position with mattress sutures in cases of anterior
      valvular disturbance. The upper lateral cartilages are also fixed in a more
      convex position, particularly in cases of posterior valvular disturbance. In both
      anomalies a slightly convex septal or auricular slice cartilage graft placed over
      the concerned cartilage helps to keep the valve more open and the lateral wall in
      proper position. If necessary, in extreme secondary cases, one needs the help of
      bilateral cartilaginous or bony supports embedded subperiostally at the nasal
      bones.

PMID- 8661597
TI  - Superficial liposuction.
AB  - Over a period of 12 years, the authors have seen that skin retracts after the
      judicious treatment of deep and superficial layers of fat tissue, laying to rest
      what has been one of the biggest fears of this treatment of lipoaspiration,
      namely cutaneous flaccidity. The adequate and judicious approach to these two
      layers, along with the increasing use and help of lipo-injection, permits the
      lessening of irregularities such as undulations and/or depressions.

PMID- 8661598
TI  - The lost muscles of the nose.
AB  - This is a review of the muscular anatomy of the nose. Areas of inconsistency in
      the main anatomy texts are highlighted and concentrate particularly on the
      omission of three identifiable muscles from modern textbooks. Two topographical
      areas of the nose in need of further anatomical development are identified. In a
      sample of 121 subjects from the general population, 40% were found to be
      incapable of flaring the nostrils voluntarily or subconsciously in conjunction
      with energetic inspiration with the mouth closed. The authors recommend
      systematic clinical assessment of the nasal musculature be incorporated in the
      pre- and postoperative examination of the rhinoplasty patient. The division of
      the nose into five sections for assessment is proposed and the muscles
      contributing to each area are defined together with their individual surgical
      relevance.

PMID- 8661599
TI  - Reduction mammoplasty by the central pedicle, avoiding a vertical scar.
AB  - Reduction of the macromamma that causes posture malformations, neck and back
      pain, and psychological problems is very important. I performed the technique on
      13 patients whose ages ranged between 17 and 60 years during 1990 and 1993. I
      observed no complications in the controls. To obtain a better result in reduction
      mammoplasty, I use a technique that can be performed on patients of any age,
      without causing any problems in vascularization, sensitivity, and lactation, and
      that avoids the vertical scar.

PMID- 8661601
TI  - Nontraditional Settlement Patterns and Typhoon Hazard on Contemporary Majuro
      Atoll, Republic of the Marshall Islands
AB  - Low-lying islands and atolls are particularly prone to storm surges created by
      tropical depressions and typhoons. This paper presents a case study of
      traditional and contemporary settlement patterns of Majuro, the capital of the
      Republic of the Marshall Islands, and discusses its vulnerability to such storm
      surges. The paper shows that the application of traditional knowledge extends to
      the realm of urban planning and that, in fact, ignoring this traditional
      knowledge as expressed in pre-World War II settlement patterns, exposes urban
      development to increased flood hazards, a risk which may exact a price too high
      in life and property.

PMID- 8661602
TI  - Landscape-Level Ecological Regions: Linking State-Level Ecoregion Frameworks with
      Stream Habitat Classifications
AB  - Regionalization is a form of spatial classification, where boundaries are drawn
      around areas that are relatively homogeneous in landscape characteristics. The
      process of delineating ecological regions, or ecoregions, includes the analysis
      of ecosystem structure. To date, ecoregions have been developed at national and
      state scales for research and resource management. Stream classification is
      another method to order the variability of aquatic habitats that spans spatial
      scales from microhabitat to valley segment. In this study, landscape-level
      ecoregions are developed for the upper Grande Ronde River basin in northeastern
      Oregon, 3000 sq km in area. The ecoregion framework presented here is proposed to
      bridge the gap between stream habitat and state-level ecoregion classifications.
      Classification at this scale is meant to address issues of management at local
      scales: to aid in sampling design, in extrapolation of the results of site
      specific studies, and in the development of best management practices that are
      more predictive of ecosystem response than current methods.

PMID- 8661603
TI  - Jobs and the Environment: An Overview
AB  - This paper provides an overview of economic research on the relationship between
      environmental protection and employment. The paper addresses, first, the impact
      of existing regulation on overall employment rates, shutdowns and layoffs, and
      regulation-induced capital flight from developed countries. Second, the paper
      provides a framework for evaluating claims that, over the longer run,
      environmental protection measures will boost overall employment and provide the
      foundation for a robust, sustainable economy.

PMID- 8661604
TI  - Irrigation Development and Its Environmental Consequences in Arid Regions of
      India
AB  - The present paper examines the nature and dimensions of environmental
      transformation induced by canal irrigation in the arid region of India. The case
      study pertains to the Indira Gandhi Canal comand area in Rajasthan where the
      density and area of vegetation cover have increased due to afforestation, and the
      cultivated area has expanded due to irrigation. Consequently, there has been a
      perceptible improvement in the structure and fertility of sandy soils, but it
      would require a herculean effort on the part of the canal authority and local
      people to reduce soil erosion and siltation in the lower parts of stage I and the
      entire command area of stage II. Moreover, the water table has been rising
      rapidly throughout the command area of stage I. About half of the command area
      and adjoining Ghaggar basin in Ganganagar District will be facing the danger of
      waterlogging by the turn of the century. The incidence of irrigation-induced
      alkalization is higher in the lower parts of stage I. Soil alkalinity has
      appeared within five years of the introduction of irrigation in the interdunal
      basins and is manifested as a strong salt regime or calcareous pans near surface.
      This calls for immediate reclamation of the affected area and prevention of its
      expansion by altering the strategy of irrigation development, by changing
      cropping patterns, and by providing soil drainage.

PMID- 8661605
TI  - Integrating Ecology into Natural Resource Management Policy
AB  - Traditional natural resource management policy has largely focused on
      implementing prescriptive solutions to maximize a production function. The
      fundamental assumptions of this approach were: (1) that ecosystems behaved in a
      linear, deterministic manner; (2) that there was general community agreement on
      the value of different ecosystem services; and (3) that land managers would
      accept and adopt the recommended technology. The result has generally been an
      unpredictable performance by ecosystems, conflicting expectations among users,
      and low adoption rates for the outputs of research and development (R&D). We
      propose that an approach that integrates the fundamentals of nonequilibrium
      ecology and "soft" systems methodologies to define options, make management
      decision recommendations, and implement programs will result in improved
      predictability of ecosystem response, more realistic expectations on the part of
      users of ecosystem services, and better uptake of technology by land managers.

PMID- 8661606
TI  - Prairie Dog Poisoning in Northern Great Plains:An Analysis of Programs and
      Policies
AB  - This paper describes the programs and policies regarding prairie dog control in
      the northern Great Plains states of Montana, South Dakota, and Wyoming. The
      poisoning programs of federal and state agencies are described, along with the
      statutes and legal mandates that shape agency management of prairie dogs. Current
      policies on National Grasslands and other federal lands typically limit prairie
      dogs to small percentages of available potential habitat, to the detriment of
      prairie dogs and associated species. State programs to assist landowners in
      prairie dog control differ greatly, employing cost-share incentives (Wyoming) and
      regulatory fines (South Dakota) to encourage the poisoning of prairie dogs.
      Prairie dog control is not actively funded or practiced by state or county
      agencies in Montana. We document federal and state involvement in more than 1
      million acres of prairie dog poisoning in the study area during 1978-1992. In
      combination with undocumented poisoning by private landowners, plague, and
      shooting, prairie dogs may be experiencing net regional declines, contributing to
      the disintegration of the prairie dog ecosystem. We recommend that Animal Damage
      Control operations concerning prairie dogs be terminated, on the basis that they
      duplicate state programs and are at cross purposes with federal wildlife
      management programs that seek to perpetuate and/or recover wildlife species that
      depend on the prairie dog ecosystem. We further recommend that federal range
      improvement funds be offered as subsidies for the integration of prairie dogs in
      range management, as opposed to funding prairie dog eradication programs.

PMID- 8661607
TI  - Sludge-Grown Algae for Culturing Aquatic Organisms: Part I. Algal Growth in
      Sludge Extracts
AB  - This project is aimed at studying the feasibility of using sewage sludge to
      prepare culture media for microalgae (Chlorella-HKBU) and the use of the sludge
      grown algae as a feed for some aquatic organisms. Part I of the project included
      results on preparing sludge extracts and their use on algal culture. By comparing
      two culturing techniques, "aeration" and "shaking," it was noted that both lag
      and log phases were shortened in the aeration system. A subsequent experiment
      noted that algal growth subject to aeration rates of 1.0 and 1.5 liters/min had
      similar lag and log phases. In addition, both aeration rates had a significantly
      higher (P<0.05) final cell density than that of 0.5 liters/min. A detailed study
      on the variation of growth conditions on the algal growth was done. The results
      indicated that pH values of all the cultures declined below 5 at day 12. The
      removal rates of ammonia N ranged from 62% to 70%. The sludge-grown algae
      contained a rather substantial amount of heavy metals (&mgr;g/g): Zn 289-581, Cu
      443-682, Ni 310-963, Mn 96-126, Cr 25-118, and Fe 438-653. This implied that the
      rather high levels of heavy metals may impose adverse effects on higher trophic
      organisms.

PMID- 8661608
TI  - Sludge-Grown Algae for Culturing Aquatic Organisms: Part II. Sludge-Grown Algae
      as Feeds for Aquatic Organisms
AB  - This project investigated the feasibility of using sewage sludge to culture
      microalgae (Chlorella-HKBU) and their subsequent usage as feeds for rearing
      different organisms. Part II of the project evaluated the results of applying the
      sludge-grown algae to feed Oreochromis mossambicus (fish), Macrobrachium
      hainenese (shrimp), and Moina macrocopa (cladocera). In general, the yields of
      the cultivated organisms were unsatisfactory when they were fed the sludge-grown
      algae directly. The body weights of O. mossambicus and M. macrocopa dropped 21%
      and 37%, respectively, although there was a slight increase (4.4%) in M.
      hainenese. However, when feeding the algal-fed cladocerans to fish and shrimp,
      the body weights of the fish and shrimp were increased 7% and 11% accordingly.
      Protein contents of the cultivated organisms were comparable to the control diet,
      although they contained a rather high amount of heavy metals. When comparing
      absolute heavy metal contents in the cultivated organisms, the following order
      was observed: alga > cladocera > shrimp, fish > sludge extracts. Bioelimination
      of heavy metals may account for the decreasing heavy metal concentrations in
      higher trophic organisms.

PMID- 8661609
TI  - Cumulative Impact of Marinas on Estuarine Water Quality
AB  - The purpose of this work is to present a modeling approach for assessing and
      managing the cumulative impact of marinas on estuarine systems. In doing so, both
      a water-quality model and a planning and management model are developed. The
      water-quality model predicts biochemical oxygen demand (BOD) and fecal coliform
      (FC) loadings from marina sources in a hypothetical North Carolina estuary. By
      running the water-quality model repeatedly with varied loading input, impact
      coefficients are determined. These impact coefficients are used in the planning
      and management model, the output of which gives the sizes and locations of
      marinas in the estuarine system such that dissolved oxygen (DO) and FC water
      quality standards are maintained.Five different estuarine development scenarios
      are considered. Each scenario is evaluated with respect to both maximum and
      uniform land development constraints. In addition, two alternative fecal coliform
      standards are used with each of the development options.

PMID- 8661610
TI  - Environmental Change in the Mid-Boteti Area of North-Central Botswana:
      Biophysical Processes.and Human Perceptions
AB  - Increased interest in environmental change issues has led researchers to consider
      more integrated approaches to change dynamics. This paper examines change in
      terms of land degradation in north-central Botswana from both biophysical and
      human perspectives. Although seasonal and periodic droughts were prevalent,
      analysis of rainfall data over the past 70 years revealed no downward trend.
      However, indicators of declining productivity such as soil erosion, loss of
      vegetation cover, and a declining groundwater table were amply evident. The GIS
      analysis of remotely sensed data has shown that complete vegetation recovery
      after drought is not taking place, particularly in the south-central part of the
      study area. These areas contained the highest human and livestock population
      densities. The local people acknowledged facing increasing resource depletion and
      indicated drought as the main cause. Pressures on available resources,
      particularly during drought periods, appeared to have impeded the regenerative
      capacity of the natural vegetation cover, thereby inducing land degradation. This
      situation may not easily be rectified because of widespread poverty and
      inappropriate local perceptions of the solutions. Both of these hinder the
      adoption of sustainable land management.

PMID- 8661611
TI  - Monitoring Wetland Changes with Remote Sensing: An East African Example
AB  - Environmental managers need current, accurate information upon which to base
      decisions. Viable information, especially in developing countries, is often
      unavailable. Satellite remote sensing is an appropriate and effective data source
      for mapping the surface of the earth, including a variety of environmental
      features. Remote-sensing-derived information is enhanced by being one component
      within a geographic information system (GIS). These techniques were employed to
      study an expanding delta in East Africa.The Omo River flows from the Ethiopian
      Highlands into the northern end of Lake Turkana, creating a large delta extending
      between Ethiopia and Kenya. This isolated and unique wetland feature has expanded
      by over 500 sq km in the last 15 years as measured by space-borne remote sensing
      techniques and corroborated by low-altitude aircraft reconnaissance flights.The
      growth of the delta appears to be a function of both increased sedimentation and
      decreased lake levels and river flows. Within the delta there has been a
      selective decline in wildlife and an increase in human activity, both pastoral
      and agricultural. The uniqueness of this isolated delta suggests that
      consideration be given to its possible protection and management.

PMID- 8661612
TI  - An Introduction to Digital Methods in Remote Sensing of Forested Ecosystems:
      Focus on the Pacific Northwest, USA
AB  - Aerial photography has been routinely used for several decades by natural
      resource scientists and managers to map and monitor the condition of forested
      landscapes. Recently, along with the emergence of concepts in managing forests as
      ecosystems, has come a significant shift in emphasis from smaller to larger
      spatial scales and the widespread use of geographic information systems. These
      developments have precipitated an increasing need for vegetation information
      derived from other remote sensing imagery, especially digital data acquired from
      high-elevation aircraft and satellite platforms. This paper introduces
      fundamental concepts in digital remote sensing and describes numerous
      applications of the technology. The intent is to provide a balanced, nontechnical
      view, discussing the shortcomings, successes, and future potential for digital
      remote sensing of forested ecosystems.

PMID- 8661614
TI  - Analysis of Lower Green Bay and Fox River, Collingwood Harbour, Spanish Harbour,
      and the.Metro Toronto and Region Remedial Action Plan.(RAP) Processes
AB  - This article presents a model of remedial action planning, which includes four
      key variables that determine progress in plan development and implementation and
      explain the differing level of achievement in individual sites. The model is
      illustrated by the characteristics and developments of four remedial action plan
      (RAP) processes (Lower Green Bay and Fox River, Collingwood Harbour, Spanish
      Harbour, and the Metro Toronto and Region RAPs). Differences in the local context
      of the plans have, to a significant degree, predisposed individual planning and
      implementation experiences. Local context includes three variables, namely
      geographical-technical and sociopolitical aspects and the previous history of
      water pollution management in the area. RAP precursors are a necessary
      precondition for progress in planning and substantive achievements. While there
      is a tendency that most geographically focused RAPs in administratively simple
      areas accomplish most, the motivation and political clout of RAP participants are
      strongly intervening factors. Resource input from upper levels of government, in
      particular financial commitment for plan implementation, is the fourth necessary
      ingredient for progress due to the RAPs' weak regulatory and institutional
      framework. Unfortunately, upper levels of government have shown widespread
      reluctance to lead in remedial action planning. This was only in part offset by
      local commitment and support for RAP and its cause.

PMID- 8661615
TI  - Proliferation of Nonconforming Land Uses in Agricultural Envelope of Urban Hong
      Kong
AB  - Until the late 1960s rural Hong Kong had an attractive rustic landscape and a
      small but active farming population. The recent widespread agricultural decline
      provided opportunities for urban-oriented activities to invade, mainly as open
      storage and workshops unsuitable in city areas. Rapid container-port expansion
      and cross-border China trade generate demands for cheap and accessible land for
      non-conforming uses (NCU). Rural development control and land-use planning are
      inherently weak, and formal provision for such uses is lacking. An unfavorable
      landmark court judgement allows landowners to degrade the countryside. The
      activities have caused acute environmental problems, telescoped into a small
      territory, including visual blight, pollution, drainage blockage, loss of wetland
      habitats, and increased flooding hazard. The distinction between urban and rural
      has been blurred in the destruction of the valuable countryside heritage. An
      interim legislative amendment fails to stop unauthorized conversion of farmland.
      In the long term, an integrated and comprehensive rural planning strategy to
      conserve inherent elements, as well as accommodating selected urban spillover in
      properly located and serviced sites, is needed.

PMID- 8661613
TI  - Costs and Effectiveness of Education and Enforcement, Cairns Section of the Great
      Barrier Reef Marine Park
AB  - Education, not enforcement, is the preferred management tool to gain acceptance
      for management prescriptions in marine protected areas. The cost and
      effectiveness of education and enforcement programs is difficult to estimate. In
      the management of the Cairns Section of the Great Barrier Reef Marine Park from
      1985 to 1991, the cost and effectiveness of the two programs were evaluated using
      an awareness survey and an analysis of annual reports. Both programs were
      effective in meeting program objectives. Education costs per person were
      approximately a tenth the cost of enforcement; however, the total cost for
      education programs was twice that of enforcement programs. Education and
      enforcement programs interact together with other management activities, and
      neither program can totally replace the other. Some users will willingly comply
      with management measures, other users will comply in response to education, but
      there will be another group who will only respond to enforcement activities.
      There will also be users who persistently disregard park rules and regulations
      and will continue to present a problem to managers. For these individuals,
      education in association with enforcement actions are necessary.

PMID- 8661616
TI  - A Framework to Assess Regional Environmental Impacts of Dedicated Energy Crop
      Production
AB  - Numerous studies have evaluated air quality and greenhouse gas mitigation
      benefits of biomass energy systems, but the potential environmental impacts
      associated with large-scale changes in land-use patterns needed to produce energy
      crops have not been quantified. This paper presents a framework to assess the
      potential soil, water, and biodiversity impacts that may result from the large
      scale production of dedicated energy crops. The framework incorporates producer
      economic decision models with environmental models to assess changes in land use
      patterns and to quantify the consequent environmental impacts. Economic and
      policy issues that will affect decisions to produce energy crops are discussed.
      The framework is used to evaluate erosion and chemical runoff in two Tennessee
      regions. The analysis shows that production of dedicated energy crops in place of
      conventional crops will significantly reduce erosion and chemical runoff.

PMID- 8661617
TI  - Salt Enrichment of Municipal Sewage: New Prevention Approaches in Israel
AB  - Wastewater irrigation is an environmentally sound wastewater disposal practice,
      but sewage is more saline than the supplied fresh water and the salts are
      recycled together with the water. Salts have negative environmental effects on
      crops, soils, and groundwater. There are no inexpensive ways to remove the salts
      once they enter sewage, and the prevention of sewage salt enrichment is the most
      immediately available solution. The body of initiatives presently structured by
      the Ministry of the Environment of Israel are herein described, with the aim to
      contribute to the search for a long-term solution of salinity problems in arid
      countries. The new initiatives are based on: (1) search for new technologies to
      reduce salt consumption and discharge into sewage; (2) different technologies to
      cope with different situations; (3) raising the awareness of the public and
      industry on the environmental implications of salinity pollution; and (4) an
      elastic legal approach expressed through new state-of-the-art regulations. The
      main contributor to the salinity of sewage in Israel is the water-softening
      process followed by the meat koshering process. Some of the adopted technical
      solutions are: the discharge of the brine into the sea, the substitution of
      sodium by potassium salts in the ion-exchangers, the construction of centralized
      systems for the supply of soft water in industrial areas, the precipitation of Ca
      and Mg in the effluents from ion-exchangers and recycling of the NaCl solution, a
      reduction of the discharge of salts by the meat koshering process, and new
      membrane technology for salt recovery.

PMID- 8661618
TI  - Ecosystem Management to Achieve Ecological Sustainability: The Case of South
      Florida
AB  - The ecosystems of South Florida are unique in the world. The defining features of
      the natural Everglades (large spatial scale, temporal patterns of water storage
      and sheetflow, and low nutrient levels) historically allowed a mosaic of habitats
      with characteristic animals. Massive hydrological alterations have halved the
      Everglades, and ecological sustainability requires fundamental changes in
      management.The US Man and the Biosphere Human-Dominated Systems Directorate is
      conducting a case study of South Florida using ecosystem management as a
      framework for exploring options for mutually dependent sustainability of society
      and the environment. A new methodology was developed to specify sustainability
      goals, characterize human factors affecting the ecosystem, and conduct
      scenario/consequence analyses to examine ecological and societal implications.
      South Florida has sufficient water for urban, agricultural, and ecological needs,
      but most water drains to the sea through the system of canals; thus, the issue is
      not competition for resources but storage and management of water. The goal is to
      reestablish the natural system for water quantity, timing, and distribution over
      a sufficient area to restore the essence of the Everglades.The societal
      sustainability in the Everglades Agricultural Area (EAA) is at risk because of
      soil degradation, vulnerability of sugar price supports, policies affecting Cuban
      sugar imports, and political/economic forces aligned against sugar production.
      One scenario suggested using the EAA for water storage while under private sugar
      production, thereby linking sustainability of the ecological system with societal
      sustainability. Further analyses are needed, but the US MAB project suggests
      achieving ecological sustainability consistent with societal sustainability may
      be feasible.

PMID- 8661619
TI  - Impact of Water Control Projects on Fisheries Resources in Bangladesh
AB  - Bangladesh is a very flat delta built up by the Ganges-Brahmaputra-Meghna/Barak
      river systems. Because of its geographical location, floods cause huge
      destruction of lives and properties almost every year. Water control programs
      have been undertaken to enhance development through mitigating the threat of
      disasters. This structural approach to flood hazard has severely affected
      floodplain fisheries that supply the major share of protein to rural Bangladesh,
      as exemplified by the Chandpur Irrigation Project. Although the regulated
      environment of the Chandpur project has become favorable for closed-water
      cultured fish farming, the natural open-water fishery loss has been substantial.
      Results from research show that fish yields were better under preproject
      conditions. Under project conditions per capita fish consumption has dropped
      significantly, and the price of fish has risen beyond the means of the poor
      people, so that fish protein in the diet of poor people is gradually declining.
      Bangladesh is planning to expand water control facilities to the remaining flood
      prone areas in the next 15-20 years. This will cause further loss of floodplain
      fisheries. If prices for closed-water fish remain beyond the buying power of the
      poor, alternative sources of cheap protein will be required.

PMID- 8661620
TI  - Adaptive Management: Promises and Pitfalls
AB  - Proponents of the scientific adaptive management approach argue that it increases
      knowledge acquisition rates, enhances information flow among policy actors, and
      provides opportunities for creating shared understandings. However, evidence from
      efforts to implement the approach in New Brunswick, British Columbia, Canada, and
      the Columbia River Basin indicates that these promises have not been met. The
      data show that scientific adaptive management relies excessively on the use of
      linear systems models, discounts nonscientific forms of knowledge, and pays
      inadequate attention to policy processes that promote the development of shared
      understandings among diverse stakeholders. To be effective, new adaptive
      management efforts will need to incorporate knowledge from multiple sources, make
      use of multiple systems models, and support new forms of cooperation among
      stakeholders.

PMID- 8661621
TI  - Testing of a GIS Model of Eucalyptus largiflorens Health on a Semiarid, Saline
      Floodplain
AB  - Irrigated agriculture has resulted in substantial changes in water flows to the
      lower reaches of the River Murray. These changes have led to large-scale
      occurrences of dieback in Eucalyptus largiflorens (black box) woodlands as well
      as increased inputs of salt to the river. Management options to address problems
      of this scale call for the use of spatial data sets via geographic information
      systems (GIS). A GIS exists for one floodplain of the River Murray at Chowilla,
      and a simple model predicted six health classes of Eucalyptus largiflorens based
      on groundwater salinity, flooding frequency, and groundwater depth.To determine
      the usefulness of the model for vegetation management, the quality of both the
      model and the GIS data sets were tested. Success of the testing procedure was
      judged by the degree of spatial matching between the model's predictions of
      health and that assessed from aerial photographs and by field truthing. Analyses
      at 80 sites showed that tree health was significantly greater where groundwater
      salinity was less than 40 dS/m or flooding occurred more frequently than 1 in 10
      years or depth to groundwater exceeded 4 m. Testing of the GIS data sets found
      that vegetation was misclassified at 15% of sites. Association was shown between
      GIS-predicted values and field-truthed values of groundwater salinity but not
      groundwater depth. The GIS model of health is a useful starting point for future
      vegetation management and can be further improved by increasing the quality of
      the data coverages and further refining of the model to optimize parameters and
      thresholds.

PMID- 8661622
TI  - Forest Planning in an Oregon Case Study: Defining the Problem and Attempting to
      Meet Goals with a Spatial-Analysis Technique
AB  - Five major management goals were identified for the upper Grande Ronde River
      Basin on the Wallowa-Whitman National Forest in northeastern Oregon: to produce
      high-quality fish habitat, to maintain elk habitat, to restore and maintain
      forest conditions within the natural range of viability, and to contribute to
      community economic stability. From the broad goals, specific goals for stream
      temperature, habitat effectiveness index (HEI), habitat corridors, maintenance of
      land in late or old seral stages, and a nondeclining even flow of timber were
      selected. A case study was undertaken in a small watershed that is under typical
      societal constraints to determine whether one decision-support tool, SNAP II+,
      could evaluate the selected goals in a single planning exercise. Three riparian
      management strategies and two forest road scenarios were used. The exclusion of
      harvest and road-building from riparian zones in order to increase habitat
      protection decreased harvest levels and net present value but maintained
      preactivity stream temperatures. Other resources were generally maintained within
      prescribed management levels. Although the technique has limitations (e.g., it
      does not account for riparian zones in calculations of forage and cover for HEI,
      and it can use the maximum but not minimum acreage goal for some resources), it
      shows promise for evaluating management tradeoffs in watershed analysis.

PMID- 8661623
TI  - Decreased Carbon and Nutrient Input to Boreal Lakes from Particulate Organic
      Matter Following Riparian Clear-Cutting
AB  - The plankton communities of oligotrophic Canadian Shield lakes are strongly
      regulated by the allochthonous supply of total phosphorus (TP) and dissolved
      organic carbon (DOC), a proportion of both of which originate from particulate
      organic matter. Although decreased inputs of allochthonous leaf litter have been
      documented for small streams whose riparian forests have been removed, no such
      data exist for boreal lakes. Through estimates of airborne litter input from
      forested and clear-cut shorelines and laboratory measurements of concentrations
      released from leaf leachate, we determined that riparian deforestation resulted
      in reductions of DOC from 17.8 to 0.4 g/m shoreline/yr and of TP from 2.9 to 0.3
      g/m shoreline/yr. Previous predictive models indicate that such reductions may be
      substantial enough to decrease basic metabolic processes of lake plankton
      communities by as much as 9% in primary production and 17% in respiration.

PMID- 8661624
TI  - Results of a Program to Control Phosphorus Discharges from Dairy Operations in
      South-Central Florida, USA
AB  - During 1987-1992, a mandatory program to control phosphorus discharges was
      implemented at dairy operations located to the north of Lake Okeechobee, Florida,
      USA. Thirty of 48 dairies participated in this program and implemented best
      management practices (BMPs), which included the construction of intensive animal
      waste management systems. Eighteen dairies closed their milk-producing operations
      under a government-funded buyout program. In this paper, we compare trends in
      runoff total phosphorus (TP) concentrations among the dairies that remained
      active and implemented BMPs. A central feature of the dairy waste management
      system is the high intensity area (HIA), defined as the milking barn and adjacent
      vegetation-free land, encircled by a drainage ditch and dike. Animal waste from
      the HIA is diverted into anaerobic lagoons and storage ponds, from which water is
      periodically removed and used for irrigation of field crops. The impacts of BMP
      construction on runoff TP concentrations were immediate and, in most cases,
      dramatic. Average TP concentrations declined significantly (P<0.001), from 9.0 to
      1.2 mg TP liter-1 at dairies in one basin (Lower Kissimmee River), and from 2.6
      to 1.0 mg TP liter-1 in another (Taylor Creek/Nubbin Slough). Some sites
      experienced greater declines in TP than others. To elucidate possible causes for
      the difference in response, a multivariate statistical model was utilized.
      Independent variables included soil pH, soil drainage characteristics, spodic
      horizon depth, and the areas of different BMP components (pasture, HIA, spray
      fields). The analysis significantly separated dairies with the highest and lowest
      runoff TP concentrations. Lowest TP occurred at dairies having particular soil
      characteristic (shallow spodic horizon) and certain BMP features (large HIA and
      small heard pastures).

PMID- 8661625
TI  - Laparoscopic treatment of nonparasitic liver cysts: adequate selection of
      patients and surgical technique.
AB  - Results of laparoscopic fenestration in patients with a highly symptomatic
      solitary liver cyst (17 patients) or polycystic liver disease (PLD) (9 patients)
      were prospectively evaluated in a multicenter practice of general surgeons.
      Conversion to laparotomy was required in two patients because of inaccessible
      deep liver cyst in one and a diffuse form of PLD in the other. There was no
      mortality or major morbidity. Mean postoperative hospital stay was 4.6 days after
      successful laparoscopic procedures. During a mean follow-up of 9 months, 23% of
      the patients had recurrence of symptoms and 38% had radiographic reappearance of
      cysts. Factors predicting failure included previous surgical treatment, deepsited
      cysts, incomplete deroofing technique, location in the right posterior segments
      of the liver, and a diffuse form of PLD with small cysts. Adequate selection of
      patients and type of cystic liver disease and meticulous and aggressive surgical
      technique are recommended.

PMID- 8661626
TI  - Acute phase is the only significantly reduced component of the injury response
      after laparoscopic cholecystectomy.
AB  - The objective demonstration of improved postoperative recovery suggests that the
      surgical injury response induced by the laparoscopic approach is less intensive
      than that after open surgery. Twenty-five patients diagnosed as having
      noncomplicated gallstones were studied prospectively. They were operated by
      laparoscopy (group I, n = 12) or open surgery (group II, n = 13). Analgesia
      requirements (p < 0.026) and postoperative stay (p < 0.001) were significantly
      less in group 1. Cholecystectomy performed by either technical options induced a
      significant increase over basal values of glucose, lactate, white blood cell
      count, prolactin, ACTH, cortisol, interleukin 6, C-reactive protein, and PCO2.
      Both surgical procedures induced a significant reduction of total proteins,
      albumin, prealbumin, free fatty acids hemoglobin, hematocrit, and pH. There were
      no differences between the levels of growth hormone, insulin, glucagon, or PO2
      during any of the periods studied. Comparison of the results of the two
      cholecystectomy techniques showed that laparoscopic cholecystectomy induced a
      significantly less intensive acute-phase response (area under the curve) of
      interleukin 6 (17 +/- 17 versus 47 +/- 26 pg/ml x hr x 10(2); p < 0.003), C
      reactive protein (16 +/- 12 versus 35 +/-16 mg/dl x hr x 10; p < 0.004), and
      prealbumin (16 +/- 2.7 versus 13.8 +/- 2.3 mg/dl x hr x 10(2); p < 0.05). The
      surgical injury response after laparoscopic cholecystectomy is similar to that
      after open cholecystectomy, but the aeute-phase response component is less
      intense. This finding may be a consequence of the reduced size of the operative
      wound with laparoscopic cholecystectomy.

PMID- 8661627
TI  - Laparoscopic treatment of gallbladder and common bile duct stones: a prospective
      study.
AB  - The aim of this study was to investigate prospectively the feasibility, success
      rate, safety, and short-term results of single-stage laparoscopic treatment of
      gallstones and ductal stones in 100 consecutive, unselected patients. Common bile
      duct (CBD) stones were diagnoses at routine intraoperative cholangiography and
      choledochoscopy in 100 of 950 patients with gallstones undergoing laparoscopic
      cholecystectomy (LC). Unsuspected CBD stones were present in 39 patients (4.1% of
      950; 39% of 100); 26 patients were referred for surgery after failed endoscopic
      sphinctertomy (ES) performed elsewhere. Transcystic duct CBD exploration (TC
      CBDE) was the procedure of choice. When it was not feasible, choledochotomy and
      direct CBD exploration (D-CBDE) was performed. Use of biliary drainage was
      liberal. A completion cholangiogram was obtained for all patients. Laparoscopic
      treatment of CBD stones was successful in 96 patients: after TC-CBDE in 63 and
      after D-CBDE in 33. Four operations were converted to open surgery (4%). Retained
      stones, observed in five patients, were treated by ES in two cases and by
      percutaneous endoscopic/fluoroscopic lithotripsy in three. Minor morbidity
      included biloma (n = 2), port site infection (n = 2), and subumbilical hematoma
      (n = 1). Major morbidity was bile leakage from the cystic duct stump in two cases
      due to clips or transcystic duct drainage displacement, respectively. One
      elderly, high risk patient died after being referred for several failed attempts
      of endoscopic clearance; she died from cardiogenic shock 3 days after successful
      laparoscopic treatment. Laparoscopic CBD exploration is feasible and safe in most
      patients, with short-term results that compare favorably with the results of
      sequential ES/LC reported in the literature.

PMID- 8661628
TI  - Pancreaticobiliary maljunction-associated pancreatitis: an experimental study on
      the activation of pancreatic phospholipase A2.
AB  - Congenital dilatation of the bile duct (CDBD), or choledochalcyst, is often
      complicated by recurrent pancreatitis. Reflux of pancreatic juice into the bile
      duct through pancreaticobiliary maljunction (PBM), an anomaly commonly associated
      with CDBD, and ensuing activation of pancreatic enzymes could be involved in the
      pathophysiologic mechanism of recurrent pancreatitis. A study was undertaken to
      follow the time course of the activity of phospholipase A2 (PLA2) in animal
      models of PBM. The assay procedures for PLA2 were evaluated, as were the
      conditions for separating the active enzyme from its inactive proenzyme (pro
      PLA2) by immunoblotting. A rat model was designed according to Block's method
      with some modifications. The kinetics of prophospholipase A2 (proPLA2) activation
      in bile was examined by measuring PLA2 activity and by immunoblotting using anti
      rat pancreatic enzyme antibody after separating PLA2 from its zymogen under
      nonreducing conditions. Experimental animals were divided into three groups:
      group 1 (PBM group) in which bile and pancreatic juice were mixed with occlusion
      of the papilla; group 2, in which the papilla and hepatic hillus were occluded
      without mixing the two juices; and group 3, in which simple laparotomy was done.
      In group 1 animals, pro-PLA2 in bile was activated to its active form. In group 2
      animals, where proPLA2 was predominant, there was only slight elevation of PLA2
      activity in bile. In group 1 an immunohistologic study demonstrated localization
      of PLA2 around necrotic foci in the pancreatic parenchyma. These results suggest
      the involvement of activated PLA2 in the pathogenesis of choledochal
      cystassociated pancreatitis.

PMID- 8661629
TI  - Disadvantages of muscle-sparing thoracotomy in patients with lung cancer.
AB  - At our institute patients with lung cancer had traditionally undergone lobectomy
      with mediastinal lymph node dissection using a standard posterolateral approach.
      The considerable morbidity associated with the standard posterolateral
      thoracotomy led us to investigate an alternative muscle-sparing approach. A
      prospective, randomized study of 30 patients with primary lung cancer (stage I or
      II) was performed to compare the following: operative field size, number of
      dissected lymph nodes, surgery time, postoperative pain, shoulder range of
      motion, and pulmonary function test results between patients who underwent either
      standard thoracotomy (SP group, n = 15) or the muscle-sparing thoracotomy (MS
      group, n = 15). The procedure should provide enough operative field size to
      access to mediastinum. Compared with the standard posterior thoracotomy, the
      muscle-sparing thoracotomy supplied a smaller operative field (218 +/- 31 versus
      165 +/- 41 cm2) and required more surgery time (87 +/- 13 minutes) than the
      standard posterior thoracotomy (66 +/- 12 minutes). There were no significant
      differences in the number of dissected mediastinal lymph nodes. During the early
      postoperative days, pain and restriction of shoulder flexion were significantly
      less in the MS group than in the SP group. There were no significant differences
      in pulmonary function between the two groups. In terms of the operative field
      there is a marked disadvantage with the muscle-sparing incision compared with
      standard thoracotomy. The operative field is significantly smaller than with a
      standard thoracotomy, requiring more time to dissect the mediastinum; however,
      the pain is less and shoulder range of motion is superior to what is seen after
      standard thoracotomy during the early postoperative period. We conclude that
      there is no overall advantage to using the muscle-sparing incision in patients
      with lung cancer.

PMID- 8661630
TI  - Low-molecular-weight heparin versus warfarin for prevention of recurrent venous
      thromboembolism: a randomized trial.
AB  - A group of 105 consecutive patients with venographically proved major acute deep
      vein thrombosis (DVT) were randomized in an open prospective study to evaluate
      the comparative efficacy and safety of a fixed dose of subcutaneous low-molecular
      weight heparin (LMWH) and warfarin for the prevention of recurrent venous
      thromboembolism. Four patients developed venographically proved recurrent DVT
      during the 3 months of treatment: three in the LMWH group and one in the warfarin
      group. Nonfatal pulmonary embolism occurred in two patients in the LMWH group and
      in one in the warfarin group. Five of the 55 patients (10%) in the warfarin group
      and none of the 50 patients in the LMWH developed bleeding complications (two
      tailed Fisher exact test, p = 0.06). A preliminary assessment of the costs
      indicated that treatment with LMWH was less expensive by Pounds 900 per patient
      than warfarin. In conclusion, the fixed daily dose of LMWH and the adjusted dose
      of warfarin therapy were of similar efficacy in preventing recurrence of DVT.
      However, warfarin therapy, despite strict laboratory control, is associated with
      more frequent side effects and is expensive. Another study with a higher dose of
      LMWH is recommended.

PMID- 8661631
TI  - Surgical treatment of hepatocellular carcinoma originating from the caudate lobe.
AB  - Hepatocellular carcinoma (HCC) originating from the caudate lobe is rare, and its
      surgical management is difficult because of its unique anatomic location. We have
      seen six such cases at our hospital. For patients with fair to excellent liver
      reserve, we advocated caudate lobectomy combining other types of hepatic
      resection. For patients with marked liver cirrhosis and poor liver reserve or a
      small HCC, we advocated simple partial caudate lobectomy (limited hepatic
      resection). There was no operative mortality or major operative morbidity. We
      conclude that such approaches are safer, less time-consuming, and less technique
      demanding, and they produce a fair survival result compared with the approaches
      of other procedures. With such approaches, it is our experience that patients
      with HCC from the caudate lobe have a prognosis comparable to that of patients
      with HCC in other parts of the liver.

PMID- 8661632
TI  - Disseminated epithelial tumor cells in bone marrow of patients with esophageal
      cancer: detection and prognostic significance.
AB  - Minimal residual disease in patients with operable esophageal cancer is
      frequently missed by current noninvasive tumor staging. Here we applied an
      immunocytochemical cytokeratin assay that allows identification of individual
      esophageal carcinoma cells disseminated to bone marrow. Prior to therapy, bone
      marrow was aspirated from the upper iliac crest of 71 patients with esophageal
      cancer at various disease stages as well as an age-matched control group of 20
      noncarcinoma patients. Tumor cells in cytologic bone marrow preparations were
      detected with monoclonal antibodies (mAbs) CK2, KL1, and A45-B/B3 to epithelial
      cytokeratins (CKs) using the alkaline phosphatase antialkaline phosphatase
      method. CK-positive cells were found in 14 (36.8%) of 38 cancer patients treated
      with curative intent and 16 (48.5%) of 33 patients with extended disease. The
      overall frequency of these cells was 1 per 4 x 10(5) to 82 per 4 x 10(5)
      mononuclear cells with no significant differences between patients at different
      tumor stages. After a short median follow-up of 9.5 months (3-24 months), 7 of 11
      patients who underwent complete surgical resection but had tumor cells in bone
      marrow presented with tumor relapse compared to 2 of 19 corresponding patients
      without such cells (p < 0.01). It was concluded that although bone marrow is not
      a preferential site of overt metastasis of esophageal cancer, the frequent
      occurrence of isolated tumor cells at this distant site indicates that
      hematogenous dissemination of viable malignant cells occurs early in tumor
      progression.

PMID- 8661633
TI  - Acute surgical treatment of complicated peptic ulcers with special reference to
      the elderly.
AB  - The results of 136 consecutive patients treated surgically for the acute
      complications of peptic ulcers between 1990 and 1993 are reviewed. All patients
      required emergency operation. Among 136 patients, 91 had perforations, 42
      hemorrhage, and 3 a penetrated peptic ulcer. The median age was 77 years; 65%
      were women; and 83% were more than 60 years old. Concurrent disease requiring
      medical treatment were present in 92 patients; 79 patients (58%) were currently
      or recently taking antiinflammatory drugs at the time of admission; 66% of the
      patients had duodenal ulcer. Only 46 patients (34%) had no postoperative
      complications; pneumonia, arrhythmia, bleeding, and septic complications were the
      most frequent. The overall mortality was 30%. Sepsis and multiple organ failure
      was the leading cause of death in most of the patients. It was concluded that
      elderly individuals using two or more antiinflammatory drugs should be considered
      potential peptic ulcer patients and should be treated prophylactically with ulcer
      healing drugs.

PMID- 8661634
TI  - Screening by genomic linkage studies and mutation analysis of hereditary
      adenomatous polyposis coli: usefulness for clinical practice.
AB  - A heterogeneous group of patients suffering from adenomatous polyposis coli (APC)
      were evaluated by clinical and genetic investigations for the first time in
      Austria. The patients belonged to eight unrelated APC families. In six families
      several family members were affected with APC, and linkage analysis with highly
      informative markers was used to estimate the risk of single individuals in these
      families to develop APC. All index patients were also tested for the most
      frequent mutation in the APC gene (mutation cluster region, exon 15). Clinical
      investigations included ophthalmologic tests for congenital hypertrophy of
      retinal pigment epithelium and colonoscopy. According to DNA analysis, 5 of 19 at
      risk individuals had to be considered to be at high risk of having inherited the
      disease. Four of them underwent proctocolectomy, one patient at risk is under
      colonoscopic surveillance. The predictive value of indirect genotype analyses
      reached 83.3%; direct mutation analyses allowed risk estimation in 50% of cases.
      Ophthalmologic investigation was informative in 75% of the families. Direct and
      indirect genotyping using a panel of highly polymorphic, closely linked
      microsatellite markers is a valuable, rapid, reliable method for establishing a
      presymptomatic diagnosis of APC, especially in families in which more than one
      affected individual is available for analysis. With regard to the onset of APC
      and extracolonic manifestations, the variability of APC demands clinical
      investigations in addition to the molecular tests for all patients and their
      first-degree relatives.

PMID- 8661635
TI  - Peritoneal carcinomatosis from adenocarcinoma of the colon.
AB  - Peritoneal carcinomatosis is a major cause of surgical treatment failure in
      patients with colorectal cancer. In the past patients with this condition have
      had a lethal outcome. In this study, 64 consecutive patients were treated by the
      cytoreductive approach, which involved surgery to maximally resect all cancer in
      the abdomen and pelvis, early postoperative intraperitoneal chemotherapy with 5
      fluorouracil (5-FU) and mitomycin C, and three cycles of adjuvant intraperitoneal
      5-FU with systemic mitomycin C. The clinical features that may affect prognosis
      were assessed and critically analyzed statistically. Peritoneal implant size of <
      5 cm present in the abdomen and pelvis at the time of exploration correlated with
      a good prognosis (p < 0.0001), as did complete cytoreduction with tumor removed
      to nodules < 2.5 mm (p < 0.0001). Involvement of only one or two of the five
      abdominopelvic regions, compared to three or more regions, was a significant
      determinant of prognosis (p < 0.0001). Finally, a mucinous histologic type
      correlated adversely with prognosis when compared to intestinal-type
      adenocarcinomas (p < 0.001). These data suggest that patients with small-volume
      peritoneal seeding from colon cancer should be treated with cytoreductive surgery
      and aggressive regional and systemic chemotherapy in an attempt to achieve long
      term disease-free survival.

PMID- 8661636
TI  - Thyroid gland surgery in an endemic region.
AB  - To assess the incidence, indications, and complications of (reoperative) thyroid
      gland surgery in an endemic region, we have retrospectively analyzed 1318
      patients operated on between 1983 and 1994. There were 166 reoperations (13.5%).
      In comparison to the primary operation the indication for reoperation showed an
      increased rate of premalignant and malignant tumors (+16%) and a decreased rate
      of hyperthyroid disorders (-30%). The largest group operated on had benign
      multinodular goiters, with the same rate of indication for primary (57.4%) and
      secondary (57.8%) surgery. Permanent recurrent laryngeal nerve palsy rate
      following primary operation occurred at rates of 1.7% (1983-1990) and 0.7% (1991
      1994) and for secondary operation 3.5% (1983-1990) and 5.6% (1991-1994),
      respectively. The change in recurrent nerve palsy rate in the later years was due
      to a more extensive resection policy at the primary operation and a more liberal
      approach to reoperative surgery. The high rate of reoperation for benign goiters
      (13%) and the new data of goitrogenesis have therefore directed our policy to
      more extensive resection of the thyroid tissue at the initial operation,
      increasing the rate of lobectomy from 27% (1982-1990) to > 90% (1991-1994) and at
      the same time lowering morbidity. Extensive resection of nodular tissue during
      the initial operation safely reduces the incidence of recurrent goiter and
      subsequently reduces the rate of reoperation and eliminates the high risk of
      morbidity associated with reoperative thyroid surgery. The indications for
      reoperation should be strict, and when unavoidable a modified lateral approach
      may be helpful.

PMID- 8661637
TI  - Blood supply and parathyroid hormone secretion in pathological parathyroid
      glands.
AB  - The blood supply of pathologic parathyroid glands and the relation between
      parathyroid hormone secretion and parathyroid blood perfusion was studied during
      surgery for hyperparathyroidism. Blood flow in 39 single adenomas and 20 glands
      classified as primary or secondary hyperplasia were studied intraoperatively with
      laser Doppler flowmetry. The ipsilateral inferior thyroid artery was occluded
      during continuous flowmetry recording, which resulted in a 40% reduction of
      parathyroid blood flow in both groups. In 12 patients with single adenomas,
      intact parathormone (iPTH) was measured intraoperatively before and during
      occlusion of the ipsilateral inferior thyroid artery and after extirpation of the
      adenoma. During occlusion the iPTH levels were mainly unchanged despite blood
      flow reduction of up to 80%. After removal of the adenoma the iPTH normalized
      within 15 minutes. In a control group of eight single adenomas, iPTH was measured
      similarly without vascular occlusion, demonstrating comparable iPTH levels. This
      study demonstrates similar routes of vascularization for single adenomas and
      hyperplastic glands, as was earlier seen for normal parathyroid glands. The
      increased parathyroid hormone secretion from single adenomas appears to remain
      mainly unchanged during significant blood flow reduction.

PMID- 8661638
TI  - Highlights from endocrine surgical history.
AB  - Endocrine surgery includes excision of diseased or sometimes normal endocrine
      glands and occasionally the transplantation of endocrine tissues. Male castration
      was performed for social reasons in prehistoric times, and thyroid operations
      were described during the twelfth century. Until the end of the nineteenth
      century most operations were undertaken to relieve the local effects of
      pathologic enlargement of the thyroid, ovaries, pituitary, and adrenals; and with
      the development of anesthesia, antisepsis, and effective hemostasis,
      thyroidectomy for benign, nontoxic goiter was perfected. Thyroid deficiency
      followed total thyroidectomy, and thyroid replacement therapy was developed.
      Toxic goiter was sometimes relieved by partial thyroidectomy. After the discovery
      of hormones early this century, knowledge of endocrinology increased, and many
      syndromes of hormonal excess were described. Surgeons began to operate to relieve
      them. Results improved with mastery of surgical technique, especially for
      operations on the thyroid, parathyroids, and pituitary; with the development of
      methods for diagnosis of syndromes and the localization of lesions; with
      teamwork; and with the use of hormones, drugs, and radiotherapy as alternative or
      additional forms of therapy before, during, and after operation. Notable advances
      followed adequate resection of thyroid tissue and the use of iodine and
      antithyroid drugs before operation for toxic goiter. The use of cortisone
      rendered adrenalectomy safe for the relief of cancer of the breast and prostate
      and of Cushing's syndrome. For about 40 years increasing numbers of surgeons have
      specialized in endocrine surgery as a discipline within general surgery, and
      results of treatment have improved greatly.

PMID- 8661639
TI  - Tropical pyomyositis.
AB  - Tropical pyomyositis (TP), a suppurative disease caused predominantly by
      Staphylococcus aureus, is responsible for 3% to 4% of surgical admissions in some
      hospitals in certain tropical countries. This study describes the clinical
      features of 35 patients with TP (20 males, 15 females; mean +/- SD age 28.3 +/-
      14.1 years) admitted to our hospital during a 1-year period and analyzes the
      causal association between ancylostomiasis, human immunodeficiency virus (HIV)
      infection, and TP. Concerning the supposed etiologic association between
      Ancylostoma duodenale infection and TP, among the 35 patients with TP the stool
      examination of 22 (62.8%) revealed the presence of eggs of A. duodenale. In a
      control group of 100 asymptomatic subjects the prevalence of ancylostomiasis was
      55%. The Odds ration between the two groups is 1.38 (exact 95% confidence limits
      = 0.59 < OR < 3.34). Furthermore, the pus from all TP abscesses (41 in 35
      patients) was carefully collected and examined microscopically, but nematode
      larvae were not detected in any of the specimens. Hence these results do not
      support an association between ancylostomiasis and TP. With the aim of
      correlating TP with HIV infection, I carried out a case-control comparison of HIV
      seroprevalence among the patients affected by TP and an age- and sex-matched
      control group of healthy subjects. Eleven patients with TP were HIV antibody
      positive (seroprevalence 31.42%), as were two controls (seroprevalence 5.71%).
      The matched analysis produced a Mantel-Haenszel matched Odds ratio of 5.50 and a
      maximum likelihood estimate of OR (MLE) of 5.50 (exact 95% confidence limits for
      MLE: 1.20 < OR < 51.07). Among the 11 patients HIV-seropositive, 9 (81.8%)
      fulfilled the World Health Organization clinical case definition (CCD) for AIDS,
      compared with 1 of 24 (4.1%) HIV-negative subjects. The chi-square test for
      difference in fulfilling the CCD for AIDS between patients with TP seropositive
      and seronegative result was statistically significant (p < 0.0001). It is
      concluded that TP is a bacterial infection highly significantly associated with
      HIV infection and thus must be considered a strong sign of stage III-IV of HIV
      disease.

PMID- 8661640
TI  - Comparison of self-expanding polyethylene terephthalate and metallic stents
      implanted in porcine iliac arteries.
AB  - PURPOSE: Comparison of the biocompatibility of self-expanding polyethylene
      terephthalate (PET) stents with self-expanding metallic stents (Wallstents).
      METHODS: Diameter- and length-matched PET stents and Wallstents were
      symmetrically implanted in the paired iliac arteries of 13 crossbred domestic
      swine. Stent deployment was studied angiographically and with intravascular
      ultrasound immediately after stent implantation. The angiographic stented lumen
      diameter was measured using quantitative vessel analysis before, immediately
      after stenting, and at 6-week follow-up. Cross-section histopathology and area
      morphometry were performed. RESULTS: Immediately poststenting, intravascular
      ultrasound revealed proximal dislocation of 5 of the 13 PET stents, whereas all
      metal stents were firmly embedded at the implantation site. At 6-week follow-up,
      three of the remaining PET stents were totally or subtotally occluded by
      organized thrombus, whereas all metal stents were patent. Compared with
      immediately poststenting, the angiographic lumen diameter within the five
      remaining PET stents was reduced by 30%, and that of the metallic stents was
      virtually unaltered (p < 0.02). This observation was confirmed by postmortem
      morphometry, wherein the PET-stented vessel segments a diameter stenosis of 40%
      was measured vs only 9% in the metallic stents (p < 0.0001). CONCLUSION: PET
      stent deployment is difficult to control due to the lack of radiopacity of this
      stent. PET stents seem to be more thrombogenic and lead to significantly more
      neointimal proliferation than metallic stents.

PMID- 8661642
TI  - Arterial complications of percutaneous transhepatic biliary drainage.
AB  - PURPOSE: To report on the frequency and treatment of arterial complications due
      to percutaneous transhepatic biliary drainage (PTBD). MATERIALS: Lesions of the
      intrahepatic artery were encountered in 10 of 525 patients treated by PTBD (2%).
      Hemobilia followed in 9 patients and subcapsular hematoma in 1. Seven patients
      had a benign biliary stenosis and 3 had a malignant stenosis. RESULTS: The
      bleeding resolved spontaneously in 3 patients. In 7 it required arterial
      embolization, which was successfully achieved either through the percutaneous
      catheter (n = 3) or by arteriography (n = 4). CONCLUSION: Arterial bleeding is a
      relatively rare complication of PTBD that can easily be treated by selective
      arterial embolization when it does not resolve spontaneously. In this series its
      frequency was much higher (16%) when the stenosis was benign than when it was
      malignant (0.6%).

PMID- 8661641
TI  - Evaluation of the pullback atherectomy catheter in the treatment of lower limb
      vascular disease.
AB  - PURPOSE: To evaluate prospectively the Pullback Atherectomy Catheter (PAC) in
      terms of its technical success and 1-year patency in the treatment of lower limb
      vascular disease.M ETHODS: Thirty-nine PAC procedures were performed in 34
      patients to treat atherosclerotic disease (occlusive in 51%) of the
      femoropopliteal arteries, including four cases of graft neointimal hyperplasia
      and three dissection flaps. Follow-up was by ankle-brachial indices at 24 hr and
      1 month, and arteriography at 6 and 12 months. RESULTS: Technical success was
      achieved in 38 of 39 procedures (97.4%). There was a reduction in mean stenosis
      from 89.4% to 12.1%, but 69.2% of procedures required additional balloon
      dilatation to achieve an adequate arterial lumen. Complications followed 15.4% of
      procedures, a third of which required surgery. CONCLUSION: The PAC is an easy and
      relatively safe catheter to use, but does not provide a satisfactory arterial
      lumen without additional percutaneous transluminal angioplasty (PTA). It proved
      to be effective, however, in the treatment of graft neointimal hyperplasia and in
      the resection of obstructive intimal flaps following PTA.

PMID- 8661643
TI  - Fragmentation of pulmonary emboli: in vivo experimental evaluation of two high
      speed rotating catheters.
AB  - PURPOSE: To test two over-the-wire systems for fragmentation of pulmonary emboli.
      METHODS: In 11 dogs, 22 embolic occlusions of lobar or central pulmonary arteries
      were performed by injection of preformed emboli through a jugular vein sheath. A
      commercially available device (thrombolizer) and a modified version of the
      impeller catheter were introduced via the femoral vein and positioned at the
      embolus site. RESULTS: Catheter placement at the site of the emboli was possible.
      In more than half of the cases a hydrophilic or an extra-stiff guidewire was
      necessary. The thrombolizer did not rotate properly with its original pneumatic
      drive and required a major modification. When sufficient rotation was provided,
      both fragmentation catheters were able to clear the occluded main arteries. Side
      branches were partly obstructed by the resulting fragments. Recanalization led to
      a reduction of the emboli-induced elevation of the pulmonary arterial pressure by
      two-thirds. Histology of the recanalized pulmonary artery segments revealed
      localized (impeller catheter) and widespread (thrombolizer) periarterial
      hemorrhage. CONCLUSION: Embolus fragmentation led to a hemodynamic improvement.
      The impeller catheter was less traumatic compared with the thrombolizer, which
      was technically insufficient.

PMID- 8661644
TI  - Occlusion of the neonatal patent ductus arteriosus with a simple retrievable
      device: a feasibility study.
AB  - PURPOSE: To examine the feasibility of transvenous placement of a new memory
      shaped, small, retrievable coil that has a smaller-caliber delivery system than
      currently available devices, for closure of the patent ductus arteriosus (PDA).
      METHODS: Through 4 or 5 Fr vascular sheaths and 4 or 5 Fr end-hold catheters, the
      coils were delivered and placed in piglets (n = 10) with PDA. The coils were made
      from 0.018" (0.46 mm) or 0.028" (0.71 mm) stainless steel guidewire. Mounted for
      delivery, the new device has the appearance of a conventional guidewire. This
      neonatal PDA model was created without major surgery or drugs by stenting the
      ductus arteriosus. RESULTS: The memory-shaped coils were easily delivered. Coils
      not optimally placed were retrieved and repositioned. Occlusion of the ductus
      arteriosus as early as a half-hour after delivery was shown angiographically and
      confirmed by histopathology. CONCLUSION: This new, small-caliber, simple device
      was found to be effective for closure of the PDA in this animal model. Longer
      term observations are needed.

PMID- 8661645
TI  - Extended intraarterial cisplatin infusion for treatment of gynecologic cancer
      after alteration of intrapelvic blood flow and implantation of a vascular access
      device.
AB  - PURPOSE: Twenty-two patients with advanced gynecologic cancer underwent extended
      intraarterial cisplatin infusion after alteration of the intrapelvic blood flow
      and implantation of a vascular access device (VAD). METHODS: To maximize
      concentrations of cisplatin at the target lesion, the superior and inferior
      gluteal arteries were embolized with steel coils. The tip of the catheter was
      inserted into the internal iliac artery; the opposite end of the catheter was
      connected to the VAD. RESULTS: Intensive radioisotope accumulation was
      demonstrated in the anterior division of the pelvis, seen by scintigraphy
      performed with technetium 99m macroaggregated albumin via the VAD. Local
      perfusion in the tumor was well seen by ultrasonographic angiography with CO2
      microbubbles via the VAD. Continuous consecutive infusion of cisplatin at a rate
      of 12.5 mg/day via the VAD minimized the toxicity. The overall response rate was
      73%. Radical surgery was possible in 16 of the 22 patients after this
      intraarterial infusion. CONCLUSION: This method was useful for treating advanced
      gynecologic cancer without significant toxicity.

PMID- 8661646
TI  - Spasms of the hepatic artery following percutaneous transluminal angioplasty and
      tolazoline administration in a liver transplant patient.
AB  - Vascular complications after liver transplantation include occlusion or stenosis
      near the sites of anastomosis in the hepatic artery, portal vein, and vena cava.
      Balloon angioplasty of these stenoses carries little risk and is a useful
      procedure for the treatment of these problems. Here we describe the case of a
      liver transplant patient who underwent balloon angioplasty for stenosis of the
      hepatic artery and who developed spasms of the hepatic artery which were
      aggravated following intraarterial administration of Tolazoline.

PMID- 8661647
TI  - Percutaneous extraluminal (subintimal) recanalization of a brachial artery
      occlusion following cardiac catheterization.
AB  - A 47-year-old woman presented with disabling right arm claudication 10 weeks
      after Sones cardiac catheterization via a brachial artery cut-down. A technique
      of extraluminal recanalization of the brachial artery occlusion, used to treat
      this patient, is described.

PMID- 8661649
TI  - Late thromboembolic complication from a Palmaz stent in the common iliac artery.
AB  - A 56-year-old smoker presented with rest pain in his left leg and
      hyperfibrinogenemia. He was found to have a high-grade stenosing thrombus in a
      Palmaz stent which had been placed 4 years ago across a stenosing ulcerating
      plaque in the left common iliac artery. Systemic thrombolysis was successful but
      the patient refused long-term anticoagulation. He presented 2 months later with
      recurrent stent thrombosis and an embolus to the tibioperoneal trunk. Systemic
      lysis was successfully performed for the stent reobstruction but the distal
      embolic occlusion responded neither to systemic nor to local thrombolysis. This
      case suggests that patients with vascular stents and hyperfibrinogenemia and/or
      nicotine abuse should be considered candidates for long-term anticoagulation.

PMID- 8661648
TI  - Evaluation of hydatid disease of the heart with magnetic resonance imaging.
AB  - Two patients with cardiac involvement of hydatid disease are presented: one with
      hydatid cyst of the interventricular septum and pulmonary arteries and the other
      with multiple pulmonary cysts associated with intracardiac and pericardial cysts.
      The ability of magnetic resonance imaging (MRI) to provide a global view of
      cardiac anatomy in any plane with high contrast between flowing blood and soft
      tissue ensures it an important role in the diagnosis and preoperative assessment
      of hydatid disease of the heart.

PMID- 8661650
TI  - Use of a snare wire to perform nephrostomy access in the presence of obstructive
      staghorn calculi.
AB  - We describe a technique for gaining access to the central collecting system via a
      chosen calyx, utilizing an alternative entry point to that calyx. An Amplatz
      nitinol loop snare is then used to convert this access to a traditional approach.

PMID- 8661674
TI  - Oleyl Oleate and Homologous Wax Esters Synthesized Coordinately from Oleic Acid
      by Acinetobacter and Coryneform Strains
AB  - Newly isolated Acinetobacter (NRRL B-14920, B-14921, B-14923) and coryneform
      (NRRL B-14922) strains accumulated oleyl oleate and homologous liquid wax esters
      (C30:2-C36:2) in culture broths. Diunsaturated oleyl oleate preponderated in 75
      mg liquid wax esters (280 mg lipid extract) recovered from 100-ml cultures of
      Acinetobacter B-14920 supplemented with 810 mg oleic acid-oleyl alcohol. With
      soybean oil instead of oleic acid, wax esters (260 mg) were increased to
      approximately 50% of the lipid extract. Production of wax esters by cultures
      supplemented with combined fatty (C8-C18) alcohols and acids suggests a
      coordinated synthesis whereby the exogenous alcohol remains unaltered, and the
      fatty acid is partially oxidized with removal of C2 units before esterification.
      Consequently, C8-C18 primary alcohols control chain lengths of the wax esters.
      Exogenous fatty acids are presumed to enter an intracellular oxidation pool from
      which is produced a homologous series of liquid wax esters.

PMID- 8661675
TI  - Process of Carbonate Precipitation by Deleya halophila
AB  - Scanning electron microscopy and X-ray dispersive energy microanalysis were used
      to investigate the formation of carbonate crystals by Deleya halophila. The
      formation of calcium carbonate crystals (polymorphous aragonite) by D. halophila
      is a sequential process that commences with a nucleus formed by the aggregation
      of a few calcified bacterial cells and the subsequent accumulation of more
      calcified cells and carbonate, which acts to weld the bacteria together. The
      process leads to the formation of spherical bioliths measuring approximately 50
      &mgr;m in diameter. The mechanism of carbonate precipitation by D. halophila
      under our working conditions represents a process of induced biomineralization.

PMID- 8661676
TI  - Temperature Ranges, Growth Optima, and Growth Rates of Spiroplasma
      (Spiroplasmataceae, class Mollicutes) Species
AB  - A new method was developed for determination of the doubling times of
      spiroplasmas. In this procedure, the time required for medium acidification of
      tubes in tenfold dilution series was recorded. Sixty-four spiroplasma strains,
      representing 24 groups and 11 subgroups, were studied. Eight strains representing
      putative new groups were also included in the study. Doubling times at 5, 10, 15,
      20, 25, 30, 32, 37, 41, and 43&deg;C were determined. The range of temperatures
      for spiroplasma growth was 5&deg;-41&deg;C. Twenty-three spiroplasmas had optima
      of 30&deg;C, 29 had optima of 32&deg;C, and 13 had optima of 37&deg;C. The
      fastest growing spiroplasma was the MQ-4 strain (group XI), with a doubling time
      at optimal temperature of 0.6 h. The slowest was the Jamaican corn stunt strain
      B655 (subgroup I-3), with an optimal doubling time of 36.7 h. Spiroplasma strain
      B31 (group IV) had the widest range (5&deg;-41&deg;C), while the DW-1 strain and
      some subgroup I-3 strains had the narrowest, growing only at 25&deg; and
      30&deg;C. Some spiroplasmas grew well at 41&deg;C, but none grew at 43&deg;C. The
      ability of spiroplasmas to withstand a wide range of temperatures may reflect the
      conditions to which they are exposed in nature, including the temperatures of the
      insect, tick, and/or plant hosts in which they are carried and the plant surfaces
      from which they may be acquired by arthropods.

PMID- 8661677
TI  - Natroniella acetigena gen. nov. sp. nov., an Extremely Haloalkaliphilic,
      Homoacetic Bacterium: A New Member of Haloanaerobiales
AB  - A new extremely haloalkaliphilic, chemoorganotrophic, homoacetogenic bacterium
      strain Z-7937(T)(T-type strain) was isolated from the bottom mud of the soda
      depositing Lake Magadi, Kenya. It is an obligately anaerobic, motile, Gram
      negative, spore-forming rod growing in the pH range pH 8.1 to 10.7 and optimally
      in the range pH 9.7 to 10.0 under conditions of high alkalinity caused by
      saturation with trona. It has an obligate requirement for sodium carbonate and
      chloride ions. The optimum salt concentration for growth is in the range 12-15%
      wt/vol, and growth occurs within the range from 10% to 26%. Strain Z-7937(T) is a
      mesophile with an optimal temperature for growth of 37&deg;C, and a maximum of
      42&deg;C. The G + C content of strain Z-7937(T) is 31.9 mol%. A limited number of
      compounds are utilized, including lactate, ethanol, pyruvate, glutamate, and
      propanol. Acetate is the main end product. 16S rDNA sequence analysis shows
      strain Z-7937(T) to be a member of the order Haloanaerobiales and to represent a
      new branch within the family Halobacteroidaceae. On the basis of its novel
      physiology and phylogenetic position, we propose strain Z-7937 as a new species
      of a new genus, Natroniella acetigena gen. nov. sp. nov. The type strain is Z
      7937(T) (= DSM 9952).

PMID- 8661678
TI  - Ca2+ Uptake and Its Regulation in the Cyanobacterium Nostoc MAC
AB  - The uptake of Ca2+ and its regulation in the cyanobacterium Nostoc MAC were
      investigated. Cation uptake pattern was found to be biphasic, consisting of (a)
      rapid binding of cations to the negatively charged cell surface and (b) its
      metabolism dependent on intracellular import at least up to 60 min with the
      saturation at 2 mM Ca2+ (Km, 1.5 mM, Vmax 42.1 nmol Ca2+ mg-1 protein min-1 ).
      The cellular Ca2+ uptake was light and ATP dependent, and the addition of 3(3,4
      dichlorophenyl)-1,1-dimethyl urea (DCMU) or exogenous ATP proved the vital role
      of PS II-generated energy to drive the process. The significant inhibition of
      Ca2+ uptake by different metabolic inhibitors and uncouplers like p
      chloromercuribenzoate (pCMB), carbonylcyanide-p-nitrofluoromethoxylphenyl
      hydrazone (FCCP), N'N-dicyclohexylcarbodiimide (DCCD) and azide revealed that -SH
      group(s), proton gradient across the cell membrane, and ATP hydrolysis were
      involved in the transmembrane movement of Ca2+ in Nostoc MAC cells. Verapamil
      showed antagonism, abscisic acid (ABA) agonism, while trifluoroperazine (TFP) and
      N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) exerted no effect on
      Ca2+ uptake.

PMID- 8661679
TI  - Isolation and Characterization of Microorganisms with Alternan Hydrolytic
      Activity
AB  - Alternan is an unusual alpha-D-glucan containing alternating (1 --> 3), (1 --> 6)
      linkages that exhibits remarkable resistance to enzymatic hydrolysis. The
      commercial potential of the polysaccharide may be enhanced by the ability to
      economically modify the native form into fractions of varying molecular weight.
      By employing isolation procedures with covalently dyed alternan as the substrate,
      several bacterial isolates that produced endohydrolytic activity were obtained in
      pure culture. The activity was confirmed by decreases in viscosity and by direct
      examination of the hydrolysis products with thin layer chromatography. Analysis
      of the hydrolysis products established that all isolates produced enzymes with
      identical alternan depolymerizing activity, producing a cyclic tetrasaccharide as
      a major product. All alternanase activity was shown to be extracellularly
      located. A single strain exhibited constitutive production of alternanase, while
      all other isolates required the presence of alternan in the growth media for
      enzyme production. All isolates were phenotypically similar, produced heat
      resistant spores, and were tentatively identified as members of the genus
      Bacillus.

PMID- 8661680
TI  - Isolation and Characterization of Chemotaxis Mutants of Chlamydomonas reinhardtii
AB  - Zoospores of Chlamydomonas reinhardtii exhibit chemotaxis towards maltose,
      sucrose, xylose, mannitol, and ammonium. Ten independent mutants defective in
      chemotaxis towards sugars have been isolated. These mutants form five phenotypic
      classes. Genetic analysis of two mutant strains defective in chemotaxis to
      maltose (CHE1, CHE3) and two mutant strains defective in chemotaxis to sucrose
      (CHE2, CHE4) indicated that the defect in them depended on single nuclear
      recessive mutant alleles. Mutations mal1, mal2, suc1, and suc2 represent four
      chemotactic loci that are unlinked to the marker mt located on the linkage group
      VI. Four loci are unlinked to each other. These observations suggest that the mal
      and the suc loci do not constitute a spatially single functional group.

PMID- 8661681
TI  - Identification of a Rhodococcus gene cluster encoding a homolog of the 17-kDa
      antigen of Brucella and a putative regulatory protein of the AsnC-Lrp family.
AB  - By sequence analysis, a gene encoding a homolog of the 17-kDa protein antigen of
      the Gram-negative pathogen Brucella abortus (Hemmen et al., Clin Diagn Lab
      Immunol 2: 263, 1995) was identified in the nocardioform actinomycete Rhodococcus
      sp. NI86/21. Database searching also revealed a partial human cDNA sequence for a
      putative eukaryotic homolog of this presumptive Brucella-specific protein. These
      proteins display a low but significant level of similarity with lumazine
      synthases involved in bacterial riboflavin biosynthesis. In the upstream region,
      a Rhodococcus gene for a putative regulatory protein of the AsnC family is
      located.

PMID- 8661682
TI  - Induction of H2-Uptake and Nitrogenase Activities in the Cyanobacterium Anabaena
      variabilis ATCC 29413: Effects of Hydrogen and Organic Substrate
AB  - A comparative study of the development of uptake hydrogenase and nitrogenase
      activities in cells of the cyanobacterium Anabaena variabilis was performed. The
      induction of heterocysts is followed by the induction of both in vivo hydrogen
      uptake and nitrogenase activities. Interestingly, a low but significant H2-uptake
      [2-7 MUmoles of H2 . mg-1 (Chl a) . h-1] occurs in cultures with no heterocysts
      and with no nitrogenase activity. A slight stimulatory effect (30-40%) of H2 on
      in vivo H2-uptake was observed during the early stages of nitrogenase induction.
      However, exogenous H2 does not further stimulate the induction of in vivo
      hydrogen uptake observed during heterocyst differentiation. Similarly, organic
      carbon (fructose) did not influence the induction of either in vivo hydrogen
      uptake or nitrogenase activities. Exogenous fructose supports higher in vivo
      hydrogen uptake and nitrogenase activities when the cells enter late exponential
      phase of growth.

PMID- 8661683
TI  - Effect of Different Temperature Upshifts on Protein Synthesis by the
      Psychrotrophic Bacterium Pseudomonas fragi
AB  - Pseudomonas fragi, a psychrotroph bacterium involved in meat product spoilage,
      was shifted either from 5degrees to 20degreesC or 30degreesC and from 28degrees
      to 34degreesC. The heat-shocked cells in the mid-log phase rapidly reached the
      characteristic growth rate of the postshock temperature. The patterns of
      synthesized proteins were compared by autoradiography of two-dimensional gel
      electrophoregrams. The rates of synthesis, after transfer of cells from 5degrees
      to 30degreesC, 5degrees to 20degreesC, and 28degrees to 34degreesC, changed for
      30, 26, and 21 proteins respectively, of which 19, 17, and 12 were increased
      respectively. Thirteen proteins changed similarly for the three treatments, and
      two of the seven overexpressed proteins were immunologically related to the
      Escherichia coli DnaK and GroEL heat shock proteins. From the four low-molecular
      mass proteins, belonging to the family of DNA-binding cold shock proteins (CSPs)
      such as CS7.4, the major E. coli CSP [15], the amounts of C7.0 and C8.0 decreased
      rapidly after the upshifts, whereas that of E7.0 and E8.0 increased greatly.

PMID- 8661684
TI  - In vitro evaluation of the efficacy of a silver-coated catheter.
AB  - Bacteria commonly associated with nosocomial urinary tract infections were
      examined in vitro for their relative adherence to latex, 100% silicone-, hydrogel
      coated latex-, and hydrogel/silver-coated latex urinary catheters. Degrees of
      adherence within 2 h were determined with cells radiolabeled with leucine.
      Adherence was greatest and equivalent on silicone and latex catheters. Adherence
      of four strains of Escherichia coli to the hydrogel/silver-coated catheter was
      decreased by 50% to 99% in comparison with the other catheters. Repeat testing
      with strains of E. coli and Pseudomonas aeruginosa with over 50 catheters
      demonstrated a consistency in the inhibition. The hydrophilic coating of the
      catheter appeared to be primary in the decreased adherence phenomenon followed by
      a secondary biocidal effect of the silver ion.

PMID- 8661685
TI  - Adhesion of Lactobacillus fermentum 104-S to porcine stomach mucus.
AB  - The adhesion to whole and fractionated porcine gastric mucus of both
      Lactobacillus fermentum 104-S cells and a saccharide extracted from this strain
      was investigated. It has been shown previously that this saccharide had affinity
      for nonsecreting gastric epithelium. The mucus component(s) with affinity the
      bacterial cells was partly characterized by gel filtration and treatment with
      protease or metaperiodate. L. fermentum 104-S extracts containing the saccharide
      were radioactively labeled, fractionated by gel filtration, and tested for
      affinity for the gastric mucus component showing receptor activity for the whole
      cells of strain 104-S. The mucus material with affinity for the bacterial cells
      had a relative molecular weight of 30-70 K. From the results of treatment with
      protease or metaperiodate, it is proposed that the mucus components(s) that
      adhered to the whole bacterial cells contained glycoprotein groups. The
      radioactively labeled saccharide extracted from L. fermentum 104-S cells did not
      bind to the mucus fraction that had affinity for the whole cells. Conclusively,
      we suggest that the mechanism by which cells of L. fermentum 104-S adhere to the
      gastric mucus is different from the mechanism mediating the adhesion of this
      strain to the nonsecreting gastric epithelium. Cells of L. fermentum 104-S adhere
      to a glycoproteinaceous mucus component with a relative molecular weight of 30-70
      K.

PMID- 8661686
TI  - Cloning vectors for lactococci based on a plasmid encoding resistance to cadmium.
AB  - An 8.8-kb plasmid (pND302) was identified in Lactococcus lacti spp lactis M71
      which encodes cadmium resistance (CdR). Most of the commercial lactococcal
      strains tested were sensitive to cadmium. Therefore, CdR should provide a useful
      selectable marker for constructing cloning vectors in lactococci. pND302 was
      mapped with a number of restriction enzymes and found to contain a unique EcoRI
      site suitable for cloning. Two E. coli/L lactis shuttle cloning vectors, pND304
      and pND624, were constructed by subcloning of the E. coli plasmids pBR322 and
      pGEM-7Zf(+) containing a 1.6-kb gene encoding nisin resistance (NisR) of
      lactococcal origin into the EcoRI site of pND302, separately. The E. coli DNA
      component of pND624 was removed and the resulting plasmid, pND625, consisted of
      only lactococcal DNA, expressing NisR and CdR, with two synthetic polylinkers
      that contain multiple restriction sites for versatile cloning. Both pND302 and
      pND625 can be transformed by electroporation into L. lactis LMO230 at
      10(3)/micrograms DNA and maintained stably in LMO230. The results indicated that
      pND302 and pND625 are potential food-grade cloning vectors for lactococci.

PMID- 8661688
TI  - Production, purification, and properties of serine carboxypeptidase from
      Paecilomyces carneus.
AB  - Seventeen strains of the genus Paecilomyces were examined for their ability to
      produce serine carboxypeptidase. Paecilomyces carneus IFO 7012 exhibited the
      highest potency for serine carboxypeptidase production. A maximum yield of serine
      carboxypeptidase was obtained by koji culture of the strain at 22 degrees C for 7
      days. The serine carboxypeptidase was purified to homogeneity from an extract of
      the koji culture. The molecular weight of the enzyme was estimated to be 47,000
      by HPLC. The isoelectric point of the enzyme was determined to be 4.0, and the
      optimum pH was 4.0 toward benzyloxycarbonyl-L-glutamyl-L-tyrosine (Z-Glu-Tyr) and
      benzyloxycarbonyl-L-phenylalanyl-L-alanine (Z-Phe-Ala), respectively. The enzyme
      was strongly inhibited by phenylmethylsulfonyl fluoride and p
      chloromercurybenzoate. Relative hydrolysis rates of N-acylpeptides and kinetic
      studies indicated that the enzyme preferred substrates having bulky amino acids
      in the penultimate position from their carboxy-termini.

PMID- 8661687
TI  - The novel antibacterial peptide ceratotoxin A alters permeability of the inner
      and outer membrane of Escherichia coli K-12.
AB  - Ceratotoxins are antibacterial 3-kDa amphiphilic peptides isolated from the
      female reproductive apparatus of the medfly Ceratitis capitata. The antibacterial
      activity of a chemically synthesized ceratotoxin A (ctx A) has been investigated.
      Ctx A was mainly active against Gram-negative organisms, and it had a lytic
      effect on nongrowing Escherichia coli K-12. Data showed that ctx A alters both
      the outer and the inner membrane of E.coli K-12 cells.

PMID- 8661689
TI  - Regulation by Galacturonic Acid of Pectinolytic Enzyme Production by Sclerotinia
      sclerotiorum
AB  - Production of polygalacturonases and pectinases from Sclerotinia sclerotiorum was
      induced in vitro by galacturonic acid. The inductive effect of galacturonic acid
      was abolished by the presence of glucose, leading to a basal enzyme production.
      Zymograms of extracellular enzymes showed that galacturonic acid induced the
      synthesis of six polygalacturonase and one pectin-methylesterase isoforms.
      Immunoblotting revealed that an exo-polygalacturonase and an exo
      polymethylgalacturonase were secreted in all conditions. They are not glucose
      repressed and not regulated by galacturonic acid. These constitutive enzymes
      provide the pathogen with the inherent ability to release galacturonic acid from
      plant cell walls and to trigger inducible enzyme synthesis.

PMID- 8661690
TI  - Contribution of Bacillus thuringiensis Spores to Toxicity of Purified Cry
      Proteins Towards Indianmeal Moth Larvae
AB  - The influence of Bacillus thuringiensis subsp. kurstaki HD-1 spores upon the
      toxicity of purified Cry1Ab and Cry1C crystal proteins toward susceptible and BT
      resistant Indianmeal moth (IMM, Plodia interpunctella) larvae was investigated.
      With susceptible larvae, HD-1 spores were toxic in the absence of crystal protein
      and highly synergistic (approximately 35- to 50-fold) with either Cry1Ab or Cry1C
      protein. With BT-resistant IMM larvae, HD-1 spores were synergistic with Cry1Ab
      and Cry1C protein in all three resistant strains examined. Synergism was highest
      (approximately 25- to 44-fold) in insects with primary resistance toward Cry1C
      (IMM larvae with resistance to B. thuringiensis subsp. aizawai or entomocidus).
      However, HD-1 spores also synergized either Cry1Ab or Cry1C toxicity toward
      larvae resistant to B. thuringiensis subsp. kurstaki at a lower level
      (approximately five- to sixfold). With susceptible larvae, the presence of spores
      reduced the time of death when combined with each of the purified Cry proteins.
      Without spores, the speed of intoxication and eventual death for larvae treated
      with Cry1C and Cry1Ab proteins was much slower than for the HD-1 preparation
      containing both spores and crystals together. Neither spores nor toxin dose
      affected the mean time of death of resistant larvae treated with either Cry1Ab or
      Cry1C toxins. Both Cry1Ab and Cry1C toxins appeared to reduce feeding and
      consequently toxin consumption.

PMID- 8661691
TI  - Cloning and Characterization of Two Closely Linked Cellulase Genes from
      Cellvibrio mixtus
AB  - A 16.5-kb BamHI fragment of the Cellvibrio mixtus chromosome was found to direct
      carboxymethylcellulase, xylanase, and avicel hydrolysis. Two closely linked genes
      were subcloned from this insert. The gene, cmcI, was cloned as a 2.7-kb fragment
      and expressed in Escherichia coli. It encoded an enzyme of approximately 74 kDa
      which degraded carboxymethylcellulose and xylan but did not attack the
      microcrystalline cellulose substrate avicel. A second cellulase capable of
      degrading avicel, encoded by exoI, was found 5.5 kb downstream of cmcI. Two
      translation products of 53.7 kDa and 51.5 kDa were produced in E. coli strains
      expressing exoI. Northern analysis of total mRNA of C. mixtus grown on avicel,
      with a probe generated from cmcI, showed that cmcI and exoI were not
      cotranscribed in an operon.

PMID- 8661692
TI  - Production of an emetic toxin, cereulide, is associated with a specific class of
      Bacillus cereus.
AB  - The emetic toxin (cereulide) of Bacillus cereus was quantified in several
      isolates of B. cereus and in various food sources. When the emetic toxin was
      produced, vomiting-type food poisoning was observed in humans. We also found that
      the H-1 serovar phenotype was strongly associated with the production of
      cereulide and that none of the isolates that hydrolyzed starch or expressed
      diarrheal enterotoxin activity produced cereulide.

PMID- 8661693
TI  - Construction of a cytogenetically characterized porcine somatic cell hybrid panel
      and its use as a mapping tool.
AB  - A new panel of cytogenetically characterized pig-rodent somatic cell hybrids was
      constructed and tested for twelve microsatellite markers with PCR. Cytogenetic
      characterization of hybrids was accomplished by fluorescence painting and GTG
      banding of metaphase chromosomes. The panel consists of 15 independent pig
      hamster and 6 independent pig-mouse cell lines. In the panel, all pig autosomes
      and the X Chromosome (Chr) are represented, and it is informative for all
      chromosome pairs except 2-14, 2-15, 3-9, 14-15, 14-16, and 16-17. The
      microsatellites tested were S0022, S0023, S0084, S0098, S0112, S0113, S0114,
      S0115, S0117, S0118, S0119, and S0120. The PCR results obtained in the 21 hybrids
      were compared with the cytogenetic data and analyzed for concordancy and
      correlation. Eight microsatellites could be assigned to specific pig chromosomes,
      confirming seven assignments based on linkage analysis.

PMID- 8661694
TI  - Cloning and characterization of the mouse short-chain acyl-CoA dehydrogenase
      gene.
AB  - Short-chain acyl-CoA dehydrogenase (SCAD) is one of four straight-chain length
      specific enzymes involved in the first step of fatty acid beta-oxidation. To
      further understand the similarities between the members of this gene family, to
      characterize how the gene is regulated, and to determine if there is coordinate
      regulation between these similar genes, we have isolated genomic clones
      containing the mouse Acads gene. We show that Acads is a compact, single-copy
      gene approximately 5000 bp in size. We sequenced the entire coding portion of the
      gene, all of the intron/exon junctions, and an 850-bp segment upstream of the
      translation start site. We have determined that the gene consists of 10 exons
      ranging in size from 57 bp to 703 bp, and 9 introns ranging in size from 80 bp to
      approximately 700 bp. The 5' region of the mouse Acads gene lacks a TATA box or a
      CAAT box, is GC rich, and also lacks any similarity to the related gene, medium
      chain acyl-CoA dehydrogenase. This is the initial report of the gene structure
      and 5' regulatory sequence of the short-chain acyl-CoA dehydrogenase gene in any
      species.

PMID- 8661695
TI  - Chromosome localization of the loci for PEPA, PEPB, PEPS, IDH1, GSR, MPI, PGM1,
      NP, SOD1, and ME1 in the common shrew (Sorex araneus).
AB  - This report extends the genetic map of the common shrew (Sorex araneus) by adding
      chromosome assignments for ten genes to the seven already mapped (Pack et al.
      1995). A somatic cell hybrid panel was used for the mapping. The genes for
      peptidase A (PEPA) and isocitrate dehydrogenase-1 (IDH1) map to chromosome de;
      the genes for phosphoglucomutase-1 (PGM1), superoxide dismutase-1 (SOD1), and
      mannosephosphate isomerase (MPI) are located on chromosome af; the genes for
      nucleoside phosphorylase (NP) and glutathione reductase (GSR) are on chromosome
      ik; and the genes for peptidase S (PEPS), malic enzyme-1 (ME1), peptidase B
      (PEPB) are found on chromosomes jl, go, and mp respectively.

PMID- 8661696
TI  - Chromosomal assignment of seven genes on canine chromosomes by fluorescence in
      situ hybridization.
AB  - Our group has developed more than 600 DNA markers to build a map of the canine
      genome. Of these markers, 125 correspond to genes (anchor loci). Here we report
      the first six autosomal genes assigned to canine chromosomes by fluorescence in
      situ hybridization (FISH), using cosmid DNA: adenine phosphoribosyl transferase
      on Chromosome (Chr) 3; creatine kinase muscle type on Chr 4; pyruvate kinase
      liver and red blood cell type on Chr 2; and colony-stimulating factor-1 receptor,
      glucose transporter protein-2, and tumor protein p53 on Chr 5. These assignments
      are based on the karyotype proposed by Stone and associates (Genome 34, 407,
      1991) using high-resolution techniques. In addition, we have assigned the Menkes
      gene to the X Chr of the dog.

PMID- 8661697
TI  - Isolation of the canine alpha-L-fucosidase cDNA and definition of the fucosidosis
      mutation in English Springer Spaniels.
AB  - Fucosidosis is a lysosomal storage disorder caused by deficiency of alpha-L
      fucosidase. A biochemically and clinically well characterized canine model of
      fucosidosis exists in a colony of English Springer Spaniels. To facilitate its
      use as a model for gene therapy and enzyme replacement therapy in lysosomal
      storage disorders displaying neurological symptoms, isolation of the canine alpha
      L-fucosidase cDNA was undertaken. Both the nucleotide sequence and the predicted
      amino acid sequence of canine fucosidase show high levels of identity with the
      human and rat sequences. Fucosidosis dogs were found to have a greatly reduced
      level of alpha-L-fucosidase mRNA when compared with normal dogs by Northern blot
      analysis. Direct PCR sequencing of products generated from cDNA demonstrated a 14
      bp deletion in mRNA from affected dogs. This deletion creates a frameshift
      mutation and introduces a premature translation termination codon at amino acid
      position 152 and was shown to correspond to a deletion of the last 14 base pairs
      of exon 1 of the canine alpha-L-fucosidase gene. Rapid PCR-based screening for
      the mutation has now been performed on genomic DNA from dogs within the colony,
      enabling detection of both carriers and homozygotes.

PMID- 8661698
TI  - Assignment of 19 porcine type I loci by somatic cell hybrid analysis detects new
      regions of conserved synteny between human and pig.
AB  - Nineteen so-called type I-loci, including ACO2, ADRA2, CAST, CCK, CHAT, IGKC,
      IGLV, IL4, IL6, INHA, LIF, MX1, PTH, RBP2, TCRA, TCRB, TGFB2, TGFB3, and UOX have
      been mapped in the pig with an informative somatic cell hybrid panel. By
      analyzing these new assignments in the knowledge of heterologous chromosome
      painting (Zoo-FISH) data for the porcine genome, it is possible to predict
      subchromosomal locations for most of these loci. Previously defined regions of
      conserved synteny were confirmed, and the extent of six of these regions was
      refined. These improvements in the porcine gene map facilitate the transfer of
      gene mapping data from "map-rich" species such as humans and mice.

PMID- 8661699
TI  - YAC clone contigs covering 5 Mb of a repeat sequence island on the mouse X
      chromosome.
AB  - We have initiated work towards the construction of YAC clone contigs across a
      repeat sequence island region on the mouse X Chromosome (Chr). The repeat
      sequence island region-the 141 island-located at band A3 contains 50 copies of a
      localized long complex repeat unit (LCRU). We have isolated 87 YAC clones from
      the 141 island and have used a dual faceted approach towards the construction of
      contigs across the repeat sequence island. First, we have identified YAC clones
      originating from the same region of the island by the identification of commonly
      held LCRU restriction site variants. Second, we have constructed rare cutter
      restriction maps of each YAC clone. Taken together, we have been able to assemble
      one large contig of 2.8 Mb and a number of smaller contigs. In total, contigs
      covering 5Mb of the island region have been identified. The island region would
      appear to represent a major component of the A3 Giemsa dark band on the mouse X
      Chr.

PMID- 8661700
TI  - A comparative map of the porcine and human genomes demonstrates ZOO-FISH and gene
      mapping-based chromosomal homologies.
AB  - ZOO-FISH with chromosome-specific DNA libraries (CSLs) from individual flow
      sorted human chromosomes was applied on porcine metaphase chromosomes to
      establish segment homology between the pig and human karyotypes. Forty-seven
      porcine chromosomal segments corresponding to all human chromosomes except the Y
      were delineated, resulting in a nearly complete coverage of the porcine
      karyotype. The syntenic segments detected were further confirmed by the gene
      mapping information available in the two species. A map demarcating physical
      boundaries of human homologies on individual pig chromosomes is complemented with
      a detail survey of the physical and genetic linkage mapping data in the two
      species. The resultant map, thus, provides a comprehensive and updated
      comparative status of the human and porcine genomes.

PMID- 8661701
TI  - Generation of chromosome fragment specific bovine DNA sequences by
      microdissection and DOP-PCR.
AB  - A rapid procedure for the defined isolation and characterization of single bovine
      chromosome fragment specific probes is described. This has been developed as a
      technical prerequisite for the directed generation of bovine DNA sequences. The
      specific regions 1q13-24, 5q21-24, 6q31-32, 7q21-22, 12q24-ter, and 20q12-ter of
      bovine GTG-banded metaphase chromosomes were microdissected and amplified by PCR
      with a degenerate oligonucleotide primer and subsequently cloned into pBluescript
      II SK. The DNA probes generated were characterized by gel electrophoresis, dot
      blot analysis and rehybridization in situ to GTG-banded metaphase spreads. The
      position and size of the hybridization sites on the chromosomes correspond
      exactly to the dissected chromosome areas and indicate the complexity and
      specificity of the microdissected and amplified chromosome material.

PMID- 8661702
TI  - Comparative analysis of the cattle and human genomes: detection of ZOO-FISH and
      gene mapping-based chromosomal homologies.
AB  - Comparative chromosome painting with individual human chromosome-specific
      libraries (CSLs) on cattle metaphase chromosomes delineated 46 homologous
      chromosomal segments between the two species. Continuous arrangement of these
      segments on individual cattle chromosomes demonstrates a nearly complete coverage
      of the bovine karyotype and shows physical boundaries of bovine chromosomal
      segments homologous to individual human chromosomes. Alignment of the available
      comparative gene mapping data with the homologous segments strongly supports the
      detected gross homologies between the karyotypes of the two species. In addition
      to cattle, four human CSLs were hybridized to sheep metaphase chromosomes also,
      to further verify the known karyotype homology within the Bovidae. Besides its
      application to karyotype evolution research, the comparative knowledge provides
      for rapid expansion of the much needed Type I locus-based bovine gene map.

PMID- 8661704
TI  - Fine genetic mapping of the region surrounding the high growth (hg) locus in
      mouse chromosome 10: targeting random amplified polymorphic DNA (RAPD) markers.

PMID- 8661703
TI  - A long-range physical map of human chromosome 21q22.1 band from the YAC
      continuum.
AB  - The human Chromosome (Chr) 21q22.1 region contains several genes for cytokines
      and neurotransmitters and the gene for superoxide dismutase (mutant forms of
      which can cause familial amyotrophic lateral sclerosis). A region of
      approximately 5.8 Mb encompassing D21S82 and the glycinamide ribonucleotide
      transformylase (GART) loci was covered by overlapping YAC clones, which were
      contiguously ordered by clone walking with sequence-tagged site (STSs). A total
      of 76 markers, including 29 YAC end-specific STSs, were unambiguously ordered in
      this 5.8-Mb region, and the average interval between markers was 76 kb.
      Restriction maps of the YAC clones with rare-cutting enzymes were simultaneously
      prepared, and the restriction sites were aligned to obtain a consensus
      restriction map of the proximal region of the 21q22.1 band. The restriction map
      made from 44 overlapping YACs contains 54 physically assigned STSs. By
      integrating the consensus map of the adjacent 1.8-Mb region, we obtained a fine
      physical map spanning 6.5 Mb of human Chr 21q22.1. This map contains 24 precisely
      positioned end-specific STSs and 12 NotI-linking markers. More than 39 potential
      CpG islands were identified in this region and were found to be unevenly
      distributed. This physical map and the YACs should be useful as a reference map
      and as a resource for further structural analysis of the Giemsa-negative band (R
      band) of Chr 21q22.1.

PMID- 8661705
TI  - Molecular analysis of the cDNAs encoded by the pun and pJ alleles of the pink
      eyed dilution locus.

PMID- 8661706
TI  - Red coat color in Holstein cattle is associated with a deletion in the MSHR gene.

PMID- 8661707
TI  - Localization of mtv44 to the centromeric region of mouse chromosome 11.

PMID- 8661708
TI  - The gene encoding adenylyl cyclase VII is located in central mouse chromosome 8.

PMID- 8661709
TI  - Genetic mapping of the gene for the mouse interferon-gamma receptor signaling
      subunit to the distal end of chromosome 16.

PMID- 8661710
TI  - Assignment of the porcine IKBA gene (IkappaBalpha) encoding a cytoplasmic
      inhibitor of the NF-kappaB to chromosome 7q15-q21 by FISH.

PMID- 8661711
TI  - Assignment of pig immunoglobulin kappa gene IGKC, to chromosome 3q12-q14 by
      fluorescence in situ hybridization (FISH).

PMID- 8661712
TI  - Assignment of the choline acetyltransferase gene to porcine chromosome 14q25-27
      by fluorescence in situ hybridization.

PMID- 8661713
TI  - The gene encoding the thrombin receptor (Cf2r) maps to mouse chromosome 13.

PMID- 8661714
TI  - Mapping of the porcine immunoglobulin lambda gene, IGL, by fluorescence in situ
      hybridization (FISH) to chromosome 14q17-q21.

PMID- 8661715
TI  - Chromosomal assignment of the porcine gene for apolipoprotein C3 (APOC3) to
      chromosome 9 by somatic cell hybrids.

PMID- 8661716
TI  - Genetic mapping of the gene encoding the alpha1 subunit of neuronal calcium
      channels.

PMID- 8661717
TI  - A class of highly polymorphic tetranucleotide repeats for canine genetic mapping.
AB  - We have identified and characterized a new class of polymorphic markers for the
      canine genome from a simple tetranucleotide repeat sequence, (GAAA)n. Genetic
      markers derived from this repeat are highly polymorphic compared with other
      canine microsatellites, yet are stable enough to be useful for following
      Mendelian inheritance in multigeneration pedigrees. We show further that (GAAA)n
      repeats are distributed throughout the canine genome and occur with sufficient
      frequency to be useful in the development of a framework map of the canine
      genome.

PMID- 8661718
TI  - Production of congenic mouse strains carrying genomic intervals containing SLE
      susceptibility genes derived from the SLE-prone NZM2410 strain.
AB  - Systemic lupus erythematosus is inherited as a complex polygenic trait. Four
      genomic intervals containing major SLE-susceptibility loci were previously
      identified by interval mapping in the NZM2410 mouse model. In this paper, we
      utilized a marker-assisted selection protocol to produce four congenic mouse
      strains, each carrying an NZM2410-derived SLE-susceptibility interval on a
      C57BL/6-resistant background. Each strain carries only one susceptibility allele
      derived from this polygenic model and consequently can be used to characterize
      the specific component phenotypes contributed by individual SLE-susceptibility
      genes. We illustrate the efficacy of this approach with phenotypic data for one
      of our congenic strains, B6.NZMH2(z). Our results indicate that this single
      genomic interval from Chromosome (Chr) 17 of NZM2410 can mediate increased levels
      of IgG autoantibodies specific for chromatin and that, similar to results
      obtained in our original genetic cross, B6.NZMH2(z/b) heterozygotes are more
      prone than B6.NZMH2(z) homozygotes to the development of humoral autoimmunity to
      nuclear antigens. These results illustrate the feasibility of using congenic
      strains to dissect the complex pathogenic mechanisms that mediate polygenic SLE.
      These congenic strains will be valuable tools in the genetic analysis of SLE
      susceptibility. In future studies, these congenic strains will be interbred to
      produce bi- and tri-congenic strains in order to assess the role of genetic
      interactions in the expression of specific components of SLE pathogenesis. They
      will also be instrumental to the positional cloning and identification of the
      genes responsible for SLE susceptibility, via the production of congenic
      recombinants.

PMID- 8661719
TI  - Generation and mapping of Mus spretus strain-specific markers for rapid genomic
      scanning.
AB  - We describe here a set of genetic markers, based on IRS-PCR amplification
      difference, that are specifically designed for efficient, high throughput genetic
      mapping in [(M. domesticus x wild-derived) F1 x M. domesticus] interspecific
      backcrosses. 146 new genetic loci have been mapped, and strain distribution for
      these markers has been determined in 96 mouse strains. 103 (81%) of 127 tested
      markers are present only in one or more wild-derived strains, but absent in 76
      other commonly used strains, demonstrating their utility in a variety of mouse
      pair combinations. Because of the ease of genotyping with this marker set, rapid
      genome scans for complex genetic trait loci involving crosses between wild
      derived strains and other commonly used strains can now be carried out
      efficiently with large numbers of animals.

PMID- 8661721
TI  - Mouse uroporphyrinogen decarboxylase: cDNA cloning, expression, and mapping.
AB  - Uroporphyrinogen decarboxylase (URO-decarboxylase; EC 4.1.1.37), the heme
      biosynthetic enzyme responsible for the conversion of uroporphyrinogen III to
      coproporphyrinogen III, is the enzymatic defect in porphyria cutanea tarda, the
      most common porphyria. The mouse URO-decarboxylase cDNA was isolated from a mouse
      adult liver cDNA library. The longest clone of 1.5 kb, designated pmUROD-1, had
      5' and 3' untranslated sequences of 281 and 97 bp, respectively, and an open
      reading frame of 1104 bp encoding a 367-amino acid polypeptide with a predicted
      molecular mass of 40,595 Da. The mouse and human coding sequences had 87.8% and
      90.0% nucleotide and amino acid identity, respectively. The authenticity of the
      mouse cDNA was established by expression of the active enzyme in Escherichia
      coli. In addition, the analysis of two sets of multilocus genetic crosses
      localized the mouse gene, Urod, on Chromosome (Chr) 4, consistent with the map
      location of the human gene to a position of conserved synteny on Chr 1. The
      availability of the mouse URO-decarboxylase should facilitate studies of the
      structure and organization of the mouse genomic sequence and the development of a
      mouse model of this inherited porphyria.

PMID- 8661720
TI  - Characterization of the mouse Tdgf1 gene and Tdgf pseudogenes.
AB  - Cripto protein is a member of the "EGF family" of growth factors present in colon
      tumors and in human and mouse undifferentiated teratocarcinoma cells. During
      gastrulation in the mouse, cripto-encoding transcripts are expressed in the
      forming mesoderm and later in the truncus arteriosus of the developing heart. As
      a necessary step prior to investigating the in vivo role of cripto through gene
      disruption, we have isolated all the genomic cripto-related sequences in the
      mouse. One gene (Tdgf1) and two pseudogenes (Tdgf2 and Tdgf3) have been isolated
      and characterized. The mouse Tdgf1 (coding for cripto), like the human gene, is
      divided into six exons. Comparison of the human and mouse genomic sequences
      reveals that mouse exons 1 and 3 are shorter than the corresponding human exons.
      The pseudogene Tdgf2 corresponds to about 1 kb of the mRNA and contains five base
      substitutions in the coding region that represent both silent and replacement
      substitutions. The pseudogene Tdgf3 corresponds only to the coding portion of
      Tdgf. Many mutations have been introduced in this pseudogene, suggesting its
      early origin. Alignments of the Tdgf3, human and mouse mRNA sequences, shows that
      this pseudogene has retained the 33 nucleotides of the human exon 3 that are
      missed in the Tdgf1 gene. Taken together, these data suggest that Tdgf3 is
      derived from an ancestral gene and that the human and mouse genes are probably
      evolving separately.

PMID- 8661722
TI  - Molecular cloning, chromosomal mapping, and expression of the mouse p107 gene.
AB  - Progression through the G1 phase of the cell cycle is regulated, in part, by the
      pRB-family proteins, pRB and p107. The basis for this regulation is due to a
      network of interactions between the pRB-family proteins, pRB, p107, and p130; the
      E2F-family of transcription factors; and cyclins D, E, and A. One of the pRB
      family proteins, p107, has also been found to bind to the transactivation domain
      of the c-Myc proto-oncogene. This region in c-Myc is frequently mutated in tumors
      such as Burkitt's lymphoma, HIV-associated lymphoma, and multiple myeloma. The
      binding of p107 and regulation of c-Myc may conceivably be disrupted not only by
      mutations in c-Myc, but possibly by mutations in p107. In order to determine if
      mutations in p107 are indeed present in mouse B-cell tumors which exhibit a lower
      frequency of c-Myc mutation, we have cloned the mouse p107 cDNA and compared this
      sequence with its human counterpart. We find that the extreme N-terminal and C
      terminal regions are the most conserved between human and mouse p107 sequences.
      Chromosomal positioning of the locus for p107 (designated Rbl1) as well as E2f1
      to the distal end of mouse Chromosome (Chr) 2 also suggests a close but unlinked
      genetic relationship between these cell cycle regulatory transcription factors.

PMID- 8661723
TI  - A rat homolog of the mouse deafness mutant jerker (je).
AB  - An autosomal recessive deafness mutant was discovered in our colony of Zucker
      (ZUC) rats. These mutants behave like shaker-waltzer deafness mutants, and their
      inner ear pathology classifies them among neuroepithelial degeneration type of
      deafness mutants. To determine whether this rat deafness mutation (-) defines a
      unique locus or one that has been previously described, we mapped its chromosomal
      location. F2 progeny of (Pbrc:ZUC x BN/Crl) A/a B/b H/h +/- F1 rats were scored
      for coat color and behavioral phenotypes. Segregation analysis indicated that the
      deafness locus might be loosely linked with B on rat Chromosome (Chr) 5 (RNO5).
      Therefore, 40 -/- rats were scored for BN and ZUC alleles at four additional
      loci, D5Mit11, D5Mit13, Oprd1, and Gnb1, known to map to RNO5 or its homolog,
      mouse Chr 4 (MMU4). Linkage analysis established the gene order (cM distance) as
      D5Mit11-(19.3)-B-(17.9)-D5Mit13-(19. 2)-Oprd1-(21.5) - (1.2) Gnb1, placing the
      deafness locus on distal RNO5. The position of the deafness locus on RNO5 is
      similar to that ofjerker (je) on MMU4; the phenotypes and patterns of inheritance
      of the deafness mutation and je are also similar. It seems likely that the
      mutation affects the rat homolog of je. The rat deafness locus should, therefore,
      be named jerker and assigned the gene symbol Je.

PMID- 8661724
TI  - Production of congenic mouse strains carrying NOD-derived diabetogenic genetic
      intervals: an approach for the genetic dissection of complex traits.
AB  - Insulin-dependent (Type 1) diabetes (IDD) in the NOD mouse is inherited as a
      complex polygenic trait making the identification of susceptibility genes
      difficult. Currently none of the non-MHC IDD susceptibility genes in NOD have
      been identified. In this paper we describe the congenic mouse approach that we
      are using for the dissection of complex traits, such as IDD. We produced a series
      of six congenic strains carrying NOD-derived diabetogenic genomic intervals,
      which were previously identified by linkage analysis, on a resistant background.
      These congenic strains were produced for the purpose of characterizing the
      function of each of these genes, alone and in combinations, in IDD pathogenesis
      and to allow fine mapping of the NOD IDD susceptibility genes. Histological
      examination of pancreata from 6 to 8-month-old congenic mice reveals that
      intervals on Chromosomes (Chrs) 1 and 17, but not 3, 6, and 11, contain NOD
      derived genes that can increase the trafficking of mononuclear cells into the
      pancreas. Insulitis was observed only very rarely, even in older congenic mice,
      indicating that multiple genes are required for this phenotype. These results
      demonstrate the utility of this congenic approach for the study of complex
      genetic traits.

PMID- 8661725
TI  - A detailed physical map of the porcine major histocompatibility complex (MHC)
      class III region: comparison with human and mouse MHC class III regions.
AB  - A detailed physical map of the porcine MHC class III region on Chr 7 was
      constructed with a panel of probes in a series of hybridizations on genomic
      pulsed field gel electrophoresis (PFGE) Southern blots. A precise organization of
      the 700-kb segment of DNA between G18 and BAT1 can now be proposed, with more
      than 30 genes mapped to it. Comparison of this region with homologous regions in
      human and mouse showed only minor differences. The biggest difference was
      observed in the CYP21/C4 locus with only one CYP21 gene and one C4 gene found,
      whereas in human and mouse these genes are duplicated. These results show the
      class III region is very well conserved between pig, human, and mouse, in
      contrast with the class I and class II regions, which seem more prone to
      rearrangements.

PMID- 8661726
TI  - Physical assignments of 68 porcine cosmid and lambda clones containing
      polymorphic microsatellites.
AB  - Two lambda phage and 66 cosmids containing informative porcine microsatellites
      were assigned to 17 of 18 porcine autosomes and the X Chromosome (Chr) by
      fluorescence in situ hybridization (FISH). These assignments provide additional
      physically anchored markers to integrate the porcine physical and genetic maps.

PMID- 8661727
TI  - The linkage map of sheep Chromosome 6 compared with orthologous regions in other
      species.
AB  - The genetic linkage map of sheep Chromosome (Chr) 6 has been extended to include
      35 loci with the addition of 11 RFLP and 12 microsatellite loci. The sex-averaged
      linkage map now spans 154 cM from phosphodiesterase cyclic GMP beta polypeptide
      (PDE6B) to OarCP125, an anonymous sheep microsatellite. The male and female map
      lengths, at 180 cM and 132 cM respectively, did not differ significantly. The
      physical assignment of PDE6B to Chr 6q33-qter orientates the linkage map on sheep
      Chr 6 with PDE6B near the telomere and OarCP125 towards the centromere. The order
      and genetic distances between loci are similar for the sheep Chr 6 and cattle Chr
      6 maps, except for the position of the casein genes. The sheep Chr 6 linkage map
      is also comparable to portions of human Chr 4, mouse Chrs 5 and 3, and pig Chr 8.
      The synteny between sheep Chr 6 and human Chr 4 has been extended from PDE6B
      (4p16.3) to epidermal growth factor (EGF, 4q25-q27). However, a region from
      platelet-derived growth factor receptor alpha polypeptide (PDGFRA) to bone
      morphogenetic protein 3 (BMP3), which spans 19 cM on sheep Chr 6, appears to be
      inverted with respect to the human and mouse loci. Other differences in the gene
      order between sheep, pig, and mouse suggest more complex rearrangements.

PMID- 8661728
TI  - Molecular cloning of mouse canp3, the gene associated with limb-girdle muscular
      dystrophy 2A in human.

PMID- 8661729
TI  - Chromosomal mapping of the rat Slc4a family of anion exchanger genes, Ae1, Ae2,
      and Ae3.

PMID- 8661730
TI  - Short tandem repeat polymorphisms in Japanese macaques: their short repeat
      lengths and low informativeness.

PMID- 8661731
TI  - Microsatellites at a common site in the second ORF of L1 elements in mammalian
      genomes.

PMID- 8661732
TI  - Localization of bovine lymphocyte antigen (BoLA) DYA and class I loci to
      different regions of chromosome 23.

PMID- 8661733
TI  - The interleukin-12 beta subunit (p40) maps to mouse chromosome 11.

PMID- 8661734
TI  - Assignment of the mouse vesicular monoamine transporter genes, Slc18a1 and
      Slc18a2, to chromosomes 8 and 19 by linkage analysis.

PMID- 8661735
TI  - Genetic mapping of the IL-12 alpha chain gene (Il12a) on mouse chromosome 3.

PMID- 8661736
TI  - Receptor tyrosine kinase gene Tyro3 maps to mouse chromosome 2, closely linked to
      Ltk.

PMID- 8661737
TI  - Linkage mapping of the retinol-binding protein 4 (RBP4) gene to porcine
      chromosome 14.

PMID- 8661739
TI  - The bovine homolog of the obese gene maps to chromosome 4.

PMID- 8661738
TI  - Chromosomal localization of the bovine obesity (OBS) gene.

PMID- 8661741
TI  - The gene encoding tripeptidyl peptidase II maps to chromosome 1 in the mouse.

PMID- 8661740
TI  - Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p).

PMID- 8661742
TI  - Assignment of c-KIT gene to swine chromosome 8p12-p21 by fluorescence in situ
      hybridization.

PMID- 8661743
TI  - Localization of mouse peroxisome proliferator-activated receptor gamma on
      chromosome 6.

PMID- 8661744
TI  - Localization of the antigen CD3, zeta polypeptide (CD3Z) to cattle chromosome
      3q11-q14.

PMID- 8661751
TI  - News and notices

PMID- 8661750
TI  - Fourth International Congress of the European Association for Endoscopic Surgery
      (E.A.E.S.) Trondheim, Norway, 23-26 June 1996Oral Presentations

PMID- 8661752
TI  - The role of ERCP in choledocholithiasis.

PMID- 8661753
TI  - Usefulness of endoscopic ultrasonography in the diagnosis of choledocholithiasis.

PMID- 8661754
TI  - Helical CT cholangiography.

PMID- 8661755
TI  - MR cholangiopancreatography.

PMID- 8661756
TI  - Caroli's disease: evaluation with MR cholangiopancreatography (MRCP).

PMID- 8661757
TI  - Choledocholithiasis and the pancreatobiliary ductal system: advances in imaging.
      Introduction.

PMID- 8661758
TI  - Radiographic findings of intractable gastric ulcers with H2-receptor antagonists.
AB  - BACKGROUND: To clarify the radiographic characteristics of intractable gastric
      ulcers with H2-receptor antagonists. METHODS: The radiographic findings at the
      time of starting treatment were compared between 42 patients with gastric ulcers
      that did not heal within eight weeks of starting treatment with H2-receptor
      antagonists (the intractable group) and 58 patients whose ulcers healed within
      the eight-week period (the tractable group). RESULTS: The following radiographic
      findings in the intractable group were observed at a significantly higher
      incidence than those in the tractable group and included: an ulcer located on the
      angle, linear ulcers, a greater depth, an uneven mound surrounding an ulcer,
      prominent folds' convergence, an overhanging gastric mucosa, an irregular ulcer
      base, a shortening of the lesser curvature and a U-shaped deformity of the angle.
      A multiple logistic regression analysis showed that the following three factors
      had a significant and independent delaying effect on healing: a U-shaped
      deformity of the angle, an uneven mound surrounding an ulcer and prominent folds'
      convergence. The relative risk of these factors were 12.7, 14.4 and 12.5,
      respectively. CONCLUSIONS: Intractable gastric ulcer with H2-receptor antagonists
      can be predicted based on the characteristic radiographic findings at the start
      of treatment.

PMID- 8661759
TI  - Small bowel Procardia XL tablet bezoar mimicking cystic pneumatosis intestinalis.
AB  - Procardia XL Extended Release Tablets are being used with increasing frequency in
      the treatment of angina and hypertension. Bezoar formation, secondary to retained
      insoluble medication shells, is an important but less well-known complication. We
      report the first case of a small bowel bezoar due to this unique medication
      system.

PMID- 8661760
TI  - Lesser sac hernia through the gastrocolic ligament: CT diagnosis.
AB  - We present a case of a lesser sac hernia of the ileum through a defect in the
      gastrocolic ligament with reemergence through a defect in the gastrohepatic
      ligament. Computed tomography (CT) revealed the herniated bowel surrounded by the
      liver, the stomach and the pancreas, and demonstrated the defect in the
      gastrocolic ligament between the stomach and the transverse colon.

PMID- 8661761
TI  - CT findings in symptomatic left paraduodenal hernia.
AB  - Two cases of symptomatic, surgically proven left paraduodenal hernias were shown
      with computed tomography (CT) imaging. A small bowel loop was seen behind the
      pancreatic tail in one case, and a ring-oriented bowel loop was shown between the
      transverse colon and the left adrenal gland in the other.

PMID- 8661762
TI  - Large lipomas of the colon: CT and MR findings in three symptomatic cases.
AB  - We report on three patients with large lipomas in the wall of the cecum, causing
      intussusception. Endoscopy is the preferred modality for small lipomas, whereas
      CT and MR imaging are more useful in their ability in detecting fatty masses and
      assessing the location of lesions. Barium enema study may contribute to the
      preoperative planning in selected cases.

PMID- 8661763
TI  - Intussuscepted colonic lipomas: loss of fat attenuation on CT with pathologic
      correlation in 10 cases.
AB  - BACKGROUND: To determine if infarction and necrosis is the cause of the confusing
      soft tissue density on CT within intussuscepting lipomas of the colon. METHODS:
      The clinical records, radiologic examinations, and pathologic specimens of all 13
      cases of colonic lipomas collected from 1988 to 1994 studied by CT and surgically
      resected were retrospectively reviewed. Ten of these cases were associated with
      intussusception; the CT attenuation of the lead point was graded according to its
      relative fat/soft tissue density. Pathologic specimens were graded independently
      by a GI pathologist and graded according to the degree of infarction/fat
      necrosis. RESULTS: The lipomas ranged from 4 to 7 cm in diameter (mean = 5 cm).
      Only one case with intussusception, and all three cases without, demonstrated
      pure fat attenuation on CT and demonstrated pure fat histologically. One case
      demonstrated soft tissue attenuation and corresponded with the most severely
      infarcted specimen histologically; two cases with similar but less severe
      infarction/fat necrosis corresponded with less than 25% fat attenuation. These
      latter three cases were originally misinterpreted as malignancies rather than
      lipomas. Six cases maintained greater than 50% fat density and intermediate
      amounts of infarction/fat necrosis. CONCLUSION: Lipomas may have an atypical
      appearance when intussuscepted due to varying degrees of infarction/fat necrosis.

PMID- 8661764
TI  - Primary liver leiomyosarcoma: CT appearance.
AB  - Primary hepatic leiomyosarcomas are exceedingly rare tumors. To the best of our
      knowledge, only 17 cases have been reported in literature. We report the computed
      tomographic findings of two cases of primary location in the liver. We also
      discuss the differential diagnosis of such lesions.

PMID- 8661765
TI  - Significance of the computed tomography finding of subcapsular hepatic necrosis
      in liver transplantation.
AB  - BACKGROUND: To evaluate the clinical significance of the computed tomographic
      finding of subcapsular hepatic necrosis following liver transplantation. METHODS:
      105 computed tomography scans performed in 50 allografts, 6 days to 4 years
      following transplantation, were retrospectively reviewed and divided into two
      groups: those with and those without the computed tomographic finding of
      subcapsular hepatic necrosis. Extrahepatic fluid, biliary dilatation, circumcaval
      rings, periportal collar, biochemistry, and random biopsies were correlated with
      the computed tomographic finding of subcapsular hepatic necrosis. RESULTS:
      Computed tomographic finding of subcapsular hepatic necrosis was demonstrated at
      some point in 21 (42%) patients and was never demonstrated in 29 (58%) patients.
      The association of periportal collar with the computed tomographic finding of
      subcapsular hepatic necrosis was significant; there was no significant
      association with other computed tomographic findings. There was no significant
      difference in serum transaminases between the two groups. There was no
      significant difference in necrosis on biopsy between the two groups; however, the
      association of acute cellular rejection with the computed tomographic finding of
      subcapsular hepatic necrosis was significant. CONCLUSIONS: Computed tomographic
      finding of subcapsular hepatic necrosis is a common finding following liver
      transplantation, which has little clinical prognostic significance.

PMID- 8661766
TI  - Ruptured renal artery aneurysm due to Behcet's disease.
AB  - We describe a patient with Behcet's disease who developed multiple aneurysms and
      retroperitoneal hemorrhage due to rupture of a renal artery aneurysm. Despite
      successful transcatheter arterial embolization, the patient died due to
      pneumonia. Our retrospective review of the case revealed that the CT scan
      obtained 3 months before the rupture had demonstrated dilatation of bilateral
      renal arteries.

PMID- 8661767
TI  - Adrenal insufficiency with enlarged adrenals.
AB  - Five patients with adrenal insufficiency and large adrenal glands at presentation
      are reported. Addison's disease was due to adrenal tuberculosis in three
      patients, with important changes in adrenal configuration on CT reflecting the
      natural history of the disease. Adrenal infiltration by non-Hodgkin lymphoma and
      metastatic carcinoma of the lung was the cause of the disease in the fourth and
      fifth patients, respectively, who developed signs of adrenal insufficiency before
      the diagnosis of the primary lesion became apparent. Histologic confirmation was
      established after unilateral adrenalectomy in three patients. In two patients
      with adrenal tuberculosis, long clinical and laboratory follow-up confirmed the
      diagnosis. This report indicates that Addison's disease is not infrequently
      associated with adrenal enlargement. Adrenal size is related to the cause and
      duration of the various disease states leading to adrenal insufficiency.
      Moreover, adrenal insufficiency associated with enlarged adrenal glands can be
      the presenting manifestation of lymphoma or metastasis.

PMID- 8661768
TI  - Renal abscesses: appearance on gadolinium-enhanced magnetic resonance images.
AB  - PURPOSE: To determine the appearance of renal abscesses on gadolinium-enhanced
      magnetic resonance (MR) images, we reviewed 12 MR studies of eight patients with
      renal abscesses. These findings were compared with findings on other imaging
      modalities. METHODS: Eight patients underwent 12 MR studies at 1.5 T, including
      T1-weighted gradient echo and fat-suppressed spin echo pre- and post-Gd-DTPA
      enhancement. Two radiologists retrospectively reviewed the MR images and compared
      MR findings to the findings on contrast-enhanced computed tomography (CECT) in
      five patients, noncontrast computed tomography (NCCT) in two patients, and
      ultrasound in all patients. RESULTS: On contrast-enhanced MR images, renal
      abscesses were clearly depicted as heterogeneously low-signal-intensity lesions.
      Four patients had solitary abscesses, and four had multiple abscesses. Prominent
      perinephric inflammatory stranding was observed in six patients and was best
      shown on gadolinium-enhanced T1 fat-suppressed images. CECT findings were
      comparable to contrast-enhanced MR images, although contrast resolution was less
      on CECT images in all cases. Renal abscesses were poorly shown on NCCT and
      ultrasound images. CONCLUSION: Renal abscesses are clearly shown on gadolinium
      enhanced MR images as low-signal-intensity lesions associated with prominent
      perinephric inflammatory strands. In this study, NCCT and ultrasound studies are
      poor at defining abscesses. Despite lesser contrast resolution of CECT versus
      MRI, the findings in cases of renal abscesses are similar. In patients with
      elevated serum creatinine, iodine contrast allergy, or the need for serial exams,
      MRI may be the best imaging technique to evaluate renal abscesses.

PMID- 8661769
TI  - Bilateral abdominoscrotal hydrocele.
AB  - Abdominoscrotal hydrocele is rare in children, especially in infants. The
      presented case is a 3.5-month-old baby with abdominoscrotal hydrocele. This is
      the first reported bilateral and the youngest case. Diagnostic work-up based on
      sonography established the diagnosis.

PMID- 8661770
TI  - Carcinoma in a choledochal cyst.

PMID- 8661773
TI  - Functional characterization of canine connexin45.
AB  - Three gap junctional proteins have been identified in canine ventricular
      myocytes: connexin 43 (Cx43), connexin 45 (Cx45), and connexin 40 (Cx40). We have
      characterized the functional properties of canine Cx45 and examined how Cx45
      functionally interacts with Cx43 in Xenopus oocyte pairs. Homotypic pairs
      expressing Cx45 were well coupled. Heterotypic pairs composed of Cx45 paired with
      either Cx43 or Cx38 also developed high levels of conductance. Junctional
      currents in the heterotypic pairs displayed a highly asymmetrical voltage
      dependence. The kinetics and steadystate voltage dependence of the heterotypic
      channels more closely resembled those of the Cx45 channels when the Cx45 cRNA
      injected cell was relatively negative suggesting that the Cx45 connexin closes
      for relative negativity at the cytoplasmic end of the channel. We also show that
      homotypic and heterotypic channels composed of Cx45 and Cx43 exhibit differences
      in pHi sensitivity.

PMID- 8661774
TI  - Control of the amiloride-sensitive Na+ current in salivary duct cells by
      extracellular sodium.
AB  - We have previously reported that intralobular salivary duct cells contain an
      amiloride-sensitive Na+ conductance (probably located in the apical membranes).
      Since the amiloride-sensitive Na+ conductances in other tight epithelia have been
      reported to be controlled by extracellular (luminal) Na+, we decided to use whole
      cell patch clamp techniques to investigate whether the Na+ conductance in
      salivary duct cells is also regulated by extracellular Na+. Using Na(+)-free
      pipette solutions, we observed that the whole-cell Na+ conductance increased when
      the extracellular Na+ was increased, whereas the whole-cell Na+ permeability, as
      defined in the Goldman equation, decreased. The dependency of the whole-cell Na+
      conductance on extracellular Na+ could be described by the Michaelis-Menten
      equation with a K(m) of 47.3 mmol/1 and a maximum conductance (Gmax) of 2.18 nS.
      To investigate whether this saturation of the Na+ conductance with increasing
      extracellular Na+ was due to a reduction in channel activity or to saturation of
      the single-channel current, we used fluctuation analysis of the noise generated
      during the onset of blockade of the Na+ current with 200 mumol/l 6-chloro-3,5
      diaminopyrazine-2-carboxamide. Using this technique, we estimated the single
      channel conductance to be 4 pS when the channel was bathed symmetrically in 150
      mmol/l Na+ solutions. We found that Na+ channel activity, defined as the open
      probability multiplied by the number of available channels, did not alter with
      increasing extracellular Na+. On the other hand, the single-channel current
      saturated with increasing extracellular Na+ and, consequently, whole-cell Na+
      permeability declined. In other words, the decline in Na+ permeability in
      salivary duct cells with increasing extracellular Na+ concentration is due simply
      to saturation of the single-channel Na+ conductance rather than to inactivation
      of channel activity.

PMID- 8661775
TI  - Effect of mutation of potassium-efflux system, KefA, on mechanosensitive channels
      in the cytoplasmic membrane of Escherichia coli.
AB  - The effect of a kefA mutation on the mechanosensitive channels in the cytoplasmic
      membrane of Escherichia coli was established by introducing a mutation of the
      kefA gene into wild-type E. coli by P1 transduction. The mutation of the kefA
      gene not only made the cells sensitive to K+ in the medium but also changed the
      mechanosensitive channel activity. The kefA mutation did not change the
      conductances of the two mechanosensitive channels in the cytoplasmic membrane of
      E. coli, but it prolonged the channel open time. Also, the kefA mutation made the
      cells more sensitive to pressure in comparison to wild-type cells. The high
      sensitivity to pressure of the kefA mutant was not modulated by betaine or by the
      potassium gradient across the membrane. The effect of the kefA mutation on
      mechanosensitive channels was not due to a membrane fluidity change. KefA might
      be a regulator for mechanosensitive channels.

PMID- 8661776
TI  - Ion channels formed by NB, an influenza B virus protein.
AB  - The influenza B virus protein, NB, was expressed in Escherichia coli, either with
      a C-terminal polyhistidine tag or with NB fused to the C-terminus of glutathione
      S-transferase (GST), and purified by affinity chromatography. NB produced ion
      channel activity when added to artificial lipid bilayers separating NaCl
      solutions with unequal concentrations (150-500 mM cis, 50 mM trans). An antibody
      to a peptide mimicking the 25 residues at the C-terminal end of NB, and
      amantadine at high concentration (2-3 mM), both depressed ion channel activity.
      Ion channels had a variable conductance, the lowest conductance observed being
      approximately 10 picosiemens. At a pH of 5.5 to 6.5, currents reversed at
      positive potentials indicating that the channel was more permeable to sodium than
      to chloride ions (PNa/PCl approximately 9). In asymmetrical NaCl solutions at a
      pH of 2.5, currents reversed closer to the chloride than to the sodium
      equilibrium potential indicating that the channel had become more permeable to
      chloride than to sodium ions (PCl/PNa approximately 4). It was concluded that, at
      normal pHs, NB forms cation-selective channels.

PMID- 8661777
TI  - An effect of Ca2+ on the Intrinsic Cl(-)-conductance of rat kidney cortex brush
      border membrane vesicles.
AB  - Brush-border membrane vesicles (BBMV) were prepared from superficial rat renal
      cortex by a divalent(2+)-precipitation technique using either CaCl2 or MgCl2. The
      dependence of the initial [14C]-D-glucose (or [3H]-L-proline) uptake rate and the
      extent of the overshoot of D-glucose or L-proline uphill accumulation from
      solutions containing 100 mM Na+ salt, was found to be dependent upon the
      precipitating divalent cation. With Mg2+ precipitation the initial uptake and
      overshoot accumulation of either D-glucose or L-proline were enhanced compared to
      BBMV prepared by Ca2+ precipitation. When the anion composition of the media was
      varied (uptake in Cl- media in comparison to gluconate(-)-containing media) it
      was found that the Cl(-)-dependent component of the initial uptake was markedly
      depressed with Ca(2+)-prepared BBMV (104.99 +/- 33.31 vs. 13.83 +/- 1.44
      pmoles/sec/mg protein for Mg2+ and Ca2+ prepared vesicles respectively). When
      Ca2+ was loaded into Mg2+ prepared BBMV using a freeze-thaw technique, it was
      found that the magnitude and Cl- enhancement of D-glucose transport was reduced
      in a dose-dependent manner. Neomycin, an inhibitor of phospholipase C, had no
      effect on the reduction of D-glucose uptake by Ca2+ in Mg2+ prepared vesicles. In
      contrast, phosphatase inhibitors such as vanadate and fluoride were able to
      partially reverse the Ca2+ inhibition of D-glucose uptake and restore the
      enhancement due to Cl- media. In addition, inhibitors of protein phosphatase 2B,
      deltamethrin (50 nM) and trifluoperazine (10 microM), caused partial reversal of
      Ca2(+)-dependent inhibition of D-glucose uptake. Direct measurement of changes in
      the bi-ionic (Cl-vs. gluconate-) transmembrane electrical potential differences
      using the cyanine dye, 3,3'-dipropylthiodicarbocyanine iodide DiSC3-(5) confirmed
      that Cl- conductance was reduced in Ca(2+)-prepared vesicles. We conclude that a
      Cl- conductance coexists with Na+ cotransport in rat renal BBMV and this may be
      subject to negative regulation by Ca2+ via stimulation of protein phosphatase
      (PP2B).

PMID- 8661778
TI  - Activation of maxi-K channels by parathyroid hormone and prostaglandin E2 in
      human osteoblast bone cells.
AB  - Patch clamp experiments were performed on two human osteosarcoma cell lines (MG
      63 and SaOS-2 cells) that show an osteoblasticlike phenotype to identify and
      characterize the specific K channels present in these cells. In case of MG-63
      cells, in the cell-attached patch configuration (CAP) no channel activity was
      observed in 2 mM Ca Ringer (control condition) at resting potential. In contrast,
      a maxi-K channel was observed in previously silent CAP upon addition of 50 nM
      parathyroid hormone (PTH), 5 nM prostaglandin E2 (PGE2) or 0.1 mM dibutyryl cAMP
      + 1 microM forskolin to the bath solution. However, maxi-K channels were present
      in excised patches from both stimulated and nonstimulated cells in 50% of total
      patches tested. A similar K channel was also observed in SaOS-2 cells.
      Characterization of this maxi-K channel showed that in symmetrical solutions (140
      mM K) the channel has a conductance of 246 +/- 4.5 pS (n = 7 patches) and, when
      Na was added to the bath solution, the permeability ratio (PK/PNa) was 10 and 11
      for MG-63 and SaOS-2 cells respectively. In excised patches from MG-63 cells, the
      channel open probability (Po) is both voltage- (channel opening with
      depolarization) and Ca-dependent; the presence of Ca shifts the Po vs. voltage
      curve toward negative membrane potential. Direct modulation of this maxi-K
      channel via protein kinase A (PKA) is very unlikely since in excised patches the
      activity of this channel is not sensitive to the addition of 1 mM ATP + 20 U/ml
      catalytic subunit of PKA. We next evaluated the possibility that PGE2 or PTH
      stimulated the channel through a rise in intracellular calcium. First, calcium
      uptake (45Ca2+) by MG-63 cells was stimulated in the presence of PTH and PGE2 an
      effect inhibited by Nitrendipine (10 microM). Second, whereas PGE2 stimulated the
      calcium-activated maxi-K channel in 2 mM Ca Ringer in 60% of patches studied, in
      Ca-free Ringer bath solution, PGE2 did not open any channels (n = 10 patches) nor
      did cAMP + forskolin (n = 3 patches), although K channels were present under the
      patch upon excision. In addition, in the presence of 2 mM Ca Ringer and 10 microM
      Nitrendipine in CAP configuration, PGE2 (n = 5 patches) and cAMP + forskolin (n =
      2 patches) failed to open K channels present under the patch. As channel
      activation by phosphorylation with the catalytic subunit of PKA was not observed,
      and Nitrendipine addition to the bath or the absence of calcium prevented the
      opening of this channel, it is concluded that activation of this channel by PTH,
      PGE2 or dibutyryl cAMP + forskolin is due to an increase in intracellular calcium
      concentration via Ca influx.

PMID- 8661779
TI  - An inactivating inward-rectifying K current present in prolactin cells from the
      pituitary of lactating rats.
AB  - Primary cultures containing a high percentage of lactotrophs were obtained by
      dissociating the pituitary of rats following 14-18 days of lactation. Lactotrophs
      with a distinctive appearance were recorded after 1-35 days in vitro and
      identified by immunocytochemical staining for prolactin. Whole-cell voltage clamp
      measurements in isotonic KCl solution from a holding potential of -40 mV revealed
      the presence of inward-rectifying K currents with a time-dependent, Na(+)
      independent inactivation at potentials negative to -60 mV. The time for complete
      inactivation was strikingly different between lactotrophs, varying between 1 sec
      and more than 5 sec at -120 mV, and was not related to time in culture. The
      reversal potential shifted 59 mV (25 degree C) for a tenfold change in external
      K+ concentration, demonstrating the selectivity of the channel for K+ over Na+.
      The inward-rectifying K current was blocked by 5 mM Ba2+ and partially blocked by
      10 mM TEA. Chloramine-T (1 and 2 mM) produced a total block of the inward
      rectifying K current in lactotrophs. Thyrotropin-releasing hormone (500 nM)
      significantly reduced the inward-rectifying K current in about half of the
      lactotrophs. This current is similar to the inward-rectifying K current
      previously characterized in clonal somatomammotrophic pituitary cells (GH3B6).
      The variability of the rate of inactivation of this current in lactotrophs and
      its responsiveness to TRH is discussed.

PMID- 8661780
TI  - Association of ClC-3 channel with Cl- transport by human nonpigmented ciliary
      epithelial cells.
AB  - Electrophysiologic and volumetric evidence link the swelling-activated Cl-
      channels [gCl(Vol)] of nonpigmented ciliary epithelial (NPE) cells with the Cl(-)
      channel/Cl(-)-channel regulator protein pICln. However, inhibitors (verapamil and
      dideoxyforskolin) of another Cl- channel/regulator (MDR1) have been found to
      inhibit the volume-activated transport response [the regulatory volume decrease
      (RVD)] of bovine NPE cells. We have addressed the possible molecular basis for
      the NPE Cl- channels by volumetric measurements of ODM human NPE cells in
      hypotonic and isotonic test solutions, and by polymerase chain reaction (PCR)
      cloning and Northern analyses of the same cells. Verapamil and dideoxyforskolin
      did inhibit the RVD. However, at a concentration (100 microM) which blocks > 90%
      of the MDR1-associated Cl- currents, forskolin had no effect on the volume
      activated Cl- channels or on the inhibition of those channels by protein kinase
      C. High concentrations of ATP (3.5 and 10 mM) and niflumic acid (IC50
      approximately 200 microM) also block [gCl(Vol)]. The RVD is inhibited by 9
      phenylanthranilic acid (DPC) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB),
      unaffected by anthracene-9-carboxylic acid (9-AC), and stimulated by ionomycin.
      The Cl(-)-channel blockers NPPB, niflumic acid, DPC and 9-AC, and the Ca2(+)
      ionophore ionomycin had qualitatively similar effects on the rate of
      staurosporine-activated isotonic cell shrink-age. These results support the
      concept that the volume-sensitive protein pICln regulates the Cl- channels, and
      that the same conduits subserve volume- and staurosporine-activated Cl- release.
      Of the cloned and sequenced Cl- channels, ClC-3 uniquely conforms to the
      stationary currents and PKC sensitivity of the NPE Cl- channels. PCR
      amplifications of human cDNA libraries from ciliary body, NPE cells and retina
      with primers based on human ClC-3 and ClC-4 cDNA, and Northern analyses using the
      products generated indicated that ciliary epithelial cells express transcripts
      for ClC-3 (but not ClC-4). We suggest that ClC-3 provides the same conduit for
      both volume-activated and isotonically staurosporine-activated Cl- channels of
      human nonpigmented ciliary epithelial cells.

PMID- 8661781
TI  - Regulatory volume increase in rat lacrimal gland acinar cells.
AB  - The volume of acinar cells isolated from rat lacrimal glands was measured during
      hypertonic shock. Cells shrank in hypertonic solutions, but a regulatory volume
      increase (RVI) was only observed under certain conditions. In HEPES-buffered
      solutions at 37 degrees C, an RVI was observed. This was inhibited by 20 microM
      bumetanide, an inhibitor of Na(+)-K(+)-2Cl- cotransport. RVI did not occur in
      HEPES-buffered solutions at 20 degrees C suggesting that Na(+)-K(+)-2Cl-
      cotransport is inactive at this temperature. In HCO3- buffered solutions however,
      an RVI was observed at 20 degrees C. In these conditions, the RVI was inhibited
      by 500 microM 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (H2-DIDS)
      and 10 microM 5-(N-methyl-N-isobutyl)-amiloride (MIBA) indicating the involvement
      of Cl(-)-HCO3- exchange and Na(+) -H+ exchange respectively. RVI was also
      supported by a mixture of neutral amino acids, and by the nonmetabolizable amino
      acids 5 mM alpha-(methylamino)isobutyric acid (MeAIB) and 5 mM alpha
      aminoisobutyric acid (AIB). These data suggest that the accumulation of amino
      acids, possibly by the system A Na(+)-coupled amino acid cotransporter,
      contributes to RVI in these cells. In conclusion, rat lacrimal gland acinar cells
      are capable of undergoing RVI following shrinkage by hypertonic shock.

PMID- 8661782
TI  - Charles McBurney (1845-1913). Afield from the appendix.

PMID- 8661783
TI  - Is laparoscopic splenectomy appropriate for the management of hematologic and
      oncologic diseases?

PMID- 8661786
TI  - Static electricity as a mechanism of bacterial transfer during endoscopic
      surgery.
AB  - BACKGROUND: During endoscopic surgery it is often difficult to describe the
      procedure based on the video screen image. To compensate, the surgeon may point
      to the monitor to define more exactly what is intended by the verbal cues.
      Experiments were conducted to determine if the electrostatic field of the monitor
      could serve as a mechanism of bacterial transfer from the video screen to the
      patient. METHODS: A gloved hand traversed the monitor in a standard fashion at
      varying distances from the screen. The fingertips were then cultured onto blood
      agar plates. RESULTS: Bacterial growth occurred on 28 of the 30 cultures taken at
      1, 2, and 4 cm from the video screen. No growth occurred on any of the 8 cm
      cultures, or the 20 controls. The number of bacterial colonies cultured from the
      glove was inversely related to the distance between the glove and video screen (p
      < 0.001). CONCLUSIONS: We conclude the electrostatic field generated by the video
      monitor could serve as a mechanism of bacterial contamination during endoscopic
      surgery. Also, we conclude that placing the gloved hand in proximity to the video
      monitor screen during an operative procedure constitutes a break in sterile
      technique and must be avoided.

PMID- 8661785
TI  - Laparoscopic splenectomy. The suspended pedicle technique.
AB  - BACKGROUND: Elective splenectomy is often performed for hematological diseases,
      some of which cause only moderate enlargement of the spleen. The avoidance of an
      extensive upper abdominal incision is desirable in such cases and laparoscopic
      splenectomy offers significant potential advantages over the open operation if it
      can be performed safely and economically. METHODS: Eight consecutive patients
      underwent laparoscopic splenectomy. The operation was carried out with the
      patient at 40 degrees in the right lateral position so that rotating the
      operating table would make a full right lateral position possible. After
      fenestration of the gastrocolic omentum and division of the short gastric
      vessels, this position allowed the spleen to be pushed up under the diaphragm to
      facilitate access to the splenic vessels and the hilum. Vessels were divided
      individually between clips. RESULTS: All eight cases were completed
      laparoscopically. Mean length of operation was 259 min (range 230-285).
      Postoperative stay ranged from 2 to 7 days (median 4 days). There was no
      mortality, although minor complications did occur in three patients. CONCLUSIONS:
      We found laparoscopic splenectomy to be a safe and feasible procedure for the
      elective removal of the moderately enlarged spleen.

PMID- 8661784
TI  - Laparoscopic splenectomy: an evolving technique. A comparison between anterior
      and lateral approaches.
AB  - BACKGROUND: The success of laparoscopic cholecystectomy has favored the
      application of this technique in abdominal surgery. Laparoscopic splenectomy (LS)
      suffers from several technical problems for mobilization and manipulation of a
      solid organ. Lateral approach has been proposed as an alternative to the anterior
      approach which facilitates LS. The aim of this paper is to compare the results of
      LS using and anterior or lateral approach. METHODS: Between February 1993 and May
      1995, 27 LS were performed (group I, Ant-LS, n: 10; group II, Lat-SL, n: 17). LS
      was indicated in 19 patients for treatment of an idiopathic purpura, for
      spherocytosis in four; for AIDS-related thrombocytopenia in two; and for
      autoimmune anemia and leucopenia in two. Gallstones were associated in two cases
      and an ovarian cyst in another. RESULTS: LS was completed in 8 patients of group
      I (80%) and 17 of group II (100%). Operative time (236 +/- 21 min vs 159 +/- 71
      min p < 0.003), number of trocars (4.5 +/- 0.5 vs 4 +/- 0.5, p < 0.02),
      transfusion requirements (60 vs 17%, p < 0.04) and mean stay (6.5 +/- 3.6 days vs
      4 +/- 2 days, p < 0.05) were significantly lower in the group of LS with a
      lateral approach. CONCLUSIONS: The lateral approach significantly facilitates the
      performance of LS compared with the anterior approach.

PMID- 8661787
TI  - Laparoscopic transgastric suturing for bleeding peptic ulcers.
AB  - BACKGROUND: Peptic ulcers are a frequent cause of upper G.I. bleeding. Since
      endoscopic methods may be unsuccessful, we have studied the feasibility of a new
      laparoscopic approach on a porcine model to control the bleeding of these ulcers
      with transgastric suturing. METHODS: After approval of the Animal Ethics
      Committee, 20 pigs (20 kg) were anticoagulated with intravenous sodium heparin
      (400 U/kg), and anesthetized. A nasogastric tube was inserted and a 15 mmHg
      pneumoperitoneum was created. Two 10-mm trocars and one 5-mm trocar were inserted
      through the abdominal cavity for laparoscopic guidance of three 7-mm endoluminal
      trocars inside the stomach through the anterior wall. Two posterior gastric
      ulcers were mechanically made on each pig by a "lift and cut technique." Ulcers
      were observed for at least 1 min for evidence of continued bleeding. First,
      bleeding ulcers were treated with sclerosing agents (epinephrine and ethanolmine
      oleate 5%); following sclerotherapy, ulcers were sutured intraluminaly with 2-0
      silk, with intracorporeal knots. RESULTS: Ulcers created extended into the
      vascular submucosa and averaged 7 mm in diameter. Bleeding rate was variable, but
      significant (2 cm3/min) in 40%. It was technically possible to suture these
      ulcers in 80%. Bleeding was controlled in 95% of cases with sclerotherapy and
      intraluminal sutures. One perforation of the posterior gastric wall occurred and
      four endoluminal trocars had to be reinserted after dislodgement. CONCLUSIONS: It
      is possible to technically control bleeding ulcers in most cases with a
      laparoscopic transgastric technique using sclerosing agent and intraluminal
      sutures. This approach is promising for future human application; also, the
      intragastric suturing skills developed may be useful for other surgical
      interventions.

PMID- 8661789
TI  - Benign gastric tumors. Minimally invasive approach.
AB  - BACKGROUNDS: Historically, major subsets of benign gastric tumors requiring
      surgical excision have required open laparotomy. METHODS: We have used
      laparoscopy to resect lesions in eight such patients. Lesion locations were
      gastroesophageal junction (one), gastric body (three), and pylorus (four). Four
      lesions were successfully located by instrument palpation. Six lesions were
      excised using gastrotomy, eversion of tumor, and resection, followed by stapled
      gastrotomy closure. The lesion at the posterior GE junction was evaluated through
      a gastrotomy and resected transgastrically. The two pyloric lesions were removed
      by laparoscopic distal gastrectomy and gastrojejunostomy. RESULTS: Procedure
      times were 55-210 min; oral feeding was instituted on postoperative day 1-5;
      patients were discharged 1-6 days postoperatively. CONCLUSIONS: Benign tumors of
      the stomach may be approached and resected laparoscopically; a transgastric,
      intra-organ approach is safe and efficient; laparoscopic distal gastrectomy is
      safe and technically feasible; patients have a shorter recovery interval and
      shorter postoperative hospital stay. Cautious progress in this field is
      recommended.

PMID- 8661788
TI  - ERCP in the era of laparoscopic biliary surgery. Experience with 407 patients.
AB  - BACKGROUND: The combined endoscopic and laparoscopic treatment of biliary stones
      is now highly debated, especially as regards possible complications compared to
      one-step laparoscopic treatment. METHODS: This study analyzes 407 cases (116
      males, 291 females, average age 49 years, range 2-87) observed in the period from
      May 1991 to July 1994. All patients were evaluated preoperatively for the
      presence of biliary stones. Considering clinical presentation, blood analysis,
      ultrasonography, and medical history, 99 patients (24%) were selected for
      preoperative endoscopic retrograde cholangiopancreatography (ERCP). One patient
      refused preoperative ERCP. RESULTS: Thirty-nine patients (40%) were found to have
      biliary stones and were submitted to therapeutic endoscopic sphincterotomy (ES).
      Endoscopic clearance of the bile ducts was achieved in all patients, with one
      complication (pancreatitis). In performing laparoscopic cholecystectomy, no
      technical difficulties could be attributed to ERCP, nor were there any
      conversions in patients who had had preoperative ERCP. Average postoperative
      hospital stay was 2.5 days. During a follow-up period of from 2 to 39 months, we
      diagnosed three patients (0.7%) with symptomatic residual stones. They were
      submitted to successful ERCP and extraction of the stones. CONCLUSIONS: We
      conclude that ERCP offers an accurate preoperative selection of patients, allows
      for effective planning of treatment, and simplifies laparoscopic surgery.

PMID- 8661790
TI  - The anterior abdominal wall in laparoscopic procedures and limitations of
      laparoscopic simulators.
AB  - BACKGROUND: Maneuvers involving two-handed techniques such as intracorporeal
      suturing and knot-tying during laparoscopy are intrinsically more difficult than
      ones performed during open surgery. METHODS: The use of simulators to practice
      and teach specialized techniques is established. However, simulators vary
      greatly, and few, as yet, represent the abdominal wall well. RESULTS: This study
      has shown that the working angle between instruments during laparoscopic
      cholecystectomy is 78 degrees, and this can be increased to 117 degrees by moving
      the instruments laterally. In contrast, the working angle in four trainers
      assessed was never greater than 77 degrees. CONCLUSIONS: This suggests that some
      maneuvers may be more difficult in trainers than at surgery. This has
      implications for training and the further development of more realistic
      simulators.

PMID- 8661791
TI  - Argon coagulation in laparoscopic cholecystectomy.
AB  - BACKGROUND: The purpose of this study is to compare argon coagulation with
      standard electrocoagulation. METHODS: Twenty-four consecutive patients submitted
      to laparoscopic cholecystectomy (LC) were divided randomly into two equal groups.
      Group 1 used standard electrocoagulation and group 2 argon coagulation. The
      operative time and amount of blood loss were measured. RESULTS: Operative time
      (minutes): Group 1 65.33 +/- 4.07 SE. Group 2 55.83 +/- 2.82 SE (P < 0.10).
      Amount of blood loss (ml): Group 1 105.58 +/- 6.37 SE. Group 2 62.92 +/- 5.82 SE
      (p < 0.001). CONCLUSIONS: Preliminary results support our opinion that argon
      coagulation is to be favored over standard coagulation.

PMID- 8661792
TI  - Gastroduodenal polyps in familial adenomatous polyposis.
AB  - BACKGROUND: Malignant degeneration of gastroduodenal polyps has been noted in
      patients with familial adenomatous polyposis. To evaluate this problem further,
      patients with familial adenomatous polyposis were contacted and offered upper
      gastrointestinal tract endoscopy. METHODS: A prospective endoscopic examination
      was performed in 42 patients. RESULTS: The median age of patients at endoscopy
      was 35 years. The duration of known familial adenomatous polyposis at the time of
      endoscopy was 8 years. Polyps were visualized in 21 patients (50%). Gastric
      polyps were seen in 14 patients (33%), duodenal polyps were seen in 11 patients
      (26%), and ampullary polyps were seen in 7 patients (17%). Nine patients (43%)
      had polyps in more than one site. Adenomatous change was noted in 73% of duodenal
      lesions and in only 14% of gastric polyps. Surgical intervention was required in
      four patients; one patient had an early ampullary carcinoma, and three patients
      had severe dysplasia involving the duodenum or ampulla. All four patients had
      undergone a previous screening examination, results of which were normal in three
      patients. Compared with other patients, these four patients were older (median
      age, 58 years; p = 0.02) and had a longer duration of disease (median duration,
      25 years; p = 0.002). CONCLUSIONS: All patients with familial adenomatous
      polyposis require lifelong endoscopic surveillance to detect malignant
      degeneration, which may appear later in life.

PMID- 8661794
TI  - Laparoscopic cholecystostomy with delayed cholecystectomy as an alternative to
      conversion to open procedure.
AB  - BACKGROUND: Acute cholecystitis carries the highest incidence of conversion from
      planned laparoscopic cholecystectomy to open surgery due to unclear anatomy,
      excessive bleeding, complications, or other technical reasons. METHODS:
      Laparoscopic tube cholecystostomy was performed instead of immediate conversion
      to laparotomy in 9 patients with acute cholecystitis after unsuccessful attempts
      at laparoscopic dissection. Elective laparoscopic cholecystectomy was done 3
      months later. RESULTS: Following this approach eight patients were treated
      successfully. After 3 months the acute process had subsided sufficiently to allow
      a safe laparoscopic cholecystectomy. One additional patient died of acute
      leukemia 6 weeks after cholecystostomy. Before adopting this technique we
      subjected 171 patients with acute calculous cholecystitis to laparoscopic
      cholecystectomy; there was an 11% (19 cases) rate of conversion. Since
      cholecystostomy has begun to be offered as an alternative to conversion, 121
      patients with acute cholecystitis have had laparoscopic cholecystectomy and only
      2 cases (1.5%) have been converted to immediate open cholecystectomy.
      CONCLUSIONS: We recommend the alternative of performing a cholecystostomy with
      delayed laparoscopic cholecystectomy instead of conversion to open procedure when
      facing a case of acute cholecystitis not amenable to laparoscopic
      cholecystectomy.

PMID- 8661793
TI  - Removal of gonads in Y-chromosome-bearing gonadal dysgenesis and in androgen
      insensitivity syndrome by laparoscopic surgery.
AB  - BACKGROUND: This paper addresses the value of laparoscopic surgery for the
      removal of gonads in patients with Y-chromosome-bearing gonadal dysgenesis and
      androgen insensitivity syndrome, who are otherwise faced with a high rate of
      gonadal malignancy. METHODS: Three patients with Y-chromosome-bearing gonadal
      dysgenesis and one patient with androgen insensitivity syndrome were operated
      upon laparoscopically. Removal of gonads was accomplished by their mobilization
      and dissection from the pelvic side walls, with ligation and transection of the
      utero-ovarian and infundibulopelvic ligaments. RESULTS: Surgery was without
      complications. Histological examination of the gonads showed complete removal and
      absence of malignancy in each patient. Patients were discharged the day after
      surgery. CONCLUSIONS: The laparoscopic approach is a safe and effective
      alternative to laparotomy in the management of patients with Y-chromosome-bearing
      gonadal dysgenesis and with androgen insensitivity syndrome.

PMID- 8661795
TI  - Laparoscopic treatment of paraesophageal and large mixed hiatal hernias.
AB  - BACKGROUND: Laparoscopic treatment of large mixed hiatal hernias was attempted in
      eight patients. METHODS: One patient (12.5%) was converted to open surgery due to
      difficulty in repositioning the LES into the abdomen resulting from a shortened
      esophagus. One left pleural tear occurred intraoperatively and was repaired
      without further consequence. Median duration of the operation was 150 min (range
      120-300 min). RESULTS: No postoperative complications were recorded. All patients
      are asymptomatic after a median follow-up of 14 months (range 7-15 months).
      Correct repositioning of the stomach was confirmed by radiological evaluation 1
      month after surgery. Early functional results are good. (One asymptomatic
      gastroesophageal reflux was detected and medical treatment was undertaken).
      CONCLUSIONS: Laparoscopic crural repair and fundoplication are feasible even in
      paraesophageal and large mixed hiatal hernias. Advantages of the minimally
      invasive approach are clear in terms of morbidity, patient comfort, and duration
      of hospital stay. Nevertheless, long-term assessment is required to confirm the
      effectiveness of the laparoscopic approach in patients with large mixed hiatal
      hernias.

PMID- 8661796
TI  - Comparison of manual and ultrasonographic evaluation of bladder size in patients
      prior to laparoscopy.
AB  - BACKGROUND: Catheterization of the bladder may reduce laparoscopic complications
      although an enlarged bladder may be impalpable in overweight patients or
      following previous lower abdominal surgery. METHODS: This study assessed bladder
      size by manual examination and transcutaneous ultrasound (US). Consecutive
      patients (n = 90; median age 55 years [20-85]; 61 females) undergoing laparoscopy
      were studied prospectively. All patients voided preoperatively and
      catheterization was performed if estimated US bladder volumes exceeded 300 ml.
      RESULTS: Manual assessment failed to detect bladder enlargement in any patients
      (sensitivity: 0%; specificity: 4.4%), whereas ultrasound identified four patients
      at risk of bladder injury due to unsuspected enlargement (4.4%). Three of these
      patients were either overweight or obese and one patient had previous lower
      abdominal surgery. Of 12 patients (13%) catheterized, three had or developed
      urinary tract infections. CONCLUSIONS: Preoperative voiding does not guarantee
      bladder emptying. Manual examination does not detect bladder enlargement reliably
      in the obese patient. Ultrasonography may improve patient selection for
      catheterization.

PMID- 8661797
TI  - Videolaparoscopic treatment of liver hydatid cysts with partial cystectomy and
      omentoplasty. A report of two cases.
AB  - Hydatid disease is one of the world's most important health problems. Although
      several conservative approaches have been used for the management of this
      condition, surgery remains the ideal choice in most of the cases.
      Videolaparoscopic approach can safely be applied for the management of liver
      hydatid cysts if several precautions are undertaken. In this study, we present
      two liver hydatid cyst cases successfully treated with partial cystectomy and
      omentoplasty using videolaparoscopic approach.

PMID- 8661798
TI  - Laparoscopic repair of an incarcerated obturator hernia.
AB  - Obturator hernia is a rare cause of bowel obstruction. Occurring primarily in
      elderly women, it has a high incidence of incarceration and a high mortality
      rate. This report describes the successful laparoscopic reduction and repair of
      an incarcerated obturator hernia. Using open laparoscopy, an incarcerated
      obturator hernia was diagnosed intraoperatively. After laparoscopic reduction, a
      transabdominal preperitoneal repair was completed using polypropylene mesh. The
      patient recovered uneventfully with no recurrence at 6 months. Laparoscopic
      techniques have been successfully applied to diagnose, reduce, and repair an
      incarcerated obturator hernia.

PMID- 8661799
TI  - Thoracoscopic lobectomy for an infected intrapulmonary bronchogenic cyst.
AB  - A 19-year-old male who presented with cough and fever was found to have an 8-cm
      cyst in his left lung. Video-assisted thoracoscopic left lower lobectomy was
      performed. The cyst had to be decompressed by needle aspiration prior to
      retrieval through a 5-cm minithoracotomy. The patient was discharged on
      postoperative day 4 in good condition. The technical aspects form the basis of
      this report.

PMID- 8661800
TI  - Laparoscopic splenectomy in the management of hematological diseases. Surgical
      technique and outcome of 17 patients.
AB  - After being successfully applied to other intraabdominal organs, the laparoscopic
      approach has been applied to the spleen since 1991. The experience with 17 cases
      of laparoscopic splenectomy performed due to immune thrombocytopenia purpura (10
      instances), hereditary spherocytosis (2 cases), and Hodgkin's disease where the
      staging was done according to Standford (5 cases), have been reported. With the
      patient in anti-Trendelenburg position, and the surgeon between the patient's
      legs, four or five trocars are introduced into the upper abdominal quadrants and
      the spleen hilum is isolated. Hilar vessels are dissected and ligated with a
      surgical stapler. A plastic bag is introduced into the abdomen cavity and the
      spleen is slipped inside; it is then extracted through an umbilical incision
      after morcellation. Advantages of the open operation include a decrease in
      postoperative pain, a decrease in pulmonary sequelae, a reduced incidence of
      subphnic abscesses, and cosmetic advantages. The decrease of postoperative
      sequelae reduces hospitalization and costs, which are higher for the operation
      itself (materials and staff's training).

PMID- 8661801
TI  - A new T-tube applier in laparoscopic surgery.
AB  - In the majority of patients undergoing laparoscopic choledochotomy, it is
      advisable to insert a T-tube into the duct after ductal exploration, as bile
      sludge or fibrin deposits may obstruct the papilla and cause postoperative
      cholangitis. Based on our experience in open surgery, a limited transverse
      choledochotomy is preferred, which reduces the possibility of damaging the common
      bile duct blood supply. Such a technique can complicate laparoscopic T-tube
      positioning, however. After experimenting with the method described by Kitano et
      al. [Surg Endosc 7:104-105 (1993)], which was abandoned because it was difficult
      to carry out with the type of soft silicone rubber tubes that we normally use,
      two subsequent techniques were developed and are described. They were employed in
      3 and 10 patients, respectively, out of 21 who underwent laparoscopic transverse
      choledochotomy. The most satisfying results were obtained using a system
      employing two sets of telescopic cannulae of different diameters. Laparoscopic T
      tube introduction through a transverse choledochotomy using two telescopic
      cannulae was rapid and safe and allowed to precisely guide T-tube positioning
      inside the common duct.

PMID- 8661802
TI  - Laparoscopic intra-arterial catheter implantation for regional chemotherapy of
      liver metastasis.
AB  - In patients with unresectable metastatic disease confined to the liver, intra
      arterial regional chemotherapy with implantable systems in an attractive option.
      Since April 1992, laparoscopic colorectal resections have been performed in our
      institution. Within this series of patients, three cases with bilateral liver
      metastasis from colon cancer were observed and underwent laparoscopic intra
      arterial catheter implantation in the gastroduodenal artery for regional
      chemotherapy. In two patients the metastases were synchronous, and in both cases
      a laparoscopic colon resection was also performed, for tumors located in the
      cecum and in the sigmoid colon, respectively. The laparoscopic surgical technique
      for intra-arterial catheter implantation is described in detail. In this limited
      experience the procedure, from a purely technical point of view, was not
      considered difficult and was completed in 70 min on average. No complications
      were observed and the patient with metachronous liver metastasis was discharged
      on 3rd postoperative day.

PMID- 8661804
TI  - Combined endoluminal-intracavitary thoracoscopic enucleation of leiomyoma of the
      esophagus. A new method.
AB  - Thoracoscopic enucleation of leiomyoma of the esophagus was successfully
      performed in three cases with a new technique called the "balloon push-out
      method." Instead of pulling the tumor, which is hard to grasp because of its
      delicate nature, we pushed it out of the esophageal wall with a balloon-mounted
      intraluminal endoscope in order to perform the operation faster and more safely.
      We found this technique to be very useful in this kind of operation.

PMID- 8661805
TI  - Inferior brachial plexus injury during thoracoscopic sympathectomy.

PMID- 8661803
TI  - Endoscopic surgery of the rhinobasis with a computer-assisted localizer.
AB  - The endoscope is useful for the diagnosis and surgical therapy of diseases of the
      nose, the paranasal sinuses and its neighboring regions, and allows for
      microinvasive, functional approaches. The reduced invasiveness of therapeutic
      procedures is sometimes accompanied by insufficient clearness of the surgical
      field, however. This significant problem is solved by the computer-assisted
      surgery (CAS) system, an intraoperative localizer. It allows continuous
      orientation based on three-dimensional reconstructed preoperative CT scans with
      superimposed positioning of the endoscope. We have now adapted CAS for endoscopic
      sinus surgery, which meant that a variety of visualization methods were tested. A
      conventional straightforward endoscope was used in combination with, or as, the
      localizing probe. A dual-display technique was adjusted to video-endoscopic
      procedures: the information of the localizer is displayed on one monitor while
      the video-endoscopic picture is viewed on a second screen. In addition, a single
      display technique with both images on one monitor was developed. It proved to be
      the most promising way of combining endoscopy and intraoperative CT-image-guided
      localization.

PMID- 8661806
TI  - News and notices

PMID- 8661807
TI  - Carcinoid tumors: development of our knowledge.
AB  - Historically, carcinoids have long been known to be a morphologically distinct
      class of rare intestinal tumors that behave less aggressively than the more
      common intestinal adenocarcinomas. It was not until much later that their
      endocrine nature was recognized. Some authors restrict the term carcinoid to
      intestinal endocrine tumors, whereas others include a large variety of
      neuroendocrine tumors. In the WHO classification of 1980, carcinoids were defined
      as tumors of the diffuse neuroendocrine system that are either benign or
      neoplasms with a more favored prognosis than carcinomas. They are characterized
      by a typical growth pattern, silver affinity, and positive immunohistochemical
      reaction with neuron-specific markers; and they can express different peptides
      and biogenic amines. Neuroendocrine tumors originating from endocrine glands
      (pituitary, thyroid, adrenals, pancreas) and highly malignant neuroendocrine
      carcinomas are excluded from the carcinoid group of neoplasms. For the natural
      history of carcinoid tumors several independent predictive parameters can be
      defined: size, site of origin, growth pattern, and hormone dependence. The number
      of neuropeptides and amines expressed by a carcinoid or the amount of
      biologically active neurohormones secreted are of no prognostic significance
      regarding malignant behavior. The carcinoid syndrome is a rare clinical entity
      that occurs with a prevalence of 1.6% for carcinoid tumors and almost only if
      liver metastases are present. The complex clinical symptoms are only partially
      explained by the secretion of serotonin and tachykinins.

PMID- 8661808
TI  - Pathology and nomenclature of human gastrointestinal neuroendocrine (carcinoid)
      tumors and related lesions.
AB  - The pathology and nomenclature of the neuroendocrine cell proliferations in the
      gut are reviewed. The neoplastic lesions are discussed within the light of a new
      classification system that attempts to consider the morphologic, functional, and
      biologic features of the tumors.

PMID- 8661809
TI  - Clinical manifestations of carcinoid disease.
AB  - Carcinoid tumors are relatively uncommon tumors and their presentation is varied.
      For these reasons, a high index of suspicion is necessary in order to consider
      the diagnosis. It is important to separate the "syndrome" from the primary tumor.
      It is obviously more effective to diagnose the tumor itself before the syndrome
      manifests itself, usually as a result of metastatic disease. Since the tumors are
      characteristically slow-growing, the physician may be misled into thinking the
      patient has functional problems rather than a tumor. Some data and guidelines are
      given for focusing on the signs and symptoms of carcinoid disease.

PMID- 8661811
TI  - Somatostatin receptor scintigraphy in patients with carcinoid tumors.
AB  - In 80% to 90% of patients with carcinoids, tumor sites can be detected with
      [111In-DTPA-d-Phe1]-octreotide scintigraphy. Unexpected, additional localizations
      are reported in one-third to two-thirds of patients. In a group of 52 patients,
      we analyzed the results of various combinations of octreotide scintigraphy and
      conventional imaging. Octreotide scintigraphy, alone or in combination with other
      imaging modalities, led to the detection of more tumor sites than any combination
      of conventional imaging techniques. The combination of octreotide scintigraphy,
      chest radiography, and ultrasonography of the upper abdomen led to the detection
      of lesions in all patients in whom they could be demonstrated by any imaging
      means, with a sensitivity of 87% in terms of the number of detected lesions. The
      calculated cost for this imaging regimen was higher than for the combination of
      conventional imaging as applied in our group. However, the benefit was the
      detection of at least one lesion in 11% of patients in whom with conventional
      imaging no abnormalities were found. Moreover, if the results from our patient
      group were extrapolated to a group of 100 patients, the advantage in terms of the
      number of extra lesions detected would be 65 extra lesions per 100 patients. The
      detection of more tumor sites in patients who are known to have one tumor
      localization with conventional imaging may be essential when deciding whether to
      perform surgery. Octreotide scintigraphy can be used to localize tumors, direct
      the choice of medical therapy, and (expected in the near future) select patients
      for radiotherapy. The impact on patient management is fourfold: Octreotide
      scintigraphy may detect resectable tumors that would be unrecognized with
      conventional imaging techniques; it may prevent surgery in patients whose tumors
      have metastasized to a greater extent than can be detected with conventional
      imaging; it may direct the choice of therapy in patients with inoperable tumors;
      and in the future it may be used to select patients for radionuclide therapy.

PMID- 8661810
TI  - Carcinoid tumors: imaging procedures and interventional radiology.
AB  - The hypervascular nature of carcinoid tumors and their metastases allows a more
      aggressive role by the radiologist in diagnosis and interventional management.
      Double-contrast gastrointestinal studies still best define the primary neoplasms.
      Appendiceal tumors, the most frequent site of carcinoids, frequently escape
      radiologic detection until large enough to be discovered by computed tomography
      (CT). Superior mesenteric arteriography of the small bowel and cecum is useful
      when the scanning procedures are not revealing. The "spokewheel" configuration of
      the desmoplastic mesenteric masses and lymph node metastases are best seen by CT,
      whereas hepatic metastases can be demonstrated by CT, CT-angioportography (CTAP),
      ultrasonography (US), magnetic resonance imaging (MRI), and octreotide
      scintigraphy. Percutaneous needle biopsy with radiologic guidance confirms the
      diagnosis of carcinoid tumors and their metastases. Hepatic arteriography is
      frequently performed in preparation for hepatic embolization or
      chemoembolization. Hepatic vascular occlusion therapy, the procedure of choice
      for the management of inoperable carcinoid liver metastases, results in a partial
      response in at least 50% of patients and a mortality rate of 5%.
      Chemoembolization with microencapsulated cytotoxic agents and direct percutaneous
      ethanol injection should also be considered for the treatment of liver
      metastases.

PMID- 8661812
TI  - Value of somatostatin receptor scintigraphy for preoperative localization of
      carcinoids.
AB  - Most carcinoid primary tumors are small and do not cause symptoms until
      complications (e.g. intestinal obstruction) or symptoms and signs of the
      carcinoid syndrome occur. Therefore in most cases an assessment of the primary
      tumor and its metastases must be performed. To determine the value of
      somatostatin receptor scintigraphy (SRS) for localizing carcinoid tumors, we
      compared the results of SRS with those obtained with computed tomography (CT) and
      ultrasonography (US) in 22 patients who had not undergone surgery for removal of
      the primary tumor. We could not find an advantage of SRS over CT and US for
      detecting the primary lesions. Tumors > 2 cm in diameter were regularly detected
      using all methods. SRS was not superior to CT or US for the detection of liver
      metastases. SRS showed the liver metastases in 16 of 18 patients, whereas CT and
      US detected liver metastases in all patients. For localization of extrahepatic
      abdominal and extraabdominal metastases (lymph nodes, bone), whole-body SRS
      showed an advantage over CT and US. We conclude that SRS is not superior to CT or
      US for localization of primary carcinoid tumors or liver metastases, although it
      did prove successful for visualizing extrahepatic and extraabdominal tumor
      spread. Additionally, SRS is useful for identifying receptor-positive metastases
      that may be treated by somatostatin analogs. Thus SRS should be performed in
      patients with a known carcinoid tumor, except those with an appendiceal carcinoid
      measuring < 1 cm in diameter.

PMID- 8661813
TI  - Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and
      behavior.
AB  - The goal of this study was to provide information of prognostic value for gastric
      endocrine tumors. A total of 205 gastric endocrine tumors have been studied: 193
      well differentiated tumors [2 gastrin cell tumors, 191 enterochromaffin-like
      (ECL) cell tumors] and 12 poorly differentiated carcinomas. Subtyping of ECL cell
      tumors (carcinoids) resulted in 152 associated with chronic atrophic gastritis
      (CAG) (type 1); 12 associated with hypertrophic gastropathy (HG) due to Zollinger
      Ellison syndrome with multiple endocrine neoplasia type I (type 2), and 27 with
      no specific association (type 3, sporadic). Type 1 cases occurred most often in
      female (108 of 152), elderly (mean 63 years) patients, with no tumor-related
      death at an overall mean follow-up of 53 months. The 12 type 2 cases were equally
      distributed between the sexes (six of each), with a mean age of 45 years; there
      was one tumor-related death (49 months after diagnosis) and an overall mean
      survival of 84 months. Type 3 cases were mostly in men (20 of 27), with a mean
      age of 55 years; there were seven tumor-related deaths at a mean follow-up of 28
      months. Poorly differentiated neuroendocrine carcinomas were observed in elderly
      patients (mean 63 years, range 41-76 years) of both sexes, with nine tumor
      related deaths and a mean survival of 7 months. It was concluded that correct
      clinicopathologic subtyping may predict the clinical behavior of gastric
      endocrine tumors.

PMID- 8661814
TI  - Management of carcinoid tumors of the stomach, duodenum, and pancreas.
AB  - Carcinoids of the stomach, duodenum, and pancreas are represented by a variety of
      tumors with variable histologic and clinical features. Multicentric gastric
      carcinoids and concomitant nonantral argyrophilic hyperplasia are common in
      chronic atrophic gastritis, more rarely due to a multiple endocrine neoplasia
      (MEN)-related Zollinger-Ellison syndrome (ZES). These tumors are infrequently
      associated with metastases and may generally be dealt with by repeated endoscopic
      fulguration. Sporadic carcinoids tend to be larger, invasive, and more often
      metastatic, especially in the presence of atypical histology. Small tumors may be
      removed by endoscopy, but larger lesions need to be surgically excised. In
      association with metastases a histamine-related atypical carcinoid syndrome may
      evolve and require treatment with a somatostatin analog. Poorly differentiated
      neuroendocrine carcinomas of the stomach constitute markedly aggressive tumors
      that rarely are suitable for radical surgery. Gastrinomas are the most prevalent
      duodenal carcinoids and a common cause of ZES especially in MEN-I. Despite a
      marked tendency for regional lymph node dissemination, liver metastases occur
      late and duodenal gastrinomas are often excisable, thereby offering favorable
      odds for cure in ZES. Unusual somatostatin-rich carcinoids in the ampulla of
      Vater relate to von Recklinghausen's disease and may be the cause of obstructive
      jaundice; depending on their size, these tumors may be removed by local excision
      or pancreaticoduodenectomy. Gangliocytic paragangliomas are unusual, generally
      benign lesions of the duodenum. Rare pancreatic tumors with serotonin
      immunoreactivity may be classified as carcinoids and constitute an unusual cause
      of the carcinoid syndrome.

PMID- 8661815
TI  - Surgical management for carcinoid tumors of small bowel, appendix, colon, and
      rectum.
AB  - Carcinoid tumors occur most frequently in the gastrointestinal tract. Despite
      their ability to produce hormones, most of the midgut and hindgut carcinoids
      covered in this study are clinically silent, and the diagnosis is often not made
      before emergency surgery or evaluation for liver metastases. Because the rate of
      lymph node involvement and the prognosis of carcinoid tumors depend on their site
      and size, surgery refers to these two factors too. Lymph node metastases are most
      commonly found with small bowel carcinoids (20-45%), providing the rationale for
      an extended resection including the adjacent lymph node drainage area. Carcinoid
      tumors of the appendix < 1 cm in diameter rarely metastasize, simply requiring
      appendectomy for treatment. Lesions > 2 cm should be treated by right
      hemicolectomy because of their approximately 30% risk of lymph node metastases.
      Resection should always be done for carcinoid tumors of the colon resection as
      for adenocarcinomas. Rectal carcinoids < 2 cm rarely metastasize, directing the
      conclusion that for these smaller lesions local excision is sufficient; for
      lesions >2 cm a standard cancer resection should be performed provided distant
      metastases are absent. In general, the younger the patient or the larger the
      primary tumor, the more aggressive the treatment should be.

PMID- 8661816
TI  - Pulmonary and thymic carcinoid tumors.
AB  - Carcinoid tumors of the lung and bronchi are usually benign lesions with no
      influence on life expectancy, although occasionally, they are malignant with a
      poor prognosis. Between these two extremes are atypical carcinoids, which can be
      slow-growing tumors with an average 5-year survival of 60% and an average 10-year
      survival of 40%. The myriad names used to describe these lesions complicates the
      understanding of their behavior, especially as the term carcinoid is used to
      describe the complete spectrum of disease or exclusively the benign well
      differentiated lesions with an excellent prognosis. Thymic carcinoids are
      uncommon lesions. Their prognosis is poor, even in cases that appear favorable in
      terms of resectability and histology. Pulmonary carcinoids present uncommonly
      with a paraneoplasic syndrome. Both carcinoid and Cushing syndromes are seen with
      approximately 2% of these lesions. Cushing syndrome can be present in as many as
      one-third of patients with thymic carcinoids but an association with the
      carcinoid syndrome has never been described.

PMID- 8661817
TI  - Treatment of liver metastases of carcinoid tumors.
AB  - Liver metastases imply a major problem in patients with carcinoid tumors.
      Patients with localized disease should always undergo resection for cure.
      Patients with distant metastatic disease can also undergo resection for potential
      cure or symptom palliation because of the slow growth rate of many carcinoid
      tumors. In patients with the midgut carcinoid syndrome and bilobar hepatic
      disease we have performed primary surgery to relieve such symptoms as intestinal
      obstruction and ischemia, followed by successive embolizations of the hepatic
      arteries to reduce functional tumor burden in the liver. For optimal palliation,
      all patients with residual tumor were treated by octreotide. In a consecutive
      series of 64 patients with the midgut carcinoid syndrome we thus attained a 5
      year survival rate of 70%. Fourteen of the patients underwent intentionally
      curative surgery (e.g., primary surgery followed by liver surgery). Of these
      patients, none died from their tumor disease during the period of study. The
      value of adjunctive interferon therapy is currently under evaluation.

PMID- 8661818
TI  - Medical treatment of metastasizing carcinoid tumors.
AB  - Long-acting somatostatin analogs, such as octreotide, comprise the therapeutic
      modality of choice for the symptomatic relief of flush and diarrhea in patients
      with carcinoid syndrome. The sequelae of gastric acid hypersecretion in patients
      with gastrin-producing duodenal carcinoids (gastrinoma) are perfectly controlled
      by proton pump inhibitors. Antiproliferative medical strategies to control the
      growth of metastatic carcinoid tumors include long-acting somatostatin analogs,
      interferon alpha, and the combination of the two. However, the success rate is
      less than 50%, and it is questionable whether true tumor regression can be
      expected. Controlled prospective studies are mandatory to address the question
      whether interferon or somatostatin analogs or the combination of the two should
      be used as first-line medical strategies and if hepatic artery embolization in
      patients with liver metastases should be performed before beginning medical
      therapy. Chemotherapy, including etoposide and cisplatin, has been shown to be
      effective only for purely differentiated neuroendocrine carcinomas and not for
      slowly growing carcinoids.

PMID- 8661819
TI  - Inhibition of unstimulated exocrine pancreatic secretion by peptide YY in the
      rat.
AB  - Peptide YY is an ileocolonic peptide known to inhibit postprandial and
      cholecystokinin-induced pancreatic exocrine secretion. It has also been shown to
      increase intestinal water and electrolyte absorption. These findings implicate
      PYY as being potentially useful for controlling watery diarrhea. Although its
      inhibitory effect on stimulated pancreatic secretion has been well established,
      PYY effects on interdigestive, unstimulated pancreatic secretion is not known.
      This study was designed to evaluate the effect of PYY on basal pancreatic
      exocrine secretion in a conscious rat. Male Sprague-Dawley rats were prepared
      with catheters for internal biliary bypass, pancreatic juice collection, and
      intraduodenal reinfusion of pancreatic juice. Jugular and carotid catheters were
      inserted for drug infusions and blood sampling. After overnight recovery, fasting
      rats were infused over 6 hours with saline or PYY (400 or 800 pmol/kg/hr).
      Pancreatic juice was measured and sampled at 60-minute intervals for volume and
      its protein and bicarbonate content. The remainder was reinfused into the
      duodenum. Before and after the experiment, pancreatic juice was automatically
      reinfused by a photocell-controlled peristaltic pump system. Intraductal
      pancreatic secretion was not affected by PYY at a dose of 400 pmol/kg/hr. PYY at
      a dose of 800 pmol/kg/hr significantly reduced the volume of pancreatic secretion
      and its protein and bicarbonate content. Pancreatic secretory response normalized
      within 24 hours. In conclusion, unstimulated pancreatic exocrine secretion can be
      inhibited by exogenous PYY in the rat.

PMID- 8661820
TI  - Characteristic histologic features of human hepatocellular carcinoma with mutant
      p53 protein.
AB  - To characterize hepatocellular carcinoma (HCC) cells with mutant (m) p53 protein
      histologically, we examined 68 main nodules and 20 accessory lesions of 72
      patients with HCC who underwent hepatic resection between October 1990 and
      September 1993. Some sections were fixed in periodate-lysine-paraformaldehyde,
      embedded in OCT compound, and stained with the mouse monoclonal antibody PAb1801
      to m-p53 protein by the immunoperoxidase technique with avidin-biotin complexes.
      Other sections were fixed in 20% buffered formalin, embedded in paraffin, and
      stained with the mouse monoclonal antibody DO-1 to m-p53 protein in the same way.
      Lesions in which cells had nuclei stained for m-p53 protein were defined as being
      positive for the protein; 25 of the 68 main nodules and 14 of the 20 accessory
      lesions were positive. Large main nodules were more likely to be positive than
      small ones. Microscopic examination showed that a larger proportion of poorly
      differentiated main nodules than well differentiated nodules were positive.
      Larger proportions of main nodules with extracapsular invasion, septa, portal
      thrombi, or intrahepatic metastases were positive than main nodules without these
      features. Accessory lesions that seemed to be metastatic were almost all
      positive, but few accessory lesions that seemed to be of multicentric occurrence
      were positive. Our results suggest that lesions with m-p53 protein had a high
      grade of malignancy and metastasized readily.

PMID- 8661821
TI  - Cholecystokinin mediation of colonic absorption via peptide YY: foregut-hindgut
      axis.
AB  - Peptide YY (PYY), a 36-amino-acid polypeptide, is found in abundance in the
      colon, a region where its physiologic roles are unknown. Previous studies have
      revealed a substantial increase in plasma PYY after cholecystokinin (CCK)
      administration. PYY is released from the hindgut in response to a meal and
      inhibits CCK release. In this study we evaluated the effects of CCK and PYY on
      intestinal absorption of water and electrolytes. Colonic, ileal, or jejunal Thiry
      Vella fistulas (TVFs) were created in 12 dogs, and intestinal continuity was
      reestablished. The TVFs were perfused with an isotonic buffer solution containing
      [14C] PEG as a volume marker. Electrolyte and water transport were measured every
      15 minutes, and plasma PYY and CCK levels were measured by radioimmunoassay.
      Group 1 dogs received an intravenous bolus of MK329, a specific CCK receptor
      antagonist, at 20 nmol/kg after a standard mixed meal; group 2 colonic TVF dogs
      received a meal and an intravenous bolus of PYY polyclonal antibody at 1 mg/kg.
      Postprandially, all three regions of the bowel became significantly proabsorptive
      for water, sodium, and chloride. In the colon postprandial absorption was
      abolished by MK329 starting 60 minutes after a meal, whereas specific CCK
      receptor blockade blunted ileal absorption. CCK receptor blockade did not affect
      postprandial absorption in the jejunum. Postprandial PYY levels did not rise in
      MK329-treated animals. PYY antibody reduced colonic absorption during the
      postprandial phase. Reduction of meal-induced colonic absorption and PYY release
      by MK329 in awake dogs suggests an important foregut-hindgut hormonal feedback
      loop. Foregut-derived CCK stimulates hindgut PYY release, which in turn
      stimulates colonic absorption while inhibiting further CCK release.

PMID- 8661822
TI  - Enhanced expression of manganese superoxide dismutase mRNA and increased TNFalpha
      mRNA expression by gastric mucosa in gastric cancer.
AB  - Manganese superoxide dismutase (Mn-SOD), a mitochondrial enzyme, is a cytokine
      regulated acute-phase protein that protects cells from free radicals. The current
      investigations examined the in vivo regulation of the expression of Mn-SOD mRNA
      and tumor necrosis factor alpha (TNFalpha) mRNA in gastric carcinoma tissue. The
      expression of these transcripts in breast carcinoma tissue also was examined
      because breast cancer is a much more TNF-sensitive tumor than gastric cancer.
      TNFalpha mRNA was markedly increased in gastric carcinoma tissue (p < 0.005).
      There were significantly higher levels of Mn-SOD mRNA in gastric carcinoma tissue
      than in noncancerous tissue (p < 0.0001). The level of Mn-SOD mRNA in gastric
      carcinoma tissue was higher than that in breast carcinoma tissue (p < 0.005). Up
      regulation of Mn-SOD mRNA in gastric carcinoma tissue most likely serves as a
      protective mechanism against superoxide radicals and TNF cytotoxicity.

PMID- 8661823
TI  - Effect of pneumoperitoneum on interatrial pressure gradient during laparoscopic
      cholecystectomy.
AB  - Alterations of the left atrial/right atrial pressure gradient were determined
      using a Swan-Ganz thermodilution catheter in 20 patients who underwent
      laparoscopic cholecystectomy with 12 mmHg pneumoperitoneum (LAP) and 13 patients
      who underwent minilaparotomy cholecystectomy (MINI). Right and left atrial
      pressures were both elevated by pneumoperitoneum. A diminished or reversed
      left/right interatrial pressure gradient was recognized during pneumoperitoneum
      in 4 of the 20 patients (20%) in the LAP group, whereas it was not recognized
      during operation in any of the 13 patients in the MINI group. Evaluation of the
      elevation of intrathoracic pressure during pneumoperitoneum using peak
      inspiratory airway pressure or pulmonary arterial pressure could not predict the
      occurrence of this paradoxical interatrial pressure gradient.

PMID- 8661824
TI  - Use of monoclonal antibodies in colorectal cancer: a review.
AB  - This is a review article covering the development of monoclonal antibodies
      attached to a radioactive isotope which are used in scanning for metastatic
      adenocarcinoma of the colon. The most recent and complete study described 223
      patients, of which 169 were evaluated. All patients required an operation. At
      operation, biopsies were taken of the resected tumor. Some false negative areas,
      such as dilated varicosities and inflammatory areas, were encountered. The latter
      can be seen as a chronic inflammatory process such as a leaking anastomosis with
      a diverticulum or old traumas in the pelvis. This technique allows a physician to
      follow patients, especially those who have had an abdominal perineal or
      exoneration of their pelvic organs, for possible recurrence in this area. There
      is also some discussion about possible future uses in the treatment of the
      metastatic disease.

PMID- 8661825
TI  - Somatostatin receptor localization of pancreatic endocrine tumors.
AB  - Gastroenteropancreatic endocrine tumors are difficult to localize. At the same
      time the tumor is localized, though, there is an opportunity for cure or to
      remove tumor tissue. In this study we have prospectively examined the ability of
      111In-octreotide scintigraphy, magnetic resonance imaging (MRI), and computed
      tomography (CT) to localize tumor lesions in 24 patients with a biochemical or
      histologic diagnosis of neuroendocrine tumor. In eight patients a surgical
      assessment of the imaging results was prospectively performed. Planar and
      abdominal single-photon emission tomography (SPET) images acquired 4 and 24 hours
      after 180 to 220 MBq of 111In-octreotide injection were evaluated and compared
      with conventional imaging techniques. SPET scintigraphy visualized more presumed
      tumor lesions (n = 39) than conventional imaging studies (MRI,n = 25; CT,n = 13);
      23 of 24 patients had positive octreotide scintigraphy, 17 of 24 had positive MRI
      scans, and 12 of 24 patients had positive CT scans. It was concluded that 111In
      octreotide scintigraphy combined with conventional imaging improves the
      preoperative localization of presumably tumorous lesions in patients with
      gastroenterohepatic endocrine tumors.

PMID- 8661826
TI  - PET scans of abdominal malignancy.
AB  - Positron emission tomography (PET) with fluorine-18-2-d-deoxyglucose (FDG)
      currently is being integrated into clinical oncology because it provides unique
      functional information that can be applied to the management of cancer. In
      particular, it is useful for assessing tumor activity and growth, evaluating
      efficacy of therapy, and detecting tumor recurrence. Studies have demonstrated
      the value of whole-body PET-FDG imaging when staging and managing abdominal
      malignancy.

PMID- 8661827
TI  - Helical computed tomography for abdominal imaging.
AB  - Significant technologic advances have taken place in computed tomography (CT).
      Current-generation conventional CT scanners are able to image a slice of tissue
      in as little as 2 to 3 seconds and can acquire several consecutive images.
      Although it is a substantial improvement from the CT of 5 years ago, there remain
      practical limits to the utility of conventional CT imaging within the abdomen.
      Recently, a new type of CT gantry design ("slip-ring") and faster computers have
      contributed to the development of a new generation of CT scanners, the "helical"
      or "spiral" CT scanners.

PMID- 8661828
TI  - Prospective randomized comparison of open versus laparoscopic appendectomy in
      men.
AB  - A prospective, randomized trial was performed to compare open appendectomy with
      laparoscopic appendectomy in men with a clinical diagnosis of acute appendicitis.
      Sixty-four patients with a median age of 25 years (range 18-84 years) were
      randomized to open appendectomy (n = 31) or laparoscopic (n = 33) appendectomy.
      Of the 64 men, 56 (87.5%) had appendicitis (27 open, 29 laparoscopic procedures).
      The mean operating times were 50.6 +/- 3.7 minutes (+/- SEM) for open and 58.9 +/
      4.0 minutes for laparoscopic appendectomy (p = 0.13). Five (15%) patients
      randomized to laparoscopic appendectomy had an open operation. The mean
      postoperative hospital stay was significantly longer for open appendectomy (3.8
      +/- 0.4 days) than for laparoscopic appendectomy (2.9 +/- 0.3 days) (t = 2. 05,df
      = 62,p = 0.045). The complication rate after open appendectomy (25.8%) was not
      significantly different from that after laparoscopic appendectomy (12.1%). There
      was a single postoperative death due to a pulmonary embolus in the laparoscopic
      group and a single death due to cardiac and renal failure in the open group. The
      mean time to return to normal activities was significantly longer following open
      appendectomy (19.7 +/- 2.4 days) than after laparoscopic appendectomy (10.4 +/-
      0.9 days), (t = 3.75,df = 49,p = 0.001). In conclusion, laparoscopic appendectomy
      in men has significant advantages in terms of a more rapid recovery compared to
      open appendectomy. There were no significant disadvantages to laparoscopic
      appendectomy compared to open appendectomy.

PMID- 8661829
TI  - Comparison of routine and selective endoscopic retrograde cholangiography before
      laparoscopic cholecystectomy.
AB  - To evaluate the role of endoscopic retrograde cholangiography (ERC) before
      laparoscopic cholecystectomy, we compared the frequency of concomitant common
      bile duct stones, their clinical outcome, and the frequency of bile duct injury
      between a group of 128 patients with routine preoperative ERC (group A) and 1010
      patients with selective ERC (group B). Overall, 48 patients (4.2%) had duct
      stones, but the predictive signs were absent in six of them (12.5%). The stones
      were demonstrated by ERC and removed by sphincterotomy in all 11 patients in
      group A. Of 37 patients in group B, 22 were diagnosed by selective ERC and
      underwent endoscopic removal. Of four patients whose stones were found by
      operative cholangiography, one had immediate open surgery, another passed a stone
      spontaneously, and the other two underwent postoperative sphincterotomy, which
      failed in one. The stones were not recognized until pain recurred in the
      remaining 11 patients. Sphincterotomy was successful in nine patients but failed
      in the other two. Thus postoperative sphincterotomy failed in 3 of 13 patients
      (23%), necessitating open surgery. Forty-two patients overall (3.7%) had aberrant
      biliary tract anatomy, which did not lead to bile duct injury in any of the
      patients. Morbidity of routine ERC (3.1%) was lower than that of selective ERC
      (7.4%) (p < 0.05). It should be noted that a certain proportion of duct stones
      may be missed by selective ERC, necessitating laparotomy when sphincterotomy
      fails. The routine use of preoperative ERC may be justified at institutions where
      the expertise is available, at least until laparoscopic lithotomy becomes easy.

PMID- 8661830
TI  - Long-term follow-up after endoscopic treatment of bile duct calculi in
      cholecystectomized patients.
AB  - Endoscopic sphincterotomy (EST) is an established method for treatment of
      retained or recurrent common bile duct (CBD) calculi after cholecystectomy.
      Present experience shows that few patients have recurrent biliary tract
      complications, but follow-up periods are most often short. EST was performed in
      147 patients with bile duct calculi and remote cholecystectomy in our department
      from 1981 to 1992. In 8 of 147 patients (5.4%) complete removal of calculi
      failed. A total of 135 patients with a median age of 71 years (range 24-96 years)
      were eligible for a follow-up of 23 to 153 months (median 86 months). Thirty
      seven patients have died without recurrent symptoms (a recurrent stone was
      revealed at postmortem examination in one patient), and four patients (two with
      calculi and two with cholangiocarcinoma) died with recurrent symptoms from the
      biliary tract. Ninety-four patients are alive; and with the exception of two who
      have had cholangitis without or with post-EST stenosis, respectively, they are
      all symptom-free. Jaundice, cholangitis, and biliary pancreatitis prior to EST
      were the only factors that significantly (p = 0.006, Fisher's exact test)
      predicted late biliary complications after EST in patients with recurrent
      calculi. These findings confirm that endoscopic treatment of CBD calculi in
      cholecystectomized patients has a low long-term rate (5 of 135; 3.7%) of
      recurrent nonmalignant bile duct disease (three patients with CBD calculi and two
      with cholangitis).

PMID- 8661831
TI  - Laparoscopic colorectal surgery: ascending the learning curve.
AB  - The aim of this study was to prospectively assess the results of our first 100
      consecutive patients who underwent laparoscopic or laparoscopy-assisted
      colorectal operations. The parameters studied included the type and length of
      procedure, intra- and postoperative complications, conversion to open surgery,
      length of ileus, and hospitalization. A total of 100 laparoscopic and laparoscopy
      assisted procedures were performed between May 1991 and April 1994. The mean
      patient age was 49 years (12-88 years). The procedures included 36 total
      abdominal colectomies (TACs) (ileoanal reservoir 28, ileorectal anastomosis 6,
      end-ileostomy 2), 39 segmental resections of the colon and small bowel, 8
      resections of the rectum, 7 diverting stoma creations, 7 reversals of Hartmann's
      procedure, and 3 other procedures. In seven cases (7%) the laparoscopic procedure
      was converted to a laparotomy. A group of 22 patients sustained 26 complications
      that included enterostomy (n = 5), hemorrhage (n = 6), intraabdominal abscess (n
      = 4), prolonged ileus (n = 4), wound infection (n = 2), anastomotic leak (n = 1),
      aspiration (n = 1), cardiac arrhythmia (n = 1), upper intestinal bleeding (n =
      1), and postoperative small bowel obstruction (n = 1). There were no deaths. When
      divided into three equal, consecutive groups, the patients in the early (n = 33)
      and intermediate (n = 33) groups had a significantly higher complication rate
      (42% and 27%, respectively), than those in the late group (n = 34, 12%;p < 0.05).
      The complication rate in each group was also directly related to the number of
      TACs performed (18 in the early, 13 in the intermediate, and 5 in the late
      group). The overall complication rate in TAC cases was significantly higher (42%)
      when compared to that of all other procedures (segmental resection 9%,
      nonresectional 12%;p < 0.01). The mean operating time was 4 hours (2.5-6.5 hours)
      for TAC, 2.5 hours (1.5-5.5 hours) for segmental colonic resection, and 1.6 hours
      (1.0-2.5 hours) for the nonresectional procedures. The length of ileus was 3.5
      days (2-7 days) after TAC, 3 days (2-7 days) after the segmental resections, and
      2 days (1-4 days) after the nonresectional procedures. The mean hospital stay was
      7.3 days (2-40 days): 8.4 (5-40), 7.0 (4-12), and 6.8 (2-11) days for the TAC,
      segmental resection, and nonresectional procedures, respectively. We conclude
      that the feasibility of laparoscopic colorectal surgery has been well
      established. The morbidity associated with laparoscopic colorectal surgery
      correlates with a steep learning curve but is also related to the type of
      procedure. TAC is associated with a higher complication rate than are other
      laparoscopic colorectal procedures.

PMID- 8661832
TI  - Percutaneous needle biopsy of the pancreas: when should it be performed?
AB  - Is it appropriate for a good risk patient with a clinical history or imaging
      studies suggestive of an operable pancreatic neoplasm to undergo a percutaneous
      fine-needle aspiration biopsy (FNAB) prior to operation? A group of 118 patients
      who underwent percutaneous FNAB of the pancreas between 1987 and 1993 were
      evaluated retrospectively. The initial readings of the biopsies were positive for
      neoplasm in 78 patients and negative in 32. Four suspicious biopsies were
      included with the positive biopsies for analysis, and four unsatisfactory
      biopsies were added to the negative biopsies. Operation was performed on 57 of
      the 118 patients; 39 of these patients had a positive and 18 a negative FNAB. Of
      the 18 patients with a negative biopsy, 12 were proved to have neoplasia at
      operation. No operation was performed on 61 patients; 43 of these patients had a
      positive and 18 a negative FNAB. Three patients with a negative biopsy were
      treated with chemotherapy, and three subsequently died of pancreatic cancer. It
      was concluded that because the sensitivity of percutaneous FNAB is only 84% the
      procedure should be limited to patients suspected of having pancreatic cancer
      deemed technically inoperable or medically unsuitable for operation.

PMID- 8661833
TI  - Total pancreatectomy for cancer of the pancreas: is it appropriate?
AB  - During the late 1960s total pancreatectomy was advocated on theoretic grounds as
      an operation superior to subtotal (Whipple) resection in patients with pancreatic
      cancer. There are, however, no prospective randomized studies and only few
      institutional comparisons between the two operations. The aim of the present
      paper was to report the clinical outcome of total and subtotal pancreatectomy,
      respectively, in a consecutive series of patients with exocrine pancreatic
      cancer. The short- and long-term results of 89 consecutive patients who underwent
      total pancreatectomy (1959-1984) for pancreatic cancer were retrospectively
      compared with a similar group of 36 patients who had a subtotal pancreatectomy
      (1985-1992) for the same diagnosis. The clinical characteristics were on the
      whole similar in the two groups. Postoperative mortality and morbidity, the
      amount of intraoperative bleeding, operation time, reoperation rate,
      postoperative days in the intensive care unit, and duration of hospital stay were
      statistically significantly increased after total pancreatectomy. The 5-year
      survival rate was lower after total pancreatectomy when hospital deaths were
      included in the analysis. At multivariate analysis total pancreatectomy adversely
      influenced long-term survival compared to subtotal resection, as did positive
      lymph nodes and poor histologic differentiation. Better early and long-term
      results were found after subtotal than after total pancreatectomy in patients
      with exocrine pancreatic cancer. Although the two operations were done during
      different time periods, we believe the results suggest that total pancreatectomy
      cannot be recommended as a routine treatment for this patient group.

PMID- 8661835
TI  - Gut origin sepsis, macrophage function, and oxygen extraction associated with
      acute pancreatitis in the rat.
AB  - It has been suggested that the gut plays a role in the development of bacterial
      complications, which are important contributors to morbidity and mortality in
      patients with acute pancreatitis. The present study evaluated the enteric
      bacterial translocation, bacterial homeostasis, and reticuloendothelial system
      function in experimental acute pancreatitis induced by intraductal injection of
      5% sodium taurodeoxycholate in the rat. The incidence of bacterial translocation
      from the gut to mesenteric lymph nodes (MLNs) and lungs significantly increased
      after 12 hours and to the systemic circulation, ascites, and pancreas at 24
      hours. The number of anaerobic bacteria and lactobacilli decreased in the colon
      and distal ileum from 6 or 12 hours, whereas the number of Escherichia coli
      increased from 12 hours. The systemic uptake rate of radiolabeled bacteria
      decreased from 6 hours after induction of acute pancreatitis. The uptake of
      radiolabeled bacteria by Kupffer cells decreased from 6 hours, whereas the uptake
      by macrophages from blood, lungs, and the intestine increased. A decrease in
      macrophage killing capacity was noted, reflected by an increase in the number of
      cultured viable bacteria from isolated macrophages. The whole-body oxygen
      extraction rate increased 4 to 24 hours after induction of pancreatitis, whereas
      the gut oxygen extraction rate decreased at 2 and 4 hours, followed by an
      increase at 12 to 24 hours. These data show that translocation of enteric
      bacteria occurs during the early stage of acute pancreatitis and that the MLN
      thoracic duct-circulation may be a major route of bacterial dissemination.
      Compromised gut oxygen metabolism, overexaggerated intestinal macrophages, and
      impaired host immune function may be involved in the development of infectious
      complications associated with acute pancreatitis.

PMID- 8661834
TI  - Pseudotumor developing in heterotopic pancreas.
AB  - Cystic dystrophy in heterotopic pancreas (CDHP) is characterized by the presence
      of cystic formations surrounded by inflammation and scarring. It usually involves
      the duodenal wall and can be responsible for strictures and pain. The diagnosis
      of this disorder was previously based on pancreatoduodenectomy specimens removed
      for a suspected pancreatic tumor. Six cases were observed in young men (mean age
      40 years) between 1989 and 1993. Computed tomography (CT) and endoscopic
      ultrasonography (EUS) features allowed definitive preoperative diagnosis of CDHP.
      After surgical resection of the tissue-bearing segments that included five
      pancreatoduodenectomies and one antrectomy, symptoms disappeared in all patients.
      Patients were followed 2 to 45 months; one patient experienced recurrence of pain
      and hyperamylasemia 17 months after surgery. The preoperative diagnosis of CDHP
      is presently possible because of modern imaging procedures and improved knowledge
      of specific signs. Resection is the most appropriate treatment.

PMID- 8661836
TI  - Reuse of liver grafts after early death of the first recipient.
AB  - Three cases are reported of reuse of a transplanted liver graft after early death
      of the first recipient due to cerebral hemorrhage. The good condition of the
      donors; the excellent biochemical evolution of the graft in the first recipients;
      total ABO compatibility and donor-recipient crossmatch; the absence of positivity
      to hepatitis B virus (HBV), hepatitis C virus (HCV), and bacteriologic cultures;
      and early death made reuse possible. The shortage of donors in relation to
      patients on the waiting list and the poor clinical condition of the second
      recipients made it necessary to adopt the decision to reuse the graft in an
      attempt to save their lives. The evolution of the patients and the reused grafts
      was satisfactory, and there were no complications that could be attributed to the
      fact that the graft had been transplanted before.

PMID- 8661837
TI  - Anterior approach for difficult major right hepatectomy.
AB  - In selected patients with huge right hepatic tumors that had infiltrated the
      surrounding structures, injudicious mobilization of the liver before transection,
      as in the conventional manner, may result in excessive bleeding, prolonged
      ischemia from rotation of the hepatoduodenal ligament, and spillage of cancer
      cells into the systemic circulation. Alternatively, the "anterior" approach,
      which involves initial completion of the parenchymal transection before the right
      hepatic lobe is mobilized, can be adopted for these patients with difficult right
      hepatic tumors. After hilar control of the inflow vessels, liver parenchyma was
      transected using an ultrasonic dissector until the anterior surface of the
      inferior vena cava is exposed. The right hepatic lobe is then mobilized laterally
      by securing all venous tributaries, including the right hepatic vein. The
      prospective data of 25 patients who had major right hepatectomy using the
      "anterior" approach were compared with data from 34 patients who had their
      operation performed in the conventional manner. Despite the facts that larger
      tumors (p < 0.004), more extrahepatic structures (p < 0.05), and the caudate
      lobes (p < 0.03) were resected, the amount of perioperative blood transfusion,
      fluid replacement, and outcome between the two groups of patients were
      comparable. There were three hospital deaths, among which one could be attributed
      to an intraoperative catastrophe during hepatectomy using the conventional
      approach. The "anterior" approach is a safe, effective option for selected
      patients undergoing complicated major right hepatectomy.

PMID- 8661838
TI  - Modified Sujura operation: long-term results.
AB  - From January 1980 to January 1986 a total of 93 patients with portal hypertension
      (59 males, 34 females; average age 51.5 years) underwent the modified Sujura's
      operation. All patients presented with esophageal varices during the preoperative
      endoscopic workup. Child's risk category was A in 6 patients and B in the
      remaining 87. Our technique consisted of: (1) devascularization of the upper half
      of the gastric corpus and fundus; (2) devascularization of the last 10 to 12 cm
      of the thoracic esophagus; (3) pyloric divulsion; (4) resection and anastomosis
      at the esophagogastric junction; and (5) antireflux fundoplication. In the
      presence of severe hypersplenism we added splenectomy. The surgical approach was
      through a xiphoumbilical laparotomy, extended to the left side when splenectomy
      was anticipated. We observed 19.8% early mortality (10% with elective procedures
      and 27.2% with emergency operations) and two cases of early rebleeding from acute
      mucosal lesions. Long-term follow-up of 82 patients revealed 30 cases of
      rebleeding (36.6%). Ruptured esophageal varices occurred in 12 patients (11 were
      treated with endoscopic sclerotherapy), whereas in 11 patients the cause of
      bleeding was a hemorrhagic gastritis. Of the remaining patients, two had
      rebleeding from a gastric ulcer, one from gastric varices, one from duodenal
      varices; in three patients the source of the hemorrhage remains unknown. The
      survival for elective procedure patients was 59.2% at 5 years and 40.7% at 10
      years.

PMID- 8661839
TI  - Role of preoperative transcatheter arterial oily chemoembolization for resectable
      hepatocellular carcinoma.
AB  - To clarify the effect of preoperative transcatheter arterial oily
      chemoembolization (TAOE) for resectable hepatocellular carcinoma (HCC) on long
      term survival after curative resection, we retrospectively evaluated 60 patients
      with and 68 patients without preoperative TAOE. Although there was no substantial
      difference in the clinical backgrounds between the two groups, the 5-year
      survival rate was lower for the patients with preoperative TAOE than for those
      without TAOE: 24% versus 63%, respectively (p < 0.05). A worse survival rate was
      particularly observed for the cirrhotic patients with TAOE than for those without
      TAOE: 35% and 72% at 4 years, respectively (p < 0.01). As the cause of death,
      liver failure and gastrointestinal bleeding were more frequent in the patients
      with TAOE (13.3% versus 1.5%;p < 0.05). Although the TAOE seemed to retard
      intrahepatic recurrence during the first 1.5 years after operation (1.7% versus
      10.3%;p < 0.05), the overall cancer death rate was similar between the two groups
      (18.3% versus 11.8%). Therefore we suggest that preoperative TAOE must not be
      performed for resectable HCC as a routine procedure, particularly in patients
      with cirrhosis. A prospective randomized trial is warranted to elucidate the
      merits and demerits of preoperative TAOE for surgically resectable HCC.

PMID- 8661841
TI  - Peritoneal echinococcosis.
AB  - Peritoneal echinococcosis is rare, even in areas where hydatid disease is
      endemic. Although the liver and lungs are the organs most commonly involved,
      peritoneal echinococcosis, either primary or secondary, represents an uncommon
      but significant manifestation of the disease. We reviewed the medical records of
      121 patients with abdominal echinococcosis operated on in our department over the
      past 12 years. Peritoneal echinococcosis was found in 17 patients, usually
      combined with liver disease. The presenting symptoms were mostly atypical, and a
      few cases were discovered accidentally during routine follow-up after operations
      for hepatic echinococcosis. Surgery remains the best curative or palliative
      treatment for peritoneal echinococcosis, although anthelmintics can be an
      effective alternative for the treatment of small and asymptomatic cysts.

PMID- 8661840
TI  - Clinicopathologic characteristics and postoperative outcome in Japanese and
      Chinese patients with thoracic esophageal cancer.
AB  - We evaluated the clinicopathologic findings and surgical results of 140 patients
      with thoracic esophageal cancer treated at Shinshu University, Japan (Shinshu
      group), and compared them with those from 1164 patients treated at Hebei Medical
      College, China (Hebei group) to determine if the two groups showed any
      differences. The Shinshu group had significantly higher incidences of elderly
      patients (>70 years of age), male patients, and tumors located at the lower
      esophagus (p < 0.01). In the Hebei group, although the depth of tumor invasion
      was more advanced, the incidence of nodal metastasis was significantly lower (p <
      0.01). Operative death and postoperative complications were more frequent in the
      Shinshu group. Comparison of the postoperative survival curves revealed
      significantly longer survival of patients with pT2 or pT3 tumor in the Hebei
      group (p < 0.01), but there were no significant differences between the two
      groups when the lesions were classified by pTNM stage. This study demonstrated
      several differences between the patients in the two areas in regard to the
      clinicopathologic characteristics of thoracic esophageal cancer. The most
      important characteristic of the esophageal cancer in the Hebei group appears to
      be the low incidence of nodal metastasis.

PMID- 8661842
TI  - Cecal-colic adult intussusception as a cause of intestinal obstruction in Central
      Africa.
AB  - During a 5-year experience in Central Africa, the most common cause of 78 adult
      intestinal obstructions was primary adult cecal-colic intussusception (n = 43;
      55%). The symptom complex of colicky abdominal pain and obstipation was present
      in 100% of the patients with intussusception. Operative repair in 90% of patients
      consisted of simple reduction of the intussusceptum. There were no known
      recurrences. The etiology of adult cecal-colic intussusception is unknown.
      Patients typically present with a 3- to 4-day history of abdominal pain,
      obstipation, and usually a palpable mass. Treatment is surgical reduction. Right
      colectomy is reserved for intestinal gangrene. We treated 43 cases during a 5
      year period with only one death.

PMID- 8661843
TI  - Major vessel resection during limb-preserving surgery for soft tissue sarcomas.
AB  - There is uncertainty in the literature as to whether major vessel involvement in
      extremity soft tissue sarcomas constitutes an indication for amputation. This
      retrospective review includes 21 patients who underwent major vessel resection in
      the context of limb preservation for soft tissue sarcomas. Resected vessels were
      the common iliac in one, external iliac and common femoral in six, common and
      superficial femoral in five, superficial femoral in six, distal superficial and
      popliteal in two, and subclavian vessels in one. Wound infection occurred
      postoperatively in five patients (24%). One Gore-tex and one vein graft became
      exposed, but the wounds healed by secondary intention with routine wound care.
      Three patients (14%) manifested local recurrence, of which one required an
      amputation. The estimated 5-year survival rate is 63%. Involvement of major
      vessel(s) by soft tissue sarcomas of the extremities is not in itself an
      indication for amputation, as with en bloc resection of major vessels the local
      recurrence and 5-year survival rates parallel those of patients with soft tissue
      sarcomas not requiring major vessel resection.

PMID- 8661844
TI  - Long-term observation of serum thyroglobulin after resection of nontoxic goiter
      and relation to ultrasonographically demonstrated relapse.
AB  - The object was to carry out a prospective study of the changes in serum thyroid
      hormones and thyroglobulin (Tg) following resection of nontoxic goiter and to
      investigate if there was a correlation to the pattern of relapse. A group of 39
      consecutive patients, mainly with nodular, nontoxic goiter, were studied for 13
      years following thyroidectomy. No thyroid hormone replacement therapy was given
      after surgery. The preoperative serum Tg level was elevated. After operation the
      mean serum Tg declined to a nadir of 43 micrograms/L at 1 year and subsequently
      increased to 90 micrograms/L at 10 years, with large individual differences. In
      19 patients the serum Tg increased, in 1 it decreased, and in 19 no significant
      alteration was observed. Serum free thyroxine and triiodothyronine indices
      decreased following resection but achieved normal levels within 6 to 12 months.
      Serum thyroid-stimulating hormone increased after resection, with a peak level 1
      month after surgery, but it returned to normal levels at 1 year and remained
      stable for the rest of the period. At 13 years after resection the thyroid volume
      was determined by ultrasonography in 30 of the patients. In 10 patients the
      thyroid volume was enlarged (>/= 28 ml). In this group a rise of average serum Tg
      after resection [DeltaTg(10-1 year)] of 133 micrograms/L was observed, compared
      to 26 micrograms/L in the 20 patients without sonographic relapse (volume < 28
      ml). A positive correlation was demonstrated between serum DeltaTg(10-1 year)
      postsurgically and thyroid volume 13 years after surgery. However, an overlap was
      observed between the groups with and without ultrasonographic relapse, probably
      in part due to large differences in the Tg synthesis activity of different
      follicle cell clones. It is concluded that repeated serum Tg determinations may
      provide biochemical evidence of increased growth activity of thyroid remnants
      monitored after goiter resection.

PMID- 8661845
TI  - Side localization of parathyroid adenomas by simplified intraoperative venous
      sampling for parathyroid hormone.
AB  - Side localization of parathyroid adenomas was performed by venous sampling for
      intact parathyroid hormone (PTH) in 20 consecutive patients with primary
      hyperparathyroidism (pHPT) after induction of anesthesia. The results were thus
      available during surgery. Nineteen of the patients had solitary parathyroid
      adenoma, and one had hyperplasia. There was no complication to the procedure. A
      lateralizing PTH gradient for a parathyroid adenoma was obtained in 13 patients.
      At surgery 12 of them (92%) were proved correct; that is, the adenoma was
      localized on the same side. Thus the technique correctly lateralized the adenoma
      in 12 of 19 patients (63%). We therefore conclude that the method of
      intraoperative venous sampling for intact PTH is safe, and the predictive value
      of a lateralizing gradient is high. It could therefore be used as an adjunct to
      surgical skill and noninvasive localization procedures in selected cases, for
      instance in patients with prior neck surgery and hypercalcemic crisis.

PMID- 8661846
TI  - Assessment of proliferative activity of glandular cells in hyperfunctioning
      parathyroid gland using flow cytometric and immunohistochemical methods.
AB  - The proliferative activity of epithelial cells in hyperfunctioning parathyroid
      glands was estimated by flow cytometric and immunohistochemical procedures. A
      total of 30 parathyroid glands, 29 hyperfunctioning glands, and 1 normal gland
      were studied. The pathology of the 29 glands was determined to be hyperplasia in
      19 and adenoma in 10. The S-phase cell population was expressed in terms of the S
      phase fraction (%SPF) calculated from the histogram by DNA flow cytometry and in
      terms of the BrdU immunostaining labeling index (BrdU LI). Cells in all stages of
      the cell cycle were studied by Ki-67 immunostaining and expressed in terms of the
      labeling index (Ki-67 LI). Both BrdU LI and Ki-67 LI values were low, ranging
      from 0% to 0.58% and from 0.21% to 2.62%, respectively. The BrdU LIs were lower
      than the Ki-67 LIs, ranging from one-sixth to one-twelfth of the values depending
      on the disease. There were significant correlations between the two indices (p <
      0.001). The %SPF determined by flow cytometry was consistently higher than both
      the BrdU LI and the Ki-67 LI. This discrepancy cannot be explained precisely, and
      further improvements are required for the flow cytometric analysis of %SPF. The
      cell cycle study by BrdU and Ki-67 immunohistochemistry suggested that the
      glandular cells of the hyperfunctioning parathyroid were characterized by low
      proliferative activity. No evidence of rapid cell turnover rate assumed from the
      flow cytometric study could be observed in the hyperfunctioning parathyroid
      gland.

PMID- 8661847
TI  - Adrenal surgery in the elderly: too risky?
AB  - Surgical treatment for adrenal disease may be withheld from elderly patients
      because of concern about prohibitive operative morbidity and mortality. To obtain
      objective data in our practice, we analyzed the results of adrenalectomy for
      patients aged 65 years and older. From 1984 to 1993 there were 85 patients (41
      men, 44 women) with ages ranging from 65 to 84 years (median 69 years) who
      underwent adrenalectomy for Cushing syndrome (n = 19), pheochromocytoma (n = 16),
      adrenocortical carcinoma (n = 7), benign adenoma (n = 26), or primary
      hyperaldosteronism (n = 17) at our institution. Median follow-up was 26 months
      (range 1 month to 9.1 years). A retrospective review with respect to preoperative
      risks and postoperative morbidity and mortality was performed utilizing the
      American Society of Anesthesiologists (ASA) physical status classification and
      the modified Goldman multifactorial cardiac risk scheme. Survival was estimated
      by the Kaplan-Meier methods. Operative mortality was 7% (six patients). No
      patients with pheochromocytoma or primary hyperaldosteronism died during the
      postoperative period. Patients undergoing adrenalectomy for adrenocortical
      carcinoma had a significantly higher operative mortality (43%) (p = 0.006).
      Postoperative complications developed in 19 patients (22%), and there was a
      reoperation rate of 6% (5 patients). Nineteen percent of patients required
      postoperative intensive care admission and had a median stay of 2 days (range, 1
      38 days). Median hospital stay was 7 days (range 3-47 days). Seventy-three
      patients (86%) remained alive at study completion. Two- and five-year survivals
      were 86% and 84%, respectively. Goldman class II or greater was an excellent
      predictor of increased morbidity (p = 0.032) and mortality (p = 0.036). With the
      exception of adrenocortical carcinoma, adrenal surgery for elderly patients can
      be performed with acceptable morbidity and mortality. The Goldman multifactorial
      cardiac risk scheme reliably predicts postoperative outcome in this elderly group
      of patients.

PMID- 8661848
TI  - Uptake and trophic transfer of barium in a terrestrial ecosystem.

PMID- 8661849
TI  - Coal fly ash exposure at agronomic levels does not induce triploidy in maize.

PMID- 8661850
TI  - Development of reference sediment samples for solid phase toxicity screening
      tests.

PMID- 8661851
TI  - Distribution of arsenic and sulphate in the vicinity of Ashanti goldmine at
      Obuasi, Ghana.

PMID- 8661852
TI  - The prediction of soil sorption coefficients of heterocyclic nitrogen compounds
      by octanol/water partition coefficient, water solubility, and by molecular
      connectivity indices.

PMID- 8661853
TI  - Effect of the reduction of petrol lead on blood lead levels of the population of
      Barcelona (Spain).

PMID- 8661854
TI  - Factors affecting soil adherence to skin in hand-press trials.

PMID- 8661855
TI  - Lead contamination in the mallard (Anas platyrhynchos) in Italy.

PMID- 8661856
TI  - Metal accumulation in terrestrial pulmonates at a lead/zinc smelter site in
      Arnoldstein, Austria.

PMID- 8661857
TI  - Comparison of recirculating, static, and elutriate aquatic sediment bioassay
      procedures.

PMID- 8661858
TI  - New algal enzyme bioassay for the rapid assessment of aquatic toxicity.

PMID- 8661859
TI  - Applications of frontier molecular orbital energies in QSAR studies.

PMID- 8661860
TI  - Heavy metals in different fishes from the middle eastern coast of Tunisia.

PMID- 8661861
TI  - Acute effect of organotin compounds to red sea bream and red carp using
      biological parameters.

PMID- 8661862
TI  - Blood plasma levels of sex steroid hormones and vitellogenin in striped bass
      (Morone saxatilis) exposed to 3,3',4,4'-tetrachlorobiphenyl (TCB).

PMID- 8661863
TI  - Effects of tetrachloroguaiacol (TeCG) on the osmoregulation of adult coho salmon
      (Oncorhynchus kisutch).

PMID- 8661864
TI  - Comparative study on the synergistic and individual effects of dimecron and cuman
      L on oxygen uptake and haematological parameters of a freshwater edible fish,
      sarotherodon mossambicus (Peters).

PMID- 8661866
TI  - In vitro photoconversion of gamma-hexachlorocyclohexane in the presence of
      chlorophyll.

PMID- 8661865
TI  - Mutagenicity of organic pollutants and their active components in the Xi River
      water at Shenyang.

PMID- 8661867
TI  - Role of methanogenic and sulfate-reducing bacteria in the reductive
      dechlorination of tetrachloroethylene in mixed culture.

PMID- 8661868
TI  - Effects of mercury on the white rot fungus Phanerochaete chrysosporium.

PMID- 8661869
TI  - Cesium stress and adaptation in Pseudomonas fluorescens.

PMID- 8661870
TI  - Effects on PCBs on liver ultrastructure and monooxygenase activities in Japanese
      quail.

PMID- 8661871
TI  - Acute effects of low doses of zineb and ethylenethiourea on thyroid function in
      the male rat.

PMID- 8661872
TI  - Accumulation and depuration of DDTs in the food chain from Artemia to brook trout
      (Salvelinus fontinalis).

PMID- 8661873
TI  - Levels of mercury in scalp hair of fishermen and their families from Camara de
      Lobos-Madeira (Portugal): a preliminary study.

PMID- 8661874
TI  - Environmental contaminants and cholinesterase activity in the brain of fisher
      (Martes pennanti) harvested in northern Wisconsin.

PMID- 8661875
TI  - Organochlorine pesticide residues in mothers' milk in Uganda.

PMID- 8661876
TI  - Acaricide residue determination in honey.

PMID- 8661877
TI  - Identification of a major human urinary metabolite of alachlor by LC-MS/MS.

PMID- 8661879
TI  - Kinetics and photophysical mechanism of sunlight photolysis of unstable
      resmethrin and phenothrin in aerosols and thin films.

PMID- 8661878
TI  - Bioaccumulation of HCH isomers in different tissues of young and old rats: a
      comparison.

PMID- 8661880
TI  - Detection of genotoxic effects on cells of liver and gills of B. rerio by means
      of single cell gel electrophoresis.

PMID- 8661881
TI  - Evaluation of low-dosage environmental mutagens with a long-term, cultured
      epithelial cell line.

PMID- 8661882
TI  - Protein biomarkers of phytotoxicity in hazard evaluation.

PMID- 8661883
TI  - Effect of abrasion on protective properties of polyester and cotton/polyester
      blend fabrics.

PMID- 8661884
TI  - Effect of temperature on the biodegradation of sodium monofluoroacetate (1080) in
      water and in Elodea canadensis.

PMID- 8661885
TI  - Bacteria associated with disintegrating plastic films under simulated aquatic
      environments.

PMID- 8661886
TI  - Hazard evaluation of soil contaminants with aquatic animals and plant toxicity
      tests.

PMID- 8661887
TI  - Effect of Magnacide(R) H herbicide residuals on water quality within wildlife
      refuges of the Klamath Basin, CA.

PMID- 8661888
TI  - Toxicity of chlorine and other chlorinated compounds to some Australian aquatic
      organisms.

PMID- 8661889
TI  - Effects of thiobencarb on the growth of three species of phytoplankton.

PMID- 8661890
TI  - Effect of barium and nickel on the growth of Anacystis nidulans.

PMID- 8661891
TI  - Respirometric toxicity test: freshwater alga Scenedesmus quadricauda sensitivity
      to organotin compounds.

PMID- 8661892
TI  - Uptake of lead by Lemna gibba L.: influence on specific growth rate and basic
      biochemical changes.

PMID- 8661893
TI  - Concentrations of selected heavy metals in benthic diatoms and sediment in the
      Westerschelde estuary.

PMID- 8661894
TI  - Effect of aldrin on carbohydrate, protein, and ionic metabolism of a freshwater
      catfish, Heteropneustes fossilis.

PMID- 8661895
TI  - Induction of micronuclei in peripheral erythrocytes of Misgurnus anguillicaudatus
      by polychlorinated biphenyls.

PMID- 8661896
TI  - Effect of organic four solvents on natural phytoplankton assemblages:
      consequences for ecotoxicological experiments on herbicides.

PMID- 8661897
TI  - Toxic effects of organic solvents on the growth of Chlorella vulgaris and
      Selenastrum capricornutum.

PMID- 8661898
TI  - Sensitivity of selected zooplankton exposed to phosphamidon, fenitrothion, and
      fenthion.

PMID- 8661899
TI  - Cytotoxicity of phenolic compounds on Dicentrarchus labrax erythrocytes.

PMID- 8661900
TI  - Elimination of cadmium from Cd-contaminated Tilapia zilli in media containing
      EDTA and freshwater: changes in protein levels.

PMID- 8661901
TI  - Toxicological and kinetic study of musk xylene in rainbow trout, Oncorhynchus
      mykiss.

PMID- 8661902
TI  - Alterations in protein metabolism of muscle tissue in the fish Clarias batrachus
      (Linn) by commercial grade dimethoate.

PMID- 8661903
TI  - Comparative acute toxicity of two herbicides, paraquat and glyphosate, to Daphnia
      magna and D. spinulata.

PMID- 8661904
TI  - Toxic emission factor determination using median lethal time data.

PMID- 8661905
TI  - Quantitative structure-activity relationships of organic acids and bases.

PMID- 8661906
TI  - Organochlorine pesticides and triazines in the drinking water of Athens.

PMID- 8661907
TI  - Effects of copper-chrome-arsenate (CCA) components on PCP degradation by
      Arthrobacter strain ATCC 33790.

PMID- 8661908
TI  - Regulatory application of ELISA: compliance monitoring of bromacil in soil.

PMID- 8661909
TI  - Validation of an immunoassay for methomyl in water and dislodgeable residues on
      grape leaves.

PMID- 8661910
TI  - Comparison of techniques for monitoring water-borne polycyclic mutagens:
      efficiency of blue rayon, Sep-Pak C18, and a biota, Corbicula, in concentrating
      benzo(a)pyrene in a model water system.

PMID- 8661911
TI  - Occurrence of dicofol in the San Joaquin River, California.

PMID- 8661912
TI  - Long term sorption studies of benzene and toluene onto soils.

PMID- 8661913
TI  - Growth of corn (Zea mays) and sunflower (Helianthus annuus) plants is affected by
      water and sludge from a sewage treatment plant.

PMID- 8661914
TI  - Growth responses of Typha latifolia and Scirpus acutus to atrazine contamination.

PMID- 8661915
TI  - Methylmercury in hair of fishermen from Turkish coasts.

PMID- 8661916
TI  - Human hair lead and copper levels in three occupationally unexposed population
      groups in Calcutta.

PMID- 8661917
TI  - Embryo- and fetotoxicity of chromium in pregestationally exposed mice.

PMID- 8661918
TI  - Dimethoate induced lipid peroxidation and inhibition of type-I iodothyronine 5'
      monodeiodinase activity in young cockerel.

PMID- 8661921
TI  - Influence of growth conditions on fatty acid composition of a polyunsaturated
      fatty-acid-producing Vibrio species
AB  - The influence on fatty acid composition of growth medium composition and phase of
      growth during batch culture and of dilution rate and growth temperature during
      continuous culture was studied in the eicosapentaenoic-acid (20:5 n-3)-producing
      Vibrio CCUG 35308. In glucose-mineral medium, even-numbered normal fatty acyl
      residues, primarily 16:0, 16:1, 18:1, and 20:5, strongly dominated (ca. 90%), and
      the fatty acid profile remained practically unchanged throughout a batch-growth
      cycle. In nutrient broth, the contribution by "uncommon" fatty acids, mainly i
      13:0, 15:0, i-15:0, and 17:1 was generally higher, and increased from 15.4% of
      total fatty acids in early exponential growth phase to 33.2% in the stationary
      phase. Reduction of the dilution rate in a chemostat from 0.27 to 0.065 h-1 also
      led to an almost threefold increase in the proportion of odd-numbered residues at
      the expense of the even-numbered normal ones. Contrary to this plasticity in the
      overall fatty acid profile influenced by variations in nutrient composition and
      availability, the level of eicosapentaenoic acid seemed exclusively dictated by
      growth temperature. The synthesis of this polyunsaturated fatty acid may be a key
      regulatory process in maintaining membrane fluidity.

PMID- 8661920
TI  - The Bradyrhizobium japonicum fixGHIS genes are required for the formation of the
      high-affinity cbb3-type cytochrome oxidase.
AB  - We report structural and functional analyses of the Bradyrhizobium japonicum
      fixGHIS genes, which map immediately downstream of the fixNOQP operon for the
      symbiotically essential cbb3-type heme-copper oxidase complex. Expression of
      fixGHIS, like that of fixNOQP, is strongly induced in cells grown
      microaerobically or anaerobically. A fixGHI deletion led to the same prominent
      phenotypes as those known from a fixNOQP deletion: defective symbiotic nitrogen
      fixation (Fix-) and decreased cytochrome oxidase activity in cells grown under
      oxygen deprivation. Only traces, if any, of cytochrome cbb3 subunits were present
      in membranes isolated from the delta fixGHI strain, as revealed by Western blot
      analysis with subunit-specific antibodies. This effect was not due to lack of
      fixNOQP transcription. The results suggested a critical involvement of the
      fixGHIS gene products in the assembly and/or stability of the cbb3-type heme
      copper oxidase. On the basis of sequence similarities between the FixI protein
      and a Cu-transporting P-type ATPase (CopA) of Enterococcus hirae, and between
      FixG and a membrane-bound oxidoreductase (RdxA) of Rhodobacter sphaeroides, we
      postulate that a membrane-bound FixGHIS complex might play a role in uptake and
      metabolism of copper required for the cbb3-type heme-copper oxidase.

PMID- 8661919
TI  - Purification and characterization of the hydrogenase from Thiobacillus
      ferrooxidans.
AB  - Hydrogenase of Thiobacillus ferrooxidans ATCC 19859 was purified from cells grown
      lithoautotrophically with 80% hydrogen, 8.6% carbon dioxide, and 11.4% air.
      Hydrogenase was located in the 140,000 x g supernatant in cell-free extracts. The
      enzyme was purified 7.3-fold after chromatography on Procion Red and Q-Sepharose
      with a yield of 19%, resulting in a 85% pure preparation with a specific activity
      of 6.0 U (mg protein)-1. With native PAGE, a mol. mass of 100 and 200 kDa was
      determined. With SDS-PAGE, two subunits of 64 (HoxG) and of 34 kDa (HoxK) were
      observed. Hydrogenase reacted with methylene blue and other artificial electron
      acceptors, but not with NAD. The optimum of enzyme activity was at pH 9 and at 49
      degrees C. Hydrogenase contained 0.72 mol nickel and 6.02 mol iron per mol
      enzyme. The relationship of the T. ferrooxidans hydrogenase to other proteins was
      examined. A 9.5-kb EcoRI fragment of T. ferrooxidans ATCC 19859 hybridized with a
      2.2-kb XhoI fragment from Alcaligenes eutrophus encoding the membrane-bound
      hydrogenase. Antibodies against this enzyme did not react with the T.
      ferrooxidans hydrogenase in Western blot analysis. The N-terminal amino acid
      sequence (40 amino acids) of HoxK was 46% identical to that of the hydrogen
      sensor HupU of Bradyrhizobium japonicum and 39% identical to that of the HupS
      subunit of the Desulfovibrio baculatus hydrogenase. The N-terminal sequence of 20
      amino acids of HoxG of T. ferrooxidans was 83.3% identical to that of the 60-kDa
      subunit. HupL, of the hydrogenase of Anabaena sp. Sequences of ten internal
      peptides of HoxG were 50-100% identical to the respective sequences of HupL of
      the Anabaena sp. hydrogenase.

PMID- 8661922
TI  - Ornithine decarboxylase in Paracoccidioides brasiliensis.
AB  - Ornithine decarboxylase in Paracoccidioides brasiliensis, a dimorphic human
      pathogenic fungus, was more active at 37 degrees C in the yeast phase and at 30
      degrees C in the mycelial phase. In contrast to other fungal systems, yeast
      growth and mycelium-to-yeast transition in P. brasiliensis were accompanied by a
      high activity of ornithine decarboxylase at the onset of the budding process, the
      activity of which was inhibited by 1,4-diamino-2-butanone. The activity of
      ornithine decarboxylase remained at a basal level during vegetative growth of
      both the mycelial phase and the late stage of yeast phase, and also through the
      yeast-to-mycelium transition.

PMID- 8661923
TI  - Defense against lethal treatments and de novo protein synthesis induced by NaCl
      in Enterococcus faecalis ATCC 19433.
AB  - Enterococcus faecalis was strongly resistant to high osmotic pressure in complex
      medium; however, when it was subjected to a moderate osmotic stress [6.5% (w/v)
      NaCl or 52% (w/v) sucrose] for 2 h, it showed cross-protection against ethanol
      (22%), detergents stresses [bile sales (0.3%) and SDS (0.017%)], hydrogen
      peroxide challenge (45 mM), and to a minor extent against lethal temperature (62
      degrees C). In response to salt stress [6.5% (w/v) NaCl], E. faecalis induced a
      large number of stress proteins. In addition, NaCl strongly induced the synthesis
      of many proteins more than tenfold. Although the acquired thermotolerance was
      inhibited markedly by chloramphenicol, the other NaCl-induced cross-tolerances
      seemed not to be correlated with de novo protein synthesis. The relationship
      between the stress protein synthesis and the induction of different types of
      cross-protection is discussed.

PMID- 8661924
TI  - The gluEMP operon from Zymomonas mobilis encodes a high-affinity glutamate
      carrier with similarity to binding-protein-dependent transport systems.
AB  - The nucleotide sequence downstream of the grp gene, encoding the glutamate uptake
      regulatory protein of Zymomonas mobilis, was determined. Three clustered genes
      (gluE, gluM, and gluP) close to ghe grp gene, but on the opposite strand, were
      identified. These genes encode a high-affinity transport system for glutamate and
      aspartate. The gluP gene product is a polypeptide of 25.4 kDa and contains
      segments with significant similarity to the ATP-binding proteins of binding
      protein-dependent transport systems. The GluM polypeptide (22.9 kDa) is highly
      hydrophobic and consists of four potential membrane-spanning domains. The
      hydrophilic gluE gene product, with a molecular mass of 22.1 kDa, contains a
      region with sequence similarity to some of the periplasmic binding proteins and a
      sequence motif of a signal peptide for periplasmic localization. The transport
      system could not be functionally expressed in Z. mobilis. However, when
      heterologously expressed in Escherichia coli, it catalyzed uptake of glutamate,
      which was characterized kinetically. Our results suggest that the glutamate
      transport system encoded by the gluEMP operon is repressed in Z. mobilis by the
      regulatory protein Grp.

PMID- 8661926
TI  - Thermocryptoxanthins: novel intermediates in the carotenoid biosynthetic pathway
      of Thermus thermophilus
AB  - Various thermozeaxanthins are the end products of the carotenoid biosynthetic
      pathway of the thermophilic eubacterium Thermus thermophilus. These compounds are
      zeaxanthin glucoside esters. Carotenoid analysis and inhibitory studies led to
      the identification of most of the intermediates of the pathway: beta-carotene,
      beta-cryptoxanthin, zeaxanthin, and several new carotenoids. The intermediates,
      identified by various spectroscopic methods as beta-cryptoxanthin glucoside
      esters carrying fatty acid moieties of different chain lengths, were designated
      as thermocryptoxanthins. The use of the inhibitors diphenylamine and 2-(4
      chlorophenylthio)-triethylamine-HCl resulted in the accumulation of the
      intermediates phytoene, lycopene, and gamma-carotene derivatives, which normally
      are present in amounts below the detection limit. The levels of non-esterified
      glycosides were extremely low. The results presented were used to establish the
      complete carotenoid biosynthetic pathway of T. thermophilus.

PMID- 8661925
TI  - Analysis of the hydA locus of Escherichia coli: two genes (hydN and hypF)
      involved in formate and hydrogen metabolism.
AB  - The hydA locus of Escherichia coli is known to encode some function necessary for
      formation of hydrogenase activity. The locus contains two open reading frames,
      hydN and hypF. In this communication, an analysis of the regulation of these two
      genes and of the phenotype of respective mutants is presented, Both genes were
      expressed in a T7 promoter/polymerase system, yielding a 19-kDa (HydN) and a 81
      kDa (HypF) protein. In-frame deletions were constructed for each gene and
      transferred to the chromosome by homologous recombination. The mutation in hydN
      led to a decrease of the activity of formate dehydrogenase H (FDH-H) in crude
      extracts, but the activity and maturation of hydrogenases were nearly unaffected.
      In contrast, a deletion in hypF resulted in the loss of hydrogenase activity and
      in the synthesis of the large subunits of the hydrogenase isoenzymes 1, 2 and 3
      in the inactive precursor form. For hydrogenase 3, it was shown that this is due
      to a lack of incorporation of nickel into the large subunit. hydN and hypF are
      organised in an operon that is a member of the formate regulon. Transcription was
      shown to be dependent on sigma 54 and FhlA, and an FhlA-binding site upstream of
      hydN was identified. The sigma 54-dependent promoter shows a rare deviation from
      the consensus at positions -24/-12, namely GG/GA instead of GG/GC. In conclusion,
      the product of hydN appears to have some role in electron flow from or to FDH-H,
      and the product of hypF is connected with maturation of all three hydrogenases of
      E. coli.

PMID- 8661927
TI  - Malate dehydrogenase from the green gliding bacterium Chloroflexus aurantiacus is
      phylogenetically related to lactic dehydrogenases.
AB  - The gene encoding malate dehydrogenase (MDH) from Chloroflexus aurantiacus was
      cloned, sequenced, and analyzed. The mdh gene corresponded to a polypeptide of
      309 amino acids with a molecular mass of 32,717 Da. The primary structure and the
      coenzyme-binding domain showed a high degree of similarity to lactate
      dehydrogenase (LDH), whereas the conserved amino acids that participate in
      substrate binding were those typical of MDHs. Using PCR techniques, the mdh gene
      was cloned in the expression vector pET 11a, and large amounts of active C.
      aurantiacus MDH were produced in Escherichia coli after induction with isopropyl
      beta-D-thiogalactoside. The expressed enzyme thus obtained was purified and
      retained full activity at 55 degrees C. High levels of expression of mdh were
      also observed when the gene and its flanking sequences were cloned into pUC18/19,
      indicating that the putative sigma 70 promoter sequences found upstream of the C.
      aurantiacus mdh functioned in E. coli. When these sequences were deleted, the
      expression in E. coli was reduced dramatically.

PMID- 8661928
TI  - Sensitivity of selected members of the family Halobacteriaceae to quinolone
      antimicrobial compounds.
AB  - Many members of the Halobacteriaceae are inhibited by quinolone compounds, which
      inhibit type II DNA topoisomerase. Ciprofloxacin was the most potent inhibitor,
      followed by ofloxacin and norfloxacin. Ciprofloxacin concentration between 25 and
      60 micrograms/ml caused 50% inhibition of the growth of most Haloferax and
      Haloarcula species. Halobacterium species were less sensitive, At sublethal
      concentrations, formation of elongated and/or swollen cells was observed in many
      species. The alkaliphilic Natronobacterium pharaonis was very sensitive (50%
      inhibition by ciprofloxacin, ofloxacin, and norfloxacin at concentrations between
      4 and 15 micrograms/ml). The resistance of many members of the Halobacteriaceae
      to high concentrations of quinolone compounds may in part be due to the high
      magnesium concentrations present in the growth media. Haloferax volcanii was
      sensitive to 40 micrograms/ml ciprofloxacin when grown at suboptimal magnesium
      concentrations (0.1 M), but was hardly affected by 100 micrograms/ml of the
      inhibitor when grown in the presence of 0.5-0.75 M MgCl2. It is suggested that
      the putative archaeal type II DNA topoisomerase has properties similar to those
      of the enzyme from Bacteria, although its sensitivity to quinolone antimicrobial
      compounds may be lower.

PMID- 8661929
TI  - Tetracyclines: antibiotic action, uptake, and resistance mechanisms.
AB  - Tetracyclines probably penetrate bacterial cells by passive diffusion and inhibit
      bacterial growth by interfering with protein synthesis or by destroying the
      membrane. A growing number of various bacterial species acquire resistance to the
      bacteriostatic activity of tetracycline. The two widespread mechanisms of
      bacterial resistance do not destroy tetracycline: one is mediated by efflux
      pumps, the other involves an EF-G-like protein that confers ribosome protection.
      Oxidative destruction of tetracycline has been found in a few species. Several
      efflux transporters, including multidrug-resistance pumps and tetracycline
      specific exporters, confer bacterial resistance against tetracycline. Single
      amino acids of these carrier proteins important for tetracycline transport and
      substrate specificity have been identified, allowing the mechanism of
      tetracycline transport to begin to emerge.

PMID- 8661930
TI  - Geovibrio ferrireducens, a phylogenetically distinct dissimilatory Fe(III)
      reducing bacterium.
AB  - A new, phylogenetically distinct, dissimilatory, Fe(III)-reducing bacterium was
      isolated from surface sediment of a hydrocarbon-contaminated ditch. The isolate,
      designated strain PAL-1, was an obligately anaerobic, non-fermentative, motile,
      gram-negative vibrio. PAL-1 grew in a defined medium with acetate as electron
      donor and ferric pyrophosphate, ferric oxyhydroxide, ferric citrate, Co(III)
      EDTA, or elemental sulfur as sole electron acceptor. PAL-1 also used proline,
      hydrogen, lactate, propionate, succinate, fumarate, pyruvate, or yeast extract as
      electron donors for Fe(III) reduction. It is the first bacterium known to couple
      the oxidation of an amino acid to Fe(III) reduction. PAl-1 did not reduce oxygen,
      Mn(IV), U(VI), Cr(VI), nitrate, sulfate, sulfite, or thiosulfate with acetate as
      the electron donor. Cell suspensions of PAL-1 exhibited dithionite-reduced minus
      air-oxidized difference spectra that were characteristic of c-type cytochromes.
      Analysis of the 16S rRNA gene sequence of PAL-1 showed that the strain is not
      related to any of the described metal-reducing bacteria in the Proteobacteria
      and, together with Flexistipes sinusarabici, forms a separate line of descent
      within the Bacteria. Phenotypically and phylogenetically, strain PAl-1 differs
      from all other described bacteria, and represents the type strain of a new genus
      and species, Geovibrio ferrireducens.

PMID- 8661931
TI  - Formation of intracytoplasmic lipid inclusions by Rhodococcus opacus strain
      PD630.
AB  - An oleaginous hydrocarbon-degrading Rhodococcus opacus strain (PD630) was
      isolated from a soil sample. The cells were able to grow on a variety of
      substrates and to produce large amounts of three different types of intracellular
      inclusions during growth on alkanes, phenylalkanes, or non-hydrocarbon
      substrates. Electron microscopy revealed large numbers of electron-transparent
      inclusions with a sphere-like structure. In addition, electron-dense inclusions
      representing polyphosphate and electron-transparent inclusions with an elongated
      disc-shaped morphology occurred in small amounts. The electron-transparent
      inclusions of alkane- or gluconate-grown cells were composed of neutral lipids
      (98%, w/w), phospholipids (1.2%, w/w), and protein (0.8%, w/w). The major
      component of the cellular inclusions was triacylglycerols; minor amounts of
      diacylglycerols and probably also some free fatty acids were also present. Free
      fatty acids and/or fatty acids in acylglycerols in cells of R. opacus amounted up
      to 76 or 87% of the cellular dry weight in gluconate- or olive-oil-grown cells,
      respectively. The fatty acid composition of the inclusions depended on the
      substrate used for cultivation. In cells cultivated on n-alkanes, the composition
      of the fatty acids was related to the substrate, and intermediates of the beta
      oxidation pathway, such as hexadecanoic or pentadecanoic acid, were among the
      acylglycerols. Hexadecanoic acid was also the major fatty acid (up 36% of total
      fatty acids) occurring in the lipid inclusions of gluconate-grown cells. This
      indicated that strain PD630 utilized beta-oxidation and de novo fatty acid
      biosynthesis for the synthesis of storage lipids. Inclusions isolated from
      phenyldecane-grown cells contained mainly the non-modified substrate and
      phenylalkanoic acids derived from the hydrocarbon oxidation, such as
      phenyldecanoic acid, phenyloctanoic acid, and phenylhexanoic acid, and
      approximately 5% (w/w) of diacylglycerols. The lipid inclusions seemed to have
      definite structures, probably with membranes at their surfaces, which allow them
      to maintain their shape, and with some associated proteins, probably involved in
      the inclusion formation.

PMID- 8661932
TI  - C3-carboxylation as an anaplerotic reaction in phosphoenolpyruvate carboxylase
      deficient Corynebacterium glutamicum.
AB  - Phosphoenolpyruvate carboxylase (PEPCx) has recently been found to be dispensable
      as an anaplerotic enzyme for growth and lysine production of Corynebacterium
      glutamicum. To clarify the role of the glyoxylate cycle as a possible alternative
      anaplerotic sequence, defined PEPCx- and isocitrate-lyase (ICL)-negative double
      mutants of C. glutamicum wild-type and of the l-lysine-producing strain MH20-22B
      were constructed by disruption of the respective genes. Analysis of these mutants
      revealed that the growth on glucose and the lysine productivity were identical to
      that of the parental strains. These results show that PEPCx and the glyoxylate
      cycle are not essential for growth of C. glutamicum on glucose and for lysine
      production and prove the presence of another anaplerotic reaction in this
      organism. To study the anaplerotic pathways in C. glutamicum further, H13CO3-
      labeling experiments were performed with cells of the wild-type and a PEPCx
      negative strain growing on glucose. Proton nuclear magnetic resonance analysis of
      threonine isolated from cell protein of both strains revealed the same labeling
      pattern: about 37% 13C enrichment in C-4 and 3.5% 13C enrichment in C-1. Since
      the carbon backbone of threonine corresponds to that of oxaloacetate, the label
      in C-4 of threonine positively identifies the anaplerotic pathway as a C3
      carboxylation reaction that also takes place in the absence of PEPCx.

PMID- 8661933
TI  - Complete assimilation of cysteine by a newly isolated non-sulfur purple bacterium
      resembling Rhodovulum sulfidophilum (Rhodobacter sulfidophilus).
AB  - A rod-shaped, motile, phototrophic bacterium, strain SiCys, was enriched and
      isolated from a marine microbial mat, with cysteine as sole substrate. During
      phototrophic anaerobic growth with cysteine, sulfide was produced as an
      intermediate, which was subsequently oxidized to sulfate. The molar growth yield
      with cysteine was 103 g mol-1, in accordance with complete assimilation of
      electrons from the carbon and the sulfur moiety into cell material. Growth yields
      with alanine and serine were proportionally lower. Thiosulfate, sulfide,
      hydrogen, and several organic compounds were used as electron donors in the
      light, whereas cystine, sulfite, or elemental sulfur did not support phototrophic
      anaerobic growth. Aerobic growth in the dark was possible with fructose as
      substrate. Cultures of strain SiCys were yellowish-brown in color and contained
      bacteriochlorophyll a, spheroidene, spheroidenone, and OH-spheroidene as major
      photosynthetic pigments. Taking the morphology, photosynthetic pigments, aerobic
      growth in the dark, and utilization of sulfide for phototrophic growth into
      account, strain SiCys was assigned to the genus Rhodovulum (formerly Rhodobacter)
      and tentatively classified as a strain of R. sulfidophilum. In cell-free extracts
      in the presence of pyridoxal phosphate, cysteine was converted to pyruvate and
      sulfide, which is characteristic for cysteine desulfhydrase activity (l
      cystathionine gamma-lyase, EC 4.4. 1.1).

PMID- 8661934
TI  - Anaerobic metabolism of 2-hydroxybenzoic acid (salicylic acid) by a denitrifying
      bacterium.
AB  - The anaerobic metabolism of 2-hydroxybenzoic acid (salicylic acid) was studied in
      a denitrifying bacterium. Cells grown with 2-hydroxybenzoate were simultaneously
      adapted to degrade benzoate. Extract of these cells formed benzoate or benzoyl
      CoA when incubated under reducing conditions with salicylate, MgATP, and coenzyme
      A, suggesting a degradation of 2-hydroxybenzoate via benzoate or benzoyl-CoA.
      This suggestion was supported by enzyme activity measurements. In extracts of 2
      hydroxybenzoate-grown cells, the following enzyme activities were detected: two
      CoA ligases, one specific for 2-hydroxybenzoate, the other for benzoate, and two
      different enzyme activities catalyzing the reductive transformation of 2
      hydroxybenzoyl-CoA. These findings suggest a degradation of salicylic acid by two
      new enzymes, 2-hydroxybenzoate-CoA ligase (AMP-forming) and 2-hydroxybenzoyl-CoA
      reductase (dehydroxylating), catalyzing (1) 2-hydroxybenzoate + MgATP + CoASH -->
      2-hydroxybenzoyl-CoA + MgAMP + PPi (2) 2-hydroxybenzoyl-CoA + 2[H] --> benzoyl
      CoA + H2O Benzoyl-CoA was dearomatized by reduction of the ring. This represents
      another case in which benzoyl-CoA is a central intermediate in anaerobic aromatic
      metabolism.

PMID- 8661935
TI  - An intracellular aminopeptidase from Streptomyces rimosus that prefers basic
      amino acids.
AB  - An aminopeptidase from the mycelia of Streptomyces rimosus was isolated in an
      electrophoretically homogeneous form. It was shown to be a monomeric, acidic
      protein (pI = 4.4, mol. wt. approx. 83,000), with optimal activity at pH 7.1-7.8
      and at 35-41 degrees C. The enzyme was fully inhibited by 0.1 mM EDTA or 1 mM o
      phenanthroline; the activity was restored upon addition of 0.05 mM Co2+, Zn2+, or
      Ni2+. Amastatin, bestatin, and puromycin also inhibited the enzyme. The
      aminopeptidase hydrolyzed amino-acid-2-naphthylamides and various di- to
      heptapeptides. The highest catalytic coefficients (23 and 19 microM-1 s-1) were
      obtained with Arg- and Lys-2-naphthylamide, followed by Leu-, Phe- and Met
      derivatives with one order of magnitude lower catalytic coefficients. Basic or
      bulky hydrophobic amino acids at the P1 and/or P1' position of peptide substrates
      were preferred. Acidic amino acids and proline were not accepted. The affinity of
      the enzyme increased with the length of peptide. According to these properties,
      S. rimosus intracellular aminopeptidase is distinct from the extracellular
      leucine aminopeptidase of the same organism and can be classified as an Arg(Lys)
      preferring metalloaminopeptidase.

PMID- 8661936
TI  - Identification of activities that catalyze the cis-trans isomerization of the
      double bond of a mono-unsaturated fatty acid in Pseudomonas sp. strain E-3.
AB  - A cell-free extract of Pseudomonas sp. strain E-3 catalyzed the conversion of 9
      cis-hexadecenoic acid [16:1(9c)] to 9-trans-hexadecenoic acid [16:1(9t)] in the
      free acid form and when 16:1(9c) was esterified to phosphatidylethanolamine (PE).
      The cytosolic fraction catalyzed the isomerizations of free 16:1(9c) by itself
      and of 16:1(9c) esterified to PE in the presence of the membrane fraction. Tracer
      experiments using [2,2-2H2]16:1(9c) demonstrated that the isomerization of free
      16:1(9c) occurred independently of the isomerization of 16:1(9c) esterified to
      PE, indicating that this bacterium has two types of activities that catalyze the
      cis-trans isomerization of the double bond of a mono-unsaturated fatty acid.

PMID- 8661937
TI  - Hydrogen oxidation by membranes from autotrophically grown Alcaligenes eutrophus
      H16: role of the cyanide-resistant pathway in energy transduction.
AB  - Eighty percent of the ATP and proton electrochemical gradient (-ZDeltapH) formed
      during H2 oxidation in membranes from autotrophically grown exponential-phase
      cells of Alcaligenes eutrophus H16 was derived from a redox pathway that includes
      the membrane-bound hydrogenase complex and the cyanide-resistant (bo-type)
      oxidase. The H2/ubiquinone-1 oxidoreductase activity was coupled to energy
      transduction and was fully inhibited by the quinone along 2-n-hepthyl-4
      hydroxyquinoline-N-oxide. We conclude that the cytochrome-c-containing pathway in
      exponential-phase A. eutrophus H16 cells plays a minor role in energy
      conservation.

PMID- 8661938
TI  - Only C-2 specific glucose oxidase activity is expressed in ligninolytic cultures
      of the white rot fungus Phanerochaete chrysosporium.
AB  - Two d-glucose-oxidizing enzymes, glucose 1-oxidase (G1O) and pyranose 2-oxidase
      (P2O, glucose 2-oxidase), have been proposed to play an important role in the
      ligninolytic system of the white rot fungus Phanerochaete chrysosporium by
      producing hydrogen peroxide. The possible simultaneous expression and metabolic
      cooperation of the two oxidases was studied in strains ME-446 (reported as G1O
      positive) and K-3 (P2O positive) grown in liquid media and under near natural
      conditions on birch wood blocks. The presence of G1O and P2O in extracts from
      mycelia and decayed wood was determined by chromatographic, electrophoretic, and
      immunological methods. Attempts to separate these enzymes and to detect G1O and
      its reaction product, d-glucono-1,5-lactone, failed. Evidence was obtained only
      for P2O expression in both strains. Accordingly, P2O, rather than G1O, represents
      a major source of sugar-derived H2O2 under the culture conditions used.

PMID- 8661939
TI  - Conversion of energy in halobacteria: ATP synthesis and phototaxis
AB  - Halobacteria are aerobic chemo-organotroph archaea that grow optimally between pH
      8 and 9 using a wide range of carbon sources. These archaea have developed
      alternative processes of energy provision for conditions of high cell densities
      and the reduced solubility of molecular oxygen in concentrated brines. The
      halobacteria can switch to anaerobic metabolism by using an alternative final
      acceptor in the respiratory chain or by fermentation, or alternatively, they can
      employ photophosphorylation. Light energy is converted by several retinal
      containing membrane proteins that, in addition to generating a proton gradient
      across the cell membrane, also make phototaxis possible in order to approach
      optimal light conditions. The structural and functional features of ATP synthesis
      in archaea are discussed, and similarities to F-ATPases (functional aspects) or
      vacuolar ATPases (structural aspects) are presented.

PMID- 8661940
TI  - Morphological, physiological, and molecular characterization of actinomycetes
      isolated from dry soil, rocks, and monument surfaces.
AB  - In an extended study on the biodiversity of rock-dwelling bacteria, the colony
      and cell morphology, physiology, protein patterns, and 16S rDNA sequences of 17
      bacterial strains isolated from different surfaces of rocks, stones, and
      monuments and from various geographical locations were characterized. All except
      one strain, which was found to be a Bacillus, were members of the order
      Actinomycetales. The majority of the strains either were closely related to
      Geodermatophilus obscurus, which was also analyzed in this study, or formed a
      closely related sister taxon. All of these strains were isolated from the surface
      of marble in Namibia and Greece and from limestone from the Negev desert, Israel.
      One strain, G10, of Namibia origin was equidistantly related to Geodermatophilus
      obscurus, Frankia alni, Sporichthya polymorpha, and Acidothermus cellulolyticus.
      Three strains from rock varnish in the Mojave desert, California, were found to
      be highly related to Arthrobacter (formerly Micrococcus) agilis. All clusters
      could be confirmed from results of studies on morphological and physiological
      properties and from banding patterns of whole cell proteins. Based on the results
      of tests, four additional strains were assigned to the lineage defined by strain
      G10.

PMID- 8661941
TI  - Oxidation of nitric oxide by a new heterotrophic Pseudomonas sp.
AB  - A new bacterial strain isolated from soil consumed nitric oxide (NO) under oxic
      conditions by oxidation to nitrate. Phenotypic and phylogenetic characterization
      of the new strain PS88 showed that it represents a previously unknown species of
      the genus Pseudomonas, closely related to Pseudomonas fluorescens and Pseudomonas
      putida. The heterotrophic, obligately aerobic strain PS88 was not able to
      denitrify or nitrify; however, strain PS88 oxidized NO to nitrate. NO was not
      reduced to nitrous oxide (N2O). Nitrogen dioxide (NO2) and nitrite (NO2-) as
      possible intermediates of NO oxidation to nitrate (NO3-) could not be detected.
      NO oxidation was inhibited under anoxic conditions and by high osmolarity, but
      not by nitrite. NO oxidation activity was inhibited by addition of formaldehyde,
      HgCl2, and antimycin, and by autoclaving or disintegrating the cells, indicating
      that the process was enzyme-mediated. However, the mechanism remains unclear. A
      stepwise oxidation at a metalloenzyme and a radical mechanism are discussed. NO
      oxidation in strain PS88 seems to be a detoxification or a co-oxidation
      mechanism, rather than an energy-yielding process.

PMID- 8661942
TI  - Export of the periplasmic NADP-containing glucose-fructose oxidoreductase of
      Zymomonas mobilis.
AB  - Glucose-fructose oxidoreductase (GFOR) of the gram-negative bacterium Zymomonas
      mobilis is a periplasmic enzyme with the tightly bound cofactor NADP. The
      preprotein carries an unusually long N-terminal signal sequence of 52 amino acid
      residues. A sorbitol-negative mutant strain (ACM3963) was found to be deficient
      in GFOR activity and was used for the expression of plasmid-borne copies of the
      wild-type gfo gene or of alleles encoding alterations in the signal sequence of
      the pre-GFOR protein. Z. mobilis cells with the wild-type gfo allele translocated
      pre-GFOR, at least partially, via the Sec pathway since CCCP (carboxylcyanide-m
      chlorophenylhydrazone; uncoupler of proton motive force) or sodium azide
      (inhibitor of SecA) abolished the processing of GFOR. A gfo allele with the
      hydrophobic region of the signal sequence removed (residues 32-46; Delta32-46)
      led to a protein that was no longer processed, but showed full enzymatic activity
      (180 U/mg) and had the cofactor NADP firmly bound. A deletion in the n-region of
      the signal sequence (residues 2-20; Delta2-20) or exchange of the entire GFOR
      signal sequence with the signal sequence of gluconolactonase of Z. mobilis led to
      active and processed GFOR. Strain ACM3963 could not grow in the presence of high
      sugar concentrations (1 M sucrose) unless sorbitol was added. The presence of the
      plasmid-borne gfo wild-type allele or of the Delta2-20 deletion led to the
      restoration of growth on media with 1 M sucrose, whereas the presence of the
      Delta32-46 deletion led to a growth behavior similar to that of strain ACM3963,
      with no sorbitol formation from sucrose.

PMID- 8661943
TI  - Characterisation of a chromosomally encoded catechol 1,2-dioxygenase (E.C.
      1.13.11.1) from Alcaligenes eutrophus CH34.
AB  - Alcaligenes eutrophus CH34 used benzoate as a sole source of carbon and energy,
      degrading it through the 3-oxoadipate pathway. All the enzymes required for this
      degradation were shown to be encoded by chromosomal genes. Catechol 1,2
      dioxygenase activity was induced by benzoate, catechol, 4-chlorocatechol, and
      muconate. The enzyme is most likely a homodimer, with an apparent molecular
      weight of 76,000 +/- 500. According to several criteria, its properties are
      intermediate between those of catechol 1,2-dioxygenases (CatA) and chlorocatechol
      1,2-dioxygenases (ClcA). The determined Km for catechol is the lowest among known
      catechol and chlorocatechol dioxygenases. Similar Km values were found for para
      substituted catechols, although the catalytic constants were much lower. The
      catechol 1,2-dioxygenase from strain CH34 is unique in its property to transform
      tetrachlorocatechol; however, excess substrate led to a marked reversible
      inhibition. Some meta- and multi-substituted catechols behaved similarly. The
      determined Km (or Ki) values for para- or meta-substituted catechols suggest that
      the presence of an electron-withdrawing substituent at one of these positions
      results in a higher affinity of the enzyme for the ligand. Results of studies of
      recognition by the enzyme of various nonmetabolised aromatic compounds are also
      discussed.

PMID- 8661944
TI  - Extracellular iron reductase activity produced by Listeria monocytogenes.
AB  - Little is known about how pathogenic microorganisms that do not produce low
      molecular-weight iron-chelating agents, termed siderophores, acquire iron from
      their environment. We have identified an extracellular enzyme produced by
      Listeria monocytogenes that can mobilize iron from a variety of iron-chelate
      complexes via reduction of the metal. The iron reductase requires Mg2+, flavin
      mononucleotide (FMN), and reduced nicotinamide adenine dinucleotide (NADH) for
      activity. Saturation kinetics were found when initial velocity studies of iron
      reduction were carried out as a function of variable FMN concentrations in the
      presence of 100 microM NADH and 10 mM Mg2+. Hyperbolic kinetics were also found
      when these studies were repeated as a function of variable NADH concentrations
      along with 20 microM FMN and 10 mM Mg2+. This process of extracellular reduction,
      in all likelihood, could be involved in the mobilization of iron from soils and
      aqueous environments and from host tissues in pathogenic processes. This is the
      first report of the extracellular enzymic reduction of iron by microorganisms.

PMID- 8661945
TI  - Identification of two classes of transcriptional regulator genes in the
      cyanobacterium Synechococcus sp. strain PCC 7942.
AB  - We designed a strategy to isolate and characterize response regulator genes from
      the cyanobacterium Synechococcus sp. strain PCC 7942 based on the premise that
      cyanobacterial response regulators would bear strong similarity to their
      counterparts from other eubacteria. Two response regulator genes, srrA and srrB,
      were isolated from Synechococcus and found to encode proteins similar to the OmpR
      subclass of response regulators. Disruption of either gene by insertional
      mutagenesis did not produce an obvious phenotype and did not affect the
      accumulation of psbAII mRNA under high-light conditions, indicating that these
      gene products are not involved in mediating the well characterized standard- to
      high-light transition response of photosystem II genes in this cyanobacterium.
      Analysis of the chromosomal region adjacent to srrA revealed the presence of
      another presumptive transcriptional activator gene. This gene, named lrrA,
      belongs to the lysR family. Attempts to disrupt lrrA or an adjacent ORF (orfG)
      were not successful, suggesting that these genes are important for the growth of
      Synechococcus.

PMID- 8661946
TI  - Culturability and survival of an extreme thermophile isolated from deep-sea
      hydrothermal vents
AB  - The culturability of a strictly anaerobic, extremely thermophilic archaeon,
      Thermococcus peptonophilus (optimal growth temperature: 85&deg; C), was studied
      during survival stages at various temperatures (98, 85, 70, and 4&deg; C). Total
      cell number (determined by DAPI staining), active cells (rhodamine-stained
      cells), and culturable cells (using most-probable-number) were counted over time.
      The number of culturable cells decreased under each condition tested. The total
      number of cells significantly decreased only at temperatures close to the maximum
      for growth (98&deg; C); at this temperature, the cells spontaneously lysed. Our
      results suggested that survival at 4&deg; C in oxygenated waters might be a
      mechanism for the dispersion of extreme thermophiles in the ocean. In addition,
      we proved the existence of T. peptonophilus cells in several physiological
      states: culturable cells, active non-culturable cells, inactive non-culturable
      cells, and dead cells. Cell death was caused by cellular lysis.

PMID- 8661947
TI  - Major differences between the rrnA operons of two strains of Agrobacterium vitis.
AB  - The sequence of the rrnA operon and its flanking regions was determined for the
      Agrobacterium vitis type strain NCPPB3554. Compared to the earlier obtained rrnA
      sequence of A. vitis strain S4, several important differences were noted: the
      sequences diverged at the 5'-flanking region, within the 16S-23S intergenic
      region, and within the 23S rRNA sequence. The B8 stem-loop structure at the 5'
      end of the 23S rRNA of strain NCPPB3554 was 142 nt shorter than that of strain
      S4. These findings have important consequences for the use of ribosomal RNA gene
      sequences in phylogenetic comparisons.

PMID- 8661949
TI  - Calcium intake, calcium absorption, and osteoporosis.

PMID- 8661948
TI  - Consensus of an international panel on the clinical utility of bone mass
      measurements in the detection of low bone mass in the adult population.
AB  - Low bone mass, in the asymptomatic patient, predicts future fracture risk as well
      as high cholesterol or high blood pressure predicts the risk of heart disease or
      stroke. In patients without fractures, osteoporosis can be diagnosed based on the
      extent of reduction in bone mass below mean peak bone mass of healthy young
      individuals. As bone mass decreases, fracture risk increases exponentially.
      Prevention of the first fracture is a clinical goal. Clinical situations in which
      an assessment of bone mass and fracture risk affects therapeutic decisions
      include estrogen deficiency, vertebral abnormalities, radiographic osteopenia,
      asymptomatic primary hyperparathyroidism, and longterm corticosteroid therapy.
      Serial measurements can also be used to monitor the effects of osteoporosis
      treatment in certain situations. The appropriate technique and skeletal site for
      bone mass measurements should be chosen based on the patient's circumstances. A
      clinical interpretation can enhance the value of computer-generated bone mass
      measurement reports and enhance decision making.

PMID- 8661950
TI  - The effect of intranasal salmon calcitonin on postmenopausal bone turnover as
      assessed by biochemical markers: evidence of maximal effect after 8 weeks of
      continuous treatment.
AB  - Although treatment with intranasal salmon calcitonin (sCT) has been shown to
      effectively inhibit postmenopausal bone loss, there is still controversy over
      both timing and the duration of its application. In an open prospective study, we
      therefore assessed the effect of shortterm intranasal sCT on postmenopausal bone
      turnover, employing biochemical markers of bone metabolism. Ten early
      postmenopausal, previously untreated women (1-5 years after menopause) with
      biochemical evidence of increased bone resorption and a low bone mineral density
      at baseline were treated with intranasal sCT (100 IU B.I.D.) for a period of 3
      months. Oral calcium (500 mg/day) was administered simultaneously, and during a
      further 3 month follow-up interval. Treatment with sCT resulted in a pronounced
      suppression of bone resorption markers with a maximum effect reached after 8
      weeks of therapy: as compared to the respective baseline values, mean levels
      decreased by -26.2% +/- 3.4% (P < 0.001) for pyridinoline, -32.7% +/- 3.5% (P <
      0.001) for deoxypyridinoline, -32.7% +/- 3.3% (P < 0.001) for hydroxyproline, and
      -24.1% +/- 8.2% (P < 0.001) for the amino-terminal telopeptide. In contrast,
      changes in bone formation markers of osteocalcin (-14.4% +/- 4.8%, P < 0.05) and
      C-terminal procollagen type I propetide (-7.9% +/- 3.9%, ns) were much less
      pronounced. Unexpectedly, after week 8 of the study all resorption markers showed
      a plateau and a trend to increase, although intranasal sCT was continued for a
      total of 12 weeks. This effect could not be attributed to the formation of anti
      sCT antibodies. After cessation of treatment, both bone formation and resorption
      markers rapidly returned to baseline levels. Bone mineral density of both spine
      and hip showed no significant change during the observation period. Our results
      demonstrate that in postmenopausal women with a high bone turnover, intranasal
      treatment with 200 IU of sCT effectively reduces bone turnover and maintains bone
      mass, the maximum effect being reached after 8 weeks of treatment.

PMID- 8661951
TI  - The effects of brisk walking on markers of bone and calcium metabolism in
      postmenopausal women.
AB  - Weight-bearing exercise has been shown to maintain or increase bone mass in
      younger as well as older individuals but the mechanisms by which mechanical
      loading affects bone metabolism are not known in detail. Twelve postmenopausal
      women participated in a single bout of brisk walking (50% of VO2 max) for 90
      minutes. Calciotropic hormones and markers of type I collagen formation (PICP)
      and degradation (ICTP) were measured before the exercise, and 1, 24, and 72 hours
      following the exercise. Total body bone mineral content (BMC) and density (BMD)
      were measured by dual energy X-ray absorptiometry (DXA). Brisk walking did not
      induce any significant changes in the concentrations of ionized calcium,
      parathyroid hormone (PTH), calcitonin, or osteocalcin. A significant increase of
      PICP was noted 24 and 72 hours (P < 0.01) after exertion and a significant
      decrease in the concentration of serum ICTP at 1 hour (P < 0.05) was followed by
      an increase at 72 hours (P < 0.001). There was no significant difference between
      the increases in the concentrations of PICP and ICTP at 72 hours. Strong inverse
      correlations between the basal levels of PTH and BMD (r = -0.78; P < 0.01) as
      well as between osteocalcin and BMD (r = -0.83; P < 0.01) were noticed. The
      changes in serum levels of bone collagen markers indicate an altered bone
      collagen turnover due to this moderate endurance exercise. The results also
      support the fact that serum levels of PTH as well as those of osteocalcin are
      associated with total body BMD in postmenopausal women.

PMID- 8661952
TI  - Heated oyster shell-seaweed calcium (AAA Ca) on osteoporosis.
AB  - A randomized, prospective, double-blind test was carried out to compare the
      effects of heated oyster shell-seaweed calcium (AAA Ca), calcium carbonate, and
      placebo in 58 elderly, hospitalized women with the mean age of 80 divided into
      three groups. Group A received 900 mg/day Ca as AAA Ca, Group B 900 mg/day Ca as
      CaCO3, and Group C placebo besides regular hospital diet containing approximately
      600 mg Ca/day for 24 months. From the 25th to the 30th month, all groups were
      given AAA Ca. Lumbar spine and radial bone mineral density (BMD) were measured at
      3-month intervals. Urinary Ca/Cr and serum alkaline phosphatase, intact and
      midportion serum parathyroid hormone (PTH), and calcitonin were also measured at
      intervals. From the 6th to the 24th month of the study, the ratio of lumbar spine
      BMD (L2-L4 by DPX, Lunar) to the basal pretest value was consistently and
      significantly higher in Group A than Group C but not higher in Group B than in
      Group C. PTH, measured 12 months after the beginning of the study, was lower in
      Group A than in Group C, but no significant difference was found between Groups B
      and C. At 3 months after the placebo was switched to AAA Ca in Group C, serum PTH
      was significantly decreased from the level during placebo supplement. Morning
      urine Ca/Cr decreased in Groups A after 18 months and in B after 12 months, but
      not in C. Serum alkaline phosphatase decreased in Group A significantly compared
      with Group C, but not in Group B. AAA Ca appears to be effective for increasing
      BMD in elderly subjects.

PMID- 8661953
TI  - Impact direction from a fall influences the failure load of the proximal femur as
      much as age-related bone loss.
AB  - Recent studies have shown that factors related to fall biomechanics may play as
      important a role in the etiology of hip fracture as age-related bone loss.
      Motivated by finite element analyses that showed failure of the proximal femur to
      be sensitive to loading direction, our objective with the current investigation
      was to determine experimentally if changes in impact direction affect the failure
      load of the elderly proximal femur. Thirty-three cadaveric femurs were assigned
      randomly to three groups of 11 and tested at one of three loading angles, 0
      degree, 15 degrees, or 30 degrees, representing a fall on the hip rolled slightly
      forward, to the side, or rolled slightly backwards, respectively. Femurs were
      scanned using dual-energy X-ray absorptiometry (DXA) to assess bone mineral
      density (BMD) and tested to failure in a fall loading configuration at a
      displacement rate of 100 mm/second. Using an analysis of covariance to adjust for
      total hip BMD, we found that failure load decreased by 24% as the loading angle
      changed from 0 degree to 30 degrees. This reduction in failure load is comparable
      to that associated with about 25 years of age-related bone loss after the age of
      65. Therefore, the impact direction associated primarily with a fall is a
      critical determinant of hip fracture risk that is both independent of bone
      density and associated with fall biomechanics.

PMID- 8661954
TI  - Bone density change and biochemical indices of skeletal turnover.
AB  - Although biochemical markers of skeletal turnover cannot replace bone density
      scanning for the diagnosis of osteoporosis, it is thought that they may help add
      to prediction of fracture risk and help determine adequacy of osteoporosis
      therapy. Nevertheless, whether biochemical markers in the serum or urine can
      predict individual rates of bone loss in the spine or hip region is unknown. We
      studied a heterogeneous group of women (n = 81) who were premenopausal, untreated
      postmenopausal, and estrogen-treated postmenopausal with baseline determination
      of body mass index (BMI), calcium intake, biochemical measurements, and serial
      bone densitometry over 3 years. Serum assays included bone Gla protein (BGP),
      total and bone-specific alkaline phosphatase (AP, BSAP), carboxyterminal
      propeptide of type I procollagen (PICP), carboxyterminal telopeptide of type I
      collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). Urine assays
      included hydroxyproline (OHP), calcium, total pyridinoline, and total
      deoxypyridinoline. Individual biochemical markers and calcium intake were
      modestly correlated with bone density changes but were inconsistent regarding the
      spine versus the hip. All of the formation variables were significantly
      correlated to spine density change (r = -0.24 to -0.49) whereas the only
      resorption variable that correlated was urine OHp/Cr (r = -0.31). The only
      formation variable that correlated with hip density change was serum PICP whereas
      all of the resorption variables except serum TRAP were correlated (r = -0.23 to 
      0.35). "High turnover" individuals were defined at those with levels of
      biochemical variables at least 1 SD above the mean young normal for each
      variable. Higher bone loss rates were seen in this group for several of the
      turnover markers compared with bone loss rates in all other individuals. However,
      the sensitivity of this "high turnover" status for identifying high bone losers
      did not exceed 60% for any of the variables. In untreated postmenopausal women, a
      model using urine OHp, serum ICTP, serum BSAP, and calcium intake was able to
      predict 42% of the variance of change in BMD of the lumbar spine. A model using
      BMI, serum ICTP, and serum BGP could predict 32% of the variance of change in BMD
      of the femoral neck. No combination of markers could predict variance in bone
      density change at either site in estrogenized women (premenopausal and estrogen
      treated postmenopausal). We conclude that measuring individual serum and urine
      markers of bone turnover cannot accurately predict bone loss rates in the spine
      and hip; however, combinations of demographic and biochemical variables could
      predict some of the variance in untreated postmenopausal women. Biochemical
      markers cannot replace serial bone densitometry for accurate determination of
      change in bone mass at the most clinically relevant sites.

PMID- 8661955
TI  - Expression of inflammatory cytokine genes in vivo by human alveolar bone-derived
      polymorphonuclear leukocytes isolated from chronically inflamed sites of bone
      resorption.
AB  - Alveolar bone-derived polymorphonuclear leukocytes (PMNs) were characterized for
      their ability to produce inflammatory cytokines such as interleukin-1 alpha (IL-1
      alpha), IL-1 beta, tumor necrosis factor alpha (TNF alpha), and IL-6 in vivo.
      Periapical exudates (PE) were collected from periapical lesions with chronic
      periapical periodontitis through root canals. Cells and noncellular supernatants
      were then isolated by centrifugation. The concentration of cytokines present in
      the noncellular supernatants were determined by ELISA. High concentrations of IL
      1 alpha, IL-1 beta, and IL-6 were detected in PE, however, TNF alpha was not. PE
      contains predominantly PMNs ( > 95% of residing cells) with a few percent of
      lymphocytes and/or macrophages. These alveolar bone-derived PMNs were purified by
      the Ficoll-Hypaque gradient method and were analyzed for cytokine mRNA expression
      using the cytokine-specific reverse-transcription polymerase chain reaction.
      Highly purified PMNs ( > 99.5%) isolated from PE expressed significant levels of
      mRNA for IL-alpha, IL-1 beta, and TNF alpha. IL-6 mRNA was not detected, although
      a high concentration of IL-6 was detected in supernatants of PE by ELISA. The IL
      6 secretion in PE could be derived from macrophages, T lymphocytes, osteoblasts,
      or fibroblasts around periapical lesions. These data strongly suggest that human
      PMNs derived from alveolar bone can spontaneously produce IL-1 alpha, IL-1 beta,
      and TNF alpha at sites of inflammation, and probably initiate inflammation and
      regulate augmentation of bone resorption in vivo.

PMID- 8661956
TI  - Subtle differences in the mitogenic effects of recombinant human bone
      morphogenetic proteins -2 to -7 on DNA synthesis on primary bone-forming cells
      and identification of BMP-2/4 receptor.
AB  - The bone morphogenetic proteins (BMPs) are a group of related proteins capable of
      inducing the formation of new cartilage and bone. We report here a direct
      comparison of members of the BMP family in their capability to induce DNA
      synthesis in bone cell cultures. The promotion of DNA synthesis was determined in
      periosteal cells and epiphyseal and sternal chondrocytes of embryonic chick. We
      demonstrate that structurally homologous BMP-2 and BMP-4 exhibit the highest
      specific activity in the three tested cell types, whereas BMP-5, BMP-6 activity
      is moderately reduced in periosteal cells and highly reduced in epiphyseal and
      sternal chondrocytes. The specific activity of BMP-7 is the lowest in the three
      tested cell cultures. Receptor binding characteristics demonstrate a binding of
      BMP-2 with high affinity (KD = 0.45 nM) on periosteal cells, and excess of TGF
      beta 1 does not displace BMP-4 binding. Chemical cross-linking with iodinated BMP
      2 generates an affinity complex of 90 kDa. These findings suggest the presence of
      a BMP-2/BMP-4 receptor that discriminates subtle differences in function among
      homologous members of the BMP family.

PMID- 8661957
TI  - Influence of ovariectomy on bone metabolism in very old rats.
AB  - Twenty-five 30-month-old Lou rats fed a diet (6 g/100 g BW/day) containing 0.9%
      Ca and 0.8% Pi were divided into five groups. Four groups were surgically
      ovariectomized. From day 2 until day 29 after ovariectomy, they were S.C.
      injected either with 17 beta estradiol (E2; 10 micrograms/kg BW/48 hours) or
      progesterone (P; 140 micrograms/kg BW/48 hours), or 17 beta estradiol +
      progesterone (E2P) at the same doses, or solvent alone (OVX). The fifth group was
      sham operated (SH) and injected with solvent. Urine was collected in metabolic
      cages from day 24 to 29 after ovx, and urinary pyridinoline (PYD) and
      deoxypyridinoline (DPD) excretion (markers of bone resorption) was measured by
      HPLC. All animals were killed 30 days after ovariectomy. Serum was then collected
      for measurement of osteocalcin (OC), alkaline phosphatase (ALP), parathyroid
      hormone (PTH), and calcitonin (CT). At necropsy, the success of ovariectomy was
      checked by marked atrophy of the uterine horns. Left and right femur were
      harvested for densitometric and mineral analysis, respectively. Ovariectomy had
      no significant effect upon plasma calcium and PTH concentrations. E2 or E2P
      treatment significantly increased plasma PTH and calcitonin concentrations.
      Plasma OC concentrations and ALP were not different in any of the groups. In
      contrast, urinary excretion of PYD and DPD was higher in OVX than in SH rats.
      Bone mineral density (BMD) of the distal femur was decreased by OVX, but was not
      different in the E2P and SH groups. A similar pattern was observed for the
      mineral or Ca content of whole femur. Thus, OVX decreased BMD and bone mineral
      content (BMC) in very old female rats. Plasma OC concentration and ALP activity
      failed to demonstrate any significant effect of OVX, whereas PYD and DPD were
      elevated. These results suggest that bone resorption is increased in OVX rats,
      even when supplemented with E2 or P alone. However, no significant difference was
      observed between SH and OVX rats treated with supplementation of both E2 and P.
      Thus, in very old rats, a combination of E2 and P is much more effective than E2
      or P alone to prevent bone loss following ovariectomy.

PMID- 8661958
TI  - Skeletal effects of calcitonin treatment and withdrawal in ovariectomized rats.
AB  - The study was designed to determine, by histomorphometric techniques, bone
      changes as a function of time during long-term treatment with salmon calcitonin
      (CT) and after withdrawal of the hormone in ovariectomized (OVX) rats. Groups of
      OVX rats were treated with vehicle alone or CT on alternate days for 30, 60, or
      90 days. Additional groups of sham-operated control rats were treated with
      vehicle alone. Rats from each of the three groups were sacrificed at each time
      point. All treatments in the remaining rats were then terminated at 90 days,
      followed by sacrifice of rats from each group at 30 and 60 days after withdrawal
      of vehicle or CT treatment. The proximal tibia from each animal was processed
      undecalcified for quantitative bone histomorphometry. Compared with control rats,
      the proximal tibiae of vehicle-treated OVX rats were characterized by cancellous
      osteopenia and significant increases in osteoclast surface, osteoblast surface,
      mineralizing surface, mineral apposition rate, and bone formation rate. CT
      treatment of OVX rats partially prevented cancellous bone loss by approximately
      50% and significantly decreased most of the above indices of bone turnover
      relative to vehicle-treated OVX rats. However, soon after withdrawal of CT, OVX
      rats previously treated with the hormone exhibited rapid loss of cancellous bone
      associated with increased bone turnover. These results in an animal model of
      estrogen depletion suggest that early postmenopausal women who are withdrawn from
      prophylactic CT treatment may be at high risk for subsequent bone loss.

PMID- 8661959
TI  - Casodex (a nonsteroidal antiandrogen) reduces cancellous, endosteal, and
      periosteal bone formation in estrogen-replete female rats.
AB  - Testosterone has been implicated in the preservation of the skeleton in women and
      female rats. In this study we investigated the role of androgens in estrogen
      replete female rats by giving Casodex (pure nonsteroidal anti-androgen) daily and
      analyzing the effects on the skeleton using static and dynamic histomorphometric
      parameters after 3 weeks. There was a significant reduction in the bone formation
      rate in both the cancellous bone of the tibial metaphysis and in the periosteal
      and corticoendosteal diaphyseal bone (90%, 30%, and 100% reduction,
      respectively), compared with control animals, which was unaccompanied by a change
      in the indices of bone resorption. Casodex had no effect on cancellous bone
      volume and cortical bone area but this can be accounted for by the short duration
      of the experiment. The serum levels of dehydroepiandrosterone-sulfate and
      androstenedione were significantly reduced in the Casodex-treated rats compared
      with the control animals and there was no difference in the plasma levels of
      estrone, estradiol, or testosterone between the two groups. This study
      demonstrates that androgens play a physiological role in regulating osteoblast
      activity in female rats.

PMID- 8661961
TI  - SEIOMM (Spanish Society for Bone and Mineral Research) Symposium. Alicante,
      Spain, October 4-7, 1995. Abstracts.

PMID- 8661960
TI  - Matrix vesicles and focal proteoglycan aggregates are the nucleation sites
      revealed by the lanthanum incubation method: a correlated study on the
      hypertrophic zone of the rat epiphyseal cartilage.
AB  - Correlated studies were performed with light and electron microscopy, and
      backscattered electron image in conjunction with X-ray microanalysis, of
      lanthanum-incubated epiphyseal cartilage of the young rat. The hall-mark of this
      procedure is the appearance of LaP electron-dense deposits (not present in
      control sections) in precise sites of the hypertrophic zone. The ultrastructural
      study revealed a dual nature of these sites: "dense matrix vesicles" and "focal
      filament aggregates". The dense matrix vesicles are a specific type of matrix
      vesicle with the intrinsic capacity of precipitating LaP mineral, as soon as they
      originate from the hypertrophic chondrocytes. Furthermore, the matrix vesicles
      were found to be heterogeneous because lanthanum-devoid, "light matrix vesicles"
      were also present. The focal filament aggregates, which were not recognized in
      unstained sections and in controls, are apparently focal concentrations of
      proteoglycans with high lanthanum binding capacity, although the presence in them
      of other components (e.g., type X collagen, C-propeptide of type II collagen)
      cannot be excluded. The were in close connection with the light matrix vesicles
      in the upper hypertrophic zone, and were loaded with a variable quantity of LaP
      irregular electron-dense deposits in the lower hypertrophic zone. These irregular
      deposits are similar to, but distinct from, calcification nodules. The lanthanum
      incubation method indirectly detects the matrix Ca-binding components (which bind
      La ions), and the calcification initiation sites (which precipitate a LaP-mineral
      phase). A sequence is proposed of successive steps of LaP nucleation within the
      focal filament aggregates, which possibly mimics calcium phosphate deposition.
      Such a sequence seems to require the participation not only of dense matrix
      vesicles, but also of the filamentous components of the focal aggregates,
      possibly together with the activity of alkaline phosphatase.

PMID- 8661962
TI  - Immunocytochemical localization of vacuolar H+-ATPase and Cl--HCO3- anion
      exchanger (erythrocyte band-3 protein) in avian osteoclasts: effect of calcium
      deficient diet on polar expression of the H+-ATPase pump.
AB  - Osteoclasts attach to the bone surface and resorb bone by secreting protons into
      an isolated subosteoclastic compartment. Previous studies have shown the presence
      of a vacuolar type H+-ATPase, and a functional Cl--HCO3- anion exchanger in the
      osteoclast. In the present studies, using a monoclonal antibody to the 31-kDa
      subunit of H+-ATPase and a rabbit antiserum to the erythrocyte band-3 protein (Cl
      -HCO3- anion exchanger) we have immunocytochemically localized the respective
      pumps in bone sections obtained from chickens fed a normal or a calcium-deficient
      diet for 4 weeks. Our results indicate that although H+-ATPase is either evenly
      distributed throughout the osteoclast or is more polarized at its ruffled
      membrane juxtaposed to the bone surface, the band-3 protein immunoreactivity is
      always localized to the plasma membrane which is not attached to the bone surface
      (basolateral membrane). Four weeks of a calcium-deficient diet resulted in a
      significant increase in the percentage of osteoclasts that were polarized for the
      H+-ATPase pump at their ruffled membrane, and a trend toward increased total
      number of osteoclasts, although the latter did not reach statistical significance
      (P = 0.09). These changes were not accompanied by a significant increase in the
      intensity of staining for H+-ATPase. Band-3 protein immunoreactivity was always
      prominent, limited to the basolateral membrane, and did not alter with calcium
      deficient diet or with changes in the degree of H+-ATPase polarization.

PMID- 8661963
TI  - Bone mass in Parkinson's disease: a study with three methods.
AB  - Recent reports suggest the presence of osteopenia in a high percentage of
      patients with Parkinson's disease (PD). These data contrast with previous reports
      of our group, perhaps due to the different methods used. We studied bone mass in
      52 PD patients (28 males, 24 females) and in 80 age- and sex-matched controls (40
      males, 40 females) who had no other disease that could affect bone mass. We
      measured the totally body bone mineral content (TBBMC) and the ultrasound bone
      velocity (UBV) of transmission in phalanx, and performed metacarpal
      radiogrammetry with computerized radiography (CCT). We also measured serum levels
      of total alkaline phosphatase and tartrate-resistant acid phosphatase, which were
      significantly increased in PD patients compared with controls (P < 0.0001). TBBMC
      was significantly lower in males (P < 0.05) and females (P < 0.05) with PD with
      respect to their controls. CCT did not differ significantly between the study
      groups. UBV was significantly lower in males with PD (P < 0.005), but similar in
      female PD and controls. These data suggest that the changes reported in bone mass
      in PD patients can depend on the sex and the study methods. We only found severe
      osteopenia in one male (3.6%) and five females (20.8%) with PD according to z
      score. Only in women was no relationship found between TBBMC and severity of PD.

PMID- 8661964
TI  - Bone mineral density measured by dual X-ray absorptiometry in Spanish patients
      with insulin-dependent diabetes mellitus.
AB  - Previous studies suggest that low bone mass is a potential complication of
      insulin-dependent diabetes mellitus. Nevertheless, the factors that influence
      diabetic osteopenia are not well established. In order to evaluate the prevalence
      and magnitude of diabetic osteopenia and its association with clinical and
      metabolic variables, we studied 94 consecutive patients with insulin-dependent
      diabetes mellitus. Their age ranged from 20 to 56 years and duration of diabetes
      varied from 1 to 35 years. Bone mineral density (BMD) was measured by dual X-ray
      absorptiometry at lumbar spine and proximal femur and the values were expressed
      as z-score. The presence and extent of microvascular complications, degree of
      metabolic control, and other risk factors for osteoporosis were recorded and some
      biochemical markers of bone metabolism were assessed. Diabetic patients showed
      reduced BMD in all sites (lumbar spine: -0.89 +/- 1.21; femoral neck: -0.99 +/-
      1.24; Ward triangle: -1.05 +/- 1.24; P < 0.0001). Of the 94 patients 19.1% met
      diagnostic criteria for osteoporosis. BMD correlated with body mass index in all
      sites and with the duration of disease in Ward's triangle. Presence and extent of
      diabetic complications were associated with lower BMD, as was smoking. No
      correlation was found between BMD and biochemical markers. In conclusion,
      osteopenia is a common complication in patients with insulin-dependent diabetes
      mellitus. Microvascular complications are a critical point in the progression of
      diabetic osteopenia. Other risk factors for osteoporosis (nutritional status and
      smoking) must be taken into account.

PMID- 8661965
TI  - Dietary protein intake and bone mass in women.
AB  - Population-based strategies to combat osteoporosis are urgently needed. The role
      of nutrition in such strategies has been particularly contentious. We examined
      the relationship among six key nutrients that are thought to affect bone
      metabolism and bone mineral density in the axial and appendicular skeleton using
      data from a population-based study in the northern United States. Data on the
      dietary intake of calcium, phosphorus, vitamin D, protein, fat, and total energy
      were obtained from a 7-day dietary record. Bone density measurements were made by
      dual photon absorptiometry in the lumbar spine and proximal femur, and by single
      photon absorptiometry in the distal and midradius. Among the 72 premenopausal
      women studied, there was a statistically significant positive association between
      protein intake and bone mineral in the distal radius and proximal femur, which
      was not altered by adjustment for age, weight, and physical activity. Among 218
      postmenopausal women, no such relationship was found between protein intake and
      bone mineral, and the only significant findings in this group were negative
      associations between fat consumption and bone density in the lumbar spine and
      radius. Our results suggest that dietary protein intake may be a determinant of
      the peak bone mass attained by premenopausal white women. The relevance of this
      finding for the design of population strategies to maximize skeletal growth
      requires further investigation.

PMID- 8661967
TI  - Right and left proximal femur analyses: is there a need to do both?
AB  - The purpose of this study was to determine if differences existed between right
      and left proximal femur bone mineral density (BMD) in a group of women.
      Participants for the study were 198 women ranging in age from 16 to 73 years.
      Bone mineral densities of both proximal femurs (femoral neck, Ward's area, and
      trochanter) were assessed using dual energy X-ray absorptiometry (Lunar DPX).
      Mean (+/-SD) age, height, and weight of the participants were 32.9 +/- 18 years,
      164 +/- 7.4 cm, and 64.9 +/- 12.1 kg, respectively. Significant differences
      between right and left femoral BMDs were found only in the trochanter. Overall,
      mean differences in BMD were low (neck = 0. 7%, Ward's = 0.2%, and trochanter =
      1.9%) but individual variations were as high as 22%. Based on BMD z-scores of <
      1.0, 84 women were classified as "at risk" for osteoporosis. When right and left
      z-scores were compared, misclassifications of at risk women were 4, 15, and 11
      for neck, Ward's area, and trochanter, respectively. In conclusion, analyses of
      both right and left proximal femurs may not be necessary for either the
      researcher or the clinician.

PMID- 8661966
TI  - Ultrasound parametric imaging of the calcaneus: in vivo results with a new
      device.
AB  - An ultrasound transmission scanning system was constructed to make in vivo
      parametric images of the acoustic properties of the heel. Broadband ultrasonic
      attenuation (BUA) images were obtained in transmit mode by using a pair of
      broadband focused transducers (center frequency 0.5 MHz, diameter 29 mm, focus 50
      mm) immersed in a water bath at room temperature. With these characteristics, the
      theoretical beam width at the focus was approximately 5 mm. The total duration of
      the acquisition period was 3 minutes. Comparison of the BUA image and the
      radiograph of the calcaneus was possible in one case and showed that all the
      anatomical details could be identified. The images reported here demonstrate the
      wide range of BUA found in both the whole bone and within a ROI centered in the
      posterior part of the bone thus reinforcing the idea of tremendous heterogeneity
      of the acoustic properties of bone. This suggests that the accurate control of
      the position of the measurement site is of the utmost importance for between
      subject comparison and for repetitive measurements. We proposed a new method, the
      likelihood image, as an efficient way of highlighting the regions of the image
      suspected to be subject to waveform distortion. It could be used to guide the
      selection of the optimal measurement site. Our results suggest that ultrasound
      parametric imaging has the potential for enhancing the current ultrasound
      technique by (1) allowing reproducible, repetitive measurements, (2) permitting
      the selection of similar optimal measurement sites in all subjects, and (3)
      avoiding accuracy errors due to waveform distortion.

PMID- 8661968
TI  - Effect of recombinant human granulocyte colony-stimulating factor (rh G-CSF) on
      rat bone: inhibition of bone formation at the endosteal surface of vertebra and
      tibia.
AB  - The effect of recombinant human granulocyte colony-stimulating factor (rh G-CSF)
      on bone was evaluated by histomorphometry using Sprague-Dawley rats. rh G-CSF was
      injected at doses of 0, 50, 150, and 450 microg/kg for 6 weeks. In vivo double
      fluorochrome labeling was performed before sacrifice. No significant change in
      body weight was observed. Bone mineral density (BMD) of lumbar vertebrae and
      femora was significantly decreased in G-CSF-treated groups. In the lumbar
      vertebra, osteoid surface, osteoid thickness, trabecular thickness, and labeled
      surface in G-CSF-treated groups were also significantly lower. In addition,
      osteoclast number and osteoclast surface were significantly higher in the G-CSF
      treated groups. The endocortical surface at the mid-tibia showed lower labeled
      surface and mineral apposition rate in G-CSF-treated groups, without significant
      changes at the periosteal surface. Furthermore, numerous granulocytes fully
      occupied the bone marrow area. We conclude that proliferating granulocytes in the
      bone marrow may inhibit bone-forming cells from contacting the bone surface,
      resulting in reduction of bone formation; and increased osteoclastic bone
      resorption induced by G-CSF treatment contributed to the reduction of BMD.

PMID- 8661969
TI  - Characterization of bone mineral crystals in horse radius by small-angle X-ray
      scattering.
AB  - The size and the orientation of the bone salt (mineral) crystals in the cranial
      and caudal zones in the transverse midshaft section of the equine radius were
      investigated by small-angle X-ray scattering (SAXS). The results are interpreted
      as indicating that the crystals had an elongated shape with an average thickness
      of T = 3.17 +/- 0. 15 nm in the caudal region and T = 3.79 +/- 0.20 nm in the
      cranial region. Their orientation was predominantly in the longitudinal direction
      of the bone. There was no preferential orientation within the transverse plane.
      The distribution of tilt angles with respect to the longitudinal direction was
      determined directly from the SAXS data: the average angle was about 30 degrees
      for the cranial region and 45 degrees for the caudal region. Assuming that the
      needle-like crystals are parallel with the collagen fibrils, the angular
      distribution of the crystals is in good agreement with previous measurements of
      collagen orientation using circularly polarized light microscopy.

PMID- 8661970
TI  - In vitro inhibition of membrane-mediated calcification by novel phosphonates.
AB  - The effects of a series of novel phosphonates on the kinetics of mineral
      development in an ionophore-primed 7:2:1 phosphatidylcholine (PC):
      dicetylphosphate (DCP): cholesterol (Chol) liposomal model system are reported.
      When present at 2.5 micromol/liter or 25 micromol/liter concentrations in the
      solution surrounding the liposomes, the investigated phosphonates did not
      significantly delay the initial formation of hydroxyapatite-like calcium
      phosphate salts (HAP) within the liposomes or the penetration of HAP crystals
      through the enclosing membranes. However, the phosphonates variably retarded the
      subsequent growth and proliferation of the HAP crystals once they became directly
      exposed to the phosphonate-containing solution. The effectiveness of phosphonates
      in inhibiting extraliposomal precipitation strongly depended on their structure.
      The inhibitory action on active surface growth sites of released intraliposomal
      crystals was found to be the most effective if the phosphonate molecule contained
      two phosphonic groups linked to the same C atom. At a phosphonate concentration
      of 25 micromol/liter, the following general order of effectiveness was
      established: geminal bisphosphonate >/= geminal tetrakisphosphonate >
      bisacylphosphonates > monoacylphosphonate > bisalkylphosphonate. Within the
      bisacylphosphonate family, the highest inhibitory action was observed when four
      or five -CH2- groups separated the ketophosphonic groups.

PMID- 8661972
TI  - Influence of marrow on ultrasonic velocity and attenuation in bovine trabecular
      bone.
AB  - Measurements of ultrasonic velocity and specific differential attenuation (SDA)
      were obtained on 24 bovine trabecular bone specimens from the femoral condyles.
      The measurements were obtained using two pairs of ultrasonic transducers, one
      with a low nominal center frequency (500 kHz) and the other pair with a high
      nominal center frequency (1 MHz). The ultrasonic velocity and specific
      differential attenuation associated with the bone samples were determined both
      with and without marrow, i.e., replacing the marrow with water in the pores of
      the trabecular bone. Significant increases (2.1% and 2.9%) in the velocity of
      ultrasound were observed after removal of the marrow, for the low and high
      frequency transducer pairs, respectively. In contrast, significant decreases (
      6.5% and -8.8%) in SDA were observed after removal of the marrow, for the low and
      high frequency transducer pairs, respectively. The bone densities (BD) of the
      samples were also determined using single photon absorptiometry (SPA).
      Correlations between ultrasonic parameters and bone densities for samples both
      with and without marrow were found to be similar. For example, for the 1 MHz
      transducer pair, the correlation between BD and velocity was r = 0. 86 with
      marrow, and r = 0.89 without marrow. This study also compared the results
      obtained using a contact (no water bath) technique and an insertion (with a water
      bath) technique of ultrasonic measurements. For the high frequency transducer
      pair, the correlation coefficients between the two methods were r = 0.99 and r =
      0.93, for the velocity and specific differential attenuation, respectively.
      Similar results were found for the low frequency transducer pair as well. In
      addition, approximately equal correlations between BD and ultrasonic velocity and
      SDA were also found, indicating that contact and insertion measurements provide
      essentially equivalent information.

PMID- 8661971
TI  - Dexamethasone enhances the osteogenic effects of fluoride in human TE85
      osteosarcoma cells in vitro.
AB  - The in vitro osteogenic effects of fluoride have not always been consistently
      observed in human bone cells. The present study sought to test if dexamethasone
      (Dex) could potentiate the action of fluoride to increase the detectability of
      the stimulatory effects of fluoride on [3H]thymidine incorporation, alkaline
      phosphatase (ALP) specific activity, collagen synthesis, and osteocalcin
      secretion in human TE85 osteosarcoma cells. Neither Dex at 10(-10)-10(-6) M or
      fluoride at a mitogenic dose (100 microM) had any consistent stimulatory effects
      on thymidine incorporation. When the cells were treated with both agents
      simultaneously, significant and highly reproducible stimulations were observed.
      The mitogenic effects of the two agents were confirmed with cell number counting.
      Analysis of variance (ANOVA) revealed a significant interaction (P < 0.001)
      between fluoride and Dex on cell proliferation. The enhancing effect of Dex on
      [3H]thymidine incorporation was not due to a shift of the optimal dose response
      of fluoride. Though fluoride alone or Dex alone also had no consistent effect on
      ALP specific activity, the co-treatment with fluoride and Dex for 24 hours
      produced significant (P < 0.001, ANOVA) stimulation in ALP specific activity.
      Fluoride alone had no consistent effect on collagen synthesis and on 1, 25(OH)2D3
      dependent osteocalcin secretion, whereas Dex treatment consistently inhibited
      these two osteoblastic parameters in a dose-dependent manner. However, both the
      collagen synthesis and osteocalcin secretion rates were significantly higher (P <
      0.001 ANOVA for each) when the cells were co-treated with Dex and fluoride (100
      microM) than when they were treated with Dex alone. Thus, these data indicate
      that the response in collagen synthesis and osteocalcin secretion to fluoride
      stimulation was more readily observed in the presence of Dex than in its absence.
      ANOVA analysis revealed that the interaction between fluoride and Dex on collagen
      synthesis, but not the 1,25(OH)2D3-dependent osteocalcin secretion, was
      significant (P < 0.02). In summary, we have demonstrated for the first time that
      in TE85 cells (1) Dex potentiated the effects of fluoride on cell proliferation,
      ALP specific activity, and collagen synthesis; (2) while Dex at 10(-7)-10(-6) M
      alone inhibited the collagen synthesis and at 10(-9)-10(-6) M reduced osteocalcin
      secretion, Dex at 10(-8)-10(-6) M significantly stimulated the proliferation of
      TE85 cells; and (3) Dex interacted with fluoride to increase the percentage of
      experiments showing an osteogenic action of fluoride. In conclusion, the in vitro
      osteogenic actions of fluoride in human TE85 cells are more consistently observed
      in the presence than in the absence of Dex.

PMID- 8661973
TI  - Dual incorporation of (35S)sulfate into dentin proteoglycans acting as
      mineralization promotors in rat molars and predentin proteoglycans.
AB  - Autoradiographic investigations were carried out 0.5, 1, 2, 4, 24, 48, 72, and
      120 hours after the injection of a single dose of [35S]-sulfate on
      undemineralized molars of 7-15-day-old rats. In predentin, labeling was detected
      at 0.5 hours. Silver grain density reached a plateau value between 1 and 24
      hours, then decreased and disappeared 120 hours after injection. In dentin, the
      mineralization front started to be labeled as early as 0.5 hours after injection.
      Labeling increased at the dentin edge between 1 and 2 hours, reached a maxima at
      4 hours, then started to decrease, the labeled band seen 24 hours after injection
      being further incorporated into dentin. This band stood at constant distance from
      the dentin-enamel junction with stable grain density, even at 120 hours. This
      investigation proves the existence of two distinct groups of [35S]-labeled
      proteoglycans, one exclusively related to predentin and disappearing with time,
      and the second one located in dentin behaves as a stable component. The fact that
      an early labeling appeared at the mineralization front which was further
      incorporated into dentin, confirms that dentin proteoglycans constitute an
      individual group of molecules that are not derived from predentin proteoglycans,
      and act as mineralization promotors.

PMID- 8661974
TI  - Effects of androgens on subpopulations of the human osteosarcoma cell line SaOS2.
AB  - Previously, we showed that androgens stimulate murine and human osteoblast-like
      cell proliferation and differentiation by mechanisms involving increased
      responses to mitogenic growth factors (GF) and increased GF production. To
      explain this dual action of androgens on primary osteoblastic cell populations we
      advanced the hypothesis that androgens exert differential effects on osteoblastic
      subpopulations. We subcloned a human osteosarcoma cell line (SaOS2) into
      subpopulations expressing high (HAS) and low (LAS) levels of alkaline phosphatase
      (ALP). The obtained subclones differed significantly in their ALP production and
      expressed a high and low ALP phenotype, respectively, for the entire experimental
      period. Dihydrotestosterone (DHT) increased specific ALP activity and type-I
      procollagen peptide secretion in both HAS and LAS. DHT pretreatment enhanced the
      mitogenic action of basic fibroblast growth factor (bFGF) and insulinlike growth
      factor 2 (IGF2) only in HAS. The enhanced mitogenic effect of IGF2 in HAS after
      DHT pretreatment was associated with increased IGF2-receptor mRNA levels.
      Therefore, we conclude that androgens exert their osteoanabolic action (1) by
      stimulating differentiated functions of osteoblastic cells with a high and a low
      ALP phenotype, and (2) via increased growth factor receptor expression and
      thereby enhancing mitogenic growth factor responses only in HAS.

PMID- 8661975
TI  - Assessment of the relationship between standard probe and implantable fiber
      measurements of cortical bone blood flow: a canine study.
AB  - Laser Doppler flowmetry (LDF) has been used to assess cortical bone blood flow in
      various clinical situations, such as osteomyelitis and osteonecrosis. Standard
      metal-sheathed probes containing optical fibers, applied to cortical bone for
      perfusion measurements, require direct exposure of the bone surface for each
      measurement, making nonanesthetized assessments over time impractical.
      Implantable optical fibers offer a noninvasive method for evaluating cortical
      bone perfusion without repeated surgical exposure of the bone after initial
      surgical implantation of the fibers. In vitro studies have shown the reliability
      of laser Doppler (LD) fibers compared with those of the standard probe. This
      investigation studied the relationship between measurements of cortical bone
      perfusion obtained by implanted optical (LD) fibers and standard (LDF) probes in
      vivo. Midshaft tibial fractures were created in the right hindlimb of 11 adult,
      large (>25 kg) dogs and stabilized by low contact-dynamic compression plate
      fixation. Cortical bone blood flow was measured by LDF using standard probes and
      implantable fibers at five sites along the tibia prefracture, postfracture,
      immediately postplate application, and at 10 weeks postplating, immediately prior
      to euthanasia. The implantable fibers were secured onto the cortical bone via the
      plate and led through a percutaneous exit site. Histological examination of the
      inguinal and popliteal lymph nodes and soft tissue surrounding the fibers
      revealed mild inflammation. No significant correlation of blood flow assessed by
      the implantable fibers and standard probe occurred immediately postfracture (r <
      0. 13, p > 0.62). However, a statistically significant correlation was seen
      postplate application at one of the measurement sites in the distal fracture
      fragment (r = 0.78, P < 0.003). The fibers remained intact and functional until
      an average of 3 weeks at which time they either fractured or were removed by the
      animals. This is the first in vivo study assessing the reliability of implantable
      fibers for the measurement of cortical bone blood flow. Further modification of
      the fibers will be necessary to improve their longevity and durability for
      assessment of cortical bone blood flow.

PMID- 8661976
TI  - Intranasal salmon calcitonin for the prevention and treatment of postmenopausal
      osteoporosis.
AB  - In a randomized, double-blind, placebo-controlled trial, we have studied the
      effects of intranasal salmon calcitonin (SCT) on bone mineral density (BMD) and
      biochemical markers of bone turnover over a period of 2 years. Our study
      comprised 117 Caucasian postmenopausal women, otherwise healthy apart from
      reduced bone density. They received either intranasal synthetic SCT (200 IU
      either three times weekly or daily) or placebo. Compared with placebo, daily
      intranasal calcitonin resulted in no significant bone loss in the lumbar spine,
      as assessed by dual photon absorptiometry, over the 2-year study period (P <
      0.02). In this group, women more than 5 years postmenopause, with the lowest
      baseline bone mass, showed the greatest response to this treatment, with a total
      increase placebo in lumbar spine BMD of 3.1%. Significant spinal bone loss (P <
      0.005) occurred in women receiving either placebo or thrice-weekly calcitonin.
      Although the rates of bone loss in the proximal femur were not significantly
      different in the three groups, there were differences over time. Whereas bone
      loss in the daily calcitonin group was insignificant, women who received placebo
      or thrice-weekly calcitonin experienced significant bone loss (P < 0. 001). No
      significant changes in biochemical markers were observed in any group. Therapy
      was well tolerated and there were no significant treatment-related adverse
      events. We conclude that intranasal SCT 200 IU daily is effective and safe for
      the prevention of bone loss in postmenopausal women with reduced bone mass.

PMID- 8661977
TI  - A new biochemical marker of bone resorption for follow-up on treatment with nasal
      salmon calcitonin.
AB  - In a double-blind, placebo-controlled, randomized group comparison, new and
      specific biochemical markers for bone resorption as follow-up parameters on the
      therapeutic response to nasal salmon calcitonin (sCT) were evaluated. Evaluation
      took place at an outpatient clinic where osteoporosis was being researched. The
      subjects included 208 women aged 68-72 treated for 2 years with either 50 IU, 100
      IU, or 200 IU of nasal sCT or placebo; all groups received a daily calcium
      supplementation of 500 mg. Only 164 women fulfilled the study as valid
      completers. Markers were applied to frozen urine samples of a previously
      published intervention study of a new fasting urinary (fU) biochemical marker for
      bone resorption (CrossLapstrade mark, ELISA) and the urinary excretion of cross
      links (pyridinoline and deoxypyridinoline) was measured, all corrected for
      creatinine. Bone mineral density of the lumbar spine and rates of vertebral and
      peripheral fractures were measured after 2 years of treatment. The creatinine
      corrected urinary pyridinoline, deoxypyridinoline, and CrossLaps showed maximum
      decreases of 10-43% (95% confidence interval -29.5% to 9.6% and -75.1% to 9.3%; P
      < 0. 01-0.001) after 6-9 months, after which the response leveled off. A
      significant difference among the four treatment groups was seen in fU CrossLaps
      (P < 0.01). The changes in spinal bone mass were significantly related to the
      decreases in fU CrossLaps: women with the highest response in spinal bone mass
      had decreases in fU CrossLaps of 44% (-83.5% to 7.4%) and women without response
      of 5% (-57.6% to 99.9%) P < 0.001). In women who fractured during the 2-year
      period, fU CrossLaps remained unchanged, whereas decreases of 30% (-75.1% to
      44.7%) were seen in women who did not fracture (P = 0. 002). The results suggest
      that biochemical markers can be used to determine the optimum treatment regimen
      of nasal sCT. The response of the new marker, fU CrossLaps, significantly
      reflects the responses in bone mass of the spine and fracture rates.

PMID- 8661978
TI  - Remission of hypercalciuria in patients with tuberculosis after treatment.
AB  - The hypercalciuria evolution and other bone metabolism parameters were evaluated
      in patients with tuberculosis after treatment. Twenty-two patients with
      tuberculosis and 54 normal subjects were studied; they consumed an average diet
      (calcium intake 1000 mg/day). Ten of these patients and nine normal subjects were
      also studied after a low calcium diet (400 mg/calcium/day) and after a load of
      oral calcium of 1000 mg (calcium absorption test). The study with an average diet
      was performed after 1 week (basal) and 3, 6, and 12 months after the
      antituberculosis treatment was started; the calcium absorption test was carried
      out 2 weeks, 3 and 12 months after the treatment was started. On an average diet,
      patients with tuberculosis presented, at baseline state, lower calcidiol levels
      than normal controls. Serum calcitriol levels at baseline were higher than at 6
      and 12 months. Serum parathyroid hormone (PTH) levels in patients with
      tuberculosis were lower than in normal controls at baseline, but these levels
      were similar to controls at 3, 6, and 12 months after treatment. During the
      calcium absorption test and under basal conditions, patients with tuberculosis
      showed lower serum PTH and calcidiol levels in all the dietetic situations than
      in normal controls. However, serum calcitriol levels were higher than in controls
      after the restrictive diet. After 3 months of treatment, urinary calcium
      excretion was normal in patients with tuberculosis during the average and low
      diets, but higher than in control group after calcium load. After 12 months of
      treatment, all the biochemical parameters of the patients with tuberculosis were
      similar to the control group under all the dietetic situations. These data
      indicate that antituberculous treatment, although it may contribute to the
      production of some alteration in the calcium and vitamin D metabolism, basically
      favors the correction of disturbances associated with tuberculosis.

PMID- 8661979
TI  - The influence of aortic calcification on spinal bone mineral density in vitro.
AB  - We examined the influence of aortic calcification on the spine phantom bone
      mineral density (BMD). Soft X-ray photographs of human aortae were taken to
      calculate the percent calcification of aortic tissues. Human aorta laid on lumber
      spine phantom was placed in the bottom of 15 cm of water and BMD and bone mineral
      content (BMC) were measured in the anteroposterior view. Samples with severe
      aortic calcification (over 30%) caused a 2.5% increase of BMD. There might be a
      relatively small influence of aortic calcification on the value of L2-L4 BMD, but
      changes over time in a patient could falsely elevate values.

PMID- 8661980
TI  - Effect of periosteal stripping on cortical bone perfusion: a laser doppler study
      in sheep.
AB  - The goals of internal fixation are an accurate reduction and stable fixation in
      the presence of adequate bony vascularity. This can be achieved by a variety of
      means including plate fixation. A certain amount of periosteal stripping is
      necessary for proper open reduction of a fracture and for proper plate
      application. With displaced diaphyseal fractures, cortical bone perfusion (CBP)
      is already compromised. Further damage, in terms of periosteal stripping for
      plate fixation, may not be acceptable. Little information is available as to what
      extent the periosteum contributes to cortical bone perfusion. The purpose of this
      study was to determine the acute effects of periosteal stripping on cortical bone
      perfusion in a sheep tibia model. Twenty-three sheep were operated on and had the
      medial aspect of their right tibia exposed. Cortical bone perfusion measurements
      were obtained using laser Doppler flowmetry prior to periosteal stripping and
      after periosteal stripping. The results of this study show that the cortical bone
      perfusion significantly decreased by 20% after periosteal stripping over the
      entire length of the tibia. We therefore conclude that the periosteum contributes
      to diaphyseal bone perfusion and that it is important to preserve this source
      with fractures where blood supply is already significantly compromised.

PMID- 8661981
TI  - Effect of essential trace metal on bone metabolism in the femoral-metaphyseal
      tissues of rats with skeletal unloading: comparison with zinc-chelating
      dipeptide.
AB  - The effect of essential trace metals on bone metabolism was investigated in the
      femoral-metaphyseal tissues obtained from skeletal-unloaded rats. Skeletal
      unloading was designed by using the model of hindlimb suspension in rats; the
      animals were fed for 4 days with the unloading. Femoral-metaphyseal tissues were
      cultured for 24 hours in a medium containing either vehicle (control), nickel,
      manganese, cobalt, copper, zinc, or zinc-chelating dipeptide (beta-alanyl-L
      histidinato zinc; AHZ) in the concentration range of 10(-6) to 10(-4) M. Bone
      biochemical components (alkaline phosphatase activity, glucose consumption, and
      DNA content) were significantly decreased by skeletal unloading. The presence of
      zinc sulfate or AHZ (10(-5) and 10(-4) M) caused a significant increase of
      alkaline phosphatase activity in the bone tissues from unloaded rats. This effect
      was not seen by nickel, manganese, cobalt and copper (10(-6) to 10(-4) M). The
      culture medium glucose was clearly consumed by the bone tissues. This consumption
      was inhibited by nickel, manganese, or copper (10(-5) and 10(-4) M), while
      cobalt, zinc, and AHZ had no effect. DNA content in the bone tissues from
      unloaded rats was significantly increased by all metal compounds (10(-5) M). The
      effect of AHZ on bone components was greater than zinc sulfate. The AHZ (10(-5)
      M)-increased alkaline phosphatase activity in the bone tissues from unloaded rats
      was clearly blocked by the presence of cycloheximide (10(-6) M), staurosporine
      (10(-7) M), dibucaine (10(-4) M), or okadaic acid (10(-7) M). The present study
      demonstrates that, of various essential trace metals, zinc compounds have an
      unique anabolic effect on bone metabolism in the femoral-metaphyseal tissues of
      rats with skeletal unloading. Zinc-chelating dipeptide may stimulate bone protein
      synthesis through the mechanism that is involved in protein kinases.

PMID- 8661982
TI  - Calcium carbonate crystals promote calcium oxalate crystallization by
      heterogeneous or epitaxial nucleation: possible involvement in the control of
      urinary lithogenesis.
AB  - A large proportion of urinary stones have calcium oxalate (CaOx) as the major
      mineral phase. In these stones, CaOx is generally associated with minor amounts
      of other calcium salts. Several reports showing the presence of calcium carbonate
      (CaCO3) and calcium phosphate in renal stones suggested that crystals of those
      salts might be present in the early steps of stone formation. Such crystals might
      therefore promote CaOx crystallization from supersaturated urine by providing an
      appropriate substrate for heterogeneous nucleation. That possibility was
      investigated by seeding a metastable solution of 45Ca oxalate with vaterite or
      calcite crystallites. Accretion of CaOx was monitored by 45Ca incorporation. We
      showed that (1) seeds of vaterite (the hexagonal polymorph of CaCO3) and calcite
      (the rhomboedric form) could initiate calcium oxalate crystal growth; (2) in the
      presence of lithostathine, an inhibitor of CaCO3 crystal growth, such accretion
      was not observed. In addition, scanning electron microscopy demonstrated that
      growth occurred by epitaxy onto calcite seeds whereas no special orientation was
      observed onto vaterite. It was concluded that calcium carbonate crystals promote
      crystallization of calcium oxalate and that inhibitors controlling calcium
      carbonate crystal formation in Henle's loop might play an important role in the
      prevention of calcium oxalate stone formation.

PMID- 8661984
TI  - Trabecular bone cell proliferation ex vivo increases with donor age in the rat:
      it is correlated with the extent of bone loss and not with histomorphometric
      indices of bone formation.
AB  - Morphometric parameters of bone formation are markedly depressed in senescent, 21
      month old rats and even in middle-aged, 12-month-old animals when compared with
      mature, 4-month old adults. However, osteoblast-like cells obtained from the
      metaphyseal trabeculae of the distal femur of 21-month-old female and male rats
      proliferate more rapidly in primary and secondary cultures than cells from 4
      month-old donors. In females the increase in proliferation is significant for
      donor ages from 4 to 12 months and from 12 to 21 months. Ex vivo cell
      proliferation is inversely correlated with trabecular bone volume and bone
      surface in females and with bone surface in males. The relationships are being
      maintained in females (not tested in males) when cells are grown in serum-free
      medium. We interpret age and bone loss-dependent stimulated cell proliferation as
      the in vitro response to an in vivo signal to proliferate resulting from higher
      strains on less trabeculae. The absence of response in vivo could result from the
      local deficiency of factors brought back to the cells by the serum-enriched
      culture medium, or from proliferation inhibitors developing with age.

PMID- 8661983
TI  - Short-term systemic insulin-like growth factor-1 is unable to prevent cyclosporin
      A-induced osteopenia in the rat.
AB  - Immunosuppression with cyclosporin A (CsA) is effective in a number of immune
      mediated diseases and in preventing rejection following organ transplantation. We
      have repeatedly demonstrated that CsA in the rat model produces accelerated bone
      remodelling with net bone loss, best characterized in trabecular bone. IGF-I
      holds promise as a treatment for various osteopenic conditions. Although
      currently a subject of much controversy, various studies have suggested that in
      vivo it is anabolic to cortical as well as trabecular bone. The purpose of this
      study was, in part, to further characterize the effects of CsA and IGF-I on
      trabecular and cortical bone, and to see whether systemic IGF-I is able to
      modulate CsA's deleterious skeletal effects. Sixty 10 week-old, male, Sprague
      Dawley rats were randomized to receive the following daily for 3 weeks: (1) CsA
      vehicle (veh) per os (po) + recombinant human (rh) IGF-1 veh subcutaneously (sc);
      (2) CsA 15 mg/kg po + rhIGF-I-veh; (3) CsA-veh + rhIGF-I 200 microg/kg sc; (4)
      CsA-veh + rhIGF-I 600 microg/kg sc; (5) CsA 15 mg/kg + rhIGF-I 200 microg/kg, and
      (6) CsA 15 mg/kg + rhIGF-I 600 microg/kg. Rats were weighed and venous blood was
      sampled serially for determination of glucose, ionized calcium (Ca2+), PTH,
      vitamin D, and osteocalcin. Following sacrifice on day 20, histomorphometry was
      performed on double calcein-labeled tibial metaphysis and diaphysis. All rats
      receiving CsA had elevated levels of blood glucose and osteocalcin by day 9 and
      vitamin D at day 20. PTH was similar in all groups, and Ca2+ was only raised in
      the CsA and CsA + IGF-I 200 microg/kg groups. Rats receiving IGF-I 200 microg/kg
      and IGF-I 600 microg/kg gained more weight than either vehicle- or CsA-treated
      animals, attesting to IGF-1's anabolic properties. CsA caused severe trabecular
      bone loss, not prevented by IGF-I; it even further increased the eroded surface.
      CsA and IGF-I had little effect on cortical bone volume or marrow area. IGF-I
      increased endocortical matrix synthesis, as evidenced by the increases in the
      percent endocortical osteoid perimeter, an effect negated by the addition of CsA.
      This experiment demonstrates that trabecular bone is more susceptible than
      cortical bone to the deleterious effects of CsA and indicates little role for IGF
      1 in the pathophysiology or treatment of CsA-induced bone disease at the given
      doses and duration of treatment.

PMID- 8661985
TI  - Sex differences in absolute rates of bone resorption in young rats: appendicular
      versus axial bones.
AB  - This study compares absolute rates of bone resorption and formation at the organ
      level in adolescent Sprague-Dawley rats as a function of sex and type of bone.
      Bone resorption and formation were quantified in rapidly growing male and female
      rats (4-7 weeks of age) who were multiply prelabeled with [3H]tetracycline. Ten
      different whole bones were compared: four cranial or appendicular bones and six
      axial bones. Absolure rate of bone resorption was measured isotopically by the
      loss of 3H-tetracycline from each whole bone. Bone growth was quantified in terms
      of relative and absolute increase in bone calcium mass. When the rates of bone
      resorption (loss of [3H]-tetracycline as percent of whole bone per 3 weeks) were
      compared between sexes, the six axial bones showed significantly higher rates (P
      < 0.05-0.001) in males (64-73) than in females (37-66). No significant sex
      differences were observed in rate for the two cranial and two appendicular bones.
      During 4-7 weeks of age, a comparison of bone masses showed that only one bone
      (calvaria) gained more mass in the male and two bones (mandible and humerus)
      gained more mass in the female. In contrast, five of six axial bones gained more
      mass in the female. Thus, 7 out of 10 bones were larger in the female. In growing
      male and female rats, an inverse relationship appears between rate of bone
      resorption and mass for most of the axial bones; this relationship was not
      apparent for cranial or appendicular bones. Sexual dimorphism was consistently
      seen by greater axial bone mass in females. However, greater rates of bone
      resorption were seen in male axial bones but not in cranial or appendicular
      bones. It is apparent that the different types of bones are heterogeneous in
      their rates of resorption and formation during this period of growth.

PMID- 8661986
TI  - X-ray diffraction, electron microscopy, and Fourier transform infrared
      spectroscopy of apatite crystals isolated from chicken and bovine calcified
      cartilage.
AB  - Apatite crystals of the calcified zone of the subarticular cartilaginous growth
      plates of the long bones of young growing chickens and calves were isolated by
      low temperature reaction with hydrazine and plasma ashing and examined by
      electron microscopy, electron diffraction and microprobe analysis, and computer
      generated deconvolution of the spectra obtained by Fourier transform infrared
      spectroscopy. The crystal habit was that of wide, very thin, relatively long
      rectangular plates, which tended to form small clusters of crystals, possibly
      because reaction with hydrazine alone did not remove all of the organic matrix
      constituents. Further reaction with low power plasma ashing released more of the
      isolated crystals although to a lesser extent than was possible with bone.
      Stereograms of the small clusters showed that many of the crystals in the small
      isolated aggregates of crystals were bent and/or curved. Together with the
      resultant overlap of individual adjacent crystals, they also produced images of
      sharp, very dense lines, reminiscent of the electron-dense needle or rod-like
      appearances frequently observed by transmission electron microscopy of thin
      sections of calcified cartilage and thought to represent the habit of the apatite
      crystals. No true rod or needle-like crystals were observed in the isolated
      crystals. Although the overall general apatitic structure of the apatite crystals
      was similar to that of the apatitic crystals of bone, the individual crystals
      were significantly larger than those of bone from the same specimen, and there
      were small but significant differences in the concentrations of acid phosphate
      and carbonate groups and in their short range order.

PMID- 8661987
TI  - Replacing DXA scanners: cross-calibration with phantoms may be misleading.
AB  - The high precision and stable calibration of dual X-ray absorptiometry (DXA) has
      led to its widespread use in clinical trials of new therapies for osteoporosis.
      Daily scanning of phantoms provides a check on the continuity of the bone mineral
      density (BMD) calibration and allows for correction of minor changes. However,
      because clinical trials may last up to 5 years, it is likely that the scanner
      will need replacing during the course of a study. We report the upgrade of a
      Hologic QDR-2000 to a QDR-2000plus. The new scanner was cross-calibrated with the
      old according to the manufacturer's instructions using the Hologic spine phantom.
      The accuracy of cross-calibration was checked by in vivo scans of patients in
      clinical trials and also using the European spine phantom (ESP). Daily QC scans
      with the Hologic phantom over the 6-week period of the in vivo study showed that
      the new scanner agreed within 0.2% with the old. However, in vivo scans at 10
      sites in the spine, hip, total body, and forearm showed significant mismatch
      between the two systems with five sites differing by more than 2%. Results for
      the ESP phantom lay closer to the in vivo spine data than the Hologic phantom.
      The mismatch revealed was larger than anticipated and emphasized the importance
      of performing adequate in vivo cross-calibration studies whenever DXA systems are
      replaced. Typically, scans of 20-30 subjects are required at each scan site to
      achieve an accuracy of 1%. Such studies require careful planning and make
      significant demands on space, patient cooperation, scanning time, scientific
      resources, and, not least, the implementation of the findings.

PMID- 8661988
TI  - Mineral density gain in vertebrae of osteoporotic women on oral pamidronate
      reverts a year after treatment discontinuance.
AB  - Long-term treatment with 200 mg dry weight/day of pamidronate (APD) by oral route
      has been proposed to increase bone mineral density (BMD) in postmenopausal
      osteoporotic women. However, there is widespread concern over the possibility of
      bone metabolism "freezing" by protracted use of medication liable to inhibit bone
      resorption. Accordingly, an open population of 39 osteoporotic women was studied
      in order to determine BMD variations in lumbar vertebrae and femoral neck and to
      confirm whether given APD doses increase bone mineralization. A parallel group of
      osteoporotic women was likewise evaluated to determine the potential
      reversibility of such effect on discontinuing treatment. Results were beneficial
      at both skeletal sites in subjects on APD therapy, disclosing at 18 months
      treatment 9.0% mean peak mineral gain versus basal status at lumbar spine. In the
      few responders completing 4 years of treatment, mean differences versus basal
      status were +4.9% in vertebrae and +6.2% at femoral neck. In lumbar vertebrae
      there was a rapid trend in mineral gain up to 18 months on treatment, which
      declined thereafter to a quarter of its early rate. Concurrently, in the group of
      21 baseline-matched women, effects were evaluated after discontinuing daily APD
      administration one year (n = 11) or two years (n = 7) later. In both subgroups,
      there was a loss in lumbar (-7.1% and -9.8% respectively; p<0.01) and femoral
      neck BMD (-2.2% and -4.2% respectively; p: n.s.) on performing measurement one
      year after APD withdrawal. Furthermore, after three years treatment and
      subsequent discontinuance, three patients presented bone loss in lumbar vertebrae
      and minimal changes at femoral neck one year after APD withdrawal. Therefore, APD
      induces moderate BMD gain which proves reversible on discontinuing therapy, so
      that it seems unlikely that this compound should "freeze" bone metabolism to a
      significant extent. However, the precise degree of such reversibility requires
      evaluation in larger series.

PMID- 8661989
TI  - Effect of antipeptide antibodies directed against three domains of connexin43 on
      the gap junctional permeability of cultured heart cells.
AB  - Cell-to-cell communication can be blocked by intracellular injections of
      antibodies raised against gap junction proteins, but the mechanism of channel
      obstruction is unknown. Binding to connexins could lead to a conformational
      change, interfere with regulatory domains or cause a steric hindrance. To address
      these questions, the effects on cell-to-cell communication of affinity purified
      polyclonal antibodies raised against peptides reproducing the intracellular
      sequences 5-17, 314-322 and 363-382 of rat connexin43 were investigated in
      cultured rat ventricular cells. The antibodies against sequence 363-382 were
      characterized by immunoblotting and immunocytochemistry. Characterization of
      antibodies 5-17 and 314-322 has been previously reported. In a first series of
      experiments, the effect on gap junctional communication was assessed by injecting
      a junction-permeant fluorescent dye into cells adjacent to one cell previously
      microinjected with antibodies. In a second series, junctional permeability was
      quantitatively determined on records of fluorescence recovery after the
      photobleaching of 6-carboxyfluorescein-loaded cells. Antibodies 5-17 marked a 43
      kDa band on immunoblots, but did not immunolabel gap junctions and had no
      functional effect. Antibodies 314-322 recognized the 43 kDa protein and labeled
      the intercalated disks, but failed to interfere with junctional permeability.
      Antibodies to the nearby sequence 363-382, for which all immunospecific tests had
      been positive, caused a delayed diffusional uncoupling in 50% of the
      microinjected cells. It is suggested that the blocking of junctional
      communication by antibodies results from interference with a regulatory domain of
      the connexin.

PMID- 8661990
TI  - Reaction kinetics of the vacuolar H(+)-pumping ATPase in beta vulgaris.
AB  - Vacuolar-type H(+)-ATPases (V-ATPases) are ubiquitous in eukaryote endomembranes,
      where they are responsible for lumenal acidification. The ratios of H+
      translocated per ATP hydrolyzed (which may be important in controlling the
      activity of these pumps) have previously been found to be variable, noninteger
      and sensitive to cytosolic as well as lumenal pH. The mechanistic implications of
      these findings are explored here with reaction kinetics. Experimental data for
      this analysis comprise supra- and superlinear V-ATPase current-voltage
      relationships, isolated as bafilomycin-sensitive currents in vacuolar membranes
      from Beta using the "whole vacuole" patch clamp configuration. Whereas simple
      models with one reaction cycle fail to provide an adequate description of the
      data (mainly because of a weak sensitivity of the zero-current voltage to the
      transmembrane pH gradient), a model with two linked reaction loops allowing
      partial coupling of H+ translocation to ATP hydrolysis does provide good
      descriptions. All experimental data obtained with the same vacuolar pH (4.3)
      could be reduced to a model with eleven independent parameters. Best fits have
      been obtained on the basis of a binding domain possessing 3 H+ binding sites per
      ATP hydrolyzed and a net charge of -2 when unoccupied. The enzyme could
      reorientate its access site between the vacuolar and cytoplasmic side when zero,
      one or three H+ are bound.

PMID- 8661991
TI  - Large-conductance calcium-activated potassium channels of cultured rat
      melanotrophs.
AB  - A large conductance, Ca(2+)-activated K+ channel of the BK type was examined in
      cultured pituitary melanotrophs obtained from adult male rats. In cell-attached
      recordings the slope conductance for the BK channel was approximately 190 pS and
      the probability (Po) of finding the channel in the open state at the resting
      membrane potential was low (< < 0.1). Channels in inside-out patches and in
      symmetrical 150 mM K+ had a conductance of approximately 260 pS. The lower
      conductance in the cell-attached recordings is provisionally attributed to an
      intracellular K+ concentration of approximately 113 mM. The permeability
      sequence, relative to K+, was K+ > Rb+ (0.87) > NH4+ (0.17) > Cs+ > or = Na+ (<
      or = 0.02). The slope conductance for Rb+ was much less than for K+. Neither Na+
      nor Cs+ carried measurable currents and 150 mM internal Cs+ caused a flickery
      block of the channel. Internal tetraethylammonium ions (TEA+) produced a fast
      block for which the dissociation constant at 0 mV (KD(0 mV)) was 50 mM. The KD(0
      mV) for external TEA+ was much lower, 0.25 mM, and the blocking reaction was
      slower as evidenced by flickery open channel currents. With both internal and
      external TEA+ the blocking reaction was bimolecular and weakly voltage dependent.
      External charybdotoxin (40 nM) caused a large and reversible decrease of Po. The
      Po was increased by depolarization and/or by increasing the concentration of
      internal Ca2+. In 0.1 microM Ca2+ the half-maximal Po occurred at approximately
      100 mV; increasing Ca2+ to 1 microM shifted the voltage for the half-maximal Po
      to -75 mV. The Ca2+ dependence of the gating was approximated by a fourth power
      relationship suggesting the presence of four Ca2+ binding sites on the BK
      channel.

PMID- 8661992
TI  - Chloride currents activated by calcitonin and cAMP in primary cultures of rabbit
      distal convoluted tubule.
AB  - Chloride (Cl-) conductances were studied in primary cultures of the bright part
      of rabbit distal convoluted tubule (DCTb) by the whole cell patch clamp
      technique. The bath solution (33 degrees C) contained (in mM): 140 NaCl, 1 CaCl2,
      10 N-2-hydroxy-ethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH 7.4 and the
      pipette solution 140 N-methyl-D-glucamine (NMDG)-Cl, 5 MgATP, 1 ethylene-glycol
      bis(b-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 10 HEPES, pH 7.4. We
      identified a Cl- current activated by 10(-5) M forskolin, 10(-3) M 8-bromo
      adenosine 3',5'-cyclic monophophosphate (8 Br-cAMP), 10(-6) M phorbol 12
      myristate 13-acetate (PMA), 10(-3) M intracellular adenosine 3',5'-cyclic
      monophophosphate (cAMP) and 10(-7) M calcitonin. The current-voltage relationship
      was linear and the relative ion selectivity was Br- > Cl- > > I- > glutamate.
      This current was inhibited by 10(-3) M diphenylamine-2-carboxylate (DPC) and 10(
      4) M 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) and was insensitive to 10(
      3) M 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). These
      characteristics are similar to those described for the cystic fibrosis
      transmembrane conductance regulator (CFTR) Cl- conductance. In a few cases,
      forskolin and calcitonin induced an outwardly rectifying Cl- current blocked by
      DIDS. To determine the exact location of the Cl- conductance 6-methoxy-1-(3
      sulfonatopropyl) quinolinium (SPQ) fluorescence experiments were carried out.
      Cultures seeded on collagen-coated permeable filters were loaded overnight with 5
      mM SPQ and the emitted fluorescence analyzed by laser-scan cytometry. Cl- removal
      from the apical solution induced a Cl- efflux which was stimulated by 10(-5) M
      forskolin, 10(-7) calcitonin and inhibited by 10(-5) M NPPB. In 140 mM NaBr,
      forskolin stimulated an apical Br- influx through the Cl- pathway. Forskolin and
      calcitonin had no effect on the basolateral Cl- permeability. Thus in DCTb
      cultured cells, exposure to calcitonin activates a Cl- conductance in the apical
      membrane through a cAMP-dependent mechanism.

PMID- 8661993
TI  - Inhibition of high-conductance, calcium-activated potassium channels of rabbit
      colon epithelium by magnesium.
AB  - High-conductance, Ca(2+)-activated K+ channels from the basolateral membrane of
      rabbit distal colon epithelial cells were reconstituted into planar phospholipid
      bilayers to examine the effect of Mg2+ on the single-channel properties. Mg2+
      decreases channel current and conductance in a concentration-dependent manner
      from both the cytoplasmic and the extracellular side of the channel. In contrast
      to other K+ channels, Mg2+ does not cause rectification of current through
      colonic Ca(2+)-activated K+ channels. In addition, cytoplasmic Mg2+ decreases the
      reversal potential of the channel. The Mg(2+)-induced decrease in channel
      conductance is relieved by high K+ concentrations, indicating competitive
      interaction between K+ and Mg2+. The monovalent organic cation choline also
      decreases channel conductance and reversal potential, suggesting that the effect
      is unspecific. The inhibition of channel current by Mg2+ and choline most likely
      is a result of electrostatic screening of negative charges located superficially
      in the channel entrance. But in addition to charge, other properties appear to be
      necessary for channel inhibition, as Na+ and Ba2+ are no (or only weak)
      inhibitors. Mg2+ and possibly other cations may play a role in the regulation of
      current through these channels.

PMID- 8661995
TI  - Evolutionary histories of highly repeated DNA families among the Artiodactyla
      (Mammalia).
AB  - Six highly repeated DNA families were analyzed using Southern blotting and
      fluorescence in situ hybridization in a comparative study of 46 species of
      artiodactyls belonging to seven of the eight extant taxonomic families. Two of
      the repeats, the dispersed bovine-Pst family and the localized 1.715 component,
      were found to have the broadest taxonomic distributions, being present in all
      pecoran ruminants (Giraffidae, Cervidae, Antilocapridae, and Bovidae), indicating
      that these repeats may be 25-40 million years old. Different 1.715 restriction
      patterns were observed in different taxonomic families, indicating that
      independent concerted evolution events have homogenized different motifs in
      different lineages. The other four satellite arrays were restricted to the Bovini
      and sometimes to the related Boselaphini and Tragelaphini. Results reveal that
      among the two compound satellites studied, the two components of the 1.711a
      originated simultaneously, whereas the two components of the 1.711b originated at
      two different historical times, perhaps as many as 15 million years apart.
      Systematic conclusions support the monophyly of the infraorder Pecora, the
      monophyly of the subfamily Bovinae (containing the Boselaphini, Bovini, and
      Tragelaphini), an inability to resolve any interrelationships among the other
      tribes of bovids, paraphyly of the genus Bos with respect to Bison, and a lack of
      molecular variation among two morphologically and ecologically distinct
      subspecies of African buffaloes (Syncerus caffer cafer and S. c. nanus).
      Cytogenetically, a reduction in diploid chromosome numbers through centric fusion
      in derived karyotypes is accompanied by a loss of centromeric satellite DNA. The
      nilgai karyotype contains an apparent dicentric chromosome as evidenced by the
      sites of 1.715 hybridization. Telomeric sequences have been translocated to the
      centromeres without concomitant chromosomal rearrangement in Thompson's gazelle.

PMID- 8661994
TI  - Ferritin gene organization: differences between plants and animals suggest
      possible kingdom-specific selective constraints.
AB  - Ferritin, a protein widespread in nature, concentrates iron approximately 10(11)
      10(12)-fold above the solubility within a spherical shell of 24 subunits; it
      derives in plants and animals from a common ancestor (based on sequence) but
      displays a cytoplasmic location in animals compared to the plastid in
      contemporary plants. Ferritin gene regulation in plants and animals is altered by
      development, hormones, and excess iron; iron signals target DNA in plants but
      mRNA in animals. Evolution has thus conserved the two end points of ferritin gene
      expression, the physiological signals and the protein structure, while allowing
      some divergence of the genetic mechanisms. Comparison of ferritin gene
      organization in plants and animals, made possible by the cloning of a dicot
      (soybean) ferritin gene presented here and the recent cloning of two monocot
      (maize) ferritin genes, shows evolutionary divergence in ferritin gene
      organization between plants and animals but conservation among plants or among
      animals; divergence in the genetic mechanism for iron regulation is reflected by
      the absence in all three plant genes of the IRE, a highly conserved, noncoding
      sequence in vertebrate animal ferritin mRNA. In plant ferritin genes, the number
      of introns (n = 7) is higher than in animals (n = 3). Second, no intron positions
      are conserved when ferritin genes of plants and animals are compared, although
      all ferritin gene introns are in the coding region; within kingdoms, the intron
      positions in ferritin genes are conserved. Finally, secondary protein structure
      has no apparent relationship to intron/exon boundaries in plant ferritin genes,
      whereas in animal ferritin genes the correspondence is high. The structural
      differences in introns/exons among phylogenetically related ferritin coding
      sequences and the high conservation of the gene structure within plant or animal
      kingdoms of the gene structure within plant or animal kingdoms suggest that
      kingdom-specific functional constraints may exist to maintain a particular
      intron/exon pattern within ferritin genes. In the case of plants, where ferritin
      gene intron placement is unrelated to triplet codons or protein structure, and
      where ferritin is targeted to the plastid, the selection pressure on gene
      organization may relate to RNA function and plastid/nuclear signaling.

PMID- 8661996
TI  - Evolution of Tribolium madens (Insecta, Coleoptera) satellite DNA through DNA
      inversion and insertion.
AB  - Two different satellite DNAs from tenebrionid species Tribolium madens (Insecta,
      Coleoptera) have been detected, cloned, and sequenced. Satellite I comprises 30%
      of the genome; it has a monomer size of 225 bp and a high A + T content of 74%.
      Satellite II, with a monomer size of 711 bp and A + T content of 70%, is less
      abundant, making 4% of the total DNA. Sequence variability of the monomers
      relative to consensus sequence is 4.1% and 1.2% for satellite I and II,
      respectively. Both satellites are localized in the heterochromatic regions of all
      chromosomes. A search for internal motifs showed that both satellites contain a
      related subsequences, about 100 bp long. The creation of satellite I monomer is
      explained by duplication of the basic subunit, followed by subsequent divergence
      by single point mutations, deletions, and gene conversion. Inversion of the
      subsequence in addition to its duplication has occurred in satellite II. The
      result of this inversion is possible formation of a long, stable dyad structure.
      The 408-bp sequence, inserted within satellite II monomer, shares no similarity
      with a basic subunit. Frequent direct repeats found within the inserted sequence
      point to its evolution by duplication of shorter motifs. It is proposed that both
      satellites have been derived from a common ancestral sequence whose duplication
      played a major role in the formation of satellite I monomer, while insertion of a
      new sequence together with inversion of an ancestral one induced the occurrence
      of satellite II.

PMID- 8661998
TI  - Tirant: a new retrotransposon-like element in Drosophila melanogaster.
AB  - In this paper we report a new retrotransposon-like element of Drosophila
      melanogaster called Tirant. This sequence is moderately repeated in the genome of
      this species and it has been found to be widely dispersed throughout its
      distribution area. From Southern blot and in situ analyses, this sequence appears
      to be mobile in D. melanogaster, since its chromosome location and the
      hybridization patterns vary among the different strains analyzed. In this way,
      partial sequencing of Tirant ends suggests that it is a retrotransposon, since it
      is flanked by two LTRs. The presence of sequences homologous to Tirant has been
      also investigated in 28 species of the genus Drosophila by means of Southern
      analyses. These sequences were only detected in species from melanogaster and
      obscura groups. These data suggest that ancestral sequences of Tirant appeared
      after the Sophophora radiation and before the divergence of those groups.

PMID- 8661997
TI  - Relationships between transposable elements based upon the integrase-transposase
      domains: is there a common ancestor?
AB  - The integrase domain of RNA-mediated elements (class I) and the transposase
      domain of DNA-mediated transposable elements (class II) were compared. A number
      of elements contain the DDE signature, which plays an important role in their
      integration. The possible relationships between mariner-Tc1 and IS elements,
      retrotransposons, and retroviruses were analyzed from an alignment of this
      region. The mariner-Tc1 superfamily, and LTR retrotransposons and retroviruses
      were found to be monophyletic groups. However, the IS elements of bacteria were
      found in several groups. These results were used to propose an evolutionary
      history that suggests a common ancestor for some integrases and transposases.

PMID- 8661999
TI  - Cloning and sequencing analysis of three amylase cDNAs in the shrimp Penaeus
      vannamei (Crustacea decapoda): evolutionary aspects.
AB  - In Penaeus vannamei, alpha-amylase is the most important glucosidase and is
      present as at least two major isoenzymes which have been purified. In order to
      obtain information on their structure, a hepatopancreas cDNA library constructed
      in phage lambda-Zap II (Strategene) was screened using a synthetic
      oligonucleotide based on the amino acid sequence of a V8 staphylococcal protease
      peptide of P. vannamei alpha-amylase. Three clones were selected: AMY SK 37 (EMBL
      sequence accession number: X 77318) is the most complete of the analyzed clones
      and was completely sequenced. It contains the complete cDNA sequence coding for
      one of the major isoenzymes of shrimp amylase. The deduced amino acid sequence
      shows the existence of a 511-residue-long pre-enzyme containing a highly
      hydrophobic signal peptide of 16 amino acids. Northern hybridization of total RNA
      with the amylase cDNA confirms the size of the messenger at around 1,600 bases.
      AMY SK 28, which contains the complete mature sequence of amylase, belonged to
      the same family characterized by a common 3' terminus and presented four amino
      acid changes. Some other variants of this family were also partially sequenced.
      AMY SK 20 was found to encode a minor variant of the protein with a different 3'
      terminus and 57 amino acid changes. Phylogenetic analysis established with the
      conserved amino acid regions of the (beta/alpha) eight-barrel domain and with the
      total sequence of P. vannamei showed close evolutionary relationships with
      mammals (59-63% identity) and with insect alpha-amylase (52-62% identity). The
      use of conserved sequences increased the level of similarity but it did not alter
      the ordering of the groupings. Location of the secondary structure elements
      confirmed the high level of sequence similarity of shrimp alpha-amylase with pig
      alpha-amylase.

PMID- 8662001
TI  - De Novo Synthesis of DNA-Like Molecules by Polynucleotide Phosphorylase In Vitro
AB  - In the presence of Mg2+ ions, polynucleotide phosphorylase (PNPase, EC 2.7.7.8)
      is known to synthesize RNA-like polymers using ribonucleoside-5'-diphosphate
      (NDP) substrates but to be unable to utilize deoxyribonucleoside substrates. Our
      experiments show that when MgCl2 is replaced by FeCl3, PNPase becomes able to
      synthesize deoxyheteropolymers using deoxyribonucleoside-5'-diphosphates (dNDPs).
      The deoxyheteropolymer formed from the four dNDPs is degraded by pancreatic
      DNase, but not by RNase, and is readily used as a template by DNA-dependent DNA
      polymerase. Synthesis of this DNA-like polymer is accomplished de novo without
      the help of any primer or preexisting template. What is more, dA/dG and dC/dT
      ratios of polymers synthesized by different bacterial PNPases closely match
      ratios found in DNA of the bacterial species the enzyme came from.

PMID- 8662000
TI  - Free-radical-induced mutation vs redox regulation: costs and benefits of genes in
      organelles.

PMID- 8662002
TI  - Sequence divergence in a family of variant surface glycoprotein genes from
      trypanosomes: coding region hypervariability and downstream recombinogenic
      repeats.
AB  - The surface of the parasitic protozoan Trypanosoma brucei spp. is covered with a
      dense coat consisting of a single type of glycoprotein molecule, the variant
      surface glycoprotein (VSG). There may be as many as 1,000 genes for VSG within
      the genome of T. brucei, and the switch of expression from one to another is the
      phenomenon of antigenic variation. As an approach to understanding the evolution
      of VSG genes we have determined the genomic DNA sequences of the eight genes
      encoding the variant surface glycoprotein 117 (VSG) family. From these data we
      have observed a number of features concerning the relationships between these
      genes: (1) there is a region of high variability confined to the N-terminus of
      the coding sequence, and comparison of the sequences with the available X-ray
      diffraction crystal structures suggests that two of the most variable stretches
      within the N-terminal domain are present on surface-exposed loops, indicating a
      role for epitope selection in evolution of these genes; (2) the 29 nucleotides
      surrounding the splice acceptor site are absolutely conserved in all eight 117
      VSG genes; (3) numerous insertion/deletion mutations are located within or
      immediately downstream of the C-terminal protein-coding sequences: (4) within 500
      bp downstream of the insertion/deletion mutations are one or two copies of a
      repeat motif highly homologous to the recombinogenic 76-bp repeat sequences
      present upstream of many VSG basic copy genes and the expression-linked copy.

PMID- 8662003
TI  - The amplification of oligonucleotide themes in the evolution of the myc
      protooncogene family.
AB  - The evolutionary past of intragenic repeats in protein-coding exons of c-, N-, L
      , and s-myc-protooncogene subfamilies was elucidated. Apparently these genes
      evolved by succession of distinct unit events rather than by a steady flow of
      random point mutations. An evolutionary event probably involved a duplication of
      the whole gene, which was followed by amplification of progressively shorter
      oligonucleotide themes and motifs. The repeats were either joined in tandem or
      one of the copies was transposed and integrated elsewhere within the same exon.
      In some instances multiple fragments of an amplified theme were integrated at
      several sites. Direct repeats were found to prevail over inverted ones. By
      reconstructing the fate of repeats in the course of evolution of vertebrates, the
      origins of some functional domains could be traced to the initial amplification
      event. For example, an N-myc-specific domain was created by tandem duplication of
      a single-copy theme of L-myc exon; at the time of divergence of the c-myc and N
      myc, the tandem duplex underwent a new round of duplication followed by
      transposition of the new copy, thus accounting for the formation of a new domain
      specific for c-myc. The model proposed here may be regarded as a molecular-level
      equivalent of the theory of punctuated equilibria.

PMID- 8662006
TI  - The Third Huxley

PMID- 8662004
TI  - Codon usage and base composition in Rickettsia prowazekii.
AB  - Codon usage and base composition in sequences from the A + T-rich genome of
      Rickettsia prowazekii, a member of the alpha Proteobacteria, have been
      investigated. Synonymous codon usage patterns are roughly similar among genes,
      even though the data set includes genes expected to be expressed at very
      different levels, indicating that translational selection has been ineffective in
      this species. However, multivariate statistical analysis differentiates genes
      according to their G + C contents at the first two codon positions. To study this
      variation, we have compared the amino acid composition patterns of 21 R.
      prowazekii proteins with that of a homologous set of proteins from Escherichia
      coli. The analysis shows that individual genes have been affected by biased
      mutation rates to very different extents: genes encoding proteins highly
      conserved among other species being the least affected. Overall, protein coding
      and intergenic spacer regions have G + C content values of 32.5% and 21.4%,
      respectively. Extrapolation from these values suggests that R. prowazekii has
      around 800 genes and that 60-70% of the genome may be coding.

PMID- 8662005
TI  - Phylogenetic analysis of the isopenicillin-N-synthetase horizontal gene transfer.
AB  - A phylogenetic study of the isopenicillin-N-synthetase (IPNS) gene sequence from
      prokaryotic and lower eukaryotic producers of beta-lactam antibiotics by means of
      a maximum-likelihood approach has been carried out. After performing an extensive
      search, rather than invoking a global molecular clock, the results obtained are
      best explained by a model with three rates of evolution. Grouped in decreasing
      order, these correspond to A. nidulans and then to the rest of the eukaryotes and
      prokaryotes, respectively. The estimated branching date between prokaryotic and
      fungal IPNS sequences (852 +/- 106 MY) strongly supports the hypothesis that the
      IPNS gene was horizontally transferred from bacterial beta-lactam producers to
      filamentous fungi.

PMID- 8662007
TI  - 18S rRNA suggests that Entoprocta are protostomes, unrelated to Ectoprocta.
AB  - The Ento- and Ectoprocta are sometimes placed together in the Bryozoa, which have
      variously been regarded as proto- or deuterostomes. However, Entoprocta have also
      been allied to the pseudocoelomates, while Ectoprocta are often united with the
      Brachiopoda and Phoronida in the (super)phylum Lophophorata. Hence, the
      phylogenetic relationships of these taxa are still much debated. We determined
      complete 18S rRNA sequences of two entoprocts, an ectoproct, an inarticulate
      brachiopod, a phoronid, two annelids, and a platyhelminth. Phylogenetic analyses
      of these data show that (1) entoprocts and lophophorates have spiralian,
      protostomous affinities, (2) Ento- and Ectoprocta are not sister taxa, (3)
      phoronids and brachiopods form a monophyletic clade, and (4) neither Ectoprocta
      or Annelida appear to be monophyletic. Both deuterostomous and pseudocoelomate
      features may have arisen at least two times in evolutionary history. These
      results advocate a Spiralia-Radialia-based classification rather than one based
      on the Protostomia-Deuterostomia concept.

PMID- 8662008
TI  - Analysis of the amino acid sequences of plant Bowman-Birk inhibitors.
AB  - Plant seeds contain a large number of protease inhibitors of animal, fungal, and
      bacterial origin. One of the well-studied families of these inhibitors is the
      Bowman-Birk family(BBI). The BBIs from dicotyledonous seeds are 8K, double-headed
      proteins. In contrast, the 8K inhibitors from monocotyledonous seeds are single
      headed. Monocots also have a 16K, double-headed inhibitor. We have determined the
      primary structure of a Bowman-Birk inhibitor from a dicot, horsegram, by
      sequential edman analysis of the intact protein and peptides derived from
      enzymatic and chemical cleavage. The 76-residue-long inhibitor is very similar to
      that of Macrotyloma axillare. An analysis of this inhibitor along with 26 other
      Bowman-Birk inhibitor domains (MW 8K) available in the SWISSPROT databank
      revealed that the proteins from monocots and dicots belong to related but
      distinct families. Inhibitors from monocots show larger variation in sequence.
      Sequence comparison shows that a crucial disulphide which connects the amino and
      carboxy termini of the active site loop is lost in monocots. The loss of a
      reactive site in monocots seems to be correlated to this. However, it appears
      that this disulphide is not absolutely essential for retention of inhibitory
      function. Our analysis suggests that gene duplication leading to a 16K inhibitor
      in monocots has occurred, probably after the divergence of monocots and dicots,
      and also after the loss of second reactive site in monocots.

PMID- 8662009
TI  - Molecular evolution of maize catalases and their relationship to other eukaryotic
      and prokaryotic catalases.
AB  - We have compared the nucleotide and protein sequences of the three maize catalase
      genes with other plant catalases to reconstruct the evolutionary relationship
      among these catalases. These sequences were also compared with other eukaryotic
      and prokaryotic catalases. Phylogenies based on distances and parsimony analysis
      show that all plant catalases derive from a common ancestral catalase gene and
      can be divided into three distinct groups. The first, and major, group includes
      maize Cat1, barley Cat1, rice CatB, and most of the dicot catalases. The second
      group is an apparent dicot-specific catalase group encompassing the tobacco Cat2
      and tomato Cat. The third is a monocot-specific catalase class including the
      maize Cat3, barley Cat2, and rice CatA. The maize Cat2 gene is loosely related to
      the first group. The distinctive features of monocot-specific catalases are their
      extreme high codon bias at the third position and low degree of sequence
      similarity to other plant catalases. Similarities in the intron positions for
      several plant catalase genes support the conclusion of derivation from a common
      ancestral gene. The similar intron position between bean catalases and human
      catalase implies that the animal and plant catalases might have derived from a
      common progenitor gene sequence.

PMID- 8662011
TI  - Maximum-Likelihood Models for Combined Analyses of Multiple Sequence Data
AB  - Abstract. Models of nucleotide substitution were constructed for combined
      analyses of heterogeneous sequence data (such as those of multiple genes) from
      the same set of species. The models account for different aspects of the
      heterogeneity in the evolutionary process of different genes, such as differences
      in nucleotide frequencies, in substitution rate bias (for example, the
      transition/transversion rate bias), and in the extent of rate variation across
      sites. Model parameters were estimated by maximum likelihood and the likelihood
      ratio test was used to test hypotheses concerning sequence evolution, such as
      rate constancy among lineages (the assumption of a molecular clock) and
      proportionality of branch lengths for different genes. The example data from a
      segment of the mitochondrial genome of six hominoid species (human, common and
      pygmy chimpanzees, gorilla, orangutan, and siamang) were analyzed. Nucleotides at
      the three codon positions in the protein-coding regions and from the tRNA-coding
      regions were considered heterogeneous data sets. Statistical tests showed that
      the amount of evolution in the sequence data reflected in the estimated branch
      lengths can be explained by the codon-position effect and lineage effect of
      substitution rates. The assumption of a molecular clock could not be rejected
      when the data were analyzed separately or when the rate variation among sites was
      ignored. However, significant differences in substitution rate among lineages
      were found when the data sets were combined and when the rate variation among
      sites was accounted for in the models. Under the assumption that the orangutan
      and African apes diverged 13 million years ago, the combined analysis of the
      sequence data estimated the times for the human-chimpanzee separation and for the
      separation of the gorilla as 4.3 and 6.8 million years ago, respectively.

PMID- 8662010
TI  - Protein sequences indicate that turtles branched off from the amniote tree after
      mammals.
AB  - The phylogenetic relationships among the major groups of amniote vertebrates
      remain a matter of controversy. Various alternatives for the position of the
      turtles have been proposed, branching off either before or after the mammals. To
      discover the phylogenetic position of turtles in relation to mammals and birds,
      we have determined cDNA sequences for the eye lens proteins alpha A- and alpha B
      crystallin of the red-eared slider turtle (Trachemys scripta elegans). In
      addition, databases were searched for turtle protein sequences, for which
      mammalian, avian, and outgroup orthologs were available. All sequences were
      analyzed by three phylogenetic tree reconstruction methods (neighbor-joining,
      maximum parsimony, and maximum likelihood). Including the alpha-crystallins, 7
      out of 12 proteins support a sister-group relation of turtles and birds with all
      3 methods. For each of the other five proteins no topology was consistently
      preferred by the three approaches. Analyses of the combined amino acid data
      (1,695 aligned sites) also give extremely strong evidence that turtles are nearer
      to birds, indicating that mammals branched off before the divergence between
      turtles and birds occurred.

PMID- 8662013
TI  - ISME Membership Listing

PMID- 8662012
TI  - On malleability in the genetic code.
AB  - To explain now-numerous cases of codon reassignment (departure from the
      "universal" code), we suggest a pathway in which the transformed codon is
      temporarily ambiguous. All the unusual tRNA activities required have been
      demonstrated. In addition, the repetitive use of certain reassignments, the
      phylogenetic distribution of reassignments, and the properties of present-day
      reassinged tRNAs are each consistent with evolution of the code via an ambiguous
      translational intermediate.

PMID- 8662014
TI  - Polymorphism and concerted evolution in a tandemly repeated gene family: 5S
      ribosomal DNA in diploid and allopolyploid cottons.
AB  - 5S RNA genes and their nontranscribed spacers are tandemly repeated in plant
      genomes at one or more chromosomal loci. To facilitate an understanding of the
      forces that govern 5S rDNA evolution, copy-number estimation and DNA sequencing
      were conducted for a phylogenetically well-characterized set of 16 diploid
      species of cotton (Gossypium) and 4 species representing allopolyploid
      derivatives of the diploids. Copy number varies over twentyfold in the genus,
      from approximately 1,000 to 20,000 copies/2C genome. When superimposed on the
      organismal phylogeny, these data reveal examples of both array expansion and
      contraction. Across species, a mean of 12% of nucleotide positions are
      polymorphic within individual arrays, for both gene and spacer sequences. This
      shows, in conjunction with phylogenetic evidence for ancestral polymorphisms that
      survive speciation events, that intralocus concerted evolutionary forces are
      relatively weak and that the rate of interrepeat homogenization is approximately
      equal to the rate of speciation. Evidence presented also shows that duplicated 5S
      rDNA arrays in allopolyploids have retained their subgenomic identity since
      polyploid formation, thereby indicating that interlocus concerted evolution has
      not been an important factor in the evolution of these arrays. A descriptive
      model, one which incorporates the opposing forces of mutation and homogenization
      within a selective framework, is outlined to account for the empirical data
      presented. Weak homogenizing forces allow equivalent levels of sequence
      polymorphism to accumulate in the 5S gene and spacer sequences, but fixation of
      mutations is nearly prohibited in the 5S gene. As a consequence, fixed
      interspecific differences are statistically underrepresented for 5S genes. This
      result explains the apparent paradox that despite similar levels of gene and
      spacer diversity, phylogenetic analysis of spacer sequences yields highly
      resolved trees, whereas analyses based on 5S gene sequences do not.

PMID- 8662015
TI  - Strong evolutionary conservation of broadly expressed protein isoforms in the
      troponin I gene family and other vertebrate gene families.
AB  - It is well established that different protein classes undergo molecular evolution
      at different rates, presumably reflecting differing functional constraints.
      However, it is also the case that different isoforms of the "same" protein,
      encoded by a multigene family, may evolve at different rates. Here I report a
      relationship within gene families between isoform evolutionary rate and gene
      expression profile: Broadly expressed isoforms show stronger sequence
      conservation than do narrowly expressed isoforms. This observation emerged
      initially from cDNA cloning and sequencing studies, described here, of a
      vertebrate gene family encoding three differentially expressed isoforms of the
      muscle protein troponin I. However, the expression breadth/sequence conservation
      relationship applies to vertebrate gene families in general. In a broad and
      arbitrary survey sampling of sequence data on well-characterized vertebrate gene
      families, I found that in 14/15 families the most strongly conserved isoform was
      the most broadly expressed isoform, or one of several similarly broadly expressed
      isoforms. Broadly expressed isoforms are presumably subjected to greater negative
      selection pressure because they must function in a more diverse biochemical
      environment than do narrowly expressed isoforms. The expression
      breadth/evolutionary rate relationship has several interesting implications
      regarding the overall process of gene family evolution by duplication/divergence
      from ancestral genes.

PMID- 8662016
TI  - Evolutionary history of introns in a multidomain globin gene.
AB  - The Artemia hemoglobin contains two subunits that are similar or different chains
      of nine globin domains. The domains are ancestrally related and are presumed to
      be derived from copies of an original single-domain parent gene. Since the gene
      copies have remained in the same environment for several hundred million years
      they provide an excellent model for the investigation of intron stability. The
      cDNA for one of the two types of nine-domain subunit (domains T1-T9) has been
      sequenced. Comparison with the corresponding genomic DNA reveals a total of 17
      intradomain introns. Fourteen of the introns are in locations on the protein that
      are conventional in globins of other species. In eight of the nine domains an
      intron corresponds to the B helix, amino acid B12, following the second
      nucleotide (phase 2), and in six domains a G-helix intron is located between G6
      and G7 (phase 0). The consistency of this pattern is supportive of the introns
      having been inherited from a single-domain parent gene. The remaining three
      introns are in unconventional locations. Two occur in the F helix, either in
      amino acid F3 (phase 1) in domain T3, or between F2 and F3 (phase 0) in domain
      T6. The two F introns strengthen an interpretation of intron inheritance since
      globin F introns are rare, and in domains T3 and T6 they replace rather than
      supplement the conventional G introns, as though displacement from G to F
      occurred before that part of the gene became duplicated. It is inferred that one
      of the F introns subsequently moved by one nucleotide. Similarly, the third
      unconventional intron location is the G intron in domain T4 which is in G6, phase
      2, one nucleotide earlier than the other G introns. Domain T4 is also unusual in
      lacking a B intron. The pattern of introns in the Artemia globin gene supports a
      concept of general positional stability but the exceptions, where introns have
      moved out of reading frame, or have moved by several codons, or have been
      deleted, suggest that intron displacements can occur after inheritance from an
      ancient source.

PMID- 8662017
TI  - Evolutionary relationship of HLA-DRB genes inferred from intron sequences.
AB  - The major histocompatibility complex (Mhc) consists of class I and class II
      genes. In the human Mhc (HLA) class II genes, nine DRB loci have been identified.
      To elucidate the origin of these duplicated loci and allelic divergences at the
      most polymorphic DRB1 locus, introns 4 and 5 as well as the 3' untranslated
      region (altogether approximately 1,000 base pairs) of seven HLA-DRB loci, three
      HLA-DRB1 alleles, and nine nonhuman primate DRB genes were examined. It is shown
      that there were two major diversification events in HLA-DRB genes, each involving
      gene duplications and allelic divergences. Approximately 50 million years (my)
      ago, DRB1*04 and an ancestor of the DRB1*03 cluster (DRB1*03, DRB1*15, and DRB3)
      diverged from each other and DRB5, DRB7, DRB8, and an ancestor of the DRB2
      cluster (DRB2, DRB4, and DRB6) arose by gene duplication. Later, about 25 my ago,
      DRB1*15 diverged from DRB1*03, and DRB3 was duplicated from DRB1*03. Then, some
      20 my ago, the lineage leading to the DRB2 cluster produced two new loci, DRB4
      and DRB6. The DRB1*03 and DRB1*04 allelic lineages are extraordinarily old and
      have persisted longer than some duplicated genes. The orthologous relationships
      of DRB genes between human and Old World monkeys are apparent, but those between
      Catarrhini and New World monkeys are equivocal because of a rather rapid
      expansion and contraction of primate DRB genes by duplication and deletion.

PMID- 8662018
TI  - Investigation of the RH locus in gorillas and chimpanzees.
AB  - The human Rh blood-group system is encoded by two homologous genes, RhD and RhCE.
      The RH genes in gorillas and chimpanzees were investigated to delineate the
      phylogeny of the human RH genes. Southern blot analysis with an exon 7-specific
      probe suggested that gorillas have more than two RH genes, as has recently been
      reported for chimpanzees. Exon 7 was well conserved between humans, gorillas, and
      chimpanzees, although the exon 7 nucleotide sequences from gorillas were more
      similar to the human D gene, whereas the nucleotide sequences of this exon in
      chimpanzees were more similar to the human CE gene. The intron between exon 4 and
      exon 5 is polymorphic and can be used to distinguish the human D gene from the CE
      gene. Nucleotide sequencing revealed that the basis for the intron polymorphism
      is an Alu element in CE which is not present in the D gene. Examination of
      gorilla and chimpanzee genomic DNA for this intron polymorphism demonstrated that
      the D intron was present in all the chimpanzees and in all but one gorilla. The
      CE intron was found in three of six gorillas, but in none of the seven
      chimpanzees. Sequence data suggested that the Alu element might have previously
      been present in the chimpanzee RH genes but was eliminated by excision or
      recombination. Conservation of the RhD gene was also apparent from the complete
      identity between the 3'-noncoding region of the human D cDNA and a gorilla
      genomic clone, including an Alu element which is present in both species. The
      data suggest that at least two RH genes were present in a common ancestor of
      humans, chimpanzees, and gorillas, and that additional RH gene duplication has
      taken place in gorillas and chimpanzees. The RhCE gene appears to have diverged
      more than RhD among primates. In addition, the RhD gene deletion associated with
      the Rh-negative phenotype in humans seems to have occurred after speciation.

PMID- 8662019
TI  - The mariner transposable element in natural populations of Drosophila teissieri.
AB  - The mariner transposable elements of several natural populations of Drosophila
      teissieri, a rainforest species endemic to tropical Africa, were studied. Natural
      populations trapped along a transect from Zimbabwe to the Ivory Coast were
      analyzed by Southern blotting, in situ hybridization, cloning, and sequencing of
      PCR products. The Brazzaville population had some full-length elements, while the
      remaining populations had mainly deleted elements. The main class of deleted
      elements lacked a 500-bp segment. A mechanism is proposed that could generate
      such elements rapidly. In situ hybridizations showed that there are no mariner
      elements in pericentromeric heterochromatin. Finally, the phylogeny of the Mos1
      like mariner full-length elements is consistent with vertical transmission from
      the ancestor of the melanogaster subgroup.

PMID- 8662020
TI  - Molecular genetics and evolution of stomach and nonstomach lysozymes in the
      hoatzin.
AB  - Multiple genes of the hoatzin encoding stomach lysozyme c and closely related
      members of this calcium-binding lysozyme c group were cloned from a genomic DNA
      library and sequenced. There are a minimum of five genes represented among these
      sequences that encode two distinct groups of protein sequences. One group of
      three genes corresponds to the stomach lysozyme amino acid sequences, and the
      remaining genes encode predicted proteins that are more basic in character and
      share several sequence identities with the pigeon egg-white lysozyme rather than
      with the hoatzin stomach lysozymes. Despite these structural similarities between
      some of the hoatzin gene products and the pigeon lysozyme, phylogenetic analyses
      indicate that all of the hoatzin sequences are closely related to one another.
      This is borne out by the relatively small genetic distances even in the intronic
      regions, which are not subject to the selective pressures operating on the coding
      regions of the stomach lysozymes. These results suggest that multiple gene
      duplication events have occurred during the evolution of hoatzin lysozymes.

PMID- 8662021
TI  - The distance between bacterial species in sequence space.
AB  - Despite the revolution caused by information from macromolecular sequences, the
      basis of bacterial classification remains the genus and the species. How do these
      terms relate to the variety of bacteria that exist on earth? In this paper, the
      inter- and intraspecies differences in amino acid sequence of several bacterial
      electron transport proteins, cytochromes c, and blue copper proteins are
      compared. For the soil and water organisms studied, bacterial species can be
      classed as "tight" when there is little intraspecies variation, or "loose" when
      this variation is large. For this set of proteins and organisms, interspecies
      variation is much larger than that within a species. Examples of "tight" species
      are Pseudomonas aeruginosa and Rhodobacter sphaeroides, while Pseudomonas
      stutzeri and Rhodopseudomonas palustris are loose species. The results are
      discussed in the context of the origin and age of bacterial species, and the
      distribution of genomes in "sequence space." The situation is probably different
      for commensal or pathogenic bacteria, whose population structure and evolution
      are linked to the properties of another organism.

PMID- 8662022
TI  - Evolution of structure and substrate specificity in D-alanine:D-alanine ligases
      and related enzymes.
AB  - The D-alanine:D-alanine-ligase-related enzymes can have three preferential
      substrate specificities. Usually, these enzymes synthesize D-alanyl-D-alanine. In
      vancomycin-resistant Gram-positive bacteria, structurally related enzymes
      synthesize D-alanyl-D-lactate or d-alanyl-d-serine. The sequence of internal
      fragments of eight structural d-alanine:d-alanine ligase genes from enterococci
      has been determined. Alignment of the deduced amino acid sequences with those of
      other related enzymes from Gram-negative and Gram-positive bacteria revealed the
      presence of four distinct sequence patterns in the putative substrate-binding
      sites, each correlating with specificity to a particular substrate (D-alanine:D
      lactate ligases exhibited two patterns). Phylogenetic analysis showed different
      clusters. The enterococcal subtree was largely superimposable on that derived
      from 16S rRNA sequences. In lactic acid bacteria, structural divergence due to
      differences in substrate specificity was observed. Glycopeptide resistance
      proteins VanA and VanB, the VanC-type ligases, and DdlA and DdlB from enteric
      bacteria and Haemophilus influenzae constituted separate clusters.

PMID- 8662023
TI  - Common origin of arthropod tyrosinase, arthropod hemocyanin, insect hexamerin,
      and dipteran arylphorin receptor.
AB  - Dipteran arylphorin receptors, insect hexamerins, cheliceratan and crustacean
      hemocyanins, and crustacean and insect tyrosinases display significant sequence
      similarities. We have undertaken a systematic comparison of primary and secondary
      structures of these proteins. On the basis of multiple sequence alignments the
      phylogeny of these proteins was investigated. Hexamerin subunits, hemocyanin
      subunits, and tyrosinases share extensive similarities throughout the entire
      amino acid sequence. Our studies suggest the origin of arthropod hemocyanins from
      ancient tyrosinase-like proteins. Insect hexamerins likely evolved from
      hemocyanins of ancient crustaceans, supporting the proposed sister-group position
      of these subphyla. Arylphorin receptors, responsible for incorporation of
      hexamerins into the larval fat body of diptera, are related to hexamerins,
      hemocyanins, and tyrosinase. The receptor sequences display extensive
      similarities to the first and third domains of hemocyanins and hexamerins. In the
      middle region only limited amino acid conservation was observed. Elements
      important for hexamer formation are deleted in the receptors. Phylogenetic
      analysis indicated that dipteran arylphorin receptors diverged from ancient
      hexamerins, probably early in insect evolution.

PMID- 8662024
TI  - Influence of stenotic valve geometry on measured pressure gradients and
      ventricular work: the relationship between morphology and flow.
AB  - The physiologic impact of aortic valve stenosis is most directly reflected by an
      increased workload placed on the ventricle. In the pediatric population the
      morphology of aortic stenosis varies considerably. Fluid dynamic principles
      suggest that different morphologies may require the ventricle to accelerate blood
      to different maximal velocities for constant cardiac outputs and valve areas,
      resulting in different ventricular workloads. This study examined this important
      concept in in vitro models designed to isolate the effect of valve geometry on
      distal velocity, pressure gradients, and proximal work. Four stenotic valve
      morphologies were examined using a variable-voltage pump system. For constant
      orifice areas and flows, markedly different workloads were required by the pump,
      and this difference was reflected in direct measurements of pressure gradient and
      Doppler predictions of gradient. These fundamental fluid dynamic studies isolate
      the relationship between flow, work, and stenotic valve morphology. Different
      orifice geometries affect the value of the coefficient of contraction, which is
      reflected in different maximum velocity values for stenosis with constant
      anatomic areas and flows. The proximal pumping chamber must generate different
      levels of force to achieve these different velocities, and this variability is
      reflected in the clinically measured pressure gradient.

PMID- 8662025
TI  - Electrogram patterns associated with successful radiofrequency ablation of
      accessory pathways in children.
AB  - Electrograms observed prior to successful and unsuccessful ablation trials in 33
      patients (362 attempts) with manifest pathways and 18 patients (194 attempts)
      with concealed pathways were compared to identify the electrogram patterns that
      are associated with successful radiofrequency ablation of accessory
      atrioventricular connections in young patients (mean age 12.7 years; range 4-22
      years). Success was defined as permanent or transient interruption of conduction
      in the accessory connection. Predictors of success in patients with manifest
      pathways were local ventricular preexcitation (p &equals 0.0001), left-sidedness
      (43 or 174) of the accessory connection compared (p &equals 0.04) to right
      sidedness (27 of 172), a probable Kent bundle potential (29 of 84 versus 39 of
      256; p &equals 0.0001), and short antegrade atrioventricular conduction intervals
      (53.1 +/- 31.9 ms versus 64.6 +/- 32.0 ms; p &equals 0.02). Predictors of success
      in patients with concealed pathways were short ventriculoatrial conduction times
      (103.3 +/- 35.8 ms versus 117.9 +/- 34.8 ms; p &equals 0.01), and left-sided (42
      of 125) pathways (p &equals 0.03; versus right-sided, 11 of 60). The presence of
      a Kent bundle potential was not significant. We conclude that specific
      electrogram patterns can predict successful ablation of either manifest or
      concealed accessory pathways. Use of these criteria may reduce the delivery of
      unnecessary energy to young myocardium.

PMID- 8662026
TI  - Abnormalities in lymphocyte populations in infants with neural crest
      cardiovascular defects.
AB  - The DiGeorge syndrome has been associated with various immune deficits.
      Embryologically, defects of the neural crest are associated with conotruncal and
      aortic arch abnormalities. The objective of this study was to determine if
      children with neural crest congenital heart defects can have subtle but
      significant immunodeficiencies. Complete blood counts with differential counts
      and a standard lymphocyte immunophenotyping panel of selected monoclonal
      antibodies were performed on peripheral blood from 20 children with neural crest
      cardiac disease and 34 normal newborns. The children with cardiac disease were
      grouped as survivors and nonsurvivors. The mean total white blood cell count was
      similar for all groups, but the percent lymphocytes was significantly less in the
      nonsurvivors than in the survivors and normal newborns (p < 0. 02). The
      lymphocyte subsets affected were CD2, CD3, and CD4. When the cardiac patients
      were compared to the normal newborns, again differences in lymphocyte subsets
      CD2, CD3, and CD4 were seen. When comparing nonsurvivors with survivors, the mean
      percentages of the CD2, CD3, and CD4 T lymphocyte markers, as well as the mean
      lymphocyte, B cell (CD20), and natural killer cell (CD16) percentages were all
      lower in the nonsurvivors. It was concluded that abnormalities in specific
      lymphocyte populations and their subsets may be predictors of infants at greatest
      risk for immunodeficiency complications. Therefore children with neural crest
      cardiac defects should have evaluations of lymphocyte subsets at birth and be
      treated as if potentially immunodeficient.

PMID- 8662028
TI  - Effects of gender, age, and heart rate on QT intervals in children.
AB  - The objective of this study was to determine if gender, age, and heart rate
      affect corrected QT intervals in children. Electrocardiograms were obtained from
      781 healthy children 10-18 years of age. Corrected QT intervals were
      significantly (p < 0.0005) greater for girls than for boys in the entire
      population and for each age group over 14 years. The corrected QT interval varied
      inversely with age and directly with heart rate. Hence gender, age, and heart
      rate should be considered when diagnosing long QT syndrome.

PMID- 8662027
TI  - Parameters of iron deficiency in children with cyanotic congenital heart disease.
AB  - A group of 67 children with cyanotic congenital heart disease (CCHD) were
      studied, and 35 were given iron treatment according to a regimen that gives iron
      to patients with a hematocrit (Hct) below 60%. The patients were categorized as
      iron-deficient and iron-sufficient according to their transferrin saturation and
      ferritin values. The pretreatment hemoglobin (Hb) and Hct values of the groups
      were similar. The mean Hct was nearly three times as much as the mean Hb in the
      iron-sufficient group and more than three times as much as the Hb in the iron
      deficient group. Excessive erythrocytosis in the iron-deficient group was
      impressive. Mean corpuscular volume (MCV) values were below 72.7 fl in all of the
      iron-deficient patients. After treatment the Hb, Hct, transferrin saturation, and
      ferritin increased significantly in both groups, with the increments greater in
      the iron-deficient group. Increments in the erythrocyte (RBC) count were
      significant in the iron-sufficient group but insignificant in the iron-deficient
      one. Increments of MCV in the iron-deficient group were significant but
      insignificant in the iron-sufficient group. Our study demonstrated that
      prediction of Hb, RBC count, and MCV, measurements of which are easy and
      inexpensive and require little blood, can suffice for the diagnosis of iron
      deficiency in patients with CCHD without altering systemic perfusion.

PMID- 8662029
TI  - Respiratory syncytial virus infection in children with congenital heart disease:
      a review.
AB  - This paper reviews recent changes in morbidity and mortality of respiratory
      syncytial virus (RSV) infection in infants with congenital heart disease.
      Mortality since the late 1970s has declined substantially, from approximately 37%
      to 3%. Although the frequency of admission to intensive care units has declined
      from approximately 60% to 30%, the frequency for mechanical ventilatory support
      has not changed significantly. Because mortality dropped prior to the widespread
      use of ribavirin, it is difficult to ascribe the improvement to this therapy. In
      infants with congenital heart disease (CHD), nosocomial infection remains a
      significant problem, accounting for approximately 33% of the RSV cases. Some
      authors report significant reductions in hospital-acquired RSV by use of gloves
      and gowns for contacts with infectious cases. Efforts at primary prevention have
      encountered problems with development of an RSV vaccine. Preliminary data from
      studies of passive immunization using immune globulins with high RSV antibody
      titers suggest that this therapy may reduce the severity of RSV infection in
      infants with serious heart disease.

PMID- 8662030
TI  - Longitudinal observations of left ventricular end-diastolic dimension in children
      using echocardiography.
AB  - Previous studies have evaluated left ventricular dimensions in children using two
      dimensional echocardiography, but there is little information on gender
      differences and on the longitudinal development of the dimensions of the left
      ventricle. Our objective was to assess, by two-dimensional echocardiography, the
      normal size of the left ventricular end-diastolic dimension (LVDd) in children,
      its differences by sex, and the rate of its development using height, weight, and
      body surface area as indices. The study group consisted of 437 patients (264
      males, 173 females) with a history of Kawasaki disease but with no coronary
      artery lesions, as determined by repeated echocardiographic and other
      examinations. A total of 1595 examinations were done over an average of 6.7
      years. The increase in LVDd was significantly more rapid in (1) children below 2
      years of age than in older children of either sex and (2) in males who were 11
      and 12 years old than in males who were 10 years old. Significant gender
      differences were observed in the increase in LVDd by all indices (p < 0.001).

PMID- 8662032
TI  - Transcatheter vascular occlusion of the small patent ductus arteriosus: an
      alternative method.
AB  - The current strategies concerning a small (</=2 mm) patent ductus arteriosus
      (PDA) include surgical ligation, transcatheter implantation of the Rashkind
      occluder device, or no intervention requiring indefinite endocarditis
      precautions. Five patients have undergone successful transcatheter closure of a
      small-caliber PDA utilizing a single 3 mm Gianturco occluder coil as an
      alternative to surgical ligation. The coil was delivered to traverse the
      narrowest dimension of the PDA, leaving loops of coil in both the pulmonary and
      aortic ends of the ductus. All PDAs were successfully occluded, and the duration
      of hospitalization for all patients was 1 day. At latest follow-up (11 +/- 2
      months), echocardiography demonstrates complete ductus occlusion in all patients,
      with no obstruction to left pulmonary arterial or descending aortic flow.
      Transcatheter coil occlusion of the small ductus is an easily accomplished, safe,
      effective alternative to surgical ligation, thereby avoiding a lateral
      thoracotomy incision, shortening hospitalization, and reducing costs.

PMID- 8662031
TI  - Noninvasive evaluation of systolic pressures of pulmonary artery and right
      ventricle using contrast-enhanced doppler echocardiography: comparative study
      using sonicated albumin or glucose solution.
AB  - Evaluation of pulmonary arterial pressure is essential for the diagnosis and
      management of patients with congenital heart disease; it is usually done by
      cardiac catheterization. An alternative, noninvasive method may be clinically
      more useful. The purpose of this study was to assess the usefulness of the
      noninvasive determination of systolic pressure of the pulmonary artery and right
      ventricle by contrast-enhanced Doppler echocardiography. We selected 30 pediatric
      patients (28 with trivial or nonsignificant tricuspid regurgitant Doppler signals
      and 2 with significant tricuspid regurgitant Doppler signals) aged 2 months to 21
      years. The flow velocity of tricuspid regurgitation was measured with continuous
      wave Doppler of the right ventricular inflow view or left parasternal or apical
      four-chamber view before and after injection of two types of contrast medium
      (hand-agitated 5% glucose or sonicated albumin). The systolic pressure of the
      pulmonary artery was assessed as the estimated right ventricular systolic
      pressure (albumin method) minus the peak pressure gradient across the pulmonary
      valve (nonenhanced Doppler method). After injection of hand-agitated 5% glucose
      and sonicated albumin, trivial tricuspid regurgitation signals were enhanced in
      25 of 28 patients (89%). In two patients, spectral envelopes were well defined
      enough to obtain the peak systolic velocity of the tricuspid regurgitation jet
      without contrast medium injection. Peak velocity was not altered by injection of
      contrast medium in these patients. There was significant correlation between the
      estimation by contrast-enhanced Doppler using hand-agitated 5% glucose and the
      cardiac catheterization measurement of the transtricuspid pressure gradient (r =
      0.88). The transtricuspid pressure gradients obtained by continuous-wave Doppler
      during sonicated albumin enhancement corresponded closely to those measured by
      cardiac catheterization (r = 0.95). Pulmonary arterial and right ventricular
      systolic pressures measured by Doppler using sonicated albumin and those obtained
      by cardiac catheterization were highly correlated (right ventricle, r = 0.96;
      pulmonary artery, r = 0.95). In conclusion, this technique may be a valuable
      noninvasive method for determining accurate right ventricular and pulmonary
      arterial systolic pressures.

PMID- 8662033
TI  - Magnetic resonance imaging demonstration of "remodeling" of the aorta following
      balloon angioplasty of discrete native coarctation.
AB  - Assessment of the hemodynamic and anatomic results following balloon angioplasty
      of discrete native coarctation of the aorta, with particular attention to
      "remodeling," has required repeat cardiac catheterization and angiography, which
      is invasive and has limited resolution. Eight patients with hypertension and
      discrete native coarctation with an otherwise normally developed aortic arch
      underwent angioplasty at 5.0 +/- 6.8 years of age. Angiographic cross-sectional
      areas of the aorta indexed to body surface area at the isthmus (I), coarctation
      site (C), and 1 cm distal to the coarctation site (Cd) pre- and postangioplasty
      were compared with MRI-indexed cross-sectional areas 18 +/- 10 months (MRI-1) and
      35 +/- 11 months (MRI-2) postangioplasty. From preangioplasty to MRI-2, the
      isthmus was smaller (149 +/- 22 versus 127 +/- 27 mm2/m2; p < 0. 05). The
      coarctation site was larger postangioplasty (25 +/- 9 versus 116 +/- 40 mm2/m2; p
      < 0.001) with continued growth at latest follow-up (116 +/- 40 versus 164 +/- 36
      mm2/m2; p < 0.01). The segment 1 cm distal to the coarctation site continued to
      decrease in area at latest follow-up (267 +/- 78 versus 163 +/- 38 mm2/m2; p < 0.
      001). I versus C versus Cd at MRI-2 were similar, whereas postangioplasty and MRI
      1 cross-sectional area measurements were significantly different. Following
      angioplasty of discrete native coarctation, the aorta becomes more uniform or
      undergoes "remodeling." Noninvasive MRI is an effective means of evaluating the
      anatomic result following balloon angioplasty, obviating the need for repeated
      invasive cardiac catheterizations.

PMID- 8662034
TI  - Ventricular conduction defect in isolated noncompaction of the ventricular
      myocardium.
AB  - A 9-month-old boy and 4-month-old girl presented with severe heart failure. The
      electrocardiogram showed complete and "incomplete" left bundle branch block,
      respectively. In both infants noncompaction of the ventricular myocardium was
      diagnosed with two-dimensional echocardiography. These cases are thought to be
      the first descriptions of the occurrence of left bundle branch block with
      noncompaction of the ventricular myocardium. Noncompaction of the ventricular
      myocardium should be added to the list of the causes for left bundle branch block
      in children.

PMID- 8662035
TI  - Fetal idiopathic ventricular tachycardia with nonimmune hydrops: benign course.
AB  - A case of idiopathic ventricular tachycardia of left ventricular origin in a
      hydropic fetus is presented. The accuracy of fetal echocardiography for
      diagnosing this type of arrhythmia is emphasized, as is its importance in
      determining appropriate postnatal treatment which in this case resulted in an
      unusually benign course.

PMID- 8662036
TI  - Papillary fibroelastoma of the mitral valve in a 3-year-old child: case report.
AB  - A 3.5-year-old boy with stroke secondary to embolization of a primary cardiac
      tumor is presented. The diagnosis was made by two-dimensional echocardiography
      and confirmed intraoperatively. A papillary fibroelastoma was identified
      histologically. It is a rare condition and a diagnostic challenge, as patients
      are asymptomatic before embolization. In view of the severe consequences, prompt
      surgery is recommended.

PMID- 8662037
TI  - Intracardiac yolk sac tumor: echocardiographic evaluation.
AB  - To our knowledge, this case of an abdominal yolk sac tumor with extensive cardiac
      involvement is the first to be reported in a pediatric patient. The report
      describes the echocardiographic findings of the tumor and the role of
      echocardiography in providing important information for patient management
      decisions.

PMID- 8662038
TI  - Hemopericardium and cardiac tamponade as presenting findings of anomalous left
      coronary artery syndrome complicated by transmural myocardial infarction.
AB  - Anomalous origin of the left coronary artery from the pulmonary artery most
      commonly presents in infancy with clinical features of dilated cardiomyopathy,
      congestive heart failure or cardiogenic shock as a result of myocardial ischemia.
      We report the first presentation of this disorder with hemorrhagic pericardial
      effusion and cardiac tamponade as a result of a transmural myocardial infarction.
      The list of other causes of hemorrhagic pericardial effusion must now include
      anomalous left coronary artery syndrome.

PMID- 8662039
TI  - Therapeutic strategy in a 9-month-old child with pulmonary sling: need for
      bronchoscopic evaluation.
AB  - A 9-month-old child presented suffering from repeated severe infections of the
      lower respiratory tract. Bronchoscopy revealed a tracheal stenosis, suggestive of
      a vascular anomaly of the great arteries. A second significant stenosis of the
      left main stem bronchus was observed that was suspected to be due to a ligamentum
      arteriosum. Heart catheterization confirmed the diagnosis of an abnormal origin
      of the left pulmonary artery (pulmonary sling). Based on the bronchoscopic and
      angiographic findings a pulmonary ring was suspected. A dissection of the
      ligamentum arteriosum was performed. At readmission 4 weeks postoperatively the
      child was asymptomatic and the left main bronchus was patent.

PMID- 8662040
TI  - Congenital heart disease in partial trisomy 8p with special reference to
      pulmonary hypertension in two siblings.

PMID- 8662041
TI  - Left ventricular pannus causing inflow obstruction late after mitral valve
      replacement for endocardial fibroelastosis.
AB  - A case of mitral stenosis following mitral valve replacement in a patient with
      endocardial fibroelastosis is reported. A 14-year-old boy presented with cardiac
      failure. He had been diagnosed as having endocardial fibroelastosis at the age of
      7 months and had undergone resection of endocardial fibrous tissue in the left
      ventricle at that time. Five years later his mitral valve was resected owing to
      mitral stenosis, with Bjork-Shiley valve replacement. Cross-sectional
      echocardiography on this admission showed restrictive left ventricular inflow due
      to a thickened immobile prosthetic valve with severely dyskinetic left ventricle
      (ejection fraction 8%). The electrocardiogram showed atrioventricular reentry
      tachycardia. Despite direct current cardioversion and continual amiodarone
      infusion he suffered a cardiac arrest and died 12 days after admission.
      Postmortem examination showed left ventricular endocardial fibroelastosis with
      severe inflow obstruction due to the formation of a complete fibrous ring of
      pannus/fibrosis around the prosthetic margin on the ventricular aspect of the
      left ventricle. This complication has not previously been described in children
      after mitral valve replacement.

PMID- 8662042
TI  - Increased turnover of serotonin in children with pulmonary hypertension secondary
      to congenital heart disease.
AB  - Serotonin (5HT) is a potent vasoconstrictor of the pulmonary vascular bed and may
      be involved in the pathophysiology of secondary pulmonary hypertension in
      children with a left-to-right shunt due to a congenital heart defect. To test
      this hypothesis we measured the total and free 5HT concentration in blood as well
      as the urinary excretion of its main metabolite 5-hydroxyindoleacetic acid (HIAA)
      in children showing a left-to-right shunt with (n = 10) and without (n = 18)
      pulmonary hypertension. 5HT and HIAA were also measured in children after
      corrective cardiac surgery using cardiopulmonary bypass (n = 14) and in controls
      without congenital heart disease (n = 18). The concentrations of total and free
      5HT were not significantly different between controls and patients with a left-to
      right shunt. After cardiac surgery total 5HT concentration was significantly
      reduced by about 65% owing to a postoperatively reduced platelet count. In
      patients with a left-to-right shunt the total 5HT content was similar in the
      right atrium (204.0 +/- 17.3 ng/ml), pulmonary artery (189.0 +/- 19.1 ng/ml), and
      aorta (195.0 +/- 19.3 ng/ml), as was the free 5HT concentration. Therefore no net
      release of 5HT from platelets occurred between these sampling sites. In patients
      with pulmonary hypertension, the urinary excretion of HIAA was significantly
      increased when compared with controls and patients without pulmonary
      hypertension. It is concluded that turbulent blood flow in children with a left
      to-right shunt does not lead to a significant release of 5HT from platelets.
      However, the increased urinary excretion of HIAA in patients with pulmonary
      hypertension indicates an increased turnover of 5HT, probably due to an increased
      number of intrapulmonary neuroepithelial cells or a higher metabolic rate of 5HT
      within those cells.

PMID- 8662043
TI  - Effects of low-dose dobutamine on left ventricular diastolic filling in children.
AB  - To investigate the effects of dobutamine on the Doppler transmitral flow pattern
      in children with normal left ventricular function, Doppler echocardiography was
      used to measure the transmitral flow in 14 healthy children before and during
      infusion of dobutamine (5 micrograms/kg per minute). Cardiac output was measured
      by the thermodilution method, and stroke volume was calculated as the cardiac
      output divided by the heart rate. Dobutamine increased the peak velocity and flow
      velocity-time integral of early diastolic filling without changing those of
      atrial contraction and normalized peak velocity of early diastolic filling,
      suggesting an increase in left ventricular relaxation. Dobutamine increased the
      stroke volume and rate-corrected mean velocity of fiber shortening with reduced
      end-systolic wall stress, indicating an increase in left ventricular
      contractility. The percentage of increase in the flow velocity-time integral of
      early diastolic filling during dobutamine infusion tended to correlate with the
      increase in stroke volume (r = 0.67, p < 0.05) and with the decrease in end
      systolic wall stress (r = -0.61, p < 0.05). Our results suggest that low-dose
      dobutamine increases left ventricular relaxation with enhanced systolic function.
      The observed decreased endsystolic wall stress might have caused enhanced
      relaxation characteristics with dobutamine.

PMID- 8662044
TI  - Aerobic exercise function of patients with persistent coronary artery aneurysms
      secondary to Kawasaki disease.
AB  - Nine patients with persistent coronary artery aneurysms 1.7-14.0 years after an
      episode of Kawasaki disease underwent progressive bicycle ergometry with
      expiratory gas analysis. Two of the patients had aneurysms complicated by
      angiographically documented coronary artery stenosis. Results of the exercise
      tests were compared to those obtained from a group of age- and gender-matched
      normal control subjects. The Kawasaki disease patients did not differ
      significantly from the control subjects with regard to peak oxygen consumption
      (81 +/- 7% versus 79 +/- 12% predicted), peak workload (75 +/- 13% versus 77 +/-
      9% predicted), anaerobic threshold (21.9 +/- 6.5 versus 18.9 +/- 4.0 ml/kg per
      minute) or oxygen pulse (96 +/- 7% versus 90 +/- 14% predicted). None of the
      patients developed significant ST segment changes or rhythm disturbances during
      exercise. The exercise function of the patients with coronary artery stenosis did
      not differ from that of patients without stenosis. It was concluded that the
      aerobic exercise function of patients with persistent coronary artery aneurysms
      after an episode of Kawasaki disease appears to be well preserved. Kawasaki
      disease patients with significant coronary artery pathology are not accurately
      identified by a single assessment of aerobic exercise function.

PMID- 8662045
TI  - Long-term efficacy and safety of atenolol for supraventricular tachycardia in
      children.
AB  - Propranolol, a first-generation nonselective beta-adrenoceptor blocking agent, is
      commonly used to treat pediatric arrhythmias. Atenolol, relatively long-acting,
      cardioselective beta-adrenoceptor blocking agent, has been successfully used in
      adults with supraventricular tachycardia (SVT). There is only one report on the
      use of atenolol in children with SVT; and our report is on the first long-term
      prospective study to evaluate the use of atenolol in children. A group of 22
      children < 18 years of age with clinical SVT were enrolled in the study. The
      tachycardia was documented on electrocardiograms in each case and was confirmed
      by electrophysiologic studies in some. Once-a-day oral atenolol was started as a
      monotherapy. Of the 22 children with various types of SVT, 13 (59%) were well
      controlled on long-term oral atenolol therapy. The effective dose of atenolol
      ranged between 0.3 and 1.3 mg/kg/day (median effective dose 0.7 mg/kg/day). Five
      children had some adverse effects. However, none in the successful group of 13
      patients required drug discontinuation because of such effects. Once-a-day oral
      atenolol as a monotherapy is effective and relatively safe for long-term
      management of SVT during childhood. It is an attractive alternative beta
      adrenoceptor blocking agent for the management of pediatric arrhythmias.

PMID- 8662046
TI  - Body surface isopotential T map for assessment of right ventricular volume and
      pressure overloads in secundum atrial septal defect.
AB  - The body surface isopotential T map was analyzed to detect right ventricular
      volume and pressure overloads in 25 patients with secundum atrial septal defect.
      Three patterns were distinguished: a T map resembling normal (type A, n = 9);
      that with an isolated negative area in a positive area (type B, n = 11); and that
      with rightward movement of maximum (type C, n = 5). Right ventricular end
      diastolic volumes in types B (161 +/- 19% of normal; %N) and C (175 +/- 40% N)
      were significantly (p < 0.01) greater than those in controls (100 +/- 9% N) and
      type A (113 +/- 18% N). Right ventricular systolic pressure in type C (48 +/- 11
      mmHg) was significantly (p < 0.01) higher than those in the controls (30 +/- 5
      mmHg), type A (31 +/- 4 mmHg), or type B (34 +/- 5 mmHg). These results suggest
      that the patients with type B have right ventricular volume overload and those
      with type C have both volume and pressure overloads.

PMID- 8662047
TI  - Role of gestational age and body weight on Doppler transmitral flow velocity
      pattern in very low birth weight infants.
AB  - Doppler transmitral flow velocity was measured in premature infants. The early
      diastolic peak velocity, the peak velocity of early diastole/peak velocity of
      atrial contraction ratio, and total flow velocity-time integral increased
      significantly with advancing gestational age and body weight. The peak filling
      rate normalized to stroke volume (NPFR) did not correlate with gestational age or
      body weight. Moreover, mean NPFR was not significantly different between
      premature and term infants. Thus NPFR demonstrates that changes in the left
      ventricular filling patterns with advancing gestational age and increasing body
      size are related to the progressive increase in loading conditions, rather than
      to sequential changes in myocardial properties.

PMID- 8662049
TI  - Noonan syndrome with double-chambered right ventricle.
AB  - The association of Noonan syndrome and a double-chambered right ventricle has not
      been reported previously in the medical literature. We report two patients with
      Noonan syndrome associated with pulmonary valve stenosis and double-chambered
      right ventricle due to anomalous hypertrophied muscle bundles. Pulmonary valve
      stenosis was operated on. However, hypertrophied muscle bundles were not
      resected, as they caused no obstruction to blood passage. Postoperative follow-up
      examinations revealed no symptoms. In conclusion, in those with Noonan syndrome
      there may be anomalous muscle bundles in the right ventricular cavity. It may not
      be necessary to resect them if they do not obstruct the right ventricular outflow
      tract.

PMID- 8662048
TI  - Effects of oxygen and nitric oxide in oxygen on pulmonary arterial pressures of
      children with congenital cardiac defects.
AB  - Inhaled nitric oxide is a specific pulmonary vasodilator. This study was
      undertaken to assess the effect on pulmonary arterial pressure of administering
      100% oxygen compared with nitric oxide in oxygen. Thirteen mechanically
      ventilated children undergoing routine cardiac catheterization for the
      investigation of congenital heart disease were studied. Pulmonary arterial
      pressures were measured during inhalation of 30% oxygen (baseline), 100% oxygen,
      and nitric oxide (40 parts per million) in oxygen. In addition, in six children
      the pulmonary/systemic blood flow ratio and pulmonary vascular resistance were
      calculated using oxygen content, an assumed value for oxygen uptake, and the Fick
      principle. Results were compared using analysis of variance and the Wilcoxon
      signed-rank test. Pulmonary arterial pressure decreased from a mean value of 29.5
      mmHg (SD 15.1) to 25.6 mmHg (SD 9.3), p = 0.048, after increasing the inspired
      oxygen fraction from 0.3 to 1.0. The addition of nitric oxide caused a further
      reduction to 22.9 mmHg (SD 7.9), p = 0.0001. There was no change in systemic
      arterial pressure or heart rate during the study period, but a small increase
      occurred in the mean methemoglobin level (1.1% to 1.3%) p = 0.039. Changes in the
      pulmonary/systemic blood flow ratio and pulmonary vascular resistance (n = 6)
      were not significant. Nitric oxide in oxygen appears to be a more potent
      pulmonary vasodilator than oxygen alone in pediatric patients with congenital
      cardiac defects.

PMID- 8662050
TI  - Isolated congenital left ventricular diverticulum.
AB  - Congenital diverticulum of the left ventricle, a rare malformation, is usually
      associated with midline thoracoabdominal defect. We describe a case with
      congenital left ventricular diverticulum presenting as an isolated lesion. The
      lesion was suspected on two-dimensional echocardiography and was confirmed by
      cardiac catheterization and magnetic resonance imaging.

PMID- 8662051
TI  - Oxygen consumption in infants and children during heart catheterization.
AB  - Oxygen consumption was measured in infants, children, and adolescents during
      diagnostic heart catheterizations. A total of 825 measurements of oxygen
      consumption (VO2) was performed in 504 subjects using a semiopen hood system and
      a paramagnetic oxygen analyzer. In 256 subjects under 3 years of age, body
      dimensions and heart rate were found to be significant factors for oxygen
      consumption. The regression equation for both sexes was: VO2/BSA (ml/min.m2) =
      3.42.height (cm) - 7.83.weight (kg) + 0.38.HR - 54.1 (r2 = 0.39, SD = 38.7),
      where BSA is body surface area and HR is heart rate. VO2/BSA was significantly
      lower in infants less than 3 months of age (133 +/- 33 ml/min.m2) compared with
      infants of 3-12 months (171 +/- 37 ml/ min.m2; p < 0.01). In 272 children aged 3
      years and older and adolescents, gender was a significant factor in oxygen
      consumption together with BSA and HR. The regression line equation for males was
      VO2/BSA (ml/ min.m2) = 0.79.HR - 7.4.BSA(m2) + 108.1 (r2 = 0.45, SD = 34.2). The
      regression line equation for females is VO2/BSA (ml/min.m2) = 0.77.HR -
      5.2.BSA(m2) + 106.8 (r2 = 0.43, SD = 34.4). Hematocrit, systemic oxygen
      saturation, and blood pressure were not significant factors. The predictive value
      of nomograms for oxygen consumption is limited because of the large
      interindividual variations not explained by differences in gender, body size, or
      simple hemodynamic variables. Preferably, oxygen consumption is measured; but if
      nomograms for oxygen consumption are used for hemodynamic assessment, the wide
      confidence intervals should be considered.

PMID- 8662052
TI  - Primary rhabdomyosarcoma of the heart presenting with increased intracranial
      pressure.
AB  - An 18-month-old boy presented with signs of increased intracranial pressure.
      Computed tomographic scans of the brain and lungs showed multiple masses in the
      brain and lungs. Echocardiography revealed homogeneous, irregular pericardial
      thickening, minimal pericardial effusion, and irregular echogenic areas in the
      left ventricular inferoposterior and apical regions. Postmortem examination of
      tumor tissue showed that the masses were primary rhabdomyosarcoma of the left
      ventricle with multiple metastases. Primary rhabdomyosarcoma of the heart is
      uncommon, especially in patients under 2 years of age.

PMID- 8662053
TI  - Pulmonary vascular disease in a child with atrial septal defect of the secundum
      type and type I glycogen storage disease.
AB  - A rare combination of atrial septal defect of the secundum type and type I
      glycogen storage disease was seen with early fatal outcome due to rapidly
      progressive severe pulmonary vascular disease. Possible reasons for the
      unexpected, rapidly progressive pulmonary vascular disease are discussed.

PMID- 8662054
TI  - Cardiac echinococcsis with multivisceral involvement.
AB  - Cardiac hydatid cyst is an uncommon lesion. The infection, often acquired by
      children during play with infected dogs, is most common in sheep-raising areas of
      the world. We report our clinical and surgical experience in the treatment of one
      of the youngest reported cardiac hydatidosis patients with multivisceral
      involvement.

PMID- 8662055
TI  - Mitral valve replacement for severe mitral regurgitation in infants with
      anomalous left coronary artery from the pulmonary artery.
AB  - Infants with anomalous left coronary artery from the pulmonary artery (ALCAPA)
      may present with heart failure, mitral regurgitation, and dilated cardiomyopathy.
      Reestablishment of a two coronary artery system markedly improves the morbidity
      and mortality. However, the mitral regurgitation may continue to deteriorate
      despite surgical correction of the ALCAPA because of previous ischemic damage to
      the papillary muscles and chordae. Surgical intervention, including mitral valve
      replacement, may be required even during infancy. We present two infants with
      ALCAPA who required early mitral valve replacement for severe mitral
      regurgitation and have done well subsequently.

PMID- 8662056
TI  - Percutaneous balloon aortoplasty for restenosis after extended aortic arch
      anastomosis for type B interrupted aortic arch.
AB  - A 4-month-old boy underwent a percutaneous balloon aortoplasty for restenosis
      after extended aortic arch anastomosis for type B interrupted aortic arch (IAA).
      Balloon aortoplasty resulted in a decrease in the peak systolic pressure gradient
      across the obstructive segment from 84 mmHg to 19 mmHg and in an increase in
      diameter from 2.5 mm to 4.3 mm. No complications related to the procedure were
      observed. We assume that balloon aortoplasty can be effective and safe for
      relieving postoperative aortic obstruction associated with IAA.

PMID- 8662057
TI  - Partial atrioventricular canal with left-sided obstruction in patients with
      Noonan syndrome.

PMID- 8662058
TI  - Effects of umbilical arterial catheterization on mesenteric hemodynamics.
AB  - Impairment of mesenteric blood flow due to the use of umbilical artery catheters
      (UAC) may increase the risk of necrotizing enterocolitis (NEC) in newborn
      infants. We used Duplex Doppler sonography to investigate the degree of vessel
      obstruction due to UAC and their effect on visceral hemodynamics in 12 newborn
      infants. Ultrasonography was performed before and immediately after removal of
      the UAC, which was positioned above the ostia of the celiac and superior
      mesenteric arteries (SMA). Vessel diameter, peak systolic blood flow velocity
      (PSFV), end diastolic blood flow velocity (EDFV), and Pourcelot's resistance
      index (RI) were measured in the celiac trunk and the SMA within 1 cm of their
      origins. Removal of the UAC led to a significant increase in mean PSFV (celiac
      trunk: 50 cm/s +/- 15 vs 62 cm/s +/- 0.22, P < 0.05; SMA: 52 cm/s +/- 0.17 vs 72
      cm/s +/- 0.21, P < 0.05). RI increased from 0.7 +/- 0.14 to 0.74 +/- 0.13 and
      from 0.73 +/- 0.1 to 0.76 +/- 0.13 for the celiac trunk and SMA, respectively.
      The EDFV and vessel diameters did not change significantly after UAC removal. Our
      results suggest that UAC cause a decrease in mesenteric blood flow. Therefore,
      their use in hemodynamically unstable neonates or in those with gastrointestinal
      disease should be very carefully considered.

PMID- 8662059
TI  - Migration of jugular or subclavian venous catheters into inferior tributaries of
      the brachiocephalic veins or into the azygos vein, with possible complications.
AB  - Six children are reported in whom a central venous catheter from the internal
      jugular or the subclavian vein migrated to an anomalous position: the left
      superior intercostal vein in the first two cases, the thymic vein in the third,
      and the azygos vein in the last three. Resultant complications in five cases
      were: extravasation of the infusate in the first and third case; local vascular
      stenosis or complete vascular occlusion in the second and fifth case; and
      obstruction of the azygos arch due to local thrombosis and possible stenosis,
      with a likely extravasation of the infusate, in the sixth case. The mediastinal
      vascular anatomy related to these central venous catheters is reviewed with
      reference to similar and related cases in the literature.

PMID- 8662060
TI  - Latex allergy in patients with myelomeningocele presenting for imaging studies of
      the urinary tract.
AB  - OBJECTIVE: We prospectively surveyed patients with myelomeningocele who presented
      in our department over a 3-month period to determine the frequency of latex
      allergy in this population. MATERIALS AND METHODS: A questionnaire assessed
      history of allergy to latex and attitudes toward and use or avoidance of latex
      containing products in both medical and nonmedical environments. RESULTS: Surveys
      were completed by 118 patients (56 boys, 62 girls; mean age 10.4 years, range 0.6
      30.9 years). Seventy-two (61%) had heard of latex allergy and 25 (21%) reported
      being allergic to latex. Most allergic patients were performing intermittent self
      catheterization (92%) and tended to be slightly older (mean age 12.7 years) than
      those not reporting allergy (mean age 9.8 years). Although most reactions were
      limited to rashes and mucosal irritation, two patients experienced anaphylaxis
      with severe respiratory symptoms or hypotension or both. No reactions had
      occurred in the Department of Radiology. While 84% of patients with previous
      allergic reactions reported trying to avoid further exposure to latex in the
      hospital, at home, or in school, only 14% of non-allergic patients took any
      special precautions. CONCLUSION: Allergy to latex is common in patients with
      myelomeningocele who are examined in our department. We have developed a policy
      designed to prevent exposure of such patients to latex during imaging studies.

PMID- 8662061
TI  - Kawasaki disease presenting as focal colitis.
AB  - Kawasaki disease (mucocutaneous lymph node syndrome) typically presents with
      fever, rash, lymphadenitis, and mucositis. The colon is rarely involved and, to
      date, colitis has not been described as the presenting symptom. We report the
      imaging findings of a child with Kawasaki disease who presented with fever and
      focal left colitis.

PMID- 8662062
TI  - Mesenteric cystic lymphangioma: radiologic appearance mimicking cystic teratoma.
AB  - Lymphangiomas are benign multiloculated cystic tumors. We present radiologic and
      pathologic findings of a mesenteric lymphangioma containing calcification and
      mimicking a mesenteric teratoma. This may broaden the differential diagnosis of a
      cystic mesenteric mass containing calcification.

PMID- 8662063
TI  - Hemoperitoneum in a newborn secondary to antenatal hemorrhage into a
      retroperitoneal lymphangioma.
AB  - Hemoperitoneum in the newborn is an uncommon event, occurring most often in the
      setting of traumatic delivery. Hemoperitoneum resulting from antenatal hemorrhage
      into an abdominal mass is rare. We present a case of neonatal hemoperitoneum
      secondary to antenatal hemorrhage into a retroperitoneal lymphangioma. The
      differential diagnosis of neonatal hemoperitoneum is discussed.

PMID- 8662064
TI  - Sonographic prediction of chronic lung disease in the premature undergoing
      mechanical ventilation.
AB  - The aims of the study are to investigate the possible role of ultrasound (US) of
      the chest in predicting the development of chronic lung disease (CLD) in patients
      with hyaline membrane disease (HMD) and to determine the optimal age for the
      sonographic examination. One hundred and five consecutive prematures undergoing
      mechanical ventilation were prospectively studied by US of the chest. The US
      examinations were performed at birth and at least once a week until discharge
      from the neonatal unit. The sonographic patterns observed behind the diaphragm
      and their evolutions were recorded and correlated with the clinical and
      radiological data at day 28, which corresponds to the currently accepted limit
      for determining the presence of CLD. CLD is currently defined as oxygen
      dependency on day 28 with radiographic abnormalities. A diffuse
      retrodiaphragmatic hyperechogenicity was observed in all the patients with HMD.
      The hyperechogenicity resolved completely in patients with an uncomplicated
      clinical evolution. In contrast, in patients with CLD the hyperechogenicity
      resolved only partially, resulting in less diffuse and less extensive
      hyperechogenicity. Day 18 was the earliest day where the persistence of the
      abnormal retrodiaphragmatic hyperechogenicity was observed in 100% of the
      patients presenting CLD at day 28. At that time, 95.2% of the patients without
      abnormal hyperechogenicity showed uncomplicated evolution and no CLD. US can be a
      useful diagnostic tool to determine the occurrence of CLD and to predict as early
      as day 18 the prematures at risk for the disease.

PMID- 8662065
TI  - Complex congenital heart malformation evaluated with MR imaging at 0.3 T.
AB  - The aim of this study was to evaluate the efficiency of MR imaging at 0.3 T as
      the single modality in diagnosing complex congenital heart disease (CHD). Films
      from 45 cases were reviewed in two stages by four specialists and one fellow in
      pediatric radiology, who were unfamiliar with the patients. First a general
      review of CHD diagnosis was made, then a detailed study of anomalous venous
      return was performed. Regarding the general diagnosis of cardiovascular anomalies
      the results were good, with sensitivity of 80%, specificity of 96%, a positive
      predictive value of 88%, a negative predictive value of 93% and accuracy of 92%.
      As expected, the less experienced reviewer had somewhat lower figures. As for
      detailed evaluation of the anomalous veins, the diagnostic results were again
      good (sensitivity 85%), although less so when also the connection sites of the
      anomalous veins were considered (sensitivity 79%). The specificity of the
      findings was high at 97%. MR imaging at 0.3 T is valuable in the diagnosis of
      complex CHD, especially for anomalous vessels and their connections.

PMID- 8662066
TI  - MRI findings in children with neurofibromatosis type 1: a prospective study.
AB  - To determine the frequency and nature of MRI lesions in children with
      neurofibromatosis type I (NF1), 50 patients aged 8 to 16 years were evaluated
      prospectively with cranial MRI. Forty-one children were asymptomatic with respect
      to central nervous system pathology, and 50% were macrocephalic. Sixteen patients
      (32%) had normal MRI examinations. Thirty-two patients (64%) had high intensity
      lesions on T2-weighted images and 16 patients (32%) had hyperintense lesions on
      T1-weighted images. Seven patients (14%) had ventricular dilatation (associated
      with increased intracranial pressure in 2) and 11 patients (22%) had optic
      pathway lesions (optic glioma in 7). MRI was superior to CT in differentiating
      optic sheath thickening and optic nerve tortuosity from optic glioma in four
      patients. An intracranial tumour (ependymoma) and sphenoid wing dysplasia were
      evident in individual patients. Findings previously unreported in NF1 included an
      aqueductal web resulting in hydrocephalus, intraocular neurofibroma resulting in
      retinal detachment, and asymptomatic enlargement of the septum pellucidum. T1 and
      T2 signal abnormalities in isolation were not associated with neurological
      deficits or the occurrence of macrocephaly, and all lesions that required
      intervention were suspected clinically. Macrocephaly in the absence of increased
      intracranial pressure or accelerated head growth is not an indication for
      neuroimaging in children with NF1. However, the majority of children (68%) had
      disease-specific abnormalities and thus MRI may provide a useful adjunct to
      clinical evaluation in the diagnosis of equivocal cases.

PMID- 8662067
TI  - Laryngeal involvement in pediatric neurofibromatosis: a case report and review of
      the literature.
AB  - A case of neurofibroma of the larynx occurring in generalized neurofibromatosis
      (von Recklinghausen's disease) is presented, and the previously reported
      pediatric cases are reviewed. Laryngeal involvement in neurofibromatosis is rare
      and the predominant signs and symptoms include dyspnea, stridor, loss or change
      of voice and dysphagia. Problems posed related to diagnosis, management and
      course of this infrequent laryngeal localization are discussed.

PMID- 8662068
TI  - Definitive diagnosis of fracture-separation of the distal humeral epiphysis in
      neonates by ultrasonography.
AB  - Fracture-separation of the distal humeral epiphysis in neonates is difficult to
      diagnose radiologically because the cartilaginous epiphysis is radiolucent. We
      report a case in which fracture-separation of the distal humeral epiphysis in a
      neonate was diagnosed with the help of ultrasonography, which provided a clear
      delineation of the injury.

PMID- 8662069
TI  - The sheep CD1 gene family contains at least four CD1B homologues.
AB  - We identified four cDNA sequences encoding sheep homologues of the CD1 molecule.
      The sheep sequences were selected from lambdagt11 thymocyte cDNA libraries by
      hybridization with a human CD1C probe and a homologous sheep probe. The SCD1B-42
      and SCD1A25 sequences encode complete CD1 molecules. The third sequence, SCD1B
      52, which is closely related to SCD1B-42 and may be an allele, has the sequence
      encoding the alpha3 region precisely deleted. The fourth sequence, SCD1T10, is
      truncated at the 5' end. All four sequences are related to the human CD1B and
      domestic rabbit CD1B-like sequences at both nucleotide and amino acid level.
      Comparison of the derived CD1 amino acid sequences with the sequence of major
      histocompatibility complex class I molecules showed that the sheep CD1 molecules,
      like human CD1 molecules, lack most of the conserved class I residues known to be
      involved in interaction with beta2-microglobulin and the CD8 molecule. They do
      not contain the peptide docking residues involved in anchoring peptides in the
      peptide binding groove of class I molecules. Southern hybridization of sheep DNA
      with a sheep CD1 exon 4/alpha3 probe showed that the sheep genome encodes at
      least seven CD1 genes. The implications of these analyses for CD1 function are
      discussed.

PMID- 8662070
TI  - Identification of seven new human MHC class I region genes around the HLA-F
      locus.
AB  - Using cDNA hybridization selection techniques, we identified seven new genes in a
      280 kilobase YAC covering the HLA-F locus. The new genes were mapped back to the
      YAC by a combination of optical restriction mapping and pulse field gel
      electrophoresis. Northern analysis of individual clones demonstrated the presence
      of either different mRNA sizes or different expression patterns. Two of the cDNA
      clones were expressed only in lymphoid cell lines: one in Jurkat cells (T cell)
      and another in JY cells (B cell). All the genes lacked sequence similarity to any
      known classical and non-classical major histocompatibility complex (MHC) class I
      genes, indicating that the MHC class I region has more functions than
      anticipated. Of the seven new genes, one is highly similar (97%) to mouse 60S
      ribosomal protein, and another is homologous to diubiquitin proteins. Of the two
      G-coupled receptor-like cDNAs, one was fully sequenced and found to be an
      olfactory receptor-like gene. The study strengthens evidence that the MHC complex
      not only plays a key role in the immune system, but also contributes to non
      immunological functions.

PMID- 8662071
TI  - DNA sequence analysis of the C4 antigen WH: evidence for two mechanisms of
      expression.
AB  - Amino acid and protein analyses have allowed the construction of a model for the
      C4-based Rodgers and Chido blood group antigens. The single low-frequency allele
      (WH) in this blood group system, however, has not been characterized at the
      molecular level. Two WH+ donors were studied by C4 agarose gel electrophoreses,
      immunoblot studies using monoclonal anti-Rg: 1 or anti-Ch: 1, serological
      phenotyping, polymerase chain reaction-restriction fragment length polymorphism
      of their C4 genes, and DNA sequencing of the WH allele. The first donor had the
      C4A1, A3 phenotype; the C4A1 carried Ch: 1, 3, 6 (thus exhibiting reversed
      antigenicity) and the C4A3 carried the WH antigen. The amino acid sequence of the
      WH allele was PCPVLD at positions 1101 - 1106, S at position 1157, and VDLL at
      positions 1188 - 1191. A second donor typed as C4A2, A4, B1 and was also WH+.
      Immunoblot analysis showed that a C4B1 protein expressed Rg: 1. Sequence analysis
      of the C4B genes showed the amino acids LSPVIH at positions 1101 - 1106, S at
      position 1157, and ADLR at positions 1188 - 1191. Thus, the WH antigen is a
      conformational epitope that can arise through different mechanisms on either a
      C4A or C4B gene.

PMID- 8662072
TI  - The mouse CD7 gene: identification of a new element common to the human CD7 and
      mouse Thy-1 promoters.
AB  - Human CD7 (hCD7) is a 40 000 Mr member of the immunoglobulin gene superfamily
      that is expressed early in natural killer (NK) and T-lymphocyte development. CD7
      is involved in lymphocyte activation, as ligation of CD7 activates NK and
      TCRgammadelta T lymphocytes, and ligation of CD7 on TCRalphabeta T lymphocytes
      induces a non-mitogenic calcium flux. We have previously cloned and characterized
      the gene for human CD7 (hCD7) and have described its expression in transgenic
      mice. Recently a mouse cDNA homologous to hCD7 was reported, which we mapped to
      the corresponding mouse chromosomal location as hCD7. We now report the
      identification and characterization of a mouse CD7 (mCD7) genomic clone. We
      demonstrated that the mCD7 gene was similar both in size and structural
      organization to hCD7. Comparison of the 5' flanking sequences of the mCD7 and
      hCD7 genes revealed two regions of sequence similarity. Electrophoretic mobility
      shift assay confirmed both of these regions to be sites of tissue-restricted
      protein binding in vitro. The more 3' similarity region also shared sequence with
      a region in the mouse Thy-1 gene 5' flanking region, suggesting that this
      sequence may be a cis-acting regulatory element common to all three genes. Thus,
      the promoter regions and exonic organization were similar in the human CD7, mouse
      CD7, and mouse Thy-1 genes.

PMID- 8662073
TI  - New alleles of IGKV genes A2 and A18 suggest significant human IGKV locus
      polymorphism.
AB  - The human kappa light chain consists of approximately 35 potentially functional
      IGKV genes. However, an estimation of the diversity in the IGKV repertoire of an
      individual will be affected by the extent of polymorphisms for the different IGKV
      genes and their patterns of inheritance. To date, little information is available
      to indicate the extent of allelic variation of the IGKV genes. We examined the
      extent of allelism for one IGKV gene pair, the distal region A2 gene and its
      closely related proximal region duplicate A18. We found two new alleles for A2
      and one new allele for A18, and sequenced approximately 1 kilobase flanking each
      gene. The new A18 allele, unlike the originally described allele, appears to be
      functional. All these alleles were found at relatively high frequencies in the
      four ethnic populations studied, with the exception of the defective A2b allele
      which was highly represented only in Navajos. The originally described A2a allele
      encodes for the predominant protective antibody against Haemophilus influenzae.
      Therefore, the patterns of allelic inheritance described for this IGKV gene pair
      indicate that allelism in the IGKV locus is likely to have a significant impact
      on immune responses.

PMID- 8662075
TI  - Interallelic recombination has not played a major role in the history of the HLA
      C locus.
AB  - The human major histocompatibility complex class I loci HLA-A and HLA-B have
      previously been shown to differ with regard to the rate of interallelic
      recombination, with a much higher rate being observed in the case of HLA-B. Until
      recently, there were very few HLA-C transcripts available for analysis. In the
      present study, we analyzed C locus alleles from human (n = 24), chimpanzee (n =
      1), and gorilla (n = 5). Both phylogenetic analysis and a method for detecting
      clusters of sites indicative of recombination showed relatively little evidence
      of interallelic recombination. Thus, in spite of the close evolutionary
      relationship between HLA-C and HLA-B, HLA-C is evolving more similarly to the HLA
      A locus than is HLA-B, further emphasizing the uniqueness of HLA-B.

PMID- 8662074
TI  - Identifying DNA polymorphisms in human TCRA/D variable genes by direct sequencing
      of PCR products.
AB  - The T-cell receptor (TCR) is a highly variable molecule composed of two
      polypeptide chains that recognize antigenic peptides in the context of major
      histocompatibility complex (MHC) molecules. In this study, we describe a sequence
      based search for germline polymorphisms in the variable (V) gene segments of the
      human TCRA/D locus. Thirty different V gene segments were amplified from six to
      eight unrelated individuals and sequenced from low melting point agarose. Twenty
      seven polymorphisms were identified in 15 V gene segments. These polymorphisms
      are mainly single nucleotide substitutions, but an insertion/deletion
      polymorphism and a single dinucleotide repeat with variable length were also
      seen. Of the 15 sequence variations found in the coding regions, six are silent
      and nine encode amino acid changes. All of the amino acid changes are found at
      non-conserved residues, frequently in the hypervariable regions, where they may
      influence MHC and/or peptide recognition. Therefore, it is possible that germline
      variations in TCR genes could influence an individual's immune response, and may
      also contribute to susceptibility to diseases such as autoimmunity.

PMID- 8662077
TI  - The cloning of cattle interferon-A subtypes isolated from the gut epithelium of
      rotavirus-infected calves.

PMID- 8662076
TI  - Sequence and characterization of two HSP70 genes in the colonial protochordate
      Botryllus schlosseri.
AB  - Two genes belonging to the heat shock protein 70 gene family have been cloned
      from the colonial protochordate Botryllus schlosseri. The two intronless genes
      (HSP70.1 and HSP70.2) exhibit 93.6% sequence identity within the predicted coding
      region, and 83.3% and 81.7% sequence identity in the 5' and 3' flanking regions,
      respectively. The predicted amino acid sequences are 95% identical and contain
      several signatures characteristic of cytoplasmic eukaryotic HSP70 genes (Gupta et
      al. 1994; Rensing and Maier 1994). Northern blotting and sequence analysis
      suggest that both genes are heat-inducible members of the HSP70 gene family.
      Given these characteristics, HSP70.1 and HSP70.2 appear to be good candidates for
      protochordate homologues of the major histocompatibility complex-linked HSP70
      genes of human, mouse, and rat (Milner and Campbell 1990; Walter et al. 1994).
      Further experiments to determine whether there is functional evidence for such
      similarity are in progress.

PMID- 8662078
TI  - Mouse RSS spacer sequences affect the rate of V(D)J recombination.

PMID- 8662079
TI  - DNA sequence analysis of the genetic recombination between Igh6 and Myc in an
      uncommon BALB/c plasmacytoma, TEPC 1194.

PMID- 8662080
TI  - The central region of the major histocompatibility complex contains a sequence
      with similarity to the pol gene of Moloney retroviruses.

PMID- 8662081
TI  - Nucleotide sequence of a new HLA-DPB1 allele, DPB1*02013.

PMID- 8662082
TI  - Expressed Peromyscus maniculatus (Pema) MHC class I genes: evolutionary
      implications and the identification of a gene encoding a Qa1-like antigen.
AB  - To gain insight into the evolution of rodent major histocompatibility complex
      (MHC) class I genes and identify important (conserved) nonclassical class I
      (class I b) gene products and residues in these proteins, six Peromyscus
      maniculatus MHC (Pema) class I cDNA clones were isolated and sequenced. Five Pema
      class I cDNAs appeared most similar to mouse and rat classical class I (class I
      a) genes. One exhibited highest similarity to an H2 class I b gene, H2-T23
      (encoding the Qa1 antigen). Phylogenetic trees constructed with Pema, RT1, and H2
      class I sequences suggested that the lineages of some rodent class I b genes (e.
      g., T23 and T24) originated prior to Mus and Peromyscus speciation [>50 million
      years (My) ago]. Sequences of four Qa1-like proteins from three species permitted
      the identification of ten Qa1-specific amino acids. On the basis of molecular
      modeling, three residues showed the potential to interact with T-cell receptors
      and three residues (all corresponding to polymorphic positions among H2 class I a
      proteins) were predicted to influence antigen binding. The recognition of mouse
      Qa1 proteins by a subset of T-cells in influenced by a locus, Qdm, which encodes
      the H2-D leader peptide. One of the Pema class I cDNA clones classified as H2-K,
      D/L-like (class I a) is predicted to encode an identical peptide, implying that
      an antigen binding protein (Qa1) and the antigen to which it binds (the product
      of Qdm) has been conserved for over 50 My.

PMID- 8662083
TI  - Systematic screening for genetic polymorphism in human platelet glycoprotein
      Ibalpha.
AB  - Glycoprotein Ibalpha (GP Ibalpha; CD 42b; hereafter GPIBA) is a component of the
      cell surface receptor for the von Willebrand factor (vWf) on platelets.
      Immunizations against various platelet surface antigens play a major role in
      neonatal alloimmune thrombocytopenia and in post-transfusion purpura. Only one
      antigenic polymorphism in GPIBA has thus far been established: the HPA-2 (Ko)
      alloantigen system. To screen other polymorphisms in GPIBA systematically, we
      analyzed the whole coding sequence of the GPIBA gene in 50 Finnish blood donors
      using the single-strand conformation polymorphism method. In addition to the
      known polymorphisms, we detected three others. Sequencing of the gene segments
      carrying the new polymorphisms revealed that none of them changed the predicted
      amino acid sequence. Polymorphism designated RS was located five base pairs
      upstream from the initiation codon at position 3064 and had the gene frequency of
      16% for R and 84% for S, respectively, in the Finnish population, and it was
      detectable by the restriction enzyme Hae III. The EF polymorphism was at position
      3842 (Asn242) and the gene frequencies were 97% for E and 3% for F. The KL
      polymorphism was at position 4142 (Arg342) and the gene frequencies were 98% for
      K and 2% for L. The five polymorphic positions in GPIBA formed altogether six
      different alleles of the gene. The data suggest that there are only a few
      variable amino acids in GPIBA.

PMID- 8662084
TI  - Identification of new TAP2 alleles in gorilla: evolution of the locus within
      hominoids.
AB  - Transporters associated with antigen processing molecules (TAP1 and TAP2) mediate
      the transfer of cytosolic peptides into the lumen of the endoplasmic reticulum
      for association with newly synthesized class I molecules of the major
      histocompatibility complex. Previous molecular and functional analyses of rat and
      human TAP2 homologues indicated major differences in gene diversification
      patterns and selectivity of peptides transported. Therefore, in this study, we
      analyzed the alleles of the gorilla TAP2 locus to determine whether the pattern
      of diversification resembled that in either of those two species. Sequence
      analysis of the TAP2 cDNAs from gorilla Epstein-Barr virus-transformed B-cell
      lines revealed four alleles with a genetic distance of less than 1%. The
      nucleotide substitutions distinguishing the alleles are confined to the 3' half
      of the coding region and occur individually or within two small clusters of
      variability. Diversification of the locus appears to have resulted from point
      substitutions and recombinational events. Evolutionary-rate estimates for the
      TAP2 gene in gorilla and human closely approximate those observed for other
      hominoid genes. The amino acid polymorphisms within the gorilla molecules are
      distinct from those in the human homologues. The absence of ancestral
      polymorphisms suggests that gorilla and human TAP2 genes have not evolved in a
      trans-species fashion but rather have diversified since the divergence of the
      lineages.

PMID- 8662085
TI  - HLA-G gene polymorphism in a Japanese population.
AB  - Polymorphism of the HLA-G gene in a Japanese population was investigated
      employing polymerase chain reaction (PCR)-single-strand conformation polymorphism
      (SSCP) analysis, PCR sequence-specific oligonucleotide (SSO) analysis, and DNA
      direct sequencing. Nucleotide sequence variations in exons 2, 3, and 4 of the HLA
      G gene in 54 healthy Japanese individuals were examined. In addition, seven
      Japanese samples carrying common HLA haplotypes were analyzed. In total, nine
      single-base substitutions compared with the sequence of G*01011 were identified:
      one in intron 1 (nucleotide position 970), one in exon 2 (the third base of codon
      57: G --> A), three in intron 2 (1264, 1276, and 1292), three in exon 3 (the
      third base of codon 93: C --> T, the third base of codon 107: A --> T, and the
      first base of codon 110: C --> A), and one in intron 3 (2334). The substitution
      at codon 110 was non-synonymous and led to an amino acid substitution from
      leucine to isoleucine. The other three nucleotide substitutions in exons were
      synonymous. Through analysis of combinations of the exon 2, 3, and 4 nucleotide
      sequences we identified four alleles, which we provisionally designated GJ1, GJ2,
      GJ3, and GJ4. The allele frequencies were estimated to be 0.33, 0.16, 0.45, and
      0.06, respectively. Nucleotide sequences of GJ1, GJ2, and GJ4 were identical to
      G*01011, the clone 7.0E, and G*01013, respectively. GJ3 was a newly observed
      allele and was officially designated G*0104 by the WHO Nomenclature Committee in
      January 1996. Strong positive associations were observed between HLA-G alleles
      and HLA-A, -B, or -DRB1 alleles.

PMID- 8662086
TI  - Characterization of class II A and B genes in a gynogenetic carp clone.
AB  - A prerequisite for carrying out functional studies on major histocompatibility
      complex (Mhc) molecules of fish is the availability of genetically well-defined
      homozygous strains. Previously we have applied gynogenetic reproduction to
      generate isogenic carp, denoted clone A410. This clone has recently been
      demonstrated to express a single class I gene, Cyca-UA1(*)01, and in the present
      study two class II B and two class II A transcripts were obtained. The two class
      II B transcripts, Cyca-D(CB3)B and Cyca-D(CB4)B, as well as the class II A
      transcripts, Cyca-D(10A)A and Cyca-D(15A)A, appear to be bona fide class II
      transcripts, based on the presence of conserved protein characteristics of the
      inferred class II molecules. With the isolation of class II A sequences,
      representatives of all major classes of Mhc genes have been identified in the
      carp. To assess the relationship between the different class II genes,
      segregation studies, comparison of cDNA and intron 1 sequence data, and
      phylogenetic analyses were undertaken. These showed that the class II B
      transcripts, Cyca-D(CB3)B and Cyca-D(CB4)B, are derived from related, closely
      linked loci. In addition, these studies indicated that the previously described
      Cyca-DAB*01 and Cyca-DAB*02 are also closely linked, but that this linked pair
      segregates independently from the Cyca-D(CB3)B and Cyca-D(CB4)B loci. The class
      II A transcripts are most likely derived from separate loci and do not represent
      alleles, as they were found not to segregate in the individuals of the clone
      which was generated by meiogenetic gynogenesis.

PMID- 8662087
TI  - The recombination activating gene 2 (RAG2) of the rainbow trout Oncorhynchus
      mykiss.
AB  - We have previously described the isolation and expression of RAG1 in trout to
      provide an initial understanding regarding the tissues involved in V(D)J
      recombination of antigen receptors in this teleost. Here we report that the
      recombination activating gene 2 (RAG2) of rainbow trout has now been cloned and
      characterized. The rainbow trout genomic RAG2 gene (1602 base pairs) displays an
      average of 60% and 75% similarity at the nucleotide and amino acid level when
      compared with clones from other species and was found to contain an acidic region
      in the carboxyl terminal end, which is typical of RAG2 sequences. The proximity
      of RAG1 and -2 within this teleost is similar to that found in other vertebrates.
      The genes are convergently transcribed and share a 3' untranslated (UT) region
      [2. 8 kilobases (kb)] which is much shorter than that found in higher vertebrates
      (6 - 8 kb). The entire 3' UT region was also sequenced and used in conjunction
      with cDNA clones to identify the polyadenylation sites for both RAG genes.
      Northern blot analysis of one-year-old trout demonstrated strong expression of
      RAG2 in the thymus, with a much weaker signal being detected in the pronephros.
      Using reverse transcriptase-polymerase chain reaction, we detected the highest
      expression of both RAG1 and -2 in the thymus followed by the pronephros, with
      much fainter signals being observed in the spleen, mesonephros, and liver.
      Finally, both genes are expressed in embryos beginning at approximately day 10
      post-fertilization. Taken together, these findings indicate that the thymus and
      pronephros most likely serve as the primary lymphoid tissues in trout, based upon
      RAG expression. In addition, the trout sequences may provide further insight into
      the evolution and origins of the RAG genes as well as that of the immune system
      itself.

PMID- 8662088
TI  - Chicken B-cell marker chB6 (Bu-1) is a highly glycosylated protein of unique
      structure.
AB  - The chB6 molecule is expressed on chicken B cells throughout most of their
      development, as well as on some non-lymphoid cells. It has long been used as an
      allotypic marker in important studies of B-cell development, though its function
      is unknown. We isolated a chB6 cDNA by expression cloning and sequenced two
      further alleles following polymerase chain reaction amplification. The results
      show that chB6 is a typical type I transmembrane protein, highly glycosylated in
      the extracellular region and carrying a large intracellular region. It has no
      recognizable similarity to known mammalian molecules and thus represents a unique
      B-cell marker. Its presence in chickens may be related to differences in the
      properties of B-cell development between chickens and mammalian species. The
      sequences of the different alleles of this gene revealed a higher level of
      polymorphism than expected. A restriction fragment length polymorphism linked to
      the CHB6 gene has been used to determine its location on the linkage map of the
      chicken genome, which will allow the definitive evaluation of reported
      associations with disease resistance.

PMID- 8662090
TI  - Genomic organization and expression of mouse thymic shared antigen-1 (TSA-1):
      evidence for a processed pseudogene.

PMID- 8662089
TI  - Physical mapping of the Ring1, Ring2, Ke6, Ke4, Rxrb, Col11a2, and RT1.Hb genes
      in the rat major histocompatibility complex.
AB  - A contig of cosmids containing the Ring1, Ring2, Ke6, Ke4, Rxrb, and Col11a2
      genes in the rat major histocompatibility complex has been established and
      aligned to the class II cluster (RT1.Hb). The relative order and the
      transcriptional orientations of these rat genes are the same as in their human
      and mouse homologues. The distances are also similar, except for the Col11a2 -
      class II interval, which is clearly shorter in rat and mouse compared with human.
      The previously defined Ke5 probe could be shown to map into the large Col11a2
      gene.

PMID- 8662091
TI  - Alternatively spliced forms of human killer inhibitory receptors.

PMID- 8662092
TI  - Sequence analysis of MHC class II Eb cDNAs from H2r and H2p haplotypes.

PMID- 8662093
TI  - Quantitative exercise technetium-99m tetrofosmin myocardial tomography for the
      identification and localization of coronary artery disease.
AB  - The aim of this study was to evaluate the accuracy of quantitative 1-day exercise
      rest technetium-99m tetrofosmin tomography in the identification of patients with
      coronary artery disease (CAD) and in the detection of individual stenosed
      coronary vessels. Sixty-one patients with suspected CAD who underwent coronary
      angiography and 13 normal volunteers were studied. All patients were submitted to
      two i.v. injections of 99mTc-tetrofosmin, one at peak exercise (370 MBq) and the
      other (1110 MBq) at rest 3 h after exercise (images 15-30 min after injection for
      both studies). All patients with CAD (>/=50% luminal stenosis) (n=50) had an
      abnormal 99mTc-tetrofosmin tomogram. Only one patient without significant
      coronary narrowing showed abnormal findings. Overall sensitivity, specificity and
      diagnostic accuracy in the detection of individual stenosed vessels were 77%, 93%
      and 85%, respectively. Sensitivity and diagnostic accuracy in the identification
      of individuals stenosed coronary vessels were significantly higher (P<0.05) in
      patients with single-vessel disease (n=21) than in those with multivessel disease
      (n=29). Sensitivity, specificity and accuracy for detecting individual diseased
      vessels were similar in patients without previous myocardial infarction (n=26)
      and in those with previous myocardial infarction (n=35). In myocardial
      territories related to non-infarcted areas (n=128), sensitivity and specificity
      in the detection of stenosed vessels were 70% and 95%, respectively. In infarcted
      areas (n=55), sensitivity and specificity in the detection of stenosed vessels
      were 85% (P=NS vs non-infarcted areas) and 75% (P<0.05 vs non-infarcted areas),
      respectively. Finally, sensitivity was significantly lower (P<0.05) in vascular
      territories supplied by vessels with moderate stenosis (50%-75%) than in those
      supplied by vessels with severe stenosis (>75%). The results of this study
      demonstrate that quantitative 1-day exercise-rest 99mTc-tetrofosmin single-photon
      emission tomographic imaging is a suitable and accurate technique to identify
      patients with CAD and to detect individual stenosed coronary vessels.

PMID- 8662095
TI  - Value of radioimmunoscintigraphy with technetium-99m labelled anti-CEA monoclonal
      antibody (BW431/26) in the detection of colorectal cancer.
AB  - This study was undertaken as part of a Coordinated Research Programme initiated
      by the International Atomic Energy Agency to evaluate the usefulness of
      radioimmunoscintigraphy (RIS) in the management of patients with colorectal
      cancer. Technetium-99m labelled BW431/26, a monoclonal antibody against
      carcinoembryonic antigen (CEA), was used. The study included 73 patients (31
      females and 42 males). Sixty-eight patients were suspected of having recurrent
      colorectal adenocarcinoma while another five were suspected to have primary
      colorectal cancer. Images were acquired at 10 min and 4 and 24 h following the
      injection of radioantibody. The efficacy of RIS in tumour detection was evaluated
      by the findings at surgery, histological investigation and/or other diagnostic
      modalities and clinical follow-up. Four of five patients with suspected primary
      colorectal cancer gave true-positive results (three at primary sites, one at the
      site of a metastatic lesion) while one was false-positive. The overall accuracy
      of RIS in the diagnosis of recurrent colorectal cancer was 87%. Its sensitivity
      in the detection of locoregional or abdominal recurrence and liver metastases was
      97% and 89% respectively. RIS was more accurate than computed tomography (CT)
      scan in the detection of pelvic recurrence and liver metastases while CT scan was
      far superior to RIS in detecting lung metastases. RIS proved most useful in
      patents who had rising CEA levels on clinical follow-up but in whom other work
      up, including CT scan, was negative. The advantages of RIS include the ability to
      detect tumour recurrence prior to other investigations and to identify tumour
      recurrence in areas such as the pelvis, where CT and magnetic resonance imaging
      have their greatest weaknesses in diagnosing recurrent disease. The imaging
      accuracy is significantly increased when combined CT and antibody imaging is
      performed.

PMID- 8662094
TI  - Qualitative [18F]FDG positron emission tomography in primary breast cancer:
      clinical relevance and practicability.
AB  - Positron emission tomography (PET) using fluorine-18 2-deoxy-2-fluoro-d-glucose
      (FDG) is of potential value for the diagnosis of malignant tumours. The aim of
      this study was to evaluate the use of FDG PET in patients with breast tumours,
      appraising its applicability in visualising primary carcinomas and regional
      metastases in a clinical setting. Results of FDG PET were compared with those of
      mammography, breast ultrasonography and histology in 30 patients with
      inconclusive breast findings. For PET, transmission and emission images were
      taken in one or two scan positions, depending on the available time and the
      clinical status of patients. PET showed focal FDG uptake with high contrast in 21
      of 23 primary carcinomas. In one patient, only PET correctly visualized
      multifocal disease (three foci, O 0.4-1 cm). The accuracy of PET in the detection
      of primary breast cancer was 90%, and in the detection of involved axillary lymph
      nodes, 94%. All metastases (lymph nodes, lungs, bones, soft tissues) covered by
      the field of view and demonstrated by other methods (X-ray, computed tomography,
      magnetic resonance imaging, bone scan) showed FDG uptake. In three patients, only
      PET initiated further diagnostic procedures. The results indicate that FDG PET
      can provide a rapid diagnostic study (45-60 min) and allows accurate tumour
      staging of several organ systems for primary tumour and metastases with a single
      imaging study in a routine clinical setting.

PMID- 8662096
TI  - Indium-111 bleomycin complex for radiochemotherapy of head and neck cancer-
      dosimetric and biokinetic aspects.
AB  - Bleomycin (BLM) is used for the treatment of head and neck cancer. In order to
      improve the effectiveness of this chemotherapeutic drug, BLM was combined with
      indium-111. A complex of these agents (111In-BLMC), formed at low pH, was
      injected intravenously into ten head and neck cancer patients in escalating
      activities of 75, 175 and 375 MBq. The internally delivered dose to the tumours
      varied from 0.20 to 2.73 mGy at 75 MBq, from 0.33 to 2.51 mGy at 175 MBq, and
      from 0.87 to 31.3 mGy at the 375 MBq activity level. Uptake of radioactivity was
      0.45+/-0.24x10(-3)% ID/g in primary tumours and 0. 52+/-0.20x10(-3)% ID/g in
      metastases (at 48 h). Tumour volumes varied from 0.51 to 49.0 cm3. The
      radioactivity half-lives in the tumours were 30+/-7 h. The activity distribution
      and penetration into tumour tissue were not affected by increasing the injected
      activity. There was a positive correlation between BLMC uptake and Ki-67/Mib
      activity as well as number of mitoses in tumour tissue. These data indicate that
      111In-BLMC has potential as a radiochemotherapeutic agent in head and neck cancer
      and that adjuvant Auger-electron therapy is possible using 114mIn-labelled BLMC.

PMID- 8662097
TI  - Technetium-99m tetrofosmin rest/stress myocardial SPET with a same-day 2-hour
      protocol: comparison with coronary angiography. A Spanish-Portuguese multicentre
      clinical trial.
AB  - Technetium-99m tetrofosmin (Myoview) has unique properties for myocardial
      perfusion imaging very early after injection of the tracer. We used a very short
      same-day rest/stress protocol, to be performed within 2 h and evaluated its
      diagnostic accuracy. The study included 144 patients from seven Spanish and four
      Portuguese centres with a diagnosis of uncomplicated coronary artery disease
      (CAD); 78 patients (54%) had no history of prior myocardial infarction. Patients
      were injected with </=300 MBq 99mTc-tetrofosmin at rest and </=900 MBq
      approximately 1 h later at peak exercise. Single-photon emission tomographic
      (SPET) acquisitions were initiated within 5-30 min post injection. The results
      were compared with those of coronary angiography (CA). The data of 142 patients
      were completely evaluable (two with non-evaluable images were excluded). The
      quality of rest images was excellent or good in 86%, regionally problematic in
      7%, poor but well interpretable in 5% and non-evaluable in 2%. The overall
      sensitivity for the detection of CAD was 93%, the specificity 38% and the
      accuracy 85%. The localization of defects by SPET in relation to the perfusion
      territories of stenosed vessels (>/=50%) was achieved with a sensitivity of 64%
      for the left anterior descending artery, 49% for the left circumflex artery and
      86% for the right coronary artery, and an accuracy of 71%, 72% and 73%
      respectively. Concordance of SPET and CA was 62% for single-vessel disease and
      68% for multivessel disease. In conclusion, this Spanish-Portuguese multicentre
      clinical trial confirmed, in a considerable number of patients who underwent
      coronary angiography, the feasibility of 99mTc tetrofosmin (Myoview) rest/stress
      myocardial SPET using a very short protocol (2 h).

PMID- 8662098
TI  - Somatostatin-receptor scintigraphy in Graves' orbitopathy.

PMID- 8662099
TI  - A new iterative reconstruction technique for attenuation correction in high
      resolution positron emission tomography.
AB  - A new iterative reconstruction technique (NIRT) for positron emission computed
      tomography (PET), which uses transmission data for nonuniform attenuation
      correction, is described. Utilizing the general inverse problem theory, a cost
      functional which includes a noise term was derived. The cost functional was
      minimized using a weighted-least-square maximum a posteriori conjugate gradient
      (CG) method. The procedure involves a change in the Hessian of the cost function
      by adding an additional term. Two phantoms were used in a real data acquisition.
      The first was a cylinder phantom filled with uniformly distributed activity of 74
      MBq of fluorine-18. Two different inserts were placed in the phantom. The second
      was a Hoffman brain phantom filled with uniformly distributed activity of 7.4 MBq
      of 18F. Resulting reconstructed images were used to test and compare a new
      iterative reconstruction technique with a standard filtered backprojection (FBP)
      method. The results confirmed that NIRT, based on the conjugate gradient method,
      converges rapidly and provides good reconstructed images. In comparison with
      standard results obtained by the FBP method, the images reconstructed by NIRT
      showed better noise properties. The noise was measured as rms% noise and was
      less, by a factor of 1.75, in images reconstructed by NIRT than in the same
      images reconstructed by FBP. The distance between the Hoffman brain slice
      reconstructed by FBP and the perfect PET Hoffman brain slice created from the MRI
      image was 0.526, while the same distance for the Hoffman brain slice
      reconstructed by NIRT was 0.328. The NIRT method suppressed the propagation of
      the noise without visible loss of resolution in the reconstructed PET images.

PMID- 8662100
TI  - Validation of a knowledge-based boundary detection algorithm: a multicenter
      study.
AB  - A completely operator-independent boundary detection algorithm for multigated
      blood pool (MGBP) studies has been evaluated at four medical centers. The
      knowledge-based boundary detector (KBBD) algorithm is nondeterministic, utilizing
      a priori domain knowledge in the form of rule sets for the localization of
      cardiac chambers and image features, providing a case-by-case method for the
      identification and boundary definition of the left ventricle (LV). The
      nondeterministic algorithm employs multiple processing pathways, where KBBD rules
      have been designed for conventional (CONV) imaging geometries (nominal 45 degrees
      LAO, nonzoom) as well as for highly zoomed and/or caudally tilted (ZOOM) studies.
      The resultant ejection fractions (LVEF) from the KBBD program have been compared
      with the standard LVEF calculations in 253 total cases in four institutions, 157
      utilizing CONV geometry and 96 utilizing ZOOM geometries. The criteria for
      success was a KBBD boundary adequately defined over the LV as judged by an
      experienced observer, and the correlation of KBBD LVEFs to the standard
      calculation of LVEFs for the institution. The overall success rate for all
      institutions combined was 99.2%, with an overall correlation coefficient of
      r=0.95 (P<0.001). The individual success rates and EF correlations (r), for CONV
      and ZOOM geometers were: 98%, r=0.93 (CONV) and 100%, r=0.95 (ZOOM). The KBBD
      algorithm can be adapted to varying clinical situations, employing automatic
      processing using artificial intelligence, with performance close to that of a
      human operator.

PMID- 8662101
TI  - Labelling of leucocytes with technetium-99m exametazime causes in vitro
      upregulation of granulocyte CD11b without correlation to tissue uptake in vivo.
AB  - The aims of this study were to investigate whether labelling with technetium-99m
      exametazime alters the expression of adhesion molecule CD11b on granulocytes and
      monocytes, and to study whether the expression of CD11b on unlabelled or labelled
      cells correlates with uptake of the labelled cells in the inflamed bowel, in the
      lungs or in the reticuloendothelial system. Leucocytes were obtained from 25
      patients with inflammatory bowel disease who underwent leucocyte scan. The
      cellular expression of CD11b was analysed using flow cytometry. Labelling with
      99mTc-exametazime induced an increased surface expression of CD11b on
      granulocytes (P<0.01), but not on monocytes. The increase in CD11b expression on
      granulocytes was lower than the spontaneous mobilization that occurred at 37
      degrees C and correlated neither with this, nor with N-formyl-methionyl
      phenylalanine induced expression of the same receptor. Basal expression of CD11b
      on unlabelled granulocytes, but not on monocytes, correlated with bowel and lung
      uptake 45 min after reinjection of labelled cells, but not with uptake on later
      images. No correlation was found between the CD11b expression on labelled
      granulocytes or monocytes and scintigraphic uptake. Our findings show that
      labelling with 99mTc-exametazime increases the expression of adhesion protein
      CD11b on granulocytes. The increase in surface expression of CD11b does not
      correlate with the scintigraphic uptake of labelled cells in the bowel, in the
      lungs or in the reticuloendothelial system.

PMID- 8662102
TI  - Vascular risk factors, atherosclerosis, cerebral white matter lesions and
      cerebral perfusion in a population-based study.
AB  - We studied risk factors for cerebral vascular disease (blood pressure and
      hypertension, factor VIIc, factor VIIIc, fibrinogen), indicators of
      atherosclerosis (intima-media thickness and plaques in the carotid artery) and
      cerebral white matter lesions in relation to regional cerebral blood flow (rCBF)
      in 60 persons (aged 65-85 years) recruited from a population-based study. rCBF
      was assessed with single-photon emission tomography using technetium-99m d, l
      hexamethylpropylene amine oxime (99mTc-HMPAO). Statistical analysis was performed
      with multiple linear regression with adjustment for age, sex and ventricle-to
      brain ratio. A significant positive association was found between systolic and
      diastolic blood pressure and temporo-parietal rCBF. In analysis with quartiles of
      the distribution, we found a threshold effect for the relation of low diastolic
      blood pressure (</=60 mmHg) and low temporo-parietal rCBF. Levels of plasma
      fibrinogen were inversely related to parietal rCBF, with a threshold effect of
      high fibrinogen levels (>3.2 g/l) and low rCBF. Increased atherosclerosis was
      related to low rCBF in all cortical regions, but these associations were not
      significant. No consistent relation was observed between severity of cerebral
      white matter lesions and rCBF. Our results may have implications for blood
      pressure control in the elderly population.

PMID- 8662103
TI  - Cerebellar vascular response to acetazolamide in crossed cerebellar diaschisis: a
      comparison of 99mTc-HMPAO single-photon emission tomography with 15O-H2O positron
      emission tomography.
AB  - Various observations on the cerebellar vasoreactivity in crossed cerebellar
      diaschisis (CCD) have previously been reported. The purpose of this study is to
      clarify the difference between oxygen-15 H2O positron emission tomographic (PET)
      and technetium-99m hexamethylpropylene amine oxime (HMPAO) single-photon emission
      tomograph (SPET) findings in CCD and to evaluate the effect of the absolute
      values of the cerebellar blood flow as measured by 15O-H2O PET on the 99mTc-HMPAO
      SPET findings. The subjects comprised 15 patients with a supratentorial infarct
      and CCD. The cerebellar blood flow increased by about 40% at 5 and 20 min after
      acetazolamide i.v. on both the CCD and the non-CCD side, as measured by 15O-H2O
      PET. The percentage differences in cerebellar blood flow between the CCD and the
      non-CCD side were -22.3%+/-5.7% in the resting state, -19. 6%+/-6.4% at 5 min
      after acetazolamide i.v. and 21.5%+/-6.7% at 20 min after acetazolamide i.v., as
      measured by 15O-H2O PET, while they were -10.6%+/-5.5% in the resting state and 
      5.6%+/-5.1% at 5 min after acetazolamide i.v., as measured by 99mTc-HMPAO SPET.
      After Lassen's linearization correction, the latter two measurements were 
      16.2%+/-7.7% and -9.6%+/-8.9%, respectively. The effect of acetazolamide did not
      differ between the CCD and the non-CCD side in 15O-H2O PET, while a greater
      response on the CCD side was observed in 99mTc-HMPAO SPET, even after Lassen's
      linearization correction. It is concluded that acetazolamide HMPAO SPET may
      overestimate the cerebellar vascular response on the CCD side (or underestimate
      it on the non-CCD side).

PMID- 8662104
TI  - Bone mineral density in patients receiving suppressive doses of thyroxine for
      differentiated thyroid carcinoma.
AB  - To determine bone mineral density in patients with differentiated thyroid
      carcinoma receiving thyroxine replacement therapy in suppressive doses, we
      studied 65 patients (47 women and 18 men; age 25-83 years, mean+/-SD 52.5+/-15.4
      years). Patients were free of thyroid cancer in clinical and laboratory
      examinations at the time of the study. Bone mineral density of the lumbar spine
      and both hips was measured by dual-energy X-ray absorptiometry. There was no
      decrease in bone density in either 32 postmenopausal or 15 premenopausal women
      compared with an age- and sex-matched control group, nor was any decrease in bone
      density found in men. Our data suggest that thyroxine treatment in suppressive
      doses in patients with differentiated thyroid carcinoma is not a risk factor for
      the development of osteoporosis.

PMID- 8662105
TI  - Parathyroid scintigraphy: comparison of technetium-99m methoxyisobutylisonitrile
      and technetium-99m tetrofosmin studies.
AB  - We report the preliminary results of a prospective study demonstrating
      tetrofosmin uptake in surgically and histologically proven parathyroid adenomas.
      In ten patients with primary chronic hyperparathyroidism, parathyroid imaging was
      performed using (1) technetium-99m methoxyisobutylisonitrile (MIBI) and (2) 99mTc
      1, 2-bis(bis(2-ethoxyethyl)phosphino)ethane (tetrofosmin) within a time interval
      of 3-5 days. Both tracers correctly identified the parathyroid adenomas by focal
      prolonged tracer retention. On visual inspection image contrast was generally
      higher with MIBI than with tetrofosmin in all the patients studied. Tetrofosmin
      showed a slower elimination from the parathyroid adenomas than MIBI in six of the
      ten cases. Our preliminary results show that tetrofosmin, like MIBI, as a
      feasible, sensitive tracer for parathyroid scintigraphy. For routine use, the
      rapid kit preparation without heating and the lower radiation dose to the patient
      make tetrofosmin an alternative tracer for parathyroid scintigraphy. Further
      evaluation is needed to determine which of the two tracers is the more sensitive
      for the detection of parathyroid adenomas, and which tracer properties better
      reflect the degree of endocrine activity.

PMID- 8662106
TI  - Nuclear medicine at the crossroads.
AB  - Many nuclear medicine procedures, originally developed more than 20 years ago,
      are now performed with new radiopharmaceuticals or instruments; it is therefore
      apposite to reappraise what we are doing and why we are doing it. The clinical
      utility of nuclear medicine is discussed with reference, by way of example, to
      gated blood pools scans and myocardial perfusion imaging; the importance of the
      referred population for the outcome of studies is stressed. Attention is drawn to
      the likelihood that the detection of ischemia would be enhanced by the
      administration of nitroglycerin prior to rest thallium injection. Emphasis is
      also placed on the increasing acceptance of dual-tracer studies. The significance
      of expression of p-glycoprotein by some tumors for sestamibi imaging is
      discussed, and advances in respect of fluorodeoxyglucose imaging are reviewed.
      The final section covers issues relating to the development of new procedures,
      such as the value of nuclear medicine in the detection and characterization of
      tissue oxygen levels and the possible future role of nuclear medicine in the
      management of sleeping and eating disorders.

PMID- 8662107
TI  - Nuclear medicine and mathematics.
AB  - The purpose of this review is not to present a comprehensive description of all
      the mathematical tools used in nuclear medicine, but to emphasize the importance
      of the mathematical method in nuclear medicine and to elucidate some of the
      mathematical concepts currently used. We can distinguish three different areas in
      which mathematical support has been offered to nuclear medicine: physiology,
      methodology and data processing. Nevertheless, the boundaries between these areas
      can be indistinct. It is impossible in a single article to give even an idea of
      the extent and complexity of the procedures currently used in nuclear medicine,
      such as image processing, reconstruction from projections and artificial
      intelligence. These disciplines do not belong to nuclear medicine: they are
      already branches of engineering, and my interest will reside simply in revealing
      a little of the elegance and the fantastic potential of these new "allies" of
      nuclear medicine. In this review the mathematics of physiological interpretation
      and methodology are considered together in the same section. General aspects of
      data-processing methods, including image processing and artificial intelligence,
      are briefly analysed. The mathematical tools that are most often used to assist
      the interpretation of biological phenomena in nuclear medicine are considered;
      these include convolution and deconvolution methods, Fourier analysis, factorial
      analysis and neural networking.

PMID- 8662108
TI  - Lateral collateral ligament tear of the knee: appearances on bone scintigraphy
      with single-photon emission tomography.
AB  - We report two cases, with magnetic resonance imaging correlation, of acute
      lateral collateral ligament tear of the knee following trauma with findings on
      bone scintigraphy with single-photon emission tomography (SPET). The typical bone
      scan features are presented. In addition, the advantages of the use of SPET in
      the detection of associated lesions are discussed.

PMID- 8662109
TI  - Increased uptake of indium-111 pentetreotide up to 10 years after external
      thoracic irradiation: report of two cases.
AB  - Indium-111 pentetreotide scintigraphy was performed in two patients for the
      localization of recurrent medullary thyroid carcinoma treated by surgery and
      external radiotherapy 1 and 10 years earlier. A marked uptake of the
      radiopharmaceutical was demonstrated in the lung areas that had been irradiated.
      These cases strongly suggest that this uptake is related to pulmonary fibrosis, a
      well-known complication of radiotherapy, even long after the irradiation.
      Therefore, attention must be paid to the avoidance of false-positive
      interpretation of somatostatin receptor scintigraphy in patients previously
      treated by radiotherapy.

PMID- 8662110
TI  - Future of functional brain imaging.

PMID- 8662111
TI  - The usefulness of FDG positron emission tomography for the detection of
      mediastinal lymph node metastases in patients with non-small cell lung cancer: a
      comparative study with X-ray computed tomography.
AB  - We evaluated the usefulness of fluorine-18-fluoro-2-deoxy-d-glucose positron
      emission tomography (FDG PET) in the detection of mediastinal lymph node
      metastases in patients with non-small cell lung cancer and then compared the
      findings with the results of X-ray CT by region based on the histological
      diagnoses. We examined 29 patients with non-small cell lung cancer. One hundred
      and thirty-two mediastinal lymph nodes were surgically removed and the
      histological diagnoses were confirmed. FDG PET images, including 146 mediastinal
      regions, were visually analysed and the mediastinal lymph nodes were scored as
      positive when the FDG uptake was higher than that in the other mediastinal
      structures. On the X-ray CT scans, any mediastinal lymph nodes with a diameter of
      10 mm or larger were scored as positive. All three examinations were successfully
      performed on 71 regions. For FDG PET, we found a sensitivity of 76%, a
      specificity of 98% and an accuracy of 93%. On the other hand, for X-ray CT a
      sensitivity of 65%, a specificity of 87% and an accuracy of 82% were observed. A
      significant difference was observed in respect of both specificity and accuracy
      (P<0.05). Based on the above findings, FDG PET is suggested to be superior to X
      ray CT when used for the detection of mediastinal lymph node metastases in
      patients with non-small cell lung cancer.

PMID- 8662112
TI  - Comparative study of rest technetium-99m sestamibi SPET and low-dose dobutamine
      stress echocardiography for the early assessment of myocardial viability after
      acute myocardial infarction: importance of the severity of the infarct-related
      stenosis.
AB  - Rest technetium-99m sestamibi single-photon emission tomography (SPET) has been
      shown to underestimate viability in some patients with chronic ischaemic
      myocardial dysfunction. The present study was designed to appraise the value of
      99mTc-sestamibi as a viability tracer in patients with a recent myocardial
      infarction and to determine factors that might influence its accuracy in
      assessing infarct size. Therefore, rest 99mTc-sestamibi SPET, low-dose
      dobutamines stress echocardiography and quantitative coronary angiography were
      performed in 51 patients with a recent myocardial infarction. Perfusion activity
      and regional wall motion were scored semi-quantitatively using the same segmental
      division of the left ventricle. Assessment of 99mTc-sestamibi uptake as a marker
      of viability was performed by comparing a binary uptake score (viable=>50% vs
      necrotic =</=50% of the maximal tracer activity) with a binary wall motion
      classification during low-dose dobutamine infusion (viable=normal/hypokinetic vs
      necrotic=akinetic/dyskinetic). Infarct size, expressed as the number of segments
      with evidence of necrotic tissue, was significantly greater in the scintigraphic
      study than in the echocardiographic study (2.8+/-1.5 vs 2.2+/-1.3, P=0.006). This
      overestimation of infarct size by 99mTc-sestamibi was present only in patients
      with a severe infarct-related stenosis (% diameter stenosis >/=65%-100%) and
      particularly those with "late" reperfusion therapy (time delay >/=180 min). In
      patients without a severe infarct-related stenosis, 99mTc-sestamibi was able to
      accurately distinguish viable from necrotic segments. Thus, rest 99mTc-sestamibi
      scintigraphy early after acute myocardial infarction may underestimate residual
      viability within the infarct region, particularly in patients with low flow state
      coronary anatomy, as a result of a severe infarct-related stenosis and/or late
      reperfusion therapy.

PMID- 8662113
TI  - Investigation of the relationship between regression of hypertensive cardiac
      hypertrophy and improvement of cardiac sympathetic nervous dysfunction using
      iodine-123 metaiodobenzylguanidine myocardial imaging.
AB  - Although many theories exist on the subject, the mechanisms responsible for a
      reduction of hypertensive cardiac hypertrophy in response to antihypertensive
      therapy are still unclear. In order to investigate the relationship between
      regression of hypertensive cardiac hypertrophy and cardiac nervous function, we
      studied ten patients with untreated essential hypertension (six men and four
      women, 62+/-12 years old). Both echocardiography and iodine-123
      metaiodobenzylguanidine (MIBG) myocardial imaging were performed before and after
      antihypertensive therapy. Left ventricular mass (LVM) was significantly reduced
      in conjunction with the reduction of blood pressure following treatment. MIBG
      myocardial images showed that the heart-to-mediastinum activity ratio (H/M) was
      significantly increased while the washout ratio was significantly decreased.
      Patients were divided into two groups according to the ratio of the LVM values
      before and after therapy (LVM ratio). Patients with an LVM ratio of less than
      0.75 were classified as group A and those with values higher than 0.75 as group
      B. Neither the change in blood pressure nor the length of treatment was
      significantly different between these two groups. On the other hand, both the
      increase in H/M and the decrease in the washout ratio were significantly greater
      in group A than in group B. These results indicate that an improvement in cardiac
      sympathetic nervous function may be related to the regression of hypertensive
      cardiac hypertrophy. Increasing the subject base in these studies and a more
      precise analysis of the relevance of the data obtained from MIBG myocardial
      images are recommended to clarify how changes in cardiac sympathetic nervous
      function relate to the regression of hypertensive cardiac hypertrophy.

PMID- 8662115
TI  - Optimal collimator choice for sequential iodine-123 and technetium-99m imaging.
AB  - Dual-isotope studies with technetium-99m and iodine-123 may be useful for various
      organs, including brain and myocardium. For the images obtained with each of the
      tracers to be comparable, it is important that activity ratios (activity in one
      part of the image/reference activity in the image) are preserved by the imaging
      method. We have used a Rollo phantom to study how collimator response affects
      such ratios. All investigations were performed with 123I(p,5n) and on a Siemens
      Orbiter 3700 camera fitted with either a low-energy high-resolution (LEHR) or a
      medium-energy (ME) collimator. Images were made of a Rollo phantom filled with an
      aqueous solution of either 99Tc or 123I, and placed on the collimator surface
      with 8 cm of methyl-methacrylate interposed. Count densities were measured in
      ROIs drawn in each cell of the phantom, and normalised to the maximal ROI value
      in the image. The mean square error (MSE) was used to assess how well the ratios
      of count densities approximated the known activity ratios based on the dimensions
      of the cells of the phantom. For 99mTc, regardless of the collimator used, the
      count density ratios approximated the activity ratios fairly well (LEHR:
      MSE=0.008; ME: MSE=0.020). For 123I, count density ratios obtained with the LEHR
      were consistently higher than activity ratios (MSE=0. 235), whereas the
      differences between the measured and the theoretical values were less with the ME
      collimator (MSE=0.013). Contrast fidelity of the 123I images obtained with the
      LEHR collimator could be improved with Jaszczak scatter correction with k=1, but
      this led to unfavourable signal-to-noise ratios. For sequential 99mTc/123I
      studies with extended sources, ME is to be preferred because of its higher
      contrast accuracy. Spatial resolution is less for the ME than for the LEHR
      collimator (FWHM with scatter: LEHR/99mTc=6.9 mm, LEHR/123I=7.4 mm, ME/99mTc=
      10.1 mm, ME/123I=11.1 mm), but remains similar for both tracers when the ME is
      used.

PMID- 8662114
TI  - Quantification of left ventricular size on exercise thallium-201 single-photon
      emission tomography.
AB  - The purposes of this study were to determine whether quantification of the left
      ventricular size on exercise thallium-201 single-photon emission tomography
      (SPET) correlates with echocardiographic measurements, whether the quantification
      reflects the severity of coronary artery disease, and whether it can provide
      supplementary information regarding the severity of coronary artery disease. In
      42 control subjects and 110 patients who underwent coronary angiography, we
      performed exercise 201Tl SPET and quantified six non-regional markers: lung 201Tl
      uptake on an initial planar image (Lung/Heart), left ventricular width on a
      tomogram (Width), change in the Width from the initial to delayed tomograms
      (DeltaWidth), count ratio of the left ventricular cavity to the myocardium (C/M),
      count ratio of the lung to the myocardium (L/M), and count ratio of the lung to
      the left ventricular cavity (L/C). In 76 patients, furthermore, the Width was
      compared with echocardiographic measurements. The Width correlated with
      echocardiographic measurements (P<0.001). The Width and DeltaWidth were
      significantly different among zero-, one-, two- and three-vessel disease
      (P<0.001). However, the Width and DeltaWidth could not improve the power of
      discrimination for multi-vessel disease derived from the Lung/Heart. The six non
      regional markers correlated with each other (P<0.001). Among the six markers, the
      Lung/Heart was only the independent discriminator for multi-vessel disease. In
      conclusion, quantification of the left ventricular size on exercise 201Tl SPET
      correlated with echocardiographic measurements and reflected the severity of
      coronary artery disease, but may be replaced with quantitation of the lung 201Tl
      uptake.

PMID- 8662116
TI  - Iodine-131 labelled octreotide: not an option for somatostatin receptor therapy.
AB  - Gamma-emitting radiopeptides are useful for scintigraphy of tumours on the basis
      of receptor binding. Likewise, beta-emitting radiopeptides may be used in
      radionuclide therapy of such tumours. As iodine-131 suggested to be suitable for
      this purpose, experiments were performed using three somatostatin analogues, in
      which the effects of coupling of a therapeutic dose of 131I to such peptides were
      investigated. This study deals with the radioiodination of very small amounts of
      peptide on a therapeutic scale, the required purification procedures after
      radioiodination, and the influence of high beta fluxes from 131I on a peptide
      during radioiodination and purification. Based on the regularly used therapeutic
      doses of 131I in cancer treatment and our previous experience with [111In-DTPA-D
      Phe1]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7
      GBq 131I has to be coupled to a maximum of approximately 100 microg peptide,
      representing only a slight excess of peptide over 131I. This contrasts with non
      peptide radiopharmaceuticals in which high compound to radionuclide ratios are
      usually used. Labelling at low peptide to radionuclide ratios (low labelling
      yields) results in the formation of di-iodinated compounds, whereas at high
      peptide to radionuclide ratios (high labelling yields) mono-iodinated products of
      low specific activity are formed. Thus, after radioiodination the desired mono
      iodinated peptide has to be separated from unreacted iodide, and from di
      iodinated and unreacted peptide, as both compounds compete for the receptors.
      Possible radiolysis of the peptide during labelling and separation steps were
      investigated by irradiating 30 microgram unlabelled peptide with 370 MBq 131I in
      a small volume. The peptide composition of the incubation mixtures was
      investigated by high-performance liquid chromatography after irradiation for 30
      min to 24 h. The results showed that the peptide was degraded with a half-life of
      less than 1 h. During the preparation of a real therapeutic dose (at much higher
      beta-flux) the peptide will be degraded even faster during the various steps
      required. In conclusion, intact mono-iodinated 131I-labelled somatostatin
      analogues for peptide receptor therapy will be difficult to obtain.

PMID- 8662117
TI  - A simple method for the quantification of benzodiazepine receptors using iodine
      123 iomazenil and single-photon emission tomography.
AB  - Iodine-123 iomazenil (Iomazenil) is a ligand for central type benzodiazepine
      receptors that is suitable for single-photon emission tomography (SPET). The
      purpose of this study was to develop a simple method for the quantification of
      its binding potential (BP). The method is based on a two-compartment model (K1,
      influx rate constant; k2', efflux rate constant; VT' (=K1/k2'), the total
      distribution volumes relative to the total arterial tracer concentration), and
      requires two SPET scans and one blood sampling. For a given input function, the
      radioactivity ratio of the early to delayed scans can be considered to tabulate
      as a function of k2', and a table look-up procedure provides the corresponding
      k2' value, from which K1 and VT' values are then calculated. The arterial input
      function is obtained by calibration of the standard input function by the single
      blood sampling. SPET studies were performed on 14 patients with cerebrovascular
      diseases, dementia or brain tumours (mean age+/-SD, 56.0+/-12.2). None of the
      patients had any heart, renal or liver disease. A dynamic SPET scan was performed
      following intravenous bolus injection of Iomazenil. A static SPET scan was
      performed at 180 min after injection. Frequent blood sampling from the brachial
      artery was performed on all subjects for determination of the arterial input
      function. Two-compartment model analysis was validated for calculation of the VT'
      value of Iomazenil. Good correlations were observed between VT' values calculated
      by three-compartment model analysis and those calculated by the present method,
      in which the scan time combinations (early scan/delayed scan) used were 15/180
      min, 30/180 min or 45/180 min (all combinations: r=0.92), supporting the validity
      of this method. The present method is simple and applicable for clinical use.

PMID- 8662118
TI  - Chronic osteomyelitis: diagnosis with technetium-99m-d, l-hexamethylpropylene
      amine oxime labelled leucocytes.
AB  - To evaluate the diagnostic value of technetium-99m d, l-hexamethylpropylene amine
      oxime (HMPAO) labelled leucocytes in combination with a 99mTc-methylene
      diphosphonate (MDP) bone scan in the detection of chronic osteomyelitis, we
      retrospectively reviewed 55 patients. Prior to the 99mTc-d,l-HMPAO labelled
      leucocyte scan, all patients underwent a 99mTc-MDP bone scan. The correct
      diagnosis was confirmed by long-term clinical follow-up (n=29) or by
      bacteriological cultures (n=26). We found an overall sensitivity of 94%, a
      specificity of 91% and an accuracy of 92% for 99mTc-d,l-HMPAO labelled leucocyte
      scintigraphy in the diagnosis of chronic osteomyelitis. When the patients were
      divided into three groups according to the location of the infection, our study
      results showed a sensitivity and specificity for the central location (containing
      active bone marrow) of 94% and 100% respectively; for the peripheral location
      (hands and feet) both parameters were 100%, and for the middle location (all
      sites between the central and the peripheral location) the values were 92% and
      81% respectively. Specificity and accuracy were significantly lower in the middle
      location than in the central and peripheral locations. The results of our study
      confirm that a 99mTc-d,l-HMPAO labelled leucocyte scan in combination with an
      99mTc-MDP bone scan is a reliable way to diagnose chronic osteomyelitis, except
      for vertebral osteomyelitis.

PMID- 8662119
TI  - Initial human studies with single-photon emission tomography using iodine-123
      labelled 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)- 7-iodo-5, 6-dihydro-5-methyl-6
      oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine (NNC 13-8241).
AB  - The iodine-123 labelled ligand 3-(5-cyclopropyl-1,2, 4-oxadiazo-3-yl)-7-iodo-5,6
      dihydro-5-methyl-6-oxo-4H-imidazo[1, 5-a][1,4]-benzodiazepine ([123I]NNC 13-8241)
      was evaluated as a probe for in vivo imaging of benzodiazepine receptor sites in
      the human brain. Four healthy volunteers were imaged with a high-resolution
      single-photon emission tomography (SPET) scanner. The metabolism of [123I]NNC 13
      8241 in plasma was slow. The total brain uptake was about 1.5-fold higher than
      that of [123I]iomazenil. The specific binding in the cortical areas was high and
      less intense in the thalamus. The most intense uptake was seen in the occipital
      cortex. The peak cortical uptake of [123I]NNC 13-8241 was observed 6-10 h after
      the injection of tracer. The radiation burden to the patient was moderate, being
      2.5 middle dot10(-2 )mSv/MBq (effective dose equivalent). A slow metabolism
      together with favourable kinetics indicates that [123I]NNC 13-8241 is a specific
      and promising SPET ligand for imaging benzodiazepine receptor sites in the living
      human brain.

PMID- 8662121
TI  - The imaging science of positron emission tomography.
AB  - To meet the goals of converging molecular imaging with molecular biology and
      molecular medicine, there is a need to define the strategy and structure for
      perfecting the accuracy of functional images derived using PET. This also relates
      directly to how clinical research, diagnostic questions and challenges from the
      pharmaceutical industry are addressed. In order to exploit the sensitivity and
      specificity of PET, an integrated, multidisciplinary approach is imperative. The
      structure to provide this needs to been seen in the context of an institutional
      approach, collaborations within the academic and industrial sectors and the
      funding needed to meet the challenges of addressing difficult questions.

PMID- 8662120
TI  - Preliminary results for positron emission mammography: real-time functional
      breast imaging in a conventional mammography gantry.
AB  - In order to optimally integrate radiotracer breast imaging within the breast
      clinic, anatomy and pathology should be easily correlated with functional nuclear
      medicine breast images. As a first step in the development of a hybrid
      functional/anatomic breast imaging platform with biopsy capability, a
      conventional X-ray mammography gantry was modified to image the compressed breast
      with positron emitters. Phantom studies with the positron emission mammography
      (PEM) device showed that a 1-cc hot spot could be detected within 5 min. A
      preliminary clinical trial demonstrated in vivo visualization of primary breast
      cancer within 4 min. For sites where positron-emitting radionuclides are
      available, PEM promises to achieve low-cost directed functional examination of
      breast abnormalities, with the potential for achieving X-ray correlation and
      image-guided biopsy.

PMID- 8662123
TI  - Identification of AIDS-related tuberculosis with concordant gallium-67 and three
      hour delayed thallium-201 scintigraphy.
AB  - Concordant gallium-67 and thallium-201 uptake has been described in malignant
      lesions. More recently, 201Tl accumulation has been described in some benign
      conditions. The authors report three HIV-positive patients who underwent 67Ga and
      201Tl scintigraphy. These studies revealed concordant 67Ga and 201Tl uptake and
      tumour was erroneously diagnosed. All three patients were finally diagnosed as
      having tuberculosis.

PMID- 8662124
TI  - MODS/SIRS: result of an overwhelming inflammatory response?
AB  - Multiple organ dysfunction syndrome and the systemic inflammatory response
      syndrome are expressions of an inappropriate, generalized inflammatory response
      to severe inflammatory stimuli, which may be bacterial or nonbacterial in nature.
      The clinical signs and symptoms, morphologic alterations, and changes in oxygen
      transport seem to be the direct effect of phagocyte activation. So far,
      identifying the microorganisms and neutralizing their toxins has not been helpful
      in improving prognosis. As an essential adjunct to treating the bacterial or
      nonbacterial causes, finding safe ways of modulating the phagocyte response
      should be considered.

PMID- 8662125
TI  - Early risk factors for postinjury multiple organ failure.
AB  - Epidemiologic studies, based on retrospective data from heterogeneous populations
      with poor control of confounders, led early investigators to conclude that
      infection was the overriding risk factor for multiple organ failure (MOF). More
      recent studies have convincingly shown that MOF frequently occurs in the absence
      of infection. Consequently, we have shifted our research focus away from the
      traditional infectious models of MOF to the newer "one-hit" and "two-hit"
      inflammatory models. Clinically, we have chosen to study trauma patients because
      they are a relatively homogeneous group with a low incidence of common
      confounders. Trauma also permits a clear distinction between the first insult and
      the outcome, both temporally and with respect to the definition criteria. In this
      review we discuss the background, rationale, and our initial attempts to use
      indicators of the first insult (i.e., tissue injury quantification and clinical
      signs of shock) and indicators of the host response (i.e., systemic inflammatory
      response syndrome) to predict MOF early after injury.

PMID- 8662126
TI  - Severity stratification and outcome prediction for multisystem organ failure and
      dysfunction.
AB  - Multiple organ system failure or dysfunction (MOSF/MODS) remains a major cause of
      morbidity and mortality in hospitalized adults. Among intensive care unit (ICU)
      patients the extent of physiologic derangement, the type of associated disease or
      injury, increasing age, and life-threatening comorbid conditions are the major
      determinants of risk for developing MOSF and for survival during the 1980s.
      Hospital mortality for patients with a single organ system failure (OSF) lasting
      more than 1 day approached 40%; and for those with two OSFs hospital mortality
      increased to 60%. These outcomes did not change over the decade. For patients
      with three or more OSFs persisting after 3 days of OSF, however, data suggest
      that between 1982 and 1990 the mortality has been reduced from 98% to 84% (p =
      0.0003). Because of variations in the types and combinations of OSFs, associated
      disease, and extent of physiologic derangement, it is difficult to interpret
      variations in mortality among patients with one or more OSFs defined using
      categorical criteria. For this and other reasons, outcome prediction based on a
      comprehensive assessment of patient risk factors is a more sensitive, specific,
      useful approach to quantifying MODS than a simple count of the number and
      duration of OSFs. Because repeated assessment of risk factors during subsequent
      ICU days reflects complications and response to therapy, daily outcome
      predictions are even more precise than estimates at ICU admission. The ability to
      more accurately predict survival from MODS/MOSF can improve our ability to test
      new therapies, evaluate how outcome has changed over time, and assess the
      efficacy of supportive therapy for individuals.

PMID- 8662127
TI  - Mediators of injury and inflammation.
AB  - Mediators play a key role in the development of systemic inflammatory response
      syndrome (SIRS), multiple organ dysfunction syndrome, and multiple organ failure
      of vital organs. In this short review, we update our knowledge on these mediator
      networks. First, we summarize the stimuli that occur during severe trauma
      (intraoperative stress), including polymorphonuclear neutrophil-derived tissue
      damaging substances, complement activation products, and adherence molecules such
      as selectins. The gut in shock is discussed as an important intermediate step in
      the transition from noninfectious to infectious SIRS. Second, we describe the
      mediators, including cytokines, nitric oxide, phospholipase A2, platelet
      activating factor, and procoagulatory substances, that are released during
      sepsis. The release of mediators depends primarily on the severity of the trauma,
      shock, or sepsis and secondarily on the activation of the various cascades of
      mediators during posttraumatic/postoperative complications. The mediators are
      thus of decisive importance regarding the intensity of organ damage and the
      outcome.

PMID- 8662128
TI  - Role of the gut in multiple organ failure: bacterial translocation and
      permeability changes.
AB  - It is clear that increased gut permeability and bacterial translocation play a
      role in multiple organ failure (MOF). Failure of the gut barrier remains central
      to the hypothesis that toxins escaping from the gut lumen contribute to
      activation of the host's immune inflammatory defense mechanisms, subsequently
      leading to the autointoxication and tissue destruction seen in the septic
      response characteristic of MOF. However, the role of the gut is more than that of
      a sieve, which simply allows passage of bacteria and endotoxin from the gut lumen
      to the portal or systemic circulation. It appears, in addition, that the
      translocation of bacteria and endotoxin may lead to local activation of the
      immune inflammatory system and the local production of cytokines and other immune
      inflammatory mediators. These intestinally derived mediators may then exacerbate
      the systemic inflammatory response and potentially lead to a further increase in
      gut permeability. A vicious cycle of increased intestinal permeability, leading
      to toxic mediator release, resulting in a further increase in gut permeability is
      generated. Additionally, the systemic and local inflammatory cells that become
      activated in the gut contribute to the systemic response characteristic of the
      sepsis syndrome and MOF. Thus even if the immune inflammatory system, rather than
      the gut, is the "motor of" MOF, the gut remains one of the major pistons that
      turns the motor.

PMID- 8662129
TI  - Sepsis, SIRS, and MODS: what's in a name?
AB  - Progress in the care of the critically ill patient with life-threatening
      infection has been hampered by inconsistent, often confusing terminology. The
      clinical syndrome of sepsis-familiar to all yet definable by none-describes a
      highly heterogeneous group of disorders with different causes and differing
      prognoses. The imminent availability of mediator-directed therapy has created a
      sense of urgency to develop better methods for delineating discrete clinical
      syndromes and to modulate the host response, which may bring both benefit and
      harm, depending on the clinical circumstances. The term systemic inflammatory
      response syndrome (SIRS) was introduced several years ago to describe the
      familiar clinical syndrome of sepsis, independent of its cause. SIRS can result
      from trauma, pancreatitis, drug reactions, autoimmune disease, and a host of
      other disorders; when it arises in response to infection, sepsis is said to be
      present. SIRS describes a dynamic process that has adaptive survival value for
      the host. The maladaptive consequence of this process in the critically ill
      patient is the development of progressive but potentially reversible remote organ
      dysfunction-the multiple organ dysfunction syndrome. The development of cogent
      conceptual frameworks for classification of the septic response in critically ill
      patients is more than a question of linguistic pedantry. Optimal therapy
      presupposes identification of an homogeneous patient population with a
      characteristic disease process and a predictable response to an intervention.
      Although progress has been made in identifying such groups of critically ill
      patients, the disappointing results of clinical trials of agents that so clearly
      demonstrate efficacy in animal models indicates that considerable work remains.

PMID- 8662130
TI  - Pattern of organ failure following severe trauma.
AB  - Multiple organ failure (MOF) is considered to be the leading cause of death after
      severe trauma. Although there is extensive literature on MOF, little is known
      about the pattern, sequence, and onset of this clinical syndrome. The first goal
      of this clinical study was to define MOF; the second was to assess the typical
      onset, sequence, and pattern of MOF; and the third was to define certain risk
      factors for the development of MOF in 342 multiple trauma patients. Patients with
      an Injury Severity Score (ISS): > 20 (mean 35.7) were included. Three well
      established MOF scoring methods were used to give strict definitions of MOF:
      11.4% of the total patient population developed MOF, and 88.6% did not.
      Respiratory failure was most frequent in patients developing MOF (74.4%), and
      these patients had the highest mortality rate (65.5%) compared to patients with
      failure of other organ systems (liver, cardiovascular system). Generally, the
      lung is the first organ to fail after injury (failure after 3.7 +/- 2.8 days).
      Significant renal failure and the need for dialysis decreased to < 5%; other
      signs of organ dysfunction (gastric, central nervous system) are difficult to
      verify. Typical risk factors for the development of MOF after severe trauma are
      the severity, type, and distribution of injury as well as the indicators of
      prolonged hemorrhagic shock (elevated lactate levels). The main therapeutic
      efforts, therefore, should be the effective treatment of traumatic hemorrhagic
      shock during the initial phase, adequate resuscitation, optimal oxygenation, and
      early surgical treatment.

PMID- 8662131
TI  - Ingredients of organ dysfunction or failure.
AB  - The simultaneous dysfunction of several organs (MODS, or multiple organ
      dysfunction) represents the most challenging task for the intensivist. In recent
      years more and more patients have been diagnosed as suffering from MODS due to
      several causes, including better immediate treatment of injuries that only a few
      years ago would have been considered incompatible with life or with consequent
      reduced organ reserve. Even if initially MODS has been associated with infections
      and sepsis, because of its similarity with a generalized inflammatory reaction
      mediated by a wide array of mediators, it is now clear that noninfectious
      insults, such as multiple trauma, acute pancreatitis, and retroperitoneal
      bleeding, can start a chain reaction ultimately leading to the onset of MODS. A
      specific trigger factor has not yet been identified, but experimental and
      clinical evidence suggests that the gut, endothelium, and immune system interact
      to produce the altered metabolic and cardiorespiratory patterns commonly observed
      in patients with MODS. It is thus possible that a target-oriented approach,
      including rapid correction of intestinal underperfusion, supply of specific
      nutrients, and down-regulation of the inflammatory cascade, can act as either a
      preventive measure for subjects at risk or as a main treatment for patients with
      full-blown MODS.

PMID- 8662132
TI  - Biologic control of injury and inflammation: much more than too little or too
      late.
AB  - A generalized host inflammatory response is necessary to orchestrate the
      maintenance or recovery of tissue repair and immune competence following severe
      injury or infection. When excessive in initial magnitude or duration, however,
      these otherwise beneficial inflammatory processes may eventuate in deterioration
      rather than restoration of homeostasis. Although the adverse consequences of
      excessive inflammatory stimuli may be acutely evident, their influences are more
      often insidious. A complex cascade of endogenously derived proinflammatory
      mediators are currently hypothesized to be responsible for both the beneficial
      and the adverse sequelae of infection and injury. The cytokine proteins tumor
      necrosis factor and interleukin 1 have been most widely studied as potential
      targets for antagonist intervention in both experimental models and prospective
      clinical trials. Preclinical evidence supporting these approaches is briefly
      discussed herein, as are the results of clinical trials attempting to modulate
      cytokine influences in the presence of sepsis. The present discussion focuses on
      potential insights gained from these investigations and the evolving appreciation
      for the importance of cytokine counterregulatory mechanisms. Examples of
      potentially complex interactions between inflammatory cytokines and infection
      induced antagonist proteins or counterregulatory hormones are provided. It is
      hypothesized that a sustained imbalance among these proinflammatory and
      counterregulatory influences may be a critical determinant of outcome in patients
      with severe infection.

PMID- 8662122
TI  - What is the current status of quantification and nuclear medicine in cardiology?

PMID- 8662134
TI  - Update on the mechanisms of immune suppression of injury and immune modulation.
AB  - Major trauma results in massive impairment of immunologic reactivity, the
      clinical consequence of which consists in the high susceptibility of the
      traumatized individual toward serious infection. Whereas parts of the immune
      system are stimulated within a systemic, nondiscriminant, excessive whole-body
      inflammation, other functions within the complex of cell-mediated immunity (CMI)
      are dramatically paralyzed. Immune abnormalities in the aftermath of trauma occur
      in a sequence of states of cellular activation and within a complex order of
      events that is not yet well understood. Traumatic stress is causing
      disintegration of the intact monocyte (Mphi)-T cell interaction, which is
      associated with profound changes in Mphi forward-regulatory capacities and
      substantial depression of T cell function. Extensive tissue destruction results
      in the generation of numerous stimuli, such as phagocytosis, immune complexes,
      complement split products, and endo- and exotoxins, all of which contribute to
      excessive Mphi activation. Mphi then rapidly produce and release prostaglandin E2
      (PGE2), a powerful endogenous immune suppressant. PGE2 is an inhibitor of T cell
      mitogenesis, interleukin 2 (IL-2) production, and IL-2 receptor expression; and
      it has a massive impact on the quality of B cell antibody synthesis. Most
      importantly, PGE2 represents an important cofactor for the induction of T-helper
      lymphocyte (TH) activity toward the TH2 direction. TH2 cells are associated with
      the synthesis of immunosuppressive cytokines, such as IL-4 and IL-10. Although
      immunosuppressive substrates are inhibitory for TH1 cells-the functional carriers
      of CMI-they support TH2 activity, which predisposes the host to develop
      infection. The endogenous ability of the organism to survive overwhelming trauma
      is insufficient and requires major exogenous support. Immune modulatory
      interventions, depending on the immune abnormalities seen in the traumatized
      host, should be started as early as possible after trauma in a preventive fashion
      to protect against organ tissue destruction. Ideally, it should protect all
      cellular host defense compartments from hyperactivation as well as from
      exhaustion. We do believe that only a combination of drugs can effectively
      control the posttraumatic dyshomeostasis of the various cell systems.

PMID- 8662133
TI  - Potential strategies for inflammatory mediator manipulation: retrospect and
      prospect.
AB  - Sepsis syndrome and septic shock remain significant causes of morbidity and
      mortality. To date, clinical trials of novel agents to treat sepsis have failed
      to demonstrate clinical efficacy despite considerable animal data to suggest a
      positive therapeutic benefit. This article reviews the recent major clinical
      trials on sepsis and discusses the hypotheses on which these therapies are based
      and the critical issues associated with clinical sepsis. Recommendations for
      future clinical trials on sepsis are made.

PMID- 8662135
TI  - Metabolism of sepsis and multiple organ failure.
AB  - "Septic autocannabalism" been coined to describe the metabolic response that
      follows severe sepsis in humans. The normal protein- and energy-conserving
      mechanisms evoked during simple starvation are not observed following the onset
      of sepsis. The metabolic response to sepsis entails rapid breakdown of the body's
      reserves of protein, carbohydrate, and fat. Hyperglycemia with insulin
      resistance, profound negative nitrogen balance, and diversion of protein from
      skeletal muscle to splanchnic tissues are prominent features. These responses are
      believed to be mediated in large part by inflammatory cytokines such as tumor
      necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-6.
      Secondary induction of catecholamines, cortisol, and glucagon by cytokines is
      likely to be another important effector mechanism. Infection and inflammation
      elicit a complex network of interwoven responses, and no single mediator alone
      accounts for the responses observed. Sepsis also commonly involves alterations in
      cardiovascular function with altered flow to key metabolic sites, hypoxia, damage
      to the gut's mucosal barrier, secondary organ failure, and alterations in
      capillary permeability. These structural and functional alterations also strongly
      influence the metabolic profile during infection. If these catabolic responses
      persist for more than a few days, severe malnutrition results and is likely to be
      an important risk factor for mortality in these patients. The altered metabolic
      milieu during sepsis prevents effective use of exogeneously delivered glucose and
      protein; at best, administration of these agents ameliorates but does not prevent
      the persistence of catabolism. Delivery of agents that antagonize cytokines and
      other moieties such as glutamine and growth hormone may, in the future, help to
      restore nitrogen balance during sepsis.

PMID- 8662136
TI  - Prevention and therapy of multiple organ failure.
AB  - Multiple organ failure (MOF) stems from a complex interaction between the host's
      immune response and inadequate tissue perfusion. Prevention of MOF therefore
      addresses these two components. The risk of inflammation is reduced through
      treatment of any infection and early stabilization of traumatized regions.
      Adequate respiratory and cardiocirculatory resuscitation is achieved to restore
      and maintain tissue perfusion. Although a supranormal cardiac output is often
      indicated, it is difficult to define precise endpoints for hemodynamic
      stabilization. Instead of increasing the oxygen supply to supranormal values in
      all patients, it is probably safer and more effective to increase it only in
      those patients for whom persistent ischemia is suspected. Provision of adequate
      nutritional support is important, and whenever possible the enteral route is
      preferred. Once MOF has developed, treatment turns to support of individual
      organs. Unfortunately, there is no single treatment for MOF that seems to reverse
      the associated trend of high mortality. Survival is more likely when the cause of
      MOF can be found and eliminated.

PMID- 8662137
TI  - Multiple organ failure: is it disappearing?
AB  - The incidence of multiple organ failure (MOF) during the last decade has been
      reported variously as 2% to 25%, depending on the patient population examined.
      The mortality rate from this devastating complication ranges from 40% to 80%.
      Although the incidence has not changed during the last decade, it does not mean
      that there has been no progress. Tertiary centers are now seeing trauma and
      nontrauma patients who have more significant underlying disease and injuries.
      Likewise, a higher percentage of our trauma patients are now referred from
      outside institutions where there may not be the facilities to administer the
      complex, rapid resuscitation these patients require. Prevention of MOF remains
      its best treatment. Rapid, adequate volume resuscitation, adequate nutrition,
      appropriate antibiotic usage, and aggressive pulmonary management are important
      for preventing the downward physiologic spiral that leads to MOF and death. Once
      MOF has occurred, it is not clear that these same measures are as effective in
      altering outcome.

PMID- 8662138
TI  - Nutritional support to prevent and treat multiple organ failure.
AB  - Enteral nutrition (EN) has several advantages over parenteral nutrition (PN) for
      postoperative/posttrauma patients. Modern technologies for tube-feeding have made
      early EN possible. Jejunal tube-feeding has advantages over gastric tube-feeding:
      faster metabolic recovery, less vomiting, and less risk of regurgitation and
      aspiration. Immediate or early EN stimulates the splanchnic and hepatic
      circulations, improves mucosal blood flow, prevents intramucosal acidosis and
      permeability disturbances, and eliminates the need for stress ulcer prophylaxis.
      Saliva containing important antimicrobial substances and gastric acidity are
      important in sepsis prevention. Chewing, saliva, and gastric acidity support
      gastric nitric oxide (NO) release, important for mucosal blood flow,
      gastrointestinal (GI) motility, mucus formation, and bacteriostasis. An oral
      supply of NO-donating substances and chewing of nitrate-rich food, such as
      lettuce or spinach, can be useful. Oral and mucosa-protective lipids are
      recommended. H2 blockers and saliva-inhibiting drugs are avoided. Immediate EN
      should be given, starting with 25 ml/hr and increasing to 100 ml/hr over 24 to 48
      hours. For the immunocompromised patient special attention should be given to the
      purity of water. Bottled water can contain bacteria such as Pseudomonas. Food
      antioxidants such as glutathione, vitamin E, and beta-carotenes are important.
      Ingredients for the colonic mucosa are important. Approximately 10% of caloric
      need is satisfied by so-called colonic food (prebiotics), fermented at the level
      of the colonic mucosa to produce colonic mucosa nutrients and to prevent gut
      origin sepsis. More than 10 g of fiber per day is recommended. The fermenting
      flora (probiotic flora) is deranged owing to disease or antibiotic treatment, and
      resupply of flora is important. A new concept of ecoimmune nutrition is presented
      for enteral supply of mucosa-reconditioning ingredients: new surfactants,
      pseudomucus, fiber, amino acids such as arginine, and mucosa-adhering
      Lactobacillus plantarum 299.

PMID- 8662139
TI  - Blood purification for prevention and treatment of multiple organ failure.
AB  - Blood purification has been applied conventionally as an artificial kidney or
      artificial liver in the management of patients with multiple organ failure (MOF),
      and most blood purifications have been performed intermittently. Recent advances
      in medical engineering made it possible to perform such blood purifications
      continuously (i. e., 24 hours a day, 7 days a week if necessary) even in
      critically ill patients. This modality is referred to as continuous renal
      replacement therapy (CRRT) or continuous blood purification (CBP). Among many
      kinds of CBP, continuous hemodiafiltration (CHDF) is most useful for management
      of MOF, as it can be performed without serious or hazardous side effects, and
      improvement can be expected with it. Recently, CHDF and polymyxin B immobilized
      endotoxin adsorption columns were used for the prevention or treatment of MOF,
      with the expectation that such therapy can be effective as a countermeasure
      against the pathophysiologic causes of MOF. Our data and that of others clearly
      indicate that continuous blood purification, such as with CHDF and endotoxin
      adsorption, can remove or decrease the blood levels of humoral mediators,
      including proinflammatory cytokines, and can improve tissue oxygenation,
      especially oxygen consumption (VO2) among critically ill patients including those
      with MOF. Blood purification is also useful in the careful management of fluid,
      electrolytes, and acid-base balance and for the removal of metabolic wastes.
      Blood purification is now considered to be one of the basic therapeutic tools of
      critical care, equal to nutritional support with total parenteral nutrition and
      respiratory support without a ventilator.

PMID- 8662140
TI  - Animal models as the basis of pharmacologic intervention in trauma and sepsis
      patients.
AB  - With limited resources and the current concerns about using animals for research
      purposes, the needs must be clear when setting up trauma and sepsis experiments
      for pharmacologic interventions. Such interventions are performed typically for
      four reasons: (1) to study the pathophysiologic role of certain mediators (which
      can be influenced by pharmacologic agents); (2) to study the therapeutic efficacy
      of treatment strategies; (3) to study the overall safety of new drugs under
      trauma/sepsis conditions, which are adjunct studies to standard toxicology; (4)
      to test new diagnostic procedures in a defined trauma or sepsis setting.
      Intervention in the inflammatory response may be performed at several levels: (1)
      at the primary induction site (e.g., by antilipopolysaccharide or by preventing
      complement activation); (2) at the intermediate mediator level (e.g., by
      antitumor necrosis factor); (3) at the final mediator level (e.g. , by block of
      polymorphonuclear neutrophil elastase, and (4) at the target (e.g., by membrane
      stabilization or enhanced antioxidant defense).

PMID- 8662141
TI  - Clinical trials of new and novel therapeutic agents.
AB  - Throughout this issue of World Journal of Surgery are recommendations and
      descriptions of therapy to prevent the development of multiple organ failure
      (MOF). The subjects include advances in monitoring; circulatory, pulmonary, and
      gut support; blood treatment; immune modulation; and control of the inflammatory
      process. Additional methods of organ support include recommendations for
      resuscitation and initial care and for early definitive operations. New
      therapeutic agents such as growth factors, glucan, ketaconazole, and antithrombin
      III are described. Finally, methods to support organ function before it fails
      (circulation, lungs, and kidneys) are described.

PMID- 8662143
TI  - Difference between carcinoma of the lower esophagus and the cardia.
AB  - We analyzed the records of patients with carcinoma of the lower esophagus and
      cardia. Mediastinal node involvement was found in 43% of the patients with
      squamous cell carcinoma of the lower esophagus, and the 5-year survival after
      mediastinal dissection for patients with mediastinal node involvement was 27%.
      Mediastinal node involvement was found in 19% of the patients with adenocarcinoma
      of the cardia involving the esophagus, and no patients with mediastinal node
      involvement survived more than 2 years. When the patients had mediastinal node
      involvement, survival curves were significantly different. There were large
      differences between these tumors in terms of the extent of lymph node involvement
      and the survival of patients with mediastinal lymph node involvement. It is
      incorrect to consider the behavior of these tumors identical and to treat the
      conditions similarly.

PMID- 8662142
TI  - Protection of the gastroduodenal mucosa from the effects of diclofenac sodium:
      role of highly selective vagotomy and misoprostol.
AB  - The aim of this study was to determine the effectiveness of highly selective
      vagotomy (HSV) or misoprostol, a prostaglandin E1 (PGE1) analog, for protecting
      the gastroduodenal mucosa (GDM) from the effects of diclofenac sodium (DS). Fifty
      mongrel dogs were randomly allocated to five groups. HSV alone was performed in
      group I dogs (controls) to standardize the operation. DS was given
      intramuscularly for 12 consecutive days to the group II dogs, whereas in the
      group III dogs HSV was performed, followed a month later by DS administration, as
      in group II. DS was given in combination with misoprostol for 12 days to the
      group IV dogs. HSV was performed on the group V dogs, and a month later DS and
      misoprostol were given, as in group IV. After sacrificing the animals the GDM was
      examined for macroscopic and histologic lesions. Statistical analysis was made by
      Fisher's exact test. HSV alone did not protect the gastric or duodenal mucosa
      from the effects of DS (p = 0.474 and p = 0.62, respectively). Misoprostol alone
      also did not offer significant protection to the gastric or the duodenal mucosa
      (p = 0.08 and p = 0.65, respectively). The combination of HSV plus misoprostol
      protected the gastric mucosa (group V, p = 0.007) but not the duodenal mucosa
      (group V, p = 0.08). Hence HSV or misoprostol alone offers no protection to the
      GDM from the effects of DS. The combination of HSV and misoprostol offers
      significant protection only to gastric mucosa. Enhancement of the mucosal defense
      mechanisms combined with strong reduction of gastric acidity may offer adequate
      protection to gastric mucosa from the effects of nonsteroidal antiinflammatory
      drugs.

PMID- 8662144
TI  - Endosonography for preoperative staging of specific nodal groups associated with
      esophageal cancer.
AB  - The results of endoscopic ultrasonography (EUS), used preoperatively in 74
      endoscopically evaluable patients, were compared with the histopathology after
      subsequent total esophagectomy with radical lymphadenectomy involving a three
      field dissection of the lower cervical, mediastinal, and abdominal nodes.
      Patients with obstruction to endoscopy were excluded from this study. Overall
      accuracy, specificity, and sensitivity were 87%, 90%, and 37%, respectively. EUS
      has an accuracy of more than 80% for detecting metastatic nodes in the cervical
      paraesophageal, supraclavicular, right recurrent laryngeal, left paratracheal,
      upper and lower paraesophageal, infraaortic, infracarinal, and lower posterior
      mediastinal regions. Its sensitivity is highest for cervical and upper thoracic
      paraesophageal, infracarinal, left paratracheal, and recurrent laryngeal nodes.
      Accuracy is maximum for periesophageal nodes and varies inversely with the axial
      distance of the nodes from the esophageal axis. We recommend that EUS be used
      routinely for preoperative assessment of the cervical and mediastinal nodal
      status.

PMID- 8662145
TI  - Indications and results of balloon angioplasty for arterial occlusive lesions.
AB  - This paper describes the current techniques for percutaneous transluminal
      angioplasty (PTA) of peripheral arteries, summarizes the long-term results of the
      procedure, and identifies the variables that are predictive of long-term success
      of PTA performed in the iliac and femoropopliteal segments.

PMID- 8662146
TI  - Current status of atherectomy for peripheral arterial occlusive disease.
AB  - Atherectomy physically removes plaque by cutting, pulverizing, or shaving it in
      atherosclerotic arteries using a mechanical, catheter-deliverable endarterectomy
      device. Theoretically, atherectomy offers the following advantages over
      percutaneous transluminal angioplasty (PTA): It shows a greater immediate success
      rate with less dissection and acute occlusion, treats complex lesions, and
      reduces the restenosis rate. This article presents the unique features of four
      atherectomy devices designed to meet the above challenges: Simpson AtheroCath,
      Transluminal Extraction Catheter (TEC), Trac-Wright Catheter, and Auth
      Rotablator. The results, complications, and limitations reported by clinical
      investigators are discussed critically and realistically. A new device, the
      OmniCath, under investigative trial, is presented briefly. Clinical studies
      evaluating the Simpson AtheroCath have reported impressively high initial success
      rates (ranging from 82% to 100%) but disparate intermediate patency results
      (ranging from 35% to 84%). Complications associated with the device include
      hematoma, pseudoaneurysm, and distal embolization. Clinical studies show that the
      device is relatively ineffective for treating diffusely diseased and long
      occluded lesions. Restenosis has also been a primary constraint of the Simpson
      device, with reported restenosis rates ranging from 11% to 55% at 6 months. The
      initial technical and clinical success rates reported with the TEC atherectomy
      device have been promising at 79% to 92%; however, short- and mid-term follow-up
      results have been either lacking or disappointing, with a reported patency of 67%
      at 6 months and 51% at 12 months. Furthermore, the problems of restenosis and
      reocclusion have limited its short-term benefits. The Trac-Wright catheter has
      demonstrated widely disparate technical success rates (from 58% to 100%) and
      clinical success rates (from 33% to 80%). Patency rates reported have been
      suboptimal, ranging from 25% to 68% at 6 months and 25% to 45% at 12 months.
      Furthermore, severe complications associated with the device include perforation,
      dissection, and embolization. Reocclusion also limits the applicability of the
      device. The reported immediate success rates of 72% to 94% using the Auth
      Rotablator are similar to those reported for other atherectomy devices. Patencies
      reported at 1 and 2 years are dismal, ranging from 31% to 61% and from 12% to
      18%, respectively. Significant complications are associated with the device,
      including thrombosis, arterial spasm, hemoglobinuria, hematoma, and embolization.
      Contrary to previous studies and expectations, perforations and dissections have
      been encountered by some investigators. Late restenosis and reocclusion are also
      significant limiting factors of the Auth Rotablator. Atherectomy currently has
      limited applications for treatment of peripheral arterial occlusive disease. The
      intermediate- and long-term results obtained with the atherectomy devices are
      worse than those reported for PTA. Furthermore, all of the atherectomy devices
      have failed to reduce the restenosis and reocclusion rates from those reported
      for PTA. The problem of restenosis, reocclusion, and other complications must be
      solved before atherectomy can be used generally as an alternative to vascular
      reconstruction procedures such as PTA.

PMID- 8662147
TI  - Indications and results of arterial stents for occlusive disease.
AB  - The application of stents for treatment of peripheral arterial occlusive disease
      has gained widespread clinical use, but their safety and efficacy remain unclear.
      Stent technology is still evolving, and long-term follow-up data are sorely
      needed. Stents have had good success in providing a scaffold to maintain the
      intraluminal structure and patency of an artery. As such, stents appear to play a
      role in improving early results after failed or inadequate balloon angioplasty.
      However, stents do not prevent restenosis due to intimal hyperplasia.
      Furthermore, stents may be thrombogenic and prone to extrinsic compression in the
      peripheral position. Thus patency results are clearly worse in the femoral artery
      (47% at 3 years) than in the iliac artery (82-84% at 6-24 months). Furthermore,
      there is no evidence so far that stents improve long-term patency over standard
      balloon angioplasty without stents; and complication rates of stent procedures
      are generally 10%. Currently in the United States stents are approved for use in
      the iliac artery position. However, routine use of stents cannot be recommended
      until studies demonstrate that the results with stents are better than those with
      balloon angioplasty alone.

PMID- 8662148
TI  - Lower limb intraarterial thrombolysis as an adjunct to the management of arterial
      and graft occlusions.
AB  - Intraarterial thrombolysis is used increasingly for management of arterial and
      bypass graft occlusions. Current research has been directed at the indications
      for and methods of catheter-directed thrombolysis. Streptokinase, urokinase, and
      tissue plasminogen activator (t-PA) are the most commonly used agents. They are
      administered by a variety of techniques and in various doses involving
      intrathrombic infusions, thrombus lacing, high-dose bolus therapy, and pulse
      spray lysis. The latter methods appear to produce thrombolysis within a few
      hours, so this chemical therapy has the potential to become the first-line
      management for all episodes of acute limb ischemia. The role of thrombolysis is
      to return patients to their prethrombotic or preembolic state, so the underlying
      condition can be treated by radiologic intervention, surgery, or anticoagulation.
      Intraarterial thrombolysis is indicated for occlusions of less than 2 weeks'
      duration where the limb is able to withstand a period of further ischemia. Older
      occlusions should be treated by surgery, reserving intraoperative lysis for
      specific situations.

PMID- 8662150
TI  - Endovascular repair of abdominal aortic aneurysms using the EGS tube and
      bifurcated graft systems.
AB  - Left untreated, aneurysmal disease of the abdominal aorta is a highly lethal
      condition. Standard transabdominal repair of aortic aneurysm, although successful
      and durable, continues to be plagued by significant morbidity, mortality, and
      cost. Placement of an endovascular graft through a femoral arteriotomy is a new
      technique that could potentially reduced this morbidity and cost without
      sacrificing efficacy. This report details the development of a U.S. Food and Drug
      Administration (FDA)-approved endovascular grafting device. In addition, we
      describe our experience screening patients and summarize our clinical experience
      with the placement of both tube and bifurcated endovascular graft systems. To
      date, 16 patients have undergone endovascular repair with a tube graft at UCLA,
      and three bifurcated grafts have been placed. Two patients required conversion to
      conventional open aneurysm repair. All the remaining procedures were successful,
      and there were no perioperative deaths or major complications. We conclude that
      endovascular grafting of aortic aneurysms is both feasible and safe. Long-term
      patency and the ability of this technique to prevent the known complications of
      aortic aneurysmal disease remain unanswered questions at this time.

PMID- 8662149
TI  - Endovascular repair of aortic aneurysms, arteriovenous fistulas, and false
      aneurysms.
AB  - Between September 1990 and June 1995, 103 patients were treated with transluminal
      placed endovascular grafts: 87 had abdominal aortic aneurysms (AAA), two had
      iliac artery aneurysms (one in association with an AAA), 3 had thoracic
      aneurysms, and 12 had vascular injuries in various localization of the arterial
      tree. The AAAs were excluded from the blood flow with a device composed of a
      balloon-expandable stent (modification of the Palmaz stent) attached to a Dacron
      graft designed to expand at both ends of the accompanying stent extension. An 18F
      sheath containing the stent-graft device was introduced through a small cut-down
      in the common femoral arteries and advanced under fluoroscopic guidance. Color
      duplex, contrast-enhanced computed tomography (CT) scanning and angiography were
      performed before the procedure and then every 6 months. (Arteriography was
      performed once during the follow-up period and whenever other studies disclosed
      an abnormal finding.) A total of 87 patients (75 men, 12 women) harboring an AAA
      were treated: Forty-five patients underwent an aortoaortic procedure (8 patients
      had only a proximal stent implanted, and 37 had proximal and distal stents).
      Forty-two patients were treated by implanting an aortoiliac graft, completing the
      procedure with a femorofemoral bypass. The contralateral common iliac artery was
      occluded by means of an occluding stent. One type A dissecting aneurysm and two
      descending thoracic aneurysms were successfully treated by the endovascular
      technique. The longest follow-up period was 60 months and the shortest 1 month.
      Initial success was obtained in 84% of the aortoaortic cases and in 75% of the
      aortoiliac procedures. Long-term follow-up (> 12 months) disclosed 78% success
      for the aortoaortic cases and 90% for the aortoiliac procedures. Late failures
      included distal aortic dilatation, distal leak into the aneurysmal cavity, and
      proximal leak into the aneurysm. All trauma cases were successful over the short
      and long terms. Trauma cases included false aneurysms (common carotid,
      subclavian, common femoral arteries) and arteriovenous fistulas (subclavian,
      aortocava, common iliac-cava and superficial femoral artery and vein). We
      concluded that stent-graft combination devices appear to be an alternative for
      treating vascular trauma and aneurysms. Initial success for treating AAAs is
      almost 100%, and late success in aortoiliac cases is also high (90%) for
      aortoaortic reconstruction. However, late failures are frequent and require
      further evaluation in relation to a persistent increase in the diameter of the
      proximal neck and distal cuff.

PMID- 8662151
TI  - Options for treatment of persistent aneurysm perfusion after endovascular repair.
AB  - Persistent aneurysm perfusion represents failure of endovascular repair. The leak
      may occur around either end of the prosthesis or through a collateral route. Most
      cases can be treated by endovascular means. Stents can be rotated, the prosthesis
      can be lengthened at either end, and collateral pathways can be occluded, all
      without recourse to open repair. This report describes the management of
      persistent aneurysm perfusion in five patients from a total experience of 32
      cases of endovascular aneurysm repair.

PMID- 8662152
TI  - Endovascular repair of aortoiliac occlusive disease.
AB  - Occlusive disease of the aorta and iliac and femoral arteries may lead to limb
      threatening ischemia when multiple levels of disease are present. The combined
      treatment of severe aortoiliac and infrainguinal disease using standard
      techniques may be hazardous or contraindicated in patients with multiple,
      previous reconstructions or severe co-morbid medical illnesses. This report
      summarizes the technical feasibility and early results of aortoiliac endovascular
      stented grafts (ESGs) in combination with conventional surgical reconstructions
      for the treatment of multilevel arterial occlusive disease. Forty-two patients
      with multilevel aortoiliofemoral limb-threatening occlusive disease had an ESG
      inserted to treat long-segment, multilevel, occlusive disease. ESGs originated
      from either the aorta or the common iliac artery and were inserted into one of
      the femoral arteries. ESG lengths ranged from 16 to 30 cm (mean 21 cm).
      Conventional surgical bypasses were constructed, when necessary, from
      polytetrafluoroethylene (PTFE) or saphenous vein and were extended using standard
      techniques to the popliteal, tibial, or contralateral femoral arteries. Technical
      success of graft insertion was achieved in 39 of 42 attempted ESG procedures
      (93%). The 18-month primary and secondary cumulative patency rates for ESGs were
      89 +/- 9 (SE) and 100%, respectively. Limb salvage was achieved in 94% of
      patients at 24 months. Four patients had minor postprocedure complications (10%),
      and there was one death. Endovascular aortoiliac grafts, often in combination
      with conventional surgical infrainguinal bypasses, are a technically feasible,
      potentially safe option for the treatment of limb-threatening aortoiliofemoral
      occlusive disease and have demonstrated encouraging early patency. Long-term
      follow-up is necessary before widespread application of this technique is
      instituted.

PMID- 8662153
TI  - Endovascular technology and its impact on the relationships among vascular
      surgeons, interventional radiologists, and other specialists.
AB  - Endovascular treatment methods that are largely catheter/guidewire-based permit
      treatment of a variety of vascular lesions from remote access sites in a
      minimally invasive manner. Because these endovascular technologies have intrinsic
      appeal to patients and physicians, they may, if proved safe and effective,
      replace a substantial proportion of current vascular surgical procedures. This
      change will have a substantial impact on the specialties involved in their
      development and use, that is, vascular surgery and interventional radiology
      (which in this discussion includes other interventional specialists devoted to
      peripheral vascular disease management). The relationship between these
      previously distinct specialties must also be influenced greatly by the
      introduction of endovascular technologies, the use of which requires skills that
      overlap the specialties. This paper considers several possible approaches for
      dealing with the altered interspecialty relationships that will result if new
      endovascular treatment methods prove to be safe and effective. Because the
      development and use of these endovascular technologies require the skills and
      talents of vascular surgeons and interventional radiologists (or other
      interventionalists), a collaborative, multispecialty approach to the use of
      endovascular technologies is recommended as the most reasonable and optimal for
      patient care. Although this approach may not be applicable for every environment,
      it is the one most likely to minimize costs and turf battles, particularly if
      interspecialty conflict can be minimized by collaboration and compromises
      developed by a conjoint executive committee representing the leadership of the
      involved specialty societies.

PMID- 8662154
TI  - Functional and morphometric study of cryopreserved human parathyroid tissue
      transplanted into nude mice.
AB  - As part of an ongoing study of the characteristics of transplanted fresh normal
      and pathologic parathyroid tissues, we transplanted cryopreserved human
      parathyroid tissue into nude mice. Hyperplastic glands cryopreserved for various
      lengths of time (<2 weeks and >1 year) were transplanted into the gluteus muscle
      of nude mice. Specimens grafted were of two sizes: 10 mg and 30 mg. Serum human
      parathyroid hormone (hPTH) concentration was estimated by a double-antibody
      immunoradiometric assay prior to transplantation and 2, 4, and 8 weeks after
      transplantation. A low-calcium diet was given to some mice to evaluate any
      effects on the grafts of low serum concentrations of calcium. All mice were
      killed 4 hours after injection of bromodeoxyuridine (Brd U) for assessment of the
      cell proliferation in grafted parathyroid tissue. Although hPTH secretion of
      cryopreserved tissue was only half that of fresh tissue, the cryopreserved tissue
      released hPTH, as did fresh tissue. hPTH secretion was accelerated by stimulation
      of a low-calcium diet, and PTH secretion was positively correlated with the
      volume of transplanted tissue. The number of Brd U-immunoreactive cells was
      correlated with the serum concentration of hPTH (r = 0.95), which indicates that
      cell proliferation is closely related to PTH secretion under the condition of
      successful transplantation. The experimental transplantation of cryopreserved
      tissue into nude mice, coupled with a concise immunohistochemical study of the
      grafts conducted prior to their transplantation into humans, can contribute to
      the evaluation of PTH secretion and cell proliferation.

PMID- 8662155
TI  - Vascular imaging before, during, and after endovascular repair.
AB  - Endovascular techniques for repair of vascular lesions are developing rapidly.
      Imaging modalities are critical in this evolution from several perspectives.
      Device development and evaluation rely on precise imaging to ensure fixation of
      devices, isolation of lesions, and assessment of healing at various intervals.
      Clinical implementation of endovascular techniques requires a spectrum of imaging
      methods to choose patients appropriately for procedures, to deploy devices
      expediently and precisely, and to evaluate long-term efficacy in a minimally
      invasive manner. This paper reviews the utility of available imaging methods for
      performing these assessments.

PMID- 8662156
TI  - Elective surgery for corrosive-induced gastric injury.
AB  - Gastric cicatrization is a well recognized late sequela of corrosive gastric
      injury, but the optimum timing and type of surgery for this complication are
      still unclear. Over a 7-year period (1988-1994) 34 patients underwent elective
      surgery for gastric lesions secondary to corrosive ingestion. A total of 18 (53%)
      patients had an associated esophageal stricture and presented with dysphagia, 15
      (44%) patients had features of gastric outlet obstruction, 6 (18%) had diffuse
      gastric injury, and 28 (82%) had a segmental lesion. A tube jejunostomy was done
      in 23 (68%) patients to improve nutrition and resulted in a significant increase
      in weight and in the serum protein level after 8 weeks of tube feeding. Elective
      surgery was performed 3 to 24 months (average 7 months) after ingestion of the
      corrosive substance. Gastric resection was done in 20 (59%) patients and
      gastrojejunostomy (without vagotomy) in 11 (32%); at follow-up the latter group
      did not exhibit development of a stomal ulcer. In patients with an associated
      esophageal stricture, endoscopic dilatation was successful in 89% patients and
      simplified the surgical approach. In conclusion, the success of surgery for
      corrosive-induced gastric injury depends on selecting the right procedure and
      intervening at the appropriate time.

PMID- 8662157
TI  - Diagnosis and therapy for ampullary tumors: 63 cases.
AB  - From 1970 to 1992 a total of 63 patients underwent operation for ampullary tumor:
      40 pancreatoduodenectomies (PDs), 3 total PDs, 8 ampullectomies, and 12 bypass or
      exploratory laparotomies. The resectability rate was 68%. There were 9 benign
      tumors, 1 anaplastic tumor, and 53 adenocarcinomas. According to Martin's
      classification, there were 7 stage I, 11 stage II, 14 stage III, and 21 stage IV
      tumors. All patients with stage I, II, and III tumors underwent resection.
      Patients with stage IV tumors had either resection (n = 11) or bypass (n = 10).
      The mean duration of hospital stay was 20.6 days. Operative mortality was 12.7%
      for the whole series and 7.5% after PD (2.5% for the last 10 years). Overall
      survival was 40% at 5 years (85% for stage I, 65% for stage II, 44% for stage
      III, and 8% for stage IV). Survival was better for stages I, II, and III after PD
      than after ampullectomy. For stage IV patients survival was 70% after PD versus
      20% after bypass at 1 year and 25% versus 0% after 2 years. In our opinion, PD
      should be proposed even for benign lesions because two of our patients had to
      undergo repeat operation (PD) 4 and 22 years later, respectively, for stage IV
      disease. PD is our choice for all tumors of the ampulla.

PMID- 8662158
TI  - Retroperitoneal nephrectomy: comparison of laparoscopy with open surgery.
AB  - Retroperitoneal laparoscopic nephrectomy (RLN) is a relatively recent technique
      whose performance needs to be firmly established. The aim of this study was to
      compare the results of RLNs in 19 patients with retrospective results for 10
      cases of open surgery. Ten of the RLN patients had transplanted kidneys. We used
      a slightly modified, already published technique with only three trocars that did
      not require balloon dilatation of the retroperitoneal space. It was successful in
      patients with and without transplants. The average operative times of RLN and
      open surgery were 115 and 110 minutes, respectively. In no instance did the
      laparoscopic procedure need to be converted to open surgery. There were no peri-
      or postoperative complications that could be related to the RLN technique. The
      average length of hospitalization after RLN was considerably shorter (3.8 days)
      than after open surgery (7.9 days). In conclusion, our experience shows that RLN
      is a safe, reproducible technique that reduces recovery time. It has become our
      first-line approach for simple nephrectomy, nephroureterectomy for ureteral
      tumors, and removal of the native kidney in transplant recipients.

PMID- 8662159
TI  - Sacrococcygeal chordoma: review of 50 consecutive patients.
AB  - Fifty consecutive patients with sacrococcygeal chordomas treated during 1941-1991
      at the Tata Memorial Hospital in India were studied retrospectively. Pain was the
      commonest presenting symptom (82%). An average time lapse of 14 months between
      the onset of pain and definitive diagnosis emphasizes the importance of a high
      index of suspicion and prompt use of sophisticated imaging techniques leading to
      an early diagnosis. All patients underwent a partial sacrococcygectomy, through a
      sacral approach in 22 patients (44%) and an abdominosacral approach in 28 (56%).
      Postoperative complications included urinary incontinence (14%), rectal
      incontinence (6%), hemorrhage (4%), and rectal injury (2%). Radiotherapy offered
      significant pain relief to patients with widespread recurrence. A total of 38
      patients were ambulatory, and 12 needed support. The average disease-free
      survival was 63 months, and the overall survival was 7 years. Aggressive
      resection through a combined abdominosacral approach offers the best results.
      Because postrecurrence salvage rates are poor, the primary surgery must be
      complete and curative.

PMID- 8662160
TI  - Comparison of computed tomography and cineangiography in the demonstration of
      central pulmonary arteries in cyanotic congenital heart disease.
AB  - PURPOSE: To assess the diagnostic accuracy of contrast-enhanced computed
      tomography (CT) for central pulmonary artery pathology in patients with cyanotic
      congenital heart disease (CCHD) and right ventricular outflow obstruction.
      METHODS: We compared contrast-enhanced CT and cine pulmonary arteriography in 24
      patients including hte confluence. Both investigations were interpreted by a
      cardiac radiologist in a double-blinded manner at an interval of 3 weeks.
      Angiography was used as the gold standard for comparison. RESULTS: The
      sensitivity for visualization of main pulmonary artery (MPA), right pulmonary
      artery (RPA), left pulmonary artery (LPA), and confluence on CT was 94%, 100%,
      92.8%, and 92.8%, respectively. Diagnostic specificity for the same entities was
      28.5%, 100%, 80% and 50%, respectively. The positive predictive value for each
      was 76.2%, 100%, 94.1%, and 72.2%, respectively. The low specificity of CT in the
      evaluation of the MPA and the confluence is perhaps due to distorted right
      ventricular outflow anatomy in CCHD. Large aortopulmonary collaterals in this
      region were mistaken for the MPA in some patients with pulmonary atresia.
      CONCLUSION: CT is a useful, relatively noninvasive, imaging technique for the
      central pulmonary arteries in selected patients. It can supplement diagnostic
      information from angiography but cannot replace it. LPA demonstration on axial
      images alone is inadequate.

PMID- 8662161
TI  - Percutaneous cholecystectomy for patients with acute cholecystitis and an
      increased surgical risk.
AB  - PURPOSE: To evaluate percutaneous cholecystostomy in patients with acute
      cholecystitis and an increased surgical risk. METHODS: Thirty-three patients with
      acute cholecystitis (calculous, n = 22; acalculous, n = 11) underwent
      percutaneous cholecystostomy by means of a transhepatic (n = 21) or
      transperitoneal (n = 12) access route. Clinical and laboratory parameters were
      retrospectively studied to determine the benefit from cholecystostomy. RESULTS:
      All procedures were technically successful. Twenty-two (67%) patients improved
      clinically within 48 hr; showing a significant decrease in body temperature (n =
      13), normalization of the white blood cell count (n = 3), or both (n = 6). There
      were 6 (18%) minor-moderate complications (transhepatic access, n = 3;
      transperitoneal access, n = 3). Further treatment for patients with calculous
      cholecystitis was cholecystectomy (n = 9) and percutaneous and endoscopic stone
      removal (n = 3). Further treatment for patients with acalculous cholecystitis was
      cholecystectomy (n = 2) and gallbladder ablation (n = 2). There were 4 deaths
      (12%) either in hospital or within 30 days of drainage; none of the deaths was
      procedure-related. CONCLUSIONS: Percutaneous cholecystostomy is a safe and
      effective procedure for patients with acute cholecystitis. For most patients with
      acalculous cholecystitis percutaneous cholecystostomy may be considered a
      definitive therapy. In calculous disease this treatment is often only temporizing
      and a definitive surgical, endoscopic, or radiologic treatment becomes necessary.

PMID- 8662162
TI  - Diagnostic angioscintigraphic evaluation of malignant hepatic tumors before
      catheter embolization: determination of shunt, flow distribution, and reflux.
AB  - PURPOSE: The aim of this study was to evaluate quantitatively arteriovenous
      shunts in malignant liver tumors by injection of 99mTc macroaggregates of albumin
      (MAA) into the tumor-feeding artery after selective catheterization. METHODS: In
      40 patients with malignant liver tumors (33 hepatocellular carcinomas and 7
      metastases of colorectal cancer), a mean dose of 200 MBq 99mTC MAA was injected
      arterially during angiography. The embolized area and the lungs were then
      visualized using a gamma camera. A dedicated computer program calculated
      pulmonary shunt rates. RESULTS: The majority of patients (n = 30) with
      hepatocellular carcinoma showed small shunts varying from 0 to 15%; only 3 of
      these patients had shunts ranging from 18% to 37%. In patients with colorectal
      carcinoma metastases (n = 7) the shunt varied from 0 to 3% (2 +/- 1%), probably
      due to a physiological shunt in normal liver tissue in the embolized area.
      Importantly, the degree of shunt found bore no correlation to the tumor volume or
      to the pattern of vascularity on angiography. CONCLUSION: Diagnostic
      angioscintigraphy is a useful tool for pretherapeutic evaluation of the capacity
      of an individual tumor to retain particles and to measure extratumoral shunting;
      these are essential for therapy planning, as they can help to increase the safety
      and effectiveness of embolization.

PMID- 8662163
TI  - Evaluation and complications of direct graft puncture in thrombolysis and other
      interventional techniques.
AB  - PURPOSE: To evaluate the value and complications of direct graft puncture in
      conducting interventional procedures in synthetic vascular bypass grafts.
      METHODS: We retrospectively reviewed 65 direct graft punctures in 50 patients
      undergoing a variety of interventional vascular procedures. In two patients the
      grafts were found to be infected and the procedures abandoned. RESULTS:
      Complications encountered included hematomas that did not require treatment in
      three patients, and four hematomas requiring surgical drainage. One graft became
      infected (despite prophylactic cefuroxime), after three consecutive punctures
      over a 10-day period for a variety of interventions. All the patients who
      developed hematomas had undergone pharmacological thrombolysis. CONCLUSION:
      Direct graft puncture is a relatively safe technique, with a minimal risk of
      infection and hemostatic complications attributable to thrombolysis. In 31 of the
      41 patients undergoing successful thrombolysis, additional percutaneous
      procedures were undertaken, and these were facilitated by the direct graft
      puncture route.

PMID- 8662164
TI  - Interlocking detachable platinum coils, a controlled embolization device: early
      clinical experience.
AB  - PURPOSE: To present the early clinical experience of a new mechanically
      controlled-release embolization device--the interlocking detachable coil (IDC)-
      in complex embolization outside the head. METHODS: IDCs were used only when
      conventional embolization techniques were considered too risky or unsafe. The
      coils consist of unfibered coiled platinum (0.012 inch), mechanically connected
      to a pusher wire and deployed through a Tracker 18 catheter. IDCs come in a range
      of diameters (2-8 mm) and lengths (1-30 cm). RESULTS: A total of 87 IDCs were
      used for 27 procedures in 25 patients (mean 14.5 years) to occlude 31 arteries or
      vascular lesions. Control of the coil and its release were satisfactory and all
      coils ere fully retrievable up to the point of deployment. Two IDC coils
      embolized inadvertently but were retrieved; there were no other complications.
      The IDC coils could not be satisfactorily placed one high-flow arteriovenous (AV)
      fistula, and in another case there was a small residual fistula. Occlusion was
      produced in 29 of 31 lesions. Ancillary techniques were needed in 5 patients:
      temporary balloon occlusion in 2 and 0.038-inch coils in 3. CONCLUSION: The IDC
      coil is an effective device that allows controlled embolization to be performed,
      especially in aneurysms and in high-flow AV fistulas in children.

PMID- 8662165
TI  - Metallic endoprostheses for malignant tracheobronchial obstruction: initial
      experience.
AB  - PURPOSE: To assess the efficacy of the Wallstent endoprosthesis in malignant
      tracheobronchial obstruction. METHODS: Seven patients with irresectable carcinoma
      of the bronchus were treated with nine Wallstent endoprostheses. The procedures
      were performed under endoscopic and fluoroscopic guidance. Wallstent
      endoprostheses ranging from 8-16 mm in diameter and 26-49 mm in length were
      deployed after balloon dilatation of the strictures. RESULTS: All stents were
      successfully deployed in the desired positions. There was one procedural
      complication and one procedure related death. Three patients showed significant
      improvement in respiratory status after stenting. At a mean follow-up of 5.1
      months, there has been no stent migration, fracture, or collapse. One patient had
      proximal tumor overgrowth that was treated with additional stent insertion. One
      patient died after a bout of massive hemoptysis 3 months poststenting and it was
      difficult to tell whether this was related to the endoprosthesis. CONCLUSION: The
      use of the Wallstent endoprosthesis in malignant tracheobronchial obstruction is
      technically feasible.

PMID- 8662168
TI  - Transjugular insertion of biliary stents (TIBS) in two patients with malignant
      obstruction, ascites, and coagulopathy.
AB  - Two patients with pancreatic malignancies presented with biliary obstruction
      which could not be treated from an endoscopic approach. Standard transhepatic
      biliary drainage was relatively contraindicated because of moderate ascites and
      coagulopathy related to underlying liver disease. In one patient, a transjugular,
      transvenous approach was used to deliver a Wallstent endoprosthesis across the
      distal common bile duct obstruction in a single step procedure. In the second
      case, a previously placed biliary Wallstent was revised with an additional stent
      from a similar approach. Transjugular biliary catheterization offers a valuable
      alternative approach for primary stent placement or revision in patients with
      contraindication to standard transhepatic drainage.

PMID- 8662167
TI  - Spiral computed tomographic angiography of the renal arteries: a prospective
      comparison with intravenous and intraarterial digital subtraction angiography.
AB  - PURPOSE: To assess the accuracy of computed tomographic angiography (CTA) in the
      evaluation of the renal arteries in comparison with intravenous (IVDSA) and
      intraarterial digital subtraction angiography (IADSA). METHODS: In 18 patients,
      35 CTAs and DSAs (27 IADSA, 8 IVDSA) of the renal arteries were performed. CTA
      was done with 2-3 mm collimation,2-4 mm/sec table speed, after intravenous
      injection of 80 ml of contrast medium at 4 ml/sec with a scanning delay time of
      14-21 sec. No previous circulation time curve was performed. CTA data were
      reconstructed with maximum intensity projection (MIP) and shaded surface display
      (SSD). The presence of stenosis was assessed on a three-point rating scale (grade
      1-3). The quality of the examinations; visualization of the ostium, the main
      artery, and its branches; vessel sharpness, linearity, and intraluminal contrast
      filling were evaluated. We compared CTA with DSA. RESULTS: CTA had 96%
      sensitivity, 77% specificity, and 89% accuracy in the detection of stenoses >
      50%. Due to technical errors two stenoses were erroneously diagnosed as positive
      but there were no false negative diagnoses. The quality of CTA was good in 56%
      and moderate in 34% of cases. Visualization of the ostium and main artery was
      graded as 1.74 (out of 2) points and of the renal branches as 1.02 (out of 2)
      points and of the renal branches as 1.02 (out of 2) points. The quality of CTA
      images was worse than that of IADSA in 52%, equal in 41%, and better in 7% of
      cases. CTA was equal to IVDSA in 25% and better in 75% of the cases. CONCLUSION:
      CTA is an accurate noninvasive method for the evaluation of renal arteries.
      Examination quality is essential for the diagnosis. CTA is limited in its ability
      to visualize the branches of the renal artery and accessory arteries. CTA seems
      to be superior to IVDSA.

PMID- 8662170
TI  - Total anomalous pulmonary venous connection to the portal vein.
AB  - Anomalous pulmonary venous return represents a rare congenital anomaly with wide
      anatomic and physiologic variability. We report a case of the newborn with a rare
      form of total infracardiac anomalous pulmonary venous connection (TAPVC). The
      pulmonary veins draining both lungs formed two vertical veins, which joined to a
      common pulmonary trunk below the diaphragm. This venous channel connected to the
      portal vein through the esophageal hiatus. The diagnosis was suggested by color
      Doppler sonography and confirmed by intravenous digital subtraction angiography,
      which allowed definition of the anatomy.

PMID- 8662171
TI  - Successful exclusion of a large femoropopliteal aneurysm with a covered nitinol
      stent.
AB  - A 70-year-old woman presented with a large femoro-popliteal aneurysm. A covered
      nitinol stent was implanted successfully and complete exclusion of the aneurysm
      was achieved. At follow-up 5 months later the stent was still patent and the
      patient was free of symptoms. However, moderate stenosis was seen at the proximal
      end of the stent.

PMID- 8662172
TI  - Percutaneous endoluminal stent-graft repair of an old traumatic femoral
      arteriovenous fistula.
AB  - A stent-graft was custom made to close a high-flow traumatic arteriovenous
      fistula of the left superficial femoral artery, present for 30 years, in a 60
      year-old man with congestive heart failure and ischemic ulceration in the left
      foot. A balloon expandable Palmaz stent (P394; 2.5 mm X 3.9 cm) was covered with
      a polytetrafluoroethylene (PTFE) graft and was inserted percutaneously through an
      11 Fr vascular sheath. Follow-up Doppler ultrasound at 6 months demonstrated
      occlusion of the arteriovenous fistula, patency of the artery, and luminal
      integrity of the artery and vein.

PMID- 8662173
TI  - The heparin-induced thrombocytopenia and thrombosis syndrome: treatment with
      intraarterial urokinase and systemic platelet aggregation inhibitors.
AB  - We report a case of the heparin-induced thrombocytopenia and thrombosis syndrome
      presenting with acute ischemia of a lower limb. The patient was successfully
      treated by withdrawal of heparin products, intraarterial urokinase, and platelet
      anti-aggregation therapy consisting of Dextran and aspirin.

PMID- 8662174
TI  - Percutaneous cystogastrostomy with a new catheter for drainage of pancreatic
      pseudocysts and fluid collections.
AB  - We describe a new catheter for the initial percutaneous drainage of large
      symptomatic pancreatic fluid collections and abscesses using a transgastric
      approach to allow fluid drainage into the gastric lumen. A double-mushroom stent
      is placed secondarily for long-term internal drainage to the stomach, avoiding
      the need for an extended period of external catheter drainage. This technique,
      termed percutaneous cystogastrostomy (PCG), has been used in 19 consecutive
      patients with one recurrent symptomatic pseudocyst in the follow-up period fo 9
      43 months. There was one death within 30 days of PCG and 1 patient proceeded to
      surgical necrosectomy. After evidence of resolution of the pseudocysts, the
      internal stent was retrieved in 17 patients by endoscopic snare.

PMID- 8662175
TI  - The lytA gene and the DNA region located downstream of this gene are not involved
      in the formation of the type 3 capsular polysaccharide of Streptococcus
      pneumoniae.
AB  - Streptococcus pneumoniae strain M31, an unencapsulated, serotype 2 (S2(-)) mutant
      having a deletion of at least 5.5 kb containing the gene lytA that encodes the
      main pneumococcal autolysin, was transformed to the encapsulated serotype 3
      (S3(+)) with DNA from the clinical pneumococcal strain 406. Hybridization
      analysis revealed that the S3(+) transformants also have the deletion
      demonstrating that lytA and the DNA region located downstream of this gene are
      not involved in the encapsulation of S. pneumoniae.

PMID- 8662177
TI  - Identification of a group I intron in the nuclear small subunit rDNA of
      Pseudohalonectria lignicola.
AB  - A 865-bp insertion was detected within the nuclear small subunit (SSU) rDNA in
      two isolates (intron+) of the freshwater ascomycete Pseudohalonectria lignicola
      by the polymerase chain reaction (PCR). The intron sequences from the two
      isolates were identical to each other, and the exon sequences from the two
      intron+ isolates were identical to those in the intron- isolates in the PCR
      amplified region of rDNA. Reverse transcription PCR (RT-PCR) indicated that the
      intron was absent in the mature rRNA. The intron sequence has all the
      characteristics of a group I intron, including four conserved sequence elements
      (P, Q, R, and S), the presence of a U at the 5' splice site of the exon, a G at
      the 3' splice site of the intron, a putative internal guiding sequence, and the
      sequence fit a secondary structure model for group I introns. Like most introns
      found in nuclear rDNA, this intron was located at a highly conserved region and
      was devoid of long open reading frames.

PMID- 8662176
TI  - Inhibition of bacterial translocation from the gastrointestinal tract of mice
      injected with cyclophosphamide.
AB  - Effects of intraperitoneal injection of cyclophosphamide, an immunosuppressant,
      on the degree of bacterial translocation and morphological changes of Peyer's
      patches (PP) in the intestine were investigated with antibiotic-decontaminated
      SPF mice and germfree mice monoassociated with Escherichia coli C25. It has been
      reported that treatment with cyclophosphamide induces bacterial translocation.
      Cyclophosphamide treatment in this study, however, significantly decreased E.
      coli C25 translocation from the gastrointestinal tract to the mesenteric lymph
      nodes (MLN), although the numbers of lymphoid cells, especially B cells, in the
      PP, MLN, and spleen were remarkably reduced. Four injections of cyclophosphamide
      at a dose of 100 mg/kg inhibited bacterial translocation more than one injection
      at a dose of 200 mg/kg in SPF mice. Germfree mice, however, treated with one dose
      of 200 mg/kg showed the same inhibition of bacterial translocation as those given
      100 mg/kg four times. In cyclophosphamide-treated mice, lymph follicles in the PP
      were obviously smaller than those in control mice, M-cells were similar in
      appearance to absorption epithelial cells except for short microvilli, and immune
      cells among the M-cells had disappeared. These data suggested that inhibition of
      bacterial translocation in mice treated with cyclophosphamide may be the result
      of morphological and physiological changes of epithelial cells in the
      gastrointestinal tract, especially M-cells, as a point of entry of invading
      bacteria, independent of the changes in immunological function.

PMID- 8662178
TI  - Flexibacter japonensis sp. nov., a new species that produces a novel inhibitor of
      human leukocyte elastase isolated from soil.
AB  - This strain 758 of a new member of Flexibacter species isolated from a soil is a
      Gram-negative, nonflagellated, gliding, long rod or filamentous. The GC contents
      of the deoxyribonucleic acid of this strain is 49.8 mol %GC. The isolate can be
      distinguished from other Flexibacter species on the basis of physiological and
      biochemical properties and DNA relatedness data. Therefore, we propose a new
      species, Flexibacter japonensis, for this strain. The strain 758 is deposited to
      the Japan Collection of Microorganisms as JCM 9735.

PMID- 8662179
TI  - Diversity of H2/CO2-utilizing acetogenic bacteria from feces of non-methane
      producing humans.
AB  - The purpose of this work was to study H2/CO2-utilizing acetogenic population in
      the colons of non-methane-producing individuals harboring low numbers of
      methanogenic archaea. Among the 50 H2-consuming acetogenic strains isolated from
      four fecal samples and an in vitro semi-continuous culture enrichment, with
      H2/CO2 as sole energy source, 20 were chosen for further studies. All isolates
      were Gram-positive strict anaerobes. Different morphological types were
      identified, providing evidence of generic diversity. All acetogenic strains
      characterized used H2/CO2 to form acetate as the sole metabolite, following the
      stoichiometric equation of reductive acetogenesis. These bacteria were also able
      to use a variety of organic compounds for growth. The major end product of
      glucose fermentation was acetate, except for strains of cocci that mainly
      produced lactate. Yeast extract was not necessary, but was stimulatory for growth
      and acetogenesis from H2/CO2.

PMID- 8662180
TI  - PCR methods for identification and specific detection of probiotic lactic acid
      bacteria.
AB  - Probiotics are defined as "microbes improving animal feed." Three lactic acid
      bacteria, previously selected as probiotic for pig feeding, were identified by
      sequencing the variable V1 region of the 16S rDNA after PCR amplification primed
      in the flanking constant region. A VR region showing strong nucleotide
      differences between the three probiotic and the reference strains was delimited.
      Oligonucleotides specific for each strain were designed. A specific assay for
      probiotic detection was developed, based on a PCR reaction with three primers.

PMID- 8662181
TI  - Characterization of Aeromonas hydrophila strains of clinical, animal, and
      environmental origin expressing the O:34 antigen.
AB  - A collection of Aeromonas strains of different origins were characterized for
      isolates expressing the O:34 somatic antigen. Of over 200 strains tested,
      approximately 14% belonged to serogroup O:34 with >85% of these strains
      identified as A. hydrophila regardless of source. A subset of 14 A. hydrophila
      O:34 strains were further analyzed for a number of structural and pathogenic
      features. Most O:34 strains expressed similar whole-cell protein profiles with
      regards to minor bands, but major band differences were noted in outer membrane
      proteins (OMPs) migrating between the 31K and 58K region. OMP profiles could be
      subdivided into three distinct patterns. All O:34 strains expressed a
      heterogeneous O polysaccharide side chain profile in their lipopolysaccharide
      (LPS), although some variation in the electrophoretic migration of lower and
      higher molecular weight LPS bands was noted. Polyclonal antisera raised against a
      45-K OMP-associated protein of one O:34 strain (AH-195) reacted in immunoblot
      assays with a major 43 to 46-K OMP in 11 of 14 (79%) O:34 strains tested. Most
      O:34 strains (69%) were found to be pathogenic in mice with LD-50 values (i.p.)
      of <1.0 x 10(7) CFU; pathogenicity appeared to correlate best with elevated
      protease activity. The collective results suggest significant differences in both
      structural and pathogenic properties between some members of the O:34 group
      originating from human and nonhuman (fish, water) sources.

PMID- 8662182
TI  - Inhibition of macrophage phagocytosis by Pseudomonas aeruginosa rhamnolipids in
      vitro and in vivo.
AB  - Patients with cystic fibrosis often have chronic and ultimately lethal pulmonary
      infections with Pseudomonas aeruginosa. In order to understand why these bacteria
      resist pulmonary clearance, we have investigated the interaction of P. aeruginosa
      and phagocytic cells. In an earlier study we reported that sub-lytic
      concentrations of two glycolipids produced by P. aeruginosa (the mono- and
      dirhamnolipids) caused structural changes in human monocyte-derived macrophages,
      and at lower concentrations inhibited the phagocytosis of Staphylococcus
      epidermidis by these cells. In the present study we demonstrate that rhamnolipids
      also inhibit the in vitro phagocytosis of both P. aeruginosa and Saccharomyces
      cerevisiae by thioglycollate-elicited mouse peritoneal macrophages. Using lucifer
      yellow to label the lysosomal compartments of macrophages, we determined that
      rhamnolipids interfere with the internalization of attached particles and reduce
      the level of phagosome-lysosome fusion of internalized targets within
      macrophages. We also demonstrate that physiologically relevant concentrations of
      rhamnolipids injected intratracheally into rat lungs inhibited the response of
      alveolar macrophages to a challenge of zymosan particles in vivo. These studies
      further demonstrate the profound inhibitory effects of P. aeruginosa rhamnolipids
      on macrophage function and are consistent with our hypothesis that the in situ
      production of these rhamnolipids directly contributes to the persistence of this
      pathogen in cystic fibrosis patient lungs.

PMID- 8662183
TI  - Effect of the current antimicrobial therapeutic strategy on fungal colonization
      in patients with hematologic malignancies.
AB  - A "quasi-experimental" trial was carried out to investigate the effect of three
      antimicrobial regimens on oral and fecal yeast colonization in patients with
      hematologic malignancies. Fifty-four patients received ciprofloxacin and oral
      amphotericin B (group 1); 45 received ceftazidime, amikacin, vancomycin, and oral
      amphotericin B (group 2); and 30 received ceftazidime, amikacin, vancomycin, and
      intravenous amphotericin B (group 3). The oral yeast isolation rate showed a
      decrease in group 1 (from 59.3% to 40.7%) and group 3 (from 56.7% to 46.7%), and
      a marked increase in group 2 (from 51.1% to 84. 4%). All the groups showed a
      reduction in their fecal yeast isolation rate. An overgrowth of Candida
      parapsilosis, C. krusei, and C. tropicalis was observed in all the groups, but it
      was much higher in group 2. Our findings provide evidence that ceftazidime,
      amikacin, and vancomycin, given with oral amphotericin B, induce an
      overgrowth/persistence of Candida species in the mouth and gut, which might be
      attributable to inclusion of vancomycin. Treatment with intravenous amphotericin
      B has at least the capacity of counterbalancing yeast proliferation induced by
      that antibacterial regimen.

PMID- 8662184
TI  - A new rickettsia from a herbivorous insect, the pea aphid Acyrthosiphon pisum
      (Harris).
AB  - An undescribed, maternally heritable, rod-shaped bacterium (or "tertiary
      symbiont") was detected by microscopy in hemolymph of about half (59/122) of pea
      aphid [Acyrthosiphon pisum (Harris)] clones collected from widely separated
      locations in California. On the basis of molecular phylogenetic analysis of 16S
      rDNA sequences, the bacterium was clearly placed among other Rickettsia in the
      alpha-subgroup of Proteobacteria, close to Rickettsia bellii-a rickettsia found
      in ticks. A PCR assay was developed to detect this bacterium in pea aphid clones
      with specific 16S rDNA PCR primers. Results of PCR-based assays completely
      correlated with detection by microscopy. This is the first confirmed detection of
      a Rickettsia in a herbivorous insect.

PMID- 8662185
TI  - Isolation of Vibrio harveyi from diseased kuruma prawns Penaeus japonicus.
AB  - Outbreaks of high mortality among the cultured kuruma prawn Penaeus japonicus
      without overt gross signs occurred during August and December of 1994 in I-Lan,
      Taiwan. Eleven luminous bacterial strains were isolated from the hepatopancreas
      of moribund prawns from five different farms by use of tryptic soy agar (TSA,
      supplemented with 2% NaCl) and/or thiosulfate citrate bile salt sucrose (TCBS)
      agar. These strains, together with our two previously unpublished isolates, were
      characterized and identified to be Vibrio harveyi in comparison with two ATCC
      Type strains and one strain previously isolated from the tiger prawn, P. monodon.

PMID- 8662186
TI  - Production of beta-xylosidase activity by Trichoderma harzianum strains.
AB  - Nine Trichoderma harzianum strains were screened for beta-xylosidase activity
      when grown in solid-state cultures on media containing wheat bran as the carbon
      source. All strains produced beta-xylosidase activity, the most active being in
      extracts of cultures of T. harzianum strain 4. A beta-xylosidase was purified by
      ammonium sulfate precipitation, ultrafiltration, gel filtration, and ion exchange
      chromatography from solid-state cultures of T. harzianum strain C. Enzyme
      preparations yielded a single band when stained for protein following
      eletrophoresis. The molecular weight value, calculated following SDS-PAGE, was
      determined to be 60 kDa. beta-Xylosidase was most active at pH 4.0-4.5 and 70
      degrees C. This enzyme had a Km value of 0.053 mM. The phenol-sulfuric acid
      method detected the presence of a small amount of carbohydrate in the purified
      enzyme preparation. beta-Xylosidase was active against some p
      nitrophenylglycosides. The enzyme was inactive against xylan and PNPG. beta
      xylosidase activity was inhibited by xylose and SDS. Iodoacetamide,
      dithiothreitol, gluconolactone, glucose, and mercuric chloride failed to
      inactivate this enzyme's activity. A synergistic effect was observed when beta
      xylosidase from T. harzianum strain C and beta-xylanase from Aspergillus
      fumigatus were incubated with pretreated arabinoxylan.

PMID- 8662187
TI  - Purification and N-terminal amino acid sequence of dextranicin 24, a bacteriocin
      of Leuconostoc sp.
AB  - Leuconostoc mesenteroides subsp. dextranicum strain J24 synthesized a bacteriocin
      named Dextranicin 24 (Dex-24), which inhibited only other Leuconostoc sp.
      strains. It was purified by a two-step procedure from the fraction of the
      bacteriocin bound to the producer cells at the end of the growth: desorption form
      the cells at acidic pH, followed by reserve phase HPLC. The N-terminal sequence
      of Dex-24 was the following: NH2(-) K G V L G W L S M A S S A L T G P Q Q . . .

PMID- 8662188
TI  - Expression of functional HIV-1 integrase in the yeast Saccharomyces cerevisiae
      leads to the emergence of a lethal phenotype: potential use for inhibitor
      screening.
AB  - The integrase of the human immunodeficiency virus type 1 (HIV-1) has been
      expressed in yeast in order to investigate its potential lethal effect mediated
      by DNA damage. To this end, we have constructed an expression plasmid containing
      the retroviral integrase gene under the control of the inducible promotor
      ADH2/GAPDH which is regulated by the glucose concentration of the medium. Haploid
      yeast strain W303-1A did not appear to be clearly sensitive to HIV-1 integrase
      expression. However, disruption of the RAD 52 gene, which is involved in the
      repair of double-strand DNA breaks, strongly increased the deleterious effects of
      the retroviral enzyme in this yeast strain. The diploid strain constructed with
      W303-1A and an isogenic strain of the opposite mating type also showed a strong
      sensitivity to the HIV-1 integrase. Under yeast culture conditions allowing
      moderate integrase synthesis, the deleterious effect was totally abolished by
      missense integrase mutations, which are known to abolish HIV-1 integrase
      activities in vitro. We conclude that the lethal phenotype due to HIV-1 integrase
      expression in yeast may be closely related to the HIV-1 integration reaction in
      infected human cells, and that yeast may be a useful tool to study the HIV-1
      integration process and to screen drugs capable of inhibiting HIV-1 integration
      in vivo.

PMID- 8662189
TI  - Glutathione is an essential metabolite required for resistance to oxidative
      stress in the yeast Saccharomyces cerevisiae.
AB  - Glutathione (GSH) is an abundant cellular thiol which has been implicated in
      numerous cellular processes and in protection against stress caused by
      xenobiotics, carcinogens and radiation. Our experiments address the requirement
      for GSH in yeast, and its role in protection against oxidative stress. Mutants
      which are unable to synthesis GSH due to a gene disruption in GSH 1, encoding the
      enzyme for the first step in the biosynthesis of GSH, require exogenous GSH for
      growth under non-stress conditions. Growth can also be restored with reducing
      agents containing a sulphydryl group, including dithiothreitol, beta
      mercaptoethanol and cysteine, indicating that GSH is essential only as a
      reductant during normal cellular processes. In addition, the GSH 1-disruption
      strain is sensitive to oxidative stress caused by H2O2 and tert-butyl
      hydroperoxide. The requirement for GSH in protection against oxidative stress is
      analogous to that in higher eukaryotes, but unlike the situation in bacteria
      where it is dispensable for growth during both normal and oxidative stress
      conditions.

PMID- 8662190
TI  - Molecular and functional characterization of a mutant allele of the mitogen
      activated protein-kinase gene SLT2(MPK1) rescued from yeast autolytic mutants.
AB  - We have further characterized the functionality of the Saccharomyces cerevisiae
      gene SLT2(MPK1), coding for a MAP-kinase homolog essential for cell integrity,
      which is involved in the Pkc1p signalling pathway. This gene was isolated on the
      basis of its capacity to complement the thermosensitive-autolytic, osmotic
      remediable phenotype of lyt2 mutants. Both slt2delta and lyt2 mutants displayed a
      caffeine-sensitive phenotype consisting of cell lysis that was not dependent on
      temperature. Caffeine concentrations affecting the growth of these mutant strains
      were dependent on the genetic background, the SSD1 allele being very significant
      in this regard. The SLT2 allele of several lyt2 strains was both rescued and
      amplified by PCR. The recovered allele was shown to be non-functional as it could
      not complement the lytic phenotype of both deletion (slt2delta) and lyt2 strains.
      After nucleotide sequencing of the recovered allele, we found that the defect of
      lyt2 mutants consists in a substitution of an aspartic acid for a glycine at
      position 35 of the amino-acid sequence of Slt2p. Gly35 is the third glycine of a
      glycine cluster (Gly-X-Gly-X-X-Gly), a conserved region in protein kinases and
      other nucleotide-binding proteins. Keywords Yeast middle dot SLT2 middle dot MAP
      kinase middle dot Caffeine

PMID- 8662191
TI  - A multicopy suppressor gene, MSS10, restores STA2 expression in Saccharomyces
      cerevisiae strains containing the STA10 repressor gene.
AB  - Transcription of the three unlinked, homologous STA1-3 glucoamylase-encoding
      genes, involved in starch degradation by Saccharomyces cerevisiae, was previously
      shown to be down-regulated by the presence of STA10, acting via three upstream
      repression sequence regions that were identified in the STA2 promoter. Here we
      report the cloning and characterization of a putative transcriptional activator
      gene, MSS10 (multicopy suppressor of STA10), which, when present in multiple
      copies, overcomes STA10 repression. Deletion of MSS10, located on chromosome XV,
      resulted in media-specific extinction of glucoamylase synthesis. The nucleotide
      sequence of MSS10 is identical to three other genes from S. cerevisiae identified
      as: FUP1, a gene that enhances iron-limited growth; PHD2, a gene identified for
      its ability to induce pseudohyphal growth in diploid cells grown on nitrogen
      limited media; and MSN1, a gene encoding a transcriptional activator involved in
      invertase regulation.

PMID- 8662192
TI  - The distance-dependence of the fission yeast ade6-M26 marker effect in two-factor
      crosses.
AB  - Random spore analysis of crosses between a strain bearing the ade6-M26 hotspot
      mutation and strains bearing other ade6 mutations was performed. Recombinant
      prototroph frequencies increase with increasing distance from M26 for mutations
      both 5' and 3' of M26. Maximum prototroph frequencies are obtained for mutations
      lying more than 700 nucleotides downstream from M26. Similar results are obtained
      for crosses with the ade6-M375 control mutation, but the prototroph frequencies
      are lower. The factor of stimulation of recombination by M26 as compared to the
      M375 control (M26 marker effect) also displays distance-dependence. These results
      are discussed in the context of the mechanism of M26 recombination, as well as in
      relation to recombination initiation, hybrid DNA formation, and mismatch repair
      at ade6. Keywords Conversion middle dot M26 hotspot middle dot Recombination
      middle dot Schizosaccharomyces pombe

PMID- 8662193
TI  - The regulatory protein NIT4 that mediates nitrate induction in Neurospora crassa
      contains a complex tripartite activation domain with a novel leucine-rich, acidic
      motif.
AB  - Expression of nit-3 and nit-6, the structural genes which encode nitrate
      reductase and nitrite reductase in Neurospora crassa, requires the global-acting
      NIT2 and the pathway specific NIT4 regulatory proteins. NIT4, which consists of
      1090 amino-acid residues, possesses a Cys6/Zn2 zinc cluster DNA-binding-domain.
      NIT4 was dissected to localize transactivation domains by fusion of various
      segments of NIT4 to the DNA-binding domain of GAL4 for in vivo analysis in yeast.
      Three separate activation subdomains, and one negative-acting region, which
      function in yeast were located in the carboxyl-terminal region of NIT4. The C
      terminal tail of 28 amino-acid residues was identified as a minimal activation
      domain and consists of a novel leucine-rich, acidic region. Most deletions which
      removed even small segments of the NIT4 protein were found to lead to the loss of
      NIT4 function in vivo in N. crassa, implying that the central region of the
      protein which lies between the DNA-binding and activation domains is essential
      for function. The yeast two-hybrid system was employed to identify regions of
      NIT4 responsible for dimer formation. A short isoleucine-rich segment downstream
      from the zinc cluster, predicted to form a coiled coil, allowed dimerization in
      vivo; this same isoleucine-rich region also showed dimerization in vitro when
      examined via chemical cross linking. The enzyme nitrate reductase has been
      postulated to exert autogenous regulation by directly interacting with the NIT4
      protein. This possible nitrate reductase-NIT4 interaction was investigated with
      the yeast two-hybrid system and by direct in vitro binding assays; both assays
      failed to identify such a protein-protein interaction.

PMID- 8662194
TI  - Conservation of structure and function of the aflatoxin regulatory gene aflR from
      Aspergillus nidulans and A. flavus.
AB  - Under limiting growth conditions, Aspergillus nidulans produces a carcinogenic
      secondary metabolite related to aflatoxin and called sterigmatocystin (ST). The
      genes for ST biosynthesis are co-ordinately regulated and are all found within an
      approximately 60-kilobase segment of DNA. One of the genes within this region is
      predicted to encode a CX2CX6CX6CX2CX6CX2 zinc binuclear cluster DNA-binding
      protein that is related to the Aspergillus flavus and Aspergillus parasiticus
      aflatoxin regulatory gene aflR. Deletion of the A. nidulans aflR homolog resulted
      in an inability to induce expression of genes within the ST gene cluster and a
      loss of ST production. Because A. nidulans aflR mRNA accumulates specifically
      under conditions that favor ST production we expect that activation of ST
      biosynthetic genes is determined by A. nidulans aflR. In support of this
      hypothesis, we demonstrated that induced expression of the A. flavus aflR gene in
      A. nidulans, under conditions that normally suppress ST gene expression, resulted
      in activation of genes in the ST biosynthetic pathway. This result demonstrates
      that AflR function is conserved between Aspergillus spp. and that aflR expression
      is sufficient to activate genes in the ST pathway.

PMID- 8662195
TI  - Developmental- and tissue-specificity of RNA editing in mitochondria of
      suspension-cultured maize cells and seedlings.
AB  - C to U editing of apt9, nad3, and cox2 mRNAs was investigated in maize seedlings
      at various developmental stages as well as in suspension-cultured cells.
      Heterogeneity of mRNAs that result from incomplete editing was analyzed for each
      gene and from five tissues or developmental conditions. The editing status of
      approximately 30 cDNA clones was determined by digestion with a restriction
      enzyme that discriminates between unedited and edited DNA sequences. The atp9 and
      spliced cox2 cDNAs were essentially completely edited in all samples examined.
      Analysis of three editing sites of nad3 cDNAs indicated that incompletely edited
      cDNAs were detected in all tissues and treatments with a temporal increase in the
      overall editing status, from 50% at 3 days to about 75% at 7 days. These results
      indicate that incompletely edited mRNAs are prevalent for some plant
      mitochondrial genes, and can change with developmental or growth conditions.

PMID- 8662196
TI  - Characterization of the radish mitochondrial nad3/rps12 locus: analysis of
      recombination repeats and RNA editing.
AB  - In order to further investigate sequences that are responsible for low-frequency
      recombination in plant mitochondrial DNAs and RNA editing in radish mitochondria,
      the nad3/rps12 locus has been isolated and characterized from a normal cultivar
      of radish and the male-sterile Ogura cytoplasm. A repeated sequence that has been
      implicated in other radish mitochondrial DNA rearrangements was identified at the
      breakpoint between the two loci indicating that it was also involved in the
      nad3/rps12 rearrangement. Similar to some other radish mitochondrial genes,
      nad3/rps12 genomic sequences already contain several, but not all, of the bases
      that are typically edited in plant mitochondrial nad3 and rps12 genes. Analysis
      of nad3/rps12 cDNAs indicated that the mRNAs are not edited. One partially edited
      transcript was identified out of the twenty two that were examined. This finding,
      along with the observation that nad3/rps12 RNAs are present at very low levels,
      raises the possibility that radish mitochondria may not encode functional copies
      of these genes. Consistent with this hypothesis, DNA-blot analysis detects
      nad3/rps12 sequences in the nucleus.

PMID- 8662197
TI  - Phylogenetic affinities of the grasses to other monocots as revealed by molecular
      analysis of chloroplast DNA.
AB  - The distribution of structural alterations of the chloroplast genome found in
      grass chloroplast (cp) DNA in comparison with that of tobacco was systematically
      surveyed in the cpDNAs of monocots. Southern hybridization and/or PCR analyses
      for the detection of (1) three inversions in the large single-copy region, (2)
      loss of an intron in the rpoC1 gene, (3) an extra-sequence insertion in the rpoC2
      gene, (4) the deletion of ORF2280, (5) rearrangements of the accD (ORF512) gene,
      and (6) non-reciprocal translocation of the rpl23 gene, were carried out on
      cpDNAs isolated from 58 species, 22 families, and 11 orders, which covered almost
      all families of monocots. These structural alterations of cpDNA mostly occurred
      at the family level. However, only part of the Restionaceae possessed the
      inversion that characterizes the lineage of grass differentiation. The order of
      mutational events made it possible to reconstruct grass phylogeny in monocots.
      Since no variations in structural alterations of the cpDNA were found among the
      Poaceae, grass plants were inferred to have originated from an ancestor harboring
      these structural alterations of the chloroplast genome. These phylogenetic
      relationships were supported by the sequence data of rbcL.

PMID- 8662198
TI  - A small insertion in the SSU rDNA of the lichen fungus Arthonia lapidicola is a
      degenerate group-I intron.
AB  - Insertions of less than 100 nt occurring in highly conserved regions of the small
      subunit ribosomal DNA (SSU rDNA) may represent degenerate forms of the group-I
      introns observed at the same positions in other organisms. A 63-nt insertion at
      SSU rDNA position 1512 (relative to the Escherichia coli SSU rDNA) of the lichen
      forming fungus Arthonia lapidicola can be folded into a secondary structure with
      two stem loops and a pairing of the insertion and flanking sequences. The two
      stem loops may correspond to the P1 and P2, and the insertion-flanking pairing to
      the P10, of a group-I intron. Considering these small insertions as degenerate
      introns provides important clues to the evolution and catalytic function of group
      I introns. Keywords Ribosomal DNA middle dot Small subunit middle dot 18s middle
      dot Degenerate introns middle dot Ascomycetes

PMID- 8662199
TI  - Transformation of the plant pathogenic fungus, Rhynchosporium secalis.
AB  - The barley leaf scald fungus, Rhynchosporium secalis, was transformed to
      hygromycin-B and phleomycin resistance using the hph gene from E. coli and the
      ble gene from Streptoalloteichus hindustanus under the control of Aspergillus
      nidulans promoter and terminator sequences. Plasmid DNA was introduced into
      fungal protoplasts by PEG/CaCl2 treatment. Transformation frequencies varied from
      59 to 493 transformants per 10 microg of DNA and 5 x 10(7) protoplasts. The
      antibiotic-resistant phenotype appeared to be stable under selective, as well as
      under non-selective, conditions for several generations. Co-transformation using
      the E. coli uidA gene under the control of A. nidulans promoter and terminator
      sequences on a non-selectable plasmid occurred at frequencies of up to 66%.

PMID- 8662200
TI  - Intramolecular recombination of a mitochondrial minicircular plasmid-like DNA of
      date-palm mediated by a set of short direct-repeat sequences.
AB  - A molecular clone containing the complete sequence of a mitochondrial circular
      plasmid-like DNA (the R plasmid) isolated from the date-palm variety V3DP was
      used as a probe in Southern analyses of mitochondrial DNA prepared from other
      varieties. Another circular structure (the S plasmid) was detected in some of
      these varieties, and sequenced from variety V2DP. It appears that the R plasmid
      could have arisen from the S plasmid by an intermolecular recombination event at
      a set of 26-bp imperfect short direct repeats.

PMID- 8662202
TI  - Michael Ciriacy, 1947-1996

PMID- 8662201
TI  - Complementation of a pgk deletion mutation in Saccharomyces cerevisiae with
      expression of the phosphoglycerate-kinase gene from the hyperthermophilic
      Archaeon Sulfolobus solfataricus.
AB  - The gene encoding phosphoglycerate kinase (PGK) from the Archaeon Sulfolobus
      solfataricus, an organism growing optimally at 87 degrees C, was inserted into a
      yeast expression vector under the control of the galactose-inducible GAL1 yeast
      promoter. This vector was then transformed into a pgk::TRP1 yeast mutant, a
      strain inhibited for growth on galactose or glucose due to its lack of PGK
      enzyme. Slow-growing transformants were obtained on galactose plates at 37
      degrees C, but not 28 degrees C. These transformants contained low levels of
      transcripts of the heterologous gene and low amounts of thermostable PGK
      activity. Weak expression of the hyperthermophile gene in yeast, a mesophile,
      therefore enabled complementation of the yeast pgk defect at 37 degrees C but not
      at 28 degrees C.

PMID- 8662203
TI  - Moving pictures and pulsed-field gel electrophoresis show only linear
      mitochondrial DNA molecules from yeasts with linear-mapping and circular-mapping
      mitochondrial genomes.
AB  - The mobility of mitochondrial DNA (mtDNA) in pulsed-field gel electrophoresis
      (PFGE) and its appearance in moving pictures from fluorescence microscopy were
      used to investigate the mitochondrial genome structure for five Pichia and
      Williopsis strains of yeast. An apocytochrome b-gene hybridization probe
      identified only linear mtDNA molecules for each strain when total cellular DNA
      was fractionated by PFGE. Most of the mass of DNA isolated from mitochondria for
      one linear-mapping and one circular-mapping mitochondrial genome was found in
      linear molecules much larger than the genome size of 50 kb; some molecules were
      as long as 1500 kb, but only a trace amount of apparently circular mtDNA was
      found for the strain with the circular-mapping genome. Probes for both the
      apocytochrome-b and mitochondrial small rRNA subunit genes hybridized strongly to
      mtDNA of approximately 50-100 kb, but weakly to the larger DNA from mitochondria
      of these two strains. For the four linear-mapping strains, PFGE revealed two or
      three distinct bands of linear mtDNA, larger than the genome size, within a smear
      of approximately 50-100 kb, but a smear without bands was found for the circular
      mapping strain.

PMID- 8662204
TI  - Molecular genetic analysis of the central hydrophobic domain of subunit 8 of
      yeast mitochondrial ATP synthase.
AB  - Subunit 8 (Y8) of yeast mitochondrial ATP synthase (mtATPase) is a hydrophobic
      component of the membrane Fo sector. Encoded by the mitochondrial aap1 gene, Y8
      is a 48-amino-acid polypeptide having a central hydrophobic domain (CHD) spanning
      19 residues. Site-directed mutagenesis was carried out on a nuclear code
      equivalent gene encoding Y8, to introduce either adjacent charged amino acids
      (positive or negative) or proline residues into the CHD, or to alter the length
      of this domain by deletion or insertion of additional non-polar residues. We
      report a functional resilience of Y8 in tolerating the introduction of charged
      residues implanted within the CHD. Thus, expression of variants having adjacent
      positively charged amino acids (arginines) in Y8-deficient cells restored growth
      on the non-fermentable substrate ethanol, though in some cases this was impaired
      compared to that conferred by the parent Y8 construct. Introduction of adjacent
      negative charges (aspartate residues) was less well tolerated, but in all cases a
      measurable rate of cell growth on ethanol was retained. These results underscore
      the interpretation that it is not necessary for Y8 to maintain a transmembrane
      stem in its role as an integral component of functional mtATPase. Further, the
      impaired growth properties of cells expressing variants of Y8 having changes
      designed to perturb the structure (proline substitutions) and length (insertions
      or deletions) of the CHD lead us to conclude that the overall shape and
      dimensions of Y8 are important for its function in mtATPase.

PMID- 8662205
TI  - The nuclear Kluyveromyces lactis MRF1 gene encodes a mitochondrial class I
      peptide chain release factor that is important for cell viability.
AB  - We report the isolation and characterization of the Kluyveromyces lactis MRF1
      gene encoding mitochondrial peptide chain release factor mRF-1. Over-expression
      of the KlMRF1 gene has a strong antisuppressive effect in a Saccharomyces
      cerevisiae mitochondrial nonsense suppressor strain. Inactivation of KlMRF1
      results in a dual phenotype: most cells die after about 10-13 generations, while
      a small number of cells exceed this limit. We propose that the lethality is
      related to a loss of mitochondrial genome integrity. Surviving Klmrf1 cells are
      able to grow slowly on the non-fermentable substrate glycerol, indicating the
      existence of a second mitochondrial release factor activity. Our previous
      comparative analysis of class I release factors is refined by the incorporation
      of KlmRF-1 and ten recently identified prokaryotic release factor
      sequences.Keywords Kluyveromyces lactis middle dot Mitochondrial release factor
      middle dot MRF1 middle dot Peptide chain termination

PMID- 8662206
TI  - UAG is a sense codon in several chlorophycean mitochondria.
AB  - The mitochondrial genetic code of those land plants and green algae that have
      been examined does not deviate from the universal one. A red alga, Chondrus
      crispus, is the sole reported example throughout the algae that uses a deviant
      (non-universal) mitochondrial genetic code (UGA=Trp). We have analyzed 366-bp DNA
      sequences of the gene for mitochondrial cytochrome oxidase subunit I (COXI) from
      ten chlorophyceaen algae, and detected 3-8 in-frame UAG codons in the sequences
      of five species. Comparisons of these sequences with those of other algae and
      land plants have shown that most of the UAG sites in Hydrodictyon reticulatum,
      Pediastrum boryanum and Tetraedron bitridens correspond to alanine, and those of
      Coelastrum microporum and Scenedesmus quadricauda to leucine. The three species
      in which UAG probably codes for alanine are characterized by zoospore formation
      in asexual reproduction and form a clade in the COXI phylogenetic tree. The two
      species in which UAG codes for leucine are known to form daughter coenobia and
      pair in the tree. This is the first report on a deviant mitochondrial genetic
      code in green algae. Mutational change(s) in the release factor corresponding to
      UAG would be involved in these code changes. No genetic code deviation has been
      found in five other species examined.

PMID- 8662208
TI  - Sensitivity of sup35 and sup45 suppressor mutants in Saccharomyces cerevisiae to
      the anti-microtubule drug benomyl.
AB  - SUP35 and SUP45 genes determine the accuracy of translation at the stage of
      termination. We present indirect evidence indicating that these genes may also
      control some cellular process mediated by microtubules. A majority of sup35 and
      sup45 suppressor mutations confer supersensitivity to benomyl, the drug which de
      polymerizes microtubules. In addition, data correlating phenotypic manifestations
      of sup45 suppressor mutations, involving sensitivity to benomyl, respiratory
      deficiency and a suppressor effect, are also presented.

PMID- 8662207
TI  - Physical and genetic map of the mitochondrial genome of Cryphonectria parasitica
      Ep155.
AB  - In the chestnut-blight fungus, Cryphonectria parasitica, a cytoplasmically
      transmissible (infectious) form of hypovirulence is associated with mitochondrial
      DNA (mtDNA) mutations that cause respiratory deficiencies. To facilitate the
      characterization of such mutations, a restriction map including the probable
      location of 13 genes was constructed for a relatively well-characterized virulent
      strain of the fungus, Ep155. The physical map is based on the order of all
      fragments generated by cleavage of the mtDNA by the PstI restriction endonuclease
      and includes some of the cleavage sites for HindIII, EcoRI, and XbaI. It was
      constructed from hybridization patterns of cloned mtDNA fragments with Southern
      blots of mtDNA digested with the four restriction enzymes. On this map, the
      probable locations of genes commonly found in the mitochondrial genomes of
      ascomycetes were determined by low-stringency hybridization of cloned Neurospora
      crassa mitochondrial gene probes to Southern blots of C. parasitica mtDNA. The
      data indicate that the mtDNA of strain Ep155 is a circular molecule of
      approximately 157 kbp and ranks among the largest mitochondrial chromosomes
      observed so far in fungi. The mtDNAs of 11 different C. parasitica isolates range
      in size from 135 to 157 kbp and in relatedness from 68 to 100 percent, as
      estimated from restriction-fragment polymorphisms. In addition to the typical
      mtDNA, the mitochondria of some isolates of the fungus contain double-stranded
      DNA plasmids consisting of nucleotide sequences not represented in the mtDNA of
      Ep155.

PMID- 8662209
TI  - Over-expression of the NUD1-coded endo-exonuclease in Saccharomyces cerevisiae
      enhances DNA recombination and repair.
AB  - The NUD1(=NUC2) gene of Saccharomyces cerevisiae has been subcloned and over
      expressed in multi-copy plasmids. Enhanced expression of this nuclear endo
      exonuclease gene was confirmed by Northern hybridization (>10-fold increase), and
      increased enzymatic activity (2.4-fold increase) was demonstrated by direct
      immunological assay using antibody raised against the purified Neurospora crassa
      endo-exonuclease. We found that increased expression of NUD1 was associated with
      an increase in cell survival after irradiation treatment with gamma rays, and an
      increase in radiation-induced mitotic recombination frequencies between
      duplicated gene sequences. The results presented here are consistent with
      previous biochemical data and confirm a role for the NUD1 gene product in
      recombination/repair processes.

PMID- 8662210
TI  - Correlation of exons with functional domains and folding regions in a cellulase
      from Agaricus bisporus.
AB  - The cellulase gene cel3 has been isolated from Agaricus bisporus and sequenced.
      The 5'-end of the cel3 transcript was determined by primer extension and S1
      nuclease protection. Putative regulatory elements have been identified in the
      cel3 promoter and 3'-untranslated regions. The cel3 coding region is interrupted
      by six short introns, two of which separate the coding regions for the three
      modules in the CEL3 protein: cellulose-binding domain, linker region, and
      catalytic domain. Three of the remaining four introns are positioned in regions
      coding for loops between structural moieties. Intron positions are conserved
      between cel3 and other related cellulases.

PMID- 8662211
TI  - Molecular cloning of thi-4, a gene necessary for the biosynthesis of thiamine in
      Neurospora crassa.
AB  - The thiamine-4 (thi-4) gene was cloned by functional complementation of a thi-4
      mutant of Neurospora crassa. The product of this gene is believed to be involved
      in the condensation of pyrimidine and thiazole precursors, which is necessary for
      the synthesis of thiamine. The thi-4 gene has ten introns which vary in length
      from 57 to 200 bp and the junction and internal (lariat) sequences are in good
      agreement with the consensus sequences for the splicing of introns in N. crassa.
      The thi-4 gene encodes a protein of 538 amino acids which is similar in terms of
      amino-acid sequence to proteins encoded by Saccharomyces cerevisiae whose
      function is unknown. The expression of the thi-4 gene in N. crassa was not
      repressed by thiamine.

PMID- 8662212
TI  - Characterization of the Aspergillus parasiticus niaD and niiA gene cluster.
AB  - The nitrate reductase gene (niaD) and nitrite reductase gene (niiA) of
      Aspergillus parasiticus are clustered and are divergently transcribed from a 1.6
      kb intergenic region (niaD-niiA). The deduced aminoacid sequence of the A.
      parasiticus nitrate reductase demonstrated a high degree of homology to those of
      other Aspergillus species, as well as to Leptosphaeria maculans, Fusarium
      oxysporum, Gibberella fujikuroi and Neurospora crassa, particularly in the
      cofactor-binding domains for molybdenum, heme and FAD. A portion of the deduced
      nitrite reductase sequence was homologous to those of A. nidulans and N. crassa.
      The nucleotide sequences in niaD-niiA of A. parasiticus and of A. oryzae were 95%
      identical, indicating that these two species are closely related. Several GATA
      motifs, the recognition sites for the N. crassa positive-acting global regulatory
      protein NIT2 in nitrogen metabolism, were found in A. parasiticus niaD-niiA. Two
      copies of the palindrome TCCGCGGA and other partial palindromic sequences similar
      to the target sites for the pathway specific regulatory proteins, N. crassa NIT4
      and A. nidulans NirA, in nitrate assimilation, were also identified. A
      recombinant protein containing the A. nidulans AreA (the NIT2 equivalent) zinc
      finger and an adjacent basic region was able to bind to segments of niaD-niiA
      encompassing the GATA motifs. These results suggest that the catalytic and
      regulatory mechanisms of nitrate assimilation are well conserved in Aspergillus.

PMID- 8662213
TI  - Selection of multiple disruption events in Aspergillus fumigatus using the
      orotidine-5'-decarboxylase gene, pyrG, as a unique transformation marker.
AB  - A 8.6-kb disruption cassette, referred to here as a pyrG-blaster and consisting
      of the Aspergillus niger pyrG gene flanked by a direct repeat that encodes the
      neomycin phosphotransferase of transposon Tn5 was constructed. Following
      transformation of a uridine/uracil auxotrophic pyrG strain of A. fumigatus,
      genomic insertions of the pyrG-blaster were obtained either by targeted gene
      replacement at the rodA locus, resulting in the formation of hydrophilic spores,
      or by ectopic integration. In both cases, recombination between the two elements
      of the direct repeat could be selected in the presence of 5-fluoro-orotic acid
      and resulted in the excision of the A. niger pyrG gene, producing A. fumigatus
      uridine/uracil auxotrophs that retained their additional mutant phenotype because
      of the persistence of one of the two elements of the direct repeat at the site of
      insertion of the pyrG-blaster. Selection for uracil/uridine prototrophy can
      therefore be used again to disrupt another gene.

PMID- 8662214
TI  - Electrophoretic karyotype of the amylolytic yeast Lipomyces starkeyi and cloning,
      sequencing and chromosomal localization of its TRP1 gene.
AB  - The genome of the amylolytic yeast strain Lipomyces starkeyi NCYC 1436 was
      analysed using contour-clamped homogeneous electric field gel electrophoresis
      (CHEF). The banding pattern under a variety of running conditions indicating the
      presence of 11 different chromosome-sized DNA molecules. The sizes of these
      chromosome bands were determined by comparison with chromosomes from standard
      strains of Schizosaccharomyces pombe and Saccharomyces cerevisiae. The
      chromosomal bands were estimated to be within the range 0.7-2.8 Mb, with the
      genome (excluding mitochondrial DNA) estimated at 15 Mb. The molecular cloning of
      the TRP1 gene, isolated from a genomic library of this strain, is also reported:
      the gene was present on a 6.5-kb Sau3A DNA fragment, and complemented the trpC
      gene of E. coli. The DNA sequence was determined (EMBL accession No. Z68292) and
      compared to other tryptophan biosynthetic genes encoding N-(5'-phosphoribosyl)
      anthranilate isomerase (PRAI) activity. The gene was also used as a probe in
      hybridization studies, and by this means, its chromosomal location was
      identified.

PMID- 8662215
TI  - Isolation and characterization of mutants as an approach to a transformation
      system in Kluyveromyces marxianus.
AB  - A method to obtain K. marxianus mutants has been developed. Different auxotrophic
      mutants were isolated by nystatin and snail-enzyme enrichment procedures using an
      incubation time of 2 h before adding the antibiotic or the enzyme respectively.
      All his mutants analyzed by complementation tests turned out to belong to the
      same complementation group. Some of them were transformed and complemented by the
      S. cerevisiae HIS3 gene. These non-reverting his3 mutants contain no heterologous
      sequence, which is essential to make them acceptable for application in the food
      industry.

PMID- 8662216
TI  - Mapping of the Prkar1a gene to mouse chromosome 11.

PMID- 8662217
TI  - Potential CpG-rich islands clustering around single-minded gene in Down syndrome
      chromosomal region.

PMID- 8662218
TI  - Beta-mannosidase maps to cattle chromosome 6.

PMID- 8662219
TI  - Isolation and mapping of three STSs on mouse chromosome 19.

PMID- 8662220
TI  - Strain distribution patterns for genetic markers in the LSXSS recombinant-inbred
      series.
AB  - We present the strain distribution patterns (SDPs) of 118 SSLP markers and three
      pigmentation genes that have been characterized in 27 strains from the LSXSS RI
      series. This coarse map provides a resource for linkage studies of phenotypes
      that are heritable in the LSXSS RI series. The LSXSS recombinant inbred (RI)
      strains were derived from the Long-Sleep (LS) and Short-Sleep (SS) selected lines
      of mice that were selected for differential sensitivity to ethanol but are also
      differentially sensitive to a variety of other alcohols, barbiturates, sedative
      hypnotics, and general anesthetics. Since the parents were not inbred, two
      atypical factors are present in these SDPs. First, more than two alleles are
      frequently found in these RIs, and second, some alleles can be uniquely
      associated with one or the other parent while other alleles may be found in both
      parental lines. To validate the markers found in the parental line, we genotyped
      all parental mice from one generation of both the LS and SS lines, thus leading
      to a set of marker SDPs that are useful for further phenotypic association and
      identification of provisional QTLs.

PMID- 8662221
TI  - Chromosomal location of fifteen unique mouse KRAB-containing zinc finger loci.
AB  - The mammalian genome contains hundreds if not thousands of zinc finger protein
      (Zfp) genes. While the function of most of these genes remains to be determined,
      it is clear that a few of them play important roles in gene regulation and
      development. In studies described here, we have used an interspecific mouse
      backcross mapping panel to determine the chromosomal location of 15 KRAB
      containing zinc finger loci. These loci map to nine different mouse autosomes and
      the X Chromosome (Chr). Two Chrs, 7 and 9, contain cosegregating pairs of KRAB
      containing Zfp genes, indicating that the KRAB-containing Zfp genes have evolved
      through processes involving regional as well as genome-wide duplication events.

PMID- 8662222
TI  - Location of the 9257 and ataxia mutations on mouse chromosome 18.
AB  - The location of three mutations on proximal Chromosome (Chr) 18 was determined by
      analysis of the offspring of several backcrosses. The results demonstrate that
      ataxia and the insertional mutation TgN9257Mm are separated by less than 1 cM and
      are located approximately 3 cM from the centromere, while the balding locus is 7
      cM more distal. Previous data demonstrated that the twirler locus also maps
      within 1 cM of ataxia. The corrected locations will contribute to identification
      of appropriate candidate genes for these mutations. Two polymorphic
      microsatellite markers for proximal Chr 18 are described, D18Umi1 and D18Umi2.
      The Lama3 locus encoding the alpha 3 subunit of nicein was mapped distal to
      ataxia and did not recombine with Tg9257.

PMID- 8662223
TI  - Cloning of the rat steroid sulfatase gene (Sts), a non-pseudoautosomal X-linked
      gene that undergoes X inactivation.
AB  - Although the human steroid sulfatase (STS) gene has been cloned and characterized
      in detail, several attempts to clone its mouse homologue, with either anti-human
      STS antibodies or human STS cDNA probes, have failed, suggesting a substantial
      divergence between these genes. However, partial amino-terminal sequence from
      purified rat liver STS is very similar to its human counterpart, and sequence
      comparisons have revealed several domains that are conserved among all the
      sulfatases characterized to date. Thus, we used a degenerate-primer RT-PCR
      approach to amplify a 321-bp fragment from rat liver cDNA, which was used as a
      probe to clone and characterize the complete cDNA. Comparison of the protein
      coding region between the rat and human genes showed 66% homology both at the DNA
      and the protein levels. STS activity was conferred to STS(-) A9 cells upon
      transfection with a rat Sts expression construct, indicating the authenticity of
      the cloned cDNA. While Sts has been shown to be located in the mouse
      pseudoautosomal region, both physical and genetic mapping demonstrate that Sts is
      not pseudoautosomal in the rat. The overall genomic organization of rat Sts and
      human STS is very similar, except that the insertion site for intron 1 in the rat
      is 26 bp upstream from that in the human. Rat Sts is only 8.2 kb long, while the
      human STS spans over 146 kb.

PMID- 8662224
TI  - A genetic, physical, and comparative map of rat chromosome 10.
AB  - A map of rat Chromosome (Chr) 10 was generated from 21 markers, mostly of
      conserved structural genes, by linkage analysis and fluorescence in situ
      hybridization. The study emphasizes the proximal third of the chromosome which,
      until now, has been relatively devoid of markers. Based on comparative analysis,
      our data suggest that genes on rat Chr 10 are conserved on mouse Chr 11, 16, 17
      and human Chr 16, 5, and 17.

PMID- 8662225
TI  - GNAI3, GNAT2, AMPD2, GSTM are clustered in 120 kb of Chinese hamster chromosome
      1q.
AB  - We studied a polygenic region located on Chromosome (Chr) 1q in Chinese hamster
      cells that is coamplified along with the AMPD2 gene. Previous sequence analysis
      identified both members of the GSTM family and the GNAI3 gene within a cloned 120
      kb region surrounding the AMPD2 locus. We show here that the GNAT2 gene, which is
      inactive in the fibroblastic cells, lies within the 20 kb separating the
      transcriptionally active GNAI3 and AMPD2 genes. We map most gene ends by sequence
      comparison with human homologs; one is inferred from the presence of an
      unmethylated CpG island. This Chinese hamster locus corresponds to a region of
      conserved linkage between human Chr 1 (locus 1p13) and mouse Chr 3 (position 52.5
      cM), where Gnai-3 and Gnat-2 have been mapped. The AMPD2 gene is presently
      unlocalized in human genome; its proposed position on mouse Chr 3 is at 53.4 cM.
      Our results, obtained by physical mapping, strongly suggest that the order and
      possibly the tight linkage of these genes are conserved on all three genomes.

PMID- 8662226
TI  - A panel of VNTR markers in pigs.
AB  - By cloning tandemly repeated sequences from the pig genome by use of non-porcine
      minisatellite probes for library screening, five novel polymorphic VNTR loci were
      isolated: three minisatellites and two satellite-like loci. Four of them could be
      mapped onto chromosomes by linkage analysis and/or in situ hybridization. They
      were assigned to Chromosomes (Chrs) 5, 6, 14, and 16. Physical mapping on both
      presumed satellites and on one of the minisatellites revealed that the former
      resided near or at the centromere and the latter towards the chromosome ends. The
      location of the minisatellite is of particular interest since, together with data
      on three other minisatellites previously isolated, it supports the idea that, as
      in humans, minisatellites may preferentially be subtelomeric also in pigs.

PMID- 8662227
TI  - Porcine linkage and cytogenetic maps integrated by regional mapping of 100
      microsatellites on somatic cell hybrid panel.
AB  - Recently two main genetic maps [Rohrer et al. Genetics 136, 231 (1994); Archibald
      et al. Mamm. Genome 6, 157 (1995)] and a cytogenetic map [Yerle et al. Mamm.
      Genome 6, 175 (1995)] for the porcine genome were reported. As only a very few
      micro-satellites are located on the cytogenetic map, it appears to be important
      to increase the relationships between the genetic and cytogenetic maps. This
      document describes the regional mapping of 100 genetic markers with a somatic
      cell hybrid panel. Among the markers, 91 correspond to new localizations. Our
      study enabled the localization of 14 new markers found on both maps, of 54 found
      on the USDA map, and of 23 found on the PiGMaP map. Now 21% and 43% of the
      markers on the USDA and PiGMaP linkage maps respectively are physically mapped.
      This new cytogenetic information was then integrated within the framework of each
      genetic map. The cytogenetic orientation of the USDA linkage maps for Chromosomes
      (Chrs) 3, 8, 9, and 16 and of PiGMaP for Chr 8 was determined. USDA and PiGMaP
      linkage maps are now oriented for all chromosomes, except for Chrs 17 and 18.
      Moreover, the linkage group "R" from the USDA linkage map was assigned to Chr 6.

PMID- 8662228
TI  - Regional assignment of human ESTs by whole-genome radiation hybrid mapping.
AB  - The UK HGMP Resource Centre's collection of human partial cDNA sequences (ESTs)
      have been examined for suitability for mapping by PCR on a panel of somatic cell
      hybrids. The chromosomal assignments of 92 ESTs were determined with a
      monochromosomal hybrid panel, and a subset of 45 were linked to genetic markers
      with a panel of whole-genome radiation hybrids (WG-RHs). These results
      demonstrate the potential of WG-RHs to construct a transcript map of the human
      genome.

PMID- 8662229
TI  - 5S rRNA genes in Macaca fascicularis map to chromosome 1p in three loci.

PMID- 8662230
TI  - Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb
      region of chromosome 2p23.
AB  - The glucokinase regulator (GCKR) is a 65-kDa protein that inhibits glucokinase
      (hexokinase IV) in liver and pancreatic islet. The role of glucokinase (GCK) as
      pancreatic beta cell glucose sensor and the finding of GCK mutations in maturity
      onset diabetes of the young (MODY) suggest GCKR as a further candidate gene for
      type 2 diabetes. The inhibition of GCK by GCKR is relieved by the binding of
      fructose-1-phosphate (F-1-P) to GCKR. F-1-P is the end product of ketohexokinase
      (KHK, fructokinase), which, like GCK and GCKR, is present in both liver and
      pancreatic islet. KHK is the first enzyme of the specialized pathway that
      catabolizes dietary fructose. We have isolated genomic clones containing the
      human GCKR and KHK genes. By fluorescent in situ hybridization (FISH), KHK maps
      to Chromosome (Chr) 2p23.2-23.3, a new assignment corroborated by somatic cell
      hybrid analysis. The localization of GCKR, originally reported by others as
      2p22.3, has been reassessed by high-resolution FISH, indicating that, like KHK,
      GCKR maps to 2p23.2-23.3. The proximity of GCKR and KHK was further demonstrated
      both by two-color interphase FISH, which suggests that the two genes lie within
      500 kb of each other, and by analysis of overlapping YAC and P1 clones spanning
      the interval between GCKR and KHK. A new microsatellite polymorphism was used to
      place the GCKR-KHK locus between D2S305 and D2S165 on the genetic map. The
      colocalization of these two metabolically connected genes has implications for
      the interpretation of linkage or allele association studies in type 2 diabetes.
      It also raises the possibility of coordinate regulation of GCKR and KHK by common
      cis-acting regulatory elements.

PMID- 8662231
TI  - Linkage mapping of murine homolog of the yeast SPT6 gene to MMU11B1.

PMID- 8662232
TI  - The lidgap-Gates (lgGa) mutation for open eyelids at birth maps to mouse
      chromosome 13.
AB  - Complex nonadditive interactions between specific alleles at multiple loci may
      underlie many so-called multifactorial threshold birth defects. The open-eyelids
      at-birth defect in mice is a good model for these defects, and an understanding
      of its genetic complexity begins with mapping the participating loci. The open
      eyelids defect can be part of a syndrome or can occur with no other obvious
      phenotypic effects. Of the latter nonsyndromic forms, the lidgap series includes
      four extant mutations that are considered to be alleles based on complementation
      tests. All show genetic complexity in segregation ratios. None has been mapped
      previously. On the basis of a strategy of mapping the mutation with the simplest
      inheritance pattern first, we generated an extensive exclusion map for lidgap
      Gates, lgGa, using morphological and protein polymorphisms. We then screened the
      non-excluded regions in a congenic strain, AEJ.LGG-lgGa, for SSLP markers and
      located the differential chromosome segment containing the lgGa locus in a region
      near the distal end of mouse Chromosome (Chr) 13. This linkage was confirmed and
      refined by typing SSLPs in 64 F2 and 74 BC1 progeny of a cross of LGG/Bc
      (lgGa/lgGa) to SWV/Bc. The lgGa mutation maps to a 1- to 2-cM region between
      D13Mit76 and D13Mit53. Integrin alpha 1 and integrin alpha 2, which map to the
      same general region, are possible candidate loci, based on their embryonic
      expression and cellular function. Evidence is also presented for a common
      unlinked recessive suppressor of the open eyelids trait caused by lgGa.

PMID- 8662233
TI  - The glutathione peroxidase gene, Gpx1, maps to mouse chromosome 9.

PMID- 8662234
TI  - Absence of coding sequence polymorphism in the serum amyloid P component gene
      (Sap) in autoimmune New Zealand black mice.

PMID- 8662235
TI  - LAF4 maps to mouse chromosome 1 and human chromosome 2q11.2-q12.

PMID- 8662236
TI  - Comparative mapping of the reeler gene on human chromosome 7q22, rat chromosome
      4q11.2, and mouse chromosome 5 A3-B1.

PMID- 8662237
TI  - Assignment of the mu-class glutathione S-transferase gene (hGSTYBX) to Syrian
      hamster chromosome 15 by FISH.

PMID- 8662238
TI  - Mapping of the interferon gamma gene (IFNG) to chromosomes 3 in sheep and 5 in
      goat by FISH.

PMID- 8662239
TI  - Assignment of the porcine obese (leptin) gene to chromosome 18 by linkage
      analysis of a new PCR-based polymorphism.

PMID- 8662240
TI  - Ovine stem cell factor gene is located within a syntenic group on chromosome 3
      conserved across mammalian species.

PMID- 8662241
TI  - In situ hybridization mapping of LDHA and IGF2 to cattle chromosome 29.

PMID- 8662242
TI  - Dishevelled-2 maps to human chromosome 17 and distal to Wnt3a and vestigial tail
      (vt) on mouse chromosome 11.

PMID- 8662243
TI  - Jak3 maps to chromosome 8.

PMID- 8662245
TI  - Tyrosinase-related protein-2 (DCT; TYRP2) maps to bovine chromosome 12.

PMID- 8662246
TI  - Region-specific YAC banding and painting probes for comparative genome mapping:
      implications for the evolution of human chromosome 2.
AB  - To date, several hundred nonchimeric yeast artificial chromosomes (YACs) from the
      Centre d'Etude du Polymorphisme Humain containing polymorphic sequence-tagged
      sites have been mapped by fluoresence in situ hybridization (FISH) on human
      metaphase chromosomes. Because they carry an average of 1 Mb of human genomic
      DNA, CEPH YACs generate high-intensity in situ hybridization signals. The
      available set of cytogenetically and genetically anchored YACs, approximately one
      every 5-10 cM evenly spaced over almost the entire human genome, provides complex
      region-specific probes for molecular cytogenetics. YAC probes can be adapted with
      unlimited flexibility to specific FISH applications such as the study of
      chromosomal evolution. We have generated representational probes for YAC banding
      and painting of human chromosome 2 and its great ape homologs. Convergent
      inversions were found in the pericentric region of the gorilla and orangutan
      homologs of chromosome 2p.

PMID- 8662247
TI  - High resolution physical mapping of 45S (5.8S, 18S and 25S) rDNA gene loci in the
      tomato genome using a combination of karyotyping and FISH of pachytene
      chromosomes.
AB  - Karyotyping in combination with fluorescence in situ hybridization (FISH) on
      tomato pachytene chromosomes allowed identification and mapping of a major 45S
      (5.8S, 18S and 25S) rDNA site on the satellite of 2S and four minor loci, each at
      a proximal knob on 2L, 6S, 9S and 11S. Thus, the 45S rDNA loci are all located in
      heterochromatic regions. The five 45S sites are all transcriptionally active as
      evidenced by a maximum of ten nucleoli in meiotic cells at telophase or
      interphase. The 45S rDNA loci, as well as the 5S rDNA locus on 1S, were
      highlighted by chromomycin A3, a GC-specific DNA ligand; this result is
      consistent with the high GC content of the rDNA genes. Satellite size varied
      dramatically between genotypes. Enzymatic maceration of tomato anthers followed
      by squashing in acetocarmine produced high quality chromosomal preparations and
      subsequent FISH images by reducing the strong autofluorescence inherent in the
      nucleolus and cytoplasm of tomato meiotic cells. Our protocol has potential in
      the construction of an integrated cytological, classical and molecular map of
      tomato.

PMID- 8662248
TI  - Disruption of CENP antigen function perturbs dynein anchoring to the mitotic
      kinetochore.
AB  - Injection of purified autoantibodies against human centromeric proteins into HeLa
      cells during interphase disrupts the organization of the kinetochore and
      interferes with chromosomal movements during the subsequent mitosis even though
      the chromosomes retain the ability to bind microtubules. We have investigated the
      hypothesis that this phenotype arises from effects on cytoplasmic dynein, the
      microtubule motor protein. In previous experiments we found that introduction of
      anticentromere antibodies into cell nuclei during the G1- or S-phases causes a
      prometaphase-like arrest, while injections during G2-phase cause a metaphase
      arrest. We show here that, in both cases, the level of detectable cytoplasmic
      dynein at kinetochores is significantly decreased. In contrast, when injected
      cells were permitted to enter mitosis in the absence of microtubules (conditions
      where trilaminar kinetochores could be detected by electron microscopy), the
      intensity of dynein labeling on the kinetochores was identical to that seen in
      uninjected control cells exposed to colcemid. Therefore, the loss of dynein label
      on mitotic kinetochores was correlated both with the injection of anticentromere
      antibodies and with the presence of intact spindle microtubules. We suggest that
      the injection of anticentromere antibodies somehow weakens the association of
      dynein with the kinetochore, so that when microtubules are present, these motor
      molecules are pulled away from the kinetochores as they generate force. This
      model offers an explanation for the failure of chromosomes of injected cells to
      move normally in mitosis even though they have attached microtubules.

PMID- 8662250
TI  - An unstable minichromosome generates variegated oil yellow maize seedlings.
AB  - An unstable minichromosome comprising part of the short arm of chromosome 10 of
      maize was recovered from an oil yellow variegated plant as a consequence of gamma
      irradiation of pollen. The cytological and gene dosage observations are
      consistent with the minichromosome being a partial isochromosome, which lags at
      mitotic and meiotic anaphase. Loss of the minichromosome, which carries two doses
      of the +gene, causes phenotypic variegation in otherwise yellow lethal (Oy/Oy or
      Oy/oy) and olive (Oy/+ or oy/oy) genotypes. The minichromosome was transmitted to
      8.1% of progeny via the pollen and 0.5% via the egg. Variations in the number and
      size of the minichromosome were recovered in progeny from a large test cross
      designed to test the feasibility for the detection of genetic variants including
      apomicts. No apomicts were recovered. All progeny with the appropriate maternal
      olive phenotype and the paternally derived coloured aleurone proved to be
      haploids. The recovery of a large minichromosome provides evidence for rare
      pairing and exchange with the short arm of chromosome 10. The variants of
      chromosome 10S generated from this programme provide useful material for further
      cytological, genetic and molecular analysis.

PMID- 8662249
TI  - Fine structural cytochemical and immunocytochemical analysis of nucleic acids and
      ribonucleoprotein distribution in nuclei of pig oocytes and early preimplantation
      embryos.
AB  - The fine structure of pig oocytes at the germinal vesicle (GV) stage and early
      preimplantation embryos (one to four blastomeres) isolated at slaughter was
      investigated by cytochemical and immunocytochemical methods. The distribution of
      nucleic acids and ribonucleoproteins (RNPs) in "compact nucleoli" [denominated
      nucleolus-like bodies (NLB) in oocytes and nucleolus precursor bodies (NPB) in
      early embryos] and in intranuclear bodies or granules was investigated by
      staining methods preferential for nuclear RNPs or using the osmium ammine or
      ethidium bromide-phosphotungstic acid (EB-PTA) reactions for nucleic acids. The
      distributions of the Sm antigen of nucleoplasmic small nuclear RNPs (snRNPs), the
      methyl-3 guanosine (m3G) cap of snRNAs and the splicing factor SC-35 were
      detected by immunoelectron microscopy using specific antibodies. The RNP nature
      of both NLBs and NPBs, and of nuclear granules in oocytes and embryos, and of
      fibrillar strands radially projecting from NLBs was revealed. Cytochemical
      evidence for RNA as a component of NLBs was further provided by EB-PTA staining
      in combination with the enzymatic removal of RNA, or by osmium-ammine staining
      without previous acid hydrolysis, while the absence of DNA in NLBs was
      established by Feulgen-like osmium-ammine staining. In addition, autoradiography
      demonstrated the absence of [6-3H]thymidine incorporation into NPBs. Other
      autoradiographic evidence attested the accumulation of RNA in NLBs of oocytes
      after a 60 min in vitro pulse of [5-3H]uridine. Immunoelectron microscopy using
      specific antibodies revealed the occurrence of nucleoplasmic snRNPs in both NLBs
      and NPBs. The presence of snRNA in NLB was confirmed by means of an antibody
      recognizing the m3G-cap structure. Another spliceosomal component, the protein SC
      35 was also detected in NLBs. Among the numerous and variable intranuclear
      granules occurring mostly in aggregates, the Sm antigen was clearly detected only
      in the interchromatin granule-type component. Some Sm labeling was occasionally
      seen in other categories of larger granules. No reaction was detected over any
      granules when using the anti-m3G-cap antibody. The aggregates consisting of large
      granules and a finely fibrillar component were intensely immunolabeled by the
      anti-SC-35 splicing factor probe. Our observations suggest that the compact
      nucleoli, known to be present before and after fertilization in mammals (NLBs of
      oocytes and NPBs of early embryos), represent nuclear structural elements
      containing nonnucleolar, spliceosomal components.

PMID- 8662252
TI  - Spontaneous and radiation-induced chromosomal breakage at interstitial telomeric
      sites.
AB  - The Chinese hamster genome contains a total of 18 cytologically detectable arrays
      of interstitial telomeric sequences. A combination of G-banding and two-colour
      fluorescence in situ hybridization revealed that 25 out of 27 (93%) breakpoints
      of spontaneously occurring terminal deletions in four immortalized Chinese
      hamster cell lines were located in chromosomal regions containing interstitial
      telomeric sequences. Each of the four immortalized Chinese hamster cell lines
      expressed telomerase. Radiation experiments revealed the sensitivity of
      interstitial telomeric sequences to radiation-induced chromosomal breakage in all
      telomerase-positive cell lines. However, radiation-induced chromosomal breakage
      at interstitial telomeric sites in non-transformed, primary Chinese hamster cells
      was almost non-existent. Telomerase activity in primary Chinese hamster cells was
      not detected. These results indirectly suggest that interstitial telomeric sites
      represent a favourable substrate for chromosomal healing.

PMID- 8662251
TI  - Distribution of T1, Q, Pegasus and mariner transposable elements on the polytene
      chromosomes of PEST, a standard strain of Anopheles gambiae.
AB  - The chromosomal locations of four families of transposable elements, T1, Q,
      Pegasus and mariner, have been determined by in situ hybridization to polytene
      chromosomes of ovarian nurse cells of the mosquito Anopheles gambiae. As part of
      this effort, we have developed a vigorous pink-eyed laboratory strain of A.
      gambiae (PEST), rendered homozygous standard for chromosomal inversions on all
      autosomes. Ten different individuals of this strain were studied with each
      transposable element probe. The average number of hybridization sites per genome
      was 83.9 for T1, 63.4 for Q, 31.5 for Pegasus and 64.7 for mariner, excluding
      pericentric and centromeric regions. However, some degree of polymorphism was
      observed within each family such that, considering all ten individuals, 94
      different sites were detected for T1, 82 sites for Q, 45 sites for Pegasus and 71
      sites for mariner. The mean occupancy per site varied from 0.70 (Pegasus) to 0.91
      (mariner), which, while significantly higher than that seen for transposable
      elements in natural populations of Drosophila melanogaster, is comparable to that
      seen in established laboratory stocks. In addition, these element families were
      not randomly distributed. All but Pegasus were concentrated in centromeric
      heterochromatin and centromere-proximal euchromatin, most showed a deficit of
      hybridization sites in the distal section of chromosomes, and a significant
      proportion of sites were coincident between families. These results provide the
      first detailed examination of the cytogenetic location of transposable elements
      in a nondrosophilid insect, and, through comparison with the behavior of
      transposable elements in Drosophila, may provide insight into the interaction
      between elements and host. The mapped elements are also expected to serve as
      landmarks useful in integrating the developing physical map of the PEST strain
      with the chromosomal banding pattern.

PMID- 8662253
TI  - Nuclear morphogenesis and the onset of transcriptional activity in early hamster
      embryos.
AB  - Coiled bodies and interchromatin granules are distinct subnuclear domains that
      contain splicing small nuclear ribonucleoproteins (snRNPs) and protein-splicing
      factors. Here we have studied the morphogenesis of coiled bodies and clusters of
      interchromatin granules in relation to the onset of transcriptional activity in
      early hamster embryos. The results indicate that major embryonic transcription by
      RNA polymerase II is first detected during the early two-cell stage (15-20 h post
      fertilization), whereas RNA polymerase I activity and nucleologenesis are only
      observed in late two-cell embryos (30-40 h postfertilization). Splicing snRNPs
      and heterogeneous nuclear RNP (hnRNP) proteins are shown to be imported into the
      pronuclei following fertilization, and prominent clusters of interchromatin
      granules containing the splicing factor SC-35 are already observed in both
      maternal and paternal pronuclei of one-cell embryos. Interestingly, these large
      clusters of interchromatin granules do not appear to concentrate splicing snRNPs.
      In contrast, coiled bodies are first detected during the two-cell stage after the
      onset of transcription, and they are clearly enriched in snRNPs. Taken together
      with results previously obtained in mouse embryos, these data suggest that the
      assembly of coiled bodies and clusters of interchromatin granules is independent
      from the onset of embryonic transcriptional activity, and that coiled bodies
      represent the major snRNP-enriched subnuclear domain in the early mammalian
      embryo.

PMID- 8662254
TI  - Nucleolar organizer expression in Allium cepa L. chromosomes.
AB  - Roots from Allium cepa L. (cv. Francesa) bulbs in which a maximum of two nucleoli
      per nucleus developed were selected for this study. Five rDNA clusters were
      detected by fluorescent in situ hybridization on chromosomal squashes (2n = 16)
      with a rhodamine-labelled wheat rDNA repeat. The rDNA clusters were located on
      four chromosomes: the largest cluster occurred on the small arm of a single
      homologue of the smallest pair 8. Its homologue showed two different small rDNA
      clusters, one near each telomere. The two homologues of the satellited
      chromosomes 6 also showed different rDNA contents, which were intermediate to
      those found in pair 8. The same five well-differentiated hybridization signals
      were observed in interphase cells that were inactive in transcription because
      they were in dormant roots, or in proliferating ones in which the synthesis of
      the large rRNA precursor was prevented. After multipolarizing agent was applied
      in anaphase followed by inhibition of cytokinesis, multinucleate autotetraploid
      cells were formed, which often contained more than four nucleoli. Thus, at least
      two of the three nucleolar organizer regions that consistently failed to develop
      a nucleolus in normal mononucleate cells were capable of developing nucleoli when
      segregated into different nuclei in multinucleate cells.

PMID- 8662255
TI  - Tau as a nucleolar protein in human nonneural cells in vitro and in vivo.
AB  - The Tau-1 monoclonal antibody was localized to the nucleolus of interphase cells
      and the nucleolar organizing regions (NORs) of acrocentric chromosomes in
      cultured human cells. Putative nucleolar and NOR tau was found in HeLa cells and
      lymphoblasts as well as in nontransformed fibroblasts and lymphocytes. To confirm
      the presence of tau in the nuclei of these nonneural cells, immunoblotting
      analysis was performed on isolated nuclei from lymphoblasts. Several tau bands
      were noted on the blot of the nuclear extract suggesting the presence of multiple
      tau isoforms. Tau-1 immunostaining demonstrated variable staining intensities
      between individual acrocentric chromosomes in all cells tested. In cultured
      peripheral lymphocytes, these staining patterns were the same from one chromosome
      spread to the next within an individual. This consistency of Tau-1 staining and
      its variability among NORs was reminiscent of staining patterns obtained using
      the silver-NOR procedure. Comparisons of Tau-1 immunostaining with silver
      staining of chromosome spreads from human lymphocytes demonstrated that Tau-1 did
      not immunostain all of the NORs that were silver stained. The intensity of Tau-1
      fluorescence in nucleoli was further shown to be increased in phytohemagglutinin
      stimulated lymphocytes, indicating an upregulation of nuclear tau when cells
      reentered the cell cycle. These results contribute to a growing body of evidence
      defining tau as a multifunctional protein that may be involved in ribosomal
      biogenesis and/or rRNA transcription in the nucleus of all cells as well as
      microtubule-stabilizing functions in the neuronal cytoplasm.

PMID- 8662256
TI  - Postmetaphase nuclear formation: loss of a chromosomal epitope coincident with
      apparent chromatid coalescence.
AB  - Previously, we have conceptualized mitotic nuclear formation following metaphase
      as a morphogenic process and have suggested that sets of chromatids, after
      separation from a metaphase plate, can be thought of as prenuclei. Such
      structures can be grouped temporally as either early or late prenuclei based on
      morphologic, morphometric and density characteristics. Sequential ordering of
      early prenuclei is of particular interest because it reveals that condensed
      chromatids coalesce with the resulting formation of a unique chambered structure.
      In this paper we describe data obtained with a newly raised monoclonal antibody
      (mAb-2) that initially recognizes an epitope(s) on metaphase chromosomes. Light
      and confocal fluorescent microscopy of early prenuclei reveal that the
      chromosomal epitope can no longer be detected about chromatids after their
      apparent coalescence. Immunoblot analysis of dispersed polypeptides of metaphase
      plates and early prenuclei indicates that the major protein antigens recognized
      by mAb-2 have apparent molecular masses of approximately 106000 and 80500 and
      that each is likely composed of multiple charge isomers. A dual fluorescent
      analysis using mAb-2 and high-titer anti-lamin B serum provides additional
      evidence that chromatid coalescence is a separate, early event that precedes
      nuclear lamina formation.

PMID- 8662257
TI  - Activity banding of human chromosomes as shown by histone acetylation.
AB  - The expression of genes in mammalian cells depends on many factors including
      position in the cell cycle, stage of differentiation, age, and environmental
      influences. As different groups of genes are expressed, their packaging within
      chromatin changes and may be detected at the chromosomal level. The organization
      of DNA within a chromosome is determined to a large extent by the positively
      charged, highly conserved histones. Histone subtypes and the reversible chemical
      modifications of histones have been associated with gene activity. Active or
      potentially active genes have been associated with hyperacetylated histones and
      inactive genes with nonacetylated histones. Sodium butyrate increases the
      acetylation levels of histones in cell cultures and acts as both an inducer of
      gene activity and as a cell-cycle block. We describe a method to label the
      interphase distribution of DNA associated with various histone acetylation stages
      on chromosomes. Nucleosomes from untreated and butyrate-treated HeLa cells were
      fractionated by their acetylation level and the associated DNA labeled, and
      hybridized to normal human chromosomes. In the sodium butyrate-treated cells the
      resulting banding patterns of the high- and low-acetylated fractions were
      strikingly different. DNA from low-acetylated chromatin labeled several
      pericentric regions, whereas hybridization with DNA from highly acetylated
      chromatin resulted in a pattern similar to inverse G-bands on many chromosomes.
      The results from noninduced cells at both high and low acetylation levels were
      noticeably different from their induced counterparts. The capture and
      hybridization of DNA from interphase chromatin at different acetylation states
      provides a "snapshot" of the distribution of gene activity on chromosomes at the
      time of cell harvest.

PMID- 8662258
TI  - The diplochromosome of endoreduplicated cells: a new approach to highlight the
      mechanism of sister chromatid exchange.
AB  - Chinese hamster lung embryonic cells (CL1) were treated with colchicine in order
      to induce endoreduplication and subsequently with mitomycin-C (MMC) to induce
      exchanges within the diplochromosome. The use of chromosomal differential
      staining through incorporation of 5-bromodeoxyuridine, resulting in only one
      stained chromatid, has allowed the analysis of all classes of exchanges among the
      four chromatids of the diplochromosome. Three classes of exchanges may occur:
      intradiplochromatid exchanges (ICEs) between the two inner chromatids, cousin
      chromatid exchanges (CCEs) between one inner and one outer chromatid, and sister
      chromatid exchanges (SCEs) between the two sister chromatids of the
      diplochromosome. The results show that MMC treatment, in the last cell cycle of
      endoreduplication, as expected, significantly increases only the frequency of
      SCEs, whereas the frequency of ICEs and CCEs remains unchanged. This result
      supports replication models of formation of SCEs. Furthermore the fact that the
      number of ICEs does not increase means that the molecular mechanism of somatic
      crossing over is not related to that of SCE formation, or very rarely. The
      results also indicate a statistically significant lower induction of SCEs in
      endoreduplicated metaphases as compared with diploid ones both in control and MMC
      treated cells. Such a result may be due to structural restrictions within the
      diplochromosome.

PMID- 8662259
TI  - Distribution of 5S and 18S-28S rDNA loci in a tetraploid cotton (Gossypium
      hirsutum L.) and its putative diploid ancestors.
AB  - The most widely cultivated species of cotton, Gossypium hirsutum, is a disomic
      tetraploid (2n=4x=52). It has been proposed previously that extant A- and D
      genome species are most closely related to the diploid progenitors of the
      tetraploid. We used fluorescent in situ hybridization (FISH) to determine the
      distribution of 5S and 18S-28S rDNA loci in the A-genome species G. herbaceum and
      G. arboreum, the D-genome species G. raimondii and G. thurberi, and the AD
      tetraploid G. hirsutum. High signal-to-noise, single-label FISH was used to
      enumerate rDNA loci, and simultaneous, dual-label FISH was used to determine the
      syntenic relationships of 5S rDNA loci relative to 18S-28S rDNA loci. These
      techniques provided greater sensitivity than our previous methods and permitted
      detection of six new G. hirsutum 18S-28S rDNA loci, bringing the total number of
      observed loci to 11. Differences in the intensity of the hybridization signal at
      these loci allowed us to designate them as major, intermediate, or minor 18S-28S
      loci. Using genomic painting with labeled A-genome DNA, five 18S-28S loci were
      localized to the G. hirsutum A-subgenome and six to the D-subgenome. Four of the
      11 18S-28S rDNA loci in G. hirsutum could not be accounted for in its presumed
      diploid progenitors, as both A-genome species had three loci and both D-genome
      species had four. G. hirsutum has two 5S rDNA loci, both of which are syntenic to
      major 18S-28S rDNA loci. All four of the diploid genomes we examined contained a
      single 5S locus. In g. herbaceum (A1) and G. thurberi (D1), the 5S locus is
      syntenic to a major 18S-28S locus, but in G. arboreum (A2) and G. raimondii (D5),
      the proposed D-genome progenitor of G. hirsutum, the 5S loci are syntenic to
      minor and intermediate 18S-28S loci, respectively. The multiplicity, variation in
      size and site number, and lack of additivity between the tetraploid species and
      its putative diploid ancestors indicate that the behavior of rDNA loci in cotton
      is nondogmatic, and considerably more complex and dynamic than previously
      envisioned. The relative variability of 18S-28S rDNA loci versus 5S rDNA loci
      suggests that the behavior of tandem repeats can differ widely.

PMID- 8662260
TI  - Resolving ambiguities in the karyotype of domestic sheep (Ovis aries). II. G-, Q
      , and R-banded idiograms, and chromosome-specific molecular markers.
AB  - Internally consistent G-, Q- and R-banded karyotypes and idiograms for sheep
      chromosomes at the 422-band level of resolution are presented. These were derived
      by sequential Q- to G-staining, and sequential Q- to R-staining of prometaphase
      spreads prepared from sheep with normal and Robertsonian chromosomes. The fused
      chromosomes served as stable morphological markers. To minimise confusion due to
      chromosomal nomenclature, we have listed chromosome-specific (reference)
      molecular markers that have been mapped by in situ hybridization to sheep
      chromosomes. The use of molecular markers in conjunction with the sequential Q-
      to G- and sequential Q- to R-banded karyotypes and iodiograms provided here will
      elimiate ambiguities in identifying and numbering sheep chromosomes and will
      facilitate their comparison with cattle chromosomes.

PMID- 8662261
TI  - Calcium transport pathways in the nucleus.
AB  - Due to the availability of new biophysical and biochemical techniques, there has
      recently been considerable progress in our understanding of Ca2+ transport
      inside, as well as into and out of, the nucleus. A number of Ca2+ transport
      pathways have been localized specifically in the outer or inner nuclear membrane
      and the Ca2+ permeability through the nuclear pore complex has been assessed. The
      nuclear envelope has characteristics similar to those of a leaky epithelium. The
      leak is through the nuclear pore complex. The outer nuclear membrane contains the
      Ca2+ ATPase whereas the functionally important inositol trisphosphate (IP3)
      activated Ca2+ release channels are specifically localized in the inner nuclear
      membrane.

PMID- 8662262
TI  - Myosin light chain diphosphorylation is enhanced by growth promotion of cultured
      smooth muscle cells.
AB  - The characteristics of actively growing smooth muscle cells (a variant, SM-3)
      were compared with those of growth-arrested cells with regard to response of
      myosin light chain (MLC) phosphorylation. Augmented MLC phosphorylation, in
      particular diphosphorylation, was observed in actively growing cells when
      stimulated with 30 microM prostaglandin F2alpha (PGF2alpha). The maximum level of
      diphosphorylation in growing cells was significantly higher than that in growth
      arrested cells. The MLC diphosphorylation was sensitive to protein kinase C down
      regulation by phorbol dibutylate and pretreatment by the protein kinase
      inhibitors, staurosporine (30 nM) and isoquinoline sulphonamide HA1077 (20
      microM). The actively growing cells contained larger amounts of protein kinase C
      than growth-arrested cells. The phosphorylation sites of mono- and diphospho-MLC
      were determined to be MLC kinase-dependent sites (Thr18, Ser19). The PGF2alpha
      concentration/response curves of MLC diphosphorylation were shifted to the left
      and upwards in the presence of the protein phosphatase inhibitor calyculin A.
      These results suggest that PGF2alpha stimulation of actively growing SM-3 cells
      augments MLC kinase-dependent MLC diphosphorylation. Protein kinase C is involved
      indirectly in this reaction, possibly through MLC phosphatase-sensitive
      regulatory mechanisms.

PMID- 8662263
TI  - Effects of protein phosphorylation on the regulation of capacitative calcium
      influx in Xenopus oocytes.
AB  - The regulation of capacitative Ca2+ influx in Xenopus oocytes was investigated
      using both the two electrode voltage-clamp (where Ca2+ is monitored through the
      Ca2+-dependent Cl- current) and patch-clamp techniques. Following stimulation of
      expressed 5-hydroxytryptamine (5-HT) receptors, capacitative Ca2+ influx
      deactivated in around 15 min. Following injection of [adenosine 5'-O-(3
      Thiotriphosphate)] (ATP [gamma-S]), an ATP analogue that is readily used by
      protein kinases, capacitative Ca2+ influx activated by 5-HT application either
      did not deactivate or was prolonged around twofold. However, injection of
      adenylyl 5'-(beta,gamma-methylene)-diphosphonate (AMP-PCP), another ATP analogue
      that is not utilised by kinases, did not affect the time-course of Ca2+ influx.
      When capacitative Ca2+ influx was activated by readmission of Ca2+ to oocytes
      incubated in thapsigargin/0 Ca2+ solution for several hours, Ca2+ influx occurred
      and a weakly saturating relationship between external Ca2+ and Ca2+ influx was
      found. Ca2+ influx in thapsigargin-treated cells was unaffected by ATP [gamma-S].
      ATP [gamma-s] and several kinases had no effect on the Ca2+-dependent Cl- current
      when the latter was activated by elevation of Ca2+ independent of capacitative
      Ca2+ influx. Protein kinase C slowly and partially inhibited the Cl- current.
      Outside-out patches taken from thapsigargin-treated cells failed to demonstrated
      any Ca2+ current or Ca2+-dependent Cl- current on reapplying high Ca2+ to the
      patch, despite the oocyte showing a large capacitative Ca2+ influx. The results
      suggest that a kinase, activated on receptor stimulation, prolongs the activation
      time-course of capacitative Ca2+ influx.

PMID- 8662264
TI  - Rb+, Cs+ ions and the inwardly rectifying K+ channels in guinea-pig ventricular
      cells.
AB  - Rb+ and Cs+ ion permeability and the effects of these ions from the inside on the
      inwardly rectifying K+ channel were studied in guinea-pig ventricular cells. A
      total substitution of either Rb+ or Cs+ for external K+ in the outside-out
      configuration of the patch-clamp technique abolished the inward current. The
      outward current carried by K+ was recorded. The unitary amplitude was reduced to
      about half of the control value with Rb+ but was not changed with Cs+. Internal
      Rb+ and Cs+, at a concentration of 10-40 mM, reduced the unitary amplitude of the
      outward current. No substate behaviour was observed. The reversal potential was
      +18 mV after replacing 105 mM internal K+ with Rb+ at 150 mM external K+. This
      value gives a permeability ratio of Rb+ to K+ of 0.27. Under a total substitution
      of Rb+ or Cs+ for internal K+, the outward currents were not measurable. Cs+
      induced flickering in the inward current carried by K+. It is thus concluded that
      Rb+ and Cs+ ions are not measurably permeant at the single-channel level but
      permit K+ permeation in place of external K+ and that internal Rb+ and Cs+
      produce a voltage-dependent block of the channel with fast kinetics.

PMID- 8662265
TI  - The delayed rectifier, IKI, is the major conductance in type I vestibular hair
      cells across vestibular end organs.
AB  - Hair cells were dissociated from the semicircular canal, utricle, lagena and
      saccule of white king pigeons. Type I hair cells were identified morphologically
      based on the ratios of neck width to cuticular plate width (NPR < 0.72) as well
      as neck width to cell body width (NBR < 0.64). The perforated patch variant of
      the whole-cell recording technique was used to measure electrical properties from
      type I hair cells. In voltage-clamp, the membrane properties of all identified
      type I cells were dominated by a predominantly outward potassium current,
      previously characterized in semicircular canal as IKI. Zero-current potential,
      activation, deactivation, slope conductance, pharmacologic and steady-state
      properties of the complex currents were not statistically different between type
      I hair cells of different vestibular end organs. The voltage dependence causes a
      significant proportion of this conductance to be active about the cell's zero
      current potential. The first report of the whole-cell activation kinetics of the
      conductance is presented, showing a voltage dependence that could be best fit by
      an equation for a single exponential. Results presented here are the first data
      from pigeon dissociated type I hair cells from utricle, saccule and lagena
      suggesting that the basolateral conductances of a morphologically identified
      population of type I hair cells are conserved between functionally different
      vestibular end organs; the major conductance being a delayed rectifier
      characterized previously in semicircular canal hair cells as IKI.

PMID- 8662266
TI  - The relationship between plasma potassium, muscle membrane excitability and force
      following quadriceps fatigue.
AB  - To examine the simultaneous changes in plasma [K+], muscle excitability and force
      during fatigue, ten male adults (mean age = 22 +/- 0.5 years) held an isometric
      contraction of their right quadriceps muscle at an intensity of 30% maximum
      voluntary contraction (MVC) for 3 min. Femoral venous and brachial arterial [K+]
      were determined from serial samples drawn before, during, and for 15 min
      following the 3-min contraction. Each blood sample was synchronized with a
      maximal stimulation of the right femoral nerve to evoke a twitch and compound
      muscle action potential (M-wave). Immediately post-exercise, twitch torque was
      only 42% of baseline and femoral venous plasma [K+] had increased significantly
      from 4.02 +/- 0.08 mmol/l to 5.9 +/- 0.22 mmol/l. Femoral venous plasma lactate
      rose to a peak level of 10.0 +/- 0.8 mmol/l at 1 min post exercise. The recovery
      of the twitch torque was exponentially related to the recovery of femoral venous
      plasma [K+] (r2 = 0.93, P < 0.01). There was no evidence for any loss of muscle
      membrane excitability during the period of increased extracellular [K+], in fact,
      the M-waves tended to be potentiated in the early phases of the recovery period.
      These results suggest that muscle membrane excitability is maintained in spite of
      increased extracellular [K+] following fatigue induced by a sustained submaximal
      quadriceps contraction. However, the strong relationship between twitch torque
      and femoral venous plasma [K+] suggests that K+ may be exerting its effect distal
      to surface membrane action potential propagation, most likely in the T-tubular
      region.

PMID- 8662267
TI  - Effects of prolonged exposure to and physical training in hypobaric conditions on
      skeletal muscle morphology and metabolic enzymes in rats.
AB  - Adaptations of skeletal muscle morphology and metabolic enzymes were studied
      after prolonged training in and exposure to hypobaric (740 -770 mbar) as well as
      normobaric conditions in rats performing treadmill running training for 10, 21
      and 56 days. Animals sacrificed after 91 days served as recovery groups from
      training and hypobaric exposure for 56 days. The rats were divided into
      normobaric sedentary (NS) and training (NT) groups and hypobaric sedentary (HS)
      and training (HT) groups. The weights of extensor digitorum longus (EDL) and
      soleus (SOL) muscles increased significantly in the 56HS and the 56HT groups
      compared with the 56NS group, the increase being greatest in the 56HS group. No
      differences in the mean fibre areas (MFA) of these muscles could be seen, whereas
      clearly reduced MFAs of type IIA and IIB were observed in the tibialis anterior
      (TA) muscle. However, fibre area distribution analyses in the EDL and TA muscles
      showed a higher proportion of larger fibers in the 56HS and 56HT groups than in
      the respective normobaric groups. On the contrary, in SOL muscles the proportion
      of smaller fibers was higher in the hypobaric than in normobaric groups at 56
      days. Increased activities of citrate synthase and beta-hydroxyacyl-CoA
      dehydrogenase in SOL and TA muscles in the 56HT group indicate an increase in
      oxidative capacity. It is concluded that exposure to, and training in moderate
      hypobaric conditions leads to a positive muscle protein balance which is
      reflected in increased muscle weights. However, the sites of increased protein
      synthesis and the possible hyperplasia remain to be studied further.

PMID- 8662268
TI  - Effects of thapsigargin and cyclopiazonic acid on sarcoplasmic reticulum Ca2+
      uptake, spontaneous force oscillations and myofilament Ca2+ sensitivity in
      skinned rat ventricular trabeculae.
AB  - Thapsigargin (TG) and cyclopiazonic acid (CPA) have been reported to be potent
      inhibitors of the sarcoplasmic reticulum (SR) Ca2+ uptake in isolated SR vesicles
      and cells. We have examined the effect of TG and CPA on (1) the Ca2+ uptake by
      the SR in saponin-skinned rat ventricular trabeculae, using the amplitude of the
      caffeine-induced contraction to estimate the Ca2+ content loaded into the SR, (2)
      the spontaneous Ca2+ oscillations at pCa 6.6 using force oscillation as the
      indicator, and (3) the myofilament Ca2+ sensitivity in Triton X-100-treated
      preparations. Inhibition of Ca2+ loading by TG and CPA increased with time of
      exposure to the inhibitor over 18-24 min. TG and CPA produced half inhibition of
      Ca2+ loading at 34.9 and 35.7 microM respectively, when 18-24 min were allowed
      for diffusion. The spontaneous force oscillations were more sensitive to the
      inhibitors: 10 microM TG and 30 microM CPA both abolished the oscillations in
      this time. The myofilament Ca2+ sensitivity was not affected by 10 and 300 microM
      TG or CPA. The results show that the concentrations of TG and CPA necessary to
      inhibit the SR Ca2+ uptake of skinned ventricular trabeculae are much higher than
      the reported values for single intact myocytes. One reason for this may be slow
      diffusion of the inhibitors into the multicellular trabecula preparation.

PMID- 8662269
TI  - Thermosensitivity is reduced during fever induced by Staphylococcus aureus cells
      walls in rabbits.
AB  - Thermosensitivity (TS) and threshold core temperature for metabolic cold defence
      were determined in six conscious rabbits before, and at seven different times
      after i.v. injection of killed Staphylococcus aureus (8 x 10(7) or 2 x 10(7) cell
      walls x kg(-1)) by exposure to short periods (5-10 min) of body cooling. Heat was
      extracted with a chronically implanted intravascular heat exchanger. TS was
      calculated by regression of metabolic heat production (M) and core temperature,
      as indicated by hypothalamic temperature. Threshold for cold defence (shivering
      threshold) was calculated as the core temperature at which the thermosensitivity
      line crossed preinjection resting M. The shivering thresholds followed the shape
      of the fever response. TS was significantly reduced (up to 49%) during the time
      course of fever induced by the highest dose of pyrogen only. At both high and low
      doses of pyrogen TS correlated negatively with shivering threshold (r = 0.66 and
      0.79 respectively) with similar slopes. The reduction in TS during fever was thus
      associated with the increase in shivering threshold resulting from the pyrogen
      injection and not by the dose of pyrogen. Model considerations indicate, however,
      that changes in sensitivity of the thermosensory input to the hypothalamic
      controller may affect threshold changes but cause negligible TS changes. It is
      more likely that the reduction in TS is effected in the specific hypothalamic
      effector pathways.

PMID- 8662270
TI  - Simultaneous recording of ATP-sensitive K+ current and intracellular Ca2+ in
      anoxic rat ventricular myocytes. Effects of glibenclamide.
AB  - We investigated the temporal relationship between the adenosine triphosphate
      sensitive K current (KATP current), hypoxic shortening and Ca accumulation in
      cardiomyocytes exposed to anoxia or metabolic inhibition. Whole-cell, patch-clamp
      experiments were performed with nonstimulated isolated rat heart ventricular
      muscle cells loaded with the Ca-sensitive fluorescent dye 1-[2-(5-carboxyoxazol-2
      yl)-6-aminobenzofuran-5-oxy]-2-(2'- amino-5'-methylphenoxy) ethane-N,N,N',N'
      tetraacetic acid (fura-2) via the patch pipette. After approximately 8 min
      anoxia, the KATP current started to rise and reached a maximum of 21.3 +/- 3.7 nA
      (n = 5, recorded at 0 mV clamp potential) within 1-3 min. At that time hypoxic
      contracture also occurred. Resting cytoplasmic free calcium (Cai) did not change
      significantly before hypoxic shortening. After hypoxic contracture, the KATP
      current decreased and Cai started to rise, reaching about 1 micromol/l. The
      presence of glibenclamide (10 micromol/l) in the bath reduced the anoxia-induced
      KATP current by more than 50%, but did not significantly influence the time
      dependence of current, hypoxic shortening and Cai, or the magnitude of Cai.
      Metabolic inhibition with 1.5 mmol/l CN resulted in KATP current increase and
      hypoxic shortening, occurring somewhat earlier than under anoxia, but all other
      parameters were comparable. In non-patch-clamped cells loaded with fura-2 AM
      ester and field-stimulated with 1 Hz, 1 micronol/l glibenclamide had no
      significant effect on the magnitude of the Cai increase caused by exposure of the
      cells to 1.5 mmol/l CN-. After CN- wash-out in non-patch-clamped cells, Cai
      declined, oscillated and finally returned to control values. It can be concluded
      that glibenclamide inhibits anoxia-induced KATP currents only partially and has
      no significant effect on anoxia-induced rise in resting Cai.

PMID- 8662271
TI  - The cAMP-regulated and 293B-inhibited K+ conductance of rat colonic crypt base
      cells.
AB  - We have shown previously that secretagogues acting via the second messenger
      adenosine 3',5'-cyclic monophosphate (cAMP) activate, besides their marked effect
      on the luminal Cl- conductance, a K+ conductance in the basolateral membrane of
      colonic crypt cells. This conductance is blocked by the chromanol 293B. This K+
      conductance is examined here in more detail in cell-attached (c.a.) and cell
      excised (c.e.) patch- clamp studies. Addition of forskolin (5 micromol/l) to the
      bath led to the activation of very small-conductance (probably < 3 pS) K+
      channels in c.a. patches (n = 54). These channels were reversibly inhibited by
      the addition of 0.1 mmol/l of 293B to the bath (n = 21). Noise analysis revealed
      that these channels had fast kinetics and produced a Lorentzian noise component
      with a corner frequency (fc) of 308 +/- 10 Hz (n = 30). The current/voltage
      curves of this noise indicated that the underlying ion channels were K+
      selective. 293B reduced the power density of the noise (So) to 46 +/- 8.7% of its
      control value and shifted fc from 291 +/- 26 to 468 +/- 54 Hz (n = 8). In c.e.
      patches from cells previously stimulated by forskolin, the same type of current
      persisted in 3 out of 18 experiments when the bath solution was a cytosolic-type
      solution without adenosine 5'-triphosphate (ATP) (CYT). In 15 experiments the
      addition of ATP (1 mmol/l) to CYT solution was necessary to induce or augment
      channel activity. In six experiments excision was performed into CYT + ATP
      solution and channel activity persisted. 293B exerted a reversible inhibitory
      effect. The channel activity was reduced by 5 mmol/l Ba2+ and was completely
      absent when K+ in the bath was replaced by Na+. These data suggest that forskolin
      activates a K+ channel of very small conductance which can be inhibited directly
      and reversibly by 293B.

PMID- 8662272
TI  - Adrenaline-, not somatostatin-induced hyperpolarization is accompanied by a
      sustained inhibition of insulin secretion in INS-1 cells. Activation of
      sulphonylurea K+ATP channels is not involved.
AB  - Adrenaline and somatostatin inhibit insulin secretion via pertussis toxin (PTX)
      sensitive mechanisms. Since glucose-stimulated release involves inhibition of ATP
      sensitive K+ (K+ATP) channels and activation of Ca2+ influx, we took advantage of
      the glucose-sensitive, insulin-secreting cell line INS-1 to investigate whether
      inhibitors of insulin release modulate membrane voltage and K+ATP channel
      activity in cell-attached patch-clamp experiments. We found that adrenaline,
      through alpha2-adrenoceptors, and somatostatin counteracted glucose-induced
      depolarization and action potentials. As expected, these effects were mediated
      via PTX-sensitive G proteins since PTX pretreatment of the cells eliminated the
      effects of adrenaline and somatostatin on membrane voltage. When INS-1 cells were
      activated by adding both the K+ATP channel inhibitor tolbutamide and the adenylyl
      cyclase activator forskolin, adrenaline and somatostatin still repolarized the
      plasma membrane. Single-channel measurements in the cell-attached mode revealed
      that tolbutamide closed a 40 to 70 pS K+ channel which was neither reopened by
      adrenaline nor by somatostatin. In parallel cell preparations, insulin secretion
      was measured by radioimmunoassay. Insulin release induced by glucose, forskolin
      and tolbutamide was abolished by adrenaline. In contrast, somatostatin attenuated
      insulin secretion by only 30%. After comparing the potency of adrenaline and
      somatostatin on membrane voltage and on insulin secretion, it is concluded that
      the repolarizing effect of adrenaline on membrane voltage is not sufficient to
      explain its potent inhibitory effect on insulin secretion.

PMID- 8662273
TI  - Evidence for vacuolar-type proton pumps in nonmitochondrial and inositol 1,4,5
      trisphosphate-sensitive calcium stores of insulin-secreting cells.
AB  - This study examines whether acidic, vacuolar-type, proton-pump-carrying
      organelles of insulin-secreting cells (clonal endocrine pancreatic cell line INS
      1) function as rapidly exchanging, inositol 1,4,5-trisphosphate-sensitive calcium
      stores. Calcium uptake into calcium stores will be modulated by the proton
      concentration within the stores, since calcium pumps in general appear to mediate
      a countertransport of calcium with protons. We therefore tested for sensitivity
      of calcium sequestration by nonmitochondrial stores (inhibition of mitochondrial
      calcium uptake by 2 microM ruthenium red) in saponin-permeabilized cells to
      proton-conducting ionophores and proton pump inhibition, using this as a marker
      for involvement of acidic organelles. Calcium sequestration was partially
      inhibited by the protonophores nigericin (10-50 microM) and carbonylcyanide m
      chlorophenylhydrazone (CCCP; 20-50 microM), as well as by inclusion of 30 mM
      NH4Cl. Bafilomycin A1, a potent and selective inhibitor of vacuolar-type proton
      pumps, alone (1 - 500 nM) had no effect on calcium sequestration. however, it
      induced an inhibitory effect in the presence of nigericin or CCCP, even at low
      concentrations (5 microM) of these ionophores, lacking itself an inhibitory
      action on calcium sequestration. Bafilomycin A1 then was already maximally active
      at a concentration as low as 10 nM. Corres ponding to inhibition of total
      nonmitochondrial calcium sequestration, filling of inositol 1,4,5-trisphosphate
      sensitive stores was decreased or even abolished by the protonophores alone or
      the protonophores combined with bafilomycin A1. We conclude that vacuolar-type
      proton pumps are present in at least a part of nonmitochondrial and inositol
      1,4,5-trisphosphate-sensitive calcium stores in INS-1 cells. This assigns these
      stores to organelles such as secretory granules, the trans Golgi network, or
      endosomes. Luminal acidity of these stores will stimulate calcium sequestration
      by providing more protons for countertransport of calcium by calcium pumps. High
      concentrations of protonophores may be required for inhibitory effects because
      otherwise the proton pumps may be able to compensate sufficiently for ionophore
      mediated proton loss. The lack of effect of bafilomycin A1 without protonophores
      may be due to a sufficient luminal buffering capacity or to preceding inhibition
      of the pump by an inside-positive transmembrane potential.

PMID- 8662274
TI  - Presence of two Ca2+ influx components in internal Ca2+-pool-depleted rat parotid
      acinar cells.
AB  - The molecular mechanism(s) involved in mediating Ca2+ entry into rat parotid
      acinar and other non-excitable cells is not known. In this study we have examined
      the kinetics of Ca2+ entry in fura-2-loaded parotid acinar cells, which were
      treated with thapsigargin to deplete internal Ca2+ pools (Ca2+-pool-depleted
      cells). The rate of Ca2+ entry was determined by measuring the initial increase
      in free cytosolic [Ca2+] ([Ca2+]i) in Ca2+-pool-depleted, and control
      (untreated), cells upon addition of various [Ca2+] to the medium. In untreated
      cells, a low-affinity component was detected with KCa = 3. 4 +/- 0.7 mM (where
      KCa denotes affinity for Ca2+) and Vmax = 9.8 +/- 0.4 nM [Ca2+]i /s. In
      thapsigargin-treated cells, two Ca2+ influx components were detected with KCa
      values of 152 +/- 79 microM (Vmax = 5.1 +/- 1.9 nM [Ca2+]i/s) and 2.4 +/- 0.9 mM
      (Vmax = 37.6 +/- 13.6 nM [Ca2+]i/s), respectively. We have also examined the
      effect of Ca2+ and depolarization on these two putative Ca2+ influx components.
      When cells were treated with thapsigargin in a Ca2+-free medium, Ca2+ influx was
      higher than into cells treated in a Ca2+-containing medium and, while there was a
      46% increase in the Vmax of the low-affinity component (no change in KCa), the
      high-affinity component was not clearly detected. In depolarized Ca2+-pool
      depleted cells (with 50 mM KCl in the medium) the high-affinity component was
      considerably decreased while there was an apparent increase in the KCa of the low
      affinity component, without any change in the Vmax. These results demonstrate
      that Ca2+ influx into parotid acinar cells (1) is increased (four- to five-fold)
      upon internal Ca2+ pool depletion, and (2) is mediated via at least two
      components, with low and high affinities for Ca2+.

PMID- 8662275
TI  - Whole-cell conductive properties of rat pancreatic acini.
AB  - Acetylcholine-controlled exocrine secretion by pancreatic acini has been
      explained by two hypotheses. One suggests that NaCl secretion occurs by secondary
      active secretion as has been originally described for the rectal gland of Squalus
      acanthias. The other is based on a "push-pull" model whereby Cl- is extruded
      luminally and sequentially taken up basolaterally. In the former model Cl- uptake
      is coupled to Na+ and basolateral K+ conductances play a crucial role, in the
      latter model, Na+ uptake supposedly occurs via basolateral non-selective cation
      channels. The present whole-cell patch-clamp studies were designed to further
      explore the conductive properties of rat pancreatic acini. Pilot studies in
      approximately 300 cells revealed that viable cells usually had a membrane voltage
      (Vm) more hyperpolarized than -30 mV. In all further studies Vm had to meet this
      criterion. Under control conditions Vm was -49 +/- 1 mV (n = 149). The fractional
      K+ conductance (fK) was 0.13 +/- 0.1 (n = 49). Carbachol (CCH, 0.5 micromol/l)
      depolarized to -19 +/- 1.1 mV (n = 63) and increased the membrane conductance
      (Gm) by a factor of 2-3. In the seeming absence of Na+ [replacement by N-methyl-D
      glucamine (NMDG+)] Vm hyperpolarized slowly to -59 +/- 2 mV (n = 90) and CCH
      still induced depolarizations to -24 +/- 2 mV (n = 34). The hyperpolarization
      induced by NMDG+ was accompanied by a fall in cytosolic pH by 0.4 units, and a
      very slow and slight increase in cytosolic Ca2+. fK increased to 0.34. The effect
      of NMDG+ on Vm was mimicked by the acidifying agents propionate and acetate (10
      mmol/l) added to the bath. The present study suggests that fK makes a substantial
      contribution to Gm under control conditions. The NMDG+ experiments indicate that
      the non- selective cation conductance contributes little to Vm in the presence of
      CCH. Hence the present data in rat pancreatic acinar cells do not support the
      push-pull model.

PMID- 8662276
TI  - Influence of cold and hot conditions on postactivation in human skeletal muscles.
AB  - The influence of cold (+5 degrees C), room temperature (+22 degrees C) and hot
      (+75 degrees C) air exposures on postactivation effects (PAE) in brachial biceps
      (BBs) and triceps (TBs) muscles were investigated bilaterally in six male
      subjects. PAE were evoked by 1 min volitional isometric contraction (VIC) at
      submaximal level in BBs by holding an inertial weight by palms, with right-angled
      elbows. At room temperature, average EMG during PAE (PAEav) usually was 2-4% and
      the integral of EMG (PAEint) was 3-7% of that of VIC respectively. PEA duration
      was 1-6 min. Cold exposure evoked an approximately two-fold increase of PAEint (P
      < 0.01). Hot exposure decreased PAEint (P < 0.01) and shortened PAE duration by
      approximately 50% (P < 0.01). In two subjects, long- term modulation of EMG
      intensity during PAE was observed. Cold increased the frequency and amplitude of
      these waves, while heat decreased them. In two subjects, alternation of BBs and
      TBs in EMG activity during PAE was observed. The data obtained suggest that
      postactivation of muscles strongly depends on the environmental temperature.

PMID- 8662277
TI  - Effect of alkalinization of cytosolic pH by amines on intracellular Ca2+ activity
      in HT29 cells.
AB  - The effect of secondary, tertiary and quaternary methyl- and ethylamines on
      intracellular pH (pHi) and intracellular Ca2+ activity ([Ca2+]i) of HT29 cells
      was investigated microspectrofluorimetrically using pH- and Ca2+- sensitive
      fluorescent indicators, [i.e. 2', 7'-biscarboxyethyl-5(6)-carboxyfluorescein
      (BCECF) and fura-2 respectively]. Membrane voltage (Vm) was studied by the patch
      clamp technique. Secondary and tertiary amines led to a rapid and stable
      concentration-dependent alkalinization which was independent of their pKa value.
      Trimethylamine (20 mmol/l) increased pHi by 0.78 +/- 0.03 pH units (n = 9) and pH
      remained stable for the application time. Removal led to an undershoot of pHi and
      a slow and incomplete recovery: pHi stayed 0.26 +/- 0.06 pH units more acid than
      the resting value. The quaternary amines, tetramethyl- and tetraethylamine were
      without influence on pHi. All tested secondary and tertiary amines (dimethyl-,
      diethyl-, trimethyl-, and triethyl-amine) induced a [Ca2+]i transient which
      reached a peak value within 10-25 s and then slowly declined to a [Ca2+]i
      plateau. The initial Delta[Ca2+]i induced by trimethylamine (20 mmol/l) was 160
      +/- 15 nmol/l (n = 17). The [Ca2+]i peak was independent of the Ca2+ activity in
      the bath solution, but the [Ca2+]i plateau was significantly lower under Ca2+
      free conditions and could be immediately interrupted by application of CO2 (10%;
      n = 6), a manoeuvre to acidify pHi in HT29 cells. Emptying of the carbachol- or
      neurotensin-sensitive intracellular Ca2+ stores completely abolished this [Ca2+]i
      transient. Tetramethylamine led to higher [Ca2+]i changes than the other amines
      tested and only this transient could be completely blocked by atropine (10(-6)
      mol/l). Trimethylamine (20 mmol/l) hyperpolarized Vm by 22.5 +/- 3.7 mV (n = 16)
      and increased the whole-cell conductance by 2.3 +/- 0.5 nS (n = 16). We conclude
      that secondary and tertiary amines induce stable alkaline pHi changes, release
      Ca2+ from intracellular, inositol-1,4, 5-trisphosphate-sensitive Ca2+ stores and
      increase Ca2+ influx into HT29 cells. The latter may be related to both the store
      depletion and the hyperpolarization.

PMID- 8662278
TI  - Functional characterization of two 5-HT3 receptor splice variants isolated from a
      mouse hippocampal cell line.
AB  - Two splice variants of the ligand-gated 5-hydroxytryptamine or serotonin 5-HT3
      receptor that differ in a six-amino-acid deletion were cloned by polymerase chain
      reaction from the hippocampus x neuroblastoma cell line HN9.10e. When expressed
      in Xenopus oocytes, both variants individually formed 5-HT3 receptors that
      revealed no significant differences in current responses to the agonists 5-HT and
      1-phenylbiguanide and block by the specific antagonist LY-278, 584-maleate. For
      both receptors, the monovalent cations Na+, K+, Rb+ and Li+ showed the same
      relative permeability; NH4(+)permeated approximately 2.7 times better than Na+,
      and Tris+ was only poorly permeable. In contrast to other reports, the receptors
      were completely and reversibly blocked by extracellular Cs+ in both oocytes and
      native HN9.10 cells. Moreover, Ca2+ was not permeant and exhibited a
      concentration-dependent decrease (0.9-18 mM) of the 5-HT-induced currents without
      affecting the inward rectification of the current/voltage relation. The two
      receptors were reversibly inhibited by nanomolar concentrations of the specific
      inhibitor of protein kinase C (PKC) bisindolylmaleimide, but not by the
      equipotent and less specific inhibitor staurosporine. A regulatory effect on both
      5-HT3 receptor subunits by PKC-mediated protein phosphorylation might be
      possible, however, a functional role of the two splice variants present in one
      cell remains to be determined.

PMID- 8662280
TI  - Regulation of the purified Ca2+ release channel/ryanodine receptor complex of
      skeletal muscle sarcoplasmic reticulum by luminal calcium.
AB  - 45Ca2+ flux and single channel measurements have related that the Ca2+ release
      channel/ryanodine receptor complex of striated muscle is regulated by micromolar
      cytoplasmic Ca2+. The effect of luminal Ca2+, however, remains controversial. In
      the experiments presented here, we reconstituted the isolated Ca2+ release
      channel of rabbit skeletal muscle sarcoplasmic reticulum into planar lipid
      bilayers in the presence of symmetrical K+ solutions. Using K+ as the charge
      carrier, we were able to examine the effect of changes in luminal calcium in the
      micro- to millimolar range. In the presence of activating cytoplasmic Ca2+, the
      release channel was activated and inactivated in a concentration-dependent manner
      by luminal Ca2+. Since increasing cytoplasmic EGTA concentrations shifted the
      dependence of channel open probability on luminal Ca2+ to higher Ca2+
      concentrations, it is suggested that luminal Ca2+ exerts ist regulating effect by
      acting on Ca2+ binding sites accessible from the cytoplasmic side of the channel.

PMID- 8662279
TI  - Adenine nucleotides and intracellular Ca2+ regulate a voltage-dependent and
      glucose-sensitive potassium channel in neurosecretory cells.
AB  - Effects of membrane potential, intracellular Ca2+ and adenine nucleotides on
      glucose-sensitive channels from X organ (XO) neurons of the crayfish were studied
      in excised inside-out patches. Glucose- sensitive channels were selective to K+
      ions; the unitary conductance was 112 pS in symmetrical K+, and the K+
      permeability (PK) was 1.3 x 10(-13) cm x s(-1). An inward rectification was
      observed when intracellular K+ was reduced. Using a quasi-physiological K+
      gradient, a non-linear K+ current/voltage relationship was found showing an
      outward rectification and a slope conductance of 51 pS. The open-state
      probability (Po) increased with membrane depolarization as a result of an
      enhancement of the mean open time and a shortening of the longer period of
      closures. In quasi-physio- logical K+ concentrations, the channel was activated
      from a threshold of about -60 mV, and the activation midpoint was -2 mV. Po
      decreased noticeably at 50 microM internal adenosine 5'-triphosphate (ATP), and
      single-channel activity was totally abolished at 1 mM ATP. Hill analysis shows
      that this inhibition was the result of simultaneous binding of two ATP molecules
      to the channel, and the half-blocking concentration of ATP was 174 microM.
      Internal application of 5'-adenylylimidodiphosphate (AMP-PNP) as well as
      glibenclamide also decreased Po. By contrast, the application of internal ADP
      (0.1 to 2 mM) activated this channel. An optimal range of internal free Ca2+ ions
      (0.1 to 10 microM) was required for the activation of this channel. The glucose-
      sensitive K+ channel of XO neurons could be considered as a subtype of ATP
      sensitive K+ channel, contributing substantially to macroscopic outward current.

PMID- 8662282
TI  - Contractile properties of rat soleus motor units following 14 days of hindlimb
      unloading.
AB  - The purpose of this study was to compare the isometric contractile properties of
      rat soleus motor units after 14 days of hindlimb unloading (HU) to those under
      control conditions. The motor units (MU) were classified using two mechanical
      criteria: the presence or not of a sag during unfused tetani and the value of the
      twitch time-to-peak (TTP). Under control conditions, the soleus muscle was
      composed of 85% of slow-type (sag -, TTP > 20 ms) and 15% of fast-type (sag +,
      TTP < 20 ms) units. Following HU, these two populations were still present and
      results showed: (1) large decreases in their maximal tetanic tensions (of -67%
      and -60% for slow- and fast-type, respectively), and (2) changes in their
      relative proportions, i.e. a decrease in the percentage of slow-type units and a
      twofold increase in the percentage of fast-type units were observed. These latter
      changes might be the consequence of a complete transformation of slow-towards
      fast-type units. A third population appeared in the HU solei, 26% of the samples,
      combining the presence of a sag and speed-related properties between those of
      slow- and fast-type units. These slow-intermediate units might come from slow
      units partially transformed into a faster type during HU. Thus the present study
      showed that unloading conditions induced a reorganisation of the soleus motor
      unit profile. The complete or partial transformation of the motor units could be
      related to the changes in the electromyographical activity of the unloaded
      soleus.

PMID- 8662283
TI  - Effects of removal of weight-bearing function on contractility and myosin isoform
      composition in single human skeletal muscle cells.
AB  - The purpose of this study was to investigate the effects of a 6-week period
      without weight bearing, achieved by bed rest, on the contractile behaviour,
      myosin isoform expression and myofibrillar protein content of single human muscle
      fibres. Percutaneous biopsied specimens of the quadriceps muscle were taken from
      three healthy male volunteers before and at the end of the experimental period.
      Maximum force normalised to cross-sectional area (specific tension), maximum
      velocity of unloaded shortening (V0), and myosin heavy chain (MyHC) and light
      chain (MyLC) isoform composition were measured in single membrane-permeabilised
      muscle cells obtained from these specimens. At the end of the experimental
      period, specific tension was reduced (P < 0.001) by 40% and there was a parallel
      decline in myofibrillar protein content per muscle cell volume. V0 did not change
      significantly in response to bed rest when data from all muscle cells were
      pooled. In two of the subjects, however, V0 decreased (P < 0.01-0.001) in muscle
      cells expressing the beta/slow (type I) MyHC isoform, but there was no change in
      fibres expressing type IIA or a combination of type IIA and IIB MyHCs. The
      slowing in type I MyHC fibres was associated with a change in the isoform
      composition of the regulatory MyLC.

PMID- 8662285
TI  - Renal type II Na/Pi-cotransporter is strongly impaired whereas the Na/sulphate
      cotransporter and aquaporin 1 are unchanged in cadmium-treated rats.
AB  - The cellular mechanisms of cadmium (Cd) nephrotoxicity are poorly understood. In
      this study we investigated the cellular causes of the Cd-induced phosphaturia in
      the rat. Compared to controls, Cd-treated rats (2 mg Cd/kg body weight, s.c. for
      14 days) showed a marked polyuria, proteinuria and phosphaturia. As studied by
      the rapid filtration technique in isolated cortical brush-border membrane
      vesicles (BBMV), Na+-gradient-driven uptake of phosphate ([32Pi]) and of [3H]
      glucose were markedly decreased in Cd-treated rats, whereas uptake of sulphate
      ([35S]) remained unchanged. By Western blotting of BBMV proteins and by indirect
      immunocytochemistry in 4-micron thick frozen fixed kidney sections, using an
      antibody against the type II Na/Pi-cotransporter (NaPi-2), we found a diminished
      expression of this protein in the brush-border membrane from Cd-treated rats. How
      ever, the expression of the water channel aquaporin 1, estimated from the
      specific antibody staining in brush-border membranes, remained unchanged by Cd.
      Northern blot analysis showed a strong reduction of 2.7 kb NaPi-2-related mRNA in
      Cd-affected kidneys. Our data indicate that: (1) Cd may reduce reabsorption of Pi
      in proximal tubules by affecting the expression of the functional Na/Pi
      cotransporters in the luminal membrane, and (2) Cd effects on brush-border
      transporters are selective.

PMID- 8662284
TI  - Increased sodium-dependent D-glucose transport in the jejunal brush-border
      membrane of spontaneously hypertensive rat.
AB  - The current studies explore the effect of hypertension on D-glucose transport
      into jejunal brush-border membrane vesicles (BBMV). Spontaneously hypertensive
      rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, as a control group, were
      used. The purity of the BBMV from both groups of animals was validated by the
      finding that the specific activity of brush-border enzyme marker, sucrase, was
      severalfold greater in membrane vesicles compared with corresponding values in
      mucosal homogenate. D-glucose uptake was Na+ dependent in both groups of animals,
      with a transient increase in the intravesicular concentration of D-glucose.
      However, the initial rate and the magnitude of the accumulation of Na+-dependent
      D-glucose was significantly higher in SHR compared with WKY rats. In order to
      investigate the mechanism(s) for the increase in Na+-dependent D-glucose
      transport in SHR, several experiments were performed: (1) an experiment that
      indicated 22Na uptake, as an indicator for Na+ permeability, was similar between
      SHR and WKY rats, (2) kinetic studies that indicated that Vmax values of SHR were
      significantly greater that those of WKY rats. In contrast, similar Km values for
      glucose were found between SHR and WKY rats, (3) Na+-dependent phlorizin binding
      measurements that were not altered by hypertension and (4) a study of the brush
      border membrane lipid composition that showed a significant increase in the free
      cholesterol/phospholipid ratio in SHR. We conclude that altered membrane
      cholesterol content and consequently altered lipid fluidity could be, at least in
      part, responsible for the observed increase in Na+-dependent D-glucose transport
      in SHR.

PMID- 8662286
TI  - Exogenous lysophosphatidylcholine increases non-selective cation current in
      guinea-pig ventricular myocytes.
AB  - Whole cell, patch-clamp studies were performed to examine the effect of
      lysophosphatidylcholine (LPC) on the membrane current in guinea-pig ventricular
      myocytes. The addition of 10 microM LPC to the external solution induced a
      membrane current which had a reversal potential of 0 mV. When Na+, the main
      cation in the external solution, was replaced by either K+, N-methyl-D-glucamine
      (NMG) or 90 mM Ca2+, LPC induced a current with the reversal potential near 0 mV,
      indicating that the current passed through a Ca2+-permeable non-selective cation
      channel. The order of the cationic permeability calculated from the reversal
      potential of the current was Cs+ > K+ > NMG > Na+ > Ca2+. Cl- did not pass
      through the LPC-induced channel. The LPC-induced current was not blocked by Gd3+
      in the external solution, nor by the absence of Ca2+ in the pipette solution. In
      conclusion, LPC induces a Ca2+-permeable non-selective cation channel in guinea
      pig ventricular myocytes.

PMID- 8662288
TI  - Evidence against the association of the sulphonylurea receptor with endogenous
      Kir family members other than KATP in coronary vascular smooth muscle.
AB  - We used whole-cell patch clamp to record inward rectifier (KIR) and ATP-sensitive
      (KATP) K+ currents from pig coronary arterial myocytes. KIR currents were blocked
      by Ba2+ ions with a KD around 3 microM, but were unaffected by 10 microM
      glibenclamide, and only reduced 16% by 100 microM of the sulphonlyurea (n=4). In
      contrast, pinacidil-activated KATP currents were over 1000 times more sensitive
      to glibenclamide, being inhibited with a KD close to 100 nM (n=5). Our findings
      suggest that the sulphonylurea receptor (SUR) in these cells associates with the
      appropriate subunits of the Kir family to form KATP channels, but does not show
      promiscuous association with subunits that form the strong inward rectifier KIR.

PMID- 8662287
TI  - Fast local superfusion technique.
AB  - A system for rapid, local superfusion of cultured neurones and their neurites
      with various different test drugs is elucidated. An area of down to 30 micron
      diameter was superfused with the aid of two micropipettes, one for delivering the
      test solution and the other for its removal. Active removal of solution within
      the deadspace of the delivery pipette guarantees, on the one hand, fast and
      flexible pressure control and, on the other, enables the quick exchange (<1 s) of
      multiple solutions. By increasing the pressure in the superfusion pipette, the
      laminar stream between the pipettes was forced down onto the cell layer. The
      change from bath to superfusion solutions, evaluated by liquid junction potential
      changes, occurs in the order of 1 ms.

PMID- 8662289
TI  - Effect of stretch on calcium channel currents recorded from the antral circular
      myocytes of guinea-pig stomach.
AB  - The effect of membrane stretch on voltage-activated Ba2+ current (IBa) was
      studied in antral circular myocytes of guinea-pig using the whole- cell patch
      clamp technique. The changes in cell volume were elicited by superfusing the
      myocytes with anisosmotic solutions. Hyposmotic superfusate (202 mosmol/l)
      induced cell swelling and increased peak values of IBa at 0 mV (from -406.6 +/-
      45.5 pA to -547.5 +/- 65.6 pA, mean +/- SEM, n = 8) and hyperosmotic superfusate
      (350 mosmol/l) induced cell shrinkage and decreased peak values of IBa at 0 mV
      (to -269.5 +/- 39.1 pA, n = 8). Such changes were reversible and the extent of
      change was dependent on the osmolarity of superfusate. The values of normalized
      IBa at 0 mV were 1.43 +/- 0.04, 1.30 +/- 0.06, 1.23 +/- 0.04, 1.19 +/- 0.04, 1
      and 0. 68 +/- 0.06 at 202, 220, 245, 267, 290 and 350 mosmol/l, respectively (n =
      8). IBa was almost completely blocked by nicardipine (5 microM) under hyposmotic
      conditions. The values of steady-state half-inactivation voltage (-37.7 +/- 3.3
      and -36.5 +/- 2.6 mV, under control and hyposmotic conditions, respectively) or
      the half-activation voltage (-13.6 +/- 2.3 and -13.9 +/- 1.9 mV) of IBa were not
      significantly changed (P > 0.05, n = 6). Cell membrane capacitance was slightly
      increased from 50.00 +/- 2.86 pF to 50.22 +/- 2.82 pF by a hyposmotic superfusate
      (P < 0.05, n = 6). It is suggested that cell swelling increases voltage-operated
      L-type calcium channel current and that such a property is related to the
      response of gastric smooth muscle to mechanical stimuli.

PMID- 8662291
TI  - Two distinct receptors operate the cAMP cascade to up-regulate L-type Ca
      channels.
AB  - Previously we have reported that serotonin's (5-hydroxytryptamine or 5-HT)
      potentiating action on L-type Ca channels is present only in definite neurones
      from pedal ganglia of the mollusc Helix pomatia [Kostyuk PG, Lu kyanetz EA,
      Doroshenko PA (1992) Effects of serotonin and cAMP on calcium currents in
      different neurones of Helix pomatia. Pflugers Arch 420:9-15]. The potentiation is
      mediated by the cAMP second messenger system and is triggered by 5-HT1-like type
      receptors. To understand the physiological and pharmacological significance of
      this phenomenon, we analysed the comparative effects of dopamine (DA) and 5-HT on
      voltage-operated Ca currents (Ica) in isolated, intracellularly perfused H.
      pomatia neurones in whole- cell patch-clamp experiments. Two types of effects of
      DA (1-10 mircoM) and 5-HT (1-10 microM) on Ica were observed in different
      neurones: reversible inhibition (by about 40% and 20% respectively) or reversible
      potentiation (up to 65% and 40% respectively) of current amplitude. Neurones
      insensitive to neurotransmitter application were also observed. Da could induce
      potentiation of ica only in the same neurones that were similarly sensitive to 5
      ht. However, a similar correlation between inhibitory action of neurotransmitters
      on Ica was not observed. The potentiating effects of 5-HT and DA on Ica were not
      additive and were mimicked by intracellular cAMP (100 microM) or 20 microgram/ml
      of the catalytic subunit of protein kinase A. We established that the
      potentiating effects of neurotransmitters were mediated by two distinct
      receptors, as the DA receptor antagonist ergometrin (1 microM) selectively
      inhibited the enhancement of Ica by DA and did not affect the action of 5-HT in
      the same cell. A similar specificity was observed for the dopaminergic compound,
      5-chlortryptamine (10 microM), whereas the classical neuroleptic fluphenazine (10
      microM) effectively blocked the 5-HT-evoked effect without significantly changing
      the action of DA. Methiothepin, an antagonist of 5-HT1 and 5-HT2 receptors,
      blocked both 5-HT-and DA-evoked effects. The results point out a possible
      convergence of the two different receptors (5-HT1-like and D1) on the same cAMP
      dependent system of phosphorylation in the up-regulation of L-type Ca channel
      activity in mollusc neurones.

PMID- 8662290
TI  - Different endothelin receptor subtypes are involved in phospholipid signalling in
      the proximal tubule of rat kidney.
AB  - Phospholipid signalling mediated by endothelin (ET) receptor subtypes was studied
      in the rat proximal tubule. In freshly isolated proximal tubule cells, ET-1, ET-2
      and sarafotoxin S6c (S6c) evoked an increase in 1,2-diacylglycerol (DAG),
      inositol 1,4,5-trisphosphate (InsP3) and phosphocholine (PCho), suggesting
      stimulation of both phosphatidyl-inositol 4,5-bisphosphate- and phosphatidyl
      choline-specific phospholipase C (PLC), while ET-3 increased only DAG and PCho,
      presumably via phosphatidyl-choline-dependent PLC. Renal cortical slices were
      also stimulated by the above-mentioned agonists, followed by isolation of either
      brush border (BBM) or basolateral (BLM) membranes for which mass measurements of
      inositol lipids and DAG were performed. In BBM, DAG increased in response to ET
      1, ET-2 and ET-3, and was followed by protein kinase C (PKC) translocation to the
      BBM, while in BLM, DAG formation and translocation of PKC were observed only in
      response to ET-3, suggesting spatial segregation of signalling systems between
      two membane domains of proximal tubule cells. Tyrphostine, pertussis toxin (PTX)
      or cholera toxin (CTX) did not influence ET-mediated signalling in either of the
      membranes, suggesting involvement of PTX- and CTX-insensitive G-protein-mediated
      stimulation of PLCbeta by ET receptors. ET-dependent stimulation of PLC in BBM
      and BLM was used as a tool to examine the presence of different ET receptor
      subtypes in these two cell membrane domains. BQ123, an inhibitor of ETA
      receptors, did not prevent ET-1-mediated signalling in BBM, but an ETA,B
      antagonist, bosentan, inhibited ET-3-mediated signalling in BBM. In addition, an
      ETB agonist, S6c, stimulated PLC in BBM. Neither BQ123 nor bosentan inhibited ET
      3 signalling in BLM. Therefore, these data strongly suggest the presence of ETB
      receptors coupled to phosphatidyl-inositol 4,5-bisphosphate- and phosphatidyl
      choline-dependent PLC in BBM and ETC receptors linked to phosphatidyl-choline
      dependent PLC in BLM.

PMID- 8662292
TI  - Role of perfusate hydrogen ion activity in kallikrein release from isolated rat
      kidneys.
AB  - The present experiments were performed to investigate whether renal kallikrein
      release by isolated perfused rat kidneys correlates with acid-base-related
      parameters. Kallikrein excretion per millilitre of glomerular filtrate was
      inversely correlated with perfusate pH (r = -0.49, P < 0.001) and HCO3-
      concentration (r = -0.46, P < 0.005). A direct relationship between kallikrein
      excretion per millilitre of glomerular filtrate and urinary Na+/K+ ratio was
      found (r = 0.59, P < 0.001). Some 86% of the variability (F ratio 110, P <
      0.00001) of urinary kallikrein activity was attributable to the perfusate pH and
      the urinary cation ratio. Therefore, urinary kallikrein activity was highly
      correlated with perfusate H+ activity corrected by the urinary Na+/K+ ratio (r =
      0.92, P < 0.0001). Kallikrein secretion into the distal tubular fluid appears to
      be regulated by blood H+ activity, and modulated by factors that affect the
      distal Na+ and K+ handling. The HCO3 - excretion rate was inversely correlated
      with the urinary kallikrein activity (r = -0.62, P < 0.001). This finding
      confirms previous data from the author's laboratory showing a kallikrein
      involvement in the regulation of HCO3- secretion in rats and rabbits. Kallikrein
      probably transduces the sensing of interstitial fluid H+ activity by the
      connecting tubule cells into an appropriate translocation of HCO3- or H+ to the
      tubular lumen by the intercalated cells.

PMID- 8662293
TI  - Blockade of nitric oxide formation inhibits the stimulation of the renin system
      by a low salt intake.
AB  - This study aimed to investigate the possible involvement of endothelial autacoids
      such as nitric oxide or prostaglandins in the well-known stimulatory effect of a
      low salt intake on renin secretion and renin gene expression in the kidney. To
      this end, plasma renin activity (PRA) and kidney renin mRNA levels were
      determined in male Sprague-Dawley rats fed either a normal (0.6% w/w) or a low
      (0.03%) NaCl diet for 10 days. To inhibit nitric oxide formation, the animals
      received L-nitro-argininemethylester (L-NAME, 40 mg/ kg twice a day), to inhibit
      prostaglandin formation the animals received meclofenamate (8 mg/kg twice a day)
      during the last 2 days. In animals fed a normal salt diet, L-NAME decreased PRA
      from 6.5 to 4.9 ng angiotensin I x h(-1) x ml(-1) and decreased renin mRNA levels
      by about 15%. Meclofenamate did not change PRA or renin mRNA in animals fed on
      normal salt diet. In vehicle-treated animals fed a low salt diet, PRA increased
      from 6.5 to 20.2 ng ANGI x h(-1) x ml(-1) and renin mRNA levels increased by
      100%. Meclofenamate treatment did not alter these changes of PRA and renin mRNA
      during the intake of a low salt diet. In animals treated with L-NAME, PRA
      increased to only 7.2 ng ANGI x h(-1) x ml(-1) and renin mRNA increased by 20%.
      These findings indicate that inhibition of nitric oxide formation but not of
      prostaglandin formation substantially attenuates the stimulatory effect of a low
      salt intake on the renin system, suggesting that nitric oxide is required for
      this process.

PMID- 8662294
TI  - The regulation of GLUT5 and GLUT2 activity in the adaptation of intestinal brush
      border fructose transport in diabetes.
AB  - The adaptation of d-fructose transport in rat jejunum to experimental diabetes
      has been studied. In vivo and in vitro perfusions of intact jejunum with d
      fructose revealed the appearance of a phloretin-sensitive transporter in the
      brush-border membrane of streptozotocin-diabetic rats which was not detectable in
      normal rats. The nature of the transporters involved was investigated by Western
      blotting and by d-fructose transport studies using highly purified brush-border
      and basolateral membrane vesicles. GLUT5, the major transporter in the brush
      border membrane of normal rats, was not inhibited by d-glucose or phloretin. In
      contrast, GLUT2, the major transporter in the basolateral membrane of normal
      rats, was strongly inhibited by both D-glucose and phloretin. In brush-border
      membrane vesicles from diabetic rats, GLUT5 levels were significantly enhanced;
      moreover the presence of GLUT2 was readily detectable and increased markedly as
      diabetes progressed. The differences in stereospecificity between GLUT2 and GLUT5
      were used to show that both transporters contributed to the overall enhancement
      of d-fructose transport measured in brush-border membrane vesicles and in vitro
      isolated loops from diabetic rats. However, overall d-fructose uptake in vivo was
      diminished. The underlying mechanisms and functional consequences are discussed.

PMID- 8662295
TI  - Effect of metabolic alkalosis and metabolic acidosis on urinary kallikrein
      excretion of anaesthetized rats: evidence for a role of blood pH as regulator of
      renal kallikrein secretion.
AB  - The effect of altering the acid-base status on urinary kallikrein excretion of
      barbiturate-anaesthetized rats was investigated. Alkalosis was induced in a group
      of rats by intravenous (i.v.) infusion of NaOH at 0.45 mmol x h(-1) for 30 min.
      Acidosis was induced in two groups of rats by i.v. infusion of HCl at 1.5 mmol x
      h(-1) for 30 min (uncompensated acidosis) or 0.15 mmol x h(-1) for 3 h
      (compensated acidosis), respectively. Time controls received 0.45 mmol x h(-1)
      NaCl. Rats with alkalosis excreted less kallikrein than their controls (P <
      0.05). Rats with uncompensated acidosis excreted more active kallikrein (P <
      0.05), whereas rats with compensated acidosis excreted similar amounts when
      compared with their respective controls. In rats with uncompensated acid-base
      derangements, the urinary kallikrein excreted per millilitre of glomerular
      filtrate was correlated with blood H+ activity (r = 0.99, P < 0.01). Arterial
      blood pressure, haematocrit, glomerular filtration rate, urine flow rate and Na+
      and K+ excretions of experimental and control animals did not differ. Thus, renal
      kallikrein secretion into the tubular fluid appears to be regulated by blood
      proton activity. This, along with our previous demonstration that kallikrein
      inhibits HCO3- secretion into the tubular lumen (Renal Physiol 17:301-306, 1994;
      J Physiol (Lond) 488:163-170, 1995), indicates that this enzyme is part of a
      feedback loop regulating acid-base balance.

PMID- 8662296
TI  - Caffeine-evoked contractures in single slow (tonic) muscle fibres of the frog
      (Rana temporaria and R. esculenta).
AB  - Single slow (tonic) muscle fibres were dissected from cruralis muscles of Rana
      temporaria and R. esculenta. Increasing concentrations of caffeine were applied
      in Ringer solution, and contractures were measured isometrically. Sigmoid
      caffeine concentration-response curves were obtained, the threshold value being
      near 1.2 mmol/l, and maximum contractures being obtained with 10 to 20 mmol/l
      concentrations of caffeine. Contracture solutions were modified by varying the
      Ca2+ concentration or by replacing Ca2+ with 1.8 mmol/l Mg2+, Ni2+, Co2+ or with
      0.1-5.0 mmol/l La3+. The effects of low pH (5.3), K+ (6,10 and 95 mmol/l),
      adenosine (10 mmol/l) and gallopamil (D600; 30 micromol/l) were examined too. The
      caffeine threshold was lowered by Mg2+, K+, 0 .1 mmol/l La3+ and D600, while all
      other substances including 0.5-5.0 mmol/l La3+ increased it. The amplitude of
      contractures evoked by high caffeine concentrations was unaffected. Caffeine (1
      40 mmol/l) was also pressure injected into slow fibres. The composition of the
      solution was modified in a number of ways, but a contractile response was not
      observed or measured. Extracellular application of caffeine from the same
      pipettes evoked local contractures. Similar injection experiments in twitch
      fibres revealed the same results. These observations suggest that an
      extracellular binding site seems to be involved in the initiation of caffeine
      evoked contractures in intact frog muscle fibres. Possible reasons for the
      ineffectiveness of intracellular caffeine are discussed.

PMID- 8662297
TI  - The Fura-2 transient can show two types of voltage dependence at 36 degrees C in
      ventricular myocytes isolated from the rat heart.
AB  - We used the whole-cell patch-clamp method to investigate the voltage dependence
      of the L-type Ca current (ICa,L) and intracellular Ca (Cai) transient in
      ventricular myocytes isolated from the rat heart. Intracellular Ca was monitored
      using Fura-2 and the experiments were carried out at 36 degrees C. We measured
      ICa,L by using a caesium-based internal dialysis solution to eliminate
      interfering K currents. The voltage dependence of peak ICa,L amplitude was bell
      shaped: ICa,L was maximal at +10 mV and declined at more positive potentials.
      When ICa,L was integrated over the first 25 ms to estimate the magnitude of Ca
      entry, this had a very similar voltage dependence to peak ICa,L. In all cells,
      phasic Fura-2 transients were abolished by 5 microM ryanodine (a blocker of the
      sarcoplasmic reticulum, SR) showing that the Fura-2 transient provided an index
      of the magnitude of SR Ca release. For experiments measuring the Cai transient,
      we used a K-based internal dialysis solution to preserve normal excitation
      contraction coupling. In 30-40% of cells, we found that the Fura-2 transient had
      a bell-shaped voltage dependence. This suggests that, in these cells, the primary
      trigger mechanism for Ca-induced Ca-release might have been Ca entry via ICa,L.
      In the remaining 60-70% of cells, the voltage dependence of the Fura-2 transient
      was not bell-shaped. The Fura-2 transient reached a maximum with a pulse to +10
      mV, and the amplitude of the transient did not decline significantly at more
      positive potentials to this. In cells with a non-bell-shaped voltage dependence
      of the Fura-2 transient, pulses to potentials as far positive as +140 mV elicited
      phasic Fura-2 transients. Since this potential exceeded the Nernst potential for
      Ca, it was unlikely there was any trigger Ca entry via ICa,L at this potential.
      This would suggest that, in these cells, another trigger for SR Ca release (in
      addition to ICa,L) might be present. We conclude that rat ventricular myocytes,
      produced using a standard isolation technique and under standard recording
      conditions, can show either a bell-shaped or a sigmoidal voltage dependence of
      the Fura-2 transient.

PMID- 8662298
TI  - Evidence for a rapid, direct effect on epithelial monolayer integrity and
      transepithelial transport in response to Salmonella invasion.
AB  - In cultured monolayers of high-resistance Madin-Darby Canine Kidney (MDCK) cells,
      infection with Salmonella typhimurium SL1344 resulted in a dose- and time
      dependent increase in transepithelial conductance (Gt) and short-circuit current
      (Isc). There was a direct linear relationship between the S. typhimurium-induced
      increments in Isc and Gt suggesting that this early change in epithelial
      parameters is, in part, the result of a cellular conductance change most probably
      at the apical membrane. An additional wild-type S. typhimurium strain, SR11, and
      an invasion-deficient isogenic mutant SB111 carrying a non-polar mutation in invA
      were used to confirm that the S. typhimurium-induced change in epithelial
      electrical parameters is directly linked to the invasion process. The S.
      typhimurium-induced change in epithelial electrical parameters was markedly
      attenuated in Na+-free choline medium. Addition of piretanide (10(-4) M, basal
      side) failed to affect the increased epithelial conductance and Isc after a 40
      min incubation with S. typhimurium. NPPB (5x10(-4) M) added to the apical medium
      reduced the S. typhimurium-stimulated Isc by 28%, but Gt was not significantly
      reduced. It is unlikely that the S. typhimurium-induced Isc is due to Cl-
      secretion. Staining of S. typhimurium-infected MDCK I monolayers with TRITC
      phalloidin revealed marked alterations of F-actin; diffuse intracellular
      accumulations of F-actin corresponding to the presence of invading bacteria were
      observed by 15 min. After 60 min, prominent extrusions of the apical membrane
      corresponding to previously described "membrane ruffles" were noted. Marked
      accumulations of perijunctional F-actin in infected cells corresponded to
      contraction of the perijunctional actin ring at the apical pole. In adjacent
      cells marked distortion and stretch of the apical surface was evident. The
      invasion-deficient invA mutant SB111 failed to induce these morphological
      changes. These data demonstrate that S. typhimurium invasion induces increased
      transcellular conductance which does not result from stimulation of Cl- secretion
      but instead appears to be predominantly due to increased Na+ permeability. The
      increased membrane conductance is coincident with increased transepithelial
      inulin permeability indicating that the increment in Gt has an additional
      "paracellular" component. The S. typhimurium-induced alterations in epithelial
      parameters may be related to "membrane ruffling" and/or to the accompanying
      changes in cell shape.

PMID- 8662299
TI  - Hypotonicity-induced anion fluxes in cells expressing the multidrug-resistance
      associated protein, MRP.
AB  - Anion transport in human multidrug-resistant large cell lung tumour cells (COR
      L23/R) which overexpress the multidrug-resistance-associated protein (MRP) has
      been compared with that in cells of the parent line (COR-L23/P). Whole-cell patch
      clamp recordings reveal variability between individual cells in basal anion
      conductance and in anion conductance increases following exposure to hypotonic
      media. The increase of stimulated over basal conductance is significantly larger
      for resistant cells than for parent cells. The chloride channel blocker,
      diisothiocyanatostilbene-2-2'-disulphonic acid (DIDS), rapidly and reversibly
      inhibits the increase in outward but not inward conductance when applied
      externally at 10(-4) M during recording, but it is without effect when introduced
      into the cells via the patch pipette. Preincubation with DIDS greatly reduces
      both inward and outward conductance. 125I- efflux has been used to measure anion
      movement in cell populations. Basal efflux is similar in the two cell lines, but
      following a hypotonic challenge, the increase in rate constant for efflux from
      COR-L23/R cells is at least double that from COR-L23/P cells. This increase in
      efflux is greatly reduced by incubation with DIDS at 10(-4) M. Replacement of
      external chloride by gluconate does not affect efflux, thus excluding the
      possible involvement of DIDS-sensitive chloride exchange. Results from both
      techniques suggest that DIDS-sensitive, hypotonicity-induced anion channel
      activity is augmented in COR-L23/R multidrug-resistant variant cells which
      overexpress MRP. This augmentation may be caused by MRP itself or by other genes
      coexpressed with MRP.

PMID- 8662300
TI  - The effects of caldesmon extraction on mechanical properties of skinned smooth
      muscle fibre preparations.
AB  - The role of caldesmon in the regulation of smooth muscle contraction was
      investigated in chemically skinned smooth muscle fibres from the guinea-pig
      taenia coli. A 19-kDa C-terminal fragment of caldesmon gave a minor (<5%)
      reduction of force in fully thiophosphorylated fibres, but reduced force by about
      50% at intermediate activation levels without affecting the level of light chain
      phosphorylation. An extraction procedure was developed using incubation in
      solutions containing high Mg2+ concentrations. Protein analysis revealed a
      selective decrease in the amount of caldesmon in the fibres. Maximal active force
      per cross-sectional area was unaffected. The Ca2+ dependence of active force was
      shifted towards lower Ca2+ concentrations and became less steep. The effects of
      extraction of caldesmon could in part be reversed by incubation in a solution
      containing purified caldesmon. The results are consistent with the hypothesis
      that caldesmon in smooth muscle thin filaments inhibits force generation and
      plays a role in regulating cooperative attachment of cross-bridges at sub-maximal
      levels of activation in smooth muscle.

PMID- 8662301
TI  - Calcium channel types contributing to excitatory and inhibitory synaptic
      transmission between individual hypothalamic neurons.
AB  - The contribution of L-, N-, P- and Q-type Ca2+ channels to excitatory and
      inhibitory synaptic transmission and to whole-cell Ba2+ currents through Ca2+
      channels (Ba2+ currents) was investigated in rat hypothalamic neurons grown in
      dissociated cell culture. Excitatory and inhibitory postsynaptic currents (EPSCs
      and IPSCs) were evoked by stimulating individual neurons under whole-cell patch
      clamp conditions. The different types of high-voltage-activated (HVA) Ca2+
      channels were identified using nifedipine, omega-Conus geographus toxin VIA
      (omega-CTx GVIA), omega-Agelenopsis aperta toxin IVA (omega-Aga IVA), and omega
      Conus magus toxin VIIC (omega-CTx MVIIC). N-, but not P- or Q-type Ca2+ channels
      contributed to excitatory as well as inhibitory synaptic transmission together
      with Ca2+ channels resistant to the aforementioned Ca2+ channel blockers
      (resistant Ca2+ channels). Reduction of postsynaptic current (PSC) amplitudes by
      N-type Ca2+ channel blockers was significantly stronger for IPSCs than for EPSCs.
      In most neurons whole-cell Ba2+ currents were carried by L-type Ca2+ channels and
      by at least two other Ca2+ channel types, one of which is probably of the Q-type
      and the others are resistant Ca2+ channels. These results indicate a different
      contribution of the various Ca2+ channel types to excitatory and inhibitory
      synaptic transmission and to whole-cell currents in these neurons and suggest
      different functional roles for the distinct Ca2+ channel types.

PMID- 8662303
TI  - The effects of oxygenation upon the Cl-dependent K flux pathway in equine red
      cells.
AB  - The effects of oxygen tension (PO2) upon the K influx pathways of equine red
      cells have been studied using 86Rb+ as congener for K. Equilibration of cells in
      100% nitrogen led to a low and Cl-independent K flux. Change to an atmosphere of
      100% air led to a rapid sixfold increase in K flux. The oxygen-activated flux was
      entirely Cl dependent and was maintained for up to 3 h. Oxygenation-evoked
      activation was dependent upon PO2 over the physiological range with little effect
      up to 70% saturation of haemoglobin with oxygen but significant effects between
      70 and 100%. K flux at low PO2 was unaffected by acidification to pH 7 or by
      hypotonic cell swelling. By contrast, at high PO2 both manipulations caused a
      substantial increase in Cl-dependent K flux. N-Ethylmaleimide (NEM; 1 mM) caused
      a progressive activation of KCl cotransport in cells held under nitrogen. The
      protein phosphatase inhibitor, calyculin A (100 nM), applied during NEM-evoked
      activation caused a "clamping" of K influx at that level. This "clamped" activity
      was unaffected by subsequent oxygenation. We conclude that oxygenation exerts a
      primary control over cotransport activity and that acidification and cell
      swelling are secondary modulators. It appears that oxygenation-evoked activation
      of the Cl-dependent K flux involves a serine/threonine phosphorylation event.
      Regulating the PO2 of the solution before and during experiments is important in
      controlling the activity of the KCl cotransporter and cell volume.

PMID- 8662302
TI  - Calcium- and barium-dependent exocytosis from the rat insulinoma cell line RINm5F
      assayed using membrane capacitance measurements and serotonin release.
AB  - Electrophysiological measurements of cell capacitance (Cm) and biochemical assays
      of [3H] serotonin ([3H]5-hydroxytryptamine or [3H]5-HT) release were combined to
      study the control of secretion in rat insulinoma RINm5F cells. Depolarizing
      pulses produced Cm changes (DeltaCm), indicative of exocytosis, with the same
      voltage and Ca2+ dependency as the inward Ca2+ currents (ICa). Ba2+ was able to
      substitute for Ca2+ in stimulating exocytosis, but not endocytosis. However, both
      the relative potency and kinetics of Ca2+-versus Ba2+-triggered exocytosis
      differed significantly. 5-HT synthesis and uptake were demonstrated in RINm5F
      cells. This allowed the use of [3H]5-HT to study hormone release from cell
      populations. [3H]5-HT was released in a depolarization-, Ca2+- and time-dependent
      manner. Ba2+ also substituted for Ca2+ in depolarization-induced [3H]5-HT
      release. Thapsigargin, used to deplete Ca2+ stores, had no effects on Ca2+
      triggered Cm increases, but Ca2+-triggered [3H]5-HT release was abolished. Ba2+
      triggered [3H]5-HT release, however, was only slightly affected by Ca2+ store
      depletion. Ba2+ was found to act directly as a secretagogue of [3H]5-HT in intact
      cells, but not in Cm measurements of voltage-clamped cells, suggesting that cell
      depolarization is a prerequisite for this action.

PMID- 8662304
TI  - Calcium influx pathways in rat pancreatic ducts.
AB  - A number of agonists increase intracellular Ca2+ activity, [Ca2+]i, in pancreatic
      ducts, but the influx/efflux pathways and intracellular Ca2+ stores in this
      epithelium are unknown. The aim of the present study was to characterise the Ca2+
      influx pathways, especially their pH sensitivity, in native pancreatic ducts
      stimulated by ATP and carbachol, CCH. Under control conditions both agonists led
      to similar changes in [Ca2+]i. However, these Ca2+ transients, consisting of peak
      and plateau phases, showed different sensitivities to various experimental
      manoeuvres. In extracellular Ca2+-free solutions, the ATP-induced [Ca2+]i peak
      decreased by 25%, but the CCH-induced peak was unaffected; both plateaus were
      inhibited by 90%. Flufenamate inhibited the ATP-induced peak by 35%, but not the
      CCH-evoked peak; the plateaus were inhibited by 75-80%. La3+ inhibited the ATP
      induced plateau fully, but that induced by CCH by 55%. In resting ducts, an
      increase in extracellular pH, pHe, by means of HEPES and HCO3-/CO2 buffers,
      increased [Ca2+]i; a decrease in pHe had the opposite effect. In stimulated ducts
      the pH-evoked effects on Ca2+ influx were more pronounced and depended on the
      agonist used. At pHe 6.5 both ATP- and CCH-evoked plateaus were inhibited by
      about 50%. At pH 8.0 the ATP-stimulated plateau was inhibited by 27%, but that
      stimulated by CCH was increased by 72%. Taken together, we show that CCH
      stimulates Ca2+ release followed by Ca2+ influx that is moderately sensitive to
      flufenamate, La3+, depolarisation, it is inhibited by low pH, but stimulated by
      high pH. ATP stimulates Ca2+ release and probably an early Ca2+ influx, which is
      more markedly sensitive to flufenamate and La3+, and is both inhibited by low and
      high pH. Thus our study indicates that there are at least two separate Ca2+
      influx pathways in pancreatic ducts cells.

PMID- 8662305
TI  - Capacitative calcium entry is colocalised with calcium release in Xenopus
      oocytes: evidence against a highly diffusible calcium influx factor.
AB  - Depletion of intracellular calcium stores activates the plasma membrane
      capacitative calcium entry pathway in many cell types. The nature of the signal
      that couples the depletion of the intracellular calcium stores to the activation
      of the plasma membrane calcium influx pathway is as yet unknown. It has recently
      been suggested that a highly diffusible calcium influx factor is involved in the
      activation of capacitative calcium entry, and that its action is potentiated by
      the protein phosphatase inhibitor okadaic acid. Depletion of intracellular
      calcium stores in a localised region of a Xenopus oocyte was found to evoke
      capacitative calcium entry exclusively colocalised across the stimulated area of
      the plasma membrane, arguing against the involvement of a highly diffusible
      calcium influx factor. Equally, no evidence could be found for the presence of a
      soluble calcium influx factor in the bulk cytosol of Xenopus oocytes. The
      potentiation of capacitative calcium entry by okadaic acid resembled that
      mediated by the activation of protein kinase C, thus suggesting that okadaic acid
      activity may not necessarily be related to the action of a putative calcium
      influx factor.

PMID- 8662306
TI  - Segmental heterogeneity of swelling-induced Cl- transport in rat small intestine.
AB  - The effect of cell swelling induced by hypotonic media was studied in segments of
      rat small intestine. In the Ussing chamber, exposure to a hypotonic medium caused
      a decrease in short-circuit current (Isc) and potential difference (Vms) in the
      jejunum, whereas the ileum responded with an increase in Isc and Vms. The
      transition from one pattern to the other was located about in the middle of the
      small intestine. Tissue conductance decreased in both segments, probably due to a
      reduction of paracellular shunt conductance induced by the cell swelling. Voltage
      scanning experiments revealed that the observed decrease in total tissue
      conductance in the ileum was caused solely by a decrease in local conductance in
      the villus region while the crypt conductance did not change, suggesting that the
      decrease in paracellular conductance of the crypts is compensated by an increase
      in cellular conductance. The response in both segments was dependent on the
      presence of Cl- and was blocked by the Cl- channel blocker 5-nitro-2-(3
      phenylpropylamino)-benzoate (NPPB). It was not affected by the neurotoxin
      tetrodotoxin. In the jejunum the swelling-induced decrease in Isc was reduced in
      the presence of the cyclooxygenase inhibitor, indomethacin, or the lipoxygenase
      inhibitor, nordihydroguaiaretic acid. In the ileum the Cl- secretion induced by
      hypotonicity was blocked by the K+ channel blocker quinine and was reversed into
      a decrease in Isc when serosal Ca2+ was zero. We conclude that the observed
      volume regulatory changes are initiated in the jejunum by an eicosanoid-mediated
      opening of basolateral Cl- channels and in the ileum by a Ca2+-mediated opening
      of K+ channels which enhances apical Cl- efflux.

PMID- 8662353
TI  - Ultrastructural and cytochemical study of the Golgi complex of molluscan (Mytilus
      galloprovincialis) digestive cells
AB  - The present study has been performed to investigate the ultrastructure and
      subcellular distribution of several marker enzymes within the Golgi complex of
      digestive cells of the mussel, Mytilus galloprovincialis. This cell type is
      involved in the intracellular digestion of food and contains a well-developed
      lysosomal-vacuolar system and a characteristic cup-shaped Golgi complex. The
      number and degree of compaction of the tubulo-filamentous structures extending
      across the distended regions of the cisternae, the number of Golgi stacks per
      cell and the number of cisternae per stack vary with season and nutritional
      status of the animals. The degree of compaction of the tubulo-filamentous
      structures defines the cis- and trans-portions of the Golgi apparatus, the less
      compacted structures being associated with the cis-portion. Acid phosphatase and
      arylsulphatase activities are located within some tubules and vesicles in the
      trans-Golgi network and in some membrane-bounded organelles comprising the
      lysosomal-vacuolar system. The tubulo-filamentous structures of the dilated rims
      are reactive for arylsulphatase activity only when located in the trans-portion.
      Osmium impregnation techniques label all the cisternae of the Golgi complex. No
      nicotinamide adenine dinucleotide phosphatase activity is present in Golgi bodies
      or other associated structures in digestive cells. Thiamine pyrophosphatase
      activity only rarely occurs in some elongate tubules that are interpreted as
      belonging to trans-cisternae.

PMID- 8662354
TI  - Ultrastructural evidence for transepithelial calcium transport in the anterior
      sternal epithelium of the terrestrial isopod Porcellio scaber (Crustacea) during
      the formation and resorption of CaCO3 deposits
AB  - Before the molt, terrestrial isopods store large amounts of calcium carbonate
      between the epithelium and the old cuticle of the first four anterior sternites.
      In order to test whether the anterior sternal epithelium has specific structural
      differentiations indicative of transepithelial ion transport, the anterior
      sternal epithelium and, as a control, the posterior sternal epithelium were
      studied using electron-microscopical techniques. During the formation of calcium
      carbonate deposits, the basolateral plasma membrane of the anterior sternal
      epithelium forms an elaborate interconnected network of interstitial dilations
      and channels. Numerous osmiophilic granules occur within this basolateral
      intercellular network during resorption of the calcium carbonate deposits.
      Electron energy-loss spectroscopy of the osmiophilic granules indicates that they
      contain calcium. During the resorption of the calcium carbonate deposits, the
      apical plasma membrane of the anterior sternal epithelium has many subcuticular
      folds. An interstitial network, osmiophilic granules, and apical, subcuticular
      folds do not occur in the posterior sternal epithelium. Taken together, these
      structural features are indicative of transepithelial ion transport and are
      probably necessary for the formation and resorption of the anterior sternal
      calcium carbonate deposits.

PMID- 8662307
TI  - Extracellular Mg2+ regulates activation of rat eag potassium channel.
AB  - The rat homologue of Drosophila ether a gogo cDNA (rat eag) encodes voltage
      activated potassium (K) channels with distinct activation properties. Using the
      Xenopus expression system, we examined the importance of extracellular Mg2+ on
      the activation of rat eag. Extracellular Mg2+ at physiological concentrations
      dramatically slowed the activation in a dose- and voltage-dependent manner. Other
      divalent cations exerted similar effects on the activation kinetics that
      correlated with their enthalpy of hydration. Lowering the external pH also
      resulted in a slowing of the activation. Protons competed with Mg2+ as the effect
      of Mg2+ was abolished at low pH. A kinetic model for rat eag activation was
      derived from the data indicating that all four channel subunits undergo a Mg2+
      dependent conformational transition prior to final channel activation. The strong
      dependence of rat eag activation on both the resting potential and the
      extracellular Mg2+ concentration constitutes a system for fine-tuning K channel
      availability in neuronal cells.

PMID- 8662355
TI  - Immunolocalization of cytoskeletal proteins in the previtellogenic ovarian
      follicle of the lizard Podarcis sicula
AB  - We report the immunolocalization of intermediate filament proteins (vimentin and
      cytokeratins) in the previtellogenic ovarian follicle of the lizard Podarcis
      sicula. Vimentin is present, in accordance with their mesenchymal origin, in all
      the cells of the polymorphic follicular epithelium (small, intermediate and
      pyriform). Cytokeratin, absent from the small follicle cells, is present in those
      cells (intermediate and pyriform) connected to the oocyte by an intercellular
      bridge. In particular, this protein surrounds the nucleus in the pyriform cells
      and is mainly localized at the apex adjacent to the oocyte surface; it forms a
      network, that crosses the zona pellucida through the intercellular bridge and
      appears to be continuous with a cortical ring of cytokeratin in the oocyte. The
      presence of a cytokeratin cytoskeleton in the pyriform cells in continuity with
      that of the oocyte lends support to the previously reported hypothesis that,
      during oogenesis in Podarcis sicula, somatic cells constitute an integral system
      with the germ cell and provide for its growth. Preliminary observations
      indicating the presence of actin and tubulin inside the cytoplasmic bridges
      connecting the pyriform cells to the oocyte are in agreement with an involvement
      of these connections in the transfer of cytoplasmic materials.

PMID- 8662356
TI  - Immunoreactive localization of vasoactive hormones (atrial natriuretic peptide
      and endothelin) in the heart of Protopterus annectens, an African lungfish
AB  - The present study demonstrated, by immunohistochemistry and Western blotting, the
      presence of immunoreacting atrial natriuretic peptide (ANP) and endothelin in the
      heart of Protopterus annectens by both light and electron microscopy. The
      distribution of ANP granules was investigated. ANP granules were localised in
      myocytes from the atrium, ventricle and conus arteriosus; endothelin-1 (ET-1) was
      demonstrated in subendocardial myocytes of the atrium and the conus. No ET-1
      immunoreactivity was observed in the ventricle wall. At the light-microscopical
      level, ET-1 appeared to occur in the endocardium, but at the electron
      microscopical level no immunogold labelling was seen on the granules of the
      endocardial cells. It is suggested that ET-1 is produced and stored in the
      subendocardial cells and released into the subendocardial space to reach the ANP
      producing myocytes and the endothelial cells.

PMID- 8662396
TI  - Results of endoscopic retroperitoneal adrenalectomy.
AB  - BACKGROUND: From March 1994 to August 1995 we performed extraperitoneal
      endoscopic adrenalectomy in 18 patients with adrenal gland tumors. METHODS: Two
      of these patients underwent bilateral adrenalectomy. For the extraperitoneal
      approach a pneumoretroperitoneum was established and three 10-mm trocars were
      inserted in the area of the conventional flank incision. Adrenalectomy was
      performed via these ports. Endoscopic retroperitoneal adrenalectomy was
      successful in 15 patients; three patients required a conventional operation via
      an extraperitoneal lumbar approach because of inadequate exposure of the adrenal
      gland. In patients with endoscopic retroperitoneal adrenalectomy median operative
      time amounted to 180 min (95-330). RESULTS: No postoperative complications were
      observed; median postoperative hospital stay was 5 days (3-12). CONCLUSIONS: The
      described approach produces rapid recovery and creates less postoperative pain.

PMID- 8662397
TI  - No surgeon he. John C. Ruddock, M.D., F.A.C.P., pioneer in laparoscopy.

PMID- 8662398
TI  - Ultrasonography in the management of acute appendicitis.
AB  - BACKGROUND: Ultrasonography (US) shows promise in the diagnosis of acute
      appendicitis. METHODS: The authors present their own experience in
      ultrasonography (US) employed in the diagnosis of appendicitis, based on 40
      patients admitted to the Department of Surgery of the University of Perugia.
      RESULTS: US was found to be easily obtainable and reliable; it had good
      specificity and sensitivity, was not very time consuming, and had a good
      cost/benefit ratio. CONCLUSIONS: The authors believe US is an important
      diagnostic tool that can reduce useless laparotomies for false acute
      appendicitis, particularly in cases presenting with unclear clinical findings.

PMID- 8662399
TI  - Intraoperative ultrasonography (IOUS) during laparoscopic cholecystectomy.
AB  - BACKGROUND: The purpose of this study was to evaluate the usefulness of
      intraoperative ultrasonography (IOUS), a new method of imaging the biliary tree
      and related structures, during laparoscopic cholecystectomy. METHOD: An IOUS
      probe (Aloka, Tokyo, Japan) with a 7.5-MHz linear-array transducer was used
      during cholecystectomy in 124 patients with symptomatic cholelithiasis (45 men,
      79 women; mean age, 48 +/- 14 years). RESULTS: The examination of the common bile
      duct (CBD) was excellent in 117 patients but unsatisfactory in 7 cases (5.6%) at
      the level of the head of the pancreas. In 5 patients, IOUS showed unsuspected
      choledocholithiasis: a subsequent intraoperational cholangiogram confirmed this.
      In five cases IOUS was able to help the surgeon to localize a Calot area obscured
      by inflammation. Postoperatively, one patient had an injury of the cystic duct
      stump: a nasobiliary tube resolved the bile leakage after 7 days. Another patient
      was submitted to postoperative endoscopic retrograde cholangiopancreatography
      (ERCP) for a choledocholithiasis recognized by a trans-cystic-tube
      cholangiography: the stone was suspected but not demonstrated either by
      laparoscopic IOUS or by intraoperative cholangiography. During the follow-up
      period, one patient had an episode of acute pancreatitis. ERCP showed a small
      stone wedged in the sphincter of Oddi. CONCLUSIONS: IOUS may be a real
      alternative to cholangiography during laparoscopic cholecystectomy since it is
      safer and offers a complete examination of the biliary tree. It has some
      disadvantages which can solved by additional experience.

PMID- 8662400
TI  - Metabolic responses after laparoscopic or open hernia repair.
AB  - BACKGROUND: The purpose of a prospective randomized study was to compare the
      surgical trauma in patients undergoing laparoscopic or open hernia repair.
      METHODS: Postoperative pain, analgesic consumption, and metabolic response to
      surgery were assessed in 30 patients undergoing laparoscopic (group 1; n = 15) or
      open (group II; n = 15; Shouldice repair) unilateral inguinal hernia repair. Both
      groups were comparable with respect to age, sex, and type and size of inguinal
      hernia. RESULTS: Postoperative visual analogue scales (VAS) for pain were reduced
      on mobilization for patients of group I with a significant difference (P = 0.02)
      on the operative day, whereas pain scores at rest and analgesic requirements were
      similar for both groups. No differences between groups I and II were found in
      postoperative levels of interleukin-1, interleukin-6, tumor necrosis factor
      alpha, C-reactive protein, fibrinogen, transferrin, alpha-1-antitrypsin, and
      white blood cells. Postoperative polymorphonuclear (PMN) elastase concentrations
      remained within normal range in group II but showed a significant increase in
      patients operated laparoscopically for postoperative days 1 and 2. CONCLUSIONS:
      No major surgical trauma was found after herniorraphy compared to open hernia
      repair.

PMID- 8662401
TI  - Ultrasonography and the surgeon.

PMID- 8662402
TI  - Laparoscopic gastric bypass. Another option in bariatric surgery.
AB  - BACKGROUND: The present report describes the technical details of laparoscopic
      bypass for morbid obesity. METHODS: The laparoscopic approach was attempted in
      eight patients and completed in six. In these latter patients the stomach was
      divided with an endoscopic linear cutter (ETC 60 Ethicon), and a antecolic
      jejunal loop was brought to the proximal pouch and anastomosed by use of manual
      suture technique supported with locking clips for knotting substitutes [Lapra-Ty
      (Ethicon)]. Distal to the gastrojejunostomy a side-to-side enteroanastomosis was
      also performed. RESULTS: Five patients in whom the laparoscopic procedure was
      completed had an uneventful postoperative period and a rapid recovery. However,
      one patient had a postoperative left-sided pleuropneumonia that required
      prolonged hospital stay. Of those who were converted, one was because of a large
      steatotic left liver lobe and another was due to a perforation of the small
      intestine. CONCLUSIONS: These early results indicate that gastric bypass for the
      treatment of morbid obesity can be safely performed with laparoscopic techniques.
      Further development in this field should be encouraged.

PMID- 8662403
TI  - Palliation for pancreatic cancer. Feasibility of laparoscopic
      cholecystojejunostomy and gastrojejunostomy in a porcine model.
AB  - BACKGROUND: Although laparoscopy reveals undetected metastases in many patients
      with pancreatic cancer, most surgeons have chosen to proceed directly with
      laparotomy in an attempt at resection or for palliation of biliary and gastric
      outlet obstruction. In an effort to overcome this limitation, this study
      attempted to determine the feasibility of laparoscopic cholecystojejunostomy and
      gastrojejunostomy. METHODS: Under general anesthesia, seven pigs underwent
      laparoscopic cholecystojejunostomy and gastrojejunostomy using either a hand
      sutured or the stapled/sutured technique. RESULTS: Mean operating time was less
      with the stapled/sutured vs hand-sutured technique (150 +/- 21 vs 230 +/- 13 min,
      P < 0.05). All animals recovered completely and there was no change in their
      weight or liver function tests as a result of the procedure. At sacrifice, all
      anastomoses were patent, although some were significantly narrowed in these
      unobstructed animals. CONCLUSIONS: These results suggest that simultaneous
      laparoscopic palliation of biliary and gastric outlet obstruction is feasible. We
      believe these results warrant further study in the clinical setting.

PMID- 8662404
TI  - Sequential intraluminal endoscopic and laparoscopic treatment for bile duct
      stones associated with gallstones.
AB  - BACKGROUND: On the basis of a flowchart including prior or current jaundice or
      pancreatitis, abnormal liver function, ultrasound or IV cholangiography, bile
      duct (BD) stones were suspected in 71/593 patients referred for gallstones.
      METHODS: When endoscopic retrograde cholangiography detected BD stones,
      endoscopic sphincterotomy (ES) and endoscopic BD clearance were attempted,
      followed by laparoscopic cholecystectomy (LC). BD stones were found in 44/71
      patients. The sensitivity values of preoperative conditions were: 92% for IV
      cholangiography, 88% for abnormal liver function, 50% for ultrasound, and 37% for
      jaundice at admission. RESULTS: Endoscopic clearance succeeded in 37 patients and
      LC was completed in 33 patients. Conversion to open surgery (9%) was comparable
      with the rate in patients without BD stones. The median hospital stay for the
      sequential endoscopic and laparoscopic treatments was 13 days (range 4-54) or 22
      days if open surgery was used. CONCLUSIONS: In conclusion, BD stones can be
      endoscopically cleared preoperatively in most patients without interfering with
      LC.

PMID- 8662405
TI  - Laparoscopic cholecystectomy (LC), intraoperative endoscopic sphincterotomy (ES),
      and common bile duct stones (CBDS) extraction for management of patients with
      cholecystocholedocholithiasis.
AB  - BACKGROUND: A combined method of endoscopic sphincterotomy (ES) with common bile
      duct stone (CBDS) extraction and laparoscopic cholecystectomy (LC) under general
      anesthesia for a single-session treatment of patients with colecysto
      choledocholithiasis is described. METHODS: From June 1994 to January 1995, 15
      consecutive cases considered for elective LC with preoperative diagnosis of CBDS
      underwent this procedure. Following orotracheal intubation, the patient is turned
      on the left lateral decubitus for ES and CBDS extraction. Nasobiliary drainage is
      positioned for per-laparoscopic cholangiogram. Routine LC is finally performed.
      RESULTS: These two interventions were successfully accomplished in all patients.
      Mean duration of the operative time for the combined procedure was 97.7 +/- 30.4
      min, range 60-140 min. In four (26.6%) cases an accessory trocar with retracting
      instrument was used to obviate the bowel distension. CONCLUSIONS: No
      complications of ES or LC were observed. Mean hospital stay was 3 days (range 2-5
      days). Routine follow-up (mean 3 +/- 2 months, range 1-12 months) did not reveal
      biliary-related problems in any of the observed patients.

PMID- 8662406
TI  - The role of ERCP in laparoscopic cholecystectomy-related cystic duct stump leaks.
AB  - BACKGROUND: Laparoscopic cholecystectomy has resulted in an increase in the
      incidence of cystic duct stump leaks. To assess the role of endoscopic retrograde
      cholangiopancreatography (ERCP) a review of 14 cystic duct stump leaks following
      laparoscopic cholecystectomy was carried out. METHODS: A retrospective chart
      review of fourteen patients was carried out. There were 11 females and 3 males.
      Laparoscopic cholecystectomy was carried out without any difficulty. Three
      patients became very ill soon after surgery while 11 patients were minimally ill.
      All were still hospitalized after the cholecystectomy. RESULTS: Urgent ERCP on
      the 3 very ill patients demonstrated a cystic duct bile leak. In the 11 minimally
      ill patients, ultrasonography demonstrated intraabdominal fluid collections and
      initial treatment was percutaneous drainage. Only 2 of the 11 patients improved.
      The remaining nine patients developed a septic course. ERCP was carried out and
      demonstrated cystic duct bile leak in all 9 patients. Endoscopic papillotomy
      alone or endoscopic papillotomy plus stenting resolved the clinical picture.
      CONCLUSIONS: Patients who are ill post laparoscopic cholecystectomy should have
      urgent ERCP. Cystic duct bile leaks should be managed by endoscopic papillotomy
      and in select cases, stenting.

PMID- 8662407
TI  - Laparoscopic suture closure of perforated peptic ulcer. A nonrandomized
      comparison with open surgery.
AB  - BACKGROUND: Laparoscopic vs open suture in the surgical treatment of perforated
      peptic ulcer were compared in a retrospective study. METHODS: The outcome of 10
      patients having the laparoscopic procedure was compared with the outcome of 17
      patients treated with suture via laparotomy during the same time period. RESULTS:
      The mortality rate and the complication rate were comparable. The laparoscopic
      procedure was more time consuming; hospital stay did not differ. CONCLUSIONS: The
      results indicate that surgery for perforated peptic ulcer can be performed with
      the laparoscopic technique with an outcome comparable to open surgery. No obvious
      advantages to the patient were noted with the laparoscopic method.

PMID- 8662408
TI  - Laparoscopic Thal fundoplication in mentally retarded children.
AB  - BACKGROUND: An increasing number of reports indicate that Thal fundoplication is
      the procedure of choice in mentally retarded children. With the advent of
      laparoscopy, Nissen's fundoplication seems to have been repopularized. However,
      the choice of the operative technique should be based on the merits of the
      procedure itself rather than the laparoscopic feasibility. The aim of this study
      is to determine if laparoscopic Thal fundoplication is beneficial for mentally
      retarded children. METHODS: Between November 1993 and 1994 laparoscopic Thal
      fundoplication was performed in 15 mentally handicapped children; 13 also had a
      feeding gastrostomy. Age varied from 1.5 to almost 17 years (mean 7 years). Mean
      weight was 18 kg (5-50 kg). All patients underwent an upper GI study and
      endoscopy as well as pre- and 3 months postoperative pH study. Indications for
      the procedure were reflux esophagitis in 11 and feeding problems with silent
      reflux in 4. RESULTS: The laparoscopic procedure was converted in the second
      patient because of bleeding in the hiatus. No further procedure-related intra- or
      postoperative complications occurred. The mean hospitalization was 3.7 days. No
      symptomatic postoperative gastroesophageal reflux has been observed. All children
      have undergone postoperative pH studies, which displayed silent reflux in two.
      Gastrostomy feeding is well tolerated. CONCLUSION: We conclude that Thal
      fundoplication can be performed laparoscopically in mentally retarded children.
      The laparoscopic results are comparable to the open Thal procedure.

PMID- 8662409
TI  - Laparoscopic resection of gastric leiomyoblastoma.
AB  - Smooth muscle gastric tumors represent 2% of resected neoplasms of the stomach.
      Clinically, they are often silent and incidentally found at endoscopy or
      radiologic examination. These tumors can be histologically classified as benign
      (leiomyoma) or malignant (leiomyoblastoma), but clinical behavior is not strictly
      related to this classification. When symptomatic, they are present with anemia in
      50% of cases due to mucosal ulceration. Surgical removal of the tumor is the
      accepted therapy, leaving a margin of surrounding free tissue: this treatment can
      be performed by laparoscopy, usefully associated with gastroscopy. We present one
      case of a patient with severe anemia due to bleeding from an ulcerated
      leiomyoblastoma 5 cm in diameter that we resected with combined gastroscopic
      laparoscopic technique. We isolated the portion of gastric wall where the mass
      was located and resected the specimen under gastroscopic control. The
      postoperative period was uneventful, and the patient recovered promptly with
      minimal pain and discomfort.

PMID- 8662410
TI  - Laparoscopic treatment of a sigmoid perforation after colonoscopy. Case report
      and review of literature.
AB  - The authors report a case of sigmoid colon perforation post colonoscopic
      polypectomy. Such perforation is rare and has been estimated to occur between 0.1
      and 3% of the time. Surgical treatment is necessary when there is deterioration
      of the clinical state. In this reported case, surgical closure of the perforation
      was achieved by laparoscopy. We believe that this approach is effective for
      colonic suture, peritoneal lavage, and drainage.

PMID- 8662411
TI  - Laparoscopic fundoplication 1 month prior to lung transplantation.
AB  - Upper midline laparotomy in the presence of pulmonary failure is often
      complicated by a prolonged period of mechanical ventilation postoperatively. We
      report the successful performance of laparoscopic fundoplication, without
      ventilatory support, in a woman with end stage pulmonary disease and resting
      hypercarbia, one month prior to lung transplantation.

PMID- 8662412
TI  - Intussusception treated laparoscopically after failed air enema reduction.
AB  - We report the case of a 10-month-old boy with intussusception. Following two
      failed air enemas, successful reduction of his ileocolic intussusception was
      achieved laparoscopically. We do not advocate abandoning safe and established
      surgical techniques used to treat irreducible lesions, but we are encouraged by
      this experience to further explore the role of laparoscopy in the treatment of
      this common condition.

PMID- 8662413
TI  - Laparoscopic cholecystostomy for acute acalculous cholecystitis.
AB  - Acute acalculous cholecystitis (AAC) can occur in up to 18% of severely injured
      patients. Diagnosis is made by positive ultrasound findings of gallbladder
      sludge, hydrox, and wall thickening. There may also be recent-onset jaundice,
      positive ultrasound induced Murphy's sign, and unexplained sepsis. Mortality can
      be as high as 50%. Laparoscopic confirmation was obtained in six ICU trauma
      patients when omentum was drawn up over a distended gallbladder. Laparoscopic
      cholecystectomy (LC) was done by first directly decompressing the gallbladder
      through the fundus. This trocar was replaced by a 16 French Foley catheter passed
      through an Endoloop into the gallbladder and secured by tightening the loop
      around a cuff of gallbladder. Sepsis resolved in all cases. Only one required
      subsequent laparoscopic cholecystectomy. LC has a low morbidity and may be life
      saving during the early stages of AAC. It is not indicated in gangrene or
      perforation of the gallbladder.

PMID- 8662414
TI  - Laparoscopic introduction of a continuous ambulatory peritoneal dialysis (capd)
      catheter by a two-puncture technique.
AB  - We describe a laparoscopic two-puncture technique for the placement of a
      continuous ambulatory peritoneal dialysis catheter. With a mean follow-up period
      of 8 months the short-term results of the first 19 laparoscopic catheter
      insertions are evaluated and discussed. It appears to be a simple, safe, and
      viable procedure with a low morbidity and very good results in the short term.
      The same technique can also be used in catheter salvage in case of outflow
      obstruction or catheter migration, thus increasing catheter longevity.

PMID- 8662415
TI  - A simple method for endoscopic placement of a nasoduodenal feeding tube.
AB  - The key to short-term enteral feeding in patients with gastroparesis is to
      deliver the nutrition beyond the pylorus. Endoscopic assisted methods allow the
      precise placement of the feeding tube to the small bowel. However, the main
      difficulty in association with these procedures is feeding-tube migration into
      the stomach during the withdrawal of the endoscope. We have developed an
      endoscopic method with a high success rate which prevents this problem. A
      reusable angiocatheter guidewire was threaded through the feeding tube, passing
      beyond the distal opening prior to the withdrawal of the scope. Counterpressure
      was applied to the feeding tube during the withdrawal of the endoscope. We have
      successfully placed feeding tubes in 22 out of 23 patients with no complications.

PMID- 8662416
TI  - Technique of laparoscopic ultrasound examination of the liver and pancreas.
AB  - Since the introduction of a recent laparoscopic ultrasound (LU), the value of
      this modality in examining the liver and pancreas has been reported. However, a
      precise scanning technique of LU has not previously been described. Based on our
      experience with intraoperative ultrasound during laparotomy, we have developed a
      technique for complete examination of the entire organs using a rigid LU probe. A
      7.5-MHz rigid probe, 10 mm in diameter, was employed. The scanning was performed
      through three trocar ports: right subcostal, subxiphoid, and umbilical. For the
      liver, the subcostal scanning provided fundamental transverse views. The
      subxiphoid and umbilical scanning delineated the areas unable to be imaged by the
      subcostal scanning. For the pancreas, the subcostal and umbilical scanning
      demonstrated longitudinal and transverse views, respectively. The subxiphoid
      scanning enhanced examination of the pancreatic head. Three basic probe maneuvers
      (advancement-withdrawal, lateral movement, and rotation) and various scanning
      techniques (contact, probe-standoff, and compression scanning) should be utilized
      appropriately. With a rigid probe, complete LU examination of the liver and
      pancreas is possible using these techniques. We believe the present scanning
      method will help more surgeons learn LU.

PMID- 8662417
TI  - Percutaneous endoscopic external ring (PEER) hernioplasty.
AB  - This pilot study was conducted to determine if percutaneous endoscopic external
      ring (PEER) hernioplasty would be a viable alternative to the conventional and
      laparoscopic methods of tension-free repair. The procedure consists of (1) a 2.0
      2.5-cm incision over the external inguinal ring to reach the emerging spermatic
      cord structures, and ligation and excision of the hernia sac and (2) insertion of
      an endoscope-attached retractor through the external ring, into the inguinal
      canal for visualization, dissection of posterior inguinal wall, and placement of
      mesh to complete tension-free repair. PEER hernioplasty was used to treat 48
      patients with 60 primary hernias (bilateral in 12 patients) between January 1993
      and December 1994. Median follow-up was 12 months and ranged from 5 to 22 months.
      All patients were discharged within 24 h after surgery except for one. All
      patients resumed their normal activity within 2-3 weeks. Only three complications
      were encountered (two scrotal hematomas and one inguinal seroma). To date, there
      has been recurrence of two hernias in one patient. We conclude that PEER
      hernioplasty is an effective method of repair of primary hernias that is less
      invasive than the conventional approach and both less invasive and more cost
      effective than laparoscopic approaches.

PMID- 8662419
TI  - The author replies

PMID- 8662418
TI  - Laparoscopic surgery and the management of traumatic hemoperitoneum in stable
      patients.

PMID- 8662420
TI  - Laparoscopic surgery and the management of traumatic hemoperitoneum in stable
      patients.

PMID- 8662421
TI  - Ligamentum teres not the ideal ulcer patch.

PMID- 8662422
TI  - News and notices

PMID- 8662424
TI  - Kock pouch dysfunction during pregnancy. Management of a case.
AB  - The Kock continent ileostomy is a surgical alternative to a Brooke ileostomy
      after total proctocolectomy. Complications resulting from an improperly
      functioning nipple valve are not infrequent and when they occur most often
      require surgical revision. A 19-year-old female with a functioning Kock pouch of
      4 years presented at 6 months of pregnancy with complete bowel obstruction due to
      nipple valve dysfunction. Operative management was avoided and her bowel
      obstruction was relieved by endoscopic placement of a stent through the nipple
      valve and into the abdominal reservoir. The stent was removed at 1 week
      postpartum with immediate return to normal function of her Kock pouch nipple
      valve. Temporary malfunction of the Kock pouch nipple valve can occur during
      pregnancy, probably due to distortion of the valve mechanism by the enlarging
      uterus. The endoscopic placement of a stent can maintain proper bowel evacuation
      until delivery and normal Kock pouch function can be expected after stent
      removal.

PMID- 8662425
TI  - Thoracoscopic surgery in the management of mediastinal masses. Indications,
      complications, limitations.
AB  - BACKGROUND: In recent times thoracoscopy has been used for diagnoses and
      treatment of mediastinal masses. This study is a preliminary review of
      indications, complications, and limitations in this field of surgery. METHODS:
      Twenty-eight patients with mediastinal masses were operated in the Clinical
      Oncological Centre, Kazan. Twenty-two of them had anterior mediastinal growths;
      six had posterior mediastinal tumors. Thoracoscopy was diagnostic in 14 cases; it
      was therapeutic in 14 cases. RESULTS: The definite diagnosis was achieved in all
      patients. In cases of benign lesions the operations were successfully completed
      thoracoscopically. All patients underwent a postoperative period with low pain
      and short postoperative time. CONCLUSIONS: Video-assisted thoracoscopy is
      indicated in cases of mediastinal masses, both for diagnosis and treatment. It
      has significant advantages compared to normal thoracoscopy and mediastinoscopy.

PMID- 8662427
TI  - Clinical and manometric results of laparoscopic partial (Toupet) and complete
      (Rosetti-Nissen) fundoplication.
AB  - It is unclear whether a partial or complete gastric fundoplication done
      laparoscopically will offer the best control of reflux with the fewest side
      effects. Prospective evaluation of laparoscopic Rosetti-Nissen (360) and Toupet
      (180) fundoplication was performed with assessment of clinical and manometric
      data. METHODS: Patients with severe gastroesophageal reflux referred for surgical
      correction underwent preoperative motility and upper endoscopy. A Rosetti-Nissen
      or Toupet fundoplication was then performed laparoscopically. Short gastrics were
      not divided. No bougie was used in the Toupet, which was sutured
      intracorporeally. A 2-cm, loose, floppy wrap about a 50-Fr bougie was performed
      in the Nissen. Eleven patients underwent Rosetti-Nissen and 11 Toupet
      fundoplication. Mean ages, duration symptoms, weight, and baseline LES, were not
      different. Preop esophagitis grades were similar, as were Visick Scores and
      presence of dysphagia. RESULTS: Visick scores at 6 months were better in the
      Toupet group than the Rosetti-Nissen (P = 0.07). Persistent Dysphagia in four,
      Gas-Bloat in two, and Odynophagia in one within the Rosetti-Nissen group
      accounted for the difference, and were not seen in Toupets. LES pressures
      differed significantly pre and postop (P < 0.001). The change in LES pressure was
      significantly different between Toupet and Rosetti-Nissen (chart). Seven patients
      had postop 24-h pH tests; all had no reflux. Three Rosettis have required
      revision to Toupet, with resolution of their symptoms. CONCLUSIONS: In patients
      with severe GERD, laparoscopic Toupet and Rosetti-Nissen control symptoms and
      esophageal pH similarly. LES pressures are higher postop in the Rosetti-Nissen.
      Dysphagia and gas-bloat are more prevalent in the Nissen group. Laparoscopic
      Toupet fundoplication may be superior to Rosetti-Nissen in reducing the frequency
      of side effects frequently associated with antireflux surgery, yet with equal
      control of reflux.

PMID- 8662426
TI  - Advantages of limited thoracoscopic sympathectomy.
AB  - BACKGROUND: Thoracoscopic resection of the first through the fourth thoracic
      sympathetic ganglion for palmary and axillary hyperhidrosis and Raynaud's
      syndrome is associated with a high initial success rate. However, the reported
      incidence of compensatory hyperhidrosis of the trunk and legs and Horner's
      syndrome are high. This study assesses the results of thoracoscopic sympathectomy
      limited to transection of the interganglionic trunk or resection of one or two
      thoracic ganglia. METHODS: Twenty-eight thoracoscopic sympathectomies were done
      for dystrophy of the hand (n = 9), palmar and axillary hyperhidrosis (n = 6), and
      Raynaud's syndrome (n = 4). The extent of sympathectomy varied from
      interganglionic division between the second and third ganglion (n = 12), to
      resection of the third ganglion (n = 12), to resection of the second and third
      ganglion (n = 4). RESULTS: Sympathectomy resulted initially in relief of symptoms
      in all cases. Horner's syndrome did not occur. CONCLUSIONS: After a median follow
      up of 11 months, two of nine patients with dystrophy judged the result of
      operation as good. All patients with hyperhidrosis and Raynaud's syndrome judged
      the result of sympathectomy as good. Compensatory hyperhidrosis was experienced
      by two patients with dystrophy of the hand who had removal of the second and
      third sympathetic ganglion.

PMID- 8662428
TI  - The laparoscopic second look for ischemic bowel disease.
AB  - BACKGROUND: Survival after acute vascular ischemia depends on a second look
      laparotomy to detect extending bowel compromise and to verify the integrity of
      the anastomosis. In a series of five consecutive patients with acute ischemic
      bowel disease, we used laparoscopic technique to determine if a formal laparotomy
      could be avoided. METHODS: following the resection of ischemic bowel in five
      consecutive patients, two laparoscopic trocars were inserted in the lower
      abdominal quadrants and covered by sterile gloves. Forty-eight to 72 h following
      the primary operation, the abdomen was inflated via a trocar and secondary
      assessment done by laparoscopy. RESULTS: In all patients, the integrity of the
      anastomosis and viability of the remaining bowel was accurately assessed by
      laparoscopy. CONCLUSIONS: Using minimally invasive techniques, a second look
      laparotomy was avoided in 5 patients with ischemic bowel disease.

PMID- 8662429
TI  - Controlled trial of laparoscopic-assisted vs open colon resection in a porcine
      model.
AB  - BACKGROUND: Several series of laparoscopic colon resection have been reported in
      the literature with varied results; however, no controlled series of laparoscopic
      vs open colon resection has been reported. The purpose of this study was to
      determine the relative safety and adequacy of laparoscopic colon resection in a
      controlled trial using a porcine model. METHODS: Domestic pigs (n = 23) were
      randomly divided into two groups. Animals underwent either an open or
      laparoscopic-assisted segmental resection of the sigmoid colon. The open
      resections were performed through a 20-cm midline incision and the laparoscopic
      technique utilized five 12-mm ports. Laparoscopic resection took twice as long to
      complete as open resection (P < 0.001). Return of gastric function was
      significantly faster in the laparoscopic group than in the open group (P <
      0.032). RESULTS: No significant differences were found in total length of
      resection, proximal or distal margins, number of lymph nodes recovered, length of
      mesenteric vessel resected, or time to return of bowel function. At vivisection,
      more adhesions to the abdominal wall were noted in the open group (P < 0.002).
      One death occurred in the laparoscopic group 2 h postoperatively (8.3% mortality)
      while all open group pigs survived. However, there was no statistically
      significant difference in mortality rates by chi-square analysis (P > 0.5).
      CONCLUSIONS: Despite longer operative time, laparoscopic intervention is
      technically feasible, safe, and may offer significant postoperative benefits due
      to fewer abdominal adhesions.

PMID- 8662430
TI  - Is transanal endoscopic microsurgery (TEM) a valid treatment for rectal tumors?
AB  - BACKGROUND: In 1983 G. Buess, in Germany, developed transanal endoscopic
      microsurgery (TEM), a new minimally invasive technique for the treatment of
      rectal tumors. METHODS: Rectal lesions are excised through a modified rectoscope
      of 40 mm in diameter under stereoscopic control in the gas-dilated rectal cavity.
      Full-thickness excision, partial-wall excision, or mucosectomy can be performed.
      Seventy-one patients were treated with the TEM technique in our department. Major
      complications were observed in one patient (1.4%). No mortality was reported.
      RESULTS: Histological examination revealed 40 (56.3%) villous adenomas, 6 (8.4%)
      pT1; 17 (23.9%) pT2; 5 (7%) pT3 carcinomas; and 3 ((4.2%) other lesions. The
      recurrence rate was 2.8% for adenomas and 2.8% for carcinomas. The overall
      survival at mean follow-up of 17 months was 96.4%. CONCLUSIONS: The advantages of
      TEM are less or no postoperative pain, unrestricted mobility, short
      hospitalization, quick rehabilitation, and absence of skin scars.

PMID- 8662431
TI  - Conversion of laparoscopic to open cholecystectomy. An analysis of risk factors.
AB  - BACKGROUND: Identifying patients who are at risk for conversion from laparoscopic
      (LC) to open cholecystectomy (OC) has proven to be difficult. The purpose of this
      review was to identify factors that may be predictive of cases which will require
      conversion to laparotomy for completion of cholecystectomy. METHODS: We reviewed
      581 LCs initiated between July 1990 and August 1993 at a university medical
      center and recorded reasons for conversion to OC. Statistical analysis was then
      performed to identify factors predictive of increased risk for conversion.
      RESULTS: Of the 581 LC initiated, 45 (8%) required OC for completion. Reasons for
      conversion included technical and mandatory reasons and equipment failure. By
      multivariate analysis, statistically significant risk factors for conversion
      included increasing age, acute cholecystitis, a history of previous upper
      abdominal surgery, and being a patient at the Veterans Affairs Medical Center
      (VAMC). Factors not increasing risk of conversion included gender and operating
      surgeon. CONCLUSIONS: We conclude that no factor alone can reliably predict
      unsuccessful LC, but that combinations of increasing age, acute cholecystitis,
      previous upper abdominal surgery, and VAMC patient result in high conversion
      rates. Patients with the defined risk factors may be counseled on the increased
      likelihood of conversion. However, LC can be safely initiated for gallbladder
      removal with no excess morbidity or mortality should conversion be required.

PMID- 8662432
TI  - The impact of laparoscopic cholecystectomy on the treatment of symptomatic
      cholelithiasis.
AB  - BACKGROUND: There has been a debate about the cost-effectiveness of laparoscopic
      cholecystectomy (LC), as well as a concern regarding its possible overutilization
      and changes in the indication for surgery. METHODS: A retrospective analysis of
      all cholecystectomies performed at UCDMC from 1988 to 1994 was done. The annual
      rate of cholecystectomy increased by 50% in 1990 when LC was introduced but has
      since stabilized at a rate 11% higher than the rate before LC. The disease status
      and severity did not change. RESULTS: The incidence of nonelective surgery
      remained stable at 31.2% to 37.5%. Elective cholecystectomy had lower mortality
      (0.16% vs 1.8%, P = 0. 029), morbidity (2.6% vs 11.2%, P = 0.0001), and
      conversion rate (2. 6% vs 16%, P = 0.0001) and a shorter length of stay (2.1 days
      vs 5.4 days), compared with nonelective procedure. CONCLUSIONS: The indication
      for surgery in cholelithiasis has not changed since the introduction of LC. In
      patients with symptomatic gallstones, early elective surgery is recommended and
      may be more cost-effective.

PMID- 8662433
TI  - Necrotizing fasciitis following laparoscopic surgery. Case report and review of
      the literature.
AB  - Necrotizing fasciitis is a rare and potentially fatal infection characterized by
      rapid and progressive involvement of the fascia and subcutaneous tissues. Early
      diagnosis, aggressive initial debridement followed by planned redebridements in
      conjunction with nutritional support and antibiotics remain the mainstay of
      therapy. We present a case of necrotizing fasciitis of the abdominal wall
      following a laparoscopically assisted vaginal hysterectomy. Literature is
      reviewed and discussed with reference to this catastrophic infection in the age
      of laparoscopic surgery.

PMID- 8662435
TI  - Laparoscopic anatomical (hepatic) left lateral segmentectomy-technical aspects.
AB  - Laparoscopic liver surgery is a tremendous challenge. The authors report a left
      liver lobectomy and removal by a total laparoscopic approach. Anatomical left
      lateral laparoscopic segmentectomy was performed on a woman who had a symptomatic
      hepatic adenoma. The patient was discharged after an uncomplicated postoperative
      recovery; the hospital stay and convalescence period were very short. The
      cosmetic result was good.

PMID- 8662434
TI  - Videothoracoscopy for the management of mediastinal mass lesions.
AB  - BACKGROUND: The indications for video-assisted thoracoscopy have steadily
      expanded during recent years and include now the management of various
      mediastinal disorders. METHODS: Until now we have used videothoracoscopy for the
      diagnosis or treatment of mediastinal mass lesions in 28 patients. The indication
      for the procedure was bilateral or unilateral mediastinal adenopathy in 16, a
      suspected malignant anterior mediastinal mass lesion in six, and a presumable
      benign tumor of the posterior or anterior mediastinum in six patients. RESULTS:
      Video-assisted thoracoscopy provided an accurate tissue diagnosis in all patients
      with adenopathy and in all but one patient with a malignant mass lesion of the
      anterior mediastinum. It further allowed complete excision of all benign tumors
      of the anterior or posterior mediastinum. There were no intra- or postoperative
      complications, but conversion to open thoracotomy was necessary in one patient.
      CONCLUSIONS: Video-assisted thoracoscopy is a valuable adjunct to traditional
      surgical techniques for the diagnosis of malignant mediastinal disease and may
      overcome some of the limitations of mediastinoscopy and mediastinotomy. In the
      future, it may become the procedure of choice for the resection of small benign
      tumors of the anterior or posterior mediastinum.

PMID- 8662437
TI  - EndoScope: world literature reviews

PMID- 8662436
TI  - Sonographic features of liver metastases from pancreatic glucagonoma and acinar
      cell carcinoma. Case reports.
AB  - The previously unreported ultrasonographic (US) features of liver metastases of
      pancreatic glucagonoma and of pancreatic acinar cell carcinoma are described.
      They present as complex masses with hyperechoic solid component, containing echo
      free cystic areas; these sonographic features markedly differ from the echo-poor
      US pattern of the much more common metastases of pancreatic ductal carcinoma.
      Survival from diagnosis of liver metastases was 45 months in the patient with
      pancreatic glucagonoma and 23 months in the patient with acinar cell carcinoma.
      These survivals were much longer than the expected survival of patients with
      pancreatic ductal carcinoma metastatic to the liver. The US finding of highly
      reflective lesions in the liver, containing echo-free cystic areas, should alert
      one that the primary pancreatic tumor has a histotype different from ductal
      carcinoma. Such US findings could affect the decision to resect the pancreatic
      tumor and its liver metastases, if histology confirms a malignancy less
      aggressive than ductal carcinoma.

PMID- 8662438
TI  - Head-mounted video monitor for global visual access in mini-invasive surgery. An
      initial report.
AB  - Video-assisted technology for minimally invasive surgery uses the coaxial
      approach (working field between surgeon and video monitor). Complex procedures
      and two-team approaches disrupt this relationship causing paradoxic motion. In an
      effort to obviate these issues, a head-mounted monitor display has been used by
      the surgeon in 74 of these complex operative procedures. The head-mounted display
      (HMD) eliminates the negative effects of yaw, roll, and pitch - each of which is
      detrimental to the performance of complex operative procedures. There has been no
      visual strain or ocular fatigue observed. In contrast, the HMD allowed increased
      concentration without subjective muscle strain for as long as 640 mins. The
      authors conclude that the HMD improves efficiency in complex procedures,
      increases safety, diminishes cost, and allows optimum visualization of the
      operative field by the surgeon and assistants in congested operating-room
      environments.

PMID- 8662439
TI  - A quick and simple method to close vascular, biliary, and urinary tract incisions
      using the new Vascular Closure Staples: a preliminary report.
AB  - Traditional suture reconstruction of tubular organs creates a perforating needle
      injury, leaves suture material on the endothelial or mucosal surfaces, and is
      cumbersome when done endoscopically. One alternative method of reconstruction of
      tubular organs could use the new nonpenetrating clip to create an everted
      closure. In five pigs, a longitudinal incision of the infrarenal aorta, inferior
      vena cava, left ureter, gallbladder, and the common bile duct (in two) was closed
      with Vascular Closure Staples (VCS-clips). Four weeks after surgery, all ten
      blood vessels remained patent with no thrombosis. There was a well-healed wound
      with continuous intimal layer. The ureteral, gallbladder, and common bile duct
      wounds healed without leakage or obstruction in all animals. There was complete
      mucosal bridging of the wound, although in some specimens one or two clips were
      exposed to the lumen. The VCS-clips are easily and quickly applied and are safe
      insofar as can be determined by short-term follow-up.

PMID- 8662440
TI  - Radially expanding dilatation. A superior method of laparoscopic trocar access.
AB  - Trocars used in laparoscopic surgery occasionally produce serious complications,
      such as bleeding, visceral injury, or incisional hernia. We report the evaluation
      of a new, potentially safer laparoscopic access device in which the cutting
      obturator of a standard trocar is replaced by a blunt, radially expanding device.
      Conventional and radially expanding trocars were used in laparoscopic
      cholecystectomies in 12 pigs. Their abdominal walls were excised and the defects
      caused by the trocars were examined. The defects caused by the radially expanding
      devices were about 50% narrower (P < 0.001), and the incidence of abdominal wall
      bleeding was considerably less (0% vs 21%) with the radially expanding trocars.
      Since incisional hernias at trocar sites are related to the size of the abdominal
      wall defect, the use of radially expanding trocars should decrease the incidence
      of this complication. There should also be less risk of visceral injury.

PMID- 8662441
TI  - Can laparoscopic surgery improve the immune response to surgery in an HIV
      positive patient?

PMID- 8662443
TI  - The author replies

PMID- 8662442
TI  - Laparoscopic-assisted abdominal aortic aneurysm repair.

PMID- 8662444
TI  - News and notices

PMID- 8662445
TI  - A "Schrodinger Cat" Superposition State of an Atom
AB  - A "Schrodinger cat"-like state of matter was generated at the single atom level.
      A trapped 9Be+ ion was laser-cooled to the zero-point energy and then prepared in
      a superposition of spatially separated coherent harmonic oscillator states. This
      state was created by application of a sequence of laser pulses, which entangles
      internal (electronic) and external (motional) states of the ion. The Schrodinger
      cat superposition was verified by detection of the quantum mechanical
      interference between the localized wave packets. This mesoscopic system may
      provide insight into the fuzzy boundary between the classical and quantum worlds
      by allowing controlled studies of quantum measurement and quantum decoherence.

PMID- 8662446
TI  - The Self-Assembly Mechanism of Alkanethiols on Au(111)
AB  - The self-assembly mechanism of alkanethiol monolayers on the (111) surface of
      gold was discovered with the use of an ultrahigh-vacuum scanning tunneling
      microscope. Monolayer formation follows a two-step process that begins with
      condensation of low-density crystalline islands, characterized by surface-aligned
      molecular axes, from a lower density lattice-gas phase. At saturation coverage of
      this phase, the monolayer undergoes a phase transition to a denser phase by
      realignment of the molecular axes with the surface normal. These studies reveal
      the important role of molecule-substrate and molecule-molecule interactions in
      the self-assembly of these technologically important material systems.

PMID- 8662447
TI  - Dynamic Ocean-Atmosphere Coupling: A Thermostat for the Tropics
AB  - The ocean currents connecting the western tropical Pacific Ocean with the eastern
      tropical Pacific Ocean are driven by surface winds. The surface winds are in turn
      driven by the sea-surface temperature (SST) differences between these two
      regions. This dynamic coupling between the atmosphere and ocean may limit the SST
      in the tropical Pacific Ocean to below 305 kelvin even in the absence of cloud
      feedbacks.

PMID- 8662448
TI  - Fossil Evidence for a Late Cretaceous Origin of "Hoofed" Mammals
AB  - Seventeen of eighteen orders of living placental mammals are not known before 65
      million years ago. The monophyly of each order is well established, but
      interrelations have been less certain. A superordinal grouping of up to seven
      extant orders plus a variety of extinct orders, all included within Ungulata
      ("hoofed" mammals), can be linked to Late Cretaceous mammals from the 85-million
      year-old Bissekty Formation, Uzbekistan (and, less certainly, North America and
      Europe), thus pushing the origin of this major clade back by 20 million years.
      Ungulatomorphs are not closely related to primates, rodents, or rabbits.

PMID- 8662449
TI  - Bacteria as Mediators of Copper Sulfide Enrichment During Weathering
AB  - Supergene chalcocite enrichment during weathering is an economically vital
      natural process that may lead to severalfold increases in the copper content of
      sulfide deposits. A scanning electron microscope study of chalcocite (Cu2S) from
      major enriched copper deposits in northern Chile revealed myriad bacterioform
      bodies in original growth positions near replacement interfaces with remnant
      hypogene sulfide grains. These minute (0.03 to 0.2 micrometers) chalcocite bodies
      are interpreted as fossilized and metallized nannobacteria that promoted the
      fixation of mobilized copper ions. Bacterial activity may thus be a fundamental
      factor in supergene enrichment of copper deposits.

PMID- 8662450
TI  - Oceanic Anoxia and the End Permian Mass Extinction
AB  - Data on rocks from Spitsbergen and the equatorial sections of Italy and Slovenia
      indicate that the world's oceans became anoxic at both low and high
      paleolatitudes in the Late Permian. Such conditions may have been responsible for
      the mass extinction at this time. This event affected a wide range of shelf
      depths and extended into shallow water well above the storm wave base.

PMID- 8662451
TI  - Nanotribology and Nanofabrication of MoO3 Structures by Atomic Force Microscopy
AB  - Atomic force microscopy was used to characterize the sliding of molybdenum oxide
      (MoO3) nanocrystals on single-crystal molybdenum disulfide (MoS2) surfaces.
      Highly anisotropic friction was observed whereby MoO3 nanocrystals moved only
      along specific directions of the MoS2 surface lattice. The energy per unit area
      to move the MoO3 nanocrystals along their preferred sliding direction was an
      order of magnitude less than required to slide macroscopic MoS2-bearing contacts.
      This extreme friction anisotropy was exploited to fabricate multicomponent MoO3
      nanostructures. These reversibly interlocking structures could serve as the basis
      for devices such as mechanical logic gates.

PMID- 8662452
TI  - Vertical Flux of Biogenic Carbon in the Ocean: Is There Food Web Control?
AB  - Models of biogenic carbon (BC) flux assume that short herbivorous food chains
      lead to high export, whereas complex microbial or omnivorous food webs lead to
      recycling and low export, and that export of BC from the euphotic zone equals new
      production (NP). In the Gulf of St. Lawrence, particulate organic carbon fluxes
      were similar during the spring phytoplankton bloom, when herbivory dominated, and
      during nonbloom conditions, when microbial and omnivorous food webs dominated. In
      contrast, NP was 1.2 to 161 times greater during the bloom than after it. Thus,
      neither food web structure nor NP can predict the magnitude or patterns of BC
      export, particularly on time scales over which the ocean is in nonequilibrium
      conditions.

PMID- 8662454
TI  - Perspectives in Helioseismology
AB  - Helioseismology is probing the interior structure and dynamics of the sun with
      ever-increasing precision, providing a well-calibrated laboratory in which
      physical processes can be studied under conditions that are unattainable on
      Earth. Nearly 10 million resonant modes of oscillation are observable in the
      solar atmosphere, and their frequencies need to be known with great accuracy in
      order to gauge the sun's interior. The advent of nearly continuous imaged
      observations from the complementary ground-based Global Oscillation Network Group
      (GONG) observatories and the space-based Solar and Heliospheric Observatory
      instruments augurs a new era of discovery. The flow of early results from GONG
      resolves some issues and raises a number of theoretical questions whose answers
      are required for understanding how a seemingly ordinary star actually operates.

PMID- 8662455
TI  - The Global Oscillation Network Group (GONG) Project
AB  - Helioseismology requires nearly continuous observations of the oscillations of
      the solar surface for long periods of time in order to obtain precise
      measurements of the sun's normal modes of oscillation. The GONG project acquires
      velocity images from a network of six identical instruments distributed around
      the world. The GONG network began full operation in October 1995. It has achieved
      a duty cycle of 89 percent and reduced the magnitude of spectral artifacts by a
      factor of 280 in power, compared with single-site observations. The instrumental
      noise is less than the observed solar background.

PMID- 8662456
TI  - The Current State of Solar Modeling
AB  - Data from the Global Oscillation Network Group (GONG) project and other
      helioseismic experiments provide a test for models of stellar interiors and for
      the thermodynamic and radiative properties, on which the models depend, of matter
      under the extreme conditions found in the sun. Current models are in agreement
      with the helioseismic inferences, which suggests, for example, that the
      disagreement between the predicted and observed fluxes of neutrinos from the sun
      is not caused by errors in the models. However, the GONG data reveal subtle
      errors in the models, such as an excess in sound speed just beneath the
      convection zone. These discrepancies indicate effects that have so far not been
      correctly accounted for; for example, it is plausible that the sound-speed
      differences reflect weak mixing in stellar interiors, of potential importance to
      the overall evolution of stars and ultimately to estimates of the age of the
      galaxy based on stellar evolution calculations.

PMID- 8662457
TI  - The Solar Acoustic Spectrum and Eigenmode Parameters
AB  - The Global Oscillation Network Group (GONG) project estimates the frequencies,
      amplitudes, and linewidths of more than 250,000 acoustic resonances of the sun
      from data sets lasting 36 days. The frequency resolution of a single data set is
      0.321 microhertz. For frequencies averaged over the azimuthal order m, the median
      formal error is 0.044 microhertz, and the associated median fractional error is
      1.6 x 10(-5). For a 3-year data set, the fractional error is expected to be 3 x
      10(-6). The GONG m-averaged frequency measurements differ from other helioseismic
      data sets by 0.03 to 0.08 microhertz. The differences arise from a combination of
      systematic errors, random errors, and possible changes in solar structure.

PMID- 8662458
TI  - The Seismic Structure of the Sun
AB  - Global Oscillation Network Group data reveal that the internal structure of the
      sun can be well represented by a calibrated standard model. However, immediately
      beneath the convection zone and at the edge of the energy-generating core, the
      sound-speed variation is somewhat smoother in the sun than it is in the model.
      This could be a consequence of chemical inhomogeneity that is too severe in the
      model, perhaps owing to inaccurate modeling of gravitational settling or to
      neglected macroscopic motion that may be present in the sun. Accurate knowledge
      of the sun's structure enables inferences to be made about the physics that
      controls the sun; for example, through the opacity, the equation of state, or
      wave motion. Those inferences can then be used elsewhere in astrophysics.

PMID- 8662459
TI  - Differential Rotation and Dynamics of the Solar Interior
AB  - Splitting of the sun's global oscillation frequencies by large-scale flows can be
      used to investigate how rotation varies with radius and latitude within the solar
      interior. The nearly uninterrupted observations by the Global Oscillation Network
      Group (GONG) yield oscillation power spectra with high duty cycles and high
      signal-to-noise ratios. Frequency splittings derived from GONG observations
      confirm that the variation of rotation rate with latitude seen at the surface
      carries through much of the convection zone, at the base of which is an
      adjustment layer leading to latitudinally independent rotation at greater depths.
      A distinctive shear layer just below the surface is discernible at low to mid
      latitudes.

PMID- 8662460
TI  - GONG Observations of Solar Surface Flows
AB  - Doppler velocity observations obtained by the Global Oscillation Network Group
      (GONG) instruments directly measure the nearly steady flows in the solar
      photosphere. The sun's differential rotation is accurately determined from single
      observations. The rotation profile with respect to latitude agrees well with
      previous measures, but it also shows a slight north-south asymmetry. Rotation
      profiles averaged over 27-day rotations of the sun reveal the torsional
      oscillation signal-weak, jetlike features, with amplitudes of 5 meters per
      second, that are associated with the sunspot latitude activity belts. A
      meridional circulation with a poleward flow of about 20 meters per second is also
      evident. Several characteristics of the surface flows suggest the presence of
      large convection cells.

PMID- 8662461
TI  - Type II Supernova Matter in a Silicon Carbide Grain from the Murchison Meteorite
AB  - The circumstellar silicon carbide (SiC) grain X57 from the Murchison meteorite
      contains large amounts of radiogenic calcium-44 (20 times its solar system
      abundance) and has an anomalous silicon isotopic composition, different from
      other circumstellar SiC grains. Its inferred initial 44Ti/Si and 44Ti/48Ti ratios
      are 1.6 x 10(-4) and 0.37. In addition, it contains radiogenic magnesium-26; the
      inferred initial 26Al/27Al ratio is 0.11. The isotopic and elemental data of X57
      can be explained by selective mixing of matter from different zones of a typical
      type II supernova of 25 solar masses during its explosion. The high 44Ti/Si ratio
      requires contributions from the innermost nickel zone of the supernova to the SiC
      condensation site, as similarly suggested by astronomical observations.

PMID- 8662462
TI  - Corundum, rutile, periclase, and CaO in Ca,Al-rich inclusions from carbonaceous
      chondrites.
AB  - Four calcium,aluminum-rich inclusions from four carbonaceous chondrites-Allende,
      Acfer 082, Acfer 086, and Acfer 094-were studied by transmission electron
      microscopy. All inclusions contained at least two of the oxides periclase (MgO),
      rutile (TiO2), calcium oxide (CaO), and corundum (Al2O3). The oxides (50 to 200
      nanometers in size) were found inside and at grain boundaries of the constituent
      minerals of the inclusions. Determining how these oxides formed may provide
      insight about condensation processes in the early solar nebula and the origin of
      refractory inclusions in chondrites. Formation of these oxides by exsolution is
      considered unlikely. An origin by kinetically controlled condensation appears
      more probable.

PMID- 8662463
TI  - Decline in the Tropospheric Abundance of Halogen from Halocarbons: Implications
      for Stratospheric Ozone Depletion
AB  - Analyses of air sampled from remote locations across the globe reveal that
      tropospheric chlorine attributable to anthropogenic halocarbons peaked near the
      beginning of 1994 and was decreasing at a rate of 25 &plusmn; 5 parts per
      trillion per year by mid-1995. Although bromine from halons was still increasing
      in mid-1995, the summed abundance of these halogens in the troposphere is
      decreasing. To assess the effect of this trend on stratospheric ozone, estimates
      of the future stratospheric abundance of ozone-depleting gases were made for mid
      latitude and polar regions on the basis of these tropospheric measurements. These
      results suggest that the amount of reactive chlorine and bromine will reach a
      maximum in the stratosphere between 1997 and 1999 and will decline thereafter if
      limits outlined in the adjusted and amended Montreal Protocol on Substances That
      Deplete the Ozone Layer are not exceeded in future years.

PMID- 8662464
TI  - "Coulomb Staircase" at Room Temperature in a Self-Assembled Molecular
      Nanostructure
AB  - Double-ended aryl dithiols [alpha,alpha'-xylyldithiol (XYL) and 4,4'
      biphenyldithiol] formed self-assembled monolayers (SAMs) on gold(111) substrates
      and were used to tether nanometer-sized gold clusters deposited from a cluster
      beam. An ultrahigh-vacuum scanning tunneling microscope was used to image these
      nanostructures and to measure their current-voltage characteristics as a function
      of the separation between the probe tip and the metal cluster. At room
      temperature, when the tip was positioned over a cluster bonded to the XYL SAM,
      the current-voltage data showed "Coulomb staircase" behavior. These data are in
      good agreement with semiclassical predictions for correlated single-electron
      tunneling and permit estimation of the electrical resistance of a single XYL
      molecule (approximately18 &plusmn; 12 megohms).

PMID- 8662465
TI  - Filled Skutterudite Antimonides: A New Class of Thermoelectric Materials
AB  - A class of thermoelectric materials has been synthesized with a thermoelectric
      figure of merit ZT (where T is temperature and Z is a function of thermopower,
      electrical resistivity, and thermal conductivity) near 1 at 800 kelvin. Although
      these materials have not been optimized, this value is comparable to the best ZT
      values obtained for any previously studied thermoelectric material. Calculations
      indicate that the optimized material should have ZT values of 1.4. These ternary
      semiconductors have the general formula RM4X12 (where R is lanthanum, cerium,
      praseodymium, neodymium, or europium; M is iron, ruthenium, or osmium; and X is
      phosphorus, arsenic, or antimony) and represent a new approach to creating
      improved thermoelectric materials. Several alloys in the composition range CeFe4
      xCoxSb12 or LaFe4-xCoxSb12 (0 < x < 4) have large values of ZT.

PMID- 8662466
TI  - Long-Range (Casimir) Interactions
AB  - Normally, nonrelativistic electromagnetic theory with two-particle Coulombic
      interactions adequately determines the interaction potential of systems A and B
      if the systems are composed of particles with characteristic velocities much less
      than the speed of light. If, however, the time it takes light to travel between A
      and B exceeds a characteristic oscillation period of A or B, the way in which the
      potential function depends on the separation of the systems can be altered.
      Called the Casimir effect, it has only recently been confirmed, and it arises in
      physics, chemistry, and biology. It is the clearest physical manifestation of the
      fact that, even in a vacuum, electromagnetic fields cannot all vanish.

PMID- 8662467
TI  - Transition-State Spectroscopy of Cyclooctatetraene
AB  - The 351-nanometer photoelectron spectrum of the planar cyclooctatetraene radical
      anion (COT&middot;-) shows transitions to two electronic states of
      cyclooctatetraene (COT). These states correspond to the D4h 1A1g state, which is
      the transition state for COT ring inversion, and the D8h 3A2u state. The electron
      binding energy of the 1A1g transition state is 1.099 &plusmn; 0.010 electron
      volts, which is lower by 12.1 &plusmn; 0.3 kilocalories per mole than that of the
      3A2u state. The photoelectron spectrum shows that the singlet lies well below the
      triplet in D8h COT and confirms ab initio predictions that the molecule violates
      Hund's rule. Vibrational structure is observed for both features and is readily
      assigned by use of a simple potential energy surface.

PMID- 8662468
TI  - Intrinsic Transport Properties and Performance Limits of Organic Field-Effect
      Transistors
AB  - The field-effect mobility in thin-film transistors based on alpha-sexithiophene
      (alpha-6T) and related materials displays a temperature dependence that is
      remarkably nonmonotonic. Above a transition temperature TT (specific to a given
      material) the transport is thermally activated, whereas below TT there is a very
      steep enhancement of the mobility. In the activated regime, the results are well
      described by the theoretical predictions for small polaron motion made by
      Holstein in 1959. An analysis of the transistor characteristics shows that the
      hopping transport in these devices is intrinsic. Performance limits for devices
      based on alpha-6T and related materials were established; these limits point to
      the strong possibility that better molecular materials for transistor
      applications may be designed from first principles.

PMID- 8662469
TI  - Lithospheric Contributions to Arc Magmatism: Isotope Variations Along Strike in
      Volcanoes of Honshu, Japan
AB  - Major chemical exchange between the crust and mantle occurs in subduction zone
      environments, profoundly affecting the chemical evolution of Earth. The relative
      contributions of the subducting slab, mantle wedge, and arc lithosphere to the
      generation of island arc magmas, and ultimately new continental crust, are
      controversial. Isotopic data for lavas from a transect of volcanoes in a single
      arc segment of northern Honshu, Japan, have distinct variations coincident with
      changes in crustal lithology. These data imply that the relatively thin crustal
      lithosphere is an active geochemical filter for all traversing magmas and is
      responsible for significant modification of primary mantle melts.

PMID- 8662470
TI  - Amorphization of Serpentine at High Pressure and High Temperature
AB  - Pressure-induced amorphization of serpentine was observed at temperatures of
      200&deg; to 300&deg;C and pressures of 14 to 27 gigapascals with a combination of
      a multianvil apparatus and synchrotron radiation. High-pressure phases then
      crystallized rapidly when the temperature was increased to 400&deg;C. These
      results suggest that amorphization of serpentine is an unlikely mechanism for
      generating deep-focus earthquakes, as the temperatures of subducting slabs are
      significantly higher than those of the rapid crystallization regime.

PMID- 8662471
TI  - Spatial Response of Mammals to Late Quaternary Environmental Fluctuations
AB  - Analyses of fossil mammal faunas from 2945 localities in the United States
      demonstrate that the geographic ranges of individual species shifted at different
      times, in different directions, and at different rates in response to late
      Quaternary environmental fluctuations. The geographic pattern of faunal provinces
      was similar for the late Pleistocene and late Holocene, but differing
      environmental gradients resulted in dissimilar species composition for these
      biogeographic regions. Modern community patterns emerged only in the last few
      thousand years, and many late Pleistocene communities do not have modern analogs.
      Faunal heterogeneity was greater in the late Pleistocene.

PMID- 8662472
TI  - Microscopic Particle Motions in Strongly Coupled Dusty Plasmas
AB  - The microscopic particle motions from the crystal to the disordered state of a
      dusty plasma with micrometer-sized silicon dioxide particle suspensions in a
      radio-frequency glow discharge system were studied through an optical
      microimaging system. Small-amplitude random motion around the lattice sites of
      the crystal state, relative domain motion with varying boundaries, cooperative
      hopping in the liquid state, and highly disordered motion with increasing radio
      frequency power were observed. Chaotic states with different spatial scales under
      the coherent and stochastic coupling between dust particles and self-organized
      background plasma fluctuations were also demonstrated.

PMID- 8662473
TI  - Electrical Properties of the Venus Surface from Bistatic Radar Observations
AB  - A bistatic radar experiment in 1994, involving reception on Earth of a specularly
      reflected, linearly polarized 13-centimeter-wavelength signal transmitted from
      the Magellan spacecraft in orbit around Venus, has established that the surface
      materials viewed at low and intermediate altitudes on Venus have a relative
      dielectric permittivity of 4.0 &plusmn; 0.5. However, bistatic results for the
      Maxwell Montes highlands imply an electrically lossy surface with an imaginary
      dielectric permittivity of -i 100 &plusmn; 50, probably associated with a
      specific conductivity of about 13 mhos per meter. Candidates for highlands
      surface composition include ferroelectrics, a thin frost of elemental tellurium,
      or a plating of magnetite or pyrites.

PMID- 8662474
TI  - High-Resolution Molecular Spectroscopy of van der Waals Clusters in Liquid Helium
      Droplets
AB  - Small van der Waals clusters of sulfur hexafluoride (SF6) and mixed SF6-rare gas
      clusters were prepared inside large droplets of helium-4, with each droplet
      consisting of about 4000 helium atoms. A diode laser was used to measure the high
      resolution infrared spectra of these clusters in the vicinity of the nu3
      vibrational mode. In all cases rotational structure was observed, indicating that
      the embedded species rotate nearly freely, although they had been cooled to a
      temperature of 0.37 kelvin. The results indicate that helium droplets are
      probably superfluid and thereby provide a uniquely cold yet gentle matrix for
      high-resolution spectroscopy.

PMID- 8662475
TI  - Direct pH Measurement of NaCl-Bearing Fluid with an in Situ Sensor at 400&deg;C
      and 40 Megapascals
AB  - The pH of concentrated NaCl-HCl fluids (0.57 mole of NaCl per kilogram of water)
      has been measured at supercritical conditions of water with a yttria-stabilized
      zirconia sensor in a titanium flow reactor. At 400&deg;C and 40 megapascals, the
      in situ pH of the fluids, ranging from 3.3 to 6.2, differs greatly from its
      original value of 1.9 to 7.6 at ambient conditions. The measurements agree well
      with theoretical predictions, showing strong associations of HCl&deg; and
      NaOH&deg; complexes in high-temperature fluids. The pH sensor provides a powerful
      tool to investigate unambiguously the distribution of species in aqueous fluids
      at elevated temperatures and pressures.

PMID- 8662476
TI  - Climate Change During the Last Deglaciation in Antarctica
AB  - Greenland ice core records provide clear evidence of rapid changes in climate in
      a variety of climate indicators. In this work, rapid climate change events in the
      Northern and Southern hemispheres are compared on the basis of an examination of
      changes in atmospheric circulation developed from two ice cores. High-resolution
      glaciochemical series, covering the period 10,000 to 16,000 years ago, from a
      central Greenland ice core and a new site in east Antarctica display similar
      variability. These findings suggest that rapid climate change events occur more
      frequently in Antarctica than previously demonstrated.

PMID- 8662477
TI  - Melting of H2SO4&middot;4H2O Particles upon Cooling: Implications for Polar
      Stratospheric Clouds
AB  - Polar stratospheric clouds (PSCs) are important for the chemical activation of
      chlorine compounds and subsequent ozone depletion. Solid PSCs can form on
      sulfuric acid tetrahydrate (SAT) (H2SO4&middot;4H2O) nuclei, but recent
      laboratory experiments have shown that PSC nucleation on SAT is strongly
      hindered. A PSC formation mechanism is proposed in which SAT particles melt upon
      cooling in the presence of HNO3 to form liquid HNO3-H2SO4-H2O droplets 2 to 3
      kelvin above the ice frost point. This mechanism offers a PSC formation
      temperature that is defined by the ambient conditions and sets a temperature
      limit below which PSCs should form.

PMID- 8662478
TI  - Quantifying Transport Between the Tropical and Mid-Latitude Lower Stratosphere
AB  - Airborne in situ observations of molecules with a wide range of lifetimes
      (methane, nitrous oxide, reactive nitrogen, ozone, chlorinated halocarbons, and
      halon-1211), used in a tropical tracer model, show that mid-latitude air is
      entrained into the tropical lower stratosphere within about 13.5 months;
      transport is faster in the reverse direction. Because exchange with the tropics
      is slower than global photochemical models generally assume, ozone at mid
      latitudes appears to be more sensitive to elevated levels of industrial chlorine
      than is currently predicted. Nevertheless, about 45 percent of air in the
      tropical ascent region at 21 kilometers is of mid-latitude origin, implying that
      emissions from supersonic aircraft could reach the middle stratosphere.

PMID- 8662479
TI  - High-Pressure Framework Silicates
AB  - Recent syntheses of high-pressure alkali and alkaline earth silicates reveal a
      class of framework structures with corner-linked 4- and 6-coordinated silicon.
      These compounds possess the structural formula (A4
      2x1+Bx2+)SimVI(SinIVO2(m+n)+2), where x, m, and n specify the amounts of alkaline
      earth, 6-coordinated silicon, and 4-coordinated silicon, respectively.
      Appropriate values of m and n yield a range of high-pressure structures, from
      fully 4-coordinated to fully 6-coordinated silicate frameworks. Recognition of
      this class of framework silicates leads to predictions of high-pressure
      structures as well as room-pressure isomorphs of high-pressure silicates.

PMID- 8662480
TI  - Evidence for Glacial Control of Rapid Sea Level Changes in the Early Cretaceous
AB  - Lower Cretaceous bulk carbonate from deep sea sediments records sudden inputs of
      strontium resulting from the exposure of continental shelves. Strontium data from
      an interval spanning 7 million years in the Berriasian-Valanginian imply that
      global sea level fluctuated about 50 meters over time scales of 200,000 to
      500,000 years, which is in agreement with the Exxon sea level curve. Oxygen
      isotope measurements indicate that the growth of continental ice sheets caused
      these rapid sea level changes. If glaciation caused all the rapid sea level
      changes in the Cretaceous that are indicated by the Exxon curve, then an
      Antarctic ice sheet may have existed despite overall climatic warmth.

PMID- 8662481
TI  - Fine-Scale Doppler Radar Observations of Tornadoes
AB  - Observations obtained with a mobile pencil-beam Doppler radar revealed many
      previously unresolved structures within tornadic storms and tornadoes and helped
      verify various aspects of conceptual models. Radar data from the parent
      circulations indicate the existence of spiral reflectivity bands, intense radial
      wind shear zones, and multiple larger-scale velocity maxima. Tornado structures
      observed include debris shields, clear axial (eye) regions, multiple reflectivity
      bands surrounding the center of the eye, and occasional reflectivity protrusions
      into the eye. Velocity and reflectivity data from tornado-scale circulations show
      evidence of axial downdrafts.

PMID- 8662482
TI  - Ion-Induced Morphological Changes in "Crew-Cut" Aggregates of Amphiphilic Block
      Copolymers
AB  - The addition of ions in micromolar (CaCl2 or HCl) or millimolar (NaCl)
      concentrations can change the morphology of "crew-cut" aggregates of amphiphilic
      block copolymers in dilute solutions. In addition to spherical, rodlike, and
      univesicular or lamellar aggregates, an unusual large compound vesicle morphology
      can be obtained from a single block copolymer. Some features of the spontaneously
      formed large compound vesicles may make them especially useful as vehicles for
      delivering drugs and as models of biological cells. Gelation of a dilute
      spherical micelle solution can also be induced by ions as the result of the
      formation of a cross-linked "pearl necklace" morphology.

PMID- 8662483
TI  - Nanoscale Magnetic Domains in Mesoscopic Magnets
AB  - The basic magnetic properties of three-dimensional nanostructured materials can
      be drastically different from those of a continuous film. High-resolution
      magnetic force microscopy studies of magnetic submicrometer-sized cobalt dots
      with geometrical dimensions comparable to the width of magnetic domains reveal a
      variety of intricate domain patterns controlled by the details of the dot
      geometry. By changing the thickness of the dots, the width of the geometrically
      constrained magnetic domains can be tuned. Concentric rings and spirals with
      vortex configurations have been stabilized, with particular incidence in the
      magnetization reversal process as observed in the ensemble-averaged hysteresis
      loops.

PMID- 8662490
TI  - Minimal Energy Requirements in Communication
AB  - The literature describing the energy needs for a communications channel has been
      dominated by analyses of linear electromagnetic transmission, often without
      awareness that this is a special case. This case leads to the conclusion that an
      amount of energy equal to kTln 2, where kT is the thermal noise per unit
      bandwidth, is needed to transmit a bit, and more if quantized channels are used
      with photon energies hnu > kT. Alternative communication methods are proposed to
      show that there is no unavoidable minimal energy requirement per transmitted bit.
      These methods are invoked as part of an analysis of ultimate limits and not as
      practical procedures.

PMID- 8662491
TI  - Off-Resonance Conduction Through Atomic Wires
AB  - The electrical resistance of wires consisting of either a single xenon atom or
      two xenon atoms in series was measured and calculated on the basis of an atom
      jellium model. Both the measurement and the calculation yielded a resistance of
      10(5) ohms for the single-xenon atom system and 10(7) ohms for the two-xenon atom
      system. These resistances greatly exceeded the 12,900-ohm resistance of an ideal
      one-dimensional conduction channel because conduction through the xenon atoms
      occurs through the tail of the xenon 6s resonance, which lies far above the Fermi
      level. This conduction process in an atom-sized system can now be understood in
      terms of the electronic states of individual atoms.

PMID- 8662492
TI  - Shape-Controlled Synthesis of Colloidal Platinum Nanoparticles
AB  - The shapes and sizes of platinum nanoparticles were controlled by changes in the
      ratio of the concentration of the capping polymer material to the concentration
      of the platinum cations used in the reductive synthesis of colloidal particles in
      solution at room temperature. Tetrahedral, cubic, irregular-prismatic,
      icosahedral, and cubo-octahedral particle shapes were observed, whose
      distribution was dependent on the concentration ratio of the capping polymer
      material to the platinum cation. Controlling the shape of platinum nanoparticles
      is potentially important in the field of catalysis.

PMID- 8662493
TI  - A Benzene-Thermal Synthetic Route to Nanocrystalline GaN
AB  - A thermal reaction of Li3N and GaCl3 in which benzene was used as the solvent
      under pressure has been carried out for the preparation of 30-nanometer particles
      of gallium nitride (GaN) at 280&deg;C. This temperature is much lower than that
      of traditional methods, and the yield of GaN reached 80%. The x-ray powder
      diffraction pattern indicated that sample was mainly hexagonal-phase GaN with a
      small fraction of rocksalt-phase GaN, which has a lattice constant a = 4.100
      angstroms. This rocksalt structure, which had been observed previously only under
      high pressure (at least 37 gigapascals) was observed directly with high
      resolution electron microscopy.

PMID- 8662494
TI  - Experimental Constraints on Recycling of Potassium from Subducted Oceanic Crust
AB  - Petrological experiments on oceanic crust samples characterize the recycling of
      potassium from mid-ocean ridge basalts and sediments. Metasomatism could develop
      directly and continuously from subducted potassium-bearing crust from shallow
      levels to a maximum depth of 300 kilometers. Phengite (a potassium-rich mica) is
      the principal potassium host at subsolidus conditions. It transports potassium
      and water to depths of up to 300 kilometers and could yield over the entire depth
      range potassium-rich fluids or melts (depending on the specific geotherm), which
      are likely to constitute one of the primary metasomatic agents for generation of
      calc-alkaline magmas.

PMID- 8662495
TI  - Pore Fluid Constraints on the Temperature and Oxygen Isotopic Composition of the
      Glacial Ocean
AB  - Pore fluids from the upper 60 meters of sediment 3000 meters below the surface of
      the tropical Atlantic indicate that the oxygen isotopic composition (delta18O) of
      seawater at this site during the last glacial maximum was 0.8 &plusmn; 0.1 per
      mil higher than it is today. Combined with the delta18O change in benthic
      foraminifera from this region, the elevated ratio indicates that the temperature
      of deep water in the tropical Atlantic Ocean was 4&deg;C colder during the last
      glacial maximum. Extrapolation from this site to a global average suggests that
      the ice volume contribution to the change in delta18O of foraminifera is 1.0 per
      mil, which partially reconciles the foraminiferal oxygen isotope record of
      tropical sea surface temperatures with estimates from Barbados corals and
      terrestrial climate proxies.

PMID- 8662497
TI  - A Chemoautotrophically Based Cave Ecosystem
AB  - Microbial mats discovered in a ground-water ecosystem in southern Romania contain
      chemoautotrophic bacteria that fix inorganic carbon, using hydrogen sulfide as an
      energy source. Analysis of stable carbon and nitrogen isotopes showed that this
      chemoautotrophic production is the food base for 48 species of cave-adapted
      terrestrial and aquatic invertebrates, 33 of which are endemic to this ecosystem.
      This is the only cave ecosystem known to be supported by in situ autotrophic
      production, and it contains the only terrestrial community known to be
      chemoautotrophically based.

PMID- 8662498
TI  - New designs of macroporous polymers and supports: from separation to
      biocatalysis.
AB  - Reactive polymers play many roles, from supports for solid-phase synthesis or
      catalysis to media for separations. Although macroporous polymer beads that
      provide high reactive capacities and excellent solvent tolerance are well
      established, approaches to monosized beads with optimized pore structures or
      multiple chemistries segregated within pores of different sizes have expanded
      their realm of application. Polymer monoliths containing intricate pore networks
      can be obtained in any desired shape by a simple molding process and provide
      unique advantages such as fast kinetics, high reactivity, and high throughput.
      Applications ranging from immobilized enzyme reactors to fast media for the
      separation of synthetic or biopolymers are presented.

PMID- 8662499
TI  - Transcription processivity: protein-DNA interactions holding together the
      elongation complex.
AB  - The elongation of RNA chains during transcription occurs in a ternary complex
      containing RNA polymerase (RNAP), DNA template, and nascent RNA. It is shown here
      that elongating RNAP from Escherichia coli can switch DNA templates by means of
      end-to-end transposition without loss of the transcript. After the switch,
      transcription continues on the new template. With the use of defined short DNA
      fragments as switching templates, RNAP-DNA interactions were dissected into two
      spatially distinct components, each contributing to the stability of the
      elongating complex. The front (F) interaction occurs ahead of the growing end of
      RNA. This interaction is non-ionic and requires 7 to 9 base pairs of intact DNA
      duplex. The rear (R) interaction is ionic and requires approximately six
      nucleotides of the template DNA strand behind the active site and one nucleotide
      ahead of it. The nontemplate strand is not involved. With the use of protein-DNA
      crosslinking, the F interaction was mapped to the conserved zinc finger motif in
      the NH2-terminus of the beta' subunit and the R interaction, to the COOH-terminal
      catalytic domain of the beta subunit. Mutational disruption of the zinc finger
      selectively destroyed the F interaction and produced a salt-sensitive ternary
      complex with diminished processivity. A model of the ternary complex is proposed
      here that suggests that trilateral contacts in the active center maintain the
      nonprocessive complex, whereas a front-end domain including the zinc finger
      ensures processivity.

PMID- 8662500
TI  - Compression of Ice to 210 Gigapascals: Infrared Evidence for a Symmetric Hydrogen
      Bonded Phase
AB  - Protonated and deuterated ices (H2O and D2O) compressed to a maximum pressure of
      210 gigapascals at 85 to 300 kelvin exhibit a phase transition at 60 gigapascals
      in H2O ice (70 gigapascals in D2O ice) on the basis of their infrared reflectance
      spectra determined with synchrotron radiation. The transition is characterized by
      soft-mode behavior of the nu3 O-H or O-D stretch below the transition, followed
      by a hardening (positive pressure shift) above it. This behavior is interpreted
      as the transformation of ice phase VII to a structure with symmetric hydrogen
      bonds. The spectroscopic features of the phase persisted to the maximum pressures
      (210 gigapascals) of the measurements, although changes in vibrational mode
      coupling were observed at 150 to 160 gigapascals.

PMID- 8662501
TI  - Making DNA add.
AB  - Recent studies have demonstrated the feasibility of using DNA-based experiments
      to compute solutions to combinatorial problems. However, a prerequisite for
      designing a computer useful in a wide range of applications is the ability to
      perform mathematical calculations. The development of a DNA-based algorithm for
      addition is presented. The DNA representation of two nonnegative binary numbers
      is presented in a form permitting a chain of primer extension reactions to carry
      out the addition operation. To demonstrate the feasibility of this algorithm, a
      simple example was executed biochemically.

PMID- 8662502
TI  - Maya Blue Paint: An Ancient Nanostructured Material
AB  - Maya blue paint was often used in Mesoamerica. The origin of its color and its
      resistance to acids and biocorrosion have not been fully understood. High
      resolution transmission electron microscopy, electron energy loss spectroscopy,
      and x-ray microanalysis studies of authentic samples show that palygorskite
      crystals in the paint form a superlattice that probably occurs as a result of
      mixing with indigo molecules. An amorphous silicate substrate contains inclusions
      of metal nanoparticles encapsulated in the substrate and oxide nanoparticles on
      the surface. The beautiful tone of the color is obtained only when both the
      particles and the superlattice are present.

PMID- 8662503
TI  - Formation of Atomically Flat Silver Films on GaAs with a "Silver Mean" Quasi
      Periodicity
AB  - A flat epitaxial silver film on a gallium arsenide [GaAs(110)] surface was
      synthesized in a two-step process. Deposition of a critical thickness of silver
      at low temperature led to the formation of a dense nanocluster film. Upon
      annealing, all atoms rearranged themselves into an atomically flat film. This
      silver film has a close-packed (111) structure modulated by a "silver mean" quasi
      periodic sequence. The ability to grow such epitaxial overlayers of metals on
      semiconductors enables the testing of theoretical models and provides a
      connection between metal and semiconductor technologies.

PMID- 8662504
TI  - Mechanism of suppression of cell-mediated immunity by measles virus.
AB  - The mechanisms underlying the profound suppression of cell-mediated immunity
      (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived
      principally from monocytes and macrophages, is critical for the generation of
      CMI. Measles virus (MV) infection of primary human monocytes specifically down
      regulated IL-12 production. Cross-linking of CD46, a complement regulatory
      protein that is the cellular receptor for MV, with antibody or with the
      complement activation product C3b similarly inhibited monocyte IL-12 production,
      providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a
      regulatory link between the complement system and cellular immune responses.

PMID- 8662505
TI  - Structure of the amino-terminal core domain of the HIV-1 capsid protein.
AB  - The three-dimensional structure of the amino-terminal core domain (residues 1
      through 151) of the human immunodeficiency virus-type 1 (HIV-1) capsid protein
      has been solved by multidimensional heteronuclear magnetic resonance
      spectroscopy. The structure is unlike those of previously characterized viral
      coat proteins and is composed of seven alpha helices, two beta hairpins, and an
      exposed partially ordered loop. The domain is shaped like an arrowhead, with the
      beta hairpins and loop exposed at the trailing edge and the carboxyl-terminal
      helix projecting from the tip. The proline residue Pro1 forms a salt bridge with
      a conserved, buried aspartate residue (Asp51), which suggests that the amino
      terminus of the protein rearranges upon proteolytic maturation. The binding site
      for cyclophilin A, a cellular rotamase that is packaged into the HIV-1 virion, is
      located on the exposed loop and encompasses the essential proline residue Pro90.
      In the free monomeric domain, Pro90 adopts kinetically trapped cis and trans
      conformations, raising the possibility that cyclophilin A catalyzes
      interconversion of the cis- and trans-Pro90 loop structures.

PMID- 8662506
TI  - Polar overdominance at the ovine callipyge locus.
AB  - An inheritable muscular hypertrophy was recently described in sheep and shown to
      be determined by the callipyge gene mapped to ovine chromosome 18. Here, the
      callipyge phenotype was found to be characterized by a nonmendelian inheritance
      pattern, referred to as polar overdominance, where only heterozygous individuals
      having inherited the callipyge mutation from their sire express the phenotype.
      The possible role of parental imprinting in the determinism of polar
      overdominance is envisaged.

PMID- 8662507
TI  - Structure of the FKBP12-rapamycin complex interacting with the binding domain of
      human FRAP.
AB  - Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506
      binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A
      crystal structure of the ternary complex of human FKBP12, rapamycin, and the
      FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7
      angstroms revealed the two proteins bound together as a result of the ability of
      rapamycin to occupy two different hydrophobic binding pockets simultaneously. The
      structure shows extensive interactions between rapamycin and both proteins, but
      fewer interactions between the proteins. The structure of the FRB domain of FRAP
      clarifies both rapamycin-independent and -dependent effects observed for mutants
      of FRAP and its homologs in the family of proteins related to the ataxia
      telangiectasia mutant gene product, and it illustrates how a small cell-permeable
      molecule can mediate protein dimerization.

PMID- 8662508
TI  - Long-term lymphohematopoietic reconstitution by a single CD34-low/negative
      hematopoietic stem cell.
AB  - Hematopoietic stem cells (HSCs) supply all blood cells throughout life by making
      use of their self-renewal and multilineage differentiation capabilities. A
      monoclonal antibody raised to the mouse homolog of CD34 (mCD34) was used to
      purify mouse HSCs to near homogeneity. Unlike in humans, primitive adult mouse
      bone marrow HSCs were detected in the mCD34 low to negative fraction. Injection
      of a single mCD34(lo/-), c-Kit+, Sca-1(+), lineage markers negative (Lin-) cell
      resulted in long-term reconstitution of the lymphohematopoietic system in 21
      percent of recipients. Thus, the purified HSC population should enable analysis
      of the self-renewal and multilineage differentiation of individual HSCs.

PMID- 8662509
TI  - Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase)
AB  - The small guanosine triphosphatase Rho is implicated in myosin light chain (MLC)
      phosphorylation, which results in contraction of smooth muscle and interaction of
      actin and myosin in nonmuscle cells. The guanosine triphosphate (GTP)-bound,
      active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding
      subunit (MBS) of myosin phosphatase, which regulates the extent of
      phosphorylation of MLC. Rho-associated kinase (Rho-kinase), which is activated by
      GTP.RhoA, phosphorylated MBS and consequently inactivated myosin phosphatase.
      Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased
      phosphorylation of MBS and MLC. Thus, Rho appears to inhibit myosin phosphatase
      through the action of Rho-kinase.

PMID- 8662510
TI  - Bipartite Ca2+-binding motif in C2 domains of synaptotagmin and protein kinase C.
AB  - C2 domains are found in many proteins involved in membrane traffic or signal
      transduction. Although C2 domains are thought to bind calcium ions, the
      structural basis for calcium binding is unclear. Analysis of calcium binding to
      C2 domains of synaptotagmin I and protein kinase C-beta by nuclear magnetic
      resonance spectroscopy revealed a bipartite calcium-binding motif that involves
      the coordination of two calcium ions by five aspartate residues located on two
      separate loops. Sequence comparisons indicated that this may be a widely used
      calcium-binding motif, designated here as the C2 motif.

PMID- 8662512
TI  - Excitation Gap in the Normal State of Underdoped Bi2Sr2CaCu2O8+delta
AB  - Angle-resolved photoemission experiments reveal evidence of an energy gap in the
      normal state excitation spectrum of the cuprate superconductor
      Bi2Sr2CaCu2O8+delta. This gap exists only in underdoped samples and closes around
      the doping level at which the superconducting transition temperature Tc is a
      maximum. The momentum dependence and magnitude of the gap closely resemble those
      of the dx2-y2 gap observed in the superconducting state. This observation is
      consistent with results from several other experimental techniques, which also
      indicate the presence of a gap in the normal state. Some possible theoretical
      explanations for this effect are reviewed.

PMID- 8662511
TI  - Platelet-mediated lymphocyte delivery to high endothelial venules.
AB  - Circulating lymphocytes gain access to lymph nodes owing to their ability to
      initiate rolling along specialized high endothelial venules (HEVs). One mechanism
      of rolling involves L-selectin binding to peripheral node addressin (PNAd) on
      HEVs. Activated platelets are shown to bind to circulating lymphocytes and to
      mediate rolling in HEVs, in vivo, through another molecule, P-selectin, which
      also interacts with PNAd. In vitro, activated platelets enhanced tethering of
      lymphocytes to PNAd and sustained lymphocyte rolling, even in the absence of
      functional L-selectin. Thus, a platelet pathway operating through P-selectin
      provides a second mechanism for lymphocyte delivery to HEVs.

PMID- 8662514
TI  - Hydrogen-Bond Breaking and Proton Exchange in Collisions of Gaseous Formic Acid
      with Liquid Sulfuric Acid
AB  - Gas-liquid scattering experiments provide direct observations of the fate of
      hydrogen-bonding molecules striking the surfaces of acidic liquids. Collisions of
      gaseous formic acid with concentrated sulfuric acid show that impinging monomers
      (HCOOH and DCOOD) scatter inelastically from the interface or become trapped by
      surface H2SO4. Most trapped DCOOD molecules undergo proton exchange before
      desorbing from the acid, indicating that gas-surface accommodation almost always
      leads to reaction with H2SO4 molecules. This proton transfer is not inhibited by
      dimerization of the formic acid: The dimers readily undergo intramolecular
      hydrogen bond cleavage and D-H exchange before desorbing from the acid.

PMID- 8662513
TI  - Role of lipid polymorphism in pulmonary surfactant.
AB  - The development of artificial surfactants for the treatment of respiratory
      distress syndrome (RDS) requires lipid systems that can spread rapidly from
      solution to the air-water interface. Because hydration-repulsion forces stabilize
      liposomal bilayers and oppose spreading, liposome systems that undergo geometric
      rearrangement from the bilayer (lamellar) phase to the hexagonal II (HII) phase
      could hasten lipid transfer to the air-water interface through unstable
      transition intermediates. A liposome system containing
      dipalmitoylphosphatidylcholine was designed; the system is stable at 23 degrees C
      but undergoes transformation to the HII phase as the temperature increases to 37
      degrees C. The spreading of lipid from this system to the air-water interface was
      rapid at 37 degrees C but slow at 23 degrees C. When tested in vivo in a neonatal
      rabbit model, such systems elicited an onset of action equal to that of native
      human surfactant. These findings suggest that lipid polymorphic phase behavior
      may have a crucial role in the effective functioning of pulmonary surfactant.

PMID- 8662515
TI  - The Morphogenesis of Bands and Zonal Winds in the Atmospheres on the Giant Outer
      Planets
AB  - The atmospheres of Jupiter, Saturn, Uranus, and Neptune were modeled as shallow
      layers of turbulent fluid overlying a smooth, spherical interior. With only the
      observed values of radius, rotation rate, average wind velocity, and mean layer
      thickness as model parameters, bands and jets spontaneously emerged from random
      initial conditions. The number, width, and amplitude of the jets, as well as the
      dominance of anticyclonic vortices, are in good agreement with observations for
      all four planets.

PMID- 8662516
TI  - A Magnetic Signature at Io: Initial Report from the Galileo Magnetometer
AB  - During the inbound pass of the Galileo spacecraft, the magnetometer acquired 1
      minute averaged measurements of the magnetic field along the trajectory as the
      spacecraft flew by Io. A field decrease, of nearly 40 percent of the background
      jovian field at closest approach to Io, was recorded. Plasma sources alone appear
      incapable of generating perturbations as large as those observed and an induced
      source for the observed moment implies an amount of free iron in the mantle much
      greater than expected. On the other hand, an intrinsic magnetic field of
      amplitude consistent with dynamo action at Io would explain the observations. It
      seems plausible that Io, like Earth and Mercury, is a magnetized solid planet.

PMID- 8662517
TI  - Detection of ozone on Ganymede.
AB  - An absorption band at 260 nanometers on the trailing hemisphere of Ganymede,
      identified as the Hartley band of Ozone (O3), was measured with the Hubble Space
      Telescope. The column abundance of ozone, 4.5 x 10(16) per square centimeter, can
      be produced by ion impacts or by photochemical equilibrium with previously
      detected molecular oxygen (O2). An estimated number density ratio of [O3]/[O2] =
      10(-4) to 10(-3) requires an atmospheric density orders of magnitude higher than
      upper limits from spacecraft occultation experiments. Apparently, this O2-O3
      "atmosphere" is trapped in Ganymede's surface ice, an inference consistent with
      the shift and broadening of the band compared with the gas-phase O3 band.

PMID- 8662518
TI  - Self-Assembled Smectic Phases in Rod-Coil Block Copolymers
AB  - Rod-coil block copolymers are self-assembling polymers that combine the physics
      of orientational ordering of rodlike polymers and the microphase separation of
      coil-coil block copolymers. Several new solid-state morphologies were observed in
      a series of anionically synthesized model poly(hexyl isocyanate-b-styrene) rod
      coil diblock copolymers examined by transmission electron microscopy and selected
      area electron diffraction. The rod-coils formed smectic C-like and O-like
      morphologies with domain sizes ranging from tens of nanometers to almost 1
      micrometer. Both structural and orientational changes were found for increasing
      rod volume fractions. In addition, some morphologies exhibited spontaneous long
      range orientational order over many tens of micrometers.

PMID- 8662519
TI  - Complex Optical Surfaces Formed by Replica Molding Against Elastomeric Masters
AB  - Complex, optically functional surfaces in organic polymers can be fabricated by
      replicating relief structures present on the surface of an elastomeric master
      with an ultraviolet or thermally curable organic polymer, while the master is
      deformed by compression, bending, or stretching. The versatility of this
      procedure for fabricating surfaces with complex, micrometer- and submicrometer
      scale patterns was demonstrated by the production of (i) diffraction gratings
      with periods smaller than the original grating; (ii) chirped, blazed diffraction
      gratings (where the period of a chirped grating changes continuously with
      position) on planar and curved surfaces; (iii) patterned microfeatures on the
      surfaces of approximately hemispherical objects (for example, an optical surface
      similar to a fly's eye); and (iv) arrays of rhombic microlenses. These
      topologically complex, micropatterned surfaces are difficult to fabricate with
      other techniques.

PMID- 8662520
TI  - Cytoplasmic tail-dependent localization of CD1b antigen-presenting molecules to
      MIICs.
AB  - CD1 proteins have been implicated as antigen-presenting molecules for T cell
      mediated immune responses, but their intracellular localization and trafficking
      remain uncharacterized. CD1b, a member of this family that presents microbial
      lipid antigens of exogenous origin, was found to localize to endocytic
      compartments that included the same specialized subset of endosomes in which
      major histocompatibility complex (MHC) class II molecules are proposed to bind
      endocytosed antigens. Unlike MHC class II molecules, which traffic to antigen
      loading endosomal compartments [MHC class II compartments (MIICs)] primarily as a
      consequence of their association with the invariant chain, localization of CD1b
      to these compartments was dependent on a tyrosine-based motif in its own
      cytoplasmic tail.

PMID- 8662521
TI  - Immunostimulatory DNA sequences necessary for effective intradermal gene
      immunization.
AB  - Vaccination with naked DNA elicits cellular and humoral immune responses that
      have a T helper cell type 1 bias. However, plasmid vectors expressing large
      amounts of gene product do not necessarily induce immune responses to the encoded
      antigens. Instead, the immunogenicity of plasmid DNA (pDNA) requires short
      immunostimulatory DNA sequences (ISS) that contain a CpG dinucleotide in a
      particular base context. Human monocytes transfected with pDNA or double-stranded
      oligonucleotides containing the ISS, but not those transfected with ISS-deficient
      pDNA or oligonucleotides, transcribed large amounts of interferon-alpha,
      interferon-beta, and interleukin-12. Although ISS are necessary for gene
      vaccination, they down-regulate gene expression and thus may interfere with gene
      replacement therapy by inducing proinflammatory cytokines.

PMID- 8662522
TI  - The secreted product of Xenopus gene lunatic Fringe, a vertebrate signaling
      molecule.
AB  - Signaling molecules are essential for vertebrate embryonic development. Here, two
      Xenopus homologs of the Drosophila gene fringe, lunatic Fringe (lFng) and radical
      Fringe (rFng), were identified and the protein product of lFng further
      characterized. The messenger RNA of lFng is supplied as a maternal message. Its
      product is a precursor protein consisting of pre-, pro-, and mature regions. The
      mature lunatic Fringe protein is secreted extracellularly, and it induced
      mesodermal tissue formation in animal cap assays. These results indicate that
      secreted lunatic Fringe can induce mesoderm and reveal that the Fringe proteins
      are a family of vertebrate signaling molecules.

PMID- 8662523
TI  - Resistance to apoptosis conferred by Cdk inhibitors during myocyte
      differentiation.
AB  - Proliferating murine C2C12 myoblasts can undergo either terminal differentiation
      or programmed cell death under conditions of mitogen deprivation. Unlike
      myoblasts, differentiated myotubes were resistant to apoptosis. During myogenesis
      the appearance of the apoptosis-resistant phenotype was correlated with the
      induction of the cyclin-dependent kinase (Cdk) inhibitor p21(CIP1) but not with
      the appearance of myogenin, a marker expressed earlier in differentiation. Forced
      expression of the Cdk inhibitors p21(CIP1) or p16(INK4A) blocked apoptosis during
      myocyte differentiation. These data indicate that induction of Cdk inhibitors may
      serve to protect differentiating myocytes from programmed cell death as well as
      play a role in establishing the postmitotic state.

PMID- 8662524
TI  - Interaction between a putative mechanosensory membrane channel and a collagen.
AB  - The degenerin family of proteins in Caenorhabditis elegans is homologous to
      subunits of the mammalian amiloride-sensitive epithelial sodium channels.
      Mutations in nematode degenerins cause cell death, probably because of defects in
      channel function. Genetic evidence was obtained that the unc-105 gene product
      represents a degenerin homolog affecting C. elegans muscles and that this
      putative channel interacts with type IV collagen in the extracellular matrix
      underlying the muscle cell. This interaction may serve as a mechanism of stretch
      activated muscle contraction, and this system could provide a molecular model for
      the activation of mechanosensitive ion channels.

PMID- 8662525
TI  - Oxygenic Photoautotrophic Growth Without Photosystem I
AB  - Contrary to the prediction of the Z-scheme model of photosynthesis, experiments
      demonstrated that mutants of Chlamydomonas containing photosystem II (PSII) but
      lacking photosystem I (PSI) can grow photoautotrophically with O2 evolution,
      using atmospheric CO2 as the sole carbon source. Autotrophic photosynthesis by
      PSI-deficient mutants was stable both under anaerobic conditions and in air (21
      percent O2) at an actinic intensity of 200 microeinsteins per square meter per
      second. This PSII photosynthesis, which was sufficient to support cell
      development and mobility, may also occur in wild-type green algae and higher
      plants. The mutants can survive under 2000 microeinsteins per square meter per
      second with air, although they have less resistance to photoinhibition.

PMID- 8662526
TI  - Role of the Yersinia pestis hemin storage (hms) locus in the transmission of
      plague by fleas.
AB  - Yersinia pestis, the cause of bubonic plague, is transmitted by the bites of
      infected fleas. Biological transmission of plague depends on blockage of the
      foregut of the flea by a mass of plague bacilli. Blockage was found to be
      dependent on the hemin storage (hms) locus. Yersinia pestis hms mutants
      established long-term infection of the flea's midgut but failed to colonize the
      proventriculus, the site in the foregut where blockage normally develops. Thus,
      the hms locus markedly alters the course of Y. pestis infection in its insect
      vector, leading to a change in blood-feeding behavior and to efficient
      transmission of plague.

PMID- 8662528
TI  - Comparative Earth History and Late Permian Mass Extinction
AB  - The repeated association during the late Neoproterozoic Era of large carbon
      isotopic excursions, continental glaciation, and stratigraphically anomalous
      carbonate precipitation provides a framework for interpreting the reprise of
      these conditions on the Late Permian Earth. A paleoceanographic model that was
      developed to explain these stratigraphically linked phenomena suggests that the
      overturn of anoxic deep oceans during the Late Permian introduced high
      concentrations of carbon dioxide into surficial environments. The predicted
      physiological and climatic consequences for marine and terrestrial organisms are
      in good accord with the observed timing and selectivity of Late Permian mass
      extinction.

PMID- 8662527
TI  - Modification of phytohormone response by a peptide encoded by ENOD40 of legumes
      and a nonlegume.
AB  - The gene ENOD40 is expressed during early stages of legume nodule development. A
      homolog was isolated from tobacco, which, as does ENOD40 from legumes, encodes an
      oligopeptide of about 10 amino acids. In tobacco protoplasts, these peptides
      change the response to auxin at concentrations as low as 10(-12) to 10(-16)M. The
      peptides encoded by ENOD40 appear to act as plant growth regulators.

PMID- 8662529
TI  - Small peptides as potent mimetics of the protein hormone erythropoietin.
AB  - Random phage display peptide libraries and affinity selective methods were used
      to isolate small peptides that bind to and activate the receptor for the cytokine
      erythropoietin (EPO). In a panel of in vitro biological assays, the peptides act
      as full agonists and they can also stimulate erythropoiesis in mice. These
      agonists are represented by a 14- amino acid disulfide-bonded, cyclic peptide
      with the minimum consensus sequence YXCXXGPXTWXCXP, where X represents positions
      allowing occupation by several amino acids. The amino acid sequences of these
      peptides are not found in the primary sequence of EPO. The signaling pathways
      activated by these peptides appear to be identical to those induced by the
      natural ligand. This discovery may form the basis for the design of small
      molecule mimetics of EPO.

PMID- 8662531
TI  - Nonlinear Optics in Relativistic Plasmas and Laser Wake Field Acceleration of
      Electrons
AB  - When a terawatt-peak-power laser beam is focused into a gas jet, an electron
      plasma wave, driven by forward Raman scattering, is observed to accelerate a
      naturally collimated beam of electrons to relativistic energies (up to 10(9)
      total electrons, with an energy distribution maximizing at 2 megaelectron volts,
      a transverse emittance as low as 1 millimeter-milliradian, and a field gradient
      of up to 2 gigaelectron volts per centimeter). Electron acceleration and the
      appearance of high-frequency modulations in the transmitted light spectrum were
      both found to have sharp thresholds in laser power and plasma density. A hole in
      the center of the electron beam may indicate that plasma electrons were expelled
      radially.

PMID- 8662530
TI  - Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor
      complex at 2.8 A.
AB  - The functional mimicry of a protein by an unrelated small molecule has been a
      formidable challenge. Now, however, the biological activity of a 166-residue
      hematopoietic growth hormone, erythropoietin (EPO), with its class 1 cytokine
      receptor has been mimicked by a 20-residue cyclic peptide unrelated in sequence
      to the natural ligand. The crystal structure at 2.8 A resolution of a complex of
      this agonist peptide with the extracellular domain of EPO receptor reveals that a
      peptide dimer induces an almost perfect twofold dimerization of the receptor. The
      dimer assembly differs from that of the human growth hormone (hGH) receptor
      complex and suggests that more than one mode of dimerization may be able to
      induce signal transduction and cell proliferation. The EPO receptor binding site,
      defined by peptide interaction, corresponds to the smaller functional epitope
      identified for hGH receptor. Similarly, the EPO mimetic peptide ligand can be
      considered as a minimal hormone, and suggests the design of nonpeptidic small
      molecule mimetics for EPO and other cytokines may indeed be achievable.

PMID- 8662533
TI  - Low-Frequency Raman Scattering and the Fast Relaxation Process in Glycerol
AB  - Ab initio molecular orbital calculations were used to determine the structure and
      vibrational frequencies of the cyclic glycerol trimer, which represents the
      region of medium-range ordering in liquid and supercooled glycerol. The
      calculations reproduced the experimentally observed low-frequency Raman
      scattering peak (or the "boson peak") at approximately50 per centimeter, which
      suggests that the peak results from the localized collective motions of the
      cooperatively hydrogen-bonded hydroxyl groups. The calculations also suggest that
      the fast relaxation process may result from the translational motion of each
      glycerol molecule in the cyclic structure. On the basis of these results, a model
      of the glass transition was developed.

PMID- 8662532
TI  - Rates of DNA-mediated electron transfer between metallointercalators.
AB  - Ultrafast emission and absorption spectroscopies were used to measure the
      kinetics of DNA-mediated electron transfer reactions between metal complexes
      intercalated into DNA. In the presence of rhodium(III) acceptor, a substantial
      fraction of photoexcited donor exhibits fast oxidative quenching (>3 x 10(10) per
      second). Transient-absorption experiments indicate that, for a series of donors,
      the majority of back electron transfer is also very fast (approximately 10(10)
      per second). This rate is independent of the loading of acceptors on the helix,
      but is sensitive to sequence and pi stacking. The cooperative binding of donor
      and acceptor is considered unlikely on the basis of structural models and DNA
      photocleavage studies of binding. These data show that the DNA double helix
      differs significantly from proteins as a bridge for electron transfer.

PMID- 8662534
TI  - Crystalline Ropes of Metallic Carbon Nanotubes
AB  - Fullerene single-wall nanotubes (SWNTs) were produced in yields of more than 70
      percent by condensation of a laser-vaporized carbon-nickel-cobalt mixture at
      1200degreesC. X-ray diffraction and electron microscopy showed that these SWNTs
      are nearly uniform in diameter and that they self-organize into "ropes," which
      consist of 100 to 500 SWNTs in a two-dimensional triangular lattice with a
      lattice constant of 17 angstroms. The x-ray form factor is consistent with that
      of uniformly charged cylinders 13.8 +/- 0.2 angstroms in diameter. The ropes were
      metallic, with a single-rope resistivity of <10(-4) ohm-centimeters at 300
      kelvin. The uniformity of SWNT diameter is attributed to the efficient annealing
      of an initial fullerene tubelet kept open by a few metal atoms; the optimum
      diameter is determined by competition between the strain energy of curvature of
      the graphene sheet and the dangling-bond energy of the open edge, where growth
      occurs. These factors strongly favor the metallic (10,10) tube with C5v symmetry
      and an open edge stabilized by triple bonds.

PMID- 8662535
TI  - Investigation of Ancient Egyptian Baking and Brewing Methods by Correlative
      Microscopy
AB  - Ancient Egyptian methods of baking and brewing are investigated by optical and
      scanning electron microscopy of desiccated bread loaves and beer remains. The
      results suggest that current conceptions about ancient Egyptian bread and beer
      making should be modified. Bread was made not only with flour from raw grain, but
      sometimes also with malt and with yeast. Brewing blended cooked and uncooked malt
      with water; the mixture was strained free of husk before inoculation with yeast.

PMID- 8662536
TI  - Volatiles from the 1994 Eruptions of Rabaul: Understanding Large Caldera Systems
AB  - The 1994 eruption of Rabaul, in Papua New Guinea, involved a small plinian
      eruption at Vulcan and a vulcanian eruption on the opposite side of the caldera
      at Tavurvur. Vulcan's ash leachates indicate seawater interaction that is
      consistent with earlier observations of low sulfur dioxide emissions and the
      presence of ice crystals in the initial plinian eruption cloud. In contrast,
      Tavurvur ash leachates indicate no seawater interaction, and later sulfur dioxide
      emissions remained high despite low-level eruptive activity. Silicic melt
      inclusions indicate that the andesitic melt contained about 2 weight percent
      water and negligible carbon dioxide. Mafic melt inclusions in Tavurvur ash have
      water and carbon dioxide contents that vary systematically over the course of the
      eruption. The mafic melt inclusions suggest that a mafic dike intruded from below
      the silicic chamber and provide further evidence that mafic intrusions drive
      caldera unrest.

PMID- 8662537
TI  - Multicolor spectral karyotyping of human chromosomes.
AB  - The simultaneous and unequivocal discernment of all human chromosomes in
      different colors would be of significant clinical and biologic importance. Whole
      genome scanning by spectral karyotyping allowed instantaneous visualization of
      defined emission spectra for each human chromosome after fluorescence in situ
      hybridization. By means of computer separation (classification) of spectra,
      spectrally overlapping chromosome-specific DNA probes could be resolved, and all
      human chromosomes were simultaneously identified.

PMID- 8662538
TI  - Control strategies for tuberculosis epidemics: new models for old problems.
AB  - Tuberculosis, although preventable and curable, causes more adult deaths than any
      other infectious disease. A theoretical framework for designing effective control
      strategies is developed and used to determine treatment levels for eradication,
      to assess the effects of noneradicating control, and to examine the global goals
      of the World Health Organization. The theory is extended to assess how suboptimal
      control programs contribute to the evolution of drug resistance. A new evaluation
      criterion is defined and used to suggest how control strategies can be improved.
      In order to control tuberculosis, treatment failure rates must be lower in
      developing countries than in developed countries.

PMID- 8662539
TI  - A receptor for the selective uptake and degradation of proteins by lysosomes.
AB  - Multiple pathways of protein degradation operate within cells. A selective
      protein import pathway exists for the uptake and degradation of particular
      cytosolic proteins by lysosomes. Here, the lysosomal membrane glycoprotein LGP96
      was identified as a receptor for the selective import and degradation of proteins
      within lysosomes. Specific substrates of this proteolytic pathway bound to the
      cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different
      binding assays. Overexpression of human LGP96 in Chinese hamster ovary cells
      increased the activity of the selective lysosomal proteolytic pathway in vivo and
      in vitro.

PMID- 8662540
TI  - Lymphocyte apoptosis: mediation by increased type 3 inositol 1,4,5-trisphosphate
      receptor.
AB  - B and T lymphocytes undergoing apoptosis in response to anti-immunoglobulin M
      antibodies and dexamethasone, respectively, were found to have increased amounts
      of messenger RNA for the inositol 1,4,5-trisphosphate receptor (IP3R) and
      increased amounts of IP3R protein. Immunohistochemical analysis revealed that the
      augmented receptor population was localized to the plasma membrane. Type 3 IP3R
      (IP3R3) was selectively increased during apoptosis, with no enhancement of type 1
      IP3R (IP3R1). Expression of IP3R3 antisense constructs in S49 T cells blocked
      dexamethasone-induced apoptosis, whereas IP3R3 sense, IP3R1 sense, or IP3R1
      antisense control constructs did not block cell death. Thus, the increases in
      IP3R3 may be causally related to apoptosis.

PMID- 8662541
TI  - The POU factor Oct-6 and Schwann cell differentiation.
AB  - The POU transcription factor Oct-6, also known as SCIP or Tst-1, has been
      implicated as a major transcriptional regulator in Schwann cell differentiation.
      Microscopic and immunochemical analysis of sciatic nerves of Oct-6(-/-) mice at
      different stages of postnatal development reveals a delay in Schwann cell
      differentiation, with a transient arrest at the promyelination stage. Thus, Oct-6
      appears to be required for the transition of promyelin cells to myelinating
      cells. Once these cells progress past this point, Oct-6 is no longer required,
      and myelination occurs normally.

PMID- 8662542
TI  - Spinal cord repair in adult paraplegic rats: partial restoration of hind limb
      function.
AB  - Complete spinal cord gaps in adult rats were bridged with multiple intercostal
      nerve grafts that redirected specific pathways from white to gray matter. The
      grafted area was stabilized with fibrin glue containing acidic fibroblast growth
      factor and by compressive wiring of posterior spinal processes. Hind limb
      function improved progressively during the first 6 months, as assessed by two
      scoring systems. The corticospinal tract regenerated through the grafted area to
      the lumbar enlargement, as did several bulbospinal pathways. These data suggest a
      possible repair strategy for spinal cord injury.

PMID- 8662543
TI  - Persistent site-specific remodeling of a nucleosome array by transient action of
      the SWI/SNF complex.
AB  - The SWI/SNF complex participates in the restructuring of chromatin for
      transcription. The function of the yeast SWI/SNF complex in the remodeling of a
      nucleosome array has now been analyzed in vitro. Binding of the purified SWI/SNF
      complex to a nucleosome array disrupted multiple nucleosomes in an adenosine
      triphosphate-dependent reaction. However, removal of SWI/SNF left a
      deoxyribonuclease I-hypersensitive site specifically at a nucleosome that was
      bound by derivatives of the transcription factor Gal4p. Analysis of individual
      nucleosomes revealed that the SWI/SNF complex catalyzed eviction of histones from
      the Gal4-bound nucleosomes. Thus, the transient action of the SWI/SNF complex
      facilitated irreversible disruption of transcription factor-bound nucleosomes.

PMID- 8662544
TI  - Mapping the protein universe.
AB  - The comparison of the three-dimensional shapes of protein molecules poses a
      complex algorithmic problem. Its solution provides biologists with computational
      tools to organize the rapidly growing set of thousands of known protein shapes,
      to identify new types of protein architecture, and to discover unexpected
      evolutionary relations, reaching back billions of years, between protein
      molecules. Protein shape comparison also improves tools for identifying gene
      functions in genome databases by defining the essential sequence-structure
      features of a protein family. Finally, an exhaustive all-on-all shape comparison
      provides a map of physical attractor regions in the abstract shape space of
      proteins, with implications for the processes of protein folding and evolution.

PMID- 8662545
TI  - Four-dimensional imaging: computer visualization of 3D movements in living
      specimens.
AB  - The study of many biological processes requires the analysis of three-dimensional
      (3D) structures that change over time. Optical sectioning techniques can provide
      3D data from living specimens; however, when 3D data are collected over a period
      of time, the quantity of image information produced leads to difficulties in
      interpretation. A computer-based system is described that permits the analysis
      and archiving of 3D image data taken over time. The system allows a user to roam
      through the full range of time points and focal planes in the data set. The user
      can animate images as an aid to visualization and can append multicolored labels
      and text notes to identified structures during data analysis. The system provides
      a valuable tool for the study of embryogenesis and cytoplasmic movements within
      cells and has considerable potential as an educational tool.

PMID- 8662546
TI  - Regulation of rate of cartilage differentiation by Indian hedgehog and PTH
      related protein.
AB  - Proper regulation of chondrocyte differentiation is necessary for the
      morphogenesis of skeletal elements, yet little is known about the molecular
      regulation of this process. A chicken homolog of Indian hedgehog (Ihh), a member
      of the conserved Hedgehog family of secreted proteins that is expressed during
      bone formation, has now been isolated. Ihh has biological properties similar to
      those of Sonic hedgehog (Shh), including the ability to regulate the conserved
      targets Patched (Ptc) and Gli. Ihh is expressed in the prehypertrophic
      chondrocytes of cartilage elements, where it regulates the rate of hypertrophic
      differentiation. Misexpression of Ihh prevents proliferating chondrocytes from
      initiating the hypertrophic differentiation process. The direct target of Ihh
      signaling is the perichondrium, where Gli and Ptc flank the expression domain of
      Ihh. Ihh induces the expression of a second signal, parathyroid hormone-related
      protein (PTHrP), in the periarticular perichondrium. Analysis of PTHrP (-/-)
      mutant mice indicated that the PTHrP protein signals to its receptor in the
      prehypertrophic chondrocytes, thereby blocking hypertrophic differentiation. In
      vitro application of Hedgehog or PTHrP protein to normal or PTHrP (-/-) limb
      explants demonstrated that PTHrP mediates the effects of Ihh through the
      formation of a negative feedback loop that modulates the rate of chondrocyte
      differentiation.

PMID- 8662547
TI  - Support for the prion hypothesis for inheritance of a phenotypic trait in yeast.
AB  - A cytoplasmically inherited genetic element in yeast, [PSI+], was confirmed to be
      a prionlike aggregate of the cellular protein Sup35 by differential
      centrifugation analysis and microscopic localization of a Sup35-green fluorescent
      protein fusion. Aggregation depended on the intracellular concentration and
      functional state of the chaperone protein Hsp104 in the same manner as did [PSI+]
      inheritance. The amino-terminal and carboxy-terminal domains of Sup35 contributed
      to the unusual behavior of [PSI+]. [PSI+] altered the conformational state of
      newly synthesized prion proteins, inducing them to aggregate as well, thus
      fulfilling a major tenet of the prion hypothesis.

PMID- 8662549
TI  - Photoinduced Chemical Dynamics of High-Spin Alkali Trimers
AB  - Nanometer-sized helium droplets, each containing about 10(4) helium atoms, were
      used as an inert substrate on which to form previously unobserved, spin-3/2
      (quartet state) alkali trimers. Dispersed fluorescence measurements reveal that,
      upon electronic excitation, the quartet trimers undergo intersystem crossing to
      the doublet manifold, followed by dissociation of the doublet trimer into an atom
      and a covalently bound singlet dimer. As shown by this work, aggregates of spin
      polarized alkali metals represent ideal species for the optical study of
      fundamental chemical dynamics processes including nonadiabatic spin conversion,
      change of bonding nature, and unimolecular dissociation.

PMID- 8662550
TI  - X-Ray Photoconductive Nanocomposites
AB  - The successful development of digital radiography depends, to a large extent, on
      the availability of suitable x-ray photoconductors. The x-ray photoconductive
      nanocomposites reported here combine the advantages of both inorganic and organic
      compounds. An inorganic compound was finely dispersed in an organic polymer. The
      inorganic compound, with its large x-ray absorption efficiency, functioned as the
      x-ray absorber, and the polymer provided good dielectric properties and ease of
      thin-film preparation. The preparation procedures and the x-ray photoconductive
      properties of a specific example, a 50 percent by weight nanocomposite of bismuth
      triiodide and nylon-11, are discussed in detail.

PMID- 8662548
TI  - Gating as a control element in constrictive binding and guest release by
      hemicarcerands.
AB  - Theoretical modeling of the dynamics of complexation and decomplexation of guest
      molecules by container molecules reveals that gating has a critical influence on
      the ease of formation and stability of host-guest complexes. Hosts equipped with
      gates can form very stable complexes with a variety of guests under readily
      achievable conditions. Gating involves conformational processes of the host
      molecule that alter the size of the portals through which guest molecules pass.
      "French door" and "sliding door" mechanisms of gate opening are identified.

PMID- 8662551
TI  - A Fluted Point from the Uptar Site, Northeastern Siberia
AB  - Lanceolate bifacial points, including one fluted specimen, have been collected
      from beneath an early Holocene tephra at the Uptar site, northeastern Siberia.
      Thus, the technology associated with the well-known Paleoindian tradition was not
      confined to the Americas. The Uptar collection does not compare readily with
      other Beringian complexes and demonstrates that there is greater diversity in the
      archaeological record of northeastern Siberia than traditional colonization
      models imply.

PMID- 8662552
TI  - The Interdependence of Deformational and Thermal Processes in Mountain Belts
AB  - Crustal temperatures within collisional orogens are anomalously high compared
      with temperatures at comparable depths in stable continents, which is evidence of
      thermal processes that are fundamental to orogenesis. These temperatures can be
      explained by the redistribution of crust enriched in heat-producing elements
      through the accretion of crust from the down-going plate to the upper plate and
      surface erosion. With the use of geologically reasonable rates, the model results
      predict high temperatures (over 600&deg;C) and inverted upper-plate geotherms
      (about 100&deg;C over 20 kilometers) at shallow depths (20 to 40 kilometers) by
      25 to 35 million years after collision. This study emphasizes the interdependence
      of deformational, surficial, and thermal processes.

PMID- 8662553
TI  - Lithologic Control of the Depth of Earthquakes in Southern California
AB  - The depth distribution of southern California earthquakes indicates that areas
      underlain by schist basement rocks have a shallower (4 to 10 kilometers) maximum
      depth of earthquakes than do areas with other types of basement rocks. The
      predominant minerals in the schists become plastic at lower temperatures, and
      thus at shallower depths, than the minerals in the other basement rocks. The
      lateral variations in lithology will control the depth extent (and thus the
      magnitudes) of potential future earthquakes; these depths can be determined from
      the depth of the current background seismicity.

PMID- 8662554
TI  - Mechanism of Phreatic Eruptions at Aso Volcano Inferred from Near-Field Broadband
      Seismic Observations
AB  - Broadband seismometers deployed at Aso volcano in Japan have detected a
      hydrothermal reservoir 1 to 1.5 kilometers beneath the crater that is continually
      resonating with periods as long as 15 seconds. When phreatic eruptions are
      observed, broadband seismograms elucidate a dynamic interplay between the
      reservoir and discharging flow along the conduit: gradual pressurization and long
      period (approximately20 seconds) pulsations of the reservoir during the 100 to
      200 seconds before the initiation of the discharge, followed by gradual deflation
      of the reservoir concurrent with the discharging flow. The hydrothermal
      reservoir, where water and heat from the deeper magma chamber probably interact,
      appears to help control the surface activity at Aso volcano.

PMID- 8662555
TI  - Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2.
AB  - Subtype 2 of the metabotropic glutamate receptor (mGluR2) is expressed in the
      presynaptic elements of hippocampal mossy fiber-CA3 synapses. Knockout mice
      deficient in mGluR2 showed no histological changes and no alterations in basal
      synaptic transmission, paired-pulse facilitation, or tetanus-induced long-term
      potentiation (LTP) at the mossy fiber-CA3 synapses. Long-term depression (LTD)
      induced by low-frequency stimulation, however, was almost fully abolished. The
      mutant mice performed normally in water maze learning tasks. Thus, the
      presynaptic mGluR2 is essential for inducing LTD at the mossy fiber-CA3 synapses,
      but this hippocampal LTD does not seem to be required for spatial learning.

PMID- 8662556
TI  - Presynaptic long-term depression at the hippocampal mossy fiber-CA3 synapse.
AB  - Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength
      may underlie learning and memory in the brain. The induction of LTP occurs in
      postsynaptic cells in the hippocampal CA1 region but is presynaptic in CA3. LTD
      is also well characterized in CA1 but not in CA3. Low-frequency stimulation of
      mouse hippocampal slices caused homosynaptic LTD at the mossy fiber-CA3 synapse,
      which may be induced presynaptically by activation of metabotropic glutamate
      receptors. Thus, the efficacy of mossy fiber-CA3 synapses can be regulated
      bidirectionally, which may contribute to neuronal information processing.

PMID- 8662557
TI  - Coevolution of the mammalian middle ear and neocortex.
AB  - Phylogenetic analysis with x-ray computed tomography of fossilized and recent
      crania implicates differential growth of the neocortex in the evolution and
      development of the mammalian middle ear. In premammalian tetrapods, the middle
      ear evolved as a chain of bones attached to the mandible and cranium, but in
      adult mammals the chain is detached from the mandible and lies behind it. The
      neocortex evolved concurrently with detachment of the chain. In mammalian
      development the auditory chain arises connected to the mandible but later
      detaches, recapitulating the phylogenetic transformation. In modern didelphid
      development, the auditory chain reaches mature size by the third week after birth
      and is then separated from the jaw and displaced caudally as the neocortex grows
      for another 9 weeks.

PMID- 8662558
TI  - Demethylation-induced developmental pleiotropy in Arabidopsis.
AB  - The function of DNA methylation in higher plants was investigated by expression
      of a complementary DNA encoding a cytosine methyltransferase (MET1) from
      Arabidopsis thaliana as an antisense RNA in transgenic plants. This expression
      resulted in a 34 to 71 percent reduction in total genomic cytosine methylation.
      Loss of methylation was observed in both repetitive DNA and single-copy gene
      sequences. Developmental effects included altered heterochrony, changes in
      meristem identity and organ number, and female sterility. Cytosine demethylation
      prolonged both vegetative and reproductive phases of development. These findings
      implicate DNA methylation in establishing or maintaining epigenetic developmental
      states in the meristem.

PMID- 8662559
TI  - Reduction of morphine abstinence in mice with a mutation in the gene encoding
      CREB.
AB  - Chronic morphine administration induces an up-regulation of several components of
      the cyclic adenosine 5'-monophosphate (cAMP) signal transduction cascade. The
      behavioral and biochemical consequences of opiate withdrawal were investigated in
      mice with a genetic disruption of the alpha and Delta isoforms of the cAMP
      responsive element-binding protein (CREB). In CREBalphadelta mutant mice the main
      symptoms of morphine withdrawal were strongly attenuated. No change in opioid
      binding sites or in morphine-induced analgesia was observed in these mutant mice,
      and the increase of adenylyl cyclase activity and immediate early gene expression
      after morphine withdrawal was normal. Thus, CREB-dependent gene transcription is
      a factor in the onset of behavioral manifestations of opiate dependence.

PMID- 8662560
TI  - Function of myosin-V in filopodial extension of neuronal growth cones.
AB  - The molecular mechanisms underlying directed motility of growth cones have not
      been determined. The role of myosin-V, an unconventional myosin, in growth cone
      dynamics was examined by chromophore-assisted laser inactivation (CALI). CALI of
      purified chick brain myosin-V absorbed onto nitrocellulose-coated cover slips
      inhibited the ability of myosin-V to translocate actin filaments. CALI of myosin
      V in growth cones of chick dorsal root ganglion neurons resulted in rapid
      filopodial retraction. The rate of filopodial extension was significantly
      decreased, whereas the rate of filopodial retraction was not affected, which
      suggests a specific role for myosin-V in filopodial extension.

PMID- 8662561
TI  - PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone
      growth.
AB  - The PTH/PTHrP receptor binds to two ligands with distinct functions: the calcium
      regulating hormone, parathyroid hormone (PTH), and the paracrine factor, PTH
      related protein (PTHrP). Each ligand, in turn, is likely to activate more than
      one receptor. The functions of the PTH/PTHrP receptor were investigated by
      deletion of the murine gene by homologous recombination. Most PTH/PTHrP receptor
      (-/-) mutant mice died in mid-gestation, a phenotype not observed in PTHrP (-/-)
      mice, perhaps because of the effects of maternal PTHrP. Mice that survived
      exhibited accelerated differentiation of chondrocytes in bone, and their bones,
      grown in explant culture, were resistant to the effects of PTHrP and Sonic
      hedgehog. These results suggest that the PTH/PTHrP receptor mediates the effects
      of Indian Hedgehog and PTHrP on chondrocyte differentiation.

PMID- 8662562
TI  - Emergence of preferred structures in a simple model of protein folding.
AB  - Protein structures in nature often exhibit a high degree of regularity (for
      example, secondary structure and tertiary symmetries) that is absent from random
      compact conformations. With the use of a simple lattice model of protein folding,
      it was demonstrated that structural regularities are related to high
      "designability" and evolutionary stability. The designability of each compact
      structure is measured by the number of sequences that can design the structure
      that is, sequences that possess the structure as their nondegenerate ground
      state. Compact structures differ markedly in terms of their designability; highly
      designable structures emerge with a number of associated sequences much larger
      than the average. These highly designable structures possess "proteinlike"
      secondary structure and even tertiary symmetries. In addition, they are
      thermodynamically more stable than other structures. These results suggest that
      protein structures are selected in nature because they are readily designed and
      stable against mutations, and that such a selection simultaneously leads to
      thermodynamic stability.

PMID- 8662563
TI  - NMR Studies of Single-File Diffusion in Unidimensional Channel Zeolites
AB  - Single-file diffusion is the restricted propagation of particles that cannot pass
      each other. The occurrence of this phenomenon should be reflected by a change in
      the time dependence of the mean particle displacement in comparison with ordinary
      diffusion. Although this process is considered to be the rate-controlling
      mechanism in a large variety of processes, so far no direct evidence of this
      phenomenon has been provided. Diffusion measurements made with pulsed field
      gradient nuclear magnetic resonance (NMR) in unidimensional pore systems
      (zeolites AlPO4-5 and Theta-1) reflect the expected time dependence of single
      file diffusion.

PMID- 8662564
TI  - Photoinduced Magnetization of a Cobalt-Iron Cyanide
AB  - Photoinduced magnetization was observed in a Prussian blue analog, K0.2Co1.4-
      [Fe(CN)6]&middot;6.9H2O. An increase in the critical temperature from 16 to 19
      kelvin was observed as a result of red light illumination. Moreover, the
      magnetization in the ferrimagnetic region below 16 kelvin was substantially
      increased after illumination and could be restored almost to its original level
      by thermal treatment. These effects are thought to be caused by an internal
      photochemical redox reaction. Furthermore, blue light illumination could be used
      to partly remove the enhancement of the magnetization. Such control over magnetic
      properties by optical stimuli may have application in magneto-optical devices.

PMID- 8662565
TI  - Field-Induced Layering of Colloidal Crystals
AB  - An electrohydrodynamic methodology has been developed that makes possible the
      precise assembly of two- and three-dimensional colloidal crystals on electrode
      surfaces. Electrophoretically deposited colloidal particles were observed to move
      toward one another over very large distances (greater than five particle
      diameters) to form two-dimensional colloidal crystals for both micrometer- and
      nanometer-size particles. This coalescence of particles with the same charge is
      opposite to what is expected from electrostatic considerations and appears to
      result from electrohydrodynamic fluid flow arising from an ionic current flowing
      through the solution. The ability to modulate this "lateral attraction" between
      particles, by adjusting field strength or frequency, facilitates the reversible
      formation of two-dimensional fluid and crystalline colloidal states on the
      electrode surface. Further manipulation allows controlled structures to be
      assembled.

PMID- 8662566
TI  - Galileo Gravity Results and the Internal Structure of Io
AB  - Doppler data generated with the Galileo spacecraft's radio carrier wave were used
      to measure Io's external gravitational field. The resulting triaxial field is
      consistent with the assumption that Io is in tidal and rotational equilibrium.
      The inescapable conclusion is that it has a large metallic core. If the core is a
      eutectic mixture of iron and iron sulfide, it comprises 20.2 &plusmn; 7.4 percent
      of the satellite's total mass with a radius that is about 52 percent of Io's mean
      radius of 1821.3 kilometers; if the core is pure iron, it comprises 10.5 &plusmn;
      3.7 percent of the total mass with a radius of about 36 percent of the mean
      radius.

PMID- 8662567
TI  - Juvenile Skeletal Structure and the Reproductive Habits of Dinosaurs
AB  - Skeletal ontogeny in extant archosaurians (crocodilians and birds) indicates that
      the morphology of the perinatal pelvic girdle is an indicator of overall
      developmental maturity [that is, altriciality (nestbound) versus precociality
      (mobile and relatively independent)]. Comparison of the skeletal anatomy of
      perinatal extant archosaurians and perinatal dinosaurs suggests that known
      dinosaur hatchlings were precocial. These data are consistent with the overall
      similarity in nesting behavior of dinosaurs and modern crocodilians.

PMID- 8662568
TI  - Concentrations of Tropospheric Ozone from 1979 to 1992 over Tropical Pacific
      South America from TOMS Data
AB  - An estimate of tropospheric ozone concentrations was obtained from the difference
      in the Total Ozone Mapping Spectrometer (TOMS) data between the high Andes and
      the Pacific Ocean. From 1979 to 1992 the tropospheric ozone concentration
      apparently increased by 1.48 &plusmn; 0.40 percent per year or 0.21 &plusmn; 0.06
      Dobson unit per year over South America and the surrounding oceans. An increase
      in biomass burning in the Southern Hemisphere can account for this trend in
      tropospheric ozone concentrations.

PMID- 8662570
TI  - Role of Gene Interactions in Hybrid Speciation: Evidence from Ancient and
      Experimental Hybrids
AB  - The origin of a new diploid species by means of hybridization requires the
      successful merger of differentiated parental species' genomes. To study this
      process, the genomic composition of three experimentally synthesized hybrid
      lineages was compared with that of an ancient hybrid species. The genomic
      composition of the synthesized and ancient hybrids was concordant (rs = 0.68, P <
      0.0001), indicating that selection to a large extent governs hybrid species
      formation. Further, nonrandom rates of introgression and significant associations
      among unlinked markers in each of the three synthesized hybrid lineages imply
      that interactions between coadapted parental species' genes constrain the genomic
      composition of hybrid species.

PMID- 8662572
TI  - Comparison of Galileo Probe and Earth-Based Translation Rates of Jupiter's
      Equatorial Clouds
AB  - The Doppler wind speeds derived from Galileo probe data are comparable with the
      maximum translation speeds observed in the equatorial zone by Voyager 1 and the
      Hubble Space Telescope. Slower published values of east-west winds are based on
      measurements of larger features and should be interpreted as translation rates of
      large weather systems interacting with the wind. The nature of the hot-spot
      region that the Galileo probe entered is compatible with a high-speed jet at 6
      degrees north. The hot spot is associated with an equatorial weather system that
      spans 5 degrees of latitude and translates at 103 meters per second.

PMID- 8662571
TI  - Earth-Based Observations of the Galileo Probe Entry Site
AB  - Earth-based observations of Jupiter indicate that the Galileo probe probably
      entered Jupiter's atmosphere just inside a region that has less cloud cover and
      drier conditions than more than 99 percent of the rest of the planet. The visual
      appearance of the clouds at the site was generally dark at longer wavelengths.
      The tropospheric and stratospheric temperature fields have a strong longitudinal
      wave structure that is expected to manifest itself in the vertical temperature
      profile.

PMID- 8662573
TI  - Galileo Doppler Measurements of the Deep Zonal Winds at Jupiter
AB  - Changes in the speed of the Galileo probe caused by zonal winds created a small
      but measurable Doppler effect in the probe relay carrier frequency. Analysis of
      the probe relay link frequency allows direct measurements of the speed of
      Jupiter's zonal winds beneath the cloud tops. The deep winds were prograde and
      strong, reaching a sustained 190 to 200 meters per second at an altitude marked
      by a pressure of 24 bars. The depth and strength of the zonal winds severely
      constrain dynamic modeling of the deeper layers and begin to rule out many
      shallow weather theories.

PMID- 8662574
TI  - Structure of the Atmosphere of Jupiter: Galileo Probe Measurements
AB  - Temperatures and pressures measured by the Galileo probe during parachute descent
      into Jupiter's atmosphere essentially followed the dry adiabat between 0.41 and
      24 bars, consistent with the absence of a deep water cloud and with the low water
      content found by the mass spectrometer. From 5 to 15 bars, lapse rates were
      slightly stable relative to the adiabat calculated for the observed H2/He ratio,
      which suggests that upward heat transport in that range is not attributable to
      simple radial convection. In the upper atmosphere, temperatures of >1000 kelvin
      at the 0.01-microbar level confirmed the hot exosphere that had been inferred
      from Voyager occultations. The thermal gradient increased sharply to 5 kelvin per
      kilometer at a reconstructed altitude of 350 kilometers, as was recently
      predicted. Densities at 1000 kilometers were 100 times those in the pre-encounter
      engineering model.

PMID- 8662575
TI  - High-Energy Charged Particles in the Innermost Jovian Magnetosphere
AB  - The energetic particles investigation carried by the Galileo probe measured the
      energy and angular distributions of the high-energy particles from near the orbit
      of Io to probe entry into the jovian atmosphere. Jupiter's inner radiation region
      had extremely large fluxes of energetic electrons and protons; intensities peaked
      at approximately2.2RJ (where RJ is the radius of Jupiter). Absorption of the
      measured particles was found near the outer edge of the bright dust ring. The
      instrument measured intense fluxes of high-energy helium ions (approximately62
      megaelectron volts per nucleon) that peaked at approximately1.5RJ inside the
      bright dust ring. The abundances of all particle species decreased sharply at
      approximately1.35RJ; this decrease defines the innermost edge of the equatorial
      jovian radiation.

PMID- 8662576
TI  - Radio Frequency Signals in Jupiter's Atmosphere
AB  - During the Galileo probe's descent through Jupiter's atmosphere, under the
      ionosphere, the lightning and radio emission detector measured radio frequency
      signals at levels significantly above the probe's electromagnetic noise. The
      signal strengths at 3 and 15 kilohertz were relatively large at the beginning of
      the descent, decreased with depth to a pressure level of about 5 bars, and then
      increased slowly until the end of the mission. The 15-kilohertz signals show
      arrival direction anisotropies. Measurements of radio frequency wave forms show
      that the probe passed through an atmospheric region that did not support
      lightning within at least 100 kilometers and more likely a few thousand
      kilometers of the descent trajectory. The apparent opacity of the jovian
      atmosphere increases sharply at pressures greater than about 4 bars.

PMID- 8662577
TI  - Osmium Recycling in Subduction Zones
AB  - Peridotite xenoliths from the Cascade arc in the United States and in the Japan
      arc have neodymium and osmium isotopic compositions that are consistent with
      addition of 5 to 15 percent of subducted material to the present-day depleted
      mantle. These observations suggest that osmium can be partitioned into oxidized
      and chlorine-rich slab-derived fluids or melts. These results place new
      constraints on the behavior of osmium (and possibly other platinum group
      elements) during subduction of oceanic crust by showing that osmium can be
      transported into the mantle wedge.

PMID- 8662578
TI  - Polymers with Very Low Polydispersities from Atom Transfer Radical Polymerization
AB  - A radical polymerization process that yields well-defined polymers normally
      obtained only through anionic polymerizations is reported. Atom transfer radical
      polymerizations of styrene were conducted with several solubilizing ligands for
      the copper(I) halides: 4,4'-di-tert-butyl, 4,4'-di-n-heptyl, and 4,4'-di-(5
      nonyl)-2,2'-dipyridyl. The resulting polymerizations have all of the
      characteristics of a living polymerization and displayed linear semilogarithmic
      kinetic plots, a linear correlation between the number-average molecular weight
      and the monomer conversion, and low polydispersities (ratio of the weight-average
      to number-average molecular weights of 1.04 to 1.05). Similar results were
      obtained for the polymerization of acrylates.

PMID- 8662579
TI  - Chemical Usurpation of a Nest by Paper Wasp Parasites
AB  - The paper wasp Polistes atrimandibularis is an obligatory social parasite of
      another Polistes species, P. biglumis bimaculatus. To control the host nest, the
      parasite sequentially changes the composition of its chemical signature, the
      cuticular hydrocarbons, during the colonial cycle. Gas chromatography-mass
      spectrometry of the cuticular hydrocarbons at every stage of the cycle showed
      that the parasite can switch on and off an entire chemical family, namely, the
      unsaturated hydrocarbons. In this way the parasite can match the host signature
      at a critical moment of the colonial cycle.

PMID- 8662580
TI  - A Far-Field Hydrothermal Plume from Loihi Seamount
AB  - An extensive helium plume in the north central Pacific emanates from Loihi
      Seamount on the flanks of Hawaii. The maximum helium signal is found at a depth
      of about 1100 meters, the same depth as the near-field plume directly above Loihi
      Seamount. Although this helium plume is strongest near Hawaii, where the 3He/4He
      ratio at a depth of about 1100 meters reaches values 28 percent above the
      atmospheric ratio, it can be detected quite clearly at latitude 24&deg;N, over
      400 kilometers to the north. Excess 3He is also present on the same isopycnal
      between 15&deg;N and 20&deg;N at 135&deg;W, some 2000 kilometers east of the
      Hawaiian Islands.

PMID- 8662581
TI  - Selected Elastic Moduli of Single-Crystal Olivines from Ultrasonic Experiments to
      Mantle Pressures
AB  - Ultrasonic interferometric measurements, developed for polycrystalline samples in
      a multi-anvil apparatus, were extended to single-crystal samples of San Carlos
      olivine and forsterite. The elastic moduli, C22 and C55 of San Carlos olivine and
      C55 of pure forsterite, were measured to about 13 gigapascals. These data on C22
      for San Carlos olivine and C55 for forsterite are consistent with earlier
      measurements and extrapolations. The C55 for San Carlos olivine increases
      linearly as a function of increasing pressure, unlike the earlier nonlinear
      behavior observed at high pressure with impulsive stimulated scattering
      techniques.

PMID- 8662582
TI  - The Impact of Solar Variability on Climate
AB  - A general circulation model that simulated changes in solar irradiance and
      stratospheric ozone was used to investigate the response of the atmosphere to the
      11-year solar activity cycle. At solar maximum, a warming of the summer
      stratosphere was found to strengthen easterly winds, which penetrated into the
      equatorial upper troposphere, causing poleward shifts in the positions of the
      subtropical westerly jets, broadening of the tropical Hadley circulations, and
      poleward shifts of the storm tracks. These effects are similar to, although
      generally smaller in magnitude than, those observed in nature. A simulation in
      which only solar irradiance was changed showed a much weaker response.

PMID- 8662583
TI  - Universality Classes of Optimal Channel Networks
AB  - Energy minimization of both homogeneous and heterogeneous river networks shows
      that, over a range of parameter values, there are only three distinct
      universality classes. The exponents for all three classes of behavior are
      calculated.

PMID- 8662584
TI  - Predatory Dinosaurs from the Sahara and Late Cretaceous Faunal Differentiation
AB  - Late Cretaceous (Cenomanian) fossils discovered in the Kem Kem region of Morocco
      include large predatory dinosaurs that inhabited Africa as it drifted into
      geographic isolation. One, represented by a skull approximately 1.6 meters in
      length, is an advanced allosauroid referable to the African genus
      Carcharodontosaurus. Another, represented by a partial skeleton with slender
      proportions, is a new basal coelurosaur closely resembling the Egyptian genus
      Bahariasaurus. Comparisons with Cretaceous theropods from other continents reveal
      a previously unrecognized global radiation of carcharodontosaurid predators.
      Substantial geographic differentiation of dinosaurian faunas in response to
      continental drift appears to have arisen abruptly at the beginning of the Late
      Cretaceous.

PMID- 8662585
TI  - Lead and Helium Isotope Evidence from Oceanic Basalts for a Common Deep Source of
      Mantle Plumes
AB  - Linear arrays in lead isotope space for mid-ocean ridge basalts (MORBs) converge
      on a single end-member component that has intermediate lead, strontium, and
      neodymium isotope ratios compared with the total database for oceanic island
      basalts (OIBs) and MORBs. The MORB data are consistent with the presence of a
      common mantle source region for OIBs that is sampled by mantle plumes. 3He/4He
      ratios for MORBs show both positive and negative correlation with the 206Pb/204Pb
      ratios, depending on the MORB suite. These data suggest that the common mantle
      source is located in the transition zone region. This region contains recycled,
      oceanic crustal protoliths that incorporated some continental lead before their
      subduction during the past 300 to 2000 million years.

PMID- 8662586
TI  - Pre-Main-Sequence Star Candidates in the Bar of the Large Magellanic Cloud
AB  - Candidate pre-main-sequence stars were observed in the bar of the Large
      Magellanic Cloud during the search for dark matter in the galactic halo. Seven
      blue stars of apparent visual magnitude 15 to 17 had irregular photometric
      variations and hydrogen emission lines in their optical spectra, which suggested
      that these stars are pre-main-sequence stars of about 10 solar masses. These
      stars are slightly more massive and definitely more luminous than are Herbig AeBe
      pre-main-sequence stars in our own galaxy. Continued observations of these very
      young stars from another galaxy, which are probably at the pre-hydrogen-burning
      stage, should provide important clues about early stages of star formation.

PMID- 8662589
TI  - Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase.
AB  - A phosphatidylinositol (PI) 4-kinase cDNA was cloned from a rat brain cDNA
      library. This cDNA encoded a protein of 2041 amino acids with a calculated
      molecular weight of 231,317. The deduced amino acid sequence shared the identity
      of 52.3 and 34.4% in the presumed catalytic domain with two yeast PI 4-kinases,
      STT4 and PIK1, respectively, and showed 31.7% identity to p110alpha subunit of
      rat PI 3-kinase in the same domain. In addition, a 3' half coding region of the
      present cDNA was 89.6% identical to and its deduced amino acid sequence was 98.2%
      identical to the sequence for P14Kalpha, a recently reported human PI 4-kinase of
      type II, suggesting that P14Kalpha is an alternative form of the present PI 4
      kinase molecule. The present cDNA contained sequences encoding the ankyrin repeat
      domain, lipid kinase unique domain, pleckstrin homology domain, presumed lipid
      kinase/protein kinase homology domain, proline-rich region, and SH3 domain. By
      examining PI kinase activity in transfected COS-7 cells using the epitope tag
      immunoprecipitation as well as the conventional way, the product
      phosphatidylinositol phosphate was identified as phosphatidylinositol 4-phosphate
      but not phosphatidylinositol 3-phosphate. This PI 4-kinase activity was markedly
      enhanced in the presence of Triton X-100 but relatively insensitive to inhibition
      by adenosine. By epitope tag immunohistochemistry, the immunoreactivity for this
      PI 4-kinase molecule was largely localized in close association with the
      membranes of the Golgi vesicles and vacuoles. By in situ hybridization analysis,
      the expression of mRNA for this PI 4-kinase was evident throughout the gray
      matter of entire brain with higher expression intensity in fetal brain. These
      data imply that this novel PI 4-kinase is involved in some processes essential to
      neuronal differentiation and maturation including the synaptogenesis and synaptic
      plasticity.

PMID- 8662591
TI  - Differential activation of acute phase response factor/STAT3 and STAT1 via the
      cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of
      a novel phosphotyrosine motif mediating STAT1 activation.
AB  - Interleukin-6 (IL-6) and gamma-interferon (IFNgamma) activate an overlapping set
      of genes via the Jak/STAT pathway. However, at least in human cells, a
      differential activation of STAT transcription factors was observed: IL-6
      activates both acute phase response factor (APRF)/STAT3 and STAT1, whereas
      IFNgamma leads only to STAT1 activation. All STATs cloned so far contain SH2
      domains. Since all cytokine receptors using the Jak/STAT pathway were found to be
      tyrosine-phosphorylated after ligand binding, it has been proposed that specific
      phosphotyrosine modules within the cytoplasmic domain of the receptor chains
      recruit different STAT factors. We have analyzed by mutational studies and by
      phosphopeptide competition assays which of the tyrosine modules of the IL-6
      signal transducer gp130 are capable of recruiting either APRF or STAT1. We found
      that two of the four tyrosine modules that are important for APRF activation also
      activate STAT1. For these modules, we propose the new consensus sequence YXPQ. We
      further present evidence that STAT1 is activated independently from APRF
      suggesting that gp130 contains multiple independent STAT binding sites. We
      compare the APRF and STAT1 activation motifs of gp130 with the STAT1 activation
      motif of the IFNgamma receptor and demonstrate that the specificity of activation
      can be changed from APRF to STAT1 and vice versa by only two point mutations
      within a tyrosine module. These data strongly support the concept that the
      activation of a specific STAT is determined mainly by the phosphotyrosine module.
      The significance of these findings for other receptor systems is discussed.

PMID- 8662593
TI  - The architecture of human acetylcholinesterase active center probed by
      interactions with selected organophosphate inhibitors.
AB  - The role of the functional architecture of human acetylcholinesterase (HuAChE)
      active center in facilitating reactions with organophosphorus inhibitors was
      examined by a combination of site-directed mutagenesis and kinetic studies of
      phosphorylation with organophosphates differing in size of their alkoxy
      substituents and in the nature of the leaving group. Replacements of residues Phe
      295 and Phe-297, constituting the HuAChE acyl pocket, increase up to 80-fold the
      reactivity of the enzymes toward diisopropyl phosphorofluoridate, diethyl
      phosphorofluoridate, and p-nitrophenyl diethyl phosphate (paraoxon), indicating
      the role of this subsite in accommodating the phosphate alkoxy substituent. On
      the other hand, a decrease of up to 160-fold in reactivity was observed for
      enzymes carrying replacements of residues Tyr-133, Glu-202, and Glu-450, which
      are constituents of the hydrogen bond network in the HuAChE active center, which
      maintains its unique functional architecture. Replacement of residues Trp-86, Tyr
      337, and Phe-338 in the alkoxy pocket affected reactivity toward diisopropyl
      phosphorofluoridate and paraoxon, but to a lesser extent that toward diethyl
      phosphorofluoridate, indicating that both the alkoxy substituent and the p
      nitrophenoxy leaving group interact with this subsite. In all cases the effects
      on reactivity toward organophosphates, demonstrated in up to 10,000-fold
      differences in the values of bimolecular rate constants, were mainly a result of
      altered affinity of the HuAChE mutants, while the apparent first order rate
      constants of phosphorylation varied within a narrow range. This finding indicates
      that the main role of the functional architecture of HuAChE active center in
      phosphorylation is to facilitate the formation of enzyme-inhibitor Michaelis
      complexes and that this affinity, rather than the nucleophilic activity of the
      enzyme catalytic machinery, is a major determinant of HuAChE reactivity toward
      organophosphates.

PMID- 8662595
TI  - Characterization of the receptor binding sites of human leukemia inhibitory
      factor and creation of antagonists.
AB  - Residues in human leukemia inhibitory factor (hLIF) crucial for binding to both
      the human LIF receptor (R) and gp130 were identified by analysis of alanine
      scanning mutants of hLIF in assays for both receptor binding and bioactivity. The
      region of hLIF most important for binding to the hLIF-R is composed of residues
      from the amino terminus of the D-helix, carboxyl terminus of the B-helix, and C-D
      loop. This site forms a distinct surface at the end of the four-helix bundle in
      the tertiary structure of the closely related murine LIF. The two residues of
      hLIF that contribute the majority of free energy for hLIF-R binding, Phe-156 and
      Lys-159 are surrounded by other residues which have only a moderate impact. This
      arrangement of a few key residues surrounded by less important ones is analogous
      to the functional binding epitope of human growth hormone for its receptor. A
      second region of hLIF that includes residues from the carboxyl terminus of the D
      helix and A-B loop also had a weak influence on hLIF-R binding. Residues in hLIF
      from both the A- and C-helices are involved in binding the gp130 co-receptor.
      Abolition of the gp130 binding site in hLIF created antagonists of LIF action.

PMID- 8662598
TI  - Purification, identification, and properties of a Saccharomyces cerevisiae oleate
      activated upstream activating sequence-binding protein that is involved in the
      activation of POX1.
AB  - Peroxisomes have a central function in lipid metabolism, and it is well
      established that these organelles are inducible by many compounds including fatty
      acids. Peroxisomes are the sole site for the beta-oxidation of fatty acids in
      yeast. The first and rate-limiting enzyme of this cycle is fatty acyl-CoA
      oxidase. The gene encoding this enzyme in Saccharomyces cerevisiae (POX1)
      undergoes a complex regulation that is dependent on the growth environment. When
      this yeast is grown in medium containing oleic acid as the main carbon source,
      peroxisomes are induced and POX1 expression is activated. When cells are grown in
      the presence of glucose, the expression of POX1 mRNA is repressed, whereas growth
      on a carbon source such as glycerol or raffinose causes derepression. This
      rigorous regulation is brought about by the complex interactions between trans
      acting factors and cis-elements in the POX1 promoter. Previously, we
      characterized regulatory elements in the promoter region of POX1 that are
      involved in the repression and activation of this gene (Wang, T., Luo, Y., and
      Small, G. M. (1994) J. Biol. Chem. 269, 24480-24485). In this study we have
      purified and identified an oleate-activated transcription factor (Oaf1p) that
      binds to the activating sequence (UAS1) in the POX1 gene. The protein has a
      predicted molecular mass of approximately 118 kDa.

PMID- 8662599
TI  - Transgenic mice that overexpress mouse apolipoprotein B. Evidence that the DNA
      sequences controlling intestinal expression of the apolipoprotein B gene are
      distant from the structural gene.
AB  - An 87-kilobase (kb) P1 bacteriophage clone (p649) spanning the mouse
      apolipoprotein (apo) B gene was used to generate transgenic mice that express
      high levels of mouse apoB. Plasma levels of apoB, low density lipoprotein
      cholesterol, and low density lipoprotein triglycerides were increased, and high
      density lipoprotein cholesterol levels were decreased in the transgenic mice,
      compared with nontransgenic littermate controls. Although p649 contained 33 kb of
      5'-flanking sequences and 11 kb of 3'-flanking sequences, the tissue pattern of
      transgene expression was different from that of the endogenous apoB gene. RNA
      slot blots and RNase protection analysis indicated that the transgene was
      expressed in the liver but not in the intestine, whereas the endogenous apoB gene
      was expressed in both tissues. To confirm the absence of transgene expression in
      the intestine, the mouse apoB transgenic mice were mated with the apoB knockout
      mice, and transgenic mice that were homozygous for the apoB knockout mutation
      were obtained. Because of the absence of transgene expression in the intestine,
      those mice lacked all intestinal apoB synthesis, resulting in a marked
      accumulation of fats within the intestinal villus enterocytes. The current
      studies, along with prior studies of human apoB transgenic animals, strongly
      suggest that the DNA sequence element(s) controlling intestinal expression of the
      apoB gene is located many kilobases from the structural gene.

PMID- 8662601
TI  - Mechanism of uptake of copper-oxidized low density lipoprotein in macrophages is
      dependent on its extent of oxidation.
AB  - Several investigators have reported nonreciprocal cross-competition between
      unlabeled acetyl low density lipoprotein (LDL) and oxidized LDL for the
      degradation of the corresponding labeled LDLs. The failure of acetyl LDL to
      compete fully for the degradation of oxidized LDL has been interpreted as
      evidence for additional receptor(s) specific for oxidized LDL. In the present
      study, it is demonstrated that the ability of oxidized LDL to compete for the
      degradation of acetyl LDL is determined largely by its extent of oxidation.
      Extensively oxidized LDL competed for 90% of acetyl LDL degradation in murine
      macrophages, and hence there appears to be no pathway in these cells that is
      specific for acetyl LDL but not oxidized LDL. The reciprocal situation
      (competition by acetyl LDL for uptake and degradation of oxidized LDL) proved to
      be more complicated. Oxidized LDL is known to be susceptible to aggregation, and
      less than half of the aggregates found in the present experiments were large
      enough to be removed by filtration or centrifugation at 10,000 x g. When oxidized
      LDL was prepared under conditions that resulted in minimal aggregation, acetyl
      LDL competed for greater than 80% of oxidized LDL degradation. With more
      extensive oxidation and aggregation of LDL, acetyl LDL only competed for about
      45% of oxidized LDL degradation, while polyinosinic acid remained an effective
      competitor. Individual preparations of oxidized LDL that differed in degree of
      oxidation were separated into aggregated and nonaggregated fractions, and it was
      shown that both fractions were competed to a similar degree by acetyl LDL in
      mouse peritoneal macrophages and in Chinese hamster ovary cells transfected with
      human scavenger receptor type I cDNA. Hence, aggregation by itself did not alter
      the apparent rate of uptake by the scavenger receptor pathway. These results
      indicate that the extent of oxidation of LDL affects its mechanism of uptake and
      that about half of the uptake of very extensively oxidized LDL appears to be via
      a pathway distinct from the scavenger receptor type I/II. The uptake of very
      extensively oxidized LDL was not affected by cytochalasin D, an inhibitor of
      phagocytosis. As well, it was not affected by an antibody to CD36 in human
      monocyte-derived macrophages or in THP-1 cells, suggesting that this alternate
      pathway does not involve CD36.

PMID- 8662602
TI  - Probing the active-site residues in Saccharomyces cerevisiae ferrochelatase by
      directed mutagenesis. In vivo and in vitro analyses.
AB  - Ferrochelatase is a mitochondrial inner membrane-bound enzyme that catalyzes the
      insertion of ferrous iron into protoporphyrin, the terminal step in protoheme
      biosynthesis. The functional/structural roles of 10 invariant amino acid residues
      were investigated by site-directed mutagenesis in the yeast Saccharomyces
      cerevisiae ferrochelatase. The mutant enzymes were expressed in a yeast strain
      lacking the ferrochelatase gene HEM15 and in Escherichia coli. The kinetic
      parameters of the mutant enzymes were determined for the enzymes associated with
      the yeast membranes and the enzymes in the bacterial soluble fraction. They were
      compared with the in vivo functioning of the mutant enzymes. The main conclusions
      are the following. Glu-314 is critical for catalysis, and we suggest that it is
      the base responsible for abstracting the N-pyrrole proton(s). His-235 is
      essential for metal binding. Asp-246 and Tyr-248 are also involved in metal
      binding in a synergistic manner. The Km for protoporphyrin was also increased in
      the H235L, D246A, and Y248L mutants, suggesting that the binding sites of the two
      substrates are not independent of each other. The R87A, Y95L, Q111E, Q273E,
      W282L, and F308A mutants had 1.2-2-fold increased Vm and 4-10-fold increased Km
      values for protoporphyrin, but the amount of heme made in vivo was 10-100% of the
      normal value. These mutations probably affected the geometry of the active
      center, resulting in improper positioning of protoporphyrin.

PMID- 8662603
TI  - Structure and domain-domain interactions of the gelatin binding site of human 72
      kilodalton type IV collagenase (gelatinase A, matrix metalloproteinase 2).
AB  - We have shown previously that all three fibronectin type II modules of gelatinase
      A contribute to its gelatin affinity. In the present investigation we have
      studied the structure and module-module interactions of this gelatin-binding
      domain by circular dichroism spectroscopy and differential scanning calorimetry.
      Comparison of the Tm values of the thermal transitions of isolated type II
      modules with those of bimodular or trimodular proteins has shown that the second
      type II module is significantly more stable in the trimodular protein coll 123
      (Tm = 54 degrees C) than in the single-module protein coll 2 (Tm = 44 degrees C)
      or in the bimodular proteins coll 23 (Tm = 47 degrees C) and coll 12 (Tm = 48
      degrees C). Analysis of the enthalpy changes associated with thermal unfolding of
      the second type II module suggests that it is stabilized by domain-domain
      interactions in coll 123. We propose that intimate contacts exist between the
      three tandem type 11 units and they form a single gelatin-binding site. Based on
      the three-dimensional structures of homologous metalloproteases and type II
      modules, a model is proposed in which the three type II units form an extension
      of the substrate binding cleft of gelatinase A.

PMID- 8662604
TI  - Purification and characterization of an alpha1,2,-L-fucosyltransferase, which
      modifies the cytosolic protein FP21,from the cytosol of Dictyostelium.
AB  - A novel fucosyltransferase (cFTase) activity has been enriched over 10(6)-fold
      from the cytosolic compartment of Dictyostelium based on transfer of [3H]fucose
      from GDP-[3H]fucose to Galbeta1,3 GlcNAc beta-paranitrophenyl (paranitrophenyl
      lacto-N-bioside or pNP-LNB). The activity behaved as a single component during
      purification over DEAE-, phenyl-, Reactive Blue-4-, GDP-adipate-, GDP
      hexanolamine-, and Superdex gel filtration resins. The purified activity
      possessed an apparent Mr of 95 X 10(3), was Mg2+-dependent with a neutral pH
      optimum, and exhibited a Km for GDP-fucose of 0.34 microM, a Km for pNP-LNB of
      0.6 mM, and a Vmax for pN-P-LNB of 620 nmol/min/mg protein. SDS-polyacrylamide
      gel electrophoresis analysis of the Superdex elution profile identified a
      polypeptide with an apparent Mr of 85 X 10(3), which coeluted with the cFTase
      activity and could be specifically photolabeled with the donor substrate
      inhibitor GDP-hexanolaminyl-azido-125I-salicylate. Based on substrate analogue
      studies, exoglycosidase digestions, and co-chromatography with fucosylated
      standards, the product of the reaction with pNP-LNB was Fucalpha1,
      2Galbeta1,3GIcNAcbeta-pNP. The cFTase preferred substrates with a
      Galbeta1,3linkage, and thus its acceptor substrate specificity resembles the
      human Secretor-type alpha1,2- FTase. Afucosyl isoforms of the FP21 glycoprotein,
      GP21-I and GP21-II, were purified from the cytosol of a Dictyostelium mutant and
      found to be substrates for the cFTase, which exhibited an apparent K(m) of 0.21
      microM and an apparent V(max) of 460 nmol/min/mg protein toward GP21-II. The
      highly purified cFTase was inhibited by the reaction products
      Fucalpha1,2Galbeta1,3GlcNAcbeta-pNP and FP21-II. FP21-I and recombinant FP21 were
      not inhibitory, suggesting that acceptor substrate specificity is based primarily
      on carbohydrate recognition. A cytosolic location for this step of FP21
      glycosylation is implied by the isolation of the cFTase from the cytosolic
      fraction, its high affinity for its substrates, and its failure to be detected in
      crude membrane preparations.

PMID- 8662605
TI  - Metalloproteinase-mediated regulation of L-selectin levels on leucocytes.
AB  - Leucocyte (L)-selectin can be proteolytically cleaved in the membrane proximal
      extracellular region to yield a soluble fragment that contains the functional
      lectin and epidermal growth factor domains. A variety of stimuli are known to
      stimulate L-selectin shedding including chemoattractants, phorbol esters, and L
      selectin cross-linking; however, the enzymes that regulate L-selectin expression
      are not characterized. In this study we have used phorbol ester to stimulate
      endoproteolytic release of L-selectin and identified a major role for a cell
      surface metalloproteinase (L-selectin sheddase) in this process. The hydroxamic
      acid-based inhibitor of zinc-dependent matrix metalloproteinases Ro 31-9790
      completely prevented shedding of cell surface L-selectin from leucocytes in
      mouse, rat, and man. L-selectin was susceptible to cleavage by known matrix
      metalloproteinases. Recombinant human fibroblast collagenase (MMP1) reduced the
      number of L-selectin-positive lymphocytes to a similar extent as phorbol ester
      activation, and stromelysin (MMP3) had a partial effect on L-selectin expression.
      Gelatinases A (MMP2) and B (MMP9) were without effect. Lymphocytes did not
      express fibroblast collagenase or stromelysin at the cell surface, and tissue
      inhibitor of metalloproteinases (TIMP) did not affect L-selectin levels. L
      selectin sheddase was not detected in media harvested from phorbol ester
      stimulated lymphocytes and was only able to cleave L-selectin in the cis but not
      the trans configuration. These results suggest that endoproteolytic release of L
      selectin from the leucocyte surface is mediated by a metalloproteinase (L
      selectin sheddase), which is distinguishable from known matrix
      metalloproteinases. Understanding the regulation of L-selectin sheddase will be
      critical for controlling leucocyte migration from the blood.

PMID- 8662607
TI  - A new glycosaminoglycan from the giant African snail Achatina fulica.
AB  - A new glycosaminoglycan has been isolated from the giant African snail Achatina
      fulica. This polysaccharide had a molecular weight of 29,000, calculated based on
      the viscometry, and a uniform repeating disaccharide structure of -->4)-2
      acetyl,2-deoxy-alpha-D-glucopyranose (1-->4)-2-sulfo-alpha-L-idopyranosyluronic
      acid (1-->. This polysaccharide represents a new, previously undescribed
      glycosaminoglycan. It is related to the heparin and heparan sulfate families of
      glycosaminoglycans but is distinctly different from all known members of these
      classes of glycosaminoglycans. The structure of this polysaccharide, with
      adjacent N-acetylglucosamine and 2-sulfo-iduronic acid residues, also poses
      interesting questions about how it is made in light of our current understanding
      of the biosynthesis of heparin and heparan sulfate. This glycosaminoglycan
      represents 3-5% of the dry weight of this snail's soft body tissues, suggesting
      important biological roles for the survival of this organism, and may offer new
      means to control this pest. Snail glycosaminoglycan tightly binds divalent
      cations, such as copper(II), suggesting a primary role in metal uptake in the
      snail. Finally, this new polysaccharide might be applied, like the Escherichia
      coli K5 capsular polysaccharide, to the study of glycosaminoglycan biosynthesis
      and to the semisynthesis of new glycosaminoglycan analogs having important
      biological activities.

PMID- 8662608
TI  - Evolution of the creative kinases. The chicken acidic type mitochondrial creatine
      kinase gene as the first nonmammalian gene.
AB  - In both mammals and birds, the creatine kinase (CK) family consists of four types
      of genes: cytosolic brain type (B-CK); cytosolic muscle type (M-CK);
      mitochondrial ubiquitous, acidic type (Mia-CK); and mitochondrial sarcomeric,
      basic type (Mib-CK). We report here the cloning of the chicken Mia-CK cDNA and
      its gene. Amino acid sequences of the mature chicken Mi-CK proteins show about
      90% identity to the homologous mammalian isoforms. The leader peptides, however,
      which are isoenzyme-specifically conserved among the mammalian Mi-CKs, are quite
      different in the chicken with amino acid identity values compared with the
      mammalian leader peptides of 38.5-51.3%. The chicken Mia-CK gene spans about 7.6
      kilobases and contains 9 exons. The region around exon 1 shows a peculiar base
      composition, with more than 80% GC, and has the characteristics of a CpG island.
      The upstream sequences lack TATA or CCAAT boxes and display further properties of
      housekeeping genes. Several transcription factor binding sites known from
      mammalian Mi-CK genes are absent from the chicken gene. Although the promoter
      structure suggests a ubiquitous range of expression, analysis of Mia-CK
      transcripts in chicken tissues shows a restricted pattern and therefore does not
      fulfill all criteria of a housekeeping enzyme.

PMID- 8662610
TI  - Regulation of glutamate transport into synaptic vesicles by chloride and proton
      gradient.
AB  - Glutamate uptake into synaptic vesicles is driven by an electrochemical proton
      gradient formed across the membrane by a vacuolar H+-ATPase. Chloride has a
      biphasic effect on glutamate transport, which it activates at low concentrations
      (2-8 mM) and inhibits at high concentrations (>20 mM). Stimulation with 4 mM
      chloride was due to an increase in the Vmax of transport, whereas inhibition by
      high chloride concentrations was related to an increase in Km to glutamate. Both
      stimulation and inhibition by Cl- were observed in the presence of A23187 or
      (NH4)2SO4, two substances that dissipate the proton gradient (deltapH). With the
      use of these agents, we show that the transmembrane potential regulates the
      apparent affinity for glutamate, whereas the deltapH antagonizes the effect of
      high chloride concentrations and is important for retaining glutamate inside the
      vesicles. Selective dissipation of deltapH in the presence of chloride led to a
      significant glutamate efflux from the vesicles and promoted a decrease in the
      velocity of glutamate uptake. The H+-ATPase activity was stimulated when the
      deltapH component was dissipated. Glutamate efflux induced by chloride was
      saturable, and half-maximal effect was attained in the presence of 30 mM Cl-. The
      results indicate that: (i) both transmembrane potential and deltapH modulate the
      glutamate uptake at different levels and (ii) chloride affects glutamate
      transport by two different mechanisms. One is related to a change of the
      proportions between the transmembrane potential and the deltapH components of the
      electrochemical proton gradient, and the other involves a direct interaction of
      the anion with the glutamate transporter.

PMID- 8662609
TI  - Changing the structural context of a functional beta-hairpin. Synthesis and
      characterization of a chimera containing the curaremimetic loop of a snake toxin
      in the scorpion alpha/beta scaffold.
AB  - An approach to obtain new active proteins is the incorporation of all or a part
      of a well defined active site onto a natural structure acting as a structural
      scaffold. According to this strategy we tentatively engineered a new
      curaremimetic molecule by transferring the functional central loop of a snake
      toxin, sequence 26-37, sandwiched between two hairpins, onto the structurally
      similar beta-hairpin of the scorpion toxin charybdotoxin, stabilized by a short
      helix. The resulting chimeric molecule, only 31 amino acids long, was produced by
      solid phase synthesis, refolded, and purified to homogeneity. As shown by
      structural analysis performed by CD and NMR spectroscopy, the chimera maintained
      the expected alpha/beta fold characteristic of scorpion toxins and presented a
      remarkable structural stability. The chimera competitively displaces the snake
      curaremimetic toxin alpha from the acetylcholine receptor at 10(-5) M
      concentrations. Antibodies, elicited in rabbits against the chimera, recognize
      the parent snake toxin and prevent its binding to the acetylcholine receptor,
      thus neutralizing its toxic function. All these data demonstrate that the
      strategy of active site transfer to the charybdotoxin scaffold has general
      applications in the engineering of novel ligands for membrane receptors and in
      vaccine design.

PMID- 8662611
TI  - Interaction of wild-type and truncated forms of transcription factor IIIA from
      Saccharomyces cerevisiae with the 5 S RNA gene.
AB  - Transcription factor (TF) IIIA, which contains nine zinc finger motifs, binds to
      the internal control region of the 5S RNA gene as the first step in the assembly
      of a multifactor complex that promotes accurate initiation of transcription by
      RNA polymerase III. We have monitored the interaction of wild-type and truncated
      forms of yeast TFIIIA with the 5 S RNA gene. The DNase I footprints obtained with
      full-length TFIIIA and a polypeptide containing the amino-terminal five zinc
      fingers (TF5) were indistinguishable, extending from nucleotides +64 to +99 of
      the 5 S RNA gene. This suggests that fingers 6 through 9 of yeast TFIIIA are not
      in tight association with DNA. The DNase I footprint obtained with a polypeptide
      containing the amino-terminal four zinc fingers (TF4) was 14 base pairs shorter
      than that of TF5, extending from nucleotides +78 to +99 on the nontranscribed
      strand and from nucleotides +79 to +98 on the transcribed strand of the 5 S RNA
      gene. Protection provided by a polypeptide containing the first three zinc
      fingers (TF3) was similar to that provided by TF4, with the exception that
      protection on the nontranscribed strand ended at nucleotide +80, rather than
      nucleotide +78. Methylation protection analysis indicated that finger 5 makes
      major groove contacts with guanines +73 and +74. The amino-terminal four zinc
      fingers make contacts that span the internal control region, which extends from
      nucleotides +81 to +94 of the 5 S RNA gene, with finger 4 appearing to contact
      guanine +82. Measurements of the apparent Kd values of the TFIIIA.DNA complexes
      indicated that the amino-terminal three zinc fingers of TFIIIA have a binding
      energy that is similar to that of the full-length protein.

PMID- 8662612
TI  - The membrane guanylyl cyclase, retinal guanylyl cyclase-1, is activated through
      its intracellular domain.
AB  - Retinal guanylyl cyclase-1 (RetGC-1) is a membrane guanylyl cyclase found in
      photoreceptor outer segments. It consists of an apparent extracellular domain
      (ECD) linked by a single transmembrane segment to an intracellular domain (ICD).
      Guanylyl cyclase activating protein-2 (GCAP-2) is a Ca2+-binding protein that
      activates RetGC-1 in a Ca2+-sensitive manner. To establish whether GCAP-2
      stimulates RetGC-1 through the ECD or ICD, we made deletion mutants lacking
      either the ECD or both the ECD and transmembrane domains (TMD) of RetGC-1.
      Recombinant wild type RetGC-1 and both deletion mutants were expressed in HEK 293
      cells, and their sensitivities to GCAP-2, Ca2+, and ATP were compared. Our data
      demonstrate that both deletion mutants are regulated similarly to wild type RetGC
      1 with indistinguishable EC50 values for Ca2+ and similar K1/2 values for
      activation by GCAP-2. This shows that GCAP-2 functions through the ICD of RetGC-1
      and that removal of the ECD and TMD do not significantly alter regulation by
      these factors. Our data also show that ATP potentiates stimulation of guanylyl
      cyclase activity by GCAP-2 and that neither the ECD nor the TMD of RetGC-1
      participate in its regulation by ATP.

PMID- 8662614
TI  - High mobility group protein 14 and 17 can prevent the close packing of
      nucleosomes by increasing the strength of protein contacts in the linker DNA.
AB  - High mobility group (HMG) proteins 14 and 17 are abundant chromatin-associated
      proteins found in all higher eukaryotic nuclei. This observation demonstrates
      that HMGs 14 and 17 must have an important and universal function with regard to
      the structure and function of chromatin. What this function is, including how
      they interact with a nucleosomal array in vivo, is not known. Recently, we have
      demonstrated that HMGs 14 and 17 can organize nucleosomes into a regular array
      and increase the repeat length from 145 to about 160-165 base pairs in vitro. In
      addition, they can increase the apparent repeat length of chromatin deficient in
      histones H2A/H2B from 125 to approximately 145 base pairs. Importantly, this
      template was transcriptionally active. In this study, we report five new
      observations that begin to address the mechanism by which HMGs 14 and 17 space
      nucleosomal particles. First, we demonstrate that both human placenta HMG 14 and
      HMG 17 can space nucleosomes to produce a chromatin template with a repeat length
      around 160 base pairs. This result further highlights the similarity between
      these proteins in terms of protein structure and perhaps function. Second, we
      show that digestion of HMG containing chromatin with micrococcal nuclease
      produces DNA fragments that were approximately 10 and 20 base pairs longer than
      nucleosome core-particle DNA. This suggests that HMG 14 or HMG 17 can protect,
      directly or indirectly, at least an additional 10 base pairs of linker DNA from
      micrococcal digestion. However, this HMG-containing particle does not produce a
      strong kinetic block, and further digestion results in the eventual accumulation
      of DNA fragments 145 base pairs in length. Third, by comparing the full-length
      protein with different domains, we demonstrate that the acidic carboxyl-terminal
      domain is absolutely required for nucleosome spacing, neither the nucleosome
      binding domain of HMG 14 or HMG 17 nor the amino-terminal domain plus the
      nucleosome binding domain of HMG 14 could space nucleosomes. Fourth, we
      demonstrate that extensive micrococcal nuclease digestion of chromatin deficient
      in histones H2A/H2B led to the accumulation of DNA fragments about 110 base pairs
      in length, which is presumably the length of DNA associated with a nucleosomal
      particle deficient in one H2A/H2B dimer. Incorporation of either HMG 14 or HMG 17
      into this chromatin results in the disappearance of this band and increase in the
      accumulation of fragments around 140-150 base pairs in length. Finally, in
      contrast to spacing of complete nucleosomes, we find that the nucleosome binding
      domain of HMG 17 (but not the nucleosome binding of HMG 14) is the only domain
      required for spacing of H2A/H2B-deficient chromatin.

PMID- 8662613
TI  - Function of the htrB high temperature requirement gene of Escherichia coli in the
      acylation of lipid A: HtrB catalyzed incorporation of laurate.
AB  - By assaying lysates of Escherichia coli generated with the hybrid lambda
      bacteriophages of an ordered library (Kohara, Y., Akiyama, K., and Isono, K.
      (1987) Cell 50, 495-508), we identified two clones (lambda232 and lambda233)
      capable of overexpressing the lauroyl transferase that functions after 3-deoxy-D
      manno-octulosonic acid (Kdo) addition in lipid A biosynthesis (Brozek, K. A., and
      Raetz, C. R. H. (1990) J. Biol. Chem. 265, 15410-15417). The E. coli DNA inserts
      in lambda232 and lambda233 suggested that a known gene (htrB) required for rapid
      growth above 33 degrees C might encode the lauroyl transferase. Using the
      intermediate (Kdo)2-lipid IVA as the laurate acceptor, extracts of strains with
      transposon insertions in htrB were found to contain no lauroyl transferase
      activity. Cells harboring hybrid htrB+ plasmids overproduced transferase activity
      100-200-fold. The overproduced transferase was solubilized with a non-ionic
      detergent and purified further by DEAE-Sepharose chromatography. With lauroyl
      acyl carrier protein as the donor, the purified enzyme rapidly incorporated one
      laurate residue into (Kdo)2-lipid IVA. The rate of laurate incorporation was
      reduced by several orders of magnitude when either one or both Kdos were absent
      in the acceptor. With a matched set of acyl-acyl carrier proteins, the enzyme
      incorporated laurate 3-8 times faster than decanoate or myristate, respectively.
      Transfer of palmitate, palmitoleate, or R-3-hydroxymyristate was very slow. Taken
      together with previous studies, our findings indicate that htrB encodes a key,
      late functioning acyltransferase of lipid A biosynthesis.

PMID- 8662615
TI  - Dimerization of transcobalamin II receptor. Requirement of a structurally ordered
      lipid bilayer.
AB  - Transcobalamin II receptor (TC II-R) exists as a monomer and a dimer of molecular
      masses of 62 and 124 kDa in the microsomal and plasma membranes, respectively,
      and in vitro, pure TC II-R monomer dimerizes upon insertion into egg
      PC/cholesterol (molar ratio, 4:1) liposomes (Bose, S., Seetharam, S., and
      Seetharam, B. (1995) J. Biol Chem. 270, 8152-8157 and Bose, S., Seetharam, S.,
      Hammond, T., and Seetharam, B. (1995) Biochem. J. 310, 923-929). The current
      studies were carried out to define the mechanism of TC II-R dimerization. Both
      the mature TC II-R (62 kDa) and the enzymatically deglycosylated TC II-R (45-47
      kDa) demonstrated optimal association and formed dimers of molecular masses of 95
      and 124 kDa, respectively, at 22 degrees C when bound to egg PC vesicles
      containing at least 10 mol % of cholesterol. Mature TC II-R dimerized upon
      insertion into synthetic phosphatidylcholine vesicles of different fatty acyl
      chain length (dimyristoyl, dipalmitoyl, and disteroyl phosphatidylcholine) in the
      absence or the presence of cholesterol at temperatures below or above their
      transition temperatures, respectively. Dimerization of TC II-R also occurred with
      vesicles prepared using lipid extract from the plasma but not microsomal
      membranes. Cholesterol depletion of native intestinal plasma membranes or its
      enrichment in the microsomal membranes resulted in the in situ conversion of the
      124-kDa dimer to the 62-kDa monomer or of the monomer into the dimer form,
      respectively. Treatment of plasma membranes with phospholipase A2 resulted in the
      conversion of the dimer form of the receptor to the monomer form and spin label
      studies using 1-palmitoyl, 12 doxylsteroyl phosphatidylcholine revealed that
      interactions of TC II-R with PC vesicles increased order around the probe. Based
      on these results we suggest that dimerization of TC II-R is mediated by its
      interactions with a rigid more ordered lipid bilayer membrane, is regulated in
      plasma membranes by cholesterol levels, and is independent of glycosylation
      mediated folding.

PMID- 8662616
TI  - cDNA cloning and expression of HIP, a novel cell surface heparan sulfate/heparin
      binding protein of human uterine epithelial cells and cell lines.
AB  - Heparan sulfate proteoglycans and their corresponding binding sites have been
      suggested to play an important role during the initial attachment of murine
      blastocysts to uterine epithelium and human trophoblastic cell lines to uterine
      epithelial cell lines. Previous studies on RL95 cells, a human uterine epithelial
      cell line, had characterized a single class of cell surface heparin/heparan
      sulfate (HP/HS)-binding sites. Three major HP/HS-binding peptide fragments were
      isolated from cell surfaces by tryptic digestion, and partial amino-terminal
      amino acid sequence for each peptide fragment was obtained (Raboudi, N., Julian,
      J., Rohde, L. H., and Carson, D. D. (1992) J. Biol. Chem. 267, 11930-11939). In
      the current study, using approaches of reverse transcription-polymerase chain
      reaction and cDNA library screening, we have cloned and expressed a novel, cell
      surface HP/HS-binding protein, named HP/HS interacting protein (HIP), from RL95
      cells. The full-length cDNA of HIP encodes a protein of 159 amino acids with a
      calculated molecular mass of 17,754 Da and pI of 11.75. Transfection of HIP full
      length cDNA into NIH-3T3 cells demonstrated cell surface expression and a size
      similar to that of HIP expressed by human cells. Predicted amino acid sequence
      indicates that HIP lacks a membrane spanning region and has no consensus sites
      for glycosylation. Northern blot analysis detected a single transcript of 1.3
      kilobases in both total RNA and poly(A+) RNA. Examination of human cell lines and
      normal tissues using both Northern blot and Western blot analyses revealed that
      HIP is expressed at different levels in a variety of human cell lines and normal
      tissues but absent in some cell lines and some cell types of normal tissues
      examined. HIP has relatively high homology (approximately 80% both at the levels
      of nucleotide and protein sequence) to a rodent ribosomal protein L29. Thus,
      members of the L29 family may be displayed on cell surfaces where they may
      participate in HP/HS binding events.

PMID- 8662618
TI  - Molecular cloning and expression of an avian macrophage nitric-oxide synthase
      cDNA and the analysis of the genomic 5'-flanking region.
AB  - We report the first nonmammalian inducible nitric-oxide synthase (NOS) cDNA
      obtained from chicken macrophages. It exhibits an open reading frame encoding
      1,136 amino acid residues, predicting a protein of 129,648-Da molecular mass. The
      deduced NOS protein sequence showed 66.6%, 70.4%, 54.2%, and 48.7% sequence
      identity to mouse and human inducible NOS and to two constitutive NOSs from rat
      brain and bovine endothelium. Overall, NOS appears to be a moderately conserved
      protein. Northern analysis showed that chicken iNOS mRNA is approximately 4.5
      kilobases (kb), a size similar to mammalian inducible NOS. Analysis of 3.2 kb of
      5'-flanking sequence of the chicken iNOS gene showed a putative TATA box at 30
      base pairs (bp) upstream of the transcription initiation site. The functional
      importance of the upstream region was determined by transient expression of
      deletion constructs. An endotoxin regulatory region was located exclusively
      within 300 bp upstream of the transcription initiation site. This is in contrast
      to the two distinct sites identified in the mouse macrophage NOS promoter.
      Transcription factor binding sites such as NF-kappaB, PEA1, PEA3, and C/EBP were
      identified. Using a NF-kappaB inhibitor, we showed that NF-kappaB is indeed
      involved in the induction of chicken iNOS gene by lipopolysaccharide. Our results
      suggest that NF-kappaB is a common regulatory component in the expression of both
      mammalian and nonmammalian iNOS genes.

PMID- 8662617
TI  - Cell surface expression of HIP, a novel heparin/heparan sulfate binding protein,
      of human uterine epithelial cells and cell lines.
AB  - Previous studies established that uterine epithelial cells and cell lines express
      cell surface heparin/heparan sulfate (HP/HS)-binding proteins (Wilson, O.,
      Jacobs, A. L., Stewart, S., and Carson, D. D. (1990) J. Cell. Physiol. 143, 60
      67; Raboudi, N., Julian, J., Rohde, L. H., and Carson, D. D. (1992) J. Biol.
      Chem. 267, 11930-11939). The accompanying paper (Liu, S., Smith, S. E., Julian,
      J., Rohde, L. H., Karin, N. J., and Carson, D. D. (1996) J. Biol. Chem. 271,
      11817-11823) describes the cloning of a full-length cDNA corresponding to a
      candidate cell surface HP/HS interacting protein, HIP, expressed by a variety of
      human epithelia. A synthetic peptide was synthesized corresponding to an amino
      acid sequence predicted from the cDNA sequence and used to prepare a rabbit
      polyclonal antibody. This antibody reacted with a protein with an apparent Mr of
      24,000 by SDS-polyacrylamide gel electrophoresis that was highly enriched in the
      100,000 x g particulate fraction of RL95 cells. This molecular weight is similar
      to that of the protein expressed by 3T3 cells transfected with HIP cDNA. HIP was
      solubilized from this particulate fraction with NaCl concentrations > or = 0.8 M
      demonstrating a peripheral association consistent with the lack of a membrane
      spanning domain in the predicted cDNA sequence. HIP was not released by
      heparinase digestion suggesting that the association is not via membrane-bound HS
      proteoglycans. NaCl-solubilized HIP bound to heparin-agarose in physiological
      saline and eluted with NaCl concentrations of 0.75 M and above. Furthermore,
      incubation of 125I-HP with transblots of the NaCl-solubilized HIP preparations
      separated by two-dimensional gel electrophoresis demonstrated direct binding of
      HP to HIP. Indirect immunofluorescence studies demonstrated that HIP is expressed
      on the surfaces of intact RL95 cells. Binding of HIP antibodies to RL95 cell
      surfaces at 4 degrees C was saturable and blocked by preincubation with the
      peptide antigen. Single cell suspensions of RL95 cells formed large aggregates
      when incubated with antibodies directed against HIP but not irrelevant
      antibodies. Finally, indirect immunofluorescence studies demonstrate that HIP is
      expressed in both lumenal and glandular epithelium of normal human endometrium
      throughout the menstrual cycle. In addition, HIP expression increases in the
      predecidual cells of post-ovulatory day 13-15 stroma. Collectively, these data
      indicate that HIP is a membrane-associated HP-binding protein expressed on the
      surface of normal human uterine epithelia and uterine epithelial cell lines.

PMID- 8662620
TI  - Recombinant N-terminal nucleotide-binding domain from mouse P-glycoprotein.
      Overexpression, purification, and role of cysteine 430.
AB  - Varying length cDNAs encoding the N-terminal nucleotide-binding domain (NBD1)
      from mouse mdr1 P-glyco- protein were prepared on the basis of structure
      predictions. Corresponding recombinant proteins were overexpressed in Escherichia
      coli, and the shortest one containing amino acids 395-581 exhibited the highest
      solubility. Insertion of an N-terminal hexahistidine tag allowed domain
      purification by nickel-chelate affinity chromatography. NBD1 efficiently
      interacted with nucleotides. Fluorescence methods showed that ATP bound at
      millimolar concentrations and its 2',3'-O-(2,4,6-trinitrophenyl) derivative at
      micromolar concentrations, while the 2'(3')-N-methylanthraniloyl derivative had
      intermediate affinity. Photoaffinity labeling was achieved upon irradiation with
      8-azido-ATP. The domain exhibited ATPase activity with a Km for MgATP in the
      millimolar range, and ATP hydrolysis was competitively inhibited by micromolar
      2',3'-O-(2,4,6-trinitrophenyl)-ATP. NBD1 contained a single cysteine residue, at
      position 430, that was derivatized with radiolabeled N-ethylmaleimide. Cysteine
      modification increased 6-fold the Kd for 2'(3')-N-methylanthraniloyl-ATP and
      prevented 8-azido-ATP photolabeling. ATPase activity was inhibited with a 5-fold
      increase in the Km for MgATP. The results suggest that chemical modification of
      Cys-430 is involved in the N-ethylmaleimide inhibition of whole P-glycoprotein by
      altering substrate interaction.

PMID- 8662621
TI  - Translocation of GLUT1 does not account for elevated glucose transport in glucose
      deprived 3T3-L1 adipocytes.
AB  - Glucose deprivation increases the rate of glucose transport in 3T3-L1 adipocytes
      in a protein synthesis-dependent fashion. To determine if translocation of either
      GLUT1 or GLUT4 is responsible for this phenomenon, we adapted existing
      fractionation procedures toward isolating 3T3-L1 adipocyte membranes. By Western
      blot analysis of equal protein, GLUT1 was distributed between plasma membranes,
      high density "microsomal" membranes, and low density "microsomal" membranes
      isolated from control cells. GLUT4 comigrated with high density and low density
      membranes. Glucose deprivation for 12 h did not alter the distribution of either
      GLUT1 or GLUT4, despite an 8-10-fold increase in glucose transport activity in
      intact cells. Importantly, increased transport activity was retained in plasma
      membrane vesicles isolated from glucose-deprived cells. These data show for the
      first time that the increase in transport activity associated with glucose
      deprivation does not result from the translocation of either of the glucose
      transporters known to exist in 3T3-L1 adipocytes. As GLUT4 is excluded from the
      plasma membrane, these data provide evidence for activation of GLUT1.

PMID- 8662622
TI  - Transfer of L-type calcium channel IVS6 segment increases phenylalkylamine
      sensitivity of alpha1A.
AB  - Conditioned ("use-dependent") inhibition by phenylalkylamines (PAAs) is a
      characteristic property of L- type calcium (Ca2+) channels. To determine the
      structural elements of the PAA binding domain we transferred sequence stretches
      of the pore-forming regions of repeat III and/or IV from the skeletal muscle
      alpha1 subunit (alpha1S) to the class A alpha1 subunit (alpha1A and expressed
      these chimeras together with beta1a and alpha2/delta subunits in Xenopus oocytes.
      The corresponding barium currents (IBa) were tested for PAA sensitivity during
      trains of depolarizing test pulses (conditioned block). IBa of oocytes expressing
      the alpha1A subunit were only weakly inhibited by PAAs (less than 10% conditioned
      block of IBa during a 100-ms pulse train of 0.1 Hz). Transfer of the
      transmembrane segment IVS6 from alpha1S to alpha1A produced an enhancement of PAA
      sensitivity of the resulting alpha1A/alpha1S chimera comparable to L-type alpha1
      subunits (about 35% conditioned block Of IBa during a 100-ms pulse train of 0.1
      Hz). Our results demonstrate that substitution of 11 amino acids within the
      segment RVS6 of alpha1A with the corresponding residues of alpha1S is sufficient
      to transfer L-type PAA sensitivity into the low sensitive class A Ca2+ channel.

PMID- 8662624
TI  - Regulation of the inositol 1,4,5-trisphosphate-activated Ca2+ channel by
      activation of G proteins.
AB  - Streptolysin O-permeable pancreatic acini were used to study the regulation of
      the inositol 1,4,5-trisphosphate (IP3)-activated Ca2+ channel (IPACC) by agonists
      and antagonists. Measurements of the apparent affinity for IP3 (KappIP3) showed
      that the IPACC is dynamically controlled during cell stimulation and inhibition,
      i.e. agonists decreased and antagonists increased KappIP3. KappIP3 was also
      independently regulated by thimerosal, Ca2+ content of the stores, the incubation
      temperature, activation of protein kinases, and inhibition of protein
      phosphatases, but none of these mechanisms contributed to the regulation by
      agonists and antagonists. Incubating the cells with low concentration of
      GTPgammaS or AIF3 reproduced the effect of the agonist on KappIP3. Moreover, low
      [GTPgammaS] allowed activation of the IPACC by agonists at basal levels of IP3
      and markedly impaired channel inactivation by antagonists. Channel sensitization
      by GTPgammaS also restored the ability of thimerosal to mobilize Ca2+ from
      internal stores with no change in cellular IP3 levels. The combination of low
      [GTPgammaS] and thimerosal locked the channel in an open, antagonist-insensitive
      state. All modulatory effects of GTPgammaS are independent of phospholipase C
      activation and IP3 production. We propose that the dynamic regulation of the
      IPACC by a G protein-dependent mechanism can play a major role in triggering and
      maintaining Ca2+ oscillations at low agonist concentrations when minimal or no
      changes in IP3 level take place.

PMID- 8662625
TI  - Arginine 343 and 350 are two active residues involved in substrate binding by
      human Type I D-myo-inositol 1,4,5,-trisphosphate 5-phosphatase.
AB  - The crucial role of two reactive arginyl residues within the substrate binding
      domain of human Type I D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) 5
      phosphatase has been investigated by chemical modification and site-directed
      mutagenesis. Chemical modification of the enzyme by phenylglyoxal is accompanied
      by irreversible inhibition of enzymic activity. Our studies demonstrate that
      phenylglyoxal forms an enzyme-inhibitor complex and that the modification
      reaction is prevented in the presence of either Ins(1,4,5)P3, D-myo-inositol
      1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) or 2,3-bisphosphoglycerate (2,3-BPG).
      Direct [3H]Ins(1,4,5)P3 binding to the covalently modified enzyme is dramatically
      reduced. The stoichiometry of labeling with 14C-labeled phenylglyoxal is shown to
      be 2.1 mol of phenylglyoxal incorporated per mol of enzyme. A single
      [14C]phenylglyoxal-modified peptide is isolated following alpha-chymotrypsin
      proteolysis of the radiolabeled Ins(1,4,5)P3 5-phosphatase and reverse-phase high
      performance liquid chromatography (HPLC). The peptide sequence (i.e. M-N-T-R-C-P
      A-W-C-D-R-I-L) corresponds to amino acids 340-352 of Ins(1,4,5)P3 5-phosphatase.
      An estimate of the radioactivity of the different phenylthiohydantoin amino acid
      derivatives shows the modified amino acids to be Arg-343 and Arg-350.
      Furthermore, two mutant enzymes were obtained by site-directed mutagenesis of the
      two arginyl residues to alanine, and both mutant enzymes have identical UV
      circular dichroism (CD) spectra. The two mutants (i.e. R343A and R350A) show
      increased Km values for Ins(l,4,5)P3 (10- and 15-fold, respectively) resulting in
      a dramatic loss in enzymic activity. In conclusion, we have directly identified
      two reactive arginyl residues as part of the active site of Ins(1,4,5)P3 5
      phosphatase. These results point out the crucial role for substrate recognition
      of a 10 amino acids-long sequence segment which is conserved among the primary
      structure of inositol and phosphatidylinositol polyphosphate 5-phosphatases.

PMID- 8662626
TI  - Thyroid hormone modulates the interaction between iron regulatory proteins and
      the ferritin mRNA iron-responsive element.
AB  - The cytoplasmic iron regulatory protein (IRP) modulates iron homeostasis by
      binding to iron-responsive elements (IREs) in the transferrin receptor and
      ferritin mRNAs to coordinately regulate transferrin receptor mRNA stability and
      ferritin mRNA translational efficiency, respectively. These studies demonstrate
      that thyroid hormone (T3) can modulate the binding activity of the IRP to an IRE
      in vitro and in vivo. T3 augmented an iron-induced reduction in IRP binding
      activity to a ferritin IRE in RNA electrophoretic mobility shift assays using
      cytoplasmic extracts from human liver hepatoma (HepG2) cells. Hepatic IRP binding
      to the ferritin IRE also diminished after in vivo administration of T3 with iron
      to rats. In transient transfection studies using HepG2 cells and a human ferritin
      IRE-chloramphenicol acetyltransferase (H-IRE-CAT) construct, T3 augmented an iron
      induced increase in CAT activity by approximately 45%. RNase protection analysis
      showed that this increase in CAT activity was not due to a change in the steady
      state level of CAT mRNA. Nuclear T3-receptors may be necessary for this T3
      induced response, because the effect could not be reproduced by the addition of
      T3 directly to cytoplasmic extracts and was absent in CV-1 cells which lack T3
      receptors. We conclude that T3 can functionally regulate the IRE binding activity
      of the IRP. These observations provide evidence of a novel mechanism for T3 to up
      regulate hepatic ferritin expression, which may in part contribute to the
      elevated serum ferritin levels seen in hyperthyroidism.

PMID- 8662627
TI  - The ear of alpha-adaptin interacts with the COOH-terminal domain of the Eps 15
      protein.
AB  - The role of Eps15 in clathrin-mediated endocytosis is supported by two
      observations. First, it interacts specifically and constitutively with the plasma
      membrane adaptor AP-2. Second, its NH2 terminus shows significant homology to the
      NH2 terminus of yeast End3p, necessary for endocytosis of alpha-factor. To gain
      further insight into the role of Eps15-AP-2 association, we have now delineated
      their sites of interactions. AP-2 binds to a domain of 72 amino acids (767-739)
      present in the COOH terminus of Eps15. This domain contains 4 of the 15 DPF
      repeats characteristic of the COOH-terminal domain of Eps15 and shares no
      homology with known proteins, including the related Epsl5r protein. Precipitation
      of proteolytic fragments of AP-2 with Eps15-derived fusion proteins containing
      the binding site for AP-2 showed that Eps15 binds specifically to a 40-kDa
      fragment corresponding to the ear of alpha-adaptin, a result confirmed by
      precipitation of Eps15 by alpha-adaptin-derived fusion proteins. Our data
      indicate that this specific part of AP-2 binds to a cellular component and
      provide the tools for investigating the functions of the association between AP-2
      and Eps15.

PMID- 8662628
TI  - A novel class of retinoid antagonists and their mechanism of action.
AB  - Retinoids regulate a broad range of biological processes through two subfamilies
      of nuclear retinoid receptors, the retinoic acid receptors (RARs) and the
      retinoid X receptors (RXRs). Recently, we reported a novel type of retinoic acid
      antagonist (SR11335) and showed that this compound can inhibit retinoic acid (RA)
      induced activation of a human immunodeficiency virus type 1 (HIV-1) promoter
      construct that contains a special RA response element (RARE). We have now further
      characterized the antagonism mediated by SR11335 and of newly synthesized
      structurally related compounds. Two compounds, SR11330 and SR11334, which are
      poor transactivators, also showed antagonist activities, inhibiting all-trans-RA
      (tRA) and 9-cis-RA. The retinoids inhibited transcriptional activation of RAR/RXR
      heterodimers effectively, while inhibition of RXR homodimers was less efficient.
      Inhibition was observed on several RAREs, including the TREpal, betaRARE, apoAI
      RARE, and CRBPI-RARE. In addition, the antagonists inhibited tRA-induced
      differentiation of HL-60 cells. The antagonist did not interfere with DNA binding
      of the receptors. In limited proteolytic digestion assays, SR11335 induced
      resistance of the receptors to proteolysis, but the pattern of the degradation
      was not altered from that induced by tRA, suggesting that these antagonists
      induce their biological effects by competing with agonists for binding to RARs,
      thereby preventing the induction of conformational changes of the receptors
      necessary for transcriptional activation.

PMID- 8662629
TI  - Histones associated with non-nucleosomal rat ribosomal genes are acetylated while
      those bound to nucleosome-organized gene copies are not.
AB  - Acetylation of histones bound to rat rRNA genes has been studied relative to
      their organization in chromatin, either as canonical nucleosomes, containing the
      inactive copies, or as anucleosomal nonrepeating structures, corresponding to the
      transcribed genes (Conconi, A., Widmer, R. M., Koller, T., and Sogo, J. M. (1989)
      Cell 57, 753-761). Nuclei from butyrate-treated rat tumor cells were irradiated
      with a UV laser to cross-link proteins to DNA, and the purified covalent
      complexes were immunofractionated by an antibody that specifically recognized the
      acetylated histones. Upon probing with sequences coding for mature rat 28 S RNA,
      DNA of the antibody-bound complexes was 5-20-fold enriched relative to the total
      rat DNA. Since the laser cross-links histones to DNA in both active and inactive
      genes, one cannot distinguish which one of them, or both, are bound to acetylated
      histones. Alternatively, purified mononucleosomes were immunofractionated, but
      DNA from the antibody-bound monosomes was not enriched in coding rDNA. Taken
      together, these results suggest that nucleosome-organized rRNA genes are bound to
      nonmodified histones and that the acetylated histones are associated with the
      active, anucleosomal gene copies.

PMID- 8662630
TI  - TFII is required for transcription of the naturally TATA-less but initiator
      containing Vbeta promoter.
AB  - The proximal or core promoter of a typical eukaryotic protein coding gene
      comprises distinct elements, TATA and/or initiator (Inr). The existence of TATA
      or Inr at the core promoter suggests that the mechanism of transcription
      initiation mediated by these two genetic elements may be different. Accordingly,
      it has been demonstrated that the transcriptional requirements for the TATA
      containing, Inr-less (TATA+Inr-) promoters are different from the transcriptional
      requirements for the TATA-less, Inr-containing (TATA-Inr+) promoters. Although
      both types of promoters require the transcription initiation factor (TFIID) in
      addition to other common initiation factors, a TATA-Inr+ promoter requires
      accessory components. Here we have employed in vitro analyses to address the
      transcription factor requirements for a TATA-Inr+ promoter. We demonstrate that
      in addition to TFIID, a naturally occurring TATA-Inr+ promoter requires TFII-I,
      an Inr element-dependent transcription factor. Consistent with its Inr element
      dependent activities, TFII-I is dispensable for a TATA+Inr- promoter.
      Furthermore, we demonstrate that both TFII-I and TFIID activities in nuclear
      extracts are temperature-sensitive. However, TFII-I is heat-inactivated at
      temperatures lower than that required to inactivate TFIID. Therefore,
      differential heat treatment of nuclear extracts provides an assay to discriminate
      between transcriptional requirements at TATA+Inr- and TATA-Inr+ promoters.

PMID- 8662631
TI  - Characterization of human type III collagen expressed in a baculovirus system.
      Production of a protein with a stable triple helix requires coexpression with the
      two types of recombinant prolyl 4-hydroxylase subunit.
AB  - An efficient expression system for recombinant collagens would have numerous
      scientific and practical applications. Nevertheless, most recombinant systems are
      not suitable for this purpose, as they do not have sufficient amounts of prolyl 4
      hydroxylase activity. Pro-alpha 1 chains of human type III collagen expressed in
      insect cells by a baculovirus vector are reported here to contain significant
      amounts of 4-hydroxyproline and to form triple-helical molecules, although the Tm
      of the triple helices was only about 32-34 degrees C. Coexpression of the pro
      alpha1(III) chains with the alpha and beta subunits of human prolyl 4-hydroxylase
      increased the Tm to about 40 degrees C, provided that ascorbate was added to the
      culture medium. The level of expression of type III procollagen was also
      increased in the presence of the recombinant prolyl 4-hydroxylase, and the pro
      alpha 1(III) chains and alpha1(III) chains were found to be present in disulfide
      bonded molecules. Most of the triple-helical collagen produced was retained
      within the insect cells and could be extracted from the cell pellet. The highest
      expression levels were obtained in High Five cells, which produced up to about 80
      microg of cellular type III collagen (120 microg of procollagen) per 5 X 10(6)
      cells in monolayer culture and up to 40 mg/liter of cellular type III collagen
      (60 mg/liter procollagen) in suspension. The 4-hydroxyproline content and Tm of
      the purified recombinant type III collagen were very similar to those of the
      nonrecombinant protein, but the hydroxylysine content was slightly lower, being
      about 3 residues/1000 in the former and 5/1000 in the latter.

PMID- 8662632
TI  - Intragenic suppressors of P-loop mutations in the beta-subunit of the
      mitochondrial ATPase in the yeast Saccharomyces cerevisiae.
AB  - Three intragenic second-site suppressors, P353L, T237I, and L390F, were
      identified that suppressed two mutations in, and one adjacent to, the P-loop in
      the beta-subunit of the yeast F1-ATPase. The crystal structure of bovine F1
      ATPase (Abrahams, J. P., Leslie, A. G. W., Lutter, R., and Walker, J. E. (1994)
      Nature 370, 621-628) shows that these suppressor residues are located in the
      nucleotide-binding domain. Specific hypotheses have been formulated that suggest
      the conformational coupling of the P-loop with the suppressor sites. P353L is in
      a "catch" region, which forms unique interactions with the gamma-subunit in the
      three different conformational states of the catalytic site. The identification
      of this suppressor mutation demonstrates genetically that the catch region is
      conformationally coupled to the P-loop. T237I is shown to interact with Lys-209,
      which occurs just after the P-loop. This suggests that this interaction changes
      the conformation of the P-loop to suppress the initial mutation. L390F interacts
      with Ala-181, which is adjacent to the P-loop. The mechanism of this suppression
      is suggested to occur through the interactions of L390F with Ala-181. These
      results identify critical interactions that modulate the structure of the P-loop
      and thus the biochemistry of the enzyme.

PMID- 8662633
TI  - Mutational analysis of photosystem I polypeptides. Role of PsaD and the lysyl 106
      residue in the reductase activity of the photosystem I.
AB  - The ADC4 mutant of the cyanobacterium Synechocystis sp. PCC 6803 was studied to
      determine the structural and functional consequences of the absence of PsaD in
      photosystem I. Isolated ADC4 membranes were shown to be deficient in ferredoxin
      mediated NADP(+) reduction, even though charge separation between P700 and FA/FB
      occurred with high efficiency. Unlike the wild type, FB became preferentially
      photoreduced when ADC4 membranes were illuminated at 15 K, and the EPR line
      shapes were relatively broad. Membrane fragments oriented in two dimensions on
      thin mylar films showed that the g tensor axes of FA- and FB- were identical in
      the ADC4 and wild type strains, implying that PsaC is oriented similarly on the
      reaction center. PsaC and the FA/FB iron-sulfur clusters are lost more readily
      from the ADC4 membranes after treatment with Triton X-100 or chaotropic agents,
      implying a stabilizing role for PsaD. The specific role of Lys106 of PsaD, which
      can be crosslinked to Glu93 of ferredoxin (Lelong et al. (1994) J. Biol. Chem.
      269, 10034-10039), was probed by site-directed mutagenesis. Chemical cross
      linking and protease treatment experiments did not reveal any drastic alterations
      in the conformation of the mutant PsaD proteins. The EPR spectra of FA and FB in
      membranes of the Lys106 mutants were similar to those of the wild type. Membranes
      of all Lys106 mutants showed wild type rates of flavodoxin reduction and
      flavodoxin-mediated NADP+ reduction, but had 10-54% decrease in the ferredoxin
      mediated NADP+ reduction rates. This implies that Lys106 is a dispensable
      component of the docking site on the reducing side of photosystem I and an ionic
      interaction between Lys106 of PsaD and Glu93 of ferredoxin is not essential for
      electron transfer to ferredoxin. These results demonstrate that PsaD serves
      distinct roles in modulating the EPR spectral characteristics of FA and FB, in
      stabilizing PsaC on the reaction center, and in facilitating ferredoxin-mediated
      NADP+ photoreduction on the reducing side of photosystem I.

PMID- 8662634
TI  - Phosphorylation of the InaD gene product, a photoreceptor membrane protein
      required for recovery of visual excitation.
AB  - In an approach directed to isolate and characterize key proteins of the
      transduction cascade in photoreceptors using the phosphoinositide signaling
      pathway, we have isolated the Calliphora homolog of the Drosophila InaD gene
      product, which in Drosophila InaD mutants causes slow deactivation of the light
      response. By screening a retinal cDNA library with antibodies directed against
      photoreceptor membrane proteins, we have isolated a cDNA coding for an amino acid
      sequence of 665 residues (Mr = 73,349). The sequence displays 65.3% identity
      (77.3% similarity) with the Drosophila InaD gene product. Probing Western blots
      with monospecific antibodies directed against peptides comprising amino acids 272
      542 (anti-InaD-(272-542)) or amino acids 643-655 (anti-InaD-(643-655)) of the
      InaD gene product revealed that the Calliphora InaD protein is specifically
      associated with the signal-transducing rhabdomeral photoreceptor membrane from
      which it can be extracted by high salt buffer containing 1.5 M NaCl. As five out
      of eight consensus sequences for protein kinase C phosphorylation reside within
      stretches of 10-16 amino acids that are identical in the Drosophila and
      Calliphora InaD protein, the InaD gene product is likely to be a target of
      protein kinase C. Phosphorylation studies with isolated rhabdomeral photoreceptor
      membranes followed by InaD immunoprecipitation revealed that the InaD protein is
      a phosphoprotein. In vitro phosphorylation is, at least to some extent, Ca 2+
      dependent and activated by phorbol 12-myristate 13-acetate. The inaC-encoded eye
      specific form of a protein kinase C (eye-PKC) is co-precipitated by antibodies
      specific for the InaD protein from detergent extracts of rhabdomeral
      photoreceptor membranes, suggesting that the InaD protein and eye-PKC are
      interacting in these membranes. Co-precipitating with the InaD protein and eye
      PKC are two other key components of the transduction pathway, namely the trp
      protein, which is proposed to form a Ca2+ channel, and the norpA-encoded
      phospholipase C, the primary target enzyme of the transduction pathway. It is
      proposed that the rise of the intracellular Ca2+ concentration upon visual
      excitation initiates the phosphorylation of the InaD protein by eye-PKC and
      thereby modulates its function in the control of the light response.

PMID- 8662635
TI  - Domain structure of the vaccinia virus mRNA capping enzyme. Expression in
      Escherichia coli of a subdomain possessing the RNA 5'-triphosphatase and
      guanylyltransferase activities and a kinetic comparison to the full-size enzyme.
AB  - The RNA 5'-triphosphatase, nucleoside triphosphate phosphohydrolase, and
      guanylyltransferase activities of the vaccinia virus mRNA capping enzyme were
      previously localized to an NH2-terminal 60-kDa domain of the D1R subunit.
      Measurement of the relative ATPase and guanylyltransferase activities remaining
      in D1R carboxyl-terminal deletion variants expressed in Escherichia coli
      BL21(DE3)plysS localizes the carboxyl terminus of the active domain to between
      amino acids 520 and 545. Failure to obtain a deletion mutant with the loss of one
      activity indicates that the catalysis of both reactions requires a common domain
      structure. Based on these results, a truncated D1R protein terminating at amino
      acid 545 was expressed in E. coli and purified to homogeneity. D1R1-545 was found
      to be kinetically equivalent to the holoenzyme in regard to ATPase, RNA 5'
      triphosphatase, and guanylyltransferase activities. Measurement of RNA binding by
      mobility shift and UV photo-cross-linking analyses also demonstrates the ability
      of this domain to bind RNA independent of the methyltransferase domain, comprised
      of the carboxyl terminus of D1R from amino acids 498-844 and the entire D12L
      subunit. RNA binding to D1R1-545 is substantially weaker than binding to either
      the methyltransferase domain or the holoenzyme. Binding is inhibited by 5'-OH RNA
      and to a lesser extent by DNA oligonucleotides in a concentration dependent
      manner which correlates with the inhibition of RNA 5'-triphosphatase activity by
      these same oligonucleotides. We conclude that D1R1-545 represents a functionally
      independent domain of the mRNA capping enzyme, fully competent in substrate
      binding and catalysis at both the triphosphatase and guanylyltransferase active
      sites.

PMID- 8662637
TI  - Role of CYP2E1 in the hepatotoxicity of acetaminophen.
AB  - CYP2El, a cytochrome P-450 that is well conserved across mammalian species,
      metabolizes ethanol and many low molecular weight toxins and cancer suspect
      agents. The cyp2e1 gene was isolated, and a mouse line that lacks expression of
      CYP2E1 was generated by homologous recombination in embryonic stem cells. Animals
      deficient in expression of the enzyme were fertile, developed normally, and
      exhibited no obvious phenotypic abnormalities, thus indicating that CYP2E1 has no
      critical role in mammalian development and physiology in the absence of external
      stimuli. When cyp2el knockout mice were challenged with the common analgesic
      acetaminophen, they were found to be considerably less sensitive to its
      hepatotoxic effects than wild-type animals, indicating that this P-450 is the
      principal enzyme responsible for the metabolic conversion of the drug to its
      active hepatotoxic metabolite.

PMID- 8662636
TI  - Characterization of the vaccinia virus RNA 5'-triphosphatase and nucleotide
      triphosphate phosphohydrolase activities. Demonstrate that both activities are
      carried out at the same active site.
AB  - D1R1-545, an active subdomain of the large subunit of vaccinia virus mRNA capping
      enzyme possessing ATPase, RNA 5'-triphosphatase, and guanylyltransferase
      activities, was expressed in Escherichia coli and shown to be functionally
      equivalent to the heterodimeric enzyme (Myette, J. R., and Niles, E. G. (1996) J.
      Biol. Chem. 271, 11936-11944). A detailed characterization of the
      phosphohydrolytic activities of D1R1-545 demonstrates that, in addition to ATPase
      and RNA 5'-triphosphatase activities, the capping enzyme also possesses a general
      nucleoside triphosphate phosphohydrolase activity that lacks a preference for the
      nucleoside base or sugar. Nucleoside triphosphate and mRNA saturation kinetics
      are markedly different, with RNA exhibiting a Km and turnover number 100- and 10
      fold less, respectively, than those values measured for any NTP. The linear
      competitive inhibition of RNA 5'-triphosphatase activity by ATP, and the relative
      manner by which both ATPase and RNA 5'-triphosphatase activities are inhibited by
      specific oligonucleotides, kinetically demonstrate that each activity is carried
      out at a common active site. Direct UV photo-cross-linking of either 32P
      radiolabeled ATP or 23-mer triphosphorylated RNA, followed by cyanogen bromide
      cleavage of the photo-linked enzyme, localizes the major binding site for both
      ATP and RNA to a region between amino acids 1 and 221. The inability of ATP to
      competitively inhibit either E approximately GMP formation or the transfer of GMP
      to RNA kinetically differentiates the phosphohydrolase active site from the
      guanylyltransferase active site.

PMID- 8662638
TI  - Isolation of inositol 1,3,4-trisphosphate 5/6-kinase, cDNA cloning and expression
      of the recombinant enzyme.
AB  - Inositol 1,3,4-trisphosphate 5/6-kinase was purified 12,900-fold from calf brain
      using chromatography on heparin-agarose and affinity elution with inositol
      hexakisphosphate. The final preparation contained proteins of 48 and 36-38 kDa.
      All of these proteins had the same amino-terminal sequence and were enzymatically
      active. The smaller species represent proteolysis products with carboxyl-terminal
      truncation. The Km of the enzyme for inositol 1,3,4-trisphosphate was 80 nM with
      a Vmax of 60 nmol of product/min/mg of protein. The amino acid sequence of the
      tryptic peptide HSKLLARPAGGLVGERTCNAXP matched the protein sequence encoded by a
      human expressed sequence tag clone (GB T09063) at 16 of 22 residues. The
      expressed sequence tag clone was used to screen a human fetal brain cDNA library
      to obtain a cDNA clone of 1991 base pairs (bp) that predicts a protein of 46 kDa.
      The clone encodes the amino-terminal amino acid sequence obtained from the
      purified calf brain preparation, suggesting that it represents its human
      homologue. The cDNA was expressed as a fusion protein in Escherichia coli and was
      found to have inositol 1,3,4-trisphosphate 5/6-kinase activity. Remarkably, both
      the purified calf brain and recombinant proteins produced both inositol 1,3,4,6
      tetrakisphosphate and inositol 1,3,4,5-tetrakisphosphate as products in a ratio
      of 2.3-5:1. This finding proves that a single kinase phosphorylates inositol in
      both the D5 and D6 positions. Northern blot analysis identified a transcript of
      3.6 kilobases in all tissues with the highest levels in brain. The composite cDNA
      isolated contains 3054 bp with a poly(A) tail, suggesting that 500-600 bp of 5'
      sequence remains to be identified.

PMID- 8662639
TI  - Sls1p, an endoplasmic reticulum component, is involved in the protein
      translocation process in the yeast Yarrowia lipolytica.
AB  - Signal recognition particle-dependent targeting of secretory proteins to the
      endoplasmic reticulum membrane is predominant in the yeast Yarrowia lipolytica. A
      conditional lethal mutant of the SCR2-encoded 7S RNA provided the first in vivo
      evidence for involvement of this particle in cotranslational translocation (He,
      F., Beckerich, J. M., and Gaillardin, C. M. (1992) J. Biol. Chem. 267, 1932
      1937). In order to identify partners of 7S RNA or signal recognition particle in
      their function, we selected synthetic lethal mutations with the 7S RNA mutation
      (sls). The SLS1 gene, cloned by complementation of the sls1 mutant growth defect,
      encodes a 426-amino acid polypeptide containing a NH2-terminal signal peptide and
      a COOH-terminal endoplasmic reticulum (ER) retention motif. The SLS1 gene product
      behaves as a lumenal protein of the ER. Sls1p was sedimented with membrane-rich
      organelles and was resistant to protease degradation without prior membrane
      solubilization. Immunofluorescence microscopy showed a typical endoplasmic
      reticulum perinuclear staining. Co-immunoprecipitation revealed that Sls1p
      resides close to the major translocation apparatus component, Sec61p. Deletion of
      the SLS1 gene led to a temperature-sensitive growth phenotype. Synthesis of
      several secretory proteins was shown to be specifically reduced in delta sls1
      cells. We propose that Sls1p acts in the preprotein translocation process,
      interacting directly with translocating polypeptides to facilitate their transfer
      and/or help their folding in the ER.

PMID- 8662640
TI  - The DNA binding site(s) of the Escherichia coli RecA protein.
AB  - Photochemical cross-linking has been used to identify residues in the Escherichia
      coli RecA protein that are proximal to and may directly mediate binding of DNA.
      Ultraviolet irradiation promotes specific and efficient cross-linking of the RecA
      protein to poly(deoxythymidylic) acid. Cross-linked peptides remaining covalently
      attached to the polynucleotide following proteolytic digestion with trypsin
      correspond to amino acids 61-72, 178-183, and 233-243 of the RecA protein primary
      sequence. Their location and surface accessibility in the crystal structure,
      along with the behavior of various recA mutants, support the assignment of the
      cross-linked regions to the DNA binding site(s) of the RecA protein. Functional
      overlap of amino acids 61-72 with an element of the ATP binding site suggests a
      structural mechanism by which nucleotide cofactors allosterically affect the RecA
      nucleoprotein filament.

PMID- 8662641
TI  - A mutant RNA polymerase reveals a kinetic mechanisms for the switch between
      nonproductive stuttering synthesis and productive initiation during promoter
      clearance.
AB  - During transcription initiation from galP2, one of the two promoters of the
      Escherichia coli galactose operon with an initially transcribed sequence of
      pppAUUUC, RNA polymerase (RNAP) is known to engage nonproductive stuttering
      synthesis, which is sensitive to the concentration of UTP. This study examines
      the effect of this nonproductive synthesis on promoter clearance and determines
      other parameters that might affect stuttering synthesis by analyzing a mutant
      RNAP, RpoB3449, that has altered its function at this process at galP2. RpoB3449
      has dramatically diminished stuttering synthesis, and consequently, it has
      increased the rate of productive initiation due to its enhanced rate of promoter
      clearance of galP2 compared with wild-type RNAP. Thus, a direct linkage between
      promoter clearance and productive transcription is demonstrated. The mechanism by
      which the mutant RNAP has altered the switch between nonproductive stuttering
      synthesis and productive initiation during promoter clearance is studied.
      Apparently, RpoB3449 has increased its efficiency in incorporating CTP at the +5
      position of the galP2 transcript leading to its reduced stuttering synthesis,
      indicating that the rate of an RNAP incorporating the CTP after a stretch of
      uridine residues is important for promoter clearance at galP2. Because RpoB3449
      demonstrates "wild-type" stuttering synthesis at the mutant galP2 promoter, which
      contains the 6 residue at the +5 position, it indicates that the mutant RNAP has
      altered in binding CTP at this context. Further experiments indicate that it is
      the +5 position per se of the galP2 sequence rather than a particular nucleotide
      at that position that is critical in determining the switch between the two
      alternate pathways during transcription initiation. A checkpoint model for the
      switch between nonproductive and productive initiations during promoter clearance
      is discussed.

PMID- 8662642
TI  - Multiple pathways for vacuolar sorting of yeast proteinase A.
AB  - The sorting of the yeast proteases proteinase A and carboxypeptidase Y to the
      vacuole is a saturable, receptor-mediated process. Information sufficient for
      vacuolar sorting of the normally secreted protein invertase has in fusion
      constructs previously been found to reside in the propeptide of proteinase A. We
      found that sorting of such a hybrid protein is dependent on the vacuolar protein
      sorting receptor Vps10p. This was unexpected, as strains disrupted for VPS10 sort
      more than 85% of the proteinase A to the vacuole. Consistent with a role for
      Vps10p in sorting of proteinase A, we found that 1) overproduction of Vps10p
      suppressed the missorting phenotype associated with overproduction of proteinase
      A, 2) overproduction of proteinase A induced missorting of carboxypeptidase Y, 3)
      vacuolar sorting of proteinase A in a deltavps10 strain was readily saturated by
      modest overproduction of proteinase A, and 4) Vps10p and proteinase A interact
      directly and specifically as shown by chemical cross-linking. Interestingly,
      overexpression of two telomere-linked VPS10 homologues, VTH1 and VTH2 suppressed
      the missorting phenotypes of a deltavps10 strain. However, disruption of the VTH1
      and VTH2 genes did not affect the sorting of proteinase A. We conclude that
      proteinase A utilizes at least two mechanisms for sorting, a Vps10p-dependent
      path and a Vth1p/Vth2p/Vps10p-independent path.

PMID- 8662643
TI  - Wortmannin inhibits mitogen-activated protein kinase activation by platelet
      activating factor through a mechanism independent of p85/p110-type
      phosphatidylinositol 3-kinase.
AB  - We have shown previously that wortmannin partially inhibits mitogen-activated
      protein kinase (MAPK) activated by platelet-activating factor (PAF) in guinea pig
      neutrophils (Ferby, M. I., Waga, I., Sakanaka, C., Kume, K., and Shimizu, T.
      (1994) J. Biol. Chem. 269, 30485-30488). To identify whether p85-dependent
      phosphatidylinositol 3-kinase is a target molecule of wortmannin in this
      inhibitory process, we established a murine macrophage cell line (P388D1),
      inducibly expressing a dominant-negative p85, delta p85. Upon induction of delta
      p85 by isopropyl-beta-D-thiogalactopyranoside, PAF still induced unaltered
      activation of MAPK, which was inhibited completely by wortmannin and 1,2-bis-(O
      aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester in an
      additive manner. Thus, PAF activates MAPK in P388D1 cells via two distinct
      pathways, one calcium-dependent and another calcium-independent, but wortmannin
      sensitive. The inhibition of calcium-independent activation of MAPK by wortmannin
      does not involve p85-dependent phosphatidylinositol 3-kinase.

PMID- 8662645
TI  - Induction of neurite outgrowth by interleukin-6 is accompanied by activation of
      Stat3 signaling pathway in a variant PC12 cell (E2) line.
AB  - PC12-E2 cells, a stable variant subcloned from native cell populations, produce
      neurites in a rapid, transcription-independent manner upon exposure to nerve
      growth factor (NGF) or basic fibroblast growth factor (bFGF). They also give a
      similar morphological response to interleukin-6 (IL-6), which is, however,
      transcription-dependent and with a slower onset, a phenomenon basically not
      observed in native PC12 cells. The response profile of PC12-E2 cells to NGF and
      bFGF is similar to that observed for native PC12 cells pre-exposed (primed) to
      NGF, and such cells also respond to IL-6 in a fashion indistinguishable from PC12
      E2 cells. Mechanistically, NGF and bFGF induce a sustained phosphorylation and
      activation of ERK1 and ERK2 in both cells, while IL-6 produces only a transient
      and weak tyrosine phosphorylation. However, it does stimulate a prolonged and
      biphasic tyrosine phosphorylation and nuclear translocation of Stat3 (signal
      transducers and activators of transcription 3; at least 24 h) and, to a lesser
      extent, Stat1. Gel shift and supershift analyses confirm that IL-6 predominantly
      activates Stat3 (and some Stat1) and stimulates sis-inducible element binding
      activity. Other members of the same cytokine subfamily, including ciliary
      neurotrophic factor and leukemia inhibitory factor, also cause a transient
      initial phase of tyrosine phosphorylation and activation of Stat1 and Stat3 (up
      to 1 h) but fail to stimulate a second phase of response and do not produce
      significant neurites. These results suggest that sustained signaling of either
      STAT or ERK pathways in PC12-E2 cells leads to induction of neuronal
      differentiation. However, only the latter is effective in native PC12 cells as
      the activation of Stat3 and Stat1 in native PC12 cells by IL-6 fails to induce
      neuronal differentiation. Thus, the response of PC12-E2 cells to IL-6 suggests
      the constitutive expression of a required factor(s) for differentiation, that is
      induced in native PC12 cells by NGF or bFGF (possibly by ERK activation), but not
      by IL-6 via Janus kinase/STAT activation. This factor(s), which has a sufficient
      half-life to allow primed cells to remain responsive to IL-6 for several days, is
      necessary but not sufficient for differentiation (as measured by neurite
      proliferation) to occur.

PMID- 8662646
TI  - Mitogen-activated protein kinase in neutrophils and enucleate neutrophil
      cytoplasts: evidence for regulation of cell-cell adhesion.
AB  - We employed neutrophils and enucleate neutrophil cytoplasts to study the
      activation of the mitogen-activated protein kinases (MAPKs) p44erk1 and p42erk2
      in neutrophils by inflammatory agonists that engage G protein-linked receptors.
      Formyl-methionyl-leucyl-phenylalanine (FMLP) rapidly and transiently activated
      MAPK in neutrophils and cytoplasts, consistent with a role in signaling for
      neutrophil functions. FMLP stimulated p2lras activation in neutrophils and Raf-1
      translocation from cytosol to plasma membrane in cytoplasts, with kinetics
      consistent with events upstream of MAPK activation. Insulin, a protein tyrosine
      kinase receptor (PTKR) agonist, stimulated neutrophil MAPK activation,
      demonstrating an intact system of PTKR signaling in these post-mitotic cells.
      FMLP- and insulin-stimulated MAPK activation in cytoplasts were inhibited by
      Bt2cAMP, consistent with signaling through Raf-1 and suggesting a mechanism for
      cAMP inhibition of neutrophil function. However, Bt2cAMP had no effect on FMLP
      stimulated MAPK activation in neutrophils. The extent of MAPK activation by
      various chemoattractants correlated with their capacity to stimulate neutrophil
      and cytoplast homotypic aggregation. Consistent with its effects on MAPK, Bt2cAMP
      inhibited FMLP-stimulated aggregation in cytoplasts but not neutrophils. Insulin
      had no independent effect but primed neutrophils for aggregation in response to
      FMLP. Our studies support a p2lras-, Raf-1-dependent pathway for MAPK activation
      in neutrophils and suggest that neutrophil adhesion may be regulated, in part, by
      MAPK.

PMID- 8662647
TI  - Transcriptional regulation of the SIS/PDGF-B gene in human osteosarcoma cells by
      the Sp family of transcription factors.
AB  - Expression of PDGF-B, the gene encoding the platelet-derived growth factor B
      chain, has been implicated as a participant in an autocrine growth loop in the
      human osteosarcoma cell line U2-OS. In previous work, we identified a primary
      site in the PDGF-B promoter, the SIS proximal element (SPE), which is critical
      for transcription of the PDGF-B gene in U2-OS cells. We also identified Sp1 as
      one of the SPE-binding proteins in U2-OS nuclear extracts. In the present work,
      we have identified another SPE-binding protein to be Sp3. Gel mobility shift
      assays showed that both Sp1 and Sp3 require the CACCC motif within the SPE for
      binding. In vitro transcription assays showed that Sp1 or/and Sp3 is necessary
      for transcription of the PDGF-B gene. Cotransfection experiments functionally
      demonstrated that Sp1 and Sp3 can independently or additively activate the PDGF-B
      promoter through the SPE as well as a synthetic promoter. However, the CACCC
      motif within the SPE is not the only site within the minimal PDGF-B promoter
      through which Sp1/Sp3 acts; additional nested deletion analyses showed that
      multiple cis-acting elements within the minimal promoter are required for full
      level transcription of the PDGF-B gene in U2-OS cells.

PMID- 8662648
TI  - The testis isoform of the phosphorylase kinase catalytic subunit (PhK-gammaT)
      plays a critical role in regulation of glycogen mobilization in developing lung.
AB  - In order to identify the form of phosphorylase kinase catalytic subunit expressed
      in developing lung, degenerate polymerase chain reaction primers were designed
      based on conserved domains of the two known catalytic subunits, expressed
      primarily in muscle and testis. Amplification of cDNA from day 19 fetal rat lung
      followed by cloning and sequence analyses indicated that only the testis isoform
      of phosphorylase kinase (PhK-gammaT) was detectable in fetal lung. In situ
      hybridization analyses indicated that expression of PhK-gammaT RNA in developing
      lung tissue was widespread and not restricted to Type II epithelial cells; PhK
      gammaT protein expression was temporally and spatially correlated with expression
      of PhK-gammaT RNA. PhK-gammaT RNA and protein expression was also characterized
      in the PhK-deficient glycogen storage disease (gsd) rat. PhK-gammaT RNA levels
      were similar in Type II cells isolated from wild type and gsd/gsd fetuses; in
      contrast, PhK-gammaT protein was virtually undetectable in gsd/ gsd Type II cells
      and enzyme activity was very low. These results suggest that PhK-gammaT plays a
      critical role in mobilization of glycogen during fetal lung development and that
      failure to catabolize glycogen in the gsd/gsd rat is related to an untranslatable
      PhK-gammaT RNA or unstable protein.

PMID- 8662649
TI  - Characterization of a protein kinase that phosphorylates serine 189 of the
      mitogen-activated protein kinase homolog ERK3.
AB  - A novel protein kinase activity present in nuclear and cytosolic extracts has
      been identified and partially purified as a consequence of its tight binding to
      and phosphorylation of the extracellular signal-regulated protein kinase (ERK) 3.
      This novel protein kinase is inactivated by treatment with phosphoprotein
      phosphatase 2A. The ERK3 protein kinase was immunologically distinct from mitogen
      activated protein (MAP) kinase/ERK kinases (MEK) 1 and 2 which phosphorylate the
      ERK3-related MAP kinases ERK1 and ERK2. This ERK3 kinase phosphorylated a single
      site on ERK3, Ser189, comparable to Thr183, one of the two activating
      phosphorylation sites of ERK2. To test the specificity of the ERK3 kinase,
      mutants of ERK3 and ERK2 were made in which the phosphorylated residues were
      exchanged. The double mutant S189T,G191Y ERK3, in which the phosphorylated
      residues from ERK2 replaced the comparable residues in ERK3, was phosphorylated
      by the ERK3 kinase but only on threonine. The ERK3 kinase did not phosphorylate
      ERK2 or ERK2 mutants. These findings indicate that although the ERK3 kinase is
      highly specific for ERK3, it does not recognize tyrosine, a feature that
      distinguishes it from MEKs that phosphorylate other ERK/MAP kinase family
      members.

PMID- 8662650
TI  - Change in expression of heart carnitine palmitoyltransferase I isoforms with
      electrical stimulation of cultured rat neonatal cardiac myocytes.
AB  - Electrical stimulation of neonatal rat cardiac myocytes in culture produces
      increases in myocyte size (hypertrophy) and organization of actin into
      myofibrillar arrays. The maturation of the cells is associated with enhanced
      contractile parameters and cellular calcium content. The numbers and intensity of
      cellular mitochondrial profiles increase, as measured by scanning laser confocal
      microscopy. Consistent with the hypertrophic response is increased cellular
      content of beta-myosin heavy chain and cytochrome oxidase subunit Va messages, as
      well as increases in cytochrome oxidase activity in the stimulated cardiac
      myocytes. Myocyte contractile capacity is associated with increased expression of
      the muscle carnitine palmitoyltransferase (CPT-I) isoform as measured by Northern
      analysis, immunoblotting, and altered sensitivity of CPT-I activity to malonyl
      CoA in the stimulated cells. The data suggest that a switch from the liver
      isoform of CPT-I, prominent in the neonatal rat heart, to the muscle CPT-I which
      predominates in adult rat heart, takes place in the neonatal cardiac myocytes
      over the same time period as the hypertrophic-mediated changes in myofibrillar
      assembly and increased contractile activity.

PMID- 8662651
TI  - Transmembrane movement of phosphatidylcholine in mitochondrial outer membrane
      vesicles.
AB  - One of the steps in the import of phosphatidylcholine (PC) in mitochondria is
      transmembrane movement across the outer membrane. This process was investigated
      in vitro using isolated mitochondrial outer membrane vesicles (OMV) from rat
      liver. 14C-Labeled PC was introduced into the OMV from small unilamellar vesicles
      by a PC-specific transfer protein (PCTP). The membrane topology of the newly
      introduced PC was determined from its accessibility to phospholipase A2. Under
      conditions where the OMV stay intact, externally added phospholipase A2 is able
      to hydrolyze up to 50% of both the introduced [14C]PC and the endogenous PC. Pool
      size calculations showed that close to 100% of the PC in the OMV can be exchanged
      by PCTP. A back-exchange experiment revealed that the introduction of the labeled
      PC is reversible. The results demonstrate that newly introduced PC molecules
      readily equilibrate over both leaflets of the OMV membrane. The kinetics of the
      PCTP-mediated exchange process indicate that the t1/2 of the transmembrane
      movement at 30 degrees C is 2 min or less.

PMID- 8662652
TI  - Role of DNA sequences outside the cores of DNase hypersensitive sites (HSs) in
      functions of the beta-globin locus control region. Domain opening and synergism
      between HS2 and HS3.
AB  - The roles of each DNase hypersensitive site (HS), and the DNA sequences between
      them, in the activity of the locus control region of the mammalian beta-globin
      gene domain were examined by placing human and rabbit restriction fragments
      containing the cores of HS2, HS3, HS4, and HS5, along with varying amounts of
      flanking DNA, upstream of a hybrid epsilon-globin-luciferase reporter gene and
      testing for effects on expression both prior to and after integration into the
      chromosomes of K562 cells, a human erythroid cell line. Prior to integration,
      fragments containing HS2 enhanced expression to the greatest extent, and the
      modest enhancement by some fragments containing HS3 correlated with the presence
      of a well-conserved binding site for AP1/NFE2. The stronger effects of larger
      locus control region DNA fragments in clones of stably transfected cells
      indicates a role for sequences outside the HS cores after integration into the
      genome. The strong effect of a 1.9-kilobase HindIII fragment containing HS3
      after, but not prior to, integration argues for the presence of a chromatin
      domain-opening activity. Use of a rabbit DNA fragment containing both HS2 and HS3
      demonstrated a synergistic interaction between the two HSs when their natural
      context and spacing are preserved.

PMID- 8662653
TI  - An ATP-dependent iron transport system in isolated rat liver nuclei.
AB  - A concerted translational control is responsible for maintaining an iron level in
      the cytosol that is both adequate for the synthesis of iron-containing proteins
      and does not represent a danger to the cell. However, little is known about how
      iron level is controlled in the nucleus. Nuclei of rat liver take up iron from
      ferric citrate by a process that is dependent on ATP. This system shares several
      properties with known P-type ATPases, suggesting that a P-type ATPase in the
      nuclear membrane is responsible for iron transport. (i) Adenosine 5'-(beta,gamma
      iminodiphosphate), a non-hydrolyzable ATP analogue, does not support iron uptake;
      (ii) the uptake is strongly inhibited by vanadate; (iii) there is an absolute
      requirement for Mg2+; and (iv) reagents that oxidize SH groups inhibit uptake,
      and this inhibition can be prevented by dithiothreitol. The energy of activation
      for the uptake (11.5 kcal/mol) and the Km for ATP (0.4 mM) are similar to values
      for other known cation transport ATPases. Inhibitors of Na+,K+-ATPase,
      sarcoplasmic reticulum Ca2+-ATPase, proton V-ATPase, and nuclear Ca2+-ATPase have
      no effect on uptake. Ferric citrate can be replaced by Fe-ATP as a source of iron
      for the transport system; however, two other stronger iron chelators, Tiron and
      desferrioxamine, completely inhibit the uptake. Taken together, these data
      strongly suggest that an Fe-ATPase, distinct from other known P-type ATPases, is
      responsible for iron transport in the nucleus.

PMID- 8662655
TI  - Interactions of phosducin with defined G protein beta gamma-subunits.
AB  - Phosducin has recently been identified as a cytosolic protein that interacts with
      the beta gamma-subunits of G proteins and thereby may regulate transmembrane
      signaling. It is expressed predominantly in the retina but also in many other
      tissues, which raises the question of its potential specificity for retinal
      versus nonretinal beta gamma-subunits. We have therefore expressed and purified
      different combinations of beta- and gamma-subunits from Sf9 cells and have also
      purified transducin-beta gamma from bovine retina and a mixture of beta gamma
      complexes from bovine brain. Their interactions with phosducin were determined in
      a variety of assays for beta gamma function: support of ADP-ribosylation of alpha
      0 by pertussis toxin, enhancement of the GTPase activity of alpha 0, and
      enhancement of rhodopsin phosphorylation by the beta-adrenergic receptor kinase 1
      (betaARK1). There were only moderate differences in the effects of the various
      beta gamma complexes alone on alpha 0, but there were marked differences in their
      ability to support betaARK1 catalyzed rhodopsin phosphorylation. Phosducin
      inhibited all beta gamma-mediated effects and showed little specificity toward
      specific defined beta gamma complexes with the exception of transducin-beta gamma
      (beta1 gamma1), which was inhibited more efficiently than the other beta gamma
      combinations. In a direct binding assay, there was no apparent selectivity of
      phosducin for any beta gamma combination tested. Thus, in contrast to betaARK1,
      phosducin does not appear to discriminate strongly between different G protein
      beta- and gamma-subunits.

PMID- 8662658
TI  - De novo expression of transfected human class 1 aldehyde dehydrogenase (ALDH)
      causes resistance to oxazaphosphorine anti-cancer alkylating agents in hamster
      V79 cell lines. Elevated class 1 ALDH activity is closely correlated with
      reduction in DNA interstrand cross-linking and lethality.
AB  - Human class 1 aldehyde dehydrogenase (hALDH-1) can oxidize aldophosphamide, a key
      aldehyde intermediate in the activation pathway of cyclophosphamide and other
      oxazaphosphorine (OAP) anti-cancer alkylating agents. Overexpression of class 1
      ALDH (ALDH-1) has been observed in cells selected for survival in the presence of
      OAPs. We used transfection to induce de novo expression of human ALDH-1 in
      V79/SD1 Chinese hamster cells to clearly quantitate the role of hALDH-1
      expression in OAP resistance. Messenger RNA levels correlated well with hALDH-1
      protein levels and enzyme activities (1.5-13.6 milliunits/mg with
      propionaldehyde/NAD+ substrate, compared to < 1 milliunit/mg in controls) in
      individual clonal transfectant lines, and slot blot analysis confirmed the
      presence of the transfected cDNA. Expressed ALDH activity was closely correlated
      (r = 0.99) with resistance to mafosfamide, up to 21-fold relative to controls.
      Transfectants were cross-resistant to other OAPs but not to phosphoramide
      mustard, ifosfamide mustard, melphalan, or acrolein. Resistance was completely
      reversed by pretreatment with 25 microM diethylaminobenzaldehyde, a potent ALDH
      inhibitor. Alkaline elution studies showed that expression of ALDH-1 reduced the
      number of DNA cross-links commensurate with mafosfamide resistance, and this
      reduction in cross-links was fully reversed by the inhibitor. Thus,
      overexpression of human class 1 ALDH alone is sufficient to confer OAP-specific
      drug resistance.

PMID- 8662657
TI  - Cyclooxygenase-1 and -2 of endothelial cells utilize exogenous or endogenous
      arachidonic acid for transcellular production of thromboxane.
AB  - The presence of prostaglandin (PG) H2 in the supernatant of human umbilical vein
      endothelial cells (HUVEC) stimulated by thrombin restores the capacity of aspirin
      treated platelets to generate thromboxane (TX) B2. Induction of cyclooxygenase-2
      (Cox-2) by interleukin (IL)-1alpha or a phorbol ester increases this formation.
      HUVEC treated with aspirin lost their capacity to generate PGs but recovery
      occurred after 3- or 6-h induction of Cox-2 with phorbol ester or IL-1alpha.
      Enzyme activity of the newly synthesized Cox-2 in aspirin-treated cells,
      evaluated after immunoprecipitation, was similar to untreated cells but after 18
      h of cell stimulation only 50-60% recovery of Cox-1 was observed. The use of
      SC58125, a selective Cox-2 inhibitor, confirmed these findings in intact cells.
      Cyclooxygenase activity was related to the amount of Cox proteins present in the
      cells, but after induction of Cox-2, contribution of the latter to PG production
      was 6-8-fold that of Cox-1. Aspirin-treated or untreated cells were incubated in
      the absence or presence of SC58125 and stimulated by thrombin, the ionophore
      A23187, or exogenous arachidonic acid. The production of endogenous (6-keto
      PGF1alpha, PGE2, PGF2alpha) versus transcellular (TXB2) metabolites was
      independent of the inducer, the source of arachidonic acid and the Cox isozyme.
      However, in acetylsalicylic acid-treated cells, after 6-h stimulation with IL
      1alpha, newly synthesized Cox-2 produced less TXB2 than 6-keto-PGF1alpha compared
      to untreated cells. At later times (>18 h), there was no metabolic difference
      between the cells. These studies suggest that in HUVEC, Cox compartmentalization
      occurring after short-term activation may selectively affect transcellular
      metabolism, but not constitutive production, of PGs.

PMID- 8662660
TI  - RNA polymerase II-associated protein (RAP) 74 binds transcription factor (TF) IIB
      and blocks TFIIB-RAP30 binding.
AB  - A set of deletion mutants of human RNA polymerase II-associated protein (RAP) 30,
      the small subunit of transcription factor IIF (TFIIF; RAP30/74), was constructed
      to map functional domains. Mutants were tested for accurate transcriptional
      activity, RAP74 binding, and TFIIB binding. Transcription assays indicate the
      importance of both N- and C-terminal sequences for RAP30 function. RAP74 binds to
      the N-terminal region of RAP30 between amino acids 1 and 98. TFIIB binds to an
      overlapping region of RAP30, localized to amino acids 1-176 (amino acids 27-152
      comprise a minimal binding region). The C-terminal region of RAP74 (amino acids
      358-517) binds directly and independently to TFIIB. Interestingly, RAP74 blocks
      TFIIB-RAP30 binding, both by binding TFIIB and by binding RAP30. When the TFIIF
      complex is intact, therefore, TFIIB-TFIIF contact is maintained through RAP74. If
      the TFIIB-RAP30 interaction is physiologically important, the TFIIF complex must
      dissociate within some transcription complexes.

PMID- 8662659
TI  - Protection by transfected rat or human class 3 aldehyde dehydrogenase against the
      cytotoxic effects of oxazaphosphorine alkylating agents in hamster V79 cell
      lines. Demonstration of aldophosphamide metabolism by the human cytosolic class 3
      isozyme.
AB  - Expression of class 3 aldehyde dehydrogenase (ALDH-3) has been associated with
      acquired or inherent resistance to oxazaphosphorine (OAP) antineoplastic
      alkylating agents (eg. cyclophosphamide). We previously demonstrated that
      expression of transfected rat ALDH-3 can confer OAP-specific resistance in human
      MCF-7 cells (Bunting, K. D., Lindahl, R., and Townsend, A. J. (1994) J. Biol.
      Chem. 269, 23197-23203). However, the aldophosphamide intermediate inactivated by
      human class 1 ALDH (hALDH-1) has not proven to be a good substrate for the
      purified hALDH-3. We have examined the ability of transfected human or rat ALDH-3
      to confer OAP resistance in V79/SDl cells. Clones expressing elevated human (386
      5938 milliunits/mg) or rat (4-597 milliunits/mg, benzaldehyde/NADP+ substrate)
      ALDH-3 activity were 1.3- to 12-fold resistant to mafosfamide relative to control
      cells (<1 milliunit/mg). Resistance was correlated with hALDH-3 activity, and was
      reversed by pretreatment with the ALDH inhibitor diethylaminobenzaldehyde.
      Transfectants were cross-resistant to 4-hydroperoxycyclophosphamide and 4
      hydroperoxyifosfamide but not to phosphoramide mustard, ifosfamide mustard,
      melphalan, or acrolein. DNA interstrand cross-links were reduced commensurately
      with the fold resistance to mafosfamide in the highest activity clone. A key
      finding was the detection of a metabolite, most likely carboxyphosphamide, that
      is formed only by cytosols from cells expressing either class 3 or class 1 ALDH.

PMID- 8662661
TI  - Transient intermediates in the thrombin activation of fibrinogen. Evidence for
      only the desAA species.
AB  - The structure of a fibrin gel depends on the nature of the fibrinogen activation
      products produced by thrombin and the physical condition under which assembly
      occurs. Two different structures of the intermediate fibrin protofibril have been
      proposed, the production of which requires different extents of fibrinopeptide A
      (FpA) cleavage from fibrinogen. The fibrin activation intermediates must be
      stable since time is required for the intermediates to diffuse to growing
      protofibrils. The classic Hall-Slayter model requires cleavage of both FpAs to
      form a desAA intermediate. The Hunziker model requires cleavage of only one FpA
      to form an AdesA intermediate. Electrophoretic quasi elastic light scattering has
      been used to show the time-dependent production of the relevant fibrinogen
      activation intermediates that includes desAA but not AdesA.

PMID- 8662662
TI  - Antioxidants inhibit interleukin-1-induced cyclooxygenase and nitric-oxide
      synthase expression in rat mesangial cells. Evidence for post-transcriptional
      regulation.
AB  - Glomerular mesangial cells produce reactive oxygen intermediates when stimulated
      by interleukin-1 (IL-1) or tumor necrosis factor. Recent observations suggest
      that reactive oxygen intermediates may play a role in IL-1 and tumor necrosis
      factor signaling and may upregulate gene expression. We therefore evaluated the
      effects of antioxidants on IL-1beta-induced cyclooxygenase-2 (Cox-2) and
      inducible nitric-oxide synthase (iNOS) expression in rat mesangial cells. The
      oxidant scavenger, pyrrolidine dithiocarbamate (PDTC), inhibited iNOS expression
      at the transcriptional level, since PDTC abolished iNOS mRNA accumulation. In
      contrast, PDTC inhibited Cox-2 expression at the post-transcriptional level,
      since PDTC did not affect IL-1beta-induced Cox-2 mRNA levels but inhibited Cox-2
      protein expression and prostaglandin E2 production. Another antioxidant,
      rotenone, which inhibits reactive oxygen intermediate production by inhibiting
      the mitochondrial electron transport system, did not inhibit IL-1beta-induced
      iNOS and Cox-2 mRNA expression but inhibited iNOS and Cox-2 protein expression,
      suggesting a post-transcriptional target for the inhibition of NOS and Cox-2
      expression induced by IL-1beta. These results suggest that not only
      transcriptional regulation but also post-transcriptional mechanisms are involved
      in redox-sensitive inhibition of cytokine induced Cox-2 and NOS expression. These
      results suggest a novel approach for intervention in cytokine-mediated
      inflammatory processes.

PMID- 8662663
TI  - Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the
      translational repressors, 4E-binding proteins.
AB  - Translation initiation in eukaryotes is facilitated by the mRNA 5' cap structure
      (m7GpppX, where X is any nucleotide) that binds the multisubunit initiation
      factor eIF4F through one of its subunits, eIF4E. eIF4E is a phosphoprotein whose
      phosphorylation state positively correlates with cell growth. Protein kinase C
      phosphorylates eIF4E in vitro, and possibly in vivo. Using recombinant eIF4E
      incubated in vitro with purified protein kinase C and analyzed by solid-phase
      phosphopeptide sequencing in combination with high performance liquid
      chromatography coupled to mass spectrometry, we demonstrated that the third amino
      acid of the peptide SGSTTK (Ser209) is the major site of phosphorylation. This
      finding is consistent with the newly assigned in vivo phosphorylation site of
      eIF4E (Joshi, B., Cai, A. L., Keiper, B. D., Minich, W. B., Mendez, R., Beach, C.
      M., Stepinski, J., Stolarski, R., Darzynkiewicz, E., and Rhoads, R. E. (1995) J.
      Biol. Chem. 270, 14597-14603). A S209A mutation resulted in dramatically reduced
      phosphorylation, both in vitro and in vivo. Furthermore, the mutant protein was
      phosphorylated on threonine (most probably threonine 210) in vivo. Here we show
      that in the presence of the recently characterized translational repressors 4E
      BP1 or 4E-BP2, phosphorylation of eIF4E by protein kinase C is strongly reduced.
      This suggests a two-step model for the phosphorylation (and activation) of eIF4E
      by growth factors and hormones: first, dissociation of eIF4E from 4E-BPs,
      followed by eIF4E phosphorylation.

PMID- 8662666
TI  - DNA triplex formation selectively inhibits granulocyte-macrophage colony
      stimulating factor gene expression in human T cells.
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hemopoietic growth
      factor that is expressed in activated T cells, fibroblasts, macrophages, and
      endothelial cells. Although GM-CSF does not appear to be essential for normal
      hemopoiesis, overexpression of GM-CSF has been implicated in the pathogenesis of
      some diseases such as myeloid leukemia and chronic inflammation. An NF-kappaB/Rel
      binding site within the GM-CSF promoter, termed the kappaB element appears to be
      important for controlling expression in reporter gene assays in response to a
      number of stimuli in T cells. We investigated oligonucleotide-directed triple
      helix formation across this regulatory sequence as a potential tool to inhibit GM
      CSF gene transcription. A 15-base oligonucleotide, GM3, was targeted to a purine
      rich region in the GM-CSF proximal promoter, which overlaps the kappaB element.
      Gel mobility shift assays and DNase I footprinting demonstrated that GM3 formed a
      sequence-specific collinear triplex with its double-stranded DNA target. Triplex
      formation by GM3 blocked recombinant and nuclear NF-kappaB proteins binding to
      the GM-CSF element. GM3 also caused selective inhibition of the human T-cell
      lymphotrophic virus-1 Tax transactivator-induced luciferase activity from a
      reporter construct driven by the GM-CSF promoter in Jurkat T cells. Finally, GM3
      greatly reduced the concentration of endogenous GM-CSF mRNA induced by different
      stimuli in Jurkat T cells but did not affect interleukin 3 mRNA levels in the
      same cells. We conclude that the kappaB element in the GM-CSF promoter plays a
      central role in the transcriptional activation of the endogenous GM-CSF gene.
      Colinear triplex formation acts as a selective transcriptional repressor of the
      GM-CSF gene and may have potential therapeutic application in cases of
      undesirable overexpression of this protein.

PMID- 8662667
TI  - Localization of epidermal growth factor-stimulated Ras/Raf-1 interaction to
      caveolae membrane.
AB  - An essential step in the epidermal growth factor (EGF)-dependent activation of
      MAP kinase is the recruitment of Raf-1 to the plasma membrane. Here we present
      evidence that caveolae are the membrane site where Raf-1 is recruited. Caveolae
      fractions prepared from normal Rat-1 cells grown in the absence of serum were
      highly enriched in both EGF receptors and Ras. Thirty seconds after EGF was added
      to these cells Raf-1 began to appear in caveolae but not in non-caveolae membrane
      fractions. The maximum concentration was reached at 3 min followed by a decline
      over the next 60 min. During this time EGF receptors disappeared from the
      caveolae fraction while the concentration of Ras remained constant. The Raf-1 in
      this fraction was able to phosphorylate MAP kinase kinase, whereas cytoplasmic
      Raf-1 in the same cell was inactive. Elevation of cellular cAMP blocked the
      recruitment of Raf-1 to caveolae. Overexpression of Ha-RasV12 caused the
      recruitment of Raf-1 to caveolae independently of EGF stimulation, and this was
      blocked by the farnesyltransferase inhibitor BZA-5B. Finally, prenylation
      appeared to be required for localization of Ras to caveolae.

PMID- 8662669
TI  - Autocatalytic folding of the folding catalyst FKBP12.
AB  - Prolyl isomerases are folding enzymes and thus have the potential to catalyze
      their own folding. We show here that the folding of cytosolic FKBP12 (FK 506
      binding protein) is an autocatalytic process both for the mature protein and for
      a fusion protein with an amino-terminal extension of 16 residues. Native FKBP
      contains seven trans-prolyl peptide bonds, and the cis-to-trans isomerizations of
      some or all of them constitute the slow, rate-limiting events in folding. The
      rate of an autocatalytic reaction increases with reactant concentration, because
      the product catalyzes its own formation. Accordingly, the folding of the fusion
      protein was more than 10-fold accelerated when the protein concentration was
      increased from 0.05 microM to 10 microM. At high concentrations of both forms of
      FKBP12 autocatalysis was very efficient, and the observed folding rate seemed to
      approach the rate of the fast direct folding reaction of the protein molecules
      with the correct (all trans) peptidyl-prolyl bond conformation.

PMID- 8662668
TI  - Platelet-derived growth factor regulates vascular smooth muscle cell
      proliferation by inducing cationic amino acid transporter gene expression.
AB  - Since recent studies demonstrated that platelet-derived growth factor (PDGF)
      induces vascular smooth muscle cell (SMC) proliferation by stimulating polyamine
      synthesis, we examined whether the transcellular transport of L-ornithine, the
      cationic amino acid precursor of polyamines, could regulate the mitogenic
      response of PDGF. Treatment of SMC with PDGF stimulated DNA and putrescine
      synthesis, and this was enhanced further by increasing the extracellular
      concentration of L-ornithine. The potentiating effect of L-ornithine was reversed
      by the competitive inhibitor of cationic amino acid transport, methyl-L-arginine,
      or by preventing putrescine formation with alpha-difluoromethylornithine.
      Cationic amino acid uptake by SMC was Na+-independent and was mediated by both a
      high and low affinity carrier system. Treatment of SMC with PDGF initially (0-2
      h) decreased basic amino acid transport, while longer exposures (6-24 h)
      progressively increased uptake. Kinetic studies indicated that PDGF-induced
      inhibition was associated with a decrease in affinity for cationic amino acids,
      while the stimulation was mediated by an increase in transport capacity.
      Endogenous PDGF released by collagen-activated platelets likewise up-regulated
      cationic amino acid transport in SMC. Reverse transcriptase-polymerase chain
      reaction detected the presence of mRNA encoding two distinct cationic amino acid
      transporter (CAT) proteins, CAT-1 and CAT-2B. Treatment of SMC with PDGF strongly
      induced the expression CAT-2B mRNA and modestly elevated the level of CAT-1 mRNA.
      These results demonstrate that PDGF-induced polyamine synthesis and SMC
      mitogenesis are dependent on the transcellular transport of L-ornithine. The
      capacity of PDGF to up-regulate the transport of L-ornithine by inducing the
      expression of the genes for CAT-1 and CAT-2B may modulate its mitogenic effect by
      providing SMC with the necessary intracellular precursor for polyamine
      biosynthesis.

PMID- 8662670
TI  - Interaction of mtTFB and mtRNA polymerase at core promoters for transcription of
      Xenopus laevis mtDNA.
AB  - Transcription of Xenopus laevis mitochondrial DNA requires mtRNA polymerase and a
      dissociable factor, xl-mtTFB, that is distinct from the HMG-box factor known as
      mtTFA. This paper presents the purification of mtTFB and characterizes its DNA
      binding properties. xl-mtTFB activity copurifies with a 40-kDa polypeptide on
      silver-stained protein gels. Activity can be recovered following elution of this
      40-kDa polypeptide from an SDS-polyacrylamide gel. xl-mtTFB is capable of binding
      to DNA, but this binding is relatively nonspecific and is easily competed by
      heterologous DNA.

PMID- 8662671
TI  - Purification, sequence analysis, and cellular localization of a prodynorphin
      derived peptide related to the alpha-neo-endorphin in the rhynchobdellid leech
      Theromyzon tessulatum.
AB  - Cells immunoreactive to an antiserum specifically directed against vertebrate
      alpha-Neo-endorphin (alpha-NE) were detected in the internal wall of anterior and
      posterior suckers of the rhynchobdellid leech Theromyzon tessulatum. These cells
      have morphological and ultrastructural characteristics close to the "releasing
      gland cells" of adhesive organs. The epitope recognized by anti-alpha-NE was
      contained in granules having a diameter of 0.2-0.3 microm. Previous works
      involving the brain of this leech demonstrate the existence of approximately 14
      neurons immunoreactive to the anti-alpha-NE. Following an extensive purification
      including high pressure gel permeation and reversed-phase high performance liquid
      chromatography, epitopes contained in both suckers and central nervous system
      were isolated. Purity of the isolated peptides was controlled by capillary
      electrophoresis. Their sequences were determined by a combination of automated
      Edman degradation, electrospray mass spectrometry measurement, and coelution
      experiments in reversed-phase high performance liquid chromatography with
      synthetic alpha-NE. The results demonstrate that epitopes recognized by the anti
      alpha-NE in the suckers and the central nervous system are identical to
      vertebrate alpha-NE (YGGFLRKYPK). This finding constitutes the first biochemical
      characterization of a prodynorphin-derived peptide in invertebrates. Moreover the
      isolation of this peptide in the annelida establishes the very ancient
      phylogenetic origin of alpha-NE as well as its conservation in evolution.

PMID- 8662672
TI  - Alteration of cell cycle-dependent histone phosphorylations by okadaic acid.
      Induction of mitosis-specific H3 phosphorylation and chromatin condensation in
      mammalian interphase cells.
AB  - Effects of okadaic acid (OA), a protein phosphatase inhibitor, on chromatin
      structure and phosphorylation of histones were examined using HeLa and N18 cells.
      The chromatin condensation in HeLa cells was mild and resemble prometaphase
      nuclei, while the condensation in N18 cells was extensive and chromatin became a
      compact body. H2A in HeLa cells was extensively and consistently phosphorylated
      at the same site throughout the cell cycle, and H3 was demonstrated to be
      phosphorylated at the mitosis-specific site Ser10. In contrast, H1
      phosphorylation was rapidly decreased in most sites within 3 h. The reduction of
      H1 phosphorylation was accompanied by a quantitative change in the set of H1
      phosphopeptides. During the early phase of the OA treatment, H1 phosphorylation
      was transiently elevated in tandem, whereas H3 phosphorylation reached a maximum
      somewhat later. The results suggest that mitosis-specific events (cdc2/H1 kinase
      activation, H1 superphosphorylation, mitosis-specific H3 phosphorylation and
      chromatin condensation) induced by OA are sequentially associated. The changes
      appear to reflect a molecular mechanism similar to that operating in normal
      mitosis.

PMID- 8662673
TI  - Isolation and characterization of the kininogen-binding protein p33 from
      endothelial cells. Identity with the gC1q receptor.
AB  - Kininogens, the precursor proteins of the vasoactive kinins, bind specifically,
      reversibly, and saturably to platelets, neutrophils, and endothelial cells. Two
      domains of the kininogens expose major cell binding sites: domain D3 that is
      shared by H- and L-kininogen and domain D5H that is exclusively present in H
      kininogen. Previously we have mapped the kininogen cell binding sites to 27
      residues of D3 ("LDC27") and 20 residues of D5H ("HKH20"", respectively (Herwald,
      H., Hasan, A. A. K., Godovac-Zimmermann, J., Schmaier, A. H., and Muller-Esterl,
      W. (1995) J. Biol. Chem. 270, 14634-14642; Hasan, A. A. K., Cines, D. B.,
      Herwald, H., Schmaier, A. H., and Muller-Esterl, W. (1995) J. Biol. Chem. 270,
      19256-19261). The corresponding kininogen acceptor site(s) exposed by the cell
      surfaces are still poorly defined. Using a non-ionic detergent, Nonidet P-40, we
      have been able to solubilize kininogen binding sites from an endothelial cell
      line, EA.hy926, in their functionally active form. Affinity chromatography of the
      solubilized kininogen binding sites on HKH20, a synthetic peptide representing
      the D5H cell binding site, allowed us to isolate a 33-kDa protein ("p33") that
      binds specifically and reversibly to H-kininogen with a KD (apparent dissociation
      constant) of 9 +/- 2 nM. Preparative SDS electrophoresis followed by NH2-terminal
      amino acid sequence analysis identified the kininogen-binding protein p33 as the
      gC1q receptor ("gC1qR"), an extrinsic membrane protein that interacts with the
      globular domains of the complement component C1q. The purified p33 binds C1q with
      moderate affinity, KD = 240 +/- 10 nM. Recombinant expression of the
      corresponding cDNA in Escherichia coli demonstrated that p33 binds H-kininogen,
      but not L-kininogen. Peptide HKH20 but not peptide LDC27 inhibited binding of H
      kininogen to the recombinant p33 in a concentration-dependent manner, indicating
      that H-kininogen binds to p33 via domain D5H. Recombinant p33 efficiently
      inhibited the binding of H-kininogen to EA.hy926 cells. Factor XII, but not
      prekallikrein, competed with H-kininogen binding to p33. These findings suggest
      that an endothelial binding protein mediates the assembly of critical components
      of the kinin-generating pathway on the surface of endothelial cells, thereby
      linking the early events of kinin formation and complement activation.

PMID- 8662674
TI  - Cytokines and insulin induce cationic amino acid transporter (CAT) expression in
      cardiac myocytes. Regulation of L-arginine transport and no production by CAT-1,
      CAT-2A, and CAT-2B.
AB  - Cytokine-dependent production of nitric oxide (NO) by rat cardiac myocytes is a
      consequence of increased expression of the inducible isoform of nitric oxide
      synthase (iNOS or NOS2) and, in the presence of insulin, depresses the
      contractile function of these cells in vivo and in vitro. Experiments reported
      here show that L-lysine, a competitive antagonist of L-arginine uptake,
      suppressed NO production (detected as nitrite accumulation) by interleukin (IL)
      1beta and interferon (IFN) gamma-pretreated cardiac myocytes by 70%,
      demonstrating that NO production is dependent on L-arginine uptake. Cardiac
      myocytes constitutively exhibit a high-affinity L-arginine transport system (Km =
      125 microM; Vmax = 44 pmol/2 X 10(5) cells/min). Following a 24-h exposure to IL
      1beta and IFNgamma, arginine uptake increases Vmax = 167 pmol/2 X 10(5)
      cells/min) and a second low-affinity L-arginine transporter activity appears (Km
      = 1.2 mM). To examine the molecular basis for these cytokine-induced changes in
      arginine transport, we examined expression of three related arginine transporters
      previously identified in other cell types. mRNA for the high-affinity cationic
      amino acid transporter-1 (CAT-1) is expressed in resting myocytes and steady
      state levels increase by 10-fold following exposure to IL-1beta and IFNgamma.
      Only cytokine-pretreated myocytes expressed a second high-affinity L-arginine
      transporter, CAT-2B, as well as a low-affinity L-arginine transporter, CAT-2A. In
      addition, insulin, which potentiated cytokine-dependent NO production independent
      of any change in NOS activity, increased myocyte L-arginine uptake by 2-fold and
      steady-state levels of CAT-1, but not CAT-2A or CAT-2B mRNA. Thus, NO production
      by cardiac myocytes exposed to IL-1beta plus IFNgamma appears to be dependent on
      the coinduction of CAT-1, CAT-2A, and CAT-2B, while insulin independently
      augments L-arginine transport through CAT- 1.

PMID- 8662675
TI  - An additional form of rat Bcl-x, Bcl-xbeta, generated by an unspliced RNA,
      promotes apoptosis in promyeloid cells.
AB  - The bcl-2 oncogene product delays apoptotic cell death and prolongs the cell
      survival. We cloned two bcl-2-related cDNAs from a rat thymus cDNA library by low
      stringency hybridization with a rat bcl-2 fragment as a probe. One of these,
      designated bcl-xalpha, was a counterpart of the human bcl-xL reported previously
      as a bcl-2-related gene (Boise, L. H., Gonzalez-Garcia, M., Postema, C. E. ,
      Ding, L., Lindsten, T., Turka, L. A., Mao, M., Nunez, G., and Thompson, C. B.
      (1993) Cell 74, 597-608). The other, designated bcl-xbeta, was novel and found to
      be generated by an unspliced mRNA, whereas bcl-xalpha was generated from a
      spliced transcript. The splice junction exactly corresponded to that found in the
      bcl-2 gene. bcl-xbeta was specifically expressed in cerebellum, heart, and
      thymus. When bcl-xbeta directed by a strong promoter was introduced into an
      interleukin-3-dependent promyeloid cell line, FDC-P1, DNA fragmentation was
      observed even in the growing state in the presence of interleukin-3 although not
      in the control transfectants. This finding suggests that the rat bcl-xbeta gene
      product promotes apoptosis in the promyeloid cells.

PMID- 8662677
TI  - Urea inducibility of egr-1 in murine inner medullary collecting duct cells is
      mediated by the serum response element and adjacent Ets motifs.
AB  - The renal medullary solute urea increases transcription and protein expression of
      the zinc finger-containing transcription factor Egr-1 in a renal epithelial cell
      specific fashion. Transient transfection of mIMCD3 cells with a luciferase
      reporter gene driven by 1.2 kilobases of the murine egr-1 5'-flanking sequence
      showed 4-fold increase in reporter gene activity with 200 mM urea treatment. The
      effect of impermeant solutes such as NaCl was much less pronounced, whereas the
      permeant solute glycerol had no effect. In addition, this same sequence, minus
      the egr-1 minimal promoter, conferred urea responsiveness to a heterologous
      (thymidine kinase) promoter. Whereas deletion of two putative AP-1 sites from the
      sequence had no effect upon urea inducibility, elimination of the five putative
      serum response elements (SREs) abolished the urea effect. Progressive deletion of
      the SREs caused a corresponding diminution in urea effect. Two key tandem SREs
      (SRE-3 and SRE-4), in conjunction with their two adjacent clusters of Ets motifs,
      were sufficient to confer urea responsiveness to a reporter gene. This response
      was markedly attenuated in the absence of either cluster of Ets motifs and was
      abolished if both clusters were deleted. By electrophoretic mobility shift assay,
      formation of the ternary complex was constitutive and was demonstrable in vitro
      despite the presence of 200 mosm urea or NaCl. Therefore urea-inducible egr-1
      transcription in renal medullary cells is mediated through the SRE and adjacent
      Ets motifs; ternary complex formation is not inhibited even in the presence of
      physiological hyperosmolality.

PMID- 8662678
TI  - Modification of the pH profile and tetrabenazine sensitivity of rat VMAT1 by
      replacement of aspartate 404 with glutamate.
AB  - Vesicular monoamine transporters (VMAT) catalyze transport of serotonin,
      dopamine, epinephrine, and norepinephrine into subcellular storage organelles in
      a variety of cells. Accumulation of the neurotransmitter depends on the proton
      electrochemical gradient (Delta micro H+) across the organelle membrane and
      involves VMAT-mediated exchange of two lumenal protons with one cytoplasmic
      amine. Mutagenic analysis of the role of two conserved Asp residues located in
      transmembrane segments X and XI of rat VMAT type I reveals an important role of
      these two residues in catalysis. Replacement of Asp 431 with either Glu or Ser
      inhibits VMAT-mediated [3H]serotonin transport. The mutated proteins are
      unimpaired in ligand recognition as measured with the high affinity ligand
      [3H]reserpine or coupling to the proton electrochemical gradient as judged by its
      ability to accelerate [3H]reserpine binding. Therefore, the Asp residue is needed
      as such in this position and even a conservative replacement with Glu generates a
      protein that can catalyze only partial reactions but cannot complete the
      transport cycle. Replacement of Asp 404 with either Ser or Cys inhibits all VMAT
      mediated reactions measured. However, replacement with Glu generated a protein
      that catalyzed [3H]serotonin transport with modified properties. Whereas the
      mutated protein binds [3H]reserpine to normal levels and the pH optimum of this
      reaction is only slightly affected, the optimum pH for transport activity shifted
      to the acid side and became very sharp; in addition the sensitivity to the
      inhibitor tetrabenazine increased significantly in this mutated protein. The
      results point to the need of a carboxyl moiety in position 404. A slight change
      in its relative location or in the environment around it has a significant effect
      on the pK of group(s) involved in steps after ligand recognition and coupling to
      the first H+.

PMID- 8662680
TI  - The role of passive transbilayer drug movement in multidrug resistance and its
      modulation.
AB  - The successful lowering of the intracellular concentration of multidrug
      resistance (MDR)-type drugs by P-glycoprotein (Pgp) relies on its ability to
      overcome the passive influx rate of each MDR-type drug. Thus, the aim of the
      present work was to study the effect of passive transbilayer drug movement on the
      multidrug resistance and its modulation. Fluorescence quenching studies indicated
      that whereas the Pgp substrate rhodamine 123 traverses an artificial lipid
      membrane with a lifetime of 3 min, the transbilayer movement rate of the MDR
      modulators, quinidine and quinine, was too fast to be detected with present
      methods. Transbilayer movement rates of drugs and modulators were estimated from
      their equilibration rate throughout artificial multilamellar vesicles. The
      equilibration rate of five selected modulators was faster than the equilibration
      rate of five representative MDR-type drugs tested, which was comparable with the
      rate of rhodamine 123 equilibration. Moreover, the carrier-type peptide
      ionophore, valinomycin, which is freely mobile in the membrane, inhibited Pgp
      mediated efflux of rhodamine 123 from MDR cells. In contrast, the channel-forming
      ionophore gramicidin D, a Pgp substrate that flip-flops slowly across the
      membrane, did not modulate cellular Pgp activity. Pgp, with a turnover number of
      about 900 min-1 can keep pace with the influx of an MDR-drug like rhodamine 123
      exhibiting a transbilayer movement with a lifetime of minutes. On the other hand,
      Pgp would fail to protect MDR cells against cytotoxic drugs that are freely
      mobile through biological membranes and that re-enter cells faster than their Pgp
      mediated active efflux rate. The relatively fast transbilayer movement exhibited
      by MDR modulators suggest that in contrast to MDR-type drugs, MDR modulators
      traverse the plasma membrane faster than the maximal expulsion rate of Pgp.

PMID- 8662679
TI  - Modulation of contact system proteases by glycosaminoglycans. Selective
      enhancement of the inhibition of factor XIa.
AB  - We investigated the influence of dextran sulfate, heparin, heparan sulfate, and
      dermatan sulfate on the inhibition of FXIa (where FXIa is activated factor XI,
      for example), FXIIa, and kallikrein by C1 inhibitor, alpha1-antitrypsin, alpha2
      antiplasmin, and antithrombin III. The second-order rate constants for the
      inhibition of FXIa by C1 inhibitor, alpha1-antitrypsin, alpha2-antiplasmin, and
      antithrombin III, in the absence of glycosaminoglycans, were 1.8, 0.1, 0.43, and
      0.32 x 10(3) M-1 s-1, respectively. The rate constants of the inactivation of
      FXIa by C1 inhibitor and by antithrombin III increased up to 117-fold in the
      presence of glycosaminoglycans. These data predicted that considering the plasma
      concentration of the inhibitors, C1 inhibitor would be the main inhibitor of FXIa
      in plasma in the presence of glycosaminoglycans. Results of experiments in which
      the formation of complexes between serine protease inhibitors and FXIa was
      studied in plasma agreed with this prediction. Glycosaminoglycans did not enhance
      the inhibition of alpha-FXIIa, beta-FXIIa, or kallikrein by C1 inhibitor. Thus,
      physiological glycosaminoglycans selectively enhance inhibition of FXIa without
      affecting the activity of FXIIa and kallikrein, suggesting that
      glycosaminoglycans may modulate the biological effects of contact activation, by
      inhibiting intrinsic coagulation without affecting the fibrinolytic potential of
      FXIIa/kallikrein.

PMID- 8662681
TI  - Different architecture of the combining site of the two chicken galectins
      revealed by chemical mapping studies with synthetic ligand derivatives.
AB  - The detailed comparison of the carbohydrate-binding properties of related
      galectins from one organism can be facilitated by the application of an array of
      deliberately tailored methyl beta-lactoside derivatives. Focusing on chicken due
      to its expression of two galectins as a model for this approach, the combining
      site architecture of the lectin from adult liver (CL-16) is apparently homologous
      to that previously observed for bovine galectin-1 (Solis, D., Jimenez-Barbero,
      J., Martin-Lomas, M., and Diaz-Maurino, T. (1994) Eur. J. Biochem. 223, 107-114).
      Besides preservation of the key interactions and minor differences, the lectin
      from adult intestine (CL-14) is able to accommodate an axial HO-3 at the glucose
      moiety. Homology-based modeling enabled us to tentatively attribute the observed
      differences to a slightly different orientation of pivotal side chains in the
      binding pocket due to distinct substitutions of amino acid residues in the
      variable region within the carbohydrate-recognition domain. Thus, the results
      suggest overlapping but distinct ranges of potential ligands for the two chicken
      lectins and provide new information on their relationship to mammalian galectins.
      The described approach is suggested to be of relevance to design pharmaceuticals
      with enhanced selectivity to a certain member within a family of related lectins.

PMID- 8662682
TI  - Phosphorylation of actin-binding protein 280 by growth factors is mediated by p90
      ribosomal protein S6 kinase.
AB  - Although Ras-related small GTPases are believed to control cell proliferation and
      motility through activation of protein kinase cascades, little is known about the
      intracellular protein targets of activated kinases. Here we show that the p90
      ribosomal S6 kinase 2 (RSK2) phosphorylates actin-binding protein (ABP-280) in
      intact rat 3Y1 fibroblasts. Growth factors such as fetal calf serum, epidermal
      growth factor, phorbol 12-myristate 13-acetate, and lysophosphatidic acid
      stimulate the phosphorylation of serine residues in ABP-280 in quiescent 3Y1
      cells. Extracts from 3Y1 cells prepared after stimulation by lysophosphatidic
      acid, fetal calf serum, and epidermal growth factor retain activated protein
      kinase activity(s) toward ABP-280 in vitro. ABP kinase activities in lysates from
      lysophosphatidic acid-stimulated 3Y1 cells can be fractionated by MonoQ anion
      exchange column chromatography into three peaks having ABP kinase activities. One
      (ABP kinase peak 1) coelutes with the peak of RSK2 as judged by immunoblotting
      and S6 peptide kinase assays. Two-dimensional phosphopeptide maps show RSK2
      phosphorylated ABP-280 to be phosphorylated at the same site(s) as those
      stimulated by growth factors in vivo. Incubation of ABP kinase peak 1
      fractionated from unstimulated cells with activated ERK2 activates latent ABP
      kinase activity. These results show RSK2 to phosphorylate ABP-280 in vivo.

PMID- 8662683
TI  - Helix pomatia lectin, an inducer of Drosophila immune response, binds to
      hemomucin, a novel surface mucin.
AB  - We describe the isolation and initial characterization of hemomucin, a novel
      Drosophila surface mucin that is likely to be involved in the induction of
      antibacterial effector molecules after binding a snail lectin (Helix pomatia A
      hemagglutinin). Two proteins of 100 and 220 kDa were purified from the membrane
      fraction of a Drosophila blood cell line using lectin columns. The two proteins
      are products of the same gene, as demonstrated by peptide sequencing. The
      corresponding cDNAs code for a product that contains an amino-terminal putative
      transmembrane domain, a domain related to the plant enzyme strictosidine
      synthase, and a mucin-like domain in the carboxyl-terminal part of the protein.
      The gene is expressed throughout development. In adult flies, high expression is
      found in hemocytes, in specialized regions of the gut, and in the ovary, where
      the protein is deposited onto the egg surface. In the gut, the mucin co-localizes
      with the peritrophic membrane. The cytogenetic location of the gene is on the
      third chromosome in the region 97F-98A.

PMID- 8662685
TI  - Structure and significance of mandibular organ-inhibiting hormone in the crab,
      Cancer pagurus. Involvement in multihormonal regulation of growth and
      reproduction.
AB  - Current evidence indicates that methyl farnesoate is the crustacean equivalent of
      the juvenile hormones of insects. This putative hormone is produced by the
      mandibular organs and is negatively regulated by a neuropeptide produced and
      secreted by the X-organ-sinus gland complex of the eyestalk. To identify this
      neuropeptide, a bioassay was developed which measures the inhibition of methyl
      farnesoate synthesis by mandibular organs exposed to fractionated sinus gland
      extracts from the crab, Cancer pagurus. Two neuropeptides, named mandibular organ
      inhibiting hormones (MOIH-1 and -2) repressed methyl farnesoate synthesis. MOIH-1
      was fully sequenced by automated Edman degradation of endoproteinase-derived
      fragments and further characterized by mass spectrometry. This peptide consisted
      of 78 residues (Mr 9235.6), with unblocked termini and three intrachain disulfide
      bridges. MOIH-2 appeared to be almost identical to MOIH-1 with the exception of a
      Gln for Lys substitution at position 33. Comparison with previously sequenced
      crustacean neuropeptides shows that these MOIHs are members of the ever expanding
      crustacean hyperglycemic hormone family, with significant sequence similarity to
      molt-inhibiting hormones (MIHs). It is possible that these two structurally
      similar peptides (MIH, MOIH) may control mutually exclusive physiological
      phenomena (somatic and gonadal growth), suggesting a complex hormonal integration
      of these processes in crustaceans.

PMID- 8662686
TI  - Identification of residues in alpha-macroglobulins important for binding to the
      alpha2-macroglobulin receptor/Low density lipoprotein receptor-related protein.
AB  - Variants of the receptor binding domain of both human alpha2-macroglobulin and
      the corresponding domain of hen egg white ovomacroglobulin have been expressed in
      Escherichia coli and refolded in vitro. Competition experiments with methylamine
      treated alpha2-macroglobulin for binding to the multifunctional alpha2
      macroglobulin receptor identify two Lys residues (residues 1370 and 1374 in human
      alpha2-macroglobulin) spaced by three amino acid residues as crucial for receptor
      binding. From this result and mutational evidence from other ligands for the
      alpha2-macroglobulin receptor, a tentative sequence motif for receptor binding is
      proposed.

PMID- 8662687
TI  - Purification to homogeneity and properties of UDP-GlcNAc (GalNAc)
      pyrophosphorylase.
AB  - The pyrophosphorylase that condenses UTP and GlcNAc-1-P was purified 9500-fold to
      near homogeneity from the soluble fraction of pig liver extracts. At the final
      stage of purification, the enzyme was quite stable and could be kept for at least
      4 months in the freezer with only slight loss of activity. On native gels, the
      purified enzyme showed a single protein band, and this band was estimated to have
      a molecular mass of approximately125 kDa on Sephacryl S-300. SDS-polyacrylamide
      gel electrophoresis analysis of the enzyme gave three protein bands of 64, 57,
      and 49 kDa, but these polypeptides are all closely related based on the
      following. 1) All three polypeptides show strong cross-reactivity with antibody
      prepared against the 64-kDa band. 2) All three proteins become labeled with
      either the UDP-GlcNAc photoaffinity probe azido-125I-salicylate-allylamine-UDP
      GlcNAc or a similar UDP-GalNAc photoaffinity probe, and either labeling was
      inhibited in a specific and concentration-dependent manner by unlabeled UDP
      GlcNAc or UDP-GalNAc. Thus, the enzyme is probably a homodimer composed of two 64
      kDa subunits. The purified enzyme had an unusual specificity in that, at higher
      substrate concentrations, it utilized UDP-GalNAc as a substrate as well as UDP
      GlcNAc in the reverse direction and GalNAc-1-P as well as GlcNAc-1-P in the
      forward direction. However, the Km for the GalNAc substrates was considerably
      higher than that for GlcNAc derivatives. This activity for synthesizing UDP
      GalNAc was not due to epimerase activity since no UDP-GalNAc could be detected
      when the enzyme was incubated with UDP-GlcNAc for various periods of time. The
      pyrophosphorylase required a divalent cation, with Mn2+ being best at 0.5-1 mM,
      and the pH optimum was between 8.5 and 8.9.

PMID- 8662688
TI  - Structural and functional analysis of the plasminogen activator inhibitor-1
      binding motif in the somatomedin B domain of vitronectin.
AB  - Plasminogen activator inhibitor 1 (PAI-1) binds to the somatomedin B (SMB) domain
      of vitronectin (VN), a domain present in at least seven other proteins. In this
      study, we investigate the PAI-1 binding activity of these SMB homologs and
      attempt to more specifically localize the PAI-1 binding site within this domain.
      SMBVN and several of its homologs were expressed in Escherichia coli, purified,
      and tested for PAI-1 binding activity in a competitive ligand binding assay.
      Although recombinant SMBVN was fully active in this assay, none of the homologs
      bound to PAI-1 or competed with VN for PAI-1 binding. These inactive homologs are
      structurally related to SMBVN, having 33-45% sequence identity and containing all
      8 cysteines at conserved positions. Thus, homolog-scanning experiments were
      conducted by exchanging progressively larger portions of the NH2- or COOH
      terminal regions of active SMBVN with the corresponding regions of the inactive
      homologs. These experiments revealed that the minimum PAI-1-binding sequence was
      present in the central region (residues 12-30) of SMBVN. Alanine scanning
      mutagenesis further demonstrated that each of the 8 cysteines as well as Gly12,
      Asp22, Leu24, Try27, Tyr28, and Asp34 were critical for PAI-1 binding and were
      required to stabilize PAI-1 activity. These results indicate that the PAI-1
      binding motif is localized to residues 12-30 of SMBVN and suggest that this motif
      is anchored in the active conformation by disulfide bonds.

PMID- 8662689
TI  - Isolation and characterization of the versicolorin B synthase gene from
      Aspergillus parasiticus. Expansion of the aflatoxin b1 biosynthetic gene cluster.
AB  - Versicolorin B synthase catalyzes the side chain cyclization of racemic
      versiconal hemiacetal to the bisfuran ring system of(-)-versicolorin B, an
      essential transformation in the aflatoxin biosynthetic pathway of Aspergillus
      parasiticus. The dihydrobisfuran is key to the mutagenic nature of aflatoxin B1.
      The protein, which shows 58% similarity and 38% identity with glucose oxidase
      from Aspergillus niger, possesses an amino-terminal sequence homologous to the
      ADP-binding region of other flavoenzymes. However, this enzyme does not require
      flavin or nicotinamide cofactors for its cyclase activity. The 643-amino acid
      native enzyme contains three potential sites for N-linked glycosylation, Asn-Xaa
      Thr or Asn-Xaa-Ser. The cDNA and genomic clones of versicolorin B synthase were
      isolated by screening the respective libraries with random-primed DNA probes
      generated from an exact copy of an internal vbs sequence. This probe was created
      through polymerase chain reaction by using nondegenerate polymerase chain
      reaction primers derived from the amino acid sequences of peptide fragments of
      the enzyme. The 1985-base genomic vbs DNA sequence is interrupted by one intron
      of 53 nucleotides. Southern blotting, nucleotide sequencing, and detailed
      restriction mapping of the vbs-containing genomic clones revealed the presence of
      omtA, a methyltransferase active in the biosynthesis, 3.3 kilobases upstream of
      vbs and oriented in the opposite direction from vbs. The presence of omtA in
      close proximity to vbs supports the theory that the genes encoding the aflatoxin
      biosynthetic enzymes in A. parasiticus are clustered.

PMID- 8662690
TI  - Calmodulin N-methyltransferase. Kinetics, mechanism, and inhibitors.
AB  - The present study was undertaken to determine kinetic and inhibition parameters
      and the mechanism of S-adenosyl-L-methionine:calmodulin-L-lysine N6
      methyltransferase (EC 2.1.1.60, CLNMT), an enzyme for which calmodulin is a
      substrate. Partially purified CLNMT isolated from rat testes had a Vmax of 540
      pmol/min/mg and Km values for mushroom demethylcalmodulin and S-adenosyl-L
      methionine of 230 nM and 2.0 microM, respectively. Kinetic analysis indicated a
      complex Bi Bi sequential kinetic mechanism for CLNMT where S-adenosyl-L
      methionine binds initially and is followed by demethylcalmodulin binding. When
      the effects of 20 different compounds that are either inhibitors of calmodulin
      specific or methylation-specific functions were examined, CLNMT displayed a
      pattern of inhibition which differs from that seen with calmodulin-activated
      enzymes. The product of calmodulin methylation, fully trimethylated calmodulin,
      and nonmethylatable VU-3 calmodulin acted as competitive inhibitors of CLNMT,
      with Ki values of 310 and 400 nM, respectively. Of the 13 compounds tested, which
      are inhibitors of calmodulin-dependent cyclic nucleotide phosphodiesterase, only
      the calmodulin-binding domain from Ca2+/calmodulin-dependent kinase II, melittin,
      and calmidazolium were effective inhibitors of CLNMT and each exhibited a complex
      pattern of inhibition with Kis values of 21, 50, and 65 nM, respectively. The
      only potent methylation-specific inhibitor was S-adenosyl-L-homocysteine, which
      also displayed a complex pattern of inhibition.

PMID- 8662692
TI  - Progression of coronary atherosclerosis is associated with a common genetic
      variant of the human stromelysin-1 promoter which results in reduced gene
      expression.
AB  - There is a common polymorphism in the promoter sequence of the human stromelysin
      1 gene, with one allele having a run of six adenosines (6A) and the other five
      adenosines (5A). We have previously reported, in a 3-year follow-up study of
      patients with coronary atherosclerosis, that those patients who are homozygous
      for the 6A allele show a more rapid progression of the disease. In this study, we
      have investigated whether the 5A/6A promoter polymorphism plays a role in the
      regulation of stromelysin-1 gene expression. In transient transfection
      experiments, a stromelysin-1 promoter construct with 6A at the polymorphic site
      was found to express less of the chloramphenicol acetyltransferase reporter gene
      than a construct containing 5A. Electrophoretic mobility shift assay and DNase I
      footprinting revealed the interaction of one or more nuclear protein(s) with the
      DNA sequence at the 5A/6A polymorphic site. The binding of one of the
      nucleoprotein factors was more readily detectable with an oligonucleotide probe
      corresponding to the 6A allele as compared with a probe corresponding to the 5A
      allele. Replacing the core binding sequence with a random DNA sequence abolished
      the interaction between the nuclear protein(s) and the probe and also increased
      reporter gene expression in transiently transfected cells. Thus, the common 5A/6A
      polymorphism of the human stromelysin-1 promoter appears to play an important
      role in regulating stromelysin-1 gene expression and may be involved in the
      progression of coronary heart disease.

PMID- 8662691
TI  - The glut 1 glucose transporter interacts with calnexin and calreticulin.
AB  - Calnexin is an integral membrane protein that acts as a chaperone during
      glycoprotein folding in the endoplasmic reticulum. Cross-linking studies were
      carried out with the aim of investigating the interactions of calnexin with
      glycoproteins in vitro. A truncated version of the integral membrane glycoprotein
      Glut 1 (GT155) was synthesized in a rabbit reticulocyte translation system in the
      presence of canine pancreatic microsomes. Following immunoprecipitation with an
      anticalnexin antiserum, a cross-linker-independent association was observed
      between GT155 and calnexin. In addition, the anti-calnexin antiserum
      immunoprecipitated a UV-dependent cross-linking product consisting of GT155 and a
      protein of approximately 60 kDa designated CAP-60 (calnexin-associated protein of
      60 kDa). Both the GT155-calnexin and the GT155-CAP-60 interactions were dependent
      on the presence of a correctly modified oligosaccharide group on GT155, a
      characteristic of many calnexin interactions. A GT155 mutant that was not
      glycosylated (AGGT155) did not associate with calnexin or CAP-60. Calreticulin,
      the soluble homologue of calnexin, was also shown to interact with GT155 only
      when the protein bore a correctly modified oligosaccharide group. Thus, our data
      show that both calnexin and calreticulin with Glut 1 in a glycosylation-dependent
      manner.

PMID- 8662693
TI  - 27-hydroxylated low density lipoprotein (LDL) cholesterol can be converted to
      7alpha,27-dihydroxy-4-cholesten-3-one (cytosterone) before suppressing
      cholesterol production in normal human fibroblasts. Evidence that an altered
      metabolism of ldl cholesterol can underlie a defective feedback control in
      malignant cells.
AB  - The formation of oxysterols in cultured human fibroblasts and their physiological
      roles as intracellular regulators of cholesterol production have been
      investigated. In the presence of low density lipoproteins (LDL), normal
      fibroblasts converted LDL cholesterol to 27hydroxycholesterol, which was further
      metabolized to 7alpha, 27-dihydroxycholesterol, 7alpha,27-dihydroxy-4-cholesten-3
      one, and 7alpha-hydroxy-3-oxo-4-cholestenoic acid. Autooxidation products of
      cholesterol contaminating the lipoproteins were also metabolized in the cells.
      7alpha-Hydroxycholesterol was converted to 7alpha-hydroxy-4-cholesten-3-one prior
      to 27-hydroxylation and further oxidation to 7alpha-hydroxy-3-oxo-4-cholestenoic
      acid. 7beta-Hydroxycholesterol and 7-oxocholesterol were 27-hydroxylated and then
      oxidized to C27-acids. Oxidation of the 7beta-hydroxy group also occurred. 25
      Hydroxycholesterol was 7alpha-hydroxylated and further oxidized to 7alpha,25
      dihydroxy-4-cholesten-3-one. 25-Hydroxylation of sterols was observed only under
      specific conditions. In contrast, only small amounts of oxysterols were formed in
      virus-transformed human fibroblasts when incubated with lipoproteins. This was
      due to very low activities of the 27- and 7alpha-hydroxylating enzymes. The rate
      of oxidation at C-3 was also decreased moderately. A defective suppression of 3
      hydroxy-3-methylglutaryl coenzyme A reductase by LDL and autooxidation products
      of cholesterol observed in the transformed fibroblasts could be caused by the
      deficiencies of the sterol-metabolizing enzymes, since these cells responded
      normally to the sterol metabolites 7alpha,27-dihydroxy-4-cholesten-3-one, 7alpha,
      25-dihydroxy-4-cholesten-3-one, and 27-hydroxy-7-oxo-cholesterol. These
      metabolites, which all possessed an oxo group with a conjugated double bond in
      the steroid nucleus and a hydroxyl group in the side chain, did not seem to
      require further metabolism in order to be active. An impaired response to LDL was
      also seen in other human tumor cells, including breast carcinoma, colonic
      carcinoma, and malignant melanoma cells. Common to all the malignant cells was an
      intracellular shortage of 7alpha, 27-dihydroxy-4-cholesten-3-one caused by a
      decreased formation or an increased metabolism.

PMID- 8662694
TI  - Inhibition of mitochondrial function by interferon.
AB  - We showed previously that type I interferon causes a down-regulation of
      mitochondrial gene expression. We show here that IFN treatment leads to
      functional impairment of mitochondria. Western blot analysis indicated that
      interferon treatment reduces the steady-state level of cytochrome b in murine L
      929 cells. Interferon produced a reduction in cytochrome c oxidase and NADH
      cytochrome c reductase activities of isolated mitochondria as well as inhibiting
      electron transport in isolated mitochondria and in intact cells. Several
      mitochondrial mRNAs are affected by interferon treatment in human Daudi
      lymphoblastoid cells, which are highly sensitive to the antiproliferative effects
      of interferon. Electron transport in Daudi cells was also inhibited by interferon
      both in intact cells and isolated mitochondria with a dose response identical to
      that for the antiproliferative response. In contrast, a Daudi strain resistant to
      the antiproliferative effects of interferon showed no down-regulation of mRNA
      expression and no inhibition of electron transport. Possibly as a consequence of
      the inhibitory effect on mitochondrial gene expression, treatment with interferon
      causes a reduction in cellular ATP levels. The inhibition of cellular growth by
      interferon may thus be partly a consequence of a reduction in cellular ATP
      levels.

PMID- 8662697
TI  - Vasoactive intestinal peptide (VIP)1 receptor. Three nonadjacent amino acids are
      responsible for species selectivity with respect to recognition of peptide
      histidine isoleucineamide.
AB  - Vasoactive intestinal peptide (VIP)1 receptors in rats and humans recognize
      peptide histidine isoleucineamide (PHI) with high and low affinity, respectively.
      We took advantage of this phenotypic difference to identify the domain
      responsible for the selective recognition of PHI by rat and human receptors which
      display >80% sequence identity. After transfection of human and rat receptors in
      COS cells, the ratio of IC50 for PHI/IC50 for VIP (referred to as P/V) in
      inhibiting 125I-VIP binding was shown to be >1,000 and <40, respectively.
      Construction of eight rat/human receptor chimerae by overlap polymerase chain
      reaction and determination of their P/V ratios demonstrated that the critical
      domain for PHI recognition is present within a sequence comprising part of the
      first extracellular loop and third transmembrane domain. This domain contains
      three different amino acids numbered according to human and rat sequences,
      respectively, e.g. Gln207 (human) versus His208 (rat), Gly211 versus Ala212 and
      Met219 versus Val220. Site-directed mutagenesis introducing individual, double,
      or triple mutations in a chimeric construct revealed that all three amino acids
      were involved in the recognition of PHI. Triple mutations were then introduced in
      the wild-type receptors i.e. Q207H, G211A, M219V human VIP1 receptor and H208Q,
      A212G, V220M rat VIP1 receptor, resulting in a complete change in their phenotype
      from human to rat and from rat to human, respectively. The results demonstrate
      that three nonadjacent amino acids are responsible for the selective recognition
      of PHI by human and rat VIP1 receptors.

PMID- 8662698
TI  - Physical association of Gi2alpha with interleukin-8 receptors.
AB  - Interleukin-8 (IL-8), one of the major mediators of the inflammatory response,
      belongs to a family of chemokines that includes NAP-2 (neutrophil-activating
      peptide-2) and Gro-alpha and whose biological activities are directed to a great
      extent toward neutrophils. Two distinct receptors have been described with
      overlapping, but not identical, binding affinities for IL-8, NAP-2, and Gro
      alpha. This study was designed to examine the intracellular pathways activated
      upon the occupation of each of the IL-8 receptors (IL-8R). The formation of a
      physical coupling between IL-8 receptors and the alpha-subunit of heterotrimeric
      G proteins was tested in neutrophils by examining the presence of the former in
      anti-Galpha immune precipitates. The addition of IL-8 to a suspension of human
      neutrophils led to a time-dependent detection of IL-8 in anti-Gi2alpha (raised
      against amino acids 159-168 (LERIAQSDYI) of Gi2alpha) and anti-Gtalpha (raised
      against the COOH-terminal 10 amino acids (KENLKDCGLF) of Gtalpha), but not anti
      Gq, immunoprecipitates. Similar results were obtained in human 293 cells stably
      transfected with IL-8RA or IL-8RB. The peptide derived from the COOH-terminal
      sequence of Gt inhibited the co-immunoprecipitation of IL-8R and Gi observed in
      response to the anti-Gtalpha and anti-Gi2alpha antibodies. On the other hand, the
      Gi2alpha peptide only inhibited the immunoprecipitation induced by the anti
      Gi2alpha antibody. Peptides derived from Gi1alpha or Gi3alpha had no effect in
      this assay. The introduction of the anti-Gi2alpha or anti-Gtalpha antibodies or
      their neutralizing peptides, but not the Gi1alpha or Gi3alpha peptides, into 293
      IL-8RA or 293 IL-8RB cells completely blocked the calcium responses obtained upon
      stimulation with IL-8. These results demonstrate that the occupation of either
      type of IL-8 receptor leads to a physical coupling to the alpha-subunit of Gi2.
      In addition, the use of the subunit-specific peptides identified two functionally
      important but distinct regions of Gialpha, one involved in receptor/Gialpha
      interaction (KENLKDCGLF) and the other mediating downstream signal transmission
      (LERIAQSDYI). Finally, the results of this study also validate the use of the
      transfected 293 cell line as a model for the study of the signal transduction
      pathway(s) initiated by IL-8.

PMID- 8662699
TI  - Involvement of hydrogen peroxide in collagen cross-linking by high glucose in
      vitro and in vivo.
AB  - The Maillard reaction has been implicated in cross-linking and fluorescence
      formation of collagen exposed to high glucose in vitro. However, several
      pharmacologic agents, whose action seems unrelated to pathways of nonenzymatic
      glycation, have been demonstrated to prevent cross-linking in diabetes. To
      clarify this discrepancy, kinetic changes in glycation, glycoxidation
      (carboxymethyllysine, CML), and cross-linking (measured as tendon breaking time,
      TBT) were evaluated in rat tail tendons incubated in 5 and 30 mM glucose in vitro
      and in tendons implanted in vivo into diabetic rat peritoneal cavity. In vitro,
      rates were found to be both O2- and glucose-dependent. Tendon preglycation and
      presence of added 2 mM glycosylamine and Amadori compounds (Amadori product of
      glucose and propylamine) catalyzed these changes in a primarily O2-dependent
      manner. In the presence of Amadori compounds, kinetic changes were dramatically
      increased and were preventable by addition of catalase to the medium. Tendons
      implanted into diabetic rat peritoneum became more rapidly glycoxidized and cross
      linked when implanted at day 30 from diabetes onset (high tissue glycation)
      compared to day 3 (low tissue glycation) in spite of similar glycation kinetics,
      suggesting a mechanistic dissociation between glycation, glycoxidation, and cross
      linking in diabetes. Indeed, intraperitoneal injection of catalase and other
      antioxidants dramatically suppressed cross-linking, fluorescence formation, and,
      to some extent, glycoxidation, without affecting glycation. This study confirms
      the role of oxidative stress in protein cross-linking by the Maillard reaction in
      vitro and provides the first evidence for a role of H2O2 in cross-linking in
      diabetes. Whereas Amadori products are a potent source of H2O2 formation in
      vitro, their precise contribution to H2O2 generation and the actual role of
      Maillard reaction products in collagen cross-linking in diabetes requires further
      investigation.

PMID- 8662700
TI  - Lipoylation of acyltransferase components of alpha-ketoacid dehydrogenase
      complexes.
AB  - Lipoic acid is a prosthetic group of the acyltransferase components of the
      pyruvate, alpha-ketoglutarate, and branched chain alpha-ketoacid dehydrogenase
      complexes, protein X of the eukaryotic pyruvate dehydrogenase complex, and H
      protein of the glycine cleavage system. We have purified lipoyl-AMP:Nepsilon
      lysine lipoyltransferase I and II from bovine liver mitochondria employing apoH
      protein as an acceptor of lipoic acid (Fujiwara, K., Okamura-Ikeda, K., and
      Motokawa, Y. (1994) J. Biol. Chem. 269, 16605-16609). In this study, we
      demonstrated the lipoylation of the lipoyl domains of the mammalian pyruvate
      (LE2p), alpha-ketoglutarate (LE2k), and branched chain alpha-keto acid (LE2b)
      dehydrogenase complexes using the purified lipoyltransferase I and II.
      Lipoyltransferase I and II lipoylated LE2p and LE2k as efficiently as H-protein,
      but the lipoylation rate of LE2b was extremely low. Comparison of amino acid
      sequences surrounding the lipoylation site of these proteins shows that the
      conserved glutamic acid residue situated 3 residues to the N-terminal side of the
      lipoylation site is replaced by glutamine (Gln-41) in LE2b. When Gln-41 of LE2b
      was changed to Glu, the rate of lipoylation increased about 100-fold and became
      comparable to that of LE2p and LE2k. The replacement of the glutamic acid residue
      of LE2p (Glu-169) and LE2k (Glu-40) by glutamine resulted in decrease in the
      lipoylation rate more than 100-fold. These results suggest that the glutamic acid
      residue plays an important role in the lipoylation reaction possibly functioning
      as a recognition signal. Gly-27 and Gly-54 of LE2k are also well conserved among
      the lipoyl domains of the alpha-ketoacid dehydrogenase complexes and H-protein.
      The mutagenesis experiments of these residues indicated that the glycine residue
      situated 11 residues to the C-terminal side of the lipoylation site (Gly-54 of
      LE2k) is important for the folding of lipoyl domain, and that existence of a
      small residue such as Gly or Cys at the position is essential for the lipoylation
      of these proteins.

PMID- 8662701
TI  - Structural organization of the human and mouse laminin beta2 chain genes, and
      alternative splicing at the 5' end of the human transcript.
AB  - We have determined the structural organization of the human and mouse genes that
      encode the laminin beta2 chain (s-laminin), an essential component of the
      basement membranes of the neuromuscular synapse and the kidney glomerulus. The
      human and mouse genes have a nearly identical exon-intron organization and are
      the smallest laminin chain genes characterized to date, due to the unusually
      small size of their introns. The laminin beta2 chain genes of both species
      consist of 33 exons that span </=12 kilobase pairs of genomic DNA. The exon
      intron pattern of the laminin beta2 chain gene is also highly similar to that of
      the human genes encoding the homologous laminin beta1 and beta3 chains. The
      putative promoter regions of the human and mouse laminin beta2 chain genes have
      features characteristic of the promoters of genes that have a limited tissue
      expression. Considerable conservation of the intron sequences of the mouse and
      human genes was observed. The first intron of the human gene, located 1 base pair
      upstream of the translation start codon, contains a non-consensus 5' splice site.
      This intron was shown to be inefficiently spliced in humans, suggesting that post
      transcriptional mechanisms may be involved in the regulation of laminin beta2
      chain gene expression.

PMID- 8662703
TI  - Alpha-branched 1,2-diacyl phosphatidylcholines as effectors of activity of
      cytochrome P450SCC (CYP11A1). Modeling the structure of the fatty acyl chain
      region of cardiolipin.
AB  - Cardiolipin has been shown to be the most effective activator of cholesterol side
      chain cleavage activity of cytochrome P450SCC, and evidence has been provided for
      a lipid effector site on the enzyme. Results suggested the headgroup of
      cardiolipin as major determinant of lipid interaction with P450SCC (Lambeth, J.
      D. (1981) J. Biol. Chem. 256, 4757-4762). The role of unsaturation is
      contradictory and open to question (Igarashi, Y. and Kimura, T. (1986)
      Biochemistry 25, 6461-6466). We synthesized phosphatidylcholines with fully
      saturated branched fatty acyl chains substituted in the 2-positions of the main
      chains and studied the influence of these lipids on the activity and other
      properties of P450SCC in vesicle-reconstituted systems. These saturated branched
      lipids, with regard to the fatty acyl moiety in molecular shape similar to
      cardiolipin but with the headgroup of phosphatidylcholines retained, showed a
      stimulatory efficiency higher than any other phospholipid and at least comparable
      to cardiolipin. Activation is sensitive to the acyl chain structure and
      composition. Results suggest that the shape of the molecule at least partially
      plays an important role in the process of stimulation of the activity of P450SCC.
      Because binding of cholesterol was increased by the branched lipids monitored
      optically by the fraction of P450SCC in the high spin form, it was concluded that
      these lipids, like cardiolipin and other lipids, exert their effects by
      regulating the binding of cholesterol to P450SCC. These data suggest that
      polymorphic lipids such as branched phosphatidylcholines and cardiolipin might
      influence P450SCC function by maintenance of the membrane curvature at a value
      optimal for activity.

PMID- 8662702
TI  - Endothelial cell inflammatory responses to tumor necrosis factor alpha. Ceramide
      dependent and -independent mitogen-activated protein kinase cascades.
AB  - Ceramide generation by stimulated sphingomyelinase activity has been implicated
      in tumor necrosis factor alpha (TNF) signaling of apoptosis and differentiation.
      We examined the role of ceramide in a major action of TNF: the initiation of
      inflammatory events. Sphingomyelinase C at high levels induced inflammatory
      protein expression in endothelial cells resulting in leukocyte adhesion, but the
      pattern of induction of adhesion molecules (E-selectin, ICAM-1, VCAM-1) and
      cytokines (interleukins 6 and 8) differed from that induced by TNF. TNF induced
      only a small increase in ceramide: using lower doses of sphingomyelinase to mimic
      this we found that small amounts of ceramide did not induce protein expression,
      but still rapidly activated Raf-1, mitogen-activated protein/extracellular
      regulated kinase (ERK) kinase (MEK) and ERKs. TNF additionally caused rapid p38
      and JNK-1 mitogen-activated protein kinase activation and efficient NF-kappaB
      translocation, which could not be achieved even by high levels of ceramide. Thus
      activation of the ERK cascade alone is an incomplete endothelial cell stimulus,
      and the TNF receptor generates at least two signals: Raf-1 activation, which
      could be ceramide-dependent; and ceramide-independent efficient NF-kappaB
      translocation and activation of p38 and JNK-1 mitogen-activated kinases.

PMID- 8662704
TI  - Disparate tissue-specific expression of members of the tissue kallikrein
      multigene family of the rat.
AB  - To understand the regulatory diversity of the rat family of linked kallikrein
      genes, we have assayed the expression of family members in 20 major organs.
      Reverse transcription-polymerase chain reaction analysis using primers and
      hybridization probes specific for each of the 10 expressed kallikrein genes
      showed that no two family members share the same organ-specific pattern of
      expression. The only common site of expression for all 10 known active genes is
      the submandibular gland. The presence of the mRNA for at least one family member
      is detected in 19 of these 20 organs (liver excepted), from as few as three
      organs to as many as 18 for individual family members. For individual genes there
      can be more than a 10(5)-fold variation in mRNA levels among organs, from a limit
      of detection of slightly less than 1 mRNA molecule/10 cells to more than 10,000
      mRNA molecules/cell. Despite high sequence conservation and close linkage, the
      members of this family are expressed in very different and complex patterns. A
      gradient of diversity of expression corresponds to the order of the genes within
      the kallikrein family locus.

PMID- 8662707
TI  - Additions and Corrections to The catalytic cysteine and histidine in the plant
      acyl-acyl carrier protein thioesterases.

PMID- 8662705
TI  - Mapping of the discontinuous kininogen binding site of prekallikrein. A distal
      binding segment is located in the heavy chain domain A4.
AB  - Prekallikrein, the precursor to the serine proteinase kallikrein, circulates in
      plasma in an equimolar complex with H-kininogen. The binding to H-kininogen is
      mediated by the kallikrein heavy chain consisting of four "apple" domains, A1-A4,
      which attaches to H-kininogen with high specificity and affinity (KD = 83 nM). At
      least two distinct portions of the kallikrein heavy chain form this H-kininogen
      binding site: a proximal segment located in the NH2-terminal fragment of the
      heavy chain encompassing A1, and distal segment(s) located in COOH-terminal
      fragment spanning domains A2-A4. The proximal binding segment has been located to
      amino acid positions 56-86 of A1. To precisely map the distal binding segment, we
      have identified monoclonal antibodies directed to the COOH-terminal fragment
      which interfere with the H-kininogen-prekallikrein complex formation. Monoclonal
      antibody 13G11 binds to recombinant apple domain A4 but not to domain A3 of the
      prekallikrein heavy chain. Deletion mutagenesis of domain A4 narrowed down the
      target epitope of 13G11 to the center portion of domain A4, positions 284-331.
      Direct binding studies of H-kininogen to various domain A4 constructs revealed
      that the distal H-kininogen binding portion is located on a segment of 48
      residues, which overlaps the 13G11 epitope. Hence the tight interaction of H
      kininogen and prekallikrein is mediated by at least two separate sequence
      segments located in domains A1 and A4, respectively, of the prekallikrein heavy
      chain. The isolated distal binding segment significantly prolongs the partial
      thromboplastin time of reconstituted Williams plasma thus stressing the critical
      role of the prekallikrein-H-kininogen complex formation in the initiation of the
      endogenous blood coagulation cascade.

PMID- 8662709
TI  - gp130 transducing receptor cross-linking is sufficient to induce interleukin-6
      type responses.
AB  - gP130 transducing receptor is involved in the formation of high affinity
      receptors for the cytokines of the interleukin-6 (IL-6) family. Recruitment of
      gp130 by IL-6 associated to its receptor leads to the dimerization of the
      transducing component. In the present study we did characterize the B-S12
      monoclonal antibody raised against gp130 and able to elicit IL-6 type biological
      activities. B-S12 antibody triggered strongly the proliferation of TF1 and XGI
      hematopoietic cell lines and was able to increase the synthesis of acute phase
      proteins in HepG2 hepatoma cell line. B-S12 also behaved as a synergistic factor
      with granulocyte-macrophage colony-stimulating factor for both proliferation and
      differentiation of CD34-positive hematopoietic cell progenitors. By using a
      symmetric enzyme-linked immunosorbent assay, allowing the detection of dimeric
      forms of soluble gp130, we found that addition of B-S12 to gp130 led to its
      dimerization. Analysis of the tyrosine phosphorylation events in gp130 and Jak
      kinase family members revealed that B-S12 quickly induced the phosphorylation of
      gp130 in a neural derived cell line, and that Jak1 and Jak2 were also recruited.
      In conclusion, we show that gp130 cross-linking with the B-S12 monoclonal
      antibody was sufficient to generate functional IL-6 type responses in
      hematopoietic, neural, and hepatic cells.

PMID- 8662712
TI  - Systematic replacement of amino acid residues within an Arg-Gly-Asp-containing
      loop of foot-and-mouth disease virus and effect on cell recognition.
AB  - The conserved Arg-Gly-Asp (RGD) motif found in a hypervariable, mobile antigenic
      loop of foot-and-mouth disease virus (FMDV) is critically involved in virus
      attachment to cells by binding to an integrin, probably related to alphavbeta3.
      Here we describe (i) the synthesis of 241 15-mer peptides, which represent this
      loop of FMDV (isolate C-S8c1) and single variants in which each amino acid
      residue was replaced by 16 others and (ii) the inhibitory activity of these
      peptides on the ability of FMDV C-S8c1 to recognize and infect susceptible cells.
      This approach has allowed a first detailed evaluation of the specificity of each
      residue within a RGD-containing protein loop on cell recognition. The results
      indicate that, in addition to the exquisitely specific RGD triplet, two highly
      conserved Leu residues located at positions +1 and +4 downstream of the RGD and,
      to a lesser extent, the residue at position +2 are the only critical and specific
      determinants within the loop in promoting cell recognition of a viral ligand. The
      results support the proposal that, in spite of their involvement in antibody
      recognition, RGD and other FMDV loop residues are remarkably conserved because of
      their essential role in cell recognition.

PMID- 8662713
TI  - Function of the major synthetase subdomains of carbamyl-phosphate synthetase.
AB  - The amidotransferase domain (GLNase) of mammalian carbamyl-phosphate synthetase
      II hydrolyzes glutamine and transfers ammonia to the synthetase domain where
      carbamyl phosphate is formed in a three-step reaction sequence. The synthetase
      domain consists of two homologous subdomains, CPS.A and CPS.B. Recent studies
      suggest that CPS.A catalyzes the initial ATP dependent-activation of bicarbonate,
      whereas CPS.B uses a second ATP to form carbamyl phosphate. To establish the
      function of these substructural elements, we have cloned and expressed the
      mammalian protein and its subdomains in Escherichia coli. Recombinant CPSase
      (GLNase-CPS.A-CPS.B) was found to be fully functional. Two other proteins were
      made; the first consisted of only GLNase and CPS.A, whereas the second lacked
      CPS.A and had the GLNase domain fused directly to CPS.B. Remarkably, both
      proteins catalyzed the entire series of reactions involved in glutamine-dependent
      carbamyl phosphate synthesis. The stoichiometry, like that of the native enzyme,
      was 2 mol of ATP utilized per mol of carbamyl phosphate formed. GLN-CPS.B is
      allosterically regulated, whereas GLN-CPS.A was insensitive to effectors, a
      result consistent with evidence showing that allosteric effectors bind to CPS.B.
      These properties are not peculiar to the mammalian protein, because the
      separately cloned CPS.A subdomain of the E. coli enzyme was also found to
      catalyze carbamyl phosphate synthesis. Gel filtration chromatography and chemical
      cross-linking studies showed that these molecules are dimers, a structural
      organization that may be a prerequisite for the overall reaction. Thus, the
      homologous CPS.A and CPS.B subdomains are functionally equivalent, although in
      the native enzyme they may have different functions resulting from their
      juxtaposition relative to the other components in the complex.

PMID- 8662714
TI  - Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase.
AB  - Hydrolytic deamination of 5-methylcytosine leads to the formation of G/T
      mismatches. We have shown previously that these G/T mispairs are corrected to G/C
      pairs by a mismatch-specific thymine-DNA glycosylase, TDG, which we subsequently
      purified from human cells. Here we describe the cloning of the human cDNA
      encoding TDG. We have identified two distinct cDNA species that differ by 100
      nucleotides at the 3'-untranslated region. These cDNAs contain a 410-amino acid
      open reading frame that encodes a 46-kDa polypeptide. The G/T glycosylase,
      expressed both in vitro and in Escherichia coli, migrated in denaturing
      polyacrylamide gels with an apparent size of 60 kDa. The substrate specificity of
      the recombinant protein corresponded to that of the cellular enzyme, and
      polyclonal antisera raised against the recombinant protein neutralized both
      activities. We therefore conclude that the cDNA described below encodes human
      TDG. Data base searches identified a serendipitously cloned mouse cDNA sequence
      that could be shown to encode the murine TDG homologue. No common amino acid
      sequence motifs between the G/T-specific enzyme and other DNA glycosylases could
      be found, suggesting that TDG belongs to a new class of base-excision repair
      enzymes.

PMID- 8662715
TI  - Expression of vaccinia virus K3L protein in yeast inhibits eukaryotic initiation
      factor-2 kinase GCN2 and the general amino acid control pathway.
AB  - Phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF-2) is
      a well characterized mechanism regulating protein synthesis. Viral and cellular
      proteins have been identified that regulate the activity of the eIF-2alpha
      kinases. The regulatory protein, K3L, from vaccinia virus is homologous to the
      amino terminus of eIF-2alpha and is thought to inhibit the activity of the double
      stranded RNA-dependent kinase suppressing the antiviral mechanism mediated by
      this kinase. We investigated whether K3L can inhibit the activity of the yeast
      eIF-2alpha kinase GCN2. Expression of K3L protein in yeast reduced the level of
      eIF-2alpha phosphorylation by GCN2 and blocked the stimulation of the general
      amino acid control pathway in response to starvation conditions. Accompanying in
      vitro studies showed that recombinant K3L protein reduced GCN2
      autophosphorylation and phosphorylation eIF-2alpha. In agreement with the
      hypothesis that K3L inhibits eIF-2alpha kinases by functioning as a
      pseudosubstrate, we observed that K3L directly interacted with the kinase
      catalytic domain of GCN2. Together, these results indicate that K3L is a specific
      inhibitor of eIF-2alpha kinases from mammals and yeast and suggest that the
      kinases contain common structural features important for recognition of their
      substrate eIF-2alpha.

PMID- 8662716
TI  - Purification and characterization of two isoenzymes of DL-glycerol-3-phosphatase
      from Saccharomyces cerevisiae. Identification of the corresponding GPP1 and GPP2
      genes and evidence for osmotic regulation of Gpp2p expression by the osmosensing
      mitogen-activated protein kinase signal transduction pathway.
AB  - The existence of specific dl-glycerol-3-phosphatase (EC 3.1.3.21) activity in
      extracts of Saccharomyces cerevisiae was confirmed by examining strains lacking
      nonspecific acid and alkaline phosphatase activities. During purification of the
      glycerol-3-phosphatase, two isozymes having very similar molecular weights were
      isolated by gel filtration and anion exchange chromatography. By microsequencing
      of trypsin-generated peptides the corresponding genes were identified as
      previously sequenced open reading frames of unknown function. The two genes, GPP1
      (YIL053W) and GPP2 (YER062C) encode proteins that show 95% amino acid identity
      and have molecular masses of 30.4 and 27.8 kDa, respectively. The intracellular
      concentration of Gpp2p increases in cells subjected to osmotic stress, while the
      production of Gpp1p is unaffected by changes of external osmolarity. Both
      isoforms have a high specificity for dl-glycerol-3-phosphate, pH optima at 6.5,
      and KmG3P in the range of 3-4 mM. The osmotic induction of Gpp2p is blocked in
      cells that are defective in the HOG-mitogen-activated protein kinase pathway,
      indicating that GPP2 is a target gene for this osmosensing signal transduction
      pathway. Together with DOG1 and DOG2, encoding two highly homologous enzymes that
      dephosphorylate 2-deoxyglucose-6-phosphate, GPP1 and GPP2 constitute a new family
      of genes for low molecular weight phosphatases.

PMID- 8662717
TI  - Ca2+/calmodulin-dependent and -independent down-regulation of c-myb mRNA levels
      in erythropoietin-responsive murine erythroleukemia cells. The role of
      calcineurin.
AB  - Down-regulation of c-myb mRNA levels by [Ca2+]i-increasing agents (A23187,
      thapsigargin, cyclopiazonic acid) and erythropoietin was comparatively studied in
      the erythropoietin-responsive murine erythroleukemia cell line, ELM-I-1. The Ca2+
      induced suppression of c-myb mRNA could be inhibited by the calmodulin
      antagonists trifluoperazine and calmidazolium, as well as by cyclosporin A, an
      inhibitor of the Ca2+/calmodulin-dependent protein phosphatase 2B (calcineurin).
      KN-62, an inhibitor of Ca2+/calmodulin-dependent protein kinases, did not
      antagonize the Ca2+-mediated decrease in c-myb mRNA. In cyclosporin A-treated ELM
      I-1 cells, a close correlation could be demonstrated between the antagonization
      of the Ca2+ effect on c-myb mRNA levels and inhibition of the calcineurin
      phophatase activity. On the other hand, FK506, which did not inhibit calcineurin
      activity in ELM-I-1 cells, failed to prevent the Ca2+-mediated decrease in c-myb
      mRNA. The erythropoietin-induced down-regulation of c-myb mRNA levels could be
      demonstrated also in the presence of EGTA and was resistant to calmodulin
      antagonists and cyclosporin A. In addition, no increase in [Ca2+]i was observed
      in ELM-I-1 cells in response to erythropoietin. Cyclosporin A inhibited the Ca2+
      induced hemoglobin production, while the erythropoietin-mediated increase in
      hemoglobin synthesis was not affected. The results indicate that the Ca2+-induced
      decrease in c-myb mRNA and increase in hemoglobin synthesis is mediated by
      calcineurin, while these effects of erythropoietin occur independently of Ca2+ in
      ELM-I-1 cells. Calcineurin may be involved in the regulation of c-myb expression
      in erythroid precursor cells and Ca2+ signals via calcineurin may positively
      modulate the differentiation inducing action of erythropoietin.

PMID- 8662718
TI  - Cooperative interactions between the amino- and carboxyl-terminal lobes
      contribute to the unique iron-binding stability of lactoferrin.
AB  - Lactoferrin is a member of the transferrin family of iron-binding proteins.
      Several functions have been ascribed to lactoferrin, including regulation of iron
      homeostasis, antibacterial properties, and regulation of myelopoiesis. However,
      the structural features of lactoferrin that are required for most of these
      functions are unknown. Previously, we reported the development of an efficient
      fungal expression system to produce recombinant human lactoferrin. The
      availability of this production system demonstrated the feasibility of producing
      mutant lactoferrins to address the structure/function relationship of the
      protein. In the present study, we used a site-directed mutagenesis approach to
      address the contribution of the bilobal structure of lactoferrin to its unique
      iron-binding stability. Like transferrin, lactoferrin consists of two repeated
      iron-binding lobes that bind one iron atom each. However, unlike transferrin,
      lactoferrin retains iron over a broad pH range, a key property that contributes
      to the unique iron-binding functions of the protein. Using mutants that
      selectively ablate the iron-binding function in either lobe, we demonstrate
      differential iron-binding stability of the amino- and carboxyl-terminal iron
      binding lobes of lactoferrin. Further, we show that the unique iron-binding
      stability of the protein is imparted primarily by the carboxyl-terminal domain
      which functions cooperatively to stabilize iron-binding to the amino-terminal
      domain of lactoferrin.

PMID- 8662719
TI  - Analysis of the structural properties of cAMP-responsive element-binding protein
      (CREB) and phosphorylated CREB.
AB  - The transcription factor CREB (cAMP responsive element binding protein) is
      activated by protein kinase A (PKA) phosphorylation of a single serine residue.
      To investigate possible mechanisms of CREB regulation by phosphorylation, we
      initiated a structural and biophysical characterization of the full-length, wild
      type CREB protein, an altered CREB protein (CREB/SER) in which the three cysteine
      residues in the DNA-binding domain were replaced with serine residues and a
      truncated protein (ACT265) which encompasses the entire activation domain of
      CREB. Circular dichroism (CD) reveals that CREB and CREB/SER have identical
      secondary structures and contain approximately 20% alpha-helix, 9% beta-strand,
      34% beta-turn, and 37% random coil structures. PKA phosphorylation does not alter
      the CD spectra, and therefore the secondary structure, of CREB or of CREB bound
      to DNA. Protease cleavage patterns indicate that PKA phosphorylation does not
      induce a global conformational change in CREB. Furthermore, PKA phosphorylation
      does not change the DNA binding affinity of CREB for either canonical or non
      canonical CRE sequences as measured by a fluorescence anisotropy DNA binding
      assay. Since PKA phosphorylation of CREB results in its specific binding to the
      transcriptional co-activators CREB-binding protein and p300, we suggest that the
      PKA activation of CREB occurs by the production of specific, complementary
      interactions with these proteins, rather than through the previously proposed
      mechanisms of a phosphorylation-dependent conformational change or increased DNA
      binding affinity.

PMID- 8662721
TI  - Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II
      receptor mimic and cytokine antagonist.
AB  - The serum glycoprotein fetuin is expressed during embryogenesis in multiple
      tissues including limb buds and has been shown to promote bone remodeling and
      stimulate cell proliferation in vitro. In this report, we demonstrate that fetuin
      antagonizes the antiproliferative action of transforming growth factor-beta1 (TGF
      beta1) in cell cultures. Surface plasmon resonance measurements show that fetuin
      binds directly to TGF-beta1 and TGF-beta2 and with greater affinity to the TGF
      beta-related bone morphogenetic proteins (BMP-2, BMP-4, and BMP-6). In a
      competitive enzyme-linked immunosorbent assay, fetuin blocked binding of TGF
      beta1 to the extracellular domain of TGF-beta receptor type II (TbetaRII), one of
      the primary TGF-beta-binding receptors. A comparison of fetuin and TbetaRII shows
      homology in an 18-19-amino acid sequence, which we have designated TGF-beta
      receptor II homology 1 domain (TRH1). Since the TRH1 sequence is known to form a
      disulfide loop in fetuin, cyclized TRH1 peptides from both fetuin and TbetaRII
      were chemically synthesized and tested for cytokine binding activity. Cyclized
      TRH1 peptide from TbetaRII bound to TGF-beta1 with greater affinity than to BMP
      2, while the cyclized TRH1 peptide from fetuin bound preferentially to BMP-2.
      Finally, fetuin or neutralizing anti-TGF-beta antibodies blocked osteogenesis and
      deposition of calcium-containing matrix in cultures of dexamethasone-treated rat
      bone marrow cells. In summary, these experiments define the TRH1 peptide loop as
      a cytokine-binding domain in both TbetaRII and fetuin and suggest that fetuin is
      a natural antagonist of TGF-beta and BMP activities.

PMID- 8662720
TI  - Purification and properties of human cytosolic folylpoly-gamma-glutamate
      synthetase and organization, localization, and differential splicing of its gene.
AB  - Human cytosolic folylpolyglutamate synthetase (FPGS) was expressed in Escherichia
      coli and purified to homogeneity. Tetrahydrofolate and dihydrofolate were the
      most effective substrates, while 5-substituted folates were poor substrates. Most
      pteroyldiglutamates were better substrates than monoglutamates. The human FPGS
      gene spans 12 kilobases and contains 15 exons and 14 introns. A single FPGS gene
      was located to chromosome region 9q34.1. Four exon 1 variants were identified,
      each of which was spliced to exon 2. The exon 1 variant corresponding to the
      isolated cDNA contains two ATG codons and multiple transcription start sites in
      this region generates mitochondrial and cytosolic FPGS (Freemantle, S. J.,
      Taylor, S. M., Krystal, G., and Moran, R. G. (1995) J. Biol. Chem. 270, 9579
      9584). Exons 1B and 1C, generated by alternate splicing in intron 1, and exon 1A,
      which is 5' to exon 1 and may encode an additional mitochondrial isoform, are
      preceded by a number of potential promoter sites. Chinese hamster ovary cell
      transfectants expressing FPGS activity in the mitochondria contained normal
      mitochondrial and low cytosolic folylpolyglutamate pools. Mitochondrial FPGS
      activity is required for mitochondrial folate accumulation, while cytosolic FPGS
      activity is needed for establishment of normal cytosolic folate pools. The
      reconstructed FPGS gene restored normal cytosolic and mitochondrial folate
      metabolism in hamster cells.

PMID- 8662722
TI  - Purification and characterization of a Src-related p57 protein-tyrosine kinase
      from Xenopus oocytes. Isolation of an inactive form of the enzyme and its
      activation and translocation upon fertilization.
AB  - In the previous study (Fukami, Y., Sato, K.-I., Ikeda, K., Kamisango, K.,
      Koizumi, K., and Matsuno, T. (1993) J. Biol. Chem. 268, 1132-1140), we found that
      an antibody termed anti-pepY antibody causes a severalfold activation of bovine
      brain c-Src. The anti-pepY antibody was raised against a synthetic peptide
      corresponding to residues 410-428 of chicken c-Src, one of the most conserved
      regions among the Src family protein-tyrosine kinases. In this study, we have
      used this antibody as an in vitro activator and purified a c-Src-related protein
      tyrosine kinase from the particulate fraction of Xenopus laevis oocytes. A
      synthetic peptide corresponding to residues 7-26 of fission yeast Cdc2 was used
      as substrate. Immunoreactivity toward the antibody was also monitored during the
      purification. The purified kinase displayed a single polypeptide of 57 kDa on SDS
      gel electrophoresis and showed a specific activity of 2.37 and 20.1 nmol/min/mg
      protein in the absence and the presence of the anti-pepY antibody, respectively.
      The purified enzyme underwent autophosphorylation and phosphorylated actin and
      the Cdc2 peptide exclusively on tyrosine residues. Specific antibodies against c
      Src, Fyn, c-Yes, c-Fgr, Lck, Lyn, Hck, and Blk proteins did not recognize the p57
      Xenopus tyrosine kinase. The kinase activity of the Xenopus enzyme was not
      affected by oocyte maturation but was found to be elevated severalfold upon
      fertilization. Fertilization also caused a translocation of the activated enzyme
      from the particulate fraction to the cytosolic fraction. The activation and
      translocation was observed within 1 min after fertilization. These results
      suggest a possible involvement of the p57 Xenopus tyrosine kinase in the signal
      transduction of fertilization.

PMID- 8662723
TI  - Sp1 family proteins recognize the U5 repressive element of the long terminal
      repeat of human T cell leukemia virus type I through binding to the CACCC core
      motif.
AB  - We have identified several nuclear proteins binding to the U5 repressive element
      (U5RE) at the U5 region of the human T cell leukemia virus type I (HTLV-I) long
      terminal repeat (LTR). In gel mobility shift assays with the U5RE DNA probe,
      Jurkat T cell nuclear proteins generated five different complexes, named U5RE
      binding protein complexes (U5RP)-A1, -A2, -A3, -B, and -C. Only U5RP-C was
      affected by pretreatment with an excess of poly(dI-dC) and was immunodepressed by
      anti-Ku/p80 antibodies, suggesting that U5RP-C is a nonspecific complex involving
      Ku antigen. UV cross-linking showed at least six nuclear proteins involved in the
      other complexes, including U5RP-A1, -A2, -A3, and -B. The sequence of the binding
      core element of these specific complexes, determined by competition assays and
      gel mobility shift assays using a series of the U5RE mutants, is CACCC which is
      identical to that for the Sp1 transcription factor. LTR with a mutant U5RE, which
      has no ability to bind with the nuclear proteins, showed stronger promoter
      activity than LTR with the wild U5RE, suggesting that the specific interaction of
      these U5RE-binding proteins might result in the U5-mediated repression. U5RP-A1
      was supershifted by anti-Sp1 antibodies and U5RP-A2 and -B were supershifted by
      anti-Sp3 antibodies, suggesting that Sp1 or Sp3 is involved in U5RP-A1 or U5RP-A2
      and -B, respectively. Although the other nuclear proteins remain to be
      characterized, these findings suggest that U5RE-binding proteins in U5RP-A1, -A2,
      -A3, and -B are involved in HTLV-I gene repression.

PMID- 8662724
TI  - Purification, cloning, and sequence analysis of a Mr = 30,000 protein from sea
      urchin axonemes that is important for sperm motility. Relationship of the protein
      to a dynein light chain.
AB  - We have generated a series of monoclonal antibodies against axonemal proteins
      from sea urchin spermatozoa in order to identify novel proteins involved in the
      regulation of flagellar motility. The monoclonal antibody D405-14 inhibited the
      motility of demembranated-reactivated sperm models at low concentrations and
      recognized a single polypeptide of 33 kDa (p33) on immunoblots of sea urchin
      axonemal proteins. Fractionation of the axonemes with high salt solutions, heat,
      and detergent resulted in the selective extraction of p33 into a 0.6 M NaCl
      soluble and a 0.5% sodium lauryl sarcosinate (Sarkosyl)-soluble form. Both forms
      of p33 were purified to apparent homogeneity by immunoaffinity chromatography on
      monoclonal antibody D405-14-Sepharose. We have also isolated and sequenced a full
      length cDNA clone encoding the 33-kDa protein. The sequence predicts a
      polypeptide of 260 amino acids having a mass of 29,730 Da and an isoelectric
      point of 9.3. Sequence comparison indicates that p33 is 66% identical (74%
      similar) to the p28 light chain of axonemal inner dynein arm of Chlamydomonas
      reinhardtii. Taken together, these results suggest that we have identified a p28
      light chain homolog in sea urchin sperm axoneme and that this protein may play a
      dynamic role in flagellar motility.

PMID- 8662725
TI  - Isolation and characterization of TAF25, an essential yeast gene that encodes an
      RNA polymerase II-specific TATA-binding protein-associated factor.
AB  - We describe the cloning and analysis of TAF25, a previously uncharacterized yeast
      gene that encodes a yeast TATA-binding protein-associated factor or yTAF of Mr =
      25,000. The gene encoding yTAF25 is a single copy essential gene, and the protein
      sequence deduced from TAF25 exhibits sequence similarity to a metazoan hTAFII.
      The results from immunological studies confirm that yTAF25 is a subunit of a
      large multiprotein TATA-binding protein-yeast TATA-binding protein-associated
      factor complex that contains a subset of the total number of the yTAFs present in
      yeast cell extracts. Both genetic and biochemical analyses demonstrate that
      yTAF25 can interact directly with itself. Transcriptional data show that the
      activity of the multiprotein complex containing yTAF25 is RNA polymerase II
      specific, thus indicating that TAF25 encodes a bona fide yeast RNA polymerase II
      TAF. Hence the protein encoded by TAF25 has been termed yTAFII25.

PMID- 8662726
TI  - Mechanisms of initiation and termination reactions in conjugative DNA processing.
      Independence of tight substrate binding and catalytic activity of relaxase (TraI)
      of IncPalpha plasmid RP4.
AB  - The relaxase (TraI) of plasmid RP4 (IncPalpha) plays a key role in initiation and
      termination of transfer DNA replication during conjugative transmission of the
      plasmid. TraI functions as a DNA strand transferase that cleaves a unique
      phosphodiester bond at nic of the transfer origin. The cleavage reaction consists
      in a reversible transesterification that leads to transfer of the 5' phosphoryl
      at nic to the hydroxyl group of TraI Tyr-22. Hence, cleavage results in the
      covalent attachment of TraI to the 5' terminus of the plasmid strand destined for
      transfer. To investigate the protein's ability to function in a "second cleavage"
      reaction proposed to terminate rolling circle mode transfer DNA replication,
      single-stranded oligonucleotides containing the nic region were immobilized at
      their 3' ends on magnetic beads and cleaved by TraI. The resulting covalent TraI
      oligonucleotide adducts were active in the joining reaction but unable to cleave
      oligonucleotides containing an intact nic region, indicating that second cleavage
      probably requires a TraI dimer, since a monomer is insufficient. The covalently
      attached oligonucleotide determines the affinity of the relaxase for the 3'
      terminus of the T-strand. To further the biochemical characterization of TraI
      catalyzed reactions, we used specific TraI mutants, showing that amino acid
      residues in each relaxase motif are involved in substrate binding. To uncouple
      substrate binding and cleaving-joining, we applied partially biotinylated TraI
      mutant proteins that were immobilized to magnetic beads. Using this approach we
      could demonstrate that tight DNA substrate binding and cleaving-joining are
      independent processes. Enhanced topoisomerase activity of some TraI mutants was
      correlated with low specific substrate binding affinity in conjunction with high
      cleaving-joining activity.

PMID- 8662727
TI  - Identification of protein synthesis elongation factor G as a 4.5 S RNA-binding
      protein in Escherichia coli.
AB  - Escherichia coli 4.5 S RNA is metabolically stable and abundant. It consists of
      114 nucleotides, and it is structurally homologous to domain IV of mammalian
      signal recognition particle (SRP) RNA. In this study, we found two 4.5 S RNA
      binding proteins in cell extracts by means of a gel mobility shift assay. One
      protein was identified as Ffh, which has been characterized as 4.5 S RNA-binding
      protein. The other protein was separated from Ffh by two consecutive column
      chromatographic elutions and by monitoring the 4.5 S RNA binding activity. After
      the second chromatography, a dominant protein with an approximate molecular
      weight of 78,000 was associated with 4.5 S RNA binding activity. A sequence of
      the NH2-terminal 19 residues of the 78-kDa protein was completely identical to
      that of the protein elongation factor G (EF-G) of E. coli, and further it cross
      reacted with antiserum against E. coli EF-G. The results obtained using a
      synthetic oligo RNA corresponding to the 23 S rRNA defining the EF-G binding site
      indicated that 4.5 S RNA and 23 S rRNA are competitive in 4.5 S RNA binding and
      that a decanucleotide sequence conserved between them serves as a binding site
      for EF-G. Conservation of the SRP RNA binding activity of EF-G from Bacillus
      subtilis suggests that the binding of EF-G to SRP RNA is essential for its
      function.

PMID- 8662728
TI  - Differential expression of glutamate receptor subtypes in rat pancreatic islets.
AB  - Immunocytochemistry was carried out on sections of rat pancreas to localize the
      expression of glutamate receptor subunits and the major pancreatic peptide
      hormones. Glutamate receptor expression was concentrated in pancreatic islets,
      and each islet cell type expressed different neuronal glutamate receptors of the
      alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate
      classes. AMPA receptor subunits were expressed in alpha, beta, and pancreatic
      polypeptide cells, whereas kainate receptors were found predominantly in alpha
      and delta cells. Patch clamp electrophysiology was used to measure the functional
      properties of islet cell glutamate receptors. L-glutamate and other glutamate
      receptor agonists evoked currents in islet cells that were blocked by the
      selective AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione and
      potentiated by cyclothiazide in a manner indistinguishable from that of neuronal
      AMPA receptors. Activation of islet cell AMPA receptors produced steady-state
      cation currents that depolarized the cells an average of 20.7 +/- 5.4 mV (n = 6).
      Currents mediated by functional kainate receptors were also observed in a line of
      transformed pancreatic alpha cells. Thus, L-glutamate probably regulates islet
      physiology via actions at both AMPA and kainate receptor classes. The pattern of
      receptor expression suggests that glutamate receptor activation may have
      multiple, complex consequences for islet physiology.

PMID- 8662729
TI  - Transmembrane residues of the parathyroid hormone (PTH)/PTH-related peptide
      receptor that specifically affect binding and signaling by agonist ligands.
AB  - Polar residues within the transmembrane domains (TMs) of G protein-coupled
      receptors have been implicated to be important determinants of receptor function.
      We have identified mutations at two polar sites in the TM regions of the rat
      parathyroid hormone (PTH)/PTH-related peptide receptor, Arg-233 in TM 2 and Gln
      451 in TM 7, that caused 17-200-fold reductions in the binding affinity of the
      agonist peptide PTH-(1-34) without affecting the binding affinity of the
      antagonist/partial agonist PTH-(3-34). When mutations at the TM 2 and TM 7 sites
      were combined, binding affinity for PTH-(1-34) was restored to nearly that of the
      wild type receptor. The double mutant receptors, however, were completely
      defective in signaling cAMP or inositol phosphate production in response to PTH
      (1-34) agonist ligand. The results demonstrate that Arg-233 and Gln-451 have
      important roles in determining agonist binding affinity and transmembrane
      signaling. Furthermore, the finding that residues in TM 2 and TM 7 are
      functionally linked suggests that the TM domain topology of the PTH/PTH-related
      peptide receptor may resemble that of receptors in the rhodopsin/beta-adrenergic
      receptor family, for which structural and mutagenesis data suggest interactions
      between TMs 2 and 7.

PMID- 8662730
TI  - Identification of a region of Bacillus subtilis Ffh, a homologue of mammalian
      SRP54 protein, that is essential for binding to small cytoplasmic RNA.
AB  - Bacillus subtilis Ffh and scRNA are homologues of mammalian SRP54 and SRP RNA,
      respectively, which are components of the eukaryotic signal recognition particle
      (SRP). Ffh (446 amino acids) interacts with scRNA to form a stable complex in
      vivo. Here, we identified an RNA-binding domain of Ffh. The results obtained
      using a series of deletion mutants show that amino acid positions 364 to 432 in
      the C-terminal region of Ffh correlates with its ability to bind RNA. The amino
      acid sequence of this region is well conserved among members of the SRP54 protein
      family. This sequence contains two hydrophobic regions (h2, 364 to 391, and h3,
      416 to 435), separated by the positively charged amino acid motif,
      398RRKRIAKGSG407. Among the basic amino acid residues in this region, Arg-401 was
      essential for binding to scRNA, but Arg-399 and Lys-400 were not. The co
      existence of Arg-398 and Lys-404 was necessary for the same affinity as wild type
      Ffh. The two glycine residues of the 405GSG407 were also essential. MH23 peptide
      (91 amino acids) encompassing from 356 to 446, consisting of h2-RRKRIAKGSG-h3,
      bound scRNA with the same affinity as wild type Ffh, whereas a 24-amino acid
      synthetic peptide 392DIINASRRKRIAKGSGTSVQEVNR415 did not. The region containing
      two hydrophobic segments separated by the positively charged motif is the minimal
      requirement of Ffh for RNA binding.

PMID- 8662731
TI  - DNA polymerases alpha and beta are required for DNA repair in an efficient
      nuclear extract from Xenopus oocytes.
AB  - Xenopus oocytes and an oocyte nuclear extract efficiently repair the bulky DNA
      lesions cyclobutane pyrimidine dimers,(6-4) photoproducts, and N-acetoxy-2
      aminofluorene (AAF) adducts by an excision repair mechanism. Nearly all (>95%) of
      the input damaged DNA was repaired within 5 h in both injected cells and extracts
      with no significant incorporation of label into control undamaged DNA.
      Remarkably, more than 10(10) cyclobutane pyrimidine dimers or(6-4) photoproducts
      are repaired/nuclei. The extracts are free from nuclease activity, and repair is
      independent of exogenous light. Both the high efficiency and DNA polymerase
      requirements of this system appear to be different from extracts derived from
      human cells. We demonstrated a requirement for DNA polymerases alpha and beta in
      repair of both photoproducts and AAF by inhibiting repair with several
      independent antibodies specific to either DNA polymerases alpha or beta and then
      restoring repair by adding the appropriate purified polymerase. Repair is
      inhibited by aphidicolin at concentrations specific for blocking DNA polymerase
      alpha and dideoxynucleotide triphosphates at concentrations specific for
      inhibiting DNA polymerase beta.

PMID- 8662732
TI  - Site-directed mutagenesis of Cys-15 and Cys-20 of pulmonary surfactant protein D.
      Expression of a trimeric protein with altered anti-viral properties.
AB  - Surfactant protein D (SP-D) molecules are preferentially assembled as dodecamers
      consisting of trimeric subunits associated at their amino termini. The NH2
      terminal sequence of each monomer contains two conserved cysteine residues, which
      participate in interchain disulfide bonds. In order to study the roles of these
      residues in SP-D assembly and function, we employed site-directed mutagenesis to
      substitute serine for cysteine 15 and 20 in recombinant rat SP-D (RrSP-D), and
      have expressed the mutant (RrSP-Dser15/20) in Chinese hamster ovary (CHO-K1)
      cells. The mutant, which was efficiently secreted, bound to maltosyl-agarose, but
      unlike RrSP-D, was assembled exclusively as trimers. The constituent monomers
      showed a decreased mobility on SDS-polyacrylamide gel electrophoresis resulting
      from an increase in the size and sialylation of the N-linked oligosaccharide at
      Asn-70. Although RrSP-Dser15/20 contained a pepsin-resistant triple helical
      domain, it showed a decreased Tm, and acquired susceptibility to proteolytic
      degradation. Like RrSP-D, RrSP-Dser15/20 bound to the hemagglutinin of influenza
      A. However, it showed no viral aggregation and did not enhance the binding of
      influenza A to neutrophils (PMN), augment PMN respiratory burst, or protect PMNs
      from deactivation. These studies indicate that amino-terminal disulfides are
      required to stabilize dodecamers, and support our hypothesis that the
      oligomerization of trimeric subunits contributes to the anti-microbial properties
      of SP-D.

PMID- 8662733
TI  - Pathways downstream of Shc and Grb2 are required for cell transformation by the
      tpr-Met oncoprotein.
AB  - The Tpr-Met oncoprotein, which is a member of a family of tyrosine kinase
      oncoproteins generated following genomic rearrangement, consists of the catalytic
      kinase domain of the hepatocyte growth factor/scatter factor receptor tyrosine
      kinase (Met) fused downstream from sequences encoded by the tpr gene. We have
      previously demonstrated that a single tyrosine residue in the carboxyl terminus,
      Tyr489, is highly phosphorylated and is essential for efficient transformation of
      Fr3T3 fibroblasts by Tpr-Met and for the association of Tpr-Met with the Grb2
      adaptor protein and phosphatidylinositol 3'-kinase. We show here that Tyr489 is
      also required for association of Tpr-Met with phospholipase Cgamma and the
      tyrosine phosphatase, SHPTP2/Syp. To distinguish which of these substrates are
      required for cell transformation by the Tpr-Met oncoprotein, we generated a novel
      Tpr-Met mutant that selectively fails to associate with the Grb2 adaptor protein.
      Utilizing this mutant, together with additional Tpr-Met mutants containing Tyr to
      Phe substitutions, we have demonstrated that transformation of Fr3T3 fibroblasts
      by the Tpr-Met oncoprotein is dependent upon pathways downstream of Shc and Grb2
      and that pathways downstream of phosphatidylinositol 3'-kinase, phospholipase
      Cgamma, and SHPTP2/Syp are insufficient for transformation.

PMID- 8662734
TI  - RNase E cleaves at multiple sites in bubble regions of RNA I stem loops yielding
      products that dissociate differentially from the enzyme.
AB  - Earlier work has shown that RNase E cleaves RNAI, the antisense repressor of
      replication of ColE1-type plasmids, producing pRNAI-5, whose further decay is
      mediated by the poly(A)-dependent activity of polynucleotide phosphorylase and
      other 3' to 5' exonucleases. Using a poly(A) polymerase-deficient strain to
      impede exonucleolytic decay, we show that RNAI is additionally cleaved by RNase E
      at multiple sites, generating a series of decay intermediates that are
      differentially retained by the RNA binding domain (RBD) of RNase E. Primer
      extension analysis of RNAI decay intermediates and RNase T1 mapping of the
      cleavage products of RNAI generated in vitro by affinity-purified RNase E showed
      that RNase E can cleave internucleotide bonds in the bubble regions of duplex RNA
      segments and in single-stranded regions. Chemical in situ probing of a complex
      formed between RNAI and the RBD indicates that binding to the RBD destabilizes
      RNAI secondary structure. Our results suggest a model in which a series of
      sequential RNase E-mediated cleavages occurring at multiple sites of RNAI, some
      of which may be made more accessible to RNase E by the destabilizing effects of
      its RBD, generate RNA fragments that are further degraded by poly(A)-dependent 3'
      to 5' exonucleases.

PMID- 8662735
TI  - Inhibition of adenylyl cyclase by a family of newly synthesized adenine
      nucleoside 3'-polyphosphates.
AB  - The synthesis of a number of adenine nucleoside 3'-polyphosphates has been
      devised via a phosphotriester approach that combines the method of alkoxide
      activation with the use of 2,2,2-tribromoethyl phosphoromorpholinochloridate as a
      phosphorylating agent. The family of compounds included 3'ADP, 3'ATP, 2'-deoxy
      3'ADP, 2'-deoxy-3'ATP, 2',5'-dideoxy-3'ADP, and 2',5'-dideoxy-3'ATP. Potency as
      inhibitors of adenylyl cyclases followed the order: 3'-mono- < 3'-di- < 3'
      triphosphate and adenosine (Ado) < 2'-d-Ado < 2',5'-dd-Ado derivatives, with
      2',5'-dideoxy-3'ATP exhibiting an IC50 of approximately 40 nM. This order was
      maintained with purified and recombinant forms of the type I enzyme. The
      nucleoside 3'-phosphates caused noncompetitive inhibition of the type I adenylyl
      cyclase from bovine brain, consistent with inhibition via the P-site. Inhibition
      was not due to hydrolytic products because this was minimal and inhibition
      kinetics by inorganic polyphosphates were inconsistent with those caused by the
      nucleoside 3'-polyphosphates. Only 3'ATP underwent cation-catalyzed, nonenzymatic
      hydrolysis, with the primary product being 2':3'-cAMP. Because 3'-ADP and 3'-ATP
      are naturally occurring, this class of compounds may physiologically regulate
      adenylyl cyclases and possibly other enzymes, mediating responses that include a
      reduction in 3':5'-cAMP levels and consequent reductions in protein kinase A
      activated pathways.

PMID- 8662736
TI  - Purification and characterization of linoleate 8-dioxygenase from the fungus
      Gaeumannomyces graminis as a novel hemoprotein.
AB  - The fungus Gaeumannomyces graminis, which causes the major root disease of wheat
      known as "take-all," can metabolize linoleic acid to (8R)-hydroperoxylinoleic
      acid. The enzyme linoleate 8-dioxygenase abstracts hydrogen and introduces
      molecular oxygen in an antarafacial way at C-8. We have now purified the enzyme
      1000-fold to a specific activity of 1.8 micronol/min/mg of protein. Acetone
      powder of mycelia of G. graminis was subjected to extraction and ammonium sulfate
      precipitation with solubilization. The 8-dioxygenase was purified by hydrophobic
      interaction chromatography, size-exclusion chromatography, anion-exchange
      chromatography, and immobilized metal ion affinity chromatography. The active
      enzyme appeared to consist of four subunits since the active enzyme had an
      apparent molecular mass of 520 kDa determined by gel filtration, while SDS
      polyacrylamide gel electrophoresis showed a protein band of 130 kDa. Spectroscopy
      indicated the presence of heme. The characteristic pyridine ferrohemochrome alpha
      band was found at 557 nm and the beta-band at 525 nm. The purified protein showed
      an absorption maximum at 408 nm (gamma, Soret). The absorption maximum shifted to
      429 nm after reduction with dithionite and to 421 nm after treatment of the
      reduced enzyme with carbon monoxide. BW A4C, a hydroxamic acid derivative,
      inhibited the enzyme by >90% at 10 microM. The pH optimum was 7.2-7.4, the
      isoelectric point was 5.2 by chromatofocusing, and the Km values were 8 microM
      for linoleic acid and 30 microM for oxygen. We conclude that linoleate 8
      dioxygenase appears to be a tetrameric hemoprotein distinct from other fatty-acid
      dioxygenases.

PMID- 8662737
TI  - Invasion of the CAG triplet repeats by a complementary peptide nucleic acid
      inhibits transcription of the androgen receptor and TATA-binding protein genes
      and correlates with refolding of an active nucleosome containing a unique AR gene
      sequence.
AB  - The DNA sequence of the genes for the androgen receptor (AR) and TATA-binding
      protein (TBP), like many other genes encoding transcription factors, contains a
      series of tandem CAG repeats. Here we explore the capacity of complementary
      peptide nucleic acids (PNAs) to invade the CAG triplets of the AR and TBP genes
      in human prostatic cancer cells and show that the PNAs readily entered the nuclei
      of lysolecithin-permeabilized cells and effectively inhibited sense transcription
      of unique AR and TBP DNA sequences downstream of the site of PNA.DNA
      hybridization, but not upstream of that site. These PNAs had little or no effect
      on transcription of the c-myc gene, which lacks a CAG triplet domain. Conversely,
      a PNA complementary to a unique sequence of the c-myc gene did not inhibit
      transcription of the AR or TBP genes but did inhibit c-myc transcription.
      Comparisons of PNA effects on sense and antisense transcription of the AR, TBP,
      and c-myc genes confirm that progression of the RNA polymerase complex beyond the
      site of PNA.DNA hybridization is impaired in both directions. Suppression of the
      AR gene results in refolding of a transcriptionally active nucleosome containing
      a unique 17-mer AR DNA sequence.

PMID- 8662738
TI  - Two classes of plant cDNA clones differentially complement yeast calcineurin
      mutants and increase salt tolerance of wild-type yeast.
AB  - The salt-sensitive phenotype of yeast cells deficient in the phosphoprotein
      phosphatase, calcineurin, was used to identify genes from the higher plant
      Arabidopsis thaliana that complement this phenotype. cDNA clones corresponding to
      two different sequences, designated STO (salt tolerance) and STZ (salt tolerance
      zinc finger), were found to increased tolerance of calcineurin mutants and of
      wild-type yeast to both Li+ and Na+ ions. STZ is related to Cys2/His2-type zinc
      finger proteins found in higher plants, and STO is similar to the Arabidopsis
      CONSTANS protein in regions that may also be zinc fingers. Although neither
      protein has sequence similarity to any protein phosphatase, STO was able to at
      least partially compensate for all tested additional phenotypic effects of
      calcineurin deficiency, and STZ compensated for a subset of these effects. Salt
      tolerance produced by STZ appeared to be partially dependent on ENA1/PMR2, a P
      type ATPase required for Li+ and Na+ efflux in yeast, whereas the effect of STO
      on salt tolerance was independent of ENA1/PMR2. STZ and STO were found to be
      expressed in Arabidopsis roots and leaves, whereas only STO message was
      detectable in flowers. An apparent increase in the level of STZ mRNA was observed
      in response NaCl exposure in Arabidopsis seedlings, but the level of STO mRNA was
      not altered by this treatment.

PMID- 8662739
TI  - Human cytoplasmic antiproteinase neutralizes rapidly and efficiently chymotrypsin
      and trypsin-like proteases utilizing distinct reactive site residues.
AB  - Human cytoplasmic antiproteinase (CAP) is an intracellular serpin that has been
      reported to utilize Arg341 as the reactive site P1 residue to neutralize a broad
      variety of extracellular serine proteases with trypsin-like specificity. Both
      native CAP and recombinant CAP purified from Escherichia coli were observed to
      form SDS-stable complexes not only with 125I-thrombin and 125I-urokinase, but
      also with 125I-chymotrypsin. Kinetic studies indicated that the amidolytic
      activity of chymotrypsin is inhibited efficiently and rapidly by CAP in a two
      step process with a dissociation constant Ki of an initial loose complex of 3.3
      nM, a forward isomerization rate constant k2 to the tight complex of 0.014 s-1,
      and an overall second order association rate constant of 6 x 10(6) M-1 s-1,
      similar to the kinetic constants obtained for the formation of the trypsin-CAP
      complex. N-terminal amino acid sequencing and mass spectrometry indicated that
      chymotrypsin interacts with CAP at Met340, in contrast to thrombin, which
      interacts as expected at Arg341. Thus, CAP is the first serpin that has been
      shown to be capable to inhibit efficiently and with similar association rate
      constants different proteases at distinct reactive site residues, strongly
      supporting the notion of a highly mobile and flexible serpin reactive site loop
      and suggesting that this inhibitor may have evolved separate reactive sites for
      the specific regulation of different proteolytic activities.

PMID- 8662740
TI  - High affinity interactions of GTPgammaS with the heterotrimeric G protein,
      transducin. Evidence at high and low protein concentrations.
AB  - A well known difference in nucleotide binding characteristics between
      heterotrimeric G proteins and small GTP binding proteins of the Ras superfamily
      is that the former bind GTP or guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)
      with a much lower affinity (Kd approximately 10(-8)-10(-7) M) than the latter (Kd
      approximately 10(-11)-10(-10)M). We report here that the alpha subunit of the
      heterotrimeric G protein transducin (Gt) binds GTPgammaS with an affinity
      comparable to that of Ras. High affinity binding was suggested by GTPgammaS
      titrations of rod outer segment samples with Gt concentrations in the range of 7
      nM to 300 nM; the results were more consistent with a dissociation constant for
      GTPgammaS in the subnanomolar range, than with one in the 10(-8)-10(-7) M range
      typically reported for heterotrimeric G proteins. Equilibrium binding experiments
      with G protein concentrations in the subnanomolar to nanomolar range confirmed
      this conclusion and revealed a dissociation constant of 50 pM. Thus, transducin's
      affinity for GTPgammaS, and by inference, for GTP, appears to be approximately
      three orders of magnitude higher than previously reported. These results raise
      the possibility that some results obtained with high concentrations of nucleotide
      analogues may be due to minute traces of contaminants such as GTP, GTPgammaS, or
      GTPalphaS, that have high affinities for Gtalpha.

PMID- 8662741
TI  - Low affinity interactions of GDPbetaS and ribose- or phosphoryl-substituted GTP
      analogues with the heterotrimeric G protein, transducin.
AB  - We have examined the effects of three commonly used classes of guanine nucleotide
      analogues on the retinal G protein, transducin (Gt), and found them to be quite
      different from those that might be expected from results with other GTP-binding
      proteins. The most surprising results were with guanosine 5'-O-(2
      thiodiphosphate) (GDPbetaS); rather than inhibiting activation of Gt, GDPbetaS
      addition activated Gt as a result of a trace contaminant. Even when the
      contaminant levels were reduced 5-fold by chromatography, its effects dominated
      those of GDPbetaS, which binds Gt at least 1500-fold more weakly than guanosine
      5'-O-(3-thiotriphosphate) (GTPgammaS). The affinity of Gt for GDP was found to be
      at least 300-fold weaker than for GTPgammaS, while the affinities of GTP and
      GTPgammaS were similar. Ribose-modified GTP analogues, including 2'(3')-O-(N
      methylanthraniloyl) GTP (mantGTP), 2'(3')-O-[(2-aminoethyl)carbamyl] GTP (edGTP),
      and adducts of fluorescein 5-isothiocyanate and rhodamine B-isothiocyanate with
      edGTP, interacted extremely weakly, if at all, with the GTP binding site of the
      alpha subunit of Gt. They were neither effective activators of Gt nor effective
      inhibitors of activation by GTP or GTPgammaS. A gamma-phosphoryl-modified
      analogue, an adduct of GTPgammaS and (5
      (2(iodoacetyl)aminoethyl)amino)naphthalene-1-sulfonic acid (dnsGTP), also
      activated Gt weakly, if at all, and did not inhibit its activation. The exclusion
      of these analogues points to the highly restrictive and specific nature of the
      GTP binding site of Gt, in contrast to those of numerous other GTP-binding
      proteins which are potently activated or inhibited by these analogues.

PMID- 8662742
TI  - Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and
      interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2.
AB  - Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis
      toxin-sensitive GTP-binding protein. In the present studies, signaling via the
      adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T
      cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence
      of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern
      analysis of genomic DNA digests for the CB2 receptor demonstrated identical
      banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were
      dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either
      cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by
      inhibiting forskolin-stimulated cAMP accumulation which consequently led to a
      decrease in protein kinase A activity and the binding of transcription factors to
      a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13
      acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which
      correlated to decreased IL-2 gene transcription, was induced by both cannabinol
      and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin
      induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter.
      Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings
      suggest that inhibition of signal transduction via the adenylate cyclase/cAMP
      pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene
      transcription.

PMID- 8662743
TI  - In vitro insertion and assembly of outer membrane protein PhoE of Escherichia
      coli K-12 into the outer membrane. Role of Triton X-100.
AB  - The assembly of the in vitro synthesized outer membrane protein PhoE into
      purified outer membranes was investigated. The assembly appeared to be strongly
      stimulated by the presence of low amounts of Triton X-100 (optimal 0.08%, w/v).
      The role of Triton X-100 in the in vitro system was further examined. Pretreating
      outer membranes with Triton X-100 did not make the membranes competent for
      correct assembly, indicating that the detergent did not act on the membrane but
      at the protein level. PhoE became assembly-incompetent with a half-life of
      approximately 12 min and 90 s at 37 degrees C in the absence and presence,
      respectively, of 0.08% Triton X-100. Apparently, Triton X-100 induces an assembly
      competent state in the PhoE protein with a very short half-life. Furthermore, the
      efficiency of correct assembly of PhoE was greatly reduced when outer membranes
      of deep rough lipopolysaccharide mutants were used, indicating an important role
      of lipopolysaccharides in the assembly of the porin.

PMID- 8662744
TI  - Regulatory function of delta/YY-1 on the locus control region-like sequence of
      mouse glycophorin gene in erythroleukemia cells.
AB  - The far upstream region (-1.2-0.9 kilobase pairs) of the mouse glycophorin gene
      contains the locus control region (LCR)-like region, which acts as an erythroid
      specific enhancer dependent on chromosomal integration in murine erythroleukemia
      (MEL) cells. In the present study, we demonstrated that this region binds six
      nuclear factors. The binding of GATA-1 to corresponding sites did not show any
      change before or after induction with dimethyl sulfoxide, but the binding of Spi
      1/PU.l and an unidentified factor called glycophorin regulatory element binding
      factor (GRBF) showed a change during induction. While binding activity of Spi
      l/PU.l dropped soon after induction, the GRBF activity increased after induction
      when expression of the glycophorin gene began. After identification of the
      consensus binding site of GRBF, we cloned cDNA for that factor by Southwestern
      method, and it was identified as a previously reported transcription factor,
      delta, a murine form of YY-l which is a versatile transcription factor. Mutation
      analysis in the delta/YY-1 binding site within the LCR-like region indicated that
      delta/YY-1 acts as a regulatory protein in combination with the E-box-binding
      protein that binds to the neighboring sequence.

PMID- 8662745
TI  - Studies on protein-protein interaction between copper-containing nitrite
      reductase and pseudoazurin from Alcaligenes faecalis S-6.
AB  - Site-directed mutagenesis of a copper-containing nitrite reductase (NIR) from
      Alcaligenes faecalis S-6 was carried out to identify the amino acid residues
      involved in interaction with its redox partner, pseudoazurin, in which four
      positively charged residues were previously shown to be important in the
      interaction. Ten negatively charged residues located on the surface of NIR were
      replaced independently by alanine or serine. All the altered NIRs showed CD
      spectra and optical spectra identical to those of wild-type NIR, suggesting that
      all the replacements caused no gross change in the overall structure or in the
      environment of type 1 copper site. Kinetic analysis of electron transfer between
      pseudoazurin and altered NIRs revealed that the replacement of Glu-118, Glu-197,
      Asp-201, Glu-204, or Asp-205 by Ala caused a significant increase in the Km value
      for pseudoazurin compared with that of wild-type NIR. Furthermore, the
      simultaneous replacement of three of these residues (Glu-118, Glu-197, and Asp
      201) caused a further increase in the Km value. These results suggested that the
      negatively charged residues are involved in electrostatic interaction with
      pseudoazurin. Kinetic analyses of the altered NIRs (E118A, E197A, or D201A) with
      altered pseudoazurins (K10A, K57A, or K77A) implicate specific pairs of the
      charged residues that are involved in electrostatic interaction between NIR and
      pseudoazurin.

PMID- 8662746
TI  - A role for Shc, Grb2, and Raf-1 in FcgammaRI signal relay.
AB  - The activation of the serine/threonine kinase, Raf-1, serves to connect upstream
      protein tyrosine kinases to downstream signaling events. We previously reported
      that FcgammaRI stimulation of interferon gamma-differentiated U937 cells (termed
      U937IF cells) induces a mobility shift in Erk2. Herein, we report that cross
      linking of FcgammaRI receptor in U937IF cells induces a marked tyrosine
      phosphorylation of Raf-1 (10-fold increase). Tyrosine phosphorylation of Raf-1 is
      induced by FcgammaRI activation and not by PMA (1 microg/ml), N-formyl-Met-Leu
      Phe (1 microM), calcium ionophore (1 microM), thrombin (0.05 unit/ml),
      FcgammaRII, or FcgammaRIII stimulation. The kinetics of Raf-1 tyrosine
      phosphorylation is rapid, reaching peak levels 1-2 min after FcgammaRI
      activation, and the tyrosine phosphorylation of Raf-1 precedes the activation of
      the respiratory burst. FcgammaRI cross-linking induces the tyrosine
      phosphorylation of Shc; tyrosine-phosphorylated Shc binds to Grb2 forming a Shc
      Grb2 complex. The data provide evidence that the FcgammaRI receptor signals via
      the upstream activation of nonreceptor protein tyrosine kinases, which leads to
      the subsequent activation of Ras family GTPases and serine/threonine kinases, Raf
      1 and mitogen-activated protein kinase.

PMID- 8662747
TI  - Suppression of creatine kinase-catalyzed phosphotransfer results in increased
      phosphoryl transfer by adenylate kinase in intact skeletal muscle.
AB  - The kinetics of creatine kinase (CK) and adenylate kinase (AK) activities were
      monitored in intact diaphragm muscle by 18O phosphoryl oxygen exchange to assess
      whether these two phosphotransferases provide an interrelated function integral
      to high energy phosphoryl metabolism. This possibility was examined by
      quantitating the net rates of CK- and AK-catalyzed phosphoryl transfer in
      comparison to the total cellular ATP metabolic rate when CK activity in the
      intact diaphragm muscle was progressively inhibited by 2,4-dinitrofluorobenzene.
      In noncontracting muscle from untreated rats, net rates of CK- and AK-catalyzed
      phosphotransfer were equivalent to 88 and 7%, respectively, of the total ATP
      metabolic rate. These results were compared with reported 31P NMR analyses of
      total creatine phosphate flux to estimate that each creatine phosphate molecule
      produced undergoes about 50 unidirectional CK-catalyzed phosphotransfers in
      transit to an ATP consumption site in the intact muscles. Graded inhibition by
      2,4-dinitrofluorobenzene of intracellular CK activity by up to 98% resulted in a
      progressive shift in phosphotransferase catalysis from the CK to the AK system;
      the sum of the net rates of phosphoryl transfer by combining the increasing AK
      and decreasing CK activities continued to approximate the total cellular ATP
      metabolic rate. These results indicate that in diaphragm muscle CK and AK operate
      as interrelated cellular high energy phosphoryl transfer systems through which
      the majority of newly generated ATP is processed prior to its utilization.

PMID- 8662748
TI  - Interaction with the phosphotyrosine binding domain/phosphotyrosine interacting
      domain of SHC is required for the transforming activity of the FLT4/VEGFR3
      receptor tyrosine kinase.
AB  - The FLT4 gene encodes two isoforms of a tyrosine kinase receptor, which belongs
      to the family of receptors for vascular endothelial growth factor. As the result
      of an alternative processing of primary mRNA transcripts, the long isoform
      differs from the short isoform by an additional stretch of 65 amino acid residues
      located at the C terminus and containing three tyrosine residues, Tyr1333,
      Tyr1337, and Tyr1363. Only the long isoform is endowed with a transforming
      capacity in fibroblasts. We show that this activity is related to the capacity of
      the tyrosine 1337-containing sequence to interact with the phosphotyrosine
      binding domain of the SHC protein. This demonstrates that a functional property
      of this newly described domain includes relay of mitogenic signals. In addition,
      it shows that the same receptor can mediate different functions through the
      optional binding of the phosphotyrosine binding domain and that the alternative
      use of this domain is sufficient to direct the signal toward different pathways.

PMID- 8662749
TI  - Nuclear matrix interactions within the sperm genome.
AB  - Analysis of the haploid-expressed human PRM1 --> PRM2 --> TNP2 genic domain has
      revealed two regions of attachment to the sperm nuclear matrix. These sperm
      nuclear matrix attachment regions delimit the DNase I-sensitive domain of this
      haploid-expressed locus. The domain is intermediately associated with but not
      attached to the nuclear matrix. DNase I-sensitive genes within the mature sperm
      nucleus, such as protamine 1, protamine 2, transition protein 2, alpha-globin,
      and beta-actin, display this intermediate affinity for the sperm nuclear matrix.
      This may denote their role in templating the male genome prior to fertilization,
      thus ensuring the formation of a viable male pronucleus during early embryonic
      development.

PMID- 8662750
TI  - A phospholipid acts as a chaperone in assembly of a membrane transport protein.
AB  - A mutant of Escherichia coli lacking phosphatidylethanolamine (PE) and a
      monoclonal antibody (mAb 4B1) directed against a conformationally sensitive
      epitope (4B1) of lactose permease were used to establish a novel role for a
      phospholipid in the assembly of a membrane protein. Epitope 4B1 is readily
      detectable in spheroplasts and right-side-out membrane vesicles from PE
      containing but not from PE-deficient cells expressing lactose permease. Lactose
      permease from PE-containing membranes, but not from PE-deficient membranes,
      subjected to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and
      Western blot analysis is also recognized by mAb 4B1. If total E. coli
      phospholipids or PE (but not phosphatidylcholine, phosphatidylglycerol, or
      cardiolipin) are blotted on nitrocellulose sheets (Eastern blot) prior to
      transfer of proteins from SDS-polyacrylamide gels, the permease from PE-deficient
      cells regains its recognition by mAb 4B1. Therefore, PE is required during
      assembly to form epitope 4B1, but, once formed, sufficient "conformational
      memory" is retained in the permease to either retain or reform this epitope in
      the absence of PE. Lactose permease lacking epitope 4B1 can be induced to form
      the epitope if partially denatured and then renatured in the presence of PE
      specifically. These results establish for the first time a role for PE as a
      molecular chaperone in the assembly of the lactose permease.

PMID- 8662751
TI  - Purified cystic fibrosis transmembrane conductance regulator (CFTR) does not
      function as an ATP channel.
AB  - The gene mutated in cystic fibrosis codes for the cystic fibrosis transmembrane
      conductance regulator (CFTR). Previously, we provided definitive evidence that
      CFTR functions as a phosphorylation-regulated chloride channel in our planar
      lipid bilayer studies of the purified, reconstituted protein. Recent patch-clamp
      studies have lead to the suggestion that CFTR may also be capable of conducting
      ATP or inducing this function in neighboring channels. In the present study, we
      assessed the ATP channel activity of purified CFTR and found that the purified
      protein does not function as an ATP channel in planar bilayer studies of single
      channel activity nor in ATP flux measurements in proteoliposomes. Hence, CFTR
      does not possess intrinsic ATP channel activity and its putative role in cellular
      ATP transport may be indirect.

PMID- 8662752
TI  - The endoplasmic reticulum degradation pathway for mutant secretory proteins
      alpha1-antitrypsin Z and S is distinct from that for an unassembled membrane
      protein.
AB  - We have theorized that a subset of PiZZ alpha1-antitrypsin (alpha1-AT)-deficient
      individuals is more susceptible to liver injury by virtue of second inherited
      trait(s) or environmental factor(s), which exaggerate the accumulation of mutant
      alpha1-AT Z within the endoplasmic reticulum (ER) of liver cells. Using a
      complementation approach in which cell lines from PiZZ individuals with liver
      disease ("susceptible" hosts) and from PiZZ individuals without liver disease
      ("protected" hosts) are transduced with the mutant alpha1-AT Z gene, we have
      recently shown that there is a delay in ER degradation of mutant alpha1-AT Z
      protein that is only present in cell lines from susceptible hosts and correlates
      with the liver disease phenotype. In the present study we examined the
      specificity of this ER degradation pathway to determine if it is responsible for
      degrading other misfolded mutants of alpha1-AT and/or for unassembled membrane
      proteins. The S mutant of alpha1-AT and H2a subunit of the asialoglycoprotein
      receptor (ASGPR H2a) were expressed in skin fibroblast cell lines from
      susceptible and protected hosts. The results showed in both susceptible and
      protected hosts that alpha1-AT S was associated with a delay in secretion as
      compared with wild type alpha1-AT. The alpha1-AT S mutant was retained in ER,
      albeit to a lesser extent than the alpha1-AT Z mutant. There was, however, a
      significant increase in retention of alpha1-AT S in the ER of susceptible as
      compared with protected host cells. The same host cell lines were transduced to
      express an unassembled membrane protein, ASGPR H2a. There was no difference in
      the kinetics of ER degradation of ASGPR H2a in susceptible as compared with
      protected hosts. Taken together, the results show that alpha1-AT S is associated
      with a defect in biogenesis, intracellular retention, which is similar to but
      milder than alpha1-AT Z. Like alpha1-AT Z, alpha1-AT S is degraded by a pathway
      in the ER, which is relatively inefficient in PiZZ individuals with the liver
      disease phenotype. However, this pathway appears to be different from that
      previously described for a model unassembled membrane protein.

PMID- 8662753
TI  - MEK kinase is involved in tumor necrosis factor alpha-induced NF-kappaB
      activation and degradation of IkappaB-alpha.
AB  - Signal-dependent activation of the transcription factor NF-kappaB is dominantly
      regulated by degradation of IkappaB-alpha protein. However, the signaling
      pathways that lead to the degradation are not clear. Here we report that mitogen
      activated protein kinase/extracellular signal-regulated kinase kinase (MEK)
      kinase, an activator of stress-activated protein kinases/jun kinase-1
      (SAPKs/JNK1), is involved in such signaling pathways. The transient
      overexpression of MEK kinase in NIH3T3 fibroblasts activates kappaB-CAT reporter
      expression in a synergistic manner with TNFalpha stimulation. In contrast,
      overexpression of kinase-negative MEK kinase suppresses TNFalpha-induced reporter
      expression. The overexpression of MEK kinase suppresses the inhibitory activity
      of co-transfected IkappaB-alpha on the kappaB-CAT or human immunodeficiency virus
      long terminal repeat-luciferase reporter expression and causes the simultaneous
      disappearance of the overexpressed IkappaB-alpha. The disappearance of exogenous
      IkappaB-alpha by the overexpression of MEK kinase is prevented by calpain
      inhibitor-I, an inhibitor of IkappaB-alpha degradation. These results suggest
      that MEK kinase is a signal mediator involved in TNFalpha-induced NF-kappaB
      activation and that the activation of NF-kappaB by MEK kinase is regulated
      through the degradation of IkappaB-alpha.

PMID- 8662754
TI  - 3'-O-(4-Benzoyl)benzoyladenosine 5'-triphosphate inhibits activity of the
      vacuolar (H+)-ATPase from bovine brain clathrin-coated vesicles by modification
      of a rapidly exchangeable, noncatalytic nucleotide binding site on the B subunit.
AB  - It was previously observed that the B subunit of the tonoplast V-ATPase is
      modified by the photoactivated nucleotide analog 3'-O-(4-benzoyl)benzoyladenosine
      5'-triphosphate (BzATP) (Manolson, M. F., Rea, P. A., and Poole, R. J. (1985) J.
      Biol. Chem. 260, 12273-12279). We have further characterized the nucleotide
      binding sites on the V-ATPase and the interaction between BzATP and the B
      subunit. We observe that the V-ATPase isolated from bovine clathrin-coated
      vesicles possesses approximately 1 mol of endogenous, tightly bound ATP/mol of V
      ATPase complex. BzATP is not a substrate for the V-ATPase, but does act as a
      noncovalent inhibitor in the absence of irradiation, changing the kinetic
      characteristics of ATP hydrolysis. Irradiation of the V-ATPase in the presence of
      [3H]BzATP results primarily in modification of the 58-kDa B subunit, with
      complete inhibition of V-ATPase activity occurring upon modification of one B
      subunit per V-ATPase complex. Inhibition occurs as the result of modification of
      a rapidly (t1/2 < 2 min) exchangeable site, and yet this site does not correspond
      to a catalytic site, as indicated by the effects of cysteine-modifying reagents
      which react with Cys254 located at the catalytic sites on the A subunit. Thus,
      the noncatalytic nucleotide binding site modified by BzATP appears to be rapidly
      exchangeable. The site of [3H]BzATP modification of the B subunit was localized
      to the region Ile164 to Gln171, which from the x-ray crystal structure of the
      homologous F-ATPase alpha subunit, is within 10 A of the ribose ring of ATP bound
      to the noncatalytic nucleotide binding site. Thus, despite the absence of a
      glycine-rich loop region in the B subunit, these data are consistent with a
      similar overall folding pattern for the V-ATPase B subunit and the F-ATPase alpha
      subunit.

PMID- 8662755
TI  - Phosphorylation-dependent regulation of cardiac Na+/Ca2+ exchanger via protein
      kinase C.
AB  - The cardiac Na+/Ca2+ exchanger (NCX1) plays a major role in the extrusion of Ca2+
      from cardiomyocytes. We studied the role of protein phosphorylation in the
      regulation of cardiac NCX1 using CCL39 stably overexpressing the canine cardiac
      NCX1 and rat neonatal cardiomyocytes. In both cell types, the NCX1 protein
      immunoprecipitated with a chicken anti-NCX1 antibody exhibited a significant
      basal phosphorylation that was further enhanced by treatment with endothelin-1,
      acidic fibroblast growth factor, phorbol 12-myristate 13-acetate, or okadaic
      acid. In contrast, calphostin C, K252a, or EGTA inhibited the phosphorylation.
      The phosphorylation occurred on two major tryptic phosphopeptides (P1 and P2)
      exclusively on serine residues. Evidence is presented suggesting that P2 was
      derived from an N-terminal half (amino acids 240-475) of the central cytoplasmic
      domain of NCX1 and was phosphorylated directly by protein kinase C (PKC). The
      agents that increased NCX1 phosphorylation significantly enhanced both the
      forward and reverse modes of Na+/Ca2+ exchange. This exchange activation
      exhibited a very good correlation with the NCX1 phosphorylation. In NCX1
      transfected cells, PKC down-regulation following prolonged exposure to phorbol 12
      myristate 13-acetate abolished the acidic fibroblast growth factor-induced
      activation of exchange activity. On the other hand, cell ATP depletion reduced
      the exchange activity and abolished the effects of the above agents on exchange
      activity. These results indicate that the cardiac NCX1 is up-regulated by PKC
      catalyzed phosphorylation. The cardiac NCX1 thus could play an important role in
      the previously reported negative inotropic actions of phorbol esters and other
      PKC-activating agents.

PMID- 8662756
TI  - Expression and function of voltage-dependent potassium channel genes in human
      airway smooth muscle.
AB  - Patch clamp and RNA-polymerase chain reaction methods were used to determine the
      expression of voltage-dependent potassium channel currents and mRNAs in human
      airway smooth muscle cells, and tension measurements were used to examine the
      functional role of specific potassium channel gene products in human bronchial
      smooth muscle. RNA from airway smooth muscle tissue revealed the presence of
      Kv1.2 (11 kilobases (kb)) and Kv1.5 (3.5 and 4.4 kb) transcripts, as well as
      Kv1.1 mRNA (9.5 kb), which has not previously been reported in smooth muscle;
      transcripts from other gene families were not detected. RNA-polymerase chain
      reaction from cultured human myocytes confirmed that the identified transcripts
      were expressed by smooth muscle cells. The available voltage-dependent potassium
      current in human airway myocytes was insensitive to charybdotoxin (200 nM) but
      blocked by 4-aminopyridine. Dendrotoxin (1-300 nM; inhibits Kv1.1 and Kv1.2
      channels), charybdotoxin (10 nM to 1 microM; inhibits KCa and Kv1.2 channels),
      and glybenclamide (0.1-100 microM; inhibits KATP channels) had no effect on
      resting tone. Conversely, 4-aminopyridine increased resting tension with an EC50
      (1.8 mM) equivalent to that observed for current inhibition (1.9 mM). Human
      airway myocytes express mRNA from several members of the Kv1 gene family; the
      channel that underlies the predominate voltage-dependent current and the
      regulation of basal tone appears to be Kv1.5.

PMID- 8662758
TI  - Human fatty-acid synthase gene. Evidence for the presence of two promoters and
      their functional interaction.
AB  - We have isolated and sequenced a genomic clone coding for the first three exons
      and the 5'-flanking region of the human fatty-acid synthase gene. The translation
      initiation site, ATG, is located in exon II. Primer extension and S1 nuclease
      analyses showed the presence of three transcription initiation (Ti) sites: Ti I,
      Ti II, and Ti III. The Ti I site is mapped to the beginning of the untranslated
      exon I and preceded by a promoter with recognizable TATA and CAAT boxes. The Ti
      II and Ti III sites are located in intron I, at 60 and 49 nucleotides upstream of
      the translation initiation site ATG in exon II, respectively. These two Ti sites
      are preceded by four putative Sp1 boxes, but lack TATA and CAAT boxes. Analysis
      of luciferase reporter gene expression in transient transfection assays confirmed
      the existence of two promoters. A 200-base pair 5'-flanking region, which has
      strong promoter activity comparable with that of the CMV promoter, is considered
      human fatty-acid synthase promoter I. In a wild-type human fatty-acid synthase
      luciferase construct, in which promoter I and intron I are present in their
      natural configuration, the reporter gene activity is only 1% of that of promoter
      I. Deletion analysis showed the existence of promoter II, which is located in
      intron I immediately upstream of the Ti II site. The strength of promoter II is
      approximately th of that of promoter I in transient transfection assays. Further
      analysis of reporter gene constructs showed that promoter II inhibited the
      reporter gene activity of the wild-type construct that contained promoter I and
      intron I and that the spatial separation of the two promoters is important for
      this inhibition. A model is proposed based on the possibility that the assembly
      of transcription complexes on promoter II creates a "roadblock" and reduces the
      overall expression of the fatty-acid synthase gene by interfering with the
      progression of transcription from promoter I.

PMID- 8662757
TI  - Respiration and growth defects in transmitochondrial cell lines carrying the
      11778 mutation associated with Leber's hereditary optic neuropathy.
AB  - Mitochondrial DNA from two genetically unrelated patients carrying the mutation
      at position 11778 that causes Leber's hereditary optic neuropathy has been
      transferred with mitochondria into human mtDNA-less rho0206 cells. As analyzed in
      several transmitochondrial cell lines thus obtained, the mutation, which is in
      the gene encoding subunit ND4 of the respiratory chain NADH dehydrogenase (ND),
      did not affect the synthesis, size, or stability of ND4, nor its incorporation
      into the enzyme complex. However, NADH dehydrogenase-dependent respiration, as
      measured in digitonin-permeabilized cells, was specifically decreased by
      approximately 40% in cells carrying the mutation. This decrease, which was
      significant at the 99.99% confidence level, was correlated with a significantly
      reduced ability of the mutant cells to grow in a medium containing galactose
      instead of glucose, indicating a clear impairment in their oxidative
      phosphorylation capacity. On the contrary, no decrease in rotenone-sensitive NADH
      dehydrogenase activity, using a water-soluble ubiquinone analogue as electron
      acceptor, was detected in disrupted mitochondrial membranes. This is the first
      cellular model exhibiting in a foreign nuclear background mitochondrial DNA
      linked biochemical defects underlying the optic neuropathy phenotype.

PMID- 8662759
TI  - Casein kinase II associates with Egr-1 and acts as a negative modulator of its
      DNA binding and transcription activities in NIH 3T3 cells.
AB  - Although the activation domains within early growth response gene protein 1 (Egr
      1) have been mapped, little is known of the kinases which phosphorylate Egr-1 and
      how phosphorylation correlates with the transcriptional activity of Egr-1. In
      this study we report that casein kinase II (CKII) co-immunoprecipitates with Egr
      1 from NIH 3T3 cell lysates. The association of Egr-1 and CKII requires the C
      terminus of Egr-1 and CKII phosphorylates Egr-1 in vitro. The in vitro
      phosphorylation of Egr-1 by CKII and that induced by serum in vivo was compared
      by examining the CNBr-digested fragments of the phosphorylated Egr-1. CKII
      strongly phosphorylates fragments 7 and 10 which cover part of the
      activation/nuclear localization and DNA binding domains of Egr-1. CKII also
      phosphorylates, albeit weakly, fragments 5 and 8 which cover part of activation
      domain and the entire repression domain of Egr-1, respectively. Strong
      phosphorylation on fragment 10 as well as fragment 5 was also observed in Egr-1
      immunoprecipitated from serum-induced, 32P-labeled cells. CKII phosphorylation of
      Egr-1 resulted in a decrease of its DNA binding as well as its transcriptional
      activities.

PMID- 8662760
TI  - Activation of the mitogen-activated protein kinase pathway by fMet-leu-Phe in the
      absence of Lyn and tyrosine phosphorylation of SHC in transfected cells.
AB  - The chemotactic peptide f-Met-Leu-Phe (fMLP) stimulates leukocyte functions
      through binding and activation of a specific G-protein-coupled formyl peptide
      receptor (FPR). Recent studies have shown that stimulation of neutrophils with
      fMLP induces the activation of two members of the mitogen-activated protein
      kinase (MAP kinase) family, ERK1 and ERK2, through mechanisms that are not
      completely understood but may involve the phosphorylation of the adapter protein
      SHC by the Src-related kinase Lyn. In this study, transfected fibroblasts
      expressing the rabbit FPR were used to investigate further the role of Lyn and
      SHC phosphorylation in fMLP-stimulated MAP kinase activation. Stimulation of
      transfected cells with fMLP resulted in the time- and dose-dependent increase in
      tyrosine phosphorylation and activation of ERK1 and ERK2 and the activation of
      MEK, the MAP kinase/ERK kinase. The activation of both ERKs and MEK was inhibited
      by preincubation of the cells with pertussis toxin, indicating that activation
      was dependent upon a Gi/Go-like protein that couples to the receptor. Our data
      also show that, unlike neutrophils, FPR-transfected fibroblasts do not express
      the Src-related kinase Lyn. In the absence of Lyn, fMLP stimulation did not
      result in an increased tyrosine phosphorylation of the adapter protein SHC,
      whereas it was still able to induce MAP kinase activation. These data suggest
      that Lyn and SHC are not the only upstream signals for activation of the MAP
      kinase/ERK pathway by fMLP and demonstrate the potential application of the FPR
      transfected cells for the delineation of additional signaling mechanisms
      stimulated by fMLP.

PMID- 8662761
TI  - Phosphocreatine-dependent glutamate uptake by synaptic vesicles. A comparison
      with atp-dependent glutamate uptake.
AB  - ATP-dependent uptake of glutamate into synaptic vesicles has been well
      documented. Stimulation of glutamate uptake into synaptic vesicles by other high
      energy phosphates has not been described. In this paper, we examine the
      stimulation of phosphocreatine (PCr)-induced glutamate uptake and determine
      whether this stimulation is secondary to conversion of PCr to ATP. We found the
      following. 1) PCr stimulates glutamate uptake into synaptic vesicles in the
      absence of added ATP. 2) At a glutamate concentration of 50 microM, no
      concentration of added ATP could produce the degree of stimulation seen in the
      presence of PCr. 3) 0.5 mM iodoacetamide completely inhibits synaptic vesicle
      creatine kinase activity but does not inhibit PCr-stimulated glutamate uptake. 4)
      PCr-dependent glutamate uptake, unlike ATP-dependent uptake, is not magnesium- or
      chloride-dependent. 5) 0.5 mM N-ethylmaleimide, a selective H+-ATPase inhibitor,
      completely inhibits ATP-dependent glutamate uptake but only slightly inhibits PCr
      dependent glutamate uptake. 6) PCr-dependent glutamate uptake is sensitive to
      valinomycin, a K+/H+ translocator, whereas the ATP-dependent uptake is not.
      Therefore, it appears that in addition to the well-known ATP-dependent glutamate
      uptake system, there is a previously unreported PCr-dependent glutamate uptake
      system in synaptic vesicles. The total glutamate uptake by synaptic vesicles is
      likely the sum of both ATP- and PCr-dependent glutamate uptake.

PMID- 8662762
TI  - Purification of a peptidoglycan recognition protein from hemolymph of the
      silkworm, Bombyx mori.
AB  - A method was developed for obtaining a homogeneous silkworm hemolymph protein
      (peptidoglycan recognition protein, PGRP) which has affinity for peptidoglycan
      and the ability to trigger the prophenoloxidase cascade upon its binding to
      peptidoglycan. The purified PGRP had a molecular mass of about 19 kDa and is
      composed of a single polypeptide with an isoelectric point of 6.5. It bound to
      peptidoglycan in the absence of divalent cation, whereas its binding to beta1,3
      glucan and chitin was not detected. N-Acetyl-D-glucosaminyl-(beta1-4)-N
      acetylmuramyl-L-alanyl-D-isogluta mine did not inhibit purified PGRP to bind
      insoluble peptidoglycan, but fragmented soluble peptidoglycan did. PGRP seemed to
      require peptidoglycan as a possible ligand to keep its glycan portion consisting
      of at least two or more of the repeating unit. PGRP did not have any detectable
      lysozyme activity, and its amino acid composition and amino-terminal sequence of
      20 amino acid residues were shown to be different from those of silkworm
      lysozyme. PGRP seems to be a hitherto unknown protein. In the absence of PGRP,
      the prophenoloxidase cascade in the plasma fraction of hemolymph could not be
      triggered by peptidoglycan, indicating that some type of activity, capable of
      activating the cascade, is generated upon their binding. However, the exact
      nature of this activity is not yet known. The purified PGRP bound to
      peptidoglycan did not hydrolyze significantly any of the 26 commercially
      available peptidyl-7-amino-4-methylcoumarins, substrates for various proteases.

PMID- 8662763
TI  - Activated human plasma carboxypeptidase B is retained in the blood by binding to
      alpha2-macroglobulin and pregnancy zone protein.
AB  - A 66-kDa glycosylated carboxypeptidase, plasma pro-carboxypeptidase B (pro-plasma
      CPB), has recently been identified in human blood (Eaton, D. L., Malloy, B. E.,
      Tsai, S. P., Henzel, W., and Drayna, D. (1991) J. Biol. Chem. 266, 21833-21838).
      The pro-enzyme binds to plasminogen and the active enzyme is specific for COOH
      terminal Lys or Arg residues. These properties implicate a role in the
      fibrinolytic or coagulation system. However, we show that the molecular mass of
      the active plasma CPB is approximately 36 kDa, which is below the glomerular
      filtration limit. Since activated plasma CPB no longer binds plasminogen, the
      active enzyme may not be retained in the circulation. To investigate this, we
      performed plasma elimination studies in mice which showed that 125I-plasma CPB
      remains in the circulation despite its small size. Native polyacrylamide gel
      electrophoresis of blood samples removed from the mice revealed that plasma CPB
      migrated as a high molecular weight band. Similar bands were observed in vitro
      when 125I-plasma CPB was added to plasma from humans and other species. The
      plasma CPB-binding proteins were purified from human plasma and identified as
      alpha2-macroglobulin (alpha2M) and pregnancy zone protein. Only the active enzyme
      bound to the two alpha-macroglobulins, and the interaction was specific for
      alpha2M in its native conformation, but not its receptor recognized forms. The
      complex between human alpha2M and plasma CPB dissociated during SDS
      polyacrylamide gel electrophoresis and transverse urea gel electrophoresis
      suggesting that the interaction was noncovalent and depended on the tertiary
      structure of the native alpha2M molecule. The catalytic activity of plasma CPB
      was not significantly affected by its binding to alpha2M. The specific binding of
      plasma CPB to alpha-macroglobulins suggest that these proteins may function as a
      "shuttle" in vivo to modulate the clearance of plasma CPB from the circulatory
      system.

PMID- 8662764
TI  - Comparative topology studies in Saccharomyces cerevisiae and in Escherichia coli.
      The N-terminal half of the yeast ABC protein Ste6.
AB  - Gene fusions have provided a strategy for determining the topology of polytopic
      membrane proteins in Escherichia coli. To evaluate whether this highly effective
      approach is applicable to heterologously expressed eukaryotic integral membrane
      proteins, we have carried out a comparative topological study of the eukaryotic
      membrane protein Ste6 both in bacteria and in yeast. Ste6, is an ATP binding
      cassette (ABC) protein, essential for export of the a-factor mating pheromone in
      Saccharomyces cerevisiae. The topogenic reporters, invertase in S. cerevisiae and
      alkaline phosphatase in E. coli, were fused to Ste6 at identical sites and the
      fusions were expressed in yeast and bacteria, respectively. The results obtained
      in both systems are similar, although more definitive in E. coli, and support the
      predicted six-transmembrane spans organization of the N-terminal half of Ste6.
      Thus, the topological determinants for membrane insertion of polytopic proteins
      in prokaryotic and in eukaryotic systems appear to be highly similar. In this
      study we also demonstrate that Ste6 does not contain a cleaved signal sequence.

PMID- 8662765
TI  - The synthesis and assembly of functional high and low light LH2 antenna complexes
      from Rhodopseudomonas palustris in Rhodobacter sphaeroides.
AB  - Photosynthetic bacteria respond to lowered light intensity by increasing the
      level of the peripheral light-harvesting (LH2) complex. Several species possess
      an additional mechanism, responding to variations in light conditions by making
      different types of LH2 complex. However, the study of these complexes in
      isolation and in the native membrane environment has not been possible. Therefore
      two LH2 gene pairs from Rhodopseudomonas palustris, associated, respectively,
      with high light (pucBAa) and low light (pucBAd) growth conditions, were expressed
      in Rhodobacter sphaeroides. The high light LH2 complex PucBAa was synthesized at
      appreciable levels in R. sphaeroides, had near-infrared absorption bands at
      approximately 800-855 nm, and was able to transfer energy efficiently to the
      native LH1 complex. In contrast, the low light complex PucBAd was found at
      comparatively low levels, had absorption bands at approximately 797-830 nm, and
      did not transfer energy to the native LH1 complex efficiently. These observations
      are discussed in the light of site-directed studies on the R. sphaeroides LH2
      complex, and the recently elucidated Rhodopseudomonas acidophila 10050 LH2
      structure. Potentially important residues for energy transfer between LH2 and LH1
      complexes are identified, as well as some of the factors that influence stability
      and assembly of LH2 complexes, such as the N-terminal sequences of their protein
      subunits and their carotenoid binding sites.

PMID- 8662767
TI  - Cloning and functional characterization of a system ASC-like Na+-dependent
      neutral amino acid transporter.
AB  - A cDNA was isolated from mouse testis which encodes a Na+-dependent neutral amino
      acid transporter. The encoded protein, designated ASCT2, showed amino acid
      sequence similarity to the mammalian glutamate transporters (40-44% identity),
      Na+-dependent neutral amino acid transporter ASCT1 (57% identity; Arriza, J. L.,
      Kavanaugh, M. P., Fairman, W. A., Wu, Y.-N., Murdoch, G. H., North, R. A., and
      Amara, S. G.(1993) J. Biol. Chem. 268, 15329-15332; Shafqat, S., Tamarappoo, B.
      K., Kilberg, M. S., Puranam, R. S., McNamara, J. O., Guadano-Ferraz, A., and
      Fremeau, T., Jr. (1993) J. Biol. Chem. 268, 15351-15355) and a mouse adipocyte
      differentiation-associated gene product AAAT (94% identity; Liao, K., and Lane,
      D.(1995) Biochem. Biophys. Res. Commun. 208, 1008-1015). When expressed in
      Xenopus laevis oocytes, ASCT2 exhibited Na+-dependent uptakes of neutral amino
      acids such as L-alanine, L-serine, L-threonine, L-cysteine, and L-glutamine at
      high affinity with Km values around 20 microM. L-Methionine, L-leucine, L
      glycine, and L-valine were also transported by ASCT2 but with lower affinity. The
      substrate selectivity of ASCT2 was typical of amino acid transport system ASC,
      which prefers neutral amino acids without bulky or branched side chains. ASCT2
      also transported L-glutamate at low affinity (Km = 1.6 mM). L-Glutamate transport
      was enhanced by lowering extracellular pH, suggesting that L-glutamate was
      transported as protonated form. In contrast to electrogenic transport of
      glutamate transporters and the other ASC isoform ASCT1, ASCT2-mediated amino acid
      transport was electroneutral. Na+ dependence of L-alanine uptake fits to the
      Michaelis-Menten equation, suggesting a single Na+ cotransported with one amino
      acid, which was distinct from glutamate transporters coupled to two Na+. Northern
      blot hybridization revealed that ASCT2 was mainly expressed in kidney, large
      intestine, lung, skeletal muscle, testis, and adipose tissue. Functional
      characterization of ASCT2 provided fruitful information on the properties of
      substrate binding sites and the mechanisms of transport of Na+-dependent neutral
      and acidic amino acid transporter family, which would facilitate the structure
      function analyses based on the comparison of the primary structures of ASCT2 and
      the other members of the family.

PMID- 8662768
TI  - Protein kinase C-mediated phosphorylation does not regulate drug transport by the
      human multidrug resistance P-glycoprotein.
AB  - P-glycoprotein (P-gp) is an active transporter that can confer multidrug
      resistance by pumping cytotoxic drugs out of cells and tumors. P-gp is
      phosphorylated at several sites in the "linker" region, which separates the two
      halves of the molecule. To examine the role of phosphorylation in drug transport,
      we mutated P-gp such that it could no longer be phosphorylated by protein kinase
      C (PKC). When expressed in yeast, the ability of the mutant proteins to confer
      drug resistance, or to mediate [3H]vinblastine accumulation in secretory
      vesicles, was indistinguishable from that of wild type P-gp. A matched pair of
      mammalian cell lines were generated expressing wild type P-gp and a non
      phosphorylatable mutant protein. Mutation of the phosphorylation sites did not
      alter P-gp expression or its subcellular localization. The transport properties
      of the mutant and wild type proteins were indistinguishable. Thus,
      phosphorylation of the linker of P-gp by PKC does not affect the rate of drug
      transport. In light of these data, the use of agents that alter PKC activity to
      reverse multidrug resistance in the clinic should be considered with caution.

PMID- 8662769
TI  - The role of the N and C termini of recombinant Neurospora mitochondrial porin in
      channel formation and voltage-dependent gating.
AB  - To investigate the role of the N and C termini in channel function and voltage
      dependent gating of mitochondrial porin, we expressed wild-type and mutant porins
      from Neurospora crassa as His-tag fusion products in Escherichia coli. Large
      quantities of the proteins were purified by chromatography across a nickle
      nitrilotriacetic acid-agarose column under denaturing conditions. The purified
      His-tagged wild-type protein could be functionally reconstituted in the presence
      of detergent and sterol and behaved in black lipid bilayer membranes
      indistinguishably from native porin isolated from Neurospora crassa mitochondria.
      Mutants of porin lacking part of the N terminus (DeltaN2-12porin, DeltaN3
      20porin), part of the C terminus (DeltaC269-283porin), or both (DeltaN2
      12/DeltaC269-283porin) also showed channel forming activity. The mutant porin
      lacking the C terminus had a smaller single channel conductance than the wild
      type protein, but its other biophysical properties were identical. DeltaN2
      12porin and DeltaN3-20porin formed noisy channels with decreased channel
      stability. These channels were still voltage-dependent. DeltaN2-12/DeltaC269
      283porin lost channel stability and had altered gating characteristics. These
      results are discussed with respect to different models that have been proposed in
      the literature for the structure of mitochondrial porin channels.

PMID- 8662770
TI  - H+-induced membrane insertion of influenza virus hemagglutinin involves the HA2
      amino-terminal fusion peptide but not the coiled coil region.
AB  - Fusion of influenza virus with target membranes is induced by acid and involves
      complex changes in the viral envelope protein hemagglutinin (HA). In a first,
      kinetically distinct step, the HA polypeptide chain 2 (HA2) is inserted into the
      target membrane bilayer. Using hydrophobic photolabeling with the phospholipid
      analogue 1-O-hexadecanoyl-2-O-[9-[[[2-[125I]iodo-4(trifluoromethyl-3H-diazirin -3
      yl)benzyl]oxy]carbonyl]nonanoyl]-sn-glycero-3-phosphocholine, we identified the
      segment within HA2 that interacts with the membrane. The sole part of the HA2
      ectodomain that was labeled with the membrane-restricted reagent is the NH2
      terminal fusion peptide (residues 1-22). No labeling occurred within the long
      coiled coil region generated during the acid-induced conformational transition
      (Bullough, P. A., Hughson, F. M., Skehel, J. J., and Wiley, D. C. (1994) Nature
      371, 37-43). These data strongly suggest that the coiled coil region of HA2 does
      not insert into the lipid bilayer. This conclusion is at variance with the recent
      suggestion (Yu, Y. G., King, D. S., and Shin, Y.-K.(1994) Science 266, 274-276)
      that the coiled coil of HA may splay apart and insert into the target membrane,
      providing a mechanism by which the viral and the target membrane may come in
      close apposition.

PMID- 8662771
TI  - A new low density lipoprotein receptor homologue with 8 ligand binding repeats in
      brain of chicken and mouse.
AB  - The blood-brain barrier necessitates disparate macromolecular transport systems
      in the brain and central nervous system. We now report the discovery of a new
      member of the low density lipoprotein receptor (LDLR) family whose expression is
      highly restricted to the brain. The full-length cDNA specifying the chicken
      receptor (open reading frame, 2754 base pairs) as well as a cDNA for the major
      portion of its murine homologue have been obtained. The novel receptor shows the
      greatest similarity to the group of LDLR relatives with 8 ligand binding repeats,
      in chicken termed LR8 and in mammals, very low density lipoprotein receptors.
      Thus, in addition to 8 tandemly arranged ligand binding repeats, the five-domain
      receptor contains an O-linked sugar region and the internalization signal, Phe
      Asp-Asn-Pro-Val-Tyr, typical for all LDLR gene family members. In chicken, the
      6.5-kb receptor transcript is present at high levels in brain and at much lower
      levels in extraoocytic cells of the ovary; in mouse, the same transcript of 6.5
      kb was detected in brain, but not in heart (the major site of very low density
      lipoprotein receptor expression), lung, liver, kidney, and ovary. An antibody
      directed against the predicted carboxyl terminus of the avian receptor detected a
      130-kDa protein in brain extracts. The apparent size of the immunoreactive
      protein is compatible with extensive glycosylation of the 894-residue mature form
      of the receptor. The presence of this novel receptor in brain of a bird and a
      rodent suggests an important and evolutionary conserved function.

PMID- 8662772
TI  - Binding specificity and mutational analysis of the phosphotyrosine binding domain
      of the brain-specific adaptor protein ShcC.
AB  - Shc proteins (hereafter referred to as ShcA) represent major substrates of
      tyrosine phosphorylation by a wide variety of growth factors and cytokines. We
      have recently described a novel ShcA-like protein, ShcC, which like ShcA contains
      an NH2-terminal phosphotyrosine binding domain (PTB), a central effector region
      (CH1) and a COOH-terminal Src homology 2 domain (SH2). Both the SH2 and PTB
      domains of ShcC bind a similar profile of proteins as the comparable regions of
      ShcA. In an effort to define the functional differences or similarities between
      ShcA and ShcC, we have further characterized the PTB domain of ShcC. Using a
      degenerate phosphopeptide library screen, we show that the PTB domain of ShcC
      preferentially binds the sequence His-hydrophobic-Asn/hydrophobic-Asn-Pro-Ser/Thr
      Tyr(P). This sequence is similar to the binding site for the ShcA PTB domain,
      suggesting that these two proteins may have overlapping specificities. In
      addition, random mutagenesis of the ShcC PTB domain has identified several amino
      acids important for PTB function (Gly32, Glu63, Ala136, Gly139, and Asp140).
      Mutation of these amino acids dramatically reduces the affinity of the ShcC PTB
      domain for the activated epidermal growth factor receptor in vitro.

PMID- 8662773
TI  - Unique inactivation properties of NAADP-sensitive Ca2+ release.
AB  - Ca2+ mobilization from intracellular stores constitutes an important mechanism
      for generating cytoplasmic Ca2+ signals. Inositol trisphosphate (InsP3) and
      ryanodine receptors are the two families of intracellular Ca2+ release channels
      that have been identified, which may be regulated by separate intracellular
      messengers, InsP3, and cyclic adenosine 5'-diphosphate ribose, respectively. A
      third molecule, nicotinic acid adenine dinucleotide phosphate (NAADP), has
      recently been recognized as a potent Ca2+ releasing agent in sea urchin eggs and
      microsomes. We now report that non-releasing concentrations of NAADP fully and
      irreversibly inactivate the NAADP-sensitive Ca2+ release mechanism. This
      phenomenon occurred both in intact sea urchin eggs and in homogenates and is not
      shared by either InsP3 or cyclic adenosine 5'-diphosphate ribose. The novel
      properties of this Ca2+ release mechanism, giving a one-shot Ca2+ release, may be
      suited to irreversible cellular events.

PMID- 8662774
TI  - A single amino acid change converts an inhibitory transcription factor into an
      activator.
AB  - The closely related POU family transcription factors Brn-3a and Brn-3b differ in
      their functional activity with Brn-3a activating several target promoters, which
      are repressed by Brn-3b. Brn-3b also prevents promoter activation by Brn-3a. Here
      we have altered a single isoleucine residue in the POU homeodomain of Brn-3b to
      the valine residue found at the equivalent position in Brn-3a. This change not
      only abolishes the ability of Brn-3b to repress basal and Brn-3a-stimulated
      promoter activity but also converts it to an activator of similar potency to Brn
      3a. Hence a single amino acid difference determines the difference between an
      activator and a repressor in the Brn-3 family.

PMID- 8662776
TI  - The mechanism of velocity modulated allosteric regulation in D-3-phosphoglycerate
      dehydrogenase. Cross-linking adjacent regulatory domains with engineered
      disulfides mimics effector binding.
AB  - D-3-Phosphoglycerate dehydrogenase (PGDH) (EC 1.1.1.95) from Escherichia coli is
      an allosterically regulated enzyme of the Vmax type. It is a tetramer of
      identical subunits and each subunit is made up of three identifiable domains, the
      cofactor binding domain, the substrate binding domain, and the regulatory domain.
      Each subunit contacts two other subunits through adjacent cofactor binding
      domains and through adjacent regulatory domains. L-Serine, the physiological
      effector, inhibits catalytic activity by apparently tethering regulatory domains
      from adjacent subunits together through the formation of hydrogen bonds to each
      subunit. This investigation demonstrates that cross-linking adjacent regulatory
      domains with engineered disulfides produces catalytic inhibition in the absence
      of inhibitor in a manner similar to that produced by the inhibitor. The
      inhibition due to cross-linking can be completely reversed in a concentration
      dependent manner by dithiothreitol. The active mutant enzyme, containing the
      engineered cysteines in the reduced state, retains its ability to be inhibited by
      L-serine, although at a 100-fold higher concentration. Hill plots of the serine
      inhibition of mutant and native enzyme indicate that the number of interacting
      sites remains at 2 in the mutant enzyme. The reversible inhibition of enzyme
      activity that results from tethering adjacent regulatory domains with engineered
      disulfides suggests that these domains move in some manner relative to one
      another during the active to inhibited state transition. These observations
      support the model which predicts that catalytic activity is regulated by the
      movement of rigid domains about flexible hinges and that effector binding
      prevents this by locking the regulatory domains in a state that produces an open
      active site cleft.

PMID- 8662775
TI  - Mutation of amino acid residues in the putative transmembrane segments of the
      cardiac sarcolemmal Na+-Ca2+ exchanger.
AB  - We have examined the role of conserved regions and acidic or basic residues
      located in the putative transmembrane segments of the cardiac sarcolemmal Na+
      Ca2+ exchanger by site-directed mutagenesis. The alpha-1 and alpha-2 repeats are
      transmembrane regions of internal similarity, which are highly conserved among
      Na+-Ca2+ exchangers. We find that Na+-Ca2+ exchange activity is highly sensitive
      to mutagenesis in the alpha-repeats. Mutation at residues Ser-109, Ser-110, Glu
      113, Ser-139, Asn-143, Thr-810, Ser-811, Asp-814, Ser-818, or Ser-838 resulted in
      loss of exchanger activity. Mutation at residues Thr-103, Gly-108, Pro-112, Glu
      120, Gly-138, Gly-809, Gly-837, and Asn-842 resulted in reduced exchanger
      activity, and altered current-voltage relationships were observed with mutations
      at residues Gly-138 and Gly-837. Only mutation at residue Ser-117 appeared to
      leave exchanger activity unaffected. Thus, the alpha-repeats appear to be
      important components for ion binding and translocation. Another region implicated
      in exchanger function is a region of similarity to the Na+,K+ pump (Nicoll, D.
      A., Longoni, S., Philipson, K. D. (1990) Science 250, 562-565). Mutations at two
      residues in the pump-like region, Glu-199 and Thr-203, resulted in nonfunctional
      exchangers, while mutation at two other residues, Glu-196 and Gly-200, had no
      effect. The role of acidic and basic residues in the transmembrane segments was
      also examined. Mutation of several basic residues (Arg-42, His-744, Lys-751, Lys
      797, and His-858) did not affect exchange activity. Of the acidic residues
      located outside of the alpha-repeat and pump-like regions (Asp-740, Asp-785, and
      Asp-798), only mutation at Asp-785 resulted in reduction of exchanger activity.

PMID- 8662777
TI  - The distal pathway of lipoprotein-induced cholesterol esterification, but not
      sphingomyelinase-induced cholesterol esterification, is energy-dependent.
AB  - The stimulation of the intracellular cholesterol esterification pathway by
      atherogenic lipoproteins in macrophages is a key step in the development of
      atheroma foam cells. The esterification pathway can also be stimulated by
      hydrolysis of cell-surface sphingomyelin by the enzyme sphingomyelinase (SMase).
      In both cases, intracellular cholesterol transport to the cholesterol esterifying
      enzyme, acyl-CoA:cholesterol O-acyltransferase (ACAT), is thought to be critical,
      although the mechanism of cholesterol transport is not known. In this report, we
      explore two fundamental properties of the cholesterol esterification pathway,
      namely its dependence on energy and the effect of other treatments that block
      membrane vesicle trafficking. After the atherogenic lipoprotein, beta-very low
      density lipoprotein (beta-VLDL), was internalized by macrophages and hydrolyzed
      in lysosomes, the cells were depleted of energy by treatment with sodium azide
      and 2-deoxyglucose or by permeabilization. Under these conditions, which allowed
      equal beta-VLDL-cholesteryl ester hydrolysis, cholesterol esterification was
      markedly decreased in the energy-depleted cells. This effect was not due to
      blockage of lysosomal cholesterol export. In the permeabilized cell system,
      energy repletion restored beta-VLDL-induced cholesterol esterification.
      Remarkably, stimulation of cholesterol esterification by SMase was not inhibited
      by energy depletion. Energy depletion also inhibited beta-VLDL-induced, but not
      SMase-induced, cholesterol esterification in Chinese hamster ovary cells. Similar
      experiments were carried out using N-ethylmaleimide, low potassium medium, or
      inhibitors of phosphatidylinositol 3-kinase, each of which blocks intracellular
      membrane vesicle trafficking. These treatments also inhibited beta-VLDL-induced,
      but not SMase-induced, cholesterol esterification. Finally, we show here that
      SMase treatment of cells leads to an increase in plasma membrane vesiculation
      that is relatively resistant to energy depletion. In summary, the stimulation of
      cholesterol esterification by lipoproteins, but not by SMase, is energy
      dependent, N-ethylmaleimide-sensitive, and blocked by both low potassium and
      phosphatidylinositol 3-kinase inhibitors. The affected step or steps are distal
      to cholesterol export from lysosomes and not due to direct inhibition of the ACAT
      enzyme. Thus, the mechanisms involved in lipoprotein-induced versus SMase-induced
      cholesterol esterification are different, perhaps due to the involvement of
      energy-dependent vesicular cholesterol transport in the lipoprotein pathway and a
      novel, energy-independent vesicular transport mechanism in the SMase pathway.

PMID- 8662778
TI  - Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non
      myeloid cells.
AB  - Members of the Janus kinase (Jak) family of protein tyrosine kinases have
      recently been implicated in the proximal signal transduction events of cytokine
      receptors. Jak3, a newly discovered member of this family, is believed to be
      normally limited in its expression to cells of the lymphoid and myeloid lineages.
      Herein we show that Jak3 is expressed in primary human vascular cells, as well as
      other non-lymphoid and non-myeloid cell types. Reverse transcriptase-polymerase
      chain reaction and Northern blot analysis revealed that Jak3 mRNA was expressed
      at low levels in human umbilical vein endothelial cells (HUVEC), human aortic
      smooth muscle cells (HASMC), A549 (human lung carcinoma), and DLD-1 (human colon
      adenocarcinoma) cells. Higher basal levels of Jak3 mRNA were detected in HMEC-1
      (human microvascular cell line) and HepG2 (human hepatocellular carcinoma) cells.
      Jak3 mRNA expression was induced in HUVEC, HMEC-1, and HASMC by treatment with
      interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and
      lipopolysaccharide. Jak3 protein was detectable at low levels in untreated HMEC
      1, and these levels increased significantly with cytokine treatment. Furthermore,
      Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4.
      This work shows that Jak3 is expressed or inducible in human vascular
      endothelial, vascular smooth muscle, and other non-lymphoid and non-myeloid
      cells, suggesting a broader role for Jak3 in the cytokine signal transduction of
      these cells.

PMID- 8662779
TI  - Isolation of a 25-kDa protein binding to a curved DNA upstream the origin of the
      L strand replication in the rat mitochondrial genome.
AB  - The presence of a curved DNA sequence in the gene for the NADH-dehydrogenase
      subunit 2 of rat mitochondrial genome, upstream from the origin of the light
      strand replication have been demonstrated through theoretical analysis and
      experimental approaches. Gel retardation assays showed that this structure makes
      a complex with a protein component extracted from the mitochondrial matrix. The
      isolation and purification of this protein is reported. With a Sepharose CL-6B
      and magnetic DNA affinity chromatography a polypeptide was purified to
      homogeneity having 25-kDa mass as shown by gel electrophoresis. To functionally
      characterize this protein, its capability to bind to other sequences of the
      homologous or heterologous DNA and to specific riboprobes was also investigated.
      A role for this protein as a trans-acting agent required for the expression of
      the mammalian mitochondrial genome is suggested.

PMID- 8662780
TI  - Contribution of arginine residues in the RP135 peptide derived from the V3 loop
      of gp120 to its interaction with the Fv fragment of the 0.5beta HIV-1
      neutralizing antibody.
AB  - The construction, expression, and purification of an active Fv fragment of the
      0.5beta monoclonal human immunodeficiency virus type 1 (HIV-1) neutralizing
      antibody is reported. The interaction between the Fv fragment and the RP135
      peptide derived from the V3 loop of gp120 from HIV-1IIIB was studied by varying
      the salt concentration and by mutating arginine residues in the peptide. The
      mutations R4A, R8A and R11A (which correspond to residues 311, 315, and 318 in
      gp120 of HIV-1IIIB) reduce the binding free energy by 0.22 (+/- 0. 20), 4.32 (+/-
      0.16), and 1.58 (+/- 0.17) kcal mol-1, respectively. The salt-dependent
      components of their contributions to binding are 0.02 (+/- 0.22), -0.55 (+/-
      0.18), and -0.97 (+/- 0.19) kcal mol-1, respectively. The magnitudes of the
      mutational effects and the extent of shielding by 1 M NaCl suggest that Arg-8 is
      involved in a buried salt bridge in the peptide-Fv fragment complex, whereas Arg
      11 is involved in a more solvent-exposed electrostatic interaction.

PMID- 8662781
TI  - Ceramide inactivates cellular protein kinase Calpha.
AB  - Ceramide mediates the effects of extracellular agents on cellular growth,
      differentiation and apoptosis. In this study, we explored the mechanisms by which
      ceramide induces its cellular effects. In Molt-4 cells, phorbol 12-myristate 13
      acetate (PMA) induced retinoblastoma gene product (Rb) phosphorylation, and
      ceramide inhibited this effect, suggesting an inhibitory effect of ceramide on
      the protein kinase C (PKC) pathway, the primary target of PMA. Molt-4 cells
      contained primarily PKCalpha and betaII isoforms of PKC. To determine the effects
      of ceramide on PKC, we developed an immunoprecipitation assay for PKCalpha
      activity. Exposure of Molt-4 cells to C6-ceramide resulted in a concentration and
      time-dependent inhibition of immunoprecipitated protein kinase Calpha (PKCalpha).
      Initial inhibition was observed as early as 4.5 h after treatment of cells with
      C6-ceramide, and the activity was completely lost by 13 h. Inhibition of PKCalpha
      activity was seen at concentrations of ceramide as low as 5 microM with maximal
      effects occurring at a concentration of 15 microM. Both C2 and C6-ceramide were
      inhibitory, but C2 and C6 dihydroceramides were not. Ceramide did not directly
      inhibit PKCalpha in vitro or modulate the levels of PKCalpha protein, suggesting
      that ceramide acted indirectly. Moreover, ceramide did not inhibit PMA-induced
      translocation of PKCalpha. Taken together, these results suggested that ceramide
      caused inactivation of PKCalpha. Since PKC requires phosphorylation for activity,
      we determined the effects of ceramide on phosphorylation of PKCalpha. C6-ceramide
      inhibited basal and PMA-induced phosphorylation of PKCalpha. In addition, okadaic
      acid, a potent phosphatase inhibitor, slightly stimulated PKC activity and
      blocked the effects of ceramide on PKCalpha inhibition. These results demonstrate
      that ceramide causes inhibition/inactivation of PKCalpha and suggest these
      effects of ceramide may be mediated by a protein phosphatase.

PMID- 8662782
TI  - Role of MacMARCKS in integrin-dependent macrophage spreading and tyrosine
      phosphorylation of paxillin.
AB  - The cellular function of the MARCKS family of protein kinase C substrates is
      unknown. In this report, we present evidence that indicates a role for MacMARCKS,
      a member of the MARCKS family, in the integrin-dependent signal transduction
      pathways in macrophages. Using a dominant negative mutant of MacMARCKS, we showed
      that MacMARCKS participates in several integrin-dependent macrophage functions,
      including the phorbol ester-stimulated macrophage spreading, a process involving
      multiple integrins. The dominant negative mutant also blocks macrophage spreading
      on immune complex-coated surfaces, a process again requiring beta2 integrin. More
      direct evidence of the role of MacMARCKS in the integrin-dependent pathway is the
      ablation of macrophage binding to complement iC3b-coated sheep erythrocytes by
      MacMARCKS mutant, suggesting an effect of this mutant on the avidity of
      complement receptor 3, a member of the beta2 integrin family. To further evaluate
      the possible mechanism of MacMARCKS function, the integrin-dependent tyrosine
      phosphorylation of paxillin was examined. Concomitant with the inhibition of
      macrophage spreading and rosette formation, MacMARCKS mutant also inhibits
      integrin-dependent tyrosine phosphorylation of paxillin. Furthermore,
      immunofluorescent microscopy data showed that MacMARCKS and paxillin colocalize
      in the membrane ruffles at the leading edge of the spreading cells, providing a
      potential site and opportunity for MacMARCKS to participate in the regulation of
      integrin-dependent tyrosine phosphorylation of paxillin. Together, these data
      strongly suggest that MacMARCKS plays a role in integrin-dependent signal
      transduction pathways in macrophages.

PMID- 8662783
TI  - The bradykinin B2 receptor is a delayed early response gene for platelet-derived
      growth factor in arterial smooth muscle cells.
AB  - Bradykinin and platelet-derived growth factor (PDGF) are inflammatory mediators
      important in the response to vascular injury. Based upon the known effect of
      oncogenic Ras to increase bradykinin receptor expression and the ability of PDGF
      to stimulate Ras, we examined whether PDGF regulates bradykinin B2 receptor
      expression in cultured arterial smooth muscle cells. Treatment with PDGF (AB and
      BB, but not AA) produced a dose- and time-dependent increase in both mRNA (6-7
      fold increase at 2-4 h) and cell surface receptors (2-4-fold at 6-12 h) for the
      B2 receptor. There was a 60-min delay between exposure to PDGF and the initial
      increase in B2 receptor mRNA. Transcriptional inhibitors, actinomycin D or 5, 6
      dichloro-1-beta-D-ribofuranosylbenzimidazole, completely blocked the increase in
      B2 receptor mRNA when added up to 60 min after stimulation with PDGF. However,
      protein synthesis was not required, as treatment with cycloheximide did not block
      but rather superinduced the PDGF-induced increase in B2 receptor mRNA. Comparison
      with the immediate early response gene c-fos demonstrated that the increase in B2
      receptor mRNA was similarly inhibited by the tyrosine kinase inhibitor,
      tyrphostin, as well as staurosporine. However, stimulation of c-fos was slightly
      more sensitive to genistein, while the B2 receptor mRNA was more sensitive to
      inhibition by the protein kinase C inhibitor, calphostin C. The increase in cell
      surface B2 receptors were functionally coupled to an increase in phosphoinositide
      specific phospholipase C, and the effects of PDGF were selective as there was no
      increase in either angiotensin II- or arginine vasopressin-induced inositol
      phosphate formation or intracellular calcium release. Taken together, these
      results demonstrate that the B2 receptor is a delayed early response gene for
      PDGF in vascular smooth muscle cells.

PMID- 8662784
TI  - Chimeric mutagenesis of putative G-protein coupling domains of the alpha2A
      adrenergic receptor. Localization of two redundant and fully competent gi
      coupling domains.
AB  - We have investigated potential Gi and Gs coupling domains within the
      intracellular regions of the alpha2AAR subtype using a series of nine chimeric
      mutations. The second intracellular loop (ICL2, amino acids 133-149) and the
      amino- and carboxyl-terminal regions of the third intracellular loop (ICL3, amino
      acids 218-235 and 355-371, respectively) of the cloned human alpha2AAR were
      substituted with the analogous sequence from either the Gs-coupled beta2AR or the
      Gi-coupled serotonin type 1A receptor (5-HT1AR). Mutant and wild type alpha2AAR
      were stably expressed in Chinese hamster ovary cells and functional coupling of
      each receptor to Gi and Gs was assessed in membrane adenylyl cyclase assays.
      Substitution of 5-HT1AR sequence into ICL2 ablated coupling to Gs but not to Gi,
      whereas substitution of beta2AR sequence significantly depressed coupling to Gi
      but not to Gs. Thus, the ICL2 of the alpha2AAR contains elements essential for
      both signaling pathways. Substitution of either the amino- or carboxyl-terminal
      segments of ICL3 with 5-HT1AR sequence ablated agonist stimulation of adenylyl
      cyclase activity (without affecting inhibition), suggesting that both domains are
      necessary for alpha2AAR coupling to Gs. In contrast, individual substitution of
      beta2AR sequence into ICL3 amino or carboxyl termini had no appreciable effect on
      Gi coupling. Concomitant substitution of beta2AR sequence into both regions
      substantially impaired Gi coupling, implying that each is capable of
      independently supporting functional coupling. Substitution of 5-HT1AR at either
      locus had no effect on Gi coupling. Thus, for Gs coupling, these two domains
      within ICL3 are both required for functional coupling. However, for Gi coupling,
      the alpha2AAR appears to have two distinct regions within ICL3 that are capable
      of supporting Gi coupling independently. There has been no previous elucidation
      of a receptor having redundant, fully competent domains for coupling to a single
      class of G-protein. Such duplicity of functional domains within alpha2AR may
      suggest strong evolutionary pressure to maintain Gi coupling.

PMID- 8662785
TI  - Reconstitution of the steroid receptor.hsp90 heterocomplex assembly system of
      rabbit reticulocyte lysate.
AB  - Rabbit reticulocyte lysate contains a multiprotein system that assembles steroid
      receptors into a heterocomplex with hsp90. In the case of the glucocorticoid
      receptor (GR), the receptor must be bound to hsp90 to bind steroid, and assembly
      of the GR.hsp90 complex restores the hormone binding domain of the receptor to
      the steroid binding conformation. Using both direct assay of heterocomplex
      assembly by Western blotting and indirect assay of assembly by steroid binding,
      it has previously been determined that the assembly system is both ATP/Mg2+
      dependent and K+-dependent and that hsp70 and an acidic 23-kDa protein (p23) are
      required to form a functional GR.hsp90 complex. It is also thought that a 60-kDa
      protein (p60) may be required for progesterone receptor.hsp90 heterocomplex
      assembly, but a complete heterocomplex assembly system has never been
      reconstituted from individual components. In this work, we separate the proteins
      of rabbit reticulocyte lysate into three fractions by DEAE chromatography and
      then reconstitute the GR.hsp90 heterocomplex assembly system in a manner that
      requires the presence of each fraction. Fraction A contains most of the hsp70 and
      all of the p60 in lysate, and elimination of p60 by immunoadsorption inactivates
      this fraction, with bioactivity being restored by the addition of bacterially
      expressed human p60. The activity of fraction A is replaced by a combination of
      highly purified rabbit hsp70 and lysate from p60-expressing bacteria. Fraction B
      contains hsp90, and its activity is replaced by purified rabbit hsp90. Fraction C
      contains p23, and its activity is replaced in the recombined system by highly
      purified bacterially expressed human p23. A minimal GR.hsp90 heterocomplex
      assembly system was reconstituted with purified rabbit hsp70 and hsp90 and
      bacterially expressed human p23 and p60. This reports the first reconstitution of
      this apparently ubiquitous protein folding/heterocomplex assembly system.

PMID- 8662786
TI  - Oct-4 regulates alternative platelet-derived growth factor alpha receptor gene
      promoter in human embryonal carcinoma cells.
AB  - Expression of the platelet-derived growth factor alpha-receptor (PDGFalphaR) gene
      is tightly controlled in mammalian embryogenesis. A well established model system
      to study human embryogenesis is the embryonal carcinoma cell line Tera2. We have
      shown previously that retinoic acid-differentiated Tera2 cells express two
      PDGFalphaR transcripts of 6.4 kilobase pairs (kb) (encoding the full-length
      receptor) and 3.0 kb, respectively, whereas in contrast, undifferentiated Tera2
      cells express PDFGalphaR transcripts of 1.5 kb and 5.0 kb. Here we show that this
      switch in PDGFalphaR expression pattern during differentiation of Tera2 cells
      results from alternative promoter use. In undifferentiated cells, a second
      promoter is used, which is located in intron 12 of the PDGFalphaR gene.
      Functional analysis shows that this promoter contains a consensus octamer motif,
      which can be bound by the POU domain transcription factor Oct-4. Oct-4 is
      expressed in undifferentiated Tera2 cells but not in retinoic acid-induced
      differentiated cells. Mutation of the octamer motif decreases promoter activity,
      while ectopic expression of Oct-4 in differentiated Tera2 cells specifically
      enhances the activity of this PDGFalphaR promoter. Therefore, we suggest that an
      important aspect in the maintenance of the undifferentiated state of human
      embryonal carcinoma cells results from Oct-4 expression, which thereupon
      activates this PDGFalphaR promoter.

PMID- 8662788
TI  - S6 kinase p90rsk in granulocyte-macrophage colony-stimulating factor-stimulated
      proliferative and mature hematopoietic cells.
AB  - The ribosomal S6 kinase p90(rsk) was studied in mature and proliferating
      hemopoietic cells in response to the human cytokine granulocyte-macrophage colony
      stimulating factor (GM-CSF). In neutrophils, GM-CSF induced time-dependent
      electrophoretic mobility shifts in immunoreactive p90(rsk). Although these shifts
      suggested changes in the phosphorylation status of the molecule, a kinase assay
      with whole cell lysates detected minimal (1.5-fold) increments in enzymatic
      activity. Only immunoprecipitation followed by immune complex kinase assay or in
      gel kinase assay performed against the RSK substrate RRLSSLRA evidenced an
      increase in p90(rsk) activity (3.4-fold). p90(rsk) was also detected in the GM
      CSF-dependent erythroleukemia cell line TF-1. Normally cultured, cytokine
      supplemented cells did not respond to further GM-CSF stimulation. However, the
      activity of p90(rsk) in cytokine-starved cells increased dramatically in response
      to short term GM-CSF challenge. This effect was readily observable in total cell
      lysates (6.6-fold increase over controls) and was paralleled by changes in
      mitogen-activated protein kinase activity (a substrate of p90(rsk)). Thus,
      p90(rsk) is present in mature hemopoietic cells, but the extent of the enzymatic
      response to GM-CSF is significantly lower than that seen in proliferative cells.

PMID- 8662787
TI  - Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and
      glutathione S-transferase gene expression.
AB  - Transcription factors AP-1 and NF-kappaB have been implicated in the inducible
      expression of a variety of genes in response to oxidative stress. Recently, based
      on the observation that butylated hydroxyanisole (BHA) and pyrrolidine
      dithiocarbamate (PDTC) induce AP-1 binding activity and AP-1-dependent gene
      expression and assuming that these compounds exert an antioxidant effect, it was
      claimed that AP-1 is an antioxidant-responsive factor. To determine whether AP-1
      can be responsive to both oxidant and antioxidant, we examined the nature of BHA
      and PDTC inducing activity. Using EPR spectroscopy to detect semiquinone
      radicals, we demonstrate the autoxidation of BHA metabolite tert
      butylhydroquinone (TBHQ) to tert-butylquinone. The kinetics of TBHQ-mediated
      generation of .OH radicals were monitored in intact hepatoma HepG2 cells by EPR
      spin trapping technique. Exogenous catalase inhibited the rate and amount of .OH
      radical formation and the induction of AP-1-mediated glutathione S-transferase
      (GST) Ya gene expression by BHA and TBHQ, thus indicating the intermediate
      formation of H2O2 in the metabolism of these chemicals. Furthermore, we show that
      the induction of AP-1 and NF-kappaB activities and GST Ya gene expression by BHA
      and TBHQ is due to a pro-oxidant activity, since this induction was inhibited by
      thiol compounds N-acetyl cysteine and GSH. Similarly, induction of AP-1 and GST
      Ya gene expression by PDTC was inhibited by N-acetyl cysteine and GSH. The
      present findings do not support the notion that the induction of AP-1 by BHA,
      TBHQ, or PDTC is an antioxidant response and demonstrate that both AP-1 and NF
      kappaB activities are induced by oxygen radicals.

PMID- 8662789
TI  - The yeast homolog of mammalian ribosomal protein S30 is expressed from a
      duplicated gene without a ubiquitin-like protein fusion sequence. Evolutionary
      implications.
AB  - In mammals, the 59-residue ribosomal protein S30 (rpS30) is synthesized as a
      fusion to a 74-residue ubiquitin-like protein, which is cleaved to yield mature
      rpS30. An artificial fusion of this ubiquitin-like protein to E. coli beta
      galactosidase was not cleaved when expressed in yeast (Saccharomyces cerevisiae),
      indicating that yeast lack this cleaving activity. The yeast rpS30 homolog
      (yrpS30) was purified and sequenced to reveal a 63-residue protein with 61%
      sequence identity to mammalian rpS30. Degenerate oligonucleotides based on the
      yrpS30 sequence were used to isolate full-length yrpS30 cDNAs. Sequence analysis
      of five cDNA clones revealed that yrpS30 is not synthesized as a fusion to a
      ubiquitin-like protein but is extended at its N terminus by a single methionine
      residue. The corresponding gene was identified in the GenBankTM data base by
      sequence alignment and termed RPS30A. The gene consists of two exons separated by
      a 430-base pair intron, which contains consensus splicing elements. Exon 1
      encodes the initiator methionine residue and is preceded by canonical yeast
      ribosomal protein gene promoter elements. Exon 2 encodes the 62-residue mature
      yrpS30. Genomic hybridization reveals that the RPS30A gene is duplicated.
      Disruption of the RPS30A gene is not lethal but confers a slow growth phenotype.
      Ribosomes in the mutant strains contain an authentic yrpS30 protein, indicating
      that a functional yrpS30 is expressed from the duplicated gene but that the
      reduced capacity for yrpS30 synthesis restricted the growth rate. Analysis of
      available DNA sequence data bases reveals that rpS30 is synthesized as a fusion
      to a ubiquitin-like protein in nematodes and mammals but unfused in yeast,
      plants, and protazoa.

PMID- 8662790
TI  - cAMP-mediated growth inhibition in fibroblasts is not mediated via mitogen
      activated protein (MAP) kinase (ERK) inhibition. cAMP-dependent protein kinase
      induces a temporal shift in growth factor-stimulated MAP kinases.
AB  - Growth factors stimulate fibroblast cell division by activating the recently
      identified mitogen-activated protein kinase (MAP kinase) signaling cascade. In
      contrast to our previous work (Kahan, K., Seuwen, K., Meloche, S. and Pouyssegur,
      J. (1992) J. Biol. Chem. 267, 13369-13375), several reports have suggested that
      an elevation in intracellular cAMP blocks cell proliferation by attenuating MAP
      kinase activation. Hence we re-examined the effect of a long term increase in
      intracellular cAMP and therefore cAMP-dependent protein kinase (PKA) activation
      on the MAP kinase cascade in CCL39 fibroblasts. The concomitant addition of cAMP
      elevating agents prostaglandin E, (PGE1) and IBMX did not inhibit the mitogen
      mediated activation of p44 MAP kinase. However, a 5-min PGE1/IBMX pretreatment
      abolished the MAP kinase response, in a manner correlating with the extent of PKA
      activity. This inhibition was temporal in nature, and while modifying the time
      course of growth factor-mediated p44 MAP kinase, activation did not diminish the
      magnitude of the response. Thus the major peak of MAP kinase activity normally
      present 5 min after alpha-thrombin addition was now evident at 10 min in the
      presence of PGE1/IBMX. CCL39 cell proliferation is inhibited by elevated cAMP
      levels. Such an inhibition could reflect either a reduction in the number of
      cells entering the cell cycle or a delay in the time required to go through the
      cycle. Bromodeoxyuridine labeling experiments revealed that the cAMP-mediated
      inhibition of DNA synthesis in CCL39 cells was not due to a delay in S phase
      entry, but was due to a reduction in the number of cells entering S phase. Thus
      we conclude that although PKA activation may slightly modify the time course of
      MAP kinase activation in response to mitogens in CCL39 cells, the PKA-mediated
      inhibition of cell division occurs through modulation of an intracellular target,
      distinct from the p42/p44 MAP kinase cascade.

PMID- 8662791
TI  - Phagocytosed live Listeria monocytogenes influences Rab5-regulated in vitro
      phagosome-endosome fusion.
AB  - Survival or destruction of a pathogen following phagocytosis depends, in part, on
      fusion events between the phagosome and the endosomal or lysosomal compartments.
      Here we use an in vitro assay to show that phagosome-endosome fusion is regulated
      by the small GTPase rab5 and that fusion events are influenced by an internalized
      live organism, Listeria monocytogenes (LM). We compare the in vitro fusion of
      phagosomes containing heat-killed organisms (dead LM) with that of phagosomes
      containing a live nonhemolytic mutant (live LMhly-). Unlike the wild-type
      organism, LMhly- remains trapped inside the phagosome. Phagosome-endosome fusion
      was reconstituted using biotinylated organisms and endosomes containing
      horseradish peroxidase conjugated with avidin. With both live LMhly- and dead LM
      preparations, in vitro phagosome-endosome fusion was time-, temperature-, and
      cytosol-dependent. Live LMhly- phagosomes exhibited a faster rate of fusion.
      Fusion in both preparations was regulated by rab5 and possibly by other GTPases.
      Anti-rab5 antibodies and immunodepletion of cytosolic rab5 inhibited fusion.
      Addition of glutatione S-transferase-rab5 in the GTP form stimulated phagosome
      endosome fusion, whereas addition of a dominant negative mutant of rab5 blocked
      fusion. Purified live LMhly- phagosomal membranes were enriched in rab5 as
      revealed by Western blotting, compared with dead LM phagosomes. Fusion of
      endosomes with dead LM containing phagosomes required ATP and was inhibited by
      ATP depletion and by N-ethylmaleimide (NEM) and anti-NEM-sensitive factor (NSF)
      antibodies. Unexpectedly, phagosome-endosome fusion with live LMhly--containing
      phagosomes was not inhibited by ATP depletion nor by NEM or anti-NSF antibodies.
      Western blot analysis revealed that live LMhly--containing phagosomes were
      enriched for membrane-bound NSF, while dead LM containing phagosomes contained
      low or undetectable quantities. Washing live LMhly--containing phagosomes with
      0.5 M KCl removed NSF associated with the membranes and rendered them NEM, ATP,
      anti-NSF antibody sensitive for fusion. We conclude that rab5 regulates phagosome
      endosome fusion and that live microorganisms can up-regulate this process by
      recruiting rab5 to the membrane.

PMID- 8662792
TI  - Differential phosphorylation of the T lymphocyte costimulatory receptor CD28.
      Activation-dependent changes and regulation by protein kinase C.
AB  - Treatment of T lymphocytes with phorbol ester and anti-CD28 monoclonal antibody
      (mAb) can induce proliferation and interleukin 2 production by triggering still
      undefined intracellular signaling pathways. We have developed a deglycosylation
      procedure that allows the precise identification of a distinct CD28 protein band,
      facilitating the analysis of activation-dependent changes in the phosphorylation
      state of CD28. Phorbol 12-myristate 13-acetate (PMA) treatment induced the in
      vitro phosphorylation of CD28 on threonine as detected in immune complex kinase
      assays. This effect of PMA was (i) rapid, preceding a PMA-induced increase in
      CD28 surface expression; (ii) occurred using kinase buffer containing either
      manganese or magnesium; and (iii) was found in human peripheral T cells, Jurkat T
      cells, and in a Jurkat subclone, J.Cam1, that is deficient in Lck tyrosine kinase
      activity. In contrast, anti-CD28 monoclonal antibody stimulation led to in vitro
      phosphorylation of CD28 on tyrosine that was manganese-dependent and required Lck
      tyrosine kinase activity, as it was undetectable in J.Cam1 cells. Importantly,
      CD28 was phosphorylated on tyrosine in vivo as detected with anti-phosphotyrosine
      antibodies after stimulation with anti-CD28 monoclonal antibody. The in vivo
      tyrosine phosphorylation of CD28 was inhibited by PMA treatment and was absent in
      J.Cam1 cells. Thus, the CD28 coreceptor can trigger different intracellular
      signaling pathways, depending upon the nature of the initial costimulatory
      signal.

PMID- 8662793
TI  - Purification, characterization, and cDNA cloning of a novel growth factor from
      the conditioned medium of NIH-Sape-4, an embryonic cell line of Sarcophaga
      peregrina (flesh fly).
AB  - A growth factor from the conditioned medium of NIH-Sape-4, an embryonic cell line
      of the flesh fly, was purified to homogeneity. This growth factor, termed IDGF,
      stimulated the proliferation of NIH-Sape-4 cells in an autocrine manner; it was a
      homodimer of a protein with a molecular mass of 52 kDa, and its specific activity
      was comparable with those of mammalian growth factors. Immunoblotting experiments
      revealed that unfertilized mature eggs of the flesh fly contained this growth
      factor, a certain level of which was maintained throughout embryonic development.
      Analysis of cDNA for this growth factor showed that this factor is a novel
      protein consisting of 553 amino acid residues. No significant sequence similarity
      was found between this factor and other proteins except atrial gland granule
      specific antigen of Aplysia californica.

PMID- 8662794
TI  - Alzheimer's disease betaA4 protein release and amyloid precursor protein sorting
      are regulated by alternative splicing.
AB  - We show here that alternative splicing influences the polarized secretion of
      amyloid precursor protein (APP) as well as the release of its proteolytic 3-4-kDa
      fragments betaA4 and p3. In Madin-Darby canine kidney II cells stably transfected
      with various APP isoforms and APP mutants, APPsec was consistently secreted
      basolaterally. In contrast, Madin-Darby canine kidney II cells transfected with L
      APP677, which occurs naturally by alternative splicing of exon 15, secreted this
      isoform both apically and basolaterally, while maintaining the basolateral
      sorting of endogenous APPsec. This suggests that the alternative splicing of APP
      exon 15 modulates the polarized sorting of secretory APP. The same alternative
      splicing event also decreased the production of betaA4 relative to p3. This is
      the first example of alternative splicing regulating polarized trafficking of a
      secretory protein.

PMID- 8662795
TI  - Differential activation of acute phase response factor/Stat3 and Stat1 via the
      cytoplasmic domain of the interleukin 6 signal transducer gp130. II. Src homology
      SH2 domains define the specificity of stat factor activation.
AB  - Distinct yet overlapping sets of STAT transcription factors are activated by
      different cytokines. One example is the differential activation of acute phase
      response factor (APRF, also called Stat3) and Stat1 by interleukin 6 and
      interferon-gamma. Interleukin 6 activates both factors while, at least in human
      cells, interferon-gamma recruits only Stat1. Stat1 activation by interferon-gamma
      is mediated through a cytosolic tyrosine motif, Y440, of the interferon-gamma
      receptor. In an accompanying paper (Gerhartz, C., Heesel, B., Sasse, J., Hemmann,
      U., Landgraf, C., Schneider-Mergener, J., Horn, F., Heinrich, P. C., and Graeve,
      L. (1996) J. Biol. Chem. 271, 12991-12998), we demonstrated that two tyrosine
      motifs within the cytoplasmic part of the interleukin 6 signal transducer gp130
      specifically mediate APRF activation while two others can recruit both APRF and
      Stat1. By expressing a series of Stat1/APRF domain swap mutants in COS-7 cells,
      we now determined which domains of Stat1 and APRF are involved in the specific
      recognition of phosphotyrosine motifs. Our data demonstrate that the SH2 domain
      is the sole determinant of specific STAT factor recruitment. Furthermore, the SH2
      domain of Stat1 is able to recognize two unrelated types of phosphotyrosine
      motifs, one represented by the interferon-gamma receptor Y440DKPH peptide, and
      the other by two gp130 YXPQ motifs. By molecular modeling, we propose three
      dimensional model structures of the Stat1 and APRF SH2 domains which allow us to
      explain the different binding preferences of these factors and to predict amino
      acids crucial for specific peptide recognition.

PMID- 8662796
TI  - Ligand-independent activation of transforming growth factor (TGF) beta signaling
      pathways by heteromeric cytoplasmic domains of TGF-beta receptors.
AB  - Transforming growth factor beta (TGF-beta) transduces signals through two related
      serine/threonine kinase receptors, the type I and type II receptors, which have
      the ability to interact with each other. In the heteromeric complex, the type II
      receptor is the primary determinant of ligand binding and phosphorylates the
      cytoplasmic domain of the type I receptor. Using a chimeric receptor strategy, we
      and others have shown previously that a functional TGF-beta receptor complex
      requires heteromerization of both extracellular and intracellular domains of type
      I and type II receptors. In the current study, we show that overexpression of two
      receptors carrying a heteromeric combination of cytoplasmic domains resulted in
      ligand-independent responses, further supporting the functional requirement of
      the two heterologous cytoplasmic domains in TGF-beta signaling. Furthermore,
      coexpression of only the cytoplasmic domains of both the type I and II receptors
      or tethering the type II to the type I cytoplasmic domain activated TGF-beta
      responses in a ligand-independent manner. In cotransfected COS-1 cells, both
      cytoplasmic domains are associated with each other. Our results indicate that the
      cytoplasmic domains of the type I and type II TGF-beta receptors physically and
      functionally interact with each other in the heteromeric complex.

PMID- 8662797
TI  - Ubiquitinylation and ubiquitin-dependent proteolysis in vertebrate photoreceptors
      (rod outer segments). Evidence for ubiquitinylation of Gt and rhodopsin.
AB  - In corroboration of the hypothesized regulation of phototransduction proteins by
      the ubiquitin-dependent pathway, we identified free ubiquitin (8 kDa) and
      ubiquitin-protein conjugates (50 to >200 kDa; pI 5.3-6.8 by two-dimensional
      electrophoresis) in bovine rod outer segments (ROS). A 38-kDa ubiquitinylated
      protein and transducin (Gt) were eluted together from light-adapted ROS membranes
      with GTP. When ROS were dark-adapted, this 38-kDa ubiquitinylated species and Gt
      were readily solubilized in buffer lacking GTP. These data are consistent with
      ubiquitinylation of Gt and corroborate previous cell-free experiments identifying
      Gt as a substrate for ubiquitin-dependent proteolysis (Obin, M. S., Nowell, T.,
      and Taylor, A. (1994) Biochem. Biophys. Res. Commun. 200, 1169-1176). Evidence
      for ubiquitinylation of rhodopsin (36 kDa), the (photo)receptor coupled to Gt,
      included (i) the presence in ROS membranes "stripped" of peripheral membrane
      proteins of numerous ubiquitin-protein conjugates, including two whose masses (44
      and 50 kDa) are consistent with mono- and diubiquitinylated rhodopsin; (ii)
      catalysis by permeabilized ROS of 125I-labeled ubiquitin-protein conjugates whose
      masses (42, 50, and 58 kDa) suggest a "ladder" of mono-, di-, and
      triubiquitinylated rhodopsin; (iii) parallel mobility shifts on SDS
      polyacrylamide gels of rhodopsin and these 125I-labeled ubiquitin-protein
      conjugates; and (iv) generation of enhanced levels of 125I-labeled ubiquitin
      protein conjugates when stripped, detergent-solubilized ROS membranes (95%
      rhodopsin) were incubated with reticulocyte lysate. A functional ubiquitin
      dependent pathway in ROS is demonstrated by the presence of (i) the ubiquitin
      activating enzyme (E1); (ii) four ubiquitin carrier proteins (E214K, E220K,
      E225K, and E235K) and pronounced activity of E214K, an enzyme required for "N-end
      rule" proteolysis; (iii) ATP-dependent 26 S proteasome activity that rapidly
      degrades high mass 125I-labeled ubiquitin-ROS protein conjugates; and (iv)
      distinct ubiquitin C-terminal isopeptidase/hydrolase activities, including potent
      ubiquitin-aldehyde-insensitive activity directed at high mass ubiquitinylated
      moieties. Considered together, the data support a novel role for the ubiquitin
      dependent pathway in the regulation of mammalian phototransduction protein levels
      and/or activities and provide the first identification of a non-calpain
      proteolytic system in photoreceptors.

PMID- 8662798
TI  - Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF/scatter factor
      variant with partial agonist/antagonist activity.
AB  - Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proliferation,
      motility, and morphogenesis by activation of its receptor, the c-Met tyrosine
      kinase. HGF/SF is structurally related to plasminogen, including an amino
      terminal hairpin loop, four kringle domains, and a serine protease-like region. A
      truncated HGF/SF isoform, designated HGF/NK2, which extends through the second
      kringle domain and behaves as a competitive HGF/SF antagonist, was previously
      shown to be encoded by an alternative HGF/SF transcript. In this study, we
      describe a second naturally occurring HGF/SF variant, HGF/NK1, consisting of the
      HGF/SF amino-terminal sequence and first kringle domain. This product is encoded
      by a 2-kilobase alternative transcript containing intronic sequence that was
      contiguous with exon K1b. Analysis of baculovirus-expressed HGF/NK1 revealed that
      this isoform possesses the heparin binding properties of HGF/SF and modest
      mitogenic and scattering activity relative to HGF/SF. However, at a 40-fold molar
      excess, HGF/NK1 inhibited HGF/SF-dependent DNA synthesis. HGF/NK1 stimulated
      tyrosine phosphorylation of Met, and covalent affinity cross-linking demonstrated
      a direct HGF/NK1-receptor interaction. These findings establish that the HGF/SF
      gene encodes multiple alternative products, which include not only a mitogenic
      agonist (HGF/SF) and a pure antagonist (HGF/NK2) but also a molecule with partial
      agonist/antagonist properties.

PMID- 8662799
TI  - Inhibition of NAD+ glycohydrolase and ADP-ribosyl cyclase activities of leukocyte
      cell surface antigen CD38 by gangliosides.
AB  - We have recently reported that gangliosides act as inhibitors of ADP
      ribosyltransferases and NAD+ glycohydrolases (NADase) of pertussis toxin and the
      C3 exoenzyme from Clostridium botulinum (Hara-Yokoyama, M., Hirabayashi, Y.,
      Irie, F., Syuto, B., Moriishi, K., Sugiya, H., and Furuyama, S. (1995) J. Biol.
      Chem. 270, 8115-8121). Here, we investigated the effect of gangliosides on the
      enzymatic activity of leukocyte cell surface antigen CD38, which is identified as
      an ecto-NADase (Kontani, K., Nishina, H., Ohoka, Y., Takahashi, K., and Katada,
      T. (1993) J. Biol. Chem. 268, 16895-16898). Gangliosides GM1a and GQ1balpha
      inhibited the NADase activity in the immunoprecipitate of anti-CD38 antibody from
      the membrane extract of retinoic acid-treated human leukemic HL-60 cells.
      Gangliosides also inhibited the NADase activity of the extracellular domain of
      CD38 antigen that was deprived of the transmembrane domain and was expressed in
      Escherichia coli as a fusion protein with maltose-binding protein (MBP-CD38). The
      order of the inhibitory effect of purified ganglioside species on the NADase
      activity on MBP-CD38 was as follows: GQ1balpha > GT1b, GQ1b > GD1a, GD1b, GM1a,
      GM1b, GD3, GM3. GQ1balpha inhibited the NADase of MBP-CD38 in a noncompetitive
      manner versus NAD+ with a Ki value of about 0.3 microM. Neither ceramide nor the
      oligosaccharide moiety of GQ1balpha had an effect on the NADase activity.
      GQ1balpha, GT1b, and GQ1b also efficiently inhibited the ADP-ribosyl cyclase
      activity of MBP-CD38. At present, gangliosides are the only endogenous species
      that can block the enzymatic activity of CD38 antigen. The present results
      suggest a potential role of gangliosides as inhibitors of the ecto-NADases.

PMID- 8662800
TI  - Liganded and unliganded receptors interact with equal affinity with the membrane
      complex of periplasmic permeases, a subfamily of traffic ATPases.
AB  - The histidine-binding protein, HisJ, is the soluble receptor for the periplasmic
      histidine permease of Salmonella typhimurium. The receptor binds the substrate in
      the periplasm, interacts with the membrane-bound complex, transmits a
      transmembrane signal to hydrolyze ATP, and releases the ligand for translocation.
      HisJ, like other periplasmic receptors, has two lobes that are apart in the
      unliganded structure (open conformation) and drawn close together in the liganded
      structure (closed conformation), burying deeply the ligand. Such receptors are
      postulated to interact with the membrane-bound complex with high affinity in
      their liganded conformation, and, upon substrate translocation, to undergo a
      reduction in affinity and therefore be released. Here we show that in contrast to
      the current postulate, liganded and unliganded receptors have equal affinity for
      the membrane-bound complex. The affinity is measured both by chemical cross
      linking and co-sedimentation procedures. An ATPase activity assay is also used to
      demonstrate the interaction of unliganded receptor with the membrane-bound
      complex. These findings support a new model for the transport mechanism, in which
      the soluble receptor functions independently of the commonly accepted high-low
      affinity switch.

PMID- 8662801
TI  - Differential responsiveness of a splice variant of the human type I interferon
      receptor to interferons.
AB  - Chinese hamster ovary cells containing the yeast artificial chromosome F136C5
      (alphaYAC) respond to all type I human interferons including IFN-alphaA, IFN
      beta, and IFN-omega. The alphaYAC contains at least two genes encoding interferon
      alpha receptor (IFN-alphaR) chains that are required for response to type I human
      interferons: Hu-IFN-alphaR1 and Hu-IFN-alphaR2. We previously isolated a splice
      variant of the Hu-IFN-alphaR1 chain designated Hu-IFN-alphaR1s. Chinese hamster
      ovary cells containing a disrupted alphaYAC, which contains a deletion in the
      human IFNAR1 gene, were transfected with expression vectors for the Hu-IFN
      alphaR1 and Hu-IFN-alphaR1s chains. With these cells, two type I interferons have
      been identified which can interact with the splice variant (Hu-IFN-alphaR1s) and
      with the Hu-IFN-alphaR1 chains: Hu-IFN-alphaA and IFN-omega. Two other type I
      interferons, Hu-IFN-alphaB2 and Hu-IFN-alphaF, are capable of signaling through
      the Hu-IFN-alphaR1 chain only and cannot utilize the splice variant Hu-IFN
      alphaR1s. Hu-IFN-alphaR1 and Hu-IFN-alphaR1s differ in that the latter is missing
      a single subdomain of the receptor extracellular domain encoded by exons 4 and 5
      of the IFNAR1 gene. These results therefore indicate that different type I
      interferons require different subdomains of the Hu-IFN-alphaR1 receptor chain,
      and that the splice variant chain (Hu-IFN-alphaR1s) is functional.

PMID- 8662802
TI  - Structural analysis of the gene encoding the murine interleukin-11 receptor alpha
      chain and a related locus.
AB  - In this study the gene for the murine interleukin-11 receptor alpha chain (IL
      11Ralpha) has been characterized. The gene spans 9 kilobase pairs of DNA, and the
      organization of its 14 exons conforms to the pattern observed for other members
      of the hematopoietin receptor family. Analysis of the 5' end of the cDNA using 5'
      RACE showed that the first two exons, designated exons 1a and 1b, are spliced to
      form alternate transcripts. Transcripts initiating from exon 1b were not found in
      adult tissues but were present in embryonic stem cells. S1 nuclease and 5' rapid
      amplification of cDNA ends assays demonstrated multiple major and minor sites of
      transcription initiation for each exon. The putative promoter regions of both
      exons lacked TATA boxes, although potential recognition sites for several
      transcription factors including Sp1, AP1, and AP2 were present. A comparison of
      the murine and human IL-11Ralpha revealed that the 5' sequence upstream of the
      major site of transcription initiation site for exon 1b is highly conserved.
      Northern analysis showed that IL-11Ralpha is expressed in many adult murine
      tissues. A second IL-11Ralpha-like locus containing a sequence homologous to
      exons 2-13 was also identified.

PMID- 8662804
TI  - Phosphorylation of Ser211 in the chicken progesterone receptor modulates its
      transcriptional activity.
AB  - The chicken progesterone receptor has been shown to be phosphorylated in vivo at
      four major sites. Previous studies have shown that mutation of one of the hormone
      dependent phosphorylation sites, Ser530, to alanine decreases the transcriptional
      activity of the receptor under conditions where ligand is limited. Here, we
      present evidence for the functional significance of another phosphorylation site,
      Ser211. Mutation of Ser211 to alanine results in a decrease in the
      transcriptional activity of the receptor and affects the phosphorylation
      dependent decrease in mobility of the receptor in SDS-polyacrylamide gel
      electrophoresis. The degree of reduction in transcriptional activity is dependent
      on both the cell type and the reporters used in the studies but is independent of
      hormone concentration, suggesting that phosphorylation at Ser211 regulates the
      activity of the receptor through a mechanism distinct from Ser530
      phosphorylation.

PMID- 8662803
TI  - Aggregation of the FcepsilonRI on mast cells stimulates c-Jun amino-terminal
      kinase activity. A response inhibited by wortmannin.
AB  - Aggregation of the high-affinity Fc receptors for immunoglobulin E (IgE)
      (FcepsilonRI) on the surface of mast cells initiates intracellular signal
      transduction pathways including the tyrosine phosphorylation of cellular
      proteins, phosphoinositide hydrolysis, an increase in intracellular calcium, and
      protein kinase C activation. These signals are believed to be involved in the
      exocytic release of inflammatory mediators such as vasoactive amines, cytokines,
      and lipid metabolites. However, the downstream consequences of these early
      activation events are not well defined. One exception is the activation of the
      extracellular signal-regulated kinases/mitogen-activated protein kinases. One
      member of the mitogen-activated protein kinase superfamily, designated c-Jun
      amino-terminal kinase (JNK), has been recently identified. JNK is activated
      following dual phosphorylation at a Thr-Pro-Tyr motif in response to diverse
      stimuli including tumor necrosis factor-alpha, heat shock, or ultraviolet
      irradiation. We found that JNK was strongly activated by antigen cross-linking in
      a mouse mast cell line passively sensitized with ovalbumin-specific IgE. Anti
      mouse IgE antibody also activated JNK. MEK kinase 1 (MEKK1) which activates the
      JNK activator, JNK kinase (JNKK), was similarly activated by antigen stimulation.
      JNK but not p42(erk2) activation induced by antigen was significantly inhibited
      in the presence of wortmannin, a known inhibitor of phosphatidylinositol 3
      kinase. These results indicate that in response to the aggregation of FcepsilonRI
      on mast cells, phosphatidylinositol 3-kinase activation is involved in the
      stimulation of the MEKK1, JNKK, JNK pathway.

PMID- 8662805
TI  - Exchange of beta- for alpha-tropomyosin in hearts of transgenic mice induces
      changes in thin filament response to Ca2+, strong cross-bridge binding, and
      protein phosphorylation.
AB  - Despite its potential as a key determinant of the functional state of striated
      muscle, the impact of tropomyosin (Tm) isoform switching on mammalian myofilament
      activation and regulation in the intact lattice remains unclear. Using a
      transgenic approach to specifically exchange beta-Tm for the native alpha-Tm in
      mouse hearts, we have been able to uncover novel functions of Tm isoform
      switching in the heart. The myofilaments containing beta-Tm demonstrated an
      increase in the activation of the thin filament by strongly bound cross-bridges,
      an increase in Ca2+ sensitivity of steady state force, and a decrease in the
      rightward shift of the Ca2+-force relation induced by cAMP-dependent
      phosphorylation. Our results are the first to demonstrate the specific effects of
      Tm isoform switching on mammalian thin filament activation in the intact lattice
      and suggest an important role for Tm in modulation of myofilament activity by
      phosphorylation of troponin.

PMID- 8662806
TI  - Interaction of insulin receptor substrate-2 (IRS-2) with the insulin and insulin
      like growth factor I receptors. Evidence for two distinct phosphotyrosine
      dependent interaction domains within IRS-2.
AB  - Insulin receptor substrate 2 (IRS-2) has recently been shown to be a substrate of
      the insulin receptor (IR). In this study we utilize the yeast two-hybrid system
      and assays of in vitro interaction to demonstrate that IRS-2 interacts directly
      with the IR and the insulin-like growth factor I receptor. We show that, like IRS
      1, the region of IRS-2 that contains the putative phosphotyrosine binding and
      SAIN elements (188-591) is sufficient for receptor interaction and that this
      interaction is dependent upon the NPX(p)Y (where (p)Y is phosphotyrosine) motifs
      within the juxtamembrane domains of the receptors. In addition to this amino
      terminal NPX(p)Y-binding domain, an additional domain of strong interaction was
      identified in the central region of IRS-2 and was localized between amino acids
      591 and 733. This interaction was found to be dependent upon receptor
      phosphorylation but was NPX(p)Y-independent. This region does not appear to have
      either an SH2 or a phosphotyrosine binding domain. Both of the interactions could
      also be demonstrated in vitro using IRS-2 glutathione S-transferase fusion
      proteins. We conclude that IRS-2, unlike IRS-1, can interact with tyrosine
      phosphorylated receptors such as the IR and insulin-like growth factor I receptor
      via multiple independent binding motifs. Our findings suggest the existence of a
      previously unidentified phosphotyrosine-dependent binding domain within the
      central region of IRS-2.

PMID- 8662807
TI  - Site-directed mutagenesis of human type X collagen. Expression of alpha1(X) NC1,
      NC2, and helical mutations in vitro and in transfected cells.
AB  - Type X collagen is a short chain collagen expressed in the hypertrophic zone of
      calcifying cartilage during skeletal development and bone growth. The alpha1(X)
      homotrimer consists of three protein domains, a short triple helix (COL1) flanked
      by nonhelical amino-terminal (NC2) and carboxyl-terminal (NC1) domains. While
      mutations of the NC1 domain result in Schmid metaphyseal chondrodysplasia, which
      suggests a critical role for this protein domain, little biochemical detail is
      known about type X collagen synthesis, secretion, and the mechanisms of molecular
      assembly. To study these processes, a range of mutations were produced in human
      alpha1(X) cDNA and the biochemical consequences determined by in vitro
      expression, using T7-driven coupled transcription and translation, and by
      transient transfection of cells. Three NC1 mutants, which were designed to be
      analogous to Schmid mutations (1952delC, 1963del10, and Y598D), were unable to
      assemble into type X collagen homotrimers in vitro, but the mutant chains did not
      associate with, or interfere with, the efficiency of normal chain assembly in co
      translations with a normal construct. Expression in transiently transfected cells
      confirmed that mutant type X collagen assembly was also compromised in vivo. The
      mutant chains were not secreted from the cells but did not accumulate
      intracellularly, suggesting that the unassociated mutant chains were rapidly
      degraded. In-frame deletions within the helix (amino acid residues 72-354) and
      the NC2 domain (amino acid residues 21-54) were also produced. In contrast to the
      NC1 mutations, these mutations did not prevent assembly. Mutant homotrimers and
      mutant-normal heterotrimers were formed in vitro, and the mutant homotrimers
      formed in transiently transfected cells had assembled into pepsin-stable triple
      helical molecules which were secreted.

PMID- 8662809
TI  - Suppression of interleukin-1beta-induced nitric-oxide synthase promoter/enhancer
      activity by transforming growth factor-beta1 in vascular smooth muscle cells.
      Evidence for mechanisms other than NF-kappaB.
AB  - Nitric-oxide synthases (NOS) utilize L-arginine to produce NO, a potent
      vasodilator that contributes to the regulation of vascular tone. We demonstrated
      previously that transforming growth factor (TGF)-beta1 down-regulates inducible
      NOS after its induction by interleukin (IL)-1beta by decreasing the rate of
      inducible NOS gene transcription. In the present study we transfected reporter
      plasmids containing various lengths of the inducible NOS 5'-flanking region into
      primary cultured rat aortic smooth muscle cells and stimulated the cells with IL
      1beta or vehicle. IL-1beta increased the activity of the plasmid containing -1485
      to +31 of the inducible NOS gene by more than 10-fold, indicating the presence of
      IL-1beta-responsive elements. Further deletion analysis revealed that a construct
      containing -234 to +31 of the inducible NOS gene contained the majority of
      promoter/enhancer activity after IL-1beta stimulation. Mutation of the NF-kappaB
      site within this region partially reduced IL-1beta-inducible activity; however, a
      large portion of activity remained independent of the NF-kappaB site. TGF-beta1
      suppressed promoter/enhancer activity after IL-1beta stimulation, and this
      suppression was complete in the construct with a mutated NF-kappaB site. In
      addition, TGF-beta1 did not decrease the binding of nuclear proteins to the NF
      kappaB site. These data suggest that the ability of TGF-beta1 to suppress
      inducible NOS promoter/enhancer activity occurs through a site(s) other than the
      NF-kappaB motif in vascular smooth muscle cells.

PMID- 8662808
TI  - Type IX collagen NC1 domain peptides can trimerize in vitro without forming a
      triple helix.
AB  - Synthetic peptides of the three chains of type IX collagen consisting of the
      carboxyl-terminal end of the COL1 domain and the complete NC1 domain were
      characterized by circular dichroism spectroscopy and analyzed for their ability
      to assemble into trimers. In vitro association and oxidation result in disulfide
      linked oligomers as shown by molecular sieve chromatography and SDS
      polyacrylamide electrophoresis. Whereas the individual peptides show a tendency
      to self-associate, when an equimolar amount of the three peptides was oxidized, a
      heterotrimer of the three chains was observed. This heterotrimer is recognized by
      a monoclonal antibody against the disulfide-linked NC1 domain of chicken type IX
      collagen, indicating the correct formation of the disulfide bonds. Circular
      dichroism measurements show that under the association conditions used, a triple
      helix does not form between the chains. These results indicate that these
      peptides contain all the necessary information for chain selection and assembly.

PMID- 8662810
TI  - Opposite effects of myosin subfragment 1 on binding of cardiac troponin and
      tropomyosin to the thin filament.
AB  - To better understand the regulation of striated muscle contraction, the effects
      of myosin subfragment 1 (S-1) on the actin binding of cardiac troponin and
      tropomyosin were investigated. Troponin's affinity for actin-tropomyosin was 4
      fold stronger in the absence than in the presence of myosin S-1. CaCl2 had no
      effect on troponin binding to the thin filament in the presence of myosin S-1.
      The binding curve was weakly cooperative, implying interactions between adjacent
      troponin molecules. Myosin S-1 increased (40-200-fold) the affinity of
      tropomyosin for the thin filament, an effect opposite to the effect of myosin on
      troponin. This effect was highly cooperative and occurred in the presence of ADP
      or in the absence of nucleotide. Myosin altered the effect of ionic conditions on
      tropomyosin-actin binding, consistent with tropomyosin binding to a different
      site on F-actin in the presence of myosin. The results indicate that troponin
      tropomyosin and strongly binding myosin cross-bridges do not compete for an F
      actin binding site. Although repositioning of troponin-tropomyosin on the actin
      filament may be sterically required for tight myosin-actin binding, a myosin
      induced conformational change in actin provides a better explanation for the
      complex effects of myosin on thin filament assembly.

PMID- 8662811
TI  - Differential translocation of protein kinase C epsilon during HeLa cell adhesion
      to a gelatin substratum.
AB  - The spreading of HeLa cells, following attachment to a collagen or gelatin
      substratum, requires the activation of protein kinase C (PKC). Membrane-bound PKC
      was previously shown to be activated during cell attachment and in response to
      the activation of a series of lipid second messengers turned on by the ligation
      of beta1-integrin collagen receptors. HeLa cells express the alpha, gamma,
      epsilon, zeta, lambda, and iota isozymes of PKC as determined by Western blotting
      with specific antibodies. Only PKCepsilon redistributed from the cytosol to the
      membrane during cell adhesion. Most of the PKCepsilon in cells that were in
      suspension was in the cytosolic fraction. During cell attachment to a gelatin
      matrix, all of the PKCepsilon moved out of the cytosol, with most going to the
      membrane fraction. After the cells became fully spread, PKCepsilon began to
      reappear in the cytosol. Translocation of PKCepsilon was not observed during the
      adhesion of cells to culture dishes where cells nonspecifically attach but do not
      spread. The conventional PKCalpha and -gamma isozymes were translocated from the
      cytosol to the membrane only when phorbol ester was present at a concentration
      that increases the rate and extent of cell spreading. Under normal conditions,
      i.e. in the absence of phorbol ester, PKCepsilon appears to be the PKC isozyme
      responsible for the regulation of HeLa cell adhesion to the extracellular matrix.

PMID- 8662812
TI  - Cell surface proteoglycans modulate net synthesis and secretion of macrophage
      apolipoprotein E.
AB  - Using a macrophage cell line that constitutively expresses a human apolipoprotein
      E (apoE) cDNA, we have investigated the post-translational metabolism of
      endogenously produced apoE. Inhibition of lysosomal or cysteine proteases led to
      significant inhibition of apoE degradation but did not increase apoE secretion,
      indicating that cellular degradation is not limiting for apoE secretion in
      macrophages. Treatment of macrophages with inhibitors of proteoglycan synthesis
      (4-methylumbelliferyl-beta-D-xyloside) or sulfation (sodium chlorate) enhanced
      the release of apoE from cells and significantly attenuated the increase in
      secretion produced by incubation with phosphatidylcholine vesicles (PV). These
      observations suggested that a significant fraction of the apoE retained by cells
      (and released by incubation with PV) was associated with proteoglycans. Treatment
      of cells with exogenous heparinase led to a greater than 4-fold increase in apoE
      secretion and similarly attenuated the response to PV, suggesting that apoE was
      trapped in an extracellular proteoglycan matrix. This conclusion was confirmed in
      studies showing that PV could enhance the release of apoE from cells during an
      incubation at 4 degrees C, but this enhanced release was abolished in
      proteoglycan-depleted cells. Incubation with lactoferrin at 4 or 37 degrees C
      produced a similar decrement in cellular apoE, again indicating the existence of
      a cell surface pool of apoE. Pulse-chase studies showed that the apoE trapped in
      the proteoglycan matrix was susceptible to rapid cellular degradation such that
      net synthesis of apoE (secreted plus cell-associated) was increased significantly
      in proteoglycan-depleted cells compared with control cells as early as 45 min
      during a chase period.

PMID- 8662813
TI  - Identification of the extracellular matrix binding sites for insulin-like growth
      factor-binding protein 5.
AB  - Fibroblast extracellular matrix (ECM) contains two forms of insulin-like growth
      factor-binding proteins (IGFBPs), IGFBP-3 and IGFBP-5. These studies were
      undertaken to identify the regions within IGFBP-5 that mediate its binding to
      fibroblast ECM. Synthetic peptides were prepared that were homologous with two
      regions of basic amino acids within IGFBP-5 (Arg201-Arg218 and Ala131-Thr141).
      Increasing concentrations of both peptides competed with IGFBP-5 for binding to
      ECM but the Arg201-Arg218 peptide was more potent. Mutagenesis was used to define
      the effect of substituting for these basic residues on ECM binding. Substitution
      for two peptide B residues K134A and R136A reduced binding by 40%. Substitution
      of a single basic residue within the peptide A region (K211N) reduced binding to
      ECM by 49%. Substitution for K211N, K134A, and R136A reduced binding by 52%. More
      extensive substitutions in the peptide A region, e.g. K211N,R214A,K217A,R218N,
      resulted in a greater (e.g. 88%) decrease. The positional location of basic
      residues appeared to be more important than the total number of substitutions
      since the mutant K202N,K206A,R207A had a 79% reduction in ECM binding. Two basic
      regions of IGFBP-5 contribute to its binding to ECM, but the region containing
      amino acids 201-218 has a greater contribution. ECM binding is mediated by
      charged residues and acts to stabilize IGFBP-5 by protecting it from proteolysis.

PMID- 8662814
TI  - Identification and characterization of a widely expressed form of adenylyl
      cyclase.
AB  - A novel mammalian adenylyl cyclase was identified by reverse transcription
      polymerase chain reaction amplification using degenerate primers based on a
      conserved region of previously described adenylyl cyclases (Premont, R. T. (1994)
      Methods Enzymol. 238, 116-127). The full-length cDNA sequence obtained from mouse
      brain predicts a 1353-amino acid protein possessing a 12-membrane span topology,
      and containing two regions of high similarity with the catalytic domains of
      adenylyl cyclases. Comparison of this novel adenylyl cyclase with the eight
      previously described mammalian enzymes indicates that this type 9 adenylyl
      cyclase sequence is the most divergent, defining a sixth distinct subclass of
      mammalian adenylyl cyclases. The AC9 gene has been localized to human chromosome
      band 16p13.3-13.2. The 8.5-kb mRNA encoding the type 9 adenylyl cyclase is widely
      distributed, being readily detected in all tissues tested, and is found at very
      high levels in skeletal muscle and brain. AC9 mRNA is found throughout rat brain
      but is particularly abundant in hippocampus, cerebellum, and neocortex. An
      antiserum directed against the carboxyl terminus of the type 9 adenylyl cyclase
      detects native and expressed recombinant AC9 protein in tissue and cell
      membranes. Levels of the AC9 protein are highest in mouse brain membranes.
      Characterization of expressed recombinant AC9 reveals that the protein is a
      functional adenylyl cyclase that is stimulated by Mg2+, forskolin, and
      mutationally activated Gsalpha. AC9 activity is not affected by Ca2+/calmodulin
      or by G protein betagamma-subunits. Thus AC9 represents a functional G protein
      regulated adenylyl cyclase found in brain and in most somatic tissues.

PMID- 8662815
TI  - The major vault protein (MVP100) is contained in cholinergic nerve terminals of
      electric ray electric organ.
AB  - A protein of Mr 100,000 (MVP100) is highly enriched in the electromotor system of
      electric rays. Biochemical analysis indicates that MVP100 is contained in the
      cholinergic nerve terminals of Torpedo electric organ as part of a large
      cytosolic complex. On sucrose density gradient centrifugation MVP100 comigrates
      with synaptic vesicles or synaptosomes. It can be partially separated from
      synaptic vesicles by gel filtration or glycerol velocity gradient centrifugation.
      Within the complex MVP100 behaves like a hydrophobic protein and is protected
      against proteolytic attack. MVP100 can be immunodetected by an antibody against
      phosphotyrosine, and it becomes phosphorylated on incubation with [gamma-32P]ATP.
      By screening an electric ray electric lobe cDNA library the primary structure of
      MVP100 was analyzed. MVP100 is highly homologous to the major vault proteins of
      slime mold and rat and to the human lung resistance-related protein. Compared
      with non-neural tissues the expression of MVP100 is highest in brain and enriched
      in the electric lobe that contains the somata of the electromotor neurons.
      Immunoelectron microscopic analysis reveals a close association of MVP100 and
      synaptic vesicles in the nerve terminals of the electric organ.

PMID- 8662816
TI  - Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled
      receptor kinases and protein kinase C.
AB  - The type 1A angiotensin II receptor (AT1A-R), which mediates cardiovascular
      effects of angiotensin II, has been shown to undergo rapid agonist-induced
      desensitization. We investigated the potential role of second messenger-activated
      kinases and G protein-coupled receptor kinases (GRKs) in the regulation of this
      receptor. In 293 cells transfected with the AT1A-R, a 3-min challenge with
      angiotensin II engendered a 46% decrease in subsequent angiotensin II-stimulated
      phosphoinositide hydrolysis in intact cells. This agonist-induced desensitization
      correlated temporally and dose-dependently with the phosphorylation of the
      receptor to a stoichiometry of 1 mol of phosphate/mol of receptor, as assessed by
      immunoprecipitation of receptors from cells metabolically labeled with 32Pi.
      Agonist-induced receptor phosphorylation was reduced by 40-50% by either
      overexpression of a dominant negative K220R mutant GRK2 or treatment of the cells
      with the protein kinase C (PKC) inhibitor staurosporine, in a virtually additive
      fashion. Cellular overexpression of GRK2K220R not only inhibited agonist-induced
      AT1A-R phosphorylation, but also prevented receptor desensitization, as assessed
      by angiotensin II-stimulated GTPase activity in membranes prepared from agonist
      treated and control cells. In contrast, PKC inhibition by staurosporine did not
      affect homologous desensitization of the AT1A-R. Overexpression of GRKs 2, 3, or
      5 significantly augmented the agonist-induced AT1A-R phosphorylation 1.5- to 1.7
      fold (p < 0.001). These findings suggest a role for receptor phosphorylation by
      one or several GRKs in the rapid agonist-induced desensitization of the AT1A-R.

PMID- 8662817
TI  - Conformation of human leukocyte antigen class II molecules. Evidence for
      superdimers and empty molecules on human antigen presenting cells.
AB  - Subpopulations of human leukocyte antigen (HLA) class II molecules were studied
      in antigen presenting cells. We present evidence for double dimers or
      "superdimers" of HLA class II molecules that were stable in an SDS solution at
      room temperature but dissociated when heated to 50 degrees C into 60-kDa
      alphabeta heterodimers. Development of an immunofluorescence assay allowed us to
      quantify the expression of HLA antigens as reflected by the number of bound
      isotype-specific monoclonal antibodies per cell. The total expression of class II
      (DR, DQ, and DP) augmented 6-fold after a 36-h interferon-gamma (IFNgamma)
      treatment of freshly isolated monocytes. Next, we used a recombinant and
      fluorescein-conjugated form of the class II-associated invariant chain as a
      quantitative probe for empty peptide-binding sites. The fraction of empty class
      II molecules was 0.73-2.9% in resting monocytes but was reduced to 0. 12-0.5% of
      the total after IFNgamma treatment. The fraction of empty sites in B lymphocytes
      was 0.09-0.36%. The mean number of empty sites per cell were: 6.3 x 10(3)
      (monocytes), 7.2 x 10(3) (IFNgamma-activated monocytes), 5.2 x 10(2) (B
      lymphocytes), and 3.6 x 10(3) (Raji B cells). A minor population (4.3-7.4% of
      total cells), which expressed a much higher number of empty sites, was
      consistently present in all cell types studied.

PMID- 8662818
TI  - Interaction between the mRNA of the 55-kDa tumor necrosis factor receptor and
      cellular proteins. Possible involvement in post-transcriptional regulation of
      receptor expression.
AB  - Numerous effects of tumor necrosis factor are signaled by its 55-kDa receptors.
      Studying their expression we found that the level of receptor mRNA was decreased
      during the phorbol ester-induced differentiation of myelomonocytic cell lines.
      While only minor changes in transcription were noted, the half-life of receptor
      mRNA in the differentiated cells was markedly decreased, indicating the
      involvement of post-transcriptional regulation. In an electrophoretic mobility
      shift assay, formation of complexes between radiolabeled receptor mRNA and
      cellular proteins was observed. The decrease in receptor mRNA levels during
      phorbol ester-induced differentiation was paralleled by a change in the pattern
      of those complexes. Protein-RNA interaction was selective, as it was not competed
      by unrelated RNAs. Yet, certain mRNAs that contain AU-rich sequences, known to be
      involved in the control of their stability, did compete with the receptor mRNA,
      although the latter is devoid of such sequences. A region of 18 nucleotides
      within its coding region was found to contain an element essential for the
      formation of all complexes and sufficient for the formation of those with lower
      molecular mass. Adjacent bases were required in addition for the formation of the
      complexes with higher molecular mass. The results suggest that proteins
      interacting with this region of the 55-kDa tumor necrosis factor receptor mRNA
      contribute to the regulation of its expression.

PMID- 8662819
TI  - Role of mitogen-activated protein kinase kinase in regulation of the epidermal
      growth factor receptor by protein kinase C.
AB  - The epidermal growth factor receptor (EGFR) is regulated by at least two
      mechanisms involving protein kinase C (PKC), inhibition of EGF binding and
      inhibition of EGF-stimulated tyrosine kinase activity. In this study we
      investigated whether mitogen-activated protein kinase (MAPK) mediates the
      inhibitory effects of PKC on EGFR binding or kinase activity by pretreating
      NIH3T3 and Chinese hamster ovary cells expressing the EGFR with PD98059, an
      inhibitor of MAPK/extracellular signal-regulated kinase kinase (MEK). We also
      determined whether substitution of cysteine for threonine at residue 669, the
      site of MAPK phosphorylation of the EGFR, alters the inhibition of kinase
      activity by PKC. The results indicate that 1) PKC down-regulates EGFR tyrosine
      kinase activity by an MEK-dependent mechanism presumably involving MAPK; 2) the
      inhibition by PKC is not a direct result of phosphorylation of the EGFR by PKC or
      MAPK; 3) activation of MAPK is not sufficient to regulate EGFR kinase activity;
      and 4) PKC-mediated down-regulation of EGF binding and EGFR kinase activity occur
      by different mechanisms. These data are consistent with a model for regulation of
      the EGFR by other receptors whereby their activation of PKC, in conjunction with
      MAPK, results in the phosphorylation of a protein(s) that modulates EGFR kinase
      activity.

PMID- 8662820
TI  - The contributions of aspartyl residues in the acetylcholine receptor gamma and
      delta subunits to the binding of agonists and competitive antagonists.
AB  - The acetylcholine (ACh) receptors in muscle have the composition
      alpha2betagammadelta and contain two ACh binding sites. One is formed between an
      alpha subunit and the gamma subunit, and the other is formed between an alpha
      subunit and the delta subunit. Among the residues in the ACh binding sites are
      alphaCys-192 and alphaCys-193. The negatively charged deltaAsp-180 is at an
      appropriate distance from alphaCys-192/193 also to be in the ACh binding site and
      to interact electrostatically with the positively charged ammonium group common
      to agonists and competitive antagonists. Mutation to Asn of either deltaAsp-180
      or the aligned residue in the gamma subunit, gammaAsp-174, decreased the
      affinities of three agonists, acetylcholine, tetramethylammonium, and
      succinyldicholine 170-560-fold. By contrast, these mutations decreased the
      affinities of three competitive antagonists, (+)-tubocurarine, hexamethonium, and
      dihydro-beta-erythroidine, only 2-15-fold. Agonists, but not antagonists, promote
      the transitions of the receptor from the resting state to the higher affinity
      active and desensitized states, and the greater effects of the mutations of
      gammaAsp-174 and deltaAsp-180 on the apparent affinities of agonists could
      reflect the involvement of these residues in the conformational changes of the
      receptor corresponding to its transitions to higher affinity states. In these
      transitions, one possibility is that gammaAsp-174 and deltaAsp-180 move closer to
      bound agonist.

PMID- 8662821
TI  - Individual leaflets of a membrane bilayer can independently regulate
      permeability.
AB  - Water rapidly crosses most membranes, but only slowly crosses apical membranes of
      barrier epithelia such as bladder and kidney collecting duct, a feature essential
      to barrier function. How apical membrane structure reduces permeabilities remains
      unclear. Cell plasma membranes contain two leaflets of distinct lipid
      composition; the role of this bilayer asymmetry in membrane permeability is
      unclear. To determine how asymmetry of leaflet composition affects membrane
      permeability, effects on bilayer permeation of reducing single leaflet
      permeability were determined using two approaches: formation of asymmetric
      bilayers in an Ussing chamber, with only one of two leaflets containing
      cholesterol sulfate, and stabilization of the external leaflet of unilamellar
      vesicles with praeseodymium (Pr3+). In both systems, permeability measurements
      showed that each leaflet acts as an independent resistor of water permeation.
      These results show that a single bilayer leaflet can act as the barrier to
      permeation and provide direct evidence that segregation of lipids to create a low
      permeability of barrier epithelial apical membranes.

PMID- 8662824
TI  - High resolution NMR solution structure of the leucine zipper domain of the c-Jun
      homodimer.
AB  - The solution structure of the c-Jun leucine zipper domain has been determined to
      high resolution using a new calculation protocol designed to handle highly
      ambiguous sets of interproton distance restraints. The domain comprises a coiled
      coil of parallel alpha-helices in which most of the hydrophobic residues are
      buried at the highly symmetrical dimer interface; this interface extends over 10
      helical turns and is the most elongated protein domain solved to date using NMR
      methods. The backbone fold is very similar to that seen in crystal structures of
      the GCN4 and Jun-Fos leucine zippers; however, in contrast with these crystal
      structures, the Jun leucine zipper dimer appears to be devoid of favorable
      intermolecular electrostatic interactions. A polar asparagine residue, located at
      the dimer interface, forms the sole point of asymmetry in the structure;
      furthermore, the side chain of this residue is disordered due to motional
      averaging. This residue, which is highly conserved in the leucine zipper family
      of transcription factors, provides a destabilizing influence that is likely to
      facilitate the rapid exchange of zipper strands in vivo.

PMID- 8662823
TI  - Cloning and functional expression of mCCR2, a murine receptor for the C-C
      chemokines JE and FIC.
AB  - The C-C chemokines human monocyte chemoattractant protein-1 and -3 (MCP-1 and MCP
      3) and mouse JE and FIC are potent activators of monocytes. Several receptors for
      MCP-1 and MCP-3 have been cloned from human monocytic cell lines, and one of
      these receptors, CCR2B, binds both MCP-l and MCP-3. Thus far, no murine receptors
      for JE or FIC have been reported. We have cloned a novel murine C-C chemokine
      receptor, designated mouse CCR2 (mCCR2), from the mouse monocyte cell line
      WEHI265.1. The predicted 373-amino acid sequence of mCCR2 shows highest identity
      (80%) with CCR2B. When stably expressed in human embryonic kidney 293 cells,
      mCCR2 specifically bound 125I-JE with high affinity. FIC was less potent than JE
      in competing 125I-JE binding to mCCR2-expressing cells, while three other mouse
      chemokines, MIP-1alpha, C10, and N51/KC, did not compete. mccr2 mRNA expression
      was detected in elicited peritoneal macrophages as well as in several mouse
      organs. The cloning of mCCR2 provides an important tool to investigate
      monocyte/macrophage responses to JE and FIC, to identify other targets for their
      action, and potentially to study models of CCR2 function in the mouse.

PMID- 8662825
TI  - Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr
      15 phosphorylation after UV-induced DNA damage.
AB  - The cyclin-dependent kinase (CDK) inhibitor p21 is induced by the tumor
      suppressor gene product p53 and is thought to be important for the arrest of the
      cell cycle following DNA damage. Here we have investigated the contribution of
      p21 in inhibiting different cyclin-CDK complexes that drive different cell cycle
      transitions following UV irradiation-induced DNA damage in normal human
      fibroblasts and immortalized rodent fibroblasts. When cells were exposed to a low
      dose of UV irradiation, both p53 and p21 were induced; the protein kinase
      activities associated with Cdc2, Cdk2, and Cdk4 were inhibited; and there was a
      good correlation between their inhibition and binding to p21. p21 alone is likely
      to be sufficient for the inhibition of Cdk2 because all the cyclin-complexed
      forms of Cdk2 were associated with p21 after irradiation. In contrast, only a
      small proportion of Cdk4 and Cdc2 was complexed with p21, although the level of
      Cdk4 associated with either p21 or p27 was increased after irradiation.
      Furthermore, recombinant p21 added to an unirradiated cell lysate at the same
      level as that induced by irradiation damage inhibited only the kinase activity
      associated with Cdk2. Cdc2 is likely to be inhibited by Thr-14/Tyr-15
      phosphorylation after irradiation because Cdc2 was tyrosine-phosphorylated, and
      recombinant Cdc25 was able to increase its kinase activity significantly. Taken
      together, these results suggest that different CDKs are inhibited by different
      mechanisms following UV-induced DNA damage: Cdk2 is inhibited by the elevated
      level of p21; Cdk4 is inhibited by cooperation of p21 with other CDK inhibitors,
      like p27, and possibly by phosphorylation; and Cdc2 is inhibited by Thr-14/Tyr-15
      phosphorylation. It is likely that these underlying mechanisms that inactivate
      CDKs are similar for other kinds of DNA damage.

PMID- 8662826
TI  - Evidence for the Saccharomyces cerevisiae ferrireductase system being a
      multicomponent electron transport chain.
AB  - We have studied the relationships between in vivo (whole cells) and in vitro
      (plasma membranes) ferrireductase activity in Saccharomyces cerevisiae. Isolated
      plasma membranes were enriched in the product of the FRE1 gene and had NADPH
      dehydrogenase activity that was increased when the cells were grown in
      iron/copper-deprived medium. The diaphorase activity was, however, independent of
      Fre1p, and Fre1p itself had no ferrireductase activity in vitro. There were
      striking similarities between the yeast ferrireductase system and the neutrophil
      NADPH oxidase: oxygen could act as an electron acceptor in the ferrireductase
      system, and Fre1p, like gp91, is a glycosylated hemoprotein with a b-type
      cytochrome spectrum. The ferrireductase system was sensitive to the NADPH oxidase
      inhibitor diphenylene iodonium (DPI). DPI inhibition proceeded with two apparent
      Ki values (high and low affinity binding) in whole wild-type and Deltafre2 cells
      and with one apparent Ki in Deltafre1 cells (high affinity binding) and in plasma
      membranes (low affinity binding). These results suggest that the Fre1-dependent
      ferrireductase system involves at least two components (Fre1p and an NADPH
      dehydrogenase component) differing in their sensitivities to DPI, as in the
      neutrophil NADPH oxidase. A third component, the product of the UTR1 gene, was
      shown to act synergistically with Fre1p to increase the cell ferrireductase
      activity.

PMID- 8662827
TI  - Neoplastic transformation induced by insulin receptor substrate-1 overexpression
      requires an interaction with both Grb2 and Syp signaling molecules.
AB  - The insulin receptor substrate-1 (IRS-1) is the major intracellular substrate of
      insulin and insulin-like growth factor-I (IGF-I) receptor tyrosine kinase
      activity, and this protein has been found to be overexpressed in human
      hepatocellular carcinomas. IRS-1 contains several src homology 2 (SH2) binding
      motifs that interact following tyrosyl phosphorylation with SH2-containing
      proteins, and this interaction may be essential for transmitting the growth
      signal from the cell surface to the nucleus. We have previously reported that
      overexpression of IRS-1 may induce neoplastic transformation of NIH 3T3 cells.
      This study examines the role of two SH2-containing molecules, namely the Grb2
      adapter and Syp tyrosine phosphatase proteins as important components of the
      cellular transforming activity of IRS-1. Mutations of tyrosine 897 in the YVNI
      motif (Y897F) and of tyrosine 1180 in the YIDL motif (Y1180F) reduced the
      intracellular interaction of IRS-1 with Grb2 and Syp proteins, respectively.
      Furthermore, a single mutation at either Phe-897 or Phe-1180 substantially but
      not completely reduced IGF-I-dependent transforming activity of IRS-1, whereas
      creation of a double mutation of both tyrosine residues (Y897F/Y1180F) strikingly
      attenuated the transforming activity of IRS-1. Stable expression of the IRS-1
      mutant constructs in NIH 3T3 cells was associated with a lower level of
      activation of the mitogen-activated protein kinase kinase (MAPKK)/MAPK cascade
      following IGF-I stimulation compared with cells stably transfected with the "wild
      type" IRS-1 gene. These results suggest that IRS-1-induced cellular
      transformation requires an interaction with both Grb2 and Syp signal transduction
      molecules since neither interaction alone appears to be required, and this event
      subsequently leads to activation of the MAPKK/MAPK cascade.

PMID- 8662829
TI  - Reaction of the C30A mutant of trimethylamine dehydrogenase with
      diethylmethylamine.
AB  - The role played by the 6-S-cysteinyl-FMN bond of trimethylamine dehydrogenase in
      the reductive half-reaction of the enzyme has been studied by following the
      reaction of the slow substrate diethylmethylamine with a C30A mutant of the
      enzyme lacking the covalent flavin attachment to the polypeptide. Removal of the
      6-S-cysteinyl-FMN bond diminishes the limiting rate for the first of the three
      observed kinetic phases of the reaction by a factor of 6, but has no effect on
      the rate constants for the two subsequent kinetic phases. The flavin in the C30A
      enzyme recovered from the reaction of the C30A enzyme with excess substrate is
      found to have been converted to the 6-hydroxy derivative, rendering the enzyme
      inactive. The noncovalently bound FMN of the C30A mutant enzyme is also converted
      to 6-hydroxy-FMN and rendered inactive upon reduction with excess trimethylamine,
      but not by reduction with dithionite, even at high pH or in the presence of the
      effector tetramethylammonium chloride. These results suggest that one significant
      role of the 6-S-cysteinyl-FMN bond is to prevent the inactivation of the enzyme
      during catalysis. A reaction mechanism is proposed whereby OH- attacks C-6 of a
      flavin-substrate covalent adduct in the course of steady-state turnover to form 6
      hydroxy-FMN.

PMID- 8662828
TI  - Purification and characterization of the heat shock proteins HslV and HslU that
      form a new ATP-dependent protease in Escherichia coli.
AB  - The hslVU operon in Escherichia coli encodes two heat shock proteins, HslV, a 19
      kDa protein homologous to beta-type subunits of the 20 S proteasomes, and HslU, a
      50-kDa protein related to the ATPase ClpX. We have recently shown that HslV and
      HslU can function together as a novel ATP-dependent protease, the HslVU protease.
      We have now purified both proteins to apparent homogeneity from extracts of E.
      coli carrying the hslVU operon on a multicopy plasmid. HslU by itself cleaved
      ATP, and pure HslV is a weak peptidase degrading certain hydrophobic peptides.
      HslU dramatically stimulated peptide hydrolysis by HslV when ATP is present. With
      a 1:4 molar ratio of HslV to HslU, approximately a 200-fold increase in peptide
      hydrolysis was observed. HslV stimulated the ATPase activity of HslU 2-4-fold,
      but had little influence on the affinity of HslU to ATP. The nonhydrolyzable ATP
      analog, beta,gamma-methylene-ATP, did not support peptide hydrolysis. Other
      nucleotides (CTP, dATP) that were slowly hydrolyzed by HslU allowed some peptide
      hydrolysis. Therefore, ATP cleavage appears essential for the HslV activity. Upon
      gel filtration on a Sephacryl S-300 column, HslV behaved as a 250-kDa oligomer
      (i.e. 12-14 subunits), and HslU behaved as a 100-kDa protein (i.e. a dimer) in
      the absence of ATP, but as a 450-kDa multimer (8-10 subunits) in its presence.
      Therefore ATP appears necessary for oligomerization of HslU. Thus the HslVU
      protease appears to be a two-component protease in which HslV harbors the
      peptidase activity, while HslU provides an essential ATPase activity.

PMID- 8662830
TI  - Human Ku autoantigen binds cisplatin-damaged DNA but fails to stimulate human DNA
      activated protein kinase.
AB  - We have identified a series of proteins based on an affinity for cisplatin
      damaged DNA. One protein termed DRP-1 has been purified to homogeneity and was
      isolated as two distinct complexes. The first complex is a heterodimer of 83- and
      68-kDa subunits, while the second complex is a heterotrimer of 350-, 83-, and 68
      kDa subunits in a 1:1:1 ratio. The 83- and 68-kDa subunits in each complex are
      identical. The 83-kDa subunit of DRP-1 was identified as the p80 subunit of Ku
      autoantigen by N-terminal protein sequence analysis and reactivity with a
      monoclonal antibody directed against human Ku p80 subunit. The 68-kDa subunit of
      DRP-1 cross-reacted with monoclonal antisera raised against the Ku autoantigen
      p70 subunit. The 350-kDa subunit was identified as DNA-PKcs, the catalytic
      subunit of the human DNA-activated protein kinase, DNA-PK. DRP-1/Ku DNA binding
      was assessed in mobility shift assays and competition binding assays using
      cisplatin-damaged DNA. Results indicate that DNA binding was essentially
      unaffected by cisplatin-DNA adducts in the presence or absence of DNA-PKcs. DNA
      PK activity was only stimulated with undamaged DNA, despite the ability of Ku to
      bind to cisplatin-damaged DNA. The lack of DNA-PK stimulation by cisplatin
      damaged DNA correlated with the extent of cisplatin-DNA adduct formation. These
      results demonstrate that Ku can bind cisplatin-damaged DNA but fails to activate
      DNA-PK. These results are discussed with respect to the repair of cisplatin-DNA
      adducts and the role of DNA-PK in coordinating DNA repair processes.

PMID- 8662831
TI  - Synergistic induction of neurite outgrowth by nerve growth factor or epidermal
      growth factor and interleukin-6 in PC12 cells.
AB  - Native PC12 cells respond differentially to nerve growth factor (NGF) but not
      interleukin-6 (IL-6); PC12-E2 cells, a stable variant, respond to both stimuli
      (and more rapidly to NGF). Neither responds to epidermal growth factor (EGF). NGF
      primarily induces the RAS/extracellular signal-regulated kinase (ERK) pathway and
      IL-6 activates a JAK (Janus tyrosine kinase)/STAT (signal transducers and
      activators of transcription) response. EGF also stimulates RAS/ERK but in a
      transient manner. When either cell type is treated with combinations of NGF, EGF,
      and IL-6, at concentrations that produce modest or no response, a substantial
      augmentation of neurite outgrowth is observed. With PC12-E2 cells, a subthreshold
      concentration of IL-6 increases NGF response by approximately 2-3-fold after 1-2
      days; the increase with EGF is more pronounced. Native PC12 cells show even
      greater synergistic effects with NGF and IL-6. The most dramatic effect was
      observed with low levels of EGF, where IL-6 increased the percentage of
      responsive cells from zero to approximately 60% after 3 days. In addition, two
      neural-specific transcripts, GAP-43 and SCG-10, are synergistically increased by
      the combinations of growth factors. Importantly, IL-6 does not enhance ERK
      phosphorylation in the presence of either NGF or EGF. In contrast, NGF and EGF,
      in the presence or absence of IL-6, cause mobility shifts of Stat3 that are
      consistent with serine phosphorylations. Although these modifications do not lead
      to activation and translocation by themselves, in the presence of the tyrosine
      phosphorylation induced by IL-6, they may play a role in the synergistic
      responses. These observations suggest a differentially regulated two-stage
      mechanism for the differentiative response of PC12 cells to NGF.

PMID- 8662832
TI  - Aberrant glycosylation of E-cadherin enhances cell-cell binding to suppress
      metastasis.
AB  - Introduction of the beta1-4 N-acetylglucosaminyltransferase (GnT-III) gene was
      reported to suppress metastasis in highly metastatic B16-hm murine melanoma cells
      (Yoshimura, M., Nishikawa, A. , Ihara, Y., Taniguchi, S., and Taniguchi, N.(1995)
      Proc. Natl. Acad. Sci. U. S. A. 92, 8754-8758). In this study, the effect of GnT
      III gene transfer on E-cadherin was studied, since E-cadherin acts as a
      suppressor of metastasis. E-cadherin expression at cell-cell contacts of B16-hm
      cells expressing high GnT-III activity was greater than controls without
      affecting transcription. Lectin blotting showed that E-cadherin from GnT-III
      transfectants was glycosylated by ectopically expressed GnT-III. The glycosylated
      E-cadherin exhibited the delayed turnover and the decreased release from cell
      surface, as compared with the native E-cadherin, resulting in the elevated
      expression at the cell-cell border of GnT-III transfectants. Furthermore, cell
      cell aggregation was enhanced in GnT-III transfectants, indicating that the
      glycosylated E-cadherin is biologically functional. These results suggest that
      the glycosylated E-cadherin contributes to the suppression of metastasis by the
      introduction of GnT-III gene into melanoma cells.

PMID- 8662833
TI  - Purification and characterization of an interleukin-1beta-converting enzyme
      family protease that activates cysteine protease P32 (CPP32).
AB  - CPP32, a member of the interleukin-1beta-converting enzyme (ICE) family of
      cysteine proteases, cleaves poly(ADP-ribose) polymerase and sterol regulatory
      element binding proteins during apoptosis. CPP32 normally exists in the cytosol
      as a 32-kDa inactive precursor and only becomes activated when cells are
      undergoing apoptosis. The activation is a proteolytic event that generates a
      p20/p11 heterodimer. We report here the identification, purification, and
      characterization of a hamster CPP32-activating protease (CAP) that cleaves and
      activates CPP32. The biochemical properties of CAP suggest that it is another
      member of the ICE family of proteases. Purified CAP consists of two prominent
      polypeptides of 19 and 13 kDa. Protein sequencing revealed that CAP is derived
      from the hamster homolog of Mch2alpha, a member of the ICE family recently
      identified based on the sequence conservation among the ICE family members. CAP
      activity is inhibited by CrmA, a cowpox virus protein that prevents host cell
      apoptosis. CAP itself is also activated through proteolytic cleavage. These data
      are consistent with the idea that the activation of the ICE family of proteases
      during apoptosis proceeds through a cascade of proteolytic events.

PMID- 8662834
TI  - Vesicle-associated membrane protein 2 is essential for cAMP-regulated exocytosis
      in rat parotid acinar cells. The inhibition of cAMP-dependent amylase release by
      botulinum neurotoxin B.
AB  - Amylase exocytosis of the parotid gland is mediated by intracellular cAMP. To
      investigate whether cAMP-dependent secretion has a mechanism similar to that of
      regulated neuroexocytosis, we examined the expression of synaptosome-associated
      proteins. In rat parotid acinar cells, we found 25 (p25) and 18 kDa (p18)
      proteins reacted with antibodies against Rab3A and vesicle-associated membrane
      protein 2 (VAMP-2), respectively. On the other hand, syntaxin 1 and SNAP-25,
      which interact with VAMP-2 at synapses, were undetectable. Rab3A-like p25 and
      VAMP-2-like p18 were also expressed in other exocrine acinar cells. The latter
      was localized at secretory granule membranes, and the former was detected in
      secretory granule and cytosolic fractions. The antibody against VAMP-2 used in
      this study did not react with cellubrevin, and p18 was cleaved with botulinum
      neurotoxin B. Thus, we identified p18 as VAMP-2. Botulinum neurotoxin B inhibited
      the cAMP-induced amylase release from streptolysin O-permeabilized acinar cells.
      Therefore, VAMP-2 is required for cAMP-regulated amylase release in rat parotid
      acinar cells. This is the first report that VAMP-2 is involved in regulated
      exocytosis that is independent of Ca2+.

PMID- 8662835
TI  - Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z
      receptor/retinoid acid receptor-related orphan receptor alpha with potent
      antiarthritic activity.
AB  - Rat adjuvant arthritis is a chronic T cell-dependent autoimmune disease with many
      similarities to rheumatoid arthritis. We have identified a class of thiazolidine
      diones with high potency in suppressing chronic inflammation and joint
      destruction in this experimental model. The lead compound CGP 52608 (1-(3-allyl-4
      oxothiazolidine-2-ylidene)-4-methylthiosemicarbazone) exhibits antiarthritic
      activity at daily oral doses between 0.01 and 1 mg/kg and was shown to
      specifically activate the retinoid Z receptor/retinoid acid receptor-related
      orphan receptor alpha (RZR/RORalpha) in low nanomolar concentrations. This
      receptor is a novel member of the superfamily of ligand-inducible transcription
      factors, and we have recently identified the pineal gland hormone melatonin as a
      natural ligand. Structure-activity relationship studies with 13 closely related
      analogues of CGP 52608 revealed a striking correlation between RZR/RORalpha
      activation and antiarthritic activity. We therefore suggest that nuclear
      signaling via RZR/RORalpha is a key mechanism in mediating the antiarthritic
      effects of these thiazolidine diones and may open a novel therapeutic approach
      for the treatment of rheumatoid arthritis and other autoimmune diseases. The
      existence of a nuclear melatonin receptor may lead to a better understanding of
      the immunomodulatory actions of melatonin.

PMID- 8662836
TI  - Fatty acid transfer from liver and intestinal fatty acid-binding proteins to
      membranes occurs by different mechanisms.
AB  - Intestinal absorptive cells contain high levels of expression of two homologous
      fatty acid-binding proteins (FABP), liver FABP (L-FABP), and intestinal FABP (I
      FABP). Both bind long chain fatty acids with relatively high affinity. The
      functional distinction, if any, between these two proteins remains unknown. It is
      often hypothesized that FABP are important in intracellular transport of fatty
      acids. To assess whether fatty acid transport properties might differ between the
      two enterocyte FABPs, we examined the rate and mechanism of transfer of
      fluorescent anthroyloxy fatty acids (AOFA) from these proteins to model membranes
      using a resonance energy transfer assay. The results show that the absolute rate
      of AOFA transfer from I-FABP is faster than from L-FABP. Moreover, the apparent
      mechanism of fatty acid transfer is different between the two proteins. The rate
      of AOFA transfer from I-FABP is independent of ionic strength, directly dependent
      on the concentration of acceptor membrane vesicles, and dramatically regulated by
      the lipid composition of the membranes. These data strongly suggest that fatty
      acid transfer from I-FABP to membranes occurs by direct collisional interaction
      of the protein with the phospholipid bilayer. In contrast, the characteristics of
      fatty acid transfer from L-FABP are consistent with an aqueous diffusion-mediated
      process. Thus the two enterocyte FABPs may perform different functions within the
      intestinal absorptive cell in the regulation of fatty acid transport and
      utilization. It is hypothesized that L-FABP may act as a cytosolic buffer for
      fatty acids, maintaining the unbound fatty acid concentration, whereas I-FABP may
      be involved in the uptake and/or specific targeting of fatty acid to subcellular
      membrane sites.

PMID- 8662837
TI  - Myxoma virus T2 protein, a tumor necrosis factor (TNF) receptor homolog, is
      secreted as a monomer and dimer that each bind rabbit TNFalpha, but the dimer is
      a more potent TNF inhibitor.
AB  - The myxoma virus T2 (M-T2) gene expresses a secreted protein that contains
      significant sequence similarity to the ligand binding domains of the cellular
      tumor necrosis factor (TNF) receptors, specifically inhibits the cytolytic
      activity of rabbit TNFalpha and is an important virulence factor for myxoma virus
      infection in rabbits. M-T2 protein was overexpressed from vaccinia virus vectors,
      purified to apparent homogeneity, and found to specifically protect mouse and
      rabbit cells from lysis by rabbit TNFalpha at molar ratios comparable with the
      soluble versions of the host tumor necrosis factor receptors. M-T2 secreted from
      virus-infected cells is detected as both a monomer and a disulfide-linked dimer,
      both of which were shown by Scatchard analysis to bind rabbit TNFalpha (Kd values
      of 170 pM and 195 pM, respectively), values that are comparable with the
      affinities of mammalian TNFs with their receptors. In contrast to the rabbit
      ligand, M-T2 interacts with mouse TNFalpha with a much lower affinity, Kd of 1.7
      nM, and was unable to inhibit the cytolytic activity of this ligand on mouse
      cells. Although both monomeric and dimeric forms bound rabbit TNFalpha with
      comparable affinity, the dimeric M-T2 protein was a far more potent inhibitor of
      rabbit TNFalpha, presumably because it can more effectively prevent dimerization
      of TNF receptors than can the M-T2 monomer.

PMID- 8662838
TI  - Molecular cloning and characterization of lysosomal sialic acid O-acetylesterase.
AB  - O-Acetylation and de-O-acetylation of sialic acids have been implicated in the
      regulation of a variety of biological phenomena, including endogenous lectin
      recognition, tumor antigenicity, virus binding, and complement activation.
      Applying a strategy designed to identify genes preferentially expressed in active
      sites of embryonic hematopoiesis, we isolated a novel cDNA from the pluripotent
      hematopoietic cell line FDCPmixA4 whose open reading frame contained sequences
      homologous to peptide fragments of a lysosomal sialic acid O-acetylesterase (Lse)
      previously purified from rat liver, but with no evident similarity to endoplasmic
      reticulum-derived acetylesterases. The expressed Lse protein exhibits sialic-acid
      O-acetylesterase activity that is not attributable to a typical serine esterase
      active site. lse expression is spatially and temporally restricted during
      embryogenesis, and its mRNA levels correlate with differences in O-acetylesterase
      activity described in adult tissues and blood cell types. Using interspecific
      backcross analysis, we further mapped the lse gene to the central region of mouse
      chromosome 9. This constitutes the first report on the molecular cloning of a
      sialic acid-specific O-acetylesterase in vertebrates and suggests novel roles for
      the 9-O-acetyl modification of sialic acids during the development and
      differentiation of mammalian organisms.

PMID- 8662839
TI  - Demonstration of the molecular shape of BP180, a 180-kDa bullous pemphigoid
      antigen and its potential for trimer formation.
AB  - The 180-kDa bullous pemphigoid antigen (BP180) is a hemidesmosomal transmembrane
      glycoprotein comprising interrupted collagen domains in its extracellular part.
      BP180 is also termed type XVII collagen. But the question of whether it actually
      takes a collagen-like triple helical conformation in vivo has remained
      unanswered. Using a monoclonal antibody, we found that a subpopulation of BP180
      localizes at the lateral surfaces of corneal basal cells and cultured cells, in
      addition to the basal surface. This subpopulation of BP180 could be solubilized
      by 0.5% Triton X-100 and, among examined cell lines, was found to be most
      abundant in BMGE+H, a bovine mammary gland epithelial cell line. The Triton
      soluble fraction of BMGE+H cells was used for characterization. On sucrose
      gradient centrifugation, the soluble BP180 demonstrated a value of approximately
      7 S, and chemical cross-linking experiments revealed a trimer form. The
      calculated frictional ratio, f/f0 = 2.8, suggests an asymmetric configuration.
      For further characterization, we purified the soluble BP180 by immunoaffinity
      column chromatography using an anti-BP180 monoclonal antibody. Rotary shadowing
      images of the purified BP180 showed a quaver-like molecule consisting of a
      globular head, a central rod, and a flexible tail. With regard to the primary
      structure and species comparisons, the central rod, 60-70 nm in length, probably
      corresponds to the largest collagenous region, forming a collagen-like triple
      helix, in human form. The globular head and the flexible tail seem to correspond
      to the cytoplasmic and the interrupted collagenous region, respectively, of the
      extracellular portions. In conclusion, the present demonstration of the entire
      configuration of BP180, with a collagen-like trimer in its extracellular part,
      suggests that BP180 is one of the major components of anchoring filaments.

PMID- 8662840
TI  - Induced and spontaneous mutations at Ser202 of carboxypeptidase E. Effect on
      enzyme expression, activity, and intracellular routing.
AB  - Carboxypeptidase E (CPE) is involved in peptide processing in the brain and
      various neuroendocrine tissues. In mice homozygous for the Cpefat mutation, the
      virtual absence of CPE activity in islets of Langerhans and pituitary was
      associated with a missense mutation effecting a Ser202 to Pro shift (Naggert, J.
      K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F.,
      Carroll, R. J., Paigen, B. J., and Leiter, E. H. (1995) Nat. Genet. 10, 135-142).
      To examine the importance of Ser202 in CPE function, several mutations in this
      position were generated (Pro202, Ala202, Gly202, and Phe202). When the mutant
      proteins were expressed in a Baculovirus system, both Phe202 and Pro202CPE were
      enzymatically inactive, were unable to bind to a substrate affinity column, and
      were not secreted from Sf9 cells. In contrast, Ala202CPE or Gly202CPE exhibited
      enzymatic properties similar to those of wild-type CPE and were secreted from Sf9
      cells. When expressed in AtT-20 cells, a mouse pituitary-derived cell line, CPE
      with Pro202 and Phe202 were not secreted. Pulse-chase analysis with [35S]Met
      indicated that Pro202CPE was degraded in AtT-20 cells within several hours. This
      degradative process was blocked by incubation at 15 degrees C but not by
      brefeldin A or by lysosomotrophic drugs. Pulse-chase analysis using dispersed
      pituitary cells from C57BLKS/Lt-Cpefat/Cpefat mutant mice shows similar results;
      Pro202-CPE produced in these cells was not secreted but rather was degraded
      within 5 h. Immunofluorescence analysis of epitope-tagged CPE revealed Ser202CPE
      to be present primarily in secretory vesicles, whereas Pro202CPE was localized to
      the endoplasmic reticulum and not the secretory vesicle-like structures. These
      results support the previous finding that Cpefat/Cpefat mice are defective in CPE
      activity because of the point mutation producing the Ser202 to Pro substitution.
      Furthermore, these results are consistent with a model that Ser202 is important
      for the intracellular folding of CPE.

PMID- 8662841
TI  - Pertussis toxin-sensitive activation of phospholipase C by the C5a and fMet-Leu
      Phe receptors.
AB  - Signal transduction pathways that mediate C5a and fMet-Leu-Phe (fMLP)-induced
      pertussis toxin (PTx)-sensitive activation of phospholipase C (PLC) have been
      investigated using a cotransfection assay system in COS-7 cells. The abilities of
      the receptors for C5a and fMLP to activate PLC beta2 and PLC beta3 through the
      Gbetagamma subunits of endogenous Gi proteins in COS-7 cells were tested because
      both PLC beta2 and PLC beta3 were shown to be activated by the betagamma subunits
      of G proteins in in vitro reconstitution assays. Neither of the receptors can
      activate endogenous PLC beta3 or recombinant PLC beta3 in transfected COS-7
      cells. However, both receptors can clearly activate PLC beta2 in a PTx-sensitive
      manner, suggesting that the receptors may interact with endogenous PTx-sensitive
      G proteins and activate PLC beta2 probably through the Gbetagamma subunits. These
      findings were further corroborated by the results that PLC beta3 could only be
      slightly activated by Gbeta1gamma1 or Gbeta1gamma5 in the cotransfection assay,
      whereas the Gbetagamma subunits strongly activated PLC beta2 under the same
      conditions. PLC beta3 can be activated by Galphaq, Galpha11, and Galpha16 in the
      cotransfection assay. In addition, the Ggamma2 and Ggamma3 mutants with
      substitution of the C-terminal Cys residue by a Ser residue, which can inhibit
      wild type Gbetagamma-mediated activation of PLC beta2, were able to inhibit C5a
      or fMLP-mediated activation of PLC beta2. These Ggamma mutants, however, showed
      little effect on m1-muscarinic receptor-mediated PLC activation, which is
      mediated by the Gq class of G proteins. These results all confirm that the
      Gbetagamma subunits are involved in PLC beta2 activation by the two
      chemoattractant receptors and suggest that in COS-7 cells activation of PLC beta3
      by Gbetagamma may not be the primary pathway for the receptors.

PMID- 8662842
TI  - CD30 contains two binding sites with different specificities for members of the
      tumor necrosis factor receptor-associated factor family of signal transducing
      proteins.
AB  - CD30 is a member of the tumor necrosis factor (TNF) receptor family of proteins.
      CD30 can regulate proliferation of lymphocytes and may also play an important
      role in human immunodeficiency virus replication. However, little is known about
      CD30 signal transduction. We performed a yeast two-hybrid library screen with the
      cytoplasmic domain of CD30 and isolated multiple independent cDNAs encoding human
      tumor necrosis factor receptor-associated factor (TRAF) 1, TRAF2, and CRAF1
      (TRAF3). The ability of TRAF1, TRAF2, and CRAF1 to associate with CD30 was
      confirmed using an in vitro coprecipitation assay, further demonstrating that the
      interaction was specific and direct. The TRAF-binding domain of CD30 was mapped
      to the COOH-terminal 36 amino acid residues, which contained two independent
      binding sites. CRAF1 bound only a single site, which contained the sequence
      PEQET, whereas TRAF1 and TRAF2 were capable of binding to either the PEQET site
      or an additional downstream domain. These data indicate that the TRAF protein
      binding pattern of CD30 differs from other TNF receptor family members and
      suggest that signaling specificity through TNF receptor family proteins may be
      achieved through differences in their abilities to bind TRAF proteins.

PMID- 8662844
TI  - Evidence for Rho-mediated agonist stimulation of phospholipase D in rat1
      fibroblasts. Effects of Clostridium botulinum C3 exoenzyme.
AB  - Small GTP-binding proteins of the Rho family are implicated in the in vitro
      regulation of phosphatidylcholine hydrolysis by phospholipase D (PLD). However,
      their role in agonist-stimulated PLD activity in whole cells is not clear. The
      ribosyltransferase C3 from Clostridium botulinum modifies Rho proteins and
      inhibits their function. When introduced into rat1 fibroblasts by scrape-loading,
      C3 inhibited PLD activity stimulated by lysophosphatidic acid (LPA), endothelin
      1, or phorbol ester. Neither the time course nor agonist dose response for LPA
      stimulated PLD activity was altered in C3-treated cells. In contrast to the
      effects of C3 on PLD activity, agonist-stimulated phosphatidylinositol
      phospholipase C activity was not altered in C3-treated cells. Surprisingly, C3
      treatment led to a decrease in the amount of RhoA protein, indicating that the
      loss of PLD activity in response to agonist was partly due to the loss of Rho
      proteins. As described previously, C3 treatment led to the inhibition of LPA
      stimulated actin filament formation. However, disruption of actin filaments with
      cytochalasin D caused only a minor inhibition of LPA-stimulated PLD activity.
      Interestingly, stimulation of cells with LPA caused a rapid enrichment of RhoA in
      the particulate fraction of cell lysates. These data support an in vivo role for
      RhoA in agonist-stimulated PLD activity that is separate from its role in actin
      fiber formation.

PMID- 8662843
TI  - Activation of the native 45-kDa precursor form of interleukin-1-converting
      enzyme.
AB  - Active interleukin-1beta-converting enzyme (ICE) is composed of 20- and 10-kDa
      polypeptides (p20 and p10) derived from the processing of a cytosolic 45-kDa
      precursor protein (p45). The cleavage and activation of the native p45 ICE
      precursor have been characterized by use of specific inhibitors and antibodies
      recognizing various regions of ICE. The processing of p45 in vitro in THP.1
      monocytic cell cytoplasmic extracts is inhibited only by protease inhibitors that
      inhibit ICE and not by inhibitors of other protease classes. The addition of L
      742,395, a biotinylated irreversible ICE inhibitor, to these extracts labels only
      p45 and simultaneously inhibits p45 processing, demonstrating that the p45 has
      catalytic activity. Following a cleavage of p45 at a site that becomes the COOH
      terminus of p20, a more active intermediate is formed which migrates on SDS
      polyacrylamide gel electrophoresis with an molecular mass of 35 kDa (ED50 of
      approximately 0.1 microM L-742,395 labeling versus 5 microM for p45). This new
      more active ICE form serves both as an intermediate enzyme to cleave p45 as well
      as a substrate for the formation of the final active ICE (ED50 of 1 nM L-742,395
      labeling of p20 and for p22, an NH2-terminally extended form of p20). While
      initial cleavage of p45 can be found at the sites corresponding to both the NH2
      termini of p22 and p20, these fragments cannot be labeled by L-742,395 and are
      hence inactive. p45 is not processed at the site corresponding to the NH2
      terminus of the p10. Less than 50% of the p45 is cleaved down to active p20 or
      p22 ICE as determined by band shift on SDS-polyacrylamide gel electrophoresis of
      the biotinylated fragments, indicating that the in vitro activation is highly
      inefficient. The ICE fragmentation occurs by an intermolecular process and is
      highly dilution sensitive. Cleavage of p45 by exogenous p20/p10 ICE differs from
      that of the endogenous p45 cleavage activity in that the p20/p10 activity is more
      salt sensitive, and it produces a different pattern of cleavage fragments,
      principally 35- and 12-kDa fragments. These results indicate that the nature of
      the ICE activity changes as p45 is processed down to the p20/p10 form of the
      enzyme.

PMID- 8662845
TI  - Cooperation between core binding factor and adjacent promoter elements
      contributes to the tissue-specific expression of interleukin-3.
AB  - Tissue-specific expression of interleukin-3 (IL-3) is mediated via cis-acting
      elements located within 315 base pairs of the transcription start. This is
      achieved in part through the positive activities of the AP-1 and Elf-1 sites in
      the IL-3 promoter. The contribution to T cell-specific expression by other
      promoter sites was assessed in a transient expression assay with IL-3 promoter
      constructs linked to a luciferase gene, focusing initially on the core binding
      factor (CBF) site, which is footprinted in vivo upon T cell activation. Activity
      of the CBF site is shown to be critically dependent on the adjacent activator
      site Act-1. Together the Act-1 and CBF sites form a functional unit (AC unit)
      with dual activity. The AC unit is demonstrated to enhance basal activity of
      promoters both in fibroblasts and T cells. This activity is further inducible in
      activated T cells, but not in fibroblasts. In addition to the already identified
      NIP repressor site, evidence is presented for a second repressor region that
      restricts promoter activity in fibroblasts. Finally, a novel positive regulatory
      element has been mapped in the IL-3 promoter between nucleotide -180 and -210
      that leads to increased expression in T cells. Together these results demonstrate
      that T cell expression of IL-3 is not specified by the activity of a single
      tissue-specific element, but instead involves multiple interacting elements that
      provide both specific positive regulation in T cells and specific negative
      regulation in fibroblasts.

PMID- 8662846
TI  - Chimeric rat/human neurotensin receptors localize a region of the receptor
      sensitive to binding of a novel, species-specific, picomolar affinity peptide.
AB  - Recently, we reported the development of a species-specific neurotensin analog
      that displays selective binding affinity at the rat and human neurotensin (NT)
      receptor, L-[3,2'-Nal11]NT(8-13) (where Nal is naphthylalanine) (NT19). We have
      developed another neurotensin analog, L-[3,1'-Nal11]NT(8-13), (NT34), that
      exhibits a 126-fold difference in binding affinities between the rat and human
      receptors. This compound differs from our previous reported species-specific
      ligand in the steric positioning of the naphthyl ring on the L-alanine side
      chain. For NT34, the observed Kd values at the rat and human neurotensin
      receptors were 0.046 and 5.8 nM, respectively. In stimulating
      phosphatidylinositol turnover, the observed EC50 values were 2.8 nM and 130 nM in
      rat and human, respectively. We constructed a series of chimeric rat/human
      neurotensin receptor genes and expressed them by transient transfection into
      human embryonic kidney (HEK-293) cells. Radioligand binding assays were then
      performed using neurotensin and NT34. Our results led us to propose a region of
      the neurotensin receptor that may be involved in determining species specificity,
      i. e. the transmembrane VI, the third extracellular loop, and transmembrane VII
      regions of the neurotensin receptor.

PMID- 8662847
TI  - Insulin regulates heregulin binding and ErbB3 expression in rat hepatocytes.
AB  - The heregulin-ErbB system of ligands and receptors are newly described epidermal
      growth factor (EGF) and EGF receptor-related proteins that regulate growth,
      differentiation, and gene expression in numerous cell types. This study describes
      a receptor for heregulin beta-1 (HRGbeta1) on cultured rat hepatocytes and an
      inhibitory influence of insulin on HRGbeta1 binding. HRGbeta1 (30 nM) stimulated
      DNA synthesis 2-fold and was not augmented by insulin as is the case with EGF
      receptor ligands. A labeled peptide corresponding to the EGF domain of HRGbeta1
      bound to a single population of 19,600 +/- 1,800 binding sites/cell with a Kd of
      360 +/- 22 pM. Cross-linking experiments showed binding of HRGbeta1 to ErbB3 but
      not ErbB2 or ErbB4. HRGbeta1 induced phosphorylation of ErbB3 and decreased ErbB3
      protein levels, suggesting that HRGbeta1 activates signaling through the ErbB3
      receptor and influences receptor trafficking. Following plating, [125I]HRGbeta1
      binding and ErbB3 protein levels increased 8- and 3-fold, respectively, over the
      first 12 h in culture. These increases required de novo protein synthesis and
      were inhibited with 50 nM insulin resulting in 3500 binding sites with a Kd of
      265 pM. These data suggest that the heregulin-ErbB system can regulate liver
      functions and may be linked to the metabolic and nutritional status of the
      animal.

PMID- 8662848
TI  - Rapid and specific efflux of reduced glutathione during apoptosis induced by anti
      Fas/APO-1 antibody.
AB  - Although human JURKAT T lymphocytes induced to undergo apoptosis with anti
      Fas/APO-1 antibody were observed to rapidly lose reduced glutathione (GSH),
      increased concentrations of oxidized products were not detectable. Unexpectedly,
      the reduced tripeptide was instead quantitatively recovered in the incubation
      medium of the cells. As GSH loss was blocked by bromosulfophthalein and
      dibromosulfophthalein, known inhibitors of hepatocyte GSH transport, a specific
      export rather than nonspecific leakiness through plasma membranes is proposed to
      be responsible. Apoptosis was delayed when GSH-diethylesters were used to elevate
      intracellular GSH, although the high capacity of the activated efflux system
      quickly negated the benefit of this treatment. Stimulation of GSH efflux provides
      a novel mechanism whereby Fas/APO-1 ligation can deplete GSH. We speculate that
      it enhances the oxidative tonus of a responding cell without requiring an
      increase in the production of reactive oxygen species.

PMID- 8662849
TI  - Epidermal growth factor receptor interaction with clathrin adaptors is mediated
      by the Tyr974-containing internalization motif.
AB  - The carboxyl-terminal regulatory domain of the epidermal growth factor (EGF)
      receptor is essential for its endocytosis and interaction with the clathrin
      associated protein complex AP-2. To identify AP-2 binding motif in the receptor,
      several single and multiple-point mutations within the region between residues
      966 and 977 of the human EGF receptor were made, and the mutant receptors were
      expressed in NIH3T3 cells. Mutation of tyrosine 974 alone or together with
      surrounding residues and the deletion of residues 973-975 essentially eliminated
      AP-2 co-immunoprecipitation with the EGF receptor. Furthermore, a synthetic
      peptide corresponding to receptor residues 964-978 blocked AP-2 association with
      the wild-type EGF receptor. These data suggest that AP-2 has only one high
      affinity binding site in the EGF receptor composed of Tyr974-containing motif.
      Receptor mutants that did not bind AP-2 displayed a lower rate of
      internalization, down-regulation, and turnover compared to wild-type receptors
      when expressed at high levels. However, similar receptor mutants expressed at low
      levels were internalized and down-regulated as efficiently as wild-type
      receptors. Internalization of the mutant receptors lacking the high-affinity
      binding site for AP-2 was inhibited by K+-depletion of the cells, indicating that
      their endocytosis required intact coated pits. We suggest that whereas one
      mechanism of EGF receptor recruitment into coated pits involves high-affinity
      binding of AP-2 to Tyr974-containing motif, another pathway may be mediated by
      weak receptor/AP-2 interactions or by proteins other than AP-2.

PMID- 8662850
TI  - Amino acid substitutions in the two largest subunits of Escherichia coli RNA
      polymerase that suppress a defective Rho termination factor affect different
      parts of the transcription complex.
AB  - Among the earliest rpoBC mutations identified are three suppressors of the
      conditional lethal rho allele, rho201. These three mutations are of particular
      interest because, unlike rpoB8, they do not increase termination at all rho
      dependent and rho-independent terminators. rpoB211 and rpoB212 both change Asn
      1072 to His in conserved region H of rpoB (betaN1072H), whereas rpoC214 changes
      Arg-352 to Cys in conserved region C of rpoC (beta'R352C). Both substitutions
      significantly reduce the overall rate of transcript elongation in vitro relative
      to wild-type RNA polymerase; however, they probably slow elongation for different
      reasons. The nucleotide triphosphate concentrations required at the T7 A1
      promoter for both abortive trinucleotide synthesis and for promoter escape are
      much greater for betaN1072H. In contrast, beta'R352C and two adjacent
      substitutions (beta'G351S and beta'S350F), but not betaN1072H, formed open
      complexes of greatly reduced stability. The sequence in this region of beta'
      modestly resembles a region of Escherichia coli DNA polymerase I that contacts
      the phosphate backbone of DNA in co-crystals. Core determinants affecting open
      complex formation do not reside exclusively in beta', however, since the Rifr
      mutation rpoB2 in beta also dramatically destabilized open complexes. We suggest
      that the principal defects of the two Rho-suppressing substitutions may differ,
      perhaps reflecting a greater role of beta region H in nucleoside triphosphate
      binding and nucleotide addition and of beta' region C in contacts to the DNA
      strands that could be important for translocation. Although both probably
      suppress rho201 by slowing RNA chain elongation, these differences may lead to
      terminator specificity that depends on the rate-limiting step at different sites.

PMID- 8662851
TI  - Phosphorylation of 25-kDa synaptosome-associated protein. Possible involvement in
      protein kinase C-mediated regulation of neurotransmitter release.
AB  - Protein kinase C-mediated phosphorylation of a 25-kDa synaptosome-associated
      protein (SNAP-25) was examined in living PC12 cells. Phorbol 12-myristate 13
      acetate treatment enhanced high potassium-induced [3H]-norepinephrine release,
      and a 28-kDa protein recognized by an anti-SNAP-25 antibody was phosphorylated on
      Ser residues. The molecular size of the phosphorylated band decreased slightly
      following treatment with Clostridium botulinum type A neurotoxin, whereas the
      band disappeared after treatment with botulinum type E neurotoxin, indicating
      that the 28-kDa protein was SNAP-25. A phosphorylation is likely to occur at
      Ser187, as this is the only Ser residue located between the cleavage sites of
      botulinum type A and E neurotoxins. SNAP-25 of PC12 cells was phosphorylated by
      purified protein kinase C in vitro, and the amount of syntaxin co
      immunoprecipitated with SNAP-25 was decreased by phosphorylation. These results
      suggest that the phosphorylation of SNAP-25 may be involved in protein kinase C
      mediated regulation of catecholamine release from PC12 cells.

PMID- 8662853
TI  - The biology of left-handed Z-DNA.

PMID- 8662852
TI  - Identification of the G protein-coupled receptor kinase phosphorylation sites in
      the human beta2-adrenergic receptor.
AB  - Rapid desensitization of G protein-coupled receptors is mediated, at least in
      part, by their phosphorylation by the G protein-coupled receptor kinases (GRKs).
      However, only in the case of rhodopsin have the actual sites of receptor
      phosphorylation been unambiguously determined. Although previous studies have
      implicated the cytoplasmic tail of the beta2-adrenergic receptor (beta2AR) as the
      site of GRK-mediated phosphorylation, the identities of the phosphorylated
      residues were unknown. Here we report the identification of the sites of GRK2-
      and GRK5-mediated beta2AR phosphorylation. The phosphorylation sites of both
      serine/threonine kinases reside exclusively in a 40-amino acid peptide located at
      the extreme carboxyl terminus of the beta2AR. Of the seven phosphorylatable
      residues within this peptide, six are phosphorylated by GRK5 (Thr-384, Thr-393,
      Ser-396, Ser-401, Ser-407, and Ser-411) and four are phosphorylated by GRK2 (Thr
      384, Ser-396, Ser-401, and Ser-407) at equivalent phosphorylation stoichiometries
      (approximately 1.0 mol Pi/mol receptor). In addition to the GRK5-specific
      phosphorylation of Thr-393 and Ser-411, differences in the distribution of
      phosphate between sites are observed for GRK2 and GRK5. Increasing the
      stoichiometry of GRK2-mediated beta2AR phosphorylation from approximately 1.0 to
      5.0 mol Pi/mol receptor increases the stoichiometry of phosphorylation of Thr
      384, Ser-396, Ser-401, and Ser-407 rather than increasing the number of
      phosphoacceptor sites. The location of multiple GRK2 and GRK5 phosphoacceptor
      sites at the extreme carboxyl terminus of the beta2AR is highly reminiscent of
      GRK1-mediated phosphorylation of rhodopsin.

PMID- 8662854
TI  - Nuclease resistance and antisense activity of modified oligonucleotides targeted
      to Ha-ras.
AB  - We have previously described structure-activity studies on a 17-mer uniform
      phosphorothioate antisense sequence targeted to human Ha-ras. In an effort to
      further improve the pharmacological properties of antisense oligonucleotides,
      structure-activity studies on this 17-mer sequence were expanded to examine both
      the effects of replacing phosphorothioate backbone linkages with phosphodiester
      linkages and the effects of incorporating various 2'-sugar modifications into
      phosphorothioate and phosphodiester oligonucleotides on oligonucleotide stability
      against nucleases in vitro and on antisense activity in cells. Replacement of
      three or more phosphorothioate linkages with phosphodiester linkages greatly
      compromised both nuclease resistance and antisense activity, and these effects
      correlated directly with the number of phosphodiester linkages incorporated into
      the oligonucleotide. However, substantial nuclease resistance, sufficient for
      obtaining potent antisense effects in cells, was conferred to phosphodiester
      oligonucleotides by incorporation of appropriate 2'-alkoxy sugar modifications.
      Nuclease stability and antisense activity imparted by these sugar modifications
      in phosphodiester backbones correlated with the size of the 2'-alkoxy substituent
      (pentoxy > propoxy > methoxy > deoxy). Furthermore, antisense activity mediated
      by oligonucleotides that exhibit partial resistance to nucleolytic degradation
      was dependent on both oligonucleotide concentration and the duration of
      oligonucleotide treatment.

PMID- 8662855
TI  - Arachidonic acid diols produced by cytochrome P-450 monooxygenases are
      incorporated into phospholipids of vascular endothelial cells.
AB  - Epoxyeicosatrienoic acids (EETs) are synthesized by cytochrome P-450
      monooxygenases and released into the blood. When taken up by vascular endothelial
      and smooth muscle cells, the EETs are primarily esterified to phospholipids or
      converted to dihydroxyeicosatetraenoic acids (DHETs) and released. In the present
      studies, radiolabeled 8,9-, 11,12-, and 14,15-DHETs released into the medium from
      vascular smooth muscle cells were isolated and incubated for 4-16 h with cultured
      bovine aortic endothelial cells. The uptake ranged from 2 to 50% for the three
      regioisomers. Hydrolysis of the endothelial lipids and gas chromatographic-mass
      spectral analyses of the products indicated that all three DHET regioisomers were
      incorporated intact into phosphatidylcholine and phosphatidylinositol. Similar
      incubations with EETs confirmed that small amounts of DHETs were also esterified
      to endothelial phospholipids. These studies indicate that DHETs are incorporated
      into phospholipids either at the time of EET conversion to DHET or upon release
      and re-uptake of DHETs. Beside demonstrating for the first time that fatty acid
      diols are incorporated intact into endothelial lipids, these studies raise the
      possibility that both EETs and DHETs remain long enough in the vascular wall to
      produce chronic vasoactive effects.

PMID- 8662856
TI  - Cpk is a novel class of Drosophila PtdIns 3-kinase containing a C2 domain.
AB  - We report the identification of a novel class of phosphatidylinositol (PtdIns) 3
      kinases whose members contain C-terminal C2 domains. We have isolated Drosophila
      and murine genes (termed cpk and cpk-m respectively) by polymerase chain reaction
      amplification of cDNA libraries with degenerate primers corresponding to
      conserved regions of PtdIns kinases. The amino acid sequences of Cpk and Cpk-m
      are most similar to that of p110, a family of PtdIns 3-kinases that mediates the
      responses of cells to mitogenic stimuli. The Cpk and Cpk-m sequences are similar
      to a large, central region of p110, but differ from p110 at their N and C
      termini. The N termini of the Cpk proteins do not contain any recognizable
      protein motif, while the C termini contain "C2 domains," a feature unique among
      PtdIns kinases. Cpk has an intrinsic PtdIns kinase activity and can phosphorylate
      PtdIns and PtdIns-4-P, but not PtdIns(4,5)P2, at the D3 position of the inositol
      ring. Cpk is the first PtdIns 3-kinase identified with this particular substrate
      specificity. We have identified two potential Cpk-binding proteins, p90 and p190,
      and have determined that both Cpk and p190 may be tyrosine phosphorylated. This
      finding suggests that Cpk function may be regulated by tyrosine kinases.

PMID- 8662857
TI  - Mechanisms of murine RANTES chemokine gene induction by Newcastle disease virus.
AB  - We have previously defined the lipopolysaccharide (LPS)-responsive element (LRE)
      in the promoters of murine RANTES (regulated on activation normal T-cell
      expressed) (MuRantes) and murine IP-10/crg-2, chemokines which have potent
      chemotactic properties for inflammatory cells including monocytes and T
      lymphocytes. In the present work, we studied the transcriptional mechanism of
      MuRantes gene induction by virus and compared it with that of LPS in an effort to
      understand the host responses to virus and bacterial toxins at the molecular
      level. MuRantes mRNA expression is induced by Newcastle disease virus (NDV) and
      LPS in the RAW 264.7 macrophage cell line and peritoneal macrophages of LPS
      responsive C3HeB/FeJ mice. In LPS-hyporesponsive C3H/HeJ mice, only NDV induces
      this chemokine gene, indicating that the pathways of transcriptional activation
      by NDV and LPS are not identical. Using a transient transfection assay, the
      minimal virus-responsive element (VRE) was localized between nt -175 and -116.
      The VRE contains previously defined LRE motif 1 (TCAYRCTT) and motif 3
      ((T/A)GRTTTCA(G/C)TTT), which were shown to also be important for initiation of
      transcription by virus. NDV-stimulated nuclear extracts were tested for trans
      activating factors able to bind the VRE. The chromosomal protein HMG-I(C) was
      shown to bind the 3'-A.T-rich domains of the VRE, and the presence of HMG-I(C)
      was demonstrated in the VRE-protein complex formed with nuclear extracts from NDV
      stimulated, but not unstimulated cells. These findings demonstrate the role of
      HMG-I(C) in activation of MuRantes promoter by NDV.

PMID- 8662858
TI  - Purification and characterization of N-beta-alanyl-5-S-glutathionyl-3,4
      dihydroxyphenylalanine, a novel antibacterial substance of Sarcophaga peregrina
      (flesh fly).
AB  - We purified a novel antibacterial substance from immunized adult Sarcophaga and
      determined its molecular structure to be N-beta-alanyl-5-S-glutathionyl-3,4
      dihydroxyphenylalanine (5-S-GAD). We synthesized 5-S-GAD enzymatically from N
      beta-alanyl-3, 4-dihydroxyphenylalanine (beta-Ala-Dopa) and reduced glutathione
      (GSH). The antibacterial activity of 5-S-GAD was found to be due to its
      production of H2O2. This is a novel antibacterial mechanism as it differs from
      the mechanisms of known antibacterial peptides. Two possible roles of 5-S-GAD in
      insect immunity, suppression of bacterial growth and activation of a Rel family
      transcription factor, are proposed.

PMID- 8662859
TI  - Insertional tagging, cloning, and expression of the Toxoplasma gondii
      hypoxanthine-xanthine-guanine phosphoribosyltransferase gene. Use as a selectable
      marker for stable transformation.
AB  - A nonhomologous integration vector was used to identify the Toxoplasma gondii
      hypoxanthine-xanthine-guanine phosphoribosyl transferase (HXGPRT) gene by
      insertional mutagenesis. Parasite mutants resistant to 6-thioxanthine arose at a
      frequency of approximately3 x 10(-7). Genomic DNA flanking the insertion sites
      was retrieved by marker rescue and used to identify molecular clones exhibiting
      unambiguous homology to H(X)GPRT genes from other species. Sequence analysis of
      vector/genome junction sites reveals that integration of the linearized vector
      occurred with minimal rearrangement of either vector or target sequences,
      although the addition of filler DNA and small duplications or deletions of
      genomic sequences at the transgene termini was observed. Two differentially
      spliced classes of cDNA clones were identified, both of which complement hpt and
      gpt mutations in Escherichia coli. Kinetic analysis of purified recombinant
      enzyme revealed no significant differences between the two isoforms. Internally
      deleted clones spanning the genomic locus were used to create "knock-out"
      parasites, which lack all detectable HXGPRT activity. Complete activity could be
      restored to these knock-out mutants by transient transformation with either
      genomic DNA or cDNA-derived minigenes encoding both enzyme isoforms. Stable
      HXGPRT+ transformants were isolated under selection with mycophenolic acid,
      demonstrating the feasibility of HXGPRT as both a positive and negative
      selectable marker for stable transformation of T. gondii.

PMID- 8662860
TI  - Methylation of CpG island transcription factor binding sites is unnecessary for
      aberrant silencing of the human MGMT gene.
AB  - Aberrant transcriptional inactivation of the non-X-linked human O-6-methylguanine
      DNA methyltransferase (MGMT) gene has been associated with loss of open chromatin
      structure and increases in cytosine methylation in the Sp1-binding region of the
      5'-CpG island of the gene. To examine the necessity of these events for gene
      silencing, we have isolated and characterized a subline of human MGMT+ T98G
      glioma cells. The subline, T98Gs, does not express MGMT activity or MGMT mRNA,
      and exhibits no in vivo DNA-protein interactions at Sp1-like binding sites in the
      MGMT 5'-CpG island. While the MGMT CpG island is less accessible to exogenously
      added restriction enzymes in T98Gs nuclei than in T98G nuclei, it is similarly
      methylated in both T98G and T98Gs cell lines 5' and 3' to the transcription
      factor binding sites, and similarly unmethylated in the region encompassing the
      binding sites. Inappropriate transcriptional inactivation of MGMT, therefore,
      does not require methylation of transcription factor binding sites within the 5'
      CpG island. Rather, MGMT gene silencing and transcription factor exclusion from
      T98Gs MGMT CpG island binding sites is most closely associated with condensed
      chromatin structure, which is in turn indirectly influenced by distant sites of
      methylation.

PMID- 8662861
TI  - Structure-function analysis of the zinc finger region of the DnaJ molecular
      chaperone.
AB  - DnaJ is a molecular chaperone, which not only binds to its various protein
      substrates, but can also activate the DnaK cochaperone to bind to its various
      protein substrates as well. DnaJ is a modular protein, which contains a putative
      zinc finger motif of unknown function. Quantitation of the released Zn(II) ions,
      upon challenge with p-hydroxymercuriphenylsulfonic acid, and by atomic absorption
      showed that two Zn(II) ions interact with each monomer of DnaJ. Following the
      release of Zn(II) ions, the free cysteine residues probably form disulfide
      bridge(s), which contribute to overcoming the destabilizing effect of losing
      Zn(II). Supporting this view, infrared and circular dichroism studies show that
      the DnaJ secondary structure is largely unaffected by the release of Zn(II).
      Moreover, infrared spectra recorded at different temperatures, as well as
      scanning calorimetry, show that the Zn(II) ions help to stabilize DnaJ's tertiary
      structure. An internal 57-amino acid deletion of the cysteine-reach region did
      not noticeably affect the affinity of this mutant protein, DnaJDelta144-200, to
      bind DnaK nor its ability to stimulate DnaK's ATPase activity. However, the
      DnaJDelta144-200 was unable to induce DnaK to a conformation required for the
      stabilization of the DnaK-substrate complex. Additionally, the DnaJDelta144-200
      mutant protein alone was unimpaired in its ability to interact with its final
      sigma32 transcription factor substrate, but exhibited reduced affinity toward its
      P1 RepA and lambdaP substrates. Finally, these in vitro results correlate well
      with the in vivo observed partial inhibition of bacteriophage lambda growth in a
      DnaJDelta144-200 mutant background.

PMID- 8662862
TI  - The caa3 terminal oxidase of Bacillus stearothermophilus. Transient spectroscopy
      of electron transfer and ligand binding.
AB  - The thermophilic bacterium Bacillus stearothermophilus possesses a caa3-type
      terminal oxidase, which was previously purified (De Vrij, W., Heyne, R. I. R.,
      and Konings, W. N. (1989) Eur. J. Biochem. 178, 763-770). We have carried out
      extensive kinetic experiments on the purified enzyme by stopped-flow time
      resolved optical spectroscopy combined with singular value decomposition
      analysis. The results indicate a striking similarity of behavior between this
      enzyme and the electrostatic complex between mammalian cytochrome c and
      cytochrome c oxidase. CO binding to fully reduced caa3 occurs with a second order
      rate constant (k = 7.8 x 10(4)M-1 s-1) and an activation energy (E* = 6.1 kcal
      mol-1) similar to those reported for beef heart cytochrome c oxidase. Dithionite
      reduces cytochrome a with bimolecular kinetics, while cytochrome a3 (and CuB) is
      reduced via intramolecular electron transfer. When the fully reduced enzyme is
      mixed with O2, cytochrome a3, and cytochrome c are rapidly oxidized, whereas
      cytochrome a remains largely reduced in the first few milliseconds. When cyanide
      bound caa3 is mixed with ascorbate plus TMPD, cytochrome c and cytochrome a are
      synchronously reduced; the value of the second order rate constant (k = 3 x 10(5)
      M-1 s-1 at 30 degrees C) suggests that cytochrome c is the electron entry site.
      Steady-state experiments indicate that cytochrome a has a redox potential higher
      than cytochrome c. The data from the reaction with O2 reveal a remarkable
      similarity in the kinetic, equilibrium, and optical properties of caa3 and the
      electrostatic complex cytochrome c/cytochrome c oxidase.

PMID- 8662863
TI  - Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor
      negative breast cancer cells.
AB  - Nonsteroidal agent tamoxifen (Tam), a therapeutic/chemopreventive agent for
      breast cancer, inhibits protein kinase C (PKC), which is considered to be one of
      its extra-estrogen receptor sites of action. This drug is required at higher
      (>100 microM) concentrations to inhibit PKC in the test tube, whereas it is
      required at lower (1-10 microM) concentrations to induce inhibition of cell
      growth in estrogen receptor-negative cell types. To identify additional
      mechanisms of action of Tam on PKC and cell growth, studies with MDA-MB-231, an
      estrogen receptor-negative breast carcinoma cell type, have been carried out.
      Upon treatment with 5-20 microM Tam, a cytosol to membrane translocation of PKC
      occurred within 30 min, which was then followed by a down-regulation of the
      enzyme within 2 h. A transient generation of Ca2+/lipid-independent activated
      form of PKC was observed during this period. Rapidly growing cells require nearly
      2-3-fold lower concentrations (2-5 microM) of Tam than do confluent cells to
      induce changes in PKC. Furthermore, phorbol ester binding observed with intact
      cells also decreased in Tam-treated cells only under the conditions PKC was
      inactivated. Unlike phorbol esters, Tam did not directly support the membrane
      association of PKC. The release of arachidonic acid correlated with the PKC
      membrane translocation. Studies carried out with [3H]Tam revealed that Tam
      partitioned into the membrane, and there was no appreciable covalent association
      of [3H]Tam with cellular proteins within this limited time period (2 h). Various
      antioxidants (vitamin E, vitamin C, beta-carotene, catalase, and superoxide
      dismutase) inhibited all these cellular effects of Tam. Moreover, vitamin E
      strikingly blocked Tam-induced growth inhibition. To determine whether
      oxymetabolites of Tam can affect PKC permanently, OH-Tam was tested with purified
      PKC. In contrast to Tam, which reversibly inhibited PKC, OH-Tam permanently
      inactivated the enzyme by modifying the catalytic domain at lower concentrations.
      The vicinal thiols present within this domain were found to be required to induce
      this inactivation. This effect was partially blocked by various antioxidants.
      This is the first report showing the role of oxidative stress in mediating the
      actions of Tam. Taken together these results suggest that Tam, by initially
      partitioning into the membranes, induces a generation of transmembrane signals
      and an oxidative stress to elicit the membrane association of PKC, followed by an
      irreversible activation, and subsequent down-regulation of this enzyme, which, in
      part, may lead to cell growth inhibition.

PMID- 8662864
TI  - DNA knotting abolishes in vitro chromatin assembly.
AB  - Topological knots can be formed in vitro by incubating covalently closed double
      stranded DNA and purified topoisomerase II from the yeast Saccharomyces
      cerevisiae in an ATP-dependent reaction. Knotting production requires a starting
      enzyme/DNA mass ratio of 1. Analysis of knotted DNA was carried out by using both
      one- and two-dimensional agarose gel electrophoresis. The knots generated are
      efficiently untied, and give relaxed DNA rings, by catalytic amounts of
      topoisomerase II, but not by topoisomerase I. Time course analysis shows the
      knotting formation over relaxed and supercoiled DNA. When supercoiled DNA was
      used as a susbtrate, knots appear immediately whereas no transient relaxed rings
      were observed. The cell-free extract from Xenopus oocytes S-150 cannot assemble
      nucleosomes on knotted DNA templates as revealed by topological and micrococcal
      nuclease analysis. Nevertheless, the presence of knotted DNA templates does not
      inhibit the assembly over the relaxed plasmid. Finally, a pretreatment of knotted
      DNA with trace amounts of topoisomerase II before the addition of the S-150
      yields a canonical minichromosome assembled in vitro. Taking into account these
      results, I suggest a mechanism of chromatin assembly regulation directed by
      topoisomerase II.

PMID- 8662865
TI  - Role of phosphorylation on DNA binding and transcriptional functions of human
      progesterone receptors.
AB  - To study the function of human progesterone receptor (hPR) phosphorylation, we
      have tested four sets of serine to alanine substitution mutants: 10 serine
      clusters, located in regions common to both hPR isoforms (the M-series mutants)
      were mutated in A-receptors and B-receptors; 6 serine clusters located in the B
      upstream segment (BUS; the B-series mutants) were mutated individually and
      collectively and cloned into B-receptors and into BUS-DBD-NLS, a constitutive
      transactivator, in which the AF3 function of BUS is fused to the DNA binding
      domain (DBD) and nuclear localization signal (NLS) of hPR. Transcription by most
      of the M-series mutants resembles that of wild-type A- or B-receptors. Mutation
      of 3 sites, Ser190 at the N terminus of A-receptors, a cluster of serines just
      upstream of the DBD, or Ser676 in the hinge region, inhibits transcription by 20
      50% depending on cell or promoter context. These sites lie outside the AF1
      activation function. M-series mutants are substrates for a hormone-dependent
      phosphorylation step, and they all bind well to DNA. Progressive mutation of the
      B-series clusters leads to the gradual dephosphorylation of BUS, but only the 6
      site mutant, involving 10 serine residues, is completely dephosphorylated. These
      data suggest that in BUS alternate serines are phosphorylated or dephosphorylated
      at any time. However, even when BUS is completely dephosphorylated, both BUS-DBD
      NLS and full-length B-receptors remain strong transactivators. Mutant B-receptors
      also do not acquire the dominant negative properties of A-receptors, and they
      retain the ability to activate transcription in synergy with 8-Br-cAMP and
      antiprogestins. We conclude that phosphorylation has subtle effects on the
      complex transcriptional repertoire that distinguishes the two hPR isoforms and
      does not influence transactivation mediated by AF1 or AF3, but subserves other
      functions.

PMID- 8662866
TI  - Coordinate gene expression of the alpha3, alpha4, and alpha5 chains of collagen
      type IV. Evidence from a canine model of X-linked nephritis with a COL4A5 gene
      mutation.
AB  - Canine X-linked hereditary nephritis is an animal model for human X-linked
      hereditary nephritis with a premature stop codon in the alpha5(IV) gene of
      collagen type IV. We used this model to examine the other alpha(IV) chains at the
      mRNA and protein level in the kidney, since in human X-linked hereditary
      nephritis, the alpha3(IV) and alpha4(IV) chains are often absent from the
      glomerular basement membrane, although both are encoded by autosomal genes. cDNA
      probes for the alpha1(IV)-alpha6(IV) chains were generated from normal dog kidney
      using the polymerase chain reaction. Sequences were >/=88% identical at the DNA
      level and >/=92% identical at the protein level to the respective human alpha(IV)
      chains. By Northern analysis, transcripts for the alpha1(IV), alpha2(IV), and
      alpha6(IV) chains were detected at comparable levels in both normal and affected
      male dog kidney RNA. As previously shown, the transcript for the alpha5(IV) chain
      was reduced to approximately 10% of normal. Unexpectedly, the alpha3(IV) and
      alpha4(IV) transcripts were both decreased >/=77% in affected male dog kidney,
      suggesting a mechanism coordinating the expression of these three basement
      membrane components. The NC1 domain of collagen type IV isolated from normal dog
      glomeruli was positive for the alpha3(IV), alpha4(IV), and alpha5(IV) chains by
      Western blotting. In contrast, in the NC1 domain isolated from affected dog
      glomeruli, these three chains were not detectable, except for a trace of
      alpha3(IV) dimer. In X-linked hereditary nephritis, the absence of the alpha3(IV)
      and alpha4(IV) chains from glomerular basement membrane may reflect factors
      acting at the transcriptional and/or translational level in addition to the
      protein assembly level.

PMID- 8662867
TI  - Cloning and expression of acetylcholinesterase from Bungarus fasciatus venom. A
      new type of cooh-terminal domain; involvement of a positively charged residue in
      the peripheral site.
AB  - As deduced from cDNA clones, the catalytic domain of Bungarus fasciatus venom
      acetylcholinesterase (AChE) is highly homologous to those of other AChEs. It is,
      however, associated with a short hydrophilic carboxyl-terminal region, containing
      no cysteine, that bears no resemblance to the alternative COOH-terminal peptides
      of the GPI-anchored molecules (H) or of other homomeric or heteromeric tailed
      molecules (T). Expression of complete and truncated AChE in COS cells showed that
      active hydrophilic monomers are produced and secreted in all cases, and that
      cleavage of a very basic 8-residue carboxyl-terminal fragment occurs upon
      secretion. The COS cells produced Bungarus AChE about 30 times more efficiently
      than an equivalent secreted monomeric rat AChE. The recombinant Bungarus AChE,
      like the natural venom enzyme, showed a distinctive ladder pattern in
      nondenaturing electrophoresis, probably reflecting a variation in the number of
      sialic acids. By mutagenesis, we showed that two differences (methionine instead
      of tyrosine at position 70; lysine instead of aspartate or glutamate at position
      285) explain the low sensitivity of Bungarus AChE to peripheral site inhibitors,
      compared to the Torpedo or mammalian AChEs. These results illustrate the
      importance of both the aromatic and the charged residues, and the fact that
      peripheral site ligands (propidium, gallamine, D-tubocurarine, and fasciculin 2)
      interact with diverse subsets of residues.

PMID- 8662868
TI  - Covalent structure, synthesis, and structure-function studies of mesentericin Y
      105(37), a defensive peptide from gram-positive bacteria Leuconostoc
      mesenteroides.
AB  - A 37-residue cationic antimicrobial peptide named mesentericin Y 105(37) was
      purified to homogeneity from cell-free culture supernatant of the Gram-positive
      bacterium Leuconostoc mesenteroides. The complete amino acid sequence of the
      peptide, KYYGNGVHCTKSGCSVNWGEAASAGIHRLANGGNGFW, has been established by automated
      Edman degradation, mass spectrometry, and solid phase synthesis. Mesentericin Y
      105(37) contains a single intramolecular disulfide bond that forms a 6-membered
      ring within the molecule. Mesentericin Y 105(37) was synthesized by the solid
      phase method. The synthetic replicate was shown to be indistinguishable from the
      natural peptide with respect to electrophoretic and chromatographic properties,
      mass spectrometry analysis, automated amino acid sequence determination, and
      antimicrobial properties. At nanomolar concentrations, synthetic mesentericin Y
      105(37) is active against Gram+ bacteria in the genera Lactobacillus and
      Carnobacterium. Most interestingly, the peptide is inhibitory to the growth of
      the food-borne pathogen Listeria. CD spectra of mesentericin Y 105(37) in low
      polarity medium, which mimic the lipophilicity of the membrane of target
      organisms, indicated 30-40% alpha-helical conformation, and predictions of
      secondary structure suggested that the peptide can be configured as an
      amphipathic helix spanning over residues 17-31. To reveal the molecular basis of
      the specificity of mesentericin Y 105(37) targetting and mode of action, NH2- or
      COOH-terminally truncated analogs together with point-substituted analogs were
      synthesized and evaluated for their ability to inhibit the growth of Listeria
      ivanovii. In sharp contrast with broad spectrum alpha-helical antimicrobial
      peptides from vertebrate animals, which can be shortened to 14-18 residues
      without deleterious effect on potency, molecular elements responsible for anti
      Listeria activity of mesentericin Y 105(37) are to be traced at once to the NH2
      terminal tripeptide KYY, the disulfide bridge, the putative alpha-helical domain
      17-31, and the COOH-terminal tryptophan residue of the molecule. It is proposed
      that the amphipathic helical domain of the peptide interacts with lipid bilayers,
      leading subsequently to alteration of the membrane functions, whereas residues 1
      14 form part of a recognition structure for a membrane-bound receptor, which may
      be critical for peptide targetting. Because mesentericin Y 105(37) is easy to
      synthesize at low cost, it may represent a useful and tractable tool as a
      starting point for the design of more potent analogs that may be of potential
      applicability in foods preservation.

PMID- 8662869
TI  - N-linked glycoproteins are related to schizogony of the intraerythrocytic stage
      in Plasmodium falciparum.
AB  - Although the existence of O-linked oligosaccharide residues in glycoproteins of
      Plasmodium falciparum has been shown, the existence of N-linked glycoproteins is
      still a matter of controversy and skepticism. This report demonstrates the
      unequivocal presence of N-linked glycoproteins in P. falciparum, principally in
      the ring and young trophozoite stages of the intraerythrocytic cycle. These
      glycoproteins lose their capacity to bind to concanavalin A-Sepharose after
      treatment of cultures with tunicamycin under conditions that do not affect
      protein synthesis. When the glycoproteins were treated with N-Glycanase(R),
      oligosaccharides were released. It was possible to identify an N-linked
      glycoprotein of >200 kDa in the ring stage and also N-linked glycoproteins in the
      range of 200-30 kDa in the trophozoite stage. Treatment of trophozoites with 12
      microM tunicamycin inhibited differentiation to the schizont stage. To our
      knowledge, this is the first report in the literature unequivocally showing N
      linked glycoproteins in trophozoites of P. falciparum as well as their importance
      for the differentiation of the intraerythrocytic stages of this parasite.

PMID- 8662871
TI  - Complete removal of sphingolipids from the plasma membrane disrupts cell to
      substratum adhesion of mouse melanoma cells.
AB  - GM-95, a mutant cell line derived from mouse melanoma MEB-4 cells, is deficient
      in glycosphingolipids (GSLs) due to the lack of ceramide glucosyltransferase-1
      activity (Ichikawa, S., Nakajo, N., Sakiyama, H., and Hirabayashi, Y. (1994)
      Proc. Natl. Acad. Sci. U. S. A. 91, 2703-2707). In this study, we examined the
      involvement of the complex sphingolipids in cell to substratum adhesion.
      Immunofluorescent and chemical analyses revealed that the complex sphingolipids
      were significantly concentrated in the detergent-insoluble substrate attachment
      matrix of both GM-95 and MEB-4 cells. In spite of the absence of GSLs, GM-95
      cells retained the ability to adhere to extracellular matrix (ECM) proteins such
      as fibronectin, collagen, and laminin. When both GM-95 and MEB-4 cells were
      treated with neutral sphingomyelinase, GM-95 cells were rounded up and detached
      from all ECM proteins examined. In contrast, neither the morphology nor the
      adherence of MEB-4 cells was altered. Under this treatment, sphingomyelin (SM)
      became undetectable in both cells. A similar inhibition was observed upon
      pretreatment of cells with fumonisin B1 or ISP-1, both of which block the
      synthesis of ceramide, a common precursor of both GSLs and SM. Stable
      transfectants expressing GSLs, which were established by transfection of
      glucosyltransferase-1 cDNA into GM-95 cells, became resistant to neutral
      sphingomyelinase-mediated rounding up and detachment from ECM proteins. In
      conclusion, the complex sphingolipids play critical roles in cell to substratum
      adhesion, and the presence of either GSLs or SM is sufficient for the adhesion.

PMID- 8662872
TI  - Replacement of gly815 in helicase motif V alters the single-stranded DNA
      dependent ATPase activity of the herpes simplex virus type 1 helicase-primase.
AB  - Herpes simplex virus type 1 encodes a helicase-primase complex composed of the
      products of the UL5, UL52, and UL8 genes. A subcomplex consisting of the UL5 and
      UL52 proteins purified from insect cells also displays ATPase, helicase, and
      primase activities. UL5 contains six motifs conserved in superfamily I of known
      and/or putative helicase proteins. Consistent with the ability to hydrolyze ATP,
      motifs I and II resemble a nucleotide binding site. Although the role of the
      other four motifs is not known, single amino acid substitutions created in
      conserved residues in all six motifs abolish the ability of UL5 to support viral
      DNA replication in vivo (Zhu, L., and Weller, S. K. (1992) J. Virol. 66, 469
      479). In one such mutation, a highly conserved glycine in motif V (Gly815) is
      replaced with an alanine. Although the UL5(G815A) protein does not support viral
      DNA replication in vivo, the purified UL5(G815A).52 subcomplex retains primase
      and helicase activities and supports strand displacement DNA synthesis on a
      preformed replication fork in the presence of the other HSV-1 replication
      proteins. The major difference between the wild-type and variant protein is that
      the UL5(G815A).52 subcomplex displays an increased Km for single-stranded DNA and
      decreased Kcat for single-stranded DNA-dependent ATPase activity. Several
      hypotheses for the role of motif V in the function of the UL5 helicase in HSV-1
      DNA replication are considered. This is the first report of a biochemical
      analysis of a motif V variant in any member of helicase superfamily I.

PMID- 8662873
TI  - Stoichiometry and DNA unwinding by the bacteriophage T4 41:59 helicase.
AB  - The bacteriophage T4 41 protein is a replicative helicase that forms a hexamer in
      the presence of ATP and associates with the T4 59 protein. The stoichiometry of
      the 41:59 helicase complex and its mechanism for DNA unwinding have been
      investigated using steady-state and single-turnover kinetics. A partial duplex
      DNA fork containing two regions of single-stranded DNA (ssDNA) of 30 nucleotides
      each, and 30 base pairs served as the substrate. 59 was found to increase the
      steady-state unwinding rate of the substrate by 200-fold over the rate of 41
      alone. Maximum unwinding occurred when 59 and 41 were equimolar, revealing a 1:1
      stoichiometry for the complex. Varying 41 while holding 59 constant resulted in
      sigmoidal kinetics suggesting strong cooperativity for formation of the 41
      hexamer and providing a lower limit for hexamer assembly of 65 nM. Substrates
      were prepared that contained a biotin-streptavidin block in either the leading or
      lagging strand of the duplex region of the substrate. The first order rate
      constant for unwinding was reduced only when the block was placed in the lagging
      strand of the DNA fork, indicating that the helicase interacts primarily with the
      lagging DNA strand.

PMID- 8662875
TI  - Down-regulation of platelet-derived growth factor receptor expression during
      terminal differentiation of 3T3-L1 pre-adipocyte fibroblasts.
AB  - The transcription and expression of platelet-derived growth factor (PDGF)
      receptors (PDGFRs) is down-regulated as a consequence of entry into the
      replicative cell cycle (Vaziri, C., and Faller, D. V. (1995) Mol. Cell. Biol. 15,
      1244-1253). In this study, we have investigated the expression of PDGFRs during
      terminal differentiation, a process in which cells exit from the cell cycle. When
      treated with appropriate hormonal stimuli, 3T3-L1 fibroblasts initiate a
      differentiation program resulting in conversion to lipid-accumulating, adipocyte
      like cells. Pre-adipocytes express amounts of PDGFalphaR and PDGFbetaR mRNA and
      protein that are similar to levels expressed in other murine 3T3 fibroblasts. In
      contrast, the expression of both alpha and beta receptor transcripts is greatly
      reduced in differentiated 3T3-L1 cells. The loss of PDGFR mRNA following
      induction of differentiation precedes morphological conversion as well as the
      induction of many adipocyte-specific genes. The amounts of cell surface PDGFR
      protein diminish in parallel with the mRNA levels during differentiation, as
      shown by Western blotting and PDGF-binding assays. The reduced expression of
      PDGFRs does not reflect a general down-regulation of growth factor receptors, as
      expression of the type 1 FGFR is unaffected by terminal differentiation. The
      PDGFbetaR promoter drives strong expression of a luciferase reporter gene in pre
      adipocytes, but not in differentiated cells, indicating that the decrease in
      PDGFR expression following induction of differentiation is a transcriptionally
      regulated event. Decreased PDGFR expression in differentiated cells is associated
      with impaired biological responsiveness to PDGF, as shown by reduced activation
      of mitogen-activated protein-kinase following PDGF stimulation, and decreased
      chemotactic responsiveness to PDGF. Our data suggest that PDGFR down-regulation
      is an important mechanism for reducing PDGF-responsiveness in terminally
      differentiated 3T3-L1 cells.

PMID- 8662874
TI  - A model of protein targeting mediated by immunophilins and other proteins that
      bind to hsp90 via tetratricopeptide repeat domains.
AB  - We have shown recently that the immunophilins CyP-40 and FKBP52/hsp56 bind to a
      common site on hsp90 and that they exist in separate heterocomplexes with the
      glucocorticoid receptor (GR). FKBP52/hsp56 binds to hsp90 via its
      tetratricopeptide repeat (TPR) domains, it is not required for GR.hsp90
      heterocomplex assembly, and it is thought to play a role in targeted movement of
      the GR. In this work we examine the hsp90 binding of four proteins (FKBP52/hsp56,
      CyP-40, p50, Mas70p) thought to be involved in targeted protein trafficking.
      FKBP52/hsp56 and CyP-40 (each with three TPRs), localize to the nucleus and
      nucleoli, respectively, and form relatively weak complexes with hsp90 that are
      competed by a CyP-40 fragment containing its three TPRs. The p50 component of the
      Src.hsp90 and Raf.hsp90 heterocomplexes localizes to cytoskeletal fibers
      extending from the perinuclear region to the plasma membrane and forming a rim
      under the plasma membrane of endothelial cells. p50, Mas70p (seven TPRs), which
      is a receptor for mitochondrial import, and the p60 (six to eight TPRs) component
      of the steroid receptor.hsp90 heterocomplex assembly system bind very tightly to
      hsp90 in a manner that is not competed by the CyP-40 fragment. However,
      bacterially expressed p60 blocks the binding of p50, Mas70p, FKBP52/hsp56, and
      CyP-40 to purified hsp90. The data are consistent with binding of all of these
      proteins to a site on hsp90 that is a general TPR domain acceptor. Our
      localization and binding data are used to develop a model in which proteins that
      are chaperoned by hsp90 move as dynamic complexes to their cellular sites of
      action, with the TPR-containing protein participating in targeting the movement
      of the complexes.

PMID- 8662876
TI  - A point mutation in interleukin-2 that alters ligand internalization.
AB  - In previous studies, we have identified an interleukin-2 (IL-2) analog containing
      a point mutation at position 51 (T51P) that expresses nearly wild-type
      bioactivity, yet has approximately 10-fold lower receptor binding affinity. Since
      ligand-dependent receptor internalization may be the rate-limiting step
      controlling the duration of IL-2 receptor signaling, a reduction in the receptor
      internalization rate could contribute to the observed response enhancement for
      this analog. To evaluate this possibility, we compared the internalization of IL
      2 and T51P in three separate assays. While the internalization rate for IL-2
      agreed with values determined by others, the internalization of T51P was markedly
      reduced. The receptor binding rate constants for this analog were only slightly
      different; thus, altered binding kinetics could not explain the decreased
      internalization rate. The effects of reduced internalization were also observable
      in bioassays, where T51P maintained T-cell proliferation for a longer period
      compared with IL-2. These results indicate that the T51P point mutation reduces
      the receptor internalization rate compared with IL-2 in a fashion that is
      independent of the dissociation rate. This analog may represent a new approach to
      the preparation of cytokine analogs with potentiated agonist and antagonist
      properties.

PMID- 8662877
TI  - Cloning and characterization of a novel serine/threonine protein kinase expressed
      in early Xenopus embryos.
AB  - We have cloned from a Xenopus ovary cDNA library a novel protein kinase gene
      whose expression peaks in the oocyte and unfertilized egg, begins to decrease
      gradually after fertilization, and disappears during the gastrulation stage of
      embryogenesis. The cloned gene, termed XEEK1 (for Xenopus egg and embryo kinase),
      encodes a protein with a predicted molecular mass of 49 kDa. Bacterially
      expressed XEEK1 migrates at 57 kDa upon polyacrylamide gel electrophoresis
      analysis, and a XEEK1-specific antibody recognizes a protein of 57 kDa in Xenopus
      oocyte and egg extracts. The XEEK1 kinase domain shares 35% identity
      (approximately 65% similarity) with the yeast SNF1 kinase and related kinases.
      However, expression of XEEK1 does not complement a snf1 deletion mutation in
      yeast, which suggests that it is probably not a Xenopus homolog of SNF1.
      Recombinant XEEK1 protein autophosphorylates on threonine residues in vitro in a
      reaction that prefers Mn2+ to Mg2+ ions. Site-directed mutagenesis of the
      conserved lysine residue (Lys-81) within the kinase domain to isoleucine totally
      abolishes kinase activity, and threonine 192 has been identified as the
      autophosphorylation site. This site is distinct from the conserved threonine (Thr
      215 in XEEK1) present in the protein kinase activation loop that is the site of
      autophosphorylation for many protein kinases. XEEK1 is a substrate for the cyclic
      AMP-dependent protein kinase both in vitro and in vivo, suggesting a possible
      mode of regulation of XEEK1. An immunoprecipitate of oocyte/egg extracts with
      anti-XEEK1 serum contains a protein of approximately 155 kDa that may be a
      substrate and/or a regulatory component of the kinase.

PMID- 8662878
TI  - c-sis/PDGF-B promoter transactivation by the Yax protein of human T-cell leukemia
      virus type 1.
AB  - The human c-sis proto-oncogene promoter is transactivated by the human T-cell
      leukemia virus type 1 Tax protein in human Jurkat T-cells. Transactivation was >7
      fold in Jurkat cells stably expressing the Tax protein (Jurkat-Tax) than in
      Jurkat E6.1 cells and was further enhanced in Jurkat-Tax cells stimulated with 12
      O-tetradecanoylphorbol-13-acetate and the calcium ionophore, ionomycin. Deletion
      analysis showed that a 167-base pair promoter fragment retained full Tax
      responsiveness. Insertion of this minimal Tax-responsive region into a
      heterologous, minimal promoter resulted in approximately a 7-fold increase of
      transcriptional activation in the presence of Tax. Linker-scanning insertion
      analysis of this region identified Tax-responsive elements at nucleotides -64 to 
      45 (TRE1) and -34 to -15 (TATA box region). TRE1 contains a consensus binding
      site for the Sp family of transcription factors. The TATA box region corresponds
      to the TATA box and its 3'-neighboring sequence. Gel-shift and antibody
      supershift analysis of TRE1-binding proteins in unstimulated Jurkat E6.1 and
      Jurkat-Tax nuclear extracts identified Sp1 and Sp3 as the main TRE1 binding
      factors. Nuclear extracts from stimulated Jurkat E6.1 and Jurkat-Tax cells
      identified an additional TRE1 binding factor, Egr-1. These studies define a novel
      mechanism whereby Tax transactivates the c-sis promoter.

PMID- 8662879
TI  - Re-expression of the mannose 6-phosphate receptors in receptor-deficient
      fibroblasts. Complementary function of the two mannose 6-phosphate receptors in
      lysosomal enzyme targeting.
AB  - We have previously generated primary embryonic fibroblasts lacking either the
      cation-independent mannose 6-phosphate/insulin-like growth factor II receptor
      (MPR) or the cation-dependent MPR, two trans-membrane proteins that bind the
      mannose 6-phosphate (Man-6-P) recognition marker on soluble lysosomal enzymes
      (Ludwig, T., Munier-Lehmann, H., Bauer, U., Hollinshead, M., Ovitt, C., Lobel,
      P., and Hoflack, B.(1994) EMBO J. 13, 3430-3437). These two cell types partially
      missort phosphorylated lysosomal enzymes. Using two-dimensional gel
      electrophoresis, we show here that they secrete, in a large part, different
      phosphorylated ligands. In order to better understand the sorting function of the
      MPRs, we have re-expressed each MPR in MPR-negative fibroblasts. We show that the
      MPRs have similar capacities for transporting the bulk of the newly synthesized
      lysosomal enzymes and that they target individual ligands with various
      efficiencies. However, high levels of one MPR do not fully compensate for the
      absence of the other, demonstrating that the two MPRs have complementary
      targeting functions, perhaps by recognizing different features on lysosomal
      enzymes. The analysis of the phosphorylated oligosaccharides shows that the
      ligands missorted in the absence of the cation-dependent MPR are slightly but
      significantly depleted in oligosaccharides with two Man-6-P residues, when
      compared with those missorted in the absence of the cation-independent MPR. While
      these results could explain some differences between the structure and the
      sorting function of the two MPRs, they strongly suggest that the reason why cells
      express two different but related MPRs is to maintain an efficient Man-6-P
      dependent targeting process that could be potentially regulated by MPR
      expression.

PMID- 8662880
TI  - Bioactive 6-nitronorepinephrine identified in mammalian brain.
AB  - Norepinephrine (NE) (von Euler, U. S. (1972) in Catecholamines (Blaschko, H., and
      Muscholl, E., eds.) pp. 186-230, Springer-Verlag, Berlin) and nitric oxide (NO.)
      function as neurotransmitters in the nervous system. We have shown that NE levels
      in the rat hypothalamic paraventricular nucleus (Shintani, F., Kato, R.,
      Kinoshita, N., Kanba, S., Asai, M., and Nakaki, T.(1995) Proceedings of the
      Satellite Symposium, 4th IBRO World Congress on Neuroscience, Otsu, 1995)
      diminish in the presence of NO.. This observation prompted us to explore the
      possibility of an in vivo interaction between NE and NO. or NO.-related
      molecules. In fact, nitration of NE has been shown to occur in vitro (d'Ischia,
      M., and Costantini, C. (1995) Bioorg. Med. Chem. 3, 923-927). We now report the
      identification of 6-nitronorepinephrine in the mammalian brain. Amounts of 6
      nitronorepinephrine in the rat brain were attenuated by intraperitoneal
      administration of an inhibitor of nitric oxide synthase, NG-nitro-L-arginine
      methyl ester (L-NAME). This was reversed by coadministration of L-arginine,
      suggesting that nitric oxide synthase participated in the formation of 6
      nitronorepinephrine. Moreover, we found that 6-nitronorepinephrine inhibits the
      activity of catechol O-methyltransferase, as well as NE transport into rat
      synaptosomes. A rat brain microdialysis experiment showed that perfusion of 6
      nitronorepinephrine into the rat paraventricular nucleus significantly elevated
      NE while decreasing 3-methoxy-4-hydroxyphenylglycol and that L-NAME administered
      intraperitoneally decreased NE and increased 3-methoxy-4-hydroxyphenylglycol.
      These observations suggest that 6-nitronorepinephrine generated in nuclei
      containing both adrenergic and nitrergic neurons inhibits NE inactivation. We
      propose that 6-nitronorepinephrine is a potential signal molecule linking the
      actions of NE and NO..

PMID- 8662881
TI  - Selective mutations in cloned and expressed alpha-macroglobulin receptor binding
      fragment alter binding to either the alpha2-macroglobulin signaling receptor or
      the low density lipoprotein receptor-related protein/alpha2-macroglobulin
      receptor.
AB  - alpha2-Macroglobulin (alpha2M) activated with methylamine binds to two distinct
      cell-surface receptors: low density-lipoprotein receptor-related protein/alpha2M
      receptors and alpha2M signaling receptors. Binding to lipoprotein receptor
      related protein/alpha2M receptor but not alpha2M signal receptor is inhibitable
      by another ligand, receptor-associated protein. Direct binding studies with a
      recombinant receptor binding fragment (RBF) from rat alpha1M and murine
      macrophages demonstrate two classes of binding sites of apparent Kd = 90 pM (1500
      sites/cell) and 40 nM (60,400 sites/cell). Receptor-associated protein competes
      with RBF for binding to the lower but not the higher affinity site. Site-directed
      mutation of Lys-1374 (human numbering) in RBF to Arg or Ile residues almost
      completely abolishes signal transduction as compared to wild-type RBF. Direct
      binding studies with K1374R demonstrated no significant alteration in binding to
      the lower affinity site; however, binding to the high affinity site is reduced by
      83%. Mutation of Lys-1370 to Ala resulted in a 4-5-fold increase in the Kd for
      binding to the lower affinity site with no significant alteration in binding to
      the high affinity site or signal transduction properties. Studies demonstrate
      comparable internalization and degradation of wild-type RBF and K1374R; however,
      internalization and degradation of K1370A is negligible. These studies suggest
      that regions around Lys-1370 and Lys-1374 are involved in lipoprotein receptor
      related protein/alpha2M receptor and alpha2M signaling receptor binding,
      respectively.

PMID- 8662882
TI  - Exchanging interleukin-8 and melanoma growth-stimulating activity receptor
      binding specificities.
AB  - Interleukin-8 (IL-8), a CXC chemokine, is known to bring about chemotaxis and
      activation of neutrophils through high affinity binding to at least two distinct
      receptors, receptor-A and receptor-B. The IL-8 homolog melanoma growth
      stimulating activity (MGSA) is also active toward neutrophils. In contrast to IL
      8, MGSA binds receptor-B with high affinity and binds receptor-A with
      approximately 400-fold lower affinity. Using the structure of IL-8 (Clore et
      al.(1990) Biochemistry, 29, 1689-1696; Baldwin et al. (1991) Proc. Natl. Acad.
      Sci. U.S.A. 88, 502-506) and the NMR-determined structure of MGSA (Fairbrother et
      al. (1994) J. Mol. Biol. 242, 252-270), we designed variants of both IL-8 and
      MGSA to investigate the basis of specificity for binding of these chemokines to
      the IL-8 receptors. The most outstanding structural difference between IL-8 and
      MGSA lies in the loop preceding the first beta-strand. When the corresponding
      (shorter) loop from MGSA was swapped into IL-8, both receptor-A and receptor-B
      binding affinities were significantly (>300-fold) reduced. However, with
      additional mutations that affect packing interactions, an IL-8 variant specific
      for receptor-B binding was produced. Conversely, when the same loop from IL-8 was
      swapped into MGSA, receptor-B binding was maintained with only a approximately 30
      fold reduction in receptor-A affinity. Again, mutations affecting packing of the
      loop yielded a MGSA variant with high affinity for both receptors, like IL-8.
      Finally, we show, through point mutations in a monomeric IL-8 framework, that
      individual side chain substitutions can affect receptor specificity.

PMID- 8662883
TI  - Role of tetrahydrobiopterin availability in the regulation of nitric-oxide
      synthase expression in human mesangial cells.
AB  - Human mesangial cells express an inducible form of nitric-oxide synthase (iNOS)
      after treatment with cytokines. Tetrahydrobiopterin (BH4), an essential cofactor
      for NOS, is required for cytokine-induced NO generation. We report here that BH4
      is necessary not only for the activity but also for the expression of iNOS in
      human mesangial cells. Inhibition of de novo BH4 synthesis with 2,4-diamino-6
      hydroxypyrimidine (DAHP) significantly attenuated iNOS activity as well as mRNA
      and protein expression in response to interleukin 1beta plus tumor necrosis
      factor alpha (IL-1beta/TNF-alpha). In contrast, sepiapterin, which provides BH4
      through the pterin salvage pathway, strongly potentiated IL-1beta/TNF-alpha
      induced iNOS expression and abrogated the inhibitory effect of DAHP. Inhibition
      of the pterin salvage pathway with methotrexate abolished sepiapterin
      potentiation of iNOS induction but did not alter the effect of IL-1beta/TNF
      alpha. Determination of intracellular pteridines confirmed that sepiapterin
      markedly raised BH4 content, an effect that was blocked by methotrexate. These
      results suggest that BH4 availability plays an important role in the regulation
      of iNOS expression. The effect of BH4 appears to be mediated, at least in part,
      by an increase in mRNA stability, as indicated by the observation that DAHP
      shortened, whereas sepiapterin prolonged the half-life of IL-1beta/TNF-alpha
      induced iNOS mRNA. Taken together, our results suggest that the biosynthesis of
      BH4 contributes to cytokine induction of iNOS expression in human mesangial cells
      through the stabilization of iNOS mRNA.

PMID- 8662884
TI  - Schwann cells secrete a novel collagen-like adhesive protein that binds N
      syndecan.
AB  - A heparin-binding glycoprotein was purified from conditioned medium of cultured
      rat Schwann cells. The protein, p200, which has an apparent molecular mass of
      approximately 200 kDa, was identified by its ability to bind the cell surface
      heparan sulfate proteoglycan N-syndecan (syndecan-3) in a membrane overlay assay.
      Soluble heparin but not chondroitin sulfate inhibited the binding, suggesting the
      involvement of heparan sulfate chains of proteoglycan in the interaction.
      Purified p200 promoted the attachment and spreading of Schwann cells. Adhesion to
      p200 was blocked by heparin, suggesting that heparan sulfate proteoglycans are
      cell surface receptors for p200. The tissue distribution of p200 was determined
      by immunoblot analysis with anti-p200 antibodies. Among neonatal rat tissues
      examined p200 was detected only in sciatic nerve and, at lower levels, in
      skeletal muscle. p200 expression in sciatic nerve was detectable only during the
      first 2-3 weeks of postnatal development and was not detected in adult rats.
      Immunofluorescent staining of rat sciatic nerve showed that p200 was localized in
      the extracellular matrix surrounding individual Schwann cells-axon units. Two
      tryptic peptides from p200 were purified and sequenced. These contained multiple
      GXX collagen-like repeats. Bacterial collagenase digestion of p200 produced a
      product with an apparent molecular mass of approximately 90 kDa. These data
      suggest that Schwann cells secrete an apparently novel collagen-like adhesive
      protein that interacts with cells through cell surface heparan sulfate
      proteoglycans.

PMID- 8662885
TI  - Dependence of epithelial intercellular junction biogenesis on thapsigargin
      sensitive intracellular calcium stores.
AB  - Perturbation of potentially regulatable endoplasmic reticulum (ER) calcium stores
      with the Ca-ATPase inhibitor, thapsigargin (TG), perturbs the formation of
      desmosomes and tight junctions during polarized epithelial cell biogenesis,
      despite the development of cell contact. In a Madin-Darby canine kidney cell
      model for intercellular junction assembly, TG treatment inhibited the development
      of transepithelial electrical resistance (TER), a measure of tight junction
      assembly, in a dose-dependent manner. The TG-induced inhibition of tight junction
      assembly was paralleled by a defect in the sorting of the tight junction protein,
      ZO-1. An even more dramatic delay in sorting of the desmosomal protein,
      desmoplakin, was observed in the presence of TG. In addition, while both ZO-1 and
      desmoplakin-I in control cells were shown to become associated with the Triton X
      100 insoluble cytoskeleton during intercellular junction assembly, prior
      treatment with 100 nM TG diminished this biochemical stabilization into the
      detergent-insoluble fraction, particularly in the case of ZO-1. Although
      spectrofluorimetric measurements in fura-2 loaded Madin-Darby canine kidney cells
      confirmed the occurrence of TG-mediated release of calcium from internal stores,
      total cytosolic calcium during junction assembly remained similar to untreated
      cells. Therefore, the presence of cytosolic calcium alone is not sufficient for
      normal intercellular junction biogenesis if intracellular stores are perturbed by
      TG. The results indicate the presence of calcium-sensitive intracellular
      mechanisms involved in the sorting and cytoskeletal stabilization of both tight
      junction and desmosomes and suggest a role for calcium-dependent signaling
      pathways at an early (possibly common) step in polarized epithelial biogenesis.

PMID- 8662886
TI  - The microsomal triglyceride transfer protein facilitates assembly and secretion
      of apolipoprotein B-containing lipoproteins and decreases cotranslational
      degradation of apolipoprotein B in transfected COS-7 cells.
AB  - We studied the role of microsomal triglyceride transfer protein (MTP) in the
      synthesis, secretion, and cotranslational degradation of apolipoprotein (apo) B
      using nonhepatic COS-7 cells that expressed C-terminally truncated forms of apoB
      (from apoB15 to apoB94) with or without the large subunit of human MTP. With the
      exception of apoB15 and apoB18, secretion of all of the apoB forms was stimulated
      by expression of MTP, even though a small amount of short apoB forms (</=apoB48)
      could be secreted by cells transfected with apoB alone. The majority of the apoB
      protein, including apoB72 and apoB94, was secreted as high density lipoprotein
      (1.08-1.17 g/ml). Pulse-chase experiments revealed that the secretion efficiency
      of apoB94 and apoB72 was low (ranging from 2 to 12%). The failure to secrete
      buoyant lipoproteins and the low secretion efficiency were associated with
      insufficient lipid synthesis by the cells. The incorporation of [3H]oleate into
      cellular triglyceride and phosphatidylcholine by COS cells over a 2-h period was
      28 and 38%, respectively, of that by rat hepatoma (McA-RH7777) cells. In addition
      to the desired full-length apoB, cells transfected with large constructs
      (>/=apoB60) also produced smaller species with a size of approximately220 kDa
      (designated B48-like protein). Coexpression with MTP decreased formation of the
      B48-like proteins by 40-60%. The reduction in B48-like protein formation was
      specific to MTP expression; coexpression with other proteins (e.g. apoA-I or
      apoB15) did not alter B48-like protein production. Kinetic analysis suggested
      that B48-like proteins were produced concurrently (cotranslational) with the full
      length apoB94 and apoB72 and were not products of post-translational degradation.
      Although some of the B48-like proteins might be derived from truncated species
      (approximately 7 kb in size) of apoB mRNA that were found in cells transfected
      with large apoB constructs, MTP coexpression did not affect the relative levels
      of the aberrant 7-kb RNA with respect to the full-length mRNA. However,
      coexpression of MTP decreased the accessibility of apoB to exogenous trypsin by 2
      fold for apoB72 and by 10-fold for apoB94 in isolated microsomes. Thus, the
      reduced B48-like protein formation by MTP may be a consequence of attenuated
      cotranslational degradation during apoB translocation across the ER membrane.
      Formation of B48-like proteins was insensitive to N-acetyl-leucyl-leucyl
      norleucinal, a cysteine protease inhibitor known to block post-translational
      degradation of apoB. These results indicate that MTP facilitates the assembly and
      secretion of lipoproteins containing apoB and also attenuates the formation of
      B48-like proteins, probably by assisting apoB translocation across the ER
      membrane.

PMID- 8662887
TI  - Carbon monoxide dehydrogenase from Methanosarcina frisia Go1. Characterization of
      the enzyme and the regulated expression of two operon-like cdh gene clusters.
AB  - Carbon monoxide dehydrogenase (Cdh) has been anaerobically purified from
      Methanosarcina frisia Go1. The enzyme is a Ni2+-, Fe2+-, and S2--containing
      alpha2beta2 heterotetramer of 214 kDa with a pI of 5.2 and subunits of 94 and 19
      kDa. It has a Vmax of 0.3 mmol of CO min-1 mg-1 and Km values for CO and methyl
      viologen of approximately 0.9 mM and 0.12 mM, respectively. EPR spectroscopy on
      the reduced enzyme showed two overlapping signals: one indicative for 2 (4Fe-4S)+
      clusters and a second signal that is atypical for standard Fe/S clusters. The
      latter was, together with high-spin EPR signals of the oxidized enzyme
      tentatively assigned to an Fe/S cluster of high nuclearity.

PMID- 8662888
TI  - Identification of three subunits of the high affinity omega-conotoxin MVIIC
      sensitive Ca2+ channel.
AB  - N-, P- and Q-type voltage-dependent Ca2+ channels control neurotransmitter
      release in the nervous system and are blocked by omega-conotoxin MVIIC. In this
      study, both a high affinity and a low affinity binding site for omega-conotoxin
      MVIIC were detected in rabbit brain. The low affinity binding site is shown to be
      present on the N-type Ca2+ channel. Using optimized conditions for specific
      labeling of the high affinity omega-conotoxin MVIIC receptor and a panel of
      subunit specific antibodies, the molecular structure of the high affinity
      receptor was investigated. We demonstrate for the first time that this receptor
      is composed of at least alpha1A, alpha2delta, and any one of the four brain beta
      subunits. Such association of different beta subunits with alpha1A and
      alpha2delta components may produce Ca2+ channels with distinct functional
      properties, such as P- and Q-type.

PMID- 8662889
TI  - Specific uncoupling of GRB2 from the Met receptor. Differential effects on
      transformation and motility.
AB  - The biological effects of hepatocyte growth factor/scatter factor are mediated by
      autophosphorylation of its receptor, the Met tyrosine kinase, on two carboxyl
      terminal tyrosines. These phosphotyrosines (Y1349VHVNATY1356VNV) are
      multifunctional docking sites for several effectors. Grb2, the adaptor for the
      Ras guanyl-nucleotide exchanger SOS, binds to Tyr1356 in the YVNV motif. By site
      directed mutagenesis we either abrogated or duplicated the Grb2 consensus,
      without interfering with the other effectors. Loss of the link with Grb2 severely
      impaired transformation. The same mutation, however, had no effect on the
      "scattering" response, indicating that the level of signal which can be reached
      by Grb2-independent routes is permissive for motility. Duplication of the Grb2
      binding site enhanced transformation and left motility unchanged. Thus, two Met
      mediated biological responses, motility and growth, can be dissociated on the
      basis of their differential requirement for a direct link with Ras.

PMID- 8662890
TI  - Cloning and characterization of a novel murine macrophage inflammatory protein-1
      alpha receptor.
AB  - We have cloned a novel CC chemokine receptor cDNA from mouse thymus. The deduced
      amino acid sequence shows 74% identity to the human monocyte chemotactic protein
      (MCP)-1 receptor (CC CKR-2b) and 54% to a recently cloned murine macrophage
      inflammatory protein (MIP)-1alpha receptor (Gao, J. L., and Murphy, P. M.(1995)
      J. Biol. Chem. 270, 17494-17501). Northern blot analysis of mouse tissues showed
      that the mRNA was also expressed in heart, spleen and liver, and to a lesser
      extent in lung and brain. The rank order of CC chemokine competition for 125I
      labeled human RANTES (regulated on activation, normal T-cell expressed and
      secreted) binding to human embryonic kidney (HEK) 293 cells stably transfected
      with the receptor cDNA was murine MIP-1alpha >> human MIP-1beta > human RANTES >
      murine RANTES > murine MIP-1beta > human MCP-2 > murine MCP-1 (JE) > human MIP
      1alpha > human MCP-3 > human MCP-1. Of the chemokines tested, only murine MIP
      1alpha, human and murine MIP-1beta and RANTES, human MCP-2, and JE were able to
      induce mobilization of intracellular Ca2+ from fura-2-loaded HEK 293 cells
      expressing the receptor. These results suggest that this receptor functions as a
      high affinity murine MIP-1alpha receptor; however, it is likely to be an
      important target for the biological activities of several CC chemokines in mouse.

PMID- 8662891
TI  - Rhotekin, a new putative target for Rho bearing homology to a serine/threonine
      kinase, PKN, and rhophilin in the rho-binding domain.
AB  - Using a mouse embryo cDNA library, we conducted a two-hybrid screening to
      identify new partners for the small GTPase Rho. One clone obtained by this
      procedure contained a novel cDNA of 291 base pairs and interacted strongly with
      RhoA and RhoC, weakly with RhoB, and not at all with Rac1 and Cdc42Hs. Full
      length cDNAs were then isolated from a mouse brain library. While multiple
      splicing variants were common, we identified three cDNAs with an identical open
      reading frame encoding a 61-kDa protein that we named rhotekin (from the Japanese
      "teki," meaning target). The N-terminal part of rhotekin, encoded by the initial
      cDNA and produced in bacteria as a glutathione S-transferase fusion protein,
      exhibited in vitro binding to 35S-labeled guanosine 5'-3-O-(thio)triphosphate
      bound Rho, but not to Rac1 or Cdc42Hs in ligand overlay assays. In addition, this
      peptide inhibited both endogenous and GTPase-activating protein-stimulated Rho
      GTPase activity. The amino acid sequence of this region shares approximately 30%
      identity with the Rho-binding domains of rhophilin and a serine/threonine kinase,
      PKN, two other Rho target proteins that we recently identified (Watanabe, G.,
      Saito, Y., Madaule, P., Ishizaki, T., Fujisawa, K., Morii, N., Mukai, H., Ono,
      Y., Kakizuka, A., and Narumiya, S. (1996) Science 271, 645-648). Thus, not only
      is rhotekin a novel partner for Rho, but it also belongs to a wide family of
      proteins that bear a consensus Rho-binding sequence at the N terminus. To our
      knowledge, this is the first conserved sequence for Rho effectors, and we have
      termed this region Rho effector motif class 1.

PMID- 8662892
TI  - Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis
      transmembrane conductance regulator compromise biosynthetic processing and
      chloride channel activity.
AB  - A cluster of 18 point mutations in exon 17b of the cystic fibrosis transmembrane
      conductance regulator (CFTR) gene has been detected in patients with cystic
      fibrosis. These mutations cause single amino acid substitutions in the most C
      terminal cytoplasmic loop (CL4, residues 1035-1102) of the CFTR chloride channel.
      Heterologous expression of the mutants showed that 12 produced only core
      glycosylated CFTR, which was retained in the endoplasmic reticulum; the other six
      mutants matured and reached the cell surface. In some cases substitution of one
      member of pairs of adjacent residues resulted in misprocessing, whereas the other
      did not. Thus, the secondary structure of CL4 may contribute crucially to the
      proper folding of the entire CFTR molecule. Cyclic AMP-stimulated iodide efflux
      was not detected from cells expressing the misprocessed variants but was from the
      other six, indicating that their mutations cause relatively subtle channel
      defects. Consistent with this, these latter mutations generally are present in
      patients who are pancreatic-sufficient, while the processing mutants are mostly
      from patients who are pancreatic-insufficient. Single-channel patch-clamp
      analysis demonstrated that the processed mutants had the same ohmic conductance
      as wild-type CFTR, but a lower open probability, generally due to an increase in
      channel mean closed time and a reduction in mean open time. This suggests that
      mutations in CL4 do not affect pore properties of CFTR, but disrupt the mechanism
      of channel gating.

PMID- 8662893
TI  - Specific interaction of glyceraldehyde 3-phosphate dehydrogenase with the 5'
      nontranslated RNA of hepatitis A virus.
AB  - Initiation of translation of hepatitis A virus (HAV) RNA occurs by internal entry
      and is likely to involve the interaction of trans-acting cellular protein factors
      with cis-acting structural elements of an internal ribosomal entry segment (IRES)
      within the 5'-nontranslated RNA. To characterize interactions between African
      green monkey kidney (BS-C-1) cell proteins and the predicted stem-loop IIIa
      (nucleotides 155-235) located at the 5' border of the HAV IRES, we utilized an
      electrophoresis mobility shift assay (EMSA) to identify a 39-kDa RNA-binding
      protein (p39). Amino-terminal amino acid sequencing of highly purified p39
      revealed absolute identity with human glyceraldehyde 3-phosphate dehydrogenase
      (GAPDH). The identity of p39 as simian GAPDH was further confirmed by antigenic
      and biochemical similarities between p39 and human GAPDH. Analysis of the RNA
      binding properties of simian GAPDH revealed that this cellular protein interacts
      with two additional sites in the HAV 5'-nontranslated RNA, one located between
      nucleotides 1-148 and the other between nucleotides 597-746. Competitive EMSAs
      also demonstrated that GAPDH and human polypyrimidine tract-binding protein, a
      putative picornavirus translation initiation factor, compete with each other for
      binding to stem-loop IIIa, suggesting that the relative cytoplasmic abundance of
      GAPDH and polypyrimidine tract-binding protein in individual cell-types may be an
      important determinant of viral translation activity. Human GAPDH was found to
      destabilize the folded structure of the stem-loop IIIa RNA based upon observed
      decreases in the circular dichroism spectra of this RNA following binding of the
      protein. This RNA helix-destabilizing activity of GAPDH could directly influence
      IRES-dependent translation and/or replication of picornavirus RNA.

PMID- 8662894
TI  - A missense mutation in the FUT6 gene results in total absence of alpha3
      fucosylation of human alpha1-acid glycoprotein.
AB  - The major alpha3-fucosyltransferase activity in human plasma is encoded by the
      gene for fucosyltransferase VI (FUT6). A missense mutation (Gly-739 --> Ala) in
      this gene is responsible for deficiency of enzyme activity in plasma. To examine
      whether this fucosyltransferase is the sole enzyme responsible for the alpha3
      fucosylation of serum glycoproteins in the liver, we studied the fucosylation of
      three glycoproteins in sera of individuals with or without inactivated FUT3
      and/or FUT6 gene(s) but with a functional FUT5 gene. alpha1-Acid glycoprotein was
      used as the principal reporter protein for liver alpha3-fucosyltransferase
      activity, because of its high fucose content. In all individuals with the FUT6
      missense mutation Gly-739 --> Ala in double dose, no fucosylation of alpha1-acid
      glycoprotein was found. This alpha1-acid glycoprotein was not intrinsically
      resistant to fucosylation, since it was susceptible to in vitro fucosylation
      using an alpha3/4-fucosyltransferase isolated from human milk. The same result
      was found for alpha1-antichymotrypsin and alpha1-protease inhibitor. On the other
      hand in all individuals with alpha3-fucosyltransferase activity in plasma, alpha3
      fucosylated glycoforms of the glycoproteins studied were found. The degree of
      fucosylation of alpha1-acid glycoprotein was correlated with alpha3
      fucosyltransferase activity (Rs = 0.82). These data indicate that the product of
      FUT6, but not of FUT3 or of FUT5, is responsible for the alpha3-fucosylation of
      glycoproteins produced in liver and suggest that this organ is a major source of
      alpha3-fucosyltransferase activity in plasma.

PMID- 8662895
TI  - Ouabain interactions with the H5-H6 hairpin of the Na,K-ATPase reveal a possible
      inhibition mechanism via the cation binding domain.
AB  - Cardiac glycosides such as ouabain and digoxin specifically inhibit the Na,K
      ATPase. Three new residues in the carboxyl half of the Na, K-ATPase, Phe-786, Leu
      793 (PFLIF786IIANIPL793PLGT797), and Phe-863 (FTYF863VIM) have been identified as
      ouabain sensitivity determinants using random mutagenesis. Polymerase chain
      reaction was utilized to randomly mutate the DNA sequence encoding the amino
      acids between Lys-691 and Lys-945 in the alpha subunit of the Na, K-ATPase. This
      region contains four transmembrane segments (H5, H6, H7, and H8) and the
      connecting extracellular and cytoplasmic loops. Diverse substitutions of these
      three residues resulted in proteins displaying 2.8-48-fold increases in the I50
      of different cardiac glycosides for inhibition of the Na,K-ATPase activity. By
      locating these residues, in conjunction with Thr-797 (Feng, J., and Lingrel, J. B
      (1994) Biochemistry 33, 4218-4224), a new region of the protein containing the H5
      H6 hairpin and the H7 transmembrane segment emerges as a major determinant of
      ouabain inhibition. Thus, a link between the cardiac glycoside binding site and
      the cation transport sites of the Na,K-ATPase transpires giving a structural base
      to the cation antagonism of ouabain binding. Furthermore, this link suggests a
      possible mechanism for cardiac glycoside inhibition of the Na,K-ATPase, such that
      ouabain binding to the implicated region blocks the movement of the H5 and H6
      transmembrane domains which may be required for energy transduction and cation
      transport.

PMID- 8662896
TI  - Characterization of a Ku86 variant protein that results in altered DNA binding
      and diminished DNA-dependent protein kinase activity.
AB  - Three proteins known to play a critical role in mammalian DNA double-strand break
      repair and lymphoid V(D)J recombination are the autoantigens Ku86 and Ku70 and a
      465-kDa serine/threonine protein kinase catalytic subunit (DNA-PKcs). These
      proteins physically associate to form a complex (DNA.PK) with DNA-dependent
      protein kinase activity. In this study, we demonstrate using electrophoretic
      mobility shift assays (EMSAs) that the nuclear DNA end-binding activity of Ku is
      altered in the human promyelocytic leukemic HL-60 cell line. Western blot and
      EMSA supershift analyses revealed that HL-60 cells expressed both full-length and
      variant Ku86 proteins. However, a combined EMSA and immunoanalysis revealed that
      the Ku heterodimers complexed with DNA in HL-60 cells contained only the variant
      Ku86 proteins. Finally, UV cross-linking experiments and DNA.PK assays
      demonstrated that the Ku complexes containing variant Ku86 had a greatly reduced
      ability to interact with DNA-PKcs and that consequently HL-60 cells had severely
      diminished DNA.K activity. These data provide important insights into the
      interaction between Ku and DNA-PKcs and into the role of DNA.PK in DNA double
      strand break repair.

PMID- 8662897
TI  - Normal development of mice lacking metablastin (P19), a phosphoprotein implicated
      in cell cycle regulation.
AB  - Metablastin, also called P19, stathmin, prosolin, Lap18, and oncoprotein18, is a
      highly conserved cytosolic protein that undergoes extracellular factor- and cell
      cycle-regulated serine phosphorylation and developmentally regulated expression
      in mammals. It has been implicated in a variety of cellular functions including
      growth and differentiation, and recent evidence suggests an involvement in cell
      cycle control. To explore its potential role in mammalian development, we have
      disrupted the gene encoding metablastin by gene targeting in mice. The
      metablastin null mutants have no overt phenotype regarding development, growth
      rate, behavior, T cell maturation, or fertility and do not exhibit an increased
      predisposition to tumors. SCG10, a protein closely related in structure to
      metablastin, shows no compensatory up-regulation in metablastin-/- mice. Although
      the data suggest that metablastin is not essential for mammalian development, the
      knockout mice should prove valuable in exploring the role of this protein in cell
      cycle regulation.

PMID- 8662898
TI  - Atrial natriuretic peptide inhibits mitogen-activated protein kinase through the
      clearance receptor. Potential role in the inhibition of astrocyte proliferation.
AB  - The modulation of the activity of mitogen-activated protein kinase (MAPK) by
      endogenous growth factors or growth inhibitors provides a potential means of
      regulating cell proliferation. We determined the effect of the endogenous anti
      proliferative peptide, atrial natriuretic peptide (ANP), on the ability of MAPK
      to phosphorylate myelin basic protein. In astrocytes, MAPK activity was
      significantly stimulated (up to 3-fold) by three known glial mitogens, endothelin
      3, platelet-derived growth factor, or phorbol 12-myristate 13-acetate. ANP
      inhibited by 55-70% the ability of each of these mitogens to activate MAPK. The
      effects of ANP were equipotent to those caused by C-ANP 4-23, a peptide that
      specifically binds to the natriuretic peptide clearance receptor. Additionally,
      both natriuretic peptides caused a 70-80% inhibition of the sodium vanadate
      stimulated MAPK activity, complete inhibition of the okadaic acid-stimulated
      activity, and inhibition of the mitogen-stimulated phosphorylation of MAPK. To
      understand the potential mechanism by which the natriuretic peptides act, we
      found that both ANP and C-ANP inhibited the mitogen-stimulated activity of the
      immediate upstream kinase in the cascade, MAPK kinase (MEK). C-ANP also strongly
      inhibited the endothelin-3-, platelet-derived growth factor-, and phorbol 12
      myristate 13-acetate-induced stimulation of DNA synthesis in the astrocytes,
      while both okadaic acid and sodium vanadate significantly reversed these anti
      proliferative actions. Our results identify ANP as a peptide hormone that
      inhibits growth factor-stimulated MAPK. These data suggest that the ability of
      the natriuretic peptides to inhibit MAPK may be important for their anti-growth
      actions. This effect likely occurs via the inhibition of upstream kinase(s),
      including MEK, uniquely resulting from ligand binding to the natriuretic peptide
      clearance receptor.

PMID- 8662899
TI  - A continuous transition from A-DNA to B-DNA in the 1:1 complex between
      nogalamycin and the hexamer dCCCGGG.
AB  - The antibiotic nogalamycin, a drug with high specificity for TG and CG steps in
      double-stranded DNA, has been crystallized as a 1:1 complex with the hexamer
      d(CCCGGG). The antibiotic is inserted at the central CG step of the duplex, with
      the two sugars oriented in the same direction and with strong interactions with
      the DNA within the grooves. The amino-glucose residue makes an integral part of a
      well defined major groove hydration network with van der Waals contacts and
      several strong hydrogen bonds to the duplex. The nogalose residue resides in the
      minor groove, making primarily van der Waals contacts. The single site allows an
      accurate molecular description of the intercalation, without perturbations from
      end effects observed previously. The local unwinding induced by nogalamycin is
      completely relaxed 2 base pairs away from the intercalation site. The two strands
      of the DNA show a continuous deformation from the A to the B form: 1) the
      cytosines toward the 5' end of the nogalomycin site in each strand have c3'-endo
      conformations while 5 guanosines toward the 3' ends have c2'-endo conformations;
      2) within each strand, the phosphate-phosphate distances increase in a continuous
      manner from 5.7 A (A-form) to 7.1 A (B-form).

PMID- 8662900
TI  - Active site phosphorylation of enzyme I of the bacterial phosphotransferase
      system by an ATP-dependent kinase.
AB  - Enzyme I (EI) of the bacterial phosphoenolpyruvate:glycose phosphotransferase
      system (PTS) is autocatalytically phosphorylated by P-enolpyruvate. We report
      here an ATP-dependent kinase (EI-K) from Escherichia coli that reversibly
      phosphorylates EI at its active site histidine; ATP and EI-K can therefore
      replace P-enolpyruvate. EI-K contains a bound cofactor that is lost during
      purification with concomitant loss of activity. NAD+ and NADP+ substitute for the
      cofactor and restore activity to the apoenzyme, whereas their analogues are
      inactive. The pyridine nucleotides do not activate EI-K by covalent modification
      (e.g. ADP-ribosylation), but must be present during the kinase reaction. NADH and
      NADPH are potent inhibitors of EI-K at all stages of purity, and enzyme activity
      in a mixture of NAD+ and NADH depends on the ratio of the two pyridine
      nucleotides. Inhibition is observed with reduced beta-NMN and alpha-NADH, but
      neither is as effective as beta-NADH. The reverse reaction, the transfer of the
      phosphoryl moiety from phospho-EI to ADP, also requires NAD+ or NADP+. In the
      absence of NAD+ or NADH, [32P]phospho-EI is hydrolyzed to 32Pi, suggesting that
      EI-K can act as a phospho-EI phosphatase. EI kinase may serve as a link between
      PTS-driven sugar transport and the electron transport chain.

PMID- 8662901
TI  - Biosensor measurement of the binding of insulin-like growth factors I and II and
      their analogues to the insulin-like growth factor-binding protein-3.
AB  - Most insulin-like growth factor (IGF) molecules in the circulation are found in a
      150-kDa complex containing IGF-binding protein-3 (IGFBP-3) and an acid-labile
      subunit, which does not itself bind IGF. Affinities (Kd values) between 0.03 and
      0.5 nM have been reported for IGF-I/IGFBP-3 binding, but no kinetic data are
      available. In this study we measured the high affinity binding of unlabeled IGFs
      and IGF analogues to recombinant unglycosylated IGFBP-3, using a BIAcoretrade
      mark instrument (Pharmacia Biosensor AB). IGF-I binding showed fast association
      and slow non-first-order dissociation kinetics, and an equilibrium Kd of 0.23 nM.
      IGF-II had similar kinetics with slightly higher affinity. Analogues with
      mutations in the first 3 amino acids of the B-region (des(1-3) IGF-I and long IGF
      I) showed 25 and 50 times lower affinity than IGF-I. Replacement of residues 28
      37 by Gly-Gly-Gly-Gly or deletion of residues 29-41 in the C-region had little
      effect on the kinetic parameters, contrasting with the markedly impaired binding
      of these analogues to the IGF-I receptor. Swapping of the disulfide bridges in
      IGF-I and the C-region mutants decreased the affinity dramatically for IGFBP-3,
      primarily by decreasing the association rate. Insulin had approximately 1000
      times lower affinity than IGF-I.

PMID- 8662902
TI  - Inositol 3,4,5,6-tetrakisphosphate inhibits the calmodulin-dependent protein
      kinase II-activated chloride conductance in T84 colonic epithelial cells.
AB  - The mechanism by which inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5, 6)P4)
      regulates chloride (Cl-) secretion was evaluated in the colonic epithelial cell
      line T84 using whole cell voltage clamp techniques. Our studies focused on the
      calcium-dependent chloride conductance (gClCa) that was activated either by
      mobilizing intracellular calcium (Cai) stores with thapsigargin or by
      introduction of the autonomous, autophosphorylated calmodulin-dependent protein
      kinase II (CaMKII) into the cell via the patch pipette. Basal concentrations of
      Ins(3,4,5,6)P4 (1 microM) present in the pipette solution had no significant
      effect on Cl- current; however, as the concentration of the polyphosphate was
      increased there was a corresponding reduction in anion current, with near
      complete inhibition at 8-10 microM Ins(3,4,5,6)P4. Corresponding levels are found
      in cells after sustained receptor-dependent activation of phospholipase C. The
      Ins(3,4,5, 6)P4-induced inhibition of gClCa was isomer specific; neither Ins(1,
      3,4,5)P4, Ins(1,3,4,6)P4, Ins(1,4,5,6)P4, nor Ins(1,3,4,5,6)P5 induced current
      inhibition at concentrations of up to 100 microM. Annexin IV also plays an
      inhibitory role in modulating gClCa in T84 cells. When 2 microM annexin IV was
      present in the pipette solution, a concentration that by itself has no effect on
      gClCa, the potency of Ins(3,4,5,6)P4 was approximately doubled. The combination
      of Ins(3,4,5,6)P4 and annexin IV did not alter the in vitro activity of CaMKII.
      These data demonstrate that Ins(3,4,5,6)P4 is an additional cellular signal that
      participates in the control of salt and fluid secretion, pH balance,
      osmoregulation, and other physiological activities that depend upon gClCa
      activation. Ins(3,4,5,6)P4 metabolism and action should also be taken into
      account when designing treatment strategies for cystic fibrosis.

PMID- 8662903
TI  - Ku80-deficient cells exhibit excess degradation of extrachromosomal DNA.
AB  - Mammalian cells possess a protein complex, termed DNA-PK, which binds to DNA
      double strand breaks in vitro. The complex consists of the heterodimeric Ku
      autoantigen and a DNA-dependent protein kinase, DNA-PKcs. Cell lines that are
      deficient for components of this complex are sensitive to ionizing radiation and
      have impaired V(D)J recombination, a site-specific recombination process. We have
      tested these cell lines for their ability to repair double strand breaks in
      transfected DNA. The xrs-6 cell line, which is deficient for the 80-kDa subunit
      of the Ku autoantigen, exhibited reduced stability of transfected DNA. Prior to
      obvious reductions in DNA stability, the levels of homologous recombination and
      DNA end joining were unaffected. However, the recovery of end joining products
      with precisely joined ends was reduced, with a concomitant increase in products
      containing deletions. Unlike the Ku80-deficient cells, no reduction in DNA
      stability was detected in DNA-PKcs-deficient scid cells. Scid cells also
      exhibited normal levels of homologous recombination and DNA end joining. These
      experiments implicate the Ku autoantigen, but not DNA-PKcs, in a direct role in
      protecting DNA ends from degradation.

PMID- 8662904
TI  - Acid-activatable cysteine proteinases in the cellular slime mold Dictyostelium
      discoideum.
AB  - Studies of the cysteine proteinases of the cellular slime mold Dictyostelium
      discoideum have been aided by a simple acid treatment step that was incorporated
      into the standard one-dimensional gelatin-sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis assay procedure. The step involved immersing the separating
      gel in 10% (v/v) glacial acetic acid for 30-60 s immediately after
      electrophoresis. This modified approach revealed the presence of acid-activatable
      forms of some enzymes with noticeable increases in their ability to hydrolyze
      gelatin, a substrate present in the sodium dodecyl sulfate-polyacrylamide gels,
      and peptidyl amidomethylcoumarins. The activation has been analyzed using
      extracts of dormant spores from which cysteine proteinase activity had previously
      appeared low or virtually absent. The major acid-activatable proteinase had an
      apparent molecular mass of 48 kDa. Its activation was not due to autocatalysis as
      it was not prevented by mercuric chloride, an inhibitor of the enzyme, and was
      not accompanied by a significant change in electrophoretic mobility. It was most
      likely due to a conformational change and/or the removal of a low molecular
      weight inhibitor. The acid treatment has also revealed the presence of acid
      activatable cysteine proteinases in vegetative cells, in which cysteine
      proteinase activity is present at high levels, as well as among enzymes from the
      developmental cells which have much lower cysteine proteinase activity. Indeed
      novel developmental forms were detected at some stages. These results provide
      additional insight concerning cysteine proteinase expression at various stages
      during development in the slime molds. A developmental model is presented which
      suggests that the crypticity of the cysteine proteinases in dormant spores may be
      governed by proton pumps and endogenous lysosomotropic agents.

PMID- 8662905
TI  - Membrane insertion characteristics of the various transmembrane domains of the
      Escherichia coli TolQ protein.
AB  - The Escherichia coli TolQ protein is a 230-amino acid integral cytoplasmic
      membrane protein required for the import of group A colicins, for infection by
      the filamentous phage, and for maintenance of the integrity of the bacterial
      envelope. TolQ is a polytopic protein with three membrane-spanning regions. The
      first membrane-spanning region has a 19-residue periplasmic NH2-terminal tail,
      while the second and third membrane-spanning segments are separated by a short 17
      amino acid periplasmic loop. To study the membrane assembly of TolQ, fusions of
      different membrane-spanning regions were examined for their ability to insert in
      the absence of functional SecA or the membrane potential. Fusions containing the
      first membrane-spanning region plus the adjacent cytoplasmic domain and a
      construct containing the "hairpin loop," formed by the second and third membrane
      spanning regions, insert in the absence of functional SecA. The fusion containing
      the second and third membrane-spanning regions required the membrane potential
      for insertion while the first membrane-spanning region was able to insert even in
      the absence of a membrane potential. Taken together, these results suggest that
      insertion of intact TolQ is not dependent on the Sec system, but does require the
      membrane potential.

PMID- 8662906
TI  - The cooperative interaction of two different signaling pathways in response to
      bufalin induces apoptosis in human leukemia U937 cells.
AB  - Bufalin, an active principle of Chinese medicine, chan'su, induced typical
      apoptosis in human leukemia U937 cells. When U937 cells were treated with 10(-8)
      M bufalin in the absence of serum, mitogen-activated protein (MAP) kinase
      activity was markedly increased 6 h after the start of treatment and elevated so
      for 12 h. Prior to the activation of MAP kinase, increased activities of Ras, Raf
      1, and MAP kinase kinase were found, but these enzymes were transiently activated
      by the treatment with bufalin. These results suggest that the signal was
      transmitted sequentially from Ras, Raf-1, and MAP kinase kinase to MAP kinase. In
      association with this signal transduction, the concentration of cAMP in the cells
      decreased markedly, suggesting that Raf-1 was also activated by a decrease in the
      extent of phosphorylation by protein kinase A. In fact, pretreatment of U937
      cells with forskolin and 3-isobutyl-1-methylxanthine, which are known to increase
      the concentration of cAMP in the cells, and subsequent treatment with bufalin
      resulted in a decrease in both Raf-1 activity and DNA fragmentation. To confirm
      the participation of MAP kinase in the apoptotic process, antisense cDNA for MAP
      kinase kinase 1 was expressed in U937 cells. The transformants were significantly
      resistant to both DNA fragmentation and cell death in response to bufalin. Our
      findings suggest that a pathway with the persistent activation of MAP kinase in
      U937 cells in response to bufalin is at least one of the signal transduction
      pathways involved in the induction of apoptosis.

PMID- 8662907
TI  - Interaction between the amino-terminal SH3 domain of CRK and its natural target
      proteins.
AB  - CRK is a human homolog of chichen v-Crk, which is an adaptor protein. The SH2
      domain of CRK binds to several tyrosine-phosphorylated proteins, including the
      epidermal growth factor receptor, p130(Cas), Shc, and paxillin. The SH3 domain,
      in turn, binds to cytosolic proteins of 135-145, 160, 180, and 220 kDa. We
      screened expression libraries by Far Western blotting, using CRK SH3 as a probe,
      and identified partial cDNA sequences of four distinct proteins, including C3G,
      DOCK180, EPS15, and clone ST12. The consensus sequence of the CRK SH3 binding
      sites as deduced from their amino acid sequences was Pro+3-Pro+2-X+1-Leu0-Pro-1-X
      2-Lys-3. The interaction of the CRK SH3 domain with the DOCK180 peptide was
      examined with an optical biosensor, based on the principles of surface plasmon
      resonance. A low dissociation constant of the order of 10(-7) resulted from a
      high association rate constant (kassoc = 3 x 10(4)) and low dissociation rate
      constant (kdiss = 3 x 10(-3)). All CRK-binding proteins except clone ST12 also
      bound to another adaptor protein, Grb2. Mutational analysis revealed that glycine
      at position +1 of ST12 inhibited the binding to Grb2 while retaining the high
      affinity binding to CRK SH3. The result suggests that the amino acid at position
      +1 also contributes to the high affinity binding of the peptides to the SH3
      domain of Grb2, but not to that of CRK.

PMID- 8662909
TI  - Human immunodeficiency virus type-1 reverse transcriptase. Contribution of Met
      184 to binding of nucleoside 5'-triphosphate.
AB  - Mutations were made in recombinant human immunodeficiency virus type-1 reverse
      transcriptase (RT) by substituting methionine 184 with alanine (M184A) or valine
      (M184V), and steady-state and pre-steady-state kinetic constants were determined.
      The Km values of M184A RT for dNTPs were larger than those of wt RT for RNA
      directed synthesis; the kcat values of M184A RT for processive or distributive
      synthesis were similar. In contrast to M184A RT, the Km and kcat values of M184V
      RT for dNTP substrates were similar to those of wt RT. The Ki values of M184V RT
      for 1-beta-L-nucleoside analogs were increased 30-500-fold relative to wt RT for
      both RNA- and DNA-directed synthesis. The Kd and kp values of wt RT and M184V RT
      for dCTP and cis-5-fluoro-1-[2-(hydroxymethyl)-1, 3-oxathiolan-5-yl]cytosine 5'
      triphosphate (1-beta-L-FTCTP) were estimated from pre-steady-state kinetics for
      single nucleotide incorporation. The Kd value of M184V RT for 1-beta-L-FTCTP was
      19-fold greater than that of wt RT; the kpvalues of the two enzymes were similar.
      These results support the hypothesis that methionine 184 in the highly conserved
      YMDD region of wt RT participates in the binding of the nucleoside (analog) 5'
      triphosphate.

PMID- 8662910
TI  - In vitro activity of 1,3-beta-D-glucan synthase requires the GTP-binding protein
      Rho1.
AB  - In the yeast Saccharomyces cerevisiae, the family of RHO genes are implicated in
      the control of morphogenetic events although the molecular targets of these GTP
      binding proteins remain largely unknown. The activity of 1,3-beta-D-glucan
      synthase, the product of which is essential for cell wall integrity, is regulated
      by a GTP-binding protein, which we here present evidence to be Rho1p. Rho1p was
      found to copurify with Fks1p, a glucan synthase subunit, in preparations of the
      enzyme purified by product entrapment and was also shown to be depleted by a
      detergent extraction procedure known to remove the GTP-binding regulatory
      component. Specific ADP-ribosylation of Rho1p by exoenzyme C3 inactivates glucan
      synthase activity specified by FKS1 and FKS2 as demonstrated in membrane
      preparations from fks2 and fks1 deletion strains, respectively, and in the
      purified enzyme containing Fks1p. Rho1p and Fks1p were co-immunoprecipitated from
      purified glucan synthase under conditions that maintained enzyme activity in the
      immunoprecipitate. Putative Rho homologs were also identified and implicated in
      the regulation of glucan synthase activity from Candida albicans, Aspergillus
      nidulans, and Cryptococcus neoformans by ribosylation studies. The regulation of
      1,3-beta-D-glucan synthase activity by RHO1 is consistent with its observed role
      in morphogenetic control and osmotic integrity.

PMID- 8662911
TI  - Characterization of lactogen receptor-binding site 1 of human prolactin.
AB  - Prolactin (PRL) binds to two molecules of PRL receptor (PRLR) through two regions
      referred to as binding sites 1 and 2. Although binding site 1 has been generally
      assigned to the pocket delimited by helix 1, helix 4, and the second half of loop
      1, the residues involved in receptor binding have not yet all been precisely
      identified. In an earlier alanine-scanning mutational study, we identified three
      major binding determinants in loop 1 of human PRL (hPRL) (Goffin, V., Norman, M.
      & Martial, J. A.(1992) Mol. Endocrinol. 6, 1381-1392). Here we focus on the two
      other regions that form binding site 1, namely helices 1 and 4. Putative binding
      residues, selected on the basis of a three-dimensional model of hPRL constructed
      in this laboratory, were mutated to alanine, and recombinant hPRL mutants
      produced in Escherichia coli were tested for their ability to bind to the PRLR
      and to stimulate Nb2 cell proliferation. We thus identified nine single mutations
      (three in helix 1 and six in helix 4) whose effect was to reduce both binding and
      mitogenic activity by more than half as compared with wild-type hPRL, indicating
      the functional involvement of the corresponding residues. Adding these to the
      three binding determinants identified in loop 1, we now propose a complete
      picture of PRLR-binding site 1 of hPRL. As we earlier hypothesized, the binding
      site 1 determinants of hPRL differ from those of human growth hormone, a hPRL
      homolog.

PMID- 8662913
TI  - Mechanism of Ca2+-dependent activity of human neutrophil gelatinase B.
AB  - Progelatinase B can be activated in vitro by organomercurial compounds and by
      proteolytic enzymes such as trypsin, chymotrypsin, and stromelysin. Activation of
      the proenzyme by either 4-aminophenylmercuric acetate or chymotrypsin yielded
      proteins that absolutely required Ca2+ for activity, regardless of the pH of the
      reaction mixture. The trypsin- and stromelysin-activated gelatinases, on the
      other hand, did not require Ca2+ for activity at pH 7.5, but the activity of the
      trypsin-activated enzyme became Ca2+ dependent as the pH increased. The pH study
      revealed that an amino acid residue with an apparent pKa of 8.8 was involved in
      this process. The NH2-terminal analyses showed that trypsin- and stromelysin
      activated enzymes had the same NH2 termini (Phe88), but 4-aminophenylmercuric
      acetate- and chymotrypsin-activated enzymes had Met75 and Gln89 or Glu92 as the
      NH2-terminal amino acid, respectively. These data, in conjunction with the x-ray
      crystal structure of collagenase, suggest that a salt linkage involving Phe88 is
      responsible for the Ca2+-independent activity of trypsin- and stromelysin
      activated gelatinase. Replacing Asp432 in progelatinase with either Glu, Asn,
      Gly, or Lys resulted in the proteins that, upon activation by trypsin, required
      Ca2+ for activity. These substitutions did not significantly affect Km for the
      synthetic substrate but decreased the kcat and increased the half-maximal Ca2+
      concentration required for enzyme activity (KCa) by severalfold. The effects on
      kcat and KCa depended on both charge and size of the side chains of the
      substituted amino acids. The decrease in kcat correlated well with the increase
      in KCa of the mutants. The orders of decrease in kcat and increase in KCa were
      wild type >/= D432E > D432N > D432G > D432K and wild type </= D432E < D432N <
      D432G < D432K, respectively. These data suggest that in trypsin- or stromelysin
      activated enzyme, the NH2-terminal Phe88 forms a salt linkage with Asp432,
      rendering the enzyme Ca2+ independent. Ca2+ affects catalytic activity of the 4
      aminophenylmercuric acetate- and chymotrypsin-activated enzymes by substituting
      for the salt linkage and interacting with Asp432. This interaction generates a
      similar, if not identical, conformational change to that generated by the salt
      linkage in the protein, leading to catalysis.

PMID- 8662912
TI  - Identification of an essential signaling cascade for mitogen-activated protein
      kinase activation by angiotensin II in cultured rat vascular smooth muscle cells.
      Possible requirement of Gq-mediated p21ras activation coupled to a
      Ca2+/calmodulin-sensitive tyrosine kinase.
AB  - In cultured rat vascular smooth muscle cells, angiotensin II (Ang II) induced a
      rapid increase in mitogen-activated protein kinase (MAPK) activity through the
      Ang II type 1 receptor, which was insensitive to pertussis toxin but was
      abolished by the phospholipase C inhibitor, U73122. The Ang II-induced MAPK
      activation was not affected by the protein kinase C inhibitor, GF109203X, and was
      only partially impaired by pretreatment with a phorbol ester, whereas both
      treatments completely prevented MAPK activation by the phorbol ester.
      Intracellular Ca2+ chelation by TMB-8, but not extracellular Ca2+ chelation or
      inhibition of Ca2+ influx, abolished Ang II-induced MAPK activation. The
      calmodulin inhibitor, calmidazolium, and the tyrosine kinase inhibitor,
      genistein, completely blocked MAPK activation by Ang II as well as by the Ca2+
      ionophore A23187. Ang II caused a rapid increase in the binding of GTP to
      p21(ras), and this was inhibited by genistein, TMB-8, and calmidazolium but not
      by pertussis toxin or GF109203X. These data suggest that Ang II-induced MAPK
      activation through the Ang II type 1 receptor could be mediated by
      p21(ras)activation through a currently unidentified tyrosine kinase that lies
      downstream of Gq-coupled Ca2+/calmodulin signals.

PMID- 8662914
TI  - SV40 large T antigen transactivates the human cdc2 promoter by inducing a CCAAT
      box binding factor.
AB  - Cyclin-dependent protein kinases (Cdks) play a key role in the cell division
      cycle of eukaryotic cells. Cdc2, the first mammalian Cdk that was discovered, is
      expressed in S phase and functions in the G2 to M phase transition. By
      transfecting segments of the human cdc2 promoter linked to a reporter gene into
      monkey kidney (CV-1) cells, we identified the region containing the Sp1, E2F, and
      two CCAAT box binding sites as essential and sufficient for basal transcription.
      SV40 large T antigen (SV40-LT) is a viral oncoprotein that transactivates viral
      and cellular promoters and induces DNA synthesis in quiescent cells. SV40-LT
      transactivated wild-type cdc2 promoter/reporter constructs in a dose-dependent
      manner, coinciding with an increase in endogenous cdc2 mRNA. A mutant promoter
      from which the two CCAAT box motifs were deleted was 8-fold less sensitive to
      SV40-LT. Activation by SV40-LT did not require its ability to bind the
      retinoblastoma or p53 tumor suppressor proteins. SV40-LT induced a specific CCAAT
      box-binding factor (CBF) in CV-1 and COS-7 cells, as judged by gel shift and
      Southwestern analyses. Similar results were obtained in human fibroblasts
      expressing a conditional SV40-LT. The SV40-LT-inducible CBF appears to be novel
      and differs from the CBF that activates heat shock protein 70 gene expression.

PMID- 8662916
TI  - On the role of helix 0 of the tryptophan synthetase alpha chain of Escherichia
      coli.
AB  - The role of helix 0 of the alpha chain (TrpA) of the tryptophan synthetase
      alpha2beta2 multi-functional enzyme complex of Escherichia coli was examined by
      deleting amino-terminal residues 2-6, 2-11, or 2-19 of TrpA. Selected
      substitutions were also introduced at TrpA positions 2-6. The altered genes
      encoding these polypeptides were overexpressed from a foreign promoter on a
      multicopy plasmid and following insertion at their normal chromosomal location.
      Each deletion polypeptide was functional in vivo. However all appeared to be
      somewhat more labile and insoluble and less active enzymatically than wild type
      TrpA. The deletion polypeptides were overproduced and solubilized from cell
      debris by denaturation and refolding. Several were partially purified and assayed
      in various reactions in the presence of tryptophan synthetase beta2 (TrpB). The
      purified TrpADelta2-6 and TrpADelta2-11 deletion polypeptides had low activity in
      both the indole + serine --> tryptophan reaction and the indoleglycerol phosphate
      + serine --> tryptophan reaction. Poor activity in each reaction was partly due
      to reduced association of TrpA with TrpB. The addition of the TrpA ligands, alpha
      glycerophosphate or indoleglycerol phosphate, during catalysis of the indole +
      serine --> tryptophan reaction increased association and activity. These findings
      suggest that removal of helix 0 of TrpA decreases TrpA-TrpB association as well
      as the activity of the TrpA active site. Alignment of the TrpA sequences from
      different species indicates that several lack part or all of helix 0. In some of
      these polypeptides, extra residues at the carboxyl end may substitute for helix
      0.

PMID- 8662915
TI  - Control of apolipoprotein AI gene expression through synergistic interactions
      between hepatocyte nuclear factors 3 and 4.
AB  - Apolipoprotein AI (apoAI) gene expression in liver depends on synergistic
      interactions between transcription factors bound to three distinct sites (A, B,
      and C) within a hepatocyte-specific enhancer in the 5'-flanking region of the
      gene. In this study, we showed that a segment spanning sites A and B retains
      substantial levels of enhancer activity in hepatoblastoma HepG2 cells and that
      sites A and B are occupied by the liver-enriched hepatocyte nuclear factors
      (HNFs) 4 and 3, respectively, in these cells. In non-hepatic CV-1 cells, HNF-4
      and HNF-3beta activated this minimal enhancer synergistically. This synergy was
      dependent upon simultaneous binding of these factors to their cognate sites, but
      it was not due to cooperativity in DNA binding. Separation of these sites by
      varying helical turns of DNA did not affect simultaneous binding of HNF-3beta and
      HNF-4 nor did it influence their functional synergy. The synergy was, however,
      dependent upon the cell type used for functional analysis. In addition, this
      synergy was further potentiated by estrogen treatment of cells cotransfected with
      the estrogen receptor. These data indicate that a cell type-restricted
      intermediary factor jointly recruited by HNF-4 and HNF-3 participates in
      activation of the apoAI enhancer in liver cells and suggest that the activity of
      this factor is regulated by estrogen.

PMID- 8662917
TI  - Purification by Ni2+ affinity chromatography, and functional reconstitution of
      the transporter for N-acetylglucosamine of Escherichia coli.
AB  - The N-acetyl-D-glucosamine transporter (IIGlcNAc) of the bacterial
      phosphotransferase system couples vectorial translocation to phosphorylation of
      the transported GlcNAc. IIGlcNAc of Escherichia coli containing a carboxyl
      terminal affinity tag of six histidines was purified by Ni2+ chelate affinity
      chromatography. 4 mg of purified protein was obtained from 10 g (wet weight) of
      cells. Purified IIGlcNAc was reconstituted into phospholipid vesicles by
      detergent dialysis and freeze/thaw sonication. IIGlcNAc was oriented randomly in
      the vesicles as inferred from protein phosphorylation studies. Import and
      subsequent phosphorylation of GlcNAc were measured with proteoliposomes preloaded
      with enzyme I, histidine-containing phosphocarrier protein, and
      phosphoenolpyruvate. Uptake and phosphorylation occurred in a 1:1 ratio. Active
      extrusion of GlcNAc entrapped in vesicles was also measured by the addition of
      enzyme I, histidine-containing phosphocarrier protein, and phosphoenolpyruvate to
      the outside of the vesicles. The Km for vectorial phosphorylation and non
      vectorial phosphorylation were 66. 6 +/- 8.2 microM and 750 +/- 19.6 microM,
      respectively. Non-vectorial phosphorylation was faster than vectorial
      phosphorylation with kcat 15.8 +/- 0.9 s-1 and 6.2 +/- 0.7 s-1, respectively.
      Using exactly the same conditions, the purified transporters for mannose
      (IIABMan, IICMan, IIDMan) and glucose (IICBGlc, IIAGlc) were also reconstituted
      for comparison. Although the vectorial transport activities of IICBAGlcNAc and
      IICBGlc. IIAGlc are inhibited by non-vectorial phosphorylation, no such effect
      was observed with the IIABMan.IICMan.IIDMan complex. This suggests that the
      molecular mechanisms underlying solute transport and phosphorylation are
      different for different transporters of the phosphotransferase system.

PMID- 8662918
TI  - Interleukin-6 family of cytokines induced activation of different functional
      sites expressed by gp130 transducing protein.
AB  - Gp130 transducing protein was shown to be involved in the formation of the high
      affinity receptors for interleukin 6 (IL-6), interleukin-11 (IL-11), leukemia
      inhibitory factor, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and
      cardiotrophin-1. In the present study we have characterized the functional
      properties of antibodies directed against this protein and identified a group of
      monoclonal antibodies able to antagonize the biological activities of all the
      cytokines belonging to the IL-6 cytokine family. The B-R3 pan-blocking antibody
      weakly interfered with the binding of the radiolabeled ligands (with the
      exception of OSM, whose binding was abrogated in the presence of B-R3 monoclonal
      antibody) but inhibited the gp130 homodimerization or its association with
      gp190/leukemia inhibitory factor receptor, as well as the subsequent tyrosine
      phosphorylation events. In addition we identified antibodies that were able to
      neutralize only one single cytokine of the IL-6 family. This was the case for the
      B-K5 antibody, which antagonized the binding of OSM to gp130 but did not
      interfere with the signals provided by the related cytokines triggering the
      proliferation of the TF1 erythroleukemia cell line or the induction of
      haptoglobin synthesis in the HepG2 hepatoma cell line. Similarly, we also
      characterized two additional antibodies B-P8 and B-P4, which inhibited the TF1
      cell proliferation observed in the presence of CNTF and IL-11, respectively. B-P8
      antibody only faintly interfered with the binding of the gp130-ligands and might
      modulate the signal transduction pathways. This study indicates that in addition
      to functional site(s) required by the whole family of IL-6 type cytokines to
      transduce the signal insight the cell, specific cognate functional sites were
      recruited by OSM, CNTF, or IL-11.

PMID- 8662919
TI  - The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via
      an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
AB  - SR-12813 (tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1, 1
      bisphosphonate) lowers plasma cholesterol in five species. In this paper we
      investigate the underlying mechanism using Hep G2 cells. SR-12813 inhibited
      incorporation of tritiated water into cholesterol with an IC50 of 1.2 microM but
      had no effect on fatty acid synthesis. Furthermore, SR-12813 reduced cellular 3
      hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity with an IC50 of
      0.85 microM. The inhibition of HMG-CoA reductase activity was rapid with a T1/2
      of 10 min. After a 16-h incubation with SR-12813, mRNA levels of HMG-CoA
      reductase and low density lipoprotein (LDL) receptor were increased. The
      increased expression of LDL receptor translated into a higher LDL uptake, which
      can explain the primary hypocholesterolemic effect of SR-12813 in vivo. Western
      blot analysis indicated that the amount of HMG-CoA reductase protein rapidly
      decreased in the presence of SR-12813. Pulse-chase experiments with
      [35S]methionine showed that the T1/2 of HMG-CoA reductase degradation decreased
      in the presence of SR-12813 from 90 to 20 min. Pre-incubation with 50 microM of
      lovastatin did not prevent the effects of SR-12813 on HMG-CoA reductase
      degradation, indicating that the compound does not need mevalonate-derived
      regulators for its action. It is concluded that SR-12813 inhibits cholesterol
      synthesis mainly by an enhanced degradation of HMG-CoA reductase.

PMID- 8662920
TI  - Degradation of Rhizopus niveus aspartic proteinase-I with mutated prosequences
      occurs in the endoplasmic reticulum of Saccharomyces cerevisiae.
AB  - Rhizopus niveus aspartic proteinase-I (RNAP-I) is secreted by Saccharomyces
      cerevisiae extracellularly (Horiuchi, H., Ashikari, T., Amachi, T., Yoshizumi,
      H., Takagi, M., and Yano, K. (1990) Agric. Biol. Chem. 54, 1771-1779). The
      prosequence of RNAP-I has the function to promote correct folding of its mature
      part. Deletion (Deltapro) and amino acid substitutions (M1) in the prosequence
      block secretion of RNAP-I (Fukuda, R., Horiuchi, H., Ohta, A., and Takagi, M.
      (1994) J. Biol. Chem. 269, 9556-9561). In this study, little accumulation of
      Deltapro was observed in Western blot analysis of the cell extracts of the
      transformants producing Deltapro using anti-RNAP-I antisera. In contrast, M1 was
      accumulated in the yeast cells. Pulse-chase analysis revealed that they were
      synthesized at almost the same rates and that Deltapro was degraded in the cells
      more rapidly than M1. In subcellular fractionation analysis, Deltapro was found
      in the fraction that contained most of the activity of an endoplasmic reticulum
      (ER) marker enzyme, NADPH-cytochrome c reductase. In indirect immunofluorescence
      microscopy, Deltapro was observed in the ER. Similar result was also observed in
      a mutant which is deficient of the two vacuolar proteases, proteinase A and
      proteinase B. So, the vacuolar proteases are not involved in degradation of
      Deltapro. From these results, we concluded that RNAP-Is with the mutated
      prosequences, which probably could not be folded correctly, were retained and
      degraded in the ER.

PMID- 8662921
TI  - p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal
      adhesions and binds to focal adhesion kinase.
AB  - p130(Cas) (crk associated substrate) has the structural characteristics of an
      adapter protein, containing multiple consensus SH2 binding sites, an SH3 domain,
      and a proline-rich domain. The structure of p130(Cas) suggests that it may act to
      provide a framework for protein-protein interactions; however, as yet, its
      functional role in cells is unknown. In this report we show that p130(Cas) is
      localized to focal adhesions. We demonstrate that p130(Cas) associates both in
      vitro and in vivo with pp125(FAK) (focal adhesion kinase), a kinase implicated in
      signaling by the integrin family of cell adhesion receptors. p130(Cas) also
      associates with pp41/43(FRNK) (pp125(FAK)-related, non-kinase), an autonomously
      expressed form of pp125(FAK) composed of only the C-terminal noncatalytic domain.
      We show that the association of p130(Cas) with pp125(Fak) and pp41/43(FRNK) is
      direct, and is mediated by the binding of the SH3 domain of p130(Cas) to a
      proline-rich sequence present in both the C terminus of pp125(FAK) and in
      pp41/43(FRNK). In agreement with recent studies we show that p130(Cas) is
      tyrosine-phosphorylated upon integrin mediated cell adhesion. The association of
      p130(Cas) with pp125(FAK), a kinase which is activated upon cell adhesion, is
      likely to be functionally important in integrin mediated signal transduction.

PMID- 8662922
TI  - Involvement of thrombin anion-binding exosites 1 and 2 in the activation of
      factor V and factor VIII.
AB  - The role of anion-binding exosites of thrombin in the activation of factor V and
      factor VIII was studied using thrombin Arg93 --> Ala, Arg97 --> Ala, and Arg101 -
      > Ala (thrombin RA), a recombinant exosite 2 defective mutant, and a synthetic N
      acetylated dodecapeptide, Ac-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-O-SO4Leu
      (hirugen), which competitively inhibits binding of macromolecules to exosite 1.
      The catalytic efficiency of the activation of factor VIII or of the first step of
      factor V activation by thrombin RA was approximately 10% that of wild-type
      thrombin. The overall rate of conversion to factor Va was not influenced by the
      mutation. In contrast to factor V, the slow activation of factor VIII by thrombin
      RA was associated with a decreased rate of cleavage at all three proteolytic
      sites (Arg372, Arg740, and Arg1689). Hirugen inhibited factor V and factor VIII
      activation. These results indicate that both anion-binding exosites of thrombin
      are involved in the recognition of factor V and factor VIII.

PMID- 8662923
TI  - DNA replication-related elements cooperate to enhance promoter activity of the
      drosophila DNA polymerase alpha 73-kDa subunit gene.
AB  - An analysis was carried out on the promoter region of the Drosophila DNA
      polymerase alpha 73-kDa subunit gene and the factor(s) activating the promoter.
      Transcription initiation sites were newly identified in the region downstream of
      the previously determined sites. Full promoter activity resided within the region
      from -285 to +129 base pairs with respect to the newly determined major site.
      Within this region, we found three sequences identical or similar to the DNA
      replication-related element (DRE), 5'-TATCGATA, which is known as a common
      promoter-activating element for the Drosophila DNA polymerase alpha 180-kDa
      subunit gene and the proliferating cell nuclear antigen gene. These sites were
      located at positions -77 to -70 (DREalpha-I), -44 to -37 (DREalpha-II), and +3 to
      +10 (DREalpha-III). Footprinting analysis using the recombinant DRE-binding
      factor (DREF) or Kc cell nuclear extract demonstrated that DREF can bind to all
      three DRE-related sites. Introduction of mutation in even one of the three DRE
      related sequences caused extensive reductions of the promoter activity and also
      the DREF-binding activity of the promoter-containing fragment. The results
      indicate that the three DREF-binding sites cooperate to enhance promoter activity
      of the DNA polymerase alpha 73-kDa subunit gene.

PMID- 8662924
TI  - Molecular cloning of a novel thyroid hormone-responsive gene, ZAKI-4, in human
      skin fibroblasts.
AB  - Utilizing a method called "differential display of mRNAs by means of polymerase
      chain reaction", the cDNA fragment of a thyroid hormone-responsive gene ZAKI-4
      was cloned from cultured human skin fibroblasts. Northern blot analysis revealed
      that there were two ZAKI-4 mRNA species (3.4 and 1.4 kilobases (kb)), and they
      were up-regulated by a physiological concentration of triiodothyronine (T3). This
      T3 effect was abolished by the treatment with cycloheximide, indicating the
      possibility that gene ZAKI-4 is regulated by T3 in an indirect fashion, through
      an intermediate product of T3, rather directly by T3 itself. No effect of T3 on
      ZAKI-4 mRNA stability suggested that T3 induces the mRNA at the transcriptional
      level. Rapid amplification of cDNA ends confirmed the presence of two mRNA
      species. ZAKI-4 mRNA was detected in heart, brain, liver, and skeletal muscle but
      not in placenta, lung, kidney and pancreas. In skin fibroblasts and skeletal
      muscle, 3.4-kb mRNA was the major species, whereas 1.4-kb mRNA was dominant in
      heart, brain, and liver. The sequence analysis suggested that the two mRNA
      species arise from alternative polyadenylation and code a single protein of 192
      amino acids. No homologous protein sequence was found in a data base. Elucidation
      of the function of ZAKI-4 gene product will provide new insights into an
      important role of T3 in various organs.

PMID- 8662925
TI  - Characterization of IkappaB kinases. IkappaB-alpha is not phosphorylated by Raf-1
      or protein kinase C isozymes, but is a casein kinase II substrate.
AB  - The NF-kappaB transcription factor is activated by a wide variety of stimuli,
      including phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate. In its
      inactive state, NF-kappaB is sequestered in the cytoplasm tethered to an
      inhibitor protein, IkappaB. Activation comprises the rapid phosphorylation of
      IkappaB-alpha at N-terminal sites, which presumably marks IkappaB-alpha for
      proteolytic degradation and leads to release of NF-kappaB into the nucleus. In
      addition, IkappaB-alpha is constitutively phosphorylated at the C terminus, which
      may be a prerequisite for proper IkappaB function. Protein kinase C (PKC) is
      activated by 12-O-tetradecanoylphorbol-13-acetate and has been previously
      reported to phosphorylate IkappaB-alpha in vitro. As PKC has turned out to
      constitute a multigene family encoding isozymes with different biological
      functions, we have reinvestigated IkappaB-alpha phosphorylation by PKC using
      recombinant PKC isozymes expressed in insect cells. While crude PKC preparations
      were efficient IkappaB-alpha kinases, highly purified PKC isozymes completely
      failed to phosphorylate IkappaB-alpha. Biochemical separation of porcine spleen
      yielded at least two fractions with IkappaB-alpha kinase activity, both of which
      were devoid of detectable PKC isozymes. One peak contained both Raf-1 and casein
      kinase II (CKII). Purified Raf-1 does not phosphorylate IkappaB-alpha directly,
      but associates with CKII, which efficiently phosphorylates the C terminus of
      IkappaB-alpha. Two-dimensional phosphopeptide mapping and high pressure liquid
      chromatography-mass spectroscopy analysis showed that all IkappaB-alpha kinases
      induced phosphorylation at the same prominent sites in the C terminus. Our
      results clearly indicate that PKC isozymes alpha, beta, gamma, delta, epsilon,
      eta, and zeta as well as Raf-1 are not IkappaB-alpha kinases. They furthermore
      demonstrate that IkappaB-alpha is targeted by several kinases, one of which
      appears to be CKII.

PMID- 8662926
TI  - Overexpression of hexokinase II in transgenic mice. Evidence that increased
      phosphorylation augments muscle glucose uptake.
AB  - Hexokinase II (HKII) is the predominant isozyme expressed in peripheral insulin
      responsive tissues. To explore the role of HKII in muscle glucose metabolism, two
      lines of transgenic mice were generated where overexpression was restricted to
      striated muscle; HKII protein levels and activity were increased by 3-8-fold.
      Oral glucose tolerance, intravenous insulin tolerance, and insulin and lactate
      levels were unaffected in transgenic mice. There was a trend toward increased
      levels of muscle glycogen; however, glucose-6-phosphate levels were increased by
      43% in transgenic skeletal muscle following in vivo glucose and insulin
      administration. Using 2-[3H]deoxyglucose as a tracer, in vitro basal and insulin
      stimulated glucose uptake were determined in extensor digitorum longus, soleus,
      and epitrochlearis muscles. Maximal insulin-stimulated glucose uptake was
      increased by 17% (extensor digitorum longus), 34% (soleus), and 90%
      (epitrochlearis) in transgenic muscles; basal and submaximal glucose uptake was
      also modestly increased in soleus and epitrochlearis. These data suggest that
      increased muscle HKII (corresponding to the upper end of the physiologic range)
      may not be sufficient to augment net in vivo glucose homeostasis. However,
      glucose phosphorylation can represent a rate-limiting step for skeletal muscle
      glucose utilization since muscle glucose-6-phosphate levels are increased during
      in vivo hyperinsulinemia and hyperglycemia; furthermore, basal and insulin
      mediated muscle glucose uptake can be increased by a selective increase in HKII
      expression.

PMID- 8662927
TI  - Molecular cloning and genomic analysis of mouse Galbeta1, 3GalNAc-specific GalNAc
      alpha2,6-sialyltransferase.
AB  - cDNA and genomic clones encoding mouse Galbeta1, 3GalNAc-specific GalNAc alpha2,6
      sialyltransferase (ST6GalNAc II) were isolated, and the structure organization of
      the gene was determined. The predicted amino acid sequence is 57.4% identical to
      the chick ST6GalNAc II sequence but 33.8% identical to the chick ST6GalNA I
      (GalNAc alpha2, 6-sialyltransferase) sequence. The ST6GalNAc II gene is
      constitutively expressed in various mouse tissues but highly expressed in
      lactating mammary gland and adult testis. The gene contains nine exons spanning
      about 25 kilobases of genomic DNA and encodes a messenger RNA of 1995
      nucleotides. Primer extension and S1 nuclease protection analysis of submaxillary
      gland mRNA showed that the transcription of the ST6GalNAc II gene starts from 68
      nucleotides upstream from the translation start site. Characterization of 5'
      flanking genomic regions indicated that the Galbeta1,3GalNAc-specific GalNAc
      alpha2,6-sialyltransferase promoter is embedded in a G+C-rich domain and contains
      no TATA or CAAT box but has putative binding sites for transcription factors Sp1
      and AP-2. Transient transfection experiments involving luciferase reporter genes
      demonstrated promoter activity in NIH3T3 cells.

PMID- 8662928
TI  - Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling
      mechanisms for inducing transcription through IL-6 response elements.
AB  - The cytoplasmic domain of the receptor for interleukin 10 (IL-10R) contains two
      box 3 sequence motifs that have been identified in the signal-transducing
      receptor subunits for IL-6-type cytokines and noted to be required for activating
      STAT3 and inducing transcription through IL-6-responsive elements. To determine
      whether the IL-10R has signaling functions similar to IL-6R in cells normally
      expressing these receptors, leukocytes of the B-, T-, and NK-cell lineages were
      treated with either cytokine. Both cytokines activated factors that bound to the
      sis-inducible element and included STAT1 and STAT3. The cell response to IL-10
      characteristically differed from that to IL-2/IL-15, IL-4, and interferon gamma.
      The signaling capabilities of the IL-10R for activating specific STAT proteins
      and inducing gene transcription were defined by reconstitution of receptor
      functions in transfected tissue culture cells. COS-1 cells, co-expressing the
      human IL-10R and individual STAT proteins, confirmed a preference of the IL-10R
      for STAT3 and STAT1. Unlike many hematopoietin receptors, the IL-10R did not
      detectably activate STAT5. The IL-10R, together with reporter gene constructs
      containing different IL-6-responsive gene elements, reconstituted in hepatoma
      cells an induction of transcription by IL-10 that was comparable to that by IL-6.
      This regulation could not be appreciably modified by enhanced expression of STAT
      proteins. The similar actions of IL-10R and IL-6R on the induction of endogenous
      IL-6-responsive genes were demonstrated in hepatoma cells stably expressing the
      IL-10R. These receptor functions required the presence of the box 3 motifs, as
      shown by the analysis of the mouse IL-10R constructs containing progressively
      truncated cytoplasmic domains. The data demonstrate that the IL-10R, unlike other
      members of the interferon receptor family, is highly effective in recruiting the
      signaling pathways of IL-6-type cytokine receptors.

PMID- 8662929
TI  - Widespread use of the glu-tRNAGln transamidation pathway among bacteria. A member
      of the alpha purple bacteria lacks glutaminyl-trna synthetase.
AB  - The expression of the Rhizobium meliloti glutamyl-tRNA synthetase gene in
      Escherichia coli under the control of a trc promoter results in a toxic effect
      upon isopropyl-beta-D-thiogalactopyranoside induction, which is probably caused
      by a misacylation activity. To further investigate this unexpected result, we
      looked at the pathway of Gln-tRNAGln formation in R. meliloti. No glutaminyl-tRNA
      synthetase activity has been found in R. meliloti crude extract, but we detected
      a specific aminotransferase activity that changes Glu-tRNAGln to Gln-tRNAGln. Our
      results show that R. meliloti, a member of the alpha-subdivision of the purple
      bacteria, is the first Gram-negative bacteria reported to use a transamidation
      pathway for Gln-tRNAGln synthesis. A phylogenetic analysis of the contemporary
      glutamyl-tRNA synthetase and glutaminyl-tRNA synthetase amino acid sequences
      reveals that a close evolutionary relationship exists between R. meliloti and
      yeast mitochondrial glutamyl-tRNA synthetases, which is consistent with an origin
      of mitochondria in the alpha-subdivision of Gram-negative purple bacteria. A 256
      amino acid open reading frame closely related to bacterial glutamyl-tRNA
      synthetases, which probably originates from a glutamyl-tRNA synthetase gene
      duplication, was found in the 4-min region of the E. coli chromosome. We suggest
      that this open reading frame is a relic of an ancient transamidation pathway that
      occurred in an E. coli ancestor before the horizontal transfer of a eukaryotic
      glutaminyl-tRNA synthetase (Lamour, V., Quevillon, S., Diriong, S., N'Guyen, V.
      C., Lipinski, M., and Mirande, M.(1994) Proc. Natl. Acad. Sci. U. S. A. 91, 8670
      8674) and that it favored its stable acquisition. From these observations, a
      revisited model for the evolution of the contemporary glutamyl-tRNA synthetases
      and glutaminyl-tRNA synthetases that differs from the generally accepted model
      for the evolution of aminoacyl-tRNA synthetases is proposed.

PMID- 8662930
TI  - An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid
      hormone-retinoic acid response element.
AB  - An Alu element preceding the myeloperoxidase gene (MPO) contains four hexamer
      motifs related to the consensus recognition sequence for nuclear hormone
      receptors (AGGTCA), arranged as direct repeats with spacing of 2, 4, and 2
      nucleotides (DR-2-4-2). Gel shift experiments and transient transfection assays
      demonstrate that these sequences include binding sites for retinoic acid and
      thyroid hormone receptors and function in vivo to activate transcription of a
      chloramphenicol acetyltransferase reporter gene. The first DR-2 elements of the
      series do not bind known receptors but do bind the SP1 transcription factor. Two
      alleles of the MPO gene exist that differ at one position within this element,
      resulting in one allele with and one without a strong SP1 binding site. The
      element with the SP1 site activates transcription by 25-fold in transient
      transfection assays, while the alternative allele confers severalfold less
      transcriptional activity. Most cases of acute myelocytic leukemia are homozygous
      for the allele with the SP1 binding site, suggesting this element plays an
      important role in regulating the MPO gene in myeloid leukemias. This MPO-Alu is a
      representative of an Alu subclass numbering approximately 400,000 copies,
      suggesting many genes may be regulated by such elements.

PMID- 8662932
TI  - The vmax of the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) is not
      altered by Ca2+/calmodulin-dependent phosphorylation or by interaction with
      phospholamban.
AB  - Earlier studies (Hawkins, C., Xu, A., and Narayanan, N. (1994) J. Biol. Chem.
      269, 31198-31206) have suggested that the Vmax of Ca2+ uptake is enhanced up to 2
      fold through phosphorylation of Ser38 in the cardiac Ca2+-ATPase (SERCA2a) by
      calmodulin-dependent protein kinase (CaM kinase). It is difficult, however, to
      determine whether stimulation is caused by phosphorylation of the Ca2+-ATPase or
      by phosphorylation of phospholamban in cardiac microsomes. We have expressed
      SERCA2a in HEK-293 cells in the presence or absence of phospholamban and measured
      the effects on Ca2+ uptake activity of phosphorylation of microsomal proteins by
      CaM kinase or protein kinase A (PKA). We found no effect on the Vmax of Ca2+
      uptake following phosphorylation by CaM kinase or PKA in either the presence or
      absence of phospholamban. The K0.5 for Ca2+ dependence of Ca2+ transport,
      however, was shifted following phosphorylation by either CaM kinase or PKA in
      those microsomes containing both SERCA2a and phospholamban, but not in those
      expressing only SERCA2a. Thus, we cannot confirm earlier reports of stimulation
      of SERCA2a activity by CaM kinase II phosphorylation of Ser38. Our studies,
      however, emphasize the need for adequate controls for measurement of Vmax.

PMID- 8662933
TI  - Characterization of COX17, a yeast gene involved in copper metabolism and
      assembly of cytochrome oxidase.
AB  - Mutations in the COX17 gene of Saccharomyces cerevisiae cause a respiratory
      deficiency due to a block in the production of a functional cytochrome oxidase
      complex. Because cox17 mutants are able to express both the mitochondrially and
      nuclearly encoded subunits of cytochrome oxidase, the Cox17p most likely affects
      some late posttranslational step of the assembly pathway. A fragment of yeast
      nuclear DNA capable of complementing the mutation has been cloned by
      transformation of the cox17 mutant with a library of genomic DNA. Subcloning and
      sequencing of the COX17 gene revealed that it codes for a cysteine-rich protein
      with a molecular weight of 8,057. Unlike other previously described accessory
      factors involved in cytochrome oxidase assembly, all of which are components of
      mitochondria, Cox17p is a cytoplasmic protein. The cytoplasmic location of Cox17p
      suggested that it might have a function in delivery of a prosthetic group to the
      holoenzyme. A requirement of Cox17p in providing the copper prosthetic group of
      cytochrome oxidase is supported by the finding that a cox17 null mutant is
      rescued by the addition of copper to the growth medium. Evidence is presented
      indicating that Cox17p is not involved in general copper metabolism in yeast but
      rather has a more specific function in the delivery of copper to mitochondria.

PMID- 8662934
TI  - The human histidine decarboxylase promoter is regulated by gastrin and phorbol 12
      myristate 13-acetate through a downstream cis-acting element.
AB  - Transcriptional regulation of the human histidine decarboxylase (HDC) gene by
      gastrin and the phorbol ester phorbol 12-myristate 13-acetate (PMA) was studied
      using transient transfection of human HDC promoter-luciferase constructs in a
      human gastric carcinoma cell line (AGS-B) that expresses the human
      cholecystokinin-B/gastrin receptor. The transcriptional activity of the human HDC
      promoter was stimulated 3-4-fold by gastrin and 13-fold by PMA, effects that
      could be blocked by down-regulation or antagonism of protein kinase C. 5'- and 3'
      deletion analysis demonstrated that the sequence responsible for gastrin- and PMA
      stimulated transactivation (gastrin response element (GAS-RE)) was located in a
      region (+2 to +24) downstream of the transcriptional start site (+1) in the human
      HDC promoter and contained a palindrome (5'-CCCTTTAAATAAAGGG-3'). When ligated
      upstream of the herpes simplex virus 1 thymidine kinase promoter, a single copy
      of the GAS-RE was sufficient to confer responsiveness to gastrin and PMA.
      Electrophoretic mobility shift assays with specific competitors and factor
      specific antibody supershifts showed that the labeled GAS-RE bound a novel
      nuclear factor(s). In addition, both gastrin and PMA increased binding of this
      factor to the GAS-RE. Hence, the palindromic GAS-RE site is sufficient to explain
      the gastrin/PMA responsiveness of the human HDC promoter and appears to bind a
      novel transcription factor.

PMID- 8662935
TI  - Formation of a combined H-DNA/open TATA box structure in the promoter sequence of
      the human Na,K-ATPase alpha2 gene.
AB  - Structural variation of DNA within the promoter of the human Na, K-ATPase alpha2
      gene, which contains a 35-base pair (bp) homopyrimidine.homopurine (Py.Pu) tract
      adjacent to a TATA box has been studied. The Py.Pu tract contains a 26-bp quasi
      mirror repeat sequence with a potential for intramolecular triplex formation. As
      analyzed by two-dimensional agarose gel electrophoresis, a plasmid containing 151
      bp of the promoter sequence including the 35-bp Py.Pu tract undergoes structural
      transitions under moderately acidic pH. Chemical probing with chloroacetaldehyde,
      dimethyl sulfate, and potassium permanganate is consistent with the formation of
      triplex DNA within the Py.Pu tract at native superhelical density as isolated
      from Escherichia coli. Chemical probing was used to determine a supercoil
      dependence for the formation of this combined unwound structure. At the
      superhelical density sufficient to locally unwind DNA, an H-y3 isomer of
      intermolecular triplex likely forms. However, at higher superhelical tension an H
      y5 structure forms in the Py.Pu tract, and with increasing supercoiling the local
      DNA unwinding extends into the abutting TATA box. The H-y5/open TATA box
      combination structure might be favorable at higher superhelical densities since
      it relaxes more supercoils. The possible involvement of the H-y5/open TATA box
      structure in transcription is discussed.

PMID- 8662936
TI  - Identification of a murine TEF-1-related gene expressed after mitogenic
      stimulation of quiescent fibroblasts and during myogenic differentiation.
AB  - Fibroblast growth factor (FGF)-1 binding to cell surface receptors stimulates an
      intracellular signaling pathway that ultimately promotes the transcriptional
      activation of specific genes. We have used a mRNA differential display method to
      identify FGF-1-inducible genes in mouse NIH 3T3 fibroblasts. Here, we report that
      one of these genes, FGF-regulated (FR)-19, is predicted to encode a member of the
      transcriptional enhancer factor (TEF)-1 family of structurally related DNA
      binding proteins. Specifically, the deduced FR-19 amino acid sequence has
      approximately89, 77, and 68% overall identity to chicken TEF-1A, mouse TEF-1, and
      mouse embryonic TEA domain-containing factor, respectively. Gel mobility shift
      experiments indicate that FR-19, like TEF-1, can bind the GT-IIC motif found in
      the SV40 enhancer. The FR-19 gene maps in the distal region of mouse chromosome
      6, and analysis of several FR-19 cDNA clones indicates that at least two FR-19
      isoforms may be expressed from this locus. FGF-1 induction of FR-19 mRNA
      expression in mouse fibroblasts is first detectable at 4 h after FGF-1 addition
      and is dependent on de novo RNA and protein synthesis. FGF-2, calf serum,
      platelet-derived growth factor-BB, and phorbol 12-myristate 13-acetate can also
      induce FR-19 mRNA levels. We have also found that FR-19 mRNA expression increases
      during mouse C2C12 myoblast differentiation in vitro. The FR-19 gene is expressed
      in vivo in a tissue-specific manner, with a relatively high level detected in
      lung. These results indicate that increased expression of a TEF-1-related protein
      may be important for both mitogen-stimulated fibroblast proliferation and
      skeletal muscle cell differentiation.

PMID- 8662937
TI  - The beta-galactosidase (Escherichia coli) reaction is partly facilitated by
      interactions of His-540 with the C6 hydroxyl of galactose.
AB  - beta-Galactosidases with substitutions for His-540 were only poorly reactive with
      galactosyl substrates. However, the activity with substrates that were like
      galactose but did not have a C6 hydroxyl group was not decreased much as a result
      of such substitutions. The loss of transition state stabilization for galactosyl
      substrates as a result of substitution was between -15.4 and -22.8 kJ/mol but
      only between +0.34 and -6.5 for substrates that were identical to galactose but
      lacked the C6 hydroxyl. These findings indicate that an important function of His
      540 is to aid in the stabilization of the transition state by forming a stable
      interaction with the C6 hydroxyl group. This suggestion was strengthened by the
      results of competitive inhibition studies showing that L-arabinolactone (a
      transition state analog inhibitor of beta-galactosidase without a C6
      hydroxymethyl group) was bound as well by the substituted enzymes as by wild
      type, whereas transition state analog inhibitors that contain C6 hydroxyls (L
      ribose and D-galactonolactone) were bound much more poorly by the substituted
      enzymes than by the wild type enzyme. Substrate analog inhibitor studies showed
      that His-540 was also important for binding interactions with the C6 hydroxyl
      group of the ground (substrate) state. The activation by Mg2+ was the same for
      the substituted enzymes as for the wild type, and equilibrium dialysis showed
      that H540F-beta-galactosidase bound Mg2+ as well as did normal beta
      galactosidase. The k2 and Ks values seem to have the same pH interactions as wild
      type enzyme, whereas the k3 interactions are affected differently by pH in the
      substituted enzymes than in the wild type enzyme. The rate of the
      "degalactosylation" reaction was affected more by substitutions for His-540 than
      was the rate of the "galactosylation" reaction. All three substituted beta
      galactosidases were less stable to heat than was wild type, but H540N-beta
      galactosidase was somewhat more stable than the other two substituted enzymes.
      There were some differences in activity and inhibitory properties that resulted
      from the different substitutions.

PMID- 8662938
TI  - Unidirectional reconstitution into detergent-destabilized liposomes of the
      purified lactose transport system of Streptococcus thermophilus.
AB  - The lactose transport protein (LacS) of Streptococcus thermophilus was amplified
      to levels as high as 8 and 30% of total membrane protein in Escherichia coli and
      S. thermophilus, respectively. In both organisms the protein was functional and
      the expression levels were highest with the streptococcal lacS promoter. Also a
      LacS deletion mutant, lacking the carboxyl-terminal regulatory domain, could be
      amplified to levels >20% of membrane protein. Membranes from S. thermophilus
      proved to be superior in terms of efficient solubilization and ease and extent of
      purification of LacS; >95% of LacS was solubilized with relatively low
      concentrations of Triton X-100, n-octyl-beta-D-glucoside, n-dodecyl-beta-D
      maltoside, or C12E8. The LacS protein carrying a poly-histidine tag was purified
      in large quantities (approximately 5 mg/liter of culture) and with a purity >98%
      in a two-step process involving nickel chelate affinity and anion exchange
      chromatography. The membrane reconstitution of LacS was studied systematically by
      stepwise solubilization of preformed liposomes, prepared from E. coli
      phospholipid and phosphatidylcholine, and protein incorporation at the different
      stages of liposome solubilization. The detergents were removed by adsorption onto
      polystyrene beads and H+-lactose symport and lactose counterflow were measured.
      Highest transport activities were obtained when Triton X-100 was used throughout
      the solubilization/purification procedure, whereas activity was lost irreversibly
      with n-octyl-beta-D-glucoside. For reconstitutions mediated by n-dodecyl-beta-D
      maltoside, C12E8, and to a lesser extent Triton X-100, the highest transport
      activities were obtained when the liposomes were titrated with low amounts of
      detergent (onset of liposome solubilization). Importantly, under these conditions
      proteoliposomes were obtained in which LacS was reconstituted in an inside-out
      orientation, as suggested by the outside labeling of a single cysteine mutant
      with a membrane impermeable biotin-maleimide. The results are consistent with a
      mechanism of reconstitution in which the hydrophilic regions of LacS prevent a
      random insertion of the protein into the membrane. Consistent with the in vivo
      lactose/galactose exchange catalyzed by the LacS protein, the maximal rate of
      lactose counterflow was almost 2 orders of magnitude higher than that of H+
      lactose symport.

PMID- 8662939
TI  - Identification of a critical ligand binding determinant of the human
      erythropoietin receptor. Evidence for common ligand binding motifs in the
      cytokine receptor family.
AB  - The erythropoietin receptor (EPOR) is a member of a family of cytokine and growth
      factor receptors that share conserved features in their extracellular and
      cytoplasmic domains. We have used site-specific mutagenesis within the
      extracellular domain of the EPOR to search for amino acid residues involved in
      erythropoietin (EPO) binding. Mutant proteins were expressed in bacteria as
      soluble EPO binding proteins (EBP) and characterized for EPO binding activity in
      a number of different assays. Substitution of phenylalanine at position 93
      (Phe93) with alanine (F93A mutation) resulted in a drastic reduction in EPO
      binding in the EBP. More conservative tyrosine or tryptophan substitutions at
      Phe93 resulted in much less dramatic effects on EPO binding. Biophysical studies
      indicated that the F93A mutation does not result in gross structural alterations
      in the EBP. Furthermore, the F93A mutation in full-length EPOR expressed in COS
      cells abolished detectable EPO binding. This was not a result of processing or
      transport defects, since mutant receptor was present on the surface of the cells.
      Mutations in the region immediately around Phe93 and in residues homologous to
      other reported ligand binding determinants of the cytokine receptor family had
      small to moderate effects on EPO binding. These data indicate that Phe93 is a
      critical EPO binding determinant of the EPOR. Furthermore, since Phe93 aligns
      with critical ligand binding determinants in other receptors of the cytokine
      receptor family, these data suggest that receptors of this family may use common
      structural motifs to bind their cognate ligands.

PMID- 8662940
TI  - Structure-activity relationship studies on the novel neuropeptide orphanin FQ.
AB  - The heptadecapeptide orphanin FQ (OFQ) is an endogenous ligand to an opioid-like
      G protein-coupled receptor. Although the primary structure of OFQ exhibits some
      similarity to the opioid peptides, OFQ is not recognized by opioid receptors nor
      does the OFQ receptor bind opioid ligands. In order to investigate the structural
      determinants of this ligand/receptor selectivity, we conducted a systematic
      structure-activity study on OFQ to characterize which sites of the molecule are
      important for receptor activation. Alanine- and D-amino acid-scanning mutagenesis
      revealed several residues in the amino-terminal half of OFQ which participate in
      both receptor binding and activation. Most strikingly, the Phe1 position could be
      changed to a tyrosine without loss of biological activity. In addition, the OFQ
      receptor seemed to require recognition of the complete peptide molecule for
      activation. These results indicate that the mode of interaction of OFQ with its
      receptor may be different from that of the opioid peptides with their respective
      receptors and might therefore account for the observed selectivity.

PMID- 8662941
TI  - The genomic structure of the rat corticotropin releasing factor receptor. A
      member of the class II G protein-coupled receptors.
AB  - Isolation and structural characterization of the rat corticotropin releasing
      factor receptor (CRFR) gene was performed to determine the exon/intron
      organization of the coding region and the potential for splice variants. The CRFR
      gene contains 13 exons and 12 introns, and the positions of the exon/intron
      junctions are similar to those of other Class II G protein-coupled receptor genes
      including the parathyroid hormone and glucagon receptors. The promoter resides
      within 593 base pairs of the initiation codon and the major transcriptional start
      site at nucleotide -238. This domain does not possess a TATA box but contains
      multiple Sp1 and AP-2 sites upstream and downstream of the major transcriptional
      start site. Intron junctions were identified in the extracellular, transmembrane
      (TM), and cytoplasmic (C) domains of the CRFR, giving the potential for
      differential signal transduction by splice variants. CRFR cDNAs derived from rat
      Leydig cell mRNA included the pituitary Form A, which spans exons 1-13, and two
      splice variants with deletion of exon 3 or exons 7, 11, and 12. An evolutionary
      link between the intronless TM/C module of the glycoprotein hormone receptors and
      the intron-containing TM/C module of the CRFR is suggested by the common position
      of the luteinizing hormone receptor Form D alternate acceptor splice site and the
      CRFR intron 12.

PMID- 8662942
TI  - Differential appearance of DNase I-hypersensitive sites correlates with
      differential transcription of Pgk genes during spermatogenesis in the mouse.
AB  - Two functional genes encoding phosphoglycerate kinase are differentially
      expressed during spermatogenesis in the mouse. Expression of the X-linked Pgk-1
      gene is repressed coincident with X chromosome inactivation during prophase of
      meiosis I. At this same stage, expression of the autosomal Pgk-2 gene is
      initiated by tissue-specific mechanisms. To investigate the role of chromatin
      structure in these processes, we have examined the appearance and disappearance
      of DNase I-hypersensitive (DH) sites in each gene, and correlated this with
      transcriptional activity as measured by nuclear run-off analysis at specific
      stages of spermatogenesis. Our results demonstrate that the occurrence of DH
      sites is related to periods of active transcription. Results with the Pgk-1 gene
      indicate that transcriptional inactivation of the X chromosome in spermatogenic
      cells may not be as complete as that in somatic cells, and that maximum
      repression may be limited to a very transient period during the pachytene stage
      of first meiotic prophase. Results with the Pgk-2 gene indicate that DH sites
      appear coincident with, or just prior to, transcriptional activation of this
      gene. The implications of these results are discussed with respect to the role of
      X chromosome inactivation in spermatogenic cells and the developmental order of
      molecular events that regulate differential gene expression during
      spermatogenesis.

PMID- 8662943
TI  - Membrane-bound versus secreted forms of human asialoglycoprotein receptor
      subunits. Role of a juxtamembrane pentapeptide.
AB  - The H2a alternatively spliced variant of the human asialoglycoprotein receptor H2
      subunit differs from the H2b variant by an extra pentapeptide, EGHRG, present in
      the ectodomain next to the membrane-span. This difference causes retention and
      degradation in the endoplasmic reticulum (ER) of H2a when expressed without the
      H1 subunit in 3T3 cells. In contrast, a significant portion of singly expressed
      H2b is Golgi-processed and reaches the cell surface. Using a new specific anti
      H2a antibody, we found that in HepG2 cells, H2a is rapidly cleaved to a 35-kDa
      fragment, comprising the entire ectodomain, most of which is secreted into the
      medium. The cleavage site for the secreted fragment was located at the lumenal
      end of the membrane span. No membrane-bound H2a exits the ER, indicating that the
      pentapeptide is a signal for ER retention and degradation of the membrane form
      but does not hinder secretion of the cleaved soluble form. H2a does not form a
      membrane receptor complex with H1 as H2b does. H2a is therefore not a subunit of
      the receptor but a precursor for a secreted form of the protein; signal peptidase
      is probably responsible for the cleavage to the soluble fragment. Therefore, the
      juxtamembrane sequence regulates the function of the transmembrane domain of a
      type II membrane protein as either a signal-anchor sequence (H2b) or as a cleaved
      signal sequence, which generates a secreted product (H2a).

PMID- 8662944
TI  - Identification of a second functional glutaredoxin encoded by the bacteriophage
      T4 genome.
AB  - Thioredoxins and glutaredoxins are small ubiquitous redox proteins that were
      discovered as hydrogen donors for ribonucleotide reductase, the key enzyme for
      deoxyribonucleotide biosynthesis. Some organisms encode more than one redox
      protein. In this study, we demonstrate that an open reading frame in the
      bacteriophage T4 genome, reported earlier and designated as Y55.7 (Tomaschewski,
      J., and Ruger, W. (1987) Nucleic Acids Res. 15, 3632-3633), encodes a second
      functional redox protein. Gene y55.7 was cloned and expressed in Escherichia
      coli. Purified Y55.7 protein had glutathione-dependent thioltransferase and
      dehydroascorbate reductase activities indicative of a functional glutaredoxin.
      The protein is expressed at all stages of the T4 infection cycle and can serve as
      a hydrogen donor for the phage ribonucleotide reductase in in vitro experiments.

PMID- 8662945
TI  - The transcriptional activity of the CCAAT-binding factor CBF is mediated by two
      distinct activation domains, one in the CBF-B subunit and the other in the CBF-C
      subunit.
AB  - CBF-A, CBF-B, and CBF-C together form the heterotrimeric mammalian CCAAT-binding
      factor, CBF, which binds to DNA to form a CBF-DNA complex. Here we examined the
      transcription activation function of CBF in an in vitro reconstituted system
      using the three purified recombinant CBF subunits expressed in Escherichia coli.
      Two of the subunits, CBF-A and CBF-C, were coexpressed and purified as a CBF
      A/CBF-C complex. Addition of the three wild-type recombinant CBF subunits to EL4
      cell nuclear extracts depleted of CBF stimulated transcription 5-20-fold from
      proalpha2(1) collagen promoters and 10-fold from the Rous sarcoma virus long
      terminal repeat. Two CBF deletion mutants, one containing full-length CBF-A and
      CBF-C and a CBF-B lacking the NH2-terminal residues 1-224, and the other
      containing full- length CBF-A and CBF-B and a CBF-C lacking the COOH-terminal
      residues 114-309, also stimulated transcription from these promoters, but the
      level of activation was reduced to half that obtained with the full-length CBF
      subunits. In contrast, a CBF deletion mutant protein containing full-length CBF-A
      and deleted forms of both CBF-B and CBF-C showed very little transcription
      activation from these promoters. Hence, this study demonstrates that the
      heterotrimeric CBF protein consists of two transcription activation domains, one
      present in CBF-B and the other in CBF-C, and that the two domains act additively
      in the in vitro assay. The activation domains of both CBF-B and CBF-C, which are
      rich in glutamine and hydrophobic residues, showed amino acid sequence
      similarities with each other and with the glutamine-rich activation domain of
      transcription factor Sp1.

PMID- 8662947
TI  - Cellular oxygen toxicity. Oxidant injury without apoptosis.
AB  - All forms of aerobic life are faced with the threat of oxidation from molecular
      oxygen (O2) and have evolved antioxidant defenses to cope with this potential
      problem. However, cellular antioxidants can become overwhelmed by oxidative
      insults, including supraphysiologic concentrations of O2 (hyperoxia). Oxidative
      cell injury involves the modification of cellular macromolecules by reactive
      oxygen intermediates (ROI), often leading to cell death. O2 therapy, which is a
      widely used component of life-saving intensive care, can cause lung injury. It is
      generally thought that hyperoxia injures cells by virtue of the accumulation of
      toxic levels of ROI, including H2O2 and the superoxide anion (O2-), which are not
      adequately scavenged by endogenous antioxidant defenses. These oxidants are
      cytotoxic and have been shown to kill cells via apoptosis, or programmed cell
      death. If hyperoxia-induced cell death is a result of increased ROI, then O2
      toxicity should kill cells via apoptosis. We studied cultured epithelial cells in
      95% O2 and assayed apoptosis using a DNA-binding fluorescent dye, in situ end
      labeling of DNA, and electron microscopy. Using all approaches we found that
      hyperoxia kills cells via necrosis, not apoptosis. In contrast, lethal
      concentrations of either H2O2 or O2- cause apoptosis. Paradoxically, apoptosis is
      a prominent event in the lungs of animals injured by breathing 100% O2. These
      data indicate that O2 toxicity is somewhat distinct from other forms of oxidative
      injury and suggest that apoptosis in vivo is not a direct effect of O2.

PMID- 8662946
TI  - Studies on identifying the catalytic role of Glu-204 in the active site of yeast
      invertase.
AB  - In a previous study on yeast invertase (Reddy, A., and Maley, F. (1990) J. Biol.
      Chem. 265, 10817-10820), we identified Asp-23 through the procedures of affinity
      labeling and site-directed mutagenesis as a catalytic nucleophile. In the present
      study we undertook to determine other residues involved in the catalytic process.
      Earlier studies suggested histidine as a potential proton donor in the hydrolysis
      of sucrose, but by mutagenizing each of the enzyme's four histidines this amino
      acid was eliminated from consideration. Another candidate appeared to be
      cysteine, since iodine at about a 2-fold molar excess inactivated invertase by
      modifying both of the enzyme's cysteine residues. Dithiothreitol treatment
      restored the sulfhydryl groups and enzyme activity. Replacement of each of the
      cysteines with alanines revealed that C108A invertase retained full activity
      whereas C205A was reduced about 4-fold in its kcat. A comparison of the amino
      acid sequences of fructosylhydrolases revealed a conserved region coincident with
      Glu-204/Cys-205. Mutagenizing Glu-204 to Ala resulted in a 3, 000-fold reduction
      in the kcat of invertase indicating that Glu-204 plays a major role in catalysis.
      Based on these findings, a mechanism is proposed for the hydrolysis of sucrose
      which involves Asp-23 as a nucleophile and Glu-204 as an acid/base catalyst.

PMID- 8662949
TI  - Alteration of enzyme function of the type II hexokinase C-terminal half on
      replacements of restricted regions by corresponding regions of glucokinase.
AB  - To know the structural properties responsible for the enzymic activity of the 50
      kDa C-terminal half of type II hexokinase (HKII-C) derived from rat hepatoma cell
      line AH130, we constructed cDNAs of HKII-C and its recombinants in which
      restricted regions containing highly conserved sequences, referred to as regions
      2 and 3, were replaced by the corresponding regions of glucokinase. The binding
      domains of ATP and glucose were proposed to exist in these regions, respectively.
      Then, the HKII-C and chimera HKII-Cs were overexpressed in Escherichia coli
      BL21(DE3)pLysS. They all exhibited hexokinase activity, and their activities were
      inhibited by glucose-6-phosphate (Glc-6-P) competitively for ATP and
      uncompetitively for glucose. The replacement of region 2 of HKII-C by the
      corresponding region of glucokinase increased the affinity for glucose and
      decreased the affinity for Glc-6-P, but it did not significantly affect the
      affinity for ATP. In contrast, the replacement of region 3 did not cause an
      appreciable change in hexokinase activity. These findings suggest that region 2
      is associated with the binding of ATP and Glc-6-P, and that the latter binding
      site is located close to the ATP binding site. In addition, region 2 was
      suggested to be directly related with the binding of glucose and other hexoses.

PMID- 8662948
TI  - A peptide-based protein-tyrosine phosphatase inhibitor specifically enhances
      insulin receptor function in intact cells.
AB  - 3S-peptide-I is a synthetic tris-sulfotyrosyl dodecapeptide corresponding to the
      major site of insulin receptor autophosphorylation that potently inhibits
      dephosphorylation of the insulin receptor in a cell-free system and in digitonin
      permeabilized Chinese hamster ovary (CHO) cells overexpressing the human insulin
      receptors (CHO/HIRc cells) (Liotta, A. S., Kole, H. K., Fales, H. M., Roth, J.,
      and Bernier, M. (1994) J. Biol. Chem. 269, 22996-23001). In the present study, we
      found that 3S-peptide-I was not capable of inhibiting dephosphorylation of the
      epidermal growth factor (EGF) receptors in digitonin-permeabilized CHO cells that
      overexpress human EGF receptors (CHO/EGF-R cells). Moreover, the addition of a N
      stearyl derivative of 3S-peptide-I to intact CHO/HIRc cells caused a
      concentration-dependent increase in insulin-stimulated phosphorylation of the
      insulin receptor, with a maximum effect (approximately 2.7-fold) at 50 microM. In
      contrast, ligand-stimulated EGF receptor phosphorylation in CHO/EGF-R cells was
      not affected by the presence of stearyl 3S-peptide-I. Furthermore, treatment of
      CHO/HIRc cells with this N-stearyl peptide led to a significant enhancement of
      the insulin-induced association of phosphatidylinositol (PI) 3-kinase activity
      with insulin receptor substrate 1 and the activation of mitogen-activated protein
      kinase. However, stearyl 3S-peptide-I had no effect on the EGF-stimulated
      activation of PI-3-kinase and mitogen-activated protein kinase in CHO/EGF-R
      cells. These data indicate that this tris-sulfotyrosyl dodecapeptide selectively
      enhances insulin signal transduction by specifically inhibiting dephosphorylation
      of the insulin receptor in intact cells.

PMID- 8662950
TI  - Structural analysis of bovine somatotropin using monoclonal antibodies and the
      conformation-sensitive immunoassay.
AB  - Bovine somatotropin was studied with respect to thermal stability, quantitative
      thermal denaturation kinetics, and refolding potential following thermal
      denaturation using a panel of 6 monoclonal antibodies and the Conformation
      Sensitive Immunoassay (CSI). The antibody panel consisted of 4 conformation
      dependent and 2 sequence-specific antibodies. Each of the antibodies revealed
      unique thermal stability profiles for their respective epitopes suggesting that
      they each recognize different antigenic determinants. Comparing the thermal
      stability profiles generated with these antibodies allowed the stability of
      bovine somatotropin to be "dissected" based on individual structural features.
      The degree to which bovine somatotropin is stabilized by disulfide bonds was
      examined using CSI-based quantitative thermal denaturation kinetics profiles
      generated under reducing and nonreducing conditions. All of the conformational
      epitopes unfolded faster under reducing conditions indicating that the two
      disulfide bonds within the somatotropin molecule impart some degree of global
      stabilization. The ability of bovine somatotropin to refold after reducing or
      nonreducing thermal denaturation was also examined using the antibody panel and
      the CSI. The results show that, although significant refolding was evident for
      some epitopes, bovine somatotropin cannot refold to the native state following
      thermal denaturation under either reducing or nonreducing conditions.

PMID- 8662951
TI  - Functional analysis of the cellular receptor for urokinase in plasminogen
      activation. Receptor binding has no influence on the zymogenic nature of pro
      urokinase.
AB  - Plasminogen activation catalyzed by the urokinase-type plasminogen activator
      (uPA) constitutes a reciprocal zymogen activation system, as plasmin can
      efficiently activate pro-uPA, the single-chain zymogenic form of the protease. We
      have previously shown that the overall efficiency of this plasminogen activation
      system is greatly enhanced by its assembly on the cell surface, involving binding
      of pro-uPA to its cellular binding site uPAR, and the concurrent cellular binding
      of plasminogen. We have now studied the effect of a recombinant soluble form of
      uPAR (residues 1-277) on the proteolytic reactions of this system. In contrast to
      the increased efficiencies of plasminogen activation and pro-uPA activation
      observed with cell-surface uPAR, soluble uPAR had an inhibitory effect on both of
      these individual reactions. Soluble uPAR also caused no increase in the low, but
      discernible, intrinsic activity of pro-uPA. Consistent with the observations on
      the isolated reactions, the overall activity of the pro-uPA-mediated plasminogen
      activation system was significantly inhibited. These observations confirm the
      previous interpretation of the observations made with cell-surface uPAR that the
      mechanism of the enhanced plasmin generation is due to the catalytically
      favorable interaction of uPAR-bound uPA/pro-uPA with cell-bound
      plasminogen/plasmin, rather than direct effects on the properties of uPA or pro
      uPA on binding to uPAR.

PMID- 8662952
TI  - Inhibition of cellular processing of surfactant protein C by drugs affecting
      intracellular pH gradients.
AB  - Surfactant protein C (SP-C) is a hydrophobic protein synthesized and secreted
      exclusively by alveolar type II cells through proteolysis of a 21-kDa propeptide
      (SP-C21) to produce the 3.7-kDa surface active form. Previous studies from this
      laboratory have demonstrated that early processing of proSP-C involves extensive
      intracellular proteolysis of the COOH terminus of proSP-C21 in subcellular
      compartments, which include the acidic type II cell-specific subcellular
      organelle, the lamellar body. (Beers, M. F., Kim, C. Y., Dodia, C., and Fisher,
      A. B.(1994) J. Biol. Chem. 269, 20318-20328). The role of intracellular pH
      gradients in SP-C processing was studied in freshly isolated rat type II cells.
      Using vital fluorescence microscopy, the pH indicator acridine orange (AO)
      identified intense fluorescence staining of acidic cytoplasmic vesicles within
      fresh type II cells. The AO vesicular staining pattern was similar in cells
      labeled with the lamellar body marker phosphine 3R and the phospholipid dye nile
      red. AO fluorescence was quenched by the addition of a membrane-permeable weak
      base, methylamine. Immunoprecipitation of cell lysates with anti-proSP-C antisera
      following pulse-chase labeling (0-2 h) with 35S-Translabel demonstrated rapid
      synthesis of 35S-proSP-C21 with a time-dependent appearance of 16- and 6-kDa
      intermediates (SP-C16 and SP-C6). Tricine polyacrylamide gel electrophoresis
      analysis of organic extracts of cell lysates showed time-dependent appearance of
      mature SP-C3.7. The addition of 5 mM methylamine significantly blocked the post
      translational processing of proSP-C resulting in disruption of normal precursor
      product relationships and inhibition of SP-C3.7 formation. Methylamine-treated
      cells exhibited slow accumulation of SP-C16 and SP-C6, a persistence of SP-C21,
      and an absence of SP-C3.7 for the duration of the chase period. The
      lysosomotropic agent chloroquine, the proton ionophore monensin, and bafilomycin
      A1, a specific vacuolar H+-ATPase inhibitor, each caused inhibition of proSP-C
      processing in a similar manner. These results demonstrate that normal post
      translational proteolysis of proSP-C occurs in acidic intracellular compartments,
      which include the lamellar body, and that complete processing to SP-C3.7 is
      dependent upon maintenance of transmembrane pH gradients by a vacuolar H+-ATPase.

PMID- 8662953
TI  - Nucleotide-dependent movement of the epsilon subunit between alpha and beta
      subunits in the Escherichia coli F1F0-type ATPase.
AB  - Mutants of ECF1-ATPase were generated, containing cysteine residues in one or
      more of the following positions: alphaSer-411, betaGlu-381, and epsilonSer-108,
      after which disulfide bridges could be created by CuCl2 induced oxidation in high
      yield between alpha and epsilon, beta and epsilon, alpha and gamma, beta and
      gamma (endogenous Cys-87), and alpha and beta. All of these cross-links lead to
      inhibition of ATP hydrolysis activity. In the two double mutants, containing a
      cysteine in epsilonSer-108 along with either the DELSEED region of beta (Glu-381)
      or the homologous region in alpha (Ser-411), there was a clear nucleotide
      dependence of the cross-link formation with the epsilon subunit. In
      betaE381C/epsilonS108C the beta-epsilon cross-link was obtained preferentially
      when Mg2+ and ADP + Pi (addition of MgCl2 + ATP) was present, while the alpha
      epsilon cross-link product was strongly favored in the alphaS411C/epsilonS108C
      mutant in the Mg2+ ATP state (addition of MgCl2 + 5'-adenylyl-beta,gamma
      imidodiphosphate). In the triple mutant alphaS411C/betaE381C/epsilonS108C, the
      epsilon subunit bound to the beta subunit in Mg2+-ADP and to the alpha subunit in
      Mg2+-ATP, indicating a significant movement of this subunit. The gamma subunit
      cross-linked to the beta subunit in higher yield in Mg2+-ATP than in Mg2+-ADP,
      and when possible, i.e. in the triple mutant, always preferred the interaction
      with the beta over the alpha subunit.

PMID- 8662954
TI  - Physical and functional association between GADD153 and CCAAT/enhancer-binding
      protein beta during cellular stress.
AB  - GADD153, a ubiquitously expressed member of the CCAAT/enhancer-binding protein
      (C/EBP) family is induced by a wide variety of growth-arresting and DNA-damaging
      agents. Functionally, GADD153 has been postulated to act as a dominant-negative
      regulator of C/EBPs. Therefore we sought to gain evidence for interactions
      between GADD153 and other C/EBPs during cellular responses to stress. In this
      report we have demonstrated that treatment of rat pheochromocytoma PC12 cells
      with sodium arsenite leads to enhanced expression of C/EBP-beta and GADD153
      (growth arrest and DNA damage inducible gene 153) but not other C/EBPs.
      Coimmunoprecipitation experiments provided evidence for the formation of
      endogenous GADD153-C/EBP-beta complexes in arsenite-treated cells. Additional
      experiments were performed to determine the role of such complexes in regulating
      GADD153 expression. Previous studies in our laboratory demonstrated that the
      GADD153 promoter contains a C/EBP binding site through which other C/EBPs
      interact to transactivate GADD153 expression in liver hepatoma cells. Here, we
      demonstrate that extracts prepared from arsenite-treated PC12 cells likewise show
      increased amounts of factors capable of binding to the GADD153-C/EBP site and
      that these complexes are comprised at least in part of C/EBP-beta. Forced
      expression of C/EBP-beta was found to be capable of transactivating the GADD153
      promoter in PC12 cells cotransfected with plasmids expressing a GADD153 reporter
      gene and C/EBP-beta protein. However, overexpression of GADD153 inhibited the
      transactivation of the GADD153 promoter by C/EBP-beta. These findings provide
      evidence for an autoregulatory loop in which stress-induced GADD153 feeds back to
      attenuate GADD153 expression during the cellular response to stress.

PMID- 8662955
TI  - Specificity and kinetics of haloalkane dehalogenase.
AB  - Haloalkane dehalogenase converts halogenated alkanes to their corresponding
      alcohols. The active site is buried inside the protein and lined with hydrophobic
      residues. The reaction proceeds via a covalent substrate-enzyme complex. This
      paper describes a steady-state and pre-steady-state kinetic analysis of the
      conversion of a number of substrates of the dehalogenase. The kinetic mechanism
      for the "natural" substrate 1,2-dichloroethane and for the brominated analog and
      nematocide 1,2-dibromoethane are given. In general, brominated substrates had a
      lower Km, but a similar kcat than the chlorinated analogs. The rate of C-Br bond
      cleavage was higher than the rate of C-Cl bond cleavage, which is in agreement
      with the leaving group abilities of these halogens. The lower Km for brominated
      compounds therefore originates both from the higher rate of C-Br bond cleavage
      and from a lower Ks for bromo-compounds. However, the rate-determining step in
      the conversion (kcat) of 1, 2-dibromoethane and 1,2-dichloroethane was found to
      be release of the charged halide ion out of the active site cavity, explaining
      the different Km but similar kcat values for these compounds. The study provides
      a basis for the analysis of rate-determining steps in the hydrolysis of various
      environmentally important substrates.

PMID- 8662956
TI  - Cloning and functional characterization of the gene encoding the TFIIIB90 subunit
      of RNA polymerase III transcription factor TFIIIB.
AB  - The yeast RNA polymerase III (pol III) general transcription factor TFIIIB is
      composed of three subunits; the TATA-binding protein (TBP)1, the TFIIB-related
      factor (BRF1), and a third factor termed TFIIIB90 or B". Here we report the
      purification of yeast TFIIIB90, cloning of the gene encoding TFIIIB90, and
      reconstitution of TFIIIB from recombinant polypeptides. The TFIIIB90 open reading
      frame encodes a 68-kDa polypeptide and has no obvious similarity to any other
      known protein sequences. The gene encoding TFIIIB90 is essential for viability of
      yeast. Using recombinant TFIIIB subunits, we found that TFIIIB90 interacts weakly
      with TBP in the absence of BRF1, and that this interaction is enhanced at least
      25-fold by BRF1. In addition, TFIIIB90 showed pol III specificity as it could not
      interact with the pol II-specific TFIIB-TBP-DNA complex. To localize the regions
      of the TBP-DNA complex that interact with BRF1 and TFIIIB90, we tested whether
      the pol II factors TFIIA and TFIIB interfered with the binding of BRF1 and
      TFIIIB90 to TBP-DNA. Our results suggest that the binding sites for BRF1 and
      TFIIIB90 on TBP-DNA both overlap the binding sites for TFIIA and TFIIB.

PMID- 8662957
TI  - The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic
      induction of gene expression. Studies in ARNT-deficient cells.
AB  - Hypoxia-inducible factor-1 (HIF-1), a DNA-binding complex implicated in the
      regulation of gene expression by oxygen, has been shown to consist of a
      heterodimer of two basic helix-loop-helix Per-AHR-ARNT-Sim (PAS) proteins, HIF
      1alpha, and HIF-1beta. One partner, HIF-1beta, had been recognized previously as
      the aryl hydrocarbon receptor nuclear translocator (ARNT), an essential component
      of the xenobiotic response. In the present work, ARNT-deficient mutant cells,
      originally derived from the mouse hepatoma line Hepa1c1c7, have been used to
      analyze the role of ARNT/HIF-1beta in oxygen-regulated gene expression. Two
      stimuli were examined: hypoxia itself and desferrioxamine, an iron-chelating
      agent that also activates HIF-1. Induction of the DNA binding and transcriptional
      activity of HIF-1 was absent in the mutant cells, indicating an essential role
      for ARNT/HIF-1beta. Analysis of deleted ARNT/HIF-1beta genes indicated that the
      basic, helix-loop-helix, and PAS domains, but not the amino or carboxyl termini,
      were necessary for function in the response to hypoxia. Comparison of gene
      expression in wild type and mutant cells demonstrated the critical importance of
      ARNT/HIF-1beta in the hypoxic induction of a wide variety of genes. Nevertheless,
      for some genes a reduced response to hypoxia and desferrioxamine persisted in
      these mutant cells, clearly distinguishing ARNT/HIF-1beta-dependent and ARNT/HIF
      1beta-independent mechanisms of gene activation by both these stimuli.

PMID- 8662959
TI  - A novel gene cluster including the Rhodococcus rhodochrous J1 nhlBA genes
      encoding a low molecular mass nitrile hydratase (L-NHase) induced by its reaction
      product.
AB  - The 3.5 kilobases (kb) of the 5'-upstream region from nhlBA encoding a cobalt
      containing low molecular mass nitrile hydratase (L-NHase) from Rhodococcus
      rhodochrous J1 was found to be required for the amide-dependent expression of
      nhlBA in experiments using a Rhodococcus transformation system. Sequence analysis
      of the 3.5-kb fragment revealed the presence of two open reading frames (nhlD and
      nhlC) in this fragment. NhlD has similarity to regulators MerR, CadC, and ArsR.
      NhlC has similarity to the regulators AmiC, for the expression of an aliphatic
      amidase from Pseudomonas aeruginosa, and NhhC, for the expression of a high
      molecular mass nitrile hydratase from R. rhodochrous J1. Assays of NHase activity
      of transformants carrying nhlD deletion or nhlC deletion mutations suggest a
      negative regulatory role for nhlD and a positive regulatory role for nhlC in the
      process of the L-NHase formation. Assays of NHase and amidase activities and
      Western blot analyses of each Rhodococcus transformant carrying various deletion
      plasmids, have shown that nhlBA and amdA encoding an amidase, which is located
      1.9 kb downstream of nhlBA, were regulated in the same manner. These findings
      present the genetic evidence for a novel gene cluster controlling the expression
      of L-NHase, which is induced by the reaction product (amide) in the "practical
      microorganism" R. rhodochrous J1.

PMID- 8662958
TI  - Nitrosation of tryptophan residue(s) in serum albumin and model dipeptides.
      Biochemical characterization and bioactivity.
AB  - Nitrosation of bovine serum albumin with acidified NaNO2 was compared to that of
      carboxymethyl-bovine serum albumin in which the thiol group is covalently
      blocked. Differential ultraviolet-visible (UV-Vis) spectroscopy and a modified
      Saville assay indicated that a non-cysteine residue(s) in carboxymethyl-bovine
      serum albumin was nitrosated. The nitrosated carboxymethyl-bovine serum albumin
      exhibited similar vasorelaxation activity as that observed with nitrosated bovine
      serum albumin. Identification of the nitrosated non-cysteine residue(s) was
      studied using 16 model dipeptides, each of which contained a glycyl residue and a
      variable residue. Using photolysis-chemiluminescence analysis, modified Saville
      assay, differential UV-Vis spectroscopy, and bioassays, L-glycyl-L-tryptophan
      (Gly-Trp) was found to be the only dipeptide that underwent significant
      nitrosation under these conditions. Liquid chromatography-UV-Vis spectroscopy
      mass spectrometry showed that the NO group was attached to the indole nitrogen of
      tryptophan. Nitrosated Gly-Trp exhibited dose-dependent vasorelaxation and
      platelet inhibiting activity with apparent EC50 values of 1.1 +/- 0. 3 and 3.5 +/
      0.9 microM, respectively. Because N-nitroso-Gly-Trp does not release NO radical
      via spontaneous homolytic N-NO bond fission nor freely diffuse through cellular
      membranes, the ability of this compound to induce NO.-like biological effects
      suggests the existence of a (membrane-associated) transnitrosation system that
      facilitates delivery of -NO to its specific biologic target(s).

PMID- 8662960
TI  - Globin gene switching. In vivo protein-DNA interactions of the human beta-globin
      locus in erythroid cells expressing the fetal or the adult globin gene program.
AB  - To characterize the protein-DNA interactions important for the developmental
      control of the human beta-globin locus, we analyzed by in vivo dimethyl sulfate
      footprinting erythroid cells expressing either the fetal or the adult globin
      developmental program. In the locus control region (LCR) of the beta-globin
      locus, in vivo footprints on NF-E2 (or AP-1) and GATA-1 motifs remained the same
      regardless of whether the fetal or the adult globin genes are expressed. In
      contrast, in vivo footprints on GT (CACCC) motifs differed between the cells
      expressing the fetal or the adult globin program. In promoter regions, the
      actively transcribed genes demonstrated extensive and consistent footprints over
      the canonical elements, such as CACCC and CCAAT motifs. The adult globin
      expressing cells displayed more extensive footprints than the fetal globin
      expressing cells in the 3' regulatory sequences of both the Agamma- and the beta
      globin genes, suggesting a role of these 3' elements in beta-globin gene
      expression. Our results suggest that the bulk of protein-DNA interactions that
      underlies the developmental control of globin genes takes place in the gamma- and
      beta-globin gene promoters, and that GT motifs of the beta-globin locus LCR may
      play a role in the developmental regulation of human beta-globin gene expression,
      perhaps by increasing the probability of interaction of the LCR holocomplex with
      the fetal or the adult globin gene.

PMID- 8662961
TI  - PsB multiprotein complex of Dictyostelium discoideum. Demonstration of cellulose
      binding activity and order of protein subunit assembly.
AB  - The differentiated spores of Dictyostelium are surrounded by an extracellular
      matrix, the spore coat, which protects them from environmental factors allowing
      them to remain viable for extended periods of time. This presumably is a major
      evolutionary advantage. This unique extracellular matrix is composed of cellulose
      and glycoproteins. Previous work has shown that some of these spore coat
      glycoproteins exist as a preassembled multiprotein complex (the PsB multiprotein
      complex) which is stored in the prespore vesicles (Watson, N., McGuire, V., and
      Alexander, S (1994) J. Cell Sci. 107, 2567-2579). Later in development, the
      complex is synchronously secreted from the prespore vesicles and incorporated
      into the spore coat. We now have shown that the PsB complex has a specific in
      vitro cellulose binding activity. The analysis of mutants lacking individual
      subunits of the PsB complex revealed the relative order of assembly of the
      subunit proteins and demonstrated that the protein subunits must be assembled for
      cellulose binding activity. These results provide a biochemical explanation for
      the localization of this multiprotein complex in the spore coat.

PMID- 8662962
TI  - Inhibition of retinoic acid receptor function and retinoic acid-regulated gene
      expression in mouse melanoma cells by calreticulin. A potential pathway for
      cyclic AMP regulation of retinoid action.
AB  - Calcium is a second messenger that controls a wide variety of cellular functions.
      Because of its multiple actions, there is a stringent requirement for calcium
      homeostasis, and this is achieved in part by a system of transport and storage
      proteins such as calreticulin located in the endoplasmic reticulum. Calreticulin
      is also found in the nucleus, suggesting that it may have a role in
      transcriptional regulation. It has been reported that calreticulin can inhibit
      steroid-regulated gene transcription by preventing receptor binding to DNA. Here
      we report that overexpression of the calreticulin gene in B16 mouse melanoma
      cells resulted in a decrease in retinoic acid (RA)-stimulated reporter gene
      expression. Gel shift analysis showed that purified calreticulin inhibited the
      binding of endogenous RAR to a beta-RA response element oligonucleotide, only if
      added prior to the addition of the oligonucleotide. Co-immunoprecipitation
      studies suggest a physical interaction between RAR and calreticulin. Transfection
      of the calreticulin gene into B16 cells inhibited the RA induction of protein
      kinase Calpha, a marker of RA-induced differentiation. We also found that cyclic
      AMP increased the expression of calreticulin. Cyclic AMP may act to antagonize RA
      action by both decreasing RAR expression (Y. Xiao, D. Desai, T. Quick, and R. M.
      Niles, J. Cell Physiol., in press) and stimulating calreticulin levels.

PMID- 8662963
TI  - Nucleotide dependence of Rab geranylgeranylation. Rab escort protein interacts
      preferentially with GDP-bound Rab.
AB  - Geranylgeranylation of Rab GTPases is an essential post-translational
      modification that enables Rabs to associate with intracellular membranes where
      they regulate exocytic and endocytic pathways. Geranylgeranylation is initiated
      by formation of a stable complex between newly synthesized Rab proteins and Rab
      escort protein (REP). The complex is recognized by Rab geranylgeranyl (GG)
      transferase, which transfers two GG groups to Rabs. The geranylgeranylated Rabs
      regulate vesicular movement by oscillating between an inactive GDP-bound form and
      an active GTP-bound form. In this study, I show that the kinetics of
      geranylgeranylation is influenced by the nucleotide status of nascent Rab. GDP
      bound Rab is geranylgeranylated with 10-50-fold higher affinity than GTP-bound
      Rab (or GTP analog-bound Rab), as indicated by the apparent Km of the reaction.
      In vitro REP.Rab binding assays demonstrate that REP forms a stable complex only
      with the GDP-bound form of Rab but not the GTP-bound form, suggesting that the
      apparent Km effect in the prenylation reaction is due to a discrimination between
      the two different nucleotide-bound forms of Rab by REP. Inasmuch as Rabs are
      likely GTP-bound after synthesis and REP does not possess GTPase-activating
      protein activity, these results raise the possibility that a Rab GTPase
      activating protein enhances the REP*Rab interaction prior to prenylation.

PMID- 8662964
TI  - Neural specific expression of the m4 muscarinic acetylcholine receptor gene is
      mediated by a RE1/NRSE-type silencing element.
AB  - Muscarinic receptor genes are members of the G-protein receptor superfamily that,
      with the inclusion of the odorant receptors, is believed to contain over a
      thousand members. Each member of this superfamily, which has been studied to
      date, appears to have a distinct pattern of expression, but little work has been
      done on the regulation of these complex expression patterns. We have recently
      isolated the rat m4 muscarinic receptor gene and identified a genomic 1520
      nucleotide sequence that appeared capable of directing cell-specific expression
      (Wood, I. C., Roopra. A., Harrington, C., and Buckley, N. J. (1995) J. Biol.
      Chem. 270, 30933-30940). In the present study we have constructed a set of
      deletion promoter constructs to more closely define the DNA elements that are
      responsible for m4 gene expression. We have found that deletion of a RE1/NRSE
      silencer element between nucleotides -574 and -550, similar to that found in
      other neural specific genes, results in activation of reporter expression in non
      m4-expressing cells. Gel mobility shift analysis has shown that a protein present
      in nonexpressing cells is capable of binding to this element and is probably the
      recently identified neural silencer, REST/NRSF. Of the constitutively active
      proximal promoter only a tandem Sp-1 site appears to recruit DNA binding proteins
      that are present in all cells tested. This represents the first report
      documenting the role of this silencer in regulating expression of a member of the
      G-protein receptor family.

PMID- 8662965
TI  - Long exposure to high glucose concentration impairs the responsive expression of
      gamma-glutamylcysteine synthetase by interleukin-1beta and tumor necrosis factor
      alpha in mouse endothelial cells.
AB  - To elucidate the pathological metabolism of glutathione synthesis in diabetic
      endothelial cells, we studied the expression of gamma-glutamylcysteine synthetase
      (gamma-GCS) using a mouse vascular endothelial cell line. Exposing normoglycemic
      endothelial cells to tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta
      (IL-1beta) increased the activity and the mRNA expression of gamma-GCS. The
      addition of inhibitors for nuclear factor kappaB (NF-kappaB) to the cells caused
      a loss of the gamma-GCS mRNA expression in response to TNF-alpha. A shift of the
      concentration of glucose in the medium from 5.5 to 28 mM glucose and a following
      incubation for 7 days decreased the expression of gamma-GCS mRNA. These cells
      showed no apparent responses of gamma-GCS mRNA or the activity of NF-kappaB to
      TNF-alpha or IL-beta. Increase in the GSH concentration of the cells treated with
      28 mM glucose restored the expression of gamma-GCS mRNA and its response to TNF
      alpha or IL-beta, suggesting that redox regulation is involved in the expression
      of gamma-GCS. In summary, the expression of gamma-GCS is regulated by TNF-alpha
      or IL-1beta in endothelial cells mediated by NF-kappaB stimulation, and
      impairment of the regulation of gamma-GCS in hyperglycemic cells may be a cause
      of medical complications that develop in diabetes mellitus.

PMID- 8662966
TI  - Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of
      chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo.
AB  - Apolipoprotein E (apoE) is an important determinant for the liver uptake of
      triglyceride-rich lipoproteins and emulsions by the remnant receptor. In the
      current study, we assessed an additional role of apoE as modulator of the
      metabolism of triglyceride-rich lipoproteins in vitro and in vivo. Glycerol
      tri[3H]oleate [14C]cholesteryl oleate double-labeled triglyceride-rich emulsions
      were injected into fasted rats. The serum half-life of glycerol tri[3H]oleate was
      3-fold faster (5.4 min) than that of [14C]cholesteryl oleate (16.7 min),
      confirming lipoprotein lipase (LPL)-mediated processing. To establish a specific
      effect of apoE on emulsion lipolysis rather than liver uptake, rats were
      functionally hepatectomized, and hypo(apo)lipoproteinemia was induced by 17alpha
      ethinyl estradiol treatment. An apoE concentration-dependent inhibition of
      emulsion-triglyceride hydrolysis was observed, reaching a 14.8-fold increased
      half-life of glycerol tri[3H]oleate as compared with that in the absence of
      exogenous apoE. The mechanism and specificity of the effect of apoE on emulsion
      lipolysis by purified LPL was assessed in vitro. Addition of apoE to glycerol
      tri[3H]oleate-labeled emulsions led to a concentration-dependent inhibition of
      [3H]oleate release (9.5% residual LPL activity at 60 microg/ml apoE), while apoA
      I was ineffective. The inhibitory effect of apoE was not abolished by reductive
      methylation of lysine residues, whereas selective modification of arginine
      residues by 1,2-cyclohexadione completely cancelled the inhibitory effect of
      apoE. It is concluded that apoE can specifically inhibit the LPL-mediated
      hydrolysis of emulsion triglycerides both in vitro and in vivo, and that arginine
      residues in apoE are essential for this effect. We suggest that in addition to
      its role in receptor recognition, apoE also modulates the LPL-mediated processing
      of triglyceride-rich lipoproteins.

PMID- 8662967
TI  - Highly supralinear feedback inhibition of Ca2+ uptake by the Ca2+ load of
      intracellular stores.
AB  - Net Ca2+ uptake into intracellular Ca2+ stores of homogenized cells is transient,
      even when the extravesicular Ca2+ concentration is kept constant. To study the
      mechanism underlying the phenomenon, we have investigated 45Ca2+ uptake by HL-60
      cell homogenates. The initial rate of Ca2+ uptake as well as the final amount of
      stored Ca2+ were a function of the extravesicular Ca2+ concentration. However,
      Ca2+ uptake stopped independently of the extravesicular Ca2+ concentration after
      approximately 10 min. Studies using Ca2+-ATPase inhibitors demonstrated that the
      transient nature of the net uptake was not due to Ca2+ efflux. Monovalent cation
      ionophores did not influence the Ca2+ uptake curves, excluding a relevant
      involvement of pH and membrane potential. Together with the observation of a
      continued Ca2+ uptake in the presence of the intralumenal Ca2+ chelator oxalate,
      these results strongly suggest a feedback inhibition of Ca2+ uptake by the Ca2+
      load of intracellular stores. The concentration-inhibition relationship between
      the Ca2+ load and the rate of Ca2+ uptake was highly supralinear (slope factor
      >/= 4). IC50 and maximum of the dose-inhibition curve, but not the slope factor
      were a function of the extravesicular free Ca2+ concentration. A series of three
      logistic equations derived from our data allowed an appropriate description of
      the behavior of Ca2+ uptake. Our results suggest, in addition to its well known
      activation by cytosolic Ca2+ concentration, a highly supralinear feedback
      inhibition of Ca2+ uptake by the Ca2+ load of intracellular stores. The steepness
      of the feedback inhibition might have a profound effect on spatial and temporal
      behavior of the Ca2+ signal.

PMID- 8662968
TI  - A cytolytic function for a sialic acid-binding lectin that is a member of the
      pentraxin family of proteins.
AB  - A variety of invertebrates possess plasma lectins with sialic acid recognition
      capabilities. One of the best studied of these lectins is limulin, which is a
      member of the pentraxin family of proteins and is found in the plasma of the
      American horseshoe crab, Limulus polyphemus. We find that limulin is one of
      several sialic acid-binding lectins of Limulus plasma and is present at a much
      lower abundance than Limulus C-reactive protein, the other plasma pentraxin.
      Limulin was purified by sequential affinity chromatography on
      phosphorylethanolamine-agarose, which isolates the pentraxins and separates
      limulin from the other sialic acid-binding lectins of the plasma, followed by
      fetuin-Sepharose, which binds limulin and separates it from Limulus C-reactive
      protein, the most abundant pentraxin of the plasma. We show here that limulin is
      the mediator of the Ca+2-dependent hemolytic activity found in the plasma of
      Limulus. Plasma that was depleted in the pentraxins by passage over
      phosphorylethanolamine-agarose or was depleted in the sialic acid-binding lectins
      by passage over fetuin-Sepharose lacked hemolytic activity. Purified limulin was
      hemolytic at concentrations of 3-5 nM. The other sialic acid-binding lectins of
      Limulus plasma and Limulus C-reactive protein were nonhemolytic. Foreign cell
      cytolysis by limulin represents a novel function for a plasma lectin and is the
      first documented function for limulin.

PMID- 8662969
TI  - Unusual amino acid determinants of host range in the Mtx2 family of mosquitocidal
      toxins.
AB  - Five different mosquitocidal toxin (mtx2) gene homologs have been cloned from
      eight Bacillus sphaericus strains. Pairwise comparisons of the predicted amino
      acid sequences show between four and eight substitutions compared with the
      prototype Mtx2 from B. sphaericus strain SSII-1. Mtx2 from strain SSII-1 was
      approximately 7-fold more toxic to Culex mosquito larvae than the Mtx2 homolog
      from B. sphaericus strain 31-2. Conversely, Mtx2 from strain 31-2 was
      approximately 100-fold more toxic to Aedes mosquito larvae than Mtx2 from strain
      SSII-1. Lys224 in Mtx2 was found to be the most important amino acid for toxicity
      to Culex larvae, and substitution of Lys224 with threonine abolished the toxicity
      of Mtx2 from strain SSII-1 to these larvae. In complete contrast, Thr224 was
      found to be crucial for the toxicity of Mtx2 from strain 31-2 to Aedes larvae,
      and substitution of Thr224 with lysine caused a approximately 100-fold drop in
      toxicity to these larvae. Thus, amino acid 224 in the Mtx2 family of
      mosquitocidal toxins is an unusual and important determinant of mosquito
      larvicidal activity and host range.

PMID- 8662970
TI  - The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on
      their full length in mouse and human.
AB  - Specific phosphoproteins are targets of numerous extracellular signals received
      by astrocytes. One such target, which we previously described, is PEA-15, a
      protein kinase C substrate associated with microtubules. Two cDNAs differing in
      the length of their 3'-untranslated region (3'UTR) were cloned from a mouse
      astrocytic library. Accordingly, Northern blots revealed two transcripts (1.7 and
      2.5 kilobase pairs) abundant brain regions but also found in peripheral tissues.
      PEA-15-deduced protein sequence (130 amino acids) shared no similarity with known
      proteins but is 96% identical to its human counterpart. In addition, several
      regions of the 3'UTR share more than 90% identity between mouse and human.
      Different potential regulatory sequences are found in the 3'UTR, which also
      completely includes the proto-oncogene MAT1. The high level of conservation of
      both the coding and the untranslated regions and the differential tissular
      distribution of the two transcripts of this major brain phosphoprotein suggest
      that not only the protein but also the 3'UTR of PEA-15 mRNA play a role in
      astrocytic functions.

PMID- 8662972
TI  - Strand breaks are repaired efficiently in human ribosomal genes.
AB  - We examined repair of DNA strand breaks induced by the anti-cancer drug bleomycin
      in both Pol I and Pol II transcribed genes in permeabilized human fibroblasts.
      The majority of these breaks (>80%) are single strand breaks (SSBs) thought to be
      repaired by base excision repair enzymes. Repair was examined in each strand of a
      7. 2-kilobase fragment, completely within the Pol I transcribed region of
      ribosomal DNA (rDNA) and an 8.3-kilobase fragment completely within the Pol II
      transcribed region of the dihydrofolate reductase (DHFR) gene. Bleomycin dose
      response studies revealed no bias for SSBs in either strand of the rDNA fragment.
      Furthermore, repair of SSBs is rapid (approximately 80% resealed in 60 min) in
      both the transcribed and nontranscribed strands of rDNA. Rapid repair of SSBs is
      also observed in both strands of the DHFR gene (approximately 60% resealed in 60
      min). In contrast, little (or no) repair of UV photodimers occurs in either
      strand of human rDNA, regardless of whether cells are confluent or actively
      growing. Thus, DNA lesions in human ribosomal genes may be more accessible to
      base excision repair enzymes than those involved in nucleotide excision repair.

PMID- 8662974
TI  - Transcriptional regulation of the human biglycan gene.
AB  - The small leucine-rich proteoglycan biglycan is involved in several physiological
      and pathophysiological processes through the ability of its core protein to
      interact with other extracellular matrix molecules and transforming growth factor
      beta (TGF-beta). To learn more about the regulation of biglycan core protein
      expression, we have cloned and sequenced 1218 base pairs from the 5'-flanking
      region of the human biglycan gene, demonstrated functional promoter activity, and
      investigated the molecular mechanisms through which various agents modulate its
      transcriptional activity. Sequencing revealed the presence of several cis-acting
      elements including multiple AP-2 sites and interleukin-6 response elements, a NF
      kappaB site, a TGF-beta negative element, and an E-box. The TATA and CAAT box
      lacking promoter possesses many features of a growth-related gene, e.g. a GC-rich
      immediate 5' region, many Sp1 sites, and the use of multiple transcriptional
      start sites. Transient transfections of the tumor cell lines MG-63, SK-UT-1, and
      T47D with various biglycan 5'-flanking region-luciferase reporter gene constructs
      showed that the proximal 78 base pairs are sufficient for full promoter activity.
      Several agents among them interleukin-6, and tumor necrosis factor-alpha. were
      capable of altering biglycan promoter activity. However, in MG-63 cells, TGF
      beta1 failed to increase either activity of the biglycan promoter constructs or
      specific transcription from the endogenous biglycan gene. Since TGF-beta1 also
      did not alter the stability of cytoplasmic biglycan mRNA as determined from
      Northern analysis after inhibition of transcription with 5,6-dichloro-1beta-D
      ribofuranosylbenzimidazole, an as yet unidentified nuclear post-transcriptional
      mechanism was considered responsible for the TGF-beta effect in this cell type.
      These results might help to elucidate the molecular pathways leading to
      pathological alterations of biglycan expression observed in atherosclerosis,
      glomerulonephritis, and fibrosis.

PMID- 8662973
TI  - The FRE1 ferric reductase of Saccharomyces cerevisiae is a cytochrome b similar
      to that of NADPH oxidase.
AB  - Plasma membrane preparations from strains of the yeast Saccharomyces cerevisiae
      gave a reduced minus oxidized spectrum characteristic of a b-type cytochrome and
      very similar to the spectrum of flavocytochrome b558 of human neutrophils. The
      magnitude of the signal correlated with the level of ferric reductase activity
      and the copy number of the FRE1 gene, indicating that the FRE1 protein is a
      cytochrome b. Sequence similarities with the flavin binding site of
      flavocytochrome b558 and other members of the ferredoxin-NADP reductase family,
      together with increased levels of noncovalently bound FAD and
      iodonitrotetrazolium violet reductase activity in membranes from a yeast strain
      overexpressing ferric reductase, suggested that the FRE1 protein may also carry a
      flavin group. Potentiometric titrations indicated that FRE1, like neutrophil
      NADPH oxidase, has an unusually low redox potential, in the region of -250 mV,
      and binds CO.

PMID- 8662975
TI  - Cell type-specific modes of feedback regulation of capacitative calcium entry.
AB  - The Ca2+-ATPase inhibitor, thapsigargin, activated Ca2+ entry into pancreatic
      acinar cells, a process known as capacitative calcium entry. In cells loaded with
      the calcium chelator BAPTA, the transient Ca2+ release was blunted and the rise
      of [Ca2+]i on readdition of Ca2+ was slowed. However, the steady-state [Ca2+]i
      due to Ca2+ entry was substantially augmented compared with control cells. This
      indicates that [Ca2+]i exerts a negative feedback on Ca2+ entry from a
      compartment buffered by BAPTA and separated from the bulk of cytoplasmic Ca2+.
      This interaction probably occurs close to the calcium channel where [Ca2+] is
      higher than in the bulk of the cytoplasm. In support of this interpretation, the
      slower Ca2+ chelator, EGTA, also blunted the release of Ca2+ and slowed the rise
      of the sustained [Ca2+]i phase but failed to augment steady-state [Ca2+]i. In
      contrast, Ca2+ entry in NIH 3T3 cells was characterized by a transient rise of
      [Ca2+]i that decays to near prestimulus levels. This decay in Ca2+ entry also
      results from negative feedback by Ca2+ because the decrease in Ca2+ entry was
      reversed by incubation in a Ca2+-deficient medium. However, unlike its effects in
      acinar cells, BAPTA neither augmented steady-state [Ca2+]i nor prevented the
      inactivation of entry. Rather, in BAPTA-loaded cells, [Ca2+]i failed to increase
      substantially suggesting that negative regulation by Ca2+ may occur at a site
      distinct from the cytoplasmic compartment and inaccessible to cytoplasmic BAPTA.
      These two distinct types of feedback behavior may indicate subtypes of store
      operated calcium channels expressed in different cells or a single type of
      channel which is differentially regulated in a cell type-specific manner.

PMID- 8662976
TI  - Linkage-specific action of endogenous sialic acid O-acetyltransferase in Chinese
      hamster ovary cells.
AB  - 9-O-Acetylation of sialic acids shows cell type-specific and developmentally
      regulated expression in various systems. In a given cell type, O-acetylation can
      also be specific to a particular type of glycoconjugate. It is assumed that this
      regulation is achieved by control of expression of specific 9-O
      acetyltransferases. However, it has been difficult to test this hypothesis, as
      these enzymes have so far proven intractable to purification or molecular
      cloning. During a cloning attempt, we discovered that while polyoma T antigen
      positive Chinese hamster ovary cells (CHO-Tag cells) do not normally express cell
      surface 9-O-acetylation, they do so when transiently transfected with a cDNA
      encoding the lactosamine-specific alpha2-6-sialyltransferase (Galbeta1
      4GlcNAc:alpha2-6-sialyltransferase (ST6Gal I); formerly ST6N). This phenomenon is
      reproducible by stable expression of ST6Gal I in parental CHO cells, but not upon
      transfection of the competing lactosamine-specific alpha2-3-sialyltransferase
      (Galbeta1-(3)4GlcNAc:alpha2-3-sialyltransferase; (ST6Gal III) formerly ST3N) into
      either cell type. Further analyses of stably transfected parental CHO-K1 cells
      indicated that expression of the ST6Gal I gene causes selective 9-O-acetylation
      of alpha2-6-linked sialic acid residues on N-linked oligosaccharides. In a
      similar manner, while the alpha2-3-linked sialic acid residue of the endogenous
      GM3 ganglioside of CHO cells is not O-acetylated, transfection of an alpha2-8
      sialyltransferase (GM3:alpha2-8-sialyltransferase (ST8Sia I); formerly GD3
      synthase) caused expression of 9-O-acetylation of the alpha2-8-linked sialic acid
      residues of newly synthesized GD3. These data indicate either that linkage
      specific sialic acid O-acetyltransferase(s) are constitutively expressed in CHO
      cells or that expression of these enzymes is secondarily induced upon expression
      of certain sialyltransferases. The former explanation is supported by a low level
      of background 9-O-acetylation found in parental CHO-K1 cells and by the finding
      that O-acetylation is not induced when the ST6Gal I or ST8Sia I cDNAs are
      overexpressed in SV40 T antigen-expressing primate (COS) cells. Taken together,
      these results indicate that expression of sialic acid 9-O-acetylation can be
      regulated by the action of specific sialyltransferases that alter the predominant
      linkage of the terminal sialic acids found on specific classes of
      glycoconjugates.

PMID- 8662977
TI  - Neuronal activity increases the phosphorylation of the transcription factor cAMP
      response element-binding protein (CREB) in rat hippocampus and cortex.
AB  - Activity-mediated gene expression is thought to play an important role in many
      forms of neuronal plasticities. We have used pentylenetetrazol-induced seizure
      that produces synchronous and sustained neuronal activity as a model to examine
      the mechanism(s) of gene activation. The transcription factor CREB (Ca2+/cAMP
      response element-binding protein) is thought to be necessary for long-term memory
      formation both in invertebrates and vertebrates. When phosphorylated on Ser133
      either by cAMP-dependent protein kinase and/or Ca2+/calmodulin-dependent protein
      kinases, CREB increases transcription of genes containing the CRE (cAMP response
      element) sequence. Using an antibody that detects Ser133-phosphorylated CREB
      protein, we show that CREB phosphorylation is maximal between 3 and 8 min after
      the onset of seizure activity and declines slowly both in the hippocampus and the
      cortex. The total amount of CREB protein did not change at the time points
      examined. The increased phosphorylation of CREB protein is preceded by an
      increase in the amount of cAMP, suggestive of cAMP-dependent protein kinase
      activation, in the hippocampus and activation of Ca2+/calmodulin-dependent
      protein kinases in the cortex. Subsequent to CREB phosphorylation, the expression
      of the CRE-containing gene, c-fos, and the AP-1 complexes (heterodimers of Fos
      and Jun family members) is increased. These findings support the role of CREB
      mediated gene expression in activity-dependent neuronal plasticities.

PMID- 8662978
TI  - Characterization of the binding of serum amyloid P to type IV collagen.
AB  - Serum amyloid P (SAP), a member of the evolutionarily conserved pentraxin family,
      is a normal component of a number of basement membranes, including glomerular and
      alveolar. In vitro SAP binds to a variety of proteins including fibronectin,
      proteoglycans, and the collagen-like region of the complement component C1q. In
      these studies, binding of SAP to type IV collagen, a major component of basement
      membrane, was examined. Purified SAP binds to human and mouse type IV collagen
      but not type I, II, or III collagens. Binding of SAP to type IV collagen is
      dependent on the presence of Ca2+. This binding is saturable with a Kd
      approximately 1.2 x 10(-7) M based on solid phase binding and 4 x 10(-8) M based
      on the IC50 value from fluid phase binding data. Binding of SAP to type IV
      collagen was inhibited by both SAP and C-reactive protein (CRP). However, a 5
      fold molar excess of CRP as compared with SAP was required to inhibit the SAP
      binding by 50%. Binding of SAP to type IV collagen was inhibited by both collagen
      IV and C1q but not by phosphatidylethanolamine or bovine serum albumin. The
      inhibition data indicate that SAP may bind to the triple helical region of type
      IV collagen via a site distinct from its galactan binding site. The most likely
      site of SAP involved in its interaction with type IV collagen may be the region
      spanning amino acid residues 108-120, which shows a great deal of sequence
      homology (60% strict identity) with the CRP region implicated in its binding to
      the collagen-like region of the C1q molecule.

PMID- 8662979
TI  - The cytoplasmic domain of syndecan-1 is required for cytoskeleton association but
      not detergent insolubility. Identification of essential cytoplasmic domain
      residues.
AB  - Syndecan-1 is a member of a gene family of multifunctional transmembrane heparan
      sulfate proteoglycans that bind a variety of extracellular ligands and possess
      highly conserved non-catalytic cytoplasmic domains. It has been shown that
      antibody-mediated clustering of syndecan-1 causes the proteoglycan to become
      associated with microfilaments and insoluble in non-ionic detergent. A series of
      truncation and point mutations of the syndecan-1 core protein was constructed to
      identify specific structural features that were required for these
      characteristics. The transmembrane domain but not the cytoplasmic domain was
      required for cell surface expression of syndecan-1. Deletion of the COOH-terminal
      11 amino acids of the cytoplasmic domain had no effect, while deletion of an
      additional 12 amino acids abolished microfilament association. Mutation of a
      conserved tyrosine residue within the latter region also abolished microfilament
      association. In contrast, mutation of 2 tyrosine residues outside this region had
      no effect. Deletion of the entire cytoplasmic domain (except for a short stop
      transfer sequence) did not affect insolubility of the proteoglycan in detergent.
      Analysis of a form of syndecan-1 that lacked glycosaminoglycan acceptor sites
      revealed that covalently attached glycosaminoglycans were not required for cell
      surface expression, microfilament association, or detergent insolubility. These
      results demonstrate that microfilament association is a function of a subregion
      within the cytoplasmic domain and suggest that insolubility in detergent is a
      function of the transmembrane domain.

PMID- 8662981
TI  - A novel enzyme that catalyzes the esterification of N-acetylsphingosine.
      Metabolism of C2-ceramides.
AB  - A unique transacylase that catalyzes esterification of a short chain ceramide, N
      acetylsphingosine, was found in Madin-Darby canine kidney cell and mouse tissue
      homogenates. It esterified the hydroxyl group at the carbon-1 position of the
      ceramide. The enzyme has a pH optimum of 4.2 and a Km of 9.4 microM for N
      acetylsphingosine at pH 4.5. The transacylase activity is independent of free
      fatty acid or acyl-CoA and instead uses the 2-acyl group of
      phosphatidylethanolamine or phosphatidylcholine. The transacylase activity in the
      homogenate was present in the 100,000 x g supernatant, and the lipid extracted
      from the membranous fraction could function as a donor of the acyl group. When
      liposomes consisting of dioleoylphosphatidylcholine:1-palmitoyl-2
      [14C]arachidonoyl-phosphati dylethanolamine:sulfatide (70:0.2:30) were incubated
      with the supernatant and N-acetylsphingosine, the formation of free arachidonic
      acid and O-arachidonoyl-N-acetylsphingosine was observed. The ratio of the two
      products depended on the concentration of ceramide; only the free acid was formed
      if the truncated ceramide was absent. Both deacylase and transacylase activities
      were inhibited 50-60% by 20 microM D-threo-1-phenyl-2-decanoylamino-3-morpholino
      1-propanol, an inhibitor of several glucosphingolipid synthases. Neither activity
      was inhibited by nonadecyltetraenyl trifluoromethyl ketone, a potent inhibitor of
      cytosolic phospholipase A2. N-Acetyldihydrosphingosine and N-octanoylsphingosine
      were only 55 and 10%, respectively, as effective as N-acetylsphingosine as acyl
      acceptors. Oleoylsphingosine was only slightly reactive. An esterase that
      releases the truncated ceramide from its ester linkage appears to be membrane
      bound. Lecithin was less effective than phosphatidylethanolamine as an acyl donor
      in the transacylation. Madin-Darby canine kidney cell cultures treated with N
      acetyl-[3-3H]sphingosine formed radioactive polar sphingolipids, long chain
      ceramide, free sphingosine, and O-acyl-N-acetylsphingosine. This suggests that
      the deacylation and transacylation reactions observed in vitro occur in growing
      cells as well.

PMID- 8662980
TI  - Ligand-dependent cross-talk between steroid and thyroid hormone receptors.
      Evidence for common transcriptional coactivator(s).
AB  - Steroid and thyroid hormone receptors exhibit striking structural and functional
      similarity, suggesting that these nuclear receptors may enhance transcription of
      target genes by similar mechanisms. To address this issue, we studied
      transcriptional interference between progesterone and thyroid hormone receptors
      in vivo and in vitro. We observed that transcriptional interference occurred in a
      ligand-dependent manner between progesterone receptor-B (PR-B) and thyroid
      hormone receptor (TR) alpha or beta in transient transfection experiments. Ligand
      occupied TRalpha or TRbeta, but not the unliganded receptor, strongly suppressed
      transactivation of a progesterone-responsive reporter gene by endogenous PRs in
      human breast carcinoma T47D cells. Ligand-dependent inhibitory cross-talk also
      occurred between transfected PR-B and TRalpha or TRbeta and vice versa in CV1
      cells. This phenomenon did not require DNA binding by the "interfering" receptor
      but required it to be hormone-bound, indicating that a transcriptionally active
      form of the interfering receptor is essential for the interfering effect. To
      analyze further the mechanism of the ligand-dependent cross-talk, we reproduced
      transcriptional interference between PR and TR in a cell-free transcription
      system. We observed that the addition of triiodothyronine-bound recombinant
      TRbeta or a ligand binding domain (LBD) peptide(145-456) inhibited specifically
      transcriptional activation of a progesterone-responsive gene by endogenous PRs in
      nuclear extracts of T47D cells, while the basal level of transcription from a
      minimal TATA-promoter or transcription from an adenovirus major-late promoter
      remained unaffected. These results indicated that a transactivation function
      within the LBD of the interfering receptor TRbeta was likely to interact with a
      mediator protein(s), termed coactivator, that is distinct from basal
      transcription factors and is critical for efficient PR-induced transactivation.
      This concept was reinforced by biochemical evidence that treatment of T47D
      extracts with immobilized TRbeta LBD depleted the extract of the coactivator
      function in a triiodothyronine-dependent manner and markedly impaired
      progesterone-induced transactivation of progesterone response element-linked
      genes. Deletion of six amino acids(451-456) in the extreme COOH terminus of
      TRbeta resulted in a receptor that retained the ability to bind thyroid hormone
      but failed to inhibit progesterone-dependent transcription. Interestingly, these
      six amino acids are present in a region that is highly conserved among various
      nuclear hormone receptors and contains a ligand-dependent transactivation
      function, AF-2. Based on these results, we propose that a limiting coactivator
      protein(s) interacts with the AF-2 of PR or TR and mediates transactivation by
      the ligand-bound receptor. This regulatory molecule(s) may therefore serve as a
      common functional link between the pathways of hormone-inducible gene activation
      by various members of the nuclear receptor superfamily.

PMID- 8662982
TI  - Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM
      domain.
AB  - The ret/ptc2 papillary thyroid cancer oncogene, an oncogenic form of the c-Ret
      receptor tyrosine kinase, is the product of a somatic crossover event fusing the
      dimerization domain of the type Ialpha regulatory subunit of cyclic AMP-dependent
      protein kinase (RI) with the tyrosine kinase domain of c-Ret. Mitogenic activity
      of Ret/ptc2 required dimerization via the N terminus of RI and a tyrosine residue
      located C-terminal to the kinase core of Ret, Tyr-586 (Durick, K., Yao, V. J.,
      Borrello, M. G., Bongarzone, I., Pierotti, M. A. and Taylor, S. S. (1995) J.
      Biol. Chem. 270, 24642-24645). Using the yeast two-hybrid system, Ret/ptc2
      binding proteins were identified, and the sites of interaction with Ret/ptc2 were
      mapped. The SH2 domains of phospholipase Cgamma and Grb10 were both identified,
      and binding depended on phosphorylation of Tyr-539 and Tyr-429, respectively.
      These interactions, however, were not required for mitogenic signaling. The
      second of the three LIM domains in Enigma (Wu, R. Y., and Gill, G. N. (1994) J.
      Biol. Chem. 269, 25085-25090) was also identified as a Ret/ptc2 binding domain.
      Enigma, a 455-residue protein, was discovered based on its interaction with the
      insulin receptor through the C-terminal LIM domain. Although the association with
      Enigma required Tyr-586 of Ret/ptc2, the interaction was phosphorylation
      independent. In contrast to the SH2 interactions, disruption of the interaction
      with Enigma abolished Ret/ptc2 mitogenic signaling, suggesting that LIM domain
      recognition of an unphosphorylated tyrosine-based motif is required for Ret
      signal transduction.

PMID- 8662983
TI  - Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation
      of the p55 TNF receptor and activation of sphingomyelinase.
AB  - Tumor necrosis factor (TNF)-alpha plays a central role in the state of insulin
      resistance associated with obesity. It has previously been shown that one
      important mechanism by which TNF-alpha interferes with insulin signaling is
      through the serine phosphorylation of insulin receptor substrate-1 (IRS-1), which
      can then function as an inhibitor of the tyrosine kinase activity of the insulin
      receptor (IR). However, the receptors and the signaling pathway used by TNF-alpha
      that mediate the inhibition of IR activity are unknown. We show here that human
      TNF-alpha, which binds only to the murine p55 TNF receptor (TNFR), is as
      effective at inhibiting insulin-dependent tyrosine phosphorylation of IR and IRS
      1 in adipocytes and myeloid 32D cells as murine TNF-alpha, which binds to both
      p55 TNFR and p75 TNFR. Likewise, antibodies that are specific agonists for p55
      TNFR or p75 TNFR demonstrate that stimulation of p55 TNFR is sufficient to
      inhibit insulin signaling, though a small effect can also be seen with antibodies
      to p75 TNFR. Exogenous sphingomyelinase and ceramides, known to be formed by
      activation of p55 TNFR, inhibit IR and IRS-1 tyrosine phosphorylation and convert
      IRS-1 into an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D cells
      expressing IR and IRS-1 are sensitive to this inhibition, but cells expressing IR
      and IRS-2 are resistant, pointing to an important difference in the biological
      function between IRS-1 and IRS-2. These data strongly suggest that TNF-alpha
      inhibits insulin signaling via stimulation of p55 TNFR and sphingomyelinase
      activity, which results in the production of an inhibitory form of IRS-1.

PMID- 8662984
TI  - Phosphorylation of the high molecular weight neurofilament protein (NF-H) by Cdk5
      and p35.
AB  - The high molecular weight neurofilament protein (NF-H) is highly phosphorylated
      in the axon. The phosphorylation sites have been identified as KSP (Lys-Ser-Pro)
      repeats in the tail domain of NF-H. These KSP sequences are present more than 50
      times in the NF-H tail, and most of these sites are normally phosphorylated in
      vivo. These KSP sites can be further divided into two separate consensus
      sequences, KSPXK and KSPXY (where Y is not K). The extensive phosphorylation of
      NF-H has been proposed to play a critical role in the determination of axonal
      diameter. Recent studies have shown that Cdk5, a kinase related to the cell cycle
      dependent kinase Cdc2, is expressed in the brain and associates with the
      cytoskeleton. In vitro phosphorylation studies have shown that Cdk5 in
      conjunction with its activator, p35, is able to phosphorylate histone H1,
      dephosphorylated NF-H, as well as a synthetic peptide with the repetitive KSP
      motif. We have cloned the cDNAs for rat Cdk5 and p35 by reverse transcription
      polymerase chain reaction and cDNA library screening and studied the
      phosphorylation of NF-H both in vivo and in vitro. By transient transfection
      assays, we have shown that NF-H can only be extensively phosphorylated in the
      presence of both Cdk5 and p35. This phosphorylation can be inhibited by a Cdk5
      dominant negative mutant, an observation which further supports that Cdk5 is a
      kinase that is able to phosphorylate NF-H. By immunoprecipitating Cdk5 and p35
      from the transfected cells, we have been able to show that the KSPXK repeats are
      the preferred phosphorylation sites for Cdk5, while the KSPXY repeats are not
      directly phosphorylated by Cdk5 and p35.

PMID- 8662985
TI  - Fibroblast growth factor-2 suppression of tumor necrosis factor alpha-mediated
      apoptosis requires Ras and the activation of mitogen-activated protein kinase.
AB  - Treatment of L929 cells with tumor necrosis factor alpha (TNFalpha) activates a
      programmed cell death pathway resulting in apoptosis. We investigated the
      intracellular signaling pathways activated in L929 cells by TNFalpha. TNFalpha
      robustly activates Jun kinase (JNK), a member of the mitogen-activated protein
      kinase (MAPK) family. In addition, p42(MAPK) is activated, but a 10-fold greater
      concentration of TNFalpha was required for substantial MAPK activation than was
      needed for maximal JNK stimulation. Simultaneous treatment of L929 cells with
      fibroblast growth factor (FGF-2) significantly reduced the apoptotic response to
      TNFalpha. FGF-2 substantially activated the Raf/MEK/MAPK (where MEK is mitogen
      activated protein kinase kinase) pathway but did not affect TNFalpha activation
      of JNK. These results indicate that although JNK may play an important role in
      transmitting the TNFalpha signal from the cell surface to the nucleus, activation
      of the JNK pathway is not sufficient to induce apoptosis. Expression of dominant
      negative Asn-17 Ras in L929 cells diminished the FGF-2 stimulation of p42(MAPK)
      and eliminated the protective effect of FGF-2. Asn-17 Ras expression did not
      affect JNK activity and had no effect on TNFalpha activation of JNK.
      Pharmacological inhibition of MEK-1 activity by incubation of cells with the
      compound PD 098059 blocked p42(MAPK) activation and FGF-2 protection against
      apoptosis. Interestingly, activated Val-12 Ras expression substantially enhanced
      TNFalpha-mediated apoptosis in L929 cells, but Val-12 Ras did not constitutively
      activate MAPK in L929 cells and FGF-2 partially protected Val-12 Ras-expressing
      cells from TNFalpha-mediated apoptosis. Our data indicate that activation of the
      MAPK pathway mediates an FGF-2 protective effect against apoptosis and highlights
      the important role that integration of multiple intracellular signaling pathways
      plays in the regulation of cell growth and death.

PMID- 8662986
TI  - Influence of specific signal peptide mutations on the expression and secretion of
      the alpha-amylase inhibitor tendamistat in Streptomyces lividans.
AB  - The Streptomyces alpha-amylase inhibitor tendamistat is secreted by a signal
      peptide with an amino-terminal charge of +3. To elucidate the influence of the
      charged residues on protein secretion in Streptomyces, the amino-terminal charge
      was varied from +6 to neutral net charge. The effects of charge variation were
      analyzed in combination with three Streptomyces promoters and two transcriptional
      terminators. Introduction of additional positive charges significantly decreased
      the amount of secreted tendamistat. On the contrary, a charge reduction to +2
      resulted in the doubling of inhibitor production. After exclusion of
      transcriptional effects, the observed alterations of inhibitor secretion by the
      mutants with a charge of +6 to +2 were attributed to a modulation of precursor
      synthesis. Furthermore, a tight coupling of synthesis and export was stated.
      Charge reduction to +1 or neutral charge generally reduced the yield of secreted
      tendamistat, yet remarkable differences were found for mutants with identical net
      charge. Elimination of the positive charge at a defined position resulted in the
      release of tendamistat precursor protein, which suggested a specific uncoupling
      of synthesis and translocation.

PMID- 8662987
TI  - Functional and physical interactions between mammalian achaete-scute homolog 1
      and myocyte enhancer factor 2A.
AB  - The mammalian achaete-scute homolog 1 (MASH1) protein is required for the early
      development of the nervous system. However, the molecular and biochemical
      mechanism by which MASH1 acts to determine neurogenesis are still unknown. The
      myocyte enhancer factor 2A (MEF2A) is a MADS transcription factor that is
      essential for the specification and differentiation of the muscle lineage. Here
      we show that MEF2A and MASH1 are coordinately induced during the differentiation
      of the teratocarcinoma cell line P19 along a neuronal lineage and that in
      transient transfection assays, MEF2A and MASH1 cooperatively activate gene
      expression. This cooperativity appears to be due to a specific physical
      interaction between MEF2A and MASH1. Taken together, these findings suggest that
      MASH1 via a cooperative interaction with MEF2A may regulate the expression of
      specific genes that are critical for neuronal differentiation.

PMID- 8662988
TI  - Identification of a promoter that controls aromatase expression in human breast
      cancer and adipose stromal cells.
AB  - Aromatase, a cytochrome P450, catalyzes three consecutive hydroxylation reactions
      converting C19 androgens to aromatic C18 estrogens. In this study, the regulatory
      properties of a 696-base pair region, that contains the promoter II and is
      situated immediately upstream of exon II of the human aromatase gene, were
      investigated. Chloramphenicol acetyltransferase (CAT) functional studies with DNA
      segments derived from this genomic region and primer-extension analysis revealed
      the presence of a second promoter which is functional in adipose stromal cells
      and in breast cancer cells. Detailed DNase-1 footprinting analysis, DNA mobility
      shift assays, and CAT functional studies of this genomic region were performed
      and led to the identification of a segment (B1) that could act as a promoter
      (probably promoter I.3) in adipose stromal and breast cancer cells. The study
      revealed further that the B1 region could be divided into two domains which were
      designated RE1 and RE2. RE1 was found to have the promoter activity, and RE2 was
      found to regulate the promoter activity of RE1, but in different manners in MCF-7
      cells (as an example of breast cancer cells) and in adipose stromal cells. RE2
      was found to function as a positive regulatory element in MCF-7 cells and as a
      negative regulatory element in adipose stromal cells, respectively. DNA mobility
      shift and UV-cross-linking experiments with BrUrd-substituted B1 fragment and
      nuclear extracts isolated from two types of cells were performed. The experiments
      identified DNA-bound proteins with molecular masses around 50 kDa. These findings
      serve as the basis for further examination of the regulatory mechanism of
      aromatase expression in human breast cancer and adipose stromal cells.

PMID- 8662989
TI  - The major catalytic subunit isoforms of cAMP-dependent protein kinase have
      distinct biochemical properties in vitro and in vivo.
AB  - Two isoforms of the catalytic subunit of cAMP-dependent protein kinase, Calpha
      and Cbeta1, are known to be widely expressed in mammals. Although much is known
      about the structure and function of Calpha, few studies have addressed the
      possibility of a distinct role for the Cbeta proteins. The present study is a
      detailed comparison of the biochemical properties of these two isoforms, which
      were initially expressed in Escherichia coli and purified to homogeneity. Cbeta1
      demonstrated higher Km values for some peptide substrates than did Calpha, but
      Cbeta1 was insensitive to substrate inhibition, a phenomenon that was observed
      with Calpha at substrate concentrations above 100 microM. Calpha and Cbeta1
      displayed distinct IC50 values for the alpha and beta isoforms of the protein
      kinase inhibitor, protein kinase inhibitorpeptide, and the type IIalpha
      regulatory subunit (RIIalpha). Of particular interest, purified type II
      holoenzyme containing Cbeta1 exhibited a 5-fold lower Ka value for cAMP (13 nM)
      than did type II holoenzyme containing Calpha (63 nM). This latter result was
      extended to in vivo conditions by employing a transcriptional activation assay.
      In these experiments, luciferase reporter activity in COS-1 cells expressing
      RIIalpha2Cbeta12 holoenzyme was half-maximal at 12-fold lower concentrations of 8
      (4-chlorophenylthio)-cAMP and 5-fold lower concentrations of forskolin than in
      COS-1 cells expressing RIIalpha2Calpha2 holoenzyme. These results provide
      evidence that type II holoenzyme formed with Cbeta1 is preferentially activated
      by cAMP in vivo and suggest that activation of the holoenzyme is determined in
      part by interactions between the regulatory and catalytic subunits that have not
      been described previously.

PMID- 8662990
TI  - Glycan-dependent and -independent association of vesicular stomatitis virus G
      protein with calnexin.
AB  - Calnexin (CNX) is a membrane-bound molecular chaperone that associates with newly
      synthesized proteins in the endoplasmic reticulum. Although several studies have
      indicated that it interacts exclusively with glycoproteins that carry
      monoglucosylated N-linked oligosaccharides, others have reported that it can bind
      to proteins that have no glycans. To address this discrepancy, we translated wild
      type vesicular stomatitis virus G protein and nonglycosylated mutant forms in the
      presence of microsomes and examined their association with CNX. Individual G
      protein molecules were found to efficiently associate with CNX when both glycans
      were present and less efficiently if there was only a single glycan.
      Nonglycosylated G protein also interacted with CNX, but only when misfolded and
      present in high molecular weight aggregates. The results indicated that CNX can
      interact with G protein in two ways: through an oligosaccharide-dependent
      mechanism that involves individual substrate proteins; and in an oligosaccharide
      independent association with large aggregates.

PMID- 8662991
TI  - Complementation of mutation in acyl-CoA:cholesterol acyltransferase (ACAT) fails
      to restore sterol regulation in ACAT-defective sterol-resistant hamster cells.
AB  - A previously described mutant line of Chinese hamster ovary cells, designated SRD
      4, fails to synthesize cholesteryl esters, owing to a deficiency in the activity
      of acyl-CoA:cholesterol acyltransferase (ACAT). These cells also fail to suppress
      low density lipoprotein receptors or cholesterol synthesizing enzymes in the
      presence of 25-hydroxycholesterol. In the current studies we show that SRD-4
      cells have three defects: 1) a point mutation in one allele at the ACAT locus
      that changes codon 265 from Ser to Leu, resulting in an inactive enzyme; 2) a
      silent allele at the other ACAT locus that does not produce detectable mRNA; and
      3) a mutation, as yet undefined, that abolishes the ability of 25
      hydroxycholesterol to inhibit the cleavage of both sterol regulatory element
      binding proteins (SREBP-1 and SREBP-2). Correction of the ACAT deficiency by
      transfection of a wild-type cDNA failed to restore inhibition of SREBP cleavage
      by 25-hydroxycholesterol, indicating that the ACAT deficiency and the sterol
      regulatory defect are caused by independent mutations. These data provide further
      insight into the interplay between ACAT activation and inhibition of SREBP
      cleavage by 25-hydroxycholesterol, and they indicate that these two processes can
      be disrupted independently by mutation.

PMID- 8662992
TI  - cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance
      protein, cMrp, reveals a novel conjugate export pump deficient in
      hyperbilirubinemic mutant rats.
AB  - ATP-dependent transport of glutathione and glucuronate conjugates from
      hepatocytes into bile is mediated by a distinct member of the ATP-binding
      cassette superfamily. We have cloned and sequenced the canalicular isoform of the
      multidrug resistance protein from rat liver, and termed it cMrp. This membrane
      glycoprotein is composed of 1541 amino acids with an identity of 47.8% with the
      human multidrug resistance protein (MRP) and of 41.9% with the yeast cadmium
      factor (YCF1). The carboxyl-terminal 130 amino acids of the human hepatocyte
      canalicular isoform of MRP (cMRP) were 80.2% identical with rat cMrp. cMrp was
      not expressed in the liver of two mutant rat strains, the Eisai
      hyperbilirubinemic rat and the GY/TR- mutant, which are deficient in the ATP
      dependent transport of conjugates across the canalicular membrane. Immunoblotting
      using an antibody raised against the carboxyl terminus of cMrp detected the
      glycoprotein of about 190 kDa only in the canalicular membrane from normal liver.
      Double immunofluorescence and confocal laser scanning microscopy localized cMrp
      exclusively to the canalicular membrane domain of hepatocytes and demonstrated
      its loss in the hyperbilirubinemic mutant rat. The results identify cMrp as a
      canalicular transport protein with a novel sequence and with a function similar
      to the one of the MRP.

PMID- 8662993
TI  - Agonist recognition by proteinase-activated receptor 2 and thrombin receptor.
      Importance of extracellular loop interactions for receptor function.
AB  - Thrombin receptor and proteinase-activated receptor 2 (PAR2) define a family of G
      protein-coupled receptors that are activated by a novel proteolytic mechanism.
      Specific cleavage of their amino-terminal exodomains unmasks a new amino terminus
      which then serves as a tethered ligand, docking intramolecularly to the body of
      the receptor to effect signaling. Identification of the docking interactions
      between tethered ligand domain and receptor is critical for understanding
      transmembrane signaling by these receptors. Synthetic "agonist peptides" that
      mimic the tethered ligand domains of thrombin receptor and PAR2 act as agonists
      at their respective receptors. Toward defining the docking interactions which
      mediate receptor activation, we determined the specificity of the thrombin
      receptor and PAR2 for their respective agonist peptides and used receptor
      chimeras to identify the receptor domains responsible for such specificity. PAR2
      responded to both thrombin receptor and PAR2 agonist peptides. In contrast,
      thrombin receptor was selective for its own agonist peptide. Substitution of the
      extracellular face of PAR2, its amino-terminal exodomain and three extracellular
      loops, for the cognate thrombin receptor structures yielded a chimeric receptor
      with PAR2-like agonist specificity. Substitution of individual extracellular
      domains revealed that the primary determinant of agonist specificity was
      extracellular loop 2. Strikingly, substitution of either the amino-terminal
      exodomain or third extracellular loop alone caused marked loss of receptor
      function, but the double substitution yielded a functional receptor. Thus, the
      extracellular domains of these G protein-coupled receptors are more than simply
      passive links between transmembrane domains. They participate in agonist
      recognition and must interact, directly or indirectly, for proper receptor
      function.

PMID- 8662995
TI  - The role of a 21-kDa viral membrane protein in the assembly of vaccinia virus
      from the intermediate compartment.
AB  - We have recently provided morphological evidence that a key event in the assembly
      of vaccinia virus is the formation of a novel cisternal domain of the
      intermediate compartment (IC) between the endoplasmic reticulum and the Golgi
      complex (Sodeik, B., Doms, R. W., Ericsson, M., Hiller, G., Machamer, C. E.,
      van't Hof, W., van Meer, G., Moss, B., and Griffiths, G. (1993) J. Cell Biol.
      121, 521-541). This tightly apposed cisternal domain incompletely surrounds the
      spherical immature virus that matures into the first of the two distinct
      infectious forms of vaccinia, the intracellular mature virus (IMV). In this study
      we describe the characterization of an abundant membrane protein of the IMV, the
      gene product of A17L, a 21-kDa protein that has recently been shown to be
      essential for the formation of the viral membranes (Rodriguez, D., Esteban, M.,
      and Rodriguez, J. R. (1995) J. Virol. 69, 4640-4648). Upon translation in vitro,
      p21 associated with rough microsomal membranes in a co-translational manner.
      Using NH2- and COOH-terminal specific antibodies, we show that both in vitro as
      well as in vivo, p21 adopts a topology where the NH2 and COOH termini are
      cytoplasmically orientated. Immunocytochemical experiments demonstrated that p21
      is a component of the inner of the two cisternal membranes of the immature virus
      as well as of membranes of the IC, identified using antibodies against Rab1.
      Taken together, these data provide the first molecular evidence in support of our
      assembly model; they show that an essential membrane protein of the IMV inserts
      into the rough endoplasmic reticulum, but gets efficiently targeted to the IC and
      membranes of the viral factory.

PMID- 8662994
TI  - Multiple factors regulate the rat liver basolateral sodium-dependent bile acid
      cotransporter gene promoter.
AB  - The hepatic uptake of bile acids from the portal circulation is primarily
      dependent upon a sodium-dependent basolateral membrane transporter. In order to
      begin to investigate the factors controlling rat liver sodium-dependent bile acid
      cotransporter (ntcp) gene expression, we isolated approximately 30 kilobase pairs
      of rat genomic DNA in three overlapping lambdaphage clones. The rat ntcp gene is
      distributed over 16.5 kilobase pairs as five exons. Primer extension analysis
      revealed two closely spaced transcription initiation sites, 27 and 41 nucleotides
      downstream of a TATA sequence. Regulation of transcription was investigated first
      by transfection of primary rat hepatocytes by a series of 5'-deleted rat ntcp
      promoter-driven luciferase constructs (from approximately -6 kilobase pairs to 
      59 base pairs of upstream sequences, terminating at nucleotide +47), identifying
      a minimal promoter element: nucleotide -158 to +47. This minimal promoter was
      active in transfected HepG2, but inactive in NIH3T3, Caco-2, and Madin-Darby
      canine kidney cells, indicating that the determinants of hepatocyte-specific
      expression reside within this region. The individual elements within the minimal
      promoter were investigated via transfection of HepG2 cells by a series of 20
      mutant plasmids, each containing a 10-base pair sequential block mutation. Eight
      mutant constructs profoundly suppressed promoter activity; encompassing sequences
      from -66 to +4 nt, and +15 to +24 nucleotides, while no other 10-base pair
      mutation significantly interfered with minimal promoter activity.
      Deoxyribonuclease I footprint analysis of the minimal promoter revealed three
      bound regions; -92 to -74 (footprint C), -50 to -37 (footprint B), and -17 to +12
      (footprint A). Gel mobility shift assays provided evidence for hepatocyte nuclear
      factor 1 binding within footprint A and a liver-enriched factor(s) that binds
      within a novel palindrome in footprint B. These studies indicate that three
      elements direct the basal and tissue-restricted expression of the rat ntcp
      promoter; a TATA element, the liver-enriched transcription factor hepatocyte
      nuclear factor 1, and an unknown liver-enriched factor that binds within a novel
      palindrome in footprint B.

PMID- 8662996
TI  - p53-dependent induction of WAF1 by heat treatment in human glioblastoma cells.
AB  - Induction of WAF1 expression was investigated after heat treatment (44 degrees C,
      30 min) in two human glioblastoma cell lines with the wild-type or a mutant p53
      gene. WAF1 accumulation was induced by heat treatment in A-172 cells carrying the
      wild-type p53 gene but not in T98G cells carrying the mutant p53 gene. We
      examined whether this phenomenon was due to the induction of WAF1 expression.
      Northern blot analysis showed that heat treatment not only activated WAF1 but
      also up-regulated p53 expression only in A-172 cells carrying the wild-type p53
      gene. Gel mobility shift assay indicated an increase in p53 DNA binding activity
      after heat treatment. These findings suggest that the WAF1 expression is heat
      inducible in human glioblastoma cells and that this induction may be due to
      signal transduction mediated by p53 in response to heat stress.

PMID- 8662997
TI  - Assembly in vitro of thin and thick fibrils of collagen II from recombinant
      procollagen II. The monomers in the tips of thick fibrils have the opposite
      orientation from monomers in the growing tips of collagen I fibrils.
AB  - Human type II procollagen was prepared in a recombinant system and cleaved to pC
      collagen II by procollagen N-proteinase. The pC-collagen II was then used as a
      substrate to generate collagen II fibrils by cleavage with procollagen C
      proteinase at 37 degrees C. Electron microscopy of the fibrils demonstrated that,
      at the early stages of fibril assembly, very thin fibrils were formed. As the
      system approached equilibrium over 7-12 h, however, the thin fibrils were largely
      but not completely replaced by thick fibrils that had diameters of about 240 nm
      and a distinct D-period banding pattern. One typical fibril was photographed and
      analyzed in its entirety. The fibril was 776 D-periods (52 microM) long. It had a
      central shaft with a uniform diameter that was about 516 D-periods long and two
      tips of about 100 D-periods each. Most of the central shaft had a symmetrical
      banding pattern flanked by two transition regions of about 30 D-periods each.
      Measurements by scanning transmission electron microscopy demonstrated that the
      mass per unit length from the tips to the shafts increased linearly over
      approximately 100 D-periods from the fibril end. The linear increase in mass per
      unit length was consistent with previous observations for collagen I fibrils and
      established that the tips of collagen II also had a near paraboloidal shape.
      However, the orientation of monomers in the tips differed from the tips of
      collagen I fibrils in that the C termini instead of the N termini were directed
      toward the tips. The thin fibrils that were present at early stages of assembly
      and at equilibrium were comparable to the collagen II fibrils seen in embryonic
      tissues and probably represented intermediates on the pathway of thick fibrils
      formation. The results indicated that the molecular events in the self-assembly
      of collagen II fibrils are apparently similar to those in self-assembly of
      collagen I fibrils, but that there are also important differences in the
      structural information contained in collagen I and collagen II monomers.

PMID- 8662998
TI  - Tyrosine phosphorylation of Cbl upon epidermal growth factor (EGF) stimulation
      and its association with EGF receptor and downstream signaling proteins.
AB  - We and others have shown that Cbl, the protein product of the c-cbl proto
      oncogene, is an early target of tyrosine phosphorylation upon stimulation through
      the immune cell surface receptors, which signal through noncovalently associated
      cytoplasmic tyrosine kinases. Using human mammary epithelial cells that express a
      natural epidermal growth factor (EGF) receptor and require EGF as an essential
      growth factor, we demonstrate here that Cbl is a prominent target of tyrosine
      phosphorylation upon stimulation through the EGF receptor tyrosine kinase.
      Phosphorylation of Cbl was EGF dose-dependent, rapid (detectable as early as 5 s
      and maximal by 2 min), and relatively sustained (detectable even after 1 h). Co
      immunoprecipitation studies demonstrated that Cbl became associated with the EGF
      receptor in an EGF-dependent manner. Cbl was basally associated with the adaptor
      protein growth factor receptor-binding protein 2 (Grb2), and this interaction was
      further enhanced by EGF stimulation; however, the interaction was entirely
      mediated via the Grb2 Src homology 3 (SH3) domains, suggesting that binding of
      Grb2 SH2 domain to EGF receptor provides one mechanism of Cbl's association with
      the EGF receptor. EGF stimulation also induced the association of Cbl with Src
      homology and collagen (Shc) protein, p85 subunit of the phosphatidylinositol 3
      kinase and Crk proteins, in particular with the CrkL isoform. Interactions of Cbl
      with the EGF receptor and multiple downstream signaling proteins suggest a role
      for this proto-oncogene product in mitogenic signaling through growth factor
      receptor kinases.

PMID- 8662999
TI  - The nuclear trafficking of extracellular fibroblast growth factor (FGF)-1
      correlates with the perinuclear association of the FGF receptor-1alpha isoforms
      but not the FGF receptor-1beta isoforms.
AB  - The alternatively spliced fibroblast growth factor receptor (FGFR)-1 isoforms,
      FGFR-1alpha and FGFR-1beta, are characterized by the presence of either three or
      two Ig-like loops in the extracellular domain and are differentially expressed
      during embryonic development and tumor progression. We have previously shown that
      in cells irreversibly committed to DNA synthesis by FGF-1, approximately 15% of
      cell surface FGFR-1 traffics to a perinuclear locale as a structurally intact and
      functional tyrosine kinase (Prudovsky, I., Savion, N., Zhan, X., Friesel, R., Xu,
      J., Hou, J., McKeehan, W. L., and Maciag, T. (1994) J. Biol. Chem. 269, 31720
      31724). In order to define the structural requirement for association of FGFR-1
      with the nucleus, the expression and trafficking of FGFR-1 in FGFR-1alpha and
      FGFR-1beta L6 myoblast transfectants was studied. Although FGFR-1alpha was
      expressed as p145 and p125 forms, FGFR-1beta was expressed as p120 and p100 forms
      in the L6 myoblast transfectants. Tunicamycin and N-glyconase experiments suggest
      that these forms of FGFR-1alpha and FGFR-1beta are the result of differential
      glycosylation. However, only the p145 form of FGFR-1alpha and the p120 form of
      FGFR-1beta were able to bind FGF-1 and activate tyrosine phosphorylation. Pulse
      chase analysis of FGFR-1 biosynthesis suggests that the p125 and p100 proteins
      are the precursor forms of p145 FGFR-1alpha and p120 FGFR-1beta, respectively.
      Because ligand-chase analysis demonstrated that FGFR-1beta L6 myoblast
      transfectants exhibited a reduced efficiency of nuclear translocation of
      exogenous FGF-1 when compared with FGFR-1alpha transfectants, the intracellular
      trafficking of the FGFR-1alpha and FGFR-1beta isoforms was studied using an in
      vitro kinase assay to amplify immunoprecipitated FGFR-1. Indeed, the appearance
      of the FGFR-1alpha but not FGFR-1beta isoform in the nuclear fraction of L6
      myoblast transfectants suggests that the distal Ig-like loop in FGFR-1alpha
      mediates the differential nuclear association of FGFR-1alpha as a structurally
      intact and functional tyrosine kinase. Further, the FGFR-1beta L6 myoblast
      transfectants but not the FGFR-1alpha myoblast transfectants exhibited a
      pronounced morphologic change in response to exogenous FGF-1. Because this
      phenotype change involves the induction of a rounded cellular shape, it is
      possible that the FGFR-1alpha and FGFR-1beta may ultimately exhibit differential
      trafficking to adhesion sites.

PMID- 8663000
TI  - Transforming growth factor-beta1 stimulates multiple protein interactions at a
      unique cis-element in the 3'-untranslated region of the hyaluronan receptor RHAMM
      mRNA.
AB  - The receptor for hyaluronan mediated motility (RHAMM) gene expression is markedly
      elevated in fibrosarcomas exposed to transforming growth factor-beta1 (TGF
      beta1). The half-life of RHAMM mRNA was increased by 3 fold in cells treated with
      TGF-beta1, indicating that growth factor regulation of RHAMM gene expression at
      least in part involves a posttranscriptional mechanism. Our studies demonstrated
      that a unique 30-nucleotide (nt) region that has three copies of the sequence,
      GCUUGC, was the TGF-beta1-responsive region in the 3'-untranslated region (3'
      UTR) that mediated message stability. This region interacted specifically with
      cytoplasmic trans-factors to form multiple protein complexes of approximately
      175, 97, 63, 26, and 17 kDa post-TGF-beta1 treatment, suggesting a role for these
      complexes in the mechanism of action of TGF-beta1-induced message stabilization.
      Insertion of the 3'-UTR into the chloramphenicol acetyltransferase gene conferred
      TGF-beta1 induced stability of chloramphenicol acetyltransferase-hybrid RNA in
      stably transfected cells, while the same insert carrying a deletion containing
      the 30-nt region had no significant effect on mRNA stability. These results
      provide a model of RHAMM message regulation in which TGF-beta1-mediated
      alteration of RHAMM message stability involves the up-regulation of multiple
      protein interactions with a 30-nt cis-element stability determinant in the 3'
      UTR. This model also suggests that this 30-nt base region functions in cis to
      destabilize RHAMM mRNA in resting normal cells.

PMID- 8663001
TI  - Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by
      heavy metals in human leukemia cells.
AB  - We recently reported that GS-X pump activity, as assessed by ATP-dependent
      transport of the glutathione-platinum complex and leukotriene C4, and
      intracellular glutathione (GSH) levels were remarkably enhanced in cis
      diamminedichloroplatinum(II) (cisplatin)-resistant human leukemia HL-60 cells
      (Ishikawa, T., Wright, C. D., and Ishizuka, H. (1994) J. Biol. Chem. 269, 29085
      29093). Now, using Northern hybridization and RNase protection assay, we provide
      evidence that the multidrug resistance-associated protein (MRP) gene, which
      encodes a human GS-X pump, is expressed at higher levels in cisplatin-resistant
      (HL-60/R-CP) cells than in sensitive cells, whereas amplification of the MRP gene
      is not detected by Southern hybridization. Culturing HL-60/R-CP cells in
      cisplatin-free medium resulted in reduced MRP mRNA levels, but these levels could
      be induced to rise within 30 h by cisplatin and heavy metals such as arsenite,
      cadmium, and zinc. The increased levels of MRP mRNA were closely related with
      enhanced activities of ATP-dependent transport of leukotriene C4 (LTC4) in plasma
      membrane vesicles. The glutathione-platinum (GS-Pt) complex, but not cisplatin,
      inhibited ATP-dependent LTC4 transport, suggesting that the MRP/GS-X pump
      transports both LTC4 and the GS-Pt complex. Expression of gamma-glutamylcysteine
      synthetase in the cisplatin-resistant cells was also co-induced within 24 h in
      response to cisplatin exposure, resulting in a significant increase in cellular
      GSH level. The resistant cells exposed to cisplatin were cross-resistant to
      melphalan, chlorambucil, arsenite, and cadmium. These observations suggest that
      elevated expression of the MRP/GS-X pump and increased GSH biosynthesis together
      may be important factors in the cellular metabolism and disposition of cisplatin,
      alkylating agents, and heavy metals.

PMID- 8663002
TI  - Identification of a novel binding site to the integrin alphaIIbbeta3 located in
      the C-terminal heparin-binding domain of human plasma fibronectin.
AB  - Fibronectin has been shown to bind to integrin alphaIIbbeta3 in Arg-Gly-Asp (RGD)
      dependent and -independent manners. A recent study has indicated that a 29-kDa
      dispase-digestive fragment from the C-terminal heparin-binding domain of human
      plasma fibronectin (lacking RGD sequence) inhibits binding of fibronectin to
      thrombin-stimulated platelets and ADP-induced aggregation (Tanabe, J. , Fujita,
      H., Iwamatsu, A., Mohri, H., and Ohkubo, T.(1993) J. Biol. Chem. 268, 27143
      27147). We provide here the evidence that a peptide corresponding to residues
      from Ala1704 to Glu1718 (designated F1) from this fragment inhibited binding of
      125I-labeled 29-kDa fragment of fibronectin to thrombin-stimulated platelets and
      ADP-induced aggregation. The F1 peptide bound directly to alphaIIbbeta3 integrin
      receptor. These results indicate that a novel binding site in the C-terminal
      heparin-binding region of fibronectin is localized within the residues from
      Ala1704 to Glu1718. Binding of 125I-labeled 29-kDa fragment of fibronectin to
      thrombin-stimulated platelets was not inhibited by RGDS peptide and the 12
      residue peptide from the cell-binding domain of fibronectin, suggesting that
      binding site in the C-terminal heparin-binding domain may be different from those
      of RGDS and the 12-residue peptide. This additional alphaIIbbeta3-binding
      domain(s) in fibronectin may also play some role for prevention of thrombus
      formation by direct interaction with alphaIIbbeta3.

PMID- 8663004
TI  - Characterization of interactions between the neurofilament triplet proteins by
      the yeast two-hybrid system.
AB  - In the adult axon, the neurofilaments (NFs) are heteropolymers formed from the
      low (NFL), middle (NFM), and high (NFH) molecular weight neurofilament triplet
      proteins (NFTPs). All three proteins have the basic intermediate filament protein
      tripartite structure, which consists of a short amino-terminal head region, an
      alpha-helical rod region of approximately310 amino acids, and a carboxyl-terminal
      tail region of variable length. In vitro polymerization studies have shown that
      only NFL can assemble into homopolymeric 10-nm filaments. The assembly of
      intermediate filaments, including the NFs, begins with the formation of a coiled
      coil dimer involving the alpha-helical rod domains of two molecules. In order to
      determine whether homodimers or heterodimers of NFTPs are the preferred
      intermediates in the assembly of NFs, we have used the yeast two-hybrid system to
      study the interactions between the different NFTPs. By monitoring the activity of
      the lacZ reporter gene product, we are able to show that the interactions of NFL
      with NFL, NFM, or NFH are stronger than the interactions of NFM with NFM or NFH
      and the interaction of NFH with NFH. These results imply that NFM and NFH are
      more likely to form heterodimers with NFL than homodimers and are consistent with
      the inability of NFM and NFH to self-polymerize in vitro and in vivo.

PMID- 8663003
TI  - Immunochemical analysis of the human erythrocyte Rh polypeptides.
AB  - We have used rabbit polyclonal antisera raised against synthetic peptides
      complementary to different domains of the Rh polypeptides and Rh glycoprotein to
      examine the topography and organization of these proteins in the human
      erythrocyte membrane. Previously unrecognized exofacial protease sites have been
      identified on Rh CcEe, D proteins, and Rh glycoprotein. The Rh D protein has two
      specific bromelain cleavage sites located within the first and sixth predicted
      external domains, with the site of cleavage localized in the sixth domain to lie
      between residues 353 and 354. All Rh polypeptide species were found to be
      susceptible to cleavage with trypsin and subtilisin within the first external
      domain of these proteins. The Rh glycoprotein has two bromelain cleavage sites
      within the first external domain. These flank the single N-glycosylation site
      (Asn37), with the cleavage site toward the C-terminal side of this residue being
      between residues 39 and 40. Bromelain treatment was found to deglycosylate the Rh
      glycoprotein. Immunoprecipitation experiments have revealed that anti-C, -c,E, 
      e, and -D immune complexes are reactive with antisera raised against the fourth
      predicted external loop of the Rh proteins and the C-terminal domain. These data
      indicate that the hypothesis that suggests Rh C/c antigens are expressed on
      truncated Rh polypeptides by a mechanism of alternate splicing is incorrect and
      support the hypothesis that Rh Cc and Ee antigens are expressed on a single
      polypeptide chain.

PMID- 8663005
TI  - Fluxes of nicotinamide adenine dinucleotides through mitochondrial membranes in
      human cultured cells.
AB  - We report on the loss of mitochondrial nicotinamide adenine dinucleotides in
      human cultured cells along with cell culture and acidification of the culture
      medium. This was established both by the direct measurement of the decrease in
      the mitochondrial NAD content and by the alteration of the oxidative properties
      of the mitochondria. In situ, this loss could be reversed in less than 2 h by
      changing the culture medium or by readjusting the pH of the medium at
      physiological pH values. By studying the oxidative properties of intact, but NAD
      depleted, mitochondria in digitonin-permeabilized cells, we found that a rapid
      influx of NAD could replenish the mitochondrial NAD pool. This allowed the
      restoration of an active NAD+-dependent substrate oxidation. Depletion of
      mitochondrial NAD in cells grown under quiescent conditions was further confirmed
      by fluorimetric measurement of mitochondrial NAD, as was the influx of NAD+ into
      the mitochondrial matrix. These data constitute the first evidence of rapid
      fluxes of NAD through mitochondrial membranes in animal cells. They also point to
      the possible confusion between a loss of mitochondrial NAD and a defect of
      respiratory chain complex I in the context of screening procedures for
      respiratory chain disorder in human.

PMID- 8663006
TI  - Differential D1 dephosphorylation in functional and photodamaged photosystem II
      centers. Dephosphorylation is a prerequisite for degradation of damaged D1.
AB  - Light dependence and kinetics of reversible phosphorylation of the D1 reaction
      center protein of Photosystem II was studied in pumpkin leaves. At growth light,
      maximal phosphorylation of D1 was observed after illumination of 1 h, with higher
      phosphorylation rates at stronger irradiances. 70-85% of D1 became
      phosphorylated, corresponding to the proportion of the protein in appressed
      thylakoid membranes. Comparison of the kinetics of D1 phosphorylation and
      photoinactivation of Photosystem II revealed that D1 phosphorylation became
      saturated before any significant photoinhibition of Photosystem II could be
      detected. Dephosphorylation of D1 in both dim light and darkness was determined
      in leaves preilluminated with high light for various periods. Similar rates of D1
      dephosphorylation were observed after short preillumination conditions that
      induce no significant loss of functional Photosystem II centers. In contrast,
      photodamage to Photosystem II centers significantly decreased the
      dephosphorylation rate of D1 in darkness, and no dephosphorylation occurred in
      leaves containing mainly damaged Photosystem II centers. Darkness also blocked
      the degradation of damaged D1 after photoinhibitory preillumination. Degradation
      of damaged D1 could be prevented even in dim light by sodium fluoride, an
      inhibitor of protein phosphatases, indicating that dephosphorylation is a
      prerequisite for D1 proteolysis. We conclude that in higher plants (i) high light
      induced photodamage to Photosystem II occurs in the centers containing
      phosphorylated D1. (ii) Dephosphorylation of phosphorylated and photodamaged D1
      is associated with the repair cycle of inactivated Photosystem II and is a light
      dependent reaction in vivo. (iii) Dephosphorylation of D1 in functional
      Photosystem II centers, however, occurs rapidly and independent of light. We
      suggest that two reversible phosphorylation cycles with spatially segregated
      protein phosphatases are involved in dephosphorylation of functional and damaged
      phosphorylated D1, respectively.

PMID- 8663007
TI  - Ganglioside synthesis during the development of neuronal polarity. Major changes
      occur during axonogenesis and axon elongation, but not during dendrite growth or
      synaptogenesis.
AB  - Changes in the levels and types of gangliosides occur during neuronal
      differentiation and development, but no studies have correlated these changes
      with defined events in neuronal morphogenesis. Here, we have analyzed the
      relationship between ganglioside synthesis and the development of axons and
      dendrites in polarized neurons, using hippocampal neurons cultured in such a way
      that axons and dendrites are generated by a defined sequence of events and in
      which there is virtually no contamination by glial cells. Neurons were labeled
      with [4,5-3H]dihydrosphingosine, which was rapidly incorporated into cells and
      metabolized to 3H-labeled glycosphingolipids. The rate of 3H-labeled
      glycosphingolipid synthesis was directly proportional to the initial rate of [4,5
      3H]dihydrosphingosine uptake and was linear versus time for up to 9 h of
      incubation. The major changes in 3H-labeled ganglioside synthesis occurred during
      the period of axonogenesis and rapid axon growth. During axonogenesis, there was
      a significant increase in the synthesis of complex gangliosides (i.e. GM1, GD1a,
      GD1b, and GT1b) with a corresponding reduction in the synthesis of
      glucosylceramide and ganglioside GD3. During the stage of rapid axon growth, the
      ratio of a- to b-series gangliosides increased significantly. However, during
      dendritogenesis, dendrite growth, and synaptogenesis, there was little change in
      ganglioside synthesis, with a small and gradual increase in the ratio of a- to b
      series gangliosides and an increase in the synthesis of gangliosides GD1a and
      GT1b. These results indicate that despite major changes in neuronal morphology
      and functionality as neurons mature, changes in ganglioside synthesis are
      restricted to early stages of neuronal development, namely axonogenesis and rapid
      axon elongation.

PMID- 8663008
TI  - Contribution of proline residues in the membrane-spanning domains of cystic
      fibrosis transmembrane conductance regulator to chloride channel function.
AB  - Proline residues located in membrane-spanning domains of transport proteins are
      thought to play an important structural role. In the cystic fibrosis
      transmembrane conductance regulator (CFTR), the predicted transmembrane segments
      contain four prolines: Pro99, Pro205, Pro324, and Pro1021. These residues are
      conserved across species, and mutations of two (P99L and P205S) are associated
      with cystic fibrosis. To evaluate the contribution of these prolines to CFTR Cl-
      channel function, we mutated each residue individually to either alanine or
      glycine or mutated all four simultaneously to alanine (P-Quad-A). We also
      constructed the two cystic fibrosis-associated mutations. cAMP agonists
      stimulated whole cell Cl- currents in HeLa cells expressing the individual
      constructs that resembled those produced by wild-type CFTR. However, the amount
      of current was decreased in the rank order: wild-type CFTR = Pro324 > Pro1021 >
      Pro99 >/= Pro205 mutants. The anion selectivity sequence of the mutants (Br- >/=
      Cl- > I-) resembled wild-type except for P99L (Br- >/= Cl- = I-). Although the
      Pro99, Pro324, and Pro1021 mutants produced mature protein, the amount of mature
      protein was much reduced with the Pro205 mutants, and the P-Quad-A made none.
      Because the Pro99 constructs produced mature protein but had altered whole cell
      currents, we investigated their single-channel properties. Mutant channels were
      regulated like wild-type CFTR; however, single-channel conductance was decreased
      in the rank order: wild-type CFTR >/= P99G > P99L >/= P99A. These results suggest
      that proline residues in the transmembrane segments are important for CFTR
      function, Pro205 is critical for correct protein processing, and Pro99 may
      contribute either directly or indirectly to the Cl- channel pore.

PMID- 8663009
TI  - Molecular basis for subtype-specific desensitization of inhibitory adenosine
      receptors. Analysis of a chimeric A1-A3 adenosine receptor.
AB  - The differing effects of short-term agonist exposure on the two inhibitory
      adenosine receptor (AR) subtypes have been examined using Chinese hamster ovary
      cells stably expressing the hemagglutinin epitope-tagged human A1AR and rat A3AR.
      Under conditions in which exposure of transfected cells to 5 microM (-)-(R)-N6
      (phenylisopropyl)adenosine resulted in the functional desensitization and
      phosphorylation of the A3AR, neither property was exhibited by the A1AR. However,
      a stably expressed chimeric A1-A3AR, termed A1CT3AR, in which the C-terminal
      domain of the A1AR distal to its predicted palmitoylation site was replaced by
      the corresponding region of the A3AR, was able to undergo functional
      desensitization and agonist-stimulated phosphorylation in a manner similar to
      that exhibited by the A3AR. Moreover, purified G-protein-coupled receptor kinases
      2, 3, and 5 were each capable of enhancing the agonist-dependent phosphorylation
      of the A3AR and A1CT3AR in vitro. Taken together, these data demonstrate that the
      C-terminal domain of the A3AR distal to its predicted palmitoylation site is
      responsible for this receptor's ability to undergo a rapid agonist-dependent
      desensitization and are consistent with a model in which phosphorylation of the
      A3AR within this domain by one or more G-protein-coupled receptor kinases
      initiates the desensitization process.

PMID- 8663011
TI  - The proteinase-activated receptor 2 is induced by inflammatory mediators in human
      endothelial cells. Comparison with the thrombin receptor.
AB  - The proteinase-activated receptor 2 (PAR-2) belongs to the family of seven
      transmembrane region receptors, and, like the related thrombin receptor, it is
      activated by specific proteolytic cleavage of its extracellular amino terminus.
      It is not known which proteinase is the physiological activator of the PAR-2, but
      candidates can be found among the enzymes involved in the inflammatory cascade
      systems. Here, we have studied the effects of various mediators on the expression
      of the PAR-2 and the thrombin receptor in cultured human umbilical vein
      endothelial cells. Stimulation with the cytokines tumor necrosis factor alpha or
      interleukin-1 alpha as well as bacterial lipopolysaccharide elevated the
      expression of PAR-2 in a dose-dependent manner. The time course of induction
      after cytokine stimulation was similar to those published for the adhesion
      molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule
      1. After 20 h of stimulation, PAR-2 mRNA and protein levels were increased to 5
      10-fold basal values, and, in the continued presence of tumor necrosis factor
      alpha, PAR-2 mRNA expression was found to remain elevated for up to 4 days. In
      contrast, the thrombin receptor gene was not induced by any of these inflammatory
      mediators. The responses to phorbol ester treatment also differed between the two
      genes. Thrombin receptor mRNA levels decreased steadily up to 20 h, whereas PAR-2
      mRNA levels first rose to about 3-fold basal values at 4 h before decreasing
      again. Cell surface protein levels of both receptors were decreased after 20 h of
      phorbol ester stimulation. Elevating intracellular cAMP levels by treatment with
      forskolin resulted in decreased expression of both receptors, and inhibition of
      cAMP degradation appeared to blunt the cytokine-induced increase in PAR-2
      expression. The induction of the PAR-2 by cytokine treatment supports the concept
      of PAR-2 involvement in the acute inflammatory response.

PMID- 8663010
TI  - Differential translocation of phospholipase C isozymes to integrin-mediated
      cytoskeletal complexes in thrombin-stimulated human platelets.
AB  - To investigate a role of phospholipase C (PLC) isozymes in the integrin
      alphaIIbbeta3-mediated signaling, their location was examined in thrombin
      activated human platelets, revealing different regulation of their translocation
      to the cytoskeleton (CSK). In resting platelets, the major PLCs such as PLCbeta2,
      PLCbeta3a (155 kDa), and PLCgamma2 and the minor PLCs (PLCbeta1 and PLCgamma1)
      were located in the Triton X-100-soluble (Tx.Sol) fraction and the membrane
      skeleton, whereas PLCbeta3b (140 kDa) was present only in Tx.Sol fraction when
      examined by Western immunoblotting. Thrombin stimulation caused a rapid and
      transient translocation of PLCbeta3a and PLCbeta3b and a slower accumulation of
      PLCbeta2 and PLCgamma2 in the reorganized CSK. The translocation to CSK of both
      PLCbeta3a and PLCbeta3b, but not PLCbeta2, was dependent on integrin
      alphaIIbbeta3-mediated aggregation. Furthermore, an actin polymerization
      inhibitor, cytochalasin D, or a protein tyrosine kinase inhibitor, genistein,
      abolished the CSK association of alphaIIbbeta3, PLCbeta3a, and PLCbeta3b. In the
      genistein-pretreated platelets, pp60(c-)src, Gq, and protein kinase Calpha were
      no longer able to associate with CSK. In contrast, these agents had no or
      marginal inhibitory effects on the CSK association of PLCbeta2 and Gi2. The late
      diacylglycerol generation induced by thrombin stimulation was significantly
      reduced by the genistein treatment. These results suggest that the integrin
      alphaIIbbeta3-mediated cytoskeletal association of PLCbeta3 is regulated by
      protein tyrosine kinase and also that the activation of the relocated PLC may
      play a role in the late platelet-to-platelet aggregation in thrombin-stimulated
      human platelets.

PMID- 8663012
TI  - Different effects of various phospholipids on Ki-Ras-, Ha-Ras-, and Rap1B-induced
      B-Raf activation.
AB  - We have recently purified a Ki-Ras- and Ha-Ras-dependent extracellular signal
      regulated kinase kinase from bovine brain and identified it as B-Raf protein
      kinase complexed with 14-3-3 proteins (Yamamori, B., Kuroda, S., Shimizu, K.,
      Fukui, K., Ohtsuka, T., and Takai, Y. (1995) J. Biol. Chem. 270, 11723-11726).
      Moreover, we found that Rap1B as well as Ki-Ras and Ha-Ras stimulate the B-Raf
      activity. Since B-Raf contains a cysteine-rich domain originally found in protein
      kinase C as a domain responsible for interaction with phosphatidylserine (PS) and
      diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate, we have examined here the
      effect of these compounds on the Ki-Ras-, Ha-Ras-, and Rap1B-induced activation
      of bovine brain B-Raf. Bovine brain PS enhanced Ki-Ras-stimulated B-Raf activity.
      Phosphatidic acid was slightly active, but other phospholipids, such as
      phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol (PI), PI-4
      monophosphate, PI-4,5-bisphosphate, and PI-3,4,5-trisphosphate, were inactive.
      However, none of the above phospholipids affected the Ha-Ras-stimulated B-Raf
      activity, whereas PI, PS, phosphatidylethanolamine, and phosphatidic acid
      inhibited the Rap1B-stimulated B-Raf activity. Phosphatidylcholine or PI-4
      monophosphate did not show any effect on the Rap1B-stimulated B-Raf activity.
      Synthetic PS with two unsaturated fatty acids, such as 1,2-dioleoyl-PS or 1,2
      dilinoleoyl-PS, showed the same effect toward the Ki-Ras- and Rap1B-stimulated B
      Raf activities, but synthetic PS with two saturated fatty acids, such as 1, 2
      distearoyl-PS, was inactive. 12-O-Tetradecanoylphorbol-13-acetate did not affect
      the stimulatory or inhibitory effect of PS on the Ki-Ras- and Rap1B-stimulated B
      Raf activities, respectively. PS did not affect the Ki-Ras-, Ha-Ras-, or Rap1B
      independent basal B-Raf activity or the mitogen-activated protein kinase kinase
      or extracellular signal-regulated kinase activity. These results indicate that
      various phospholipids differently affect Ki-Ras-, Ha-Ras, and Rap1B-induced B-Raf
      activation.

PMID- 8663013
TI  - Kinetics and stoichiometry of a proton/myo-inositol cotransporter.
AB  - Voltage clamp recording was used to measure steady-state and presteady-state
      currents mediated by a myo-inositol transporter cloned from Leishmania donovani
      and expressed in Xenopus oocytes. Application of myo-inositol resulted in inward
      currents, which did not require external sodium and which were increased by
      increasing the extracellular proton concentration and by membrane
      hyperpolarization. Alkalinization of the extracellular space occurred
      concomitantly with myo-inositol influx. Correlation of membrane currents with
      radiolabeled myo-inositol flux revealed that one positive charge is translocated
      with each molecule of myo-inositol, consistent with cotransport of one proton.
      The transport concentration dependence on both species suggested ordered binding
      of a proton followed by a molecule of myo-inositol. In the absence of myo
      inositol, a voltage-dependent capacitance was observed that correlated with the
      transporter expression level. This charge movement obeyed a Boltzmann function,
      which was used to estimate a turnover of 0.70 +/- 0.06 s-1 at -60 mV. The pH and
      voltage dependence of the charge movements were simulated with a model involving
      alternating access of internal and external protons to sites within an occluded
      pore.

PMID- 8663014
TI  - A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates
      the neutral sphingomyelinase pathway.
AB  - The human p55 tumor necrosis factor (TNF) receptor (TR55) initiates at least two
      independent signaling cascades. The acidic sphingomyelinase (A-SMase) pathway
      involves a phosphatidylcholine-specific phospholipase C, an endosomal A-SMase,
      and controls expression of multiple TNF-responsive genes through induction of
      transcription factors such as NF-kappaB. The neutral sphingomyelinase (N-SMase)
      pathway comprises a membrane-bound N-SMase, proline-directed protein kinases, as
      well as phospholipase A2 and appears critical for the inflammatory responses
      induced by TNF. While the domain of TR55 that induces A-SMase is probably
      identical to the death domain, the exact location and extent of a putative N
      SMase activation domain are still unknown. Structure-function analysis of TR55
      deletion mutants revealed a novel region of 11 amino acids at position 309-319
      that is both necessary and sufficient for activation of N-SMase. The N-SMase
      activation domain is distinct from the death domain and incapable of induction of
      A-SMase, NF-kappaB, and cytotoxicity. Taken together, our results suggest that a
      functionally independent region of TR55 is responsible for selectively initiating
      the N-SMase pathway that couples to an important inflammatory signaling cascade.

PMID- 8663015
TI  - Local amplification of platelet function by 8-Epi prostaglandin F2alpha is not
      mediated by thromboxane receptor isoforms.
AB  - 8-epi-Prostaglandin (PG) F2alpha may be formed by cyclooxygenases 1 and 2 or by a
      free radical catalyzed process as an isoprostane. Concentrations of 8-epi
      PGF2alpha in the range 1 nM to 1 microM induce a dose-dependent increase in
      platelet shape change, in calcium release from intracellular stores [Ca2+]iand in
      inositol phosphates; it also causes irreversible platelet aggregation, dependent
      on thromboxane generation, when incubated with subthreshold concentrations of
      ADP, thrombin, collagen, and arachidonic acid. Much higher concentrations of 8
      epi-PGF2alpha (10-20 microM) alone induce weak, reversible aggregation. Although
      these effects are prevented by pharmacological thromboxane receptor antagonists,
      they are unlikely to be mediated by thromboxane receptors. Thus, 8-epi-PGF2alpha
      does not compete for binding at the stably expressed placental or endothelial
      isoforms of the thromboxane receptor or for binding of thromboxane ligands to
      human platelets. Furthermore, the response to 8-epi PGF2alpha exhibits structural
      specificity versus 8-epi PGF3alpha and PGF2alpha. Concentrations in the range
      that evoke its effects on platelets do not desensitize the aggregation response
      stimulated by thromboxane or PGH2 analogs. Unlike primary prostaglandins, which
      are rapidly metabolized to inactive products, 8-epi PGF2alpha circulates in
      plasma. However, the systemic concentrations found in healthy volunteers (median
      48 pmol/liter) and in patients with hepatic cirrhosis (median 147 pmol/liter), a
      syndrome of oxidant stress in vivo, fall well below those which modulate platelet
      function. 8-Epi PGF2alpha may amplify the response to platelet agonists in
      syndromes where oxidant stress and platelet activation coincide. Despite blockade
      by thromboxane antagonists, 8-epi PGF2alpha does not activate either of the
      thromboxane receptor isoforms described in platelets. Activation of a distinct
      receptor would be consistent with the enzymatic formation of 8-epi PGF2alpha by
      cyclooxygenases. However, incidental activation of such a receptor by systemic
      concentrations of 8-epi PGF2alpha is unlikely to occur, even in syndromes of
      excessive free radical generation in vivo.

PMID- 8663016
TI  - Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin
      3 is a component of the sarcolemma and co-fractionates with dystrophin and
      dystrophin-associated glycoproteins.
AB  - Caveolae are microdomains of the plasma membrane that have been implicated in
      signal transduction. Caveolin, a 21-24-kDa integral membrane protein, is a
      principal component of the caveolae membrane. Recently, we and others have
      identified a family of caveolin-related proteins; caveolin has been retermed
      caveolin-1. Caveolin-3 is most closely related to caveolin-1, but caveolin-3 mRNA
      is expressed only in muscle tissue types. Here, we examine (i) the expression of
      caveolin-3 protein in muscle tissue types and (ii) its localization within
      skeletal muscle fibers by immunofluorescence microscopy and subcellular
      fractionation. For this purpose, we generated a novel monoclonal antibody (mAb)
      probe that recognizes the unique N-terminal region of caveolin-3, but not other
      members of the caveolin gene family. A survey of tissues and muscle cell types by
      Western blot analysis reveals that the caveolin-3 protein is selectively
      expressed only in heart and skeletal muscle tissues, cardiac myocytes, and smooth
      muscle cells. Immunolocalization of caveolin-3 in skeletal muscle fibers
      demonstrates that caveolin-3 is localized to the sarcolemma (muscle cell plasma
      membrane) and coincides with the distribution of another muscle-specific plasma
      membrane marker protein, dystrophin. In addition, caveolin-3 protein expression
      is dramatically induced during the differentiation of C2C12 skeletal myoblasts in
      culture. Using differentiated C2C12 skeletal myoblasts as a model system, we
      observe that caveolin-3 co-fractionates with cytoplasmic signaling molecules (G
      proteins and Src-like kinases) and members of the dystrophin complex (dystrophin,
      alpha-sarcoglycan, and beta-dystroglycan), but is clearly separated from the bulk
      of cellular proteins. Caveolin-3 co-immunoprecipitates with antibodies directed
      against dystrophin, suggesting that they are physically associated as a discrete
      complex. These results are consistent with previous immunoelectron microscopic
      studies demonstrating that dystrophin is localized to plasma membrane caveolae in
      smooth muscle cells.

PMID- 8663017
TI  - Characterization of the ligand-binding domains of glutamate receptor (GluR)-B and
      GluR-D subunits expressed in Escherichia coli as periplasmic proteins.
AB  - We recently reported that a functional ligand-binding site of an alpha-amino-5
      methyl-3-hydroxy-4-isoxazole propionate (AMPA)-selective glutamate receptor
      (GluR)-D subunit can be expressed in insect cells as a soluble, N-glycosylated
      fusion protein consisting of two segments (S1 and S2) that are related by amino
      acid sequence to bacterial periplasmic binding proteins (Kuusinen, A., Arvola,
      M., and Keinanen, K., EMBO J. 14, 6327-6332). In an attempt to further
      characterize the structural determinants for ligand binding, we have now
      expressed the ligand-binding sites of GluR-B and GluR-D subunits in Escherichia
      coli as soluble periplasmic proteins. The bacterially expressed S1-S2 fusion
      proteins bound [3H]AMPA with a high affinity (Kd of 12 nM for GluR-B, Kd of 60 nM
      for GluR-D) and with a ligand pharmacology typical of native AMPA receptors,
      indicating that N-linked glycosylation is not required for the formation or the
      maintenance of the ligand-binding site. The flip and flop splice variants of the
      GluR-D S1-S2 fusion protein bound [3H]AMPA with equal affinities, whereas
      deletion of the C-terminal one-third of the S2 segment including the flip/flop
      sequence resulted in a loss of binding activity. Our results highlight the
      potential of bacterial expression for the analysis of the binding site and
      support a close structural similarity between glutamate receptors and bacterial
      proteins.

PMID- 8663018
TI  - The multidrug resistance-associated protein (MRP) subfamily (Yrs1/Yor1) of
      Saccharomyces cerevisiae is important for the tolerance to a broad range of
      organic anions.
AB  - We have cloned and characterized a Saccharomyces cerevisiae gene YRS1 that
      complements the phenotype of the mutant sensitive to the anionic drug reveromycin
      A. The YRS1 gene, which is identical to the recently identified YOR1 gene,
      encodes a protein with extensive homology to the human multidrug resistance
      associated protein (MRP) and the yeast cadmium factor (Ycf1). A chromosomal
      deletion of YRS1 lead to viable Deltayrs1 cells, which exhibited hypersensitivity
      to reveromycin A. Elevation of the YRS1 gene dosage in wild type cells conferred
      increased resistance to reveromycin A. By analyzing the effect of YRS1 disruption
      and overexpression it was demonstrated that Yrs1 is involved in the
      detoxification of a wide range of the organic anions that contain carboxyl
      group(s) but none of the other type of toxic compounds examined. Fluorescence
      activated cell sorter analysis indicated the increased accumulation of the
      anionic fluorescent compound rhodamine B in Deltayrs1 cells. The expression of
      YRS1 was induced strikingly by reveromycin A. These results suggest that Yrs1 is
      a multispecific organic anion transporter important for tolerance against toxic
      environmental organic anions. Yrs1 had an overlapping specificity with Ycf1 in
      the resistance to cadmium.

PMID- 8663019
TI  - Phospholipase D-derived products in the regulation of 12-O-tetradecanoylphorbol
      13-acetate-stimulated prostaglandin synthesis in madin-darby canine kidney cells.
AB  - Madin-Darby canine kidney (MDCK) cells stimulated with 12-O-tetradecanoylphorbol
      13-acetate (TPA) in the presence of ethanol synthesize phosphatidylethanol (PEt)
      instead of phosphatidic acid (PA) and diglyceride (DG). We have used ethanol to
      block the production of phospholipase D (PLD)-derived PA and DG (from PA
      hydrolysis) to study their role in signal transduction. In MDCK cells, TPA
      stimulated prostaglandin E2 (PGE2) synthesis was inhibited by ethanol at
      concentrations which inhibit PA and DG formation. In addition, TPA elicited a
      prolonged increase in PGE2 synthesis that is dependent upon continuous activation
      of PLD. The TPA-stimulated translocation of protein kinase Calpha (PKCalpha) from
      cytosol to membrane was unaffected by ethanol. This suggests that PLD-derived
      products act downstream of PKC in TPA-stimulated prostaglandin synthesis. The
      calcium ionophore, A23187, did not activate PLD, and PGE2 synthesis in response
      to A23187 was unaffected by ethanol. TPA increased prostaglandin endoperoxide H
      synthase (PGHS) activity and increased the amount of immunodetectable
      prostaglandin endoperoxide H synthase 2 (PGHS-2). A23187 did not induce PGHS-2
      and A23187-stimulated PGE2 synthesis appears to be due to the constitutively
      expressed PGHS-1. Blocking the formation of PLD-derived products, PA and DG,
      inhibited the induction of PGHS-2 by TPA. These results indicate that prolonged
      PGE2 synthesis in response to TPA is due to the continuous induction of PGHS-2,
      which is dependent upon PLD activation. In contrast, induction of PGHS-2 by
      epidermal growth factor was not affected by ethanol. Epidermal growth factor did
      not induce PKCalpha translocation nor activate PLD. Taken together, these data
      suggest that PLD-derived PA or DG act as second messengers in the induction of
      PGHS-2 by PKC-dependent pathways. The demonstration that inhibition of TPA
      induced PA formation inhibits Raf-1 translocation in MDCK cells (Ghosh, S.,
      Strum, J. C., Sciorra, V. A., Daniel, L. W. , and Bell, R. M. (1996) J. Biol.
      Chem. 271, 8472-8480) suggests that PA is the active PLD metabolite in TPA
      stimulated signaling.

PMID- 8663020
TI  - Ceruloplasmin enhances smooth muscle cell- and endothelial cell-mediated low
      density lipoprotein oxidation by a superoxide-dependent mechanism.
AB  - Cultured vascular smooth muscle cells (SMC) and endothelial cells (EC) stimulate
      low density lipoprotein (LDL) oxidation by free radical-mediated, transition
      metal-dependent mechanisms. The physiological source(s) of metal ions is not
      known; however, purified ceruloplasmin, a plasma protein containing 7 coppers,
      oxidizes LDL in vitro. We now show that ceruloplasmin also increases LDL
      oxidation by vascular cells. In metal ion-free medium, human ceruloplasmin
      increased bovine aortic SMC- and EC-mediated LDL oxidation by up to 30- and 15
      fold, respectively. The maximal response was at 100-300 microg ceruloplasmin/ml,
      a level at or below the unevoked physiological plasma concentration. Oxidant
      activity was dependent on protein structure as a specific proteolytic cleavage or
      removal of one of the seven ceruloplasmin copper atoms inhibited activity. Three
      lines of evidence indicated a critical role for cellular superoxide (O2.) in
      ceruloplasmin-stimulated oxidation. First, the rate of production of O2. by cells
      correlated with their rates of LDL oxidation. Second, superoxide dismutase
      effectively blocked ceruloplasmin-stimulated oxidation by both cell types.
      Finally, O2. production by SMC quantitatively accounted for the observed rate of
      LDL oxidation. To show this, the course of O2. production by SMC was simulated by
      repeated addition of xanthine and xanthine oxidase to culture medium under cell
      free conditions. Neither ceruloplasmin nor O2. alone increased LDL oxidation, but
      together they completely reconstituted the oxidation rate of ceruloplasmin
      stimulated SMC. These results are the first to show that ceruloplasmin stimulates
      EC- and SMC-mediated oxidation of LDL and that cell-derived O2. accounts
      quantitatively for metal-dependent, free radical-initiated oxidation of LDL by
      these cells.

PMID- 8663021
TI  - A segment of five amino acids in the second extracellular loop of the
      cholecystokinin-B receptor is essential for selectivity of the peptide agonist
      gastrin.
AB  - The two known receptors mediating the actions of cholecystokinin (CCK) and
      gastrin, CCK type A (CCKAR) and CCK type B (CCKBR) receptors, are G protein
      coupled receptors having approximately 50% amino acid homology. Both the CCKAR
      and CCKBR have high affinity for sulfated CCK peptides, while only the CCKBR has
      high affinity for gastrin peptides. To determine the structural basis for the
      selectivity of the CCKBR for gastrin, we first constructed a series of CCKB/AR
      chimeras in which restriction endonuclease-defined segments of the CCKBR were
      replaced with the corresponding segments of the CCKAR. Chimeras transiently
      expressed in COS-1 cells were screened for the selective loss of gastrin affinity
      according to the displacement of 125I-labeled Bolton-Hunter-CCK-8 binding by
      gastrin-17-I and CCK-8. The sequence spanning from transmembrane domain III (TM
      III) to TM V was the only segment that resulted in the selective loss of gastrin
      affinity. This segment could account for 100 of the expected 300-fold lower
      affinity of gastrin-17-I observed for the control CCKAR compared to the control
      CCKBR. Using site-directed mutagenesis in this segment of the CCKBR, we
      identified a sequence of 5 amino acids in the second extracellular loop
      responsible for this 100-fold selective loss in gastrin affinity. 125I-labeled
      Bolton-Hunter-CCK-8 binding displacement by L365,260 (a CCKBR selective
      antagonist) was unaffected by the changes in these 5 amino acids. These results
      present for the first time the identification of the amino acid sequence of the
      CCKBR conferring the majority of the selectivity for gastrin.

PMID- 8663022
TI  - Octamer binding factors and their coactivator can activate the murine PU.1 (spi
      1) promoter.
AB  - PU.1 (spi-1), a member of the Ets transcription factor family, is predominantly
      expressed in myeloid and B cells, activates many B cell and myeloid genes, and is
      critical for development of both of these lineages. Our previous studies (Chen,
      H. M., Ray-Gallet, D., Zhang, P., Hetherington, C. J., Gonzalez, D. A., Zhang, D.
      E., Moreau-Gachelin, F., and Tenen, D. G. (1995) Oncogene 11, 1549-1560)
      demonstrate that the PU.1 promoter directs cell type-specific reporter gene
      expression in myeloid cell lines, and that PU.1 activates its own promoter in an
      autoregulatory loop. Here we show that the murine PU.1 promoter is also
      specifically and highly functional in B cell lines as well. Oct-1 and Oct-2 can
      bind specifically to a site at base pair -55 in vitro, and this site is
      specifically protected in B cells in vivo. We also demonstrate that two other
      sites contribute to promoter activity in B cells; an Sp1 binding site adjacent to
      the octamer site, and the PU.1 autoregulatory site. Finally, we show that the B
      cell coactivator OBF-1/Bob1/OCA-B is only expressed in B cells and not in myeloid
      cells, and that OBF-1/Bob1/OCA-B can transactivate the PU.1 promoter in HeLa and
      myeloid cells. This B cell restricted coactivator may be responsible for the B
      cell specific expression of PU.1 mediated by the octamer site.

PMID- 8663023
TI  - Isoforms of selenoprotein P in rat plasma. Evidence for a full-length form and
      another form that terminates at the second UGA in the open reading frame.
AB  - Several forms of selenoprotein P that share the same N-terminal sequence have
      been identified in rat plasma, but only one selenoprotein P mRNA has been
      characterized. The open reading frame of the mRNA contains 10 UGAs that
      presumably code for selenocysteine residues. Using heparin-Sepharose, we isolated
      two of the protein forms from immunoaffinity-purified selenoprotein P. One of the
      forms, Se-P45B, migrates at 45 kDa on SDS-polyacrylamide gel electrophoresis, and
      the other, Se-P57B, migrates at 57 kDa. These two forms were cleaved with
      cyanogen bromide, and both yielded 40-kDa fragments that were consistent with
      those fragments being an inter-methionine peptide near the N terminus of the
      predicted polypeptide. A 20-kDa fragment present in the cleavage products of Se
      P57B was absent from the products of Se-P45B. This result suggested that Se-P45B
      lacks the C-terminal region of the predicted polypeptide. Carboxypeptidase P
      digestion of Se-P45B indicated that its C-terminal amino acid is Ser244, the
      amino acid immediately upstream from the predicted second selenocysteine. C
      terminal analysis of Se-P57B indicated that its final residue is Asn366, the last
      amino acid predicted by the cDNA sequence. Amino acid composition analyses of the
      two forms were consistent with both arising from the same mRNA. Immunoaffinity
      purified selenoprotein P was digested with proteases, and the resulting peptides
      were separated and sequenced. Only amino acid sequences predicted by the cDNA
      were found, and 80% of the predicted amino acid sequence was confirmed. These
      results are compatible with Se-P45B arising from termination of translation at
      the second in-frame UGA codon and all of the 10 in-frame UGA codons being read
      through to produce Se-P57B. These findings demonstrate that selenoprotein P
      isoforms of differing peptide lengths are present in plasma. They raise the
      possibility that the second UGA codon in selenoprotein P mRNA can have
      alternative functions: coding for the incorporation of selenocysteine or coding
      for termination of translation.

PMID- 8663024
TI  - p120 Ras GTPase-activating protein interacts with Ras-GTP through specific
      conserved residues.
AB  - Previous structural studies of RasGAP have failed to clearly localize sites of
      Ras interaction to individual amino acids. Hypothesizing that sites of
      interaction with Ras-GTP would be conserved, 11 of the most highly conserved
      amino acid residues of RasGAP were changed by mutation. Each mutant protein was
      purified as a glutathione S-transferase catalytic domain fusion and analyzed for
      protein stability, Ras GTPase stimulating activity, affinity for Ras-GTP, and
      when possible, secondary structure. The majority of conserved positions were
      found to be important structurally but with no direct role in Ras interactions.
      However, Arg786, Lys831, and Arg925 were observed to be essential for binding to
      Ras-GTP but not for protein structure. RasGAP residues 890-902 (block 3A) were
      observed to be homologous to residues 1540-1552 of the yeast adenylyl cyclase
      with amino acid substitutions in both regions resulting in increased affinity for
      Ras. This is the first example of a conserved Ras interaction motif in distinct
      Ras effector proteins. Our data are supportive of a model for GAP/Ras-GTP
      association in which the conserved, positively charged Arg786, Lys831, and Arg925
      residues form salt bridges with the conserved, negatively charged residues in the
      Ras effector loop.

PMID- 8663025
TI  - Heat shock protein 84 forms a complex with mutant p53 protein predominantly
      within a cytoplasmic compartment of the cell.
AB  - Cellular DNA damage results in the increased expression and accumulation of the
      p53 tumor suppressor protein within the nucleus which leads to cell cycle arrest
      or apoptosis. In some cases, however, wild-type p53 and some mutant forms of p53
      reside in the cytoplasm of cancer cells. To understand the mechanism responsible
      for its cytoplasmic retention, studies were undertaken to determine if unique
      proteins form a complex with mutant p53 within the cytoplasm of transformed
      cells. One protein, with an apparent molecular mass of 92 kDa (p92), was observed
      to form a complex with a temperature-sensitive mutant p53 (TSp53(Val-135)) in the
      cytoplasm of transformed rat embryo fibroblasts at the non-permissive
      temperature. p92 copurified with TSp53(Val-135) on a p53-specific immunoaffinity
      column and a gel filtration column. The protein was purified to homogeneity and
      identified as hsp84 by partial amino acid sequence analysis. hsp84 is a member of
      the hsp90 class of proteins. At the non-permissive temperature, TSp53(Val-135)
      and hsp84 colocalized in the cytoplasm near the nuclear envelope. At the
      permissive temperature, TSp53(Val-135) resides in the nucleus and expresses a
      "wild-type like" conformation. Under these conditions hsp84 continued to reside
      in the cytoplasm and little or no hsp84 formed a complex with p53. The results
      suggest that hsp84 binds mutant p53 in a spatial and/or conformation dependent
      manner.

PMID- 8663026
TI  - Membrane topology of the colicin A pore-forming domain analyzed by disulfide bond
      engineering.
AB  - Four colicin A double-cysteine mutants possessing a disulfide bond in their pore
      forming domain were constructed to study the translocation and the pore formation
      of colicin A. The disulfide bonds connected alpha-helices 1 and 2, 2 and 10, 3
      and 9, or 3 and 10 of the pore-forming domain. The disulfide bonds did not
      prevent the colicin A translocation through the Escherichia coli envelope.
      However, the mutated colicins were able to exert their in vivo channel activity
      only after reduction of their disulfide bonds. In vitro studies with brominated
      phospholipid vesicles and planar lipid bilayers revealed that the disulfide bond
      that connects the alpha-helices 2 and 10 prevented the colicin A membrane
      insertion, whereas the other double-cysteine mutants inserted into lipid
      vesicles. The disulfide bonds that connect either the alpha-helices 1 and 2 or 3
      and 10 were unable to prevent the formation of a conducting channel in presence
      of membrane potential. These results indicate that alpha-helices 1, 2, 3, and 10
      remain at the membrane surface after application of a membrane potential.

PMID- 8663027
TI  - Nucleosome assembly on CTG triplet repeats.
AB  - Expansion of CTG repeat sequences is associated with several human genetic
      diseases. We have examined the consequences of CTG repeat expansion for
      nucleosome assembly and positioning. Short CTG repeats are found within the most
      favored DNA sequences yet defined for nucleosome assembly. We find that as few as
      six CTG repeats will facilitate nucleosome assembly to a similar extent as the 50
      or more repeats found in disease genes. Thus an increase in nucleosome stability
      on expansion of existing triplet repeats is unlikely to explain the acquisition
      of the disease phenotype. However, the CTG repeat sequence is efficiently wrapped
      around the histone octamer, preferring to associate with histones at the
      nucleosomal dyad. Thus short segments CTG repeat sequence will facilitate the
      assembly of a stable positioned nucleosome which might contribute to the
      expansion phenomenon and the functional organization of chromatin.

PMID- 8663028
TI  - Phosphatidylinositol phospholipase C is activated allosterically by the
      aminoglycoside G418. 2-deoxy-2-fluoro-scyllo-inositol-1-O-dodecylphosphonate and
      its analogs inhibit glycosylphosphatidylinositol phospholipase C.
AB  - Phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus is
      inhibited by myo-inositol-1-O-dodecylphosphonate (Ins-1-O-dodecylphosphonate)
      (Morris, J. C., Ping-Sheng, L., Shen, T. Y., and Mensa-Wilmot, K.(1995) J. Biol.
      Chem. 270, 2517-2524). A set of novel fluorinated 2-deoxy-Ins-1-O
      dodecylphosphonates were tested against PI-PLC, with potent competitive
      inhibition by 2-deoxy-2-fluoro-scyllo-Ins-1-O-dodecylphosphonate (VP-616L)
      (Xi(50) = 0.09). 2-Deoxy-2-fluoro-myo-Ins-1-O-dodecylphosphonate and 2-deoxy-2,2
      difluoro-myo-Ins-1-O-dodecylphosphonate were 8.3-fold and 4.8-fold less
      effective, respectively, than VP-616L. Methyl 2-deoxy-2,2-difluoro-myo-Ins-1-O
      dodecylphosphonate was inactive. Also, a hundredfold less PI-PLC is required to
      cleave a glycosylphosphatidylinositol (GPI) than is needed to cleave PI. Implied
      in these observations are the following: (i) in powerful inhibitors an active
      site residue probably interacts with the equatorially oriented fluoro
      substituent; (ii) substrate recognition requires a negative charge on the
      phosphoryl at the Ins-1 position, and (iii) a GPI is better substrate than PI,
      for PI-PLC. Aminoglycoside antibiotics kanamycin A, gentamycin, and G418
      stimulated PI-PLC cleavage of the GPI anchor of variant surface glycoprotein
      (VSG) from Trypanosoma brucei 2- to 4-fold. G418, which appears to act on the
      enzyme.substrate complex, increased kcat and Km 6.4-fold and 9.9-fold,
      respectively. PI-PLC was activated by G418 even in the presence of the inhibitor
      VP-616L. In control experiments, the lectin concanavalin A (ConA), which probably
      acts by substrate sequestration, inhibited both PI-PLC (Xi(50) = 0.00025) and GPI
      specific phospholipase D (Xi(50) = 0.00018). G418 failed to activate PI-PLC when
      ConA was present. These observations indicate that G418 is an allosteric
      activator of Bacillus cereus PI-PLC. Since G418 stimulates a purified enzyme that
      is not involved in aminoglycoside metabolism, we propose that binding of
      aminoglycosides to cellular proteins could contribute to the development of the
      nephrotoxicity associated with the use of these aminoglycoside antibiotics.

PMID- 8663029
TI  - Fungal membrane responses induced by plant defensins and thionins.
AB  - Treatment of hyphae of Neurospora crassa with antifungal plant defensins, i.e. Rs
      AFP2 and Dm-AMP1 isolated from radish and dahlia seed, respectively, induced a
      rapid K+ efflux, Ca2+ uptake, and alkalinization of the incubation medium. The Rs
      AFP2-induced alkalinization of the incubation medium could be inhibited with G
      protein inhibitors. alpha-Hordothionin, an antifungal thionin from barley seed,
      caused a sustained increased Ca2+ uptake at subinhibitory concentrations but only
      a transient increased uptake at inhibitory concentrations. alpha-Hordothionin
      also caused increased K+ efflux and alkalinization of the medium, but these
      fluxes occurred more rapidly compared to those caused by plant defensins.
      Furthermore, alpha-hordothionin caused permeabilization of fungal hyphae to the
      non-metabolite alpha-aminoisobutyric acid and, in addition, altered the
      electrical properties of artificial lipid bilayers, consistently leading to
      rupture of the lipid bilayers. The plant defensins did not form ion-permeable
      pores in artificial membranes and did not exhibit substantial hyphal membrane
      permeabilization activity. Our results are consistent with the notion that
      thionins inhibit fungal growth as a result of direct protein-membrane
      interactions, whereas plant defensins might act via a different, possibly
      receptor-mediated, mechanism.

PMID- 8663030
TI  - Stimulation of myogenic differentiation by a neuregulin, glial growth factor 2.
      Are neuregulins the long-sought muscle trophic factors secreted by nerves?
AB  - It has long been known that nerves stimulate growth and maintenance of skeletal
      muscles in ways not dependent on physical contacts, but numerous attempts to
      identify and characterize the myotrophic agent(s) secreted by nerves have been
      unsuccessful. We here suggest that products of the neuregulin gene may be these
      agents. The neuregulins are a family of proteins made by alternative splicing of
      a single transcript to give as many as 15 protein products. One member of this
      family, glial growth factor 2 (rhGGF2) is a very potent stimulator of myogenesis
      in L6A1 myoblasts, giving a maximal stimulation of cell fusion and creatine
      kinase elevation at a concentration of 1 ng/ml (18 pM). The stimulation of
      myogenesis is not rapid, but it is prolonged, continuing over a period of at
      least 6 days. The effects of rhGGF2 are additive with those of insulin-like
      growth factor I (IGF-I) or its analog R3-IGF-I, suggesting that the actions of
      these two myotrophic agents differ in at least one rate-limiting step. We have
      observed one possible difference; unlike the IGFs, rhGGF2 does not induce
      elevation of the steady state level of myogenin mRNA.

PMID- 8663032
TI  - Diminished cell proliferation associated with the death-protective activity of
      Bcl-2.
AB  - The oncogene product Bcl-2 effectively spares cells from programmed cell death
      (apoptosis). The molecular mechanism underlying this death-protective activity
      has, however, remained enigmatic. Here we show that induction of Bcl-2 expression
      is consistently associated with a retardation of mammalian cell proliferation due
      to a prolongation of the G1 phase of the cell cycle. Whereas cells lacking Bcl-2
      expression die from any point of the cell cycle in response to apoptotic agents,
      Bcl-2-overexpressing cells accumulate in the G0/G1 phase and are protected from
      cell death. Co-expression of Bax, a negative regulator of Bcl-2, reverts both the
      cell death protective and proliferation retarding activities of Bcl-2. Moreover,
      a Bcl-2 mutant defective in death protection does not affect cell division. These
      findings indicate that Bcl-2 contributes to cell survival by diminishing the rate
      of cell proliferation.

PMID- 8663031
TI  - A novel class of cell surface glycolipids of mammalian cells. Free glycosyl
      phosphatidylinositols.
AB  - Glycosyl phosphatidylinositol (GPI) lipids function as anchors of membrane
      proteins, and free GPI units serve as intermediates along the path of GPI-anchor
      biosynthesis. By using in vivo cell surface biotinylation, we show that free
      GPIs: 1) can exit the rough endoplasmic reticulum and are present on the surface
      of a murine EL-4 T-lymphoma and a human carcinoma cell (HeLa), 2) arrive at the
      cell surface in a time and temperature-dependent fashion, and 3) are built on a
      base-labile glycerol backbone, unlike GPI anchors of surface proteins of the same
      cells. The free GPIs described in this study may serve as a source of hormone
      sensitive phosphoinositol glycans. The absence of free GPIs from the cell surface
      may also account for the growth advantage of blood cells in paroxysmal nocturnal
      hemoglobinuria.

PMID- 8663033
TI  - Endothelial nitric-oxide synthase. Evidence for bidomain structure and successful
      reconstitution of catalytic activity from two separate domains generated by a
      baculovirus expression system.
AB  - A baculovirus system was used to express the oxygenase and reductase domains of
      human endothelial nitric-oxide synthase (ecNOS) as distinct proteins. The
      oxygenase domain (residues 1-491) was expressed using a vector containing a His6
      tag at the N terminus. The purified oxygenase domain had an apparent molecular
      mass of approximately 54 kDa, and retained the ability to bind L-arginine and
      form the ferrous CO complex. The purified reductase domain (residues 492-1244)
      had an apparent molecular mass of approximately 82 kDa and retained the ability
      to catalyze NADPH-dependent cytochrome c reduction, which was enhanced 10-fold by
      the presence of Ca2+/calmodulin. Both purified domains exhibited immunoreactivity
      to rabbit anti-ecNOS IgG. The NOS activity was successfully reconstituted by
      mixing the two domains. These results demonstrate for the first time that the two
      domains of ecNOS are catalytically intact and can be reconstituted in vitro.

PMID- 8663034
TI  - Expression and spectroscopic characterization of the hydrogenosomal [2Fe-2S]
      ferredoxin from the protozoan Trichomonas vaginalis.
AB  - The heterologous expression and spectroscopic characterization of the [2Fe-2S]
      ferredoxin from the sexually transmitted human parasite Trichomonas vaginalis is
      described. Using oligonucleotide primers based on the deduced DNA sequence, the
      gene encoding the ferredoxin was amplified by polymerase chain reaction and
      cloned into a T7 RNA polymerase expression vector. Expression of the gene in
      Escherichia coli host HMS174(DE3) resulted in the high level production of the
      protein with the correctly assembled iron-sulfur cluster. The absorption,
      circular dichroism, resonance Raman, and EPR spectra of the recombinant protein
      revealed many differences from those of other [2Fe-2S] ferredoxins. The redox
      potential of the protein (-347 mV versus normal hydrogen electrode) was also
      determined. Whereas the amino acid sequence of T. vaginalis ferredoxin showed
      greatest homology to the [2Fe-2S] ferredoxins found in bacteria and vertebrate
      mitochondria which function in cytochrome P450 oxidation pathways, the
      spectroscopic properties showed substantial dissimilarity. Differences in the
      biophysical properties and function of T. vaginalis ferredoxin are proposed to
      result from the characteristic amino acid sequence of the parasite protein near
      the cysteine residues that ligate the valence-localized Fe(III) site of the
      reduced cluster.

PMID- 8663035
TI  - Structure and function of the glutamine phosphoribosylpyrophosphate
      amidotransferase glutamine site and communication with the
      phosphoribosylpyrophosphate site.
AB  - Glutamine phosphoribosylpyrophosphate (PRPP) amidotransferase from Escherichia
      coli exhibits a basal PRPP-independent glutaminase activity having a kcat/Km that
      is 0.3% of fully active enzyme. Binding of PRPP activates the enzyme by a
      structural change that lowers the Km for glutamine 100-fold and couples glutamine
      hydrolysis to synthesis of 5-phosphoribosylamine. By analysis of the x-ray
      structure of the glutamine site containing bound 6-diazo-5-oxonorleucine, a
      glutamine affinity analog, and by site-directed mutagenesis we have identified
      residues important for glutamine binding, catalysis, and coupling with PRPP.
      Tyr74 is a key residue in the coupling between the sites for glutamine in the NH2
      terminal domain and PRPP in the COOH-terminal domain. Arg73 and Asp127 have roles
      in glutamine binding. The x-ray structure indicates that there are no amino acid
      side chains sufficiently close to Cys1 to participate as a proton acceptor in
      formation of the thiolate needed for nucleophilic attack on the carboxamide of
      glutamine, nor as a general acid for amide nitrogen transfer. Based on the x-ray
      model of the glutamine site and analysis of a mutant enzyme we propose that the
      free NH2 terminus of Cys1 functions as the proton acceptor and donor. The results
      indicate that the side chain of Asn101 and the backbone nitrogen of Gly102
      function to stabilize a tetrahedral oxyanion resulting from attack of Cys1 on the
      glutamine carboxamide. Cys1, Arg73, Asn101, Gly102, and Asp127 are conserved in
      the NH2-terminal domain of a subfamily of amidotransferases that includes
      asparagine synthetase, glucosamine 6-phosphate synthase, and glutamate synthase,
      implying a common function in the four enzymes. Tyr74, on the other hand, is
      conserved only in glutamine PRPP amidotransferase sequences consistent with a
      specific role in interdomain coupling. The catalytic framework of key glutamine
      site residues supports the assignment of glutamine PRPP amidotransferase to a
      recently described Ntn (NH2-terminal nucleophile) hydrolase family of enzymes.

PMID- 8663036
TI  - Rescue of the catalytic activity of an H42A mutant of horseradish peroxidase by
      exogenous imidazoles.
AB  - His-42 plays a critical role in the H2O2-dependent catalytic turnover of
      horseradish peroxidase (HRP). This is clearly illustrated by the finding that an
      H42A mutation decreases the rate of Compound I formation by a factor of
      approximately10(6). As shown here, the addition of 2-substituted imidazoles
      partially rescues both the rate of formation of Compound I and the peroxidase
      activity of the H42A mutant. 2-Substituted imidazoles are the most effective
      because they do not coordinate to the iron. In contrast to native HRP, which
      exhibits a parabolic pH profile, and the H42A mutant, for which the activity
      increases linearly with increasing pH, the activity of the H42A mutant in the
      presence of 1,2-dimethylimidazole (pKa = 8.0) exhibits a sigmoidal pH dependence
      with a midpoint at pH 8.0 +/- 0.2. Similar results are obtained with 2
      methylimidazole. These results establish that the free base forms of these
      imidazoles facilitate HRP turnover. The spectroscopic binding constants for 1, 2
      dimethylimidazole and 2-methylimidazole are Kd = 2.9 +/- 1.3 and 2. 5 +/- 0.2 M,
      respectively. When cyanide is bound to the heme, the Kd for 1,2-dimethylimidazole
      is 0.17 M. This >10-fold decrease in Kd may reflect hydrogen bonding of the
      protonated imidazole to the iron-coordinated cyanide. The log of the rate of
      Compound I formation exhibits a linear dependence on the molecular volume of the
      imidazoles used to rescue the activity. If the rates are corrected for
      differences in the size of the imidazoles, the log of the rates is linearly
      related to the pKa of the imidazoles. This Bronsted analysis predicts that
      approximately 60% of a positive charge develops on the imidazole in the
      transition state of Compound I formation. The results confirm the acid-base role
      of the distal histidine, demonstrate that exogenous histidines can function as
      surrogates for the missing histidine in the H42A mutant, and provide a transition
      state model of relevance to the formation of Compound I in the native protein.

PMID- 8663037
TI  - Fetal globin expression in New World monkeys.
AB  - Reverse phase chromatography of the globin chains of adult, newborn, and fetal
      erythrocytes from three species of New World monkeys (Cebus apella, Aotus azarae,
      and Callithrix jacchus) representing three of the seven platyrrhine clades showed
      that gamma-globin expression was fetal in these animals. The globins were
      identified by a combination of chemical sequencing and mass spectrometric
      analysis. Since gamma-globin expression is fetal in the other major simian
      branch, the catarrhines, but embryonic in prosimian primates and nonprimate
      placental mammals, the evolution of fetal recruitment can now be assigned to the
      period between the simian-prosimian divergence (55 million years ago) and the
      platyrrhine-catarrhine divergence (35 million years ago). The gamma-globin gene
      underwent tandem duplication during the same evolutionary epoch, in accord with a
      model that suggests that the downstream duplicated gamma-gene (gamma2) was free
      to acquire the mutations necessary for fetal recruitment. Mass spectrometric
      analysis of tryptic digests of the gamma-globins verified the amino acid
      sequences deduced from genomic sequencing. Detailed analysis of high performance
      liquid chromatography and matrix-assisted laser desorption/ionization mass
      spectrometry data showed that gamma2-globin in Cebus was expressed to a far
      greater extent than gamma1-globin, supporting inferences drawn from a study of
      the promoter sequences. A "pre-gamma"-globin was observed in C. apella and shown
      to be primarily the glutathionyl adduct. The other species, A. azarae and C.
      jacchus, also express only one gamma-globin polypeptide. This work provides
      biochemical evidence of an evolutionary trend in the platyrrhines to alter the
      duplicated gamma-globin gene locus so that only one gamma-globin polypeptide is
      expressed.

PMID- 8663038
TI  - Localization of the vinblastine-binding site on beta-tubulin.
AB  - A fluorescent vinblastine derivative, vinblastine-4'-anthranilate, has been shown
      to inhibit polymerization of rat brain tubulin (IC50 = 4.8 microM). Binding of
      the drug to tubulin increases fluorescence intensity, causes a small emission
      blue shift, and has a quantum yield of 0.037. Fluorescence increases as a
      function of drug concentration, with a high affinity site and an undetermined
      number of lower affinity sites. Photolabeling, by exciting the fluorescent drug
      tubulin complex at the absorption maximum of anthranilate, yields a covalent
      adduct confined to beta-tubulin. Its formation is specific in that it is blocked
      by maytansine or vinblastine. Tryptic hydrolysis identifies a single fluorescent
      beta-peptide coinciding with residues 175-213. The interactions between various
      ligands at this central portion of beta-tubulin are discussed.

PMID- 8663039
TI  - HDA1 and HDA3 are components of a yeast histone deacetylase (HDA) complex.
AB  - Histone acetylation is maintained through the action of histone
      acetyltransferases and deacetylases and has been correlated with increased gene
      activity. To investigate the functional role of these enzymes in the regulation
      of transcription, we have purified from Saccharomyces cerevisiae two histone
      deacetylase activities, HDA and HDB, with molecular masses of approximately 350
      and 600 kDa, respectively. In vitro, the HDA activity deacetylates all four core
      histones, has a preference for histone H3, and is strongly inhibited by
      trichostatin A (a specific inhibitor of histone deacetylases). HDB is
      considerably less sensitive to trichostatin A. We report the extensive
      purification of the HDA activity and the identification of peptides (p75, p73,
      p72, and p71) whose presence correlates with deacetylase activity on native
      polyacrylamide gels. An antibody to p75 immunoprecipitates peptides with
      molecular masses similar to those in the 350-kDa complex. Additionally,
      antibodies to p75 and p71 specifically precipitate histone deacetylase activity
      and co-immunoprecipitate each other. Gene disruptions of p75 (HDA1) or p71 (HDA3)
      cause the loss of the 350-kDa (but not the 600-kDa) activity from our
      chromatography profiles. These data argue strongly that HDA1 and HDA3 are
      subunits of the HDA complex, which is structurally distinct from the second, HDB
      complex.

PMID- 8663040
TI  - Metabolic and immunologic consequences of limited adenosine deaminase expression
      in mice.
AB  - Adenosine deaminase (ADA; EC 3.5.4.4) deficiency in humans is an autosomal
      recessive genetic disorder that results in severe combined immunodeficiency
      disease. ADA-deficient mice generated by targeted gene disruption die
      perinatally, preventing postnatal analysis of ADA deficiency. We have recently
      rescued ADA-deficient fetuses from perinatal lethality by expression of an ADA
      minigene in the placentas of ADA-deficient fetuses, thus generating postnatal
      mice admissible to analysis of ADA deficiency. The minigene used also directed
      ADA expression to the forestomach postnatally, producing adult animals that
      lacked ADA enzymatic activity in all tissues outside the gastrointestinal tract.
      Mice with limited ADA expression exhibited profound disturbances in purine
      metabolism, including thymus-specific accumulations of deoxyadenosine and dATP,
      and inhibition of S-adenosylhomocysteine hydrolase in the thymus, spleen, and, to
      a lesser extent, the liver. Lymphopenia and mild immunodeficiency were associated
      with these tissue-specific metabolic disturbances. These mice represent the first
      genetic animal model for ADA deficiency and provide insight into the tissue
      specific requirements of ADA.

PMID- 8663041
TI  - Relationship between N-methyl-D-aspartate receptor NR1 splice variants and NR2
      subunits.
AB  - The N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor is
      assembled from one NR1 subunit, expressed in eight splice variants, and four NR2
      subunits (NR2A-D). The combination of subunits and splice variants determines the
      pharmacological and physiological properties of the receptor. In the present
      study we investigated the relationship between NR1 splice variants and NR2
      subunits in rat brain using a series of antibodies selective for the four NR1
      cassettes, which vary in the NR1 splice variants, and for NR2A and NR2B. Sodium
      deoxycholate at pH 9.0 solubilized about 35% of the receptor, which was intact
      based on co-immunoprecipitation of NR1 and NR2 subunits and chemical cross
      linking of the solubilized receptor. The cross-linked product contained three
      high molecular weight components, Mr = 603,000, 700,000, and 750,000, which were
      immunolabeled with antibodies to NR1 and to NR2 subunits. Immunoprecipitation
      analyses using antibodies selective for NR2A and NR2B showed no preferential
      assembly between NR2 subunits and NR1 splice variants. There was little co
      immunoprecipitation of NR2A and NR2B, suggesting that most NMDA receptor
      complexes contain only one of these subunits. However, receptor complexes can
      contain at least two different NR1 splice variants. In developing conditions for
      the solubilization of intact NMDA receptor complexes, we observed a differential
      solubilization of NR1 and NR2 subunits. NR2 was nearly insoluble in Triton X-100
      in both microsomal and synaptic membrane fractions, while NR1 was readily soluble
      in the microsomal fraction but insoluble in the synaptic membrane fraction. These
      results suggest that the NR1 subunit is modified when it is incorporated into the
      synaptic membrane, possibly by strengthening its interaction with NR2 or another
      synaptic protein.

PMID- 8663042
TI  - Structurally diverse N-terminal peptides of parathyroid hormone (PTH) and PTH
      related peptide (PTHRP) inhibit the Na+/H+ exchanger NHE3 isoform by binding to
      the PTH/PTHRP receptor type I and activating distinct signaling pathways.
AB  - N-terminal peptides of parathyroid hormone (PTH) and PTH-related peptide (PTHRP)
      elicit a wide variety of biological responses in target cells, including the
      inhibition of Na+/H+ exchanger NHE3 activity in renal cells. This response is
      believed to be mediated by ligand binding to a common receptor (i.e. PTH/PTHRP
      receptor type I) and activation of cAMP-dependent and/or Ca2+/phospholipid
      dependent protein kinases (PKA and PKC, respectively). However, the mechanism of
      action of these N-terminal peptides is now unclear because of recent data
      reporting the existence of additional receptor isoforms. Therefore, to directly
      examine the ligand binding and signaling characteristics of the PTH/PTHRP
      receptor type I and its ability to elicit a biological response, cDNAs encoding
      the rat type I receptor and the rat NHE3 isoform were transfected into Chinese
      hamster ovary (AP-1) cells that lack endogenous expression of these proteins.
      Competition binding assays using [125I-Tyr36]PTHRP-(1-36)-NH2 radioligand
      indicated that several biologically active human N-terminal PTH and PTHRP
      fragments (PTH-(1-34), PTH-(3-34), PTH-(28-42), PTH-(28-48), and PTHRP-(1-34))
      were capable of binding to the type I receptor. Both PTH-(1-34) and PTHRP-(1-34)
      stimulated adenylate cyclase and PKC activities in these cells, whereas PTH-(3
      34), PTH-(28-42), and PTH-(28-48) selectively enhanced only PKC activity. PTHRP
      (1-16), a biologically inert fragment, was incapable of binding to this receptor
      and influencing either the PKA or PKC pathway. Furthermore, all the analogues
      with the exception of PTHRP-(1-16) inhibited NHE3 activity. Inhibition of PKC by
      the potent antagonist chelerythrine chloride abolished the depression of NHE3
      activity by PTH-(3-34), PTH-(28-42), and PTH-(28-48) but did not alleviate the
      effects of PTH-(1-34). Likewise, antagonism of PKA by H-89 was unable to prevent
      the inhibition caused by PTH-(1-34). However, inhibition of both PKA and PKC by
      the nonselective protein kinase antagonist H-7 abolished the reduction of NHE3
      activity by PTH-(1-34). These data indicate that discrete N-terminal analogues of
      PTH and PTHRP can interact with the classical PTH/PTHRP receptor type I and
      activate PKA and/or PKC. Activation of either signaling pathway independently
      leads to inhibition of NHE3.

PMID- 8663043
TI  - An analysis of retinoic acid-induced gene expression and metabolism in AB1
      embryonic stem cells.
AB  - Murine embryonic stem cells such as the AB1 cell line undergo differentiation in
      the presence of retinoic acid (RA) into an extraembryonic epithelial cell type.
      This results in the activation of genes such as Hoxa-1, Hoxb-1, laminin, collagen
      IV(alpha1), tissue plasminogen activator, RARbeta, and CRABPII. The CRABPI gene
      is regulated in an unusual fashion; CRABPI message and protein levels are induced
      at low concentrations of RA, but induction is diminished at higher
      concentrations. AB1 cells take up RA rapidly from the medium, and the addition of
      low, exogenous concentrations of RA to the culture medium results in very high
      intracellular RA concentrations. For example, AB1 stem cells cultured in 5 nM
      [3H]RA have an internal [3H]RA concentration of 1-2 microM within the first hour.
      AB1 cells also metabolize [3H]RA to more polar RA derivatives. The half-life of
      RA in AB1 cells not previously exposed to RA is about 2-2.5 h versus 40-45 min in
      cells cultured for 2-3 days in 1 microM exogenous RA. Thus, the enzyme(s) which
      metabolize RA are induced or activated by RA. Furthermore, the local
      concentration of RA required to elicit some biological responses may be higher
      than previously thought.

PMID- 8663044
TI  - Receptor specificity of the fibroblast growth factor family.
AB  - Fibroblast growth factors (FGFs) are essential molecules for mammalian
      development. The nine known FGF ligands and the four signaling FGF receptors (and
      their alternatively spliced variants) are expressed in specific spatial and
      temporal patterns. The activity of this signaling pathway is regulated by ligand
      binding specificity, heparan sulfate proteoglycans, and the differential
      signaling capacity of individual FGF receptors. To determine potentially relevant
      ligand-receptor pairs we have engineered mitogenically responsive cell lines
      expressing the major splice variants of all the known FGF receptors. We have
      assayed the mitogenic activity of the nine known FGF ligands on these cell lines.
      These studies demonstrate that FGF 1 is the only FGF that can activate all FGF
      receptor splice variants. Using FGF 1 as an internal standard we have determined
      the relative activity of all the other members of the FGF family. These data
      should serve as a biochemical foundation for determining developmental,
      physiological, and pathophysiological processes that involve FGF signaling
      pathways.

PMID- 8663045
TI  - Cloning and characterization of an ovarian-specific protein that associates with
      the short form of the prolactin receptor.
AB  - Prolactin (PRL) is essential for progesterone biosynthesis and luteal cell
      hypertrophy of the rat corpus luteum during pregnancy. Both the long and short
      form of the PRL receptor have been identified in the corpus luteum of pregnant
      rat. The long form has been shown to transduce PRL signal in other cells, whereas
      no information is available on the role of the short form, especially in the
      corpus luteum. In the present study, we have cloned a rat ovarian-specific
      phosphoprotein, PRAP (PRL Receptor Associated Protein), which has no significant
      homology to other known proteins. We have demonstrated that this protein is
      immunoprecipitated by anti-PRL receptor and anti-phosphotyrosine antibodies. To
      determine whether PRAP associates with either the long or the short form of the
      PRL receptor, fusion proteins with glutathione S-transferase containing the
      cytoplasmic domain of the long or short form of the PRL receptor were produced,
      purified, and incubated with luteal proteins. Our results indicate that PRAP
      preferentially binds to the short form of the PRL receptor. Thus, the long form
      and short forms of the PRL receptor may signal through distinct pathways. These
      data provide evidence for the involvement of a novel protein in PRL signal
      transduction and suggest that PRAP may contribute to the luteotropic effects of
      PRL on the corpus luteum during pregnancy.

PMID- 8663046
TI  - Regulation of Na+/glucose cotransporter expression by protein kinases in Xenopus
      laevis oocytes.
AB  - Cotransporters are proteins responsible for the accumulation of nutrients,
      neurotransmitters, and drugs in cells. As forskolin has been shown to stimulate
      intestinal Na+/glucose cotransport, we have used electrophysiological techniques
      to examine the role of protein kinases in regulating Na+/glucose cotransporters,
      SGLT1, expressed in Xenopus laevis oocytes. We monitored SGLT1 kinetics, the
      number of SGLT1 cotransporters in the plasma membrane, and plasma membrane area
      before and after activation of protein kinases. 8-Bromoadenosine 3',5'-cyclic
      monophosphate (8-Br-cAMP) and sn-1, 2-dioctanoylglycerol (DOG) were used as
      membrane permeable activators of protein kinases A (PKA) and C (PKC),
      respectively. In oocytes expressing rabbit SGLT1 8-Br-cAMP increased by 28 +/- 4%
      (n = 10), and DOG decreased by 51 +/- 5% (n = 13) the maximum rate of Na+/glucose
      cotransport. These reversible changes in the maximum transport rate occurred
      within minutes, and were accompanied by proportional changes in the number of
      cotransporters in the membrane and area of the plasma membrane. This suggests
      that protein kinases regulate rabbit SGLT1 activity by controlling the
      distribution of transporters between intracellular compartments and the plasma
      membrane, and that this occurs by exo- and endocytosis. Similar increases in
      maximum transport were obtained with activation of PKA in oocytes expressing
      rabbit, human, and rat SGLT1 isoforms, but with activation of PKC the response
      was isoform-dependent. PKC activation decreased the maximum rate of transport by
      rabbit and rat SGLT1, but increased transport by human SGLT1. We conclude that:
      (i) the regulation of SGLT1 expression in oocytes by protein kinases occurs
      mainly by regulated endo- and exocytosis; (ii) it is independent of consensus
      phosphorylation sites in the transporter; and (iii) the effect of a given kinase
      depends upon the actual sequence of the cotransporter expressed. These
      considerations may also apply to the regulation of other cotransporters by
      protein kinases in oocytes, cells, and tissues.

PMID- 8663047
TI  - Physical states of surface and core lipids in lipid emulsions and apolipoprotein
      binding to the emulsion surface.
AB  - Plasma triglyceride-rich lipoproteins vary in lipid composition during their
      metabolism. We investigated the effects of the lipid composition of emulsion
      particles, specifically those of cholesterol enrichment and core replacement
      (replacing core triglyceride with cholesteryl oleate), on the physical states of
      surface and core lipids. Steady-state and time-resolved fluorescence anisotropies
      were measured in lipid emulsions using 1,6-diphenylhexatriene to probe the core
      and 1,6-diphenylhexatriene analogues for the outer and inner hydrophobic portions
      of surface phospholipids. In the absence of cholesterol, core replacement had
      little effect on the surface rigidity, despite the large difference in core
      mobility. However, core replacement caused a marked increase in surface rigidity
      in the presence of cholesterol. Quenching experiments using the fluorescent
      cholesterol analogue, dehydroergosterol, indicated that core replacement allowed
      surface dehydroergosterol to redistribute from the inner to the outer regions in
      the emulsion surface. These results indicated that core replacement modulates the
      surface properties of the emulsion particles through the redistribution of
      cholesterol in the surface layers. Furthermore, core replacement significantly
      decreased the binding of apolipoprotein E to the emulsion surface, whereas the
      binding of apolipoprotein CII responded to the cholesterol enrichment. This
      binding behavior of exchangeable apolipoproteins may closely correlate with the
      location of surface cholesterol and the mobility of core lipids.

PMID- 8663048
TI  - Purification, cloning, and expression of a cytidine 5'-monophosphate N
      acetylneuraminic acid synthetase from Haemophilus ducreyi.
AB  - An N-acetylneuraminic acid cytidylyltransferase (EC 2.7.7.43) (CMP-NeuAc
      synthetase) was isolated from a Haemophilus ducreyi strain 35000 cell lysate and
      partially characterized. The enzyme catalyzes the reaction of CTP and NeuAc to
      form CMP-NeuAc, which is the nucleotide sugar donor used by sialyltransferases.
      Previous studies have shown that the outer membrane lipooligosaccharides of H.
      ducreyi contain terminal sialic acid attached to N-acetyllactosamine and that
      this modification is likely important to its pathogenesis. Therefore, to
      investigate the role of sialic acid in H. ducreyi pathogenesis, the gene encoding
      the CMP-NeuAc synthetase was cloned using degenerate oligonucleotide probes
      derived from NH2-terminal sequence data, and the nucleotide sequence was
      determined. The derived amino acid sequence of the CMP-NeuAc synthetase gene has
      homology to other CMP-NeuAc synthetases and to a lesser extent to CMP-2-keto-3
      deoxy-D-manno-octulosonic acid synthetases. The gene was cloned into a T7
      expression vector, the protein expressed in Escherichia coli, and purified to
      apparent homogeneity by anion exchange, Green 19 dye, and hydrophobic interaction
      chromatography. The final step yielded 20 mg of pure protein/liter of culture.
      The protein has a predicted molecular mass of 25440.6 Da, which was confirmed by
      electrospray mass spectrometry (Mexpt = 25439.9 +/- 1.4 Da). The enzyme appears
      to exist as a dimer by size exclusion chromatography. In contrast to other
      bacterial CMP-NeuAc synthetases, the H. ducreyi enzyme exhibited a different
      substrate specificity, being capable of also using N-glycolylneuraminic acid as a
      substrate.

PMID- 8663049
TI  - A retinaldehyde dehydrogenase as a structural protein in a mammalian eye lens.
      Gene recruitment of eta-crystallin.
AB  - eta-Crystallin is a taxon-specific crystallin, a major component of the eye lens
      in elephant shrews (Macroscelidea). Sequence analysis of eta-crystallin from two
      genera of elephant shrews and expression of recombinant eta-crystallin show that
      the protein is a cytoplasmic (class 1) aldehyde dehydrogenase (ALDH1, EC 1.2.1.3)
      with activity for the oxidation of retinaldehyde to retinoic acid. Unlike many
      other mammals, elephant shrews have two ALDH1 genes. One encodes ALDH1/eta
      crystallin which, in addition to its very high expression in lens, is also the
      predominant form of ALDH1 expressed in other parts of the eye. The second gene
      encodes a "non-lens" ALDH1 (ALDH1-nl) which is the predominant form expressed in
      liver. This pattern of tissue preference contrasts with other mammals which make
      use of the same major ALDH1 transcript in both ocular and non-ocular tissues.
      Thus the gene recruitment of ALDH1/eta-crystallin as a structural protein in
      elephant shrew lenses is associated with its collateral recruitment as the major
      form of ALDH1 expressed in other parts of the eye.

PMID- 8663050
TI  - Purification and partial characterization of a lutein-binding protein from the
      midgut of the silkworm Bombyx mori.
AB  - A lutein-binding protein was purified from fifth instar larval midgut of Bombyx
      mori by a combination of ammonium sulfate fractionation and three chromatographic
      procedures, gel filtration, chromatofocusing, and anion exchange chromatography.
      The protein has a pI of 5.4 and an apparent molecular mass of 35,000 Da, as
      determined by a linear gradient SDS-polyacrylamide gel electrophoresis. The
      lutein-protein complex is water-soluble and more stable than the carotenoid or
      protein alone. The carotenoid moiety was identified by thin layer chromatography,
      light absorption spectroscopy, and high performance liquid chromatography as all
      trans-lutein. Lutein is specifically and stoichiometrically bound to the protein,
      with a ratio of 3 mol of lutein per mol of protein. Binding of lutein (absorption
      maximum in hexane at 454 nm) to the apoprotein results in a marked red spectral
      shift of about 38 nm, giving rise to absorption maxima at 432, 462, and 492 nm in
      20 mM Tris-HCl, pH 7.0. The lutein-protein complex is characterized by fine
      spectral structure indicating that lutein is in a relatively rigid environment.
      This protein is distributed in equal amounts throughout the midgut and in all
      developmental stages of the larval B. mori.

PMID- 8663051
TI  - Self-activation of recombinant human lysosomal procathepsin D at a newly
      engineered cleavage junction, "short" pseudocathepsin D.
AB  - To obtain a recombinant model of human cathepsin D with kinetic properties that
      are identical with native human liver enzyme, we have addressed the significant
      differences in structure and catalytic function between naturally occurring
      enzyme and bacterially derived pseudocathepsin D. Human procathepsin D was
      expressed in a baculovirus system to obtain correctly folded, glycosylated enzyme
      that upon acidification completely converts to the active intermediate,
      pseudocathepsin D. The oligosaccharide moieties of this recombinant enzyme
      contributed to about 5% of the apparent molecular mass of the enzyme, and the
      carbohydrate composition was quite similar to the native material. However,
      specificity constants (kcat/Km) of this glycosylated pseudoform for several
      synthetic chromogenic substrates were considerably less (33%-50%) than those for
      the native enzyme and were virtually identical with those observed with
      nonglycosylated pseudocathepsin D. A cleavable junction suitable for self
      processing at the normal maturation point of human cathepsin D was engineered
      into procathepsin D according to known specificity requirements of this enzyme,
      and the construct was expressed using baculovirus. Following experiments that
      demonstrated that the new proenzyme failed to process to the expected point, the
      new cleavage junction was moved 6 residues toward the amino terminus of
      procathepsin D and expressed in Escherichia coli. After refolding, the protein
      containing the newly engineered junction self-processed, generating a shortened
      mutant form of pseudocathepsin D that is 6 residues longer at the amino terminus
      than the native material. The kinetic properties of this newly engineered
      pseudoform proved to be identical with those of the native enzyme, thus
      establishing an improved recombinant model for this important aspartic
      proteinase.

PMID- 8663052
TI  - Proposed ligand binding site of the transmembrane receptor for neurotensin(8-13).
AB  - We report here the first proposed ligand binding site of the transmembrane
      receptor for neurotensin(8-13) in human and rat, the corresponding bound
      conformation of the peptide ligand, and site-directed mutagenesis studies that
      support the binding site model. These three-dimensional structures were generated
      by using a heuristic approach in conjunction with experimental data. The proposed
      neurotensin(8-13) binding site is primarily composed of eight residues (i.e.,
      Phe326, Ile329, Trp334, Phe337, Tyr339, Phe341, Tyr342, and Tyr344 in the human
      receptor; Phe331, Ile334, Trp339, Phe342, Phe344, Phe346, Tyr347, and Tyr349 in
      the rat receptor) located in the third extracellular loop. The seven aromatic
      residues form an aromatic pocket on the extracellular surface of the neurotensin
      receptor to accommodate its ligands apparently by cation-pi, pi-pi, and hydrogen
      bonding interactions. The neurotensin(8-13) ligand adopts a compact conformation
      at the proposed binding site. In the bound conformation of neurotensin(8-13), the
      backbone of Arg9-Pro10-Tyr11-Ile12 forms the proline type I turn, and the hydroxy
      group of Tyr11 interacts with the two guanidinium groups of Arg8 and Arg9. These
      guanidinium groups are curled toward the hydroxy group so that they interact
      electrostatically with the hydroxy group, and that the guanidinium group of Arg9
      forms an intra-hydrogen bond with the hydroxy group. The proposed three
      dimensional structure may not only provide a basis for rationalizing mutations of
      the neurotensin receptor gene but also offer insights into understanding the
      binding of many neurotensin analogs, biological functions of the neurotensin
      receptors, and structural elements for species specificity of the neurotensin
      receptors, and may expedite developing nonpeptidic neurotensin mimetics for the
      potential treatment of the neuropsychiatric diseases.

PMID- 8663053
TI  - The AT2 receptor selectively associates with Gialpha2 and Gialpha3 in the rat
      fetus.
AB  - The effects of angiotensin II are mediated by a family of seven transmembrane
      receptors. In the adult, the majority of the receptors are of the AT1 isoform,
      which is coupled to heterotrimeric G proteins (either Gqalpha or Gialpha). In
      contrast, the AT2 receptor is expressed at low levels in the adult but is the
      major form expressed in the fetal and neonatal animal. Previous results have
      failed to show G protein coupling of the AT2 receptor in the fetus. We now
      provide evidence that the AT2 receptor is G protein-coupled. An antibody that
      binds several Galpha subunits immunoselected angiotensin II receptor-Galpha
      complexes. In addition, Gialpha1-3 antibody, which recognizes Gialpha1, Gialpha2
      and Gialpha3, also co-immunoselect the AT2 receptor. Anti-Gialpha2 and anti
      Gialpha3 antibodies were both able to co-immunoselected AT2 receptor-Gialpha
      complexes, but consistent with the lack of Gialpha1 in the fetal extracts, anti
      Gialpha1 antibodies did not nor did any other G protein-directed antisera. The
      finding that AT2 receptor couples to both Gialpha2 and Gialpha3 raises the
      possibility that selective interactions between AT2 receptor and different G
      proteins may result in specific cellular effects mediated by AT2 stimulation.

PMID- 8663054
TI  - Matrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell
      proliferation and differentiation.
AB  - A biologic role for the 72-kDa gelatinase A (matrix metalloproteinase 2; MMP-2),
      beyond simple extracellular matrix turnover, was evaluated in glomerular
      mesangial cells. To determine the significance of MMP-2 secretion for the
      acquisition of the inflammatory phenotype, we reduced the constitutive secretion
      of MMP-2 by cultured mesangial cells with antisense RNA expressed by an
      episomally replicating vector or with specific anti-MMP-2 ribozymes expressed by
      a retroviral transducing vector. The phenotype of the transfected, or
      retrovirally infected, cells was profoundly altered from the activated state and
      closely approximated that of quiescent cells in vivo. The prominent differences
      included a change in the synthesis and organization of the extracellular matrix,
      loss of activation markers, and a virtually total exit from the cell cycle.
      Reconstitution with exogenous active, but not latent MMP-2, induced a rapid
      return to the inflammatory phenotype in vitro. This effect was specific to MMP-2,
      because the closely related MMP-9 did not reproduce these changes. Furthermore,
      this pro-inflammatory effect of MMP-2 is dependent upon the active form of the
      enzyme, which can be produced by an autocatalytic activation process on the
      mesangial cell plasma membrane. It is concluded that MMP-2 acts directly upon
      mesangial cells to permit the development of an inflammatory phenotype. Specific
      inhibition of MMP-2 activity in vivo may represent an alternate means of
      ameliorating complex inflammatory processes by affecting the phenotype of the
      synthesizing cells, per se.

PMID- 8663055
TI  - Studies on the synthesis of the Fe-S cluster of dihydroxy-acid dehydratase in
      escherichia coli crude extract. Isolation of O-acetylserine sulfhydrylases A and
      B and beta-cystathionase based on their ability to mobilize sulfur from cysteine
      and to participate in Fe-S cluster synthesis.
AB  - The apoprotein of Escherichia coli dihydroxy-acid dehydratase, which contains a
      catalytically essential [4Fe-4S] cluster in its active form, has been used as a
      substrate to investigate Fe-S cluster synthesis. The inactive apoprotein could be
      reactivated in vitro by factors present in the crude extract of E. coli and to a
      much smaller extent in the presence of Fe3+, S2-, and dithiothreitol. This
      reactivation occurs as a result of Fe-S cluster synthesis. It is anticipated that
      the Fe-S cluster synthesis observed in crude extracts in vitro may involve some
      of the components that participate in Fe-S cluster synthesis in vivo. The origin
      of the sulfur used to form Fe-S clusters was investigated. Four enzymatic
      activities in the crude extract of E. coli were found that can provide sulfur for
      Fe-S cluster synthesis in vitro by mobilizing the sulfur from cysteine. The
      purification of the proteins responsible for three of these activities is
      reported in this paper. The three proteins have been identified as O-acetylserine
      sulfhydrylase A, O-acetylserine sulfhydrylase B, and beta-cystathionase. The rate
      and extent of sulfide mobilization from cysteine in the reaction catalyzed by O
      acetylserine sulfhydrylases A and B depend on the presence of nucleophiles that
      can add to the aminoacrylate formed on the enzyme following the removal of
      sulfide from cysteine. A new amino acid is formed when the nucleophiles add to
      the aminoacrylate. Sulfur mobilization by beta-cystathionase does not require a
      nucleophile, and the reaction is a minor variation on the cleavage of beta
      cystathionine, with pyruvate, ammonia, and sulfide being the products. Once
      sulfur is mobilized by these enzymes, its efficient use in Fe-S cluster synthesis
      seems to be affected by the presence of yet unidentified factors present in crude
      extract. In crude extract and partially purified preparations from E. coli where
      these factors are present, the rapidity with which Fe-S clusters are formed and
      the efficiency with which sulfur is used imply an orderly controlled formation of
      Fe-S clusters that is generally typified by enzymatic reactions.

PMID- 8663056
TI  - Escherichia coli contains a protein that is homologous in function and N-terminal
      sequence to the protein encoded by the nifS gene of Azotobacter vinelandii and
      that can participate in the synthesis of the Fe-S cluster of dihydroxy-acid
      dehydratase.
AB  - In this paper, I report the purification of a protein from Escherichia coli that
      is very similar in sequence, molecular weight, and the reactions it can catalyze
      to the protein encoded by the Azotobacter vinelandii nifS gene. This E. coli
      protein contains pyridoxal phosphate as a cofactor and catalyzes the removal of
      sulfur from cysteine to form alanine and S0. When dithiothreitol is present along
      with cysteine, the S0 formed is reduced to S2-. This protein has a reactive
      sulfhydryl group that is essential for activity. As isolated, this sulfhydryl
      group appears to be in a disulfide linkage with the sulfhydryl group from the
      phosphopantetheine moiety of the acyl carrier protein. The purified E. coli
      protein can mobilize the sulfur from cysteine and contribute it to the formation
      of a [4Fe-4S] cluster on the apoprotein of E. coli dihydroxy-acid dehydratase. A
      mechanism is proposed for the early stages of the synthesis of Fe-S clusters
      using this protein and sulfur in the S0 oxidation state.

PMID- 8663058
TI  - Hormonal regulation of the human pepsinogen C gene in breast cancer cells.
      Identification of a cis-acting element mediating its induction by androgens,
      glucocorticoids, and progesterone.
AB  - Pepsinogen C is an aspartic proteinase mainly involved in the digestion of
      proteins in the stomach, which is also synthesized by certain human breast
      tumors. To examine the possibility that extragastric production of this
      proteolytic enzyme could be mediated by hormonal factors, we have analyzed
      pepsinogen C gene expression in human breast cancer cells subjected to different
      hormonal treatments. Northern blot analyses revealed the expression of pepsinogen
      C gene by T-47D breast cancer cells after induction with dihydrotestosterone,
      dexamethasone, and progesterone but not with estradiol, retinoic acid, or
      ethanol. Reverse transcription-polymerase chain reaction analysis in a series of
      breast cancer cell lines confirmed the amplification of pepsinogen C mRNA after
      induction with dihydrotestosterone, in those cells expressing the androgen
      receptor mRNA. The promoter region of the pepsinogen C gene was functionally
      characterized by transient expression of a vector containing the promoter region
      cloned in front of the chloramphenicol acetyltransferase (CAT) reporter gene. CAT
      activity in T-47D cells was stimulated in the presence of dihydrotestosterone,
      dexamethasone, and progesterone but not by estradiol. By further deletion mapping
      of the pepsinogen C promoter, a minimal region (AGAACTattTGTTCC) was identified
      as being responsible for glucocorticoid-, androgen-, and progesterone-regulated
      gene expression.

PMID- 8663057
TI  - Direct or C5a-induced activation of heterotrimeric Gi2 proteins in human
      neutrophils is associated with interaction between formyl peptide receptors and
      the cytoskeleton.
AB  - The binding of ligands to N-formyl peptide chemoattractant receptors in human
      neutrophils results in a rapid association of these receptors with a cytoskeletal
      fraction and a specific activation and release of Gi2 alpha-subunits from this
      fraction. In the present study we could show that pretreating neutrophils with
      GDPbetaS prevented the fMet-Leu-Phe-induced association of its receptor with a
      cytoskeletal fraction and also blocked the release of Gi2 alpha-subunits from the
      same cytoskeletal fraction. In contrast, direct activation of Gi2 proteins by
      addition of GTPgammaS or AlF4- not only caused a release of Gi2 alpha-subunits
      from the cytoskeleton but also an association of formyl peptide receptors with
      the cytoskeleton. The receptor for complement fragment 5a, which transduces its
      signaling through the same Gi2 protein, triggers both a release of Gi2 alpha
      subunits from the cytoskeleton fraction and, of even greater interest, an
      association between formyl peptide receptors and the cytoskeleton. The close
      relationship between the activation and release of Gi2 alpha-subunits from the
      cytoskeleton and the association of formyl peptide receptors with the
      cytoskeleton might, however, not be a matter of protein-protein exchange, since
      the increased binding of formyl peptide receptors to the cytoskeleton occurs more
      rapidly than the release of Gi2 alpha-subunits from the cytoskeleton. The present
      findings suggest a possible mechanism for the initiation of formyl peptide
      receptor desensitization during neutrophil locomotion.

PMID- 8663059
TI  - Isolation and characterization of the 102-kilodalton RNA-binding protein that
      binds to the 5' and 3' translational enhancers of tobacco mosaic virus RNA.
AB  - Tobacco mosaic virus (TMV) is a positive-sense, single-stranded RNA virus the
      genome of which acts as a mRNA in the cytoplasm. On infection, TMV mRNA is
      efficiently and selectively translated by the host translation machinery despite
      the lack of a poly(A) tail, which is normally required for efficient translation.
      Both the 68-base 5' leader (Omega) and the 205-base 3' untranslated region of TMV
      promote efficient translation. A 25-base poly(CAA) region within Omega and the
      upstream pseudoknot domain, a 72-base region composed of three RNA pseudoknots,
      are responsible for the translational regulation. We have identified, purified,
      and characterized a 102-kDa RNA-binding protein (p102) from wheat that binds
      specifically to the poly(CAA) region within Omega and the upstream pseudoknot
      domain within the TMV 3' untranslated region. Polyclonal antibodies raised
      against wheat p102 were used to demonstrate that p102 is widely conserved in
      plant species. Moreover, specific RNA binding activity was detected in all plant
      species tested. Addition of anti-p102 antibodies to an in vitro translation
      lysate derived from wheat germ repressed translation, which was subsequently
      reversed by supplementing the lysate with p102. These findings suggest that this
      protein may play an important role in determining translational efficiency in
      plants.

PMID- 8663060
TI  - Tissue-specific activity of the gammac chain gene promoter depends upon an Ets
      binding site and is regulated by GA-binding protein.
AB  - The gammac chain is a subunit of multiple cytokine receptors (interleukin (IL)-2,
      IL-4, IL-7, IL-9, and IL-15), the expression of which is restricted to
      hematopoietic lineages. A defect in gammac leads to the X-linked severe combined
      immunodeficiency characterized by a block in T cell differentiation. In order to
      better characterize the human gammac promoter and define the minimal tissue
      specific promoter region, progressive 5'-deletion constructs of a segment
      extending 1053 base pairs upstream of the major transcription start site were
      generated and tested for promoter activity in various hematopoietic and
      nonhematopoietic cell types. The -1053/+34 construct allowed promoter activity
      only in cells of hematopoietic origin, and tissue specificity was conserved in
      all other constructs tested. The region downstream of -90 appeared critical for
      basal promoter activity. It contains two potential Ets binding sites conserved in
      the murine gammac promoter gene, one of which was found essential for functional
      promoter activity as determined by mutational analysis. The functional Ets
      binding site was found to bind Ets family proteins, principally GA-binding
      protein and Elf-1 and could be transactivated by GABPalpha and -beta
      synergistically. These results indicate that, as already reported for the
      IL2Rbeta promoter, GA-binding protein is an essential component of gammac basal
      promoter activity. Although GABP expression is not restricted to the
      hematopoietic lineage, its interaction with other specific factors may contribute
      to the tissue-specific expression of the gammac gene.

PMID- 8663061
TI  - Expression of matrix metalloproteinase gelatinases A and B by cultured epithelial
      cells from human bronchial explants.
AB  - To investigate the role of human bronchial epithelial cells (HBECs) in the
      maintenance and remodeling of the extracellular matrix, we evaluated the
      expression by HBECs of 72- and 92-kDa gelatinases under basal conditions and
      after exposure to bacterial lipopolysaccharides (LPS). Confluent HBECs from
      explants were cultured in plastic dishes coated with type I and III collagens.
      Gelatin zymography of HBEC-conditioned media showed constitutive major 92-kDa and
      minor 72-kDa gelatinases recognized by specific human antibodies and totally
      inhibited by the metalloproteinase inhibitor EDTA. The identification of the two
      matrix metalloproteinases was confirmed by quantitative reverse transcription
      polymerase chain reaction. Identical patterns of gelatinase expression were
      observed with repetitive primary cultures issued from the same explants.
      Zymography showed that exposure of HBECs to LPS induced 2- and 20-fold increases
      in 92-kDa gelatinase production and activation, respectively, as well as a
      smaller increase in activated 68-kDa gelatinase. With [3H]gelatin substrate,
      elevated metallogelatinolytic activity (138 microgram of hydrolyzed gelatin/48
      h/10(6) cells) was also observed, whereas no activity was detected in the absence
      of LPS. A human epithelial cell line (16HBE14o-) exhibited the same basal profile
      of gelatinase activity, but this profile remained unchanged after exposure to
      LPS. Quantitative reverse transcription-polymerase chain reaction demonstrated
      only minimal changes in 92-kDa mRNA levels in response to LPS, but the half-life
      of 92-kDa gelatinase mRNA was increased with exposure to LPS. In contrast,
      concomitant slight increases in 72-kDa gelatinase protein and mRNA were found,
      suggesting that the control mechanisms regulating the expression of 92- and 72
      kDa gelatinases by HBECs in response to LPS are divergent. All these data allowed
      us to propose that HBECs may be actively involved in the physiological and
      physiopathological remodeling of the airway basement membrane.

PMID- 8663062
TI  - Ligand-independent cell surface expression of the human soluble granulocyte
      macrophage colony-stimulating factor receptor alpha subunit depends on co
      expression of the membrane-associated receptor beta subunit.
AB  - The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM
      CSF) mediates its activity through binding to cell surface receptors. The
      receptor for GM-CSF belongs to a superfamily of cytokine receptors characterized
      by a conserved extracellular motif. The high affinity GM-CSF receptor (GMR)
      consists of two transmembrane anchored subunits; a ligand binding alpha subunit
      (transmembrane GMRalpha) and a signal transducing beta subunit (GMRbeta), both of
      which belong to the cytokine receptor superfamily. The human GM-CSF receptor
      alpha subunit also exists in a soluble form (solGMRalpha), which antagonizes GM
      CSF activity in vitro. We directly tested the potential for solGMRalpha to
      interact with GMRbeta in vitro. Our experiments demonstrated that exogenous
      solGMRalpha, even in the presence of GM-CSF, does not interact with GMRbeta on
      the cell surface. However, when solGMRalpha and GMRbeta are co-expressed in baby
      hamster kidney cells, solGMRalpha is retained on the cell surface and forms a
      functional intermediate affinity GM-CSF binding complex (Kd = 331 pM). In
      addition, the cell surface expression of solGMRalpha is independent of the
      presence of GM-CSF as demonstrated using flow cytometry. Cells expressing only
      solGMRalpha do not show cell surface retention or form functional GM-CSF cell
      surface binding complexes. Sequencing of our GMRbeta clone revealed a nucleotide
      substitution (A --> C) resulting in the substitution of Ala for Glu at position 9
      from the amino terminus of the mature GMRbeta peptide. Because the GMRbeta (A -->
      C) clone is capable of forming functional high affinity receptors with
      transmembrane GMRalpha (Kd = 64 pM), we feel that the cell surface retention of
      solGMRalpha is independent of the GMRbeta mutation. We suggest that the co
      expression and interaction of solGMRalpha and GMRbeta represents a previously
      unrecognized GM-CSF receptor complex and a novel, ligand-independent mechanism of
      cytokine receptor assembly.

PMID- 8663063
TI  - Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is
      required for the proliferative but not the antiinflammatory effects of the
      cytokine.
AB  - Interleukin-10 (IL-10) is a powerful suppressor of the proinflammatory monokine
      production by lipopolysaccharide-stimulated monocytes as well as a T- and B-cell
      growth cofactor. The signal transduction cascades initiated by IL-10 ligation to
      its cognate receptor remain to be elucidated. Here, we demonstrate that in both
      primary monocytes and the D36 cell line, IL-10 rapidly and transiently stimulated
      phosphatidylinositol 3-kinase activity associated with the p85 subunit of the
      enzyme. IL-10 also activated p70 S6 kinase in both cell types. The activation of
      both of these kinases was sensitive to wortmannin, an inhibitor of
      phosphatidylinositol 3-kinase. The activation of p70 S6 kinase was also inhibited
      by the immunosuppressive drug rapamycin. Both rapamycin and wortmannin inhibited
      the IL-10-induced proliferation of D36 cells but in contrast had no effect on the
      antiinflammatory effects of the cytokine on lipopolysaccharide-stimulated
      monocytes. Similar results on D36 proliferation and lipopolysaccharide-stimulated
      monocyte inhibition by IL-10 were obtained with another phosphatidylinositol 3
      kinase inhibitor, LY294002. This suggests that the activation of
      phosphatidylinositol 3-kinase and p70 S6 kinase is involved in the proliferative
      functions of IL-10 and that other as yet uncharacterized pathways affect the
      suppressive effects on monocytes, indicating that multiple and distinct signaling
      pathways mediate the various pleiotropic activities of IL-10. Furthermore, these
      findings suggest that it may be possible in the future to modulate the
      antiinflammatory effects of IL-10 for therapeutic benefit without disrupting
      other functions of the cytokine.

PMID- 8663064
TI  - The dimerization property of glutathione S-transferase partially reactivates Bcr
      Abl lacking the oligomerization domain.
AB  - Bcr-Abl oncoproteins are responsible for the pathogenesis of human leukemias with
      a reciprocal chromosome translocation t(9;22). The amino-terminal Bcr sequence
      has a potential to form a homotetramer (tetramer domain), and destructions of the
      tetramer domain cause a complete loss of biological activities in Bcr-Abl. Here
      we show that Bcr-Abl in which the tetramer domain is replaced with glutathione S
      transferase (GST) with a dimerizing ability (GST/Bcr-Abl-(Delta1-160)) can no
      longer induce an interleukin-3 (IL-3) independence in Ba/F3 cells or transform
      mouse bone marrow cells but still retains by 30-40% the ability to transform Rat1
      cells. Compared with the wild type Bcr-Abl, autophosphorylation of GST/Bcr-Abl
      (Delta1-160) in vivo was reduced by more than 50%. The Grb-2 binding to GST/Bcr
      Abl-(Delta1-160) was 50% reduced in Rat1 cells and undetectable in Ba/F3 cells.
      In Rat1 cells expressing GST/Bcr-Abl-(Delta1-160), phosphotyrosine contents of
      p62 and Shc were 70% decreased.

PMID- 8663065
TI  - A single point mutation in CTP synthetase of Chlamydia trachomatis confers
      resistance to cyclopentenyl cytosine.
AB  - A Chlamydia trachomatis strain (L2/CPEC) resistant to the cytotoxic effects of
      cyclopentenyl cytosine (CPEC) was isolated by a stepwise selection procedure.
      This strain showed an approximate 350-fold increase in resistance to CPEC.
      Sequencing of the gene encoding CTP synthetase from this resistant strain
      revealed a single point mutation, resulting in a change of amino acid 149 from
      Asp to Glu. This appeared to be the only mutation in L2/CPEC, because no changes
      in CTP transport, CTP synthetase expression, or incorporation of CPEC into DNA or
      RNA could be detected. The mutation in the chlamydial CTP synthetase resulted in
      a loss of CTP feedback inhibition. This was demonstrated both in vivo using
      Escherichia coli cells carrying the cloned gene, and an in vitro assay using
      partially purified preparations of CTP synthetase. As a result of the loss of
      feedback inhibition, E. coli cells carrying the CPECR CTP synthetase showed a 22
      fold increase in their CTP pools. However, examination of the CTP pools of
      L2/CPEC revealed no change in CTP levels when compared with wild type C.
      trachomatis.

PMID- 8663066
TI  - FcgammaRII-mediated adhesion and phagocytosis induce L-plastin phosphorylation in
      human neutrophils.
AB  - L-Plastin is a calcium-regulated actin bundling protein expressed in leukocytes
      and some transformed cells, which is phosphorylated on serine in response to
      several different leukocyte-activating stimuli. Adhesion to immune complexes
      induced L-plastin phosphorylation in neutrophils, as did phagocytosis of IgG
      opsonized particles, but insoluble immune complexes in suspension were very
      inefficient activators of L-plastin phosphorylation. Neutrophils express two IgG
      Fc receptors, the transmembrane FcgammaRII and the glycan phosphoinositol-linked
      FcgammaRIIIB. Use of monoclonal antibodies that distinguished the two Fc
      receptors demonstrated that FcgammaRII ligation was 100-fold more potent at
      signaling L-plastin phosphorylation than occupancy of FcgammaRIIIB. Depletion of
      intracellular calcium did not affect FcgammaRII-activated L-plastin
      phosphorylation, demonstrating that any potential regulation of plastin function
      by calcium did not affect its phosphorylation. Adhesion to immune complexes
      caused L-plastin to localize to podosomes, since it colocalized with actin to
      discrete, punctate Triton X-100-insoluble sites on the adherent neutrophil
      surface in a pattern indistinguishable from vinculin and alpha-actinin.
      Nonetheless, localization to podosomes was not required for L-plastin
      phosphorylation, since both neutrophils from a patient with leukocyte adhesion
      deficiency (CD18 deficiency) and neutrophils treated with anti-CD18 F(ab')2,
      which do not form podosomes upon adhesion to immune complexes, phosphorylated L
      plastin normally. Indeed, L-plastin was normally phosphorylated in response to
      adhesion to immune complexes even when the actin cytoskeleton was disrupted with
      cytochalasin D. We conclude that efficient FcgammaRII-mediated phosphorylation of
      L-plastin requires cell adhesion but does not require IgG-induced rearrangements
      of the actin cytoskeleton. These data suggest a model in which plastin
      phosphorylation and localization to the actin cytoskeleton can act as two
      distinct mechanisms regulating L-plastin functions in neutrophils adherent to
      immune complexes.

PMID- 8663067
TI  - Regulation of hexokinase II gene expression by glucose flux in skeletal muscle.
AB  - The in vivo studies of transcriptional regulation by glucose, in general, have
      yielded ambiguous interpretations due to the closed loop relationship between
      insulin and glucose. Insulin cannot be held as a constant since elevated glucose
      levels will elicit a corresponding rise in insulin and current animal models of
      insulinopenia are associated with a plethora of counter-regulatory hormone
      responses. One potential solution to increase intracellular glucose flux without
      a further increase in insulin was achieved by transgenic overexpression of the
      insulin-sensitive glucose transporter, GLUT4, in specific skeletal muscles
      (previously described in Tsao, T.-S., Burcelin, R., Katz, E. B., Huang, L., and
      Charron, M. J. (1996) Diabetes 45, 28-36). Using these MLC-GLUT4 transgenic mice
      as a model, we investigated the effects of increased glucose flux on hexokinase
      II (HK II) gene expression in skeletal muscle. Under conditions where blood
      glucose levels were normal and insulin levels decreased by 36%, HK II mRNA level
      was reduced in non-GLUT4-overexpressing tissues (i.e. heart and adipose tissue)
      of 2-4-month-old male MLC-GLUT4 transgenic mice. This reduction in HK II mRNA was
      prevented in skeletal muscle, where overexpression of GLUT4 caused a 2.5-fold
      increase in basal and insulin-stimulated glucose uptake. The levels of HK II mRNA
      in heart, muscle, and adipose tissue are paralleled by HK II enzymatic activity.
      IN CONCLUSION: 1) due to relative mild insulinopenia, HK II expression is
      decreased in non-GLUT4-overexpressing tissues of MLC-GLUT4 mice compared to
      age/sex-matched controls, and 2) GLUT4-mediated increase in cellular glucose flux
      can prevent the decrease in HK II expression (in GLUT4-overexpressing tissues) as
      a result of relative mild insulinopenia. Indeed, during the process of aging, the
      return of circulating insulin levels of MLC-GLUT4 mice to normal levels is
      associated with the normalization of HK II expression in all tissues of MLC-GLUT4
      and age/sex-matched control mice. We propose that: 1) glucose flux has an
      amplifying effect on the ability of insulin to stimulate skeletal muscle HK II
      gene expression and 2) insulin-dependent glucose flux may be a potential
      mechanism by which HK II gene expression is regulated by sensitivity to insulin.

PMID- 8663068
TI  - Selection of linkers for a catalytic single-chain antibody using phage display
      technology.
AB  - Phage display has been evaluated as a means of rapidly selecting tailored linkers
      for single-chain antibodies (scFvs) from protein linker libraries. Preliminary
      experiments with a conventional linker failed to yield a functional single-chain
      version of a catalytic antibody with chorismate mutase activity. A random linker
      library was therefore constructed in which the genes for the heavy and light
      chain variable domains were linked by a segment encoding an 18-amino acid
      polypeptide of variable composition. The scFv repertoire ( approximately 5 x
      10(6) different members) was displayed on filamentous phage and subjected to
      affinity selection with hapten. The population of selected variants exhibited
      significant increases in binding activity but retained considerable sequence
      diversity. Screening 1054 individual variants subsequently yielded a
      catalytically active scFv that was produced efficiently in soluble form. Sequence
      analysis revealed a conserved proline in the linker two residues after the VH C
      terminus and an abundance of arginines and prolines at other positions as the
      only common features of the selected tethers. There are apparently many viable
      solutions to the problem of linking individual VH and VL domains, but subtle
      differences in sequence dramatically influence the production, stability, and
      recognition properties of the scFv. The success of these experiments suggests
      that phage display will be generally useful for identifying peptide sequences for
      covalently linking any two protein domains.

PMID- 8663069
TI  - P2U agonists induce chemotaxis and actin polymerization in human neutrophils and
      differentiated HL60 cells.
AB  - Human neutrophils or HL60 cells express P2U receptors and respond to micromolar
      concentrations of ATP, adenosine 5'-O-(thiotriphosphate) (ATPgammaS), or UTP with
      immediate increases in intracellular Ca2+ through activation of phosphoinositide
      phospholipase C (Cowen, D. S., Lazarus, H. M., Shurin, S. B., Stoll, S. E., and
      Dubyak, G. R. (1989) J. Clin. Invest. 83, 1651-1660). P2U agonists reportedly
      induce limited enzyme secretion and enhance the respiratory burst in response to
      chemotactic factors. We demonstrate here that P2U agonists are chemotactic for
      neutrophils or differentiated HL60 cells. Rhodamine phalloidin staining indicates
      that ATPgammaS treatment induces actin polymerization and shape changes similar
      to those seen when these cells are treated with chemotactic peptide fMet-Leu-Phe.
      Although undifferentiated HL60 cells fail to mount a rise in Ca2+ when challenged
      with fMet-Leu-Phe, they increase Ca2+ in response to P2U agonists. However,
      functional expression of phospholipase C-coupled receptors is not sufficient for
      chemotaxis since HL60 cell migration in response to these agonists or to fMet-Leu
      Phe occurs only after exposure to differentiating agents such as BT2cAMP. In
      addition to the well known G protein-linked receptors for lipid or peptide
      chemotactic factors, neutrophils apparently also can utilize G protein-linked
      purino/pyrimidino receptors to recognize nucleotides as chemoattractants. High
      concentrations of ATP and UTP generated at sites of platelet aggregation and
      tissue injury could thus be important mediators of inflammation.

PMID- 8663070
TI  - The significance of valine 33 as a ligand-specific epitope of transforming growth
      factor alpha.
AB  - Although binding of epidermal growth factor (EGF) and transforming growth factor
      alpha (TGFalpha) to the EGF receptor (EGFR) is mutually competitive, their
      binding is not identical, and their biological activities are not always
      equivalent. To probe for ligand-specific interactions, we have synthesized
      analogues of TGFalpha with modifications to the residue lying between the fourth
      and fifth cysteines (the "hinge"). Although this residue lies in a structurally
      conserved region of the protein, it is not conserved within the EGFR ligand
      family. Our results show that in TGFalpha there is a preference for a bulky
      hydrophobic hinge residue; this contrasts with EGF, for which a hydrogen bond
      donor functionality is preferred. Sequence analysis of the human EGFR ligands
      revealed that the nature of the hinge residue correlated with the sequence in the
      B-loop beta-sheet. As this region is an important determinant in recognition of
      TGFalpha by the chicken EGFR, we assessed the mitogenicity of the TGFalpha hinge
      mutants, as well as the other EGFR ligands, using chicken embryo fibroblasts. The
      preference of the chicken EGFR for TGFalpha hinge mutants with hydrophobic side
      chains paralleled that of the human EGFR. Betacellulin and heparin-binding EGF
      like growth factor also possess an hydrophobic hinge; both were at least as
      potent as TGFalpha for chicken embryo fibroblasts. EGF and amphiregulin, both
      with hydrogen bond donor functionalities at their hinge, displayed markedly
      decreased in potency by comparison with TGFalpha. We propose that EGFR ligands
      can be subclassified into TGFalpha-like and EGF-like and that this is of
      functional significance, identifying a potential mechanism whereby EGFR can
      discriminate between its ligands.

PMID- 8663071
TI  - betaII protein kinase C is required for the G2/M phase transition of cell cycle.
AB  - Entry into mitosis requires the coordinated action of multiple mitotic protein
      kinases. In this report, we investigate the involvement of protein kinase C in
      the control of mitosis in human cells. Treatment of synchronized HL60 cells with
      the highly selective protein kinase C (PKC) inhibitor chelerythrine chloride
      leads to profound cell cycle arrest in G2 phase. The cellular effects of
      chelerythrine are not due to either direct or indirect inhibition of the known
      mitotic regulator p34(cdc2)/cyclin B kinase. Rather, several lines of evidence
      demonstrate that chelerythrine-mediated G2 phase arrest results from selective
      inhibition and degradation of betaII protein kinase C. First, chelerythrine
      causes dose-dependent inhibition of betaII PKC in vitro with an IC50 identical to
      that for G2 phase blockade in whole cells. Second, chelerythrine specifically
      inhibits betaII PKC-mediated lamin B phosphorylation and mitotic nuclear lamina
      disassembly. Third, chelerythrine leads to selective loss of betaII PKC during G2
      phase in synchronized cells. Fourth, chelerythrine mediates activation-dependent
      degradation of PKC, indicating that betaII PKC is selectively activated during G2
      phase of cell cycle. Taken together, these data demonstrate that betaII PKC
      activation at G2 phase is required for mitotic nuclear lamina disassembly and
      entry into mitosis and that betaII PKC-mediated phosphorylation of nuclear lamin
      B is important in these events.

PMID- 8663072
TI  - Structural flexibility modulates the activity of human glutathione transferase P1
      1. Role of helix 2 flexibility in the catalytic mechanism.
AB  - Presteady-state and steady-state kinetic studies performed on human glutathione
      transferase P1-1 (EC 2.5.1.18) with 1-chloro-2, 4-dinitrobenzene as co-substrate
      indicate that the rate-determining step is a physical event that occurs after
      binding of the two substrates and before the final sigma-complex formation. It
      may be a structural transition involving the ternary complex. This event can be
      related to diffusion-controlled motions of protein portions as kcat degrees /kcat
      linearly increases by raising the relative viscosity of the solution. Similar
      viscosity dependence has been observed for Km GSH, while Km CDNB is independent.
      No change of the enzyme structure by viscosogen has been found by circular
      dichroism analysis. Thus, kcat and Km GSH seem to be related to the frequency and
      extent of enzyme structural motions modulated by viscosity. Interestingly, the
      reactivity of Cys-47 which can act as a probe for the flexibility of helix 2 is
      also modulated by viscosity. Its viscosity dependence parallels that observed for
      kcat and Km GSH, thereby suggesting a possible correlation between kcat, Km GSH,
      and diffusion-controlled motion of helix 2. The viscosity effect on the kinetic
      parameters of C47S and C47S/C101S mutants confirms the involvement of helix 2
      motions in the modulation of Km GSH, whereas a similar role on kcat cannot be
      ascertained unequivocally. The flexibility of helix 2 modulates also the
      homotropic behavior of GSH in these mutants. Furthermore, fluorescence
      experiments support a structural motion of about 4 A occurring between helix 2
      and helix 4 when GSH binds to the G-site.

PMID- 8663073
TI  - Structural flexibility modulates the activity of human glutathione transferase P1
      1. Influence of a poor co-substrate on dynamics and kinetics of human glutathione
      transferase.
AB  - Presteady-state and steady-state kinetics of human glutathione transferase P1-1
      (EC 2.5.1.18) have been studied at pH 5.0 by using 7-chloro-4-nitrobenzo-2-oxa
      1,3-diazole, a poor co-substrate for this isoenzyme. Steady-state kinetics fits
      well with the simplest rapid equilibrium random sequential bi-bi mechanism and
      reveals a strong intrasubunit synergistic modulation between the GSH-binding site
      (G-site) and the hydrophobic binding site for the co-substrate (H-site); the
      affinity of the G-site for GSH increases about 30 times at saturating co
      substrate and vice versa. Presteady-state experiments and thermodynamic data
      indicate that the rate-limiting step is a physical event and, probably, a
      structural transition of the ternary complex. Similar to that observed with 1
      chloro-2, 4-dinitrobenzene (Ricci, G., Caccuri, A. M., Lo Bello, M., Rosato, N. ,
      Mei, G., Nicotra, M., Chiessi, E., Mazzetti, A. P., and Federici, G.(1996) J.
      Biol. Chem. 271, 16187-16192), this event may be related to the frequency of
      enzyme motions. The observed low, viscosity-independent kcat value suggests that
      these motions are slow and diffusion-independent for an increased internal
      viscosity. In fact, molecular modeling suggests that the hydroxyl group of Tyr
      108, which resides in helix 4, may be in hydrogen bonding distance of the oxygen
      atom of this new substrate, thus yielding a less flexible H-site. This effect
      might be transmitted to the G-site via helix 4. In addition, a new homotropic
      behavior exhibited by 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole is found in Cys-47
      mutants revealing a structural intersubunit communication between the two H
      sites.

PMID- 8663075
TI  - Denitrification, a novel type of respiratory metabolism in fungal mitochondrion.
AB  - Subcellular localization and coupling to ATP synthesis were investigated with
      respect to the denitrifying systems of two fungi, Fusarium oxysporum and
      Cylindrocarpon tonkinense. Dissimilatory nitrate reductase of F. oxysporum or
      nitrite reductase of C. tonkinense could be detected in the mitochondrial
      fraction prepared from denitrifying cells of each fungus. Fluorescence
      immunolocalization, cofractionation with mitochondrial marker enzymes, and
      cytochromes provided evidence that the denitrifying enzymes are co-purified with
      mitochondria. Respiratory substrates such as malate plus pyruvate, succinate, and
      formate were effective donors of electrons to these activities in the
      mitochondrial fractions. Moreover, nitrite and nitrate reduction were shown to be
      coupled to the synthesis of ATP with energy yields (P:NO3- or P:2e ratios) of
      0.88 to 1.4, depending upon whether malate/pyruvate or succinate were provided as
      substrates. Nitrate or nitrite reductase activity was inhibited by inhibitors
      such as rotenone, antimycin A, and thenoyltrifluoroacetone. Thus, fungal
      denitrification activities are localized to mitochondria and are coupled to the
      synthesis of ATP. The existence of these novel respiration systems are discussed
      with regard to the origin and evolution of mitochondria.

PMID- 8663074
TI  - A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and
      MKK3.
AB  - A cDNA encoding a novel member of the mitogen-activated protein kinase kinase
      (MAPKK) family, MAPKK6, was isolated and found to encode a protein of 334 amino
      acids, with a calculated molecular mass of 37 kDa that is 79% identical to MKK3.
      MAPKK6 was shown to phosphorylate and specifically activate the p38/MPK2 subgroup
      of the mitogen-activated protein kinase superfamily and could be demonstrated to
      be phosphorylated and activated in vitro by TAK1, a recently identified MAPKK
      kinase. MKK3 was also shown to be a good substrate for TAK1 in vitro.
      Furthermore, when co-expressed with TAK1 in cells in culture, both MAPKK6 and
      MKK3 were strongly activated. In addition, co-expression of TAK1 and p38/MPK2 in
      cells resulted in activation of p38/MPK2. These results indicate the existence of
      a novel kinase cascade consisting of TAK1, MAPKK6/MKK3, and p38/MPK2.

PMID- 8663076
TI  - Purification of a novel calcium-independent phospholipase A2 from rabbit kidney.
AB  - We have recently identified a cytosolic calcium-independent phospholipase A2
      (PLA2) that represents the major measurable PLA2 activity in rabbit proximal
      tubules (Portilla, D., Shah, S. V., Lehman, P. A., and Creer, M. H.(1994) J.
      Clin. Invest. 93, 1609-1615). We now report the 3200-fold purification of this
      PLA2 to homogeneity from rabbit kidney cortex through sequential column
      chromatography including anion exchange, hydrophobic interaction, Mono Q,
      hydroxylapatite, phenyl-Sepharose, and chromatofocusing fast protein liquid
      chromatography from rabbit kidney cortex. The purified enzyme had a molecular
      mass of 28 kDa, possessed a specific activity of 1.2 micronol/mg min and a
      neutral pH optimum, and exhibited a preferential hydrolysis toward sn-2 fatty
      acid from diradylglycerophospholipids. The purified polypeptide hydrolyzed
      plasmenylcholine > phosphatidylcholine glycerophospholipids and selectively
      cleaved phospholipids containing arachidonic acid at the sn-2 position in
      comparison to oleic acid. Antibodies against the purified protein precipitated
      all of the soluble calcium-independent PLA2 activity from rabbit kidney cortex.
      These data altogether suggest that the 28-kDa protein in the kidney represents a
      novel class of calcium-independent PLA2.

PMID- 8663077
TI  - Regulation of human involucrin promoter activity by POU domain proteins.
AB  - POU domain transcription factors are expressed in the epidermis and are thought
      to be important regulators of keratinocyte gene expression. In the present
      article we demonstrate that POU transcription factors suppress transcription of
      the human involucrin (hINV) promoter. Cotransfection of pINV-2473, a construct
      containing 2473 base pairs of hINV upstream sequence linked to luciferase, with
      POU homeodomain transcription factors Oct1, Oct2, Brn4, SCIP, Skn1a or Skn1i,
      results in a strong suppression of basal promoter activity. The hINV upstream
      region includes a consensus POU transcription factor binding site, 5'-ATGCAAAT
      3', centered around nucleotide -1277. Although this site interacts with POU
      factors, assays of promoter activity for a series of progressive 5' end
      truncations demonstrate that this site is not required for POU factor-dependent
      transcriptional suppression. Suppression is observed with the shortest truncation
      construct tested, pINV-41, suggesting that this inhibition may be mediated by
      effects on TATA box proteins. SCIP mutants that lack transactivation or DNA
      binding domains were shown to suppress transcription, suggesting that the DNA
      binding and transactivation domains are not required for suppression. Moreover,
      cotransfection of the pINV-2473 with pKSM13(+)OCT, which contains a single
      consensus OCT binding site, results in an increase in basal promoter activity,
      suggesting that endogenous POU factors suppress hINV promoter activity. In
      addition to inhibiting basal transcription, POU transcription factors also
      suppress phorbol ester-stimulated hINV promoter activity. These studies suggest
      that suppression of hINV promoter activity does not require the amino-terminal
      segment of the POU factor or direct POU factor interaction with DNA and suggest
      that the suppression may be via indirect interaction with other proteins in the
      vicinity of the TATA box. Thus, involucrin joins the ranks of a small set of
      genes that are regulated by POU factors in an octamer binding site-independent
      manner.

PMID- 8663078
TI  - Glucose metabolism to glucosamine is necessary for glucose stimulation of
      transforming growth factor-alpha gene transcription.
AB  - Transforming growth factor-alpha (TGFalpha) gene transcription can be increased
      when arterial smooth muscle cells are exposed to supraphysiological
      concentrations of glucose, and this effect of glucose can be mimicked by
      glucosamine. To determine whether the metabolism of glucose to glucosamine is
      required for this glucose effect, the rate-limiting step in glucose metabolism to
      glucosamine through the enzyme glutamine:fructose-6-phosphate amidotransferase
      (GFAT) was blocked using pharmacological and antisense strategies. We found that
      blockage of GFAT activity or expression significantly blunted the glucose-induced
      increase of TGFalpha expression. Blockage of GFAT also resulted in a decreased
      RL2 signal on intracellular proteins as detected by Western blotting and indirect
      immunofluorescence. The RL2 monoclonal antibody recognizes an epitope on proteins
      that contain N-acetylglucosamine and thus is a measure of protein glycosylation.
      Conversely, treatment of the cells with glucose and glucosamine resulted in an
      increase in the RL2 epitope on intracellular proteins. These results indicate
      that the metabolism of glucose to glucosamine is necessary for the
      transcriptional stimulation of TGFalpha expression in vascular smooth muscle
      cells by glucose. Furthermore, the level of glycosylation of some intracellular
      proteins can be modulated in response to physiological changes in the
      extracellular glucose concentration and the net activity of GFAT.

PMID- 8663079
TI  - Purified, reconstituted cardiac Ca2+-ATPase is regulated by phospholamban but not
      by direct phosphorylation with Ca2+/calmodulin-dependent protein kinase.
AB  - Regulation of calcium transport by sarcoplasmic reticulum provides increased
      cardiac contractility in response to beta-adrenergic stimulation. This is due to
      phosphorylation of phospholamban by cAMP-dependent protein kinase or by
      calcium/calmodulin-dependent protein kinase, which activates the calcium pump
      (Ca2+-ATPase). Recently, direct phosphorylation of Ca2+-ATPase by
      calcium/calmodulin-dependent protein kinase has been proposed to provide
      additional regulation. To investigate these effects in detail, we have purified
      Ca2+-ATPase from cardiac sarcoplasmic reticulum using affinity chromatography and
      reconstituted it with purified, recombinant phospholamban. The resulting
      proteoliposomes had high rates of calcium transport, which was tightly coupled to
      ATP hydrolysis (approximately 1.7 calcium ions transported per ATP molecule
      hydrolyzed). Co-reconstitution with phospholamban suppressed both calcium uptake
      and ATPase activities by approximately 50%, and this suppression was fully
      relieved by a phospholamban monoclonal antibody or by phosphorylation either with
      cAMP-dependent protein kinase or with calcium/calmodulin-dependent protein
      kinase. These effects were consistent with a change in the apparent calcium
      affinity of Ca2+-ATPase and not with a change in Vmax. Neither the purified,
      reconstituted cardiac Ca2+-ATPase nor the Ca2+-ATPase in longitudinal cardiac
      sarcoplasmic reticulum vesicles was a substrate for calcium/calmodulin-dependent
      protein kinase, and accordingly, we found no effect of calcium/calmodulin
      dependent protein kinase phosphorylation on Vmax for calcium transport.

PMID- 8663080
TI  - Removal of hydrogen peroxide by thiol-specific antioxidant enzyme (TSA) is
      involved with its antioxidant properties. TSA possesses thiol peroxidase
      activity.
AB  - The thiol-specific antioxidant protein (TSA) protects glutamine synthetase from
      inactivation by a metal-catalyzed oxidation (MCO) system comprised of
      dithiothreitol (DTT)/Fe3+/O2 but not by the ascorbate/Fe3+/O2 MCO system. The
      removal of sulfur-centered radicals or H2O2 has been proposed as the protective
      mechanism of TSA. Like catalase, TSA prevents the initiation of the rapid O2
      uptake phase during MCO of DTT but causes only partial inhibition when added
      after the reaction is well into the propagation phase. Stoichiometric studies
      showed that the antioxidant property of TSA is, at least in part, due to its
      ability to catalyze the destruction of H2O2 by the overall reaction 2 RSH + H2O2 
      -> RSSR + H2O. Results of kinetic studies demonstrate that the removal of H2O2 by
      TSA correlates with its ability to protect glutamine synthetase from
      inactivation. In the presence of thioredoxin, TSA is more active, whereas C170S
      (an active mutant of TSA in which cysteine 170 was replaced by a serine) and open
      reading frame 6 (a human antioxidant protein homologous to TSA with only one
      conserved cysteine residue) are only slightly affected. The thiol specificity of
      the protective activity of TSA derives from the fact that the oxidized form of
      TSA can be converted back to its sulfhydryl form by treatment with thiols but not
      by ascorbate.

PMID- 8663081
TI  - Auto-regulation of retinoic acid biosynthesis through regulation of retinol
      esterification in human keratinocytes.
AB  - In this report, we describe an auto-regulatory loop in human keratinocytes,
      whereby all-trans retinoic acid (retinoic acid) regulates its own biosynthesis
      from all-trans retinol (retinol) through regulation of retinol esterification.
      Retinol esterification activity was low in normal proliferating human
      keratinocytes, cultured in retinoid-free media. Treatment of keratinocytes with
      retinoic acid induced retinol esterifying activity (8-fold). Induction of retinol
      esterifying activity was blocked by either actinomycin D or cycloheximide. Based
      on substrate specificity and inhibitor sensitivity, lecithin:retinol
      acyltransferase (LRAT) was identified as the retinoic acid-inducible retinol
      esterifying enzyme. Induction of LRAT by retinoic acid reduced conversion of
      retinol to retinoic acid by 50%. This reduction in retinoic acid synthesis
      resulted from sequestration of retinol as retinyl esters, since inhibition of
      LRAT restored retinoic acid synthesis to control levels. In normal human skin,
      undifferentiated keratinocytes, in the lowest cell layer, esterified retinol 4
      times greater, than differentiating keratinocytes, in upper cell layers,
      reflecting an induced state, under conditions of retinol sufficiency. Regulation
      of LRAT activity by retinoic acid provides a novel mechanism through which
      retinoic acid can regulate its own level by controlling availability of retinol
      for conversion to retinoic acid. In human skin in vivo, retinyl esters
      synthesized in basal keratinocytes could undergo hydrolysis during
      differentiation and thus serve as a source of retinol for keratinocytes in upper
      layers of skin.

PMID- 8663082
TI  - In vitro bypass replication of the cisplatin-d(GpG) lesion by calf thymus DNA
      polymerase beta and human immunodeficiency virus type I reverse transcriptase is
      highly mutagenic.
AB  - Eukaryotic DNA polymerase beta and the reverse transcriptases are the most
      inaccurate of the known DNA polymerases. We report here mutagenic replication in
      vitro past intrastrand N(7)G-N(7)G chelates of the cis
      diamminedichloroplatinum(II), the major DNA adduct of the antitumor agent
      cisplatin by calf thymus DNA polymerase beta and human immunodeficiency virus
      type I reverse transcriptase (42% and 26% mutations, respectively). The most
      frequent modifications generated by both enzymes were one-base frameshift
      deletions. Only one mutational hot spot opposite the platinated guanines was
      observed with human immunodeficiency virus type I reverse transcriptase, while
      two hot spots were generated by DNA polymerase beta, one at the base situated 5'
      to the lesion and the other situated 4-6 nucleotides 5' to the adduct. An unusual
      mutagenic event, tandem replication of a 12-base pair sequence, was observed with
      DNA polymerase beta. The mutational spectra of the two DNA polymerases suggest
      that template slippage occurred with higher frequency in the presence of the more
      distributive DNA polymerase beta.

PMID- 8663083
TI  - Dephosphorylation of Sp1 by protein phosphatase 1 is involved in the glucose
      mediated activation of the acetyl-CoA carboxylase gene.
AB  - When mouse 30A5 preadipocytes are exposed to high glucose concentrations, acetyl
      CoA carboxylase is induced through glucose activation of promoter II of the
      acetyl-CoA carboxylase gene. Glucose treatment of the cells increases Sp1 binding
      to two GC-rich glucose response elements in promoter II. We have investigated the
      mechanism by which glucose increases Sp1 binding and transactivation of promoter
      II in 30A5 cells. DNA mobility shift assays have shown that nuclear extracts from
      glucose-treated cells exhibit increased Sp1 binding activity. This increase in
      the binding activity is not due to glucose-mediated changes in the amount of Sp1
      in the nucleus but to an increase in the activity that modifies Sp1 so that it
      binds more effectively to the promoter sequence. This Sp1 modifying activity is
      inhibited by okadaic acid and phosphatase inhibitor 2, and has a molecular mass
      of 38-42 kDa. The catalytic subunit of type 1 protein phosphatase, whose
      molecular mass is 38 kDa, also increased the ability of Sp1 to bind to promoter
      II. Treatment of nuclear extract with antibodies against the catalytic subunit
      partially suppressed the nuclear activity for Sp1 activation. From these results,
      we conclude that the Sp1 transcription factor exhibits enhanced binding to
      promoter II and transcriptional activation is the result of glucose-induced
      dephosphorylation by type 1 phosphatase.

PMID- 8663084
TI  - Characterization of the denaturation and renaturation of human plasma
      vitronectin. I. Biophysical characterization of protein unfolding and
      multimerization.
AB  - Upon treatment with denaturing agents, vitronectin has been observed to exhibit
      conformational alterations which are similar to the structural changes detected
      when vitronectin binds the thrombin-antithrombin complex or associates with the
      terminal attack complex of complement. Denaturation and renaturation of
      vitronectin isolated from human plasma were characterized by changes in intrinsic
      fluorescence. Unfolding by chemical denaturants was irreversible and accompanied
      by self-association of the protein to form vitronectin multimers. Self
      association was evaluated by equilibrium analytical ultracentrifugation which
      demonstrated that multimers form only during the refolding process after removal
      of denaturant, that multimeric vitronectin dissociates to constituent subunits
      readily upon treatment with chemical denaturant, and that intermolecular
      disulfide cross-linking occurs primarily at the dimer level among a subset of
      constituent vitronectin subunits within the multimer. The monomeric form of
      vitronectin isolated from human plasma partially unfolds at intermediate
      concentrations of denaturant to an altered conformation with a high propensity to
      associate into multimers. Folding of vitronectin in vivo appears to be regulated
      by partitioning of folding intermediates toward either of two conformations, one
      that exists as a stable monomer and another that associates into a multimeric
      form.

PMID- 8663085
TI  - Characterization of the denaturation and renaturation of human plasma
      vitronectin. II. Investigation into the mechanism of formation of multimers.
AB  - Unfolding and refolding of plasma vitronectin appear irreversible under near
      physiological conditions, with rearrangements of disulfides and self-association
      to a multimeric form observed as prominent structural alterations which accompany
      denaturation. A mechanism for the folding reactions of vitronectin has been
      proposed (Zhuang, P., Blackburn, M. N., and Peterson, C. B.(1996) J. Biol. Chem.
      270, 14323-14332) in which vitronectin acquires a partially folded intermediate
      structure which is highly prone to oligomerize into a multimeric form. Strongly
      oxidizing conditions adopted for refolding from urea were effective at preventing
      disulfide rearrangement which disrupts distal disulfides near the C terminus of
      the protein. Prohibiting disulfide rearrangement under these conditions, however,
      was not sufficient to achieve reversibility in folding. In contrast, variations
      in the ionic strength of the refolding medium affect the partitioning of species
      so that refolded monomers are obtained at high ionic strength, and self
      association is precluded. The effects of ionic strength on the partially folded
      intermediate in the vitronectin folding pathway appear to favor intramolecular
      hydrophobic collapse to form a stable hydrophobic core for the monomer versus
      intermolecular hydrophobic interactions which stabilize multimeric vitronectin.
      Although both ionic and hydrophobic interactions presumably contribute to subunit
      interfaces within the multimer, the basic heparin-binding region near the C
      terminus of the protein does not provide binding interactions which are important
      for self-association of vitronectin.

PMID- 8663086
TI  - Asn102 of the gonadotropin-releasing hormone receptor is a critical determinant
      of potency for agonists containing C-terminal glycinamide.
AB  - We demonstrate a critical role for Asn102 of the human gonadotropin-releasing
      hormone (GnRH) receptor in the binding of GnRH. Mutation of Asn102, located at
      the top of the second transmembrane helix, to Ala resulted in a 225-fold loss of
      potency for GnRH. Eight GnRH analogs, all containing glycinamide C termini like
      GnRH, showed similar losses of potency between 95- and 750-fold for the
      [Ala102]GnRHR, compared with wild-type receptor. In contrast, four GnRH analogs
      that had ethylamide in place of the C-terminal glycinamide residue, showed much
      smaller decreases in potency between 2.4- and 11-fold. In comparisons of three
      agonist pairs, differing only at the C terminus, glycinamide derivatives showed
      an 11-20-fold greater loss of potency for the mutant receptor than their
      respective ethylamide derivatives. Thus Asn102 is a critical determinant of
      potency specifically for ligands with C-terminal glycinamide, while ligands with
      C-terminal ethylamide are less dependent on Asn102. These findings indicate a
      role for Asn102 in the docking of the glycinamide C terminus and are consistent
      with hydrogen bonding of the Asn102 side chain with the C-terminal amide moiety.
      Taken with previous data, they suggest a region of the GnRH receptor formed by
      the top of helices 2 and 7 as a binding pocket for the C-terminal part of the
      ligand.

PMID- 8663087
TI  - Endothelial cells synthesize and process apolipoprotein B.
AB  - We reported previously that a 116-kDa lipoprotein lipase (LPL)-binding protein
      from endothelial cells has sequence homology to the amino-terminal region of
      apolipoprotein (apo) B. We now tested whether endothelial cells synthesize apoB
      mRNA and protein. Primers were designed to the human apoB cDNA sequence and
      reverse transcription polymerase chain reaction was performed using total RNA
      isolated from bovine and human endothelial cells. With primers to the 5' region
      of the apoB mRNA (amino-terminal region of apoB protein) expected size PCR
      products were generated from both bovine and human endothelial cells as well as
      from mouse liver RNA, which was used as a control. Primers designed to the 3'
      region of apoB mRNA generated PCR products from human endothelial cells and HepG2
      cells but not from bovine or mouse cells. These data suggest that endothelial
      cells contain full-length apoB mRNA and that the 5' or the amino-terminal region
      of apoB is highly conserved from mouse to human. This was confirmed by direct
      sequencing of the mouse and bovine PCR products. To test whether apoB protein was
      produced, bovine endothelial cell proteins were metabolically labeled with
      [35S]methionine/cysteine or [3H]leucine and immunoprecipitated with anti-human
      apoB antibodies. Using extracts from cells labeled for 1 h, monoclonal antibody
      47, directed to the low density lipoprotein receptor binding region of apoB,
      precipitated a protein of approximate molecular mass 550,000, the size of full
      length apoB. Immunoprecipitation of the 550-kDa protein was abolished in the
      presence of added unlabeled low density lipoprotein. From cells labeled for 16 h,
      a 116-kDa protein was immunoprecipitated by polyclonal anti-apoB antibodies. This
      protein was partly released from cells by heparin treatment. Pulse-chase analysis
      showed that the 116-kDa fragment appeared at the same time as the full-length
      apoB began disappearing. The immunoprecipitated 116-kDa fragment also bound
      labeled LPL on ligand blot, further suggesting that it is an amino-terminal
      fragment of apoB. Incubation of endothelial cells with oleic acid (0.25 and 0.5
      mM) did not significantly alter the production of either the full-length apoB or
      the 116-kDa fragment. These data show that endothelial cells synthesize apoB. The
      full-length apoB appears to be cleaved to form a 116-kDa fragment that can
      function as a LPL-binding protein.

PMID- 8663088
TI  - Specificity of DnaK for arginine/lysine and effect of DnaJ on the amino acid
      specificity of DnaK.
AB  - Molecular chaperones form a class of proteins that bind selectively to nascent,
      unfolded, misfolded, or aggregated polypeptides and are involved in protein
      folding, protein targeting to membranes, and protein renaturation after stress.
      Chaperones70, including the DnaK chaperone of Escherichia coli, interact
      specifically with peptides enriched in internal hydrophobic residues, with a
      preference for positively charged peptides. We previously reported that DnaK
      interacts with the hydrophobic amino acids Ile, Leu, Val, Ala, Phe, Trp, and Tyr.
      In the present study, we show that DnaK also possesses a specific binding site
      for the positively charged amino acids arginine and lysine. Furthermore, the
      binding of arginine and lysine to DnaK is strengthened when its hydrophobic
      binding sites are occupied. The specificity of DnaK for Arg/Lys is supported by
      DnaK-peptide binding studies; the homopolypeptides poly-Arg and poly-Lys interact
      with DnaK, contrasting with other hydrophilic homopolypeptides, and hydrophobic
      peptides interact more strongly with DnaK if they contain Arg/Lys at their N
      terminus. Interestingly, the cochaperone DnaJ attenuates the interaction of DnaK
      with hydrophobic amino acids while strengthening its interaction with arginine or
      lysine. The interaction of DnaK with both hydrophobic sequences and with arginine
      and lysine, and its modulation by DnaJ, may have important implications in both
      protein folding and protein insertion into membranes.

PMID- 8663089
TI  - Identification of the spectrin subunit and domains required for formation of
      spectrin/adducin/actin complexes.
AB  - Adducin is an actin-binding protein that has been proposed to function as a
      regulated assembly factor for the spectrin/actin network. This study has
      addressed the question of the subunit and domains of spectrin required for
      formation of spectrin/adducin/actin complexes in in vitro assays. Quantitative
      evidence is presented that the beta-spectrin N-terminal domain plus the first two
      alpha-helical domains are required for optimal participation of spectrin in
      spectrin/adducin/actin complexes. The alpha subunit exhibited no detectable
      activity either alone or following association with beta-spectrin. The critical
      domains of beta-spectrin involved in complex formation were determined using
      recombinant proteins expressed in bacteria. The N-terminal domain (residues 1
      313) of beta-spectrin associated with F-actin with a Kd of 26 microM, and
      promoted adducin binding to F-actin with half-maximal activation at 110 nM.
      Addition of the first alpha-helical domain (residues 1-422) lowered the Kdfor F
      actin by 4-fold to 6 microM, but also reduced the capacity by 3-fold and had no
      effect on interaction with adducin. Further addition of the second alpha-helical
      domain (residues 1-528) did not alter binding to F-actin but resulted in a 2-fold
      increased activity in promoting adducin binding with half-maximal activation at
      50 nM. Addition of up to eight additional alpha-helical domains (residues 1-1388)
      resulted in no further change in F-actin binding or association with adducin.
      These results demonstrate an unanticipated role of the first repeat of beta
      spectrin in actin binding activity and of the second repeat in association with
      adducin/actin, and imply the possibility of an extended contact between adducin,
      spectrin, and actin involving several actin subunits.

PMID- 8663090
TI  - Characterization of the transcription unit of mouse Kv1.4, a voltage-gated
      potassium channel gene.
AB  - The mouse voltage-gated K+ channel gene, Kv1.4, is expressed in brain and heart
      as approximately 4.5- and approximately 3.5-kilobase (kb) transcripts. Both mRNAs
      begin at a common site 1338 bp upstream of the initiation codon, contain 3477 and
      4411 nucleotides, respectively, and are encoded by two exons; exon 1 contains 0.5
      kb of the 5'-noncoding region (NCR), while exon 2 encodes the remaining 0.8 kb of
      the 5'-NCR, the entire coding region (2 kb), and all of the 3'-NCR. The 3.5-kb
      transcript terminates at a polyadenylation signal 177 bp 3' of the stop codon,
      while the 4.5-kb mRNA utilizes a signal 94 bp farther downstream. Although the
      proteins generated from either transcript are identical, the two mRNAs are
      functionally different, the 3.5-kb transcript producing approximately 4-5-fold
      larger currents when expressed in Xenopus oocytes compared to the 4. 5-kb mRNA.
      The decreased expression of the longer transcript is due to the presence of five
      ATTTA repeats in the 3'-NCR which inhibit translation; such motifs have also been
      reported to destabilize the messages of many other genes and might therefore
      shorten the life of the 4.5-kb transcript during its natural expression. The
      Kv1.4 basal promoter is GC-rich, contains three SP1 repeats (CCGCCC, -65 to -35),
      lacks canonical TATAAA and GGCAATCT motifs, and has no apparent tissue
      specificity. One region enhances activity of this promoter. Thus, transcriptional
      and post-transcriptional regulation of mKv1.4, coupled with selective usage of
      the two alternate Kv1.4 mRNAs, may modulate the levels of functional Kv1.4
      channels.

PMID- 8663091
TI  - A mass isotopomer study of urea and glutamine synthesis from 15N-labeled ammonia
      in the perfused rat liver.
AB  - This study examines the incorporation of 15N from 15NH4Cl into urea and
      glutamine, predicts the pattern of isotopomers produced as a function of the 15N
      enrichment of the relevant precursor pools, and presents a means of determining
      the isotopic enrichment of these pools. Rat livers were perfused, in the
      nonrecirculating mode, with 0.3 mM 15NH4Cl, and the isotopomers of urea and of
      glutamine produced were determined by gas chromatography-mass spectrometry
      methodology. Three different nitrogen mass isotopomers of urea were found,
      containing no, one, or two atoms of 15N. Four glutamine isotopomers were found,
      containing no 15N, one atom of 15N in either the amino or amide position, or two
      15N atoms. A mathematical relationship was deduced that predicts that the
      relative proportions of the urea isotopomers depends not only on the relative
      enrichment of 15N in the two precursor pools of urea nitrogen (mitochondrial
      ammonia and cytoplasmic aspartate) but on their absolute enrichment. This
      relationship was validated in experiments in which the isotopic enrichment of the
      substrate, 15NH4Cl, was varied. The proportions of the urea isotopomers produced
      can be predicted if one knows the 15N enrichment in the two precursor pools. We
      found that when the 15N enrichment of citrulline and aspartate in the perfusate
      were used as proxies for that in the mitochondrial ammonia and cytoplasmic
      aspartate pools we could accurately predict the relative proportion of the three
      isotopomers. The production of the four nitrogen isotopomers of glutamine could
      be used to determine the 15N enrichment in the two precursor pools of glutamine
      nitrogen, the cytoplasmic ammonia and glutamate pools of the perivenous
      hepatocytes.

PMID- 8663093
TI  - Additions and Corrections to Cloning of a novel phosphoprotein regulated by
      colony-stimulating factor 1 shares a domain with the Drosophila disabled gene
      product.

PMID- 8663094
TI  - Additions and Corrections to Structure and function of a novel voltage-gated,
      tetrodotoxin-resistant sodium channel specific to sensory neurons.

PMID- 8663092
TI  - Mechanical effects of neurofilament cross-bridges. Modulation by phosphorylation,
      lipids, and interactions with F-actin.
AB  - The structure of gels formed by bovine spinal cord neurofilaments was determined
      by fluorescence and electron microscopy and compared to mechanical properties
      measured by their elastic and viscous response to shear forces. Neurofilaments
      formed gels of high elastic modulus (>100 Pa) after addition of millimolar Mg2+.
      Gelation caused a slow increase in shear moduli to levels similar to those of
      vimentin intermediate filament networks, followed by a rapid rise due to
      formation of links between neurofilaments, mediated by cross-bridging structures
      that vimentin filaments lack. Neurofilament gels are more resistant to large
      deformations than are vimentin networks, suggesting the importance of cross
      bridges for neurofilament mechanical properties. Fluorescence imaging of single
      neurofilaments showed flexible filaments that became straighter when they adhered
      to glass or were incorporated into filament bundles. Electron microscopy of
      neurofilament gels showed a system of bundles intertwined within a more isotropic
      network of individual filaments. Neurofilament gel formation was stimulated in
      vitro by acid phosphatase treatment or by inositol phospholipids. In contrast,
      addition of actin filaments reduced the resistance of neurofilament gels to large
      stresses. These results suggest that dynamic and regulated interactions occur
      between neurofilaments to form viscoelastic networks with properties distinct
      from other cytoskeletal structures.

PMID- 8663095
TI  - Additions and Corrections to Intra-Golgi transport inhibition by megalomicin.

PMID- 8663096
TI  - Pathways for oxalate transport in rabbit renal microvillus membrane vesicles.
AB  - Recent evidence suggests that apical membrane Cl--oxalate exchange plays a major
      role in mediating Cl- absorption in the renal proximal tubule. To sustain steady
      state Cl- absorption by a mechanism of exchange for intracellular oxalate
      requires the presence of one or more pathways for recycling oxalate from lumen to
      cell. Accordingly, we evaluated the mechanisms of oxalate transport in luminal
      membrane vesicles isolated from the rabbit renal cortex. We found that transport
      of oxalate by Na+ cotransport is negligible compared to the transport of sulfate.
      In contrast, we demonstrated that oxalate shares the electroneutral pathway
      mediating Na+-independent sulfate-carbonate exchange. We also demonstrated the
      presence of OH--oxalate exchange (indistinguishable from H+-oxalate cotransport).
      The process of OH--oxalate exchange was electrogenic and partially inhibited by
      Cl-, indicating that it occurs, at least in part, as a mode of the Cl--oxalate
      exchanger described previously. An additional component of OH--oxalate exchange
      was insensitive to inhibition by either Cl- or sulfate, suggesting that it takes
      place by neither the Cl--oxalate exchanger nor the sulfate-carbonate exchanger.
      We conclude that multiple anion exchange mechanisms exist by which oxalate can
      recycle from lumen to cell to sustain Cl- absorption occurring via apical
      membrane Cl--oxalate exchange in the renal proximal tubule.

PMID- 8663097
TI  - Investigation of myotonic dystrophy kinase isoform translocation and membrane
      association.
AB  - Myotonic dystrophy is caused by the expansion of a CTG repeat found in the 3'
      untranslated region of the myotonic dystrophy kinase. The mechanism of disease
      and the role of the kinase are currently obscure. Here we begin the investigation
      of domain structure/function correlations to aid in determining its normal
      function. Expressed full-length protein and protein truncated before a C-terminal
      hydrophobic domain were compared. In vitro, signal peptide function and
      protection of kinase by microsomal membranes were absent; thus, it is not
      translocated, as previously proposed. However, full-length kinase expressed in
      insect cells was found in fractions enriched for membranes and decorated
      mitochondria. The truncated form was found primarily in the cytosol. The kinase
      was present as two self-associated, disulfide-linked complexes. The majority of
      full-length kinase was found in the larger of the two complexes, while almost all
      of the truncated form was found in the smaller. Thus, the C-terminal region
      confers a higher order of self-association. Furthermore, full-length kinase
      expressed in COS-1 cells was present as high molecular weight complex, while the
      truncated form was present as monomer species. These experiments indicate that
      the myotonic dystrophy kinase is not membrane-integrated, but that it may have a
      molecular organization which favors peripheral association with membranes.

PMID- 8663099
TI  - Identification of promoter elements involved in cell-specific regulation of rat
      smooth muscle myosin heavy chain gene transcription.
AB  - In order to identify cis-acting regulatory elements involved in smooth muscle
      cell-specific gene regulation, we have cloned a 4. 7-kilobase pair fragment of
      the promoter for the rat smooth muscle myosin heavy chain, a protein expressed in
      differentiated smooth muscle cells. Sequence analysis of a 1.7-kilobase pair
      portion of this clone reveals potential binding sites for known transcription
      factors. A comparison of the primary sequence between the rat and rabbit smooth
      muscle myosin heavy chain promoters reveals numerous conserved consensus binding
      sites. Transient transfection analysis of promoter deletion constructs in rat
      aorta and tracheal smooth muscle cells, L8 myoblast cells, and rat pulmonary
      aorta endothelial cells suggests that a region of the promoter located between 
      1,249 and -1,317 base pairs is important for the restriction of gene expression
      to smooth muscle cells. Electrophoretic mobility shift analysis of a highly
      conserved region located between -1,317 and -1, 085 base pairs reveals specific
      DNA-protein complexes formed in smooth muscle cell extracts, which can be
      competed with an oligonucleotide containing a nuclear factor 1 binding site.

PMID- 8663098
TI  - cAMP- and Ca2+-independent activation of cystic fibrosis transmembrane
      conductance regulator channels by phenylimidazothiazole drugs.
AB  - Patch-clamp, iodide efflux, and biochemical techniques were used to evaluate the
      ability of phenylimidazothiazoles to open normal and mutated cystic fibrosis
      transmembrane conductance regulator (CFTR) chloride channels and to investigate
      the mechanism of activation. As reported previously for bromotetramisole,
      levamisole activated wild-type CFTR channels stably expressed in Chinese hamster
      ovary cells in the absence of other secretagogues and without elevating
      intracellular cAMP or calcium. The protein kinase A (PKA) inhibitor N - (2-(p
      bromocinnamylamino)ethyl)-5-isoquinolinesul-fonamid e abolished activation by
      forskolin but only partially inhibited stimulation by levamisole, suggesting the
      involvement of other kinases. CFTR channels bearing mutations at multiple
      phosphorylation sites, in the membrane domains, and in the first nucleotide
      binding domain (including the disease-causing mutations G551D and DeltaF508) all
      responded to phenylimidazothiazoles. Moreover, levamisole and bromotetramisole
      increased the activity of wild-type and mutant channels already exposed to PKA +
      MgATP, consistent with the inhibition of a constitutive, membrane-associated
      phosphatase activity. We conclude that phenylimidazothiazole drugs can open
      normal and mutated CFTR channels by stabilization of phosphoforms of CFTR that
      are produced by basal activity of PKA and alternative protein kinases. If similar
      stimulation is observed in humans in vivo, phenylimidazothiazoles may be useful
      in the development of pharmacological therapies for cystic fibrosis.

PMID- 8663100
TI  - Stimulation of mitogen-activated protein kinase and Na+/H+ exchanger in human
      platelets. Differential effect of phorbol ester and vasopressin.
AB  - Treatment of human platelets with phorbol 12-myristate 13-acetate (PMA) and
      arginine vasopressin (AVP) increase the phosphorylation and activation of mitogen
      activated protein kinase (MAPK). Electrophoretic retardation of MAPK mobility on
      SDS-polyacrylamide gels was used for determination of MAPK phosphorylation. The
      activity of MAPK was tested in myelin basic protein (MBP)-containing
      polyacrylamide gels. In this study we compared the PMA and AVP signal
      transduction pathways leading to the activation of MAPKs and Na+/H+ exchanger
      (NHE). Both agonists stimulate MAPK and NHE activities in a similar time frame
      and concentration dependence. The MAPK and NHE activities induced by PMA were
      inhibited by staurosporine, a potent inhibitor for protein kinase C (PKC), and by
      MAPK kinase (MEK) inhibitor, PD98059, but were not affected by the tyrosine
      kinase inhibitor genistein. In contrast, both AVP-induced MAPK and NHE activities
      were inhibited by genistein and MEK inhibitor but were not affected by
      staurosporine. Immunoprecipitation studies demonstrate that PMA, but not AVP,
      enhances the basal phosphorylation of the NHE-1. In this study, MAPKs are
      suggested to be a part of converging signaling leading to NHE activation by PKC
      dependent and AVP-tyrosine kinase-dependent pathways. We propose that the MAPK
      activation of the NHE-1 does not involve phosphorylation of this exchanger
      protein. On the other hand, PKC can lead to phosphorylation and to additional
      activation of the NHE-1 through a MAPK-independent pathway.

PMID- 8663101
TI  - Intracellular events in the "selective" transport of lipoprotein-derived
      cholesteryl esters.
AB  - The current study utilizes human, apoE-free high density lipoprotein
      reconstituted with a highly specific fluorescent-cholesteryl ester probe to
      define the initial steps and regulatory sites associated with the "selective"
      uptake and intracellular itinerary of lipoprotein-derived cholesteryl esters.
      Bt2cAMP-stimulated ovarian granulosa cells were used as the experimental model,
      and both morphological and biochemical fluorescence data were obtained. The data
      show that cholesteryl ester provided through the selective pathway is a process
      which begins with a temperature-independent transfer of cholesteryl ester to the
      cell's plasma membrane. Thereafter transfer of the lipid proceeds rapidly and
      accumulates prominently in a perinuclear region (presumed to be the
      Golgi/membrane sorting compartment) and in lipid storage droplets of the cells.
      The data suggest that lipid transfer proteins (or other small soluble proteins)
      are not required for the intracellular transport of the cholesteryl esters, nor
      is an intact Golgi complex or an intact cell cytoskeleton (although the transfer
      is less efficient in the presence of certain microtubule-disrupting agents). The
      intracellular transfer of the cholesteryl esters is also somewhat dependent on an
      energy source in that a glucose-deficient culture medium or a combination of
      metabolic inhibitors reduces the efficiency of the transfer. A protein-mediated
      event may be required for cholesteryl ester internalization from the plasma
      membrane, in that N-ethylmaleimide dramatically blocks the internalization phase
      of the selective uptake process. Taken together these data suggest that the
      selective pathway is a factor-dependent, energy-requiring cholesteryl ester
      transport system, in which lipoprotein-donated cholesteryl esters probably flow
      through vesicles or intracellular membrane sheets and their connections, rather
      than through the cell cytosol.

PMID- 8663102
TI  - Transcriptional activation by yeast PDR1p is inhibited by its association with
      NGG1p/ADA3p.
AB  - NGG1p/ADA3p forms a coactivator/repressor complex (ADA complex) in association
      with at least two other yeast proteins, ADA2p and GCN5p, that is involved in
      regulating transcriptional activator proteins including GAL4p and GCN4p. Using a
      two-hybrid analysis, we found that the carboxyl-terminal transcriptional
      activation domain of PDR1p, the primary regulatory protein involved in yeast
      pleiotropic drug resistance, interacts with the amino-terminal 373 amino acids of
      NGG1p (NGG1p1-373). This interaction was confirmed by coimmunoprecipitation of
      epitope-tagged derivatives of NGG1p and PDR1p from crude extracts. An overlapping
      region of the related transcriptional activator PDR3p was also found to interact
      with NGG1p. Amino acids 274-307 of NGG1p were required for interaction with
      PDR1p. This same region is required for inhibition of transcriptional activation
      by GAL4p. The association between NGG1p1-373 and PDR1p may be indirect, possibly
      mediated by the ADA complex since the two-hybrid interaction required the
      presence of full-length NGG1. A partial requirement for ADA2 was also found. This
      suggests that an additional component of the ADA complex, regulated by ADA2p, may
      mediate the interaction. Transcriptional activation by a GAL4p DNA binding domain
      fusion of PDR1p was enhanced in ngg1 and ada2 disruption strains. Similar to its
      action on GAL4p, the ADA complex acts to inhibit the activation domain of PDR1p.

PMID- 8663104
TI  - The ordered assembly of the phiX174-type primosome. I. Isolation and
      identification of intermediate protein-DNA complexes.
AB  - The phiX-type primosome was discovered during the resolution and reconstitution
      in vitro of the complementary strand DNA replication step of the phiX174 viral
      life cycle. This multienzyme bidirectional helicase-primase complex can provide
      the DNA unwinding and Okazaki fragment-priming functions at the replication fork
      and has been implicated in cellular DNA replication, repair, and recombination.
      We have used gel mobility shift assays and enhanced chemiluminescence Western
      analysis to isolate and identify the pathway of primosome assembly at a primosome
      assembly site (PAS) on a 300-nucleotide-long single-stranded DNA fragment. The
      first three steps do not require ATP and are as follows: (i) PriA recognition and
      binding to the PAS, (ii) stabilization of the PriA-PAS complex by the addition of
      PriB, and (iii) formation of a PriA-PriB-DnaT-PAS complex. Subsequent formation
      of the preprimosome involves the ATP-dependent transfer of DnaB from a DnaB-DnaC
      complex to the PriA-PriB-DnaT-PAS complex. The final preprimosomal complex
      contains PriA, PriB, DnaT, and DnaB but not DnaC. A transient interaction between
      the preprimosome and DnaG generates the five-protein primosome. As described in
      an accompanying article (Ng, J. Y., and Marians, K. J. (1996) J. Biol. Chem. 271,
      15649-15655), when assembled on intact phiX174 phage DNA, the primosome also
      contains PriC.

PMID- 8663103
TI  - Alterations in calcium channel currents underlie defective insulin secretion in a
      transgenic mouse.
AB  - A transgenic mouse overexpressing a mutant form of calmodulin (CaM-8) that is
      selectively targeted to pancreatic beta-cells has an impaired ability to secrete
      insulin in response to elevated blood glucose. Fluorescence measurements of
      cytosolic Ca2+ concentration ([Ca2+]i) showed that intracellular Ca2+ rises
      produced by glucose were smaller than normal in beta-cells of CaM-8 mice. Glucose
      utilization rates were not different between the CaM-8 and control beta-cells,
      suggesting that glucose metabolism was unperturbed by CaM-8. Ion channel defects
      were implicated in the phenotype of CaM-8 beta-cells because treatment of these
      cells with tolbutamide, a blocker of ATP-sensitive K+ channels, produced smaller
      than normal amounts of insulin secretion and Ca2+ rises. Depolarization with
      elevated extracellular K+ also produced smaller Ca2+ rises in beta-cells from CaM
      8 mice. Whole-cell patch-clamp recordings revealed that Ca2+ channel currents of
      beta-cells from CaM-8 mice were half as large as Ca2+ currents in control cells,
      while the currents carried by delayed rectifier and ATP-sensitive K+ channels
      were similar in magnitude in both cell types. We conclude that expression of the
      CaM-8 form of calmodulin causes a down-regulation of Ca2+ channel currents, which
      reduces Ca2+ entry and accumulation when glucose stimulates closure of the ATP
      sensitive K+ channels. The reduction in intracellular Ca2+ accumulation then
      prevents an adequate amount of insulin from being secreted from beta-cells of CaM
      8 mice.

PMID- 8663105
TI  - The ordered assembly of the phiX174-type primosome. II. Preservation of primosome
      composition from assembly through replication.
AB  - Gel filtration chromatography was used to isolate both preprimosomal and
      primosomal complexes formed on single-stranded DNA-binding protein-coated phiX174
      DNA by the combination of PriA, PriB, PriC, DnaT, DnaB, DnaC, and DnaG. The
      presence and relative amounts of primosomal proteins in these complexes were
      determined by Western blotting. Protein-DNA complexes isolated (i) after assembly
      in the presence of 10 microM ATP, (ii) after preprimosome movement in the
      presence of 1 mM ATP, (iii) after priming in the presence of the four
      ribonucleoside triphosphates, or (iv) after complementary strand DNA replication
      in the presence of the DNA polymerase III holoenzyme all had the same protein
      composition; preprimosomes contained PriA, PriB, PriC, DnaT, and DnaB, whereas
      primosomes included DnaG. The stable association of DnaG with the protein-DNA
      complex could be attributed partially to its ability to remain bound to the
      primers synthesized. In the absence of PriC, the efficiencies of priming and
      replication were reduced by one-third and one-half, respectively, even though
      PriC was not required for the formation of stable protein-DNA complexes on a 304
      nucleotide-long single strand of DNA containing a primosome assembly site (Ng, J.
      Y., and Marians, K. J. (1996) J. Biol. Chem. 271, 15642-15648). We hypothesize
      that maintenance of the primosome on the replicated DNA may provide a mechanism
      to allow primosomes to participate in the resolution of recombination
      intermediates and intermediates formed during double strand break repair by
      permitting the re-establishment of a replication fork.

PMID- 8663106
TI  - The ordered assembly of the phiX174-type primosome. III. PriB facilitates complex
      formation between PriA and DnaT.
AB  - The properties of two mutant PriA proteins, PriA C439Y and PriA C445Y have been
      used to reveal the role of PriB during assembly of the phiX174-type primosome.
      The replication defects of both mutant PriA proteins could be rescued by high
      concentrations of DnaT. Analysis of the formation of intermediate complexes in
      primosome assembly and the effect of PriB on PriA binding to DNA demonstrated
      that the mutant PriA proteins could not form a PriA-PriB complex on DNA carrying
      a primosome assembly site. Consequently, the mutant proteins also could not form
      PriA-PriB-DnaT complexes at concentrations of DnaT sufficient to form such a
      complex with wild-type PriA. In addition, PriB was found to stabilize wild-type
      but not mutant PriA proteins on DNA. At high concentrations of DnaT, both mutant
      and wild-type PriA proteins could form a PriA-DnaT complex and support PriB
      independent phiX174 complementary strand DNA replication. Thus, during primosome
      assembly, PriB facilitates complex formation between PriA and DnaT.

PMID- 8663107
TI  - Purification of a cell-surface receptor for surfactant protein A.
AB  - In the present report we have characterized the binding of surfactant protein A
      (SP-A) to bone marrow-derived macrophages, U937 cells, alveolar macrophages, and
      type II epithelial cells. The binding of SP-A to all cell types is Ca2+-dependent
      and trypsin-sensitive, but type II cells express distinct Ca2+-independent
      binding sites. The binding of SP-A to macrophages is independent of known cell
      surface carbohydrate-specific receptors and of glycoconjugate binding sites on
      the surface of the cells and is distinct from binding to C1q receptors. Based on
      ligand blot analysis, both type II cells and macrophages express a 210-kDa SP-A
      binding protein. The 210-kDa protein was purified to apparent homogeneity from
      U937 macrophage membranes using affinity chromatography with noncovalently
      immobilized surfactant protein A, and was purified from rat lung by differential
      detergent and salt extraction of isolated rat lung membranes. Polyclonal
      antibodies against the rat lung SP-A-binding protein inhibit binding of SP-A to
      both type II cells and macrophages, indicating that the 210-kDa protein is
      expressed on the cell surface. The polyclonal antibodies also block the SP-A
      mediated inhibition of phospholipid secretion by type II cells, indicating that
      the 210-kDa protein is a functional cell-surface receptor on type II cells. In a
      separate report we have determined that antibodies to the SP-A receptor block the
      SP-A-mediated uptake of Mycobacterium bovis, indicating that the macrophage SP-A
      receptor is involved in SP-A-mediated clearance of pathogens.

PMID- 8663108
TI  - Random mutagenesis of the sheep Na,K-ATPase alpha1 subunit generating the ouabain
      resistant mutant L793P.
AB  - The polymerase chain reaction was used to randomly mutagenize a cDNA cassette
      encoding amino acids 691-946 of the sheep Na,K-ATPase alpha subunit. The
      mutagenized cassettes were used to replace the wild-type region in the full
      length cDNA, and pools of mutants were transfected into HeLa cells. After the
      generation of resistant cells via selection in 0.5 microM ouabain, polymerase
      chain reaction was used to amplify the mutagenized cassette from the genomic DNA
      of the stable transfectants. Sequence analysis of the polymerase chain reaction
      product revealed three amino acid substitutions: I729V, L793P, and K836R.
      Subsequent site-directed mutagenesis experiments showed that only L793P was
      important for resistance. To elucidate the role of L793 in ouabain inhibition,
      additional mutations at this position were prepared. L793A and L793I mutants were
      constructed and expressed in HeLa cells. Only L793A survived selection using
      ouabain, which suggested that resistance is not due to the specific substitution
      of leucine with proline. To explore the mechanism of resistance, apparent
      affinities of the L793P mutant for sodium and potassium were compared to the wild
      type HeLa pump. Although the apparent affinities were comparable for sodium, the
      mutant had a 2-fold higher apparent affinity for potassium. This suggests that
      the mechanism of ouabain insensitivity of L793P is due to a perturbation in the
      region of the enzyme that may include the K+ binding site.

PMID- 8663109
TI  - Refined crystal structures of guanine nucleotide complexes of adenylosuccinate
      synthetase from Escherichia coli.
AB  - Structures of adenylosuccinate synthetase from Escherichia coli complexed with
      guanosine-5'-(beta,gamma-imido) triphosphate and guanosine-5'-(beta,gamma
      methylene)triphosphate in the presence and the absence of Mg2+ have been refined
      to R-factors below 0.2 against data to a nominal resolution of 2.7 A. Asp333 of
      the synthetase hydrogen bonds to the exocyclic 2-amino and endocyclic N1 groups
      of the guanine nucleotide base, whereas the hydroxyl of Ser414 and the backbone
      amide of Lys331 hydrogen bond to the 6-oxo position. The side chains of Lys331
      and Pro417 pack against opposite faces of the guanine nucleotide base. The
      synthetase recognizes neither the N7 position of guanine nucleotides nor the
      ribose group. Electron density for the guanine-5'-(beta,gamma-imido) triphosphate
      complex is consistent with a mixture of the triphosphate nucleoside and its
      hydrolyzed diphosphate nucleoside bound to the active site. The base, ribose, and
      alpha-phosphate positions overlap, but the beta-phosphates occupy different
      binding sites. The binding of guanosine-5'-(beta,gamma-methylene)triphosphate to
      the active site is comparable with that of guanosine-5'-(beta, gamma
      imido)triphosphate. No electron density, however, for the corresponding
      diphosphate nucleoside is observed. In addition, electron density for bound Mg2+
      is absent in these nucleotide complexes. The guanine nucleotide complexes of the
      synthetase are compared with complexes of other GTP-binding proteins and to a
      preliminary structure of the complex of GDP, IMP, Mg2+, and succinate with the
      synthetase. The enzyme, under conditions reported here, does not undergo a
      conformational change in response to the binding of guanine nucleotides, and
      minimally IMP and/or Mg2+ must be present in order to facilitate the complete
      recognition of the guanine nucleotide by the synthetase.

PMID- 8663110
TI  - Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor
      cytokine family.
AB  - Cytokines in the tumor necrosis factor (TNF) family regulate development and
      function of the immune system. We have isolated a new member of this family,
      designated Apo-2 ligand (Apo-2L), via an expressed sequence tag. Apo-2L is a 281
      amino acid protein, related most closely to Fas/Apo-1 ligand. Transfected Apo-2L
      is expressed at the cell surface with its C terminus exposed, indicating a type
      II transmembrane protein topology. Like Fas/Apo-1 ligand and TNF, the C-terminal
      extracellular region of Apo-2L (amino acids 114-281) exhibits a homotrimeric
      subunit structure. Soluble Apo-2L induces extensive apoptosis in lymphoid as well
      as non-lymphoid tumor cell lines. The effect of Apo-2L is not inhibited by
      soluble Fas/Apo-1 and TNF receptors; moreover, expression of human Fas/Apo-1 in
      mouse fibroblasts, which confers sensitivity to induction of apoptosis by
      agonistic anti-Fas/Apo-1 antibody, does not confer sensitivity to Apo-2L. Hence,
      Apo-2L acts via a receptor which is distinct from Fas/Apo-1 and TNF receptors.
      These results suggest that, along with other family members such as Fas/Apo-1
      ligand and TNF, Apo-2L may serve as an extracellular signal that triggers
      programmed cell death.

PMID- 8663111
TI  - Role of the 70-kDa subunit of human replication protein A (I). Single-stranded
      dna binding activity, but not polymerase stimulatory activity, is required for
      DNA replication.
AB  - Replication protein A (RPA), also known as human single-stranded DNA-binding
      protein, is a three-subunit protein complex with multiple functions. Here, we
      investigated the role of the 70-kDa RPA subunit (p70) in DNA replication, by
      generating a series of deletion mutants. Mutant p70, which lacked 50 amino acids
      at the C-terminus, failed to interact with the 11-kDa RPA subunit (p11) and, when
      deleted further at the C terminus, was unable to interact with either the 34-kDa
      subunit (p34) or with p11, suggesting that p70 directly interacts with both p34
      and p11. Studies with purified RPA mutants indicated that deletions at the N
      terminal domain of p70 had very little effect on RPA's single-stranded DNA
      (ssDNA) binding activity, whereas deletion of amino acids 169-246 significantly
      weakened the DNA binding ability of RPA. By deleting amino acids 296-373 or 374
      458, we totally abolished p70's ssDNA binding activity, suggesting that multiple
      p70 domains are involved in DNA binding. Two p70 domains, the N-terminal domain
      and the DNA binding domain, were required to stimulate DNA polymerase (pol)
      alpha, yet the DNA binding domain alone supported pol delta activity.
      Interestingly, RPA containing p70 with a zinc-finger domain deletion retained its
      DNA binding activity, but inhibited pol alpha and delta activity. RPA that lacked
      ssDNA binding activity failed to support simian virus 40 (SV40) DNA replication
      in vitro, whereas mutant RPA that lacked pol alpha stimulatory activity
      (including the zinc-finger p70 mutant) functioned normally. We conclude that
      RPA's DNA binding activity, but not its pol alpha stimulatory activity, is
      required for DNA replication.

PMID- 8663112
TI  - Sequential structural changes upon zinc and calcium binding to metal-free
      concanavalin A.
AB  - The lectin concanavalin A (ConA) sequentially binds a transition metal ion in the
      metal-binding site S1 and a calcium ion in the metal-binding site S2 to form its
      saccharide-binding site. Metal-free ConA crystals soaked with either Zn2+ (apoZn
      ConA) or Co2+ (apoCo-ConA) display partial binding of these ions in the proto
      transition metal-binding site, but no further conformational changes are
      observed. These structures can represent the very first step in going from metal
      free ConA toward the holoprotein. In the co-crystals of metal-free ConA with Zn2+
      (Zn-ConA), the zinc ion can fully occupy the S1 site. The positions of the
      carboxylate ligands Asp10 and Asp19 that bridge the S1 and S2 sites are affected.
      The ligation to Zn2+ orients Asp10 optimally for calcium ligation and stabilizes
      Asp19 by a hydrogen bond to one of its water ligands. The neutralizing and
      stabilizing effect of the binding of Zn2+ in S1 is necessary to allow for
      subsequent Ca2+ binding in the S2 site. However, the S2 site of monometallized
      ConA is still disrupted. The co-crystals of metal-free ConA with both Zn2+ and
      Ca2+ contain the active holoprotein (ConA ZnCa). Ca2+ has induced large
      conformational changes to stabilize its hepta-coordination in the S2 site, which
      comprise the trans to cis isomerization of the Ala207-Asp208 peptide bond
      accompanied by the formation of the saccharide-binding site. The Zn2+ ligation in
      ConA ZnCa is similar to Mn2+, Cd2+, Co2+, or Ni2+ ligation in the S1 site, in
      disagreement with earlier extended x-ray absorption fine structure results that
      suggested a lower coordination number for Zn2+.

PMID- 8663113
TI  - The KRAB zinc finger gene ZNF74 encodes an RNA-binding protein tightly associated
      with the nuclear matrix.
AB  - We previously cloned ZNF74, a developmentally expressed zinc finger gene commonly
      deleted in DiGeorge syndrome. Here, the intron/exon organization of the human
      gene and the functional properties of the expressed protein are presented. This
      zinc finger gene from the transcription factor IIIA/Kruppel family contains three
      exons. A truncated Kruppel-associated box (KRAB) located at the N terminus of the
      predicted 64-kDa zinc finger protein is encoded by exon 2. The remainder of the
      protein including the zinc finger domain as well as the 3'-untranslated region
      (UTR) is encoded by exon 3. Both 5'-UTR (exon 1) and 3'-UTR contain repetitive
      Alu elements. In vitro translation of a cDNA encoding the entire ZNF74 coding
      region produced a 63-kDa protein as determined on sodium dodecyl sulfate
      polyacrylamide gel. A bacterially expressed fusion protein shown to bind tightly
      to 65zinc was used to test the nucleic acid binding properties of ZNF74. By RNA
      binding assays, ZNF74 was found to bind specifically to poly(U) and poly(G) RNA
      homopolymers. The restricted binding to these homopolymers and not to poly(A) and
      poly(C) suggested that ZNF74 displays RNA sequence preferences. RNA binding was
      mediated by the zinc finger domain. Immunofluorescence studies on transfected
      cells revealed ZNF74 nuclear localization. The labeling pattern observed in the
      nuclei clearly excluded the nucleoli. The zinc finger region lacks a classical
      nuclear localization signal but was found to be responsible for nuclear
      targeting. Subcellular and in situ sequential fractionations further showed that
      ZNF74 is associated with the nuclear matrix. The RNA binding properties of this
      protein and its tight association with the nuclear matrix, a subnuclear
      compartment involved in DNA replication as well as RNA synthesis and processing,
      suggest a role for ZNF74 in RNA metabolism.

PMID- 8663114
TI  - Molecular cloning and identification of N-acyl-D-glucosamine 2-epimerase from
      porcine kidney as a renin-binding protein.
AB  - N-Acetylneuraminic acid (NeuAc) is an important molecule in biological
      recognition systems. NeuAc is known to be biosynthesized either from UDP-N-acetyl
      D-glucosamine by an action of UDP-N-acetyl-D-glucosamine 2-epimerase or from N
      acetyl-D-glucosamine by N-acyl-D-glucosamine 2-epimerase (GlcNAc 2-epimerase).
      However, the physiological function of the GlcNAc 2-epimerase in NeuAc
      biosynthesis has not been fully evaluated. To clarify the role of GlcNAc 2
      epimerase in NeuAc biosynthesis, the enzyme and its gene were isolated from
      porcine kidney cortex. Escherichia coli cells transformed with the gene expressed
      the GlcNAc 2-epimerase having the same properties as those of the GlcNAc 2
      epimerase from porcine kidney. Sequence analysis indicated that the gene was
      capable of synthesizing a 46.5-kDa protein (402 amino acids) with a conserved
      leucine zipper motif. Homology search for the cloned gene revealed that the
      GlcNAc 2-epimerase was identical with renin-binding protein (RnBP) in porcine
      kidney (Inoue, H., Fukui, K., Takahashi, S., and Miyake, Y.(1990) J. Biol. Chem.
      265, 6556-6561) (identity: 99.6% in nucleotide sequence, 99.0% in amino acid
      sequence). That GlcNAc 2-epimerase is a RnBP was confirmed by its ability to bind
      porcine kidney renin and mask its protease activity. These findings provide
      unequivocal evidence that the enzyme GlcNAc 2-epimerase is a RnBP.

PMID- 8663115
TI  - Differential sensitivities of portions of the mRNA for ribosomal protein S20 to
      3'-exonucleases dependent on oligoadenylation and RNA secondary structure.
AB  - The 3'-exonucleolytic decay of the mRNA for ribosomal protein S20 has been
      reconstituted in vitro using purified RNase II and crude extracts enriched for
      polynucleotide phosphorylase (PNPase) activity. We show that RNase II can
      catalyze the degradation of the 5' two-thirds of the S20 mRNA and that prior
      oligoadenylation of the 3' termini of truncated S20 mRNA substrates can
      significantly stimulate the initiation of degradation by RNase II. The intact S20
      mRNA is, however, insensitive to attack by RNase II and polyadenylation of its 3'
      end cannot overcome the natural resistance of the S20 mRNA to RNase II. Complete
      degradation of either the entire S20 mRNA without prior endonucleolytic cleavage
      or the 3'-terminal 147-residue fragment is dependent on both oligoadenylation and
      PNPase activity. Moreover, this process can take place in the absence of RNase E
      activity. Our data point to the importance of oligoadenylation in facilitating 3'
      exonucleolytic activity and indicate that there are alternative degradative
      pathways. The implications for mRNA decay are discussed.

PMID- 8663116
TI  - Identification of diacylglycerol pyrophosphate as a novel metabolic product of
      phosphatidic acid during G-protein activation in plants.
AB  - We provide evidence that phosphatidic acid (PtdOH) formed during signaling in
      plants is metabolized by a novel pathway. In much of this study, 32Pi-labeled
      Chlamydomonas cells were used, and signaling was activated by adding the G
      protein activator mastoparan. Within seconds of activation, large amounts of
      [32P]PtdOH were formed, with peak production at about 4 min, when the level was 5
      25-fold higher than the control. As the level of [32P]PtdOH subsequently
      decreased, an unknown phospholipid (PLX) increased in radiolabeling; before
      activation it was barely detectable. The chromatographic properties of PLX
      resembled those of lyso-PtdOH and CMP.PtdOH but on close inspection were found to
      be different. PLX was shown to be diacylglycerol pyrophosphate (DGPP), the
      product of a newly discovered enzyme, phosphatidate kinase, whose in vitro
      activity was described recently (Wissing, J. B., and Behrbohm, H. (1993) Plant
      Physiol. 102, 1243-1249). The identity of DGPP was established by co
      chromatrography with a standard and by degradation analysis as follows: [32P]DGPP
      was deacylated, and the product (glycerolpyrophosphate, GroPP) was hydrolyzed by
      mild acid treatment or pyrophosphatase to produce GroP and Pi as the only
      radioactive products. Since DGPP is the pyrophosphate derivative of PtdOH and is
      formed as the concentration of PtdOH decreases, we assumed that PtdOH was
      converted in vivo to DGPP. This was confirmed by showing that during a short
      labeling protocol while the specific radioactivity of DGPP was increasing, the
      specific radioactivity of the 32Pi derived from DGPP as above was higher than
      that of [32P]GroP. DGPP was also formed in suspension cultures of tomato and
      potato cells, and its synthesis was activated by mastoparan. Moreover, it was
      also found in intact tissues of a number of higher plants, for example, carnation
      flower petals, vetch roots, leaves of fig-leaved goosefoot, and common persicaria
      and microspores of rape seed. Our results suggest that DGPP is a common but minor
      plant lipid that increases in concentration when signaling is activated. Possible
      functions of DGPP in phospholpase C and D signaling cascades are discussed.

PMID- 8663117
TI  - The FcgammaRII receptor triggers pp125FAK phosphorylation in platelets.
AB  - Platelets express a single low affinity receptor for immunoglobulin, FcgammaRII,
      that triggers multiple cellular responses upon interaction with multivalent
      immune complexes. In this study we show that immobilized IgG is also a potent
      stimulant of platelet activation triggering adhesion, aggregation, massive dense
      granule secretion, and thromboxane production. Platelet adhesion to IgG was
      blocked by the FcgammaRII receptor-specific monoclonal antibody, IV. 3.
      Pretreatment of the platelets with cytochalasin D to inhibit actin polymerization
      similarly prevented cell binding to IgG having no effect on platelet binding to
      fibrinogen. Platelet adhesion to IgG also led to the induction of tyrosine
      phosphorylation of multiple proteins including pp125(FAK) and p72(SYK). These
      proteins were also tyrosine-phosphorylated in alphaIIbbeta3-deficient IgG
      adherent platelets from patients with Glanzmann's thrombasthenia. These data
      demonstrate that FcgammaRII mediates pp125(FAK) phosphorylation and platelet
      adhesion to IgG independent of the integrin alphaIIbbeta3. Treatment of the
      platelets with bisindolylmaleimide to inhibit protein kinase C prevented
      phosphorylation of pp125(FAK) as well as several other proteins, but not p72(SYK)
      phosphorylation. This study establishes that the FcgammaRII receptor mediates
      pp125(FAK) phosphorylation via protein kinase C.

PMID- 8663118
TI  - Cloning and characterization of a specific interleukin (IL)-13 binding protein
      structurally related to the IL-5 receptor alpha chain.
AB  - Interleukin-13 (IL-13) is a cytokine secreted by activated T lymphocytes that
      shares many, but not all, biological activities with IL-4. These overlapping
      activities are probably due to the existence of common receptor components. Two
      proteins have been described as constituents of the IL-4 receptor, a
      approximately 140-kDa glycoprotein (IL-4R) and the gamma chain (gammac) of the IL
      2 receptor, but neither of these proteins binds IL-13. We have cloned a cDNA
      encoding an IL-13 binding protein (IL-13R) from the Caki-1 human renal carcinoma
      cell line. The cloned cDNA encodes a 380-amino acid protein with two consensus
      patterns characteristic of the hematopoietic cytokine receptor family and a short
      cytoplasmic tail. The IL-13R shows homology with the IL-5 receptor, and to a
      lesser extent, with the prolactin receptor. COS-7 cells transfected with the IL
      13R cDNA bind IL-13 with high affinity but do not bind IL-4. COS-7 cells co
      transfected with the cloned IL-13R cDNA and IL-4R cDNA resulted in the
      reconstitution of a small number of receptors that recognized both IL-4 and IL
      13. Reverse transcription-polymerase chain reaction analysis detected the
      receptor transcript only in cell lines known to bind IL-13.

PMID- 8663119
TI  - Interaction of human immunodeficiency virus nucleocapsid protein with a structure
      mimicking a replication intermediate. Effects on stability, reverse transcriptase
      binding, and strand transfer.
AB  - The interaction of human immunodeficiency virus (HIV) nucleocapsid protein (NCp)
      with a substrate closely mimicking a retrovirus replication intermediate was
      studied. The heteroduplex substrate consisted of a DNA and RNA of 80 and 63
      nucleotides, respectively. The nucleotides at the 3' end of the DNA were
      complementary to those at the 3' end of the RNA such that a hybrid region of 30
      base pairs could form. HIV-reverse transcriptase (RT) extended the DNA and
      cleaved the RNA strand of the substrate. The rates of extension and cleavage were
      significantly decreased when the substrate was prebound with NCp before HIV-RT
      addition. In assays assessing the integrity of the substrate by measuring release
      of the DNA strand from the heteroduplex, prebinding with NCp protected the
      substrate when HIV-RT was added, a result consistent with resistance to RT
      mediated cleavage. In contrast, NCp significantly decreased the thermal stability
      of the substrate as judged by incubation of the substrate at various
      temperatures. In strand transfer assays, a 189-nucleotide RNA (acceptor) with an
      internal region complementary to all 80 nucleotides of the substrate DNA was
      incubated with the substrate in the presence or absence of NCp. Nucleocapsid
      protein stimulated strand transfer in which the substrate RNA was displaced upon
      binding of the DNA to the acceptor. Results are discussed with respect to the
      role of NCp in retroviral recombination.

PMID- 8663120
TI  - Oncogenic Raf-1 activates p70 S6 kinase via a mitogen-activated protein kinase
      independent pathway.
AB  - Cell proliferation requires the co-ordinate triggering of several protein kinases
      of Ser/Thr specificity such as p70 S6 kinase (S6K), which phosphorylates the
      ribosomal S6 protein and thus increases translation of mRNAs with polypyrimidine
      tracts. The multiplicity of signaling pathways leading to p70 S6K activation are
      not fully elucidated. However, several reports have indicated that the activation
      of p70 S6K is independent of mitogen-activated protein kinase (MAPK) activation.
      Interestingly, we and others have shown that constitutive activation of the MAPK
      pathway promotes cell proliferation, suggesting that this cascade is able to
      activate p70 S6K, a key step to trigger cell cycle entry. In this report we
      demonstrate that transfection of constitutively active mitogen-activated protein
      kinase kinase 1 in CCL 39 cells leads to activation of p70 S6K. Furthermore, we
      have established a cell line that stably expresses DeltaRaf-1:ER, an estradiol
      regulated form of oncogenic Raf-1. The addition of estradiol to these cells was
      sufficient to elicit rapid activation of mitogen-activated protein kinase kinase
      1, MAPK, and p70 S6K. Surprisingly, the activation of p70 S6K is not mediated by
      MAPK because blocking MAPK activation by expression of the phosphatase MKP-1 did
      not prevent p70 S6K activation by DeltaRaf-1:ER. In conclusion, we have
      demonstrated that activation of p70 S6K by DeltaRaf-1:ER is mediated by a new
      MAPK-independent pathway. This pathway is resistant to low nanomolar
      concentrations of wortmannin, indicating that it does not involve membrane-bound
      phosphatidylinositol-trisphosphate kinase activation.

PMID- 8663122
TI  - Subcellular localization of the type 2 11beta-hydroxysteroid dehydrogenase. A
      green fluorescent protein study.
AB  - 11beta-Hydroxysteroid dehydrogenase (11beta-HSD) is thought to confer aldosterone
      specificity to mineralocorticoid target cells by protecting the inherently non
      selective mineralocorticoid receptor (MR) from occupancy by endogenous
      glucocorticoids. Recently, we characterized a novel isoform of 11beta-HSD in
      aldosterone target cells, which has high affinity for its substrate, is
      unidirectional, and prefers NAD as cofactor. In this study we utilized a green
      fluorescent protein (GFP) technique to determine the subcellular localization of
      this isoform, 11beta-HSD2. We generated a chimeric gene encoding the full-length
      rabbit 11beta-HSD2 and, fused to its C terminus, the coding sequence of GFP. This
      construct was stably transfected into CHO cells. The enzymatic characteristics of
      the expressed 11beta-HSD2/GFP fusion protein were undistinguishable from those of
      the native enzyme: high affinity for corticosterone (KM 8-10 nM), NAD dependence,
      and lack of reductase activity. The intracellular location of the recombinant
      protein was determined by fluorescence microscopy. 11beta-HSD2-associated
      fluorescence was observed as a reticular network over the cytoplasm and nuclear
      envelope, whereas the plasma membrane and the nucleus were negative, suggesting
      endoplasmic reticulum (ER) localization. Staining of CHO cells expressing 11beta
      HSD2/GFP with established subcellular organelle markers revealed a colocalization
      of 11beta-HSD2/GFP only with ER markers and tubulin. To examine the orientation
      of 11beta-HSD2 within the ER, we selectively permeabilized CHO cells and stained
      them with an anti-GFP antibody. Fluorescence microscopy indicated that the C
      terminal region of 11beta-HSD2 is on the cytoplasmic surface of the ER membrane,
      since it was accessible to the GFP antibody. This conclusion was confirmed by
      trypsin treatment of permeabilized cells followed by Western blotting. The C
      terminal region of 11beta-HSD2 was accessible to trypsin, indicating that it is
      on the cytoplasmic side of the ER membrane. These results indicate that 11beta
      HSD2 is localized exclusively to the ER. Since 11beta-HSD2 does not contain any
      known ER retrieval signal, experiments are currently under way to determine what
      structural motifs are responsible for its ER localization.

PMID- 8663121
TI  - A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2)
      reverses the selectivity of COX-2 specific inhibitors.
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) currently available for clinical
      use inhibit both COX-1 and COX-2. This suggests that clinically useful NSAIDs
      inhibit pro-inflammatory prostaglandins (PGs) derived from the activity of COX-2,
      as well as PGs in tissues like the stomach and kidney (via COX-1). A new class of
      compounds has recently been developed (SC-58125) that have a high degree of
      selectivity for the inducible form of cyxlooxygenase (COX-2) over the
      constitutive form (COX-1). This unique class of compounds exhibit a time
      dependent irreversible inhibition of COX-2, while reversibly inhibiting COX-1.
      The molecular basis of this selectivity was probed by site-directed mutagenesis
      of the active site of COX-2. The sequence differences in the active site were
      determined by amino acid replacement of the COX-2 sequences based on the known
      crystal structure of COX-1, which revealed a single amino acid difference in the
      active site (valine 509 to isoleucine) and a series of differences at the mouth
      of the active site. Mutants with the single amino acid substitution in the active
      site and a combination of three changes in the mouth of the active site were made
      in human COX-2, expressed in insect cells and purified. The single amino acid
      change of valine 509 to isoleucine confers selectivity of COX-2 inhibitors in the
      class of SC-58125 and others of the same class (SC-236, NS-398), while commonly
      used NSAIDs such as indomethacin showed no change in selectivity. Substitutions
      of COX-1 sequences in COX-2 at the mouth of the active site of COX-2 did not
      change the selectivity of SC-58125. This indicates that the single amino acid
      substitution of isoleucine at position 509 for a valine is sufficient to confer
      COX-2 selectivity in this example of a diaryl-heterocycle COX inhibitor.

PMID- 8663123
TI  - The ubiquitin-activating enzyme E1 is phosphorylated and localized to the nucleus
      in a cell cycle-dependent manner.
AB  - The ubiquitin-activating enzyme E1 exists as two isoforms, E1a (117 kDa) and E1b
      (110 kDa). E1a is phosphorylated, whereas E1b is not. In the present study we
      have demonstrated the cell cycle dependence of E1a phosphorylation: a 2-fold
      increase in the specific phosphorylation of E1a in G2 compared with the basal
      level of phosphorylation in the other stages of the cell cycle. Two-dimensional
      gel electrophoresis resolved E1 into the two isoforms E1a and E1b; E1a resolved
      further as three phosphorylated forms and one nonphosphorylated form, while E1b
      resolved as one nonphosphorylated form. E1a is found predominantly in the
      phosphorylated forms. However, the distribution of E1a among these different
      phosphorylated forms was not cell cycle-dependent. We next evaluated the
      enzymatic activity of E1 as well as its subcellular localization throughout the
      cell cycle. 32P-Pyrophosphate exchange activity of E1 did not vary along the cell
      cycle; however, the amount of ubiquitin-protein conjugates decreased by 50% in
      G2. Nuclear and cytosolic fractionation of cells revealed the nuclear to
      cytosolic ratio of phosphorylated E1a was 3-fold greater in G2 compared with the
      other stages of the cell cycle. Finally, purified nuclear extracts supported E1
      dependent ubiquitin conjugation of exogenous substrates as did purified cytosol.
      However, in nuclear extracts but not in cytosol the amount of E1 activity was
      rate-limiting. Thus we establish nuclear E1-dependent protein ubiquitination and
      propose that an increase in phosphorylation of E1a in G2 functions to increase
      the import and/or retention of E1a in the nucleus and may modulate nuclear
      protein ubiquitination.

PMID- 8663124
TI  - Molecular cloning and expression of the gene for elastin-binding protein (ebpS)
      in Staphylococcus aureus.
AB  - Interactions between staphylococci and components of the extracellular matrix
      mediate attachment of the bacteria to host tissues and organs and define an
      important mechanism leading to colonization, invasion, and formation of
      metastatic abscesses. We have previously demonstrated a specific binding
      interaction between Staphylococcus aureus and elastin, one of the major protein
      components of the extracellular matrix. Available evidence suggests that this
      association is mediated by a 25-kDa elastin-binding protein on the surface of S.
      aureus (EbpS). To study the molecular structure and function of EbpS, the gene
      encoding EbpS was cloned, sequenced, and expressed in Escherichia coli. DNA
      sequence data indicate that the ebpS open reading frame consists of 606 base
      pairs and encodes a novel polypeptide with a predicted molecular mass of 23,345
      daltons and pI of 4.9. A polyclonal antibody raised against recombinant EbpS
      interacted with the native 25-kDa cell surface EbpS and inhibited staphylococcal
      elastin binding. Furthermore, recombinant EbpS bound specifically to immobilized
      elastin and inhibited binding of S. aureus to elastin. A degradation product of
      recombinant EbpS lacking the first 59 amino acids of the molecule and a C
      terminal fragment of CNBr-cleaved recombinant EbpS, however, did not interact
      with elastin. Together, these results confirm that EbpS is the cell surface
      molecule mediating binding of S. aureus to elastin. The inability of truncated
      forms of recombinant EbpS to bind to elastin suggests that the elastin binding
      site in EbpS is contained in the first 59 amino acids of the molecule.

PMID- 8663125
TI  - Camstatins are peptide antagonists of calmodulin based upon a conserved
      structural motif in PEP-19, neurogranin, and neuromodulin.
AB  - Unbridled increases in intracellular ionized calcium can result in neuronal
      damage and death. Since many of the deleterious effects of calcium are mediated
      by calmodulin, we have sought to identify neuronal proteins that inhibit
      activation of this ubiquitous protein. PEP-19 is a 7.6-kDa neuron-specific
      protein, which contains a motif similar to the calmodulin binding domains of
      neuromodulin (GAP-43) and neurogranin (RC3). Here we show that PEP-19 binds
      calmodulin in an analogous calcium-independent manner with an apparent Kd near
      1.2 microM. Furthermore, using the calmodulin-dependent enzyme neuronal nitric
      oxide synthase, we demonstrate that native PEP-19 is also an antagonist of enzyme
      activity. Based on the PEP-19 sequence, a series of peptide calmodulin
      antagonists termed camstatins were synthesized. These analogs define the
      minimally active domain of PEP-19 and provide a structure/activity relationship
      for calmodulin antagonism. There was a positive correlation between the binding
      affinities of the camstatins for calmodulin and their potencies as neuronal
      nitric oxide synthase inhibitors. Despite the similar IQ motif in PEP-19 and
      neuromodulin or neurogranin, PEP-19 was not a substrate for protein kinase C. The
      properties of PEP-19 suggest that it could fulfill a role in neuroprotection.

PMID- 8663126
TI  - Probing a role of subunit IV of the Escherichia coli bo-type ubiquinol oxidase by
      deletion and cross-linking analyses.
AB  - Subunit IV of the Escherichia coli bo-type ubiquinol oxidase is a 12-kDa membrane
      protein encoded by the cyoD gene and is conserved in the bacterial heme-copper
      terminal oxidases. To probe the functional role of subunit IV, we carried out
      deletion analysis and chemical cross-linking experiments with a homobifunctional
      and cleavable reagent. Spectroscopic properties of the mutant oxidases suggest
      that the C-terminal two-third (Val45 to His109) containing helices II and III is
      essential for the functional expression of the oxidase complex and for the CuB
      binding to the heme-copper binuclear center in subunit I. Cross-linking studies
      indicate that subunit IV is in close vicinity to subunit III. Based on these
      observations, we propose that subunit IV is present in a cleft formed by subunits
      I and III and assists the CuB binding to subunit I during biosynthesis or
      assembly of the oxidase complex.

PMID- 8663127
TI  - Molecular cloning and functional expression of the K-Cl cotransporter from
      rabbit, rat, and human. A new member of the cation-chloride cotransporter family.
AB  - We report the cloning, sequence analysis, tissue distribution, and functional
      expression of the K-Cl cotransport protein, KCC1. KCC1 was identified by
      searching the human expressed sequence tag data base, based on the expectation
      that it would be distantly related to the Na-K-Cl cotransporter. Rabbit KCC1
      (rbKCC1) and rat KCC1 (rtKCC1) were cloned by screening rabbit kidney and rat
      brain cDNA libraries using homologous cDNA probes. Human KCC1 (hKCC1) was
      obtained from I.M.A.G.E. clones and in part by reverse transcription-polymerase
      chain reaction; it exhibits 97% identity with rbKCC1. KCC1 encodes a 1085-residue
      polypeptide with substantial sequence homology (24-25% identity) to the
      bumetanide-sensitive Na-K-Cl cotransporter (NKCC or BSC) and the thiazide
      sensitive Na-Cl cotransporter (NCC or TSC). Hydropathy analysis of KCC1 indicates
      structural homology to NKCC, including 12 transmembrane domains, a large
      extracellular loop with potential N-linked glycosylation sites, and cytoplasmic N
      and C-terminal regions. Northern blot analysis revealed a ubiquitously expressed
      3. 8-kilobase transcript. Much of the genomic sequence of hKCC1 is in the data
      base, and the gene has been previously localized to 16q22.1 (Larsen, F., Solhein,
      J., Kristensen, T., Kolsto, A. B., and Prydz, H.(1993) Hum. Mol. Genet. 2, 1589
      1595). Epitope-tagged rbKCC1 was stably expressed in human embryonic kidney (HEK
      293) cells, resulting in production of a approximately150-kDa glycoprotein. The
      initial rate of 86Rb efflux from cells expressing rbKCC1 was more than 7 times
      greater than efflux from control cells and was inhibited by 2 mM furosemide; 86Rb
      efflux was stimulated by cell swelling. Uptake of 86Rb into rbKCC1 cells after a
      15-min pretreatment with 1 mM N-ethylmaleimide was dependent on external chloride
      but not on external sodium, and was inhibited by furosemide with a Ki of
      approximately 40 microM and by bumetanide with a Ki of approximately 60 microM.
      These data demonstrate that the KCC1 cDNAs encode a widely expressed K-Cl
      cotransporter with the characteristics of the K-Cl transporter that has been
      characterized in red cells.

PMID- 8663128
TI  - The hepatitis B virus transactivator protein, HBx, interacts with single-stranded
      DNA (ssDNA). Biochemical characterizations of the HBx-ssDNA interactions.
AB  - Human hepatitis B virus X protein, HBx, is widely acknowledged as a
      transcriptional transactivator. While HBx has been shown to increase gene
      expression in trans, it is generally believed that it does not bind double
      stranded DNA. Using several experimental approaches, we show that HBx interacts
      with single-stranded DNA in a manner that is not sequence-specific. Various
      heterologous single-stranded DNA (ssDNA) oligonucleotides were able to compete in
      HBx-ssDNA interactions in gel shift assays. Escherichia coli non-sequence
      specific, single-stranded DNA binding protein, E. coli SSB, displaced the HBx
      ssDNA interactions, confirming the ability of HBx to interact with single
      stranded DNA in a non-sequence-specific manner. We have further characterized the
      HBx-ssDNA interactions under various biochemical conditions. These include the
      effects of mono- and divalent cations, the effect of cardiolipin and heparin, pH
      and temperature dependence, and variations in the incubation time. HBx bound more
      tightly to d(pyrimidines)25 than to d(purines)25, a property that is
      characteristic of other single-stranded DNA-binding proteins (SSBs). Collectively
      the results presented here provide the first evidence of HBx's interaction with
      ssDNA. The biochemical parameters of these interactions were similar to those of
      known viral and cellular SSBs.

PMID- 8663129
TI  - Molecular cloning and characterization of a novel form of neuropeptide gene as a
      developmentally regulated molecule.
AB  - To examine the molecular basis controlling neuronal differentiation, subtraction
      library construction and differential screening were used to identify cDNAs whose
      mRNA levels are regulated in mouse NS20Y cells by dibutyryl cyclic AMP treatment.
      One of them, N27K, whose mRNA increases transiently during both neuronal
      differentiation in NS20Y cells and development in mouse brain. The deduced amino
      acid sequence of N27K comprises 212 amino acid residues and is a novel form of a
      precursor protein for a new neuropeptide nociceptin/orphanin FQ, which we
      independently cloned as N23K. That is, the putative protein encoded by N27K is 25
      amino acids longer than that encoded by N23K. Using an antibody against a C
      terminal peptide of the N27K protein that recognizes a 27-kDa protein in Western
      blot analysis, a punctate structure in the perinuclear region and areas near the
      tip of neurites is visualized in neurally differentiating NS20Y cells. The time
      of maximal expression correlates with periods of neurite extension, and
      expression decreases as the neuritic network develops. Immunohistochemistry of
      tissue sections of the mouse central nervous system revealed that reactivity for
      the anti-N27K protein antibody can detected in early generated neurons at
      embryonic day 14, in virtually all immature neurons at postnatal day 1, and in
      subsets of neurons of discrete brain regions such as the hypothalamus and spinal
      cord in adults. This remarkable redistribution suggests that N27K may be involved
      in a process in neurite outgrowth and nervous system development.

PMID- 8663130
TI  - Identification of a domain (155-183) on CD36 implicated in the phagocytosis of
      apoptotic neutrophils.
AB  - Clearance of apoptotic neutrophils by macrophages is a crucial event following
      the resolution of acute inflammation. CD36, together with alphavbeta3, has been
      identified as one of the adhesion molecules on the surface of macrophages
      implicated in the clearance of polymorphonuclear leukocytes. The domain on CD36
      implicated in the phagocytosis of aged neutrophils remains to be elucidated. In
      this study, COS cells transfected with human CD36 cDNA had a significantly higher
      capacity to phagocytose human apoptotic neutrophils compared with murine CD36
      cDNA. Moreover, monoclonal antibodies 10/5 or OKM5 (epitopes identified on amino
      acids 155-183) but not monoclonal antibody 13/10 (epitope identified on amino
      acids 30-76) inhibited phagocytosis of apoptotic neutrophils by COS cells
      transfected by human CD36. Swapping the human CD36 155-183 domain from human to
      murine CD36 (human-murine CD36 chimera) imparted to murine CD36-transfected COS
      cells an increased capacity to phagocytose apoptotic neutrophils. Conversely,
      when the murine domain 155-183 was inserted in human CD36, a decreased phagocytic
      capacity was observed. In addition, a synthetic peptide(155-169) but not its
      scrambled form significantly inhibited phagocytosis. These results identify for
      the first time a functional domain encompassing amino acids 155-183 on human CD36
      implicated in the recognition and phagocytosis of apoptotic neutrophils.

PMID- 8663131
TI  - Biochemical characterization of p16INK4- and p18-containing complexes in human
      cell lines.
AB  - The regulation of the D-type cyclin-dependent kinase (CDK4 and CDK6) activity
      appears to be the key step in the progression of eukaryotic cells through the G1
      cell cycle phase. One of the mechanisms involved in this process is the binding
      of some small proteic inhibitors, with a molecular mass ranging between 14 and 20
      kDa, to these CDKs. We have evaluated the amount of two such inhibitors, namely
      p16(INK4) and p18, in normal and transformed cells, as well as the biochemical
      features of the macromolecular complexes containing these proteins. The results
      obtained indicated that (i) p18 gene expression, unlike p16(INK4) gene, is not
      regulated by pRb status, (ii) no evident relationship exists between the
      expression of p16(INK4) and p18 genes, (iii) significant amounts of the two
      proteins are not bound to CDKs but occur as free molecules, (iv) each inhibitor
      forms a complex with the CDK protein with a 1:1 stoichiometry, and (v) a
      competition exists between cyclin D and the inhibitor protein toward the CDK
      protein resulting in the absence of detectable cellular free kinase. Moreover,
      employing the human native partially purified p16(INK4)or the pure recombinant
      protein, we have been able to demonstrate in vitro the dissociation of CDK4
      cyclin D1 complex and the formation of CDK4-p16(INK4) bimolecular complex. Our
      findings suggest that during the cell division cycle the members of the p16(INK4)
      protein family and cyclin Ds compete for binding to CDK4/CDK6 and that their
      quantitative ratio is essential for G1 --> S transition.

PMID- 8663132
TI  - Functional analysis of a p21WAF1,CIP1,SDI1 mutant (Arg94 --> Trp) identified in a
      human breast carcinoma. Evidence that the mutation impairs the ability of p21 to
      inhibit cyclin-dependent kinases.
AB  - Human p21 (also known as WAF1, CIP1, or SDI1) is a dual inhibitor of cyclin
      dependent kinases (CDKs) and the replication factor PCNA, which plays a role as a
      downstream mediator of the cell-cycle arrest induced by the tumor suppressor p53.
      To determine whether inactivation of downstream targets of p53 might contribute
      to cellular transformation, we have examined the integrity of the p21 gene in 36
      invasive ductal breast carcinomas. Direct sequence analysis of the polymerase
      chain reaction-amplified p21 gene revealed a C to T transition in codon 94 that
      caused the substitution of a tryptophan for an arginine in a tumor specimen. This
      mutation was not detected in normal DNA extracted from the same patient nor in a
      polymerase chain reaction-restriction fragment length polymorphism of 50
      unrelated individuals, indicating that it corresponds to a tumor-specific
      alteration. Functional analysis of the p21(R94W) protein produced in different
      eukaryotic and prokaryotic expression systems revealed that this mutation
      impaired the ability of p21 to inhibit CDKs. By contrast, the R94W mutant was
      unaltered in its ability to promote cyclin-CDK association as well as in its
      ability to bind proliferating cell nuclear antigen, thus leaving its putative
      functions as kinase activator or as inhibitor of replicative DNA synthesis
      intact. On the basis of these functional analysis, we propose that the Arg
      residue at position 94 is important for the CDK inhibitory role of p21.

PMID- 8663133
TI  - Chicken oviductal ecto-ATP-diphosphohydrolase. Purification and characterization.
AB  - An ecto-ATP diphosphohydrolase (ATPDase) was purified to homogeneity from
      vesiculosomes shed from chicken oviduct. First, the ecto-ATPDase-enriched
      vesiculosomes were concentrated by filtration, differential centrifugation, and
      exclusion chromatography. Next, the nonionic detergent, Nonidet P-40, was used to
      extract the ecto-ATPDase from vesiculosomal membranes, and the solubilized enzyme
      was further purified by ion exchange (DEAE-Bio-Gel) and lentil-lectin-Sepharose
      4B chromatography. In the final stage, immunoaffinity chromatography was utilized
      to obtain purified ecto-ATPDase. More than 25,000-fold purification was achieved.
      Specific activity of the purified enzyme was greater than 800 micronol/min/mg of
      protein with MgATP as the substrate, the highest ever reported for an ATPDase.
      The enzyme also hydrolyzed other nucleoside triphosphates in the presence of
      magnesium at similar rates and CaATP and MgADP at lower rates. The molecular mass
      of the purified glycoprotein was 80 kDa as determined by SDS-polyacrylamide gel
      electrophoresis and Western blot analysis. Based on its enzymatic properties, the
      relationship of the chicken oviduct ecto-ATPDase with other reported ATPDases and
      ecto-ATPases is discussed.

PMID- 8663134
TI  - Degradation of oxidized proteins in K562 human hematopoietic cells by proteasome.
AB  - Exposure to various forms of oxidative stress (H2O2 and O2.-) significantly
      increased the intracellular degradation of both "short-lived" and "long-lived"
      cellular proteins in the human hematopoietic cell line K562. Oxidatively modified
      hemoglobin and superoxide dismutase used as purified proteolytic substrates were
      also selectively degraded by K562 cell lysates, but exposure of these protein
      substrates to very high hydrogen peroxide concentrations actually decreased their
      proteolytic susceptibility. Our studies found little or no change in the overall
      capacity of cells and cell lysates to degrade "foreign" oxidized proteins after
      treatment of K562 cells with hydrogen peroxide or paraquat, a finding supported
      by proteasome Western blots and unchanged capacity of cell lysates to degrade the
      fluorogenic peptide succinyl-leucine-leucine-valine-tyrosine-4-methylcoumarin-7
      amide. Six days of daily treatment of K562 cells with an antisense
      oligodeoxynucleotide directed against the initiation codon region of the human
      proteasome C2 subunit gene dramatically depressed hydrogen peroxide-induced
      degradation of metabolically radiolabeled intracellular proteins. The actual
      amount of proteasome in antisense-treated K562 cells was also severely depressed,
      as revealed by Western blots and by measurements of the degradation of the
      fluorogenic peptide succinyl-leucine-leucine-valine-tyrosine-4-methylcoumarin-7
      amide. The degradation of oxidatively modified foreign protein substrates was
      also markedly depressed in lysates prepared from K562 cells treated with the
      proteasome C2 antisense dideoxynucleotide. The inhibitor profile for the
      degradation of H2O2-modified hemoglobin by K562 cell lysates was consistent with
      a major role for the ATP-independent 20 S "core" proteasome complex. We conclude
      that proteasome, probably the 20 S core proteasome complex, is primarily
      responsible for the selective degradation of oxidatively damaged proteins in
      human hematopoietic cells. Since "oxidative marking" of cellular proteins by
      lipoxygenase has been proposed as an important step in red blood cell maturation,
      it is important to determine which protease or proteases could recognize and
      degrade such modified substrates. Our results provide evidence that proteasome
      can, indeed, conduct such selective degradation and appears to be the major
      cellular protease capable of fulfilling such a role in maturation.

PMID- 8663135
TI  - Identification of the structural and functional domains of MutY, an Escherichia
      coli DNA mismatch repair enzyme.
AB  - The linear amino acid sequences of the Escherichia coli DNA repair proteins, MutY
      and endonuclease III, show significant homology, even though these enzymes
      recognize entirely different substrates. In this study, proteolysis and molecular
      modeling of MutY were used to elucidate its domain organization. Proteolysis by
      trypsin cleaved the enzyme into 26- and 13-kDa fragments. NH2-terminal sequencing
      showed that the p13 domain begins at Gln226, indicating that the COOH-terminal
      portion of MutY, absent in endonuclease III, is organized as a separate domain.
      The large p26 domain is almost equivalent to the size of endonuclease III.
      Binding activity of the p26 domain to a DNA substrate containing an A.G mismatch
      was comparable with that of the intact enzyme. In vitro studies show that the p26
      domain retains adenine glycosylase and AP lyase activity on DNA containing
      undamaged adenine opposite guanine or 8-oxo-7,8-dihydro-2'-deoxyguanine. Although
      the activity was somewhat reduced, the above results show that the critical amino
      acid residues involved in substrate binding and catalysis are present in this
      domain. The structure predicted by molecular modeling indicates that the region
      of MutY (Met1-Trp216), which is homologous to endonuclease III exhibits a two
      domain structure, even though this portion is resistant to proteolysis by
      trypsin.

PMID- 8663136
TI  - A weakly inward rectifying potassium channel of the salmon brain. Glutamate 179
      in the second transmembrane domain is insufficient for strong rectification.
AB  - A cDNA encoding for a weakly inward rectifying K+ channel (sWIRK: salmon weakly
      inward rectifying K+ channel) was isolated from the masu salmon brain by
      expression cloning. The sWIRK channel exhibited the highest similarity with
      members of the ROMK1 subfamily, BIR10/KAB-2 (70% amino acid identity) and ROMK1
      (46%). An ATP binding motif which is characteristic of this subfamily was also
      conserved. The sWIRK RNA was detected in the brain, but not in the heart, kidney,
      skeletal muscle, liver, testis, and ovary. In the brain, the expression was
      observed in the ependymoglial cells on the surface of the ventricles as well as
      in the small perineuronal glia-like cells in the midbrain and the medulla. When
      compared with the strong inward rectifier IRK1 channel, the sWIRK channel showed
      a much weaker inward rectification property, and the activation kinetics upon
      hyperpolarization was slower and less voltage-dependent. The slope conductance of
      the single channel inward current was 37 pS (140 mM K+o), and outward current
      channel events were also observed. The weak rectification of sWIRK is significant
      in that it has a negatively charged residue (glutamate) in the M2 region which is
      reported to cause strong inward rectification. By introducing a point mutation to
      remove this negative charge (glutamine), the sWIRK E179Q mutant channel lost its
      inward rectification property completely, and the single channel property (45 pS;
      140 mM K+o) was ohmic up to highly depolarized potential, even in the presence of
      the physiological cytoplasmic blockers such as Mg2+ and polyamines.

PMID- 8663137
TI  - Additions and Corrections to The ligand binding site of the neurokinin 2
      receptor. Site-directed mutagenesis and identification of neurokinin A binding
      residues in the human neurokinin 2 receptor.

PMID- 8663140
TI  - Mouse p170 is a novel phosphatidylinositol 3-kinase containing a C2 domain.
AB  - Phosphatidylinositol (PI) 3-kinases catalyze the formation of 3'
      phosphoinositides, which appear to promote cellular responses to growth factors
      and such membrane trafficking events as insulin-stimulated translocation of
      intracellular glucose transporters. We report here the cloning of a novel PI 3
      kinase, p170, from cDNA of insulin-sensitive mouse 3T3-L1 adipocytes. Mouse p170
      utilizes PI and to a limited extent PI 4-P as substrates, in contrast to the PI
      specific yeast VPS34 homolog PtdIns 3-kinase and the p110 PI 3-kinases, which
      phosphorylate PI, PI 4-P, and PI 4,5-P2. Mouse p170 is also distinct from PtdIns
      3-kinase or the p110 PI 3-kinases in exhibiting a 10-fold lower sensitivity to
      wortmannin. Unique structural elements of p170 include C-terminal sequences
      strikingly similar to the phosphoinositide-binding C2 domain of protein kinase C
      isoforms, synaptotagmins, and other proteins. These features of mouse p170 are
      shared with a recently cloned Drosophila PI 3-kinase, DmPI3K_68D. Together, these
      proteins define a new class of PI 3-kinase likely influenced by cellular
      regulators distinct from those acting upon p110- or VPS34-like PI 3-kinases.

PMID- 8663141
TI  - A cis-acting DNA element located between TATA box and transcription initiation
      site is critical in response to regulatory sequences in human angiotensinogen
      gene.
AB  - The promoter of the human angiotensinogen (hAG) gene functioned in its own core
      promoter context but not when replaced with simian virus 40 (SV40) core promoter,
      suggesting the presence of a transcriptionally important cis-acting sequence.
      Electrophoretic mobility shift assays demonstrated that a ubiquitously expressed
      nuclear factor, AGCF1, bound to AGCE1 (hAG core promoter element 1; positions -25
      to -1) located between the TATA box and transcription initiation site.
      Substitution mutation in AGCE1 which disrupted AGCF1 binding affected the
      promoter activity more severely than a nonsense mutation of the hAG TATA
      sequences did. When AGCE1 was placed at the downstream of SV40 core promoter, the
      responsiveness to hAG upstream region was significantly restored. Furthermore,
      mutation and in vivo competition experiments suggested that AGCF1 acts as a
      critical regulator of hAG transcription by mediating the activity of the hAG
      upstream and downstream enhancer elements. DNase I footprinting and UV cross
      linking analyses showed that AGCF1 with apparent molecular masses of 31, 33, and
      43 kDa as the components protected the region from -26 to -9 which partially
      overlapped with the TATA box consensus sequences. These findings indicate that
      AGCE1 in addition to the TATA box plays a key role in mediating the hAG
      regulatory elements.

PMID- 8663142
TI  - Antigen binding properties of purified immunoglobulin A and reconstituted
      secretory immunoglobulin A antibodies.
AB  - The hybridoma cell line ZAC3 expresses Vibrio cholerae lipopolysaccharide (LPS)
      specific mouse IgA molecules as a heterogeneous population of monomeric (IgAm),
      dimeric (IgAd), and polymeric (IgAp) forms. We describe a gentle method combining
      ultrafiltration, ion-exchange chromatography, and size exclusion chromatography
      for the simultaneous and qualitative separation of the three molecular forms.
      Milligram quantities of purified IgA molecules were recovered allowing for direct
      comparison of the biological properties of the three forms. LPS binding
      specificity was tested after purification; IgAd and IgAp were found to bind
      strongly to LPS whereas IgAm did not. Secretory IgA (sIgA) could be reconstituted
      in vitro by combining recombinant secretory component (rSC) and purified IgAd or
      IgAp, but not IgAm. Surface plasmon resonance-based binding experiments using LPS
      monolayers indicated that purified reconstituted sIgA and IgA molecules recognize
      LPS with identical affinity (KA 1.0 x 10(8)M-1). Thus, this very sensitive assay
      provides the first evidence that the function of SC in sIgA complex is not to
      modify the affinity for the antigen. KA falls to 6.6 x 10(5) M-1 when measured by
      calorimetry using detergent-solubilized LPS and IgA, suggesting that the LPS
      environment is critical for recognition by the antibody.

PMID- 8663143
TI  - Activation of proton pumping in human neutrophils occurs by exocytosis of
      vesicles bearing vacuolar-type H+-ATPases.
AB  - Proton pump activity is not measurable in the plasma membrane of unstimulated
      neutrophils but becomes readily detectable upon activation by soluble agonists.
      The mechanism of pump activation was investigated in this report. V-type H+ pump
      activity, estimated as a bafilomycin A1-sensitive elevation of the cytosolic pH,
      was stimulated in suspended neutrophils by chemotactic peptides and by phorbol
      esters. Stimulation of pump activity induced by the agonists was greatly enhanced
      by cytochalasin B, an agent known to potentiate granular secretion in
      neutrophils. We therefore compared the rate and extent of pump activation with
      the pattern of exocytosis of the four types of secretory organelles present in
      neutrophils, using flow cytometry and enzyme-linked immunosorbent assay. The
      kinetics of exocytosis of secretory vesicles and secondary and tertiary granules
      but not primary granules paralleled the appearance of pump activity. The
      subcellular localization of the pump was defined by cellular fractionation and
      immunoblotting using an antibody to the C subunit of the V-type ATPase. The pump
      was abundant in tertiary granules, with significant amounts present also in
      primary granules and secretory vesicles. The pump was scarce in secondary
      granules and not detectable in the cytosol. Finally, the agonists failed to
      stimulate pump activity in neutrophil cytoplasts, which are intact cell fragments
      devoid of acidic granules. Together, our results suggest that the V-type H+
      ATPase is not constitutively present in the plasma membrane of neutrophils but is
      delivered to the surface membrane by exocytosis during cellular activation.
      Tertiary granules and secretory vesicles are the most likely source of V-ATPases.
      Following insertion in the plasma membrane, the pump is poised to effectively
      extrude the excess metabolic acid that is generated during chemotaxis and
      bacterial killing.

PMID- 8663144
TI  - Control of starch composition and structure through substrate supply in the
      monocellular alga Chlamydomonas reinhardtii.
AB  - In Chlamydomonas, as in higher plants, synthesis of ADP glucose catalyzed by ADP
      glucose pyrophosphorylase is rate-limiting for the building of starch in the
      chloroplast. We have isolated disruptions of the STA1 ADP-glucose
      pyrophosphorylase structural gene that rendered the enzyme less responsive to the
      allosteric activator 3-phosphoglycerate. The structure and composition of the
      residual starch synthesized by all mutants of the STA1 locus is dramatically
      altered. The residual polysaccharide is shown to be devoid of amylose despite the
      presence of granule-bound starch synthase, the amylose biosynthetic enzyme. In
      addition, the fine structure of the mutant amylopectin revealed the presence of
      an altered chain-length distribution. This distribution mimicks that which is
      observed during growth and photosynthesis and differs markedly from that observed
      during storage. We therefore propose that low nucleotide sugar concentrations are
      either directly or indirectly responsible for the major differences observed in
      the composition or structure of starch during storage and photosynthesis.

PMID- 8663145
TI  - Interleukin-1beta and glutamate activate the NF-kappaB/Rel binding site from the
      regulatory region of the amyloid precursor protein gene in primary neuronal
      cultures.
AB  - We originally reported that members of the family of transcription factors NF
      kappaB/Rel can specifically recognize two identical sequences, referred to as
      APPkappaB sites, which are present in the 5'-regulatory region of the APP gene.
      Here we show that the APPkappaB sites interact specifically with a complex which
      contains one of the subunits of the family, defined as p50 protein, and that they
      act as positive modulators of gene transcription in cells of neural origin.
      Additionally, the nuclear complex specifically binding to the APPkappaB sites is
      constitutively expressed in primary neurons from rat cerebellum and it is up
      regulated in response to both the inflammatory cytokine interleukin-1beta (IL
      1beta) and the excitatory amino acid glutamate. Since IL-1, whose levels are
      known to be induced in brain of individuals affected by Alzheimer's disease, and
      glutamate, are stimuli which have been regarded as major actors on the stage of
      neurodegenerative processes, we believe our evidence as potentially relevant for
      understanding the neuropathology associated with Alzheimer's disease.

PMID- 8663147
TI  - TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic
      cascades through the thrombin-thrombomodulin complex.
AB  - TAFI (thrombin-activatable fibrinolysis inhibitor) is a recently discovered
      plasma protein that can be activated by thrombin-catalyzed proteolysis to a
      carboxypeptidase B-like enzyme that inhibits fibrinolysis. This work shows that
      the thrombin-thrombomodulin complex, rather than free thrombin, is the most
      likely physiologic activator. Thrombomodulin increases the catalytic efficiency
      of the reaction by a factor of 1250, an effect expressed almost exclusively
      through an increase in kcat. The kinetics of the reaction conform to a model
      whereby thrombin can interact with either TAFI (Km = 1.0 microM) or
      thrombomodulin (Kd = 8.6 nM), and either binary complex so formed can then
      interact with the third component to form the ternary thrombin-thrombomodulin
      TAFI complex from which activated TAFI is produced with kcat = 1.2 s-1. This work
      also shows that activated TAFI down-regulates tPA-induced fibrinolysis half
      maximally at a concentration of 1.0 nM in a system of purified components. This
      concentration of TAFI is about 2% of the level of the zymogen in plasma, which
      indicates that ample activated TAFI could be generated to very significantly
      modulate fibrinolysis in vivo. Therefore, TAFI in vitro and possibly in vivo
      defines an explicit molecular connection between the coagulation and fibrinolytic
      cascades, such that expression of activity in the former down-regulates the
      activity of the latter.

PMID- 8663146
TI  - The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1
      protein interact with a protein-arginine N-methyltransferase.
AB  - The TIS21 immediate-early gene and leukemia-associated BTG1 gene encode proteins
      with similar sequences. Two-hybrid analysis identified a protein that interacts
      with TIS21 and BTG1. Sequence motifs associated with S-adenosyl-L-methionine
      binding suggested this protein might have methyltransferase activity. A
      glutathione S-transferase (GST) fusion of the putative methyltransferase modifies
      arginine residues, in appropriate protein substrates, to form NG-monomethyl and
      NG,NG-dimethylarginine (asymmetric). We term the protein- arginine N
      methyltransferase (EC 2.1.1.23) gene "PRMT1, " for protein-arginine
      methyltransferase 1. GST-TIS21 and GST-BTG1 fusion proteins qualitatively and
      quantitatively modulate endogenous PRMT1 activity, using control and
      hypomethylated RAT1 cell extracts as methyl-accepting substrates. PRMT1 message
      appears ubiquitous, and is constitutive in mitogen-stimulated cells. Modulation
      of PRMT1 activity by transiently expressed regulatory subunits may be an
      additional mode of signal transduction following ligand stimulation.

PMID- 8663148
TI  - A 3' --> 5' XPB helicase defect in repair/transcription factor TFIIH of xeroderma
      pigmentosum group B affects both DNA repair and transcription.
AB  - XPB is a subunit of the basal transcription factor TFIIH, which is also involved
      in nucleotide excision repair (NER) and potentially in cell cycle regulation. A
      frameshift mutation in the 3'-end of the XPB gene is responsible for a
      concurrence of two disorders: xeroderma pigmentosum (XP) and Cockayne's syndrome
      (CS). We have isolated TFIIH from cells derived from a patient (XP11BE) who
      carries this frameshift mutation (TFIIHmut) and from the mother of this patient
      (TFIIHwt) to determine the biochemical consequences of the mutation. Although
      identical in composition and stoichiometry to TFIIHwt, TFIIHmut shows a reduced
      3' --> 5' XPB helicase activity. A decrease in helicase and DNA-dependent ATPase
      activities was also observed with the mutated recombinant XPB protein. The XPB
      mutation causes a severe NER defect. In addition, we provide evidence for a
      decrease in basal transcription activity in vitro. The latter defect may provide
      an explanation for many of the XP and CS symptoms that are difficult to
      rationalize based solely on an NER defect. Thus, this work presents the first
      detailed analysis of a naturally occurring mutation in a basal transcription
      factor and supports the concept that the combined XP/CS clinical entity is
      actually the result of a combined transcription/repair deficiency.

PMID- 8663149
TI  - Protein kinase C beta II specifically binds to and is activated by F-actin.
AB  - The two most closely related isoenzymes of protein kinase C (PKC), PKC betaI and
      betaII, are distinct but highly homologous isoenzymes derived via alternative
      splicing of the same gene product. In this study, PKC betaII, but not PKC betaI,
      translocated to the actin cytoskeleton upon stimulation of cells with phorbol
      esters. In cells, antibodies to PKC betaII, but not to PKC betaI, co
      immunoprecipitated actin. Using an actin-binding co-sedimentation assay, we show
      in vitro that PKC betaII, but not PKC betaI, binds to actin specifically. This
      binding was inhibited by peptides based on sequences unique to PKC betaII; thus
      defining an actin-binding site in PKC betaII that is not present in PKC betaI.
      The binding of PKC betaII to actin was not inhibited by kinase inhibitors of PKC
      (sphingosine and staurosporine), suggesting that prior activation and/or
      substrate phosphorylation are not required for the interaction of PKC betaII with
      actin. On the other hand, the interaction of PKC betaII with actin resulted in
      marked enhancement of autophosphorylation of PKC betaII and in an alteration in
      substrate specificity. These studies serve to define a novel functional domain in
      the carboxyl-terminal region of PKC beta, which is involved in directing
      isoenzyme-specific protein-protein interactions, and consequently, isoenzyme
      specific functions in vivo.

PMID- 8663150
TI  - Post-translational modification of CD38 protein into a high molecular weight form
      alters its catalytic properties.
AB  - Human CD38 is a 45-kDa transmembrane protein that acts as a bifunctional
      ectoenzyme, catalyzing the synthesis of cyclic ADP-ribose (cADPR) from NAD+ and
      the hydrolysis of cADPR to ADP-ribose. All-trans-retinoic acid (RA) is a potent
      and specific inducer of CD38 in myeloid cells. In this report, we demonstrate
      that RA-induced CD38 protein from human myeloid (HL-60) leukemia cells
      coimmunoprecipitates with another protein of molecular mass approximately190 kDa
      (p190). The p190 protein is localized exclusively in the membranes and is a
      consequence of post-translational cross-linking of CD38 protein. This conclusion
      was based on the observations that purified CD38 effectively competes with p190,
      its accumulation is preceded by the accumulation of CD38, it immunoreacted with
      three different monospecific anti-CD38 antibodies on immunoblots, and its peptide
      map revealed several peptides in common with CD38. Furthermore, CD38 could serve
      as a suitable substrate for transglutaminase (TGase)-catalyzed cross-linking
      reactions in vitro, and the accumulation of p190 in RA-treated HL-60 cells is
      effectively blocked by the presence of TGase-specific inhibitor. The purified
      p190 showed at least three times more cyclase activity than CD38. Conversely,
      p190 was at least 2.5-fold less active than CD38 in hydrolyzing cADPR to ADPR.
      These results suggest that post-translational modification of CD38 may represent
      an important mechanism for regulating the two catalytic activities of this
      bifunctional enzyme.

PMID- 8663151
TI  - Adenovirus-mediated transfer of a truncated transforming growth factor-beta (TGF
      beta) type II receptor completely and specifically abolishes diverse signaling by
      TGF-beta in vascular wall cells in primary culture.
AB  - We constructed an adenoviral vector expressing a mutated human type II
      transforming growth factor-beta (TGF-beta) receptor that was truncated of its
      kinase domain (AdexCATbetaTR) and examined whether this truncated receptor could
      abolish signaling by TGF-beta using arterial endothelial cells and smooth muscle
      cells, as well as a lung epithelial cell line (Mv1Lu). Infection of cells with
      AdexCATbetaTR induced expression of the truncated receptor, the amount of which
      would be excessive compared with those of both full-length type I and type II
      receptors, as assessed by levels of their mRNAs. The antiproliferative effect of
      TGF-beta was completely eliminated in both endothelial cells and Mv1Lu that were
      infected with AdexCATbetaTR. The transcriptional activation by TGF-beta of
      plasminogen activator inhibitor-1 and fibronectin was entirely suppressed.
      Abrogation of the TGF-beta-enhanced production of type I collagen in infected
      smooth muscle cells was confirmed by immunocytostaining and by [14C]proline
      incorporation in a quantitative manner. Mitogenic response to other growth
      factors remained unaffected in infected cells. Our data demonstrated that the
      adenovirus-mediated transfer of a truncated type II TGF-beta receptor completely
      and specifically abolishes the diverse effects of TGF-beta as a dominant-negative
      mutation, supporting the hypothesis that both the type I and type II receptors
      are required for all signaling by TGF-beta. This method may facilitate the
      clarification of the role of TGF-beta both in vitro and in vivo.

PMID- 8663152
TI  - Spontaneous and protein-mediated sterol transfer between intracellular membranes.
AB  - Relatively little is known regarding intracellular cholesterol trafficking
      pathways. To resolve some of these potential pathways, spontaneous and protein
      mediated sterol transfer was examined between different donor-acceptor membrane
      pairs in vitro using L-cell fibroblast plasma membrane (PM) and microsomal
      (MICRO) and mitochondrial (MITO) membranes. Several new exciting insights were
      provided. First, the initial rate of spontaneous molecular sterol transfer was
      more dependent on the type of acceptor than donor membrane, i.e. spontaneous
      intracellular sterol trafficking was vectorial. Therefore, the rate of sterol
      desorption from the donor membrane was not necessarily the rate-limiting step in
      molecular sterol transfer. Second, the rate of molecular sterol transfer was not
      obligatorily correlated with the direction of the cholesterol gradient. For
      example, although PM had a 3.2-fold higher cholesterol/phospholipid ratio than
      MITO, spontaneous sterol transfer was 4-5-fold faster up (MITO to PM) rather than
      down (PM to MITO) the concentration gradient. Third, sterol carrier protein-2
      differentially stimulated the initial rate of sterol transfer for all donor
      acceptor combinations, being most effective with PM donors: PM-MICRO, 27-fold;
      and PM-MITO, 12-fold. Sterol carrier protein-2 was less effective in enhancing
      sterol transfer in the reverse direction, i.e. MICRO-PM and MITO-PM (5- and 4
      fold, respectively). Fourth, liver fatty acid-binding protein was limited in
      stimulating the initial rate of sterol transfer from PM to PM (1.5-fold), from PM
      to MITO (3-fold), and from MICRO to MITO (3-fold). In summary, these observations
      present important insights into potential sterol trafficking pathways between the
      major membrane components of the cell.

PMID- 8663153
TI  - Chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptor
      polypeptide subunits in mouse cortical neurons in culture.
AB  - The goal of this study was to determine whether chronic ethanol-mediated up
      regulation of the N-methyl-D-aspartate receptors (NMDAR) was associated with an
      augmentation of the NMDAR polypeptide subunits in the mammalian cortical neurons.
      The results show that chronic ethanol treatment produced an increase in the R1
      and R2B polypeptide subunits. The R2A subunit was not expressed in these neurons.
      Chronic NMDAR antagonist ((+)-3-2-(carboxypiperazin-4-yl)propyl-1-phosphonic acid
      (CPP)) treatment also increased the R1 and R2B polypeptide subunits. A similar
      increase was observed when ethanol and CPP were used in combination. Binding
      studies using [3H]MK-801 ((+)-5-methyl-10, 11-dihydro-5H
      dibenzo[a,d]cyclophenptan-5,10-imine maleate), a noncompetitive NMDAR antagonist,
      confirmed that concomitant exposure of ethanol and CPP up-regulated the NMDAR.
      Our results demonstrate for the first time that chronic ethanol treatment
      increased the NMDA receptor polypeptide subunit synthesis and that it was
      associated with an increase in [3H]MK-801 binding sites.

PMID- 8663154
TI  - Identification of a novel syntaxin- and synaptobrevin/VAMP-binding protein, SNAP
      23, expressed in non-neuronal tissues.
AB  - The specificity of vesicular transport is regulated, in part, by the interaction
      of a vesicle-associated membrane protein termed synaptobrevin/VAMP with a target
      compartment membrane protein termed syntaxin. These proteins, together with SNAP
      25 (synaptosome-associated protein of 25 kDa), form a complex which serves as a
      binding site for the general membrane fusion machinery. Synaptobrevin/VAMP and
      syntaxin are ubiquitously expressed proteins and are believed to be involved in
      vesicular transport in most (if not all) cells. However, SNAP-25 is present
      almost exclusively in the brain, suggesting that a ubiquitously expressed homolog
      of SNAP-25 exists to facilitate transport vesicle/target membrane fusion in other
      tissues. Using the yeast two-hybrid system, we have identified a 23-kDa protein
      from human B lymphocytes (termed SNAP-23) that binds tightly to multiple
      syntaxins and synaptobrevins/VAMPs in vitro. SNAP-23 is 59% identical with SNAP
      25. Unlike SNAP-25, SNAP-23 was expressed in all tissues examined. These findings
      suggest that SNAP-23 is an essential component of the high affinity receptor for
      the general membrane fusion machinery and an important regulator of transport
      vesicle docking and fusion in all mammalian cells.

PMID- 8663155
TI  - Purification and characterization of human ZAP-70 protein-tyrosine kinase from a
      baculovirus expression system.
AB  - The ZAP-70 protein tyrosine kinase is essential for T cell antigen receptor (TCR)
      mediated signaling. The absence of ZAP-70 results in impaired differentiation of
      T cells and a lack of responsiveness to antigenic stimulation. In order to study
      the characteristics of ZAP-70 in vitro, we overexpressed an epitopically tagged
      human ZAP-70 in a recombinant baculovirus expression system and purified it by
      column chromatography. The kinase activity of purified, recombinant ZAP-70
      required cation and exhibited a strong preference for Mn2+ over Mg2+. The
      apparent Km of ZAP-70 for ATP was approximately 3.0 microM. The activity of the
      recombinant ZAP-70, unlike that of the homologous protein tyrosine kinase, Syk,
      was not affected by binding of TCR-derived tyrosine phosphorylated immunoreceptor
      tyrosine-based activation motif peptides. Several proteins were tested as
      potential in vitro substrates of ZAP-70. Only alpha-tubulin and the cytoplasmic
      fragment of human erythrocyte band 3 (cfb3), which have a region of sequence
      identity at the phosphorylation site, proved to be good substrates, exhibiting
      Kmvalues of approximately 3.3 and approximately 2.5 microM, respectively ([ATP] =
      50 microM). alpha- and beta-Casein were poor substrates for ZAP-70, and no
      activity toward enolase, myelin basic protein, calmodulin, histone proteins, or
      angiotensin could be detected. In contrast to the T cell protein tyrosine kinase,
      Lck, ZAP-70 did not phosphorylate the cytoplasmic portion of the TCRzeta chain or
      short peptides corresponding to the CD3epsilon or the TCRzeta immunoreceptor
      tyrosine-based activation motifs. Our studies suggest that ZAP-70 exhibits a high
      degree of substrate specificity.

PMID- 8663156
TI  - An amino acid substitution in the pore region of a glutamate-gated chloride
      channel enables the coupling of ligand binding to channel gating.
AB  - Many of the subunits of ligand-gated ion channels respond poorly, if at all, when
      expressed as homomeric channels in Xenopus oocytes. This lack of a ligand
      response has been thought to result from poor surface expression, poor assembly,
      or lack of an agonist binding domain. The Caenorhabditis elegans glutamate-gated
      chloride channel subunit GluClbeta responds to glutamate as a homomeric channel
      while the GluClalpha subunit is insensitive. A chimera between GluClalpha and
      GluClbeta was used to suggest that major determinants for glutamate binding are
      present on the GluClalpha N terminus. Amino acid substitutions in the presumed
      pore of GluClalpha conferred direct glutamate gating indicating that GluClalpha
      is deficient in coupling of ligand binding to channel gating. Heteromeric
      channels of GluClalpha+beta may differ from the prototypic muscle nicotinic
      acetylcholine receptor in that they have the potential to bind ligand to all of
      the subunits forming the channel.

PMID- 8663157
TI  - Molecular determinants of high affinity binding of alpha-scorpion toxin and sea
      anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel
      alpha subunit.
AB  - alpha-Scorpion toxins and sea anemone toxins bind to a common extracellular site
      on the Na+ channel and inhibit fast inactivation. Basic amino acids of the toxins
      and domains I and IV of the Na+ channel alpha subunit have been previously
      implicated in toxin binding. To identify acidic residues required for toxin
      binding, extracellular acidic amino acids in domains I and IV of the type IIa Na+
      channel alpha subunit were converted to neutral or basic amino acids using site
      directed mutagenesis, and altered channels were transiently expressed in tsA-201
      cells and tested for 125I-alpha-scorpion toxin binding. Conversion of Glu1613 at
      the extracellular end of transmembrane segment IVS3 to Arg or His blocked
      measurable alpha-scorpion toxin binding, but did not affect the level of
      expression or saxitoxin binding affinity. Conversion of individual residues in
      the IVS3-S4 extracellular loop to differently charged residues or to Ala
      identified seven additional residues whose mutation caused significant effects on
      binding of alpha-scorpion toxin or sea anemone toxin. Moreover, chimeric Na+
      channels in which amino acid residues at the extracellular end of segment IVS3 of
      the alpha subunit of cardiac Na+ channels were substituted into the type IIa
      channel sequence had reduced affinity for alpha-scorpion toxin characteristic of
      cardiac Na+ channels. Electrophysiological analysis showed that E1613R has 62-
      and 82-fold lower affinities for alpha-scorpion and sea anemone toxins,
      respectively. Dissociation of alpha-scorpion toxin is substantially accelerated
      at all potentials compared to wild-type channels. alpha-Scorpion toxin binding to
      wild type and E1613R had similar voltage dependence, which was slightly more
      positive and steeper than the voltage dependence of steady-state inactivation.
      These results indicate that nonidentical amino acids of the IVS3-S4 loop
      participate in alpha-scorpion toxin and sea anemone toxin binding to overlapping
      sites and that neighboring amino acid residues in the IVS3 segment contribute to
      the difference in alpha-scorpion toxin binding affinity between cardiac and
      neuronal Na+ channels. The results also support the hypothesis that this region
      of the Na+ channel is important for coupling channel activation to fast
      inactivation.

PMID- 8663158
TI  - Evidence against defective trans-Golgi acidification in cystic fibrosis.
AB  - Defective organelle acidification has been proposed as a unifying hypothesis to
      explain the pleiotropic cellular abnormalities associated with cystic fibrosis.
      To test whether cystic fibrosis transmembrane conductance regulator (CFTR)
      participates in trans-Golgi pH regulation, intraluminal trans-Golgi pH was
      measured in stably transfected Swiss 3T3 fibroblasts (expressing CFTR or
      DeltaF508-CFTR) and CFTR-expressing and nonexpressing epithelial cells. trans
      Golgi pH was measured by ratio-imaging confocal microscopy using a liposome
      injection procedure to label the lumen of trans-Golgi with fluid phase
      fluorescein and rhodamine chromophores (Seksek, O., Biwersi, J., and Verkman, A.
      S.(1995) J. Biol. Chem. 270, 4967-4970). Selective labeling of trans-Golgi was
      confirmed by colocalization of the delivered fluid phase fluorophores with N-(6
      [(7-nitrobenzo-2-oxa-1, 3-diazol-4-yl)amino]caproyl)-sphingosine. In unstimulated
      fibroblasts in HCO3--free buffer, trans- Golgi pH was 6.25 +/- 0.04 (mean +/-
      S.E.; n = 80, vector control), 6.30 +/- 0.03 (n = 74, CFTR) and 6.23 +/- 0.06 (n
      = 60, DeltaF508) (not significant). After stimulation of plasma membrane Cl-
      conductance by 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), trans-Golgi pH was 6.42 +/
      0.07 (n = 22, control), 6.47 +/- 0.07 (n = 20, CFTR), and 6.35 +/- 0. 07 (n =
      22, DeltaF508) (not significant). Similarly, significant pH differences were not
      found for control versus CFTR-expressing cells in 25 mM HCO3- buffer. In
      epithelial cells, which do not express CFTR, trans-Golgi pH was (in 25 mM HCO3-)
      6.36 +/- 0.04 (n = 33) and 6.34 +/- 0.08 (n = 23, CPT-cAMP) in MDCK cells and
      6.25 +/- 0.04 (n = 18) and 6.24 +/- 0.06 (n = 15, CPT-cAMP) in SK-MES-1 cells. In
      Calu-3 cells, which natively express CFTR, trans-Golgi pH was (in 25 mM HCO3-)
      6.19 +/- 0.05 (n = 25) and 6.17 +/- 0.08 (n = 23, CPT-cAMP). To test whether CFTR
      expression affects pH in the endosomal compartment in HCO3- buffer, pH was
      measured by ratio imaging in individual endosomes labeled with fluorescein
      rhodamine dextrans. Comparing control and CFTR-expressing fibroblasts, average
      endosome pH (range, 5.40-5.53 after 10 min; 4.79-4.89, 30 min) differed by <0.13
      unit, both before and after cAMP stimulation. These results indicate that CFTR
      expression and activation do not influence pH in the trans-Golgi and endosomal
      compartments, providing direct evidence against the defective acidification
      hypothesis.

PMID- 8663159
TI  - Schizosaccharomyces pombe proliferating cell nuclear antigen mutations affect DNA
      polymerase delta processivity.
AB  - We introduced nine site-directed mutations into seven conserved fission yeast
      proliferative cell nuclear antigen (PCNA) residues, Leu2, Asp63, Arg64, Gly69,
      Gln201, Glu259, and Glu260, either as single or as double mutants. Both the
      recombinant wild type and mutant PCNAs were able to form homotrimers in solution
      and to sustain growth of a null pcna strain (Deltapcna). Wild type
      Schizosaccharomyces pombe PCNA and PCNA proteins with mutations in Asp63, Gln201,
      Glu259, or Glu260 to Ala were able to stimulate DNA synthetic activity and to
      enhance the processivity of calf thymus DNA polymerase delta holoenzyme similar
      to calf thymus PCNA. Mutations of Leu2 to Val or Arg64 to Ala, either singly or
      as a double mutant, yielded PCNA mutant proteins that had reduced capacity in
      enhancing the processivity of DNA polymerase delta but showed no deficiency in
      stimulation of the ATPase activity of replication factor C. S. pombe Deltapcna
      strains sustained by these two mutant-pcna alleles had moderate defects in growth
      and displayed elongated phenotypes. These cells, however, were not sensitive to
      UV irradiation. Together, these in vitro and in vivo studies suggest that the
      side chains of Leu2 and Arg64 in one face of the PCNA trimer ring structure are
      two of the several sites involved in tethering DNA polymerase delta for
      processive DNA synthesis during DNA replication.

PMID- 8663160
TI  - ESR spin-trapping of a protein-derived tyrosyl radical from the reaction of
      cytochrome c with hydrogen peroxide.
AB  - The reaction of horse heart cytochrome c with hydrogen peroxide was investigated
      using the ESR spin-trapping technique and the nitroso spin traps 3,5-dibromo-4
      nitrosobenzenesulfonic acid (DBNBS) and 2-methyl-2-nitrosopropane (MNP). The ESR
      spectra obtained using both spin traps were typical of an immobilized nitroxide
      and indicated that the adduct was a macromolecule. The intensity of the ESR
      spectrum corresponding to the DBNBS/*cytochrome c radical adduct was greatly
      enhanced by performing the reaction under anaerobic conditions, which suggested
      that the spin trap was competing with O2 for reaction with the radical site(s).
      Nonspecific proteolysis of either the DBNBS or the MNP adducts revealed isotropic
      three-line spectra. In addition, a high resolution ESR spectrum for the protease
      treated MNP cytochrome c-derived protein radical adduct was obtained. The
      superhyperfine couplings detected in this spectra were identical to those
      detected from an authentic MNP/tyrosyl adduct. Carbon-13 labeling of the aromatic
      ring positions of tyrosine yielded additional hyperfine coupling, demonstrating
      that the radical site was definitely located on the ring of tyrosine. Mass
      spectrometry detected as many as four DBNBS/.cytochrome c-derived adducts from
      the reaction of cytochrome with H2O2. Thus, it would appear four radical sites
      are formed during the reaction, at least one of which is tyrosine.

PMID- 8663161
TI  - Multiple extracellular loop domains contribute critical determinants for agonist
      binding and activation of the secretin receptor.
AB  - Distinct themes exist for ligand-binding domains of G protein-coupled receptors.
      The secretin receptor is prototypic of a recently described family in this
      superfamily which binds moderate-sized peptides possessing a diffuse
      pharmacophore. We recently demonstrated the importance of the N terminus and
      first loop of this receptor for secretin binding (Holtmann, M. H., Hadac, E. M.,
      and Miller, L. J. (1995) J. Biol. Chem. 270:14394-14398). Here, we extend those
      findings to define another receptor domain important for agonist recognition and
      to focus on critical determinants within each of these domains. Extending the
      secretin-vasoactive intestinal polypeptide (VIP) chimeric receptor approach, we
      confirmed and refined the critical importance of the N terminus and the need to
      complement this with other domains of the secretin receptor. There was redundancy
      in the complementary determinants required, with the second extracellular loop
      able to compensate for the absence of the first loop. The first 10 residues of
      the N terminus of the secretin receptor were critical. Sequential segmental and
      site replacements permitted focusing on the His189-Lys190 sequence at the C
      terminus of the first extracellular loop, and on four residues (Phe257, Leu258,
      Asn260, and Thr261) in the N-terminal half of the second loop as providing
      critical determinants. All receptor constructs which expressed sensitive cAMP
      responses to secretin (EC50 <5 nM) bound this peptide with high affinity. Of
      note, one construct dissociated high affinity binding of secretin from its
      biological responsiveness, providing a clue to the conformational "switch" that
      activates this receptor.

PMID- 8663162
TI  - Regulation of the biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid.
AB  - The synthesis of 4,7,10,13,16,19-docosahexaenoic acid (22:6(n-3)) requires that
      when 6,9,12,15,18,21-tetracosahexaenoic acid (24:6(n-3)) is produced in the
      endoplasmic reticulum, it preferentially moves to peroxisomes for one cycle of
      beta-oxidation rather than serving as a substrate for membrane lipid synthesis.
      Both 24:6(n-3) and its precursor, 9,12,15,18,21-tetracosapentaenoic acid (24:5(n
      3)), were poor substrates for acylation into 1-acyl-sn-glycero-3-phosphocholine
      (1-acyl-GPC) by rat liver microsomes. When peroxisomes were incubated with 1-14C-
      or 3-14C-labeled 7,10,13,16,19-docosapentaenoic acid (22:5(n-3)), [1-14C]22:6(n
      3), [3-14C]24:5(n-3), or [3-14C]24:6(n-3), only small amounts of acid-soluble
      radioactivity were produced when double bond removal at positions 4 and 5 was
      required. When microsomes and 1-acyl-GPC were included in incubations, the
      preferred metabolic fate of acids, with their first double bond at either
      positions 4 or 5, was to move out of peroxisomes for esterification into the
      acceptor rather than serving as substrates for continued beta-oxidation. When [1
      14C]22:6(n-3) or [3-14C]24:6(n-3) was incubated with peroxisomes, 2-trans
      4,7,10,13,16,19-22:7 accumulated. The first cycle of 20:5(n-3) beta-oxidation
      proceeds through 2-trans-4,8,11,14,17-20:6 and thus requires both
      Delta3,5,Delta2, 4-dienoyl-CoA isomerase and 2,4-dienoyl-CoA reductase. The
      accumulation of the substrate for 2,4-dienoyl-CoA reductase, as generated from
      22:6(n-3), but not from 20:5(n-3), suggests that this enzyme distinguishes
      between subtle structural differences. When 22:6(n-3) is produced from 24:6(n-3),
      its continued degradation is impaired because of low 2,4-dienoyl-CoA reductase
      activity. This slow reaction rate likely contributes to the transport of 22:6(n
      3) out of peroxisomes for rapid acylation into 1-acyl-GPC by microsomes.

PMID- 8663164
TI  - Amino acid resolution of halothane binding sites in serum albumin.
AB  - Saturable binding of various inhaled anesthetics to serum albumin has been shown
      with a variety of approaches. In order to determine the location of halothane
      binding sites in serum albumin, both human and bovine serum albumins (HSA and
      BSA) were photolabeled with [14C]halothane, and subjected to proteolysis and
      microsequencing. BSA was found to have a higher affinity for halothane than HSA,
      and it contained two specifically labeled sites. One site was characterized by
      diffuse labeling from Trp212-Leu217, and the other by a more discrete and higher
      affinity labeling at Trp134-Gly135. HSA contained only a single labeled site, and
      although lower affinity, was determined to be analogous to BSA Trp212. The
      position 130-140 region of HSA, having a leucine instead of tryptophan at
      position 134, was not labeled. These results demonstrate specific and discrete
      binding of an inhaled anesthetic to a mammalian-soluble protein, and further
      suggest the importance of aromatic residues as one feature of inhaled anesthetic
      binding sites.

PMID- 8663163
TI  - A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits
      both receptor dimerization and activation.
AB  - One of the assumptions of the mobile receptor hypothesis as it relates to G
      protein-coupled receptors is that the stoichiometry of receptor, G protein, and
      effector is 1:1:1 (Bourne, H. R., Sanders, D. A., and McCormick, F.(1990) Nature
      348, 125-132). Many studies on the cooperativity of agonist binding are
      incompatible with this notion and have suggested that both G proteins and their
      associated receptors can be oligomeric. However, a clear physical demonstration
      that G protein-coupled receptors can indeed interact as dimers and that such
      interactions may have functional consequences was lacking. Here, using
      differential epitope tagging we demonstrate that beta2-adrenergic receptors do
      form SDS-resistant homodimers and that transmembrane domain VI of the receptor
      may represent part of an interface for receptor dimerization. The functional
      importance of dimerization is supported by the observation that a peptide derived
      from this domain that inhibits dimerization also inhibits beta-adrenergic agonist
      promoted stimulation of adenylyl cyclase activity. Moreover, agonist stimulation
      was found to stabilize the dimeric state of the receptor, while inverse agonists
      favored the monomeric species, which suggests that interconversion between
      monomeric and dimeric forms may be important for biological activity.

PMID- 8663165
TI  - Identification of the phospholipid binding site in the vitamin K-dependent blood
      coagulation protein factor IX.
AB  - The blood coagulation and regulatory proteins that contain gamma-carboxyglutamic
      acid are a part of a unique class of membrane binding proteins that require
      calcium for their interaction with cell membranes. Following protein
      biosynthesis, glutamic acids on these proteins are converted to gamma
      carboxyglutamic acid (Gla) in a reaction that requires vitamin K as a cofactor.
      The vitamin K-dependent proteins undergo a conformational transition upon metal
      ion binding, but only calcium ions mediate protein-phospholipid interaction. To
      identify the site on Factor IX that is required for phospholipid binding, we have
      determined the three-dimensional structure of the Factor IX Gla domain bound to
      magnesium ions by NMR spectroscopy. By comparison of this structure to that of
      the Gla domain bound to calcium ions, we localize the membrane binding site to a
      highly ordered structure including residues 1-11 of the Gla domain. In the
      presence of Ca2+, Factor IX Gla domain peptides that contain the photoactivatable
      amino acid p-benzoyl-L-phenylalanine at positions 6 or 9 cross-link to
      phospholipid following irradiation, while peptides lacking this amino acid analog
      or with this analog at position 46 did not cross-link. These results indicate
      that the NH2 terminus of the Gla domain, specifically including leucine 6 and
      phenylalanine 9 in the hydrophobic patch, is the contact surface on Factor IX
      that interacts with the phospholipid bilayer.

PMID- 8663166
TI  - A yeast phosphofructokinase insensitive to the allosteric activator fructose 2,6
      bisphosphate. Glycolysis/metabolic regulation/allosteric control.
AB  - In this work we used in vitro mutagenesis to modify the allosteric properties of
      the heterooctameric yeast phosphofructokinase. Specifically, we identified two
      amino acids involved in the binding of the most potent allosteric activator
      fructose 2,6-bisphosphate. Thus, Ser724 was replaced by an aspartate and His859
      by a serine in each of the enzyme subunits. Whereas the substitutions had no
      drastic effects when introduced only in one of the two types of subunits, kinetic
      parameters were modified when both subunits carried the mutation. Thus, the
      enzyme with His859 --> Ser showed an increase in Ka for binding of the activator,
      whereas the one with Ser724 --> Asp failed to react to the addition of fructose
      2, 6-bisphosphate, at all. The enzymes still responded to other allosteric
      activators, such as AMP. Stabilities of the mutant subunits were not
      significantly altered in vivo, as judged from Western blot analysis.
      Phenotypically, strains expressing the mutant PFK genes showed a pronounced
      effect on the level of intermediary metabolites after growth on glucose. Mutants
      not responding to the activator at all (Ser724 --> Asp) also displayed higher
      generation times on glucose medium. This could be suppressed by increasing the
      gene dosage of the mutant alleles. These results indicate that fructose 2,6
      bisphosphate through its activation of phosphofructokinase plays an important
      role in regulation of the glycolytic flux.

PMID- 8663167
TI  - Transport between cis and medial Golgi cisternae requires the function of the Ras
      related protein Rab6.
AB  - The small GTP-binding protein Rab6, a member of the Ras superfamily, is localized
      on the membranes of the Golgi apparatus and the trans Golgi network. Recent
      studies revealed that the Rab6 protein might be involved in the transit of
      proteins through the Golgi complex. In this report we demonstrate the essential
      function of the Rab6 protein in a distinct step of reconstituted Golgi transport.
      Polyclonal antibodies and Fab fragments directed against the C-terminal part of
      the Rab6 protein inhibit transport between the cis and the medial Golgi
      cisternae. Inhibition also occurred when a trans-dominant mutant form of the Rab6
      protein (N126I) was added to the reconstituted transport. Furthermore, Rab6
      antibodies inhibit uncoupled fusion of Golgi membranes. From these data we
      conclude that Rab6 is involved in a process related to membrane fusion at the
      cisternal membranes of the Golgi apparatus and therefore is needed for the
      consumption of Golgi-derived vesicles by their target membranes.

PMID- 8663168
TI  - Molecular cloning and expression of a third type of rabbit GDP-L-fucose:beta-D
      galactoside 2-alpha-L-fucosyltransferase.
AB  - Recent molecular investigation revealed that two closely related structural genes
      encode distinct GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferases
      (alpha1,2-fucosyltransferases). Some human cancer cells or tissues may express an
      aberrant alpha1, 2-fucosyltransferase other than H- and Secretor-type alpha1, 2
      fucosyltransferase. However, definite evidence of the existence of a third type
      of alpha1,2-fucosyltransferase has not been demonstrated. Here we report the
      molecular cloning of a third type of rabbit alpha1,2-fucosyltransferase (RFT-III)
      from a rabbit genomic DNA library. The DNA sequence included an open reading
      frame coding for 347 amino acids, and the deduced amino acid sequence of RFT-III
      showed 59 and 80% identity with those of the previously reported two types of
      rabbit alpha1,2-fucosyltransferase, RFT-I and RFT-II, respectively. COS-7 cells
      transfected with the RFT-III gene exhibited alpha1,2-fucosyltransferase activity
      toward phenyl-beta-Gal as a substrate. Neuro2a (a murine neuroblastoma cell line)
      cells transfected with the RFT-III gene expressed fucosyl GM1 (type 3 H) but not
      Ulex europaeus agglutinin-1 lectin reactive antigens (type 2 H). Kinetic studies
      revealed that RFT-III exhibits higher affinity to types 1 (Galbeta1, 3GlcNAc) and
      3 (Galbeta1, 3GalNAc) than to type 2 (Galbeta1, 4GlcNAc) oligosaccharides, which
      suggests that RFT-III as well as RFT-II is a Secretor-type alpha1, 2
      fucosyltransferase. RFT-III was expressed in the adult gastrointestinal tract.
      The RFT-I, -II, and -III genes were assigned within 90 kilobases on pulsed field
      gel electrophoresis analysis. These results constitute direct evidence that, at
      least in one mammalian species, three active alpha1,2-fucosyltransferases exist.

PMID- 8663169
TI  - Catalytic activity of type II iodothyronine 5'-deiodinase polypeptide is
      dependent upon a cyclic AMP activation factor.
AB  - Type II iodothyronine 5'-deiodinase is an approximately 200-kDa multimeric enzyme
      in the brain that catalyzes the deiodination of thyroxine (T4) to its active
      metabolite, 3,5,3'-triiodothyronine. In astrocytes, cAMP stimulation is required
      to express catalytically active type II iodothyronine 5'-deiodinase. The affinity
      ligand N-bromoacetyl-L-T4 specifically labels the 29-kDa substrate-binding
      subunit (p29) of this enzyme in cAMP-stimulated astrocytes. To determine the
      requirements for cAMP-induced activation of this enzyme, we optimized N
      bromoacetyl-L-T4 labeling of p29 in astrocytes lacking type II iodothyronine 5'
      deiodinase activity and examined the effects of cAMP on the hydrodynamic
      properties and subcellular location of the enzyme. We show that the p29 subunit
      is expressed in unstimulated astrocytes and requires 10-fold higher
      concentrations of N-bromoacetyl-L-T4 to achieve incorporation levels equal to
      those of p29 in cAMP-stimulated cells. Gel filtration showed that p29 was part of
      a multimeric membrane-associated complex in both cAMP-stimulated and unstimulated
      astrocytes and that cAMP stimulation led to an increase of approximately 60 kDa
      in the mass of the holoenzyme. In unstimulated astrocytes, p29 resides in the
      perinuclear space. Cyclic AMP stimulation leads to the translocation of p29 to
      the plasma membrane coincident with the appearance of deiodinating activity.
      These data show that cAMP-dependent activation of type II iodothyronine 5'
      deiodinase activity results from the synthesis of additional activating factor(s)
      that associates with inactive enzyme and leads to the translocation of enzyme
      polypeptide(s) from the perinuclear space to the plasma membrane.

PMID- 8663170
TI  - Degradation and recycling of the substrate-binding subunit of type II
      iodothyronine 5'-deiodinase in astrocytes.
AB  - Thyroxine dynamically regulates levels of type II iodothyronine 5'-deiodinase
      (5'D-II) by modulating enzyme inactivation and targeting the enzyme to different
      pathways of internalization. 5'D-II is an approximately 200-kDa multimeric
      protein containing a 29-kDa substrate-binding subunit (p29) and an unknown number
      of other subunits. In the absence of thyroxine (T4), p29 is slowly endocytosed
      and transported to the lysosomes. T4 treatment rapidly activates an actin
      mediated endocytotic pathway and targets the enzyme to the endosomes. In this
      study, we have characterized the influence of T4 on the intracellular trafficking
      of 5'D-II. We show that T4 accelerates the rate of 5'D-II inactivation by
      translocating the enzyme to the interior of the cell and by sequestering p29 in
      the endosomal pool without accelerating the rate of degradation of p29. This
      dichotomy between the rapid inactivation of catalytic activity and the much
      slower degradation of p29 is consistent with the reuse of p29 in the production
      of 5'D-II activity. Immunocytochemical analysis with a specific anti-p29 IgG
      shows that pulse affinity-labeled p29 reappears on the plasma membrane
      approximately 2 h after enzyme internalization in the presence of T4, indicating
      that p29 is recycled. Despite the ability of p29 to be recycled in the T4-treated
      cell, 5'D-II catalytic activity requires ongoing protein synthesis, presumably of
      another enzyme component(s) or an accessory enzyme-related protein. In the
      absence of T4, enzyme inactivation and p29 degradation are temporally linked, and
      pulse affinity-labeled p29 is internalized and sequestered in discrete
      intracellular pools. These data suggest that T4 regulates fundamental processes
      involved with the turnover of integral membrane proteins and participates in
      regulating the inter-relationships between the degradation, recycling, and
      synthetic pathways.

PMID- 8663171
TI  - A major tyrosine-phosphorylated protein of Trypanosoma brucei is a nucleolar RNA
      binding protein.
AB  - We have previously identified a set of tyrosine-phosphorylated proteins with
      apparent molecular masses of 44-46 kDa as some of the major tyrosine
      phosphorylated species in the protozoan parasite Trypanosoma brucei. We now show
      that these molecules, herein named Nopp44/46, are localized in the nucleolus.
      Using monoclonal antibodies, we have isolated Nopp44/46 cDNA clones from
      expression libraries. Sequence analysis reveals that the predicted amino acid
      sequence of the molecule is composed of an N-terminal unique region, an internal
      acidic region, and C-terminal repeat region. Analysis of the cDNA clones and
      genomic Southern analysis indicated that Nopp44/46 belongs to a multigene family
      in which different gene copies are very similar but vary in the number of
      repeats. Interestingly, the repetitive amino acid sequence motif contains
      multiple RGG (Arg-Gly-Gly) boxes characteristic of RNA-binding proteins. In vitro
      binding experiments demonstrated that Nopp44/46 is indeed capable of binding
      nucleic acids. Competition experiments with different RNA homopolymers
      demonstrated that Nopp44/46 preferentially binds to poly(U). These studies
      suggest that Nopp44/46 may play a role in RNA metabolism in trypanosomes and
      raise the possibility that tyrosine phosphorylation may regulate the process.

PMID- 8663172
TI  - Structure and expression of the rat mRNA encoding a novel member of the
      fibroblast growth factor family.
AB  - We isolated the cDNA encoding a novel member of the fibroblast growth factor
      (FGF) family from rat embryos by homology-based polymerase chain reaction. The
      FGF-related cDNA encodes a protein of 215 amino acids (approximately 24 kDa),
      which has a conserved approximately 120-amino acid core with approximately 30-60%
      amino acid sequence identity with the FGF family. This protein with a hydrophobic
      amino terminus appears to be a secreted protein. The cDNA was translated in a
      coupled in vitro transcription-translation system. The molecular mass of the
      translation product was observed to be approximately 26 kDa. The expression of
      the FGF-related mRNA in the rat embryo and adult tissues was determined by
      Northern analysis and in situ hybridization. The mRNA was expressed in several
      discrete regions of the embryo. In adult tissues, the mRNA was preferentially
      expressed in the lung. The expression profile of the FGF-related mRNA was
      different from those of other FGF family mRNAs. As this protein is the 10th
      documented protein related to FGFs, we tentatively term this protein FGF-10.

PMID- 8663173
TI  - Interactions of protein kinase C with insulin signaling. Influence on GAP and Sos
      activities.
AB  - In this study, we investigated the influence of the protein kinase C (PKC)
      dependent system upon the ability of insulin to stimulate p21(ras).GTP loading in
      3T3-L1 adipocytes. Activation of PKC by 12-0-tetradecanoylphorbol-13-acetate
      (TPA) did not affect the basal amount of p21(ras).GTP but significantly reduced
      insulin-induced increases in p21(ras).GTP. This reduction was due to inhibition
      of the insulin's ability to stimulate guanine nucleotide exchange activity of Sos
      in cells incubated with 100 nM TPA for either 30 min or 3 h. TPA had no effect on
      basal activity of Sos. Depletion of PKC by an 18-h incubation with TPA or
      inhibition by bisindolylmaleimide resulted in profound inhibition of the insulin
      induced p21(ras).GTP loading. In contrast to PKC activation, removal of PKC did
      not influence Sos activity but resulted in a 2-fold stimulation of GTPase
      activating protein (GAP). This effect of PKC depletion is unique to 3T3-L1
      adipocytes and was not observed in either 3T3-L1 fibroblasts or Rat-1
      fibroblasts. Thus, it appears that in 3T3-L1 adipocytes, PKC has a constitutive
      inhibitory effect on GAP that permits insulin to activate Sos and p21(ras).
      Removal of this inhibitory influence activates GAP and reduces insulin-stimulated
      p21(ras).GTP loading.

PMID- 8663174
TI  - Multiple transcription factors are required for activation of human interleukin 9
      gene in T cells.
AB  - The genetic elements and regulatory mechanisms responsible for human interleukin
      9 (IL-9) gene expression in a human T cell leukemia virus type I-transformed
      human T cell line, C5MJ2, were investigated. We demonstrated that IL-9 gene
      expression is controlled, at least in part, by transcriptional activation.
      Transient expression of the luciferase reporter gene linked to serially deleted
      sequences of the 5'-flanking region of the IL-9 gene has revealed several
      positive and negative regulatory elements involved in the basal and inducible
      expression of the IL-9 gene in C5MJ2 cells. An AP-1 site at -146 to -140 was
      shown to be involved in the expression of the IL-9 gene. A proximal region
      between -46 and -80 was identified as the minimum sequence for the basal and
      inducible expression of the IL-9 gene in C5MJ2 cells. Within this region, an NF
      kappaB site at -59 to -50 and its adjacent 20-base pair upstream sequence were
      demonstrated to play a critical role for the IL-9 promoter activity. DNA-protein
      binding studies indicated that NF-kappaB, c-Jun, and potentially novel proteins
      (around 35 kDa) can bind to this important sequence. Mutations at different sites
      within this proximal promoter region abolished the promoter activity as well as
      the DNA binding. Taken together, these results suggest that the cooperation of
      different transcription factors is essential for IL-9 gene expression in T cells.

PMID- 8663175
TI  - Mitogen-activated protein kinases in rat brain neuronal cultures are activated by
      angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors.
AB  - Neurons cultured from neonatal rat hypothalamus and brainstem contain many
      angiotensin II (Ang II) type 2 (AT2) receptors, and we previously determined that
      activation of these sites elicited a stimulation of serine/threonine phosphatase
      2A (PP2A). Here, we have investigated the effects of Ang II on neuronal mitogen
      activated protein (MAP) kinases, potential targets for PP2A. Using in-gel kinase
      assays and immunoprecipitation analyses we have shown that Ang II (10 nM-1
      microM) elicits significant increases in p44(MAPK) (Erk1) and p42(MAPK) (Erk2)
      activities in cultured neurons, mediated via Ang II type 1 (AT1) receptors. This
      stimulatory effect of Ang II on Erk1 and Erk2 activities was potentiated by
      blockade of AT2 receptors with (S)-1-[4-(dimethylamino)-3-methylphenyl]methyl-5
      (diphenylacetyl)- 4, 5,6,7-tetrahydro-1H-imidazo[4,5-C]pyridine-6-carboxylic acid
      (PD 123319, 1 microM). Furthermore, the AT2 receptor agonist N-alpha-nicotinoyl
      Tyr-Lys-(N-alphaCBZ-Arg)-His-Pro-Ile-OH (CGP42112A) (10-50 nM) caused significant
      decreases in neuronal Erk1 and Erk2 activities, which were abolished by PD 123319
      (1 microM) and by the PP2A inhibitor okadaic acid (3 nM). This indicates that AT1
      and AT2 receptors have opposite actions on Erk1 and Erk2 activities in neonatal
      neurons. Since MAP kinases are involved in the regulation of
      growth/differentiation and apoptosis, our data may provide an intracellular basis
      for modulatory effects of Ang II receptors on these processes.

PMID- 8663176
TI  - Mutational analysis of the predicted first transmembrane segment of each
      homologous half of human P-glycoprotein suggests that they are symmetrically
      arranged in the membrane.
AB  - A recent study of P-glycoprotein membrane topology using phoA gene fusions
      provided evidence that the orientation of the first transmembrane segment of each
      homologous half of P-glycoprotein was different (Beja, O., and Bibi, E. (1995) J.
      Biol. Chem. 270, 12351-12354). To test this hypothesis, we compared the
      functional consequences of mutations to residues in transmembrane segments (TMs)
      TM1 and TM7. Mutations to 3 residues occupying homologous positions in TM1 and
      TM7 resulted in mutant P-glycoproteins that were inactive. These mutants were
      found to be misprocessed. By contrast, mutations to other residues in TM1
      resulted in functional P-glycoproteins. When putative TM1 was replaced with TM7
      or TM7 with TM1 to yield TM7/TM7 or TM1/TM1 chimeras, both constructs yielded P
      glycoproteins that were capable of conferring drug resistance in transfected
      cells. The purified P-glycoproteins from mutants TM7/TM7 and TM1/TM1 retained 59
      and 28% of verapamil-stimulated ATPase activity, respectively. By contrast,
      interchanging TM6 and TM12 to yield TM6/TM6, TM12/TM12, or TM12/TM6 constructs
      resulted in P-glycoproteins that did not have any detectable ATPase activity and
      did not confer drug resistance in transfected cells. These results suggest that
      TM1 and TM7 likely have similar structural and functional roles in P-glycoprotein
      and that they have identical topologies.

PMID- 8663177
TI  - Interaction of transforming growth factor-beta receptor I with farnesyl-protein
      transferase-alpha in yeast and mammalian cells.
AB  - Transforming growth factor beta (TGF-beta) signals through two transmembrane
      serine/threonine kinases, known as TbetaR-I and TbetaR-II. Several lines of
      evidence suggest that TbetaR-II acts as a primary receptor, binding TGF-beta and
      phosphorylating TbetaR-I whose kinase activity then propagates the signal to
      unknown substrates. We report an interaction between TbetaR-I and the farnesyl
      protein transferase-alpha subunit (FT-alpha) both in a yeast two-hybrid system
      and in mammalian cells. These findings raise the possibility that TGF-beta might
      regulate cellular functions by altering the ability of FT-alpha to catalyze
      isoprenylation of targets such as G proteins, lamins, or cytoskeletal components.
      However, we provide evidence that TGF-beta action does not alter the overall
      protein isoprenyl transferase activity in Mv1Lu mink lung epithelial cells. In
      fact, the beta subunits of farnesyl transferase and geranylgeranyl transferase,
      which are necessary for the activity of FT-alpha, prevent the association of FT
      alpha with TbetaR-I. Furthermore, farnesyl transferase activity is shown to be
      dispensable for TGF-beta signaling of growth inhibitory and transcriptional
      responses in these cells. These results suggest that the interaction between
      TbetaR-I and FT-alpha does not affect the known functions of these two proteins.

PMID- 8663178
TI  - Rapid identification of phosphopeptide ligands for SH2 domains. Screening of
      peptide libraries by fluorescence-activated bead sorting.
AB  - A method for the identification of high-affinity ligands to SH2 domains by
      fluorescence-activated bead sorting (FABS) was established. Recombinant SH2
      domains, expressed as glutathione S-transferase (GST) fusion proteins, were
      incubated with a phosphotyrosine (Y*)-containing peptide library. 6.4 x 10(5)
      individual peptides of nine amino acids in length (EPX6Y*X19X7X19X7X6) were each
      displayed on beads. Phosphopeptide interaction of a given SH2 domain was
      monitored by binding of fluorescein isothiocyanate-labeled antibodies directed
      against GST. High-fluorescence beads were isolated by flow cytometric sorting.
      Subsequent pool sequencing of the selected beads revealed a distinct pattern of
      phosphotyrosine-containing motifs for each individual SH2 domain: the SH2 domain
      of the adapter protein Grb2 predominantly selected beads with the sequence
      Y*ENDP, whereas the C-terminal SH2 domain of the tyrosine kinase Syk selected
      Y*EELD, each motif representing the most frequently found residues C-terminal to
      the phosphotyrosine. For deconvolution studies, soluble phosphopeptides
      comprising variations of the Grb2 motifs were resynthesized and analyzed by
      surface plasmon resonance.

PMID- 8663179
TI  - Regulation of interleukin-8 gene expression by interleukin-1beta, osteotropic
      hormones, and protein kinase inhibitors in normal human bone marrow stromal
      cells.
AB  - Interleukin-8 (IL-8), a potent neutrophil chemotactic peptide that elicits
      pleiotropic biological effects is secreted in large amounts by normal human
      osteoblastic and bone marrow osteoprogenitor stromal (HBMS) cells in response to
      IL-1beta and tumor necrosis factor-alpha. In the present study we investigated
      the regulation of IL-8 gene expression by IL-1beta, osteotropic hormones, and
      protein kinase inhibitors in primary cultures of HBMS cells. The treatment of
      HBMS cells with IL-1beta increased the steady-state levels of IL-8 mRNA in a dose
      and time-dependent fashion and was detectable within 1 h, reached maximal by 4
      h, and remained elevated at 24 h, whereas parathyroid hormone (10(-7) and 10(-8)
      M) had no effect on IL-8 mRNA. Both synthetic and natural glucocorticoids
      dexamethasone (10(-7)-10(-10) M) and hydrocortisone (10(-6)-10(-8) M) inhibited
      IL-1beta-stimulated IL-8 mRNA expression. The suppressive effect of dexamethasone
      on IL-1beta-induced IL-8 mRNA was not observed in the presence of cycloheximide
      (5 microg/ml), indicating that the dexamethasone-mediated repression of IL-8 gene
      expression also depends on new protein synthesis. Experiments with actinomycin D
      demonstrated that IL-8 mRNA is long-lived and that glucocorticoids down-regulate
      IL-8 gene expression mainly by decreasing the mRNA stability in normal HBMS
      cells. Furthermore, as determined by nuclear run-on analysis, IL-1beta increased
      the rate of transcription of IL-8 gene and dexamethasone did not affect the IL
      1beta-induced transcription of IL-8. 1-(5-Isoquinolinesulfonyl)-2
      methylpiperazine, HCl (50 microM) and staurosporine (1 microM), potent inhibitors
      of protein kinase C, and genistein (100 microM), a specific protein tyrosine
      kinase inhibitor blocked IL-1beta-induced IL-8 gene expression. Because curcumin
      (20 microM), an inhibitor of c-jun/AP-1 and protein kinases, also blocked IL
      1beta-stimulated IL-8 gene expression implicating c-JUN/AP-1 and protein
      phosphorylation in the induction of IL-8 gene expression by IL-1beta, we conclude
      that the regulation of IL-8 mRNA by IL-1beta is mediated via protein kinase
      dependent signal transduction pathways. Our accumulated results have demonstrated
      that glucocorticoid suppression of IL-1beta-induced IL-8 mRNA occurs at the
      levels of post-transcription (mRNA stability) and protein synthesis.

PMID- 8663180
TI  - Phosphatidylinositol hydrolysis by Trypanosoma brucei
      glycosylphosphatidylinositol phospholipase C.
AB  - Detergent-solubilized glycosylphosphatidylinositol (GPI)-anchored structures can
      be cleaved by C-type phospholipases isolated from peanuts and bloodstream cells
      of the African trypanosome, Trypanosoma brucei. The two enzymes differ in their
      reported ability to hydrolyze phosphatidylinositol (PI); while the peanut enzyme
      readily hydrolyzes PI in vitro, the T. brucei enzyme was reported to be virtually
      inactive against PI and consequently named GPI-specific phospholipase C (GPI
      PLC). In this paper, we describe experiments in which we reinvestigated the
      substrate specificity of T. brucei GPI-PLC by incubating the purified enzyme with
      Triton X-100/PI-mixed micelles and by studying PI hydrolysis. We found that PI
      hydrolysis occurred in a detergent-dependent fashion over the range of
      concentrations tested (5 microM to 1 mM PI). At 5 microM PI, hydrolysis was
      maximal at 0.005% Triton X-100, whereas at 1 mM PI, maximal hydrolysis required
      0.05% Triton X-100. Hydrolysis of both PI and GPI was strongly affected by the
      presence of phospholipids. Endogenous PI was hydrolyzed during osmotic and
      detergent lysis of trypanosomes under conditions used to obtain quantitative
      hydrolysis of the GPI-anchored trypanosome variant surface glycoprotein. PI
      hydrolysis in the lysates was inhibited by sodium p-chloromercuriphenylsulfonate
      but unaffected by EGTA, consistent with the proposal that hydrolysis is due to
      GPI-PLC. These results suggest that the function of T. brucei GPI-PLC may be to
      regulate PI as well as (or instead of) GPI levels.

PMID- 8663181
TI  - Determination of the structure of the N-terminal splice region of the cyclic AMP
      specific phosphodiesterase RD1 (RNPDE4A1) by 1H NMR and identification of the
      membrane association domain using chimeric constructs.
AB  - A 25-residue peptide representing the membrane targeting N-terminal splice region
      of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1) was synthesized, and its
      structure was determined by 1H NMR. Two independently folding helical regions
      were identified, separated by a highly mobile "hinge" region. The first helical
      region was formed by an N-terminal amphipathic alpha-helix, and the second
      consisted of multiple overlapping turns and contained a distinct compact,
      hydrophobic, tryptophan-rich domain (residues 14-20). Chimeric molecules, formed
      between the N-terminal region of RD1 and the soluble bacterial protein
      chloramphenicol acetyltransferase, were used in an in vitro system to determine
      the features within the splice region that were required for membrane
      association. The ability of RD1-chloramphenicol acetyltransferase chimera to
      become membrane-associated was not affected by deletion of any of the following
      regions: the apolar section (residues 2-7) of the first helical region, the polar
      part of this region together with the hinge region (residues 8-13), or the polar
      end of the C-terminal helical region (residues 21-25). In marked contrast,
      deletion of the compact, hydrophobic tryptophan-rich domain (residues 14-20)
      found in the second helical region obliterated membrane association. Replacement
      of this domain with a hydrophobic cassette of seven alanine residues also
      abolished membrane association, indicating that membrane-association occurred by
      virtue of specific hydrophobic interactions with residues within the compact,
      tryptophan-rich domain. The structure of this domain is well defined in the
      peptide, and although the region is helical, both the backbone and the
      distribution of side chains are somewhat distorted as compared with an ideal
      alpha-helix. Hydrophobic interactions, such as the "stacked" rings of residues
      Pro14 and Trp15, stabilize this domain with the side chain of residue Leu16
      adopting a central position, interacting with the side chains of all three
      tryptophan residues 15, 19, and 20. These bulky side chains thus form a
      hydrophobic cluster. In contrast, the side chain of residue Val17 is relatively
      exposed, pointing out from the opposite "face" of the peptide. Although it
      appears that this compact, tryptophan-rich domain is responsible for membrane
      association, at present the target site and hence the specific interactions
      involved in membrane targeting by the RD1 splice region remain unidentified.

PMID- 8663182
TI  - Cloning and expression of cDNA encoding protein synthesis elongation factor-2
      kinase.
AB  - A cDNA from rat skeletal muscle encoding calcium/calmodulin-dependent eukaryotic
      elongation factor-2 kinase (eEF-2K) has been cloned and sequenced, and the amino
      acid sequence of the protein has been deduced. The kinase is composed of 724
      amino acids and has a predicted molecular mass of 81,499 Da. The cDNA was judged
      to be full-length, as the protein, expressed in rabbit reticulocyte lysate or
      wheat germ extract, migrated upon SDS-PAGE with the same apparent molecular
      weight as the purified kinase and possessed eEF-2K activity. eEF-2K contains all
      of the 12 catalytic subdomains present in the majority of protein kinases, but
      they are atypical and display only limited homology with other kinases. A
      putative calmodulin-binding domain is present C-terminal to the catalytic domain
      as is a putative pseudosubstrate sequence. Two antipeptide antibodies raised
      against sequences derived from a partial rabbit cDNA clone, cross-reacted with
      purified eEF-2K, and one also immunoprecipitated eEF-2K activity from cell
      extracts. Northern blot analysis demonstrated that eEF-2K mRNA is expressed in a
      number of different tissues and that it may exist in multiple forms.

PMID- 8663183
TI  - An isoleucine to valine substitution in Escherichia coli acyl carrier protein
      results in a functional protein of decreased molecular radius at elevated pH.
AB  - Escherichia coli acyl carrier protein (ACP) has been reported to exist in at
      least two distinct conformers in solution. A novel form of ACP having an
      increased electrophoretic mobility on polyacrylamide gel electrophoresis was
      noted previously during work on beta-ketoacyl-acyl carrier protein synthase II
      (fabF) mutants of E. coli (Jackowski, S., and Rock, C. O.(1987) J. Bacteriol.
      169, 1469-1473). These workers reported that the increased electrophoretic
      mobility of the ACP from fabF strains occurred irrespective of prosthetic group
      attachment or the state of acylation of the prosthetic group. Since these workers
      were unable to detect a difference between the amino acid sequence of the ACP
      from the fabF mutants and that of wild type ACP, they suggested that the
      increased electrophoretic mobility was due to an unknown post-translational
      modification of the polypeptide chain. We have reinvestigated these mutants and
      report that the increased electrophoretic mobility is due to a mutation within
      the gene (acpP) that encodes ACP. This mutation results in substitution of
      isoleucine for valine 43 of ACP. Site-directed mutagenesis of a synthetic ACP
      gene demonstrated that the amino acid substitution at residue 43 is the cause of
      the increased electrophoretic mobility. Gel filtration experiments indicated that
      the increased electrophoretic mobility results from the more compact structure of
      V43I ACP at high pH. The altered residue lies within the ACP region of greatest
      conformational lability, and thus the V43I substitution may shift the equilibrium
      toward the more compact conformation(s). The disulfide-linked dimer of V43I ACP
      was readily formed and had an electrophoretic migration greater than the dimer of
      wild type ACP, suggesting that formation of ACP.ACP dimers does not require
      structural deformation of the protein.

PMID- 8663185
TI  - Is the NAD(P)H:flavin oxidoreductase from Escherichia coli a member of the
      ferredoxin-NADP+ reductase family?. Evidence for the catalytic role of serine 49
      residue.
AB  - The NAD(P)H:flavin oxidoreductase from Escherichia coli, Fre, is a monomer of
      26.1 kDa which catalyzes the reduction of free flavins by NADPH or NADH. The
      flavin reductase Fre is the prototype of a new class of flavin reductases able to
      transfer electrons with no prosthetic group. It has been suggested that the
      flavin reductase could belong to the ferredoxin-NADP+ reductase (FNR) family, on
      the basis of limited sequence homologies. A sequence, conserved within the
      ferredoxin-NADP+ reductase family and present in the flavin reductase, is
      important for recognition of the isoalloxazine ring. Within this sequence, we
      have mutated serine 49 of the flavin reductase into alanine or threonine. kcat
      value of the S49A mutant was 35-fold lower than kcat of the wild-type enzyme.
      Determination of real Kd values for NADPH and lumichrome, a flavin analog, showed
      that recognition of the flavin is strongly affected by the S49A mutation, whereas
      affinity for the nicotinamide cofactor is only weakly modified. This suggests
      that serine 49 is involved in the binding of the isoalloxazine ring. Moreover,
      the Kd value for 5-deazariboflavin, in which the N-5 position of the
      isoalloxazine ring has been changed to a carbon atom, is not affected by the
      serine 49 to alanine mutation. This is consistent with the concept that the N-5
      position is the main site for serine 49-flavin interaction. In the ferredoxin
      NADP+ reductase family, the equivalent serine residue, which has been shown to be
      essential for activity, is hydrogen-bonded to the N-5 of the FAD cofactor. Taken
      together, these data provide the first experimental support to the hypothesis
      that the flavin reductase Fre may belong to the ferredoxin-NADP+ reductase
      family.

PMID- 8663186
TI  - Expression of the chlI, chlD, and chlH genes from the Cyanobacterium
      synechocystis PCC6803 in Escherichia coli and demonstration that the three
      cognate proteins are required for magnesium-protoporphyrin chelatase activity.
AB  - Magnesium-protoporphyrin chelatase catalyzes the first step unique to chlorophyll
      synthesis: the insertion of Mg2+ into protoporphyrin IX. Genes from Synechocystis
      sp. PCC6803 with homology to the bchI and bchD genes of Rhodobacter sp. were
      cloned using degenerate oligonucleotides. The function of these genes, putatively
      encoding subunits of magnesium chelatase, was established by overexpression in
      Escherichia coli, including the overexpression of Synechocystis chlH, previously
      cloned as a homolog of the Rhodobacter bchH gene. The combined cell-free extracts
      were able to catalyze the insertion of Mg2+ into protoporphyrin IX in an ATP
      dependent manner and only when the products of all three genes were present. The
      ChlH, ChlI, and ChlD gene products are therefore assigned to the magnesium
      chelatase step in chlorophyll a biosynthesis in Synechocystis PCC6803. The
      primary structure of the Synechocystis ChlD protein reveals some interesting
      features; the N-terminal half of the protein shows 40-41% identity to Rhodobacter
      BchI and Synechocystis ChlI, whereas the C-terminal half displays 33% identity to
      Rhodobacter BchD. This suggests a functional as well as an evolutionary
      relationship between the "I" and "D" genes.

PMID- 8663184
TI  - Effects of truncation of the COOH-terminal region of a Na+-independent neutral
      and basic amino acid transporter on amino acid transport in Xenopus oocytes.
AB  - To determine the role of a neutral and basic amino acid transporter (NBAT) in
      amino acid transport, we microinjected several COOH-terminal deletion mutants of
      NBAT cRNA into Xenopus oocytes and measured transport activity for arginine,
      leucine, and cystine in the presence and absence of sodium. Wild-type NBAT
      significantly stimulated the uptake of all three amino acids 10-20-fold compared
      with controls. On the other hand, no mutant, except a Delta511-685 mutant,
      stimulated the uptake of these amino acids. The Delta511-685 mutant significantly
      increased the uptake of arginine. In the presence of sodium, the Delta511-685
      mutant also increased the uptake of leucine. The Delta511-685 mutant did not
      stimulate cystine uptake in the presence or absence of sodium. The stimulation of
      arginine uptake by the Delta511-685 mutant was inhibited by a 100-fold excess of
      unlabeled leucine in the presence of sodium. Inhibition of L-arginine uptake by L
      homoserine was seen only in the presence of sodium, and an increase in the
      inhibition of L-arginine uptake by L-histidine was seen when the extracellular pH
      was decreased. Furthermore, an inward current in oocytes injected with the
      Delta511-685 mutant was recorded electrophysiologically when basic amino acids
      were applied. Homoserine was also taken up, but sodium was necessary for their
      transport. These properties of the Delta511-685 mutant correspond to those of the
      y+ amino acid transporter. If NBAT is a component of the b0,+-like amino acid
      transport system, it is unlikely that a mutant protein (Delta511-685) is able to
      stimulate an endogenous y+-like transport system. These results suggest that NBAT
      functions as a activator of the amino acid transport system in Xenopus oocytes.

PMID- 8663187
TI  - Ligand-induced conformational changes of GroEL are dependent on the bound
      substrate polypeptide.
AB  - Ligand-induced conformational changes of GroEL alone and with bound rhodanese,
      citrate synthase, or dihydrofolate reductase were studied by limited proteolysis.
      Similar digestion patterns of GroEL, with or without bound substrate polypeptide,
      were obtained in the absence and presence of the chaperonin ligands, K+, Mg2+, or
      ATP. The rates of formation and degradation of the six produced proteolytic
      fragments were significantly different, however. Strikingly, only with Mg2+/ATP
      or K+/Mg2+/ATP an additional fragment of approximately 25 kDa was generated
      during digestion of GroEL alone or with bound rhodanese or dihydrofolate
      reductase, but not with bound citrate synthase. Most of the trypsin-sensitive
      sites in GroEL were localized in the flexible apical domain, which contains the
      putative polypeptide-binding region. Our data indicate that subtle structural
      changes in the trypsin-sensitive regions of GroEL occur as a result of the
      binding of the chaperonin ligands. However, these structural changes are
      influenced by the GroEL substrate polypeptides.

PMID- 8663189
TI  - Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal
      kinases.
AB  - Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha) are known to
      induce production of reactive oxygen species (ROS), which have been suggested to
      act as second messengers. Here we demonstrate that ROS production by bovine
      chondrocytes upon cytokine stimulation induces c-jun expression. Since c-jun
      expression is regulated by its own gene product via phosphorylation by c-Jun NH2
      terminal kinases (JNKs), we investigated if cytokines and ROS could modulate JNK
      activity in chondrocyte monolayer cultures. Treatment of bovine chondrocytes with
      both IL-1 and TNFalpha leads to rapid induction of JNK activity, stimulating JNK
      activity 7- and 20-fold, respectively. Importantly, the observation that
      antioxidant treatment antagonizes IL-1 and TNFalpha activation of JNK provides
      strong evidence that ROS can act as mediators of JNK activity. Moreover, potent
      activation of JNK is also observed by direct addition of the ROS hydrogen
      peroxide (H2O2) to the chondrocyte cultures. Nitric oxide (NO), a multifunctional
      ROS, also appears to simulate JNK, albeit to a lesser extent. These findings
      identify JNK as another molecular target for the actions of NO and H2O2. In
      addition, the inhibitory effect of diphenyleneiodonium on JNK activation
      implicates the involvement of flavonoid-containing enzymes in the ROS-mediated
      signaling process. Overstimulation of JNK activity by excessive production of ROS
      may, therefore, underlie pathological conditions such as arthritis and cancer.

PMID- 8663188
TI  - Cellular cholesterol efflux mediated by cyclodextrins. Demonstration Of kinetic
      pools and mechanism of efflux.
AB  - The efflux of cholesterol from cells in culture to cyclodextrin acceptors has
      been reported to be substantially more rapid than efflux induced by other known
      acceptors of cholesterol (Kilsdonk, E. P. C., Yancey, P., Stoudt, G., Bangerter,
      F. W., Johnson, W. J., Phillips, M. C., and Rothblat, G. H. (1995) J. Biol. Chem.
      270, 17250-17256). In this study, we compared the kinetics of cholesterol efflux
      from cells with 2-hydroxypropyl-beta-cyclodextrins and with discoidal high
      density lipoprotein (HDL) particles to probe the mechanisms governing the
      remarkably rapid rates of cyclodextrin-mediated efflux. The rate of cholesterol
      efflux was enhanced by shaking cells growing in a monolayer and further enhanced
      by placing cells in suspension to achieve maximal efflux rates. The extent of
      efflux was dependent on cyclodextrin concentration, and maximal efflux was
      observed at concentrations >50 mM. For several cell types, biexponential kinetics
      of cellular cholesterol efflux were observed, indicating the existence of two
      kinetic pools of cholesterol: a fast pool (half-time (t1/2) approximately 19-23
      s) and a slow pool with t1/2 of 15-30 min. Two distinct kinetic pools of
      cholesterol were also observed with model membranes (large unilamellar
      cholesterol-containing vesicles), implying that the cellular pools are in the
      plasma membrane. Cellular cholesterol content was altered by incubating cells
      with solutions of cyclodextrins complexed with increasing levels of cholesterol.
      The number of kinetic pools was unaffected by raising the cellular cholesterol
      content, but the size of the fast pool increased. After depleting cells of the
      fast pool of cholesterol, this pool was completely restored after a 40-min
      recovery period. The temperature dependence of cyclodextrin-mediated cholesterol
      efflux from cells and model membranes was compared; the activation energies were
      7 kcal/mol and 2 kcal/mol, respectively. The equivalent activation energy
      observed with apo-HDL-phospholipid acceptor particles was 20 kcal/mol. It seems
      that cyclodextrin molecules are substantially more efficient than phospholipid
      acceptors, because cholesterol molecules desorbing from a membrane surface can
      diffuse directly into the hydrophobic core of a cyclodextrin molecule without
      having to desorb completely into the aqueous phase before being sequestered by
      the acceptor.

PMID- 8663190
TI  - Four distinct membrane-bound dipeptidase RNAs are differentially expressed and
      show discordant regulation with gamma-glutamyl transpeptidase.
AB  - Membrane-bound dipeptidase (MBD) participates in the degradation of glutathione
      by cleaving the cysteinyl-glycine bond of cystinyl bisglycine (oxidized cysteinyl
      glycine) following removal of a gamma-glutamyl group by gamma-glutamyl
      transpeptidase (GGT). In the mouse, MBD RNA is most abundant in small intestine,
      kidney, and lung and is represented by four distinct RNA species. These are
      generated by transcription from two promoters located 6 kilobases apart in the 5'
      flanking region of the gene and by the use of two different poly(A) addition
      sites. Promoter I is used primarily in small intestine and kidney, whereas
      promoter II is most active in lung and kidney. We found a discordance in the
      expected co-expression of MBD and GGT; as expected, MBD and GGT are both
      expressed at high levels in the kidney and small intestine. However, in the lung,
      MBD is expressed at high levels, whereas GGT is almost undetectable. The reverse
      is true in the seminal vesicles and fetal liver. Thus, although both enzymes may
      function in concert to metabolize glutathione in kidney and small intestine, in
      other tissues they appear to act independently, suggesting that they have
      independent roles in other biological processes.

PMID- 8663192
TI  - Regulation of phospholipid biosynthesis in the yeast Saccharomyces cerevisiae.

PMID- 8663191
TI  - A sustained reduction in IkappaB-beta may contribute to persistent NF-kappaB
      activation in human endothelial cells.
AB  - The responses of vascular endothelial cells (EC) to tumor necrosis factor-alpha
      (TNF), interleukin-1alpha (IL-1), and phorbol myristate acetate (PMA) were
      compared with respect to the kinetics of (i) NF-kappaB activation, (ii) IkappaB
      alpha and IkappaB-beta degradation, and (iii) NF-kappaB-dependent cell surface
      molecule expression. TNF rapidly (</=20 min) and persistently (>20 h) activates
      NF-kappaB; IL-1 rapidly activates NF-kappaB, but activity declines by 3 h and
      further by 20 h; PMA slowly and transiently activates NF-kappaB. Untreated EC
      contain the inhibitory proteins IkappaB-alpha and IkappaB-beta. The onset of NF
      kappaB activation correlates with degradation of IkappaB-alpha, but IkappaB-alpha
      reappears by 4 h without resequestration of NF-kappaB. TNF causes a rapid but
      partial (50%) reduction in IkappaB-beta, which does not recover by 22 h; IL-1 and
      PMA cause slower and less sustained reductions in IkappaB-beta. All three
      agonists induce de novo expression of E-selectin (CD62E) and vascular cell
      adhesion molecule-1 (CD106) and increase expression of intercellular adhesion
      molecule-1 (CD54) at 4 h. TNF induces sustained increases in vascular cell
      adhesion molecule-1 and intercellular adhesion molecule-1 and increases human
      leukocyte antigen class I molecules at 24 h. We conclude that TNF causes
      persistent activation of NF-kappaB in human EC and that this may result from
      sustained reductions in IkappaB-beta levels.

PMID- 8663193
TI  - Tissue-specific and hormonal regulation of calbindin-D9K fusion genes in
      transgenic mice.
AB  - The rat Calbindin-D9K (CaBP9K) gene is mainly expressed in intestine, uterus, and
      lung and is regulated in a complex tissue-specific manner. To analyze the role of
      potential regulatory elements, previously defined by DNaseI hypersensivity, we
      made transgenic mice containing truncated rat CaBP9K fusion gene with simian
      virus 40 large T antigen and the chloramphenicol acetyltransferase as reporter
      genes. The transgenes contained CaBP9K promoter fragments with 5' end points at 
      4400, -1011, and -117 base pairs (bp), whereas the 3' end points was at +365 bp.
      Northern blot analysis of T antigen expression and chloramphenicol
      acetyltransferase enzyme-linked immunosorbent assay indicated that a positive
      element, probably the distal intestine-specific DNaseI HS, necessary to target
      the expression of the transgene in the intestine, is present between -4400 and 
      1011 bp. The cephalo-caudal gradient of expression of the transgene along the
      small intestine was similar to those of the endogenous gene, but an ectopic
      expression of the transgene was observed in the colon. The -1011 transgene was
      expressed in epithelial alveolar cells of the lung, in renal proximal tubule
      cells, and in uterine myometrium, as judged from immunocytochemical,
      histological, and Northern blot analyses. The shortest, -117 construct was only
      expressed in uterine myometrium, and it was under a strict estrogen dependence
      like the endogenous gene. Finally, responsiveness to vitamin D in the duodenum
      was observed with the largest, -4400 construct. Thus, different tissues utilize
      distinct cis-acting elements to direct and regulate the expression of the rat
      CaBP9K gene.

PMID- 8663194
TI  - Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase.
AB  - Mitogen-activated protein (MAP) kinases are a multigene family activated by many
      extracellular stimuli. There are three groups of MAP kinases based on their dual
      phosphorylation motifs, TEY, TPY, and TGY, which are termed extracellular signal
      regulated protein kinases (ERK1/2), c-Jun N-terminal kinases, and p38,
      respectively. A new MAP kinase family member termed Big MAP kinase 1 (BMK1) or
      ERK5 was recently cloned. BMK1 has a TEY sequence similar to ERK1/2 but has
      unique COOH-terminal and loop-12 domains. To define BMK1 regulation, its
      activation in cultured rat vascular smooth muscle cells was characterized.
      Angiotensin II, phorbol ester, platelet-derived growth factor, and tumor necrosis
      factor-alpha were the strongest stimuli for ERK1/2 but were weak activators of
      BMK1. In contrast, H2O2 caused concentration-dependent activation of BMK1 but not
      ERK1/2. Sorbitol activated both BMK1 and ERK1/2. BMK1 activation by H2O2 was
      calcium-dependent and appeared ubiquitous as shown by stimulation in human skin
      fibroblasts, human vascular smooth muscle cells, and human umbilical vein
      endothelial cells. These findings demonstrate that activation of BMK1 is
      different from ERK1/2 and suggest an important role for BMK1 as a redox-sensitive
      kinase.

PMID- 8663195
TI  - Isolation of a sponge-derived extracellular matrix adhesion protein.
AB  - The development of stable intercellular adhesions in the animal kingdom permitted
      the evolution of the metazoans, of which the sponges are primitive examples.
      Intercellular adhesion in these simple animals is mediated by a high affinity
      interaction between the sponge cell surface and aggregation factor, a 2 x 10(7)
      Da proteoglycan that is one of the major components of the sponge extracellular
      matrix. This report describes a sponge cell surface and extracellular matrix
      ligand for the sponge proteoglycan, aggregation factor. The 210-kDa protein binds
      aggregation factor proteoglycan with high affinity (Kd = 7 x 10(-9) M).
      Importantly, in soluble form, it also inhibits aggregation factor-mediated cell
      adhesion. This glycoprotein is expressed on the sponge cell surface and within
      the extracellular matrix. This novel sponge extracellular matrix protein may
      represent a primitive antecedent of the extracellular matrix adhesion proteins of
      higher organisms.

PMID- 8663196
TI  - The multiple carrier model of nonribosomal peptide biosynthesis at modular
      multienzymatic templates.
AB  - Gramicidin S synthetase 1 and 2 were affinity-labeled at their thiolation centers
      either by thioesterification with the amino acid substrate or by specific
      alkylation with the thiol reagent N-ethylmaleimide in combination with a
      substrate protection technique. The labeled proteins were digested either
      chemically by cyanogen bromide or by proteases. An efficient multistep high
      pressure liquid chromatography methodology was developed and used to isolate the
      active site peptide fragments of all five thiolation centers of gramicidin S
      synthetase in pure form. The structures of these fragments are investigated by N
      terminal sequencing, mass spectrometry, and amino acid analysis. Each of the
      active site peptide fragments contains the consensus motif LGG(H/D)S(L/I), which
      is specific for thioester formation in nonribosomal peptide biosynthesis. It was
      demonstrated that a 4'-phosphopantetheine cofactor is attached to the central
      serine of the thiolation motif in each amino acid-activating module of the
      gramicidin S synthetase multienzyme system forming the thioester binding sites
      for the amino acid substrates and catalyzing the elongation process. Our data are
      strong support for a "multiple carrier model" of nonribosomal peptide
      biosynthesis at multifunctional templates, which is discussed in detail.

PMID- 8663197
TI  - Protein kinase C-delta mRNA is down-regulated transcriptionally and post
      transcriptionally by 12-O-tetradecanoylphorbol-13-acetate.
AB  - Activation of protein kinase C-delta (PKC-delta) by 12-O-tetradecanoylphorbol-13
      acetate (TPA) is followed by a gradual decrease in detectable protein 12-24 h
      later in the mouse B lymphoma cell line A20. Down-regulation is associated with
      TPA-induced proteolysis and a 50-86% decrease in PKC-delta mRNA 0.5-24 h post
      treatment which is due to both a 50% decrease in transcription and accelerated
      degradation of PKC-delta mRNA as determined using the pulse-chase method.
      Destabilization of PKC-delta mRNA is also observed when actinomycin D is added to
      cells pretreated with TPA for 2 h; however, addition of actinomycin D or
      cycloheximide prior to TPA treatment blocks destabilization. Addition of PKC
      inhibitors to TPA-treated cells also blocks destabilization of PKC-delta mRNA.
      Cells treated with TPA for 4 h contain an activity not found in control cells
      which destabilizes PKC-delta mRNA but not glyceraldehyde-3-phosphate
      dehydrogenase mRNA in vitro. Addition of TPA to control extracts fails to
      increase degradation of PKC-delta mRNA in vitro, suggesting that treatment of
      intact cells is required to induce the synthesis of a factor(s) that destabilizes
      PKC-delta mRNA. This factor(s) then acts along with transcriptional and post
      translational regulatory mechanisms to down-regulate PKC-delta.

PMID- 8663198
TI  - Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in
      Escherichia coli. Recognition of retinal as substrate.
AB  - The biosynthesis of the hormone retinoic acid from retinol (vitamin A) involves
      two sequential steps, catalyzed by retinol dehydrogenases and retinal
      dehydrogenases, respectively. This report describes the cloning of a cDNA
      encoding a heretofore unknown aldehyde dehydrogenase from a rat testis library
      and its expression in Escherichia coli. This enzyme has been designated retinal
      dehydrogenase, type II, RalDH(II). The deduced amino acid sequence of RalDH(II)
      had the highest identity with mammalian aldehyde dehydrogenases that feature low
      Km values (microM) for retinal: human ALDH1 (72.2%), rat retinal dehydrogenase,
      type I (71.5%), bovine retina (72.7%), and mouse AHD-2 (71.5%). RalDH(II)
      expressed in E. coli recognizes as substrates free retinal, with a Km of
      approximately 0.7 microM, and cellular retinol-binding protein-bound retinal,
      with a Km of approximately 0.2 microM. RalDH(II) also can utilize as substrate
      retinal generated in situ by microsomal retinol dehydrogenases, from the
      physiologically most abundant substrate: retinol bound to cellular retinol
      binding protein. Rat testis expresses RalDH(II) mRNA most abundantly, followed by
      (relative to testis): lung (6.7%), brain (6.3%), heart (5.2%), liver (4.4%), and
      kidney (2.7%). RalDH(II) does not recognize citral, benzaldehyde, acetaldehyde,
      and propanal efficiently as substrates, but does metabolize octanal and decanal
      efficiently. These data support a function for RalDH(II) in the pathway of
      retinoic acid biogenesis.

PMID- 8663199
TI  - Purification and characterization of tetrachloroethene reductive dehalogenase
      from Dehalospirillum multivorans.
AB  - Tetrachloroethene reductive dehalogenase from the tetrachloroethene-utilizing
      anaerobe, Dehalospirillum multivorans, was purified approximately 100-fold to
      apparent homogeneity. The purified dehalogenase catalyzed the reductive
      dechlorination of tetrachloroethene (PCE) to trichloroethene and of
      trichloroethene to cis-1,2-dichloroethene with reduced methyl viologen as the
      electron donor at a specific activity of 2.6 microkatal/mg. The apparent Km
      values for tetrachloroethene and trichloroethene were 0.20 and 0.24 mM,
      respectively. The apparent molecular mass of the native enzyme was determined by
      gel filtration to be 58 kDa. Sodium dodecyl sulfate-gel electrophoresis revealed
      a single protein band with a molecular mass of 57 kDa. One mol of dehalogenase
      contained 1.0 mol of corrinoid, 9.8 mol of iron, and 8.0 mol of acid-labile
      sulfur. The pH optimum was about 8.0. The enzyme had a temperature optimum of 42
      degrees C. It was slightly oxygen-sensitive and was thermolabile above 50 degrees
      C. The dechlorination of PCE was stimulated by ammonium ions. Chlorinated
      methanes severely inhibited PCE dehalogenase activity.

PMID- 8663200
TI  - Alternatively spliced transcripts from the Drosophila eIF4E gene produce two
      different Cap-binding proteins.
AB  - Eukaryotic initiation factor 4E (eIF4E) is the subunit of eIF4F that binds to the
      cap structure at the 5' end of messenger RNA and is a critical component for the
      regulation of translation initiation. Using 7-methyl-GTP-Sepharose affinity
      chromatography, two distinct cap-binding proteins that migrate on SDS
      polyacrylamide gel electrophoresis at approximately 35 kDa were purified from
      Drosophila adults. Peptide microsequence analysis indicated that these two
      proteins differ at their amino termini. Analysis of a set of cDNA clones encoding
      eIF4E led to the conclusion that the two different protein isoforms, which we
      term eIF4EI and eIF4EII, result from three alternatively spliced transcripts from
      a single eIF4E gene, which maps to region 67A8-B2 on polytene chromosomes. The
      three eIF4E transcripts also vary greatly in the lengths of their 5'-UTRs,
      suggesting the possibility of complex translational control of expression of the
      two eIF4E isoforms.

PMID- 8663201
TI  - Role of the activation peptide domain in human factor X activation by the
      extrinsic Xase complex.
AB  - The activation of factor X by the extrinsic coagulation system results from the
      action of an enzyme complex composed of factor VIIa bound to tissue factor on
      phospholipid membranes in the presence of calcium ions (extrinsic Xase complex).
      Proteolysis at the Arg52-Ile53 peptide bond in the heavy chain of factor X leads
      to the formation of the serine protease, factor Xa, and the generation of a
      heavily glycosylated activation peptide comprising residues 1-52 of the heavy
      chain. The role of the activation peptide region in mediating substrate
      recognition and cleavage by the extrinsic Xase complex is unclear. The protease
      Agkistrodon rhodostoma hydrolase gamma (ARHgamma), from the venom of the Malayan
      pit viper, was used to selectively cleave human factor X in the activation
      peptide region. Three cleavage sites were found within this region and gave
      products designated Xdes1-34, Xdes1-43, and Xdes1-49. The products were purified
      to yield Xdes 1-49 and a mixture of Xdes 1-34 and Xdes 1-43. Reversed phase high
      pressure liquid chromatography analysis indicated that the cleaved portion of the
      activation peptide was likely removed during purification. All cleaved species
      were inactive and could be completely activated to factor Xa by the extrinsic
      Xase complex or by a purified activator from Russell's viper venom. Steady state
      kinetic studies using tissue factor reconstituted into membranes yielded
      essentially equivalent kinetic constants for the activation of intact factor X
      and the cleaved derivatives under a wide range of conditions. Since Xdes 1-49
      lacks all but three residues of the activation peptide and is devoid of the
      carbohydrate present in this region, the data suggest that the specific
      recognition of human factor X by the extrinsic Xase complex is not achieved
      through specific interactions with residues 1-49 of the activation peptide or
      with carbohydrate structures attached to these residues.

PMID- 8663202
TI  - Regulation of BiP gene expression by cyclopentenone prostaglandins through
      unfolded protein response element.
AB  - Delta12-Prostaglandin (PG) J2, a cyclopentenone prostaglandin, plays a role in
      various stress responses. BiP, a stress-inducible chaperone protein, is
      implicated in protein folding and translocation in endoplasmic reticulum and
      induced in the condition of accumulation of unfolded proteins. Here, we examined
      the effect of Delta12-PGJ2 on the expression of the BiP gene. Delta12-PGJ2
      markedly stimulated the expression of the BiP gene in a time- and concentration
      dependent manner in HeLa cells. This stimulation was specific for cyclopentenone
      PGs among various PGs. Cycloheximide pretreatment completely inhibited the
      Delta12-PGJ2-induced expression of the BiP gene, suggesting that the effects on
      nascent protein synthesis are involved in the signaling mechanism. Delta12-PGJ2
      markedly stimulated the promoter activity of the 5'-flanking region of the BiP
      gene through the unfolded protein response element. Furthermore, Delta12-PGJ2
      stimulated the enhancer activity of the 3'-half of the unfolded protein response
      element, and this stimulation required three nucleotides within this region. Gel
      mobility shift assay demonstrated that this region was occupied with two specific
      nuclear protein factors with different mobilities in the control cells, and
      Delta12-PGJ2 induced the dissociation of the protein-DNA complex with lower
      mobility. These findings indicate that Delta12-PGJ2 stimulates the expression of
      BiP gene through the 3'-half of the unfolded protein response element.

PMID- 8663203
TI  - cDNA cloning and expression of a novel human UDP-N-acetyl-alpha-D-galactosamine.
      Polypeptide N-acetylgalactosaminyltransferase, GalNAc-t3.
AB  - The glycosylation of serine and threonine residues during mucin-type O-linked
      protein glycosylation is carried out by a family of UDP-GalNAc:polypeptide N
      acetylgalactosaminyltransferases (GalNAc-transferase). Previously two members,
      GalNAc-T1 and -T2, have been isolated and the genes cloned and characterized.
      Here we report the cDNA cloning and expression of a novel GalNAc-transferase
      termed GalNAc-T3. The gene was isolated and cloned based on the identification of
      a GalNAc-transferase motif (61 amino acids) that is shared between GalNAc-T1 and 
      T2 as well as a homologous Caenorhabditis elegans gene. The cDNA sequence has a
      633-amino acid coding region indicating a protein of 72.5 kDa with a type II
      domain structure. The overall amino acid sequence similarity with GalNAc-T1 and 
      T2 is approximately 45%; 12 cysteine residues that are shared between GalNAc-T1
      and -T2 are also found in GalNAc-T3. GalNAc-T3 was expressed as a soluble protein
      without the hydrophobic transmembrane domain in insect cells using a Baculo-virus
      vector, and the expressed GalNAc-transferase activity showed substrate
      specificity different from that previously reported for GalNAc-T1 and -T2.
      Northern analysis of human organs revealed a very restricted expression pattern
      of GalNAc-T3.

PMID- 8663204
TI  - Extensive alternative splicing within the amino-propeptide coding domain of
      alpha2(XI) procollagen mRNAs. Expression of transcripts encoding truncated pro
      alpha chains.
AB  - Heterogeneity in type XI procollagen structure is extensive because all three
      alpha(XI) collagen genes undergo complex alternative splicing within the amino
      propeptide coding domain. Exon 7 of the human and exons 6-8 of the mouse
      alpha2(XI) collagen genes, encoding part of the amino-propeptide variable region,
      have recently been shown to be alternatively spliced. We show that exon 6
      containing mRNAs for human alpha2(XI) procollagen are expressed at 28 weeks in
      fetal tendon and cartilage but not at 38-44 days or 11 weeks. In the mouse, exon
      6 is expressed in chondrocytes from 13.5 days onward. We recently identified
      conserved sequences within intron 6 of the human and mouse alpha2(XI) collagen
      genes, containing additional consensus splice acceptor and donor sites that
      potentially increase the size of exon 7, dividing it into three parts, designated
      7A, 7B, and 7C. We show by reverse transcription polymerase chain reaction and in
      situ hybridization that these potential splice sites are used to yield additional
      alpha2(XI) procollagen mRNA splice variants that are expressed in fetal tissues.
      In human, expression of exon 7B-containing transcripts may be developmental stage
      specific. Interestingly, inclusion of exon 7A or exon 7B in human and mouse
      alpha2(XI) procollagen mRNAs, respectively, would result in the insertion of an
      in-frame termination codon, suggesting that some of the additional splice
      variants encode a truncated pro-alpha2(XI) chain.

PMID- 8663205
TI  - Isolation of a Chinese hamster ovary cell clone possessing decreased mu-calpain
      content and a reduced proliferative growth rate.
AB  - A Chinese hamster ovary cell line (CHOp) was cultured in the presence of
      benzyloxycarbonyl-Leu-Leu-Tyr diazomethyl ketone (ZLLY-CHN2), to select for
      resistance to this cell-permeant calpain inhibitor. A clone isolated after
      several courses of exposure (SHI cells) demonstrated decreased sensitivity to
      ZLLY-CHN2 toxicity and a decreased growth rate. SHI cells also possessed less mu
      calpain isozyme relative to CHOp cells, as determined by activity measurement or
      by protein immunoblotting. Activities of m-calpain, calpastatin, cathepsin B,
      cathepsin L, and glycogen phosphorylase were not altered. SHI mu-calpain was
      partially purified by sequential chromatography on Bio-Gel A-1.5m and DEAE
      Sepharose. Its chromatographic behavior in either system was the same as for CHOp
      mu-calpain. Further studies with the partially purified SHI and CHOp mu-calpain
      fractions failed to distinguish any difference in Ca2+ requirement or in
      sensitivity to inhibition by calpastatin or ZLLY-CHN2 for these enzymes. These
      experiments suggest that SHI cells underproduce a form of mu-calpain which is
      very similar to, if not identical with, CHOp mu-calpain. SHI cells displayed a
      population doubling time of 29 h compared with 19 h for CHOp cells. The decreased
      growth rate of SHI cells was the result of a prolonged G1 phase. Introduction of
      purified human mu-calpain into SHI cells by electroporation transiently restored
      the growth rate and also increased toxicity associated with exposure to ZLLY
      CHN2. SHI cells should be a valuable model in further studies to delineate the
      function of mu-calpain in cell proliferative growth.

PMID- 8663206
TI  - Heparin decreases the blood clearance of interferon-gamma and increases its
      activity by limiting the processing of its carboxyl-terminal sequence.
AB  - Interferon-gamma (IFN-gamma) binds with high affinity to heparan sulfate and
      heparin molecules through its carboxyl-terminal domain. In vivo, IFN-gamma is
      eliminated from the bloodstream with a half-life (t1/2) of 1.1 min, due to
      binding to heparan sulfate. Unbound IFN-gamma is cleaved rapidly at the carboxyl
      terminal side, a process that removes at least 18 amino acids and inactivates the
      cytokine. When bound to heparin, the plasma clearance of IFN-gamma is decreased
      greatly (t1/2 = 99 min), and the area under the curve obtained with IFN-gamma
      alone represented only 15% of that obtained with injected IFN-gamma bound to
      heparin. Furthermore, the binding of heparin to IFN-gamma limits the extent of
      its carboxyl-terminal domain degradation to less than 10 amino acids.
      Importantly, this process increases the cytokine activity by as much as 600%.
      These data demonstrate that the blood clearance of the cytokine is a non-receptor
      mediated process and that in vivo the local concentration of heparan
      sulfate/heparin-like molecules regulates IFN-gamma activity by a unique mechanism
      involving a controlled processing of its carboxyl-terminal sequence.

PMID- 8663207
TI  - Effect of scrapie infection on the activity of neuronal nitric-oxide synthase in
      brain and neuroblastoma cells.
AB  - Nitric-oxide synthase (NOS) is responsible for the synthesis of nitric oxide
      which serves as a neural messenger in the central nervous system. NOS activity
      was markedly inhibited in brains of mice and hamsters and neuroblastoma cells
      infected with scrapie (ScN2a). The decrease in activity was in accordance with
      decreased NADPH-diaphorase-positive cells and decreased staining of NOS-positive
      cells demonstrated by specific anti-NOS antibodies. However, the specific nNOS
      mRNA in ScN2a was elevated when compared with normal neuroblastoma cells (N2a).
      Immunoblotting of fractions from these cell lines with an anti-nNOS monoclonal
      antibody revealed a band of nNOS from N2a and two bands with a lower molecular
      weight in ScN2a cells. Furthermore, NOS in ScN2a cells was insoluble in
      nondenaturing detergents. This insolubility is one of the landmark properties of
      PrPSc. It is, therefore, possible that nNOS in scrapie-infected cells and brains
      is aberrantly folded, resulting in an insoluble and inactive enzyme.

PMID- 8663208
TI  - Regulation of endothelial nitric-oxide synthase during hypoxia.
AB  - The mechanism by which nitric-oxide (NO) production increases during hypoxia is
      unknown. To explore the effect of hypoxia upon endothelial nitric-oxide synthase
      (ecNOS) activity and expression, we exposed bovine aortic endothelial cells
      (BAEC) to hypoxia (1% O2) for 0-24 h and measured levels of ecNOS mRNA, protein,
      and activity. The amount of ecNOS mRNA increases to more than twice the basal
      level after 6 h of hypoxia. Incubation of BAEC with actinomycin D during hypoxia
      prevents this increase, demonstrating that higher levels of mRNA observed during
      hypoxia are due to increased synthesis, not to increased stability of ecNOS mRNA.
      Levels of ecNOS protein increase throughout 24 h of hypoxia to more than twice
      normoxic levels. Although ecNOS expression increases within 2 h of hypoxia, total
      activity remains unchanged. To explore the transcriptional regulation of ecNOS,
      we constructed a reporter plasmid containing the ecNOS promoter region upstream
      of the luc gene and transfected this reporter plasmid into BAEC. In this system,
      hypoxia induces a linear increase over time in the expression of luciferase
      driven by the ecNOS promoter. It is concluded that hypoxia induces an increase in
      transcription of ecNOS in endothelial cells, activating the regulatory region of
      ecNOS by undefined transcription factors.

PMID- 8663209
TI  - Identification of complete precursors for the glycosylphosphatidylinositol
      protein anchors of Trypanosoma cruzi.
AB  - The survival of Trypanosoma cruzi, the causative agent of Chagas' disease,
      depends vitally on proteins and glycoconjugates that mediate the parasite/host
      interaction. Since most of these molecules are attached to the membrane by
      glycosylphosphatidylinositol (GPI), alternative means of chemotherapeutic
      intervention might emerge from GPI biosynthesis studies. The structure of the
      major 1G7 antigen GPI has been fully characterized by us (Guther, M. L. S.,
      Cardoso de Almeida, M. L., Yoshida, N., and Ferguson, M. A. J.(1992) J. Biol.
      Chem. 267, 6820-6828; Heise, N., Cardoso de Almeida, M. L., and Ferguson, M. A.
      J.(1995) Mol. Biochem. Parasitol. 70, 71-84), and based on its properties we now
      report the complete precursor glycolipids predicted to be transferred to the
      nascent protein. Migrating closely to Trypanosoma brucei glycolipid A on TLC,
      such species, named glycolipids A-like 1 and A-like 2, were labeled with
      tritiated palmitic acid, myo-inositol, glucosamine, and mannose, but surprisingly
      only the less polar glycolipid A-like 1 incorporated ethanolamine. The predicted
      products following nitrous acid deamination and digestion with phospholipases A2,
      C, and D confirmed their GPI nature. Evidence that they may represent the anchor
      transferred to the 1G7 antigen came from the following analyses: (i) alpha
      mannosidase treatments indicated that only one mannose was amenable to removal;
      (ii) their lipid moiety was identified as sn-1-alkyl-2-acylglycerol due to their
      sensitivity to phospholipase A2 (PLA2), mild base and by direct high performance
      TLC analysis of the corresponding benzoylated diradylglycerol components; and
      (iii) both glycolipids incorporated 3H-fatty acid only in the sn-2- and not in
      the sn-1-alkyl position as previously found in the GPI of the mature 1G7 antigen.
      Based on the differential [3H]ethanolamine incorporation pattern and the recent
      report that an aminoethylphosphonic acid (AEP) replaces ethanolamine phosphate
      (EtNH2-PO4) in the GPI in epimastigote sialoglycoproteins (Previato, J. O.,
      Jones, C., Xavier, M. T., Wait, R., Travassos, L. R., Parodi, A. J., and Mendonca
      Previato, L.(1995) J. Biol. Chem. 270, 7241-7250) it is proposed that glycolipid
      A-like 2 contains AEP and A-like 1 EtNH2-PO4. In the in vitro cell-free system
      both glycolipids were synthesized simultaneously and do not seem to bear a
      precursor/product relationship. Among the various components synthesized in vitro
      a glycolipid C-like corresponding to a form of glycolipid A-like 1 acylated on
      the inositol was also characterized. Phenylmethylsulfonyl fluoride, an inhibitor
      known to block the addition of ethanolamine phosphate in T. brucei but not in
      mammalian cells, also inhibits the synthesis of glycolipids A-like and C-like in
      T. cruzi, indicating that the putative trypanosome EtNH2-PO4/AEP transferase(s)
      might represent a potential target for chemotherapy.

PMID- 8663210
TI  - The antitumor drug aclacinomycin A, which inhibits the degradation of
      ubiquitinated proteins, shows selectivity for the chymotrypsin-like activity of
      the bovine pituitary 20 S proteasome.
AB  - The antitumor drug aclacinomycin A was previously shown to inhibit the
      degradation of ubiquitinated proteins in rabbit reticulocyte lysates with an IC50
      of 52 microM (Isoe, T., Naito, M., Shirai, A., Hirai, R., and Tsuruo, T.(1992)
      Biochim. Biophys. Acta 1117, 131-135). We report here that from all the catalytic
      activities of the 20 S proteasome tested, the chymotrypsin-like activity was the
      only one affected by the antitumor drug. An important requirement for inhibition
      of the chymotrypsin-like activity seemed to be the presence of hydrophobic
      nonpolar residues in positions P1 to P3. Degradation of Z-E(OtBu)AL-pNA and Z-LLL
      AMC at pH 7.5 was dramatically (87-98%) inhibited by 50 microM of the drug, while
      that of Z-GGL-pNA (containing uncharged polar residues in positions P2 and P3)
      and succinyl-LLVY-AMC (containing an uncharged polar residue in the P1 position)
      was inhibited only 11 and 24%, respectively. Aclacinomycin A had no effect on
      cathepsin B, stimulated trypsin, and inhibited chymotrypsin and, to a lesser
      extent, calpain. The aglycone and sugar moieties of the cytotoxic drug are
      essential for inhibition. The results presented here support a major role for the
      chymotrypsin-like activity in the degradation of ubiquitinated proteins.
      Aclacinomycin A is the first described non-peptidic inhibitor showing discrete
      selectivity for the chymotrypsin-like activity of the 20 S proteasome.

PMID- 8663211
TI  - Identification of a TAAT-containing motif required for high level expression of
      the COL1A1 promoter in differentiated osteoblasts of transgenic mice.
AB  - Our previous studies have shown that the 49-base pair region of promoter DNA
      between -1719 and -1670 base pairs is necessary for transcription of the rat
      COL1A1 gene in transgenic mouse calvariae. In this study, we further define this
      element to the 13-base pair region between -1683 and -1670. This element contains
      a TAAT motif that binds homeodomain-containing proteins. Site-directed
      mutagenesis of this element in the context of a COL1A1-chloramphenicol
      acetyltransferase construct extending to -3518 base pairs decreased the ratio of
      reporter gene activity in calvariae to tendon from 3:1 to 1:1, suggesting a
      preferential effect on activity in calvariae. Moreover, chloramphenicol
      acetyltransferase-specific immunofluorescence microscopy of transgenic calvariae
      showed that the mutation preferentially reduced levels of chloramphenicol
      acetyltransferase protein in differentiated osteoblasts. Gel mobility shift
      assays demonstrate that differentiated osteoblasts contain a nuclear factor that
      binds to this site. This binding activity is not present in undifferentiated
      osteoblasts. We show that Msx2, a homeodomain protein, binds to this motif;
      however, Northern blot analysis revealed that Msx2 mRNA is present in
      undifferentiated bone cells but not in fully differentiated osteoblasts. In
      addition, cotransfection studies in ROS 17/2.8 osteosarcoma cells using an Msx2
      expression vector showed that Msx2 inhibits a COL1A1 promoter-chloramphenicol
      acetyltransferase construct. Our results suggest that high COL1A1 expression in
      bone is mediated by a protein that is induced during osteoblast differentiation.
      This protein may contain a homeodomain; however, it is distinct from homeodomain
      proteins reported previously to be present in bone.

PMID- 8663212
TI  - Structural differences in the minimal catalytic domains of the GTPase-activating
      proteins p120GAP and neurofibromin.
AB  - The kinetic properties for the enzymatic stimulation of the GTPase reaction of
      p21(ras) by the two GTPase-activating proteins (GAPs) p120(GAP) and neurofibromin
      are different. In order to understand these differences and since crystallization
      attempts have only been successful with truncated fragments, structure/function
      requirements of the catalytic core of these proteins were investigated.
      Differences in size of the minimal catalytic domains of these two proteins were
      found as determined by limited proteolysis. The minimal catalytic domain has a
      molecular mass of 30 kDa in the case of p120(GAP) and of 26 kDa in the case of
      neurofibromin. Both catalytic domains contain the homology boxes as well as the
      residues perfectly conserved among all Ras GAPs. The C termini of these fragments
      are identical, whereas the N-terminal part of the minimal p120(GAP) domain is 47
      amino acids longer. These newly identified minimal catalytic fragments were as
      active in stimulating GTPase activity toward p21(ras) as the corresponding larger
      fragments GAP-334 and NF1-333 from which they had been generated via proteolytic
      digestion. Recently it was postulated that a fragment of 91 amino acids from
      neurofibromin located outside the conserved domain contains catalytic activity.
      In our hands this protein is unstable and has no catalytic activity. Thus, we
      believe that we have defined the true minimal domains of p120(GAP) (GAP-273,
      residues Met714-His986) and neurofibromin (NF1-230, residues Asp1248-Phe1477),
      which can be expressed via LMM fusion vectors in Escherichia coli and isolated in
      high purity.

PMID- 8663213
TI  - Identification and characterization of 1,25-dihydroxyvitamin D3-responsive
      repressor sequences in the rat parathyroid hormone-related peptide gene.
AB  - Parathyroid hormone-related peptide (PTHRP) gene transcription is suppressed by
      1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D3. In
      the present report, we examined 1, 25(OH)2D3-mediated repression of PTHRP
      expression by transfection of PTHRP promoter/reporter constructs in normal human
      keratinocytes and by DNA binding. We localized an element conferring 1, 25(OH)2D3
      mediated repression in vivo to a 47-base pair (bp) region located -1121 to -1075
      from the transcriptional start site. Mobility shift analysis revealed that this
      vitamin D response element (VDRE) forms DNA-protein complexes. The addition of a
      monoclonal antibody that recognizes the DNA binding region of the vitamin D
      receptor (VDR) attenuated binding of the receptor to the 47-bp sequence, whereas
      the addition of monoclonal antibody raised against the retinoid X receptor (RXR)
      further retarded the mobility of the protein-DNA complex. Consequently, the PTHRP
      promoter element binds a VDR.RXR heterodimer. Examination of this VDRE revealed
      complete sequence homology with a half-site of the human and rat osteocalcin VDRE
      (GGGTGA). Furthermore, mutation analysis suggests that a 16-bp domain consisting
      of an almost perfect repeat separated by a 3-base pair "spacer" GGGTGGAGAGGGGTGA
      is responsible for the DNA-protein interaction within this 47-bp sequence. Our
      results therefore indicate the existence of an inhibitory VDRE within the PTHRP
      promoter that is similar in sequence composition and cellular factor requirement
      to classical up-regulatory VDREs.

PMID- 8663214
TI  - Antagonistic properties of human prolactin analogs that show paradoxical
      agonistic activity in the Nb2 bioassay.
AB  - Based on the assumption that the prolactin receptor (PRLR) is activated by PRL
      induced sequential dimerization, potential human PRL (hPRL) antagonists were
      designed that sterically interfere with binding site 2. We previously reported
      the unexpected agonistic properties of these hPRL analogs in the rat Nb2 bioassay
      (Goffin, V., Struman, I., Mainfroid, V., Kinet, S., and Martial, J. A. (1994) J.
      Biol. Chem. 269, 32598-32606). In order to investigate whether such paradoxical
      agonistic behavior might result from characteristic features of the Nb2 assay
      (e.g. species specificity), we transfected in the same cell system the cDNA
      encoding the PRLR from rat or human species along with reporter genes containing
      PRL-responsive DNA sequences. We characterized the agonistic, self-antagonistic
      and/or antagonistic effects of wild type rat PRL, wild type hPRL, and three hPRL
      analogs, mutated either at binding site 1 or at binding site 2. Our results
      clearly show that the agonistic/antagonistic properties of PRLs are species
      specific. We thus propose different models of receptor activation, depending on
      the relative affinities of each hormonal binding site, which is directed by
      species specificity. Finally, this is the first report of hPRL binding site 2
      analogs showing antagonistic properties on human and, to a lesser extent, rat
      receptors.

PMID- 8663215
TI  - A zinc finger gene from Onchocerca volvulus encodes a protein with a functional
      signal peptide and an unusual Ser-His finger motif.
AB  - The filarial parasite Onchocerca volvulus is the causative agent of river
      blindness. In order to identify genes potentially involved in parasite
      development we cloned a zinc finger-encoding gene from this species. The ovzf-1
      gene represents one member of a family of related zinc finger genes. The
      predicted ovzf-1 translation product of 447 amino acids includes a hydrophobic
      signal peptide, which is followed by 13 contiguous finger motifs. The domains of
      fingers II-XIII display several conserved amino acids and a typical Kruppel-like
      Cys2-His2 motif. The first finger domain has the two conserved Cys residues
      replaced with Ser residues; however, it includes all additional amino acids
      typical of zinc finger domains. The N-terminal domain functions as a signal
      peptide, as it directs secretion of a reporter protein and a truncated Ovzf
      protein. Expression of an Ovzf protein via the secretory pathway was also
      confirmed by demonstrating attachment of N-linked carbohydrates to the
      recombinant protein. Although the recombinant Ovzf protein also includes a signal
      peptide, immunofluorescence analyses localize it inside a specific compartment of
      the infected insect cell. Expression of ovzf mRNA is developmentally regulated;
      no specific transcript is detected in adult female worms but in the infective L3.
      Identification of a secreted protein that might function in modulating gene
      expression of host cells provides an interesting tool for the study of parasite
      host interaction on a biochemical and molecular level.

PMID- 8663216
TI  - Purification, cloning, and bacterial expression of retinol dehydratase from
      Spodoptera frugiperda.
AB  - Anhydroretinol and 14-hydroxy-4,14-retro-retinol, retro-retinoids endogenous to
      both mammals and insects, act as agonist and antagonist, respectively, in
      controlling proliferation in lymphoblasts and other retinol-dependent cells. We
      describe here the identification, purification, cloning, and bacterial expression
      of the enzyme retinol dehydratase, which converts retinol to anhydroretinol in
      Spodoptera frugiperda. Retinol dehydratase has nanomolar affinity for its
      substrate and is, therefore, the first enzyme characterized able to utilize free
      retinol at physiological intracellular concentrations. The enzyme shows sequence
      homology to the sulfotransferases and requires 3'-phosphoadenosine 5'
      phosphosulfate for activity.

PMID- 8663217
TI  - Identification of domains in human beta-hexosaminidase that determine substrate
      specificity.
AB  - The lysosomal beta-hexosaminidases are dimers composed of alpha and beta
      subunits. beta-Hexosaminidase A (alphabeta) is a heterodimer, whereas
      hexosaminidase B (betabeta) and S (alphaalpha) are homodimers. Although
      containing a high degree of amino acid identity, each subunit expresses a unique
      active site that can be distinguished by a differential ability to hydrolyze
      charged substrates. The site on the beta-subunit primarily degrades neutral
      substrates, whereas the alpha-subunit site is, in addition, active against
      sulfated substrates. Isozyme specificity is also exhibited with glycolipid
      substrates. Among human isozymes, only beta-hexosaminidase A together with the
      GM2 activator protein can degrade the natural substrate, GM2 ganglioside, at
      physiologically significant rates. To identify the domains of the human beta
      hexosaminidase subunits that determine substrate specificity, we have generated
      chimeric subunits containing both alpha- and beta-subunit sequences. The chimeric
      constructs were expressed in HeLa cells to screen for activity and then selected
      constructs were produced in the baculovirus expression system to assess their
      ability to degrade GM2 ganglioside in the presence of GM2 activator protein.
      Generation of activity against the sulfated substrate required the substitution
      of two noncontinuous alpha-subunit sequences (amino acids 1-191 and 403-529) into
      analogous positions of the beta-subunit. Chimeric constructs containing only one
      of these regions linked to the beta-subunit sequence showed either neutral
      substrate activity only (amino acids 1-191) or lacked enzyme activity entirely
      (amino acids 403-529). Neither the chimeras nor the wild-type subunits displayed
      activator-dependent GM2-hydrolyzing activity when expressed alone. However, one
      chimeric subunit containing alpha amino acids 1-191 fused with beta amino acids
      225 to 556, when co-expressed with the wild-type alpha-subunit, showed activity
      comparable with that of recombinant beta-hexosaminidase A formed by the co
      expression of the alpha- and beta-subunits. This result indicates that the beta
      subunit amino acids 225-556 contribute an essential function in the GM2
      hydrolyzing activity of beta-hexosaminidase A.

PMID- 8663218
TI  - Platelet-derived growth factor induces a long-term inhibition of N-methyl-D
      aspartate receptor function.
AB  - Platelet-derived growth factor (PDGF) is a multifunctional protein that plays
      important roles in many tissues, including the mammalian central nervous system.
      PDGF and PDGF receptors (PDGFRs) are expressed in virtually every region of the
      central nervous system where they are involved in the development, survival,
      growth, and differentiation of both neuronal and glial cells. We now report that
      a brief activation of PDGFRs produced a long-lasting inhibition of N-methyl-D
      aspartate (NMDA)-dependent excitatory postsynaptic currents in CA1 pyramidal
      neurons in rat hippocampal slices. PDGF also inhibited NMDA receptors (NMDA-Rs)
      in cultured hippocampal neurons by a mechanism that involves a decrease in single
      channel open probability. Non-NMDA receptor function was not affected by PDGF in
      hippocampal neurons. Experiments with mutant PDGFRs and chelation of
      intracellular Ca2+ in Xenopus oocytes indicate that this inhibition depends on a
      phospholipase C-gamma-induced elevation of intracellular Ca2+ levels. The PDGF
      induced inhibition of NMDA-Rs is produced by a mechanism different than the well
      characterized phenomenon of Ca2+-dependent NMDA-R run down because the effect of
      PDGF was blocked by the phosphatase inhibitor, calyculin A, and was not affected
      by the microtubule polymerizing agent, phalloidin. Because elevations of PDGF
      levels are associated with neurological trauma or disease, we propose that PDGF
      can exert neuroprotective effects by inhibiting NMDA-R-dependent excitotoxicity.

PMID- 8663219
TI  - An E-box region within the prostaglandin endoperoxide synthase-2 (PGS-2) promoter
      is required for transcription in rat ovarian granulosa cells.
AB  - The prostaglandin endoperoxide synthase-2 (PGS-2) gene encodes an isoform of
      prostaglandin synthase that is transiently induced by protein kinase A
      (luteinizing hormone/cAMP) and protein kinase C (gonadotropin-releasing hormone)
      agonists in granulosa cells of ovulating follicles. The promoter of the rat PGS-2
      gene contains a CAAT enhancer-binding protein consensus site (CAAT box) which can
      confer hormone inducibility to a PGS-2.CAT reporter gene, as well as a putative E
      box region. To determine if the E-box region was involved in hormone induced
      trans-activation of the rat PGS-2 gene, constructs with the CAAT box and E-box
      regions (-192 PGS-2.CAT), only the putative E-box (-110 PGS-2.CAT), or neither
      region (-52 PGS-2.CAT) were transiently transfected into rat granulosa cell
      cultures. CAT activity was induced in both the -192 and -110 PGS-2*CAT vectors by
      luteinizing hormone (10-fold) and gonadotropin-releasing hormone (6-fold),
      whereas CAT activity of the -52 PGS-2.CAT construct did not differ from the
      promoterless vector (pCAT-Basic). Deletion of 1 base pair from the E-box within
      the -110 PGS-2.CAT construct, as well as point mutations within the CAAT box, E
      box, or both regions of the -192 PGS-2.CAT construct, demonstrated that the E-box
      is critical for basal transcription, and that regions, in addition to the CAAT
      box, are involved in hormone induction of the PGS-2 gene. An oligonucleotide
      spanning the rat PGS-2 E-box bound two specific protein complexes which were
      supershifted in the presence of antibody specific for the upstream stimulatory
      factor. Thus, in rat granulosa cells, the PGS-2 E-box region appears to interact
      with upstream cis-acting elements other than the CAAT box to confer hormonal
      regulation of the gene. The E-box region of the rat PGS-2 promoter does not
      contain ATF/CRE activity found in the human and mouse PGS-2 promoters, but is
      critical for basal transcription of the PGS-2 gene in rat granulosa cells and
      binds the upstream stimulatory factor (as do E-box regions of other genes
      regulated in the ovary).

PMID- 8663220
TI  - Acylglycerol recycling from triacylglycerol to phospholipid, not lipase activity,
      is defective in neutral lipid storage disease fibroblasts.
AB  - Neutral lipid storage disease (NLSD) is an autosomal recessive disorder in which
      excess triacylglycerol (TG) accumulates in most cells. Although it has been
      hypothesized that the TG accumulation is caused by a functional defect in
      cytosolic lipase activity, we were able to expose TG hydrolysis in NLSD cells by
      using triacsin C, an inhibitor of acyl-CoA synthetase that blocks the
      reincorporation of hydrolyzed fatty acids into glycerolipids. Our data suggest
      that TG lipolysis in NLSD cells is masked by rapid TG resynthesis, occurring
      because released acylglycerols cannot be used for phospholipid synthesis. In
      uptake studies, triacsin C blocked the incorporation of [3H]glycerol into
      glycerolipids, incorporation of [14C]oleate into TG, but not incorporation of
      [14C]oleate into phospholipid. Thus, the drug inhibited both de novo synthesis of
      glycerolipids via the glycerol-3-phosphate pathway and the synthesis of TG from
      diacylglycerol. The drug did not appear to block reacylation of
      lysophospholipids. Triacsin C caused a loss of about 60% of the TG mass from both
      NLSD and oleate-loaded control cells. Rates of TG lipolysis were similar in NLSD
      cells and oleate-loaded control cells labeled with [6-(7-nitro-2,1,3
      benzoxadiazol-4-yl)-amino]hexanoic acid or labeled with [14C]oleate or
      [3H]glycerol and chased in the presence of triacsin C. During a 96-h chase,
      [14C]oleate reincorporation into the different phospholipid species increased
      only in control cells. Similar results were observed when NLSD, and control cells
      were chased after labeling with [3H]glycerol. These data strongly suggest that
      normal human fibroblasts mobilize stored TG for phospholipid synthesis and that
      recycling to PC occurs via a TG-derived mono- or diacylglycerol intermediate.
      Normal recycling to phosphatidylethanolamine may primarily involve TG-derived
      acyl groups rather than an acylglycerol precursor. NLSD cells appear to have a
      block in this recycling pathway with the result that both hydrolyzed fatty acids
      and the acylglycerol backbone are re-esterified to form TG. Because the NLSD
      phenotype includes ichthyosis, fatty liver, myopathy, cardiomyopathy, and mental
      retardation, the recycling pathway appears to be critical for the normal function
      of skin, liver, muscle, heart, and the central nervous system.

PMID- 8663221
TI  - Autoproteolysis or plasmin-mediated cleavage of factor Xaalpha exposes a
      plasminogen binding site and inhibits coagulation.
AB  - Blood coagulation factor Xa (FXa) has recently been shown to function as a
      plasminogen receptor in the presence of procoagulant phospholipid
      (phosphatidylserine; PS) and Ca2+. In the current work, the possible effect of
      autoproteolytic and plasmin-mediated cleavage of FXa on complex formation with
      plasminogen was investigated. 125I-plasminogen binding to derivatives of FXa
      electrotransferred to polyvinylidene difluoride revealed that the autoproteolytic
      conversion of FXaalpha to FXabeta was required for the expression of a
      plasminogen binding site. In the presence of PS and Ca2+, plasmin was shown to
      convert FXaalpha to a FXabeta-like species at least 3 orders of magnitude faster
      than the autoproteolytic mechanism. This also resulted in the exposure of a
      plasminogen binding site. Further processing by plasmin generated a fragment (33
      kDa) due to cleavage at Gly331 in the FXa heavy chain. Production of this species
      enhanced apparent plasminogen binding compared with FXabeta and resulted in the
      loss of FXa amidolytic and clotting activity. In the absence of either PS or
      Ca2+, the plasmin-mediated fragmentation of FXaalpha was altered to include a
      FXabeta-like molecule and a species (40 kDa) with intact beta-heavy chain
      disulfide linked to a COOH-terminal fragment of the light chain starting at
      Tyr44. Neither of these products was observed to interact with plasminogen. The
      40-kDa species had amidolytic activity comparable with FXaalpha but inhibited
      clotting activity. Cumulatively the data provide the first evidence for a
      functional difference between the FXa subforms and suggest a mechanism where
      autoproteolysis and plasmin-mediated cleavage modulate the function of FXaalpha
      from a procoagulant enzyme to a profibrinolytic plasminogen receptor.

PMID- 8663222
TI  - Kinetics of blood coagulation factor Xaalpha autoproteolytic conversion to factor
      Xabeta. Effect on inhibition by antithrombin, prothrombinase assembly, and enzyme
      activity.
AB  - Autoproteolysis of blood coagulation factor Xa (FXa) results in the excision of a
      4-kDa fragment (beta-peptide) from the intact subform, factor Xaalpha (FXaalpha),
      to yield factor Xabeta (FXabeta). In the preceding paper, we showed that
      generation of FXabeta leads to expression of a plasminogen binding site. FXabeta
      may consequently participate in fibrinolysis; therefore, the timing of subform
      conversion compared with thrombin production is important. In the current study
      we evaluated the kinetics of FXabeta generation, which showed that
      autoproteolysis of FXaalpha followed a second order mechanism where FXaalpha and
      FXabeta behaved as identical enzymes. Rate constants of 9 and 172 M-1 s-1 were
      derived, respectively, in the absence and presence of FXaalpha binding to
      procoagulant phospholipid. Under identical conditions the latter is estimated to
      be 6 orders of magnitude slower than thrombin generation by prothrombinase. Since
      heparin binding and prothrombin recognition have been previously attributed to a
      region of FXaalpha proximal to the beta-peptide, functional comparisons were
      conducted using homogeneous and stabilized preparations of FXaalpha and FXabeta.
      Comparisons included 1) the recognition of small substrates; 2) the rate of
      interaction with antithrombin/heparin; 3) the assembly of prothrombinase; and 4)
      the activation of prothrombin by prothrombinase. Although the beta-peptide
      neighbors a probable functional region in FXaalpha, conversion to FXabeta was not
      observed to influence these functions. The data support a model where FXaalpha is
      predominantly responsible for thrombin generation and where slow conversion to
      FXabeta coordinates coagulation and the initiation of fibrinolysis at sites of
      prothrombinase assembly.

PMID- 8663223
TI  - The HIV nef protein associates with protein kinase C theta.
AB  - Expression of the human immunodeficiency virus (HIV) Nef protein has been linked
      to both decreased cell surface expression of CD4 and an impairment of signal
      transduction. The recently reported association of Nef with an unidentified
      serine kinase provides a clue as to how Nef might exert its effects. Considering
      the key role of protein kinase C (PKC) in T cell activation, we investigated the
      possibility that Nef interacts with PKC. Our results, using two approaches for
      detecting interactions between Nef and PKC isozymes in Jurkat cells, show that
      Nef interacts preferentially with thetaPKC. The interaction of Nef and thetaPKC
      is independent of calcium, enhanced by phospholipid activators of PKC and not
      affected by a PKC pseudosubstrate peptide. Phorbol 12-myristate 13-acetate and
      phytohemagglutinin stimulation of Jurkat cells expressing Nef fails to produce
      the usual translocation of thetaPKC from the cytosol to the particulate fraction;
      translocation of betaPKC and epsilonPKC was unaffected. Indeed, there appears to
      be a net loss of thetaPKC in Nef-expressing cells following stimulation. The loss
      of thetaPKC, which may be a result of inhibition of its binding to RACKs due to
      Nef binding, could contribute to the various impairments of T cell function
      associated with HIV infection and Nef expression.

PMID- 8663224
TI  - Oligomerization of the hemolytic lectin CEL-III from the marine invertebrate
      Cucumaria echinata induced by the binding of carbohydrate ligands.
AB  - The hemolytic lectin CEL-III is a Ca2+-dependent, galactose/GalNAc-specific
      lectin purified from the marine invertebrate Cucumaria echinata (Holothuroidea).
      We found that this lectin forms ion-permeable pores in erythrocyte and artificial
      lipid membranes that have specific carbohydrate ligands on the surface. The
      hemolytic activity of CEL-III exhibited characteristic pH dependence; activity
      increased remarkably with pH in the alkaline region, especially above pH 9. When
      rabbit erythrocyte membrane was examined by immunoblotting using anti-CEL-III
      antiserum after treatment with CEL-III, the irreversible binding of the CEL-III
      oligomer increased with pH, indicating that the increase in hemolytic activity at
      higher pH is associated closely with the amount of oligomer irreversibly bound to
      the membrane. Surface hydrophobicity of CEL-III, as measured by the fluorescent
      probe 8-anilino-1-naphthalenesulfonate, increased markedly with the binding of
      specific ligands such as lactose, lactulose, and N-acetyllactosamine at pH 9-10
      in the presence of 1 M NaCl. The enhancement of surface hydrophobicity induced by
      the binding of carbohydrates was also accompanied by the formation of a CEL-III
      oligomer, which was found to be the same size on sodium dodecyl sulfate
      polyacrylamide gel electrophoresis as the oligomer that formed in CEL-III-treated
      erythrocyte membranes. Far-UV circular dichroism spectra of CEL-III and the
      oligomer revealed a definite difference in secondary structure. These data
      suggest that the binding of CEL-III to specific carbohydrate ligands on the
      erythrocyte surface induces a conformational change in the protein, leading to
      the exposure of a hydrophobic region which triggers oligomerization and the
      irreversible binding of the protein to the membrane.

PMID- 8663225
TI  - Mutation of the Rab6 homologue of Saccharomyces cerevisiae, YPT6, inhibits both
      early Golgi function and ribosome biosynthesis.
AB  - A screen was designed to identify temperature-sensitive mutants of Saccharomyces
      cerevisiae, whose transcription of both ribosomal RNA and ribosomal protein genes
      is repressed at the nonpermissive temperature. The gene from one such mutant was
      cloned by complementation. The gene encodes a predicted product that is nearly
      65% identical to the human GTPase, Rab6, and is likely to be identical to the
      yeast gene YPT6. It is essential for growth only at elevated temperatures. The
      mutant strain is partially defective in the maturation of the vacuolar protein
      carboxypeptidase Y, as well as in the secretion of invertase, which accumulates
      as a core-glycosylated form characteristic of the endoplasmic reticulum or the
      cis-Golgi, suggesting that Ypt6p is involved in an early step of the secretory
      pathway, earlier than that reported for the mammalian Rab6. The mutant protein, a
      truncation at codon 64 of 215, has a stronger phenotype than the null allele of
      YPT6. Four other mutants selected for defective ribosome synthesis at the
      nonpermissive temperature were also found to have defects in carboxypeptidase Y
      maturation, giving emphasis to our previous finding that a functional secretory
      pathway is essential for continued ribosome synthesis. Cloning of extragenic
      suppressors of the ts allele of YPT6 has revealed two additional proteins that
      influence the secretory pathway: Ssd1p, a suppressor of many mutations, and
      Imh1p, which bears some homology to the C-terminal portion of the cytoskeletal
      proteins integrin and myosin.

PMID- 8663226
TI  - Involvement of Gs and Gi proteins in dual coupling of the luteinizing hormone
      receptor to adenylyl cyclase and phospholipase C.
AB  - Binding of lutropin/choriogonadotropin to its cognate receptor results in the
      activation of adenylyl cyclase and phospholipase C. The mechanism underlying the
      generation of this bifurcating signal is presently not known. To analyze the
      coupling mechanism of the LH receptor, activated G proteins were labeled with
      [alpha-32P]GTP azidoanilide and identified by selective immunoprecipitation. In
      membranes of bovine corpora lutea and of L cells stably expressing the murine LH
      receptor (LHR cells), human chorionic gonadotropin (hCG) led to incorporation of
      the label into alphas and alphai2. Stimulation of LHR cells or of L cells
      expressing the M5 muscarinic receptor (LM5 cells) with the respective agonist
      resulted in activation of phospholipase C in both cell lines. However, alphaq and
      alpha11 were only labeled upon stimulation of the M5 muscarinic receptor. Agonist
      induced Ca2+ mobilization and inositol phosphate accumulation were partially
      sensitive to pertussis toxin, and the expression of the betagamma-stimulable
      phospholipase C isoforms beta2 and beta3 could be demonstrated in LHR cells.
      Overexpression of phospholipase C-beta2 led to increased hCG-stimulated inositol
      phosphate accumulation, and expression of a beta-ARK1 C-terminal polypeptide
      effectively suppressed hCG-mediated phosphatidylinositol hydrolysis. Thus, the LH
      receptor couples to both Gs and Gi, and betagamma-subunits released from either G
      protein contribute to the stimulation of phospholipase C-beta isoforms.

PMID- 8663227
TI  - Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP
      dependent protein kinase. Involvement of serine 54 in the enzyme activation.
AB  - A cAMP-specific phosphodiesterase (PDE4D3) is activated in rat thyroid cells by
      TSH through a cAMP-dependent phosphorylation (Sette, C., Iona, S., and Conti,
      M.(1994) J. Biol. Chem. 269, 9245-9252). This short term activation may be
      involved in the termination of the hormonal stimulation and/or in the induction
      of desensitization. Here, we have further characterized the protein kinase A
      (PKA)-dependent phosphorylation of this PDE4D3 variant and identified the
      phosphorylation site involved in the PDE activation. The PKA-dependent
      incorporation of phosphate in the partially purified, recombinant rat PDE4D3
      followed a time course similar to that of activation. Half-maximal activation of
      the enzyme was obtained with 0.6 microM ATP and 30 nM of the catalytic subunit of
      PKA. Phosphorylation altered the Vmax of the PDE without affecting the Km for
      cAMP. Phosphorylation also modified the Mg2+ requirements and the pattern of
      inhibition by rolipram. Cyanogen bromide cleavage of the 32P-labeled rat PDE4D3
      yielded two or three major phosphopeptide bands, providing a first indication
      that the enzyme may be phosphorylated at multiple sites in a cell-free system.
      Site-directed mutagenesis was performed on the serine residues present at the
      amino terminus of this PDE in the context of preferred motifs for PKA
      phosphorylation. The PKA-dependent incorporation of 32P was reduced to the
      largest extent in mutants with both Ser13 --> Ala and Ser54 --> Ala
      substitutions, confirming the presence of more than one phosphorylation site in
      rat PDE4D3. While substitution of serine 13 with alanine did not affect the
      activation by PKA, substitution of Ser54 completely suppressed the kinase
      activation. Similar conclusions were reached with wild type and mutated PDE4D3
      proteins expressed in MA-10 cells, where the endogenous PKA was activated by
      dibutyryl cAMP. Again, the PDE with the Ser54 --> Ala substitution could not be
      activated by the endogenous PKA in the intact cell. These findings support the
      hypothesis that the PDE4D3 variant contains a regulatory domain target for
      phosphorylation at the amino terminus of the protein and that Ser54 in this
      domain plays a crucial role in activation.

PMID- 8663228
TI  - Beta-amyloid peptide secretion by a microglial cell line is induced by beta
      amyloid-(25-35) and lipopolysaccharide.
AB  - beta-Amyloid protein (betaAP) deposition is a neuropathologic hallmark of
      Alzheimer's disease (AD). Yet, the source of cerebral betaAP in AD is
      controversial. We examined the production of betaAP by the BV-2 immortalized
      microglial cell line using a sensitive enzyme immunoassay. Constitutive
      production of betaAP was detected in conditioned media from unstimulated BV-2
      cells. Further, production of betaAP was induced by treatment of cultures by
      lipopolysaccharide (LPS) or betaAP-(25-35) and was inhibited by the calpain
      protease inhibitor MDL 28170. Treatment of BV-2 cells with LPS or betaAP-(25-35)
      did not affect cell-associated beta-amyloid precursor protein levels. These
      findings suggest that microglia may be an important source of betaAP in AD, and
      that microglial production of betaAP may be augmented by proinflammatory stimuli
      or by betaAP itself.

PMID- 8663229
TI  - Protein kinase C delta specifically associates with phosphatidylinositol 3-kinase
      following cytokine stimulation.
AB  - Phosphatidylinositol (PI) 3-kinase is activated as a result of cytokine-induced
      association of the enzyme with specific tyrosine-phosphorylated proteins. PI 3
      kinase lipid products, PI 3, 4-P2 and PI 3,4,5-P3, have been shown, in vitro, to
      directly activate novel and atypical protein kinase C (PKC) isozymes. However,
      the mechanism by which PI 3-kinase may be involved in regulation of PKC isoforms
      in vivo is presently unknown. We investigated a possible relationship by looking
      for associations between these enzymes. We found that in a human erythroleukemia
      cell line, as well as in rabbit platelets, PI 3-kinase and PKCdelta associate in
      a specific manner that is modulated by cell activation. Granulocyte-macrophage
      colony-stimulating factor treatment of cells caused increased association of
      PKCdelta and PI 3-kinase as did treatment of platelets with platelet-activating
      factor. Results using two PI 3-kinase inhibitors, wortmannin and LY-294002,
      showed that the former inhibited this association, while the latter did not,
      suggesting that PI 3-kinase lipid products may not be a prerequisite for the PI 3
      kinase/PKCdelta association. Our results also suggest that tyrosine
      phosphorylation of PKCdelta is not involved in its association with PI 3-kinase.

PMID- 8663230
TI  - Mapping of the transcriptional repression domain of the lymphoid-specific
      transcription factor oct-2A.
AB  - The lymphoid-specific transcription factor Oct-2a is implicated in B cell
      specific transcriptional activity via the octamer motif. Structure/function
      analysis of various Oct-2a effector regions in the context of the GAL4 DNA
      binding domain revealed that Oct-2a contains two functionally different
      activation domains at the N and the C termini. The transcriptional activity of
      both domains is strongly potentiated by interactions with distinct B cell
      specific coactivators. Recently, we have identified a repression domain located
      within the N terminus of Oct-2a (amino acids 2-99). When this domain was
      transferred to a potent activator, transcription was strongly inhibited. In this
      study we present a deletion analysis of the N-terminal region of Oct-2a to
      determine the minimal repression domain. We identified a stretch of 23 amino
      acids, rich in serine and threonine residues, which was responsible for most of
      the repression activity. We show that repression is strongly dependent on the
      type of enhancer present in the reporter plasmid as well as on the cell line
      tested. The possibility that Oct-2a can act as an activator and/or a repressor
      may have important consequences for the function of Oct-2a in B cell
      differentiation and other developmental processes.

PMID- 8663231
TI  - Activation-modulated association of 14-3-3 proteins with Cbl in T cells.
AB  - 14-3-3 proteins have recently been implicated in the regulation of intracellular
      signaling pathways via their interaction with several oncogene and protooncogene
      products. We found recently that 14-3-3 associates with several tyrosine
      phosphorylated proteins and phosphatidylinositol 3-kinase (PI3-K) in T cells. We
      report here the identification of the 120-kDa 14-3-3tau-binding phosphoprotein
      present in activated T cell lysates as Cbl, a protooncogene product of unknown
      function which was found recently to be a major protein-tyrosine kinase (PTK)
      substrate, and to interact with several signaling molecules including PI3-K, in T
      lymphocytes. The association between 14-3-3tau and Cbl was detected both in vitro
      and in intact T cells and, in contrast to Raf-1, was markedly increased following
      T cell activation. The use of truncated 14-3-3tau fusion proteins demonstrated
      that the 15 C-terminal residues are required for the association between 14-3-3
      and three of its target proteins, namely, Cbl, Raf-1, and PI3-K. The findings
      that 14-3-3tau binds both PI3-K and Cbl, together with recent reports of an
      association between Cbl and PI3-K, suggest that 14-3-3 dimers play a critical
      role in signal transduction processes by promoting and coordinating protein
      protein interactions of signaling proteins.

PMID- 8663232
TI  - Structural requirements for the ectodomain cleavage of human cell surface
      macrophage colony-stimulating factor.
AB  - One form of human macrophage colony-stimulating factor (CSF-1(256), M-CSFalpha)
      is a member of a restricted set of cell surface transmembrane proteins, which is
      selected to undergo proteolytic ectodomain cleavage. To determine the substrate
      requirements for this cleavage, we have constructed a series of mutations in the
      cytoplasmic tail, transmembrane domain, and juxtamembrane region of CSF-1(256)
      and stably expressed the mutated genes in NIH 3T3 cells. Our results demonstrate
      that membrane association of the CSF-1 precursor is required for cleavage of its
      growth factor ectodomain and furthermore that the juxtamembrane region Pro161
      Gln162-Leu163-Gln164-Glu165 (PQLQE) (residues 161-165 of the ectodomain) is an
      essential determinant of cell surface CSF-1(256) cleavage and that the cleavage
      site is partially sequence-specific. Furthermore, a mechanism of steric
      hindrance, which likely involves interference with protease accessibility, is
      postulated to explain the observed decreases in the cleavage efficiency in
      certain CSF-1 mutants. Finally, our results strongly suggest that the CSF-1
      ectodomain is cleaved at or very near the cell surface by a membrane-associated
      proteolytic system.

PMID- 8663233
TI  - Specificity of LIM domain interactions with receptor tyrosine kinases.
AB  - LIM domains, Cys-rich motifs containing approximately 50 amino acids found in a
      variety of proteins, are proposed to direct protein*protein interactions. To
      identify structural targets recognized by LIM domains, we have utilized random
      peptide library selection, the yeast two-hybrid system, and glutathione S
      transferase fusions. Enigma contains three LIM domains within its carboxyl
      terminus and LIM3 of Enigma specifically recognizes active but not mutant
      endocytic codes of the insulin receptor (InsR) (Wu, R. Y., and Gill, G. N. (1994)
      J. Biol. Chem. 269, 25085-25090). Interaction of two random peptide libraries
      with glutathione S-transferase-LIM3 of Enigma indicated specific binding to Gly
      Pro-Hyd-Gly-Pro-Hyd-Tyr-Ala corresponding to the major endocytic code of InsR.
      Peptide competition demonstrated that both Pro and Tyr residues were required for
      specific interaction of InsR with Enigma. In contrast to LIM3 of Enigma binding
      to InsR, LIM2 of Enigma associated specifically with the receptor tyrosine
      kinase, Ret. Ret was specific for LIM2 of Enigma and did not bind other LIM
      domains tested. Mutational analysis indicated that the residues responsible for
      binding to Enigma were localized to the carboxyl-terminal 61 amino acids of Ret.
      A peptide corresponding to the carboxyl-terminal 20 amino acids of Ret
      dissociated Enigma and Ret complexes, while a mutant that changed Asn-Lys-Leu-Tyr
      in the peptide to Ala-Lys-Leu-Ala or a peptide corresponding to exon16 of InsR
      failed to disrupt the complexes, indicating the Asn-Lys-Leu-Tyr sequence of Ret
      is essential to the recognition motif for LIM2 of Enigma. We conclude that LIM
      domains of Enigma recognize tyrosine-containing motifs with specificity residing
      in both the LIM domains and in the target structures.

PMID- 8663234
TI  - 1,25-Dihydroxyvitamin D3 stimulates expression and translocation of protein
      kinase Calpha and Cdelta via a nongenomic mechanism and rapidly induces
      phosphorylation of a 33-kDa protein in acute promyelocytic NB4 cells.
AB  - 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) primes NB4 cells for 12-O
      tetradecanoylphorbol-13-acetate-induced monocytic differentiation in a dose- and
      sequence-dependent fashion. Experiments utilizing 1,25-(OH)2D3 analogues and
      kinase/phosphatase inhibitors suggested that tyrosine kinase and serine/threonine
      phosphorylation cascades, rather than vitamin D3 receptor-mediated signals, were
      involved in 1,25-(OH)2D3 action. Here we show that NB4 cells express the alpha
      and delta (but not the beta, epsilon, and theta) isoforms of protein kinase C
      (PKC). Both authentic 1, 25-(OH)2D3 and the nongenomic analogue 1alpha,25
      dihydroxyprevitamin D3 (HF) increased expression of PKCalpha and PKCdelta.
      PKCalpha and PKCdelta were translocated to the nucleus of the cell in response to
      1,25-(OH)2D3 or HF. The effects of HF were attenuated by the nongenomic
      antagonist 1beta,25-dihydroxyvitamin D3, suggesting that changes in PKC
      expression are mediated by a nongenomic signaling pathway. Consistent with the
      involvement of serine, threonine, and tyrosine phosphorylation cascades mediating
      1,25-(OH)2D3 action, enhanced phosphorylation of a variety of cellular proteins
      at serine and threonine residues and the specific enhanced phosphotyrosyl content
      of a 33-kDa protein (vdrp33) were observed immediately after 1,25-(OH)2D3
      addition. We propose that 1,25-(OH)2D3 primes NB4 cells for 12-O
      tetradecanoylphorbol-13-acetate-induced monocytic differentiation by increasing
      the expression of specific PKC isoforms and inducing the specific phosphorylation
      of key protein signaling intermediates.

PMID- 8663235
TI  - Syk tyrosine kinase is required for immunoreceptor tyrosine activation motif
      dependent actin assembly.
AB  - Clustering of several multisubunit receptors on hematopoetic cells results in a
      signaling cascade involving the phosphorylation of immunoreceptor tyrosine
      activation motifs, or "ITAMs," and actin polymerization. Recent experiments
      indicate that direct clustering of the ITAM-binding protein, p72(syk) (Syk), is
      capable of transmitting a phagocytic signal in COS cells (Greenberg, S., Chang,
      P., Wang, D., Xavier, R., and Seed, B.(1996) Proc. Natl. Acad. Sci. U. S. A. 93,
      1103-1107). However, the possibility of redundant signaling pathways makes it
      difficult to test the requirement for Syk in ITAM-dependent actin polymerization
      in hematopoetic cells. We developed a model system to study ITAM-dependent actin
      assembly. DT40 lymphocytes were transfected with fusion proteins encoding the
      transmembrane and cytosolic domains of the ITAM-containing gamma subunit of Fc
      receptors. Clustering the gamma-containing fusion proteins with IgG-coated
      erythrocytes triggered submembranous actin assembly. This response depended on an
      intact ITAM, was absent in cell lines that had been engineered to lack Syk, and
      was augmented in cell lines that stably overexpressed Syk. These experiments
      demonstrate an absolute requirement for Syk tyrosine kinase in ITAM-dependent
      actin assembly in transfected lymphocytes.

PMID- 8663236
TI  - Direct binding of the platelet integrin alphaIIbbeta3 (GPIIb-IIIa) to talin.
      Evidence that interaction is mediated through the cytoplasmic domains of both
      alphaIIb and beta3.
AB  - As a consequence of platelet activation and fibrinogen binding, glycoprotein
      (GP)IIb-IIIa (integrin alphaIIbbeta3) becomes associated with the cytoskeleton.
      Although talin has been suggested to act as a linkage protein mediating the
      attachment of GPIIb-IIIa to actin filaments, direct binding of GPIIb-IIIa to this
      cytoskeletal protein has not been demonstrated. In the present study, we examined
      the interaction of GPIIb-IIIa with purified talin using a solid-phase binding
      assay. Soluble GPIIb-IIIa bound in a time- and dose-dependent manner to
      microtiter wells coated with talin but not with BSA. Time course studies
      demonstrated that steady-state binding was achieved after 4-5 h incubation at 37
      degrees C. Binding isotherms with varying concentrations of GPIIb-IIIa showed
      that half-saturation binding was achieved at approximately 15 nM GPIIb-IIIa. At
      saturation, there was 211 +/- 8 fmol of GPIIb-IIIa bound per well containing 117
      +/- 10 fmol of immobilized talin. Besides binding to immobilized talin, GPIIb
      IIIa also bound to talin captured by the anti-talin monoclonal antibody 8d4.
      Moreover, the interaction of GPIIb-IIIa to 8d4-captured talin was blocked by
      mAb10B2, a monoclonal antibody raised against a synthetic peptide encompassing
      the entire cytoplasmic sequence of GPIIb. The interaction of talin with the
      cytoplasmic domain of GPIIb-IIIa was further investigated using peptide-coated
      wells. Purified talin was found to bind to both synthetic peptides corresponding
      to the cytoplasmic sequences of GPIIb (P2b) and GPIIIa (P3a). As expected, the
      binding of talin to P2b-coated wells was specifically blocked by mAb10B2. Thus,
      these results demonstrate direct binding of GPIIb-IIIa to talin and suggest a
      role of the cytoplasmic sequences of both GPIIb and GPIIIa in mediating this
      interaction.

PMID- 8663237
TI  - Association of human protein-tyrosine phosphatase kappa with members of the
      armadillo family.
AB  - We have identified a human receptor-like protein-tyrosine phosphatase (PTP) in
      the mammary carcinoma cell line SK-BR-3, which represents the human homolog of
      murine PTPkappa (Jiang, Y.-P., Wang, H., D'Eustachio, P., Musacchio, J. M.,
      Schlessinger, J., and Sap, J. (1993) Mol. Cell. Biol. 13, 2942-2951) and was
      therefore termed hPTPkappa. We show here that hPTPkappa expression is dependent
      on cell density and find it colocalized with two members of the arm family of
      proteins, beta-catenin and gamma-catenin/plakoglobin, at adherens junctions.
      Using both in vitro and in vivo binding assays, we demonstrate specific complex
      formation between endogenous hPTPkappa and beta- and gamma-catenin/plakoglobin.
      In addition, we present evidence that suggests that beta-catenin may represent a
      substrate for the catalytic activity of hPTPkappa. The identification of specific
      binding partners for this receptor-like PTP provides insight into the mechanisms
      of its biological action and suggests a role for hPTPkappa in the regulation of
      processes involving cell contact and adhesion such as growth control, tumor
      invasion, and metastasis.

PMID- 8663238
TI  - The amino-terminal immunoglobulin-like domain of activated leukocyte cell
      adhesion molecule binds specifically to the membrane-proximal scavenger receptor
      cysteine-rich domain of CD6 with a 1:1 stoichiometry.
AB  - Activated leukocyte cell adhesion molecule (ALCAM) was recently identified as a
      ligand for CD6, a signaling receptor expressed on T cells, a subset of B cells,
      and some cells in the brain. Receptor-ligand binding assays, antibody blocking
      experiments, and examination of the tissue distribution of these two cell surface
      proteins suggest that CD6-ALCAM interactions play an important role in mediating
      the binding of thymocytes to thymic epithelial cells and of T cells to activated
      leukocytes. Presently, the details of CD6-ALCAM interactions and of signaling
      through CD6 are unknown. A series of truncated human ALCAM and CD6 immunoglobulin
      fusion proteins were produced and tested in different binding assays to analyze
      ALCAM-CD6 interactions in more detail. In this study, we report that the amino
      terminal Ig-like domain of human ALCAM specifically binds to the third membrane
      proximal scavenger receptor cysteine-rich (SRCR) domain of human CD6. Using
      thrombin-cleaved Ig fusion proteins containing single or multiple ALCAM or CD6
      domains, we were able to determine that the stoichiometry of the interaction
      between the amino-terminal ALCAM domains and the membrane-proximal CD6 SRCR
      domain is 1:1. These results provide the first example of an Ig-like domain
      mediating an interaction with an SRCR domain.

PMID- 8663239
TI  - Mevalonic acid is limiting for N-linked glycosylation and translocation of the
      insulin-like growth factor-1 receptor to the cell surface. Evidence for a new
      link between 3-hydroxy-3-methylglutaryl-coenzyme a reductase and cell growth.
AB  - Depletion of mevalonic acid (MVA), obtained by inhibition of 3-hydroxy-3
      methylglutaryl-coenzyme A (HMG-CoA) reductase using lovastatin, depressed the
      biosynthesis of dolichyl-phosphate and the rate of N-linked glycosylation and
      caused growth arrest in the melanoma cell line SK-MEL-2. The growth arrest was
      partially prevented by addition of high concentrations of insulin-like growth
      factor-1 (IGF-1) to the cells, indicating that MVA depletion may inhibit cell
      growth through decreasing the number of IGF-1 receptors (IGF-1R) at the cell
      surface. Such a decrease in receptor number might be a result of a lowered
      translocation of de novo synthesized receptors to the cell membrane which in turn
      might be a result of a decreased N-linked glycosylation of the receptor proteins.
      We could also demonstrate that IGF-1R became underglycosylated and that the
      amount of de novo synthesized IGF-1R proteins at the cell membrane was
      drastically decreased upon MVA depletion. Analysis of receptor proteins cross
      linked with IGF-1, as well as binding assays and immunocytostaining confirmed
      that the number of functional membrane-bound IGF-1R was substantially reduced.
      The N-linked glycosylation and the expression of de novo synthesized IGF-1R
      proteins at the cell surface as well as the number of IGF-1 binding sites were
      completely restored upon replenishment of MVA. These effects of MVA were
      efficiently abrogated by the glycosylation inhibitor tunicamycin. The
      translocation of IGF-1R to the cell membrane was shown to take place just prior
      to initiation of DNA synthesis in arrested cells stimulated with MVA.
      Additionally, there was a clear correlation between IGF-1 binding and initiation
      of DNA synthesis with regard to the MVA dose requirement. It was confirmed that
      inhibition of HMG-CoA reductase activity and N-linked glycosylation also
      depressed the expression of functional IGF-1R in other cell types (i.e.
      hepatoblastoma cells and colon cancer cells). Our data suggest that this
      mechanism is involved in MVA-regulated cell growth.

PMID- 8663240
TI  - Suppression of adenylate kinase catalyzed phosphotransfer precedes and is
      associated with glucose-induced insulin secretion in intact HIT-T15 cells.
AB  - Adenine nucleotide metabolism was characterized in intact insulin secreting HIT
      T15 cells during the transition from non-stimulated (i. e. 0.2 mM glucose) to the
      glucose-stimulated secretory state. Metabolic dynamics were monitored by
      assessing rates of appearance of 18O-labeled phosphoryls of endogenous
      nucleotides in cells incubated in medium enriched in [18O]water. Most prominent
      of the metabolic alterations associated with stimulated insulin secretion was the
      suppression in the rate of adenylate kinase (AK)-catalyzed phosphorylation of AMP
      by ATP. This was manifest as a graded decrease of up to 50% in the rate of
      appearance of beta-18O-labeled species of ADP and ATP and corresponded to the
      magnitude of the secretory response elicited over a range of stimulatory glucose
      concentrations. The only nucleotide exhibiting a significant concentration change
      associated with suppression of AK activity was AMP, which decreased by about 50%,
      irrespective of the glucose concentration. Leucine-stimulated secretion also
      decreased the rate of AK-catalyzed phosphotransfer. This secretory stimulus
      related suppression of AK-catalyzed phosphotransfer occurs within 45 s of glucose
      addition, precedes insulin secretion, depends on the internalization and
      metabolism of glucose, and is independent of membrane depolarization and the
      influx of extracellular calcium. The secretory stimulus-induced decrease in AK
      catalyzed phosphotransfer, therefore occurs prior to or at the time of KATP+
      channel closure but it is not associated with or a consequence of events
      occurring subsequent to KATP+ channel closure. These results indicate that AK
      catalyzed phosphotransfer may be a determinant of ATP to ADP conversion rates in
      the KATP+ channel microenvironment; secretory stimuli-linked decreased rates of
      AK-catalyzed ADP generation from ATP (and AMP) would translate into an increased
      probability of ATP-liganded and, therefore, closed state of the channel.

PMID- 8663241
TI  - Persistence of tyrosine-phosphorylated FcepsilonRI in deactivated cells.
AB  - Engagement of the high affinity IgE receptor (FcepsilonRI) with a multimeric
      antigen leads to immediate tyrosine phosphorylation of its beta and gamma
      subunits, recruitment, and activation of the tyrosine kinase Syk, and later to
      cell degranulation. Monovalent hapten treatment reverses these events, resulting
      in receptor dephosphorylation and an abrupt arrest of cell degranulation. Thus
      far, it has been assumed that there is a direct linkage between receptor tyrosine
      phosphorylation, Syk activation and phosphorylation, and cell degranulation.
      However, we show here that when FcepsilonRI receptors are cross-linked for
      extended periods of time, hapten-mediated receptor dephosphorylation is delayed.
      These receptors, which remain tyrosine-phosphorylated despite the addition of
      hapten, are progressively targeted to a Triton X-100-insoluble fraction,
      suggesting their progressive association with the membrane skeleton. In contrast
      to FcepsilonRI receptors, hapten-induced Syk dephosphorylation and the consequent
      arrest of degranulation are not affected by prolonged cross-linking. Thus, some
      tyrosine-phosphorylated receptors persist in deactivated cells. We propose that,
      with time, some tyrosine-phosphorylated receptors become unaccessible to
      phosphatases and, in addition, unable to activate Syk. This inactive status of
      tyrosine-phosphorylated FcepsilonRI may be the result of membrane skeleton
      compartmentalization. However, another population of clustered receptors that
      includes the ones most recently formed is still immediately sensitive to hapten
      deactivation. This latter population is critical in maintaining Syk activity and
      cell degranulation. The shift from a transiently active state of phosphorylated
      receptors toward an inactive state could be a general mechanism of
      desensitization also utilized by other antigen receptors.

PMID- 8663242
TI  - Inhibition of growth factor-induced protein synthesis by a selective MEK
      inhibitor in aortic smooth muscle cells.
AB  - A common response of cells to mitogenic and hypertrophic factors is the
      activation of high rates of protein synthesis. To investigate the molecular basis
      of this action, we have used the recently developed MAP kinase/extracellular
      signal-regulated kinase (ERK) kinase (MEK) inhibitor PD 98059 to examine the
      involvement of the ERK pathway in the regulation of global protein synthesis by
      growth factors in rat aortic smooth muscle cells (SMC). Incubation with PD 98059
      blocked angiotensin II (AII)-dependent phosphorylation and enzymatic activity of
      both MEK1 and MEK2 isoforms, leading to inhibition of the phosphorylation and
      activation of p44(mapk) and p42(mapk). The compound was found to selectively
      inhibit activation of the ERK pathway by AII, but not the stimulation of p70 S6
      kinase, phospholipase C, or tyrosine phosphorylation. Most importantly, treatment
      of aortic SMC with PD 98059 potently inhibited AII-stimulated protein synthesis
      with a half-maximal inhibitory concentration of 4.3 microM. The effect of PD
      98059 was not restricted to AII, since the compound also blocked to various
      extent the induction of protein synthesis by growth factors acting through
      tyrosine kinase receptors, G protein-coupled receptors, or protein kinase C.
      These results provide strong evidence that activation of ERK isoforms is an
      obligatory step for growth factor-induced protein synthesis in aortic SMC.

PMID- 8663243
TI  - Molecular cloning and characterization of DdCAD-1, a Ca2+-dependent cell-cell
      adhesion molecule, in Dictyostelium discoideum.
AB  - Dictyostelium discoideum expresses EDTA-sensitive cell-cell adhesion sites soon
      after the initiation of development, and a Ca2+-binding protein of Mr 24,000
      (designated DdCAD-1) has been implicated in this type of adhesiveness. We have
      previously purified DdCAD-1 to homogeneity and characterized its cell binding
      activity (Brar, S. K., and Siu, C.-H. (1993) J. Biol. Chem. 268, 24902-24909). In
      this report, we describe the cloning of DdCAD-1 cDNAs. DNA sequencing revealed a
      single open reading frame coding for a polypeptide containing 213 amino acids.
      The identity of the cDNA was confirmed by amino acid sequences of two cyanogen
      bromide peptides. The deduced amino acid sequence of DdCAD-1 exhibits a
      relatively high degree of sequence similarity with members of the cadherin family
      and protein S of Myxococcus xanthus. Unlike the other cadherins, the carboxyl
      terminal region of DdCAD-1 contains a Ca2+-binding motif. Although analyses of
      the sequence suggest that the polypeptide lacks a signal peptide sequence and a
      transmembrane domain, immunofluorescence microscopy demonstrates the association
      of DdCAD-1 with the ecto-surface of the plasma membrane. To investigate the
      structure/function relationships of DdCAD-1, glutathione S-transferase fusion
      proteins containing different DdCAD-1 fragments were expressed and assayed for
      their 45Ca2+ and cell binding activities. These studies revealed that the cell
      binding activity is dependent on the amino-terminal segment and not the carboxyl
      terminal Ca2+-binding domain and showed additional Ca2+-binding site(s) within
      the amino-terminal segment.

PMID- 8663244
TI  - Metabolism of thrombospondin 2. Binding and degradation by 3t3 cells and
      glycosaminoglycan-variant Chinese hamster ovary cells.
AB  - Thrombospondin 1 (TSP1) and thrombospondin 2 (TSP2) are members of the
      thrombospondin family that have a similar structural organization but somewhat
      different functional activities. Iodinated recombinant mouse TSP2 bound to NIH
      3T3 cells and was internalized and degraded through a chloroquine-inhibitable
      pathway. TSP2 degradation was saturable, specific, and similar to the kinetics of
      degradation of TSP1. Human platelet TSP1, recombinant mouse TSP1, and recombinant
      mouse TSP2 cross-competed with one another for degradation by 3T3 cells.
      Degradation of TSP2 was less sensitive to inhibition by heparin than degradation
      of TSP1. This is in agreement with differences in heparin-binding affinity of the
      two TSPs. Degradation of TSP2 was slower in cultures of Chinese hamster ovary
      (CHO) cells lacking heparan sulfate proteoglycans than in wild type CHO cells or
      in cultures of 3T3 cells treated with heparitinase than in untreated 3T3 cells.
      Degradation of TSP2 was inhibited by antibodies against the low density
      lipoprotein receptor-related protein (LRP) or by the 39-kDa receptor-associated
      protein, a known antagonist of LRP. This study indicates that TSP2 and TSP1 are
      metabolized by a common internalization and degradation pathway involving heparan
      sulfate proteoglycan and LRP. Competition for this pathway is a possible
      mechanism whereby cells can control the levels and ratio of TSP1 and TSP2 in the
      extracellular milieu.

PMID- 8663245
TI  - Occupation of the QB-binding pocket by a photosystem II inhibitor triggers dark
      cleavage of the D1 protein subjected to brief preillumination.
AB  - The D1 protein of the photosystem (PS) II reaction center turns over very rapidly
      in a light-dependent manner initiated by its selective and specific cleavage. The
      cleavage of D1 was studied by using a PS II inhibitor, N-octyl-3-nitro-2,4,6
      trihydroxybenzamide (PNO8), as a molecular probe. The following results were
      obtained. (i) D1 was selectively cleaved into 23-kDa N-terminal and 9-kDa C
      terminal fragments in complete darkness by PNO8 at a single site in a D-E loop
      connecting membrane-spanning helices D and E. (ii) The cleavage was markedly
      enhanced when PS II was illuminated for a brief period before the addition of
      PNO8 in darkness. (iii) The effect of preillumination was slowly lost during
      incubation in the dark, with a decay half-time of approximately 1 h at 25 degrees
      C. (iv) The light intensity of preillumination required for the cleavage was much
      lower than that required for O2 evolution. (v) The light-triggered cleavage of D1
      was observed in thylakoids, PS II membranes, and PS II core particles, but not in
      purified PS II reaction centers. More than 60% of D1 was cleaved into the two
      fragments with no other by-products. (vi) The cleavage reaction revealed a marked
      pH dependence that was considerably different from that for inhibition of PS II
      activity. The results are interpreted as indicating that the binding of PNO8 to
      the QB-binding pocket triggers proteolytic cleavage of D1 that has been
      previously modified during illumination.

PMID- 8663246
TI  - Activation of phospholipase D and phosphatidylinositol 4-phosphate 5-kinase in
      HL60 membranes is mediated by endogenous Arf but not Rho.
AB  - Membrane-associated phospholipase D (PLD) in HL60 cells can be activated by the
      small GTP-binding proteins Arf and RhoA, but polyphosphorylated inositol lipids
      were required for maximum activity. The intact lipid was required because neither
      inositol 1,4, 5-trisphosphate nor stearoyl-arachidonyl glycerol could substitute
      for phosphatidylinositol 4,5-bisphosphate (PIP2). Arf-stimulated but not Rho
      stimulated PLD activity was increased by the inclusion of Mg2+ and ATP. ATP
      dependent PLD activation occurred when phosphatidylinositol 4-phosphate (PIP),
      PIP2, or phosphatidylinositol 3,4,5-trisphosphate (PIP3) were included, but PIP2
      formation was only detected with PIP; no PIP3 production was detected under any
      conditions. Therefore, the ATP-dependent increase in PLD activity cannot be
      explained by PIP2 or PIP3 formation. Association of endogenous Arf and RhoA with
      membranes was increased by incubation with GTPgammaS. This treatment increased
      membrane PLD and PIP kinase activities in the absence of exogenous p21 proteins.
      Reduction of Arf translocation suppressed the increase in PLD and PIP kinase
      activities, whereas complete removal of Rho but not Arf from membranes with
      RhoGDI was without effect on PLD activity but increased PIP kinase activity.
      Therefore, although recombinant Arf and Rho can activate PLD and PIP kinase in
      HL60 cells, it is the endogenous Arf but not Rho that regulates PLD, and thus a
      role for Rho in the physiological regulation of PLD in HL60 cells is unlikely.

PMID- 8663247
TI  - A genetic defect in phosphatidylcholine biosynthesis triggers apoptosis in
      Chinese hamster ovary cells.
AB  - We have investigated the cell death of a Chinese hamster ovary mutant (MT-58)
      with a thermo-sensitive CTP:phosphocholine cytidylyltransferase, the rate
      limiting enzyme of the CDP-choline pathway for phosphatidylcholine biosynthesis
      (Esko, J. D., Wermuth, M. M., and Raetz, C. R. H. (1981) J. Biol. Chem. 256, 7388
      7393). After MT-58 cells were shifted to the restrictive temperature of 40
      degrees C, the cytidylyltransferase was inactivated immediately leading to a
      decrease in phosphatidylcholine biosynthesis and cell death. DNA content and
      number of cells in the S phase decreased significantly in the dying MT-58 cells
      according to flow cytometrical analyses. The fragmentation of genomic DNA was
      detected by DNA ladders in agarose gel and release of the prelabeled genomic DNA
      into cytosolic fractions 14 h after the temperature shift. The dying cells
      underwent a dramatic reduction of cellular volume while maintaining the membrane
      containment of cellular contents. These events indicated that the inactivation of
      cytidylyltransferase triggered apoptosis in Chinese hamster ovary cells. This is
      the first report that apoptosis was induced in cultured cells, not by an added
      agent, but by a mutation in phospholipid biosynthesis.

PMID- 8663248
TI  - Expression cloning of a novel suppressor of the Lec15 and Lec35 glycosylation
      mutations of Chinese hamster ovary cells.
AB  - Lec15 and Lec35 are recessive Chinese hamster ovary (CHO) cell glycosylation
      mutations characterized by inefficient synthesis and utilization, respectively,
      of mannose-P-dolichol (MPD). Consequently, Lec15 and Lec35 cells accumulate
      Man5GlcNAc2-P-P-dolichol and glucosaminyl-acylphosphatidylinositol. This report
      describes the cloning of a suppressor (termed SL15) of the Lec15 and Lec35
      mutations from a CHO cDNA library by functional expression in Lec15 cells,
      employing phytohemagglutinin/swainsonine selection. The SL15 protein has a
      predicted molecular weight of 26,693 with two potential membrane spanning regions
      and a likely C-terminal endoplasmic reticulum retention signal (Lys-Lys-Glu-Gln).
      Lec15 cells transfected with SL15 have normal levels of MPD synthase activity in
      vitro and convert Man5GlcNAc2-P-P-dolichol to Glc0-3Man9GlcNAc2-P-P-dolichol in
      vivo. Surprisingly, SL15 also corrects the defective mannosylation in Lec35
      cells. The SL15 protein bears no apparent similarity to Saccharomyces cerevisiae
      MPD synthase (the DPM1 protein), but is highly similar to the hypothetical
      F38E1.9 protein encoded on Caenorhabditis elegans chromosome 5. These results
      indicate a novel function for the SL15 protein and suggest that MPD synthesis is
      more complex than previously suspected.

PMID- 8663249
TI  - Mapping the binding site pocket of the serotonin 5-Hydroxytryptamine2A receptor.
      Ser3.36(159) provides a second interaction site for the protonated amine of
      serotonin but not of lysergic acid diethylamide or bufotenin.
AB  - Like other amine neurotransmitters that activate G-protein-coupled receptors, 5
      hydroxytryptamine (5-HT) binds to the 5-HT2A receptor through the interaction of
      its cationic primary amino group with the conserved Asp3.32(155) in transmembrane
      helix 3. Computational experiments with a 5-HT2A receptor model suggest that the
      same functional group of 5-hydroxytryptamine also forms a hydrogen bond with the
      side chain of Ser3.36(159), which is adjacent in space to Asp3.32(155). However,
      other 5-HT2A receptor ligands like lysergic acid diethylamide (LSD), in which the
      amine nitrogen is embedded in a heterocycle, or N,N-dimethyl 5-HT, in which the
      side chain is a tertiary amine, are found in the computational simulations to
      interact with the aspartate but not with the serine, due mainly to steric
      hindrance. The predicted difference in the interaction of various ligands in the
      same receptor binding pocket was tested with site-directed mutagenesis of
      Ser3.36(159) --> Ala and Ser3.36(159) --> Cys. The alanine substitution led to an
      18-fold reduction in 5-HT affinity and the cysteine substitution to an
      intermediate 5-fold decrease. LSD affinity, in contrast, was unaffected by either
      mutation. N,N-Dimethyl 5-HT affinity was unaffected by the cysteine mutation and
      had a comparatively small 3-fold decrease in affinity for the alanine mutant.
      These findings identify a mode of ligand-receptor complexation that involves two
      receptor side chains interacting with the same functional group of specific
      serotonergic ligands. This interaction serves to orient the ligands in the
      binding pocket and may influence the degree of receptor activation.

PMID- 8663250
TI  - DNA binding specificities of YPF1, a Drosophila homolog to the DNA binding
      subunit of human DNA-dependent protein kinase, Ku.
AB  - YPF1, a heterodimeric protein from Drosophila melanogaster, is a homolog to Ku,
      the DNA binding subunit of human DNA-dependent protein kinase. This kinase is
      crucial in transcriptional activation, V(D)J recombination, double-strand break
      repair, and both topoisomerase and helicase activities. To investigate functional
      homology between YPF1 and Ku, we examined DNA binding properties of YPF1. Like
      Ku, at 100 mM KCl, YPF1 binding has no detectable DNA sequence specificity,
      requires a DNA terminus, and has a concentration-dependent stoichiometry
      consistent with subsequent translocation along DNA. YPF1 differs from Ku by
      having a 10(5)-fold higher affinity. At 400 mM KCl, YPF1 still prefers DNA
      termini but shows binding specificities not observed previously with Ku. In
      descending order of affinity, YPF1 binds to: specific DNA sequences with a
      specific polarity and spacing relative to DNA termini; nonspecific linear DNA;
      and circular DNA. At this higher ionic strength, binding stoichiometry is
      concentration independent, indicating that YPF1 remains bound to ends. These
      results demonstrate a strong functional homology between YPF1 and Ku at
      physiological ionic strength. The strong binding of YPF1 has also allowed us to
      detect underlying binding specificities that may be specific to YPF1 and its
      function.

PMID- 8663251
TI  - Obese gene expression alters the ability of 30A5 preadipocytes to respond to
      lipogenic hormones.
AB  - Leptin, the product of the ob gene, controls food-intake and weight loss in the
      ob mouse. Although the target(s) of the circulating leptin is presumed to be the
      brain which then orchestrates food-intake and weight loss, how leptin functions
      in the process of weight loss is unknown. In this report, we present evidence
      that ob gene expression in cultured cells suppresses acetyl-CoA carboxylase gene
      expression and lipid synthesis which are induced by hormone treatment. This is
      the first example in which leptin has been found to suppress defined biochemical
      reactions that contribute to lipid accumulation without the participation of the
      brain.

PMID- 8663252
TI  - The yeast transcription terminator for RNA polymerase I is designed to prevent
      polymerase slippage.
AB  - A transcription terminator for RNA polymerase I (polI) in the yeast,
      Saccharomyces cerevisiae, is composed of two essential elements, the 11bp binding
      site for Reb1p and an upstream T-rich element coding for the last 10-12
      nucleotides of the terminated transcript. We now show that, if the upstream
      element is changed to homopolymer T residues, polI undergoes iterative slippage,
      long poly(U) tails are added to the transcript, and termination is impaired.
      Reinsertion of one or two non-T residues within a critical region prevents
      iterative slippage and reinstates termination. A survey of naturally occurring
      terminators reveals that many contain T-rich upstream regions with non-T residues
      situated appropriately to prevent slippage. We discuss the possibility that the
      first step in slippage, backward sliding of both the transcript and the catalytic
      center of the polymerase, may be an obligatory step in the normal termination
      process.

PMID- 8663253
TI  - Aging-dependent functional alterations of mitochondrial DNA (mtDNA) from human
      fibroblasts transferred into mtDNA-less cells.
AB  - To investigate the role that aging-dependent accumulation of mitochondrial DNA
      (mtDNA) mutations plays in the senescence processes, mitochondria from
      fibroblasts of 21 normal human individuals between 20 weeks (fetal) and 103 years
      of age were introduced into human mtDNA-less (rhoo) 206 cells by cytoplast x rhoo
      cell fusion, and 7-31 transformant clones were isolated from each fusion. A
      slight cell donor age-dependent decrease in growth rate was detected in the
      transformants. Using an O2 consumption rate of 1 fmol/min/cell, which was not
      observed in any transformant among 158 derived from individuals 20 weeks (fetal)
      to 37 years of age, as a cut-off to identify respiratory-deficient clones, 11
      such clones were found among 198 transformants derived from individuals 39-103
      years of age. Furthermore, conventional and nonparametric analysis of the
      respiratory rates of 356 clones revealed a very significant decrease with donor
      age. In other analyses, a very significant age-dependent decline in the mtDNA
      content of the clones was observed, without, however, any significant correlation
      with the decrease in O2 consumption rate in the defective transformants. These
      observations clearly indicate the occurrence in the fibroblast-derived
      transformants of two independent, age-related functional alterations of mtDNA,
      presumably resulting from structural damage to this genome.

PMID- 8663254
TI  - In vivo and in vitro effect of glucocorticoids on fibroblast growth factor (FGF)
      2 and FGF receptor 1 expression.
AB  - In order to clarify the physiological function of fibroblast growth factor (FGF
      2) in the adrenal medulla the regulation of FGF-2 and FGF receptor 1 (FGFR1) was
      studied in vitro and in vivo in response to glucocorticoids. To assess the
      effects of glucocorticoids, in vivo extracts of adrenal medulla and adrenal
      cortex were analyzed by RNase protection assay and Western blot analysis. PC12
      cells were chosen as a model system to study the effects of glucocorticoids in
      vitro. In PC12 cells, dexamethasone (DEX) was found to stimulate dramatically the
      expression of both FGF-2 mRNA and protein. Western blot analysis revealed that
      exclusively the 21-kDa FGF-2 isoform was enhanced. In contrast to the FGF-2 mRNA
      level FGFR1 was not affected by treatment with glucocorticoids. In vivo FGF-2
      mRNA level and 21-kDa FGF-2 isoform level are significantly enhanced in the
      adrenal medulla 24 h after DEX injection. In vivo application of DEX leads to an
      increase of the medullary and cortical FGFR1 transcript levels. Glucocorticoid
      effects on FGF-2 expression were not found in adrenal cortex, heart, skeletal
      muscle, and kidney, respectively, in vivo and in L6 rat myoblasts in vitro. In
      addition to adrenal medullary cells glucocorticoids elevated the FGF-2 mRNA and
      protein level also in vivo in the brain and in vitro in immortalized Schwann
      cells. The present results suggest that the 21-kDa FGF-2 isoform mediates a
      physiological function specific for neuronal tissue which is modulated by
      glucocorticoids.

PMID- 8663256
TI  - Fluorescence detection of symmetric GroEL14(GroES7)2 heterooligomers involved in
      protein release during the chaperonin cycle.
AB  - The GroEL14 chaperonin from Escherichia coli was labeled with 5-((((2
      iodoacetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid (I-AEDANS), a
      hydrophobic probe whose fluorescent emission is sensitive to structural changes
      within the protein. Increasing concentrations of ATP or adenylyl imidodiphosphate
      but not ADP caused two successive GroES7-dependent changes in the fluorescence
      intensity of AEDANS-GroEL14, corresponding to the sequential binding of two
      GroES7 heptamers and the formation of two types of chaperonin heterooligomers,
      GroEL14GroES7 and GroEL14(GroES7)2. The binding of thermally denatured malate
      dehydrogenase (MDH) caused a specific increase in fluorescence intensity of
      AEDANS-GroEL14 that allowed the direct measurement in solution at equilibrium of
      ATP- and GroES7-dependent protein release from the chaperonin. Structure/function
      analysis during the generation of ATP from ADP indicated the following sequence
      of events: 1) ADP-stabilized MDH-GroEL14GroES7 particles bind newly formed ATP.
      2) MDH-GroEL14GroES7 particles bind a second GroES7. 3) MDH-GroEL14(GroES7)2
      particles productively release MDH. 4) Released MDH completes folding. Therefore,
      the symmetrical GroEL14(GroES7)2 heterooligomer is an intermediate after the
      formation of which the protein substrate is productively released during the
      chaperonin-mediated protein folding cycle.

PMID- 8663255
TI  - Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that
      MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme.
AB  - Gelatinase A and membrane-type metalloproteinase (MT1-MMP) were able to process
      human procollagenase-3 (Mr 60,000) to the fully active enzyme (Tyr85 N terminus;
      Mr 48,000). MT1-MMP activated procollagenase-3 via a Mr 56,000 intermediate
      (Ile36 N terminus) to 48,000 which was the result of the cleavage of the Glu84
      Tyr85 peptide bond. We have established that the activation rate of
      procollagenase-3 by MT1-MMP was enhanced in the presence of progelatinase A,
      thereby demonstrating a unique new activation cascade consisting of three members
      of the matrix metalloproteinase family. In addition, procollagenase-3 can be
      activated by plasmin, which cleaved the Lys38-Glu39 and Arg76-Cys77 peptide bonds
      in the propeptide domain. Autoproteolysis then resulted in the release of the
      rest of the propeptide domain generating Tyr85 N-terminal active collagenase-3.
      However, plasmin cleaved the C-terminal domain of collagenase-3 which results in
      the loss of its collagenolytic activity. Concanavalin A-stimulated fibroblasts
      expressing MT1-MMP and fibroblast-derived plasma membranes were able to process
      human procollagenase-3 via a Mr 56,000 intermediate form to the final Mr 48,000
      active enzyme which, by analogy with progelatinase A activation, may represent a
      model system for in vivo activation. Inhibition experiments using tissue
      inhibitor of metalloproteinases, plasminogen activator inhibitor-2, or aprotinin
      demonstrated that activation in the cellular model system was due to MT1
      MMP/gelatinase A and excluded the participation of serine proteinases such as
      plasmin during procollagenase-3 activation. We have established that
      progelatinase A can considerably potentiate the activation rate of procollagenase
      3 by crude plasma membrane preparations from concanavalin A-stimulated
      fibroblasts, thus confirming our results using purified progelatinase A and MT1
      MMP. This new activation cascade may be significant in human breast cancer
      pathology, where all three enzymes have been implicated as playing important
      roles.

PMID- 8663257
TI  - Pathways for degradation of the catalytic subunit of cAMP-dependent protein
      kinase differ in wild-type and kinase-negative S49 mouse lymphoma cells.
AB  - The catalytic subunit of cAMP-dependent protein kinase radiolabeled with
      [35S]methionine in wild-type S49 mouse lymphoma cells was degraded with half
      lives of approximately 9.2 h in unstimulated cells and approximately 4.5 h in
      cells stimulated with a membrane-permeable cAMP analog. Turnover in kinase
      negative mutant cells was about three times faster than in stimulated wild-type
      cells and appeared to involve a unique 47-kDa intermediate. Levels of catalytic
      subunit protein revealed by Western immunoblotting were consistent with the
      measured differences in turnover, but whereas the protein was mostly soluble in
      wild-type cell extracts, it was almost entirely insoluble in the mutant cell
      extracts. A substantial fraction of the catalytic subunit labeled in a 5-min
      pulse was soluble in kinase-negative cell extracts, but most of this material was
      rendered insoluble by incubating the cells for an additional 30 min before
      extraction. Degradation of the catalytic subunit in kinase-negative, but not in
      wild-type, cells was inhibited strongly by two specific peptide aldehyde
      inhibitors of the proteasomal chymotrypsin-like activity. An inhibitor of the
      proteasomal protease that prefers branched-chain amino acids had less of an
      effect on catalytic subunit degradation in the mutant cells.

PMID- 8663258
TI  - The physical association of casein kinase 2 with nucleolin.
AB  - CK2 (formerly called casein kinase 2) is a ubiquitous messenger-independent
      serine/threonine protein kinase implicated in cell growth and proliferation. To
      investigate the regulation and functions of this enzyme, experiments were carried
      out to search for CK2-interacting proteins. The methods employed included an
      overlay technique, co-purification, co-immunoprecipitation, and the use of
      glutathione S-transferase (GST) CK2 fusion proteins. By the CK2 overlay
      technique, one protein of 110 kDa was found to bind to CK2 with very high
      affinity. The binding was inhibited by CK2 effectors such as heparin,
      polyarginine, and histone H1, but was not affected by the CK2 substrate, casein.
      Protein p110 was also detected by co-immunoprecipitation using anti-CK2
      antiserum, suggesting an in vivo association of this protein with CK2. Co
      purification of p110 with CK2 from Sf-9 cells that overexpressed CK2 was also
      observed through sequential chromatographic steps. Using GST fusion proteins of
      CK2, the CK2-p110 interaction was investigated further and was found to occur
      primarily through CK2 alpha or alpha' subunits, but not the beta subunit. Protein
      p110 was purified from 3T3 L1 mouse fibroblast cell lines using a GST-CK2
      affinity resin. Amino acid sequence analysis of peptides obtained from the
      protein indicated that it is the nuclear protein, nucleolin. Furthermore, p110
      was recognized by anti-nucleolin antiserum. At present, the physiological
      significance of the strong interaction between CK2 and nucleolin, an excellent
      substrate for the enzyme, is not clear. However, this association may be
      important for regulating rDNA transcription.

PMID- 8663259
TI  - Structural and electron microscopic analysis of neurocan and recombinant neurocan
      fragments.
AB  - Neurocan, a nervous tissue-specific chondroitin sulfate proteoglycan of the
      aggrecan family which has been shown to interact with neural cell adhesion
      molecules and tenascin, could be visualized by rotary shadowing electron
      microscopy as two globular domains interconnected by an extended flexible
      filament of 60-90 nm. Several recombinant neurocan fragments generated in the
      human embryonic kidney cell line 293 represent as observed by electron microscopy
      the expected parts of this structure, which indicates a correct folding of these
      molecules. Biological activity of the recombinant N-terminal globular domain
      could be demonstrated by its coelution with hyaluronan in gel permeation
      chromatography. In addition, the modification of the recombinant fragments with
      certain carbohydrate structures was analyzed. High mannose oligosaccharides could
      be mapped to the N-terminal globular domain of the brain-derived molecule. Only
      recombinant fragments containing parts of the central region of the molecule were
      modified with chondroitin sulfate chains and with the HNK-1 epitope, and could be
      considerably altered in their migratory behavior on SDS-polyacrylamide gel
      electrophoresis by neuraminidase treatment. These findings and the electron
      microscopic shape indicate a mucin-like character for the central neurocan
      region.

PMID- 8663260
TI  - Silencing of the gene for the beta subunit of human chorionic gonadotropin by the
      embryonic transcription factor Oct-3/4.
AB  - The transcription factor Oct-3/4 may be important in maintaining embryonic cells
      in an undifferentiated state. It is probably down-regulated at about the time
      that human chorionic gonadotropin (hCG) is first expressed in embryonic
      trophectoderm. Here we report that Oct-3/4 strongly inhibits the hCGbeta subunit
      (hCGbeta) promoter in JAr choriocarcinoma cells. Oct-3/4 reduced chloramphenicol
      acetyltransferase (CAT) reporter expression from the -305hCGbeta promoter by
      about 90% in transient co-transfection assays, but had no effect on expression
      from the -249hCGbeta promoter. The -305/-249 hCGbeta fragment specifically bound
      synthetic Oct-3/4 protein as measured in electrophoretic mobility shift assays,
      and the Oct-3/4-binding site was localized around -270 by methylation
      interference footprinting. Site-directed mutagenesis of this binding site
      abolished Oct-3/4 repression. When stably transfected into JAr cells, Oct-3/4
      reduced the amounts of both endogenous hCGbeta messenger RNA and hCG protein to
      less than 10% of controls. We suggest that silencing of Oct-3/4 in trophectoderm
      is a prerequisite for hCG up-regulation in early human embryos at the time of
      maternal recognition of pregnancy.

PMID- 8663261
TI  - Characterization of the bone morphogenetic protein-2 as a neurotrophic factor.
      Induction of neuronal differentiation of PC12 cells in the absence of mitogen
      activated protein kinase activation.
AB  - Rat pheochromocytoma PC12 cells are shown to express a single class of high
      affinity binding sites for bone morphogenetic protein (BMP)-2 (1,300
      receptors/cell, Kd = 31.3 pM). Affinity cross-linking using radiolabeled BMP-2
      demonstrated the presence of six components with apparent molecular masses of
      170, 155, 105, 90, 80, and 70 kDa. BMP-2 induced morphological changes in PC12
      cells with the concomitant expression of three neurofilament proteins. Thus, BMP
      2 would appear to be another neurotrophic factor that, like nerve growth factor
      or basic fibroblast growth factor, stimulates the neuronal differentiation of
      PC12 cells. Unlike nerve growth factor and basic fibroblast growth factor,
      however, BMP-2 failed to induce the activation of either 41- and 43-kDa mitogen
      activated protein (MAP) kinases or the MAP kinase/extracellular signal-regulated
      kinase kinase (MEK). Also, BMP-2 did not induce the expression of the c-fos gene
      in PC12 cells. Activin A was also capable of inducing the neuronal
      differentiation of PC12 cells without activating MAP kinases and MEK. These
      findings show a clear dissociation between the requirement for the activation of
      the MAP kinase cascade and the ability of BMP-2 and activin A to induce PC12 cell
      neuronal differentiation. In addition, these results suggest that the activation
      of MAP kinases and MEK is not an absolute requirement for PC12 cell
      differentiation.

PMID- 8663262
TI  - Molecular dissection of a protein SopB essential for Escherichia coli F plasmid
      partition.
AB  - Biochemical and genetic experiments were carried out to deduce the structural and
      functional domains of SopB protein involved in the equipartition of F plasmid.
      The protein is dimeric. Proteolytic and chemical footprinting studies support
      earlier genetic analyses that the binding of SopB to specific sites within the F
      plasmid sopC locus involves mainly the C-terminal region. In vivo, the expression
      of a high level of SopB protein is known to repress sopC-linked genes. This
      silencing activity is shown to be unaffected by the deletion of 35 N-terminal
      residues, but abolished when 71 or more were removed from the N terminus. An
      excess of SopB protein does not extend its in vitro binding outside sopC,
      implicating participation of a host factor(s) in SopB-mediated gene silencing. A
      data base search identified a number of SopB homologues, including both
      chromosomally encoded bacterial proteins and phage- and plasmid-encoded proteins
      known to be involved in partition. Sequence homology is limited to the N-terminal
      half, suggesting that the N-terminal regions of these proteins are conserved to
      interact with a conserved cellular structure(s), whereas the C-terminal regions
      have diverged to bind different nucleotide sequences.

PMID- 8663263
TI  - Characterization of a polypyrimidine/polypurine tract in the promoter of the gene
      for chicken malic enzyme.
AB  - Starvation inhibits and refeeding stimulates transcription of the malic enzyme
      gene in chick liver. DNA between -320 and +72 base pairs (bp) is DNase I
      hypersensitive in hepatic nuclei from fed but not starved chicks (Ma, X. J., and
      Goodridge, A. G. (1992) Nucleic Acids Res. 20, 4997-5002). A
      polypyrimidine/polypurine (PPY/PPU) tract lies within the DNase I-hypersensitive
      region. In hepatocytes transiently transfected with plasmids containing
      triiodothyronine response elements and a minimal promoter from the malic enzyme
      gene linked to the chloramphenicol acetyltransferase gene, deletion of the
      PPY/PPU tract inhibited chloramphenicol acetyltransferase activity by about 90%
      with or without triiodothyronine. Fine mapping of S1 nuclease-sensitive sites
      suggests that the PPY/PPU tract can assume different isoforms of non-B-DNA, some
      of which may be triplex structures. The PPY/PPU tract contains specific binding
      sites for single- and double-stranded DNA binding proteins and, with 8 bp 3' of
      the tract, can function as a promoter. A (CT)7 repeat binds single-stranded DNA
      binding protein and is essential for promoter activity. Two C-rich elements bind
      single-stranded DNA-binding proteins and may mediate inhibition of promoter
      function. The single- and double-stranded DNA-binding proteins that interact with
      the PPY/PPU tract may regulate transcription of the malic enzyme gene.

PMID- 8663264
TI  - In vivo regulation of murine granzyme B gene transcription in activated primary T
      cells.
AB  - A murine granzyme B promoter fragment that extends 243 base pairs upstream of the
      transcription start site confers high levels of luciferase reporter gene activity
      in transient transfection assays into T cells and mouse L cell fibroblasts. This
      promoter fragment contains canonical binding sites for the transcription factors
      AP-1, core binding factor (CBF), Ikaros, and the cyclic AMP responsive element
      binding protein (CREB). Oligonucleotides containing the granzyme B AP-1 or CBF
      elements form specific complexes with proteins present in nuclear extracts from
      activated CD8(+) splenocytes, MTL cells, EL4 T cells, and L cells. A strong
      DNase1 hypersensitive site that coincides with the closely associated AP-1, CBF,
      Ikaros, and CRE elements is present in activated CD8(+) T cells but not in
      resting T cells or L cells. Both in vitro and in vivo footprints are observed at
      these sequence elements in activated cytotoxic T cells (CTL) but not in resting T
      cells. The endogenous granzyme B gene is CTL-specific as no mRNA is detectable in
      EL4 or L cells. We propose that a condensed chromatin structure at the granzyme B
      promoter is responsible for transcription factor inaccessibility and repression
      of transcription in non-T cells.

PMID- 8663265
TI  - Regulation of conformation and ligand binding function of integrin alpha5beta1 by
      the beta1 cytoplasmic domain.
AB  - We have studied the role of the cytoplasmic domain in the conformation and
      affinity modulation of the integrin beta1. Expression of a conformation-dependent
      anti-beta1 antibody 15/7 correlates with activation in wild-type beta1.
      Truncation of 16 carboxyl-terminal residues in the cytoplasmic domain (the 762t
      beta1 mutant) induces constitutive expression of the 15/7 epitope at a high level
      (which probably reflects a major conformational change of the extracellular
      domain) but does not activate ligand binding. The dissociation of epitope
      expression and affinity suggests that the epitope expression reflects the
      conformation of nonligand binding sites of the extracellular domain of beta1 but
      does not necessarily reflect that of the ligand binding sites. Indeed we
      discovered that the 15/7 epitope is in fact located in the nonligand binding
      region of beta1 (within residues 354-425). The 762t mutant has apparently normal
      alpha/beta association, suggesting that the overexpression of the 15/7 epitope is
      not due to alpha/beta dissociation. The data suggest that the carboxyl-terminal
      16 residues of the beta1 cytoplasmic domain are critical for properly modulating
      conformation and affinity of beta1 integrins.

PMID- 8663266
TI  - Domain structure of heparan sulfates from bovine organs.
AB  - Samples of heparan sulfate, isolated from bovine aorta, lung, intestine, and
      kidney, were degraded by digestion with a mixture of heparitinases or by
      treatment with nitrous acid, with or without previous N-deacetylation. Analysis
      of the resulting oligosaccharides showed that the various heparan sulfate samples
      all contained regions of up to 8 or 9 consecutive N-acetylated glucosamine
      residues, as well as contiguous N-sulfated sequences. L-Iduronic acid accounted
      for a remarkably constant proportion, 50-60%, of the total hexuronic acid units
      within the latter structures. Of the total iduronic acid units, 36-55% were
      located outside the contiguous N-sulfated regions, presumably in sequences
      composed of alternating N-acetylated and N-sulfated disaccharide residues. While
      most of the iduronic acid units within the N-sulfated blocks were 2-O-sulfated,
      those located outside were almost exclusively nonsulfated. The heparan sulfate
      preparations differed markedly with regard to the content of 6-O-sulfated
      glucosamine units, more than half of which were located outside the N-sulfated
      block regions. These findings suggest that the formation of iduronic acid
      residues and their subsequent 2-O-sulfation are coupled within but not outside
      the contiguous N-sulfated regions of the heparan sulfate chains and, furthermore,
      that the 2-O- and 6-O-sulfotransferase reactions are differentially regulated
      during heparan sulfate biosynthesis.

PMID- 8663267
TI  - Phosphorylation of purified bovine bone sialoprotein and osteopontin by protein
      kinases.
AB  - The large number of covalently bound phosphates on the extracellular
      phosphoproteins osteopontin (OPN) and bone sialoprotein (BSP) have been
      implicated in biological functions such as mineral deposition and osteoclast
      binding. In the present study the state of phosphorylation of BSP and OPN was
      evaluated by in vitro 32P labeling using a series of protein kinases and
      quantification. Both the purified bovine BSP and OPN were radiolabeled by
      [32P]ATP and factor-independent protein kinase. Quantification of 32P
      radioactivity incorporated on dephosphorylated BSP and OPN provided 6.6 and 8.9
      mol of phosphate incorporated/mol, respectively. Native OPN incorporated 1.07 and
      BSP 2.46 mol of phosphate/mol by factor-independent protein kinase. These data
      led to calculations that OPN and BSP, respectively, contain 7.83 and 4.14 mol of
      phosphate/mol in their natural state. Thrombin digests of 32P-labeled BSP showed
      radioactivity to be associated with fragment of approximately molecular mass
      values 30 kDa (N-terminal half), with no observable radioactivity associated with
      the 40-kDa fragment (C-terminal half). Similar experiments with 32P-labeled OPN
      provided two radiolabeled thrombin fragments, with molecular mass 30 kDa (N
      terminal half) and 20 kDa (C-terminal half), both were radioactive. The major
      phosphorylation was associated with the N-terminal half containing 7.0 mol of
      phosphate, and 1.9 mol of phosphate were associated with the C-terminal half.
      Additional experiments of in vitro phosphorylation of OPN and BSP by several
      other known protein kinases were carried out. cAMP-dependent protein kinase
      showed no phosphorylation of OPN or BSP, while protein kinase C and cGMP
      dependent protein kinase led to minor phosphorylation, each of the latter
      introduced about 1 mol of phosphate/mol of OPN and BSP molecule.

PMID- 8663268
TI  - Distal switch II region of Ras2p is required for interaction with guanine
      nucleotide exchange factor.
AB  - The interaction of Saccharomyces cerevisiae Ras2p with the catalytic domain of
      the GDP/GTP exchange factors (GEFs) mouse CDC25(Mm), yeast Cdc25p, and Sdc25p was
      analyzed by introducing the substitution R80D/N81D into Ras2p S24N, a mutant that
      is shown to interfere with the Ras2p wild type (wt)-GEF interaction by forming a
      stable complex. The triple mutant, like Ras2p R80D/N81D, did not interfere with
      the action of GEF on Ras2p wt (or H-Ras p21) and was unable to form a stable
      complex with GEF. The GEF stimulation of the nucleotide dissociation of the
      triple mutant was virtually abolished and strongly decreased with the double
      mutant. The affinity of Ras2p S24N/R80D/N81D for GDP and GTP was decreased 3 and
      4 orders of magnitude, respectively, like that of Ras2p S24N, whereas the double
      mutant behaved as Ras2p wt. Like Ras2p S24N and unlike Ras2p R80D/N81D, the GTP
      bound triple mutant did not activate adenylyl cyclase. Thus, the triple mutant
      and Ras2p S24N have opposite properties toward the binding to GEF but similarly
      modified behaviors toward GDP, GTP, and adenylyl cyclase. This work emphasizes
      the determinant role of the distal switch II region of Ras2p for the interaction
      with GEF and the different structural background of the interaction with adenylyl
      cyclase.

PMID- 8663269
TI  - Molecular characterization and expression of rat acyl-CoA synthetase 3.
AB  - Isolation and characterization of a rat brain cDNA identified a third acyl-CoA
      synthetase (ACS) designated ACS3. The deduced amino acid sequence of the cDNA
      revealed that ACS3 consists of 720 amino acids and exhibits a structural
      architecture common to ACSs from various origins. ACS3 expressed in COS cells was
      purified to near homogeneity. The purified ACS3 resolved by SDS-polyacrylamide
      gel electrophoresis into two major proteins of 79 and 80 kDa. Cell-free
      translation of a synthetic mRNA encoding the entire region of ACS3 revealed that
      the two isoforms were derived from the same mRNA. The purified ACS3 utilizes
      laurate and myristate most efficiently among C8-C22 saturated fatty acids and
      arachidonate and eicosapentaenoate among C16-C20 unsaturated fatty acids.
      Northern blot analysis revealed that ACS3 mRNA is most abundant in brain and, to
      a much lesser extent, in lung, adrenal gland, kidney, and small intestine. During
      the development of the rat brain, expression of ACS3 mRNA reached a maximum level
      at 15 days after birth and then declined gradually to 10% of the maximum in the
      adult brain.

PMID- 8663270
TI  - CAAT/enhancer-binding proteins are involved in beta-globin gene expression and
      are differentially expressed in murine erythroleukemia and K562 cells.
AB  - Acting in cis with the beta-globin locus control region, the CAAT box of the beta
      globin gene promoter stimulates transcription 10-fold in murine erythroleukemia
      (MEL) cells but is without effect in K562 cells. Our previous studies suggested
      that of four proteins from MEL cells that bind to this CAAT box region (CP1, GATA
      1, and two factors that were denoted DSFr and DSF1) DSFr is involved in the up
      regulation of transcription. In the present report, the DSFr protein in MEL cells
      was identified as C/EBPgamma through expression cloning and antibody studies.
      C/EBPgamma DNA binding activity could not be detected in K562 cells. However,
      K562 cells, but not MEL cells, were found to express LIP, which is a truncated
      form of C/EBPbeta and is an inhibitor of transcription. Thus, the differential
      expression of C/EBP members could account for the ability of the beta-globin CAAT
      box to stimulate transcription in MEL cells, but not function in K562 cells.
      Juxtaposing a specific C/EBP binding sequence next to the beta-globin promoter,
      in constructs in which the CAAT box had been rendered inactive by mutation or
      deletion, restored full promoter activity in MEL cells only if CP1 still bound to
      the promoter. In conjunction with previous mutation analyses, these results
      suggest that C/EBPgamma may collaborate with CP1 to enhance transcription through
      the beta-globin CAAT box.

PMID- 8663271
TI  - Inhibition of HSP70 expression by calcium ionophore A23187 in human cells. An
      effect independent of the acquisition of DNA-binding activity by the heat shock
      transcription factor.
AB  - Heat shock proteins (HSPs) are induced in mammalian cells in a variety of
      pathophysiological states and have an important role in cytoprotection in vitro
      and in vivo. In this study, we report that the calcium ionophore A23187, a
      glucose-regulated protein (GRP) inducer, dramatically inhibits HSP70 synthesis
      and HSP70 mRNA transcription after induction by heat shock, sodium arsenite, or
      prostaglandin A1 treatment in human K562 cells. A23187 does not suppress, and it
      actually prolongs, the DNA-binding activity of the human heat shock transcription
      factor (HSF), while it alters HSF1 phosphorylation in heat shock-treated cells.
      To inhibit HSP70 expression, A23187 needs to be present during heat shock, while
      treatment before or after heat shock does not affect HSP70 mRNA transcription.
      The GRP inducer thapsigargin, which specifically inhibits the endoplasmic
      reticulum Ca2+-ATPase, has no effect on heat-induced HSP70 synthesis, indicating
      that A23187 inhibitory activity is not due to depletion of intracellular calcium
      stores and is independent of the concomitant induction of GRP genes. Inhibition
      of HSP70 expression is correlated with alterations in HSF1 phosphorylation in
      heat-shocked cells, but not in sodium arsenite-treated cells, indicating that
      different mechanisms may be involved in mediating A23187 inhibitory activity.

PMID- 8663272
TI  - Conformational studies on analogs of recombinant parathyroid hormone and their
      interactions with phospholipids.
AB  - Through the use of oligonucleotide-directed mutagenesis we have generated
      variants of a recombinant human parathyroid (PTH) hormone-(1-34)-homoserine
      (RPTH) in which a positively charged residue (Arg or Lys), a negatively charged
      residue (Glu), or a neutral residue (Gly) has been substituted at every position
      throughout the peptide. These 106 PTH analogs have been tested for their ability
      to stimulate cAMP production in the rat osteosarcoma cell line, UMR106. Analysis
      of these peptides led to the construction of several analogs containing multiple
      substitutions at sites of potential structural importance. Several of these
      analogs were shown to have 3-5-fold enhanced activity and receptor affinity.
      Circular dichroism (CD) and lipid binding studies were then performed on these
      analogs. Circular dichroism demonstrates enhanced helical content in the presence
      of lipid vesicles, particularly anionic lipid. The [Arg15,19,22,Lys29]RPTH
      (+6RPTH) analog requires higher concentrations of trifluoroethanol to attain
      enhanced helicity. The intrinsic tryptophan fluorescence of the peptides are blue
      shifted more in the presence of the anionic lipid dimyristoyl
      phosphatidylglycerol (DMPG) than with the zwitterionic lipid dimyristoyl
      phosphatidylcholine (DMPC). Effects of the peptides on the phase transition
      behavior of DMPC shows that +6RPTH has less effect on the lipid than does RPTH.
      This difference in lipid interaction is also exhibited with isothermal titration
      calorimetry, in which RPTH reacts exothermally with DMPG, while +6RPTH shows
      little or no heat change. The pH dependence of binding of the hydrophobic probe
      1,1'-bis(4-anilino)-naphthalene-5,5'-trisulfonic acid, also shows a difference in
      exposure of hydrophobic sites between RPTH and +6RPTH. The +6RPTH has about a 5
      fold greater affinity for receptor binding. We suggest that this enhanced
      activity is a consequence of the altered lipid interaction of +6RPTH, combined
      with increased conformational flexibility, particularly in the carboxyl-terminal
      region of the molecule.

PMID- 8663273
TI  - Processivity of the gene 41 DNA helicase at the bacteriophage T4 DNA replication
      fork.
AB  - The gene 41 protein is the DNA helicase associated with the bacteriophage T4 DNA
      replication fork. This protein is a major component of the primosome, being
      essential for coordinated leading and lagging strand DNA synthesis. Models
      suggest that such DNA helicases are loaded only onto DNA at origins of
      replication, and that they remain with the ensuing replication fork until
      replication is terminated. To test this idea, we have measured the extent of
      processivity of the 41 protein in the context of an in vitro DNA replication
      system composed of eight purified proteins (the gene 43, 44/62, 45, 32, 41, 59,
      and 61 proteins). After starting DNA replication in the presence of these
      proteins, we diluted the 41 helicase enough to prevent any association of new
      helicase molecules and analyzed the replication products. We measured an
      association half-life of 11 min, revealing that the 41 protein is processive
      enough to finish replicating the entire 169-kilobase T4 genome at the observed
      replication rate of approximately 400 nucleotides/s. This processivity of the 41
      protein does not require the 59 protein, the protein that catalyzes 41 protein
      assembly onto 32 protein-covered single-stranded DNA. The stability we measure
      for the 41 protein as part of the replication fork is greater than estimated for
      it alone on single-stranded DNA. We suggest that the 41 protein interacts with
      the polymerase holoenzyme at the fork, both stabilizing the other protein
      components and being stabilized thereby.

PMID- 8663274
TI  - Specific interaction of DNA polymerase beta and DNA ligase I in a multiprotein
      base excision repair complex from bovine testis.
AB  - Base excision repair (BER) is a cellular defense mechanism repairing modified
      bases in DNA. Recently, a G:U repair reaction has been reconstituted with several
      purified enzymes from Escherichia coli (Dianov, G., and Lindahl, T.(1994) Curr.
      Biol. 4, 1069-1076). Using bovine testis crude nuclear extract, we have shown
      that G:U is repaired efficiently in vitro, and DNA polymerase beta (beta-pol) is
      responsible for the single nucleotide gap-filling synthesis (Singhal, R. K.,
      Prasad, R., and Wilson, S. H.(1995) J. Biol. Chem. 270, 949-957). To investigate
      potential interaction of beta-pol with other BER protein(s), we developed
      affinity chromatography matrices by cross-linking purified rat beta-pol or
      antibody against beta-pol to solid supports. Crude nuclear extract from bovine
      testis was applied to these affinity columns, which were then extensively washed.
      Proteins that bound specifically to the affinity columns were co-eluted in a
      complex with beta-pol. This complex had a molecular mass of approximately 180 kDa
      and was able to conduct the complete uracil-initiated BER reaction. The BER
      complex contained both beta-pol and DNA ligase I. An antibody to beta-pol was
      able to shift the complex in sucrose gradients to a much larger molecular mass
      (>300 kDa) that again contained both beta-pol and DNA ligase I. Furthermore, DNA
      ligase I and beta-pol were co-immunoprecipitated from the testis nuclear extract
      with anti beta-pol IgG. Thus, we conclude that beta-pol and DNA ligase I are
      components of a multiprotein complex that performs BER.

PMID- 8663275
TI  - Peroxisome proliferator-activated receptor alpha inhibits hepatic S14 gene
      transcription. Evidence against the peroxisome proliferator-activated receptor
      alpha as the mediator of polyunsaturated fatty acid regulation of s14 gene
      transcription.
AB  - The peroxisome proliferator-activated receptor (PPARalpha) has been implicated in
      fatty acid regulation of gene transcription. Lipogenic gene transcription is
      inhibited by polyunsaturated fatty acids (PUFA). We have used the PUFA-sensitive
      rat liver S14 gene as a model to examine the role PPARalpha plays in fatty acid
      regulation of hepatic lipogenic gene transcription. Both PPARalpha and the potent
      peroxisome proliferator, WY14643, inhibit S14CAT activity in transfected primary
      hepatocytes. WY14643 and PPARalpha target the S14 T3 regulatory region (TRR, -2.8
      to -2.5 kilobases), a region containing 3 T3 response elements (TRE). Transfer of
      the TRR to the thymidine kinase (TK) promoter conferred negative control to the
      TKCAT gene following WY14643 and PPARalpha treatment. Gel shift analysis showed
      that PPARalpha, either alone or with RXRalpha, did not bind the S14TRR. However,
      PPARalpha interfered with TRbeta/RXRalpha binding to a TRE (DR+4). Functional
      studies showed that co-transfected RXRalpha, but not T3 receptor beta1 (TRbeta1),
      abrogated the inhibitory effect of PPARalpha on S14 gene transcription. These
      results suggest that WY14643 and PPARalpha functionally interfere with T3
      regulation of S14 gene transcription by inhibiting TRbeta1/RXR binding to S14
      TREs. Previous studies had established that the cis-regulatory targets of PUFA
      control were located within the proximal promoter region of the S14 gene, i.e.
      between -220 and -80 bp. Finding that the cis-regulatory elements for
      WY14643/PPARalpha and PUFA are functionally and spatially distinct argues against
      PPARalpha as the mediator of PUFA suppression of S14 gene transcription.

PMID- 8663276
TI  - ATP and SH3 binding sites in the protein kinase of the large subunit of herpes
      simplex virus type 2 of ribonucleotide reductase (ICP10).
AB  - The large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10)
      is a multifunctional protein. It consists of a ribonucleotide reductase and a
      serine/threonine protein kinase (PK) domain, which has three proline-rich motifs
      consistent with SH3-binding sites at positions 140, 149, and 396. We used site
      directed mutagenesis to identify amino acids required for kinase activity and
      interaction with signaling proteins. Mutation of Lys176 or Lys259 reduced PK
      activity (5-8-fold) and binding of the 14C-labeled ATP analog rho
      fluorosulfonylbenzoyl 5'-adenosine (FSBA) but did not abrogate them. Enzymatic
      activity and FSBA binding were abrogated by mutation of both Lys residues,
      suggesting that either one can bind ATP. Mutation of Glu209 (PK catalytic motif
      III) virtually abrogated kinase activity in the presence of Mg2+ or Mn2+ ions,
      suggesting that Glu209 functions in ion-dependent PK activity. ICP10 bound the
      adaptor protein Grb2 in vitro. Mutation of the ICP10 proline-rich motifs at
      positions 396 and 149 reduced Grb2 binding 20- and 2-fold, respectively. Binding
      was abrogated by mutation of both motifs. Grb2 binding to wild type ICP10 was
      competed by a peptide for the Grb2 C-terminal SH3 motif, indicating that it
      involves the Grb2 C-terminal SH3.

PMID- 8663277
TI  - Solution structure of nodularin. An inhibitor of serine/threonine-specific
      protein phosphatases.
AB  - The three-dimensional solution structure of nodularin was studied by NMR and
      molecular dynamics simulations. The conformation in water was determined from the
      distance and dihedral data by distance geometry and refined by iterative
      relaxation matrix analysis. The cyclic backbone adopts a well defined
      conformation but the remote parts of the side chains of arginine as well as the
      amino acid derivative Adda have a large spatial dispersion. For the unusual amino
      acids the partial charges were calculated and nodularin was subjected to
      molecular dynamic simulations in water. A good agreement was found between
      experimental and computational data with hydrogen bonds, solvent accessibility,
      molecular motion, and conformational exchange. The three-dimensional structure
      resembles very closely that of microcystin-LR in the chemically equivalent
      segment. Therefore, it is expected that the binding of both microcystins and
      nodularins to serine/threonine-specific protein phosphatases is similar on an
      atomic level.

PMID- 8663278
TI  - Syk-dependent phosphorylation of Shc. A potential link between FcepsilonRI and
      the Ras/mitogen-activated protein kinase signaling pathway through SOS and Grb2.
AB  - Antigen receptors on T- and B-cells activate Ras through a signaling pathway that
      results in the tyrosine phosphorylation of Shc and the formation of a complex of
      Shc with the Grb2 adaptor protein. The high affinity receptor for immunoglobulin
      E (FcepsilonRI) in cultured mast (RBL-2H3) cells has been reported to function
      differently. Here we show to the contrary that engagement of FcepsilonRI with
      antigen leads to increased tyrosine phosphorylation of Shc and the association of
      Shc with Grb2 and other proteins (p120 and p140). Like the FcepsilonRI-mediated
      activation of the mitogen-activated protein kinase cascade, these responses are
      dependent on the tyrosine kinase Syk; they are enhanced by overexpression of Syk
      and are blocked by expression of dominant-negative Syk. Sos is constitutively
      associated with Grb2 in these cells but dissociates from Shc on stimulation with
      antigen. These reactions are rapid, reversible, and associated with the
      activation of Ras. Therefore, the Syk-dependent tyrosine phosphorylation of Shc
      and its association with Grb2 may provide a pathway through Sos for activation of
      Ras by FcepsilonRI.

PMID- 8663279
TI  - A kinase anchor protein 75 targets regulatory (RII) subunits of cAMP-dependent
      protein kinase II to the cortical actin cytoskeleton in non-neuronal cells.
AB  - Neuronal A kinase anchor protein (AKAP) homologs, such as AKAPs 75 and 150,
      tether cAMP-dependent protein kinase II (PKAII) isoforms to the postsynaptic
      cytoskeleton, thereby creating target sites for cAMP action. These AKAPs, which
      bind regulatory subunits (RIIs) of PKAII, are also expressed in certain non
      neuronal cells. Non-neuronal cell lines that stably express wild type and mutant
      AKAP75 transgenes were generated to investigate the extraneuronal function of
      AKAPs. In non-neuronal cells, AKAP75 accumulates selectively in the actin-rich,
      cortical cytoskeleton in close proximity with the plasma membrane. AKAP75
      efficiently sequesters cytoplasmic RIIalpha and RIIbeta (PKAII isoforms) and
      translocates these polypeptides to the cell cortex. Two structural modules in
      AKAP75, T1 (residues 27-48), and T2 (residues 77-100), are essential for
      targeting AKAP75.RII complexes to the cortical cytoskeleton. Deletions or amino
      acid substitutions in T1 and/or T2 result in the dispersion of both AKAP75 and
      RII subunits throughout the cytoplasm. AKAP75 is co-localized with F-actin and
      fodrin in the cortical cytoskeleton. Incubation of cells with 5 microM
      cytochalasin D disrupts actin filaments and dissociates actin from the cell
      cortex. In contrast, the bulk of AKAP75 and fodrin remain associated with the
      cortical region of cytochalasin D-treated cells. Thus, targeting of AKAP75 does
      not depend upon direct binding with F-actin. Rather, AKAP75 (like fodrin) may be
      associated with a multiprotein complex that interacts with integral plasma
      membrane proteins.

PMID- 8663280
TI  - Ribonuclease P of Tetrahymena thermophila.
AB  - Ribonuclease P (RNase P) is responsible for the generation of mature 5' termini
      of tRNA. The RNA component of this complex encodes the enzymatic activity in
      bacteria and is itself catalytically active under appropriate conditions in
      vitro. The role of the subunits in eucaryotes has not yet been established. We
      have partially purified RNase P activity from the ciliate protozoan Tetrahymena
      thermophila to learn more about the biochemical characteristics of RNase P from a
      lower eucaryote. The Tetrahymena RNase P displays a pH optimum and temperature
      optimum characteristic of RNase P enzymes isolated from other organisms. The Km
      of the T. thermophila enzyme for pre-tRNAGln is 1.6 x 10(-7)M, which is
      comparable to the values reported for other examples of RNase P. The Tetrahymena
      RNase P is a ribonucleoprotein complex, as supported by its sensitivity to
      micrococcal nuclease and proteinase K. The buoyant density of the enzyme in
      Cs2SO4 is 1.42 g/ml, which suggests that the RNA component of the Tetrahymena
      enzyme comprises a significantly greater percentage of the holoenzyme than that
      determined for RNase P of other Eucarya or Archaea. The holoenzyme has a
      requirement for divalent cations displaying characteristics that are unique for
      RNase P but closely resemble preferences reported for the Tetrahymena group I
      intron RNA. Puromycin inhibits pre-tRNA processing by the Tetrahymena complex,
      and implications of the similarities between recognition of tRNA by ribosomal
      components and RNase P are discussed.

PMID- 8663281
TI  - Sequencing analysis of cDNA clones encoding the American cockroach Cr-PI
      allergens. Homology with insect hemolymph proteins.
AB  - A previous article described the isolation of several lambdagt22A cDNA clones
      expressing the American cockroach (Periplaneta americana) Cr-PI allergens
      recognized by both human atopic IgE antibodies and anti-Cr-PI monoclonal
      antibodies (Wu, C. H., Lee, M. F., and Liao, S. C.(1995) J. Allergy Clin.
      Immunol. 96, 352-359). This article presents the nucleotide and deduced amino
      acid sequences of two cDNA clones encoding major allergens of P. americana.
      Clones C12 and C20 encode proteins of 685 and 631 amino acids with two potential
      N-glycosylation sites each. The predicted molecular weights for C12 and C20
      cloned proteins are 79,300 and 75, 500 with isoelectric point values of 6.26 and
      6.63, which are compatible with the determined sizes (Mr 78,000 and 72,000) and
      isoelectric point value (6.2) of the Cr-PI allergens of P. americana. A high
      degree of identity (69.1%), including several overlapped predicted central
      antigenic determinant residues, was found between two allergens. The anti-fusion
      protein antibody-based enzyme-linked immunosorbent assay was able to detect crude
      American cockroach extract, Cr-PI, recombinant proteins, and commercial cockroach
      extracts, which provides further evidence that two allergens share common antigen
      determinants. Recombinant allergens of clones C12 and C20 both showed 47.4% skin
      reactivities on 19 cockroach-sensitive asthmatic patients. Unexpectedly, although
      no sequence similarity was found to other known allergens, two aromatic amino
      acid-rich allergens were found to have a striking sequence identity to insect
      storage proteins (20.1-33.9%), insect juvenile hormone-suppressible proteins
      (30.9-36.4%), and arthropod hemocyanins (29.7-34.6%). Results suggested that two
      prominent allergens of P. americana are ancestrally related to these insect
      hemolymph proteins and represent a new group of proteins in the hemocyanin
      superfamily. These data will now facilitate epitope-mapping studies, and the
      recombinant allergens may be valuable for diagnostic and therapeutic purposes.

PMID- 8663283
TI  - Extracellular mutations of non-obese diabetic mouse FcgammaRI modify surface
      expression and ligand binding.
AB  - The non-obese diabetic mouse (NOD) expresses a unique form of the high affinity
      receptor for IgG (FcgammaRI), containing multiple mutations that result in
      substitutions and insertions of amino acids and a truncated cytoplasmic tail. As
      a result of these major changes, receptor affinity for IgG increases 10-fold over
      that of wild-type FcgammaRI from BALB/c mice, while the specificity for ligand is
      retained. Kinetic analysis revealed that while the association rate of IgG with
      FcgammaRI from NOD mice (FcgammaRI-NOD) and FcgammaRI from BALB/c mice (FcgammaRI
      BALB) is similar, IgG bound much more tightly to FcgammaRI-NOD as revealed by a
      profoundly diminished dissociation rate. Transfection studies demonstrated that
      FcgammaRI-NOD was expressed at one-tenth of the level of FcgammaRI-BALB. Although
      mouse FcgammaRI was previously not known to associate with the FcepsilonRI gamma
      subunit, transfection of COS-7 cells demonstrates that like human FcgammaRI,
      mouse FcgammaRI is also able to associate with this signaling subunit.
      Furthermore, expression levels of FcgammaRI-NOD were not restored by the presence
      of the FcepsilonRI gamma-subunit. The difference in the levels of expression was
      mapped to mutations in the extracellular region of FcgammaRI-NOD as replacement
      of the extracellular domains with those of human FcgammaRI or FcgammaRI-BALB
      restored expression to that of human FcgammaRI or FcgammaRI-BALB.

PMID- 8663282
TI  - Single amino acid residues in the E- and P-selectin epidermal growth factor
      domains can determine carbohydrate binding specificity.
AB  - E-selectin and P-selectin are two closely related vascular cell adhesion
      proteins. Each selectin has an amino-terminal C-type lectin domain that is
      thought to possess the carbohydrate binding site that binds the sialylated Lewisx
      antigen (sLex or CD15s) (Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc). In
      addition to the sLex carbohydrate, P-selectin binds sulfated proteoglycan, 3
      sulfated galactosyl ceramide (sulfatide), and heparin. Both E- and P-selectin
      have an EGF-like (EGF) domain that is immediately adjacent to and COOH-terminal
      to the lectin domain. We report that mutagenic substitution of single amino acid
      residues in either the P- or E-selectin EGF domain can dramatically alter
      selectin binding to sLex, heparin, or sulfatide. Substitution of E- and P
      selectin EGF domain residue Ser128 with an arginine results in E- and P-selectin
      proteins that have lost the requirement for alpha1-3-linked fucose and are thus
      able to bind to sialyllactosamine. A similar phenotype is reported for an E
      selectin mutation within the lectin domain. Additionally, we have determined that
      conservative substitution of EGF domain residues 124 and 128 can alter E-selectin
      binding such that it is able to adhere to heparin or sulfatide and can reduce P
      selectin adherence to these ligands. The distance between the substituted EGF
      domain amino acid residues and the primary carbohydrate binding site within the
      lectin domain and their relative positioning as determined by the three
      dimensional crystal structure of the E-selectin lectin and EGF domains (Graves,
      B. J., Crowther, R. L., Chandran, C., Rumberger, J. B., Li, S., Huang, D.-S.,
      Presky, D. H., Familletti, P. C., Wolitzky, B. A., and Burns, D. K. (1994) Nature
      367, 532-538) suggest that there is little direct contact between the two
      domains. However, we report mutant binding characteristics which indicate that
      selectin oligosaccharide binding may be modulated by both domains and that wild
      type E- and P-selectin/sLex binding interactions may be significantly different
      from those previously hypothesized.

PMID- 8663284
TI  - Purification and characterization of cannabidiolic-acid synthase from Cannabis
      sativa L.. Biochemical analysis of a novel enzyme that catalyzes the
      oxidocyclization of cannabigerolic acid to cannabidiolic acid.
AB  - We identified a unique enzyme that catalyzes the oxidocyclization of
      cannabigerolic acid to cannabidiolic acid (CBDA) in Cannabis sativa L. (CBDA
      strain). The enzyme, named CBDA synthase, was purified to apparent homogeneity by
      a four-step procedure: ammonium sulfate precipitation followed by chromatography
      on DEAE-cellulose, phenyl-Sepharose CL-4B, and hydroxylapatite. The active enzyme
      consists of a single polypeptide with a molecular mass of 74 kDa and a pI of 6.1.
      The NH2-terminal amino acid sequence of CBDA synthase is similar to that of
      Delta1-tetrahydrocannabinolic-acid synthase. CBDA synthase does not require
      coenzymes, molecular oxygen, hydrogen peroxide, and metal ion cofactors for the
      oxidocyclization reaction. These results indicate that CBDA synthase is neither
      an oxygenase nor a peroxidase and that the enzymatic cyclization does not proceed
      via oxygenated intermediates. CBDA synthase catalyzes the formation of CBDA from
      cannabinerolic acid as well as cannabigerolic acid, although the kcat for the
      former (0.03 s-1) is lower than that for the latter (0.19 s-1). Therefore, we
      conclude that CBDA is predominantly biosynthesized from cannabigerolic acid
      rather than cannabinerolic acid.

PMID- 8663285
TI  - Recombinant protein synthesis in Chinese hamster ovary cells using a vaccinia
      virus/bacteriophage T7 hybrid expression system.
AB  - The vaccinia virus/bacteriophage T7 expression system was adapted to Chinese
      hamster ovary (CHO) cells. Vaccinia virus undergoes abortive infection in CHO
      cells, which is characterized by a sharp reduction in protein synthesis at the
      stage of viral intermediate gene expression. We determined that expression of a
      T7 promoter-regulated chloramphenicol acetyltransferase gene was at least 20
      times more efficient in permissive BS-C-1 than in CHO cells. The
      encephalomyocarditis virus 5'-untranslated region, which confers cap-independent
      translatability to mRNA, stimulated recombinant protein synthesis by 10-fold in
      both cell lines, maintaining the advantage of the BS-C-1 cells over CHO cells.
      Since the cowpox virus hr gene overcomes vaccinia virus host range restriction in
      CHO cells, we constructed a recombinant virus that carries an intact hr gene in
      addition to the T7 RNA polymerase gene. With this virus, synthesis of T7 RNA
      polymerase was enhanced and production of a recombinant protein occurred in CHO
      cells at the level observed in permissive cell lines. Extension of the vaccinia
      virus/bacteriophage T7 expression system to CHO cells should be of wide interest,
      as these cells have advantages for preparation of recombinant proteins in
      research and biotechnology.

PMID- 8663286
TI  - Characterization of multiple mRNAs that encode mammalian translation initiation
      factor 5 (eIF-5).
AB  - Eukaryotic translation initiation factor 5 (eIF-5) interacts with the 40 S
      initiation complex (40S.mRNA.MettRNAf.eIF-2.GTP) to promote the hydrolysis of
      bound GTP with the concomitant joining of the 60 S ribosomal subunit to the 40 S
      initiation complex to form a functional 80 S initiation complex. In this paper,
      the multiple mRNAs that encode mammalian eIF-5 have been characterized. In rat
      tissues, three major eIF-5 mRNAs of 3.5, 2.8, and 2.2 kilobases in length are
      detected. All major eIF-5 mRNAs are initiated from a single transcription
      initiation site, contain identical 5'-untranslated and coding regions, but differ
      from one another only in the length of their 3'-untranslated regions. The
      different lengths of the 3'-untranslated region of eIF-5 mRNAs are generated by
      the use of alternative polyadenylation signals. Additionally, we demonstrate
      tissue-specific variations in eIF-5 mRNA expression as well as preference for
      polyadenylation sites. These results should lead to increased understanding of
      the regulation of eIF-5 gene expression.

PMID- 8663287
TI  - Platelet-derived growth factor induction of the immediate-early gene MCP-1 is
      mediated by NF-kappaB and a 90-kDa phosphoprotein coactivator.
AB  - A broad panel of agents including serum, interleukin-1, double-stranded RNA, and
      platelet-derived growth factor (PDGF) stimulate transcription of the "slow"
      immediate-early gene MCP-1. These disparate inducers act through a tight cluster
      of regulatory elements in the distal 5'-flanking sequences of the MCP-1 gene. We
      describe a 22-base element in this cluster which, in single copy, confers PDGF
      inducibility to a tagged MCP-1 reporter gene. In mobility shift assays, the
      element binds a PDGF-activated form of NF-kappaB, and a 90-kDa protein (p90)
      which binds constitutively. Antibody supershift and UV cross-linking experiments
      indicate that the PDGF-activated NF-kappaB species is a Rel A homodimer. The DNA
      binding form of p90 is a nuclear-restricted serine/threonine phosphoprotein.
      Mutagenesis of the 22-base element shows that the NF-kappaB and p90 binding sites
      overlap, but binding of the two species is mutually independent. Both sites,
      however, are required for optimum PDGF induction of MCP-1. Therefore, p90 appears
      to be a coactivator with NF-kappaB in PDGF-mediated induction of MCP-1.

PMID- 8663288
TI  - Ca2+-dependent antifreeze proteins. Modulation of conformation and activity by
      divalent metal ions.
AB  - The antifreeze proteins (AFPs) are structurally diverse molecules that share an
      ability to bind to ice crystals and inhibit their growth. The type II fish AFPs
      of Atlantic herring and smelt are unique among known AFPs in their requirement of
      a cofactor for antifreeze activity. These AFPs are homologous with the
      carbohydrate-recognition domains of Ca2+-dependent (C-type) lectins and require
      Ca2+ for their activity. To investigate the role of metal ions in the structure
      and function of type II AFPs, the binding of Ca2+ and other divalent cations to
      herring AFP was investigated. Binding studies using 45Ca2+ demonstrated that the
      AFP has a single Ca2+-binding site with a Kd of 9 microM. Proteolysis protection
      studies and measurement of antifreeze activity revealed a conformational change
      from a protease-sensitive and inactive apoAFP to a protease-resistant active AFP
      upon Ca2+ binding. Other divalent metal ions including Mn2+, Ba2+, and Zn2+ bind
      at the Ca2+-binding site and induce a similar change. A saturatable increase in
      tryptophan emission intensity at 340 nm also occurred upon Ca2+ addition. Whereas
      antifreeze activity appeared normal when Ca2+ or Mn2+ were bound, it was much
      lower in the presence of other metal ions. When Ba2+ was bound to the AFP, ice
      crystals showed a distinct difference in morphology. These studies demonstrate
      that herring AFP specifically binds Ca2+ and, consequently, adopts a conformation
      that is essential for its ice-binding activity.

PMID- 8663289
TI  - Chinese hamster ovary cells expressing a cell surface-anchored form of hepatic
      lipase. Characterization of low density lipoprotein and chylomicron remnant
      uptake and selective uptake of high density lipoprotein-cholesteryl ester.
AB  - The enzyme hepatic lipase may play several roles in lipoprotein metabolism.
      Recent investigation has suggested a role for the enzyme in lipoprotein and/or
      lipoprotein lipid uptake. To study this, a simple isolated system that mimics the
      in vivo system would be desirable. The enzyme is secreted by the hepatic
      parenchymal cell but exists, and presumably exerts its effects, while bound to
      capillary endothelial cells in the liver, adrenal gland, and the ovary. We
      constructed a cDNA that encodes the expression of a chimeric protein composed of
      rat hepatic lipase and the signal sequence for the addition of the
      glycophosphatidylinositol (GPI) anchor from human decay-accelerating factor. When
      transfected into Chinese hamster ovary (CHO) cells this gave rise to a cell
      population that had immunoreactive hepatic lipase on the cell surface. Cloning of
      the transfected cells produced several cell lines that expressed the chimeric
      protein bound to the cell surface by a GPI anchor. This was documented by
      demonstrating incorporation of [3H]ethanolamine into anti-hepatic lipase
      immunoprecipitable material; in addition, hepatic lipase was released from the
      cells by phosphatidylinositol-specific phospholipase C but not by heparin.
      Phosphatidylinositol-phospholipase C treatment of cells expressing the anchored
      lipase released material that comigrated with hepatic lipase on SDS
      polyacrylamide gel electrophoresis and was immunoreactive with antibody to the
      cross-reacting determinant of GPI anchors. Cell lysates containing the anchored
      protein contained salt-resistant lipase activity, a known feature of the secreted
      hepatic lipase; thus it appears that these cells have a surface-anchored hepatic
      lipase molecule. Although it was not possible to demonstrate lipolysis by the
      enzyme while it was on the cell surface for technical reasons, the protein
      produced by these cells was active when studied in cell membranes. The ability of
      the cells to take up lipoproteins was studied. The cells demonstrated an
      increased affinity for low density lipoprotein (LDL) receptor mediated uptake of
      LDL. They did not, however, demonstrate any enhanced binding or removal of
      chylomicron remnants. With respect to LDL and remnants, the cells expressing
      anchored lipase behaved similarly to CHO cell that expressed secreted hepatic
      lipase. The cells expressing anchored hepatic lipase had a marked increase in the
      uptake of high density lipoprotein and high density lipoprotein cholesteryl ester
      when compared to that seen with CHO cells secreting hepatic lipase. This increase
      occurred primarily via the selective pathway, and was not reduced by addition of
      anti-LDL receptor or anti-hepatic lipase antibodies or the receptor-associated
      protein. Together the results suggest that hepatic lipase, when bound to the cell
      surface by a GPI anchor, plays a role in enhancing lipoprotein uptake. For LDL
      this may involve the provision of a second foot for particle binding, thus
      enhancing affinity for the LDL receptor. For chylomicron remnants an additional
      molecule or molecules are necessary to mediate this effect. For HDL, the enzyme
      facilitates uptake of cholesteryl ester primarily by the selective pathway.

PMID- 8663290
TI  - Heterologous complementation of a Rieske iron-sulfur protein-deficient
      Saccharomyces cerevisiae by the Rip1 gene of Schizosaccharomyces pombe.
AB  - A cDNA carrying the Rip1 gene, which encodes the Rieske iron-sulfur protein of
      Schizosaccharomyces pombe, has been cloned by complementing the respiratory
      deficiency of a Saccharomyces cerevisiae strain in which the endogenous copy of
      the RIP1 gene has been deleted. The deduced amino acid sequences of the S. pombe
      and S. cerevisiae iron-sulfur proteins are 50% identical, with the highest region
      of identity being in the C termini of the proteins, where the 2Fe:2S cluster is
      bound. When expressed in the S. cerevisiae deletion strain, the S. pombe iron
      sulfur protein restores 25-30% of the ubiquinol-cytochrome c reductase activity.
      The kinetics of cytochrome c reduction, the effects of inhibitors which act at
      defined sites in the cytochrome bc1 complex, and the optical properties of
      cytochrome b in membranes from the S. cerevisiae deletion strain complemented
      with S. pombe iron-sulfur protein indicate that the S. pombe protein interacts
      with cytochrome b to restore an apparently normal ubiquinol oxidase site, but
      that interaction between the iron-sulfur protein and cytochrome c1 is partially
      impaired. This is the first heterologous replacement of an electron transfer
      protein in a respiratory enzyme complex in S. cerevisiae.

PMID- 8663291
TI  - Small stress proteins as novel regulators of apoptosis. Heat shock protein 27
      blocks Fas/APO-1- and staurosporine-induced cell death.
AB  - Small stress protein expression enhances the survival of mammalian cells exposed
      to numerous injuries that induce necrotic cell death. The cell surface receptor
      Fas/APO-1 and its ligand have been recently identified as important mediators of
      apoptosis. Here, we show that constitutive expression of human heat shock protein
      (hsp)27 in murine L929 cells blocks Fas/APO-1-mediated cell death. Expression of
      human hsp27 prevented anti-APO-1-induced DNA fragmentation and morphological
      changes. These results strongly suggest that human hsp27 acts as a cellular
      inhibitor of Fas/APO-1-induced apoptosis. We also report that the expression of
      small stress proteins from different species, such as human hsp27, Drosophila
      Dhsp27, or human alphaB-crystallin, confers resistance to apoptotic cell death
      induced by staurosporine, a protein kinase C inhibitor. Hence, small stress
      proteins are novel regulators that are able to block apoptosis induced by
      different pathways.

PMID- 8663292
TI  - Lipoprotein lipase binds to low density lipoprotein receptors and induces
      receptor-mediated catabolism of very low density lipoproteins in vitro.
AB  - Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of
      plasma triglycerides, promotes binding and catabolism of triglyceride-rich
      lipoproteins by various cultured cells. Recent studies demonstrate that LPL binds
      to three members of the low density lipoprotein (LDL) receptor family, including
      the LDL receptor-related protein (LRP), GP330/LRP-2, and very low density
      lipoprotein (VLDL) receptors and induces receptor-mediated lipoprotein
      catabolism. We show here that LDL receptors also bind LPL and mediate LPL
      dependent catabolism of large VLDL with Sf 100-400. Up-regulation of LDL
      receptors by lovastatin treatment of normal human foreskin fibroblasts (FSF
      cells) resulted in an increase in LPL-induced VLDL binding and catabolism to a
      level that was 10-15-fold greater than in LDL receptor-negative fibroblasts,
      despite similar LRP activity in both cell lines. This indicates that the
      contribution of LRP to LPL-dependent degradation of VLDL is small when LDL
      receptors are maximally up-regulated. Furthermore studies in LRP-deficient murine
      embryonic fibroblasts showed that the level of LPL-dependent degradation of VLDL
      was similar to that in normal murine embryonic fibroblasts. LPL also promoted the
      internalization of protein-free triglyceride emulsions; lovastatin-treatment
      resulted in 2-fold higher uptake in FSF cells, indicating that LPL itself could
      bind to LDL receptors. However, the lower induction of emulsion catabolism as
      compared with native VLDL suggests that LPL-induced catabolism via LDL receptors
      is only partially dependent on receptor binding by LPL and instead is primarily
      due to activation of apolipoproteins such as apoE. A fusion protein between
      glutathione S-transferase and the catalytically inactive carboxyl-terminal domain
      of LPL (GST-LPLC) also induced binding and catabolism of VLDL. However GST-LPLC
      was not as active as native LPL, indicating that lipolysis is required for a
      maximal LPL effect. Mutations of critical tryptophan residues in GST-LPLC that
      abolished binding to VLDL converted the protein to an inhibitor of lipoprotein
      binding to LDL receptors. In solid-phase assays using immobilized receptors, LDL
      receptors bound to LPL in a dose-dependent manner. Both LPL and GST-LPLC promoted
      binding of VLDL to LDL receptor-coated wells. These results indicate that LPL
      binds to LDL receptors and suggest that the carboxyl-terminal domain of LPL
      contributes to this interaction.

PMID- 8663293
TI  - Phosphatidate phosphohydrolase catalyzes the hydrolysis of ceramide 1-phosphate,
      lysophosphatidate, and sphingosine 1-phosphate.
AB  - A Mg2+-independent phosphatidate phosphohydrolase was purified from rat liver
      plasma membranes in two distinct forms, an anionic protein and a cationic
      protein. Both forms of the enzyme dephosphorylated phosphatidate, ceramide 1
      phosphate, lysophosphatidate, and sphingosine 1-phosphate. When assayed at a
      constant molar ratio of lipid to Triton X-100 of 1:500, the apparent Km values of
      the anionic phosphohydrolase for the lipid substrates was 3.5, 1.9, 0.4, and 4.0
      microM, respectively. The relative catalytic efficiency of the enzyme for
      phosphatidate, ceramide 1-phosphate, lysophosphatidate, and sphingosine 1
      phosphate was 0.16, 0.14, 0.48, and 0.04 liter (min x mg)-1, respectively. The
      hydrolysis of phosphatidate was inhibited competitively by ceramide 1-phosphate,
      lysophosphatidate, and sphingosine 1-phosphate. The Ki(app) values were 5.5, 5.9,
      and 4.0 microM, respectively. The hydrolysis of phosphatidate by the
      phosphohydrolase conformed to a surface dilution kinetic model. It is concluded
      that the enzyme is a lipid phosphomonoesterase that could modify the balance of
      phosphatidate, ceramide 1-phosphate, lysophosphatidate, and sphingosine 1
      phosphate relative to diacylglycerol, ceramide, monoacylglycerol, and
      sphingosine, respectively. The enzyme could thus play an important role in
      regulating cell activation and signal transduction.

PMID- 8663294
TI  - ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the
      cytotoxic T cell protease granzyme B.
AB  - Members of the ICE/Ced-3 gene family are likely effector components of the cell
      death machinery. Here, we characterize a novel member of this family designated
      ICE-LAP6. By phylogenetic analysis, ICE-LAP6 is classified into the Ced-3
      subfamily which includes Ced-3, Yama/CPP32/apopain, Mch2, and ICE-LAP3/Mch3/CMH
      1. Interestingly, ICE-LAP6 contains an active site QACGG pentapeptide, rather
      than the QACRG pentapeptide shared by other family members. Overexpression of ICE
      LAP6 induces apoptosis in MCF7 breast carcinoma cells. More importantly, ICE-LAP6
      is proteolytically processed into an active cysteine protease by granzyme B, an
      important component of cytotoxic T cell-mediated apoptosis. Once activated, ICE
      LAP6 is able to cleave the death substrate poly(ADP-ribose) polymerase into
      signature apoptotic fragments.

PMID- 8663295
TI  - Role of the Raf/mitogen-activated protein kinase pathway in p21ras
      desensitization.
AB  - Desensitization of p21(ras) after stimulation of cells by growth factors and
      phorbol 12-myristate 13-acetate (PMA) correlates with hyperphosphorylation of the
      guanine nucleotide exchange factor Son-of-sevenless (Sos) and its dissociation
      from the adaptor protein Grb2 (Cherniack, A., Klarlund, J. K., Conway, B. R., and
      Czech, M. P. (1995) J. Biol. Chem. 270, 1485-1488). To test the role of the
      Raf/mitogen-activated protein (MAP) kinase pathway, we utilized cells expressing
      a chimera composed of the catalytic domain of p74Raf-1 and the hormone binding
      domain of the estradiol receptor (DeltaRaf-1:ER). Estradiol markedly stimulated
      DeltaRaf-1:ER and the downstream MEK and MAP kinases in these cells as well as
      Sos phosphorylation. However, the dissociation of Grb2 from Sos observed in
      response to PMA was not apparent upon DeltaRaf-1:ER activation. Furthermore,
      stimulation of DeltaRaf-1:ER did not impair GTP loading of p21(ras) in response
      to platelet-derived growth factor or epidermal growth factor. We conclude that
      activation of the Raf/MAP kinase pathway alone in these cells is insufficient to
      cause disassembly of Sos from Grb2 or to interrupt the ability of Sos to catalyze
      activation of p21(ras).

PMID- 8663296
TI  - Dissection of functional domains of the human DNA replication protein complex
      replication protein A.
AB  - Replication protein A (RPA) is a mammalian single-stranded DNA binding factor
      essential for DNA replication, repair, and recombination. It is composed of three
      subunits of 70, 34, and 13 kDa (Rpa1, Rpa2, and Rpa3, respectively). Deletion
      mapping of the Rpa2 subunit identified the domain required for interaction with
      Rpa1 and Rpa3 which does not include the N-terminal domain that is phosphorylated
      during S phase. Deletion mapping of Rpa1 defined three domains. The C-terminal
      third of the Rpa1 polypeptide binds Rpa2 which itself forms a bridge between Rpa1
      and Rpa3. The N-terminal third of Rpa1 bound single-stranded DNA under low
      stringency conditions only (0.1 M NaCl), while a central domain binds to single
      stranded DNA under both low and high stringency conditions (0.5 M NaCl). Binding
      to p53 requires the N-terminal third of Rpa1 with some contribution from the C
      terminal third. The evolutionarily conserved putative zinc finger near the C
      terminus of Rpa1 was not required for binding to single-stranded DNA, Rpa2, or
      p53. However, all three subdomains of Rpa1 and the zinc finger were essential for
      supporting DNA replication in vitro. These experiments are a first step toward
      defining peptide components responsible for the many functions of the RPA protein
      complex.

PMID- 8663297
TI  - Degradation of interleukin 1beta by matrix metalloproteinases.
AB  - Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in
      inflammation and tissue destruction, where IL-1 is a potent stimulator of
      connective tissue cells to produce the extracellular matrix-degrading MMPs. Here,
      we report that IL-1beta, but not IL-1alpha, is degraded by MMP-1 (interstitial
      collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase
      B). This degradation was effectively blocked by tissue inhibitor of
      metalloproteinases (TIMP)-1. When IL-1beta was treated with MMPs it lost the
      ability to enhance the synthesis of prostaglandin E2 and pro-MMP-3 in human
      fibroblasts. The primary cleavage site of IL-1beta by MMP-2 was identified at the
      Glu25-Leu26 bond. These results suggest that IL-1beta stimulates connective
      tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the
      activity of IL-1beta.

PMID- 8663298
TI  - Characterization of glycosaminoglycan-binding domains present in insulin-like
      growth factor-binding protein-3.
AB  - Matrix metalloproteinase 3 cleaves insulin-like growth factor-binding protein-3
      (IGFBP-3) into six fragments, four of which bind heparin-Sepharose (Fowlkes, J.
      L., Enghild, J. J., Suzuki, K., and Nagase, H. (1994) J. Biol. Chem. 269, 25742
      25746). Sequence analysis of IGFBP-3 heparin-binding fragments shows that all
      fragments contain at least one of two highly basic, putative heparin-binding
      consensus sequences present in IGFBP-3. Epitope-specific antibodies generated
      against synthetic peptides containing these domains recognized IGFBP-3, yet were
      significantly inhibited from binding in the presence of heparin, demonstrating
      that these regions of IGFBP-3 contain functional heparin-binding domains. IGFBP-3
      peptides containing one of the two heparin-binding consensus sequences bound
      heparin in a solid phase binding assay in a dose-dependent and saturable manner.
      However, the IGFBP-3 peptide containing the heparin-binding consensus sequence
      149KKGHA153 bound heparin with approximately 4-fold less affinity than the IGFBP
      3 peptide containing the longer heparin-binding consensus sequence
      219YKKKQCRP226. Examination of several well characterized glycosaminoglycans to
      inhibit the binding of heparin to both heparin-binding IGFBP-3 peptides revealed
      that the most potent inhibitors were heparin, heparan sulfate, and dermatan
      sulfate; chondroitin sulfate A and hyaluronic acid were intermediate in their
      inhibitory activities; and chondroitin sulfate C caused no inhibition. These
      studies identify and characterize the glycosaminoglycan-binding domains in IGFBP
      3, providing a basis for the better understanding of IGFBP-3-glycosaminoglycan
      interactions at the cellular and extracellular interface.

PMID- 8663299
TI  - TRAF5, an activator of NF-kappaB and putative signal transducer for the
      lymphotoxin-beta receptor.
AB  - Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are signal
      transducers for several members of the TNF receptor superfamily. We have
      identified a novel member of the TRAF family by degenerate oligonucleotide
      polymerase chain reaction amplification that contains a zinc RING finger and zinc
      finger motifs, a coiled-coil region, and a C-terminal "TRAF" homology domain. In
      vitro translated TRAF5 binds to the cytoplasmic region of the lymphotoxin-beta
      receptor (LT-betaR) but not to several other related receptors including CD40,
      both TNF receptors, Fas, and nerve growth factor receptor. TRAF5 and LT-betaR
      coimmunoprecipitate when overexpressed in COS7 cells. TRAF5 mRNA expression is
      found in all visceral organs and overlaps with LT-betaR. These features
      distinguish TRAF5 from the other members of the TRAF family. The transcription
      factor NF-kappaB is activated in HEK293 cells by overexpression of full-length
      TRAF5 but not a truncated form lacking the zinc binding region. Furthermore,
      overexpression of LT-betaR in HEK293 cells also results in activation of NF
      kappaB, which is partially inhibited by the truncated TRAF5 mutant. These results
      show TRAF5 is functionally similar to TRAF2 in that both mediate activation NF
      kappaB and implicate TRAF5 as a signal transducer for LT-betaR.

PMID- 8663300
TI  - Oxidized low density lipoprotein and lysophosphatidylcholine stimulate cell cycle
      entry in vascular smooth muscle cells. Evidence for release of fibroblast growth
      factor-2.
AB  - We have previously shown that oxidized low density lipoprotein (LDL) but not
      native LDL stimulated DNA synthesis in cultured smooth muscle cells (SMC) and
      that alpha-tocopherol (vitamin E) inhibited this proliferative response (Lafont,
      A., Chai, Y. C., Cornhill, J. F. , Whitlow, P. L., Howe, P. H., and Chisolm, G.
      M.(1995) J. Clin. Invest. 95, 1018-1025). The moiety of oxidized LDL that
      stimulates DNA synthesis and the cellular mechanism for this potentially
      mitogenic effect are not known. We now report that lipid fractions containing
      lysophospholipids from oxidized LDL or phospholipase A2-treated native LDL
      stimulated SMC DNA synthesis as did palmitoyl lysophosphatidylcholine (lysoPC).
      Protein kinase C inhibitors and down-regulation of protein kinase C activity by
      phorbol ester inhibited oxidized LDL- and lysoPC-induced DNA synthesis. A
      neutralizing monoclonal antibody against fibroblast growth factor-2 significantly
      inhibited oxidized LDL and lysoPC-induced DNA synthesis in SMC; irrelevant
      antibodies were ineffective. Vitamin E inhibited the DNA synthesis stimulated by
      lysoPC, an observation that distinguished this effect from DNA synthesis induced
      by another detergent, digitonin. These results suggest that oxidized LDL and its
      lysoPC moiety stimulate SMC to enter the cell cycle via an oxidative mechanism
      that causes the release of fibroblast growth factor-2 and a subsequent autocrine
      or paracrine response.

PMID- 8663301
TI  - Protein kinase signaling pathway triggered by cell swelling and involved in the
      activation of glycogen synthase and acetyl-CoA carboxylase in isolated rat
      hepatocytes.
AB  - Incubation of isolated hepatocytes with glutamine or proline or in hypotonic
      media is known to activate glycogen synthase and acetyl-CoA carboxylase as a
      result of cell swelling. We report here that the same experimental conditions
      caused an activation of phosphatidylinositol 3-kinase and p70 ribosomal protein
      S6 kinase (p70 S6 kinase) but did not modify the activity of p42 mitogen
      activated protein kinase. In addition, rapamycin, an inhibitor of p70 S6 kinase
      activation, prevented the amino acid- and hypotonicity-induced activation of p70
      S6 kinase but did not block the activation of glycogen synthase and acetyl-CoA
      carboxylase, thus ruling out p70 S6 kinase as a necessary component in the
      activation pathway. By contrast, wortmannin or LY294002, inhibitors of
      phosphatidylinositol 3-kinase, completely blocked the activation of
      phosphatidylinositol 3-kinase and p70 S6 kinase and partly blocked the activation
      of glycogen synthase and acetyl-CoA carboxylase. Therefore, phosphatidylinositol
      3-kinase might be a component of the signaling pathway that is triggered by cell
      swelling and is responsible, at least in part, for the activation of glycogen
      synthase and acetyl-CoA carboxylase. Incubation of hepatocytes with 0.1 microM
      epidermal growth factor doubled the activity of p42 mitogen-activated protein
      kinase without activating glycogen synthase.

PMID- 8663302
TI  - Lysine 71 of the chaperone protein Hsc70 Is essential for ATP hydrolysis.
AB  - It has been proposed that lysine 71 of the bovine 70-kDa heat shock cognate
      protein might participate in catalysis of ATP hydrolysis by stabilizing an H2O
      molecule or an OH- ion for nucleophilic attack on the gamma-phosphate of the
      nucleotide (Flaherty, K. M., Wilbanks, S. M., DeLuca-Flaherty, C., and McKay, D.
      B. (1994) J. Biol. Chem. 12899-12907; Wilbanks, S. M., DeLuca-Flaherty, C., and
      McKay, D. B. (1994) J. Biol. Chem. 269, 12893-12898). To test this hypothesis,
      lysine 71 of the ATPase fragment 70-kDa heat shock cognate protein has been
      mutated to glutamic acid, methionine, and alanine; and the kinetic and structural
      properties of the mutant proteins have been determined. All three mutant proteins
      are devoid of measurable ATP hydrolysis activity. Crystal structures of the
      mutant proteins have been determined to a resolution of 1.7 A; all three have ATP
      in the nucleotide binding site. These data identify lysine 71 as a residue that
      is essential for chemical hydrolysis of ATP.

PMID- 8663303
TI  - Regulation of the human topoisomerase IIalpha gene promoter in confluence
      arrested cells.
AB  - Expression of DNA topoisomerase IIalpha mRNA and protein reflects the
      proliferative state of mammalian cell lines and tissues with high levels in
      actively cycling cells but marked down-regulation during serum deprivation or
      cell density-induced growth arrest. Using stably integrated gene fusions
      comprising the human topoisomerase IIalpha promoter with a growth hormone
      reporter gene, we have localized elements required for the differential activity
      of the topoisomerase IIalpha promoter in proliferating and confluence-arrested
      cells. Deletion analysis localized the region of the promoter that responded to
      changes in the cellular growth state to between -101 and -144 base pairs.
      Mutation analysis identified an inverted CCAAT box (ICB) located at -108 to -104
      as necessary for promoter down-regulation in confluence-arrested cells, while
      several other potential cis-acting elements, including four additional ICBs, were
      shown not to be required. The critical ICB was recognized in vitro by the CCAAT
      box binding factor, NF-Y, with levels of binding activity higher in extracts from
      proliferating cells than from confluence-arrested cells. We conclude that the
      differential regulation of topoisomerase IIalpha gene expression in cycling and
      confluence-arrested cells is mediated, at least in part, through proliferation
      specific binding of factors to an ICB element in the gene promoter.

PMID- 8663304
TI  - Purification and characterization of a soluble form of mammalian adenylyl
      cyclase.
AB  - An engineered, soluble form of mammalian adenylyl cyclase has been expressed in
      Escherichia coli and purified by three chromatographic steps. The enzyme utilizes
      one molecule of ATP to synthesize one molecule of cyclic AMP and pyrophosphate at
      a maximal specific activity of 12.8 micromol/min/mg, corresponding to a turnover
      number of 720 min-1. Although devoid of membrane spans, the enzyme displays all
      of the regulatory properties that are common to mammalian adenylyl cyclases. It
      is activated synergistically by Gsalpha and forskolin and is inhibited by
      adenosine (P-site) analogs with kinetic patterns that are identical to those
      displayed by the native enzymes. The purified enzyme is also inhibited directly
      by the G protein betagamma subunit complex. After adenovirus-mediated expression
      in adenylyl cyclase-deficient HC-1 cells, the enzyme can be stimulated
      synergistically by Gs-coupled receptors and forskolin.

PMID- 8663305
TI  - Lysosomal targeting of palmitoyl-protein thioesterase.
AB  - Palmitoyl-protein thioesterase is a newly described long chain fatty-acid
      hydrolase that removes fatty acyl groups from modified cysteines in proteins. We
      have recently identified palmitoyl-protein thioesterase as the defective enzyme
      in the recessive hereditary neurological degenerative disorder infantile neuronal
      ceroid lipofuscinosis (Vesa, J., Hellsten, E., Verkruyse, L. A., Camp, L. A. ,
      Rapola, J., Santavuori, P., Hofmann, S. L., and Peltonen, L. (1995) Nature 376,
      584-587). A defect in a lysosomal enzyme had been postulated for the disease, but
      until recently, the relevant defective lysosomal enzyme had not been identified.
      In this paper, we present evidence for the lysosomal localization of palmitoyl
      protein thioesterase. We show that COS cells take up exogenously supplied
      palmitoyl-protein thioesterase intracellularly and that the cellular uptake is
      blocked by mannose 6-phosphate, a hallmark of lysosomal enzyme trafficking. The
      enzyme contains endoglycosidase H-sensitive oligosaccharides that contain
      phosphate groups. Furthermore, palmitoyl-protein thioesterase cosediments with
      lysosomal enzyme markers by Percoll density gradient centrifugation.
      Interestingly, the pH optimum for the enzyme is in the neutral range, a property
      shared by two other lysosomal enzymes that remove post-translational protein
      modifications. These findings suggest that palmitoyl-protein thioesterase is a
      lysosomal enzyme and that infantile neuronal ceroid lipofuscinosis is properly
      classified as a lysosomal storage disorder.

PMID- 8663306
TI  - Characterization of ATP transport into chromaffin granule ghosts. Synergy of ATP
      and serotonin accumulation in chromaffin granule ghosts.
AB  - ATP is an excitatory neurotransmitter that is stored and cosecreted with
      catecholamines from cells of the adrenal medulla. While the transport of
      catecholamines into chromaffin granule ghosts has been extensively characterized,
      there is little information on the mechanism of ATP transport into these
      structures. Here we show that ATP transport is driven by the electrical component
      of the electrochemical proton gradient created by the chromaffin granule membrane
      H+-ATPase, and that the accumulated nucleotide is released from the vesicles by
      inhibition of the H+-ATPase. GTP and UTP are also substrates for this
      transporter, distinguishing it from the mitochondrial ADP/ATP exchanger.
      Accumulation of ADP and ATP (rather than exchange with intravesicular ATP) is
      demonstrated by high pressure liquid chromatography measurements. The anion
      transport inhibitor 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (Ki = 27
      microM) inhibits ATP transport, while atractyloside, the inhibitor of the
      mitochondrial ATP/ADP exchanger, is a very poor inhibitor. Finally, we have
      demonstrated a synergy between the accumulation of ATP and that of serotonin
      (i.e. more of each solute accumulates when the two are accumulated together),
      supporting the view that there is an interaction between serotonin and ATP that
      reduces their effective concentration within the ghosts.

PMID- 8663307
TI  - Events in apoptosis. Acidification is downstream of protease activation and BCL-2
      protection.
AB  - Cytoplasmic acidification is now recognized as a feature of apoptosis in a
      variety of systems. However, its relation to other events in the process of
      apoptosis is not yet characterized. In this work, we examined the effect of BCL-2
      overexpression on acidification mediated by cycloheximide treatment or Fas
      ligation in Jurkat T-lymphoblasts. We find that BCL-2 overexpression attenuates
      cytoplasmic acidification and apoptosis detected by annexin V labeling.
      Acidification and phosphatidylserine externalization were found to occur
      concurrently. We also examined the requirement for protease activation for
      cytoplasmic acidification to occur and found that inhibition of interleukin-1beta
      converting enzyme/CED-3 family proteases (using carbobenzoxy-Val-Ala-Asp
      fluoromethylketone, an inhibitor of these proteases) prevents acidification and
      apoptosis mediated by Fas ligation. These studies suggest that BCL-2 acts at a
      point upstream of acidification and that protease activation is also upstream of
      acidification.

PMID- 8663308
TI  - Degradation of inositol 1,4,5-trisphosphate receptors during cell stimulation is
      a specific process mediated by cysteine protease activity.
AB  - Inositol 1,4,5-trisphosphate (InsP3) receptors are down-regulated in response to
      chronic activation of certain cell surface receptors because their degradation is
      accelerated. Studies on the nature of the down-regulatory process and the
      protease(s) responsible for receptor degradation are described here. InsP3
      receptor down-regulation was not accompanied by parallel changes in the
      concentrations of several other relevant proteins (endoplasmic reticulum Ca2+
      ATPase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and protein kinases
      alpha and epsilon). Thus, the down-regulatory process selectively targets InsP3
      receptors for degradation. Furthermore, down-regulation was unaffected by
      brefeldin A and NH4Cl, indicating that InsP3 receptor degradation occurs without
      removal of receptors from the endoplasmic reticulum and independently of
      functional lysosomes. Analysis of InsP3 receptor immunofluorescence confirmed
      that the receptors are not redistributed prior to or during down-regulation.
      Finally, of a range of protease inhibitors tested, only N-acetyl-Leu-Leu
      norleucinal blocked down-regulation. Thus, cysteine protease activity accounts
      for InsP3 receptor degradation and analysis of proteolysis in permeabilized cells
      indicates that this activity is calpain. Thus, InsP3 receptor down-regulation
      appears to result from the highly selective calpain-mediated degradation of InsP3
      receptors. Calpain activity may be stimulated by the high concentrations of Ca2+
      that are thought to be found in the vicinity of activated InsP3 receptors.

PMID- 8663309
TI  - The Pem homeobox gene. Androgen-dependent and -independent promoters and tissue
      specific alternative RNA splicing.
AB  - The Pem gene encodes an atypical homeodomain protein, distantly related to
      Prd/Pax family members, that we demonstrate is regulated in a complex
      transcriptional and post-transcriptional manner. We show that the rat Pem genomic
      structure includes three 5'-untranslated (5'-UT) exons and four coding exons,
      three of which encode the homeodomain. Several alternatively spliced transcripts
      were identified, including one that skips an internal coding exon, enabling this
      mRNA to express a novel form of the Pem protein. Other alternatively spliced
      mRNAs were characterized that possess different 5'-UT regions, including a muscle
      specific transcript. The different 5'-UT termini present in Pem transcripts
      conferred different levels of translatability in vitro. Two promoters containing
      multiple transcription initiation sites were identified: a distal promoter (Pd)
      in the first 5'-UT exon and a proximal promoter (Pp) located in the "intron"
      upstream of the first coding exon. The Pd was active in placenta, ovary, tumor
      cell lines, and to a lesser extent in skeletal muscle. In contrast, transcripts
      from the Pp were only detectable in testis and epididymis and were only expressed
      in epididymis in the presence of testosterone. To our knowledge no transcription
      factors have previously been identified that exhibit androgen-dependent
      expression in the epididymis.

PMID- 8663310
TI  - Expression of the serum response factor gene is regulated by serum response
      factor binding sites.
AB  - The serum response factor (SRF) is a ubiquitous transcription factor that plays a
      central role in the transcriptional response of mammalian cells to a variety of
      extracellular signals. Notably, SRF has been found to be a key regulator of
      members of a class of cellular response genes termed immediate-early genes
      (IEGs), many of which are believed to be involved in regulating cell growth and
      differentiation. The mechanism by which SRF activates transcription of IEGs in
      response to mitogenic agents has been extensively studied. Significantly less is
      known about how expression of the SRF gene itself is mediated. We and others have
      previously shown that the SRF gene is itself transiently induced by a variety of
      mitogenic agents and belongs to a class of "delayed" early response genes. We
      have cloned the SRF promoter and in the present study have analyzed the upstream
      regulatory sequences involved in mediating serum responsiveness of the SRF gene.
      Our analysis indicates that inducible SRF expression requires both SRF binding
      sites located within the first 63 nucleotides upstream from the start site of
      transcriptional initiation and an Sp1 site located 83 nucleotides upstream from
      the start site. Maximal transcriptional activity of the promoter also requires
      two CCAATT box sites located 90 and 123 nucleotides upstream of the start site.

PMID- 8663311
TI  - Molecular characterization of a putative K-Cl cotransporter in rat brain. A
      neuronal-specific isoform.
AB  - Using a combination of data base searching, polymerase chain reaction, and
      library screening, we have identified a putative K-Cl cotransporter isoform
      (KCC2) in rat brain that is specifically localized in neurons. A cDNA of 5566
      bases was obtained from overlapping clones and encoded a protein of 1116 amino
      acids with a deduced molecular mass of 123.6 kDa. Over its full length, the amino
      acid sequence of KCC2 is 67% identical to the widely distributed K-Cl
      cotransporter isoform (KCC1) identified in rat brain and rabbit kidney (Gillen,
      C., Brill, S., Payne, J.A., and Forbush, B., III(1996) J. Biol. Chem. 271, 16237
      16244) but only approximately25% identical to other members of the cation
      chloride cotransporter gene family, including "loop" diuretic-sensitive Na-K-Cl
      cotransport and thiazide-sensitive Na-Cl cotransport. Based on analysis of the
      primary structure as well as homology with other cation-chloride cotransporters,
      we predict 12 transmembrane segments bounded by N- and C-terminal cytoplasmic
      regions. Four sites for N-linked glycosylation are predicted on an extracellular
      intermembrane loop between putative transmembrane segments 5 and 6. Northern blot
      analysis using a KCC2-specific cDNA probe revealed a very highly expressed
      approximately5.6-kilobase transcript only in brain. Reverse transcriptase
      polymerase chain reaction revealed that KCC1 was present in rat primary
      astrocytes and rat C6 glioma cells but that KCC2 was completely absent from these
      cells, suggesting KCC2 was not of glial cell origin. In situ hybridization
      studies demonstrated that the KCC2 transcript was expressed at high levels in
      neurons throughout the central nervous system, including CA1-CA4 pyramidal
      neurons of the hippocampus, granular cells and Purkinje neurons of the
      cerebellum, and many groups of neurons throughout the brainstem.

PMID- 8663312
TI  - Membrane topology and retention of microsomal aldehyde dehydrogenase in the
      endoplasmic reticulum.
AB  - Microsomal aldehyde dehydrogenase (msALDH) is anchored to the endoplasmic
      reticulum (ER) membrane by the hydrophobic domain at its carboxyl terminus, and
      most of the molecule is exposed to the cytoplasm (Masaki, R., Yamamoto, A., and
      Tashiro, Y.(1994) J. Cell Biol. 126, 1407-1420). To determine the membrane
      topology and the intracellular localization of msALDH, the amino-terminal region
      of bovine opsin containing N-glycosylation sites was fused to the carboxyl
      terminus of msALDH, and three chimeric proteins with extensions of different
      sizes were expressed in COS cells. Indirect immunofluorescence microscopy showed
      the ER localization of all of the chimeric proteins similar to wild-type msALDH.
      Immunoblotting revealed that the two chimeric proteins containing longer
      extensions, those with the N-glycosylation site at distances of 13 and 21 amino
      acids from the membrane anchor, respectively, were glycosylated. These results
      indicate that the membrane binding domain of msALDH spans the bilayer of the ER.
      The carbohydrate chain of the chimeras was sensitive to endoglycosidase H but
      resistant to endoglycosidase D. Upon treatment of transfected COS cells with
      brefeldin A, the carbohydrate chain was processed to an endoglycosidase H
      resistant form, presumably by cis/medial Golgi-specific enzymes redistributed in
      the ER. These biochemical results in addition to immunofluorescence microscopic
      observations suggest that msALDH is retained in the ER by blockading of the exit
      from the ER.

PMID- 8663313
TI  - Cloning, characterization, and modeling of mouse and human guanylate kinases.
AB  - Guanylate kinase catalyzes the phosphorylation of either GMP to GDP or dGMP to
      dGDP and is an essential enzyme in nucleotide metabolism pathways. Despite its
      involvement in antiviral drug activation in humans and in mouse model systems and
      as a target for chemotherapy, the human and mouse primary structures have never
      been elucidated. Full-length cDNA clones encoding enzymatically active guanylate
      kinase were isolated from mouse B-cell lymphoma and human peripheral blood
      lymphocyte cDNA libraries. Multiple tissue Northern blots demonstrated an mRNA
      species of approximately 1 kilobase for both mice and humans in all tissue types
      examined. The mouse cDNA is predicted to encode a 198-amino acid protein with a
      molecular mass of 21,904 daltons. The human cDNA is predicted to encode a 197
      amino acid protein with a molecular mass of 21,696 daltons. These proteins share
      88% sequence identity with each other and 52-54% identity with the yeast
      guanylate kinase. Molecular modeling using the yeast diffraction coordinates
      indicates a high degree of conservation within the active site and maintenance of
      the overall structural integrity, despite a lack of similarity along the
      periphery of the enzyme.

PMID- 8663314
TI  - Molecular cloning and functional characterization of a novel human CC chemokine
      receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha.
AB  - Chemokines affect leukocyte chemotactic and activation activities through
      specific G protein-coupled receptors. In an effort to map the closely linked CC
      chemokine receptor genes, we identified a novel chemokine receptor encoded 18
      kilobase pairs downstream of the monocyte chemoattractant protein-1 (MCP-1)
      receptor (CCR2) gene on human chromosome 3p21. The deduced amino acid sequence of
      this novel receptor, designated CCR5, is most similar to CCR2B, sharing 71%
      identical residues. Transfected cells expressing the receptor bind RANTES
      (regulated on activation normal T cell expressed), MIP-1beta, and MIP-1alpha with
      high affinity and generate inositol phosphates in response to these chemokines.
      This same combination of chemokines has recently been shown to potently inhibit
      human immunodeficiency virus replication in human peripheral blood leukocytes
      (Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., and
      Lusso, P.(1995) Science 270, 1811-1815). CCR5 is expressed in lymphoid organs
      such as thymus and spleen, as well as in peripheral blood leukocytes, including
      macrophages and T cells, and is the first example of a human chemokine receptor
      that signals in response to MIP-1beta.

PMID- 8663315
TI  - Analysis of the signaling pathway involved in the regulation of hexokinase II
      gene transcription by insulin.
AB  - The hexokinases, by converting glucose to glucose 6-phosphate, help maintain the
      glucose concentration gradient that results in the movement of glucose into cells
      through the facilitative glucose transporters. Hexokinase II (HKII) is the major
      hexokinase isoform in skeletal muscle, heart, and adipose tissue. Insulin induces
      HKII gene transcription in L6 myotubes, and this, in turn, increases HKII mRNA
      and the rates of HKII protein synthesis and glucose phosphorylation in these
      cells. Inhibitors of distinct insulin signaling pathways were used to dissect the
      molecular mechanism by which HKII gene expression is induced by insulin in L6
      myotubes. Treatment with wortmannin, an inhibitor of phosphatidylinositol 3
      kinase (PI 3-kinase), or with rapamycin, an inhibitor of the pathway from the
      insulin receptor to p70/p85 ribosomal S6 protein kinase (p70(s6k)), prevented the
      induction of HKII mRNA by insulin. In contrast, treatment with PD98059, an
      inhibitor of mitogen-activated protein kinase activation, had no effect on
      insulin-induced HKII mRNA. In addition, rapamycin blocked the insulin-induced
      expression of an HKII promoter-chloramphenicol acetyltransferase fusion gene
      transiently transfected into L6 myotubes, whereas PD98059 had no such effect.
      These results suggest that a phosphatidylinositol 3-kinase/p70(s6k)-dependent
      pathway is required for regulation of HKII gene transcription by insulin and that
      the Ras-mitogen-activated protein kinase-dependent pathway is probably not
      involved.

PMID- 8663316
TI  - Identification of an element crucial for the sub-synaptic expression of the
      acetylcholine receptor epsilon-subunit gene.
AB  - The adult neuromuscular junction displays an accumulation of both the
      acetylcholine receptor (AChR) protein in the subneural domain of the post
      synaptic membrane and the mRNAs coding for all its subunits at the level of the
      subjunctional "fundamental nuclei." In the course of end plate development, the
      epsilon-subunit, at variance with other subunits, becomes exclusively expressed
      at the level of the fundamental nuclei, yet at a rather late stage (around
      birth). To analyze the promoter region of the epsilon-subunit gene which directs
      its specific expression at the synapse, we used a quantitative transient in vivo
      expression assay in intact muscle tissue using constructs of the epsilon-subunit
      promoter placed upstream of the beta-galactosidase reporter gene. One crucial
      element for synapse-specific expression was detected between the -11 and -6
      positions. Disruption of this element, either by a scanning mutation or single
      base mutations, greatly diminishes, or even completely inhibits, preferential
      expression of the transgene at the end plate. Gel shift experiments reveal the
      presence of a complex in nuclear muscle extracts that bind the core sequence of
      this element. The identification of such a site opens the possibility to identify
      regulatory factors responsible for compartmentalized expression at the
      neuromuscular junction.

PMID- 8663317
TI  - Calmodulin-dependent protein kinase II potentiates transcriptional activation
      through activating transcription factor 1 but not cAMP response element-binding
      protein.
AB  - Activating transcription factor 1 (ATF1) and the cAMP response element-binding
      protein (CREB) are members of the CREB/ATF family implicated in cAMP- and calcium
      induced transcriptional activation. Although ATF1 and CREB share extensive
      homology, the function of ATF1 is poorly understood. Its phosphorylation state
      and activation by Ca2+- and calmodulin-dependent protein kinase (CaMK) II were
      therefore examined. Phosphopeptide mapping analysis and Western blotting studies
      demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to
      Ser133 of CREB), which is essential for the activation, and not Ser72
      (corresponding to Ser142 of CREB), which is a negative regulation site. Both ATF1
      and CREB bound CBP in a phosphorylation-dependent manner. As expected from these
      in vitro studies, transient transfection studies revealed that ATF1 is activated
      by CaMK II. Our findings suggest that CaMK II mediates transactivation of cAMP
      responsive genes via ATF1.

PMID- 8663318
TI  - Proteasome subunits X and Y alter peptidase activities in opposite ways to the
      interferon-gamma-induced subunits LMP2 and LMP7.
AB  - Most antigenic peptides presented on major histocompatibility complex class I
      molecules are generated by proteasomes. Interferon-gamma, which stimulates
      antigen presentation, induces new proteasome beta-subunits LMP2 and LMP7, which
      replace the homologous beta-subunits Y (delta) and X (epsilon). As a result, the
      capacity of the proteasome to cleave model peptides increases after hydrophobic
      and basic residues and falls after acidic residues. To clarify the function of
      these subunits, we examined the effects of overexpressing subunits X (delta) and
      Y (epsilon). Transfection of the Y gene into HeLa cells stimulated the
      proteasomal cleavage after acidic residues without altering other peptidase
      activities. This effect was proportional to the amount of the Y subunits and
      opposite to the effect of its homolog, LMP2. Y appears to promote cleavages after
      acidic residues. Furthermore, in mutants lacking the LMP genes (in contrast to
      wild-type cells), interferon-gamma treatment increased the proteasome content of
      Y subunits and enhanced postacidic cleavages. Transfection with cDNA for the X
      subunit reduced hydrolysis after hydrophobic and basic residues, an effect
      opposite to transfection of LMP2 and LMP7. Surprisingly, transfection of X
      increased the amounts not only of X, but also of Y, while decreasing LMP2
      content. Thus, the loss of the Y subunit upon interferon-gamma treatment or LMP2
      transfection accounts for the suppression of postacidic cleavages, and the loss
      of X contributes to the increased hydrolysis after hydrophobic and basic
      residues. These adaptations should favor the production of the kinds of peptides
      that are presented on major histocompatibility complex class I molecules.

PMID- 8663319
TI  - Extensive sequencing of tryptic peptides of a rabbit reticulocyte 66-kDa protein
      that promotes recycling of Hsp 70. Homology To stress-related proteins.
AB  - Trypsinization and sequence analysis of the 66-kDa rabbit reticulocyte protein
      (RF-hsp 70), shown in the preceding article to function as a recycling protein
      for hsp 70, demonstrates striking similarity to the transformation-sensitive
      human protein IEF SSP 3521 (Honore, B., Leffers, H., Madsen, P., Rasmussen, H.
      H., Vandekerckhove, J., and Celis, J. E.(1992) J. Biol. Chem. 267, 8485-8491) and
      mouse extendin (Blatch, G. L., Lassle, M., Takatori, T., Gandhi, T., Kundra, V.,
      and Zetter, B. R.(1995) Proc. Am. Assoc. Cancer Res. 36, 68). The human and mouse
      proteins share 97% sequence identity, and sequencing of 20 polypeptides (225
      residues) from RF-hsp 70 reveals only 10 differences between the rabbit and human
      proteins and 13 differences between the rabbit and mouse proteins (96 and 94%
      identity, respectively). In addition, all three proteins are of similar size, and
      each contains 11 cysteines. These findings strongly suggest that these three
      proteins are homologs of the same activity. All differences (but one) between the
      human and mouse proteins occur within the amino-terminal half of the protein, and
      there is only one difference among 121 sequenced residues between RF-hsp 70 and
      the human or mouse protein which occurs within the carboxyl-terminal 70% of the
      molecule. In addition, where partial sequences of RF-hsp 70 and p60, a chick
      oviduct protein that shows 70% identity to the human protein (Smith, D. F.,
      Sullivan, W. P., Marion, T. N., Zaitsu, K., Madden, B., McCormick, D. J., and
      Toft, D. O. (1993) Mol. Cell. Biol. 13, 869-876), overlap (a total of 54
      residues), RF-hsp 70 and chick p60 show 78% sequence identity. Studies of the
      initial digestion of RF-hsp 70 by trypsin indicate that it is first converted to
      58- and 54-kDa components, each of which is then converted to a 43-kDa
      polypeptide. This 43-kDa component is located in the human and mouse proteins at
      position 124 to about 470. It is converted subsequently to a 31-kDa polypeptide
      by trypsin hydrolysis at position 207. This 31-kDa component is finally split
      into 17- and 14-kDa polypeptides that are located at positions 208 to
      approximately 351 and 352 to approximately 470, respectively. The 14-kDa
      polypeptide is relatively resistant to further digestion with trypsin, and seven
      tryptic peptides from other parts of RF-hsp 70 contain internal lysine and/or
      arginine residues (as do several tryptic peptides produced from IEF SSP 3521 and
      chick p60). Both features may be due to interference with trypsin action by
      secondary structure in the protein, since trypsinization of reduced and
      carboxymethylated RF-hsp 70 results in hydrolysis of the 14-kDa polypeptide and
      reduces the level of peptides that contain internal lysine and/or arginine,
      although it does not eliminate them.

PMID- 8663320
TI  - Purification and characterization of a 66-kDa protein from rabbit reticulocyte
      lysate which promotes the recycling of hsp 70.
AB  - We have purified to apparent homogeneity a 66-kDa protein from rabbit
      reticulocyte lysate which is associated with hsp 70. Our characterization of this
      66-kDa protein demonstrates that its physiological role is to promote the
      recycling of hsp 70 by catalyzing the dissociation of hsp 70-bound ADP in
      exchange for ATP. We have therefore termed the 66-kDa protein RF-hsp 70, a
      recycling factor for hsp 70. RF-hsp 70 promotes stoichiometric binding of ATP to
      hsp 70, and it increases about 5-fold the rate of dissociation of hsp 70.ADP in
      the presence of ATP. This process represents adenine nucleotide exchange, since
      dissociation of ADP does not occur unless ATP is added; dATP, GTP, and ITP cannot
      substitute for ATP. The mechanism of action of RF-hsp 70 is to lower the KD of
      hsp 70 for ATP about 6-7-fold to a value that is close to the KDof hsp 70 for
      ADP. RF-hsp 70 also stimulates the ATPase activity of hsp 70, including the 42
      kDa amino-terminal portion of hsp 70 generated by chymotrypsin, demonstrating
      that RF-hsp 70 interacts with that part of hsp 70 known to contain the ATP/ADP
      binding site. Confirming its recycling function, RF-hsp 70 stimulates about 7-10
      fold the ability of hsp 70 to reactivate heat-denatured firefly luciferase. In
      addition, RF-hsp 70 acts catalytically to recycle hsp 70, since, at 0.2 times the
      molar concentration of hsp 70, RF-hsp 70 increases the rate of renaturation of
      luciferase by hsp 70 about 3-4-fold. The action of RF-hsp 70 is also partially
      species-specific since it is most effective with rabbit reticulocyte hsp 70, less
      effective with bovine brain hsp 70, even less effective with human hsp 70, and
      ineffective with broad bean hsp 70.

PMID- 8663321
TI  - Functionally heterogenous ryanodine receptors in avian cerebellum.
AB  - The functional heterogeneity of the ryanodine receptor (RyR) channels in avian
      cerebellum was defined. Heavy endoplasmic reticulum microsomes had significant
      levels of ryanodine and inositol 1,4,5-trisphosphate binding. Scatchard analysis
      and kinetic studies indicated the existence of at least two distinct ryanodine
      binding sites. Ryanodine binding was calcium-dependent but was not significantly
      enhanced by caffeine. Incorporation of microsomes into planar lipid bilayers
      revealed ion channels with pharmacological features (calcium, magnesium, ATP, and
      caffeine sensitivity) similar to the RyR channels found in mammalian striated
      muscle. Despite a wide range of unitary conductances (220-500 picosiemens,
      symmetrical cesium methanesulfonate), ryanodine locked both channels into a
      characteristic slow gating subconductance state, positively identifying them as
      RyR channels. Two populations of avian RyR channels were functionally
      distinguished by single channel calcium sensitivity. One population was defined
      by a bell-shaped calcium sensitivity analogous to the skeletal muscle RyR isoform
      (type I). The calcium sensitivity of the second RyR population was sigmoidal and
      analogous to the cardiac muscle RyR isoform (type II). These data show that there
      are at least two functionally distinct RyR channel populations in avian
      cerebellum. This leads to the possibility that these functionally distinct RyR
      channels are involved in different intracellular calcium signaling pathways.

PMID- 8663322
TI  - Controlling substrate preference and transglycosylation activity of
      neopullulanase by manipulating steric constraint and hydrophobicity in active
      center.
AB  - The substrate specificity and the transglycosylation activity of neopullulanase
      was altered by site-directed mutagenesis on the basis of information from a three
      dimensional structure predicted by computer-aided molecular modeling. According
      to the predicted three-dimensional structure of the enzyme-substrate complex, it
      was most likely that Ile-358 affected the substrate preference of the enzyme.
      Replacing Ile-358 with Trp, which has a bulky side chain, reduced the
      acceptability of alpha-(1-->6)-branched oligo- and polysaccharides as substrates.
      The characteristics of the I358W-mutated enzyme were quite different from those
      of wild-type neopullulanase and rather similar to those of typical starch
      saccharifying alpha-amylase. In contrast, replacing Ile-358 with Val, which has a
      smaller side chain, increased the preference for alpha-(1-->6)-branched
      oligosaccharides and pullulan as substrates. The transglycosylation activity of
      neopullulanase appeared to be controlled by manipulating the hydrophobicity
      around the attacking water molecule, which is most likely used to cleave the
      glucosidic linkage in the hydrolysis reaction. We predicted three residues, Tyr
      377, Met-375, and Ser-422, which were located on the entrance path of the water
      molecule might be involved. The transglycosylation activity of neopullulanase was
      increased by replacing one of the three residues with more hydrophobic amino acid
      residues; Y377F, M375L, and S422V. In contrast, the transglycosylation activity
      of the enzyme was decreased by replacing Tyr-377 with hydrophilic amino acid
      residues, Asp or Ser.

PMID- 8663323
TI  - Isolation and characterization of an avian slow myosin heavy chain gene expressed
      during embryonic skeletal muscle fiber formation.
AB  - We have isolated and begun characterization of the quail slow myosin heavy chain
      (MyHC) 3 gene, the first reported avian slow MyHC gene. Expression of slow MyHC 3
      in skeletal muscle is restricted to the embryonic period of development, when the
      fiber pattern of future fast and slow muscle is established. In embryonic
      hindlimb development, slow MyHC 3 gene expression coincides with slow muscle
      fiber formation as distinguished by slow MyHC-specific antibody staining. In
      addition to expression in embryonic appendicular muscle, slow MyHC 3 is expressed
      continuously in the atria. Transfection of slow MyHC 3 promoter-reporter
      constructs into embryonic myoblasts that form slow MyHC-expressing fibers
      identified two regions regulating expression of this gene in skeletal muscle. The
      proximal promoter, containing potential muscle-specific regulatory motifs,
      permits expression of a reporter gene in embryonic slow muscle fibers, while a
      distal element, located greater than 2600 base pairs upstream, further enhances
      expression 3-fold. The slow muscle fiber-restricted expression of slow MyHC 3
      during embryonic development, and expression of slow MyHC 3 promoter-reporter
      constructs in embryonic muscle fibers in vitro, makes this gene a useful marker
      to study the mechanism establishing the slow fiber lineage in the embryo.

PMID- 8663324
TI  - Characterization of dual leucine zipper-bearing kinase, a mixed lineage kinase
      present in synaptic terminals whose phosphorylation state is regulated by
      membrane depolarization via calcineurin.
AB  - The biochemistry and regulation of dual leucine zipper bearing kinase (DLK), a
      member of the mixed lineage kinase or MLK subfamily of protein kinases, was
      examined in the nervous system. DLK transcript expression in the nervous system
      was predominantly neuronal. DLK protein was present in synaptic terminals where
      it was associated with both plasma membrane and cytosol fractions. Within these
      two fractions, DLK had differing characteristics. Cytosolic DLK existed in both a
      phosphorylated and dephosphorylated state; DLK associated with plasma membrane
      existed in the dephosphorylated state only. On nonreducing SDS-polyacrylamide gel
      electrophoresis, cytosolic DLK migrated at 130 kDa, while membrane associated DLK
      migrated with an apparent Mr >/= 260,000. Similarly, DLK transiently expressed in
      COS 7 cells autophosphorylated in vivo and migrated at approximately 260 kDa when
      separated by nonreducing SDS-polyacrylamide gel electrophoresis. In
      cotransfection experiments, FLAG-tagged DLK or a FLAG-tagged truncated DLK mutant
      (F-Delta520) was coimmunoprecipitated with Myc-tagged DLK and formed complexes
      under nonreducing conditions consistent with the conclusion that DLK formed
      covalently associated homodimers in overexpressing COS 7 cells. In aggregating
      neuronal-glial cultures, depolarization of plasma membrane lead to
      dephosphorylation of DLK. Treatment of aggregates with 5 nM or 200 nM okadaic
      acid lead to a shift in electrophoretic mobility consistent with phosphorylation
      of DLK. Treatment with cyclosporin A, a specific inhibitor of the
      calcium/calmodulin-dependent protein phosphatase 2B (calcineurin), had no effect
      on DLK phosphorylation under basal conditions. However, cyclosporin A completely
      inhibited DLK dephosphorylation upon membrane depolarization.

PMID- 8663325
TI  - Mutation detection in the med and medJ alleles of the sodium channel Scn8a.
      Unusual splicing due to a minor class AT-AC intron.
AB  - Analysis of a transgene-induced mutation at the mouse med locus led to the
      identification of the novel voltage-gated sodium channel gene Scn8a (Burgess, D.
      L., Kohrman, D. C., Galt, J., Plummer, N. W., Jones, J. M., Spear, B., and
      Meisler, M. H.(1995) Nat. Genet. 10, 461-465). We now report the identification
      of splicing defects in two spontaneous mutations of Scn8a. The original med
      mutation was caused by insertion of a truncated LINE element into exon 2 of
      Scn8a. The med transcript is spliced from exon 1 to a cryptic acceptor site in
      intron 2. A 4-base pair deletion within the 5' donor site of exon 3 in the medJ
      allele results in splicing from exon 1 to exon 4. Both mutant transcripts have
      altered reading frames with premature stop codons close to the N terminus of the
      protein. Loss of Scn8a expression results in progressive paralysis and early
      death. Intron 2 of Scn8a is flanked by minor class AT-AC splice sites. The
      observed splicing patterns of the med and medJ mutant transcripts provide the
      first evidence for preferential in vivo splicing between donor and acceptor sites
      of the same class. The apparent functional incompatibility may be a consequence
      of the different composition of spliceosomes bound to major and minor splice
      sites.

PMID- 8663326
TI  - Genetic evidence for interdomain regulation of the phenol-responsive final
      sigma54-dependent activator DmpR.
AB  - The final sigma54-dependent DmpR activator regulates transcription of the dmp
      operon that encodes the enzymes for catabolism of (methyl)phenols. DmpR is
      expressed constitutively, but its transcriptional promoting activity is
      controlled positively in direct response to the presence of aromatic pathway
      substrates (effectors). DmpR has a distinct domain structure with the amino
      terminal A-domain controlling the specificity of activation of the regulator by
      aromatic effectors (signal reception), a central C-domain mediating an ATPase
      activity essential for transcriptional activation, and a carboxyl-terminal D
      domain involved in DNA binding. Deletion of the A-domain has been shown
      previously to result in an effector-independent transcriptional activator with
      constitutive ATPase activity. These results, in conjunction with the location of
      mutations within the A- and C-domains which exhibit an effector-independent
      (semiconstitutive) property, have led to a working model in which the A-domain
      serves to mask the ATPase and transcriptional promoting activity of the C-domain
      in the absence of effectors. To investigate the mechanism by which the A-domain
      exerts its repressive effect, we developed a genetic system to select positively
      for intramolecular second site revertants of DmpR. The results demonstrate (i)
      that mutations within the A-domain can suppress the semiconstitutive activity of
      C-domain located mutations and vice versa; (ii) that the C-domain located
      mutations do not influence the intrinsic ATPase and transcriptional promoting
      property of the C-domain in the absence of the A-domain; and (iii) that
      semiconstitutive mutations of the A- and C-domain have an additive effect. Taken
      together these results support a model in which the A-domain represses the
      function(s) of the C-domain by direct interactions between residues of the two
      domains.

PMID- 8663327
TI  - Tumor necrosis factor alpha promotes nuclear localization of cytokine-inducible
      CCAAT/enhancer binding protein isoforms in hepatocytes.
AB  - Hepatocytes were cultured in the presence of recombinant tumor necrosis factor
      (TNF) alpha or mutated TNF alpha peptides that specifically activate either p55
      or p75 TNF receptors to determine if TNF alpha can activate cytokine-inducible
      CCAAT/enhancer binding protein (C/EBP) isoforms by post-transcriptional
      mechanisms that are initiated by TNF receptors. Within 5-10 min after treatment
      with any of these agents, nuclear concentrations of C/EBP beta and C/EBP delta
      double and remain 2-4-fold greater than control cultures for 30 min (p < 0.01).
      Consistent with these results, gel mobility shift assays demonstrate 3-fold
      increased nuclear C/EBP beta- and C/EBP delta-DNA binding activity in TNF alpha
      treated cells, and immunocytochemistry confirms rapid redistribution of these
      C/EBP isoforms into the nucleus. In contrast, mRNA and whole cell protein
      concentrations of C/EBP beta and delta are not altered by TNF alpha exposure, and
      nuclear concentrations of another C/EBP isoform, C/EBP alpha, are decreased by
      80%. This novel evidence that TNF alpha initiates post-transcriptional activation
      of cytokine-inducible C/EBP isoforms identifies a mechanism that enables
      hepatocytes to respond immediately to inflammatory stress.

PMID- 8663328
TI  - The Src SH3 domain is required for DNA synthesis induced by platelet-derived
      growth factor and epidermal growth factor.
AB  - The Src family of protein tyrosine kinases has been implicated in the response of
      cells to platelet-derived growth factor (PDGF) or epidermal growth factor (EGF).
      We recently described a microinjection approach that we used to demonstrate that
      kinase activity of Src family members is required for PDGF- and EGF-induced S
      phase entry of fibroblasts. We have now used this approach to ask whether a
      functional SH3 domain of Src is required to transduce the mitogenic signal upon
      PDGF or EGF stimulation. Microinjection of plasmids encoding Src mutants lacking
      the SH3 domain (SrcDeltaSH3) or point-mutated within the ligand binding surface
      of the SH3 domain, but with intact kinase domains, inhibited the mitogenic effect
      of PDGF and EGF in fibroblasts. SrcDeltaSH3 could still associate with the PDGF
      receptor, suggesting that the inhibitory effect of the Src SH3 mutants was
      brought about by a failure of the PDGF receptor.SrcDeltaSH3 complex to relay the
      mitogenic signal further downstream. Chimeric molecules in which the Src SH3
      domain was replaced with that of spectrin or Lck also blocked PDGF-induced DNA
      synthesis, whereas a chimera containing the Fyn SH3 domain did not. These data
      suggest that the Src or Fyn SH3 domain is required either for correct substrate
      selection or to recruit other proteins to the PDGF receptor.

PMID- 8663329
TI  - Requirement for c-Src catalytic activity and the SH3 domain in platelet-derived
      growth factor BB and epidermal growth factor mitogenic signaling.
AB  - The Src family protein-tyrosine kinases are required for mitogenic signaling from
      the platelet-derived growth factor (PDGF), colony stimulating factor-1, and
      epidermal growth factor (EGF) receptor protein-tyrosine kinases (RPTK) (Twamley
      Stein, G. M., Pepperkok, R., Ansorge, W., and Courtneidge, S. A. (1993) Proc.
      Natl. Acad. Sci. U. S. A. 90, 7696-7700; Roche, S., Koegl, M., Barone, M. V.,
      Roussel, M. F., and Courtneidge, S. A.(1995) Mol. Cell. Biol. 15, 1102-1109). In
      NIH3T3 fibroblasts, c-Src, Fyn, and c-Yes associate with the activated PDGF
      receptor, are substrates for receptor phosphorylation, and are themselves
      activated. Src family catalytic function is required for RPTK mitogenic signaling
      as evidenced by the SH2-dependent dominant negative phenotype exhibited by kinase
      inactive Src and Fyn mutants (Twamley-Stein, G. M., Pepperkok, R., Ansorge, W.,
      and Courtneidge, S. A.(1993) Proc. Natl. Acad. Sci. U. S. A. 90, 7696-7700).
      Here, we have generated clonal Src- murine fibroblast cell lines overexpressing
      various murine c-Src mutants and studied the effect of these mutant Src proteins
      on PDGF- and EGF-induced mitogenesis. Two c-Src SH3 domain mutants, Y133F and
      Y138F, each inhibited PDGF BB- and EGF-induced DNA synthesis in quiescent cells.
      This demonstrates an involvement of the Src SH3 domain in PDGFbeta and EGF
      receptor mitogenic signaling. Since both Tyr-133 and Tyr-138 are located on the
      ligand binding surface of the SH3 domain, these results suggest that the c-Src
      SH3 domain is required for PDGF and EGF mitogenic signaling. The dominant
      negative effect of either single mutant on PDGF receptor signaling was reversed
      by a second SH2-inactivating mutation. We conclude that the c-Src SH3 domain
      function requires the SH2 domain in the case of the PDGF receptor, presumably
      because binding of c-Src to the receptor via its SH2 domain is a prerequisite for
      the SH3 domain function. In contrast, SH2 function is apparently not essential
      for the SH3 function in EGF receptor signaling.

PMID- 8663330
TI  - Functional studies and polymerization of recombinant hemoglobin Glu
      alpha2beta26(A3) --> Val/Glu-7(A4) --> Ala.
AB  - In hemoglobin (Hb) S the hydrophobic mutated residue Val-beta6(A3) (donor site)
      closely interacts with the hydrophobic side groups of Phe-beta85(F1) and Leu
      beta88(F4) (EF pocket, acceptor site) of a neighboring tetramer, resulting in
      decreased solubility and polymerization of the deoxy-Hb. The beta6(A3) residue is
      followed by two charged residues Glu-beta7(A4) and Lys-beta8(A5). This cluster
      has no attraction for the hydrophobic EF pocket. We have modified the beta7(A4)
      residue next to the donor site Val-beta6(A3), replacing the charged Glu by a
      hydrophobic Ala-(rHb betaE6V/E7A). The single mutant Glu-beta7 --> Ala-(rHb
      betaE7A) was also engineered. Both rHbs exhibit a heat instability and an
      increased oxygen affinity compared to Hb A and Hb S. There was a concentration
      dependence of the ligand binding properties (1-300 microM in heme) indicating an
      increased amount of dimers relative to Hb A. The deoxy form of rHb betaE6V/E7A
      polymerizes in vitro, with a decreased rate of polymer formation relative to Hb
      S, while the single mutant betaE7A does not polymerize in the same experimental
      conditions. The Glu-beta7(A4) --> Ala substitution does not increase the
      hydrophobic interaction between donor and acceptor site. We speculate that the
      loss of the normal saline bridge between Glu-beta7(A4) and Lys-beta132(H10) leads
      to an increased flexibility of the A helix and may account for the difference of
      the polymerization for this Hb S mutant.

PMID- 8663331
TI  - Extracellular signal-regulated kinase and the small GTP-binding protein, Rac,
      contribute to the effects of transforming growth factor-beta1 on gene expression.
AB  - The kinases and regulatory proteins that convey signals initiated by transforming
      growth factor-beta (TGF-beta) to the nucleus are poorly characterized. To study
      the role of the extracellular signal-regulated kinase (ERK) pathway in this
      process, we transiently transfected NIH 3T3 fibroblasts with TGF-beta-responsive
      luciferase reporter genes and expression vectors designed to interrupt this
      kinase cascade. Mitogen-activated protein (MAP) kinase phosphatase-1 and a
      dominant negative MAP/ERK kinase 1 mutant reduced stimulation of plasminogen
      activator inhibitor-1 (PAI-1) promoter activity by TGF-beta1 from 11.5- to 4-fold
      and 4.9-fold, respectively. Similar results were observed with the type I
      collagen promoters. TGF-beta1 increased ERK1 activity 4.5-fold at 5 min and 3. 1
      fold at 3 h, while Jun kinase and p38 activity were not affected. Cotransfection
      of a dominant negative mutant of the small G protein, Rac, but not dominant
      negative Ras, Cdc42, or Rho mutants, reduced the effects of TGF-beta1 on the PAI
      1 promoter by approximately half. In support of a role for Rac in signaling by
      TGF-beta, GTP binding to Rac was increased 3.7-fold following exposure of NIH 3T3
      cells to TGF-beta1 for 3 min. These findings indicate that TGF-beta1 modulates
      gene expression partly through ERK and Rac in NIH 3T3 cells.

PMID- 8663332
TI  - The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves
      the propeptide of progelatinase A and initiates autoproteolytic activation.
      Regulation by TIMP-2 and TIMP-3.
AB  - It has been proposed that the cell-mediated activation of progelatinase A
      requires binding of the C-terminal domain of the proenzyme to a membrane
      associated complex of the membrane type matrix metalloproteinase MT1-MMP and TIMP
      2. Subsequent sequential proteolysis of the propeptide by MT1-MMP and gelatinase
      A is thought to generate the active form of gelatinase A. We have prepared the
      proform of the catalytic domain of the MT1-MMP and demonstrated that this may be
      activated in vitro by trypsin proteolysis to yield a functional proteinase
      capable of cleaving typical metalloproteinase peptide substrates, gelatin and
      casein. The active catalytic domain of MT1-MMP was also shown to activate
      progelatinase A to a fully active form. Using the inactive mutant pro-E375A
      gelatinase A, we dissected the propeptide processing events that occur. MT1-MMP
      cleaves the propeptide at the sequence Asn37-Leu38 only. Further cleavage of the
      mutant enzyme propeptide at Asn80-Tyr81, equivalent to that of the active wild
      type gelatinase A, could only be effected by addition of gelatinase A to the
      system. TIMP-1 was essentially unable to prevent MT1-MMP processing of wild type
      or E375A progelatinase A, whereas TIMP-2 and TIMP-3 were good inhibitors of these
      events. Analysis of the rate of binding of TIMPs to the catalytic domain of MT1
      MMP using kinetic methods showed that TIMP-1 is an extremely poor inhibitor of
      MT1-MMP. In comparison, TIMP-2 and TIMP-3 are excellent inhibitors, binding more
      rapidly to the catalytic domain of MT1-MMP than to the catalytic domain of
      gelatinase A. These data demonstrate the basic mechanism of MT1-MMP action on
      progelatinase A and the reason for the lack of inhibition by TIMP-1 previously
      demonstrated in cell-based activation studies.

PMID- 8663333
TI  - Assembly of the human neutrophil NADPH oxidase involves binding of p67phox and
      flavocytochrome b to a common functional domain in p47phox.
AB  - The human neutrophil NADPH oxidase is a multi-component complex composed of
      membrane-bound and cytosolic proteins. During activation, cytosolic proteins
      p47(phox), p67(phox), Rac2, and possibly p40(phox) translocate to the plasma
      membrane and associate with flavocytochrome b to form the active superoxide
      generating system. To further investigate the role of p67(phox) in this complex
      assembly process, experiments were performed to identify possible regions of
      interaction between p67(phox) and other NADPH oxidase proteins. Using random
      sequence peptide phage-display library analysis of p67(phox), we identified a
      novel region in p47(phox) encompassing residues 323-332 and a previously
      identified SH3 binding domain encompassing p47(phox) residues 361-370 as
      p67(phox) binding sites. Synthetic peptides mimicking p47(phox) residues 323-332
      inhibited the p47(phox)-p67(phox) binding interaction in an affinity binding
      assay; however, peptides mimicking flanking regions were inactive. Surprisingly,
      this same region of p47(phox) was found previously to represent a site of binding
      interaction for flavocytochrome b (DeLeo, F. R., Nauseef, W. M., Jesaitis, A. J.,
      Burritt, J. B., Clark, R. A., and Quinn, M. T.(1995) J. Biol. Chem. 270, 26246
      26251), and this observation was confirmed in the present report using two
      different in vitro assays that were not evaluated previously. Using affinity
      binding assays, we also found that p67(phox) and flavocytochrome b competed for
      binding to p47(phox)after activation, suggesting that prior to full NADPH oxidase
      assembly the 323-332 region of p47(phox) is associated with p67(phox) and at some
      point in the activation process is transferred to flavocytochrome b. Thus, taken
      together our data demonstrate that both p67(phox) and flavocytochrome b utilize a
      common binding site in p47(phox), presumably at distinct stages during the
      activation process, and this p47(phox) region plays a key role in regulating
      NADPH oxidase assembly.

PMID- 8663334
TI  - Ordered and sequential binding of DnaA protein to oriC, the chromosomal origin of
      Escherichia coli.
AB  - DnaA protein of Escherichia coli acts in initiation of chromosomal DNA
      replication by binding specific sequences, termed DnaA boxes in the chromosomal
      origin, oriC. On binding, it induces a localized unwinding to create a structure
      recognized by other replication proteins that act subsequently in the initiation
      process. In this report, we examined the binding of DnaA protein to each of the
      DnaA boxes in oriC. By gel mobility shift assays, DnaA protein formed at least
      six discrete complexes. ATP or ADP included in the reaction mixture prior to
      electrophoresis was required. Chemical cleavage of isolated complexes with 1,10
      phenanthroline-copper revealed that DnaA protein binds in an ordered manner to
      the DnaA boxes in oriC. Preferential binding to one DnaA box (R4) was confirmed
      by demonstration that a DNA fragment containing it was bound with greater
      affinity than another DnaA box sequence (R1). In vitro replication activity
      correlated with a complex formed at a ratio of 30 DnaA monomers/oriC in which all
      DnaA boxes are occupied. The last site bound is DnaA box R3. This event may be
      critical in promoting initiation from oriC as it correlates with in vivo
      observations that binding of DnaA protein to box R3 occurs at the time of
      initiation of chromosomal replication, whereas other DnaA boxes are bound by DnaA
      protein throughout the cell cycle (Cassler, M. R., Grimwade, J. E., and Leonard,
      A. C.(1995) EMBO J. 14, 5833-5841).

PMID- 8663335
TI  - Ligand cross-reactivity within the protease-activated receptor family.
AB  - Recently, a second member of the protease-activated receptor (PAR) family, named
      PAR-2, has been identified. Similar to the thrombin receptor, PAR-2 appears to be
      activated by proteolytic-mediated exposure of a "tethered ligand" sequence and
      can also be activated by the corresponding synthetic peptides. Similarities in
      the amino acid sequence of the receptors' tethered ligand sequences suggest that
      their respective agonist peptides might not be absolutely specific for their
      particular receptors. To test this, the receptor specificity of each agonist has
      been determined by measuring the responses of Xenopus oocytes expressing the
      thrombin receptor or PAR-2 to agonist peptides or enzymes. Thrombin receptors
      responded to thrombin, the human thrombin receptor-activating peptide SFLLRNP-NH2
      (TRAP) (EC50 = 0.1 microM), and Xenopus TRAP, TFRIFD-NH2 (EC50 = 1 microM), but
      did not show any increase in calcium efflux over control levels with trypsin (50
      nM) or PAR-2 agonist peptides (100 microM). Human and murine PAR-2 receptors
      responded comparably to human and murine PAR-2 agonist peptides (SLIGKVD and
      SLIGRL, respectively) (EC50 = 0.5-2.0 microM) and trypsin, but not to thrombin.
      PAR-2 was also found to be responsive to TRAP (EC50 = 1 microM) but was
      unresponsive to Xenopus TRAP (50 microM). Responses to additional peptide agonist
      analogs suggest that an amino-terminal serine is critical for PAR-2 agonist
      activity.

PMID- 8663336
TI  - Interleukin-1beta activates protein kinase C zeta in renal mesangial cells.
      Potential role in prostaglandin E2 up-regulation.
AB  - Protein kinase C (PKC) plays a role in signal transduction mediated by
      interleukin-1beta (IL-1beta) leading to the increase in prostaglandin E2 (PGE2)
      production. In the present study we suggest that there are at least two distinct
      PKC isotypes involved in the signaling mechanism. Staurosporine potentiated the
      effect of IL-1beta on coxII mRNA expression while calphostin C totally inhibited
      mRNA expression. The down-regulation of PKC by growing mesangial cells in the
      presence of phorbol 12-myristate 13-acetate for 24 h failed to modify the up
      regulated response in PGE2 formation by IL-1beta. Furthermore, incubation of
      mesangial cells with IL-1beta causes translocation of PKCzeta from cytosol to a
      presumed membrane compartment, and this translocation phenomenon was not
      inhibited by incubating the cells with staurosporine but was inhibited with
      calphostin C. Gel retardation assays also demonstrated that staurosporine did not
      inhibit the IL-1beta-stimulated binding of nuclear extracts to the NFkappaB
      motif. In contrast, calphostin C inhibited binding to the kappaB motif in a dose
      dependent manner. Finally, antisense oligonucleotides to PKCzeta partially
      inhibited the IL-1beta-induced PGE2 formation while control sense
      oligonucleotides were without effect. Taken together, these data suggest that
      PKCzeta is involved in the IL-1beta signaling responses.

PMID- 8663337
TI  - Expression and regulation of the lipoprotein lipase gene in human adrenal cortex.
AB  - Lipoprotein lipase (LPL), an enzyme which hydrolyzes triglycerides and
      participates in the catabolism of remnant lipoproteins, plays a crucial role in
      energy and lipid metabolism. The goal of this study was to analyze the expression
      and regulation of the LPL gene in human adrenals. Reverse transcriptase
      polymerase chain reaction amplification and sequence analysis demonstrated the
      presence of LPL mRNA in fetal and adult human adrenal cortex. Furthermore, the
      human adrenocortical carcinoma cell line, NCI-H295, expresses LPL mRNA and
      protein, which is localized to the outer cellular membrane as demonstrated by
      immunofluorescence confocal microscopy and can be released in the medium by
      heparin addition. To asses whether the LPL gene is regulated by agents regulating
      adrenal steroidogenesis, NCI-H295 cells were treated with activators of second
      messenger systems. Whereas the calcium-ionophore A23187 did not affect LPL gene
      expression, treatment with phorbol 12-myristate 13-acetate decreased LPL mRNA
      levels in a time- and dose-dependent manner. This decrease after phorbol 12
      myristate 13-acetate was associated with diminished heparin-releasable LPL mass
      and activity in the culture medium. Addition of the cAMP analog 8-Br-cAMP to NCI
      H295 cells resulted in a rapid, but transient dose-dependent induction of LPL
      mRNA. Treatment with the protein synthesis inhibitor cycloheximide gradually
      induced, whereas simultaneous addition of cAMP and cycloheximide superinduced LPL
      mRNA levels. Nuclear run-on analysis indicated that the effects of cAMP and
      cycloheximide occurred at the transcriptional and post-transcriptional level,
      respectively. Transient co-transfection assays demonstrated that the first 230
      base pairs of the proximal LPL promoter contain a cAMP-responsive element
      activated by protein kinase A and transcription factors belonging to the
      CREB/CREM family. These data indicate that LPL is expressed in human adrenal
      cortex and regulated in NCI-H295 adrenocortical carcinoma cells by activators of
      the protein kinase A and protein kinase C second messenger pathways in a manner
      comparable to P450scc, which catalyzes the first step in adrenal steroidogenesis.
      These observations suggest a role for LPL in adrenal energy and/or lipid
      metabolism and possibly in steroidogenesis.

PMID- 8663338
TI  - The box1 domain of the erythropoietin receptor specifies Janus kinase 2
      activation and functions mitogenically within an interleukin 2 beta-receptor
      chimera.
AB  - Several distinct classes of cytokine receptors engage Jak kinases as primary
      effectors. Among type 1 receptors, Janus-activated kinase (Jak) recruitment is
      mediated by membrane-proximal cytoplasmic domains, which typically contain
      conserved box motifs. In the erythropoietin receptor (Epo-R), two such motifs
      (box1 and box2) have been suggested to be essential for the activation of Jak2
      and mitogenesis. Presently, an Epo-R chimera containing the extracellular and
      box1 domains of the Epo-R (Jak2-associated receptor) and the box2 and carboxyl
      terminal domains of the interleukin 2 beta-receptor (IL2beta-R; a Jak1-associated
      subunit) is shown to activate Jak2. Interestingly, Jak2 also was activated in FDC
      P1 cells by a control Epo-R chimera containing the complete IL2beta-R cytoplasmic
      domain, and mitogenesis was supported by each of these above chimeras. By
      comparison, in BaF3 cells expressing IL2 receptor alpha and gamma subunits, an
      ectopically expressed IL2beta-R chimera containing the box1 domain of the Epo-R,
      activated Jak2 and Jak3 and was as mitogenically active as the wild-type IL2beta
      R (Jak1 and Jak3 activation). Thus, the box1 domain of the Epo-R specifies Jak2
      activation and functions efficiently within a heterologous IL2 receptor complex
      that normally activates Jak1 and Jak3.

PMID- 8663339
TI  - Phosphorylation of chromogranin A and catecholamine secretion stimulated by
      elevation of intracellular Ca2+ in cultured bovine adrenal medullary cells.
AB  - We have recently isolated a new endogenous substrate of 70 kDa for
      Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) from bovine adrenal
      medullary cells (Yanagihara, N., Toyohira, Y., Yamamoto, H., Ohta, Y., Tsutsui,
      M., Miyamoto, E., and Izumi, F. (1994) Mol. Pharmacol. 46, 423-430). Here we
      report the sequence analysis of the 70-kDa protein and examine its
      phosphorylation by various protein kinases in vitro and by depolarization of the
      cultured cells. Protein sequencing and immunoblotting revealed that the 70-kDa
      protein is chromogranin A (CgA) or a closely related protein. Partially purified
      CgA was phosphorylated by cyclic AMP-dependent protein kinase and protein kinase
      C as well as CaM kinase II. Tryptic phosphopeptide mapping patterns of CgA
      differed among these protein kinases. In 32P-labeled bovine adrenal medullary
      cells, 56 mM K+ increased the phosphorylation of CgA and catecholamine secretion
      in similar time- and concentration-dependent manners, both of which were
      inhibited by 20 mM MgSO4, an inhibitor of voltage-dependent Ca2+ channels. These
      findings suggest that CgA serves as a substrate for several multifunctional
      protein kinases and that the elevation of the intracellular Ca2+ stimulates the
      phosphorylation of CgA associated with catecholamine secretion in cultured
      adrenal medullary cells.

PMID- 8663340
TI  - The developmental expression of Leishmania donovani A2 amastigote-specific genes
      is post-transcriptionally mediated and involves elements located in the 3'
      untranslated region.
AB  - Leishmania donovani is a protozoan parasite that exists as a free-living
      promastigote in the sandfly insect vector and as an amastigote inside the
      mammalian host macrophage phagolysosome compartment. The L. donovani A2 genes
      have been described previously as developmentally expressed in amastigotes but
      can be induced experimentally in promastigotes by a combination of pH and
      temperature shifts, conditions that mimic the phagolysosomal compartment of the
      macrophage cell. Considering the importance of the amastigote stage in human
      infections, we have examined the molecular basis for amastigote stage-specific
      gene expression. Our results provide evidence that A2 developmental expression
      during the promastigote-to-amastigote cytodifferentiation is mediated through
      differential RNA stability and involves the A2 mRNA 3'-untranslated region. The
      site of processing in the 3'-untranslated region was a major factor for the
      accumulation of A2 mRNAs in cells incubated under phagolysosomal conditions. The
      stability of reporter gene transcripts bearing the A2 3'-untranslated region was
      increased in cells incubated at low pH, further confirming the importance of pH
      shift as an inducer for A2 expression. These observations contribute to defining
      the mechanism of amastigote-specific gene regulation in L. donovani. We also
      demonstrate the feasibility of using the A2 locus to express heterologous genes
      differentially in the amastigote form of the L. donovani parasite.

PMID- 8663341
TI  - Effect of constitutive 70-kDa heat shock protein polymerization on its
      interaction with protein substrate.
AB  - Constitutive 70-kDa heat shock protein (hsc70) is a mixture of monomers and
      oligomers in ADP, while in ATP it is monomeric unless certain DnaJ homologs are
      present which induce hsc70 to form large polymers in an ATP-dependent reaction. A
      key question regarding polymerized hsc70 is whether it is able to bind protein
      substrates. Polymerized BiP, the hsc70 present in the endoplasmic reticulum, has
      been found to bind substrates in vitro although substrates appear to bind only to
      monomeric BiP in vivo. In this study, we investigated whether substrate binds to
      polymerized cytoplasmic hsc70 in vitro. Although both stoichiometric ATP and high
      concentrations of cytochrome c peptide monomerized hsc70, direct binding studies
      provided no evidence that cytochrome c peptide binds to polymerized hsc70.
      Furthermore, the time course of cytochrome c peptide and clathrin binding to
      hsc70 suggested that rather than binding to polymerized hsc70, they monomerized
      it by reducing free monomer, thereby shifting the monomer-polymer equilibrium
      toward monomer. We conclude that peptide and protein substrates bind at least an
      order of magnitude more weakly to polymerized hsc70 than to monomer, suggesting
      that polymerization of hsc70 in vivo, perhaps by DnaJ homologs, may store it in
      an inactive form.

PMID- 8663342
TI  - Adenosine A2 receptor occupancy regulates stimulated neutrophil function via
      activation of a serine/threonine protein phosphatase.
AB  - Adenosine modulates generation of superoxide anion by neutrophils via occupancy
      of specific adenosine A2A receptors. However, the intracellular signal
      transduction pathways by which occupancy of neutrophil adenosine A2A receptors
      inhibits superoxide anion generation (O2.-) are not well understood. We,
      therefore, tested the hypothesis that signaling at polymorphonuclear leukocyte
      (PMN) adenosine receptors proceeds via activation of a serine/threonine protein
      phosphatase (pp). Both the specific pp1 inhibitor calyculin A (10 nM) and the
      pp2A inhibitor okadaic acid (10 microM) enhanced O2.- generation (185 +/- 24 and
      189 +/- 35% of control, respectively, p < 0.0001 for both, n = 8), as reported
      previously. Calyculin A, but not okadaic acid, completely reversed inhibition of
      stimulated O2.- generation by the adenosine A2 receptor agonist 5'-N
      ethylcarboxamidoadenosine (NECA; IC50 = 30 nM; p < 0.0001, analysis of variance).
      Calyculin A also reversed the adenosine receptor-mediated desensitization of
      bound chemoattractant receptors in neutrophils. Treatment of PMNs with NECA
      increased the pp1 activity of crude membrane preparations in a time- and dose
      dependent fashion (EC50 = 40 nM; p < 0.001, analysis of variance, n = 5). NECA
      inhibited cytosolic protein phosphatase activity by 78 +/- 12% (p < 0.003, n = 6)
      but did not shift pp1 catalytic subunit from cytosol to plasma membrane. Similar
      changes were observed in neutrophil cytoplasts depleted of organelles and
      nucleus. Moreover, the selective protein kinase A inhibitor KT5720 (10 microM)
      reversed the capacity of dibutyryl cAMP but not NECA to increase pp1 activity (p
      < 0.01, n = 5) in keeping with its effects on O2.- generation. Western blot
      analysis of PMN subcellular fractions demonstrated the presence of pp1alpha and
      pp1gamma1 but not pp1gamma2 isotypes in both cytosol and plasma membrane but not
      in azurophil or specific granules. We conclude from these studies that signal
      transduction by adenosine in PMN proceeds via a novel pathway: cAMP-independent
      activation of a serine/threonine protein phosphatase in the plasma membrane.

PMID- 8663343
TI  - Reduced expression of transforming growth factor beta type I receptor contributes
      to the malignancy of human colon carcinoma cells.
AB  - Transforming growth factor beta (TGFbeta) type I (RI) and type II (RII) receptors
      are essential for TGFbeta signal transduction. A human colon carcinoma cell line,
      designated GEO, is marginally responsive to TGFbeta and expresses a low level of
      RI mRNA relative to colon carcinoma cells, which are highly responsive to
      TGFbeta. Hence, the role of RI as a limiting factor for TGFbeta sensitivity and
      the contribution of low RI levels to the malignant phenotype of GEO cells were
      examined. Stable transfection of a tetracycline-regulatable rat RI cDNA increased
      TGFbeta1 binding to RI and resulted in increased growth inhibition by exogenous
      TGFbeta1. In contrast, although stable transfection of an RII expression vector
      into the same GEO cells increased TGFbeta1 binding to RII, growth inhibition by
      exogenous TGFbeta1 was not altered. This indicated that the low level of RI is a
      limiting factor for the growth-inhibitory effects of TGFbeta in GEO cells. RI
      transfected cells were growth-arrested at a lower saturation density than GEO
      control cells. They also showed reduced growth and clonogenicity in plating
      efficiency and soft agarose assays, whereas RII-transfected cells did not show
      any differences from the NEO control cells in these assays. Tetracycline
      repressed RI expression in transfected cells and reversed the reduction in
      plating efficiency of RI-transfected clones, confirming that growth effects were
      due to increased RI expression in transfected cells. TGFbeta1 neutralizing
      antibody stimulated the proliferation of RI-transfected cells but had little
      effect on GEO control cells, indicating that increased autocrine-negative TGFbeta
      activity also resulted from increased RI expression. Tumorigenicity in athymic
      nude mice was significantly delayed in RI-transfected cells. These results
      indicate that low RI expression can be a limiting factor for response to
      exogenous TGFbeta, as well as TGFbeta autocrine-negative activity, and that
      reduction of RI expression can contribute to malignant progression.

PMID- 8663344
TI  - Effects of pH and Ca2+ on heterodimer and heterotetramer formation by
      chromogranin A and chromogranin B.
AB  - The two major proteins of the secretory vesicles of neuroendocrine cells,
      chromogranin A (CGA) and chromogranin B (CGB), have been shown to undergo pH- and
      Ca2+-dependent conformational changes and aggregation and have been suggested to
      play essential roles during secretory vesicle biogenesis in the trans-Golgi
      network. CGA has been shown to exist primarily in a tetrameric state at pH 5.5
      and primarily in a dimeric state at pH 7.5, and CGB has been shown to exist in a
      monomeric state at both pH 5.5 and pH 7.5. Using purified CGA and CGB, it
      recently has been shown that CGA interacts with CGB at pH 5.5 (Yoo, S. H.(1996)
      J. Biol. Chem. 271, 1558-1565). In expanding this investigation, we have studied
      the temperature dependence of the pH-dependent interaction of CGA and CGB by
      analytical ultracentrifugation and found that two molecules of CGA bound to two
      molecules of CGB at pH 5.5 with DeltaG0 values of -43.6 kcal/mol in the absence
      of Ca2+ at 37 degrees C and -40.3 kcal/mol in the presence of 0.1 mM Ca2+.
      However, one molecule of CGA bound to one molecule of CGB at pH 7.5 with DeltaG0
      values of -13.6 kcal/mol in the absence of Ca2+ at 37 degrees C. The magnitude of
      DeltaG0 values increased with increasing temperatures at both pH values. However,
      the values for enthalpy and entropy changes decreased with increasing
      temperatures in both pH levels, suggesting formation of more ordered structures.
      In the absence of Ca2+ at pH 5. 5, the heterotetramerization reaction at 37
      degrees C was entropically driven, whereas in the presence of Ca2+ (0.1 mM) the
      heterotetramerization was virtually an enthalpic reaction. On the other hand, the
      heterodimer formation in the absence of Ca2+ at pH 7. 5 showed large negative
      enthalpy and entropy changes at 37 degrees C, indicating an enthalpic interaction
      compensated by entropic changes. In view of the interaction of tetrameric CGA
      with tetrameric inositol 1,4,5-trisphosphate (IP3) receptor and the existence of
      heterotetrameric IP3 receptor in the cell, the heterotetramer formation by CGA
      and CGB not only raises the possibility of interaction between the
      heterotetrameric chromogranin and heterotetrameric IP3 receptor but also appears
      to reflect their important roles in the cell.

PMID- 8663345
TI  - Inducing the loss of immunoglobulin lambda light chain production and the
      rearrangement of a previously excluded allele in human plasma B cell lines with
      concanavalin A.
AB  - We investigated the expression of differential lambda light chains in human B
      cell lines secreting immunoglobulin (Ig). When these cell lines were cultured
      with concanavalin A for a long period of time, a subpopulation of some but not
      all of these cell lines was induced to express new lambda light chains replacing
      the original lambda chain (light chain shifting). Production of the new lambda
      chain, which replaces the original lambda chain, results from a VJ rearrangement
      at a previously excluded allele and a dramatic reduction of the original lambda
      chain transcript, although no difference was found in the level of heavy chain
      transcript. Recombination activating genes RAG-1 and RAG-2, which are normally
      expressed during specific early stages of lymphocyte development, were expressed
      in not only the light chain shifting-inducible lines but also in the non
      inducible cells. Treatment of these Ig secreting cell lines with dibutyryl cAMP,
      which is known to enhance expression of the RAG genes, could not induce the
      creation of new lambda light chain-producing cells from the inducible lines,
      suggesting that the expression of the two RAG genes is not sufficient for
      inducing new lambda light chain production. Concanavalin A induced a gradual but
      significant production lost of the original lambda chain in a subpopulation of
      the light chain shifting-inducible cells but not in the non-inducible cells.
      Association of new lambda light chain production with loss of original lambda
      chain raises the possibility that, when the RAG genes are expressed, concanavalin
      A may act on a novel intracellular mechanism controlling lambda light chain
      allelic exclusion in these plasma cell lines.

PMID- 8663346
TI  - Distinct cytoplasmic domains of the growth hormone receptor are required for
      glucocorticoid- and phorbol ester-induced decreases in growth hormone (GH)
      binding. These domains are different from that reported for GH-induced receptor
      internalization.
AB  - Glucocorticoids inhibit growth in children and antagonize the growth-promoting
      action of GH in peripheral tissues. Recently, they have been shown to decrease GH
      binding. In this study we examine the molecular mechanisms by which the
      glucocorticoid dexamethasone (DEX) and the phorbol ester phorbol myristate
      acetate (PMA) decrease cellular GH binding. In 3T3-F442A fibroblasts, DEX and PMA
      decrease the number of GH receptors (GHRs) capable of binding GH by 50% (t1/2 = 6
      h) and 70% (t1/2 = 15 min), respectively. Neither appear to decrease the total
      number of cellular GHR. Rather, they appear to redistribute GHRs away from the
      plasma membrane or inactivate GHRs on the membrane such that they cannot bind GH.
      DEX and PMA also decrease GH-induced tyrosyl phosphorylation of GHR and JAK2 with
      a magnitude and time course correlating with that of inhibition of GH binding.
      DEX- and PMA-induced reductions of GH binding are also observed in a Chinese
      hamster ovary (CHO) cell line stably transfected with a rat liver GHR cDNA,
      further arguing that DEX and PMA act post-translationally on GHR. Using mutant
      GHRs stably expressed in CHO cells, amino acids 455-506 and tyrosines 333 and/or
      338 of GHR were shown to be required for maximal DEX-induced inhibition of GH
      binding. DEX decreased GH binding to a GHR mutant F346A, which is reported to be
      deficient in ligand-induced internalization, suggesting that DEX decreases GH
      binding by a mechanism distinct from that of ligand-induced GHR internalization.
      PMA reduced GH binding to CHO cells expressing all GHR mutants tested. However,
      deletion of the C-terminal 132 amino acids decreased this effect, suggesting that
      at least one component of PMA action on GHR requires amino acids 507-638. These
      data suggest that distinct pathways mediate the effects of GH, DEX, and PMA on
      GHR number in the plasma membrane.

PMID- 8663347
TI  - Premature chromatin condensation induced by loss of RCC1 is inhibited by GTP- and
      GTPgammaS-Ran, but not GDP-Ran.
AB  - RCC1 is a guanine nucleotide exchanging factor acting on nuclear G protein Ran.
      Premature chromatin condensation occurs in the temperature-sensitive rcc1- mutant
      of the BHK21 cell line, tsBN2, at the restrictive temperature. This observation
      can be explained if the premature activation of MPF is normally inhibited by GTP
      Ran. In the absence of RCC1, GDP-Ran predominates, resulting in MPF activation.
      However, experiments with Ran mutants to determine whether GTP- or GDP-Ran
      prevents activation of MPF have yielded conflicting results. In order to clarify
      this point, we have microinjected nucleotide-bound Ran, instead of mutated Ran,
      into the nuclei of tsBN2 cells treated to reduce RCC1-mediated guanine nucleotide
      exchange. GTP-Ran, GTPgammaS-Ran, and GDP-Ran all inhibited chromatin
      condensation. However, the inhibition of chromatin condensation by GDP-Ran could
      be completely abolished by co-injection with GDP, but not GTP. Thus, we conclude
      that GTP-Ran blocks the activation of MPF and that hydrolysis of GTP is not
      required to prevent MPF activation.

PMID- 8663348
TI  - Ras activation is necessary for integrin-mediated activation of extracellular
      signal-regulated kinase 2 and cytosolic phospholipase A2 but not for cytoskeletal
      organization.
AB  - Cell adhesion to the extracellular matrix triggers a cascade of intracellular
      biochemical signals regulated by the integrin family of receptors. Recent
      evidence suggests that integrin engagement may activate a mitogen-activated
      protein (MAP) kinase cascade that may cooperate with more clearly defined
      mitogenic signaling pathways to regulate cell proliferation, adhesion, and
      migration. Here we report that the adhesion-dependent activation of the MAP
      kinase Erk2 (extracellular signal-regulated kinase 2) occurs in serum-starved
      NIH3T3 cells, and that this activation of Erk2 is preceded by the activation of
      the small GTP-binding protein Ras in fibronectin-adherent cells. Inhibition of
      Ras signaling by expression of a dominant-inhibitory mutant of Ras (N17Ras) in
      NIH3T3 cells blocked adhesion-dependent activation of Erk2, although the focal
      adhesion kinase (FAK) was still activated in these cells. Furthermore, activation
      of this Ras-MAP kinase pathway activated cytosolic phospholipase A2, leading to
      the release of arachidonic acid metabolites, and N17Ras also inhibited these
      events. However, N17Ras expression does not inhibit cell adhesion, spreading, or
      focal contact and stress fiber formation. These results suggest that, while
      integrin-dependent activation of this MAP kinase pathway is Ras-dependent, the
      integrin-dependent activation of FAK and several morphological events are Ras
      independent. Thus, integrin-mediated signals involved in regulating cell
      morphology appear to diverge from those regulating MAP kinase activation at a
      level upstream of Ras activation.

PMID- 8663349
TI  - Interaction between an integral protein of the nuclear envelope inner membrane
      and human chromodomain proteins homologous to Drosophila HP1.
AB  - At the nuclear envelope in higher eukaryotic cells, the nuclear lamina and the
      heterochromatin are adjacent to the inner nuclear membrane, and their attachment
      is presumably mediated by integral membrane proteins. In a yeast two-hybrid
      screen, the nucleoplasmic domain of lamin B receptor (LBR), an integral protein
      of the inner nuclear membrane, associated with two human polypeptides homologous
      to Drosophila HP1, a heterochromatin protein involved in position-effect
      variegation. LBR fusion proteins bound to HP1 proteins synthesized by in vitro
      translation and present in cell lysates. Antibodies against LBR also co
      immunoprecipitated HP1 proteins from cell extracts. LBR can interact with
      chromodomain proteins that are highly conserved in eukaryotic species and may
      function in the attachment of heterochromatin to the inner nuclear membrane in
      cells.

PMID- 8663350
TI  - p53 is a mediator for radiation-repressed human TR2 orphan receptor expression in
      MCF-7 cells, a new pathway from tumor suppressor to member of the steroid
      receptor superfamily.
AB  - p53 may function as a checkpoint by arresting the G1 cell cycle in response to
      DNA damage induced by radiation or other stimuli. We have found that the
      expression of the TR2 orphan receptor (TR2), a member of the steroid receptor
      superfamily, was down-regulated by ionizing irradiation. Our data shown in the
      present study demonstrate that irradiation can repress TR2 at both the
      translational and transcriptional levels. Transient transfection assays further
      link p53 to this repression by proving that endogenously induced or exogenously
      transfected p53 can repress TR2 gene expression, and this repression can be
      reversed by the co-transfection of SV40 large T antigen. Together, our data
      demonstrate for the first time that radiation and p53 can repress TR2, possibly
      providing a new pathway to link ionizing irradiation and p53 to members of the
      steroid receptor superfamily.

PMID- 8663351
TI  - Mrs5p, an essential protein of the mitochondrial intermembrane space, affects
      protein import into yeast mitochondria.
AB  - We have isolated a yeast nuclear gene that suppresses the previously described
      respiration-deficient mrs2-1 mutation when present on a multicopy plasmid.
      Elevated gene dosage of this new gene, termed MRS5, suppresses also the pet
      phenotype of a mitochondrial splicing-deficient group II intron mutation M1301.
      The MRS5 gene product, a 13-kDa protein of low abundance, shows no similarity to
      other known proteins and is associated with the inner mitochondrial membrane,
      protruding into the intermembrane space. MRS5 codes for an essential protein, as
      the disruption of this gene is lethal even during growth on fermentable carbon
      sources. Thus, the Mrs5 protein seems to be involved in mitochondrial key
      functions aside from oxidative energy conservation, which is dispensable in
      fermenting yeast cells. Depletion of Mrs5p in yeast cells causes accumulation of
      unprocessed precursors of the mitochondrial hsp60 protein and defects in all
      cytochrome complexes. These findings suggest an essential role of Mrs5p in
      mitochondrial biogenesis.

PMID- 8663352
TI  - An FK506-sensitive transporter selectively decreases intracellular levels and
      potency of steroid hormones.
AB  - Steroid hormones bind and activate intracellular receptors that are ligand
      regulated transcription factors. Mammalian steroid receptors can confer hormone
      dependent transcriptional enhancement when expressed in yeast, thereby enabling
      the genetic identification of nonreceptor proteins that function in the hormone
      signal transduction pathway. Pdr5p (Lem1/Sts1/Ydr1p), a yeast ATP-binding
      cassette transporter, selectively decreases the intracellular levels of
      particular steroid hormones, indicating that active processes can affect the
      passage of steroids across biological membranes. In yeast, the immunosuppressive
      drug FK506 inhibited Pdr5p, thereby potentiating activation of the glucocorticoid
      receptor by dexamethasone, a ligand that is exported by Pdr5p. In mammalian L929
      cells but not in HeLa cells, FK506 potentiated dexamethasone responsiveness and
      increased dexamethasone accumulation, without altering the hormone-binding
      properties of the glucocorticoid receptor. We suggest that an FK506-sensitive
      transporter in L929 cells selectively decreases intracellular hormone levels and,
      consequently, the potency of particular steroids. Thus, steroid transporters may
      modulate, in a cell-specific manner, an initial step in signaling, the
      availability of hormone to the receptor.

PMID- 8663353
TI  - Thyroid hormone export regulates cellular hormone content and response.
AB  - Actions of thyroid hormones (THs) are determined by intracellular free hormone
      concentration. Here we report that enhanced TH extrusion via a saturable, cold
      sensitive mechanism lowers intracellular TH and causes TH resistance in hepatoma
      cells. Since these cells overexpress multidrug resistance P-glycoproteins and TH
      extrusion and resistance are blunted by verapamil, P-glycoproteins may mediate
      this resistance. Verapamil-inhibitable TH efflux was also found in primary
      hepatocytes, cardiocytes, and fibroblasts. These findings demonstrate that TH
      extrusion can modulate TH availability and action in mammalian cells.

PMID- 8663354
TI  - Characterization of a potential catalytic residue, Asp-133, in the high affinity
      ATP-binding site of Escherichia coli SecA, translocation ATPase.
AB  - The high affinity ATP-binding site of SecA is located in its amino-terminal
      domain possessing amino acid sequences, the Walker A (GXXXXGKT) and B (ZZZZD)
      motifs, that are characteristic of a major class of nucleotide-binding sites
      (Walker, J. E., Saraste, M., Runswick, M. J., and Gay, N. J. (1982) EMBO J. 1,
      945-951). Recently, we proposed that proteins possessing a typical set of Walker
      A and B motifs contain a conserved Glu or Asp between the two motifs. This Glu or
      Asp acts as a "catalytic residue" that activates a water molecule for an in-line
      attack on the gamma-phosphate of ATP (Amano, T., Yoshida, M., Matsuo, Y., and
      Nishikawa, K.(1995) FEBS Lett. 359, 1-5). In the present study, the aspartate
      residue at position 133 in Escherichia coli SecA, which could be the "catalytic
      residue," was mutated to an asparagine. The mutant SecA (SecA D133N) protein was
      expressed in E. coli CK4706, encoding a duplication of the secA gene, and
      purified to homogeneity. The in vitro protein translocation activity and membrane
      vesicle stimulated ATPase activity of SecA D133N were drastically reduced.
      Proteolytic studies indicated that the conformational changes of the mutant SecA
      occurring on interaction with ATP, presecretory proteins, phospholipids, and
      membrane vesicles, were similar to those of wild-type SecA. The mutant SecA
      allowed the signal peptide cleavage of proOmpA during translocation, indicating
      that the mutant retains the ability to bind ATP to perform the initial step of
      the translocation reaction. These data indicate that the carboxyl group of Asp
      133 plays a role as a catalytic carboxylate, which activates a water molecule to
      attack gamma-phosphate of ATP, and the mutant lacking this residue cannot perform
      the total translocation but can still perform the initial step of the protein
      translocation.

PMID- 8663355
TI  - The functional expression of sodium-dependent bile acid transport in Madin-Darby
      canine kidney cells transfected with the cDNA for microsomal epoxide hydrolase.
AB  - Previous studies have suggested that the enzyme microsomal epoxide hydrolase
      (mEH) is able to mediate sodium-dependent transport of bile acids such as
      taurocholate into hepatocytes (von Dippe, P., Amoui, M., Alves, C., and Levy,
      D.(1993) Am. J. Physiol. 264, G528-G534). In order to characterize directly the
      putative transport properties of the enzyme, a pCB6 vector containing the cDNA
      for this protein (pCB6-mEH) was transfected into Madin-Darby canine kidney (MDCK)
      cells, and stable transformants were isolated that could express mEH at levels
      comparable with the levels expressed in hepatocytes. Sodium-dependent transport
      of taurocholate was shown to be dependent on the expression of mEH and to be
      inhibited by the bile acid transport inhibitor 4,4'-diisothiocyanostilbene
      2,2'disulfonic acid (DIDS), as well as by other bile acids. Kinetic analysis of
      this system indicated a Km of 26.3 microM and a Vmax of 117 pmol/mg protein/min.
      The Km value is essentially the same as that observed in intact hepatocytes. The
      transfected MDCK cells also exhibited sodium-dependent transport of cholate at
      levels 150% of taurocholate in contrast to hepatocytes where cholate transport is
      only 30% of taurocholate levels, suggesting that total hepatocyte bile acid
      transport is a function of multiple transport systems with different substrate
      specificities, where mEH preferentially transports cholate. This hypothesis is
      further supported by the observation that a monoclonal antibody that partially
      protects (26%) taurocholate transport from inhibition by DIDS in hepatocytes
      provides almost complete protection (88%) from DIDS inhibition of hepatocyte
      cholate transport, suggesting that taurocholate is also taken up by an
      alternative system not recognized by this antibody. Additional support for this
      concept is provided by the observation that the taurocholate transport system is
      almost completely protected (92%) from DIDS inhibition by this antibody in MDCK
      cells that express mEH as the only bile acid transporter. These results
      demonstrate that mEH is expressed on the surface of hepatocytes as well as on
      transfected MDCK cells and is able to mediate sodium-dependent transport of
      taurocholate and cholate.

PMID- 8663356
TI  - Sterol efflux is impaired from macrophage foam cells selectively enriched with 7
      ketocholesterol.
AB  - The aim of the present study was to investigate whether impairment of cholesterol
      efflux previously found from mouse peritoneal macrophages loaded with oxidized
      low density lipoprotein (OxLDL) could be ascribed to the presence of oxysterols
      in these cells. 7-Ketocholesterol (7KC), the major oxysterol present in OxLDL
      loaded cells, was selectively incorporated into unoxidized LDL, which was
      subsequently acetylated to produce a high uptake form. Mouse macrophages
      incubated with 7KC-enriched acetylated LDL (7kAcLDL) did not reveal cytotoxicity
      judged by cell protein and trypan blue exclusion. A large proportion of cellular
      7KC was esterified, indicating that it is a substrate for acyl CoA:cholesterol
      acyltransferase. Cholesterol efflux from mouse macrophages loaded with 7kAcLDL,
      using apoA-I as a sterol acceptor, was impaired in cells containing >50 nmol of
      7KC/mg of cell protein compared with cells loaded with oxysterol-free acetylated
      LDL. Thus impairment of cholesterol efflux could be reproduced in cells loaded
      with 7kAcLDL containing similar proportions of 7KC as OxLDL. 7KC itself was
      exported very poorly, even when the levels of 7KC in the cells were low. These
      results suggest that oxysterols present in foam cells in vitro can affect reverse
      sterol transport and may be potentially important in foam cell formation in vivo.

PMID- 8663357
TI  - Obligatory amino acid exchange via systems bo,+-like and y+L-like. A tertiary
      active transport mechanism for renal reabsorption of cystine and dibasic amino
      acids.
AB  - Mutations in the rBAT gene cause type I cystinuria, a common inherited
      aminoaciduria of cystine and dibasic amino acids due to their defective renal and
      intestinal reabsorption (Calonge, M. J., Gasparini, P., Chillaron, J., Chillon,
      M., Gallucci, M., Rousaud, F., Zelante, L., Testar, X., Dallapiccola, B., Di
      Silverio, F., Barcelo, P., Estivill, X., Zorzano, A., Nunes, V., and Palacin, M.
      (1994) Nat. Genet. 6, 420-426; Calonge, M. J., Volipini, V., Bisceglia, L.,
      Rousaud, F., De Sanctis, L., Beccia, E., Zelante, L., Testar, X., Zorzano, A.,
      Estivill, X., Gasparini, P., Nunes, V., and Palacin, M.(1995) Proc. Natl. Acad.
      Sci. U. S. A. 92, 9667-9671). One important question that remains to be clarified
      is how the apparently non-concentrative system bo,+-like, associated with rBAT
      expression, participates in the active renal reabsorption of these amino acids.
      Several studies have demonstrated exchange of amino acids induced by rBAT in
      Xenopus oocytes. Here we offer evidence that system bo,+-like is an obligatory
      amino acid exchanger in oocytes and in the "renal proximal tubular" cell line OK.
      System bo, +-like showed a 1:1 stoichiometry of exchange, and the hetero-exchange
      dibasic (inward) with neutral (outward) amino acids were favored in oocytes.
      Obligatory exchange of amino acids via system bo,+-like fully explained the amino
      acid-induced current in rBAT-injected oocytes. Exchange via system bo,+-like is
      coupled enough to ensure a specific accumulation of substrates until the complete
      replacement of the internal oocyte substrates. Due to structural and functional
      analogies of the cell surface antigen 4F2hc to rBAT, we tested for amino acid
      exchange via system y+L-like. 4F2hc-injected oocytes accumulated substrates to a
      level higher than CAT1-injected oocytes (i.e. oocytes expressing system y+) and
      showed exchange of amino acids with the substrate specificity of system y+L and L
      leucine-induced outward currents in the absence of extracellular sodium. In
      contrast to L-arginine, system y+L-like did not mediate measurable L-leucine
      efflux from the oocyte. We propose a role of systems bo,+-like and y+L-like in
      the renal reabsorption of cystine and dibasic amino acids that is based on their
      active tertiary transport mechanism and on the apical and basolateral
      localization of rBAT and 4F2hc, respectively, in the epithelial cells of the
      proximal tubule of the nephron.

PMID- 8663358
TI  - Characterization of yeast methyl sterol oxidase (ERG25) and identification of a
      human homologue.
AB  - A yeast mutant (LT06) was isolated that showed no growth on iron-limited medium
      but normal growth on iron-replete medium. A gene cloned from a genomic yeast
      library complemented the defect, allowing growth on low iron medium. Allelic
      segregation analysis demonstrated that the cloned gene was the normal allele
      rather than a high copy suppressor. A disruption mutant was nonviable, indicating
      that the gene was essential. Sequence analysis and functional assays indicated
      that the cloned gene was identical to ERG25, a gene that codes for methyl sterol
      oxidase. Incubation of LT06 in low iron medium resulted in marked changes in
      lipid metabolism, including the accumulation of fatty acids, triglycerides,
      methyl sterols, and other sterol precursors. A human homologue of ERG25 was
      cloned, sequenced, and mapped to human chromosome 4q32-34. Analysis of the data
      base with both ERG25 and the human homologue resulted in the identification of a
      putative set of metal binding motifs with similarity to that seen in a family of
      membrane desaturases-hydroxylases. Western analysis using antibodies to an Erg25
      GST fusion protein detected two proteins of 34 and 75 kDa. Both proteins are
      membrane bound and contain one N-glycosyl unit. Immunofluorescence data suggest
      that the proteins are present in the endoplasmic reticulum and plasma membrane.
      Although ERG25 transcripts are not iron regulated, there is a large increase in
      the concentration of transcript in the mutant LT06 grown in low iron medium.
      These results suggest that the enzyme is regulated not by iron but by an end
      product of the ergosterol pathway.

PMID- 8663359
TI  - Characterization of Trypanosoma brucei gamma-glutamylcysteine synthetase, an
      essential enzyme in the biosynthesis of trypanothione (diglutathionylspermidine).
AB  - The parasitic protozoan Trypanosoma brucei maintains redox balance by
      synthesizing a conjugate of glutathione and spermidine termed trypanothione. The
      first committed step in the biosynthesis of glutathione, and thereby
      trypanothione, is catalyzed by the enzyme gamma-glutamylcysteine synthetase
      (gammaGCS). We have cloned and sequenced the 2037-base pair gene coding for the
      catalytic subunit of T. brucei gammaGCS. T. brucei gammaGCS appears to be encoded
      by a single copy gene. A transcript of about 2.3 kilobases was observed in
      procyclic trypomastigotes. The deduced amino acid sequence of 679 amino acids
      shares 45, 41, and 36% sequence identity with mammalian, Caenorhabditis elegans,
      and yeast gammaGCS, respectively. The T. brucei gammaGCS gene was expressed in E.
      coli; the purified 77.4-kDa enzyme catalyzes the ligation of L-Glu to L-Cys with
      a kcat of 10 s-1, confirming that the gene encodes the functional catalytic
      subunit of gammaGCS. The apparent Km values measured for the three natural
      substrates L-Glu, L-Cys, and ATP are 0.24, 0.69, and 0.07 mM, respectively.
      Unlike the mammalian enzyme, L-alpha-aminobutyrate (apparent Km = 10 mM) is a
      poor substitute for L-Cys in the T. brucei gammaGCS-catalyzed reaction. T. brucei
      gammaGCS is feedback-inhibited by glutathione (apparent KI = 1.1 mM), and it is
      inactivated by cystamine and buthionine sulfoximine. The kinetic properties of
      recombinant T. brucei gammaGCS suggest that the substrate binding pocket and the
      mechanism of enzyme regulation differ from the mammalian enzyme, providing
      evidence that T. brucei gammaGCS could be a selective chemotherapeutic target for
      the treatment of trypanosomiasis.

PMID- 8663360
TI  - Heparin inhibits mitogen-activated protein kinase-dependent and -independent c
      fos induction in mesangial cells.
AB  - Heparin suppresses mitogenic responses in renal mesangial cells, and when
      quiescent mesangial cells are stimulated with serum, heparin blocks the induction
      of c-fos seen at 15 min. Because heparin is taken up by cells over a much longer
      time course, we addressed mechanisms whereby extracellular heparin might suppress
      c-fos induction at such early times. Quiescent cells were treated with serum, 12
      O-tetradecanoylphorbol-13-acetate, or low concentrations of Ca2+ ionophores that
      produced increases in intracellular Ca2+ concentration ([Ca2+]i) in the
      physiological range. Each treatment caused an increase in c-fos mRNA, but they
      did so by different mechanisms. Serum activated mitogen-activated protein kinase
      (MAPK) and increased [Ca2+]i without affecting protein kinase C. Activation of
      protein kinase C with phorbol ester activated MAPK without much effect on
      [Ca2+]i. Ionophores increased [Ca2+]i without affecting basal levels of protein
      kinase C or MAPK. Heparin (1 microg/ml) suppressed the induction of c-fos
      initiated by all three treatments. It did not affect the activity of protein
      kinase C, but inhibited activation of MAPK by either serum or phorbol ester,
      suggesting a common site of action at or below the probable convergence of the
      induced signals at Ras/Raf-1 activation. Heparin also inhibited the serum
      stimulated entry of extracellular Ca2+ to the same extent as verapamil,
      consistent with the ability of verapamil to block L-type Ca2+ channels and the
      known presence of these channels in mesangial cells. However, this effect does
      not appear to be related to heparin's ability to inhibit induction of c-fos.
      First, verapamil had no effect on induction of c-fos by serum. Second, heparin
      had no effect on changes in [Ca2+]i achieved by ionophores. We conclude that
      heparin suppresses induction of c-fos in mesangial cells by blocking at least two
      different points in signal transduction cascades, one upstream of MAPK and the
      other independent of MAPK, but dependent on intracellular Ca2+.

PMID- 8663361
TI  - Okadaic acid exerts a full insulin-like effect on glucose transport and glucose
      transporter 4 translocation in human adipocytes. Evidence for a
      phosphatidylinositol 3-kinase-independent pathway.
AB  - The effects of the serine/threonine phosphatase inhibitor, okadaic acid, and
      insulin on glucose transport activity, glucose transporter 4 translocation to the
      plasma membrane, and the signaling pathway of insulin were examined in human
      adipocytes. Okadaic acid consistently produced a greater increase than insulin in
      the rate of glucose transport, and both agents together had a partial additive
      effect. Both insulin alone and okadaic acid alone stimulated the translocation of
      glucose transporter 4 to the plasma membrane. Insulin, but not okadaic acid,
      stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity, and wortmannin
      completely inhibited the effect of insulin on glucose transport. When the cells
      were incubated with both agents, okadaic acid inhibited insulin-stimulated PI 3
      kinase activity but did not block the association of the p85 or p110 subunits of
      PI 3-kinase with insulin receptor substrate 1. Insulin-stimulated tyrosine
      phosphorylation of insulin receptor substrate 1 was only slightly reduced (15
      30%) by okadaic acid. These data demonstrate that okadaic acid exerts a full
      insulin-like effect independent of the activation of PI 3-kinase. Thus, PI 3
      kinase lipid kinase is not essential for glucose transporter 4 translocation in
      human adipocytes, and different pathways exist that lead to glucose transporter 4
      translocation and increased glucose transport.

PMID- 8663362
TI  - Lipase activation by nonionic detergents. The crystal structure of the porcine
      lipase-colipase-tetraethylene glycol monooctyl ether complex.
AB  - The crystal structure of the ternary porcine lipase-colipase-tetra ethylene
      glycol monooctyl ether (TGME) complex has been determined at 2.8 A resolution.
      The crystals belong to the cubic space group F23 with a = 289.1 A and display a
      strong pseudo-symmetry corresponding to a P23 lattice. Unexpectedly, the
      crystalline two-domain lipase is found in its open configuration. This indicates
      that in the presence of colipase, pure micelles of the nonionic detergent TGME
      are able to activate the enzyme; a process that includes the movement of an N
      terminal domain loop (the flap). The effects of TGME and colipase have been
      confirmed by chemical modification of the active site serine residue using
      diisopropyl p-nitrophenylphosphate (E600). In addition, the presence of a TGME
      molecule tightly bound to the active site pocket shows that TGME acts as a
      substrate analog, thus possibly explaining the inhibitory effect of this nonionic
      detergent on emulsified substrate hydrolysis at submicellar concentrations. A
      comparison of the lipase-colipase interactions between our porcine complex and
      the human-porcine complex (van Tilbeurgh, H., Egloff, M.-P., Martinez, C.,
      Rugani, N., Verger, R., and Cambillau, C.(1993) Nature 362, 814-820) indicates
      that except for one salt bridge interaction, they are conserved. Analysis of the
      superimposed complexes shows a 5.4 degrees rotation on the relative position of
      the N-terminal domains excepting the flap that moves in a concerted fashion with
      the C-terminal domain. This flexibility may be important for the binding of the
      complex to the water-lipid interface.

PMID- 8663363
TI  - Cloning and characterization of the signal transduction of four splice variants
      of the human pituitary adenylate cyclase activating polypeptide receptor.
      Evidence for dual coupling to adenylate cyclase and phospholipase C.
AB  - Alternative splicing of two exons of the rat pituitary adenylate cyclase
      activating polypeptide (PACAP) receptor gene generates four major splice variants
      that are differentially expressed in specific tissues and variably coupled to
      intracellular second messengers. To evaluate the potential implications of these
      findings in human physiology, the human PACAP receptor gene was cloned.
      Alternative splicing about two exons of the gene allowed for four major splice
      variants that were subsequently identified on cDNA cloning. Each of the four
      splice variant cDNAs (null, SV-1, SV-2, and SV-3) was stably expressed in NIH/3T3
      cells at similar receptor densities. For each splice variant, PACAP (both PACAP
      38 and PACAP-27) had similar affinity and potency for stimulating either
      adenylate cyclase or phospholipase C. However, each receptor splice variant
      differed in their ligand-stimulated maximal response (efficacy) for total
      inositol phosphate accumulation with the SV-2 showing the greatest efficacy,
      followed by the null, SV-1, and SV-3 splice variants. Therefore, unlike the rat,
      PACAP binds and stimulates signal transduction with nearly equal affinity and
      potency for each of the receptor splice variants although with varying efficacy
      for the stimulation of phospholipase C. These results suggest a novel and
      potentially important mechanism for a single hormone to not only couple to dual
      signal transduction cascades but also elicit tissue-specific differential
      activation of phospholipase C in humans.

PMID- 8663364
TI  - Profactor IX propeptide and glutamate substrate binding sites on the vitamin K
      dependent carboxylase identified by site-directed mutagenesis.
AB  - The vitamin K-dependent carboxylase, a constituent of the endoplasmic reticulum
      membrane, catalyzes the conversion of reduced vitamin K to vitamin K epoxide and
      the concomitant conversion of glutamic acid to gamma-carboxyglutamic acid. To
      study structure-function relationships in the enzyme, seventeen clusters of
      charged residues of the bovine gamma-glutamyl carboxylase were substituted with
      alanines using site-specific mutagenesis. Wild-type and mutant carboxylase
      species were expressed in Chinese hamster ovary cells with an immunodetectable
      octapeptide inserted at their amino-terminal ends. Out of 17 mutant carboxylase
      species that contain a total of 41 charged residue to alanine substitutions,
      K217A/K218A (CBX217/218), R234A/H235A (CBX234/235), R359A/H360A/K361A
      (CBX359/360/361), R406A/H408A (CBX406/408), and R513A/K515A (CBX513/515) had
      impaired carboxylase activity compared with the wild-type enzyme. The vitamin K
      epoxidase activities of these mutants were reduced in parallel with the
      carboxylase activities. CBX217/218 appears to be inactive. High propeptide
      concentrations were required for stimulation of carboxylation of FLEEL by
      CBX234/235, CBX406/408, and CBX513/515, suggesting defects in the propeptide
      binding site. CBX359/360/361 showed normal affinity for the propeptide, FLEEL,
      proPT28, and vitamin K hydroquinone but exhibited a low catalytic rate for
      carboxylation. These results suggest that residue 217, residue 218, or both are
      either critical for catalysis or for maintaining the structure of a catalytically
      active enzyme. Regions around residues 234, 406, and 513 define in part the
      propeptide binding site, while the regions around residue 359 are involved in
      catalysis.

PMID- 8663365
TI  - A venus flytrap mechanism for activation and desensitization of alpha-amino-3
      hydroxy-5-methyl-4-isoxazole propionic acid receptors.
AB  - Desensitization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
      (AMPA) subtype of glutamate receptor channels is an important process shaping the
      time course of synaptic excitation. Upon desensitization, the receptor channel
      closes and the agonist affinity increases. So far, the nature of the structural
      rearrangements leading to these events was unknown. On the basis of the
      structural homology of the ligand binding domains of AMPA receptors and of the
      bilobated bacterial periplasmic proteins, we now show that agonist interaction
      with one lobe of the GluR1 subunit of homomeric AMPA receptors controls channel
      activation while additional interactions with the other lobe cause channel
      desensitization. Accordingly, we suggest that the transition of the AMPA receptor
      channel to the desensitized state involves the agonist-mediated stabilization of
      the closed lobe conformation of its binding domain and is a process akin to that
      used by the venus flytrap.

PMID- 8663366
TI  - A salt-resistant plasma membrane carbonic anhydrase is induced by salt in
      Dunaliella salina.
AB  - The mechanisms allowing proliferation of the unicellular green alga Dunaliella
      salina in up to saturating NaCl concentrations are only partially understood at
      present. Previously, the level of a plasma membrane Mr 60,000 protein, p60, was
      found to increase with rising external salinities. Based on cDNA cloning and
      enzymatic assays, it is now shown that p60 is an internally duplicated carbonic
      anhydrase, with each repeat homologous to animal and Chlamydomonas reinhardtii
      carbonic anhydrases, but exceptional in the excess of acidic over basic residues.
      Increasing salinities, alkaline shift, or removal of bicarbonate induced in D.
      salina parallel increases in the levels of p60, its mRNA, and external carbonic
      anhydrase activity. Moreover, purified p60 exhibited carbonic anhydrase activity
      comparable to other carbonic anhydrases. A p60-enriched soluble preparation
      showed maximal carbonic anhydrase activity at approximately 1.0 M NaCl and
      retained considerable activity at higher salt concentrations. In contrast, a
      similar preparation from C. reinhardtii was approximately 90% inhibited in 0.6 M
      NaCl. These results identified p60 as a structurally novel carbonic anhydrase
      transcriptionally regulated by CO2 availability and exhibiting halophilic-like
      characteristics. This enzyme is potentially suited to optimize CO2 uptake by
      cells growing in hypersaline media.

PMID- 8663367
TI  - Extracellular K+ and intracellular pH allosterically regulate renal Kir1.1
      channels.
AB  - The channels that control K+ homeostasis by mediating K+ secretion across the
      apical membrane of renal tubular cells have recently been cloned and designated
      ROMK1, -2, and -3. Native apical K+ channels are indirectly regulated by the K+
      concentration at the basolateral membrane through a cascade of intracellular
      second messengers. It is shown here that ROMK1 (Kir1.1) channels are also
      directly regulated by the extracellular (apical) K+ concentration, and that this
      K+ regulation is coupled to intracellular pH. The K+ regulation and its coupling
      to pH were assigned to different structural parts of the channel protein. K+
      regulation is determined by the core region, which comprises the two hydrophobic
      segments M1 and M2 and the P region. Decoupling from pH was achieved by
      exchanging the N terminus of ROMK1 by that of the pH-insensitive channel IRK1
      (Kir2.1). These results suggest an allosteric regulation of ROMK1 channels by
      extracellular K+ and intracellular pH, which may represent a novel link between
      K+ homeostasis and pH control.

PMID- 8663368
TI  - Reversible Ca2+-dependent translocation of protein kinase C and glucose-induced
      insulin release.
AB  - It has been reported that protein kinase C (PKC) interacts at multiple sites in
      beta-cell stimulus-secretion coupling. Nevertheless, there is still controversy
      concerning the importance of this enzyme in glucose-induced insulin release. The
      present study was undertaken to clarify whether glucose, directly, or through
      changes in cytoplasmic free Ca2+ concentration, [Ca2+]i, could promote
      translocation of PKC from the soluble to the membrane compartment. Whereas
      glucose, which increases [Ca2+]i, did not affect long-term distribution of PKC
      activity between soluble and membrane fractions, this distribution was reversibly
      affected acutely by the Ca2+ concentration in the extraction media. Translocation
      of PKC to the membrane by incubation of HIT cells for 10 min in the presence of
      20 nM phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in a 5
      fold increase in glucose-induced insulin release. This was prevented by 50 nM
      concentration of the PKC inhibitor staurosporine, provided that the cells were
      exposed to the inhibitor before the phorbol ester. Cells pretreated with TPA
      demonstrated increased insulin secretion in response to glucose for several
      hours. This time course extended beyond the disappearance of [3H]TPA from the
      cells, which was complete after 1 h. Activation of PKC increased both average
      insulin release and the amplitude of oscillations 2-fold, but did not affect
      oscillation frequency. The stimulatory effect of increased PKC activity on
      insulin release was not matched by changes in [Ca2+]i. We suggest that
      stimulation of the pancreatic beta-cell with glucose promotes transient
      translocation of certain PKC isoforms from the cytoplasm to the plasma membrane
      as a direct consequence of the increase in [Ca2+]i. Such a translocation may
      promote phosphorylation of one or several proteins involved in the regulation of
      the beta-cell stimulus-secretion coupling. This results in potentiation of
      glucose-induced activation of insulin exocytosis, an effect then not mediated by
      an increase in [Ca2+]i per se. Hence, pulsatile insulin release can be obtained
      under conditions where overall [Ca2+]i does not change, challenging the view that
      oscillations in [Ca2+ ]i are indeed driving the oscillations in hormone release.

PMID- 8663370
TI  - Thermal stability of hexameric and tetrameric nucleoside diphosphate kinases.
      Effect of subunit interaction.
AB  - The eukaryotic nucleoside diphosphate (NDP) kinases are hexamers, while the
      bacterial NDP kinases are tetramers made of small, single domain subunits. These
      enzymes represent an ideal model for studying the effect of subunit interaction
      on protein stability. The thermostability of NDP kinases of each class was
      studied by differential scanning calorimetry and biochemical methods. The
      hexameric NDP kinase from Dictyostelium discoideum displays one single,
      irreversible differential scanning calorimetry peak (Tm 62 degrees C) over a
      broad protein concentration, indicating a single step denaturation. The thermal
      stability of the protein was increased by ADP. The P105G substitution, which
      affects a loop implicated in subunit contacts, yields a protein that reversibly
      dissociates to folded monomers at 38 degrees C before the irreversible
      denaturation occurs (Tm 47 degrees C). ADP delays the dissociation, but does not
      change the Tm. These data indicate a "coupling" of the quaternary structure with
      the tertiary structure in the wild-type, but not in the mutated protein. We
      describe the x-ray structure of the P105G mutant at 2.2-A resolution. It is very
      similar to that of the wild-type protein. Therefore, a minimal change in the
      structure leads to a dramatic change of protein thermostability. The NDP kinase
      from Escherichia coli behaves like the P105G mutant of the Dictyostelium NDP
      kinase. The detailed study of their thermostability is important, since
      biological effects of thermolabile NDP kinases have been described in several
      organisms.

PMID- 8663371
TI  - The in vitro generation of post-Golgi vesicles carrying viral envelope
      glycoproteins requires an ARF-like GTP-binding protein and a protein kinase C
      associated with the Golgi apparatus.
AB  - We have developed a system that recreates in vitro the generation of post-Golgi
      vesicles from an isolated Golgi fraction prepared from vesicular stomatitis virus
      or influenza virus-infected Madin-Darby canine kidney or HepG2 cells. In this
      system, vesicle generation is temperature- and ATP-dependent and requires a
      supply of cytosolic proteins, including an N-ethylmaleimide-sensitive factor
      distinct from NSF. Cytosolic proteins obtained from yeast were as effective as
      mammalian cytosolic proteins in supporting vesicle formation and had the same
      requirements. The vesicles produced (50-80 nm in diameter) are depleted of the
      trans Golgi marker sialyltransferase, contain the viral glycoprotein molecules
      with their cytoplasmic tails exposed, and do not show an easily recognizable
      protein coat. Vesicle generation was inhibited by brefeldin A, which indicates
      that it requires the activation of an Arf-like GTP-binding protein that promotes
      assembly of a vesicle coat. Vesicles formed in the presence of the
      nonhydrolyzable GTP analogue guanosine 5'-3-O-(thio)triphosphate retained a
      nonclathrin protein coat resembling that of COP-coated vesicles, and sedimented
      more rapidly in a sucrose gradient than the uncoated ones generated in its
      absence. This indicates that GTP hydrolysis is not required for vesicle
      generation but that it is for vesicle uncoating. The activity of a Golgi
      associated protein kinase C (PKC) was found to be necessary for the release of
      post-Golgi vesicles, as indicated by the capacity of a variety of inhibitors and
      antibodies to PKC to suppress it, as well as by the stimulatory effect of the PKC
      activator 12-O-tetradecanoylphorbol-13-acetate.

PMID- 8663372
TI  - The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta
      peptide but not aggregated, cytotoxic amyloid-beta peptide.
AB  - There is now extensive evidence that amyloid-beta peptide is toxic to neurons and
      that its cytotoxic effects can be attributed to a domain corresponding to amyloid
      beta 25-35, GSNKGAIIGLM. We have shown recently that the serine proteinase
      inhibitor (serpin)-enzyme complex receptor (SEC-R), a receptor initially
      identified for binding of alpha1-antitrypsin (alpha1-AT) and other serine
      protease inhibitors, also recognizes the amyloid-beta 25-35 domain. In fact, by
      recognizing the amyloid-beta 25-35 domain, SEC-R mediates cell surface binding,
      internalization, and degradation of soluble amyloid-beta peptide. In this study,
      we examined the possibility that SEC-R mediates the neurotoxic effect of amyloid
      beta peptide. A series of peptides based on the sequences of amyloid-beta peptide
      and alpha1-AT was prepared soluble in dimethyl sulfoxide or insoluble in water
      and examined in assays for SEC-R binding, for cytotoxicity in neuronal PC12 cells
      and murine cortical neurons in primary culture, and for aggregation in sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The
      results show that amyloid-beta peptide 25-35 and amyloid-beta peptide 1-40
      prepared soluble in dimethyl sulfoxide compete for binding to SEC-R, are
      nontoxic, and migrate as monomers in SDS-PAGE analysis. In contrast, the same
      peptides aged in water did not compete for binding to SEC-R but were toxic and
      migrated as aggregates in SDS-PAGE. An all-D-amyloid-beta 25-35 peptide was not
      recognized at all by SEC-R but retained full toxic/aggregating properties. Using
      a series of deleted, substituted, and chimeric ambeta/alpha1-AT peptides,
      toxicity correlated well with aggregation but poorly with SEC-R recognition. In a
      subclone of PC12 cells which developed resistance to the toxic effect of
      aggregated amyloid-beta 25-35 there was a 2.5-3-fold increase in the number of
      SEC-R molecules/cell compared with the parent PC12 cell line. These data show
      that SEC-R does not mediate the cytotoxic effect of aggregated amyloid-beta
      peptide. Rather, SEC-R could play a protective role by mediating clearance and
      catabolism of soluble, monomeric amyloid-beta peptide, if soluble amyloid-beta
      peptide proves to be an in vivo precursor of the insoluble, toxic peptide.

PMID- 8663373
TI  - The RNA chain elongation rate of the lambda late mRNA is unaffected by high
      levels of ppGpp in the absence of amino acid starvation.
AB  - In this study, the effects of high levels of guanosine tetraphosphate (ppGpp) on
      the decay and RNA chain elongation kinetics of the bacteriophage lambda late
      transcript in Escherichia coli were examined in the absence of amino acid
      starvation. The accumulation, mRNA decay kinetics, and RNA chain elongation rate
      of the lambda late mRNA were determined after heat induction of lambdacI857
      lysogens in the presence of high levels of ppGpp induced from a RelAalpha
      fragment-overproducing plasmid. The accumulation kinetics and elongation rate
      determinations of the late mRNA were made at long times after induction to allow
      a new steady state of transcriptional activities under conditions of elevated
      intracellular levels of ppGpp. The results indicate no prolonged or significant
      effect on either mRNA decay or the RNA chain elongation rate of the late mRNA as
      a result of elevated ppGpp levels. Surprisingly, the RNA chain elongation rate
      determinations indicate an RNA polymerase processivity of approximately 90-100
      nucleotides/s for the lambda late transcript despite the presence of high levels
      of ppGpp. The results are discussed in terms of various models for regulation of
      stable and messenger RNA synthesis in E. coli.

PMID- 8663375
TI  - Role of Arg112 of cytochrome p450cam in the electron transfer from reduced
      putidaredoxin. Analyses with site-directed mutants.
AB  - The mechanism for the reduction of ferric cytochrome P450cam by reduced
      putidaredoxin, the physiological electron donor for the cytochrome, has been
      studied by using site-directed mutants of cytochrome P450cam, in which Arg112, an
      amino acid residue at the presumed binding site for putidaredoxin, was changed to
      several other amino acid residues. The affinity of reduced putidaredoxin for
      ferric cytochrome P450cam to form a diprotein complex was decreased greatly by
      changing Arg112 to a neutral amino acid such as Cys, Met, or Tyr. The rate of
      intracomplex electron transfer from putidaredoxin to cytochrome P450cam also
      diminished upon replacing the basic residue with neutral ones, being 42, 18, 4.0,
      1.3, and 0. 16 s-1 for Arg (wild type), Lys, Cys, Met, and Tyr enzymes,
      respectively. Furthermore, the oxidation-reduction potential of cytochrome
      P450cam (Fe3+/Fe2+ couple) decreased in a similar way to the decrease in the rate
      of electron transfer upon amino acid substitution; the values were -138, -162, 
      182, -200, and -195 mV for Arg (wild type), Lys, Cys, Met, and Tyr enzymes,
      respectively. These results indicate that the amino acid substitution at position
      112 affects the oxidation-reduction potential of the heme iron in cytochrome
      P450cam, thereby diminishing the rate of electron transfer between the two metal
      centers. The rate of electron transfer from putidaredoxin to oxyferrous
      cytochrome P450cam also diminished upon substitution of Arg112 with a neutral
      amino acid.

PMID- 8663374
TI  - Binding of viral antigens to major histocompatibility complex class I H-2Db
      molecules is controlled by dominant negative elements at peptide non-anchor
      residues. Implications for peptide selection and presentation.
AB  - Binding of viral antigens to major histocompatibility complex (MHC) class I
      molecules is a critical step in the activation process of CD8(+) cytotoxic T
      lymphocytes. In this study, we investigated the impact of structural factors at
      non-anchor residues in peptide-MHC interaction using the model of lymphocytic
      choriomeningitis virus (LCMV) infection of its natural host, the mouse. Altering
      viral genes by making reassortants, recombinants, and using synthetic peptides,
      CD8(+) cytotoxic T lymphocytes were shown to recognize only three H-2Db
      restricted epitopes, GP amino acids 33-41/43, GP 276-286, and NP 396-404.
      However, LCMV NP and GP proteins contain 31 other peptides bearing the H-2Db
      motif. These 34 LCMV peptides and 11 other known H2-Db-restricted peptides were
      synthesized and examined for MHC binding properties. Despite the presence of the
      H-2Db binding motif, the majority of LCMV peptides showed weak or no affinity for
      H-2Db. We observed that dominant negative structural elements located at non
      anchor positions played a crucial role in peptide-MHC interaction. By comparative
      sequence analysis of strong versus non-binders and using molecular modeling, we
      delineated these negative elements and evaluated their impact on peptide-MHC
      interaction. Our findings were validated by showing that a single mutation of a
      favorable non-anchor residue in the sequence of known viral epitopes for a
      negative element resulted in dramatic reduction of antigen presentation
      properties, while conversely, substitution of one negative for a positive element
      in the sequence of a non-binder conferred to the peptide an ability to now bind
      to MHC molecules.

PMID- 8663376
TI  - Swapping between Fas and granulocyte colony-stimulating factor receptor.
AB  - Fas belongs to the tumor necrosis factor/nerve growth factor receptor family. The
      Fas ligand binds to its receptor, Fas, and induces apoptosis in Fas-bearing
      cells. The granulocyte colony-stimulating factor receptor (G-CSFR) is a member of
      the hemopoietic growth factor receptor family. G-CSF induces its dimerization and
      regulates the proliferation and differentiation of neutrophilic granulocytes. We
      constructed hybrid receptors between Fas and G-CSFR and expressed them in the
      mouse T cell line WR19L or the mouse myeloid interleukin-3-dependent FDC-P1 cell
      line. The Fas ligand or an agonistic anti-Fas antibody stimulated proliferation
      of the FDC-P1 transformants expressing a chimera consisting of the Fas
      extracellular and G-CSFR cytoplasmic regions. On the other hand, G-CSF could not
      induce apoptosis in the transformants expressing the chimera consisting of the G
      CSFR extracellular and Fas cytoplasmic regions, but these cells were killed by a
      polyclonal antibody against G-CSFR. These results indicated that receptors
      belonging to different receptor families can be functionally exchanged and
      confirm that a homodimer of G-CSFR can transduce the growth signal, whereas Fas
      must be oligomerized (probably trimerized) to transduce the apoptotic signal.

PMID- 8663377
TI  - Cloning, characterization, and properties of seven triplet repeat DNA sequences.
AB  - Several neuromuscular and neurodegenerative diseases are caused by genetically
      unstable triplet repeat sequences (CTG.CAG, CGG.CCG, or AAG.CTT) in or near the
      responsible genes. We implemented novel cloning strategies with chemically
      synthesized oligonucleotides to clone seven of the triplet repeat sequences
      (GTA.TAC, GAT.ATC, GTT.AAC, CAC.GTG, AGG.CCT, TCG.CGA, and AAG.CTT), and the
      adjoining paper (Ohshima, K., Kang, S., Larson, J. E., and Wells, R. D.(1996) J.
      Biol. Chem. 271, 16784-16791) describes studies on TTA.TAA. This approach in
      conjunction with in vivo expansion studies in Escherichia coli enabled the
      preparation of at least 81 plasmids containing the repeat sequences with lengths
      of approximately 16 up to 158 triplets in both orientations with varying extents
      of polymorphisms. The inserts were characterized by DNA sequencing as well as DNA
      polymerase pausings, two-dimensional agarose gel electrophoresis, and chemical
      probe analyses to evaluate the capacity to adopt negative supercoil induced non-B
      DNA conformations. AAG.CTT and AGG.CCT form intramolecular triplexes, and the
      other five repeat sequences do not form any previously characterized non-B
      structures. However, long tracts of TCG.CGA showed strong inhibition of DNA
      synthesis at specific loci in the repeats as seen in the cases of CTG.CAG and
      CGG.CCG (Kang, S., Ohshima, K., Shimizu, M., Amirhaeri, S., and Wells, R.
      D.(1995) J. Biol. Chem. 270, 27014-27021). This work along with other studies
      (Wells, R. D.(1996) J. Biol. Chem. 271, 2875-2878) on CTG.CAG, CGG.CCG, and
      TTA.TAA makes available long inserts of all 10 triplet repeat sequences for a
      variety of physical, molecular biological, genetic, and medical investigations. A
      model to explain the reduction in mRNA abundance in Friedreich's ataxia based on
      intermolecular triplex formation is proposed.

PMID- 8663378
TI  - TTA.TAA triplet repeats in plasmids form a non-H bonded structure.
AB  - CTG.CAG, CGG.CCG, and AAG.CTT triplet repeats proximal to or in disease genes
      expand by a non-Mendelian genetic process to cause several human hereditary
      syndromes. As part of our physical, biological, and genetic studies on the 10
      possible triplet repeats, we discovered that the TTA.TAA repeat, isolated from
      the upstream region of the variant surface glycoprotein gene of Trypanosoma
      brucei, shows a propensity to adopt a non-H bonded structure under appropriate
      conditions. The other nine triplet repeat sequences do not exhibit this property.
      (TTA.TAA)n, where n = 90, 60, 30, and 18, cloned into pUC19 was studied by
      chemical and enzymatic probes as well as two-dimensional gel electrophoretic
      analyses under a variety of conditions. The helix opening was observed for all
      four inserts in supercoiled plasmids as a function of temperature, pH, metal
      ions, and buffer conditions using OsO4, diethyl pyrocarbonate, and
      chloroacetaldehyde probes. This unusual property of the TTA.TAA repeat suggests
      that it plays a different role from the other nine triplet repeats in gene
      expression.

PMID- 8663379
TI  - A novel factor required for the assembly of the DnaK and DnaJ chaperones of
      Thermus thermophilus.
AB  - We previously reported the isolation of T.DnaK.DnaJ chaperone complex from
      Thermus thermophilus. Here, we show that a novel factor is necessary for the
      assembly of T.DnaK and T.DnaJ into the complex. A dnaK gene cluster of T.
      thermophilus contained five genes, dnaK-grpE-dnaJ-orf4-clpB. Interestingly,
      T.DnaJ lacks the whole "cysteine-rich region" that has been postulated to be
      necessary to bind unfolded proteins. The orf4 gene encodes a novel 78-amino acid
      protein. Curiously, T.DnaK and T.DnaJ expressed in Escherichia coli did not form
      the complex. Careful reexamination of the T.DnaK.DnaJ complex revealed the
      presence of a small protein in the complex, which turned out to be a product of
      orf4. As expected, expression of three genes, dnaK-dnaJ-orf4, resulted in
      production of a T.DnaK.DnaJ complex in E. coli that was indistinguishable from
      the authentic complex in its ability to interact with nucleotide and denatured
      protein. The product of orf4 was also required for in vitro reconstitution of the
      complex and named T.DafA (T.DnaK.DnaJ assembly factor A). The complex comprises
      three copies each of T.DnaK, T.DnaJ, and T.DafA. Even though a definite homolog
      of T.DafA has not been found in the data base, this finding raises a possibility
      that interaction between DnaK and DnaJ chaperones in other organisms is also
      mediated by a small protein yet unnoticed.

PMID- 8663380
TI  - The c-Jun delta-domain inhibits neuroendocrine promoter activity in a DNA
      sequence- and pituitary-specific manner.
AB  - The transcription and transformation activity of c-Jun is governed by a 27-amino
      acid regulatory motif, labeled the delta-domain, which is deleted in v-Jun. We
      have previously shown that c-Jun is a potent inhibitor of the rat prolactin
      (rPRL) promoter activity induced by either oncogenic Ras or phorbol esters. Here,
      we have characterized the structural and cell-specific requirements for this c
      Jun inhibitory response, and we show that this c-Jun inhibitory response mapped
      to the rPRL footprint II repressor site, was pituitary-specific and required the
      c-Jun delta-domain. Moreover, alteration of any one of these features (e.g., cis
      element, trans-factor, or cell-specific background) switched c-Jun to a
      transcriptional activator of the rPRL promoter. In HeLa nonpituitary cells, c-Jun
      alone activated the rPRL promoter via the most proximal GHF-1/Pit-1 binding site,
      footprint I, and synergized with GHF-1. Finally, recombinant GHF-1 interacted
      directly with c-Jun but not c-Fos proteins. These data provide important
      fundamental insights into the molecular mechanisms by which the c-Jun delta
      domain functions as a modulatory switch and further imply that the functional
      role of c-Jun is dictated by cell-specific influences and the delta-domain motif.

PMID- 8663381
TI  - Isotope dilution mass spectrometric measurements indicate that
      arachidonylethanolamide, the proposed endogenous ligand of the cannabinoid
      receptor, accumulates in rat brain tissue post mortem but is contained at low
      levels in or is absent from fresh tissue.
AB  - Arachidonylethanolamide (AEA) isolated from porcine brain binds to cannabinoid
      receptors, mimics cannabinoid pharmacologic effects, and has been proposed as an
      endogenous cannabinoid receptor ligand. Demonstration of co-distribution of AEA
      and cannabinoid receptors in various brain regions could provide supportive
      evidence for this role. We have performed isotope dilution mass spectrometric
      measurements of AEA and have demonstrated AEA production by rat tissue
      homogenates in vitro from exogenous arachidonate and ethanolamine. No detectable
      endogenous AEA (<3.5 pmol/g of tissue) was observed in fresh rat brain, whether
      or not inhibitors of AEA hydrolysis were present during tissue processing. AEA
      (>1 nmol/g) was produced during saponification of brain phospholipid extracts.
      This appears not to reflect hydrolysis of N-arachidonylethanolamine phospholipid
      precursors of AEA, because Streptomyces chromfucsis phospholipase D, which is
      active against NAPE, failed to generate AEA from brain phospholipids despite
      substantial conversion of phospholipids to phosphatidic acid. Such experiments
      suggested that the abundance of N-arachidonylethanolamine phospholipid in fresh
      rat brain may be less than 1 in 10(6) phospholipid molecules. AEA generated
      during saponification of tissue phospholipids appears to arise from base
      catalyzed aminolysis of arachidonate-containing glycerolipids, because AEA was
      produced from synthetic (1-stearoyl, 2-arachidonoyl)-phosphatidylethanolamine
      under saponification conditions, and the amount produced increased 300-fold when
      free ethanolamine was included in the hydrolysis solution. Although AEA was not
      detectable (<0.17 pmol/mg of protein) in fresh rat brain, AEA accumulated post
      mortem to levels of 126 pmol/mg of brain protein. These findings do not exclude
      the possibility that AEA is rapidly synthesized and degraded locally in vivo, but
      they indicate that the AEA content of fresh rat brain and of NAPE precursors from
      which AEA might be derived are exceedingly low and that AEA can be produced
      artifactually from biological materials.

PMID- 8663382
TI  - Refolding of denatured and denatured/reduced lysozyme at high concentrations.
AB  - Refolding of proteins at high concentrations often results in aggregation. To
      gain insight into the molecular aspects of refolding and to improve the yield of
      active protein, we have studied the refolding of lysozyme either from its
      denatured state or from its denatured/reduced state. Refolding of denatured
      lysozyme, even at 1 mg/ml, yields fully active enzyme without aggregation.
      However, refolding of denatured/reduced lysozyme into buffer that lacks
      thiol/disulfide reagents leads to aggregation. Thiol/disulfide redox reagents
      such as cysteine/cystine and reduced/oxidized glutathione facilitate the
      renaturation, with the yield depending on their absolute concentrations. We have
      obtained an approximately 70% renaturation yield upon refolding of lysozyme at
      150 microgram/ml. The cysteine/cystine redox system is more efficient compared
      with the glutathione redox system. When lysozyme is refolded in the absence of
      redox reagents, a transient intermediate that has regained a significant amount
      of secondary structure is formed. The tryptophans in this intermediate are as
      exposed to water as in the fully unfolded protein. It shows increased exposure of
      hydrophobic surfaces compared with the native or completely unfolded enzyme. This
      aggregation-prone intermediate folds to active enzyme upon addition of oxidized
      glutathione before the aggregation process starts. These properties of the
      intermediate in the refolding pathway of lysozyme are similar to those proposed
      for the molten globule.

PMID- 8663383
TI  - Site-directed mutagenesis of glycine 99 to alanine in L-lactate monooxygenase
      from Mycobacterium smegmatis.
AB  - L-Lactate monooxygenase (LMO) from Mycobacterium smegmatis was mutated at glycine
      99 to alanine, and the properties of the resulting mutant (referred to as G99A)
      were studied. Mutant G99A of LMO was designed to test the postulate that the
      smaller glycine residue in the vicinity of the alpha-carbon methyl group of
      lactate in wild-type LMO has less steric hindrance, leading to the retention and
      oxidative decarboxylation of pyruvate in the active site, a unique property of
      LMO in contrast to other members of the FMN-dependent oxidase/dehydrogenase
      family. G99A has been shown to be readily reduced by L-lactate at a rate similar
      to that of the wild-type enzyme. The binding of pyruvate to reduced G99A is 4
      fold weaker than that to the wild-type enzyme. A dramatic change of this mutation
      is that G99A has a much lower oxygen reactivity than the wild-type enzyme.
      Pyruvate-bound reduced G99A reacts with O2 at a rate approximately 10(5)-fold
      slower than the wild-type enzyme, and free reduced G99A reacts with O2 at a rate
      approximately 100-fold slower than the wild-type enzyme. Due to the very low
      oxygen reactivity of the pyruvate-bound reduced enzyme, G99A has been shown to
      catalyze the oxidation of L-lactate to pyruvate and hydrogen peroxide instead of
      acetate, carbon dioxide, and water, the normal decarboxylation products of
      pyruvate and hydrogen peroxide. Thus, the mutation alters the enzyme from its L
      lactate monooxygenase activity to L-lactate oxidase activity. However, compared
      with L-lactate oxidase, G99A has a much lower reactivity toward oxygen. Our
      results also reveal that the small steric change around N-5 of the flavin causes
      a profound change in the electronic distribution in the catalytic cavity of the
      enzyme and imply that electrostatic interactions in the active site provide an
      important factor for control of O2 reactivity.

PMID- 8663384
TI  - Modulation of the thermosensing profile of the Escherichia coli aspartate
      receptor tar by covalent modification of its methyl-accepting sites.
AB  - The Escherichia coli aspartate receptor Tar is involved in the thermotactic
      response. We have studied how its thermosensing function is affected by the
      modification of the four methyl-accepting residues (Gln295, Glu302, Gln309, and
      Glu491), which play essential roles in adaptation. We found that the primary
      translational product of tar mediates a chemoresponse, but not a thermoresponse,
      and that Tar comes to function as a thermoreceptor, once Gln295 or Gln309 is
      deamidated. This is the first identification of a thermosensing-specific mutant
      form, suggesting that the methylation sites of Tar constitute at least a part of
      the region required for thermoreception, signaling, or both. We have also
      investigated the inverted thermoresponse mediated by Tar in the presence of
      aspartate. We found that, whereas the deamidated-and-unmethylated form functions
      as a warm receptor, eliciting a smooth-swimming signal upon increase of
      temperature, the heavily methylated form functions as a cold receptor, eliciting
      a smooth-swimming signal upon decrease of temperature. Thus, it is suggested that
      Tar exists in at least three distinct states, each of which allows it to function
      as a warm, cold, or null thermoreceptor, depending on the modification patterns
      of its methylation sites.

PMID- 8663386
TI  - Identification of amino acids critical for the DNA binding and dimerization
      properties of the human retinoic acid receptor alpha. Importance of lysine 360,
      lysine 365, and valine 361.
AB  - Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) activate target
      genes by binding to retinoic acid response elements (RAREs) as heterodimeric,
      asymmetrical complexes, and display a high degree of cooperativity in binding to
      RAREs. We have examined here the effect of lysine, cysteine, arginine, histidine,
      and tyrosine side chain chemical modification on the DNA binding, homo- and
      heterodimerization properties of the full-length human retinoic acid receptor
      alpha (hRARalpha). Lysines are the only residues to be engaged in the
      dimerization with human retinoid X receptor alpha (hRXRalpha) in the absence of
      DNA, whereas histidines are selectively involved in the homodimerization of
      hRARalpha in the presence of a RARE. Arginine modification affected the DNA
      binding activity of each type of dimer, whereas cysteines and tyrosines were
      primarily involved in the homo- or heterodimerization process in the presence of
      the same RARE. Modified lysines, interfering with the dimerization with
      hRXRalpha, were identified by receptor labeling and peptide mapping. They are
      located in the hormone binding domain eighth heptad repeat, at positions 360 and
      365. In keeping with these results, mutation of Lys360, Val361, and Lys365
      diminished strongly the DNA binding activity of hRARalpha as a homodimer or a
      heterodimer. Our results thus provide direct evidence for the differential
      involvement of basic, polar, or aromatic amino acids in the DNA binding,
      homodimerization, and heterodimerization properties of hRARalpha. Furthermore,
      they demonstrate the use of distinct dimerization interfaces and identify the
      type of amino acids involved in these protein-protein interactions.

PMID- 8663385
TI  - Human muscarinic cholinergic receptor Hm1 internalizes via clathrin-coated
      vesicles.
AB  - The mechanism by which muscarinic receptors internalize upon agonist exposure is
      poorly understood. To determine the endocytic pathways responsible for muscarinic
      receptor internalization, we have stably transfected human embryonic kidney (HEK
      293) cells with the Hm1 (human muscarinic subtype 1) receptor tagged at the amino
      terminus with the epitope EYMPME. The subcellular location of the receptor was
      visualized by immunofluorescence confocal microscopy and quantified with the use
      of binding studies. The receptor redistributed into intracellular compartments
      following agonist treatment. This process was reversible upon removal of agonist
      and inhibited by antagonist. Acid treatment of the cells, which disrupts
      internalization via clathrin-coated vesicles, inhibited carbachol-stimulated
      internalization. Phorbol 12-myristate 13-acetate, on the other hand, which
      inhibits caveolae-mediated endocytosis, had no effect on carbachol-induced
      endocytosis. Double-labeling confocal microscopy was used to characterize the
      intracellular vesicles containing Hm1 receptor following agonist treatment. The
      Hm1 receptor was shown to be colocalized with clathrin and alpha-adaptin, a
      subunit of the AP2 adaptor protein which links endocytosed proteins with clathrin
      in the intracellular vesicles. In addition, endosomes containing Hm1 also
      contained the transferrin receptor, which internalizes via clathrin-coated
      vesicles. In contrast, caveolin, the protein that comprises caveolae, did not
      colocalize with Hm1 in intracellular vesicles following agonist treatment,
      indicating that caveolae are not involved in the agonist-induced internalization
      of Hm1. These results indicate that agonist-induced internalization of the Hm1
      receptor occurs via clathrin-coated vesicles in HEK cells.

PMID- 8663387
TI  - X-ray structure of human beta3beta3 alcohol dehydrogenase. The contribution of
      ionic interactions to coenzyme binding.
AB  - The three-dimensional structure of the human beta3beta3 dimeric alcohol
      dehydrogenase (beta3) was determined to 2.4-A resolution. beta3 was crystallized
      as a ternary complex with the coenzyme NAD+ and the competitive inhibitor 4
      iodopyrazole. beta3 is a polymorphic variant at ADH2 that differs from beta1 by a
      single amino acid substitution of Arg-369 --> Cys. The available x-ray structures
      of mammalian alcohol dehydrogenases show that the side chain of Arg-369 forms an
      ion pair with the NAD(H) pyrophosphate to stabilize the E.NAD(H) complex. The Cys
      369 side chain of beta3 cannot form this interaction. The three-dimensional
      structures of beta3 and beta1 are virtually identical, with the exception that
      Cys-369 and two water molecules in beta3 occupy the position of Arg-369 in beta1.
      The two waters occupy the same positions as two guanidino nitrogens of Arg-369.
      Hence, the number of hydrogen bonding interactions between the enzyme and NAD(H)
      are the same for both isoenzymes. However, beta3 differs from beta1 by the loss
      of the electrostatic interaction between the NAD(H) pyrophosphate and the Arg-369
      side chain. The equilibrium dissociation constants of beta3 for NAD+ and NADH are
      350-fold and 4000-fold higher, respectively, than those for beta1. These changes
      correspond to binding free energy differences of 3.5 kcal/mol for NAD+ and 4.9
      kcal/mol for NADH. Thus, the Arg-369 --> Cys substitution of beta3 isoenzyme
      destabilizes the interaction between coenzyme and beta3 alcohol dehydrogenase.

PMID- 8663388
TI  - Identification and characterization of basal and cyclic AMP response elements in
      the promoter of the rat hexokinase II gene.
AB  - Hexokinases catalyze the phosphorylation of glucose and initiate cellular glucose
      metabolism. Hexokinase II (HKII) is the principal hexokinase isoform in skeletal
      muscle, heart, and adipose tissue. Isoproterenol and exogenous cyclic AMP (cAMP)
      increase HKII gene transcription in L6 myotubes. Various segments of the HKII
      promoter that direct the expression of the chloramphenicol acetyltransferase
      reporter gene were transfected into L6 myotubes to identify basal and cAMP
      response elements. The 5'-flanking region that extends 90 base pairs upstream of
      the transcription start site includes a CCAAT box and a cAMP response element
      (CRE); both contribute to basal promoter activity and each provides an
      independent, maximal response to cAMP. An inverted CCAAT motif, or Y box, located
      just upstream of the CCAAT box, contributes to basal promoter activity but is not
      involved in the cAMP response. Homo- and heterodimers composed of the CRE-binding
      protein and activating transcription factor-1 bind specifically to the CRE. The Y
      box and the CCAAT box specifically bind the factor NF-Y (also known as CBF).

PMID- 8663389
TI  - Plasma lipopolysaccharide-binding protein is found associated with a particle
      containing apolipoprotein A-I, phospholipid, and factor H-related proteins.
AB  - Neutrophils exhibit a dramatic enhancement of integrin-mediated cell adhesion in
      response to lipopolysaccharide (LPS). This response requires CD14 on the
      neutrophil and plasma proteins in solution. We have purified the factor from
      plasma that facilitates the adhesive response of neutrophil to LPS by using a
      combination of affinity and ion-exchange chromatography. Previous work has shown
      that the activity is associated with apolipoprotein A-I (apoA-I), and here we
      show that this activity is associated with an apoA-I-bearing complex of protein
      and phospholipid. Native polyacrylamide gel electrophoresis (PAGE) analysis
      showed a ladder of bands in the Mr 200,000 region, and electron microscopy
      revealed round, indented particles of 11.4 +/- 0.12 nm in diameter.
      Characterization of these particles revealed a density of 1.219-1.264 g/ml and
      approximately 10 molecules of lipid phosphate per Mr 200,000 complex. SDS-PAGE
      showed that each of the bands seen in native PAGE was composed of several
      polypeptides. These were identified as apoA-I, LPS binding protein (LBP), and
      factor H-related proteins (FHRPs). Physical association of apoA-I, LBP, and FHRP
      in these particles was further confirmed using double immunodiffusion, and
      association of LBP and FHRP in plasma was confirmed by coimmunoprecipitation.
      FHRPs are the numerically dominant protein components in these particles, and all
      plasma FHRP-1 appears to be associated with these particles. We suggest that
      FHRPs may be the defining constituent of this novel "lipoprotein" particle.

PMID- 8663390
TI  - Promoter-specific modulation of insulin-like growth factor II genomic imprinting
      by inhibitors of DNA methylation.
AB  - The insulin-like growth factor II (IGF-II) gene is maternally imprinted in most
      normal tissues with only the paternal allele being transcribed. In several human
      tumors, however, IGF-II is expressed from both parental alleles. To explore the
      underlying mechanism of IGF-II imprinting, we have examined the effect of DNA
      demethylation in cultured human and mouse astrocyte cells. An increased
      expression of IGF-II was observed when these cells were treated with the DNA
      demethylating agents, 5-azacytidine or 2-deoxy-5-azacytidine. Allelic analysis
      indicated that, following DNA demethylation, the increment in IGF-II mRNA was
      primarily derived from the normally suppressed maternal allele. Examination of
      promoter usage revealed that only the most proximal promoter (mP3 in mouse and
      hP4 in human) responded to DNA demethylating agents, whereas the expression of
      IGF-II from the other promoters remained unchanged. The enhanced expression of
      IGF-II from these promoters suggests the presence of a methylation-response
      element in or near mP3 and hP4. This study indicates that DNA demethylating
      agents increase IGF-II expression primarily by stimulating the normally imprinted
      allele through the activation of the most proximal IGF-II promoter.

PMID- 8663391
TI  - Identification and molecular characterization of a m5 muscarinic receptor in
      A2058 human melanoma cells. Coupling to inhibition of adenylyl cyclase and
      stimulation of phospholipase A2.
AB  - We report the identification and biochemical characterization of an endogenous m5
      muscarinic acetylcholine receptor (mAChR) in the A2058 human melanoma cell line.
      This is the first demonstration of a m5AChR outside the central nervous system.
      The unusual effector coupling of this endogenous m5AChR is presented. The coding
      region amplified by polymerase chain reaction was identical to the known m5AChR
      sequence. Binding studies indicated a Kd of 99 +/- 6 pM and a Bmax of 45 +/- 4
      fmol/mg membrane protein. This m5AChR coupled to stimulation of arachidonic acid
      release and to a 50% inhibition of forskolin-stimulated cAMP accumulation. The
      inhibition of cAMP production was insensitive to pertussis toxin treatment, but
      was dependent upon extracellular calcium. In contrast to the odd mAChR pattern,
      no cAMP was produced in response to carbachol (CC) stimulation. Moreover, no
      release of inositol phosphates could be measured after CC treatment despite the
      presence of at least 2 phospholipase C isoforms in A2058 cells. CC-stimulated
      arachidonic acid release (EC50 = 17.8 +/- 0.1 microM) was dependent upon external
      Ca2+, with marked reduction after coincubation with EGTA, Co2+, or high doses of
      verapamil (IC50 = 166 microM) or diltiazem (IC50 = 243 microM). Brief exposure to
      phorbol 12-myristate 13-acetate augmented CC-stimulated arachidonic acid release,
      whereas prolonged phorbol 12-myristate 13-acetate treatment resulted in down
      regulation of release. Activation of the m5AChR resulted in Ca2+ influx that was
      attenuated by muscarinic antagonism and removal of extracellular Ca2+. A2058
      cells exposed to CC had no alteration of cell shape or growth potential in
      monolayer culture, however, a statistically significant reduction in density
      independent growth was observed over the range of CC concentrations from 0.1 to
      100 microM. This endogenous m5AChR has a novel signal transduction coupling
      profile and receptor activation reduces clonogenic potential.

PMID- 8663392
TI  - Cloning of the gene for human pemphigus vulgaris antigen (desmoglein 3), a
      desmosomal cadherin. Characterization of the promoter region and identification
      of a keratinocyte-specific cis-element.
AB  - Pemphigus vulgaris antigen is a cadherin-like desmosomal cell adhesion molecule
      expressed primarily in suprabasal keratinocytes within the epidermis. Previously
      characterized structural features have defined this molecule as a desmoglein,
      DSG3. In this study, we have cloned the human DSG3 gene and examined the
      transcriptional regulation of its expression. The total gene consisted of 15
      exons and was estimated to span >23 kilobases. Comparison of exon-intron
      organization of DSG3 with bovine DSG1 and several classical cadherin genes
      revealed striking conservation of the structure. Up to 2.8 kilobases of the
      upstream genomic sequences were sequenced and found to contain several putative
      cis-regulatory elements. The promoter region was GC-rich and TATA-less, similar
      to previously characterized mammalian cadherin promoters. The putative promoter
      region was subcloned into a vector containing chloramphenicol acetyl transferase
      reporter gene. Transient transfections with a series of deletion clones indicated
      that the DSG3 promoter demonstrated keratinocyte-specific expression, as compared
      with dermal fibroblasts examined in parallel, and fine mapping identified a 30
      base pair segment at -200 to -170 capable of conferring epidermal specific
      expression. The results provide evidence for the transcriptional regulation of
      the pemphigus vulgaris antigen gene, potentially critical for development of the
      epidermis and physiologic terminal differentiation of keratinocytes.

PMID- 8663393
TI  - Binding of the vesicle docking protein p115 to Golgi membranes is inhibited under
      mitotic conditions.
AB  - The vesicle docking protein p115 showed saturable, high affinity binding to
      interphase Golgi membranes. The affinity of binding was up to 20-fold lower using
      membranes preincubated with mitotic cytosol. In contrast, binding was not
      affected by mitotic pretreatment of p115. The reduction in p115 binding was
      mediated by phosphorylation, could be induced by a cyclin-dependent kinase, and
      was fully reversible. A shift of p115 from membranes to cytosol was also found
      after fractionating mitotic cells. The functional significance of the decreased
      binding was addressed by in vitro mitotic incubations which disassemble Golgi
      cisternae, predominantly producing transport vesicles. The addition of excess
      p115 decreased loss of membrane from cisternae, indicating that p115's action is
      limiting while transport vesicles accumulate. The cessation of intra-Golgi
      traffic in mitosis has been hypothesized to result from an inhibition of membrane
      fusion while budding of transport vesicles continues. This process also
      contributes to mitotic Golgi disassembly. Our results imply that there is a
      mitotic modification to Golgi membranes leading to a reduction in the affinity of
      the p115 receptor. Reduced p115 binding may play a part in the inhibition of
      membrane fusion by preventing prior vesicle docking.

PMID- 8663394
TI  - Tom71, a novel homologue of the mitochondrial preprotein receptor Tom70.
AB  - The protein Tom71 is encoded by the open reading frame YHR117w (yeast chromosome
      VIII) and shares 53% amino acid sequence identity with Tom70, a protein import
      receptor of the mitochondrial outer membrane. We investigated the cellular
      function of Tom71 and addressed the question of whether Tom71 and Tom70 fulfill
      similar functions. Like Tom70, Tom71 is anchored to the mitochondrial outer
      membrane via its N terminus, thereby exposing a large C-terminal domain to the
      cytosol. Tom71 is associated with the protein import complex of this membrane and
      can be cross-linked to a protein with a molecular mass of 30-35 kDa. Disruption
      of the TOM71 gene does not reduce cell growth, except on nonfermentable carbon
      sources at elevated temperatures. Deletion of both the TOM71 and TOM70 genes does
      not acerbate this growth defect. In vitro import studies demonstrated no
      functional requirement for Tom71 in the import of several preproteins destined
      for each of the mitochondrial subcompartments. In particular, the import of Tom70
      dependent preproteins is minimally affected by the deletion of Tom71,
      irrespective of the presence or absence of the Tom70 receptor. Thus, despite
      their strikingly similar biochemical properties, Tom71 and Tom70 do not perform
      identical functions.

PMID- 8663395
TI  - Two GC boxes (Sp1 sites) are involved in regulation of the activity of the
      epithelium-specific MUC1 promoter.
AB  - In this report, we have analyzed the function of two Sp1 sites present in the
      epithelium-specific MUC1 promoter. Using promoter-reporter gene (CAT) constructs,
      we found that mutagenesis of either of the Sp1 binding motifs at -576/-568 and 
      99/-90, reduced transcription in MUC1-expressing epithelial cell lines. However,
      abolition of the binding site at -99/-91 by mutagenesis also resulted in
      increased transcriptional activity in non-epithelial cell lines, suggesting
      involvement of the site in tissue-specific expression. In vitro binding assays
      revealed a novel binding motif at -101/-89 (AGGGGGCGGGGTT), which overlaps but
      differs from the Sp1 consensus motif by having an adenine residue in the 5'
      flanking sequence. The 5'-flanking sequence appeared to be important for binding
      of an Sp1-unrelated factor (SpA) but not for binding of Sp1. Site-directed
      mutagenesis of the motif into a site able to bind Sp1, but unable to bind SpA,
      resulted in an increased level of transcription of the CAT reporter gene in all
      cell lines tested, suggesting a repressive effect of the novel factor on
      transcription. The ratio between the Sp1 and SpA binding activity in nuclear
      extracts correlated with both promoter activity and the levels of endogenous
      transcription in different breast cancer cell lines. Our results are consistent
      with the idea that the relative activities of the two factors may be involved in
      the up-regulation of expression of the MUC1 gene seen in breast and other
      carcinomas.

PMID- 8663396
TI  - Inhibition of myogenesis in mouse C2 cells by double-stranded phosphorothioate
      oligodeoxynucleotides containing mef-1 sequence.
AB  - Phosphorothioate oligonucleotides containing the muscle creatinine kinase
      enhancer sequence (mef-1) and a mutant of the enhancer sequence (mmef-1) were
      tested for their ability to block muscle differentiation in mouse C2 cells in
      culture. Maximum inhibition of fusion of myoblasts was observed at 10 microM
      concentration of mef-1 oligomer. No appreciable inhibition of fusion with the
      mmef-1 oligomer at the same concentration was observed. Synthesis of myogenin,
      muscle creatinine kinase, and myosin heavy chain polypeptides were reduced in mef
      1 oligomer-treated cells. In contrast, no significant reduction in the synthesis
      of these polypeptides in mmef-1-treated cells was detected. The overall protein
      synthesis was not affected. These results suggest that muscle differentiation may
      be disrupted by competition of the oligomer with the endogenous promoter for
      specific transcription factor(s).

PMID- 8663397
TI  - Role of alpha-helical coiled-coil interactions in receptor dimerization,
      signaling, and adaptation during bacterial chemotaxis.
AB  - The aspartate receptor, Tar, is a member of a large family of signal transducing
      membrane receptors that interact with CheA and CheW proteins to mediate the
      chemotactic responses of bacteria. A highly conserved cytoplasmic region, the
      signaling domain, is flanked by two sequences, methylated helices 1 and 2 (MH1
      and MH2), that are predicted to form alpha-helical coiled-coils. MH1 and MH2
      contain glutamine and glutamate residues that are subject to deamidation,
      methylation, and demethylation. We show that the signaling domain is an
      independently folding unit that binds CheW. When expressed in vivo the signaling
      domain inhibits CheA kinase activity, but if MH1 or an unrelated leucine zipper
      coiled-coil sequence is attached to the signaling domain, CheA is activated. A
      construct that contains a leucine zipper fused to MH1-signaling domain-MH2 also
      activates the kinase, both in vivo and in vitro, and this activation is regulated
      by the level of glutamate modification. These findings support a model for
      receptor signaling where aspartate binding controls the relative orientation of
      receptor monomers to favor the formation of coiled-coils between MH1 and/or MH2
      between subunits. Glutamate modification may stabilize these coiled-coils by
      reducing electrostatic repulsion between helices.

PMID- 8663398
TI  - Proteolytic processing patterns of prosaposin in insect and mammalian cells.
AB  - Prosaposin is a multifunctional protein encoded at a single locus in humans and
      mice. The precursor contains, in tandem, four glycoprotein activators or
      saposins, termed A, B, C, and D, that are essential for specific
      glycosphingolipid hydrolase activities. Prosaposin appears to be a potent
      neurotrophic factor. To explore the proteolytic processing from prosaposin to
      mature activator proteins, metabolic labeling was done with human prosaposin
      expressed in insect cells, human fibroblasts, neuronal stem cells (NT2) and
      retinoic acid-differentiated NT2 neurons. In all cell types, the major processing
      pathway was through a tetrasaposin, A-B-C-D, from which saposin A was then
      removed. In mammalian cells monosaposins were derived from the trisaposin B-C-D
      by cleavage to the disaposins, B-C and C-D, that were processed to monosaposins.
      In insect cells the major end products were the disaposins, with A-B and C-D
      derived from the tetrasaposin, A-B-C-D, or with B-C and C-D derived from the
      trisaposin, B-C-D. In insect and mammalian cells, the nonsignal NH2-terminal
      peptide preceding saposin A (termed Nter) was usually removed prior to saposin A
      cleavage. In NT2-derived differentiated neurons, precursor tetrasaposins
      containing A-B-C-D were secreted with and without Nter. Immunofluorescence
      studies using prosaposin-specific antisera showed large steady state amounts of
      uncleaved prosaposin in Purkinje cells, cortical neurons, and other specific cell
      types in adult mice. These studies indicate that prosaposin processing is highly
      regulated at a proteolytic level to produce prosaposin, tetrasaposins, or mature
      monosaposins in specific mammalian cells.

PMID- 8663399
TI  - The homologue of mammalian SPC12 is important for efficient signal peptidase
      activity in Saccharomyces cerevisiae.
AB  - The multisubunit signal peptidase catalyzes the cleavage of signal peptides and
      the degradation of some membrane proteins within the endoplasmic reticulum (ER).
      The only subunit of this enzyme functionally examined to date, yeast Sec11p, is
      related to signal peptidase I from bacteria. Since bacterial signal peptidase is
      capable of processing both prokaryotic and eukaryotic signal sequences as a
      monomer, it is unclear why the analogous enzyme in the ER contains proteins
      unrelated to signal peptidase I. To address this issue, the gene encoding Spc1p,
      the yeast homologue to mammalian SPC12, is isolated from the yeast Saccharomyces
      cerevisiae. Spc1p co-purifies and genetically interacts with Sec11p, but unlike
      Sec11p, Spc1p is not required for cell growth or the proteolytic processing of
      tested proteins in yeast. This indicates that only a subset of the ER signal
      peptidase subunits is required for signal peptidase and protein degradation
      activities in vivo. Through both genetic and biochemical criteria, Spc1p appears,
      however, to be important for efficient signal peptidase activity.

PMID- 8663400
TI  - Maltose-binding protein containing an interdomain disulfide bridge confers a
      dominant-negative phenotype for transport and chemotaxis.
AB  - Bacterial substrate-binding proteins exist in an equilibrium among four forms:
      open/substrate-free, open/substrate-bound, closed/substrate-free, and
      closed/substrate-bound. Ligands stabilize the closed conformation, whereas the
      open conformation predominates in the substrate-free species. In its closed form,
      the NH2-terminal and COOH-terminal domains of maltose-binding protein (MBP) are
      proposed to be aligned to allow residues in both domains to interact
      simultaneously with complementary sites on the MalF and MalG proteins of the
      maltodextrin uptake system or with the Tar chemotactic signal transducer.
      However, the initial interaction might occur with an open/substrate-bound form of
      the binding protein, which would then close in contact with MalFG or Tar. Ligand
      would help stabilize this complex. We introduced cysteines (G69C and S337C) by
      site-directed mutagenesis into each domain of MBP and found that they formed an
      interdomain disulfide cross-link that should hold the protein in a closed
      conformation. This mutant MBP confers a dominant-negative phenotype for growth on
      maltose, for maltose transport, and for maltose chemotaxis. The growth and
      transport defects are partially reversed when the cells are exposed to the
      reducing agent dithiothreitol. We conclude that the cross-linked form of MBP
      competes with wild-type MBP in vivo for interaction with MalFG and Tar.

PMID- 8663401
TI  - Two separate functions are encoded by the carboxyl-terminal domains of the yeast
      cyclase-associated protein and its mammalian homologs. Dimerization and actin
      binding.
AB  - The yeast adenylyl cyclase-associated protein, CAP, was identified as a component
      of the RAS-activated cyclase complex. CAP consists of two functional domains
      separated by a proline-rich region. One domain, which localizes to the amino
      terminus, mediates RAS signaling through adenylyl cyclase, while a domain at the
      carboxyl terminus is involved in the regulation of cell growth and morphogenesis.
      Recently, the carboxyl terminus of yeast CAP was shown to sequester actin, but
      whether this function has been conserved, and is the sole function of this
      domain, is unclear. Here, we demonstrate that the carboxyl-terminal domains of
      CAP and CAP homologs have two separate functions. We show that carboxyl-terminals
      of both yeast CAP and a mammalian CAP homolog, MCH1, bind to actin. We also show
      that this domain contains a signal for dimerization, allowing both CAP and MCH1
      to form homodimers and heterodimers. The properties of actin binding and
      dimerization are mediated by separate regions on the carboxyl terminus; the last
      27 amino acids of CAP being critical for actin binding. Finally, we present
      evidence that links a segment of the proline-rich region of CAP to its
      localization in yeast. Together, these results suggest that all three domains of
      CAP proteins are functional.

PMID- 8663403
TI  - Phosphorylation of the MADS-Box transcription factor MEF2C enhances its DNA
      binding activity.
AB  - Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors
      activate muscle gene expression by binding an A/T-rich DNA sequence in the
      control regions of muscle-specific genes. There are four MEF2 factors in
      vertebrates, MEF2A-D, which share homology in an amino-terminal MADS domain and
      an adjacent region known as the MEF2 domain, that together mediate DNA binding
      and dimerization. We show that serine 59 located between the MADS and MEF2
      domains of MEF2C is phosphorylated in vivo and can be phosphorylated in vitro by
      casein kinase-II (CKII). Phosphorylation of this site enhanced the DNA binding
      and transcriptional activity of MEF2C by increasing its DNA binding activity 5
      fold. In vivo 32P labeling experiments showed that serine 59 is the only
      phosphorylation site in the MADS and MEF2 domains. Mutagenesis of this serine to
      an aspartic acid resulted in an increase in DNA binding and transcriptional
      activity of MEF2C comparable to that observed when this site was phosphorylated,
      suggesting that phosphorylation augments DNA binding activity by introducing
      negative charge. This phosphorylation site, which corresponds to a CKII
      recognition site, is conserved in all known MEF2 factors in organisms ranging
      from flies to humans, consistent with its importance for the functions of MEF2C.

PMID- 8663405
TI  - Double-stranded internucleosomal cleavage of apoptotic DNA is dependent on the
      degree of differentiation in muscle cells.
AB  - Apoptotic cell death has been correlated to DNA fragmentation into discrete
      segments corresponding to the length of nucleosomal protected fragments of 180
      200 base pairs or multiples of it. This DNA degradation has been ascribed to
      endonuclease activity that cleaves internucleosomally, thus giving rise to a
      ladder distribution upon electrophoretic migration. This strict correlation was,
      however, shown to have notable exceptions, since in some cases only single strand
      cleavage in the internucleosomal DNA regions has been observed (Tomei, D. L.,
      Shapiro, P. J., and Cope, O. F. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 853
      857). In the present work we show that mouse muscle cells, able to differentiate
      in vitro, if subjected to apoptosis present no DNA degradation into ladder form
      unless differentiation is previously induced. Furthermore, C3H/10T1/2 fibroblast
      cells, known to undergo apoptosis without DNA ladder formation, if converted to a
      myogenic program by MyoD expression, display internucleosomal DNA degradation
      upon induction of differentiation.

PMID- 8663406
TI  - Mammalian Sly1 regulates syntaxin 5 function in endoplasmic reticulum to Golgi
      transport.
AB  - Members of the syntaxin gene family are components of protein complexes which
      regulate vesicle docking and/or fusion during transport of cargo through the
      secretory pathway of eukaryotic cells. We have previously demonstrated that
      syntaxin 5 is specifically required for endoplasmic reticulum to Golgi transport
      (Dascher, C., Matteson, J., and Balch, W. E.(1994) J. Biol. Chem. 269, 29363
      29366). To extend these observations we have now cloned a protein from rat liver
      membranes which forms a native complex with syntaxin 5. We demonstrate that this
      protein is the mammalian homologue to yeast Sly1p, previously identified as a
      protein which genetically and biochemically interacts with the small GTPase Ypt1p
      and Sed5p, proteins involved in docking/fusion in the early secretory pathway of
      yeast. Using transient expression we find that overexpression of rat liver Sly1
      (rSly1) can neutralize the dominant negative effects of excess syntaxin 5 on
      endoplasmic reticulum to Golgi transport. These results suggest that rSly1
      functions to positively regulate syntaxin 5 function.

PMID- 8663407
TI  - Tmp21 and p24A, two type I proteins enriched in pancreatic microsomal membranes,
      are members of a protein family involved in vesicular trafficking.
AB  - We report here on the isolation, cloning, and expression of two Mr 21,000
      proteins from rat pancreatic acinar cells, the rat-Tmp21 (transmembrane protein,
      Mr 21,000) and the rat-p24A. Both proteins are transmembrane proteins with type I
      topology and share weak but significant homology to one another (23% identity).
      We further show the cloning and characterization of the human homologs, hum
      Tmp21, which is expressed in two variants (Tmp21-I and Tmp21-II), and hum-p24A.
      Tmp21 proteins and p24A have highly conserved COOH-terminal tails, which contain
      motifs related to the endoplasmic reticulum retention and retrieval consensus
      sequence KKXX. The rat-p24 sequence is identical to the hamster CHOp24, a
      recently characterized component of coatomer-coated transport vesicles, which
      defines a family of proteins (called the p24 family) proposed to be involved in
      vesicular transport processes (Stamnes, M. A., Craighead, M. W., Hoe, M. H.,
      Lampen, N., Geromanos, S., Tempst, P., and Rothman, J. E.(1995) Proc. Natl. Acad.
      Sci. U. S. A. 92, 8011-8015). Sequence alignment and structural features identify
      the Tmp21 protein as a new member of this p24 family. Northern analysis of
      various tissues indicates that the Tmp21 proteins and the p24A protein are
      ubiquitously expressed. The integral membrane components Tmp21 and p24A are
      localized in microsomal membranes, zymogen granule membranes, and the plasma
      membrane and are absent from the cytosol. Both p24A and Tmp21 show weak homology
      to the yeast protein Emp24p, which recently has been shown to be involved in
      secretory protein transport from the endoplasmic reticulum to the Golgi
      apparatus. This leads us to conclude that the receptor-like Tmp21 and p24A are
      involved in vesicular targeting and protein transport.

PMID- 8663408
TI  - A synthetic conformational epitope from the C4 domain of HIV Gp120 that binds
      CD4.
AB  - The fourth conserved domain of the human immunodeficiency virus type 1 (HIV-1)
      envelope, the C4 region of glycoprotein 120 (gp120), is believed to be a major
      part of gp120 that is necessary for binding to CD4. Recently, we found that C4 in
      gp120 is probably an alpha-helix, because antibodies made against helical
      constructs of C4 react with native and recombinant gp120 but antibodies against
      linear C4 constructs do not. For the present study, we performed experiments to
      determine, first, if CD4 could bind to the helical C4 constructs and, second, if
      the binding was comparable with CD4 binding to gp120. Immobilized helical
      constructs derived from the C4s from HIV-1 and HIV-2 bound biotinylated
      recombinant CD4 with Kd values of 8.59 nM and 14.59 nM, respectively. Recombinant
      soluble CD4 inhibited the binding of biotinylated CD4 to the C4 construct from
      HIV-1 with a Kd of 9.88 nM, and recombinant gp120 blocked the binding of CD4 to
      the immobilized helical construct from C4 of HIV-1 with a Kd of 8.08 nM. The C4
      peptide-(419-436) from HIV-1 (KIKQIINMWQEVGKAMYA-NH2) blocked CD4 binding to
      gp120 but only in a buffer containing 0.03% Brij 35 where the peptide displayed
      17 +/- 1% alpha-helix; without the Brij 35, peptide-(419-436) displayed no
      helical content. The Kd for the peptide-(419-436) blocking CD4 binding to gp120
      in Brij 35-containing buffer was found to be 42 microM. These results indicate
      that C4 constructs from HIV-1 and HIV-2 do bind CD4, but the constructs must
      display an alpha-helical conformation to do so. In addition, the results reported
      here will provide answers to key questions about structural requirements for HIV
      vaccines and therapeutics that hinge on understanding the molecular nature of the
      gp120-CD4 interaction as the first step in the HIV infection process.

PMID- 8663409
TI  - Kinetic characterization of human immunodeficiency virus type-1 protease
      resistant variants.
AB  - Passage of human immunodeficiency virus type-1 (HIV-1) in T-lymphocyte cell lines
      in the presence of increasing concentrations of the hydroxylethylamino
      sulfonamide inhibitor VX-478 or VB-11328 results in sequential accumulation of
      mutations in HIV-1 protease. We have characterized recombinant HIV-1 proteases
      that contain these mutations either individually (L10F, M46I, I47V, I50V) or in
      combination (the double mutant L10F/I50V and the triple mutant M46I/I47V/I50V).
      The catalytic properties and affinities for sulfonamide inhibitors and other
      classes of inhibitors were determined. For the I50V mutant, the efficiency
      (kcat/Km) of processing peptides designed to mimic cleavage junctions in the HIV
      1 gag-pol polypeptide was decreased up to 25-fold. The triple mutant had a 2-fold
      higher processing efficiency than the I50V single mutant for peptide substrates
      with Phe/Pro and Tyr/Pro cleavage sites, suggesting that the M46I and I47V
      mutations are compensatory. The effects of mutation on processing efficiency were
      used in conjunction with the inhibition constant (Ki) to evaluate the advantage
      of the mutation for viral replication in the presence of drug. These analyses
      support the virological observation that the addition of M46I and I47V mutations
      on the I50V mutant background enables increased survival of the HIV-1 virus as it
      replicates in the presence of VX-478. Crystal structures and molecular models of
      the active site of the HIV-1 protease mutants suggest that changes in the active
      site can selectively affect the binding energy of inhibitors with little
      corresponding change in substrate binding.

PMID- 8663410
TI  - Cell internalization of the third helix of the Antennapedia homeodomain is
      receptor-independent.
AB  - We have recently reported that a 16-amino acid long polypeptide corresponding to
      the third helix of the DNA binding domain (homeodomain) of Antennapedia, a
      Drosophila transcription factor, is internalized by cells in culture (Derossi,
      D., Joliot, A. H., Chassaing, G., and Prochiantz, A.(1994) J. Biol. Chem. 269,
      10444-10450). The capture of the homeodomain and of its third helix at
      temperatures below 10 degrees C raised the problem of the mechanism of
      internalization. The present demonstration, that a reverse helix and a helix
      composed of D-enantiomers still translocate across biological membranes at 4 and
      37 degrees C strongly suggests that the third helix of the homeodomain is
      internalized by a receptor-independent mechanism. The finding that introducing 1
      or 3 prolines in the structure does not hamper internalization also demonstrates
      that the alpha-helical structure is not necessary. The data presented are
      compatible with a translocation process based on the establishment of direct
      interactions with the membrane phospholipids. The third helix of the homeodomain
      has been used successfully to address biologically active substances to the
      cytoplasm and nucleus of cells in culture (Theodore, L., Derossi, D., Chassaing,
      G., Llirbat, B., Kubes, M., Jordan, P., Chneiweiss, H., Godement, P., and
      Prochiantz, A.(1995) J. Neurosci. 15, 7158-7167). Therefore, in addition to their
      physiological implications (Prochiantz, A., and Theodore, L.(1995) BioEssays 17,
      39-45), the present results open the way to the molecular design of cellular
      vectors.

PMID- 8663411
TI  - Identification of routing determinants in the cytosolic domain of a secretory
      granule-associated integral membrane protein.
AB  - We have investigated the trafficking of integral membrane peptidylglycine alpha
      amidating monooxygenase (PAM) in the neuroendocrine AtT-20 cell line. This
      bifunctional enzyme has two domains which together catalyze the COOH-terminal
      alpha-amidation of peptidylglycine substrates yielding amidated products stored
      in secretory granules. As soluble proteins, both catalytic domains were
      independently targeted to secretory granules. In contrast, membrane PAM was
      largely localized to the trans-Golgi network (TGN). Upon truncation of its
      cytoplasmic COOH-terminal domain, membrane PAM was less efficiently cleaved by
      secretory granule enzymes and accumulated on the plasma membrane. When
      transferred to the lumenal domain of the interleukin 2 receptor alpha-chain (Tac
      protein), the cytoplasmic domain of PAM caused rerouting of Tac from the surface
      to the TGN and supported internalization of Tac antibody from the plasma
      membrane. To define sequences in the cytoplasmic domain of integral membrane PAM
      involved in its trafficking, we expressed PAM proteins containing truncations,
      deletions, or point mutations in the COOH-terminal cytoplasmic domain. PAM
      proteins were not retained in the TGN when half of the cytoplasmic domain was
      deleted; such proteins accumulated on the plasma membrane, were not efficiently
      internalized, and were cleaved to generate a bifunctional PAM protein that was
      not stored in secretory granules. A tyrosine-based internalization motif was
      identified, which was not required for efficient cleavage of full-length integral
      membrane PAM by secretory granule enzymes. Deletion of an 18-amino acid domain
      surrounding this Tyr residue both diminished cleavage of membrane PAM by
      secretory granule enzymes and eliminated internalization of PAM from the plasma
      membrane. The cytoplasmic domain is responsible for retaining membrane PAM in the
      TGN and for retrieving membrane PAM from the cell surface, while the lumenal
      catalytic domains of PAM appear to be responsible for targeting the protein to
      secretory granules.

PMID- 8663412
TI  - Identification and characterization of the protective hepatocyte erythrocyte
      protein 17 kDa gene of Plasmodium yoelii, homolog of Plasmodium falciparum
      exported protein 1.
AB  - We recently reported the discovery of a 17-kDa Plasmodium yoelii protein
      expressed in infected hepatocytes and erythrocytes, P. yoelii hepatocyte
      erythrocyte protein 17 (PyHEP17), and have demonstrated that this protein is a
      target of protective antibodies and T cells. Here, we report the identification
      and characterization of the gene encoding this protein and reveal that it is
      composed of two exons. Immunization of mice with PyHEP17 plasmid DNA induces
      antibodies, cytotoxic T lymphocytes, and protective immunity directed against the
      infected hepatocyte. Based on extensive sequence homology, expression pattern,
      and antigenic cross-reactivity, the Plasmodium falciparum homolog of PyHEP17 is
      identified as the protein known as exported protein-1 (PfExp-1), also called
      antigen 5.1, circumsporozoite related antigen, or QF116. Identity between PyHEP17
      and PfExp-1 is 37% at the amino acid level (60/161 residues), mapping primarily
      to two regions within the second exon of 73% (16/22 residues) and 71% (25/35
      residues) identity. On this basis, PfExp-1 is proposed as an important component
      of pre-erythrocytic human malaria vaccines.

PMID- 8663413
TI  - In vitro efficacy of morpholino-modified antisense oligomers directed against
      tumor necrosis factor-alpha mRNA.
AB  - Chemical modification of antisense oligonucleotides to increase nuclease
      resistance may improve their efficacy within enzyme-rich cellular targets (e.g.
      macrophages). We evaluated a panel of morpholino antisense oligomers (M-AS) for
      their ability to inhibit macrophage tumor necrosis factor-alpha (TNF-alpha)
      release and compared them to phosphodiester (O-AS) and phosphorothioate (S-AS)
      types of oligonucleotides. M-AS inhibited translation in vitro (rabbit
      reticulocyte lysate) of target mRNA at concentrations as low as 200 nM (e.g.
      percent inhibition by M-AS 2 at 0.2, 1.0, and 2.0 microM was 40.9 +/- 5.3%, 50.2
      +/- 4.6%, and 57.7 +/- 3.6%, respectively, n = 4, p </= 0.002 versus control).
      Similarly, M-AS 2 effectively, albeit partially, inhibited TNF-alpha production
      by LPS-stimulated macrophages (RAW 264.7 cells). Incubation of cells with 25
      microM M-AS 2 resulted in 32.6 +/- 2.6% (n = 3, p = 0.002 versus control)
      decrease in TNF-alpha release. In contrast, S-AS inhibited translation of the
      target mRNA in the rabbit reticulocyte lysate assay, but not in the cell-based
      assay. In fact, S-AS nonspecifically augmented TNF-alpha release. O-AS were
      without effect in either system. Uptake studies with fluorescent M-AS revealed
      that inhibitory effects were seen despite relatively low cellular uptake
      (intracellular concentration 30.5 +/- 6.7 nM; efficiency of uptake 0.1%). In
      contrast, flow cytometric and confocal analysis revealed that S-AS were avidly
      taken up by RAW 264. 7 cells, confirming that their lack of efficacy was not due
      to lack of uptake. With improved methods of delivery, M-AS may represent an
      important therapeutic modality.

PMID- 8663414
TI  - Other kinases can substitute for Jak2 in signal transduction by interferon-gamma.
AB  - Each cytokine which utilizes the Jak-Stat signal transduction pathway activates a
      distinct combination of members of the Jak and Stat families. Thus, either the
      Jaks, the Stats, or both could contribute to the specificity of ligand action.
      With the use of chimeric receptors involving the interferon gamma receptor (IFN
      gammaR) complex as a model system, we demonstrate that Jak2 activation is not an
      absolute requirement for IFN-gamma signaling. Other members of the Jak family can
      functionally substitute for Jak2. IFN-gamma can signal through the activation of
      Jak family members other than Jak2 as measured by Statlalpha homodimerization and
      major histocompatibility complex class I antigen expression. This indicates that
      Jaks are interchangeable and indiscriminative in the Jak-Stat signal transduction
      pathway. The necessity for the activation of one particular kinase during
      signaling can be overcome by recruiting another kinase to the receptor complex.
      The results may suggest that the Jaks do not contribute to the specificity of
      signal transduction in the Jak-Stat pathway to the same degree as Stats.

PMID- 8663415
TI  - Fast and slow cyclic nucleotide-dissociation sites in cAMP-dependent protein
      kinase are transposed in type Ibeta cGMP-dependent protein kinase.
AB  - Both cyclic GMP-dependent protein kinase (cGK) and cyclic AMP-dependent protein
      kinase (cAK) contain two distinct cyclic nucleotide-binding sites referred to as
      fast and slow sites based on cyclic nucleotide dissociation behavior. In cAK, the
      fast site lies amino-terminal to the slow site, and sequence homologies between
      cAK and cGK have suggested similar positioning for the sites in cGK. Recombinant
      human type Ibeta cGK (wild type (WT) cGK) was overexpressed, and the properties
      of purified WT cGK and native type Ibeta cGK were similar. cGK was mutated singly
      at Thr-193 (T193A, T193V, and T193S) and Thr-317 (T317A, T317V, and T317S), which
      have been predicted to provide cGMP specificity in the cGMP-binding sites of cGK;
      a double mutant (T193A/T317A) was produced also. Compared with WT cGK, half
      maximal activation (Ka) of mutant cGKs by cGMP was increased 2- (T317A), 27-
      (T193A), or 63-fold (T193A/T317A), but the Ka for cAMP of these mutants was
      essentially unchanged. The T193A and T193V mutants had a large increase in the
      rate of the slow component of [3H]cGMP dissociation, but in the T317A and T317V
      mutants, there was no change in the slow component. The T193S and T317S mutants
      had only minor effects on [3H]cGMP dissociation, thus establishing the importance
      of the hydroxyl group of Thr-193 and -317 for cGMP binding to cGK. Thus, in type
      Ibeta cGK, the slow cGMP-binding site is identified as the amino-terminal site in
      contrast to the order assigned to the fast and slow cAMP-binding sites of cAK.

PMID- 8663416
TI  - Reversible desensitization of inositol trisphosphate-induced calcium release
      provides a mechanism for repetitive calcium spikes.
AB  - Repetitive transient increases in cytosolic calcium concentration (calcium spikes
      or calcium oscillations) are a common mode of signal transduction in receptor
      mediated cell activation. Repetitive calcium spikes are initiated by
      phospholipase C-mediated production of inositol 1,4,5-trisphosphate (InsP3) and
      are thought to be generated by a positive feedback mechanism in which calcium
      potentiates its own release, a negative feedback mechanism by which calcium
      release is terminated, and a slow recovery process that defines the time interval
      between calcium spikes. The molecular mechanisms that terminate each calcium
      spike and define the spike frequency are not yet known. Here we show, in intact
      rat basophilic leukemia cells, that calcium responses induced by InsP3 are
      diminished for a period of 30-60 s following an InsP3-induced calcium spike. The
      sensitivity of calcium release for InsP3 was probed by UV laser-mediated
      photorelease of InsP3, and calcium responses were monitored by fluorescence
      calcium imaging. A maximal loss in sensitivity (desensitization) was observed for
      InsP3 increases that resulted in a near maximal calcium spike and was expressed
      as an 80-100% reduction in the calcium response to an equal amount of InsP3,
      released 10 s after the first UV pulse. When the amount of released InsP3 in the
      second pulse was increased 2-3-fold, desensitization was overcome and a second
      calcium response of equal amplitude to the first was produced. A power dependence
      of 3.2 was measured between the amount of released InsP3 and the amplitude of the
      triggered calcium response, explaining how a small decrease in InsP3 sensitivity
      can lead to a nearly complete reduction in the calcium response. Desensitization
      was abolished by the addition of the calcium buffers BAPTA and EGTA and could be
      induced by microinjection of calcium, suggesting that it is a calcium-dependent
      process. Half-maximal desensitization was observed at a free calcium
      concentration of 290 nM and increased with a power of 3.7 with peak calcium
      concentration. These studies suggest that reversible desensitization of InsP3
      induced calcium release serves as a "saw-tooth" parameter that controls the
      termination of each spike and the frequency of calcium spikes.

PMID- 8663417
TI  - Solvent-accessible residues on the metal ion-dependent adhesion site face of
      integrin CR3 mediate its binding to the neutrophil inhibitory factor.
AB  - Neutrophil adhesion-dependent functions such as chemotaxis, spreading, and
      phagocytosis are inhibited by neutrophil inhibitory factor (NIF), a glycoprotein
      produced by the hookworm Ancylostoma caninum. The NIF binding site has been
      localized to the A-domain of integrin CR3 (CD11b/CD18) and shown to be metal
      dependent. The recently solved crystal structure of the A-domain from CD11b
      revealed a putative metal ion-dependent adhesion site (MIDAS) on the top of the
      structure. To determine if NIF binds to the A-domain at its MIDAS face, amino
      acid substitutions involving 24 residues present in surface loops and adjacent
      helices in the structure were created. The expressed CD11b A-domain and CR3
      heterodimers were then tested in a blinded manner for their ability to bind to
      biotinylated NIF. The solvent-exposed Gly143, Asp149, Glu178-Glu179, and Arg208,
      all located on the MIDAS face, in close proximity to the metal ion, were involved
      in CR3-NIF interaction. These data show that the natural integrin antagonist,
      NIF, binds to CR3 through the MIDAS region and identify putative contact residues
      in this region that could be targeted therapeutically.

PMID- 8663418
TI  - Overlapping, but not identical, sites are involved in the recognition of C3bi,
      neutrophil inhibitory factor, and adhesive ligands by the alphaMbeta2 integrin.
AB  - The alphaMbeta2 (CD11b/CD18, Mac-1) integrin receptor binds numerous ligands,
      including neutrophil inhibitory factor (NIF), C3bi, and certain immobilized
      protein substrates, represented by denatured ovalbumin. These ligands share no
      obvious structural similarities, yet their interactions with receptor are
      inhibited by NIF and involve the I domain, a stretch of approximately 200 amino
      acids in the alphaM subunit. Recombinant wild-type and mutant forms of
      alphaMbeta2 have been used to compare the recognition requirements of these
      ligands. The various constructs were expressed efficiently on the surface of
      human embryonic kidney 293 cells and formed alpha.beta heterodimeric complexes.
      The wild-type transfectants bound the three ligands in a similar fashion to
      naturally occurring alphaMbeta2. NIF inhibited these interactions, and deletion
      of the D248PLGY from within the I domain abolished binding of all three ligands,
      suggesting an overlapping recognition specificity. A single point mutation of
      Ser138 to Ala in the beta2 subunit abolished C3bi binding and cell adhesion but
      did not affect NIF binding. A switch of the R281QELNTI sequence in helix 6 of the
      alphaM I domain to the corresponding sequence in the I domain of the alphaL
      (QETLHKF) subunit completely abrogated adhesion while not affecting C3bi and NIF
      binding. The two mutant receptors also did not support activation-dependent
      adhesion to fibrinogen. Thus, the contact sites for NIF, C3bi, and adhesive
      proteins, represented by denatured ovalbumin and fibrinogen, in alphaMbeta2 are
      overlapping but not identical.

PMID- 8663419
TI  - Thermodynamics of monosaccharide and disaccharide binding to Erythrina
      corallodendron lectin.
AB  - Isothermal titration calorimetry measurements of the binding of 2'
      fucosyllactose, lactose, N-acetyllactosamine, galactopyranose, 2-acetamido-2
      deoxygalactopyranoside, methyl alpha-N-dansylgalactosaminide (Me-alpha-DNS-GalN),
      methyl alpha-D-galactopyranoside, methyl beta-D-galactopyranoside, and fucose to
      Erythrina corallodendron lectin (ECorL), a dimer with one binding site per
      subunit, were performed at 283-286 and 297-299 K. The site binding enthalpies,
      DeltaHb, with the exception of Me-alpha-DNS-GalN, are the same at both
      temperatures and range from -47.1 +/- 1.0 kJ mol-1 for N-acetyllactosamine to 
      4.4 +/- 0.3 kJ mol-1 for fucose, and the site binding constants range from 3.82
      +/- 0.9 x 10(5)M-1 for Me-alpha-DNS-GalN at 283.2 K to 0.46 +/- 0.05 x 10(3) M-1
      for fucose at 297.2 K. The binding reactions are mainly enthalpically driven
      except for fucose and exhibit enthalpy-entropy compensation. The binding
      enthalpies of the disaccharides are about twice the binding enthalpies of the
      monosaccharides in contrast to concanavalin A where the binding enthalpies do not
      double for the disaccharides. Differential scanning calorimetry measurements show
      that denaturation of the ECorL dimer results in dissociation into its monomer
      subunits. The binding constants from the increase in denaturation temperature of
      ECorL in the presence of saccharides are in agreement with values from isothermal
      titration calorimetry results. The thermal denaturation of ECorL occurs around
      333 K, well below the 344-360 K denaturation temperature of other legume lectins
      of similar size and tertiary structure, undoubtedly due to the difference in its
      quaternary structure relative to other legume lectins. This is also apparent from
      the independent unfolding of its two domains.

PMID- 8663420
TI  - A conserved cysteine residue in the runt homology domain of AML1 is required for
      the DNA binding ability and the transforming activity on fibroblasts.
AB  - The AML1 gene encodes DNA-binding proteins that contain the runt homology domain
      and is found at the breakpoints of t(8;21), t(3;21), and t(12;21) translocations
      associated with myelogenous leukemias. AML1 heterodimerizes with
      PEBP2beta/CBFbeta, resulting in the enhanced affinity with DNA. The runt homology
      domain is responsible for binding with DNA and heterodimerizing with
      PEBP2beta/CBFbeta. AML1 is suggested to perform a pivotal role in myeloid cell
      differentiation, whereas it can cause neoplastic transformation when
      overexpressed in fibroblasts. In this study, we demonstrated that the reducing
      reagent, dithiothreitol (DTT), markedly enhances the DNA binding of AML1
      expressed in COS7 cells. Oxidation by diamide or modification by N-ethylmaleimide
      of the free sulfhydryl residues inhibited the interaction of AML1 with DNA. The
      diamide effect was reversible with excess of DTT, whereas DTT could not restore
      the DNA binding of AML1 treated with N-ethylmaleimide. Site-directed mutagenesis
      of the amino acid residue 72, a highly conserved cysteine in the runt homology
      domain of AML1, to serine almost completely abolished DNA binding without
      altering the interaction with PEBP2beta/CBFbeta. This substitution also impaired
      transactivation through the consensus DNA sequence and transformation of
      fibroblasts induced by AML1b. These data indicate an essential role of the
      conserved cysteine residue in DNA binding of AML1, and it is possible that the
      redox state of AML1 could contribute to the regulation of its function.

PMID- 8663421
TI  - Secretogranin III is a sulfated protein undergoing proteolytic processing in the
      regulated secretory pathway.
AB  - Secretogranin III (SgIII) is an acidic protein of unknown function that is
      present in the storage vesicles of many neuroendocrine cells. It is coexpressed
      with the prohormone proopiomelanocortin in the intermediate pituitary of Xenopus
      laevis. We developed an antiserum to investigate the biosynthesis of SgIII in
      pulse-chase incubated Xenopus neurointermediate lobes. SgIII was synthesized as a
      61- or 63-kDa (N-glycosylated) protein and processed to a 48-kDa form which, in
      turn, was partially cleaved to fragments of 28 and 20 kDa. The 48-, 28-, and 20
      kDa cleavage products, but not their precursors, were secreted. This secretion is
      regulated and can be blocked in parallel with that of proopiomelanocortin-derived
      peptides by the hypothalamic factors dopamine, gamma-aminobutyric acid, and
      neuropeptide Y. Coexpression of Xenopus SgIII with prohormone convertase (PC)1 or
      PC2 in transfected fibroblasts was sufficient to reconstitute the processing
      events observed in the neurointermediate lobes. Site-directed mutagenesis
      revealed that Xenopus SgIII is cleaved at two dibasic sites, namely Lys68-Arg69
      and Arg237-Arg238. Pulse-chase incubations of lobes with Na2[35S]SO4 showed that
      SgIII is sulfated in the trans-Golgi network before it is processed. Finally,
      SgIII processing was found in several neuroendocrine cell types from various
      species. We conclude that SgIII is a precursor protein and that the intact
      molecule can only have an intracellular function, whereas an extracellular role
      can only be attributed to its cleavage products.

PMID- 8663424
TI  - The vascular endothelial growth factor receptor Flt-1 mediates biological
      activities. Implications for a functional role of placenta growth factor in
      monocyte activation and chemotaxis.
AB  - Two distinct receptors for vascular endothelial growth factor (VEGF), the
      tyrosine kinase receptors Flt-1 and Flk-1/KDR, have been described. In this study
      we show that monocytes, in contrast to endothelium, express only the VEGF
      receptor Flt-1, and that this receptor specifically binds also the VEGF homolog
      placenta growth factor (PlGF). Both VEGF and PlGF stimulate tissue factor
      production and chemotaxis in monocytes at equivalent doses. In contrast,
      endothelial cells expressing both the Flt-1 and the Flk-1/KDR receptors produce
      more tissue factor upon stimulation with VEGF than after stimulation with PlGF.
      Neutralizing antibodies to the KDR receptor reduce the VEGF-stimulated tissue
      factor induction in endothelial cells to levels obtained by stimulation with PlGF
      alone, but do not affect PlGF-induced tissue factor induction in endothelial
      cells nor the VEGF-dependent tissue factor production in monocytes. These
      findings strongly suggest Flt-1 as a functional receptor for VEGF and PlGF in
      monocytes and endothelial cells and identify this receptor as a mediator of
      monocyte recruitment and procoagulant activity.

PMID- 8663425
TI  - Identification of the nuclear localization signal of the POU domain protein Tst
      1/Oct6.
AB  - POU domain proteins are important regulators of development and terminal
      differentiation based upon their transcriptional activity in the nucleus. Here,
      we analyzed the mechanism underlying the nuclear localization of Tst-1/Oct6, a
      member of this family that regulates events during neurogenesis and myelination.
      Nuclear localization of Tst-1/Oct6 was dependent on the POU domain, as its
      deletion prevented access to the nucleus, whereas its transfer to the amino
      terminus of beta-galactosidase was sufficient to prompt nuclear accumulation of
      this normally cytosolic protein. Interestingly, nuclear localization and high
      affinity DNA binding were two independent functions of the POU domain and could
      be separated in several mutants. While specific high affinity binding to DNA
      required the presence of both the POU-specific and the POU homeodomain, the POU
      specific domain was dispensable for nuclear localization of Tst-1/Oct6. Rather,
      the nuclear localization function was selectively contained within the POU
      homeodomain. Specifically, a basic cluster (GRKRKKRT) preceding helix 1 of the
      homeodomain was shown by deletion mutagenesis to be involved in the nuclear
      localization of Tst-1/Oct6. This sequence, which is highly conserved among POU
      domain proteins, was by itself capable of translocating beta-galactosidase to the
      nucleus defining it as the bona fide nuclear localization signal of Tst-1/Oct6
      and presumably other POU domain factors.

PMID- 8663422
TI  - Phenobarbital induction of CYP1A1 gene expression in a primary culture of rainbow
      trout hepatocytes.
AB  - In mammals, phenobarbital (PB) is an in vivo inducer of the cytochrome P4502B
      (CYP2B) family, whereas in teleosts PB induction of cytochrome P450 is unclear.
      We show that teleost cytochrome P4502K1 (CYP2K1) protein levels and 7
      pentoxyresorufin-O-deethylase activity were not induced by exposure of primary
      cultures of rainbow trout hepatocytes to PB. Instead, cytochrome P4501A1 (CYP1A1)
      gene expression was strongly induced by PB, based upon observations of marked
      increases in CYP1A1 mRNA, CYP1A1 protein, and 7-ethoxyresorufin-O-deethylase
      activity. In accordance with these data we provide a temporal study employing
      antibodies for the aromatic hydrocarbon (Ah) receptor that showed an increase in
      Ah receptor in nuclear extracts prepared from cells exposed to PB. Employment of
      the electrophoretic mobility shift assay (EMSA) showed PB to cause activation or
      "transformation" of the Ah receptor in nuclear extracts. Studies employing
      actinomycin D and cycloheximide indicated that PB induction of CYP1A1 was
      regulated at both the transcriptional and post-transcriptional levels. Nuclear
      run-off experiments confirm that PB causes an increase in CYP1A1 transcription.
      Inhibition of protein synthesis led to the superinduction of CYP1A1 mRNA,
      suggesting the regulation of teleost CYP1A1 may involve a labile repressor
      protein. These findings suggest that PB induction of the CYP1A1 gene involves the
      Ah receptor and is via transcriptional activation.

PMID- 8663426
TI  - A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming
      activity and association with shc adaptor proteins.
AB  - Germ line mutations of the ret proto-oncogene are associated with the development
      of three dominantly inherited neoplastic disorders, multiple endocrine neoplasia
      (MEN) 2A, MEN 2B, and familial medullary thyroid carcinoma. It has been
      demonstrated that the mutations result in constitutive activation of the Ret
      protein, leading to transformation of NIH 3T3 cells. In the present study we
      investigated the role of tyrosine residues present in the carboxyl-terminal
      sequence for the transforming activity of Ret with the MEN 2A or MEN 2B mutation
      (MEN2A-Ret or MEN2B-Ret). Substitution of phenylalanine for tyrosine 1062
      (designated Y1062F) markedly impaired the transforming activity of both MEN2A-Ret
      and MEN2B-Ret, whereas substitution or deletion for four other tyrosines (codons
      981, 1015, 1090, and 1096) did not affect their activity. The Shc adaptor
      proteins bound to the MEN2A-Ret and MEN2B-Ret proteins and were phosphorylated on
      tyrosine in the transfectants. The binding of Shc to the Y1062F mutant proteins
      was reduced by approximately 80%, indicating that tyrosine 1062 is a major
      binding site for Shc. In addition, phosphopeptide analysis of MEN2A-Ret
      demonstrated that tyrosine 1062 represents an autophosphorylation site of the
      mutant Ret proteins.

PMID- 8663427
TI  - Autophosphorylation of the Fes tyrosine kinase. Evidence for an intermolecular
      mechanism involving two kinase domain tyrosine residues.
AB  - The human c-fes proto-oncogene encodes a cytoplasmic tyrosine kinase (Fes) that
      is associated with multiple hematopoietic cytokine receptors. Fes tyrosine
      autophosphorylation sites may regulate kinase activity and recruit downstream
      signaling proteins with SH2 domains. To localize the Fes autophosphorylation
      sites, full-length Fes and deletion mutants lacking either the unique N-terminal
      or SH2 domain were autophosphorylated in vitro and analyzed by CNBr cleavage.
      Identical phosphopeptides of 10 and 4 kDa were produced with all three proteins,
      localizing the tyrosine autophosphorylation sites to the C-terminal kinase
      domain. Substitution of kinase domain tyrosine residues 713 or 811 with
      phenylalanine resulted in a loss of the 10- and 4-kDa phosphopeptides,
      respectively, identifying these tyrosines as in vitro autophosphorylation sites.
      CNBr cleavage analysis of Fes isolated from 32PO4-labeled 293T cells showed that
      Tyr-713 and Tyr-811 are also autophosphorylated in vivo. Mutagenesis of Tyr-713
      reduced both autophosphorylation of Tyr-811 and transphosphorylation of Bcr, a
      recently identified Fes substrate, supporting a major regulatory role for Tyr
      713. Wild-type Fes transphosphorylated a kinase-inactive Fes mutant on Tyr-713
      and Tyr-811, suggesting that Fes autophosphorylation occurs via an intermolecular
      mechanism analogous to receptor tyrosine kinases.

PMID- 8663428
TI  - Galpha12 stimulates c-Jun NH2-terminal kinase through the small G proteins Ras
      and Rac.
AB  - The pertussis toxin (PTX) insensitive heterotrimeric G protein G12 has been
      implicated in mitogenesis and transformation, but its direct effectors remain
      unknown. To define potential signaling pathways utilized by G12, we expressed an
      activated mutant of its alpha subunit, Galpha12(Q229L), in HEK293 cells and
      examined its effects on Ras and mitogen-activated protein kinases (MAPKs).
      Transient expression of activated Galpha12 increased the percentage of Ras in the
      active, GTP-bound state, stimulated c-Jun NH2-terminal kinase (JNK) activity, and
      enhanced the transcriptional activity of c-Jun. Dominant negative Ras (N17Ras)
      inhibited Galpha12-mediated JNK activation in NIH3T3 cells but failed to do so in
      HEK293 cells. In contrast, dominant negative Rac (N17Rac1) inhibited JNK
      activation by Galpha12 in HEK293 cells as well as three other cell lines. In
      1321N1 cells, where thrombin stimulates G12-dependent mitogenesis, coexpression
      of N17Rac1 or a dominant negative mutant of MEKK1 (MEKKDelta(K432M)) inhibits c
      Jun/AP-1 sensitive reporter gene expression stimulated by thrombin or Galpha12.
      These data demonstrate that the alpha subunit of the heterotrimeric G protein
      G12, like tyrosine kinase growth factor receptors, activates Ras and recruits a
      signal transduction pathway involving the small GTP-binding protein Rac that
      leads to JNK activation.

PMID- 8663429
TI  - Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality
      reversed by bile acid and vitamin supplementation.
AB  - Mice deficient in cholesterol 7alpha-hydroxylase, the rate-limiting enzyme of
      bile acid biosynthesis, were constructed by targeted disruption of the Cyp7 gene.
      The introduced mutation removed exons 3-5 of the gene and gave rise to a null
      allele that encoded no immunoreactive or enzymatically active protein.
      Heterozygous carriers of the disrupted gene (Cyp7+/-) were phenotypically normal.
      Homozygous animals (Cyp7-/-) appeared normal at birth, but died within the first
      18 days of life. Approximately 40% of the animals died between postnatal days 1
      and 4 and 45% between days 11 and 18. The addition of vitamins to the water of
      nursing mothers prevented deaths in the early period, whereas the addition of
      cholic acid to chow prevented deaths in the later period. Newborn Cyp7-/- mice
      whose mothers were maintained on unsupplemented chow failed to gain weight at a
      normal rate and developed oily coats, hyperkeratosis, and apparent vision
      defects. These symptoms waned at 3 weeks of life, and their disappearance was
      accompanied by a marked increase in survival. In the accompanying study, the
      induction of an alternate pathway of bile acid biosynthesis is shown to underlie
      this unusual time course (Schwarz, M., Lund, E. G., Setchell, K. D. R., Kayden,
      H. J., Zerwekh, J. E., Bjorkhem, I., Herz, J., and Russell, D. W. (1996) J. Biol.
      Chem. 271, 18024-18031). We conclude that cholesterol 7alpha-hydroxylase is an
      essential enzyme for normal postnatal development.

PMID- 8663430
TI  - Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid
      deficiency is overcome by induction of oxysterol 7alpha-hydroxylase.
AB  - Past experiments and current paradigms of cholesterol homeostasis suggest that
      cholesterol 7alpha-hydroxylase plays a crucial role in sterol metabolism by
      controlling the conversion of cholesterol into bile acids. Consistent with this
      conclusion, we show in the accompanying paper that mice deficient in cholesterol
      7alpha-hydroxylase (Cyp7-/- mice) exhibit a complex phenotype consisting of
      abnormal lipid excretion, skin pathologies, and behavioral irregularities
      (Ishibashi, S., Schwarz, M., Frykman, P. K. , Herz, J., and Russell, D. W.(1996)
      J. Biol. Chem. 261, 18017-18023). Aspects of lipid metabolism in the Cyp7-/- mice
      are characterized here to deduce the physiological basis of this phenotype. Serum
      lipid, cholesterol, and lipoprotein contents are indistinguishable between wild
      type and Cyp7-/- mice. Vitamin D3 and E levels are low to undetectable in
      knockout animals. Stool fat content is significantly elevated in newborn Cyp7-/-
      mice and gradually declines to wild-type levels at 28 days of age. Several
      species of 7alpha-hydroxylated bile acids are detected in the bile and stool of
      adult Cyp7-/- animals. A hepatic oxysterol 7alpha-hydroxylase enzyme activity
      that may account for the 7alpha-hydroxylated bile acids is induced between days
      21 and 30 in both wild-type and deficient mice. An anomalous oily coat in the
      Cyp7-/- animals is due to the presence of excess monoglyceride esters in the fur.
      These data show that 7alpha-hydroxylase and the pathway of bile acid synthesis
      initiated by this enzyme are essential for proper absorption of dietary lipids
      and fat-soluble vitamins in newborn mice, but not for the maintenance of serum
      cholesterol and lipid levels. In older animals, an alternate pathway of bile acid
      synthesis involving an inducible oxysterol 7alpha-hydroxylase plays a crucial
      role in lipid and bile acid metabolism.

PMID- 8663431
TI  - Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent
      transbilayer movement of phospholipid.
AB  - Elevation of intracellular Ca2+ in erythrocytes, platelets, and other cells
      initiates rapid redistribution of plasma membrane phospholipids (PL) between
      inner and outer leaflets, collapsing the normal asymmetric distribution.
      Consequently, phosphatidylserine and other lipids normally sequestered to the
      inner leaflet become exposed at the cell surface. This Ca2+-induced mobilization
      of phosphatidylserine to the surface of activated, injured, or apoptotic cells
      confers a procoagulant property to the plasma membrane, which promotes fibrin
      clotting and provides a signal for cell removal by the reticuloendothelial
      system. To identify the constituent of the membrane that mediates this Ca2+
      dependent "PL scramblase" activity, we undertook purification and reconstitution
      of membrane component(s) with this activity from detergent extracts of
      erythrocyte ghosts depleted of cytoskeleton. Active fractions were identified by
      their capacity to mediate the Ca2+-dependent redistribution of 7-nitrobenz-2-oxa
      1,3-diazol-4-yl-labeled PL between leaflets of reconstituted proteoliposomes.
      This PL scramblase activity co-eluted through multiple chromatographic steps with
      a single polypeptide of approximately 37 kDa, which was purified to apparent
      homogeneity as resolved by silver staining. The activity associated with this
      protein band was inactivated by trypsin. The isolated protein reconstituted in
      proteoliposomes mediated nonselective, bidirectional transport of 7-nitrobenz-2
      oxa-1, 3-diazol-4-yl-PL between membrane leaflets, with half-maximal activation
      between 20 and 60 microM Ca2+ (saturation >100 microM), mimicking the Ca2+
      dependent transbilayer lipid movement intrinsic to the erythrocyte membrane.

PMID- 8663432
TI  - 5-Oxo-eicosanoids and hematopoietic cytokines cooperate in stimulating neutrophil
      function and the mitogen-activated protein kinase pathway.
AB  - The newly defined eicosatetraenoates (ETEs), 5-oxoETE and 5-oxo-15(OH)-ETE, share
      structural motifs, synthetic origins, and bioactions with leukotriene B4 (LTB4).
      All three eicosanoids stimulate Ca2+ transients and chemotaxis in human
      neutrophils (PMN). However, unlike LTB4, 5-oxoETE and 5-oxo-15(OH)-ETE alone
      cause little degranulation and no superoxide anion production. However, we show
      herein that, in PMN pretreated with granulocyte-macrophage or granulocyte colony
      stimulating factor (GM-CSF or G-CSF), the oxoETEs become potent activators of the
      last responses. The oxoETEs also induce translocation of secretory vesicles from
      the cytosol to the plasmalemma, an effect not requiring cytokine priming. To
      study the mechanism of PMN activation in response to the eicosanoids, we examined
      the activation of mitogen-activated protein kinase (MAPK) and cytosolic
      phospholipase A2 (cPLA2). PMN expressed three proteins (40, 42, and 44 kDa) that
      reacted with anti-MAPK antibodies. The oxoETEs, LTB4, GM-CSF, and G-CSF all
      stimulated PMN to activate the MAPKs and cPLA2, as defined by shifts in these
      proteins' electrophoretic mobility and tyrosine phosphorylation of the MAPKs.
      However, the speed and duration of the MAPK response varied markedly depending on
      the stimulus. 5-OxoETE caused a very rapid and transient activation of MAPK. In
      contrast, the response to the cytokines was rather slow and persistent. PMN
      pretreated with GM-CSF demonstrated a dramatic increase in the extent of MAPK
      tyrosine phosphorylation and electrophoretic mobility shift in response to 5
      oxoETE. Similarly, 5-oxoETE induced PMN to release some preincorporated
      [14C]arachidonic acid, while GM-CSF greatly enhanced the extent of this release.
      Thus, the synergism exhibited by these agents is prominent at the level of MAPK
      stimulation and phospholipid deacylation. Pertussis toxin, but not Ca2+
      depletion, inhibited MAPK responses to 5-oxoETE and LTB4, indicating that
      responses to both agents are coupled through G proteins but not dependent upon
      Ca2+ transients. 15-OxoETE and 15(OH)-ETE were inactive while 5-oxo-15(OH)-ETE
      and 5(OH)-ETE had 3- and 10-fold less potency than 5-oxoETE, indicating a rather
      strict structural specificity for the 5-keto group. LY 255283, a LTB4 antagonist,
      blocked the responses to LTB4 but not to 5-oxoETE. Therefore, the oxoETEs do not
      appear to operate through the LTB4 receptor. In summary, the oxoETEs are potent
      activators of PMN that share some but not all activities with LTB4. The response
      to the oxoETEs is greatly enhanced by pretreatment with cytokines, indicating
      that combinations of these mediators may be very important in the pathogenesis of
      inflammation.

PMID- 8663433
TI  - G protein-coupled receptor kinase specificity for phosphorylation and
      desensitization of alpha2-adrenergic receptor subtypes.
AB  - The alpha2-adrenergic receptor (alpha2AR) subtype alpha2C10 undergoes rapid
      agonist-promoted desensitization which is due to phosphorylation of the receptor.
      One kinase that has been shown to phosphorylate alpha2C10 in an agonist-dependent
      manner is the betaAR kinase (betaARK), a member of the family of G protein
      coupled receptor kinases (GRKs). In contrast, the alpha2C4 subtype has not been
      observed to undergo agonist-promoted desensitization or phosphorylation by
      betaARK. However, the substrate specificities of the GRKs for phosphorylating
      alpha2AR subtypes are not known. We considered that differential capacities of
      various GRKs to phosphorylate alpha2C10 and alpha2C4 might be a key factor in
      dictating in a given cell the presence or extent of agonist-promoted
      desensitization of these receptors. COS-7 cells were co-transfected with
      alpha2C10 or alpha2C4 without or with the following GRKs: betaARK, betaARK2,
      GRK5, or GRK6. Intact cell phosphorylation studies were carried out by labeling
      cells with 32Pi, exposing some to agonist, and purifying the alpha2AR by
      immunoprecipitation and SDS-polyacrylamide gel electrophoresis. BetaARK and
      betaARK2 were both found to phosphorylate alpha2C10 to equal extents (>2-fold
      over that of the endogenous kinases). On the other hand, GRK5 and GRK6 did not
      phosphorylate alpha2C10. In contrast to the findings with alpha2C10, alpha2C4 was
      not phosphorylated by any of these kinases. Functional studies carried out in
      transfected HEK293 cells expressing alpha2C10 or alpha2C4 and selected GRKs were
      consistent with these phosphorylation results. With the marked expression of
      these receptors, no agonist-promoted desensitization was observed in the absence
      of GRK co-expression. However, desensitization was imparted to alpha2C10 by co
      expression of betaARK but not GRK6, while alpha2C4 failed to desensitize with co
      expression of betaARK. These results indicate that short term agonist-promoted
      desensitization of alpha2ARs by phosphorylation is dependent on both the receptor
      subtype and the expressed GRK isoform.

PMID- 8663434
TI  - Molecular cloning of phogrin, a protein-tyrosine phosphatase homologue localized
      to insulin secretory granule membranes.
AB  - An insulin granule membrane protein-tyrosine phosphatase (PTP) homologue,
      phogrin, was cloned by expression screening of a rat insulinoma cDNA library. The
      3723-base pair cDNA encoded a transmembrane glycoprotein of 1004 amino acids (Mr
      111876) that underwent post-translational proteolysis to 60-64-kDa products after
      a 30-min delay. The kinetics of proteolytic conversion (t1/2 = 45 min) and
      turnover (t1/2 = 12 h) were consistent with sorting and conversion in a late
      compartment of the secretory pathway. Studies on the native beta-cell protein
      suggested that the COOH-terminal PTP domain was on the cytosolic face of the
      secretory granule. The lumenal segment was comprised of a protease-resistant
      globular domain of around 25 kDa. Its localization and topology is thus
      consistent with a transmembrane receptor function related to granule biogenesis,
      exocytosis, or subsequent membrane recovery, and it should prove to be a useful
      cell biological marker for the granule membrane. High expression of the mRNA (5.4
      kilobases) and protein was evident in islets, pancreatic alpha- and beta-cell
      tumor lines, brain cells, and other cells of neuroendocrine lineage. It is
      closely related to the diabetic autoantigen ICA512 (IA-2) (42% identity overall;
      80% in the 260-amino acid PTP domain) and thus a potential target of autoimmunity
      in diabetes mellitus.

PMID- 8663435
TI  - Tumor necrosis factor alpha inhibits glutamate uptake by primary human
      astrocytes. Implications for pathogenesis of HIV-1 dementia.
AB  - Human immunodeficiency virus (HIV) infection is commonly associated with
      neurological disease that occurs in the apparent absence of extensive infection
      of brain cells by HIV, suggesting that indirect mechanisms account for
      neuropathogenesis in the CNS, perhaps including changes in the normal
      neuroprotective functions of astrocytes. To test this hypothesis, we examined the
      effect of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFalpha),
      produced by HIV-1-infected macrophages and microglia, on glutamate transport by
      primary human fetal astrocytes (PHFAs). A dose-dependent inhibition of high
      affinity glutamate uptake sites was observed 12-24 h after addition of exogenous
      recombinant human TNFalpha to PHFAs. This effect was specific since it was
      blocked by a neutralizing monoclonal antibody directed against TNFalpha.
      Furthermore, the inhibitory effect was reproduced by a monoclonal antibody that
      is an agonist at the 55-kDa TNF receptor. These results suggest that the
      neurotoxic effects of TNFalpha may be due in part to its ability to inhibit
      glutamate uptake by astrocytes, which in turn may result in excitotoxic
      concentrations of glutamate in synapses.

PMID- 8663436
TI  - Integrin-mediated activation of MEK and mitogen-activated protein kinase is
      independent of Ras [corrected].
AB  - The integrins are a family of cell surface receptors that mediate adhesive
      interactions with the extracellular matrix and also generate signals that
      influence cell growth and differentiation. Ligation and clustering of integrins
      causes activation and autophosphorylation of focal adhesion kinase (FAK), a
      cytoplasmic tyrosine kinase, and results in the transient activation of p42 and
      p44 mitogen-activated protein (MAP) kinases. Initial evidence has suggested that
      the integrin signaling pathway may share common elements with the canonical Ras
      signal transduction cascade activated by peptide mitogens such as epidermal
      growth factor (EGF). In this report we demonstrate that Raf-1 and MAP or
      extracellular signal-related kinase kinase (MEK), key cytoplasmic kinases of the
      Ras cascade, are activated subsequent to integrin-mediated adhesion of mouse NIH
      3T3 fibroblasts. We also show that MAP kinase is downstream of MEK in the
      integrin signaling pathway. However, in contrast to the receptor tyrosine kinase
      signaling cascade, integrin-mediated signal transduction seems to be largely
      independent of Ras. Dominant negative inhibitors of Ras-dependent signaling
      failed to block integrin-mediated activation of MEK. In addition, while treatment
      with the peptide mitogen EGF clearly increased GTP-loading of Ras, little effect
      was observed in response to integrin-dependent cell adhesion. Thus, integrin
      mediated activation of MEK and MAP kinase in 3T3 cells occurs primarily by a
      mechanism that is distinct from the Ras signal transduction cascade.

PMID- 8663438
TI  - Release of leukotriene A4 versus leukotriene B4 from human polymorphonuclear
      leukocytes.
AB  - The reactive intermediate formed by 5-lipoxygenase metabolism of arachidonic
      acid, leukotriene A4, is known to be released from cells and subsequently taken
      up by other cells for biochemical processing. The objective of this study was to
      determine the relative amount of leukotriene A4 synthesized by human
      polymorphonuclear leukocytes (PMNL) that is available for transcellular
      biosynthetic processes. This was accomplished by diluting cell suspensions and
      measuring the relative amounts of enzymatic versus nonenzymatic leukotriene A4
      derived metabolites after challenge with the Ca2+ ionophore A23187. Nonenzymatic
      leukotriene A4-derived metabolites were used as a quantitative index of the
      amount of leukotriene A4 released into the extracellular milieu. The results
      obtained demonstrated that in human PMNL, the relative amounts of nonenzymatic
      versus enzymatic leukotriene A4-derived metabolites increased with decreasing
      cell concentrations. After a 20-fold dilution of PMNL in cell preparations, a
      doubling in the amount of nonenzymatic leukotriene A4-derived metabolites was
      observed following challenge (from 53.9 +/- 1.3 to 110.4 +/- 8.9 pmol/10(6) PMNL,
      p < 0.01). Reduction of possible cell-cell interactions by dilution suggested
      that over 50% of leukotriene A4 synthesized is released from the PMNL. These data
      provide evidence that, in human PMNL preparations, transfer of leukotriene A4 to
      neighboring PMNL is taking place, resulting in additional formation of
      leukotriene B4 and its omega-oxidized metabolites 20-hydroxy- and 20-carboxy
      leukotriene B4. Neutrophil reuptake of extracellular leukotriene A4 leads to an
      underestimation of the fraction of leukotriene A4 that is in fact available for
      transcellular metabolism when tight cell-cell interactions occur, such as during
      PMNL adhesion to the microvascular endothelium and diapedesis.

PMID- 8663437
TI  - Phosphatidylinositol 3-OH kinase activity is not required for activation of
      mitogen-activated protein kinase by cytokines.
AB  - Hemopoietic cells respond to cytokines by initiating tyrosine phosphorylation of
      receptors and receptor-associated proteins, leading to the activation of numerous
      cytosolic and membrane associated enzymes, including phosphatidylinositol 3-OH
      kinase (PI 3-kinase). Recent reports have suggested that PI 3-kinase may serve as
      an upstream activator of mitogen-activated protein (MAP) kinase. After
      stimulation with interleukin-3 and granulocyte-macrophage colony-stimulating
      factor, we show here that inhibition of MAP kinase activity by two inhibitors of
      PI 3-kinase, wortmannin and LY-294002, does not correlate with their ability to
      inhibit PI 3-kinase or p70 S6 kinase phosphorylation. Complete inhibition of
      phosphatidylinositol 3,4,5-trisphosphate production occurred at approximately 100
      nM WM or 25 microM LY-294002, but at these concentrations, WM significantly
      inhibited MAP kinase activation, while LY-294002 had virtually no effect on MAP
      kinase activity. Furthermore, WM does not inhibit phorbol ester-mediated MAP
      kinase activation, but LY-294002 does. Together these results suggest WM and LY
      294002 are differentially inhibiting enzymes other than PI 3-kinase that function
      upstream of MAP kinase.

PMID- 8663439
TI  - Fas-induced activation of the cell death-related protease CPP32 Is inhibited by
      Bcl-2 and by ICE family protease inhibitors.
AB  - The human proto-oncogene bcl-2 and its Caenorhabditis elegans homologue ced-9
      inhibit programmed cell death. In contrast, members of the human interleukin
      1beta converting enzyme (ICE) family of cysteine proteases and their C. elegans
      homologue CED-3 promote the death program. Genetic experiments in C. elegans have
      shown that ced-9 is formally a negative regulator of ced-3 function, but neither
      those studies nor others have determined whether CED-9 or Bcl-2 proteins act
      biochemically upstream or downstream of CED-3/ICE proteases. CPP32, like all
      known members of the CED-3/ICE family, is synthesized as a proenzyme that is
      subsequently processed into an active protease with specificity for cleavage at
      Asp-X peptide bonds. In this report, we demonstrate that the CPP32 proenzyme is
      proteolytically processed and activated in Jurkat cells induced to die by Fas
      ligation. CPP32 activation is blocked by cell-permeable inhibitors of aspartate
      directed, cysteine proteases, suggesting that pro-CPP32 is cleaved by active
      CPP32 or by other ICE family members. Heterologous expression of Bcl-2 in Jurkat
      cells prevents Fas-induced cell death as well as proteolytic processing and
      activation of CPP32. Thus, Bcl-2 acts at or upstream of the CPP32 activation step
      to inhibit apoptosis induced by Fas stimulation.

PMID- 8663440
TI  - Mass spectrometric identification of leucine zipper-like homodimer complexes of
      the autoantigen L7.
AB  - The eucaryotic protein L7 has been shown to associate in the cytoplasm with the
      large subunit of ribosomes and to interact specifically with as yet unknown
      cognate sites of mRNA, thereby inhibiting cell-free translation (Neumann, F.,
      Hemmerich, P., von Mikecz, A., Peter, H. H., and Krawinkel, U.(1995) Nucleic
      Acids Res. 23, 195-202). The N-terminal region of protein L7 contains a sequence
      motif similar to the leucine zipper domain of eucaryotic transcription factors,
      which promotes dimerization through alpha-helical coiled coil formation. Using
      electrospray-ionization mass spectrometry as a method of molecular specificity,
      we have directly identified the dimeric complexes comprising the leucine zipper
      like region of protein L7 and have determined the dissociation constant of L7
      homodimers in an affinity binding assay. We also demonstrate the high content of
      alpha-helicity of the dimer by circular dichroism spectra and computer-based
      structure simulation and show that the leucine zipper region of protein L7 is
      fully sufficient to mediate the inhibition of cell-free mRNA translation. A
      structural basis for the function of L7 to regulate translation is discussed.
      From the present results we conclude that L7 interacts with double stranded mRNA
      in a similar fashion as leucine zipper proteins with specific cognate sites on
      double stranded DNA.

PMID- 8663442
TI  - Intermediate channeling on the trifunctional beta-oxidation complex from pig
      heart mitochondria.
AB  - The kinetic properties of the purified trifunctional beta-oxidation complex (TOC)
      from pig heart mitochondria were analyzed with the aim of elucidating the
      functional consequence of having three sequentially acting enzymes of beta
      oxidation associated in one complex. The kinetic parameters of TOC and of the
      component enzymes of TOC, long-chain enoyl-CoA hydratase, long-chain 3
      hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase, were
      determined with substrates having acyl chains with 16 carbon atoms.
      Quantification by high performance liquid chromatography of intermediates formed
      during the degradation of 2-trans-hexadecanoyl-CoA to myristoyl-CoA and acetyl
      CoA by TOC revealed the accumulation of 3-hydroxyhexadecanoyl-CoA, whereas 3
      ketohexadecanoyl-CoA was undetectable. The observed rates of NADH and acetyl-CoA
      formation were higher than the theoretical rates calculated by use of the kinetic
      parameters and measured concentrations of intermediates. When the sequence of
      reactions catalyzed by TOC was inhibited by acetyl-CoA, the steady-state
      concentration of the 3-hydroxyacyl-CoA intermediate was not affected, whereas a
      small amount of 3-ketohexadecanoyl-CoA was detected. The differences between
      observed and predicted reaction rates and between measured and expected
      concentrations of intermediates are best explained by the operation of a
      channeling mechanism. As a consequence of intermediate channeling between the
      active sites on the complex, more coenzyme A is available in the mitochondrial
      matrix and metabolites like 3-ketoacyl-CoA thioesters, which are strong
      inhibitors of several beta-oxidation enzymes, do not accumulate.

PMID- 8663443
TI  - The type 2 ryanodine receptor of neurosecretory PC12 cells is activated by cyclic
      ADP-ribose. Role of the nitric oxide/cGMP pathway.
AB  - Of two neurosecretory PC12 cell clones that respond to NO donors and 8-bromo-cGMP
      with similar increases in cADP-ribose and that possess molecularly similar Ca2+
      stores, only one (clone 16A) expresses the type 2 ryanodine receptor, whereas the
      other (clone 27) is devoid of ryanodine receptors. In PC12-16A cells, activation
      of the NO/cGMP pathway induced slow [Ca2+]i responses, sustained by release from
      Ca2+ stores. In contrast, PC12-27 cells were insensitive to NO donors. Likewise,
      in PC12-16A cells preincubated with NO donors, Ca2+ stores were partially
      depleted, as revealed by a test with thapsigargin, whereas those in clone 27 were
      unchanged. The NO-induced Ca2+ release was increased synergistically by caffeine,
      and the corresponding store depletion was magnified by ryanodine. The specificity
      for the NO/cGMP pathway was confirmed by the effects of two blockers of cGMP
      dependent protein kinase I, while the role of cADP-ribose was demonstrated by the
      effects of its antagonist, 8-amino-cADP-ribose, administered to permeabilized
      cells. These results demonstrate in neurosecretory cells a ryanodine receptor
      activation pathway similar to that known in sea urchin oocytes. The signaling
      events described here could be of great physiological importance, especially in
      the nervous system.

PMID- 8663445
TI  - The ATP-binding site in the 2-kinase domain of liver 6-phosphofructo-2
      kinase/fructose-2,6-bisphosphatase. Study of the role of Lys-54 and Thr-55 by
      site-directed mutagenesis.
AB  - All known 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isozymes contain a
      sequence (GX4GK(S/T)) in the 6-phosphofructo-2-kinase domain corresponding to the
      so-called nucleotide binding fold signature or Walker A motif. Mutagenesis and
      crystal structure data from several nucleotide binding proteins, which also
      contain this sequence, showed the importance of the lysine and serine/threonine
      residues in nucleotide binding. We have studied the role of Lys-54 and Thr-55 in
      MgATP binding in the 6-phosphofructo-2-kinase domain of rat liver 6-phosphofructo
      2-kinase/fructose-2,6-bisphosphatase by site-directed mutagenesis. Lys-54 was
      mutated to methionine, whereas Thr-55 was mutated to valine, serine, and
      cysteine. Three mutants, Lys-54 to Met and Thr-55 to Cys or Val, displayed more
      than a 5000-fold decrease in 6-phosphofructo-2-kinase activity compared with the
      wild type. The mutations had no effect on fructose-2, 6-bisphosphatase activity
      and did not affect the activation of fructose-2,6-bisphosphatase after
      phosphorylation by cyclic 3', 5'-AMP-dependent protein kinase. Binding
      experiments with ATP, ADP, and their analogs (3'-N-methylanthraniloyl
      derivatives) showed that these two residues do not play the same role. Lys-54 is
      involved in ATP binding, whereas Thr-55 is important for catalysis.

PMID- 8663446
TI  - Regulation of 5'-AMP-activated protein kinase activity by the noncatalytic beta
      and gamma subunits.
AB  - The mammalian 5'-AMP-activated protein kinase is a heterotrimer consisting of an
      alpha catalytic subunit and beta and gamma noncatalytic subunits, each of which
      is represented in a larger isoprotein family, related to the SNF1 kinase and its
      interacting proteins in yeast. In this study, we have used mammalian cell
      transfection to compare the activities of the two alpha subunit isoforms, alpha-1
      and alpha-2, and to study the influence of the noncatalytic subunits on enzyme
      subunit association and activity. Expression of epitope-tagged protein subunits
      in COS7 cells indicates detectable but low level kinase activity for each of the
      two catalytic alpha subunits. Co-expression of alpha subunits with the beta or
      gamma subunits modestly increases kinase activity accompanied by the formation of
      alpha/beta or alpha/gamma heterodimers. Co-expression of all three subunits,
      however, is accompanied by a 50-110-fold increase in kinase activity with the
      formation of a heterotrimeric complex. In addition to binding of each
      noncatalytic subunit to the alpha subunit, the beta and gamma subunits bind to
      each other, likely resulting in a more stable heterotrimeric complex. The
      increase in kinase activity associated with expression of this heterotrimer is
      due both to an increase in enzyme-specific activity (units/enzyme mass) and to an
      apparent enhanced alpha subunit expression. Co-expression of a catalytically
      defective alpha subunit or the beta/gamma-binding COOH-terminal domain of the
      alpha subunit results in reduced heterotrimeric kinase activity. The synergistic
      positive regulatory roles for both the noncatalytic beta and gamma subunits of 5'
      AMP-activated protein kinase contrasts with the Snf1p kinase, where only
      heterodimers of Snf1p and Snf4p seem to be required for maximum kinase activity.

PMID- 8663448
TI  - A new syntaxin family member implicated in targeting of intracellular transport
      vesicles.
AB  - Despite the central role vesicular trafficking occupies in protein targeting, the
      molecular coding of the trafficking signals and the mechanism of vesicle docking
      and fusion are just beginning to be understood. We report here the cloning and
      initial characterization of a new member of the syntaxin family of vesicular
      transport receptors. Syntaxin 6 is a 255-amino acid protein with two domains
      predicted to form coiled-coils, as well as a carboxyl-terminal membrane anchor.
      Syntaxin 6 is broadly expressed and localizes in the region of the Golgi
      apparatus. In vitro binding studies established that syntaxin 6 binds to alpha
      soluble NSF attachment protein (alpha-SNAP). The sequence homology, topology,
      localization, and alpha-SNAP binding suggest that syntaxin 6 is involved in
      intracellular vesicle trafficking.

PMID- 8663447
TI  - Enzymatic characterization and functional domain mapping of brain myosin-V.
AB  - The actin binding and ATPase properties, as well as the functional domain
      structure of chick brain myosin-V, a two-headed, unconventional myosin, is
      reported here. Compared to conventional myosin from skeletal muscle, brain myosin
      V exhibits low K-EDTA- and Ca-ATPase activities (1.8 and 0.8 ATP/s per head). The
      physiologically relevant Mg-ATPase is also low (approximately 0.3 ATP/s), unless
      activated by the presence of both F-actin and Ca2+ (Vmax of 27 ATP/s). Ca2+
      stimulates the actin-activated Mg-ATPase over a narrow concentration range
      between 1 and 3 microM. In the presence of saturating Ca2+ and 75 mM KCl,
      surprisingly low concentrations of F-actin activate the Mg-ATPase in a hyperbolic
      manner (KATPase of 1.3 microM). Brain myosin-V also binds with relatively high
      affinity (compared to other known myosins) to F-actin in the presence of ATP, as
      assayed by cosedimentation. Digestion of brain myosin-V with calpain yielded a 65
      kDa head domain fragment that cosediments with actin in an ATP-sensitive manner
      and a 80-kDa tail fragment that does not interact with F-actin. The 80-kDa
      fragment results from cleavage one residue beyond the proline-, glutamate-,
      serine-, threonine-rich region. Our data indicate that the Mg-ATPase cycle of
      brain myosin-V is tightly regulated by Ca2+, probably via direct binding to the
      calmodulin light chains in the neck domain, which like brush border myosin-I,
      results in partial (approximately 30%) dissociation of the calmodulin associated
      with brain myosin-V. The effect of Ca2+ binding, which appears to relieve
      suppression by the neck domain, can be mimicked by calpain cleavage near the
      head/neck junction.

PMID- 8663449
TI  - APEG-1, a novel gene preferentially expressed in aortic smooth muscle cells, is
      down-regulated by vascular injury.
AB  - Despite the importance of phenotypic alterations in arterial smooth muscle cells
      (ASMC) during the pathogenesis of arteriosclerosis, little is known about genes
      that define differentiated ASMC. Using differential mRNA display, we isolated a
      novel gene preferentially expressed in the rat aorta and termed this gene APEG-1.
      The cDNA of rat APEG-1 contained an open reading frame encoding 113 amino acids,
      which would predict a basic protein of 12.7 kDa. The amino acid sequence of rat
      APEG-1 was highly conserved among human and mouse homologues (97 and 98%,
      respectively). Using an APEG-1 fusion protein containing an N-terminal c-Myc tag,
      we identified APEG-1 as a nuclear protein. By in situ hybridization, APEG-1 mRNA
      was expressed in rat ASMC. Although APEG-1 was expressed highly in differentiated
      ASMC in vivo, its expression was quickly down-regulated and disappeared in
      dedifferentiated ASMC in culture. In vivo, APEG-1 mRNA levels decreased by more
      than 80% in response to vascular injury as ASMC changed from a quiescent to a
      proliferative phenotype. Taken together, these data indicate that APEG-1 is a
      novel marker for differentiated ASMC and may have a role in regulating growth and
      differentiation of this cell type.

PMID- 8663450
TI  - An activated epidermal growth factor receptor/Lck chimera restores early T cell
      receptor-mediated calcium response in a CD45-deficient T cell line.
AB  - In T cells, cell surface expression of CD45, a transmembrane tyrosine
      phosphatase, is required for T cell receptor (TCR) signal transduction. Indirect
      evidence suggests that CD45 function in TCR signaling involves the
      dephosphorylation of the C-terminal negative regulatory site of p56(lck), Tyr
      505. To evaluate the importance of CD45-mediated dephosphorylation of p56(lck)
      Tyr-505 in TCR signaling, we established CD45(-) Jurkat cell lines expressing
      various forms of a chimera containing the extracellular and transmembrane domains
      of the epidermal growth factor receptor (EGFR) fused to p56(lck). We report that
      an activated EGFR/Lck chimera is able to reconstitute a Ca2+ response after CD3
      stimulation in the absence of CD45 expression. In addition, the wild-type and
      kinase inactive versions of the EGFR/Lck chimera fail to restore early signaling.
      Restoration of the response by EGFR/LckF505 required EGF binding to the chimeric
      kinase. Altogether, these results provide the first direct evidence that the lack
      of efficient dephosphorylation of p56(lck) Tyr-505 is, in part, responsible for
      the unresponsiveness of CD45(-) cells. They also indicate that a second event is
      required for p56(lck) function in TCR signaling in addition to its
      dephosphorylation at Tyr-505.

PMID- 8663452
TI  - Forskolin stimulates detoxification of brefeldin A.
AB  - Forskolin has been shown to prevent the effects brefeldin A (BFA) exerts on many
      mammalian cells with respect to the disassembly of the Golgi apparatus as well as
      an increase of sphingomyelin synthesis (Lippincott, S. J., Glickman, J.,
      Donaldson, J. G., Robbins, J., Kreis, T. E., Seamon, K. B., Sheetz, M. P., and
      Klausner, R. D. (1991) J. Cell Biol. 112, 567-577). It has been speculated that
      forskolin interferes with the action of BFA by competition for the binding of BFA
      to its target protein, which is most likely the Golgi-localized nucleotide
      exchange factor specific for ADP-ribosylation factor 1. Here we show that in
      vitro forskolin does not prevent inhibition of Golgi-catalyzed nucleotide
      exchange by BFA. Therefore it appears unlikely that forskolin and BFA bind to the
      same target protein. Using [3H]BFA we have measured detoxification of BFA by
      Chinese hamster ovary (CHO) cells. BFA is secreted from CHO cells as cysteine and
      glutathione conjugates (Bruning, A., Ishikawa, T., Kneusel, R. E., Matern, U.,
      Lottspeich, F., and Wieland, F. T. (1992) J. Biol. Chem. 267, 7726-7732). We
      present evidence that forskolin treatment of CHO cells results in increased
      levels of Cys-BFA, the major BFA conjugate secreted by CHO cells, in the medium.
      Elevated levels of Cys-BFA are also found intracellularly. The effect of
      forskolin is shown to be independent of its ability to raise the intracellular
      concentration of cyclic AMP. Therefore, we suggest that the effect of forskolin
      on BFA-induced disassembly of the Golgi apparatus might be due to an enhanced
      detoxification of the drug.

PMID- 8663453
TI  - Archaebacterial DNA polymerases tightly bind uracil-containing DNA.
AB  - We show that archaebacterial DNA polymerases are strongly inhibited by the
      presence of small amounts of uracil-containing DNA. Inhibition appears to be
      competitive, with the DNA polymerase exhibiting approximately 6500-fold greater
      affinity for binding the inhibitor than a DNase I-activated DNA substrate. All
      six archaebacterial DNA polymerases tested were inhibited, while no eubacterial,
      eukaryotic, or bacteriophage enzymes showed this effect. Only a small inhibition
      resulted when uracil was present as the deoxynucleoside triphosphate, dUTP. The
      rate of DNA synthesis was reduced by approximately 40% when dUTP was used in
      place of dTTP for archaebacterial DNA polymerases. Furthermore, an incorporated
      dUMP served as a productive 3'-primer terminus for subsequent elongation. In
      contrast, the presence of an oligonucleotide containing as little as a single
      dUrd residue was extremely inhibitory to DNA polymerase activity on other primer
      template DNA.

PMID- 8663454
TI  - An animal cell mutant defective in heparan sulfate hexuronic acid 2-O-sulfation.
AB  - The interaction of heparan sulfate with protein ligands depends on unique
      oligosaccharide sequences containing iduronic acid (IdUA), N-sulfated glucosamine
      residues, and O-sulfated sugars. To study the role of O-sulfation in greater
      detail, we isolated a Chinese hamster ovary cell mutant defective in 2-O
      sulfation of iduronic acid. The mutant, pgsF-17, was identified by a colony
      blotting assay in which colonies of mutagen-treated cells were replica plated to
      two disks of polyester cloth. One disk was blotted with 125I-labeled basic
      fibroblast growth factor (bFGF) to measure binding to cell surface proteoglycans.
      The other disk was incubated with 35SO4 to measure proteoglycan biosynthesis.
      Autoradiography revealed a colony that did not bind 125I-bFGF, but incorporated
      35SO4 normally (mutant pgsF-17). Complete deaminative cleavage of heparan sulfate
      revealed that material from pgsF-17 lacked IdUA(2OSO3)-GlcNSO3 and IdUA(2OSO3)
      GlcNSO3(6OSO3), but contained a higher proportion of glucuronic acid GlcUA
      GlcNSO3(6OSO3) and IdUA-GlcNSO3(6OSO3). Assay of the 2-O-sulfotransferase that
      acts on IdUA residues showed that mutant 17 lacked enzyme activity.
      Interestingly, the alteration resulted in accumulation of GlcNSO3 groups,
      suggesting that under normal conditions 2-O-sulfation decreases GlcNAc N
      deacetylation/N-sulfation, and that the reactions occur simultaneously. The
      formation of IdUA and 6-O-sulfated glucosaminyl residues appears to be
      independent of 2-O-sulfation. pgsF-17 also lacks 2-O-sulfated GlcUA residues,
      suggesting that the same enzyme is responsible for 2-O-sulfation of IdUA and
      GlcUA residues. Mutant 17 provides a useful tool for studying the regulation of
      heparan sulfate biosynthesis and the relationship of heparan sulfate fine
      structure to its biological function.

PMID- 8663455
TI  - Glycolipid-independent sorting of a secretory glycoprotein to the apical surface
      of polarized epithelial cells.
AB  - Proteins attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor
      cluster together with glycolipids in detergent-insoluble complexes at the site of
      sorting in the trans-Golgi network. This process has been shown to be critical
      for the targeting of these proteins to the apical cell surface in polarized
      epithelial cells. We show in this study that gp80 (clusterin), an apically
      secreted glycoprotein, is not included in detergent-insoluble complexes in Madin
      Darby canine kidney cells. Furthermore in Fisher rat thyroid cells, which target
      GPI-anchored proteins preferentially to the basolateral cell surface, gp80 is
      secreted apically. Together these results suggest that this secretory
      glycoprotein and GPI-linked proteins use different mechanisms to reach the apical
      membrane.

PMID- 8663456
TI  - Cloning and characterization of human TAF20/15. Multiple interactions suggest a
      central role in TFIID complex formation.
AB  - TFIID is a multiprotein complex that plays a central role in the initiation and
      regulation of class II transcription. Transcription factor IID (TFIID) nucleates
      transcription initiation complex formation by direct core promoter binding and
      mediates the action of transcriptional activators, in part via direct
      interactions with them. Molecular studies of the TFIID complex have identified
      multiple subunits whose potential interactions can be recapitulated in vitro with
      recombinant polypeptides. Here we report the cloning of human TATA box binding
      protein (TBP)-associated factor 20 (TAF20) and the consequent identification of
      an additional, related TFIID subunit, human TAF15 (hTAF15). Multiple TAF20/15
      interactions have been detected within native TFIID preparations and further
      analyzed with recombinant subunits. Along with the demonstration of a high
      affinity association between TAF20/15 and TBP, the present results suggest that
      hTAF20/15 may complement hTAF250 in directing the association of TAFs with TBP to
      form a TFIID complex. Finally, we present detailed mutagenesis studies that
      reveal multiple, distinct interaction surfaces on the presumed globular domain of
      hTAF20/15 and may be used, in conjunction with structural data, to model the
      architecture of the TFIID multiprotein complex.

PMID- 8663457
TI  - Differential interactions of the CREB/ATF family of transcription factors with
      p300 and adenovirus E1A.
AB  - The adenovirus E1A-associated protein p300 is a transcriptional cofactor that
      interacts with YY1 and mediates the relief of YY1 transcriptional repression by
      E1A. These observations raise the possibility that p300 may function as a
      bridging factor between E1A and cellular transcription factors. Here we show that
      p300, but not a mutant defective for binding to E1A, activated cAMP-responsive
      element-binding protein/activating transcription factor (CREB/ATF) binding site
      mediated transcription in the presence of E1A. Among proteins that can recognize
      the CREB/ATF site, CREB appeared to be modulated by E1A in a p300 binding
      dependent manner. This effect of E1A was correlated with a specific physical
      interaction between CREB and p300. These results suggest that p300 plays a
      crucial role in mediating the functional interplay between E1A and certain
      members of the CREB/ATF family. Two separate domains within p300 were identified
      that are capable of activating transcription. One of the domains interacted with
      the basal factor TFIIB, suggesting that p300 may function as a coactivator by
      making contacts with both sequence-specific transcription factors and the basal
      transcriptional machinery. This pivotal role of p300 may make it a prime target
      for viral proteins such as E1A in programming the cellular transcription
      machinery.

PMID- 8663458
TI  - The unfolded protein response pathway in Saccharomyces cerevisiae.
      Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for
      kinase activation.
AB  - In eukaryotic cells, accumulation of unfolded proteins in the endoplasmic
      reticulum (ER) results in a transcriptional induction of a number of ER chaperone
      proteins. In Saccharomyces cerevisiae, the putative transmembrane receptor
      kinase, Ire1p (Ern1p), has been implicated as the sensor of unfolded proteins in
      the ER that initiates transmittance of the unfolded protein signal from the ER to
      the nucleus. We have shown that the cytoplasmic domain of Ire1p receptor indeed
      has intrinsic Ser/Thr kinase activity and contains Ser/Thr phosphorylation sites
      as well. The cytoplasmic domain is also shown to form oligomers in vivo and in
      vitro. The ability to form oligomers primarily resides within the last 130 amino
      acids of the cytoplasmic domain, a region that is dispensable for in vitro kinase
      activity of the receptor. Oligomerization of the cytoplasmic domains is required
      for receptor trans-phosphorylation and subsequent activation of the kinase
      function. The activated kinase may transmit the unfolded protein signal from the
      ER to the nucleus to activate the transcription of the chaperone genes in the
      nucleus.

PMID- 8663460
TI  - Tyrosine phosphorylation of the Fc receptor gamma-chain in collagen-stimulated
      platelets.
AB  - Stimulation of platelets by the extracellular matrix protein collagen leads to
      activation of a tyrosine kinase-dependent mechanism resulting in secretion and
      aggregation. Tyrosine phosphorylation of the tyrosine kinase Syk and
      phospholipase Cgamma2 are early events in collagen-induced activation. We
      recently proposed that collagen-signaling in platelets involves a receptor or a
      receptor-associated protein containing an immunoreceptor tyrosine-based
      activation motif (ITAM) enabling interaction with Syk. In this report we show
      that collagen stimulation of platelets causes rapid tyrosine phosphorylation of
      the ITAM containing Fc receptor gamma-chain and that this is precipitated by the
      tandem Src homology 2 (SH2) domains of Syk expressed as a fusion protein. In
      addition we demonstrate an association between the Fc receptor gamma-chain with
      endogenous Syk in collagen-stimulated platelets. The Fc receptor gamma-chain
      undergoes tyrosine phosphorylation in platelets stimulated by a collagen-related
      peptide which does not bind the integrin alpha2beta1 and by the lectin wheat germ
      agglutinin. In contrast, cross-linking of the platelet low affinity receptor for
      immune complexes, FcgammaRIIA, or stimulation by thrombin does not induce
      phosphorylation of the Fc receptor gamma-chain. The present results provide a
      molecular basis for collagen activation of platelets which is independent of the
      integrin alpha2beta1 and involves phosphorylation of the Fc receptor gamma-chain,
      its association with Syk and subsequent phosphorylation of phospholipase Cgamma2.
      Collagen is the first example of a nonimmune receptor stimulus to signal through
      a pathway closely related to signaling by immune receptors.

PMID- 8663461
TI  - Insulin and epidermal growth factor receptors regulate distinct pools of Grb2-SOS
      in the control of Ras activation.
AB  - Insulin and epidermal growth factor (EGF) stimulate a rapid but transient
      increase in the amount of GTP bound to Ras that returns to the basal GDP-bound
      state within 10-30 min. Although insulin stimulation resulted in a dissociation
      of the Grb2.SOS complex, EGF did not affect the Grb2.SOS complex but instead
      induced dissociation of Grb2-SOS from tyrosine-phosphorylated Shc. The
      dissociation of Grb2-SOS from Shc was not due to dephosphorylation as Shc
      remained persistently tyrosine-phosphorylated during this time. Furthermore,
      there was no decrease in the extent of insulin receptor substrate 1, insulin
      receptor, or EGF receptor tyrosine phosphorylation. Surprisingly, however,
      despite the EGF-induced decrease in the amount of Grb2-SOS bound to Shc, the
      extent of Grb2 associated with Shc remained constant, and there was a concomitant
      increase in the amount of SOS associated with Grb2. In addition, after the
      insulin-stimulated dissociation of Grb2 from SOS, EGF treatment induced the
      reassociation of the Grb2.SOS complex. Quantitative immunoprecipitation
      demonstrated that only a small fraction of the total cellular pool of Grb2 was
      associated with SOS. Similarly, only a small fraction of SOS and Grb2 were co
      immunoprecipitated with Shc. Together, these data suggest the presence of
      distinct Grb2-SOS pools that are independently utilized by insulin and EGF in
      their recruitment to tyrosine-phosphorylated Shc.

PMID- 8663463
TI  - Catalytic activities of alpha3beta3gamma complexes of F1-ATPase with 1, 2, or 3
      incompetent catalytic sites.
AB  - In order to know how many functional catalytic sites are necessary for ATPase
      activity of F1-ATPase from a thermophilic Bacillus PS3, a new method of isolating
      homogeneous preparations of the alpha3beta3gamma complex with 1, 2, or 3
      incompetent catalytic sites was developed. Ten glutamic acids (Glu.Tag) were
      linked to the C terminus of the catalytically incompetent beta(E190Q) subunit.
      The Glu.Tag itself did not affect ATPase activity of the complexes. Two kinds of
      alpha3beta3gamma complexes, one containing beta(wild-type) and the other Glu.Tag
      linked beta(E190Q), were mixed, urea-denatured, and dialyzed, and
      alpha3beta3gamma complexes were reconstituted. Each of the complexes containing a
      different number of Glu.Tag-linked beta(E190Q) was separated by anion-exchange
      chromatography and analyzed. The results were as follows. 1) Normal steady-state
      ATPase activity requires three intact catalytic sites. 2) Chase-acceleration, a
      catalytic cooperativity, requires at least two intact catalytic sites. 3) Single
      site catalysis can be mediated by a single intact catalytic site alone.
      Rescrambling of subunits between complexes could occur when the complex was aged
      under certain conditions, and this might be one of the reasons for previous
      contradictory results (Miwa, K., Ohtsubo, M., Denda, K., Hisabori, T., Date, T.,
      and Yoshida, M.(1989) J. Biochem. (Tokyo) 106, 730-734).

PMID- 8663465
TI  - Catalytic properties of human manganese superoxide dismutase.
AB  - The depletion of superoxide catalyzed by human manganese superoxide dismutase
      (MnSOD) was observed spectrophotometrically by measuring the absorbance of
      superoxide at 250-280 nm following pulse radiolysis and by stopped-flow
      spectrophotometry. Catalysis showed an initial burst of activity lasting
      approximately 1 ms followed by the rapid emergence of a greatly inhibited
      catalysis of zero-order rate. These catalytic properties of human MnSOD are
      qualitatively similar to those reported for MnSOD from Thermus thermophilus
      (Bull, C., Niederhoffer, E. C., Yoshida, T., and Fee, J. A.(1991) J. Am. Chem.
      Soc. 113, 4069-4076). However, there are significant quantitative differences;
      the emergence of the inhibited form is approximately 30-fold more rapid for human
      MnSOD. The turnover number for human MnSOD at pH 9.4 and 20 degrees C was kcat =
      4 x 10(4) s-1 and kcat/Km = 8 x 10(8) M-1 s-1, determined by a simulated fit of
      the model of Bull et al. (1991) to the pulse radiolysis data. We also report that
      the maximum of the visible absorption spectrum of human MnSOD (epsilon480 = 525 M
      1 cm-1) showed a strong dependence on pH that could be described by an ionization
      of pKa 9.4 +/- 0.1 with a maximum at low pH.

PMID- 8663466
TI  - Required allosteric effector site for N-acetylglutamate on carbamoyl-phosphate
      synthetase I.
AB  - Carbamoyl-phosphate synthetase I (CPSase I) catalyzes the entry and rate-limiting
      step in the urea cycle, the pathway by which mammals detoxify ammonia. One facet
      of CPSase I regulation is a requirement for N-acetylglutamate (AGA), which
      induces an active enzyme conformation and does not participate directly in the
      chemical reaction. We have utilized labeling with carbodiimide-activated [14C]AGA
      to identify peptides 120-127, 234-237, 625-630, and 1351-1356 as potentially
      being near the binding site for AGA. Identification of peptide 1351-1356 confirms
      the previous demonstration (Rodriquez-Aparicio, L. B., Guadalajara, A. M., and
      Rubio, V.(1989) Biochemistry 28, 3070-3074) that the C-terminal region is
      involved in binding AGA. Identification of peptides 120-127 and 234-237
      constitutes the first evidence that the N-terminal region of the synthetase is
      involved in ligand binding. Since peptides 631-638 and 1327-1348 have been
      identified near the ATP site of CPSase I (Potter, M. D., and Powers-Lee, S.
      G.(1992) J. Biol. Chem. 267, 2023-2031), the present finding of involvement of
      peptides 625-630 and 1351-1356 at an "allosteric" activator site was unexpected.
      The idea that portions of the AGA effector site might be derived from an
      ancestral glutamine substrate site via a gene duplication and diversification
      event was considered.

PMID- 8663468
TI  - An activation function in Pit-1 required selectively for synergistic
      transcription.
AB  - Synergistic transcription activation is a key component in the generation of the
      spectrum of eukaryotic promoter activities by a limited number of transcription
      factors. Various mechanisms could account for synergy, but a central question
      remains of whether synergism requires transcription factor functions that differ
      from those that direct independent activation. The rat growth hormone promoter is
      synergistically activated by the pituitary-specific transcription factor, Pit-1,
      and the thyroid hormone receptor (TR). Mutations that disrupted the previously
      described DNA binding and transcriptional activation domains of both Pit-1 and TR
      reduced Pit-1/TR synergy in parallel with their effects on the much weaker,
      independent Pit-1 and TR activations of the rat growth hormone promoter. Thus,
      Pit-1 and TR amplify each other's intrinsic activities. Mutations of Pit-1 that
      selectively inhibited synergism with the TR without affecting independent Pit-1
      activity were also identified. Pit-1/TR synergy is therefore a consequence of a
      novel synergism-selective activity and synergism-independent Pit-1 and TR
      functions.

PMID- 8663471
TI  - Purification of a lysophospholipase from bovine brain that selectively deacylates
      arachidonoyl-substituted lysophosphatidylcholine.
AB  - A high activity lysophospholipase A (lysoPLA) was purified from the soluble
      fraction of bovine brain. The separation included sequential DEAE-Sephacel,
      phenyl-Sepharose FF, heparin-Sepharose CL-6B, and Q-Sepharose FF column
      chromatography. Mono Q, Sephacryl S300HR, and hydroxylapatite column
      chromatography in the presence of the detergent CHAPS (3-[(3-cholamidopropyl)
      dimethylammonio]-1-propanesulfonate) and glycerol further purified the activity
      to 17,000-fold. The enzyme was purified to homogeneity by polyacrylamide gel
      electrophoresis using nondenaturing conditions. The pure enzyme migrated as a
      single polypeptide of 95 kDa mass by SDS-polyacrylamide gel electrophoresis and
      deacylated arachidonoyl-lysophosphatidylcholine (ara-lysoPC) at rate of 70
      micromol/(min mg). The enzyme showed selectivity for arachidonoyl-substituted
      lysoPC, since palmitoyl-lysoPC was deacylated at a much lower rate (7
      micromol/(min mg)). LysoPLA activity was maximal at pH 7.4-8.0 and was increased
      1.3-fold by MgCl2 (5 mM). By including MgCl2, however, the range of optimal
      activity was expanded to pH values up to 9.0. The 95-kDa protein also deacylated
      arachidonoyl groups from 1-O-hexadecyl-2-arachidonoyl-PC (PLA2 activity) at a
      rate of 15 micromol/(min mg). Moreover, the deacylation of arachidonoyl groups
      from diacylPC was greatly increased by including purified bovine brain PLA1 in
      the reaction mixture. Thus, the same 95-kDa polypeptide catalyzed both lysoPLA
      and PLA2 activities, but the rate of arachidonoyl group deacylation was increased
      by prior sn-1 deacylation. Finally, the 95-kDa polypeptide cross-reacted with
      antibodies raised against a human recombinant cPLA2, implying that the 95-kDa
      protein is structurally similar to cPLA2. Additionally, these data suggest that
      the combined actions of PLA1 and the 95-kDa protein generate significant amounts
      of free arachidonic acid in the brain.

PMID- 8663472
TI  - Metabolic stress opens K+ channels in hepatoma cells through a Ca2+- and protein
      kinase calpha-dependent mechanism.
AB  - These studies of a model liver cell line evaluate the mechanisms responsible for
      regulated release of K+ ions during metabolic stress. Metabolic inhibition of HTC
      hepatoma cells by exposure to 2, 4-dinitrophenol (50 microM) and 2-deoxy-D
      glucose (10 mM) stimulated outward currents carried by K+ of 974 +/- 75 pA at 0
      mV (n = 20, p < 0.001). Currents were inhibited by chelation of intracellular
      Ca2+ or exposure to apamin (50 nM), an inhibitor of SKCa channels. In cell
      attached recordings from intact cells, removal of metabolic substrates (25/28
      cells) or exposure to metabolic inhibitors (32/40 cells) opened K+-selective
      channels with a conductance of 6.5 +/- 0. 2 pS. Channels had an open probability
      of 0.31 +/- 0.08 and opened in bursts averaging 3.55 +/- 0.27 ms in duration (n =
      6). Metabolic stress was associated with rapid translocation of the alpha isoform
      of protein kinase C (PKCalpha) from cytosol to membrane; and down-regulation of
      PKCalpha by phorbol esters or exposure to the PKC inhibitor chelerythrine (10
      microM) each inhibited currents. Moreover, intracellular perfusion with purified
      PKCalpha activated currents in a Ca2+- and concentration-dependent manner. These
      findings indicate that metabolic stress leads to opening of apamin-sensitive SKCa
      channels in hepatoma cells through a Ca2+- and PKC-dependent mechanism and
      suggest that PKCalpha may be selectively involved in the response. This mechanism
      functionally couples the metabolic state of cells to membrane K+ permeability and
      represents a potential target for modification of liver injury associated with
      ischemia and preservation.

PMID- 8663474
TI  - The endothelial cell protein C receptor. Inhibition of activated protein C
      anticoagulant function without modulation of reaction with proteinase inhibitors.
AB  - A soluble form of the endothelial cell protein C receptor (EPCR) was analyzed for
      the ability to modulate the functional properties of protein C and activated
      protein C (APC). In a plasma clotting system initiated with factor Xa, EPCR
      blocked the anticoagulant activity of APC in a dose-dependent fashion. EPCR had
      no influence on clotting in the absence of APC. Consistent with the plasma
      results, EPCR slowed the proteolytic inactivation of factor Va by slowing both of
      the key proteolytic cleavages in the heavy chain of factor Va. EPCR did not
      prevent protein C activation by the soluble thrombin-thrombomodulin complex, did
      not alter the inactivation of APC by alpha1-antitrypsin or protein C inhibitor,
      and did not influence the kinetics of peptide paranitroanilide substrate cleavage
      significantly. We conclude that EPCR binds to an exosite on APC that selectively
      modulates the enzyme specificity in a manner reminiscent of the influence of
      thrombomodulin on thrombin.

PMID- 8663475
TI  - The endothelial cell protein C receptor. Cell surface expression and direct
      ligand binding by the soluble receptor.
AB  - Expression of the endothelial cell protein C receptor (EPCR) gene in mammalian
      cells imparts the capacity to bind activated protein C (APC) or protein C.
      Immunochemical analysis of CCD41, apparently the murine homologue of EPCR,
      suggested centrosomal localization, raising questions about the location of the
      EPCR gene product and its role in protein C binding. In this study, we express a
      soluble form of EPCR, demonstrate EPCR expression on the cell surface, and direct
      binding between soluble EPCR and protein C/APC. Affinity purified polyclonal and
      a monoclonal antibody against EPCR bound to the cell surface of EPCR-transfected
      cells but not to control cells. A 49-kDa protein, a mass similar to soluble EPCR,
      was immunoprecipitated from the cell surface of endothelium and cells transfected
      with human EPCR but not from control cells. The FLAGtrade mark antibody and APC
      bound to cells expressing an EPCR construct containing the FLAGtrade mark epitope
      located in a putative extracellular domain, whereas an EPCR construct truncated
      just before the putative transmembrane domain produced only soluble EPCR antigen.
      Soluble EPCR inhibited APC binding to EPCR expressing cells in a concentration
      dependent fashion, Kd (app) = 29 nM and bound to immobilized protein C in a Ca2+
      dependent fashion. Thus, EPCR is a type 1 transmembrane protein that binds
      directly to APC.

PMID- 8663478
TI  - Cross-talk between different enhancer elements during mitogenic induction of the
      human stromelysin-1 gene.
AB  - Platelet-derived growth factor (PDGF) induces the expression of human stromelysin
      1, a matrix metalloproteinase involved in tumor invasion and metastasis. Here it
      is shown that stromelysin-1 gene induction by PDGF depends on Ras and involves
      three previously identified promoter elements (the stromelysin-1 PDGF-responsive
      element (SPRE) site, the two head-to-head polyomavirus enhancer A-binding protein
      3 (PEA3) sites, and the activator protein-1 (AP-1) binding site). During
      mitogenic induction, these responsive elements appear to be organized in two
      independent transcriptional units, SPRE-AP-1 and PEA3-AP-1, which result from
      specific element cross-talking. Interestingly, expression of a dominant negative
      mutant of Raf-1 significantly interfered with the induction through PEA3-AP-1 but
      not with that operating through SPRE-AP-1. Conversely, only the induction
      operating through SPRE-AP-1 was affected significantly by the expression of a
      dominant negative mutant of the atypical lambda/iota protein kinase C
      (lambda/iotaPKC). These data strongly suggest that the signal triggered by PDGF
      flows through Ras and bifurcates toward two distinct pathways, one operating
      through Raf and involving PEA3-AP-1 and the other one Raf-independent, operating
      through lambda/iotaPKC and SPRE-AP-1. Furthermore, we present evidence suggesting
      that the novel SPRE-binding transcription factor SPBP cross-couples with c-Jun to
      transactivate the SPRE site.

PMID- 8663482
TI  - Potential for H-DNA in the human MUC1 mucin gene promoter.
AB  - Similar imperfect purine/pyrimidine mirror repeat (PMR) elements have previously
      been identified upstream of the human MUC1 mucin and CFTR genes. These elements
      confer S1 nuclease sensitivity on isolated plasmid DNA at low pH. We now present
      a detailed characterization of the non-B DNA structure responsible for S1
      nuclease sensitivity upstream of the MUC1 gene. A approximately 90-base pair (bp)
      DNA fragment containing a 32-bp PMR element termed M-PMR3 was subcloned into a
      recombinant vector. This fragment conferred S1 nuclease sensitivity on the
      resulting supercoiled plasmid. High resolution mapping of sites reactive to S1
      and P1 nucleases demonstrates that cleavage occurs within the M-PMR3 element.
      High resolution mapping with chemical agents selective for non-B DNA provides
      evidence that M-PMR3 adopts an H-DNA structure (intramolecular triple helix) in
      the less common H-y5 isomer at low pH. This result is observed in the presence or
      absence of Mg2+. Mutation of the native M-PMR3 element to create perfect
      homopurine/homopyrimidine mirror symmetry alters the preferred folding to the
      more common H-y3 triplex DNA isomer. These results demonstrate that imperfections
      in mirror symmetry can alter the relative stabilities of different H-DNA isomers.

PMID- 8663485
TI  - Ca2+-dependent exocytotic pathways in Chinese hamster ovary fibroblasts revealed
      by a caged-Ca2+ compound.
AB  - Ca2+-dependent exocytosis and endocytosis of Chinese hamster ovary (CHO)
      fibroblasts were investigated using capacitance measurement and rapid photolysis
      of a caged-Ca2+ compound, dimethoxynitrophenamine tetrasodium salt. CHO cells
      exhibited large and fast increases in membrane capacitance (1.9 +/- 1 picofarads,
      or 13 +/- 7% of total membrane area, mean +/- S.D., n = 37) upon Ca2+ jumps to
      [Ca2+]i larger than 20 microM. The fast exocytosis occurred with a delay (20-80
      ms), and exhibited a rate constant that was strongly dependent on [Ca2+]i. The
      maximal rate constant of exocytosis was 2.8/s, and a half-maximal rate was
      achieved at 30 microM. The fast exocytosis was followed by rapid endocytosis in
      28% of the cells. The endocytosis often began after a delay of 0.5-2 s. Ca2+
      jumps also induced stepwise increases in membrane capacitance of 10-134
      femtofarads in 40% of the cells, indicating fusion of large vesicles with
      diameters of 0.4-1.5 micron. The exocytosis of the large vesicles could
      selectively be induced with smaller Ca2+ jumps (6-20 microM), and occurred slowly
      with a rate constant of 0. 3/s. These data indicate that CHO fibroblasts possess
      Ca2+-dependent exocytotic mechanisms. Moreover, two parallel exocytotic pathways
      may exist reminiscent of those of neurons and endocrine cells. A kinetic model
      was constructed to account for the fast exocytosis of CHO cells.

PMID- 8663484
TI  - The involvement of protein phosphatases in the activation of ICE/CED-3 protease,
      intracellular acidification, DNA digestion, and apoptosis.
AB  - Many events in apoptosis have been identified but their temporal relationships
      remain obscure. Apoptosis in human ML-1 cells induced by etoposide is
      characterized by intracellular acidification, enhanced Hoechst 33342
      fluorescence, DNA digestion, chromatin condensation, and proteolysis of poly(ADP
      ribose) polymerase. This proteolysis is a marker for the action of ICE/CED-3
      proteases, which are critical activators of apoptosis. We observed that three
      serine/threonine protein phosphatase inhibitors, okadaic acid, calyculin A, and
      cantharidin, prevented all of these apoptotic characteristics. To determine which
      protein phosphatase was involved, we investigated the dephosphorylation of the
      retinoblastoma susceptibility protein Rb, a substrate for protein phosphatase 1
      but not protein phosphatase 2A. Rb was dephosphorylated during apoptosis, and
      each inhibitor prevented this dephosphorylation at the same concentrations that
      prevented apoptosis. No increase in protein phosphatase 1 activity was observed
      in apoptotic cells suggesting that dephosphorylation of Rb may result from loss
      of Rb kinase activity in the presence of a constant level of protein phosphatase
      activity. Long term inhibition of protein phosphatase 1 (>8 h) also led to the
      appearance of dephosphorylated Rb, cleavage of poly(ADP-ribose) polymerase and
      apoptosis, suggesting these events are not solely dependent upon protein
      phosphatase 1. Rb dephosphorylation was also observed in several other models of
      apoptosis. Hence, an imbalance between protein phosphatase 1 and Rb kinase may be
      a common means to activate ICE/CED-3 proteases resulting in the subsequent events
      of apoptosis.

PMID- 8663488
TI  - Differentially expressed forms of 1-L-myo-inositol-1-phosphate synthase (EC
      5.5.1.4) in Phaseolus vulgaris.
AB  - We have characterized two distinct polypeptides with 1-L-myo-inositol-1-phosphate
      synthase (MI-1-P synthase) activity that are differentially expressed during
      development in Phaseolus vulgaris. Western analyses, enzyme assays, and partial
      purification of MI-1-P synthase during embryonic and postembryonic development
      show that its expression is temporally and spatially regulated. Developmental
      Western analyses of soluble proteins detect a small protein, approximately 33
      kDa, with MI-1-P synthase activity during the globular stage (stage II) of
      embryogenesis and in mature roots. Expression of this small protein is also
      enriched in thylakoidal membranes of fractionated leaf chloroplasts, although
      Western analyses of total soluble leaf proteins show no cross-reacting material.
      In contrast, a larger protein, approximately 56 kDa, with MI-1-P synthase
      activity is present during the cotyledonary phase (stage IV) of embryogenesis in
      green cotyledons of seedlings and in young roots.

PMID- 8663493
TI  - Involvement of p90rsk in neurite outgrowth mediated by the cell adhesion molecule
      L1.
AB  - L1 is a neural cell adhesion molecule that has been shown to help guide nascent
      axons to their targets. This guidance is based on specific interactions of L1
      with its binding partners and is likely to involve signaling cascades that alter
      cytoskeletal elements in response to these binding events. We have examined the
      phosphorylation of L1 and the role it may have in L1-directed neurite outgrowth.
      Cytosolic extracts from nerve growth factor-stimulated PC12 cells were
      fractionated by anion-exchange chromatography, and an activity was found that
      phosphorylated the cytoplasmic domain of L1. This activity was then assayed using
      a battery of L1-derived synthetic peptides. Based on these peptide assays and
      sequencing of radiolabeled L1 proteolytic fragments, the phosphorylation site was
      determined to be Ser1152. Western blot analysis demonstrated that the L1 kinase
      activity from PC12 cells that phosphorylated this site was co-eluted with the S6
      kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co
      immunoprecipitate with L1 from brain, and metabolic labeling studies have
      demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain.
      The phosphorylation site is located in a region of high conservation between
      mammalian L1 sequences as well as L1-related molecules in vertebrates from fish
      to birds. We performed studies to investigate the functional significance of this
      phosphorylation. Neurons were loaded with peptides that encompass the
      phosphorylation site, as well as the flanking regions, and their effects on
      neurite outgrowth were observed. The peptides, which include Ser1152, inhibit
      neurite outgrowth on L1 but not on a control substrate, laminin. A
      nonphosphorylatable peptide carrying a Ser to Ala mutation did not affect neurite
      outgrowth on either substrate. These data demonstrate that the membrane-proximal
      15 amino acids of the cytoplasmic domain of L1 are important for neurite
      outgrowth on L1, and the interactions it mediates may be regulated by
      phosphorylation of Ser1152.

PMID- 8663494
TI  - Assembly of human neuronal nicotinic receptor alpha5 subunits with alpha3, beta2,
      and beta4 subunits.
AB  - Nicotinic acetylcholine receptors formed from combinations of alpha3, beta2,
      beta4, and alpha5 subunits are found in chicken ciliary ganglion neurons and some
      human neuroblastoma cell lines. We studied the co-expression of various
      combinations of cloned human alpha3, beta2, beta4, and alpha5 subunits in Xenopus
      oocytes. Expression on the surface membrane was found only for combinations of
      alpha3beta2, alpha3beta4, alpha3beta2alpha5, and alpha3beta4alpha5 subunits but
      not for other combinations of one, two, or three of these subunits. alpha5
      subunits assembled inside the oocyte with beta2 but not with alpha3 subunits or
      other alpha5 subunits. alpha5 subunits coassembled very efficiently with
      alpha3beta2 or alpha3beta4 combinations. The presence of alpha5 subunits had very
      little effect on the binding affinities for epibatidine of receptors containing
      also alpha3 and beta2 or alpha3 and beta4 subunits. The presence of alpha5
      subunits increased the rate of desensitization of both receptors containing also
      alpha3 and beta2 or alpha3 and beta4 subunits. In the case of receptors
      containing alpha3 and beta4 subunits, the addition of alpha5 subunits had little
      effect on the responses to acetylcholine or nicotine. However, in the case of
      receptors containing alpha3 and beta2 subunits, the addition of alpha5 subunits
      reduced the EC50 for acetylcholine from 28 to 0.5 microM and the EC50 for
      nicotine from 6.8 to 1.9 microM, while increasing the efficacy of nicotine from
      50% on alpha3beta2 receptors to 100% on alpha3beta2alpha5 receptors. Both
      alpha3beta2 and alpha3beta2alpha5 receptors expressed in oocytes sedimented at
      the same 11 S value as native alpha3-containing receptors from the human
      neuroblastoma cell line SH-SY5Y. In the receptors from the neuroblastoma alpha3,
      beta2, and alpha5 subunits were co-assembled, and 56% of the receptor subtypes
      containing alpha3 subunits also contained beta2 subunits. The beta2 subunit
      containing receptors from SH-SY5Y cells exhibited the high affinity for
      epibatidine characteristic of receptors formed from alpha3 and beta2 or alpha3,
      beta2, and alpha5 subunits rather than the low affinity exhibited by receptors
      formed from alpha3 and beta4 or alpha3, beta4, and alpha5 subunits. Nicotine,
      like the structurally similar toxin epibatidine, also distinguishes by binding
      affinity two subtypes of receptors containing alpha3 subunits in SH-SY5Y cells.
      The affinities of alpha3beta2 receptors expressed in oocytes were similar to the
      affinities of native alpha3 containing receptors from SH-SY5Y cells for
      acetylcholine, cytisine, and 1,1-dimethyl-4-phenylpiperazinium.

PMID- 8663495
TI  - Defensin modulates tissue-type plasminogen activator and plasminogen binding to
      fibrin and endothelial cells.
AB  - Defensins are naturally occurring antimicrobial peptides that may participate in
      host defense against microorganisms. We previously reported that the amino acid
      sequence of leukocyte defensins resembles the lysine-binding site in the kringles
      of plasminogen and that defensin inhibits fibrinolysis mediated by tissue-type
      plasminogen activator (tPA) and plasminogen. In the present paper we analyze the
      mechanisms of this inhibition. Defensin binds specifically to cultured human
      umbilical vein endothelial cells (HUVEC) (half-maximal binding = 3 microM) as
      well as to fibrin. At saturating concentrations (5-10 microM), defensin
      stimulates the maximum binding of plasminogen to HUVEC and to fibrin
      approximately 10-fold. However, defensin inhibits plasminogen binding to both
      surfaces at concentrations >10 microM. Defensin also inhibits tPA and plasminogen
      mediated fibrinolysis in a dose-dependent manner at all concentrations tested.
      Fibrinolysis is almost totally inhibited by 6 microM defensin, a concentration
      that stimulates the binding of plasminogen to fibrin. Discordance between the
      enhancement of plasminogen binding and its activation cannot be explained by an
      inhibitory effect of defensin on tPA binding nor by inhibition of plasmin
      activity, each of which occur only at higher concentrations. Rather, these
      results suggest that plasminogen bound to fibrin in the presence of defensin is
      less susceptible to activation by tPA.

PMID- 8663496
TI  - The structural basis of the myosin ATPase activity.

PMID- 8663497
TI  - Vertebrate Unconventional Myosins

PMID- 8663500
TI  - Conformational changes in the Escherichia coli ATP synthase (ECF1F0) monitored by
      nucleotide-dependent differences in the reactivity of Cys-87 of the gamma subunit
      in the mutant betaGlu-381 --> Ala.
AB  - Cys-87, one of two intrinsic cysteines of the gamma subunit of the Escherichia
      coli ATP synthase (ECF1F0), is in a short segment of this subunit that binds to
      the bottom domain of a beta subunit close to a glutamate (Glu-381). Cys-87 was
      unreactive to maleimides under all conditions in wild-type ECF1 and ECF1F0 but
      became reactive when Glu-381 of beta was replaced by a cysteine or alanine. The
      reactivity of Cys-87 with maleimides was nucleotide-dependent, occurring with ATP
      or ADP + EDTA in catalytic sites, in the presence of AMP.PNP + Mg2+ but not with
      ADP + Mg2+ bound, whether Pi was present or not, and not when nucleotide binding
      sites were empty. Binding of N-ethylmaleimide had no effect, whereas 7-diethyl
      amino-3-(4'-maleimidylphenyl)-4-methylcoumarin increased the ATPase activity of
      ECF1 more than 2-fold by reaction with Cys-87. In ECF1F0, these reagents
      inhibited activity. The nucleotide dependence of the reaction of Cys-87 of the
      gamma subunit depended on the presence of the epsilon subunit. In epsilon subunit
      free ECF1, maleimides reacted with Cys-87 under all nucleotide conditions,
      including when catalytic sites were empty. These results are discussed in terms
      of nucleotide-dependent movements of the gamma subunit during functioning of the
      F1F0-type ATPase.

PMID- 8663499
TI  - A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism.
AB  - The A20 gene product is a novel zinc finger protein originally described as a
      tumor necrosis factor alpha (TNF)-inducible early response gene in human
      umbilical vein endothelial cells (HUVEC). Its described function is to block TNF
      induced apoptosis in fibroblasts and B lymphocytes, but more recently it has also
      been shown to play a role in lymphoid cell maturation. The mechanism of action of
      A20 is unknown. The aim of our study was to assess the effect of A20 upon
      endothelial cell activation. By transfecting bovine aortic endothelial cells
      (BAEC) with A20 as well as reporter constructs consisting of the promoters of
      genes known to be up-regulated during endothelial cell activation, i.e. E
      selectin, interleukin (IL)-8, tissue factor (TF), and inhibitor of nuclear factor
      kappaBalpha (IkappaBalpha), we demonstrate that A20 expression inhibits gene up
      regulation associated with TNF, lipopolysaccharide (LPS), phorbol 12-myristate 13
      acetate (PMA), and hydrogen peroxide (H2O2)-induced endothelial cell (EC)
      activation. The mechanism of action of A20 is in part, or totally, due to the
      blockade of nuclear factor kappaB (NF-kappaB), as shown by its ability to
      suppress the activity of a NF-kappaB reporter. This effect is specific, as A20
      does not block a noninducible, constitutively expressed reporter, Rous sarcoma
      virus-luciferase (RSV-LUC); nor does it block the c-Tat-inducible, NF-kappaB
      independent reporter, human immunodeficiency virus-chloramphenicol
      acetyltransferase (HIV-CAT). How A20 blocks NF-kappaB is unclear, although we
      demonstrate that it does not affect p65 (RelA)-mediated gene transactivation. The
      inhibition of endothelial cell activation by A20 is a novel function for A20.

PMID- 8663504
TI  - Conserved neuron promoting activity in Drosophila and vertebrate laminin alpha1.
AB  - Drosophila S2 cells were transfected with constructs that code for two portions
      of the Drosophila laminin alpha chain. Construct recalphaL coded for domains III,
      I/II, and G of laminin alpha. Construct recalphaS coded for only the COOH-most
      12% of the I/II domain and the G domain. The corresponding polypeptides were
      isolated and characterized from the culture media. The recalphaL chain partly
      formed disulfide-linked heterotrimers with the endogenously produced beta and
      gamma laminin chains. Like normal Drosophila laminin, a substrate coating of
      either recalphaL or recalphaS supported neuron differentiation and neurite
      extension of primary Drosophila embryo cell cultures. However, at the same low
      concentrations, only Drosophila laminin-1, but neither recalphaL nor recalphaS
      supported myogenesis in these cultures. Previously, an overlapping set of
      dodecapeptides that covered a region of the murine laminin alpha1 chain similar
      to recalphaS had been synthesized and tested for cell culture support properties
      (Nomizu, M., Kim, W. H., Yamamura, K., Utani, A., Otaka, A., Roller, P. P.,
      Kleinman, H. K., and Yamada, Y. (1995) J. Biol. Chem. 270, 20583-20590). The
      Drosophila laminin alpha homologues of the six most active vertebrate
      dodecapeptides were now synthesized and tested as substrates for differentiation
      of primary Drosophila embryo cells. Peptides that contained either the Drosophila
      sequence SIKVGV or the murine homologue, SIKVAV, provided support for neurite
      extension.

PMID- 8663509
TI  - Molecular cloning and functional expression of mouse connexin-30,a gap junction
      gene highly expressed in adult brain and skin.
AB  - A new gap junction gene isolated from the mouse genome codes for a connexin
      protein of 261 amino acids. Because of its theoretical molecular mass of 30.366
      kDa, it is named connexin-30. Within the connexin gene family, this protein is
      most closely related to connexin-26 (77% amino acid sequence identity). The
      coding region of mouse connexin-30 is uninterrupted by introns and is detected in
      the mouse genome as a single copy gene that is assigned to mouse chromosome 14 by
      analysis of mouse x hamster somatic cell hybrids. Abundant amounts of connexin-30
      mRNA (two transcripts of 2.0 and 2.3 kilobase pairs) were found after 4 weeks of
      postnatal development in mouse brain and skin. Microinjection of connexin-30 cRNA
      into Xenopus oocytes induced formation of functional gap junction channels that
      gated somewhat asymmetrically in response to transjunctional voltage and at
      significantly lower voltage (Vo = +38 and -46 mV) than the closely homologous
      connexin-26 channels (Vo = 89 mV). Heterotypic pairings of connexin-30 with
      connexin-26 and connexin-32 produced channels with highly asymmetric and
      rectifying voltage gating, respectively. This suggests that the polarity of
      voltage gating and the cationic selectivity of connexin-30 are similar to those
      of its closest homologue, connexin-26.

PMID- 8663510
TI  - Regulation of epithelial sodium channels by short actin filaments.
AB  - Cytoskeletal elements play an important role in the regulation of ion transport
      in epithelia. We have studied the effects of actin filaments of different length
      on the alpha, beta, gamma-rENaC (rat epithelial Na+ channel) in planar lipid
      bilayers. We found the following. 1) Short actin filaments caused a 2-fold
      decrease in unitary conductance and a 2-fold increase in open probability (Po) of
      alpha,beta,gamma-rENaC. 2) alpha,beta,gamma-rENaC could be transiently activated
      by protein kinase A (PKA) plus ATP in the presence, but not in the absence, of
      actin. 3) ATP in the presence of actin was also able to induce a transitory
      activation of alpha, beta,gamma-rENaC, although with a shortened time course and
      with a lower magnitude of change in Po. 4) DNase I, an agent known to prohibit
      elongation of actin filaments, prevented activation of alpha,beta,gamma-rENaC by
      ATP or PKA plus ATP. 5) Cytochalasin D, added after rundown of alpha,beta,gamma
      rENaC activity following ATP or PKA plus ATP treatment, produced a second
      transient activation of alpha,beta,gamma-rENaC. 6) Gelsolin, a protein that
      stabilizes polymerization of actin filaments at certain lengths, evoked a
      sustained activation of alpha,beta,gamma-rENaC at actin/gelsolin ratios of <32:1,
      with a maximal effect at an actin/gelsolin ratio of 2:1. These results suggest
      that short actin filaments activate alpha, beta,gamma-rENaC. PKA-mediated
      phosphorylation augments activation of this channel by decreasing the rate of
      elongation of actin filaments. These results are consistent with the hypothesis
      that cloned alpha,beta,gamma-rENaCs form a core conduction unit of epithelial Na+
      channels and that interaction of these channels with other associated proteins,
      such as short actin filaments, confers regulation to channel activity.

PMID- 8663511
TI  - Costimulation of fibroblast collagen and transforming growth factor beta1 gene
      expression by monocyte chemoattractant protein-1 via specific receptors.
AB  - Recent studies indicate potential roles of monocyte chemotactic protein-1 (MCP-1)
      in recruitment of monocytes to sites of inflammation. However, their increased
      expression does not always correlate with monocyte influx, suggesting other
      possible biological activities for this member of the C-C chemokine family. In
      view of its potential role in regulating extracellular matrix expression in
      fibrotic disorders, the effects of MCP-1 on lung fibroblast collagen expression
      were evaluated. Isolated rat lung fibroblasts were treated with increasing doses
      of MCP-1 for variable periods of time and examined for effects on collagen
      synthesis and expression of procollagen alpha1(I) mRNA expression. The results
      show that MCP-1 was able to stimulate collagen expression in these cells in a
      dose-dependent manner but required over 24 h for significant elevation to occur.
      In view of this delayed time course, the possibility of mediation via endogenous
      transforming growth factor beta (TGFbeta) was tested by the ability of anti
      TGFbeta antibody to inhibit this MCP-1 stimulation of collagen expression.
      Significant but incomplete inhibition by this antibody was observed. Pretreatment
      of the cells with antisense but not by sense or missense TGFbeta1
      oligodeoxyribonucleotides caused essentially complete inhibition of this MCP-1
      stimulatory effect. Furthermore, MCP-1 treatment was found to also stimulate
      TGFbeta secretion and mRNA expression, which was also abolished by pretreatment
      with antisense TGFbeta1 oligodeoxyribonucleotides. The kinetics of TGFbeta
      expression indicates that significant increase preceded that for collagen
      expression. Binding studies using 125I-labeled MCP-1 indicated the presence of
      specific and saturable binding sites with a dissociation constant consistent with
      the dose response curves for stimulation of fibroblast collagen synthesis and
      TGFbeta activity by MCP-1. These results taken together suggest that MCP-1
      stimulates fibroblast collagen expression via specific receptors and endogenous
      up-regulation of TGFbeta expression. The latter then results in autocrine and/or
      juxtacrine stimulation of collagen gene expression.

PMID- 8663512
TI  - Basic fibroblast growth factor binds its receptors, is internalized, and
      stimulates DNA synthesis in Balb/c3T3 cells in the absence of heparan sulfate.
AB  - We have investigated the interaction of basic fibroblast growth factor (bFGF)
      with its receptors and heparan sulfate proteoglycans (HSPG). It has been
      suggested that in the absence of HSPG, cells are not able to bind bFGF or respond
      to treatment with bFGF. In our studies, Balb/c3T3 fibroblasts were treated with
      50 mM sodium chlorate to completely inhibit (99%) sulfation of proteoglycans. We
      found that bFGF was able to bind, be internalized, and stimulate DNA synthesis in
      the absence of HSPG in a dose-dependent manner. bFGF bound to its receptors on
      chlorate-treated cells with a lower apparent affinity and no change in receptor
      number. To determine if this decreased affinity bFGF-receptor interaction is
      functional, we quantitatively analyzed bFGF internalization and stimulation of
      DNA synthesis in control and chlorate-treated cells. Endocytotic rate constants
      (ke) for chlorate-treated and control cells were ke = 0. 078 +/- 0.022 min-1 and
      ke = 0.043 +/- 0.012 min-1, respectively, suggesting that the process of bFGF
      internalization is not dramatically altered by HSPG. bFGF stimulated DNA
      synthesis to the same maximal level under both conditions, but chlorate-treated
      cells were significantly less responsive at low bFGF doses (approximately 10-fold
      increase in ED50). The differences observed for control and chlorate-treated
      cells in the dose-response curves for stimulation of DNA synthesis and receptor
      binding correlated directly, suggesting that receptors are equally capable of
      eliciting a mitogenic signal under both conditions. It is unlikely that these
      results are due to residual HSPG since heparinase (I and III) digestion of
      chlorate-treated cells had little effect. Although the presence of HSPG on the
      cell surface increases the affinity of bFGF for its receptors, our observations
      suggest that HSPG are not "absolutely" required for binding, internalization, or
      stimulation of mitogenic activity.

PMID- 8663513
TI  - Variabilin, a novel RGD-containing antagonist of glycoprotein IIb-IIIa and
      platelet aggregation inhibitor from the hard tick Dermacentor variabilis.
AB  - A novel inhibitor of human platelet aggregation, named variabilin, was isolated
      from salivary glands of the hard tick Dermacentor variabilis using a combination
      of gel filtration and high pressure liquid chromatography. Variabilin was a
      potent antagonist of the fibrinogen receptor glycoprotein IIb-IIIa (GPIIb-IIIa;
      alphaIIbbeta3) and the vitronectin receptor alphavbeta3. Amino acid sequence
      analysis by Edman degradation revealed that it has 47 residues, with a molecular
      weight of 4968.5. Like many other naturally occurring antagonists of GPIIb-IIIa,
      variabilin contains the RGD (Arg-Gly-Asp) motif. However, unlike the RGD
      containing antagonists of GPIIb-IIIa, the RGD sequence of variabilin is not
      positioned in a loop bracketed by cysteine residues. It has little sequence
      homology to the other known naturally occurring antagonists of GPIIb-IIIa,
      including the disintegrins from snakes, decorsin and ornatin from leeches, and
      disagregin from soft ticks. Variabilin is the first RGD-containing antagonist
      isolated from ticks.

PMID- 8663515
TI  - TAG-1/axonin-1 is a high-affinity ligand of neurocan, phosphacan/protein-tyrosine
      phosphatase-zeta/beta, and N-CAM.
AB  - Proteoglycans appear to play an important role in modulating cell-cell and cell
      matrix interactions during nervous tissue histogenesis. The nervous tissue
      specific chondroitin sulfate proteoglycans neurocan and phosphacan/protein
      tyrosine phosphatase-zeta/beta were found to be high-affinity ligands of the
      neural cell adhesion molecule TAG-1/axonin-1, with dissociation constants of 0.3
      nM and 0.04 nM, respectively. Phosphacan binding was decreased by approximately
      70% following chondroitinase treatment, whereas binding of neurocan was not
      affected. The contribution of chondroitin sulfate chains to the binding of
      neurocan and phosphacan to TAG-1/axonin-1 is therefore the opposite of that
      previously observed for their binding to two other Ig-superfamily neural cell
      adhesion molecules, Ng-CAM/L1 and N-CAM. Moreover, whereas phosphacan
      interactions with certain proteins are mediated at least in part by N-linked
      oligosaccharides on the proteoglycan, N-deglycosylation of phosphacan had no
      effect on its binding to TAG-1/axonin-1. In addition to the chondroitin sulfate
      proteoglycans described above, we have demonstrated that N-CAM is a high-affinity
      ligand of TAG-1/axonin-1 (Kd approximately 1 nM), and specific binding of TAG
      1/axonin-1 to tenascin-C was also observed (Kd approximately 9 nM).
      Immunocytochemical studies of embryonic and early postnatal nervous tissue showed
      an overlapping localization of TAG-1/axonin-1 with all four of these ligands,
      further supporting the biological significance of their ability to interact in
      vitro.

PMID- 8663520
TI  - In vivo characterization of the proteasome regulator PA28.
AB  - A proteasome regulator, termed PA28, has been shown to modulate peptidase
      activities of the proteasomes in vitro. Two different but homologous PA28
      molecules, designated as PA28alpha and PA28beta, have been cloned. Both alpha and
      beta polypeptides of PA28 are found in PA28 complexes isolated from cells,
      indicating that both are constituents of functional PA28 complexes. Using
      antisera specific to PA28alpha, PA28beta, and epitope-tagged PA28 molecules, we
      show that expression of PA28alpha and PA28beta is coordinately induced by various
      cytokines in different cell lines and that PA28 subunits and proteasomes have
      almost identical half-lives. In addition, we show that PA28 complexes are
      associated with 20 S but not 26 S proteasomes in vivo. Moreover, we demonstrate
      that PA28 complex is a heterohexamer composed of both alpha and beta subunits
      with a stoichiometry of alpha3beta3 in an alternating order.

PMID- 8663524
TI  - Characterization of the structure and function of a new mitogen-activated protein
      kinase (p38beta).
AB  - Mitogen-activated protein (MAP) kinase cascades represent one of the major signal
      systems used by eukaryotic cells to transduce extracellular signals into cellular
      responses. Four MAP kinase subgroups have been identified in humans: ERK, JNK
      (SAPK), ERK5 (BMK), and p38. Here we characterize a new MAP kinase, p38beta.
      p38beta is a 372-amino acid protein most closely related to p38. It contains a
      TGY dual phosphorylation site, which is required for its kinase activity. Like
      p38, p38beta is activated by proinflammatory cytokines and environmental stress.
      A comparison of events associated with the activation of p38beta and p38 revealed
      differences, most notably in the preferred activation of p38beta by MAP kinase
      kinase 6 (MKK6), whereas p38 was activated nearly equally by MKK3, MKK4, and
      MKK6. Moreover, in vitro and in vivo experiments showed a strong substrate
      preference by p38beta for activating transcription factor 2 (ATF2). Enhancement
      of ATF2-dependent gene expression by p38beta was approximately20-fold greater
      than that of p38 and other MAP kinases tested. The data reported here suggest
      that while closely related, p38beta and p38 may be regulated by differing
      mechanisms and may exert their actions on separate downstream targets.

PMID- 8663528
TI  - CCAAT displacement protein competes with multiple transcriptional activators for
      binding to four sites in the proximal gp91phox promoter.
AB  - CCAAT displacement protein (CDP) competes with transcriptional activating
      proteins for binding to each of four elements within the myeloid-specific
      gp91(phox) promoter. CDP exhibits the strongest affinity for a site centered at 
      110 base pairs (bp) of the promoter and progressively weaker affinities for three
      more distal binding sites. CDP binding to each site is down-regulated during
      terminal phagocytic differentiation, coincident with induction of gp91(phox)
      expression. Deletion of the high affinity CDP-binding site at -110 bp leads to
      inappropriate gp91(phox) promoter activity in HeLa, K562, and HEL cells. An
      overlapping binding site for the CCAAT box-binding factor CP1 is required for
      derepressed promoter activity in HeLa and K562 cells, but is dispensable in HEL
      cells, indicating that different cell types require distinct cis-elements for
      gp91(phox) promoter activity. Derepressed gp91(phox) promoter activity is further
      increased upon removal of a second CDP-binding site centered at -150 bp,
      revealing that CDP represses gp91(phox) expression via multiple cis-elements. We
      present a model in which restriction of gp91(phox) expression to mature myeloid
      cells involves competition between transcriptional activators and repressors for
      binding to multiple sites within the promoter.

PMID- 8663526
TI  - Mutational analysis of the ligand binding site of the inositol 1,4,5
      trisphosphate receptor.
AB  - To define the structural determinants for inositol 1,4, 5-trisphosphate (IP3)
      binding of the type 1 inositol 1,4, 5-trisphosphate receptor (IP3R1), we
      developed a means of expressing the N-terminal 734 amino acids of IP3R1 (T734),
      which contain the IP3 binding region, in Escherichia coli. The T734 protein
      expressed in E. coli exhibited a similar binding specificity and affinity for IP3
      as the native IP3R from mouse cerebellum. Deletion mutagenesis, in which T734 was
      serially deleted from the N terminus up to residue 215, markedly reduced IP3
      binding activity. However, when deleted a little more toward the C terminus (to
      residues 220, 223, and 225), the binding activity was retrieved. Further N
      terminal deletions over the first 228 amino acids completely abolished it again.
      C-terminal deletions up to residue 579 did not affect the binding activity,
      whereas those up to residue 568 completely abolished it. In addition, the
      expressed 356-amino acid polypeptide (residues 224-579) exhibited specific
      binding activity. Taken together, residues 226-578 were sufficient and close
      enough to the minimum region for the specific IP3 binding, and thus formed an IP3
      binding "core." Site-directed mutagenesis was performed on 41 basic Arg and Lys
      residues within the N-terminal 650 amino acids of T734. We showed that single
      amino acid substitutions for 10 residues, which were widely distributed within
      the binding core and conserved among all members of the IP3R family,
      significantly reduced the binding activity. Among them, three (Arg-265, Lys-508,
      and Arg-511) were critical for the specific binding, and Arg-568 was implicated
      in the binding specificity for various inositol phosphates. We suggest that some
      of these 10 residues form a basic pocket that interacts with the negatively
      charged phosphate groups of IP3.

PMID- 8663533
TI  - The discovery of a novel R-phycoerythrin from an antarctic red alga.
AB  - A novel biliprotein, named R-phycoerythrin IV, has been discovered. It absorbs
      blue light better than any other known red algal biliprotein. The protein was
      found in Phyllophora antarctica, a benthic macroalga, which grows beneath the
      coastal waters of McMurdo Sound, Antarctica. Fluorescence emission and
      fluorescence excitation polarization spectroscopy demonstrated that R
      phycoerythrin IV behaved as a typical R-phycoerythrin in the functioning of
      energy migration and has an emission maximum at 577 nm. The circular dichroism
      (CD) spectrum of the chromophores was compared with visible absorption spectrum,
      and both were deconvoluted. This process showed the energy states of various
      individual chromophores. The molecular weight of the protein suggested a
      alpha6beta6gamma polypeptide structure, and far UV CD studies revealed
      polypeptides with highly alpha-helical secondary structures. Dynamic light
      scattering indicated that the protein had a 5.54 nm radius, and its shape was
      nonspherical. R-phycoerythrin was also purified from a second benthic Antarctic
      red alga, Iridaea cordata. Its spectroscopic properties were similar to those of
      some R-phycoerythrins from nonpolar regions. The unique spectroscopic properties
      of R-phycocerythrin IV may help enable the alga to occupy its niche deeper in the
      water column than the red alga that has the typical R-phycoerythrin.

PMID- 8663535
TI  - COOH-terminal extended recombinant amphiregulin with bioactivity comparable with
      naturally derived growth factor.
AB  - The mature secreted form of the epidermal growth factor (EGF) receptor ligand
      amphiregulin (AR) is reported to be an 84-amino acid residue polypeptide, which
      is generated by proteolytic processing of a 252-amino acid precursor. This form
      of recombinant AR (rAR84) and two forms with COOH-terminal extensions
      corresponding to sequences from the AR precursor (rAR87 and rAR92) were expressed
      at high levels in Escherichia coli, oxidized to the correct disulfide
      arrangement, and purified to homogeneity. rAR84 competed poorly for binding of
      radiolabeled EGF to the EGF receptor and had little ability to stimulate growth
      of Balb/c/3T3 cells. In striking contrast, rAR87 and rAR92 possessed 42- and 20
      fold greater receptor binding activity and 55- and 14-fold greater bioactivity,
      respectively. Furthermore, addition of the COOH-terminal four amino acids from
      transforming growth factor alpha to the COOH terminus of rAR84 improved the
      activity of rAR84 by 100- and 1000-fold, respectively, in these assays. rAR87 was
      found to have approximately 32% of the specific activity of natural AR from MCF-7
      cells when compared in two different bioassays. These findings strongly suggest
      that the 84-amino acid sequence is not the correct structure of the naturally
      occurring secreted form of AR and that natural AR contains additional amino acid
      residues at the COOH-terminal end.

PMID- 8663536
TI  - The SH2 domain-containing tyrosine phosphatase PTP1D is required for interferon
      alpha/beta-induced gene expression.
AB  - Interferons (IFNs) induce early response genes by stimulating Janus family (Jak)
      tyrosine kinases, leading to tyrosine phosphorylation of Stat (signal transducer
      and activator of transcription) proteins. Previous studies demonstrated that a
      protein-tyrosine phosphatase (PTP) is required for activation of the ISGF3
      transcription complex by IFNalpha/beta, but the specific PTP responsible remained
      unidentified. We now show that the SH2 domain containing tyrosine phosphatase
      PTP1D (also designated as SHPTP2, SHPTP3, PTP2C, or Syp) is constitutively
      associated with the IFNalpha/beta receptor and becomes tyrosine-phosphorylated in
      response to ligand. Furthermore, transient expression of a phosphatase-inactive
      mutant or the COOH-terminal SH2 domain of PTP1D causes a dominant negative effect
      on IFNalpha/beta-induced early response gene expression. These results provide
      strong evidence that PTP1D functions as a positive regulator of the IFNalpha/beta
      induced Jak/Stat signal transduction pathway.

PMID- 8663537
TI  - Isolated Sos1 PH domain exhibits germinal vesicle breakdown-inducing activity in
      Xenopus oocytes.
AB  - Purified, bacterially expressed PH domains of Sos1, IRS-1, betaARK, and PLCdelta1
      were analyzed functionally by means of microinjection into full grown, stage VI
      Xenopus laevis oocytes. Whereas the PH domains from IRS-1, betaARK, or PLCdelta1
      did not show any effect in the oocytes, injection of the purified Sos1 PH domain
      resulted in induction of significant rates of germinal vesicle breakdown and
      meiotic maturation. Furthermore, the Sos1 PH domain exhibited also significant
      synergy with insulin or coinjected normal Ras protein in induction of germinal
      vesicle breakdown, although it did not affect the rate of progesterone-induced
      maturation. These results suggest that purified, isolated PH domains retain, at
      least in part, their functional specificity and that Xenopus oocytes may
      constitute a useful biological system to analyze the functional role of the Sos1
      PH domain in Ras signaling pathways.

PMID- 8663540
TI  - Dimerization, DNA binding, and transactivation properties of hypoxia-inducible
      factor 1.
AB  - Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix
      transcription factor that regulates hypoxia-inducible genes including the human
      erythropoietin (EPO) gene. In this study, we report structural features of the
      HIF-1alpha subunit that are required for heterodimerization, DNA binding, and
      transactivation. The HIF-1alpha and HIF-1beta (ARNT; aryl hydrocarbon receptor
      nuclear translocator) subunits were coimmunoprecipitated from nuclear extracts,
      indicating that these proteins heterodimerize in the absence of DNA. In vitro
      translated HIF-1alpha and HIF-1beta generated a HIF-1/DNA complex with similar
      electrophoretic mobility and sequence specificity as HIF-1 present in nuclear
      extracts from hypoxic cells. Compared to 826-amino acid, full-length HIF-1alpha,
      amino acids 1-166 mediated heterodimerization with HIF-1beta (ARNT), but amino
      acids 1-390 were required for optimal DNA binding. A deletion involving the basic
      domain of HIF-1alpha eliminated DNA binding without affecting heterodimerization.
      In cotransfection assays, forced expression of recombinant HIF-1alpha and HIF
      1beta (ARNT) activated transcription of reporter genes containing EPO enhancer
      sequences with intact, but not mutant, HIF-1 binding sites. Deletion of the
      carboxy terminus of HIF-1alpha (amino acids 391-826) markedly decreased the
      ability of recombinant HIF-1 to activate transcription. Overexpression of a HIF
      1alpha construct with deletions of the basic domain and carboxy terminus blocked
      reporter gene activation by endogenous HIF-1 in hypoxic cells.

PMID- 8663541
TI  - Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response
      elements in interferon-gamma-inducible expression of human indoleamine 2,3
      dioxygenase gene.
AB  - Interferon (IFN)-gamma induces the expression of the indoleamine 2, 3-dioxygenase
      (INDO) gene in human cells, which plays a role in the inhibitory effect of IFN
      gamma on intracellular pathogens and on cell proliferation. Earlier studies
      established that the IFN-gamma-inducible expression of the INDO gene was
      dependent on two upstream elements: (i) a 14-base pair sequence homologous to an
      interferon-stimulated response element (ISRE) sequence found in IFN-alpha
      inducible genes and (ii) a 9-base pair palindromic sequence (palindromic element
      (PE) II) homologous to an interferon-gamma-activated site (GAS) element found in
      IFN-gamma-inducible genes. A second GAS element (PE I), between ISRE and PE II,
      was ineffective in supporting a response to IFN-gamma. Studies were carried out
      to determine the distinction between the two GAS elements and the relative role
      of the two elements (ISRE and PE II) required for a response to IFN-gamma. The PE
      I element was able to form a complex with IFN-gamma-activated p91 (STAT1) factor
      but with lower efficiency than the complex formed with PE II sequence. However,
      switching the positions of PE I and II sequences in reporter plasmid constructs
      (containing chloramphenicol acetyltransferase gene) showed that both PE I and PE
      II were able to support a response to IFN-gamma if located at the position of PE
      II but not at the position of PE I. Increasing the distance between the ISRE and
      PE II also affected the level of response, suggesting that the relative position
      of the two elements is important for optimal stimulus. To explore whether an
      interaction between the IFN-gamma-regulated factors (IRF-1 and p91) binding to
      the ISRE and PE II might be important, we tested whether the ISRE sequence could
      be replaced by another response element, NF-kappaB. The plasmid construct with NF
      kappaB element in place of the ISRE was responsive to IFN-gamma, indicating that
      an interaction between the IRF-1 and p91 factors was not required. The results
      indicate that the response of INDO gene to IFN-gamma depends on a cooperative
      role of IFN-gamma-responsive factors binding to the ISRE and GAS elements.

PMID- 8663555
TI  - Myosin minireview series.

PMID- 8663546
TI  - Functional modulation by lactate of myoglobin. A monomeric allosteric
      hemoprotein.
AB  - The effect of lactate on O2 binding properties of sperm whale and horse heart
      myoglobins (Mb) has been investigated at moderately acid pH (i.e. pH 6.5, a
      condition which may be achieved in vivo under a physical effort). Addition of
      lactate brings about a decrease of O2 affinity (i.e. an increase of P50) in sperm
      whale and horse heart myoglobins. Accordingly, lactate shows a different affinity
      for the deoxygenated and oxygenated form, behaving as a heterotropic modulator.
      The lactate effect on O2 affinity appears to differ for sperm whale and horse
      heart Mb, deltalogP50 being approximately 1.0 and approximately 0.4,
      respectively. From the kinetic viewpoint, the variation of O2 affinity for both
      myoglobins can be attributed mainly to a decrease of the kinetic association rate
      constant for ligand binding.

PMID- 8663556
TI  - Kinetic Pathways and Barriers for Ligand Binding to Myoglobin

PMID- 8663566
TI  - Renal epithelial protein (Apx) is an actin cytoskeleton-regulated Na+ channel.
AB  - Apx, the amphibian protein associated with renal amiloride-sensitive Na+ channel
      activity and with properties consistent with the pore-forming 150-kDa subunit of
      an epithelial Na+ channel complex initially purified by Benos et al. (Benos, D.
      J., Saccomani, G., and Sariban-Sohraby, S.(1987) J. Biol. Chem. 262, 10613
      10618), has previously failed to generate amiloride-sensitive Na+ currents
      (Staub, O., Verrey, F., Kleyman, T. R., Benos, D. J., Rossier, B. C., and
      Kraehenbuhl, J.-P.(1992) J. Cell Biol. 119, 1497-1506). Renal epithelial Na+
      channel activity is tonically inhibited by endogenous actin filaments (Cantiello,
      H. F., Stow, J., Prat, A. G., and Ausiello, D. A.(1991) Am. J. Physiol. 261, C882
      C888). Thus, Apx was expressed and its function examined in human melanoma cells
      with a defective actin-based cytoskeleton. Apx-transfection was associated with a
      60-900% increase in amiloride-sensitive (Ki = 3 microM) Na+ currents. Single
      channel Na+ currents had a similar functional fingerprint to the vasopressin
      sensitive, and actin-regulated epithelial Na+ channel of A6 cells, including a 6
      7 pS single channel conductance and a perm-selectivity of Na+:K+ of 4:1. Na+
      channel activity was either spontaneous, or induced by addition of actin or
      protein kinase A plus ATP to the bathing solution of excised inside-out patches.
      Therefore, Apx may be responsible for the ionic conductance involved in the
      vasopressin-activated Na+ reabsorption in the amphibian kidney.

PMID- 8663567
TI  - The organic crystallizing agent 2-methyl-2,4-pentanediol reduces DNA curvature by
      means of structural changes in A-tracts.
AB  - Contemporary predictive models for sequence-dependent DNA structure provide a
      good estimation of overall DNA curvature in most cases. However, the two current
      models differ fundamentally in their view of the origin of DNA curvature. An
      earlier model that associates DNA bending primarily, although not exclusively,
      with stretches of adenines (A-tracts) is based on results of comparative gel
      retardation, cyclization kinetics, hydroxyl radical cutting, and other solution
      measurements. It represents an intersection of wedge and junction models. More
      recently, a non-A-tract bending model has been proposed, built on structural
      results from x-ray crystallography and molecular modeling. In this view, A-tracts
      are proposed to be straight and rigid, whereas mixed sequence DNA is bent.
      Because a key premise of the non-A-tract bending model is the crystallographic
      observation that A-tracts are straight, we have examined the effect in solution
      of 2-methyl-2,4-pentanediol (MPD), an organic solvent used in crystal preparation
      for crystallographic DNA structure determinations. Using cyclization analysis,
      DNase I cutting, chemical probing, and electron microscopy on DNA oligomers with
      and without A-tracts, we show that the presence of MPD in solution dramatically
      affects A-tracts and that the effect is specific to these sequence elements.
      Combined with the previous observation that MPD affects gel mobility of curved
      sequences with A-tracts, our findings support the bent A-tract model and call for
      caution in the interpretation of crystallographic results on DNA structure as
      these are presently obtained.

PMID- 8663568
TI  - Cloning and expression of a novel neuropeptide Y receptor.
AB  - The neuropeptide Y family of peptides, which includes neuropeptide Y (NPY),
      peptide YY (PYY), and pancreatic polypeptide (PP), are found in the central and
      peripheral nervous system and display a wide array of biological activities.
      These actions are believed to be mediated through pharmacologically distinct G
      protein-coupled receptors, and, to date, three members of the NPY receptor family
      have been cloned. In this study we describe the cloning and expression of a novel
      NPY receptor from mouse genomic DNA. This receptor, designated NPY Y5, shares 60%
      amino acid identity to the murine NPY Y1 receptor. The pharmacology of this novel
      receptor resembles that of the NPY Y1 receptor and is distinct from that
      described for the NPY Y2, Y3, and Y4 receptors. In situ hybridization of mouse
      brain sections reveals expression of this receptor within discrete regions of the
      hypothalamus including the suprachiasmatic nucleus, anterior hypothalamus, bed
      nucleus stria terminalis, and the ventromedial nucleus with no localization
      apparent elsewhere in the brain.

PMID- 8663569
TI  - Divergent secretory behavior of the opposite ends of aggrecan.
AB  - The proteoglycan, aggrecan has a globular domain, G1, at the N terminus and a
      different globular domain, G3, at the C terminus. Aggrecan produced by mutant
      nanomelic chickens is truncated due to a premature stop codon and consequently
      lacks G3 and a minor portion of its chondroitin sulfate domain (Li, H., Schwartz,
      N. B., and Vertel, B. M.(1993) J. Biol. Chem. 268, 23504-23511). The mutant
      protein is retained in the endoplasmic reticulum and fails to enter the Golgi
      stacks (Vertel, B. M., Walters, L. M., Grier, B., Maine, N. , and Goetinck, P.
      F.(1993) J. Cell Sci. 104, 939-948). The homozygous mutant is lethal because of
      failure of chondrogenesis and osteogenesis, while the heterozygous mutant is
      dwarfed. To further elucidate the pathogenetic mechanisms underlying nanomelia
      and to determine if G1 and G3 are themselves secreted, we expressed them in
      transfected host cells. Expression was performed in wild type Chinese hamster
      ovary (CHO) cells and in mutant CHO cells which are unable to link
      glycosaminoglycan (GAG) chains to core proteins. We compared: (a) secretion of
      expressed G1 and G3 constructs containing contiguous GAG chain consensus sites
      and (b) GAG chain modification of the secreted proteins. We find that: 1) G3 is
      24-100 times more rapidly secreted than G1; 2) secreted G3 contains contiguous
      chondroitin sulfate GAG chains, while secreted G1 lacks contiguous GAG chains; 3)
      G3 secretion is not coupled to xylosylation of contiguous GAG chain consensus
      sites. These results imply that G1 and G3 intrinsically differ in passage through
      the cell secretory route.

PMID- 8663573
TI  - Cell-specific sorting of biogenic amine transporters expressed in epithelial
      cells.
AB  - We have utilized polarized epithelial cells stably expressing neurotransmitter
      transporters to analyze the sorting behavior of these membrane proteins. The
      transporters for serotonin (5-HT), dopamine (DA), and norepinephrine (NE) are
      expected to be present in situ in the most distal extremities of axonal
      membranes, where they terminate the action of their biogenic amine substrates.
      Both Madin-Darby canine kidney (MDCK) and LLC-PK1 cells were stably transfected
      with cDNAs encoding either the rat 5-HT transporter (SERT), the human NE
      transporter (NET), or the rat or human DA transporter (DAT). These cells were
      grown on permeable filter supports, and the transporters were localized by three
      independent techniques. Confocal immunofluorescence microscopy indicated that
      each of the transporters expressed in LLC-PK1 cells was sorted to the basolateral
      membrane, co-localizing with the Na+/K+-ATPase. In MDCK cells, however, DAT was
      located primarily on the apical surface, while SERT and NET were found on the
      basolateral membranes. Cell surface biotinylation using an impermeant
      biotinylating reagent confirmed the immunocytochemistry results. Thus, SERT and
      NET in MDCK cells were labeled more efficiently from the basolateral medium than
      the apical medium, and DAT in MDCK cells was labeled more efficiently from the
      apical side than the basolateral side. Transport measurements in transfected MDCK
      cells agreed with the immunocytochemistry and biotinylation results. These
      results suggest the existence of cell-specific mechanisms that discriminate
      between neurotransmitter transporters for surface expression and render unlikely
      any simple hypothesis that sorting mechanisms in neurons and epithelia are
      identical.

PMID- 8663580
TI  - The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the
      death substrate lamin A.
AB  - Phylogenetic analysis of the CED-3/ICE family of cysteine proteases suggests the
      existence of a subfamily most related to the Caenorhabditis elegans death gene
      ced-3 and includes Yama (CPP32, apopain), LAP3 (Mch3, CMH1), and Mch2. Here, we
      show that Mch2 is processed from its zymogen form to a proteolytically active
      dimeric species during execution of the apoptotic program and by the cytotoxic T
      cell death protease granzyme B. Additionally, like Yama and LAP3, Mch2 functions
      downstream of the death inhibitors Bcl-2, Bcl-xL, and CrmA. Importantly, Mch2,
      but not Yama or LAP3, is capable of cleaving lamin A to its signature apoptotic
      fragment, indicating that Mch2 is an apoptotic laminase.

PMID- 8663582
TI  - Evidence that phospholipase delta1 is the effector in the Gh (transglutaminase
      II)-mediated signaling.
AB  - A new class of GTP-binding protein transglutaminase II (Gh) couples to a 69-kDa
      phospholipase C (PLC). An 8-amino acid region (Leu665-Lys672) of the alpha
      subunit of Gh (Galphah) is involved in interaction and activation of PLC, an
      observation that has now been used to characterize the 69-kDa PLC further. A 20
      amino acid peptide corresponding to Leu654-Leu673 of Galphah was used to prepare
      an affinity resin. On incubation with a partially purified PLC preparation from
      rat liver membranes, the affinity resin-bound approximately69- and 85-kDa
      proteins were recognized by an antibody to the 69-kDa PLC. Both purified 69-kDa
      PLC and PLC-delta1 bound to the affinity resin; moreover, antibodies to PLC
      delta1 recognized the 69-kDa PLC, and antibodies to the 69-kDa PLC recognized PLC
      delta1. A synthetic peptide corresponding to Leu661-Lys672 of Galphah inhibited
      the binding of PLC-delta1 to the affinity resin and also stimulated PLC-delta1.
      Reconstitution of PLC-delta1 with GTPgammaS (guanosine 5'-3-O-(thio)triphosphate)
      activated Gh resulted in activation of PLC-delta1. Antibodies to Galphah also
      coimmunoprecipitated PLC-delta1 upon activation of Gh. These findings indicate
      that PLC-delta1 is the effector of Gh-mediated signaling.

PMID- 8663584
TI  - Overexpression of catalytic subunit p110alpha of phosphatidylinositol 3-kinase
      increases glucose transport activity with translocation of glucose transporters
      in 3T3-L1 adipocytes.
AB  - To elucidate the mechanisms of phosphatidylinositol (PI) 3-kinase involvement in
      insulin-stimulated glucose transport activity, the epitope-tagged p110alpha
      subunit of PI 3-kinase was overexpressed in 3T3-L1 adipocytes using an adenovirus
      mediated gene transduction system. Overexpression of p110alpha was confirmed by
      immunoblot using anti-tagged epitope antibody. p110alpha overexpression induced a
      2.5-fold increase in PI 3-kinase activity associated with its regulatory subunits
      in the basal state, an increase exceeding that of the maximally insulin
      stimulated control cells, while PI 3-kinase activity associated with
      phosphotyrosyl protein was only modestly elevated. Overexpression of p110alpha
      induced an approximately 14-fold increase in the basal glucose transport rate,
      which was also greater than that observed in the stimulated control. No apparent
      difference was observed in the cellular expression level of either GLUT1 or GLUT4
      proteins between control and p110alpha-overexpressing 3T3-L1 adipocytes.
      Subcellular fractionation revealed translocation of glucose transporters from
      intracellular to plasma membranes in basal p110alpha-overexpressing cells. The
      translocation of GLUT4 protein to the plasma membrane was further confirmed using
      a membrane sheet assay. These findings indicate that an increment in PI 3-kinase
      activity induced by overexpression of p110alpha of PI 3-kinase stimulates glucose
      transport activity with translocation of glucose transporters, i.e., mimics the
      effect of insulin.

PMID- 8663585
TI  - A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras
      induced transformation.
AB  - Oncogenic Ras transforms cells through the activation of multiple downstream
      pathways mediated by separate effector molecules, one of which is Raf. Here we
      report the identification of a second ras-binding protein that can induce
      cellular transformation in parallel with activation of the Raf/mitogen-activated
      protein kinase cascade. The Ral guanine nucleotide dissociation stimulator
      (RalGDS) was isolated from a screen for Ras-binding proteins that specifically
      interact with a Ras effector-loop mutant, ras(12V,37G), that uncouples Ras from
      activation of Raf1. RalGDS, like ras(12V, 37G), cooperates synergistically with
      mutationally activated Raf to induce foci of growth and morphologically
      transformed NIH 3T3 cells. RalGDS does not significantly enhance MAP kinase
      activation by activated Raf, suggesting that the cooperativity in focus formation
      is due to a distinct pathway acting downstream of Ras and parallel to Raf.

PMID- 8663586
TI  - Protein orientation in the Tat-TAR complex determined by psoralen photocross
      linking.
AB  - Replication of human immunodeficiency virus type 1 (HIV-1) requires specific
      interactions of Tat protein with the trans-activation responsive region (TAR)
      RNA, a 59-base stem-loop structure located at the 5'-end of all HIV mRNAs. We
      have used a new method based on psoralen photochemistry to identify a specific
      contact between a fragment of Tat protein (residues 38-72) and TAR RNA. We
      synthesized a 35-amino acid fragment containing arginine-rich RNA-binding domain
      of Tat (38-72), and replaced Arg57 with Cys to introduce a unique thiol group (
      SH) in our model peptide. A psoralen derivative, which can react with thiol
      groups, was synthesized and used for specific chemical modification of Cys57-Tat
      (38-72). We used this psoralen-Tat conjugate (psoralen-Cys57-Tat-(38-72)) to form
      a specific complex with TAR RNA. Upon near-ultraviolet irradiation (360 nm), this
      synthetic psoralen-peptide cross-linked to a single site in the TAR RNA sequence.
      The RNA-protein complex was purified and the cross-link site on TAR RNA was
      determined by RNA sequencing, which revealed that Cys57 of Tat is close to U31 of
      TAR RNA. Our results provide high-resolution proximity and orientation
      information about Tat-TAR complex. Such psoralen-peptide conjugates provide a new
      class of probes for sequence-specific protein-nucleic acid interactions and could
      be used to selectively control gene expression or to induce site-directed
      mutations.

PMID- 8663588
TI  - Targeting the plant alternative oxidase protein to Schizosaccharomyces pombe
      mitochondria confers cyanide-insensitive respiration.
AB  - The Sauromatum guttatum alternative oxidase has been expressed in
      Schizosaccharomyces pombe under the control of the thiamine-repressible nmt1
      promoter. Alternative oxidase protein and activity were detected both in
      spheroplasts and isolated mitochondria, indicating that the enzyme is expressed
      in a functional form and confers cyanide-resistant respiration to S. pombe, which
      is sensitive to inhibition by octyl-gallate. Protein import studies revealed that
      the precursor form of the alternative oxidase protein is efficiently imported
      into isolated mitochondria and processed to its mature form comparable to that
      observed with potato mitochondria. Western blot analysis and respiratory studies
      revealed that the alternative oxidase protein is expressed in the inner
      mitochondrial membrane in its reduced (active) form. Treatment of mitochondria
      with diamide and dithiothreitol resulted in interconversion of the reduced and
      oxidized species and modulation of respiratory activity. The addition of pyruvate
      did not effect either the respiratory rate or expression of the reduced species
      of the protein. To our knowledge this is the first time that the alternative
      oxidase has been effectively targeted to and integrated into the inner
      mitochondrial membrane of S. pombe, and we conclude that the expression of a
      single polypeptide is sufficient for alternative oxidase activity.

PMID- 8663590
TI  - Selective loss of cerebral keratan sulfate in Alzheimer's disease.
AB  - Proteoglycans, especially heparan sulfate-substituted species, are known to be
      associated with the deposition of amyloid in Alzheimer's disease. We previously
      found that heparan sulfate from afflicted brains, and from control subjects,
      differed minimally in quantity and structure (Lindahl, B., Eriksson, L., and
      Lindahl, U.(1995) Biochem. J. 306, 177-184). In the present study, a
      glycosaminoglycan fraction, shown to contain heparan sulfate and keratan sulfate,
      was radiolabeled by partial N-deacetylation (hydrazinolysis) followed by re-N
      acetylation using [3H]acetic anhydride. Quantitation of the 3H-labeled
      polysaccharides, based on digestion with heparitinase I from Flavobacterium
      heparinum and keratanase from Pseudomonas sp., revealed that the amounts of
      keratan sulfate in Alzheimer cerebral cortex are reduced to less than half of
      control values. Moreover, a monoclonal antibody against a highly sulfated keratan
      sulfate epitope bound to the majority of the neurons in normal cortex but not in
      the diseased tissue. The lack of highly sulfated keratan sulfate structures may
      reflect a specific functional defect of the cells.

PMID- 8663593
TI  - Additions and Corrections to TFII-I is required for transcription of the
      naturally TATA-less but initiator-containing Vbeta promoter.

PMID- 8663592
TI  - A domain on the G protein beta subunit interacts with both adenylyl cyclase 2 and
      the muscarinic atrial potassium channel.
AB  - The G protein betagamma complex modulates the function of a variety of effectors
      in biological signaling. However, the individual roles of the beta and gamma
      subunits in this interaction are unknown. Unlike in the case of the alpha
      subunit, domains on the betagamma complex that contact effectors have not yet
      been identified. We show here using the yeast two-hybrid system that the beta
      subunit and not the gamma subunit interacts with domains specific to adenylyl
      cyclase type 2 (AC2) and the muscarinic receptor-gated atrial inwardly rectifying
      potassium channel, GIRK1. Different beta subunit types interact with these
      effector domains with different efficacies. Furthermore, an N-terminal fragment
      of 100 residues interacts with both these effector domains as effectively as the
      whole beta subunit. This domain includes the region where the beta subunit
      contacts with the alpha subunit in the crystal structure and may therefore
      explain the ability of the alpha subunit to shut off the activity of the
      betagamma complex.

PMID- 8663595
TI  - Activated phosphatidylinositol 3-kinase is sufficient to mediate actin
      rearrangement and GLUT4 translocation in 3T3-L1 adipocytes.
AB  - Insulin stimulation of 3T3-L1 adipocytes causes rapid translocation of actin and
      the GLUT4 glucose transporter to the plasma membrane. Both processes depend on
      the activity of phosphatidylinositol 3-kinase. Using single cell microinjection,
      we have transiently expressed a constitutively activated mutant of
      phosphatidylinositol 3-kinase, p110*, in 3T3-L1 adipocytes. Fluorescent detection
      of GLUT4 protein and actin within these cells demonstrates that expression of
      p110* is sufficient to cause translocation of GLUT4 to the plasma membrane and
      the formation of actin membrane ruffles. These effects are inhibited by
      wortmannin in the p110*-expressing cells, indicating that the
      phosphatidylinositol 3-kinase activity of the protein is required. Overexpression
      of an identical protein containing a point mutation in the kinase domain,
      p110*Deltakin, was incapable of mediating either action, confirming that neither
      the microinjection process nor a nonspecific effect of the protein was
      responsible for the observed effects. These data suggest that although insulin is
      capable of inducing numerous signaling pathways, the isolated activation of
      phosphatidylinositol 3-kinase can initiate the signaling cascade leading to both
      actin rearrangement and GLUT4 translocation in the absence of insulin
      stimulation.

PMID- 8663598
TI  - Neuron-specific alternative splicing of nonmuscle myosin II heavy chain-B pre
      mRNA requires a cis-acting intron sequence.
AB  - In addition to the ubiquitously expressed form of nonmuscle myosin II heavy chain
      B (MHC-B), the existence of a neuron-specific MHC-B isoform, which contains a 30
      nucleotide inserted sequence near the ATP binding region, has been reported
      (Takahashi, M., Kawamoto, S., and Adelstein, R. S.(1992) J. Biol. Chem. 267,
      17864-17871). In this study, the genomic location of the neuron-specific inserted
      30-nucleotide sequence found in the cDNA is determined to be a single cassette
      type exon, N30, in the human nonmuscle MHC-B gene. Inclusion or exclusion of exon
      N30 is cell type-specific, with inclusion being restricted to neuronal cells and
      being regulated during cell differentiation. Expression of a minigene construct
      that contains the alternative exon N30 along with the flanking introns and exons
      was studied in human neuronal retinoblastoma Y79 cells. Inclusion of the N30 exon
      in the mRNA from the transfected minigene occurs in differentiated Y79 cells that
      have been treated with butyrate but not in the undifferentiated Y79 cells and non
      neuronal cell lines. Systematic deletion and mutation analysis of the minigene
      construct established that neuron-specific N30 exon recognition requires a cis
      acting RNA sequence located approximately 1.5 kilobases downstream of the N30
      exon.

PMID- 8663599
TI  - Molecular cloning of human phosphomevalonate kinase and identification of a
      consensus peroxisomal targeting sequence.
AB  - Two overlapping cDNAs which encode human liver phosphomevalonate kinase (PMKase)
      were isolated. The human PMKase cDNAs predict a 191-amino acid protein with a
      molecular weight of 21,862, consistent with previous reports for mammalian PMKase
      (Mr = 21,000-22,500). Further verification of the clones was obtained by
      expression of PMKase activity in bacteria using a composite 1024-base pair cDNA
      clone. Northern blot analysis of several human tissues revealed a doublet of
      transcripts at approximately 1 kilobase (kb) in heart, liver, skeletal muscle,
      kidney, and pancreas and lower but detectable transcript levels in brain,
      placenta, and lung. Analysis of transcripts from human lymphoblasts subcultured
      in lipid-depleted sera (LDS) and LDS supplemented with lovastatin indicated that
      PMKase gene expression is subject to regulation by sterol at the level of
      transcription. Southern blotting indicated that PMKase is a single copy gene
      covering less than 15 kb in the human genome. The human PMKase amino acid
      sequence contains a consensus peroxisomal targeting sequence (PTS-1), Ser-Arg
      Leu, at the C terminus of the protein. This is the first report of a cholesterol
      biosynthetic protein which contains a consensus PTS-1, providing further evidence
      for the concept that early cholesterol and nonsterol isoprenoid biosynthesis may
      occur in the peroxisome.

PMID- 8663600
TI  - A Drosophila protein-tyrosine phosphatase associates with an adapter protein
      required for axonal guidance.
AB  - We have used the yeast two-hybrid system to isolate a novel Drosophila adapter
      protein, which interacts with the Drosophila protein-tyrosine phosphatase (PTP)
      dPTP61F. Absence of this protein in Drosophila causes the mutant photoreceptor
      axon phenotype dreadlocks (dock) (Garrity, P. A., Rao, Y., Salecker, I., and
      Zipursky, S. L.(1996) Cell 85, 639-650). Dock is similar to the mammalian
      oncoprotein Nck and contains three Src homology 3 (SH3) domains and one Src
      homology 2 (SH2) domain. The interaction of dPTP61F with Dock was confirmed in
      vivo by immune precipitation experiments. A sequence containing five PXXP motifs
      from the non-catalytic domain of the PTP is sufficient for interaction with Dock.
      This suggests that binding to the PTP is mediated by one or more of the SH3
      domains of Dock. Immune precipitations of Dock also co-precipitate two tyrosine
      phosphorylated proteins having molecular masses of 190 and 145 kDa. Interactions
      between Dock and these tyrosine-phosphorylated proteins are likely mediated by
      the Dock SH2 domain. These findings identify potential signal-transducing
      partners of Dock and propose a role for dPTP61F and the unidentified
      phosphoproteins in axonal guidance.

PMID- 8663601
TI  - Serine phosphorylation, chromosomal localization, and transforming growth factor
      beta signal transduction by human bsp-1.
AB  - The transforming growth factor-beta (TGF-beta) superfamily regulates a multitude
      of cellular and developmental events. TGF-beta family ligands signal through
      transmembrane serine/threonine kinase receptors whose downstream effectors are
      largely unknown. Using genetic data from the fruit fly, we have identified a
      downstream effector of TGF-beta-induced signaling. TGF-beta signaling protein-1
      (BSP-1) is rapidly phosphorylated in response to TGF-beta. Localization of bsp-1
      to chromosome 4q28 suggests a role in carcinogenesis. These data suggest that BSP
      1 is the prototype of a new class of signaling molecules.

PMID- 8663602
TI  - Additions and Corrections to DNA binding exerted by a bacterial gene regulator
      with an extensive coiled-coil domain.

PMID- 8663603
TI  - Identification and characterization of a novel transcriptional activation domain
      in the CREB-binding protein.
AB  - The CREB-binding protein (CBP) plays a central role in the regulation of gene
      expression by several different second messenger pathways including serum growth
      factors, cAMP and phorbol esters. CBP specifically binds to the phosphorylated
      forms of CREB and c-Jun and is thought to activate transcription through a C
      terminal activation domain. In this report, we demonstrate that the C terminus of
      CBP is dispensable for its ability to stimulate phospho-CREB activity, and,
      further, that the deletion of this domain produces highly active, mutant forms of
      CBP. The novel N-terminal activation identified by this deletional analysis
      consists of the first 714 amino acids of CBP and is sufficient for high levels of
      transcriptional activity. This domain is also capable of stimulating the activity
      of a second cAMP-regulated factor, ATF-1. Surprisingly, ATF-1 activity is not
      significantly stimulated by full-length CBP suggesting that the C-terminal domain
      of CBP may also serve to regulate ATF-1/CBP activity. Additionally, the
      demonstration that one of our hyperactive CBP mutants is able to activate a
      nonphosphorylatable mutant of CREB (M1 CREB) provides the first evidence that CBP
      may play a role in regulating the basal transcriptional activity of CREB.

PMID- 8663604
TI  - Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase
      expression by decreasing NFkappaB activation.
AB  - In brain glial cells, expression of calcium independent nitric-oxide synthase
      (NOS-2) is induced following stimulation with bacterial endotoxin
      (lipopolysaccharide (LPS)) and/or pro-inflammatory cytokines. We have
      investigated the effects of heat shock (HS), which can reduce inflammatory
      responses in several cell types, on the induction of glial NOS-2 expression.
      Preincubation of cells for 20-60 min at 43 degrees C decreased subsequent levels
      of NOS-2 induction, with a maximal 80% reduction after 60 min of HS. Following
      HS, cells were refractory to NOS inducers for up to 4 h, after which time little
      or no suppression was observed. HS reduced cytosolic NOS-2 enzymatic activity (3
      fold), steady state mRNA levels (2-3-fold), and gene promoter activity (by 50%).
      HS also reduced LPS-induced nuclear accumulation of transcription factor NFkappaB
      p65 subunit, suggesting perturbation of NFkappaB activation. A role for HS
      protein (HSP) 70 in NOS-2 suppression by HS is supported by the demonstration
      that 1) transfection with human HSP70 cDNA partially replicated HS effects; 2)
      antisense, but not sense, oligonucleotides directed against rat HSP70 partially
      blocked HS effects; and 3) rat fibroblasts stably expressing human HSP70 did not
      express NOS-2 in response to LPS plus cytokines. As with heat-shocked cells,
      HSP70-expressing cells also exhibited decreased NFkappaB p65 subunit nuclear
      accumulation. These results demonstrate that in glial cells, as well as other
      cell types, NOS-2 induction can be modulated by the HS response, mediated at
      least in part by HSP70 expression.

PMID- 8663605
TI  - Developmental and tissue-specific expression of mouse pelle-like protein kinase.
AB  - The NF-kappaB/c-Rel proteins are a family of evolutionarily conserved
      transcription factors activated during development that in the adult, mediate
      many processes including the immune response. A high degree of sequence
      similarity is shared between the NF-kappaB/c-Rel family of transcription factors
      and the Drosophila Dorsal protein as well as between its cytoplasmic inhibitor,
      IkappaBalpha, and the Drosophila Cactus protein. Genetic analyses of Dorsal have
      defined components of a signaling pathway for Dorsal activation, including a
      serine/threonine kinase, Pelle, placed upstream of Dorsal and Cactus. We
      demonstrate that this pathway is likely to be conserved in mammals by the
      isolation of a cDNA that encodes a novel mouse protein highly related to Pelle,
      mPLK (mouse Pelle-like protein kinase). Expression of mPLK mRNA is
      developmentally regulated in the mouse and in adult tissue mPLK expression is
      greatest in the liver, a tissue that expresses a high level of NF-kappaB.
      Recombinant mPLK produced in bacteria is a protein kinase capable of
      autophosphorylating and phosphorylating IkappaBalpha.

PMID- 8663606
TI  - Saturable ethanol binding in rat liver microsomes.
AB  - The binding of ethanol to rat liver microsomes is shown to be saturable at
      clinically relevant ethanol concentrations, whereas this effect is not observed
      in extracted microsomal phospholipids. Brief exposure of the microsomes to heat
      abolishes saturable ethanol binding. Equilibrium binding data analysis, although
      only approximate in this context, suggests the presence of at least two groups of
      specific sites: high capacity sites with affinities near the pharmacological
      range and low capacity sites at lesser levels. The results indicate that the
      specificity of ethanol for tissue is considerably greater than previously
      recognized.

PMID- 8663607
TI  - Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole
      protein targeting pathway.
AB  - We have explored the phenotypic and genetic overlap between autophagocytosis and
      cytoplasm to vacuole targeting in the yeast Saccharomyces cerevisiae.
      Complementation analysis was performed with mutants in each of these groups (aut
      and cvt, respectively), and three complementation groups were found to overlap.
      Also, most of the unique aut mutants accumulated precursor aminopeptidase I in
      the cytoplasm, while maintaining wild type kinetics and maturation of proteins
      targeted to the vacuole via the secretory pathway. The majority of the non
      overlapping cvt mutants were found to be at least partially defective in
      autophagy. Some mutants in each group, however, appear to be only marginally
      affected in the other phenotype, implying that these pathways only partially
      overlap. We propose that import of aminopeptidase I into the vacuole shares a
      number of components required for bulk autophagocytosis, but is made specific,
      saturable, and constitutive by the presence of a receptor or other interacting
      protein(s).

PMID- 8663611
TI  - Activation of the CPP32 apoptotic protease by distinct signaling pathways with
      differential sensitivity to Bcl-xL.
AB  - In the absence of growth factors, many types of mammalian cells undergo
      apoptosis. We and others have shown recently that growth factors promote cell
      survival by activating phosphatidylinositol 3-kinase (PI 3-kinase) in several
      cell types. In the present study, we have compared downstream elements of the
      apoptotic pathways induced by PI 3-kinase inhibitors and other stimuli. In U937
      cells, both PI 3-kinase inhibitors (wortmannin and LY294002) and etoposide
      activated the CPP32 apoptotic protease by cleavage to active p17 subunits. In
      contrast, treatment with tumor necrosis factor alpha (TNFalpha) resulted in the
      accumulation of a distinct active CPP32 subunit, p20. Furthermore, overexpression
      of Bcl-xL blocked DNA fragmentation, CPP32 activation and cleavage of poly(ADP
      ribose) polymerase in U937 cells treated with both PI 3-kinase inhibitors and
      etoposide, but not in cells treated with TNFalpha. Distinct patterns of CPP32
      activation and differential sensitivities to Bcl-xL thus distinguish the cell
      death pathways activated by PI 3-kinase inhibition and DNA damage from that
      activated by TNFalpha.

PMID- 8663612
TI  - Evidence for an imino intermediate in the DNA polymerase beta deoxyribose
      phosphate excision reaction.
AB  - A recent study demonstrated that rat DNA polymerase beta (beta-pol) releases 5'
      deoxyribose phosphate (dRP) termini from preincised apurinic/apyrimidinic DNA, a
      substrate generated during certain types of base excision repair. This catalytic
      activity resides within the amino-terminal, 8-kDa domain of beta-pol and occurs
      via beta-elimination as opposed to hydrolysis (Matsumoto, Y., and Kim, K. (1995)
      Science 269, 699-702). The latter finding suggested that the dRP excision
      reaction might proceed via an imine intermediate. In order to test this
      hypothesis, we attempted to trap beta-pol on preincised apurinic/apyrimidinic DNA
      using NaBH4 as the reducing agent. Both 8-kDa domain-DNA and intact beta-pol-DNA
      complexes were detected and identified by autoradiography coupled to
      immunoblotting. Our results indicate that the chemical mechanism of the beta-pol
      dRpase reaction does proceed through an imine enzyme-DNA intermediate and that
      the active site residue responsible for dRP release must therefore contain a
      primary amine.

PMID- 8663853
TI  - Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against
      tumor necrosis factor alpha.
AB  - BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis
      infection), antimicrobial treatment is often followed by sudden fever, rigors,
      and persistent hypotension (Jarisch-Herxheimer reactions) that are associated
      with increases in plasma concentrations of tumor necrosis factor alpha (TNF
      alpha), interleukin-6, and interleukin-8. We attempted to determine whether sheep
      polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could
      suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized,
      double-blind, placebo-controlled trial in 49 patients with proven louse-borne
      relapsing fever. Immediately before the intramuscular injection of penicillin,
      the patients received an intravenous infusion of either anti-TNF-alpha Fab or a
      control solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had
      Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control
      patients (P = 0.006). The controls had significantly greater mean maximal
      increases in temperature (1.5 vs. 0.8 degrees C, P < 0.001), pulse rate (31 vs.
      13 per minute, P < 0.001), and systolic blood pressure (25 vs. 15 mm Hg, P <
      0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50
      vs. 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P <
      0.001 for both comparisons). Levels of TNF-alpha were undetectable after
      treatment with anti-TNF-alpha Fab. CONCLUSIONS: Pretreatment with sheep anti-TNF
      alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin
      treatment for louse-borne relapsing fever, reduces the associated increases in
      plasma concentrations of interleukin-6 and interleukin-8, and may be useful in
      other forms of sepsis.

PMID- 8663854
TI  - Secular trends in coronary atherosclerosis--analysis in patients with valvular
      regurgitation.
AB  - BACKGROUND: Between 1980 and 1989, mortality due to coronary artery disease
      decreased considerably in the United States, suggesting a possible decrease in
      the prevalence of coronary atherosclerosis. We examined this possibility in
      patients with valvular regurgitation who, often in the absence of angina,
      underwent coronary angiography before valve-replacement surgery. METHODS: We
      studied 601 patients with isolated, nonischemic valvular regurgitation who were
      operated on between 1980 and 1989 and who had undergone preoperative coronary
      angiography. From the angiograms we determined the prevalence of clinically
      significant coronary artery disease and of multivessel disease, assessed the mean
      degree of stenosis, and analyzed the trends in the data over the years of the
      study. RESULTS: The prevalence of coronary artery disease (35 percent in 1980
      1981, 37 percent in 1982-1983, 34 percent in 1984-1985, 37 percent in 1986-1987,
      and 35 percent in 1988-1989; P = 0.97) did not change significantly during the
      study period. We found no significant change in the prevalence of multivessel
      disease (24 percent in 1980-1981 and 23 percent in 1988-1989, P = 0.99) or in the
      mean ( +/- SD) degree of stenosis (11 +/- 13 percent in 1980-1981 and 13 +/- 14
      percent in 1988-1989, P = 0.07). When these measures of coronary atherosclerosis
      were adjusted for age and sex, there were still no significant changes over time
      (P = 0.39 for the prevalence of coronary artery disease, P = 0.81 for that of
      multivessel disease, and P = 0.57 for the mean degree of stenosis). The patients'
      mean total cholesterol level decreased from 219 +/- 48 mg per deciliter (5.66 +/-
      1.24 mmol per liter) to 206 +/- 44 mg per deciliter (5.33 +/- 1.14 mmol per
      liter) between 1980 and 1989 (P = 0.04). CONCLUSIONS: From 1980 to 1989, no
      significant change was observed in angiographic measures of coronary
      atherosclerosis in patients with nonischemic valvular regurgitation, in contrast
      to the marked decrease in mortality due to coronary disease in the general
      population. These findings suggest that the well-documented reduction in
      mortality due to coronary disease may not be due to a reduction in the prevalence
      of coronary atherosclerosis.

PMID- 8663855
TI  - The use of Medicare home health care services.
AB  - BACKGROUND: Medicare's home health care program, consisting primarily of home
      visits by nurses and health aides, was conceived as a means to facilitate
      hospital discharge. Because home health care is now one of the fastest-growing
      categories of Medicare expenditures, we analyzed Medicare claims data to
      determine current patterns of use. METHODS: We used 1993 data from Medicare's
      National Claims History File to examine the temporal relation between home visits
      and hospital discharge, as well as the number of months Medicare enrollees
      received home health care. To determine whether home visits replaced hospital
      services, we calculated population-based utilization rates, adjusted for age and
      sex, for enrollees living in the 310 U.S. metropolitan statistical areas and
      determined whether the areas with higher rates of home health care also had lower
      admission rates or shorter lengths of stay. Finally, we compared the geographic
      variation in use of home health care with that of other Medicare services.
      RESULTS: Roughly 3 million Medicare enrollees received over 160 million home
      health care visits in 1993. Seventy-eight percent of the visits either occurred
      more than a month after hospital discharge (35 percent) or were not associated
      with any inpatient care during the previous six months (43%). Home health care
      often represented a long-term intervention: 61 percent of the visits were to
      enrollees who received home health care for six months or more. We could find no
      evidence that home health care was substituted for hospital care; the
      metropolitan statistical areas with higher rates of home health care did not have
      fewer hospital admissions or shorter lengths of stay. There was more geographic
      variation in the use of home health care than in the use of other major
      categories of Medicare services (e.g., hospital admissions and physicians'
      services). Five states (all in the South) had more than 9000 visits per 1000
      enrollees, and 14 states had fewer than 3000 visits per 1000 enrollees.
      CONCLUSIONS: Home health care visits are used primarily to provide long-term
      care. There is no evidence that services provided at home replace hospital
      services, and the dramatic geographic variation in home visits suggests a lack of
      consensus about their appropriate use.

PMID- 8663856
TI  - The march of AIDS through Asia.

PMID- 8663857
TI  - Clinical problem-solving. The domino principle.

PMID- 8663858
TI  - Gene transfer to hematopoietic cells.

PMID- 8663859
TI  - Tumor necrosis factor and the Jarisch-Herxheimer reaction.

PMID- 8663860
TI  - Age-specific reference ranges for serum PSA.

PMID- 8663861
TI  - Changes in sexual behavior and a decline in HIV infection among young men in
      Thailand.
AB  - BACKGROUND: In Thailand the epidemic of human immunodeficiency virus (HIV)
      infection is of recent origin. Because of the high seroprevalence of HIV among
      sex workers, the Ministry of Public Health began a program in 1990 and 1991 to
      promote the use of condoms during commercial sex. We evaluated the effect of this
      and other programs to prevent HIV infection in Thailand. METHODS: Using direct
      interviews, we studied five cohorts of 21-year-old men from northern Thailand who
      were conscripted into the army by a lottery in 1991, 1993, and 1995. In all, 4311
      men were tested for HIV antibodies by enzyme-linked immunosorbent assay, with
      confirmation by Western blot assay. RESULTS: In the 1991 and 1993 cohorts, the
      prevalence of HIV infection was 10.4 to 12.5 percent. In 1995, it fell to 6.7
      percent (P < 0.001). The seroprevalence was only 0.7 percent among men who did
      not have sexual relations with a sex worker before 1992. Over the study period,
      the proportion of men who reported having sexual relations with a sex worker fell
      from 81.4 percent to 63.8 percent (P < 0.001). From 1991 to 1995, the men's
      reported use of condoms during the most recent sexual contacts with sex workers
      increased from 61.0 percent to 92.5 percent (P < 0.001); and in 1995, 15.2
      percent of men had a history of a sexually transmitted disease, as compared with
      42.2 percent in 1991 (P < 0.001). CONCLUSIONS: Public health programs in Thailand
      have led to substantial changes in sexual behavior among young men, especially an
      increased use of condoms, and the rate of new HIV infections has declined.

PMID- 8663868
TI  - Evaluation of dementia.

PMID- 8663870
TI  - Age-specific reference ranges for serum prostate-specific antigen in black men.
AB  - BACKGROUND: The detection of prostate cancer by screening for prostate-specific
      antigen (PSA) in serum is improved when age-specific reference ranges are used,
      but these ranges have been derived from white populations. We determined the
      distribution of PSA and age-specific reference ranges in black men both with and
      without prostate cancer. METHODS: From January 1991 through May 1995, we measured
      serum PSA in 3475 men with no clinical evidence of prostate cancer (1802 white
      and 1673 black) and 1783 men with prostate cancer (1372 white and 411 black). We
      studied the data as a function of age and race to determine the usefulness of
      measuring PSA in diagnosing prostate cancer. RESULTS: Serum PSA concentrations in
      black men (geometric mean in controls, 1.48 ng per milliliter; in patients, 7.46)
      were significantly higher than those in white men (geometric mean in controls,
      1.33 ng per milliliter; in patients, 6.28). The values in the controls correlated
      directly with age. The area under the receiver-operating-characteristic curve was
      0.91 for blacks and 0.94 for whites. If traditional age-specific reference ranges
      were used in screening black men, with the test specificity kept at 95 percent,
      41 percent of cases of prostate cancer would be missed. For the test to have 95
      percent sensitivity among black men, the following normal reference ranges should
      be used: for men in their 40s, 0 to 2.0 ng of PSA per milliliter (test
      specificity, 93 percent); for men in their 50s, 0 to 4.0 ng per milliliter
      (specificity, 88 percent); for men in their 60s, 0 to 4.5 ng per milliliter
      (specificity, 81 percent); and for men in their 70s, 0 to 5.5 ng per milliliter
      (specificity, 78 percent). CONCLUSIONS: Serum PSA concentrations can be used to
      discriminate between men with prostate cancer and those without it among both
      blacks and whites. Over 40 percent of cases of prostate cancer in black men would
      not be detected by tests using traditional age-specific reference ranges, which
      maintain specificity at 95 percent. In this high-risk population, the alternative
      approach--maintaining sensitivity at 95 percent--may be used with acceptable
      decrements in specificity.

PMID- 8663875
TI  - Advances in the prevention and treatment of Mycobacterium avium disease.

PMID- 8663871
TI  - A randomized trial of clarithromycin as prophylaxis against disseminated
      Mycobacterium avium complex infection in patients with advanced acquired
      immunodeficiency syndrome.
AB  - BACKGROUND: Disseminated infection with Mycobacterium avium complex is the most
      common opportunistic infection in patients with advanced stages of the acquired
      immunodeficiency syndrome (AIDS). We studied the efficacy and safety of
      prophylactic treatment with clarithromycin, a macrolide antibiotic. METHODS: We
      conducted a randomized, placebo-controlled, double-blind study of clarithromycin
      in patients with AIDS in the United States and Europe. Entry criteria included
      blood cultures that were negative for M. avium complex, a Karnofsky performance
      score of 50 or higher, a CD4 cell count of 100 or less per cubic millimeter, and
      a life expectancy of at least six months. RESULTS: After the first interim
      analysis, the study was stopped. M. avium complex infection developed in 19 of
      the 333 patients (6 percent) assigned to clarithromycin and in 53 of the 334 (16
      percent) assigned to placebo (adjusted hazard ratio, 0.31; 95 percent confidence
      interval, 0.18 to 0.53; P<0.001). During the follow-up period of about 10 months,
      32 percent of the patients in the clarithromycin group died and 41 percent of
      those in the placebo group died (hazard ratio, 0.75; P=0.026). In the
      clarithromycin group, isolates from 11 of the 19 patients with M. avium complex
      infection were resistant to clarithromycin. Prophylaxis with clarithromycin was
      associated with an increased incidence of taste perversion (11 percent in the
      clarithromycin group vs. 2 percent in the placebo group, P<0.001) and rectal
      disorders (8 percent vs. 3 percent, P = 0.007); however, the frequency of more
      severe adverse events was similar in the two groups (7 percent and 6 percent,
      respectively). CONCLUSIONS: In patients with advanced AIDS, the prophylactic
      administration of clarithromycin is well tolerated, prevents M. avium complex
      infection, and reduces mortality.

PMID- 8663876
TI  - Bone marrow transplantation in sickle cell anemia--the dilemma of choice.

PMID- 8663877
TI  - The new health care game.

PMID- 8663878
TI  - Economic reform and health--lessons from China.

PMID- 8663882
TI  - Effect of economic reforms on child growth in urban and rural areas of China.
AB  - BACKGROUND: Beginning in 1978, China implemented economic reforms to transform
      the economy to a free-market system. We compared the effect of the reforms on the
      growth of children in urban and rural areas. METHODS: Using data from five large
      cross-sectional surveys conducted between 1975 and 1992, we examined the trends
      in height for age of children two to five years of age in urban and rural areas.
      Mean height for age was expressed as the height in centimeters adjusted to a
      reference value of 99.1 cm for a 42-month-old boy. RESULTS: Height increased
      before and during the economic reforms. In 1975, the average height of children
      in periurban rural areas was about 3.5 cm less than that of children in urban
      areas. Between 1975 and 1985, the average height of children in periurban rural
      areas increased by 2.0 cm, as compared with 1.3 cm in urban children. Between
      1987 and 1992, the average height of both urban and rural children increased, but
      the net increase for rural children was only one fifth that for urban children
      (0.5 vs. 2.5 cm). In a 1990 survey of seven provinces, the rural mean height was
      92.5 cm, as compared with the urban mean of 96.9 cm and the reference value of
      99.1 cm; 38 percent of rural children had moderate stunting of growth and 15
      percent had severe stunting, as compared with 10 percent and 3 percent of urban
      children, respectively. Differences in height between rural and urban children
      were greater in provinces in which the average height of children was lower.
      CONCLUSIONS: Despite an overall improvement in child growth during the economic
      reforms in China, the improvement has not been equitable, as judged by increased
      differences in height between rural and urban children and increased disparities
      within rural area.

PMID- 8663884
TI  - Bone marrow transplantation for sickle cell disease.
AB  - BACKGROUND: We investigated the risks and benefits of allogeneic bone marrow
      transplantation in children with complications of sickle cell disease. METHODS:
      Twenty-two children less than 16 years of age who had symptomatic sickle cell
      disease received marrow allografts from HLA-identical siblings between September
      1991 and April 1995. The indications for transplantation included a history of
      stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful
      crises (n = 5). Patients were prepared for transplantation with busulfan,
      cyclophosphamide, and antithymocyte globulin. RESULTS: Twenty of the 22 patients
      survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16
      patients had stable engraftment of donor hematopoietic cells. In three patients
      the graft was rejected and sickle cell disease recurred; in a fourth patient
      graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with
      engraftment, there was stable mixed chimerism. Two patients died of central
      nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of
      survival and event-free survival at four years were 91 percent and 73 percent,
      respectively. Among patients with a history of acute chest syndrome, lung
      function stabilized; among patients with prior central nervous system
      vasculopathy who had engraftment, stabilization of cerebrovascular disease was
      documented by magnetic resonance imaging. CONCLUSIONS: Allogeneic stem-cell
      transplantation can be curative in young patients with symptomatic sickle cell
      disease.

PMID- 8663888
TI  - The wear of cross-linked polyethylene against itself.
AB  - Cross-linked polyethylene (XLPE) may have an application as a material for an all
      plastic surface replacement finger joint. It is inexpensive, biocompatible and
      can be injection-moulded into the complex shapes that are found on the ends of
      the finger bones. Further, the cross-linking of polyethylene has significantly
      improved its mechanical properties. Therefore, the opportunity exists for an all
      XLPE joint, and so the wear characteristics of XLPE sliding against itself have
      been investigated. Wear tests were carried out on both reciprocating pin-on-plate
      machines and a finger function simulator. The reciprocating pin-on-plate machines
      had pins loaded at 10 N and 40 N. All pin-on-plate tests show wear factors from
      the plates very much greater than those of the pins. After 349 km of sliding, a
      mean wear factor of 0.46 x 10(-6) mm3/N m was found for the plates compared with
      0.021 x 10(-6) mm3/N m for the pins. A fatigue mechanism may be causing this
      phenomenon of greater plate wear. Tests using the finger function simulator give
      an average wear rate of 0.22 x 10(-6) mm3/N m after 368 km. This sliding distance
      is equivalent to 12.5 years of use in vivo. The wear factors found were
      comparable with those of ultra-high molecular weight polyethylene (UHMWPE)
      against a metallic counterface and, therefore, as the loads across the finger
      joint are much less than those across the knee or the hip, it is probable that an
      all-XLPE finger joint will be viable from a wear point of view.

PMID- 8663889
TI  - Three-dimensional joint co-ordination strategies of the upper limb during
      functional activities.
AB  - A triaxial flexible electrogoniometer has been developed to measure the three
      dimensional angular motion of the shoulder joint during simulated activities of
      daily living. The motion of the elbow, forearm and wrist were also recorded and
      angle-angle diagrams were mathematically analysed to provide quantitative
      parameters regarding the control and co-ordination of the joints of the normal
      and the arthritic upper limb. Two parameters (slope and movement area quotient)
      were derived and used in the interpretation of joint motion during different
      activities.

PMID- 8663890
TI  - Transmission of rapidly applied loads through articular cartilage. Part 1:
      Uncracked cartilage.
AB  - An elastostatic model of rapidly loaded articular cartilage is presented. It is
      assumed that the cartilage experiences little volumetric change or interstitial
      fluid flow while loaded instantaneously. Subchondral bone compliance and
      articular surface friction are incorporated. Integral representations of the
      stress distributions within cartilage are derived using Fourier transform
      techniques and the integrals are solved numerically. Localized tensile stresses
      are found and occur in regions close to the cartilage-bone interface as well as
      at the articular surface, outside the embrace of the load. The qualitative
      similarity between the results and those of previous investigations is explained
      by an elementary equilibrium analysis. The stress distributions suggest that the
      splits and cracks observed in diseased cartilage may be initiated, or propagated,
      by tensile stress.

PMID- 8663891
TI  - Ultra-high molecular weight polyethylene wear debris generated in vivo and in
      laboratory tests; the influence of counterface roughness.
AB  - The objective of this study was to investigate the effect of counterface
      roughness and lubricant on the morphology of ultra-high molecular weight
      polyethylene (UHMWPE) wear debris generated in laboratory wear tests, and to
      compare this with debris isolated from explanted tissue. Laboratory tests used
      UHMWPE pins sliding against stainless steel counterfaces. Both water and serum
      lubricants were used in conjunction with rough and smooth counterfaces. The
      lubricants and tissue from revision hip surgery were processed to digest the
      proteins and permit filtration. This involved denaturing the proteins with
      potassium hydroxide (KOH), sedimentation of any remaining proteins, and further
      digestion of these proteins with chromic acid. All fractions were then passed
      through a 0.2 micron membrane, and the debris examined using scanning electron
      microscopy. The laboratory studies showed that the major variable influencing
      debris morphology was counterface roughness. The rougher counterfaces produced
      larger numbers of smaller particles, with a size range extending below 1 micron.
      For smooth counterfaces there were fewer of these small particles, and evidence
      of larger platelets, greater than 10 microns in diameter. Analysis of the debris
      from explanted tissues showed a wide variation in the particle size distribution,
      ranging from below 1 micron up to several millimetres in size. Of major clinical
      significance in relation to osteolysis and loosening is roughening of the femoral
      components, which may lead to greater numbers of the sub-micron-sized particles.

PMID- 8663892
TI  - Transmission of rapidly applied loads through articular cartilage. Part 2:
      Cracked cartilage.
AB  - A model of articular cartilage suffering rapidly applied loads and containing
      splits and fissures is presented. The possibility of cracks propagating through
      the cartilage collagen network is analysed using elastic fracture mechanics.
      Cracks are modelled using the distributed dislocation technique and the crack tip
      stress intensity factors are thereby evaluated. The mode I (tensile) stress
      intensity factors are generally much larger than the mode II (shearing) factors
      for cracks at the articular surface and close to, and at oblique angles to, the
      cartilage-bone interface, two regions where cartilage cracks have been observed.
      This suggests an opening, tensile mode of failure. The mode II factors are larger
      for cracks running along the interface. The rapidly loaded cracked cartilage
      model may explain the splits observed in osteoarthrotic cartilage.

PMID- 8663893
TI  - Finite element analysis of a total knee replacement by using Gauss point contact
      constraints.
AB  - Finite element methods have been applied extensively and with much success in the
      analysis of orthopaedic hip and knee implants. Very recently a burgeoning
      interest has developed, in the finite element community, in how numerical models
      can be constructed for the solution of problems in contact mechanics. New
      developments in this area are of paramount importance in the design of implants
      for orthopaedic surgery. Modern techniques are described for finite element
      contact analysis and applied to two problems of stress analysis in a plastic
      tibial component. In the former, results are compared with a previous finite
      element analysis and with Hertzian solutions. In the latter, an estimate of the
      extent of convergence of the finite element solutions is provided.

PMID- 8663894
TI  - Physical modelling of hip joint forces in stair climbing.
AB  - A test device has been developed and validated to simulate physiologic loading of
      the hip during stair climbing. Forces about the hip joint were measured in static
      simulations of stair climbing using simulated extensor, abductor and adductor
      muscle groups to support the joint. Femoral flexion angle (to model step length
      and height) and applied hip flexion moment (to model trunk lean) were varied to
      examine the effects of different loading conditions on the hip. In stair climbing
      the maximum total joint force was six times body weight at 34 degrees of femoral
      flexion and 60 N m of hip flexion moment. Joint forces increased with hip flexion
      moment and varied little with femoral flexion angle, except for the posteriorly
      directed force. This component, which twists implants about the femoral shaft,
      increased with femoral flexion angle but changed little with hip flexion moment.

PMID- 8663895
TI  - Rubisco, an old challenge with new perspectives.

PMID- 8663896
TI  - Antibacterial diterpenic acids from Brazilian propolis.
AB  - Four labdane-type diterpenic acids and syringaldehyde were isolated and
      identified from Brazilian propolis. All the compounds exhibit antibacterial
      activity. The diterpenes, found for the first time in propolis, are typical for
      some Araucaria species and thus indicate a possible plant source of Brazilian
      propolis.

PMID- 8663897
TI  - Comparative immunological detection of lipids and carotenoids on peptides of
      photosystem I from higher plants and cyanobacteria.
AB  - Photosystem I preparations were obtained from wild-type tobacco Nicotiana tabacum
      var. JWB, three chlorophyll-deficient tobacco mutants: Su/su, Su/su var. Aurea
      and yellow-green leaf patches of the variegated mutant NC 95, Spinacia oleracea
      and furthermore from the mesophilic cyanobacterium Synechococcus PCC 7942 and the
      thermophilic cyanobacterium Synechococcus sp.. Peptides from these preparations
      were analyzed by SDS polyacrylamide gel electrophoresis and transferred for
      detection of bound lipids and carotenoids according to the Western blot procedure
      to nitrocellulose membranes. The PS I preparations from the Nicotiana tabacum
      species and spinach consist of the core complex and the LHCP I complex, the
      latter containing, however, traces of the LHCP II polypeptides. The core complex
      consists of the two core peptides with the apparent molecular mass of 66 kDa each
      and peptides with molecular masses of 22, 20, 19, 17, 16, 10 and 9 kDa. The LHCP
      I complex contains 4 subunits with molecular masses of 28, 26, 25 and 24 kDa. The
      PS I preparations of the two mutants Su/su and Su/su var. Aurea contain as
      impurities traces of the core peptides (D1/D2) and the two chlorophyll-binding
      peptides (CP43/CP47) of photosystem II. The PS I preparation from the mesophilic
      and thermophilic cyanobacterium consists of the two core peptides with the
      apparent molecular mass of 66 kDa and peptides with molecular masses of 16, 14
      and 10 kDa. The peptides of the PS I preparations were characterized by specific
      PS I, CP I and LHCP I antisera. The antiserum to the PS I complex reacts in the
      Western blot with the homologous peptides of PS I from higher plants, but only
      with the CP I complex from the two cyanobacteria. In comparative studies with PS
      II from higher plants the PS I antiserum reacts with the LHCP II complex as
      expected. The antiserum to the CP I complex reacts only with the 66 kDa peptides
      of PS I from all objects. There is no cross reaction with the 66 kDa peptides
      (heterodimer of the D1/D2 peptides) of PS II. The antiserum to the LHCP I complex
      reacts only with the four LHCP I peptides of PS I from higher plants and as
      expected with the LHCP II of PS II: Because cyanobacteria do not have LHCP
      complexes, there is no reaction with the LHCP I antiserum. By means of polyclonal
      monospecific antisera to lipids it was shown by Western blot procedure that only
      two lipid species are bound to PS I peptides. The galactolipid
      monogalactosyldiglyceride is bound to the CP I complex of the Nicotiana tabacum
      species, spinach and the two cyanobacteria as well as to the LHCP I complex of
      the higher plants. The phospholipid phosphatidylglycerol is only associated with
      the CP I complex of the analyzed higher plants and cyanobacteria. With polyclonal
      monospecific antisera to carotenoids it was demonstrated that beta-carotene,
      lutein, neoxanthin and zeaxanthin are associated with the CP I complex of the
      higher plants and the cyanobacteria analyzed. Violaxanthin is also bound to the
      CP I complex of the two cyanobacteria, whereas it is bound together with
      neoxanthin to the LHCP I complex of the higher plants.

PMID- 8663898
TI  - The catalytic mechanism of tyrosine phenol-lyase from Erwinia herbicola: the
      effect of substrate structure on pH-dependence of kinetic parameters in the
      reactions with ring-substituted tyrosines.
AB  - Apparently homogeneous tyrosine phenol-lyase (TPL) from Erwinia herbicola has
      been prepared by a new method. The pH-dependencies of the main kinetic parameters
      for the reactions of Erwinia TPL with tyrosine, 2-fluorotyrosine, 3
      fluorotyrosine, 2-chlorotyrosine, and 3,4-dihydroxyphenylalanine (DOPA) have been
      studied. The pattern of pH-dependence of V(max) depends on the nature of the
      substituent in the aromatic ring. For the substrates bearing small substituents
      (H, 2-F, 3-F) V(max) values were found to be pH-independent. For 2-chlorotyrosine
      and DOPA V(max) decreased at lower pH, the effect being described by equation
      with one pKa. Generally two bases are reflected in the pH dependence of
      V(max)/Km. The first base, probably is responsible for the abstraction of alpha
      proton, while the second one, interacts with the phenolic hydroxyl at the stage
      of binding. The reaction of TPL with DOPA differs from the reactions with other
      tyrosines by the requirement of an additional base which is reflected in the pH
      profiles of both V(max) and V(max)/Km. For the reaction of TPL from Citrobacter
      intermedius with DOPA only V(max)/Km values could be determined. The activity of
      Citrobacter enzyme towards DOPA is considerably less than that of E. herbicola
      enzyme, and its maximal value is attained at higher pH.

PMID- 8663899
TI  - Conformational changes involved in the switch from ovalbumin to S-ovalbumin.
AB  - For the first time a comparative study on conformational differences between
      native ovalbumin and its heat-stable form, called S-ovalbumin, using small angle
      x-ray scattering, is reported. To detect a different pathway in the folding
      mechanism of the two proteins, scattering measurements have been performed on
      ovalbumin and S-ovalbumin denatured with different concentrations of guanidine
      hydrochloride, and by heating the proteins at acid pH. The intensity scattering
      curves provide evidence that the intermediate states in the unfolding process are
      globular for both proteins while their compactness changes. The reported
      experimental results suggest that the ovalbumin to S-ovalbumin transformation can
      be considered a protein-switch triggered by changes in the chemical conditions of
      the protein environment. Because the conformational changes are likely to be of
      functional importance, we infer that the occurrence in vivo of S-ovalbumin is
      thus determined by the transformation of ovalbumin, with a functional role for
      embryonic development, into a new protein with a different function.

PMID- 8663900
TI  - Desialylation of low density lipoprotein--metabolic function versus oxidative
      damage?
AB  - Low density lipoproteins are generally considered to play a major role in the
      development of atherosclerotic vascular diseases. There is growing interest in
      LDL subspecies, especially in their density, carbohydrate content and
      oxidizability, which is supposed to enhance atherogenicity. We investigated the
      influence of desialylation on the resistance of the lipoprotein particles towards
      Cu(II) prooxidative activity.

PMID- 8663901
TI  - Altered fatty acid, cholesterol and Na+/K+ ATPase activity in erythrocyte
      membrane of rheumatoid arthritis patients.
AB  - Rheumatoid arthritis (RA) is a chronic inflammatory disease whose cause remains
      obscure. Blood from 15 RA patients and controls was taken and their ghosts
      separated. The ghosts were analysed for cholesterol content, Na+/K+ ATPase
      activity and eicosapentaenoic acid. The cholesterol content in the ghosts of RA
      patients was significantly lower as compared with the set of controls. There was
      a major difference in the activity of Na+/K+ ATPase between the two groups with
      RA patients showing significantly elevated activity. The ghosts of the RA
      patients exhibited major abnormality in the polyunsaturated fatty acids of
      phospholipids with the level of eicosapentaenoic acid (omega-3, 20:5) being
      significantly reduced.

PMID- 8663902
TI  - Aspects of the cell growth of Candida guilliermondii in sugar cane bagasse
      hydrolysate.
AB  - In this work the behavior of the growth of Candida guilliermondii FTI 20037 in
      sugar cane bagasse hemicellulosic hydrolysate on various oxygen transfer rates
      was investigated. The yeast was able to grow and produced xylitol at different
      performance levels. At 1.0 vvm (volume of air per volume of medium per minute)
      the highest growth with 24.4 g/l was observed, but no xylitol was produced. At
      aeration rate of 0.5 vvm the growth was lower, but therefore slight amounts of
      xylitol (xylitol yield factor-Yp/s = 0.15 g/g) were observed. The lowest cell
      concentration (10.7 g/l) and the highest xylitol yield (Yp/s = 0.46 g/g) was
      observed when aeration was changed from 0.5 vvm to 0.05 vvm after 14 h.

PMID- 8663903
TI  - Radiation-induced apoptosis in thymocytes: pH sensitization.
AB  - Thymocytes were used as a model system to study the effect of microenvironmental
      pH changes on the radiation-induced apoptosis. We found that the sensitivity of
      thymocytes toward radiation induced apoptosis is increased by increasing the pH
      of the incubation medium. The major sensitivity change occurs between pH 7 and 8.
      In a given cell suspension the results obtained where similar when the apoptosis
      evaluation was carried out either by counting the picnotic nuclei, or monitoring
      the fraction of apoptotic nuclei by flow cytometry; both methods show a
      radiosensitization when the pH value of incubation media rises from 7 to 8. These
      results may be important when "in vitro" experiments are performed with lymphoid
      cells, since changes in pH of the media may determine important changes in the
      results.

PMID- 8663904
TI  - Painting of human chromosome 8 in fifteen minutes.
AB  - The technique of chromosome-in-situ suppression (CISS)-hybridization (chromosome
      painting) has now been well established. However, all standard protocols so far
      require long renaturation times (typically 12 hours and more). Here, we describe
      a new, extremely fast protocol for chromosome painting using a commercially
      available, directly fluorescence labelled probe for chromosome 8. The
      hybridization conditions used omit separate preannealing procedures and
      denaturing chemical agents. The renaturation time required for chromosome
      painting was reduced to 15 minutes. In addition, most washing steps were
      eliminated. As a consequence, the entire painting procedure was feasible in less
      than half an hour.

PMID- 8663905
TI  - SRC as a target for anti-cancer drugs.

PMID- 8663906
TI  - The direct reduction of cytochrome c by some anthraquinone antitumor compounds.
AB  - The ability of various anthraquinone antitumor agents to undergo oxidative
      metabolism with concomitant cytochrome c reduction has been examined. The
      reduction of cytochrome c by the compounds had enzymatic character and occurred
      without the formation of oxygen radicals. We have found that the presence of at
      least two phenolic groups in ring A of the compounds studied was indispensable
      for their oxidative metabolism. It is suggested that these groups are essential
      for the binding to cytochrome c. Furthermore, it has been shown that the
      existence of hydroxy groups in side chains of these compounds augments their
      interaction with this hemoprotein. On the basis of the results obtained for a
      series of analogs of mitoxantrone, we can conclude that the structural factor
      directly responsible for cytochrome c reduction is the primary or secondary amino
      group of the side chains.

PMID- 8663908
TI  - Biophysical and biological evaluation of porphyrin-bisacridine conjugates.
AB  - Two novel porphyrin-bisacridine conjugates (1 and 2) were designed as
      bifunctional antitumour agents to combine the DNA-binding character of the
      acridines and the photosensitizing capacity of porphyrin, and have been subjected
      to biophysical and biological evaluation. The interactions of the conjugates with
      calf thymus DNA were evaluated using viscometric, spectrophotometric and stopped
      flow sodium dodecyl sulphate (SDS) sequestration methods. Both conjugates acted
      as bis-intercalators via the two acridine chromophores and displayed a longer
      residence time on DNA relative to the parent acridine ligand. Their biological
      activity in vitro was studied against the C6 rat glioma, MCF-7, GBM and A431 cell
      lines. Both conjugates were cytotoxic to all four cell lines. The ID50 (C6
      glioma) was essentially the same as that of the parent acridine for one
      conjugate, but was increased 20-fold for the other, while both conjugates were
      approximately 10-fold more cytotoxic than the parent porphyrin component. The
      tissue distribution of the two conjugates was assessed in nude mice xenografted
      with a human small cell lung carcinoma (POVD). There were large differences in
      the tissue distribution of the two conjugates, with conjugate 2 localizing 8-fold
      more in the tumour than conjugate 1.

PMID- 8663907
TI  - Pyrazole-related nucleosides. 4. Synthesis and antitumor activity of some 1
      tetrahydropyranyl-4-substituted pyrazoles.
AB  - Continuing our studies on the structure-activity relationships of some pyrazole
      nucleosides (1a-h) structurally related to ribavirin, tiazofurin and
      selenazofurin, we describe here the synthesis and
      antitumor/antiviral/antimicrobial activity of a new series of 1-tetrahydropyranyl
      4-substituted pyrazoles. In this study, the tetrahydropyranyl moiety (THP),
      designed as a mimic of the glycosidic portion of the parent compounds 1a-h, has
      led to a few derivatives with moderate cytotoxic activity against
      leukemia/lymphoma and solid tumor-derived cell lines (IC50 14-100 microM). The
      compounds obtained through substitution of the ribofuranosyl moiety by the THP
      moiety were still active, the free heterocyclic bases were devoid of any
      activity.

PMID- 8663909
TI  - Potent antitumor activity of quinolone compounds with an unsaturated
      aminoazabicyclo group at the C-7 position of the quinolone ring.
AB  - Relationships between the substituents on the quinolone nucleus of 2 and related
      compounds and their biological activities were studied. 2, 3 and 1 carrying a
      (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl group at the C-7 position
      increased the rate of formation of DNA-protein complexes in cells, and inhibited
      the growth of tumor cells more strongly than the compounds with other
      substituents. The introduction of a fluorine atom or a methoxy group at the 8
      position and an amino group at the 5-position increased the activity still
      further. The three compounds listed were all effective against P388 leukemia in
      mice. Subcutaneous injection of 2 at 2 mg/kg strongly suppressed the growth of
      human MX-1 breast cancer cells in nude mice. 1 has various functional groups that
      increase the cytotoxic potential of quinolone derivatives: a (1R, 2R, 6R)-2-amino
      8-azabicyclo[4.3.0.]non-3-en-8-yl moiety at C-7, a cyclopropyl group at the 1
      position, fluorine atoms at the 6- and 8-positions, and an amino group at the 5
      position of the quinoline carboxylic acid. These data suggest that this series of
      compounds provide good models for the further design of potent antitumor
      quinolones.

PMID- 8663910
TI  - The pharmacokinetics, bioavailability and biodistribution in mice of a rationally
      designed 2-nitroimidazole hypoxia probe SR-4554.
AB  - N-(2-Hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554)
      is a fluorinated 2-nitroimidazole which has been rationally designed as a non
      invasive probe for tumor hypoxia. The key selection criteria for this molecule
      were low central nervous system penetration and toxicity, high metabolic
      stability other than nitroreduction, good tumor uptake and high sensitivity for
      detection by magnetic resonance spectroscopy. As part of the pre-clinical
      development strategy, pharmacokinetic, bioavailability and biodistribution
      studies were performed in mice. Pharmacokinetic studies in mice demonstrated that
      SR-4554 was rapidly absorbed into plasma following i.p. administration and
      eliminated with a half-life of 42 min, similar to other 2-nitroimidazoles. By
      comparing the areas under the concentration-time curve (AUC), the tumor exposure
      towards SR-4554 was on average 84% of the value obtained for the plasma exposure.
      SR-4554 penetrated tumor tissue extremely well but, in contrast to misonidazole
      and certain other fluorinated analogues, its distribution into brain tissue was
      poor (AUCbrain/AUCplasma = 0.07), suggesting potentially lower toxicity in spite
      of its higher lipophilicity (P = 0.43 versus 0.63, respectively). The
      bioavailability of SR-4554 from i.p. and p.o. routes was 100 and 96%
      respectively. In non-tumor-bearing mice, SR-4554 was excreted mainly as unchanged
      drug. The percentage of the injected i.p. dose of SR-4554 excreted unchanged in
      the urine over 24 h was 68 +/- 8%. Neither SR-4554 nor its metabolites were
      detected in mouse feces. We propose that these favorable pharmacokinetic
      properties of SR-4554 are due to the hydrophilic character and hydrogen-bonding
      capability of the amide and hydroxyl functions in the compound.

PMID- 8663911
TI  - Synthesis and antitumor activity of some analogues of flavone acetic acid.
AB  - Some coumarin-, flavonol- and flavanon-acetic acids are described. The
      cytotoxicity of the synthesized compounds was determined on a human colon
      carcinoma cell line (LoVo) through evaluation of neutral red uptake, performed by
      the Riddel method. All tested derivatives were able to induce a statistically
      significant reduction of lysosomal neutral red uptake at 5 x 10(-5) M
      concentration. Some compounds were more active than the reference compound flavon
      8-acetic acid.

PMID- 8663912
TI  - Synthesis and preliminary in vitro screening of lipophilic alpha, gamma
      bis(amides) as potential prodrugs of methotrexate.
AB  - As part of a program aimed at studying the feasibility of amide derivatives of
      methotrexate (MTX) as lipophilic prodrugs, with the aims of increasing passive
      cellular uptake and obtaining prolonged-release agents, we describe the synthesis
      of five long-chain alkyl bis(amides) of MTX, from decyl- to octadecylamide, by
      direct transamidation to the MTX diethyl ester. Compounds were subjected to a
      preliminary biological screening, to assess their inhibitory activity against
      bovine liver dihydrofolate reductase (DHFR) and in vitro antitumor activity
      against human leukemia CCRF-CEM cells. As a general trend, an increase in
      lipophilicity led to a linear reduction of enzyme inhibition; however, the
      bis(decyl)amide derivative showed a good intrinsic affinity for DHFR (IC50 6.41
      nM), comparable to that of MTX diethyl ester and close to that of MTX (IC50 2.90
      nM). In the antitumor assay, lower homologues (C10-C14) displayed an interesting
      activity profile, suggesting the desirability of additional studies with these
      and similar compounds.

PMID- 8663913
TI  - Control of voluntary intake of precision-chopped silages by ruminants: a review.
AB  - The aim of this review is to provide a better understanding of the ways in which
      ruminants control their voluntary intake of finely-chopped silages. Silages with
      an excellent conservation quality can be ingested at similar levels to the
      corresponding fresh or dry forages. Intake levels decrease when conservation
      quality decreases. The implicated physiological mechanisms for this phenomenon
      are discussed in this review. Poorly preserved silages may have low palatibility,
      decreasing the animal's motivation to ingest. At the ruminal level, the physical
      control of intake is generally not involved. On the other hand the fermentation
      products present in silage seem to induce a high and rapid level of satiation,
      out of proportion to their relatively low quantity. At the metabolical level some
      limiting factors may also exist (eg, a poor balance between amino acids and
      energy, and high levels of acids to be metabolized). Fermentation products induce
      most of the observed reactions. For well-preserved silages, high quantities of
      lactic and acetic acids limit intake. Their effects seem to be additive, which
      explains the observation that low pH often has a negative action. The negative
      effect of moisture is generally strengthened by that of the acids. For poorly
      preserved silages, products of protein decomposition must be considered in
      addition to volatile fatty acids. The effect of N-compounds is less clearly
      explained than that of acids. For example, ammonia alone generally seems to have
      no direct effect. However it is clear that N-compounds taken together have a
      negative effect on appetite. It can be concluded that the negative effects of
      poor quality silages are multifactorial; each fermentation product alone has a
      low effect, but the sum of all the components must be considered. Moreover, it is
      apparent that some physiological mechanisms are used to control silage intake,
      which explains the complexity of the studies on this subject.

PMID- 8663914
TI  - Quantitative aspects of blood and amino acid flows in cattle.
AB  - A quantitative literature review was undertaken on the amino acid fluxes in
      ruminants and the factors which influence them. Two aspects were considered:
      blood flow and amino acid uptake by tissues. The statistical relationships
      indicated that blood flow was influenced by feed intake, metabolizable energy and
      milk production. The rates of amino acid uptake and release by tissues and organs
      varied greatly between compartments and between amino acids. The net rates of
      appearance were the result of a combination of inter- and intratissue phenomena.
      Simulated balances between supply and requirements revealed the limiting role of
      certain amino acids, depending on milk production level and growth rate. In
      conclusion, this approach underlined the technical difficulties involved in
      obtaining this type of data, and also revealed a lack of data in certain areas.
      Nevertheless, the observations in this review supported the implementation of the
      feed units used at the present time, notably for the addition of amino acids.

PMID- 8663915
TI  - Subtypes of active cell death in the granulosa of ovarian atretic follicles in
      the quail (Coturnix coturnix japonica).
AB  - Follicular atresia in the ovaries of Japanese quail was studied by cytochemistry
      and electron microscopy. Three different types of cell death coexisted in the
      granulosa. A large number of cells showed signs of apoptosis. The DNA
      fragmentation in these cells was demonstrated in a previous study using in situ
      end-labeling. A second and non-negligible type of cell death consisted of
      extensive autophagocytosis of the cytoplasm occurring simultaneously with late
      nuclear alterations. Finally, a few detached cells displayed cytoplasmic
      disintegration and small irregular clumps of chromatin condensation indicative of
      primary cell necrosis. Apoptotic versus autophagic cell death revealed a
      different pattern of acid phosphatase activity (lysosomal versus cytoplasmic). We
      propose that these observations may be linked to the existence of distinct
      subpopulations in the granulosa as has been shown by others. This study confirms
      the biochemical data on granulosa cell death, but demonstrates that apoptosis is
      not the exclusive mode of active cell death in follicular atresia.

PMID- 8663916
TI  - The response of highly productive rabbits to dietary sulphur amino acid content
      for reproduction and growth.
AB  - This study investigated the sulphur amino acid (SAA) requirements of rabbits.
      Five diets, containing 0.48-0.72% crude SAA, were formulated by supplementing a
      basal diet with DL-methionine. The apparent methionine digestibility (%) was 71.4
      +/- 1.1 in the basal diet and 102.9 +/- 0.9 for DL-methionine, as estimated by
      the difference method. Feeding trials were carried out using 370 rabbit does and
      1 195 weanling rabbits slaughtered at 2-2.1 kg body weight. Milk production was
      measured in 80 lactations. Carcass traits were determined in 125 rabbits. The
      dietary SAA content affected several productive traits, such as milk production,
      parturition interval, growth rate, carcass quality and feed efficiency. When the
      diets were compared using orthogonal contrasts, a minimum requirement of 0.54%
      crude or 0.40% digestible SAA was determined. Further responses in performance
      were observed, however, when the data were analysed by regression methods. The
      values of crude and digestible SAA for optimal production were, respectively,
      0.63 and 0.49% (rabbit does) and, at least, 0.72 and 0.58% (growing rabbits).

PMID- 8663917
TI  - Ultrastructural demonstration of glucose-6-phosphatase activity and glycogen in
      skeletal muscles of newborn piglets with the splayleg syndrome.
AB  - The ultrastructural localization of glucose-6-phosphatase activity and glycogen
      were investigated in the longissimus dorsi and biceps femoris muscles of normal
      and splaylegged newborn piglets. Significant differences were ascertained in the
      distribution of the reaction product of glucose-6-phosphatase activity between
      the two groups of animals. A fine precipitate was found in the sarcoplasmic
      reticulum and in the perinuclear cisternae of normal piglet muscles. In
      splaylegged muscles, variable deposits of coarse reaction product were observed
      within the extremely dilated cisternae of sarcoplasmic reticulum at their
      periphery. Moreover, both longitudinal and transversal ultrathin sections of
      these muscles showed a reduced number of myofibrils and an increased accumulation
      of glycogen (especially within the large extramyofibrillar spaces) in comparison
      with muscles of normal piglets.

PMID- 8663918
TI  - Immunological cross-reaction between sperm dynein heavy chains from different
      species.
AB  - The 19S outer arm dynein of trout sperm flagella is a complex of proteins
      composed of two heavy chains, five intermediate chains and at least six light
      chains. After dialysis against a low ionic strength buffer, its beta subunit was
      purified and used to generate a rabbit polyclonal antibody. This polyclonal
      antibody reacted strongly with the trout beta dynein heavy chain (DHC) but not
      with the trout alpha dynein heavy chain; it also recognised the dynein
      intermediate chains and tubulins. A specific antibody directed against the beta
      DHC was obtained by blot-affinity purification. This specific anti-trout beta DHC
      reacted with the beta DHC from the sea-urchin sperm 21S dynein and also with one
      heavy chain (> 400 kDa) of demembranated ram sperm. This anti-beta DHC antibody,
      and also the whole polyclonal, did not react with heavy chains in trout brain or
      liver extracts, sheep brain extract or purified brain and testicular cytoplasmic
      dyneins. These results suggest that a specific epitope of one of the sperm outer
      arm dynein heavy chains is conserved throughout evolution and that this epitope
      is not present on cytoplasmic dynein.

PMID- 8663920
TI  - [Causes of epidemic neuropathy in Cuba].

PMID- 8663919
TI  - Adenylate cyclase activity increases concomitantly with the onset of capacitation
      in heparin-treated bovine spermatozoa.
AB  - This study examined the effect of metal ions Ca2+, Mg2+, and Mn2+ and sonication
      on ejaculated frozen-thawed bovine sperm adenylate cyclase activity, and whether
      cAMP levels in sperm changed during capacitation with heparin. The sperm
      adenylate cyclase was almost insensitive to Ca2+ at concentrations up to 10 mM
      when cold-shocked homogenized spermatozoa were used. Adenylate cyclase activity,
      as observed by cAMP formation (pmol/mg protein/min), did not increase
      significantly in the presence of 5 mM Mg2+. However, a 40-fold stimulation (cAMP
      400-800 pmol/mg protein/min) occurred in the presence of 5 mM Mn2+. Although Ca2+
      per se had no effect, it acted synergistically with Mg2+ and Mn2+ in stimulating
      sperm adenylate cyclase. Adenylate cyclase activity was highest in cold-shocked,
      homogenized spermatozoa. Sonication of cold-shocked spermatozoa resulted in loss
      of adenylate cyclase activity, and a logarithmic decrease in cAMP production
      (1,155.5 to 109.7 pmol cAMP) occurred when sonication was increased from 2 x 5 to
      2 x 25 s on ice. Cyclic AMP levels in spermatozoa incubated under non
      capacitating conditions, both untreated and treated with glucose or heparin plus
      glucose, remained higher (P < 0.01) compared with those incubated with heparin
      for the first 4 h of incubation. When spermatozoa were incubated under non
      capacitating conditions, cAMP levels increased (P < 0.01), especially during the
      first hour of incubation, and then declined gradually throughout the incubation.
      In contrast, cAMP levels of heparin-treated spermatozoa declined gradually for 3
      h, at which time they began to rise, peaked at 4 h and then remained fairly
      stable until 6 h. Glucose antagonized the effect of heparin on adenylate cyclase
      activity but not for more than 4 h. We conclude that: i) Ca2+ stimulates
      adenylate cyclase in the presence of Mg2+; ii) homogenization by sonication
      reduces cyclase activity in frozen-thawed, cold-shocked spermatozoa; iii)
      adenylate cyclase activity is inhibited by heparin but rises concomitantly with
      the onset of capacitation (after 4 h) in spermatozoa incubated under capacitating
      conditions; and iv) glucose, which prevents capacitation by heparin, antagonizes
      heparin action on adenylate cyclase.

PMID- 8663921
TI  - Unless an operation is necessary.

PMID- 8663922
TI  - Upper limb nerve entrapments in elite wheelchair racers.
AB  - The prevalence of upper limb nerve injuries has been reported to be as high as
      73% in individuals who rely on manual wheelchairs for mobility. Many authors
      hypothesize that the repetitive trauma to carpal canal structures caused by
      propelling a wheelchair is the reason for this high prevalence. The purpose of
      this study was to determine the prevalence of nerve conduction abnormalities in a
      group of elite wheelchair racers whose wrists are exposed to additional
      propulsion-related trauma during training and competition. We performed bilateral
      upper limb nerve conduction studies on each athlete (n = 12). The racers pushed
      their chairs an average of 56 miles a week for training purposes. Fifty percent
      of the athletes (n = 6) had evidence of median mononeuropathy by nerve
      conduction. Of these 6 racers, 5 had evidence of mononeuropathy bilaterally,
      making a total of 11 positive hands of the 23 tested. Twenty-five percent of the
      athletes had evidence of ulnar mononeuropathy at the wrist, and 25% had evidence
      of ulnar mononeuropathy at the elbow. Seventeen percent of athletes had evidence
      of radial nerve injury. Years with a disability accounted for a significant
      amount of the variance in the mean median sensory amplitude (R2 = 0.511; P =
      0.020) and the mean ulnar palmar amplitude (R2 = 0.605; P = 0.008). Variables not
      correlated with nerve conduction studies include age, hours per day in a
      wheelchair not spent training, years competing, and number of miles pushed in
      training. Despite the amount of time spent training these wheelchair athletes
      have a similar or lower prevalence of median mononeuropathy then reported in the
      general wheelchair-using population.

PMID- 8663923
TI  - Functional outcome of hemorrhagic and nonhemorrhagic stroke patients after in
      patient rehabilitation.
AB  - Differences in functional prognosis for patients with hemorrhagic and
      nonhemorrhagic strokes are unclear. The purpose of this study is to compare the
      functional outcome of hemorrhagic and nonhemorrhagic stroke patients after
      inpatient stroke rehabilitation. By retrospective review, 25 hemorrhagic stroke
      patients were matched with 25 nonhemorrhagic stroke patients on the basis of age
      and onset to admission interval. Discharge Functional Independence Measure (FIM),
      FIM gain, FIM efficiency, length of stay (LOS), and discharge disposition were
      compared. Admission FIM, gender, and comorbidities were similar between the two
      groups. There were no differences in discharge FIM, FIM gain, and discharge to
      home rates between groups. However, the hemorrhagic group had a significantly
      shorter LOS (31.7 v 37.6 days; P = 0.05) with higher FIM-total efficiency (0.84 v
      0.60; P = 0.02). The FIM-motor scale accounted for most of the gains in
      efficiency (0.71 v 0.53; P = 0.05) with no significant difference in FIM
      cognition efficiency between groups. Post hoc analysis revealed that onset to
      admission interval was a strong predictor of LOS (r = 0.62; P < 0.0001).
      Hemorrhagic stroke patients appear to exhibit functional gains somewhat faster
      than nonhemorrhagic counterparts. Confirmation of these preliminary findings must
      await future studies.

PMID- 8663924
TI  - Physical disability among American medical students.
AB  - The present survey aimed to assess the prevalence and nature of physical
      disabilities among medical school graduates and to investigate the academic
      performance of these new physicians with disabilities. A questionnaire was sent
      to the deans of student affairs of each of the then existing 128 United States
      and Puerto Rican medical schools, addressing the profiles of students with
      physical disabilities in the 1987 through 1990 graduating classes. Seventy-seven
      (60%) United States and Puerto Rican medical schools responded to the
      questionnaire, of which 67 were able to complete it. A total of 67 students with
      physical disabilities (40 males and 27 females) were reported. Three of the 67
      students were excluded from the study because their conditions did not match our
      definition of physical disability. The remaining 64 students (38 males and 26
      females), ranging from 0 to 10 per school, comprised 0.19% of the 33,138 students
      who graduated from the 67 medical schools during these 4 academic yr. The
      disabilities represented by the 64 students encompassed a wide spectrum of
      etiologies, including neurologic (39%), musculoskeletal (20%), medical-surgical
      (13%), visual (13%), and auditory (9%) problems. The majority of students with
      disabilities had above average (36%) to average (48%) academic standings. The
      actual prevalence of medical students with disabilities might be higher than
      reported because of the underreporting of the less noticeable types of
      disabilities.

PMID- 8663925
TI  - Three-dimensional vector graphing of the H reflex.
AB  - Comparison of latencies of the H reflex from side-to-side is considered a valid
      indicator of pathology, but amplitudes are too variable to allow similar
      comparison. Three pairs of electrodes were placed circumferentially and
      longitudinally along the calf to record the H reflex in three axes
      simultaneously. An H reflex with the greatest amplitude was produced by
      incrementally increasing submaximal stimulation to the tibial nerve. Three
      dimensional vector graphs were constructed at three levels in each calf in ten
      normal individuals. Best fit curve Procrustes statistical analysis showed an
      average of 82.2 to 90.6% agreement of 3-D shape left-to-right with greater
      agreement at distal levels. Standard deviation ranged from 11.3% proximally to
      8.2% distally. This represents much closer agreement than established norms for
      amplitude, which can vary from two to four times side-to-side. Three-dimensional
      vector analysis holds promise to further understanding of peripheral and central
      electrophysiologic phenomena.

PMID- 8663926
TI  - Effect of lumbar orthotics on trunk muscle strength.
AB  - Weakening of the trunk muscles is thought to be one disadvantage of prolonged
      lumbar orthotic use. This study examines weakness of the trunk flexor and
      extensor muscles in patients who are wearing lumbar orthotics for extended
      periods. Strength of the trunk flexor and trunk extensor muscles was tested in 24
      individuals, using the Kinetic computer. Both concentric and eccentric forces
      were recorded. Four groups of patients were studied. Group 1 (n = 6) consisted of
      patients with low back pain who had used a lumbar orthotic for a prolonged period
      of time. Group 2 (n = 6) consisted of hospital employees with no history of low
      back pain, who wore lumbar orthotics prophylactically, for back protection. Group
      1C (n = 6) consisted of healthy controls, with no history of either back pain or
      lumbar orthotic use, who were individually age- and gender-matched to each
      patient in Group 1. Group 2C (n = 6) consisted of healthy controls matched in the
      same fashion to each patient in Group 2. After consultation with a statistician,
      statistical analysis was performed using the Wilcoxon's test. Nonparametric
      statistics were chosen because of the lack of evidence of a normal distribution
      of the parameters being studied. This analysis revealed significant weakness in
      concentric flexion (P = 0.0464), concentric extension (P = 0.0277), and eccentric
      extension (P = 0.0464) in Group 1 compared with matched controls in Group 1C. The
      only significant weakness compared with controls in Group 2 was in eccentric
      flexion (P = 0.0277). Trends were toward weakness in the orthotic users for the
      other motions studied, with a P value of less than 0.1 for eccentric extension.
      Prolonged use of lumbar orthotics may be associated with trunk muscle weakness in
      the population studied. Prescribers should continue to limit duration of use when
      possible and to consider strengthening exercises when prolonged use is
      anticipated.

PMID- 8663927
TI  - Clinical experience with a new hip-knee-ankle-foot orthotic system using a medial
      single hip joint for paraplegic standing and walking.
AB  - The Walkabout is a new hip-knee-ankle-foot orthotic (HKAFO) system with a medial
      single hip joint (MSH-KAFO) invented by S. McKay in 1992. Compared with other
      HKAFO systems, the hip joint part is compact and removable, so it has
      distinguishable, real merits: ease in donning and doffing the device,
      compatibility with a wheelchair, and cosmesis. We clinically tested five
      patients, paraplegic because of spinal cord injury, using the MSH-KAFO system.
      All were males, aged 26-36 yr old. Their functional levels were L-1 (2 cases), T
      10 (2 cases), and T-5 (1 case). All patients could stand stably without crutches
      and walk in parallel bars immediately the first time they wore the braces. After
      a few hours of crutch-walking exercises, all could walk independently with
      Lofstrand crutches. Their walking velocities ranged from 10 to 37.5 (mean, 19.9)
      m/min at the follow-up points (mean, 7.1 mo). With four cases, we measured oxygen
      uptake for predictions of energy consumption. At comfortable walking, predicted
      energy consumptions were from 1.31 to 3.89 (mean, 2.75) METs. Compared with the
      data in literature, these seemed to be at the same level with normal walking and
      lower than the KAFOs walking level. Our results suggest that MSH-KAFO is a very
      convenient standing and walking device for paraplegics and is compatible with
      wheelchair use.

PMID- 8663928
TI  - Bladder neck dysynergia in spinal cord injury.
AB  - Urodynamic evaluations were performed in 43 male patients with spinal cord
      injuries, before any therapeutic decisions, and a minimum of 5 mo following the
      injury. Results were subdivided according to level of injury. Mean detrusor
      contraction pressures, incidence of detrusor-sphincter dysynergia (DSD), and
      incidence of detrusor-bladder neck dysynergia (DBND) were calculated. The
      incidence pattern of DBND was found to follow closely the incidence pattern of
      DSD, with the highest incidence among the upper thoracic injuries, considerably
      more than among the cervical injuries. A significantly higher resting detrusor
      pressure differential was found among the patients with DBND. This was felt to
      represent sympathetic dysfunction and poor accommodation and is proposed to be
      secondary to adrenergic detrusor neoinnervation.

PMID- 8663929
TI  - Telephone and in-person proxy agreement between stroke patients and caregivers
      for the functional independence measure.
AB  - This study examined patient/proxy agreement for telephone administration of the
      Functional Independence Measure (FIM) to a sample of 25 community-living stroke
      patients 18 mo post-stroke and their caregivers. Patients had all received in
      patient rehabilitation for stroke. Because use of the FIM is increasing for
      follow-up purposes, it is important to document whether it is appropriate to
      administer a telephone version to proxy caregivers in situations in which
      patients cannot answer for themselves. Proxy agreement results were then compared
      with those obtained for in-person administration of the FIM to the same sample 1
      yr earlier. Overall, proxy agreement for telephone administration was excellent
      for total scores (intraclass correlation was 0.91) and the physical dimension
      (0.94) and lower for the cognitive dimension (0.52), closely paralleling results
      obtained for the earlier in-person administration. Reasons for lower agreement on
      the cognitive dimension are discussed.

PMID- 8663930
TI  - Long-term follow-up of outpatient interdisciplinary pain management with a no
      treatment comparison group.
AB  - The long-term psychosocial and physical functioning impact of an outpatient
      interdisciplinary pain management program was evaluated by comparison of pain
      management completors and a no-treatment group. Although pain intensity did not
      change and there were no significant differences between groups in several
      aspects of daily activity, the group that completed the program reported a
      greater sense of control over pain, had a more hopeful outlook on the future,
      perceived pain as interfering less with their life, and used strategies that are
      considered adaptive for long-term management of pain. The results suggest that
      patients with chronic, complex pain problems can improve perceptions regarding
      pain control and reduce the interference of pain in their lives. Outlook
      regarding the future was identified as a critical assessment and treatment
      variable. Individuals who were more optimistic about the future perceived a
      greater control over pain and endorsed coping strategies that involve diverting
      attention, ignoring pain sensations, and making coping self-statements. Although
      pain intensity rating did not differ, individuals who had a more pessimistic
      outlook on life considered pain to interfere with their work activity, mood,
      relations with other people, and overall enjoyment of life to a greater extent
      than individuals who were more optimistic.

PMID- 8663932
TI  - "Guided" intramuscular fine wire electrode placement. A new technique.
AB  - This report describes a new technique for placing intramuscular fine wire
      electrodes into muscles for kinesiologic electromyographic (EMG) studies.
      Currently, a pair of fine wire electrodes (one active, one reference) within a
      hypodermic needle is inserted into the selected muscle. The needle is then
      withdrawn, leaving the two fine wires positioned within the muscle. Electrical
      stimulation of the muscle through these fine wire electrodes confirms their
      correct placement. However, if positioning is incorrect, additional pairs of
      wires are inserted within needles until correct placement is achieved. Our
      "guided" method combines this "blind" technique with diagnostic needle EMG
      techniques. Using a conventional EMG machine and selective activation of the
      desired muscle, the electromyographer inserts the hypodermic needle while
      monitoring the muscle's electrical signal through the advancing fine wire
      electrodes. This signal is used to "guide" the needle into the proper muscle.
      Once correct positioning of the wires is confirmed by the EMG signal, the needle
      is removed. With this techniques additional needle insertions are avoided,
      electrical stimulation is seldom needed, and rarely studied muscles are accessed
      as easily as commonly studied ones. We have used this technique with pediatric
      and adult patients as well as in kinesiologic EMG research and have found it to
      be well tolerated and reliable.

PMID- 8663931
TI  - Bilateral musculocutaneous nerve palsy. A case report.
AB  - A case of bilateral, isolated, proximal musculocutaneous nerve palsy is reported.
      Initial physical and electromyographic examinations demonstrated complete
      denervation of the biceps brachii, brachialis, and coracobrachialis muscles
      bilaterally. Nerve conduction studies of the musculocutaneous nerves initially
      revealed no evoked potentials. The patient underwent resection with end-to-end
      anastomosis on the left and neurolysis without resection on the right.
      Significant functional recovery was noted bilaterally but was more rapid and
      complete on the side that underwent neurolysis without resection.

PMID- 8663933
TI  - Personal factors and blood volume movement in causation of median neuropathy at
      the carpal tunnel. A commentary.

PMID- 8663934
TI  - The historical role of the physiatrist in the management of Duchenne muscular
      dystrophy. A commentary.

PMID- 8663935
TI  - Integration of physical medicine and rehabilitation into the undergraduate
      medical curriculum. The Undergraduate Education Committee of the Association of
      Academic Physiatrists Workgroup.
AB  - The incorporation of PM&R into the medical student curriculum thus provides
      benefits at multiple levels: to patients, to medical students, and to
      practitioners already in the field. The knowledge about PM&R gained by the
      medical student is spread to disciplines outside of PM&R through the learning of
      principles and specific factual data that can be applicable for practitioners
      caring for a variety of patients. It is the position of this organization that
      each academic department work to integrate education in PM&R into the medical
      school curriculum.

PMID- 8663936
TI  - Factors influencing the specialty choice of the PM&R graduating class of 1994 and
      the entering class of 1995.

PMID- 8663937
TI  - Cell culture engineering.

PMID- 8663938
TI  - Identifying microbial diversity in the natural environment: a molecular
      phylogenetic approach.
AB  - Our knowledge of microbial biodiversity has been severely limited by relying on
      microorganisms that have been cultured; these represent only a tiny fraction of
      the microbial diversity in the environment. Recently, however, recombinant DNA
      and molecular phylogenetic techniques have provided methods for characterizing
      natural microbial communities without the need to cultivate organisms. These
      techniques have allowed a glimpse of the complexity of microbial communities and
      the huge, largely untapped, biotechnological resource that they represent.

PMID- 8663939
TI  - Manipulating metabolic partitioning in transgenic plants.
AB  - Various strategies can be used to influence the partitioning of metabolites, both
      between competing pathways and within a given biochemical pathway. Changes in
      metabolic partitioning in transgenic plants can be brought about by either
      expressing heterologous genes or suppressing endogenous ones. Strategies for
      altering metabolic partitioning can include accelerating, circumventing or
      inhibiting enzymatic, regulatory or transport steps. In addition, metabolic
      pathways can be modified, through the use of collections of novel enzymes, to
      synthesize novel products.

PMID- 8663940
TI  - Preoperative vascular imaging for the fibular osteocutaneous flap.
AB  - The fibular osteocutaneous free flap has become a well-accepted method of
      mandibular reconstruction. Aberrations in the blood supply to the foot affect 5%
      to 7% of the population, and substantial atherosclerotic disease of the lower
      extremities is often found in elderly individuals, many of whom have been
      smokers. Therefore, the use of preoperative vascular imaging is justified in all
      patients scheduled for fibular osteocutaneous free-flap harvest. In a series of
      25 consecutive patients clinically judged to be satisfactory candidates for
      fibular free-flap reconstruction, preoperative arteriograms excluded 4 patients
      from use of this donor site and determined which leg was used in 2 other
      patients.

PMID- 8663941
TI  - Balancing pediatric otolaryngology training for fellows and residents at a
      children's hospital.
AB  - OBJECTIVE: To determine the feasibility of providing surgical, endoscopic, and
      patient contact experience of high educational value at a children's hospital
      sufficient for adequately training contemporaneously both residents in
      otolaryngology-head and neck surgery and fellows in pediatric otolaryngology.
      DESIGN: Retrospective review of operating room case logs and assignment of cases
      based on arbitrary perception of inherent case complexity and skill and
      experience that are required to manage the case. SETTING: Tertiary care
      children's hospital located in a major metropolitan area. MAIN OUTCOME MEASURES:
      (1) Volume of surgical and endoscopic cases assigned retrospectively to junior
      resident, senior resident, or fellow. (2) Score on newly developed self
      assessment skill list in pediatric otolaryngology. RESULTS: During 1 year, there
      were 3224 surgical and endoscopic procedures performed in the operating room. Of
      the total number of procedures, only 44 (1.4%) were designated as being
      exclusively assigned for hands-on experience to a fellow, but 380 (11.8%) were
      appropriate for both a senior resident and a fellow and therefore were
      apportioned in an alternating fashion. A self-assessment instrument has been
      developed to assess competency and comfort in the management of otolaryngic
      disorders, both surgical and nonsurgical, in children. CONCLUSIONS: The volume
      and assortment of surgical and endoscopy cases at a tertiary care children's
      hospital can provide the basis for a rich, practical hands-on experience for
      residents and fellows. Since few surgical or endoscopic cases require pediatric
      fellowship training for mastery, becoming a pediatric otolaryngologist depends on
      acquiring skills and competence that exceed the technical skills acquired in the
      operating room.

PMID- 8663942
TI  - Polysomnography in the evaluation of readiness for decannulation in children.
AB  - OBJECTIVE: To determine whether polysomnography is useful in the evaluation of
      readiness for decannulation in children with long-term tracheotomy. DESIGN:
      Descriptive, retrospective case series. SETTING: Tertiary care pediatric center,
      pediatric sleep disorders laboratory, and pediatric otolaryngology referral
      center. PATIENTS: Children (younger than 18 years) with tracheotomy undergoing
      polysomnography to assess their dependence on tracheotomy. INTERVENTION:
      Polysomnography in all patients; endoscopy and decannulation in those judged
      clinically ready. MAIN OUTCOME MEASURES: Success of decannulation. RESULTS:
      Thirteen of 16 patients with favorable polysomnographic data were successfully
      decannulated. CONCLUSION: Polysomnography is a useful supplement to airway
      endoscopy in the evaluation of readiness for decannulation in children with long
      term tracheotomy and dynamic airway issues.

PMID- 8663943
TI  - Odontogenic keratocysts in the pediatric population.
AB  - OBJECTIVE: To review the characteristics and treatment of odontogenic keratocysts
      in the pediatric population at our institution in light of a comprehensive
      literature review of odontogenic keratocysts in the general population in the
      hope of elucidating clinical, radiological, or pathological factors that would
      suggest a different therapeutic approach to odontogenic keratocysts in the
      pediatric as opposed to the adult population. DESIGN: A 19-year retrospective
      medical chart review of children with mandibular or maxillary masses of
      odontogenic keratocyst origin. SETTING: Two academic tertiary care institutions.
      PATIENTS: Eleven children had pathologically confirmed odontogenic keratocysts.
      Age at diagnosis ranged from 8 to 18 years (mean, 13.4 years). RESULTS: A cystic
      mass with dentition displacement was characteristic clinically and
      radiographically. Treatment principally consisted of enucleation with or without
      extraction of teeth. Follow-up ranged from 1 to 8 years. Seven patients remained
      free of disease. Recurrences or second primary lesions occurred in 4 patients,
      all of whom had a family history of nevoid basal cell carcinoma syndrome or
      multiple cysts suggestive of this diagnosis. The maximum 8-year interval between
      initial treatment and recurrence is noteworthy. CONCLUSIONS: The diagnosis of
      odontogenic keratocyst deserves consideration in children who have a mass of the
      mandible or maxilla. The clinical behavior of this lesion in its initial
      occurrence and response to conservative treatment seems to be similar to that
      reported in adults. Odontogenic keratocysts, especially those that are multiple
      or recurrent, should alert the clinician to the possible underlying diagnosis of
      nevoid basal cell carcinoma syndrome.

PMID- 8663944
TI  - Fluticasone propionate is associated with severe infection after endoscopic
      polypectomy.
AB  - OBJECTIVE: To test whether the use of fluticasone dipropionate nasal spray after
      endoscopic ethmoidectomy for multiple polyps is associated with a high incidence
      of infection. DESIGN. Randomized control study comparing the incidence of
      infection with the use of beclomethasone dipropionate or fluticasone propionate
      nasal spray after functional endoscopic sphenoethmoidectomy. Patients were
      followed up for 6 to 12 months. PATIENTS AND METHODS: Sixty patients with
      recurrent bilateral nasal polyps underwent functional endoscopic
      sphenoethmoidectomy and were then randomly allocated into 2 groups of 30 patients
      each. One group received beclomethasone dipropionate spray (100 micrograms in
      each nostril every 12 hours), and the other group received fluticasone propionate
      spray (100 micrograms/d in each nostril). RESULTS: In the fluticasone propionate
      group, 6 patients (20%) developed acute gram-positive pansinusitis requiring
      hospitalization and discontinuation of treatment. CONCLUSION: The use of
      fluticasone dipropionate aqueous nasal spray for the postoperative control of
      recurrent nasal polyps seems to be associated with a high incidence of acute
      pansinusitis.

PMID- 8663945
TI  - Management of dural lesions occurring during endonasal sinus surgery.
AB  - BACKGROUND: Dural lesions incurred during endonasal sinus surgery must be
      repaired surgically because of the risk of potentially fatal late meningitis.
      DESIGN: Retrospective survey. SETTING: Ear, nose, and throat department of a
      university teaching hospital. PATIENTS: Consecutive sample of 47 patients who had
      undergone duraplasty for repair of a dural lesion that occurred as a complication
      of endonasal sinus surgery. Forty-two patients were interviewed after an average
      postoperative period of more than 5 years. INTERVENTION: Endonasal duraplasty,
      external duraplasty (fronto-orbital or transfrontal extradural approach) by
      underlay or onlay technique. MAIN OUTCOME MEASURES: Fluorescein test (intrathecal
      administration of fluorescein sodium and subsequent nasal endoscopy), subjective
      complaints, history of meningitis, cerebrospinal fluid rhinorrhea, or hyposmia.
      RESULTS: There were 44 endonasal and 3 external duraplasties (2 by the fronto
      orbital and 1 by the transfrontal extradural approach); the underlay technique
      was used in 25 and the onlay technique in 22. The fluorescein test, performed in
      43% (20/47) of the patients was negative in all cases. Twenty-six percent of the
      patients had had 1 or more episodes of bacterial sinusitis without meningitis.
      Duraplasty was clinically intact in 100%. Postoperative olfactory disturbances
      were reported in 17%. CONCLUSIONS: Duraplasty can be performed satisfactorily by
      the endonasal route, thus avoiding the disadvantages of the fronto-orbital
      approach (visible scar, risk of damage to the supraorbital nerve, and removal of
      bone from the floor of the frontal sinus with a tendency to stenosis of the
      nasofrontal duct and subsequent mucocele). Allogeneic connective tissue in
      combination with fibrin glue has proved suitable as a graft material.

PMID- 8663946
TI  - Endoscopic vs external drainage of orbital subperiosteal abscess.
AB  - Periorbital cellulitis is frequently limited to the preseptal region. However,
      there may be associated postseptal inflammation and orbital subperiosteal abscess
      (SPA). Surgical management of orbital SPA includes open drainage through an
      external ethmoidectomy approach, although recently the use of endoscopic
      techniques has been reported. This study was undertaken to evaluate postseptal
      cellulitis and orbital SPA in patients with periorbital cellulitis and to assess
      the safety and effectiveness of endoscopic management of orbital SPA. From 1989
      through 1994, 158 patients were admitted with a diagnosis of periorbital
      cellulitis. Nineteen of these patients were diagnosed with postseptal orbital
      inflammation, and 14 underwent surgical drainage via an external approach, an
      endoscopic approach, or a combination of both. Issues addressed include (1) the
      role of sinus disease as the cause of periorbital cellulitis; (2) the role of
      computed tomographic scanning; (3) the effectiveness of aggressive medical
      therapy; and (4) the results of endoscopic drainage of orbital SPA compared with
      the external approach.

PMID- 8663947
TI  - Critical appraisal of watchful waiting policy in the management of N0 neck of
      advanced laryngeal carcinoma.
AB  - OBJECTIVE: To analyze the problem of nodal recurrence of N0 neck advanced
      laryngeal carcinoma. DESIGN: Retrospective analysis. SETTING: Hospital referral
      center. PATIENTS: One hundred thirty-three patients with cancer stages T3-T4, N0,
      M0 who had total laryngectomy between January 1981 and December 1990. MAIN
      OUTCOME MEASURE: Nodal recurrence. RESULTS: Of the 11 patients who had elective
      radical neck dissections, there was no nodal recurrence. Of the other 122
      patients who had no elective neck dissection, 19 patients (16%) developed nodal
      recurrence and all nodal recurrence was at levels II, III, and IV. Twelve
      patients (63%) underwent salvage radical neck dissection for nodal recurrence and
      they had a 38% adjusted 5-year actuarial survival rate. Of these 122 patients who
      had no elective neck dissection for the N0 neck, 12 patients (10%) eventually
      died of nodal recurrence. CONCLUSIONS: The watchful waiting policy is a
      satisfactory management option of N0 neck of advanced laryngeal carcinoma.

PMID- 8663948
TI  - HSV-tk gene therapy in head and neck squamous cell carcinoma. Enhancement by the
      local and distant bystander effect.
AB  - OBJECTIVES: To determine whether the bystander effect demonstrated in vitro for
      ganciclovir-mediated killing of a herpes simplex virus thymidine kinase (HSV-tk)
      gene-infected human squamous cell carcinoma is operative in vivo in a nude mouse
      model. DESIGN: Prospective study in a murine model. INTERVENTION: Human head and
      neck squamous cell carcinoma tumors were grown as xenografts on the flanks of 20
      nude mice. The tumors in the left flank were then infected with the HSV-tk gene.
      Then, after 48 hours, the animals were treated with intraperitoneal ganciclovir
      twice daily. Assessment of the tumors on both flanks was performed over a 31-day
      period. MAIN OUTCOME MEASURES: Resolution of tumors infected with HSV-tk gene in
      animals treated with ganciclovir; resolution of tumors uninfected with HSV-tk
      gene on the contralateral flank in animals treated with ganciclovir. RESULTS:
      Following HSV-tk gene therapy in nude mice, complete resolution of HSV-tk-gene
      infected human head and neck squamous cell carcinoma tumors was observed
      following ganciclovir treatment. Uninfected tumors were also noted to regress,
      but not completely resolve, in response to intraperitoneal ganciclovir (distant
      bystander effect). CONCLUSIONS: This study confirms that the local and distant
      bystander effects exist in this murine model, enhancing the possibility of its
      role for treatment of human squamous cell carcinoma of the head and neck.

PMID- 8663949
TI  - Interleukin-1 receptor antagonist in head and neck squamous cell carcinoma.
AB  - BACKGROUND: We hypothesized that in head and neck squamous cell carcinoma, the
      overexpression of protumorigenic interleukin-1 (IL-1) activity within the tumor
      tissue is a result of decreased expression of the specific antagonist or
      inhibitor (ie, IL-1 receptor antagonist) by the tumor cells. Ultimately, this
      local overexpression of IL-1 activity increases tumor growth and metastasis.
      DESIGN: To test our hypotheses, immunologic analysis for IL-1 alpha, IL-1 beta,
      and IL-1 receptor antagonist was performed on histologic sections and tumor
      homogenates of human head and neck squamous cell carcinomas. SETTING: University
      teaching hospital. PATIENTS OR OTHER PARTICIPANTS: Normal and tumor specimens
      were obtained from patients undergoing surgical resections of the head and neck
      for benign and malignant disease. RESULTS: Immunohistochemical analysis
      demonstrated the presence of IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist
      within tumor cells and inflammatory cells in the tumor stroma in 19 of 19 tumor
      specimens. Quantitatively, IL-1 alpha was present in 19 of 19 tumor specimens
      (1.97 +/- 0.46 ng/mg of total protein [mean +/- SD]) and 5 of 9 normal specimens
      (0.23 +/- 0.12 ng/mg of total protein). All specimens contained IL-1 beta in
      detectable quantities (1.60 +/- 0.29 ng/mg of total protein in tumor specimens
      and 0.189 +/- 0.04 ng/mg of total protein in normal specimens). All specimens
      contained IL-1 receptor antagonist (368.87 +/- 57.63 ng/mg of total protein in
      tumor specimens and 585.10 +/- 166.03 ng/mg of total protein in normal
      specimens). The mean total IL-1/IL-1 receptor antagonist ratio was 13.26 +/- 2.31
      in patients with cancer compared with 0.997 +/- 0.26 in normal patients.
      CONCLUSIONS: The increased IL-1 index in the cancer state compared with the
      normal state reflects an imbalance of IL-1 and IL-1 receptor antagonist, which
      may contribute to unrestricted growth and metastasis of head and neck squamous
      cell carcinoma.

PMID- 8663950
TI  - Using botulinum toxin A to improve speech and swallowing function following total
      laryngectomy.
AB  - OBJECTIVE: To evaluate a technique to reduce dysfunctional spasm in the
      pharyngoesophageal segment (PES) in patients after laryngectomy. DESIGN:
      Pharyngoesophageal segment function related to voice and/or swallowing in
      patients who had undergone a laryngectomy was evaluated before and after the
      injection of botulinum toxin A. SETTING: Academic referral medical center.
      PATIENTS: Eight outpatients with voice and/or swallowing complaints after
      undergoing a total laryngectomy. INTERVENTIONS: Videofluoroscopic contrast
      examination was completed to identify stricture vs spasm in the PES in patients
      with voice and/or swallowing complaints after undergoing a laryngectomy.
      Lidocaine hydrochloride injection under fluoroscopic guidance was completed to
      facilitate immediate relaxation of spasm. After positive results with lidocaine,
      botulinum toxin was injected into the same area to facilitate longer-lasting
      benefit. MAIN OUTCOME MEASURE: Patient report of benefit and videofluoroscopic
      evaluation of PES function. RESULTS: Six of 8 patients demonstrated improved
      function within the PES after lidocaine injection. Five of these 6 received
      transcutaneous injection of botulinum toxin. Four of the 5 patients demonstrated
      improved swallowing and/or voice function, and 3 of these 4 received subsequent
      injections of botulinum. No serious complications were encountered. CONCLUSIONS:
      Transcutaneous injection of botulinum toxin in the PES under videofluoroscopic
      guidance provides improvement in voice and/or swallowing function without
      significant complications. Additional clinical study will be required to evaluate
      dose and technique influences on degree and duration of benefit and
      complications.

PMID- 8663951
TI  - Cisplatin-based neoadjuvant chemotherapy and combined resection for ethmoid sinus
      adenocarcinoma reaching and/or invading the skull base.
AB  - OBJECTIVE: To review our experience with cisplatin-based neoadjuvant chemotherapy
      before en bloc resection via a combined neurosurgical and transfacial approach
      for ethmoid sinus adenocarcinoma reaching and/or invading the skull base. DESIGN:
      Case series. SETTING: A tertiary care center and university teaching hospital.
      PATIENTS: Twenty-two patients with primary untreated ethmoid sinus adenocarcinoma
      reaching and/or invading the skull base consecutively treated between 1984 and
      1992 with cisplatin-based neoadjuvant chemotherapy and combined neurosurgical and
      transfacial approach. MAIN OUTCOME MEASURES: Statistical analysis of survival,
      local control, nodal recurrence, distant metastasis, and metachronous second
      primary tumor incidence based on the Kaplan-Meier actuarial method. Univariate
      analysis was performed to analyze the relationships between various factors,
      survival, and local recurrence. Clinical response, histological response, toxic
      effects of chemotherapy, and postoperative course were also reported. RESULTS:
      The Kaplan-Meier 3-year survival, local control, nodal recurrence, and distant
      metastasis estimates were 68.1%, 65.7%, 5.3%, and 10%, respectively. Metachronous
      second primary tumor was not encountered in our series. Survival was
      statistically more likely to be reduced in patients with intrasphenoidal tumor
      extent (P = .04) and local recurrence (P = .01). Local recurrence was
      statistically more likely in patients with intrasphenoidal tumor extent (P =
      .002) and no response to cisplatin-based neoadjuvant chemotherapy (P = .03).
      CONCLUSIONS: The results achieved suggest that cisplatin-based neoadjuvant
      chemotherapy before combined neurosurgical and transfacial approach should be
      further investigated for the treatment of ethmoid sinus adenocarcinoma reaching
      and/or invading the skull base.

PMID- 8663953
TI  - Otoplasty. Clinical protocol and long-term results.
AB  - OBJECTIVE: To evaluate the long-term results after otoplasty on prominent ears.
      DESIGN: Between 1988 and 1993, ear protrusion was measured preoperatively and
      postoperatively in pediatric patients undergoing otoplasty by means of a standard
      protocol based on the Frankfort horizontal line. Patients were asked to return
      for follow-up measurements a minimum of 1 year after surgery. At the time of
      follow-up, a patient satisfaction survey was completed by the patients and their
      families. SETTING: The Hospital for Sick Children, Toronto, Ontario, a tertiary
      care children's hospital. PARTICIPANTS: Thirty-one of 51 patients returned for
      follow-up an average of 3.7 years after surgery. RESULTS: One third of ears
      returned to their original position, one third of ears stayed in a position equal
      to the immediate postoperative position, and one third of ears had final
      positions between the preoperative and post-operative positions. At the superior
      rim, an average of 58% of the operative medialization was lost. Good to excellent
      ear-to-ear symmetry was obtained in 78% of patients who returned for follow-up.
      Retrospective chart review showed a revision surgery rate of 3%; stitch
      granulomas were removed in 9% of patients. The patient satisfaction survey found
      that 85% of patients were happy or very happy with their ears. CONCLUSIONS: With
      time, a substantial loss of correction can be expected in most (but not all)
      patients who undergo otoplasty, particularly at the upper pole. Overall, patients
      and their families are happy with the results of otoplasty surgery.

PMID- 8663952
TI  - Detection of p53 protein in oropharyngeal carcinoma. Prognostic implications.
AB  - OBJECTIVE: To demonstrate how the detection of p53 protein in formaldehyde-fixed,
      paraffin-embedded oropharyngeal carcinoma may be used as a factor in estimating
      prognosis. SETTING: University medical centers. DESIGN: Validation cohort.
      Formaldehyde-fixed, paraffin-embedded squamous cell carcinoma of the oropharynx
      tissues from 106 patients who underwent surgical therapy between 1975 and 1988
      were immunostained by using M-7001 antibody (IgG class). RESULTS: Overexpression
      of p53 was observed in 46 tumors (43.4%). The detection of nuclear p53 was
      significantly associated with an increased risk of recurrence of oropharyngeal
      carcinoma (P = .05). Similar results were obtained when the presence or absence
      of p53 in the nuclei of the tumor cells was studied in relation to overall
      survival (P < .001). In a multivariate analysis stratified according to grade,
      pathological stage, and lymph node status, nuclear p53 status was an independent
      predictor of overall survival (P < .001). CONCLUSIONS: In patients with squamous
      cell carcinoma of the oropharynx, an accumulation of p53 in the tumor cell nuclei
      detected by immunohistochemical methods predicts a significantly increased risk
      of death, independent of tumor grade, stage, and lymph node status. The p53
      overexpression appears to be a useful prognostic factor.

PMID- 8663954
TI  - Alar reductions in rhinoplasty.
AB  - OBJECTIVE: To ascertain if avoiding the vestibular portion of alar reductions
      during rhinoplasty could improve the cosmetic result of the postoperative nasal
      sill. DESIGN: Blind, randomized review of base-view photographs (40 patients) 1
      year after rhinoplasty. SETTING: A surgical clinic, accredited by the
      Accreditation Association of Ambulatory Health Care. PARTICIPANTS: A consecutive
      sample of 40 patients (2 groups) who underwent alar reduction as a part of their
      rhinoplasty and whose 1-year postoperative photographs were reviewed by 2 facial
      plastic surgeons and 3 plastic surgeons. MAIN OUTCOME MEASURES: Midway through a
      2-year period, the method of alar reduction was changed to include only the
      cutaneous portion of the nostril. Twenty-two patients had cutaneous-vestibular
      excisions; 18 patients had cutaneous-only excisions. The surgeon participants
      reviewed randomized photographs taken 1 year postoperatively and were asked to
      rate the alar sill for the degree of scarring and notching. RESULTS: Tabulation
      of the surgeons' ratings revealed significantly less perception of notching and
      scarring in the alar reduction group with the cutaneous-only excisions.
      CONCLUSION: Modification of alar reduction to avoid crossing the nostril rim
      appears to improve the aesthetic result.

PMID- 8663955
TI  - A functional model of nerve repair. Reanastomosis vs entubulation repair.
AB  - OBJECTIVE: To compare reanastomosis and entubulation repair after transection of
      the peroneal nerve in rats with the use of 2 functional models: gait analysis and
      a tension transduction device. DESIGN: Prospective, randomized, blinded control
      study. Each animal served as its own control. The injured site was alternated
      between the left and the right. Gait analysis was evaluated in a blind fashion at
      postoperative weeks 1, 3, 7, and 13, and the tension transduction device at week
      13, for injured and uninjured legs. SUBJECTS: Animals underwent unilateral
      peroneal nerve transection injury, half with entubulation and half with end-to
      end reanastomosis repair. INTERVENTION: Nerve transection was performed 6 mm
      proximal to the anterior tibialis muscle insertion followed by reanastomosis
      (epineurial suture placement to align the sectioned nerve ends) or entubulation
      (placement of nerve ends into a 4-mm-long sterile Silastic tube secured with 2
      epineurial sutures). RESULTS: Gait analysis demonstrated a poorer ankle angle in
      all injured legs compared with uninjured legs at each postoperative period. Ankle
      angles for reanastomosis were statistically better than those for entubulation at
      weeks 3, 7, and 13. The tension transduction device demonstrated poorer force in
      injured than uninjured animals at 13 weeks. Reanastomosis repair groups
      demonstrated no difference in force development compared with entubulation repair
      groups. CONCLUSIONS: Reanastomosis of the transected rat peroneal nerve
      demonstrated improved functional return by gait analysis when compared with
      entubulation-repaired nerves at postoperative weeks 3, 7, and 13. Force
      development of injured nerve groups measured by the tension transduction device
      was decreased compared with control, but no difference was detected between the 2
      repair methods. Further studies are needed to evaluate the possible functional
      benefit of reanastomosis.

PMID- 8663957
TI  - Imaging quiz case 1. Ectopic internal carotid artery (ICA) within the petrous
      temporal bone.

PMID- 8663956
TI  - Cytomegalovirus sinusitis. A new manifestation of AIDS.
AB  - Cytomegalovirus is a common pathogen in patients infected with the human
      immunodeficiency virus. In this article, cytomegalovirus sinusitis is described
      and documented for the first time, to our knowledge. Cytomegalovirus was cultured
      from the sinuses of four patients who were positive for the human
      immunodeficiency virus and who had antibiotic-resistant infections. In one
      patient who underwent surgery, cytomegalovirus inclusions were documented
      consistent with invasive infection. Optimal treatment has yet to be determined,
      but in this case surgery did provide temporary relief of sinus symptoms.

PMID- 8663958
TI  - Imaging quiz case 2. Bilateral osteomas of the petrous temporal bones.

PMID- 8663959
TI  - [Study on inactivation of waste solutions of VIRKON].

PMID- 8663960
TI  - [Evaluation of the efficacy of a peroxide system (VIRKON) with special reference
      to in vitro kinetics of disinfection].

PMID- 8663961
TI  - [Evaluation of the disinfectant activity of the compound VIRKON].

PMID- 8663962
TI  - [Presentation of the Proceedings of the Round Table, Experimental Updates on a
      Biodegradable Peroxide System. 5 February 1994].

PMID- 8663963
TI  - [Germicidal activity of the detergent VIRKON].

PMID- 8663964
TI  - [Sporicidal activity of VIRKON].

PMID- 8663965
TI  - [Evaluation of mycobactericidal activity of the disinfectant VIRKON by polymerase
      chain reaction (PCR)].

PMID- 8663966
TI  - [Chemical characteristics and mechanisms of action of VIRKON].

PMID- 8663968
TI  - [New tests of virucidal activity of 2 disinfectants versus HBV DNA positive sera:
      slot-blot and polymerase chain reaction (PCR)].

PMID- 8663967
TI  - [Evaluation of the antiviral activity of the disinfectant VIRKON].

PMID- 8663969
TI  - [Mandatory and non-mandatory vaccinations in childhood: estimation of vaccination
      coverage in Apulia].

PMID- 8663970
TI  - [Recommended vaccinations: first assessment in a local health area in Abruzzi].

PMID- 8663971
TI  - [Poliomyelitis immunity status in the centro-meridional Italy].

PMID- 8663973
TI  - Viral hepatitis C in Basilicata in the years 1992-1993: a retrospective study.

PMID- 8663972
TI  - An epidemic of viral hepatitis A in Apulia.

PMID- 8663974
TI  - [Seroepidemiological studies on zoonoses in farm workers in Apulia].

PMID- 8663975
TI  - [A large outbreak of botulism caused by home cured ham consumption].

PMID- 8663976
TI  - ["Clean fruit and health": results of a consumer health protection program
      concerning risks of pesticide residues in apples].

PMID- 8663977
TI  - [Public Health activities in natural disasters].

PMID- 8663978
TI  - [Water supply in the Le Marche region].

PMID- 8663980
TI  - Neuronal chain gangs: homotypic contacts support migration into the olfactory
      bulb.

PMID- 8663979
TI  - [Importance of health education at a secondary school: experience with a course
      on viral hepatitis].

PMID- 8663981
TI  - PY in the fly receptor-like tyrosine phosphatases in axonal pathfinding.

PMID- 8663982
TI  - TRP is cracked but is CRAC TRP?

PMID- 8663983
TI  - Identification of the weaver mouse mutation: the end of the beginning.

PMID- 8663984
TI  - Nicotinic receptors in the development and modulation of CNS synapses.

PMID- 8663985
TI  - Changing patterns of spontaneous bursting activity of on and off retinal ganglion
      cells during development.
AB  - In adult ferrets, retinal ganglion cells (RGCs) responsive to increased (On) or
      decreased (Off) illumination convey information to different cellular layers of
      the dorsal lateral geniculate nucleus (dLGN). These dLGN sublaminae emerge during
      development when RGCs are found to undergo correlated spontaneous bursting
      activity. Using Ca2+ imaging and intracellular dye-filling techniques, we
      demonstrate here that in ferret neonates, morphologically identified On and Off
      beta RGCs have similar burst frequencies prior to the segregation of their inputs
      in the dLGN, but during the segregation period, they develop distinct burst
      frequencies. Although the bursts of On cells and Off cells occur synchronously,
      On cells burst only 25%-35% of the time that Off cells do. This change in the
      temporal bursting patterns of On and Off RGCs may underlie the segregation of
      their inputs on dLGN neurons.

PMID- 8663986
TI  - Developmental down-regulation of LTD in cortical layer IV and its independence of
      modulation by inhibition.
AB  - For in vitro LTD to remain viable as a model for synaptic weakening in visual
      cortical plasticity, it is crucial that it display a critical period for its
      induction within layer IV. A complicating factor, however, is that LTD in layer
      IV is modulated by inhibitory postsynaptic potentials (IPSPs); postsynaptic
      responses characterized as containing IPSPs do not depress in response to 1 Hz
      afferent stimulation. By blocking IPSPs intracellularly, we find that the ability
      to induce LTD in layer IV neurons is restored in juvenile, but not in mature
      animals. This developmental down-regulation of LTD induction is specific for
      layer IV when compared with LTD induction in layers II/III. These data are
      consistent with the hypothesis that an LTD-like phenomenon is involved in
      critical period plasticity and is apparently independent of developmental changes
      in inhibitory circuitry.

PMID- 8663987
TI  - Disruption of the gene for the myelin-associated glycoprotein improves axonal
      regrowth along myelin in C57BL/Wlds mice.
AB  - The myelin-associated glycoprotein (MAG) has been shown to be inhibitory for
      certain neurons in vitro (Mukhopadhyay et al., 1994; McKerracher et al., 1994).
      To investigate whether MAG is an inhibitory component in peripheral myelin in
      vivo, MAG-deficient mutant mice were cross-bred with C57BL/Wlds mice that have
      delayed lesion-induced myelin degeneration and axon regrowth. While in crushed
      nerves of C57BL/Wlds mice expressing MAG, only 16% of myelin sheaths were
      associated with regrowing axons, this number was doubled in MAG-deficient
      C57BL/Wlds mice. These observations suggest that the absence of MAG may
      contribute to the improved axonal regrowth in the double mutants. Therefore,
      degeneration of MAG-containing myelin might be an important prerequisite to
      optimize axonal regrowth after peripheral nerve injury.

PMID- 8663988
TI  - Parallel evolution and coexpression of the proteolipid proteins and protein zero
      in vertebrate myelin.
AB  - Vertebrate myelin contains two proteins that mediate compaction: protein zero
      (P0), an immunoglobulin gene superfamily member, or proteolipid proteins, 4
      hydrophobic domain-motif proteins biogenetically unrelated to P0. The prevailing
      view has been that expression of P0 and proteolipid proteins is mutually
      exclusive; P0, which mediates myelin compaction in fish, is thought to be
      completely replaced by the newer proteolipid proteins in the terrestrial
      vertebrate CNS. However, we now find that proteolipid proteins are actually major
      myelin constituents in bony fish and amphibia, and so are coexpressed with P0.
      Clearly, myelin proteolipids are not new additions to the myelin protein
      repertoire, but instead were ancestral sheath components, expressed approximately
      440 million years ago in the first myelinated fish that existed at least
      approximately 100 million years before the origin of amphibians. In conclusion,
      P0 and the proteolipid proteins are evolving in parallel in myelinating cells of
      most vertebrate species.

PMID- 8663989
TI  - DAMB, a novel dopamine receptor expressed specifically in Drosophila mushroom
      bodies.
AB  - The modulatory neurotransmitters that trigger biochemical cascades underlying
      olfactory learning in Drosophila mushroom bodies have remained unknown. To
      identify molecules that may perform this role, putative biogenic amine receptors
      were cloned using the polymerase chain reaction (PCR) and single-strand
      conformation polymorphism analysis. One new receptor, DAMB, was identified as a
      dopamine D1 receptor by sequence analysis and pharmacological characterization.
      In situ hybridization and immunohistochemical analyses revealed highly enriched
      expression of DAMB in mushroom bodies, in a pattern coincident with the rutabaga
      encoded adenylyl cyclase. The spatial coexpression of DAMB and the cyclase, along
      with DAMB's capacity to mediate dopamine-induced increases in cAMP make this
      receptor an attractive candidate for initiating biochemical cascades underlying
      learning.

PMID- 8663990
TI  - Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal
      LTP in BDNF knockout mice.
AB  - Brain-derived neurotrophic factor (BDNF) is expressed at high levels in
      hippocampal neurons, and its expression is modulated by neural activity. Knockout
      mice can be used to study the roles of molecules like BDNF in synaptic plasticity
      with more molecular specificity than is possible using pharmacological
      approaches. Because in conventional knockouts the disrupted gene product is
      absent in all tissues throughout the life of the animal, developmental effects
      may complicate the interpretation of deficits in the adult. Rescue experiments
      can help to distinguish between developmental and acute requirements for the
      missing gene product. We here demonstrate that treatment of hippocampal slices
      from BDNF knockout mice with recombinant BDNF completely reverses deficits in
      long-term potentiation and significantly improves deficits in basal synaptic
      transmission at the Schaffer collateral-CA1 synapse. Thus, BDNF has an acute role
      in hippocampal synaptic function.

PMID- 8663991
TI  - Long-term potentiation in cultures of single hippocampal granule cells: a
      presynaptic form of plasticity.
AB  - We have explored the mechanisms of mossy fiber long-term potentiation (LTP) at
      autapses in single-cell cultures of guinea pig hippocampal dentate granule cells.
      L-AP4-sensitive, but not insensitive, cells responded to a brief tetanus with a
      sustained potentiation in the synaptic responses. The induction of this LTP
      appeared identical to that observed in hippocampal mossy fiber synapses in situ,
      in that it required a rise in presynaptic Ca2+ and activation of protein kinase
      A. Its expression also appeared to be presynaptic and was due, at least in part,
      to events that occurred after the entry of Ca2+ and to the switching on of
      previously silent release sites.

PMID- 8663992
TI  - Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel.
AB  - The activation of Shaker K+ channels is steeply voltage dependent. To determine
      whether conserved charged amino acids in putative transmembrane segments S2, S3,
      and S4 contribute to the gating charge of the channel, the total gating charge
      movement per channel was measured in channels containing neutralization
      mutations. Of eight residues tested, four contributed significantly to the gating
      charge: E293, an acidic residue in S2, and R365, R368, and R371, three basic
      residues in the S4 segment. The results indicate that these residues are a major
      component of the voltage sensor. Furthermore, the S4 segment is not solely
      responsible for gating charge movement in Shaker K+ channels.

PMID- 8663993
TI  - Contribution of the S4 segment to gating charge in the Shaker K+ channel.
AB  - Voltage-activated ion channels respond to changes in membrane voltage by coupling
      the movement of charges to channel opening. A K+ channel-specific radioligand was
      designed and used to determine the origin of these gating charges in the Shaker
      K+ channel. Opening of a Shaker K+ channel is associated with a displacement of
      13.6 electron charge units. Gating charge contributions were determined for six
      of the seven positive charges in the S4 segment, an unusual amino acid sequence
      in voltage-activated cation channels consisting of repeating basic residues at
      every third position. Charge-neutralizing mutations of the first four positive
      charges led to large decreases (approximately 4 electron charge units each) in
      the gating charge; however, the gating charge of Shaker delta 10, a Shaker K+
      channel with 10 altered nonbasic residues in its S4 segment, was found to be
      identical to the wild-type channel. These findings show that movement of the NH2
      terminal half but not the CO2H-terminal end of the S4 segment underlies gating
      charge, and that this portion of the S4 segment appears to move across the entire
      transmembrane voltage difference in association with channel activation.

PMID- 8663994
TI  - Characterization of multiple phosphorylation sites on the AMPA receptor GluR1
      subunit.
AB  - We have characterized the phosphorylation of the glutamate receptor subunit
      GluR1, using biochemical and electrophysiological techniques. GluR1 is
      phosphorylated on multiple sites that are all located on the C-terminus of the
      protein. Cyclic AMP-dependent protein kinase specifically phosphorylates SER-845
      of GluR1 in transfected HEK cells and in neurons in culture. Phosphorylation of
      this residue results in a 40% potentiation of the peak current through GluR1
      homomeric channels. In addition, protein kinase C specifically phosphorylates Ser
      831 of GluR1 in HEK-293 cells and in cultured neurons. These results are
      consistent with the recently proposed transmembrane topology models of glutamate
      receptors, in which the C-terminus is intracellular. In addition, the modulation
      of GluR1 by PKA phosphorylation of Ser-845 suggests that phosphorylation of this
      residue may underlie the PKA-induced potentiation of AMPA receptors in neurons.

PMID- 8663995
TI  - Cloning and functional expression of a human Ca2+-permeable cation channel
      activated by calcium store depletion.
AB  - Depletion of intracellular calcium stores generates a signal that activates Ca2+
      permeable channels in the plasma membrane. We have identified a human cDNA,
      TRPC1A, from a human fetal brain cDNA library. TRPC1A is homologous to the cation
      channels trp and trpl in Drosophila and is a splice variant of the recently
      identified cDNA Htrp-1. Expression of TRPC1A in CHO cells induced nonselective
      cation currents with similar permeabilities for Na+, Ca2+, and Cs+. The currents
      were activated by intracellular infusion of myo inositol 1,4,5-trisphosphate or
      thapsigargin. Expression of TRPC1A significantly enhanced increases in the
      intracellular free calcium concentration induced by Ca2+ restitution after
      prolonged depletion. Similar results were obtained in Sf9 cells. We conclude that
      TRPC1A encodes a Ca2+-permeable cation channel activated by depletion of
      intracellular calcium stores.

PMID- 8663996
TI  - Definition of the readily releasable pool of vesicles at hippocampal synapses.
AB  - A readily releasable pool of quanta, tentatively identified with docked synaptic
      vesicles, has been defined by analysis of the neurotransmitter release caused by
      application of hypertonic solutions. The goal of this work is to determine the
      relationship of this functionally defined readily releasable pool to the one
      drawn upon by action potential-evoked release. We find that hypertonic solutions
      do not act through changes in intracellular calcium. Since the release produced
      by action potentials and hypertonic solutions varies in parallel as the pool size
      is changed, we conclude that the same pool is shared by both mechanisms. This
      conclusion, taken together with other observations in the literature, means that
      the synaptic release probability depends on the size of the readily releasable
      pool.

PMID- 8663997
TI  - Protein kinase C enhances exocytosis from chromaffin cells by increasing the size
      of the readily releasable pool of secretory granules.
AB  - We have used membrane capacitance measurements to assay Ca2+-triggered exocytosis
      in single bovine adrenal chromatin cells. Brief application of phorbol ester
      (PMA) enhances depolarization-evoked exocytosis severalfold while actually
      decreasing the Ca2+ current. Ca2+ metabolism is unchanged. Three different
      protocols were used to show that PMA increases the size of the readily releasable
      pool of secretory granules. PMA treatment leads to a large increase in amplitude,
      but little change in the time course of the exocytic burst that results from
      rapid elevation of [Ca2+]i upon photolysis of DMI-Nitrophen. Thus, PKC appears to
      affect a late step in secretion but not the Ca2+ sensitivity of the final step.

PMID- 8663998
TI  - Evidence that vesicles on the synaptic ribbon of retinal bipolar neurons can be
      rapidly released.
AB  - We relate the ultrastructure of the giant bipolar synapse in goldfish retina to
      the jump in capacitance that accompanies depolarization-evoked exocytosis. Mean
      vesicle diameter is 29 +/- 4 nm, giving 26.4 aF/vesicle, so the maximum evoked
      capacitance (150 fF within 200 ms) represents fusion of about 5700 vesicles. Two
      terminals contained, respectively, 45 and 65 ribbon-type synaptic outputs, and a
      fully loaded ribbon tethers about 110 vesicles. Thus, the tethered pool, about
      6000 vesicles, corresponds to the rapidly released pool. Further, the difference
      between small and large terminals in number of tethered vesicles matches their
      difference in capacitance jump. This suggests, within a "fire and reload" model
      of exocytosis, that the ribbon translocates synaptic vesicles very rapidly to
      membrane docking sites, supporting a maximum release rate of 500 vesicles/active
      zone/s, until the population of tethered vesicles is exhausted.

PMID- 8663999
TI  - Nitric oxide modulates synaptic vesicle docking fusion reactions.
AB  - Nitric oxide (NO) stimulates calcium-independent neurotransmitter release from
      synaptosomes. NO-stimulated release was found to be inhibited by Botulinum
      neurotoxins that inactivate the core complex of synaptic proteins involved in the
      docking and fusion of synaptic vesicles. In experiments using recombinant
      proteins, NO donors increased formation of the VAMP/SNAP-25/syntaxin 1a core
      complex and inhibited the binding of n-sec1 to syntaxin 1a. The combined effects
      of these activities is predicted to promote vesicle docking/fusion. The
      sulfhydryl reagent NEM inhibited the binding of n-sec1 to syntaxin 1a, while beta
      ME could reverse the NO-enhanced association of VAMP/SNAP-25/syntaxin 1a. These
      data suggest that post-translational modification of sulfhydryl groups by a
      nitrogen monoxide (likely to be NO+) alters the synaptic protein interactions
      that regulate neurotransmitter release and synaptic plasticity.

PMID- 8664000
TI  - Is use of the pulmonary valve allograft justified as an aortic valve substitute?
AB  - Between January 1, 1990, and March 20, 1994, 56 patients had a homograft valve
      device placed in the aortic position. The mean age at operation was 53.3 years
      (range 5-77 years). Diagnosis included dominant aortic stenosis in 27 patients
      (48.2%) and aortic incompetence in 29 (51.8%). Thirteen patients (23.2%) had
      subacute bacterial endocarditis. Forty-three aortic homografts and 13 pulmonary
      homografts were placed. Concomitant procedures were performed in 12 patients
      (21.8%). The hospital mortality was 7.3% (four patients). On follow-up, three
      pulmonary valves have failed, two between 1 and 5 weeks post implantation. At
      reoperation a linear cusp fracture was found in all with no evidence of
      infection. All remaining patients have no, trivial, or mild, aortic regurgitation
      on echo and remain well. Pulmonary and aortic valves were compared for failure, P
      = 0.02 suggesting a significant difference between valve substitutes. In
      conclusion we advise caution in using pulmonary allografts in the aortic
      position.

PMID- 8664001
TI  - Spontaneous right ventricular rupture after sternal dehiscence: a preventable
      complication?
AB  - Mediastinitis and/or sternal dehiscence developed in 143 out of 10,263 patients
      (1.4%) who underwent cardiac surgery between January 1979-December 1993.
      Mediastinal drainage, sternal debridement and early wound closure with pectoralis
      major and/or rectus abdominalis muscle flaps was the treatment employed. Between
      these two stages of treatment, massive hemorrhage developed in seven patients
      (0.07%) from a tear of the anterior wall of the right ventricle (RV). Six
      patients survived. Temporary control of the bleeding was achieved with digital or
      full palm pressure control of the ventricular tear. This was followed by
      immediate repair in the operating room (OR). The only death was due to
      exsanguination in the intensive care unit. The other six patients were taken to
      the OR. The anterior RV was freed from the underside of the sternum and the RV
      tear repaired with or without the aid of femoral-femoral bypass. These six then
      had muscle flap wound closures at that time or shortly after. All six were
      hospital survivors and are currently alive. We believe that RV rupture results
      from the sternal edges pulling the anterior surface of the RV apart, since the RV
      is stuck to the underside of the sternum. This experience indicates that the RV
      must be freed in all cases during initial sternal debridement. Hopefully this
      simple maneuver will prevent this horrendous complication.

PMID- 8664002
TI  - Critical aortic stenosis in the neonate. Results of aortic commissurotomy.
AB  - Critical aortic stenosis has been a challenging congenital heart defect in the
      neonate commonly due to severe circulatory failure and multiple organ
      dysfunction. Since January, 1982, 20 neonates with a mean age of 5.6 +/- 1.6 days
      and weight of 3.25 +/- 0.1 kg underwent aortic commissurotomy. Early surgical
      intervention, cardiopulmonary bypass with hypothermia at 30 degrees C, careful
      assessment of the aortic leaflets, commissures and sinuses, and extensive
      commissurotomy short of causing aortic regurgitation, were essential principles
      of the operation. There were three operative deaths (15.0%) and three late
      deaths. One-year and 7-year survival rates are 74 +/- 10% and 69 +/- 11%. There
      were five reoperations for recurrent stenosis and two of these are late deaths.
      At 7 years 80 +/- 11% of patients remain free of a reoperation. Growth curves of
      survivors have been excellent with only two patients below the 5th percentile for
      both height and weight; 80% of the patients are totally asymptomatic. Despite
      substantial improvements in the treatments of most heart defects in neonates in
      the past decade, critical aortic stenosis still carries a malignant behavior with
      significant early mortality and the need for reoperations. Close follow-up of the
      patients is essential due to recurrence of the stenosis and progressive left
      ventricular hypertrophy, even when patients are totally asymptomatic.

PMID- 8664003
TI  - Open heart surgery in Europe 1993.
AB  - Since 1990 the Institute of Cardiac Survey has compiled data on open heart
      surgery. In 1993 247,943 operations were performed. Subsets have been performed
      as follows: 61.9%: 153,670 of the operations were on the coronaries (CABG),
      22.8%: 56,574 for valve replacement, 9.7%: 24,174 for congenital lesions, 2.5%:
      6,308 other operations, 1.9%: 4,689 aortic aneurysms, 1.0%: 2,528 for heart
      replacement. 1993 was the first year that the data for direct surgery on the
      aorta (ascending, descending) in dissection or aneurysm were collected
      effectively. This subset was 1.9%, e.g. 4,689, of the total number. The
      increasing rate of open heart surgery in Europe was 8.3%, whereby the highest
      increasing rate could be observed in CABG.

PMID- 8664004
TI  - Arterial and venous conduits for coronary artery bypass. A current review.
AB  - Poor long-term patency of saphenous vein grafts limits the long-term success of
      the coronary artery bypass operation. If this is to be improved, either measures
      that increase the patency of saphenous vein grafts or alternative conduits are
      required. The benefits of using the left internal mammary artery as a pedicled
      graft to the left anterior descending coronary artery have prompted increasing
      use of arterial grafts to further improve outcome. Concurrently advances in the
      understanding of the pathological processes underlying saphenous vein graft
      occlusion raise the possibility of improving vein graft patency. In this paper we
      review the problem of vein graft occlusion and possible solutions, the
      theoretical benefits of arterial grafts and the clinical results associated with
      their use.

PMID- 8664005
TI  - Pleuropneumonectomy and postoperative adjuvant chemotherapy for carcinomatous
      pleuritis in primary lung cancer: a case report of long-term survival.
AB  - We present a 5-year survivor with lung adenocarcinoma accompanied by
      carcinomatous pleuritis who underwent pleuropneumonectomy followed by systemic
      chemotherapy. The pleural disease was not detectable on the chest roentgenograms
      or computed tomographic scans. The combination of the surgical procedure and
      postoperative adjuvant chemotherapy may be a potentially curative treatment in
      selected patients with carcinomatous pleuritis of lung cancer.

PMID- 8664007
TI  - Bronchial obstruction secondary to aneurysm of a persistent ductus arteriosus.
AB  - A 4-month-old infant presented with aneurysm of patent ductus arteriosus (PDA)
      which was causing obstruction of the left main bronchus. The patient had elevated
      pulmonary vascular resistance (PVR) at 6.1 um2. The aneurysm was resected on
      cardiopulmonary bypass. The patient required phenoxybenzamine and prostacycline
      after the operation for elevated PVR. Postoperative progress was prolonged but 12
      months after surgery the patient is well, growing normally without any
      respiratory symptoms.

PMID- 8664006
TI  - Late empyema after lobectomy for echinococcal disease of the lung.
AB  - The case of a 57-year-old man who had previously undergone left lobectomy for
      echinococcal disease of the lung is described. Sixteen years later he presented
      with empyema and bronchopleural fistula, which were treated using a pedicled
      intercostal muscle bundle, an omental pedicle and partial thoracoplasty. The
      patient recovered and is well 6 years later.

PMID- 8664008
TI  - Role of pulmonary artery banding in congenital heart disease.

PMID- 8664009
TI  - A European surgeon's odyssey--experiences and conclusions.

PMID- 8664011
TI  - Pediatric and adult tracheobronchomalacia.
AB  - Twelve cases of tracheobronchomalacia (TBM) cases were reviewed: five were
      pediatric, and seven were adult, two of which were due to relapsing
      polychondritis (RPC). In pediatric TBM, the malacic segments were short.
      Resection of the malacic segment in one case and laryngotracheoplasty with
      autologous costal cartilage in one case were unsuccessful. However, aortopexy
      gained good results. Two cases managed conservatively experienced gradual
      improvement of their symptoms. In adult TBM, plication of pars membranacea was
      not effective in one case. The insertion of a stent was minimally effective in
      one case, and distinctly in one polychondritic case. The other four cases managed
      conservatively have deteriorated gradually. From these findings, a new
      classification system is proposed.

PMID- 8664010
TI  - Transsternal transpericardial operations in the treatment of bronchopleural
      fistulas after pneumonectomy.
AB  - Between 1972 and 1993, 19 patients (15 males and 4 females) with bronchopleural
      fistulae and pleural empyema after pneumonectomy were treated with transsternal
      transpericardial operations and closure of the fistula. The underlying malignant
      disease was a non-small cell carcinoma in 12, a malignant epithelial mesothelioma
      in two, and an atypical carcinoid tumor in one case. One patient each presented
      with tuberculosis, chest trauma, and lung destroyed by bronchiectasis. Fistulas
      affected the right bronchial stump in 17, and the left in 2, cases after
      pneumonectomy. The time between pneumonectomy and transsternal transpericardial
      operation ranged between 1 month and 4 years. All patients were submitted to
      drainage and irrigation of the empyema cavity (2-4 weeks). In 16 patients a long
      bronchial stump was sutured or stapled, in three cases resection of a short stump
      with the distal trachea was followed by anastomosis of the trachea and left main
      stem bronchus. Irrigation of the pneumonectomy cavity was continued in all
      patients for 2 weeks. Transsternal transpericardial operation was successful in
      15 patients. Two patients died in the first 30 days, of renal or respiratory
      failure without fistula recurrence. In two cases the fistula recurred; definitive
      healing was achieved using a great omentum flap and endoscopic application of
      fibrin glue and bone spongiosa. Transsternal transpericardial management of
      bronchus stump fistula after pneumonectomy is highly effective and offers
      advantages over the direct approach through the infected empyema cavity.

PMID- 8664012
TI  - Multilevel somatosensory evoked potentials (SEPs) for spinal cord monitoring in
      descending thoracic and thoraco-abdominal aortic surgery.
AB  - The usefulness of somatosensory evoked potential (SEP) monitoring as a means of
      preventing paraplegia in descending aorta surgery was evaluated in 47 consecutive
      cases operated on for isthmic (14 cases), thoracic (22 cases), or thoraco
      abdominal (11 cases) repair. An aortic dissection was found in 11 cases (acute in
      6). Somatosensory evoked potentials were obtained by unilateral left and right
      posterior tibial nerve (PTN) stimulation at the ankle and recordings were
      performed on four channels: peripheral nerve, lumbar spinal, brain-stem, and
      cortical recordings. Our experience led to the following current strategy: the
      establishment of atrio(aorto)-femoral(aortic) bypass (29 cases), proximal and
      distal aortic cross-clamping, aortic repair with reimplantation of the culprit
      artery(ies) as indicated by SEP alterations. Five types of SEP alterations were
      defined on the basis of the neural level involved: type I (27.7% of cases) =
      distal spinal ischemia due to proximal aortic cross-clamping in the absence of
      bypass; type II (21.3%) = PTN ischemia due to left common femoral artery cross
      clamping; type III (12.8%) = segmental spinal ischemia due to the exclusion of
      critical feeding arteries; type IV (4.3%) = ischemia in the left carotid artery
      territory; type V (4.3%) = global brain hypoperfusion due to systemic
      hypotension. Forty-five patients survived the operation and could be tested for
      neurological dysfunction. Three patients presented a postoperative spinal cord
      deficit, but this deficit was already present preoperatively in one case, so that
      the actual incidence of a new paraplegia in our series was 2/45 cases (4.4%). One
      of the two cases was clearly a delayed paraplegia with SEP alterations appearing
      several hours after the operation. Somatosensory evoked potentials were evaluated
      on the basis of their sensitivity, specificity, and impact on the surgical
      strategy. Regarding SEP sensitivity, we did not encounter any unexpected
      immediate paraplegia, but the critical factor appeared to be the duration of SEP
      absence due to spinal cord ischemia, which, according to the literature, should
      never exceed 30 min; after a longer absence, SEP return does not guarantee
      neurological recovery. Somatosensory evoked potential specificity was also 100%,
      but only 58% of the abnormalities found were actually consequent to spinal cord
      ischemia, the rest of the abnormalities being consequent to peripheral nerve or
      brain ischemia. Finally, SEP monitoring had a significant impact on surgical
      strategy in 19% of the cases. It is concluded that distal aortic perfusion and
      multilevel SEP monitoring play a significant role in preventing paraplegia in
      descending aorta surgery.

PMID- 8664013
TI  - The Marfan syndrome and the cardiovascular surgeon.
AB  - The authors present the current status of surgery for the cardiovascular
      manifestations of the Marfan syndrome. In addition, a brief review of current
      Marfan genetic research is presented. Data on all Marfan patients undergoing
      aortic root replacement at the Johns Hopkins Hospital (September 1976-June 1995)
      were analyzed. Survival and event-free curves were calculated and risk factors
      for early and late death were determined by univariate and multivariate analysis.
      Two hundred twelve Marfan patients underwent aortic root replacement using
      composite graft (202), homograft (8) or valve-sparing procedures (2). One hundred
      eighty-five patients underwent elective repair with no 30-day mortality. Twenty
      seven patients underwent urgent surgery, primarily for acute dissection; two
      patients with aortic rupture died in the operating room. Actuarial survival of
      the 212 patients was 88% at 5 years, 78% at 10 years and 71% at 14 years. By
      multivariate analysis, only poor NYHA class, male gender and urgent surgery
      emerged as significant independent predictors of early or late mortality.
      Histologic examination of excised Marfan aortic leaflets by immunofluorescent
      staining for fibrillin showed fragmentation of elastin-associated microfibrils.
      These studies suggest cautious use of valve-sparing procedures in Marfan
      patients. Over the last 5 years significant progress has been made in identifying
      mutant genes that code for defective fibrillin microfibrils in Marfan patients.
      Attempts are underway to develop animal models of Marfan disease for study of
      possible gene therapy. Aortic root replacement can be performed in Marfan
      patients with operative risk under 5%. Long-term results are gratifying. At
      present, valve-sparing procedures should be used cautiously in Marfan patients
      because of fibrillin abnormalities in the preserved aortic valve leaflets.

PMID- 8664014
TI  - Video-assisted thoracoscopic surgery of the lung (VATS) comes of age--where to
      next?

PMID- 8664015
TI  - Video-assisted thoracoscopic pulmonary surgery--current status and potential
      evolution.
AB  - The current status of video-assisted thoracoscopic surgery (VATS) of the lung has
      been reviewed. The published data support the view that VATS pulmonary surgery is
      feasible and safe. It is associated with decreased perioperative pain and opiate
      requirement, better postoperative pulmonary function, and probable overall
      neutral cost impact. A VATS approach is functionally superior to open thoracotomy
      for wedge resection, pneumothorax surgery and bullous lung disease and may allow
      surgical intervention in patients with pulmonary function which is in adequate
      for open resection. Major VATS pulmonary resection with lobectomy and
      pneumonectomy can be performed for early malignant disease without compromising
      established surgical principles. Specific training is needed in VATS surgery and
      background skills in general thoracic surgery are necessary to underwrite major
      interventions. Decreased cytokine activation and enhanced post surgical immune
      function may prove to be long-term benefits of VATS surgery.

PMID- 8664016
TI  - Endoscopic versus transaxillary thoracic sympathectomy for primary axillary and
      palmar hyperhidrosis and/or facial blushing: 5-year-experience.
AB  - Thoracic sympathectomy is effective in the permanent cure of primary axillary and
      palmar hyperhidrosis and facial blushing, which can be so troublesome for
      patients that their social and professional relations can be affected. Between
      October 1988 and April 1994, a total of 50 thoracic sympathectomies (10 surgical
      and 40 endoscopic) were performed on 5 and 23 patients, respectively. The
      operations were performed unilaterally, followed by the contralateral
      intervention after a period of 6-8 weeks. The thoracic ganglia T2-T5 were
      resected for hyperhidrosis. If the patient suffered from blushing, the lower 1/3
      of the stellate ganglion was also resected. Postoperatively, all the operated
      limbs were warm and dry. In the group of patients who were operated bilaterally,
      only one had persistent facial blushing. The efficacy for blushing in this series
      was therefore 93.3%. The late relapse rate of sympathetic activity was 14.3%.
      Compensatory sweating was seen in 67%, gustatory sweating in 37.5% and phantom
      sweating in 29% of the patients. None of them considered these side effects to be
      troublesome. Although there is no difference between transaxillary thoracic
      sympathectomy and the endoscopic intervention in terms of efficacy, the latter is
      associated with less postoperative pain, shorter hospital stay and a rapid
      recovery. The thoracic sympathectomy is the treatment of choice for primary
      hyperhidrosis and excessive facial blushing.

PMID- 8664018
TI  - Randomized trial comparing intermittent antegrade warm blood cardioplegia with
      multidose cold blood cardioplegia for coronary artery bypass.
AB  - Forty patients were randomized to receive antegrade multidose warm (WBC) or cold
      blood cardioplegia (CBC) during coronary artery bypass. Cardioplegia was infused
      at a predetermined dose every 10 min during cardioplegia arrest and core
      temperature was maintained at 37 degrees C in both groups during extracorporeal
      circulation. Patient profiles were similar in the two groups. Cardiac index, left
      ventricular stroke work index, and myocardial oxygen consumption were measured
      before bypass and during the first 7 h of reperfusion. There was no significant
      difference in myocardial metabolic and function recovery, the incidence of
      myocardial infarction, low cardiac output or death. Our data suggests that
      similar protection is provided with the two techniques of myocardial protection.

PMID- 8664017
TI  - Risk factors of recurrent angina pectoris and of non-fatal myocardial infarction
      after coronary artery bypass surgery.
AB  - The long-term results of 1025 patients, 912 men and 113 women, undergoing
      coronary artery bypass grafting (CABG) at the Cardiovascular Unit of
      Rikshospitalet, Oslo, between 1982 and 1986, were analyzed on factors associated
      with the return of angina pectoris and of non-fatal post CABG myocardial
      infarction. The closing date was 1st January 1993, with a mean follow-up time of
      7.4 years. Recurrent angina pectoris was experienced by 118 (11.6%) patients and
      102 (10%) patients experienced non-fatal post CABG myocardial infarction during
      the observation period. Altogether 30 possible risk factors were analyzed. The
      cumulative incidence of recurrent angina was initially low after operation,
      followed by a rise after 4 years. One, 5 and 10 years after the operation,
      survival free from angina rates were 97.8%, 91.8% and 80.6%, respectively. The
      cumulative incidence of post CABG myocardial infarction was also low initially,
      followed by a rise after 4 years. The survival free of non-fatal post CABG
      myocardial infarction rate was 98.9%, 96% and 83.5%, at 1, 5 and 10 years after
      surgery, respectively. The incremental risk factor of recurrent angina pectoris
      was hypertension. The independent risk factors of non-fatal post CABG myocardial
      infarction were hypertension and preoperative stenosis of the left-sided, versus
      right-sided, coronary arteries. The study emphasizes the favorable effect of
      coronary bypass surgery on the functional outcome in patients with symptomatic
      coronary artery disease.

PMID- 8664019
TI  - Perioperative myocardial injury with different modes of antegrade and retrograde
      cardioplegic delivery.
AB  - The effect of three cardioplegic protocols on perioperative myocardial injury was
      studied in 62 coronary artery bypass grafting (CABG) patients randomized into
      three groups with either antegrade or retrograde cold blood cardioplegia, or
      coronary sinus occlusion during antegrade supply. During the aortic cross-clamp
      time anterior and posterior septal temperatures were recorded, indicating the
      distribution of cardioplegic solution within the myocardium. Serum creatine
      kinase (CK), CK-isoenzyme MB and myoglobin as well as 12-lead electrocardiograms
      (ECG) were analyzed. Statistical analysis showed no effect of the cardioplegic
      protocol, whereas the patient's preoperative status, aortic cross-clamp time and
      intraoperative myocardial temperature had significant (P < 0.05) effects on
      immediate postoperative CK and CK-MB enzyme release. Creatine kinase-MB peak
      values were significantly increased in patients with major vessel disease and
      reduced left ventricular function (92 +/- 53 U/l versus 67 +/- 25 U/l). Both CK
      and CK-MB values were significantly higher in patients with aortic cross-clamp
      times of more than 1 h than in patients with shorter clamping times (661 +/- 188
      and 78 +/- 40 U/l versus 500 +/- 200 and 57 +/- 24 U/l). Patients with 22 +/- 3
      degrees C myocardial temperature before terminal cardioplegia had significantly
      elevated CK as compared to patients with temperatures of 15 +/- 2 degrees C (665
      +/- 185 U/l versus 510 +/- 211 U/l). However, enzyme peak values had only poor
      predictive power for postoperative ECG changes, suggesting that enzyme peaks were
      not necessarily a sign of perioperative ischemia. Patients with major vessel
      disease and reduced myocardial function, with aortic cross-clamp time of more
      than 1 h and/or inadequate intraoperative myocardial cooling may be highly
      susceptible to global ischemia and operative procedures, and therefore show
      elevated peak enzyme levels shortly after surgery. In contrast, elevated
      myoglobin peaks within 1 h after aortic declamping were significantly correlated
      to perioperative signs of transient ischemia (P < 0.02).

PMID- 8664020
TI  - Surgical anatomy of the coronary circulation in hearts with discordant
      atrioventricular connections.
AB  - We examined the arrangement of the coronary arterial and cardiac venous systems
      in 46 specimens with discordant atrioventricular connections so as to identify
      any structural abnormalities and to consider their surgical implications in terms
      of anatomical biventricular repair. Grossly abnormal arterial courses were seen
      in 11 hearts (24%). A substantial branch supplying the morphologically right
      ventricular outflow tract, which could restrict a ventriculotomy, was found in
      61% of cases. The coronary sinus received all the morphologically right
      ventricular veins, as well as the posterior interventricular vein, in 40 hearts,
      this pattern being in contrast to the pattern in the normal heart. The
      morphologically left ventricular and anterior interventricular veins, all of
      which drain via the coronary sinus in the normal heart, were frequently connected
      independently to the morphologically right atrium in the specimens with
      discordant connections, the drainage occurring through the spaces between the
      pectinate muscles. These direct drainages are at risk of potential damage either
      by extensive intra-atrial maneuvers or by postoperative intraatrial thrombosis.
      It is predicted, therefore, that surgical results can be improved still further
      when account is taken of this vascular anatomy of the heart itself.

PMID- 8664021
TI  - Hemodynamics of various designs of 19 mm pericardial aortic valve bioprosthesis.
AB  - The hemodynamics of five designs of 19 mm pericardial aortic valve bioprostheses
      were examined in 47 resting patients by Doppler echocardiography. The salient
      differences among the five designs are that valve leaflets are mounted inside the
      support frame in one (the Carpentier-Edwards valve, evaluated in 4 patients) and
      outside the frame in the other four (the Ionescu-Shiley (16 patients), Mitroflow
      (4), Bioflo (8) and Labcor-Santiago (15)); and that two models have either total
      (Bioflo) or partial (Labcor-Santiago) protective pericardial sheaths on the
      stent, while the other three do not. The hemodynamic parameters determined
      included transvalvular pressure drop, valve area, left ventricular outflow tract
      diameter, subvalvular/valvular velocity ratio and subvalvular/valvular velocity
      time integral ratio. There were no significant differences among the various
      valves as regards left ventricular outflow tract diameter, subvalvular/valvular
      velocity ratio or subvalvular/valvular velocity-time integral ratio. Negative
      correlation between left ventricular outflow tract diameter and subvalvular
      velocity (r = -0.66, P < 0.001) confirmed the need to correct for prevalvular
      velocities when using the Bernouilli equation to calculate the pressure drop
      across small pericardial aortic valve bioprostheses. The Bioflo design caused
      significantly greater pressure drops (peak 38.3 +/- 8.3 mmHg, mean 24.6 +/- 4.8
      mmHg) and smaller areas (0.82 +/- 0.17 cm2) than the Ionescu-Shiley (20.3 +/- 5.6
      and 11.7 +/- 3.8 mmHg, 1.19 +/- 5.3 and 10.1 +/- 3.1 mmHg, 1.27 +/- 0.12 cm2)
      valves.

PMID- 8664022
TI  - Aortic root replacement with a composite graft. Factors influencing immediate and
      long-term results.
AB  - From April 73 to June 94, 203 patients (167 men, 36 women) aged from 10 to 74
      years (mean: 44.8 +/- 15) underwent ascending aortic replacement with composite
      graft for: dystrophic aneurysm (AN) (130 cases, 64.5%), chronic dissection (CD)
      (35 cases, 17.2%), type A acute dissection (AD) (38 cases, 18.7%). Forty-six
      patients (22.6%) suffered from Marfan syndrome (24 AN, 13 AD, 9 CD). Thirty
      patients (14.7%) had undergone a previous cardiac or aortic operation. The
      ascending aortic replacement was extended to the transverse arch in 28 patients
      (13.7%). A mechanical valve was used in 193 cases (95%). Since 1986, the
      ascending aorta has been totally resected and a gelatin-or collagen-coated
      vascular prosthesis used. The technique of coronary reattachment has varied with
      time and according to the aortic lesions. The classic "Bentall" technique was
      used in 87 patients (43%), the "button" technique in 74 (36%), the "Cabrol"
      technique in 26 (13%) and a "mixed" technique in 16 cases (8%). The hospital
      mortality rate was 7.3% (15/203) (AN: 2.3%, CD: 11.4%, AD: 21%). The only
      predictors of hospital death were emergency AD (P < 0.03) and arch replacement (P
      < 0.02). Mean follow-up was 46 +/- 10 months (2-246). The overall long-term
      survival rate was (Kaplan Meier) 89 +/- 6% at 1 year, 77.9 +/- 9% at 5 years,
      67.7 +/- 12% at 10 years and 61.3 +/- 15% at 12 years. The 10-year survival rate
      is significantly higher in patients with AN (77.8 +/- 11%) than in those with AD
      (61.6 +/- 17%) (log. rank: P < 0.01). The late survival rate is also
      significantly higher after the "button" or Bentall reimplantation than after the
      "Cabrol" or "mixed" methods (90 +/- 5% in the "button" group and 88.7 +/- 6%,
      83.8 +/- 9% and 76.6 +/- 12% in the "Bentall" group vs 80 +/- 18%, 63 +/- 21% and
      58 +/- 35% in the "Cabrol" group at 1, 5 and 8 years, respectively). In
      conclusion, ascending aortic replacement with a composite graft is a safe
      procedure especially when performed electively in patients with dystrophic
      aneurysm or Marfan syndrome. The technique of coronary reimplantation has a
      significant influence on the long-term results. The reimplantation of choice is
      the "button" technique, especially in the presence of a fragile aortic wall (AD).
      The "Cabrol" technique must be used when the "button" or the "Bentall"
      reimplantation is not feasible, for instance during redo procedures.

PMID- 8664023
TI  - A case of giant cell tumor of the rib with magnetic resonance imaging.
AB  - A surgical case of giant cell tumor originating from the right seventh rib in a
      51-year-old Japanese man is reported. Surgical resection without radiation
      therapy is preferable, because radiation may cause malignant transformation of
      this kind of tumor. Magnetic resonance imaging (MRI) of the tumor, reported for
      the first time in the English literature, was useful in planning complete
      resection, because both the excellent soft-tissue contrast resolution and the
      multiplanar images could demonstrate accurately the tumor extent both in the bone
      marrow and to the surrounding soft tissue.

PMID- 8664024
TI  - Sternal resection for primary presternal and retrosternal mediastinal
      liposarcoma.
AB  - In a 34-year-old patient, sternal resection was necessary for complete removal of
      a primary mediastinal myxoid liposarcoma grade I, which had grown around the
      right sternal border. Reconstruction was by the methylmethacrylate sandwich
      technique. Five months postoperatively part of the device had to be removed due
      to persistent inflammation. Two years after the initial operation there is no
      evidence of local recurrence or distant metastases.

PMID- 8664025
TI  - Thoracoscopic creation of a pericardial window for recurrent pericardial effusion
      after heart transplantation.
AB  - A 56-year-old man underwent orthotopic heart transplantation (Htx) for dilative
      cardiomyopathy. The postoperative course was uneventful despite the appearance of
      pericardial effusions during the first 6 months, which required repeated drainage
      therapy. Six months postoperatively a pericardial window was created using a
      thoracoscopic approach via the right pleural cavity. The course after this
      intervention was uncomplicated and there was no recurrence of the pericardial
      effusion during 18 months of follow-up.

PMID- 8664026
TI  - Extrapleural haematoma secondary to blunt chest trauma.

PMID- 8664027
TI  - Radon and childhood cancers.
AB  - The effective radiation doses received by children living in high radon areas are
      similar to those which have been associated with an excess risk of malignant
      disease elsewhere. However, the only cancer known to be associated with radon is
      lung cancer--a disease which is not a condition of childhood. Thorne and his
      colleagues have conducted a study which could have demonstrated an excess of
      childhood malignancy only if the risk associated with radon was very high. The
      risk to health of high levels of radon in the environment remains uncertain. The
      United Kingdom Case Control Study of Childhood Cancers, under the chairmanship of
      Sir Richard Doll, is assessing risk from many factors including measured radon
      exposure and it is with great interest that we await the results.

PMID- 8664028
TI  - High-dose chemotherapy for breast cancer.
AB  - What can we conclude and hope to see in the next few years? Laboratory studies
      and imperfect retrospective analysis of conventional chemotherapy have created a
      climate of active interest to experiment with dose-intensive chemotherapy. There
      seems to be a consensus in favour of combination alkylating agents to maximise
      anticancer and rescuable antimarrow stem cell effects, whilst producing sublethal
      second-organ toxicity. PBPC has replaced ABMT as the routine rescue technique, on
      grounds of cost and recovery time. The mature results of this changed technology
      for support have yet to be seen in terms of the risks of late, poor engraftment
      and the potential benefits in terms of acute complications (faster engraftment)
      and tumour kill (reduced tumour contamination?). Whilst experiments continue to
      examine the impact of tumour contamination of blood harvests or BM harvests,
      inadequate attention has been paid in metastatic disease to patient selection.
      There seems to be a continuing growth of interest in multiple high-dose therapy
      regimens using stem cells collected earlier in the therapy to rescue sequential
      myeloablative treatments. This possibility has been realised by the stem cell
      technology and is being pursued with enthusiasm and with promising early results.
      Media-driven public interest in this increasingly political disease is pushing us
      to 'do more'. In future years, our worst nightmares may be realised if this means
      aping the experience of Halsted's disciples, "don't test, just believe"--the
      economic and human costs of high-dose treatment cannot justify our avoiding the
      rigorous examination of controlled trials.

PMID- 8664029
TI  - Current and future trends in the multidisciplinary approach for high-risk breast
      cancer. The experience of the Milan Cancer Institute.

PMID- 8664030
TI  - Expression of p53 protein as a prognostic factor in patients with gastric cancer.
AB  - The prognostic value of overexpression of the p53-encoded protein was evaluated
      in 242 patients with gastric cancer. Formalin-fixed paraffin-embedded specimens
      of gastric adenocarcinomas were stained with the monoclonal antibody DO-7. 95
      patients (39%) showed a high level of immunoreactivity (> or = 20% of cell nuclei
      staining positively), suggesting the presence of a mutation in the TP53 coding
      sequence. Overexpression of the p53 protein correlated significantly with stage
      of disease (P = 0.01), the presence of distant metastases (P = 0.04) and with the
      intestinal type of cancer (P = 0.04). No correlation between p53 overexpression
      and age, gender or the presence of the lymph node metastases was found. In
      univariate analysis, p53 immunoreactivity correlated significantly with survival
      (P = 0.0005). The median survival in the p53 high-level group was 19 months
      compared with 65 months in the p53 low-level group. In multivariate analyses,
      stage of disease and the presence of distant metastases emerged as independent
      prognostic factors, whereas p53 immunoreactivity did not (P = 0.08). The present
      results indicate that overexpression of the p53 protein is not an independent
      prognostic factor in patients with gastric cancer.

PMID- 8664031
TI  - Prognostic value of serum alpha-1-antitrypsin in hepatocellular carcinoma.
AB  - To evaluate serum alpha-1-antitrypsin (A1AT) as a prognostic factor in
      hepatocellular carcinoma, we studied 75 consecutive patients (60 male, 15 female,
      mean age +/- SD 63.0 +/- 9.3 years) in whom hepatocellular carcinoma developed
      with pre-existing cirrhosis. Median survival time was 245 days (range 4-1568+).
      30 patients had serum A1AT concentration of < or = 2.20 g/l (Group A) while 45
      (Group B) had alpha-1-antitrypsin > 2.20 g/l. Median survival was 518 days in
      Group A and 81 days in Group B (Mantel-Cox 20.95, P < 0.0001; hazard ratio 0.26,
      95% confidence limits 0.15-0.46). By stepwise survival analysis, alpha-1
      antitrypsin together with bilirubin, tumour size and blood urea nitrogen were
      chosen among 17 variables as the only independent predictors of survival. We
      conclude that measurement of serum A1AT concentration might be useful as an
      inexpensive, widely available prognostic marker of hepatocellular carcinoma.

PMID- 8664032
TI  - Evaluation of antitumour effects of docetaxel (Taxotere) on human gastric cancers
      in vitro and in vivo.
AB  - In vitro antitumour effects of docetaxel (Taxotere) were examined in nine
      cultured human gastric cancer cell lines and 18 clinical gastric cancer
      specimens. In vivo antitumour effects were examined in human gastric cancer
      xenografts in nude mice. The activity was compared with paclitaxel (Taxol).
      Docetaxel was more effective than paclitaxel in six of the nine cell lines and
      the effectiveness rates of docetaxel and paclitaxel were 56% (10/18) and 6%
      (1/17), respectively, in the clinical gastric cancer specimens. In vivo docetaxel
      showed superior antitumour effect on well differentiated (MKN-28), poorly
      differentiated (MKN-45) and undifferentiated (KKLS) gastric cancer xenografts. We
      conclude that docetaxel promises to be clinically active against gastric
      carcinomas.

PMID- 8664033
TI  - Plasma c-erbB2 concentrations in relation to chemotherapy in breast cancer
      patients.
AB  - Amplification and overexpression of the C-ERBB2 oncogene have been associated
      with a poor prognosis and a lower response to chemotherapy in human breast
      cancer. In this study, plasma c-erbB2 concentrations were determined using an
      enzyme immunoassay in patients with breast cancer. The links between c-erbB2
      concentration and tumoral response to chemotherapy were established. The patients
      with a c-erbB2 concentration higher than the cut-off value (27 U/ml) were
      considered as c-erbB2+. Ten of the 33 metastatic breast cancers were c-erbB2+. No
      statistically significant difference in response to chemotherapy was noted
      between c-erbB2+ and c-erbB2- patients (4/10 objective responses versus 10/23).
      Variations in c-erbB2 concentrations during treatment were not related to
      response to treatment.

PMID- 8664034
TI  - Postoperative adjuvant randomised trial comparing chemoendocrine therapy,
      chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year
      results from the Nishinihon Cooperative Study Group of Adjuvant Chemoendocrine
      Therapy for Breast Cancer (ACETBC) of Japan.
AB  - Between 1985 and 1988, the effect of using ftorafur (FT) or PSK (an immunotherapy
      agent) in combination with the conventional postoperative adjuvant therapy using
      mitomycin (MMC) plus tamoxifen (TAM) was assessed in stage II, oestrogen receptor
      positive (ER+) breast cancer patients. Furthermore, in ER- breast cancer stage II
      patients, the effects of postoperative adjuvant therapy using MMC plus FT were
      compared with the effects of postoperative adjuvant therapy using MMC plus PSK.
      Patients had primary stage II breast cancer and had undergone total mastectomy
      plus axillary dissection or more radical surgery. On the day of surgery, MMC (13
      mg/m2) was administered intravenously. Then, ER+ patients received one of three
      regimens of drug therapy, starting 2 weeks after surgery: regimen A (daily oral
      treatment with 30 mg of TAM), regimen B (daily oral treatment with 30 mg of TAM
      and 600 mg of FT) or regimen C (daily oral treatment with 30 mg of TAM and 3 g of
      PSK) [corrected]. ER- patients received either regimen D (daily oral treatment
      with 600 mg of FT) or regimen E (daily oral treatment with 3 g of PSK), starting
      2 weeks after surgery. Of the 540 ER+ patients registered, 525 were evaluated.
      The 5-year overall survival rate for ER+ patients was higher for patients who
      received regimen B (94.2%) than for those who received regimen A (86.9%) or
      regimen C (89.9%) (P = 0.063). The 5-year relapse-free survival rate was higher
      for regimen B (88.9%) than for regimen A (78.6%) and regimen C (77.2%) (P =
      0.010). Stratified analysis revealed better results with the FT-combined therapy
      in patients positive for lymph node metastasis and premenopausal patients. These
      results indicate the effectiveness of using FT in combination with TAM. Of the
      376 ER- patients registered, 364 were evaluated. The 5-year overall and relapse
      free survival rate for ER- patients did not differ significantly between patients
      who received regimen D and those who received regimen E.

PMID- 8664035
TI  - Activity of gemcitabine in patients with non-small cell lung cancer: a
      multicentre, extended phase II study.
AB  - Gemcitabine is a novel nucleoside analogue with activity in solid tumours. This
      study assessed the objective response rate to gemcitabine given weekly
      intravenously at a dose of 1250 mg/m2 for 3 weeks followed by 1 week of rest (one
      cycle) in chemonaive patients with inoperable non-small cell lung cancer (NSCLC).
      161 patients with NSCLC were recruited from 10 sites in nine countries. Most
      patients had stage IIIb (31.3%) or IV (64.6%) disease, and 93.8% had a
      performance status of 0 or 1 according to the WHO scale. Of 151 evaluable
      patients, there were 3 complete responses and 30 partial responses lasting at
      least 4 weeks for an objective response rate of 21.8% (95% CI 15.5-29.3%). All
      responses were validated by an extramural Oncology Review Board. The mean
      duration of response was 8.8 months. The mean survival for all patients (16.1% of
      patients still alive 26 months after last patient started treatment) was 11.5
      months. Improvements were also observed in secondary efficacy parameters such as
      performance status, weight, analgesic requirement, pain, and other disease
      related symptoms including cough, dyspnoea, haemoptysis, anorexia, somnolence and
      hoarseness. Haematological and non-haematological toxicity was mild given the
      biological activity of gemcitabine. This study confirms gemcitabine as one of the
      most active agents in NSCLC with the added benefit of a modest toxicity profile
      and ease of administration on an out-patient basis. Gemcitabine is a suitable
      candidate for combination chemotherapy in patients with NSCLC.

PMID- 8664036
TI  - Concurrent radiotherapy and continuous ambulatory infusion 5-fluorouracil in
      advanced head and neck cancer.
AB  - Patients with locally advanced stage 3 or 4 recurrent squamous cell carcinoma of
      the head and neck received 5-fluorouracil (5-FU) 200 or 300 mg/m2/day by
      prolonged ambulatory infusion concomitantly with radiotherapy (60-66 Gy) to the
      primary site and neck nodes in 30-33 fractions at five fractions per week,
      boosting to smaller volumes after 60 Gy. Of 39 patients, the complete response
      rate was 82% (95% CI: 67-93%). The estimated percentage without failure at 2
      years was 59% (S.E. 8%) and at 4 years was 50% (S.E. 8%). Estimated head and neck
      cancer specific survival was 64% (S.E. 8%) at 2 years and 52% (S.E. 8%) at 4
      years. Acute toxicities included moist desquamation in 49% and dry desquamation
      in 28%, confluent mucositis in 56% and patchy mucositis in 44%. Late effects,
      more than 6 months after completing treatment, assessed in 35 patients, included
      severe salivary dysfunction in 3 patients and moderate in 21, severe
      osteonecrosis in 4 patients and moderate toxicity in subcutaneous tissues in 13,
      skin in 3 and mucosa in 2 patients. It is feasible to give continuous 5-FU
      concurrently with radiotherapy in locally advanced or recurrent head and neck
      cancer, albeit with increased toxicity. The response rate and survival obtained
      in this trial justify further investigation of the combined treatment in a
      randomised trial.

PMID- 8664037
TI  - Well-differentiated papillary mesothelioma of the peritoneum: a separate entity.
AB  - Three female patients with a diffuse well-differentiated papillary mesothelioma
      of the peritoneum are presented. They did not have a history of exposure to
      asbestos. The peritoneal biopsies were studied extensively, including electron
      microscopy, nuclear morphometry and DNA ploidy analysis. The results from these
      more sophisticated investigations confirmed the mesothelial origin and further
      characterised these lesions. One of the 3 patients has continuing elevated serum
      CA-125 levels, which increased transiently during and after pregnancy. All 3
      patients have done well without therapy, 2 patients being alive and non
      symptomatic 6 and 7 years after the initial diagnosis. It is important to
      distinguish this disorder from the malignant diseases of the peritoneum and the
      ovary. In view of the indolent course of this subtype of mesothelioma, avoidance
      of treatment is justified unless there is evidence of progressive disease.

PMID- 8664038
TI  - Multiple tumour marker assays in advanced cervical cancer: relationship to
      chemotherapy response and clinical outcome.
AB  - Serum levels of squamous cell carcinoma antigen (SCC), CA 125 and CA 15.3 were
      measured in 102 patients with locally advanced cervical cancer undergoing
      neoadjuvant chemotherapy (NACT) and radical surgery. We found a significant
      correlation between SCC concentration and stage, histotype, cervical tumour size
      and lymph node status. For CA 125 and CA 15.3, no significant difference in the
      distribution of marker levels according to histopathological variables was found.
      In a multivariate analysis, histological type, FIGO stage and SCC positivity (> 5
      ng/ml) proved to be independent predictors of response to neoadjuvant
      chemotherapy. Moreover, logistic regression analysis showed that CA 15.3 may be a
      significant adjunct to SCC in the prediction of chemotherapy response. Of the
      three markers tested, only CA 125 was significantly related to patient survival.
      In the multivariate analysis, clinical response to chemotherapy and CA 125 status
      (> 35 U/ml) retained an independent prognostic value. Our data suggest that the
      tumour markers used in this study could be useful in the management of locally
      advanced cervical cancer. Pretreatment serum levels of SCC, together with CA 15.3
      assay, may be a useful tool in the determination of response to chemotherapy,
      while CA 125 assay could be evaluated as a prognostic risk factor in these
      patients.

PMID- 8664039
TI  - Identification of lymph node metastases by use of polymerase chain reaction (PCR)
      in melanoma patients.
AB  - Diagnosis of clinically suspected lymph node metastases in melanoma patients can
      be confirmed with high sensitivity and specificity by fine needle aspiration
      (FNA) cytology. However, small lymph nodes or haemorrhagic metastases may yield
      negative or unevaluable cytology. We tested whether the sensitivity and
      specificity of presurgical diagnosis could be improved by a polymerase chain
      reaction (PCR) method, identifying tyrosine-mRNA in samples obtained by fine
      needle aspiration (FNA-PCR). PCR was positive in 17 of 18 histopathologically
      proven melanoma metastases, while conventional cytopathology detected 16 of 18. 4
      of 9 disease-free melanoma patients with negative FNA cytology had positive PCR
      results, but controls gave negative results. FNA-PCR analysis cannot be
      recommended as superior to conventional FNA cytological examination. Whether the
      positive FNA-PCR in four of the nine clinically unsuspicious regional lymph nodes
      correlates with earlier disease progression or indicates lower specificity of the
      method will need further investigation.

PMID- 8664040
TI  - The importance of a multidisciplinary group in the treatment of soft tissue
      sarcomas.
AB  - In 1987, a multidisciplinary soft tissue sarcoma (STS) group was established and
      a treatment protocol was set up. By 1993, there were 193 patients with a
      diagnosis of STS of the superficial trunk or extremities. 134 patients were
      referred with primary (stage M0) tumours and treated with curative or palliative
      intention. Nine amputations were performed. 94 (70%) patients were treated with
      wide or compartment surgery (n = 62) or marginal surgery combined with
      postoperative radiotherapy (n = 32). According to the protocol, these patients
      had received adequate treatment. 18 patients have recurred locally (13%) (median
      follow-up: 36 months). 12 were salvaged. 33 had metastases. The estimated 3-year
      survival, local control and disease-free survival rates are 79, 87 and 69%,
      respectively. These results compare favourably with previously published results
      from this hospital and from a nationwide study. The improved results emphasise
      the importance of a multidisciplinary STS group.

PMID- 8664041
TI  - Spiritual healing among Norwegian hospitalised cancer patients and patients'
      religious needs and preferences of pastoral services.
AB  - In a national questionnaire-based multicentre study, the use of 'alternative
      medicine', here called non-proven therapy (NPT), was examined. Five questions
      about the patients' religious beliefs and their preferences concerning pastoral
      services in the hospitals were included. Among the 911 invited patients, 642
      (70.5%) were included in the analysis. Spiritual healing, defined as faith
      healing and healing by hand, was the most frequently used NPT among Norwegian
      cancer patients. Almost 50% of cancer patients using spiritual healing had used
      NPTs, mainly spiritual healing, prior to the diagnosis of cancer. Women, elderly
      people and patients using faith healing described themselves more often as
      religious. 139 (23%) of the responding patients reported a strengthening of their
      religious belief after the diagnosis of cancer. Patients less than 45 years of
      age and better educated patients expressed more frequently that all patients
      should be offered pastoral services during the hospital stay. Older patients, in
      spite of being more religious, expressed that the patients themselves had to
      request such services.

PMID- 8664042
TI  - Radon in Devon and Cornwall and paediatric malignancies.
AB  - Exposure to radon in dwellings may cause cancer including paediatric
      malignancies. Devon and Cornwall have the highest exposure to radon of the
      counties of England. However, within these counties there is considerable
      variation in exposure. Exposure to radon in the 283 postcode sectors of the two
      counties has been published. The incidence of childhood malignancies between 1976
      and 1985 was studied to compare postcode sectors of radon exposures > or = 100
      Bq/m3 with sectors < 100 Bq/m3. No significant difference in the incidence rate
      of 106.7 per million child years in the high radon postcode sectors and 121.7 in
      the low (P = 0.29) was found. When the incidences of individual tumours were
      examined, a significantly increased rate of neuroblastoma (P = 0.02) and a non
      significant increased rate of acute myeloid leukaemia were found in the high
      exposure postcode sectors. No association between radon exposure and overall rate
      of childhood malignancy was found.

PMID- 8664043
TI  - Small influence of parental educational level on the survival of children with
      leukaemia in The Netherlands between 1973 and 1979.
AB  - We studied the effect of parental educational level (PEL), an indicator of socio
      economic status (SES), on survival of children with acute lymphoblastic (ALL) and
      non-lymphoblastic leukaemia (ANLL). All children with ALL and ANLL diagnosed in
      The Netherlands in the period 1973-1979, registered by the Dutch Childhood
      Leukaemia Study Group and followed until 1991 were included. Bone marrow and
      blood smears had been uniformly classified in a central laboratory; cases with
      acute lymphoblastic leukaemia (ALL) were subdivided into standard risk (SR) and
      high risk (HR). PEL, assessed as a risk indicator in a separately conducted
      population-based case-control study of the same children (response rate: 88%),
      was divided into low, when neither of the parents had more than elementary school
      or lower vocational education, and high when either had more. Children with SR
      ALL of high PEL parents had a slightly higher 10-year survival rate than of low
      PEL parents (58% versus 54%, P = 0.25), whereas survival for the latter increased
      more (P = 0.06) from a lower level in the period 1973-1975. However, children of
      low PEL parents with HR ALL and ANLL had a higher 10-year survival rate compared
      with children of high PEL parents (P = 0.10 and 0.22, respectively). Children
      without information on PEL, non-responders, migrants and with missing values
      exhibited slightly worse survival rates. The influence of PEL on survival of
      acute leukaemia in children in The Netherlands during 1973-1979 appeared small or
      even equivocal. Small differences in SES and optimal geographic and financial
      access to care, delivered through national treatment protocols, may be
      responsible for these results.

PMID- 8664044
TI  - Information about diagnosis and prognosis related to anxiety and depression in
      children with cancer aged 8-16 years.
AB  - The aim of this study was to test the hypothesis that being openly informed about
      the diagnosis and prognosis benefits the emotional well-being of children with
      cancer. A stratified sample of 56 children with cancer aged 8-16 years and their
      parents participated. The parents were interviewed about the information they had
      given to their child. Self-report questionnaires were administered to the
      children measuring anxiety and depression. Children who received open information
      about their diagnosis and prognosis at the initial stage of the disease showed
      significantly less anxiety and depression. Our findings suggest that parents
      should be advised to inform their child with cancer openly and soon after the
      initial diagnosis. Physicians should offer help to the parents in dealing with
      the difficult task of confronting the child with the diagnosis, prognosis and
      treatment.

PMID- 8664045
TI  - Survival for colon and rectal cancer in a population-based cancer registry.
AB  - Dukes' stage is the most powerful indicator of patient outcome for colorectal
      cancer. Several cancer survival studies have considered other prognostic
      variables, but results are often conflicting. We sought to assess the independent
      value of several clinical and morphological variables in defining colorectal
      cancer specific survival. 397 colorectal cancer patients diagnosed from 1984 to
      1986, and registered in a large bowel cancer registry instituted in a local
      health district of Northern Italy, were actively followed-up until 31 December
      1991. Univariate and multivariate survival analyses were carried out in colon and
      rectal cancer cases, separately, using the actuarial life-table method and Cox
      proportional hazard regressions. Crude and specific 5-year survival rates were
      37.5 and 41.4%. In univariate analysis, TNM (tumour, nodes and metastases) stage
      was the strongest predictor of prognosis in both sites. Other variables
      significantly related to survival were age of patient at diagnosis and pattern of
      tumour growth in colon cancer, type of differentiation and pattern of tumour
      growth in rectal cancer. In multivariate analyses, after adjusting for stage, age
      had a weak but significant negative effect on colon cancer survival, whereas
      rectal tumours with the infiltrating type of growth had a significantly worse
      prognosis than those with the expanding type. Colorectal cancer survival should
      be analysed in the main large bowel subsites in order to define high-risk groups
      within each TNM stage category.

PMID- 8664046
TI  - The role of reproductive and menstrual factors in cancer of the breast before and
      after menopause.
AB  - The aim of the study was to elucidate the role of reproductive and menstrual
      factors in the aetiology of breast cancer, overall and by menopausal status. A
      cooperative case-control study was conducted between 1991 and 1994 in six
      different Italian areas (including three from the centre and the south). The
      study included 2569 histologically confirmed incident cases of breast cancer
      (median age 55 years, range 23-78 years) and 2588 control women (median age 56
      years, range 20-79 years) admitted to the same hospitals for a variety of acute
      conditions unrelated to the hypotheses in study. A trend of increasing risk with
      increasing age at menopause (odds ratio (OR) for age at menopause > or = 53
      versus < 45 years = 1.8; 95% confidence interval (CI) = 1.4-2.2). High parity
      reduced cancer risk (OR for > or = 4 versus 1 birth = 0.7; 95% CI = 0.5-0.9).
      Overall, nulliparous women showed a 20% lower risk than uniparous ones (OR = 0.8;
      95% CI = 0.7-1.0). Late age at first birth (or pregnancy) had an independent
      adverse effect (OR for first birth at > or = 32 versus < 20 years = 1.7; 95% CI =
      1.3-2.1) both before and after menopause. An approximately 2-fold elevation of
      breast cancer risk was evident up to 10 years after the last birth. No trend in
      risk was evident for induced abortions (OR = 1.2 for 1 and 1.1 for > or = 2
      induced abortions versus 0). Other examined menstrual and reproductive
      characteristics did not seem important. Multiparity, early age at first birth and
      early age at menopause were therefore the most important determinants of breast
      cancer risk. The effects of the timing of births was significantly heterogeneous
      in pre- and postmenopausal women because of the transient adverse effect of such
      events, evident only in premenopausal women.

PMID- 8664047
TI  - Lack of effect of corticosteroids and tamoxifen on suramin protein binding and in
      vitro activity.
AB  - Stout and colleagues [Proc Am Assoc Cancer Res 1993, 34, p. 298] previously
      reported that both hydrocortisone and tamoxifen increased the free fraction of
      suramin in human plasma. We examined several corticosteroids as well as tamoxifen
      for their effects on suramin protein binding and also evaluated hydrocortisone
      for its ability to modulate suramin activity in PC-3 and MCF-7 cells. Greater
      than 99% of the suramin was protein bound in undiluted human plasma. However, the
      free fraction of suramin was increased with the reduced plasma protein levels and
      increased suramin concentrations. At concentrations ranging from 1 to 30 microM,
      neither tamoxifen, hydrocortisone, prednisone nor dexamethasone had any effect on
      the binding of suramin to human plasma, regardless of protein concentrations.
      Similar results were observed with fetal calf serum. Hydrocortisone also had no
      effect on suramin activity against PC-3 and MCF-7 cell in vitro. We conclude from
      these studies that neither corticosteroids nor tamoxifen affect suramin protein
      binding or its cytotoxic activity.

PMID- 8664048
TI  - Red blood cell polyamines, anaemia and tumour growth in the rat.
AB  - In rats with Mat Lylu prostatic carcinoma, significant changes in blood
      composition and red blood cell (RBC) characteristics were observed. Anaemia,
      characterised by a decrease in the number of RBC and the reduction of haemoglobin
      and the iron content in plasma, was correlated with tumour size and the
      accumulation of spermidine and spermine in the RBC. In large tumours, spermidine
      levels were increased by 8-fold over normal value. Spleen weight and splenic
      spermidine concentrations were enhanced in animals with tumours. After
      splenectomy, the rate of tumour growth decreased by 30%. It is proposed that
      anaemia in tumour-bearing animals is caused by enhanced RBC lysis, owing to the
      alteration of the rheological properties of RBC. These may be caused by the
      alterated surface characteristics due to polyamine accumulation. RBC lysis and
      high concentrations of polyamines in RBC and spleen appear, not only to favour
      tumour growth, but also to compromise the immunological defence mechanisms
      against neoplastic invasion.

PMID- 8664049
TI  - Reversion of UVC-induced tumorigenic human hybrid cells to the non-tumorigenic
      phenotype.
AB  - Non-tumorigenic HeLa x skin fibroblast human hybrid cells were UVC-irradiated (10
      J/m2) and induced to neoplastic transformation with accompanying morphological
      change and expression of the HeLa tumour-associated antigen, intestinal alkaline
      phosphatase (IAP). A single-cell-derived cell line was cloned out of a
      neoplastically transformed focus and designated as UV-12. In low density culture,
      this cell line demonstrated the ability to undergo reversion to a morphology
      similar to that of the non-tumorigenic parent with accompanying, much reduced
      levels of IAP expression. The frequency of this reversion to low IAP expression
      increased with passage of low density cultures reaching 10(-2) at 26 passages. A
      revertant colony was selected and expanded into a cell line which was designated
      UV-12-RM-1. This cell line had a 67-fold reduction in IAP expression compared to
      UV-12 and demonstrated a much reduced tumorigenic phenotype. A cell line
      reconstituted from a tumour derived from this cell line demonstrated a high IAP
      expression level (3-fold less than UV-12) and was highly tumorigenic. Six single
      cell-derived lines were cloned from UV-12-RM-1 and all had low IAP expression. Of
      these, one demonstrated an aggressive tumorigenicity, four showed the reduced
      tumorigenic phenotype characteristic of UV-12-RM-1, and one (UV-12-RM-105) was
      non-tumorigenic. However, with passage in culture, this latter cell line reverted
      to a weakly tumorigenic phenotype and a much elevated IAP level. It is
      hypothesised that the phenotypic shifts demonstrated by these UV-induced
      tumorigenic cells are under epigenetic control, and that they are most likely a
      consequence of an underlying genetic instability in the survivors of UVC
      irradiation.

PMID- 8664050
TI  - Photodynamic effects of 5-aminolevulinic acid-induced porphyrin on human bladder
      carcinoma cells in vitro.
AB  - The efficiency of 5-aminolevulinic acid (ALA) in photodynamic therapy (PDT) was
      investigated in vitro using urothelial carcinoma cells of various
      differentiation. HCV29, RT4 and J82 cells were cultured in 96-well plates,
      incubated with 25-100 micrograms/ml ALA in serum-containing medium for 4 h, and
      irradiated at 630, 635 and 640 nm wavelength with light doses of 15-100 J/cm2.
      The degree of reduced tetrazolium bromide corresponding to cell viability was
      determined with a colorimetric MTT assay 0, 24 and 48 h after PDT. A remarkable
      reduction of mitochondrial activity occurred in poorly (J82) and well
      differentiated (RT4) malignant urothelial cells. Twenty-four hours after
      photodynamic treatment with 100 micrograms/ml ALA and 50 J/cm2, the metabolic
      activity of malignant cells was nearly extinguished, while HCV29 cells, derived
      from normal urothelium, behaved similarly to non-irradiated control cells. The
      photosensitivity of cells depended on presence or absence of fetal bovine serum
      (FBS) in the ALA-incubation medium. A wavelength of 635 nm was up to 60% more
      effective compared with 630 nm, which is more frequently applied in PDT. From the
      results of our in vitro studies, we can define a "therapeutic window" for
      malignant cells without damaging benign cells. The time delayed effects and the
      strong wavelength dependence are important factors for a clinical application.

PMID- 8664051
TI  - Frequent TP53 gene alterations (mutation, allelic loss, nuclear accumulation) in
      primary non-small cell lung cancer.
AB  - Mutations of the TP53 tumour suppressor gene have been reported for many human
      cancers. A variety of TP53 mutations have also been reported for both primary non
      small cell lung cancer (NSCLC) and associated metastases. To assess the
      pathogenetic significance of TP53 gene alterations in NSCLC, 24 paired samples of
      primary NSCLC and the corresponding normal lung tissue were analysed for
      mutations of the TP53 gene (exons 5-8) using exon-specific PCR, single-strand
      conformation polymorphism PCR (SSCP-PCR) and direct DNA sequencing; for p53
      protein accumulation by immunohistochemistry and for 17p allelic loss using
      restriction fragment length polymorphism (RFLP) probes on Southern blots and
      amplified fragment length polymorphism-PCR. TP53 point mutations were observed in
      9/24 (38%) tumours encompassing a total of 14 mutations. Two tumours displayed
      the same double mutation while a third harboured four different mutations.
      Seventeen of 24 NSCLCs (71%) overexpressed p53 protein and all 17 immunopositive
      tumours (100%) showed a mutation and/or allelic loss at the D17S30 locus. Of the
      17 NSCLCs informative at the DS17S30 locus, 10 (59%) showed allelic loss, of
      which five (50%) were also mutated on the remaining TP53 allele. These results
      suggest that TP53 gene alterations are involved in the pathogenesis of primary
      NSCLC and that such alterations may serve a selective role in the development of
      NSCLC by diminishing the apoptotic potential of bronchial epithelial cells
      heterozygous for a TP53 point mutation. This may also explain the accumulation of
      multiple TP53 point mutations in 3/24 of our NSCLC samples.

PMID- 8664052
TI  - Effect of tyrphostin combined with a substance P related antagonist on small cell
      lung cancer cell growth in vitro.
AB  - The protein tyrosine kinase inhibitor [(3,4,5,-trihydroxyphenyl)-methylene]
      propanedinitrile (tyrphostin) was originally designed to inhibit polypeptide
      growth factor receptor signalling, but was also found to inhibit neuropeptide
      stimulated tyrosine phosphorylation and mitogenesis in Swiss 3T3 cells [J Biol
      Chem 1993, 268, 9548-9554]. Here, we demonstrate that tyrphostin inhibits in
      vitro colony growth of the H-345 and H-69 small cell lung cancer (SCLC) cell
      lines stimulated by the neuropeptides, bombesin and bradykinin, respectively.
      This effect was dose-dependent and, at tyrphostin concentrations above 5 microM,
      both background and neuropeptide stimulated colony formation were reduced. In
      liquid culture, tyrphostin inhibited the growth of the H-345 and H-69 SCLC cell
      lines with an IC50 of 7 microM. Time course experiments in liquid culture
      revealed that tyrphostin delayed the rate of entry of both SCLC cell lines into
      rapid phase growth and reduced the number of cells reaching a plateau phase of
      growth compared with control cells. Furthermore, tyrphostin concentrations at or
      above 50 microM reduced the number of cells present over time compared with
      untreated cells. When combined with a substance P (SP) analogue, which inhibits
      the action of multiple neuropeptides and SCLC cell growth, both in semisolid
      media and liquid culture, tyrphostin additively inhibited the growth of the H-345
      and H-69 SCLC cell lines in liquid culture.

PMID- 8664053
TI  - Newly established MST-1 tumour cell line and tumour-infiltrating lymphocyte
      culture from a patient with soft tissue melanoma (clear cell sarcoma) and their
      potential applications to patient immunotherapy.
AB  - The establishment and characterisation of paired autologous tumour cell line (MST
      1) and tumour-infiltrating lymphocyte (TIL) culture from a tumour mass of a 14
      year-old Taiwanese girl with soft tissue melanoma are described. MST-1 cells
      grown in vitro were heterogeneous in morphology, ranging from floating round
      cells, loosely attached round/oval or elongated cells with prominent pseudopod
      like processes, to well-attached spindle and elongated dendritic cells without
      obvious pseudopods. Immunostaining revealed that major melanoma-associated
      antigens, such as S100 protein, HMB-45, melanotransferrin, chondroitin sulphate
      proteoglycan, and the gangliosides GD2 and GD3, were consistently expressed by
      the tumour tissue, severe combined immunodeficiency (SCID) mouse xenograft and
      derived cell lines. Flow cytometric analysis of the tumour DNA content showed an
      index of 1.8 relative to normal peripheral blood lymphocyte DNA. Chromosome
      analysis revealed all cells at a hypotetraploid level with several clonal
      chromosome aberrations, including deletions at 10p and 12q, an addition at 12q,
      translocations t(1;14) and t(5;6). Electron microscopy showed melanosome
      structures. This observation and the expression of the major melanoma-associated
      antigens were all indicative of the melanocytic origin of MST-1 tumour.
      Interleukin-2 (IL-2) expanded TILs had the predominant CD8+ phenotype and the
      capacity to lyse cells of the cultured autologous tumour. The availability of the
      soft tissue melanoma cell line, the SCID mouse xenograft tumour system as well as
      autologous TILs described herein would provide useful materials for identifying T
      cell-defined antigens as well as a model system for devising individualised
      cancer biotherapeutic strategies. This cell line can also be used for further
      studies aimed at uncovering the histogenesis of this rare cancer.

PMID- 8664054
TI  - Correlations of Ki-67 and PCNA to DNA ploidy, S-phase fraction and survival in
      uveal melanoma.
AB  - In 79 patients with uveal melanoma, the tumours were investigated by DNA flow
      cytometry and immunohistochemical staining of PCNA and Ki-67. S-phase as a
      continuous variable was significantly correlated with Ki-67 (P = 0.033), but not
      with PCNA. DNA ploidy was not correlated with either of the two antigens. Ki-67
      was significantly correlated with histopathological type (P < 0.001) and tumour
      size (P < 0.001). Large tumours and epithelioid cell type were associated with a
      high frequency of Ki-67 positive cells. A high level of Ki-67 positivity (> or =
      6.5%) was also associated with a shorter survival (P = 0.0037), and when adjusted
      for DNA ploidy, histopathological type and tumour size, Ki-67 in the multivariate
      analysis remained an important prognostic factor (P = 0.017).

PMID- 8664055
TI  - Epithelial tumour cells in bone marrow of patients with pancreatic carcinoma
      detected by immunocytochemical staining.
AB  - In the present study, epithelial cells in the bone marrow of 42 patients with
      pancreatic carcinoma were identified immunocytochemically with monoclonal
      antibodies (MAbs) CK2, KL1 and A45-B/B3 directed to epithelial cytokeratins (CK),
      using the alkaline phosphatase anti-alkaline phosphatase method. The specificity
      of the MAbs was demonstrated by negative staining of marrow from 25 non-carcinoma
      age-matched control patients. Analysis of bone marrow aspirates from cancer
      patients revealed CK-positive cells in 14 (58.3%) of 24 cancer patients treated
      with curative intent and 10 (55.6%) of 18 patients with extended disease. After a
      median follow-up of 15.6 months (range 3-31 months), 5 (35.7%) out of 14 patients
      who underwent complete surgical resection but had tumour cells in bone marrow
      presented with distant metastasis and 6 (42.9%) with local relapse as compared to
      none of 10 corresponding patients without such cells (P < 0.05). The described
      technique may help to identify patients with pancreatic cancer and potential high
      risk of early metastatic relapse. The results promise to be of important
      assistance in determining prognosis and consequences in therapy of early stage
      pancreatic cancer.

PMID- 8664056
TI  - Retinoic acid concentrations in patients with squamous cell carcinoma of the head
      and neck.
AB  - The serum concentrations of all-trans (atRA) and 13-cis (13cRA) retinoic acid
      were determined by high performance liquid chromatography in 27 patients with
      squamous cell carcinoma of the head and neck and in 80 healthy controls. This
      investigation seemed relevant as ethanol is an aetiological factor in these
      cancers and has been suggested to interfere with the synthesis of atRA. Neither
      the serum concentration of atRA nor that of 13cRA differed between patients and
      controls. The serum atRA concentration did not differ between fasting and non
      fasting patients, but the serum 13cRA concentration was significantly higher in
      non-fasting than in fasting patients, probably due to the dietary retinoid
      content.

PMID- 8664057
TI  - 5-Fluorouracil cardiotoxicity: a unique mechanism for ischaemic cardiopathy and
      cardiac failure?

PMID- 8664058
TI  - Severe 5-fluorouracil toxicity possibly secondary to dihydropyrimidine
      dehydrogenase deficiency in a breast cancer patient with osteogenesis imperfecta.

PMID- 8664059
TI  - Vinorelbine/5-FU combination in metastatic breast cancer chemotherapy. A
      retrospective study of 63 cases.

PMID- 8664060
TI  - Studies of HLA-A and DR locus deletions in human liver cancer cell lines by PCR.

PMID- 8664061
TI  - Adenocarcinoma of the eccrine sweat gland: response to both combination
      chemotherapy and local field irradiation.

PMID- 8664062
TI  - Chemotherapy-induced onycholysis.

PMID- 8664063
TI  - Prevention of second primary tumours with a second generation retinoid in
      squamous cell carcinoma of oral cavity and oropharynx: long term follow-up.

PMID- 8664064
TI  - "It feels better"--measuring clinical benefit.

PMID- 8664065
TI  - [Effects of neurotensin on the development of suckling rats with intestinal
      resection].
AB  - Massive intestinal resection produces malabsorption which, in the suckling rat,
      reduces growth. Our aim was to determine whether the proliferative action of
      neurotensin, can reduce the negative effects on growth induced by bowel
      resection. Fifteen days old suckling Wistar rats were used. Twenty rats underwent
      90% midgut resection and twelve were used as controls. Half the animals were
      treated with neurotensin (600 micrograms/kg-day) until sacrifice 30 days later.
      Body and bone weight were measured and mucosal samples obtained. All resected
      animals lost body weight and bone weight. Neurotensin treatment reduced femur
      weight loss. After bowel resection, significant trophic effects were observed at
      mucosal level (crypt and villous size) but only in the jejunum of resected
      animals neurotensin treatment had a trophic effect. In conclusion, neurotensin
      favors intestinal adaptation after resection without improving mid-term growth in
      the suckling rat.

PMID- 8664066
TI  - [Detection of liver metastases in colorectal neoplasms: use of intraoperative
      echography].
AB  - Fifty patients were consecutively operated on for colorectal cancer. Preoperative
      ultrasonography and intraoperative palpation were compared to intraoperative
      ultrasonography to determine their relative capacities in the detection of liver
      metastases. Preoperative ultrasonography detected metastases in three patients
      (6%), intraoperative palpation in four (8%) and intraoperative ultrasonography in
      5 (10%). The number of metastases detected were 7, 19 and 19 respectively. The
      comparison failed to yield significant differences. From statistical viewpoint,
      both preoperative ultrasonography and intraoperative palpation were found to be
      as effective as intraoperative ultrasonography in detecting liver metastases.

PMID- 8664067
TI  - [Pancreatic disease in patients with HIV treated with didanosine (DDI)].
AB  - Pancreatic involvement has been studied in 70 HIV infected patients, in diverse
      stages, that were treated with didanosine (ddI), both as monotherapy or
      associated to zidovudine; 38% of patients presented adverse reaction that obliged
      to withdraw the medication: pancreatitis (4%), hyperamylasemia (21%) and
      abdominal pain and/or diarrhea (12%). The possible causes in presentation of
      adverse effects were evaluated: route of infection, stage of HIV infection, use
      of pentamidine or trimethoprim-sulfamethoxazole for preventing Pneumocystis
      carinii pneumonia, administration of ddI in monotherapy or in combined form with
      zidovudine, time of treatment and level of CD4 lymphocytes. The outcome of
      adverse effects is related significantly only with the most advanced stage of HIV
      infection.

PMID- 8664068
TI  - Ambulatory manometry of the small bowel: indications and analysis.

PMID- 8664069
TI  - [Idiopathic esophageal ulcer with fistulization to the bronchial tree in a HIV
      positive patient].
AB  - Idiopathic esophageal ulcerations (IEUs) associated with human immunodeficiency
      virus (HIV) infection are now recognized as an important cause of esophageal
      disease in this population. We report one case of IEU complicated with a fistula
      to the bronchial tree. Given his variable appearance, which may mimic other
      causes of esophageal ulceration and the high response rate to oral corticosteroid
      therapy, all HIV infected patients with esophageal ulceration should undergo
      endoscopy with biopsy to obtain a definitive diagnosis. We review the literature
      about the etiology, pathogenesis, management and treatment of the IEU.

PMID- 8664070
TI  - [Molecular changes in adenocarcinoma of the small intestine associated with Peutz
      Jeghers syndrome].
AB  - The presence of molecular alterations in the c-K-ras and p53 genes in a small
      bowel adenocarcinoma arising in a case of Peutz-Jeghers syndrome is reported. The
      absence of mutations at codon 12 and 13 of the c-K-ras gene in the hamartoma and
      carcinoma indicates that this oncogene does not contribute to its development. On
      the other hand, p53 protein overexpression was detected in a small proportion (5
      10%) of adenocarcinoma cells. Our findings suggest that p53 inactivation occur in
      late stages of tumour progression.

PMID- 8664071
TI  - [Early cerebral metastasis of colonic adenocarcinoma].
AB  - Solitary and early brain metastases from colon carcinoma are unusual. This
      possibility must be kept in mind, in patients with cerebral metastasis of unknown
      adenocarcinoma. These patients could benefit from colonoscopy and CEA studies
      with the aim of achieving more early diagnosis and surgical resection. The case
      of a 48-year-old woman with brain metastasis diagnosed 4 months before the
      primary tumor, a colon cancer, is reported.

PMID- 8664072
TI  - [Liver fibrosis associated with hepatorenal polycystosis in adults].
AB  - OBJECTIVE: A case of hepatic fibrosis in adult polycystic liver disease is
      reported. This association, commonly present in infancy, is exceptional in the
      adult polycystic liver disease. PATIENT: We report a 69-years-old female with
      adult polycystic kidney and liver disease with fatal hepatic failure, portal
      hypertension and renal failure. An autopsy was performed showing hepatic and
      renal polycystic disease with hepatic fibrosis. CONCLUSION: Hepatic fibrosis is a
      rarely associated phenomenon with adult polycystic liver disease. This data may
      suggest a relation of this entity with infancy fibropolycystic liver disease.

PMID- 8664073
TI  - [Ascites caused by portal hypertension in a patient with chronic myelomonocytic
      leukemia].
AB  - The case of a 79 years old man with chronic myelomonocytic leukemia and
      transudative ascites is described. Portal hypertension was produced by hepatic
      infiltration due to the hematological disorder, confirmed by liver biopsy.

PMID- 8664074
TI  - [Acute pancreatitis and acquired immunodeficiency syndrome].
AB  - Viral acute pancreatitis in Human Immunodeficiency Virus (HIV) infected patients
      has been occasionally described. We studied nine patients with HIV antibodies and
      acute pancreatitis attributed to Cytomegalovirus and/or Cryptosporidium
      infection. In four patients the clinical picture was consistent with acute
      pancreatitis while in five clinical manifestations were unspecific, and diagnosis
      was based on ultrasonography and/or computed tomography findings. In the HIV
      infected patient pancreatic evaluation by imaging techniques may disclose acute
      pancreatitis even in the absence of abdominal pain.

PMID- 8664075
TI  - [Spontaneous rupture of splenic cavernous hemangioma].

PMID- 8664076
TI  - [Retrorectal schwannoma].

PMID- 8664077
TI  - [Solitary plasmocytoma of the cecum].

PMID- 8664078
TI  - [Self-expanding esophageal metal stents in the palliative treatment of esophageal
      cancer].
AB  - We report our experience of two years (February 1993-February 1995) in the
      endoscopic treatment with self-expanding prosthesis (Ultraflex) of 21 patients
      with inoperable malignant oesophageal stenosis. 23 prosthesis were implanted
      enabling swallowing in less than 24 h. There were no major complications. In two
      occasions the prosthesis was obstructed by tumoral growth needing replacement.
      The prosthesis was occluded by solid food in four cases, which were resolved
      endoscopically.

PMID- 8664079
TI  - [Esophageal mucosal lesions and scleroderma: prevalence, symptoms and risk
      factors].
AB  - Scleroderma or systemic sclerosis (Ssc) is a connective tissue disease which
      frequently involves the esophagus. Motility disorders, such as a low pressure
      level in the Lower Esophageal Sphincter (LES), and disturbed esophageal
      peristalsis cause a higher acid exposition and mucosal damage. We study twenty
      Ssc patients using computerized esophageal manometry, endoscopy and clinical
      interview looking for prevalence of symptoms, esophageal dysmotility and erosive
      esophagitis, and trying to find risk factors involved in esophageal damage.
      Esophagitis was found in 40% of patients. Clinical presentation (diffuse or
      limited), age and time since diagnosis wer'nt accurate predictors of esophageal
      involvement. Symptoms such as dysphagia and heartburn had not any significant
      difference in those with and without esophagitis, so 25% of patients with mucosal
      damage had no symptoms and 60% of healthy ones complained about them. LES values
      were not significantly different between the two groups, with a great degree of
      overlap with normal values. Disturbed motility pattern of aperistalsis was the
      only factor that identified high and low risk groups for esophagitis, with a high
      statistical significance (p > 0.02). Mucosal sensitivity in severe esophagitis
      and pharyngeal and upper esophageal functions were normal in all patients.
      Impaired peristalsis, with a delayed clearance of acid is the most important
      factor for mucosal damage in scleroderma. Symptoms of gastroesophageal reflux are
      not a reliable predictor of erosive esophagitis. Endoscopy should be the usual
      method of diagnosis, in order to make a proper use of therapeutic weapons.

PMID- 8664080
TI  - [Is the omeprazole and amoxicillin combination useful in the treatment
      eradicating Helicobacter pylori in Spain?].
AB  - AIM: To evaluate the efficiency of omeprazole (20 mg/12 h) plus amoxycillin (1
      gr/12 h) in eradicating Helicobacter pylori in duodenal ulcer patients studied in
      four hospitals in our country. METHODS: One-hundred and four patients (mean age:
      49 +/- 16 years, 67% males) attended at four general hospitals in Spain, who had
      a duodenal ulcer demonstrated by endoscopy. These patients were infected with H.
      pylori demonstrated by urease test and histologic methods, and in 32 by a breath
      test and 18 by culture. Omeprazole 20 mg b.i.d. plus amoxycillin 1 gr b.i.d. was
      administered for 2 weeks. Endoscopy was repeated 1 month after completing
      therapy, and the aforementioned diagnostic methods were performed again. RESULTS:
      Eradication was achieved in 29% of cases (n = 30). In multiple logistic
      regression analysis, duration of ulcer disease was the only variable which
      correlated with success in H. pylori eradication (chi(2) = 7.2; p = 0.02).
      Additional variables (age, sex, smoking, pre-treatment with omeprazole, AINEs or
      H2 antagonist, ulcer size, and antral histologic gastritis) were not correlated
      with H. pylori eradication. Ulcer healing was demonstrated in 80% of patients (n
      = 83), and the healing rate was higher when eradication was achieved (97%) than
      in H. pylori-positive patients (73%) (p < 0.01). Compliance was good in all
      cases. No adverse effects were observed. CONCLUSION: [corrected] Disappointing
      results were obtained with omeprazole (20 mg b.i.d.) plus amoxycillin (1 gr
      b.i.d.) on H. pylori eradication. This combination cannot be recommended in our
      country at the doses employed in this study.

PMID- 8664081
TI  - In pursuit of an added dimension.
AB  - For dentists working in general practice, undertaking research is not an easy
      path to take. I know from my own experience that there are many problems, such as
      cost, time, and lack of training in methodology. However, I feel it is paramount
      that GDPs do carry out research and that originality of thought and individuality
      be allowed to flourish. The profession can only benefit from such challenges.

PMID- 8664082
TI  - Endosseous implants and overdentures.

PMID- 8664084
TI  - The use of acupuncture in dentistry.

PMID- 8664083
TI  - Sedation in primary and secondary dental health care.

PMID- 8664086
TI  - Teeth for life.

PMID- 8664085
TI  - Attitudes of dental health care workers to HIV infected persons.

PMID- 8664087
TI  - Nasal supernumeries?

PMID- 8664088
TI  - Self-injecting morphine for toothache?

PMID- 8664089
TI  - Stress in dental practice: a qualitative comparison of dentists working within
      the NHS and those working within an independent capitation scheme.
AB  - A qualitative research methodology was used to compare the stress experienced by
      dentists working under two different systems of remuneration. No absolute
      difference was found in the levels of stress experienced by the two groups, as
      measured by a questionnaire measure of stress experience. Both groups of dentists
      identified patient management, time pressures and staff and practice management
      as sources of stress, though the independent capitation scheme dentists felt that
      they were under less time pressure and faced considerably less paperwork.
      Techniques for stress management identified by the dentists were limited and
      symptom-focused. The results suggest that, for dentists at least, changing from
      NHS to an independent capitation scheme is of great benefit.

PMID- 8664090
TI  - A double-blind placebo-controlled study to assess the efficacy of a compound
      analgesic to prevent postoperative pain following oral surgery.
AB  - It has been suggested that small doses of opioid drugs given prior to surgery can
      reduce postoperative pain. This study was designed to compare the effectiveness
      of a paracetamol/codeine combination and paracetamol alone in preventing the pain
      following surgical removal of impacted third molar teeth under general
      anaesthesia. Analysis of the results showed no statistical differences between
      treatment groups when compared with placebo. We suggest that the opioids may not
      be the best drugs available to prevent the moderate to severe pain present
      following some oral surgery procedures.

PMID- 8664091
TI  - Needs for dental information of adolescents from an inner city area of Liverpool.
AB  - The aim of this study was to determine the needs for dental information of
      adolescents and investigate the relationship of their desire for information with
      their opinion of who decides to make an appointment with the dentist (ie parent
      or child). In-depth interviews were conducted with 10 adolescents (aged 14 to 16
      years) to derive questions for a questionnaire to assess dental information
      needs. One hundred and fifty-eight adolescents of similar age attending a
      secondary school in Liverpool were invited to complete the questionnaire. The
      results showed that adolescents are interested in finding out more information on
      different aspects of dental health which included especially: how to keep their
      teeth for life, about the best toothpaste, what to do in case they sustain dental
      injury and whether they required an orthodontic appliance. Another important
      finding was that more than half of the adolescents (57%) felt that they were
      responsible for taking decisions for their dental attendance. These children
      expressed a desire to know more about certain dental matters. Information needs
      of young people are important because of evidence derived from this study
      suggesting that acquisitiveness for dental information in this group, has
      possible implications for future patterns of seeking dental care.

PMID- 8664093
TI  - Tooth wear--dental erosion.
AB  - This article aims to address the issues arising out of the increasing concern by
      general dental practitioners of erosion-related tooth wear. The prevalence,
      common presentation, differential diagnosis, likely aetiology, prevention and
      management of suspected cases of this form of tooth wear are considered.

PMID- 8664092
TI  - A preliminary report on the determination of the vertical dimension of occlusion
      using the principle of the mandibular position in swallowing.
AB  - When constructing replacement complete dentures, trying to estimate the correct
      occlusion vertical dimension (OVD) can be difficult. This paper describes a
      method of using the swallowing method to estimate the correct OVD and to form
      occlusal pivots on old dentures prior to constructing new ones. The method has
      been used on 21 patients. The mean increase in the OVD was 9.7 mm with the
      largest increase being 19 mm and the smallest 3 mm. All the increases in OVD were
      done in one step, there were no gradual build-ups. New dentures were constructed
      to the height of the pivots once the patients were comfortable with the modified
      old dentures. In three cases the OVD had to be reduced once the dentures had been
      constructed but in all other cases the patients continued to wear their new
      dentures. All 21 patients answered a questionnaire about their new dentures. All
      of them were wearing their new dentures, and 18 out of 21 patients thought that
      their new dentures were better than their previous ones.

PMID- 8664094
TI  - Patterns of sexual behavior and risk taking among young New York City gay men.
AB  - One-hundred and seventy-four young New York City gay men (aged 18-24) were
      studied over a two-year period. We describe patterns of HIV risk taking behavior
      and factors that predict risk taking. Among men who engaged in receptive anal
      intercourse we discerned different patterns of behaviors. We defined risk takers
      as men who engaged in receptive anal intercourse. About two-thirds of the men
      fall into this category in each year, and about half of those (one third of the
      total) engaged in unprotected anal intercourse. Most of these men seem to make
      implicit decisions in managing their risk for HIV. Men who engaged in receptive
      anal intercourse were more likely to be in a coupled relationship and to know
      their partners' HIV status. Alcohol and/or drug use during sex, earlier sexual
      experiences, and greater integration into the gay community were also related to
      receptive anal intercourse. By contrast, a significant minority of the men, about
      6% of the sample, engaged in very high risk behavior in each year of the study
      defined as unprotected receptive anal intercourse with multiple partners. It
      appears that very high risk takers are qualitatively different from other risk
      takers: They reported more mental health problems, including more drug use, and
      higher levels of internalized homophobia and AIDS-related traumatic stress
      response. Implications for AIDS education and prevention are discussed.

PMID- 8664095
TI  - Social and sexual networks: their role in the spread of HIV/AIDS among young gay
      men.
AB  - This article examines how networks of social and sexual relations affect risky
      sexual behavior and HIV seroprevalence among young gay men. Social networks can
      transmit information and cultural norms regarding safer sex, while networks of
      sexual partners channel the risk of exposure to HIV infection. These two network
      effects may help to explain some of the behavior and seroconversion differentials
      in the gay community. A number of recent studies have shown higher rates of
      unsafe sex among younger gay men. In the Longitudinal AIDS Impact Project, for
      example, younger gay men (18-24) report unsafe receptive anal sex at rates double
      that for any other age group (30% vs. 14-16%). One possible explanation is that
      younger men have watched fewer friends and colleagues contract HIV or AIDS, and
      are correspondingly less cautious. We test this hypothesis by comparing the
      personal networks of younger and older gay men to see whether those who practice
      safer sex have more exposure to persons with HIV or AIDS. The results give only
      weak support for the hypothesis that personal exposure to the effects of HIV and
      AIDS increases adherence to safer sex practices. Seroprevalence patterns among
      young men may be the result of their sexual networks, with those choosing older
      partners more likely to be exposed to HIV infection. We examine this hypothesis
      by comparing the age composition of the unsafe sexual partner network for
      seropositive and seronegative young men. The results strongly support the
      hypothesis that younger gay men with older partners are the leading edge of the
      epidemic in their cohort.

PMID- 8664096
TI  - Trends in the AIDS epidemic among men who reported sex with men in New York City:
      1981-1993.
AB  - New York City is a major urban epicenter of the AIDS epidemic in the United
      States, and has reported nearly one fifth of the nation's cases. This paper
      chronicles trends in the AIDS epidemic among men who have sex with men (MSM) from
      1981 through 1993 in New York City. Annual AIDS incidence and cumulative deaths
      are described, results of survival analysis by race/ethnicity for three time
      periods are reported, and the effects of the epidemic on premature mortality are
      shown from the beginning of the epidemic through 1993. Among 25,812 cases
      reported in MSM, 52% were white, 25% were black and 21% were Hispanic. AIDS
      incidence among whites has been declining since 1987 and is continuing to
      increase among minorities. Survival has been improving over time among all groups
      analyzed, but a persistent differential in survival between different race and
      ethnic groups is found, with whites surviving longer than minorities. Overall,
      nearly one half a million person years of life before age 65 were lost among MSM
      between 1981 and 1993. A rapid increase in AIDS cases among men born 1970-79 who
      were diagnosed after 1988 suggests a new wave of the epidemic may be occurring,
      and continued efforts in AIDS education and prevention among MSM entering the age
      of sexual activity is required.

PMID- 8664097
TI  - Effects of AIDS-related bereavement on HIV progression among New York City gay
      men.
AB  - This study investigates the relationship between early AIDS-related bereavement
      and subsequent changes in CD4 T-cell levels and health over a three- to four-year
      follow-up period in 85 HIV positive gay men. In addition, two psychological
      responses to loss, grief, and depression were distinguished and used as
      predictors of changes in health following loss. Interview data collected each
      year was used to assess psychological, behavioral and health factors. Blood
      samples drawn yearly were used to assess CD4 T-cell levels. Results indicate that
      those who had experienced an AIDS-related bereavement event prior to entry into
      the study showed a more rapid loss of CD4 T-cells over time, controlling for age,
      initial health status, use of antiretrovirals, sedatives, recreational drugs,
      cigarettes, and alcohol as well as other potential confounding factors. CD4 loss
      rate differences were observable by two years post-bereavement. In addition,
      grief reactions were distinguishable from depressive reactions. Grief reactions
      were unrelated to CD4 decline and symptom onset while aspects of depression,
      specifically self-reproach, were predictive of CD4 loss. These data suggest that
      bereavement may impact biological systems relevant to HIV progression and that
      distinguishing specific responses to loss may improve our understanding of these
      relationships.

PMID- 8664098
TI  - Assisting gay men to maintain safer sex: an evaluation of an AIDS service
      organization's safer sex maintenance program.
AB  - As the second decade of the AIDS crisis unfolds, increasing concern has been
      raised that the widespread adoption of condom use that occurred among gay men in
      the 1980s is not being maintained. Most interventions to promote condom use among
      gay men are delivered by community-based organizations via programs that are
      virtually undocumented; little is known about their effectiveness, or the
      processes by which they may work. This study describes safer sex practices among
      self-identified gay men following their participation in an intervention
      developed and implemented by a community-based organization. The intervention was
      designed to enhance men's attitudes, beliefs, and self-efficacy expectations to
      maintain safer sex. Among 150 men with complete data at both assessments, self
      reported condom use was low. Men reported using condoms more consistently for
      anal sexual behavior than oral sexual behavior, but there were men who reported
      consistent unprotected anal sexual intercourse. The intervention had little
      impact on patterns of behavior over time, although desired changes in attitudes,
      beliefs, and self-efficacy expectations were evidenced following the
      intervention. The results suggest the importance of assisting community-based
      organizations to document program models. Findings also suggest that community
      based organizations can develop interventions to successfully enhance factors
      that theoretically support maintenance of safer sexual behaviors.

PMID- 8664099
TI  - GMHC volunteers and the challenges and hopes for the second decade of AIDS.
AB  - A documentation of the impact of AIDS on New York City during the first decade of
      the epidemic must highlight the extraordinary responses of the Gay Men's Health
      Crisis (GMHC) and other community-based organizations. Data collected from
      volunteers (n = 587) at the close of this decade are presented to address
      concerns about how successfully an organization such as GMHC will be able to
      confront the challenging future of the epidemic. Questionnaire data on
      demographics and prior AIDS experiences and responses to a GMHC Reasons for
      Volunteering Scale, developed for this study through exploratory and confirmatory
      factor analysis strategies, are brought to bear on questions about the (1)
      diversity of the volunteer community, (2) the extent to which volunteers are
      burdened by potentially debilitating AIDS-related experiences, and (3) the
      promise for the continued effective and inspirational functioning of GMHC
      suggested by volunteers' reasons for choosing to volunteer at this time.
      Volunteers, 62% of whom are gay men and 28% are heterosexual women, represent a
      wide age range but little diversity in race/ethnicity and educational background.
      They arrive at GMHC 8 years after its founding with a slight majority having had
      significant prior experience with HIV-related events. There are six basic kinds
      of reasons for their volunteering, in order of importance: Joining the AIDS
      Cause, Personal Growth, Social Contact, Helping the Gay Family, Coping with AIDS,
      and Career Enhancement.

PMID- 8664100
TI  - A typology of AIDS volunteers.
AB  - Based on our research of volunteers at Gay Men's Health Crisis (GMHC) in New York
      City, we developed a typology of AIDS volunteers derived from their responses to
      our Reasons for Volunteering scale. The scale included six basic reasons, three
      of which were AIDS-specific and three of which represented more general reasons
      for doing volunteer work. Cluster analysis was used to identify sub-groups in
      this sample, from which we identified seven distinct and meaningful types of
      volunteers. One type, which we labeled Self-Sacrificers, is the closest we could
      find to a group of altruists-volunteers who indicated that self-gain was
      unimportant to them. While the volunteers who endorsed AIDS-related reasons for
      volunteering were most likely to be gay men and to have had significant prior
      AIDS-related experiences, each cluster was markedly heterogeneous in terms of
      demographic characteristics. Implications are drawn for the management of
      volunteers in community-based AIDS organizations and for further research on
      helping behavior and altruism.

PMID- 8664101
TI  - AIDS service organizations and the gay community.

PMID- 8664102
TI  - HIV prevention efforts impaired in New York City.

PMID- 8664103
TI  - On the use of 133Cs as an NMR active probe of intracellular space in vivo.
AB  - Data are presented from 133Cs NMR studies on both excised and in situ tissues
      from rats fed a regular diet and administered i.p. CsCI in aqueous solution for 6
      to 14 days. Cesium is an NMR-active potassium analog which accumulates in the
      intracellular spaces of tissues [Davies et al., Biochemistry 27, 3547 (1988);
      Shehan, B.P. et al., Magn. Reson. Med. 30,573 (1993)]. Chemical shifts,
      relaxation properties, sensitivity and detectability of cesium in tissues were
      investigated. Consistent with previous reports, two resonances (representing
      intra- and extracellular cesium) were detected in blood. Only one resonance was
      detected in brain, kidney, and muscle tissue. Efforts to resolve intra- and
      extracellular components by T1 and T2 relaxation discrimination were not
      successful. Following i.p. administration, cesium accumulates intracellularly
      with a brain-to-cerebrospinal fluid concentration (mumol/g) ratio of 9:1 and a
      thigh muscle-to-plasma concentration ratio of 40:1. Considering the small
      extracellular volume in these tissues (ca 18% and 10%, respectively), the net
      content differences between intra- and extracellular cesium are approximately 40
      fold in brain and 360-fold in muscle. The concentration ratio of cesium in brain
      to cesium in cerebrosinal fluid decreased to 3:1 1 h after death, indicating a
      relatively slow rate of leakage of cesium from the intra- to extracellular space
      in the face of bioenergetic failure. These data suggest that the cesium signal is
      dominated by the intracellularly located cesium and, thus, cesium may be useful
      as a probe of the intracellular environment despite an inability to resolve and
      directly observe distinct resonances from intra- and extracellular spaces.

PMID- 8664104
TI  - Detection and quantitation of phosphorus metabolites in crude tissue extracts by
      1H and 31P NMR: use of gradient assisted 1H-31P HMQC experiments, with selective
      pulses, for the assignment of less abundant metabolites.
AB  - The analysis of crude tissue extracts by NMR has proven to be of use in the study
      of metabolism due to the non-destructive and non-selective character of the
      technique. Lists of 1H and 31P NMR assignments of phosphorus metabolites in water
      solution at specified pH and ionic composition are of large general value but
      their usefulness may be limited when analysing complex mixtures of metabolites at
      low concentrations. In this work we report on the use of gradient-assisted proton
      detected multiple quantum 1H and 31P coherence experiments with selective pulses
      for the rapid and unambiguous assignments of some crowded regions in 1H and 31P
      spectra of crude extracts from rat liver. The amplitudes of the gradient episodes
      were calibrated to optimize the coherence transfer pathway between proton and
      phosphorus, and the delay for the evolution of the long-range coupling was
      calculated from values of 3JPH and 4JPH ranging from 1.4 to 7.5 Hz. Moreover, a
      selective 90 degrees Gaussian pulse on the 31P channel was introduced to increase
      the resolution in the F1-domain and make the method even faster. The procedure
      was then applied to unambiguously assign the ID 31P and 1H spectra of perchloric
      acid extracts of rat livers that had been stimulated with phenylephrine, dBcAMP
      and glucagon and thus detect changes in the concentration of less abundant
      metabolites such as phosphoenolpyruvate, UDP-glucose and AMP. The fact that the
      quantification of these metabolites by either 31P and 1H methods lead to
      different results is discussed, and the use of 1H NMR spectroscopy for the
      quantification of phosphorus metabolites whose signal are too weak or poorly
      resolved in a 31P spectrum is proposed.

PMID- 8664105
TI  - The design of macrocyclic ligands for monitoring magnesium in tissue by 31P NMR.
AB  - A series of ligands based upon 1,4,7-triazacyclononane, containing variable
      numbers of acetate vs methylenephosphonate ester or methylenephosphonate
      sidechains, has been synthesized and characterized as possible 31P NMR probes for
      monitoring [Mg2+]free. The diacetate monophosphonate and diacetate
      monophosphonate ester mixed ligands proved to have conditional (dissociation)
      constants at pH 7.4 in an appropriate range for measuring typical levels of
      intracellular [Mg2+]free, and binding selectivities for Mg2+ over Ca2+ that
      ranged from 1.4 to 6.8. The 31P resonances of these ligands were well downfield
      of typical tissue phosphate metabolite resonances, and addition of Mg2+ to any
      one of these ligands resulted in well-resolved resonances for HL and MgL (where L
      = ligand), in slow chemical exchange. The chemical shift differences between the
      HL and MgL species varied from 2.1 to 2.6 ppm for three different ligands. The
      conditional Mg(2+)-L binding constants were sensitive to pH in the physiological
      range, due to protonation of a single macrocyclic nitrogen at high pH (log K1
      values ranged from 10 to 12). However, given conditions that allow an independent
      assessment of pH (i.e., from the 31P chemical shift of Pi), we show that accurate
      KD values can be estimated from the known thermodynamic stability constants
      (KMgL) and ligand protonation constants (Ki). This makes these ligands
      potentially useful for monitoring [Mg2+]free by 31P NMR over a variety of
      solution conditions, even during conditions when the pH may be changing.

PMID- 8664106
TI  - Evolution of acute focal cerebral ischaemia in rats observed by localized 1H MRS,
      diffusion-weighted MRI, and electrophysiological monitoring.
AB  - Focal cerebral ischaemia was produced in 11 rats by permanent occlusion of the
      right middle cerebral artery (MCA) using a suture model modified to enable
      manipulation with the animals in situ in an NMR spectrometer. The development of
      the ischaemic insults and the resultant infarcts were observed for up to 6 h by
      localized 1H MRS and diffusion-weighted MRI while performing continuous
      monitoring of electroencephalogram and extracellular DC potential. The ischaemic
      areas were depicted as regions of hyperintensity in the diffusion-weighted
      images. Signals due to lactate became visible in the 1H spectra after MCA
      occlusion indicating the onset of anaerobic glycolysis. A depletion of N
      acetylaspartate was seen in all animals post-occlusion. Transient or stepwise
      increases of lactate were observed to occur coincidentally with the events of
      spontaneous transient peri-infarct depolarization detected by the
      electrophysiological measurements. Expansion of the ischaemic area delineated in
      the diffusion-weighted images also accompanied peri-infarct depolarizations.
      These observations are consistent with transient peri-infarct depolarization
      playing a role in the growth of infarcts.

PMID- 8664107
TI  - 31P magnetic resonance spectroscopy as predictor of clinical response in human
      extremity sarcomas treated by single dose TNF-alpha + melphalan isolated limb
      perfusion.
AB  - Irresectable extremity sarcomas are large (grade II/III) tumors requiring
      amputation of the limb for local control. Limb salvage can be achieved by
      isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha),
      interferon-gamma and melphalan. To obtain insight into the effects of single dose
      ILP on extremity tumors, phosphate metabolism was monitored by 31P magnetic
      resonance spectroscopy (MRS) using the chemical shift imaging (CSI) technique. 2D
      CSI was used in combination with a slice select gradient in the third dimension
      to obtain true 3D localization. Spectral maps obtained prior to ILP revealed
      reductions in phosphocreatine (PCr) level and increases in phosphomonoester (PME)
      and phosphodiester (PDE) in tumor compared with muscle tissue. ILP treated tumors
      showed highly divergent changes in Pi while PME decreased in all cases (n = 11).
      Tumor volume, unchanged on day 8 after ILP, was decreased by 58 +/- 29% (mean +/-
      SD) at 2 months. Linear regression analysis revealed correlation between the
      changes in tumor metabolites measured on day 8, with percent volume decrease (Pi:
      r = -0.88, p < 0.001) and percent necrosis at resection (PME: r = -0.79, p 
      0.01). Correlation between pretreatment spectra and effectiveness of ILP
      treatment was not found. It is concluded that a single ILP with TNF-alpha +
      melphalan induced changes in tumor metabolite levels (measured on day 8) that
      reflect treatment efficacy. 31P MRS can thus provide information facilitating the
      decision as to when to remove tumor (residue) and, in the case where tumor
      remains inoperable, whether or not to apply additional therapy.

PMID- 8664108
TI  - A fast method for in vivo lactate imaging.
AB  - A robust method for fast lactate imaging is presented using a combination of a
      lactate editing sequence and a one-shot imaging experiment. The lactate editing
      method is based on manipulation of the phase of the lactate CH3 signal via J
      modulation. This is applied as a preparation experiment to the U-FLARE imaging
      sequence. Phantom experiments are presented in which the quality of water and
      lipid suppression is established. Edited lactate images with a spatial resolution
      of 3 microL and total measuring time of 15.8 min are shown. These were obtained
      from a hemispherical ischemia in the gerbil brain. The images are compared with
      diffusion-weighted water images.

PMID- 8664109
TI  - Tuberculosis notifications, 1994.

PMID- 8664110
TI  - Influenza.

PMID- 8664111
TI  - Reported annual incidence of poliomyelitis and acute flaccid paralysis (AFP), by
      WHO region.

PMID- 8664112
TI  - Randomised multicentre trials of CHART vs conventional radiotherapy in head and
      neck and non-small-cell lung cancer: an interim report. CHART Steering Committee.
AB  - While radiotherapy is proceeding, tumour cells may proliferate. The use of small
      individual doses reduces late morbidity. Continuous hyperfractionated accelerated
      radiation therapy (CHART), which reduces overall treatment from 6-7 weeks to 12
      days and gives 36 small fractions, has now been tested in multicentre randomised
      controlled clinical trials. The trial in non-small-cell lung cancer included 563
      patients and showed improvement in survival; 30% of the CHART patients were alive
      at 2 years compared with 20% in the control group (P = 0.006). In the 918 head
      and neck cases, there was only a small, non-significant improvement in the
      disease-free interval. In this interim analysis there was a trend for those with
      more advanced disease (T3 and T4) to show advantage; this will be subject to
      further analysis when the data are more mature. The early mucosal reactions
      appeared sooner and were more troublesome with CHART, however they quickly
      settled; so far no difference in long-term morbidity has emerged. These results
      support the hypothesis that tumour cell repopulation can occur during a
      conventional course of radiotherapy and be a cause of treatment failure.

PMID- 8664113
TI  - Follow-up of bone lesions in an experimental multiple myeloma mouse model:
      description of an in vivo technique using radiography dedicated for mammography.
AB  - The evolution of bone lesions in transplantable C57BL/KaLwRjj 5T mouse myeloma
      (MM) has been followed in vivo. Mice were anaesthetised and a radiograph of the
      pelvis and hind legs was performed by a radiograph dedicated for mammography.
      This is the first description of an in vivo technique under experimental
      conditions whereby the development of bone lesions owing to the MM growth was
      demonstrated.

PMID- 8664114
TI  - Different biodistribution of 99mTc-labelled chimeric mouse-human monoclonal
      antibody between athymic mice model and human.
AB  - Biodistribution of chimeric mouse/human monoclonal antibody against non-specific
      cross-reacting antigen (chNCA Ab) was studied in athymic mice and patients with
      metastatic bone disease. 99mTc-chNCA Ab showed a high labelling efficiency,
      stability and also a high binding ratio to human granulocytes. Since NCA showed
      cross-reactivity with carcinoembryonic antigen (CEA), animal experiments showed
      that 99mTc-chNCA Ab was accumulated in the xenografted tumour which expressed
      CEA, suggesting the preserved immunoreactivity of labelled materials. In the
      clinical study, injected 99mTc-chNCA Ab formed a high molecular weight complex
      immediately after intravenous administration and was trapped mainly in liver. The
      first-phase plasma half-life was 6.4 +/- 1.1 min. None of the patients showed
      adverse reaction or human antimurine or anti-chimeric antibody in their serum.
      99mTc-chNCA Ab demonstrated remarkably different biodistribution between patients
      and the animal model and showed different pharmacokinetics from other murine and
      chimeric Abs reported previously. For safety HPLC analysis should be performed
      before clinical radioimmunodetection or radioimmunotherapy by incubating
      radiolabelled MAb with human serum under strict conditions.

PMID- 8664115
TI  - Distribution and photodynamic effects of meso-tetrahydroxyphenylchlorin (mTHPC)
      in the pancreas and adjacent tissues in the Syrian golden hamster.
AB  - Photodynamic therapy (PDT) has the potential to destroy small tumours with safe
      healing of adjacent normal tissue. This study looks at the effects of PDT on the
      normal pancreas and adjacent tissues in hamsters using the photosensitiser meso
      tetrahydroxyphenylchlorin (mTHPC). Pharmacokinetic studies used fluorescence
      microscopy on sections of pancreas, stomach and duodenum 1 h to 6 days after
      mTHPC. Highest levels of sensitiser were seen in the gastric and duodenal mucosa
      and in the acinar pancreas after 2-4 days. For PDT, light at 652 nm was delivered
      by placing a 0.2 mm diameter bare-ended fibre against the tissue. An energy of 50
      J was used 2 or 4 days after 0.1 or 0.3 mg kg-1 mTHPC and animals killed 1 to 7
      days later. Maximum necrosis was seen 3 days after PDT with lesions up to 4 mm in
      pancreas, 4.5 mm in duodenum and 2.5 mm in stomach. By fractionating the light
      dose, the lesion size could be increased by 30%. The main complication was free
      or sealed duodenal perforation (avoided by shielding the duodenum). Partial,
      reversible bile duct obstruction was seen occasionally. There was no macroscopic
      damage to the bile ducts or major blood vessels. Apart from the duodenum, all
      lesions healed safely. In this animal model, only the duodenum was at risk of
      serious, irreversible damage. Treatment is likely to be safer in the much thicker
      human duodenum. mTHPC is a powerful photosensitiser and suitable for further
      study for tumours in the region of the pancreas although care is required near
      the duodenum.

PMID- 8664116
TI  - The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic
      agents on xenografted human tumours.
AB  - Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive
      drugs could be significantly increased when combined with chemotherapy drugs such
      as cisplatinum, depending on the timing of administration. The aim of this study
      was to define the toxicity (animal lethality) and the activity (growth delay
      assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined
      with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing
      xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+).
      Animal lethality was markedly increased when tirapazamine at the lethal dose 10%
      was combined with the other drugs. For the HRT18 tumour the combination of
      tirapazamine and bleomycin significantly increased the delay of regrowth compared
      with bleomycin alone (P = 0.04) and was more cytotoxic than tirapazamine alone (P
      = 0.04). For the Na11+ tumours the combination of tirapazamine with VP16
      significantly increased tumour doubling time compared with the controls (P =
      0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic
      than VP16 alone (P = 0.0001). When compared with c-DDP or tirapazamine alone,
      there was a significant decrease in plating efficiency when tirapazamine and c
      DDP were given at the same time (P = 0.04), but not when tirapazamine was given 3
      h before c-DDP. In conclusion, tirapazamine was shown to be cytotoxic against
      clonogenic human tumour cells. Its efficacy in vivo may depend on its combination
      with already active chemotherapy drugs on the tumour model used. The timing of
      administration may be less important than previously thought.

PMID- 8664117
TI  - Urinary gonadotropin peptide (UGP) in Egyptian patients with benign and advanced
      malignant urological disease.
AB  - Urinary gonadotropin peptide (UGP) levels were determined in urine samples from
      450 Egyptian subjects to determine its relative level of expression in benign and
      malignant urological disease, and normal individuals. The mean UGP level in
      patients with bladder cancer was 44-fold higher than in patients with benign
      disease, and 81-fold higher than in normal individuals. At specificities of 95%
      and 100%, overall sensitivities of 73% and 60%, respectively, were observed for
      the detection of malignant disease. Mean UGP levels in patients with bladder
      cancer were significantly correlated with the stage and grade of malignant
      disease but did not vary significantly when stratified according to histological
      type of disease, nodal involvement or bilharzial association. UGP could be a
      potentially useful marker for the differentiation of benign from malignant
      urological disease.

PMID- 8664118
TI  - Immunohistochemical staining of desmosomal components in oral squamous cell
      carcinomas and its association with tumour behaviour.
AB  - Desmosomes are intercellular junctions that have been shown to be down-regulated
      in certain types of carcinomas and that may play a role in suppression of
      invasion and metastasis. We have shown previously that immunohistochemical
      staining for the major desmosomal glycoprotein, desmoglein (Dsg), is reduced in
      some cases of squamous cell carcinoma (SCC) of the head and neck, and that
      reduced staining correlates with lymph node involvement. Desmosomes are
      multicomponent organelles. We therefore sought to determine whether another major
      desmosomal molecule, desmoplakin (Dp), showed similar reduced expression to that
      shown by desmoglein. We have stained 65 specimens of primary SCC of the oral
      cavity (37 non-metastatic and 28 metatastic) with monoclonal antibodies to both
      desmoglein and desmoplakin. We show that reduction of Dp staining correlates with
      loss of differentiation of the primary tumour, degree of invasion and presence of
      lymph node metastases. Similar correlations were found with Dsg staining. There
      was also correlation between reduction in Dp staining and reduction in Dsg
      staining. It is concluded that down-regulation of desmosomal expression occurs in
      some cases of SCC of the oral cavity and is associated with invasion and
      metastasis. Desmosomes may have an invasion and metastasis suppressor function.

PMID- 8664119
TI  - Additive effect modification of hepatitis B surface antigen and e antigen on the
      development of hepatocellular carcinoma.
AB  - To assess the role of hepatitis B e antigen (HBeAg) and its interaction with
      hepatitis B surface antigen (HBsAg) on the development of hepatocellular
      carcinoma (HCC), this case-control study included 361 age- and sex-matched pairs
      of patients with histologically proven HCC and healthy control subjects. HBsAg,
      HBeAg and antibody to HBeAg (anti-HBe) were detected by radioimmunoassay.
      Antibodies to hepatitis C virus (anti-HCV) were detected by second-generation
      enzyme immunoassay. The prevalences of HBeAg (20.2%), HBsAg (80.3%) and anti-HCV
      (29.5%) in cases were higher than in controls (1.9%, 20.7%, and 2.7%
      respectively; each P < 0.0001). Using patients negative for HBsAg, HBeAg and anti
      HBe as a referent group, univariate analysis indicated that HBsAg alone or HBsAg
      and HBeAg were risk factors for HCC (P for trend < 0.0001). Calculation of
      incremental odds ratio indicated that there was additive interaction between
      HBsAg and HBeAg. Multivariate analysis indicated that HCC development was
      strongly associated with the presence of HBeAg (odds ratio, 8.1; 95% confidence
      interval, 2.4-27.1), HBsAg (odds ratio, 68.4; 95% confidence interval, 20.5
      227.8) and anti-HCV (odds ratio, 59.3; 95% confidence interval, 13.6-258.4). In
      conclusion, HBsAg, HBeAg and anti-HCV are independent risk factors for HCC. There
      is additive and independent effect modification between HBsAg and HBeAg on the
      development of HCC.

PMID- 8664120
TI  - Secretory component mRNA and protein expression in colorectal adenomas and
      carcinomas.
AB  - Secretary component (SC) is expressed basolaterally as a transmembrane protein
      (pIg receptor) on secretory epithelial cells. As pIg receptor it plays a central
      role in humoral immunity by mediating the external translocation of dimeric IgA
      and pentameric IgM. A few case reports have suggested that reduced or absent SC
      protein expression is associated with diarrhoeal disease, but there is no
      convincing evidence that a primary pIg receptor deficiency can occur. In this
      study the relative presence of SC mRNA was determined by Northern blot analysis
      and related to immunohistochemically determined SC protein expression in 33
      colorectal adenomas (31 patients) with increased risk of developing sporadic
      colorectal cancer, as well as in 19 colorectal carcinomas from 19 patients with
      such sporadic tumours. In the adenomas, SC mRNA levels were positively related to
      SC protein expression; both mRNA and SC protein were negatively related to
      histological grade. Similarly, SC mRNA levels tended to be related to the SC
      protein expression in the carcinomas. SC mRNA was detected in all adenomas, and
      only two of ten carcinomas (10.5%) deemed to be SC deficient by
      immunohistochemistry also lacked SC mRNA expression, suggesting diallelic
      alterations in the SC-encoding gene (locus PIGR). This possibility agreed with
      Southern blot analysis performed on a separate sample of 32 other colonic
      carcinomas in which the diallelic loss of D1S58 (which exhibits a close linkage
      centromerically to PIGR) was calculated to be 6.4%. Together these findings
      suggested that reduced SC protein expression in colorectal adenomas might be a
      transcriptional defect reflecting the degree of cellular dysplasia, whereas
      absent SC protein expression in colorectal carcinomas might also involve post
      transcriptional defects and occasional diallelic gene deletions representing late
      events in carcinogenesis.

PMID- 8664121
TI  - Expression of 16 kDa proteolipid of vacuolar-type H(+)-ATPase in human pancreatic
      cancer.
AB  - Recent studies have shown that bafilomycin A1-sensitive vacuolar-type H(+)-ATPase
      (V-ATPase) plays important roles in cell growth and differentiation. However,
      there is no published study that has focused on the expression of V-ATPase in
      human tumour tissues. This study was designed to examine the mRNA and protein
      levels for the 16 kilodalton (kDa) proteolipid of V-ATPase in human pancreatic
      carcinoma tissues. We first investigated the mRNA level for V-ATPase in six cases
      of invasive pancreatic cancers and two normal pancreases, using reverse
      transcription-polymerase chain reaction technique. Then, we examined
      immunohistochemically the level of V-ATPase protein in 49 pancreatic cancers and
      ten benign cystic neoplasms of the pancreas, using antisera raised against the 16
      kDa proteolipid. There was a notable difference in the level of V-ATPase mRNA
      between normal and pancreatic carcinoma tissues, with no evident difference in
      the expression of the beta-actin gene. Immunohistochemically, 42 out of 46
      invasive ductal cancers (92%) displayed a mild to marked immunoreactivity for V
      ATPase in the cytoplasm, whereas neither non-invasive ductal cancers nor benign
      cystic neoplasms expressed detectable immunoreactive proteins. These findings
      suggest that the overexpression of V-ATPase protein is characteristic of invasive
      pancreatic tumours. V-ATPase may play some crucial roles in tumour progression.

PMID- 8664122
TI  - Differential expression of the topoisomerase II alpha and beta genes in human
      breast cancers.
AB  - Topoisomerase II is a key target for several anti-cancer drugs used for breast
      cancer therapy, including doxorubicin, epirubicin and mitoxantrone. Two isoforms
      of topoisomerase II (alpha and beta) have been described in human cells which
      differ in their subcellular localisation, biochemical properties and
      susceptibility to inhibition by anti-cancer drugs. The relative level of
      expression of the alpha and beta isoforms may contribute to the degree of tumour
      responsiveness to different chemotherapeutic agents. To assess the relationship
      between expression of topoisomerase II isoforms and established prognostic
      factors and pathological variables, 56 primary breast tumour samples were
      studied. The expression of the two topoisomerase II genes was apparently not co
      ordinately regulated in these tissue samples. There was no relationship between
      any of the commonly used pathological variables [tumour size, lymph node status,
      S-phase fraction (SPF)] and the level of expression of topoisomerase II beta
      mRNA. However, high topoisomerase II alpha gene expression was significantly
      associated with a high SPF (sign-rank test; P = 0.01). Moreover, the ratio of
      mRNA levels for topoisomerase II alpha and beta showed a stronger relationship to
      SPF (median raito 0.62 for tumours with SPF < 10, and 1.64 for SPF > 10; P =
      0.0021, sign-rank test). As expected from previous studies, an SPF > 10 was
      associated with poor overall survival (P = 0.01). Immunohistochemical analysis
      revealed that topoisomerase II beta was widely distributed ( > 90% positive
      tumour cells), but that topoisomerase II alpha expression was less widely
      expressed, with a pattern of expression similar to that of the proliferation
      dependent antigen recognised by Ki67. Because topoisomerase II gene expression
      showed a log-normal distribution, log-transformed data were used in multivariate
      analysis of relapse-free survival. This showed that lymph node status and
      topoisomerase II beta mRNA expression were the only significant survival factors
      (P = 0.001 and 0.05, respectively, with relative risks of 1.3 and 1.8). These
      results indicate that topoisomerase II alpha, but not beta, expression is
      dependent upon cellular proliferation status, but that the more widely expressed
      topoisomerase II beta protein may play a significant role as a target for anti
      tumour therapy.

PMID- 8664124
TI  - Clinical significance of serum CYFRA 21-1 in gastric cancer.
AB  - We studied the clinical significance of the soluble cytokeratin 19 fragment
      detected with monoclonal antibody CYFRA 21-1 in the sera of patients with
      histologically proven gastric cancer. Sera of 110 patients with gastric cancer
      were analysed for CYFRA 21-1 levels by a two-step sandwich enzyme immunoassay.
      There were no significant differences between CYFRA 21-1 levels and the
      histotype, depth of invasion or vessel invasion. However, CYFRA 21-1 was
      significantly higher in the presence of peritoneal metastases, liver metastases
      and extensive nodal involvement. When the positive cut-off value was defined as 5
      ng ml-1, the CYFRA 21-1 in the stage IV and recurrent cases was 55.6% and 66.7%,
      respectively, which was as high as carcinoembryonic antigen (CEA) and greater
      than carbohydrate antigen 19-9 (CA 19-9). The positivities in stage I/II and III
      were zero and 5.9%, respectively, and false-positive rate in 76 patients with
      benign gastrointestinal disorders was 2.6%. There appeared to be no correlation
      between CYFRA 21-1 and CEA or CA 19-9. The patients with above 5 n ml-1 of CYFRA
      21-1 had a significantly poorer prognosis. Multivariate analysis indicated that
      CYFRA 21-1 was an independent prognostic factor, while CEA and CA 19-9 failed to
      be of prognostic value. In conclusion, CYFRA 21-1 is a reliable tumour marker for
      gastic cancer in predicting very advanced cases, recurrence of the disease and
      overall poor prognosis.

PMID- 8664123
TI  - Lysosomal protease cathepsin D is a prognostic marker in endometrial cancer.
AB  - The present study investigates the prognostic value of immunohistochemically
      detected cathepsin D expression in endometrial adenocarcinoma. Patients with
      surgically treated endometrial adenocarcinoma FIGO stages I-III and consecutive
      irradiation therapy were included in the study. When we performed
      immunohistochemistry to detect cathepsin D in 115 tissue specimens 35 cases
      showed a positive reaction. In the univariate analysis cathepsin D expression
      showed significant prognostic value for overall survival (P-value = 0.007). In
      the multivariate analysis with established prognostic parameters (stage, grade)
      we found an independent prognostic value for cathepsin D (P-value = 0.002,
      relative risk = 3.8, 95% confidence interval 1.4 - 10.0). Immunohistochemical
      detection of cathepsin D could aid in predicting prognosis and planning therapy
      for patients with endometrial adenocarcinoma.

PMID- 8664125
TI  - Differential suppression of the tumorigenicity of HeLa and SiHa cells by adeno
      associated virus.
AB  - Adeno-associated virus (AAV) is well known for suppression of oncogenesis in
      rodents, but its inhibitory effects on human carcinoma are less well understood.
      We report the differential ability of AAV to inhibit the tumorigenicity of two
      human cervical carcinoma cell lines. The wild-type AAV-2 DNA carried by a pSV2Neo
      vector was transfected into HeLa cells, which contain 50 copies of human
      papillomavirus type 18 (HPV-18), and SiHa cells, which contain 1-2 copies of HPV
      16. About 1-3 copies of AAV genome were introduced per cell. AAV transfection
      moderately reduced the growth rate and anchorage-independent activity of the
      cells. In nude mice, the size of tumours arising from SiHa cells was reduced by
      87%, in contrast to no reduction in tumour size arising from HeLa cells. This
      suggests that the differential suppression exerted by AAV may be due to
      differences in HPV copy number. To define the region that is responsible for the
      oncosuppression, mutation analyses were conducted. The results of nude mice
      assays showed that both the replication gene and inverted terminal repeats of AAV
      were important for the inhibition. This study may provide a model system for
      further studies on the underlying mechanism of AAV oncosuppressive activity.

PMID- 8664126
TI  - Analysis of cAMP RI alpha mRNA expression in breast cancer: evaluation of
      quantitative polymerase chain reaction for routine use.
AB  - A quantitative polymerase chain reaction (PCR) method for determining
      concentrations of mRNA for the cyclic AMP (cAMP)-binding protein RI alpha, a
      regulatory subunit of cAMP-dependent protein kinase, was developed using site
      directed mutagenic primers and mix-melt PCR. The PCR product for RI alpha mRNA
      was modified to include an EcoRV restriction site for use as an internal
      standard. This mutant utilised the same primers as the target mRNA and differed
      in sequence by only four bases. As only one of these base changes results in a
      purine/pyrimidine switch the effective change in labelling with [32P]dCTP was
      less than 0.5%. Reverse transcription of mRNA was performed and quantitative PCR
      was carried out using fixed levels of mutant RI alpha vs varying amounts of both
      normal RI alpha sequence of known concentration and unknown samples. Validation
      of the technique using rigourous quality control established that reverse
      transcription, determined by incorporation of labelled nucleotides, gave intra-
      and interassay variations of 16.2 and 9.3% respectively. Using crossover
      evaluation of cDNA concentrations with cloned RI alpha sequences as controls
      intra- and interassay variations of 14.3% and 4-8% respectively were obtained.
      Using compounded errors, the limits of precision for this technique demonstrate
      that values that are altered by 50% or more represent a true alteration in mRNA
      levels between samples tested. This value compares favourably to similar values
      for radioimmunoassays of between 10% and 30% precision. Analysis of a series of
      patient samples during routine follow-up of treatment demonstrated clear changes
      in mRNA levels. Using site-directed mutagenesis to establish a quantitative PCR
      based assay for expression of mRNA this study demonstrates the potential
      usefulness and some limitations of quantitative PCR for applications within a
      clinical biochemistry laboratory. However, based on compounded error, values that
      vary by less than 50% within assays, and by less than 70% in separate assays
      could not be clearly separated. Assessment of paired patient samples has
      demonstrated clear changes in mRNA for the target protein RI alpha. With the use
      of normal quality control procedures this study has established that the degree
      of reproducibility of this quantitative PCR technique would allow assessment of
      mRNA levels for markers of interest in clinical samples in a routine laboratory
      context.

PMID- 8664127
TI  - Prognostic value of steroid receptors after long-term follow-up of 2257 operable
      breast cancers.
AB  - The prognostic value of oestrogen receptor (ER) and progesterone receptor (PR)
      was estimated through a multicentric study of 2257 operable breast cancer
      patients followed up for a median of 8.5 years. None of the patients had received
      adjuvant therapy. The series included 33.3% stage I patients, 57.1% stage II,
      5.7% stage IIIa and 2.4% stage IIIb. At the end point of the study 589 metastases
      and 537 deaths from cancer were recorded. Receptor measurements were performed by
      radiolgand assay according to a uniform protocol. A total of 68.8% of the tumous
      were ER positive and 54.0% PR positive ( > or = 10 fmol mg-1 cytosol protein). In
      univariate analysis, ER and PR status (positive/negative) were of prognostic
      value (P < 0.001) for the disease-free interval (DFI), the metastases-free
      interval (MFI) and the overall survival (OS). The OS of the patients after a
      first metastasis was also significantly different between ER-positive and 
      negative tumours (P < 0.001). In multivariate analysis (Cox proportional hazard
      model, 1665 patients), only the ER status showed a significant difference (P <
      0.01) between positive and negative groups regarding the DFI, MFI and OS. By
      using Cox non-proportional, time-dependent models, we show that the predictive
      value of ER status of the primary tumour decreases by approximately 20% per year,
      losing its significance after 8 years of follow-up. Overall, when compared with
      TNM and histological grading, ER and PR status have a low prognostic value, their
      major interest remaining solely in the domain of therapeutic decision.

PMID- 8664128
TI  - Serum progesterone and prognosis in operable breast cancer.
AB  - Several studies have now shown that women with operable breast cancer undergoing
      tumour excision during the luteal phase of the menstrual cycle have a better
      prognosis than those having surgery during the follicular phase. As part of a
      prospective study of prognostic factors in breast cancer, blood was taken at the
      time of surgery. Between 1975 and 1992 this was available from 289 premenopausal
      women within 3 days of tumour excision. All were treated by either modified
      radical mastectomy or breast conservation including axillary clearance and the
      date of last menstrual period (LMP) was known in 239 (80%) cases. Blood samples
      were assayed for both oestradiol (E2) and progesterone (P). Because of the wide
      inter-individual variation in E2 levels there was no clear relationship between
      E2 and LMP. However, using a running mean smoothing technique the expected
      cyclical variation could be discerned. There was no significant association
      between E2 and survival. Smoothing of the P data yielded a pattern similar to the
      normal hormone profile. Those cases with a progesterone level of 4 ng ml-1 or
      more had a significantly better survival than those with a level < 4 ng ml-1.
      This was especially clear in node-positive patients (P < 0.01). The possibility
      of misclassification of menstrual cycle status, because of misreported LMP, has
      been minimised by applying an independent hormonal measurement (P) of cycle
      activity. This parameter will also identify women who may be undergoing anovular
      cycles. Thus this study has confirmed that a raised level of progesterone at the
      time of tumour excision is associated with an improvement in prognosis for women
      with operable breast cancer.

PMID- 8664129
TI  - Growth rate of lung metastases and S-phase fraction as determined by flow
      cytometry from the primary tumour in 25 patients with bone or soft-tissue
      sarcomas.
AB  - A significant correlation (r = -0.48) was found between the logarithm of the S
      phase fraction of the primary tumour (SPF) and the logarithm of the doubling time
      of lung metastases (T2). The estimated median cell loss factor was 88% (range 35
      99%).

PMID- 8664130
TI  - The relationship between weight loss and interleukin 6 in non-small-cell lung
      cancer.
AB  - Markers of the inflammatory response, interleukin 6, C-reactive protein, albumin
      and full blood count, were measured in non-small-cell lung cancer (NSCLC)
      patients (n = 21) with and without weight loss ( > 5%). There were significant
      increases in circulating C-reactive protein (P < 0.001), interleukin 6 (P < 0.01)
      and platelets (P < 0.01) in the weight-losing group. Moreover, there was a
      statistically significant correlation (r = 0.785, P < 0.001) between interleukin
      6 and C-reactive protein concentrations. These results are consistent with
      interleukin 6 and the acute phase response promoting weight loss in NSCLC.

PMID- 8664131
TI  - A randomised trial of low-dose/high-frequency chemotherapy as palliative
      treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign
      trial.
AB  - We report the results of a randomised trial in extensive small-cell lung cancer
      (SCLC) of a novel approach to palliative chemotherapy. A widely used 3 weekly
      regimen was compared with the same drugs given at half the dose but twice the
      frequency with the same intended overall dose intensity (DI). A total of 167
      patients defined as having extensive SCLC with adverse prognostic features were
      randomised to receive either a 3 weekly regimen of cisplatin 60 mg m-2 i.v. on
      day 1 and etoposide 120 mg m-2 i.v. on day 1 and 100 mg b.d. orally on days 2 and
      3 alternating with cyclophosphamide 600 mg m-2 i.v., doxorubicin 50 mg m-2 i.v.
      and vincristine 2 mg i.v. all on day 1 for a maximum of six courses (3 weekly);
      or treatment with the same drugs but with each course consisting of half the 3
      weekly dose given every 10 or 11 days for a maximum of 12 courses. In the 10/11
      day regimen overall response rate was 58.9% (95% CI, 47.9-69.2%) with 12.8%
      complete responses (CR). For the 3 weekly treatment the overall response rate was
      44.9% (95% CI, 35.0-55.5%) with 10.1% CR. Median survival was similar in the two
      arms at 6.4 months (95% CI, 4.9-7.3 months) and 5.8 months (95% CI, 4.0-6.6
      months) respectively. Survival at 1 year was 9.9% (95% CI, 5.0-18.5%) and 8.9%
      (95% CI, 4.6-16.6%). The 95% CI for the difference in survival at 1 year is 
      7.09% to +9.09%. Haematological toxicity and treatment delays owing to infection
      were more frequent with the 10/11 day regimen but other toxicities were equal in
      both arms. Other aspects of quality of life were measured in a small
      representative cohort of patients using a daily diary card (DDC). There was a
      trend of improved quality of life on the 10/11 day arm, but there was little
      difference between the two treatments. The trial shows that a low-dose/high
      frequency regimen with the same DI as conventionally scheduled chemotherapy gives
      similar response rates and survival. This and other modifications of the schedule
      may offer new approaches to palliative treatment of advanced cancer. However, in
      this trial there was no significant benefit in toxicity or other aspects of
      quality of life.

PMID- 8664132
TI  - Relationship between the exposure to cisplatin, DNA-adduct formation in
      leucocytes and tumour response in patients with solid tumours.
AB  - The study was designed to investigate possible relationships between tumour
      response and exposure to cisplatin (area under the curve of unbound cisplatin in
      plasma, AUC) and DNA-adduct formation in leucocytes (WBC) in patients with solid
      tumours. Patients were treated with six weekly courses of cisplatin at a dose of
      70 or 80 mg m-2. The AUC was determined during the first course and DNA-adduct
      levels in WBC during all courses at baseline, 1 h (A(max)) and 15 h after a 3 h
      infusion of cisplatin. The area under the DNA-adduct-time curve (AUA) was
      calculated. The tumour response was determined after six courses. Forty-five
      evaluable patients received 237 courses of cisplatin. Sixteen patients with head
      and neck cancer received a dose of 80 mg m-2 and 29 with various other tumour
      types received 70 mg m-2 plus daily 50 mg oral etoposide. There were 20
      responders (partial and complete) and 25 non-responders (stable and progressive
      disease). The AUC was highly variable (mean +/- s.d. = 2.48 +/- 0.51 micrograms h
      1 ml-1; range 1.10-3.82) and was closely correlated with the AUA (r = 0.78, P <
      0.0001) and A(max) (r = 0.73, P < 0.0001). The AUC, AUA and A(max) were
      significantly higher in responders than in non-responders in the total population
      (P < 0.0001) and in the two subgroups treated at 70 or 80 mg m-2. In logistic
      regression analysis AUC, AUA and A(max) were important predictors of response.
      The magnitude of exposure to cisplatin is, through DNA-adduct formation, the
      major determinant of the response rate in this population. Hence, individualised
      dosing of cisplatin using AUC or DNA-adducts should lead to increased response
      rates.

PMID- 8664133
TI  - Prospective randomised trial of two dose levels of megestrol acetate in the
      management of anorexia-cachexia syndrome in patients with metastatic cancer.
AB  - Two doses of megestrol acetate (MA) have been prospectively compared in a random
      fashion as treatment for cancer-related anorexia-cachexia syndrome (ACS) in 122
      patients with progressive soft tissue sarcoma, colorectal, lung, head and neck
      and renal cancer resistant to systemic chemotherapy. After 30 days of MA, 55% of
      patients receiving MA at 160 mg day-1 reported an increase in appetite, 27% of
      patients no variation and 18% complained of a decrease in appetite. Patients
      treated with MA at 320 mg day-1 reported an increase in appetite in 68% of cases,
      a stabilisation in 20% of cases and a decrease in 12%. Although an increase in
      appetite was more frequently observed in patients receiving MA at 320 mg day-1,
      however this difference was not statistically significant (P = 0.305). After 30
      days of MA, 31% of patients treated with MA at 160 mg day-1 showed an increase in
      body weight, 25% a stabilisation and 44% a decrease. In the group of patients
      treated with MA at 320 mg day-1, 45% reported an increase in body weight, 16% no
      change and 23% weight loss. Although there was a trend favouring the higher dose
      of MA, overall analysis however failed to detect any statistically significant
      difference between the two treatment arms (P = 0.242). Twenty-seven patients
      pretreated with 160 mg day-1 and 23 patients treated with 320 mg day-1 received
      further therapy with MA at the dose of 320 and 480 mg day-1 respectively. In the
      group of 22 patients treated with 320 mg day-1 four (18%) reported an increase in
      body weight, eight (36%) an improvement in appetite, but none had an increase in
      performance status. Among the 20 evaluable patients treated with 480 mg day-1,
      two (10%) had an increase in body weight, four (20%) an improvement in appetite,
      but none reported an increase in performance status. No difference in median
      survival was detected between the two arms. Toxicity was mild and predictable. In
      conclusion, the data achieved in the present study confirm the clinical safety
      and effectiveness of oral MA in the management of ACS in patients with advanced
      cancer resistant to systemic chemotherapy. Moreover, data concerning the dose
      escalation of MA dosage in unresponsive patients suggest that a step by step
      increase in MA dosage could be the best way of administering MA for the
      management of ACS and that the increase of MA dosage over 480 mg day-1 will
      probably be useless in the vast majority of cases. Data on body weight suggest
      that after 2 weeks' therapy MA could be stopped or its dosage tailored to
      patients' needs since the majority of patients respond after only 15 days of MA.

PMID- 8664134
TI  - Biochemical evaluation of bone turnover in cancer patients with bone metastases:
      relationship with radiograph appearances and disease extension.
AB  - Serum bone alkaline phosphatase (BALP), serum carboxy-terminal propeptide of type
      I procollagen (PICP) and serum bone gla protein (BGP) as markers of bone
      formation, serum carboxy-terminal telopeptide of type I collagen (ICTP) as a
      marker of collagen resorption and fasting molar ratio of urinary calcium to
      creatinine (CaCr) and serum parathyroid hormone (PTH) were determined in two
      groups of cancer patients: 48 with advanced or metastatic disease with negative
      bone scan and 174 with bone metastases categorised as having lytic, mixed or
      blastic lesions and with more or fewer than or equal to three sites involved. In
      patients without apparent bone involvement, bone formation markers were rarely
      elevated. Conversely, serum ICTP was frequently found to be supranormal, showing
      it to be a non-specific marker for early detection of bone metastases. As
      expected, values of bone formation markers progressively increased in patients
      with lytic, mixed and blastic lesions, but ICTP levels did not show any
      differences according to the types of bone appearances, confirming previous
      reports of elevated osteoclast activity also in patients with apparent blastic
      lesions. Serum PTH increased significantly in patients with lytic compared with
      patients with mixed and blastic appearances, paralleling the bone formation
      markers, but CaCr showed the opposite pattern. These data are compatible with
      calcium entrapment in the bone in patients with increased osteoblast activity.
      This so called 'bone hunger syndrome' is further confirmed by the finding that in
      the subgroup of blastic appearances CaCr diminished whereas both ICTP and PTH
      increased according to the extent of tumour load in the bone.

PMID- 8664135
TI  - A randomised trial of two information packages distributed to new cancer patients
      before their initial appointment at a regional cancer centre.
AB  - The purpose of this study was to evaluate the extent to which a new patient
      information package (NPIP) or a mini version of the same package (mini-NPIP)
      reduces emotional distress and meets the informational needs of patients arriving
      at a tertiary cancer centre for the first time. A comprehensive package, NPIP,
      consisting of procedural information regarding cancer centre location,
      description of the health care team, treatment services, research, educational
      activities, accommodation and community services provided at the centre; and a
      condensed version of the same package, mini-NPIP, were developed. Consecutive
      patients with newly diagnosed breast, gynaecological, lung and prostate cancer,
      referred to the centre for the first time were prerandomised to receive NPIP,
      mini-NPIP or no information package. Patients randomised to NPIP or mini-NPIP
      were mailed the information package at least one week before their first
      appointment. On arrival at the centre, patients were administered the Brief
      Symptom Inventory (BSI) which measures psychological distress, and interviewed
      regarding preferences for information and acceptability of the information
      packages. Of 465 randomised patients, 161 were excluded post-randomisation and
      304 completed the entire interview: 100 were randomised to the NPIP, 102 to the
      mini-NPIP and 102 to the control group. Emotional distress as measured by the BSI
      was similar for all groups (P = 0.98). Most patients preferred to receive the
      information (98%), receive it before the first appointment (84%) and by mail
      (79%). These preferences were more evident for those given the information
      packages. The majority of patients found the information packages easy to
      understand (88%) and useful (89%), and no differences were detected between
      packages. The cost of production and dissemination of NPIP was more than double
      the cost for mini-NPIP: $ 8.93 vs $ 3.98 (Canadian dollars) per patient. For
      patients presenting to a cancer centre for the first time, packages of procedural
      information do not appear to reduce psychological distress, but are preferred by
      patients. Given the cost of producing NPIP, mini-NPIP is the preferred approach.

PMID- 8664136
TI  - Prognostic factors and survival in a heterogeneous sample of cancer patients.
AB  - This study examines the prognostic value of clinical assessments, including a 3
      fold classification of cancer patients by treatment intention. It is based upon a
      sample of 253 patients with different cancer diagnoses who filled out a 108-item
      questionnaire. Cox regression analysis (the proportional hazards model) was used
      to analyse the relationship of the three groups of covariates (clinical,
      demographic and psychosocial) with survival. The univariate analysis showed that
      several clinical, demographic and psychosocial covariates are significantly
      related to survival. The study located two main prognostic factors: the 3-fold
      classification by treatment intention being the most important one, followed by
      physical functioning which may be seen as a proxy for performance status. Several
      additional covariates including psychosocial ones were related to survival when
      considered separately. However, their effects disappeared when controlling for
      treatment intention and physical functioning. Thus, the additional psychosocial
      covariates did no add to the prognostic value of the model.

PMID- 8664137
TI  - Decreased serum retinol levels in women with cervical dysplasia.
AB  - To examine the relationship of dietary and serum vitamin A to the risk of
      cervical dysplasia, a case-control study was conducted in Miyagi, Japan. Cases
      were 137 women who were found by Papanicolaou test screening and histological
      examination provided by Miyagi Cancer Society between October 1987 and September
      1988 to have cervical dysplasia. Controls were selected from participants of the
      general health examination provided by the Society and individually matched to
      cases on age and screening date. The consumption of retinol or carotene-rich
      foods during the past 7 days was assessed at interview. Information was also
      collected about other risk factors of cervical dysplasia, such as reproductive
      histories and sexual behaviour. The mean serum retinol levels were significantly
      lower among cases compared with controls, although dietary intake levels of
      retinol and carotene were not different between the two groups. When examined by
      tertile, the risk of cervical dysplasia was significantly higher among women in
      the highest tertile of dietary vitamin A level. An inverse association was
      observed between serum retinol level and risk of cervical dysplasia, although it
      did not achieve statistical significance.

PMID- 8664139
TI  - Non-solar ultraviolet radiation and the risk of basal and squamous cell skin
      cancer.
AB  - A case-control study of non-melanocytic skin cancer was conducted among men in
      the province of Alberta, Canada. Two hundred and twenty-six cases of basal cell
      carcinoma (BCC), 180 cases of squamous cell carcinoma (SCC) and 406 age-matched
      controls provided information concerning skin pigmentation, occupational history,
      recreational activity, exposure to sunlight and sources of non-solar ultraviolet
      radiation (NSUVR) and other potential risk factors. Our analyses show no evidence
      of elevated risk for BCC or SCC among subjects exposed to various types of NSUVR.
      This is in opposition to studies of melanoma that have shown elevated risks for
      exposure to fluorescent lighting, sunlamps and sunbeds.

PMID- 8664138
TI  - Risk of cutaneous melanoma in relation to the numbers, types and sites of naevi:
      a case-control study.
AB  - The atypical mole syndrome (AMS) phenotype, characterised by a large number of
      common naevi as well as atypical naevi, has been described in families with a
      genetic susceptibility to melanoma. However, the importance of this phenotype for
      melanoma in the general population has not been conclusively determined. This
      study was designed to examine the types and distribution of naevi as well as the
      prevalence of the AMS phenotype in melanoma patients in England compared with
      controls. A total of 426 cutaneous melanoma cases (61% of all incident cases)
      aged 16-75 years were recruited between 1989 and 1993 from the north-east Thames
      region of the UK and 416 controls from the same age group were recruited over the
      same period and from the same region. Each subject answered a questionnaire
      covering demographic details, sun exposure history and other risk factors and
      underwent a skin examination with total body naevus count performed by a
      dermatologist. The AMS phenotype was defined using a scoring system. Atypical
      naevi gave the highest relative risk for cutaneous melanoma, with an odds ratio
      (OR) of 28.7 (P < 0.0001) for four or more atypical naevi compared with none.
      Many common naevi were also an important risk factor: the OR for 100 or more
      naevi 2 mm or above in diameter compared with 0-4 naevi was 7.7 (P < 0.0001).
      Melanoma was also associated with naevi on sun-exposed sites but also with naevi
      on non-sun-exposed sites such as the dorsum of the feet, buttocks and anterior
      scalp. Sixteen per cent of the cases had the AMS phenotype compared with 2% of
      the controls (OR 10.4, P < 0.0001). The AMS phenotype was more common in males
      than females (P = 0.008). The odds ratio for the presence of the AMS phenotype
      was dependent on age, with an odds ratio of 16.1 (95% CI 4.6-57.5) for the
      presence of the AMS phenotype if aged less than 40 compared with an odds ratio of
      6.9 (95% CI 2.9-16.6) if aged 40 or more. The AMS phenotype was strongly
      predictive of an increased risk of melanoma outside the familial context.

PMID- 8664140
TI  - A prospective study of urinary oestrogen excretion and breast cancer risk.
AB  - To test the hypothesis that high levels of endogenous oestrogens increase the
      risk for developing breast cancer, concentrations of oestrone, oestradiol and
      oestriol were measured in 24 h urine samples from 1000 women participants in a
      prospective study of breast cancer on the island of Guernsey. Sixty-nine subjects
      were diagnosed with breast cancer subsequent to urine collection. Among women who
      were premenopausal at the time of urine collection, cases excreted less oestrogen
      than controls; the odds ratios (95% CI) for breast cancer in the middle and upper
      thirds of the distribution of oestrogen excretion, in comparison with the lower
      third (reference group, assigned odds ratio = 1.0), were 0.5(0.2-1.2) and 0.4(0.2
      1.1) respectively for oestrone, 0.8(0.4-1.8 and 0.4(0.2-1.1) for oestradiol,
      0.7(0.3-1.6) and 0.7(0.3-1.6) for oestriol and 0.9(0.4-2.0) and 0.5(0.2-1.3) for
      total oestrogens. Among women who were post-menopausal at the time of urine
      collection, the trend was in the opposite direction, with an increase in risk
      associated with increased oestrogen excretion; the odds ratios were 0.9(0.3-2.2)
      and 1.1(0.5-2.8) for oestrone, 0.8(0.3-2.3) and 1.9(0.8-4.6) for oestradiol,
      1.5(0.6-3.9) and 1.8(0.7-4.6) for oestriol and 0.9(0.4-2.6) and 1.9(0.7-4.7) for
      total oestrogens. The trends of increasing risk with increasing oestrogen
      excretion among post-menopausal women were statistically significant for
      oestradiol (P = 0.022) and for total oestrogens (P = 0.016). We conclude that
      high levels of endogenous oestrogens in post-menopausal women are associated with
      increased breast cancer risk, but that the relationship of oestrogens in
      premenopausal women with risk is unclear.

PMID- 8664141
TI  - Role of early vascular damage in the pathogenesis of gastric haemorrhagic mucosal
      lesions induced by indomethacin in rats.
AB  - Early vascular injury is a key element in the pathogenesis of gastric
      haemorrhagic mucosal lesions which develop rapidly after intragastric (i.g.)
      administration of ethanol, HCl or NaOH. The sequence of vascular events leading
      to gastric lesions has not, however, been investigated in detail with ulcerogenic
      non-steroidal anti-inflammatory drugs such as indomethacin (IND). Accordingly,
      experiments were performed in rats using the vascular tracer Monastral blue to
      assess whether vascular lesions precede and are subsequently associated with
      mucosal lesions induced by oral (p.o.) or subcutaneous (s.c.) administration of
      IND. Fasted female Sprague-Dawley rats (150-180 g) were given IND either at 100
      mg/kg, p.o. or 200 mg/kg s.c. and killed 15, 30, 120 or 240 minutes later.
      Monastral blue, 3% saline 1 ml/kg, was injected intravenously under ether
      anaesthesia 3 minutes before autopsy and the formalin fixed, glycerol cleared
      stomachs were examined microscopically for deposition of the dye particles on
      damaged blood vessels. The percentage area of Monastral blue labelled vessels
      (measured by stereomicroscopic planimetry) at 15 minutes after oral IND was 10.1
      +/- 1.5% (mean +/- s.e.m.) of glandular stomach and increased progressively to
      64.5 +/- 3.0% at 240 minutes. Gastric haemorrhagic lesions (also measured by
      stereomicroscopic planimetry) were first evident at 30 minutes (0.2 +/- 0.03%;
      mean +/- s.e.m.), and developed progressively to 2.0 +/- 0.3% total area of
      glandular mucosa at 240 minutes. Subcutaneous injection of IND resulted in a
      delayed time of onset for the appearance and the extent of mucosal lesions (first
      appearing at 120 minutes, 0.1 +/- 0.03% area) compared with that from oral
      administration of the drug, but as with oral IND the vascular damage (first
      appearance at 15 minutes, 7.5 +/- 3.6%) clearly preceded the occurrence of
      gastric lesions. The observations of microvascular dye labelling were paralleled
      by observations of the electron-microscopic appearance of endothelial cell
      disruption in the region adjacent to superficial mucous cells and accumulation of
      red blood cells in the interstitium at 20-60 minutes. We conclude that vascular
      injury precedes haemorrhagic mucosal damage in the pathogenesis of IND-induced
      acute gastric mucosal lesions.

PMID- 8664142
TI  - The role of complement in the acute inflammatory process in the skin and in host
      parasite interaction in hamsters inoculated with Leishmania (Leishmania) chagasi.
AB  - Tecidual reaction at the inoculation site of L. (L.)chagasi promastigotes in
      hamsters depleted and non-depleted of complement was studied within 2, 6, 12, 24,
      48 and 72 hours of infection. The inflammatory reaction was characterized by
      early predominance of polymorphonuclear cells (PMN) at 2, 6 and 12 hours of
      infection, mixed infiltrate of PMN and mononuclear cells (MN) at 24 hours,
      followed by predominance of MN at 48 and 72 hours after infection. The group
      depleted of complement showed a higher number of PMN at 2 hours and lower numbers
      of MN at 72 hours after infection (P < 0.0001). In the depleted group the
      phagocytosis by PMN was lower at 2 and 24 hours and by MN was lower at 24, 48 and
      72 hours after infection. Electron microscopy showed extracellular intact and
      degenerated parasites, and lysed intracellular parasites, in PMN; and, rarely,
      preserved intracellular parasites in MN at 2, 6 and 12 hours after infection. The
      groups examined at 24, 48 and 72 hours of infection showed only cellular and
      parasite debris in mononuclear inflammatory cells. C3b deposits were detected by
      immunofluorescence in the interstitium and in the cytoplasm of inflammatory cells
      in non-depleted group at 2, 6 and 12 hours of infection. No immunoglobulin was
      detected in either group. Visceralization was detected 240 days after infection.
      The complement system has an important role in the inflammatory reaction and
      phagocytosis. The ultrastructural findings showed that the escape of the parasite
      probably occurs soon after inoculation.

PMID- 8664143
TI  - Relation between distribution of viral RNA and development of histopathological
      changes in encephalomyocarditis virus-induced orchitis in mice.
AB  - The relation between the distribution of viral RNA and the development of
      histopathological changes was investigated in the early stage of
      encephalomyocarditis (EMC) virus-induced orchitis in mice. Signals of viral RNA
      were first detected by in situ hybridization in a few Sertoli cells in almost
      intact germinal epithelia at 2 days post-inoculation (d.p.i.). The number of
      Sertoli cells bearing signals of viral RNA increased at 3 d.p.i. when mild
      degenerative changes were exceptionally found in germinal epithelia. Signals of
      viral RNA came to be detected not only in Sertoli cells but also in a small
      number of germinal cells and spermatogonia at 4 d.p.i. when mild to moderate
      degenerative changes developed in germinal epithelia, resulting in desquamation
      of degenerated cells. At the same time, virus-like particles were observed by
      electron-microscopy in the degenerated and desquamated germinal cells. At and
      after 5 d.p.i., luminal obstruction with cellular debris and inflammatory cells
      was generally found. These results suggest that EMC virus carried to seminiferous
      tubules via the blood first attacks Sertoli cells and then damages germinal cells
      and spermatogonia.

PMID- 8664144
TI  - Insulin-like growth factor-I modulates monocyte adhesion to EAhy 926 endothelial
      cells.
AB  - IGF-I is a ubiquitous growth factor, found in platelets and elaborated by many
      other cell types. It is thought to be involved in several pathophysiological
      processes including embryonic development, angiogenesis and wound healing. We
      report that the adherence of human peripheral blood monocytes to an endothelial
      cell line (EAhy 926) is inhibited in a dose and time-dependent manner by pre
      incubating the endothelial cells with IGF-I (P < 0.001). Monocyte adhesion was
      inhibited 17.9 +/- 1.9% by IGF-I at a dose of 1000 ng/ml (P < 0.01). In contrast,
      IGF-I had no significant effect on monocyte adherence to plastic. The inhibitory
      effects of IGF-I were reversed by co-incubating the endothelial cells with the
      nitric oxide synthase inhibitor, L-NAME. These data suggest that the effects of
      IGF-I are mediated by the release of nitric oxide from the endothelial cells.

PMID- 8664145
TI  - The expression of tumour necrosis factor in the hypothalamus after treatment with
      lipopolysaccharide.
AB  - To investigate the effects of tumour necrosis factor (TNF) in the hypothalamus,
      Wistar rats received an intravenous administration of lipopolysaccharide (LPS) at
      a dose of 3.0 mg/100 g. Concentrations of TNF-alpha in the cerebral liquor and
      blood sera rapidly increased at 30 minutes after administration of LPS, rose to
      the maximum level at 1 hour, and then gradually decreased. Using horse-radish
      peroxidase as a tracer, a transient increase in paracellular permeability
      throughout the tight junctions of the ependymal cell layer covering the third
      ventricle was observed by electron microscopy at 30 minutes and in that of the
      capillary endothelium at 1 hour after administration, respectively. Following LPS
      administration, TNF was preferentially localized by immunoelectron microscopy in
      the tight junctional area of the ependymal cell layer and the capillary. These
      data indicate that TNF, synthesized in the ependymal cell layer, induces a
      deterioration in the cerebrospinal fluid-brain barrier and subsequently in the
      blood-brain barrier. The present study suggests that oedematous changes in the
      hypothalamic areas determined by ultrastructural and magnetic resonance analyses
      were mainly due to TNF conveyed from the ependymal cell layer to the hypothalamus
      after administration of LPS.

PMID- 8664146
TI  - 7,12-dimethylbenz[a]anthracene-induced 'early' squamous cell carcinoma in the
      Golden Syrian hamster: evaluation of an animal model and comparison with 'early'
      forms of human squamous cell carcinoma in the upper aero-digestive tract.
AB  - To test and optimize photodynamic therapy of early cancers in the upper aero
      digestive tract and oesophagus, we sought an appropriate animal model, which was
      found in the 7,12-dimethylbenz[a]anthracene-induced early squamous cell carcinoma
      in the Golden Syrian hamster. This chemically induced neoplasm is shown, by
      histology and immunohistochemistry, to pass through similar stages of early
      cancer development as its human counterpart. Its time sequence is highly
      reproducible, leading to a well differentiated carcinoma in situ and
      microinvasive carcinoma in the hamster cheek pouch over a period of 10 weeks.

PMID- 8664147
TI  - Penetrating gunshots to the head and lack of immediate incapacitation. II. Review
      of case reports.
AB  - Because of the enhanced intracranial tissue disruption (see companion paper) and
      the functional significance of the central nervous system, penetrating gunshot
      wounds of the head commonly result in immediate incapacitation. However, in the
      last century numerous publications reported sustained capability to act following
      penetrating gunshot wounds of the head. These are reviewed. A large number of
      case reports had to be excluded from re-examination because of doubtful
      capability to act or lack of morphological documentation. There remained 53 case
      reports from 42 sources for systematic analysis. Favourable conditions for
      sustained capability to act are present in cases where the additional wounding
      resulting from the special wound ballistic qualities of the head (see companion
      paper) are minimized. Thus, more than 70% of the guns used fired slow and
      lightweight bullets: 6.35 mm Browning, .22 rimfire or extremely ineffective
      projectiles (ancient, inappropriate or selfmade). A centre-fire rifle or a
      shotgun from close range were never employed in cases involving intracerebral
      tracts. A coincidence of several lucky circumstances made sustained capability to
      act possible in two cases of military centrefire rifle bullets passing
      longitudinally between the frontal lobes without direct contact with brain
      tissue. Only two large handguns resulting in intracerebral wounding were used:
      one firing a .38 special bullet, which solely wounded the base of the right
      temporal lobe and one firing a .45 lead bullet, which seriously injured the left
      frontal lobe but whose trajectory was limited to the anterior fossa of the skull.
      Of the trajectories, 28% were outside the neurocranium. At least 70% of the
      craniocerebral tracts passed above the anterior fossa of the skull, wounding the
      frontal parts of the brain. Apart from a neurophysiological approach, this
      preference can be explained by the fact that the base of the anterior cranial
      fossa and the sella turcica area serve as a bony barrier protecting the parts of
      the brain located in its "shadow"' relative to the trajectory against
      cavitational tissue displacement and associated overpressures. This is
      particularly true of the brain stem. Intracerebral trajectories not located above
      the anterior fossa were caused by slow and lightweight bullets preferring one
      temporal lobe. Additionally, one parietal and one occipital lobe were each
      injured once by a very ineffective projectile and by a 7.65-mm bullet reduced in
      velocity. Not a single case of injury to the brain stem, the diencephalon, the
      cerebellum or major paths of motor conduction and only one grazing shot of the
      anterior parts of the nucleus caudatus (basal ganglia) were described.
      Morphological signs of high intracranial pressure peaks (cortical contusion
      zones, indirect skull fractures, perivascular haemorrhages) and secondary
      missiles were poorly documented. It is suggested that these findings are at least
      very rare and not obvious in cases of sustained capability to act.

PMID- 8664148
TI  - A Dutch population study of the STR Loci HUMTHO1, HUMFES/FPS, HUMVWA31/1 and
      HUMF13A1, conducted for forensic purposes.
AB  - We report on a Dutch population study of the STR loci HUMTHO1, HUMFES/FPS,
      HUMVWA31/1, and HUMF13A1, in which we used multiplex amplification and automated
      fragment detection. Genotype and allele frequencies showed no deviation from
      Hardy-Weinberg and linkage equilibrium. The improved Bonferroni procedure was
      used to combine the results of several tests. The power of discrimination of a
      complete profile exceeded 0.9998. We compared the allele frequencies in the Dutch
      sample to the frequencies in other populations using a bipilot to visualize
      alleles and populations simultaneously. The Dutch sample was similar to most
      other Caucasian samples. The data demonstrate that the genetic systems in this
      report are a valuable tool for forensic identity testing in The Netherlands.

PMID- 8664149
TI  - Age estimation in biopsy specimens of dentin.
AB  - Determination of age at death on the basis of aspartic acid racemization in
      dentin is one of the most reproducible and accurate methods. In Germany, age
      estimation by this method has so far generally not been applied to living
      persons, since the extraction of a tooth exclusively for age estimation when it
      is not medically indicated is regarded as ethically and legally problematic. The
      development of a biopsy technique applicable to dentin took place against this
      background. Testing the technique and analysis of dentinal biopsy specimens
      revealed that the biopsy technique is a low-risk procedure that causes only minor
      discomfort to the affected person. It is readily practicable and facilitates
      standardized specimen removal. The relationship between the extent of aspartic
      acid racemization in dentinal biopsy specimens and age is very close,
      facilitating age estimation. A prerequisite for accurate results is the
      performance of biopsies under strictly standardized conditions. If this is
      guaranteed, age determination on the basis of aspartic acid racemization in
      dentinal biopsy specimens appears to be superior in precision to most other
      methods in living persons and can be used for all age groups.

PMID- 8664150
TI  - Characterization of haemorrhages at the origin of the sternocleidomastoid muscles
      in hanging.
AB  - Haemorrhages at the periostal-clavicular origin of the sternocleidomastoid
      muscles were found in 52 out of 54 cases of death by hanging. This cervical
      haemorrhage is most frequently found in death by hanging, but only seldomly seen
      in other causes of death and can therefore be regarded as being typical for death
      by hanging. The frequency of this finding on the side of the highest point of the
      ligature mark is significantly higher, thereby supporting the hypothesis of
      extension as the causative mechanism. External cardiac massage and assisted
      breathing have no influence on the occurrence of haemorrhages. Histology shows
      the haemorrhages to be mainly directly epiperiostal, however, many cases
      displayed concurrent sub- and intraperiostal extravasations. Artificial post
      mortem production of these findings is discussed in the light of the literature.

PMID- 8664152
TI  - A detailed study on suicides in Baranya County (Hungary).
AB  - Suicidal deaths which occurred in Baranya County, Hungary between 1983 and 1987
      were investigated with regard to biodemographical aspects. The number of suicidal
      deaths for this period was 1056 and the rate for this region was higher in
      villages than in towns. The male: female ratio was 3:1. The analysis of age
      groups showed that the rate increased with age and that the most frequent method
      was by hanging (50-55%). Moreover in 375 cases in-depth interviews were made with
      the relatives. The analysis of the interviews showed that 20% of elderly males
      could not cope with their losses and found no way out except through suicide.
      Suicide was less frequent among persons with intellectual occupations. Severe
      alcohol abuse was found in 165 cases. In 83% of the 1056 cases studied,
      pathological disorders of varying severity were observed. Toxicological analysis
      was performed in 810 cases but 17.9% of these cases should be isolated since they
      involved acute drug intoxication. Our data showed that most of the suicide
      victims contacted a doctor and received some treatment immediately before death
      or not long before. The present health and geriatric care systems in Hungary do
      not provide a level of psychotherapeutic care which could protect the population
      at risk from suicide. In our opinion, it would be reasonable to develop the
      knowledge of practitioners and health care personnel working in this field.

PMID- 8664151
TI  - Spanish population data on 7 tetrameric short tandem repeat loci.
AB  - Allele and genotype frequencies for 7 tetrameric short tandem repeat loci were
      determined in a Spanish population sample (N = 186-244) using PCR and subsequent
      analysis of the PCR products by denaturing polyacrylamide gel electrophoresis
      followed by silver staining. The loci were HUMFES/FPS, HUMVWA, HUMTHO1, HUMF13B,
      HUMCSF1PO, HUMF13A1 and HUMTPOX and all loci met Hardy-Weinberg expectations. In
      addition, little evidence was found for association of alleles among the 7 loci.
      Thus the allele frequency data can be used in identity testing to estimate the
      frequency of a multiple PCR-based DNA profile in the Spanish population.

PMID- 8664153
TI  - Extraction of high quality DNA from bloodstains using diatoms.
AB  - A simple method is described for the extraction of high quality DNA for PCR
      amplification. The DNA was extracted by using Chelex-100 ion exchange resin or a
      special cell lysis buffer containing proteinase K. For further purification the
      DNA was bound to silica in the presence of a chaotrophic agent. Hence it is
      possible to unlimitedly wash the bound DNA and inhibitory substances are removed.
      By using diatoms as a source of silicates, this method is very economical and can
      therefore be used as a routine method.

PMID- 8664154
TI  - A new approach to computer-aided comparison of skull and photograph.
AB  - A computer-based method developed for the purpose of checking the results of
      identification performed with the "traditional" method of video-superprojection
      (developed by Helmer and Gruner) is demonstrated; it does not require any special
      programs in addition to those necessary for digitising the video pictures. The
      method is suitable for filtering out "false-positive" cases. A great advantage is
      that the phase of computer evaluation can be separated from the job performed in
      the video studio, both in time and space. The process can be reconstructed, which
      means it can be checked. The results can be easily documented and interpreted for
      lay people.

PMID- 8664155
TI  - Validation of the STR system FES/FPS for forensic purposes in an Austrian
      population sample.
AB  - The short tandem repeat system FES/FPS was amplified by the polymerase chain
      reaction (PCR) in 211 unrelated Austrians and analysed by horizontal, non
      denaturing electrophoresis. The allele distribution was in Hardy-Weinberg
      equilibrium. No mutations were found in 25 families (50 meioses). The mean
      exclusion chance was 0.49, the discriminating power 0.86 and the heterozygosity
      rate 74.4%. Amplification could be achieved with as little as 100 pg of high
      molecular weight DNA, which could be reduced to 75 pg by using 32 instead of 30
      cycles. By reamplifying 1 microliter for another 15 cycles, the threshold could
      be reduced to less than 20 pg. In a degradation experiment DNA extracted from
      bloodstains stored for up to 24 days in a moist chamber and DNA boiled for up to
      18 min could be amplified.

PMID- 8664156
TI  - Short tandem repeat (STR) system HumD21S11: population genetic study on an
      Italian population.
AB  - Allele frequencies of the Short Tandem Repeat locus HumD21S11 were determined
      analysing 119 unrelated individuals from the area of Milano (Northern Italy). A
      total of 13 alleles was detected. One allele (< 26) was found which has never
      been observed in a wider German population sample. The system showed neither
      significant deviation from Hardy-Weinberg equilibrium nor significant differences
      with a German population sample.

PMID- 8664157
TI  - The STR system hTPO: population and segregation data.
AB  - A population study was carried out on a random sample of 164 individuals from
      North Portugal using the short tandem repeat (STR) system hTPO (locus: 2p23
      2pter). After electrophoresis, 7 alleles were identified of which 6 had been
      previously described and a new one, estimated to be 134 bp long. The observed
      genotype distribution is in Hardy-Weinberg equilibrium. In order to assess the
      forensic applicability of the system, namely for paternity investigations, 109
      mother-child pairs were analysed. No exclusions were found and the observed
      distribution did not deviate from the expected. Since hTPO has a relatively high
      information content (PIC = 0.60; H = 0.65) this system can be very useful in
      paternity investigations.

PMID- 8664158
TI  - Frequency of D1S80 and HLA DQ alpha alleles in a Chinese population.
AB  - Allele frequency distributions for the D1S80 (MCT118) and HLA DQ alpha loci were
      determined in a Chinese population sample using the polymerase chain reaction
      (PCR). A total of 25 alleles and 100 phenotypes were observed for D1S80. The
      frequency of allele 18 was higher than allele 24 only in this Chinese population
      when compared to other reported populations. A total of 6 alleles and 21 possible
      phenotypes were observed for HLA DQ alpha. The power of discrimination was 0.97
      and 0.93 for D1S80 and HLA DQ alpha, respectively.

PMID- 8664159
TI  - Autoinduction of nuclear receptor genes and its significance.
AB  - Although downregulation of receptors by their respective hormonal ligands is a
      well-studied phenomenon, relatively less is known about autoupregulation of
      receptors. However, an increasing number of observations of the latter process
      are now being reported. Here, we discuss the phenomenon of autoinduction of
      nuclear receptors of the steroid/thyroid hormone gene family, and its
      significance in the context of the developmental and gene regulatory function of
      the ligands. Much of this review is illustrated by recent work from our
      laboratory on the autoregulation of Xenopus estrogen (ER) and thyroid hormone
      (TR) receptors and their transcripts, accompanying or anticipating vitellogenesis
      and metamorphosis, respectively. The activation by estrogen (E2) of the silent
      vitellogenin genes and the induction of FOSP-1 genes in primary cultures of
      hepatocytes from male Xenopus and oviduct cells, respectively, are tightly
      coupled to a substantial upregulation of ER protein and its transcript. The
      developmental competence to activate vitellogenin in response to E2 was found to
      be acquired during late metamorphosis. Since the latter process is obligatorily
      controlled by thyroid hormones (TH), we extended our studies to the developmental
      and hormonal regulation of Xenopus TR genes. Although very low levels of TR alpha
      and beta mRNAs are detectable in embryos and early larvae, there is a large
      increase in the accumulation of both transcripts before the onset of
      metamorphosis (stage 54 tadpoles), by which time the larval thyroid gland has
      first begun to secrete TH. Filter and in situ hybridization revealed that the two
      transcripts were differentially regulated and were not equally distributed in all
      regions or tissues of the tadpole. Their concentration peaks at metamorphic
      climax and drops to low levels in froglets and adult Xenopus. Exogenous TH given
      to pre-metamorphic tadpoles is known to induce metamorphosis precociously.
      Administration of triiodothyronine (T3) to early tadpoles (stages 50/52) caused a
      rapid upregulation of TR alpha and beta mRNAs which was particularly marked for
      the beta transcript (20- to 50-fold increase in steady-state levels). This
      autoinduction, which is the earliest response to T3, is mimicked to variable
      degrees in some Xenopus cell lines. In XTC-2 cells, in which the in vivo process
      is fully reproduced, it was possible to show with cycloheximide that the increase
      in TR mRNA requires protein synthesis. It was also possible to show by
      transfection of XTC-2 cells with a reporter-promoter construct of Xenopus albumin
      gene, which is a target for T3, that the extra TR mRNA increases functional
      receptor in the cell. Although the role of TH is well-known in metamorphosis, we
      found that TR is also autoinduced in primary culture of adult male Xenopus
      hepatocytes. The significance of this finding lies in the fact that T3
      potentiates the autoinduction of ER and the de novo activation of vitellogenin
      genes by E2. Prolactin (PRL) is known to exert a "juvenilizing" action by
      preventing the induction of amphibian metamorphosis by TH. It is therefore highly
      significant that PRL prevented both the autoinduction of TR alpha and beta mRNAs
      in whole tadpoles and organ cultures and the activation of TR target genes, such
      as those encoding albumin and 63 kDa adult-type keratin. Although how PRL exerts
      its antimetamorphic effect is not known, these findings lead us to propose a dual
      threshold model for the autoinduction of TR, whereby the autoinduction of TR
      genes requires a very low level of TR and TH to rapidly augment the amount of
      functional TR. This higher amount of receptor would be required to achieve a
      higher threshold to activate "downstream" or target genes which specify the adult
      phenotype at the end of metamorphosis. Finally, a survey of recent literature
      shows that the phenomenon of autoinduction is not restricted to Xenopus ER and TR
      but is more widespread among members of the nuclear receptor family.

PMID- 8664160
TI  - Retinoic acid-response elements with a highly repetitive structure isolated by
      immuno-selection from genomic DNA.
AB  - In vitro binding sites of retinoic acid receptors (RARs) were isolated from mouse
      genomic DNA by immunoprecipitation of receptor/DNA complexes. PuG(G/T)TCA half
      site motifs, which constitute RA-responsive elements (RAREs), were identified in
      the immuno-selected fragments (ISFs), some of which contained highly repetitive
      arrangements of this motif. Genomic Southern analysis of a number of ISFs showed
      them to be of a single or low copy number. Several, but not all, ISFs acted as
      ligand-dependent RAREs in transient transfection assays. Two ISFs with repetitive
      RARE motifs responded preferentially to 9-cis retinoic acid-liganded retinoid X
      receptor in the presence or absence of co-transfected RAR, while little
      activation was seen with RAR alone in the presence of either all-trans or 9-cis
      retinoic acid. Another ISF, containing consensus TATA and CAAT box motifs, was
      shown to have RA-inducible promoter activity. The results suggest a high degree
      of promiscuity in response element recognition by retinoid receptors.

PMID- 8664161
TI  - Mutational analysis of the interaction between ecdysteroid receptor and its
      response element.
AB  - The interaction between the partially purified ecdysteroid receptor (EcR) and the
      mutated ecdysteroid-response element (EcRE) from the hsp27 gene promoter was
      studied using the gel retardation competition assay. The results suggest that the
      EcR-hsp27 EcRE contact sites are made predominantly by base pairs which are at
      positions -7, -6, -5, -2, -1 and +2, +5, +6 of the hsp27 EcRE palindrome. An
      increase or decrease in the spacing between the half-palindromes reduces the
      affinity of the hsp27 EcRE to the receptor, while a mutation of the central A/T
      base pair to C/G has practically no effect on EcR binding. Unlike the
      glucocorticoid-response element and the estrogen-response element, the base pairs
      placed at positions -3, -4 and +1, +3, +4 of the hsp27 EcRE palindrome can be
      mutated without effect on the EcR binding.

PMID- 8664162
TI  - Aromatase gene is amplified in MCF-7 human breast cancer cells.
AB  - The levels of the aromatase gene and its expression in MCF-7 human breast cancer
      cells and seven additional cultured cells were investigated. Using normal human
      foreskin fibroblasts as the control, the aromatase gene appeared to be amplified
      in MCF-7 cells as shown by Southern and DNA slot blot analyses utilizing human
      placental aromatase cDNA as the probe. However, the promoter I.1 and the first
      exon of the aromatase gene were not amplified in MCF-7 cells based on results
      obtained from DNA slot blot analysis using oligonucleotide probes having
      sequences derived from those regions of human aromatase gene. Aromatase was
      expressed at a very low level in this cell line as indicated by Northern blot
      analysis to measure the level of aromatase mRNA, immunoprecipitation analysis to
      measure the level of aromatase protein, and aromatase activity measurement.
      Furthermore, nucleotide sequence analysis of the aromatase cDNA obtained from MCF
      7 cells by PCR techniques, revealed no sequence difference from that of the
      enzyme expressed in placenta. These results lead us to conclude that the
      expression of aromatase in MCF-7 cells is under the control of an unusual
      promoter and aromatase gene expression is repressed at the transcriptional level
      in these cells.

PMID- 8664163
TI  - Modulation of cell proliferation and cell cycle, and inhibition of cytokinesis by
      1,25-dihydroxyvitamin D3 in C3H/10T1/2 fibroblasts.
AB  - The growth-modulating effects of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] were
      studied on three mouse embryo fibroblast cell lines. Concentrations ranging from
      0.1 to 100 nM inhibited dose-dependently proliferation in the non-tumorigenic
      C3H/10T1/2 Cl 8 (10T1/2) and the chemically transformed C3H/10T1/2 Cl 16 (Cl 16)
      cells. The hormone had a biphasic effect on the transformed cell line C3H/10T1/2
      TPA 482 (TPA 482) in which growth was stimulated by low concentrations. Exposure
      to 10 nM 1,25-(OH)2D3 for 5 days resulted in a 90% growth inhibition of 10T1/2
      cells, and the hormone was 10 and 100 times less potent in Cl 16 and TPA 482
      cells, respectively. The inhibition of cell replication was fully reversible on
      removal of the hormone. Treatment of 10T1/2 and Cl 16 cells with 10 nM 1,25
      (OH)2D3 reduced the saturation density to 30 and 37% that of controls,
      respectively, suggesting an enhancement of cell-cell contact mediated growth
      inhibition. 1,25-(OH)2D3 inhibited cytokinesis in 10T1/2 cells, inducing the
      formation of binucleated cells. Flow cytometric studies showed that 1,25-(OH)2D3
      treated cells accumulated in the Go/G1 phase while the number of cells in S phase
      decreased. This in vitro model system seems to be useful for studies of the
      molecular mechanisms of the growth modulating effect of 1,25-(OH)2D3.

PMID- 8664164
TI  - Computer modelling of estrogenic transcriptional activation can account for
      different types of dose-response curves of estrogens.
AB  - Estrogenic activity of diphenylethanes and -ethenes was determined by uterine
      growth in immature mice and analyzed by weighed regression of logit-transformed
      effect on log dose values. This resulted in a range of Hill coefficients nH from
      0.3 to 2 corresponding to the molecular mechanism of estrogenic transcriptional
      activation. Binding of agonists (hormones, H) to estrogen receptors (ER) leads to
      receptor dimerization depending on the structure of the ligand. Three hormone
      receptor complexes, H-ER, H-ER-ER, and H-ER-ER-H, which bind with different
      affinity to short palindromic DNA sequences (estrogen responsive elements), can
      be proposed. Transcriptional activating functions of the DNA-bound ER are
      subsequently induced. We have derived an equilibrium model including these steps.
      Computer simulations of Hill plots based on the model have completely reproduced
      the range of observed nH values. Hill coefficients are > 1.5 if the homodimer H
      ER-ER-H and < 0.7 if the heterodimer H-ER-ER strongly predominates. If ER
      dimerization is disturbed (H-ER monomer predominant), nH is closer to 1. Hill
      coefficients and pD2 values (negative decadic logarithms of molar estrogen doses
      causing 50% of the maximal effects) are related to parameters of ER dimerization
      and the two steps of hormone-receptor dissociation. When a series of 1,2-bis(3'
      or 4'-hydroxyphenyl)ethanes and -ethenes is studied, a rather simple dependence
      of nH and pD2 on the nature of alkyl groups symmetrically substituted at C-atoms
      1 and 2 can be observed. In terms of the model this implies that ethyl and alpha
      branched higher alkyl substituents (nH >> 1) appear to stabilize the homodimer,
      while methyl and CF3 groups (nH << 1) could lead to a rapid dissociation of the
      homodimer to the heterodimer. With longer n-alkyl and beta-branched alkyl
      substitution (nH from 0.66 to 1.3), dimerization itself can be limited or the
      ligand-homodimer dissociation is only moderately increased. Thus, a strong
      sterical constraint could exist with respect to the stabilization of the second
      ligand-receptor bond in the homodimer.

PMID- 8664166
TI  - A multivariate approach to the description of patient populations. An example of
      the analysis of the hormone profiles of patients with advanced prostate cancer.
AB  - In view of the multifactorial nature of the endocrine dysfunctions that may
      develop during prostate cancer and the unsuitability of the most widely used
      statistical methods to study such dysfunction, we have in the present study
      examined the relationships among 17 biological variables in 26 patients with
      advanced prostate cancer by two complementary multivariate methods,
      correspondence factorial analysis (CFA) and a hierarchical automatic
      classification procedure. The 17 variables included 14 hormones, their precursors
      or metabolites [LH, FSH, estradiol (E2), testosterone, dihydrotestosterone (DHT),
      androstenedione (A), androstenediol (Ediol), dehydroepiandrosterone (DHA), DHA
      sulphate (DS), cortisol (CORT), 17 alpha-hydroxyprogesterone (17-OH-PROG),
      pregnenolone (PREG), 17 alpha-hydroxypregnenolone (17-OH-PREG), and
      androstanediol glucuronide (ADG)], one plasma binding protein, namely, sex
      hormone-binding protein (SHBG) and two tumour markers, prostatic acid phosphatase
      (PAP) and prostate-specific antigen (PSA). The originality of these multivariate
      methods is that they do not preselect a dependent variable nor perform two-by-two
      correlations as in stepwise multiple regression analysis but describe the patient
      population by extracting layers of correlations (from strong to weak) from amid
      confounding variables. Compared to principal component analysis which is based on
      covariance, CFA, based on the chi 2-metric, enables the licit representation of
      both tests and patients on the same factorial maps. From an examination of
      proximity among variables, it is possible to deduce which tests are related,
      which groups of patients have similar hormone profiles, and which tests vary most
      in which patients. The most discriminant factors in this particular population of
      patients were PSA and PAP levels, which were, however, not strongly correlated
      and were apparently selectively associated with certain hormones. PAP seemed the
      more pathological marker; PSA was somewhat anticorrelated to the adrenal androgen
      (DHA and DS) and PREG levels. The hormones with the lowest variance were A, Ediol
      and CORT reflecting their key roles in metabolism. A number of patients were
      hypogonadic. SHBG levels were not closely related to total T levels but
      anticorrelated with ADG suggesting that, in the patients concerned, SHBG
      decreases the bioavailable T fraction. There was no correlation between ADG and
      precursor hormones (PREG, DHA, DS) but a slight anticorrelation between these
      precursors and DHT. Therefore the source of ADG in these patients does not seem
      to be increased levels of precursor hormones nor of DHT but increased peripheral
      tissue metabolism of androgens. In future, descriptive multivariate analyses of
      large patient cohorts should help to define subpopulations with distinctive
      hormone profiles for prospective clinical studies.

PMID- 8664165
TI  - Baculovirus-directed expression of human prostatic steroid 5 alpha-reductase 1 in
      an active form.
AB  - In the human prostate, the enzyme steroid 5 alpha-reductase (h5 alpha R)
      catalyses the conversion of testosterone into the more potent androgen,
      dihydrotestosterone. Two distinct cDNAs coding for h 5 alpha R in the human
      prostate have been previously characterized. Enzyme h5 alpha R1 shows a maximum
      activity at basic pH whereas h5 alpha R2 has an acidic pH optimum activity. We
      report here the expression of the human steroid h5 alpha R1 in a eukaryotic
      expression system: the baculovirus-directed-insect cell expression system. The
      full length cDNA was inserted into the Autographa californica nuclear
      polyhedrosis virus genome and expressed in Spodoptera frugiperda, Sf9, insect
      cells. Sf9 cells were infected with the recombinant baculovirus and homogenates
      used in h5 alpha R activity assays by high pressure liquid chromatography showed
      that a catalytically active enzyme was produced. The recombinant enzyme showed an
      apparent Km for testosterone of 2.07 microM and a V(max) of 10.1 nmol of
      dihydrotestosterone/ min/mg of protein. Recombinant h 5 alpha R1 activity was
      inhibited by specific h 5 alpha R inhibitors such as 4-MA (Ki = 2.6 nM).
      Subcellular distribution in Sf9 cells demonstrated that the enzyme was associated
      with the nuclear membrane.

PMID- 8664168
TI  - Cholera toxin directly stimulates pregnenolone generation with increasing Ca2+
      efflux in bovine adrenocortical mitochondria.
AB  - The present experiments demonstrated that the holotoxin as well as the A- and B
      subunits of cholera toxin were able to directly enhance pregnenolone synthesis
      when isolated intact mitochondria, prepared from bovine adrenocortical tissue,
      were incubated; they were not, however, able to enhance pregnenolone synthesis
      when the inner mitochondrial fraction was similarly incubated, suggesting that
      the conformational structure of mitochondria is very important for activation of
      cholesterol side-chain cleavage by cholera toxin. Data are also presented
      demonstrating that cholera toxin can enhance Ca2+ release from isolated
      mitochondria, while pertussis toxin could activate neither pregnenolone
      generation nor increase Ca2+ efflux from mitochondria. Thus it is suggested that
      cholera toxin may activate pregnenolone synthesis by regulating Ca2+ movement in
      mitochondria.

PMID- 8664167
TI  - Detection of breast cancer-associated estrone sulfatase in breast cancer biopsies
      and cell lines using polymerase chain reaction.
AB  - Steroid sulfatase (STS) is a single enzyme with a range of substrate
      specificities, including estrone sulfate. Using a 2.4 kb cDNA clone, expression
      of human STS was undetectable by Northern hybridization, but STS RNA was detected
      in human placenta, human breast cancer samples, and in breast carcinoma cell
      lines following reverse transcriptase-PCR amplification, using specific primers
      to yield a product of 472 bp. In preliminary studies, stimulation of MCF-7 cell
      lines with estradiol (10(-8) M) resulted in an increased level of amplifiable STS
      RNA, and this upregulation of STS RNA could be abolished by tamoxifen. The
      estrone sulfatase activity in mammary tumors derived from N-nitrosomethylurea
      (NMU) treated rats was significantly decreased in animals treated with tamoxifen
      compared to control animals, regardless of the response of the tumors to the
      antiestrogen (P < 0.05). Although tamoxifen does not inhibit the estrone
      sulfatase enzyme in vitro, it may modulate the expression of STS RNA and the
      enzyme activity in vivo.

PMID- 8664169
TI  - Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone
      in rat brain regions and peripheral tissues.
AB  - Carbenoxolone (CX), the succinyl ester of glycyrrhetinic acid, causes hypokalemia
      and hypernatremia. Its pharmacological effects are believed to be due to its
      inhibition of 11 beta-hydroxysteroid dehydrogenase (11-HSD). There was a marked
      inhibition of this enzyme in the liver, kidney, pituitary, hippocampus,
      hypothalamus and amygdala 1 h after intraperitoneal administration of CX (100 mg
      kg-1) to intact male rats. Intracerebral injection of CX (1.5 mg kg-1) into the
      3rd ventricle inhibited the oxidation of corticosterone to 11
      dehydrocorticosterone by 11-HSD in the pituitary and hippocampus and produced
      marked behavioral hyperactivity but had no effect in the liver or kidney. Lower
      amounts of CX (10-50 micrograms/rat) given intracerebroventricularly (i.c.v) were
      without significant effect on 11-HSD in the pituitary or amygdala 1 h after
      infusion but inhibited this enzyme differentially in the hippocampus and
      hypothalamus. Inhibition of 11-HSD activity in the hippocampus and hypothalamus
      was observed up to 6 h after i.c.v. administration of CX (50 micrograms/rat)
      together with some decrease in activity of this enzyme in the pituitary at 3 h.
      The findings that low doses of CX given i.c.v. can alter the activity of 11-HSD
      in specific brain regions without affecting its activity in peripheral tissues,
      and only marginally in the pituitary, provides a method to study the central role
      of this enzyme independently of systemic effects.

PMID- 8664170
TI  - Characterization of estrone sulfatase activity in human thrombocytes.
AB  - Estrone sulfatase is an important enzyme which catalyzes the production of
      estrone from estrone sulfate in a variety of human and animal tissues. We report,
      for the first time, on the presence of estrone sulfatase activity in thrombocytes
      from human blood. Incubation of [3H]estrone sulfate in the presence of human
      thrombocyte lysates resulted in the formation of [3H]estrone as assessed by two
      dimensional TLC. Estrone sulfatase activity was localized in the mitochondrial
      microsomal fraction in thrombocytes from human blood. The enzyme was thermostable
      and had an optimum pH of 5.60 in acetate buffer. The highest activity was
      obtained in the presence of 0.1% of either Nonidet P-40 or Triton X-100.
      Phosphate ions (1 mM) inhibited the enzyme activity by 64% and similar effects
      were observed in the presence of platelet-free plasma. Endogenous inhibitors had
      no effect on the observed enzyme activity under assay conditions as evidenced in
      this study. The apparent Km value was 3.16 +/- 0.08 microM for [3H]estrone
      sulfate and V was 188.5 +/- 2.6 (mean +/- SEM, n = 22) pmol.mg protein-1.h-1.
      Comparison between two thrombocyte preparative procedures provided evidence that
      thrombocyte estrone sulfatase activity should be measured in thrombocyte samples
      representing the whole thrombocyte population. This parameter appeared critical
      for accurate measurements of enzyme activity. The presence of estrone sulfatase
      activity in human thrombocytes provides a new non-invasive tool for the study of
      this activity both in physiological and pathological conditions which could be of
      potential clinical relevance.

PMID- 8664171
TI  - Variation in 1,25-dihydroxyvitamin D3 regulation of proliferation and alkaline
      phosphatase activity in late-passage rat osteoblastic cell lines.
AB  - The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2,D3], 1,25-dihydroxy-16ene
      23yne-vitamin D3[1,25(OH)2-16ene-23yne-D3] (a synthetic analog) and retinoic acid
      on proliferation, protein synthesis, and alkaline phosphatase activity and mRNA
      were compared in two late-passage (P > 70) clonal rat osteoblastic cell lines (G2
      and C12) in order to characterize variations in the basal and hormonally
      regulated phenotypes. All agents inhibited proliferation (measured as cell number
      after 3 days of treatment) in late-passage (P > 70) G2 and C12 cells without
      inhibiting the rate of protein synthesis ([3H]leucine incorporation into TCA
      precipitable protein) during the last 18 h of incubation. Basal and hormone
      treated alkaline phosphatase activities were lower in late-passage G2 and C12
      cells than those previously reported for early-passage G2 and C12 cells.
      1,25(OH)2D3 and 1,25(OH)2-16ene-23yne-D3, up-regulated alkaline phosphatase
      activity in late-passage C12 cells and down-regulated it in late-passage G2
      cells. The direction of these regulatory changes in late-passage cells was
      opposite to that reported for early passage of these clones, and changes were
      related to the levels of tissue-unspecific alkaline phosphatase mRNA normalized
      for actin mRNA. Effects of 1,25(OH)2D3 or 1,25(OH)2-16ene-23yne-D3 and retinoic
      acid were not additive, suggesting a competitive mechanism of action. It appears
      that increased sensitivity to the antiproliferative effects of regulatory
      hormones and defects in proliferation and specialization of the osteoblast are
      observed with increasing passage number in vitro in two model osteoblastic cell
      lines (G2 and C12).

PMID- 8664172
TI  - Metabolism of gestodene in human liver cytosol and microsomes in vitro.
AB  - The metabolism of the progestogen gestodene has been studied in human liver
      cytosol and microsomal incubations. Extraction with diethyl ether was followed by
      radiometric HPLC analysis. Metabolites were identified by co-chromatography with
      authentic standards and mass spectrometry (electron impact and chemical
      ionization). All the cytosolic incubations (n = 4 livers) produced
      dihydrogestodene as the major metabolite, with lesser amounts of a tetrahydro
      derivative. It was not possible to separate the 5 alpha- and 5 beta-isomers of
      dihydrogestodene on the chromatographic system used. Values of Km and V(max) for
      the delta 4 reductase were determined. Androstenedione (Ki = 2.85 +/- 1.5 microM;
      n = 4) and cortisol (ki = 24.1 +/- 8.9 microM; n = 4) both inhibited the delta 4
      reductase. In contrast desogestrel showed virtually no inhibition at
      concentrations up to 200 microM. The major microsomal metabolite of gestodene was
      a hydroxylated derivative although mass spectral analysis was unable to determine
      the position of insertion of the hydroxyl moiety. The hydroxylation of gestodene
      (1 microM) was markedly inhibited by ketoconazole (IC50 < 0.1 microM), and also
      by cyclosporin. This suggests that the cytochrome P450 isozyme CYP3A4 is
      important in gestodene metabolism. Theophylline and tolbutamide (substrates of
      CYPIA and CYP2C, respectively) did not affect gestodene metabolism at
      concentrations up to 100 microM. In conclusion, the major biotransformation of
      gestodene (A-ring reduction) occurs in the cytosolic fraction of human liver.
      Microsomal hydroxylation appears to be catalysed by CYP3A4.

PMID- 8664174
TI  - Progesterone and dexamethasone inhibition of uterine epithelial cell
      proliferation: studies with antiprogesterone compounds in the neonatal mouse.
AB  - Progestins and glucocorticoids inhibit uterine epithelial cell proliferation.
      Earlier studies showed that in the neonatal mouse, dexamethasone (Dex) was at
      least 100-fold more potent than progesterone (P) as an inhibitor of epithelial
      DNA synthesis. Using steroid autoradiography, we now show that the uterine cells
      of the neonatal mouse have receptors for both progestins (PR) and glucocorticoids
      (GR). Since it is known that P can interact with the GR it is possible that even
      a weak interaction might mediate the inhibitory effects of large doses of P.
      Therefore, we examined the receptor pathway specificity of the P response in
      neonatal mice using antiP steroids with reportedly strong antiglucocorticoid
      activity, RU486, or weak antiglucocorticoid activity, ZK98.734 (ZK734). Both
      RU486 and ZK734 exhibited strong binding activity in a PR assay performed on
      cytosolic preparations from adult mouse uteri. For murine thymic GR, the relative
      binding activity of RU486 was 12-fold that of ZK734. The high PR binding activity
      was reflected by the in vivo dose-response of the antagonists administered in
      conjunction with P; either antagonist completely blocked the inhibitory effect of
      P on uterine epithelial DNA synthesis when it was administered at one-tenth the
      dose of P. On the other hand, blockade of the inhibitory effect of Dex only
      occurred when the dose of antagonist was 10-fold the dosage of Dex. There were no
      significant differences between the two antagonists in blocking the effects of
      either P or Dex. These results indicate that progestins and glucocorticoids act
      through their own receptor systems to inhibit DNA synthesis in the uterine
      epithelium of the neonatal mouse. However, because of the considerable
      antiglucocorticoid activity of ZK734, a potential role for the interaction
      between P and the GR cannot be ruled out by these experiments.

PMID- 8664173
TI  - Cigarette smoking is associated with elevated adrenal androgen response to
      adrenocorticotropin.
AB  - Cigarette smoking alters the pattern of endogenous steroid levels. We examined
      this phenomenon in two separate male groups. Group A consisted of 189
      dyslipidemic men participating in the Helsinki Heart Study and group B of 100 men
      including patients with heart disease and healthy controls. The subjects in the
      latter group underwent ACTH-testing. In group A, smokers had significantly higher
      basal androstenedione and dehydroepiandrosterone sulfate (DHEAS) levels and
      androstenedione/cortisol ratios than nonsmokers. Mean concentrations of cortisol,
      dehydroepiandrosterone (DHEA), androstanediol glucuronide, testosterone, and sex
      hormone binding globulin (SHBG) did not differ between smokers and nonsmokers. In
      group B, smokers had lower high density lipoprotein (HDL)-cholesterol and
      apolipoprotein AI and higher triglyceride levels than nonsmokers. Basal
      androstenedione and ACTH stimulated androstenedione and DHEA concentrations were
      higher in smokers. No significant differences were found in basal insulin, SHBG,
      estrone, estradiol, testosterone, free testosterone, and dihydrotestosterone
      concentrations between smokers and nonsmokers. These results suggest that smoking
      decreases the activity of either 21- or 11 beta-hydroxylase in the adrenal
      cortex, which results in increased secretion of adrenal androgens.

PMID- 8664175
TI  - Biotransformation--XXXIV. Metabolism of testosterone esters in fungi cultures.
AB  - Seven esters of testosterone: acetate, propionate, enanthate, caprate,
      undecanoate, isobutyrate and isocaproate (some of them are used as drugs) were
      transformed by microorganisms: Absidia coerulea, Acremonium roseum, Aphanocladium
      album and Rhodotorula mucilaginosa to obtain some information about their
      metabolism. It was observed that the presence and structure of the acyl group
      mainly influenced the degree of transformation. The first step of the reaction
      was probably hydrolysis of ester, followed by testosterone transformation. Only
      the branched chain esters were transformed by R. mucilaginosa without hydrolysis
      of the ester bond.

PMID- 8664176
TI  - Characterization and solubilization of testosterone 17 beta-hydroxysteroid
      dehydrogenase in human hyperplastic prostate.
AB  - 17 beta-Hydroxysteroid dehydrogenase is a membrane-bound enzyme in human
      prostate. Solubilization of this enzyme can only be obtained in the presence of
      detergents. The optimal solubilization mixture contained 50 mM Tris-HCl buffer pH
      9.0, 20% glycerol, 0.1 M KCl and 5 mg/ml of the non-ionic detergent N-octyl
      glucoside. In these conditions, the soluble fraction contained more than 90% of
      the enzymatic activity. A 2.5-fold increase of specific activity was obtained
      during solubilization under optimal conditions.

PMID- 8664177
TI  - Telomerase: optimism for cancer marker grows.

PMID- 8664178
TI  - 800,000 applicants for new health care scheme in Germany.

PMID- 8664179
TI  - Cuban oncology surviving the 'periodo especial'.

PMID- 8664180
TI  - Health care reform and oncologists.

PMID- 8664182
TI  - Dose-intensive chemotherapy in breast cancer--the need for appropriate measures
      of outcome.

PMID- 8664181
TI  - Angioimmunoblastic T-cell lymphoma: new insights, but the clinical challenge
      remains.

PMID- 8664183
TI  - Chronic myeloid leukaemia: a therapeutic challenge.

PMID- 8664184
TI  - Summary of the Second International Conference on Biology, Prevention and
      Treatment of Gastrointestinal Malignancies.
AB  - R. Mayer (U.S.A.) in summarizing the data presented at the three day conference,
      raised several general issues. Therapeutic benefit in the past has been measured
      by the criterion of 'objective response'; the latter term most likely should be
      replaced by 'quality of life' and 'overall survival time' since they appear to be
      more biologically meaningful. It appears that few new cytotoxic drugs have been
      developed in recent years, and , as yet, none has an established role in the
      management of patients with gastrointestinal cancers. Of those currently under
      investigation, CPT-11 seems to represent the most promising, since its mode of
      action is something other than inhibition of thymidylate synthase. It seems that
      too many small, uncontrolled studies examining a give concept (e.g. neoadjuvant
      therapy) have been performed prior to initiating definitive, phase III trials; a
      greater degree of collaboration seems necessary so that new treatment principles
      may be objectively assessed in an efficient manner. Finally, it seems clear that
      economic realities are increasingly affecting choices in patient care and
      clinical research and this trend will undoubtedly increase in the future.

PMID- 8664185
TI  - Resistance to cytotoxic therapy: a speculative overview.
AB  - While most recent studies have focused on the MDR1 gene and other similar types
      of multidrug resistance, two other phenomena (inhibition of the apoptotic pathway
      and regrowth resistance) have the potential for producing a much broader type of
      resistance to cytotoxic therapy. This speculative review discusses the potential
      contribution of these types of resistance and the possible interrelationships
      between the various types of resistance to cytotoxic therapy. The need for new
      approaches to assess the effects of biological agents is discussed.

PMID- 8664186
TI  - Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact
      of clinical observations and laboratory findings at presentation. The Kiel
      Lymphoma Study Group.
AB  - BACKGROUND: In order to establish the clinico-pathological properties of
      angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma, we evaluated the
      type, incidence and prognostic significance of clinical and laboratory symptoms.
      PATIENTS AND METHODS: Sixty-two consecutive patients diagnosed at the Kiel lymph
      node registry participated in the study. The median patient age was 64 years
      (range 21-87 years) and the female to male ratio was 1:1.4. Ninety percent of the
      patients were in stage III and IV and B-symptoms were observed in 68%. At
      diagnosis patients presented with skin rash (49%), pruritus (32%), edema (38%),
      pleural effusion (37%), arthritis (18%) and ascites (23%). Furthermore, they
      exhibited autoimmune phenomena such as cold agglutinines, circulating immune
      complexes, a positive Coombs test, smooth muscle antibodies, rheumatoid factors,
      immune hemolysis, a paraprotein, antinuclear antibodies and cryoglobulins.
      RESULTS: In univariate analysis, survival was significantly related to age
      (p=0.032), stage (p=0.037), B symptoms (p=0.007), rash/pruritus (p=0.038), edema
      (p=0.030), ascites (p=0.013), number of clinical symptoms including B symptoms
      (p=0.004) and excluding B symptoms (p=0.017), lactate dehydrogenase (p=0.007) and
      hemoglobin (p=0.020). CONCLUSIONS: AILD type T-cell lymphoma characteristically
      differs from other non-Hodgkin's lymphomas in its clinical signs and laboratory
      symptoms.

PMID- 8664187
TI  - Accelerated chemotherapy with high-dose epirubicin and cyclophosphamide plus r
      met-HUG-CSF in locally advanced and metastatic breast cancer.
AB  - BACKGROUND: This study evaluated the toxicity of high-dose epirubicin and
      cyclophosphamide plus r-met-HUG-CSF (G-CSF) given every 2 weeks and compared the
      dose-intensity achieved with this schedule with that obtained in a previous study
      we conducted in which the same regimen was given every 3 weeks without G-SCF (EC
      21). The secondary objective was to explore the activity of this regimen.
      PATIENTS AND METHODS: Between December 1991 and March 1994, 41 patients (pts), 19
      with locally advanced breast cancer (LABC) and 22 with metastatic breast cancer
      (MBC), were given high-dose epirubicin (Hd-Epi) (120 mg/m2) and cyclophosphamide
      (CTX) (600 mg/m2) on day 1 every 14 days (EC 14) plus granulocyte colony
      stimulating factor (G-CSF) (5 mcg/kg/d s.c. on days 2-12). A total of 8 cycles in
      LABC pts (4 pre- and post-surgery), and 6-8 cycles in MCB pts were administered.
      The results were compared with those obtained in the previous study. RESULTS: The
      incidence of WHO grade 3-4 neutropenia was significantly reduced in the EC 14 + G
      CSF regimen (25.2% vs. 46.8% in 214 and 250 evaluable cycles, respectively,
      p<0.0001), as well as the incidence of neutropenic fever (7% vs. 3%, p=0.05).
      Grade 3-4 anemia (36.6% vs. 8% pts, p=0.001) and grade 3-4 thrombocytopenia
      (17.1% vs. 0 pts, p=0.002), were significantly more frequent in EC 14 + G-CSF. No
      significant differences in the other side effects were found. A total of 17 of
      207 of the cycles (8.2%) were delayed in the EC 14 + G-CSF vs. 58/271 (21.4%) in
      the EC 21 (p<0.0001). The main reasons for these treatment delays were
      neutropenia (1% vs. 15%), anemia (3% vs. 0) and thrombocytopenia (1% vs. 0). As a
      result of treatment acceleration and differences in dose delays, the patients on
      EC 14 + G-CSF received a higher dose-intensity (Epi 58.51 mg/m2/wk vs. 36.8
      mg/m2/wk; CTX 292.52 mg/m2/wk vs. 182.9 mg/m2/wk). A complete response at surgery
      was obtained in 9/19 (47.4%) LABC pts. An objective CR was obtained in 11/22 MBC
      pts (50%) and a partial response in 8/22 (36.4%), yielding an overall response
      rate of 86.4%. CONCLUSIONS: Hd-Epi + CTX is very active against both LABC and
      MBC. The administration of G-CSF allows dose intensification of both drugs (a
      59.5% increase of the actual dose intensity) with acceptable clinical tolerance
      (a lower incidence of neutropenia but a higher incidence of anemia and
      thrombocytopenia). Only a specifically designed phase III trial will lead to
      definitive conclusions regarding the greater antitumor activity of accelerated
      CSF-including regimens as compared to standard chemotherapy for advanced breast
      cancer.

PMID- 8664188
TI  - An EORTC pilot study of filgrastim (recombinant human granulocyte colony
      stimulating factor) as support to a high dose-intensive epiadriamycin
      cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or
      metastatic breast cancer.
AB  - BACKGROUND: In an attempt to increase chemotherapy dose intensity by step-wise
      reduction of the time interval between treatment cycles, filgrastim was
      administered to breast cancer patients receiving a three-month combination
      chemotherapy with epirubicin (E) and cyclophosphamide (C). PATIENTS AND METHODS:
      Chemotherapy-naive patients with locally advanced or metastatic breast cancer
      received fixed doses of E (120 mg/m2) and C 9830 mg/m2) by 15-min i.v. infusion
      on day 1 of each cycle and filgrastim at a dose of 4 micrograms/kg once daily by
      SC injection starting 24 hours after chemotherapy. Cohorts of patients were
      treated in successive schedules, each schedule corresponding to a specified time
      interval between chemotherapy cycles. The toxicity observed in each schedule was
      evaluated before patients were accrued to the next schedule, which corresponded
      to a shorter time interval between chemotherapy cycles. RESULTS: The maximum
      tolerated schedule was E (120 mg/m2) plus C 9830 mg/m2) given every 14 days with
      filgrastim support from day 2 until day 13. On this schedule, 5 of 12 patients
      experienced dose-intensity-limiting toxicities (DLT) during the 3-month study
      period. Non-hematological DLT occurred in 2/12 patients (mucositis, skin
      toxicity) while /312 experienced febrile neutropenia requiring i.v. antibiotics.
      All patients achieved recovery of ANC to >1.5 x 10(9)/l by the time of scheduled
      retreatment. The combination of filgrastim with this regimen did not seem to add
      major toxicities. The efficacy was high, with 87% of patients achieving an
      objective response and a median response duration of 18 months (range: 4-52
      months). CONCLUSIONS: Filgrastim permits at 33% increase in 'EC' dose
      intensification over that of the conventional every-3-week administration.
      Randomized studies should now be initiated to evaluate the merit, if any, of
      'accelerated' chemotherapy in advanced breast cancer.

PMID- 8664189
TI  - Prognostic relevance of P-glycoprotein expression in breast cancer.
AB  - BACKGROUND: P-glycoprotein (Pgp) expression has been reported to be associated
      with a poor prognosis in some malignancies such as neuroblastoma, soft tissue
      sarcoma and acute myeloid leukemia. The prognostic role of Pgp expression in
      breast cancer is still unclear. We investigated the expression of Pgp in primary
      and metastatic breast cancer tissues in relation to patient characteristics and
      treatment outcome. PATIENTS AND METHODS: Pgp expression was evaluated in 92
      primary and 12 metastatic breast cancers by the use of immunohisto/cytochemistry
      with three monoclonal antibodies (MAbs) (JSB-1, C219, MRK16), and an RNAse
      protection assay. Follow-up information was available for 77 primary breast
      cancer patients (median follow-up 42 months; range 2-63 months). RESULTS:
      Concordance among the anti-Pgp MAbs varied, the highest being between JSB-1 and
      MRK16 (71%; p=0.002). Pgp expression was more frequent in metastatic disease
      (58%) than in primary breast cancer (29%) (JSB-1; p=0.055). Pgp expression as
      assessed with JSB-1 (univariate analysis; p<0.05) was associated with shorter
      overall survival (OS). Nineteen (21%) primary breast cancers had Pgp expression
      in fibroblasts in desmoplastic stroma and this did not correlate with Pgp
      expression in the tumor. The combination of Pgp-positive tumor cells and Pgp
      expressing fibroblasts was the strongest prognostic factor for OS by multivariate
      analysis. Subgroup analysis suggested that Pgp expression was associated with a
      shorter OS in tamoxifen-treated patients, but not in those who received
      chemotherapy (most often CMF). CONCLUSIONS: Pgp expression in tumor cells, and
      especially when accompanied by Pgp expression in fibroblasts in desmoplastic
      stroma, has prognostic value in primary breast cancer patients and is likely to
      be a marker of a more malignant phenotype. Pgp expression of tumor cells might
      play a role in tamoxifen resistance. These findings may have important
      implications for teh treatment of breast cancer patients, and warrant further
      prospective investigation in a larger patient population.

PMID- 8664190
TI  - Solitary plasmacytoma of bone and extramedullary plasmacytoma: two different
      entities?
AB  - BACKGROUND: The objective of this study was to evaluate the similarities between
      solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EP).
      PATIENTS AND METHODS: The clinical features, treatment and survival of 54
      patients with localized plasmacytoma (LP) 1990 were carefully reviewed. Follow-up
      was expected to continue until June 1993. RESULTS: Thirty-two patients were
      classified as having SPB and 22 EP. Most of the patients were males. particularly
      those in the SPB group. Their median age at diagnosis was 54 years and no
      significant difference between the two groups was observed. SPB occurred most
      frequently in the vertebral column (42%) and EP in the upper respiratory tract
      (73%). Fifteen patients with SPB and 2 with EP had paraproteinemia at diagnosis,
      multiple myeloma (MM) became evident in 75% of the patients with persistent
      paraprotein after therapy, and in only 22% of those in whom it disappeared. Four
      patients in the SPB group had immunoparesis, and 3 developed MM. Disease
      progression toward MM was significantly different (p=0.003) in the two groups,
      while overall survival differences were not significant (p=0.07) unless unrelated
      causes were excluded (p=0.02). Adjuvant chemotherapy did not seem to limit
      diffusion of the disease. CONCLUSIONS: Although EP and SPB are both localized
      forms of plasma cell dyscrasias, SPB seems to have a greater tendency to
      progression MM. It appears, however, that the apparent stronger propensity of SPB
      to progress is actually due to the great number of cases that at diagnosis
      conceal an occult MM.

PMID- 8664191
TI  - Strategy for dose escalation using 3-dimensional conformal radiation therapy for
      lung cancer.
AB  - PURPOSE: Local failure is a major obstacle to the cure of locally advanced non
      small-cell lung cancer. 3-Dimensional conformal radiation therapy (3-DCRT)
      selects optimal treatment parameters to increase dose to tumor and reduce normal
      tissue dose, potentially permitting dose escalation. There are several ongoing
      trials of dose escalation using 3-Dimensional conformal radiation therapy for non
      small-cell lung cancer. We performed this analysis to determine if data derived
      from dose volume histograms could be used as the basis for designing the method
      of dose escalation in these trials. METHODS AND MATERIALS: Between 1990 and 1993,
      31 patients were treated with 3-DCRT and had complete normal tissue dose volume
      histograms created as part of the planning process. The stage distribution was
      stage I/II 13%, stage IIIa in 45%, and stage IIIb in 42%. The median radiation
      dose to gross disease was 70.2 Gy (52.2-72 Gy). Elective mediastinal irradiation
      (50.4 Gy) was administered to 52% (16/31) of patients. RESULTS: The major
      toxicity encountered in this experience was pulmonary. Dose-volume-histogram data
      were used to analyze the predictors of toxicity and showed a correlation between
      risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or
      higher pulmonary toxicity occurred in 38% (3/8) of pts with >30%of lung volume
      receiving > or =25 Gy, versus 4% (1/23) of pts. with < or = 30% lung receiving >
      or = 25 Gy (p=0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (4/14)
      of patients with a predicted pulmonary normal tissue complication probability of
      12% or higher versus 0% (0/17) in patients with a predicted probability of less
      than 12% (p=0.03). The single fatality occurred in a patient with a calculated
      pneumonitis probability of 85% and a high percent (49%) lung volume receiving >=
      25 GY. CONCLUSION: This preliminary experience demonstrates a correlation between
      lung dose-volume-histogram data and the risk of severe pulmonary toxicity. This
      provides an opportunity to modify the method of radiation dose escalation. Dose
      volume-histogram data can allow escalation according to the risk to the lung
      parenchyma (which is the major organ of concern) rather than escalation according
      to tumor dose levels. Because of teh major inter-patient variability of
      intrathoracic tumor bulk and anatomic distribution, this strategy is intuitively
      appropriate. This approach may facilitate completion of dose escalation studies
      and identification of maximum tolerable pulmonary dose levels.

PMID- 8664192
TI  - Pharmacokinetics of paclitaxel and three major metabolites in patients with
      advanced breast carcinoma refractory to anthracycline therapy treated with a 3
      hour paclitaxel infusion: a European Cancer Centre (ECC) trial.
AB  - BACKGROUND: Hepatic metabolism and biliary clearance play pivotal roles in the
      disposition of the anticancer drug paclitaxel. 6-alpha-hydroxypaclitaxel, 3'-p
      hydroxypaclitaxel and 6-alpha,3'-p-dihydroxypaclitaxel were the major metabolic
      products of paclitaxel found in human bile. Recently, these metabolic products
      were detected in human plasma. The pharmacokinetics of paclitaxel and its
      metabolites were investigated in anthracycline-resistant breast cancer patients
      treated with high-dose paclitaxel and granulocyte colony-stimulating factor (G
      CSF) support. PATIENTS AND METHODS: Nine patients were entered into this study in
      which paclitaxel was administered at the relatively high dose of 250 mg/m2 during
      a 3-hour infusion. G-CSF was administered daily subcutaneously (s.c.)on days 2 to
      19 following chemotherapy. Analysis of paclitaxel and metabolite concentrations
      was performed by a new highly sensitive reversed-phase high performance liquid
      chromatographic (HPLC) assay. RESULTS: The dose-limiting toxicity in this study
      was cumulative neurotoxicity. One patient had a partial response and 2 patients
      had mixed responses of their skin metastases. Relatively low peak plasma
      concentration (Cmax), with mean values of 6.91 micromol/L (range 3.08 to 8.98)
      and area under the plasma concentration time curve (AUC), with mean values of
      27.04 micromol/L.h (range 14.88 to 40.57), were observed. The total body
      clearance was 16.99 L/h (range, 10.25 to 27.39). The pharmacokinetic parameter
      for the prediction of leuko-neutropenia, the duration of the plasma concentration
      above the threshold of 0.1 micromol/L.h (T > or = 0.1 microM), was 19.72 h (range
      10.54 to 26.31). The three major metabolites detected in human plasma were
      identified as 6-alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6-alpha,3'-p
      dihydroxypaclitaxel. Cmax and AUC values of these metabolites are reported.
      CONCLUSIONS: The three main metabolic products of paclitaxel in human plasma are
      6-alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and the dihydroxymetabolite 6
      alpha,3'-p-dihydroxypaclitaxel. Two patients with liver function disturbances
      showed a tendency to higher paclitaxel and 6-alpha-hydroxypaclitaxel AUC levels,
      with more pronounced neuropathy.

PMID- 8664193
TI  - Sources of anticipatory emotional distress in women receiving chemotherapy for
      breast cancer.
AB  - BACKGROUND: The contribution of classical conditioning processes to patients'
      distress before chemotherapy infusions (anticipatory distress) was compared to
      other potential sources of distress (e.g., trait anxiety). We hypothesized that
      posttreatment distress (putative unconditioned response) would become a stronger
      predictor of anticipatory distress as patients underwent more treatment infusions
      (putative conditioning trials). MATERIALS AND METHODS: Fifty women with early
      stage breast cancer, undergoing standard chemotherapy, completed questionnaires
      in the clinic prior to each of eight consecutive treatment infusions, as well as
      telephone interviews to assess side effects following infusions. RESULTS:
      Consistent with the conditioning hypothesis, posttreatment distress became
      significantly related to anticipatory distress at the fourth infusion and became
      the strongest predictor by the sixth. Path analysis indicated that posttreatment
      distress had a direct influence on anticipatory distress, and that trait anxiety
      had an indirect influence by influencing apprehension about chemotherapy which,
      in turn, directly predicted anticipatory distress. CONCLUSIONS: The results of
      the present study contribute to an emerging view of anticipatory distress as a
      conditioned response in chemotherapy patients. Results demonstrate that
      conditioning factors may be one of the strongest predictors of anticipatory
      distress in the later phases of chemotherapy treatment.

PMID- 8664194
TI  - The management of bone metastases.

PMID- 8664195
TI  - Phase II study of subcutaneous rHu-interleukin-2 and rHu-interferon alpha-2a in
      previously treated patients with multiple myeloma.
AB  - BACKGROUND: Several studies have shown that interferon alpha as a single agent
      produces responses in multiple myeloma patients, and may produces responses in
      multiple myeloma of interleukin-2 (rHu-IL-2) in multiple myeloma models indicate
      that rHu-IL-2 may have a therapeutic effect. In this phase II clinical trial, we
      combined rHu-interferon alpha-2a (rHu-IFN-2a) and rHu-IL-2, to assess the
      feasibility, toxicity and response rate when this treatment was given as
      subcutaneous injections to previously treated patients with relapsed or
      refractory multiple myeloma. PATIENTS AND METHODS: Seventeen patients with
      measurable serum M protein or urine paraprotein were entered on the study. Three
      patients were refractory to first line treatment; fourteen had relapsed following
      response to prior treatment. rHu-IFN alpha-2a was given three times per week
      continuously. rHu-IL-2 was given three times per week for 6 weeks followed by a 2
      week break from treatment. Patients were assessed for response and toxicity at 4
      week intervals. RESULTS: All patients were eligible and evaluable for toxicity;
      two patients were invaluable for response because they did not complete 4 weeks
      of treatment. All response-evaluable patients had a best objective response of
      stable disease which lasted a median of 22 weeks and was maintained for over one
      year in 5 patients. Toxicity was tolerable and was typical of rHu-IL-2 and rHu
      IFN alpha-2a; fever, chills or rigors and lethargy were nearly universal; local
      toxicity at the injection site, headache, anorexia, nausea and vomiting were also
      common. CONCLUSIONS: No objective responses in serum M protein or urine
      paraprotein levels were noted thus we do not recommend further study of this
      combination in myeloma.

PMID- 8664196
TI  - A phase II study of Tomudex in relapsed epithelial ovarian cancer.

PMID- 8664198
TI  - Postmastectomy follow-up in patients with early breast cancer: consensus or
      controversy?

PMID- 8664197
TI  - High incidence of other neoplasms in patients with low-grade gastric MALT
      lymphoma.
AB  - BACKGROUND: Low-grade gastric MALT lymphoma is an uncommon tumour for which a
      close association with chronic Helicobacter pylori infection has been suggested.
      However, given the rarity of MALT lymphoma of the stomach despite the high
      prevalence of H. pylori infection, it seems plausible that genetic host factors
      might play a fundamental role in gastric lymphomagenesis. PATIENTS AND METHODS:
      We retrospectively reviewed the medical records of 83 patients with low-grade
      gastric MALT, all of whom resided in a geographic area (southern Switzerland and
      northern Italy) where the incidence of gastric tumours appears to be uncommonly
      high. RESULTS: One or more additional cancers were observed in 17 of 83 patients
      (20%, 95% CI 12% to 31%) for a total of 23 tumours. Of these, 5 were diagnosed
      prior to, 12 concomitantly with, and 7 after the gastric MALT lymphoma. Eleven
      patients had a single additional solid tumour (13%, 95% CI 7% to 22%); 3 patients
      had non-Hodgkin's lymphoma and one had Hodgkin's disease. Multiple additional
      cancers were present in 3 cases. Nine of 83 patients have died and 8 of them of a
      second cancer. CONCLUSIONS: Unexpectedly an extraordinarily large number of
      patients with other malignancies was observed in this series. The reasons for
      this finding are still unknown, but genetic alterations are speculated to play an
      important role.

PMID- 8664199
TI  - Lethal paraneoplastic pemphigus following treatment of chronic lymphocytic
      leukaemia with fludarabine.

PMID- 8664200
TI  - Sclerotic IgA myeloma and polyneuropathy: the POEMS syndrome. Case report.

PMID- 8664201
TI  - Long-term remission of acute promyelocytic leukemia with intermittent all-trans
      retinoic acid: a case report.

PMID- 8664202
TI  - Regional cerebral blood flow in first break and chronic schizophrenic patients
      and normal controls.
AB  - Dynamic 133Xe Single Photon Emission Computed Tomography (SPECT) was used to
      measure the resting regional cerebral blood flow (rCBF) in 16 neuroleptic free
      schizophrenic and schizophreniform male patients and 13 age-matched male normal
      controls. A subgroup consisting of 'first break' patients who had never been
      exposed to neuroleptic treatment were age-matched to a subgroup of young chronic
      patients most of whom had been previously exposed to neuroleptics. The age
      adjusted rCBF values were compared among first breaks, young chronics, normal
      controls, and a subgroup of older, more chronic patients. In first break
      patients, we found significantly lower absolute global cerebral blood flow and
      significantly lower superior frontal, middle frontal, and middle temporal
      absolute rCBF compared to normals. We also found significantly lower relative
      superior frontal rCBF in first breaks vs. normals, and higher relative superior
      frontal and relative middle frontal rCBF in older chronics vs. the other groups.
      For relative posterior temporal rCBF there was greater asymmetry (right side >
      left) in first breaks and young chronics compared to normals and older chronics.

PMID- 8664203
TI  - No difference found between winter- and non-winter-born schizophrenic cases.
AB  - The distinction between winter-born (WBS) and non-winter born (NWBS)
      schizophrenic cases has been proposed as a strategy to identify distinct
      etiologic subtypes within schizophrenia, the WBS subgroup being a predominantly
      environmental subtype. The goal of this paper is to empirically test the validity
      of this strategy by comparing WBS and NWBS groups on a broad array of clinical
      and biological variables. DSM-III-R schizophrenic, schizoaffective and
      schizophreniform subjects were comprehensively assessed using (i) the
      Comprehensive Assessment of Symptoms and History; (ii) a comprehensive
      neurological exam; (iii) a neuropsychological battery, including IQ and the
      Continuous Performance Test and (iv) an MRI scanning. The patients were divided
      into WBS and NWBS, using five alternative sets of definitions of winter birth.
      These comparisons yielded no differences between the groups on any of the 23
      variables. The results suggest that the distinction between winter-born and non
      winter-born cases has very limited power to identify distinct schizophrenic
      subtypes, and that better delineation of the correlates of environmental risk
      factors in schizophrenia will require a better identification of these factors.

PMID- 8664204
TI  - Reduced emotional response of schizophrenic patients in remission during social
      interaction.
AB  - Inappropriate emotional response during social interaction is a prominent feature
      of schizophrenia during the acute stage of illness. This study evaluates the
      course of reduced facial activity in schizophrenic patients in remission and
      compares it with healthy controls. The experimental conditions included watching
      two films, one inducing happy and the other sad emotional states. Each is
      followed by an interview eliciting happy and sad feelings. The facial actions
      were recorded (1) by a computer-based analysis of recordings of the skin movement
      and (2) by electromyography of the corrugator and zygomaticus muscles. Twenty
      schizophrenic patients in remission and 20 normal controls participated in the
      study. In contrast to previously studied acute patients, there was no overall
      reduction of facial expression in the upper face of schizophrenic patients in
      remission. Patients showed fewer movements (automatic analysis) of the lower face
      during the happy interview and more movements during the sad interview compared
      with controls. Furthermore, schizophrenic patients showed reduced zygomaticus
      activity (EMG) during both the happy film and the interview, suggesting a reduced
      ability of schizophrenic patients to express happy facial expressions, such as
      smiling, in the lower face. This may indicate a reduced variability in emotional
      response in schizophrenia.

PMID- 8664205
TI  - Memory and vigilance training to improve social perception in schizophrenia.
AB  - Previous research has suggested that social cue recognition in schizophrenia may
      be significantly associated with visual vigilance and verbal memory. Therefore,
      we predicted that subjects who participated in a cognitive rehabilitation program
      that incorporated vigilance and memory training strategies would show
      significantly better social cue recognition than subjects participating in
      vigilance training alone. Forty subjects with a DSM-III-R diagnosis of
      schizophrenia or schizoaffective disorder were randomly assigned to either a
      vigilance-alone or a vigilance-plus-memory training condition. Results showed
      that subjects in the vigilance-plus-memory condition were able to identify social
      cues in the videotaped training materials significantly better than subjects in
      the vigilance-alone condition. This difference was evident in an independent
      measure of social cue recognition and was present at a 48 h follow-up.
      Implications for future development of cognitive rehabilitation for schizophrenia
      were discussed.

PMID- 8664206
TI  - Manual performance in leukotomized and unleukotomized individuals with
      schizophrenia.
AB  - Seven leukotomized adults with schizophrenia (LS), eight unleukotomized adults
      with schizophrenia (ULS), and eight healthy control (C) individuals were required
      to reach toward and grasp a small object that was either stationary or moving.
      Reflective markers were placed on the subject's index finger, thumb and wrist,
      and movements were videotaped. As expected the LS and ULS groups moved slower
      than the C group when the target was stationary. However, when the target was
      moving, all three groups moved faster, with the LS and C groups having the same
      movement times, and the ULS group having the fastest movement time. When the
      timing of the reaching trajectory was assessed, the LS group spent less time
      decelerating and closing their hands around the object, indicating their
      movements were controlled with less precision. When grasp formation was analyzed,
      for the stationary condition, the maximum apertures of the LS and ULS groups were
      not different, and both were larger than those of the C group. For the moving
      target condition, aperture increased for all groups but was smallest for the C
      group, intermediate for the LS group and largest for the S group. There was
      actually less within subject variability in peak aperture and maximum aperture
      closing speed for the LS and ULS groups in comparison to the C group, perhaps
      indicating a limited repertoire of potential motor responses for the patient
      groups. These results suggest that individuals with schizophrenia are able to use
      redundant information as well as controls, and that leukotomized individuals with
      schizophrenia have greater motor control deficits than unleukotomized
      schizophrenics.

PMID- 8664207
TI  - Effects of naltrexone on mannerisms and water imbalance in polydipsic
      schizophrenics: a pilot study.
AB  - In an open design, the opiate antagonist, naltrexone (25 mg bid), was added for
      six weeks to the neuroleptic regimen of seven inpatient polydipsic hyponatremic
      schizophrenics. Mannerisms and diurnal weight change improved slightly, the
      latter probably not as a consequence of diminished intake alone. Further studies
      are needed to clarify if stereotypies and polydipsia are modulated by endogenous
      opiates, and if opiate antagonists are of therapeutic value in this population.

PMID- 8664208
TI  - Maintaining schizophrenic patients on benzodiazepines.
AB  - The role of benzodiazepines (BZDs) in the treatment of schizophrenia is widely
      researched since the sixties. Nevertheless the role of BZD's as sole agents for
      the maintainance phase in pharmacotherapy of schizophrenic patients received
      little attention. We have conducted a retrospective review of all medical records
      of ambulatory schizophrenic patients in an out-patient setting receiving only BZD
      maintainance treatment. Three factors characterized these patients: long duration
      of illness, few hospitalizations and a relatively low dose response to BZD's.

PMID- 8664209
TI  - Associative learning in schizophrenia: a comment to Carroll (1995)

PMID- 8664210
TI  - Schizophrenia and the ear.

PMID- 8664211
TI  - Myocarditis under therapy with clozapine.

PMID- 8664212
TI  - Intracellular calcium modulates the responses of human melanocytes to melanogenic
      stimuli.
AB  - Ultraviolet radiation (UVR), the synthetic diacyglycerol (DAG), 1-oleoyl-2
      acetylglycerol (OAG), and cyclic AMP (cAMP) stimulants, including cholera toxin
      (CT) have all been shown to increase melanogenesis in cultured human melanocytes.
      Indirect evidence suggests that an increase in intracellular free Ca2+ ([Ca2+]i)
      may be important in stimulated melanogenesis. Therefore, to determine whether
      melanogenic responses are modulated by [Ca2+]i, the Ca2+ in the culture medium of
      melanocytes ([Ca2+]o) was raised from 70 microM to 1 mM. This switch in [Ca2+]o
      was associated with a biphasic increase in [Ca2+]i, with an early transient rise,
      over minutes, and a delayed sustained rise in [Ca2+]i, over hours. The early
      increase was blocked by nickel chloride (NiCl2), but not affected by depletion of
      [Ca2+]i stores by thapsigargin, suggesting that this [Ca2+]i rise was due to Ca2+
      entry across the plasma membrane. Melanocytes cultured in the absence of CT had a
      reduced basal melanin content following the switch to 1 mM [Ca2+]o, but in the
      presence of CT, which acts by stimulating cAMP synthesis, the basal level was
      increased. Raising [Ca2+]o resulted in enhanced melanogenic responses to UVR and
      OAG, in the presence or absence of CT, suggesting that Ca(2+)-dependent
      mechanisms are important. UVR also stimulated a delayed rise in [Ca2+]i, over 24
      h, but OAG did not. These results indicate that while [Ca2+]i is not essential
      for melanogenesis, it plays an important role in modulating the responses of
      melanocytes to melanogenic stimuli.

PMID- 8664213
TI  - Elevation of serum major basic protein in patients with atopic dermatitis.
AB  - Serum levels of major basic protein (MBP) were measured in patients with atopic
      dermatitis (AD). The severity of the disease in the AD patients was examined
      using our clinical scoring system. AD patients showed significantly elevated
      serum levels of MBP compared with normal controls. There were significant
      correlations between serum MBP and clinical score. These data indicate that serum
      MBP could be a possible marker for the disease activity.

PMID- 8664214
TI  - Decreased integrin alpha 2, but normal response to TGF-beta in scleroderma
      fibroblasts.
AB  - The distribution and amount of integrin alpha2 were studied in cultured
      fibroblasts from normal subjects and scleroderma patients by immunofluorescence
      and immunoblotting using a monoclonal antibody against the human integrin alpha2
      subunit. Integrin alpha2 was concentrated at the perinuclear regions in a dot
      like pattern in normal fibroblasts on the glass coverslips until the 14th day
      after planting, and the staining pattern of integrin alpha2 was gradually changed
      to a dispersed dot-like pattern by the 19th day as examined by immunofluorescence
      microscopy by using the anti-integrin alpha2 antibody. No difference was observed
      in the distribution patterns between normal and scleroderma fibroblasts. By
      immunoblotting study, the amount of integrin alpha2 in scleroderma fibroblasts (n
      = 10) was less than that of normal fibroblasts (n = 10) (P < 0.01) in both
      cytosol and cytoskeleton-associated fractions. Furthermore, transforming growth
      factor beta (TGF-beta) increased the amount of integrin alpha2 in both normal
      fibroblasts and scleroderma cells by 33%. The total amount of integrin alpha2 in
      TGF-beta-stimulated scleroderma fibroblasts was less than that in TGF-beta
      stimulated normal fibroblasts. These findings suggest that the amount of integrin
      alpha2, a collagen receptor, is reduced in scleroderma fibroblasts, but the
      integrin alpha2 production by TGF-beta stimulation is not impaired in scleroderma
      fibroblasts.

PMID- 8664215
TI  - Female sex hormone stimulates cultured human keratinocyte proliferation and its
      RNA- and protein-synthetic activities.
AB  - The present study was carried out to assess the effect of female sex hormones,
      i.e., estrogen and progesterone, on human keratinocyte proliferation, and its RNA
      and protein-synthetic activities in a culture system. The presence of receptors
      for estrogen and progesterone and their messenger ribonucleic acids (mRNAs) in
      the cultured cells was also investigated. Human keratinocytes were cultured in
      the experimental DMEM-Ham's F12 medium containing various concentrations of
      estrogen or progesterone, which was followed by determining cell yields and
      [3H]thymidine incorporation. The keratinocytes were also tested for RNA- and
      protein-synthetic activities by measuring [3H]uridine and [3H]leucine
      incorporation. Both estrogen and progesterone receptors were determined by the
      enzyme immunoassay method using monoclonal antibodies, and mRNA expression for
      these hormone receptors was detected by in situ hybridization. Cell yields and
      [3H]thymidine incorporation increased gradually until 3 x 10(-10) M of both
      estrogen and progesterone, decreased thereafter until 3 x 10(-7) M, and peaked at
      3 x 10(-10) M. [3H]Uridine and [3H]leucine uptake followed almost the same
      pattern as the cell proliferation, peaking at 3 x 10(-10) M of both hormones.
      Small amounts of estrogen and progesterone receptors were present in the cultured
      cells, and their mRNAs were found to be present in the cell cytoplasm. These
      results clearly suggest that sex hormones play an important role in human
      keratinocyte proliferation, and its RNA- and protein-synthetic activities, at
      least in part, via their hormone receptors.

PMID- 8664216
TI  - Effects of topical treatment with budesonide on parameters for epidermal
      proliferation, keratinization and inflammation in psoriasis.
AB  - Corticosteroids are important in the treatment of inflammatory dermatoses, such
      as psoriasis. They have anti-inflammatory, anti-proliferative and
      immunosuppressive effects. In this study, the effect of budesonide on
      proliferation, inflammatory cells and cytokines in psoriasis was investigated. In
      order to elucidate the time course of the different effects of corticosteroid
      treatment in psoriasis, six patients were treated for 3 weeks with budesonide
      0.025% ointment (Preferid), and biopsies were studied immunohistochemically,
      before treatment and after 1 and 3 weeks of treatment. Clinical scores together
      with staining with antibodies indicating proliferation, keratin 16, keratin 10, T
      lymphocytes, monocytes, polymorphonuclear leukocytes, Langerhans cells,
      interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor
      necrosis factor-alpha (TNF-alpha), and intercellular adhesion molecule-1 (ICAM-1)
      were performed. 'Psoriasis area' and 'severity index' (PASI) scores were
      significantly reduced after 1 week and 3 weeks of treatment. Epidermal
      hyperproliferation (Ki-67 binding) and suprabasal keratin 16 (Ks8.12) expression
      decreased within 1 week, while keratin 10 (RKSE60) expression did not change.
      Five out of 6 patients showed cytokine levels (IL-1alpha, IL-6, IL-8, and TNF
      alpha; detected immunohistochemically) in the normal range, while 1 patient had
      highly increased cytokine levels. In this patient, cytokine levels decreased
      during treatment. In 4 patients, showing high dermal ICAM-1 expression before
      treatment, a consistent reduction of ICAM-1 on endothelial cells was observed.
      The inflammatory infiltrate (T-lymphocytes (T11), monocytes/macrophages (WT14),
      polymorphonuclear leukocytes (PMN, anti-elastase)) was reduced to some extent
      after 3 weeks. The number of Langerhans cells (OKT6) did not change. These
      results indicate that the psoriatic lesions, although clinically comparable, show
      interindividual differences in cytokine expression. Corticosteroid treatment for
      1-3 weeks improves clinical scores and hyperproliferation. Cytokine levels are
      reduced during steroid treatment in the patient who showed high levels before
      treatment. To suppress the infiltrate entirely, longer steroid treatment is
      probably necessary. This may explain the relapse seen after short term
      corticosteroid therapy.

PMID- 8664217
TI  - A diffusing sphere which delivers homogeneous laser light for use in photodynamic
      therapy.
AB  - Photodynamic therapy (PDT) exploits the selective uptake of a photosensitizer in
      tumors and other hyperproliferative target tissues, as well as the ability to
      direct the treatment light beam to a specific region. Since the photodynamic
      effect depends on light dose, tissue optical properties and photosensitizer
      concentration, uniform delivery of light is crucial to attain optimal
      photodynamic effect. Many commonly used methods for delivering laser light during
      photodynamic therapy, such as a free fiber or microlens, require fiber and laser
      adjustments to obtain a highly uniform beam. In this study, we test the ability
      of a diffusing sphere to improve the uniformity of a light field coming from an
      argon laser coupled to a free fiber, in which no attempt has been made to
      optimize beam characteristics. Light fields from the free fiber, a microlens and
      the diffusing sphere are compared for uniformity via light intensity readings. An
      in vivo comparison between the sphere and the free fiber is also made in guinea
      pigs given Photofrin-II. The diffusing sphere decreases problems with shielding,
      allows quick and easy application of light by simply applying the device over the
      desired treatment area, and optimizes the desired photodynamic effect by
      producing ad highly uniform beam of light with no necessity to optimize light
      delivery by vibrating, looping or re-cleaving fibers.

PMID- 8664218
TI  - Possible role of 1,25-dihydroxyvitamin D3-induced metallothionein in
      photoprotection against UVB injury in mouse skin and cultured rat keratinocytes.
AB  - Previously cadmium chloride was successfully used to prevent sunburn cell (SBC)
      induction in mouse skin in vivo and to promote human cell survival in vitro after
      UVB exposure, indicating a protective effect of cadmium-induced metallothionein
      (MT) with the property of anti-oxidant action. Although cadmium is a potent
      inducer of MT, the cytotoxic metal is not available for clinical use. The aim of
      this study is to affirm MT gene expression by the active for of vitamin D3, 1,25
      dihydroxyvitamin D3, [1,25(OH)2D3] in cultured keratinocytes and examine in vivo
      and in vitro the photo-protective effects of 1,25(OH)2D3. Northern hybridization
      with human MT-IIa cDNA showed a significant increase in the gene expression of MT
      in the cells treated with 1,25(OH)2D3. Intraperitoneal injection and topical
      application of 1,25(OH)2D3 caused a significant reduction in SBC formation in
      mouse skin after UVB administration. The experiment showed the existence of an
      optimum level of 1,25(OH)2D3 for reducing photodamage. The cells exposed to
      1,25(OH)2D3 showed increased tolerance (cell survival) to UVB injury. 1,25(OH)2D3
      induced MT may act as a radical scavenger in oxygen-mediated UV injury including
      SBC formation in the skin. These results indicate that 1,25(OH)2D3 may be
      practically applied to humans for the purpose of photoprotection.

PMID- 8664220
TI  - Clinical analysis of anti-cardiolipin.beta 2 glycoprotein 1 antibody positive
      patients in anti-phospholipid syndrome.
AB  - Clinical analysis was performed on anti-cardiolipin x beta2 glycoprotein 1 (ACL x
      beta2 GP1) antibody positive patients with collagen vascular diseases. Nine
      patients out of 89 showed positive aCL x beta2 GP1 antibody which was a
      relatively lower percentage compared to that of othoffanti-phospholipid
      antibodies, such as anti-cardiolipin antibody (23 out of 58), lupus anti
      coagulant (15 out of 51) or biological false positive (BFP) test for syphilis (10
      out of 50). However, 8 patients out of 9 with positive aCL x beta2 GP1 antibody
      showed thrombotic lesions, a relatively higher frequency compared to that seen in
      aCL x beta2 GP1 negative patients. Among these cutaneous manifestations, livedo
      reticularis and palmar nodules with histopathological evidence of thrombosis were
      the most characteristic features. All but one patient with palmar nodules showed
      positive aCL x beta2 GP1 antibody, anti-cardiolipin antibody and lupus
      anticoagulant.

PMID- 8664219
TI  - p53 gene mutations in skin cancers with underlying disorders.
AB  - Mutations in p53, a tumor suppressor gene, are one of the most common genetic
      lesions of human cancers. The relationship between p53 gene mutation and
      ultraviolet (UV) light has been demonstrated in skin cancers of sun-exposed
      sites. In this study, genomic DNA from 12 skin cancers was screened for mutations
      in exons 5 to 9 of this gene using the polymerase chain reaction--single strange
      configuration polymorphism (PCR-SSCP) analysis followed by DNA sequencing. DNA
      samples were obtained from 8 basal cell carcinomas (BCCs): 1 from an organoid
      nevus, 1 from a patient with basal cell nevus syndrome, 1 from a patient with
      xeroderma pigmentosum, and 1 from a recurrent and 4 from primary sporadic lesions
      on actinic damaged skin, and from 4 squamous cell carcinomas (SCCs): 1 from a
      burn scar, 1 from a patient with epidermodysplasia verruciformis, and 2 from
      actinic keratosis. Mutation of the p53 gene was detected in only 1 case of SCC
      which had arisen from actinic keratosis. The mutation occurred at codon 159 in
      exon 5 with a GCC to CCC base-pair substitution resulting in an amino acid change
      of alanine to proline. This mutation does not correspond to results of UV
      mutagenesis studies reported in the literature. Our findings imply that, although
      p53 gene mutation and UV exposure play an important role in the carcinogenesis of
      some skin cancers, they are not crucial, especially in skin cancers that develop
      from underlying skin disorders.

PMID- 8664222
TI  - Metastases to the conjunctiva.

PMID- 8664221
TI  - The influence of sex hormones on UVB induced erythema in man.
AB  - Clinical and experimental evidence suggests that sex hormones can modify the
      inflammatory response in a number of diseases. In a pilot study the influence of
      sex hormones on UV-induced inflammation, testing was done with oestradiol-17beta,
      testosterone and progesterone, as a double-blind vehicle-controlled study in 47
      healthy volunteers. Inflammation was graded using laser-doppler velocimetry.
      Oestradiol (5 mg/100 g) was found to increase the inflammatory response
      significantly when compared with placebo or testosterone treated areas (P <
      0.03). These findings support previous experimental and epidemiological
      observations of an increased inflammation following oestrogenic stimulation, and
      suggest that non-lymphocyte-mediated mechanisms may be involved as well.

PMID- 8664224
TI  - Age-related macular disease.

PMID- 8664223
TI  - Long term changes in human corneal endothelium following toxic endothelial cell
      destruction: a specular microscopic and fluorophotometric study.
AB  - AIMS: To investigate the long term relation between corneal thickness,
      endothelial morphometric variables, and endothelial permeability in patients with
      endothelial cell counts under 900 cells/mm2 as a result of endothelial cell
      destruction after cataract surgery. METHODS: Eighteen patients developed the so
      called toxic endothelial cell destruction (TECD) syndrome following routine
      cataract surgery because of the intracameral injection of a toxic detergent
      residue. Ten patients with a mean (SEM) initial cell loss of 72% (2%) were
      followed for 4 years. Data were obtained at 6 months and 4 years postoperatively
      and compared between TECD eyes and contralateral control eyes. RESULTS: Mean
      (SEM) endothelial cell density of the TECD eyes increased from 642 (41) cells/mm2
      to 849 (50) cells/mm2 at 4 years postoperatively (p = 0.005). There was no
      difference in coefficient of variation or percentage hexagonals between 6 months
      and 4 years postoperatively. Mean (SD) corneal thickness of the TECD eyes and
      control eyes was similar, 0.51 (0.02) mm and 0.49 (0.01) mm, respectively (p =
      0.65). Mean (SD) endothelial permeability was also similar for TECD eyes and
      control eyes (4.3 (0.9) x 10(-4) cm/min and 4.4 (0.6) x 10(-4) cm/min,
      respectively (p = 0.57). There was no correlation between endothelial cell
      density, coefficient of variation, or percentage of hexagonal cells and
      endothelial permeability in the TECD eyes. In three patients a permanent corneal
      decompensation occurred. CONCLUSIONS: Four years after TECD corneal endothelial
      wound healing is stable and the barrier function has been restored.

PMID- 8664225
TI  - Deep corneal stromal opacities associated with long term contact lens wear.
AB  - BACKGROUND: One male and three female long term contact lens wearers (mean age
      30.3 years; range 26-33) demonstrated unusual deep corneal stromal opacities
      which were predominantly just anterior to Descemet's membrane. None had any
      history of corneal dystrophy. These opacities were more common centrally, but
      were also identified in the corneal periphery. METHODS: All patients underwent
      routine ophthalmic examinations and, where appropriate, slit-lamp photography and
      specular microscopy. RESULTS: Mean lens wear in years and hours per day was 14.3
      (range 10-17) and 14.3 (range 12-16) respectively. Specular microscopy disclosed
      cell densities within normal limits (mean 3041.5 cells per mm2) and coefficient
      of variation of mean cell area; COV = 0.31. Refractive errors ranged from -12.25
      D to +6.25 best vision sphere and all four subjects attained at least 6/9 Snellen
      visual acuity. The subjects' contact lens wearing history included low water
      content hydroxymethylmethacrylate (HEMA) contact lenses and high water content
      HEMA contact lenses. Stromal opacity density was observed to diminish over a
      period of months on cessation of contact lens wear in two cases. CONCLUSION: The
      possible causes of these rarely reported opacities are discussed.

PMID- 8664226
TI  - PRK in patients with a keratoconic topography picture. The concept of a
      physiological 'displaced apex syndrome'.
AB  - AIMS/BACKGROUND: Keratoconus is generally held to be an absolute contraindication
      for photorefractive keratectomy (PRK). Corneas with inferior steepening on
      corneal topography are widely thought to have subclinical keratoconus. We were
      not convinced that this is always the case, as there seems to be a group of
      patients with a stable inferior steepening pattern on topography who show no
      other characteristics of clinical keratoconus. We thus decided to offer PRK to
      some of these patients under strictly defined criteria. METHOD: Four myopic
      patients with a topography pattern of inferior steepening were submitted to PRK.
      They were selected on the basis of being aged over 35, with a stable refraction,
      no slit-lamp signs of keratoconus, and a corrected vision of not less than 6/7
      (0.9) with a spherical spectacle correction. They gave fully informed consent
      that this was an experimental procedure. RESULTS: The refractive results at 6
      months after operation were within the range one would expect for PRK on corneas
      with a regular 'bow-tie' topography and similar level of myopia. No unusual
      problems were encountered. CONCLUSION: We feel that the corneal topography
      pattern of inferior steepening is not always a contraindication for PRK. The
      concept of a physiological 'displaced apex syndrome' is discussed and illustrated
      by corneal topography in different positions of gaze.

PMID- 8664228
TI  - Surgery for pterygium using a conjunctival pedunculated flap slide.
AB  - Eight hundred and eighty patients (913 eyes) with primary pterygium who were
      surgically treated from 1983-93 were followed up for 5.7 years on average. Based
      on the large number of cases and a 10 year period of practice, it was found that
      pterygium excised with a pedunculated conjunctival flap slide was effective and
      safe in the treatment of primary pterygium. The recurrence rate of 1.6% (15 out
      of 913 eyes) in this series compared favourably with other reports. The
      characteristics and techniques concerning the operating process are described in
      detail.

PMID- 8664227
TI  - Corneal temperature in patients with dry eye evaluated by infrared radiation
      thermometry.
AB  - AIMS: The corneal temperature change following each blink was investigated in
      patients with dry eye using an infrared radiation thermometer. METHODS: Twenty
      patients with dry eye and 20 normal controls were enrolled in this study.
      Subjects kept their eyes open for 10 seconds without blinking and corneal
      temperature was measured every second with a recently improved infrared radiation
      thermometer. RESULTS: In the 20 patients with dry eye, corneal temperature change
      after keeping the eye open for 10 seconds was 0.21 (SD 0.06) degree C while it
      was 0.61 (0.28) degree C in the 20 normal patients (p = 0.0001). In an
      exponential equation, the inclination of the slope of a patient with dry eye was
      smaller than the normal. The correlation coefficient was r = 0.79 (0.16) in
      patients with dry eye and r = 0.90 (0.07) in normal patients. The mean K value of
      patients with dry eye was 0.20 (0.13)/second and that of normal subjects was 0.31
      (0.19)/second (p = 0.03). CONCLUSION: Findings demonstrate the usefulness of this
      thermometer for measuring corneal temperature in the evaluation of dry eye.
      Decrease in corneal temperature with each blink in patients with dry eye was
      smaller than in normal subjects.

PMID- 8664229
TI  - Clinical evaluation of the Allergan Humphrey 500 autorefractor and the Nidek AR
      1000 autorefractor.
AB  - AIMS/BACKGROUND: The intentions of this study were to estimate agreement between
      two different autorefractors and standard subjective refraction techniques and to
      evaluate the clinical implications of relying on the autorefractor measurements.
      METHODS: Subjective refraction was carried out on 448 cycloplegic eyes and
      compared with cycloplegic readings with the Allergan Humphrey 500 autorefractor
      (448 eyes) and the Nidek AR-1000 autorefractor (160 eyes). Each refraction was
      followed by clinical visual acuity measurement. The study population comprised
      224 healthy students, 107 men and 117 women, with a mean age of 20.6 (SD 1.1)
      years. RESULTS: Both the Nidek and Humphrey autorefractors measured more negative
      or less positive refractive values compared with subjective refraction and these
      biases were statistically significant (Humphrey right eye -0.23 D, p = 0.0001,
      left eye -0.20 D, p = 0.0001), (Nidek right eye -0.13 D, p = 0.0001, left eye 
      0.11 D, p = 0.0002). Comparing the results of autorefraction with subjective
      refraction, the Nidek was better than the Humphrey autorefractor in several ways:
      a smaller mean difference, better agreement between spherical equivalent values,
      narrower limits of agreements, and better visual acuity obtained with the
      autorefraction. On the other hand, the Humphrey autorefractor agreed better with
      subjective refraction concerning cylinder axis. CONCLUSION: The results show that
      both autorefractors represent a valuable complement to subjective refraction, but
      cannot be used as a replacement.

PMID- 8664230
TI  - Laser treatment of soft drusen in age-related maculopathy.

PMID- 8664231
TI  - Analysis of visual field progression in glaucoma.
AB  - BACKGROUND: Despite the widespread use of computerised perimetry the diagnosis of
      visual field deterioration in following glaucoma patients over time remains
      particularly difficult. A new method of analysis using a novel graphical display
      of longitudinal field data is presented. METHODS: A linear regression model of
      the luminance sensitivity at each stimulus location against time of follow up
      transforms the quantitative data from a series of fields into a colour coded form
      which illustrates the spatial configuration of change to aid the interpretation
      of field loss. The method of analysis and the developed computer software
      (PROGRESSOR) is described. Comparison with STATPAC-2 glaucoma change probability
      analysis is given including levels of agreement between the techniques using
      series of fields of 10 eyes from patients with normal tension glaucoma. RESULTS:
      Examples of this new method compare well with STATPAC-2 analysis. The level of
      agreement between the techniques to separate progressing from stable retinal
      locations is good (kappa = 0.62; SE = 0.04). CONCLUSIONS: This new technique,
      which combines the change in perimetric sensitivity over time with colour coding
      of significant change into one image may provide an efficient method to detect
      true progression in glaucomatous field loss.

PMID- 8664232
TI  - Incidence of registered visual impairment in the Nordic child population.
AB  - A collaborative, population based, prospective register study on the incidence of
      visual impairment in children during the year 1993 was carried out in five Nordic
      countries with a total population of 17 million inhabitants. The child population
      was 3.8 million individuals aged 0-17 years. The following variables were taken
      into account: nationality, age, sex, diagnoses, aetiology, degree of visual
      impairment, and additional impairments. Classification routines from an earlier
      prevalence study were used. The present study included 304 children corresponding
      to an incidence of notification of 8/100,000 children, varying from 5.7 to 11.1
      in the five countries. Fifty per cent of the visually impaired children were
      reported before they were 3 years of age. In approximately 45% of the children,
      visual impairment was due to various brain disorders, with cerebral amblyopia and
      secondary optic atrophy as the two leading causes. The relative impact of
      retinopathy of prematurity had decreased from the third most frequent cause (10%)
      in the prevalence study to seventh place (4%) in the incidence study. Two thirds
      of the children had additional impairments and these children also suffered from
      the most severe visual impairments. Among aetiological factors the majority (64%)
      were prenatal. The overall male:female ratio of 1.4:1 was identical to the sex
      ratio of the prevalence study.

PMID- 8664233
TI  - Metastatic tumours to the conjunctiva: report of 10 cases.
AB  - AIMS/BACKGROUND: Ten patients with metastatic tumours to the conjunctiva and the
      clinical aspects of this rare form of ocular metastasis are described in this
      study. METHOD: All patients with ocular and adnexal metastatic tumours referred
      to an ocular oncology service were reviewed and those having conjunctival
      metastases were studied for the site of their primary tumour, clinical features,
      and treatment of the conjunctival tumour, associated ocular and systemic
      findings, and the patients' outcome. RESULTS: The primary malignancy was
      carcinoma of the breast in four, lung cancer in two, laryngeal carcinoma in one,
      cutaneous melanoma in two, and unknown in one patient. The conjunctival
      metastases appeared after the primary tumour over a mean period of 44 (8-130)
      months. They were solitary in eight cases, located in bulbar conjunctiva in six,
      palpebral conjunctiva in two, and in limbus and forniceal conjunctiva in one
      patient each. The tumour was yellow in colour in seven patients, red in two, and
      brown in one. Eight patients also had metastases to other ocular structures.
      Seven patients received external beam radiotherapy to the affected eye, two were
      managed by excisional biopsy, and one with chemotherapy. The mean survival after
      the diagnosis of conjunctival metastasis was nine (range 2-26) months.
      CONCLUSION: Metastatic tumours to the conjunctiva appear at an advanced stage of
      the systemic disease when there are other ocular and organ metastases. The
      presence of a conjunctival mass in a patient with a prior systemic cancer should
      alert the ophthalmologist to the possibility of a conjunctival metastasis and
      evaluation should be pursued.

PMID- 8664234
TI  - Retinal detachment associated with atopic dermatitis.
AB  - BACKGROUND: Retinal detachment associated with atopic dermatitis, one of the most
      common forms of dermatitis in Japan, has markedly increased in Japan in the past
      10 years. To clarify pathogenic mechanisms of retinal detachment in such cases,
      we retrospectively studied clinical characteristics of retinal detachment
      associated with atopic dermatitis. METHODS: We examined the records of 80
      patients (89 eyes) who had retinal detachment associated with atopic dermatitis.
      The patients were classified into three groups according to lens status: group A,
      eyes with clear lenses (40 eyes); group B, eyes with cataract (38 eyes), and
      group C, aphakic or pseudophakic eyes (11 eyes). RESULTS: No significant
      differences were noted in the ratio of males to females, age distribution,
      refractive error, or characteristic of retinal detachment among the three groups.
      The types of retinal breaks, however, were different in eyes with and without
      lens changes. While atrophic holes were dominant in group A, retinal dialysis was
      mainly seen in groups B and C. CONCLUSION: These findings suggested that anterior
      vitreoretinal traction may play an important role in the pathogenesis of retinal
      breaks in eyes with atopic cataract and that the same pathological process may
      affect the formation of cataract and tractional retinal breaks in patients with
      atopic dermatitis.

PMID- 8664235
TI  - Effects of bilateral orbital decompression by an endoscopic endonasal approach in
      dysthyroid orbitopathy.
AB  - AIMS: The efficacy of endoscopic endonasal orbital decompression in dysthyroid
      orbitopathy was analysed. METHODS: In 21 consecutive cases of bilateral operation
      short term (10 (SD 6) days after operation) and long term (156 (12) days after
      operation) results were recorded. RESULTS: Short term results showed that vision
      of the more affected eye improved from a mean of 0.35 to 0.59; vision improved in
      all but one eye which remained unchanged. In the fellow eyes mean visual acuity
      improved from 0.6 to 0.7; three of these eyes showed a decrease. Mean proptosis
      returned from 23.0 mm to 20.0 mm. As to motility the mean abductive capacity
      decreased from 5.5 mm to 4.0 mm of monocular excursion, whereas adduction
      increased from 7.5 mm to 8.5 mm. Upgaze and downgaze did not show any major
      change. The mean angle of horizontal squint shifted from 7.5 degrees of
      convergence to 15.5 degrees while no significant vertical or cyclorotational
      deviation was induced. These immediate postoperative results proved to be stable
      for the period of long term follow up with only slight changes. No significant
      bleeding or specific otorhinolaryngological complication without resolve occurred
      intraoperatively or perioperatively. CONCLUSION: This method is believed to be
      superior to non-endoscopic techniques because it avoids external scars and antral
      pain. With regard to the relief of intraorbital pressure, the technique gives
      good results for visual acuity improvement, but in proptosis reduction the method
      is not as efficient as external or combined procedures. There seems to be no
      difference when compared with other approaches in induction of horizontal squint.
      The method has a protective long term effect against the recurrence of
      compressive optic neuropathy.

PMID- 8664236
TI  - Effects of the cytokines on the proliferation of and collagen synthesis by human
      cataract lens epithelial cells.
AB  - AIMS: To assess the effects of the cytokines, interleukin-1 (IL-1), IL-1 receptor
      antagonist (IL-1ra), transforming growth factor-beta 2 (TGF-beta 2) and basic
      fibroblast growth factor (b-FGF), on the mitosis of and collagen synthesis by
      lens epithelial cells (LECs) of human cataracts. METHODS: The anterior lens
      capsule with attached LECs was obtained by capsulotomy during cataract surgery
      and cultured. The cultures at 2 to 3 weeks before confluency were used for the
      experiments. To quantify the mitosis and collagen synthesis, the incorporation of
      3H-thymidine and 3H-proline, respectively, into the LECs was measured by a
      scintillation counter at 48 hours and 24 hours, respectively, after addition of
      the cytokine at various concentrations into the incubation medium. RESULTS: IL-1
      and b-FGF increased the mitosis and collagen synthesis significantly, but IL-1ra
      significantly decreased the mitosis while leaving the collagen synthesis intact.
      TGF-beta 2 decreased the mitosis significantly, but increased the collagen
      synthesis significantly. CONCLUSION: These cytokines may play an important role
      in an autocrine or paracrine pathway in the proliferation of residual LECs after
      cataract surgery. Elucidation of the role of these cytokines may lead to the
      development of new therapies for the prevention of secondary cataract.

PMID- 8664237
TI  - Non-invasive assessment of the donor corneal endothelium using ocular redox
      fluorometry.
AB  - AIMS: To investigate the usefulness of ocular redox fluorometry for evaluating
      donor corneal endothelial viability. METHODS: Corneas from 42 recipients of
      penetrating keratoplasty and four donor corneas were examined by ocular redox
      fluorometry. Autofluorescence from reduced pyridine nucleotides (PN) and oxidised
      flavoproteins (Fp) of the human corneal endothelium were measured non-invasively,
      and the PN/Fp ratio was used as a tissue metabolic indicator. Specular microscopy
      and electron microscopy were also performed. RESULTS: Both the quality of
      specular microscopic image and the PN/Fp ratio were significantly correlated with
      the degree of corneal endothelial damage determined by histological examination.
      Corneas with poor specular microscopic image showed significantly decreased PN/Fp
      ratio compared with corneas with good or fair specular images (p = 0.041 and
      0.027, respectively). The PN/Fp ratio increased in corneas with mildly damaged
      endothelium but decreased in corneas with severely damaged endothelium determined
      by histological examination. Evaluation of corneal endothelium by combination of
      specular microscopy and ocular redox fluorometry showed excellent association
      with that of histopathological examination (p < 0.0001). CONCLUSION: Ocular redox
      fluorometry is useful for assessing donor corneal endothelial viability.
      Combination of ocular redox fluorometry and specular microscopy may increase the
      ability of donor cornea selection.

PMID- 8664238
TI  - Collagen synthesis activity in the aqueous humour of eyes with glaucoma surgery:
      a pilot study.
AB  - AIMS: The purpose of this pilot study was to test whether the rate of collagen
      synthesis is measurable in the aqueous humour samples in reoperated and
      previously unoperated eyes. METHODS: The material consisted of 28 eyes of 27
      patients, aged 5 to 82 years, in whom aqueous humour samples were obtained during
      eye surgery. Fifteen patients had no history of previous eye surgery (control
      group) while 12 patients were re-operated (study group). The carboxyterminal
      propeptide of type I procollagen (PICP) and the aminoterminal propeptide of type
      III procollagen (PIIINP) were measured by specific immunoassays in the aqueous
      humour samples. RESULTS: The mean concentration of PIIINP in the study group (8.4
      (SD 12.5) micrograms/l) was statistically significantly larger than that of the
      control group (0.4 (0.4) micrograms/l) (p < 0.0037). The respective values for
      PICP were 98.8 (SD 177.7) micrograms/l in the study group and 0.7 (SD 2.8)
      micrograms/l in the control group (p < 0.0005). The eyes in the study group which
      were re-operated within 1 year showed values increased 20-fold compared with the
      eyes in the control group and those eyes in the study group which had had their
      previous operation more than a year ago. In three eyes aqueous humour samples
      were also obtained from the encapsulated Molteno bleb and showed values increased
      12-fold compared with those from the anterior chamber. CONCLUSIONS: PICP and
      PIIINP immunoassays are suitable for measuring the rate of collagen synthesis in
      the aqueous humour and may be useful in studies on pharmacological modulation of
      wound healing in glaucoma surgery.

PMID- 8664240
TI  - Optic nerve vasomotor effects of topical apraclonidine hydrochloride.
AB  - AIMS: To examine, in vivo, the anterior optic nerve vasomotor effects of chronic
      apraclonidine hydrochloride in rabbits. METHODS: After local treatment in one
      randomly chosen eye with apraclonidine hydrochloride 0.5% over 21 days, the
      microvasculature of the optic nerve was examined in five rabbits using an
      intraluminal microvascular corrosion casting technique. The investigators were
      masked as to which eye was treated. The vasoconstriction near the branching point
      of arterioles supplying the optic nerve was calculated as a percentage of the
      downstream vessel calibre. An average constriction was calculated and compared
      between the treated and the contralateral, untreated, eyes by means of a two
      tailed t test for paired variables. Constriction values of a total of 72
      arterioles supplying the optic nerve were obtained for the five rabbits. RESULTS:
      The average constriction in the treated and the control eyes was comparable (p =
      0.96). CONCLUSION: Chronic administration of apraclonidine hydrochloride 0.5%
      produces no observable optic nerve vasomotor effects in the rabbit eye.

PMID- 8664239
TI  - Compensatory elevation of complex II activity in Leber's hereditary optic
      neuropathy.
AB  - AIMS: To evaluate the mitochondrial respiratory enzyme activities in blood cells
      of Leber's hereditary optic neuropathy (LHON) with 11778 point mutation of
      mitochondrial DNA. METHODS: Assays for the activities of NADH-cytochrome c
      reductase (complex I+complex III), succinate-cytochrome c reductase (complex
      II+complex III), and cytochrome c oxidase (complex IV) on blood cell mitochondria
      of seven LHON patients and 15 normal controls. RESULTS: There was no
      statistically significant difference in NADH-cytochrome c reductase and
      cytochrome c oxidase activities between LHON patients and controls, but
      activities of succinate-cytochrome c reductase in LHON patients was significantly
      elevated compared with normal controls. CONCLUSION: The observations that the
      activity of NADH-cytochrome c reductase is normal but that of succinate
      cytochrome c reductase is increased in LHON patients with 11778 point mutation of
      mitochondrial DNA indicate an elevation of complex II activity, which may be due
      to a nuclear compensatory effect for defects of the respiratory function of
      mitochondria.

PMID- 8664241
TI  - Medical treatment of glaucoma--a reappraisal of the risks.

PMID- 8664242
TI  - Is the incidence of registrable age-related macular degeneration increasing?
AB  - AIMS/BACKGROUND: Age-related macular degeneration (ARMD) is a growing public
      health problem in Britain; currently its aetiology is unclear. The aim of this
      study was to test the hypothesis that the age specific incidence of blinding ARMD
      has increased in Britain in the past 50 years, using data on cause of visual loss
      in people registered as blind, published every 10 years since 1950. METHODS: Data
      were abstracted from published sources for the years 1950, 1960, 1970, and 1980.
      Data for the standard year, 1990, were provided in a database from the Office of
      Population Censuses and Surveys. The numbers of new registrations attributed to
      ARMD per head of population were compared with registrations for cataract,
      glaucoma, and optic atrophy. Indirect standardisation was used to control for
      changes in the age structure of the population over time. RESULTS: After
      controlling for changes in the age structure of the population, registration
      rates for all causes, cataract, glaucoma, and optic atrophy have decreased while
      registrations attributed to ARMD have increased in the order of 30-40%.
      CONCLUSIONS: These findings are compatible with the hypothesis that the incidence
      of ARMD is increasing in Britain. It is difficult to exclude potential sources of
      bias in these data, however, particularly with respect to classification and
      coding of cause; more reliable population based data on ARMD in Britain are
      needed.

PMID- 8664243
TI  - Indocyanine green angiography in a case of punctate inner choroidopathy.

PMID- 8664244
TI  - A self-protecting servo-model for explanation of the mechanism involved in
      spontaneous ventricular defibrillation.
AB  - Ventricular fibrillation (VF) is the most life-threatening arrhythmia. It has
      been suggested that VF in humans is always sustained. Recent publications
      indicated that VF can be either sustained (SVF) or transient (TVF), reverting
      spontaneously into sinus rhythm. In previous studies we have hypothesized that
      TVF requires, during VF, a high cardiac catecholamine level ([CA]). Since during
      VF sympathetic activity is enhanced, the question arises of why VF is sustained
      in the majority of cases. Looking on the living body as a self-protecting servo
      mechanism, we propose a servo-model that on the one hand describes the mechanism
      involved in TVF and on the other proposes a therapeutic procedure which can help
      the heart in its effort to transform VF into TVF. Our model has been examined by
      various experimental studies. The results obtained strongly support our
      hypothesis.

PMID- 8664245
TI  - Ultrastructural-functional basis for spontaneous termination of ventricular
      fibrillation in mammals.
AB  - Ventricular fibrillation in humans is generally sustained (SVF), but it can be
      also transient (TVF), reverting spontaneously to sinus rhythm. In previous
      studies we have shown that: a) TVF appears in all young mammals and varies
      according to age and species; b) it requires synchronization of myocardial cell
      activity; c) infusion of certain drugs may change the type of ventricular
      fibrillation from sustained into transient. We hypothesize that the
      synchronization required for TVF depends on the electrical conductivity of
      intercellular structures. These intercellular couplings differ among species and
      decrease with age. Comparison between the inter- and intra-specific variations of
      intercellular connective structure described in the literature with the type of
      ventricular fibrillation found in our previous studies on various animals of
      different ages showed a clear relationship between these histological variations
      and the changes in the type of ventricular fibrillation. In this study we
      examined intercellular connective structures ultrastructurally in 3 groups of
      cats: a. control, untreated cats exhibiting sustained ventricular fibrillation;
      b. untreated cats exhibiting transient ventricular fibrillation; c. treated cats
      exhibiting sustained ventricular fibrillation before infusion of a defibrillating
      drug and transient ventricular fibrillation thereafter. It was found that the
      intercellular connective structure in cats exhibiting sustained ventricular
      fibrillation differs significantly from that in cats exhibiting transient
      fibrillation. In hearts exhibiting sustained ventricular fibrillation, many
      intercellular connective structures are widened and the degree of widening is
      pronounced, forming a continuous line, while in hearts exhibiting transient
      ventricular fibrillation the widened junctions are rare and isolated and the
      widening is relatively small. These preliminary results strongly support our
      above-mentioned hypothesis, providing an explanation for the origin of transient
      ventricular fibrillation and a tool for the development of new defibrillating
      drugs.

PMID- 8664246
TI  - The defibrillating effect of catecholamine reuptake inhibitors.
AB  - In previous studies we hypothesized that spontaneous termination of ventricular
      fibrillation (TVF) requires a high cardiac catecholamine level ([CA]) during VF.
      During VF, sympathetic activity is enhanced but in the majority of cases [CA]
      does not reach the level required for self-defibrillation, most likely due to
      their relatively high reuptake by sympathetic nerve terminals. One possibility of
      obtaining TVF is by elevation of the [CA] during VF, either by catecholamine
      intracoronary injection or by treatment with compounds that inhibit catecholamine
      reuptake. To examine this assumption, we studied the effect of VF on 3 closely
      related compounds: talopram, talsupram and citalopram, with norepinephrine uptake
      inhibition (IC50NE) of 2.9, 0.79 and 8800 and dopamine (DA) uptake inhibition
      (IC50DA) of 44000, 9300 and 41000, respectively, as well as 2 enantiomers of a
      cis-1-piperazino-3-phenylindan derivative (Lu20-037 and Lu20-036) with IC50NE of
      2.5 and 910 and IC50DA of 2.3 and 1700, respectively. The results support our
      hypothesis relating the defibrillating effect of a compound to its IC50NE, while
      its inhibitory effect on DA uptake seems to conteract the NE effect.

PMID- 8664247
TI  - Ethmozine and ethacizine--new antiarrhythmic drugs with defibrillating
      properties.
AB  - Ventricular fibrillation (VF) is a life-threatening arrhythmia that leads to
      death unless electrical defibrillation is applied in time. Recent publications
      indicate that VF can be either sustained (SVF), requiring electrical
      defibrillation, or transient (TVF), reverting spontaneously into sinus rhythm.
      Since VF cannot be totally prevented by drugs, a new antiarrhythmic therapeutic
      approach has been proposed: drug-induced enhancement of the ability of the heart
      to defibrillate by itself. In this study we examined the defibrillating potency
      of two antiarrhythmic phenothiazines, ethmozine (ETM) and ethacizine (ETA), as
      well as their effects on catecholamine uptake and on the electrophysiological
      properties of the myocardial cell membrane. The antiarrhythmic-defibrillatory
      activity was examined in cats; the inhibitory effect on [3H]-norepinephrine (NE)
      uptake was examined in rat brain synaptosomes, and the electrophysiological
      membrane effects were examined by microelectrode recordings in perfused strips of
      heart ventricle from guinea-pigs. The results indicate that: 1. ETA exhibits
      similar but stronger antiarrhythmic-defibrillating and NE reuptake inhibitory
      effects than ETM; 2. ETA at 10-6 M decreases ventricular conduction time and
      increases Vmax while ETM at this concentration does not change them; 3. The
      defibrillating ability of the drugs can be related to their inhibitory potency on
      NE reuptake. We suggest that the risk of sympathomimetic arrhythmogenicity is
      prevented by the previously described, membrane stabilizing Class 1
      antiarrhythmic properties of these drugs.

PMID- 8664248
TI  - Changes in ventricular fibrillation threshold during acute hypothermia. A model
      for future studies.
AB  - Hypothermia and rewarming are associated with an increased incidence of lethal
      arrhythmias in man. The relationship between reduction in body temperature and
      ventricular fibrillation threshold was studied in 7 pentobarbital anaesthetized
      dogs using programmable electrical stimulation while cooling and rewarming
      between 37 degrees C and 25 degrees C in steps of 3 degrees C. Fibrillation
      threshold was defined as the number of extrastimuli required to evoke ventricular
      fibrillation. QRS-durations and corrected QT-intervals (QTc) were measured from
      surface electrocardiograms. Monophasic action potential durations were recorded
      from the base and apex of the heart. Fibrillation threshold decreased with
      decreasing temperatures; e.g., at 37 degrees C ventricular fibrillation was not
      inducible after 5 extrastimuli, while at 25 degrees C only 2 extrastimuli were
      required. From 37 degrees C to 25 degrees C QRS-width, monophasic action
      potential durations and QTc increased while conduction velocity decreased. The
      differential effects on conduction and monophasic action potential duration
      provide a basis for induction of ventricular fibrillation during acute
      hypothermia. This model of hypothermia-induced ventricular fibrillation should
      prove useful for future studies aimed at understanding the mechanisms responsible
      for hypothermia-related deaths.

PMID- 8664249
TI  - Reperfusion-induced arrhythmias in isolated rat heart: an index of cellular
      damage or viability of cardiomyocytes?
AB  - Susceptibility of rat myocardium to reperfusion-induced arrhythmias after
      sustained (4 h) and brief (10 min) durations of regional ischaemia in relation to
      structurally-related impairment of heart function was studied in isolated
      Langendorff-perfused rat hearts. Reperfusion arrhythmias after 4 h ischaemia were
      characterized by low severity accompanied by only partial restoration of coronary
      flow upon reperfusion (no-reflow). Electron microscopy examination of the
      ischaemic hearts revealed severely ultrastructure of cardiac myocytes and
      capillary endothelium. These deteriorations were not reversed upon reperfusion.
      On the contrary, brief ischaemia resulted in high susceptibility of the heart to
      severe arrhythmias upon reperfusion with persisting hyperaemia. Ischaemia-induced
      minor changes in myocardial ultrastructure were reversed upon reperfusion. In
      conclusion, sustained ischaemia in the rat heart with absent collaterals renders
      myocardial tissue non-viable with consequent impaired recovery of heart function
      and loss of excitability of the myocardium upon reperfusion. Accordingly, high
      susceptibility to arrhythmias may indicate the preservation of viable myocardial
      cells.

PMID- 8664250
TI  - High arrythmogenesis during early reperfusion of ischaemic myocardium:
      participation of oxygen free radicals.
AB  - The early period of reperfusion of ischaemic myocardium leads to a high incidence
      of severe tachyarrhythmias including ventricular fibrillation (VF), accompanied
      by a sudden transitional dysfunction. Oxygen free radicals (OFR) have been
      identified as one of the principal factors responsible for reperfusion-induced
      events. However, direct evidence for participation of OFR in the arrhythmogenic
      mechanisms upon reperfusion is still lacking. In the present study, in isolated
      Langendorff-perfused rat hearts subjected to 30 min global ischaemia, the onset
      of reperfusion induced 100% incidence of both ventricular tachycardia (VT) and VF
      with their gradual cessation during 5 min of reperfusion. Generation of H2O2 in
      the myocardium in the first minutes of reperfusion was demonstrated by means of
      cerium cytochemistry. There was an increased density of cerium perhydroxide
      precipitate distributed throughout the myocytes and endothelial cells, confirmed
      by X-ray microanalysis. The mechanism of the arrhythmogenic effect of OFR may
      involve the inhibition of the sarcolemmal Na+/K+ ATPase activity, as was revealed
      by subjecting the isolated sarcolemmal fraction of rat heart to the action of an
      oxy-radical generating system (H2O2 + FeSO4).

PMID- 8664252
TI  - Sudden cardiac deaths and ventricular extrasystoles on days with four levels of
      geomagnetic activity.
AB  - Four hundred and eighty sudden deaths were studied on 4009 consecutive days from
      1976-1986, according to each of 4 levels of geomagnetic activity. Ventricular
      extrasystoles (VPCs) recorded by 24-hour Holter monitoring were studied on 364
      days. 211 cardiac outpatients were studied. It was shown that both sudden deaths
      and VPCs were significantly more frequent on days with the lowest/quiet level of
      geomagnetic activity.

PMID- 8664251
TI  - Polymorphous ventricular tachycardia in the early stages of an evolving
      myocardial infarction.

PMID- 8664254
TI  - Catalysis by Escherichia coli inorganic pyrophosphatase: pH and Mg2+ dependence.
AB  - Steady-state rates of PPi hydrolysis by Escherichia coli inorganic
      pyrophosphatase (E-PPase) were measured as a function of magnesium
      pyrophosphatase (substrate) and free Mg2+ ion (activator) in the pH range 6.0
      10.0. Computer fitting of hydrolysis data in combination with direct measures of
      Mg2+ binding to enzyme has resulted in a model that quantitatively accounts for
      our results. The major features of this model are the following: (a) E-PPase
      catalysis proceeds both with three and with four (and possibly with five) Mg2+
      ions per active site; (b) catalysis requires both an essential base and an
      essential acid, and the pKas of these groups are modulated by the stoichiometry
      of bound Mg2+; and (c) the four-metal route predominates for concentrations of
      free Mg2+>0.2mM. The model straightforwardly accounts for the apparent linkage
      between increased pKa of an essential base and activity requirements for higher
      Mg2+ concentration observed for several active site variants. Microscopic rate
      constants for overall catalysis of PPi-Pi equilibration were determined at pH 6.5
      9.3 by combined analysis of enzyme-bound PPi formation and rates of PPi
      hydrolysis, PPi synthesis, and Pi-H2O oxygen exchange. The catalytic activity of
      E-PPase at saturating substrate increases toward PPi hydrolysis and decreases
      toward PPi synthesis and Pi-H2O oxygen exchange with increasing pH. These changes
      are mainly due to an increased rate of dissociation of the second released Pi and
      a decreased rate of enzyme-bound PPi synthesis from enzyme-bound Pi,
      respectively, as the pH is raised .

PMID- 8664253
TI  - Kinetics of nonenzymatic glycation of ribonuclease A leading to advanced
      glycation end products. Paradoxical inhibition by ribose leads to facile
      isolation of protein intermediate for rapid post-Amadori studies.
AB  - Nonenzymatic glycation (Maillard reaction) of long-lived proteins is a major
      contributor to the pathology of diabetes and possibly aging and Alzheimer's
      disease. We report here kinetic studies of the glycation of the model protein
      ribonuclease A by glucose and ribose leading to the formation of antigenic
      advanced glycation end products ("AGEs"), detectable by AGE-specific polyclonal
      antibodies, and pentosidine, an acid-stable fluorescent AGE. As anticipated, the
      kinetics of glycation by ribose were considerably faster than by glucose, and the
      rate of AGE formation initially increased with increasing sugar concentrations.
      However, ribose above 0.15 M appeared to paradoxically slow the kinetics of AGE
      formation, suggesting ribose inhibits the conversion of "early" Amadori
      rearrangement products to "late" AGEs and thus favors the accumulation of
      reactive Amadori intermediates. The facile isolation of such protein
      intermediates was achieved by an "interrupted glycation" protocol which free and
      reversibly bound (Schiff base) ribose was removed following a short (24h) initial
      incubation of 0.5 M ribose at 37 degrees C. The kinetics of buildup of the
      Amadori intermediates and the kinetics of their post-Amadori conversion to
      antigenic AGEs were independently studied. A rapid and reversible inhibition of
      the post-Amadori kinetics by free ribose was verified by direct re-addition of
      ribose to the isolated, sugar-free intermediate. The pH dependence of the
      kinetics of antigenic AGE formation from such intermediates was measured and
      exhibited an unusual bell-shaped profile over the pH range of 5.0-9.5 with a
      maximum near pH 8.0. Aminoguanidine, a pharmacological AGE inhibitor, was found
      to moderately or weakly inhibit antigenic AGE formation in such post- Amadori
      steps. The isolation of the glycated ribonuclease intermediate thus simplifies
      kinetic and mechanistic studies of AGE formation, permits AGE studies in the
      absence of complications arising from free or Schiff base bound sugar, and
      provides a novel methodology for evaluating the mechanism and efficacy of
      therapeutic agents that may inhibit AGE formation.

PMID- 8664255
TI  - Effect of E20D substitution in the active site of Escherichia coli inorganic
      pyrophosphatase on its quaternary structure and catalytic properties.
AB  - Glutamic acid 20 is an evolutionarily conserved residue found within the active
      site of the inorganic pyrophosphatase of Escherichia coli (E-PPase). Here we
      determine the effect of E20D substitution on the quaternary structure and
      catalytic properties of E-PPase. In contrast to wild-type enzyme, which is
      hexameric under a variety of conditions, E20D-PPase can be dissociated by
      dilution into nearly inactive trimers, as shown by electrophoresis of cross
      linked enzyme, analytical ultracentrifugation, and measurement of catalytic
      activity as a function of enzyme concentration. Hexamer stability is increased in
      the presence of both substrate and Mg2+, is maximal at pH 6.5, and falls off
      sharply as the pH is lowered or raised from this value. Measured at saturating
      substrate, 20 mM Mg2+ and pH 7.2, E20D substitution (a) decreases activity
      towards inorganic pyrophosphate (PPi) hydrolysis and oxygen exchange between
      water and inorganic phosphate (P1), (b) increases the rate of net PPi synthesis,
      and (c) decreases the amount of enzyme-bound PPi in equilibrium with Pi in
      solution. Measurements of PPi hydrolysis rate as a function of both Mg2+
      concentration and pH for the E20D variant show that its decreased activity is
      largely accounted for on the basis of an increased pKa of the catalytically
      essential base at the active site, and the need for a Mg2+ stoichiometry of 5 in
      the enzyme-substrate complex, similar to what is seen for the D97E variant. By
      contrast, wild-type PPase catalysis over a wide range of Mg2+ concentration and
      pH is dominated by an enzyme-substrate complex having a total of four Mg2+ ions.
      These results are consistent with a supporting role for Glu20 in PPase catalysis
      and demostrate that even conservative mutation at the active site can perturb the
      quaternary structure of the enzyme.

PMID- 8664256
TI  - Crystallographic identification of metal-binding sites in Escherichia coli
      inorganic pyrophosphatase.
AB  - We report refined crystal structures of the hexameric soluble inorganic
      pyrophosphatase from Escherichia coli (E-PPase) to R-factors of 18.3% and 17.1%
      at 2.2 and 2.3 angstroms, respectively. Both structures contain two independent
      monomers in the asymmetric unit of an R32 cell. The difference between the
      structures is that the latter contains 1.5 Mg2+ ions per monomer. One metal ion
      binds to the "tight" metal-binding site identified by equilibrium dialysis
      studies, and is coordinated to Asp65, Asp70, and Asp102. The other metal ion,
      shared between two monomers at a hitherto unidentified metal-binding site in the
      dyad interface between trimers, is coordinated through water molecules to Asp26s
      and Asn24s from two monomers. The hexamers with metal bound to them are more
      tightly associated than the ones without metal bound to them. Combined with our
      other mechanistic and structural data, the results suggest that, at high metal
      concentrations, E-PPase may bind at least 4.5 metals per monomer: two in the
      active site before binding substrate, two with substrate, and 0.5 in the dyad
      interface. Glu20 interacts via a water molecule with Asp70 and appears in the
      related yeast PPase structure (Heikinheimo, manuscript in preparation) to be
      involved in binding the second metal ion. Magnesium ion therefore stabilizes the
      hexamer form through both direct and indirect effects. The direct effect is by
      tighter association at the subunit interface; the indirect effect occurs because
      magnesium stabilizes the correct conformation of the loop between Glu20 and
      Ile32, a loop involved a trimer-trimmer interactions. Our results thus provide a
      structural explanation for the solution studies that show that the E20D variant
      is partially hexameric and that the hexamer form can be stabilized by binding
      magnesium ion.

PMID- 8664257
TI  - A synthetic model for triple-helical domains in self-splicing group I introns
      studied by ultraviolet and circular dichroism spectroscopy.
AB  - Structural studies were performed on synthetic oligonucleotides with sequences
      corresponding to the P4/P6 and J3/4, J6/7 regions of the self-splicing group I
      intron of the bacteriophage T4 nrdB pre-mRNA, which correspond to the proposed
      triple-helical domain in the Tetrahymena thermophila intron. A 23-mer RNA was
      synthesized as a mixed ribo-deoxyribo oligonucleotide, modeling an expected base
      paired region of P4 along with the J3/4 and P6 (5'-end bases of P6) regions.
      strand modeling the 3'-end bases of P6 and J6/7 regions, with which a triple
      helix may form, was synthesized as a pure oligoribonucleotide (7-mer RNA). The
      interactions of these oligonucleotides have been characterized by UV and circular
      dichroism (CD) spectroscopy. The results show that the 23-mer RNA forms a stable
      hairpin modeling the P4 base-paired region. Triple helix association between the
      23-mer RNA hairpin and the 7-mer RNA single strand was detected by CD in the
      presence of Mg2+ (>5mM) but not in presence of a monovalent cation like Na+ (up
      to 500 mM). Studies on selected variants of both 7-mer and 23-mer RNAs were
      carried out. The results show that for the association of the two partner strands
      not only the formation of P6 helix but also triplet interactions between two
      strands are required. The association of the two strands in general follow a
      pattern predicted by comparative sequence analysis. Parallel studies on pure
      oligoribonucleotides having base sequence corresponding to those of the
      oligoribonucleotides showed no evidence of association under similar conditions,
      which could indicate that the 2'-hydroxyl groups of the riboses might play an
      important role in hydrogen bonding to form the required nucleoside triples.
      Molecular modeling studies on the proposed "plaited triple helix" formed by the
      association of the 23-mer RNA hairpin and 7-mer RNA single strand showed that the
      structure is sterically and energetically feasible.

PMID- 8664258
TI  - The acyl carrier protein of malonate decarboxylase of Malonomonas rubra contains
      2'-(5"-phosphoribosyl)-3'-dephosphocoenzyme A as a prosthetic group.
AB  - Malonate decarboxylase of Malonomonas rubra is composed of soluble and membrane
      bound components and contains an acetyl residue that is essential for catalytic
      activity. Upon incubation with hydroxylamine, the acetyl residue is removed,
      forming an inactive thiol enzyme, which is reactivated by acetylation with ATP,
      acetate, and a specific ligase. After incubation of the thiol enzyme with
      iodoacetate in the presence of excess dithioerythritol, the prosthetic group
      thiol residue was carboxymethylated and reactivation by acetylation was impaired.
      Radioactive labeling with [1-14C] iodoacetate revealed the site of
      carboxymethyation on a distinct cytoplasmic protein with the apparent molecular
      mass of 14 000 Da. The same protein was specifically labeled by enzymic
      acetylation of the thiol enzyme with [1-14C]acetate and ATP. Malonate
      decarboxlyation by [14C]acetyl malonate decarboxlyation resulted in the release
      of the radioactive acetyl residue from the enzyme,indicating that this acetyl
      residue is exchanged for a malonyl residue during catalysis. The acyl carrier
      protein has been purified as its [14C]carboxymethylated derivative to apparent
      homogeneity. The prosthetic group of the acyl carrier protein was isolated after
      alkaline hydrolysis, and its chemical structure was identified by high
      performance liquid chromatography (HPLC) with the corresponding compound from
      citrate lyase from Klebsiella pneumoniae as reference and by mass spectrometry.
      Malonate decarboxylase was found to carry the same prosthetic group as citrate
      lyase, i.e. 2'-(5"-phosphoribosyl)-3'-dephospho-CoA.

PMID- 8664259
TI  - Enzyme-substrate complexes of adenosine and cytidine deaminases: absence of
      accumulation of water adducts.
AB  - Adenosine deaminase has been reported to bind the product inosine (the substrate
      for the reverse reaction) as inosine 1,6-hydrate considered similar in structure
      to the transition state for adenosine deamination (Wilson & Quiocho, 1994)
      Accumulation on the enzyme of inosine 1,6-hydrate would be surprising, because
      this compound is an actual intermediate, probably approaching the transition
      state, in oxygen exchange between water and the C==O group of inosine, a reaction
      previously shown to be catalyzed by adenosine deaminase (Wolfenden & Kirsch,
      1968). The equilibrium constant for conversion of ES to ES*, in the oxygen
      exchange reaction, is less than 10-12. To investigate the structure of enzyme
      bound inosine in a different way, we labeled deoxyinosine with 13C, excepting an
      upfield shift of 70-110 ppm if significant rehybridization to sp3 had occurred at
      the carbonyl group. Instead, the results show a very small shift (1.3 ppm),
      indicating that C-6 of 2'-deoxyinosine retains its sp2 hybridization after
      binding by calf intestinal adenosine deaminase. In a separate series of
      experiments, [4,5-13C]-2'-deoxyuridine was synthesized and found to retain its
      sp2 hybridization at C-4, after binding by Escherichia coli cytidine deaminase,
      an enzyme that catalyzes 18O exchange from water into uridine. These findings are
      consistent with the general expectation, based on the unfavorable equilibrium of
      activation of enzyme-bound substrates, that enzymes should not accumulate
      appreciable concentrations of intermediates whose free energies approach that of
      the transition state in substrate transformation.

PMID- 8664260
TI  - Enzyme-monitored turnover of Escherichia coli thioredoxin reductase: insights for
      catalysis.
AB  - Thioredoxin reductase from Escherichia coli is a member of the pyridine
      nucleotide-disulfide oxidoreductase family, and contains one FAD and one redox
      active disulfide per subunit. It is known that two other well-studied members of
      this family, lipoamide dehydrogenase and glutathione reductase, cycle between the
      two electron-reduced and fully oxidized forms in catalysis. Enzyme-monitored
      turnover shows that the spectrum of thioredoxin reductase during turnover
      represents fully reduced flavin with NADP(H) bound. Whether the pyridine
      nucleotide bound is NADPH or NADP+ is dependent on the concentration of each
      species, i.e., how far turnover has progressed. It is also shown that the
      midpoint potentials of this enzyme are increased through the differential binding
      of NADP+ to the oxidized and reduced form of the enzyme. When combined with other
      kinetic and oxidation/reduction studies of this enzyme, these results indicate
      that thioredoxin reductase cycles between the four-electron-reduced and two
      electron-reduced forms in catalysis, and that it does so with pyridine nucleotide
      bound. These results clarify the mechanism of thioredoxin reductase in relation
      to the known structure the enzyme, and provide support for earlier work in which
      we proposed that this enzyme utilizes a ternary complex mechanism in catalysis.

PMID- 8664262
TI  - Probing the coenzyme and substrate binding events of CDP-D-glucose 4,6
      dehydratase: mechanistic implications.
AB  - NAD+-dependent nucleotidyl diphosphohexose 4,6-dehydratases which transform
      nucleotidyl diphosphohexoses into corresponding 4-keto-6-deoxy sugar derivatives
      are essential to the formation of all 6-deoxyhexoses. Studies of the CDP-D
      glucose 4,6-dehydratase (Eod) from Yersinia had shown that this dimeric protein
      binds only 1 equiv of NAD+/mol of enzyme and, unlike other enzymes of the same
      class, displays a unique NAD+ requirement for full catalytic activity. Analysis
      of the primary sequence revealed an extended ADP-binding fold (GHTGFKG) which
      deviates from the common Rossman consensus (GXGXXG) and thus may have contributed
      to Eod's limited NAD+ affinity. In particular, the presence of His17 in the beta
      turn region and that of Lys21 in a position typically occupied by a small
      hydrophobic residue may impose electronic or steric perturbations to this
      essential binding motif. To better understand the correlation between the binding
      properties and primary sequence, mutants (H17G and K21I) were constructed to
      provide enzymes containing an ADP binding region which more closely resembles the
      Rossman-type fold. Analysis of the cofactor and substrate binding characteristics
      of the wild-type and mutant enzymes helped define the presence of two binding
      sites for both CDP-d_glucose and NAD+ per enzyme molecule. While both mutants
      displayed enhanced NAD+ affinity, the H17G mutation resulted in an enzyme with
      slightly higher kcat and a 3-fold increase in catalytic efficiency (kcat/Km). The
      large anticooperativity found for NAD+ binding (K1=40.3 + or - 0.4 nM, K2=539.8 +
      or - 4.8 nM) may explain why the cofactor binding sites of wild-type Eod are only
      half-occupied. Further examination also revealed the purified Eod to contain
      sequestered NADH and that the affinity of Eod for NADH(K1=0.21 + or - 0.01 nM,
      K2= 7.46 + or -0.25 nM) is much higher than that for NAD+. Thus, it is possible
      that Eod's half-site saturation of NAD+ per enzyme dimer may also be attributed
      to a significant portion of the cofactor binding sites being occupied by NADH.
      Interestingly, the sequestered NADH is released upon binding with CDP-D-glucose.
      These results implicate a new kinetic mechanism for Eod catalysis.

PMID- 8664261
TI  - Electrostatic environment of the tryptophylquinone cofactor in methylamine
      dehydrogenase: evidence from resonance Raman spectroscopy of model compounds.
AB  - Methylamine dehydrogenase (MADH) utilizes its endogenous tryptophan
      tryptophylquinone (TTQ) as a cofactor in enzymatic catalysis, with the C6
      carbonyl of the quinone implicated as the site of attack by substrates and other
      nucleophiles. Resonance Raman (RR) spectroscopy provides an ideal method for
      investigating the state of this carbonyl group whose C==O stretch is distinct
      from other vibrational modes of the cofactor and is readily identified by its
      shift to lower energy in H218O. In a series of indole 6,7-quinone models for TTQ,
      the in-phase stretching vibration of the two C==O groups occurs at 1650 cm-1 in
      nonpolar solvents and shifts to 1638 cm-1 in H2O. The absorption maximum
      undergoes an analogous shift from 400 to 425 mm. The spectral properties of the
      indole quinones in H2O approach the corresponding values in Thiobacillus versutus
      MADH (C==O stretch at 1612 cm-1, lamdamax at 440mm) and are indicative of
      strongly hydrogen bonding of the C==O and NH groups of the cofactor in the native
      enzyme. Addition of monovalent cations [NH4+,Cs+, and (CH3)3NH+] to MADH causes
      further increases in the lamdamax and decreases in the frequency of the C==O
      stretch[1590 cm-1 with (CH3)3NH+]. This implies a strong electrostatic
      interaction between monovalent cations and a carbonyl oxygen (most likely at C6)
      in TTQ. The fact that these cations behave as competitive inhibitors of the
      methylamine substrate suggests that methylamine binds to the same location in the
      enzyme prior to its covalent reaction with the cofactor. Addition of monovalent
      cations to the one-electron-reduced semiquinone form MADH results in RR spectral
      shifts for a number of vibrational modes of the cofactor. Thus, the ability of
      monovalent cations to promote and stabilize the formation of the semiquinone
      intermediate is also due to their direct electrostatic interaction with the TTQ
      cofactor.

PMID- 8664263
TI  - Kinetic comparison of the specificity of the vancomycin resistance VanSfor two
      response regulators, VanR and PhoB.
AB  - Induction of vancomycin resistance in the Gram-positive Enterococci requires a
      two-componet regulatory system, VanS and VanR, for transcriptional activation of
      three genes (vanH, A, X) that encode enzymes for a cell wall biosynthetic pathway
      that produces an altered peptidoglycan intermediate with lower affinity for the
      antibiotic. The catalytic efficiency (kcat/KM) has been determined for
      phosphotransfer from the phosphohistidyl form of VanS to both its homologous
      partner VanR and the heterologous (Escherichia coli) response regulator Phob. The
      rate of formation of the phosphoaapartyl forms of VanR and PhoB were determined
      as well as the rate of appearance of inorganic phosphate. Using PhoB in excess of
      P-VanS, a pseudo-first-order rate constant (kxfer) of 0.2 min-1 for
      phosphotransfer and a KM for PhoB of 100 microM were readily determined. The
      corresponding kxfer of 96 min-1 for phosphotransfer from P-VanS to VanR required
      quench kinetics. A KM of 3 microM was estimated for VanR, leading to a 10(4)-fold
      preference in kxfer/KM for phosphotransfer to VanR compared to PhoB. No
      phosphotransfer was detachable to three other E. coli response regulators, OmpR,
      ArcB, or CreB, providing some sense of the selectivity against two-component
      regulatory system cross-talk. In the phosphotransfer from P-VanS to PhoB and
      VanR, there was evidence of competition between water, to give Pi, and the
      specific aspartyl beta-COO- moiety of either PhoB or VanR with about 25% of the
      initial flux generating inorganic phosphate. The kinetics of phosphotransfer from
      P-VanS to VanR were complicated by inhibition by free VanS but, the inhibition
      pattern could be modeled to yield at KD of 30 nM for VanR binding to free VanS,
      an affinity similar to that of the CheA-CheY pair in E. coli chemotaxis.

PMID- 8664264
TI  - Two NAD+-isocitrate dehydrogenase forms in Phycomyces blakesleeanus. Induction in
      response to acetate growth and characterization, kinetics, and regulation of both
      enzyme forms.
AB  - Two forms of NAD+-isocitrate dehydrogenase, named ICDH-1 and ICDH-2, have been
      identified and purified in Phycomyces blakesleeanus NRRL-1555(-). These enzymes
      forms may be separated by chromatography on DEAE-Sephacel. ICDH-2 induction was a
      response to the adaptation of Phycomyes growth on acetate as the carbon source.
      Both enzyme forms were octamers of 388 + or - 30 kDa with apparently identical
      subunits of 40.5 +/- 5 kDa, but they were distinguishable by their
      electrophoretic mobilities on polyacrylamide gel electrophoresis. Isoelectric pH
      values were 5.28 and 4.96 for ICDH-1 and ICDH-2, respectively. ICDH-2 was more
      stable to urea denaturation than ICDH-1. At pH 7.6, ICDH-1 showed a markedly
      sigmoidal kinetic behavior with respect to isocitrate. However, ICDH-1 and ICDH-2
      showed hyperbolic kinetics with respect to NAD+. THe tribasic form of isocitrate
      (I3-) and its magnesium complex (MI-) are the true substrates for both enzyme
      forms. Kinetic data obtained with Mg2+ as a divalent cation for both enzyme forms
      are compatible with the kinetic mechanism proposed by Cohen and Colman (1974)
      [Eur. J. Biochem. 47, 35-45] but assuming some degree of interaction between
      binding sites for the active form of isocitrate. This report describes for the
      first time the existence of two forms of NAD+-isocitrate dehydrogenase in
      filamentous fungi. From the changes in activity levels for each form, during
      adaptation of Phycomyces to growth on acetate and taking into account the kinetic
      and regulatory properties of both enzyme forms, we discuss the role of ICDH-1 and
      ICDH-2 in the control of isocitrate flux in Phycomyces.

PMID- 8664265
TI  - First-sphere and second-sphere electrostatic effects in the active site of a
      class mu gluthathione transferase.
AB  - The activation of the thiol of glutathione (GSH) bound in the active site of the
      class mu glutathione transferase M1-1 from rat involves a hydrogen-bonding
      network that includes a direct (first-sphere) interaction between the hydroxyl
      group of Y6 and the sulfur of GSH and second-sphere interactions involving a
      hydrogen bond between the main-chain amide N-H of L12 and the hydroxyl group of
      Y6 and an on-face hydrogen bond between the hydroxyl group of T13 and the pi
      electron cloud of Y6 (i.e., T13-OH---pi-Y6-OH--- -SG). The functions of these
      hydrogen bonds have been examined with a combination of site-specific mutagenesis
      and X-ray crystallography. The hydroxyl group of Y6 has a normal pKa of about 10
      even though it is shielded from solvent and is in a largely hydrophobic
      environment. The apparent pKa of GSH in the binary Y6F.GSH complex is increased
      by 1.6 log units, and the reactivity of the enzyme-bound nucleophile is reduced.
      The catalytic properties of the Y6L mutant are identical to those of Y6F,
      suggesting that the weakly polar on-edge interaction between the aromatic ring
      and sulfur has no influence on catalysis. The refined three-dimensional structure
      of the Y6F mutant in complex with GSH shows no major structural perturbation of
      the protein other than a change in the coordination environment of the sulfur.
      Removal of the second-sphere influence of the on-face hydrogen bond between the
      hydroxyl groups T13 as in the T13V and T13A mutants elevates the pKa of enzyme
      bound GSH by about 0.7 pKa units. Crystal structures of these mutants show that
      structural changes in the active site are minor and suggest that the changes in
      pKa of E.GSH are due to the presence or absence of the on-face hydrogen bond. The
      T13S mutant has a completely different side-chain hydrogen-bonding geometry than
      T13 in the native enzyme and catalytic properties similar to the T13A and T13V
      mutants consistent with the absence of an on-face hydrogen bond. The gamma-methyl
      group of T13 is essential in enforcing the on-face hydrogen bond geometry and
      preventing the hydroxyl group from forming more favorable conventional hydrogen
      bonds.

PMID- 8664266
TI  - Elucidation of a MgATP signal transduction pathway in the nitrogenase iron
      protein: formation of a conformation resembling the MgATP-bound state by protein
      engineering.
AB  - The present work defines one MgATP signal transduction pathway in the nitrogenase
      iron (Fe) protein. Deletion of an amino acid (Leu 127) by site-directed
      mutagenesis in the protein chain between Asp 125, located in the ATP binding
      site, and Cys 132, a ligand to the [4Fe-4S] cluster, resulted in protein
      conformational changes resembling the MgATP-bound state in the absence of any
      bound nucleotides. Specifically, 1H nuclear magnetic resonance, electron
      paramagnetic resonance, and circular dichroism spectroscopic properties, along
      with Fe chelation assays, suggested that deletion of Leu 127 in the Fe protein
      resulted in changes in the electronic properties of the [4Fe-4S] cluster similar
      to those normally observed upon MgATP binding to the wild-type Fe protein.
      Deletion of Leu 127 of the Fe protein lowered the redox potential of of the [4FE
      4S] cluster by 112 mV compared to the wild-typeFe protein (-412mV compared to 
      294 mV). A nearly identical lowering of the redox potential by 120 mV occurs in
      the wild-type Fe protein upon binding MgATP (-294 mV compared to 420 mV). The
      L127delta Fe protein did not contain bound nucleotides which could account for
      the observed conformational changes. The present results support a model in which
      the protein chain from ASP 125 to Cys 132 acts as one pathway for MgATP signal
      transduction and suggests a mechanism for this transduction to the [4Fe-4S]
      cluster. The L127delta Fe protein was found to still bind 2 MgATP or 2 MgADP
      molecules/Fe protein. Unlike the wild-type Fe protein, the L127delta Fe protein
      bound 2 ADP molecules/Fe protein in the absence of Mg2+. Finally, the L127delta
      protein was found to bind to the MoFe protein, although the complex did not
      catalyze MgATP hydrolysis or substrate reduction. In concurrence with previous
      models, homologies between the Asp 125 to Cys 132 transduction pathway in Fe
      protein and the switch II region of the broad class of GTPase signal transduction
      proteins (G-proteins) are discussed.

PMID- 8664267
TI  - Formation of the alpha-aminoacrylate immediate limits the overall reaction
      catalyzed by O-acetylserine sulfhydrylase.
AB  - O-Acetylserine sulfhydrylase-A (OASS-A) catalyzes the final step in the synthesis
      of L-cysteine, viz., the beta-substitution of acetate in O-acetyl-L-serine (OAS)
      by sulfide via a ping-pong kinetic mechanism . Rapid-scanning stopped-flow and
      single-wavelength absorbance and fluorescence stopped-flow experiments were
      carried out to obtain information on the location and amount of limitation of
      rate-determining steps for the overall reaction and the individual half-reactions
      of OASS-A. The first half-reaction, conversion of OAS to the alpha-aminoacrylate
      intermediate and acetate, is rate-limiting for the overall reaction catalyzed by
      OASS-A. No intermeidates are detected within the second half-reaction, and thus
      rate constants for all steps must be > or = 1000s-1 at the lowest sulfide
      concentration used. Within the first half reaction, formation of the extrernal
      Schiff base (Kassociation = 0.2 mM-1) is observed in the first milliseconds,
      followed by its slower conversion to the alpha-aminocacrylate intermediate with a
      rate constant of 300 s-1, close to the value of 130 s-1 obtained for V/Et [Tai,
      C.H., Nalabolu, S.R., Jacobson, T.M., Minter D.E., & Cook, P.F. (1993)
      Biochemistry 32, 6433-6442]. Addition of L-cysterine ot OASS-A results in a rapid
      formation of the external Schiff base (Kassociation = 6.7 mM-1), followed by
      transient formation of the alpha-aminoacylate intermediate with a slightly lower
      rate (70-100 s-1) compared to OAS. The alpha-aminoacrylate intermediate decays to
      generate a species absorbing maximally at 418 nm, resulting from attack of the
      cysteine thiol to give ether in external Schiff base linkage with the active site
      PLP.

PMID- 8664268
TI  - Differential modulation of binding loop flexibility and stability by Arg50 and
      Arg52 in Cucurbita maxima trypsin inhibitor-V deduced by trypsin-catalyzed
      hydrolysis and NMR spectroscopy.
AB  - The side chains of Arg50 and Arg52 iin Cucurbita maxima trypsin inhibitor-V (CMTI
      V) anchor the binding loop to the scaffold region [Cai, M., Gong, Y., Kao, J.L
      F., & Krishnamoorthi, R. (1995) Biochemistry 34, 5201-5211]. The consequences of
      these hydrogen-bonding and electrostatic interactions on the conformational
      flexibility and stability of the binding loop were evaluated by trypsin-catalyzed
      hydrolysis of CMTI-V mutants, in which each of the arginines was individually
      replaced with Ala, Lys, or Gln by genetic engineering methods. All mutants
      exhibited significantly increased vulnerability to the protease attack at many
      sites, including the reactive-site (Lys44-Asp45 peptide bond), with the R50
      mutants showing much more pronounced effects than the R52 counterparts. For CmTI
      V and the mutants studied, a qualitative correlation was inferred between binding
      loop flexibility and retention time on a reverse-phase high-pressure liquid
      chromatography C-18 column. The R50 mutants were found to be more flexible than
      the corresponding R52 versions. These results demonstrate that Arg50 contributes
      more to the stability and function of CMTI-V. The differing strengths of the
      hydrogen bonds made by Arg50 and Arg52 were characterized by determining the
      internal dynamics of their side chains at pH 5.0 and 2.5: 15N NMR longitudinal
      and transverse relaxation rates and 15N-1H nuclear Overhauser effect (NOE)
      enhancements were measured for the main-chain and side-chain NH groups in 15N
      labeled recombinant CMTI-V (rCMTI-V) and the model-free parameters [Lipari, G., &
      Szabo, A.(1982) J. Am. Chem. Soc. 104, 4546-59; 4559-4570] were calculated. At
      both pH 5.0 and 2.5, the arginines at positions 26, 47, 58 and 66 are found to be
      highly mobile, as the caluculated general order parameters, S2 values, of their
      NepsilonH groups fall in the range 0.03-0.18. The corresponding values for Arg50
      amd Arg52 are 0.73 and 0.63, respectively, at pH 5.0, thus confirming that the
      two arginines are rigid and hydrogen bonded. At pH 2.5, these hydrogen bonds are
      still retained with Arg50 appearing to be more restrained (S2 = 0.71) than Arg52
      (S2 = 0.56). This is consistent a greater contribution by Arg50 to the
      conformational stability of the reactive-site loop in CMTI-V. The results also
      indicate that the Arg50 and Arg52 side chains are not hydrogen-bonded to
      carboxylate groups, which would be protonated at pH 2.5 and, hence, unavailable
      for hydrogen-bonding interactions. The overall folding of rCMTI-V appears not to
      be significantly affected by the pH change, as indicated by comparisons of 1H and
      15N chemical shifts, sequential NOE cross-peaks, and S2 values of the backbone
      atoms, and the conserved side-chain dynamics of Trp9 and Trp54--residues that are
      involved in hydrophobic and hydrogen-bonding interactions with others in the
      protein core and the binding loop, respectively.

PMID- 8664269
TI  - Nonlinear free energy relationships in Arc repressor unfolding imply the
      existence of unstable, native-like folding intermediates.
AB  - Under strongly denaturing conditions, the logarithm of the rate constant for
      dissociation/unfolding of the wild-type Arc dimer varies in a nonlinear fashion
      with denaturant concentration. To assess the unfolding/dissociation behavior
      under conditions favoring the native structure, we mixed Arc variants labeled
      with fluorescence acceptor or donor groups and used energy transfer to monitor
      the increase in heterodimer with time. Under the conditions of this experiment,
      the rate at which the heterodimer concentration approaches its equilibrium value
      is determined by rate of dissociation and unfolding of the protein. Using this
      method and traditional denaturant-jump experiments, rate constants for
      unfolding/dissociation were determined over a wide range of stabilizing and
      destabilizing conditions. In each case examined, plots of log(ku) versus
      denaturant showed significant curvature under strongly denaturing conditions,
      even though other kinetic experiments indicates that the unfolding/dissociation
      reactions remain largely two-state. This curvature can be explained most readily
      by a series of unstable intermediates in the unfolding pathway, with denaturant
      induced changes in the kinetic step that is rate-limiting. Alternatively,
      curvature might result from Hammond behavior in which the structure of the
      transition state becomes more native-like as the stability of native Arc
      decreases with increasing denaturant.

PMID- 8664270
TI  - Minor influence of sialic acid on conformation of a membrane-bound
      oligosaccharide recognition site.
AB  - Wideline 2H NMR spectroscopy was used to assess the conformational and
      orientational effects of N-acetylneuraminic acid (NeuAc) (sialic acid) as a
      component of a particular oligosaccharide chain at a bilayer membrane surface.
      For this purpose, three glycosphingolipids, sharing a neutral core
      tetrasaccharide and differing only in the number of sialic acid residues, were
      compared. The starting compound was GD1A, which has terminal sialic acid attached
      to the second and fourth sugars of its neutral tetrasaccharide core. GD1A was
      probe-labeled in a non-perturbing fashion on both of these sialic acid residues
      and on its single GalNAc residue by replacement of -COCH3 with -COCD3 giving
      [(d3NeuAc)2,d3-GalNAc]GA1a. This represents the most complex glycolipid to have
      been studied by 2H NMR spectroscopy at a bilayer membrane surface. The sialic
      acid residue on the fourth sugar from the membrane was subsequently removed to
      produce the glycolipid [d3NeuAc,d3GalNAc]GM1, deuterated at the two remaining
      amino sugars. The neutral glycolipid [d3GalNAc]asialo-GM1 was then generated by
      removal of the second sialic acid residue, leaving an uncharged species
      deuterated at one (internal) oligosaccharide chain site (GalNAc). The effect of
      sialic acid was futher examined by selective deuteration of GM1 and asialo-GM1 at
      C6 of the terminal Gal residue, giving [d2Gal]GM1 and [d2Gal]asialo-GM1. Spectra
      of the three glycosphingolipids were compared at 7.7 mol % in unsoncicated fluid
      bilayers of 1-palmitoyl-2-oleoylphosphatidylcholine containing 23 mol %
      cholesterol. For liposomes suspend in buffered salt solutions with 2 mM Ca2+, 2H
      NMR spectra demonstrated the presence of well defined average conformation for
      each oligosaccharide chain. This preferred average conformation persisted over a
      wide temperature range, consistent with there being a single major
      oligosaccharide conformer in each case. Spectral features arising from both
      deuterated amino sugar (GalNAc) of asialo-GM1 could be identified, little
      changed, in spectra of GM1 and GD1A. Similarly, deuterons in the terminal Gal
      residue of asialo-Gm1 produced the same spectrum seen for this residue in GM1.
      Our findings indicate that certain major conformational and orientational
      features of this complex oligosaccharide recognition site are preserved, within
      maximum angular deviation + or -5 degrees or less upon addition or removal of a
      sialic acid residue.

PMID- 8664271
TI  - A stable mixed disulfide between thioredoxin reductase and its substrate,
      thioredoxin: preparation and characterization.
AB  - The flavoenzyme thioredoxin reductase (TrR) catalyzes the reduction of the small
      redox protein thioredoxin (Tr) by NADPH. It has been proposed that a large
      conformational change is required in catalysis by TrT in order to visualize a
      complete pathway for reduction of equivalents. The proposal is based on the
      comparison of the crystal structures of TrR and glutathione reductase, the latter
      being a well-understood member of the enzyme family [Waksman, G., et al. (1994)
      J. Mol. Biol. 236, 800-816]. Bound NADPH is perfectly positioned for electron
      transfer to the FAD in glutathione reductase, but in TrR, these two components
      are 17 angstroms apart. In order to provide evidence for the proposed
      conformational change, a complex between TrR and its substrate Tr involving a
      mixed disulfide between TrR and Tr was prepared. The redox active disulfide of
      TrR is composed of Cys135 and Cys138, and the redox active disulfide of Tr is
      made up of Cys32 and Cys35. The complex C135S-C32S is prepared from forms of TrR
      and Tr altered by site-directed mutagenesis where Cys138 and Cys35 are remaining
      in TrR and Tr, respectively. The purified C135S-C32S presents a band on a
      nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis responding
      to a molecular weight sum of one subunit of TrR and one of Tr. Several
      observations indicate that C135S-C32S can adopt only one conformation. It was
      reported previously that TrR C135S can form a charge transfer complex in the
      presence of ammonium cation in which the donor is the remaining thiolate of
      Cys138 [Prongay, A.J., et al., (1989) J. Biol. Chem. 264, 2656-2664], while
      titration of C135S-C32S with NH4Cl does not induce charge transfer, presumably
      because Cys138 is participating in the mixed dissulfide. Reduction of C135S-C32S
      with dithiothreitol (DTT) results in a decrease of epsilon454 to a value similar
      to that of TrR C135S, and subsequent NH4Cl titration leads to charge transfer
      complex formation in the nascent TrR C135S. Reductive titrations show that
      approximately 1 equiv of sodium dithionite or NADPH is required to fully reduce
      C135S-C32S, and treatment with NH4Cl and DTT demonstrates that the mixed
      disulfide between Cys138 of TrR C135S and Cys35 of TrC32S that locks the
      structure in a conformation where FAD can be reduced by NADPH, but electrons
      cannot flow from FADH2 to the mixed disulfide bond.

PMID- 8664272
TI  - Steroid treatment, accumulation, and antagonism of P-glycoprotein in multidrug
      resistant cells.
AB  - According to multiple reports, progesterone is not transported by P-glycoprotein
      (Pgp), which mediates multidrug resistance through active drug efflux. However,
      progesterone has been shown to block Pgp- mediated efflux of other drugs. To
      extend these observations and to examine the effect of modulating Pgp
      phosphorylation, the accumulation of progesterone and 14 other steroids in
      untreated and calphostin C-treated multidrug-resistant human colon carcinoma
      SW620 Ad300 cells was compared to the accumulation in parental SW620 cells.
      However, the accumlation of more hydrophilic steroids was reduced by as much as
      50%. Progesterone and progesterone-like compounds, however were potent inhibitors
      of Pgp-mediated vinblastine efflux; increased antagonism correlated with
      increased steroid hydrophobicity. Treatment with calphostin C, a PKC inhibitor
      which decreases Pgp phosphorylation, increased progesterone efflux, modulated Pgp
      antagonism by steroids, and inhibited photoaffinity labeling of Pgp by
      progesterone. These results extend previous observations that Pgp can mediate the
      transport of, and be antagonized by, a variety of steroids and that these
      properties vary with both steroid's hydrophobicity and the phosphorylated state
      of Pgp.

PMID- 8664273
TI  - Complete coordination of the four Fe-S centers of the beta subunit from
      Escherichia coli nitrate reductase. Physiological, biochemical, and EPR
      characterization of site-directed mutants lacking the highest or lowest potential
      [4Fe-4S] clusters.
AB  - The beta subunit of the nitrate reductase A from Escherichia coli contains four
      groups of cysteine residues (I-IV) which are thought to bind the four iron-sulfur
      centers (1-4) of the enzyme. The fourth Cys residue of each group was replaced by
      Ala by site-directed mutagenesis, which led to the C26A, C196A, C227A, and C263A
      mutants. Physiological and biochemical effects of the mutations were investigated
      on both the membrane-bound and the soluble forms of the enzyme. In addition,
      detailed redox titrations of the mutants were monitored by EPR spectroscopy. The
      C196A and C227A mutations resulted in the full loss of the four Fe-S clusters and
      of the Mo-cofactor, leading to inactive enzymes. In contrast, the C26A and C263A
      mutants retained significant nitrate reductase activities. The EPR analysis
      showed that the highest redox potential [4Fe-4S] cluster (center 1) was
      selectively removed by the C263A mutation and that the C26A replacement likely
      eliminated the lowest potential [4Fe-4S] cluster (center 4). In both mutants, the
      three remaining Fe-S clusters kept the same spectral and redox properties as in
      the wild type enzyme. These results enabled the determination of the Cys ligands
      of center 1 to be completed and led to a proposed model for the coordination of
      the four Fe-S centers by the four Cys groups of the beta subunit. In this model,
      the four clusters are organized in two pairs, (center 1, center 4) and (center 2,
      center 3), which is in good agreement with the magnitude of intercenter magnetic
      interactions observed by EPR and with the stability of the different mutants. The
      possible implications on the intramolecular electron transfer pathway are
      discussed.

PMID- 8664274
TI  - Probing the cytochrome c peroxidase-cytochrome c electron transfer reaction using
      site specific cross-linking.
AB  - Engineered cysteine residues in yeast cytochrome c peroxidase (CCP) and yeast iso
      1-cytochrome c have been used to generate site specifically cross-linked
      peroxidase-cytochrome c complexes for the purpose of probing interaction domains
      and the intramolecular electron transfer reaction. Complex 2 was designed earlier
      [Pappa, H.S., & Poulos, T.L. (1995) Biochemistry 34, 6573-6580] to mimic the
      known crystal structure of the peroxidase-cytochrome c noncovalent complex
      [Pelletier, H., & Kraut, J. (1992) Science 258, 1748-1755]. Complex 3 was
      designed such that cytochrome c is tethered to a region of the peroxidase near
      Asp148 which has been suggested to be a second site of interaction between the
      peroxidase and cytochrome c. Using stopped flow methods, the rate at which the
      ferrocytochrome c covalently attached to the peroxidase transfers an electron to
      peroxidase compound I is estimated to be approximately 0.5-1 s-1 in complex 3 and
      approximately 800 s-1 in complex 2. In both complexes the Trp191 radical and not
      the Fe4+=O oxyferryl center of compound I is reduced. Conversion of Trp191 to Phe
      slows electron transfer about 10(3) in complex 2. Steady state kinetic
      measurements show that complex 3 behaves like the wild type enzyme when either
      horse heart or yeast ferrocytochrome c is used as an exogenous substrate,
      indicating that the region blocked in complex 3 is not a functionally important
      interaction site. In contrast, complex 2 is inactive toward horse heart
      ferrocytochrome c at all ionic strengths tested and yeast ferrocytochrome c at
      high ionic strengths. Only at low ionic strengths and low concentrations of yeast
      ferrocytochrome c does complex 2 give wild type enzyme activity. This observation
      indicates that in complex 2 the primary site of interaction of CCP with horse
      heart and yeast ferrocytochrome c at high ionic strengths is blocked. The
      relevance of these results to the pathway versus distance models of electron
      transfer and to the interaction domains between peroxidase and cytochrome c is
      discussed.

PMID- 8664275
TI  - Proteolytic cleavage within a regulatory region of the gamma subunit of
      chloroplast coupling factor 1.
AB  - The gamma subunit of chloroplast coupling factor 1 (CF1) is susceptible to
      selective proteolysis when the enzyme is in solution and the epsilon subunit is
      removed [CF1(-epsilon)]. In spinach thylakoid membranes, rapid cleavage of gamma
      is dependent on the generation of an electrochemical proton potential. The
      tryptic cleavage sites within the gamma of oxidized CF1 in illuminated thylakoids
      as well as of reduced CF1(-epsilon) in solution were determined by N-terminal
      amino acid sequencing. Two large gamma fragments of 27 000 (gamma27) and 10 000
      (gammma10) molecular weight were generated by trypsin treatment of membrane-bound
      CF1. THe N-terminal gamma27 contains amino acids 1-215, and the C-terminal
      gamma10 contains 232-323. These polypeptides were tightly associated with the
      trypsin-resistant core of the enzyme. In contrast, three large gamma fragments
      were produced by trypsinolysis of reduced CF1(-epsilon). These polypeptides,
      which were also tightly associated with the trypsin-resistant core, have
      molecular weights of 7 900(gamma8), 14 850 (gamma15), and 10 000 (gamma10). These
      fragments contain residues 1-70, 71-204, and 232-323, respectively. The C
      terminal gamma10 fragment generated by trypsin treatment of membrane-bound and
      soluble CF1 are identical. These results suggest that the gamma subunit of CF1 in
      illuminated thylakoids resembles that of CF1(-epsilon) with respect to
      accessibility to proteolytic cleavage. Cleavage of gamma between residues 215 and
      232 is sufficient to fully activate the ATPase activity of the enzyme without
      reduction of the gamma disulfide. In addition, cutting within this region is
      responsible for loss of affinity for the inhibitory epsilon subunit.

PMID- 8664276
TI  - Structural stability of chloroplast coupling factor 1 determined by differential
      scanning calorimetry and cold inactivation.
AB  - At least part of the gamma subunit of the catalytic portion of the chloroplast
      ATP synthase (CF1) is present in the middle of the alpha3beta3 heterohexamer.
      Interactions of the alpha/beta subunits with the gamma subunit stabilize the
      hexameric structure. Surprisingly, neither reduction of the gamma disulfide nor
      selective proteolysis of alpha, beta and gamma affects the thermal stability of
      EDTA-treated CF1 preparations, as determined by differential scanning
      calorimetry. Dissociation of the enzyme in the cold may be monitored by loss of
      the ATPase activity of CF1 subunit depleted of its epsilon subunit [CF1(
      epsilon)]. The rate of cold inactivation of ATPase activity of reduced and
      alkylated CF1(-epsilon) treated with trypsin in solution was much faster than
      that CF1(-epsilon)(8.1 versus 38.7 min, respectively, for 50% loss of activity).
      The increased cold liability of the trypsin-treated enzyme was not a consequence
      of the cleavage of the gamma. CF1 incubated with trypsin under conditions in
      which gamma is not cleaved was as cold labile as CF1 with cleaved gamma. Instead,
      loss of the delta subunit and a few residues from the C-terminal of the beta
      subunits were responsible for the increased cold liability of the enzyme.

PMID- 8664277
TI  - Altering substrate specificity at the heme edge of cytochrome c peroxidase.
AB  - Two mutants of cytochrome c peroxidase (CCP) are reported which exhibit unique
      specificities toward oxidation of small substrates. Ala-147 in CCP is located
      near the delta-meso edge of the heme and along the solvent access channel through
      which H2O2 is thought to approach the active site. This residue was replaced with
      Met and Tyr to investigate the hypothesis that small molecule substrates are
      oxidized at the exposed delta-meso edge of the heme. X-ray crystallographic
      analyses confirm that the side chains of A147M and A147Y are positioned over the
      delta-meso heme position and might therefore modify small molecule access to the
      oxidized heme cofactor. Steady-state kinetic measurements show that cytochrome c
      oxidation is enhanced 3-fold for A147Y relative to wild type, while small
      molecule oxidation is altered to varying degrees depending on the substrate and
      mutant. For example, oxidation of phenols by A147Y is reduced to less than 20%
      relative to the wild-type enzyme, while Vmax/e for oxidation of other small
      molecules is less affected by either mutation. However, the "specificity" of
      aniline oxidation by A147M, i.e., (Vmax/e)/Km, is 43-fold higher than in wild
      type enzyme, suggesting that a specific interaction for aniline has been
      introduced by the mutation. Stopped-flow kinetic data show that the restricted
      heme access in A147Y or A147M slows the reaction between the enzyme and H202, but
      not to an extent that it becomes rate limiting for the oxidation of the
      substrates examined. The rate constant for compound ES formation with A147Y is
      2.5 times slower than wild-type CCP. These observations strongly support the
      suggestion that small molecule oxidations occur at sites on the enzyme distinct
      from those utilized by cytochrome c and that the specificity of small molecule
      oxidation can be significantly modulated by manipulating access to the heme edge.
      The results help to define the role of alternative electron transfer pathways in
      cytochrome c peroxidase and may have useful applications in improving the
      specificity of peroxidase with engineered function.

PMID- 8664278
TI  - Backbone dynamics of the c-Jun leucine zipper: 15N NMR relaxation studies.
AB  - The backbone dynamics of the coiled-coil leucine zipper domain of c-Jun have been
      studied using proton-detected two-dimensional 1H-15N NMR spectroscopy.
      Longitudinal (T1) and transverse (T2) 15N relaxation times, together with {1H}15N
      NOEs, were measured and analyzed by considering the protein to approximate a
      prolate ellipsoid. An analysis of the T1/T2 ratios for residues in the well
      structured section of the protein showed that a model for the spectral density
      function in which the protein is considered to reorient anisotropically fitted
      the data significantly better than an isotropic model. Order parameters (S2) in
      the range 0.7-0.9 were observed for most residues, with lower values near the C
      terminus, consistent with fraying of the two helices comprising the coiled-coil.
      Because nearly all of the N-H vectors have small angles to the long axis of the
      molecule, there was some uncertainty in the value of the rotational diffusion
      coefficient Dpar, which describes rotation about the long axis. Thus, an
      alternative method was examined for its ability to provide independent estimates
      of Dpar and Dperp (the diffusion coefficient describing rotation about axes
      perpendicular to the long axis); the transitional diffusion coefficient (Dt) of
      the protein was measured, and hydrodynamic calculations were used to predict Dpar
      and Dperp. However, the derived rotational diffusion coefficients proved to be
      very dependent on the hydrodynamic model used to relate Dt to Dpar and Dperp, and
      consequently the values obtained from the T1/T2 analysis were used in the order
      paramenter analysis. Although it has previously been reported that the side chain
      of a polar residue at the dimer interface, Asn22, undergoes a conformational
      exchange process and destabilizes the dimer, no evidence of increased backbone
      mobility in this region was detected, suggesting that this process is confined to
      the Asn side chain.

PMID- 8664279
TI  - Modulated growth of Saccharomyces cerevisiae by altering the driving force of the
      reactions of cytochrome c: Marcus' theory in vitro and in vivo.
AB  - According to Marcus' theory, rates of electron transfer reactions depend
      parabolically on the free energy of reaction. Amino acid replacements in the
      electron transport protein cytochrome c produced a series of proteins which
      changed the free energy of reaction for cytochrome c in oxidative
      phosphorylation. This study shows that Marcus' theory of electron transfer can be
      applied to the reactions of redox-altered cytochromes c with cytochrome c1 both
      in vitro and in vivo. In vitro, isolation of physiologically relevant partners of
      cytochrome c suggests that a change in free energy of reaction of cytochrome c
      changes the rate of electron transfer with cytochrome bc1 complex as would be
      predicted by Marcus' theory of electron transfer. Furthermore, the reactivity
      pattern observed in vitro is paralleled in in vivo studies. In vivo the rates of
      growth of Saccharomyces cerevisiae, in which these alternatives have been
      incorporated, also are consistent with the change in free energy of the reactions
      of cytochrome c with cytochrome bc1 complex. This study suggests that Marcus'
      theory of electron transport can predict rates not only in vitro, in isolated
      protein-protein systems, but also in vivo, where the relative growth rates of
      yeast may be predicted from the in vitro results.

PMID- 8664280
TI  - Dimerization of the extracellular domain of granuloycte-colony stimulating factor
      receptor by ligand binding: a monovalent ligand induces 2:2 complexes.
AB  - Granulocyte-colony stimulating factor (G-CSF) binds to a specific cell surface
      receptor and induces signals for growth and differentiation in cells of
      granulocyte hematopoietic lineage. In order to understand how G-CSF binding
      initiates signals into these cells, we have studied its interactions with the
      entire extracellular domain of the receptor (sG-CSFR). The sG-CSFR was purified
      from CHO cell conditioned media with a G-CSF affinity column, resting in a
      preparation fully competent for ligand binding. However, when sG-CSFR was
      purified by conventional means, i.e., without affinity chromatography, only about
      half was competent. Therefore, all studies were carried out using affinity
      purified material. The sG-CSFR exhibited a weak self-association into a dimer
      with a dissociation constant of 200microM in the absence of G-CSF. Addition of G
      CSF dimerizes the receptor, with a preferred stoichiometry of 2 G-CSF molecules
      plus 2 receptors. Unexpectedly, receptor-receptor interactions rather than
      through two receptors binding to the same G-CSF molecule; i.e., G-CSF is a
      monovalent ligand. G-CSF binding to the receptor monomer occurs with high
      affinity. The binding of G-CSF also enhances the receptor-receptor dimerization;
      when G-CSF is bound to both receptors, dimerization is enhanced 2000-fold, while
      the interaction of a 1:1 receptor-ligand complex with a second ligand-free
      receptor is enhanced 80-fold. Thus, the mechanism of receptor dimerization is
      fundamentally different than that of related cytokine receptors such as growth
      hormone and erythropoietin receptors. Circular dichroic spectra showed a small
      but significant conformational change of receptor upon binding G-CSF. This is
      consistent with the idea that G-CSF binding alters the conformation of the
      receptor, resulting in an increase in receptor-receptor interactions.

PMID- 8664281
TI  - Dissociation of the cellulosome of Clostridium thermocellum in the presence of
      ethylenediaminetetraacetic acid occurs with the formation of trucated
      polypeptides.
AB  - The cellulosome of Clostridium thermocellum JW20 consists of 14-26 different
      polypeptides as determined by sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis. The intact cellulosomes hydrolyzes crystalline cellulose in the
      presence of Ca2+ and thiols. This activity is inhibited by
      ethylenediaminetetraacetic acid (EDTA). Ca is incorporated into the cellulosome
      and tightly bound as demonstrated using 45Ca added to the growth medium. Upon
      incubation in 50 mM Tris (pH 7.5), 0.1 M NaCl, and 5 mM EDTA at 37 degrees C, Ca
      is released from the cellulosome, which disintegrates into polypeptides. The SDS
      PAGE pattern of cellulosomal polypeptides is remarkably different after the EDTA
      treatment when compared to this pattern of untreated cellulosomes. Polypeptide
      bands corresponding to molecular masses of 160, 98, 76, 91, and 54 kDa disappear,
      and new bands of masses 150, 132, 91, 71, 57, and 46 kDa appear. N-terminal
      analyses of the 98, 76, 91, and 71 kDa polypeptides show that the 91 and 71 kDa
      polypeptides are truncated products of the 98 and 76 kDa polypeptides,
      respectively. The 76 and 71 kDa polypeptides correspond to CelS [Wang, W. K.,
      Kruus K., & Wu, J. H. D. (1993) J. Bacteriol. 175, 1293-1302]. The 71 kDa
      polypeptide is formed from the 76 kDa polypeptide during the EDTA treatment, by a
      cleavage that occurs at asparagine residue 681. It involves the removal of 60
      amino acid residues from the C-terminal end. All catalytic subunits so far
      characterized contain an asparagine residue corresponding to residue 681 of CelS.
      This residue is part of the conserved duplicated region found in catalytically
      active subunits, and it is postulated that several of these subunits also are
      truncated by the EDTA treatment. The polypeptides truncated by the EDTA treatment
      reduced Ca binding capacities compared to their native subunits, indicating a Ca
      binding site within the conserved duplicated region. This region has been
      implicated in the binding of the catalytic peptides to the scaffolding
      polypeptide CipA, which is a structural protein of the cellulosome and has a
      strong affinity for calcium.

PMID- 8664282
TI  - Structural role of calcium for the organization of the cellulosome of Clostridium
      thermocellum.
AB  - The cellulosome of Clostridium thermocellum is a multipolypeptide complex of
      structural and catalytic subunits. Several of the catalytic subunits have at the
      carboxyl end a conserved duplicated region (CDR) which interacts with internally
      repeated elements (IREs) of scaffolding subunits such as CipA. This interaction
      requires calcium. The two parts of the CDR region here designated CDR1 and CDR2
      (closest to the carboxyl end) each consist of about 20 amino acids residues. As
      shown in our previous paper [Choi, S.K., & Ljungdahl, L.G. (1996) Biochemistry
      35, 4897-4905], treatment of the cellulosome with ethylenediaminetetraacetic acid
      (EDTA) under aerobic conditions disintegrates the cellulosome with formation of
      truncated catalytic subunits. The cleavage is at a specific asparagine residue
      located within CDR1 and occurs with complete loss of CDR2. Two branched peptides
      containing the amino acid sequences of CDR1 and CDR2 (designated bCDR1 and bCDR2)
      were synthesized, and specific antibodies were raised against them. These
      antibodies did not cross react with bCDR1 or bCDR2, respectively. After sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western
      blotting, it was observed that about 15 subunits of the cellulosome reacted with
      anti-bCDR1 and anti-bCDR2. In a similar experiment with EDTA-treated
      cellulosomes, these subunits reacted with anti-bCDR1 but not with anti-bCDR2,
      showing that they lost the bCDR2 epitope and were truncated. The peptide bCDR1
      binds calcium, whereas bCDR2 does not. Furthermore, bCDR1 but not bCDR2 binds to
      CipA, presumably at IRE regions. This binding requires calcium. A model is
      proposed for the binding of the catalytic subunits to CipA which involves CDR1,
      an IRE, and calcium.

PMID- 8664283
TI  - Oxidized low-density lipoprotein stimulates protein kinase C (PKC) and induces
      expression of PKC-isotypes via prostaglandin-H-synthase in P388D1 macrophage-like
      cells.
AB  - Treatment of cells with LPS-free oxLDL significantly enhanced protein kinase C
      (PKC) activity in cell extracts from P388D1 macrophage-like cells as determined
      by phosphorylation of histone H1 or Ac-MBP[4-14] substrate peptide. This effect
      was abolished by the PKC inhibitors H-7 and bisindolylmaleimide I while pertussis
      toxin failed to block stimulation. The phosphotransferase activity was also
      increased by acetylated LDL (acLDL) and maleylated albumin (malBSA), the oxLDL
      effect was inhibited by chloroquine which also blocked oxLDL-induced stimulation
      of tyrosine kinase activity. Marginal stimulation of PKC activity was observed
      when lipid extracts from oxLDL were used, indicating that uptake via scavenger
      receptors (SR) is mandatory. Polyinosinic acid (poly I) exhibited a concentration
      dependent inhibition of the oxLDL-induced effect suggesting that SR II/I but not
      CD36 interactions are critical to PKC activation. Modified (lipo)proteins
      increased the concentration of diacylglycerol and differentially affected the
      levels of individual PKC isoenzymes predominantly in the cytosolic fraction.
      Changes of activity induced by oxLDL could be primarily assigned to alterations
      of the activities and levels of the isoenzymes beta and delta. Treatment with
      oxLDL, acLDL, and malBSA was also accompanied by increased production of
      prostaglandins as well as by an enhanced level of cyclooxygenase 2 (COX 2) as
      determined by Western blot analysis. Effects (correction) of oxLDL on PKC
      activity/expression was suppressed by the cyclooxygenase, 2,2-dimethyl-6-(4
      chlorophenyl)-7-phenyl-2,2-dihydro-1H-pyrrolizine-5- ylacetic acid (ML 3000), and
      by treatment with the specific COX 2-inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)
      methane-sulfonamide (NS-398). These results indicate that oxLDL, acLDL, and
      malBSA exhibit a COX 2-dependent and isotype specific effect on PKC in P388D1
      cells following uptake via SR II/I and subsequent lysosomal degradation.

PMID- 8664284
TI  - Characterization of a Cys115 to Asp substitution in the Escherichia coli cell
      wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers
      resistance to inactivation by the antibiotic fosfomycin.
AB  - The antibiotic fosfomycin inhibits bacterial cell wall biosynthesis by
      inactivation of UDP-GlcNAc enolpyruvyl tranferase (MurA). Prior work has
      established that Cys115 of Escherichia coli and Enterobacter cloacae MurA is the
      active site nucleophile alkylated by fosfomycin and implicated this residue in
      the formation of a covalent phospholactyl-enzyme adduct derived from substrate,
      phosphoenolpyruvate (PEP). On the basis of sequencing information from putative
      MurA homolog from Mycobacterium tuberculosis, we generated a C115D mutant of E.
      coli MurA that was highly active but fully resistant to time-dependent inhibition
      by fosfomycin. Fosfomycin still bound to the active site of C115D MurA, as
      established by the observed reversible competitive inhibition by fosfomycin.
      Fosfomycin still bound to the active site of C115D MurA, as established by the
      observed reversible competitive inhibition vs PEP. In contrast to the broad pH
      independent behavior of wild-type (WT) MurA, C115D mutant activity titrated
      across the pH range examined (pH 5.5-9) with an apparent pKa approximately 6,
      with kcatC115D ranging from approximately 10kcatWT at pH 5.5 to <0.1kcatWT at
      pH9.0. Km(PEP)115D was relatively constant in the pH range examined and increased
      approximately 100-fold relative to Km(PEP)WT. A fosfomycin-resistant C115E mutant
      with -1% activity of the C115D mutant was found to follow a pH dependence similar
      to that observed for C115D MurA. The contrasting pH dependences of WT and C115D
      MurA was also observed in the reaction with the pseudosubstrate, (Z)-3
      fluorophosphoenolpyruvate, strongly suggesting a role for Cys/Asp115 as the
      general acid in the protonation of C-3 of PEP during MurA-catalyzed enol ether
      transfer. The difference in nucleophilicity between the carboxylate side chains
      of Asp115 and Glu115 and the thiolate group of Cys115 suggests that covalent
      enzyme adduct formation is not required for catalytic turnover and, furthermore,
      provides a chemical rationale for the resistance of the C115D and C115E mutants
      to fosfomycin inactivation.

PMID- 8664285
TI  - Mocarhagin, a novel cobra venom metalloproteinase, cleaves the platelet von
      Willebrand factor receptor glycoprotein Ibalpha. Identification of the sulfated
      tyrosine/anionic sequence Tyr-276-Glu-282 of glycoprotein Ibalpha as a binding
      site for von Willebrand factor and alpha-thrombin.
AB  - Platelet adhesion to the subendothelium is the initiating event in hemostasis and
      thrombosis and involves the binding of von Willebrand factor (vWF) by the
      platelet membrane glycoprotein (GP) Ib-IX complex. The alpha-chain of GP Ib
      contains binding sites for both vWF and alpha-thrombin within a 45-kDa N-terminal
      tryptic fragment. In the present study, we have further delineated these sites
      using smaller proteolytic fragments and functional antibodies. Mocarhagin, a
      cobra venom metallaproteinase, generates the fragment His-1-Glu-282, while
      cathepsin G, a neutrophil granule serine protease, generates a slightly smaller
      fragment, His-1-Leu-275. His-1-Glu-282 was as effective as intact soluble GP
      Ibalpha (glycocalicin) in inhibiting botrocetin-dependent binding of vWF to
      washed platelets (IC50 approximately 0.3 microM) whereas His-1-Leu-275 was an
      order of magnitude less effective (IC50 approximately 3 microM). Residues Tyr-276
      Glu-282 (YDYYPEE) are part of an anionic region homologous to thrombin-binding
      molecules such as hirudin. In ligand blot analysis, thrombin blotted the His-1
      Glu-282 fragment, but not His-1-Leu-275. The three tyrosine residues within Tyr
      276-Glu-282 meet the consensus criteria for O-sulfation. A method was developed
      to distinguish O-sulfated from nonsulfated tyrosine residues based on differences
      in the UV absorbance spectra. Residues Tyr-276-Glu-282 were isolated from
      glycocalicin by proteolysis with mocarhagin and cathepsin G. Ion spray mass
      spectrometry confirmed that Tyr-278 and Tyr-279 was only approximately 50% O
      sulfated. Four anti-GP Ibalpha monoclonal antibodies (SZ2, ES85, C34 and VM16d)
      were found to be modulator-specific, strongly inhibiting botrocetin-dependent
      binding of vWF, but having less or no effect on ristocetin-dependent vWF binding.
      These antibodies also inhibited the binding of thrombin to fixed platelets.
      Immunoprecipitation with GP ibalpha fragments defined the epitopes for these
      antibodies as SZ2 (Tyr-276-Glu-282), ES85 (Asp-283-Arg-293), C34 (His-1-Glu-282),
      and VM16d (His-1-Leu-275). An antibody which inhibited ristocetin-dependent, as
      well as botrocetin-dependent, vWF binding but had no effect on thrombin binding
      (Ak2) had an epitope within His-1-Leu-275. These findings indicate that the
      sulfated tyrosine/anionic GP Ibalpha residues Tyr-276-Glu-282 are important for
      the binding of thrombin and botrocetin-dependent binding of thrombin and the
      botrocetin-dependent binding of vWF, but that vWF also interacts with residues
      within His-1-Leu-275.

PMID- 8664286
TI  - Trans effects in nitric oxide binding to myoglobin cavity mutant H93G.
AB  - When nitric oxide (NO) binds to heme proteins, it exerts a repulsive trans effect
      on the proximal ligand, resulting in weakening or rupture of the proximal ligand
      iron bond. The general question of whether NO binding generates a five-coordinate
      complex with proximal ligand release is important for the function of enzymes
      such as guanylate cyclase. This question can be addressed by studying NO binding
      to the myoglobin cavity mutant H93G, where the proximal histidine has been
      replaced by glycine. When this protein is expressed in the presence of imidazole
      (Im), an imidazole molecule occupies the proximal cavity and serves as a ligand
      to the iron [Barrick, D. (1994) Biochemistry 33, 6546-6554]. This proximal
      imidazole can be exchanged for a variety of exogenous ligands [DePillis, G.D.,
      Decatur, S. M., Barrick, D., & Boxer, S.G. (1994) J. Am. Chem. Soc. 116, 6981
      6982]. While CO binds to H93G(Im) to form a stable six-coordinate complex similar
      to that of the wild type and NO binds to wild-type myoglobin to form a six
      coordinate complex, we find that the binding of NO to H93G(Im) under similar
      conditions results in the cleavage of the exogenous imidazole-iron bond at
      neutral pH, leaving a five-coordinate heme-NO complex, H93G-NO, inside the
      protein. When a large excess of imidazole is added to this five-coordinate NO
      complex, a six-coordinate complex can be formed; thus, the binding constant of a
      sixth ligand to the five-coordinate H93G-NO complex can be measured. This is
      found to be several orders of magnitude smaller than the binding constant of Im
      to the carbonmonoxy, deoxy, or the metcyano forms of protein. By replacement of
      Im with methyl-substituted imidazoles which have hindered or strained binding
      conformations, this binding constant can be reduced further and some of the
      factors responsible for favoring the five-coordinate form can be elucidated.
      Thus, the cavity mutant H93G provides a novel model system for studying the
      factors that control the coordination state of NO complexes of heme proteins and
      serves as a bridge between synthetic heme model complexes in simple solvents and
      site-directed mutants in the structured environment found in proteins.

PMID- 8664287
TI  - Relationships between bilayer structure and phospholipase A2 activity:
      interactions among temperature, diacylglycerol, lysolecithin, palmitic acid, and
      dipalmitoylphosphatidylcholine.
AB  - Bilayers composed of phosphatidylcholine initially resist catalysis by
      phospholipase A2. However, after a latency period, they become susceptible when
      sufficient reaction products (lysolecithin and fatty acid) accumulate in the
      membrane. Temperatures near the main bilayer phase transition and saturated long
      chain diacylglycerol in the bilayer modulate the effectiveness of the reaction
      products. The purpose of this study was to identify possible mechanisms for these
      effects of temperature and diacylglycerol. Various fluorescent probes were used
      to asses changes in the ability of the reaction products to perturb the bilayer
      and promote enzyme binding to he membrane surface. Temperature appeared to cause
      three effects. First, the degree of binding of enzyme at the end of the latency
      period was greatest near the phase transition temperature where the latency was
      shortest. Second, the bilayer was more sensitive to perturbation by reaction
      products near the transition. Third, the disturbance provoked by the products was
      confined to the membrane surface below the transition but affected deeper regions
      at higher temperature where the latency period was greater. The latter two
      effects of temperature required the presence of calcium. Diacylglycerol promoted
      lateral segregation of reaction products in the bilayer. This effect corresponded
      with the tendency of diacylglycerol to reduce the length of the latency period at
      temperature below the phase transition. Therefore, it appeared that temperature
      affects the latency period by alternating the binding of the enzyme and the depth
      and magnitude of the bilayer perturbation caused by reaction products.
      Alternatively, diacylglycerol may enhance the effectiveness of reaction products
      by inducing them to segregate in the bilayer and thus create local regions of
      increased impact on the bilayer surface.

PMID- 8664288
TI  - Influenza-virus-liposome lipid mixing is leaky and largely insensitive to the
      material properties of the target membrane.
AB  - Monolayer intrinsic curvature, void stabilization, and membrane rupture tension
      have been suggested as important factors determining the rate of membrane fusion.
      Here, we have studied the kinetics of fusion between influenza virus and target
      liposomes as a function of various target membrane material properties. In order
      to examine the fusion process directly, a simple prebinding step is used and
      proven to be adequate to achieve fusion-rate-limiting kinetics. To test the
      hypothesis about membrane curvature and void stabilization, we studied the lipid
      mixing kinetics with dioleoylphosphatidylcholine (DOPC)/ganglioside GD1a (GD1a)
      liposomes containing lysooleoylphosphatidylcholine (LPC, positive curvature),
      dioleoyglycerol (DOG, negative curvature), arachidonic acid (AA, negative
      curvature), and hexadecane (HD, void stabilization). DOG, AA, and HD (at 4 mol%)
      showed no significant effect on the fusion kinetics, while LPC reversibly
      inhibited influenza HA mediated fusion only at very high concentrations. Using
      target liposomes with different membrane rupture tension values, no obvious
      correlation between membrane rupture tension and the rate of lipid mixing was
      observed. Moreover, a reported potential antiviral compound, tert
      butylhydroquinone (t-b-HQ) (Bodian et al., 1993), showed no significant effect on
      the kinetics of influenza fusion. Finally leakage of liposome contents was
      detected during lipid mixing. For encapsulated molecules smaller than 450 MW, the
      kinetics of leakage is very similar to the kinetics of lipid mixing. In fact,
      leakage was also detected for encapsulated molecules up to 10 000 MW, suggesting
      that HA mediated lipid mixing is a very leaky process. Since "nonleaky fusion"
      has been the foundation of influenza fusion models, our work suggests the need
      for a major revision in the modeling of this process.

PMID- 8664289
TI  - Interaction sites between catalytic and regulatory subunits in human protein
      kinase CK2 holoenzymes as indicated by chemical cross-linking and immunological
      investigations.
AB  - Protein kinase CK2, a heterotetramer composed of two catalytic subunits (alpha
      and/or alpha') and two regulatory subunits (beta), has been examined for
      intermolecular contact sites by methods that allow investigation of the native,
      unaltered proteins. Antibodies were raised against a series of 11 subunit
      peptides, affinity purified, and ensured for site specific binding by peptide
      competition. Chemical cross-linking of CK2 subunits with a hydrophilic
      carbodiimide and analysis of fused subunits and of CNBr-digested fusion products
      by immunoblotting with the sequence specific antibodies identified a tight
      interaction between positions beta55-70 and alpha65-80 (alpha'66-81) of subunits
      beta and alpha (alpha'), respectively. This was corroborated by cross-linking of
      subunits with peptides alpha65-80 and beta55-70 by a peptide-based enzyme-linked
      immunosorbent assay in which peptides bound to wells via C-10 spacer arms are
      probed for complexing individual subunits and immunoprecipitation with antibodies
      anti-alpha65-80 and anti-beta55-70, resulting in precipitation but not
      coprecipitation of subunits. This alpha-beta (alpha'-beta) interaction site
      obviously is also of functional importance since subunits with attached
      antibodies cannot reconstitute to the fully active holoenzyme. Indeed, sites
      beta55-70 and alpha65-80 (alpha'66-81) correspond to an acidic (beta) and a basic
      (alpha or alpha') domain involved in activity and stability control and in
      substrate and cosubstrate binding (kinase domain II/III), respectively. By
      contrast, a number of suspected contact sites were found to be rather loose and
      not essential for enzyme control as concluded from precipitation behavior of
      respective antibodies and the toleration of attached antibodies when active
      holoenzymes were being constituted. At subunit beta, these include the terminal
      positions beta2-14 and beta204-213, the positions beta97-105 and beta140-156,
      and, surprisingly, also beta171-186 which have been shown by deletion mutation
      and peptide replacement studies to represent a positively affecting interaction
      site. At subunits alpha and alpha', these are the C-terminal positions alpha329 
      343 and alpha'336-350. Binding of antibodies to the positions alpha15-27
      (alpha'16-28) and position alpha151-166(alpha'152-167), on the other hand,
      inhibits activity.

PMID- 8664290
TI  - Interaction of fusogenic synthetic peptide with phospholipid bilayers:
      orientation of the peptide alpha-helix and binding isotherm.
AB  - We studied the binding characteristics of a synthetic 20-residue peptide to
      supported single planar bilayers of phosphatidylcholine, and the orientation of
      the peptide by Fourier-transform infrared spectroscopy with an attenuated total
      reflection method. This peptide, designed to resemble a putative fusion peptide
      of influenza virus hemagglutinin, assumes an amphiphilic alpha-helix and induces
      fusion of liposomes in an acidic solution (pH approximately 5). At neutral pH,
      the peptides were bound to lipid bilayers in the manner of a Langmuir's
      adsorption isotherm, and their orientation was nearly random or oblique. On the
      other hand, at acidic pH, the peptides were bound, making their helix axis
      parallel to the membrane surface, and the binding was cooperative. This
      cooperativity suggested dimerization of the peptides. These characteristics are
      expected to be important for the synthetic fusogenic peptide or the fusion
      peptide in hemagglutinin to induce membrane fusion.

PMID- 8664291
TI  - The receptor binding site for the methyltransferase of bacterial chemotaxis is
      distinct from the sites of methylation.
AB  - The principal locus for binding interactions between the aspartate and serine
      receptors of escherichia coli and the methyltransferase was found to be in the
      last five amino acids of the receptor. The thermodynamic parameters of
      transferase-receptor interactions were determined by isothermal titration
      calorimetry. the serine receptor and three C-terminal fragments (C-fragments) of
      the aspartate receptor consisting of ether the last 297, 88, or 38 amino acids
      gave comparable values for binding (n=1, deltaH approximately 13 kcal/mol, and Ka
      approximately 4 x 10(5)M-1). Truncating either 16 or 36 amino acids form the C
      terminus eliminated observable interactions. Finally the pentapeptide Asn-Trp-Glu
      Thr-Phe, which corresponds to the last five amino acids of the receptor and is
      strictly conserved among E. coli serine amd aspartate receptors and the
      Salmonella typhimurium aspartate receptor, was found to have all the binding
      activity of the full-length receptor and the C-fragments. An in vitro methylation
      assay was used to obtain evidence for the physiological significance of this
      interaction in which excess peptide was able to completely block receptor
      methylation. The location of the binding site far from the methylation sites in
      the primary structure of the receptor suggests that the principle role of this
      interaction may be to hold the transferase in close proximity to all the
      methylation sites. Intersubunit methylation implication is proposed as plausible
      consequence of this "controlled proximity" mechanism since the ribose-galactose
      and dipeptide receptors lack the transferase binding sequence, and appear unable
      to bind transferase. Intersubunit methylation implies that transferase bound to
      eother the serine or aspartate receptor subunit may catalyze methylation of
      receptor subunits in a neighboring dimer, including those that have ligand
      specificity.

PMID- 8664292
TI  - Interaction of myoinositoltrisphosphate-phytase complex with the receptor for
      intercellular Ca2+ mobilization in plants.
AB  - One of the myoinositol trisphosphates produced by the phytase-myoinositol
      hexakisphosphate (InsP6) reaction is Ins(2,4,5)P3. That Ins(2,4,5)P3 can elicit
      Ca2+ mobilization from intracellular stores in plants [Samanta, S., Dalal, B.,
      Biswas, S., & Biswas, B.B.(1993) Biochem. Biophys. Res. Commun. 191,427] prompted
      us to elucidate the mechanism. The InsP3 [Ins(1,4,5)P3/Ins(2,4,5)P3]-phytase
      complex has been found to interact with the receptor for InsP3 in vitro forming a
      ternary complex, and a nanomolar concentration of InsP3 is required. For
      enzymatic cleavage of InsP3 by phytase, micromolar concentrations are needed, and
      the affinities of the phytase for different myoinositol phosphates have been
      found to depend upon the number of phosphate groups present in the substrate.
      Fraction accessibility of tryptophan residues to a neutral fluorescence quencher,
      acrylamide in free and myoinositol phosphates bound phytase, as determined by
      Stern-Volmer plot, records a progressive decrease starting from InsP6 to InsP
      with the notable exceptions of both Ins (1,4,5)P3 and Ins(2,4,5)P3. This
      deviation from the trend of change in the accessibility of tryptophan residues in
      myoinositol phosphate bound phytase is recorded from the fact that there is a
      high affinity (dissociation constant of the nanomolar order) and noncatalytic
      binding site in phytase for the two isomers of InsP3. In the nanomolar range of
      concentrations, both isomers of InsP3 bind to a second site of phytase having
      about 40-fold higher affinity than the normal substrate binding site. InsP3, when
      bound to noncatalytic site in phytase is not hydrolyzed but induces a significant
      change in the conformation of phytase as assayed from the relative accessibility
      of tryptophan residues. This conformational change in phytase is recognized by
      the receptor for InsP3, because in absence of InsP3 no interaction between the
      receptor and phytase is detected. However, InsP3-phytase complex is a better
      elicitor of Ca2+ efflux from microsomal/vacuolar fractions than free InsP3. This
      is further confirmed by the fact that when Ins(1,3,4)P3-phytase complex can
      elicit Ca2+ efflux from intracellular stores, Ins(1,3,4)P3 per se is minimally
      effective.

PMID- 8664293
TI  - beta-Site covalent reactions trigger transitions between open and closed
      conformations of the tryptophan synthase bienzyme complex.
AB  - The tryptophan synthase bienzyme complex (alpha2beta2) from Salmonella
      tryphimurium catalyzes the final steps in the biosynthesis of L-Trp. To
      investigate the roles played by conformational change in tryptopthan synthase
      catalysis, the fluorophore 8-anilino-1-naphthalensulfonate (ANS) is used to
      identify conformational states. The binding of ANS to the alpha2beta2 bienzyme
      complex is accompanied by a dramatic enhancement of ANS fluorescence and a shift
      of the emission maximum from 520 to 482 nm. The ANS binding isotherm is biphasic
      and consists of a class of moderately high-affinity, noninteracting sites with a
      stoichiometry of 1 site/alpha beta dimeric unit (Kd' = 62 + or - 15 micrometer)
      and a much weaker set of non-specific interactions with K'd>1mM. Our findings
      show that the affinity of the enzyme for ANS is strongly decreased (> 10-fold) by
      interactions at two loci 30 angstroms apart: (i) the binding of the alpha-site
      ligands, 3-indole-D-glycerol 3'-phosphate or alpha-glycerol phosphate (GP) or
      (ii) reaction at the beta-subunit to form either the alpha-aminoacrylate Schiff
      base, E(A-A), or quinonoid species, E(Q). In contrast, formation of the L-Ser and
      L-Trp external aldimines E(Aex1) and E(Aex2) at the beta-site causes a 2-3 fold
      decrease in the affinity of the enzyme for ANS. The combination of E(A-A)or E(Q)
      with GP brings about almost complete displacement of ANS, indicating that these
      interactions drive a conformation change in alphabeta subunit pairs which
      prevents the binding of ANS. These results are consistent with a model which
      postulates that alphabeta subunit pairs undergo ligand-mediated transitions
      between open and closed conformations during the catalytic cycle. Consistent with
      the kinetic data showing that binding of alpha-site ligands increases the
      affinity of the beta site for L-Ser and that formation of E(A-A) activates the
      alpha reaction [Brzovic, P. S., Ngo, K., & Dunn, M. F. (1992) Biochemistry 31,
      3831-3839], while mutations in alpha subunit loops 2 and 6 prevent the ligand-
      mediated transition to a closed structure [Brzovic, P.S., Hyde, C.C., Miles,
      E.W., & Dunn, M.F. (1993) Biochemistry 32, 10404-10413], we conclude that
      reciprocal ligand-mediated allosteric interactions between the heterologous
      subunits promote conformational transitions between open and closed structures in
      alphabeta subunit pairs which function to coordinate catalytic activities and
      facilitate the channeling of indole between the two catalytic sites.

PMID- 8664294
TI  - Divalent cations but not other activators enhance phosphorylase kinase's affinity
      for glycogen phosphorylase.
AB  - To better understand the physical interaction between glycogen phosphorylase-b (P
      b) and its only known kinase, phosphorylase kinase (PbK) and the relationship of
      this interaction to the activation of PbK, direct binding studies are necessary.
      By utilizing an enzyme-linked immunosorbent assay, a method was developed for
      measuring the binding of PbK to immobilized P-b under a variety of experimental
      conditions. A monoclonal antibody specific for the alpha subunit of PbK that had
      no effect on the phosphorylation of P-b by PbK or on the interaction of PbK with
      known effectors was used to detect PbK bound to plated P-b. Hyperbolic binding
      curves were obtained regardless of whether the concentration of Pbk or P-b was
      varied, and the assay detected changes in relative affinity caused by certain
      effectors of the kinase. The allosteric effector ADP, alkaline pH, and
      phosphorylation by cAMP-dependent protein kinase, all activators of PbK, did not
      cause significant changes in its relative affinity for P-b; however, Ca2+ and
      Mg2+ ions, which also stimulate PbK, increased its affinity for P-b, with Mg2+
      being more effective. Mn2+, which inhibits the P-b conversion activity of PbK,
      was found to be the most potent enhancer of its affinity for P-b, although
      divalent cations may enhance binding. Inclusion of ATP analogs in the binding
      assay with Ca2+ and Mg2+ to stimulate catalytic assay conditions did not further
      affect the apparent affinity for P-b, which is consistent with the previously
      reported rapid equilibrium random bi-bi kinetic mechanism for P-b conversion.

PMID- 8664295
TI  - Stabilization of triple helical DNA by a benzopyridoquinoxaline intercalator.
AB  - Biophysical, footprinting, and chemical probing experiments are described which
      characterize the triple helix-stabilizing effects of a benzo[f]pyridoquinoxaline
      derivative BfPQ-4,3 structurally related to the previously reported
      benzo[f]pyridoindole compound BePI [Mergny et al. (1992) Science 256, 1681-1684].
      Two parallel triple helix model systems have been investigated; one in which the
      third strand matched perfectly a 27 base pair purine-pyrimidine motif in target
      DNA and another in which the third strand was one nucleotide longer, i.e., a 28
      mer. In the latter system, the pairing of the (Y)28 third strand to the (Y.R)27
      target induces the formation of a bulge containing at least one unpaired base,
      which can be evidenced by chemical probing experiments with osmium tetroxide.
      BPQ, which uinwinds a duplex DNA by 17 degrees as judged by viscometric
      experiments and otherwise behaves as a typical nonspecific intercalculating drug,
      promotes the formation of Y.R.Y parallel triple helix containing both T.A.T and
      C.G.C+ triplets. Both DNase I and MPE.FeII footprinting experiments concur that
      triplex formation with the target (Y.R)27 sequence can be detected in the
      presence of BPQ at about 10-fold lower oligonucleotide concentrations than are
      required to produce an equivalent footprint in the absence of the drug. In
      addition, BPQ will promote binding to the polypurine-polypyrimidine target
      sequence by the longer mismatched oligonucleotide, providing significant
      stabilization of the parallel bulge-containing(Y.R)27,(Y)28 triplex with nearly
      the same efficiency as the bulge-free (Y.R)27.(Y)28 triplex. Thus in vivo BPQ
      might enhance the formation of both undesired and desired DNA triplexes. By
      performing an MPE*FeII probing reaction with a 5'-32 P-labeled oligonucleotide
      third strand, we have obtained evidence that BPQ is actually bound to the triplex
      region and may distort in a sequence-specific fashion.

PMID- 8664296
TI  - Dimer-dimer interfaces of the lambda-repressor are different in liganded and free
      states.
AB  - Lambda-repressor dimers associate in solution to form tetramers and higher order
      structures. Dimer-dimer contact is also crucial in cooperative binding to
      adjacent operators. Fluorescence quenching studies indicate that the tryptophan
      230 environment is significantly different in unliganded and adjacent operator
      bound tetramers. Acrylodan attached to Cys 235, in a mutant F235C repressor, is
      also in different environments in the unliganded and adjacent operator bound
      tetramers. Thermodynamics of protein association, measured by fluorescence
      anisotropy, indicate that, whereas free repressor dimer association is strongly
      enthalpy driven, the single-operator (OR1)-bound repressor dimer association is
      largely entrophy driven with little change in enthalpy. Single-operator-bound
      dimer association to the corresponding tetramer does not lead to any significant
      change in tryptophan 230 environment, as was seen in the case of the free
      repressor. Data are also presented to support the contention that, under the
      conditions of this study, the free repressor association is predominantly from
      dimer to tetramer and then to octamer, unlike the dimer to octamer transition
      observed under a different condition. The results presented here point toward the
      conclusion that the lambda-repressor dimer-dimer interface is significantly
      different in the free and operator-bound states and that operator binding plays a
      crucial role in changing the nature of the dimer-dimer interface.

PMID- 8664297
TI  - Alternative structures in duplex DNA formed within the trinucleotide repeats of
      the myotonic dystrophy and fragile X loci.
AB  - Most models proposed to explain the disease-associated expansion of (CTG)n.(CAG)n
      and (CGG)n.(CCG)n trinucleotide repeats include the formation of slipped strand
      DNA structures during replication; however, physical evidence for these
      alternative DNA secondary structures has not been reported. Using cloned
      fragments from the myotonic dystrophy (DM) and fragile X syndrome (FRAXA) loci
      containing normal, premutation, and full mutation lengths of repeats, we report
      the formation of novel alternative DNA secondary structures that map within the
      repeat tracts during reannealing of complementary strands, containing equal
      lengths of repeats, into linear duplex DNA molecules. Linear duplex DNA molecules
      containing these alternative DNA secondary structures are characterized by
      reduced electrophoretic mobilities in polyacrylamide gels. These alternative
      secondary structures are stable at physiological ionic strengths and to
      temperatures up to at least 55 degrees C. Following reduplexing, the CAG strand
      of the (CTG)n.(CAG)n repeats is preferentially sensitive to mung bean nuclease,
      suggesting the presence of single-stranded DNA in the alternative DNA structure.
      For (CTG)17, which is a repeat length found in normal individuals, less than 3%
      of the DNA molecules formed alternative DNA structures upon reduplexing. DNA
      molecules containing (CTG)50 or (CTG)255, which represent premutation and full
      mutation lengths of triplet repeats, respectively, formed a heterogeneous
      population of alternative DNA structures in >50% of DNA molecules. The complexity
      of the structures formed increased with the length of the triplet repeat. The
      relationship between repeat length and the propensity of formation and complexity
      of the novel structures correlates with the effect of repeat length on genetic
      instability in human diseases. These are the first results consistent with the
      existence of slipped strand DNA structures. The potential involvement of these
      structures, which we term S-DNA, in the gentic instability of triplet repeats is
      discussed.

PMID- 8664298
TI  - Kinetic analysis of pausing and fidelity of human immunodeficiency virus type 1
      reverse transcription.
AB  - Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase catalyzes DNA
      synthesis from RNA and DNA templates by a sequential mechanism. This enzyme is
      neither processive nor distributive but has a rather intermediate behavior; at
      any template position, there is a certain probability that the replica strand
      will be extended, which we define as extensibility. The extensibility depends on
      the substrate concentration, i.e. on the concentration of the cognate (and to a
      smaller extent of the noncognate) deoxynucleoside triphosphates, in a typical
      Michaelis-Menten mode. The extensibility varies from position to position in a
      sequence-dependent manner, being particularly low at certain sites, accordingly
      called pause sites. The rate and fidelity of successive incorporation of
      nucleotides were measured and then compared with numerical integrations of the
      pertinent rate equations, which were composed to describe a suitable reaction
      mechanism and parameterized starting starting with rate constants reported in the
      literature. We found that agreement between stimulation and experiment requires
      two-step binding of enzyme to the template-primer. In an initial second-order
      step, an "outer" binary complex is rapidly formed; this is followed by a slower
      conformational change into an "inner" complex. During multiple rounds of
      nucleotide incorporation, the complex remains in the inner form; the rate
      determining step for enzyme release is the reversion from the inner to the outer
      complex, with a standard rate constant of 0.2s-1. This rate constant may be
      significantly increased at pause sites. In order to match the experimental
      results, the standard rate constants had to be modified for pause sites. At low
      concentrations or in the absence of the cognate nucleotide, the site-specific
      misinsertion frequency, a function of the nucleotide pool is bias and of the
      efficiency to discriminate against a noncognate nucleotide, can be determined
      from the dependence of extensibility on concentration of cognate and noncognate
      substrates. The error frequency was found to be somewhat smaller than the
      misinsertion frequency, because mismatches are extended less efficiently than
      matched pairs.

PMID- 8664299
TI  - Substrate structure influences binding of the non-histone protein HMG-I(Y) to
      free nucleosomal DNA.
AB  - High mobility group protein HMG-I(Y) selectively binds to stretches of A.T-rich B
      form DNA in vitro by recognition of substrate structure rather nucleotide
      sequence. Recognition of altered DNA structures has also been proposed to explain
      the preferential binding of this non-histone protein to four-way junction DNA as
      well as to restricted regions of DNA on random-sequence nucleosome core
      particles. Here we describe experiments that examine the influence of intrinsic
      DNA structure, and of structure imposed by folding of DNA around histone cores,
      on the binding of HMG-I(Y). As substrates for binding, we chose defined-sequence
      DNA molecules containing A.T-rich segments demonstrated previously to have very
      different structures in solution. These segments are either intrinsically bent
      (phase A.T tracts), flexible (oligo[d(A-T)]), or straight and rigid
      [oligo(dA).oligo(dT)]. DNase-I and hydroxyl radical footprinting techniques were
      employed to analyze protein binding to these DNAs either free in solution or when
      they were reconstituted into monomer or dinucleosomes in vitro. Results indicate
      that the DNA structure exerts a significant influence on HMG-I(Y) binding both
      when substrates are free in solution and when they are wrapped into nucleosomal
      structures. For example, when DNA is free in solution, HMG-I(Y) prefers to bind
      to the narrow minor groove of A.T sequences but sometimes also binds to certain
      GpC residues having narrowed major grooves that are embedded in such sequences.
      On the other hand, depending on the structure and/or orientation assumed by
      particular A.T-rich segments on the surface of reconstituted histone octamers,
      HMG-I(Y) binding site selection on individual nucleosomes differs considerably.
      Two observations are of particular importance: (i) HMG-I(Y) can preferentially
      bind to certain types of A.T-DNA located on the surface of nucleosomes; and (ii)
      HMG-I(Y) binding can induce localized alterations in the helical periodicity
      and/or rotational setting of DNA on the surface of some nucleosomes. The
      abilities of HMG-I(Y) suggests that in vivo the protein may play an important
      role in recognizing and altering the structure of localized regions of chromatin.

PMID- 8664300
TI  - A kissing complex together with a stable dimer is involved in the HIV-1Lai RNA
      dimerization process in vitro.
AB  - Retroviruses contain a dimeric RNA consisting of two identical molecules of
      genomic RNA. The interaction between the two monomers is thought to occur near
      their 5'ends. We previously identified a region upstream from the splice donor
      site, comprising an autocomplementary sequence, responsible for the formation of
      dimeric HIV-1Lai RNA [Muriaux, D., Girard, P.-M., Bonnet-Mathonire, B., &
      Paoletti, J.(1995) J. Biol. Chem. 270,8209-8216]. This region appeared to be
      confined within a putative stem-loop structure. Here we report an in vitro model
      under conditions of low inioc strength. Two dimers of RNA 77-402 were identified
      as a function of temperature, and a significant difference was found in their
      thermostability. Dimer D55, formed at 55 degrees Celsius, is more stable than
      dimer D37, formed at 37 degrees C. RNase probing experiments confirm the
      involvement of a stem-loop structure in the dimerization process. In the monomer,
      the free G257-CGCGC262 sequence forms a loop in the 240-280 region of RNA 77-402,
      whereas this sequence is engaged in base pairing when D55 and D37 dimers are
      formed. Our results show that the loop-loop interaction of the autocomplementary
      G257CGCGC262 sequence, though hydrogen bonding, is responsible for the formation
      of dimer D37 and strongly suggest that D37 is a "kissing" complex. In contrast,
      in dimer D55, all the nucleotides of the two hairpin stems, 243-254/264-277, are
      involved in a complete interstrand interaction.

PMID- 8664301
TI  - The interaction of coumarin antibiotics with fragments of DNA gyrase B protein.
AB  - DNA gyrase is the target of the coumarin group of antibacterial agents. The drugs
      are known to inhibit the ATPase activity of gyrase and bind to the 24-kDa N
      terminal subdomain of gyrase B protein. Supercoiling assays with intact DNA
      gyrase and ATPase assays with a 43-kDa N-terminal fragment of the B protein
      suggest that the drugs bind tightly, with Kd values <10(-7) M. In addition, the
      ATPase data suggest that 1 coumermycin molecule interacts with 2 molecules of the
      43-kDa protein while the other coumarins form a 1:1 complex. This result is
      confirmed by cross-linking experiments. Rapid gel-filtration experiments show
      that the binding of ADPNP(5'-adneylyl beta,gamm-imidodiphosphate) and coumarins
      to the 43-kDa protein is mutally exclusive, consistent with a competitive mode of
      action for the drugs. Rapid gel-filtration binding experiments using both the 24
      and 43-kDa proteins also show that the drugs bind with association rate constants
      of >10(5) M-1.s-1, and dissociation rate constants of approximately 3x10(-3)s-1
      and approximately 4x10(-3)s-1 for the 43-and 24-kDa proteins, respectively.
      Titration calorimetry shows that the Kd values for coumarins binding to both
      proteins are approximately 10-8M and that binding is enthalpy driven.

PMID- 8664302
TI  - Changes in chromatin structure support constitutive and developmentally regulated
      transcription of the bone-specific osteocalcin gene in osteoblastic cells.
AB  - Transcription of the osteocalcin gene, which encodes a 10 kDa bone-specific
      protein, is controlled by modularly organized basal regulatory sequences and
      hormone-responsive enhancer elements. We have previously shown that in the ROS
      17/2.8 rat osteosarcoma cell line, which continuously expresses the osteocalcin
      gene, key regulatory elements reside in two DNase I hypersensitive sites that are
      fucntionally correlated with transcriptional activity. We now report that a
      specific nucleosomal organization supports this constitutive expression in ROS
      17/2.8 cells, and that chromatin remodeling directly correlates with the
      developmentally regulated transcriptional activation of the osteocalcin gene
      during differentiation of normal diploid rat osteoblasts. By combining DNase I,
      micrococcal nuclease, and specific restriction endonuclease digestion analysis,
      we observed that the presence of DNAse I hypersensitive sites (-170 to -70 and 
      600 to -400) and a selective nucleosome positioning over the OC gene promoter are
      directly associated with developmental stage-specific transcriptional activation
      in bone-derived cells.

PMID- 8664303
TI  - The reduced minus oxidized difference spectra of cytochromes a and a3.
AB  - We have re-investigated the reduced minus oxidized difference spectra of the two
      heme centers of cytochrome oxidase, cytochromes a and a3. In contrast to data
      obtained in an earlier study (Vanneste, W.H. (1966) Biochemistry 5, 838-848), we
      find that the spectrum for cytochrome a3 agrees with that found with a 5
      coordinate high-spin heme A model compound. Small but significant additional
      differences are noted for both heme centers.

PMID- 8664304
TI  - The utilisation of creatine and its analogues by cytosolic and mitochondrial
      creatine kinase.
AB  - We have investigated the utilisation of four analogues of creatine by cytosolic
      Creatine Kinase (CK), using 31P-NMR in the porcine carotid artery, and by
      mitochondrial CK (Mt-CK), using oxygen consumption studies in isolated heart
      mitochondria and skinned fibers. Porcine carotid arteries were superfused for 12
      h with Krebs-Henseleit buffer at 22 degrees C, containing 11 mM glucose as
      substrate, and supplemented with either 20 mM beta-guanidinopropionic acid (beta
      GPA), methyl-guanidinopropionic acid (m-GPA), guanidinoacetic acid (GA) or
      cyclocreatine (cCr). All four analogues entered the tissue and became
      phosphorylated by CK as seen by 31 P-NMR, Inhibition of oxidative metabolism by 1
      mM cyanide after accumulation of the phosphorylated analogue resulted in the
      utilisation of PCr, beta-GPA-P, GA-P and GA-P over a similar time course
      (approximately 2 h), despite very different kinetic properties of these analogues
      in vitro. cCr-P was utilised at a significantly slower rate, but was rapidly
      dephosphorylated in the presence of both 1 mM iodoacetate and cyanide (to inhibit
      both glycolysis and oxidative metabolism respectively). The technique of creatine
      stimulated respiration was used to investigate the phosphorylation of the
      analogues by Mt-CK, Isolated mitochondria were subjected to increasing [ATP],
      whereas skinned fibres received a similar protocol with increasing [ADP]. There
      was a significant stimulation of respiration by creatine and cCr in isolated
      mitochondria (decreased K(m) and increased Vmax vs control), but none by GA, mGPA
      or beta-GPA (also in skinned fibres), indicating that these latter analogues were
      not utilised by Mt-CK. These results demonstrate differences in the
      phosphorylation and dephosphorylation of creatine and its analogues by cytosolic
      CK and Mt-CK in vivo and in vitro.

PMID- 8664305
TI  - Functional reconstitution of photosystem II with recombinant manganese
      stabilizing proteins containing mutations that remove the disulfide bridge.
AB  - The 33-kDa extrinsic subunit of PSII stabilizes the O2-evolving tetranuclear Mn
      cluster and accelerates O2 evolution. We have used site-directed mutagenesis to
      replace one or both Cys residues in spinach MSP with Ala. Previous experiments
      using native and reduced MSP led to the conclusion that a disulfide bridge
      between these two cysteines is essential both for its binding and its functional
      properties. We report here that the disulfide bridge, though essential for MSP
      stability, is otherwise dispensible. The mutation C51A by itself had a delayed
      effect on MSP function: [C51A]MSP restored normal rates of O2 evolution to PSII
      but was defective in stabilizing this activity during extended illumination. In
      contrast, the Cys-free double mutant, [C28A,C51A]MSP, was functionally identical
      to the wild-type protein. Based on results presented here, we propose a light
      dependent interaction between MSP and PSII that occurs only during the redox
      cycling of the Mn cluster and which is destabilized by the single mutation, C51A.

PMID- 8664306
TI  - Dielectric properties of yeast cells as simulated by the two-shell model.
AB  - The paper reports a re-evaluation of the previous studies on yeast by considering
      the influence of vacuole upon the dielectric properties of the cell. In this
      respect, relative permittivity and conductivity of yeast cells dispersed in KCI
      solutions of various concentrations were measured in the frequency range from 0.1
      to 100 MHz. The analysis of data revealed that the beta-dielectric dispersion of
      yeast cell suspensions is a composite of three (or probably four) distinct sub
      dispersions. Since the dielectric response of the cell wall was experimentally
      avoided (according to Asami et al. (1976) J. Membr. Biol. 28, 169-180), the two
      shell model, related to the plasma membrane and the vacuolar membrane,
      respectively, appeared to be the best approximation for yeast cells. The most
      relevant parameters obtained with the aid of the two-shell model were as follows.
      Specific capacitance of the plasma membrane and the vacuolar membrane were 0.703
      +/- 0.011 microF/cm2 and 0.483 +/- 0.029 microF/cm2, respectively; electrical
      conductivity of the cytoplasm and the vacuole interior were 0.515 +/- 0.028 S/m
      and 3.22 +/- 0.48 S/m; finally, the permittivity of the cytoplasm was 50.6 +/- 2.

PMID- 8664307
TI  - Metabolic control and metabolic capacity: two aspects of creatine kinase
      functioning in the cells.
AB  - In this short review, the merits and limits of three theoretical concepts
      explaining the functional role of the creatine kinase system in muscle and brain
      cells are analysed. In addition to the usual concept of an energy buffer system
      and the recently proposed metabolic capacity theory (Sweeney, H.L. (1994) Med.
      Sci. Sports Exerc. 26, 30-36), it is proposed that coupled creatine kinase
      systems are involved in effective metabolic regulation of energy fluxes and
      oxidative phosphorylation, beside their energy transfer function. This aspect of
      the system is considered on the basis of metabolic control analysis. It is shown
      by using the results of mathematical modelling that, due to amplification of ADP
      fluxes from the cytoplasm by the mechanism of metabolic channelling, coupled
      mitochondrial creatine kinase may exert a flux control coefficient significantly
      exceeding 1.

PMID- 8664308
TI  - Effect of inorganic phosphate and ADP on the myofilament sliding induced by laser
      flash photolysis of caged ATP.
AB  - Using the technique of laser flash photolysis of caged ATP, we have suggested
      that, under nearly isometric conditions, the unitary distance of myofilament
      sliding per ATP molecule (myosin head powerstroke) is about 10 nm. To give
      further information about the mechanism of myofilament sliding, we studied the
      effect of inorganic phosphate (Pi) and ADP on the photoreleased ATP-induced
      shortening of single glycerinated muscle fibers under very small external loads.
      Both the velocity and the distance of the myofilament sliding induced by 150
      microM ATP increased by Pi (20 mM), and decreased by ADP (0.4 mM). On the other
      hand, Pi and ADP showed no significant effect on the myofilament sliding induced
      by 100 and 75 microM ATP. The potentiating effect of Pi on the myofilament
      sliding with 150 microM ATP can be explained as being due to the increase in
      population of AM.ADP.Pi with corresponding decrease in population of AM.ADP, and
      also the increase in population of M.ADP.Pi and M.ATP. Meanwhile, the inhibitory
      effect of ADP can be simply accounted for to be due to an accumulation of AM.ADP
      that already finished their force generating process. The ineffectiveness of Pi
      and ADP on the myofilament sliding with 100 and 75 microM ATP is consistent with
      the view that it is caused by almost synchronized single myosin head
      powerstrokes.

PMID- 8664309
TI  - Human G(alpha q): cDNA and tissue distribution.
AB  - G(alpha q), a member of the Gq family of heterotrimeric G proteins, transduces
      signals from several G protein-coupled receptors that stimulate membrane
      phosphoinositide hydrolysis. In order to further define the role of G(alpha q) in
      the function of G protein-coupled receptors, we have cloned the cDNA encoding
      human G(alpha q) from a prostate cDNA library. Human G(alpha q) exhibits high
      homology with its mouse homolog - 94% similarity at the nucleotide level, and 99%
      similarity at the amino acid level. Northern hybridization data indicate high
      expression of G(alpha q) mRNA in organs of the human reproductive system
      including ovary, prostate, and testis.

PMID- 8664310
TI  - cDNA cloning of a mouse pituitary adenylate cyclase-activating polypeptide
      receptor.
AB  - A cDNA clone for mouse pituitary adenylate cyclase-activating polypeptide (PACAP)
      receptor (PACAP-R) was obtained from the brain using reverse transcription
      polymerase chain reaction (RT-PCR). The recombinant PACAP receptor expressed in
      COS cells bound PACAP with about 1000-times higher affinity than vasoactive
      intestinal polypeptide (VIP), and PACAP stimulated adenylate cyclase through the
      cloned PACAP receptor. The mouse PACAP receptor consists of 496 amino acids,
      contains seven transmembrane segments and has 98.4%, 93.0%, and 92.5% identity
      with the rat, bovine, and human PACAP-R, respectively.

PMID- 8664311
TI  - cDNA sequence and expression of subunit E of the vacuolar H(+)-ATPase in the
      inducible Crassulacean acid metabolism plant Mesembryanthemum crystallinum.
AB  - A cDNA coding for subunit E of the vacuolar H(+)-ATPase was cloned from
      Mesembryanthemum crystallinum, a plant which switches from C3-photosynthesis to
      Crassulacean acid metabolism under saline growth conditions. Sequence homology
      between the three subunit E-polypeptides of different higher plant species varied
      between 77.6 and 73.3%; peptide length was between 226 and 230 amino acid
      residues, 43 of which are invariant in all seven subunit E-polypeptides known so
      far from animals, fungi and plants. The deduced relative molecular mass of
      subunit E in Mesembryanthemum crystallinum is 26162 Da. Subunit E is present both
      in C3- and CAM-plants. mRNA levels increased severalfold in leaves of CAM-induced
      plants. This was accompanied by a less pronounced increase in subunit E protein.
      Obviously, expression is stimulated under conditions of increased requirement for
      tonoplast H(+)-pumping activity.

PMID- 8664312
TI  - Fate of cationic liposomes and their complex with oligonucleotide in vivo.
AB  - The present studies describe the biodistribution of cationic liposomes and
      cationic liposome/oligonucleotide complex following intravenous injection into
      mice via the tail vein. (111)In-diethylenetriaminepentaacetic acid stearylamide
      ((111)In-DTPA-SA) was used as a lipid-phase radiolabel. Inclusion of up to 5 mol%
      DTPA-SA in liposomes composed of 3beta-(N-(N',N'
      dimethylaminoethane)carbamoyl)cholesterol (DC-Chol) and
      dioleoylphosphatidylethanolamine (DOPE) did not influence liposome formation or
      size, nor the binding/uptake or fusion of the cationic liposomes with CHO cells
      in vitro. Moreover, nuclear delivery of oligonucleotide to CHO cells was
      unaffected by the probe. The biodistribution of liposomes with increasing
      concentration of DC-Chol (1:4-4:1, DC-Chol/DOPE, mol/mol) at 24 h post-injection
      revealed no dependence on lipid composition. Uptake was primarily by liver, and
      accumulation in spleen and skin was also observed. Comparatively little
      accumulation occurred in lung. Clearance of injected liposomes by liver was very
      rapid (approximately 84.5% of the injected dose by 7.5 h post-injection).
      Liposome uptake by liver and spleen were equally efficient in the dose range of
      3.33 to 33.33 mg/kg body weight, yet possible saturation of liver uptake at a
      dose of 66.80 mg/kg may have allowed for increased spleen accumulation.
      Preincubation of cationic liposomes with phosphorothioate oligonucleotide induced
      a dramatic yet transient accumulation of the lipid in lung which gradually
      redistributed to liver. Similar results were observed when monitoring iodinated
      oligonucleotide in the complex. Immuno-histochemical studies revealed large
      aggregates of oligonucleotide within pulmonary capillaries at 15 min post
      injection, suggesting the early accumulation in lung was due to embolism. Immuno
      histochemical studies further revealed labeled oligonucleotide to be localized
      primarily to Kupffer cells at 24 h post-injection. Immuno-electron microscopy
      revealed localization of oligonucleotide primarily to the lumen of pulmonary
      capillaries at 15 min post-injection. Immuno-electron microscopy revealed
      localization of oligonucleotide primarily to the lumen of pulmonary capillaries
      at 15 min post-injection, and to phagocytic vacuoles of Kupffer cells at 24 h
      post-injection. By these methods, nuclear delivery of oligonucleotide in vivo was
      not observed. Increasing concentration of mouse serum inhibited cellular
      binding/uptake of cationic liposomes in vitro, without or with complexed
      oligonucleotide. We therefore postulate that interaction with plasma components,
      including opsonin(s), inhibits cellular uptake of the injected liposomes as well
      as the liposome/oligonucleotide complex, and mediates rapid uptake by Kupffer
      cells of the liver. These results are relevant to the design of cationic
      liposomes for efficient delivery of nucleic acid in vivo.

PMID- 8664313
TI  - Interaction of alkanols and local anesthetics with spin-labeled Ca(2+)-ATPase of
      sarcoplasmic reticulum vesicles.
AB  - Alkanols and tertiary amine derivative local anesthetics modify the activity of
      Ca(2+)-ATPase. In order to investigate the primary binding sites, associated to
      the functional changes, sarcoplasmic reticulum (SR) Ca(2+)-ATPase was labeled
      with maleimide derivative spin labels which bind covalently to SH groups of
      cysteine residues and allow to probe the regions of the protein close to those
      residues. The EPR measurements showed motional constraints induced by drug
      treatment which indicate changes in the enzyme dynamics and structure. n-Alkanols
      are shown to affect some of the protein-bound labels by restricting their motion.
      There is, however, no correlation between the functional effects and the observed
      motional restriction, in the sense that concentrations of the different alcohols
      leading to the same functional effects do not induce the same degree of
      restriction. Dibucaine and tetracaine at functional relevant concentrations also
      restrict the movement of protein bound labels. But, in this case, correlation
      between spectral changes and functional effects is observed.

PMID- 8664314
TI  - Effects of ethanol on lateral and rotational mobility of plasma membrane vesicles
      isolated from cultured mouse myeloma cell line Sp2/0-Ag14.
AB  - Intramolecular excimerization of Py-3-Py and fluorescence polarization of DPH
      were used to evaluate effects of ethanol on the rate and range of the lateral
      mobility and the range of the rotational mobility of bulk bilayer structures of
      the Sp2/0-PMV. In a concentration-dependent manner, ethanol increased the rate
      and range of the lateral mobility and the range of the rotational mobility of
      bulk bilayer structures of Sp2/0-PMV. Selective quenching of DPH by
      trinitrophenyl groups was utilized to examine the range of transbilayer
      asymmetric rotational mobility of the Sp2/0-PVM. The anisotropy (r), limiting
      anisotropy (r(infinity)) and order parameter (S) of DPH in the inner monolayer
      were 0.022, 0.029 and 0.063, respectively, greater than calculated for the outer
      monolayer of the Sp2/0-PMV. Selective quenching of DPH by trinitrophenyl groups
      was also used to examine the transbilayer asymmetric effects of ethanol on the
      range of the rotational mobility of the Sp2/0-PMV. Ethanol had a greater
      increasing effect on the range of the rotational mobility of the outer monolayer
      as compared to the inner monolayer of the Sp2/0-PMV. It has been proven that
      ethanol exhibits a selective rather than nonselective fluidizing effect within
      the transbilayer domains of the Sp2/0-PMV.

PMID- 8664315
TI  - Intestinal folate transport: identification of a cDNA involved in folate
      transport and the functional expression and distribution of its mRNA.
AB  - Although the mechanism of folate intestinal transport has been the subject of
      intensive studies, very little is known about the molecular identity of the
      transport system(s) involved. In this investigation, we screened a mouse
      intestinal cDNA library using as probe the cDNA clone of a reduced folate carrier
      (RFC1) of mouse leukemia L1210 cells, and identified a positive clone,
      IFC1(RFC1). The cloned cDNA consisted of 2274 base pairs with an open reading
      frame that encodes a putative polypeptide of 512 amino acids with a predicted
      molecular mass of 58,112 daltons and 12 putative transmembrane domains. The
      polypeptide appears to carry a net positive charge (pI = 8.6) which may be
      important for its interaction with the negatively charged substrate. Functional
      identity of the IFC1(RFC1) clone was established by expression in Xenopus
      oocytes. An 11-fold increase in 5-methyltetrahydrofolate (5-MTHF) uptake was
      observed in oocytes injected with 10 ng IFC1(RFC1) cRNA compared to water
      injected controls. The expressed folate uptake in the cRNA injected oocyte was
      (1) 4,4'-diisothiocyanatosilbene-2,2'-disulfonic acid (DIDS)-sensitive; and (2)
      saturable with an apparent Km of 1.99 +/- 0.32 micrometers and a V(max) of 3782
      +/- 188 fmol/oocyte per h. The distribution of mRNA species complementary to
      IFC1(RFC1) in different mouse tissues was examined by Northern blot analysis. In
      addition to the small intestine, expression of such mRNA species were also found
      in the kidney, large intestine, brain, heart and liver. Furthermore, mRNA species
      complementary to IFC1(RFC1) were also detected by Northern blot analysis in the
      small intestine of human and other animal species (rat and rabbit). Expression of
      mRNA complementary to IFC1(RFC1) was markedly higher in rat intestinal villus
      cells than in crypt cells. These results represent the first identification of a
      folate transporter in mammalian intestine.

PMID- 8664317
TI  - Cell membrane fluidity and adriamycin retention in a tumor progression model of
      AKR lymphoma.
AB  - Counteraction of drug resistance is a major challenge in cancer therapy,
      particularly in advanced stages. The main mechanism of multidrug resistance is
      related to an increased drug efflux. In the present study we examined the effect
      of modifying cell membrane lipid fluidity on uptake of adriamycin (ADR) in cells
      of AKR lymphoma malignancy variants. Modification of cell membrane fluidity,
      either by lecithin or by lecithin-cholesterol mixtures, induced in a high
      proportion of cells of all variants a higher capacity to accumulate ADR. The
      chemosensitizing effect, for lecithin in particular, was proportional to the
      degree of malignancy of the lymphoma variants. The increased ADR uptake was up to
      1.4-fold in the variant of lowest malignancy and up to 5-fold in the one of
      highest aggressiveness. This tendency correlates with our previous studies and is
      of particular value since highly-malignant tumors are often drug resistant. The
      cholesterol-lecithin mixture, induced, however, in part of the variants the
      appearance of a small subpopulation with very low ADR permeability. Cell membrane
      rigidification is of value for exposing tumor cell cryptic antigens but may be
      deleterious when used in conjunction with chemotherapy.

PMID- 8664318
TI  - Assessment of molecular sieving across bacterial outer membrane of Pseudomonas.
AB  - The role of the permeability barrier of the outer membrane of Pseudomonas was re
      evaluated based on the physical theory of molecular sieving in view of its
      intrinsic antibiotic resistance. We developed a set of analytical procedures
      based on parametric and non-parametric statistical tests to evaluate, validate
      and adopt the better among a set of competing non-linear models of diffusion. The
      molecular mass dependence of uptake of non-electrolytes in bacteria yielded a
      quantitative measure to distinguish between sieving mechanisms and specific
      uptake/efflux mechanisms. The experimental data, supported by the physical model
      of DEAE-Sephadex and various analytical models and extensive simulation of the
      errors, both in measurement and models, yielded evidence consistent with the
      relaxation of the outer membrane matrix barrier in Pseudomonas.

PMID- 8664316
TI  - Role of palmitic acid on the isolation and properties of halorhodopsin.
AB  - Purified halorhodopsin was isolated from Halobacterium halobium as previously
      described (Duschl, A. et al. (1988) J. Biol. Chem. 263, 17016-17022). Two purple
      bands were eluted from phenyl-Sepharose column, indicating the presence of
      differently retained halorhodopsin forms; the absorption spectra of the two
      halorhodopsin bands in the dark were not different. By gas chromatography/mass
      spectrometry we could identify palmitate (which is only a minor lipid component
      of archaeal cells) among lipids associated with purple fractions. Typically the
      palmitate content of the first eluted band was higher than that of the second,
      indicating a correlation between the palmitate content and the retention time;
      from one to two fatty acid molecules per halorhodopsin molecule were present
      depending on the fraction analysed. Very little or no palmitate was released from
      denatured halorhodopsin. By adding palmitate to buffers used in the phenyl
      Sepharose chromatography, only one sharp purple band was collected, corresponding
      to the less retained halorhodopsin fraction. Pentadecanoic fatty acid could also
      affect the halorhodopsin chromatography. Chromatography of halorhodopsin in the
      presence of beta-mercaptoethanol showed only one band, corresponding to the more
      retrained halorhodopsin form. The two halorhodopsin fractions had different
      photoreactivity; the less retained halorhodopsin fraction (at higher palmitate
      content) showed an higher rate of decay of the absorbance at 570 nm upon
      illumination. By following the decay of the absorbance at 570 nm upon addition of
      alkali in the dark, we found that the two halorhodopsin fractions had different
      pKa values of deprotonation.

PMID- 8664319
TI  - Cyclic AMP-dependent protein kinase phosphorylates residues in the C-terminal
      domain of the cardiac L-type calcium channel alpha1 subunit.
AB  - The molecular basis of the regulation of cardiac L-type calcium channel activity
      by cAMP-dependent protein kinase (cA-PK) remains unclear. Direct cA-PK-dependent
      phosphorylation of the bovine ventricular alpha1 subunit in vitro has been
      demonstrated in microsomal membranes, detergent extracts and partially purified
      (+)-[3H]PN 200-110 receptor preparations. Two 32P-labeled phosphopeptides,
      derived from cyanogen bromide cleavage, of 4.7 and 9.5 kDa were
      immunoprecipitated specifically by site-directed antibodies against the rabbit
      cardiac alpha1 subunit amino acid sequences 1602-1616 and 1681-1694,
      respectively, consistent with phosphorylation at the cA-PK consensus sites at
      Ser(1627) and Ser(1700). No phosphopeptide products consistent with
      phosphorylation at three other C-terminal cA-PK consensus phosphorylation sites
      (Ser(1575), Ser(1848) and Ser(1928)) were identified using similar procedures
      suggesting that these sites are poor substrates for this kinase. Ser(1627) and
      Ser(1700) may represent sites of cA-PK phosphorylation involved in the
      physiological regulation of cardiac L-type calcium channel function.

PMID- 8664320
TI  - Transcriptional and post-translational control of the plant plasma membrane H(+)
      ATPase by mechanical treatments.
AB  - The activity of the plant plasma membrane (PM) H(+)-ATPase was studied with
      fresh, cut or aged tissues of sugar beet (Beta vulgaris L.) leaves. The rate of
      acidification of the medium by tissue samples was strongly stimulated by ageing,
      but unaffected by cutting. The proton-pumping activity and the specific activity
      of the vanadate-sensitive ATPase of purified PM vesicles prepared from aged
      tissues were much higher than that of fresh tissues, whereas cutting had no
      effect. Yet, both ageing and cutting increased the amount of PM H(+)-ATPase
      detected by enzyme-linked immunosorbent assays. Likewise, both ageing and cutting
      increased the levels of pma4 and pma2 ATPase transcripts, as assayed with the
      corresponding probes from Nicotiana plumbaginifolia. Ageing increases, within a
      few hours, the levels of the transcripts, the translation and the activity of
      several PM H(+)-ATPase families. Cutting, which represents a milder mechanical
      stress, only increases the levels of the transcripts and their translation,
      without detectable effect on the activity at the biochemical or physiological
      level, which suggests a post-translational control of this activity. Thus, upon
      mechanical stress, the activity of the H(+)-ATPase, a key enzyme of the plant PM
      is rapidly and tightly regulated by transcriptional and post-translational
      controls.

PMID- 8664321
TI  - Nature of the cation leak induced in erythrocyte membranes by Kanagawa haemolysin
      of Vibrio parahaemolyticus.
AB  - Vibrio parahaemolyticus is an important enteric pathogen that produces an
      exotoxin prepared as Kanagawa haemolysin (KH). Isotope flux techniques were used
      to analyse toxin action on the basal permeability of human erythrocytes. KH
      induced a cation leak that was (i) rapid in onset (lag phase < 1 min), (ii) 'pore
      like' in terms of kinetic characteristics, and (iii) of high magnitude initially
      (first 10 min) and then subsequently lower (but still raised with reference to
      control cells). The susceptibilities of the induced flux pathway to washout in
      initial and later periods suggested a protracted binding time course for toxin
      action. Neuraminidase treatment of erythrocytes enhanced both haemolysis and flux
      induced by KH, suggesting that the affinity of the toxin for the membrane had
      increased, possibly as a result of additional toxin receptors being unmasked by
      this enzyme. These results show that KH elevates the basal permeability of human
      erythrocytes in a complex manner, a process that probably underlies the
      deleterious effects of this toxin on cellular function.

PMID- 8664322
TI  - Diverse effects of different neutrophil organelles on truncation and membrane
      binding characteristics of annexin I.
AB  - A neutrophil annexin I-related protein, detected after translocation of cytosolic
      proteins to specific granules and secretory vesicles/plasma membrane (Sjolin et
      al. (1994) Biochem. J. 300, 325-330), has been characterized with respect to
      origin and organelle-binding properties. The annexin I-related protein is formed
      as a result of annexin I cleavage, and this occurs during translocation of
      annexin I to the specific granules and secretory vesicles/plasma membrane, but
      not when annexin I is translocated to azurophil granules. The cleavage required
      calcium and it was facilitated in the presence of specific granules or secretory
      vesicles/plasma membrane, but not in the presence of azurophil granules. We
      conclude that the membranes of specific granules and secretory vesicles/plasma
      membrane contain a protease which is able to cleave annexin I into a truncated 38
      kDa fragment, which retains the ability to bind to these organelles. The
      azurophil granules lack the capacity to cleave annexin I as well as the ability
      to bind the 38 kDa fragment. These findings may implicate a role for annexin I in
      the divergent regulation of exocytosis of the different neutrophil granules.

PMID- 8664323
TI  - Studies on the thermotropic effects of cannabinoids on phosphatidylcholine
      bilayers using differential scanning calorimetry and small angle X-ray
      diffraction.
AB  - We have studied the thermotropic properties of a wide variety of cannabinoids in
      DPPC bilayers. The molecules under study were divided into four classes: (a)
      classical cannabinoids possessing a phenolic hydroxyl group; (b) delta9-THC
      metabolites with an additional hydroxyl group on the C ring; (c) non-classical
      cannabinoids, and (d) cannabinoids with a protected phenolic hydroxyl group. The
      results showed that the first three groups have similar effects on the
      thermotropic properties of DPPC bilayers up to x = 0.05 (molar ratio) and that
      these effects do not parallel their biological activity. For concentrations less
      than x = 0.01, cannabinoids affect mainly the pretransition temperature in a
      progressive manner until its final abolishment. At x = 0.05, they further affect
      the main phase transition by lowering its phase transition temperature and
      broadening its half width. At high concentrations the thermograms have multiple
      components, indicating that membranes are no longer homogeneous but rather
      consist of different domains. At these concentrations cannabinoids with more
      hydroxyl groups give simpler thermograms. Low concentrations of cannabinoids in
      group d affect significantly the pretransition temperature, while high
      concentrations affect only marginally the main phase transition by slightly
      lowering its temperature and broadening its half width. These results point out
      the importance of the phenolic hydroxyl group in inducing membrane perturbations.
      The d-spacing data from our small angle X-ray diffraction experiments show that
      delta8-THC produces significant structural changes in the lipid bilayer,
      including the gel-phase tilting angle, the intermolecular cooperativity and the
      gauche:trans conformer ratio. Conversely, the inactive analog Me-delta8-THC does
      not cause drastic changes to the bilayer structure.

PMID- 8664324
TI  - Effect of the alkyl chain length of monocarboxylic acid on the permeation through
      bilayer lipid membranes.
AB  - Electrically silent hydrogen ion fluxes across a planar bilayer lipid membrane
      (BLM) induced by an addition of monocarboxylic acid at one side of BLM were
      studied by measuring pH changes in the unstirred layers near the BLM surface. The
      pH changes were assayed by recording protonophore-dependent potentials as well as
      by direct measurements of pH shifts in he unstirred layers close to the membrane
      by the pH microelectrode. It was shown that the mechanism of the acid transport
      changed qualitatively upon the increase of the hydrophobic chain length of the
      acid. In the case of short-chain acids at pH < pKa, the total transport was
      limited by diffusion of the anionic form of the acid across the unstirred layers,
      while at the alkaline pH (pH>>pKa) the transport was limited by diffusion of the
      neutral form across the membrane. In the alkaline pH range the pH shifts induced
      by short-chain acids were sensitive to the presence of cholesterol in the BLM as
      well as to the stirring conditions in the cell. However, in the case of long
      chain acids (more than 8 carbonic atoms) the transport was limited by diffusion
      of the anionic form of the acid in the whole range of pH studied. In the latter
      case, pH changes in the unstirred layers did not depend on the presence of
      cholesterol in the membrane, and moreover pH shifts were not dependent on the
      thickness of the unstirred layer. It was proposed that the peculiarities of the
      long-chain acid-induced proton transport were associated with the formation of
      micelles of the acid in bathing solutions.

PMID- 8664325
TI  - Mammalian platelet-activating factor acetylhydrolases.

PMID- 8664326
TI  - Conformation of human serum apolipoprotein A-I(166-185) in the presence of sodium
      dodecyl sulfate or dodecylphosphocholine by 1H-NMR and CD. Evidence for specific
      peptide-SDS interactions.
AB  - The segment, YSDELRQRLAARLEALKENG, corresponding to residues 166 to 185 of human
      serum apolipoprotein A-I, was studied by circular dichroism and NMR spectroscopy
      in sodium dodecyl sulfate and dodecylphosphocholine micelles. 2-Dimensional
      NOESY, TOCSY and DQF-COSY spectra of apoA-I(166-185) in perdeuterated sodium
      dodecyl sulfate (SDS-d25) and dodecylphosphocholine (DPC-d38) micelles were
      collected at a peptide/SDS (DPC) ratio of 1:40. Similar CD spectra and NOE
      connectivity patterns were observed for apoA-I(166-185) in SDS and DPC,
      indicating a similar helical conformation in both. Conformations of apoA-I(166
      185) in DPC-d38 micelles, and in SDS-d25 micelles at two pH values, 6.6 and 3.7,
      were determined using distance geometry calculations. Backbone superposition (N,C
      alpha,C = O) for an ensemble of twenty-nine structures in DPC at pH 6.0 gave a
      RMSD of 0.45 +/- 0.09 A for the region D168 to K182, while for all atoms it was
      1.60 +/- 0.17 A. In SDS, the ensemble of nineteen structures each at pH 6.6 and
      3.7 gave RMSDs of 0.28 +/- 0.07 A and 0.35 +/- 0.10 A, respectively, for the
      region D168 to K182. RMSD for superposition of all atoms was 1.36 +/- 0.10 A and
      1.38 +/- 0.21 A at the respective pH values. In all cases a highly defined class
      A amphipathic helical structure was found for the region R171 to K182. Since the
      same structure occurs in micelles with either negatively charged or zwitterionic
      head groups it strongly suggests a dominant role for hydrophobic interactions in
      stabilizing the complex. The Y166 aromatic ring is bent back upon the helix axis
      at the lower pH. NMR determination of pKa values for D168, E169, E179 and E183 in
      the presence of SDS or DPC indicated a micro-pH at the micellar surface
      approximately one pH unit higher than the normal residue pKa. SDS interactions
      with the peptide were examined by collecting 1H NOESY spectra in the presence of
      protiated SDS. Residues R171, R173, R177, as well as the aromatic ring of Y166,
      were shown by intermolecular NOE measurements to interact with SDS, hence a key
      interaction in stabilizing the complex appears to be between interfacial basic
      side-chains and SDS alkyl chains.

PMID- 8664327
TI  - Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 -->
      Gln) in a hyperlipidemic patient with xanthomatosis.
AB  - A new variant of apolipoprotein (apo) E, designated apo E2 Fukuoka, was
      identified in a 54-year-old Japanese woman who suffered from hyperlipoproteinemia
      (total cholesterol 29.7 mmol/l, triglyceride 12.0 mmol/l, when she was 48-year
      old) with the presence of xanthoma in the palms, bones, and ocular fundi, and
      other sites. Foam-cell macrophages were observed in bone marrow specimens.
      Analysis of apo E phenotype showed the E3/E2 isoform on isoelectric focusing
      performed on plasma, but the E3/E3 isoform on restriction-fragment-length
      polymorphism of the apo E gene. This discrepancy indicated that the apo E had an
      amino-acid substitution outside of amino-acid residues at 112 and 158. Sequence
      analysis of the patient's DNA, which was amplified by PCR and subcloned, revealed
      a single substitution from arginine (CGG) to glutamine (CAG) at residue 224,
      thereby adding one negatively charged unit to apo E3. Recombinant apo E2 Fukuoka
      produced in COS-1 cells showed almost the same binding activity to the LDL
      receptor on human skin fibroblasts as compared with recombinant apo E3.
      Recombinant apo E2 Fukuoka showed the same heparin binding ability than
      recombinant apo E3. Findings indicated that apo E2 Fukuoka was not the primary
      cause of the hyperlipoproteinemia observed in this case.

PMID- 8664328
TI  - Liver fatty acid-binding protein expression in transfected fibroblasts stimulates
      fatty acid uptake and metabolism.
AB  - The role of cytosolic liver fatty acid binding protein (L-FABP) in fatty acid
      uptake and metabolism was examined using cultured L-cell fibroblasts transfected
      with the cDNA encoding for L-FABP. [3H]Oleic acid was used to determine the
      effects of intracellular esterification on fatty acid uptake and to determine
      esterified fatty acid localization to specific lipid classes. cis-Parinaric acid,
      a poorly esterified fatty acid, was used to determine uptake in the absence of
      any appreciable esterification. High-expression L-cells had a 80% and 50% greater
      initial uptake rate for both [3H]oleic acid and cis-parinaric acid, respectively
      compared to low-expression L-cells. Maximal uptake of [3H]oleic acid did not
      plateau because of intracellular esterification. In high-expressing cells,
      maximal cis-parinaric acid uptake rapidly plateaued at a level 34% higher than in
      low-expression cells. After 1 min of incubation, the majority of cellular
      [3H]oleic acid was unesterified, with the bulk of the esterified portion
      preferentially localized to phospholipids. After 5 and 30 min, cells expressing L
      FABP esterified a significantly greater amount of [3H]oleic acid into both the
      neutral lipid and phospholipid fractions than did low-expression cells. L-FABP
      expression also selectively stimulated [3H]oleic acid incorporation into choline
      glycerophospholipids. Thus, L-FABP expression not only stimulated fatty acid
      uptake at all time points, but also stimulated intracellular esterification into
      specific lipid pools. These results show in detail for the first time using an
      intact cell culture system that L-FABP expression not only stimulated fatty acid
      uptake, but also increased intracellular esterification of exogenously supplied
      fatty acids.

PMID- 8664329
TI  - Reconstitution of the steroidogenic pathway from cholesterol to aldosterone in
      liposome membranes.
AB  - A steroidogenic pathway from cholesterol to aldosterone was reconstituted in
      liposome membranes using cytochromes P-450scc, P-450C21 and P-450(11) beta, and 3
      beta-hydroxysteroid dehydrogenase/ delta 5-delta 4 isomerase (3 beta HSD/I) with
      their electron transfer systems. All of the enzymes were purified from bovine
      adrenocortical mitochondria and microsomes. The cholesterol metabolism in the
      liposomal reconstituted system was compared with that in the combined organella
      system composed of bovine adrenocortical mitochondria and microsomes, where the
      activity of P-450(17) alpha,lyase was inhibited by bifonazole. The metabolic
      activities in these two systems were similar except for aldosterone production.
      Aldosterone was produced in the liposomal system but not in the combined
      organella system. 4-fold increase in the amount of P-450scc in the liposomal
      system enhanced the activity of 3 beta HSD/I, P-450C21 and 11 beta-hydroxylase of
      P-450(11) beta but decreased 18-hydroxycorticosterone and aldosterone production
      by P-450(11) beta, supporting our previous findings describing the regulation
      mechanism of aldosterone synthesis (Kominami, S., Harada, D. and Takemori, S.
      (1994) Biochim. Biophys. Acta 1192, 234). It was demonstrated using the liposomal
      reconstituted system that the increase in the amount of one enzyme did not only
      increase the metabolizing activity of that enzyme but also affect other enzyme in
      various ways.

PMID- 8664330
TI  - Procolipase is produced in the rat stomach--a novel source of enterostatin.
AB  - Procolipase was identified in the stomach by in situ hybridisation. A strong
      autoradiographic labelling of chief cells was seen in the fundus region,
      declining more distally and being almost absent in antrum. There was no labelling
      seen in the intestine. Colipase activity was estimated in rat gastric juice
      following pentagastrin stimulation and was found to average 2 microM.
      Furthermore, enterostatin, the N-terminal pentapeptide of procolipase, has been
      identified in the rat gut and pancreas. Extracts from gastric mucosa, intestinal
      mucosa and pancreas were purified by gel filtration (Sephadex G25), ion-exchange
      chromatography (CM-Sepharose) and HPLC (C18 reverse phase). Using an ELISA assay
      with antibodies directed against enterostatin, two forms of the peptide were
      identified both in the gut and in the pancreas, with the amino-acid sequences
      APGPR and VPGPR, respectively. APGPR was found to be the predominant form of
      enterostatin, whereas only a small amount had the structure VPGPR. Enterostatin
      in the form of APGPR, when injected intracerebroventricularly in female Sprague
      Dawley rats, significantly reduced high-fat food intake in a two-choice situation
      of low-fat (14% fat by energy) and high-fat (38% fat) food. It is concluded that
      procolipase is produced in the stomach and secreted into the gastric juice. This
      is also a novel source of enterostatin.

PMID- 8664331
TI  - Up-regulation of the low density lipoprotein receptor-related protein by
      dexamethasone in HepG2 cells.
AB  - Dexamethasone has been shown to decrease the expression of the low density
      lipoprotein (LDL) receptor, but its effect on other members of the LDL receptor
      family is not known. We studied the effect of dexamethasone in HepG2 cells on the
      expression of the LDL receptor family members using radiolabeled receptor
      associated protein (RAP) which binds to all the members of the family. Treatment
      of HepG2 cells with increasing concentrations of dexamethasone resulted in a 2
      fold increase in the binding and degradation of RAP. To identify the receptor
      responsible for the increased binding and degradation of RAP, we used specific
      ligands. For LDL receptor, we used LDL itself. For the LDL receptor-related
      protein/alpha 2-macroglobulin receptor, we used activated alpha 2-macroglobulin.
      The binding of LDL to HepG2 cells was decreased, whereas binding and degradation
      of activated alpha 2-macroglobulin was increased by 2-fold suggesting that
      dexamethasone increased LRP expression. Increased LRP expression was positively
      correlated with the increase in the steady-state levels and transcript numbers of
      the LRP mRNA; no changes in RAP or gamma-actin mRNA levels were observed.
      Increased mRNA levels were not due to an increased rate of transcription of the
      gene as assessed by nuclear run-on experiments. These studies indicate that
      dexamethasone increases cell-surface LRP activity in HepG2 cells by increasing
      the steady state mRNA levels and suggest that post-transcriptional mechanisms
      play a role in controlling LRP mRNA levels.

PMID- 8664332
TI  - Quantitation of apolipoprotein B-48 in triacylglycerol-rich lipoproteins by a
      specific enzyme-linked immunosorbent assay.
AB  - This paper describes the use of an antiserum, specific for apolipoprotein (apo) B
      48, in a competitive, enzyme-linked immunosorbent assay (ELISA) for apo B-48 in
      triacylglycerol-rich lipoprotein (TRL) fractions prepared from fasting and post
      prandial plasma samples. Previously we showed the antiserum to act as an
      effective immunoblotting agent following sodium dodecyl sulfate polyacrylamide
      gel electrophoresis (SDS-PAGE). Its use in this ELISA indicates that the
      antiserum recognises the C-terminal region of the protein on the surface of
      lipoprotein particles. The ELISA had a sensitivity of less than 37 ng/ml and
      intra- and inter-assay coefficients of variation of 3.8% and 8.6%, respectively.
      There was no cross-reaction in the ELISA against serum albumin, ovalbumin,
      thyroglobulin, or apo B-100 (purified by immunoaffinity chromatography), and high
      lipid concentrations (as Intralipid) did not interfere. A low density lipoprotein
      fraction reacted in the ELISA but SDS-PAGE-Western blot analysis confirmed the
      presence, in the fraction, of a small amount of apo B-48, indicating the
      existence of low density dietary-derived lipoprotein particles. ELISA and SDS
      PAGE-Western blot analysis were used to measure apo B-48 in 12 series of
      postprandial samples collected from 4 diabetic and 8 normal subjects, following
      test meals of varying fat content. The mean correlation between the two methods
      was r = 0.74. The mean fasting concentration of apo B-48 in the TRL fractions
      from 15 healthy men was 0.46 microgram/ml of plasma.

PMID- 8664333
TI  - Comparative effect of ursodeoxycholic acid and calcium antagonists on the
      binding, uptake and degradation of LDL in isolated hamster hepatocytes.
AB  - We have shown that ursodeoxycholic acid (UDCA) stimulates low density lipoprotein
      (LDL) metabolism (Biochem. J. 280 (1991) 589), as well as calcium mobilization
      (Am. J. Physiol. 264 (1993) G243) in isolated hepatocytes. Therefore, the effect
      of UDCA and that of different calcium antagonists on hepatic LDL metabolism was
      compared. Isolated hamster hepatocytes were incubated at 37 degrees C for 60 min
      in the presence of 125I-labelled hamster LDL, increasing concentrations (25-100
      microM) of verapamil, nifedipine, and diltiazem, respectively, and with or
      without 700 microM ursodeoxycholic acid (UDCA). At concentrations up to 100
      microM, neither verapamil nor nifedipine significantly affected cell associated
      LDL, but both agents decreased LDL degradation in a dose-dependent manner, with
      almost total inhibition with 100 microM of either agent. In contrast, 25 microM
      diltiazem stimulated LDL binding and uptake, with a maximum increase of 15-20% of
      control, while 50 and 100 microM diltiazem stimulated LDL degradation by 50 and
      100%, respectively. UDCA increased native LDL binding and uptake by 20%, and
      degradation by 50%. None of the agents tested had any effect on the binding,
      uptake and degradation of methylated LDL. The increased hepatic LDL uptake
      induced by UDCA was not altered in the presence of calcium antagonists, while the
      increased degradation of LDL by UDCA was abolished by the addition of 50 microM
      of either verapamil or nifedipine. However, 100 microM diltiazem and 700 microM
      UDCA stimulated LDL degradation without any additive effect. These studies show
      that different calcium antagonists have differential effects on hepatic LDL
      metabolism. The similarities between the effect of diltiazem and UDCA on LDL
      metabolism and the absence of any additive effect, suggest that these two agents
      have a similar mechanism of action, which may involve the integration of both
      agents into the plasma membrane lipid bilayer.

PMID- 8664334
TI  - Vastatins have a distinct effect on sterol synthesis and progesterone secretion
      in human granulosa cells in vitro.
AB  - Lovastatin and simvastatin are strong inhibitors of cholesterol synthesis in
      cultured human granulosa cells, as measured within 6 days after isolation, with
      IC50-values of respectively 27.0 and 18.2 nM obtained after 3.5 hours of
      incubation with the drugs. Pravastatin is a much weaker inhibitor of cholesterol
      synthesis (IC50-value of 977.8 nM) in these cells. Under these conditions
      inhibition of cholesterol synthesis had no influence on progesterone secretion
      into the medium which was probably due to the presence of large cholesterol pools
      in the cells. To deplete these pools, granulosa cells were cultured for 7 days
      after which the culture medium was changed into medium supplemented with 20%
      lipoprotein-depleted serum to deprive the cells of exogenous cholesterol.
      Additionally, 30 mIU of follicle-stimulating hormone and luteinizing hormone per
      ml were added to stimulate the progesterone production and secretion, thereby
      decreasing the cholesteryl ester pools. After 48 h of incubation, culture was
      continued without hormones for another two days. Thereafter, the cells were
      preincubated for 24 h without or with 1 microM of lovastatin, simvastatin or
      pravastatin in medium containing lipoprotein-deficient serum and the above
      mentioned hormones. This period is followed by incubation for another 24 h in the
      presence of [14C]acetate after which cells and media were collected for
      determination of 14C-labelled sterols synthesized and progesterone secreted into
      the media. Now, lovastatin and simvastatin, which strongly inhibited sterol
      synthesis, significantly attenuated the secretion of progesterone. One microM of
      pravastatin had no significant effect on sterol synthesis nor on progesterone
      secretion. When the latter experiment was performed under conditions in which
      exogenous cholesterol was provided in the form of human low density lipoproteins,
      no influence of the vastatins on progesterone secretion was observed. So under
      conditions in which the cholesterol pools were decreased, lovastatin and
      simvastatin attenuated the progesterone secretion, whereas pravastatin did not.
      When pools were filled by exogenous cholesterol, no effect on progesterone
      secretion by either of the drugs was observed.

PMID- 8664335
TI  - Iron-ascorbate-phospholipid mediated modification of low density lipoprotein.
AB  - LDL can be oxidized by a variety of agents to form a modified lipoprotein which
      is capable of being avidly metabolized by macrophages. While previous in vitro
      studies have focused exclusively on the oxidation of LDL, other lipids found in
      the atheroma are also subject to oxidation and its lipoperoxide byproducts may
      contribute to the process of LDL modification. To examine the relationship
      between the oxidation of phospholipids and the subsequent modification of LDL, we
      incubated 250 microM phosphatidylcholine with 10 microM ferrous sulfate and 50
      microM ascorbic acid in 10 mM Tris (pH 7.0). After 18 h at 37 degrees C,
      significant amounts of thiobarbituric acid reactive substances (TBARS) were
      formed. The inclusion of LDL (100 micrograms protein/ml) elevated the TBARS and
      increased the electrophoretic mobility of the lipoprotein. LDL treated with iron
      and ascorbate in the absence of phosphatidylcholine did not result in the
      modification of this lipoprotein. LDL that was incubated with
      phosphatidylcholine, iron and ascorbate was found to be metabolized by
      macrophages to a far greater extent than native LDL or LDL treated with
      phosphatidylcholine alone. Probucol (10 microM) inhibited the LDL modification
      process. These results demonstrate that while iron and ascorbate cannot oxidize
      LDL directly, the addition of phosphatidylcholine to these initiators of lipid
      peroxidation can mediate and lead to the modification of LDL.

PMID- 8664336
TI  - The effect of microfluidization of protein-coated liposomes on protein
      distribution on the surface of generated small vesicles.
AB  - Tetanus toxoid and immunoglobulin G (IgG), model proteins for vaccines and
      targeting ligands respectively, were covalently coupled to preformed dehydration
      rehydration vesicles (DRV) to produce vesicles with surface-bound proteins (DRV
      protein) or to preformed small unilamellar vesicles (SUV) which were used to
      generate DRV with bound protein [(SUV-protein)DRV]. Of the amount of protein
      employed for coupling (1 mg), 13.8-45.1% was recovered with the liposomes,
      depending on the type of preparations and the proteins used. Microfluidization of
      similar DRV-protein or (SUV-protein)DRV for up to 10 cycles led to the formation
      of smaller vesicles (98-136 mm diameter) which, however, had modestly reduced
      (estimated as 8.8-21.7%) bound proteins, again depending on the type of
      preparation and protein used. Treatment of DRV-protein and (SUV-protein) DRV with
      proteinase revealed that 32.9-45.6% of the total bound protein was exposed on the
      liposomal surface. With microfluidized liposomes, the proportion of surface
      exposed protein increased to 63.1-76.2%. Incubation of intact and microfluidized
      DRV-IgG and (SUV-IgG) DRV with a protein A-Sepharose 4B CL gel confirmed the
      presence of IgG on the liposomal surface (47.1-68.4 and 80.5-82.1% of total bound
      protein respectively). These studies were supplemented with freeze-fracture
      electron microscopy of (SUV-toxoid)DRV which demonstrated the presence of protein
      particles (up to 3; 12-14 nm diameter) on the surface of both intact and
      microfluidized individual liposomes.

PMID- 8664337
TI  - Phospholipid transfer protein mediated conversion of high density lipoproteins
      generates pre beta 1-HDL.
AB  - High density lipoproteins (HDL) subclasses can be differentiated by two
      dimensional non-denaturing polyacrylamide gradient gel electrophoresis (2D-PAGGE)
      and subsequent immunoblotting. The quantitatively minor HDL-subclasses pre beta 1
      LpA-I and gamma-LpE are initial acceptors of cell-derived cholesterol into the
      plasma compartment. In this study we analysed the effect of phospholipid transfer
      protein (PLTP) on the electrophoretic distribution of HDL-subclasses in plasma as
      well as the ability of plasma, pre beta 1-LpA-I, and gamma-LpE to take up
      [3H]cholesterol from labeled fibroblasts. Pre beta 1-LpA-I but not gamma-LpE
      disappeared during a 16 hours incubation in the absence of PLTP. During a one
      minute incubation pre beta 1-LpA-I of pre-incubated plasma released 75% less
      [3H]cholesterol from radiolabeled fibroblasts than pre beta 1-LpA-I of control
      plasma. Pre-incubation of plasma reduced the uptake of [3H]cholesterol by gamma
      LpE by 40%. Totally, the cholesterol efflux capacity of plasma decreased by 10%
      compared to the original sample. The amount of immunodetectable pre beta 1-LpA-I
      increased when plasma was incubated in the presence of PLTP while the amount of
      immunodetectable gamma-LpE did not change. After one minute incubation of PLTP
      conditioned plasma with [3H]cholesterol-labeled fibroblasts, the amount of
      radioactive cholesterol taken up by pre beta 1-LpA-I was twice as high as in
      control plasma whereas the amount of [3H]cholesterol taken up by gamma-LpE
      remained unchanged. As a net result, treatment with PLTP increased the
      cholesterol efflux into total plasma by 40%. Together with results of previous
      studies our data suggest that the conversion of alpha-LpA-I3 into alpha-LpA-I2 by
      PLTP generates pre beta 1-LpA-I but not gamma-LpE. PLTP helps to enhance the
      uptake of cell-derived cholesterol by pre beta 1-LpA-I and, thereby, the
      cholesterol efflux capacity of normal plasma.

PMID- 8664338
TI  - Biosynthesis of docosahexaenoic acid in human cells: evidence that two different
      delta 6-desaturase activities may exist.
AB  - It has been proposed that synthesis of docosahexaenoic acid (22:6(n-3) in rat
      hepatocytes occurs by a route independent of delta 4-desaturase, which involves
      delta 6-desaturation and retroconversion (Voss A., Reinhart M., Sankarappa S. and
      Sprecher H. (1991) J. Biol. Chem. 266, 19995-20000). However, most cells exhibit
      these enzymatic activities and nevertheless synthesize low to undectectable
      amounts of 22:6(n-3). Moreover, there are few data on the occurrence of this
      pathway in human cells. In the present work, we have analysed the biosynthetic
      pathway of 22:6(n-3) in human Y-79 retinoblastoma and Jurkat T-cells. Y-79 cells
      were supplemented with 18:3(n-3) and 20:5(n-3) or incubated with [1-14C]18:3(n-3)
      and [1-14C]20:5(n-3) and lipids analysed by argentation TLC, reverse-phase TLC
      and GLC-mass spectrometry. Pulse-chase experiments revealed that synthesis of
      22:6(n-3) from 20:5(n-3) in Y-79 cells occurred through two successive
      elongations, followed by a delta 6-desaturation of 24:5(n-3) to 24:6(n-3) and
      retroconversion to 22:6(n-3). Incubation of Y-79 cells with [1-14C]18:3(n-3) in
      medium containing 50 microM trans-9,12-18:2, a potent inhibitor of delta 6
      desaturase, caused a reduction of 22:6(n-3) synthesis mainly by interfering with
      the desaturation of 18:3(n-3). However, when [1-14C]20:5(n-3) was used as
      precursor, synthesis of 22:6(n-3) was depressed to a lesser extent and mainly by
      reduction of 24:6(n-3) retroconversion. Neuronal differentiation of Y-79 cells
      caused a great increase in delta 6-desaturase activity on 18:3(n-3), though the
      amount of 22:6(n-3) synthesized did not change or diminish, suggesting the
      existence of a particular delta 6-desaturase involved in the synthesis of 22:6(n
      3). The existence of a distinctive delta 6-desaturase activity could also explain
      why Jurkat cells growing in serum-free medium showed a near 3-fold increase in
      the synthesis of pentaenes from 18:3(n-3) and, at the same time, a large decrease
      in the synthesis of 22:6(n-3). The verification of the involvement of two delta 6
      desaturase activities in 22:6(n-3) synthesis would have important implications
      for the formulation of the nutritional requirements of this fatty acid during
      development.

PMID- 8664339
TI  - Ceramide signalling and the immune response.
AB  - Ceramide, produced through either the induction of SM hydrolysis or synthesized
      de novo transduces signals mediating differentiation, growth, growth arrest,
      apoptosis, cytokine biosynthesis and secretion, and a variety of other cellular
      functions. A generalized ceramide signal transduction scheme is shown in Fig. 2
      in which ceramide is generated through the activation of distinct SMases residing
      in separate subcellular compartments in response to specific stimuli. Clearly,
      specificity of cellular responses to ceramide depends upon many factors which
      include the nature of the stimulus, co-stimulatory signals and the cell type
      involved. Ceramide derived from neutral SMase activation is thought to be
      involved in modulating CAPK and MAP kinases, PLA2 (arachidonic acid
      mobilization), and CAPP while ceramide generated through acid SMase activation
      appears to be primarily involved in NF-kappa B activation. While there is no
      apparent cross-talk between these two ceramide-mediated signalling pathways,
      there is likely to be significant cross-talk between ceramide signalling and
      other signal transduction pathways (e.g., the PKC and MAP kinase pathways). Other
      downstream targets for ceramide action include Cox, IL-6 and IL-2 gene
      expression, PKC zeta, Vav, Rb, c-Myc, c-Fos, c-Jun and other transcriptional
      regulators. Many, if not all, of these ceramide-mediated signalling events have
      been identified in the various cells comprising the immune system and are
      integral to the optimal functioning of the immune system. Although the role of
      the SM pathway and the generation of ceramide in T and B lymphocytes have only
      recently been recognized, it is clear from these studies that signal transduction
      through SM and ceramide can strongly affect the immune response, either directly
      through cell signalling events, or indirectly through cytokines produced by other
      cells as the result of signalling through the SM pathway. An overview of the
      signalling mechanisms coupling ceramide to the modulation of the immune response
      is depicted in Fig. 3 and shows how ceramide may play pivotal roles in regulating
      a number of complex processes. The SM pathway represents a potentially valuable
      focal point for therapeutic control of immune responses, perhaps for either
      enhancement of the activity of T cells in the elimination of tumors, or the down
      regulation of lymphocyte function in instances of autoimmune disease. The recent
      explosion of knowledge regarding ceramide signalling notwithstanding, a number of
      critical questions need to be answered before a comprehensive, mechanistic
      understanding can be formulated relative to the incredibly varied effects of
      ceramide on cell function. For example, (i) how is a structurally simple molecule
      like ceramide able to mediate so many different, and sometimes paradoxical,
      physiological responses ranging from cell proliferation and differentiation to
      inhibition of cell growth and apoptosis, (ii) what are the molecular identities
      and modes of activation of the various SMase isoforms, (iii) what determines the
      distribution of the unique isoforms of SMase in cells of different lineages or at
      different stages of differentiation, (iv) what is the relative contribution of
      ceramide generated through SM hydrolysis versus de novo synthesis, and (v) by
      what means does ceramide interact with specific intracellular targets? Although a
      number of ceramide-activatable kinases, phosphatases, and their protein
      substrates have been identified, a more extensive search for additional cellular
      targets will be indispensable in determining the phosphorylation cascades linking
      the activation of the SM pathway to the regulation of nuclear events. Clearly,
      cross-talk between ceramide-induced signal transduction cascades and other
      signalling pathways adds to the inherent difficulty in distinguishing the
      specific effects of complex, intertwining signalling pathways.

PMID- 8664340
TI  - Effects of a synthetic N-terminal fragment of stanniocalcin on the metabolism of
      mammalian bone in vitro.
AB  - A synthetic peptide corresponding to the N-terminal amino acid residues of
      stanniocalcin (STC1-20) and including a region that is known to be an active site
      in teleosts was prepared and tested for its effects on the metabolism of
      mammalian bone in vitro. STC1-20 (10(-10)-10(-12) M) inhibited increases in the
      number of tartrate-resistant acid phosphatase-positive, multinucleated cells
      promoted by an N-terminal fragment of human parathyroid hormone (hPTH1-34) in
      cultures of murine hemopoietic cells. STC1-20 also slightly decreased the rate of
      loss of radioactivity from calvariae of fetal rats that had been prelabeled with
      45Ca, both with and without stimulation by hPTH1-34. The accumulation of cAMP
      induced by hPTH1-34 in ROS 17/2.8-5 cells was suppressed by STC1-20 (10(-10)-10(
      12) M). Treatment with STC1-20 (10(-11)-10(-13) M) caused increases of the rate
      of incorporation of [3H]proline into the collagenase-digestible protein of
      calvariae in newborn mice. From these results, it appears that STC1-20 has
      diverse effects on the metabolism of mammalian bone, causing a biphasic response.
      Such effects have not been observed with intact stanniocalcin or with materials
      from the corpuscles of Stannius and they are also different from the effects of
      hPTH1-34.

PMID- 8664341
TI  - Relevance of the arginine transport activity to the nitric oxide synthesis in
      mouse peritoneal macrophages stimulated with bacterial lipopolysaccharide.
AB  - Transport of arginine and production of nitrite have been investigated in mouse
      peritoneal macrophages stimulated with bacterial lipopolysaccharide (LPS). The
      arginine transport activity was induced by LPS at very low concentration
      (maximally induced at 1 ng/ml), whereas much higher concentration of LPS was
      required for the induction of nitrite production. Arginine was more concentrated
      in the cells when its transport activity was induced. Lysine, which is a
      competitive inhibitor of the transport of arginine, neutralized the concentrative
      effect of the induced transport activity and thus inhibited the nitrite
      production. Induction of the arginine transport activity seems to be prerequisite
      to the enhanced synthesis of nitric oxide in activated macrophages.

PMID- 8664342
TI  - Human astrocytoma U138MG cells express predominantly type-A endothelin receptor.
AB  - Endothelin-1 (ET-1) binding to human astrocytoma U138MG cells was time-dependent,
      and bound [125I]ET-1 was difficult to dissociate. The B(max) and Kd values of
      [125I]ET-1 binding were 70 fmol/mg and 0.07 nM, respectively. Interestingly,
      different from other astrocytoma cells and astrocytes, the U138MG cells expressed
      predominantly ETA receptor as shown by RT-PCR results and binding studies. ET-1,
      FR139317, BQ123, PD142893 and Ro46-2005 inhibited specific [125I]ET-1 binding
      with Ki values of 0.10, 0.53, 4.3, 22, and 320 nM, respectively. ETB selective
      ligands ET-3 and IRL1620 were much less potent. The inhibitory effects of
      antagonists BQ123 and PD142893 on [125I]ET-1 binding diminished following the
      incubation time. ET-1 binding caused a modest stimulation in phosphatidylinositol
      hydrolysis with an EC50 value of 24 nM. In comparison to the human U373MG cells,
      ET-1-induced receptor internalization in U138MG cells was less efficient with 42%
      of bound ET-1 internalized after 30 min of incubation. These results imply that
      human astrocytoma cells/astrocytes are able to express either ETA or ETB receptor
      under different pathophysiological conditions.

PMID- 8664344
TI  - Angiotensin II induces TIMP-1 production in rat heart endothelial cells.
AB  - Angiotensin II (AII) was found to upregulate tissue inhibitor of
      metalloproteineses-1 (TIMP-1) gene expression in rat heart endothelial cells in a
      dose and time-dependent manner. The maximal stimulation of TIMP-1 mRNA was
      achieved by 2 h after the addition of AII. This effect was blocked by losartan,
      an AT1 receptor antagonist and by calphostin C, a protein kinase C inhibitor.
      Addition of cycloheximide superinduced and actinomycin D abolished the induction.
      These results suggest that AII stimulates TIMP-1 production by a protein kinase C
      dependent pathway which is dependent upon de novo RNA synthesis.
      Immunoprecipitation experiment showed an enhanced band of 28 kDa from the
      conditioned medium of AII-treated cultures. Immunoblot analysis revealed that
      TIMP-1 was detectable in the conditioned medium 4 h after AII stimulation. Since
      endothelial cells line the blood vessels and sense the rise in AII associated
      with hypertension, the TIMP-1 released by these cells may provide an initial
      trigger leading to cardiac fibrosis in angiotensin-renin dependent hypertension.

PMID- 8664343
TI  - Variability of the thrombin- and ADP-induced Ca2+ response among human platelets
      measured using fluo-3 and fluorescent videomicroscopy.
AB  - The intracellular free Ca2+ concentration ([Ca2+]cyt) of individual human
      platelets localized between siliconized glass cover slips was determined at rest
      and after stimulation with thrombin and ADP using the Ca2+ indicator fluo-3 (0.97
      +/- 0.30 mmol/l cell volume) with fluorescence video microscopy. Resting
      [Ca2+]cyt in the presence of 2 mM external Ca2+ showed only small inter-platelet
      variability ([Ca2+]cyt = 86 +/- 30 (S.D.) nM). Resting [Ca2+]cyt of individual
      fluo-3-loaded platelets measured as a function of time had a S.D. of 10 nM or 12%
      (S.D./mean). Individual platelets showed no affinity for the siliconized support
      and their [Ca2+]cyt showed no tendency to oscillate in either the resting or in
      the activated state. When 0.2 U/ml thrombin or 20 microM ADP were added, all
      platelets showed a characteristic Ca2+ transient whereby [Ca2+]cyt increased to
      peak values within 8-12 sec and then declined. The Ca2+ transients measured with
      fluo-3 were in approximate synchrony but peak [Ca2+]cyt values showed large inter
      platelet variability. The ensemble average peak [Ca2+]cyt for thrombin and ADP
      were 672 +/- 619 (S.D.) nM and 640 +/- 642 (S.D.) nM, respectively. Thus inter
      platelet variations (S.D./mean) were 92% or 100% as large as the average measured
      values. Mathematically-constructed averages of the single platelet experiments
      agreed reasonably well with platelet-averaged values obtained in parallel
      experiments with stirred platelet suspensions in a plastic cuvette, measured with
      a conventional spectrofluorometer. Peak [Ca2+]cyt values reflecting dense tubular
      Ca2+ release alone (external Ca2+ removed) also showed large interplatelet
      variation (171 +/- 105 (S.D.) nM with thrombin and 183 +/- 134 (S.D.) nM with
      ADP). Dense tubular Ca2+ release induced by cyclopiazonic acid (a dense tubular
      Ca2+-ATPase inhibitor) gave peak [Ca2+]cyt of 289 +/- 170 nM. Thus the size of
      the dense tubular Ca2+ pool has an inter-platelet variation of 59% (S.D./mean).
      Variability of the dense tubular pool size accounts for some, but not all, of the
      large interplatelet variation in peak (Ca2+]cyt seen with thrombin and ADP
      activation.

PMID- 8664345
TI  - Characterization of human platelet GTPase activating protein for the Ral GTP
      binding protein.
AB  - RalA, a ras p21 related 27 kDa GTP-binding protein, was expressed as a fusion
      protein in Escherichia coli and purified to homogeneity using an immunoaffinity
      column. The purified protein was capable of binding and hydrolyzing GTP. Addition
      of platelet cytosolic or detergent solubilized particulate proteins stimulated
      the intrinsic GTPase activity of ralA by at least six-fold with maximal effect
      observed at pH 6.5. Addition of platelet proteins denatured by boiling had no
      effect on ralA GTPase activity. Analysis of GTPase reaction products by thin
      layer chromatography demonstrated that in samples containing ralA, 78.5 +/- 6.3%
      of the radioactivity was recovered in the GTP form while samples containing ralA
      plus platelet cytosol or particulate proteins, only 7.5 +/- 0.2% and 9.0 +/- 1.4%
      of the radioactivity was in the GTP form respectively. The GTPase activating
      protein(s) in the cytosolic and particulate fraction was further characterized by
      measuring GAP activity in proteins eluted from gel slices after sodium dodecyl
      sulfate polyacrylamide gel electrophoresis. The ralA GTPase activating protein
      present in the cytosol and particulate fractions was recovered in a single gel
      slice of identical apparent molecular weight. The molecular mass of the ral
      specific GTPase activating protein was estimated to be 34 +/- 2 kDa. This protein
      did not stimulate the intrinsic GTPase activity of ras p21, G25K/CDC42Hs or rab3A
      GTP-binding proteins. Results demonstrate that in human platelets, the
      activity/function of ral-related GTP-binding protein(s) is under the regulation
      of a specific GTPase activating protein of molecular mass of 34 +/- 2 kDa that is
      distributed equally in the cytosol and particulate fraction.

PMID- 8664346
TI  - Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids
      and by retinoic acid involves a single intracellular target, probably an enzyme
      of the aldoketoreductase family.
AB  - HL60 cells are human promyeloid cells that can be induced to differentiate by
      physiological stimuli (e.g. all-trans retinoic acid (ATRA), 1 alpha,25
      dihydroxyvitamin D3 (D3), granulocyte colony-stimulating factor (G-CSF)) and by
      non-physiological agents such as dimethysulphoxide (DMSO) and protein kinase C
      activating phorbol esters. The sensitivity of HL60 cells to physiological
      differentiating agents, but not to DMSO, is enhanced when cells are exposed to
      'anti-inflammatory agents' (e.g. indomethacin) or are 'primed' (pretreated) with
      a small amount of ATRA: alone, neither treatment induces differentiation. We
      earlier suggested that indomethacin might act by inhibiting the endogenous
      formation of a differentiation-suppressing prostanoid (Bunce, C.M., et al. (1994)
      Leukemia 8, 595-604). Studies of the formation of prostanoids by HL60 cells and
      of the effects of prostanoids on these cells failed to identify any prostanoid
      that could be implicated in sensitization by indomethacin. 3 alpha-Hydroxysteroid
      dehydrogenase (3 alpha-HSD) is another target of such 'anti-inflammatory agents'.
      Steroid inhibitors of 3 alpha-HSD sensitized HL60 cells to inducers of
      differentiation in a manner similar to indomethacin. 3 alpha-HSD is a member of
      the aldoketoreductase enzyme family, which comprises many enzymes of similar size
      and primary sequence. A protein that was recognised by an antiserum to 3 alpha
      HSD was found in HL60 cells, but the cells showed no detectable 3 alpha-HSD
      activity. The 3 alpha-HSD-like protein was strikingly down-regulated by 'priming'
      doses of ATRA. When treatment with a differentiation-sensitizing 'anti
      inflammatory agent' or steroid was combined with ATRA "priming', the effects of
      the different treatments were not additive: the resulting increase in sensitivity
      equalled that achievable by either treatment alone. We conclude that interference
      with a single intracellular regulatory mechanism underlies the increases in
      sensitivity of cells to differentiating agents that are caused by anti
      inflammatory agents, by certain steroids and by 'priming' with ATRA. Decreased
      activity of a yet-to-be-identified member of the aldoketoreductase family of
      dehydrogenases is likely to be a central feature of a previously unrecognised
      mechanism that controls the responsiveness of cells to environmental stimuli such
      as retinoids and D3.

PMID- 8664347
TI  - Human lactase-phlorizin hydrolase is not processed by furin, PC1/PC3, PC2, PACE4
      and PC5/PC6A of the family of subtilisin-like proprotein processing proteases.
AB  - Human lactase-phlorizin hydrolase (LPH, EC 3.2.1.23/62) is synthesized as a
      single-chain precursor glycoprotein (pro-LPH) with a relative molecular mass of
      just over 200 kDa. Maturation to the mature enzyme (m-LPH, 160 kDa) occurs after
      passage of pro-LPH through the Golgi complex and involves the proteolytic removal
      of a 849 amino acid propeptide. The role of this propeptide as well as its
      removal is not fully understood and the proteolytic enzyme or enzymes involved
      are unknown. We studied the potential role of five different members of the
      family of subtilisin-like proprotein processing proteases in the maturation
      process of human LPH using a vaccinia virus based coexpression system in pig
      kidney PK(15) cells. Infected/transfected PK(15) cells expressed full-length pro
      LPH but no maturation to m-LPH was observed. Coexpression of human pro-LPH with
      human furin, human PC1/PC3, human PC2, human PACE4 and mouse PC6A in PK(15) cells
      did not result in maturation of the enzyme. Cleavage and secretion of von
      Willebrand factor precursor (pro-vWF) was used as a positive control. None of the
      five proprotein processing proteases tested were capable of cleaving human pro
      LPH, strongly suggesting that they are not involved in the maturation of this
      enzyme.

PMID- 8664348
TI  - Inhibition of the expression of ornithine decarboxylase by some kappa-opioidergic
      receptor ligands in difluoromethylornithine-resistant L1210 cells.
AB  - In difluoromethylornithine resistant L1210 cells stimulated to growth from
      quiescence, the selective kappa-opioidergic agonist trans-(+/-)-3,4-dichloro-N-[2
      (1-pyrrolidinyl)cyclohexyl]benzeneaceta mid e (U-50488H) caused a dose dependent
      inhibition of the induction of ODC activity, with a half-maximal effect at about
      1 microM. U-50488H also provoked reduction of ODC mRNA level and increase of ODC
      turnover, as well as inhibition of cell growth. U-69593, another kappa-selective
      agonist, was only slightly effective. The action of U-50488H on ODC induction was
      not blocked by naloxone, beta-chlornaltrexamine or by the kappa-selective opioid
      antagonists Mr1452 and nor-binaltorphimine (nBNI). Actually Mr1452 and nBNI
      exerted some inhibitory effect. Furthermore, the separated enantiomers (+) and (
      ) of U-50488H were similarly effective. The (-)cis-(1S,2R)-U50488 stereoisomer,
      exhibiting low affinity for kappa and high affinity for sigma receptors and
      carbetapentane, another sigma ligand, also inhibited ODC induction, although less
      effectively than U-50488H. None of several other opioid ligands tested had
      significant effects on ODC induction. In conclusion, the inhibition of ODC
      expression by U-50488H does not involve classical, enantiospecific opioid
      receptors; rather, these results suggest the involvement of a distinct site of
      action linked to inhibition of lymphoid cell proliferation.

PMID- 8664350
TI  - Suicide and AIDS: lessons from a case note audit in London.
AB  - There is growing evidence that HIV infection and AIDS have an impact on a range
      of suicidal issues. The literature lacks clarity and the subject is traditionally
      problematic to research. True prevalence is often difficult to gauge and many
      researchers focus simply on death by suicide rather than exploring the extreme
      mental health burden brought about by suicidal thoughts, attempts, completions
      and bereavement. This study was set up to explore the nature and extent of
      problems in an unselected cohort of psychology clinic attenders (n = 188) in a
      London centre comprising 11% females and 89% males. For the cohort 21.4% had a
      suicide attempt recorded, 1 individual (0.5% of the sample) died by suicide and
      the level of suicidal ideation (both clear and vague) was noted for 50.5% of the
      sample. Suicidal issues were noted in 11.9% of referral letters from doctors. HIV
      seems to add an additional suicidal burden to this group where 43.9% attempted
      prior to HIV diagnosis, 41.5% after HIV diagnosis and 14.6% had attempts both pre
      and post-diagnosis. The most common means involved overdosing. HIV related
      issues were often involved in triggers as was bereavement. There was a bimodal
      distribution of suicidal acts according to diagnosis with peaks at or around
      diagnosis and again at end stage illness. The data are discussed in terms of
      prevention, intervention and postvention with specific focus on the need to
      anticipate the mental health needs of people with HIV and AIDS as well as of
      their carers.

PMID- 8664349
TI  - Evidence that autophosphorylation at Thr-286/Thr-287 is required for full
      activation of calmodulin-dependent protein kinase II.
AB  - Calmodulin-dependent protein kinase II (CaM-kinase II) undergoes a very rapid
      autophosphorylation at Thr-286/Thr-287 in the presence of Ca2+/calmodulin and
      ATP/Mg2+, and this has greatly hampered studies on the role of the
      autophosphorylation in the regulation of the enzyme activity, because it has been
      difficult to measure the activity of the non-autophosphorylated enzyme in the
      presence of Ca2+/calmodulin. In the present study, this difficulty was overcome
      by using adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) in place of ATP. When
      the enzyme was assayed with 2 microM ATP gamma S and 200 microM syntide-2 at 5
      degrees C in the presence of Ca2+/calmodulin, the linear reaction rate of
      thiophosphorylation of syntide-2 was much slower than that of the enzyme which
      had previously undergone autothiophosphorylation. Under the limiting assay
      conditions, thiophosphorylation of the enzyme did not occur significantly during
      assay. Using this assay condition, activation by autothiophosphorylation was
      examined. When CaM-kinase II was autothiophosphorylated at 5 degrees C, the
      concomitant stimulation of both activities in the presence and absence of
      Ca2+/calmodulin was observed. The activity of the recombinant wild-type enzyme in
      the presence of Ca2+/calmodulin as well as in its absence was also markedly
      activated upon autothiophosphorylation, whereas those of the recombinant mutated
      enzyme, whose Thr-287 was replaced by Ala, was not activated at all. These
      results provide strong support for the contention that CaM-kinase II initially
      possesses a basal low level of the total activity and that the initial rapid
      autophosphorylation on Thr-286/Thr-287 results in full activation of the enzyme.

PMID- 8664351
TI  - Suicidal behaviour and HIV infection--is there a link?
AB  - The association between suicidal behaviour and HIV infection has been the subject
      of much attention in recent years. In this paper we review the evidence about the
      prevalence of suicide, suicidal ideation and deliberate self-harm in individuals
      with HIV infection. Finally we discuss the significance of the findings, in
      particular some of the methodological problems encountered in this field.

PMID- 8664352
TI  - Epidemiology of suicide among persons with AIDS.
AB  - In spite of the attention devoted by researchers and clinicians to the suicidal
      risk of AIDS patients, the magnitude of the phenomenon has not yet been
      clarified. Indeed, some authors have found a rate of suicide among subjects with
      AIDS 66 times higher than that of the general population (Marzuk et al., 1988a),
      whereas others report that the number of documented suicides represents only a
      small proportion of all deaths in AIDS patients (Engelman et al., 1988).
      Methodological differences in the sampling strategies, in the definition of
      suicidality and in the criteria followed to ascertain a suicide case can account,
      at least in part, for such discrepancies. Several potential risk factors
      (neuropsychiatric morbidity, alcohol and drug abuse, behavioural disorders, etc.)
      are currently believed to increase the suicide risk of AIDS patients. Their role,
      however, is still controversial. This paper summarizes the literature published
      on completed suicide in AIDS subjects, with special emphasis on the
      methodological problems that can be identified in this research area.

PMID- 8664353
TI  - HIV and suicide in Hamburg.
AB  - Established data relating to HIV infection, AIDS, drug user related deaths and
      suicides were evaluated at the Institute of Forensic Medicine in Hamburg in order
      to gain an insight into suicide and HIV. There was no evidence of an increased
      suicide ratio among HIV infected drug users. The drug aid system appears to be
      relatively well organized. In this group the risk of death is not dependent on
      HIV infection status or concomitant disease, but on overdosing. The need for
      detailed studies is obvious. There was no obvious increase in the suicide ratio
      among all HIV infected persons and AIDS cases. From the point of view of forensic
      medicine the number of completed suicides with HIV present was low (3 cases per
      year reported from the central morgue). The work of the support system in Hamburg
      seems to be successful, but there may be a relevant number of undetected cases.
      Up to now the data available about individual cases are inconclusive. An
      interdisciplinary European effort may be helpful in order to elucidate the
      problem from the point of view of different support and registration system for
      people with HIV infection.

PMID- 8664354
TI  - AIDS and suicide issues in Spain.
AB  - Current suicidality and other characteristics were assessed in 442 HIV-infected
      patients, independent of clinical stage, who had been referred to the
      Consultation Liaison Psychiatrist from an Infectious Disease Unit of a General
      Hospital in Spain. The referrals were made over a period of 7 years (1988-1994).
      Suicidality was categorized as suicidal thoughts (5 patients), suicidal
      equivalents (5 patients) and suicidal attempts (17 cases). Of a total of 27
      cases, two died as a result of suicide. The number of known suicide deaths was
      lower than expected. However, these results may show an underestimate due to the
      difficulty of differentiating between accidental overdose and actual suicidal
      attempt in intravenous drug-using patients. Health care professionals must be
      aware of the potential for suicidal thoughts and suicidal behaviours in HIV
      positive patients to enable them to provide the necessary support.

PMID- 8664355
TI  - Suicide and custody.
AB  - Custodial settings are recognized as an important context both with respect to
      suicide and self-harm and for HIV prevention and care. This article examines
      briefly what is known about suicide and self harm in relation to custody,
      emphasizing the increased risk of suicide and self-harm with suicidal intent
      among certain subgroups within the custodial population. Subsequently the
      discussion focuses on the current lack of information as regards HIV prevalence
      in custodial settings and on HIV related policy and practice in custody. The
      writer attempts to draw out the implications for HIV related suicide in custody,
      arguing for a rethinking of traditional approaches to suicide in the light of the
      new stresses arising from the advent of HIV and AIDS in custody.

PMID- 8664356
TI  - Drug misuse and suicide: assessing the impact of HIV.
AB  - The mortality rate among drug users is higher than that of the general
      population. There is some evidence that the risk of suicide is also higher,
      although major methodological difficulties tend to cast doubt on their accuracy.
      The factors generally known to be associated with suicide such as mental and
      physical health problems, poor family relationships, social isolation and
      stressful life events are also associated with drug misuse. Illicit drugs may be
      used as a form of self-medication for anxiety and depression, but this draws an
      individual into a life that is likely to increase stress levels. For a drug user
      already stigmatized and detached from conventional society, becoming HIV positive
      can lead to greater stress and isolation. The impact of HIV on individuals
      physically and psychologically damaged by drug misuse is difficult to predict.
      There is little research that is attempting to determine who is most at risk and
      the nature of the factors that will predict an attempt at self-harm. If those who
      are most likely to attempt suicide are to be detected and adequate care provided
      by health professionals, risk and protective factors need to be identified in
      drug-using communities in which HIV is present or likely to occur.

PMID- 8664357
TI  - The risk of suicide in people with haemophilia who are HIV infected.
AB  - The incidence of suicide in the HIV infected haemophilic population of the United
      Kingdom is low. Between 1985, when most patients were tested for HIV infection,
      and 1993 3 possibly HIV-related suicides were reported to Haemophilia Centre
      Directors. It is argued that haemophilia comprehensive care may contribute to
      reducing some of the factors associated with suicide risk, and thus be a reason
      for this low incidence. It is suggested that the pattern of health care delivery
      developed for the haemophilia community might serve as a template for those
      treating others with HIV infection.

PMID- 8664360
TI  - AIDS, euthanasia and grief.
AB  - Almost 50% of people with AIDS in the Netherlands make the necessary arrangements
      for a possible death by the administration of thanatic drugs. In approximately
      50% of those who arranged for it, euthanasia is performed. Euthanasia is a well
      considered decision. By means of euthanasia people with AIDS want to prevent
      unbearable suffering and a degrading existence. Those who have arranged for
      euthanasia were proven to have adapted to the disease better than those who had
      not. No relationship was found between ending life by means of euthanasia and
      complicated grief in survivors. However, if the euthanasia process itself was
      complicated, the risk of complicated grief increased.

PMID- 8664361
TI  - Fear of AIDS and suicide in Finland: a review.
AB  - This review presents data on HIV epidemiology and suicide mortality, and
      summarizes studies on fear of AIDS in completed suicides in Finland. Finland has
      a low prevalence of HIV and a high suicide mortality. A 12-month nationwide
      suicide population, 1987-88 (n = 1397, all HIV negative) at the time of a
      sensational media campaign against HIV included 28 (2%) cases with fear of AIDS
      as a contributing factor. Triggers of fear could be classified in 20 cases:
      persistent symptoms in 10, casual sex contacts in eight, and a TV programme in
      two. The AIDS fear cases were younger, had more major depression and more health
      care contacts than the others. Suicidal fear and underlying depression were not
      being properly identified and treated. Despite recent improvement in media
      reporting, health education and identification of depression, clinical
      experience, help line calls and population surveys indicate that AIDS fear still
      persists in the population, but seems to be less often a contributing factor in
      committed suicides.

PMID- 8664362
TI  - Suicide and AIDS: problem identification during counselling.
AB  - HIV infection brings with it some pertinent aspects that might make those
      infected, and even those affected, vulnerable to suicidal thoughts or actions.
      Health care workers, from varied professional backgrounds, are well placed to
      take a lead in addressing suicidal issues more routinely in the course of
      counselling. To do this effectively they need to be aware of the general signs of
      suicidal ideation as well as those specific to people with HIV infection. Skills
      and knowledge can be acquired to facilitate problem identification during routine
      clinical follow-up of patients.

PMID- 8664363
TI  - Risk of HIV infection in psychiatrically ill patients.
AB  - The growing spread of HIV infection and AIDS incidence has led the medical milieu
      to increase efforts in the study of the at-risk population and in the development
      of prevention programmes. Nevertheless, little attention has been focused on
      psychiatric patients as a vulnerable and disadvantaged segment of the population
      with high risk of HIV infection. In fact, several studies in the last years have
      shown that high-risk behaviour, especially intravenous drug abuse and non
      protected at-risk sexual intercourse, is reported by 20-50% of psychiatric
      patients, particularly those affected by bipolar disorders and schizophrenia. The
      prevalence of HIV infection has also been found to be higher in psychiatric
      patients than in the general population. In general, only a proportion (15-50%)
      of HIV-positive psychiatric patients have knowledge about their serological
      status, while the others do not know that they have been infected. Preliminary
      studies show that educational programmes specifically developed for psychiatric
      patients improved knowledge of HIV infection and reduced the patients' HIV-risk
      behavior. Specific intervention strategies should also be known when dealing with
      mentally ill HIV-positive patients. Open problems and further issues to be
      addressed by future research are discussed.

PMID- 8664364
TI  - Responding to the AIDS epidemic in Asia and the Pacific: report on the Third
      International Conference on AIDS in Asia and the Pacific, Chiang Mai, Thailand,
      17-21 September, 1995.

PMID- 8664365
TI  - WHO Global AIDS Statistics.

PMID- 8664366
TI  - Coping and social support as determinants of quality of life in HIV/AIDS.
AB  - Coping, social support and quality of life (QOL) were examined in 120 HIV+ people
      (mean age = 37). The sample came from ambulatory clinics and drop-in centres in
      Toronto: 29% had AIDS, 35% were HIV symptomatic, and 35% were asymptomatic.
      Information was gathered from self-administered questionnaires. Respondents had
      good levels of social support and used a variety of coping strategies. Their
      scores on the behavioural and subjective measures of QOL were somewhat below
      average. The illness-related measure indicated that their diagnosis had an almost
      neutral effect on QOL and showed several areas where QOL had been positively
      affected. Data from male subjects only (n = 107) were analysed using a
      hierarchical block regression for each QOL measure. Income, emotional social
      support, and problem-oriented and perception-oriented coping were positively
      related to QOL. Tangible social support and emotion-oriented coping were
      negatively related and symptom severity was not related at all. Close friends
      provided most types of support. Although respondents indicated high levels of
      satisfaction with support generally, they expressed a need for more emotional
      support. Unemployment was high despite participants being relatively healthy and
      well-educated.

PMID- 8664367
TI  - Characteristics of pregnant HIV-1 infected women in Europe. European
      Collaborative Study.
AB  - There is a growing number of infected women in Europe and an increasing
      proportion of these have acquired their infection through heterosexual contact.
      Most infected women are of childbearing age and thus increasing numbers of
      children are at risk of acquiring infection. In this paper we examine the socio
      demographic characteristics and trends in mode of acquisition of infection of
      1690 infected women from 7 countries enrolled in the European Collaborative
      Study, a prospective multi-centre study of children born to women known to be HIV
      infected at or before the time of delivery. The majority of women were white,
      primiparae, married or cohabiting and born in Europe. Two-thirds had a history of
      injecting drug use (IDU), most commonly involving heroin. Although patterns of
      transmission varied by centre, there was a relative increase in heterosexual
      transmission over the study period. A history of needle-sharing among IDUs was
      common, but needle-sharing during pregnancy significantly declined between 1987
      and 1994.

PMID- 8664368
TI  - Trends in heterosexual tertiary students' knowledge of HIV and intentions to
      avoid people who might have HIV.
AB  - This study investigated trends in HIV knowledge and endorsement of social
      avoidance of people who might be infected with HIV. The respondents (n = 7387)
      were self-identified heterosexual students. Most of them (n = 6500) were first
      year behavioural or biological sciences students from annual surveys (1988-1995)
      at Macquarie University. The others (n = 887) were from four biennial (1987-1993)
      random samples of all students below 30 years of age at the University of Sydney.
      Students at both campuses completed self-administered questionnaires. Nine items
      were used to compute Partner Distinction Scale scores which indicated whether
      students had accurate knowledge that HIV may be transmitted through specific
      sexual practices with either casual or regular partners. Eleven items contributed
      to a Social Avoidance Scale. At Macquarie, male students had more accurate
      knowledge than female students, [F(1, 6024) = 9.20, p < 0.003], but at Sydney
      there were no significant sex differences in knowledge. Male students endorsed
      greater social avoidance at both Macquarie, [F(1, 6421) = 195.57, p < 0.00005],
      and Sydney, [F(1, 881) = 32.41, p < 0.00005]. Multiple linear regression on
      social avoidance revealed a significant reduction in social avoidance over time,
      with more rapid decrease among male students. Whereas less social avoidance was
      partly attributable to better knowledge over time, it is concluded that the
      improved social climate towards those most affected by HIV is mainly due to a
      shift in cultural norms.

PMID- 8664369
TI  - The stressors and stress of being HIV-positive.
AB  - Questionnaires were administered to 105 HIV-positive men to assess their
      stressful life events, rated stress, unhealthy behaviours, and psychological
      adjustment. Two hypotheses about the effects of stressors and stress were tested.
      It was found that HIV-positive men experience high numbers of stressors and
      elevated levels of perceived stress and depression. Stressors in the areas of
      relationships, finances, and the illness of others were the most problematic and
      were associated with more depression. Rates of alcohol consumption, smoking, and
      unsafe sexual behaviours were fairly high. There were some modest, but
      significant positive correlations between stressors, stress, and risky
      behaviours. Number of stressors was associated with more alcohol consumption and
      perceived stress was positively related to more tobacco use and unsafe sexual
      behaviours. The high levels of stress and stressors and negative effects of
      stressors have both theoretical and practical implications.

PMID- 8664370
TI  - AIDS prevention training for pharmacy workers in Mexico City.
AB  - Mexican pharmacies play an important adjunct health care role in sexually
      transmitted disease prevention and treatment. In light of the rapid spread of the
      AIDS pandemic, research was initiated in 1989 to investigate the feasibility of
      pharmacies assisting in AIDS and STD prevention and control through community
      education and condom promotion. This study was implemented in three stages: a
      needs assessment, development of a training course and complementary materials,
      and an evaluation of the course and materials. The instruments used in the needs
      assessment were a KAP questionnaire and 'mystery shopper' visits to pharmacies.
      The evaluation design utilized pre- and post-tests, condom sales tracking and
      'mystery shopper' visits. The needs assessment found that pharmacy employees have
      some basic knowledge about AIDS and STDs, but lack important information and do
      not communicate effectively with clients in spite of client interest in these
      topics. Pharmacy workers expressed great in learning more about AIDS and STDs.
      The evaluation of the intensive 8-hour course and supporting materials showed
      that, when given together, the course and materials increased short term
      knowledge about AIDS and condom use. However, the interventions were less
      successful in achieving longer term information retention, transfer of knowledge
      to clients or in influencing condom sales. Adjustments in the training course
      content and in participant recruitment strategies are recommended.

PMID- 8664371
TI  - Regional training in AIDS prevention for health and behavioural science leaders
      in north-eastern Brazil.
AB  - This article reports results of a World AIDS Foundation-funded training programme
      in North-Eastern Brazil. Training objectives were: (1) to increase the
      effectiveness of existing medical and behavioural HIV-related services; (2) to
      prepare professionals to implement and evaluate social skills-based AIDS
      prevention programmes incorporating metacontingency systems; (3) to prepare
      professionals to disseminate training content in North-Eastern Brazil; and (4) to
      promote local involvement in regional AIDS programme planning. Fifty-eight health
      and behavioural sciences leaders from 5 North-Eastern Brazilian states
      represented a variety of institutions actually or potentially involved in AIDS
      prevention. Training activities focused on programme planning and evaluation and
      social skills training. Written pre- and post-test data indicate that all
      participants had a basic understanding of AIDS transmission at baseline.
      Significant knowledge increases (p < 0.01) resulted in all domains trained except
      for programme evaluation. For the two social skills evaluated (Condom Use
      Negotiation and Social Skills Trainer), significant improvements (p < 0.01)
      resulted in verbal and non-verbal content, assertiveness and anxiety, with the
      exception of near-significant levels (p < 0.10) achieved for assertiveness and
      anxiety on the 'Trainer' skill. Participants cofacilitated follow-up trainings in
      their respective states. These trainings demonstrated a successful model for
      technology transfer. More focused training is needed in programme design and
      evaluation methods.

PMID- 8664372
TI  - Risk practices for HIV infection and other STDs amongst female prostitutes
      working in legalized brothels.
AB  - Most research investigating risk practices for HIV infection and other STDs
      amongst sex workers has focused on street prostitutes to the exclusion of those
      prostitutes who work in different sections of the industry. This is largely a
      consequence of methodological difficulties in accessing prostitutes other than
      those who work on the streets. HIV prevention research and interventions must
      address the fact that risk practices may vary according to the type of
      prostitution engaged in. This paper reports on risk practices for HIV infection
      and other STDs amongst prostitutes working in legalized brothels in Victoria,
      Australia. A self-administered questionnaire was distributed by representatives
      of a sex worker organization whose collaboration was an important factor in
      obtaining a large sample of prostitutes. The study found low levels of risk
      practices for prostitutes working in legal brothels in Victoria. The major risk
      practices indentified were injecting drug use and condom non-use with non-paying
      partners.

PMID- 8664373
TI  - Home medication injection among Latina women in Los Angeles: implications for
      health education and prevention.
AB  - Reuse of needles and syringes after home injection of medications and vitamins
      may be a risk for transmission of HIV. An exploratory study was done to determine
      (1) how commonly injectable medications were used in the home; (2) whether
      needles and syringes were reused; and (3) common practices for cleaning needles
      and syringes. A survey was conducted of low income Latina women (n = 216) who
      were attending a Public Health Foundation nutrition programme for women, infants
      and children (WIC) in Los Angeles. To clarify and expand on the survey findings,
      focus group interviews were done with an additional 55 women attending WIC.
      Quantitative data were analysed using descriptive and comparative statistics.
      Qualitative data were subjected to content analysis. The use of injectable
      medications purchased in Mexico was fairly common (43.5%); reuse of disposable
      needles and syringes (48%) and sharing (36%) among injectors were also common.
      Methods of cleaning needles and syringes were inadequate to CDC recommended
      guidelines. Injectors and non-injectors differed significantly in ethnicity,
      religion, and marital status. The only significant predictor of medication
      injection was educational level. Analysis of qualitative data revealed the
      reasons that Latina subjects were injecting medication; how they were
      transporting medicines from Mexico; and how they were cleaning their equipment.
      The practical implications for health education and prevention programmes should
      include an awareness that home use and reuse of needles for injection of
      medications may be common in some social groups and that knowledge of the
      potential dangers in reuse and sharing of needles may not extend to home
      medication injection.

PMID- 8664374
TI  - End-of-the-year potpourri--1995.

PMID- 8664375
TI  - Activation of the radiosensitive EGR-1 promoter induces expression of the herpes
      simplex virus thymidine kinase gene and sensitivity of human glioma cells to
      ganciclovir.
AB  - Herein we describe experiments showing that the early growth response gene 1 (EGR
      1) promoter is sufficient to confer selective expression of the luciferase gene
      (Luc) in glioma cell lines exposed to ionizing radiation. Activity of the EGR-1
      promoter was investigated in human glioblastoma cells using the plasmid vector,
      pEGR-Luc. The EGR-1 promoter gene directed radiosensitive expression of
      luciferase. This promoter showed high levels of activity (10-fold) in irradiated
      glioma cell lines as compared to basal levels of activity in nonirradiated cell
      lines. Maximum activation was detectable at 1-3 hr after stimulation with 20 Gy.
      The results also demonstrate that cells modified to contain the herpes simplex
      virus-thymidine kinase (HSV-tk) gene under control of the EGR-1 promoter become
      sensitive to treatment with the antiviral agent ganciclovir (GCV), whereas
      nonirradiated cells and nontransfected cells were unaffected by this agent. This
      results suggest that therapeutic genes can be expressed selectively in irradiated
      glioma cells. The results also indicate that the EGR-1 promoter can be used to
      induce exogenous genes selectively in radiation fields used for the treatment of
      malignant brain tumors.

PMID- 8664376
TI  - Lipospermine-based gene transfer into the newborn mouse brain is optimized by a
      low lipospermine/DNA charge ratio.
AB  - Nonviral, plasmid-based gene transfer into somatic tissues offers the prospect of
      various simple and safe therapeutic possibilities as well as applications in
      fundamental research. Although cationic lipids display efficient transfection
      activities in many in vitro systems, only low success rates using these vectors
      in vivo have been reported. We succeeded in defining conditions providing high
      levels of in vivo transfection in the brains of newborn mice. Our hypothesis was
      that conditions favorable for in vitro transfection (highly positively charged
      particles) were unlikely to be appropriate for in vivo conditions. When using the
      cationic lipid dioctadecylamido glycylspermine (Transfectam, DOGS) with a
      cytomegalovirus (CMV)-luciferase reporter gene, the best levels of transfection
      were obtained when using a low ratio of positive charges (supplied by the DOGS)
      to negative charges (carried by the DNA). Moreover, addition of the neutral lipid
      dioleoylphosphatidyl ethanolamine (DOPE) significantly enhanced transfection.
      Expression of the transgene diminished over time, independently of
      lipopolysaccharide content of the plasmid preparation used. This suggests that
      either a mitotic population of cells was preferentially transfected, or that
      promoter silencing was occurring. Histological examination of the spatial
      distribution of a beta-galactosidase-expressing transgene showed numerous groups
      of transfected cells both within the striatal parenchyma and in the
      paraventricular area. Thus, DNA-lipid complexes bearing overall charges close to
      neutrality open promising possibilities for modulating gene expression in the
      developing central nervous system and for therapy in the brain.

PMID- 8664377
TI  - The thymidine kinase/ganciclovir-mediated "suicide" effect is variable in
      different tumor cells.
AB  - The herpes simplex virus thymidine kinase (HSV-TK) converts ganciclovir (GCV)
      into a toxic product and allows selective elimination of TK+ cells in vitro and
      in vivo. It is currently being used in clinical gene therapy trials as a
      therapeutic gene or as a safety marker. We have analyzed the susceptibility of
      different tumor cell lines to the TK/GCV-mediated "suicide" effect. Therefore,
      tumor cells TSA, J558L, EB, and ESB and, as a control, NIH-3T3 cells were
      infected with a retrovirus containing a hygromycin/TK fusion gene. All cell lines
      were sensitive to GCV in vitro; however, the concentration of GCV and the time
      needed to eliminate tumor cells completely considerably varied between different
      tumor cell lines. TSA-TK cells were completely eliminated within 10 days in 1
      microg/ml GCV, whereas ESB-TK cells required 22 days in 10 microg/ml GCV. When
      two cell lines were examined, the differing sensitivity to GCV in vitro
      correlated with the ability to eradicate TK+ tumors in vivo. TSA-TK tumors could
      be eliminated in almost all animals by systemic GCV administration, whereas ESB
      TK tumors were completely resistant. Different sensitivity to GCV was not due to
      different TK expression levels because the cells were similarly resistant to
      hygromycin, and Western blot analysis with an anti-TK antiserum revealed similar
      protein amounts in TSA/TK and ESB-TK cells. Together, the results demonstrate
      that tumor cells are highly different concerning the susceptibility to the TK/GCV
      effect, which, however, may be tested for in vitro.

PMID- 8664378
TI  - High-efficiency transfer of the T cell co-stimulatory molecule B7-2 to lymphoid
      cells using high-titer recombinant adeno-associated virus vectors.
AB  - Adeno-associated virus (AAV) is a single-stranded DNA virus that can either
      integrate or replicate in host cells. Production of recombinant viral particles
      (rAAV) requires expression of the viral structural genes and the viral inverted
      terminal repeats in cis. By using an SV40 replicon to amplify the structural
      genes, the yield of recombinant viral particles was increased 60-fold over a
      nonreplicating helper plasmid. The rAAV particles produced by this system have
      similar physical properties to wild-type particles, including buoyant density,
      size, and morphology. This novel rAAV packaging system was used to produce rAAV
      particles that contain the gene for the T cell co-stimulatory protein B7-2.
      Transduction of the human nonadherent lymphoid cell line LP-1 with these
      particles significantly increased the percentage of cells expressing B7-2 from
      6.8% to 78.0%. Expression of B7-2 in the human lymphoid cell line RPMI-8226 was
      also substantially increased. Targeting of tumor cells grown in suspension was
      hampered by low-efficiency transduction using other viral or nonviral vector
      systems. Our new packaging system for recombinant AAV should allow generation of
      sufficient quantities of B7-2 containing particles to develop tumor vaccines for
      non-Hodgkin's lymphoma.

PMID- 8664379
TI  - Selective uptake of viral and monocrystalline particles delivered intra
      arterially to experimental brain neoplasms.
AB  - In this study we investigated the intra-arterial delivery of viral and nonviral
      particles to experimental brain tumors. A herpes simplex virus (HSV) vector and
      monocrystalline iron oxide nanoparticles (MION) were injected into the internal
      carotid artery of Fisher 344 rats harboring intracerebral 9L gliosarcomas, using
      bradykinin to disrupt the blood-tumor barrier. Brain and internal organs were
      stained both for virus-mediated gene expression and for iron. Quantitative
      comparisons of gene expression and MION uptake with and without blood-tumor
      barrier disruption were performed in the center and at the periphery of the tumor
      mass, as well as in normal brain. In addition, MION distribution was traced in
      vivo by MR imaging. Delivery of HSV into 9L gliosarcoma cells was greatly
      enhanced by intra-carotid bradykinin infusion. Virus-mediated expression of the
      HSV-thymidine kinase (TK) and beta-galactosidase gene products was highest at the
      tumor periphery as compared to the tumor center. Selective HSV infection of
      multiple tumor foci was achieved in both hemispheres without affecting normal
      brain. MION uptake was high at the tumor periphery even without blood-tumor
      barrier disruption. Bradykinin increased MION uptake predominantly in the center
      of the tumor with virtually no effect at the periphery. These findings show that
      selective blood-tumor barrier disruption by bradykinin can be used to enhance HSV
      mediated gene delivery to tumor cells in the periphery of brain tumors. A crucial
      aspect in the treatment of malignant brain tumors is the eradication of tumor
      cells infiltrating the brain; bradykinin may facilitate access of vectors to
      these areas by selective disruption of their neovasculature.

PMID- 8664380
TI  - Pulmonary inflammation induced by incomplete or inactivated adenoviral particles.
AB  - One of the major obstacles to pulmonary-directed gene therapy using adenoviral
      vectors is the induction of inflammation. We investigated whether the adenoviral
      particles that constitute the initial inoculum can serve as an inflammatory
      stimulus, independent of their ability to express genes that they contain. Viral
      particles were prepared that are defective in gene expression by (i) isolating
      particles that have incomplete genomes by selecting those that have buoyant
      densities on CsCl density gradients lighter than complete viruses; and (ii) cross
      linking viral DNA by exposure to ultraviolet light in the presence of 8
      methoxypsoralen. The defective particles retained their icosahedral appearance
      when viewed by electron microscopy but lost their plaque-forming ability on 293
      cells. High doses of intact, incomplete, or inactivated viral particles were
      instilled intratracheally into CBA/J mice, and after 6 days the amount of
      inflammation was quantified by counting inflammatory cells contained within lung
      tissue. We found that the inflammatory responses induced by the incomplete or
      inactivated viral vectors were quantitatively similar to those caused by intact,
      competent viral vectors. We conclude that high doses of adenoviral vectors that
      are used for gene therapy can induce pulmonary inflammation, independent of
      expressing the genes they contain.

PMID- 8664382
TI  - Development of cell lines capable of complementing E1, E4, and protein IX
      defective adenovirus type 5 mutants.
AB  - The cloning capacity of currently available E1- and E3-deleted adenovirus (Ad)
      vectors does not exceed 8 kb. To increase capacity and improve vector safety
      further, we have explored the possibility that Early Region 4 (E4) and the gene
      encoding protein IX (pIX) might also be deleted. To generate cell lines
      expressing sufficient levels of E4 and pIX proteins in trans in addition to E1
      encoded proteins to complement mutations in these genes, we transformed 293 cells
      with constructs containing the E4 transcription unit and pIX coding sequences
      under the control of inducible mouse mammary tumor virus (MMTV) and
      metallothionein promoters, respectively. We obtained two lines, VK2-20 and VK10
      9, that express both E4 and pIX proteins as well as E1. The lines could be
      efficiently transfected with DNA, and allowed the rescue and propagation of an
      adenovirus; recombinant, Ad5dlE3,4, containing a 2.7-kb E3 deletion and a 2.8-kb
      E4 deletion in addition to an insertion of plasmid DNA sequences in E1A. Because
      the E4 sequences within VK2-20 and VK10-9 cells do not overlap with the DNA
      sequence of Ad5dlE3,E4, the probability of regeneration of the wild-type E4
      during virus propagation should be very low. Using the cell lines described in
      this study, it should be possible to generate Ad vectors lacking E1, pIX, E3, and
      E4. This would not only increase capacity over that of currently available
      vectors (to approximately 11 kb) but would also result in more severely
      attenuated vectors than those with deletions only of E1 or of E1 and E3 and,
      hence, safer for use in gene therapy protocols.

PMID- 8664381
TI  - Intracellular immunization against HIV-1 infection of human T lymphocytes:
      utility of anti-rev single-chain variable fragments.
AB  - Genetic therapy offers a potentially promising approach with which to combat
      human immunodeficiency virus type 1 (HIV-1) infections. Several modalities, using
      protein- and RNA-based systems, have recently been shown to inhibit HIV-1
      replication. A single-chain variable fragment (SFv), constructed from the cDNA of
      a monoclonal antibody to the HIV-1 regulatory protein Rev, has been demonstrated
      to potently inhibit HIV-1 replication, when expressed intracellularly in an
      epithelial cell-line (HeLa-CD4). Murine retroviral shuttle vectors, which express
      the anti-Rev SFv moiety, have now been constructed. HIV-1 infection was
      dramatically inhibited in human T-lymphocytic cell-lines, CEM and Sup-T1,
      transduced with these anti-Rev SFv-expressing vectors. This resistance to high
      levels of HIV-1 expression was demonstrated in both mixed populations and clones
      of these cells. Of further potential clinical significance, HIV-1 infection was
      also potently inhibited in human peripheral blood mononuclear cells (PBMC),
      transduced with retroviral vectors expressing the anti-Rev SFv molecule. These
      data suggest that intracellular expression of anti-Rev SFvs, or related
      approaches, may be utilized as genetic therapy, or intracellular immunization,
      for HIV-1 infections in vivo.

PMID- 8664383
TI  - Aerosol-mediated delivery of recombinant adenovirus to the airways of nonhuman
      primates.
AB  - At present, it is conceivable that gene therapy of the cystic fibrosis airway
      epithelium is possible using the direct transfer of a functional human cystic
      fibrosis transmembrane conductance regulator (CFTR) gene to a wide variety of
      patients' tracheo-bronchial cells. Here we describe a novel approach
      (aerosolization) to deliver a replication-deficient adenovirus carrying the CFTR
      gene (Ad.CFTR) to the airways. Results obtained in vitro and in Rhesus monkeys
      suggest that the delivery of recombinant adenovirus as an aerosol is feasible and
      is not associated with severe toxicity after single or double administration
      depending on the Ad.CFTR dose. This study supports the concept of aerosolization
      as a delivery method for adenovirus-mediated lung gene therapy.

PMID- 8664384
TI  - "Prevention" and the goals of genetic medicine.
AB  - Authors participating in the renewed discussion of germ-line gene therapy have
      begun conflating two senses of the term "prevention," which I distinguish as
      "phenotypic prevention" and "genotypic prevention." Phenotypic prevention
      describes medical efforts to forestall the clinical manifestation of a genetic
      disease in an at-risk patient, like newborn screening and dietary prophylaxis for
      phenylketonuria. Genotypic prevention, by contrast, describes efforts to avoid
      the transmission of particular genotypes to the next generation, like selective
      termination following intrauterine diagnosis. Genotypic prevention is either
      performed on behalf of a prospective parent (or two) as a reproductive risk
      reduction strategy, or as a public health intervention to reduce the incidence of
      a disease in the larger population. Conflating phenotypic and genotypic
      prevention in discussions of germ-line gene therapy is dangerous, because it
      blurs the line (well-established in clinical genetics) between medical
      interventions appropriate to prescribe to individuals and families, and
      reproductive choices that should be theirs alone to make. As the new genetic
      medicine emerges, its pioneers should be careful to articulate their professional
      goals in ways that respect that important moral boundary, by explicitly excluding
      genotypic prevention from among them.

PMID- 8664385
TI  - IL-12 gene therapy using direct injection of tumors with genetically engineered
      autologous fibroblasts.

PMID- 8664386
TI  - Department of Health and Human Services, National Institutes of Health.
      Recombinant DNA Advisory Committee minutes of meeting. March 6-7, 1996.

PMID- 8664387
TI  - Beyond social class.

PMID- 8664388
TI  - Positive predictive value of ICD-9 codes in the identification of cases of
      complicated peptic ulcer disease in the Saskatchewan hospital automated database.
AB  - We examined the positive predictive value of the International Classification of
      Diseases, 9th revision (ICD-9), codes used to identify cases of complicated
      peptic ulcer disease from the Saskatchewan Hospital automated database.
      Nonspecific and site- and lesion-specific codes were used in case detection to
      increase the sensitivity of the initial computer search. Review of the hospital
      records of 1,762 potential cases resulted in 1,375 confirmed cases. The positive
      predictive value of site and lesion-specific codes was about 90% and was about
      70% for the nonspecific codes. Almost 50% of cases, however, would have been
      missed if the nonspecific codes had not been used.

PMID- 8664389
TI  - Ambiguities in the IARC criteria for evaluation of carcinogenic risks to humans,
      and a recommendation.

PMID- 8664390
TI  - What explains the public's health?--A call for epidemiologic theory.

PMID- 8664391
TI  - Feasibility of collecting maternal hair samples in studies of reproductive and
      perinatal outcomes.

PMID- 8664392
TI  - Coffee consumption and residual confounding.

PMID- 8664393
TI  - Pesticides and birth defects.

PMID- 8664394
TI  - The rewards of smoking cessation.

PMID- 8664395
TI  - Genital anomalies and risk for testicular cancer in Danish men.
AB  - In a cohort of Danish boys characterized by (1) being born between 1941 and 1957,
      (2) having attended schools in a defined area of Denmark, and (3) having a school
      health record available, 183 were registered in the Danish Cancer Registry with
      testicular cancer diagnosed before January 1, 1985. We selected 366 age- and sex
      matched controls from the same cohort. Using information recorded by school
      physicians, we performed logistic regression analyses to estimate the relative
      risks (RR) associated with various genital anomalies. We found the risk for
      testicular cancer to be raised for men with a history of cryptorchidism [RR =
      5.2; 95% confidence interval (CI) = 2.1-13.0], inguinal hernia (RR = 1.8; 95% CI
      = 0.9-3.7), hypospadias (RR = 4.2; 95% CI = 0.4-42.7), and hydrocele (RR = 2.4;
      95% CI = 0.6-9.0). We observed no decrease in the risk associated with
      cryptorchidism after correction of the maldescent in early childhood. The RR of
      testicular cancer in the contralateral, normally descended testis in unilateral
      cryptorchid men was increased to 3.6. The results add to the growing evidence for
      a common causal factor for both testicular cancer and cryptorchidism and support
      the findings from other studies of associations between other genital anomalies
      involving the closure of the processus vaginalis and the risk of testicular
      cancer.

PMID- 8664396
TI  - Air pollution and hospital admissions for respiratory disease.
AB  - Several recent studies have reported associations between short-term changes in
      air pollution and respiratory hospital admissions. Most of those studies analyzed
      locations where there was a high correlation between airborne particles and
      sulfur dioxide (SO2), and between all air pollutants and temperature. Here, I
      seek to replicate the previous findings in a location where SO2 concentrations
      were trivial, and the correlation between both airborne particles and ozone with
      temperature was considerably lower than in previous studies. I constructed daily
      counts of admissions to all hospitals in Spokane, WA, for respiratory disease
      (International Classification of Diseases, 9th revision, codes 460-519) for
      persons age 65 years and older. I computed average daily concentrations of
      airborne particles whose diameter is 10 microns or less (PM10) and ozone (O3)
      from all monitors in each city, and I obtained daily average temperature and
      humidity from the U.S. weather service. SO2 concentrations in Spokane were so low
      that monitoring was discontinued. I regressed daily respiratory admission counts
      on temperature, humidity, day of the week indicators, and air pollution. I used a
      Poisson regression analysis and removed long wavelength patterns using a
      nonparametric smooth function of day of study. I dealt with a possible U-shaped
      dependence of admissions on temperature and/or humidity by using nonparametric
      smooth functions of weather variables as well. I then examined sensitivity
      analyses to control for weather. Both PM10 and ozone were associated with
      increased risk of respiratory hospital admissions [relative risk (RR) = 1.085;
      95% confidence interval (CI) = 1.036-1.136 for a 50-microgram per m3 increase in
      PM10, and RR = 1.244; 95% CI = 1.002-1.544 for a 50-microgram per m3 increase in
      peak-hour ozone]. The PM10 association was insensitive to alternative methods of
      control for weather, including exclusion of extreme temperature days and control
      for temperature on multiple days. The ozone results were more sensitive to the
      approach for weather control. The magnitude of the PM10 effect in this location,
      where SO2 was essentially not present, and where the correlation between PM10 and
      temperature was close to zero, was similar to that reported in other locations in
      the eastern United States and Europe, where confounding by weather and SO2 is a
      more substantial concern.

PMID- 8664397
TI  - Exact estimates for a rate ratio.
AB  - The incidence rate ratio is a basic measure of association in epidemiology. We
      present a simple and efficient method for computing exact confidence limits for
      the common rate ratio in a series of 2 x 2 tables with person-time denominators.
      The method uses a polynomial multiplication (convolution) algorithm previously
      described for an odds ratio. We also present two tests, one asymptotic, the other
      exact, for evaluating rate ratio homogeneity. We extend these homogeneity tests
      to apply to data where strata have been partitioned into subgroups in which the
      rate ratio is assumed homogeneous within subgroups, but not necessarily between
      them. We conclude with a brief description of a microcomputer program that
      computes exact and asymptotic estimates for both a rate ratio and an odds ratio.

PMID- 8664398
TI  - Perinatal factors and risk of breast cancer.
AB  - A high level of endogenous estrogen in utero has been hypothesized to be a
      possible risk factor for breast cancer. We used information from two population
      based case-control studies to investigate the relation between perinatal factors
      and risk of invasive breast cancer among women age 21-45 years (746 cases, 960
      controls) and women age 50-64 years (401 cases, 439 controls). Breast cancer
      cases were ascertained through a population-based cancer registry, and controls
      were selected by random digit dialing. After adjustment for age, menopausal
      status, and maternal smoking, the birthweight-breast cancer association in women
      age 21-45 years followed a J-shaped curve, with women whose birthweight was less
      than 2,500 gm [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.9-2.0] and
      4,000 gm or more (OR = 1.7; 95% CI = 1.1-2.5) at increased risk. Women age 50-64
      years who were 4,000 gm or more at birth appeared to be at slightly reduced risk
      of breast cancer (OR = 0.6; 95% CI = 0.3-1.1). With the exception of maternal
      smoking, there was little effect of other perinatal factors on breast cancer risk
      in either group. These results support the hypothesized association between
      intrauterine estrogen exposure and subsequent risk of breast cancer.

PMID- 8664399
TI  - Physical activity, waist-to-hip ratio, and other risk factors for ovarian cancer:
      a follow-up study of older women.
AB  - We investigated the association of epithelial ovarian cancer with physical
      activity, waist-to-hip ratio, reproductive factors, and family history of cancer
      in a prospective cohort study of 31,396 postmenopausal women. Ninety-seven women
      developed incident epithelial ovarian cancer over 7 years. The number of
      livebirths was associated with lower risk (multivariate-adjusted relative risks
      for 1-2, 3-4, and > 4 livebirths compared with nulliparity were 0.64, 0.47, and
      0.43, respectively). A family history of ovarian cancer in a first-degree
      relative was associated with a 2.5 times greater risk (95% confidence interval =
      0.90-6.7). Multivariate-adjusted relative risks for the upper three quartiles of
      waist-to-hip ratio compared with the lowest quartile were 2.0, 1.6, and 2.3,
      respectively. Women with "moderate" and "high" levels of physical activity
      compared with those with "low" physical activity had relative risks of 1.4 and
      2.1, respectively. Positive associations of physical activity and waist-to-hip
      ratio with ovarian cancer seem inconsistent with existing theories of ovarian
      cancer pathogenesis.

PMID- 8664400
TI  - Socioeconomic status and the incidence of multiple myeloma.
AB  - This population-based case-control study examined the risk of multiple myeloma in
      relation to socioeconomic status. Subjects included 689 cases with newly
      diagnosed multiple myeloma during 1977-1981 from four U.S. populations and 1,680
      controls selected from residents of these same populations. We collected lifetime
      occupational histories and coded them according to the 1970 Duncan Socioeconomic
      Index and Nam-Powers Socioeconomic Status scores. We classified scores for the
      occupations held the longest, highest ever held, and held most recently into
      quartiles based on the distribution among controls. After adjusting for age
      group, race, and study site, risk of multiple myeloma was inversely associated
      with socioeconomic status scores in both men and women. Risk among persons in the
      lowest quartile of scores was 63% higher (95% confidence interval 21%-119%) than
      that among those in the highest quartile when the highest Nam-Powers score was
      used. Similar trends were evident for all three methods of classifying
      occupational history and for both Duncan and Nam-Power scores. These results
      changed little after removing from analyses occupations previously associated
      with increased risk. The occupation-based scores were stronger predictors of risk
      than years of education. As a proxy measure of occupational, environmental, or
      life-style factors, socioeconomic status may be a clue to etiologic factors for
      multiple myeloma.

PMID- 8664401
TI  - Impact of model-form selection on the accuracy of rate estimation.
AB  - A key assumption underlying the use of model-based estimates in epidemiology is
      that the structural-model form is an adequate mathematical description of the
      dependence of disease occurrence on exposures and covariates (that is, the model
      form is correctly specified). If this assumption is violated, model-based point
      estimators and variance estimators may be biased, standard confidence intervals
      may be invalid, and inferences derived from these estimators may be incorrect. In
      practice, the true structural-model form is usually unknown, and investigators
      frequently use their data to help select a model form. We conducted a simulation
      study to examine the impact of model-form selection on the accuracy of rate
      estimation in cohort-study situations resembling those found in environmental and
      occupational epidemiology. For the situations we examined, the increase in
      variance produced by using model-form selection was often more than offset by the
      corresponding reduction in bias, sometimes resulting in a dramatic increase in
      accuracy. Model-form selection was observed to be most beneficial relative to no
      selection when effects were stronger, the sample size was larger, and the
      candidate model forms included the true model form or allowed the model to more
      closely approximate the true model form. It was least beneficial when effects
      were weak and the sample size was small, even if the candidate model forms
      included the true model form.

PMID- 8664402
TI  - Intraocular melanoma linked to occupations and chemical exposures.
AB  - We conducted a case-control study in the western United States to determine the
      relation between occupations or chemical exposures and increased risk of uveal
      melanoma. Among men (221 patients, 447 controls), we found increased risks for
      occupational groups who had intense exposure to ultraviolet light [odds ratio
      (OR) = 3.0; 95% confidence interval (CI) = 1.2-7.8], welding exposure (OR = 2.2;
      95% CI = 1.3-3.5), and asbestos exposure (OR = 2.4; 95% CI = 1.5-3.9 for most
      likely exposed). The highest odds ratio was for the small number of men (nine
      cases, three controls) who were chemists, chemical engineers, and chemical
      technicians (OR = 5.9; 95% CI = 1.6-22.7). Odds ratios also were elevated for
      exposures to antifreeze, formaldehyde, pesticides, and carbon tetrachloride, but
      these findings, based on recall of specific chemical exposures, are more subject
      to recall bias than the findings based on occupational groups.

PMID- 8664403
TI  - Maternal waist-to-hip ratio as a predictor of newborn size: Results of the Diana
      Project.
AB  - Location of body fat stores, as indicated by waist-to-hip circumference ratio
      (WHR), affects a variety of metabolic processes in women, and some of these
      changes could affect fetal growth during pregnancy. We tested the hypothesis that
      WHR affects fetal growth among 702 participants of the Diana Project, a
      prospective study designed to identify preconceptual exposures related to
      reproductive outcomes. We tested the effect of maternal WHR on the outcomes of
      infant birthweight, length, and head circumference in regressional models that
      included 16 variables such as maternal body mass index, duration of gestation,
      and pregnancy weight gain previously related to birthweight. Maternal WHR was
      related to each measure of newborn size. A 0.1-unit increase in WHR predicts a
      120-gm greater birthweight, a 0.2-inch greater length, and a 0.3-cm greater head
      circumference. We conclude that WHR is related to fetal growth and that the
      effect of WHR on fetal growth may be mediated by metabolic alterations associated
      with a preponderance of central body fat stores or to other factors closely
      aligned with WHR. The common finding of an independent effect of pregnancy BMI on
      birthweight may be largely attributable to maternal WHR.

PMID- 8664404
TI  - Long-term trends in incidence of and mortality from acute myocardial infarction
      and stroke in women: Analyses of total first events and of deaths in the Uppsala
      Health Care Region, Sweden.
AB  - We studied the trends from 1969 to the mid-1980s in the incidence and mortality
      of acute myocardial infarction and stroke in Swedish women residing in the
      Uppsala Health Care Region. We used data from the Inpatient Care and Causes of
      Death registers to obtain total first event incidence and mortality rates. In our
      population, there were 20,182 acute myocardial infarctions and 30,462 stroke
      events, and 17,359 and 21,336 deaths, respectively. We found an average overall
      annual increase of 1.3% in the age-standardized incidence of acute myocardial
      infarction during the 1970s, followed by decreasing rates during the early 1980s.
      Mortality was virtually unchanged. Notably, among women 45-49 years of age, we
      observed a rising trend during the whole period, whereas in the oldest age
      groups, the increase slowed and reversed in the latter years. Both the incidence
      and mortality for stroke declined steadily: the age-standardized incidence fell
      by an average of 2.1% per year for all stroke and 7.8% for intracerebral
      hemorrhage. The falling rate of stroke was best explained by birth cohort
      effects, with a 30% reduction in women born in 1920 and later as compared with
      those born in 1890. We conclude that important changes in Swedish women's
      cardiovascular health have taken place and that increasing cigarette smoking and
      hypertensive treatment are major determinants.

PMID- 8664405
TI  - Identifying ancestry: The reliability of ancestral identification in the United
      States by self, proxy, interviewer, and funeral director.
AB  - We examined consistency in the classification of ancestry by self, proxy,
      interviewer, and funeral director (on a death certificate) in a sample of the
      U.S. population--the First National Health and Nutrition Examination Survey and
      Epidemiologic Follow-up. Among study subjects for whom comparable ethnic identity
      options were available at both interviews, 58% of subjects specified the same
      identity at two times. Persons who specified four different ethnic backgrounds
      were 3.4 times as likely to change their identity over time as persons specifying
      only one background. Self-classification of ancestry at initial interview was
      consistent with proxy reports at follow-up for 55% of subjects for whom proxy
      information was available. Comparison of the self-classification of ancestry with
      the classification of race by interviewers and by funeral directors indicates
      high consistency for Whites and Blacks and low consistency for American Indians.
      The "measurement" of ancestry (that is, race or ethnicity) is critical to the
      understanding and elimination of differences in health status among racial/ethnic
      populations, but the low reliability of these measures over time and across
      observers complicates the analysis and interpretation of health statistics by
      ancestry, particularly for populations other than White or Black.

PMID- 8664406
TI  - Reproducibility and validity of a self-administered physical activity
      questionnaire for male health professionals.
AB  - We assessed the reproducibility and validity of a self-administered physical
      activity questionnaire used in a prospective study of 51,529 men. The
      questionnaire was administered by mail twice to 238 participants 2 years apart.
      During this interval, the participants completed a past-week recall and a 1-week
      activity diary at four times corresponding to different seasons throughout a
      year. Also, a step test was taken by a subset of the study participants. The
      intraclass correlation coefficients used to measure reproducibility were 0.39 for
      inactivity, 0.42 for nonvigorous activity, and 0.52 for vigorous activity. The
      correlations between diary-based and questionnaire-based activity scores,
      adjusted for variation in the diary measurements, were 0.41 for inactivity, 0.28
      for nonvigorous activity, and 0.58 for vigorous activity. The distribution of
      activity scores was similar between the questionnaires and the average of past
      week recalls, indicating the participants' ability to incorporate seasonal
      variation into their recall on a questionnaire. The correlation between vigorous
      activity and resting pulse was -0.45, whereas, for the pulse rate after stepping,
      the correlation was -0.41. These data indicate that this physical activity
      questionnaire is reproducible and provides a useful measure of average weekly
      activity, particularly vigorous activity, over a 1-year period.

PMID- 8664407
TI  - A meta-analysis of infant diet and insulin-dependent diabetes mellitus: do biases
      play a role?
AB  - We evaluated the relation between early infant diet and insulin-dependent
      diabetes risk with a meta-analysis of 17 case-control studies. A summary of all
      studies indicated a moderate effect for exposure to breast-milk substitutes [odds
      ratio (OR) = 1.38; 95% confidence interval (CI) = 1.18-1.61] and cow's milk-based
      substitutes (OR = 1.61; 95% CI = 1.31-1.98) before 3 months of age. Fourteen
      studies relied on retrospectively collected infant diet data based on long-term
      maternal recall, which may be biased or inaccurate; three studies used existing
      infant diet records to assess exposure, thus lessening the possibility of recall
      bias or inaccurate data. The studies using existing records demonstrated little
      association compared with the studies relying on long-term recall. Studies in
      which the controls had a participation rate that was more than 20% lower than
      that of the cases showed a stronger diabetogenic effect of never being breast-fed
      (OR = 1.58) than studies whose cases and controls had similar participation rates
      (OR = 1.06). Thus, differences in the participation rates of cases and controls
      may have biased the results of these studies. This meta-analysis indicates that
      the weak association between infant diet and risk of diabetes mellitus may have
      methodologic explanations.

PMID- 8664408
TI  - Endometrial cancer following breast cancer: Effect of tamoxifen and castration by
      radiotherapy.
AB  - Tamoxifen, a synthetic antiestrogen, has been shown to be effective in reducing
      mortality from breast cancer and the occurrence of contralateral breast cancer.
      Tamoxifen is now being studied as a preventive of breast cancer among healthy
      women considered to be at high risk; preventive trials are now under way both in
      the USA and in Europe. We undertook a case-control study in Lyon and Dijon,
      France, to assess the effect of tamoxifen and other treatments for breast cancer
      on subsequent endometrial cancer. Through the use of clinicians' surveys in Lyon
      and a population-based cancer registry in Dijon, we identified 43 cases of
      endometrial cancer diagnosed at least 1 year after the diagnosis of breast
      cancer. We matched 177 controls to the cases for age, region, year of diagnosis
      of breast cancer, and survival from breast cancer. Tamoxifen had been used in 67%
      of cases and 60% of controls [odds ratio (OR) = 1.4; 95% confidence interval (CI)
      = 0.60-3.5]. Relative risk of endometrial cancer increased with duration of
      tamoxifen use: less than 2 years, 1.5; 95% CI = 0.44-4.9; 2-5 years, 1.5; 95% CI
      = 0.42-5.6; more than 5 years, 3.5; 95% CI = 0.94-12.7. Radiotherapeutic
      castration increased the risk for endometrial cancer more than tamoxifen (OR =
      7.7; 95% CI = 1.8-32.8).

PMID- 8664409
TI  - Operative factors and the long-term incidence of acute myocardial infarction
      after transurethral resection of the prostate.
AB  - We studied the association between the operative course of transurethral
      resection of the prostate (TURP) and the morbidity of acute myocardial infarction
      (AMI) in a cohort comprising 846 patients who underwent this operation between
      1983 and 1992. Up to the end of 1993, a total of 69 patients had developed AMI,
      of which 10 patients had a reinfarction. The relative risk associated with
      absorption of 500 ml or more of the irrigating medium during surgery was 1.6 [95%
      confidence interval (CI) = 0.9-3.0] for a first-time AMI after TURP, 6.1 (95% CI
      = 1.8-20.7) for a reinfarction, and 2.2 (95% CI = 1.3-3.9) for a first-time or a
      reinfarction combined. A blood loss of 275 ml or more was associated with a
      decreased relative risk (RR = 0.4; 95% CI = 0.2-0.8) of a first-time AMI after
      TURP. Patients who lost less than 275 ml of blood and absorbed 500 ml or more of
      irrigating fluid during surgery had 4.4 times the risk of having an acute
      myocardial infarction (RR = 4.4; 95% CI = 1.7-11.8). These results appear to
      indicate that the operative course of TURP is important to the development of AMI
      over an extended period of time.

PMID- 8664410
TI  - Serum steroid hormone levels, sex hormone-binding globulin, and body mass index
      in the etiology of postmenopausal breast cancer.
AB  - Serum concentrations of estrone, androstenedione, testosterone, and sex hormone
      binding globulin (SHBG) were measured postoperatively in 122 postmenopausal women
      with incident breast cancer and 122 age-matched population controls. After mutual
      adjustment, through conditional logistic regression, between the hormonal
      variables and body mass index (BMI), the odds ratios for increasing control
      defined quartiles of estrone and androstenedione, respectively, were 1.00, 1.44,
      1.76, 1.94 and 1.00, 0.83, 0.97, 2.43; there was no association of testosterone
      with breast cancer risk. Moreover, the odds ratios for increasing quartiles of
      SHBG and BMI were 1.00, 0.72, 0.28, 0.25 and 1.00, 0.39, 0.28, 0.19,
      respectively. This study reveals sharp contrasts in breast cancer risk between
      women with high estrone and low BMI and SHBG, vs women with low estrone and high
      BMI and SHBG.

PMID- 8664411
TI  - [Use of virus-induced damage markers in the diagnosis of viral hepatitis].

PMID- 8664412
TI  - [Diet and precancerous gastric lesions: preliminary results of a sampling study
      of homogeneous population].
AB  - The aim of this study was to analyse the relationship between dietary factors and
      precancerous gastric lesions in the population of a commune in the province of
      Latina which, on the basis of data published by RTP-LT, appears to present a
      striking incidence of so-called diet-dependent tumours. A series of tests was
      used to evaluate the antioxidising (protective) and pro-oxidising (encouraging)
      capacity of the following substances in terms of cancerogenesis: lutein,
      zeoxanthine, cryptoxanthine, lycopene, alpha and beta carotene, total
      carotenoids, tocopherol, retinol, ascorbic acid, cholesterol, HDL cholesterol,
      triglycerides and ceruloplasmin. Two sample populations were enrolled in the
      study: sample A (random) composed of 400 persons (202 males and 198 females) aged
      between 20 and 80 who underwent esophagogastroduodenoscopy and multiple biopsies
      of the gastric mucous; sample B (random), representative of the population,
      composed of 400 persons (200 males and 200 females) aged between 20 and 80, who
      underwent plasmatic assay of lipid and vitamin status. The results of this study
      appear to confirm the hypothesis of a correlation between diet and pre-cancerous
      lesions and suggest that the primary preventive stps take the form of: a) reduced
      intake of animal fat; b) increased consumption of fresh vegetables.

PMID- 8664413
TI  - [What do celiac children eat? Dietary analysis of a group of children with celiac
      disease on a diet].
AB  - A diagnosis of Coeliac Disease (CD) indicates a lifelong compliance to a gluten
      free diet (GFD), which implies a change in deeply ingrained dietary habits and
      may cause dietary imbalances. We studied the dietary intake in a group of
      children with CD on GFD. CD was diagnosed according to Espgan criteria. Strict
      compliance to GFD was ascertained by Hydrogen breath-test. For each patient a
      thorough dietary history was obtained; the Recommended Dietary Allowances (RDA)
      1986/1987--Istituto Nazionale della Nutrizione were used as reference
      measurements. 71.3% of our patients had a daily calorie intake lower than
      recommended (mean +/- 1SD = -110 +/- 389 kcal/day). Calorie deficiency was mainly
      due to a low carbohydrate intake (50.2 +/- 7% of daily calorie intake vs. 59%
      RDA; difference = -4.7 +/- 7%). Fast absorbed simple carbohydrates exceeded by
      46% the recommended 10% ratio to complex carbohydrates. Daily fat intake was
      higher than RDA (+7.7%) in 94.1% of our patients, who obtained from fat 35.7 +/-
      5.2% of their daily calorie intake vs 28% recommended. Saturated to unsaturated
      fat ratio was unbalanced towards saturated fat intake (2.3 +/- 1.1 vs 0.33
      recommended). Coeliac children on a GFD have low caloric and carbohydrate intakes
      and a high fat intake. An unbalance towards simple sugar and saturated fat
      ingestion was detected. A lifelong protraction of these dietary habits may favour
      the onset of metabolic diseases in mature age.

PMID- 8664414
TI  - [Development and validation of QPD 32, a specific questionnaire for measuring the
      quality of life of patients with peptic ulcer].
AB  - Drugs need to be evaluated both in terms of efficacy, safety and regarding the
      patient's perception of his own health status. For these reasons, sensible,
      reliable and patient-oriented instruments are needed, besides the methodologies
      for evaluation of drug efficacy and safety. Such instruments substantially
      evaluate Health related Quality of Life (HrQoL). Concerning gastric acid
      hypersecretion few papers are available, based on HrQoL questionnaires, both
      general and specific. A research project led us to develop through patients and
      physicians involvement, a specific instrument to evaluate HrQoL as to the various
      aspects of the peptic disease. The project started in 1993 through a series of 4
      focus groups with gastroenterologists and patients, followed by the preparation
      of a questionnaire named QPD48. Such instrument was psychometrically validated
      through a study named Herqules 1, involving 176 gastroenterologists and 1774
      patients. The psychometric analysis on QPD48 led to the re-issue of a
      questionnaire named QPD32 with Chronbach's alfa equal to 0.91, based on 3 factor
      referenced subscales evaluating pain, induced anxiety, constrained daily living
      and awareness of symptoms and agents. Concerning the concurrent validity a one
      way analysis of variance showed highly significant differences associated with
      attack frequency with substantial effect sizes ranging from 0.46 to 1.27 of a
      standard deviation in the full scale. QPD 32 is patent protected and will be used
      in clinical trials.

PMID- 8664415
TI  - [Role of the anterior resection in the surgical treatment of rectal cancer.
      Review of the literature].
AB  - In the surgical treatment of rectal cancer, local recurrence has a high incidence
      up to 40% of cases. The introduction of stapling techniques permit the execution
      of conservative surgery with increasing frequency, to which are wrongly
      associated a major rate of local recurrence. In effect in the localization of
      midrectal cancer, at the same stage, the abdominoperineal resection and the
      anterior low resection have the same long term results. Residual disease is due
      to no removing lymphatic perivisceral tissue (mesorectum, pelvic lymphatic cell
      tissue), when is respected a distal clearance from the tumour's margin of 2 cm.
      The authors on the base of their experience and reported data, examine
      pathogenetic factors responsible for local recurrence and curative surgical
      principles. Anterior resection remains the elective operation in midrectal cancer
      when it is realized with completely removal of mesorectum and with "en bloc"
      abdominopelvic lymphadenectomy in selected cases. In Duke's C-D stages the
      preservation of sphincters is always to be preferred, because abdominoperineal
      resection doesn't assure a curative result with a better quality of life in low
      anterior resection.

PMID- 8664416
TI  - [Ion transport in the colon].
AB  - The large bowel daily absorbs passively 1500 ml of water down an osmotic gradient
      created by active electrolyte transports. The system is sustained by the enzyme
      Na(+)-K+ ATPase, the so called sodium-pump, present on the basolateral membrane
      of colonocytes. Some pathologic conditions may increase the amount of
      intraluminal water by inhibiting fluid absorbtion or enhancing fluid secretion.
      Diarrhoea represents the clinical counterpart of these alterations. Three forms
      of diarrhoea can be recognized on the basis of pathophysiological alterations.
      Diarrhoea is due to reduced ionic absorbtion, increased secretion or increased
      endoluminal osmolality. The drugs used to induce bowel actions or gut lavage
      increase also intraluminal water content by modifying transmural ionic
      transports. Laxatives or purges act by increasing either water secretion on
      endoluminal osmolality and therefore may produce systemic idro-electrolyte
      imbalance. To avoid this inconvenient an isosmotic electrolyte balanced
      polyethylene glicol solution (PEG-ELS) has been achieved. In addition orally
      administred PEG-ELS solution cleans the colon during its intestinal transit
      without producing relevant transmural water-ionic movements. Aim of this article
      was to describe the normal ionic transport, and its alterations in pathologic and
      pharmacologic conditions. Details on PEG-ELS were also given. This solution
      provides for an effective colon preparation for endoscopic or surgical procedures
      and resulted to be safe for patients with delicate fluid-electrolyte balance.

PMID- 8664418
TI  - [A rare case of nonmetastatic paraneoplastic hypercalcemia (humoral hypercalcemia
      of malignancy) associated with mucinous carcinoma of the stomach].
AB  - Humoral Hypercalcemia of Malignancy (HHM) is frequently associated with neoplasms
      of lung, kidney and ovary. We described a rare case of Humoral Hypercalcemia of
      Malignancy associated with mucinous gastric carcinoma.

PMID- 8664417
TI  - [HCV superinfection in a chronic carrier of HBV].
AB  - The paper reports a case of acute hepatitis C (HCV) in a patient who was a
      chronic carrier of hepatitis B virus (HBV) during the course of which the authors
      observed a transient HBsAg clearance. The 53-year-old patient was a carrier of
      chronic HBV infection in an integrated minus variant phase. The patient presented
      an abrupt increment in aminotransferase (ALT) which was not compatible with the
      typical "a poussee" progress of atypical chronic HBV hepatitis in that it was
      associated with HbsAg clearance in the absence of signs of superinfection by
      delta hepatitis virus (HDV), with subsequent repositivisation of HBsAg and
      contemporary anti-HCV seroconversion (RIBA positive for C-22, C-33, C-100, 5-1-1)
      on clinical remission. Polymerase chain reaction (PCR) was negative on remission
      for both HBV DNA and HCV. RNA became positive six months afterwards for HCV RNA
      alone; moreover HBsAg, anti-HCV, RIBA C-22, C-33, C-100, 5-1-1 were constantly
      positive, thus further confirming the inhibitory capacity of HCV towards HBV and
      not vice versa, as also shown by the chronic nature of infection and
      deterioration of clinical conditions. The authors conclude by underlining the
      need to assay for HCV RNA using a PCR method in alla cases of re-acutisation of
      chronic hepatitis due to both wild virus B and the domestic virus during the
      course of which HBsAg becomes negative, even transiently, in the absence of Delta
      superinfection.

PMID- 8664419
TI  - [Hepatic echinococcosis].

PMID- 8664420
TI  - Retinoid receptors and keratinocytes.
AB  - In 1987, a tremendous boost in our understanding of the action of dietary vitamin
      A occurred with the discovery and characterization of nuclear receptors for
      retinoic acid, the active form of the vitamin, in the laboratories of P. Chambon
      and R. Evans. They have shown that the nuclear receptors are ligand-activated
      transcription factors capable of specific gene regulation. Since that discovery,
      it has been determined that there are at least six retinoic acid receptors
      belonging to two families, RARs and RXRs, that they are differentially expressed
      in various mammalian tissues, and that they act as homo- and heterodimers
      interacting with other ligand-activated nuclear receptors. The domain structure
      of the receptors has been described, and their DNA-binding, ligand-binding,
      dimerization, and transcriptional activation regions characterized. Among the
      most important retinoid-regulated genes are the homeobox proteins, regulatory
      transcription factors which are responsible for body axis formation, patterning,
      limb formation, and other crucial processes during development. Retinoic acid and
      its receptors also regulate many differentiation markers which are particularly
      important in stratified epithelia, such as skin and oral epithelia. Our increased
      understanding led to improved therapy of a large number of skin disorders,
      ranging from acne to wrinkles and including epidermal and oral carcinomas.

PMID- 8664421
TI  - Current trends in dental composites.
AB  - The clinical performance of dental composites has been significantly improved
      over the past decade through modifications in formulation that include: using
      more stable polymerization promoters for greater color stability; incorporating
      high concentrations of finely ground fillers to produce adequate strength and
      excellent wear resistance while retaining translucency; adding radiopacifying
      agents for improved diagnostics; and utilizing dentin adhesives. However, there
      are problems which limit the use of composites, especially in posterior teeth.
      The materials remain very technique-sensitive, due to the extensive contraction
      which accompanies polymerization and negatively influences marginal sealing. In
      addition, the materials are generally considered to have inadequate mechanical
      properties and wear resistance in contact areas to serve as total replacements
      for amalgams. Current efforts are focusing on several areas, including the
      development of non- or minimally-shrinking dental composites containing spiro
      orthocarbonates as additives to dimethacrylates or epoxy-base resins, and the
      production of alternative filler materials for ideal wear resistance and
      esthetics. This paper reviews the composition and characteristics of current
      dental composites, as well as recent areas of study.

PMID- 8664422
TI  - Genetic influences in caries and periodontal diseases.
AB  - Deciphering the relative roles of heredity and environmental factors ("nature vs.
      nurture") in the pathogenesis of dental caries and diseases of the periodontium
      has occupied clinical and basic researchers for decades. Success in the endeavor
      has come more easily in the case of caries; the complex interactions that occur
      between host-response mechanisms and putative microbiologic pathogens in
      periodontal disease have made elucidation of genetic factors in disease
      susceptibility more difficult. In addition, during the 30-year period between
      1958 and 1987, only meager resources were targeted toward the "nature" side of
      the nature/nurture dipole in periodontology. In this article, we present a brief
      history of the development of genetic epistemology, then describe the three main
      research mechanisms by which questions about the hereditary component of diseases
      in humans can be addressed. A critical discussion of the evidence for a
      hereditary component in caries susceptibility is next presented, also from a
      historical perspective. The evolution of knowledge concerning possible genetic
      ("endogenous", "idiotypic") factors in the pathogenesis of inflammatory
      periodontal disease is initiated with an analysis of some foreign-language
      (primarily German) literature that is likely to be unfamiliar to the reader. We
      identify a turning point at about 1960, when the periodontal research community
      turned away from genetics in favor of microbiology research. During the past five
      years, investigators have re-initiated the search for the hereditary component in
      susceptibility to common adult periodontal disease; this small but growing body
      of literature is reviewed. Recent applications of in vitro methods for genetic
      analyses in periodontal research are presented, with an eye toward a future in
      which persons who are at risk--genetically predisposed--to periodontal disease
      may be identified and targeted for interventive strategies. Critical is the
      realization that genes and environment do not act independently of each other;
      the appearance or magnitude of heritability may differ with various environments.

PMID- 8664423
TI  - Does variability in salivary protein concentrations influence oral microbial
      ecology and oral health?
AB  - Salivary protein interactions with oral microbes in vitro include aggregation,
      adherence, cell-killing, inhibition of metabolism, and nutrition. Such
      interactions might be expected to influence oral ecology. However, inconsistent
      results have been obtained from in vivo tests of the hypothesis that quantitative
      variation in salivary protein concentrations will affect oral disease prevalence.
      Results may have been influenced by choices made during study design, including
      saliva source, stimulation status, control for flow rate, and assay methods.
      Salivary protein concentrations also may be subject to circadian variation.
      Values for saliva collected at the same time of day tend to remain consistent
      within subjects, but events such as stress, inflammation, infection,
      menstruation, or pregnancy may induce short-term changes. Long-term factors such
      as aging, systemic disease, or medication likewise may influence salivary protein
      concentrations. Such sources of variation may increase the sample size needed to
      find statistically significant differences. Clinical studies also must consider
      factors such as human population variation, strain and species differences in
      protein-microbe interactions, protein polymorphism, and synergistic or
      antagonistic interaction between proteins. Salivary proteins may form heterotypic
      complexes with unique effects, and different proteins may exert redundant
      effects. Patterns of protein-microbe interaction also may differ between oral
      sites. Future clinical studies must take those factors into account. Promising
      approaches might involve meta-analysis or multi-center studies, retrospective and
      prospective longitudinal designs, short-term measurement of salivary protein
      effects, and consideration of individual variation in multiple protein effects
      such as aggregation, adherence, and cell-killing.

PMID- 8664424
TI  - Prenatal craniofacial development: new insights on normal and abnormal
      mechanisms.
AB  - Technical advances are radically altering our concepts of normal prenatal
      craniofacial development. These include concepts of germ layer formation, the
      establishment of the initial head plan in the neural plate, and the manner in
      which head segmentation is controlled by regulatory (homeobox) gene activity in
      neuromeres and their derived neural crest cells. There is also a much better
      appreciation of ways in which new cell associations are established. For example,
      the associations are achieved by neural crest cells primarily through cell
      migration and subsequent cell interactions that regulate induction, growth,
      programmed cell death, etc. These interactions are mediated primarily by two
      groups of regulatory molecules: "growth factors" (e.g., FGF and TGF alpha) and
      the so-called steroid/thyroid/retinoic acid superfamily. Considerable advances
      have been made with respect to our understanding of the mechanisms involved in
      primary and secondary palate formation, such as growth, morphogenetic movements,
      and the fusion/merging phenomenon. Much progress has been made on the mechanisms
      involved in the final differentiation of skeletal tissues. Molecular genetics and
      animal models for human malformations are providing many insights into abnormal
      development. A mouse model for the fetal alcohol syndrome (FAS), a mild form of
      holoprosencephaly, demonstrates a mid-line anterior neural plate deficiency which
      leads to olfactory placodes being positioned too close to the mid-line, and other
      secondary changes. Work on animal models for the retinoic acid syndrome (RAS)
      shows that there is major involvement of neural crest cells. There is also major
      crest cell involvement in similar syndromes, apparently including hemifacial
      microsomia. Later administration of retinoic acid prematurely and excessively
      kills ganglionic placodal cells and leads to a malformation complex virtually
      identical to the Treacher Collins syndrome. Most clefts of the lip and/or palate
      appear to have a multifactorial etiology. Genetic variations in TGF alpha s, RAR
      alpha s, NADH dehydrogenase, an enzyme involved in oxidative metabolism, and
      cytochrome P-450, a detoxifying enzyme, have been implicated as contributing
      genetic factors. Cigarette smoking, with the attendant hypoxia, is a probable
      contributing environmental factor. It seems likely that few clefts involve single
      major genes. In most cases, the pathogenesis appears to involve inadequate
      contact and/or fusion of the facial prominences or palatal shelves. Specific
      mutations in genes for different FGF receptor molecules have been identified for
      achondroplasia and Crouzon's syndrome, and in a regulatory gene (Msx2) for one
      type of craniosynostosis. Poorly co-ordinated control of form and size of
      structures, or groups of structures (e.g., teeth and jaws), by regulatory genes
      should do much to explain the very frequent "mismatches" found in malocclusions
      and other dentofacial "deformities". Future directions for research, including
      possibilities for prevention, are discussed.

PMID- 8664426
TI  - [The Manual of the Primary Care Tutor].

PMID- 8664425
TI  - [How to evaluate microalbuminuria?].

PMID- 8664427
TI  - [Ambulatory care of chronic headache secondary to abuse of ergot preparations].
AB  - OBJECTIVE: To analyse the results of out-patient treatment with diminishing doses
      of oral dihydroergotamine for patients with chronic migraine resulting from
      ergotics abuse. DESIGN: A prospective and descriptive intervention study.
      SETTING: County hospital. Neurology out-patient clinic. PATIENTS: All the
      patients with chronic migraine as a side-effect of abuse of ergotic preparations
      who were referred to neurology out-patients over 18 months. INTERVENTIONS: 1)
      Patients were told verbally of the causes of their migraine; 2) suppression of
      the ergotics, using diminishing doses of dihydroergotamine (Dihydergot gotas); 3)
      Prophylactic treatment with flunarizine (Sibelium); 4) Symptomatic treatment with
      sodic naproxen (Antalgin 550); 5) monthly and three-monthly check-up.
      MEASUREMENTS AND MAIN RESULTS: Over 18 months 25 patients with migraines due to
      ergotic abuse (6.7% of total migraines) were included. 4 were men; 21 women.
      Their average age was 43 (SD: 13). At one month the response was excellent in 19
      patients (76%), good in 3 (12%) and bad in 3 (12%). At three months, the response
      was excellent in 17 patients (68%), good in 4 (16%), bad in 2 (8%) and 2 did not
      attend for the check-up (8%). CONCLUSIONS: 1) Out-patient treatment with
      diminishing doses of oral dihydroergotamine is effective in treating chronic
      migraine due to ergotics abuse. 2) The general practitioner should intervene in
      the identification and prevention of ergotics abuse.

PMID- 8664428
TI  - [Prevalence of drinkers at risk and associated factors among men attending
      primary care clinics].
AB  - OBJECTIVES: To quantify the prevalence of risk drinkers among men seeking health
      care, establish consumption patterns and relate them to socio-demographic
      features and health habits. DESIGN: Crossover study. First phase of an
      experimental study. SETTING: Four primary care teams in Area 10, Madrid.
      PATIENTS: Males between 18 and 65 who attended for on-demand medical care. A
      systematic sample was selected (n = 562). MEASUREMENTS: A questionnaire
      collecting socio-demographic characteristics, health habits and alcohol
      consumption (frequency, consumption pattern, intake of Weekly Units of alcohol
      (WU) and alcohol-related problems). 94.2% replied. 38% were habitual drinkers
      (drink four or more days a week), while 18.9% were week-end drinkers. Prevalence
      of drinkers consuming over 21 WU was 24.8%; and over 35 WU, 16.2%. Whether the
      cut-off point was fixed at 21 or 35 WU. The alcohol taken was related to
      educational level, physical exercise, smoking and taking other drugs. On average,
      single people, smokers, other drug-consumers, ex-drinkers and habitual drinkers
      were those who displayed most problems connected with alcohol consumption.
      CONCLUSIONS: There is a similar profile of health habits for the groups consuming
      over 21 WU and 35 WU, which should make preventive care pay attention to both
      groups of drinkers.

PMID- 8664429
TI  - [Carpal tunnel syndrome in primary care. Impact of workplace risks].
AB  - OBJECTIVE: To describe a series of cases of carpal tunnel syndrome (CTS)
      diagnosed at our health centre, with an analysis of the influence of work
      activity. DESIGN: A retrospective and descriptive study of a series of cases.
      SETTING: Patients on two medical lists who sought health care. PARTICIPANTS: 27
      people diagnosed as having CTS. MEASUREMENTS AND MAIN RESULTS: We selected all
      the cases of CTS diagnosed according to the NIOSH criteria. We analysed symptoms,
      signs, additional tests and work risks. 24 out of the 27 cases were women. 100%
      had suggestive symptoms and 48.15% were affected bilaterally. The Tinell sign was
      positive in 5 cases, the Phalen in 7 and both in 11. 17.4% tested normal. We
      could see a diagnostic EMG in 19 cases. 59.2% were aged between 40 and 60. In all
      the cases we detected workplace risk factors: 18.5% housewives, 14.8% working in
      canning factories and dressmaking, 11.1% working in canning factories and
      dressmaking and shops/bars, 7.4% were cleaners, canning and fur operatives and
      mechanics. 3.7% worked at sewing shoes and in agriculture. As an accompanying
      pathology we detected 14.8% with obesity, 7.4% tenosynovitis and wrist fractures.
      For 3.7% CTS was a side-effect of diabetes, cervical arthrosis, ACV and
      dermatomyositis. 55.5% had non associated pathology. CONCLUSIONS: 1) The
      population of Molina de Segura can be considered at high risk of developing CTS.
      2) In our environment women seek care for CTS much more often. 3) Most of our
      patients develop the condition in the workplace.

PMID- 8664430
TI  - [Evaluation of the system of direct purchase and distribution of urinary
      incontinence pads in primary care centers].
AB  - OBJECTIVE: To evaluate the impact of the pilot experience of direct purchase and
      distribution of incontinence diapers in primary health care centres of the
      Balearic Islands after 10 months of implementation. DESIGN: Comparison of
      diapers's public expenditures and use during 10 months of pilot experience
      (9/1/1994-6/30/1995: POSTC) to a same length period prior to pilot experience
      implementation (11/1/1993-8/31/1994: PREC). SETTING: Primary health care centres
      of the Balearic Islands (Spain). MEASUREMENTS AND RESULTS: Monthly mean of
      packages used in the PREC period was 3,246 packages/month, whereas monthly mean
      of packages used in POSTC period was 4,541 packages/month. It means an increase
      of 1,295 packages/month. The mean price per package got by public tender was
      4,426 ptas., nearly half of mean unit price per package paid through the usual
      dispensing system of medical prescription (8,583 ptas.), thus producing a saving
      of 4,157 ptas. per package. A decreasing trend to the monthly mean of diapers use
      of the PREC period was observed in the last months of the experience. The monthly
      expenditures in diapers was 27,790 milions ptas. in the PREC period and 21,024
      milions ptas. during the POSTC period. CONCLUSIONS: The expected increase in
      diapers use during the first year of implementation of this measure was 34.86%.
      Of this increase, 70.5% is attributed to development of stock in centres and the
      undergoing trend of diapers demand increase observed throughout the country.

PMID- 8664431
TI  - [Analysis of activities of the preventive dentistry service in the Health Area 8
      of the Valencia Autonomous Region].
AB  - OBJECTIVES: We describe and analize the activities we carried out in a surgery
      from a preventive dentistry unit. DESIGN: Longitudinal descriptive study from
      1993 since 1994. SETTING: Health Area 8 from the Valencian Autonomous Region.
      PARTICIPANTS: Children from 3 to 14 year-old attendant to the preventive
      dentistry unit's surgery (2.497). MEASUREMENTS AND MAIN RESULTS: We visited 5.012
      children. The highest percentage of population corresponded to the zona 4, where
      began at first the preventive service. The activities distribution was as follow:
      oral explorations and plaque control (100%), fluoride topic aplication (90.38%),
      diet control (36.81%), pit and fisure sealants (6.46%), profilaxis (8.71%),
      radiological diagnosis (6.46%), dental emergencies (2.17%). The users origin was:
      38.88% school oral explorations made over 6- and 10-year-old children; 63.71%
      from self-request; and 16.45% sent by other health professionals. 41.42% were
      continuated visits. CONCLUSIONS: Demand of preventive dental services is very
      high in our health area, although incorporation of therapeutic techniques is
      wished by the population. This demand increase as well as the surgery is closer
      to the user. People from big cities are stubborn using these services from
      smallest villages, even having transport facilities. Children start coming to the
      consults between 5-6 year-old, keeping an acceptable control until 12
      approximately.

PMID- 8664432
TI  - [Clinical situation, knowledge and risky behavior of patients with human
      immunodeficiency virus infection attending a health center].
AB  - OBJECTIVE: To establish what information patients diagnosed in our health centre
      as infected by HIV have about their infection, to evaluate possible changes in
      their hazardous behaviour and to establish the monitoring level and stage of the
      condition. DESIGN: An observational study of a crossover nature. Demographic data
      and data on patients' understanding of HIV infection, their hazardous behaviour
      and clinical situation were collected by means of a semistructured survey.
      SETTING: Occidente Health Centre, Cordoba. PATIENTS AND OTHER PARTICIPANTS: 35
      people with HIV positive serology. MEASUREMENTS AND MAIN RESULTS: 92.6% were or
      had been users of parenteral drugs. 40.7% believed they had no health problem;
      33.4% thought that the fact of having HIV antibodies was reversible; and 22.2%
      did not think they transmitted the infection. Their understanding of how
      infection occurred seemed sufficient, but in spite of this 39.1% continued to
      share syringes and 52.2% did not use condoms habitually. 56% had received what
      information they had from health staff; and 56.5% of these thought the
      information was insufficient. 28% did not regularly attend for medical check-ups.
      CONCLUSIONS: Knowing you are an HIV carrier and having adequate information on
      ways of infection appeared to modify hazardous behaviour in our sample, although
      to a still insufficient extent. The establishment of strategies which not only
      inform, but also educate, would be of vital importance in slowing down the
      transmission of the infection.

PMID- 8664433
TI  - [Study of a disease outbreak in a home for the aged].
AB  - OBJECTIVE: To describe an epidemic outbreak in an elderly persons' home. DESIGN:
      A descriptive, longitudinal study. SETTING: Elderly persons' home in the Riaza
      Health District, Segovia. PATIENTS AND PARTICIPANTS: 90 elderly people resident
      at this geriatric centre. MEASUREMENTS AND MAIN RESULTS: Between January 18 and
      25, 1995, there was an epidemic outbreak. Some cases had digestive symptoms:
      diarrhoea and vomiting, but without a temperature. Other cases had respiratory
      symptoms with temperature, cough, expectoration, breathing difficulty and
      myalgia. 25 elderly people were affected: 68% suffering the respiratory symptoms;
      and 32%, the digestive ones. Three people were admitted to hospital and one died.
      The presence of Rotavirus was found in the faeces of patients with digestive
      symptoms. The study-period had the highest incidence of flu in this Health
      District. 20% of the elderly people were not vaccinated for flu. CONCLUSIONS:
      Elderly persons' homes are an environment which favours the spread of germs which
      can cause epidemic situations.

PMID- 8664435
TI  - [Erroneous interpretations of p values].

PMID- 8664434
TI  - [Inequalities in health at birth: Barcelona, 1990-1991].
AB  - OBJECTIVE: To study demographic and health related variables included in the
      municipal birth registry. Differences among municipal districts are assessed, as
      an approach to the study of inequalities in pregnancy, in birth and in its care.
      DESIGN: Observational study, based on secondary utilization of vital statistics
      data. SITE: The city of Barcelona (Catalonia, Spain), for the 1990-1991 years.
      PARTICIPANTS: Births from women who are city residents. MAIN RESULTS: Births
      concentrate around maternal ages of 25-29 years and 30-34. Adolescent mothers
      (less than 20 years) represent only a proportion of 1.9% of all births, and
      births from women above 34 years 13.7%, although only 2.1% of all births are from
      mothers above 40 years of age. Low birth weight (less than 2,500 g) occurs in
      5.6% of all births. Preterm births (less than 37 weeks) occur in 4.7% of all
      deliveries. Teen age fertility, births to women above 34 years, low birth weight
      and preterm deliveries are compared across districts. Overall, four out of ten
      women use a public hospital for delivery, but this varies greatly among
      districts. There is no information on the father for 1.6% of all births.
      CONCLUSIONS: The completeness of this information source is high and the
      municipal registry is a useful database for the analysis of inequalities in small
      areas, using health related indicators which have higher frequency than more
      traditional indicators based on rare events (such as infant mortality).
      Differences among areas are found, related to life conditions and to prenatal and
      birth care.

PMID- 8664436
TI  - [Ten years of the journal Atencion Primaria (1984-1993): a bbibliometric and
      subject analysis].

PMID- 8664437
TI  - [Diagnosis of hypercholesterolemia].

PMID- 8664438
TI  - [A health system that does not live up to expectations. A primary health care
      team attempt at an integrated approach to a case].

PMID- 8664439
TI  - [Should we assess the cost of a drug before prescribing it?].

PMID- 8664440
TI  - [Study of an outbreak of gastroenteritis transmitted by water].

PMID- 8664441
TI  - Role of IL-1 beta and corticosteroids in the regulation of the C/EBP-alpha, beta
      and delta genes in vivo.
AB  - We have examined the regulatory effects of interleukin 1 beta (IL-1 beta) on the
      activation of three different isoforms of the C/EBP family of transcription
      factors (alpha, beta and delta), in hepatocytes of normal and adrenalectomized
      (ADX) rats. C/EBP-beta and delta mRNA levels were enhanced by IL-1 beta, whereas
      that of C/EBP-alpha was not affected by treatment with this interleukin in both
      normal and adrenalectomized rats. The magnitude of the induction was strikingly
      higher for C/EBP delta in adrenalectomized animals, indicating a suppressive
      effect of corticosteroids in the IL-1 beta regulatory pathway. The pattern of
      C/EBP protein synthesis did not always reflect the mRNA findings. For C/EBP-alpha
      the protein synthesis was higher than expected in IL-1 beta treated ADX animals
      compared to normal rats. The pattern of C/EBP synthesis was the one that better
      reflected the pattern of the mRNA transcription. Differently, the induction of
      C/EBP-delta was not as pronounced as that of the corresponding mRNA in IL-1 beta
      treated ADX rats. Hormonal modulation of C/EBP transcription factors was studied
      in parallel with the hormonal induction of the Alpha-1-Acid Glycoprotein (AGP)
      gene, which is known to be highly induced in rat liver during the acute phase
      response. This short report also indicates an important role of corticosteroids
      in the regulation of transcription factors involved in IL-1 beta signalling
      during the acute phase response.

PMID- 8664442
TI  - Functional comparisons of different tumour necrosis factor receptor/IgG fusion
      proteins.
AB  - Nine different IgG fusion proteins and one non-fusion protein, all containing
      sequences from the extracellular domain of either of two human TNF receptors,
      were compared for their ability to bind and inhibit human TNF-alpha or TNF-beta.
      The fusion proteins differed with respect to TNF receptor type (p55 or p75 TNF
      receptor), receptor valency (one, two or four receptor domains per molecule), the
      presence or absence of a CH1 domain in the IgG constant region, and the
      proportion of the extracellular domain included in the construct. In vitro TNF
      binding assays and cytotoxicity assays indicated that, of the constructs that
      bound TNF, the greatest difference in affinity and neutralizing capability was
      between monovalent and bivalent receptor constructs. Differences were also noted
      between tetravalent and bivalent versions of p55 fusion proteins, as well as
      between a p75 fusion protein comprising the complete extracellular domain and one
      lacking the C-terminal 53 amino acids of the extracellular domain. p55 constructs
      that included only the second cysteine-rich domain (CRD) or only the second and
      third CRDs showed no TNF binding activity. The presence or absence of an IgG CH1
      domain made no difference in the ability of fusion proteins to neutralize TNF
      alpha or TNF-beta. Animal experiments comparing the tetravalent and bivalent p55
      fusions and the effects of the CH1 domain did not show significant differences in
      their ability to protect mice from endotoxin-induced lethality, although the p55
      fusion proteins appeared to be more protective than the p75 fusion proteins.
      Thus, this study has identified structural modifications to TNF receptor/IgG
      fusion proteins which have differing effects on their neutralizing ability
      towards TNF-alpha or TNF-beta.

PMID- 8664443
TI  - Human cytokines interleukin (IL)-3 and IL-6 affect the growth and insulin binding
      of the unicellular organism Tetrahymena.
AB  - Interleukin (IL)-3 and IL-6 significantly increase the growth rate of the
      unicellular organism, Tetrahymena. The effect elicited by IL-3 is long lasting as
      it was also detectable after 20 generations. Effect of IL-6 was detectable as
      long as the substance was present in the cell culture. Pretreatment with IL-3 did
      not enhance the proliferative response to subsequent IL-3 treatment, but the
      second exposure to IL-3 considerably depressed the active proliferation of
      Tetrahymena cells. However, a positive 'priming effect' elicited by IL-6 resulted
      in an increased growth rate following repeated IL-6 stimulation. Insulin binding
      to the plasma membrane of Tetrahymena was increased by IL-6 but not by IL-3 after
      24 hours, and this enhancement appeared even after one hour incubation. If the
      cells were pretreated with insulin, IL-6 did not influence insulin binding, while
      an inhibition by IL-3 was observed. These results direct attention to the
      similarities of actions induced by IL-3 and IL-6 at different levels of phylogeny
      probably due to the presence of cytokine receptor-like structures on this
      unicellular organism.

PMID- 8664444
TI  - Rapid and selective induction of blood eosinophilia in guinea pigs by recombinant
      human interleukin 5.
AB  - Interleukin 5 (IL-5) has been implicated as a causal mediator in the development
      of pulmonary eosinophilia and airway hyperreactivity in human asthma. Supportive
      evidence for a pathogenic role of IL-5 in this disease has been provided by
      guinea pig models in which antigen-induced lung eosinophilia and bronchial
      hyperresponsiveness have been specifically attenuated with a neutralizing
      antibody to IL-5. In the present report, we describe a rapid mechanism-based
      model of IL-5-induced eosinophilia in the guinea pig. Our results show that
      intravenous injection of human IL-5 induced a 5-10-fold increase in the
      percentage and number of eosinophils in blood within 1 hour. In contrast,
      neutrophils and mononuclear cells were not recruited during this time. The
      increase in eosinophils was blocked by pretreatment of animals with an anti-IL5
      monoclonal antibody (TRFK5) in doses similar to those which inhibit eosinophilia
      in guinea pig asthma models. Furthermore, dexamethasone, a potent inhibitor of
      eosinophilia in guinea pig asthma, profoundly suppressed the eosinophilia induced
      by human IL-5. This rapid model will be useful for elucidating the eosinophil
      activating properties of IL-5 in vivo and may potentially facilitate the
      development of IL-5 receptor antagonists for the specific blockade of the
      eosinophilic inflammation observed in human asthma.

PMID- 8664446
TI  - Production of interferon gamma messenger RNA by cells of non-immune origin.
AB  - There is general agreement that IFN-gamma is produced only by cells of immune
      origin (T-cells, NK cells, and recently macrophages). However, indirect evidence
      has suggested that undetectable, low levels of IFN-gamma produced by cells of non
      immune lineage, such as the murine line L-929, enhanced the antiviral activity of
      IFNs-alpha and/or beta following induction by agents such as the double stranded
      RNA poly ICLC. Since L-929 cells were one of the prototypic cell lines for
      studying murine IFN induction and action, we felt that it would be important to
      validate this observation by detection of the mRNA for IFN-gamma. If confirmed,
      it might indicate a role for IFN-gamma in non-immune cells. The present
      investigations revealed that mouse L-929 fibroblasts produce IFN-gamma message
      following exposure to conventional IFN-alpha/beta inducers such as poly ICLC or
      Newcastle disease virus. In addition, we found that IFN-gamma itself will induce
      its own message. We further show that this is not a phenomenon isolated to
      transformed cells since we found that normal mouse embryo fibroblasts also
      produced the message, however in a constitutive fashion.

PMID- 8664445
TI  - Leukaemia Inhibitory Factor derived from rat colon carcinoma cells increases host
      susceptibility to tumour growth.
AB  - We have tested Leukaemia Inhibitory Factor (LIF) production by 12 rat colon
      tumour clones isolated from a single cell line that display various degrees of
      tumorigenicity. A highly significantly relationship was found between levels of
      soluble LIF produced by the clones and their in vivo tumorigenicity. Such results
      suggested a role for LIF as a tumour facilitating agent. To test this hypothesis,
      the highly tumorigenic and LIF producing PROb clone was transfected with the LIF
      cDNA in antisense orientation in order to decrease LIF production. Conversely,
      REGb, a low LIF producer that is rejected by syngeneic animals, as well as nude
      mice, was transfected with the LIF cDNA to increase its production. PROb cells
      transfected with antisense cDNA were shown to have decreased LIF production along
      with decreased tumorigenicity. LIF-transfected REGb cells expressing high LIF
      levels still regressed in syngeneic rats, but could form progressive tumours in
      nude mice. We did not detect LIF receptors on PROb or REGb cells and their in
      vitro proliferation was not modified by the addition of exogenous LIF. Therefore,
      LIF was not an autocrine growth regulator for PROb and REGb cells. Instead, LIF
      appears to facilitate in vivo tumour growth, without being an immunosuppressive
      factor sufficient on its own to allow growth of immunogenic cells in fully
      immunocompetent hosts.

PMID- 8664447
TI  - Activation of IL-4 and IL-6 secreting cells by antigen.
AB  - The number, antigenic specificity and phenotype of cells secreting IL-4 and IL-6
      in mice immunized with ovalbumin or keyhole limpet haemocyanin (KLH) in Freund's
      adjuvant (FA) was studied. The frequency of cells producing either of these
      cytokines began to rise 6 days post immunization, peaked at 11-14 days post
      immunization, and fell to background by 21 days. The number of spleen cells
      secreting IL-6 was higher than the number producing IL-4 at all time points.
      Boosting elicited an anamnestic response characterized by a significant increase
      in the number of cytokine secreting cells within 4 days. Cytokine production was
      induced in multiple strains of normal mice, and was critically dependent on the
      use of Complete FA in addition to antigen. Immunization induced IL-4 and IL-6
      production in vivo while 'priming' additional cells to release these cytokines
      when reexposed to soluble antigen in vitro. The latter response was antigen
      specific and was dominated by non-B/non-T cells. Those cells may serve to boost
      the immune response in cases of persistent or repeated antigenic challenge.

PMID- 8664448
TI  - Demonstration of a TH1 cytokine profile in the late phase of NOD insulitis.
AB  - Cells infiltrating the Langerhans' islets of prediabetic NOD females were
      isolated from 6 weeks to 6 months of age. These cells were assayed at a single
      cell level for production of eight different cytokines by intracellular
      immunofluorescent staining. By in vitro stimulation with PMA and ionomycin for 4
      hours the method is enhanced also to detect in vivo preactivated cells. During
      the early phase of insulitis from 6 to 12 weeks of age, mainly the monokines IL-1
      alpha, IL-6, and TNF were detected. After stimulation, also IFN-gamma and low
      numbers of IL-10 and GM-CSF producing cells could be observed, but no IL-2 or IL
      4 was seen. This cytokine pattern correlates with an increasing insulitis, and we
      suggest that these cytokines are important in attracting inflammatory cells to
      the islets, and may cause initial beta-cell destruction. During a later phase,
      between 4 and 6 months, there is a characteristic TH1 cytokine profile with
      production of IL-2 and IFN-gamma occurring after stimulation, as well as
      lymphocytes producing TNF, supposedly TNF-beta. During this period IL-10 was very
      rarely observed, and no IL-4 production could be found throughout the study. This
      indicates the absence of a TH2 cytokine profile in this lesion. In addition IL-6
      production occurs in high frequencies at all ages, also in endocrine islet cells.
      We interpret this as a stress response caused by the inflammatory lesion. Our
      findings show that the effector phase in NOD insulitis is TH1 rather than TH2
      mediated. We also demonstrate that cytokines, that may cause initial tissue
      destruction, are produced during the recruitment of inflammatory cells.

PMID- 8664450
TI  - Nitric oxide: has it progressed from molecule of the year to wonder drug of the
      decade?

PMID- 8664449
TI  - Phenotype and frequency of cells secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF
      alpha in human peripheral blood.
AB  - The phenotype and frequency of cells in normal human peripheral blood
      spontaneously secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF-alpha ex vivo was
      determined using ELIspot assays. CD4+ T cells were the dominant source of IL-2
      and IL-4 while multiple cell types (primarily CD8+ lymphocytes) produced IFN.
      Fewer than 0.05% of mononuclear cells were spontaneously secreting these T cell
      derived factors. By comparison, IL-6, IL-10 and TNF-alpha were produced by 0.7
      20% of PBMC. The primary sources of the latter cytokines were CD14+
      macrophages/monocytes. A significant positive correlation was found in the
      frequency of cells secreting IL-6, IL-10 and TNF-alpha ex vivo, suggesting that
      the release of such factors was coordinately regulated. No such correlation was
      found among IL-2, IL-4 and IFN secreting cells, indicating that the production of
      predominantly T cell derived cytokines was regulated independently.

PMID- 8664451
TI  - Role of nitric oxide in systemic hemodynamic responses to dobutamine,
      epinephrine, and amrinone.
AB  - OBJECTIVE: This study was designed to investigate the extent to which the
      systemic vasodilator effects of dobutamine, epinephrine, and amrinone are
      modulated by the endothelium-derived relaxing factor, nitric oxide (NO). DESIGN:
      This was a prospective study of low and high doses of the agonists before and
      after inhibition of NO synthesis. SETTING: Experiments were performed in the
      basic research laboratories of the Center for Anesthesiology Research.
      PARTICIPANTS: Pentobarbital-anesthetized, intact Sprague-Dawley rats were studied
      in seven separate groups of eight rats each. INTERVENTIONS: The systemic
      vasodilator responses to the agonists were assessed before and after the
      administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester.
      MEASUREMENTS AND MAIN RESULTS: Decreases in systemic vascular resistance in
      response to dobutamine and epinephrine were not observed after inhibition of NO
      synthesis, whereas the decrease in systemic vascular resistance in response to
      amrinone was still apparent. CONCLUSIONS: The results suggest that dobutamine and
      epinephrine produce systemic vasodilation through the release of NO, whereas
      amrinone produces vasodilation independent of NO release.

PMID- 8664452
TI  - Effects of inhaled prostacyclin as compared with inhaled nitric oxide in a canine
      model of pulmonary microembolism and oleic acid edema.
AB  - OBJECTIVE: Recently, it has been shown that the inhalation of nitric oxide (NO)
      and of prostacyclin (PGI2) elicits selective pulmonary vasodilation in a canine
      model of pulmonary hypertension induced by hypoxic pulmonary vasoconstriction.
      The present study was designed to investigate whether inhaled NO or PGI2-aerosol,
      respectively, is also effective in decreasing pulmonary artery pressure in a
      canine model of acute pulmonary microembolism and oleic acid edema. DESIGN:
      Prospective, randomized, cross-over design. SETTING: University animal research
      laboratory. PARTICIPANTS: Eight anesthetized, mechanically ventilated dogs (28 +/
      1 kg). INTERVENTIONS: Acute pulmonary microembolization (PME) was induced using
      glass microbeads (mean diameter: 100 microns) and 0.01 mL/kg of oleic acid.
      Subsequently, inhaled PGI2 (concentration: 10 micrograms/mL) or NO (50 ppm),
      respectively, was randomly administered for 15 minutes each and then withdrawn.
      MEASUREMENTS AND MAIN RESULTS: Central hemodynamics (heart rate [HR], cardiac
      output [CO], stroke volume [SV], mean arterial pressure [MAP], systemic vascular
      resistance [SVR], mean pulmonary artery pressure [PAP], pulmonary vascular
      resistance [PVR]) and gas exchange (PaO2/FIO2 ratio, intrapulmonary shunt
      [Qs/Qt], alveolar-arterial oxygen difference, [AaDO2]) were assessed.
      Measurements were performed at control, after PME, and during administration of
      PGI2 and NO, respectively. PME induced a significant increase (p < 0.001) of MAP
      (+9%), PAP (+68%), and PVR (+163%), whereas HR, CO, and SV remained unchanged and
      lung function deteriorated. Inhalation of NO slightly decreased PAP (-10%; p <
      0.05) and PVR (-26%; p < 0.01) and improved AaDO2 and PaO2/FIO2. In contrast,
      inhalation of PGI2 had no consistent effect on pulmonary vascular tone or gas
      exchange. CONCLUSION: The data demonstrate that inhaled NO may elicit selective
      pulmonary vasodilation and improve gas exchange in a canine model of pulmonary
      microembolism and respiratory insufficiency. However, the degree of these effects
      was relatively small. The aerosolization of PGI2 under conditions of positive
      pressure ventilation did not exert a significant vasodilatory effect on pulmonary
      vessels and did not improve pulmonary gas exchange in this model.

PMID- 8664453
TI  - A comparison of prostacyclin and sodium nitroprusside for the treatment of heart
      failure after cardiac surgery.
AB  - OBJECTIVE: To study the effects of the two vasodilators, prostacyclin and sodium
      nitroprusside, on central hemodynamics in heart failure after cardiac surgery.
      DESIGN: Randomized cross-over study. SETTING: Multi-institutional university
      hospital. PARTICIPANTS: Ten patients. INCLUSION CRITERIA: cardiac index less than
      2.5 L/min/m2; pulmonary capillary wedge pressure greater than 15 mmHg, systemic
      vascular resistance index greater than 2,500 dynes.s.cm-5/m2, and treatment with
      inotropic support. Five patients were treated with intra-aortic balloon
      counterpulsation. INTERVENTIONS: After control measurements, mean arterial
      pressure was decreased by 10% to 20% with each vasodilator in each patient.
      MEASUREMENTS AND RESULTS: Sodium nitroprusside induced decreases in mean
      pulmonary arterial pressure (-21%), pulmonary capillary wedge pressure (-29%),
      central venous pressure (-17%), and systemic vascular resistance (-25%), and
      increases in cardiac output (+7%) and stroke volume (+6%) compared with control.
      Prostacyclin decreased mean pulmonary arterial pressure (-14%), pulmonary
      capillary wedge pressure (-19%), central venous pressure (-7%), and systemic (
      40%) and pulmonary (-25%) vascular resistances, whereas cardiac output (+25%) and
      stroke volume (+22%) increased compared with control. Prostacyclin, compared with
      sodium nitroprusside, induced a more pronounced increase in cardiac output and
      stroke volume, associated with less pronounced decreases in cardiac filling
      pressures and more profound decreases in systemic and pulmonary vascular
      resistances. CONCLUSION: Prostacyclin appears to be a useful agent, superior to
      sodium nitroprusside, in the treatment of postoperative heart failure in patients
      with normal or mildly elevated cardiac filling pressures, where vasodilator
      treatment is indicated.

PMID- 8664454
TI  - Effects of a paf-receptor antagonist on hemodynamics during and after
      cardiopulmonary bypass.
AB  - OBJECTIVES: To assess after cardiopulmonary bypass (CPB) the role of paf-acether
      (paf), a phospholipid mediator whose injection in animal mimics the hemodynamics
      observed after CPB. DESIGN: Prospective double-blind randomized study. SETTING:
      Single institutional university hospital. PARTICIPANTS: 18 patients scheduled to
      undergo coronary artery bypass graft. INTERVENTIONS: 18 patients randomly
      received a placebo (n = 8) or 120 mg BN52021 (n = 10), a paf-receptor antagonist
      injected twice just before vascular cannulation and before cross-clamp release.
      MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements were performed with a
      pulmonary artery and a radial artery catheter before and after the first
      injection of BN52021 or placebo, at the end of CPB, 1, 15, and 30 minutes after
      protamine infusion, then 6 hours and 24 hours postoperatively. BN52021 infusion,
      did not affect hemodynamic parameters. After CPB, the pulmonary artery pressures,
      the cardiac index, and the pulmonary artery occlusion pressures were
      statistically the same between groups. By contrast, the pulmonary vascular
      resistances (1.5 +/- 0.5 IU v 4.5 +/- 0.6 IU, p < 0.05), the right ventricular
      systolic work index (5.3 +/- 0.91 g m m-2 v 9.37 +/- 1.02 g m m-2, p < 0.05) and
      the transpulmonary gradient (4.7 +/- 1.1 mmHg v 12.0 +/- 1.2 mmHg, p < 0.05) were
      lower in the BN52021 group as compared with the placebo group. After protamine
      infusion, these differences between groups disappeared. CONCLUSION: Because the
      inotropic and vasodilator therapy and the volume loading were the same between
      groups, this study suggests that pretreatment with a paf-receptor antagonist
      improves post-CPB pulmonary resistance. Nevertheless, this beneficial effect is
      transient without consequences on left ventricular function indices.

PMID- 8664455
TI  - Effects of dobutamine versus insulin on cardiac performance, myocardial oxygen
      demand, and total body metabolism after coronary artery bypass grafting.
AB  - OBJECTIVE: The purpose was to study whether the hemodynamic benefit of a
      catabolic catecholamine (dobutamine) induces a certain oxygen cost for the
      myocardial energy demand and whether this effect would be less pronounced if an
      anabolic intervention, such as the administration of insulin, was used. DESIGN: A
      prospective and randomized study. SETTING: A university hospital. PARTICIPANTS:
      Investigation of two comparable groups of cardiac patients. INTERVENTIONS: The
      interventions were postoperative infusions of dobutamine, 7 micrograms/kg/min,
      and of insulin, 1.5 U/kg/h, respectively, over a period of 30 minutes.
      MEASUREMENTS AND MAIN RESULTS: The effects of the interventions were measured
      using parameters relating to cardiac work and myocardial oxygen demand. Moreover,
      parameters relating to total body metabolism were also recorded. In the
      dobutamine group, cardiac index (CI) and left ventricular stroke work index
      (LVSWI) increased significantly (p < 0.05) during therapy by 30% and 40%,
      respectively. Cardiac effort index (CEI) and tension time index (TTI) also
      increased (p < 0.05) during therapy by 41% and 30%, respectively. However, in the
      insulin group, CI and LVSWI also increased (p < 0.01 and p < 0.05) during
      therapy, although to a lesser extent (16% and 14%), but CEI and TTI did not
      change at all during therapy. Total body CO2 production (VCO2) and O2 consumption
      (VO2) in the dobutamine group increased (p < 0.05) during therapy by 9% and 11%,
      respectively, whereas in the insulin group only CO2 production increased (p <
      0.05) by 13%. O2 consumption remained unchanged in this group. CONCLUSIONS: It is
      concluded that dobutamine as well as insulin administration increase cardiac
      performance. However, in contrast to dobutamine, insulin does not appear to
      increase myocardial oxygen demand. Therefore, the anabolic insulin administration
      may represent a more economic pattern of energy-consuming hemodynamic
      intervention than does the catabolic catecholamine administration.

PMID- 8664456
TI  - Right ventricular function after coronary artery bypass grafting in patients with
      and without revascularization of the right coronary artery.
AB  - OBJECTIVES: To evaluate the influence of revascularization of a stenosis of the
      right coronary artery on right ventricular function. DESIGN: Prospective study.
      SETTING: Single institutional study in a university hospital. PARTICIPANTS: 20
      patients with different degrees of stenosis of the right coronary artery
      undergoing elective coronary artery bypass grafting. INTERVENTIONS: In 10
      patients, bypass surgery included revascularization of a significant stenosis of
      the right coronary artery (group 1). In 10 other patients, the pathology of the
      right coronary artery was judged to be not significant, without indication for
      revascularization (group 2). MEASUREMENTS AND MAIN RESULTS: Using the fast
      response thermodilution pulmonary artery catheter, right ventricular function was
      estimated perioperatively. After termination of extracorporeal circulation, there
      was an increase in right ventricular volumes in group 2 (p < 0.05) and an initial
      decrease in group 1 (p < 0.05), with higher volumes in group 2 compared with
      group 1 (p < 0.05). The ejection fraction increased in group 1 (p < 0.05) and
      decreased in group 2 after operation (p < 0.05), with higher values in group 1
      compared with group 2 (p < 0.05). In addition to these findings, the pressure
      volume relationship showed a leftward and upward shift in group 1 and a rightward
      shift in group 2 postoperatively. CONCLUSIONS: These results indicate that right
      ventricular depression can occur after bypass grafting in patients with a
      moderate stenosis of the right coronary artery that is not revascularized.
      Revascularization of more severe stenosis of the right coronary artery appears to
      preserve postoperative right ventricular function.

PMID- 8664457
TI  - A comparison of transesophageal and transthoracic echocardiographic assessment of
      left ventricular function in pediatric patients with congenital heart disease.
AB  - OBJECTIVE: To determine the quantitative utility of transesophageal
      echocardiographic assessments of left ventricular function in pediatric patients
      with congenital heart disease by evaluating the variability between observers and
      between echocardiographic windows. DESIGN: Retrospective, blinded analysis.
      SETTING: University-associated pediatric hospital. PARTICIPANTS: Transthoracic
      and transesophageal echocardiographic images of 25 pediatric patients with
      congenital heart disease were reviewed. INTERVENTIONS: None. MEASUREMENTS AND
      MAIN RESULTS: End-diastolic area, end-systolic area, and fractional area change
      were measured from short-axis images of the left ventricle at the midpapillary
      level by two separate investigators. These measurements were compared by the
      method of Bland and Altman and Sheiner and Beal. Significant differences in
      measurements of end-diastolic and end-systolic area by different observers were
      noted, but they were systematic. A similar situation was noted for the comparison
      of transthoracic and transesophageal measurements of end-diastolic and end
      systolic area. In the comparison of fractional area change between observers or
      windows, bias and absolute prediction error were lower, with 95% confidence
      limits of bias or absolute prediction error of 10% or less. CONCLUSIONS: The
      potential error in the measurement of fractional area change in 10% under optimal
      conditions. This would suggest that the assessment of ventricular function in the
      operating room or intensive care unit, under less than optimal conditions, should
      be viewed as a qualitative, rather quantitative, measurement. There may be
      significant interobserver and interwindow variability.

PMID- 8664458
TI  - Clinical estimation of left and right ventricular volume with open chest compared
      with transesophageal echocardiography and fast-response thermodilution.
AB  - OBJECTIVE: A clinical measure--inspection of the relation of the heart (acute
      margin) to the diaphragm--has shown a strong positive correlation to
      transesophageal echocardiographic (TEE) determination of left ventricular end
      diastolic area (LVEDA) during weaning from cardiopulmonary bypass (CPB). The
      present study examines the correlation between right ventricular end-diastolic
      volumes (RVEDV) before and after CPB when using the same clinical measure of left
      ventricular dimension. DESIGN: Prospective study. SETTING: Operating room,
      university hospital. PARTICIPANTS: Patients scheduled for elective coronary
      artery bypass grafting. INTERVENTIONS: After induction of anesthesia and
      endotracheal intubation, a transesophageal echo-probe was inserted. A pulmonary
      artery right ventricular ejection fraction/volumetric TD catheter was placed in
      the pulmonary artery. MEASUREMENTS AND MAIN RESULTS: Before going on CPB, a mark
      was made with cautery at the line of contact between the acute margin and the
      diaphragm. After CPB, the patients were transfused to the same level. At these
      two times, TEE recordings of the LVEDA and hemodynamic measurements including
      calculations of RVEDV were obtained. The LVEDA before and after CPB showed a
      positive correlation, r = 0.81, p < 0.001. The RVEDV after CPB showed a weak
      correlation, r = 0.54, p < 0.05, to RVEDV before CPB. There were no significant
      changes in right ventricular (RV) wall tension calculated as right atrial
      pressure x RVEDV and pulmonary artery systolic pressure x right ventricular end
      systolic volume products. The only significant change regarding hemodynamic
      parameters was a decrease in mean arterial pressure. CONCLUSIONS: It is concluded
      that there is only a weak correlation regarding RVEDV before and after CPB when
      the patient is transfused to the line of contact, whereas this clinical measure
      correlates well with LVEDA.

PMID- 8664459
TI  - The relationship between systolic pressure and stroke volume describes myocardial
      contractility.
AB  - OBJECTIVE: To develop a method of measuring end-systolic elastance from
      information obtained outside the ventricle and thereby simplify its transduction.
      DESIGN: Prospective, within-animal comparative analysis. SETTING: University
      based laboratory study. PARTICIPANTS: Six mixed-breed dogs. INTERVENTIONS:
      Instrumentation included minor axis sonomicrometry, ascending aortic flow probe,
      aortic and ventricular pressure transducers, and constricting cuffs on the vena
      cavae and aorta. MEASUREMENTS AND MAIN RESULTS: Elastance was determined from the
      equation PES = EES (VED - VES), where VED - VES is stroke volume and PES is end
      systolic arterial pressure. EES was derived from both preload and afterload
      manipulation. Cardiac performance indices were calculated automatically by
      computer under conditions of varying load and inotropy. This extraventricular
      method of elastance calculation was compared by linear regression and analysis of
      variance to preload recruitable stroke work, traditional EES determination (using
      ventricular dimension instead of volume), and LVdP/dt at 50 mmHg. EES measured
      from the aortic sites correlated well with the other contractility indicators (p
      < 0.003 in all cases) and demonstrated more sensitivity and stability under
      loading manipulation than traditional EES. A strong relationship between the
      change in stroke volume and end-systolic ventricular diameter during acute aortic
      constriction (r = 0.924, p < 0.0001) was observed, and the mean r value for the
      individual outflow elastance measurements was 0.97 +/- 0.02. CONCLUSIONS: In this
      study, measurement of EES from the ventricular outflow tract during progressive
      aortic constriction produced results more consistent and descriptive than EES by
      traditional techniques and has the potential for obtaining elastance measurements
      from possibly less invasive techniques.

PMID- 8664460
TI  - Validation testing of the spacelabs PC2 ST-segment analyzer.
AB  - OBJECTIVES: Recent studies have demonstrated that perioperative myocardial
      ischemia, detected by electrocardiography, is a risk factor for myocardial
      infarction. ST-segment analyzers and hemodynamic monitors may be useful for on
      line detection in perioperative and critical care environments. However,
      independent performance and accuracy standards for these devices have not been
      established. Therefore, a testing protocol was developed using an
      electrocardiogram (ECG) simulator that allowed selectively altered ST-segment
      displacement, in a calibrated fashion over a wide range. DESIGN: Laboratory bench
      study. SETTING: Not applicable. PARTICIPANTS: Not applicable. INTERVENTIONS: Not
      applicable. MEASUREMENTS AND MAIN RESULTS: Custom digital ECG waveform templates
      were programmed for use with a commercially available ECG simulator (M311 ECG
      simulator; Fogg Systems, Inc., Aurora, CO). For each template, ST-segment
      morphology (horizontal elevation or depression, downsloping depression), QRS
      duration, and the presence or absence of a P wave were manipulated, resulting in
      seven different QRS shapes. Within each shape, the degree of ST-segment deviation
      was altered over a wide range. A PC2 Bedside Monitor (SpaceLabs Inc., Redmond,
      WA) was tested. One hundred forty-eight measurements of ST-segment deviation
      input from the simulator were made at each of two testing sessions. The first ST
      segment value displayed by the analyzer was recorded, and the two measurements
      averaged for comparison. Placement of the J-point, J + 60 msec, and isoelectric
      reference points by the analyzer were evaluated. Simulator output was validated
      for accuracy and stability. Subtle errors in placement of the J-point marker were
      observed in all seven QRS shapes. These errors usually did not alter placement of
      the isoelectric marker before, but not exactly at the beginning of, the R-wave
      upstroke. Thus, ST-segment values returned by the monitor (J + 60 msec -
      isoelectric reference value) were unaffected. However, in two QRS shapes, the
      isoelectric point was displaced onto the upstroke of the R wave, resulting in
      erroneous ST-segment values. In one, the error may have been caused by the
      difference in QRS duration of that template (120 msec) relative to the fixed 115
      msec interval from the J point used by the analyzer and was present in all points
      tested. In the second (normal QRS duration), the error was present in some, but
      not all points tested (4/21, 24%). All QRS shapes with proper placement of the
      isoelectric point returned ST-segment values within +/- 0.5 mm of expected, and
      98% were within +/- 0.25 mm of expected. The mean difference between observed and
      expected ST-segment values for 100 measurements with normal QRS duration and
      proper isoelectric point placement was 0.08 mm +/- 0.07 mm (SD). CONCLUSIONS: The
      bench results suggest that visual confirmation of ST-segment analyzer values may
      be advisable in the clinical setting. Although most complexes with normal
      conduction and a P wave are likely to be accurately analyzed, those with
      prolonged QRS duration were problematic. The simulator protocol may be helpful in
      ensuring accuracy of ST-segment analyzers, especially in their early development
      stages.

PMID- 8664461
TI  - Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in
      blood.
AB  - OBJECTIVE: Assessment of the value of blood analysis of the astroglia protein, S
      100, and neuron-specific enolase for the detection of nervous system dysfunction
      after cardiac surgery. DESIGN: Prospective study. Neurologists blinded from
      laboratory results. SETTING: University hospital. PARTICIPANTS: 38 patients
      undergoing cardiac surgery. INTERVENTIONS: 21 patients were operated for coronary
      artery disease; seven patients with replacement of the aortic valve of whom 2
      also had coronary bypass. Four patients had mitral valve replacement of whom 2
      also had coronary bypass. One patient had both aortic and mitral valve
      replacement and coronary bypass. Two patients were operated on because of aortic
      arch aneurysm. MEASUREMENTS AND MAIN RESULTS: Neurologic examinations were
      performed before and after surgery. General behavior of the patients was
      repeatedly assessed. Blood samples for analysis were collected before operation
      and on the second day after surgery. In 8/38 patients (21%), a neurologic
      complication, one of which was lethal, occurred. In 27 patients (71%), the
      neurologic outcome was uncomplicated, and in 3 (8%), it could not be classified.
      Elevated S-100 and neuron-specific enolase levels were found in 7/8 patients who
      endured a neurologic complication and in 4/27 free of complication. (Fisher's
      exact test p < 0.001). Positive and negative predictive values were 64% and 96%,
      respectively. S-100 (range 0.5 to 1.3 micrograms/L) and neuron-specific enolase
      levels (range 8.6 to 16.7 micrograms/L) were lower for the 7 patients with
      nonlethal complications than for the patient who died (9.5 micrograms/L and 31.3
      micrograms/L, respectively). CONCLUSIONS: S-100 and neuron-specific enolase
      levels after cardiac surgery are associated with neurologic complications. The
      results have implications on patient-related treatment and prognosis as well as
      for the development of safer perfusion techniques.

PMID- 8664462
TI  - Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and
      pharmacokinetics of rocuronium.
AB  - OBJECTIVE: To study the influence of hypothermic cardiopulmonary bypass (CPB) on
      the pharmacodynamics and pharmacokinetics of rocuronium. DESIGN: Prospective,
      descriptive study. SETTING: Operating room at a university hospital.
      PARTICIPANTS: Ten ASA class III and IV patients, ranging in age from 35 to 75
      years, scheduled for elective coronary artery bypass grafting. INTERVENTIONS:
      Neuromuscular transmission was monitored mechanomyographically. The time course
      of action of maintenance doses and plasma concentration-response relationships
      were determined before, during, and after CPB. The plasma concentration decay and
      renal elimination were studied simultaneously. Plasma and urine concentration of
      rocuronium were determined by high-performance liquid chromatography.
      MEASUREMENTS AND MAIN RESULTS: Hypothermic CPB prolonged the duration of action
      of maintenance doses and coincided with a lower plasma concentration at a twitch
      response of 5% of control. The duration of action of maintenance doses returned
      to prehypothermic CPB level after rewarming to a nasopharyngeal temperature of 37
      degrees C. The plasma concentration-response relationship did not return to
      precooling control value, probably owing to persisting peripheral hypothermia.
      Both the renal elimination of rocuronium and the plasma concentration decay after
      the last maintenance dose under normothermic conditions resembled values obtained
      in patients not undergoing hypothermic CPB. CONCLUSIONS: Hypothermic CPB prolongs
      the duration of action of maintenance doses and alters the plasma concentration
      response relationship of rocuronium. These changes may be the result of, on the
      one hand, an increased sensitivity of the neuromuscular transmission and/or
      decreased muscle contractility and, on the other hand, the result of a reduced
      plasma clearance during hypothermia.

PMID- 8664463
TI  - Comparison of the alteration of cardiac function by sevoflurane, isoflurane, and
      halothane in the isolated working rat heart.
AB  - OBJECTIVES: Despite its widespread use, little is known about sevoflurane's
      physiologic effects. The direct myocardial effects of sevoflurane were compared
      with both halothane and isoflurane. DESIGN: Administration of minimum alveolar
      concentration (MAC) fractions of anesthetic (0 to 3.0) was systematically varied
      to decrease the possibility of time-related effects on measured parameters.
      SETTING: Isolated rat hearts were perfused using a working heart model where the
      parameters affecting myocardial work were carefully controlled and monitored.
      PARTICIPANTS: To avoid confounding effects of prior anesthetic administration,
      hearts were removed from rats, after decapitation, in the absence of anesthetic.
      INTERVENTIONS: In the first series, isolated perfused rat hearts were exposed to
      one of the three anesthetics in doses of 0 to 1.5 times MAC. In the second
      series, hearts were exposed to either sevoflurane or isoflurane in doses of 0 to
      3.0 times MAC. The following variables were measured: the rate of change of left
      ventricular pressure; aortic flow rate; cardiac output; left ventricular end
      diastolic pressure; the time constant of isovolumetric relaxation; and coronary
      vascular resistance. Oxygen consumption was measured during the first series.
      MEASUREMENTS AND MAIN RESULTS: In the first series, all systolic variables were
      reduced in the presence of halothane when compared with either isoflurane or
      sevoflurane. Halothane affected diastolic function to a greater degree than
      either sevoflurane or isoflurane, as measured by the rate of relaxation and end
      diastolic pressure. In the second series, at a dose of 3.0 times MAC, both
      sevoflurane and isoflurane decreased systolic and diastolic function, with a
      greater reduction in cardiac output, and peak aortic flow and higher left
      ventricular end-diastolic pressures observed with isoflurane. Coronary resistance
      and oxygen consumption were not affected by any of the anesthetics. CONCLUSIONS:
      These data suggest that sevoflurane depresses cardiac function less than either
      halothane in doses of 1.0 and 1.5 x MAC or isoflurane at doses of 3 x MAC.

PMID- 8664464
TI  - Transient effects of inhaled nitric oxide for prolonged postoperative treatment
      of hypoxemia after surgical correction of total anomalous pulmonary venous
      return.

PMID- 8664465
TI  - Beta-selective monoamine oxidase inhibitors and cardiac anesthesia.

PMID- 8664466
TI  - Drainage of tense ascites in children after cardiac surgery.

PMID- 8664467
TI  - Acute hypovolemia after weaning from isolated limb perfusion.

PMID- 8664468
TI  - Univent tube: a useful device in patients with difficult airways.

PMID- 8664469
TI  - Combined use of aprotinin and a heparin-bonded cardiopulmonary bypass system for
      aortic aneurysm repair.

PMID- 8664470
TI  - Anesthetic management of coronary artery bypass via minithoracotomy with video
      assistance.

PMID- 8664471
TI  - Anesthetic considerations for descending thoracic aortic surgery: part II.

PMID- 8664472
TI  - Nitric oxide: delivery, measurement, and clinical application.
AB  - The biologic and therapeutic roles of NO are rapidly being elucidated. Before
      inhalational NO administration is commonplace, there is a clear need for
      consensus regarding safe and accurate delivery and measurement systems. The
      potential for NO usage appears large and potentially life-saving; yet multicenter
      trials need to carefully evaluate efficacy and safety.

PMID- 8664473
TI  - Marked mixed venous hemoglobin desaturation in a patient during hypothermic
      cardiopulmonary bypass.

PMID- 8664474
TI  - Pro: The choice of muscle relaxants is important in cardiac surgery.

PMID- 8664475
TI  - Con: The choice of muscle relaxants is not important in cardiac surgery.

PMID- 8664476
TI  - Abnormal central venous pressure tracing.

PMID- 8664477
TI  - Modified bronchocath double-lumen tube.

PMID- 8664478
TI  - When should femoral artery sheaths be removed after post-PTCA emergency CABG
      surgery?

PMID- 8664479
TI  - Continuous direct left atrial pressure monitoring during closed mitral
      commissurotomy.

PMID- 8664480
TI  - [Gastric cancer].

PMID- 8664481
TI  - [Upper digestive hemorrhage in the inhabitants of high altitudes in Peru].
AB  - One hundred cases of upper gastrointestinal hemorrhage in peruvian highlanders
      were studied at a hospital in La Oroya (3850 meters above the sea level). On
      admission in all of them an esophagogastroduodenal fiberscope was performed to
      establish the diagnosis. Most of them were males (98%), between 30-39 years of
      age (38%) and presented at the same time hematemesis and melena (64%). After
      bleeding in 72% the hemoglobin was over 14 g%. As a whole the most frequent
      diagnosis were: gastric ulcer (33%). duodenal ulcer (23%) and erosive gastritis
      (23%). In those living between 3000-3500 m.a.s.l. duodenal ulcer had the highest
      incidence. At 3500 m.a.s.l. was gastric ulcer more frequent, followed by erosive
      gastritis. In 11% surgery was required and only in 27% it was necessary a blood
      transfusion. After bleeding 10% had an hemoglobin level over 20 g% and because of
      this they were considered as having Chronic Mountain Sickness, 4 of them with
      severe cardiorespiratory and consciousness disturbances required after the
      gastrointestinal hemorrhage, an immediate bleeding in order to compensate the
      patient, a completely unusual occurrence in general pathology but a peculiar
      treatment in these patients living at high altitudes of the peruvian Andes.

PMID- 8664482
TI  - [Endoscopic and clinical parameters in assessing th degree of portal
      hypertension: the value of the serum-ascitic fluid albumin gradient].
AB  - A prospective study in thirty one patients with ascites, who were hospitalized at
      Cayetano Heredia National Hospital (H.N.C.H.), to investigate the association
      between the high serum-to-ascites albumin concentration gradient (high GRAD-Alb)
      with the degree and development of oesophageal varices, studied by endoscopy, is
      here reported. It was also studied its relationship with the degree of impairment
      of liver function, determined by the Child-Pugh's score. In addition our series
      found that the degree of high GRAD-Alb could discriminate patients with
      oesophageal varices finding like a signal of its presence a value of high GRAD
      Alb greater than 1.435 +/- 0.015 g/dl. It is here demonstrated that the degree of
      high GRAD-Alb does not have any relationship with the degree of impairment of
      liver function (Child-Pugh's score), prothrombine time, serum bilirrubin, degree
      of encephalopathy neither grade of ascites; however, we found a light association
      and correlation with serum albumin.

PMID- 8664483
TI  - [The endoscopic treatment of pancreatic pseudocyst].
AB  - We define in this paper different modalities of endoscopic treatment as well as
      the criteria for this procedure. Endoscopic drainage were done through
      cystoenterostomy and nasocystic drainage and enterocystic prosthesis plus
      sphincterostomy of the principal pancreatic and biliary duct, in all patients,
      but only in eleven of them we implanted the prosthesis in both ducts. The
      complication was bleeding, in two patients (16.7%) and they were treated with
      endoscopic inyectotherapy.

PMID- 8664484
TI  - [Laparoscopy as a clinical diagnostic method at a hospital center in Peru].
AB  - Laparoscopy is an invasive endoscopic procedure, that permits the vision of the
      abdominal cavity, through a little hole in the abdominal wall. This method
      permits a almost complete vision of abnormalities. It also helps to define
      diagnosis and classify or visualize the progress of some diseases. In this study
      done in 141 patients with liver diseases detected by laparoscopy and biopsy in
      the Arzobispo Loayza General Hospital in Lima, Peru, we verified the diagnostic
      efficacy of laparoscopy in hepato-biliary diseases like cirrhosis and
      hepatocarcinoma etc., and also to establish the etiology of peritoneal diseases.
      Emphasis is made in the importance of biopsies taken under visual control.

PMID- 8664485
TI  - [Changes in the liver biopsies of pediatric cancer patients who carry the B
      virus].
AB  - Liver biopsies from 27 patients with malignant diseases and virus B carriers
      state were studied. The age of the patients ranged from 2 to 14 years. ELISA
      tests for virus B hepatitis were performed in all patients. Three of them
      resulted HBV positive at admission, whereas 24 became positive after anti-tumoral
      treatment onset. One patient was also virus C positive. Morphological disorders
      findings comprises: symptomless acute hepatitis in 7 patients (including the B-C
      carrier), minimal hepatocytes damage was found in 17 patients as the result of
      their carriers state and where also certain drug-induced hepatotoxic effect might
      be present. In this group there were also 7 biopsies with minimal portal region
      damage. Three biopsies were reported as normal liver tissue. This results
      confirmed the significance of the study of serological hepatitis viral test and
      hepatic biopsy in high risk group patients, where it is also necessary the
      vaccination against HBV before treatment onset.

PMID- 8664486
TI  - [Cholelithiasis in patients with liver cirrhosis].
AB  - We retrospectively studied 67 cirrhotic patients hospitalized in the service of
      gastroenterology of Hospital Daniel A. Carrion, Callao, Peru, between June 1993
      and July 1995, aimed to determine the frequency of cholelithiasis and its main
      clinical and epidemiological features. Twelve out of 67 cirrhotic patients
      (17.91%) had cholelithiasis. 24% of women and 14.3% of men were affected (p >
      0.05). The mean age of women and men were 57.33 and 57.5 years old respectively
      (range: 41-67 years old). The frequency of cholelithiasis did not increase with
      age and the proportionally most affected age group was 41-50 years (33.33%).
      Alcoholic etiology was the most often in cirrhotic patients with cholelithiasis
      (41.67%). The severity of liver disease influenced in the cholelithiasis
      frequency (p = 0.001) and 33.33% of patients with gallstones were in grade C of
      Child Pugh Score. Two thirds of patients were asymptomatic. We conclude: 1.
      Cholelithiasis in our cirrhotic patients more prevalent than in general
      population (17.91% vs 0.7-5%). 2. Age did not influence in cholelithiasis
      prevalence in our cirrhotic patients. 3. The severity of liver disfunction
      influenced in highly significant way (p = 0.001) on cholelithiasis prevalence. 4.
      Cirrhotic patients with gallstones had mostly (66.67%) an asymptomatic course.

PMID- 8664488
TI  - [Cancer of the gastric stump].
AB  - Several aspects of the problem are reviewed, including the estimated risk post
      gastric surgery, relationship between stomal primary cancer (SPC) and the
      previous type of surgical procedure, the more often localization,
      histopathological issues, pathogenesis, symptomatology and diagnosis and the
      rationale of surgical treatment. It is concluded, we do not know which is the
      real prevalence of SPC and the fact that the majority of cases, are diagnosed too
      late.

PMID- 8664487
TI  - [Colorectal cancer: its clinical picture and survival].
AB  - Retrospectively collected information on 77 patients who had undergone resection
      for colorectal cancer at Belen Hospital, Trujillo, Peru, from 1966 to 1993, was
      analyzed to establish their clinical features and the importance of both clinical
      and pathological factors affecting outcome. Common presenting features in right
      colon cancer were abdominal pain, pallor, and palpable mass; in left colon cancer
      were symptoms of obstruction, and in rectal carcinoma predominated bleeding. The
      diagnostic accuracy of barium enema (n = 25) and proctosigmoidoscopy (n = 18) was
      72 and 100% respectively. In 54.5% (n = 42) curative resection and in 45.5% (n =
      35) palliative resection was performed The surgical procedures performed were
      right hemicolectomy (n = 29), transverse colectomy (n = 6), left hemicolectomy (n
      = 11), sigmoid resection (n = 14), low anterior resection (n = 5), and
      abdominoperineal resection of the rectum (n = 12). The total perioperative
      mortality rate was 18%. The 5 year survival rate in this series was 28% (53% for
      curative resection and 0% for palliative resection). An univariate analysis of
      survival time using long-rank test revealed that presence of bowel obstruction or
      perforation, macroscopic appearance, tumor size, depth of invasion, lymph node
      status, number of lymph node metastasis, distant metastasis, and clinical stage
      had and individual prognostic significance. Age, sex, length of disease, serum
      hemoglobin level, blood transfusions, location of tumor, histologic type, and
      tumor grade did not affect the prognosis. Improvement in the survival probably
      depends on development of better adjuvant therapy in association with surgery.

PMID- 8664489
TI  - [A solid epithelial papillary-cystic pancreatic tumor. A report of a clinical
      case and review of the literature].
AB  - Solid and papillary epithelial tumor of the pancreas is an uncommon neoplasm of
      low malignant potential, which occurs mainly in adolescent and young adult
      females. We report the case of a 17 years old woman, who presented with an
      abdominal mass, which was diagnosed cytologically by aspiration. The surgical
      procedure was total excision. Six months post surgery the patient is healthy. As
      this is a very unusual occurrence, a review of the literature has been made on
      clinical, histological, radiological and surgical features.

PMID- 8664490
TI  - [Peutz-Jeghers syndrome. Apropos a familial case at Hospital Arzobispo Loayza].
AB  - The Peutz-Jeghers syndrome is a rare dominant autosomic, entity characterized by
      hyperpigmented lesions on the lips, hands and feet; with presence of
      gastrointestinal polyps producing acute or chronic anemia, intestinal
      obstruction, and/or abdominal pain. This polyps histologically are hamartomas;
      recent studies indicate a real risk for transformations in the malignant
      neoplasia. The high and low endoscopies and the intraoperative enteroscopy with
      polypectomy are the election treatment, improving prognosis quality on these
      patients. We describe a familiar case of a female patient 24 years old showing a
      repeated picture of intestinal subocclusion; her brother presented a similar
      clinical picture, and her mother presented the same syndrome, dying of carcinoma
      in the colon; also her child, at one and a half year old presented hyperpigmented
      lesions on the lips.

PMID- 8664491
TI  - RNA-mediated resistance with nonstructural genes from the tobacco etch virus
      genome.
AB  - Sense RNA-mediated virus resistance has been described for transgenic plants
      expressing potyviral capsid protein sequences. This study was undertaken to
      determine if expression of other viral sequences could induce this type of virus
      resistance. Plants showing highly resistant or 'recovery' phenotypes were
      generated by expressing the tobacco etch virus (TEV) 6 kDa/21 kDa reading frames.
      Expression of translatable or untranslatable versions of this TEV sequence
      produced resistant lines. Highly resistant and recovery phenotype plants
      expressing TEV coat protein sequences. High transcription rates with low steady
      state levels of the transgene transcript generally correlated with resistance.
      During recovery and induction of the resistance, RNA and protein steady-state
      levels decreased 5- to 20-fold, while transcription of the transgene continued at
      a similar level. A posttranscriptional, cellular system eliminating sequences
      contained in the transgene transcript and viral genome would be consistent with
      the results.

PMID- 8664492
TI  - Use of differential display to identify novel Sesbania rostrata genes enhanced by
      Azorhizobium caulinodans infection.
AB  - Upon infection of the tropical legume Sesbania rostrata with Azorhizobium
      caulinodans ORS571, nodules are formed on the roots as well as on the stems. Stem
      nodules appear at multiple predetermined sites consisting of dormant root
      primordia, which are positioned in vertical rows along the stem of the plant. We
      used the differential display method to isolate and characterize three cDNA
      clones (differential display; didi-2, didi-13, and didi-20), corresponding to
      genes whose expression is enhanced in the dormant root primordia after
      inoculation. Database searches revealed that the deduced (partial) didi-2 gene
      product shares significant similarity with hydroxyproline-rich cell wall
      proteins. The (partial) didi-13 and didi-20 products are similar to chitinases
      and chalcone reductases, respectively. Transcripts corresponding to the cDNA
      clones didi-2 and didi-13 were first detectable 1 day after inoculation. In
      contrast, didi-20 transcripts were found at low levels in uninfected root
      primordia and were enhanced significantly around 3 days after inoculation. In
      addition, a cDNA was isolated (didi-42) that corresponds to the previously
      identified leghemoglobin gene Srlb6. These studies show that differential display
      is a useful method for the isolation of infection-related genes.

PMID- 8664493
TI  - Complementation analyses of Pseudomonas solanacearum extracellular polysaccharide
      mutants and identification of genes responsive to EpsR.
AB  - Many plant-pathogenic bacteria require extracellular polysaccharides (EPS) for
      successful infection. For example, mutations tht prevent EPS production in the
      bacterial wilt pathogen, Pseudomonas solanacearum, will reduce the ability to
      wilt plants. While several P. solanacearum EPS genes have been identified and
      characterized, a systematic analysis of EPS mutants has not previously been
      performed. We have screened over 12,000 transposon-tagged mutants and categorized
      66EPS::lacZ mutants into nine complementation sets. Five of these are composed of
      previously characterized EPS structural and regulatory loci; four contain newly
      described EPS loci. One of the four novel complementation sets has been
      determined to be defective for both EPS and lipopolysaccharide production. We
      also used the EPS::lacZ mutants to examine the interaction between P.
      solanacearum EPS genes. Overexpression of the previously described regulator EpsR
      was found to down-regulate the expression of genes encoding production of the
      major acidic form EPS.

PMID- 8664494
TI  - Sequence and expression analysis of the hrpB pathogenicity operon of Xanthomonas
      campestris pv. vesicatoria which encodes eight proteins with similarity to
      components of the Hrp, Ysc, Spa, and Fli secretion systems.
AB  - In this paper we describe the molecular characterization of hrpB, the largest
      operon in the Xanthomonas campestris pv. vesicatoria hrp cluster. The hrpB region
      encompasses 6 kb and encodes eight putative proteins, seven of which were
      expressed in Escherichia coli. The HrpB3 protein is the only one carrying a
      signal peptide sequence at the N-terminus and is a putative lipoprotein localized
      in the outer membrane of X. campestris pv. vesicatoria. The HrpB4 and HrpB8
      proteins contain one and five putative transmembrane domains, respectively, and
      are most likely associated with the inner membrane. The HrpB3, HrpB5, HrpB6, and
      HrpB8 proteins show sequence similarity to putative components of different type
      III protein secretion pathways in bacteria. Examples include Hrp proteins from
      other plant pathogens, YscJ, YscN, YscL, and YscT of Yersinia spp., and MxiJ,
      Spa47, adn Spa29 of Shigella flexneri. The transcription start site and the hrpB
      promoter was identified. The minimal hrpB promoter region of 90 bp contains a
      novel sequence motif, the PIP-box, which might play a role in transcription
      activation of the hrpB operon and possibly other plant-induced genes of X.
      campestris pv. vesicatoria.

PMID- 8664495
TI  - Systemic acquired resistance in Arabidopsis requires salicylic acid but not
      ethylene.
AB  - Systemic acquired resistance (SAR) is an inducible plant response to infection by
      a necrotizing pathogen. In the induced plant, SAR provides broad-spectrum
      protection against not only the inducing pathogen, but also against other,
      unrelated pathogens. Both salicylic acid (SA) and SAR-gene expression have been
      implicated as playing important roles in the initiation and maintenance of SAR.
      Here, we describe the characterization of transgenic Arabidopsis plants that
      express the bacterial nahG gene encoding salicylate hydroxylase, an enzyme that
      can metabolize SA. Strong, constitutive expression of this gene prevents pathogen
      induced accumulation of SA and the activation of SAR by exogenous SA. We show
      that SAR in Arabidopsis can be induced by inoculation with Pseudomonas syringe
      pv. tomato against infection by a challenge inoculation with Peronospora
      parasitica. This response is abolished in transgenic, nahG-expressing
      Arabidopsis, but not in ethylene-insensitive mutants. These experiments support
      the critical role of SA in SAR and show that ethylene sensitivity is not required
      for SAR induction. The NahG Arabidopsis plants will be important for future
      studies aimed at understanding the role of SA in plant disease resistance
      mechanisms.

PMID- 8664496
TI  - Fusarium solani DNase is a signal for increasing expression of nonhost disease
      resistance response genes, hypersensitivity, and pisatin production.
AB  - The inoculation of pea endocarp tissue with the bean pathogen Fusarium solani f.
      sp. phaseoli results in a non-host resistance response causing a complete
      cessation of fungal growth within 6 to 8 h. In addition to previously reported
      elicitation by chitosan, we now report that components of this response are also
      induced by a DNase released from this fungus. A single band of protein
      corresponding with DNase activity elicits phytoalexin production and the
      accumulation of RnA homologous with the pathogenesis-related (PR) genes DRR49,
      DRR206, and DRR230. Both the enzyme activity and the eliciting potential of the
      Fusarium DNase (Fsp DNase) are heat stable but susceptible to digestion by
      proteinase K. Fsp DNase mimics the intact fungus in inducing resistance against
      F. solani f. sp. pisi. Also, Fsp DNase causes similar cytologically detectable
      changes in pea tissue, such as increasing hypersensitive discoloration and
      diminishing fluorescence of Hoechst 33342-stained nuclei and fluorescein
      diacetate stained cells.

PMID- 8664497
TI  - Differential induction of 3-hydroxy-3-methylglutaryl CoA reductase in two cotton
      species following inoculation with Verticillium.
AB  - Gossypium barbadense cottons are typically more resistant to wilt pathogens than
      are Gossypium hirsutum cultivars. Both species make terpenoid phytoalexins in
      response to infection, implicating isoprenoid biosynthesis as a factor in
      resistance. Conserved regions in plant 3-hydroxy-3-methylglutaryl coenzyme A
      reductase (HMGR), the first enzyme in the terpene biosynthesis pathway, were used
      to design polymerase chain reaction primers for cloning a fragment of a cotton
      HMGR gene. The clone was used as a probe on Northern blots to show that induction
      of HMGR mRNA following introduction of Verticillium dahliae spores into the
      vascular system is much more rapid in Seabrook Sea Island, a restant G.
      barbadense cotton, than it is in Rowden, a susceptible G. hirsutum. The amount of
      HMGR mRNA returned to near control levels in 4 days in the former variety but
      continued to accumulate in the latter. Specific enzyme activity of HMGR also
      increased more rapidly in stele extracts of Seabrook Sea Island than in Rowden.

PMID- 8664498
TI  - Genetic mapping of a wide spectrum nematode resistance gene (Hero) against
      Globodera rostochiensis in tomato.
AB  - The Hero gene confers resistance to a wide spectrum of pathotypes of the potato
      cyst nematode Globodera rostochiensis. This gene has been introgressed from the
      wild tomato species Lycopersicon pimpinellifolium into the cultivated tomato. We
      have used RFLP and RAPD analysis for the targeted search of the L.
      pimpinellifolium into the cultivated tomato. We have used RFLP and RAPD analysis
      for the targeted search of the L. pimpinellifolium segment. The resistant line LA
      1792 contains a single introgressed segment on chromosome 4, which is
      characterized by three RFLP markers from the high-density RFLP map of tomato. The
      map position of the Hero gene in large populations, four additional markers were
      identified in the introgressed region. After analyzing more than 800 gametes for
      recombination, we found that one marker is only 0.4 cM away from the Hero gene.
      YAC clones isolated from a region near the Hero gene indicate that in this area
      of the genome, the kb/cM ratio is relatively low (<450 kb/cM) and chromosome
      walking should be feasible in order to isolate this gene.

PMID- 8664499
TI  - Construction of secretion vectors and use of heterologous signal sequences for
      protein secretion in Clavibacter xyli subsp. cynodontis.
AB  - We have constructed a vector to assess the ability of heterologous signal
      sequences to function in the endophytic bacterium Clavibacter xyli subsp.
      cynodontis. This secretion reporter contains the phoA gene from Escherichia coli
      from which the promoter and signal sequences have been deleted. Signal sequences
      of streptomycete origin were cloned into the vector and the level of secreted
      alkaline phosphatase determined enzymatically and by Western blotting. We show
      that a number of the signal sequences of streptomycete origin function well in C.
      xyli subsp. cynodontis. By inoculating corn plants with C. xyli subsp. cynodontis
      expressing the sti2-phoA fusion, we demonstrated alkaline phosphatase activity in
      planta. Our data show that phoA can be used to detect endophytic bacteria in some
      locations in planta, and is therefore useful in the study of plant-microbe
      interactions. Furthermore, our data illustrate how phoA fusions can be useful as
      a reporter for protein secretion activity of C. xyli subsp. cynodontis in planta.

PMID- 8664500
TI  - Purification and characterization of an acidic beta-1,3-glucanase from cucumber
      and its relationship to systemic disease resistance induced by Colletotrichum
      lagenarium and tobacco necrosis virus.
AB  - An acidic beta-1,3-glucanase was detected in cucumber leaves inoculated with
      either Colletotrichum lagenarium or tobacco necrosis virus (TNV) as well as in
      the leaves above those inoculated with the pathogens. The enzyme is extracellular
      and migrates in native polyacrylamide gel electrophoresis (PAGE) together with a
      Class III chitinase, a bifunctional chitinase/lysozyme. The beta-1,3-glucanase
      was separated by ultra-narrow pH range IEF-PAGE or by SDS_PAGE and was purified
      to apparent homogeneity. Only one isoform of the enzyme was detected. Its
      apparent molecular mass in 38 kDa as estimated by SDS-PAGE, its isoelectric point
      is 3.6 and the specific activity is approximately 26 micromol glucose equivalents
      liberated from laminarin min(-1)mg(-1) protein. Partial amino acid (five peptide
      fragments with a total of 65 amino acids) sequencing of the beta-1,3-glucanase
      revealed similarities of 49% to 72% to sequences of published beta-1,3-glucanases
      from tobacco, tomato, soybean, barley, and rice plants. A time course study
      indicated that the increase of the beta-1,3-glucanase activity was associated
      with induced resistance against C. lagenarium. The implications of these results
      to coordinate defense responses in plant-microbe interactions are discussed.

PMID- 8664501
TI  - Mapping of the seed transmission determinants of barley stripe mosaic virus.
AB  - The specific mechanism(s) by which some plant viruses are transmitted through
      seed, while others are excluded, is not known. Using infectious barley stripe
      mosaic virus (BSMV) RNAs transcribed in vitro from full-length cDNA clones, the
      viral genetic determinants of seed transmission have been mapped. Both
      pseudorecombinant and chimeric viruses were constructed from BSMV strains ND18
      (seed transmitted) and CV17 (not seed transmitted). The markedly different seed
      transmissibility of these two strains facilitated the identification of RNAgamma
      as the location of the primary determinants of seed transmission phenotype.
      RNAbeta also played a role in seed transmission, but to a lesser extent than
      RNAgamma. Major genetic determinants of seed transmission on RNAgamma included
      the 5' untranslated leader, a 369-nt repeat in the gammaa gene, and the gammab
      gene. Important determinants of symptom phenotype mapped to the RNAgamma leader
      and the gammab gene as well. Some heterologous combinations of the RNAgamma
      leader and the gammab gene resulted in dramatic changes in symptomatology and
      seed transmission, depending on the parental source of RNAs alpha and beta. These
      results suggest that a complex interaction of the RNAgamma leader, the gammab
      gene, and RNAs alpha and beta are involved in BSMV pathogenesis. Considering the
      putative regulatory role of the gamma gene (Donald and Jackson 1994, Plant Cell
      6:1593-1606) and the trans effects that alterations in the gammab gene have on
      RNAbeta gene expression (Petty et al., 1990, EMBO J. 9:3453-3457), phenotypic
      effects attributed to elements of RNAgamma could result from cis or trans
      interactions involving the RNAgamma leader, the gammab gene, and RNAs alpha and
      beta. Clearly, virus replication and movement play pivotal roles in the seed
      transmission of BSMV.

PMID- 8664502
TI  - Phenotypic and genotypic variation in the interaction between Arabidopsis
      thaliana and Albugo candida.
AB  - Two biotrophic parasites of the wild crucifer Arabidopsis thaliana (L.) Heynh,
      are being used to explore the molecular basis and evolution of genotype-spcific
      recognition and host defense. Genes for recognition of Peronospora parasitica
      (downy mildew) are numerous in A. thaliana and located on four of the five
      chromosomes as described previously. Genes for recognition of the closely related
      parasite Albugo candida (white blister) are described here. In contrast to teh
      former parasite, less than 15% of the host accessions tested were capable of
      recognizing either of two isolates of A. candida. The geographic regions
      represented by these accessions included countries in eastern and western Europe,
      Asia, North America and Africa. Extensive collections from England and Germany
      were required to identify examples of incompatible interactions. Phenotypic
      variation among incompatible interactions included reduced blister formations of
      complete lack of asexual reproduction by the parasite. Variation in the extent of
      the host response was also observed. Three host genes for recognition of A.
      candida (RAC), each associated with different interactions phenotypes, were
      identified through inheritance studies with three accessions. One of these genes
      at locus RAC1 appeared to be completely dominant, whereas the other two genes
      were only partially dominant or recessive under certain conditions, possibly
      including the effect of genetic background. One of the later two genes defined a
      second locus RAC2. RAC1 was mapped to the top arm of chromosome 1 in the 1 cM
      interval between RFLP markers M254 and M253.

PMID- 8664503
TI  - The PWL host specificity gene family in the blast fungus Magnaporthe grisea.
AB  - The PWL2 gene, isolated from a Magnaporthe grisea rice pathogen, prevents this
      fungus from infecting a second host grass, weeping lovegrass. We have
      investigated the distribution of sequences homologous to PWL2 in M. grisea
      strains isolated from diverse grass species. Multiple PWL2 homologs with varying
      degrees of sequence homology were identified. The presence of PWL2 homologs does
      not correlate with an avirulent phenotype on weeping lovegrass in many cases:
      some strains were fully pathogenic on weeping lovegrass although they carry
      multiple PWL2 homologs. Three weakly hybridizing PWL2 homologs were cloned and
      characterized. One of these, the PWL1 gene previously identified by genetic
      analysis, functioned to prevent infection of weeping lovegrass. Cloned PWL3 and
      PWL4 genes were nonfunctional, although PWL4 became functional if its expression
      was driven by either the PWL1 or the PWL2 promoter. The PWL1, PWL2, and PWL3/PWL4
      genes map to different genomic locations. The amino acid sequences of the
      predicted PWL1, PWL3, and PWL4 proteins have 75, 51, and 57% identity,
      respectively, to the PWL2 protein. Our studies indicate that PWL genes are
      members of a dynamic, rapidly evolving gene family.

PMID- 8664504
TI  - Purification and characterization of beta 2-tomatinase, an enzyme involved in the
      degradation of alpha-tomatine and isolation of the gene encoding beta 2
      tomatinase from Septoria lycopersici.
AB  - Lycopersicon species often contain the toxic glycoalkaloid alpha-tomatine, which
      is proposed to protect these plants from general microbial infection. however,
      fungal pathogens of tomato often are tolerant to alpha-tomatine and
      detoxification of alpha-tomatine may be how these pathogens avoid this potential
      barrier. As an initial step to evaluate this possibility, we have purfied to
      homogeneity a beta-1,2-D glucosidase from the tomato pathogen Septoria
      lycopersici that hydrolyzes the beta-1,2-D glucosyl bond on the tetrasaccharide
      moiety of alpha-tomatine to produce beta2-tomatine. The enzyme is a 110-kDa
      protein with a pI of 4.5 and a Km for alpha-tomatine of 62 microM. Little or no
      activity was detected on a variety of other glycosides. The gene encoding this
      protein was isolated and contains an open reading frame of 803 amino acids that
      shares sequence homology with several other beta-D-glucosidases. When S.
      lycopersici was incubated with alpha-tomatine, beta2-tomatinase mRNA accumulated,
      suggesting that the enzyme is substrate inducible. Aspergillus nidulans expressed
      ?beta2-tomatinase? activity when transformed with this gene but transformants
      were still sensitive to alpha-tomatine.

PMID- 8664505
TI  - Fungal pathogens of oat roots and tomato leaves employ closely related enzymes to
      detoxify different host plant saponins.
AB  - Antifungal saponins are produced by many plants and have been implicated as
      preformed determinants of resistance to fungal attack. The importance of saponin
      detoxification in fungal pathogenesis has recently been demonstrated for the
      fungus Gaeumannomyces graminis var. avenae, which produces the enzyme
      avenacinase. Avenacinase detoxifies the triterpenoid oat root saponin avenacin A
      1, and is essential for pathogenicity of G. graminis var.avenae to oats. Here we
      demonstrate an unexpected relatedness between avenacinase and the tomatinase
      enzyme produced by Septoria lycopersici (a tomato leaf-infecting fungus), which
      acts on the steroidal glycoalkaloid alpha-tomatine. The two enzymes share common
      physicochemical properties and are immunologically cross-reactive; however, there
      are critical differences in their substrate specificities which reflect the host
      preferences of the fungi from which the enzymes were purified. The DNA encoding
      tomatinase was isolated from a S. lycopersici cDNA library using avenacinase DNA
      as a probe. Comparison of the predicted amino acid sequences of avenacinase and
      tomatinase revealed that the enzymes are clearly similar.

PMID- 8664506
TI  - Open reading frames of turnip crinkle virus involved in satellite symptom
      expression and incompatibility with Arabidopsis thaliana ecotype Dijon.
AB  - Carmoviruses are single-stranded, single component RNA viruses that include
      turnip crinkle virus (TCV) and the recently discovered cardamine chlorotic fleck
      virus (CCFV). Full-length, biologically active cDNAs were constructed for the TCV
      M isolate and the Blue Lake isolate of CCFV. Using chimeric viruses constructed
      between isolates of TCV that produce mild or severe symptoms when coinoculated
      with a virulent satellite RNA, a Glu residue at position 1,144 in the polymerase
      open reading frame was identified as being involved in satellite-mediated symptom
      expression. To analyze viral determinants involved in resistance, chimeric
      viruses with precisely exchanged open reading frames were produced between TCV,
      which does not infect the Arabidopsis thaliana ecotype Dijon (Di-0), and CCFV,
      which can infect Di-0, TCV with the coat protein of CCFV was able to systemically
      infect Di-0 although whole plant hybridizations revealed that the hybrid virus
      spread more slowly than either of the two parental viruses. These results
      indicate that the two parental viruses. These results indicate that the coat
      protein is an important viral determinant in the resistance of Di-0 to TCV.

PMID- 8664507
TI  - Phytophthora sojae avirulence genes, RAPD, and RFLP markers used to construct a
      detailed genetic linkage map.
AB  - Two crosses between different races of Phytophthora sojae were established using
      one race as a common parent in both crosses. F2 populations comprising over 200
      individuals were generated for each cross. A subset of 53 F2 individuals from
      each cross was selected at random for genetic analysis of virulence/avirulence
      and molecular markers, and finally the construction of a detailed genetic linkage
      map. The linkage map developed for P. sojae is based on a total of 257 markers
      (22 RFLP, 228 RAPD, and 7 avirulence genes). The linkage map comprises 10 major
      and 12 minor linkage groups covering a total of 830.5 cM. Close linkage was
      observed between Avr4 and Avr6 (0.0 cM), Avr1b and Avr1k (0.0 cM), and Avr3a and
      Avr5 (4.6 cM). Coupling phase linkage of RFLP and RAPD markers to all seven
      avirulence genes was identified at the minimum and maximum distances of 0.0 and
      14.7 cM, respectively.

PMID- 8664508
TI  - Characterization of a gene cluster of Phytophthora cryptogea which codes for
      elicitins, proteins inducing a hypersensitive-like response in tobacco.
AB  - Elicitins, proteinaceous elicitors secreted by Phytophthora spp., act as inducers
      of a hypersensitive-like response in tobacco during incompatible interactions. We
      have isolated and cloned sequences encoding cryptogein and related isoforms from
      P. cryptogea that belong to the elicitin family. The isolation of a genomic clone
      led to the characterization of four clustered genes. Two of these genes encode
      distinct elicitins, and two genes would encode, if expressed, a class of highly
      acidic elicitins which had not been observed so far. Northern blots indicate that
      elicitin genes are expressed in the fungus grown in vitro, though at different
      levels. Southern hybridization revealed that elicitins are encoded by a multigene
      family in several other species of Phytophthora. Moreover, isolates of
      Phytophthora parasitica var. nicotianae, pathogenic to tobacco, which do not
      produce elicitins, possess several elicitin-encoding genes. Involvement of
      elicitins in plant-pathogen interactions is discussed.

PMID- 8664509
TI  - Does re-exposure to mismatched HLA antigens decrease renal re-transplant
      allograft survival?
AB  - We analyzed 420 kidney retransplants at the University of Minnesota, 87 of which
      did and 333 which did not share HLA mismatches with the previous transplant.
      There was no difference in outcome. We conclude that exceptions to routine HLA
      matching policies do not have to be made for kidney retransplants. OBJECTIVE: To
      determine if the kidney graft functional survival rate for retransplants is
      influenced by presence of HLA mismatches in common with the previous (failed)
      transplant. SUMMARY BACKGROUND DATA: Kidney retransplants have a lower function
      rate than primary grafts. An anamnestic response to HLA antigens shared with the
      previous donor could be one factor responsible, but reports in the literature are
      conflicting. METHODS: Of 420 kidney retransplants with HLA information done at
      the University of Minnesota, 87 shared > or = 1 HLA antigens specifically
      mismatched with the previous donor (63 cadaver and 24 living donor
      retransplants), while 333 did not (247 cadaver, 86 living donor). Patient and
      graft survival rates were calculated by life-table analysis for recipients with
      vs. without repeat mismatches, with the significance of differences determined by
      the Lee-Desu statistic. RESULTS: Patient and kidney graft retransplant survival
      rate curves were not significantly different (p > or = 0.41) for those exposed or
      not exposed to the same HLA mismatches as before. At 2 years, 70% vs. 61%,
      respectively, of cadaver grafts and 71% vs. 78%, respectively, of living donor
      grafts were functioning. CONCLUSIONS: The probability of a successful outcome
      with a kidney retransplant is no different for patients who do than for those who
      do not receive an organ sharing HLA mismatches with the previous donor.
      Exceptions to routine HLA matching policies do not need to be made for kidney
      retransplants.

PMID- 8664510
TI  - Plasma magnesium during human liver transplantation.
AB  - Patients with severe liver disease and accompanying malnutrition may exhibit
      electrolyte disturbances including the magnesium balance. In 18 patients plasma
      magnesium (p-Mg) was determined at the start of the liver transplantation and
      during the anhepatic and reperfusion phases of the operation. The blood loss was
      6.9 (2.5-8.8) 1 (median and range) and the cumulative transfusion volume was 10.2
      (5.0-17.2) 1 of which 5.9 (2.5-14.2) 1 was with fresh frozen plasma. p-Mg was
      0.72 (0.58-0.88) mmol.l-1 and it did not change significantly during the
      operation. Thus, in 4 patients it was at or below the lower reference value of
      0.67 mmol.l-1. In 11 patients it changed less than 0.05 mmol.l-1, while in 4
      patients the concentration was rose, and in 3 patients we noted a fall in each of
      0.08 mmol.l-1. There was no correlation between p-Mg and the blood loss or the
      administered volume of fresh frozen plasma. In 10 randomly chosen fresh frozen
      plasma units, the p-Mg was 0.64 (0.61-0.71) mmol.l-1. These observations do not
      support a need for close monitoring or substitution of magnesium during human
      liver transplantation. On the other hand, the finding of a low value in 4 of 18
      patients suggests that plasma magnesium should be monitored and eventually
      corrected while the patient is on the waiting list.

PMID- 8664511
TI  - Disseminated histoplasmosis in renal allograft recipients.
AB  - Histoplasmosis, an opportunistic fungal infection endemic in the Ohio and
      Mississippi river valleys, is caused by a dimorphic fungus Histoplasma
      capsulatum. Most infections are asymptomatic or self-limited febrile illness.
      Immunosuppressed renal transplant recipients are susceptible to a disseminated
      disease. We report 5 cases of disseminated histoplasmosis seen in our institute
      over a period of 25 years amongst 1074 renal transplant recipients. The duration
      of immunosuppression prior to the diagnosis of infection ranged from 84 days to
      14 years. All patients had pulmonary involvement. Three patients received an
      antilymphocyte preparation and 1 patent received intravenous pulse steroids in
      the 3 months prior to the onset of infection. Histopathologic examination of the
      involved organ(s) provided rapid diagnostic information allowing early treatment
      with amphotericin B. All infections resolved with no relapses to date. In
      conclusion immunosuppressed patients are more prone to disseminated
      histoplasmosis. Early recognition and prompt treatment with amphotericin B
      resolved the infection without relapse.

PMID- 8664512
TI  - Antibody-mediated hemolytic anemia following ABO-mismatched organ
      transplantation: contributory role of HLA matching and polyclonal antilymphocyte
      globulin.
AB  - We report three instances of antibody-mediated hemolytic anemia following ABO
      mismatched, but compatible, renal (n = 2) and simultaneous pancreas-kidney (n =
      1) transplantation. The two renal allograft recipients had received a 6-antigen
      matched transplant; one received polyclonal antilymphocyte globulin to treat an
      early rejection episode. The simultaneous pancreas-kidney transplant received
      polyclonal antilymphocyte globulin (ALG) as part of a quadruple therapy induction
      regimen. All three patients developed severe, but self-limited, antibody-mediated
      hemolytic anemia within two weeks of their transplants. Serologic testing
      demonstrated the hemolysis to be antibody mediated; furthermore, testing of the
      ALG lots demonstrated high titers of anti-red blood cell antibodies. The possible
      contribution of ALG and HLA matching to the hemolysis seen in these patients
      after ABO mismatched organ transplantation is discussed.

PMID- 8664514
TI  - Occurrence and treatment of kidney graft lithiasis in a series of 1500 patients.
AB  - In a series of 1500 patients transplanted between 1976 and 1992, 12 patients
      presented urinary calculi. The symptoms presented included obstructive anuria in
      3 patients and abdominal pain in 1 patient. There were 8 asymptomatic patients.
      The risk factors were mainly hyperparathyroidism and non-absorbable sutures. The
      occurrence of renal graft calculi is now ten times less frequent than in the
      1980s. In all, 5 of the patients were treated using incisional surgery, 5 with
      ESWL and 4 using ureteroscopy; a double J stent was inserted for the 3 cases of
      obstructive anuria. Nine patients are currently calculus-free and 2 have
      relapsed. One asymptomatic patient was not treated. The renal function of these
      12 patient was not modified and no hypertension was noted after treatment.
      Calculi are generally asymptomatic when they are diagnosed by ultrasonography and
      in our experience they can be treated using ESWL or by ureteroscopy. In our
      opinion all patients can be treated successfully but with a high rate of relapse
      if the causal factors are not treated.

PMID- 8664513
TI  - Cytomegalovirus involving gastrointestinal tract in renal transplant recipients.
AB  - Infection due to cytomegalovirus (CMV) is a substantial cause of mortality and
      morbidity among renal transplant recipients but the prognosis of the disease has
      changed dramatically since the introduction of ganciclovir (GAN). During a period
      of 5 years we treated 54 patients who developed CMV disease. From this group of
      patients we identified 7 patients with primary gastrointestinal tract (GIT) CMV
      disease who received treatment with GAN. Tissue diagnosis was made by endoscopy
      of the upper GIT (6 patients) or sigmoidoscopy (one patient) and histological
      examination. All patients improved after treatment with GAN; three patients
      required additional treatment for recurrent CMV disease and recovered, and 1
      patient relapsed without GIT involvement (P = 0.014). Recurrent CMV disease was
      more severe (mean score of 15 in relapse compared to 7 in the first episode). We
      believe relapse to be more common and the disease to be more severe in the
      presence of GIT involvement suggesting that a longer duration of treatment with
      GAN may be required in this clinical manifestation of CMV disease.

PMID- 8664515
TI  - Selective use of veno-venous bypass in orthotopic liver transplantation.
AB  - The use of veno-venous bypass (VVB) during the anhepatic phase of orthotopic
      liver transplantation (OLT) remains controversial. We employ VVB on a selective
      basis: patients who tolerate intra-operative supra-hepatic IVC test cross
      clamping undergo OLT without VVB while patients who, despite maximal volume
      resuscitation, develop hemodynamic instability during test cross-clamping,
      undergo OLT with VVB. The records of 150 adult orthotopic liver allograft
      recipients transplanted at the Massachusetts General Hospital from January 1984
      to December 1994 were reviewed to identify any potential adverse affects on peri
      operative, 6 months, 1 year outcomes in recipients foregoing VVB during liver
      transplantation. Thirty-eight patients (25%) underwent OLT without VVB with
      actuarial survivals of 78.4% and 69% at 6 months and 1 year. 112 patients (75%)
      underwent OLT with VVB with actuarial survivals at 6 months and 1 year of 73% and
      72%. Demographic data, UNOS status, and diagnoses were similar in each group.
      There were no significant differences in intra-operative PRBC requirements;
      lengths of hospital stay; retransplantation rates; or 30 day, 6 months and 1 year
      survivals between these two groups. There was no significant difference in renal
      function as determined by preoperative, peak post-operative, discharge serum
      creatinine levels, or number of patients requiring HD between these two groups.
      There were two major complications (1.8%) possibly resulting from VVB. In
      conclusion, patients who tolerate IVC test cross-clamping can safely undergo
      orthotopic liver transplantation without veno-venous bypass. In our experience,
      there were no significant differences in peri-operative parameters, post
      operative renal function, or short-term survival when compared to patients who,
      due to hemodynamic instability during IVC cross-clamping, underwent OLT with VVB.
      Given the potential complications associated with VVB, we feel that in those
      patients who tolerate intra-operative IVC cross-clamping, it is better to proceed
      without the use of VVB.

PMID- 8664516
TI  - Outcome of cadaveric renal transplantation by induction treatment in the
      cyclosporine era.
AB  - A total of 358 cadaveric renal transplantations performed between 1984 and 1993
      received induction therapy with Minnesota antilymphoblast globulin (MALG) 95,
      muromonab-CD3 (OKT3) 58, antithymocyte globulin--Upjohn (ATGAM) 104, rabbit
      antithymocyte serum (RATS) 37, or cyclosporine (CyA) 64. There were no
      differences in age, gender, HLA mismatches and maintenance immunosuppression
      between these groups of recipients. A significantly higher proportion of OKT3
      induction patients were retransplants (50%, p < 0.0001). There were fewer
      diabetic recipients in the group that received RATS (8%) compared to the other
      groups (p = 0.0009). There was no significant difference in overall graft
      survival with the various forms of induction treatment (log rank test, p = 0.48).
      Similarly, primary cadaveric graft outcome was not different with various forms
      of induction treatment (p = 0.62). Acute rejection was higher with ATGAM,
      occurring in 65% of patients, compared to MALG (52%), OKT3 (55%), RATS (43%) and
      CyA (55%). A significantly lower number of patients were rejection-free with
      ATGAM (35%) compared to MALG (48%) (p = 0.04). Patients who received ATGAM
      induction also had a higher rate of rebound rejection. Patients receiving ATGAM
      induction had a significantly higher serum creatinine level at 1 and 6 months
      post-transplantation (p < 0.005) compared to other induction treatments. In
      conclusion, the prevalence of acute rejection was higher with ATGAM, which was
      also reflected by higher serum creatinine levels. However, the long-term graft
      function and survival were not different with the various induction treatments.

PMID- 8664517
TI  - Laparoscopic-assisted colectomy in heart transplant recipients.
AB  - Reports of laparoscopy in heart graft recipients are scarce and, to our
      knowledge, laparoscopic colectomy has not yet been reported in heart transplant
      patients. The magnitude and the tolerance of the hemodynamic changes induced by
      pneumoperitoneum are unknown in heart graft recipients, who have a denervated
      heart and are "preload-dependent". The authors report the clinical courses of 2
      heart graft recipients who developed acute diverticulitis without perforation or
      peritonitis and who underwent laparoscopic-assisted colectomy without
      complications.

PMID- 8664518
TI  - Successful treatment of intraoperative malignant hyperthermia during renal
      transplantation.
AB  - Malignant hyperthermia is a complication of general anesthesia that is especially
      problematic if it occurs during renal transplantation because myoglobinemia,
      shock, and ischemia play a role in injuring the transplanted kidney. In this
      report, we describe a case of malignant hyperthermia, its clinical course, and
      the measures taken to successfully treat it and preserve the function of a kidney
      allograft.

PMID- 8664519
TI  - Fate of renal allografts connected to vascular prostheses.
AB  - OBJECTIVE: The outcome of renal transplantation with an arterial anastomosis to a
      vascular prosthesis in the aortofemoral tract is evaluated. PATIENTS AND METHODS:
      All 7 Dutch transplant centers were invited to review their experience. Among a
      total of 5791 cadaveric renal transplantations performed between 1978 and 1994,
      13 cases (0.2%) in 3 different centres were identified. In 6 cases the vascular
      reconstruction and transplant operation were performed simultaneously, and in 7
      cases separately, with a mean interval of 3.5 yr. The indications for vascular
      reconstruction were aneurysmal disease in 4 and obstructive disease in 9 cases.
      RESULTS: The early vascular complications of these procedures were hemorrhage in
      4 and renal vein thrombosis in 1 and led to graft loss in 3 cases. The
      perioperative mortality was 2/13 (15%). The graft and patient survival were 68
      and 83% respectively after 1 yr and 17 and 37% after 5 yr. Late mortality was
      mainly due to cardiovascular disease. CONCLUSIONS: Renal transplantation with an
      arterial anastomosis to a vascular prosthesis in the aortofemoral tract is a
      hazardous procedure with relatively poor short- and long-term results. These
      observations should be considered in the choice of renal replacement therapy in
      this special patient population.

PMID- 8664520
TI  - Renal retransplants: effect of primary allograft nephrectomy on early function,
      acute rejection and outcome.
AB  - Although risk factors for failure of renal retransplants have been well studied,
      the impact of allograft nephrectomy on subsequent renal transplantation in the
      cyclosporin era is not well defined. The purpose of this study is to define the
      effect of nephrectomy of the primary allograft on subsequent allograft survival,
      early allograft function, incidence of acute rejection and patient sensitization.
      The records of 127 renal retransplant recipients were reviewed. Of these 127
      patients who underwent retransplantation, 40 (31%) underwent nephrectomy of the
      primary allograft prior to retransplantation whereas 40 (31%) did not.
      Nephrectomy of cadaveric primary allografts was performed more commonly (48% vs
      30%, p = 0.003) and earlier (78% vs 54% < 1 month post-transplant, p = 0.0006) in
      the pre-CSA period compared to the CSA period. Biopsy-proven acute rejection
      episodes occurred more frequently in the nephrectomy group (73% vs 42%, p =
      0.03). Although primary allograft nephrectomy was associated with higher
      preformed antibody levels, it had no effect on early graft function, frequency of
      acute rejection or allograft outcome after retransplantation, in the CSA group.
      In conclusion, in the cyclosporin era, nephrectomy of the primary allograft has
      no significant influence on retransplantation.

PMID- 8664521
TI  - Long-term outcome after switch from cyclosporine-based triple-drug
      immunosuppression to double therapy at three months.
AB  - Cyclosporin A (CyA) together with steroids and azathioprine (Aza) has been
      successfully used for prophylactic immunosuppression in numerous recipients of
      kidney allografts. The aim of this study was to evaluate the long-term effect of
      reducing this initial triple-drug therapy to double-drug therapy at 3 months. One
      hundred consecutive recipients of a cadaveric renal allograft with stable and
      good graft function were randomly allocated to continue with CyA and steroids
      (group 1) or CyA and Aza (group 2). Both groups were comparable with regard to
      all relevant patient characteristics. After a mean observation period of 55 (26
      76) months no significant difference was observed in the incidence of acute
      rejection episodes after conversion (4 in group 1 and 5 in group 2), or in the
      incidence of graft loss (4 in group 1 and 5 in group 2); all graft rejection
      episodes were easily reversed with steroid pulses and patients switched back to
      triple-drug therapy. Patient survival was 94% in group 1 and 100% in group 2 at
      55 months. In group 1, however, a higher number of viral infections and steroid
      related side effects was noted. From these data it is concluded that initial
      triple-drug therapy can safety be reduced to a CyA-based double-drug combination
      after 3 months in renal allograft recipients with stable function. The
      combination with Aza is recommended because of its fewer side effects.

PMID- 8664522
TI  - Metabolic problems in recipients of liver transplants.
AB  - We analyzed the metabolic problems in recipients of liver transplants.
      Immunosuppression consisted of cyclosporine, steroids and azathioprine. With a
      mean follow up of 3.5 yr, 37% of 71 recipients were rendered permanently diabetic
      and hyperlipidemic. Recipients who developed posttransplant diabetes had higher
      cholesterol levels and proteinuria, but decreased creatinine clearance.
      Transplant recipients who developed posttransplant hyperlipidemia had greater
      proteinuria, but their sugars and creatinine clearance were comparable to those
      who did not have hyperlipidemia. The most significant factor responsible for
      these metabolic complications was the total dosage of prednisone and
      cyclosporine. There was no effect of risk antigens on the development of
      diabetes.

PMID- 8664523
TI  - Diagnosis and management of the urologic complications of renal transplantation.
AB  - 669 patients who received a renal transplant from January 1988 to December 1993
      at a single institution were evaluated for urologic complications. Urologic
      complications were assessed and categorized by organ involvement: kidney, ureter,
      bladder, lymphatic, calculus and complicated urinary tract infection.
      Complications were also classified as "early" if they occurred within 14 d after
      transplant and those diagnosed after this period were called "late." The
      management of all complications is presented. There were a total of 98 urologic
      complications identified in 669 patients, of which 51 were complicated urinary
      tract infections. The other 47 complications were divided among renal (8),
      ureteral (19), bladder (3), lymphatic (10) and calculi (7). Preventive measures,
      such as technical management of ureteral reimplantation, periodic renal scan or
      ultrasound examinations, and long-term urinary antibiotic prophylaxis could
      further reduce the incidence of urologic complications. The result should be
      further improvement in transplant patient and graft survival.

PMID- 8664525
TI  - Arrhythmias.

PMID- 8664526
TI  - Pediatrics.

PMID- 8664524
TI  - Evidence for an increased rate of bacterial infections in liver transplant
      patients with cytomegalovirus infection.
AB  - It has been reported that cytomegalovirus (CMV) infections increase the
      susceptibility of transplant patients for other opportunistic infections. Most of
      these studies date back from a time when CMV infection was difficult to diagnose
      and antiviral treatment not available. We therefore analyzed CMV-related
      morbidity after OLT in 111 consecutive patients. CMV monitoring was done weekly
      using the antigenemia assay, a quantitative marker of the viral load, in addition
      to serology. CMV infection occurred in 66/95 (69%) evaluable patients.
      Antigenemia was detected in 94% of them. The number of CMV antigen-positive cells
      was helpful to monitor the course of infection and differentiate CMV disease from
      other complications. CMV infection was symptomatic in 48/66 (73%) patients. Mild
      disease occurred in 30 patients, and severe constitutional symptoms or organ
      involvement in 18. No patient died as a direct result of CMV infection, but
      mortality between day 30 and 180 tended to be higher in CMV-infected patients (15
      vs. 0%, p < 0.1). CMV infection was associated with a 2.45-fold higher incidence
      of major infections between day 30 and 180 after OLT (p < 0.05). Most of these
      infections were caused by gram-positive cocci. We conclude that CMV not only
      causes substantial morbidity, but also increases the risk of bacterial
      infections.

PMID- 8664527
TI  - Implantable cardioverter-defibrillator advances.
AB  - Significant advances in the basic science of implantable cardioverter
      defibrillator therapy have led to improvements in defibrillation waveforms and in
      capacitor technology. Nonthoracotomy devices with biphasic waveforms can be
      implanted with a near 100% success rate. Although fewer patients with implantable
      cardioverter-defibrillators are being treated with concomitant antiarrhythmic
      drug therapy, sotalol appears to decrease the defibrillation threshold.
      Controversy still exists over the optimal design for defibrillator sensing leads.
      Tachyarrhythmia detection enhancement increase specificity for sensing
      ventricular tachycardia but may risk undersensing. A variety of subsets of
      patients receiving implantable cardioverter-defibrillators have been identified;
      patients presenting with ventricular fibrillation appear to have the most
      unfavorable prognosis. Controversy exists as to the true impact of implantable
      cardioverter-defibrillator therapy on subsequent survival. Randomized clinical
      trials such as AVID (Antiarrhythmics Versus Implantable Defibrillators) are
      designed to determine the true benefits of implantable cardioverter
      defibrillators and may lead to expanded indications.

PMID- 8664528
TI  - Interactions between antiarrhythmic drugs and implantable cardioverter
      defibrillators.
AB  - Despite the efficacy of implantable cardioverter-defibrillators in preventing
      sudden death associated with ventricular arrhythmias, 40% to 70% of patients with
      an implantable cardioverter-defibrillator receive adjunctive antiarrhythmic drug
      therapy. The most common aims of drug therapy are to reduce the frequency of
      ventricular tachycardia and fibrillation triggering shock, to alter the
      tachycardia characteristics in order to enhance the efficacy of antitachycardia
      pacing, and to suppress supraventricular tachyarrhythmias. Antiarrhythmic drugs
      may, however, interfere with implantable cardioverter-defibrillator function by
      raising defibrillation and pacing thresholds. Furthermore, drugs may adversely
      affect the sensing of ventricular tachycardia and fibrillation by the implantable
      cardioverter defribillator. Careful prescription and follow-up electrophysiologic
      testing is critical in ensuring a cooperative effect of drug and implantable
      cardiovascular-defibrillator after initiation of new therapy.

PMID- 8664529
TI  - Evaluation and treatment of nonsustained ventricular tachycardia.
AB  - The clinical significance of nonsustained ventricular tachycardia continues to
      undergo reevaluation as clinicians attempt to optimize screening strategies for
      identifying high-risk patients and to evaluate the efficacy of therapeutic
      interventions. The utility of ambulatory monitoring and programmed stimulation as
      screening tools in the patient who has suffered an infarction remains unsettled;
      ongoing clinical trials may help resolve these issues. New data suggest that the
      survival benefit associated with angiotensin-converting enzyme inhibition is
      unrelated to effects on spontaneous arrhythmias, similar to results previously
      reported for beta-blockers. Randomized clinical trials of prophylactic amiodarone
      in patients with congestive heart failure and nonsustained ventricular
      tachycardia have produced conflicting results. A strong relationship between
      polymorphic nonsustained ventricular tachycardia and sudden death in patients
      without structural heart disease or QT prolongation has been reported. The
      significance of nonsustained ventricular tachycardia in dilated cardiomyopathy
      and hypertrophic cardiomyopathy has also been reassessed.

PMID- 8664530
TI  - Current trends in etiology, diagnosis, and management of neurocardiogenic
      syncope.
AB  - Recurrent episodes of unexplained syncope are among the most frequent of
      complaints referred to physicians for evaluation. Traditional methods of
      evaluation were both time consuming and expensive and left many patients without
      a diagnosis. Although neurocardiogenically mediated episodes of hypotension and
      bradycardia were felt to be a common cause of syncope, this was traditionally a
      diagnosis of exclusion. The emergence of head-upright tilt-table testing has
      provide a valuable method for identifying individuals predisposed to
      neurocardiogenic syncope and has also allowed for a better understanding of this
      phenomena. This article reviews the pathophysiology of neurocardiogenic syncope,
      the use of head-upright tilt-table testing in its diagnosis, and the potential
      therapies used to prevent recurrences.

PMID- 8664531
TI  - The molecular genetics of the congenital long QT syndromes.
AB  - During the past half decade, significant insight into the clinical
      electrocardiographic, and genetic features of the congenital long QT syndromes
      has emerged. Based on this foundation, recent linkage analysis studies have
      demonstrated the genetic heterogeneity of the Romano-Ward long QT syndrome and
      led to the discovery of two of the four (or more) responsible genes. Further
      functional characterization of these two genes, the HERG potassium channel and
      the SCN5A voltage-gated cardiac sodium channel, as well as the identification and
      characterization of the other long QT syndrome genes, may allow improved
      diagnosis and therapy for these disorders. Furthermore, the increased
      understanding of myocardial repolarization that is gained from characterization
      of these genes may lead to improved treatment for other ventricular arrhythmias,
      including those related to potassium-channel blockade, central nervous system
      insult, and, possibly, myocardial infarction.

PMID- 8664532
TI  - Acoustic quantification: a new tool for diagnostic echocardiography.
AB  - Acoustic quantification, a new ultrasound technique, provides a more direct
      assessment of the health of the myocardium than conventional echocardiography.
      Through software enhancements, acoustic quantification can characterize the
      myocardium as viable or nonviable, automatically track the endocardium throughout
      the cardiac cycle, and show myocardial perfusion defects when used with contrast
      enhancement. Thus, this technique shows promise in linking perfusion, viability,
      and global function in adults and perhaps in children.

PMID- 8664533
TI  - New developments in intracardiac and intravascular devices for congenital heart
      disease.
AB  - Techniques of transcatheter device placement for treatment of pediatric
      congenital heart disease have developed substantially since their introduction 20
      years ago. Patent ductus arteriosus occlusion can be accomplished by umbrella
      deployment or coil placement. Intracardiac defects can be closed with umbrella or
      buttoned devices. Stenoses of vessels or conduits that are only temporarily
      relieved with balloon dilation can be effectively expanded with intravascular
      stents. Recent procedural modifications have been introduced in an attempt to
      minimize the size of the delivery sheath and reduce complications that can arise
      from device embolization. Transcatheter device placement can be an important
      adjunct to surgery for correction or palliation of congenital heart lesions.

PMID- 8664534
TI  - Newborn and infant heart transplantation.
AB  - Over a decade has passed since the first successful neonatal heart transplant was
      performed for palliation of hypoplastic left heart syndrome. Although neonates
      and infants represent a growing group of pediatric heart transplant recipients,
      survival remains inferior to that in older children. Decisions regarding
      transplantation in infancy pose unique problems for the pediatric cardiologist,
      including limited donor availability, pre-and posttransplant management, and
      improving results of alternative palliative surgery for hypoplastic left heart
      syndrome. A number of recent articles provide important information about donor
      availability, waiting times to transplantation, and outcome after listing and
      transplantation. Other studies focus on the treatment of infants awaiting
      transplantation. Important laboratory investigations reported this year focus on
      strategies for inducing immunologic tolerance (the "Holy Grail" of the transplant
      physician) as well as ongoing research in the controversial area of
      xenotransplantation.

PMID- 8664536
TI  - Radiofrequency ablation of arrhythmias in the pediatric patient.
AB  - Advances in management of pediatric arrhythmias using radiofrequency catheter
      ablation are reviewed. Discussion begins with the most frequent arrhythmia
      experienced in childhood, supraventricular tachycardia, and its variants.
      Subsequent consideration will center on progress made in using radiofrequency
      catheter ablation to manage ventricular tachycardia, both in the normal heart as
      well as in surgically repaired tetralogy of Fallot. Potential limitations to
      radiofrequency ablation in the infant age group are addressed. Technologic
      progress as it applies to pediatric patients is also examined. Lastly, an
      enhanced appreciation for the immense contribution that radiofrequency catheter
      ablation techniques have made will emerge for the reader after reviewing recent
      results obtained using surgical techniques for arrhythmia ablation.

PMID- 8664535
TI  - Inhaled nitric oxide in the management of congenital heart disease.
AB  - Inhaled nitric oxide, with a threshold of perhaps only a few parts per million,
      is a selective pulmonary vasodilator in patients with congenital heart disease
      and increased pulmonary vascular resistance. Multiple reports suggest that it may
      be useful in managing postoperative pulmonary hypertension in the cardiac
      patient, although it is unknown to what extent inhaled nitric oxide can actually
      reduce morbidity and mortality in this setting. This agent also holds promise for
      evaluating patients with pulmonary hypertension prior to heart transplantation.
      Although special care is needed to avoid toxicity related to excess inhaled
      nitric oxide or nitric dioxide or increased methemoglobin, the risk of
      complications with inhaled nitric oxide therapy appears to be very low. Inhaled
      nitric oxide will likely continue to play a significant role in the pre-and
      postoperative management of patients with congenital heart disease.

PMID- 8664537
TI  - New indications for permanent cardiac pacing.
AB  - Data are slowly accumulating regarding the possible benefits and appropriate uses
      of permanent cardiac pacing in a variety of pathophysiologic states or syndromes
      other than the broad categories and indications of sinus node dysfunction and
      atrioventricular block. The subjective and physiologic indications for pacing in
      these disorders are not symptomatic bradycardia or fulfillment of previously
      accepted criteria for antibradycardia pacing, and pacing is not the first or only
      therapy used. Therefore, individual patient evaluation, often including
      documentation of the response to temporary pacing therapy prior to implantation
      of a permanent device, is helpful and may be necessary. Controversy regarding the
      data available, and expanding clinical use of permanent cardiac pacing in a
      number of these conditions or syndromes, remains.

PMID- 8664538
TI  - A predator-prey model with optimal suppression of reproduction in the prey.
AB  - Several time-discrete ecological models are formulated and analyzed. Common to
      these models is that a trade-off between reproductive effort and competitive
      ability is assumed. We investigate how behavioral adjustment (suppression of
      reproduction) affects the population dynamics.

PMID- 8664539
TI  - Coexistence of multiple food chains in a heterogeneous environment: interactions
      among community structure, ecosystem functioning, and nutrient dynamics.
AB  - A model is developed and analyzed for a nutrient-limited ecosystem containing an
      arbitrary number of parallel plant-herbivore-detritus food chains in a
      heterogeneous environment, with a view to exploring interactions among community
      and ecosystem processes. Physical properties of the environment and functional
      properties of the entire ecosystem such as nutrient supply, transport, and
      recycling are shown to exert a profound influence on the composition, diversity,
      and assembly of the biological community. Community structure as well as the
      physical properties of the environment in turn affect ecosystem functions such as
      nutrient and energy flow. In particular, the rate of nutrient transport in the
      physical medium plays a critical role in competition and coexistence among food
      chains. The potential for coexistence decreases continuously as the nutrient
      transport rate increases in food chains with donor-controlled or no herbivory,
      while it increases continuously or is greatest at an intermediate value of the
      nutrient transport rate in herbivore-controlled food chains. On the other hand,
      energy flow generally increases with the rate of nutrient transport. Herbivory
      also exerts a significant, predictable influence on energy flow and coexistence
      among plants and food chains.

PMID- 8664540
TI  - Inconsistency of evolutionary tree topology reconstruction methods when
      substitution rates vary across characters.
AB  - A fundamental problem in reconstructing the evolutionary history of a set of
      species is to infer the topology of the evolutionary tree that relates those
      species. A statistical method for estimating such a topology from character data
      is called consistent if, given data from more and more characters, the method is
      sure to converge to the true topology. A number of popular methods are based on
      modeling the evolution of each character as a Markov process along the
      evolutionary tree. The standard models further assume that each character has in
      fact evolved according to the same Markov process. This homogeneity assumption is
      unrealistic; for example, different types of characters are known to experience
      substitutions at different rates. Certain distance and maximum likelihood methods
      for topology estimation have been shown to be consistent under the homogeneity
      assumption. Here we give examples showing that these methods can fail to be
      consistent when the homogeneity assumption is relaxed. The examples are very
      simple, requiring only four taxa, binary characters, and characters that evolve
      at two different rates.

PMID- 8664541
TI  - Molecular mechanisms of cell-type determination in budding yeast.
AB  - Studies of cell-type determination in the yeast Saccharomyces cerevisiae have
      revealed a regulatory network of proteins that are highly conserved in
      evolutionary terms. In the past few years, genetic, biochemical, and structural
      approaches have shown what many of these components do, how they fit together,
      and how they cooperate to regulate the expression of many different target genes.

PMID- 8664542
TI  - Control of mating and development in Ustilago maydis.
AB  - In the fungus Ustilago maydis, the ability to distinguish between partners that
      are of the same or of different mating type is controlled by two mating-type
      loci. One locus allows extracellular recognition though a pheromone-based system.
      After cell fusion, the other mating-type locus, which exists in multiple alleles,
      determines intracellular recognition. Each allele encodes a pair of homeodomain
      proteins that are active only in pairwise combinations in which the two partners
      originate from different alleles of the locus. Recent discoveries suggest that
      the underlying molecular recognition mechanism is the ability to form
      heterodimers. Whereas the proteins in all different allelic combinations
      interact, it is a specific feature of proteins from the same allele not to
      interact. This suggests the existence of a code for protein-protein recognition.

PMID- 8664543
TI  - C/EBP alpha: a critical regulator of genes governing integrative metabolic
      processes.
AB  - The role of C/EBPalpha in the developmental expression of a subset of genes
      governing essential metabolic processes has recently been elucidated using a
      mutant mouse model that lacks this transcription factor. The mutation results in
      a failure of the liver and white and brown adipose tissue to develop normal
      metabolic functions in the immediate perinatal period, including hepatic glycogen
      synthesis and gluconeogenesis and the synthesis and deposition of triglyceride in
      adipose tissue. The metabolic alterations are very similar to those of human
      infants born prior to the third trimester and suggest that many of the medical
      complications of prematurity are a result of the lack of activation of C/EBPalpha
      in development.

PMID- 8664544
TI  - Regulation of adipocyte gene expression and differentiation by peroxisome
      proliferator activated receptor gamma.
AB  - Peroxisome proliferator activated receptor (PPAR)gamma is an orphan member of the
      nuclear hormone receptor superfamily and is expressed at high levels specifically
      in adipose tissue. Recent data suggest that this factor is a central regulator of
      adipocyte gene expression and differentiation. Fibroblastic cell lines that
      express PPARgamma ectopically can be induced to differentiate into fat cells by a
      variety of lipids and lipid-like activators of PPARs, suggesting that this
      protein may function to link adipogenesis with systemic lipid metabolism.

PMID- 8664545
TI  - Intestinal epithelial cell differentiation: new insights from mice, flies and
      nematodes.
AB  - Decisions commonly made during development that affect proliferation, cell fate
      specification, differentiation, migration, and death are made repeatedly in the
      mouse small intestinal epithelium throughout adulthood. The results of these
      decisions are a stratification of proliferation, differentiation, and death along
      the mouse small intestine's crypt/villus axis. Recent genetic studies in
      Caenorhabditis elegans and Drosophila melanogaster have identified factors
      involved in determining cell fate and differentiation in gut endoderm. The stem
      cell hierarchy of the adult mouse intestinal epithelium makes it ideally suited
      for using chimeric animals to examine the functions of homologs of these lower
      eukaryotic (and other) proteins.

PMID- 8664546
TI  - Prolactin-mediated gene activation in mammary epithelial cells.
AB  - Mammary epithelial cells grow and develop with the onset of sexual maturity. In
      addition, lobular alveolar structures are formed during pregnancy, and quiescent
      differentiated cells secrete high levels of milk proteins after parturition.
      These events are governed by multiple hormones and growth factors and involve the
      sequential and synergistic action of functionally distinct signal transduction
      pathways. Milk protein genes have been analyzed and composite response elements
      have been identified in the promoter sequences. Transcription factors, which
      relay the hormonal signals, bind to these sequences. The factor that confers
      prolactin simulation to milk protein gene transcription has recently been
      identified. MGF/Stat5 is a latent transcription factor that becomes activated by
      a tyrosine-specific protein kinase, Jak2, associated with the prolactin receptor.
      Tyrosine phosphorylation converts the latent factor into one with DNA-binding and
      transcriptional activation potential. The regulation of MGF/Stat5 in vitro and in
      vivo indicates that it is a central component of the lactogenic hormone signaling
      pathway. Involvement of MGF/Stat5 in the signaling by other cytokines indicates
      that the same factor might be involved in regulation of growth-promoting genes,
      primarily in hematopoietic cells.

PMID- 8664547
TI  - The role of BSAP (Pax-5) in B-cell development.
AB  - The hierarchy of transcriptional control in B-cell development has recently been
      analyzed by targeted gene inactivation in the mouse. In this manner, the paired
      box containing gene Pax-5, encoding the B cell specific transcription factor
      BSAP, has been shown to play a key role in early B lymphopoiesis. Other
      experimental strategies have implicated BSAP in the control of cell
      proliferation, isotype switching and transcription of the immunoglobulin heavy
      chain gene at late stages of B-cell differentiation.

PMID- 8664548
TI  - New perspectives on eye evolution.
AB  - The highly complex eyes of vertebrates, insects and molluscs have long been
      considered to be of independent evolutionary origin. Recently, however, Pax-6, a
      highly conserved transcription factor, has been identified as a key regulator of
      eye development in both mammals and flies. Homologues of Pax-6 have also been
      identified in species from other phyla, including molluscs. The wide variety of
      eyes in the animal kingdom may, therefore, have evolved from a single ancestral
      photosensitive origin.

PMID- 8664549
TI  - Axis formation in zebrafish.
AB  - Recent advances in our understanding of axis formation and patterning in
      zebrafish relate the developmental mode of this aspiring genetic model organism
      to higher vertebrates. The effect of UV irradiation and lithium treatment, as
      well as detailed early lineage analyses, have shed some light on dorsoventral
      axis formation. However, the molecular mechanism of axis formation, as well as
      the identity of a fish Nieuwkoop center, are still open issues. A Vg1 homolog is
      expressed in zebrafish, and activin as well as the mouse nodal gene product have
      been demonstrated to induce mesoderm and ectopic axes, respectively, in
      zebrafish. The zebrafish organizer is defined by the expression domains of
      goosecoid, axial, and lim1. The cyclops gene is involved in maintaining goosecoid
      expression in axial mesoderm of the head. Large mutagenesis screens provide the
      basis for a genetic analysis of axis formation.

PMID- 8664550
TI  - Homeobox genes in vertebrate gastrulation.
AB  - The formation and anteroposterior patterning of the three definitive germ layers,
      ectoderm, or epiblast, is the common theme of vertebrate gastrulation. What
      changes from system to system is the geometry of these events and the nature of
      the non-epiblast transient structures implicated. A number of molecular markers,
      including a few homeobox genes and in particular goosecoid and Otx2, are now
      available that will hopefully allow us to explore the underlying molecular
      mechanisms and to establish biologically relevant homologies between the various
      systems.

PMID- 8664551
TI  - MADS-box genes in plant ontogeny and phylogeny: Haeckel's 'biogenetic law'
      revisited.
AB  - Data currently accumulating with impressive speed indicate that the molecular
      evolution of MADS-box genes was a decisive aspect of the morphological evolution
      of plants. Studies on MADS-box genes in diverse plant species thus help us to
      understand the emergence of morphological novelties, such as the flower, in
      evolution. This furthers our understanding of the relationship between ontogeny
      and phylogeny, which has been a controversial issue since Ernst Haeckel published
      his 'biogenetic law' more than a century ago.

PMID- 8664552
TI  - Self-incompatibility in flowering plants.
AB  - Fertilization in flowering plants begins with a pollen grain bearing the male
      gametes landing on the female stigma. Several mechanisms enable the stigma to
      discriminate between the different types of pollen that it may receive, of which
      the best studied is self-incompatibility. The molecules that regulate self
      incompatibility are well characterized in two plant families, the Solanaceae and
      Brassicaceae. This list has recently been extended to include candidates for self
      incompatibility molecules from the Rosaceae, Papaveraceae and Poaceae. The
      information provided by the sequences of these molecules gives insight into the
      mechanisms and evolution of self-incompatibility in the different families of
      flowering plants.

PMID- 8664553
TI  - Complementation cloning of mammalian transcriptional regulators: the example of
      MHC class II gene regulators.
AB  - Cloning by complementation of mutant cell lines is a powerful way in which to
      identify and isolate important regulatory genes on the basis of functional
      assays. The recent cloning of two essential regulators of major
      histocompatibility complex (MHC) class II gene expression has not only advanced
      our understanding of the complex mechanisms controlling these genes, but also
      helps to illustrate the feasibility of this approach for the study of mammalian
      gene regulation.

PMID- 8664554
TI  - Species specificity of transcription by RNA polymerase I.
AB  - An unusual property of ribosomal gene transcription is its marked species
      specificity. This results from distinct promoter-recognition properties of the
      RNA polymerase I transcription apparatus. The purification and functional
      characterization of TIF-IB/SL1, a promoter-recognition factor containing the TATA
      binding protein, as well as the recent cloning of cDNAs encoding the three
      subunits (TAF(I)s) of the respective human and mouse factor, will facilitate the
      molecular analysis of the mechanisms underlying species-specific rDNA
      transcription and reveal how the basal transcriptional machinery has evolved.

PMID- 8664555
TI  - The genetics of olfaction.
AB  - Our understanding of olfaction has progressed rapidly in recent years as a result
      of the molecular genetic approaches being used to study this sensory system in a
      variety of model organisms. Considerable success has been achieved in identifying
      proteins of the mammalian signaling system that are analogous to those present in
      other sensory systems. More recently, genetic selection of mutations that cause
      defects in olfactory function in Drosophila melanogaster and Caenorhabditis
      elegans has led to the identification of additional proteins that play a role in
      the detection of odorants. The application of genetic, electrophysiological, and
      molecular analyses to olfactory function in mammals is also shedding light on the
      mechanisms that account for sensitivity and specificity in this system.

PMID- 8664556
TI  - Molecular control of circadian rhythms.
AB  - Circadian rhythms are virtually ubiquitous in eukaryotes and have been shown to
      exist even in some prokaryotes. The generally accepted view is that these rhythms
      are generated by an endogenous clock. Recent progress, especially in the
      Drosophila, Neurospora and mouse systems, has revealed new clock components and
      mechanisms. These include the mouse clock gene, the Drosophila timeless gene, and
      the role of light in Neurospora.

PMID- 8664558
TI  - Neuromuscular disorders: gene location.

PMID- 8664557
TI  - Differentiation and gene regulation.

PMID- 8664559
TI  - Mitochondrial encephalomyopathies: gene mutation.

PMID- 8664560
TI  - Controlled trial of nimodipine in amyotrophic lateral sclerosis.
AB  - Calcium channel blocking drugs antagonize excitatory amino acid receptor
      activation, decrease calcium entry into damaged neurons, and might help to slow
      or reverse amyotrophic lateral sclerosis (ALS). We enrolled 87 patients with ALS
      in a randomized, placebo-controlled, prospective, double-blind crossover study of
      nimodipine therapy. Monthly measures of isometric muscle strength and respiratory
      function compared the effects of drug and placebo. No difference in adverse
      events occurred in placebo vs drug-treated patients, but diarrhoea, nausea, and
      lightheadedness were more common with nimodipine. There was no significant
      difference in the rate of decline of pulmonary function or limb strength during
      treatment with drug or placebo. Nimodipine was ineffective in slowing the
      progress of ALS.

PMID- 8664561
TI  - Up-regulation of leukaemia inhibitory factor and interleukin-6 in transected
      sciatic nerve and muscle following denervation.
AB  - Leukaemia inhibitory factor (LIF) and Interleukin-6 (IL-6) are multifunctional
      cytokines that are related on the basis of their predicted structural
      similarities and shared signal transducing receptor components. Both these
      factors stimulate myoblast proliferation, and whereas LIF is neurotrophic for
      sensory neurons, and for the motor neurons which innervate muscle, IL-6 has only
      been reported to act on a population of septal neurons in the brain. We have
      looked at the effect of peripheral nerve trauma on the expression of these
      factors. We show here that whereas LIF and IL-6 mRNAs are expressed in low levels
      in normal sciatic nerve and skeletal muscle, there is significant up-regulation
      in the nerve segments after injury, with proximally and distally. There is also
      an increase in LIF and IL-6 expression in the denervated muscle located largely
      in the muscle cells. In addition, while there is retrograde axonal transport of
      LIF by the sciatic nerve, IL-6 is not retrogradely transported, and as a result,
      IL-6 does not stimulate the survival of sensory neurons in vitro. Both growth
      factors are produced by Schwann cells. These results show a rapid response in the
      expression of these genes after injury and suggest that LIF and IL-6 act as
      trauma factors but with different roles in injured peripheral nerve.

PMID- 8664562
TI  - An autosomal-recessive congenital myasthenic syndrome with tubular aggregates in
      a Libyan family.
AB  - We studied a Libyan family in which five out of seven siblings have had slowly
      progressive limb-girdle weakness accentuated by exercise since childhood. Ptosis
      or ophthalmoplegia were not observed. Pronounced decremental electromyographic
      responses on 3 Hz stimulation indicated the presence of a defect of neuromuscular
      transmission. Repeated testing for acetylcholine receptor antibodies was
      negative. Muscle biopsy revealed tubular aggregates in 34% of the type 2 muscle
      fibers. Our observation illustrates the wide clinical spectrum of congenital
      myasthenic syndromes.

PMID- 8664563
TI  - Irena Hausmanowa-Petrusewicz. 50 years for neurology and neuromuscular diseases.

PMID- 8664564
TI  - Spinal muscular atrophy. 32nd ENMC International Workshop. Naarden, The
      Netherlands, 10-12 March 1995.

PMID- 8664565
TI  - X-linked myotubular myopathy. 33rd ENMC International Workshop Soest. The
      Netherlands, 9-11 June 1995.
AB  - The research work presented at this the 2nd Workshop of the International
      Consortium on X-linked Myotubular Myopathy has clearly shown the benefits to be
      gained from a multinational research consortium with a common interest in
      identifying and cloning the MTM1 gene. The clinicians have rapid access to
      knowledge about the current state of the detailed physical map encompassing the
      disease gene, which is of particular importance when asked to carry out a linkage
      based carrier risk assessment in such families, and the molecular geneticists
      benefit by having access to a large panel of samples from clinically well
      documented XMTM patients, and their families, for the rapid testing of any new
      potential candidate genes. Strategies for the rapid exchange of information and
      material between members of the consortium to facilitate the cloning of the MTM
      gene were generated in the hope that the next Workshop will see the consortium
      discussing the clinical and histological implications of the mutations found. To
      this end it was decided to set up a Register, based in Cardiff, of all XMTM
      patients from whom tissue and DNA samples had been made available to the
      consortium. A decision was also made to collect samples from the very rare
      families with possible autosomal MTM for future study.

PMID- 8664566
TI  - Congenital myasthenic syndromes. 34th ENMC International Workshop, 10-11 June
      1995.

PMID- 8664567
TI  - Proximal myotonic myopathy: mini-review of a recently delineated clinical
      disorder.
AB  - This mini-review describes proximal myotonic myopathy, a recently delineated,
      dominantly inherited disorder that is similar to but distinct from myotonic
      dystrophy. Proximal myotonic myopathy is not linked to the gene locus for
      myotonic dystrophy or to the loci of the genes of the muscle sodium and chloride
      channels associated with other myotonic disorders. Patients often present with
      myotonia and peculiar muscle pain in early adulthood and develop weakness of the
      thigh muscles later in life. Cataracts that are indistinguishable from those in
      myotonic dystrophy also occur commonly. The gene defect responsible for proximal
      myotonic myopathy awaits discovery. Because of the clinical similarities between
      proximal myotonic myopathy and myotonic dystrophy, clarification of the genetic
      differences will not only shed light on the pathomechanism of proximal myotonic
      myopathy, but may also increase our understanding of myotonic dystrophy.

PMID- 8664568
TI  - A mild adult myopathic variant of type IV glycogenosis.
AB  - Type IV glycogenosis is usually a rapidly progressive disease of early childhood,
      causing death before 4 years of age. It is characterized by hepatosplenomegaly,
      cirrhosis, and chronic hepatic failure. Muscle involvement is generally
      overshadowed by liver disease. A mild non-infantile variant of type IV
      glycogenosis has been described in a few patients. In some of them, the patients
      suffered foremost from chronic progressive myopathy. We here report on a female
      patient aged 51 years who had experienced difficulties in climbing stairs for 2
      years due to leg weakness. EMG revealed a myopathic pattern. The muscle biopsy
      findings revealed polyglycosan bodies. Biochemical investigation showed absence
      of branching enzyme in muscle but not in leukocytes and fibroblasts.

PMID- 8664569
TI  - Automated sample preparation for monitoring groundwater pollution by carbamate
      insecticides and their transformation products.
AB  - We investigated automated on-line solid-phase extraction (SPE) followed by liquid
      chromatographic (LC) techniques for monitoring carbamates and their
      transformation products. Analytical determinations were performed by LC with UV
      or postcolumn fluorescence detection (U.S. Environmental Protection Agency Method
      531.1 for carbamate insecticides) after preconcentration with on-line SPE using
      C18 Empore extraction disks. On-line SPE/LC/thermospray mass spectrometry with
      time-scheduled selected-ion monitoring was used as confirmatory method. The
      method was used to determine pesticide traces in well waters of a typical aquifer
      in the Almeria area (Andalucia, south of Spain) from March 1993 to February 1994.
      The major pollutants, found in highest amounts, were carbofuran, methiocarb, and
      methomyl, at levels of 0.32, 0.3, and 0.8 micrograms/L, respectively. According
      to results of seasonal variation studies, pollution by carbamate insecticides is
      sporadic and exceeds the limit of 0.5 micrograms/L for total pesticides allowed
      by the European Economic Community Drinking Water Directive only twice a year. 3
      Hydroxycarbofuran and methiocarb sulfone also were detected, showing the
      importance of including the main toxic break-down products of carbamate
      insecticides in future monitoring programs.

PMID- 8664570
TI  - FDA Total Diet Study, July 1986-April 1991, dietary intakes of pesticides,
      selected elements, and other chemicals.
AB  - The U.S. Food and Drug Administration conducts the Total Diet Study to determine
      dietary intakes of selected pesticides, industrial chemicals, and elements
      (including radionuclides). This paper reports results for the sampling period
      July 1986 to April 1991. The study involves retail purchase of foods
      representative of the ?total diet? of the U.S. population, preparation for ?table
      ready? consumption, and individual analyses of 234 items making up the diets of 8
      population groups. The diets were based on 2 nationwide food consumption surveys.
      The data presented represent 21 food collections (also termed ?market baskets?)
      in regional metropolitan areas during the 5-year period. Dietary intakes of
      nearly 120 analytes are presented for 8 population groups, which range from
      infants to elderly adults. Intakes of selected population groups are compared
      with representative findings from earlier Total Diet Study sampling periods. As
      reported previously, average daily intakes are well below acceptable limits.

PMID- 8664572
TI  - Determination of tetracycline residues in bovine milk, serum, and urine by
      capillary electrophoresis.
AB  - A method was developed for simultaneous determination of oxytetracycline (OTC),
      chlortetracycline, tetracycline, and doxycycline levels in cow milk, serum, and
      urine by capillary electrophoresis (CE). The tetracyclines (TCs) were extracted
      specifically with a metal-chelating affinity column. Extracts were then applied
      to C18 cartridges treated with dimethyldichlorosilane, and the TCs were eluted
      with ethanol. Salt-free sample residues were run on CE with a diode array
      detector at 370 nm. A 50 cm x 75 micron uncoated capillary at 15 kV and 23
      degrees C was used to separate the TCs. The run buffer contained 10 mM sodium
      dodecyl sulfate, 50 mM borate, and 50 mM phosphate, pH 8.5. TC peaks were
      identified by migration times, coinjection of standards, and diode array spectra.
      Limits of detection for TCs were 1.3-5.6 ng/mL, and limits of quantitation were
      1.7-8.7 ng/mL in cow fluid samples. OTC appeared consistently at 13.3-13.4 min in
      milk, serum, and urine samples from a cow treated with OTC. OTC was further
      identified by coinjection of OTC standard and OTC diode array spectra. The CE
      method can be used to simultaneously determine 4 TC residues at low parts-per
      billion levels.

PMID- 8664571
TI  - Market basket and duplicate portion estimation of dietary intakes of cadmium,
      mercury, arsenic, copper, manganese, and zinc by Japanese adults.
AB  - Daily intakes of selected metals from meals in Shiga Prefecture (Japan) were
      investigated by the duplicate portion method and market basket method. In 1991
      and 1992, daily intakes of metals by women, determined by the duplicate portion
      method, were, respectively, 37 and 27 micrograms for Cd, 4.3 and 3.5 micrograms
      for Hg, 260 and 210 micrograms for As, 1200 and 1200 micrograms for Cu, 4700 and
      3600 micrograms for Mn, and 8000 and 7200 micrograms for Zn. Those determined by
      the market basket method were, respectively, 32 and 35 micrograms for Cd, 4.3 and
      9.9 micrograms for Hg, 160 and 280 micrograms for As, 1100 and 980 micrograms for
      Cu, 3600 and 4700 micrograms for Mn, and 8700 and 8500 micrograms for Zn. No wide
      differences between the 2 methods were found, except for Hg data in 1992. Daily
      intakes of Cd and Hg in Shiga Prefecture were lower than the provisional
      tolerable daily intakes of 57-72 micrograms for Cd and 43 micrograms for Hg,
      proposed by the Food and Agricultural Organization and the World Health
      Organization.

PMID- 8664573
TI  - Determination of 2-ethylhexyl 4-(N-methyl-N-nitrosamino) benzoate in commercial
      sunscreens and cosmetic products.
AB  - An analytical method has been developed for determination of 2-ethylhexyl 4-(N
      methyl-N-nitrosamino) benzoate (NMPABAO), a nitrosamine contaminant in sunscreen
      products containing 2-ethylhexyl 4-(N,N-dimethylamino) benzoate (Padimate O). The
      method involves extraction of NMPABAO by column chromatography followed by liquid
      chromatographic separation and analysis wit a nitric oxide detector. To confirm
      the presence of NMPABAO in sunscreen products, the N-nitrosamine was synthesized
      and its structure was determined by infrared spectrophotometry, nuclear magnetic
      resonance spectrometry, and mass spectrometry (MS). For method validation,
      recovery studies were performed on a commercial suntan lotion, cream, and gel.
      Recoveries of NMPABAO added to representative test samples averaged 83%. The
      method has an estimated detection limit of 30 ppb. The method was used to analyze
      25 commercial cosmetic and sunscreen products containing Padimate O. Eleven
      products contained NMPABAO at levels ranging from 160 to 21000 ppb. NMPABAO
      presence in 4 products was confirmed by MS at levels > or = 4000 ppb. The highest
      levels of NMPABAO were associated with products that contained the nitrite
      releasing preservative 2-bromo-2-nitro-1,3-propanediol.

PMID- 8664574
TI  - Determination of reserpine and chlorothiazide in commercial tablets by liquid
      chromatography with fluorescence and UV absorbance detectors in series.
AB  - A procedure is presented for determination of reserpine and chlorothiazide in
      commercial tablets by liquid chromatography (LC). Powdered sample, equivalent to
      the weight of one tablet, is dissolved in 10.0 mL dimethyl sulfoxide, the mixture
      is diluted to 100.0 mL with methanol, and the solution is filtered; 10 mL of the
      filtrate is then diluted to 100.0 mL with methanol. The standard solution is
      prepared in the same solvent mixture and contains the 2 ingredients in
      approximately the same quantities as in the diluted sample solution. For LC, a
      7.5 cm long normal-phase column is used; mobile phase consists of methanol
      containing a small volume of an aqueous solution of 1-pentanesulfonic acid,
      sodium salt. Two detectors are arranged in series: a fluorescence detector set at
      280 nm excitation and 360 nm emission quantitates reserpine and a UV absorbance
      detector set at 300 nm determines chlorothiazide. Several synthetic mixtures
      containing the 2 ingredients in amounts ranging from 80 to 120% of quantities
      declared in commercial tablets were analyzed by the proposed method. Two samples
      of commercial tablets were also analyzed; for each sample, 5 determinations were
      made on a ground composite of 20 tablets; 10 individual tablets were also
      analyzed. The composites were also analyzed by the current U.S. Pharmacopeia
      method for this product.

PMID- 8664575
TI  - Optimization of a liquid chromatographic method for determination of malachite
      green and its metabolites in fish tissues.
AB  - A liquid chromatographic (LC) method was adapted and optimized for the
      determination of malachite green and its metabolites in fish plasma and muscle.
      Residues in plasma were extracted with acetonitrile, the extract was evaporated
      to dryness, and residues were resolubilized for LC analysis. Residues in muscle
      were extracted with an acetonitrile-acetate buffer mixture, reextracted with
      acetonitrile, and partitioned into methylene chloride with final cleanup on
      alumni and propylsulfonic acid solid-phase extraction columns. Residue levels
      were determined by using an LC cyano column with a PbO2 postcolumn and visible
      detection (618 nm). Overall mean recoveries of parent malachite green (MG-C) and
      its major metabolite, leuco-malachite green (MG-L), from plasma were 93 and
      87%,respectively, at fortification levels ranging from 25 to 250 ppb. Overall
      mean recoveries of MG-C and MG-L from muscle were 85 and 95%, respectively, at
      fortification levels ranging from 5 to 100 ppb. Relative standard deviations
      (RSDs) of recoveries at all fortification levels ranged from 3.9 to 7.0% for
      plasma and from 2.1 to 5.2% for muscle. The method was applied to incurred
      residues in tissues sampled from catfish after waterborne exposure to [14C]MG-C.
      Mean recoveries of total radioactive residues in plasma and muscle throughout the
      extraction and cleanup process were 88 and 87%, respectively, and corresponding
      RSDs for MG-C and MG-L were in the same range as those for fortified tissues. MG
      L was confirmed as the major metabolite of MG-C in catfish.

PMID- 8664576
TI  - Determination of ractopamine hydrochloride in swine and turkey tissues by liquid
      chromatography with coulometric detection.
AB  - A liquid chromatographic (LC) method is described for determination of
      ractopamine hydrochloride (LY031537) in swine and turkey tissues. Liver, kidney,
      muscle, and fat samples were homogenized in methanol. An aliquot of the extract
      was evaporated, diluted with water, and buffered to pH 10.5 +/- 0.5 with sodium
      carbonate to convert ractopamine hydrochloride to a free base. The free base was
      extracted from the buffered sample with ethyl acetate. The extract was further
      purified on a Bond Elut acid-washed silica solid-phase extraction cartridge.
      After converting the free base back to the salt form with pH 4.5 buffer,
      analytical separation and quantitation of ractopamine hydrochloride was performed
      on an IBM C18 column with coulometric detection at +600 mV. The limit of
      detection of the method was approximately 0.5 ppb as determined in swine liver.
      Overall recovery levels ranged between 75 and 100% for samples of liver, kidney,
      muscle, and fat fortified at 1 to 100 ppb. The coefficients of variation ranged
      from 2 to 18% for samples fortified at 1 to 100 ppb.

PMID- 8664577
TI  - On-line steam distillation/purge and trap analysis of halogenated, nonpolar,
      volatile contaminants in foods.
AB  - An on-line, steam distillation/purge and trap gas chromatographic procedure is
      described for determination of halogenated analytes in foods and beverages.
      Recoveries were generally >80% (versus aqueous standards) from vegetable oil,
      flour, root beer, cream (10% butter fat), and milk spiked at 1-3 micrograms/kg
      for each of the 32 analytes studied. Analytes ranged in volatility from vinyl
      chloride to 1,2,3,4-tetrachlorobenzene. Repeatabilities from aqueous standards
      were <10% for most analytes. For a 1 g food sample, method detection limits
      ranged from 0.02 to 0.2 micrograms/kg for the 32 analytes. Reduced recoveries for
      less volatile analytes, however, occurred when steam-distillable, nonpolar food
      components were carried to the sparger. This effect was observed for citrus
      beverages containing steam-volatile limonene, roasted and ground coffees, and
      some salad dressings. The method was applied to a variety of foods.

PMID- 8664578
TI  - Determination of extractable, apparent total N-nitroso compounds in cured-meat
      products.
AB  - The modification of a newly developed method for determination of apparent total
      N-nitroso compounds by chemical denitrosation and chemiluminescence detection of
      nitric oxide (thermal energy analysis) is described. The minimum level of
      reliable measurement was 0.1 ppm, and the repeatability of the method was 0.2
      ppm, based on the response of N-nitrosoproline(NPro). Seventy-three samples of
      cured-meat products, including frankfurters, bacon, and ham, were examined; 50
      samples contained less than 1 ppm. The largest amounts, up to 24.8 ppm, were
      detected in canned corned beef. This method has several advantages over other
      methods.

PMID- 8664579
TI  - Determination of total dietary fiber in foods and food products by using a single
      enzyme, enzymatic-gravimetric method: interlaboratory study.
AB  - A simplified enzymatic-gravimetric method for total dietary fiber (TDF)
      determination has been published and used in the Food Composition Laboratory of
      the U.S. Department of Agriculture since 1988. THis method gives comparable
      results to AOAC Official Methods 985.29 and 991.43 but the AOAC methods use 100
      degrees C (water bath) to gelatinize the sample and a combination of alpha
      amylase and an amyloglucosidase to hydrolyze starches, whereas the simplified
      method incorporates an autoclaving step (121 degrees C) for gelatinization
      followed by incubation with only amyloglucosidase. The simplified method omits
      protease hydrolysis and does not require any pH adjustment. Overall, the
      simplified method cuts cost and is less labor intensive. An interlaboratory study
      was conducted to validate this method. Blind duplicates of six sample (baked
      beans, corn bran, roasted peanuts, cooked potatoes, white bread with reduced
      calories, and cooked white rice) were sent to 11 laboratories. The
      reproducibility relative standard deviations of the TDF values (without outliers)
      ranged from 3.46 to 27.6%. The repeatability standard deviations ranged from 0.91
      to 14.6%.

PMID- 8664580
TI  - Importance of cooking temperature and pancreatic amylase in determination of
      dietary fiber in dried legumes.
AB  - Total dietary fiber (TDF) was measured in large lima, roman, black turtle, light
      red kidney, white navy, pinto, black-eyed, and soya beans and in chick peas by
      the Mongeau rapid method (A), the Prosky method (B), and the Lee method (C). When
      the samples were soaked and cooked according to package instructions (gentle
      boiling, 95 degrees C), TDF values by method A were all within 19.7-22.1%, except
      for black-eyed beans (9.9%) and chick peas (11.3%) (g/100 g, cooked dry matter).
      For large lima beans (20.0-21.3%) and soya beans (19.2-19.7%), TDF values by
      methods A, B, and C were in agreement. For 7 samples, however, TDF values were up
      to 81% higher by method B (17.4-34.7%) and up to 122% higher by method C (21.1
      39.8%) than those by method A (P < or = 0.01). For 6 legumes, TDF values by
      method C were 15-28% higher (P < or = 0.013) than by method B. White navy beans
      were analyzed also after different cooking conditions, varying from no cooking to
      autoclaving for 15 min at 120 degrees C. TDF values by method A were independent
      from cooking conditions and remained between 20.2 and 22.4%. For navy beans
      cooked at 95 degrees C, TDF values by method B (up to 34.7 +/- 1.4%) and C (up to
      39.8 +/- 0.3%) were unpredictable, but autoclaving at 120 degrees C reduced them
      to about 22%. Incorporation of a pancreatic amylase in methods B and C
      consistently decreased the aforementioned analytical discrepancies, as did the
      absence of cooking. Only autoclaving (for at least 15 min at 120 degrees C) fully
      restored agreement among methods A-C.

PMID- 8664581
TI  - Passive diffusion through polymeric membranes: a novel cleanup procedure for
      analysis of azinphos-methyl and azinphos-ethyl residues in fruits and vegetables.
AB  - A novel procedure is described for simple removal of coextractives prior to
      analysis of fruits and vegetables for azinphos-methyl and azinphos-ethyl
      residues. The solvent extract is concentrated, placed in a polymeric membrane
      tube, and then dialyzed in cyclohexane. Both azinphos-methyl and azinphos-ethyl
      diffuse into the surrounding solvent while coextractants remain inside the
      membrane. The dialyzing solvent is exchanged during concentration with n-hexane
      and analyzed without further cleanup by gas-liquid chromatography with a specific
      thermionic detector. The detection limit for a 25 g grape sample with final
      volume of extract made to 15 mL was 0.01 mg/kg. Recoveries of both residues from
      grapes averaged 107% (spike levels of 0.3 to 2.0 mg/kg). From a 20 g spinach
      sample, recoveries averaged 82% for azinphos-methyl and 72% for azinphos-ethyl
      when final volume of extract was made to 5 mL (spike levels of 0.1 to 1.0 mg/kg).
      Recoveries from 20 types of fruits and vegetables (20 g sample spiked at 1 mg/kg
      for both azinphos-methyl and azinphos-ethyl) were consistently greater than 70%,
      except for strawberries (61-67%) and avocado (28-34%). The high lipid content of
      avocado may impede diffusion of azinphos-methyl and azinphos-ethyl through the
      polymeric membrane. A field evaluation of the procedure showed a strong
      correlation (r = 0.957) between azinphos-methyl residues on grapes and treatments
      with 2 spray formulations. The membrane cleanup procedure is a simple and cost
      effective alternative to other column or liquid-liquid partitioning procedures
      for azinphos-methyl and azinphos-ethyl residue analysis.

PMID- 8664582
TI  - Determination of thiabendazole residues in white and sweet potatoes by liquid
      chromatography with fluorescence detection.
AB  - A liquid chromatographic (LC) method was developed for determination of
      thiabendazole (TBZ) residues in or on whole, unwashed white potatoes (Solanum
      tuberosum) and sweet potatoes (Ipomoea batatas). TBZ is extracted from the potato
      homogenate with ethyl acetate and the extract purified and concentrated on a
      cation-exchange, solid-phase extraction column. The extract is analyzed for TBZ
      residues by column LC with a cation-exchange column and fluorescence detection.
      Recoveries of TBZ from whole white potatoes fortified with TBZ at 0.05-20 ppm and
      from whole sweet potatoes fortified with TBZ at 0.005-0.1 ppm averaged 100 and
      94%, respectively. The method is also applicable for quantitation of TBZ residues
      in white potato waste (dried peel) used as an animal feed additive. The present
      method for monitoring TBZ residues in white and sweet potatoes and white potato
      waste (dried peel) is simple, rapid, and sensitive.

PMID- 8664583
TI  - Analysis of 2,2,2-trifluoroethyl derivatives of carboxylic acid herbicides by gas
      chromatography with mass-selective and electron capture detection.
AB  - A method for derivatizing carboxylic acid herbicides with 2,2,2-trifluoroethanol
      (TFE) in preparation for gas chromatographic (GC) analysis was developed.
      Esterification efficiency was determined by GC with electron capture detection
      (ECD), and esters were identified by GC with mass-selective detection (MSD). On
      the basis of reaction temperature for optimum esterification efficiency, 13
      common carboxylic acid herbicides were separated into 2 groups before reaction
      with TFE. TFE derivatization was optimized for simultaneous analyses by altering
      reaction temperature, re action time, and concentration of sulfuric acid in
      reaction solutions. The method is simple, safe, and economical, and it gives good
      resolution without a laborious cleanup. Recovery of 13 analytes from water, taken
      from a pesticide residue well, was greater than 80% for all except 2 analytes.
      The well-water was fortified with analytes at the lower microgram-per-liter
      concentrations required for detection of pesticide residues in potable water
      systems. The method can simultaneously determine multiple herbicide residues in
      water samples with a high degree of accuracy and precision.

PMID- 8664584
TI  - Atomic emission detection for gas chromatographic analysis of nitrogen-containing
      herbicides in water.
AB  - A gas chromatography-atomic emission detection (GC-AED) system was used to
      analyze nitrogen-containing herbicides. Two methods of sample preparation were
      used to demonstrate the system's applicability. Method 1 was U.S. Environmental
      Protection Agency (EPA) Method 507. Method 2 was a modification of EPA Method 507
      using larger sample volumes and smaller extract volumes to yield compound
      detection levels 30 times lower than detection levels from method 1. Analysis of
      replicate reagent water spikes with method 1 gave analyte recoveries ranging from
      82 to 107%, with standard deviations of recovery of not more than 6.7%. Method 2
      gave recoveries ranging from 50 to 112%, with a standard deviation of recovery of
      not more than 33%. A loss in recovery and precision with method 2 compared with
      method 1 was attributed to loss of more volatile analytes during extract
      concentration. Selectivity was demonstrated with solvent spiked with fuel oil and
      atrazine. Response factors generated with the GC-AED system showed compound
      independent elemental linearity for analytes. Relative standard deviations of not
      more than 5.34% were obtained for 3 elements tested: nitrogen, sulphur, and
      chlorine. An elemental calibration mixture was prepared to validate traditional
      methods of quantitation. Samples were analyzed for nitrogen-containing
      herbicides, which were quantitated with both an analyte calibration and an
      elemental calibration, and results were compared.

PMID- 8664585
TI  - Multiresidue liquid chromatographic method for simultaneous determination of
      pyrethroid insecticides in fruits and vegetables.
AB  - A simple and rapid liquid chromatographic (LC) method has been developed for
      simultaneous determination of 9 pyrethroid insecticides (biphenthrin,
      cypermethrin, fenpropathrin, fenvalerate, flucythrinate, methothrin, permethrin,
      py-115, and tetramethrin) in fruits and vegetables. Residues are extracted from
      crops with methanol and partitioned with toluene. Extracts are cleaned up by
      Florisil-charcoal column chromatography. LC separation is performed on a
      muBondapak C18 stainless steel column with acetonitrile-deionized water as mobile
      phase. The insecticides are detected at 206 nm with 0.03 absorbance unit full
      scale. Recoveries of 9 pyrethroid insecticides from 6 crops (cucumbers, tomatoes,
      cabbages, apples, pears, and peaches) fortified at 0.5-5.0 mg/kg were 62.7
      129.2%. Detection limits were about 0.05 mg/kg, except for py-115, for which
      detection limit was 0.10 mg/kg.

PMID- 8664586
TI  - Modification of AOAC multiresidue method for determination of synthetic
      pyrethroid residues in fruits, vegetables, and grains. Part I: Acetonitrile
      extraction system and optimization of florisil cleanup and gas chromatography.
AB  - We present a multiresidue method for determination of synthetic pyrethroids in
      fruits, vegetables, and grains. The method is a modification of AOAC Method
      970.52. Residues are extracted with acetonitrile (for fruits and vegetables) or
      acetonitrile-water (2 + 1) (for grains) and then transferred to hexane.
      Coextractives are removed by acetonitrile partitioning and open-column
      chromatography with deactivated Florisil. The final extract is analyzed by gas
      chromatography with electron capture detection (GC-ECD). An HP-17 wide-bore
      column is used to determine the individual isomeric contents of each insecticide.
      The method was used to recover 8 pyrethroids (biphenthrin, fenpropathrin,
      cyhalothrin, permethrin, cypermethrin, fluvalinate, fenvalerate, and
      deltamethrin) spiked at 0.01-4.0 mg/kg in 20 crops (apple, pear, peach, banana,
      grape, strawberry, potato, tomato, cucumber, pepper, cabbage, carrot, celery,
      polished rice, wheat, green gram, buckwheat, sorghum, maize, and barley).
      Recoveries of the 8 pyrethroid insecticides in 6 crops ranged from 83.8 to
      112.8%, with a coefficient of variation (CV) of 2.00 to 12.09% for the narrow
      bore capillary GC (n = 6) and from 82.8 to 106.4%, CV = 2.93-12.19%, for the wide
      bore capillary GC (n = 6). The minimum detectable levels of 0.004-0.028 mg/kg
      (for fruits and vegetables) or 0.01-0.08 mg/kg (for grains) for the 8 pyrethroids
      are easy to detect.

PMID- 8664588
TI  - Determination of chromium and molybdenum in medical foods by graphite furnace
      atomic absorption spectrophotometry.
AB  - Graphite furnace atomic absorption spectrophotometry was used to determine
      chromium and molybdenum in 7 medical foods from 5 manufacturers. Linear standard
      curves were obtained for both elements for concentrations between 5 and 25 ng/mL.
      Detection limits were 0.24 ng/mL for Cr and 0.67 ng/mL for Mo. Characteristic
      masses were 3.1 and 14.7 pg for Cr and Mo, respectively. No difference was
      detected between wet and dry ashing methods, and dry ashing was used to complete
      the study. The method was validated by assaying various National Institute of
      Standards and Technology standard reference materials. Analysis of these products
      for Cr and Mo were within certified values. One product was evaluated by this
      method for reproducibility (n = 5). Relative standard deviations were 6.8 and
      4.8% for Cr and Mo, respectively. This product contained 0.31 +/= 0.02 micrograms
      Cr/g and 0.63 +/- 0.03 micrograms Mo/g. The remaining products contained 0.09
      1.28 micrograms Cr/g and 0.07-2.3 micrograms Mo/g. Mean recovery values were 98
      +/- 14% (n = 14) for Cr at spike levels of 0.20-1.89 micrograms/g and 102 +/- 24%
      (n = 10) for Mo at spike levels of 0.30-1.89 micrograms/g.

PMID- 8664587
TI  - Modification of AOAC multiresidue method for determination of synthetic
      pyrethroid residues in fruits, vegetables, and grains. Part II: Acetone
      extraction system.
AB  - To optimize conditions and to evaluate further a multiresidue method for
      pyrethroids, various extraction solvents and partitioning conditions were
      examined. Acetone and acetonitrile (for fruits and vegetables) and acetone-water
      and acetonitrile-water (for grains) were used as solvents with or without
      acetonitrile partitioning. Twenty crops fortified with 8 pyrethroid insecticides
      at low, medium, and high levels were analyzed. For limit of detection (LOD)
      levels, repeatability tests were completed with acetone-water as extraction
      solvent. Recoveries of 8 pyrethroid insecticides at LOD levels were 76.2-99.6%,
      with coefficients of variation (CVs) of 2.08-10.90% for narrow-bore capillary gas
      chromatography (GC) (n = 6) and 80.1-107.3% with CVs of 3.76-15.38% for wide-bore
      capillary GC (n = 6). Both acetone or acetone-water extraction with acetonitrile
      partitioning and acetonitrile or acetonitrile-water extraction with acetonitrile
      partitioning are suitable for multiresidue analysis of pyrethroid insecticides.
      However, acetonitrile and acetonitrile-water as extraction solvents were better
      than acetone and acetone-water at LOD-fortified levels. This finding was
      confirmed chromatographically with pear, cucumber, and barley control samples.

PMID- 8664589
TI  - Multiresidue method for determination of organophosphorus insecticide residues in
      fatty processed foods by gel permeation chromatography.
AB  - A multiresidue method for quantitative determination of 39 organophosphorus
      compounds (parent pesticides and their major metabolites) in 7 fatty processed
      foods is described. Samples are extracted with methylene chloride and cleaned up
      by automated gel permeation chromatography with a Biobeads SX3 column and a
      methylene chloride-cyclohexane (15 + 85) eluant. Organophosphorus compounds are
      quantitated by capillary gas-liquid chromatography with flame photometric
      detection using OV-1701 and DB-5 columns. Average recoveries from samples
      fortified at 0.025-1 mg/kg ranged from 50.6% for dichlorvos to 185% for malaoxon.
      Determination limits were between 0.005 and 0.040 micrograms/mL. Results were
      confirmed by gas chromatography/mass spectrometry with selected-ion monitoring.

PMID- 8664590
TI  - Incomplete data sets: coping with inadequate databases.
AB  - Three problems arise in handling numerical values in databases: bad data, missing
      data, and sloppy data. The effects of bad data are mitigated by using statistical
      subterfuges such as robust statistics or outlier removal. Missing data are
      replaced by creating a substitute through interpolation or by using statistics
      appropriate to unbalanced designs. Sloppy, semiquantitative data are relegated to
      innocuous positions by using nonparametric, rank, or attribute statistics. These
      techniques are illustrated by the telephone directory, a database of
      carcinogenicity test results, and a database of precision parameters derived from
      method performance (collaborative) studies.

PMID- 8664591
TI  - Rapid and simple method for determination of cholesterol in processed food.
AB  - An improved method for determination of cholesterol in processed food with only
      one extraction and without solvent removal was developed. Total time to analyze a
      sample including gas chromatographic (GC) analysis is 45 min. Food samples spiked
      with internal standard are hydrolyzed in a screw-capped vial with saturated
      methanolic KOH. Cyclohexane is added to the mixture, and the upper layer is
      analyzed by GC on a capillary column. Average recoveries of spiked white eggs are
      99 +/- 0.5%. Fifteen types of processed food containing shrimp, fish, meat,
      cheese, eggs, and vegetables were analyzed with this method and with the AOAC
      method.

PMID- 8664592
TI  - Application of triphenyltetrazolium chloride in microbial limit test of
      pharmaceuticals and cosmetics.
AB  - An alternative method was developed for counting viable microbial contaminants in
      pharmaceuticals and cosmetics with insoluble materials and low bioburden. The
      method uses triphenyltetrazolium chloride (TTC). The inhibitory effect of TTC on
      microbial growth observed by others was eliminated by adding it as an overlay,
      after incubation of sample in culture medium for 48 h. Six samples of
      pharmaceutical suspensions and 6 samples of cosmetics were evaluated by most
      probable number (MPN) and pour-plate techniques with TTC in comparison with MPN
      with subculturing. The equivalence between MPN technique with TTC and
      subculturing was demonstrated for all samples and between pour-plate and
      subculturing for 10 samples. The differences were probably due to some error
      inherent in both techniques and not from application of TTC. Comparison of
      coefficients of variation showed that plate countings were more precise than the
      MPN method, as expected.

PMID- 8664593
TI  - Detection of Salmonella spp. in eggs: DNA analyses, culture techniques, and
      serology.
AB  - A polymerase chain reaction (PCR) method for direct detection of Salmonella spp.
      in whole-shell eggs is described. The method does not require isolating strains.
      Preenrichment, rapid DNA isolation, and a nested PCR system targeting the invA
      gene enabled detection of the genus Salmonella. The specific nested PCR product
      of 283 base pairs was formed from all 21 serovars, including 43 Salmonella
      strains tested. No PCR product was formed from 56 non-Salmonella
      enterobacteriacea and other bacterial strains tested. Experiments with
      artificially contaminated eggs showed a detection limit of about 10(3)-10(4)
      colony-forming units (cfu)/egg before and about 1-10 cfu/egg after preenrichment.
      In analysis of 180 single eggs from 4 flocks and 36 pools of 5 eggs each from
      another 4 flocks from the same producer, Salmonella spp. were detected in 5 of 90
      eggs from 2 different flocks. Determination of anti-Salmonella antibodies in eggs
      yielded positive results for 2 additional and the 2 PCR-positive flocks. In
      contrast, classical selective culture detected Salmonella spp. in only 1 of 100
      eggs in one flock when 100 eggs from each flock were analyzed.

PMID- 8664594
TI  - Dairy product analysis: identification of microorganisms by mid-infrared
      spectroscopy and determination of constituents by Raman spectroscopy.
AB  - Identification of microorganisms by traditional microbiological methods is time
      consuming. The German Federal Health Office has developed a method using mid
      infrared spectroscopy to identify microorganisms rapidly. This method has been
      modified for application to microorganisms important in the dairy industry. Mid-
      and near-infrared spectroscopies are well-established methods for quantitative
      measurements of fat, protein, lactose, and solid content in a variety of
      products. A disadvantage of both methods is the huge absorption due to water;
      extraction of other components is complicated and can be achieved only
      statistically. With Raman spectroscopy, water causes less absorption. We
      investigated the use of Raman spectroscopy as a quantitative method for milk
      powder.

PMID- 8664595
TI  - Polymerase chain reaction-restriction fragment length polymorphism analysis: a
      simple method for species identification in food.
AB  - The polymerase chain reaction (PCR) technique was applied to meat species
      identification in marinated and heat-treated or fermented products and to the
      differentiation of closely related species. DNA was isolated from meat samples by
      using a DNA-binding resin and was subjected to PCR analysis. Primers used were
      complementary to conserved areas of the vertebrate mitochondrial cytochrome b
      (cytb) gene and yielded a 359 base-pair (bp) fragment, including a variable 307
      bp region. Restriction endonuclease analysis based on sequence data of those
      fragments was used for differentiation among species. Restriction fragment length
      polymorphisms (RFLPs) were detected when pig, cattle, wild boar, buffalo, sheep,
      goat, horse, chicken, and turkey amplicons were cut with AluI, RsaI, TaqI, and
      HinfI. Analysis of sausages indicates the applicability of this approach to food
      products containing meat from 3 different species. The PCR-RFLP analytical method
      detected pork in heated meat mixtures with beef at levels below 1%, and the
      method was confirmed with porcine- and bovine-specific PCR assays by amplifying
      fragments of their growth hormone genes. Inter- and intraspecific differences of
      more than 22 animal species with nearly unknown cytb DNA sequences, including
      hoofed mammals (ungulates), and poultry were determined with PCR-RFLP typing by
      using 20 different endonucleases. This typing method allowed the discrimination
      of game meats, including stag, roe deer, chamois, moose, reindeer, kangaroo,
      springbok, and other antelopes in marinated and heat-treated products.

PMID- 8664596
TI  - [The intravascular formation of kinins in the brain studied as a new approach to
      the problem of the re-circulatory complications in the surgical treatment of
      cerebral ischemia].
AB  - The improvement of blood supply in the ischemic brain (post-ischemic cerebral
      reperfusion), which results from surgical treatment, has been shown to improve
      the neurological status only in the patients who had no lower baseline levels of
      kininogens (the production of free kinins) in cerebral circulation. Poor surgical
      outcomes were noted in the cases wherein there was preoperative activated kinin
      production when blood passed through the brain. Postischemic brain reperfusion
      was concurrent with kinin production in the cerebral vascular bed in all
      examinees, but in patients with postoperative complications this process is more
      active and involves the two kinin-forming systems tissue and plasma ones. It is
      hypothesized that in the latter case kinins convert from the compensatory to the
      pathogenetic factor of secondary circulatory disorders. The correlations found
      may be used to substantiate the use of antikinin therapy and to develop a
      biochemical test that predicts possible complications after surgical treatment of
      cerebral circulatory ischemia.

PMID- 8664597
TI  - [The cholesterol content of biomembranes (an electron microscopic study)].
AB  - A new specific cholesterol marker and scanning electron microscopy were used to
      study the quantity and distribution of cholesterol in the artifical phospholipid
      membranes and in the plasmalemma of animal and human endotheliocyte and
      erythrocytes in health and in hypercholesterolemia.

PMID- 8664598
TI  - [The immunocorrective action of the new synthetic hexapeptide imunofan in
      pharmacologically induced and ecological immunodeficiency].

PMID- 8664599
TI  - [Neuroimmune interactions in normal aging and in Alzheimer disease].
AB  - The study was undertaken to examine nerve-immune processes and the specific
      visual and limbic-reticular-cortical systems by analysing visual evoked
      potentials (VEP), as well as nerve-immune relationships in 21 patients aged
      62.2e1.3 years who had Alzheimer's disease and in 15 healthy individuals of the
      same age. AD patients were found to have lower lymphocyte count, enhanced
      proliferative activity of T lymphocytes and to tend to have increased production
      of interleukin (IL-1) as compared to that in healthy individuals. In AD, latent
      periods of late EVP components are higher than normal age-specific ones. The
      relationship between VEP and immunity parameters differ in normal ageing and AD.
      In health, there is a negative correlation between the latencies of N1, P2, N2
      VEP components and the lymphocyte count and between the amplitude of a N1 VEP
      component and the production of IL-1. There is a prevalent correlation of immune
      parameters with VEP parameters in the right hemisphere. In AD, the higher
      proliferative activity of T lymphocytes is associated with more prolonged latent
      periods of N3 VEP components, suggesting that there are abnormal changes in the
      limbic-reticular-cortical systems of the brain.

PMID- 8664600
TI  - [Prostaglandins in chronic liver diseases].
AB  - The paper summarizes the results of in-depth study of the prostaglandin system in
      healthy individuals and in patients with chronic hepatic diseases.
      Radioimmunological, gas chromatographic, enzyme immunoassays, and other
      biochemical studies have first provided evidence for the relationship between the
      impaired endogenous biological synthesis of prostaglandins (PG) E, F2 alpha, I2,
      thromboxane A2, the development of metabolic and hormonal disorders and the
      severity of hepatic failure in chronic hepatitis and cirrhosis of varying
      etiology, which leads to the conclusion that PGs play an important role in the
      regulation of liver function and in the pathogenesis of chronic damages.
      Previously unknown biochemical mechanisms of decreased PGE, PGF2 alpha, and PGI2
      in this diseased organ have been revealed, which trigger the deficiency of their
      precursors (essential fatty acids), the impairment of lipid metabolism and the
      activity decline of prostaglandin synthetase and adenylate cyclase, etc. A
      concept on the multiplicity of the biochemical mechanisms responsible for
      systemic PG action, whose impairments are essential in the pathogenesis of
      chronic hepatic diseases has been forwarded. The findings are discussed by
      comparing recent data published in the literature on this problem.

PMID- 8664601
TI  - [The functional activity of anti-endotoxin factors in viral hepatitis A and B].
AB  - Bacterial endotoxins (BE) that are lipopolysaccharide complexes (LPS) are a
      structural component of the external membrane of gram-negative bacteria. In
      normalcy, BE interact with many types of cells in the mammals. In terms of the
      concentration, BE may cause cell damage or stimulate the production of many
      biological mediators, such as interleukins, prostaglandinds, alpha-TNF. Many
      gastrointestinal bacteria in humans are gram-negative and BE constantly enter the
      blood. In health, the absence of a toxic response to BE is explained by the
      presence of natural humoral and cellular antiendotoxic systems and the hepatic
      absorption of LPS. In patients with hepatitis A and B, the following indices of
      the blood antiendotoxic systems were determined: the level of antiendotoxic
      antibodies to Re-chemotype glycolipids was assessed by the passive
      hemagglutination reaction in the "Antiendotox-1-test"; the count of
      polymorphonuclear leukocyte (PMNL) fixating LPS on their own surface and
      endotoxin binding function of PMNL was in vitro measured by the strain ELISA and
      sandwich ELISA with Re-glycolipids, respectively (LPS-test); the endotoxin
      fixation function of serum high density lipoproteins (HDL) was also assessed. The
      humoral and cellular antiendotoxic systems in patients with mild advanced
      hepatitis A and B was studied when the disease was most clinically significant,
      at an early convalescence, and at convalescence itself. Finally, the findings
      indicate that there is a significant decrease in Re-antibody levels and there is
      a greater absorption ability of HDL than that in the control. Six different types
      of an antiendotoxic fixation reaction of PMNL were identified in patients with
      viral hepatitis in the different periods of the disease. The alterations observed
      may play an important role in the pathogenesis of toxemia in patients with viral
      hepatitis.

PMID- 8664602
TI  - [Collagen metabolism in hypertrophic and keloid scars].
AB  - Imbalance between the synthesis and degradation of collagen is a common sign of
      tissues of hypertrophic and cheloid scars. The fact that the collagen of abnormal
      scars of the both types have a polyfunctional linkage with a structure of
      pyridinol and high amounts of a polyfunctional linkage with a structure of
      pyrrole (Ehlich's chromogen) in the collagen of cheloid scars support the
      assumption that the collagen synthesis-degradation imbalance may be due to the
      enhanced resistance of structurally unchanged collagen to collagenolytic enzymes.
      The comparative studies of the ratio of type 1 collagen homotrimers to
      heterotrimers, that of type 1 collagen dimers to monomers, and that of types 1 to
      type 3 collagen in the pepsin extracts of abnormal scars of various age and
      patients' intact skin suggest that there are certain differences in the magnitude
      and scar age-related changes in the expression of collagen genes and
      posttranslational collagen modifications in the tissue of hypertrophic and
      cheloid scars. It is suggested that age-specific time course of collagen
      metabolic and structural changes in the abnormal scars may result from their
      alterations of the population composition of fibroblasts with a different
      phenotype.

PMID- 8664604
TI  - [The crisis of Russian medicine].

PMID- 8664603
TI  - [The ability of hemoglobin and myoglobin to evoke a spasm of the smooth
      musculature and to accelerate thrombocyte destruction. A description of serotonin
      ferroprotein receptors].
AB  - The previously unknown properties of ferroproteins (hemoglobin and myoglobin) to
      cause smooth muscle spasm and to accelerate platelet degradation are described in
      the paper. Ferroproteins are shown to interact with some serotonin receptors.
      Some serotonin receptors of smooth muscles and platelets which hemoglobin and
      myoglobin interact with are termed serotonin-ferroprotein receptors (S-Fe-pr
      receptors). The found properties of ferroproteins provide a deep insight into the
      understanding of physiological and pathophysiological processes with the
      participation of hemoglobin, myoglobin, platelets, smooth muscles, serotonin, and
      serotonin receptors.

PMID- 8664605
TI  - [The rational computer-aided design of new drugs: a review of the methods].
AB  - Progress in computer science over recent 10 years has sharply reduced both the
      cost and the time spent on designing new drugs. Various concepts in solving this
      problem are now integrated into one approach--computer-assisted rational drug
      design. It consists of two groups of methods: 1) computer-assisted analysis of
      chemical structure-biological activity relationships by QSAR, OSMR, 3D QSAR and
      CoMFA; 2) computer modelling of the interaction of a ligand (a small drug
      molecule) with its target--a biological macromolecule, which is generally a
      protein. The findings of new ligands, which would selectively bind to the well
      known protein can be done by screening the small molecules listed in some
      computer data bases. These new chemical structures can be used as a basis for
      drug designing.

PMID- 8664606
TI  - [Food safety in Russia].

PMID- 8664607
TI  - Monitoring oral anticoagulation in primary care.

PMID- 8664608
TI  - Financial meltdown for the NHS?

PMID- 8664609
TI  - Caesarean section or vaginal birth for breech presentation at term.

PMID- 8664610
TI  - Jack Kevorkian: a medical hero.

PMID- 8664612
TI  - Veterinary and industrial high pressure injection injuries.

PMID- 8664611
TI  - Heroin overdose: the case for take-home naloxone.

PMID- 8664613
TI  - HIV in plasma is best predictor of progression to AIDS.

PMID- 8664614
TI  - No cause for alarm over baby milk, says EU.

PMID- 8664615
TI  - MDU exposes drug errors.

PMID- 8664616
TI  - Britain is failing to meet targets on reducing obesity.

PMID- 8664617
TI  - Netherlands proposes tougher antismoking laws.

PMID- 8664618
TI  - Herbal stimulant causes US deaths.

PMID- 8664619
TI  - Europe's aging population.

PMID- 8664620
TI  - Cost effectiveness of lowering cholesterol concentration with statins in patients
      with and without pre-existing coronary heart disease: life table method applied
      to health authority population.
AB  - OBJECTIVES: To estimate the cost effectiveness of statins in lowering serum
      cholesterol concentration in people at varying risk of fatal cardiovascular
      disease and to explore the implications of changing the criteria for intervention
      on cost and cost effectiveness for a purchasing authority. DESIGN: A life table
      method was used to model the effect of treatment with a statin on survival over
      10 years in men and women aged 45-64. The costs of intervention were estimated
      from the direct costs of treatment, offset by savings associated with a reduction
      in coronary angiographies, non-fatal myocardial infarctions, and
      revascularisation procedures. The robustness of the model to various assumptions
      was tested in a sensitivity analysis. SETTING: Population of a typical district
      health authority. MAIN OUTCOME MEASURE: Cost per life year saved. RESULTS: The
      average cost effectiveness of treating men aged 45-64 with no history of coronary
      heart disease and a cholesterol concentration > 6.5 mmol/l for 10 years with a
      statin was 136,000 pounds per life year saved. The average cost effectiveness for
      patients with pre-existing coronary heart disease and a cholesterol concentration
      > 5.4 mmol/l was 32,000 pounds. These averages hide enormous differences in cost
      effectiveness between groups at different risk, ranging from 6000 pounds per life
      year in men aged 55-64 who have had a myocardial infarction and whose cholesterol
      concentration is above 7.2 mmol/l to 361,000 pounds per life year saved in women
      aged 45-54 with angina and a cholesterol concentration of 5.5-6.0 mmol/l.
      CONCLUSIONS: Lowering serum cholesterol concentration in patients with and
      without preexisting coronary heart disease is effective and safe, but treatment
      for all those in whom treatment is likely to be effective is not sustainable
      within current NHS resources. Data on cost effectiveness data should be taken
      into account when assessing who should be eligible for treatment.

PMID- 8664621
TI  - Relation of indoor heating with asthma, allergic sensitisation, and bronchial
      responsiveness: survey of children in south Bavaria.
AB  - OBJECTIVE: To investigate the relation between different types of heating and the
      prevalence of atopic diseases, skin test reactivity, and bronchial
      hyperresponsiveness. DESIGN: Cross sectional survey among school-children aged 9
      11 years. Skin prick tests, pulmonary function tests, and bronchial challenge in
      the children and self completion of a written questionnaire by the children's
      parents. SUBJECTS: 1958 children in a rural area in southern Bavaria, Germany.
      MAIN OUTCOME MEASURES: Prevalence of asthma, hay fever, and atopic dermatitis as
      determined by parents' answers to a questionnaire; the atopic status of the child
      assessed by skin prick tests; and bronchial responsiveness to cold air challenge
      in the children. RESULTS: After possible confounders were controlled for, the
      risk of developing hay fever (odds ratio = 0.57; 95% confidence interval 0.34 to
      0.98), atopy defined as at least one positive reaction to a panel of common
      aeroallergens (0.67; 0.49 to 0.93), sensitisation to pollen (0.60; 0.41 to 0.87),
      and of bronchial hyperresponsiveness (0.55; 0.34-0.90) was significantly lower in
      children living in homes where coal or wood was used for heating than in children
      living in homes with other heating systems. CONCLUSIONS: Factors directly or
      indirectly related to the heating system used in rural Bavarian homes decrease
      the susceptibility of children to becoming atopic and to developing bronchial
      hyperresponsiveness.

PMID- 8664622
TI  - Long-term outcome by method of delivery of fetuses in breech presentation at
      term: population based follow up.
AB  - OBJECTIVE: To compare the long-term outcome of infants delivered in breech
      presentation at term by intended mode of delivery. DESIGN: A population based
      comparison of outcomes up to school age. Data obtained from maternity, health
      visitor, and school medical records and handicap register. SETTING: Grampian
      region 1981-90. SUBJECTS: 1645 infants delivered alive at term after breech
      presentation. MAIN OUTCOME MEASURES: Handicap, developmental delay, neurological
      deficit, psychiatric referral. RESULTS: Elective caesarean section was performed
      in 590 (35.9%) cases. The remainder (1055; 64.1%) were intended vaginal
      deliveries. Handicap or other health problem was recorded in 269 (19.4%) of 1387
      infants for whom records were available. Proportions of elective caesarean
      sections and intended vaginal deliveries in this group were 37.2% (100 cases) and
      62.8% (169) respectively, almost the same as in the total cohort. There were no
      significant differences between elective caesarean section and planned vaginal
      delivery in terms of severe handicap or any other outcome measure. Case records
      were obtained for 23 of 27 infants with severe handicap. 11 (47.8%) were
      delivered by elective caesarean section. Of these, three had undiagnosed
      congenital abnormalities and seven were unexplained. Of the 12 (52.2%) planned
      vaginal deliveries, in only one was handicap possibly attributable to delivery
      and four cases were unavoidable even if elective caesarean section had been
      planned. CONCLUSION: In selected cases of breech presentation at term planned
      vaginal delivery with caesarean section if necessary remains as safe as elective
      caesarean section in terms of long term handicap. It was not possible to
      determine whether particular babies would have fared better had they been
      delivered by elective caesarean section.

PMID- 8664623
TI  - Prevalence of antibiotic resistance and serotypes in pneumococci in England and
      Wales: results of observational surveys in 1990 and 1995.
AB  - OBJECTIVE: To assess the prevalence of antibiotic resistance and serotype
      distribution among pneumococci in England and Wales in 1990 and 1995. DESIGN:
      Observational surveys in March 1990 and March 1995. During two weeks in each
      survey period all pneumococci isolated in public health laboratories in England
      and Wales were collected and assessed for sensitivity to antibiotics and the
      distribution of serogroups or serotypes. SETTING: The network of public health
      laboratories throughout England and Wales. SUBJECTS: 1127 individual patient
      isolates of Streptococcus pneumoniae obtained during the two surveys. MAIN
      OUTCOME MEASURES: Sensitivity or resistance to a range of antibiotics; serogroup
      or serotype. RESULTS: The prevalence of intermediate or full resistance to
      penicillin increased from 1.5% in 1990 to 3.9% in 1995 and resistance to
      erythromycin increased from 2.8% to 8.6%. About 92% of isolates belonged to
      serogroups or serotypes included in the currently available pneumococcal vaccine.
      CONCLUSION: Resistance to penicillin and erythromycin has increased among
      pneumococci in England and Wales. Continued surveillance to assess further
      increases in the prevalence of pneumococcal resistance to antibiotics is
      essential.

PMID- 8664624
TI  - Seasonality of birth of patients with childhood diabetes in Britain.

PMID- 8664625
TI  - Rate of bone loss from lumbar spine in women with distal forearm fracture.

PMID- 8664626
TI  - Health of cohort of heroin addicts from London clinics: 22 year follow up.

PMID- 8664628
TI  - Knowledge of emergency compulsory detention procedures among general
      practitioners in Edinburgh: sample survey.

PMID- 8664627
TI  - Treatment of urinary incontinence in women in general practice: observational
      study.
AB  - OBJECTIVE: To examine what is attainable when treating urinary incontinence in
      women in general practice. DESIGN: Observational study with 12 months' follow up.
      Interview and clinical examination before, during, and after treatment of women
      seeking help for urinary incontinence in general practice. SETTING: General
      practice in the rural district of Rissa, Norway. SUBJECTS: 105 women aged 20 or
      more with urinary incontinence. INTERVENTIONS: Treatment with pelvic floor
      exercises, electrostimulation, oestrogen, anticholinergic drugs, bladder
      training, and protective pads. MAIN OUTCOME MEASURES: Subjective and objective
      measures of urinary incontinence; number of patients referred to a specialist.
      RESULTS: After 12 months' follow up 70% (69/99) of the women were cured or much
      better; the mean score on a 100 mm visual analogue scale decreased from 37 to 20
      mm; and the proportion of women who were greatly bothered by their incontinence
      decreased by 62%. 20% (20/98) of women became continent, and the percentage of
      women with severe incontinence decreased from 64% (63/99) to 28% (27/98). Mean
      leakage per 24 hours measured by a pad test decreased from 28 g at the start of
      treatment to 13 g after 12 months. The number of light weight pads or sanitary
      towels decreased from 1.6 to 0.6 a day. In all, 17/105 (16%) patients were
      referred to a specialist. CONCLUSIONS: Urinary incontinence in women can be
      effectively managed in general practice with fairly simple treatment. Most women
      will be satisfied with the results.

PMID- 8664629
TI  - Survey of HIV patients' views on confidentiality and non-discrimination policies
      in general practice.

PMID- 8664630
TI  - Clinical immunology.

PMID- 8664631
TI  - Lessons from international experience in controlling pharmaceutical expenditure.
      I: Influencing patients.
AB  - This is the first of three papers to review international policies to control
      spending on drugs and improve the efficiency of drug use. Policies can target
      three main groups: patients, prescribing doctors, and the drugs industry. In this
      paper we examine policies aimed at patients, particularly restrictions on
      reimbursement (such as prescription charges). Rigorous experimental and quasi
      experimental studies suggest that policies to limit the level of reimbursement of
      drugs reduce the use of essential as well as non-essential drugs and may do more
      harm than good.

PMID- 8664632
TI  - Delayed diagnosis of Kawasaki disease presenting with massive lymphadenopathy and
      airway obstruction.

PMID- 8664633
TI  - Comparing several groups using analysis of variance.

PMID- 8664634
TI  - Government secrecy. Baby milk advertising is a case in point.

PMID- 8664635
TI  - Government secrecy. Ombudsman is available when codes of practice fail.

PMID- 8664636
TI  - Government secrecy. Safety of air travellers is not protected.

PMID- 8664637
TI  - Vaccines and Guillain-Barre syndrome.

PMID- 8664638
TI  - Providing intensive care. Cases of trauma can be managed in general intensive
      therapy units.

PMID- 8664639
TI  - Providing intensive care. Centralised paediatric intensive care beds are blocked.

PMID- 8664640
TI  - Providing intensive care. Service can't cope with troughs in demand, let alone
      peaks.

PMID- 8664641
TI  - Disodium pamidronate has beneficial effect in Paget's disease of bone.

PMID- 8664642
TI  - Retention of drugs in venous access port chamber. Cause of drugs' effect is not
      clear.

PMID- 8664644
TI  - Retention of drugs in venous access port chamber. Port systems can safely be used
      for anaesthesia.

PMID- 8664643
TI  - Retention of drugs in venous access port chamber. Drug did not cause collapse of
      patient.

PMID- 8664645
TI  - British urologists provide a cost effective service.

PMID- 8664646
TI  - Using condoms to prevent transmission of HIV. Abstinence and fidelity are only
      fully effective means of prevention.

PMID- 8664647
TI  - Using condoms to prevent transmission of HIV. Condoms have an appreciable failure
      rate.

PMID- 8664648
TI  - Poor diet in pregnancy may be a proxy for some other hostile influence on fetal
      growth.

PMID- 8664649
TI  - Not gaining patients' consent in trials is deceitful.

PMID- 8664650
TI  - Raised adult blood pressure linked to failure to achieve growth potential in
      utero.

PMID- 8664651
TI  - Flavonoid intake and coronary mortality. Other antinutritional factors may also
      have a role.

PMID- 8664652
TI  - Flavonoid intake and coronary mortality. Objective data trials are needed.

PMID- 8664653
TI  - GP's management of acute back pain. Is evidence based.

PMID- 8664654
TI  - GP's management of acute back pain. Referral letters are inadequate.

PMID- 8664655
TI  - GP's management of acute back pain. Research on which to base guidelines is
      possible in primary care.

PMID- 8664656
TI  - Routine feedback to GPs who request microbiological tests is effective.

PMID- 8664657
TI  - Research priorities in complementary medicine.

PMID- 8664658
TI  - British health insurers fail to learn lessons from the US.

PMID- 8664659
TI  - Rationing health care: moving the debate forward.

PMID- 8664660
TI  - Clinical guidelines in the independent health care sector.

PMID- 8664661
TI  - Contraceptive implants.

PMID- 8664662
TI  - Health workers and the baby food industry.

PMID- 8664663
TI  - Is the human testis still an organ at risk?

PMID- 8664664
TI  - Variability in risk of gastrointestinal complications with individual non
      steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.
AB  - OBJECTIVE: To compare the relative risks of serious gastrointestinal
      complications reported with individual non-steroidal anti-inflammatory drugs.
      DESIGN: Systematic review of controlled epidemiological studies that found a
      relation between use of the drugs and admission to hospital for haemorrhage or
      perforation. SETTING: Hospital and community based case-control and cohort
      studies. MAIN OUTCOME MEASURES: (a) Estimated relative risks of gastrointestinal
      complications with use of individual drugs, exposure to ibuprofen being used as
      reference; (b) a ranking that best summarised the sequence of relative risks
      observed in the studies. RESULTS: 12 studies met the inclusion criteria. 11
      provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest
      or equal lowest for risk in 10 of the 11 studies. Pooled relative risks
      calculated with exposure to ibuprofen used as reference were all significantly
      greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was
      associated with the lowest relative risk, followed by diclofenac. Azapropazone,
      tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin,
      naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of
      ibuprofen were associated with relative risks similar to those with naproxen and
      indomethacin. CONCLUSIONS: The low risk of serious gastrointestinal complications
      with ibuprofen seems to be attributable mainly to the low doses of the drug used
      in clinical practice. In higher doses ibuprofen is associated with a similar risk
      to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low
      dosage as first line treatment would substantially reduce the morbidity and
      mortality due to serious gastrointestinal toxicity from these drugs.

PMID- 8664665
TI  - Teenagers' knowledge of emergency contraception: questionnaire survey in south
      east Scotland.
AB  - OBJECTIVE: To determine the level of knowledge of emergency contraception among
      14 and 15 year olds. DESIGN: Confidential questionnaire survey. SETTING: 10
      secondary schools in Lothian, south east Scotland. SUBJECTS: 1206 pupils
      predominantly (98.7%) aged 14 and 15 in the fourth year of secondary school. MAIN
      OUTCOME MEASURES: Knowledge of the existence of emergency contraception; of its
      safety, efficacy, and time limits; and of where to obtain it. RESULTS: 1121
      (93.0%) fourth year pupils aged 14-16 had heard of emergency contraception. 194
      girls (32.7%) and 168 boys (27.5%) had experienced sexual intercourse. Of girls
      who had experienced sexual intercourse, 61 (31.4%) had used emergency
      contraception. Knowledge of correct time limits was poor, sexually active girls
      being the most knowledgeable. Pupils attending schools ranked lower than the
      national average for academic attainment were less likely to have heard of
      emergency contraception and more likely to have been sexually active. 861 (76.8%)
      pupils knew they could obtain emergency contraception from their doctor. 925
      (82.5%) pupils believed emergency contraception to be effective but 398 (35.5%)
      thought it more dangerous than the oral contraceptive pill. CONCLUSIONS: One
      third of sexually active girls aged under 16 in Lothian have used emergency
      contraception. This may help explain the fairly constant teenage pregnancy rates
      despite increasing sexual activity. Scottish teenagers are well informed about
      the existence of emergency contraception. However, many do not know when and how
      to access it properly. Health education initiatives should target teenagers from
      less academic schools as they are more likely to be sexually active at a young
      age and are less well informed about emergency contraception.

PMID- 8664667
TI  - Prevalence and patterns of smoking in Delhi: cross sectional study.
AB  - OBJECTIVE: To determine the prevalence and predictors of smoking in urban India.
      DESIGN: Cross sectional. SETTING: Delhi, urban India, 1985-6. SUBJECTS: Random
      sample of 13,558 men and women aged 25-64 years. MAIN OUTCOME MEASURES: Smoking
      prevalence; subjects who were currently smoking and who had smoked > or = 100
      cigarettes or beedis or chuttas in their lifetime were defined as smokers.
      RESULTS: 45% (95% confidence interval 43.8 to 46.2) of men and 7% (6.4 to 7.6) of
      women were smokers. Education was the strongest predictor of smoking, and men
      with no education were 1.8 (1.5 to 2.0) times more likely to be smokers than
      those with college education, and women with no education were 3.7 (2.9 to 4.8)
      times more likely. Among smokers, 52.6% of men and 4.9% of women smoked only
      cigarettes while the others also smoked beedi or chutta. Compared with cigarette
      smokers, people smoking beedi or chutta were more likely to be older and married;
      have lower education, manual occupations, incomes, and body mass index; and not
      drink alcohol or take part in leisure exercise. CONCLUSION: There are two
      subpopulations of smokers in urban India, and the prevention strategy required
      for each may be different. The educated, white collar cigarette smoker in India
      might respond to measures that make non-smoking fashionable, while the less
      educated, low income people who smoke beedi or chutta may need strategies aimed
      at socioeconomic improvement.

PMID- 8664666
TI  - Lifetime exposure to environmental lead and children's intelligence at 11-13
      years: the Port Pirie cohort study.
AB  - OBJECTIVE: To examine the association between environmental exposure to lead and
      children's intelligence at age 11-13 years, and to assess the implications of
      exposure in the first seven years of life for later childhood development.
      DESIGN: Prospective cohort study. SUBJECTS: 375 children born in or around the
      lead smelting town of Port Pirie, Australia, between 1979 and 1982. MAIN OUTCOME
      MEASURE: Children's intelligence quotient (IQ) measured at 11-13 years of age.
      RESULTS: IQ was inversely associated with both antenatal and postnatal blood lead
      concentrations. Verbal, performance, and full scale IQ were inversely related to
      blood lead concentration with no apparent threshold. Multivariate analyses
      indicated that after adjustment for a wide range of confounders, the postnatal
      blood lead concentrations (particularly within the age range 15 months to 7
      years) exhibited inverse associations with IQ. Strong associations with IQ were
      observed for lifetime average blood lead concentrations at various ages. The
      expected mean full scale IQ declined by 3.0 points (95% confidence interval 0.07
      to 5.93) for an increase in lifetime average blood lead concentration from 0.48
      to 0.96 mumol/l (10 to 20 micrograms/dl). CONCLUSION: Exposure to environmental
      lead during the first seven years of life is associated with cognitive deficits
      that seem to persist into later childhood.

PMID- 8664668
TI  - Case-control study of suicide by discharged psychiatric patients.

PMID- 8664669
TI  - Fibrinolytic activity and clotting factors in ischaemic heart disease in women.

PMID- 8664670
TI  - Needs for care from a demand led community psychiatric service: a study of
      patients with major mental illness.
AB  - OBJECTIVE--To measure needs for care of patients aged 18-65 years with major
      mental illness. DESIGN: Identification of everyone in one area seen by a health
      professional within the previous five years because of a psychotic disorder.
      Interview of a one in three sample of patients and their main carers with the
      cardinal needs schedule. SETTING--Hamilton, a socially deprived district of
      Scotland. SUBJECTS--71 subjects were interviewed from the original sample of 263
      patients. MAIN OUTCOME MEASURES--"Cardinal problems" in seven clinical and eight
      social areas of functioning; these are defined as problems requiring action.
      "Needs"-cardinal problems for which suitable interventions exist but have not
      been tried recently. RESULTS--High levels of morbidity were found. 30 interviewed
      patients (42%; 95% confidence interval 31% to 54%) had one or more clinical
      needs. 35 (49%; 38% to 61%) had one or more social needs. Skills to deal with all
      but seven needs in the sample were available at the time of investigation.
      Patients not being seen by the community mental health team were similar in
      severity and levels of need to those who were on the community team's caseload.
      Care was unequivocally and severely inadequate for four patients. Shortcomings in
      service delivery usually arose from failure to monitor some patients at home.
      Problems were not due to shortage of acute psychiatric beds nor the absence of an
      elaborate assertive community care team. CONCLUSIONS--Systematic assessment of
      needs with research instruments can give valuable insights into the successes and
      failures of community care of people with major mental illness. Most needs could
      be dealt with in these patients but in our area (and probably most other parts of
      the United Kingdom) this would entail diversion of resources from people with
      less severe disorders.

PMID- 8664671
TI  - Media coverage of the Child B case.
AB  - The case of a girl with leukaemia, known as Child B, hit the headlines in March
      1995 when her father refused to accept the advice of doctors who counselled
      against further treatment and took Cambridge and Huntingdon Health Authority to
      court for refusing to fund chemotherapy and a second bone transplant for her in
      the private sector. British national newspapers varied greatly in the way they
      covered the case. Some paid little attention to clinical considerations and
      presented the case as an example of rationing based on financial considerations.
      Their selective presentations meant that anyone reading just one newspaper would
      have received only limited and partial information. If members of the public are
      to participate in debates about treatment decisions and health care rationing,
      means other than the media will need to be found to inform and involve them.

PMID- 8664672
TI  - Setting priorities: is there a role for citizens' juries?
AB  - Citizens' juries are an attempt to meaningfully involve members of the public in
      decisions which affect them in their own communities. The Institute for Public
      Policy Research and Cambridge and Huntingdon Health Authority have recently
      piloted the first jury in the United Kingdom. Sixteen jurors sat for four days,
      hearing evidence from a number of expert witnesses. The jurors were asked to
      consider how priorities for health care should be set, according to what
      criteria, and to what extent the public should be involved in this process. This
      pilot was also an attempt to assess the process itself, and our initial
      evaluation indicates that, given enough time and information, the public is
      willing and able to contribute to the debate about priority setting in health
      care.

PMID- 8664673
TI  - The rationing agenda in the NHS. Rationing Agenda Group.
AB  - The Rationing Agenda Group has been founded to deepen the British debate on
      rationing health care. It believes that rationing in health care is inevitable
      and that the public must be involved in the debate about issues relating to
      rationing. The group comprises people from all parts of health care, none of whom
      represent either their group or their institutions. RAG has begun by producing
      this document, which attempts to set an agenda of all the issues that need to be
      considered when debating the rationing of health care. We hope for responses to
      the document. The next stage will be to incorporate the responses into the
      agenda. Then RAG will divide the agenda into manageable chunks and commission
      expert, detailed commentaries. From this material a final paper will be published
      and used to prompt public debate. This stage should be reached early in 1997.
      While these papers are being prepared RAG is developing ways to involve the
      public in the debate and evaluate the whole process. We present as neutrally as
      possible all the issues related to rationing and priority setting in the NHS. We
      focus on the NHS for two reasons. Firstly, for those of us resident in the United
      Kingdom the NHS is the health care system with which we are most familiar and
      most concerned. Secondly, focusing on one system alone allows more coherent
      analysis than would be possible if issues in other systems were included as well.
      Our concern is with the delivery of health care, not its finance, though we
      discuss the possible effects of changing the financing system of the NHS.
      Finally, though our position is neutral, we hold two substantive views--namely,
      that rationing is unavoidable and that there should be more explicit debate about
      the principles and issues concerned. We consider the issues under four headings:
      preliminaries, ethics, democracy, and empirical questions. Preliminaries deal
      with the semantics of rationing, whether rationing is necessary, and with the
      range of services to which rationing relates. Under ethics and democracy are the
      substantive issues of principle and theory. The final section deals with
      empirical questions and those relating to the practicality of various strategies.

PMID- 8664674
TI  - Addison's disease presenting as reduced insulin requirement in insulin dependent
      diabetes.

PMID- 8664675
TI  - Proposed academy of medicine. An academy would be inappropriate.

PMID- 8664676
TI  - Proposed academy of medicine. Profession is already more united than ever before.

PMID- 8664677
TI  - Physicians clarify their proposal for a National Council for Health Care
      priorities.

PMID- 8664678
TI  - Debate over NHS-wide network is centered on wrong issue.

PMID- 8664680
TI  - Rationing in the NHS. Social decisions associated with rationing are not yet
      acceptable.

PMID- 8664679
TI  - Rationing in the NHS. Public does not always favour lifesaving, acute
      interventions.

PMID- 8664681
TI  - Air pollution related to transport. Diesel is the main problem.

PMID- 8664682
TI  - Air pollution related to transport. Doctors should support parliamentary bill.

PMID- 8664683
TI  - Asthma epidemics and air pollution. Upper respiratory tract infection and fall in
      atmospheric temperature may lead to attacks of childhood asthma.

PMID- 8664684
TI  - Asthma epidemics and air pollution. Epidemic of asthma was not associated with
      episode of air pollution.

PMID- 8664685
TI  - Ozone and childhood wheezy episodes. Meteorological confounders must be
      considered.

PMID- 8664686
TI  - Ozone and childhood wheezy episodes. Needs testing as an a priori hypothesis.

PMID- 8664687
TI  - Ozone and childhood wheezy episodes. Results may have been confounded by viral
      infections and faulty equipment.

PMID- 8664688
TI  - Chickenpox and steroid cards. Patients need information.

PMID- 8664689
TI  - Metabolic effects of hormone replacement preparations.

PMID- 8664690
TI  - Chickenpox and steroid cards. Amended card is used in Oxford.

PMID- 8664691
TI  - Doctors Reform Society in Australia defends its reputation.

PMID- 8664692
TI  - Evaluation of a primary care anticoagulant clinic. Authors did not present enough
      data.

PMID- 8664693
TI  - Evaluation of a primary care anticoagulant clinic. Issue of quality control was
      not addressed.

PMID- 8664694
TI  - Evaluation of a primary care anticoagulant clinic. Reporting of results should be
      standardised.

PMID- 8664695
TI  - GPs in Glasgow are in favour of primary care emergency centres.

PMID- 8664696
TI  - Evidence-based medicine. Reviews may not be sufficiently critical of evidence.

PMID- 8664697
TI  - Evidence-based medicine. Letters pages are essential for peer review.

PMID- 8664698
TI  - Myths in medicine. Story that early retirement is associated with longevity is
      often quoted.

PMID- 8664699
TI  - Sunscreens, suntans, and skin cancer.

PMID- 8664700
TI  - European health policy: must redefine its raison d'etre.

PMID- 8664701
TI  - Specialist rehabilitation after stroke.

PMID- 8664702
TI  - Primary care: restoring the jewel in the crown.

PMID- 8664703
TI  - The rights of HIV infected healthcare workers.

PMID- 8664704
TI  - Preparing the BMJ for the electronic revolution.

PMID- 8664705
TI  - Outrage in Japan over euthanasia without consent.

PMID- 8664706
TI  - India's women get poor deal on health care, says World Bank.

PMID- 8664707
TI  - Survey finds NHS budgets pushed to the limit.

PMID- 8664708
TI  - US responds to new suggestion of Gulf War syndrome.

PMID- 8664709
TI  - US court rules on confidentiality.

PMID- 8664710
TI  - Cockroaches linked with asthma.

PMID- 8664711
TI  - US grants asylum to woman fleeing clitoridectomy.

PMID- 8664712
TI  - Non-transplanted organs can be used for research.

PMID- 8664713
TI  - US is short of contraception choices.

PMID- 8664714
TI  - Britain's over-60s are still getting around.

PMID- 8664715
TI  - Survival of 1476 patients initially resuscitated from out of hospital cardiac
      arrest.
AB  - OBJECTIVES: To determine the short and long term outcome of patients admitted to
      hospital after initially successful resuscitation from cardiac arrest out of
      hospital. DESIGN: Review of ambulance and hospital records. Follow up of
      mortality by "flagging" with the registrar general. Cox proportional hazards
      analysis of predictors of mortality in patients discharged alive from hospital.
      SETTING: Scottish Ambulance Service and acute hospitals throughout Scotland.
      SUBJECTS: 1476 patients admitted to a hospital ward, of whom 680 (46%) were
      discharged alive. MAIN OUTCOME MEASURES: Survival to hospital discharge,
      neurological status at discharge, time to death, and cause of death after
      discharge. RESULTS: The median duration of hospital stay was 10 days
      (interquartile range 8-15) in patients discharged alive and 1 (1-4) day in those
      dying in hospital. Neurological status at discharge in survivors was normal or
      mildly impaired in 605 (89%), moderately impaired in 58 (8.5%), and severely
      impaired in 13 (2%); one patient was comatose. Direct discharge to home occurred
      in 622 (91%) cases. The 680 discharged survivors were followed up for a median of
      25 (range 0-68) months. There were 176 deaths, of which 81 were sudden cardiac
      deaths, 55 were non-sudden cardiac deaths, and 40 were due to other causes. The
      product limit estimate of 4 year survival after discharge was 68%. The
      independent predictors of mortality on follow up were increased age, treatment
      for heart failure, and cardiac arrest not due to definite myocardial infarction.
      CONCLUSION: About 40% of initial survivors of resuscitation out of hospital are
      discharged home without major neurological disability. Patients at high risk of
      subsequent cardiac death can be identified and may benefit from further
      cardiological evaluation.

PMID- 8664716
TI  - Prospective evaluation of eligibility for thrombolytic therapy in acute
      myocardial infarction.
AB  - OBJECTIVES: To determine the proportion of patients presenting with acute
      myocardial infarction who are eligible for thrombolytic therapy. DESIGN: Cohort
      follow up study. SETTING: The four coronary care units in Auckland, New Zealand.
      SUBJECTS: All 3014 patients presenting to the units with suspected myocardial
      infarction in 1993. MAIN OUTCOME MEASURES: Eligibility for reperfusion with
      thrombolytic therapy (presentation within 12 hours of the onset of ischaemic
      chest pain with ST elevation > or = 2 mm in leads V1-V3, ST elevation > or = 1 mm
      in any other two contiguous leads, or new left bundle branch block); proportions
      of (a) patients eligible for reperfusion and (b) patients with contraindications
      to thrombolysis; death (including causes); definite myocardial infarction.
      RESULTS: 948 patients had definite myocardial infarction, 124 probable myocardial
      infarction, and nine ST elevation but no infarction; 1274 patients had unstable
      angina and 659 chest pain of other causes. Of patients with definite or probable
      myocardial infarction, 576 (53.3%) were eligible for reperfusion, 39 had definite
      contraindications to thrombolysis (risk of bleeding). Hence 49.7% of patients
      (537/1081) were eligible for thrombolysis and 43.5% (470) received this
      treatment. Hospital mortality among patients eligible for reperfusion was 11.7%
      (55/470 cases) among those who received thrombolysis and 17.0% (18/106) among
      those who did not. CONCLUSIONS: On current criteria about half of patients
      admitted to coronary care units with definite or probable myocardial infarction
      are eligible for thrombolytic therapy. Few eligible patients have definite
      contraindications to thrombolytic therapy. Mortality for all community admissions
      for myocardial infarction remains high.

PMID- 8664717
TI  - Specialist nurse support for patients with stroke in the community: a randomised
      controlled trial.
AB  - OBJECTIVE: To evaluate whether specialist nurse visits enhance the social
      integration and perceived health of patients with stroke or alleviate stress in
      carers in longer term stroke care. DESIGN: Stratified randomised controlled
      trial; both groups assessed at time of recruitment and at 3, 6, and 12 months.
      SETTING: Patients with disability related to new stroke who lived in their own
      homes in the Bradford Metropolitan District. SUBJECTS: 240 patients aged 60 years
      or over, randomly allocated to control group (n = 120) or intervention group (n =
      120). Intervention--Visits by specialist outreach nurses over 12 months to
      provide information, advice, and support; minimum of six visits during the first
      six months. The control group received no visits. MAIN OUTCOME MEASURES: The
      Barthel index (functional ability), the Frenchay activities index (social
      activity), the Nottingham health profile (perceived health status). Stress among
      carers was indicated by the general health questionnaire-28 (28 items). The
      nurses recorded their interventions in trial diaries. RESULTS: There were no
      significant differences in perceived health, social activities, or stress among
      carers between the treatment and control groups at any of the assessments points.
      A subgroup of mildly disabled patients with stroke (Barthel index 15-19) had an
      improved social outcome at six months (Frenchay activities index, Median
      difference 3 (95% confidence interval 0 to 6; P = 0.03) and for the full 12
      months of follow up (analysis of covariance P = 0.01) compared with the control
      group. CONCLUSIONS: The specialist nurse intervention resulted in a small
      improvement in social activities only for the mildly disabled patients. No proved
      strategy yet exists that can be recommended to address the psychosocial
      difficulties of patients with stroke and their families.

PMID- 8664718
TI  - Hormone replacement therapy and tumour grade in breast cancer: prospective study
      in screening unit.

PMID- 8664719
TI  - Community leg ulcer clinics: a comparative study in two health authorities.
AB  - OBJECTIVE: To compare the outcome and cost of care for leg ulcers in community
      leg ulcer clinics in Stockport District Health authority with Trafford District
      Health Authority as a control. DESIGN: Detailed cost and efficacy studies
      conducted prospectively over a three month period in both districts both before
      and one year after the introduction of five leg ulcer clinics in Stockport.
      SETTING: Two large district health authorities of broad socioeconomic mix and
      total population of 540,000. PATIENTS: All patients receiving treatment for an
      active leg ulcer, irrespective of the profession or location of their carer. MAIN
      OUTCOME MEASURES: The proportion of ulcerated limbs completely healed within
      three months and total cost of leg ulcer care. RESULTS: The introduction of
      community clinics in Stockport improved healing of leg ulcers from 66/252 (26%)
      in 1993 to 99/233 (42%) in 1994 (P < 0.001) compared with in Trafford, where
      47/203 (23%) healed in 1993 and only 43/213 (20%) in 1994. This improved result
      in Stockport was achieved while the annual expenditure on care of leg ulcers was
      reduced from 409,991 pounds to only 253,371 pounds. In the same year the cost of
      leg ulcer care in Trafford increased from 556,039 pounds to 673,318 pounds.
      CONCLUSION: In the first year after the introduction of community clinics, before
      most patients in Stockport had access to these clinics, healing of leg ulcers was
      already improved whereas costs were reduced.

PMID- 8664720
TI  - Improving vaccine storage in general practice refrigerators.

PMID- 8664721
TI  - High ambient temperature: a spurious cause of hypokalaemia.

PMID- 8664722
TI  - Commentary: replication of results.

PMID- 8664723
TI  - Measurement error.

PMID- 8664724
TI  - Speech and language therapy: does it work?

PMID- 8664725
TI  - Inflation in epidemiology: "the proof and measurement of association between two
      things" revisited.

PMID- 8664727
TI  - The Ljubljana Charter on reforming health care.

PMID- 8664726
TI  - Commentary: strength and importance of the relation of dietary salt to blood
      pressure. Intersalt Steering and Editorial Committee.

PMID- 8664728
TI  - Neuroleptic prescribing in residents of nursing homes. Geographical differences
      make extrapolation difficult.

PMID- 8664729
TI  - Neuroleptic prescribing in residents of nursing homes. Dangerous to extrapolate
      local audit findings.

PMID- 8664730
TI  - Neuroleptic prescribing in residents of nursing homes. Access to psychiatrists
      should be improved.

PMID- 8664731
TI  - Neuroleptic prescribing in residents of nursing homes. Behaviour problems are
      underdocumented.

PMID- 8664732
TI  - Neuroleptic prescribing in residents of nursing homes. Substantial study is
      imminent.

PMID- 8664733
TI  - Neuroleptic prescribing in residents of nursing homes. Use may be justified if
      other factors have been considered.

PMID- 8664734
TI  - Costs and getting ethical approval deter doctors from participating in
      multicentre trials.

PMID- 8664735
TI  - Diazepam is more useful than magnesium for immediate control of eclampsia.

PMID- 8664736
TI  - Screening for diabetic retinopathy. Diabetic patients should continue to be
      assessed by direct ophthalmoscopy.

PMID- 8664737
TI  - Screening for diabetic retinopathy. True costs are different from those given in
      paper.

PMID- 8664738
TI  - Drug testing has been used in schools for several years.

PMID- 8664739
TI  - Drug users and people with HIV infection need better care in prison.

PMID- 8664740
TI  - Providing intensive care. Central bed register would divert attention away from
      need for adequate resources.

PMID- 8664741
TI  - Providing intensive care. For neurosciences, proposals are "too little too late".

PMID- 8664743
TI  - Surgeons will not want jobs in hospitals that do not do emergency surgery.

PMID- 8664742
TI  - Providing intensive care. Severe problems with interhospital transfer of
      critically ill children will continue.

PMID- 8664744
TI  - Television and radio should be used to disseminate important information.

PMID- 8664745
TI  - Gynaecological problems should continue to be treated in primary care initially.

PMID- 8664746
TI  - Home versus hospital delivery. Analysis was flawed.

PMID- 8664747
TI  - Home versus hospital delivery. Good quality evidence is lacking.

PMID- 8664748
TI  - Global commissioning by GPs could be detrimental to rehabilitation services.

PMID- 8664749
TI  - Making British blood supply safer.

PMID- 8664750
TI  - Study of breast feeding and hypertrophic pyloric stenosis does not conflict with
      others.

PMID- 8664751
TI  - Wrong comparison quoted for breast screening.

PMID- 8664752
TI  - Guidelines on managing stable angina omit important point.

PMID- 8664753
TI  - Helping sick doctors. Confidential voluntary scheme has been set up in Britain.

PMID- 8664754
TI  - Helping sick doctors. Stress management interventions need to be evaluated.

PMID- 8664755
TI  - Torture continues in Algeria.

PMID- 8664756
TI  - "Coming out"--a personal dilemma.

PMID- 8664757
TI  - Storage and disposal of embryos and gametes.

PMID- 8664758
TI  - Company challenges melatonin sales ban.

PMID- 8664759
TI  - US doctors reaffirm opposition to euthanasia.

PMID- 8664760
TI  - Misdiagnosis of the vegetative state: retrospective study in a rehabilitation
      unit.
AB  - OBJECTIVE: To identify the number of patients who were misdiagnosed as being in
      the vegetative state and their characteristics. DESIGN: Retrospective study of
      the clinical records of the medical, occupational therapy, and clinical
      psychology departments. SETTING: 20 bed unit specialising in the rehabilitation
      of patients with profound brain damage, including the vegetative state. SUBJECTS:
      40 patients admitted between 1992 and 1995 with a referral diagnosis of
      vegetative state. OUTCOME MEASURES: Patients who showed an ability to communicate
      consistently using eye pointing or a touch sensitive single switch buzzer.
      RESULTS: Of the 40 patients referred as being in the vegetative state, 17 (43%)
      were considered as having been misdiagnosed; seven of these had been presumed to
      be vegetative for longer than one year, including three for over four years. Most
      of the misdiagnosed patients were blind or severely visually impaired. All
      patients remained severely physically disabled, but nearly all were able to
      communicate their preference in quality of life issues-some to a high level.
      CONCLUSIONS: The vegetative state needs considerable skill to diagnose, requiring
      assessment over a period of time; diagnosis cannot be made, even by the most
      experienced clinician, from a bedside assessment. Accurate diagnosis is possible
      but requires the skills of a multidisciplinary team experienced in the management
      of people with complex disabilities. Recognition of awareness is essential if an
      optimal quality of life is to be achieved and to avoid inappropriate approaches
      to the courts for a declaration for withdrawal of tube feeding.

PMID- 8664761
TI  - Commentary: the importance of patients' consent for publication.

PMID- 8664762
TI  - Association of common health symptoms with bullying in primary school children.
AB  - OBJECTIVE: To estimate the prevalence of bullying in primary school children and
      to examine its association with common symptoms in childhood. DESIGN:
      Semistructured health interview conducted by school nurses as part of a school
      medical. SETTING: Newham, east London. SUBJECTS: All children in year 4 of school
      during the academic year 1992-93. MAIN OUTCOME MEASURES: Reported bullying and
      common health symptoms. RESULTS: 2962 children (93.1% of those on the school
      roll) were interviewed (ages 7.6 to 10.0 years). Information about bullying was
      not recorded for 114 children, 22.4% (95% confidence interval 20.9 to 24.0) of
      children for whom information was available reported that they had been bullied.
      There was an association between children reporting being bullied sometimes or
      more often and reporting not sleeping well (odds ratio 3.6, 2.5 to 5.2), bed
      wetting (1.7, 1.3 to 2.4), feeling sad (3.6, 1.9 to 6.8), and experiencing more
      than occasional headaches (2.4, 1.8 to 3.4) and tummy aches (2.4, 1.8 to 3.3). A
      significant trend for increasing risk of symptoms with increased frequency of
      bullying was shown for all reported health symptoms (P < 0.001). CONCLUSIONS:
      Health professionals seeing primary schoolchildren who present with headaches,
      tummy ache, feeling sad or very sad, bed wetting, and sleeping difficulties
      should consider bullying as a possible contributory factor.

PMID- 8664763
TI  - Career preferences of doctors who qualified in the United Kingdom in 1993
      compared with those of doctors qualifying in 1974, 1977, 1980, and 1983.
AB  - OBJECTIVE: To report the career preferences of doctors who qualified in the
      United Kingdom in 1993 and to compare their choices with those of earlier cohorts
      of qualifiers. DESIGN: Postal questionnaires with structured questions, including
      questions about choice of future long term career, were sent to doctors a year
      after qualification. SETTING: United Kingdom. SUBJECTS: All medical qualifiers of
      1993, comparing their replies with those from earlier studies of the qualifiers
      of 1974, 1977, 1980, and 1983. MAIN OUTCOME MEASURES: Choice of future long term
      career and certainty of choice expressed at the end of the first year after
      qualification. RESULTS: Questionnaires were sent to 3657 doctors. 2621 (71.7%)
      replied. Of the 2621 respondents, 70.5% (1849) stated that their first preference
      was for a career in hospital practice, 25.8% (677) specified general practice,
      1.0% (25) specified public health medicine or community health, 1.4% (36)
      specified careers outside medicine, and 1.3% (34) did not state a choice. By
      contrast, 44.7% (1416/3168) of the doctors in the 1983 cohort had specified that
      their first preference was general practice. Among the 1993 qualifiers, general
      practice was the first career choice of 17.5% of men (227/1297) and 34.0% of
      women (450/1324). Only 7.4% of men (96/1297) stated that they definitely wanted
      to enter general practice. Only 7.8% (103/1324) of women qualifiers in 1993
      expressed a career preference for surgical specialties. Within hospital practice,
      comparing 1993 with 1983, choices for the medical specialties and for accident
      and emergency medicine rose and those for pathology fell. Women were less
      definite than men about their choice of future long term career. CONCLUSIONS: If
      the 1993 cohort is typical of the current generation of young doctors, there has
      been a substantial shift away from general practice as a career choice expressed
      at the end of the preregistration year. General practice was much more popular
      among women than men. Few women opted for surgery. The sex imbalance in the
      percentage of doctors who choose different mainstreams of medical practice seems
      set to continue.

PMID- 8664764
TI  - Career preferences of doctors.

PMID- 8664765
TI  - Posthumous storage and use of sperm and embryos: survey of opinion of treatment
      centres.

PMID- 8664766
TI  - False positive results for leucocytes in urine dipstick test with common
      antibiotics.

PMID- 8664767
TI  - Long-term outcome of patients with neurotic illness in general practice.
AB  - OBJECTIVE: To determine the 11 year outcome of neurotic disorder in general
      practice. DESIGN: Cohort study over 11 years. SETTING: Two general practices in
      Warwickshire England. SUBJECTS: 100 patients selected to be representative of
      those identified nationally by general practitioners as having neurotic
      disorders. MAIN OUTCOME MEASURES: Mortality, morbidity, and use of health
      services. RESULTS: At 11 years 87 subjects were traced. The 11 year standardised
      mortality ratio was 173 (95% confidence interval 164 to 200). 47 were cases on
      the general health questionnaire, 32 had a relapsing or chronic psychiatric
      course, and 49 a relapsing or chronic physical course. Treatment for psychiatric
      illness was mainly drugs. The mean number of consultations per year was 10.8
      (median 8.7). A persistent psychiatric diagnosis at one year follow up was
      associated with high attendance ( > 12 visits a year for 11 years) at follow up
      after age, sex, and physical illness were adjusted for. Severity of psychiatric
      illness (general health questionnaire score) at outset predicted general health
      questionnaire score at 11 year follow up, course of psychiatric illness, and high
      consultation rate. CONCLUSION: These data support the view that a neurotic
      illness can become chronic and is associated with raised mortality from all
      causes and high use of services. Such patients need effective intervention,
      particularly those with a more severe illness who do not recover within one year.

PMID- 8664768
TI  - A new short form individual quality of life measure (SEIQoL-DW): application in a
      cohort of individuals with HIV/AIDS.
AB  - Quality of life is an increasingly important outcome measure in medicine and
      health care. Many measures of quality of life present patients with predetermined
      lists of questions that may or may not be relevant to the individual patient.
      This paper describes a brief measure, the SEIQoL-DW, which is derived from the
      schedule for evaluation of individual quality of life (SEIQoL). The measure
      allows respondents to nominate the areas of life which are most important, rate
      their level of functioning or satisfaction with each, and indicate the relative
      importance of each to their overall quality of life. Given its practicality and
      brevity, the measure should prove particularly useful in clinical situations
      where patient generated data on quality of life is important. This article
      describes the first clinical application of the measure, assessing the quality of
      life of a cohort of patients with HIV/AIDS managed in general practice.

PMID- 8664769
TI  - Careers advice for doctors.

PMID- 8664770
TI  - Placebo mania.

PMID- 8664772
TI  - Trials to assess equivalence: the importance of rigorous methods.
AB  - The aim of an equivalence trial is to show the therapeutic equivalence of two
      treatments, usually a new drug under development and an existing drug for the
      same disease used as a standard active comparator. Unfortunately the principles
      that govern the design, conduct, and analysis of equivalence trials are not as
      well understood as they should be. Consequently such trials often include too few
      patients or have intrinsic design biases which tend towards the conclusion of no
      difference. In addition the application of hypothesis testing in analysing and
      interpreting data from such trials sometimes compounds the drawing of
      inappropriate conclusions, and the inclusion and exclusion of patients from
      analysis may be poorly managed. The design of equivalence trials should mirror
      that of earlier successful trials of the active comparator as closely as
      possible. Patient losses and other deviations from the protocol should be
      minimised; analysis strategies to deal with unavoidable problems should not
      centre on an "intention to treat" analysis but should seek to show the similarity
      of results from a range of approaches. Analysis should be based on confidence
      intervals, and this also carries implications for the estimation of the required
      numbers of patients at the design stage.

PMID- 8664773
TI  - Measuring diastolic blood pressure in pregnancy.

PMID- 8664771
TI  - Lessons from international experience in controlling pharmaceutical expenditure.
      III: Regulating industry.
AB  - This is the third of three papers that review international policies to control
      spending on drugs and to improve the efficiency of drug use. This paper reviews
      policies regulating the supply of drugs, particularly licensing and reimbursement
      controls, price and profit regulation. Price and profit controls contain few
      incentives for improving cost effective use of drugs, and focus on cost
      containment and profitability of domestic industry. Carefully monitored economic
      evaluation could lead to improvements in efficiency and benefits to patients and
      the health care system.

PMID- 8664774
TI  - Septic arthritis in osteoarthritic hips.

PMID- 8664775
TI  - Measurement error and correlation coefficients.

PMID- 8664776
TI  - Declining sperm count. Data from two groups should not have been combined in
      analysis.

PMID- 8664778
TI  - Declining sperm count. Results cannot be generalised.

PMID- 8664777
TI  - Declining sperm count. Semen quality has declined among men born in France since
      1950.

PMID- 8664779
TI  - Declining sperm count. Increasing evidence that Young's syndrome is associated
      with mercury.

PMID- 8664780
TI  - Declining sperm count. Recent decline may be relatively late stage of long-term
      process.

PMID- 8664781
TI  - Declining sperm count. Rise in semen quality between 1970 and 1990 in meta
      analysis was non-significant.

PMID- 8664782
TI  - Declining sperm count. Results of Scottish study may be due to confounding with
      age.

PMID- 8664783
TI  - Directly observed treatment for tuberculosis. Could be provided by community
      pharmacists supervising consumption of methadone.

PMID- 8664784
TI  - Extrapyramidal signs should be sought more often in Alzheimer's disease.

PMID- 8664786
TI  - Evidence for efficacy of topical acyclovir in recurrent herpes labialis is weak.

PMID- 8664787
TI  - Strategic plans for vascular services have not been put into effect.

PMID- 8664785
TI  - Directly observed treatment for tuberculosis. Treatment strategies will need to
      be changed because of drug resistance.

PMID- 8664788
TI  - Neonatal circumcision and penile cancer. Evidence that circumcision is protective
      is overwhelming.

PMID- 8664789
TI  - Neonatal circumcision and penile cancer. Authors ignored main conclusion of study
      that they cited.

PMID- 8664790
TI  - Prenatal and postnatal prevalence of Turner's syndrome. Data presented were
      insufficient to challenge specificity of prenatal diagnosis.

PMID- 8664791
TI  - Smoking in public places. Restaurants' policies do not reflect public's
      preferences.

PMID- 8664792
TI  - Smoking in public places. Vast majority of both smokers and non-smokers favour at
      least a partial ban.

PMID- 8664793
TI  - Vietnamese people in study may have had language difficulties.

PMID- 8664794
TI  - Medical students do not think they have authority to advise patients to stop
      smoking.

PMID- 8664796
TI  - Volunteering children for bone marrow donation. Studies show large discrepancies
      between views of surrogate decision makers and patients.

PMID- 8664795
TI  - Making decisions with children. Asking children to participate in decisions about
      their care undermines parents' position.

PMID- 8664797
TI  - Misdiagnosing the persistent vegetative state.

PMID- 8664798
TI  - Moving medical malpractice insurance to Medical Insurance Agency may be
      expensive.

PMID- 8664799
TI  - Volunteering children for bone marrow donation. Children may be able to make
      their own decisions.

PMID- 8664800
TI  - Volunteering children for bone marrow donation. Children's views should have been
      represented in discussion.

PMID- 8664801
TI  - Warfarin should be available as 0.5 mg tablet.

PMID- 8664802
TI  - Measuring health outcomes.

PMID- 8664803
TI  - WHO warns that multidrug resistant TB will spread.

PMID- 8664804
TI  - Court rules that care cannot be withdrawn due to cash cuts.

PMID- 8664806
TI  - The problem of childhood smoking.

PMID- 8664805
TI  - The role of iron in cancer.
AB  - Numerous laboratory and clinical investigations over the past few decades have
      observed that one of the dangers of iron is its ability to favour neoplastic cell
      growth. The metal is carcinogenic due to its catalytic effect on the formation of
      hydroxyl radicals, suppression of the activity of host defence cells and
      promotion of cancer cell multiplication. In both animals and humans, primary
      neoplasms develop at body sites of excessive iron deposits. The invaded host
      attempts to withhold iron from the cancer cells via sequestration of the metal in
      newly formed ferritin. The host also endeavours to withdraw the metal from cancer
      cells via macrophage synthesis of nitric oxide. Quantitative evaluation of body
      iron and of iron-withholding proteins has prognostic value in cancer patients.
      Procedures associated with lowering host iron intake and inducing host cell iron
      efflux can assist in prevention and management of neoplastic diseases.
      Pharmaceutical methods for depriving neoplastic cells of iron are being developed
      in experimental and clinical protocols.

PMID- 8664807
TI  - Breast size and mammographic pattern in relation to breast cancer risk.
AB  - The relation of Wolfe's parenchymal patterns and radiographically-assessed breast
      size with breast cancer risk was evaluated in a population-based nested case
      control study in Uppsala, Sweden. All women who attended a mammographic screening
      programme in Uppsala county starting in 1988 have been followed for the
      occurrence of breast cancer through 1993. The analysis was based on 295 cases and
      589 age-matched controls, whose mammograms were blindly evaluated for parenchymal
      pattern and breast size. Women with P2 or DY pattern had a significantly elevated
      risk of breast cancer compared with women with N1 or P1 (OR = 2.09; 95% CI = 1.52
      2.86). There was an inverse association of breast size with breast cancer risk,
      which disappeared after adjusting for parenchymal pattern, because breasts of
      smaller size tended to have high-risk parenchymal patterns. It is concluded that
      in Swedish women, and perhaps in Caucasian women in general, small breast size is
      associated with increasing breast risk through its association with high-risk
      parenchymal pattern. This is in contrast to the fact that Asian women, who in
      general have breasts of smaller size, have low prevalence of high-risk
      parenchymal pattern as well as low rates of breast cancer.

PMID- 8664808
TI  - The measurement of adenoma occurrence.
AB  - Adenomatous polyps are regarded as the dominant precursor lesion of colon cancer.
      For four decades the occurrence of adenomas has been investigated, both in
      observational studies and in controlled, randomized cancer-prevention studies.
      During this period, little consensus has been reached with regard to the data
      that should be reported in such studies. The emerging consensus on the methods of
      analysing the results does not have a firm biostatistical basis, and does not
      deal appropriately with the phenomenon of colonoscopy avoidance. We review a
      simple biostatistical method that is appropriate, and apply it to a selected
      recent series of studies. Our finding is that there are common patterns of
      adenoma occurrence across these studies, with a rate of 0.3-0.4 per year in the
      first year following polypectomy, dropping to 0.1-0.15 in subsequent years. The
      method of analysis also serves to highlight exceptions to this pattern.

PMID- 8664809
TI  - Screening for gastrointestinal neoplasia: efficacy and cost of two different
      approaches in a clinical rehabilitation centre.
AB  - Mortality from colorectal cancer (CRC) can be reduced by screening of
      asymptomatic individuals and by removal of colorectal adenomas (CRA). It is still
      under debate which screening method should be used. In a clinical rehabilitation
      centre we compared two widely different approaches: faecal occult blood testing
      (FOBT) with subsequent endoscopy of test-positives in an unselected patient
      group, and primary sigmoidoscopy of asymptomatic persons between 50 and 60 years
      of age. Between January 1988 and October 1991 a FOBT was offered to all-
      symptomatic and asymptomatic--6,500 in-patients of a clinical rehabilitation
      centre and lower/upper GI-endoscopy was suggested to test-positives (study A). In
      the latter half of this period 1,166 persons without bowel symptoms and/or
      disease and aged 50-60 years were invited to a screening sigmoidoscopy (study B).
      In study A 95% of the patients (n = 6,234) returned a complete FOBT, which was
      positive in 186 (2.98%). 126 of these 186 patients (68%) accepted further
      investigation, and a total of 78 sigmoidoscopies, 78 colonoscopies and 47
      gastroscopies were performed. Six patients in whom a malignancy was detected (1
      gastric, 1 rectal and 4 colonic; all in a curable stage) underwent surgery. In 28
      patients CRA were identified and removed by snare excision. In study B 658/1,166
      asymptomatic in-patients accepted the screening sigmoidoscopy (56%). Rectosigmoid
      adenomas were identified in 153 (23%). One rectal cancer was found. Of these
      cases, 116 underwent an additional colonoscopy, disclosing proximal adenomas in
      39 patients (33.6%). The cost of identifying one CRA-bearer was $1,436 in study A
      and $271 in study B (assuming: FOBT = $3.00; sigmoidoscopy = $63.00; colonoscopy
      = $135; gastroscopy = $108). In study A, the cost of identifying one patient with
      cancer would have been $5,435, if the cost of identifying one CRA-bearer was set
      to $271 as in study B. Screening for CRC was well-accepted in the health
      orientated environment of a rehabilitation centre. The cost of identifying a CRA
      bearer with screening sigmoidoscopy was about one-fifth of that using
      preselection with a FOBT. However, with FOBT a higher number of cancers was
      found. For the discovery of CRA, mass-screening with sigmoidoscopy of persons
      above the age of 50 years can be advised. For the detection of both CRA and CRC,
      screening with FOBT and subsequent endoscopy is an acceptable and cost-effective
      method.

PMID- 8664810
TI  - Hereditary and environmental risk factors; clinical and laboratory risk matters
      for head and neck, especially oral, cancer and precancer.
AB  - The continuing high incidence and mortality of squamous cell carcinoma of the
      upper aerodigestive tract in South Asia, parts of France and central Europe,
      together with a rising incidence and mortality from a lower base elsewhere in the
      Western world, stimulates continuing research on risk factors and risk markers.
      Tobaccos (smoked and smokeless), heavy alcohol consumption, and areca nut remain
      the dominant risk factors, with confirmation of the protective effects of diets
      rich in antioxidants. There is emerging evidence of a small, but real, risk
      associated with occupational and other air pollution, and with family, part of
      which may be hereditary. Markers in peripheral blood and saliva are
      underexploited. Clinical staging and histological grading methods continue to be
      refined, with improved prognostic value, much aided by newer and simpler methods
      for estimating cell proliferation and apoptosis. Data on the significance of
      viral genes are still inadequate, but there is good progress describing the
      epidemiology of chromosomal abnormalities and abberations of a growing list of
      oncogenes and tumour suppressor genes. Unfortunately, as yet, these have only
      limited longitudinal or prognostic data.

PMID- 8664812
TI  - Tobacco-related cancers in Madras, India.
AB  - Tobacco is the single most important cause of avoidable morbidity and early
      mortality in many countries. Tobacco-related cancer (TRC) cases constitute 48.2%
      in men and 20.1% in women of the total cancers seen in India per year. The age
      adjusted rate (AAR) of TRC ranges from 44 to 67 among males and from 23 to 27
      among females in different registries in India. Of these cases, only 15% were in
      the lung. The religion-specific risk ratio of the TRC sites in Madras suggests
      that when Muslims were compared with Hindus pharynx and lung were the two sites
      that showed higher risk in males, while the pharynx, lung and oesophagus had
      higher risk in females. When Christians were compared with Hindus, lung cancer
      was found to have higher risk and cancer of the oesophagus lower risk in males,
      while cancer of the mouth had lower risk in females. The overall percentage
      increase in AAR of TRCs in males was 39.7 and in females was 20.1 for the period
      1987-91, compared with 1982-86, with variation in the percentage increase in all
      the TRC sites in Madras. The change in the incident rate of TRCs seen in Madras
      is consistent with the change in the per capita consumption of tobacco over the
      years.

PMID- 8664811
TI  - Antioxidants, Helicobacter pylori and stomach cancer in Venezuela.
AB  - A randomized chemoprevention trial on precancerous lesions of the stomach is
      being conducted in Tachira State, Venezuela. The aims of the study are to
      evaluate the efficacy of vitamin supplementation in preventing the progression
      rate of precancerous lesions. Here we report on the pilot phase of the study in
      which two antioxidant preparations were evaluated on their ability to raise
      antioxidant levels in plasma and in gastric juice. The study aimed also to
      determine the antibiotic sensitivity profiles of Helicobacter pylori isolates
      prevalent in the area. Forty-three subjects with precancerous lesions (chronic
      gastritis, chronic atrophic gastritis, intestinal metaplasia and dysplasia) of
      the stomach were randomized to one of two antioxidant treatments. Treatment 1
      (250 mg of standard vitamin C, 200 mg of vitamin E and 6 mg of beta-carotene
      three times a day) or treatment 2 (150 mg of standard vitamin C, 500 mg of slow
      release vitamin C, 75 mg of vitamin E and 15 mg of beta-carotene once a day) for
      7 days. Blood levels of total vitamin C, beta-carotene and alpha-tocopherol and
      gastric juice levels of ascorbic acid and total vitamin C were measured before
      and after treatment on day 8. Both treatments increased the plasma levels of
      total vitamin C, beta-carotene and alpha-tocopherol/cholesterol but not those of
      ascorbic acid or total vitamin C in gastric juice. Treatment 1 was the best
      choice and resulted in a greater increase in the plasma levels of beta-carotene
      and alpha-tocopherol. H. pylori was cultured from 90% of the gastric biopsies; 35
      isolates were identified which were highly resistant to metronidazole, a front
      line antibiotic recommended against H. pylori in other settings.

PMID- 8664813
TI  - Invasive cutaneous melanoma in The Netherlands, 1989-1990.
AB  - The Breslow or tumour thickness is the most important prognostic factor for
      survival from cutaneous melanoma. We studied the occurrence of melanoma in
      relation to tumour thickness and subsite in The Netherlands. Data on all newly
      diagnosed invasive cutaneous melanomas in the Netherlands Cancer Registry in 1989
      and 1990 were used to estimate age and sex-specific incidence rates according to
      site and depth of tumour invasion. The incidence among women (9.5 per 100,000
      person-years) was relatively high compared with other European countries. The
      predominant site was the trunk among men and the leg among women. After age 70,
      one-third of the melanomas were observed in the head and neck region. According
      to data from PALGA, the national computerized archive of Dutch pathology
      laboratories, 37% of the men and 29% of the women had a melanoma > 1.5 mm thick.
      Among persons younger than age 60, 26% had a melanoma > 1.5 mm thick, compared
      with 44% among those 60 years and over. In both registries the absolute and
      relative risks for a thicker melanoma increased with age, particularly for men.
      In The Netherlands, preventive measures for population groups with thicker
      melanomas should be targeted towards men and elderly persons.

PMID- 8664814
TI  - A post-Chernobyl rise in thyroid cancer in Connecticut, USA.
AB  - Recent analyses of children in Belarus and the Ukraine are the first to document
      large numbers of excess thyroid cancer cases only 4 years after exposure to
      radiation. In Connecticut (USA), a thyroid cancer increase of a much smaller
      magnitude occurred in 1990-93, 4-7 years after the Chernobyl accident, for both
      children and adults. Similar changes also occurred in the states of Iowa and
      Utah, which like Connecticut were exposed to low levels of radionuclides from
      Chernobyl fallout during May and June of 1986. Historical data from Connecticut
      also reveal substantial increases in thyroid cancer incidence about 5 years after
      large releases of iodine-131 from distant US nuclear weapons plants, after the
      largest atmospheric US atomic weapons tests in Nevada, and after substantial
      releases of iodine-131 from the Millstone nuclear power plant in Connecticut.
      Further analysis of this apparent 5-year latency period will enhance
      understanding of ionizing radiation's effects on thyroid function and on human
      health in general.

PMID- 8664815
TI  - Taiwanese-German workshop on tumour prevention.

PMID- 8664816
TI  - Indoor air pollution in India.

PMID- 8664818
TI  - Hyponatraemia and hiccups.
AB  - BACKGROUND: Hiccups are observed in many patients with hypohatraemia. We
      performed a case-control study to evaluate their association in a referral
      teaching hospital in South India. METHODS: Fifty consecutive patients who
      developed hiccups during an 18-month period were studied. They were categorized
      according to age group and diagnosis and controls matched for age and sex were
      selected from patients admitted on the same day in the medical wards. Hiccups
      were graded on a four-point severity scale at recruitment and every day till day
      7 or till hiccups subsided. RESULTS: The step-wise logistic regression analysis
      done to establish independent association showed that for every 10 mEq/L
      reduction in serum sodium, patients were 17 times (p = 0.001; confidence
      interval: 4-87) at risk of developing hiccups. The only other significant
      determinant of the symptom was the diagnostic category of renal failure (odds
      ratio = 128; confidence interval: 1-1420). The number of patients who had
      hyponatraemia with varying severity of hiccups showed a dose-response
      relationship. The crude odds ratios were 7, 58 and 320 for mild, moderate and
      severe hiccups. CONCLUSION: There is a strong and independent association between
      hyponatraemia and hiccups in hospitalized patients. A causative association is
      suggested by the dose-response relationship demonstrated in the study. In many
      hospitals in developing countries where measurement of serum sodium is difficult
      and unreliable, it is important to be aware of this association since it can be
      easily corrected.

PMID- 8664817
TI  - Causes and treatment of persistent hiccups.

PMID- 8664819
TI  - Dynamics of contraceptive practice amongst urban Indian women.
AB  - BACKGROUND: Most studies on knowledge, attitude and practice regarding
      contraceptives have been conducted in rural areas and urban slums. In this study,
      a mixed urban population was surveyed. SUBJECTS: Two thousand parous women from
      different social and educational backgrounds residing in the metropolis of Mumbai
      (Bombay), Maharashtra were included in the study. RESULTS: Fifty per cent of
      illiterates, semi-literates and highschool educated, and 80% of college-educated
      couples said that they had no gender preferences for their children, but actual
      practice belied this. Regardless of the level of education, 25%, 75% and 95% of
      all couples were sexually active by 6 weeks, 3 months and 6 months after
      childbirth. Awareness regarding the availability of various contraceptives
      increased with education; 20% of all graduate couples used condoms or the rhythm
      method immediately after marriage. After the birth of their first child, 80% of
      educated couples used spacing methods whereas even after the birth of their third
      child more than 50% of the uneducated did not. The major complaint of the
      intrauterine device users was menorrhagia and abdominal pain, while that of pill
      users was nausea, giddiness and headache. Spacing methods were popular among the
      educated, and terminal ones among the uneducated. Steroidal contraceptive pills
      were not popular with any group, regardless of the level of education.
      CONCLUSION: Education was the main variable in the decisions regarding the family
      size, spacing interval, contraceptive awareness, its use immediately after
      marriage and during the postpartum period.

PMID- 8664820
TI  - Effect of indoor air pollution on the respiratory system of women using different
      fuels for cooking in an urban slum of Pondicherry.
AB  - BACKGROUND: Some of the highest exposures to air pollutants in developing
      countries occur inside homes where biofuels are used for daily cooking.
      Inhalation of these pollutants may cause deleterious effects on health. We
      studied the effects of exposure to indoor air pollution from the use of cooking
      fuels on lung functions and respiratory symptoms in women aged 15-60 years.
      METHODS: The study was conducted in Kuruchikuppam, an urban slum in Pondicherry.
      The study participants were 105 women using biofuels, 105 using kerosene and 105
      using liquid petroleum gas (LPG), selected from among 1117 women aged 15-60
      years, by a stratified random sampling technique. These women were interviewed at
      home to collect information about exposure to fuel smoke and presence of
      respiratory symptoms. Lung functions were assessed by measuring forced vital
      capacity (FVC), forced expiratory volume in the first second (FEV1) and peak
      expiratory flow rate (PEFR). Occurrence of respiratory symptoms over six months
      was noted by making monthly follow up visits. RESULTS: Women using biofuels
      experienced more respiratory symptoms (23%) than those using kerosene (13%;p >
      0.05) or LPG (8%; p < 0.05). Lung functions-FVC, FEV1, FEV1% and PEFR-were
      significantly lower in biofuel users compared with both kerosene (p < 0.01) and
      LPG users (p < 0.001). Lung functions in kerosene users also were significantly
      poorer when compared with LPG users (p < 0.01). Predicted pulmonary functions
      using multiple regression equations, derived from the data set of the present
      study, indicated that women using biofuels were more liable to have reduced
      pulmonary functions than women using kerosene or LPG. CONCLUSION: Women exposed
      to biofuel smoke suffer more from respiratory illnesses and have decreased
      pulmonary functions compared with women exposed to kerosene or LPG smoke. To
      reduce pollutant exposures we recommend the use of smokeless chullas or cleaner
      fuels such as charcoal, biogas and kerosene.

PMID- 8664821
TI  - The quality of life in successful live-related renal allograft recipients in
      India.
AB  - BACKGROUND: The high cost of maintenance of haemodialysis makes most patients in
      India and elsewhere opt for a renal transplant. The degree of rehabilitation can
      best be assessed by evaluating the quality of life in successful recipients.
      METHODS: We studied vocational rehabilitation, social relations, sexual and
      married life, psychological status and life satisfaction in 51 successful live
      related renal allograft recipients using Schwab's depressive scale, Bigot's life
      satisfaction index and the Kamofsky physical scale. RESULTS: Eight-four per cent
      of our patients had returned to their original jobs. Ninety-eight per cent of
      patients had a Kamofsky scale of 90-100 and 81% were leading a normal married
      life. Ninety-four per cent of them led an active social life. CONCLUSION:
      Successful live-related renal transplantation is associated with a good quality
      of life and should be the treatment of choice for patients with end-stage renal
      disease.

PMID- 8664822
TI  - Development of vaccines against falciparum malaria.
AB  - Falciparum malaria is a leading cause of death in many countries. Drug resistance
      has emerged as a major cause for concern, increasing the pathogenic potential of
      the parasite. So far vaccines have been an elusive option. We discuss here some
      of the antigens and vaccines that show promise and on which studies are in
      progress.

PMID- 8664823
TI  - Stroke and dementia with familial occurrence.

PMID- 8664824
TI  - Anticonvulsants in eclampsia: is this the final answer?

PMID- 8664825
TI  - Headache.

PMID- 8664826
TI  - UNICEF's call to greatness--an open letter to Ms Carol Bellamy, Executive
      Director, United Nations Children's Fund.

PMID- 8664827
TI  - Which are the best undergraduate medical colleges in India?

PMID- 8664829
TI  - The CPA and doctors: little cause for cheer.

PMID- 8664828
TI  - Government hospitals and the CPA.

PMID- 8664830
TI  - Do the bells toll for our public sector hospitals?

PMID- 8664831
TI  - Transplantation of Human Organs Act, 1994.

PMID- 8664832
TI  - "Kits' of anti-tubercular drugs.

PMID- 8664833
TI  - Polio eradication programme in India.

PMID- 8664834
TI  - The HIV-tobacco theorem.

PMID- 8664835
TI  - Smoking and chewing of tobacco in relation to cancer of the upper alimentary
      tract. 1955.

PMID- 8664836
TI  - [Phage T4 segE gene "mobility": high frequency of segE gene transfer from the
      plasmid into the phage genome depends on the intactness of this gene].

PMID- 8664837
TI  - [Regulation by an antioxidant of growth, composition, and physico-chemical
      features of lipids from Saccharomyces cerevisiae].

PMID- 8664838
TI  - [Negative control of proliferation depends on protein biosynthesis in resting
      cells].

PMID- 8664839
TI  - Studies on migration and orientation of elk (Alces alces L. Mammalia)

PMID- 8664840
TI  - [A new protein of the microsomal oxidation system in the retina].

PMID- 8664841
TI  - [Role of enzymes in the nonspecific cutaneous glands in the marking behavior of
      field voles of the Clethrionomys species].

PMID- 8664842
TI  - [Factors limiting performance in the triathlon].
AB  - Triathlon is a multievent sport (swimming, cycling, running). Long duration
      triathlons can induce physiological stress that can be modulated by environmental
      conditions. Certain factors promote performance, others limit it. A minimal level
      of maximal oxygen uptake is required, but it does not always determine the
      performance. For triathletes, the low hematocrit values do not reflect anemia and
      therefore do not limit performance. The appearance of clinical signs of
      dehydration and of digestive impairment may limit performance. The performance in
      swimming does not play the most important role in triathlon performance, but the
      physiological conditions in which the first transition is made can limit
      performance in the two following events; this is also the case for the second
      transition. Triathlon races cause muscle damage whose signs persist several days.
      Given the hormonal responses and the indices of muscle damage, it appears
      necessary to rest at least 5 days to avoid over-training. It is difficult to
      define precisely how much one should train for each of the three events. However,
      it can be concluded that triathlon training has to be taken as a whole.

PMID- 8664843
TI  - Comparison of aero-bars versus traditional cycling postures on physiological
      parameters during submaximal cycling.
AB  - The purpose of this investigation was to quantify the difference in energy
      expenditure between traditional cycling handlebars and aero-bars during outdoor
      submaximal cycling. Eleven trained cyclists (age = 29.3 +/- 1.9 years, weight =
      69.4 +/- 3.8 kg, VO2max = 58.1 +/- 2.0 ml.kg-1.min-1) were randomly assigned a
      sequence of three hand positions: brake hoods (BH), drop-bars (DB), and aero-bars
      (AB). Subjects cycled at 30 km.h-1 in one position for 5 minutes, then recovered
      until HR fell below 120 bpm. This was then repeated for the other hand positions.
      All cycling was completed on a standard racing bike fitted with aero-bars. Tire
      pressure was held constant for all trials. A portable telemetric system (Cosmed K
      2) was used to measure VO2, VE and heart rate (HR) during the trials. No
      statistical differences were observed between AB and DB. Significant differences
      (p < .05) were found between BH (VE = 66.1 +/- 2.7 L.min-1; HR = 152 +/- 4 bpm;
      VO2 = 1.56 +/- .15 L.min-1) and AB (VE = 61.3 +/- 2.8 L.min-1; HR = 146 +/- 4
      bpm; VO2 = 1.31 +/- .10 L.min-1). AB provides an energy savings over the
      traditional BH cycling posture.

PMID- 8664844
TI  - Simultaneous assessment of isometric forces in fast- and slow-twitch muscles of
      single rat hindlimbs in situ.
AB  - An apparatus, consisting of a pair of small strain gauge transducers, was
      designed for the simultaneous assessment of isometric contractile function in two
      muscles, composed of a predominance of either fast- or slow-twitch fibers, and
      within a single rat hindlimb in situ. This facilitates assessment of mechanical
      performance of two separate muscles under identical conditions. In anesthetized
      rats (N = 10), the voltages and frequencies required to produce isometric twitch
      and tetanic forces from the soleus (SOL) and extensor digitorum longus (EDL)
      muscles were determined. The apparatus was then used to demonstrate the
      simultaneous assessment of forces produced by the SOL and EDL from the same
      hindlimbs (n = 5) during 30 min of fatigue and 30 min of recovery. With this
      apparatus, data collected were comparable to published data. The apparatus can be
      used for the simultaneous assessment of isometric contractile function and
      fatigue in both a fast- and a slow-twitch muscle of a single rat hindlimb in
      situ.

PMID- 8664845
TI  - Anaerobic capacity: a maximal anaerobic running test versus the maximal
      accumulated oxygen deficit.
AB  - The present investigation evaluates a maximal anaerobic running test (MART)
      against the maximal accumulated oxygen deficit (MAOD) for the determination of
      anaerobic capacity. Essentially, this involved comparing 18 male students
      performing two randomly assigned supramaximal runs to exhaustion on separate
      days. Post warm-up and 1, 3, and 6 min postexercise capillary blood samples were
      taken during both tests for plasma blood lactate (BLa) determination. In the MART
      only, blood ammonia (BNH3) concentration was measured, while capillary blood
      samples were additionally taken after every second sprint for BLa determination.
      Anaerobic capacity, measured as oxygen equivalents in the MART protocol, averaged
      112.2 +/- 5.2 ml.kg-1.min-1. Oxygen deficit, representing the anaerobic capacity
      in the MAOD test, was an average of 74.6 +/- 7.3 ml.kg-1. There was a significant
      correlation between the MART and MAOD (r = .83, p < .001). BLa values obtained
      over time in the two tests showed no significant difference, nor was there any
      difference in the peak BLa recorded. Peak BNH3 concentration recorded was
      significantly increased from resting levels at exhaustion during the MART.

PMID- 8664847
TI  - Determination of accumulated O2 deficit in exhaustive short-duration exercise.
AB  - Usually, an initial step in determining accumulated O2 deficit is the estimation
      of the O2 demand of high intensity exercise by extrapolation from VO2 measured
      during steadystate submaximal exercise. It was hypothesized that O2 deficit could
      be determined without the need to estimate O2 demand by extrapolation. Ten women
      performed all-out cycle ergometer exercise tests at each of four power outputs
      selected so that exhaustion would occur after 90 to 600 s. Power output (W),
      accumulated VO2 (ml), and time to exhaustion (s) were measured in each test and
      then fit to the following equation: O2 deficit (ml) = O2 demand (ml.min-1.W
      1).time (min).power (W) - accumulated VO2 (ml). This procedure generated values
      for two parameters (O2 demand and O2 deficit) for each subject. The O2 deficit
      was also calculated for each individual using conventional methods. The values
      for O2 deficit obtained using the two methods were correlated (r = .96, p < .01),
      and the value obtained using the experimental method tended to be larger, t(9) =
      2.15, p = .06. It is concluded that O2 demand and O2 deficit can be determined
      from the results of several high-intensity tests without the need to extrapolate
      from submaximal exercise to estimate the O2 demands of supramaximal exercise.

PMID- 8664846
TI  - Allometry of anaerobic performance: a gender comparison.
AB  - Physiological variables must often be scaled for body size differences to permit
      meaningful comparisons between groups. Using multivariate allometric scaling
      (MAS), this study aimed to compare the anaerobic performance of adult males and
      females in 12 pairs matched for physical activity status. Peak power output (PPO)
      was assessed via a 30-s supramaximal cycle ergometer test. Fat-free mass (FFM)
      and thigh muscle and bone cross-sectional area (CSA) were determined
      anthropometrically and served as indicators of active musculature. The MAS
      revealed power functions of the form PPO = a.gender.FFMb (or CSAb). Common b
      exponents of 0.1 were identified for both FFM and CSA (negative allometry). Sex
      differences were found in absolute PPO (1,252 vs. 681 W, p < .05). Comparison of
      scaled PPO data via ANCOVA (FFM0.1 and CSA0.1 entered as covariates) did not
      eliminate the sex difference (adjusted means 1,243 vs. 690 W, p < .05). The
      results suggest that the superior anaerobic performance of males in this sample
      is independent of size of the involved musculature.

PMID- 8664848
TI  - Early effect of mosquito larvae extract on mouse cells proliferation in vivo.
AB  - It has been demonstrated that mosquito larvae crude extract has an inhibiting
      effect on the mitotic rate of several mouse cell populations. The sampling period
      was 16-24 h after treatment, when mitotic peak normally occurs. The present paper
      reports the effect of mosquito larvae crude extract on the proliferation of
      hepatocytes, renocytes, Lieberkhun crypt enterocytes, and sialocytes. In this
      case, the sampling period covered the dark phase of the day, during the first 12
      h after treatment. Colchicine-arrested metaphases were controlled at 20/04, 00/08
      and 04/12 (Time of Day/Time Post Injection). The mitotic rate was significantly
      increased in hepatocytes and renocytes and inhibited in duodenum enterocytes. In
      view of the time chosen to administer the treatments and the time elapsed until
      sampling, we conclude a probable effect of the extract at the G2-M point of the
      cell cycle.

PMID- 8664849
TI  - An ICAM-1 like cell adhesion molecule is responsible for CD34 positive
      haemopoietic stem cells adhesion to bone-marrow stroma.
AB  - The microenvironment in the haematopoietic organs plays an important role in
      regulating and sustaining differentiation and self-renewal of haematopoietic stem
      cells. Although crucial for stem cell maintenance and homing, the stromal cell
      stem cell interactions are poorly understood. Here we show that an ICAM-like
      molecule is responsible for stem cell adhesion to stromal cells in vitro. The
      molecule was characterized by a monoclonal antibody 3E10. Immunoblotting results
      indicated that the molecule had an electrophoretic mobility equal to that of
      intercellular cell adhesion molecule-1 (ICAM-1). Binding inhibition assays,
      however, showed that inhibition of binding of enriched CD34 cells by 3E10 was
      more prominent in comparison with that of ICAM-1.

PMID- 8664850
TI  - Keratins and skin disorders.
AB  - The epidermal keratinocytes express two major pairs of keratin polypeptides. One
      pair (K5/K14) expressed specifically in basal generative compartment and the
      other (K1/K10) expressed specifically in the differentiating suprabasal
      compartment. The switch in the expression of the keratins from proliferating to
      differentiating compartment indicates the changes that occur in the keratin
      filament organization which in turn influences the functional properties of the
      epidermis. Proper regulation of keratin gene expression and the filament
      organization are absolutely necessary for normal functioning of the skin. Keratin
      gene mutations can influence the filament integrity thereby causing several
      heritable blistering disorders of the skin such as epidermolysis bullosa, bullous
      icthyosiform erythroderma, etc. Changes in the keratin gene expression may lead
      to incomplete differentiation of the epidermal keratinocyte, causing
      hyperproliferative diseases of the skin such as psoriasis, carcinomas, etc. This
      review briefly describes the changes in keratin structure or gene expression that
      are known to result in various disorders of the skin.

PMID- 8664852
TI  - Heterogeneity in radiosensitivity of human diploid fibroblasts from keloids and
      normal skins.
AB  - Colony-forming ability was employed in evaluating the susceptibility to in vitro
      gamma ionizing radiation in human diploid skin fibroblasts (HDF). Twelve pairs of
      HDF, each composed of fibroblasts from excised keloid lesion and local normal
      skin tissue as its control, were studied in patients with clinically persistent
      keloids. Parameters of radiosensitivity, both D0 and D10, and growth kinetics
      were examined. The radiosensitivity in three of the 12 keloids (25%) were
      demonstrated significantly increased than their counterpart controls, even though
      no difference in growth kinetics in between. Moreover, a broad range in the
      radiosensitivity of fibroblast cells was demonstrated and it is suggested that
      there is a great heterogeneity of cellular response to radiation in HDF.

PMID- 8664851
TI  - Plant mitosis promoting factor disassembles the microtubule preprophase band and
      accelerates prophase progression in Tradescantia.
AB  - The regulation of mitosis in higher plant cells has been investigated by
      microinjecting protein kinase from the metaphase-arresting (met1) mutant of
      Chlamydomonas. Biochemical characterization of this enzyme complex confirms the
      presence of a p34cdc2/cyclin B-like kinase. The enzyme was injected into living
      stamen hair cells of Tradescantia virginiana in which microtubules (MTs) were
      visualized using fluorescent analogue cytochemistry and confocal laser scanning
      microscopy. Microinjection of this p34cdc2/cyclin B-like kinase caused rapid
      disassembly of the preprophase band of MTs but not of interphase-cortical,
      spindle or phragmoplast MTs. Effects of the enzyme on the cytomorphology of live
      prophase cells were also monitored using video microscopy. We found that
      injection of this enzyme accelerated chromatin condensation and nuclear envelope
      breakdown. This indicates the presence and function in plants of an enzyme that
      can initiate nuclear division similar to the maturation or mitosis promoting
      factor (MPF) of animal cells. These studies provide the first direct evidence
      that the mitotically-active form of plant MPF can drive disassembly of
      preprophase band MTs, chromosome condensation and initiation of mitosis in plant
      cells.

PMID- 8664853
TI  - Novel markers for constitutive secretion used to show that tissue plasminogen
      activator is sorted to the regulated pathway in transfected PC12 cells.
AB  - The rat pheochromocytoma cell line PC12 contains two distinct pathways of protein
      secretion. Proteins secreted via the regulated pathway are stored in secretory
      vesicles and exocytosed only in response to a specific signal, whereas proteins
      secreted via the constitutive pathway are exported continuously. Analysis of
      regulated secretion of a heterologous protein in this system often relies on
      comparison of secretion rates with those of endogenous proteins known to be
      secreted via the constitutive route. In order to improve these controls, we have
      evaluated a number of secreted enzymes, selected for the sensitivity and
      convenience of their assays, as transgenic markers for the constitutive pathway.
      We show that both human-secreted placental alkaline phosphatase (SEAP) and
      bacterial beta-lactamase operate in this way in transfected PC12 cells. In
      contrast, transfected human tissue plasminogen activator (tPA) is shown to be
      sorted to the regulated pathway.

PMID- 8664855
TI  - [Psychophysiological aspects of decision making by the dyad of operators].
AB  - Psychophysiological aspects of the process of handling with operational tasks of
      varying complexity involving cooperative taking of various decisions in standard
      and environmentally stressful conditions are considered. Optimal values of the
      quality and tension parameters, and strategies of operators' dyad functioning in
      an ergonomics system were established.

PMID- 8664854
TI  - [Bases of differentiated evaluation of mental health of flying personnel].
AB  - Relying on the authors' experimental and literary data concerning flying
      personnel, the classification criteria were substantiated and the following
      levels of mental health defined: "healthy" (level 1), "apparently healthy" (level
      2), "presence of unfavorable prognostic signs" (level 3); in the interests of
      organization/certification decision, level 4, "symptoms of psychic pathology",
      was also identified. These levels of mental health have been defined from a set
      of indices and a measure of their manifestation, e.g., inherent/anamnestic,
      personal and medical risk factors for developing psychic decompensation, failures
      in the systems of attitudes, severity of clinico-psychological deviations,
      characteristics of occupational reliability, and successful flight activity. The
      examination of flying personnel with varying levels of mental health in hospitals
      and aviation units demonstrated their significant distinction in
      clinical/anamnestic signs, psychophysiological characteristics, mean number of
      erroneous actions per 100 flight hours, and the judgement of command about
      occupational efficiency.

PMID- 8664856
TI  - [Dynamics of tolerance of +G loads by non-flying subjects: a longitudinal study].
AB  - Selected cosmonauts-investigators may be held on wait for many years. The
      longitudinal health study is of great significance in the context of prediction
      of tolerance to various flight stresses. The purpose of this work was to
      investigate the tolerance to +Gz-loads during extended (up to 18 years) dynamic
      longitudinal study of 50 male cosmonauts and candidates of non-flying occupations
      by the data of 363 medical observation runs on a centrifuge with the radius of
      7.25 m. Analysis of these data showed that 82 % of the subjects sustained good
      tolerance of G-loads and only 18 % of the subjects displayed its decrement or
      instability. A new proof received the data concerning better +Gz-tolerance by
      subjects aged 31-35 and less tolerance by the subjects younger than 30 and older
      than 46-50 years. The longitudinal study allowed to identify 4 types of G
      tolerance variation, i.e., stable, relatively stable with individual drops down
      to decreased, non-stable with periodic drops, and a distinct trend towards a
      decrease. These investigations provided new scientific data about the dynamics of
      separate physiological functions during exposure to +Gz-loads resultant from
      longitudinal study of the same group of subjects, and allowed to make an expert
      prediction of shifts in the G-tolerance.

PMID- 8664857
TI  - [Features of external respiration and pulmonary hyperemia in man during
      immersion].
AB  - Reactions of external respiration on catheterization of main blood vessels were
      studied in healthy subjects following 12 hr and 5-6 day immersion. The purpose of
      the investigation was to detect respiratory signs of hyperemia in pulmonary
      circulation under these conditions. Results of the investigation were compared
      with the data of great vessel catheterization in patients of a cardiological
      clinic afflicted with cardiac diseases with lung hyperemia and lung tissue
      hyperhydration. The results obtained failed to confirm suppositions about
      elevated blood filling of the lung and a possible increase of lung tissue
      hydration during water immersion. Catheterization of great vessels in patients
      and healthy subjects in most cases leads to an increase of respiratory minute
      volume. In patients with cardiac diseases the respiratory minute volume grew with
      an adequate rise in breathing rate, respiratory volume and gas exchange
      parameters unaltered; this suggested excessive blood filling of the lung and
      resulting higher respiratory resistance. After immersion the healthy subjects
      displayed an utterly different pattern, i.e. the growth of their respiratory
      minute volume was provided exclusively by the growth of respiratory volume while
      breathing rate did not change and gas exchange increased. These observations were
      considered an evidence of hyperemia and hyperhydration of pulmonary tissue.

PMID- 8664858
TI  - [A comparative study of external respiration, gas exchange and circulation during
      static and dynamic muscular loads].
AB  - Indices of external breathing, gas exchange, and circulation were studied during
      bicycle ergometry and static ergometry of 19 healthy male volunteers which were
      stopped at critical levels of heart rate, arterial pressure, ECG or subjective
      fatigue. The bicycle workload maximum averaged 210 Watts, the static ergometric,
      224 kg/s. Both types of exercises were characterized by unidirectional shifting
      of the external breathing and gas exchange indices; however, they were less
      pronounced at static loads. Arterial pressure and resistance of the peripheral
      vessels were the only indices of the array the dynamics of which complied with
      and even exceeded that during bicycling. In contrast to the dynamic muscular
      load, the maximal dynamics of gas exchange and external breathing during static
      ergometric workload was observed in the rehabilitation period following
      restoration of muscle blood flow; this must be taken into account in
      interpretation of test results. It is concluded that high information virtues of
      the static ergometric test in the context of predicting aerobatic load tolerance,
      and similarity of dynamics in the period of rehabilitation hold much promise for
      using the tests with static muscular loading in aviation and space medicine.

PMID- 8664859
TI  - [Intracranial pressure in monkeys during the flight of Cosmos-2229].
AB  - The paper contains data of the experiment aboard biosatellite Cosmos-2229 which
      embraced registration of the intracranial pressure (ICP) in primates during space
      flight. ICP exhibited a small increase (25-30%) comparing with mean values over
      20 hours of the prelaunch period and did not go beyond the limits of
      physiological norm. In the second part of the flight, ICP tended to return to the
      preflight level. The ICP pulse wave pattern was considerably changed on account
      of the venous component on the initial days of orbiting and nearly assumed its
      preflight form further in flight. The diurnal ICP rhythm was found to be
      gradually altering in the course of the flight.

PMID- 8664860
TI  - [Temporal organization and information in biological systems].
AB  - Analysis of the available chronobiological data leads to the following
      conclusions about the role of biorhythms in the informational interface in living
      systems: (1) temporal organization of living systems is the main channel of
      informational interface in organism (the principle of the bond between
      information and temporal organization); (2) biorhythms or, more accurately,
      temporal organization of type one postulates the fulfillment of one of the
      fundamental statements of the general information theory, i.e., correspondence of
      information to the substratum of its application (the correspondence principle);
      (3) the biorhythm phases can either unidirectionally strengthen, weaken or
      realize in different directions the biological potentials of information brought
      into organism by one and the same material carrier (the principle of
      amplification, attenuation or inversion of informational potential by biorhythm);
      (4) biorhythm is the mechanisms driving the transformation of continuous
      informational signal, if any, into discrete, i.e. the one apt to fulfil a
      substantial informational stimulus (the quantification principle); (5) as an
      oscillating reiterative process responsible for reproduction of a biological
      phenomenon or a biosystem state within nearly equal periods, biorhythm can be
      viewed as one of the mechanisms of propagation of information in biosystem (the
      multiplication principle); (6) reproduction of information through biorhythm is
      one of the universal mechanisms of information survival in biosystem (the
      information survival principle); (7) aggregation of biorhythms with different
      periodicity of the same function, i.e. temporal organization of type two, makes
      it possible for living system to cover a wide frequency spectrum of perception,
      transmission and replication of signals carrying bio-information with similar
      semantics, and to make its differential choice when necessary (the principle of
      optimality of differential choice in perception, transmission and replication of
      information); biorhythms of an integral whole (temporal organization) is the
      mechanism underlying the informational interface between biological time of
      living system and physical time of its environment (the principle of
      informational interface between biological and physical time).

PMID- 8664861
TI  - [Water-salt homeostasis in rats during space flight].
AB  - The paper generalized the results of s series of experiments aimed at studying
      liquid and electrolytes contents in various organs and tissues of rats following
      3-week space flights (SF). The results ascertain high reliability of the water
      salt homeostasis maintaining system which ensures stable water and electrolytes
      amounts in the majority of animal tissues in SF. The following alterations appear
      to be of greatest significance: deduced potassium levels in the heart ventricle
      tissues in male rats after short-duration (7-9 d) exposure in SF, zero-g-induced
      degradation of the body ability to bind potassium at injection of isotonic
      solution KCl into the stomach; redistribution of potassium ions between mother
      and developing fetuses in space experiments with pregnant animals. Simulated
      experiments showed that similar shifting of potassium ions in the mother-fetus
      system may be due not to weightlessness exclusively but other impacts, i.e. they
      are not specific.

PMID- 8664862
TI  - [Role of the hypophysis, hormonal growth inducers and physical exercises in the
      regulation of function of thyrocytes, C-cells and parathyrocytes in rats during
      simulated weightlessness].
AB  - Immunohistochemistry and histomorphometry were employed to assay thyroid and
      parathyroid glands in hypophysectomized rats following a10-day tail suspension in
      head-down position and daily injection of either physiological solution or growth
      hormone or insulin-like growth factor 1 on the background of physical exercise,
      i.e. ascent up a 1 m high staircase with a load fastened to the tail.
      Hypophysectomy was found to cause atrophic/sclerotic changes in the thyroid and
      parathyroid glands, and dramatically suppress the functional activity of
      thyrocytes, C-cells (calcitonin producers) and parathyrocytes (parathormone
      producers). Assumingly, the impairing effect of hypophysectomy on C-cells and
      parathyrocytes is consequent to the reduced production of thyroid hormones and
      concomitant moderation of metabolism. The suspension by tail added somewhat to
      the severity of changes in thyroid and parathyroid glands under the effect of
      hypophysectomy, whereas the injection of growth hormone or insulin-like growth
      factor 1 slightly stimulated thyrocytes, C-cells, and parathyrocytes activities;
      however, it failed to offset the hypophysectomy-provoked developments. Although
      the activities of thyrocytes, C-cells or parathyrocytes were not affected by
      physical exercise, there was a mild C-cell proliferation.

PMID- 8664863
TI  - [Use of the method of thoracic electric bioimpedance in medical evaluation of
      central hemodynamics in man].
AB  - Stroke and minute cardiac volumes were simultaneously determined at rest in seven
      healthy male subjects aged 28-48 and 13 patients with various forms of partial
      insufficiency of the central hemodynamics with the use of thoracic electrical
      bioimpedance and Doppler echocardiography. The bio-impedance method employed IBM
      compatible NCCOM3-R7. The Doppler echocardiograms were registered using TOSHIBA
      50. Correlative analysis of the records was performed on 4 parameters, i.e.
      minute volume (MV), stroke volume (SV), cardiac index (CI), and stroke index
      (SI). In the group with partial insufficiency the correlation coefficient
      amounted to 0.89, 0.92, 0.81 and 0.92 for MV, SV, CI and SI, respectively. In
      healthy subjects the correlation coefficient made up 0.91, 0.90, 0.89 and 0.91
      for MV, SV, CI and SI, respectively. In the combined group the correlation
      coefficient averaged 0.88, 0.92, 0.83 and 0.92 for MV, SV, CI and SI,
      respectively. These results allow to rate high the accuracy of thoracic
      electrical bio-impedance and recommend it for the program of medical selection
      and annual health check of occupational groups systematically exposed to extreme
      impacts.

PMID- 8664864
TI  - [A method of evaluation of the adaptation process].
AB  - The problem of adaptation cannot be reasonable well studied without due regard of
      the principle of reflection. The relationship between adaptation and reflection
      is realized in, for instance, the adequacy of body reactions to environmental
      impacts. The paper approaches this problem in the light of thermodynamics. A
      simple method for accounting the process of adaptation to continuous exposure in
      specially designed sealed chamber on the pattern of shift work of operators is
      proposed. The investigation embraced 29 divers aged 20-25 who stayed in shifts
      for long periods in a chamber with artificially and synthetically sustained air
      parameters. The investigation demonstrated the effectiveness of the description
      of adaptation process through probabilistic models with a high level of
      generalization, and the possibility to predict operator's functioning at various
      phases of his work cycle.

PMID- 8664865
TI  - [Man in aviation and cosmonautics: past, present and future].

PMID- 8664866
TI  - [Biotropic effects of electromagnetic fields: benefit or harm?].
AB  - An overview contains the analysis of controversial literary data on possible
      therapeutic and pathogenic effects of electromagnetic fields on humans. The non
      specific character of body shifts induced by electromagnetic fields with a
      prevalence of adaptive reactions at the onset and an emergence of dysadaptive
      processes during extremely long exposure was displayed. The leading role in the
      development of a therapeutic or pathogenic effect is played by the functional
      characteristics of an individual postulating the interaction of cumulative and
      adaptive processes in the body during long-term exposure in an electromagnetic
      field.

PMID- 8664867
TI  - [Comparative study of adaptive responses of the cardiorespiratory system in
      inhabitants of different climatic-geographic regions].
AB  - The paper reports the data of comparative study of the cardiorespiratory function
      in healthy males (19-22 year old) from the countries in Asia, Africa, and Latin
      America lying within the tropic climatic-geographical zone during acute
      adaptation to the nature and the climate of the middle zone of Russia. The
      distinctions in respiration, circulation and gas exchange functions in the
      natives of different climatic-geographical zones were found as during comparative
      rest so under the combined effects of hypoxia and hypercapnia induced by the
      rebreathing test and ascribed to the environmental-genetic constitutional
      properties of the body and the chronobiological characteristics of the place of
      abode. Reactivity to the combined effects of hypoxia and hypercapnia in different
      groups is predominantly a function of unequal contributions of hemodynamics and
      pulmonary ventilation. A relatively low effectiveness of the cardiorespiratory
      system in representatives of the South-East Asia during acute adaptation was
      established. These results demonstrate the benefits of the hypoxic-hypercapnic
      test for determining functional potentials of the cardiorespiratory system in the
      context of adaptation to a new environment.

PMID- 8664868
TI  - [Theoretical aspects of rehabilitation and occupational health of pilots].
AB  - Some theoretical aspects of the rehabilitation problem and its interaction with
      the problem of professional health of pilot have been discussed in this paper.
      The authors have proposed methodologic approaches to the essence of medical and
      professional rehabilitation; classification of the main directions and types of
      rehabilitation, the principles of its application in flying practice as well as
      the question about economic advisability have been studied. As the main lines of
      medical rehabilitation there suggests the nosologic, psychologic and physiologic,
      professional (singly) rehabilitation with consideration of the labile and base
      components of professional health of pilot. As the base principle of
      rehabilitation there advances an etiopathogenic approach to the use of different
      means and methods of rehabilitation treatment and correction of a changed
      functional state. General requirements upon provision of multilevel,
      differential, individual, accessible and adequate rehabilitation are formulated.
      The method to calculate the economic effect of rehabilitation measures at the
      expense of savings in costs of pilot personnel by increasing the flight longevity
      and decreasing the number of flights necessary for maintaining the given level of
      combat effectiveness is proposed. The classifier of the main directions and types
      of rehabilitation is presented.

PMID- 8664869
TI  - [Study of the microgravity effect on the inertia of mental tracking of moving
      objects].
AB  - Effect of microgravity on operator's ability to mentally track moving objects was
      investigated during the joint Russian-French space mission in 1992 and the
      subsequent 6 month Russian mission. Subject was to track a sequence of 4 frames
      in which 3 points were changing their locations in the manner as if they were
      moving linearly at a constant speed; after that the subject was to compare the
      last frame of the sequence with a new, 5th frame in which the points either had
      the same locations or slightly shifted on the preceding pattern or in opposite
      direction. Shifting of the points at which their locations in two last frames
      seemed to be identical was evaluated. The investigation infers that microgravity
      does not exert any significant influence on the inertia of mental tracking of
      moving object or there occurs rather quick, within a period of days, adaptation
      to a new situation.

PMID- 8664870
TI  - [Neurophysiological patterns of vestibular adaptation to microgravity].
AB  - Results of the investigation of spontaneous and evoked by vestibular, ocular, and
      combined oculo-vestibular stimulation of the oculomotor reactions within space
      experiments Optokinesis and Labyrinth are presented. The experiments were carried
      out during the early adaptation to micro-g and repeated throughout long term
      mission. As was shown, the vestibular disturbances at the start of micro-g were
      not a lot of isolated individuals but regular reactions of the body sensory
      systems to the micro-g environment. Dynamic studies of the neurovestibular
      adaptive shifts in long-term microgravity allowed to register periodically
      evolving abnormal spontaneous and induced oculomotor reactions. Adaptation
      periods interchanged with the episodes of disadaptation. The periods of
      vestibular adaptation to microgravity and possible neural mechanisms of these
      events are presented.

PMID- 8664872
TI  - [Effects of altered gravity on the culture of unicellular eucaryotic organisms,
      Bursaria truncatella (Ciliophora)].
AB  - The paper reports the results of experiments with centrifugation and
      clinostating. Growth rate, cellular division and several morphofunctional
      characteristics of unicellular organisms of infusoria Bursaria truncatella in
      culture were studied under normal (1 g), elevated (hypergravity at 2 and 5 g),
      and compensated gravity. The data point to certain changes in the functional
      activity and morphology of cells consequent to long-time cultivation under these
      conditions. The observed regularities in the dynamics of B.truncatella growth and
      shifts in its physiology and morphology due to hypergravity or compensated
      gravity support our earlier proposed working hypothesis about the dominance of
      functional activity over morphological properties in sensitivity of unicellular
      organisms to perception and realization of the gravitational stimulus.

PMID- 8664871
TI  - [Role of vestibular and visual analyzers in changes of postural activity of
      patients with childhood cerebral palsy in the process of treatment with space
      technology].
AB  - The paper presents the findings of stabiligraphic investigations of children
      afflicted with the hyperkinetic child's cerebral paralysis treated with the
      method of graduated wearing suit ADELI. This suit is a modification of space
      designated PINGUIN used to counteract the adverse effect of long-term
      microgravity on the skeletal muscles and the skeleton. 30 children were
      investigated prior to, immediately after, and in a delayed period after this
      treatment. A group of 11 healthy volunteers were also investigated as their
      control. The program of investigation included routine stabilimetry, the station
      test, and head rolling tests. The results demonstrate that in healthy subjects
      the standing pose is primarily acquired and sustained by means of the visual
      analyzer, whereas the CCP patients pose could attain this pose with a
      significantly weakened control by the visual analyzer. Application of ADELI
      increases the role of visual analyzer in the control of standing pose. Following
      the treatment, the stabilimetric indices of patients changed for the better and
      approached those in healthy subjects.

PMID- 8664873
TI  - [The concept of risk factors and flight certificate examination].
AB  - Although much winning at first look, health predicting methods based on the use
      of risk factors (RF) are still low effective. Equally ineffective are forming and
      updating diagnosis with account of RF. At present, it is worthwhile to hold onto
      the system of periodic diagnostic evaluation of the health status. On the other
      hand, parallel longitudinal studies of RF of chronically ill flight personnel
      will be also imperative. These studies may be the only ground for the most
      reliable and accessible RF to enter the system of criteria applied in flight
      certificate examination. Yet, they will serve as criteria for choosing an
      appropriate depth of diagnostic examination rather than fitness for flight
      operations.

PMID- 8664874
TI  - [An approach to formalized description of the spacecraft radiation safety task].
AB  - Relationships correlating the damage expected from radiation exposure in space
      mission with radiobiological reactions of the body, parameters of radiation
      environment along the trajectory, and shielding properties of spacecraft
      structures were established with the use of mathematical tools of the set theory
      and the theory of chances. To this end, appropriate mathematical formulas were
      introduced which aided formalization of the space crew radiation safety task in
      the form of two inequalities.

PMID- 8664876
TI  - [Biological effect of cosmic rays induced in embryo tissues of Arabidopsis seeds
      exposed in Cosmos-2044 (Bion-9)].
AB  - This paper presents the results of evaluation of the biological effect induced by
      cosmic rays in embryo tissues of Arabidopsis thaliana seeds exposed in Biocosmos
      9 (BION-9). The experiment was carried out in cooperation with the Botanical
      Institute and the Institute of nuclear Physics of J.W. Goethe University,
      Frankfurt-am-Main, Germany using the Biostack system. The data ere obtained in
      Moscow 4 months and 3 years after the flight. It was shown that in Arabidopsis
      seeds exposed outside BION-9 the effect evaluated by all the biological criteria
      used was higher than in seeds exposed inside BION-9. In some characters the
      effect in the latter did not differ from that in control seeds but in others
      (black spots, tumors, mutations) it was higher. In tetraploid line the per cent
      of plants with tumors was higher than in diploid line. The differences observed
      can be explained by the fact that the total dose of irradiation and the flow of
      heavy ions were significantly higher outside than inside BION-9. The data
      obtained cooperatively with German colleagues showed that the seeds hit by heavy
      ion could not practically develop in the normal way. It was noted that after
      prolonged storage of seeds after the flight the biological effect in control
      seeds and in seeds exposed inside BION-9 did not change, and increased in seeds
      exposed outside BION-9.

PMID- 8664875
TI  - [Combined effects of prolonged hypokinesia and ionizing radiation on the
      hematopoietic system and lymphatic organs of rats].
AB  - During interplanetary missions ionizing radiations blended with other
      debilitating non-radiation environmental agents which can modify the
      radiobiological effect make up a risk factor. Still, the experimental data about
      the direction of the modifying action are conflicting and diverge from an
      increase to a depression of radioresistance. In this work we investigated the
      influence of prolonged hypokinesia on early radiobiological effects. The
      experiment was conducted with Wistar rats exposed to acute gamma-radiation at a
      dose of 7.5 Gy after 25 days of head-down immobilization. In the period of one
      month since exposure the morphological properties of peripheral blood and bone
      marrow, cell composition and mass of thymus, spleen and adrenal masses have been
      investigated. A significant, 1.5-2-fold, inhibition of recovery rate was
      displayed by each sprout of the blood-forming and especially thymolymphatic
      systems (2.5-3 folds) resulting from combined stress, whereas the depth of
      radiation damage in terms of maximum degree of the bone marrow tissue
      depopulation, cytopenia of peripheral blood and mass losses of lymphoid organs
      was of little difference in the two groups.

PMID- 8664877
TI  - [Current problems of microbial safety of the interior environment of orbital
      stations after extended period of operation].
AB  - The authors give considerations to one of the core hygienic problems arising in
      the process of long-term operation of orbital stations, i.e. ensuring microbial
      health of the milieu interior. Data pertaining the origin, interactions, and
      transformation of the microbial risk factors are analyzed as applied to this
      class of spacecraft. A concept of microbial health of the milieu interior
      including both medical and technological aspects relating to the reliability of
      space hardware is proposed. Based on the result of investigations in space
      flight, the developed criteria and indices of microbial health can be turned to
      practical use. The currently central tasks to be solved within the context of the
      problem and in view of the construction of international space station ALPHA are
      listed.

PMID- 8664878
TI  - [Plasmo-catalytic removal of oxygen-containing organic compounds from the
      spacecraft air].
AB  - The process of removal of the vapors of oxygen-bearing harmful organic
      contaminants, i.e. acetone, ethanol, acetaldehyde, ethyl acetate from the air was
      studied. The treatment of contaminated air with a non-equilibrium discharge was
      shown to induce a series of sequentially parallel reactions purifying air by 30
      85% and synthesizing ozone. The installation of an ozone-catalytic reactor next
      to plasmochemical would make possible air decontamination up to 93-95% at 60-65
      degrees C and ambient pressure. The devised method of air revitalization offers
      some advantages over the standard system which utilizes the adsorption/catalytic
      principle, as it will not require regeneration of individual nodes.

PMID- 8664879
TI  - [Xth Moscow International Symposium on History of Aviation and Cosmonautics].

PMID- 8664880
TI  - [A morphological study of skeletal muscles of rats flown aboard the space
      laboratory SLS-2].
AB  - M. soleus and m. gastrocnemius in rats flown aboard SLS-2 during 14 days have
      been studied histologically and electron-microscopically. It is found that the
      stay in a weightless environment causes muscular atrophy which is more pronounced
      in m. soleus. In rats killed on Day 13 of the flight and in five hours post
      flight the morphological picture of the muscles was similar although in rats
      killed postflight the number of dystrophic changed fibers was greater. The
      availability of the active satellite cells, myoblasts and muscular tubes was
      indicative of a preserved regenerative capacity of the muscles. After a lapse of
      14 days of readaptation to terrestrial gravity the size of muscular fibers in the
      rats of flight group has reached the level of control animals although the
      contractile apparatus of m. soleus did not restore completely. In the rats of
      this group m. soleus had the foci of small newly forming muscular fibers
      evidently appeared at the sites of fiber destruction as a result of hemodynamic
      disorders accompanying the transition from microgravity to terrestrial
      gravitation. Total number and number of functioning capillaries in the rats of
      flight groups did not change.

PMID- 8664881
TI  - [Effects of space flight factors on production of oxygen radicals by phagocytes
      in cosmonauts].
AB  - In cosmonauts participated in space missions of various duration there changed
      one of the most important functions of phagocytes--the capacity to produce the
      active forms of oxygen during effect of corpuscular activator of zymosan. These
      changes depending on flight duration and individual peculiarities of cosmonauts
      manifested both as increase and decrease of the parameters studied. Family
      analysis of chemiluminescence of phagocytosing cells of the blood has revealed
      much importance of genotype in genesis of the variability of this function which
      points to the utility of an individual approach to evaluation of the immunity in
      cosmonauts.

PMID- 8664882
TI  - Water immersion: analysis of diurnal rhythms of water and electrolyte excretion.
AB  - The biorhythmological structure of water-electrolyte metabolism was studied in
      humans during 7-day "dry" immersion. Results were processed with a set of
      mathematical methods in order to identify a parameter which would allow to obtain
      scientifically valid, reliable data without violation of any ethic constraints
      inherent to investigations with healthy test-subjects. Even this period of
      immersion gravely impacted functioning of kidney as an executive organ in the
      system of water-electrolyte homeostasis. Data of this study point to
      applicability of Cosinor analysis for quantitative assessment of fluctuation
      patterns in parameters of close to harmonical circadian rhythms, and variation
      analysis and normalized mean for rhythms of arbitrary forms.

PMID- 8664883
TI  - [Use of dispersion analysis in the evaluation of the effects of immersion and
      individual differences on the variability of orthostatic reactions].
AB  - With the use of dispersion analysis the variation of indices of central and
      peripheral hemodynamics in healthy volunteers stayed from 1 to 7 days under
      conditions of "dry" immersion (DI) was studied. Nine persons were investigated at
      rest, 5 individuals during orthostatic tests before and after dry immersion
      sessions. The central hemodynamic indices were calculated, the arterial pressure
      (AD) was measured by Korotkoff's method, indices of rheoencephalographic and
      rheoplethysmographic indices of lower leg were found. The significant differences
      of mean values of measured parameters before and after DI at rest were not
      revealed. Two-factor dispersion analysis of the orthostatic test data revealed
      the high levels of significance of influencing immersion and personality factors
      as well as their interaction on the variation of most indices. For excluding an
      individual uniformity there has been done an analysis of dynamics of indices
      according to their relative values which allowed one to isolate qualitative
      peculiarities of changes and distinctions between persons with different
      orthostatic tolerance even before orthostatic testing.

PMID- 8664884
TI  - [Cortical mechanisms of regulation of neuron activity of Deiters vestibular
      nucleus during vibration].
AB  - The peculiarities of the effect of vestibular, somatosensory, motor and limbic
      areas of brain cortex on the activity of neurons of lateral vestibular nucleus
      (LVN) are studied in the nembutal and chloralose anesthetized rabbits by the
      extracellular lead method before and after vibration exposure. It is found that
      the responses of neurons of Deiters's nucleus at all frequency ranges to
      stimulation of different areas of the cortex were predominantly of inhibitory
      type, being more pronounced during stimulation of the vestibular and motor areas.
      The facilitating corticofugal effect was noted in 20-30 % of cells and more
      pronounced influence was during stimulation of somatosensory and limbic areas of
      the cortex. During vibration there was a multidirectional effect of cortical
      areas on the neuronal activity of LVN. The vibration stimulus decreases an
      inhibitory effect and increases stimulating influence of vestibular cortex on the
      activity of Deiters's nucleus. The noted effect was more pronounced in neurons
      with low frequency of initial activity. On stimulation of other areas of the
      cortex an increase of inhibitory and suppression of facilitating descending
      effects were noted. The greatest amount of inhibited neurons was recorded during
      stimulation of motor cortex. The peculiarities and functional significance of the
      observed effects are discussed.

PMID- 8664885
TI  - [A mathematical model of permissible integral supercritical supersaturation of
      tissues by gases under decompression].
AB  - A criterion of permissible integral supercritical gas oversaturation of the body
      tissues was established using mathematical modelling. The heart of this criterion
      is that if integral supercritical oversaturation of tissues by gases does not go
      beyond a permissible level, gas bubbles do not reach critical volumes and give
      rise to decompression sickness symptoms. An equation was also built to calculate
      integral supercritical oversaturation of tissues during and after decompression.
      Permissible integral supercritical saturation values were determined for animals
      from mice to dogs and humans basing on literary threshold pressures with
      saturation and follow-on one-step decompression.

PMID- 8664886
TI  - [Spontaneous and visually induced illusory responses in weightlessness (results
      of the Austrian-Russian experiment "Optovert" performed within the framework of
      the program "Austromir", part I)].
AB  - There presented the results of studying the mechanisms of intersensory
      interactions and sensory adaptations, the dynamics of the stability of adaptive
      changes in the short- and long-term space missions by phenomenology of
      spontaneous and visually-induced illusory responses. It is shown that adaptation
      to microgravity even under good subjective health condition and the absence of
      anomalous subjective reactions was accompanied the change in the interaction of
      the sensory systems. For the first time there recorded the previously unknown
      phenomena: an inversion of vertical vection illusion (VVI) on vertical and
      sinusoidal optokinetic stimulation; disruption of the perception of body scheme
      at the instant of VVI; the change of character and the initiation of VVI
      asymmetry; the decrease of thresholds and the intensity increase of VVI. In the
      period of long-term stay in microgravity the anomalous perceptive reactions (the
      period of predominating adaptation gave way to the period of predominance of
      disadaptation). The hypothesis for the mechanisms of revealed changes was
      suggested.

PMID- 8664887
TI  - [Biomechanical aspects of the process of formation of food vacuoles in the
      infusoria Bursaria truncatella under changed gravity].
AB  - Results from clinostatic and centrifugal laboratory experiments in which there
      has been evaluated an activity of digestive process in infusoria Bursaria
      truncatella by the content of vacuole numbers and its change in the cell under
      changed gravity are presented. It is indicated that the extended clinostatic
      exposure of infusoria stimulates their digestive activity and an increased
      gravity (centrifugation 2 g, 5 g) inhibits this process. In these examinations,
      an effort was made to explain the obtained results started from the propositions
      of cell biomechanics and bioenergetics. The mechanisms of gravity influence on
      this process have been proposed.

PMID- 8664888
TI  - [Effects of weak magnetic poles and water and model biological systems].
AB  - The effect of the weak variation magnetic fields on the model biological systems;
      i.e. the solution of dyes and proteins is investigated. The structural change of
      these systems under the action of the variation magnetic field of 156.4 Hz and
      the amplitude of 12.3 A/m was determined by the method of absorbtion and
      luminescent spectroscopy. It is suggested that this effect realizes through the
      hypothesis using the method of correlation spectroscopy of scattered light, there
      have been performed the studies of the structure of water and its changes at
      different temperatures; on dissolving of non-electrolytes and on exposure to the
      magnetic field of variable frequency. The accumulated data are indicative of
      changing the structure of water after the effect of resonance magnetic field. The
      influence of the weak magnetic fields on the structure of water is due to the
      clusters which are presented in water and controlled the optical heterogeneity of
      the medium. The cluster dimensions were evaluated.

PMID- 8664889
TI  - [Several mechanisms of adaptation to combined action of weak varying magnetic
      fields and hypokinesia].
AB  - The nervous and humoral mechanisms of an adaptation to the combined effect of
      hypokinesia and varying magnetic fields of the 8 Hz frequency and 5 Ts induction
      have been studied in the experiments performed on 2330 white inbred male rats
      characterized by the moderate motor activity and low emotional excitability
      determined on the basis of the "open field" test. It is found that under these
      conditions the stress reaction to reduced motor activity is not developed. There
      have been revealed some mechanisms of the combined effect of hypokinesia and weak
      varying magnetic fields: increased CNS inhibition processes, decreased anxiety
      level, modulated hypothalamic functional activity, epinephrine accumulation in
      the red blood cells, synchronization of diuresis with the processes of urinary
      excretion of epinephrine and norepinephrine, elevated epinephrine excretion.

PMID- 8664891
TI  - [Nanofiltration as a prospective method of regenerating potable and hygiene
      water].
AB  - This work was aimed at studying the transport and selective characteristics of
      nanofiltration membrane of the OPMN-K type with respect to solutions contained
      catamine AB and amine oxide for development of promising systems of water
      regeneration as well as at evaluating the effect of the concentrations of
      solutions and working pressure of the regeneration unit on these characteristics.
      It is found that the selectivity of membrane with respect to the solutions
      contained the single constituents (catamine AB or amine oxide) considerably
      differed from the selectivity of membrane with respect to solution containing the
      mixture of catamine AB and amine oxide. Studies of this membrane give the
      satisfactory results in transport and selective characteristics of all tested
      solutions excluding the solution containing catamine AB with low concentrations.
      The obtained results indicate that nanofiltration may be considered as a
      perspective step of reclamation of sanitary-hygienic water in space flight
      environments.

PMID- 8664890
TI  - [Plasma catalytic purification of the spacecraft air from hydrocarbons].
AB  - A process of plasmocatalytic purification of the air from hydrocarbon (toluene,
      ethylene, methane) vapours and their mixture with oxygen-bearing organic trace
      contaminants (ethanol, acetate aldehyde, ethylformiate). In "mild" conditions,
      i.e. 60-65 degrees C and the atmospheric pressure, the plasmocatalytic method was
      found to effectively clean the air from toluene by 100%, ethylene by 60%, and to
      lower methane concentrations by 10-12%. Noxious contaminants of other classes of
      compounds do not inhibit the process of hydrocarbon removal. With combined
      concentration of the air-borne organics 113.8 mg/m3 including 15.6 mg/m3 of
      toluene, 43.2 mg/m3 of acetate aldehyde, 16.2 mg/m3 of ethanol, and 2.6 mg/m3 of
      ethylformiate, the removal effectiveness made up 85.5% and allowed to reduce
      concentrations of these compounds to the levels lower than the maximum
      permissible concentrations.

PMID- 8664892
TI  - [Specificity of mass transfer processes in some photobioreactors].
AB  - In compact photo-bioreactors with high concentration of micro organisms in
      cultural medium the zone volume of photoabsorption is essentially smaller then
      general working volume of the apparatus. This discrepancy is overcome by
      providing an intensive exchange between the dark and light zones. A quantitative
      characteristic of the intensity of migration exchange is introduced. It is the
      specific coefficient of mass transfer determined on the basis of solving the
      problem of Brown convective diffusion near the photoabsorption surface. The
      structural dependence of the quantity on the problem parameters is found. The
      qualitative and quantitative difference of this dependence near solid and free
      surface is discussed.

PMID- 8664893
TI  - [Variations of solar activity and radiation situation on board MIR station during
      the period 1986-1994].
AB  - This paper is dedicated to the analysis of the radiation situation onboard Mir
      station over a period of 1986-1994, there examined the main cosmophysics
      parameters and indices of the solar activity as well as the variations of the
      parameters of the earth's magnetic field and their association with the changes
      in the power of absorbed dose onboard the station. There noted the high levels of
      radiation exposure to the cosmonauts under terrestrial conditions when carrying
      out the roentgeno-radiologic examinations and procedures comparable or exceeding
      the absorbed doses during the flights. For revealing the regular associations of
      the radiation situation onboard the station with the parameters of solar activity
      there has been analyzed the time changes of average monthly values of dose power
      since the beginning of station functioning in 1986 until returning the fifteenth
      expedition to Earth. From the analyses of the results it might be assumed that
      the best statistical associations of average monthly power of the absorbed dose
      are found with the streams of protons of GCR. Wolff numbers and background stream
      of the radio emission of the Sun which reflects the existence of the radiation
      situation upon the phase of solar activity cycle. From this paper it transpires
      that calculating the dose loads during the period of the extreme phases of solar
      activity, it is possible to make between them the interpolations of time
      dependence by analogy with the dynamics in time of the background streams of GCR
      or Wolff numbers.

PMID- 8664894
TI  - [Use of discriminant equations for individual evaluation of the effectiveness of
      phytotherapy in flying personnel].
AB  - For individual evaluation of phytotherapy in flying personnel suffered from
      neurocirculatory dystonia of a hypertonic type there have been used discriminant
      equations describing different aspects of pathogenesis of this disease. It is
      demonstrated that these equations permit to evaluate an individual efficiency of
      treatment not only at the level of the whole body but at the level of single
      systems as well which can be used for purposeful correction of the applied
      therapy. The gained results are indicative of the advisability of further
      introducing the discriminant analysis into medical practice.

PMID- 8664895
TI  - [Comparative studies of hemodynamic responses to orthostatic and LBNP tests].

PMID- 8664896
TI  - Mutations in pyruvate kinase.
AB  - Pyruvate kinase (PK) deficiency due to mutations of the PKLR gene is a common
      cause of hereditary nonspherocytic hemolytic anemia. Thus far, 55 different
      mutations have been described in patients with PK-deficient hemolytic anemia.
      Polymorphisms within the PKLR gene and in the tightly linked glucocerebrosidase
      (GBA) gene suggest that PK deficiency may represent a balanced polymorphism.

PMID- 8664897
TI  - Mucopolysaccharidosis type I: identification of common mutations that cause
      Hurler and Scheie syndromes in Japanese populations.
AB  - alpha-L-Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I; MPS-I) is an
      inborn error of lysosomal degradation of glycosaminoglycans that results in
      storage of undegraded glycosaminoglycans in lysosomes. Previous studies in
      Caucasian populations showed that (1) homozygosity or compound heterozygosity for
      the W402X and Q70X mutations are the common causes of MPS-I with a severe form
      (Hurler syndrome), and (2) the presence of R89Q may lead to a milder phenotype.
      We studied mutations in the IDUA gene from 19 MPS-I patients, including two pairs
      of siblings, with various clinical phenotypes (Hurler, 6 cases; Hurler/Scheie, 7
      cases; Scheie, 6 cases). We report the presence of two common mutations that
      account for 42% of the 38 alleles in these patients. One is a novel 5-bp
      insertion between the thymidine at nt 704 and a cytosine at nt 705 (704ins5),
      which is seen only in the Japanese population. The other is a missense mutation,
      R89Q, which is also seen in Caucasians, although uncommonly. In the 19 Japanese
      MPS-I patients, the 704ins5 mutation accounted for 7 of 38 alleles (18%), while
      the R89Q accounted for 9 of 38 (24%). No Japanese patient was found to carry the
      W402X or Q70X alleles, the two most common MPS-I mutations in Caucasians.
      Homozygosity for the 704ins5 mutation is associated with a severe phenotype, and
      for the R89Q mutation with a mild phenotype. Compound heterozygosity for these
      two mutations produced an intermediate phenotype. Haplotype analysis using
      polymorphisms linked to the IDUA locus demonstrated that each mutation occurs on
      a different specific haplotype, suggesting that individuals with each of these
      common mutations derive from common founders. These data continue to document the
      molecular heterogeneity and racial differences in mutations in MPS-I.

PMID- 8664898
TI  - Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand
      syndrome.
AB  - Craniofacial-deafness-hand syndrome (MIM 122880) is inherited as an autosomal
      dominant mutation characterized by the absence or hypoplasia of the nasal bones,
      profound sensorineural deafness, a small and short nose with slitlike nares,
      hypertelorism, short palpebral fissures, and limited movement at the wrist and
      ulnar deviations of the fingers. In a family of three affected individuals with
      this syndrome, a mother and two children, a missense mutation (Asn47Lys) in the
      paired domain of PAX3 was initially detected by SSCP analysis. PCR amplification
      using an oligonucleotide with a terminal 3'-residue match for the C-to-G
      transversion in codon 47 showed the presence of this mutation in the DNA from all
      affected members. The DNA from unaffected members were refractory to PCR
      amplification with the mutation-specific oligonucleotide but did amplify a
      control primer pair in the same PCR reaction tube. A previously described
      missense mutation in this same codon (Asn47His) is associated with Waardenburg
      syndrome type 3 (Hoth et al., 1993). Substitution of a basic amino acid for
      asparagine at residue 47, conserved in all known murine Pax and human PAX genes,
      appears to have a more drastic effect on the phenotype than missense, frameshift
      and deletion mutations of PAX3 that cause Waardenburg syndrome type 1.

PMID- 8664899
TI  - Myelin protein zero (MPZ) gene mutations in nonduplication type 1 Charcot-Marie
      Tooth disease.
AB  - The myelin protein zero gene (MPZ) maps to chromosome 1q22-q23 and encodes the
      most abundant peripheral nerve myelin protein. The Po protein functions as a
      homophilic adhesion molecule in myelin compaction. Mutations in the MPZ gene are
      associated with the demyelinating peripheral neuropathies Charcot-Marie-Tooth
      disease type 1B (CMT1B), and the more severe Dejerine-Sottas syndrome (DSS). We
      have surveyed a cohort of 70 unrelated patients with demyelinating polyneuropathy
      for additional mutations in the MPZ gene. The 1.5-Mb DNA duplication on
      chromosome 17p11.2-p12 associated with CMT type 1A (CMT1A) was not present. By
      DNA heteroduplex analysis, four base mismatches were detected in three exons of
      MPZ. Nucleotide sequence analysis identified a de novo mutation in MPZ exon 3
      that predicts an Ile(135)Thr substitution in a family with clinically severe
      early-onset CMT1, and an exon 3 mutation encoding a Gly(137)Ser substitution was
      identified in a second CMT1 family. Each predicted amino acid substitution
      resides in the extracellular domain of the Po protein. Heteroduplex analysis did
      not detect either base change in 104 unrelated controls, indicating that these
      substitutions are disease-associated mutations rather than common polymorphisms.
      In addition, two polymorphic mutations were identified in MPZ exon 5 and exon 6,
      which do not alter the codons for Gly(200) and Ser(228), respectively. These
      observations provide further confirmation of the role of MPZ in CMT1B and suggest
      that MPZ coding region mutations may account for a limited percentage of disease
      causing mutations in nonduplication CMT1 patients.

PMID- 8664901
TI  - Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase
      gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female
      patient.
AB  - Lesch-Nyhan (LN) disease is a severe X-linked recessive neurological disorder
      associated with a loss of hypoxanthine guanine phosphoribosyltransferase activity
      (HPRT, EC 2.4.2.8). We have studied the second example of a female patient with
      LN disease. The molecular basis of HPRT deficiency in this patient was a
      previously undescribed nucleotide substitution in exon 6. In this gene,
      designated HPRT PARIS, a single nucleotide substitution from T to G at base
      position 558 changed a tyrosine (TAT) to a codon STOP (TAG) (Y153X). Analysis of
      the mother revealed a normal sequence of the HPRT cDNA and demonstrated that this
      mutation arose through a de novo gametic event. Allele-specific amplification of
      exon 6 from the patient's genomic DNA confirmed the single base substitution and
      showed that the patient was heterozygous for this mutation. Investigation of X
      chromosomal inactivation by comparison of methylation patterns of patient's DNA
      isolated from fibroblasts, T lymphocytes, and polymorphonuclear cells digested
      with PstI and BstXI, with or without HpaII, and hybridized with M27 beta probe
      indicated a nonrandom pattern of X-chromosomal inactivation in which there was
      preferential inactivation of the maternal allele. The data indicate that
      nonrandom X-inactivation leading to selective inactivation of the maternal gene
      and a de novo point mutation in the paternal gene were responsible for the lack
      of HPRT activity in this patient.

PMID- 8664900
TI  - Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients
      with a pyruvate dehydrogenase complex deficiency.
AB  - Most of the mutations causing deficiency of the pyruvate dehydrogenase (PDH)
      complex are in the X-linked E1 alpha gene. We have developed a rapid screening
      method for the detection of mutations in this gene using reverse transcription of
      total RNA, polymerase chain reaction amplification of the whole coding region of
      the gene and single-strand conformation polymorphism (SSCP) analysis. With this
      method, we studied eight patients with a PDH complex deficiency, using cultured
      fibroblasts. In all patients, aberrant SSCP patterns were found and, after
      sequencing of the corresponding fragments, we were able to identify six new
      mutations and two mutations already described previously. The mutations are point
      mutations leading to amino acid substitutions (5) and direct repeat insertions
      (3). The presence of the mutations was confirmed in genomic fibroblast DNA. The 4
      female patients were shown to carry both a normal and a mutated E1 alpha gene.

PMID- 8664902
TI  - A novel G499D substitution in the alpha 1(III) chain of type III collagen
      produces variable forms of Ehlers-Danlos syndrome type IV.

PMID- 8664903
TI  - Chimeric probe-mediated ribonuclease protection assay for molecular diagnosis of
      mRNA deficiencies.
AB  - Investigations throughout the last decade have established that cytoskeleton
      integrity ensures red cell deformability and mechanical stability, and that
      defects in one of the skeletal components usually result in more or less severe
      hemolytic anemias. Although a large number of molecular defects have been
      identified to date, many others still bypass fast and commonly used methods, such
      as SSCP and DGGE, mostly because of a subtle change in mRNA transcription level
      or a complex interaction leading to the loss of other components. We describe a
      ribonuclease protection assay based on a simultaneous quantification of two
      cytoskeletal transcripts, using a chimeric probe, emphasizing the value of a
      nonspecific bridging sequence, inserted between the two specific probe sequences.
      It is anticipated that this powerful and reliable procedure would be an
      additional tool in the methodology array used for screening cytoskeletal
      inherited abnormalities.

PMID- 8664904
TI  - Identification of three novel mutations in the acid sphinogomyelinase gene of
      Japanese patients with Niemann-Pick disease type A and B.

PMID- 8664905
TI  - Identification of a novel single base insertion in the adenomatous polyposis coli
      gene.

PMID- 8664906
TI  - Molecular genetics of human antithrombin deficiency.
AB  - Human antithrombin is the major plasma inhibitor of thrombin both in the presence
      and absence of heparin. Its physiological importance is emphasised by the
      recurrent thromboses that individuals with a deficient or functionally abnormal
      protein are prone to develop. Such deficiencies are estimated to affect as many
      as 1:630 of the general population and between 3% and 5% of patients with
      thrombotic disease. The gene for antithrombin (AT3) has been cloned and shown to
      map to the long arm of chromosome 1 at 1q23-25. The gene consists of seven exons
      and six introns and spans 13,477bp of DNA. Advances in molecular genetic
      techniques have facilitated identification of the underlying DNA mutation(s) in >
      80 families with antithrombin deficiency. Such work has proved invaluable in
      structure-function studies and in helping to provide informed genetic counselling
      to "at-risk" individuals based upon the natural history of similar variants.

PMID- 8664907
TI  - A common missense mutation (C210G) in the LDL receptor gene among Norwegian
      familial hypercholesterolemia subjects.

PMID- 8664908
TI  - Nonsense mutations in a Becker muscular dystrophy and an intermediate patient.

PMID- 8664909
TI  - Mutation analysis in 20 patients with Hunter disease.

PMID- 8664910
TI  - New point mutation (R243W) in the hormone binding domain of the c-erbA beta 1
      gene in a family with generalized resistance to thyroid hormone.
AB  - Two years after the first mutation on exon 7 in the carboxy-terminal part of the
      hinge domain (D) was reported (Behr and Loos 1992), we have identified the second
      mutation on exon 7 in patients with GRTH. Interestingly, our mutation it is not
      located in the two previously described "hot spot regions", but instead very
      close to the hinge domain (D) of the receptor protein that is essential for the
      function of the hormone binding domain (E) (Lin et al., 1991). Confirming the
      observation that the majority of single base substitutions causing human genetic
      diseases or DNA polymorphisms follow the hot spot mutation rule of CG to TG and
      CG to CA transition (Barker et al., 1984), an additional CpG dinucleotide
      transition has been identified.

PMID- 8664912
TI  - Recurrent 2-bp deletion in exon 10c of the NF1 gene in two cases of von
      Recklinghausen neurofibromatosis.

PMID- 8664911
TI  - An LDL receptor promoter mutation in a heterozygous FH patient with dramatically
      skewed ratio between the two allelic mRNA variants.

PMID- 8664913
TI  - [T1G3 transitional cell carcinoma of the bladder: our experience with 44 patients
      treated with intravesical BCG after TUR].
AB  - Forty-four patients affected by poorly differentiated (G3) superficial TCC
      invading lamina propria (stage T1) were treated with intravesical BCG. They
      underwent weekly instillations of 75 mg BCG for six week after trans-urethral
      resection (TUR) of bladder cancer. An additional induction course was given to
      patients who relapsed. A maintenance course with monthly instillations for twelve
      months followed in complete responder patients. After the first induction course,
      34/44 patients (77.2%) showed complete response. In 10 patients a second
      induction course was necessary, with complete response in four. After one or two
      induction course, 38/44 patients (86.5%) showed complete response. The
      maintenance course was administered to 38 patients with 35/38 complete responses.
      After a median follow-up of 30 months, there were 29/44 (65.9%) disease free
      patients, 11/44 (25%) tumor recurrences and 4/44 (9%) tumor progressions. The
      drug has been well tolerated with few side effects. Our data suggest that
      intravescical BCG after TUR is effective in the treatment of high-risk
      superficial bladder cancer and we believe that it can be used a first approach in
      treating patients affected by T1G3 bladder cancer.

PMID- 8664914
TI  - [pT1G3 bladder carcinoma: parameters of a correct therapy].
AB  - Between 13.8% and 27% of all superficial bladder cancers are represented by pT1G3
      neoplasm. In the Department of Urology of Policlinico S. Marco-Zingonia, between
      February 1988 and June 1994, we treated 22 patients suffering for pT1G3 bladder
      tumor. TUR-B has demonstrated to be a good approach for treatment of superficial
      bladder cancer, with low morbility; on the opposite side, we have to underline
      the high rate of recurrence and of progression of the urothelium disease. Now a
      day our best approach for the treatment of pT1G3 bladder tumor is represented by
      radical cystectomy supplied by chemotherapy.

PMID- 8664915
TI  - [Conservative treatment of high-risk (T1G3) transitional carcinoma].
AB  - OBJECTIVE: This study evaluates the outcome of patients (pts) with primary T1G3
      bladder cancer treated by transurethral resection (TUR) alone or followed by
      intravesical prophylaxis (BCG/Doxorubicin). Cistectomy was considered at disease
      progression. METHODS: Between 1/89 and 5/95 thirty-one pts with primary T1G3
      bladder cancer were treated by TUR, in 24 followed by intravesical prophylaxis
      (13 with BCG, 11 with Doxorubicin). 7 pts had only TUR. RESULTS: At 42 months
      median follow up 45.2% pts (14/31) are disease free. The recurrence rate was
      25.8% (8/31) and progression of disease was seen in 29.0% (9/31); mortality rate
      was 22.6% (7/31). In 13/31 pts treated by TUR + BCG 53.8% pts (7/13) are disease
      free. The recurrance rate was 23.1% (3/13) and progression of disease was seen in
      23.1% (3/13) of cases; mortality rate was 23.1% (3/13). In 11/31 pts treated by
      TUR+Doxorubicin 54.5% pts (6/11) are disease free. The recurrance rate was 18.2%
      (2/11), progression of disease was seen in 27.3% (3/11) of cases of mortality
      rate of 9.1% (1/11). In 7/31 pts treated by TUR alone 14.3% pts (1/7) are disease
      free. The recurrance rate was 42.9% (3/7) and progression of disease was seen in
      42.9% (3/7) of cases and mortality rate of 42.9% (3/7). Cistectomy was considered
      in 4 pts (3 for disease progression and 1 because of no disease free interval).
      The other pts with progression were not treated surgically because of their poor
      performance status. CONCLUSION: At a 42 months median follow up 77.4% pts (24/31)
      are alive (83.3% pts treated by TUR+intravesical prophylaxis). 64.5% pts (20/31)
      still have their bladder (66.6% pts treated by TUR+intravesical prophylaxis
      (16/24). We did not find a significative difference between prophylaxis with
      immunotherapy or chemotherapy. In conclusion we believe that the conservative
      management of high risk bladder transitional cell carcinoma T1G3 is feasible and
      allow us to plan cistectomy only in pts with progression or recurrance with no
      free interval without losing survival.

PMID- 8664916
TI  - [Transitional carcinoma of the bladder at the T1G3 stage: personal experience].
AB  - The Bladder T.C.C. represents about 70% of urological malignancies. Superficial
      T.C.C. is generally treated with T.U.R. followed by endocavitary chemoprophylaxis
      (Mitomycin, Antraciclines etc.). Invasive tumors are cured by radical cystectomy
      and reconstructive lower urinary tract. T1G3 bladder cancer (involvement but no
      invasion of muscle layers) is a "border line" lesion and is not uniformely
      treated (some Authors choose a "conservative approach with T.U.R. and
      chemoprophylaxis, some others prefer an "aggressive" treatment with radical
      cystectomy and urinary diversion. Authors present their experience in the
      treatment of T1G3 (19 patients in 4 years with one year minimum follow-up) with a
      "conservative" approach (bladder T.U.R.) but "aggressive" post-operative
      treatement (immunotherapy with B.C.G. vaccine) and endoscopic reevaluation after
      ten weeks from the first observation. Prognostic factors are examined (number and
      dimension of the tumors, concomitant mild or severe dysplasia, positive or not
      citology) in order to extrapolate patients that will be at risk for develop an
      aggressive disease.

PMID- 8664917
TI  - [T1G3 bladder tumors].
AB  - Bladder tumors T1G3 are aggressive and difficult for their staging. Out of 176 p.
      with tumor pT1, 16 (9%) presented pT1G3. Among the latter 4 were submitted to TUR
      and chemioimmunotherapy; 5 to surgical partial resection and radiotherapy; 7 to
      radical cystectomy. After a mean interval of 21.6 months free of relapse, 5 p.
      had recurrent T1 tumor below G3: 1 out of 4 after TUR; 1 out of 5 after surgical
      resection; 1 out of 7 after cystectomy. Clinical T1G3 8 revealed a greater
      pathological staging: 7 (50%) had a relapse in spite of an aggressive therapy (2
      TUR; 4 surgical resection; 8 cystectomy); 5 out of the 7 relapsed revealed a
      greater pathological staging than T1; 2 died by metastasis. The therapeutical
      choice should be demolitive from the beginning. Should conservative therapy be
      decided, the convenience of surgical bladder resection has to be considered
      because, besides being effective, has some advantages over TUR: easier and
      unfailing staging possibility of contemporary lymphadenectomy healing of bladder
      by first intention.

PMID- 8664918
TI  - [Partial cystectomy versus TUR in T1G3 tumors].
AB  - Authors report their experience in conservative treatment of 41 patients with
      bladder cancer and they compare partial cytectomy with turv. They hold that
      partial cystectomy can represent a good therapeutical option in treatment of
      bladder cancer T1G3.

PMID- 8664919
TI  - [T1G3 bladder tumors: 5 years later].
AB  - We have evaluated 79 patients affected by bladder cancer T1G3: 31 underwent just
      endoscopy, 11 radiotherapy, 10 cystectomy and 27 topical chemotherapy. At five
      years 44 patients were alive and disease free, 7 were alive but recurrent in TA,
      3 were alive but in metastatic progression, 17 were died because of the tumor, 3
      died because of the therapy, and 5 died disease free. The authors believe that
      this patients could be treated with BCG as first treatment choice performing
      cystectomy when relapse or progression occuring.

PMID- 8664920
TI  - [T1G3 bladder tumors: our experience].
AB  - T1 G3 bladder carcinoma are classified as superficial tumours and treatment
      results are included in low stage tumour groups. A review of survival rates shows
      that there is a high risk of progression about 50-70%. The grade is by now
      considered the most significant prognostic factor and many other prognostic
      biological tests have been suggested. We treated 41 cases of T1G3 bladder tumours
      with a first therapeutic TUR and second staging TUR two months later.
      Subsequently a group of 15 has had "wait" and see" endoscopic follow-up with bad
      results, a group of 7 underwent "early cystectomy", a group of 12 has been
      treated with adjuvant cytotoxic chemotherapy with poor results on recurrence and
      good results on progression percentages, a group of 6 radiotherapy with poor
      results. We got confirmation of high risk of progression, 4 cases with high stage
      from beginning, 3 with precocious metastatic disease. Apart the cases with
      precocious metastases, the best survival rates are achieved with early
      cystectomy.

PMID- 8664921
TI  - [T1G3 bladder neoplasms: treatment and results].
AB  - The high risk of progression found in T1G3 bladder cancer influence the treatment
      and follow-up of this kind of patients. From January 1983 to December 1992, 803
      patients with superficial bladder cancer (first presentation) had observed in the
      Urology Department at the Spedali Civili in Brescia. In this group, 96 patients
      were classified as T1G3 and our retrospective study is a critical analysis about
      their treatment: 13 patients underwent cystectomy as primary treatment and 83 had
      been cured with a transurethral resection. Of this last group, 26 patients are
      still without of disease (mean follow-up: 4.2 years), 30 had a recurrence which,
      in stage and grade, was identical or lower to the initial disease and 27 patients
      had a progression. Alltogether 36 patients underwent cystectomy: 15 are tumor
      free and 21 died. The results of this retrospective study, led us to believe that
      T1G3 bladder cancer therapy is endoscopic at the beginning. Adjuvant topic
      chemotherapy treatments improve the recurrence rate tangibily; an early-operated
      cystectomy permits a good rate of recovery.

PMID- 8664922
TI  - T1G3: What to do?

PMID- 8664923
TI  - [T1G3 of the bladder: our experience].
AB  - From June 1991 to June 1995 we treated 20 patients affected by T1 G3 TCC of the
      bladder, 18 men and 2 women, with a mean age of 65.1 years (46-71). In 11
      patients the disease was monofocal, with diameter of the tumor under 3.5 cms; in
      5 patients monofocal with diameter of the tumor over 3.5 cms; in 1 patient
      multifocal and in 3 patients complex (mono or multifocal associated with CIS).
      The 11 patients with monofocal disease under 3.5 cms were treated with TUR-B, the
      other 9 (all males) were submitted to radical cystectomy with OINB diversion as
      first choice treatment. The mean follow up (all patients) was 3.2 years (6 months
      14 years). Out of the patients of the former group only 3 did not show any
      relapse, the other 8 showed multiple relapses or metachronous tumors: 5 were
      treated with TUR-B+BCG, 3 were cystectomized. The patients submitted to
      cystectomy as first choice treatment did not show any progression of the disease
      after a mean follow-up of 19.8 months.

PMID- 8664924
TI  - [Role of BCG in T1G3 bladder transitional cell carcinoma (TCC): our experience].
AB  - High grade superficial TCC of the bladder (T1 G3) has an important risk of
      recurrence and/or progression (40%) after TUR-B and a low survival rate (57% at 3
      years, 50% at 10 years). Intravescical treatment with BCG seems to be able to
      reduce these rates. 64 patients with T1 G3 vescical TCC underwent a "second look"
      TUR-B. 9/64 patients presented locally advanced tumor (T2-3) or persistent high
      risk superficial TCC (T1 G3 + Tis) and underwent to early cistectomy. BCG
      intravescical therapy has been performed in the remaining 55 patients: 10 of them
      had not been evaluated because local or sistemic toxicity and consequent early
      interruption of treatment. BCG Pasteur was given weekly at the dose of 75 mg for
      two cycles of 6 weeks with a rest period of 6 weeks between the two cycles and
      then monthly for one year and every three months during next two years too. After
      the first 6 weeks 43/45 patients resulted tumor-free and 2/45 presented
      persistent Tis: after the second 6 weeks-cycle of BCG, two other patients had
      evidence of vescical TCC (one T2 G3 and the other T1 G3); all these four patients
      were submitted to radical cystectomy or radiotherapy. Of the reamining 41
      patients, 28 presented had no recurrences, nowadays living and tumor-free; 3
      presented local neoplastic progression and dead; relapsed in T1 G2 and are living
      NED after local chemotherapy. At a mean follow-up of 18 months, the total amount
      of recurrences is 17/45 (38%), progression rate is 4/45 (8.8%), exitus 5/45 (11%)
      and living NED are 28/45 (62%). In our opinion local BCG treatment for T1 G3
      bladder cancer, after TUR--B, seems to be able to reduce the risk of recurrence
      and mortality.

PMID- 8664925
TI  - [pT1G3 tumor of the bladder].
AB  - The management of the superficial bladder tumor is commonly performed by
      transurethral resection (TUR) and a following chemotherapy or immunotherapy with
      exception of Tis. A lot of doubts and questions raise in the management of pT1G3
      bladder tumor (BT) for the high grade of recurrencies and progressions. Our
      experience from 1984 to 1994 about 109 patients (pts) with pT1G3 BT undergone to
      radical cystectomy (47 pts) and TUR (62 pts) allows us to state that when Tis is
      present a radical cystectomy is mandatory, but the TUR option must be followed to
      frequent and accurate random biopsies in order to discovery foci of Tis. In the
      case of pT1G3 monofocal there is always a therapeutic disconcerting.

PMID- 8664926
TI  - [T1G3 transitional bladder neoplasms: what to do?].
AB  - The treatment of T1 G3 bladder cancer is still an issue surrounded by much
      conflict. TUR of the bladder tumor as single treatment is considered not valid to
      be successful. TUR associated with intravescical chemotherapy or, even better,
      local immunotherapy may be the treatment of first choice in monocentric cancer,
      while radical cystectomy is, at the moment, the treatment of first choice in
      pluricentric or Cis associated T1 G3 bladder cancer. Since 1980, 25 patients with
      transitional T1 G3 bladder cancer have been observed in our department. Thirteen
      patients had a pluricentric disease while the remaining 12 cases had a
      monocentric bladder cancer. 92% of the patients (12/13) with a monocentric lesion
      and treated with TUR and local chemotherapy (Doxorubicin or BCG) are disease free
      after an average follow up of 34 Months (range 12-60 months). While 100% patients
      with a pluricentric cancer and treated with cystectomy are disease free after an
      average follow-up of 37 months (range 12-122 months); the 4 remaining cases with
      a pluricentric bladder lesion who refused cystectomy experienced a relapse of the
      disease after a follow-up of 19 months (range 9-27 months) and, despite surgery,
      they died within 12 months.

PMID- 8664927
TI  - [pT1G3 bladder carcinoma: our experience].
AB  - Approximately 6 to 23% of the patients with transitional cell carcinoma confined
      to the superficial mucosa of the bladder suffer for a pT1G3 tumor. Between 1984
      and 1994, 12 patients were treated for high grade stage T1 tumores. Trans
      urethral resection of the bladder cancer was performed in 8 patients, supported
      in two cases by immunotherapy with B.C.G. and in one case by endovesical
      chemotherapy. Radical cystectomy was carried out in 4 patients. Our results are
      similar to what reported by other Authors, but we didn't have any progression in
      all 8 patients treated with conservative therapy.

PMID- 8664928
TI  - Epidemiological, virological, and clinical features of an epidemic of hand, foot,
      and mouth disease in England and Wales.
AB  - We describe the epidemiological, virological, and clinical features of an
      epidemic of hand, foot, and mouth disease, attributed to coxsackie A virus
      serotype 16, that occurred throughout England and Wales in the last quarter of
      1994. Nine hundred and fifty-two cases were reported by spotter practices that
      make weekly returns to the Royal College of General Practitioners, which made
      this the largest epidemic of hand, foot, and mouth disease in England and Wales
      reported to date. Most patients were aged 1 to 4 years and lived in central or
      southern regions. Clinical features were unavailable from the weekly returns but
      were described in detail for 39 patients, mostly by means of a questionnaire to
      general practitioners near the PHLS Coxsackie Reference Laboratory. All cases had
      a rash on their hands and 23 also had rashes on their feet and in their mouths.
      Most cases were mild. Severity was associated with the degree of mouth
      involvement. Secondary cases in family members were rare. Data from the Royal
      College of General Practitioners since 1963 reveal a period between epidemics of
      two to three years. The epidemics in 1988 and 1990 also occurred in the last
      quarters of these years and cases were concentrated in the central and southern
      regions.

PMID- 8664929
TI  - The effect of an accelerated immunisation schedule on pertussis in England and
      Wales.
AB  - Notifications of pertussis in England and Wales have fallen dramatically from 65
      810 during the epidemic year of 1982 to 3963 cases during the epidemic year of
      1994, as vaccine coverage has risen. The incidence of pertussis has declined in
      all ages, including babies under 3 months of age who would have been at risk of
      disease from older siblings vaccinated under the accelerated schedule introduced
      in 1990 if immunity induced as result of this schedule had been short lived. To
      document the efficacy of the current whole cell vaccine under the accelerated
      schedule an enhanced surveillance scheme based on laboratory confirmed cases of
      pertussis was set up in 1994. Three deaths occurred in infants with confirmed
      pertussis, all of whom were under 8 weeks of age and unvaccinated. The overall
      vaccine efficacy for those over 6 months and under 5 years of age was 94%. This
      estimate may be inflated, as a number of biases could lead to the
      underascertainment of cases in vaccinated children, but it is similar to previous
      estimates obtained for children of the same age vaccinated under the 3, 5, and 10
      month schedule. Vaccine efficacy was 89% for children aged over 5 and under 15
      years. The enhanced surveillance scheme will enable us to monitor the duration of
      protection under the accelerated schedule and evaluate the continuing impact of
      pertussis infection.

PMID- 8664930
TI  - PHLS research initiatives on Vero cytotoxin producing Escherichia coli.

PMID- 8664932
TI  - Eradicating measles and poliomyelitis: 200 years after Jenner.

PMID- 8664931
TI  - VTEC O157 infection in West Yorkshire associated with the consumption of raw
      milk.

PMID- 8664933
TI  - The reliability and validity of the Tekdyne hand dynamometer: Part I.
AB  - The purpose of this study was to evaluate the reliability of Tekdyne hand
      dynamometer in a controlled loading environment using the Instron 1331. Test
      retest reliability, the intertool reliability of three different Tekdyne hand
      dynamometers, and the effects of surface area and the configuration of the forces
      applied to the Tekdyne hand dynamometer were studied. In addition, intertool
      reliability between a Jamar dynamometer modified with foam padding and the same
      Jamar dynamometer without padding was calculated to explore this device as an
      alternative measurement device. Intratool and intertool reliabilities of the
      three Tekdyne tools were high (ICC = 0.993-10.998, SEM = 0.106-0.045 psi and ICC
      = 0.995, SEM = 0.080 psi, respectively) when tested on the Instron. Both the
      surface area and the configuration of the force applied to the Tekdyne
      dynamometer appeared to influence the output reading of this device. The
      measurements obtained on the Tekdyne hand dynamometer correlated well with those
      obtained with the Jamar hand dynamometer when a controlled load was applied (r =
      0.988). The Tekdyne hand dynamometer is a reliable tool in a controlled loading
      environment; however, further study is needed to determine its validity with
      respect to the Jamar dynamometer for testing human grip strength.

PMID- 8664935
TI  - Altars to the hand: art and belief in southern Nigeria.

PMID- 8664934
TI  - The reliability and validity of the Tekdyne hand dynamometer: Part II.
AB  - The purpose of this study was to evaluate the reliability and validity of the
      Tekdyne hand dynamometer for measuring grip strength as compared with the Jamar
      dynamometer. Additionally, it was hypothesized that one to six weeks after carpal
      tunnel release (CTR) grip strength would appear to be greater when tested on a
      softer tool than when tested on the Jamar dynamometer. The Tekdyne, the standard
      Jamar instrument (SJ) and a Jamar dynamometer modified with foam padding (MJ)
      were compared in 48 subjects without upper-extremity abnormality and 30 subjects
      following open-palm CTR. The Tekdyne and the Jamar hand dynamometers were well
      correlated in the presence and in the absence of upper-extremity abnormality (r =
      0.975 and r = 0.871, respectively). Tekdyne intrasession reliabilities in both
      the non-surgical group and the surgical group were high (ICC = 0.954, SEM = 0.290
      psi and ICC = 0.958, SEM = 0.219 psi). The Tekdyne intersession reliability of
      the non-surgical group was high (ICC = 0.971, SEM = 0.22 psi). There was no
      statistically significant difference between the ratios of the non-operated grip
      strengths across the three measurement devices, suggesting that the softer device
      did not promote greater force production by the operated hand.

PMID- 8664936
TI  - Sequential occupational dexterity assessment (SODA): a new test to measure hand
      disability.
AB  - Measuring hand-related disability poses a problem due to a lack of validated
      tests. This report introduces the sequential occupational dexterity assessment
      (SODA), a test that measures bimanual dexterity in daily life. The design of the
      SODA is described. Validity and reliability of the SODA are demonstrated in a
      sample of patients with rheumatoid arthritis (RA), in whom impairment of the
      hands may cause serious disability in daily life. Good reliability was found, as
      measured by internal consistency, test-retest correlation, and interrater
      stability. Validity was established by relating the SODA to a number of other
      variables. Current disease activity was only weakly related to the SODA score.
      Impairment of the hands is more strongly related to dexterity than to current
      disease activity. However, dexterity could vary considerably in patients with
      similar degrees of impairment. Pain during the SODA proved to be more important
      for dexterity than general level of pain. Considerable variation was found in
      self-reported and observed dexterity. It was concluded that the SODA may guide
      the therapist in making decisions about hand therapy. The use of the SODA allows
      standardized evaluation of the effects of hand surgery on bimanual dexterity.

PMID- 8664937
TI  - Disturbed grip-force control following cerebral lesions.
AB  - Clinical routine examinations of grip force are usually restricted to
      measurements of strength; however, more detailed evaluations of grip-force
      control provide essential information about the characteristics of impaired hand
      function following cerebral lesions. A device for continuous recording of
      isometric grip force produced in a precision grip between thumb and index finger
      was used to develop a method that might be used for routine assessment of grip
      force control. Performance was tested in five different tasks involving the
      evaluation of static and dynamic precision, use of vision in force control,
      speed, variability, and strength. The authors describe the tasks and present
      clinical examples demonstrating the method's precision and subtle
      characterization of disturbed and preserved aspects of force control, which may
      vary substantially within and between patients.

PMID- 8664938
TI  - Current concepts of toe-to-hand transfer: surgery and rehabilitation.
AB  - Optimal functional recovery after toe-to-hand transfer depends on skillful
      surgery as well as aggressive motor and sensory rehabilitation. The patient
      should be well motivated and willing to incorporate the involved hand in daily
      living and carry out the rehabilitation program on a daily basis. This article
      presents the current recommendations for the different toe-to-hand transfers and
      their postoperative rehabilitation programs.

PMID- 8664939
TI  - Rapid relief of a painful, long-standing posttraumatic digital neuroma treated by
      transcutaneous vibratory stimulation (TVS).
AB  - A case of a patient with a painful posttraumatic digital neuroma that had been
      present for 13 years is presented. Treatment for the painful neuroma was twice a
      week for one month using transcutaneous vibratory stimulation (TVS). The patient
      was assessed using various tests before and after this period of treatment. There
      was a reduction in pain, and dexterity and strength improved. The method of
      treatment and the assessment techniques are described. In this case, the
      therapeutic benefit of the method could be clearly differentiated from the
      natural healing course, since no significant improvement had occurred
      spontaneously over many years.

PMID- 8664940
TI  - Evaluation of a thermoplastic splint to protect the proximal interphalangeal
      joints of volleyball players.
AB  - Due to the extreme forces to which they are exposed, hand injuries are common in
      volleyball players. This paper evaluates the effectiveness and physical tolerance
      of a thermoplastic splint developed to prevent proximal interphalangeal (PIP)
      joint hyperextension during play. The PIP-joint splint was tested by 20
      semiprofessional volleyball players (12 women and eight men), all of whom had
      been using functional taping, and whose court positions exposed them to possible
      PIP-joint injuries. After four consecutive training sessions and one match,
      effectiveness (rigidity and durability) of the splint was assessed by measuring
      any variation of its angle and subjective acceptance of the orthosis was
      investigated by a questionnaire. After three months, the athletes were asked
      whether they still used the splint, and, if so, how often. The results indicate
      that this inexpensive device is effective, does not hinder any volleyball
      maneuver, and resolves the drawbacks of taping.

PMID- 8664941
TI  - Using knowledge from fields outside hand rehabilitation to prove treatment
      efficacy.

PMID- 8664942
TI  - Attention to adl needs. Easy cutlery holder.

PMID- 8664943
TI  - Tenth Nathalie Barr Lecture. Looking back, looking forward: thoughts along the
      journey.

PMID- 8664944
TI  - Attention to adl needs. One-handed ponytail device.

PMID- 8664945
TI  - Active motion opposite to the pull of a mobilizing dynamic-assist force.

PMID- 8664946
TI  - Effect of an alternative flexion splinting protocol on mid-joint ROM.

PMID- 8664947
TI  - Working from upstream to improve health care: the IHI interdisciplinary
      professional education collaborative.
AB  - BACKGROUND: Recognizing the need to find new models for educating health
      professionals, the Institute for Healthcare Improvement (IHI) initiated the
      Interdisciplinary Professional Education Collaborative in April 1994. The goal of
      the Collaborative is to improve health care by working from upstream, to address
      the health professions workforce changes demanded by the need to deliver better
      care at a lower cost. With support and advice from IHI and others, faculty
      leaders in health professions education from the disciplines of medicine,
      nursing, and health administration framed a vision of the future in which "health
      professions education has evolved into an integrated teaching/learning
      environment in which health professionals are working together across discipline
      boundaries, using the best knowledge for improvement to continuously improve
      health care". This article describes the first year of the three-year project.
      SUMMARY: The 1994-1995 pilot year of the Collaborative involved more than 60
      learners and 50 faculty members, across multiple disciplines. At each of the four
      sites, education was integrated with efforts to improve health care delivery.
      Education-oriented outcomes include assessment of student learning (applied
      knowledge and skills) and program evaluation (student and faculty feedback on the
      effect of the project on community-based experiential learning sites). Even at
      this early stage, there is evidence of change in participating institutions. The
      Collaborative in now planning how to increase the number of students and faculty
      involved in such a way that a deeper understanding of how to prepare new health
      professionals to improve health care may be determined.

PMID- 8664948
TI  - Using learning cycles to build an interdisciplinary curriculum in CI for health
      professions students in Cleveland.

PMID- 8664949
TI  - The Pennsylvania Local Interdisciplinary Team: journey into collaborative
      learning and community health improvement.

PMID- 8664950
TI  - Institutionalizing continuous improvement in South Carolina: taking it "bird by
      bird".

PMID- 8664951
TI  - Blessed are the flexible: the George Team.
AB  - Our educational efforts produced several intersecting interdisciplinary groups:
      faculty, students, faculty/students and our community sites, with faculty,
      clinical staff, and students. As we worked through the issues, these
      interdisciplinary teams found that commitment to change, caring for patients, and
      open, honest communication were essential to keeping the project teams on track.
      We have increased our understanding of both the complexity and value of
      interdisciplinary collaborative education. The LIT faculty provided the initial
      guidance and support, the students energized the process, and our community sites
      made our learning and our contributions readily available to our patient
      populations. It is not easy to learn and teach the language and tools of
      continuous improvement, but doing so infinitely improves the educational process
      and the clinical outcome. We must learn to carefully listen to each other so that
      our patients can fully reap the benefits of our interdisciplinary team efforts.
      As a result of what we learned, the members of the George Team have expanded our
      motto to "Blessed Are the Flexible--and the Perseverant!"

PMID- 8664952
TI  - From the students: learning continuous improvement by doing it.

PMID- 8664953
TI  - The PDSA cycle at the core of learning in health professions education.
AB  - BACKGROUND: The Plan-Do-Study-Act (PDSA) cycle lies at the heart of continuous
      improvement and is a redefinition of the scientific method for application to the
      world of work. HEALTH CARE AS A CONTEXT FOR HEALTH PROFESSIONS LEARNING:
      Educational institutions could create the best "quality learning" environments
      for students by relating closely to health care organizations that create
      improvement environments for workers. When both become "learning" organizations
      and develop a relationship with each other, an important product will be the
      integration of processes for individual and organizational learning. THE PDSA
      CYCLE AS LEARNING THEORY: The PDSA cycle can be an integrating theory for both
      individual and organizational learning. It shares basic features of well-accepted
      theory about individual and organizational learning, including the concepts of
      change and action/reflection. EVALUATING LEARNING THROUGH PDSA CYCLES: An
      illustration is given of one set of implications of the PDSA cycle as learning
      theory. It describes an alternative way of thinking about the evaluation of
      learning, which surpasses the traditional emphasis on judgment in evaluation.
      CONCLUSIONS: The potential to place the PDSA cycle at the core of learning in
      health professions education is great. Contributing factors to this potential
      include the historical emphasis on the scientific method in health care, the
      relationship between clinical education and practice, recent improvements in our
      capacity to define and measure health outcomes, emergent pressures for change in
      health care and education, and compatible multiple functions of the PDSA cycle.

PMID- 8664954
TI  - Can educational accreditation drive interdisciplinary learning in the health
      professions?
AB  - BACKGROUND: Accreditation in higher education serves as a means of assuring the
      public of academic program quality and of promoting continuing review and self
      improvement by educational units. Educational program accreditation is a means of
      seeking continuous improvement in the academic activities of programs and
      institutions. Discussions of interdisciplinary education raise questions about
      the responsiveness of accreditation to such approaches. ACCREDITATION AS A
      STIMULUS FOR CONTINUOUS IMPROVEMENT: Some health professions accrediting agencies
      have followed the lead of industry and have adapted their approach and philosophy
      of evaluation to a continuous improvement philosophy, while others continue to
      perpetuate an "inspection" mentality. The perpetuation of such an approach limits
      the value of the accreditation process. Accrediting agencies need to focus
      attention instead on stimulating professional preparation to develop in students
      the knowledge, skills, and competencies needed for health professions practice.
      Since such practice frequently occurs in team or interdisciplinary settings, the
      accreditation evaluation can support practice by incorporating an
      interdisciplinary perspective. THE CHALLENGES OF INTERDISCIPLINARY EDUCATION FOR
      ACCREDITATION: As models of interdisciplinary education are developed in the
      health professions, accreditation will be challenged to evolve in its
      effectiveness to evaluate interdisciplinary learning experiences. The accrediting
      community will need to recognize the barriers posed by interdisciplinary
      learning, as well as the special skills and situations needed to offer effective
      interdisciplinary experiences. Without this perspective the usefulness of
      accreditation will be diminished. A CHARGE FOR THE FUTURE: Standards and
      procedures for accreditation will need to be revised to address the unique
      characteristics of interdisciplinary education. A set of mock accreditation
      standards to guide the evaluation of interdisciplinary health professions
      education learning experiences is proposed. Finally, questions are posed about
      the role of accreditation in the context of interdisciplinary health professions
      education.

PMID- 8664955
TI  - Accepting the Galvin challenge: increasing efficiency and productivity in health
      professions education.

PMID- 8664956
TI  - Stakeholders and reflections on improving health professions education: what's
      next?

PMID- 8664958
TI  - Relations between age at occupational exposure to ionising radiation and cancer
      risk.
AB  - OBJECTIVES: To discover how the age when a given dose of ionising radiation is
      received (exposure age) affects the subsequent cancer risk, and whether the types
      of cancer caused by repeated exposure to small doses during adult life differ
      from naturally occurring cancers at that age. METHOD: A nested case-control
      design with all possible controls in a cohort of nuclear workers, and a Mantel
      Haenszel test (requiring only one degree of freedom) to discover whether there
      was any level of exposure age where the null hypothesis of no effects of
      radiation was rejected. This analysis was followed by inspection of how different
      types of cancers were related to the cancer risk. RESULTS: For radiation received
      at least 15 years before a cancer death (to allow for cancer latency) evidence of
      a dose related risk was found which was largely the result of exposures during
      the last 10 years of working life (between 55 and 65 years of age). The relative
      frequency of site specific cancers showed no signs of being different for
      radiogenic and idiopathic cancers, and there was no evidence of the exceptionally
      strong association between radiation and leukaemia found in atomic bomb data and
      other high dose situations. CONCLUSIONS: Sensitivity to carcinogenic effects of
      radiation increases progressively with age during adult life and, provided the
      dose is too small to produce many cell deaths, the ratio of leukaemias to solid
      tumours is no different for radiogenic and idiopathic cancers.

PMID- 8664957
TI  - Survey of perceived stress and work demands of consultant doctors.
AB  - OBJECTIVES: The objectives of this study were to assess the work demands as
      potential stressors of health service consultants, and to describe the
      development of tools for measuring stress experiences of consultants. METHODS: A
      stratified random sample of 500 NHS consultants in Scotland was targeted by a
      postal questionnaire and 375 (75%) returned a valid response. They completed
      questionnaires, including information on demographic factors, work demands,
      occupational stressors, and burnout. RESULTS: Principal components analysis
      showed that professional work demands of consultants fell into three categories:
      clinical, academic, and administrative. Their perceived stressors separated into
      four main factors: clinical responsibility, demands on time, organisational
      constraints, and personal confidence. These were assessed by 25 questions in the
      specialist doctors' stress inventory. Specific questions about perceived
      stressors which resulted in a high positive response included questions about
      demands on time, and organisational change in the NHS. CONCLUSION: These self
      reported data characterise and measure the consultants' work demands and their
      role as potential stressors. These measurements could form the basis for
      strategies to reduce occupational stress in these workers.

PMID- 8664959
TI  - Incidence of cancer among Norwegian boiler welders.
AB  - OBJECTIVES: The cancer incidence among 2957 boiler welders was investigated. The
      subjects were registered electrical welders from 1942 to 1981. A subcohort of 606
      stainless steel welders was studied separately. METHODS: The investigation was a
      historical prospective cohort study based on a national registry. The loss of
      follow up was 4.9%. RESULTS: There were 625 deaths (659 expected). There were 269
      cancer cases (264 expected). An excess of lung cancer was found; 50 cases v 37.5
      expected. There were three cases of pleural mesotheliomas v 1.1 expected. The
      subcohort of stainless steel welders had six cases of lung cancer v 5.8 expected,
      and one case of pleural mesothelioma v 0.2 expected. CONCLUSIONS: The welders in
      the study were assumed to represent a qualified work force. These welders had a
      small excess risk of lung cancer. The excess risk did not seem to be associated
      with stainless steel welding. Smoking and asbestos exposure were potential
      confounders.

PMID- 8664960
TI  - Myocardial infarction among male bus, taxi, and lorry drivers in middle Sweden.
AB  - OBJECTIVES: The aim of the present case-referent study was to investigate the
      incidence of myocardial infarction among male professional drivers, taking the
      type of vehicles and area of residence into account. METHODS: The study base
      comprised all men aged 30-74 in five counties in middle Sweden during 1976-81 or
      1976-84. Incident cases of the first episode of myocardial infarction were
      identified from registers of hospital admissions and causes of deaths. Referents
      were selected randomly from the study base. Information about occupation was
      obtained from the national censuses in 1970 and 1975. The possible impact from
      tobacco smoking and overweight were evaluated by simulations in combination with
      indirect data on these factors. RESULTS: The incidence of myocardial infarction
      was increased among bus drivers in Stockholm (relative risk (RR) = 1.53, 95%
      confidence interval (95% CI) 1.15-2.05), and among taxi drivers both in Stockholm
      (RR 1.65, 95% CI 1.30-2.11) and in the surrounding rural counties (RR 1.82, 95%
      CI 1.17-2.82). A smaller increase was found among long distance lorry drivers,
      whereas the relative risk among short distance lorry drivers was close to unity.
      Indirect comparisons make it unlikely that the excess among bus drivers in
      Stockholm could be explained by uncontrolled confounding from tobacco smoking or
      overweight. A very high proportion (more than 80%) of urban bus drivers in Sweden
      report a combination of high psychological demands and low control at work.
      CONCLUSIONS: Different types of drivers are at different risk of myocardial
      infarction. Bus drivers in urban areas seem to be at an increased risk, which is
      unlikely to be explained by uncontrolled confounding from tobacco smoking or
      overweight. Psychosocial work conditions may play a part in the increased
      incidence of myocardial infarction among urban bus drivers and should be
      investigated further.

PMID- 8664961
TI  - Chronic respiratory symptoms in children and adults living along streets with
      high traffic density.
AB  - OBJECTIVES: To investigate if the population living along streets with high
      traffic density has a higher prevalence of chronic respiratory symptoms. METHODS:
      A sample of 673 adults and 106 children (0-15 years), living along busy traffic
      streets in the city of Haarlem was compared with a control sample of 812 adults
      and 185 children living along quiet streets. Exposed and control streets were
      selected on the basis of model calculations of NO2 concentrations. A postal
      questionnaire containing questions about respiratory symptoms and several
      potential confounders was used to collect information from the study subjects.
      RESULTS: After adjustment for potential confounders, children living along busy
      streets were found to have a higher prevalence of most respiratory symptoms than
      children living along quiet streets. Adjusted odds ratios were significant for
      wheeze and for respiratory medication used. Risk ratios were higher for girls
      than for boys, with significant adjusted odds ratios between 2.9 and 15.8 for
      girls. In adults, only mild dyspnoea was more often reported by subjects living
      along streets with high traffic density. CONCLUSIONS: The results suggest that
      living along busy streets increases the risk of developing chronic respiratory
      symptoms in children.

PMID- 8664962
TI  - Effects of nitrogen oxides on natural killer cells in glass craftsmen and
      braziers.
AB  - OBJECTIVES: To assess the effect of exposure to nitrogen oxides on peripheral
      blood natural killer cells. METHODS: Groups of glass craftsmen and braziers
      exposed to nitrogen oxides and non-exposed controls were studied. Air
      concentrations of nitrogen oxides were measured. Mononuclear cells isolated from
      peripheral blood samples were assayed for natural killer cell activity with K562
      target cells in a 51Cr release assay and the percentage of natural killer cells
      (CD16) was measured by flow cytometry. RESULTS: Braziers were exposed to 1.2 ppm
      nitrogen dioxide and 8.6 ppm nitric oxide and glass craftsmen to 2.9 ppm nitrogen
      dioxide and 26.5 ppm nitric oxide. The natural killer cell activity of exposed
      workers was significantly lower than in non-exposed controls (P < 0.05 ANOVA
      Scheffe test). The percentage of natural killer cells in glass craftsmen was
      significantly greater than in controls (P < 0.05 ANOVA Scheffe test). Regression
      of natural killer cell activity against age, smoking habit, number of years
      worked and current exposure to nitrogen dioxide and nitric oxide gases was not
      significant. The percentage of natural killer cells was not significantly
      correlated with age, smoking habit, or numbers of years worked, but was
      significantly related to air concentrations of nitrogen dioxide (P < 0.01) and
      nitric oxide (P < 0.001). CONCLUSION: Natural killer cell activity and the
      percentage of natural killer cells in peripheral blood cells were altered in
      workers exposed to nitrogen oxides.

PMID- 8664963
TI  - Allergy to complex platinum salts: A historical prospective cohort study.
AB  - OBJECTIVE: To assess the incidence of allergy to complex platinum salts in a
      platinum refinery. METHODS: A historical prospective cohort study was carried out
      on 77 workers (67 men) who started work between 1 January 1979 and 31 December
      1991 and who were not atopic on skin prick tests to three common allergens at the
      time of recruitment. Skin prick tests with complex platinum salts were carried
      out and diagnosis of allergy to complex platinum salts made by the company's
      doctor. Skin tests and medical examinations were carried out routinely every six
      months. Follow up was until 30 September 1992 or until leaving refinery work.
      RESULTS: 18 workers developed a positive result on skin tests and 23 developed
      symptoms, including all 18 subjects with positive skin tests; the probability of
      surviving (95% confidence interval (95% CI)) for 72 months after joining the
      company, with negative skin test results was 0.67 (0.51-0.79) or with no symptoms
      was 0.63 (0.49-0.75). The incidence of positive skin tests and symptoms was
      highest during the first two years of work. Symptoms occurred more frequently in
      September and October than during the other months of the year. The exclusion of
      atopic subjects did not seem to have resulted in a lower incidence of
      sensitisation. Smoking was a significant predictive factor for both positive skin
      tests (estimated relative risk 5.53) and symptoms (4.70). CONCLUSION: The
      findings confirm that smoking is and that atopy may not be a high risk factor for
      the development of allergy to complex platinum salts. The high incidence of
      sensitisation and the available data on the clinical course of sensitised workers
      show that sensitised workers must be promptly and completely removed from
      exposure.

PMID- 8664965
TI  - Cumulative concentrations of blood lead and postural stability.
AB  - OBJECTIVE: To study the association in a group of battery manufacturing workers
      between computerised postural sway parameters and present concentrations of blood
      lead (PPb), index of cumulative blood lead years (CBI), and cumulative blood lead
      at different years of exposure (CPbYs). METHODS: Postural stability was
      investigated with a computerised postural sway measurement system in 60 workers
      exposed to lead with exposure duration of 84 (range 3-366) months and in 60
      control subjects. An index of CBIs in 55 workers (previous blood lead results of
      five workers were not available) and CPbYs were computed for each worker by
      calculating the area under the curve of concentrations of blood lead against
      time. RESULTS: The mean (SD) PPb was 36.0 (11.7) (range 6.4 to 64.5)
      micrograms/dl for the exposed workers and 6.3 (2.4) (range 3.1-10.9)
      micrograms/dl for the 14 randomly selected control subjects. Significant
      differences between groups for the postural sway parameters obtained when the
      eyes were closed were found for length of sway path (L); mean velocity of the
      centre of pressure along its path (Vel); area included within the path of the
      centre of pressure (Ao); 95% confidence elliptical area (Ae). The Romberg ratio
      (the relation between eyes closed and open) for the Vel, L, Ao, and Ae of the
      exposed group were also significantly different from those of the controls. The
      postural sway parameters (eyes closed) were not significantly correlated with PPb
      or CBI. However, the cumulative blood lead for the past two years before the
      postural sway assessment, CPbY2, was significantly correlated with all the
      postural sway parameters. CONCLUSION: The study showed that workers exposed to
      lead had significantly poorer postural stability than a control group. Lead may
      affect certain parts of the somatosensory system resulting in postural
      instability when the visual input is cut off. The CPbY2 was significantly
      positively correlated with most of the postural sway parameters. Effects of lead
      on postural stability may be related to recent increases in blood lead
      concentration among the exposed workers rather than to cumulative body burden.

PMID- 8664964
TI  - Exposure to sheep dip and the incidence of acute symptoms in a group of Welsh
      sheep farmers.
AB  - OBJECTIVES: To measure the exposure of a group of farmers to organophosphate
      pesticide in sheep dip, and to record the incidence of symptoms after exposure.
      DESIGN: A prospective study of the autumn 1992 dipping period. Working methods
      were assessed by questionnaire. Absorption of organophosphate pesticide was
      estimated before, immediately after, and six weeks after dipping by measuring
      plasma cholinesterase, erythrocyte cholinesterase, and dialkylphosphate urinary
      metabolites of organophosphates. Symptoms were recorded by questionnaire at the
      same time as biological monitoring. Possible confounding factors were identified
      by medical examination of the subjects. SETTING: Three community council
      electoral wards in Powys, typical of hill sheep farming areas in Wales. SUBJECTS:
      All (38) men engaged in sheep dipping living in the three community council
      electoral wards. RESULTS: 23 sheep farmers and one dipping contractor completed
      the study--a response rate of 63%. A sample of seven men who refused to enter the
      full study had similar working practices to the 24 subjects. Subjects reported
      inadequate handling precautions, and significant skin contamination with dip. Two
      men reported under diluting dip concentrate for use. Both had significant
      depression of erythrocyte cholinesterase after dipping. This indicated some
      absorption of organophosphate pesticide--but this did not reach levels usually
      associated with toxicity. It was not clear whether the symptoms of these two mens
      were caused by organophosphate exposure. Measurement of dialkylphosphate urinary
      metabolites in a single specimen of urine voided shortly after the end of dipping
      could not be correlated with individual exposure. CONCLUSIONS: Sheep dipping is
      strenuous and dirty work and sheep farmers find it difficult to wear personal
      protective equipment and avoid skin contamination with dip. In this limited
      study, farmers did not seem to have significant organophosphate toxicity, despite
      using inadequate handling precautions.

PMID- 8664966
TI  - Surveillance of deaths on board Danish merchant ships, 1986-93: implications for
      prevention.
AB  - OBJECTIVE: To describe and analyse the types and circumstances of all natural and
      non-natural deaths among seamen on board Danish merchant ships. METHODS: Data on
      147 cases were obtained from maritime authorities, an insurance company, shipping
      companies, hospitals, death registers, and death certificates in the period from
      1986-93. RESULTS: The 53 natural deaths were dominated by cardiovascular diseases
      and infectious diseases. Insufficient treatment on board was identified as a
      contributing factor for death in some cases. Medical advice was not always sought
      and the advice given was in some cases insufficient. 73 fatal accidents were
      identified. The incidence of accidents of 5.29/10,000 person-years was 11.5 times
      higher than the incidence of 0.46/10,000 for the Danish male workforce ashore. 23
      accidents (31%) were due to maritime casualties and 26 (36%) were occupational
      accidents. The remaining 24 (33%) were accidents during off duty hours including
      six self intoxications. Rough weather, inadequate awareness of safety, lack of
      use of personal protection devices, and inexperience were associated with many of
      the fatal injuries directly related to work. Alcohol played a major part in 12
      out of 18 fatal injuries occurring during off duty hours. CONCLUSIONS: The
      maritime workplace was identified as a high risk workplace and in many aspects
      differs from the conditions ashore. Acute diseases and serious injuries pose
      special risks to seamen because of a lack of direct access to professional
      medical care at sea. Primary prevention of certain diseases is needed and
      possible. Improved training, improved systems of work, improved safety awareness,
      and greater use of personal protection devices are needed to prevent fatal
      injuries. Medical training of ships' officers providing medical care on board and
      specific training of doctors giving medical advise to ships should be improved to
      meet the needs.

PMID- 8664967
TI  - Local cold exposure of the hands from cryosectioning work in histopathological
      and toxicological laboratories: signs and symptoms of peripheral neuropathy and
      Raynaud's phenomenon.
AB  - OBJECTIVES: To study relations between cryosectioning work, skin temperature,
      early signs of neuropathy in the hands, and vasospastic and neurological
      symptoms. Microtome work is carried out at histological and toxicological
      laboratories all over the world. It implicates local cold exposure of -20 degrees
      C on the hands of exposed laboratory technicians. METHODS: Thirty nine laboratory
      technicians who use microtomes at the preclinical and clinical laboratories at
      the University of Uppsala, Sweden were studied. An equal number of nonexposed
      laboratory technicians served as controls, matched for workplace, sex, age, and
      smoking habits. Information on symptoms, type of work, and personal factors were
      assessed by means of a self administered questionnaire. Two point discrimination
      ability was tested, and vibration perception threshholds were measured for both
      hands by a bio-thesiometer. Also, skin temperature was measured during
      cryosectioning work in those 15 technicians performing cryosectioning work during
      the study period. RESULTS: Most laboratory technicians did not use any gloves
      during cryosectioning work, and direct contact with frozen materials sometimes
      occurred and resulted in a rapid cooling of the skin. In six of 15 exposed
      subjects (40%), the mean skin temperature during microtome work was below 20
      degrees C. A later rise in skin temperature, due to a compensatory vasodilation,
      was found in two subjects. The group exposed to cold had signs of early
      neuropathy on the right hand, indicated both by vibrametry and two point
      discrimination test. Significant work related differences in clinical signs
      within the group exposed to cold was also found. No differences between exposed
      and nonexposed people were found for symptoms of Raynaud's phenomenon, numbness,
      or musculosceletal complaints. CONCLUSION: Our study shows that cryosectioning
      laboratory work may cause adverse health effects--for example, peripheral
      neuropathy--and measures should be taken to protect the hands from the local cold
      exposure.

PMID- 8664968
TI  - An analysis of the Vietnamese system of occupational safety and health and
      setting priorities with the analytical hierarchy process.
AB  - OBJECTIVE: There were two objectives. The first was to describe the Vietnamese
      system of occupational safety and health (OSH) and its problems. The second was
      to evaluate priorities among future OSH policies by the analytical hierarchy
      process (AHP). METHODS: The Vietnamese OSH system was analysed in detail mainly
      based on various official documents. After the OSH problems in Vietnam were
      identified through discussions with Vietnamese OSH specialists they were given
      priorities in five different OSH policies, which were evaluated by the AHP.
      RESULTS AND CONCLUSION: The OSH system in Vietnam is in theory well organised:
      the government has established fundamental laws and has organised the OSH
      administrative system from the central to the grassroots level. However, this
      system does not work sufficiently well to improve working conditions. According
      to discussions with Vietnamese OSH specialists, four factors associated with OSH
      problems in Vietnam were evaluated: shortage of materials and manpower,
      inadequate OSH information system, inappropriate OSH administrative system, and
      poor awareness of workers and employers about the OSH problems. Considering the
      relative importance of these four factors, the priorities within five policies
      were evaluated by the AHP technique. The results showed that the most important
      change needed was reorganisation of the OSH administrative system, followed by
      OSH education for workers and employers, training of personnel in OSH services,
      improvement of OSH research activity, and the establishment of an adequate OSH
      information system. It is expected that developed countries will help the
      Vietnamese government to implement these programmes.

PMID- 8664969
TI  - Luteinizing hormone receptor mutations and sex differentiation.
AB  - Mutations in the luteinizing hormone (LH) receptor gene have been found in
      patients with abnormalities in their sexual differentiation. In this paper we
      review results obtained in the studies of these LH receptor mutations. Activating
      and inactivating mutations are discussed with respect to the mechanism of action
      of LH/human chorionic gonadotrophin but also in light of their impact of the
      present knowledge of the physiology of sex differentiation and gonadal function.

PMID- 8664970
TI  - Peroxisome proliferator-activated receptors: a nuclear hormone receptor involved
      in adipocyte differentiation and lipid homeostasis.

PMID- 8664971
TI  - Calcium-sensing receptor: confirmation of its pivotal function in calcium
      homeostasis, using a knock-out model.

PMID- 8664972
TI  - Leptin secretion and action: an update.

PMID- 8664973
TI  - True insulin and intact proinsulin levels in acromegalic patients.
AB  - To determine whether proinsulin (PI) contributes significantly to the
      immunoreactive insulin (IRI) concentrations in acromegalics, we measure PI, "true
      insulin" and IRI in a group of acromegalics compared with a control group. Serum
      PI was determined by the immunofluorimetric assay (IFMA). Insulin was also
      determined by an IFMA that measures true insulin and by a radioimmunoassay (RIA).
      We performed an oral glucose tolerance test (OGTT) in a total group of 46
      subjects: 10 controls with normal OGTT and body mass index < 25 kg/m2 (control
      group I), 10 controls with normal OGTT and body mass index > 25 kg/m2 (control
      group II), 15 patients with active acromegaly and normal OGTT and 11 patients
      with active acromegaly and IGT. Plasma glucose, serum GH, insulin and proinsulin
      were measured in all OGTT samples. Basal levels of insulin-like growth factor I
      (IGF-I) were measured in acromegalics. Mean body mass index in acromegalics with
      normal and impaired glucose tolerance were significantly higher compared with
      control group I and similar when compared with control group II. Proinsulin
      increased during OGTT in acromegalics with impaired glucose tolerance compared to
      control group I, and only fasting proinsulin compared to control group II. In
      normal OGTT acromegalics, only fasting proinsulin was increased. The RIA insulin
      during OGTT was significantly higher for both acromegalic groups compared to
      control group I and only at fasting when compared with control group II. This
      difference was not evident when insulin was measured by IFMA. These results
      suggest that in acromegalics, hyperinsulinism measured by RIA was at least in
      part due to hyperproinsulinism.

PMID- 8664974
TI  - Octreotide treatment increases exercise capacity in patients with acromegaly.
AB  - This prospective study was conducted to determine the effect of Octreotide
      treatment on cardiovascular function in patients with active acromegaly. Ten
      acromegalic patients who failed to suppress growth hormone (GH) to < 5 mU/l
      during a 2 h oral glucose tolerance test were treated with 100 micrograms of
      Octreotide subcutaneously three times daily for 2 months, followed by 200
      micrograms three times daily if the mean GH level was > 5 mU/l, for a total of 1
      year. All patients had GH and insulin-like growth factor I (IGF-I) estimation,
      ejection fraction determined by Echocardiogram and multigated image acquisition
      scan, electrocardiogram (ECG), exercise ECG, 24-h ECG and chest x-ray. At 6 and
      12 months, both GH and IGF-I were reduced but ECG, heart size and ejection
      fraction were unchanged. The patients improved symptomatically and had
      significant reduction in resting heart rate and increase in weight. Exercise time
      (mean +/- SD) increased from 637 +/- 137s at baseline to 787 +/- 101s at 1 year
      (p < 0.01) and work done increased from 9 +/- 3.3 to 11.9 +/- 2.7 metabolic
      equivalents (p < 0.001). We conclude that the decrease in GH and IGF-I following
      Octreotide treatment of acromegaly is accompanied by decreased heart rate and
      increased exercise capacity despite an unchanged ejection fraction.

PMID- 8664975
TI  - No correlation of growth hormone receptor gene mutation P561T with body height.
AB  - Analysis of the growth hormone receptor (GHR) gene in GH insensitivity syndrome
      revealed various mutations, mainly in the gene encoding the extracellular domain
      of GHR. On the other hand, the mutation of the gene encoding the cytoplasmic
      domain of GHR was not found. We have reported, in the cytoplasmic domain of a GHR
      gene, mutation P561T in a patient with Noonan syndrome who showed a blunted
      insulin-like growth factor I (IGF-I) response to an acute injection of GH.
      However, her mother possessing the same mutation had no growth failure. To
      clarify the significance of the GHR gene mutation P561T, 96 volunteers (41 males
      aged 21-80 years; 55 females, aged 20-80 years, were tested for the presence of
      this mutation. By the polymerase chain reaction-restriction fragment length
      polymorphism (PCR-RFLP) method, three of the 41 males and 11 of the 55 females
      examined revealed heterozygous missense mutation P561T. The body height (cm) was
      168 +/- 5.3 (mean +/- SD) in three males with the mutation and 164.1 +/- 5.8 in
      38 males without the mutation. The difference between them was not statistically
      significant. The body height in 11 females with the mutation was 152.6 +/- 5.4,
      which did not differ significantly from 151.3 +/- 6.2 in 44 females without the
      mutation. These findings suggest that the heterozygous missense mutation P561T in
      the cytoplasmic domain of GHR does not play a significant role in determining the
      final body height.

PMID- 8664976
TI  - Insulin-like growth factor I alters peripheral thyroid hormone metabolism in
      humans: comparison with growth hormone.
AB  - Insulin-like growth factor I (IGF-I) is considered to mediate some of the growth
      promoting and metabolic effects of growth hormone (GH). Growth hormone treatment
      of healthy and GH-deficient subjects is accompanied by increased conversion of
      thyroxine (T4) to triiodothyronine (T3) in peripheral tissues. Whether these
      effects are mediated by IGF-I is unknown. To assess the respective roles of these
      hormones on thyroid hormone metabolism we have treated two groups of subjects.
      The first group consisted of eight healthy subjects who were treated with IGF-I
      (10 micrograms.kg-1.h-1 sc for 5 days). The second group consisted of eight
      subjects with combined GH and thyrotropin (TSH) deficiency due to acquired
      pituitary disease. They were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 7
      days), GH (2 IU m-2 sc q.i.d.) or both hormones together. The IGF-I treatment in
      healthy subjects led to an increase in free T3 (FT3) and a reduction in TSH
      levels, whereas FT4 and total T4 (TT4) levels remained unchanged. In the second
      group-in which all subjects were substituted with oral L-thyroxine-treatment with
      IGF-I led to an elevation of FT3 in the face of unchanged T4 levels. Growth
      hormone alone and GH plus IGF-I resulted in a more pronounced elevation in T3
      level. The results suggest that IGF-I partially mediates the well-known effects
      of GH on peripheral conversion of T4 to T3. However, GH has more pronounced
      effects on thyroid hormones that apparently are not mediated by IGF-I.

PMID- 8664977
TI  - Autoimmune hypothyroidism and hyperthyroidism in patients with Turner's syndrome.
AB  - A high prevalence of autoimmune thyroid disease (AITD) has been described in
      Turner's syndrome (TS) but the extent of this association is controversial for
      the prevalence of thyroid autoantibody and the clinical impact of thyroid
      dysfunction. In this study we searched for thyroid disease and thyroid
      autoantibodies in patients with TS. Seventy-five unselected TS patients (age
      range 3-30 years) were studied. Sera were tested for thyroid hormones,
      thyrotropin (TSH), thyroglobulin (TG-ab) and thyroperoxidase (TPO-ab) antibodies.
      The TSH-receptor antibodies with thyroid-stimulating (TS-ab) or TSH-blocking
      activity (TSHB-ab) were measured in the IgG fraction using a bioassay. Ten out of
      75 (13.3%) TS patients had AITD: eight had autoimmune thyroiditis (AT) (six with
      subclinical and two with overt hypothyroidism and one with euthyroidism) and one
      had Graves' disease. The prevalence of AITD increased significantly (p < 0.05)
      from the first (15%) to the third (30%) decade of life. The prevalence of TPO-ab
      and/or TG-ab (20%) was higher (p < 0.05) in TS than in age-matched female
      controls and increased from the first (15%) to the third (30%) decade of life.
      Clinical AITD was diagnosed in 46% of TS patients with TPO-ab and/or TG-ab.
      Thyroid-stimulating antibody was detected in the hyperthyroid patient, and TSHB
      ab was found in one of eight patients with hypothyroid AT. It was concluded that:
      TS patients are at higher than average risk of developing AITD not only in
      adolescence and adult age but also in childhood; hypothyroidism, mainly
      subclinical, is the most frequent thyroid dysfunction; elevated TPO-ab and/or TG
      ab alone do not imply thyroid dysfunction; TS-ab or TSHB-ab are always associated
      with thyroid dysfunction although most cases of autoimmune hypothyroidism are not
      due to the latter antibody.

PMID- 8664978
TI  - Analysis of normal and truncated holo- and apo-retinol-binding protein (RBP) in
      human serum: altered ratios in chronic renal failure.
AB  - Retinol, the precursor of the retinoic acid hormone, is transported in the serum
      by a specific carrier, the retinol-binding protein (RBP). Compared to serum of
      healthy controls, the serum of patients with chronic renal failure (CRF) contains
      markedly increased levels of the RBP form truncated at the C terminal, des(182Leu
      183Leu), (RBP2), which suggests that RBP2 is cleared by the kidney in healthy
      people but accumulates in serum of CRF patients (Jaconi S, et al. J Lipid Res
      1995:36:1247-53). To understand better the mechanism of retinol transport, we
      have developed a new analytical strategy to analyze the various forms of RBP that
      circulate in the blood: RBP with and without retinol (holo- and apo-RBP,
      respectively), RBP bound or not to transthyretin (TTR) and to determine in which
      of these forms RBP2 circulates. We confirm, but now by direct measurement, that
      holo-RBP and, to a larger extent, apo-RBP are increased in CRF serum compared to
      normal serum. We also show that almost all apo-RBP and about 50% of total holo
      RBP, corresponding to RBP excess in CRF serum, circulate free and are not
      complexed to TTR, the remaining 50% being complexed to TTR. This observation
      suggests that the high levels of free holo-RBP, not bound to TTR, which
      correspond to the increase in total RBPs measured in CRF serum, may alter the
      tissue uptake of retinol and be responsible for the signs of hypervitaminosis A
      observed in these patients. Secondly, we found that the truncation resulting in
      RBP2 does not alter its binding properties for retinol nor those of holo-RBP2 for
      TTR. We observed that the high amounts of free holo-RBP2 and holo-RBP in sera of
      CRF patients were low in normal serum, suggesting that these forms are cleared by
      the kidney in normal conditions. The possible role of free holo-RBPs is discussed
      in the context of retinol recycling.

PMID- 8664979
TI  - Adrenocorticotropin-independent bilateral macronodular adrenocortical
      hyperplasia: immunohistochemical studies of steroidogenic enzymes and post
      operative course in two men.
AB  - We treated two men with Cushing's syndrome due to adrenocorticotropin (ACTH)
      independent bilateral macronodular adrenocortical hyperplasia (AIMAH). In both
      patients, plasma ACTH was low and plasma cortisol was not suppressed by a high
      dose of dexamethasone (8 mg) but was remarkably responsive to exogenous ACTH. The
      adrenal glands were extremely enlarged and contained multiple nodules composed of
      large clear cells and small compact cells. The immunoreactivity of P-450(17)
      alpha was predominant in the small compact cells, while that of 3 beta
      hydroxysteroid dehydrogenase (3 beta-HSD) was observed exclusively in the large
      clear cells. Among various adrenocortical disorders, differential expression of 3
      beta-HSD and P-450(17) alpha in clear and compact cells has heretofore been
      demonstrated only in AIMAH. Total adrenalectomy was done for one patient, and
      partial adrenalectomy for the other. In the former patient, the normal diurnal
      rhythm of plasma ACTH was restored 11 months postoperatively. In the latter
      patient, the normal dynamics in the hypothalamic-pituitary-adrenal axis became
      evident 15 months after surgery. Thus AIMAH is apparently a primary
      adrenocortical disorder and is not due to abnormalities of the hypothalamus or
      pituitary.

PMID- 8664980
TI  - Evidence for a role for insulin-like growth factor binding proteins in
      glucocorticoid inhibition of normal human osteoblast-like cell proliferation.
AB  - Glucocorticoids (GCs) inhibit bone formation in vivo and inhibit osteoblast
      proliferation and collagen synthesis in vitro. These effects may be mediated by
      alterations in the insulin-like growth factor (IGF) system. In the present study
      of normal human osteoblast-like (HOB) cells, we tested the hypothesis that
      dexamethasone (Dex) inhibits IGF anabolic activity in bone by altering expression
      of IGF binding proteins (IGFBPs), particularly by decreasing expression of IGFBP
      5 and IGFBP-3 (which enhance IGF activity) and increasing expression of IGFBP-4
      (which inhibits IGF actions). Dexamethasone treatment caused a dose-dependent
      inhibition of HOB cell proliferation (69 +/- 4% of control at 10(-8) mol/l Dex)
      in seven separate experiments. Dexamethasone decreased IGFBP-5 mRNA levels to 20
      30% of control (10(-8) and 10(-7) mol/l for 24 h). In six of six HOB
      preparations, 10(-8) mol/l Dex decreased IGFBP-5 mRNA levels (35 +/- 7% of
      control) and this effect was time dependent. Dexamethasone also decreased IGFBP-3
      mRNA levels (74 +/- 9% of control in three HOB preparations). Dexamethasone
      decreased secretion of 29-31-kD IGFBP-5 and 38-42-kD IGFBP-3 proteins, determined
      by Western ligand blot and IGFBP-5 immunoblot, and induced a dose-dependent
      decrease in IGFBP-3 and IGFBP-5 secretion determined by specific
      radioimmunoassays. The effects of Dex on IGFBP-4 mRNA and on secretion of 25-kD
      IGFBP-4 levels were inconsistent between different cell preparations. Results
      suggest that GC inhibition of IGFBP-5 and IGFBP-3 production could decrease IGF
      activities and contribute to GC inhibition of bone formation.

PMID- 8664981
TI  - Domestic cats show episodic variation in plasma concentrations of
      adrenocorticotropin, alpha-melanocyte-stimulating hormone (alpha-MSH), cortisol
      and thyroxine with circadian variation in plasma alpha-MSH concentrations.
AB  - Blood samples were collected from 31 healthy domestic cats to characterize
      possible episodic and/or circadian variation in plasma concentrations of
      adrenocorticotropin (ACTH), cortisol, thyroxine and alpha-melanocyte-stimulating
      hormone (alpha-MSH). Samples were collected with minimal disturbance through
      indwelling jugular cannulae at two frequencies: at 20-min intervals for 3 h for
      evaluation of episodic variation, and at 2-h intervals for 48 or 72 h to identify
      possible circadian changes. Episodic peaks in profiles of all hormones were found
      in the majority of cats. When data were compared across four bleed periods (each
      of 3 h duration), no differences were detected in average hormone concentrations
      or characteristics of episodic pulses. Correlation analyses showed a significant
      (p < 0.001) relationship between concentrations of ACTH and cortisol (r = 0.44)
      when these hormones were measured in the same plasma sample. A weaker but
      significant correlation (r = 0.13, p < 0.05) was also detected between
      concentrations of ACTH and alpha-MSH, suggesting that proopiomelanocortin peptide
      secretion from the pars distalis and pars intermedia occurs at least on occasion
      in synchrony. No differences in hormonal profiles were noted when comparing data
      across sexes. Data from the studies designed to evaluate circadian change (48 and
      72-h bleed periods) indicated that, of the four hormones, only concentrations of
      alpha-MSH changed with a significant circadian periodicity. A significant
      circadian component of period length 24-25 h was detected in 37% (seven of 19) of
      cats examined. Concentrations of alpha-MSH were greatest coincident with or
      shortly after the onset of darkness. These findings indicate that pituitary
      adrenocortical hormones are secreted episodically in domestic cats and that, in
      contrast to the patterns shown by ACTH and cortisol, secretion of the pars
      intermedia product alpha-MSH occurs with a circadian rhythm in about one-third of
      cats.

PMID- 8664982
TI  - Dopamine increases interleukin 6 release and inhibits tumor necrosis factor
      release from rat adrenal zona glomerulosa cells in vitro.
AB  - Interleukin 6 (IL-6) and tumor necrosis factor (TNF) are released from the zona
      glomerulosa of rat adrenal glands. The release of these cytokines from adrenal
      cells is regulated by interleukin 1 beta (IL-1 beta) and lipopolysaccharide
      (LPS), which are involved in the immune and inflammatory responses.
      Adrenocorticotropic hormone (ACTH) and angiotensin II, hormones that regulate the
      adrenal cortex, likewise regulate release of cytokines from adrenal glands.
      Dopamine inhibits aldosterone release from the adrenal cortex. Therefore, effects
      of dopamine on IL-6 and TNF release from rat adrenal zona glomerulosa were
      investigated. Primary cultures of rat adrenal zona glomerulosa cells were exposed
      to test agents and IL-6 and TNF release determined by the 7TD1 and WEHI
      bioassays, respectively. Dopamine increased basal IL-6 release and potentiated IL
      6 release stimulated by ACTH, LPS or IL-1 beta. Dopamine inhibited basal and
      secretagogue-stimulated (LPS and IL-1 beta) TNF release. These effects of
      dopamine were mediated by D2 receptors because N-0437, a D2 agonist, had effects
      on TNF and IL-6 release identical to those of dopamine. Therefore, dopamine,
      through D2 receptors, regulates the release of IL-6 and TNF from adrenal cells.
      Because TNF and IL-6 regulate adrenal steroid release, these cytokines may serve
      as autocrine or paracrine mediators of adrenal gland function.

PMID- 8664983
TI  - Glucose-stimulated elevation of cytoplasmic calcium is defective in the diabetic
      Chinese hamster islet B cell.
AB  - To characterize insulin release and cytoplasmic free Ca2+ ([Ca2+]i) levels in the
      diabetic Chinese hamster islet B cell, islets from genetically normal (subline M)
      and diabetic (subline L) hamsters were collagenase isolated. Insulin release and
      glucose utilization (conversion of D-[5-(3H)]glucose to 3H2O) were measured in
      whole islets; [Ca2+]i levels were measured in single islet cells using fura-2.
      The Ca2+ channel agonist, 12 mmol/l perchlorate, ClO4-, increased the subnormal
      insulin response during 20 mmol/l glucose perifusion, but did not normalize it.
      Glucose utilization measured over a 2-h period was normal. Glucose induced an
      initial decrease and then a rise in [Ca2+]i in 85% of the normal (presumably B)
      cells. In diabetic cells, the [Ca2+]i response was delayed, subnormal and only
      observed in 23% of the cells. When perchlorate or another Ca2+ channel agonist,
      10 mumol/l CGP 28392, was added with glucose, a larger proportion of the diabetic
      cells (61-67%) showed increased [Ca2+]i and the mean [Ca2+]i response was not
      different from normal. However, neither perchlorate nor CGP 28392 could normalize
      glucose-stimulated insulin release, and K(+)-induced insulin release was
      decreased in diabetic islets. The K(+)-induced [Ca2+]i rise was essentially
      normal in all the diabetic islet cells. Therefore, the diabetic hamster islet
      appears to metabolize glucose normally, but has a diminished insulin response to
      glucose and K+. The Ca2+ channel agonists markedly improve the subnormal [Ca2+]i
      response but not the insulin response. Glucose-induced elevation of [Ca2+]i and
      exocytosis appear defective in the diabetic Chinese hamster B cell.

PMID- 8664984
TI  - Immunohistochemical localization and immunoblotting of androgen receptor in
      spinal neurons of male and female rats.
AB  - Androgen activity in the central nervous system, as in other tissues, is mediated
      by the androgen receptor. We performed the precise localization of the androgen
      receptor in spinal cord of male and female adult rats by immunohistochemistry
      using polyclonal antibodies. Light microscopy indicated immunoreactivity in the
      anterior horn with a strong staining in motoneurons, but staining was also
      observed in the posterior horn. Electron microscopy showed a predominant nuclear
      immunostaining. A weaker but significant immunoreactive androgen receptor was
      also noted in the perinuclear/ intracysternal position. Moreover, no differences
      were found between male and female rats. Immunoblotting demonstrated that the
      androgen receptor is expressed in both ventral and dorsal spinal cord, with an
      apparent molecular mass identical to that noted in other androgen-dependent
      tissues. The expression of androgen receptor in motoneurons corroborates the role
      of androgens in motoneuron growth, development and regeneration and underlies the
      possibility that androgen receptor abnormality leads to the motoneuron
      degeneration observed in X-linked spinal and bulbar muscular atrophy.

PMID- 8664985
TI  - Effect of triiodothyronine administration on estrogen receptor contents in
      peripuberal Sertoli cells.
AB  - The effects of thyroid hormone on androgen metabolism in peripuberal Sertoli
      cells through the inhibition of estradiol production have been reported
      previously. It was our intention to investigate further the possible role of
      thyroid hormone on the interaction between testicular steroids and Sertoli cells
      by analyzing the effects of triiodothyronine (T3) on estrogen receptor content in
      2-, 3- and 4- week-old euthyroid rats. Triiodothyronine treatment (3
      micrograms/100 body wt per day) given during the last week prior to sacrifice
      resulted in reduced testicular growth in 2-week-old animals. Sertoli cells from
      all groups were cultured initially under basal conditions for the first 24 h and
      subsequently in the presence of testosterone and/or T3 for the additional 24 h.
      The in vitro addition of T3 induced a decrease of estrogen receptors (ERs) in 2-
      and 3-week-old animals that appeared more pronounced especially in the presence
      of T3 and testosterone. When T3 was tested in vivo we noticed that the decrease
      of ER content was even greater in all three groups under the in vitro influence
      of both T3 and testosterone. In 3-week-old animals a simultaneous assay of ERs in
      both nuclear and cytoplasmic compartments was performed. The ER concentrations in
      the nucleus were closely related to those of the cytoplasm. The in vivo
      administration of T3 was responsible for a greater decrease of ERs in the nucleus
      than in the cytosol. On the basis of these results, and in agreement with our
      previous data, we speculate that the effect of T3 in the maturational events of
      Sertoli cells could involve both estradiol production and ER content.

PMID- 8664986
TI  - Stimulation of thyroid cell proliferation by epidermal growth factor is different
      from cell growth induced by thyrotropin or insulin-like growth factor I.
AB  - Isolated intact porcine thyroid follicles free of contaminating single cells were
      embedded in "Matrigel", which is a gel-forming basement membrane preparation
      containing mainly collagen type IV, laminin, heparan sulfate proteoglycans and
      entactin. Follicles were treated with different growth factors: thyrotropin
      (TSH), insulin-like growth factor I (IGF-I), epidermal growth factor (EGF) or
      transforming growth factor beta. Cell proliferation was quantified by counting
      cell numbers. Morphological studies were done by photodocumentation and analysis
      of histology by light and electron microscopy. The thyrocytes had the
      physiological polarity with follicular cell arrangement, microvilli at the apical
      membrane, desmosomes and tight junctions. The lumen contained colloid. Iodide
      organification (10.2 +/- 2.1 vs 26.1 +/- 5.8 pmol/10(6) cells; TSH 0.1 mU/ml) and
      release of thyroid hormones (thyroxine, 1754 +/- 207 vs 2890 +/- 460 pg/10(6)
      cells; triiodothyronine, 164 +/- 22 vs 412 +/- 106 pg/10(6) cells; TSH, 1mU/ml)
      were significantly stimulated by TSH. There was no basal growth rate in serum
      free medium but proliferation was slightly stimulated with TSH (1 mU/ml; 149 +/-
      19%) and in the same order of magnitude with IGF-I (10 ng/ml; 159 +/- 23%) but
      without follicle neoformation. In contrast, BGF (1.0-5.0 ng/ml) induced thyrocyte
      proliferation dose dependently three- to sixfold. With BGF up to 2 ng/ml, buds of
      new follicles formed surrounding pre-existing follicles. With BGF higher than 3
      ng/ml, typical papillary structures developed. Transforming growth factor beta
      inhibited this dedifferentiated growth. A migration of single cells into the gel
      was never observed. Thus, three-dimensional culture of isolated thyroid follicles
      in "Matrigel" provides a tool for investigating the regulation of follicular
      growth and neoformation close to the in vivo situation.

PMID- 8664987
TI  - Effect of hypothyroidism on ovarian follicular development, granulosa cell
      proliferation and peripheral hormone levels in the prepubertal rat.
AB  - The aim of this study was to examine the effects of prepubertal hypothyroidism on
      ovarian development in rats. Therefore, from birth up to day 40 postpartum, rats
      were given 6-propyl-2-thiouracil (PTU) via the drinking water of mothers and
      pups. At ages ranging from 12 to 40 days, ovarian weights were measured and serum
      was collected to estimate thyrotrophin (TSH), follicle-stimulating hormone (FSH)
      and inhibin levels. Two hours before sacrifice the animals received an injection
      of bromodeoxyuridine (BrdU) to estimate the proliferative activity of the
      follicular granulosa cells. Ovaries were fixed in Carnoy's fluid and follicle
      counts were performed on sections stained with anti-BrdU and with haematoxylin
      and eosin. The PTU treatment resulted in increased serum TSH levels, indicative
      of hypothyroidism, and markedly lower body and ovarian weights, whereas serum FSH
      and inhibin levels were hardly affected. At day 40, ovaries of PTU-treated
      animals contained relatively more secondary and less antral follicles, smaller
      non-atretic antral follicles and more atretic follicles when compared with
      untreated rats, while corpora lutea were absent. It is concluded that this
      disturbed folliculogenesis is due to inadequate thyroid hormone supply, which
      hampers the differentiation and not the proliferation of granulosa cells because
      diameters of antral follicles were significantly smaller whereas the BrdU
      labelling index had not changed.

PMID- 8664988
TI  - Differential responses of femoral and vertebral bones to long-term excessive L
      thyroxine administration in adult rats.
AB  - Recent studies suggest that thyroid-stimulating hormone suppressive doses of
      thyroid hormone decrease bone mass in humans and growing rats. To determine the
      long-term effects of excessive L-thyroxine administration on the femur and
      vertebrae in an adult rat model, 20 male Sprague-Dawley rats (20 weeks old) were
      randomized into two groups. Group 1 received L-thyroxine (20 micrograms/100 g
      body weight ip daily), and group 2 received normal saline ip daily for 20 weeks.
      Femoral and lumbar vertebral bone mineral density measurements were performed at
      0, 6, 15, 18 and 20 weeks of treatment. After 20 weeks of treatment, total RNA
      was isolated from both femoral and lumbar bones. Northern hybridization was
      performed with 32P-labeled DNA probes for osteocalcin, osteopontin, alkaline
      phosphatase and tartrate-resistant acid phosphatase. Significant decreases in
      bone mineral density in the femur of L-thyroxine-treated rats were observed after
      15 weeks (p < 0.03). Lumbar bone mineral density was not affected. Both
      osteoblast (osteocalcin, osteopontin, alkaline phosphatase) and osteoclast
      (tartrate-resistant acid phosphatase) gene expression markers were increased
      significantly in the femoral bone (p < 0.001), but not in the lumbar vertebrae of
      the L-thyroxine-treated rats. We conclude that long-term administration of
      excessive doses of L-thyroxine to the adult rat preferentially affects femoral
      but not vertebral bone. This is manifested by decreased bone mineral density as
      well as increased gene expression markers for osteoblast and osteoclast activity
      in the femur.

PMID- 8664989
TI  - Solubilization, reconstitution and molecular properties of the triiodothyronine
      transport protein from rat erythrocyte membranes.
AB  - Triiodothyronine (T3) transport through the mammalian erythrocyte membrane is
      mediated by a transport system related to the aromatic amino acid transport
      system T. The T3-binding component of this transport system could be photolabeled
      with [125I]T3 as a 52-kD protein, and subsequently solubilized with non-ionic
      detergents. Upon purification by ion-exchange chromatography, the photolabeled 52
      kD protein solubilized with octylglucoside (OG) resolved into several peaks,
      suggesting charge heterogeneity of labeled proteins. The saturable [125I]T3
      binding to rat erythrocyte membranes was completely inhibited by non-ionic
      detergents at concentrations about 20 times lower than those that solubilized
      membrane. Therefore, detergent-free proteoliposomes were generated from the
      detergent-soluble extracts by treatment with a polystyrene adsorbent.
      Proteoliposomes prepared from OG-soluble extract contained the highest specific
      activity of T3 binding. The Kd of the T3 binding sites (4.5 nmol/l) and the
      competitive inhibition constant of tryptophan (120 mumol/l) were similar to those
      for native membranes. The photolabeling of the 52-kD protein in these
      proteoliposomes was prevented by tryptophan and T4, but not by leucine or the D
      isomer of T3, corresponding to the transport specificity of system T. The 52-kD
      protein solubilized with OG from native membranes was partially purified by ion
      exchange chromatography. The 52-kD protein was detected by photoaffinity labeling
      in the purified fraction only after addition of erythrocyte membrane
      phospholipids to generate proteoliposomes. This indicates that the association of
      52-kD protein with phospholipids is critical for T3 binding.

PMID- 8664990
TI  - Multiple painful oral ulcerations. Secondary syphilis.

PMID- 8664991
TI  - Cost-effective evaluation of heart murmurs in children.

PMID- 8664992
TI  - Comments of a consultant to primary care physicians.

PMID- 8664993
TI  - Promoting the use of advance directives: an empirical study.

PMID- 8664994
TI  - Addiction to benzodiazepines--how common?

PMID- 8664995
TI  - Addiction to benzodiazepines--how common?

PMID- 8664996
TI  - Running and its effect on family life.
AB  - OBJECTIVES: To determine the frequency with which commitment to running conflicts
      with family life, to distinguish between runners who experience conflict and
      those who do not based on their levels of commitment to the roles of runner and
      family member, and to determine whether runners who reported conflict receive
      less support for running from their significant other. DESIGN: A questionnaire
      was mailed to 1426 members of a running club. Personal demographics, running
      quantity, conflict, commitment to running, family commitment, and spouse support
      were measured. The Family APGAR scale was used to measure global family
      functioning, assessing adaptation, partnership, growth, affection, and resolve.
      RESULTS: There were 724 respondents for a response rate of 50.8%. Five hundred
      fifty-eight runners (356 men, and 202 women) lived with a partner. The mean score
      for conflict was 1.9. Only 32 (5.5%) had a score above 3 (high conflict). When
      evaluated together and separately, the women and men in the high-conflict groups
      had equal commitment to running, lower family commitment, lower spouse support,
      and a lower Family APGAR score compared with the low-conflict group. CONCLUSIONS:
      In this study running is not a major contributor to family conflict. Those
      runners who are experiencing conflict seem to have a more global conflict with
      their families that is independent of running, manifested by decreasing spouse
      support for the runner's activities. If a runner is an active, committed member
      of his or her own family and sets this commitment as a priority, it does not
      appear that the time and energy of running is by itself a source of conflict.

PMID- 8664997
TI  - Long-term incidence of lower-extremity amputations in a diabetic population.
AB  - OBJECTIVE: To describe the 10-year cumulative incidence of and risk factors for
      lower-extremity amputations in diabetics. DESIGN: Cohort study. SETTING: Primary
      care. PARTICIPANTS: Population-based sample (N = 879) of younger-onset diabetic
      persons (in whom diabetes was diagnosed before 30 years of age and who were
      taking insulin) and a stratified random sample (N = 956) of older-onset diabetic
      persons (diagnosis at or after 30 years of age) participating in baseline, 4
      year, and 10-year examinations. MAIN OUTCOME MEASURE: Amputations of the lower
      extremities as reported by the participants. RESULTS: The 10-year cumulative
      incidence of lower-extremity amputation was 5.4% in younger-onset and 7.3% in
      older-onset persons. Multivariate analyses were performed by logistic regression.
      In younger-onset persons, age (odds ratio [OR] for 10 years, 2.0; 95% confidence
      interval [CI], 1.5-2.8), history of ulcers (OR,4.8; 95% CI, 2.3-9.9), diastolic
      blood pressure (OR, 2.1 for 10 mm Hg; 95% CI, 1.5-3.0), glycosylated hemoglobin
      level (OR, 1.4 for 1%; 95% CI, 1.2-1.6), sex (OR, 5.2 for men; 95% CI, 2.2-12.3),
      and retinopathy (OR, 1.2 for 2 steps; 95% CI, 1.1-1.4) were significantly
      associated with incidence of lower-extremity amputation. In older-onset persons,
      history of ulcers (OR, 3.3; 95% CI, 1.6-6.8), glycosylated hemoglobin level (OR,
      1.3 for 1%; 95% CI, 1.1-1.5), duration of diabetes (OR, 1.6 for 10 years; 95% CI,
      1.1-2.5), sex (OR, 2.6 for men; 95% CI, 1.3-4.9), diastolic blood pressure (OR,
      0.7 for 10 mm Hg; 95% CI, 0.5-1.0), and proteinuria (OR, 2.4; 95% CI, 1.0-5.7)
      were significantly associated with incidence of lower-extremity amputation.
      CONCLUSION: These data show there are several risk factors for lower-extremity
      amputation with potential for modification and preventive strategies.

PMID- 8664998
TI  - Primary care physicians' use of office resources in the provision of preventive
      care.
AB  - OBJECTIVES: To assess (1) the extent to which office resources (eg, chart aids,
      educational materials, office staff) are used by primary care physicians in the
      provision of preventive care; (2) the characteristics of physicians associated
      with this use; and (3) the relationship of office resource use to reported
      preventive service provision. DESIGN: Survey. SUBJECTS: Randomly selected active
      members of the American Academy of Family Physicians, Kansas City, Mo, American
      Academy of Pediatrics, Elk Grove Village, III, American College of Obstetricians
      and Gynecologists, Washington, DC, and American College of Physicians,
      Philadelphia, Pa. MALE OUTCOME MEASURES: Use rates for each of 14 types of office
      resources, and scores for total office resource use, total preventive service
      provision, and counseling, screening, and immunization provision. RESULTS: Most
      types of office resources were used by less than 50% of the physicians.
      Physicians in small private practices reported less use of resources than those
      in other settings. The chart flow sheet was the resource that was most strongly
      and consistently related to preventive service provision. For all organizations,
      the total resource use score was significantly correlated with scores for total
      preventive service provision, and counseling and immunization provision. For most
      organizations, the total resource use score was more highly related to total
      preventive service provision than was the age or sex of the physician, the
      percentage of patients uninsured or with Medicaid coverage, or community size.
      CONCLUSIONS: The use of office resources is an important factor in the provision
      of preventive care. Intervention efforts to improve office resource use may
      benefit from targeting by resource type, practice setting, physician specialty,
      and other physician and practice characteristics.

PMID- 8664999
TI  - The P-450 system. Definition and relevance to the use of antidepressants in
      medical practice.
AB  - Over the last several years, several new antidepressants have been introduced
      into primary care practice. A number of these, including the selective serotonin
      reuptake inhibitors and nefazodone, have some common and potentially significant
      drug interactions as a result of interference with components of the hepatic P
      450 enzyme system. This review provides information on those drugs that interfere
      with P-450 function (inhibitors), as well as those substrates whose metabolism
      can be impaired by P-450 inhibitors. Because it is important for primary care
      clinicians to be aware of these interactions, this article presents a review of
      the P-450 system and its relevance to the use of antidepressants in medical
      practice.

PMID- 8665000
TI  - Blood pressure-lowering effect of adding grapefruit juice to nifedipine and
      terazosin in a patient with severe renovascular hypertension.
AB  - Grapefruit juice had been fortuitously noted to elevate the concentration of
      felodipine in a pharmacological study of the effect of ethanol on felodipine.
      This effect was later confirmed not only for felodipine but also for three other
      dihydropyridine calcium channel blockers. I herein present what I believe to be
      the first case report describing a marked blood pressure-lowering effect of
      grapefruit juice in a person receiving an antihypertensive regimen of a
      dihydropyridine calcium channel blocker (nifedipine) and terazosin.

PMID- 8665001
TI  - The cost of treating heart valve related complications.

PMID- 8665002
TI  - The cost of treating heart valve related complications.
AB  - BACKGROUND AND AIM OF THE STUDY: Heart valve replacement can result in serious
      complications. Therefore, it is important in decision making regarding the choice
      of valves to know the cost of such complications. METHODS: Complications were
      defined according to guidelines proposed by the Society of Thoracic Surgeons.
      They included valve thrombosis, embolism, hemorrhage due to anticoagulation, non
      structural dysfunction, structural deterioration and endocarditis. The costs of
      the pre-admission assessment, acute inpatient stay, inpatient physician fees,
      post-discharge and out-patient physician fees were estimated for each
      complication to determine the average total cost in 1995 US dollars. Cost inputs
      were obtained from existing Massachusetts databases and Medicare fee schedules.
      RESULTS: The costs of managing valve thrombosis, endocarditis and non-structural
      dysfunction were all estimated to exceed $30,000 for a single event. The costs of
      acute management of embolism and anticoagulant-related hemorrhage were between
      $8,000 and $11,500. However, it is of note that managing the sequelae of an
      embolism was calculated to be greater than $70,000 over 15 years. The greatest
      contributor to the average cost of treating a complication was determined to be
      the in-patient facility cost. CONCLUSIONS: Complications related to heart valve
      replacement can be very costly to manage in both the short term and the long
      term.

PMID- 8665004
TI  - A comparison of valve resistance, the continuity equation, and the Gorlin formula
      against directly observed orifice area in bioprosthetic valves in the mitral
      position: an in vitro study.
AB  - BACKGROUND AND AIMS OF THE STUDY: There is no consensus over how to describe
      forward flow through valves in the mitral position. There are three main
      candidate hydraulic formulae; resistance, the Gorlin formula and the continuity
      equation. However, virtually no work has been performed to validate resistance
      and the continuity equation for valves in the mitral position. The aim of this
      study, therefore, was to compare the three formulae against an independent
      standard provided by directly observed orifice areas. MATERIALS AND METHODS: Five
      bioprosthetic valves with orifice areas between 0.14 cm2 and 2.33 cm2 were
      studied in a pulse simulator at up to 20 different stroke volume/rate
      combinations using quasi-physiologic flow curves. Orifice areas were measured
      using a video camera, pressure difference using strain gauge transducers and
      Doppler signals using a 1.9 MHz Pedoff probe with a Vingmed SD50 system. RESULTS:
      The Gorlin ratio (flow/square root of mean delta P) had a direct curvilinear
      relationship with the orifice area (log(y) = 0.31 + 0.36x; r = 0.94, SEE 0.08
      cm2, p < 0.0001). Resistance (mean delta P/flow) had an indirect curvilinear
      relationship (log(y) = 0.19 - 0.55x, r = -0.93, SEE 0.13 cm2, p < 0.0001). The
      continuity equation was directly related to observed orifice area although with
      high scatter (y = 1.13 + 0.79x; r = 0.90, SEE 0.23 cm2, p < 0.0001). Although
      both the Gorlin ratio and resistance changed with flow, there was also a tendency
      for observed orifice areas to increase with flow. Empirical effective orifice
      areas calculated using the regression equations closely resembled observed
      orifice areas and agreement was reasonable, with 95% limits of -0.33 cm2 to +0.33
      cm2 (Gorlin), -0.41 cm2 to +0.42 cm2 (resistance) and -0.40 cm2 to +0.48 cm2
      (continuity). CONCLUSION: In conclusion, no single formula adequately predicted
      all observed orifice areas although resistance and the Gorlin formula gave useful
      predictions after empirical correction.

PMID- 8665003
TI  - Preoperative echocardiographic prediction of small prosthesis size for aortic
      valve replacement.
AB  - BACKGROUND AND AIMS OF THE STUDY: Prosthesis size is known to have an effect on
      long term outcome after heart valve replacement. We evaluated 115 patients
      subjected to aortic valve replacement to assess the ability by preoperative
      echocardiography to identify patients having small aortic roots and thereby
      likely to receive a small prosthesis (size 19 or 21), previously shown to be
      associated with a worse prognosis. METHODS: From an initial part of the study
      (Group A), comprising 67 patients, we evaluated the influence of image quality on
      the accuracy for prediction of patients receiving a small prosthesis. In a second
      series of 48 patients (Group B), we tested the predictive value of various limits
      of aortic annulus diameter to define patients at risk of receiving a small
      prosthesis. RESULTS: The measurement of aortic annulus diameter in Group A gave a
      reasonable correlation to subsequent prosthetic dimension (r = 0.73, n = 59).
      However, there was a considerable variation of echocardiographic aortic annulus
      diameter among patients receiving prostheses of the same size. In Group B, an
      aortic annulus diameter of < or = 22 mm correctly identified 10 of 13 patients
      receiving a small prosthesis (sensitivity 77%). Twenty-two of 25 patients (88%)
      with an aortic annulus diameter > 22 mm received a large prosthesis. CONCLUSIONS:
      We conclude that the echocardiographic measurement of the aortic annulus diameter
      is a fairly sensitive method to identify patients receiving a small prosthesis.
      However, the predictive accuracy is dependent upon training as well as image
      quality. Furthermore, the value of planning in advance the type of prosthesis,
      annuloplasty or homograft for aortic valve replacement remains to be shown.

PMID- 8665005
TI  - Assessment of immunogenicity and viability of homologous human cardiac valves in
      vitro.
AB  - Degenerative changes in a proportion of implanted homologous cardiac valves are
      considered to be due to the immunologic tissue reactions initiated by the donor
      valves. Sterilization and storage protocols can be used to modulate the
      immunogenicity of donor valves prior to implantation. Therefore, it is essential
      to assess the effect of treatment protocols on the immunogenicity and viability
      of donor valve tissue. The optimal conditions for two novel in vitro tests to
      assess the immunogenicity and viability of human cardiac valve tissue, the valve
      cusp cell/responder lymphocyte reaction to assess immunogenicity and the
      tetrazolium based colorimetric assay to assess viability of valve tissue, are
      described. The in vitro tests that have been developed in this study will be
      helpful in assessing the effect of various treatment protocols on the
      immunogenicity and viability of homologous human cardiac valves.

PMID- 8665006
TI  - Effects of surface seeding with vital cells on the calcium uptake of biological
      materials for heart valve replacement.
AB  - BACKGROUND AND AIMS OF THE STUDY: Up to 35% of bioprosthetic heart valves need to
      be replaced during the first decade after implantation because of tissue
      degeneration or calcification. The aim of the studies was to evaluate the
      influence of surface seeding with viable cells on the calcium uptake of
      biomaterials. MATERIALS AND METHODS: Samples of glutaraldehyde tanned bovine
      pericardium (GBP, n = 52) or porcine valves (GPV, n = 50), or glycerol treated
      bovine pericardium (GlyBP, n = 35), which had either been rinsed with saline
      (GBP, n = 30; GPV, n = 26; GlyBP, n = 18) or seeded with rat fibrocytes (GBP, n =
      22; GPV, n = 24; GlyBP, n = 17) were incubated with cell culture medium
      containing physiologic levels of calcium. Similarly treated material was
      implanted into the abdominal muscles of 88 rats (seeded: GBP, n = 16; GPV, n =
      16; GlyBP, n = 14; non-seeded: GBP, n = 6; GPV, n = 8; GlyBP, n = 7). The
      specimens were analyzed two and four weeks later for their calcium content.
      RESULTS: Over time untreated GBP and GlyBP calcified in vitro and in vivo while
      GPV retained low calcium levels in vivo. Surface seeding with rat fibrocytes
      significantly reduced the calcium accumulation in GBP and GlyBP in vitro and in
      vivo (p < 0.05). CONCLUSIONS: Seeding with viable cells might be a promising
      method of reducing calcium accumulation in bovine pericardial implants.

PMID- 8665007
TI  - Internal shear properties of fresh porcine aortic valve cusps: implications for
      normal valve function.
AB  - BACKGROUND AND AIMS OF THE STUDY: Several types of stress act on aortic heart
      valve tissue during the cardiac cycle. When closed the valve is subjected to
      primarily tensile stress due to the diastolic pressure, and upon opening bending
      stress occurs near the attachment with the aortic root and throughout the body of
      the cusps. Smooth bending requires internal tissue shearing. To measure the
      internal shear properties of the tissue a testing device was created which
      combined a high-precision linear actuator with a sensitive load cell. MATERIALS
      AND METHODS: Circular punch biopsy specimens from fresh porcine aortic valve
      cusps (n = 32) were examined. The shear stress versus shear strain
      characteristics were measured both in the circumferential (n = 17) and the radial
      (n = 13) direction, and the stress relaxation characteristics were also examined
      circumferentially (n = 15) and radially (n = 15). In addition seven specimens
      were tested repeatedly in both radial and circumferential directions for tissue
      isotropy. RESULTS: The results from the shear stress versus strain tests showed
      the tissue to behave non-linearly over the strain range between -0.9 and 0.9. The
      average moduli at the near zero strains were less than 300 Pa and increased to
      over 20 kPa at the extreme strains. The circumferential direction yielded
      slightly higher average moduli than the radial direction but this difference was
      not significant. The stress relaxation results indicated that valve tissue
      relaxation occurs in two distinct phases, an initial low slope region and a
      second high slope region with respective values of -7.5 log(s)-1 and -15 log(s)-1
      and with no significant difference between test directions. CONCLUSIONS: Our
      results define and describe the pattern of internal shear properties of the
      aortic valve that are particularly important during the transition between the
      open and closed positions. This behavior pattern has particular application in
      the creation of accurate mathematical models of the valve tissue and may be
      important in understanding the mechanism of tissue failure in bioprosthetic
      valves.

PMID- 8665008
TI  - Critical role of the sinuses of Valsalva in the durability of valved conduits.
AB  - BACKGROUND AND AIMS OF THE STUDY: Most work in search of an ideal extracardiac
      valved conduit has assumed that the type of tissue used for construction is the
      determining factor for its behavior and durability. The excellent results of our
      study with a valved conduit incorporating sinuses of Valsalva and made of
      autologous pericardium showed that the design plays a crucial role in addition to
      the type of material. MATERIALS AND METHODS: We report the experimental results
      of three different pericardial sinus bearing valved conduits made of 0.5%
      glutaraldehyde treated autologous pericardium (Group 1), dye mediated
      photooxidized bovine pericardium (Group 2), and glutaraldehyde treated bovine
      pericardium (Group 3) implanted in the right ventricular outflow tract of sheep.
      Groups 1, 2 and 3 had 11, 11 and four animals available for assessment out of 12,
      18 and six implantations respectively. The valved conduits were explanted at
      varying intervals between one and 11 months. The conduit function was assessed
      with hemodynamic, echocardiographic and Doppler studies both at the time of
      implantation and sacrifice. The explanted conduit was studied macroscopically and
      subjected to histopathologic examination. RESULTS: The hemodynamic and
      echocardiographic studies at implantation showed very satisfactory results in all
      three groups. At the time of sacrifice, Group 1 showed consistently good results.
      In a significant number of animals in Groups 2 and 3, one, two or even three
      cusps had become adherent to the conduit wall, resulting in severe regurgitation.
      The sinuses were well preserved in Group 1, while they were less prominent in
      Group 2 and least in Group 3. Histopathologically, the three groups basically
      showed the same feature, a process of fibrocellular proliferation resulting in
      thickening. In this study the adhesion of the cusps to the sinus wall was related
      to the degree of prominence of the sinuses of Valsalva, which in turn depended on
      the ability to shape the pericardium at the time of construction of the valved
      conduit. CONCLUSIONS: This study stresses the importance of the sinuses in the
      behavior of the semilunar valve leaflets.

PMID- 8665009
TI  - Tricuspid valve replacement.

PMID- 8665010
TI  - Reoperative mitral valve surgery via right thoracotomy: decreased blood loss and
      improved hemodynamics.
AB  - BACKGROUND AND AIMS OF THE STUDY: Reoperative mitral surgery via sternotomy can
      be associated with significant complications, including excessive blood loss and
      injuries to the heart, great vessels and patent coronary artery grafts. The right
      antero-lateral thoracotomy offers excellent exposure with less risk from re
      entry. MATERIALS AND METHODS: Between 1982 and 1992, 221 patients had repeat
      mitral valve procedures at our institution. Fifteen of these 221 underwent mitral
      valve replacement via right thoracotomy. Indications for surgery in each group
      included bioprosthetic valve failure, paravalvular leak and bacterial
      endocarditis. Fifteen patients having reoperative mitral valve surgery via right
      thoracotomy approach were compared with a control group of 33 patient who
      underwent surgery via repeat sternotomy. All thoracotomy patients underwent
      mitral replacement or repair with ventricular fibrillation without aortic cross
      clamping. Operative time, cardiopulmonary bypass time, requirement for inotropic
      support, blood loss within the first six postoperative hours, number of blood
      units transfused, length of ICU stay, days to discharge, and 30-day survival were
      compared between the two groups. In addition, the preoperative PaO2/FiO2 (P/F)
      ratio was evaluated as a prognostic indicator. RESULTS: Bypass time (162 +/- 43
      min thoracotomy group vs. 131 +/- 34 min sternotomy group), operative time (389
      +/- 100 min thoracotomy group vs. 450 +/- 25 min sternotomy group), ICU stay (6
      +/- 8 days thoracotomy group vs. 5 +/- 6 days sternotomy group), P/F ratio (352
      +/- 142 thoracotomy group vs. 423 +/- 108 sternotomy group), and 30-day survival
      (93% thoracotomy group vs. 91% sternotomy group) were not found to be
      significantly different between groups. Of great significance was the reduction
      in blood loss (277 +/- 152 ml thoracotomy vs. 651 +/- 504 ml sternotomy, p <
      0.05) and blood transfused (2.0 +/- 1.7 units thoracotomy vs. 6.5 +/- 3.3 units
      sternotomy, p < 0.01) with the thoracotomy approach. Also of significance was a
      reduction in frequency with which significant inotropic support was needed to
      separate from cardiopulmonary bypass (26% vs. 63%, p < 0.05). Despite decreased
      access to the heart for de-airing maneuvers, no cerebrovascular events whatsoever
      were noted with the thoracotomy approach. CONCLUSION: The right thoracotomy
      approach is recommended for redo mitral valve surgery. Despite these advantages,
      severe pulmonary dysfunction (as indicated by a P/F ratio less than 300)
      correlated with a prolonged hospital course in four thoracotomy patients; such
      patients should have repeat sternotomy.

PMID- 8665011
TI  - Autograft aortic valve replacement with downsized pulmonary allograft for right
      ventricular outflow tract reconstruction.
AB  - A three-week-old neonate underwent aortic valve replacement with a pulmonary
      autograft (Ross procedure). The right ventricular outflow tract was reconstructed
      with a downsized pulmonary allograft. The surgical technique is presented. Six
      months after operation the girl is doing well and both the autograft and
      allograft function are excellent.

PMID- 8665012
TI  - Reconstruction of dilated aortic annulus using short tubular Dacron graft for
      aortic root replacement by aortic homograft--a solution for size mismatch.
AB  - To circumvent the problems associated with a dilated aortic annulus we first
      reduced the diameter of the annulus with a short section of Dacron graft and then
      implanted a smaller size homograft within the graft. This procedure was
      successfully performed for complete homograft aortic root replacement in a 25
      year-old man with severe aortic insufficiency due to a dilated aortic annulus.
      The indication for homograft replacement can thus be widened, even to patients
      with a dilated aortic annulus.

PMID- 8665013
TI  - Mitral and aortic valve replacement using fresh unstented pulmonary and aortic
      homografts.
AB  - The use of prosthetic valves carries a high incidence of complications including
      thromboembolism, hemolysis, infection, impaired hemodynamic function and
      mechanical failure. Unstented homograft valves provide a good quality of life,
      particularly in terms of a reasonable freedom from these complications. This
      paper presents the first simultaneous replacement of the mitral and aortic valves
      using fresh unstented pulmonary and aortic homografts collected from the same
      donor. We believe that this technique will be especially useful in developing
      countries facing financial difficulties and problems with patient education.

PMID- 8665014
TI  - In vitro assessment of prosthetic valve function in mitral valve replacement with
      chordal preservation techniques.
AB  - BACKGROUND AND AIM OF THE STUDY: The importance of chordal preservation
      techniques in maintaining improved left ventricular function after mitral valve
      replacement has been well documented clinically. Currently, the choice of
      prosthetic valve used in chordal preservation is dependent upon the surgeon's
      preference. However, the transvalvular flow characteristics of common, clinically
      used prosthetic valves may be influenced by the mitral subvalvular apparatus, and
      may result in degraded valve function. The goal of this study was to perform an
      in vitro evaluation of the influence of chordal preservation on the transvalvular
      and left ventricular flow patterns of common valve prostheses. METHODS: Tissue
      and mechanical valves have been evaluated under physiologic pulsatile flow with
      anterior and/or posterior chordal preservation. Flow patterns were assessed by 2
      D planar flow visualization, pulsed wave Doppler velocity measurements, 2-D
      echocardiography, and selected color Doppler flow mapping. Based on changes in
      transvalvular and left ventricular flow patterns, favorable prosthetic
      valve/chordal preservation combinations were identified. Additionally, valve
      orientation was varied to determine optimal orientation. RESULTS: Baseline
      results without chordal preservation indicate that the anti-anatomic orientation
      is preferred for the bileaflet valve design while the tilting disc valve should
      be oriented with the major axis toward the posterior (free) wall of the
      ventricle, corroborating published conclusions by other investigators. Some form
      of flow restriction is observed in all test cases with chordal preservation due
      to the presence of the subvalvular tissue. In general, bioprostheses showed less
      flow restriction then the mechanical valves, particularly with lateral flow
      expansion. This flow restriction may influence pressure recovery downstream of
      the mechanical valves tested. Increased flow constriction is observed with
      anterior and posterior chordal preservation. CONCLUSIONS: This study favors the
      use of the St. Jude Medical bileaflet valve orientated in the anti-anatomic
      position, or the Carpentier-Edwards pericardial valve with chordal preservation.

PMID- 8665016
TI  - Scaling of mechanical heart valves for cavitation inception: observation and
      acoustic detection.
AB  - This paper discusses scaling laws of cavitation in mechanical heart valves based
      on analysis of leaflet operation and on hydrodynamic theory. It then suggests the
      laboratory use of large geometric scales and testing at low operating pressures
      to more easily investigate new heart valve designs. With such scaling,
      observations and measurements will become easier since the cavitation regions
      will be larger in dimension and the time scales will be increased due to
      reductions of bubble characteristic times and leaflet oscillation periods. The
      paper also discusses cavitation noise and the potential for acoustic detection of
      cavitation in a mechanical heart valve.

PMID- 8665015
TI  - Pressure distribution near the occluders and impact forces on the outlet struts
      of Bjork-Shiley convexo-concave valves during closing.
AB  - BACKGROUND AND AIMS OF THE STUDY: An in vitro study of the mechanics of closure
      of Bjork-Shiley convexo-concave (BSCC) valves is presented in order to
      investigate the mechanics of outlet strut fracture reported in a small fraction
      of the implanted valves. MATERIALS AND METHODS: Four BSCC 29 mm valves
      instrumented with strain gages on the outlet strut legs were mounted in the
      mitral position of an axisymmetric flow chamber of a mock pulsatile flow loop.
      Measurements of the pressure field in the vicinity of the occluder, closing
      velocity of the occluder tip in the major orifice, and the impact force between
      the occluder and outlet strut at the instant of valve closure were obtained at a
      range of physiologic flow rates. RESULTS: The results indicated an uneven
      pressure distribution on the occluder associated with a tendency for the occluder
      to over-rotate and induce loads on the outlet struts. The impact loads on the
      outlet struts were asymmetric with load on one leg being larger than the other by
      up to 25%. These results are consistent with single leg separation preceding
      outlet strut fracture in most of the valve failures reported. Orientation of the
      valve with respect to the mitral orifice (major orifice towards the top or
      bottom) did not significantly affect the loads on the outlet strut. A significant
      variation in the impact loads of the four valves was measured for identical
      experimental conditions suggesting that valve specific factors influence outlet
      strut loads. CONCLUSIONS: This study provided an understanding of the cause
      effect relationship between valve dynamics and outlet strut fracture.

PMID- 8665017
TI  - Mitral heart valve cavitation in an artificial heart environment.
AB  - BACKGROUND AND AIMS OF THE STUDY: The formation and subsequent collapse of
      vaporous cavities in the fluid around mechanical heart valves at valve closure
      can create stresses large enough to damage both the valve itself and blood cells.
      Improved understanding of cavitation mechanisms should lead to a reduction in the
      cavitation potential of future valve designs. MATERIALS AND METHODS: This study
      compares eight mechanical mitral valves of two different geometries (Monostrut
      and Medtronic Hall), occluder housing gaps (tight, medium, and leaky), and
      occluder materials (Delrin and pyrolytic carbon). The valves were evaluated in a
      model ventricle of the Penn State Electric Ventricular Assist Device (EVAD)
      operating within a mock circulatory loop. The EVAD represents one half of a total
      artificial heart. The mock loop consisted of silicone tubing connected to
      elements designed to mimic the compliant and resistant properties of the natural
      circulation. Cavitation was controlled by varying the degree of filling of the
      ventricle: low filling caused higher valve closing velocities resulting in
      greater cavitation intensities than complete filling of the ventricle. The
      intensity of cavitation was quantified using a parameter derived from the high
      frequency fluctuations in the mitral pressure that occur around the valve during
      cavitation events. The shape of the cavitation pressure signature and that of the
      power spectrum of the cavitation pressure signature were used in addition to the
      cavitation intensity parameter to make comparisons between valves. RESULTS: Of
      the three valve characteristics studied, occluder material showed the most
      significant influence on cavitation intensity: valves with pyrolytic carbon
      occluders demonstrated greater cavitation than did those with Delrin discs.
      CONCLUSION: It is hypothesized that the dominant form of cavitation on the valves
      studied is related to vortex formation and that occluder material influences the
      intensity of cavitation through the strength of the tension wave generated at
      valve closure, while geometry and gap have only secondary effects. Future studies
      are planned to incorporate this technique in an in vivo environment.

PMID- 8665018
TI  - Combined aortic valve replacement and left ventricular aneurysm plication in
      systemic lupus erythematosus.
AB  - The case of a 37-year-old female patient is reported with systemic lupus
      erythematosus and severe renal function impairment, and associated aortic
      insufficiency, obstructive coronary disease and aneurysm of the left ventricular
      inferior free wall. Renal failure, hematologic disorder and the need for high
      dose steroid therapy to control the autoimmune disease were considered the main
      surgical risks. Surgery included aortic valve replacement and plication of the
      ventricular aneurysm. The postoperative course was free of any major
      complications related to surgery or SLE disease.

PMID- 8665020
TI  - Aortic and mitral valve disease induced by ergotamine therapy for migraine: a
      case report and review of the literature.
AB  - A case of aortic and mitral valve disease associated with ergotamine abuse is
      reported. A 34-year-old woman presented with dyspnea after a long standing
      history of peripheral vascular pathology associated with ergotamine abuse.
      Cardiac dysfunction was rapidly progressive. At surgery, nodular thickening of
      both valves and fusion of the posterior leaflet of the mitral valve were seen.
      Microscopy revealed proliferation of myofibroblasts with little destruction of
      normal valvular elements. The similarity to lesions in carcinoid heart disease
      and in methysergide-associated valvular disease suggests direct stimulation of
      myofibroblast growth by serotonin agonist effect.

PMID- 8665019
TI  - Aortic valve replacement for aortic regurgitation due to Kawasaki disease. Report
      of two cases.
AB  - Two cases of severe aortic regurgitation due to Kawasaki disease are reported.
      Both patients were diagnosed as having Kawasaki disease in their infancy, and
      were followed up by a pediatrician. Aortic regurgitation was detected 18 months
      in one case and 36 days in the other case after onset of the illness. With the
      passage of time, the aortic regurgitation increased and aortic valve replacement
      was scheduled in both patient at the age of 13. On admission, two-dimensional
      echocardiography showed thickening of the aortic cusps, and severe aortic
      regurgitation was detected by color flow Doppler studies. Successful aortic valve
      replacement was performed, and histological studies of the cusps showed sequelae
      of valvulitis. In conclusion, aortic regurgitation is a rare complication of
      Kawasaki disease, and the aortic valve function, especially occurrence of aortic
      regurgitation, should be carefully observed in patients with a past history of
      Kawasaki disease.

PMID- 8665021
TI  - Anticoagulant therapy for deep vein thrombosis: its proper application.

PMID- 8665022
TI  - Pathogenesis and pathophysiology of the post-thrombotic syndrome: clinical
      implications.
AB  - Anticoagulant therapy can successfully prevent pulmonary embolism and
      rethrombosis in most cases, but cannot affect either early morbidity or the late
      post-thrombotic sequelae. In carefully selected cases, early clot removal by
      thrombolysis or thrombectomy may be justified by improved outcome because of the
      significant role early and late outflow obstruction plays in determining the
      ultimate severity of post-thrombotic sequelae. Nevertheless, it is recognized
      that anticoagulant therapy will continue to be used in the majority of patients
      because of serious intercurrent disease, sedentary lifestyle, limited extent of
      thrombosis, lack of tissue loss and, unfortunately, delay in referral for
      treatment.

PMID- 8665024
TI  - Duplex scanning for deep vein thrombosis: has it replaced both phlebography and
      noninvasive testing?

PMID- 8665023
TI  - Catheter-directed thrombolysis for iliofemoral venous thrombosis.
AB  - The combination of catheter-directed thrombolytic therapy and endovascular
      stenting is a new and promising approach for treating acute and chronic
      thrombotic iliofemoral venous occlusions on the basis of the authors' initial
      experience in a small group of patients. In acute DVT, catheter-directed
      techniques provide more complete lysis than systemic infusions and early,
      aggressive interventional therapy may spare the patient from the life-long
      disability associated with the postphlebitic syndrome, by preserving valve
      function and eliminating the venous outflow obstruction. Immediate
      postthrombolysis venography can evaluate the underlying vein and assess the need
      for adjunctive treatment with angioplasty and/or stents. Urokinase has a high
      degree of safety with few complications when a catheter-directed approach rather
      than systemic infusion is used. Even patients with chronic DVT can benefit by
      reducing the obstruction to venous outflow if the occlusion is limited to the
      iliac vein and/or the inferior vena cava. Long-term follow-up studies are
      necessary to evaluate patency rates of the treated veins, determine whether
      successfully treated limbs have a lower frequency of recurrent DVT, and ascertain
      the frequency of chronic venous insufficiency compared with that in patients
      treated with anticoagulation alone. Based on our initial experience, a National
      Venous Thrombosis Registry was established in October 1994. The purpose of this
      multidisciplinary Registry is to prospectively document the long-term results of
      catheter-directed thrombolytic therapy for patients with iliofemoral DVT, with
      data now being collected from 40 leading medical centers around the United
      States. We hope that endovascular techniques for iliofemoral DVT will
      significantly reduce the immediate and long-term complications commonly
      associated with this difficult and often misunderstood clinical problem.

PMID- 8665025
TI  - Is there a role for thrombectomy in iliofemoral venous thrombosis?

PMID- 8665026
TI  - Thrombolytic therapy and surgery for primary axillosubclavian vein thrombosis:
      current approach.

PMID- 8665027
TI  - Current indications for caval interruption: should they be liberalized in view of
      improving technology?
AB  - Although the impressive increase in the number of filters placed since 1988 is
      not surprising, it is appropriate to continue to review the indications for
      placement to determine whether abuse of these devices is occurring. Initially,
      there were very stringent requirements that were appropriate because there were
      few data to evaluate the efficacy and safety of the device. Now, data have been
      accumulated indicating the Greenfield filter has a high degree of efficacy (95%)
      and comparable caval patency (96%)32 for 20 years.1 Knowing that the filter is
      safe and effective, physicians are electing to place it in patients with greater
      comorbidity factors or with longer life-expectancy. In addition, advances in the
      treatment of patients with multiple trauma and malignancy have resulted in
      improved survival, leaving more patients at risk of DVT and PE. Finally, the
      number of patients older than age 60 is increasing rapidly, and the number of
      elective and emergent orthopaedic procedures is growing. All of these factors
      have led to an increased number of filter placements that should be considered
      appropriate. Although there are certainly cases in which the filter was placed
      without sufficient justification, the explosion in use can more accurately be
      correlated with changes in medical care, the established efficacy and safety of
      the device, the growing numbers of patients diagnosed with thromboembolism, and
      the increased awareness of the risk of complications from anticoagulation. When
      filter placement is preceded by a careful assessment of the patient to determine
      the risks and benefits of alternative treatments, there is little danger of
      abuse. However, more clinical investigation will be necessary to determine the
      optimal, cost-effective approach in situations in which controversy currently
      exists.

PMID- 8665028
TI  - Caval interruption methods: comparison of options.
AB  - The Stainless Steel and Titanium Greenfield filters, the Venatech filter, and the
      Bird's nest filter are most commonly used in the United States. A comparison of
      contemporary experience with these filters along with that of Simon-Nitinol
      filter is shown in Table 1. The published experience with each device is minimal
      compared with actual clinical use. The published reports available do not often
      examine experience with a view toward unbiased and accurate comparison of
      results. Each filter has an acceptably low rate of recurrent PE, but each has
      experienced the range of complications associated with vena caval filters or
      partitions. The reviewed case series are too small and the complication rates too
      similar for any of the newer designs to claim unequivocal superiority. Except for
      the Stainless Steel Greenfield filter, comparison is further complicated by the
      lack of standardized, quantitative follow-up of patients over a period long
      enough for possible extremity venous complications to be observed. Each of the
      currently available filters has at least one specific attribute that may
      recommend it for a particular situation. Detailed and comparable examination of
      IVC filtration is becoming more important as the indication for and use of these
      devices increase. Clearly, the search for the perfect device to prevent PE should
      continue.90 Any filtration device plays only a small role in the overall
      management of the patient with thromboembolic disease. It is incumbent upon the
      physician who treats this patient to assume the responsibility for the diagnosis
      of and long-term follow-up of the underlying disorder. Considerable technical
      ingenuity and continued evolution of materials and design have propelled the
      development and number of available vena cava filters for clinical use. Without
      objective clinical data, many interventional radiologists and surgeons base their
      filter selection on ease of insertion and device cost. Variable data on safety
      and effectiveness demand that physicians match the best filter to each patient's
      particular situation and anatomy. The primary objective of vena cava filtration
      is to provide a safe and effective device for permanent implantation. If this
      objective is not kept in sight, quality of care in the management of deep venous
      thrombosis and/or pulmonary embolus will be lost.

PMID- 8665029
TI  - Mycobacterium avium disease: progress at last.

PMID- 8665030
TI  - Issues in the use of inhaled glucocorticoids. The Asthma Clinical Research
      Network.

PMID- 8665031
TI  - The genetics of asthma.
AB  - In this paper we have summarized the evidence for a genetic contribution to
      asthma as well as the recent advances in techniques for identifying the location
      and function of genes that cause complex diseases. We have also reviewed how
      these techniques have been applied to the study of asthma and allergy. It is
      likely that rapid additional advances will be made over the next several years.
      There are ongoing genome-wide searches to identify additional genes. An
      understanding of the genetic variation that predisposes people to asthma and the
      atopic diseases could open a variety of potential diagnostic and therapeutic
      avenues. Firstly, the identification of the specific mutations that alter the
      immune response could provide targets for gene therapy. However, in the short run
      this is unlikely because the risks and costs associated with gene therapy do not
      presently justify application to alleviate the relatively nonlethal
      manifestations of allergic diseases. The second potential avenue will be in the
      development of specific pharmacologic therapy. For example, if variants of the IL
      4 gene with enhanced function or of the IFN-gamma gene that have deficient
      function are identified as causative factors, drug development could be directed
      toward specific modulators of their effects. However, it is possible that
      redundancy in the immune and inflammatory responses, coupled with the likelihood
      of multiple gene involvement, will make such targeting fruitless or dangerous.
      The third consequence of identifying genetic variants predisposing to asthma and
      allergy is the possibility of screening. This is perhaps the most likely
      beneficial outcome of the present search for atopy genes. Recent studies suggest
      that the clinical onset of atopic diseases can be modified by preventing exposure
      to cigarette smoke and highly allergenic proteins in the first few years of life
      (188). At present the power of such studies is limited by the inability to
      predict those at risk with any certainty. Genetic screening of children born to
      atopic parents will allow more precise identification of those carrying atopy
      genes, and this could allow a focused attempt at environmental modification. In
      the short run this will allow the design of much more powerful prospective
      studies of prophylaxis, and in the long run screening may prove an effective
      strategy for asthma prevention.

PMID- 8665032
TI  - Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50
      patients.
AB  - Intermediate results of the first 50 patients treated with clarithromycin (CLARI)
      regimens for Mycobacterium avium-intracellulare (MAI) lung disease were
      evaluated. Patients were HIV negative, and pretreatment isolates were susceptible
      to CLARI. Patients received CLARI 500 mg twice daily, ethambutol, rifampin (RMP),
      or rifabutin (RBT) and initial streptomycin, and they were treated until culture
      negative 1 yr. Eleven of 50 patients (22%) were dropped in the first 3 mo. Of the
      remaining 39 patients, 36 (92%) converted their sputa to negative, and 32 (82%)
      remain culture negative to date. This includes 11 of 16 (69%) with prior drug
      therapy and 21 of 23 (91%) with no prior therapy. One or more companion drugs
      were discontinued in 16 of 39 (41%) of patients because of adverse events.
      Isolates from six of 39 patients (15%) became CLARI-resistant. Of 23 patients who
      are alive and were culture-negative a mean of 12.0 mo while receiving therapy,
      all remain culture-negative without therapy a mean of 19.1 mo. Despite reduced
      CLARI serum levels in patients also receiving RMP, 10 of 13 patients (77%)
      receiving this regimen were successfully treated. Although not directly compared
      with previous regimens, the success of this regimen strongly suggests it is
      superior to previous non-CLARI-containing regimens.

PMID- 8665033
TI  - Increased exhaled nitric oxide in asthma is mainly derived from the lower
      respiratory tract.
AB  - Nitric oxide (NO) is detectable in the exhaled air of human subjects, and its
      concentration is increased in patients with asthma. We have investigated the
      origin of the increase in exhaled NO in asthmatic patients by using different
      expiratory maneuvers and by direct sampling from the upper and lower respiratory
      tracts. Exhaled NO was measured by a chemiluminescence analyzer. Concentrations
      of NO measured during expiration against the resistance of the analyzer with
      exhaled flow of 1 L/min, were 78 +/- 3 ppb in normal subjects (n = 46) and
      significantly elevated in patients with asthma (301 +/- 26 ppb, n = 30, p <
      0.001). Values of exhaled NO were lower when measured during unobstructed
      expiration with a flow of 5 L/min with sampling from a side-arm (7 +/- 1 ppb),
      but again were elevated in patients with asthma (46 +/- 6 ppb, p < 0.001). Breath
      holding for 20 s resulted in an initial peak of NO, but end-expiration values
      similar to the unobstructed expiration. The concentration of NO in the nose was
      considerably greater than in expired air (996 +/- 39 ppb) and was elevated in
      patients with asthma (1,390 +/- 71 ppb, p < 0.002). Direct sampling from trachea
      and right middle lobe bronchus via a fiberoptic bronchoscope gave similar values
      in five normal and 15 asthmatic subjects to the values recorded during
      unobstructed expiration, and there was a good correlation between values in
      expired air and direct sampling (trachea r = 0.91, right middle lobe r = 0.87, p
      < 0.001). We conclude that exhaled NO measured in an unobstructed breath reflects
      concentrations in the lower respiratory tract, but that breath-holding or
      expiration against resistance is contaminated by residual NO derived from the
      upper respiratory tract. We also provide evidence that the elevated levels of
      exhaled NO in asthmatic patients are derived predominantly from the lower
      respiratory tract.

PMID- 8665034
TI  - The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on
      neurokinin A-induced bronchoconstriction in asthmatics.
AB  - The tachykinins substance P and neurokinin A (NKA) are present in sensory airway
      nerves and have been implicated in the pathogenesis of asthma. FK224 is a
      cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK
      1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224
      protected against bradykinin-induced bronchoconstriction and cough in asthmatics.
      In this study we examined the reproducibility of the NKA challenge and the effect
      of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable
      asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On
      Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(
      6) mol/ml) were administered via inhalation, with intervals of 10 min. On both
      days NKA caused a concentration-dependent decrease in specific airways
      conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61
      +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4
      and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30
      min before NKA challenge in a double-blind, crossover manner. The study
      medication was well tolerated. FK224 had no significant effect on baseline lung
      function. After P and FK224, NKA caused a comparable concentration-dependent
      bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/-
      0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224
      had no effect on baseline lung function and offered no protection against NKA
      induced bronchoconstriction in a group of mild asthmatic patients.

PMID- 8665035
TI  - Development of bronchial hyperreactivity following transient absence of salivary
      IgA.
AB  - In a birth cohort of 114 normal children, this study examined the hypothesis that
      a transient absence of salivary IgA in the first year of life was associated with
      an increased risk of developing atopy, asthma, or bronchial hyperreactivity (BHR)
      later in life. Episodes of transient absence of IgA in saliva, of less than 1 mo,
      occurred in 18% of the study population in the first year of life. The children
      were assessed at age 7.5 to 12 yr for the presence of atopy (skin prick test to
      inhaled allergens), asthma (wheeze in the previous 12 mo), and BHR (histamine
      provocation). The transient absence of salivary IgA in the first year of life was
      associated with an increased risk of BHR (adjusted odds ratio [Adj OR]: 11.6; 95%
      confidence interval [CI]: 2.2 to 60.9) and a trend toward a lowered risk of atopy
      to inhaled allergens (raw OR: 0.35; CI: 0.11 to 1.11). There was no relationship
      between the transient absence of salivary IgA and a clinical diagnosis of asthma
      (Adj OR: 0.9; CI: 0.2 to 3.6). The inconsistency in the relationships between the
      transient absence of salivary IgA and atopy, asthma, and BHR supports the concept
      that atopy, wheeze, and bronchial hyperreactivity are independent clinical
      outcomes. One possible explanation for the relationships observed in this study
      is that the transient absence of IgA in saliva in the first year of life
      identifies a cohort with mucosal hypoimmunity. These subjects are thus less
      likely to develop atopy and less able to effectively respond to a mucosal
      infection. Presentation of a mucosal antigen in these subjects may subsequently
      be associated with an inappropriate inflammatory response, which conditions
      bronchial hyperreactivity, and which is independent of atopy.

PMID- 8665037
TI  - Effect of uridine 5'-triphosphate plus amiloride on mucociliary clearance in
      adult cystic fibrosis.
AB  - Cystic fibrosis (CF) is characterized by abnormal airway epithelial electrolyte
      transport leading to viscous airway secretions that are difficult to clear. By
      enhancing Cl- secretion onto and blocking Na+ absorption from the airway surface,
      treatment with aerosolized uridine 5'-triphosphate (UTP) plus amiloride may
      improve the rheology of airway secretions and enhance mucociliary clearance in
      patients with CF. After performing safety studies of aerosolized UTP/amiloride in
      adult patients with CF, we investigated the effects of inhaled vehicle and
      UTP/amiloride on mucociliary clearance of [99mTc] iron oxide particles from the
      airways of adult patients with CF (n = 14). We found no clinically significant
      adverse effects from inhalation of therapeutic doses of UTP/amiloride. Mean
      baseline peripheral clearance rates during the first 40 min of clearance
      measurements were significantly less in patients with CF than in normal subjects
      (mean +/- SE: 0.30 +/- 0.05 versus 0.54 +/- 0.07%/min, respectively; p = 0.01).
      Aerosolized UTP and amiloride in combination improved mucociliary clearance from
      the peripheral airways of the CF lungs to near normal values (0.51 +/- 0.09%/min;
      p = 0.04) during this period. These data support the concept for the use of UTP
      in combination with amiloride as therapy to improve clearance of secretions from
      the lungs of patients with CF.

PMID- 8665036
TI  - Effect of inhaled heparin on allergen-induced early and late asthmatic responses
      in patients with atopic asthma.
AB  - Heparin possesses anti-inflammatory properties, which appeared to be dependent on
      the dose, timing, and the route of administration in animal studies. In asthma, a
      single dose of inhaled heparin only slightly reduced the early asthmatic response
      (EAR) but failed to protect against the late asthmatic response (LAR) to inhaled
      allergen. We studied the effect of multiple doses of inhaled heparin on the EAR
      and LAR to inhaled house-dust mite extract in eight stable asthmatics in a two
      period, randomized, double-blind, crossover study. During both study periods, a
      standardized allergen challenge was performed and PC20 histamine was measured 24
      h before and 24 h postallergen. Five doses of unfractionated heparin sodium
      (1,000 U/kg/dose) or placebo were inhaled 90 and 30 min preallergen, and 2, 4,
      and 6 h postallergen. Airway response was measured by FEV1, and the EAR (0-3 h)
      and LAR (3-10 h) were expressed as corresponding areas under the time-response
      curves (AUC). The acute effects of heparin and placebo on baseline FEV1 were not
      different (p > 0.07). Although not reaching significance, heparin attenuated the
      EAR by an average of 40% (mean AUC(0-3) +/- SEM: 29.5 +/- 6.0 [placebo] and 17.8
      +/- 5.5% fall x h [heparin]; p = 0.08), while it significantly reduced the LAR by
      an average of 36% (AUC(3-10) +/- SEM: 169.3 +/- 20.0 [placebo] and 109.1 +/-
      23.6% fall x h [heparin]; p = 0.005). We conclude that inhaled heparin reduces
      the LAR to allergen in asthmatic subjects, which may be due to its anti
      inflammatory activity. Our finding suggests that heparin may have potential as
      anti-asthma therapy.

PMID- 8665038
TI  - Methacholine reactivity predicts changes in lung function over time in smokers
      with early chronic obstructive pulmonary disease. The Lung Health Study Research
      Group.
AB  - As part of a clinical trial of early intervention in chronic obstructive
      pulmonary disease (COPD) (the Lung Health Study), 5,733 smokers with mild to
      moderate airflow obstruction underwent methacholine challenge tests at baseline.
      All participants were randomized to receive either usual care (no intervention)
      or special intervention, consisting of intensive smoking cessation counseling and
      the prescription of a metered-dose inhaler containing either ipratropium bromide
      or placebo (two inhalations three times daily). For this report, we analyzed the
      relationship between baseline methacholine reactivity and subsequent change in
      lung function. Methacholine reactivity was expressed as a logarithmic function of
      the two-point slope of percent decline in FEV1 over the concentration of
      methacholine (LMCR). Using a random effects linear model, LMCR was found to be a
      strong predictor of change in FEV1% predicted, after controlling for baseline
      lung function, age, sex, baseline smoking history, and changes in smoking status.
      Significant interactions were found between reactivity and smoking behavior. In
      the first year, participants who quit smoking showed improvement in FEV1, whereas
      continuing smokers showed worsening, and between Years 1 and 5, lung function
      declined to a greater extent in continuing smokers than in sustained quitters.
      For both time periods, these quitter/smoker differences increased as a function
      of airway reactivity. These findings indicate that methacholine reactivity is an
      important predictor of progression of airway obstruction in continuing smokers
      with early COPD, independent of the baseline level of obstruct.

PMID- 8665039
TI  - Inspiratory muscle training and whole-body reconditioning in chronic obstructive
      pulmonary disease.
AB  - To examine the efficacy of targeted inspiratory muscle training (IMT), 25
      patients with moderate COPD were randomly assigned to one of three groups. Eight
      patients received IMT along with general exercise reconditioning, GER+IMT; nine
      patients received general exercise reconditioning, GER; eight patients received
      sham breathing exercises, CONTROL. All groups used a spring-loaded inspiratory
      muscle trainer; however, the GER and CONTROL groups breathed through these
      devices at only 15% of their maximal inspiratory pressure. The GER+IMT group
      increased the load on these devices until at 6 wk the load was equal to 80% of
      their maximal inspiratory pressure. All patients exercised three times per week
      for a 12-wk period in supervised sessions. Analysis of covariance revealed no
      significant differences in spirometric measurements, maximal inspiratory
      pressure, or maximal oxygen consumption among any of the three groups after the
      intervention (p > 0.05). Twelve-minute walk distance was significantly greater in
      the GER+IMT and GER groups than in the CONTROL group (p = 0.03). After the
      intervention, there was a trend (p = 0.08) for treadmill time to be greater for
      the GER+IMT and GER groups than for the CONTROL group. Dyspnea ratings at
      different exercise intensities were not found to be significantly different among
      the three groups after the intervention. These results demonstrate that GER+IMT
      and GER alone are equally effective in improving exercise performance in patients
      with COPD. Additionally, the combination of GER and IMT does not appear to
      provide any clinically significant improvements in exercise performance or
      perceptions of dyspnea during exercise when compared with GER alone.

PMID- 8665040
TI  - Tracheal gas insufflation: catheter effectiveness determined by expiratory flush
      volume.
AB  - Used adjunctively during mechanical ventilation, tracheal gas insufflation (TGI)
      improves CO2 elimination, principally by decreasing effective anatomic dead
      space. Continuing lung deflation at end- expiration raises the end-expiratory C02
      concentration within the proximal airway, and could theoretically reduce the
      efficiency of a given catheter flow. To test this possibility, we designed a
      series of experiments that examined the influence of TGI delivery patterns on the
      efficiency of CO2 elimination. Using a gating device, catheter flow was delivered
      selectively during desired portions of expiration. Paralyzed, ventilated dogs
      were studied at short and extended inspiratory time fractions (TI/TT) with
      inspiratory tidal volume and ventilator frequency held constant. The expiratory
      flush volume, not the pattern of gas delivery, determined the observed decline in
      PaCO2, provided that the end-expiratory period was included in the catheter flush
      period. Despite continuing end-expiratory lung deflation (extended TI/TT),
      catheter effectiveness remained the same at matched expiratory flush volumes. To
      determine if enhanced distal mixing at the higher catheter flows required during
      the extended TI/TT (to match expiratory flush volume) masked a decrease in
      efficiency, we repeated the experiment with a tip-inverted catheter. We again
      found that matched catheter delivered expiratory volumes were similarly
      effective. With or without ongoing lung deflation, the volume of gas flushed
      during the expiratory period determined the effectiveness of TGI, provided that
      inspired minute ventilation remains unchanged and end-expiration is included in
      the catheter flush period.

PMID- 8665041
TI  - Mean airway pressure as an index of mean alveolar pressure.
AB  - Mean airway pressure (Pao) has been advocated as a useful index for monitoring
      hemodynamic performance and risk for barotrauma during mechanical ventilation.
      This is based on the assumption that Pao closely reflects mean alveolar pressure
      (Palv). In the present study we have compared Pao with Palv in 12 sedated,
      paralyzed, mechanically ventilated patients. External PEEP ranged from 0.3 to 8.9
      cm H2O. Palv was estimated by measuring Pao after rapid flow interruptions made
      at different points in time of the breathing cycle, using a modification of the
      method of Fuhrman and coworkers (4). All subjects exhibited intrinsic PEEP
      (PEEPi), which ranged from 0.5 to 9.4 cm H2O. A significant negative correlation
      (p < 0.001) was found between Pao/Palv and PEEPi. On average, at PEEPi of 10 cm
      H2O, Pao underestimated Palv by about 50%. We conclude that Pao cannot be taken
      as an index of Palv in patients who exhibit dynamic hyperinflation and PEEPi
      caused by expiratory flow limitation.

PMID- 8665042
TI  - The effects of recombinant human thrombomodulin on endotoxin-induced multiple
      system organ failure in rats.
AB  - Activation of the coagulation system is postulated to play an important role in
      the pathogenesis of endotoxin-induced tissue injury. Thrombomodulin (TM) is an
      endothelial cell membrane glycoprotein receptor for thrombin. Once bound to TM,
      thrombin loses its procoagulant activity, which results in decreased clotting. In
      addition, the binding of thrombin to TM activates the endogenous anticoagulant
      pathway through protein C. We studied the effect of recombinant human TM (rh-TM)
      on endotoxin-induced multiple-system organ failure (MSOF) in Sprague-Dawley rats
      weighing 400 to 450 g: 2 mg/kg of rh-TM was injected (T1/2 = 4.5 h) 30 min prior
      to intravenous injection of 20 mg/kg of Escherichia coli endotoxin. The study
      presented here consisted of three separate experiments. Experiment 1: 24-h
      survival study. Experiment 2: multiple-system organ microthrombi study in which
      125I-human fibrinogen was injected 30 min prior to an endotoxin or saline
      injection and tissue microthrombi formation was assessed by measuring the
      percentage of organ radioactivity (lung, heart, liver, and kidney) against total
      injected radioactivity (microthrombi index, MI) 2.25 h after an endotoxin or
      saline injection. Experiment 3: endotoxin-induced MSOF study in which 125I-rat
      albumin was injected 5 h after an endotoxin or saline injection, and endotoxin
      induced organ injury was evaluated by measuring tissue wet-to-dry ratios (W/D)
      and tissue-to-plasma 125I-rat albumin concentration ratios (T/P) 8 h after the
      endotoxin or saline injection. Blood contamination in samples from Experiments 2
      and 3 was corrected by using 131I-rat albumin measurements. Pretreatment with rh
      TM improved the survival from 12 h through 23 h as compared with that of the
      endotoxin control group (p < 0.05). However, at 24 h, after essentially all
      injected rh-TM had been eliminated, there was no difference in survival.
      Significant reductions in MI, W/D, and T/P in the organs sampled were observed in
      the rh-TM pretreated groups (p < 0.05). In conclusion, rh-TM improved short-term
      but not overall survival and decreased MSOF in endotoxemic rats.

PMID- 8665043
TI  - Physiologic response and lung distribution of lavage versus bolus Exosurf in
      piglets with acute lung injury.
AB  - Despite evidence of surfactant dysfunction in the acute respiratory distress
      syndrome (ARDS), treatment with exogenous surfactant remains experimental. Uneven
      pulmonary distribution is one factor that may limit response. We investigated
      whether exogenous surfactant administered by lavage, consisting of a 35 ml/kg
      volume instilled by gravity and followed immediately by passive drainage
      (LAVAGE), would result in better lung distribution and physiologic response than
      with surfactant administered as a 5 ml/kg bolus (BOLUS). Exosurf, an artificial
      surfactant, was administered after acute lung injury induced by saline lung
      lavage in neonatal piglets. In the LAVAGE group (n= 9), 10.1 +/- 0.4 ml/kg of
      surfactant was retained, corresponding to a phospholipid dose of 136 +/- 5 mg/kg.
      In the BOLUS group (n = 9), the dose administered was 203 mg/kg phospholipid.
      Piglets in the LAVAGE group demonstrated greater improvement in pulmonary
      function, including PaO2, PaCO2, ventilation efficiency index, functional
      residual capacity (FRC), and pressure-volume curves than piglets in the BOLUS
      group. Some differences were found in lung distribution of surfactant. We
      conclude that Exosurf is more effective when administered by lavage in this lung
      injury model. We speculate that the lavage method of administration holds promise
      as an alternative method of surfactant administration in patients with ARDS.

PMID- 8665044
TI  - Change in properties of exogenous surfactant in injured rabbit lung.
AB  - We asked if the function of surfactant could be enhanced after exposure to
      injured lungs. We also asked if sensitivity to inhibition of the minimal surface
      tension-lowering properties of surfactant by plasma could be altered. Lung injury
      in rabbits was induced with N-nitroso-N-methylurethane (NMU) and 6 of 17 NMU
      injured rabbits were treated with 100 mg/kg surfactant. All rabbits were
      ventilated for 2 h, and large aggregate alveolar surfactant was isolated by
      centrifugation. In vivo function of the large aggregate surfactant was evaluated
      by treatment of preterm surfactant-deficient rabbits at 27 d gestation.
      Surfactant from NMU-injured lungs increased compliance from 0.37 +/- 0.01 in
      control preterm rabbits to 0.71 +/- 0.05, a value significantly higher than found
      for the surfactant used for treatment (0.55 +/- 0.04) (p < 0.05). The minimal
      surface tensions of large aggregate surfactant and the surfactant used for
      treatment (0.1 mg lipid/ml) were evaluated for inhibition by plasma proteins.
      Surfactant from NMU-injured and surfactant-treated rabbits was more resistant to
      inhibition (minimal surface tension, 5.7 +/- 3.9 dyne/cm in the presence of 0.6
      mg/ml plasma protein) than the surfactant used for treatment (19.7 +/- 0.8
      dyne/cm). These results indicate that after exposure to the injured lung, the
      function of the surfactant used for treatment was enhanced and made less
      sensitive to plasma inhibition of the surface-tension-lowering properties of
      surfactant. These changes probably result from the association of endogenous
      surfactant components with exogenous surfactant.

PMID- 8665045
TI  - Proinflammatory activity in bronchoalveolar lavage fluids from patients with
      ARDS, a prominent role for interleukin-1.
AB  - Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and
      interleukin-1beta (IL-1) have been found to be elevated in bronchoalveolar lavage
      (BAL) fluid and in plasma from patients with acute respiratory distress syndrome
      (ARDS). In order to measure the balance of proinflammatory cytokines and their
      inhibitors, we quantified the upregulation of intercellular adhesion molecules
      (ICAM-1) induced by ARDS BAL fluids in human alveolar type II-like (A459) cells,
      and defined proinflammatory activity as the amount of ICAM-1 induced by the SAL
      fluids. Proinflammatory activity was detected in 77% of the SAL fluids sampled
      during the first week of ARDS, was found maximal during the 3 first days after
      onset of ARDS, and was significantly greater than in BAL specimens from at risk
      patients. Blocking experiments with specific inhibitors of TNF and IL-1 added to
      the BAL fluids indicated that the bioactivity measured was mainly due to IL-1. In
      contrast, proinflammatory activity of conditioned supernates from endotoxin
      treated alveolar macrophages was mostly due to TNF. Using a bioassay that
      measures balance of cytokines with their inhibitors, our results indicate that
      the net proinflammatory activity in ARDS BAL fluids is attributable to IL-1 and
      not to TNF.

PMID- 8665046
TI  - The association of sudden unexpected infant death with obstructive sleep apnea.
AB  - We studied the relationship of sudden unexpected infant death/apparent life
      threatening events (ALTE) to obstructive sleep apnea (OSA) in 74 index probands
      who had either sleep-laboratory-confirmed OSA or a clinical diagnosis of OSA
      requiring treatment, 62 matched control probands, and their spouses and first-
      and second-degree relatives. Sleep was monitored in the home overnight, and OSA
      was defined by respiratory disturbance indices (number of apneas/hypopneas per
      hour of sleep) corrected for normal increases with age. Information on sudden
      unexpected infant death/ALTE was obtained by questionnaire and was corroborated.
      For living relatives, data were obtained by questionnaire, examination, or study
      (cephalometric radiographs, ventilatory responsiveness to hypercapnia and
      hypoxia). Eight index families had 10 infants with sudden unexpected infant
      death/ALTE; two control families had three infants with sudden death (p = 0.11).
      All told, 91 of the 136 families (index plus control) included members with OSA,
      and all 10 infant death/ALTE families were among these (versus zero of 45
      families with no OSA; p = 0.03). The sudden infant death/ALTE families had a
      greater frequency of two or more members with OSA (p = 0.06), reported more
      respiratory disease or allergy, were more frequently brachycephalic (p = 0.05),
      and had a smaller mean posterior nasal spine-basion distance (p = 0.0001) and
      ratio of anterior mandibular/anterior maxillary dental height (p < 0.05).
      Ventilatory responses to hypoxia were reduced in members of families with OSA (p
      = 0.008), with a trend toward the greatest blunting in subjects from families
      with OSA plus sudden unexpected infant death/ALTE. Thus, OSA in adults and sudden
      unexpected infant death/ALTE in their biologic relatives appear to be related.
      Familial factors influencing this association may include the degree of the
      predilection for OSA, liability for respiratory illness or allergy, dimensions of
      the oral-pharyngeal airway, and ventilatory response to hypoxia.

PMID- 8665047
TI  - Effect of zolpidem on sleep and ventilatory patterns at simulated altitude of
      4,000 meters.
AB  - The purpose of this study was to assess the effect of zolpidem 1 0 mg, a new
      imidazopyridine hypnotic drug, on sleep and respiratory patterns at a simulated
      altitude of 4,000 meters. Eight male subjects spent three nights in a
      decompression chamber. The first study night was spent at the ambient pressure
      corresponding to sea level. The two other nights were spent at a simulated
      altitude of 4,000 meters with either zolpidem or a placebo in random order
      according to a double-blind, crossover design. All subjects showed periodic
      breathing (PB) during sleep at simulated high altitude. Furthermore, altitude was
      associated with decreases in total sleep time (TST), slow-wave sleep (SWS), and
      REM sleep, and with significant increases in Stage 1 duration and in the arousal
      index. Most arousals were synchronous with the hyperpneic phase of PB. The main
      finding of our study is that zolpidem improved sleep characteristics at high
      altitude, inducing a decrease in sleep onset latency (placebo, 22 +/- 12 min
      versus zolpidem, 10 +/- 6 min), an increase in SWS duration (placebo, 46 +/- 28
      min versus zolpidem, 69 +/- 28 min), and a reduction in the arousal index during
      SWS (placebo, 7.4 +/- 4.1 per h versus zolpidem: 2.4 +/- 1.0 per h). Furthermore,
      none of the respiratory parameters were significantly affected by zolpidem in any
      sleep stage. In conclusion, zolpidem improved sleep quality at high altitude
      without adversely affecting respiration.

PMID- 8665048
TI  - Characteristics of the genioglossus and musculus uvulae in sleep apnea hypopnea
      syndrome and in snorers.
AB  - Genioglossus (GG) activity has been extensively studied by electromyographic
      recordings in the investigation of the pathophysiology of sleep apnea-hypopnea
      syndrome (SAHS). However, the effective force developed by this upper airway (UA)
      dilator muscle depends on its metabolic and histochemical characteristics. The
      aim of this study was to compare the metabolic and fiber type characteristics of
      two UA dilator muscles, musculus uvulae (MU) and GG, in 17 patients with SAHS and
      in 11 nonapneic snorers. MU and GG samples were obtained during
      uvulopalatopharyngoplasty. Anthropomorphic characteristics were similar in
      snorers and patients with SAHS, who differed only in the presence of sleep
      related breathing abnormalities. MU glycolytic, glycogenolytic, and anaerobic
      enzyme activities were significantly greater in patients with SAHS than in
      snorers. These differences were not observed for GG. MU and GG enzyme activities
      differed only in snorers. The proportion of type I muscle fiber was greater in GG
      than in MU, but it was similar in patients with SAHS and snorers for each muscle.
      Type IIA and IIB muscle fibers were, respectively, in greater and smaller
      proportions in patients with SAHS than in snorers. We conclude that (1) the
      differences in metabolic characteristics between patients with SAHS and snorers
      are not observed in all UA muscles, and (2) similar histochemical differences are
      observed in GG and MU between these two groups, thus suggesting that these
      differences may be implicated in the pathophysiology of SAHS.

PMID- 8665049
TI  - N-acetylcysteine inhibits loss of diaphragm function in streptozotocin-treated
      rats.
AB  - We examined whether streptozotocin (STZ)-induced diabetic rats have an impairment
      in diaphragm contractility, and if so, whether N-acetylcysteine (NAC), a
      nonspecific antioxidant, prevents this impairment. First, diaphragm
      contractility, assessed by tension-frequency relationships and twitch kinetics in
      in vitro diaphragm strip preparations of Wistar rats, was obtained on Days 3 and
      7 after administration of STZ of 30 or 60 mg/kg body weight, and compared with
      that of the control group. Second, NAC at 500 mg/kg body weight or vehicle
      solution was administered orally every day in rats treated with STZ at 60 mg/kg
      body weight, and diaphragm function on Day 7 after starting NAC treatment was
      compared between vehicle control and STZ-treated groups. We found that diaphragm
      function in STZ-treated rats, which had hyperglycemia, decreased in a dose- and
      time-dependent manner. NAC inhibited the decrease in diaphragm contractility in
      STZ-treated rats without reducing blood glucose. These findings suggest that the
      loss of diaphragm function in STZ-induced diabetic rats is not directly related
      to hyperglycemia. The data are consistent with secondary alterations of normal
      cytokine signaling or changes in the redox state of the cell, both of which could
      be affected by NAC treatment.

PMID- 8665050
TI  - Influence of sleep onset on upper-airway muscle activity in apnea patients versus
      normal controls.
AB  - Current evidence suggests that patients with obstructive sleep apnea (OSA) may
      have augmented pharyngeal dilator muscle activity during wakefulness, to
      compensate for deficient anatomy. However, the isolated effect of sleep on the
      activity of these muscles (comparing OSA patients with controls) has not been
      studied. We therefore determined waking levels of genioglossus (GG) and tensor
      palatini (TP) muscle activity (% of maximum electromyographic [EMG] activity) in
      10 OSA patients and eight controls, and then assessed the impact of the first two
      breaths of sleep (theta electroencephalographic [EEG] activity) following a
      period of stable wakefulness. Apnea patients demonstrated greater genioglossal
      (27.4 +/- 4.0 versus 10.7 +/- 2.1%) and tensor palatini (31.9 +/- 6.5 versus 10.6
      +/- 1.9%) EMG activity than did controls during wakefulness. This augmented
      muscle activity in apnea patients could be reduced to near control levels during
      wakefulness with the application of continuous positive airway pressure (CPAP) to
      the upper airway. At sleep onset, control subjects demonstrated small but
      consistent decrements in the activity of both the TP and GG muscles. On the other
      hand, apnea patients demonstrated large, significantly greater decrements in TP
      EMG at sleep onset than did the control subjects. The effect of sleep on GG EMG
      in apnea patients was inconsistent, with most (n = 7) demonstrating large
      (significantly larger than controls) decrements in genioglossal activity.
      However, three OSA patients demonstrated small increments in GG EMG at sleep
      onset despite falling TP EMG and obstructive apnea or hypopnea. We conclude that
      sleep onset is associated with significantly larger decrements in TP muscle EMG
      activity in OSA patients than in controls, which may represent a loss of
      neuromuscular compensation that is present during wakefulness. However, our
      results for the GG muscle were more variable, and did not always support this
      hypothesis.

PMID- 8665051
TI  - Effects of acute steroid administration on ventilatory and peripheral muscles in
      rats.
AB  - Occasional case reports have shown that acute myopathy may occur in patients
      treated with massive doses of corticosteroids. The mechanism of this myopathy is
      poorly understood. Therefore, 60 male rats were randomly assigned to receive
      daily injection of saline (C), methylprednisolone (M), or triamcinolone (T) 80
      mg/kg/d for 5 d. Nutritional intake, measured daily in 15 animals, showed a
      significant reduction of food intake in the steroid-treated groups (-50 and -79%
      in M and T, respectively). This was associated with a similar loss in body
      weight. In the 45 remaining animals, diaphragm contractility and histopathologic
      features of several muscles were studied. Weights of respiratory and peripheral
      muscles were similarly decreased after steroid treatment. Maximal twitches of the
      diaphragm were lower in the C group (653 +/- 174 g/cm(2)) than in the M group
      (837 +/- 171 g/cm(2); p < 0.05) and the T group (765 +/- 145 g/cm(2), NS). Half
      relaxation time was prolonged in both steroid groups, and time to peak tension
      was longer with M, whereas tetanic tensions were similar. Steroid treatment also
      induced a leftward shift of the force-frequency curve at 25 and 50 Hz when
      compared with saline treatment (p < 0.05). ATPase staining of the diaphragm,
      scalenus medius, and gastrocnemius showed type IIb fiber atrophy in the steroid
      groups and also diaphragmatic type IIa atrophy with T, whereas histologic
      examinations revealed a normal muscular pattern with absence of necrosis.
      Finally, a pair-fed (PF) study, performed in 18 rats (C, T, and PF), showed that
      muscle atrophy was considerably less pronounced in PF animals than in T-treated
      animals. We conclude that (1) short-term treatment with massive doses of steroids
      induced severe respiratory and limb muscle wasting; (2) both types of steroids
      induced predominantly type IIb atrophy, resulting in the expected alterations in
      diaphragm contractile properties; (3) neither steroid caused muscle necrosis; (4)
      type IIb atrophy was not caused by acute nutritional deprivation alone.

PMID- 8665052
TI  - Respiratory muscle response to flail chest.
AB  - We have previously shown that flail chest in the dog causes an inspiratory inward
      displacement of the ribs and an increased inspiratory activity in the external
      intercostal muscles, and we have speculated that this increased activity is due
      to an increased spindle afferent activity. The present studies were designed to
      test this hypothesis. Twenty-nine supine anesthetized dogs were studied, and
      flail was produced surgically by fracturing ventrally and dorsally two to four
      contiguous ribs on the right side of the chest. Although flail elicited an
      increased inspiratory activity in the external intercostal and levator costae
      muscles in the disconnected segment of the rib cage, it did not alter the
      inspiratory activity in the diaphragm and parasternal intercostals. Expiratory
      activity in the triangularis sterni, internal intercostals, and transversus
      abdominis remained unchanged also, as did the inspiratory activity in the
      external intercostals on the left side of the chest. After flail, the normal
      inspiratory shortening of the external intercostal muscles in the disconnected
      segment was also reversed into an inspiratory muscle lengthening. However, when
      the fractured ribs were connected to the adjacent ribs so that the external
      intercostals were prevented from lengthening during inspiration, external
      intercostal and levator costae inspiratory activity was unaltered. These
      observations support the hypothesis that the increased external intercostal
      muscle activity seen in flail chest results primarily from an increased
      activation of the muscle spindles.

PMID- 8665053
TI  - Asthma on Tristan da Cunha: looking for the genetic link. The University of
      Toronto Genetics of Asthma Research Group.
AB  - Although asthma has a significant heritable component, the mode of inheritance
      remains controversial because of the complexity of the disease and the influence
      of environmental factors. Isolated, inbred populations serve to reduce
      variability, thus increasing the probability of gene localization. We studied the
      inbred population of the remote island of Tristan da Cunha to document asthma
      prevalence for the purpose of genetic linkage analysis. Medical histories and
      skin atopy were determined on 282 islanders, representing 97% of the population,
      and airway responsiveness was measured in 254; 226 by methacholine challenge
      (tidal breathing method) and 28 by bronchodilator response (400 micrograms
      salbutamol aerosol). Blood samples were collected from 275 islanders.
      Participants ranged in age from 3 to 94 yr. Asthma was defined as increased
      airway responsiveness (AR+: PC20 < 4 mg/ml or > or = 15% increase in FEV1
      postbronchodilator) combined with a positive history (Hx+). Fifty-seven percent
      of the islanders had at least partial evidence of asthma (Hx+ and/or AR+) and 23%
      had a definitive diagnosis of asthma (AR+ with Hx+). Overall 47% of the
      population were atopic, atopy was proportionally higher in asthmatics (74%) than
      nonasthmatics (32%; p < 0.01). Analysis of the methacholine dose-response curves
      demonstrated that asthmatics were significantly (p < 0.01) more responsive than
      those with AR+ only, and nonasthmatics (AR-, Hx-) were more responsive than
      laboratory control subjects (p < 0.05), suggesting that these islanders may also
      carry an airway hyperresponsiveness gene. A frequency plot of the percent fall in
      FEV1 for all Hx- subjects compared with control data suggests a bimodal
      distribution consistent with a major gene mechanism for airway responsiveness.
      Genealogy mapping revealed that the islanders are direct descendants of the 15
      original settlers, and historical records suggest at least two founders may have
      been asthmatic. The data confirm previous reports of a high asthma prevalence on
      Tristan and support the postulate that this prevalence is a result of gene
      enrichment occurring in isolated populations by virtue of extensive inbreeding
      and a probable founder effect.

PMID- 8665054
TI  - Longitudinal and cross-sectional analyses of lung function in steelworkers.
AB  - We evaluated associations between dust exposure, demographic factors, and lung
      function by longitudinal and cross-sectional analyses in 475 steelworkers who
      participated in at least three spirometry tests over 5 yr between 1982 and 1991.
      Baseline and follow-up spirometry and changes between baseline and final follow
      up assessment attributable to age, height, weight, weight gain, smoking status,
      pack-years, and years worked in dusty areas were examined using stepwise multiple
      linear regression techniques. Smoking, aging, being overweight, excessive weight
      gain, and dust exposure were related to a lower level and a steeper slope of
      decline of pulmonary function. Cigarette smoking was also an important risk
      factor. Dust exposure was related to the level of lung function, with a stronger
      effect at baseline than at follow-up. Estimated loss at baseline of FEV1, FVC,
      and FEV1/FVC% was 9.3, 6.4 ml, and 0.1 % per year of employment in a dusty area,
      respectively, whereas the association between dust exposure and longitudinal
      decline of lung function was weak. However, a strong relationship between weight
      gain and longitudinal decline of FEV1 and FVC was found. Estimated decreases in
      FEV1 and FVC attributable to weight gain were 4.7 and 6.3 ml per lb/yr,
      respectively. This work suggests that weight gain is an important determinant for
      longitudinal lung function decline. This large impact of weight gain in the
      decline of lung function in a middle-age and relatively overweight working
      population has not been previously reported. Additional work needs to be
      undertaken to show the strength of this relationship in other populations.

PMID- 8665055
TI  - Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with
      acute pulmonary exacerbations.
AB  - The goal of this study was to evaluate the safety and efficacy of recombinant
      human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF)
      experiencing acute pulmonary exacerbations. Eighty patients with documented CF
      were enrolled at 11 CF centers when admitted for antibiotic therapy. Patients
      were at least 5 yr old with a forced vital capacity (FVC) > or = 35% of predicted
      and an oxygen saturation > or = 90% on a fraction of inspired oxygen (FIO2) <
      0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice
      a day (n = 43) or 2.5 ml excipient alone twice daily (n = 37) along with
      conventional treatment for exacerbations. Administration of rhDNase was not
      associated with acute adverse events or deaths, and no patients experienced
      allergic or anaphylactic reactions. Although forced expiratory volume in one
      second (FEV1) and FVC improved in both treatment groups during the double-blind
      period, there were no statistically significant differences in the mean change
      from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and
      well tolerated in CF patients with acute exacerbations requiring hospitalization,
      but the study did not demonstrate a statistically significant therapeutic effect
      of rhDNase when added to a regimen of antibiotics and chest physical therapy.

PMID- 8665056
TI  - Serum indicators of free radical activity in idiopathic pulmonary fibrosis.
AB  - Serum levels of free radical activity were measured in 37 patients with
      idiopathic pulmonary fibrosis (IPF) and 16 control subjects. Three assays used
      were (1) simultaneously measured levels of the 9,11-diene conjugate of linoleic
      acid and 9,12-linoleic acid expressed as a percent molar ratio (%MR), a measure
      of free-radical-mediated lipid peroxidation; (2) thiobarbituric acid reactive
      substances (TBARS), one of which is malondialdehyde; (3) desferrioxamine
      chelatable iron assay, a measure of the potential iron available to catalyze free
      radical generation. Mean %MR, TBARS and desferrioxamine-chelatable iron were all
      elevated initially in patients with IPF compared with control subjects (%MR, p <
      0.0001; TBARS, p = 0.0013; desferrioxamine-chelatable iron, p = 0.0029).
      Furthermore, the serum %MR was higher in a subset of patients with clinically
      worsening IPF than in those patients with clinically stable disease (p = 0.002).
      Treatment did not appear to affect the three different serum indicators of free
      radical activity. Thus, lipid peroxidation appears to be increased in patients
      with IPF and is associated with an increase in desferrioxamine-chelatable iron
      levels. Serum % MR levels appeared to correlate with clinical disease activity,
      and they may have a role in monitoring disease activity.

PMID- 8665057
TI  - Immunologic alterations in bleomycin-treated mice: role of pulmonary fibrosis in
      the modulation of immune responses.
AB  - Among the side effects of bleomycin (BLM), a drug frequently used in the
      treatment of lymphomas and squamous-cell carcinomas, is pneumonitis with
      pulmonary fibrosis. The most prominent biochemical lesion associated with
      pulmonary fibrosis, a chronic debilitating and sometimes fatal disease, is an
      increase in the levels of collagen in the lung parenchyma. The mechanisms
      involved in the induction of this disease are still unclear, although results
      have suggested that the development of fibrosis may be immunologically mediated.
      There have, however, been no reports in the literature on the frequency and
      function of lymphocytes in the regional and systemic lymphoid tissues in BLM
      induced pulmonary fibrosis. We therefore conducted a study, in which we
      inoculated C57Bl/6 mice intratracheally with BLM or saline, and tested the
      animals' lymphoid cells for various cell-mediated and humoral immune responses.
      The results indicated an increase in the number of lymphocytes in the lung
      associated hilar lymph nodes, whereas the number of splenic lymphocytes was
      reduced as compared with control mice. Moreover, there was a significant
      inhibition of the antibody response to sheep erythrocytes in both the spleen and
      hilar lymph nodes of BLM-treated mice. Inhibition of the immune system appeared
      to be associated with the development of pulmonary fibrosis, and not to result
      from BLM toxicity, since the immune response of mice was not inhibited when they
      were injected with an identical dose of BLM under conditions that did not cause
      pulmonary fibrosis. Moreover, inhibition of splenic antibody responses was also
      observed in a hapten-induced model of pulmonary fibrosis, providing additional
      evidence that the induction of fibrosis and not the chemical toxicity of BLM was
      responsible for the modulation of immune responses.

PMID- 8665058
TI  - High-affinity IgE receptor (FcepsilonRI)-bearing cells in bronchial biopsies from
      atopic and nonatopic asthma.
AB  - Asthma is characterized by bronchial mucosal inflammation. Although allergen
      induced activation of cells binding allergen-specific immunoglobulin E (IgE)
      through high-affinity receptors (Fc(epsilon)RI) is believed to play some role in
      asthma, inappropriate synthesis of total or allergen-specific IgE cannot be
      demonstrated in some ("intrinsic") patients despite the fact that the nature of
      the bronchial inflammation is similar to that in atopic ("extrinsic") asthmatics.
      We have studied the numbers and phenotype of Fc(epsilon)RI-bearing cells in
      bronchial biopsies from 12 atopic and 10 nonatopic asthmatic patients and
      compared our findings with 10 atopic and 12 nonatopic control subjects using
      single and double immunohistochemistry. Significantly increased numbers of
      Fc(epsilon)RI-bearing cells were identified in bronchial biopsies from atopic and
      nonatopic asthmatics and atopic control subjects when compared with normal
      controls (p = 0.001, 0.006, and 0.0006, respectively). In asthmatics and atopics
      the majority of Fc(epsilon)RI-bearing cells were identified as mast cells and
      macrophages; a much smaller percentage were eosinophils. We conclude that
      elevated numbers of high-affinity IgE receptor-bearing cells are a feature of
      bronchial biopsies of asthmatic subjects, irrespective of their atopic status.

PMID- 8665059
TI  - Color Doppler ultrasound signals of thoracic lesions. Correlation with resected
      histologic specimens.
AB  - Sixty-eight patients with thoracic lesions (48 with lung cancer and 20 with
      benign lesions) underwent color Doppler ultrasound (US) examinations. Of those,
      21 patients (13 with lung cancer and eight with benign lesions) also received
      resections, and the correlation between color Doppler US signals and resected
      histologic specimens was evaluated. Our results showed that three patterns of
      color Doppler US signals could be detected and confirmed: pulsatile flow
      (artery), constant flow, and triphasic flow (pulmonary vein). Among the 48
      patients with lung cancer, pulsatile flow, constant flow, and/or triphasic flow
      were detected in 34 (71%), 24 (50%), and 14 (29%), respectively. Among the 20
      patients with benign lesions, only pulsatile flow and/or triphasic flow were
      detected in nine (45%) and eight (40%), respectively. From the correlation
      between color Doppler US signals and histologic specimens, constant flow was
      representative of the true neovascularity of lung cancers, and it was valuable
      for differentiating lung cancers from benign lesions (p = 0.00008, sensitivity =
      0.50, and specificity = 1.0). Although color Doppler US still had some
      limitations in detecting blood vessels in thoracic lesions, the correlation
      between the vascularity represented by color Doppler US signals and histologic
      specimens was excellent. We conclude that color Doppler US is a valuable method
      for assessing blood flow in thoracic lesions and differentiating lung cancers
      from intrapulmonary benign lesions.

PMID- 8665060
TI  - Specific IgG4 responses during chronic and transient antigen exposure in
      aspergillosis.
AB  - The factors that lead to increased production of specific IgG subclasses are
      still largely unknown. Recent studies suggest that increased IgG4 responses may
      be related to prolonged antigen exposure. We present data showing that increased
      IgG4 responses are found under conditions of chronic exposure to Aspergillus
      fumigatus (Af) antigen. IgG(total), IgG subclass, and IgE responses were studied
      using ELISA, CAP-FEIA, and immunoblotting techniques in patients with pulmonary
      aspergilloma (PA), which is a model for chronic antigen exposure, and allergic
      bronchopulmonary aspergillosis (ABPA), characterized by transient antigen
      exposure. Af-IgG1 was increased in patients with PA compared with those with
      ABPA. Patients with PA and IgE responses to Af and/or other inhalant allergens
      showed significantly higher Af-IgG4 responses than did patients with PA and
      negative IgE responses or patients with ABPA. Surveillance studies over time in
      individual patients showed concordance in Af-IgG1 and Af-IgG4 responses. Both Af
      IgG1 and Af-IgG4 levels followed the course of disease progression and treatment.
      Immunoblotting revealed correlations between Af-IgG1 and Af-IgG4 binding to most,
      but not all, antigenic Af components. This study documents for the first time
      increased IgG4 levels under conditions of chronic exposure to fungal antigen in
      PA. Furthermore, a significantly higher IgG4 response was found in those patients
      with PA who produced IgE. The transient exposure to Af antigen during
      exacerbation of ABPA gives rise to transient elevations in IgG4 levels.

PMID- 8665061
TI  - Functional and histologic picture of steroid-induced myopathy in chronic
      obstructive pulmonary disease.
AB  - The functional and histologic picture of steroid-induced myopathy was
      systematically examined in eight patients with chronic obstructive pulmonary
      disease (COPD) and compared with control patients with COPD matched for age, sex,
      and degree of airflow obstruction. Steroid-induced myopathy was associated with
      severe peripheral muscle weakness, quadriceps force being 23 +/- 14 versus 71 +/-
      23% in control patients with COPD (p < 0.001). In addition, clear ventilatory
      muscle weakness was present. PImax was 37 +/- 15 versus 67 +/- 24% in control
      patients (p < 0.001 ), and PEmax averaged 34 +/- 10 versus 74 +/- 23% (p <
      0.001). Vital capacity tended to be slightly reduced compared with that in
      control patients (69 +/- 21 versus 80 +/- 16%, p = 0.11). The only biochemical
      abnormalities associated to steroid-induced myopathy were a moderately increased
      lactic dehydrogenase level (697 +/- 301 versus 421 +/- 128 IU/L, p < 0.001) and
      an increased creatine excretion in 24-h urine (990 +/- 609 versus 159 +/- 219
      mg/24 h, p< 0.001). On quadriceps biopsy steroid-induced myopathy was
      characterized by increased variation in diameter of fibers, with several angular
      atrophic fibers and diffuse necrotic and basophilic fibers. In addition,
      increased amount of connective tissue in between fibers and increased number of
      subsarcolemmal and central nuclei were present. On ATPase stain diffuse fiber
      atrophy predominantly affecting fast fibers was present, but there was no
      indication that atrophy was confined to type IIb fibers in contrast to
      conventional thinking. On follow-up, survival of patients with steroid-induced
      myopathy was reduced in comparison with control patients with COPD with similar
      degree of airflow obstruction (p < 0.025).

PMID- 8665062
TI  - Acid aspiration results in ileal injury without altering ileal V(O2)-D(O2)
      relationships.
AB  - Systemic organ endothelial injury and V(O2)-D(O2) relationship alterations occur
      frequently in the setting of acute lung injury, and they are believed to play an
      important role in the pathogenesis of the multiple organ dysfunction syndrome
      (MODS). However, the relationship, if any, between systemic organ endothelial
      injury and V(O2)-D(O2) relationship alterations remains unknown. We hypothesized
      that microvascular endothelial injury and attendant interstitial edema would
      result in increased diffusion distances for oxygen and altered systemic organ
      V(O2)-D(O2) relationships. To test this hypothesis, we utilized the in situ
      autoperfused feline ileal preparation to evaluate ileal V(O2)-D(O2) relationships
      in control animals (n = 5) and in animals with HCl-induced acute lung and
      systemic organ injury (n = 5). As expected, ileal endothelial protein
      permeability (CL/CP) was increased in HCl-injured animals compared to control
      animals (0.187 +/- 0.024 versus 0.097 +/- 0.009; p < 0.01). However, contrary to
      our original hypothesis and despite marked morphologic and endothelial protein
      permeability alterations, ileal V(O2)-D(O2) relationships were not altered in the
      HCl-injured animals. Moreover, V(O2)-D(O2) relationships in the ileum remained
      unchanged even when ileal venous pressures were increased to 15 mm Hg. Taken
      together, these findings do not support an important role for oxygen diffusion
      limitation in the pathogenesis of altered systemic organ V(O2)-D(O2)
      relationships.

PMID- 8665063
TI  - Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea
      syndrome.
AB  - In patients with obstructive sleep apnea syndrome (OSAS), the blood coagulation
      system may contribute to an increased risk of cardiovascular events, which occur
      most frequently in the morning. Nasal continuous positive airway pressure (NCPAP)
      treatment can improve the mortality of patients with OSAS. We measured the plasma
      fibrinogen concentration, which is an independent risk factor for cardiovascular
      events, in the afternoon (3:30 P.M.) and the next morning upon awakening (8:30
      A.M.) in 11 patients with OSAS (apnea and hypopnea index > 20) before and after
      NCPAP therapy. We also measured the hematocrit, the C-reactive protein, and the
      total plasma protein at the same time. The plasma fibrinogen and hematocrit
      levels in the morning (298 +/- 16 mg/dl and 48.5 +/- 1.5%, mean +/- SEM) were
      significantly higher than on the previous afternoon (275 +/- 14 mg/dl and 46.6 +/
      1.3%) (fibrinogen, p < 0.02; hematocrit, p < 0.005). The whole blood viscosity
      (WBV) at a shear rate of 208 inverse seconds, which can be predicted based on the
      hematocrit and total plasma protein, was also significantly higher in the morning
      (4.98 +/- 0.20/s) than in the afternoon (4.73 +/- 0.17/s) (p < 0.005). These
      increases in the plasma fibrinogen concentration and the WBV in the morning
      disappeared after NCPAP treatment. The attenuation of morning increases in the
      plasma fibrinogen concentration and WBV induced by NCPAP treatment may contribute
      to an overall improvement in the mortality from cardiovascular events in patients
      with OSAS.

PMID- 8665064
TI  - Predictors of survival in human immunodeficiency virus-infected patients with
      pulmonary tuberculosis. The Makerere University-Case Western Reserve University
      Research Collaboration.
AB  - Infection with the human immunodeficiency virus (HIV) has changed both the
      epidemiology and natural history of tuberculosis. Despite a generally good
      response to effective antituberculous therapy, the prognosis remains poor. The
      objective of this analysis was to determine the independent predictors of
      survival in HIV-infected Ugandan adults with smear-positive pulmonary
      tuberculosis. A total of 191 HIV-infected Ugandan adults with smear-positive
      pulmonary tuberculosis were enrolled into a clinical trial of chemotherapy for
      tuberculosis. The subjects received either rifampin, isoniazid, and pyrazinamide
      for two months, followed by rifampin and isoniazid for six months (n = 101) or
      streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone
      and isoniazid for eight months (n = 90). After standard measurements were made at
      baseline, the group was followed at regular intervals for a mean of 16 months to
      determine survival. During the course of follow-up, 82 (43%) of the patients
      died, six within the first month of therapy. The one-year survival proportion was
      68% with an estimated median survival of 26 months and did not differ according
      to treatment regimen. The hazard for death was biphasic, high early in the course
      of therapy, and then again after about one year. After controlling for the
      treatment regimen, four independent predictors of survival were found: anergy to
      purified protein derivative, atypical chest roentgenogram, previous HIV-related
      condition, and lymphopenia. In this cohort of Ugandan adults, four simple and
      inexpensive predictors of survival were found. These factors suggest that the
      degree of immunosuppression was a major determinant of survival.

PMID- 8665065
TI  - Reliability of anergy skin testing in persons with HIV infection. The pulmonary
      Complications of HIV Infection Study Group.
AB  - Testing with antigens that elicit delayed-type cutaneous hypersensitivity
      reactions is commonly used to evaluate immune competence in persons infected with
      the human immunodeficiency virus; however, the reliability of such testing has
      not been determined. We performed serial testing with tuberculin, mumps, and
      Candida antigens in 491 HIV-infected persons and found that 30% of persons who
      initially had no reaction (0 mm) to any of the three antigens, and, thus, were
      considered to be anergic, had reaction to the mumps or Candida antigen when they
      were retested 12 months later. We also examined the results of mumps antigen
      tests in 50 subjects who had a negative tuberculin tests after an initial
      positive test. The mumps antigen test was positive in 39% of the subjects when
      the tuberculin test was falsely negative. We conclude that tests commonly used to
      define anergy cannot reliably identify the anergic state. Moreover, using the
      mumps antigen to aid in the interpretation of the tuberculin test will often lead
      to erroneous conclusions. These data indicate that the results of anergy testing
      should not be used to make individual patient decisions concerning preventive
      therapy for tuberculosis.

PMID- 8665066
TI  - Life-threatening effects of discontinuing inhaled nitric oxide in severe
      respiratory failure.
AB  - We present the effects of abrupt discontinuation of inhaled nitric oxide (NO) in
      four patients with severe hypoxemic respiratory failure. These patients ranged
      from 9 mo to 65 yr of age. In each patient, after the initiation of inhaled NO, a
      marginal, but immediate, beneficial effect on gas exchange and, when measured, a
      reduction in pulmonary artery pressures was noted. However, during attempts to
      discontinue inhaled NO, not only did these patients develop worsening oxygenation
      and recrudescence of pulmonary hypertension but, unexpectedly, these parameters
      were worse than the baseline values, leading to life-threatening hemodynamic
      instability. These effects reversed immediately after reinstitution of inhaled
      NO. The mechanism of this severe ?rebound? in pulmonary hypertension after abrupt
      withdrawal of NO is unclear, but its existence emphasizes the need to avoid a
      substantial risk to these patients. Moreover, we believe that both unintentional
      and intentional termination of inhaled NO therapy may lead to life-threatening
      deterioration in gas exchange and circulatory hemodynamics that exceeds the
      initial therapeutic benefit.

PMID- 8665067
TI  - Oxygen cost of breathing in patients with emphysema or chronic bronchitis in
      acute respiratory failure.

PMID- 8665068
TI  - Single, high dose intramuscular triamcinolone acetonide versus weekly oral
      methotrexate in life-threatening asthma: a double blind study.

PMID- 8665069
TI  - Clarithromycin treatment for Mycobacterium avium-intracellulare complex lung
      disease.

PMID- 8665070
TI  - Survival and function of islets during culture.
AB  - Cell and tissue culture techniques have improved considerably since the first
      attempts to maintain explants of animal tissue in vitro. The two major
      developments that have allowed these improvements are the ability to produce
      continuous cell lines, thus allowing reproducible results to be obtained, and the
      definition of media for different cell types, thereby reducing the need for
      supplements of serum and other extraneous extracts. The requirements of islets in
      culture have been more difficult to define, largely because islets do not
      proliferate in culture and proliferation rate cannot therefore be used to measure
      the suitability of the medium. Further difficulties arise because islets are
      highly metabolically active "mini-organelles." Although many studies have been
      undertaken to try and optimize media for the culture islets of Langerhans, the
      media most commonly used are commercially available media developed for other
      cell types. There remains ample scope for further refinement of the composition
      of islet culture media, with the possibility of different media for islets from
      different species.

PMID- 8665071
TI  - Isolation and culture of porcine hepatocytes for artificial liver support.
AB  - The primary requirement of cells in a liver support system is the preservation of
      the in vivo metabolic functions that prevent or decrease the progress of hepatic
      encephalopathy (HE) by providing interim support to liver failure patients. While
      rodent hepatocytes offer a model for liver assist device (LAD) research, their
      limited number per animal prohibits direct scale up to human devices. Healthy
      human liver cells are seldom available in adequate numbers to support clinical
      LAD use; consequently, a large animal source of liver cells is needed. The study
      presented here explored the potential of porcine hepatocytes to proliferate and
      maintain metabolic function in vitro. Porcine hepatocytes were isolated from
      approximately 12 kg swine by a modification of Seglen's method. Hepatocytes
      cultured up to 10 days were shown to metabolize ammonia and maintain both Phase I
      and II detoxification functions. In addition, the cultures showed proliferative
      activity both as an increase in total protein content and by thymidine
      incorporation. Immunocytochemical staining identified cell proliferation through
      Day 4 to be primarily hepatocytes while Days 6 and 10 showed nonparenchymal cells
      to be increasing. The detoxification functions measured showed peak activity on
      Day 4 and gradually declined through Day 10. The ability of porcine hepatocytes
      to proliferate and maintain a diversity of hepatic functions in culture strongly
      suggests their potential for use as the biological component of artificial LADs.

PMID- 8665072
TI  - Expression and inducibility of cytochrome P450 IIIA family within
      intrasplenically transplanted fetal hepatocytes.
AB  - With the development of transplantation of hepatocytes into the spleen, interest
      has focused on the metabolic changes associated with hepatocyte proliferation. As
      these changes are important for drug metabolism in hepatocytes, we examined the
      expression and inducibility of the cytochrome P450 IIIA family within
      transplanted hepatocytes. Fetal hepatocytes were harvested at 20 days of
      gestation from spontaneously hypertensive rats (SHRs) and transplanted into
      recipient adult SHR spleens. Microscopic examination of the recipient spleens 4
      and 10 wk after transplantation revealed masses of hepatocytes with cord-like
      structures in the red pulp. Proliferating hepatocytes were detected with a
      bromodeoxyuridine (BrdU) immunohistochemical stain. Immunochemical studies
      detected cytochromes (cytos) P450 p and P450 HLp in fetal hepatocytes before
      transplantation without prior induction. And although these cytos were not
      detected by 10 wk after transplantation, they were induced with dexamethasone.
      These results demonstrated that fetal hepatocytes can be transplanted
      successfully into recipient spleens and suggested that fetal hepatocytes grow in
      the spleen, similar to the adult hepatocyte response.

PMID- 8665073
TI  - Noradrenergic and cholinergic reinnervation of islet grafts in diabetic rats.
AB  - Grafted islets become denervated due to the islet transplantation procedure. The
      aim of the present study was 1) to examine whether islet grafts in the liver, the
      spleen, and under the kidney capsule in rats become reinnervated following the
      transplantation and experimental procedures used in our laboratory, 2) whether
      there is any difference in reinnervation at these different sites, and 3) how
      these results relate to previous physiological experiments. Isogeneic isolated
      islets were transplanted into diabetic Albino Oxford rats, resulting in
      normoglycaemia. After at least 5 wk, graft-receiving organs were removed and
      several antibodies were employed to detect insulin, neuron-specific proteins, and
      cholinergic and noradrenergic nerve fibers. Islets in all three receiving organs
      contained viable insulin-positive B-cells. Neuron-specific enolase (NSE) as well
      as the growth-associated protein B-50 was observed at all sites. The cholinergic
      marker choline acetyltransferase (ChAT) was localized in islets grafts at all
      sites, but with the lowest density in the spleen. Staining for the noradrenergic
      markers tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) was
      observed in islet grafts at all sites with the lowest density in grafts under the
      kidney capsule. All these neurochemical substances were most frequently observed
      in fibers associated with blood vessels, which may be the route along which
      nerves grow into the graft. It can be concluded that 1) islet grafts in the
      liver, in the spleen and under the kidney capsule become reinnervated; 2) the
      innervation pattern of the islet grafts differs only slightly from that in the
      control pancreatic islets; and 3) in combination with our previously
      physiological data, we can conclude that these nerve fibers are, at least partly,
      functionally active.

PMID- 8665075
TI  - Protection of mouse islet isografts from nonspecific inflammatory damage by
      recipient treatment with nicotinamide and 15-deoxyspergualin.
AB  - The major cause of primary nonfunction of transplanted islets is nonspecific
      inflammation associated with the transplantation procedures. Using mouse islet
      isografts, we attempted to prevent graft loss mediated by nonspecific
      inflammation using recipient treatment with nicotinamide (NA) and 15
      deoxyspergualin (DSG). Newborn BALB/c islets, ranging in numbers between 1200 and
      1500, were transplanted into syngeneic adult mice made diabetic by intravenous
      injection of 200 mg/kg streptozotocin. Recipient mice were divided into the
      following four groups, based on the treatment protocol of NA and DSG:
      intraperitoneal injection (IP) of normal saline (Group 1), IP injection of 2500
      mg/kg NA (Group 2), IP injection of 5 mg/kg DSG (Group 3), and IP injection of NA
      + DSG (Group 4). Treatment started Day -1 and continued until Day 9 (Day 0 is day
      of transplantation). Blood and urine glucose, body weight, and intravenous
      glucose tolerance tests (IV-GTT) were examined after transplantation. Reversal of
      diabetes, as indicated by normoglycemia and negative urine glucose, was higher in
      Groups 2 (75%), 3 (50%), and 4 (85.7%), compared to Group 1 (11.1%). Especially
      in Group 4, the endocrine function and morphology of grafted islets were well
      preserved as shown by K values of IV-GTT and histological studies. These results
      suggest the importance of islet protection from irreversible damage by
      nonspecific inflammation at earlier stages of implantation, and the effectiveness
      of a short course of treatment with NA and DSG.

PMID- 8665074
TI  - Osmotic separation of pancreatic exocrine cells from crude islet cell
      preparations.
AB  - A novel approach is introduced here to selectively lyse exocrine cells in an
      islet preparation by hypo-osmotic treatment. Time to hypotonic cell lysis
      required for the islet cells was much longer than that for the exocrine cells,
      which permits a possibility of selectively killing the exocrine cells by
      hypotonic treatment. The first set of experiments was designed to select an
      appropriate osmolality for the hypotonic treatment. Kinetic changes in cell
      volume in response to extracellular anisosmolalities (30 to 90 mOsm/kg) were
      recorded using an electronic particle counter. The results indicated that, when
      exposed to a 30 mOsm/kg solution, islet cells swelled slowly to reach volumetric
      equilibrium in approximately 3 min. There was no significant hypotonic cell lysis
      observed even at the end of 4 min (n = 4). In contrast, pancreatic exocrine
      cells, when exposed to the same solution, expanded rapidly to the lytic volume
      and burst within 30 s. Significant exocrine cell lysis was invariably achieved
      within 30 s when cells were exposed to the osmolalities below 60 mOsm/kg. For
      osmolalities between 70 to 80 mOsm/kg, exocrine cell lysis was highly variable.
      When cells were exposed to 80 to 90 mOsm/kg, no significant cell lysis was
      observed. Thus, an osmolality of 50 mOsm/kg is recommended for hypotonic
      treatment, as it maximizes the lysis of exocrine cells without unnecessarily
      stressing (osmotically) the islet cells. The second set of experiments (time
      course experiments, 20 to 120 s) was designed to determine the length of exposure
      time for which the exocrine cells were irreversibly damaged but the islet cells
      had only swollen to such a degree that cell function is restored upon returning
      to an isotonic condition. Viability of the hypotonic treated cells was evaluated
      at two different levels: membrane integrity, measured by combined fluorescent dye
      staining with propidium iodide (PI) and carboxyfluorescein diacetate (CFDA), and
      mitochondrial function, measured by colorimetric MTT assay. The results showed
      that hypotonic treatment in a 50 mOsm/kg solution for 30 s resulted in over 85%
      loss of the membrane integrity for the exocrine cells. About 90% of these
      membrane lysed cells lost mitochondrial function (n = 3). By contrast, under the
      same treatment, less than 15% of the islet cells lost membrane integrity and
      mitochondrial function (n = 3). In conclusion, hypotonic treatment with a 50
      mOsm/kg solution for 20 to 30 s at room temperature is sufficient to lyse the
      majority of the contaminating exocrine cells in an islet cell preparation, while
      maintaining function in the islet cells.

PMID- 8665076
TI  - Induction of immunological tolerance to islet allografts.
AB  - T-cell dependent activation of resting B cells involves the interaction of gp39
      on T cells with its receptor, CD40, on B cells. We administered either a
      combination of T-cell-depleted splenic lymphocytes and anti-gp39 monoclonal
      antibody or antibody alone to establish islet allografts in mice without
      continuous immunosuppression. Fully allogeneic H-2q FVB islets were permanently
      accepted by chemically diabetic H-2b C57BL/6 mice provided that the recipients
      were pretreated with both T-cell-depleted donor spleen cells and anti-gp39
      antibody. Antibody alone was less effective in prolonging allograft survival, but
      we did observe that anti-gp39 mAb alone can exert an independent, primary effect
      on islet allograft survival that was dose dependent. Targeting gp39, in
      combination with lymphocyte transfusion, might prove suitable for tolerance
      induction and allotransplantation without immunosuppression.

PMID- 8665077
TI  - Indefinite survival of rat islet allografts following infusion of donor bone
      marrow without cytoablation.
AB  - We have tested the effect of donor bone marrow cell (DBMC) infusion on the
      survival of pancreatic islet allografts in the rat, without the use of
      cytoablative recipient conditioning. Lewis and diabetic Brown Norway rats were
      used as donors and recipients, respectively. Donor islets were placed beneath the
      left renal capsule. Infusion of DBMC and temporary immunosuppression followed by
      delayed islet transplantation resulted in indefinite survival of all islet grafts
      (MST > 180 days). Control animals demonstrated recurrent hyperglycemia (islet
      allografts rejection). Donor bone marrow derived cells were detected in the
      spleen and cervical lymph nodes of BN recipients of LEW bone marrow but not in
      the recipients of islet transplants alone. Second set full thickness skin grafts
      were performed in normal BN and in recipients of a previously successful ITX.
      Donor specific skin grafts were accepted in the animals that had received DBMC 40
      days before the islet allograft, while animals receiving DBMC at the time of the
      islet allograft rejected the donor specific skin graft similarly to the controls.
      However, these animals did not reject a second set donor-specific islet
      transplant. The results indicate that radiation conditioning of the recipients
      was not necessary to induce microchimerism and graft acceptance in this rodent
      model of islet allotransplantation.

PMID- 8665078
TI  - Genetically modified PC12 brain grafts: survivability and inducible nerve growth
      factor expression.
AB  - Neural transplantation of genetically modified cells has been successfully
      employed to reverse functional deficits in animal models of neurodegenerative
      disorders, including Parkinson's disease. While implanted PC12 cells secrete
      dopamine in vivo and can ameliorate dopamine deficiency in parkinsonian rat model
      systems, these cells either degenerate within 2-3 wk postimplantation (presumably
      due to the lack of neural trophic factor support at the site of implantation), or
      in some cases, form a tumor mass leading to the death of the host animal. To
      address these limitations, we have developed a genetically modified PC12 cell
      line that can synthesize nerve growth factor (NGF) under the control of a zinc
      inducible metallothionein promoter. When implanted in the rat striatum and under
      in vivo zinc stimulation, these cells will neuro-differentiate, express tyrosine
      hydroxylase, and will undergo survival through potential autocrine trophic
      support. This regulatable cell line and general approach may provide additional
      insight on the potential utilization of cell transplants for treatment of
      Parkinson's disease and other neurodegenerative disorders.

PMID- 8665079
TI  - Transplantation of human fetal tissue from spontaneous abortions to a rodent
      model of Parkinson's disease.
AB  - The use of human fetal tissue from elective abortions for cell transplantation
      therapies has been the subject of considerable controversy. Because of concerns
      regarding the use of tissue from elective abortions, tissue from spontaneous
      abortions has been suggested as an alternate donor source. In the present study
      we have evaluated human fetal tissue from spontaneous abortions to assess its
      viability, growth potential, and functional expression. Viable cells (Grade I)
      from a donor (7 wk postconception) were transplanted as a suspension into the
      striatum of rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. A
      second group of animals received solid grafts of tissue from a Grade I donor 14
      wk postconception. Tissue from Grade II and III specimens were not sufficiently
      viable for transplantation. Locomotor responses were monitored over a period of
      15 wk and revealed an amelioration of rotational asymmetry by animals that
      received tissue from the 7 wk donor. Animals receiving tissue from the 14 wk
      donor showed no functional improvement. We found numerous graft-derived tyrosine
      hydroxylase (TH) immunopositive neurons contained within the transplantation
      site, and a rich plexus of TH-immunopositive fibers extending into the striatum
      of animals receiving tissue from the 7 wk donor. Animals receiving tissue from
      the 14 wk donor exhibited tissue necrosis at the transplant site and were devoid
      of TH-immunopositive neurons. These results suggest that human fetal ventral
      mesencephalic cells from spontaneous abortions can survive and develop after
      transplantation, and rectify locomotor deficits associated with experimental
      parkinsonism if the donor tissue is of the appropriate gestational age at the
      time of implantation. Our study further suggests, however, that the availability
      of tissue from spontaneous abortions of sufficient viability is quite limited and
      may thus restrict its potential use in cell transplantation therapies for
      Parkinson's disease.

PMID- 8665082
TI  - Problems in the surveillance and control of viral diseases with special reference
      to the developing world.

PMID- 8665081
TI  - Venous reconstruction using hybrid vascular tissue composed of vascular cells and
      collagen: tissue regeneration process.
AB  - In this study, a tubular hybrid vascular tissue composed of vascular cells and
      collagen was implanted as a venous substitute, and its remodeling process was
      histologically investigated. First, a hybrid medial tissue was prepared by
      pouring a cold mixed solution of canine jugular smooth muscle cells (SMCs) and
      Type I collagen into a tubular glass mold and subsequent incubation at 37 degrees
      C. Culture in medium for 10 days produced a dense tubular tissue. Seeding of
      jugular endothelial cells (ECs) onto the luminal surface of the tissue produced a
      hybrid vascular tissue with a hierarchical structure. These vascular tissues
      (inner diameter, 7 mm; length, 3 cm; wall thickness, 1 mm; n = 14) were implanted
      autologously in the canine posterior vena cava wrapped in Dacron mesh for up to
      24 wk. Nine of 14 grafts were patent throughout implantation. In patent grafts,
      monolayered ECs were oriented in the direction of blood flow at 1 wk.
      Circumferentially oriented SMCs accumulated at the subendothelial layer and
      ingrown fibroblasts were sparsely distributed throughout the wall at 12 wk.
      Contractile phenotype of SMCs was evident at 24 wk. Collagen fibrils, which were
      sparsely distributed at an early period of implantation, gradually assembled to
      form fibrous meshes at 24 wk. Sheet-like elastic lamellae were also observed at
      this time. Marked wall thinning was observed at 12 and 24 wk. The resultant
      tissues became highly dense. The specific gravity of tissues increased with time,
      and reached those of natural vessels at 24 wk. Tissue remodeling progressed in a
      time-dependent manner and appeared to be almost complete within 6 mo of
      implantation.

PMID- 8665080
TI  - Arterial delivery of genetically labelled skeletal myoblasts to the murine heart:
      long-term survival and phenotypic modification of implanted myoblasts.
AB  - The ability to replace damaged myocardial tissue with new striated muscle would
      constitute a major advance in the treatment of diseases that irreversibly injure
      cardiac muscle cells. The creation of focal grafts of skeletal muscle has been
      reported following the intramural injection of skeletal myoblasts into both
      normal and injured myocardium. The goals of this study were to determine whether
      skeletal myoblast-derived cells can be engrafted into the murine heart following
      arterial delivery. The murine heart was seeded with genetically labeled C2C12
      myoblasts introduced into the arterial circulation of the heart via a
      transventricular injection. A transventricular injection provided access to the
      coronary and systemic circulations. Implanted cells were characterized using
      histochemical staining for beta-galactosidase, immunofluorescent staining for
      muscle-specific antigens, and electron microscopy. Initially the injected cells
      were observed entrapped in myocardial capillaries. One week after injection
      myoblasts were present in the myocardial interstitium and were largely absent
      from the myocardial capillary bed. Implanted cells underwent myogenic
      development, characterized by the expression of a fast-twitch skeletal muscle
      sarcoendoplasmic reticulum calcium ATPase (SERCA1) and formation of myofilaments.
      Four months following injection myoblast-derived cells began to express a slow
      twitch/cardiac protein, phospholamban, that is normally not expressed by C2C12
      cells in vitro. Most surprisingly, regions of close apposition between LacZ
      labeled cells and native cardiomyocytes contained structures that resembled
      desmosomes, fascia adherens junctions, and gap junctions. The cardiac gap
      junction protein, connexin43, was localized to some of the interfaces between
      implanted cells and cardiomyocytes. Collectively, these findings suggest that
      arterially delivered myoblasts can be engrafted into the heart, and that
      prolonged residence in the myocardium may alter the phenotype of these skeletal
      muscle-derived cells. Further studies are necessary to determine whether arterial
      delivery of skeletal myoblasts can be developed as treatment for myocardial
      dysfunction.

PMID- 8665083
TI  - 100th anniversary of virology.
AB  - A short review of the beginnings of virology is presented, when Beijerinck
      formulated his concept of a new category of disease agents in plants. With the
      discovery of similar etiologies in diseases of animals (foot-and-mouth disease)
      and humans (yellow fever), the universality of this concept emerged and the
      discipline of virology was born.

PMID- 8665084
TI  - Babesiosis: new insights from phylogenetic analysis.
AB  - Piroplasms of the genus Babesia, along with their relatives to the Theileridae,
      comprise a genetically and antigenically diverse group of tick-transmitted
      intraerythrocytic pathogens that together have considerable veterinary, medical,
      and economic importance. Since the first description of a human case of
      babesiosis in 1957, this zoonotic infection has now attained a worldwide
      distribution. In the northeastern and upper midwestern United States, the
      transmission cycle of Babesia microti overlaps that of another well-known
      zoonotic agent, Borrelia burgdorferi, the causative agent of Lyme disease.
      Phylogenetic analysis of Babesia and Babesia-like piroplasms from human and
      animal sources has shown that many of the small Babesia spp., including B.
      microti, B. equi, B. gibsoni, and a recently described piroplasm infectious for
      humans known as WA1, may be phylogenetically related to Theileria. Implications
      of this observation may include the possible existence of an exoerythrocytic
      stage of parasite development and attendant features of chronicity, immune
      suppression, and perhaps lymphoproliferation. In this review, we provide a brief
      summary of recent developments in the study of Babesia and related piroplasms and
      speculate on the ramifications of chronic babesial infection in humans.

PMID- 8665085
TI  - Preterm labor: emerging role of genital tract infections.
AB  - Preterm birth complicates 8-10% of all pregnancies in the United States and is
      the leading cause of infant morbidity and mortality. Neonatal morbidity and
      mortality is concentrated among very low-birthweight and extremely premature
      infants, particularly those delivered prior to 30 weeks' gestational age. In
      addition to the contribution of preterm birth to neonatal morbidity and
      mortality, the economic costs associated with this pregnancy complication are
      staggering. Efforts to reduce the preterm birth rate have been largely focused on
      prevention and early intervention with treatment for preterm labor. Mixed results
      regarding the success of prematurity prevention programs have been reported, and
      controversy continues to surround the efficacy of tocolytic therapy in the
      treatment of preterm labor. Although neonatal survival for infants born at early
      gestational ages has steadily improved in recent years, survival of infants
      delivered prior to 24 weeks' gestation remains very poor. Additionally, despite
      this decline in neonatal mortality, the United States still lags behind most
      industrialized nations in infant mortality, and no change in the rate of low
      birthweight has occurred in recent decades. Multiple lines of evidence support a
      role for infection as an etiologic factor in preterm labor. Although this
      association has been well known for many years, a wealth of new data is emerging,
      linking subclinical genital tract infection with spontaneous preterm birth,
      particularly among pregnancies that result in birth prior to 30 weeks'
      gestational age as a result of spontaneous preterm labor or preterm, premature
      rupture of membranes. Conversely, preterm birth that occurs closer to term is
      less likely to be associated with genital tract infection. Improved understanding
      of the link between genital tract infection and preterm birth now provides an
      exciting potential for the development of sensitive new markers to identify women
      at risk and effective interventions to prevent preterm birth. A review and
      comment on this growing literature is provided.

PMID- 8665086
TI  - Pathogenic potential of myeloblastosis-associated viruses.
AB  - Myeloblastosis-associated viruses (MAV) are replication competent avian
      retroviruses responsible for the induction of lymphoid leukosis, osteopetrosis,
      and nephroblastoma. Although both the route of infection and the strain of host
      used has been reported to be a critical factor in determining the outcome of
      viral infection, genetically distinct strains of MAV that exhibit a multiple
      pathogenic potential have been molcularly cloned. Osteopetrosis is a
      proliferative disease of the bones and nephroblastoma is a kidney cancer. Both
      diseases occur in chickens a few weeks after MAV injection. In both cases, the
      nature of the target cells and mechanisms of transformation induced by MAV remain
      to be established. Molecular cloning and sequencing of three MAV proviral genomes
      inducing both osteopetrosis and nephroblastoma or only nephroblastoma have
      allowed the identification of viral determinants essential for osteopetrosis
      induction. For the last decade we have focused our attention on the MAV-induced
      nephroblastoma because it is a unique animal model of the human Wilms' tumor.
      Studies that we have conducted to understand the molecular basis of MAV
      tumorigenic potential have led to the identification of viral sequences required
      for tumor induction and to the discovery of a new cellular gene (nov) likely to
      play a critical role in avian and human nephroblastoma development.

PMID- 8665087
TI  - Antifungal drug targets: Candida secreted aspartyl protease and fungal wall beta
      glucan synthesis.
AB  - The incidence of severe, life-threatening fungal infections has increased
      dramatically over the last decade. Unfortunately, in practice the arsenal of
      antifungal drugs is limited to flucytosine, a few approved azoles, and polyenes,
      mainly amphotericin B. This situation is rather precarious in view of the
      extended spectrum of fungi causing severe disease in immunocompromised patients,
      development of resistance to some of the currently used agents, and the minimal
      fungicidal activity of the azoles. Although lagging behind the need for new
      antifungal agents, the study of fungal biochemistry, physiology, and genetics has
      undergone a resurgence to new heights of activity, thus providing a framework on
      which to build drug discovery programs in several new areas, two of which will be
      discussed in detail: the biology of Candida albicans secreted aspartyl protease
      with respect to inhibitor discovery, evaluation, and possible clinical utility;
      and the fungal cell wall beta-glucans with respect to the mechanism and
      regulation of synthesis and target sites for drug inhibition.

PMID- 8665088
TI  - Nosocomial candidiasis: epidemiology and drug resistance.
AB  - The epidemiology of nosocomial Candida is complex. Molecular DNA analysis has
      provided useful information in the study of nosocomial infection. The most
      important inpatient hospital reservoir is colonized patients. Most patients are
      infected with strains they harbor. Findings from recent studies suggest that some
      nosocomial Candida colonization is the result of exogenous acquisition. Hospital
      personnel and the inanimate hospital environment may serve as reservoirs,
      reservoir and they may be sources of acquired strains. The mechanism by which
      patients acquire Candida remains unproven, but most authors agree that indirect
      contact transmission is the most likely route for exogenous nosocomial
      acquisition of strains. Environmental surfaces in contact with healthcare workers
      and/or patients should also be considered a source of some Candida organisms when
      infection control measures are designed. Antifungal drug resistance has not been
      responsible for the spread of isolates. Further prospective studies using DNA
      typing methods for analysis of cultures using control strains are needed to
      define more clearly the patient and hospital reservoirs of infection and the
      modes of transfer. With increasing knowledge of the epidemiology of nosocomial
      Candida, novel control strategies are needed.

PMID- 8665089
TI  - Battling against host phagocytes: the wherefore of the RTX family of toxins?
AB  - The RTX family of bacterial exotoxins is a group of related cytolytic proteins
      produced by a wide variety of gram-negative human and animal pathogens. While
      diverse in their associated diseases and in their target cell specificities,
      there remain several themes common to RTX toxins, including genetic organization,
      structural and functional features, and effects on target cells. In this review,
      we summarize and discuss the genetics, regulation, epidemiology,
      structure/function relationships, and in vivo and in vitro activities of the best
      characterized RTX toxins, and speculate on their roles in pathogenesis and their
      use in immunotherapy.

PMID- 8665090
TI  - Heterosexual HIV transmission.
AB  - Most of the people now living with HIV acquired the infection through
      heterosexual intercourse. HIV transmission has been facilitated by (a)
      concomitant sexually transmitted diseases (STDs), (b) the presence of social
      conditions that create core groups who have frequent and numerous partners, (c)
      sexual practices associated with bleeding (i.e., trauma, sex during menses) as
      well as noncircumcision, (d) cervical ectopy, and (e) anal sex. HIV may be found
      both cell-free and as intracellular virus in genital tract secretion, and may be
      sexually transmitted through either mechanism. HIV titers in genital tract
      secretions vary by several logs between people and within individuals over time,
      being greatest just after seroconversion and with advanced immunosuppression,
      concomitant genital tract inflammation (including STDs), and decreasing (but not
      to zero) with antiretroviral therapy. The per-contact transmission efficiency
      rate is highly variable, ranging from > 3% to < 1 per thousand contacts, with
      male-to-female HIV transmission generally being more efficient than vice versa.
      Control of the heterosexual HIV epidemic will necessitate a multidisciplinary
      approach, utilizing direct biological approaches (e.g., culturally specific and
      behavioral interventions, as well as more fundamental community changes that
      decrease societal norms that augment unsafe practices.

PMID- 8665091
TI  - Acetyl-CoA carboxylase in higher plants: most plants other than gramineae have
      both the prokaryotic and the eukaryotic forms of this enzyme.
AB  - The presence and the absence of a prokaryote type and a eukaryote type of acetyl
      CoA carboxylase (EC 6.4.1.2; ACCase) were examined in members of 28 plant
      families by two distinct methods: the detection of biotinylated subunits of
      ACCase with a streptavidin probe, and the detection of the accD gene, which
      encodes a subunit of the prokaryotic ACCase, by Southern hybridization analysis.
      The protein extracts of all the plants studied contained a biotinylated
      polypeptide of 220 kDa, which was probably the eukaryotic ACCase. All the plants
      but those belonging to Gramineae also contained a biotinylated polypeptide of ca.
      35 kDa, which is a putative subunit of the prokaryotic ACCase. In all plants but
      those in Gramineae, the ca. 35 kDa polypeptide was found in the protein extracts
      of plastids, while the 220 kDa polypeptide was absent from these plastid
      extracts. The plastid extracts of the plants in Gramineae contained the 220 kDa
      polypeptide, as did the homogenates of the leaves. Southern hybridization
      analysis demonstrated that all the plants but those in the Gramineae contained
      the accD gene. These findings suggest that most higher plants have the
      prokaryotic ACCase in the plastids and the eukaryotic ACCase in the cytosol. Only
      Gramineae plants might contain the eukaryotic ACCases both in the plastids and in
      the cytosol. The origin of the plastid-located eukaryotic ACCase in Gramineae is
      discussed as the first possible example of substitution of a plastid gene by a
      nuclear gene for a non-ribosomal component.

PMID- 8665092
TI  - Activation of 20S proteasomes from spinach leaves by fatty acids.
AB  - In order to clarify the mechanism of activation plant 20S proteasomes by fatty
      acids, we examined the effects of oleic, linoleic and linolenic acids on the
      three of peptidase activities of purified 20S proteasomes from spinach leaves and
      compared them with the effects of SDS, a previously characterized activator of
      20S proteasomes. The three fatty acids all activated the hydrolysis of succinyl
      Leu-Leu-Val-Tyr-4-methylcoumaryl-7-amide (Suc-LLVY-MCA) and benzyloxycarbonyl-Leu
      Leu-Glu-2-naphthyl-amide (Cbz-LLE-2NA) at low concentrations (one-third to one
      sixth of that required for activation by SDS). The range of concentrations of
      linolenic acid for the activation of Suc-LLVY-MCA hydrolysis was very narrow. All
      the fatty acids inhibited the hydrolysis of tert-butoxycarbonyl-Leu-Arg -Arg-4
      methylcoumaryl-7-amide (Boc-LRR-MCA) at extremely low concentrations (one-fifth
      to one-fifteenth of that required for the activation of the hydrolysis of Suc
      LLVY-MCA and Cbz-LLE-2NA). In the case of hydrolysis of Suc-LLVY-MCA, SDS and the
      three fatty acids increased the Vmax value and decreased the apparent Km value to
      similar relative extents. In the case of hydrolysis of Boc-LLE-MCA, SDS and the
      three fatty acids also decreased the Km and increased the Vmax. However, SDS
      markedly increased Vmax. the curves representing the SDS-dependent activation
      were shifted to a lower range by the addition of linoleic acid, but the maximum
      activity at the optimum concentration of SDS was essentially unchanged. These
      results suggest that the activation by SDS and that by the fatty acids has an
      additive effect. The results imply that fatty acids, such as linolenic acid,
      might act as physiological regulators in plant cells.

PMID- 8665093
TI  - Expression of the puf operon in an aerobic photosynthetic bacterium, Roseobacter
      denitrificans.
AB  - The effects of oxygen and light on the expression of the puf operon were
      investigated in Roseobacter denitrificans in a comparison with those in
      Rhodobacter sphaeroides. In darkness, the levels of the total puf mRNA in Ros.
      denitrificans were about 1.3 times those in Rb. sphaeroides at low concentrations
      of oxygen, reflecting the accumulation of bacteriochlorophyll and carotenoids.
      The oxygen tension, up to 94% saturation of dissolved oxygen, did not affect the
      levels of the total puf transcripts in Ros. denitrificans, whereas those in Rb.
      sphaeroides were reduced to 55% of the maximum level even at 50% saturation. Four
      puf-specific transcripts were detected: a 0.5-kb transcript was the most
      abundant; 1.2-kb and 1.9-kb transcripts accumulated at low levels; and a 3.5-kb
      transcript accumulated at very low levels under all conditions tested. The levels
      of the individual transcripts were barely affected by molecular oxygen. An S-1
      nuclease protection assay revealed that the 0.5-kb transcript encoded the LHI
      alpha and LHI-beta subunits (pufBA), the 1.2-kb transcript encoded puf-BA and
      part of pufL, and the 1.9-kb transcript encoded pufBAL and part of pufM. It was
      not clear whether the 3.5-kb transcript encoded the entire pufBALM and the gene
      for the polypeptide moiety of cytochrome c. The difference in levels between the
      0.5-kb transcript and the other transcripts (1.2 kb, 1.9 kb, and 3.5 kb) was
      presumed to be due to the presence of several stem-loop structures at the 3'
      terminus of the 0.5-kb transcript which acted as terminators of transcription
      and, possibly, as protection against nucleolytic digestion. Light inhibited the
      expression of the puf operon in Ros. denitrificans more effectively than that in
      Rb. sphaeroides. The insensitivity to oxygen, as well as the sensitivity to
      light, of the expression of the puf operon in Ros. denitrificans, which was
      different from that in Rb. sphaeroides, seemed to represent a mode of adaptation
      that allowed the former cells to avoid photodynamic damage by light under highly
      aerobic conditions.

PMID- 8665094
TI  - Genetic engineering of the processing site of D1 precursor protein of photosystem
      II reaction center in Chlamydomonas reinhardtii.
AB  - The D1 protein (D1) of photosystem II (PSII) reaction center is synthesized as a
      precursor (pD1) and then processed at its carboxyl terminus to establish the
      function of water cleavage. The amino acid sequence of the carboxyl terminal
      extension excised by this process is poorly conserved except for a residue after
      the cleavage site at position of 345. We have constructed a vector for site
      directed mutagenesis of the chloroplast psbA gene encoding D1 of the green alga,
      Chlamydomonas reinhardtii. The vector enables one to transform the chloroplasts
      of a psbA deletion mutant (Fud7) and directly select transformants for resistance
      to spectinomycin. Using this transforming vector, we have substituted Ser345 to
      Gly, Cys, Val and Phe in order to investigate effects of the amino acid side
      chain at this position on the processing rate. All of the resulting transformants
      exhibited the PSII activity as wild type and grew normally under photoautotrophic
      conditions even under strong light where rapid turnover of D1 protein is expected
      to occur. Western blotting analysis demonstrated that mature D1 accumulates in
      these transformants at wild type level. Pulse and chase labeling of chloroplast
      encoded proteins using [35S] sulfate revealed that the processing of D1 precursor
      protein occurs in all four transformants as efficiently as in wild type, at least
      under the experimental conditions examined. The results suggest that either the
      amino acid side chain at position of 345 (+1 position) is not crucial to the
      enzymatic cleavage of pD1 in vivo or the apparent rate of processing in vivo is
      not limited by the enzymatic cleavage.

PMID- 8665095
TI  - Seasonal variation of western white pine (Pinus monticola D. Don) foliage
      proteins.
AB  - Recently, a western white pine protein, Pin m III, was shown to be associated
      with overwintering and frost hardiness of western white pine foliage. To examine
      whether Pin m III is directly involved in frost hardiness by functioning as an
      antifreeze protein, work is underway to clone the gene encoding this protein and
      to assess the function of this gene in freezing tolerance by incorporating the
      gene in a test plant, such as tobacco. Here, we examined in more detail, by SDS
      PAGE and also by two dimensional gel electrophoresis, the seasonal variation of
      additional proteins in western pine foliage. SDS-PAGE analysis of three seedlots
      showed that different proteins reached a maximum level in different months,
      although most proteins (5 to 11) reached a maximum level in winter months
      (December, January and February). The 2-D gel analysis of foliage sampled on
      three harvest dates (October, January and April) of one seedlot revealed a
      seasonal variation of a large number proteins (76 to 184). Of the seasonally
      varied proteins, the amino terminal sequence of several proteins including Pin m
      III was determined. One of the sequences was identified by homology to that of
      the small subunit of ribulose biphosphate carboxylase, whose level increased
      substantially from fall to spring. The amino terminal sequence of Pin m III had
      89% homology to a sugar pine protein, Pin l I. The anti-photosystem II antibody
      was used to monitor the annual variation of the extrinsic 23-kDa photosystem II
      protein. The level of the extrinsic 23-kDa photosystem II protein decreased
      slowly as fall progressed and reached its lowest level in December and then
      increased in early spring indicating that this variation is due to photosynthetic
      activity of the foliage during the season.

PMID- 8665096
TI  - Structure and expression of two seed-specific cDNA clones encoding stearoyl-acyl
      carrier protein desaturase from sesame, Sesamum indicum L.
AB  - We have isolated two cDNA clones (CDES01) and 04) encoding stearoyl-acyl carrier
      protein desaturase (SACPD; EC 1.14.99.6) from immature sesame seeds, and have
      analyzed accumulation levels of the corresponding mRNAs at different stages and
      organs in sesame. Clone CDES01 contains an open reading frame coding for a 396
      amino acid protein of 45 kDa. CDES04 encodes a partial sequence of 141-amino
      acids. Deduced amino acid sequences of both clones exhibit a high identity to
      those of other plant SACPD cDNAs. Northern blots probed with CDES01 and CDES04
      indicate that both messages accumulate in a seed-specific manner with a peak at
      21 days after anthesis. However, expression patterns also indicate that
      regulation between CDES01 and CDES04 are slightly different. The CDES01 message
      accumulates at a low level in young leaves in addition to seeds, whereas
      accumulation of the RNA transcript corresponding to CDES04 is restricted to
      seeds. This observation implies the presence of at least two isozymes of SACPD
      having overlapping but slightly distinct functions in sesame.

PMID- 8665097
TI  - Molecular cloning and characterization of a cDNA for the beta subunit of a G
      protein from rice.
AB  - We isolated a cDNA for the beta subunit of a heterotrimeric G protein from rice
      (Oryza sativa L. cv. Nipponbare). The amino acid sequence deduced from the cDNA
      was 76% an 94% homologus to the sequences of the beta subunits from Arabidopsis
      and maize (AG beta 1 and ZG beta 1), respectively.

PMID- 8665098
TI  - Specific expression of the chloroplast gene for RNA polymerase (rpoB) at an early
      stage of leaf development in rice.
AB  - The rpoB gene for the beta subunit of rice chloroplast RNA polymerase was found
      to be highly expressed in unexpanded immature leaves that contained proplastids,
      indicating the specific expression of rpoB at an early stage of chloroplast
      development. A putative transcription start site (tss) was identified, but the 5'
      upstream region of the tss had no sequences resembling typical --35 and --10
      elements. A palindromic sequence and high AT-content were recognized.

PMID- 8665099
TI  - Structural and functional characterization of the intergenic spacer region of the
      rDNA in Daucus carota.
AB  - The intergenic spacer (IGS) region of rDNA in Daucus carota contains at least
      eight kinds of repeated sequence. One sequence may act as a genuine initiation
      site for a stable transcript and another may act as a spacer promoter that may be
      an entry site for proteins required for transcription.

PMID- 8665100
TI  - [Efforts to eradicate poliomyelitis in the Czech Republic].
AB  - The Czech Republic is one of the first countries where the paralytic form of
      poliomyelitis was eradicated by vaccination with the live attenuated vaccine. The
      effectiveness of vaccination was monitored every year up to 1992 by assessment of
      the immunity against polioviruses in a large group of sera from volunteers (cca
      1500 subjects). This made it possible to improve occasional drops of immunity of
      the population, in particular in type 3. However, the absence of the paralytic
      form of poliomyelitis does not imply eradication of poliomyelitis which means
      elimination of wild polioviruses from the circulation in the population of a
      country. The circulation of wild polioviruses is monitored in the Czech Republic
      in cases of acute mild pareses, in particular, however, in waste waters of some
      large towns. A wild poliovirus was not detected so far. These investigations must
      started and be conducted up to the time when the Czech Republic will be granted
      the status of "country with eradicated poliomyelitis".

PMID- 8665101
TI  - [The campaign against rabies--history and the present state].
AB  - Rabies is one of the oldest known infectious diseases and with regard to its
      present prevalence it still remains an important zoonosis. In the submitted paper
      the author presents data on the historical development of scientific findings on
      rabies, the important part played by Louis Pasteur and his pupils, the
      development of the position as regards rabies in the Czech Republic in the past
      and present time and the role of different animal species. At present we can
      define in Europe five basic ecological biovariants of rabies associated with
      specific vector animal species. The role of a dominant vector is held in this
      country by the fox. Anti-infectious provisions are concentrated mainly on the
      oral immunization of foxes, preventive immunization of domestic animals and
      therapeutic and prophylactic provisions in man. In antirabies prophylaxis highly
      immunogenic and safe tissue vaccines are preferred.

PMID- 8665103
TI  - [Taxonomy of the genus Acinetobacter].
AB  - In the last decade the taxonomy of the genus Acinetobacter showed important
      changes. Since 1986 several classification studies have been published dividing
      progressively the genus Acinetobacter, originally believed to include a single
      species, A. calcoaceticus, into 19 genomospecies. The following papers paid
      attention to practical possibilities of identification and to clinical importance
      of different species and genomospecies. In the last three years, interesting data
      on the distribution of different Acinetobacter species in the Czech Republic and
      on taxonomic position of the multiresistant strains and those isolated from
      nosocomial outbreaks have been gathered in our laboratory.

PMID- 8665102
TI  - [International cooperation on problems in acute respiratory viral infections].
AB  - The annual occurrence of acute respiratory infections (ARI) of viral origin incl.
      influenza, the serious character of influenza epidemics and pandemics were the
      reason why a network of 110 national influenza centres and four international
      collaborating centres were created. This worldwide surveillance programme is
      coordinated by WHO. With advancing integration of Europe scientific groups were
      created which implement this programme in Europe. EUROSENTINEL analyzes the
      notified morbidity from influenza and ARI in eight participating countries,
      EUROGEIG concentrates on the programme of influenza prevention and the
      preparation of anti-pandemic provisions, EUROGROG associates 27 National
      influenza centres which in the course of the season exchange information on the
      incidence of influenza and other respiratory viruses. ESWI (European Scientific
      Working Group on Influenza) organizes clinical and epidemiological investigations
      on the influence of influenza infection and the impact of anti-flu vaccination;
      it tries to harmonize the surveillance programme and raise its standard and
      strives for joint research projects. The National reference laboratory in Prague
      participates in all these programmes and takes also active part in some projects.

PMID- 8665104
TI  - [Comparison of the results of antibiotics sensitivity tests using the standard
      microdilution method on isolated bacteria and the direct disc method on positive
      hemocultures from the automatic BacT/Alert system].
AB  - During a six-month period 2,221 haemocultures obtained from patients hospitalized
      in the Faculty Hospital Olomouc were examined. In all 304 isolated bacteria the
      sensitivity was assessed by the standard dilution micromethod and moreover all
      positive haemocultures were examined the "direct" disc method. Agreement between
      the results of the two methods was proved in 84% of pairs of tests and within a
      range from 67 to 100%, depending on the type of antimicrobial preparation. Based
      on these findings it may be stated that assessment of the sensitivity by the
      "direct" method agrees significantly with assessment of the sensitivity according
      to minimal inhibitory concentrations (MIC). In patients with septicaemia this
      procedure makes it possible to change empirical antibiotherapy by 24 hours sooner
      to aimed therapy.

PMID- 8665105
TI  - [Public health care reforms achieved thus far].

PMID- 8665106
TI  - [The work of Louis Pasteur--inspiration and challenge].

PMID- 8665107
TI  - [The influence of L. Pasteur's ideas and approaches on Czech clinical
      microbiology].

PMID- 8665108
TI  - Resistance trained athletes using or not using anabolic steroids compared to
      runners: effects on cardiorespiratory variables, body composition, and plasma
      lipids.
AB  - OBJECTIVE: To determine whether there is a difference in cardiac size and
      function as well as in body composition, aerobic capacity, and blood lipids
      between resistance trained athletes who use anabolic steroids and those who do
      not, and to compare them to university cross country athletes. METHODS: Four
      groups of men were evaluated: recreational lifters, n = 11, lifting < 10 h.week
      1; heavy lifters, n = 16, lifting > 10 h.week-1; steroid users, n = 8, same as
      heavy lifters and used steroids; runners, n = 8, university track members.
      Echocardiograms, body composition (hydrostatic weighing), maximum oxygen
      consumption (Vo2), and lipids were studied. RESULTS: As expected, Vo2 (ml.kg
      1.min-1), was greatest in the runners, with no difference among the lifting
      groups. High density lipoprotein cholesterol in the steroid user group was lower
      than in heavy lifters or runners. Left ventricular internal diastolic dimension
      was similar among the groups. The left ventricular mass index of the steroid user
      group was significantly greater than recreational lifters, at 161 v 103. There
      was no difference among heavy lifters (127), runners (124), and steroid users.
      There was no compromise in diastolic function in any group. There were no
      differences among groups in resting or exercise blood pressure. CONCLUSIONS:
      Resistance training in the absence of steroid use results in the same positive
      effects on cardiac dimensions, diastolic function, and blood lipids as aerobic
      training.

PMID- 8665109
TI  - Evaluation of iron metabolism indices and their relation with physical work
      capacity in athletes.
AB  - OBJECTIVE: To evaluate the relation between iron status and physical working
      capacity, and to assess the effect of oral iron treatment on these variables, in
      athletes with borderline iron status. METHODS: Blood haemoglobin (Hb), packed
      cell volume (PCV), red blood cell count (RBC), serum iron, total iron binding
      capacity (TIBC), and ferritin determinations were compared in 71 male and 18
      female athletes participating in various sports and in matched male (n = 11) and
      female (n = 8) controls. The first aim was to assess the relations between these
      variables and performance in a physical work capacity test (PWC170). Oral iron
      treatment (175-350 mg ferrous fumarate daily) was provided for three weeks to six
      male and five female athletes with borderline Hb concentrations, to determine the
      effects of such treatment on both iron status and performance. RESULTS: Among
      females, handball players had the lowest serum ferritin concentrations (P <
      0.05), the highest TIBC values, and lowest PWC170 scores (P < 0.01); runners had
      the highest ferritin concentrations and PWC170 scores (P < 0.01). There were
      significant correlations (P < 0.01) between PWC170 and PCV, serum ferritin, and
      transferrin saturation of female athletes. Hb, serum iron, serum ferritin, and
      transferrin saturation increased with iron treatment in both males (P < 0.01) and
      females (P < 0.05). CONCLUSIONS: Serum ferritin determination may prove a
      valuable addition to the screening of athletes and may indicate the need for iron
      treatment, even though a causal effect on improvement of work capacity may not be
      present.

PMID- 8665110
TI  - The future of sports medicine.

PMID- 8665112
TI  - Water turnover rates in sedentary and exercising middle aged men.
AB  - OBJECTIVE: To assess the effect of exercise on water turnover in endurance
      trained middle aged men. METHODS: Water turnover was assessed using 2H2O as a
      tracer for water in six exercising and six sedentary middle aged men over seven
      consecutive days. The exercising subjects ran on average 14.8 km per day, while
      the sedentary group did not take part in any regular physical activity. RESULTS:
      The average median (range) rate of water turnover (ml.d-1) was higher in the
      exercising group [4673 (4320 to 9606)] than in the sedentary group [3256 (2055 to
      4185); P = 0.001]. Although there was a tendency for non-renal water losses (ml.d
      1) to be greater in the exercising group [1746 (1241 to 5196)] than in the
      sedentary group [1223 (1021 to 1950); P = 0.08], the major difference in water
      loss between the groups was the greater urine output (ml.d-1) in those who
      exercised [3021 (2484 to 4225)] compared to those who were sedentary [(1883 (925
      to 2266); P = 0.001]. CONCLUSIONS: The results suggest that fluid intake in
      middle aged men who exercise regularly must be greater than that of sedentary
      individuals of the same age group, and that the difference in volume is in excess
      of that required to replace exercise induced sweat and respiratory water losses.

PMID- 8665111
TI  - Use of radionuclide imaging to determine gastric emptying of carbohydrate
      solutions during exercise.
AB  - OBJECTIVE: To investigate the repeatability of continual assessment of the
      gastric emptying rates of carbohydrate solutions in exercising subjects using
      99mtechnetium labelling. METHODS: Gastric emptying of a 5% glucose solution and
      an iso-osmotic maltodextrin solution was measured using 3 MBq of 99mtechnetium
      labelled diethylene triamine penta-acetic acid (DTPA) and continuous gamma camera
      imaging in five male subjects. The subjects performed four 1 h trials at 70% VO2
      peak on a cycle ergometer. After 15 min, 200 ml of a radiolabelled solution of
      glucose or maltodextrin were ingested in a blind crossover protocol. The two
      solutions were each ingested on separate occasions (trial 1 and trial 2) to
      establish repeatability. RESULTS: Statistical analysis showed no differences
      between trial 1 and trial 2 for both solutions. There were no significant
      differences for the emptying rates between the two test solutions. CONCLUSIONS:
      Posterior imaging using a computer linked gamma camera following the ingestion of
      99mtechnetium labelled DTPA mixed with carbohydrate solutions provides a
      repeatable method of assessing gastric emptying characteristics in exercising
      subjects. This technique showed no significant differences between the emptying
      rates of a single dose of iso-osmotic glucose or maltodextrin solution.

PMID- 8665114
TI  - Sport and exercise medicine.

PMID- 8665113
TI  - Vibromyographic recording from human muscles with known fibre composition
      differences.
AB  - OBJECTIVE: To determine the relation between the vibromyographic (VMG) frequency
      characteristics and fibre composition in postural and non-postural human muscle
      undergoing a standardised voluntary contraction. METHODS: Two human muscles with
      different fibre compositions [soleus: postural, mainly type I (slow) fibres;
      biceps brachii: non-postural, mixed type I and II (fast) fibres] were recorded
      from 18 healthy males isometrically contracting at 50% of their maximum voluntary
      contraction (MVC). Muscle vibrations were recorded using a contact microphone and
      the frequency content of the signals calculated using fast fourier transform
      algorithms. RESULTS: The non-postural biceps brachii showed predominantly bimodal
      power spectra with significantly increased power in the 10-30 Hz bands (P <
      0.01), as compared with soleus recordings which tended to be unimodal, with the
      majority of power below 10 Hz. CONCLUSIONS: Muscles with a large proportion of
      type I fibres generate VMG signals which contain an increased percentage of low
      frequencies as compared to muscles with a mixed population of type I and type II
      fibres. The VMG appears to be generated, in part at least, by the mechanical
      twitching of motor units within the muscle; frequency domain analysis of this
      signal may provide a non-invasive measure of muscle fibre composition.

PMID- 8665115
TI  - Maternal rectal temperature and fetal heart rate responses to upright cycling in
      late pregnancy.
AB  - OBJECTIVE: To assess maternal rectal temperature and fetal heart rate responses
      to dynamic exercise. METHODS: 11 healthy women with low risk pregnancies
      completed three separate upright cycling tests at 34 to 37 weeks gestation: 15
      min at 62.5 W (mean maternal heart rate [MHR] 138 beats.min-1 (test A); 15 min at
      87.5 W (MHR 156 beats.min-1) (test B); and 30 min at 62.5 W (MHR 142 beats.min-1)
      (test C). Rectal temperature and fetal heart rate were measured. RESULTS: Mean
      temperature increase after tests B and C [by 0.4(SD 0.1) degrees C] was greater
      than after test A [0.2(0.1) degrees C] (P < 0.001). Fetal heart rate, measured in
      the recovery period immediately after exercise, increased significantly only
      after tests B and C (P < 0.01). Exercise related changes in temperature and fetal
      heart rate weakly correlated in tests B (P < 0.02) and C (P < 0.01). CONCLUSIONS:
      Temperature and fetal heart rate changes were more marked after higher intensity
      (test B) or longer duration exercise (test C) compared with moderate exercise,
      but none of the tests caused adverse fetal heart rate changes (decrease in
      accelerations, bradycardia, or decelerations) or individual temperatures above 38
      degrees C.

PMID- 8665116
TI  - Effect of low dose oral contraceptives on exercise performance.
AB  - OBJECTIVE: to examine the effect of cycle phase or a low dose oral contraceptive
      on exercise performance in young women. METHODS: As controls, 15 men were tested
      twice by a maximal treadmill test (Vo2 max) and by an endurance run 14 d apart to
      determine performance variability from causes other than hormonal fluctuations.
      Ten women ages 18-30 were then tested for Vo2 max and endurance in the same way
      in both the follicular and the luteal phase (random order, ovulation assessed by
      sonography). They were then randomly assigned to placebo (n = 3) or oral
      contraceptive (1 mg norethindrone and 35 micrograms ethinyl oestradiol) (n = 7)
      for 21 days. Tests were repeated during the first and third weeks of treatment.
      Vo2 max and endurance tests were compared in the men and control cycle of the
      women by using independent t tests on percent change. The data for both cycles in
      the women were analysed by repeated measures ANOVA. RESULTS: There was no
      difference in per cent change in total test time, Vo2 max, or breathing frequency
      between the men and women in either test. Data obtained during the Vo2 max test
      revealed no difference between the follicular and luteal phases of the menstrual
      cycle for total test time [11.8 (SD 2.3) v 12.6 (2.3) min], Vo2 [41.6 (12.1) v
      39.7 (11.4) ml.kg-1.min-1], or breathing frequency [26.8 (3.5) v 27.3 (9.9)
      breaths.min-1] respectively, or during the first and third weeks of treatment
      [total test time 12.0 (2.5) v 12.8 (2.4) min; Vo2 37.3 (7.4) v 41.0 (12.4) ml.kg
      1.min-1; breathing frequency 27.8 (4.2) v 27.7 (3.4) breaths.min-1,
      respectively]. Data obtained during the endurance test revealed no difference
      between the follicular and luteal phase of the menstrual cycle for total test
      time [20.5 (15.7) v 16.2 (8.5) min], Vo2 [37.5 (9.4) v 32.9 (8.1) ml.kg-1.min-1],
      or breathing frequency [32.0 (6.0) v 33.2 (5.1) breaths.min-1, respectively], or
      during the first and third weeks of treatment [total test time 32.3 (34.9) v 30.6
      (30.1) min; Vo2 33.9 (10.1) v 35.2 (8.6) ml.kg-1.min-1; breathing frequency 34.0
      (5.9) v 34.8 (5.3) breaths.min-1, respectively]. CONCLUSIONS: Neither cycle phase
      nor a low dose oral contraceptive containing 1 mg norethindrone adversely affects
      performance during a maximal treadmill test or endurance run.

PMID- 8665117
TI  - Influence of menstrual status on fluid replacement after exercise induced
      dehydration in healthy young women.
AB  - OBJECTIVE: To determine whether fluid replacement after exercise induced
      dehydration varies over the normal menstrual cycle. METHODS: Five subjects, with
      a regular menstrual cycle lasting 28 (SEM 2) d, were dehydrated by 1.8(0.1)% of
      their pre-exercise mass by cycle exercise in the heat. Trials were undertaken 2 d
      before (trial -2) and 5 and 19 d after the onset of menses (trials 6 and 20
      respectively). After exercise, subjects ingested a fixed volume, equivalent to
      150% of mass loss, of a commercially available sports drink over a 60 min period.
      RESULTS: Cumulative urine output [median (range)] over the 6 h following
      ingestion was the same on all trials: 714(469-750) ml on trial -2; 476(433-639)
      ml on trial 6; 534(195-852) ml on trial 20. There was no menstrual cycle effect
      on urinary electrolyte (Na+, K+, Cl-) excretion or serum electrolyte (Na+, K+, Cl
      ) concentrations. Plasma volume increased by 8-12% of the postexercise value
      following rehydration. The percentage of ingested fluid retained did not differ
      between trials at any time. Six hours after drink ingestion, net fluid balance
      was not different from the initial value on any of the trials. CONCLUSIONS: Acute
      replacement of exercise induced fluid losses is not affected by the normal
      menstrual cycle.

PMID- 8665118
TI  - Postexercise heart rates and pulse palpation as a means of determining exercising
      intensity in an aerobic dance class.
AB  - OBJECTIVE: To establish the accuracy of the traditional method of measuring the
      intensity of exercise in aerobic dance classes, that is, intermittent pulse
      palpation performed during a brief cessation of activity. METHODS: A short wave
      telemetry system was used to record heart rates during a class in a group of 12
      healthy women aged 26 (SD 6) years. Subjects palpated their pulses for 10 s
      following high and low intensity exercise [78(8)% and 69(9)% of mean predicted
      maximum heart rate respectively]. Recorded exercising heart rates, averaged over
      60 s preceding pulse palpation [ExHR(rec)], were compared with the recorded
      postexercise heart rates averaged over the 10 s palpation period [PostExHR(rec)]
      and with the palpated counts (PalpHR). Differences were assessed using Student's
      t test and Wilcoxon signed rank test. RESULTS: Differences between ExHR(rec) and
      PostExHR(rec) following high and low intensity exercise [3(6) beats.min-1 and
      5(7) beats.min-1 respectively] were not significant. However, the wide variation
      between subjects means that a postexercise heart rate is unreliable as a measure
      of individual exercise intensity. PalpHR was significantly lower than ExHR(rec)
      (P < 0.01). Every individually palpated count underestimated the exercising heart
      rate (range 9 to 95 beats.min-1). CONCLUSIONS: While postexercise heart rate
      adequately represents the exercise heart rate for a group, the individual
      variation is too wide for this to be a useful measurement.

PMID- 8665119
TI  - The athlete's heart: is big beautiful?
AB  - Development of the concept of "athlete's heart" is traced through early clinical
      and radiographic studies to modern echocardiography and magnetic resonance
      imaging. It is noted that the lower limits of criteria for the diagnosis of a
      "pathological" enlargement of the heart have frequently been revised in an upward
      direction, as the prevalence of large hearts has been recognised in both
      endurance and power sports competitors who are in good health. Belief that
      hypertrophic cardiomyopathy is the commonest cause of sports related death in
      young adults is traced to weak diagnostic criteria and frequent republication of
      a very small group of cases. Although the existence of a congenital myocardial
      dystrophy is now well established, this condition is extremely rare, and has no
      particular predilection for athletes. Genetically based screening tests may
      become available in the future, but the exclusion of young adults from sports
      participation on echocardiographic criteria appears costly and ineffective. For
      most people, the development of a large heart is not a pathological sign--rather,
      it is a desirable outcome that will enhance performance on the sports field, and
      will allow longer independence in old age.

PMID- 8665121
TI  - Thermal pants may reduce the risk of recurrent hamstring injuries in rugby
      players.
AB  - OBJECTIVE: To determine whether the use of thermal pants might reduce the risk of
      hamstring injury in rugby players. METHODS: 44 male rugby players from the Cape
      Province, South Africa, who had previously suffered a hamstring injury were given
      the choice of wearing thermal warming pants or not, and were then monitored for
      the development of hamstring injuries during the 1992 season. RESULTS: In the
      group who wore warmers some of the time, the injury rate was significantly lower
      when using the warmers (3 injuries/1000 playing hours) than when not (57/1000
      playing hours). There was no difference in injury rates between groups who either
      wore warmers all the time or none of the time, probably because the number who
      wore the warmers all the time was small (n = 5). Eighteen percent of the injuries
      recurred at exactly the same site in the muscle and within 12 d of returning to
      rugby after the initial injury. The incidence of injury was high in the first
      three weeks of the season and again in the same period after the mid-season
      break. More than 80% of all match and practice time lost by these players during
      the study was a direct result of their hamstring injuries. CONCLUSIONS: Thermal
      pants may have a role in preventing recurrent hamstring injuries but other
      factors such as inadequate preseason training and incomplete rehabilitation after
      injury are likely to be more significant risk factors for injury.

PMID- 8665120
TI  - The New Zealand rugby injury and performance project. IV. Anthropometric and
      physical performance comparisons between positional categories of senior A rugby
      players.
AB  - OBJECTIVE: To describe the anthropometric and physical performance
      characteristics of a sample of senior A club rugby players and to highlight
      differences between the positional categories of the players within the forwards
      and backs. METHODS: 94 senior A male rugby players were assessed on a number of
      anthropometric and physical performance assessments. The forwards were
      categorised into props, hookers, locks, and loose forwards. Backs were
      categorised into inside, midfield, and outside backs. Categories within the
      forwards were compared with each other, as were the categories within the backs.
      RESULTS: The anthropometric characteristics of forwards differed significantly
      between positional categories. Front row forwards (props and hookers) possessed
      highly endo-mesomorphic somatotypes, and typically rated very low for ectomorphy.
      Props possessed greater body mass than hookers. Locks and loose forwards were
      taller than the front row forwards. In terms of physical performance fewer
      differences were observed. Hookers performed better than props on an aerobic
      assessment. Locks and loose forwards were faster than the front row forwards on a
      30 m sprint from a running start. The inside backs were shorter and lighter than
      the midfield and outside backs. CONCLUSIONS: The combination of anthropometric
      characteristics and physical performance attributes observed allows players to
      best meet the demands imposed on them by their position.

PMID- 8665122
TI  - Injury surveillance in a rugby tournament.
AB  - OBJECTIVE: To investigate injuries in international rugby football. METHODS: All
      injuries that led to temporary stoppage of the game or to the substitution of a
      player during the Rugby World Cup prequalifying tournament were recorded. Six
      matches were played, involving the Arabian Gulf, Kenya, Namibia, and Zimbabwe.
      RESULTS: 47 injuries were recorded, giving an injury rate of eight per match. The
      number of injuries decreased from 38.3% in the first matches to 23.4% in the
      final ones. The most serious injury was a concussion and the majority of the
      injuries affected soft tissues. Anatomically, the lower limbs suffered most
      injuries (46.8%), followed by the head (21.3%), trunk (17.0%), and upper limbs
      (12.8%). Slightly more injuries occurred in the defensive half of the field of
      play (53.2%) than in the offensive half (46.8%). More injuries occurred in the
      second half (61.7%) than in the first half (38.3%). CONCLUSIONS: Protective
      equipment should be introduced to minimise the number and seriousness of injuries
      in rugby.

PMID- 8665123
TI  - The Harstad injury prevention study: the epidemiology of sports injuries. An 8
      year study.
AB  - OBJECTIVE: To describe the epidemiology of sports injuries occurring in a
      community during 8 years and to evaluate the outcome of an intervention
      implemented against injuries occurring in downhill skiing. METHODS: Hospital
      treated sports injuries occurring in Harstad, Norway (population 22 600) were
      recorded prospectively during an 8 year period. A prevention programme targeting
      downhill skiing injuries was evaluated. RESULTS: 2234 sports injuries accounted
      for 17.2% of recorded unintentional injuries. Two out of three injuries occurred
      in team sports. Soccer accounted for 44.8% of all sports injuries. Downhill
      skiing injuries had higher mean score on the abbreviated injury scale than all
      other sports analysed combined (P < 0.01). Postintervention injury rates for
      downhill skiing were reduced by 15% when adjusting for exposure (P = 0.24).
      Further observations are needed for assessing the effectiveness of the downhill
      skiing safety programme. CONCLUSIONS: Strategies for future sports injury
      prevention include community involvement, particularly sports organisations.
      Local data analysis seems to justify some priorities, for example, promotion of
      helmet use in downhill skiing for young adolescents and prevention of lower limb
      fractures in male soccer players 15+ years old. Prospective hospital recording of
      injuries provides a tool for the design and outcome evaluation of sports injury
      intervention research.

PMID- 8665124
TI  - Three cases of nalbuphine hydrochloride dependence associated with anabolic
      steroid use.
AB  - Three case reports are presented of nalbuphine hydrochloride dependence meeting
      DSM IIIR and ICD10 criteria for opioid dependence. Nalbuphine hydrochloride is
      being obtained from illicit sources and used by those using performance enhancing
      drugs. In some cases this leads to opioid dependence. There is a potential risks
      of crossover between the misuse of drugs of performance and the misuse of
      psychoactive drugs by injection. Further research into the dependence potential
      of nalbuphine and the extent of the crossover between steroid misuse and other
      psychoactive drug misuse is required. The legal status of nalbuphine should be
      reviewed in the light of its availability on the black market.

PMID- 8665125
TI  - Posterior sternoclavicular dislocation: an American football injury.
AB  - Posterior dislocation of the sternoclavicular joint is uncommon, accounting for
      less than 0.1% of all dislocations. Since 1824 a little more than 100 cases have
      been reported, and the majority in the past 20 years. A review of published
      reports suggests that this injury is seen particularly in connection with
      American football. A typical case is described. The importance of this injury is
      that there is often a delay in diagnosis with potentially serious complications.

PMID- 8665126
TI  - Complete avulsion of the hamstring tendons from the ischial tuberosity. A report
      of two cases sustained in judo.
AB  - Rupture of the hamstring tendon is a rare injury. Two cases of complete rupture
      of the hamstring tendons sustained while playing judo are reported. The diagnosis
      of a rupture of the hamstring tendons was difficult from physical examination
      because of severe pain on knee or hip joint movement. Magnetic resonance imaging
      was non-invasive and showed the lesion clearly. In one of these two cases the
      less satisfactory results of non-operative treatment were clearly shown in both
      isokinetic muscle force evaluation and sports activities.

PMID- 8665127
TI  - Embolization for ruptured superior mesenteric artery aneurysms.
AB  - Superior mesenteric artery (SMA) aneurysms are very uncommon. They are difficult
      to detect until they rupture and cause hypovolaemic shock. We performed
      embolization in four cases of aneurysm of branches of the superior mesenteric
      artery, succeeding in three cases without the need for surgical treatment. In the
      first case, the aneurysm was excised because of migration of a microcoil into the
      left hepatic artery. It was not retrieved because sufficient blood flow to the
      liver was shown on angiography after migration and no ischaemic change of liver
      was detected on laparotomy. In the second case, the aneurysm arose from the
      anterior pancreaticoduodenal artery. In the third case, the patient had two SMA
      aneurysms; one had been resected at surgery, another was revealed on follow-up
      angiography and embolized with microcoils. The fourth patient had a jejunal
      artery aneurysm with extravasation; haemostasis was achieved by packing it. In
      all four cases, no major complications were observed in the clinical course after
      embolization. Microcoils were considered to be the desirable embolic material, in
      order to prevent post-therapeutic ischaemic change. Embolization should be the
      treatment of choice for SMA aneurysms, because it is less invasive and takes less
      time than surgical treatment.

PMID- 8665129
TI  - Consistency of film optical density in mammographic screening programmes.
AB  - Maintaining a constant and appropriate mean film optical density in mammography
      is an essential part of quality assurance in a breast screening programme. It
      depends on stability in X-ray exposure controls, film supplies, intensifying
      screens and film processing. A programme of weekly monitoring is described which
      helps to trace the source of any irregular or step-wise changes in any of the
      relevant parameters. Its results are also used to investigate by statistical
      methods the degree of film optical density variation achieved in periods of
      several weeks of apparent general stability. Results are presented for 20 X-ray
      sets and a total of 32 record periods of 8-10 weeks each. The mean standard
      deviation for density of a single film of a Perspex block was found to be 3.5%.
      For processor speed index it was the same while for X-ray set variations it was
      less than 2%. Neither of these last two variables showed any strong correlation
      with block film optical density.

PMID- 8665128
TI  - Computerized planimetry in the objective assessment of the antispasmodic effect
      of Zamifenacin in double contrast barium enemas.
AB  - A prospective, randomized, double-blind study was undertaken to evaluate
      Zamifenacin 30 mg (Pfizer Ltd), a novel, orally-administered, gut-specific
      muscarinic receptor antagonist, as an adjuvant to the double contrast barium
      enema examination (DCBE). Zamifenacin was compared with placebo in terms of side
      effects and colonic tone. Analysis of colonic tone was carried out by two
      independent observers, using a subjective grading system and also by an objective
      method using computerized planimetry. Interobserver variability was also
      assessed. Zamifenacin is safe and well tolerated but at the prescribed dose is an
      ineffective antispasmodic for DCBE. Subjective assessment of colonic tone was
      shown to be of limited value whilst the objective analysis using computerized
      planimetry was reliable and highly reproducible.

PMID- 8665130
TI  - A study of dose reduction using digital luminescence radiography for lateral
      skull radiography.
AB  - For lateral skull radiography the minimum required radiation patient exposure to
      ensure adequate image quality was determined for digital luminescence radiography
      (DLR) in comparison with a screen-film system (speed class 200). Radiographs were
      produced with a grid technique on conventional X-ray equipment. A real prepared
      female head including a true fracture above the pars petrosa ossis temporalis was
      imaged. The tube current-time product (mAs), and thus the surface entrance dose,
      was varied systematically. Surface entrance dose was measured with TLD-100 rods.
      Image quality was judged by experienced radiologists according to the criteria:
      visual resolution, mean optical density, contrast and perceptibility of specific
      bone structures. Surface entrance dose was reduced from 0.46 to 0.20 mGy by
      application of DLR instead of speed class 200 screen-film system without loss of
      diagnostic information in clinical routine. This corresponds to a dose reduction
      potential of 57% showing a good agreement with the dose reduction potential of
      52% obtained in a previous study using the Alderson head phantom.

PMID- 8665131
TI  - Dose-area product measurements in paediatric radiography.
AB  - The dose-area product (DAP) could provide a useful quantity for monitoring doses
      for paediatric radiography, because it is a sensitive parameter, which is simple
      to record. A study of DAP measurements has been carried out for single
      radiographic projections for paediatric patients and comparisons made with
      measurements of entrance dose. The technique has been used to investigate doses
      for examinations performed with and without a grid. There is a linear
      relationship between DAP and entrance dose, with a variation of +/- 20% for
      pelvis, abdomen, spine and skull radiographs, but data for chests are more
      scattered. Logarithm of the DAP is linearly related to an equivalent patient
      diameter and reference levels could be set in terms of DAP either by patient age
      range or size. Effective doses determined from DAPs were 0.1-0.3 mSv for abdomen,
      pelvis and spine anteroposterior radiographs for 5-15 year olds, and less than
      0.03 mSv for 0 and 1 year olds. Doses for examinations performed without a grid
      were only 20% of those for which a grid was used in the X-ray room studied.
      Significant reductions in doses for paediatric radiology can be achieved, where
      the use of grids can be avoided.

PMID- 8665133
TI  - Radiological assessment of a new bone densitometer--the Lunar EXPERT.
AB  - Dual energy X-ray absorptiometry (DXA) is one of the most widely used techniques
      in the management of osteoporosis and other skeletal diseases. Although patient
      doses from DXA are generally low, it is still necessary to measure them to assess
      the risk of radiation injury. We report on a study to estimate the effective dose
      (ED) to patients and staff from a new DXA scanner--the Lunar EXPERT, and make a
      comparison with a similar study carried out on a Lunar DPX-L. The entrance
      surface doses were measured to be 895 microGy and 10.25 microGy for the EXPERT
      and DPX-L, respectively. The EXPERT maximum EDs were calculated to be 74.7
      microSv and 44.9 microSv for the anteroposterior (AP) lumbar spine and the
      proximal femur, respectively. More than 50% reduction in ED could be achieved by
      using a smaller scanning width. The maximum EDs for the DPX-L were calculated to
      be 0.21 microSv and 0.15 microSv for the AP lumbar spine and the proximal femur,
      respectively. The scattered dose rates (ambient dose equivalent) were measured to
      be less than 2 and less than 1 microSv h-1 at 50 cm and 100 cm, respectively, for
      the DPX-L, and the equivalent values for the EXPERT were 240 and 64 microSv h-1.
      Although both the patient dose and scattered dose rates are quite low relative to
      other radiological examinations, good practice aimed at dose reduction should
      still be implemented. Whilst protection for the operator is not needed for the
      DPX-L system, it may be (depending on the size of the room) for the EXPERT
      system.

PMID- 8665132
TI  - Microcalcification clustering parameters in breast disease: a morphometric
      analysis of radiographs of excision specimens.
AB  - X-ray microradiography of surgically excised breast specimens offers the
      possibility of morphological characterization of calcifications. When combined
      with digital imaging techniques there exists added potential for obtaining
      valuable basic quantitative morphometric information regarding differences
      between microcalcifications in tissues exhibiting evidence of fibrocystic change,
      benign and malignant tumours. A total of 157 excised breast specimens from 84
      patients were microradiographed using a Softex Super Soft X-ray unit and Kodak AA
      high resolution industrial film. A Quantimet 570C image analysis system was used
      to digitize and analyse the microradiographs. Of the 157 microradiographs, 51
      (from 30 patients) revealed microcalcification clusters. The existence of
      significant differences between the three identified categories of tissue were
      indicated by clustering parameters. These included the number of particles per
      cluster, area of clusters, maximum distance to nearest neighbour, and geometric
      mean distance to nearest neighbour. The distribution pattern index (DPI), another
      of the clustering parameters used in this study, has been observed to be a
      particularly powerful discriminator. The value for fibrocystic change was found
      to be significantly smaller (0.514) than that for benign tumour (0.796) whilst
      that for benign tumour was observed to be significantly larger than that for
      malignant tumour (0.604) at a p-value of less than 0.05 (Kruskal-Wallis one-way
      analysis of variance).

PMID- 8665135
TI  - Short communication: oesophageal tumour volume measurement using spiral CT.
AB  - A CT technique for measuring oesophageal cancer tumour volume in the monitoring
      of local disease response following radiotherapy or chemotherapy is described.
      Patients with newly diagnosed oesophageal carcinoma were referred for pre- and
      post-chemotherapy CT scans. IV Buscopan was given to abolish peristalsis.
      Patients were scanned in prone position. Effervescent gas granules and Calogen (a
      negative contrast of fat density) were given. Spiral scanning was performed. The
      area of tumour on each 1 cm slice was measured. The sum of these areas gave
      tumour volume in cubic centimetres. The accuracy of the method was tested on
      patients who had had surgery. The volume of the segment of oesophagus containing
      tumour was measured by its weight and water displacement. Lumenal distention
      proximal and distal to the tumour was achieved in all patients. 10 gross surgical
      specimens were available for comparison with pre-operative CT. The correlation
      coefficient was 0.95. In conclusion, accurate tumour volume assessment was
      achieved with our technique.

PMID- 8665136
TI  - Short communication: A method of brachytherapeutic treatment of tracheal stoma
      recurrence in head and neck cancer.
AB  - Tracheal stoma recurrence after external beam irradiation in patients with
      laryngeal carcinoma is a serious complication. Treatment can often only be of a
      symptomatic nature. A simple method of brachytherapeutic treatment is described,
      consisting of a special flab applicator combined with a tracheostomal tube. The
      presented applicator system is suitable for treatment of the tracheostomal
      recurrence as well as the surrounding skin. It can be applied easily and is well
      tolerated by the patient, while at the same time achieving a good palliative
      effect.

PMID- 8665134
TI  - Short communication: Prospective assessment of a new graduated hookwire for the
      localization of impalpable breast lesions.
AB  - The benefits of the addition of site specific variable graduations to a
      conventional mammographic localizing wire were assessed in a prospective
      multidistrict study. Six surgeons and five radiologists localized lesions in 31
      patients in three District General Hospitals. The advantages of the graduated
      wire were shown to be greater ease and accuracy of radiological localization with
      easier surgical excision and a smaller resected breast specimen.

PMID- 8665137
TI  - Short communication: Total craniofacial photon shell technique for radiotherapy
      of extensive angiosarcomas of the head.
AB  - Effective radiotherapy for extensive angiosarcomas of the face and scalp is
      technically difficult due to the complex shape of the volume at risk, which can
      consist of the superficial tissues of the entire head. This work reports the
      details of a rotational X-ray technique used to deliver a large part of the
      tumour dose. The technique consists of four consecutive 90 degree arcs with
      changing centre blocks to protect critical midline structures. Multilevel CT
      based treatment planning is carried out to determine the centre block dimensions
      and beam weights. As a result the radiation dose is delivered with acceptable
      uniformity over the entire shell of superficial tissues of the head. The overall
      treatment combines the rotational fields with large lateral field irradiation
      and/or local boosts with photons or electrons. Two of three patients treated with
      this technique had local control of the disease until their deaths at 13 and 18
      months. A third patient responded well, with only a small region of stable
      disease at 9 months.

PMID- 8665138
TI  - Case report: Phrenic artery injury--a rare complication of percutaneous needle
      lung biopsy.
AB  - The phrenic artery is a small vessel that is not often visualized on CT and is at
      risk of injury during biopsy of low lung lesions. This may result in
      haemoperitoneum that will not be evident on post-biopsy chest X-rays. We present
      a patient with a bleeding tendency who had this unusual complication following a
      needle aspiration lung biopsy.

PMID- 8665139
TI  - Case report: Renal pseudotumours mimicking tumour recurrence after partial
      nephrectomy.
AB  - Partial nephrectomy and tumour enucleation are increasingly accepted as an organ
      sparing approach for small renal cell carcinomas. Repeated computed tomography or
      sonography for the early detection of tumour recurrence are mandatory during the
      follow-up. We report two cases of renal pseudotumour mimicking a tumour
      recurrence: one case is related to the pseudotumoral appearance on sonography of
      a tumour defect filled by a fatty flap, and the other to the relative migration
      of an accessory spleen into the site of the cuneiform nephrectomy. The
      recognition of renal pseudotumours following partial nephrectomy prevents
      confusion with tumour recurrence on follow-up examinations.

PMID- 8665140
TI  - Case report: Acute haemorrhagic presentation of trigeminal neuroma.
AB  - The acute presentation of trigeminal neuroma, due to sudden haemorrhage, in a 26
      year-old Chinese man, is described. The clinical, CT and MRI features are
      reviewed together with the other four cases reported in the literature.

PMID- 8665141
TI  - Case report: A rapidly expanding testicular mass due to a ruptured ovarian
      follicle.
AB  - An ovotestis is the commonest gonad in the small number of patients who are true
      hermaphrodites. In the majority of ovotestes, testicular and ovarian tissue is
      arranged end-to-end. There has been only one previous report of the sonographic
      appearances of an ovotestis. We present the sonographic findings in a patient who
      developed a rapidly enlarging upper pole testicular mass, which was found on
      histology to be a ruptured ovarian follicle with spermatogenesis occurring within
      the adjacent testicular tissue.

PMID- 8665142
TI  - Case report: Pontine haemorrhage following iohexol lumbar myelography.
AB  - A case of pontine haemorrhage following lumbar myelography using iohexol is
      described. Stress, inducing transient hypertension during the procedure, with
      superimposed neurotoxicity from contrast medium (iohexol) is suggested as a
      possible mechanism. No brain stem lesion was seen on the initial brain CT scan,
      possibly because of the high attenuation of the contrast medium in the
      subarachnoid space. A delayed CT brain scan demonstrated the pontine haemorrhage
      and was necessary to confirm the diagnosis.

PMID- 8665143
TI  - Case of the month: Calcified leg.

PMID- 8665144
TI  - Dual compression mammography using computed radiography.

PMID- 8665145
TI  - Modulation of normal tissue responses to radiation.

PMID- 8665146
TI  - Comparative study of the role of professional versus semiprofessional or
      nonprofessional antigen presenting cells in the rejection of vascularized organ
      allografts.
AB  - The immune systems of transplant recipients are progressively challenged with
      exposure to the multiple lineages of donor cells that comprise the vascularized
      organ allograft. Each lineage of such donor tissue constitutively expresses or
      can be induced to express varying densities of MHC antigens ranging from no
      expression of MHC to MHC class I only to both MHC class I and class II. In
      addition, the cell surface expression of a diverse assortment of costimulatory
      and cell adhesion molecules also varies in density in a tissue specific fashion
      within the allograft. The MHC class I/II molecules displayed on the donor cells
      contain within their clefts a constellation of processed protein antigens in the
      form of peptides derived from intracellular and to some extent extracellular
      sources. Therefore, the potential for each cell lineage to induce alloactivation
      and serve as a target for allospecific immune responses is dependent on the
      diversity and density of peptide-bearing MHC molecules, costimulatory molecules,
      and cell adhesion molecules. In addition, the T cell receptor repertoire of the
      recipient also contributes to the magnitude of the allogeneic response.
      Consequently, the variety of clinical outcomes following organ transplantation
      even with the institution of potent immunosuppressive (drug) therapies is not
      surprising, as it appears reasonable for such therapies to influence the
      allogeneic response against distinct lineages differentially. Our failure to
      prevent chronic human allograft rejection may therefore be due to our limited
      appreciation of the full spectrum of alloactivating experiences encountered by
      host T cells as they interact with donor cells of diverse tissue lineages.
      Investigations by our laboratory of the immunopathogenesis of chronic cardiac
      allograft rejection have revealed an intrinsic inability of human cardiac
      myocytes to process and present antigens, not only for primary but also for
      secondary alloimmune responses. One obvious explanation for this phenomenon is
      the fact that cardiac myocytes do not constitutively express MHC class II
      molecules and express only low levels of class I molecules. However, this
      immunological unresponsiveness is maintained even after the induction of MHC
      class II and upregulation of MHC class I on these cells by interferon-gamma (IFN
      gamma). Similar results have also been reported for cells of different tissue
      lineages (e.g. chondrocytes, keratinocytes, neural cells). Until now, cells have
      been defined as professional or nonprofessional for the purposes of defining
      their potential for antigen presentation to T cells. Professional antigen
      presenting cells have been identified as cells that are of haematopoietic origin,
      that constitutively express MHC class I and class II molecules as well as potent
      costimulatory molecules, and that are able to induce both primary and secondary
      immune responses, whereas nonprofessional antigen presenting cells are not bone
      marrow derived, do not constitutively express MHC class II, but may in some cases
      initiate primary and secondary immune responses after induction of MHC class II
      antigen by proinflammatory cytokines (e.g. IFN-gamma). The findings of our
      laboratory and others suggest that cells of certain lineages be considered in the
      separate class of 'nonantigen presenting cells'. Indeed, nonprofessional antigen
      presenting cells can be reclassified into three categories: semiprofessional-,
      nonprofessional-, or nonantigen presenting cells that are able to present antigen
      to and activate naive T cells, activated T cells, or no T Cells, respectively.
      The aim of this review is to identify and (re)examine the antigen presentation
      characteristics of cells of different tissue lineages in terms of their ability
      to activate different subsets of T cells. This approach is taken in an attempt to
      synthesize these concepts into a unified picture of T cell activation in the
      context of antigen processing and presentation by different cell types.

PMID- 8665147
TI  - Elevated biliary interleukin 5 as an indicator of liver allograft rejection.
AB  - Interleukin 5 (IL-5) is a T cell-derived cytokine that acts as a potent and
      specific eosinophil differentiation factor in humans. During liver allograft
      rejection, intragraft IL-5 mRNA and eosinophilia have been observed. The
      objective of this study was to correlate the levels of IL-5 in bile and serum
      with eosinophilia and allograft rejection in paediatric liver recipients. IL-5
      levels were determined by ELISA (enzyme-linked immunosorbent assay) in bile (n =
      85) and serum (n = 106) and obtained prospectively from 15 patients during the
      first 3 weeks post-transplantation. Biliary and serum IL-5 levels were
      significantly elevated during allograft rejection compared to IL-5 levels when no
      rejection was apparent or during infectious complications. The highest IL-5
      levels were measured in the bile during the early rejection period (3 days prior
      to biopsy-proven rejection). Fifteen of 16 rejection episodes were marked by
      increases in IL-5 as revealed by analysis of sequential samples from individual
      patients. In all patients with rejection, elevations in serum IL-5 were
      associated with elevations in peripheral eosinophil counts. These results
      indicate that IL-5 is produced in the liver and may be a useful and specific
      marker of allograft rejection. Furthermore, these findings provide further
      evidence for a pathway of liver allograft rejection mediated by IL-5 activated
      eosinophils.

PMID- 8665148
TI  - Evidence that the elevation of soluble MHC class I antigens in the serum precedes
      the onset of graft-versus-host disease and is correlated with the severity of the
      disease in rats.
AB  - We examined the changes in the levels of soluble major histocompatibility antigen
      complex (MHC) class I antigens in the serum under a lethal or nonlethal state of
      graft-versus-host-disease (GVHD) induced by injecting various doses of PVG rat
      splenic lymphocytes into (DA x PVG)F1 rats. All rats receiving 4 x 10(8)
      lymphocytes (lethal dose) died on day 20-36 showing typical features of GVHD,
      while the injection of 4 x 10(7) cells (nonlethal dose) induced no sign of GVHD.
      When rats were inoculated with a nonlethal dose of lymphocytes prior to the
      injection of a lethal dose, all rats survived with or without showing transient
      GVHD. Preceding the onset of GVHD the levels of soluble class I antigens
      increased significantly to 1094 +/- 487 ng/ml (mean +/- SD, n = 4) from 3 days
      after the injection of a lethal dose to the time of death, whilst the levels in
      the nonlethal dose group remained unchanged. Rats with transient GVHD in the
      preinoculated group showed the increase of soluble class I antigens to the same
      extent as rats with lethal GVHD, suggesting that GVHD was systemically ongoing.
      The levels of soluble class I antigens also correlated with the severity of GVHD
      as judged by daily observation and histological studies. Rats receiving a lethal
      dose showed destructive alteration of spleen structure and cellular infiltration
      in the portal area of the liver before the animals started to show signs of GVHD,
      whereas rats in the nonlethal dose group exhibited no marked change. These data
      suggest the possibility of serum soluble class I antigens being not only a
      diagnostic but also a prognostic marker for GVHD.

PMID- 8665149
TI  - Human CD59 expressed in transgenic mouse hearts inhibits the activation of
      complement.
AB  - Porcine-to-human xenotransplantation offers a potential solution to the critical
      shortage of human organs. The major immunological barrier to xenotransplantation
      between these species is a rapid rejection process mediated by preformed natural
      antibodies and complement. Xenogeneic organ grafts are especially susceptible to
      complement mediated injury because complement regulatory proteins, which
      ordinarily protect cells from inadvertent injury during the activation of
      complement, function poorly in regulating activation of heterologous complement.
      Removal of xenoreactive antibodies or systemic inhibition of complement activity
      has been shown to prolong graft survival. As an alternative to the systemic
      inhibition of complement activity, we have established a model system using
      transgenic animals to test whether the expression of human membrane bound
      complement regulatory proteins on mouse endothelial cells can inhibit the
      activation of human complement. CD59, which acts at the terminal stage of
      complement activation by inhibiting the formation of the membrane attack complex,
      was used as a paradigm for this model. A CD59 construct containing the putative
      CD59 gene promoter linked to the CD59 coding region was used to demonstrate
      expression of the human CD59 protein in various tissues of transgenic mice,
      including endothelial cells in the heart. In addition, we show that the
      transgenic CD59 protein is biologically active as determined by the ability to
      inhibit the formation of membrane attack complex in transgenic mouse hearts
      perfused ex vivo with human plasma. These results demonstrate that expression of
      membrane bound complement regulatory proteins can achieve complement inhibition
      in a xenogeneic organ and suggest that this approach may be useful for successful
      xenotransplantation between discordant species.

PMID- 8665150
TI  - Effects of desferrioxamine on human cytomegalovirus replication and expression of
      HLA antigens and adhesion molecules in human vascular endothelial cells.
AB  - Desferrioxamine (DFO), commonly used in therapy as a chelator of ferric ion in
      disorders of iron overload, is a potent inhibitor of human cytomegalovirus (HCMV)
      replication in cultured fibroblast cells. Moreover, DFO has immunomodulatory
      activity both in vitro and in vivo. We studied DFO effects on HCMV replication in
      cultured human endothelial cells and on the expression of several cell surface
      molecules, which mediate interactions of endothelial cells with other cell types
      in the immune system. The concentrations of DFO required for 50% reduction in the
      number of endothelial cells expressing HCMV late antigen, ranged for several HCMV
      strains from 5.2 to 8.8 microM. DFO concentrations ranging from 5 to 40 microM
      inhibited cellular DNA synthesis in a dose-dependent manner without any
      significant effects on the cell viability. DFO at 10 microM concentration
      suppressed expression of intercellular adhesion molecule-1 (ICAM-1) and
      endothelial leucocyte adhesion molecule-1 (ELAM-1), while it had no significant
      effect on the expression of vascular cell adhesion molecule-1 (VCAM-1).
      Expression of HLA class I and class II was not influenced by DFO treatment. The
      results showed that DFO is both effective in inhibition of HCMV replication and
      expression of ICAM-1 and ELAM-1 in endothelial cells, a combination that warrants
      attention to its potential use to prevent HCMV-induced allograft rejection in
      transplant recipients.

PMID- 8665152
TI  - Renal transplantation to sensitized patients: decreased graft survival
      probability associated with a positive historical crossmatch.
AB  - Sensitized patients may reject renal transplants at a tempo or with a force
      dictated by their previous exposure to alloantigen. The patient's pretransplant
      alloimmunization status is usually assessed by the measurement of panel reactive
      antibodies (PRAs) and by the crossmatch. The test results using current patient's
      sera are of considerable predictive value. In contrast, the relevance of
      historical sera is much debated. To further investigate the correlation of PRA
      and crossmatch with clinical outcome, 852 cadaveric kidney transplants were
      evaluated. As expected, graft survival was significantly longer (p = 0.01;logrank
      test) in nonimmunized patients (n = 516) compared to immunized patients with more
      than 10% PRA (n = 297). Patients with persistently positive PRAs (n = 171) were
      then compared to patients with positive historical but negative current PRAs (n =
      126). Interestingly, their graft survival was practically identical. Finally,
      transplants across a positive historical T cell crossmatch (n = 39) had a
      significantly reduced graft survival (p = 0.015) compared to transplants in
      immunized patients (n = 297, all T cell crossmatch negative). Thus, this study
      confirms the increased risk in sensitized patients and shows that the antigen
      specific immunological memory is of clinical relevance even if donor specific
      antibodies are not detectable in current sera.

PMID- 8665151
TI  - Manipulation of xenogeneic skin and/or renal graft survival in the rat-mouse
      concordant combination by portal vein pretransplant transfusion.
AB  - We have examined whether portal venous pretransplant transfusion, which has been
      shown to produce prolongation of rodent vascularized (small intestine, kidney)
      and nonvascularized (skin) allografts, in the absence of other nonspecific
      immunosuppression, can produce similar graft prolongation in animals receiving
      vascularized or nonvascularized xeno- (not allo-) grafts. Rat kidney or skin
      grafts were transplanted into mice after portal venous pretreatment with rat or
      mouse spleen cells. Animals in some groups received additional immunosuppressive
      regimens including drug therapy (methotrexate, cyclosporin A) or monoclonal
      antibody treatment (anti-CD4, anti-CD8). Animal survival and serum creatinine was
      followed daily, and lymphoproliferation, cytokine production (including cytokine
      mRNA in grafted mice) and anti-xenograft antibody production was measured at
      distinct time points postgrafting. Both portal venous pretransplant transfusion
      and anti-CD4 monoclonal antibody treatment led to increased graft survival.
      However, unlike the rodent allograft model, graft survival in these animals was
      not simply explained by altered Th1/Th2 ratios. Other mechanism(s), possibly
      including xenoantibody production, are likely of importance in the regulation of
      xenograft rejection.

PMID- 8665153
TI  - Synergistic interaction of 3 M KCl-extracted donor antigens (e-HAg) with
      cyclosporine or cyclosporine/sirolimus for prolongation of rat heart allograft
      survival.
AB  - Extracted donor histocompatibility antigens (e-HAg) may potentiate the effects of
      drugs to protect organ allografts from rejection. We examined the capacity of e
      HAg when combined with cyclosporine (CsA) alone, sirolimus (rapamycin, RAPA)
      alone, or CsA/RAPA combinations to prolong heart allograft survival in rats.
      Wistar-Furth (WF; RT1u) rats that received CsA (10 mg/kg/day) by oral gavage for
      3 (days 0, 1 and 2) or 7 (days 0, 1, 2, 3, 4, 5 and 6) consecutive days displayed
      modest prolongation of Brown Norway (BN; RT1n) heart allograft survival from a
      mean survival time of 7.2 +/- 0.8 days in untreated controls to 12.2 +/- 1.1 days
      and 18.6 +/- 2.7 days, respectively (p < 0.01). Although administration on the
      day of transplantation (day 0) of a single intravenous (i.v.) dose of BN e-HAg (5
      mg/kg) failed to affect allograft survival, both three (days 0, 1 and 2) and five
      (days 0, 1, 2, 3 and 4) injections significantly potentiated the effect of a 3
      day course of oral CsA (18.6 +/- 1.3 days (p < 0.01) and 20.0 +/- 1.4 days (p <
      0.01), respectively) and of a 7-day course of oral CsA (25.3 +/- 4.4 days (p <
      0.05) and 33.5 +/- 9.3 days (p < 0.01), respectively). Median-effect analysis
      confirmed a synergistic interaction between CsA (0.5 mg/kg x 7 days, i.v.) and e
      HAg with combination index (CI) values less than 0.7 (CI = 1 shows additive
      interactions, CI < 1 synergistic, and CI > 1 antagonistic, interactions). In
      contrast, e-HAg failed to affect the immunosuppressive effect of RAPA. However, e
      HAg (5.0 mg/kg x 3 days) significantly potentiated the effects of a 7-day or 14
      day course of RAPA (0.01 mg/kg)/CsA (0.5 mg/kg) combination therapy, namely from
      26.0 +/- 4.8 days with a 7-day treatment of CsA/RAPA alone to 32.6 +/- 3.6 days
      (p < 0.01) and from 28.2 +/- 2.7 days with a 14-day course of CsA/RAPA alone to
      42.0 +/- 4.9 days (p < 0.05), respectively (CI = 0.2-0.5). Thus, e-HAg
      potentiates the immunosuppressive effects of CsA alone and of the CsA/RAPA
      combination, but not of sirolimus alone.

PMID- 8665154
TI  - Mycophenolate mofetil (MMF, RS-61443) inhibits inflammation and smooth muscle
      cell proliferation in rat aortic allografts.
AB  - To investigate the impact of mycophenolate mofetil (MMF) on allograft
      arteriosclerosis (chronic rejection) in rat aortic allograft model, we
      administrated MMF 20 mg/kg/day from the day of transplantation and sacrificed the
      rats at 1-12 months afterwards. MMF significantly suppressed all major
      histological manifestations of allograft arteriosclerosis, i.e. adventitial
      inflammation, media necrosis and intimal thickening and cellularity. There was a
      significant decrease in the replication rate (3H-thymidine incorporation) of
      inflammatory cells in the adventitia and of smooth muscle cells (SMC) in the
      media. MMF did not have any major effect on mRNA expression of several growth
      factors, (determined by polymerase chain reaction with inbuilt glyceraldehyde-3
      phosphate dehydrogenase control), which have previously been demonstrated to be
      elevated in nonimmunosuppressed allografts. Immunoperoxidase staining showed a
      40% reduction in the number of adventitial interleukin-2 receptors expressing
      lymphoid cells in MMF-treated allografts. The intensity of SMC alpha-actin
      staining was also significantly reduced. As the results suggested that MMF may
      have a direct antiproliferative effect on SMC, this possibility was investigated
      in primary SMC cultures in vitro and using the carotid denudation model in vivo.
      Both approaches showed inhibition of SMC proliferation by MMF. Our results
      indicate that MMF inhibits histopathological changes of chronic rejection by
      reducing the immune response and possible replication of SMC.

PMID- 8665155
TI  - Flow cytometric crossmatching in renal transplantation--the long-term outcome.
AB  - The association of a positive flow cytometric crossmatch between recipient IgG
      directed against donor T lymphocytes and poor outcome is well described in renal
      transplantation. Until now no long-term follow-up on such patients has been
      available. In this study, 117 renal transplant patients were followed up for a
      period of 5 years. Of these 21 were known to have donor T cell directed IgG and
      five had B lymphocyte directed IgG. Both groups of patients with these antibodies
      had a significantly poorer outcome at 5 years than did the group of patients
      without IgG (p < 0.0001, Handel Maenzel test). Patients with antibody detected
      preoperatively were tested again either at the time of graft failure or at 5
      years post-transplantation. The sera were tested against stored donor cells and
      the intensity of surface IgG compared with the preoperative levels. In those
      recipients who lost their grafts the levels increased in 60% of cases, but those
      who retained their grafts also had an increase in levels of donor directed
      antibody in 50% of cases. The changing levels of antibody therefore appeared to
      have little relevance to outcome. However when IgG isotypes were considered, in
      those who experienced graft failure and also had a gamma 3 isotype, a rise in IgG
      was demonstrated in all cases. Conversely, successful grafts with gamma 3 had a
      decline in levels between preoperative and 5-year samples in three of the four
      cases (not significant).

PMID- 8665156
TI  - Detection of antilineage specific leucocyte antibodies by a quantitative
      immunocytometry method in sera from candidates for renal allografts.
AB  - A sensitive and quantitative flow cytometry method for detecting antileucocyte
      antibodies was developed to study retrospectively samples from candidates using
      frozen donor cells and frozen recipient sera. This immunofluorescence method was
      used to compare levels of reactivities of serum antibodies before and after donor
      specific blood transfusion treatment and after renal transplantation. The results
      demonstrate that the flow cytometry crossmatch is a sensitive and accurate method
      which should be used prospectively before precluding transplantation in the
      presence of a positive B cell standard crossmatch. Antibodies detected by flow
      cytometry before transplantation could be responsible for an early acute
      rejection episode. Finally, combination of flow cytometry crossmatch and standard
      crossmatch assays might thus be useful before precluding transplantation in
      living related donors.

PMID- 8665157
TI  - Activation of bovine oocytes penetrated after germinal vesicle breakdown.
AB  - The present study was designed to examine the ability of bovine oocytes, after
      germinal vesicle breakdown (GVBD), to be activated by sperm penetration and the
      sequence of sperm nuclear transformation. Bovine oocytes cultured for 8 h in
      maturation medium (tissue culture medium TCM-199 containing 10% fetal calf serum)
      were inseminated in Brackett and Oliphant's medium supplemented with bovine serum
      albumin (10 mg/ml), caffeine (5 mM) and heparin (10 micrograms/ml). When oocytes
      were transferred to the maturation medium 8 h after insemination and additionally
      cultured for 5-40 h at 39 degrees C in 5% CO2 in air, 71-76% of oocytes were
      penetrated and polyspermy (67-75%) was common. The proportions of penetrated
      oocytes that were activated significantly increased with the lapse of the
      additional culture time, reaching 88% and 87% by 25 and 40 h after additional
      culture, respectively. When compared with unpenetrated oocytes, significantly
      higher proportions of penetrated oocytes reached metaphase II or beyond 15 and 25
      h after additional culture. After penetration, sperm nuclei were transformed into
      metaphase chromosomes and then to telophase chromosomes before the formation of
      male pronuclei. These results provide evidence that bovine oocytes acquire the
      ability to respond to sperm-mediated activation soon after GVBD.

PMID- 8665159
TI  - Second messenger signalling during hormone-induced Xenopus oocyte maturation.
AB  - Although much information about such processes as cell cycle control, second
      messenger systems, protein kinases and steroid hormone action has been collected
      from studies of Xenopus oocyte maturation, we still have very little idea about
      how the steroid hormone, progesterone, signals the resumption of meiosis from the
      oocyte plasma membrane. In this review we re-examine the data on second messenger
      systems in Xenopus oocytes and discuss some of the unresolved questions about
      hormone signal transduction during maturation. We outline some reasons for the
      contradictions in the literature and offer some suggestions for avenues of future
      research.

PMID- 8665158
TI  - Transcription of paternal Y-linked genes in the human zygote as early as the
      pronucleate stage.
AB  - Global activation of the embryonic genome occurs at the 4- to 8-cell stage in
      human embryos and is marked by continuation of early cleavage divisions in the
      presence of transcriptional inhibitors. Here we demonstrate, using reverse
      transcriptase-polymerase chain reaction (RT-PCR), the presence of transcripts for
      two paternal Y chromosomal genes, ZFY and SRY in human preimplantation embryos.
      ZFY transcripts were detected as early as the pronucleate stage, 20-24 h post
      insemination in vitro and at intermediate stages up to the blastocyst stage. SRY
      transcripts were also detected at 2-cell to blastocyst stages. The expression of
      SRY and ZFY at these early stages and the faster cleavage rate of male embryos
      observed in many mammalian species focuses attention on the role of events in sex
      determination prior to gonad differentiation.

PMID- 8665160
TI  - Interactions in glycine and methionine uptake, conversion and incorporation into
      proteins in the preimplantation mouse embryo.
AB  - Glycine is the most concentrated amino acid in the female genital tract. In this
      study, we report its conversion and incorporation into proteins in the presence
      or absence of methionine, in both 1-cell and blastocyst mouse embryos. The
      uptake, incorporation and conversion of radiolabelled glycine were studied in the
      presence or absence of unlabelled methionine. For control purposes, the
      reciprocal experiment was performed with labelled methionine in the presence or
      absence of unlabelled glycine. At the 1-cell stage neither glycine uptake nor its
      incorporation into proteins is inhibited by methionine. Glycine is, however,
      highly used as an oxidisable energy substrate, via glycolate. At the blastocyst
      stage, glycine conversion into other amino acids is high and mainly utilised in
      the formation of glutamic acid. Glycine is highly incorporated into proteins,
      resulting in a poor exchange of glycine from the preloaded embryos. Methionine
      competes for glycine uptake and consequently reduces its overall incorporation
      into proteins. For methionine, neither its uptake nor its incorporation into
      proteins is reduced in the presence of glycine for the two embryonic stages
      tested here. The embryo has different mechanisms for incorporation and
      utilisation of methionine and glycine. Glycine, which has an important function
      in the embryo, has an inefficient transport system compared with methionine. We
      were unable to demonstrate the presence of methylglycine since SAM-glycine
      methyltransferase (EC 2.1.1.20) was not detected. The same results were obtained
      when exogenous methionine was added. We therefore concluded that glycine does not
      compete in transmethylation within the embryo.

PMID- 8665161
TI  - Differential accumulation of mRNA and interspersed RNA during Xenopus oogenesis
      and embryogenesis.
AB  - Xenopus oocyte cytoplasmic poly(A)+ RNA has been shown to include two major
      complex classes: mRNA and interspersed RNA. The former is defined by its
      translatability, while the latter consists of non-translatable repeat-containing
      transcripts with unknown functions. In this study we compared the accumulation
      patterns of total mRNA and a subfamily of interspersed RNA, the XR family (McGrew
      & Richter, 1989, Dev. Biol. 134, 267-70). The results showed that the XR
      interspersed RNA level continued to increase throughout oogenesis, while the
      total mRNA level reached a peak at late stage II and then decreased as much as
      40% between stage II and stage VI of oogenesis. In addition we have found that,
      like mRNA, only about half of the non-translatable XR interspersed RNA underwent
      deadenylation at oocyte maturation. This result suggested that about half of the
      interspersed RNA, like certain mRNAs, also contains the U-rich element to protect
      it from the automatic deadenylation, implying the poly(A) tail of interspersed
      RNA may play a role during early development.

PMID- 8665162
TI  - Stages leading to and following fusion of sperm and egg plasma membranes.
AB  - The site of gamete interaction of electrophysiologically recorded Lytechinus
      variegatus eggs, fixed with osmium tetroxide (OsO4) and/or glutaraldehyde (GTA)
      at varying intervals after the onset of the increase in membrane conductance
      induced by an attached sperm, has been examined by high-voltage and conventional
      transmission electron microscopy. Although GTA and a GTA-OsO4 mixture induced
      different electrical responses, specimens prepared with the two fixatives were
      ultrastructurally similar. In specimens observed within 5 s of the change in
      conductance, the acrosomal process projected through the vitelline layer and
      abutted the egg plasma membrane. A conspicuous layer of bindin surrounded the
      acrosomal process and connected the sperm to the egg's vitelline layer. In a
      fortuitous specimen fixed within 4 s following the change in conductance, the
      area of contact between the gamete plasma membranes possessed a trilaminar
      structure that separated the egg's and sperm's cytoplasms. The morphology of this
      area of contact was consistent with previously proposed intermediates of membrane
      fusion. Five to six seconds after the change in conductance, the sperm was
      connected to the egg via a narrow cytoplasmic bridge that consisted of the former
      acrosomal process and a projection of the egg cortex. The region of the bridge
      midway between the fused gametes was encircled by dense material that marked the
      site of sperm-egg fusion. Gamete interactions in which the activation potential
      was recorded (unclamped egg) were comparable in time and ultrastructure to events
      taking place in voltage-clamped eggs except for one major difference. Intact
      cortical granules (one to three) were observed beneath the tip of the
      incorporating sperm in unclamped eggs fixed following the onset of the activation
      potential, whereas all cortical granules dehisced in clamped eggs.

PMID- 8665163
TI  - Development and loss of the ability of mouse oolemma to fuse with spermatozoa.
AB  - To further our knowledge on the mechanisms and molecules involved in mouse sperm
      oocyte plasma membrane interaction, experiments were carried out to determine the
      stage during oogenesis at which an oocyte acquires the capacity to fuse with
      acrosome-reacted sperm. Zona-free oocytes 10 microns in diameter do not fuse with
      sperm. Oolemma fusibility is first acquired when the oocyte reaches about 20
      microns in diameter. Fusibility is maintained even after fertilisation has
      occurred and is lost completely by the 4-cell stage.

PMID- 8665164
TI  - Recent Explorations in Gamete Biology. Proceedings from an international
      congress. Teramo, Italy, 30-31 May 1994.

PMID- 8665165
TI  - Cell-cell interactions and oocyte growth.

PMID- 8665166
TI  - Transduction mechanisms for gonadotrophin-induced oocyte maturation in mammals.

PMID- 8665167
TI  - Meiotic cycle checkpoints in mammalian oocytes.

PMID- 8665168
TI  - Oocyte reaction to penetrating sperm.

PMID- 8665169
TI  - Sperm activation in species with external fertilisation.

PMID- 8665170
TI  - Ovarian regulation of sperm progression in the fallopian tubes.

PMID- 8665171
TI  - Methods for the assessment of capacitation.

PMID- 8665172
TI  - Fertility of mammalian spermatozoa: its development and relativity.

PMID- 8665173
TI  - Oocyte activation in invertebrates and humans.

PMID- 8665174
TI  - Recent developments in cryopreservation of stallion semen with special emphasis
      on thawing procedure using thermal hysteresis proteins.

PMID- 8665175
TI  - Stability of the mammalian sperm nucleus.

PMID- 8665176
TI  - Embryonic stem cells in farm animals.

PMID- 8665177
TI  - The future of surgical journals in the electronic publishing era.

PMID- 8665178
TI  - Medicolegal action following treatment for varicose veins.

PMID- 8665179
TI  - Surgical management of locally recurrent rectal cancer.
AB  - The surgical management of locally recurrent rectal cancer may involve major
      procedures and is not for the faint-hearted. Nevertheless, such treatment is
      preferable to chemotherapy and radiotherapy; the latter will fail over a period
      of months during which the patient is likely to experience intractable pain.
      Radical surgery offers good palliation and a better quality of life. Survival is
      prolonged by such operations which may be curative in up to one-third of
      patients. Nevertheless, surgeons must be realistic in their assessment of and
      discussions with patients.

PMID- 8665180
TI  - Glutamine.
AB  - Glutamine is the most abundant free amino acid in the circulation. It is a
      primary fuel for rapidly dividing cells and plays a key role in the transport of
      nitrogen between organs. Although glutamine is absent from conventional regimens
      aimed at nutritional support, glutamine deficiency can occur during periods of
      metabolic stress; this has led to the reclassification of glutamine as a
      conditionally essential amino acid. Experiments with various animal models have
      demonstrated that the provision of glutamine can result in better nitrogen
      homoeostasis, with conservation of skeletal muscle. There is also considerable
      evidence that glutamine can enhance the barrier function of the gut. This review
      concludes by discussing the clinical evidence that supports the inclusion of
      stable forms of glutamine in solutions of nutrients.

PMID- 8665181
TI  - Role of cytokines and growth factors in promoting the local recurrence of breast
      cancer.
AB  - The pathogenesis of local recurrence in breast cancer is not well understood.
      Breast-conserving surgery is particularly prone to local recurrence as it leaves
      behind breast tissue that may harbour occult cancer, and lends itself to enhanced
      intraoperative shedding of cancer cells due to narrower resection margins and
      transection of lymphatic channels. A review of clinical breast cancer studies as
      well as experimental research strongly suggests that these persisting cancerous
      cells are unlikely to develop into clinically evident disease if their
      environment remains unstimulated. However, an inordinately high local recurrence
      rate occurs at the surgical scar, and such recurrence must be triggered by the
      release of growth factors and cytokines into the healing wound. These factors can
      stimulate any available cancer cells which express the proper growth factor
      receptors. Perioperative strategies to neutralize this tumour cell-growth factor
      interaction should maximize local control.

PMID- 8665182
TI  - Molecular genetic basis of colorectal cancer susceptibility.
AB  - The past decade has seen considerable advances in understanding of the molecular
      processes involved in the development of colorectal cancer. With an increased
      awareness of genetic aspects of the disease there have already been significant
      changes in clinical management. This is exemplified by familial adenomatous
      polyposis, where identification of mutations in the adenomatous polyposis coli
      (APC) gene in affected individuals can be used directly to reduce the requirement
      for clinical screening in at-risk relatives. In other more common but less well
      defined heritable forms of colorectal cancer, testing to identify individuals for
      early diagnosis and treatment will soon become routine practice. This review does
      not set out to discuss all aspects of the molecular genetics of colorectal cancer
      but concentrates on the roles of the APC gene and the recently discovered DNA
      mismatch repair genes in colorectal cancer. The identification of these genes and
      their functional significance in the neoplastic process is discussed, and the
      relevance of such discoveries to future research and clinical management
      explored.

PMID- 8665183
TI  - Long-term outcome after surgery for asymptomatic small hepatocellular carcinoma.
AB  - The subjects of this study were 48 asymptomatic patients who had surgery for
      small hepatocellar carcinoma (HCC). There were 42 men and six women with mean
      (s.d.) tumour size of 3.31 (1.46) cm and age 55.0 (7.4) years. Follow-up was for
      a minimum of 10 years. The main concern of this study was a univariate analysis
      of factors that might affect long-term survival after surgery, which was 50 per
      cent at 5 years and 31 per cent at 10 years. A high incidence of recurrent HCC
      (37 of 48 patients) was observed but reoperation further prolonged life in some
      cases. The significant prognostic factors detected by multivariate analysis were:
      histological classification, functional liver reserve and histology of the
      resection margin. Tumour size, gross appearance of tumour, presence of liver
      cirrhosis, serum alpha-fetoprotein level, age or sex did not affect the
      prognosis.

PMID- 8665184
TI  - Laparoscopic resection of solid liver tumours.

PMID- 8665185
TI  - Intravenous cholangiography reduces the need for endoscopic retrograde
      cholangiopancreatography before laparoscopic cholecystectomy.

PMID- 8665186
TI  - Adjuvant oral chemotherapy to prevent recurrence after curative resection for
      hepatocellular carcinoma.
AB  - Adjuvant oral chemotherapy was studied in 67 patients with stage II
      hepatocellular carcinoma who underwent curative resection between May 1988 and
      December 1990. Patients were stratified into two groups according to preoperative
      liver dysfunction: 55 had stage I disease (mild dysfunction) and 12 had stage II
      (moderate dysfunction). A randomized controlled study of postoperative oral
      administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) was conducted in each
      group. From October 1994 HCFU administration was suspended because of side
      effects in nine patients with stage I liver dysfunction and in three with stage
      II dysfunction who had received the drug for more than 4 weeks. Cumulative
      survival and recurrence-free survival rates of patients with stage I disease in
      the treatment group were higher (P = 0.08 and P = 0.04 respectively) than those
      in the control group. However, in patients with stage II disease no significant
      difference was observed (P = 0.77 and P = 1.0 respectively). This study suggests
      that the potential benefits of HCFU on tumour recurrence should be weighed
      against the risk of adverse reactions in patients with mild liver dysfunction.

PMID- 8665187
TI  - Laparoscopic common bile duct exploration: evolution of a new technique.
AB  - Laparoscopic exploration of the common bile duct (CBD) with a choledochoscope or
      a stone basket during laparoscopic cholecystectomy was attempted in 60 patients
      and was successful in 56. The cystic duct was used for entry to the CBD in 46
      patients and in 14 a choledochotomy was performed. Of 51 patients with confirmed
      common duct stones, 38 had complete laparoscopic clearance (75 per cent). In 13
      patients the duct was not cleared or was only partially cleared, of whom four
      went on to have clearance by postoperative percutaneous choledochoscopy down a
      cystic duct or T-tube track. Two patients with cystic duct tubes passed their
      remaining stones spontaneously. One patient had open exploration and six required
      endoscopic retrograde cholangiopancreatography. Of nine patients without stones,
      choledochoscopy was impossible in three patients whose cholangiogram was later
      considered to be normal. In five patients stones were excluded by choledochoscopy
      and in one patient laparoscopic choledochoscopy was undertaken to better define
      abnormal biliary anatomy; this helped to avoid major bile duct injury.
      Choledochoscopy was easier with the smaller 3.6-mm ureteroscope but stone removal
      was more difficult when the basket was too small for the stones, the cystic duct
      too small relative to stone size or the number of stones was too great.
      Successful stone clearance was proportional to the level of effort expended, and
      was limited by operating time and equipment.

PMID- 8665188
TI  - Peritoneal and systemic cytokine response to laparotomy.

PMID- 8665189
TI  - Serum concentrations of inflammatory mediators related to organ failure in
      patients with acute pancreatitis.
AB  - Leucocyte activation and proinflammatory cytokine release (tumour necrosis factor
      (TNF) and interleukin 6 (IL-6)) are thought to contribute to the induction of a
      systemic inflammatory response, an acute-phase response and multiple organ
      failure in patients with acute pancreatitis. The serum concentration of TNF,
      soluble TNF receptors (sTNFR55 and sTNFR75), IL-6 and C-reative protein (CRP) in
      58 patients with acute pancreatitis was assessed during the first 2 days of
      admission. Thirty patients had mild disease and 28 severe disease, of whom 18
      developed local pancreatic complications alone (Atlanta classification) and ten
      developed organ failure (a Goris score of 1 or more). TNF was detected in only 17
      patients on the first day of admission, while soluble TNF receptors were detected
      in all patients and IL-6 in 34. On the first and second days of admission there
      was a progressive and significant (P < 0.03) increase in the median concentration
      of sTNFR55, sTNFR75 and IL-6 in patients eventually classified into those with
      mild disease, a local pancreatic complication alone, or organ failure. This
      pattern was also evident in CRP levels from the second but not the first day of
      admission. These findings suggest that proinflammatory cytokines or their soluble
      receptors may be more accurate early predictors of outcome than CRP, Moreover,
      markers of inflammation in the sera of patients with acute pancreatitis are
      highest in those who subsequently develop organ failure.

PMID- 8665190
TI  - Reconstruction of a new inferior vena cava after right atrial disruption during
      recipient hepatectomy.

PMID- 8665191
TI  - Randomized study of antibiotic prophylaxis for general and gynaecological surgery
      from a single centre in rural Africa.
AB  - In a district rural hospital in Uganda, 850 surgical patients were evaluated
      prospectively over a 3-year period to compare the clinical efficacy of
      conventional postoperative penicillin therapy with single-dose ampicillin
      prophylaxis for hernia repair and ectopic pregnancy, and with single-dose
      ampicillin-metronidazole prophylaxis for hysterectomy and caesarean section. The
      high rate of postoperative infection usually encountered in African hospitals
      after conventional treatment with penicillin for 7 days was significantly reduced
      with the new regimen: from 7.5 to 0 per cent in hernia repair and from 10.7 to
      2.4 per cent in ectopic pregnancy; from 20.0 to 3.4 per cent in hysterectomy and
      from 38.2 to 15.2 per cent in caesarean section. Length of hospital stay and
      postoperative mortality rates were also significantly reduced. Single-dose
      ampicillin prophylaxis with or without metronidazole, although rarely used in
      developing countries, is more cost effective than standard penicillin treatment.

PMID- 8665192
TI  - Effect of transcutaneous electrical muscle stimulation on postoperative muscle
      mass and protein synthesis.
AB  - In an experimental study, 13 patients undergoing major elective abdominal surgery
      were given postoperative transcutaneous electrical muscle stimulation (TEMS) to
      the quadriceps femoris muscle on one leg; the opposite leg served as control.
      Changes in cross-sectional area (CSA) and muscle protein synthesis were assessed
      by computed tomography and ribosome analysis of percutaneous muscle biopsies
      before surgery and on the sixth postoperative day. The percentage of
      polyribosomes in the ribosome suspension decreased significantly (P < 0.03) after
      operation in control legs, but not in stimulated legs (P > 0.16). The total
      concentration of ribosomes decreased significantly in legs treated with TEMS (P <
      0.03) but not in control legs (P > 0.16). CSA decreased significantly in both
      legs. The decrease in polyribosomes and CSA after operation was significantly
      less in stimulated legs than in controls (P < 0.05). TEMS may be a simple and
      effective method for improving muscle protein synthesis and muscle mass after
      abdominal surgery and should be evaluated in other catabolic states with muscle
      wasting.

PMID- 8665193
TI  - Randomized comparison of agents for caudal anaesthesia in anal surgery.

PMID- 8665194
TI  - A better bridge for loop stomas.

PMID- 8665195
TI  - Perineal excision of the rectum.
AB  - An intersphincteric and perimuscular approach was employed for perineal excision
      of the rectum in 33 patients who had previously undergone total colectomy with
      preservation of the rectum. Laparotomy was avoided in 28 of the 29 patients who
      had had closure of the rectal stump with ileostomy. Of the four patients (two
      with ileorectal anastomoses and two with sigmoid mucous fistulas) for whom
      laparotomy was planned, this was considered to be much less extensive than would
      otherwise have been required. It is concluded that in patients who have
      previously undergone total colectomy for inflammatory bowel disease, subsequent
      perineal excision of the rectal stump without laparotomy is frequently possible.

PMID- 8665196
TI  - Salvage surgery for ileal pouch outlet obstruction.
AB  - Sixteen patients with ileal pouch outlet mechanical obstruction had major
      abdominal revision of the ileoanal anastomosis. Before operation all had severe
      difficulty in evacuation which required catheterization in 11. Eleven patients
      had a long efferent limb and/or long anorectal cuff, and five had a persistent
      stricture at the ileoanal anastomosis. None had pouchitis. The pouch was fully
      mobilized abdominally and the obstructing lesion resected. A new handsewn
      ileoanal anastomosis was formed. In two cases pouch volume was increased by
      incorporating an additional loop of ileum. All anastomoses but one were covered
      by a loop ileostomy. There were no deaths. Major complications occurred in two
      patients. Function was assessed in 15 patients; in one the ileostomy had not been
      closed. Median (interquartile range) frequency of defaecation per 24 h fell from
      15 (7.3-19.5) to 6 (4.5-6.0) (P = 0.0033). Of the 11 patients who required a
      catheter before operation six evacuated spontaneously, three were improved but
      intubated on some occasions and two were unchanged after revisional surgery. Of
      the ten incontinent patients, five became continent, four were improved and one
      remained unchanged. There was a new continence disturbance in four (minor
      nocturnal in three) of the remaining five patients. One patient underwent further
      abdominal salvage surgery and another required establishment of an ileostomy
      because of poor function. Combined abdominoanal salvage surgery for outlet
      mechanical obstruction was successful in averting an ileostomy in 13 of 16
      patients, and significantly improved pouch function in 12 of 15.

PMID- 8665197
TI  - Results from pouch salvage.
AB  - Over an 11-year period, 17 salvage procedures were performed on a failed ileal
      pouch-anal anastomosis carried out for ulcerative colitis from a series of 157
      patients. Ten pouches were saved, four excised and three defunctioned. Salvage
      procedures included five operations for fistulas (three of five successful), six
      reoperations on the ileoanal anastomosis (five of six successful), three new
      pouches after previous pouch excision (all failed), and three miscellaneous:
      excision of an efferent limb (successful), pouchpexy for a pouch prolapse
      (successful) and postanal repair for incontinence (failed). Pouch salvage may be
      successful in the motivated patient who wishes to avoid a permanent ileostomy.

PMID- 8665198
TI  - Local recurrence following total mesorectal excision for rectal cancer.
AB  - Early results after rectal cancer surgery in a defined population were compared
      before and after the introduction of total mesorectal excision. In the first
      period (1984-1986) 211 cases of rectal cancer were diagnosed and in the second
      (1990-1992) 230. Of these, 134 patients in the first period (group 1) had
      anterior resection or abdominoperineal excision which was considered curative. In
      the second period 128 curative anterior resections and abdominoperineal excisions
      were performed by a limited number of surgeons familiar with total mesorectal
      excision (group 2). No differences between the groups were found in stage
      distribution, rate of curative operations, postoperative complications or
      postoperative mortality. Local recurrence had developed in 19 patients in group 1
      and in eight in group 2, 1 year after the end of the study periods (P = 0.03).
      Local radicality was in doubt in 13 patients in group 1 and in eight in group 2.
      In the remaining 121 and 120 patients, 13 and four local recurrences respectively
      were present (P = 0.03). Actuarial analysis showed a significant reduction in
      local recurrence rate (P = 0.03) and an increase in crude survival (P = 0.03) at
      4 years in group 2 compared with group 1. Total mesorectal excision reduces the
      local recurrence rate after excision of rectal cancer.

PMID- 8665199
TI  - Randomized controlled trial of lateral internal sphincterotomy with
      haemorrhoidectomy.
AB  - A prospective trial was conducted to compare haemorrhoidectomy alone (control,
      group 1) with haemorrhoidectomy plus lateral internal sphincterotomy (group 2)
      for prolapsed piles. Some 33 patients (18 men, 15 women) of mean(s.e.m.) age
      40(2.3) years were randomized, 16 to group 1 and 17 to group 2. There were no
      significant differences in postoperative pain scores. Mean resting and maximum
      anal squeeze pressures, studied 6 weeks and 3 months after operation, were
      generally lower in group 2, but were not significantly different. Two patients in
      group 2 were distressed by incontinence to liquid faeces which persisted in one
      after 1 year. There were no other complications in either group after a
      mean(s.e.m.) follow-up of 11(0.4) months. The addition of lateral internal
      sphincterotomy to routine haemorrhoidectomy is unnecessary and carries the added
      risk of incontinence.

PMID- 8665200
TI  - Technique for full-thickness muscle closure of laparoscopic port sites.

PMID- 8665201
TI  - Anatomical basis of autonomic nerve-preserving total mesorectal excision for
      rectal cancer.
AB  - Total mesorectal excision with autonomic nerve preservation for rectal cancer is
      based on the anatomy of the mesorectum and of the pelvic autonomic nerves.
      Cadaver dissections were performed to describe the relationship between these
      structures. Between the rectum and the sacrum a retrorectal space can be
      developed, lined anteriorly by the visceral leaf and posteriorly by the parietal
      leaf of the pelvic fascia. The hypogastric nerve runs anterior to the visceral
      fascia, from the sacral promontory in a laterocaudad direction. The splanchnic
      sacral nerves originate from the sacral foramina, posterior to the parietal
      fascia, and run caudad, laterally and anteriorly. After piercing the parietal
      layer of the pelvic fascia, approximately 4 cm from the midline, the sacral
      nerves run between a double layer of the visceral part of the pelvic fascia. The
      relationship between the hypogastric nerves, the splanchnic nerves and the pelvic
      fascia was comparable in all six specimens examined.

PMID- 8665202
TI  - Laser Doppler blood flow measurement in rectal resection for carcinoma-
      comparison between the straight and colonic J pouch reconstruction.
AB  - Lower rates of anastomotic leakage have been reported after rectal resection with
      a colonic pouch-anal anastomosis than with a conventional straight anastomosis.
      The microcirculation in the bowel segment that was used for construction of a
      colonic pouch or a conventional straight anastomosis was examined. Transmural
      colonic blood flow was measured by laser Doppler flowmetry during the operation
      before the construction of a straight (n = 16) or pouch (n = 14) anastomosis. The
      blood flow recordings were first done before dissection of the bowel at one point
      close to the planned bowel end and at another point 8 cm more proximally. A
      second recording was done at the same sites after dissection and, where
      appropriate, after construction of the pouch, but before the anastomosis was
      completed. In the straight group (end-to-end anastomosis), blood flow levels at
      the site intended for the anastomosis were significantly decreased following
      dissection of the bowel. In the pouch group (side-to-end anastomosis), blood flow
      levels at the site of the anastomosis were similar following dissection of the
      bowel and pouch construction. It is concluded that unaffected blood flow at the
      site of the anastomosis of the pouch may be a favourable factor for anastomotic
      healing.

PMID- 8665203
TI  - Removal of circulating cytokines by continuous haemofiltration in patients with
      systemic inflammatory response syndrome or multiple organ dysfunction syndrome.

PMID- 8665204
TI  - Value of a weekly surgical x-ray meeting.

PMID- 8665205
TI  - Correlation between Acute Physiology and Chronic Health Evaluation (APACHE) III
      score and immunological parameters in critically ill patients with sepsis.
AB  - A relationship between physiological parameters of severe sepsis and
      immunological function has not been established. In ten severely ill patients
      with sepsis physiological risk was assessed by the Acute Physiology and Chronic
      Health Evaluation (APACHE) III score, while one component of immunological
      function was evaluated using peripheral blood mononuclear cell (PBMC) cytokine
      production after stimulation with lipopolysaccharide (LPS) in vitro. Five of the
      ten patients died. Mean (s.e.m.) APACHE III scores at admission were not
      significantly different between survivors and non-survivors (82(13) versus
      95(13)) but after 72 h they were lower in survivors (51(13) versus 111(15), P <
      0.05). Downregulation of cytokine production by PBMC on LPS stimulation was a
      transient event in survivors. Survivors had a three-fold increase in tumour
      necrosis factor alpha bioactivity within 72 h, but there was no increase in non
      survivors. A similar pattern was demonstrated for interleukin (IL) 1 beta (P <
      0.05 between survivors and non-survivors) and IL-6 (P = 0.06) immunoactivity.
      Physiological as well as immunological parameters in critically ill patients with
      sepsis independently predicted hospital survival (r2 = 0.2). These data
      demonstrate a relationship between the pattern of cytokine production in vitro
      and survival.

PMID- 8665206
TI  - Thoracoscopic implantation of an epicardial pacemaker.

PMID- 8665207
TI  - Antioxidant depletion during aortic aneurysm repair.
AB  - Ischaemia-reperfusion injury generates oxygen-derived free radicals leading to
      local and distant damage. A simple method of following oxidative activity is to
      measure the consumption of endogenous scavenging antioxidants; an enhanced
      chemiluminescent assay was used to study this phenomenon in 21 patients
      undergoing surgery for abdominal aortic aneurysm (AAA). Samples of peripheral
      venous blood were taken before induction of anaesthesia and then from a central
      venous line and the inferior mesenteric vein before, during, and after clamping
      of the aorta. Further specimens were taken from the central line at 2, 6 and 24 h
      after operation. Antioxidant concentration in the peripheral, central and
      inferior mesenteric blood were similar, indicating that anaesthesia and surgical
      dissection had no effect. Levels decreased significantly in central and inferior
      mesenteric blood during and after clamping, but returned to normal by 24 h. These
      results confirm ischaemia-reperfusion phenomena in AAA repair.

PMID- 8665208
TI  - Diagnosis of arterial disease of the lower extremities with duplex
      ultrasonography.
AB  - The development of duplex scanning carries the prospect of an entire non-invasive
      work-up of patients with peripheral arterial occlusive disease. To obtain the
      best available estimates of its diagnostic accuracy, a meta-analysis of 71
      studies evaluating duplex scanning was performed. Independent methodological
      judgement left 16 studies for data extraction. Pooled estimates (95 per cent
      confidence interval of sensitivity and specificity for detection of a stenosis
      greater than or equal to 50 per cent or occlusion in the aortoiliac tract were 86
      (80-91) per cent and 97 (95-99) per cent respectively. The results for the
      femoropopliteal tract compared well with this, with a sensitivity of 80 (74-85)
      per cent and a specificity of 96 (94-98) per cent. The accuracy of detection of a
      stenosis greater than or equal to 50 per cent or an occlusion in the
      infragenicular arteries was lower with a sensitivity and specificity of 83 (59
      96) per cent and 84 (69-93) per cent respectively. Duplex scanning is an accurate
      tool for assessment of atherosclerotic lesions in the aortoiliac and
      femoropopliteal tract and can replace routine preinterventional angiography in a
      substantial number of patients.

PMID- 8665209
TI  - Experimental autotransplantation of the parathyroid gland.
AB  - The lateral parathyroid gland of the rabbit was resected and autotransplanted
      under an ear skin flap. A skin flap at the opposite side was used as control. The
      success of autotransplantation was established by microangiography of the
      transplant and by measuring plasma concentrations of parathyroid hormone (PTH),
      calcium and phosphorus. After 4 months the animals were killed and the transplant
      was studied histologically and by electron microscopy. Fourteen animals were
      included in the study. There was an increase in PTH derived from the transplanted
      gland after 4-6 postoperative days. All animals developed hypocalcaemia during
      the 3 days after transplantation. There were no significant changes in serum
      phosphorus. Transplantation did not alter the morphology of the distribution of
      the cells in the transplanted gland, which functioned normally after the fourth
      postoperative day.

PMID- 8665210
TI  - Simple and reliable technique for local resection of early gastric cancer.

PMID- 8665211
TI  - Intestinal glycosaminoglycans in neonatal necrotizing enterocolitis.
AB  - Advanced necrotizing enterocolitis (NEC) is a common neonatal surgical emergency
      of unknown aetiology. Despite improvements in the prognosis, the aggressive form
      of the disease is still associated with significant rates of morbidity and
      mortality. Recent evidence indicates that the extracellular matrix (ECM) is
      important in gastrointestinal development and glycosaminoglycans, major
      constituents of the ECM, are attenuated in inflammatory bowel disease. The
      hypothesis of this study was that changes in the nature and distribution of
      intestinal glycosaminoglycans occur in NEC. The distribution and nature of
      glycosaminoglycans were determined in 31 sections of well preserved resection
      margins and severely diseased bowel from eight neonates affected by NEC. An
      established histological method of glycosaminoglycans analysis using cationic
      gold with silver enhancement was employed in this study. The identity of specific
      glycosaminoglycans was also elucidated using a combination of cationic gold
      staining and glycanase digestion. In well preserved tissue, staining was seen
      throughout the full thickness of the bowel. The epithelial basement membrane and
      basolateral surfaces, lamina propria and submucosa were particularly prominent.
      In moderate disease, patchy loss of anionic sites was frequently observed with
      glycosaminoglycans-deficient areas adjacent to intact sites. In severe NEC, there
      was extensive loss of glycosaminoglycans in most of the sections examined.
      Glycanase analysis revealed that the glycosaminoglycans in well preserved tissue
      were sensitive to chondroitinase ABC and only vascular sites were sensitive to
      heparinase III. The consequences of glycosaminoglycans loss in NEC as
      demonstrated in this study are not known but modulation of gastrointestinal
      glycosaminoglycans could be important in the pathogenesis of NEC and may underlie
      some of the clinical manifestations of this condition.

PMID- 8665212
TI  - Subrectus pouch for renal transplantation.

PMID- 8665213
TI  - Postoperative thromboembolism after day-case herniorrhaphy.
AB  - Thromboembolism is a serious complication of surgery and prophylaxis is therefore
      recommended. This study examines a new aspect of the problem, the incidence of
      thromboembolism after day-case surgery. From 1982 to 1992, 2281 patients
      underwent day-case repair for inguinal hernia management. Hospital admission for
      thromboembolism within the first 30 days after surgery was identified by computer
      linkage to the National In-Patient Register, which contains details of all
      hospital admissions in Denmark. One patient developed non-fatal pulmonary
      embolism. No other patients were admitted to hospital with venous thromboembolism
      within 30 days of herniorrhaphy. It is concluded that there is no need for
      routine prophylaxis for thromboembolism in day-case hernia surgery.

PMID- 8665214
TI  - Combined liver transplantation and pancreatoduodenectomy for irresectable hilar
      bile duct carcinoma.

PMID- 8665215
TI  - Randomized controlled multicentre study of the prevention of complications by
      octreotide in patients undergoing surgery for chronic pancreatitis.

PMID- 8665216
TI  - Impact of fine-needle aspiration cytology, ultrasonography and mammography on
      open biopsy rate in patients with benign breast disease.

PMID- 8665217
TI  - Quality of life assessment in patients undergoing treatment for oesophageal
      carcinoma.

PMID- 8665218
TI  - Primary soft tissue sarcoma of the extremities in adults.

PMID- 8665219
TI  - Lateral subcutaneous sphincterotomy for treatment of anal fissure in children.

PMID- 8665220
TI  - Ambulatory oesophageal bile reflux monitoring in Barrett's oesophagus.

PMID- 8665221
TI  - Bladder injury during laparoscopic abdominoperitoneal resection.

PMID- 8665222
TI  - Experimental study to show that growth hormone treatment before trauma increases
      glutamine uptake in the intestinal tract.

PMID- 8665223
TI  - Early parietal recurrence of adenocarcinoma of the colon after laparoscopic
      colectomy. Port site metastasis after laparascopic colorectal surgery for cure of
      malignancy.

PMID- 8665224
TI  - Pain relief after inguinal hernia repair: a randomized controlled trial.

PMID- 8665225
TI  - Total mesorectal excision is optimal surgery for rectal cancer: a Scandinavian
      consensus.

PMID- 8665226
TI  - Percutaneous cholecystostomy: a valuable technique in high-risk patients with
      presumed acute cholecystitis.

PMID- 8665227
TI  - Prospective evaluation of ultrasonography and liver function tests for
      preoperative assessment of the bile duct.

PMID- 8665228
TI  - Telepresence surgery.

PMID- 8665229
TI  - Thoracic outlet syndromes.

PMID- 8665230
TI  - E-cadherin and its associated protein catenins, cancer invasion and metastasis.
AB  - E-cadherin is a cell-cell adhesion molecule which is anchored to the cytoskeleton
      via catenins. There is increasing evidence which suggests that E-cadherin also
      acts as a suppressor of tumour invasion and metastasis. Both in vitro and in vivo
      studies have revealed that expression of E-cadherin correlates inversely with the
      motile and invasive behaviour of a tumour cell; it also correlates inversely with
      metastasis in patients with cancer. The function of E-cadherin is highly
      dependent on the functional activity of catenins. This review summarizes
      progress, from both basic and clinical research, in our understanding of the
      roles of E-cadherin and catenins, and discusses the clinical relevance of the
      discoveries.

PMID- 8665231
TI  - Arterial therapy of hepatic colorectal metastases.
AB  - Considerable experience of the treatment of irresectable hepatic colorectal
      metastases has accumulated over the past three decades. In this review, the
      rationale for hepatic artery treatment of colorectal metastases to the liver is
      presented and various access techniques and chemotherapeutic agents for infusion
      are discussed. Randomized trials of hepatic artery chemotherapy (HAC) are
      analysed, and the promising results of recent studies combining less toxic and
      more effective agents are summarized. Continuous infusion pumps provide the most
      reliable and long-lasting access for HAC. Appropriate surgical techniques and
      medical management can minimize complications. Although tumour progression is
      best controlled by HAC, a clear-cut survival advantage has yet to be
      demonstrated. While hepatic artery infusion chemotherapy cannot yet be
      recommended outside investigational protocols, the experience gained so far
      should stimulate further studies.

PMID- 8665232
TI  - Liver metastases from colorectal cancer: lessons from past and present clinical
      studies.
AB  - In patients with primary colorectal cancer the development of liver metastases
      has traditionally been equated with imminent demise. This metastatic event is
      remarkably common; indeed, liver metastases are present in some 25 per cent of
      patients at the time of initial colorectal resection and over 50 per cent of
      patients will eventually develop them. Some 90 per cent of patients who die from
      colorectal cancer have liver metastases. There are few cancers in which the
      metastatic pattern has such a high degree of predictability. Information from
      past and present clinical studies should, therefore, provide a basis for logical
      approaches to prevention and treatment.

PMID- 8665233
TI  - Role of endoscopic injection therapy in the treatment of bleeding peptic ulcer.
AB  - Of patients with peptic ulceration who are actively bleeding at endoscopy, 80 per
      cent will continue to bleed or rebleed in hospital; 50 per cent of those who have
      a non-bleeding visible vessel will also rebleed. Endoscopic injection treatment
      stops active bleeding and prevents further haemorrhage in most of these patients.
      The mechanism of action may include tamponade, vasoconstriction, sclerosis,
      tissue dehydration and thrombogenesis; substances injected include adrenaline,
      sclerosants, alcohol, thrombin, or a combination of agents. Although trials often
      define the need for surgery as an injection treatment failure, an alternative
      view is that endoscopic control may facilitate safe, early, elective surgery. A
      successful outcome may require a combination of endoscopic and operative
      approaches.

PMID- 8665234
TI  - Radical surgery for advanced gallbladder carcinoma.
AB  - Forty-four patients with advanced gallbladder carcinoma (18 with stage pT3 and 26
      with stage pT4 of the Union Internacional Contra la Cancrum classification) were
      aggressively managed by extended heptatic resection in 33 patients, bile duct
      resection in 28, pancreaticoduodenectomy in seven, gastrointestinal resection in
      eleven and portal vein resection and reconstruction in seven. Adjacent organ
      involvement was classified as follows: type I, hepatic involvement with or
      without gastrointestinal invasion (Ia, Ib); type II, bile duct involvement with
      or without gastrointestinal invasion (IIa, IIb); type III, hepatic and bile duct
      involvement with or without gastrointestinal invasion (IIIa, IIIb); type IV,
      gastrointestinal involvement without hepatic or bile duct invasion. Fourteen of
      15 patients with type I tumours had a curative resection compared with seven of
      26 with type III lesions (P < 0.0001). The surgical mortality rate was two of 15
      patients with type I tumours, seven of 26 with type III tumours and nine of 44
      for the whole group. The long-term survival rate after curative resection was
      four and two of 23 at 3 and 5 years respectively, significantly better than two
      and none of 21 at 1 and 2 years after non-curative resection (P < 0.01). The
      survival rate after curative resection for patients with type I tumours was four
      and two of 14 at 3 and 5 years respectively, significantly better than for other
      types (P < 0.05). This classification of advanced gallbladder carcinoma according
      to involvement of adjacent organs might be helpful in planning surgery for this
      condition; in particular, type I tumours should be treated by a radical surgical
      procedure to achieve a favourable outcome.

PMID- 8665235
TI  - Hepatic bile acid synthesis and DNA synthetic rate after partial hepatectomy.
AB  - The relationship between hepatic DNA synthetic rate and activity of cholesterol 7
      alpha-hydroxylase, the rate limiting enzyme for bile acid synthesis, was examined
      in regenerating liver after partial hepatectomy or sham operation in rats.
      Hepatic cholesterol 7 alpha-hydroxylase activity was significantly (P < 0.001)
      suppressed on days 1 and 2, returned to the control level on day 3, and was
      significantly raised on day 7 after hepatectomy. The rate of DNA synthesis was
      significantly (P < 0.001) activated during the first 3 days after hepatectomy and
      returned to the control level on day 7. Enzyme activities regulating hepatic bile
      acid synthesis and DNA synthesis change inversely during liver regeneration after
      hepatectomy.

PMID- 8665236
TI  - Effect of terminal ileal transposition on intestinal absorption following
      proctocolectomy.
AB  - A terminal ileal transposition procedure, in which a distal jejunal segment is
      interposed between the terminal ileum and the anus following proctocolectomy, is
      described. Adult mongrel dogs had either terminal ileal transposition (n = 5) or
      ileoanal anastomosis (n = 6) following two-stage proctocolectomy. Untreated dogs
      were used as controls (n = 7). Twelve weeks after the second-stage operation, a
      perfusion study was performed. After terminal ileal transposition the transposed
      terminal ileum showed a high absorptive capability for sodium, chloride and bile
      acids (P < 0.05, P < 0.05 and P < 0.001 respectively). After ileoanal anastomosis
      the absorptive capability of the terminal ileum was not enhanced significantly.
      In the mid-jejunum, the absorption of bile acids, chloride and glucose was
      enhanced (all P < 0.05) only after terminal ileal transposition. Terminal ileal
      transposition improves the absorptive capability of the terminal ileum and the
      mid-jejunum compared with conventional ileoanal anastomosis in this model.

PMID- 8665237
TI  - Nitric oxide and the rectoanal inhibitory reflex: retrograde neuronal tracing
      reveals a descending nitrergic rectoanal pathway in a guinea-pig model.
AB  - Nitric oxide has been implicated as the neurotransmitter mediating internal anal
      sphincter (IAS) relaxation during the rectoanal inhibitory reflex. However, there
      has been no direct demonstration of a nitrergic rectoanal neuronal pathway
      appropriate to mediating the reflex. This study combined retrograde neuronal
      tracing techniques with enzyme histochemistry in a guinea-pig model. Wheatgerm
      agglutinin conjugated to horseradish peroxidase was injected into the IAS.
      Transported tracer was demonstrated in neurones of the myenteric ganglia of the
      distal rectum and all labelled neurones showed co-localization with nitric oxide
      synthase as revealed by reduced nicotinamide adenine dinucleotide phosphate
      diaphorase histochemistry. In vivo anal canal manometry showed that the mean
      maximal resting pressure was 16 (8-20) cmH2O and confirmed the presence of the
      rectoanal inhibitory reflex. In vitro organ bath studies showed that strips of
      IAS developed spontaneous myogenic tone and relaxed in response to intrinsic
      nerve stimulation. Addition of N omega-nitro-L-arginine (L-NOArg) reduced the
      relaxant response in a dose-dependent fashion; the relaxant response was
      maximally reduced by a mean(s.e.m.) 35.2(3.8) per cent (P < 0.001) at a
      concentration of 3 x 10(-5) mol/l L-NOArg. This study provides direct anatomical
      evidence of a descending nitrergic rectoanal neuronal pathway in a guinea-pig
      model. In vivo anal manometry and in vitro organ bath studies provide additional
      evidence that this pathway is responsible for the inhibitory motor innervation of
      the rectoanal inhibitory reflex.

PMID- 8665238
TI  - Incidental appendicectomy for the long mobile appendix.

PMID- 8665239
TI  - Combination of skin temperature and a single white cell count does not improve
      diagnostic accuracy in acute appendicitis.

PMID- 8665240
TI  - Screening for colorectal cancer with an immunological faecal occult blood test: 2
      year follow-up.
AB  - This study is a 2-year follow-up of an average-risk population offered screening
      with both Haemoccult and Hemeselect tests to determine the interval cancer rate,
      and thus sensitivity. The effect on compliance with Hemeselect of testing over 1
      day rather than 3 days was investigated in a separate cohort. In the first study,
      3948 subjects received tests; 1489 (37.7 per cent) completed both tests and 148
      had a positive result, 17 (1.1 per cent) were Haemoccult positive and 145 (9.7
      per cent) were Hemeselect positive. Investigation of 142 patients revealed ten
      with cancer (Dukes stage A, seven; B, one; C, two). All were detected by
      Hemeselect but only one was Haemoccult positive. After a median follow-up of 35
      (range 26-43) months, seven further patients developed colorectal cancer (stage
      A, one; B, three; C, three) but none followed a negative Hemeselect test (100 per
      cent sensitivity). In the second study 2703 subjects were offered Hemeselect
      tests. Compliance for testing over 1 day (48.6 per cent) was significantly better
      than that over 3 days (43.1 per cent) (chi 2 = 8.1, 1 d.f., P < 0.01). Hemeselect
      is a promising screening test for the early detection of colorectal cancer.

PMID- 8665241
TI  - Physiological and clinical outcome of anterior sphincteroplasty.
AB  - A total of 55 women underwent sphincteroplasty for the treatment of faecal
      incontinence related to anterior defects. Patients were followed prospectively
      for a mean of 29 months to evaluate the outcome overall and according to age. All
      patients were evaluated clinically by means of a questionnaire and graded using
      an incontinence scoring system ranging from 0 (perfect continence) to 20
      (complete incontinence). Some 52 patients (95 per cent) had had a previous
      vaginal delivery and 30 (55 per cent) had a history of previous anal sphincter
      repair. Physiological and functional parameters in patients with a successful
      outcome (n = 39) were compared with those in patients with a poor outcome (n =
      16). The results were also compared in patients under (n = 39) and over (n = 16)
      60 years of age. Overall, patients with a successful outcome had a significant
      change in mean and maximal resting and squeeze pressures. These changes
      correlated well with the increase in the high-pressure zone (HPZ) length from 1.0
      2.2 cm (P = 0.0002) and with functional outcome (change in incontinence score
      from 15.3 to 5.8; P < 0.0001). In patients over 60 years of age, a significant
      change in mean squeeze pressure (P = 0.03) and HPZ length (P = 0.01) was noted
      and correlated with functional outcome (change in incontinence score from 14.3 to
      6.4; P < 0.0001). A successful outcome after anterior sphincteroplasty is related
      to improvement in sphincter function even in an older population. These results
      demonstrate that age itself does not seem to be a predictor of poor outcome.
      Patients should not be denied a repair exclusively on grounds of age.

PMID- 8665242
TI  - Carcinoma in an ileoanal pouch after restorative proctocolectomy for familial
      adenomatous polyposis.

PMID- 8665243
TI  - Ileocaecostomy: an alternative surgical procedure for antegrade colonic enema.

PMID- 8665244
TI  - Rectal ischaemia following hypovolaemic shock.

PMID- 8665245
TI  - Use of the carbon dioxide laser to manage cutaneous metastases from malignant
      melanoma.
AB  - Between October 1988 and November 1994, 100 patients with cutaneous metastases
      from malignant melanoma were treated by carbon dioxide laser ablation under local
      or general anaesthesia as appropriate. There were minimal postoperative
      complications and most wounds healed within 6 weeks. A total of 34 of the 53
      patients in this series with stage IIIa disease were controlled with four or
      fewer laser ablations during the first year from presentation. This technique
      provides a simple effective alternative to hyperthermic isolated limb perfusion
      with melphalan. Patients with disease not controlled by laser can be considered
      for isolated limb perfusion.

PMID- 8665246
TI  - Comparison of venous reflux in the affected and non-affected leg in patients with
      unilateral venous ulceration.
AB  - In 54 patients with unilateral leg ulceration of purely venous aetiology the only
      difference in venous reflux between affected and non-affected legs was with
      respect to the popliteal and crural veins. Deep and superficial venous reflux is
      common in legs without the skin changes typical of chronic venous insufficiency.
      The significance of venous reflux in an ulcerated leg cannot therefore be
      determined without reference to the contralateral, clinically normal, limb.
      Surgery should be directed at correcting reflux present in the ulcerated limb but
      not in the unaffected limb. In a minority of patients this entails superficial
      venous surgery alone, but in the majority such an approach would, ideally, entail
      correction of deep venous incompetence.

PMID- 8665247
TI  - Endovascular repair of abdominal aortic aneurysm: an initial experience.
AB  - Endovascular repair of abdominal aortic aneurysm (AAA) was attempted in ten
      patients over a 12-month period. Median age was 72 (range 61-82) years and median
      AAA diameter was 5.5 (range 5.2-6.0) cm. An aortoaortic (tube) graft was used in
      seven patients and a tapered aortoiliac reconstruction in three. There were two
      failures requiring conversion to open repair. Additional procedures included
      iliac artery angioplasty (two), coil embolization of an associated common iliac
      aneurysm (one) and femorodistal bypass (one). Median operating time was 162
      (range 95-270) min and median blood loss was 1200 (range 800-2000) ml. Median
      hospital stay was 9 (range 5-21) days. Complications included death (one),
      reversible acute tubular necrosis (one) and prolonged ventilation (one).
      Postoperative evaluation with duplex ultrasonography and computed tomography
      demonstrated three perigraft leaks (two proximal and one distal). It is concluded
      that endovascular repair of AAA is feasible but is associated with significant
      complications and requires careful evaluation before widespread use.

PMID- 8665248
TI  - Side-effect of endovascular grafting to treat aortic aneurysm.

PMID- 8665249
TI  - Surveillance imaging of the operated artery does not alter clinical outcome
      following carotid endarterectomy.
AB  - Clinical outcome was studied in 243 patients undergoing 260 carotid
      endarterectomies; 166 of these patients underwent serial postoperative
      surveillance imaging. Including perioperative events, cumulative freedom from
      ipsilateral stroke was 86 and 82 per cent at 5 and 10 years respectively; the
      mean incidence of ipsilateral stroke was 1.8 per cent per annum. Twenty patients
      (8 per cent) suffered cerebral ischaemic events in the hemisphere of the operated
      side during follow-up: eight transient ischaemic attacks (TIA) and 12 strokes
      (only two preceded by TIA). Two symptomatic patients were found to have occluded
      the operated artery but the remainder had no evidence of significant recurrent
      disease. Cumulative freedom from occlusion or severe (greater than 70 per cent)
      recurrent stenosis was 87 and 78 per cent at 5 and 10 years respectively; the
      mean incidence of recurrence of significant disease was 2.2 per cent per annum.
      No revisional surgery was performed on the operated arteries. In its current
      format, neither clinical nor surveillance imaging could have prevented any of the
      strokes observed during follow-up.

PMID- 8665250
TI  - Delayed pancreatoduodenectomy followed by delayed reconstruction for trauma.

PMID- 8665251
TI  - Adrenalectomy for metastatic disease to the adrenal glands.
AB  - A policy of supportive treatment is frequently adopted for patients with
      metastatic disease to the adrenal glands. This study reports an experience with
      adrenalectomy for adrenal metastasis. Between 1983 and 1993, adrenalectomy was
      performed in 52 patients for metastasis to the adrenal glands. Survival was
      calculated by the Kaplan-Meier method and compared with the log rank test.
      Primary tumour sites included kidney (n = 15), lung (n = 11), colon (n = 7),
      unknown (n = 5), stomach (n = 3), melanoma (n = 3) and other (n = 8).
      Adenocarcinoma (69 per cent) was the most common histological cell type. Thirty
      two patients were asymptomatic on initial evaluation. Symptomatic adrenal pain
      relief was achieved in 11 of 13 patients. Overall survival rates were 73 per cent
      at 1 year and 40 per cent at 2 years. Patients with potentially curative
      resection had better survival than those who had a palliative procedure. Patients
      with adrenal metastases due to adenocarcinoma had improved survival compared with
      that in those with other histological cell types. Although long-term survival is
      generally poor, highly selected patients with adrenal metastasis (symptomatic
      disease or adenocarcinoma) may benefit from surgical resection.

PMID- 8665252
TI  - Early postoperative plasma calcium concentration as a predictor of the need for
      calcium supplement after parathyroidectomy.
AB  - This study evaluated early postoperative serum calcium concentration as a
      predictor of hypocalcaemic symptoms and the need for calcium supplements. A total
      of 64 consecutive patients undergoing curative parathyroidectomy for primary
      hyperparathyroidism were studied. Twenty patients (31 per cent) developed
      hypocalcaemic symptoms requiring calcium supplements. Plasma calcium levels in
      the preoperative and early postoperative periods were similar in patients who
      required calcium supplements and those in whom they were not necessary. There was
      no significant difference in the percentage decrease in early calcium levels
      after operation between the two groups. In those undergoing reoperative surgery
      and subtotal parathyroidectomy the percentage decline was significantly higher in
      patients who required calcium supplements (12.8 versus 5.6 per cent, P < 0.005).
      A fall of 10 per cent or more was consistently followed by hypocalcaemic
      symptoms. Calcium determination in the early postoperative period is of little
      value in predicting the onset of hypocalcaemic symptoms.

PMID- 8665253
TI  - Laparotomy for abdominal sepsis in the critically ill.
AB  - Among 125 patients admitted to an intensive care unit (ICU) with severe abdominal
      sepsis over a 3-year period, further laparotomy was required in 60 (48 per cent).
      The median age of these 60 patients was 67 (range 22-88) years and their
      admission APACHE (Acute Physiology and Chronic Health Evaluation) II score was 24
      (range 7-40); 25 patients (42 per cent) survived to leave the ICU but only 19 (32
      per cent) survived to leave hospital. These patients underwent 95 (median 1;
      range 1-6) operations after admission to the ICU and survival fell with
      increasing number of operations in the ICU (P = 0.01). A total of 81 operations
      (85 per cent) were therapeutic in that pus was drained or dead tissue removed,
      and 41 operations (43 per cent) resulted in improvement in the patient's
      condition within 48 h of surgery. Only nine per cent of patients not improved by
      their first operation in the ICU survived (P < 0.0001). The source of sepsis was
      eradicated from the abdomen in 37 patients (62 per cent); this was a prerequisite
      for survival but was achieved less frequently with increasing number of
      operations (P < 0.002). When operations were delayed until the diagnosis was
      clear, the need for subsequent procedures was significantly increased (P < 0.05).
      Multiple operations for patients with abdominal sepsis in the ICU were associated
      with diminishing returns and alternative surgical strategies merit active
      consideration.

PMID- 8665254
TI  - Laparoscopic mobilization of the stomach for oesophageal replacement.
AB  - Nine patients of mean(s.d.) age 61(8) years underwent oesophagogastrectomy with
      laparoscopic gastric mobilization and abdominal lymphadenectomy for oesophageal
      cancer. Moderate to severe airway obstruction was present in all patients, in
      whom the mean(s.d.) value of forced expiratory flow rate at 1 s was 65(17) (range
      35-85) per cent of the predicted value. Six patients had an abdominal
      laparoscopic approach combined with a right open thoracotomy; the other three had
      a laparoscopic abdominal and transhiatal approach combined with a left
      cervicotomy. No patient required conversion to open laparotomy. All had an
      uneventful postoperative course with extubation occurring at the end of the
      surgical procedure (n = 2) or on day 1 after operation (n = 7). Mean(s.d.)
      duration of hospitalization was 10.3(3.1) (range 8-18) days. The laparoscopic
      approach for gastric mobilization and abdominal lymphadenectomy is safe and can
      be used in patients with impaired pulmonary function.

PMID- 8665255
TI  - Fc-receptor function after human splenic autotransplantation.
AB  - Mononuclear phagocytic function was studied using the Fc-receptor test in 24
      patients who underwent splenectomy, ten of whom underwent splenic
      autotransplantation. All patients undergoing autotransplantation had mononuclear
      phagocyte system (MPS) activity at the transplantation sites. In eight of the 14
      patients who did not undergo autotransplantation there was also scintigraphic MPS
      activity indicative of ectopic splenic tissue. Although the Fc-receptor test
      showed delayed and monoexponential blood clearance in all patients after
      splenectomy, there were no significant differences between the patient groups.
      Autotransplantation of small amounts of splenic tissue after splenectomy provides
      some MPS activity but is inadequate for blood clearance.

PMID- 8665256
TI  - Laparoscopic surgery for duodenal ulcer: first results of a multicentre study
      applying a personal procedure.
AB  - Between January 1991 and February 1995 data were gathered on 136 patients
      operated on in 14 surgical centres. All patients underwent posterior truncal
      vagotomy (PTV) and anterior linear gastrectomy (ALG) for chronic duodenal ulcer.
      Recurrence and repeated bleeding were the main indications for surgery. An
      antireflux technique was simultaneously carried out in 17 patients, while 13
      underwent cholecystectomy. There were no peroperative complications or deaths,
      and the mean duration of operation was 65 (range 25-180) min. Immediate
      postoperative morbidity rate was 2.9 per cent, with a mean hospital stay of 3.1
      (range 2-13) days. A total of 131 patients were evaluated between 6 and 33 (mean
      25) months after operation. Of these, 126 (96.2 per cent) were graded as Visick I
      or II. Four (3.0 per cent) were Visick III, and one patient (0.8 per cent) was
      considered Visick IV. Gastric function studies were performed in 45 patients
      before and after operation, with a maximum acid output reduction of 83 per cent 3
      months after the operation. Laparoscopic PTV with ALG constitutes a simple,
      efficient, rapid and safe method in the treatment of patients with chronic
      duodenal ulcer.

PMID- 8665257
TI  - Synergistic antitumour effect of recombinant human tumour necrosis factor alpha
      with melphalan in isolated limb perfusion in the rat.
AB  - The efficacy of isolated limb perfusion (ILP) for 'intransit' metastases from
      malignant melanoma and irresectable soft tissue sarcoma has been improved
      considerably by the addition of tumour necrosis factor (TNF) alpha. A rat sarcoma
      tumour model was, therefore, developed to evaluate the effects of TNF-alpha,
      melphalan and the combination of these drugs in the treatment of sarcoma. In BN
      rats bearing the non-immunogenic BN 175 sarcoma ILPs were performed with
      perfusate only, TNF-alpha, melphalan alone, or in combination when tumours had
      grown to approximately 1.5 cm in diameter. All rats treated with sham perfusion
      or perfusion with 50 micrograms TNF-alpha showed progressive disease. After
      perfusion with 40 micrograms melphalan no change in tumour diameter was observed
      in any rats at 4 days. After a combined perfusion with 40 micrograms melphalan
      and 50 micrograms TNF-alpha complete remission was noted in 12 of 16 rats. This
      synergistic effect in vivo between relatively ineffective doses of TNF-alpha and
      melphalan was not observed in vitro.

PMID- 8665258
TI  - Bladder injury during laparoscopic abdominoperineal resection.

PMID- 8665259
TI  - Lateral subcutaneous sphincterotomy for treatment of anal fissure in children.

PMID- 8665260
TI  - Surgical treatment for morbid obesity.

PMID- 8665261
TI  - Single-stage treatment for malignant left-sided colonic obstruction: a
      prospective randomized clinical trial comparing subtotal colectomy with segmental
      resection following intraoperative irrigation.

PMID- 8665262
TI  - Speciation of organotin and organolead compounds in drinking water by gas
      chromatography--atomic emission spectrometry.
AB  - Raw and treated water samples and distribution system water samples were
      collected in forty-five Canadian municipalities for the analysis of organotin and
      organolead compounds. After extraction from the water samples organotin and
      organolead compounds were alkylated with pentylmagnesium bromide and
      butylmagnesium chloride respectively and analysed by gas chromatography-microwave
      induced plasma atomic emission spectrometry (GC-AED) using wavelengths specific
      for tin (326.23 nm) and lead 405.78 nm). The GC-AED system was optimised for
      trace level analysis, especially for organolead compounds. Organotin compounds,
      mainly methyltin and butyltin at concentrations up to 22 ng Sn/L and 43.6 ng Sn/L
      respectively, were detected in distributed water samples from six municipalities.
      No organotin compounds were detected in raw water samples indicating that the
      organotin compounds were leaching into the water from some component of the
      distribution system. One raw water sample contained six organolead compounds at
      concentrations from 0.5 to 10 ng Pb/L and five raw water and three distributed
      water samples contained trace levels ( < 0.5 ng Pb/L) of organolead compounds.
      Due to the lack of authentic standards the identity of the organolead compounds
      could not be confirmed by gas-chromatography mass-spectrometry.

PMID- 8665263
TI  - Changed central and peripheral catecholamines and indoleamines in one-way crossed
      intestine rats: relationship to changes in feeding behavior and metabolism.
AB  - The involvement of central and peripheral catecholamines and serotonin (5-HT) in
      regulation of feeding and energy metabolism was examined in one-way crossed
      intestine rats that show large and sustained changes in daily food intake. Five
      to six weeks after the crossed-intestinal surgery, catecholamines and
      indoleamines in dissected major brain regions and in the heart, intrascapular
      brown adipose tissue (IntBAT), pancreas, and serum were determined using HPLC
      with electrochemical detection. The food-losing rats increased daily food intake
      from 70.8 to 126.3 g, whereas their partners decreased daily food intake from
      67.1 to 38.7 g (p < .001). Compared with the partners and sham-operated controls,
      the food-gaining rats had increased 5-hydroxy-indoleacetic acid (5-HIAA)
      throughout the brain [hypothalamus, 442.9 vs. 383.5 (p < .05) and 404.2 ng/g (p <
      .05), Lateral cortex plus amygdala (LC + A), 236.6 vs. 216.8 (p < .05) and 212.0
      ng/g (p < .05), brain stem, 282.9 vs. 238.7 (p < .05) and 245.1 ng/g (p = .05),
      cerebellum, 56.7 vs. 49.6 (p < .05) and 44.4 ng/g (p < .05)]. Higher 5-HIAA in
      food-gaining rats that were undereating are consistent with serotonin's role in
      inhibiting food intake. Peripherally, the rats gaining food showed significantly
      lower NE, 5-HT, and 5-HIAA in IntBAT compared with their partners (NE, 994.2 vs.
      1236 ng/g, 5-HT 338.0 vs. 527 ng/g, and 5-HIAA, 39 vs. 51 ng/g). Because NE and 5
      HT have been shown to exert stimulating effects on BAT-mediated thermogenesis,
      lower levels of NE, 5-HT, and 5-HIAA in IntBAT of food gaining rats are
      compatible with the lower metabolic rate observed in these animals. The results
      show that both central and peripheral catecholamines and serotonin are involved
      in regulation of food intake and energy metabolism.

PMID- 8665264
TI  - beta-Amyloid precursor protein (beta APP) in human gut with special reference to
      the enteric nervous system.
AB  - The distribution of the beta-amyloid precursor protein (betaAPP) in the human
      gastrointestinal tract, from esophagus trough rectum, was studied using
      immunoblotting, as well as combined immunohistochemical and image analysis (optic
      microdensitometry) techniques. The study was focused on the enteric nervous
      system. betaAPP was detected by means of a monoclonal antibody (22C11), which
      recognizes all betaAPP isoforms as well as betaAPP-like proteins. Immunoblotting
      revealed two main protein bands, one corresponding to full-length betaAPPs
      (estimated molecular masses of approximately 97-115 kDa); the other corresponded
      to a protein with estimated molecular masses of 55 kDa. Specific betaAPP
      immunoreactivity (IR) was found in the submucous and myenteric plexuses localized
      in the supporting glial cells rather than in neurons. Differences were
      encountered neither in the localization nor in the intensity of immunostaining
      among different segments of the gastrointestinal tract. Moreover, no age
      dependent changes were found. betaAPP IR was also regularly observed in blood
      vessels, primarily labelling endothelial cells. Our results provide evidence for
      the occurrence of betaAPP in human gastrointestinal tract of healthy people in
      both neuronal and nonneuronal tissues. Whether or not these findings have
      functional or clinical relevance remains to be clarified in future studies.

PMID- 8665265
TI  - Prefrontal cortical mediation of rats' place learning in a modified water maze.
AB  - The acquisition of a place learning task in a water maze modified from the
      "standard" set-up by restriction of distal cues and addition of "proximal" cues
      (ping-pong balls in fixed positions on the surface of the water) was tested in
      three groups of rats: (I) animals subjected to bilateral ablation of the
      anteromedial prefrontal cortex, (II) rats in which the parietal "association"
      cortex had been removed bilaterally, and (III) a sham operated control group. The
      task acquisition of the prefrontally ablated group was significantly impaired,
      whereas the animals in which the parietal cortex had been removed acquired the
      task as quickly as the control group. Upon reaching criterion level performance
      all animals were tested on "challenge" sessions on which the cues were
      manipulated. Such "challenges" demonstrated that the animals of all three groups
      discriminated between the distal cues and utilized such a discrimination for
      navigational purposes.

PMID- 8665266
TI  - Glucagon-like peptide-1(7-36)amide induces the release of aspartic acid and
      glutamine by the ventromedial hypothalamus of the conscious rat.
AB  - Glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and its own receptor have
      been found in the hypothalamus and brain stem of the rat. In an attempt to gain
      further insight into the role of this peptide in brain functioning we
      investigated the effects of GLP-1 (7-36)amide on the release of excitatory amino
      acid neurotransmitters by the ventromedial hypothalamus using an experimental
      microdialysis approach. GLP-1(7-36)amide produced an immediate increase in the
      extracellular concentrations of aspartic acid and glutamine, p < 0.01 and p <
      0.05, respectively. By contrast, extracellular concentrations of glutamic acid,
      alanine, threonine, and tyrosine were unaffected. The results of this study show
      a stimulatory effect of GLP-1(7-36)amide on the release of aspartic acid and
      glutamine by the ventromedial hypothalamus of the rat.

PMID- 8665267
TI  - Angiotensin II receptor subtypes and phosphoinositide hydrolysis in rat adrenal
      medulla.
AB  - Angiotensin II (ANG) receptor subtypes were characterized by quantitative
      autoradiography after incubation with the ANG agonist [124I]Sar1-ANG in rat
      adrenal medulla. ANG receptors are highly localized in adrenal medulla. Specific
      binding was displaced by 4% and by 95% with the AT, receptor blocker losartan and
      the AT2 receptor competitor CGP 42112A, respectively. Analysis of competition
      curves indicated relative binding potencies for the AT2 population of CGP
      42112A>PD 123319> PD 123177. ANG stimulated +-nositol phosphate formation in a
      dose-dependent manner in rat adrenal medulla. Losartan at concentrations of 10(
      9) to 10(-5) M antagonized the effect of ANG, whereas PD 123177 or PD 123319 had
      no antagonistic action. However, at a higher concentration (10(-5) M) PD 123177
      or PD 123319 potentiated the effect of ANG on InsP1-accumulation. In the presence
      of PD 123319 (10(-5) M) ANG dose-response curve was shifted to the left with no
      change in the maximal effect. This affect was blocked by the addition of losartan
      (10(-5) M). On the contrary, the addition of CGP 42112A (10(-6) M) inhibited ANG
      induced increase in InsP1-accumulation. On the other hand, ANG and CGP 42112A
      reduced basal cyclic GMP formation, this effect was partially reverted by sodium
      orthovanadate, a phosphotyrosine phosphatase inhibitor. Our results further
      demonstrate the presence of two ANG receptor subtypes in adrenal medulla: ANG
      binding to AT, receptor stimulates inositol phospholipid metabolism, whereas ANG
      binding to AT2 receptors decreases both inositol phosphate production and cGMP
      formation.

PMID- 8665268
TI  - Electrophysiological analysis of midbrain periaqueductal gray influence on
      cardiovascular neurons in the ventrolateral medulla oblongata.
AB  - Stimulation of sites in the rostral or caudoventral periaqueductal gray (PAG)
      results in substantial increases in mean blood pressure (MBP) and heart rate
      (HR). The efferent pathways from these PAG subregions possibly include a relay in
      the ventrolateral medulla oblongata (VLM), where neurons involved in maintaining
      vasomotor tone are located. Extracellular recordings were made from 21
      cardiovascular neurons in the rostral VLM (RVLM) and from 6 cardiovascular
      neurons in the caudal VLM (CVLM) of the rat. These neurons showed barosensitivity
      and cardiac rhythmicity. In addition, the activity of 54 non- cardiovascular and
      nonrespiratory units was recorded. Responses to electrical stimulation of sites
      in the (rostral or caudal) PAG were studied in 16 of the 21 cardiovascular RVLM
      neurons, the 6 CVLM neurons, and 46 of the 54 noncardiovascular neurons. Eight of
      the RVLM neurons were excited by rostral PAG stimulation; the poststimulus time
      histograms showed a constant latency in live units (32 +/- 3 ms). This suggests
      the presence of relatively direct (although not monosynaptic) excitatory pathways
      from the rostral PAG to cardiovascular neurons in the RVLM, consisting of slowly
      conducting fibers (0.2-0.3 m/s). Five RVLM neurons did not respond to rostral PAG
      stimulation. Three units were tested with caudal PAG stimulation: one was
      excited, one inhibited, and one was unresponsive. The six cardiovascular CVLM
      neurons did not respond to PAG stimulation. Of the 46 noncardiovascular neurons,
      14 cells were excited, 7 inhibited, and 2 cells antidromically activated. These
      results confirm earlier findings, extending them to the rostral PAG. They supply
      further evidence for the influence of the PAG on the cardiovascular function
      related neuronal circuitry in the VLM.

PMID- 8665269
TI  - Use of MRI for measuring structures in frozen postmortem brain.
AB  - A method was developed for magnetic resonance imaging (MRI) of human autopsy
      brains stored long-term at -70 degrees C. Scanning brains at temperatures between
      -70 and -8 degrees C gave minimal MRI signals consistent with protons having
      limited freedom of movement at low temperature. Raising brain temperature
      improved the signal such that scanning at -1 degree C generated images with good
      in-plane resolution, grey/white matter contrast, and fine detail of cortical
      sulcal/gyral patterns. To validate the method, volume and area measurements were
      made using computerized image analysis on stored digital images of 14 brains from
      adult subjects of both genders and various ages. The data confirmed that brain
      volume was inversely correlated with age, and female subjects had smaller brains.
      This is a valuable new method for acquiring morphometric data from previously
      unscanned pathologic brains that are to be used for neurochemical and molecular
      investigations.

PMID- 8665270
TI  - The reciprocal synaptic relations between enkephalinergic neurons and
      catecholaminergic neurons in the area postrema.
AB  - A preembedding double immunostaining technique using antibodies against
      methionine-enkephalin and tyrosine hydroxylase was used to study synaptic
      relations between enkephalinergic and catecholaminergic neurons in the area
      postrema of the rat at the electron microscopic level. The large nuclei
      containing cell bodies of the catecholaminergic neurons displayed well-developed
      Golgi apparatus. The catecholaminergic somata and dendrites received synapses
      from enkephalinergic axon terminals, and most of the synapses were symmetrical.
      Occasionally, the catecholaminergic axon terminals were also found to be
      presynaptic to the enkephalinergic dendrites. Because the enkephalinergic neurons
      have been reported to be involved in cardiovascular function and the
      catecholaminergic neurons involved in the vomiting behavior, the synapses
      observed in this study may provide morphological evidence of the relationship
      between the vomiting and cardiovascular functions that are triggered in the area
      postrema.

PMID- 8665271
TI  - Aldehyde fixation differentially affects distribution of diaphorase activity but
      not of nitric oxide synthase immunoreactivity in rat brain.
AB  - The effect of aldehyde fixation on NADPH- and NADH-dependent diaphorase (d)
      histochemistry and nitric oxide synthase (NOS) immunocytochemistry in the brain
      was investigated by comparing the distribution of these enzymes in in situ
      nitrocellulose blots of unfixed brain sections with that in aldehyde-fixed brain
      sections. Substitution of NADPH by NADH yielded no gross differences in cellular
      distribution in the native blot, whereas in fixed sections NADH produced
      nonspecific staining of the entire section. In the in situ blot NADPHd
      histochemistry therefore visualized general nitroblue tetrazolium reductase
      (NBTr) activity, which was particularly strong in hippocampal pyramidal neurons
      and cerebellar Purkinje cells. Aldehyde fixation abolished the anatomical pattern
      of general NBTr activity and changed the histochemical distribution in that of
      the NADPHd activity associated with the distribution of NOS-I immunoreactivity
      (ir). Fixation intensified NADPHd histochem- ical staining in specific neurons,
      resulting in outstanding, Golgi-like staining of these neurons in several brain
      regions, whereas the general NBTr activity in pyramidal and Purkinje cells
      disappeared. In contrast to the histochemical diaphorase distribution, the
      distribution of NOS-I ir on blots and in aldehyde-fixed brain sections was
      similar. No NOS was observed in hippocampal pyramidal and cerebellar Purkinje
      neurons. In regions like cerebral and cerebellar cortex and striatum the applied
      anti NOS-I serum had a higher affinity for the native protein. It is concluded
      that aldehydes, rather than to progressively suppress NOS-unrelated enzymes,
      differentially elicit NADPHd activity in some groups of neurons while leaving NOS
      ir unaffected.

PMID- 8665272
TI  - Nucleus reticularis thalami connections with the mediodorsal thalamic nucleus: a
      light and electron microscopic study in the monkey.
AB  - Wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) and
      biotinylated dextran amine (BDA) were used as tracers to study nucleus
      reticularis (NRT) connections with the mediodorsal nucleus (MD). Injections of
      WGA-HRP in the MD resulted in retrograde labeling of cells in the anteromedial
      segment of the NRT, the so-called rostral NRT pole. Injections of WGA-HRP and BDA
      in this NRT region resulted in dense anterograde labeling in the MD. Labeled NRT
      fibers gave off several collaterals to different MD regions ending with terminal
      plexuses of thin varicose fibers. In the neuropil, the varicosities were
      distributed at random, and no tendency to form pericellular baskets was noted.
      Postembedding immunocytochemistry for GABA was performed on the tissue containing
      anterograde WGA-HRP label for identification of NRT boutons under electron
      microscope. The double-labeled boutons were of small to medium size, contained a
      large number of pleomorphic vesicles, few mitochondria, and formed multiple
      symmetric synaptic contacts. The number of contacts established by one bouton
      ranged from 1 to 4 with an average of 1.8 per bouton. About 60% of these boutons
      made synapses on distal dendrites of GABAergic local circuit neurons; 33% of
      synaptic contacts were on distal dendrites of thalamocortical neurons, and the
      rest on their proximal dendrites and soma. NRT boutons were also found in serial
      synapses and triads. The results demonstrate that the NRT input to the MD is
      organized so that a single fiber innervates; different MD regions and its
      terminals form numerous synaptic contacts mostly on the distal dendrites of a
      large number of local circuit neurons and projection neurons.

PMID- 8665273
TI  - Nitric oxide reduces body temperature and sympathetic input to brown adipose
      tissue during PGE1-hyperthermia.
AB  - The firing rate of the nerves innervating interscapular brown adipose tissue
      (IBAT) and IBAT and colonic temperatures (TIBAT and TC were monitored in urethane
      anaesthetized male Sprague-Dawley rats. These variables were measured for 40 min
      before (baseline values) and 40 min after a 4 micromoles L-arginine (L-arg) or
      400 nmoles nitroprusside (NP) injection in a lateral cerebral ventricle and an
      intracerebroventricular administration of 500 ng prostaglandin E1 (PGE1). The
      same variables were monitored in other rats with L-arg or NP or PGE1
      administration alone. No drug was injected in control rats. The results show that
      L-arg or NP injection reduces the increases in firing rate, TIBAT, Tc induced by
      PGE1. These findings suggest that nitric oxide is important in the control of
      thermogenic changes during the PGE1 hyperthermia.

PMID- 8665274
TI  - Physiological properties of the output neurons in the deep layers of the superior
      colliculus of the rabbit.
AB  - Using antidromic and orthodromic stimulation techniques, we studied physiological
      properties of the output neurons in the deep layers of the superior colliculus
      (SC) of 34 Now Zealand rabbits. SC cells antidromically activated from the
      contralateral predorsal bundle (PDB) could also be activated by stimulation of
      the contralateral SC and ipsilateral central lateral nucleus of the thalamus
      (CL). The majority of these output neurons responded predominantly to the
      stimulation of the optic nerve, and only a small proportion of the output neurons
      were responsive to the stimulation of somatosensory and auditory (and/or
      vestibular) nerves. These results suggest that the orienting reflex might be
      elicited mainly by visual afferents in the rabbit. The output SC neurons were
      subject to a 70 ms inhibition after antidromic stimulation of the PDB and a 40 ms
      inhibition after transsynaptic (orthodromic) stimulation of the optic chiasm
      (OX), indicating that the output neurons in the deep layers of the SC might be
      subject to at least two inhibitory circuits. These results are discussed in the
      context of a putative saccadic suppression circuitry model.

PMID- 8665275
TI  - Comparative rewarding properties of morphine and butorphanol.
AB  - Because butorphanol (Stadol), a synthetic morphinan compound, has been
      demonstrated in our laboratories to produce physical dependence and withdrawal
      symptoms in rats, we have hypothesized that butorphanol has rewarding properties
      indicative of abuse potential. To test this hypothesis, the effects of equimolar
      doses of butorphanol tartrate (0.5-5.0 micrograms) and morphine sulfate (0.8-8.0
      micrograms) were assessed in inbred Lewis male rats using the conditioned place
      preference (CPP) paradigm. Unilateral microinjections (1 microl/inj) of saline or
      opioids were made into the ventral tegmental area (VTA). Microinjections of
      saline to controls were associated with both sides of modified Skinner boxes,
      whereas opioid injections were associated only with the white chambers (less
      preferred side to the naive animals). Opioids were administered alternating with
      saline in the drug-treated animals on alternating days. During eight conditioning
      sessions the rats learned to associate light and dark sides of the Skinner boxes
      with microinjections of opioids or saline, respectively. Although all doses of
      morphine induced significant preference over saline, only the higher doses of
      butorphanol (2.0-5.0 micrograms) produced significant conditioned place
      preference for the sides of the chambers associated with the drugs. These results
      suggest that, like morphine which is widely abused, butorphanol also has
      rewarding properties, and, therefore, further investigations regarding its abuse
      potential are necessary.

PMID- 8665276
TI  - Sport performance attributions: a special case of self-serving bias?
AB  - In laboratory studies, it has been found that people tend to take credit for
      success and to blame external factors for failure. In sport studies, this self
      serving bias has not been consistently demonstrated. Two studies explored factors
      hypothesized to account for differences between attributions made in laboratory
      and field settings. Study 1 was a laboratory experiment in which subjects
      performed a stair climbing task. It was hypothesized that these subjects would
      not make self-serving attributions because the laboratory setting had been
      designed to include features of athletic settings. Counter to the hypothesis,
      results indicated self-serving bias effects. Study 2 was a field study in which
      elite tennis players made attributions for their match performances. As in past
      sport research, self-serving attributions were not found. These results support
      contentions that sport settings differ from laboratory settings and that further
      theorizing is needed to explain self-serving bias processes in sport.

PMID- 8665277
TI  - Exercise-induced muscle damage and inflammation: a review.
AB  - Unaccustomed exercise may result in significant damage to skeletal muscle and
      cause delayed onset muscle soreness (DOMS) in both recreational and elite
      athletes. Two basic mechanisms-'metabolic' and 'mechanical' stress--have been
      proposed to explain how exercise initiates damage to skeletal muscle fibres. The
      extent of damage, particularly after eccentrically-biased exercise, has been
      assessed by histological and ultrastructural examination, and the measurement of
      the efflux of cytosolic enzymes into the circulation. The role of reactive oxygen
      species in the mediation of exercise-induced oxidative damage to muscle and the
      protection offered by anti-oxidant defence systems have been well studied. Free
      radical generation is normally estimated by indirect methods such as
      chemiluminescence, spectrophotometry, flow cytometry, or the measurement of
      products of lipid peroxidation such as malondialdehyde (MDA) and thiobarbituric
      acid reactive substances (TBARS). Although several theories have been proposed to
      account for the DOMS phenomenon, the underlying mechanisms are still to be
      elucidated. A group of proteins known collectively as cytokines regulate
      inflammatory and immunological processes involved in the repair of damaged
      tissue.

PMID- 8665278
TI  - Injury profile of amateur Australian rules footballers.
AB  - Australian Rules Football is played by numerous young Australians throughout
      winter each year. There have been a number of studies on professional and semi
      professional footballers, establishing the nature and frequency of injuries
      within this football code. Medical cover of an amateur football club over the
      1993 season allowed detailed recording of injuries over this period. The data
      collected revealed a markedly different injury profile to that seen previously.
      The injury rate in this study was 96 per 1000 player hours. The most common
      injury was concussion (15%), with hand fractures next most frequent (13.5%). The
      lower limb was the most common site of injury, with head and neck second and
      upper limb third. Injuries with an overuse component were seen less commonly in
      the amateur group while traumatic injuries were more frequent. The time allocated
      by amateur footballers to their sport is less than professional players, quite
      aside from the difference in skill level attained. Overuse injuries may be
      correspondingly much less frequent on a time basis alone. The increased incidence
      of traumatic injuries is postulated to be a manifestation of both less well
      developed skills and possibly less available and effective preventative measures
      such as ankle strapping and tape supplies. Considering the large number of young
      people playing amateur football and the significant time and cost of what are
      often relatively minor injuries, more work is required to establish what injuries
      are most common, and importantly, what measures can be taken to decrease their
      incidence.

PMID- 8665279
TI  - Leuko and Nessa Ankle braces: effectiveness before and after exercise.
AB  - This study compared the effectiveness of Leuko and Nessa Ankle braces in
      restricting inversion before, during and after exercise. Thirteen Australian
      Rules Footballers with a mean age of 23.7 years (range = 17-30), and who had no
      previous history of moderate to severe ankle sprains, were tested in this study.
      A pedal goniometer was used to measure active inversion with the ankle in 42
      degrees plantarflexion. Measurements were taken prior to the application of the
      brace, immediately after the brace was applied, after 20 minutes of controlled
      activity involving running, side-stepping and jumping, and after a further 20
      minutes of identical drills. A study design in which all subjects were required
      to wear each brace once was used. Analysis revealed no significant difference in
      ankle inversion between braces at any of the measurement times (p > 0.05). Both
      the Nessa and Leuko Ankle brace significantly restricted inversion immediately
      after the brace was applied, after 20 and 40 minutes of exercise. The results
      provide objective guidelines for the prescription of ankle braces in the
      prevention of ankle injuries during physical activity.

PMID- 8665280
TI  - The physiological requirements of Soccer refereeing.
AB  - The movement patterns and heart rate responses of Soccer referees during matches
      were examined. A movement analysis was performed using a grid method and subjects
      wore a PE 3000 heart rate monitor during the match. The mean distance (+/- SD)
      covered was 9,408 m (+/- 838m) which comprised: walking (18.9%), jogging (46.6%),
      running/striding (12.1%), sprinting (6.2%) and backwards movement (16.2%). If
      walking and jogging are pooled as low intensity activity and high intensity work
      is defined as running/striding and sprinting then the majority of distance was
      covered by low intensity activity (65.5%). No differences in the total distance
      covered during the two halves was evident. However, in the second half the
      subjects walked more than in the first half (p < 0.01), while they ran/strode
      more in the first when compared to the second half (p < 0.01). The subjects' mean
      heart rate during the first and second halves was not significantly different and
      were 163 and 162 beats per minute (b.min-1) respectively. If the theoretical
      maximum heart rate for each subject (220-age) is used, the major percentage of
      the time was spent at heart rates above 85% HRmax. Based upon the distance
      results of this study, the major energy source for Soccer refereeing would appear
      to be the aerobic system with the anaerobic system contributing to ATP production
      to a lesser extent. The results of this study suggest that refereeing at a high
      level places a significant physiological demand upon these athletes; they
      therefore require specialised assessment and training.

PMID- 8665281
TI  - Low-power lasers in medicine. A report by the Australian Health Technology
      Advisory Committee (AHTAC) June 1994.
AB  - Low-power lasers are those that deliver an output power in the milliwatt (mW)
      range. Output is typically between 1 and 30 mW, but can be up to 100 mW; It has
      been suggested that low power lasers cause biostimulation--a photochemical
      response to laser light inducing biochemical alterations in cells. However, there
      is no universally agreed theory to explain the mechanism of the claimed effects
      of treatment; The wavelengths, treatment protocols and conditions to be treated
      are not established; Low-power lasers are in widespread use for the treatment, in
      the main, of a range of musculoskeletal problems, despite little published
      evidence of efficacy; Evidence from controlled trials is inconclusive and
      conflicting; The Australian Health Technology Advisory Committee considers that
      the efficacy of low-power lasers in the treatment of musculoskeletal and other
      conditions is not established. The Committee therefore recommends that; those who
      use this technology should take steps to obtain unequivocal evidence of benefit
      from appropriately designed and conducted trials; and in any clinical use of such
      lasers, the treatment protocols should be clearly defined.

PMID- 8665282
TI  - Reply by Rushall and King to replies to their AJSMS (1994) article.

PMID- 8665283
TI  - Arthroscopic treatment of adhesive capsulitis.
AB  - Although conservative management with or without manipulation performed with the
      patient under anesthesia is the generally accepted treatment strategy for
      adhesive capsulitis, considerable interest is being shown in arthroscopic
      surgical procedures for this disorder. This study reviews the outcome of patients
      who underwent an arthroscopic release of the inferior capsule, reproducing in a
      controlled fashion the traumatic disruption of the inferior capsule commonly
      caused by manipulation with the patient under anesthesia. The outcome of 24
      patients (26 shoulders) was assessed with an average follow-up of 13.5 months. A
      total of 88% of patients were very satisfied with the procedure, and no operative
      complications occurred. A return to normal or near normal shoulder function in
      76% or more of the study group for forward flexion, abduction, and external
      rotation was demonstrated. A total of 50% of patients still had some restriction
      in internal rotation. The Constant Scoring system, also used to assess clinical
      shoulder function, revealed 87% of patients had achieved an excellent or good
      result when compared with the contralateral normal shoulder score. Our results
      suggest that arthroscopic capsular release is a safe and effective treatment for
      adhesive capsulitis, with patterns of recovery that compare favorably to other
      treatment modalities.

PMID- 8665284
TI  - Articular surface partial-thickness rotator cuff tears.
AB  - Between 1987 and 1992, one hundred eleven articular surface partial-thickness
      rotator cuff tears were diagnosed in 106 patients; 90 were men, and 16 were
      women. The average age was 42.5 years. Average follow-up was 32.3 months, ranging
      from 26 to 84 months. Patients were separated into three groups. Group 1
      consisted of 85 shoulders in which impingement was believed to be the primary
      cause; these shoulders were treated with debridement of the tear and arthroscopic
      subacromial decompression. Group 2 consisted of 14 shoulders with instability
      treated with debridement of the partial tear and anterior reconstruction (n = 10)
      or debridement and rehabilitation (n = 4). Group 3 contained 12 shoulders with
      tearing caused by trauma that were managed with debridement and open repair, if
      necessary. In 98 of 111 cases (88%), the patients had a satisfactory result. Five
      patients required open rotator cuff repair at a later date because of continued
      symptoms. Complications included significant postoperative stiffness in four
      shoulders, which required open release.

PMID- 8665285
TI  - Recurrent instability of the shoulder after age 40.
AB  - Twelve patients who had recurrent instability of the shoulder with onset after
      age 40 were reviewed. Eleven had anterior instability, and one had a posterior
      dislocation. The average age of the patients was 62.7 years. Symptoms began soon
      after initial injury. All patients with anterior instability had ruptured the
      subscapularis and anterior capsule from the lesser tuberosity, whereas the
      posterior dislocator had torn the infraspinatus and upper teres minor with the
      posterior capsule from the greater tuberosity. No patient had a Bankart lesion.
      Stability was restored in all cases by reattaching the ruptured tendons and
      capsule to the tuberosities. Follow-up was from 2 to 13 years. One patient
      required a reoperation. All patients now have a stable shoulder. Recurrent
      instability of the shoulder after age 40 can be caused by rotator cuff and
      capsular rupture from the tuberosities without additional significant injury to
      the ligamentolabral complex. In such cases, repairing the torn structures is
      sufficient to restore stability.

PMID- 8665286
TI  - Magnetic resonance imaging evaluation of capsulolabral tears after traumatic
      primary anterior shoulder dislocation. A prospective comparison with arthroscopy
      of 25 cases.
AB  - The purpose of our study was to evaluate the use of static magnetic resonance
      imaging (MRI) as a preoperative diagnostic tool in young patients with a
      traumatic primary anterior shoulder dislocation. Twenty-five patients who had
      acute primary traumatic anterior shoulder dislocation were examined with MRI and
      arthroscopy. The patients (18 male and 7 female) were between 16 and 39 years old
      (mean age, 27 years). They had no previous shoulder dislocations. The
      dislocations were confirmed radiographically. Examination with MRI and
      arthroscopy was performed within 10 days after the trauma. The MRI evaluation was
      performed before the arthroscopic examination, and the images were interpreted by
      an experienced magnetic resonance radiologist. No information from the MRI
      examination was available to the orthopedic surgeons before arthroscopy. The
      standard of reference for comparison was arthroscopy. Subacute MRI evaluation
      identified 15 labral tears, 12 Hill-Sachs lesions, 1 total rotator cuff lesion, 1
      partial joint side rotator cuff lesion, and 1 partial rupture of the biceps
      tendon. Arthroscopic examination revealed 22 labral tears, 15 Hill-Sachs lesions,
      1 total rotator cuff lesion, 1 partial joint side rotator cuff tear, 1 partial
      rupture of the biceps tendon, and 1 osseous Bankart lesion. Anterior
      capsulolabral tears and Hill-Sachs lesions appeared with a high incidence after
      acute anterior primary shoulder dislocation. Conventional MRI was only moderately
      reliable in the preoperative evaluation of labral tears and Hill-Sachs lesions,
      and it failed to give an accurate, differentiated preoperative diagnosis of the
      capsulolabral lesions.

PMID- 8665287
TI  - Tenodesis of the long head of biceps brachii in the painful shoulder: improving
      results in the long term.
AB  - Fifteen shoulders of 14 patients with a keyhole tenodesis of the long head of the
      biceps were reviewed at an average follow-up of 7 years (3 years, 1 month to 13
      years, 2 months). In 13 cases additional shoulder disease was noted during the
      operation. Eight patients had undergone rotator cuff decompression before the
      reference biceps tenodesis was performed. Eight (53%) cases achieved an excellent
      result; one was rated as good, four were rated as fair, and two had failures.
      Seven shoulders had an improved result from short to long term, and only two
      deteriorated. An upward migration of the humeral head on x-ray evaluation was
      noted but was without clinical significance. A local anesthetic test to the long
      head of the biceps before the operation seemed to be valuable in assessing
      chances of a good long-term result.

PMID- 8665288
TI  - Long tendon of the biceps brachii: sites of predilection for degenerative
      lesions.
AB  - The extreme stress on the long head of the biceps tendon is defined by its
      specific anatomic course, with its proximity to the rotator cuff, the
      intertubercular groove and the acromion. We studied the morphologic and cross
      sectional anatomy of the long head of the biceps tendon in 104 cadavers to
      analyze degenerative lesions. Degenerative changes in the tendon (disorganized
      collagen fibers and large mucoid deposits) occurred mainly in the distal
      bicipital groove and near the origin of the tendon from the superior part of the
      glenoid labrum. The results of histologic examination identified sites that
      possibly have a predilection for tendon rupture.

PMID- 8665289
TI  - Roentgenographic assessment of acromial morphologic condition in rotator cuff
      impingement syndrome.
AB  - Patients with an isolated diagnosis of rotator cuff impingement syndrome were
      prospectively entered into the study. Each of the 23 subjects was refractory to
      conservative therapy, had preoperative roentgenograms, and underwent an open
      acromioplasty. The roentgenograms included anteroposterior, axillary, 30 degrees
      caudal tilt, and supraspinatus outlet views. The roentgenograms were measured by
      four independent readers. The separate views were then scored for reliability,
      and the correlation of the measurements with intraoperative acromial measurements
      was assessed. Interobserver reliability was highest for the caudal tilt view
      (0.84) and lowest for the axillary view (0.09). The supraspinatus and caudal tilt
      views correlated significantly with distinct intraoperative measurements of
      acromial spur size. We continue to advocate the evaluation of both views for
      preoperative assessment of the acromial spur in the rotator cuff impingement
      syndrome.

PMID- 8665290
TI  - Reliability of radiographic assessment of acromial morphology.
AB  - The most widely used radiographic classification system for acromial morphology
      identifies three distinct acromial shapes: type I (flat), type II (curved), and
      type III (hooked). The purpose of this study was to measure the interobserver and
      intraobserver reliability of determinations of acromial morphology as defined by
      this system. Between 1990 and 1992, one hundred twenty-six supraspinatus outlet
      radiographs were obtained from 126 patients by technicians from Triangle
      Orthopaedic Associates in Durham, N.C. Six fellowship-trained shoulder surgeons
      independently reviewed each radiograph and classified it as type I, II, or III on
      the basis of established guidelines. Two surgeons classified each film a second
      time in random order. Analysis of variance was performed to obtain coefficients
      for interobserver and intraobserver reliability. Consensus ratings were then used
      to classify the 126 radiographs into consensus type I, consensus type II, or
      consensus type III groups. Percentages of type I, II, and III individual ratings
      within each consensus group were determined. The intraobserver reliability
      coefficient was 0.888, interpreted as good to excellent reliability. The
      interobserver reliability coefficient was 0.516, interpreted as poor to fair
      reliability. Of the 126 radiographs, 26 (20.6%) were rated as consensus type I,
      76 (60.3%) were rated as consensus type II, and 24 (19.1%) were rated as
      consensus type III. The reliability of observer ratings was lowest when
      delineation between acromial types II and III was required. The low interobserver
      reliability makes comparisons of studies by different authors difficult to
      interpret and obscures the true incidence of acromial morphologic types. It also
      questions reported correlations between acromial type and shoulder pathologic
      conditions. It is concluded that a system that incorporates more objective
      classification criteria and acknowledges the continuous nature of acromial
      morphologic types may improve interobserver reliability and validate the system's
      use in making clinical and surgical judgments.

PMID- 8665291
TI  - Relationship between the lateral acromion angle and rotator cuff disease.
AB  - One hundred consecutive magnetic resonance imaging (MRI) studies of the shoulder
      obtained for the purpose of evaluating rotator cuff symptoms were retrospectively
      reviewed to assess the relationship between acromion morphologic appearance and
      rotator cuff disease. The studies were reviewed simultaneously by two authors.
      Each cuff was assigned a tendon grade and an overall cuff score with MRI criteria
      previously described in the literature. A newly described "lateral acromion
      angle" was measured from a specified oblique coronal cut on each MRI study and
      was correlated with the corresponding MRI-determined rotator cuff score and
      supraspinatus tendon grade. Observed correlations were analyzed by using
      statistical methods. The average measured lateral acromion angle was 78 degrees,
      with a range from 64 degrees to 99 degrees. Eight shoulders had angles less than
      or equal to 70 degrees, and all eight of these patients were found to have full
      thickness rotator cuff tears. As the lateral acromion angle decreased, a
      statistically significant increase in rotator cuff disease was noted (p <
      0.0001). A significant correlation between increasing age and rotator cuff
      disease was also observed (p < 0.0001). Multiple regression analysis confirmed
      that both the lateral acromion angle and the age of the patient were independent
      predictors of rotator cuff score. Finally, although a trend was noted suggesting
      a correlation between acromion type (I--flat, II--curved, and III--hooked) and
      MRI-determined rotator cuff disease, this trend did not reach statistical
      significance (p = 0.12). Surgical correlation with MRI rotator cuff findings in
      35 patients showed an MRI sensitivity of 100% and specificity of 83%. A
      statistically significant correlation between the lateral acromion angle and MRI
      determined rotator cuff disease has been noted. The described angle may be a
      useful adjuvant in the evaluation and management of rotator cuff disease.

PMID- 8665292
TI  - Coracoacromial pressure recordings in a cadaveric model.
AB  - A dynamic shoulder model was used to determine the pressure distribution under
      the acromion, the coracoacromial ligament, and the coracoid process with
      simulated active glenohumeral joint motion in cadaveric specimens. Computerized
      regulation of servo-actuator forces initiated controlled cycles of glenohumeral
      joint motion. Pressures were recorded by using capacitive sensors. Peak pressures
      averaged 56.6 N/cm2 and were located at the anterolateral border of the acromion
      in most specimens. Marked pressures were present under the coracoid process. Lack
      of force of the supraspinatus muscle resulted in an 8% decrease of mean
      coracoacromial pressures, lack of force on the subscapularis and
      infraspinatus/teres minor muscles in a significant 61% increase, and lack of
      force on all rotator cuff muscles in a significant 35% increase. After anterior
      acromioplasty was performed, mean coracoacromial pressures decreased 5%.

PMID- 8665293
TI  - Recurrent acromial bone spur after open subacromial decompression.

PMID- 8665295
TI  - The components of our global exchange on surgery of the shoulder.

PMID- 8665294
TI  - Autoimmune arthritis caused by Candida septic arthritis.

PMID- 8665296
TI  - Scholarship player or walk-on.

PMID- 8665297
TI  - Oral tobacco use.

PMID- 8665298
TI  - Oral tobacco use.

PMID- 8665299
TI  - Modified condylotomy and disk position.

PMID- 8665300
TI  - The Christensen prosthesis.

PMID- 8665301
TI  - TMJ radiology.

PMID- 8665302
TI  - TMJ radiology.

PMID- 8665303
TI  - Zinc and aspergillus.

PMID- 8665304
TI  - Recurrent aphthous stomatitis. An update.
AB  - Recurrent aphthous ulceration or recurrent aphthous stomatitis is the most common
      oral mucosal disease known to human beings. Despite much clinical and research
      attention, the causes remain poorly understood, the ulcers are not preventable,
      and treatment is symptomatic. The most common presentation is minor recurrent
      aphthous stomatitis: recurrent, round, clearly defined, small, painful ulcers
      that heal in 10 to 14 days without scarring. Major recurrent aphthous stomatitis
      lesions are larger (greater than 5 mm), can last for 6 weeks or longer, and
      frequently scar. The third variety of recurrent aphthous stomatitis is
      herpetiform ulcers, which present as multiple small clusters of pinpoint lesions
      that can coalesce to form large irregular ulcers and last 7 to 10 days. Diagnosis
      of all varieties is usually made after clinical examination. Many local and
      systemic factors have been associated with these conditions, and there is
      evidence that there may be a genetic and immunopathogenic basis for recurrent
      aphthous ulceration. Management of this condition depends on the clinical
      presentation and symptoms and includes analgesic, antimicrobial, and
      immunomodulatory drugs. As dental clinicians and researchers become better
      trained in oral medicine and stomatology, it is anticipated that the
      pathophysiology, prevention, and treatment of recurrent aphthous ulceration will
      improve in the future.

PMID- 8665305
TI  - Oral stent as treatment adjunct for oral submucous fibrosis.
AB  - Oral submucous fibrosis is a chronic inflammatory disease that results in
      progressive juxtaepithelial fibrosis of the oral soft tissues that can cause
      increasing difficulty in chewing, swallowing, speaking, and mouth opening. Many
      treatment regimens for oral submucous fibrosis have been proposed to alleviate
      the signs and symptoms of the disorder. In severe cases, surgical intervention is
      the only treatment modality, but relapse is a major problem. This article
      describes the use of an oral stent as an adjunct to surgery to prevent relapse.

PMID- 8665306
TI  - Morphology of the lateral ligament in the human temporomandibular joint.
AB  - The morphology of the lateral ligament of the human temporomandibular joint is of
      two types: ligamentous and without distinct structure. Under the scanning
      electron microscope, a sheath-like structure that contained bundles of collagen
      was mainly found in the posterior region of the lateral ligament. Analysis of
      macromolecular components revealed that type III collagen was mainly present on
      the collagenous framework of the sheath-like structure. Type I collagen, laminin,
      and tenascin were found in the framework of the sheath-like structure. Supported
      collagenous bundles and the distribution of macromolecular components might be
      related to the stability of the temporomandibular joint. The sheath-like
      structure and other components of the lateral ligaments store energy and protect
      the capsule from stress and tension during movements of the jaw.

PMID- 8665307
TI  - Primary surgical repair of traumatic lacerations of the lacrimal canaliculi.
AB  - Injuries of the lacrimal system are occasionally associated with maxillofacial
      trauma. Detailed knowledge of the anatomy of the lacrimal apparatus is essential
      for optimal treatment of these injuries. The pertinent anatomy is reviewed.
      Techniques for the diagnoses and repair of lacrimal injuries specific to the
      canaliculi are presented and discussed with emphasis on early detection and
      intervention.

PMID- 8665308
TI  - Use of lag screws for the management of mandibular trauma.
AB  - OBJECTIVE: To test the effectiveness of lag screw fixation in their application
      in the treatment of mandibular fractures. MATERIAL AND METHODS: Sixty-nine
      mandibular fractures in 30 patients treated with lag screws were evaluated
      retrospectively regarding the cause, the type, and the site of fracture as well
      as the local situation and the complications encountered. RESULTS: In 19
      fractures a neutralization plate was used and in another 17 the lag screw was
      applied in combination with a compression plate. In 33 cases at least 3 lag
      screws were inserted. Seventy-five percent of the cases were in patients between
      10 and 39 years old; 70% were the result of road traffic accidents. Most patients
      presented two mandibular fractures; the symphyseal area were most frequently
      affected. Teeth in the line of fracture were not removed, and no drains were
      used. Complications included two minor malocclusions, one delayed union, two
      cases of temporary paresis, two cases of transient hypesthesia, two cases of scar
      formation on the incision line, and a case of temporary trismus. CONCLUSIONS:
      Approximately 30% of the patients treated with lag screws according to the
      methods outlined in this study developed complications that were either minor,
      transient, or both; some were related to the approach rather than the method. The
      most frequent complications were minor malocclusions, transient facial paralysis,
      hypoesthesia, and scar formation.

PMID- 8665309
TI  - Ameloblastoma in children. The Zimbabwean experience.
AB  - A retrospective study of 20 patients aged 18 years and younger with ameloblastoma
      seen over a 10-year period at Harare Central Hospital, Harare, Zimbabwe, was
      carried out. Males and females were equally affected. The mandible was the most
      commonly involved bone (95%); the premolar/canine incisor area was commonly
      affected (69.1%). Incision biopsy was done before wide surgical resection of the
      involved bone. No currettage or enucleation was used as a mode of treatment.
      Immediate reconstruction was performed with metallic implants. Twenty percent of
      the lesions had a unilocular radiologic appearance that resembled a dentigerous
      cyst. Follow-up was poor.

PMID- 8665310
TI  - Relationship of medical status, medications, and salivary flow rates in adults of
      different ages.
AB  - Multiple systemic disorders and medications have been reported to cause
      xerostomia or salivary gland hypofunction. The purpose of this study was to
      evaluate the relationship among systemic disorders, medications, and salivary
      flow rates. Sixty-three ambulatory dental patients aged 23 to 82 years were
      randomly selected. The nature, duration, and number of systemic disorders and
      medications were documented. Repeated measurements of unstimulated whole, chewing
      stimulated whole, acid-stimulated parotid, and candy-stimulated parotid salivary
      flow rates were obtained. Data were analyzed with the Wilcoxon rank-sum test,
      nonparametric multivariate analysis of variance, and Fisher's exact test. For
      persons with systemic disorders who were taking medication, all salivary flow
      rates were significantly (p = 0.03 - 0.001) lower than the flow rates in healthy
      persons. Among persons with at least one systemic disorder who were taking
      medication, those who had been taking medication for longer than 2 years had
      significantly lower unstimulated whole saliva (p = 0.002), chewing-stimulated
      whole saliva (p = 0.0004), and candy-stimulated parotid saliva (p = 0.02) flow
      rates than those who had been taking medication for 1 to 2 years. The number of
      systemic disorders significantly (p = 0.02) and negatively affected the acid
      stimulated parotid salivary rates. The prevalence of salivary hypofunction
      determined on the basis of unstimulated whole saliva and acid-stimulated parotid
      saliva was significantly higher (p = < 0.001, p = 0.007) in the those persons
      with systemic disorders and taking medications. The results suggest that salivary
      secretion is affected by the number of systemic disorders and duration of the
      potentially xerogenic medications.

PMID- 8665311
TI  - Oral Mycobacterium avium complex infection in a patient with HIV-related disease.
      A case report.
AB  - Mycobacterium avium complex infection is a common complication of the later
      stages of AIDS. Although a recognized cause of oral lesions, atypical
      mycobacteria are rarely detected in AIDS-related oral ulceration. Here we report
      a case of oral ulceration in a patient in the later stages of AIDS in which
      atypical mycobacteria were detected both histologically and microbiologically.
      The features of this case are similar to the one other case previously reported
      permitting some characterization and comparison of the clinical features of
      mycobacterium avium complex infection in AIDS.

PMID- 8665312
TI  - Clinical evaluation of an illuminated dental mirror.
AB  - The purpose of this study was to determine whether the use of an illuminated
      mirror improved a dental student's ability to detect oral disease or
      abnormalities and whether an oral examination could be conducted more efficiently
      with it when compared with the use of a conventional mirror and chair-mounted
      light source. Students examined patients with the illuminated mirror and with a
      standard dental mirror for caries, defective restorations, dental staining, etc.
      Students were observed to determine how often they adjusted the overhead light or
      shifted their positions to see better and the length of time the examination was
      noted. After each examination, students were asked to rate how well they could
      see in various intraoral sites. There was no difference in specificity ratios
      between the two techniques, and the only significant difference (p < or = 0.05)
      in sensitivity ratios was in the detection of caries. There was no difference in
      the number of position shifts or length of examinations; students made fewer
      external light adjustments when using the illuminated mirror. On a 10-point
      scale, students rated their ability to see intraorally better with the
      illuminated mirror.

PMID- 8665313
TI  - Salivary gland duct involvement in oral epithelial dysplasia and squamous cell
      carcinoma.
AB  - The clinical implications and prognostic significance of oral dysplastic or
      cancerous epithelium involving salivary gland ducts have not been previously
      investigated. Screened routine tissue sections of 1216 cases of oral epithelial
      dysplasias and squamous cell carcinomas revealed 26 examples (2.14%) that
      exhibited unequivocal ductal involvement. Ductal involvement was more likely to
      occur in floor of mouth lesions and in lesions exhibiting severe dysplasia or
      carcinoma in situ. Clinical follow-up on 23 cases showed that the recurrence rate
      of the preinvasive lesions that exhibited ductal involvement was equal to that of
      the squamous cell carcinomas. The depth of ductal dysplasia did not correlate
      with recurrence rate. These results suggest that the involvement of salivary
      gland ducts by oral epithelial dysplasias and carcinomas in situ is an uncommon
      but significant finding. Surgical stripping or ablation of such lesions should
      extend at least 3 mm below the surface to ensure eradication of these reservoirs
      of dysplastic cells.

PMID- 8665314
TI  - Giant keratoacanthoma of the lower lip. Report of a case of spontaneous
      regression.
AB  - The case of a 46-year-old man who refused treatment of a giant keratoacanthoma of
      the lower lip is presented. Complete regression took place within 10 months. The
      dilemma of a lesion of the vermilion border of the lower lip being either a
      (giant) keratoacanthoma or a squamous cell carcinoma is discussed with respect to
      the management of such lesions.

PMID- 8665316
TI  - Dentigerous cysts of inflammatory origin. A clinicopathologic study.
AB  - The exact histogenesis of dentigerous cysts remains unknown, but most authors
      favor a developmental origin from the tooth follicle. The aim of this article is
      to report a series of 15 dentigerous cysts that we believe to be of inflammatory
      origin. These inflammatory dentigerous cysts occurred in the first and early part
      of the second decades of life. Males were affected more frequently, and there did
      not appear to be any racial predilection. All of the cases involved permanent
      teeth: premolars in nine cases, canines in four cases, and second molars in two
      cases. The mandible was affected twice as frequently as the maxilla. In 13 cases,
      nonvital grossly carious or heavily restored deciduous teeth were associated with
      the cysts. Some of these teeth had been extracted before the cysts were
      diagnosed. In the remaining two cases, both of which involved the second
      permanent molars, there were no nonvital deciduous teeth, however both had
      concomitant proliferative periostitis. All of the cysts were moderately or
      intensely inflamed and were lined predominantly or entirely by nonkeratinized
      stratified squamous epithelium that in some cases was markedly hyperplastic and
      exhibited anastomosing rete ridges mimicking radicular cysts. In the majority of
      cases, parts of the cysts were lined with a 2 to 3 cell layer thick cuboidal
      epithelium that we believe was derived from reduced enamel epithelium. Rests of
      odontogenic epithelium frequently were evident in the cyst walls. We suggest that
      these cysts arose as a result of periapical inflammation from any source but
      usually from a nonvital deciduous tooth and spreading to involve the follicles of
      the unerupted permanent successors. The inflammatory exudate causes separation of
      the reduced enamel epithelium from the enamel with resultant cyst formation. This
      study proposes the existence of two types of dentigerous cysts: one developmental
      and the other inflammatory in nature.

PMID- 8665315
TI  - Xenograft growth and histodifferentiation of squamous cell carcinomas of the
      pharynx and larynx.
AB  - The potential for growth in a xenogeneic host and the pattern of
      histodifferentiation was examined in 56 human squamous cell carcinomas of the
      pharynx and larynx transplanted to nude mice. Among these 56 transplanted tumors,
      13 of 36 primary and 12 of 20 metastatic tumors were found to be tumorigenic in
      nude mice. Eleven of 24 pharyngeal and 14 of 32 laryngeal tumors grew in nude
      mice. The dynamics of transplanted tumor growth in the surrogate host took place
      independent of the tumor grade and site of tumor origin. Transplanted tumors
      exhibited a higher mitotic index compared with the original tumors. Each passage
      of a tumor line resulted in most of the xenograft tumors exhibiting an increased
      degree of differentiation without invasion of host tissues. No difference was
      observed between patients who engrafted tumors in the xenograft model and those
      who did not with respect to tumor biology or clinical findings, including
      survival.

PMID- 8665317
TI  - Lateral periodontal cyst. Multifactorial analysis of a previously unreported
      series.
AB  - The objective of the present study was to review a series of 23 lateral
      periodontal cysts and 2 botryoid odontogenic cysts retrieved from the files of
      the State University of New York at Buffalo (SUNY) Oral Pathology Biopsy Service
      for epidemiologic characteristics as well as radiographic findings, clinical
      presentation, histopathologic features, and management. This study corroborated
      some previously established characteristics of the lesion but also revealed some
      surprising aberrations. A significant difference in the age range and mean age by
      gender was detected with the Student's t test within this population at the 0.05
      level. The classic presentation of a lateral periodontal cyst seems to be that of
      an asymptomatic, small, ovoid, well-corticated radiolucency that occurs in an
      interradicular locus in the mandibular premolar segment of a middle-aged man.
      However, lateral periodontal cysts may manifest with pain and cause cortical
      perforation, may present as large expansile radiolucencies, may arise in the
      maxillary molar segment, and may develop in young females. Because of the
      tendency for aggressiveness of other lesions that may present with a similar
      picture, it is important to establish the final diagnosis of lateral periodontal
      cyst on a histologic basis in conjunction with the clinical and radiographic
      findings.

PMID- 8665318
TI  - Proliferating cell nuclear antigen staining in syndrome and nonsyndrome
      odontogenic keratocysts.
AB  - OBJECTIVES: The relatively aggressive behavior of the odontogenic keratocyst
      might be expected to correlate with the degree of proliferation of the cyst
      epithelium. The proliferation rate of odontogenic keratocyst epithelium was
      studied with the use of an antibody to the proliferating cell nuclear antigen, a
      nuclear protein expressed in cycling cells. STUDY DESIGN: We used the monoclonal
      antibody PC10 to examine 41 odontogenic keratocysts (21 associated with the
      nevoid basal cell carcinoma syndrome, 20 nonsyndrome), and assessed the number of
      positive nuclei in 1000 cells. Statistical analysis was carried out with analysis
      of variance and correlation analysis. RESULTS: Positive staining with
      proliferating cell nuclear antigen was seen in all keratocysts; in addition,
      there was a significant difference in proliferating cell nuclear antigen
      positivity between the syndrome and nonsyndrome keratocysts. CONCLUSIONS: The
      findings support the view that epithelial proliferation plays a significant role
      in the behavior of odontogenic keratocysts and suggest that the more aggressive
      behavior in nevoid basal cell carcinoma syndrome may correlate with a higher rate
      of epithelial proliferation.

PMID- 8665320
TI  - Pulpal blood flow assessed by laser Doppler flowmetry in a tooth with a
      horizontal root fracture.
AB  - Horizontal root fractures of both maxillary central incisors were diagnosed
      radiographically; neither responded to electric pulp testing nor to cold testing.
      The pulp of the right incisor was necrotic, whereas the pulpal status of the left
      incisor was uncertain. Pulpal blood flow of the teeth was measured with laser
      Doppler flowmetry. The blood flow of the left central incisor was 4.0. Eight
      months after the injury, a local anesthetic with a vasoconstrictor was
      administered to confirm pulp vitality. The blood flow of the tooth was decreased
      to 51% of the preanesthesia value after the local anesthesia. At 19 months after
      the injury, it responded to both the electric pulp test and cold test. Laser
      Doppler flowmetry is a noninvasive method of evaluating the blood flow status in
      human teeth, and it may provide a clinically reliable method of assessing pulpal
      vitality.

PMID- 8665319
TI  - Healing of apical periodontitis in dogs after apicoectomy and retrofilling with
      various filling materials.
AB  - OBJECTIVE: To histologically assess the efficacy of various retrofilling
      materials in apical surgery. STUDY DESIGN: The pulps of mandibular premolars in
      seven beagle dogs were infected; this resulted in periapical lesions. Apical
      surgery was performed without disinfection of the root canals. Super EBA (Harry
      J. Bosworth Co., Skokie, III.), two formulations of glass ionomer cement, amalgam
      with varnish, IRM,(Caulk Co., Ltd., Densply International, Milford, Del.) and a
      light-cured composite resin were the retrofilling materials used. Roots infected
      and apicoectomized without retrofilling were positive controls. After 6 months
      the dogs were killed. The experimental roots and surrounding apical tissues were
      prepared and histologically examined and relative percentages of bone and
      inflammation were calculated. RESULTS: Super EBA was consistently the best. In
      overall periapical condition, Super EBA was statistically superior to all
      materials except IRM. IRM was superior to the glass ionomer cements but not the
      other materials. As to percentage of bone, Super EBA was the best overall; it was
      superior to glass ionomer, composite resin, and the positive control but not
      different from amalgam or IRM. When comparing remaining numbers of inflammatory
      cells, Super EBA was superior with the lowest number of inflammatory cells
      present. CONCLUSION: Although not statistically different from IRM, Super EBA was
      consistently the best retrofilling material tested when compared with all
      retrofilling materials studied.

PMID- 8665321
TI  - Effects of focal spot size on caries diagnosis with D and E speed images.
AB  - Annual measurement of the x-ray unit focal spot size has been recommended by the
      American Academy of Oral and Maxillofacial radiology as part of the dental
      radiographic quality control program. This study compares the effects of focal
      spot size on caries diagnosis. Three x-ray units with small, medium, and large
      focal spot sizes were used to produce bite-wing images on extracted teeth mounted
      in acrylic bases. Randomized films were scored for lesion presence and depth by
      two general dentists. Weighted kappa statistics were used to evaluate the
      agreement of reviewer caries diagnosis by film speed and focal spot size.
      Comparisons of caries cells with small versus medium and small versus large focal
      spot size produced weighted kappa statistics = 0.72 and 0.70, respectively.
      Differences in caries calls were greater because of film speed rather than focal
      spot size. The results of this study suggest that the clinical significance of
      varied focal spot size is negligible. The value of annual measurement of focal
      spot size is questionable, and its recommendation should be revisited.

PMID- 8665322
TI  - In vitro comparison of Kodak Ultra-speed, Ektaspeed, and Ektaspeed Plus, and Agfa
      M2 Comfort dental x-ray films for the detection of caries.
AB  - The aim of this study was to compare the diagnostic accuracy of two new dental x
      ray films, Kodak Ektaspeed Plus (Plus) and Agfa M2 Comfort (M2), respectively,
      with the current Kodak Ultra-speed (Ultra) and Ektaspeed (Ekta) films for the
      detection of caries. A total of 103 occlusal and 224 proximal surfaces were
      examined independently by three observers. A histologic examination performed
      after the teeth were sectioned served as the validation method for lesion depth.
      Receiver operating characteristic curve areas were calculated to express the
      diagnostic accuracy. In the occlusal surfaces the receiver operating
      characteristic curve areas ranged from 0.764 (in Ultra films) to 0.800 (in Ekta
      films). In the proximal surfaces the receiver operating characteristic curve
      areas ranged from 0.550 (in Ultra films) to 0.696 (in Plus films). No
      statistically significant differences were found between the different film
      types.

PMID- 8665323
TI  - Spatial resolution in radiometric analysis of enamel loss. A pilot study.
AB  - This pilot study was undertaken to determine whether spatial resolution affects
      radiometric analyses aimed at detecting progressive enamel loss. Four teeth were
      weighed, attached to a positioning device, and evaluated with radiography. A 1 mm
      strip of enamel was removed from each tooth, and the teeth were weighted again
      and reexamined by radiography. This process was repeated five times until 1/2 mm
      of dentin was removed. The radiographs were digitized twice with 59 and 200
      microns pixels at 8 bits, providing two series of images with the optical
      densities converted into 256 gray levels. Each series of images was adjusted for
      contrast variation. Regions of interest were drawn on the crowns, and cumulative
      percent histograms (CPHs) were calculated. Within a series of CPHs enamel
      reduction resulted in shifts in the CPHs that were directly proportional to the
      amount of enamel removed. CPH shifts associated with the smaller 59 microns
      pixels accounted for 68% of the variation in weights caused by enamel reduction,
      whereas the shifts associated with the larger 200 microns pixels accounted for
      50%. The results indicate that pixel size does affect radiometric determinations
      of enamel reduction.

PMID- 8665324
TI  - Room for improvement? The accuracy of dental practitioners who diagnose bony
      pathoses with radiographs.
AB  - OBJECTIVES: The impact of any effort aimed at improving diagnostic accuracy by
      improving clinical decision making in diagnostic radiology will be limited by the
      ability of the clinician to correctly recognize the presence of abnormalities on
      radiographs. We carried out a study designed to examine whether dentists are able
      to correctly identify various kinds of periapical bone lesions visible on
      intraoral radiographs and diagnose their pathologic nature. STUDY DESIGN: General
      dental practitioners (n = 98) assessed 32 radiographs that showed either normal
      bone (10) or one abnormality (22) in the periapical bone. The "gold standard" for
      pathosis was histopathologic analysis. The dentists were asked to judge for the
      presence of an abnormality and to decide whether an active pathologic process was
      present. RESULTS: On average dentists identified 81% of all visible abnormalities
      correctly. Subsequently, they diagnosed 59% of all the pathologic cases
      correctly. Dentists, however, incorrectly identified 55% lesions on radiographs
      when experts had stated that no abnormality was visible. CONCLUSION: There is
      room for improvement of diagnostic accuracy of bony pathology.

PMID- 8665325
TI  - Aspergillosis of the paranasal sinuses. A case report and radiographic review.
AB  - Aspergillosis of the paranasal sinuses is uncommon; however, its incidence in
      recent years has shown a marked increase, and it is believed that it may account
      for a number of cases of nonspecific sinusitis. It may present in one of four
      forms, one of which is the noninvasive Aspergillus mycetoma. One such case
      affecting the maxillary sinus is reported, and reference is made to its possible
      sequelae and management. The significance of its presentation as a radiodense
      focus within the antrum on plain radiographs and computed tomography is
      discussed, as is the use of magnetic resonance imaging for excluding
      aspergillosis from the differential diagnosis.

PMID- 8665326
TI  - Motor proteins 2: myosin.

PMID- 8665327
TI  - Phosphoprotein phosphatases 1: tyrosine phosphatases.

PMID- 8665328
TI  - Thalamic mechanisms of chest pain in the absence of cardiac pathology.

PMID- 8665329
TI  - Out-of-hospital resuscitation: room for improvement.

PMID- 8665330
TI  - Venous thromboembolism in coronary artery surgery.

PMID- 8665331
TI  - The pathogenesis of spontaneous arterial dissection.

PMID- 8665332
TI  - Pain perception and brain evoked potentials in patients with angina despite
      normal coronary angiograms.
AB  - OBJECTIVE: To evaluate the role of nociception in patients with angina despite
      normal coronary angiograms and to investigate whether any abnormality is confined
      to visceral or somatosensory perception. METHODS: Perception, pain threshold, and
      brain evoked potentials to nociceptive electrical stimuli of the oesophageal
      mucosa and the sternal skin were investigated in 10 patients who had angina but
      normal coronary angiograms, no other signs of cardiac disease, and normal upper
      endoscopy. Controls were 10 healthy volunteers. The peaks of the evoked potential
      signal were designated N for negative deflections and P for positive. Numbers
      were given to the peaks in order of appearance after the stimulus. The peak to
      peak amplitudes (P1/N1, N1/P2) were measured in microV. RESULTS: (1) Angina
      pectoris was provoked in seven patients following continuous oesophageal
      stimulation. (2) Distant projection of pain occurred after continuous electrical
      stimulation of the oesophagus in four patients and in no controls. (3) Patients
      had higher oesophageal pain thresholds (median 16.3 mA v 7.3 mA, P = 0.02) to
      repeated stimuli than controls, whereas the values did not differ with respect to
      the skin. There were no intergroup differences in thresholds to single stimuli.
      (4) Patients had substantially reduced brain evoked potential amplitudes after
      both single oesophageal (P1/N1, median values: 7.2 microV, controls: 29.0 microV;
      N1/P2: 16.5 microV, controls: 66.0 microV; P < 0.001 for both) and skin (N1/P2:
      13.5 microV; controls: 76.0 microV; P < 0.001) stimuli despite the similar pain
      thresholds. CONCLUSION: Central nervous system responses to visceral and
      somatosensory nociceptive input are altered in patients who have angina despite
      normal coronary angiograms.

PMID- 8665334
TI  - Pacemaker endocarditis.

PMID- 8665333
TI  - Incidence of hibernating myocardium after acute myocardial infarction treated
      with thrombolysis.
AB  - OBJECTIVE: To establish the incidence of hibernating myocardium after myocardial
      infarction treated with thrombolysis and to observe differences in the clinical
      outcome between patients with and without hibernating tissue. METHODS: 41
      patients underwent gated positron emission tomography with 18-fluorodeoxyglucose
      and 13N-ammonia at a median of eight days after first myocardial infarction.
      RESULTS: All 41 subjects had a matched perfusion-metabolism deficit in the region
      of myocardium indicated as the site of infarction by an electrocardiograph; 32
      patients (78%) had scans which also showed at least one area of reduced blood
      flow and contraction with a concomitant increase in glucose uptake, representing
      hibernating myocardium. Patients were followed up at a median of six months: all
      41 were alive and none had sustained a further infarct or cardiac arrhythmia; 17
      subjects with hibernating tissue (53.1%) and two without (25%) reported chest
      pain after myocardial infarction. CONCLUSIONS: Hibernating myocardium is
      relatively common shortly after myocardial infarction treated with thrombolysis.
      It does not influence mortality or the incidence of postinfarction chest pain.

PMID- 8665335
TI  - Abrupt cessation of short-term continuous treatment with isosorbide dinitrate may
      cause a rebound increase in silent myocardial ischaemia in patients with stable
      angina pectoris.
AB  - OBJECTIVE: To examine by Holter electrocardiographic monitoring the effect of
      abruptly stopping nitrate treatment in patients with stable angina pectoris.
      PATIENTS: 12 men with confirmed ischaemic heart disease and stable exertional
      class 3 angina (Canadian). All had episodes of horizontal or down sloping ST
      segment depression during 24 hour electrocardiographic monitoring. All were
      nitrate responders. DESIGN: Each patient was given isosorbide dinitrate (10-30 mg
      four times a day) and placebo (four times a day) for three days in a randomised
      crossover trial. There was a washout period of 3-5 days between the two treatment
      periods. Holter monitoring was performed on the third day of isosorbide dinitrate
      and placebo administration and on the first day of their withdrawal. RESULTS:
      When treatment with isosorbide dinitrate was stopped there was a significant
      increase in the total number and duration of painless episodes of myocardial
      ischaemia. During placebo and isosorbide dinitrate administration 8 patients had
      episodes of painless myocardial ischaemia whereas after isosorbide dinitrate
      cessation they were recorded in all 12 patients. Episodes of silent myocardial
      ischaemia at rest appeared in 4 patients after isosorbide dinitrate withdrawal.
      CONCLUSION: Abrupt cessation of short-term continuous nitrate treatment in
      patients with severe angina may cause a rebound increase in myocardial ischaemia
      which is predominantly silent.

PMID- 8665337
TI  - Analysis of deaths in patients awaiting heart transplantation: impact on patient
      selection criteria.
AB  - OBJECTIVE: To analyse the clinical characteristics of patients who died on the
      Stanford heart transplant waiting list and to develop a method for risk
      stratifying status 2 patients (outpatients). METHODS: Data were reviewed from all
      patients over 18 years, excluding retransplants, who were accepted for heart
      transplantation over an eight year period from 1986 to 1994. RESULTS: 548
      patients were accepted for heart transplantation; 53 died on the waiting list,
      and 52 survived on the waiting list for over one year. On multivariate analysis
      only peak oxygen consumption (peak VO2: 11.7 (SD 2.7) v 15.1 (5.2) ml/kg/min, P =
      0.02) and cardiac output (3.97 (1.03) v 4.79 (1.06) litres/min, P = 0.04) were
      found to be independent prognostic risk factors. Peak VO2 and cardiac index (CI)
      were then analysed in the last 141 consecutive patients accepted for cardiac
      transplantation. All deaths and 88% of the deteriorations to status 1 on the
      waiting list occurred in patients with either a CI < 2.0 or a VO2 < 12. In those
      with a CI < 2.0 and a VO2 < 12, 38% died or deteriorated to status 1 in the first
      year on the waiting list. Patients with CI > or = 2.0 and a VO2 > or = 12 all
      survived throughout follow up. Using a Cox's proportional hazards model with CI
      and peak VO2 as covariates, tables were constructed predicting the chance of
      surviving for (a) 60 days and (b) 1 year on the waiting list. CONCLUSIONS: These
      data provide a basis for risk stratification of status 2 patients on the heart
      transplant waiting list.

PMID- 8665336
TI  - Spontaneous coronary artery dissection: a neglected cause of acute myocardial
      ischaemia and sudden death.
AB  - Spontaneous coronary artery dissection is a rare cause of acute myocardial
      ischaemia. Eight consecutive fatal cases which occurred in women aged 34-54 years
      (mean 43) are described. The dissection involved the left anterior descending
      coronary artery in four, the left main trunk in two, the right coronary artery in
      one, and both left anterior descending and circumflex arteries in one. The
      clinical presentation was sudden death in six cases, and acute myocardial
      infarction in two. Diagnosis was made at necropsy in every case but one, in which
      coronary dissection was diagnosed during life by selective coronary angiography.
      The only ascertained risk factor was hypertension in one patient; none of the
      women was in the puerperium, and Marfan syndrome was excluded in all. Histology
      showed a haematoma between the coronary tunica media and adventitia, that
      flattened and occluded the lumen; a coronary intimal tear was detected in only
      two cases. Unusual histological findings were cystic medial necrosis in one case,
      eosinophilic inflammatory infiltrates in four, and angiomatosis of the tunica
      adventitia in one. Patients dying of spontaneous coronary dissection are usually
      middle aged women, with no coronary atherosclerosis and apparently no risk
      factors. Spontaneous coronary artery dissection is unpredictable, and sudden
      death is the usual mode of clinical presentation. Prompt diagnosis and life
      saving treatment is far from being achieved.

PMID- 8665338
TI  - Cardiovascular effects of dobutamine stress testing in women with suspected
      coronary artery disease.
AB  - OBJECTIVE: To investigate the central and peripheral haemodynamic response to
      dobutamine stress testing in women with suspected ischaemic heart disease and to
      seek an explanation for the hypotension phenomenon. DESIGN: 18 women aged 54-73
      years were investigated with Doppler echocardiography and venous occlusion
      plethysmography during intravenous infusion of dobutamine 5-10 d after an episode
      of unstable angina. RESULTS: An average peak dose of 33 (SD 9.7)
      micrograms/kg/min was given. Heart rate and cardiac output increased by 49% and
      59%, respectively (P < 0.001). Total and leg peripheral vascular resistance
      decreased by 44% and 26%, respectively (P < 0.001). Four patients developed
      hypotension (decrease in systolic blood pressure > 10 mm Hg), one of whom had a
      paradoxical bradycardia and two a low increase in cardiac output. Patients with
      hypotension had a more pronounced decrease in total peripheral vascular
      resistance but a similar change in leg peripheral vascular resistance compared
      with patients without hypotension. CONCLUSIONS: Dobutamine infusion leads to
      marked peripheral vasodilatation and an increase in cardiac output. Some patients
      experience hypotension during the test for reasons which include paradoxical
      vasovagal reactions and diminished capacity for adequate increase in cardiac
      output. There is also a disparity between the pattern of total and leg peripheral
      vascular resistance in patients with hypotension which might reflect a
      baroreceptor mediated compensatory increase in vasoconstrictor tone of muscle
      vessels not matched in other vascular territories.

PMID- 8665339
TI  - Endothelial control of lower limb blood flow in chronic heart failure.
AB  - BACKGROUND: Limitation of the blood supply to skeletal muscle in chronic heart
      failure may contribute to the symptoms of fatigue and diminished exercise
      capacity. The pathophysiology underlying this abnormality is not known. The
      purpose of this study was to assess the effect of endothelium dependent and
      independent vasodilator agents on blood flow in the leg of patients with heart
      failure. METHODS AND RESULTS: Blood flow in the leg was measured in patients with
      heart failure (n = 20) and compared with that in patients with ischaemic heart
      disease and normal left ventricular function (n = 16) and patients with chest
      pain and normal coronary arteries (n = 8). External iliac artery blood flow was
      measured using intravascular Doppler ultrasound and quantitative angiography.
      Flow was recorded at rest and in response to bolus doses of the endothelium
      independent vasodilator, papaverine. Endothelium dependent responses were
      measured by infusion of acetylcholine and substance P. Mean (SEM) baseline blood
      flow was reduced at rest (2.9 (0.4) v 4.5 (0.3) ml/s, P < 0.001) and vascular
      resistance was raised (37.4 (3.6) v 27.1 (3.0) units, P < 0.05) in patients with
      heart failure compared with that in controls. The peak blood flow response to
      papaverine (8 mg), acetylcholine (10(-7)-10(-5) mol/l), and substance P (5
      pmol/min) was reduced in heart failure, with greater impairment of the response
      to acetylcholine than substance P. There was a correlation between baseline blood
      flow in the heart failure group and diuretic dose (r = -0.62, P = 0.003), New
      York Heart Association classification (r = -0.65, P = 0.002), and left
      ventricular ejection fraction (r = 0.80, P = 0.0004). CONCLUSIONS: There is
      reduced blood flow and raised vascular resistance at rest in the legs of patients
      with heart failure. The degree of impaired blood flow in the leg correlates with
      the severity of heart failure. There is impairment of the response to both
      endothelium dependent and independent vasodilators. Abnormal function of the
      vascular myocyte in heart failure may explain these results as would structural
      abnormalities of the resistance vessels.

PMID- 8665340
TI  - Ambulation three hours after elective cardiac catheterisation through the femoral
      artery.
AB  - OBJECTIVE: To test whether very early resumption of ambulation after femoral
      cardiac catheterisation is feasible and safe in patients with stable symptoms.
      DESIGN: Prospective study in a selected group of men and women undergoing
      elective cardiac catheterisation, with next day physical inspection. SETTING:
      Inpatient study. SUBJECTS: Two hundred consecutive ambulant patients submitted to
      diagnostic cardiac catheterisation through the femoral arterial route using 5F
      catheters: a femoral right heart study was done at the same time in 40 patients
      (20%). RESULTS: No patient had major complications during the study. Early
      ambulation was not allowed in two patients (1%) because of haematoma formation
      immediately after sheath removal, and in seven (3%) because of poor haemostasis
      or haematoma on inspection at 3 h. Early ambulation was interrupted in two
      patients (1%) because of transient arterial hypotension on standing in one, and
      the patient's preference in the other. Of 189 patients who resumed full
      ambulation at 3 h, one (0.5%) had a groin haematoma on discharge the next
      morning. Overall, haematoma 12 h after cardiac catheterisation was present in
      seven of the 200 patients initially included in the study (3.5%). None of the 191
      patients with attempted early mobilisation had signs or symptoms of vascular
      complications one month or later after discharge. CONCLUSION: Supervised
      resumption of ambulation 3 h after uncomplicated cardiac studies with 5F femoral
      arterial catheters is safe and feasible in most ambulant patients undergoing
      elective cardiac catheterisation.

PMID- 8665342
TI  - Colour doppler valvar and subvalvar flow diameter imaging versus echo score in
      mitral stenosis: comparison with type of surgery.
AB  - OBJECTIVE: To compare the value of echo score with that of Doppler subvalvar flow
      broadening in deciding the type of mitral stenosis surgery. PATIENTS: 30
      patients, mean age 47 years, with severe stenosis undergoing surgery were divided
      into two groups according to type of surgery: open heart commissurotomy (group 1,
      n = 12), or prosthesis (group 2, n = 18). A control group of 10 patients with
      prosthesis served as reference, representing mild stenosis without subvalvar
      connection. METHODS: For echo, the score proposed by Wilkins for cross sectional
      imaging was used. For Doppler, the flow diameters were measured in cm by an
      independent examiner from the long axis view in early diastole at two levels: (1)
      at the level of the stenosis (origin flow diameter), and (2) 1.5 cm downstream
      from the stenosis in the left ventricle (subvalvar flow diameter) with
      calculation of a Doppler ratio relating these two measurements, expressed as a
      percentage of broadening. Diagnostic value was compared for both procedures.
      RESULTS: There was no significant difference in age, mitral valve areas, or
      haemodynamics for the two groups. Mean values (SD) were: echo score: group 1,
      9.83 (1.26) v group 2, 10.8 (8.1), NS; Doppler ratio %: group 1, 44 (24) v group
      2, 12 (21) (P < 0.001); control group: 69 (15). The per cent diagnostic value for
      an open heart commissurotomy of respective cut off points was: Doppler ratio >
      25% (range 71% to 87%); echo score < 10 (range 50% to 75%). CONCLUSIONS: The new
      Doppler ratio diagnostic value agreed better with surgical management, repair or
      prosthesis, in this study. Thus, it appears to better reflect the subvalvar
      involvement and changes in kinetics than the echo score alone. This easy Doppler
      method might become a routine examination for follow up of patients with open
      heart commissurotomy, to avoid performing repeated transoesophageal
      echocardiography.

PMID- 8665341
TI  - Non-invasive diagnosis of infarct artery patency after acute myocardial
      infarction by use of serial plasma troponin T concentrations: importance of
      measurement of peak levels.
AB  - OBJECTIVE: To confirm the validity of a previously described method for
      assessment of infarct artery patency involving serial measurements of creatine
      kinase activity by use of troponin T concentration as an independent plasma
      marker. DESIGN: Streptokinase (1.5 x 10(6) units) was given intravenously to 60
      patients within 6 h of onset of prolonged chest pain and ST segment elevation,
      and blood was taken for measurement of troponin T concentration at baseline and
      at 1, 2, 3, 4, 8, 12, 16, 20, and 24 h after starting treatment. Coronary
      arteriography was performed at 2.6 (SD 0.3) h. Plasma troponin T concentration
      was assessed by two methods: (1) as the absolute rise between 0 and 3 h; and (2)
      as the proportion of the total rise (from baseline to peak) over the same period.
      Accuracy for prediction of infarct artery patency, assessed by receiver operating
      characteristic curves, was compared for both methods of assessment using troponin
      T and was in turn compared with previously reported results on the same patients
      using serial measurements of creatine kinase activity. RESULTS: Sufficient values
      for prediction of patency using troponin T were available in 53 patients. A rise
      in troponin T between 0 and 3 h to > or = 9% of peak concentration predicted
      angiographic patency with sensitivity of 94% and specificity of 100%. By
      contrast, at the optimum cutoff for absolute rate of rise (0.5 micrograms/l/h)
      sensitivity was only 66% and specificity 86%. Comparable figures for creatine
      kinase were 92% and 91% (> or = 20% of peak by 3 h) and 62% and 78% (150 IU/l/h).
      Receiver operating curves confirmed better predictive accuracy for proportions
      over absolute rates of rise for both markers (P < 0.01). CONCLUSIONS: For
      accurate diagnosis of infarct artery patency using plasma markers it is necessary
      to express the rate of rise as a proportion of the peak level. Analysed in this
      way, both creatine kinase and troponin T are suitable for use in randomised
      trials of new thrombolytic or adjuvant drugs.

PMID- 8665343
TI  - Mechanisms of regional ischaemic changes during dipyridamole echocardiography in
      patients with severe aortic valve stenosis and normal coronary arteries.
AB  - OBJECTIVE: Vasodilator stress echocardiography can cause myocardial ischaemia in
      patients with severe aortic valve stenosis and angiographically normal coronary
      arteries. The aim of the study was to determine the mechanism of ischaemia in
      this clinical model. METHODS: The study group comprised patients with severe
      aortic valve stenosis and normal coronary arteries: 25 patients (17 males, eight
      females; age 63 (SD 11) years) underwent a high dose (up to 0.84 mg/kg over 10
      min) dipyridamole echocardiography test both before (2-4 d) and after (10-15 d)
      aortic valve replacement. Mean aortic pressure gradient was 96 (15) mm Hg, with a
      left ventricular mass index of 228 (49) g/m2. The dipyridamole echocardiography
      test was well tolerated and interpretable in all patients. RESULTS: Dipyridamole
      infusion induced chest pain in seven patients before and in no patient after
      surgery (28 v 0%, P < 0.01), ST segment depression in 12 patients before and two
      after surgery (48 v 8%, P < 0.01), and a transient regional dyssynergy in 10
      patients before and two after surgery (40 v 8%, P < 0.01). In the preoperative
      evaluation, patients with an echocardiographically positive dipyridamole
      echocardiography test were comparable with patients with negative test as far as
      left ventricular mass index [240 (67) v 230 (64) g/m2, NS] and mean aortic
      pressure gradient [95 (22) v 92 (21) mm Hg, NS] were concerned. When compared to
      the preoperative assessment, the resting echo assessment in the postoperative
      evaluation showed unchanged values of left ventricular mass index [pre 228 (49)
      g/m2 v post 220 (36) g/m2, NS], but markedly decreased values of mean aortic
      gradient [pre 95 (15) mm Hg v post 22 (5) mm Hg, P < 0.01] and left ventricular
      wall stress index [pre 134 (30) g/cm2 v post 89 (19) g/cm2]. CONCLUSIONS:
      Dipyridamole echocardiography is a suitable clinical technique for assessing the
      ischaemic vulnerability of the left ventricle in severe aortic valve stenosis
      with angiographically normal coronary arteries. The frequent disappearance of the
      ischaemic response early after aortic valve replacement suggests that
      haemodynamic factors such as compressive diastolic wall stress or afterload
      reduction are important components of myocardial ischaemic vulnerability under
      these circumstances.

PMID- 8665344
TI  - QT interval and dispersion in primary autonomic failure.
AB  - OBJECTIVE: To investigate the role of the autonomic nervous system in determining
      QT interval and dispersion. PATIENTS AND METHODS: 32 patients with chronic
      primary (idiopathic) autonomic failure (19 men, mean age 60 years) and 21 normal
      controls (11 men, mean age 59) without symptoms of ischaemic heart disease were
      studied retrospectively. Autonomic failure was diagnosed by a combination of
      symptomatic postural hypotension, subnormal plasma noradrenaline response to head
      up tilt, and abnormal cardiovascular responses to standing, Valsalva manoeuvre,
      mental stress, cutaneous cold, isometric exercise, and deep breathing. QT
      intervals were measured from surface electrocardiograms and QT dispersion was
      defined as maximum QT--minimum QT occurring in any of the 12 leads. RESULTS: Mean
      heart rate (RR intervals) was similar in patients with autonomic failure and
      controls (S2 lead: 865 (132) v 857 (108) ms, P = NS; V2 lead: 865 (130) v 868
      (113) ms, P = NS). QT intervals measured from electrocardiogram leads S2 and V2
      were significantly longer in patients than in controls (401 (40) v 376 (16) ms, P
      < 0.01; and 403 (41) v 381 (20) ms, P < 0.05 respectively). The mean maximum QT
      interval in any lead, which is the best estimate of the maximum duration of
      electrical systole, was significantly longer in the patients than in controls
      (417 (48) v 388 (23) ms, P < 0.005). Linear regression analysis of QT and RR
      intervals for both groups showed a significant difference between the slopes of
      the two regression lines (F = 8.4, P < 0.001). However, QT dispersions were
      similar between patients and controls. CONCLUSIONS: Patients with primary
      autonomic failure have prolongation of QT intervals, indicating that the
      autonomic nervous system is an important determinant of QT interval. However, QT
      dispersion does not seem to be affected by chronic primary autonomic denervation.

PMID- 8665345
TI  - Effect of sequential radiofrequency ablation lesions at fast and slow
      atrioventricular nodal pathway positions in patients with paroxysmal atrial
      fibrillation.
AB  - OBJECTIVE: To examine the hypothesis that the anatomic equivalents of the fast
      and slow pathways identified in patients with atrioventricular (AV) nodal
      tachycardia may be universal and represent the principal sites of atrial input
      into the normal compact AV node. METHODS: 15 patients undergoing complete AV
      junction ablation for paroxysmal atrial fibrillation were studied. Radiofrequency
      energy was delivered first in the anterior "fast pathway" position so as to
      prolong the atrium to bundle of His (AH) interval by over 50% of baseline
      (protocol 1) and then to the "slow pathway" position using the anatomical
      technique (protocol 2). RESULTS: Ablation protocol 1 resulted in prolongation of
      AH interval in all patients. Subsequent lesions at the level of the coronary
      sinus produced complete heart block in four patients, and in five caused a
      further increase in AH interval above that produced by protocol 1. Four of these
      latter patients developed complete block after delivery of RF energy slightly
      anterior to the level of the coronary sinus os, as did three further patients in
      whom ablation at the level of the coronary sinus had no effect. In four patients
      complete heart block could not be achieved by protocol 2. CONCLUSIONS: A discrete
      anterior "fast" pathway and a posterior "slow" pathway or network of posterior
      pathways form the principal inputs to the compact AV node in most patients with
      atrial fibrillation. The absence of dual AV nodal physiology in the majority of
      these patients may be related to the functional properties of the individual
      components of this posterior network.

PMID- 8665346
TI  - Disturbance of peripheral microvascular fluid permeability by the onset of
      atrioventricular asynchrony in patients with programmable pacemakers.
AB  - BACKGROUND: In vitro and in vivo evidence suggests that atrial natriuretic
      peptide can enhance fluid flux from intravascular to extravascular compartments.
      The relevance of this to human pathophysiology remains unclear. OBJECTIVES: To
      determine whether a central haemodynamic change associated with increased plasma
      concentrations of atrial natriuretic peptide produces detectable change in the
      capillary filtration coefficient in a peripheral microvascular bed. PATIENTS: 12
      patients with programmable dual chamber permanent pacemakers. METHODS: Calf
      capillary filtration coefficient (using a modified plethysmographic technique)
      and plasma atrial natriuretic peptide concentrations were measured during
      atrioventricular synchronous and ventricular pacing. RESULTS: Atrioventricular
      asynchrony was associated with higher mean (SD) concentrations of atrial
      natriuretic peptide (231.9 (123.1) v 53.5 (38.8) pg/ml) and an increased mean
      (SD) calf capillary filtration coefficient (4.2 (1.1) v 3.6 (1.1) ml/min.mm
      Hg.100 ml x 10(-3)), but there was no correlation between the magnitude of the
      change in these variables in individual patients. CONCLUSIONS: The peripheral
      capillary filtration coefficient may change in response to altered central
      haemodynamics. Atrial natriuretic peptide remains one potential candidate
      mechanism, but other factors are also likely to be involved.

PMID- 8665347
TI  - Pulmonary blood supply in bidirectional cavopulmonary anastomosis with pulsatile
      pulmonary blood flow: quantitative analysis using radionuclide angiocardiography.
AB  - OBJECTIVE: To establish a non-invasive method for quantitative analysis of
      pulmonary perfusion in patients with bidirectional cavopulmonary anastomosis
      (BCPA) and sources of pulsatile blood flow. The method should quantify left to
      right lung flow ratio and relative contribution of BCPA and sources of pulsatile
      blood flow to perfusion of each lung. DESIGN: A pilot study using radionuclide
      angiocardiography for quantitative analysis and for visualisation of cavo-caval
      collaterals. No criterion standard is available. SETTING: Tertiary care centre,
      ambulatory and hospital inpatient care. PATIENTS: Consecutive sample of 18
      patients with BCPA and sources of pulsatile blood flow. RESULTS: In eight
      patients (44%) cavocaval collaterals prevented quantitative analysis. In 10
      patients without cavo-caval collaterals, BCPA provided 42.3 (SEM 3.4)% of total
      pulmonary blood flow. From the total BCPA flow, 67.2 (4.3)% was directed to the
      ipsilateral lung. This lung received only 16.5 (3.3)% of all the blood from
      sources of pulsatile blood flow. The blood flow to the lung at the side of BCPA
      accounted for 35.3 (1.7)% of the total pulmonary blood flow. CONCLUSIONS:
      Radionuclide angiocardiography allows the quantitative analysis of pulmonary
      blood supply in BCPA with sources of pulsatile blood flow except in patients with
      cavo-caval collaterals or bilateral BCPA. Non-pulsatile flow from BCPA is mainly
      directed to the ipsilateral lung, whereas pulsatile flow to the contralateral
      lung. Total perfusion of the ipsilateral lung is less than the perfusion of the
      contralateral lung.

PMID- 8665348
TI  - Trends in pacemaker mode prescription 1984-1994: a single centre study of 3710
      patients.
AB  - OBJECTIVE: To evaluate trends in pacemaker mode prescription from 1984 to 1994
      with particular reference to the changes in pacemaker mode prescription for
      patients aged 80 years and older at implant. DESIGN: Prospective evaluation of
      indications for pacing and pacemaker mode prescription in all patients undergoing
      new pacemaker implantation from 1992 to 1994. Comparison with retrospectively
      obtained data for patients paced from 1984 to 1991. SETTING: Tertiary referral
      cardiothoracic centre. PATIENTS: Group 1: 2622 patients paced at one centre and
      entered into the national pacing database from 1984 to 1991. Group 2: 1088
      consecutive patients paced from 1992 to 1994. RESULTS: Use of atrial (AAI) and
      dual chamber (DDD) pacemakers increased progressively in patients of all ages
      from 1984 to 1994. There was an increase in the proportion of patients aged 80
      years and older from 25.4% (group 1) to 40.5% (group 2). Patients of all ages in
      group 2 were more likely to receive DDD units for atrioventricular block (odds
      ratio (95% confidence interval) (CI) 9.0 (7.0 to 11.5)) and AAI or DDD units for
      sinus node disease (odds ratio (95% CI) 11.0 (7.7 to 15.8)) than those in group
      1. Elderly patients (age > or = 80 at implant) with atrioventricular block or
      sinus node disease and a suitable atrial rhythm were less likely to receive DDD
      or AAI pacemakers than younger patients in both groups. CONCLUSIONS: Use of
      atrial and dual chamber pacing modes has increased substantially in patients of
      all ages over the last decade. Although elderly patients represent an increasing
      proportion of the paced population, they remain less likely to receive atrial or
      dual chamber pacemakers than younger patients.

PMID- 8665350
TI  - Permanent pacing in a patient with a left ventricular assist system.
AB  - A patient with end stage heart failure underwent permanent implantation of a
      Novacor left ventricular assist system. Progressive right ventricular dysfunction
      developed during the first two postoperative weeks. Temporary and subsequently
      permanent atrioventricular pacing to correct first degree heart block improved
      the performance of the device, with sustained resolution of his right ventricular
      failure.

PMID- 8665349
TI  - Redistribution of myocardial perfusion during permanent dual chamber pacing in
      symptomatic non-obstructive hypertrophic cardiomyopathy: a quantitative positron
      emission tomography study.
AB  - Dual chamber pacing causes significant symptomatic improvement in many patients
      with hypertrophic cardiomyopathy. The mechanism behind this beneficial response
      is not fully understood. Positron emission tomography showed a redistribution of
      myocardial flow during pacing in a patient with non-obstructive hypertrophic
      cardiomyopathy. Early septal activation reduced septal fibre strain and blood
      flow and increased septal perfusion reserve.

PMID- 8665351
TI  - Autonomic control of asystolic vasovagal syncope.
AB  - A 30 year old woman with a lifelong history of severe, recurrent, vasovagal
      syncope became asystolic for 30 seconds after 37 minutes of 60 degrees head-up
      tilt. During early tilt, sympathetic activity, heart rate, left ventricular
      contractility, and cardiac output increased. Mean blood pressure was initially
      maintained. Presyncope was associated with maximal contractility and bradycardia
      despite sustained sympathetic activity. Subsequently, asystole occurred
      associated with complete withdrawal of muscle nerve sympathetic activity. In
      asystolic vasovagal reactions, presyncope may be triggered by increased left
      ventricular contractility and is associated with increased levels of
      parasympathetic and sympathetic activity. Asystole and peripheral vasodilatation
      may be caused by sudden and complete withdrawal of the increased sympathetic
      activity.

PMID- 8665352
TI  - Fatal giant cell myocarditis after resection of thymoma.
AB  - A case of fulminant, fatal myocarditis occurring 10 days after resection of a
      benign medullary thymoma is described. A rare association between thymoma and
      giant cell myocarditis is recognised, but fulminant presentation so soon after
      removal of thymoma has not previously been reported.

PMID- 8665353
TI  - Intramural aortic haematoma causing ischaemia of the spinal cord.

PMID- 8665354
TI  - Guidelines for specialist training in paediatric cardiology. British Paediatric
      Association and the Specialist Advisory Committee in Cardiology of the Joint
      Committee on Higher Medical Training of the Royal College of Physicians.

PMID- 8665355
TI  - [Prevalence of hepatocellular carcinoma in cirrhotic patients with with
      portosystemic shunt. Cohort analysis].
AB  - The development of hepatocellular carcinoma is frequent in patients with hepatic
      cirrhosis of any etiology. Despite the suggestion that portosystemic shunt may
      increase the risk of developing this neoplasm there are scarce clinical evidence
      to confirm this suggestion. The present cohort study was aimed at analyzing the
      follow up data of 232 patients included in 3 prospective randomized controlled
      studies in which the efficacy of shunt procedures (group I: portocaval or
      splenorenal anastomosis) versus techniques other than shunt (group II: esophageal
      transection or variceal sclerosis) in the treatment of upper-6I bleeding
      secondary to rupture of esophageal-gastric varices were compared. After a mean
      follow up of 50 months, no differences were observed between the two groups in
      relation with the prevalence of hepatocellular carcinoma (group I: 17%; group II:
      12%; relative risk: 1.41 [CI 95%: 0.72 - 2.75]; p = 0.41) or the actuarial
      probability of developing this neoplasm (group I: 2% at 2 years, 21% at 5 years;
      group II: 7% at 2 years, 14% at 5 years; p = 0.42). The results of this analysis
      suggest that the performance of portosystemic shunt does not increase the risk of
      developing hepatocellular carcinoma in patients with hepatic cirrhosis.

PMID- 8665356
TI  - [Sympathetic nervous activity in cirrhosis: the relationship between peripheral
      hemodynamics and renal function changes].
AB  - The relationship between the activity of the sympathetic nervous system and the
      systemic and peripheral hemodynamic and renal function changes and the
      antinatriuretic activity in a group of 30 cirrhotic patients and 8 healthy
      subjects (control group) was investigated. Plasma catecholamines (noradrenaline,
      adrenaline and dopamine), plasma renin activity, plasma aldosterone
      concentrations, mean arterial pressure, cardiac output, blood volume, right
      femoral arterial flow (RFAF) and renal function parameters were determined in all
      the participants. Cyclic GMP urinary excretion (cV-UGMP) was used as an indirect
      index of systemic nitric oxide production. The plasma concentration of
      noradrenaline was greater in the patients than in the control group and was
      directly correlated with other vasopressor and antinatriuretic systems, RFAF, cV
      UGMP, the degree of hepatic failure studied by the Pugh score and was inversely
      correlated with creatinine clearance and urinary sodium excretion. On Cox
      regression analysis, only the RFAF, creatinine clearance and plasma adrenaline
      concentration remained independently associated with plasma noradrenaline levels.
      Furthermore, plasma noradrenaline was significantly higher in patients with
      greater hyperdynamic circulation. These results indicate that extrasplanchnic
      vasodilatation substantially contributes to sympathetic nervous hyperactivity
      which may significantly influence in the renal function changes observed in these
      patients.

PMID- 8665357
TI  - [Seroepidemiology of hepatitis A virus infection in medical and nursing students.
      The role of vaccination].
AB  - BACKGROUND: Recent seroepidemiologic studies have demonstrated a decrease in the
      prevalence of hepatitis A virus infection (HAV) in relation with an improvement
      in hygienic conditions. The prevalence of anti-HAV in a group of health care
      students was studied and a vaccination program initiated in this collective.
      METHODS: Serum anti-HAV determination was performed by an enzymoimmunoanalysis
      method. A inactivated hepatitis A vaccine was administered. RESULTS: Only 18.5%
      of the subjects between 17-23 years-old presented anti-HAV antibodies. The
      prevalence of anti-HAV was related with age and the number of partners. All of
      the 129 immunized individuals responded to the HAV vaccine with protector
      antibody titles. CONCLUSION: The present study demonstrates the decrease in HAV
      infection among youths as well as the immunogenicity of the anti-hepatitis A
      vaccine.

PMID- 8665358
TI  - [Chronic hepatitis C virus infection associated with anti-LKM 1].
AB  - A case of chronic hepatitis in a 20-year-old patient in whom hepatitis C virus
      infection markers and type 1 liver and kidney antimicrosome antibodies (anti-LKM
      1) were detected, thereby allowing diagnosis of autoimmune type 2b hepatitis, is
      reported. The different types of autoimmune hepatitis (AIH) and the type 2a and
      2b AIH are discussed as are the rejection of this terminology by some authors
      followed by their proposals and the therapeutic strategy to be used in these
      patients.

PMID- 8665359
TI  - [Association of cytomegalovirus colitis and the 1st episode of ulcerative colitis
      in an immunocompetent patient].
AB  - Colitis by cytomegalovirus (CMV) is an inflammation of the large bowel which
      leads to mucous and submucous ulceration producing bloody diarrhea of uncertain
      evolution. This disease is well known in immunosuppressed (IS) patients but is
      very rare in immunocompetent (IC) patients, particularly in association with the
      initiation of the ulcerative colitis (UC). The case of an immunocompetent male
      who developed UC following colitis by primary CMV is presented. Although the
      immunologic mechanism of UC is undoubtable, this case suggests the possibility of
      CMV being a triggering factor of UC.

PMID- 8665360
TI  - [Cholestatic hepatitis and anemia induced by ticlopidine].
AB  - A new case of acute cholestatic hepatitis in a 70-years-old woman treated with
      ticlopidine following stroke occurred 2 months previously is presented. The
      patient also presented anemia which became more severe during admission, but
      which was resolved following withdrawal of the drug with no involvement of the
      other 2 series. This is the first case reported with isolated anemia related to
      ticlopidine.

PMID- 8665362
TI  - [Autoimmune cholangiopathy].

PMID- 8665361
TI  - [Biliopancreatic ascariasis: an infrequent disease in our environment].
AB  - Ascariasis is one of the most frequent helminthic diseases in man. Most cases
      follow a subclinical form but may show symptoms related to pulmonary
      hypersensitivity or digestive complications. Although biliopancreatic
      complications have been widely described in endemic areas, references in Western
      countries are scarce. The authors therefore report their experience in 3 cases of
      this infrequent disease which were recently attended in their hospital over a
      brief period of time.

PMID- 8665363
TI  - [Factors related to response to interferon in chronic hepatitis C].

PMID- 8665364
TI  - [Physiopathology of acute pancreatitis].

PMID- 8665365
TI  - Circadian rhythms and the onset of acute myocardial infarction.

PMID- 8665366
TI  - Diurnal physiologic processes and circadian variation of acute myocardial
      infarction.
AB  - The observation that acute myocardial infarction and sudden cardiac death are
      more frequent in the morning indicates that the onset of these cardiovascular
      events is not random, and provides a clue to mechanism. An atherosclerotic plaque
      is exposed to systemic physiologic processes that could increase the likelihood
      of plaque rupture and thrombosis in the presence of a vulnerable plaque. Many of
      these processes increase in intensity in the morning, including plasma
      catecholamine levels, sympathetic activity, heart rate, blood pressure, vascular
      tone, platelet aggregability and blood viscosity increase, whereas some
      protective factors such as vagal activity and fibrinolytic activity are
      decreased. Similar changes may also occur after stressful activities. The ability
      of beta-adrenergic blocking agents and aspirin preferentially to reduce the
      incidence of myocardial infarction in the morning supports the hypothesis that
      sympathetic activation and increased platelet aggregability contribute to the
      circadian pattern of acute cardiovascular disease. Although the extent of
      atherosclerosis changes slowly with time under the influence of chronic risk
      factors, it is proposed that stress, particularly in the morning, may produce a
      combination of transient hemodynamic, vasoconstrictive and prothrombotic forces
      that can be considered acute risk factors for plaque disruption and thrombosis,
      the final pathway of most myocardial infarctions.

PMID- 8665367
TI  - Triggering of acute myocardial infarction.
AB  - The mechanisms of acute coronary artery disease onset are receiving increasing
      attention. Study of these mechanisms has been stimulated by the finding that the
      onset of acute myocardial infarction is more likely during the morning hours
      after awakening, suggesting that activities of the patient often trigger the
      event. Triggering may occur when stressors placed on the body produce
      hemodynamic, vasoconstrictive, and prothrombotic forces-acute risk factors-that
      can cause disruption of a vulnerable atherosclerotic plaque leading to
      thrombosis. Insight into triggering and plaque vulnerability may lead to a new
      approach in the prevention of acute myocardial infarction.

PMID- 8665368
TI  - A circadian perspective on myocardial ischaemia.
AB  - The non-uniform occurrence of myocardial ischaemia, with a trough at night and a
      peak in the morning, is at the base of the concept of a circadian distribution of
      coronary events. Cardiovascular variables known to influence the occurrence of
      ischaemia have similar rhythms, and a likely culprit could be hidden among them.
      Nevertheless, in many cases an identifiable trigger is lacking and the prediction
      of ischaemia is still elusive.

PMID- 8665369
TI  - Circadian rhythms and the onset of myocardial infarction: clinical implications.
AB  - There is much current interest in the development of therapeutic strategies which
      may alter the circadian pattern of cardiovascular events such as myocardial
      infarction and sudden cardiac death. It is not known whether manipulating
      rhythmic processes and providing active medication at the most vulnerable periods
      during the day or night will protect patients and reduce the risk of death. This
      review examines the evidence from the limited available data and assess the
      feasibility of implementing such strategies.

PMID- 8665370
TI  - Clustering of cardiovascular risk factors in Australian adolescents: association
      with dietary excesses and deficiencies.
AB  - BACKGROUND: Effective cardiovascular disease prevention requires strategies aimed
      at those children and adolescents most at risk. This study was designed to
      identify adolescents with clustering of higher levels of cardiovascular risk
      factors related to diet, blood pressure, fitness, fatness and blood cholesterol.
      METHODS: A representative sample of 555 schoolchildren aged 15 years from the
      Perth, Australia metropolitan area, was included in a cross-sectional survey
      analysing relationships between nutrient intake, fitness, physical activity,
      percentage of body fat, blood pressure and heart rate. RESULTS: Cluster analysis
      identified 21.1% of boys and 20.7% of girls with significantly worse risk
      profiles. Higher cardiovascular risk was associated with both dietary excesses,
      particularly in fat, cholesterol and sodium intake, and deficiencies of a number
      of minerals, vitamins and dietary fibre. Socioeconomic status was inversely
      associated with cardiovascular risk and undernutrition in girls. CONCLUSIONS: The
      analysis has identified a subgroup of about 21% of 15-year-old schoolchildren who
      share features of a range of unhealthy lifestyle variables, putting them at
      substantial risk of cardiovascular disease and other ill health in later life.

PMID- 8665371
TI  - Precursors of atherosclerosis in a random sample from a Hellenic population: the
      Athens Study.
AB  - BACKGROUND: Atheromatosis, the principal lesion in atherosclerotic cardiovascular
      disease, is associated with increased levels of blood pressure, serum
      cholesterol, cigarette smoking and other variables. As these lesions are thought
      to appear first in childhood, this study was designed to assess the levels of
      these atherosclerotic precursors in children living in Athens, Greece. METHODS:
      The following parameters were measured in a random sample of 4117 school children
      aged 6-18 years, living in the centre of Athens: body mass index, blood pressure,
      serum lipids, glucose, uric acid, calcium, phosphorus, creatinine, and
      haematocrit. RESULTS: Mean levels of blood pressure, total cholesterol, cigarette
      smoking and body mass index increased with age in both sexes, levels being
      similar to those of children in developed countries. Smoking started at
      elementary school, and by puberty had reached adult levels. High levels of
      systolic blood pressure ( > or = 130 mmHg) and total cholesterol ( > or = 5.68
      mmol/l) were seen in 22% and 13% of children respectively. Triglyceride and
      glucose levels did not increase with age; high-density lipoprotein cholesterol
      decreased and uric acid increased from 14 to 18 years, but only in boys. Levels
      of body mass index, total cholesterol, triglycerides, high-density lipoprotein
      and uric acid above the mean population values were found in 25% of children, and
      glucose levels above the mean in 50%. Multiple linear regression analysis showed
      a positive correlation between systolic blood pressure and age, body mass index,
      uric acid, sex, glucose, triglycerides and high-density lipoprotein cholesterol
      (in that order), and between diastolic blood pressure and age, body mass index
      and triglycerides. CONCLUSIONS: These findings indicate that the levels and
      prevalence of precursors of atherosclerosis are higher than expected in a
      southern European population, and are similar to those found in developed
      countries. This would indicate a need for greater awareness among the Greek
      population of preventive measures against developing cardiovascular disease.

PMID- 8665372
TI  - Resting electrocardiogram and risk of coronary heart disease in middle-aged
      British men.
AB  - OBJECTIVE: To examine the relation between resting electrocardiographic (ECG)
      abnormalities and risk of coronary heart disease (CHD). DESIGN AND SETTING: This
      was a prospective study of 7735 middle-aged men aged 40-59 years at entry
      (British Regional Heart Study). At baseline assessment each man completed a
      modified World Health Organization (WHO) (Rose) chest-pain questionnaire, gave
      details of his medical history and had a three-lead orthogonal electrocardiogram
      recorded. "Symptomatic CHD' refers to a history of anginal chest pain and/or a
      prolonged episode of central chest pain on WHO questionnaire and/or recall of a
      doctor diagnosis of CHD (angina or myocardial infarction). MAIN OUTCOME MEASURES:
      These were the first major CHD events, i.e. fatal CHD and non-fatal myocardial
      infarction, occurring during 9.5 years of follow-up. RESULTS: Of 611 first major
      CHD events during follow-up, 243 (40%) were fatal. After adjustment for age,
      other ECG abnormalities and symptomatic CHD, the ECG abnormalities most strongly
      associated with risk of a major CHD event were definite myocardial infarction
      (relative risk 2.5; 95% confidence interval 1.8-7.5) and definite myocardial
      ischaemia (1.9; 1.1-2.9). Other ECG abnormalities independently associated with a
      statistically significant increase in risk were left ventricular hypertrophy
      (2.2; 1.5-3.3), left axis deviation (1.3; 1.1-1.6) and ectopic beats,
      particularly if these were ventricular (1.6; 1.1-2.4). Three ECG abnormalities
      associated with a marked increase in CHD case-fatality rate were pre-existing
      myocardial infarction (67%), major conduction defect (71%) and arrhythmia (67%);
      the rate in men with none of these abnormalities was 32%. The relative risks
      associated with each ECG abnormality were similar in men with and without
      symptomatic CHD. The increase in risk in the presence of symptomatic CHD (2.4
      fold) and ECG evidence of definite myocardial infarction (2.5-fold) was similar;
      the presence of both factors increased risk more than six-fold. The most serious
      ECG abnormalities-definite myocardial infarction and ischaemia-were useful
      predictors of future major CHD events only in men with symptomatic CHD.
      CONCLUSION: The prognostic importance of major ECG abnormalities is strongly
      influenced by the presence of symptomatic CHD. In men with symptomatic CHD the
      resting electrocardiogram may help to define a group at high risk who may benefit
      from intervention. However, it has little or no value as a screening tool in
      middle-aged men without symptomatic CHD.

PMID- 8665373
TI  - White-coat hypertension and cardiovascular risk.
AB  - OBJECTIVE: To compare cardiovascular risk in white-coat hypertensives,
      normotensives and established hypertensives. METHODS: We studied 61 hypertensive
      individuals, 27 of whom were white-coat hypertensives, and 35 normotensives. All
      subjects underwent 24 h noninvasive blood pressure monitoring and Doppler
      echocardiographic examination of the heart; urine was tested for microalbuminuria
      and the fundi of the eyes examined for retinopathy. RESULTS: The 24 h as well as
      the day- and night-time mean systolic blood pressure (SBP) was slightly but
      significantly higher in white-coat hypertensives than in normotensives; no
      significant difference was observed in diastolic blood pressure (DBP) between
      these groups. In white-coat hypertensives, 24 h SBP and DBP were lower than in
      established hypertensives (P < 0.001). The echocardiographic study showed higher
      values of posterior wall thickness, left ventricular mass index (LVMI), and
      ventricular septum thickness (P < 0.05) in white-coat hypertensives than in
      normotensives; fractional shortening and ejection fraction were similar. The E:A
      ratio, obtained from the Doppler study, was lower in white-coat hypertensives
      than in normotensives (1.14 +/- 0.3 versus 1.24 +/- 0.25; P < 0.05). LVMI values
      were smaller in white-coat hypertensives than in established hypertensives (P <
      0.05), and both ejection fraction and fractional shortening were similar in the
      two groups. Among white-coat hypertensives, eight out of 27 showed hypertensive
      retinal damage; microalbuminuria values were similar to those obtained in
      normotensives. CONCLUSIONS: The results of this cross-sectional and therefore
      limited study lead us to hypothesize that white-coat hypertensives are at higher
      risk than normotensives and lower risk than established hypertensives for
      developing cardiovascular damage.

PMID- 8665375
TI  - Bibliography of the current world literature.

PMID- 8665374
TI  - Lipid peroxidation, antioxidant defences and red-cell membrane changes in
      relation to coronary risk index and symptomatic coronary heart disease.
AB  - OBJECTIVE: To establish the normal lipoprotein profile in the population and
      identify the early warning signs of coronary heart disease (CHD). DESIGN: Random
      blood sampling of healthy adults and patients with symptomatic CHD including that
      complicated with acute myocardial infarction. METHODS: Plasma lipids,
      lipoproteins, lipid peroxidation, antioxidant enzymes and scavengers, red-cell
      membrane lipids and glycoproteins were assayed. RESULTS AND CONCLUSION: The
      normal levels of plasma lipids and lipoproteins were established. Levels of
      plasma free fatty acids, fibrinogen, white blood cell counts, echinocytes, red
      cell membrane lipids and protein-bound carbohydrate components are significantly
      higher in healthy subjects with coronary risk index above 4.5 than they are in
      normal individuals. Antioxidant defences appear to be the distinguishing factor,
      remaining higher in normal individuals and thus keeping lipid peroxidation under
      control. In symptomatic CHD, antioxidant defences are significantly lowered.

PMID- 8665376
TI  - Impregnated bednets, malaria control and child mortality in Africa.

PMID- 8665377
TI  - Insecticide-treated bednets reduce mortality and severe morbidity from malaria
      among children on the Kenyan coast.
AB  - New tools to prevent malaria morbidity and mortality are needed to improve child
      survival in sub-Saharan Africa. Insecticide treated bednets (ITBN) have been
      shown, in one setting (The Gambia, West Africa), to reduce childhood mortality.
      To assess the impact of ITBN on child survival under different epidemiological
      and cultural conditions we conducted a community randomized, controlled trial of
      permethrin treated bednets (0.5 g/m2) among a rural population on the Kenyan
      Coast. Between 1991 and 1993 continuous community-based demographic surveillance
      linked to hospital-based in-patient surveillance identified all mortality and
      severe malaria morbidity events during a 2-year period among a population of over
      11000 children under 5 years of age. In July 1993, 28 randomly selected
      communities were issued ITBN, instructed in their use and the nets re-impregnated
      every 6 months. The remaining 28 communities served as contemporaneous controls
      for the following 2 years, during which continuous demographic and hospital
      surveillance was maintained until the end of July 1995. The introduction of ITBN
      led to significant reductions in childhood mortality (PE 33%, CI 7-51%) and
      severe, life-threatening malaria among children aged 1-59 months (PE 44%, CI 19
      62). These findings confirm the value of ITBN in improving child survival and
      provide the first evidence of their specific role in reducing severe morbidity
      from malaria.

PMID- 8665379
TI  - A survey of bancroftian filariasis among South-East Asian expatriate workers in
      Saudi Arabia.
AB  - In a survey of bancroftian filariasis among expatriate workers from five South
      East Asian countries (India, Bangladesh, Sri Lanka, Thailand and the Philippines)
      where human filariasis is endemic, 762 individuals were examined in the Abha area
      (Asir) of south-western Saudi Arabia. A prevalence of microfilaraemia of 3.5% and
      a mean mf density of 6.0/20 mm3 of blood was found among 259 Indian males only.
      In three out of 9 microfilaraemic cases, clinical signs suggestive of filariasis
      were observed. The only species identified was Wuchereria bancrofti showing
      strict nocturnal periodicity. Preliminary laboratory studies on the
      susceptibility of local mosquitoes to infection with W. bancrofti in which
      laboratory-bred Culex (C.) pipiens was fed directly on a microfilaraemic
      volunteer from Madras, South India, revealed that this species was highly
      susceptible to the Madras strain of the parasite with an average infection rate
      of 57 (range 41-75)% and a worm burden of 3.5 L3/infective mosquito. This is the
      first report that local Cx. pipiens mosquitoes may act as a potential vector of
      introduced bancroftian filariasis in Saudi Arabia. The potential danger of
      bancroftian filariasis importation and, more importantly, the establishment of
      new self-sustained foci of the disease is likely to depend upon the abundance of
      mf carriers and density of vector mosquitoes feeding on carriers.

PMID- 8665378
TI  - Impact of permethrin impregnated bednets on child mortality in Kassena-Nankana
      district, Ghana: a randomized controlled trial.
AB  - A community-based randomized, controlled trial of permethrin impregnated bednets
      was carried out in a rural area of northern Ghana, between July 1993 and June
      1995, to assess the impact on the mortality of young children in an area of
      intense transmission of malaria and no tradition of bednet use. The district
      around Navrongo was divided into 96 geographical areas and in 48 randomly
      selected areas households were provided with permethrin impregnated bednets which
      were re-impregnated every 6 months. A longitudinal demographic surveillance
      system was used to record births, deaths and migrations, to evaluate compliance
      and to measure child mortality. The use of permethrin impregnated bednets was
      associated with 17% reduction in all-cause mortality in children aged 6 months to
      4 years (RR = 0.83; 95% CI 0.69-1.00; P = 0.05). The reduction in mortality was
      confined to children aged 2 years of younger, and was greater in July-December,
      during the wet season and immediately after (RR = 0.79; 95% CI 0.63-1.00), a
      period when malaria mortality is likely to be increased, than in the dry season
      (RR = 0.92, 95% CI 0.73-1.14). The ready acceptance of bednets, the high level of
      compliance in their use and the subsequent impact on all-cause mortality in this
      study has important implications for programmes to control malaria in sub-Saharan
      Africa.

PMID- 8665380
TI  - Health seeking behaviour for child illness in rural Guatemala.
AB  - Considerable efforts were made in Guatemala to cover rural areas with health
      centres, and health programmes have been launched to treat and prevent the most
      important childhood diseases. Despite this, the utilization rate of public health
      services has reportedly been low throughout the past two decades. How, and how
      effectively, do mothers resolve the health problems of their children? To gain
      better insight into health care behaviour, we conducted a health services
      utilization survey in two highland communities in the department of Sacatepequez
      in 1992-1993. We asked 324 mothers in two villages whether, and where, they had
      sought help the last time their children under 5 years of age had suffered from
      diarrhoea, fever, cough symptoms or worms. Mothers relied on home care in 63-83%
      of reported episodes and the use of health services-Western or traditional-was
      consistently low. Although Western health care was easily accessible, it was used
      in only 8-15% of cases. The only identifiable significant independent
      determinants of utilization were occupational status of the mother (RR = 1.5 if
      employed) and overall level of socioeconomic development of the community (RR =
      1.7). Inquiry into treatments used revealed that except for worms, which were
      frequently treated with herbs (31%) or external remedies (20%) alone, modern
      pharmaceuticals predominated. Antibiotics were the remedy of choice against
      diarrhoea (63%), antipyretics in case of fever (83%) and cough syrups with
      expectorants or antitussives against cough (65%). One hundred and twenty-one of
      the children born after 1975 died; in only 64 cases (53%) was a Western health
      service consulted between onset of disease and death. No relation was found
      between attendance and socioeconomic characteristics of the parents, but a
      positive linear association between duration of the fatal illness episode and age
      of the child could be identified. Independent sources report a drop in infant
      mortality of 53 and 35% respectively in the two communities between 1977 and
      1991. Our findings seem to indicate that this reduction was achieved despite
      under-utilization of Western health services.

PMID- 8665381
TI  - Recent developments in hygiene behaviour research: an emphasis on methods and
      meaning.
AB  - This paper discusses some of the recent developments in hygiene behaviour
      research, focusing on operational research. A series of "rapid' assessments of
      hygiene behaviour were carried out in Kenya, Tanzania and Ethiopia with a view to
      preparing a field handbook entitled Hygiene Evaluation Procedures (HEP). The HEP
      handbook is intended primarily for field personnel in water supply, sanitation
      and health/hygiene education projects who want to design and conduct their own
      systematic assessments of hygiene behaviour in their localities. The short
      studies provided useful practical insights into the concerns and needs of project
      staff for whom research allowances (human, material and time resources) are often
      very limited. In this paper emphasis is placed on both methodological and
      heuristic developments as the two are inseparable. It is suggested that in the
      domestic sphere, hygiene behaviour with respect to the disposal of children's
      faeces and domestic water use are two of the key areas that remain of universal
      relevance to water/sanitation related interventions. These can be assessed
      rapidly and effectively by using two indicators: means of disposal of children's
      faeces and handwashing at 'critical' times--after defaecation, after handling
      and/or disposing of children's faeces, before handling food and before feeding
      young children and eating. Appropriate combinations of anthropological methods
      and participatory tools for measuring these indicators are described. The
      practical relevance of the resulting data for project design and implementation
      is highlighted.

PMID- 8665382
TI  - Ultrasonographic organometry: liver and spleen dimensions among children in
      Zimbabwe.
AB  - Attempts have been made to develop a staging system of sonographic Schistosoma
      mansoni morbidity for use in epidemiological studies and for evaluation of
      control programmes. Therefore, normal dimensions of livers and spleens in
      children in countries with endemic S. mansoni infections need to be established.
      Normal dimensions of livers and spleens are presented, based on examination of
      144 Zimbabwean children between 8 and 16 years of age found to be S. mansoni egg
      negative 12 months after treatment with praziquantel. Based on the liver and
      spleen measurements, an index of liver size and the spleen volume were
      calculated. Height was employed as the independent variable in all multiple
      regression models. The organometric data are presented as prediction plots, with
      observed values and fitted regression line with 95% confidence and prediction
      intervals. The mean spleen volume was 30% larger for boys than for girls, whereas
      there was no consistent difference in liver size. No effect of growth Z-scores
      was seen. The measurements were compared with normal dimensions of livers of
      German children. For a given height, the mean index of liver size was lower in
      Zimbabwean than in German children, but inter-observer variation could be a
      possible explanation for this difference.

PMID- 8665383
TI  - Clinical investigation of a population recently infected with Schistosoma mansoni
      (Richard-Toll, Senegal).
AB  - Following the introduction of large-scale irrigation, an exceptional epidemic of
      intestinal schistosomiasis occurred in northern Senegal when a non-immune
      population was exposed to massive infection. Subjects infected with Schistosoma
      mansoni were followed up parasitologically and clinically from the onset of the
      epidemic. After the initial evaluation, patients received a health education
      session and were treated with praziquantel in a dose of 30 mg/kg. One year after
      this treatment, S. mansoni eggs were found in the stools of 227/301 subjects
      (75%). Twenty-three per cent of subjects excreted > 400 eggs per gram (e.p.g.)
      and 11% excreted > 1000 e.p.g. of faeces. Overall, the geometric mean was 191
      e.p.g. of faeces in infected individuals. The prevalence of diarrhoea was reduced
      from 55 to 29%, the prevalence of bloody diarrhoea from 44 to 11% and the
      prevalence of abdominal discomfort from 66 to 41%. No hepatomegaly was found in
      these patients either before or one year after treatment. Splenomegaly was
      reduced from 30% (measured by ultrasound) to 3% (on clinical examination).
      Morbidity associated with S. mansoni infection was considerably reduced one year
      after treatment with praziquantel (30 mg/kg).

PMID- 8665384
TI  - Serotype analysis of Indian patients with HIV infection.
AB  - HIV infection has established itself in India. Besides Bombay, Madras and Manipur
      it has assumed epidemic proportions in Punjab, where 24% of seropositives
      acquired infection through blood products. Preliminary observations on genetic
      analysis in 13 isolates revealed that the principal neutralizing determinant
      (PND) of the V3 loop was closely related to the South African isolate. Since
      serotyping can give reliable information about genotypic prevalence in the
      population, serotyping in the present study used 5 synthetic peptides (NOF, EL1,
      MN, IIIB, IND) of African, North American, European and Indian origin. The Indian
      consensus was derived from genotype analysis of 13 cases. Results of serotype
      analysis indicated that 82% of patients harboured a strain related to the South
      African type of HIV-1. These observations have a sinister significance for
      designing vaccine strategies for this region.

PMID- 8665385
TI  - Seroepidemiological study of retroviruses (HTLV-I/II, HIV-1, HIV-2) in the
      Department of Atacora, northern Benin.
AB  - A seroepidemiological survey to determine the prevalence of retrovirus infection
      (HTLV-I/II, HIV-1, HIV-2) by representative sampling of the general population in
      the Department of Atacora in north-western Benin is reported. The seroprevalence
      rate of HTLV-I in this sample was at 1.86% (95% CI 1.20-2.52%). This is in
      agreement with prevalence rates reported from neighbouring countries of the sub
      region. No sera were found positive for HTLV-II. Seropositivity to HIV-1 was
      0.3%; HIV-2 seropositivity was not encountered.

PMID- 8665386
TI  - High HIV seroprevalence among patients with pyomyositis in northern Uganda.
AB  - With the aim of correlating pyomyositis with HIV infection, we have carried out a
      case-control comparison of HIV seroprevalence among patients affected by
      pyomyositis and an age and sex-matched control group of healthy subjects. Over a
      one-year period, 35 patients with pyomyositis, 20 male and 15 female, mean age
      28.31 years, were admitted to Dr Ambrosoli Memorial Hospital of Kalongo (Kitgum
      District, Northern Uganda). Among these patients, II were HIV-antibody-positive,
      with a seroprevalence of 31.42%. In the age and sex-matched control group of 35
      healthy subjects, selected in the same period from volunteers admitted to the
      surgical ward for orthopaedic trauma, two were HIV-antibody-positive, with a
      seroprevalence of 5.71%. The matched analysis produced a Mantel-Haenszel matched
      odds ratio of 5.50 and a maximum likelihood estimate of OR (MLE) of 5.50 (exact
      95% confidence limits for MLE = 1.20 < OR < 51.07). Among the II HIV-seropositive
      patients, 9 (81.8%) fulfilled the World Health Organization (WHO) clinical case
      definition (CCD) for AIDS, compared with I of twenty-four (4.1%) HIV-negatives.
      The chi-square test for difference in fulfilling the CCD for AIDS between
      patients with pyomyositis seropositive and seronegative gave a statistically
      significant result (P < 0.0001). The authors conclude that pyomyositis is a
      bacterial infection very significantly associated with HIV infection, to be
      considered a strong sign of stage III-IV of HIV disease.

PMID- 8665388
TI  - Prevention of snail miracidia interactions using Phytolacca dodecandra (L'Herit)
      (endod) as a miracidiacide: an alternative approach to the focal control of
      schistosomiasis.
AB  - The effect of endod berry extract against schistosome miracidia has been tested
      to determine the sensitivity of these organisms to the molluscicide and to see
      whether miracidia subjected to sublethal doses of the toxicant will be able to
      infect their specific host snails. Short contact (30 min) LC50 of endod extract
      with miracidia of Schistosoma mansoni was 8.2 parts per million (p.p.m.) (95% CL
      5-13). However, exposure of S. haematobium to sublethal doses of 3 p.p.m. for 30
      min or overnight in open air ponds reduced their infectivity 3.5-5.6-fold when
      compared with controls. It is suggested that the toxicant could be used in low
      doses at transmission foci to reduce schistosome infection in snails. This could
      be done by using a controlled release system to apply the toxicant material at
      such foci where transmission is likely to occur.

PMID- 8665387
TI  - Pathogenetic factors of acute schistosomiasis mansoni: correlation of worm
      burden, IgE, blood eosinophilia and intensity of clinical manifestations.
AB  - A clinical study of 34 previously healthy young patients simultaneously infected
      in an endemic area of schistosomiasis mansoni is presented, emphasizing the
      initial phase of the infection. Its intensity was established according to the
      occurrence, intensity, and duration of the signs and symptoms in order to
      investigate the possible correlations between the worm burden (estimated by the
      number of eggs in faeces), the blood eosinophilia and specific levels of IgE
      (estimated by the area of immediate intradermal reaction), with the clinical
      manifestations. A significant but low-level association was found between the
      worm burden and morbidity, suggesting that multiple factors, besides worm burden
      itself, may contribute to the pathogenesis of the disease.

PMID- 8665389
TI  - Parasite-specific lactate dehydrogenase for the diagnosis of Plasmodium
      falciparum infection in an endemic area in west Uganda.
AB  - The measurement of parasite lactate dehydrogenase (pLDH) has been presented as an
      easy and rapid method for the diagnosis of malaria in humans. In order to
      evaluate the sensitivity and specificity of such a test we examined blood samples
      from 429 Ugandan patients. While pLDH activity was significantly linked to
      parasitaemia, sensitivity and specificity were found to be rather low at 58.8 and
      62.2% respectively. The positive and negative predictive values failed to meet
      necessary standards. We conclude that the methods of measurement of pLDH activity
      in malaria infection, although potentially useful for the fast diagnosis of
      malaria, need to be improved to be of true value in endemic areas.

PMID- 8665390
TI  - Efficacy of sulphadoxine/pyrimethamine for Plasmodium falciparum malaria in
      Malawian children under five years of age.
AB  - In March 1993, sulphadoxine/pyrimethamine (SP) replaced chloroquine as the first
      line drug for malaria treatment in Malawi. Since then, the Ministry of Health has
      been receiving anecdotal and written reports of SP treatment failures in
      children. To determine whether treatment failure with SP was a widespread
      problem, children < 5 years of age with axillary temperature > 38.0 degrees C and
      parasite density > 2000/mm3 attending the outpatient clinics of the Mangochi and
      Karonga District Hospitals were enrolled in the study with parental consent.
      These were then followed for 28 days or until they failed clinically. Of 159
      patients enrolled, 145 (91.2%) were followed for 28 days or until clinical
      failure. Of these, none had RII resistance and 3 (1.9%) had RIII resistance: 2/69
      (2.9%) in Mangochi and 1/76 (1.3%) in Karonga; 142/145 (97.9%) exhibited
      RI/sensitive patterns. Of those followed to day 28 or to clinical failure, 77.1%
      had parasite clearance by day 3 and 98.6% had parasite clearance by day 7. Of
      those with temperature readings (n = 140), 129 (92.1%) clinically improved on day
      3 and 98.6% improved by day 7. Other indicators of clinical improvement (from day
      0 to day 3) included, reported increased level of activity in 136 (97.1%) of the
      children, and mother's impression of child's improvement in 113 (80.7%). Of the
      14 patients not followed to day 28 or to clinical failure, 11 were lost to follow
      up by day 7. No allergic skin reactions were noted, and no deaths were observed.
      These data show that after one year of widespread use of SP in Malawi, Plasmodium
      falciparum parasite resistance remains very low, and therefore contradicts
      reports of widespread parasite resistance to SP.

PMID- 8665391
TI  - Plasma quinine concentrations in falciparum malaria with acute renal failure.
AB  - Plasma quinine (Qn) monitoring was performed in 32 patients with severe
      falciparum malaria (10 with acute renal failure (ARF) and 22 with other severe
      manifestations) who were treated with the standard regimen of 10 mg/kg body
      weight Qn dihydrochloride, with a loading dose of 20 mg/kg body weight. Median
      plasma Qn concentrations prior to the first dose on each day were approximately
      10-30% higher in ARF patients than in non-ARF patients during acute infection.
      Seven patients underwent haemodialysis; 2 died after 2 cycles. There were no
      significant changes in plasma Qn concentrations in patients with ARF during
      haemodialysis. No Qn was detectable in haemodialysate fluids. This suggests that
      dosage adjustment of Qn during haemodialysis is unnecessary. Cardiotoxity of Qn
      must be of concern in malaria patients with ARF after 3 days of Qn therapy, and
      ECG monitoring during Qn infusion is recommended in all severe malaria patients
      with persistent ARF. If there is any arrhythmia, the infusion should be
      discontinued. However, in some hospitals where ECG facilities are not available,
      reduction in Qn dosage in persistent ARF patients should be considered after the
      third day of therapy. The appropriate dosage reduction should be further studied.
      Monitoring of total plasma Qn concentrations (which has been used routinely) is
      of no value for predicting the cardiotoxicity in ARF patients; monitoring of free
      Qn would be more appropriate. However, ECG seems to be the practical procedure to
      monitor cardiotoxicity of Qn. It may be possible to use the QTc interval to
      estimate the Qn concentration in severe malaria patients without ARF, but not in
      patients with persistent ARF.

PMID- 8665392
TI  - Necrotizing and suppurative lymphadenitis in Leishmania major infections.
AB  - The pathology of lymph nodes and subcutaneous nodules in 6 patients with
      cutaneous leishmaniasis (Oriental sore) due to Leishmania major is described in
      this paper. In 3 patients enlarged epitrochlear lymph nodes were found to be
      associated with primary skin lesions in the forearm. The lymph node in one
      patient showed a necrotizing granulomatous reaction that simulated tuberculous
      lymphadenitis. Leishmania parasites were, however, found in sections of the node,
      and staining for mycobacteria was negative. The second patient presented with an
      abscess and a discharging sinus in the epitrochlear region. Parasites were found
      in smears of the pus and cultures for bacteria were negative. The lesion healed
      with antimonial therapy. In the third patient the lesion resembled cat-scratch
      disease and showed stellate abscesses and granulomas. Leishmania parasites were
      also identified in the sections. Sections of a subcutaneous nodule from the
      fourth patient showed a necrotizing granuloma. The lesion healed spontaneously
      and the patient became leishmanin-positive. In two other patients fine needle
      aspiration of the subcutaneous nodules showed parasites, granuloma and necrosis.
      We concluded that L. major disseminates from the primary cutaneous lesion via the
      lymphatics to the subcutaneous tissues and the regional lymph nodes. The
      subcutaneous nodules and lymphadenopathy may persist long after the primary
      lesion had healed. The primary lesion is sometimes inconspicuous. Necrotizing and
      suppurative lymphadenitis due to L. major have to be distinguished from other
      causes of necrosis and suppuration such as tuberculosis and cat-scratch disease.

PMID- 8665393
TI  - Leishmania tropica in Egypt: an undesirable import.
AB  - Cutaneous as well as visceral leishmaniasis has been previously reported in
      Egypt. The former clinical manifestation is attributed to Leishmania major, the
      latter to L. infantum. In this study, L. tropica was isolated from an Egyptian
      labourer returning from Saudi Arabia. Amastigotes were detected by both Giemsa
      staining and indirect immunofluorescence using rabbit anti-gp63. Promastigotes
      from Schneider's medium were typed isoenzymatically as L. tropica. In view of the
      emerging threat of visceralization of L. tropica, the potential risk for its
      transmission in Egypt is discussed.

PMID- 8665394
TI  - (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]: a purine analogue
      with trypanocidal activity in vitro and in vivo.
AB  - The unique features of purine salvage systems of pathogenic haemoflagellates
      render them selectively susceptible to the cytotoxic effects of purine analogues.
      A series of acyclic nucleoside phosphonates were evaluated for activity against
      pathogenic haemoflagellates in vitro. One of the phosphonylmethoxyalkylpurines,
      namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was active
      in vitro against bloodstream forms of Trypanosoma brucei rhodesiense, T. b.
      gambiense, multidrug-resistant T. b. brucei, T. congolense and T. evansi, but not
      against intracellular T. cruzi or Leishmania donovani. Cytotoxic effects against
      mammalian cells were observed at 4900-27 300-fold higher concentrations than
      those necessary to inhibit T. b. rhodesiense. (S)-HPMPA was able to eliminate T.
      b. rhodesiense and multidrug-resistant T. b. brucei in an acute rodent model with
      two administrations of 10 mg/kg each.

PMID- 8665395
TI  - Studies on the periodicity and intravascular distribution of Wuchereria bancrofti
      microfilariae in paired samples of capillary and venous blood from Recife,
      Brazil.
AB  - We examined the periodicity and intravascular distribution of Wuchereria
      bancrofti microfilariae (mf) and determined the effect of these parasite
      properties on the accuracy of blood filming and filtration methods for diagnosis
      of bancroftian filariasis in the endemic area of Recife, Brazil. Microfilariae in
      both venous and capillary blood exhibited a nocturnal periodicity pattern with a
      relatively high amplitude. Overall, capillary blood contained approximately 1.25
      times the number of mf present at the same time in the same volume of venous
      blood. However, the ratio of mf present in capillary and venous blood varied over
      a 24-hour period, so that the fewest mf were present in the capillary bed of the
      skin at the time when biting activity of the local Culex vector is the lowest.
      Twenty or 60 microliters blood films did not reliably detect carriers with fewer
      than 100 or 60 mf/ml venous blood, respectively, and were thus inadequate for the
      identification of low density mf carriers. In contrast, all carriers with > 1
      mf/20 or 60 microliters blood smear at night could be identified during daytime
      hours by filtration of 1 micromilligram venous blood.

PMID- 8665396
TI  - Promoting operational research on insecticide-treated netting: a joint TDR/IDRC
      initiative and call for research proposals.
AB  - The evidence in favour of insecticide-treated nets for reducing mortality from
      malaria among Africa children is becoming compelling. In order to support the
      next step in the development of this promising intervention the UNDP/World
      Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)
      and the International Development Research Centre (IDRC) decided to launch a
      joint initiative on operational research. In the first step, 3 reviews on the
      essential aspects of net technology, programme implementation and programme
      promotion were commissioned and will be published soon as a book. Secondly,
      expert opinion was sought regarding priority topics for research. Finally, a
      first round of research projects was funded and a call for more proposals is
      being widely advertised.

PMID- 8665397
TI  - Insulin inhibits changes in the phospholipid profiles in sciatic nerves from
      streptozocin-induced diabetic rats: a phosphorus-31 magnetic resonance study.
AB  - Sciatic nerve phospholipids obtained from insulin-treated streptozocin-induced
      diabetic, non-treated streptozocin-induced diabetic, and healthy, control male
      Sprague-Dawley rats after eighteen weeks of diabetes were studied by 31P NMR
      spectrometry. Eleven phospholipids resonances were identified as follows:
      Phosphatidic acid (Chemical shift, 0.30 ppm), dihydrosphingomyelin (0.13 ppm),
      ethanolamine plasmalogen (0.07 ppm), phosphatidylethanolamine (0.03 ppm),
      phosphatidylserine (-0.05 ppm), sphingomyelin (-0.09 ppm),
      lysophosphatidylcholine (-0.28 ppm), phosphatidylinositol (-0.30 ppm),
      alkylacylglycerophosphorylcholine (-0.78 ppm), choline plasmalogen (-0.80 ppm),
      and phosphatidylcholine (-0.84 ppm). Diabetic rats showed that
      phosphatidylcholine was significantly elevated (p < 0.05), and ethanolamine
      plasmalogen and choline plasmalogen were significantly lower when compared with
      both control and insulin treated rats. The choline ratio (choline-containing
      phospholipids over noncholine phospholipids) was significantly elevated in the
      diabetic group, when compared with both control and insulin-treated groups. The
      ethanolamine ratio (ethanolamine-containing phospholipids over nonethanolamine
      phospholipids) and the ratio of the ethanolamine ratio over the choline ratio,
      was significantly elevated in the control and the insulin-treated groups when
      compared with the diabetic group. The presence of phosphatidic acid and the
      significance in phosphatidylcholine and ethanolamine plasmalogen, suggested that
      insulin had a role in the phosphatidylcholine metabolism in the rat nerve.

PMID- 8665398
TI  - Effects of traditional herbal medicine on gastric mucin against ethanol-induced
      gastric injury in rats.
AB  - The effect of the traditional herbal medicine, Rikkunshi-to and its component
      crude drugs, Zingiberis Rhizoma and Glycyrrhizae Radix, on the gastric mucin was
      studied using a method developed to separate and quantify the mucin localized in
      the different layers of rat gastric mucosa. The oral administration of spray
      dried extract to Rikkunshi-to (1000 mg/kg), Zingiberis Rhizoma (500 mg/kg) and
      Glycyrrhizae Radix (500 mg/kg) significantly prevented gastric mucosal damage
      induced by 70% ethanol in rats. In ethanol-treated rats the mucin content of the
      deep mucosa was reduced, and the reduction of the deep corpus mucin content was
      significantly inhibited by pretreatment of Rikkunshi-to and Zingiberis Rhizoma.
      Rikkunshi-to and Glycyrrhizae Radix pretreatment increased the surface mucin
      content by 140 and 146%, respectively. The effect on the gastric mucin by each
      drug differed in the different layers of the gastric mucosa.

PMID- 8665399
TI  - Release of interleukin-1 beta by dermatan sulfate suppresses hepatocyte growth.
AB  - Among glycosaminoglycans, dermatan sulfate (DS) is the strongest inhibitor of DNA
      synthesis in adult rat hepatocytes in primary culture stimulated with insulin and
      epidermal growth factor. Hyaluronate also inhibited DNA synthesis, whereas
      chondroitin-6 sulfate, 4-sulfate or heparin had no effect on DNA synthesis in
      hepatocytes. Analysis of growth regulatory factors in hepatocyte culture medium
      treated with DS revealed that interleukin-1 (IL-1) was released into the medium.
      IL-1 beta mRNA was detected in DS-treated hepatocytes by reverse transcriptase
      polymerase chain reaction, but not in untreated hepatocytes. For a marked
      inhibition of DNA synthesis, more than 10 hr of exposure to DS before cultured
      hepatocytes started DNA synthesis, was required. Similarly, more than 10 hr was
      required after the addition of DS before IL-1 beta mRNA was detected. These
      findings suggest that DS in the medium induced the production of IL-1 beta which,
      in turn, reduced DNA synthesis in hepatocytes.

PMID- 8665400
TI  - Stimulation of nonshivering thermogenesis in the Syrian hamster by norepinephrine
      and beta-selective adrenergic agents: a phenomenon of refractoriness.
AB  - The ability of different adrenergic agents to stimulate nonshivering
      thermogenesis in Syrian hamsters was investigated. The hamsters were cold
      acclimated to 6 degrees C and their thermogenic response was investigated in an
      open-circuit system at 24 degrees C. Both norepinephrine and the beta 3-specific
      adrenergic agonist CGP-12177 induced a high rate of nonshivering thermogenesis.
      However, neither CGP-12177 nor other beta 3-selective agonists (BRL-37344, ICI
      D7114) could induce nonshivering thermogenesis fully to the extent induced by
      norepinephrine. It was further observed that an apparent "thermogenic
      refractoriness" was induced by certain adrenergic agents (isoprenaline, CGP
      12177) but not by others (norepinephrine, BRL-37344, ICI-D7114). It is discussed
      whether the refractoriness could be secondary to effects of these agents on the
      vascular system. It is pointed out that the thermogenic response to adrenergic
      stimulation observed in the intact animal does not always fully correspond to
      what would be predicted from corresponding studies with isolated brown-fat cells.

PMID- 8665401
TI  - P450 induction by Aroclor 1254 and 3,3',4,4'-tetrachlorobiphenyl in cultured
      hepatocytes from rat, quail and man: interspecies comparison.
AB  - Polychlorobiphenyls are potent inducers of hepatic cytochrome P450 in various
      species. Until now, no model based on cultured cells can be considered as a
      universal surrogate for in vivo metabolism. In this respect, cultured rat
      hepatocytes, quail hepatocytes, and human hepatoma (HepG2) cells were used to
      study the effects of 3,3',4,4'-tetrachlorobiphenyl (3,3',4,4'-TCB) and Aroclor
      1254 on drug-metabolizing enzymes. The presence of dexamethasone in the culture
      medium allows the expression and the induction of several cytochrome P450
      isoenzymes found in adult cells. Induction of ethoxycoumarin-(ECOD) and
      ethoxyresorufin-O-deethylase (EROD), activities were measured. Induced P450s were
      identified by immunoblotting and Northern blotting. Aroclor 1254 induced ECOD
      activity in all three cell types, but the effect was much stronger in fetal rat
      hepatocytes than in human or quail cells. Aroclor failed to induce EROD activity
      in quail cells, had a slight inducer effect in HepG2 cells, and a marked effect
      in rat hepatocytes. 3,3',4,4'-TCB had no effect in HepG2 cells but significantly
      increased EROD and ECOD activities, especially the latter, in rat and quail
      cells. On the immunoblots, specific antibodies revealed essentially CYP1A1 in
      fetal rat hepatocytes, CYP2B1/2 in quail hepatocytes and CYP3A1 in HepG2 cells.
      Analysis of Northern blots showed an hybridization with CYP1A1, 2B1 and 3A1 mRNA
      in fetal rat hepatocytes, CYP3A and 1A mRNA in HepG2 cells, and a form of CYP2
      mRNA in fetal quail hepatocytes closely related to homolog rat CYP2E or CYP2C. In
      quail hepatocytes, induction did not increase proportionally with the
      concentration of inducer in the culture medium. Instead, the dose-response curves
      (for EROD activity especially) peaked sharply at 1 muM Aroclor 1254, an effect
      attributed to changes in membrane fluidity or lipid content. Our results
      highlight the advantage of using several types of cultured hepatocytes to
      investigate fundamental aspects of drug-metabolism-linked toxicity, the balance
      between xenobiotic bioactivation and detoxication being differently affected by
      PCBs in different animal species.

PMID- 8665402
TI  - Inhibitors in tea of intestinal absorption of phenylalanine in rats.
AB  - This work studies the effect of tea extract on the mucosal and serosal transport
      of phenylalanine, and attempts to identify the active ingredient(s) therein by
      studying the effect of known tea constituents like theophylline, caffeine and
      tannic acid. Tea and all the constituents tested inhibited the mucosal uptake of
      phenylalanine. The serosal transport was unaffected by caffeine and tannic acid,
      but inhibited by theophylline and high concentrations of tea. The in vitro
      activity of the intestinal Na+-K+ATPase was also assayed from a jejunal
      homogenate in presence of theophylline, caffeine, tannic acid and cAMP. All were
      found to inhibit significantly the enzyme. The in vitro activity of a purified
      Na+-K+ATPase was however stimulated by theophylline and caffeine, and inhibited
      only by tannic acid. It was concluded that the inhibitory effect of tea is
      exerted mainly through its constituents which inhibit the Na+-K+ pump directly
      (tannic acid) or indirectly (theophylline and caffeine), possible by elevating
      cAMP levels, dissipating thus the sodium gradient needed for the mucosal uptake
      of the amino acid.

PMID- 8665403
TI  - Photoperiodic elevation of testicular zinc protects seminiferous tubules against
      fluoride toxicity in the bank vole (Clethrionomys glareolus).
AB  - Recent work has shown that a high fluoride (F) intake in rodents leads to
      histopathologic changes in the germinal epithelium of testes and to zinc
      deficiency in the testis and several other organs. The purpose of the present
      study was to determine whether an elecvation of testicular zinc concentration
      during fluoride exposure could protect the testes of bank vole from damage. The
      elevation of testicular zinc was achieved by exposing the bank voles to a long
      photoperiod (16 hr light/8 hr dark). The zinc concentration in the testes of bank
      voles kept under the long photoperiod was 38% higher than that in animals exposed
      to a moderate photoperiod (12 hr light/12 hr dark). Fluoride exposure (200
      micrograms F/ml drinking water) during 4 months decreased additionally (p < 0.05)
      zinc concentration in the testes of bank voles kept under the moderate
      photoperiod. The same animals also exhibited histopathologic changes in the
      germinal epithelium. By contrast, these disturbances were not observed in animals
      maintained in the long photoperiod. This experiment suggests that an increase in
      testicular zinc due to a long photoperiod prevents seminiferous tubules from a
      damage induced by fluoride in bank voles. The protective effects of zinc (or a
      long photoperiod) did not appear to be related to a decrease in testicular
      fluoride accumulation or lipid peroxidation.

PMID- 8665404
TI  - Effects of the nonsteroidal anti-inflammatory drug piroxicam on rat liver
      mitochondria.
AB  - 1. The effects of piroxicam, a nonsteroidal anti-inflammatory drug, on rat liver
      mitochondria were investigated in order to obtain direct evidence about a
      possible uncoupling effect, as suggested by a previous work with the perfused rat
      liver. 2. Piroxicam increased respiration in the absence of exogenous ADP and
      decreased respiration in the presence of exogenous ADP, the ADP/O ratios and the
      respiratory control ratios. 3. The ATPase activity of intact mitochondria was
      increased by piroxicam. With 2,4-dinitrophenol uncoupled mitochondria, inhibition
      was observed. The ATPase activity of freeze-thawing disrupted mitochondria was
      insensitive to piroxicam. 4. Swelling driven by the oxidation of several
      substrates and safranine uptake induced by succinate oxidation were inhibited. 5.
      The results of this work represent a direct evidence that piroxicam acts as an
      uncoupler, thus, decreasing mitochondrial ATP generation.

PMID- 8665405
TI  - Effects of the nonsteroidal anti-inflammatory drug piroxicam on energy metabolism
      in the perfused rat liver.
AB  - 1. The actions of piroxicam, a nonsteroidal and noncarboxylic anti-inflammatory
      drug, on the metabolism of the isolated perfused rat liver were investigated. The
      main purpose was to verify if piroxicam is also active on glycogenolysis and
      energy metabolism, as demonstrated for several carboxylic nonsteroidal anti
      inflammatories. 2. Piroxicam increased oxygen consumption in livers from both fed
      and fasted rats. 3. Piroxicam increased glucose release and glycolysis from
      endogenous glycogen (glycogenolysis). 4. Gluconeogenesis from lactate plus
      pyruvate was inhibited. 5. The action of piroxicam on oxygen consumption was
      blocked by antimycin A, but not by atractyloside. 6. The action of piroxicam in
      the perfused rat liver metabolism seems to be a consequence of its action on
      mitochondria. 7. It can be concluded that inhibition of energy metabolism and
      stimulation of glycogenolysis are not specific properties of carboxylic
      nonsteroidal anti-inflammatory drugs.

PMID- 8665406
TI  - Induction of S-phase entry by a gonadotropin releasing hormone agonist
      (buserelin) in the frog, Rana esculenta, primary spermatogonia.
AB  - In the testis of the frog, Rana esculenta, mitotic activity of primary
      spermatogonia is regulated by gonadotropins and synergistically by testosterone.
      In addition GnRH-like material directly stimulates gonadal activity. Intact
      animals were treated with a GnRH agonist (GnRHa, buserelin, Hoechst) and/or a
      GnRH antagonist giving injections intraperitoneally on alternate days for 15
      days. Moreover, testes were treated in vitro for 24 hr with GnRHa. 3H-thymidine
      and colchicine were used to assess the labelling and the mitotic index (LI and
      MI) of primary spermatogonia. Both LI and MI were increased by the treatment with
      GnRHa but the rate of cells measured by LI was significantly higher than that of
      cells measured by MI. Therefore, our results confirm the role of GnRH-like
      material as local regulator of the testicular activity in vertebrates and show
      its involvement in promoting the G1-S transition of spermatogonial cell cycle in
      the frog, Rana esculenta.

PMID- 8665407
TI  - Structure and function of the hammerhead ribozyme: an unfinished story.

PMID- 8665408
TI  - Mutational analysis of U1 function in Schizosaccharomyces pombe: pre-mRNAs differ
      in the extent and nature of their requirements for this snRNA in vivo.
AB  - The U1 snRNP is known to play a critical role in spliceosome assembly, at least
      in part through base pairing of its RNA moiety to the substrate, but many details
      remain to be elucidated. To further dissect U1 snRNA function, we have analyzed
      14 single point mutations in the six nucleotides complementary to the 5' splice
      site for their effects on growth and splicing in the fission yeast
      Schizosaccharomyces pombe. Three of the four alleles previously found to support
      growth of Saccharomyces cerevisiae are lethal in S. pombe, implying a more
      critical role for the 5' end of U1 in fission yeast. Furthermore, a comparison of
      phenotypes for individual nucleotide substitutions suggests that the two yeasts
      use different strategies to modulate the extent of pairing between U1 and the 5'
      splice site. The importance of U1 function in S. pombe is further underscored by
      the lethality of several single point mutants not examined previously in S.
      cerevisiae. In total, only three alleles complement the U1 gene disruption, and
      these strains are temperature-sensitive for growth. Each viable mutant was tested
      for impaired splicing of three different S. pombe introns. Among these, only the
      second intron of the cdc2 gene (cdc2-I2) showed dramatic accumulation of linear
      precursor. Notably, cdc2-I2 is spliced inefficiently even in cells containing
      wild-type U1, at least in part due to the presence of a stable hairpin
      encompassing its 5' splice site. Although point mutations at the 5' end of U1
      have no discernible effect on splicing of pre-U6, significant accumulation of
      unspliced RNA is observed in a metabolic depletion experiment. Taken together,
      these observations indicate that the repertoire of U1 activities is used to
      varying extents for splicing of different pre-mRNAs in fission yeast.

PMID- 8665410
TI  - Sequence-dependent in vivo importation of tRNAs into the mitochondrion of
      Leishmania tarentolae.
AB  - Sequence determinants for the importation of tRNAs into the mitochondrion of
      Leishmania tarentolae in vivo were investigated. tRNA(Ile)(UAU) is exclusively
      localized within the mitochondrion and tRNA(Gln)(CUG) exclusively in the cytosol
      (Lye LF, Chen DHT, Suyama Y, 1993, Mol Biochem Parasitol 58:233-246; Shi X, Chen
      DHT, Suyama Y, 1994, Mol Biochem Parasitol 65:23-37). L. tarentolae cells were
      transfected with plasmids encoding either tRNA(Ile) or tRNA (Gln) that were
      tagged with altered sequences in the D loop, permitting discrimination from the
      endogenous tRNAs. Primer extension analysis was used to show that the plasmid
      encoded genes were expressed and that the tagged tRNAs showed a similar
      intracellular localization as the endogenous tRNAs. Exchange or deletion of the
      5'-flanking genomic sequences had no effect on the expression or mitochondrial
      localization of the tagged tRNA(Ile) or on the expression or cytosolic
      localization of the tagged tRNA(Gln), suggesting that the signals for importation
      are localized within the tRNA itself. Swapping the D loop+stem from the
      exclusively cytosolic tRNA(Gln) with that from the tRNA(Ile) produced a partial
      mitochondrial localization of the plasmid-expressed mutated tRNA(Gln). However, D
      loop exchange did not eliminate the mitochondrial localization of the plasmid
      expressed mutated tRNA(Ile), suggesting that tertiary structure or additional
      sequence elements may be involved in the importation signal.

PMID- 8665409
TI  - Inhibition of vascular smooth muscle cell proliferation by ribozymes that cleave
      c-myb mRNA.
AB  - Proliferation of injured smooth muscle cells contributes to the reocclusion or
      restenosis of coronary arteries that often occurs following angioplasty
      procedures. We have identified and optimized nuclease-resistant ribozymes that
      efficiently cleave c-myb RNA. Three ribozymes targeting different sites in the c
      myb mRNA were synthesized chemically and delivered to rat aortic smooth muscle
      cells with cationic lipids; all three inhibited serum-stimulated cell
      proliferation significantly. RNA molecules with two base substitutions in the
      catalytic core that render the ribozyme catalytically inactive had little effect
      on smooth muscle cell proliferation. Ribozymes with scrambled binding arm
      sequences also failed to affect cell cycle progression of vascular smooth muscle
      cells. Furthermore, inhibition of rat smooth muscle cell proliferation correlated
      with a reduction in intact c-myb mRNA. Efficacy of the chemically-modified
      ribozyme was compared directly to phosphorothioate antisense
      oligodeoxynucleotides targeting the same site in the c-myb RNA; the ribozyme had
      superior efficacy and showed greater specificity than the antisense molecules.
      Exogenously delivered ribozymes also inhibited porcine and human smooth muscle
      cell proliferation effectively. Ribozymes targeting c-myb or other regulators of
      smooth muscle cell proliferation may represent novel therapeutics for the
      treatment of restenosis after coronary angioplasty.

PMID- 8665411
TI  - Mutational analysis of Saccharomyces cerevisiae nuclear RNase P: randomization of
      universally conserved positions in the RNA subunit.
AB  - Three regions in the Saccharomyces cerevisiae RNase P RNA have been identified,
      at positions Sce 87-94, Sce 309-316, and Sce 339-349, that contain nucleotides
      that are invariant in identity and position among all the known RNase P RNAs. To
      study the importance of these conserved RPR1 RNA regions in enzyme function,
      three independent mutational libraries were created in which the positions of
      invariant nucleotides were randomized simultaneously. Screening in vivo was used
      to identify viable RPR1 variants when reconstituted into holoenzyme in cells.
      Despite the universal evolutionary conservation, most of these positions tolerate
      certain sequence changes without severely affecting function. Most changes,
      however, produced subtle defects in cell growth and RNase P function, supporting
      the importance of these conserved regions. Isolation of conditional growth
      mutants allowed the characterization of the effects of mutations on cell growth,
      RPR1 RNA maturation, and activity of the holoenzyme in vitro. Kinetic analysis
      showed that viable variants were usually more defective in catalytic rate (Kcat)
      than in substrate recognition (Km).

PMID- 8665412
TI  - Mycoplasma fermentans simplifies our view of the catalytic core of ribonuclease P
      RNA.
AB  - The catalytic RNA moiety of (eu)bacterial RNase P is responsible for cleavage of
      the 5' leader sequence from precursor tRNAs. We report the sequence, the
      catalytic properties, and a phylogenetic-comparative structural analysis of the
      RNase P RNA from Mycoplasma fermentans, at 276 nt the smallest known RNase P RNA.
      This RNA is noteworthy in that it lacks a stem-loop structure (helix P12) that
      was thought previously to be universally present in bacterial RNase P RNAs. This
      finding suggests that helix P12 is not required for catalytic activity in vivo.
      In order to test this possibility in vitro, the kinetic properties of M.
      fermentans RNase P RNA and a mutant Escherichia coli RNase P RNA that was
      engineered to lack helix P12 were determined. These RNase P RNAs are
      catalytically active with efficiencies (Kcat/Km) comparable to that of native E.
      coli RNase P RNA. These results show that helix P12 is dispensable in vivo in
      some organisms, and therefore is unlikely to be essential for the mechanism of
      RNase P action. The notion that all phylogenetically volatile structures in RNase
      P RNA are dispensable for the catalytic mechanism was tested. A synthetic RNA
      representing the phylogenetic minimum RNase P RNA was constructed by deleting all
      evolutionarily variable structures from the M. fermentans RNA. This simplified
      RNA (Micro P RNA) was catalytically active in vitro with approximately 600-fold
      decrease in catalytic efficiency relative to the native RNA.

PMID- 8665413
TI  - Phylogenetic comparative mutational analysis of the base-pairing between RNase P
      RNA and its substrate.
AB  - We have studied the base-pairing between the 3'-terminal CCA motif of a tRNA
      precursor and RNase P RNA by a phylogenetic mutational comparative approach.
      Thus, various derivatives of the Escherichia coli tRNA(Ser)Su1 precursor
      harboring all possible substitutions at either the first or the second C of the
      3'-terminal CCA motif were generated. Cleavage site selection on these precursors
      was studied using mutant variants of M1 RNA, the catalytic subunit of E. coli
      RNase P, carrying changes at positions 292 or 293, which are involved in the
      interaction with the 3'-terminal CCA motif. From our data we conclude that these
      two C's in the substrate interact with the well-conserved G292 and G293 through
      canonical Watson-Crick base-pairing. Cleavage performed using reconstituted
      holoenzyme complexes suggests that this interaction also occurs in the presence
      of the C5 protein. Furthermore, we studied the interaction using various
      derivatives of RNase P RNAs from Mycoplasma hyopneumoniae and Mycobacterium
      tuberculosis. Our results suggest that the base-pairing between the 3'-terminal
      CCA motif and RNase P is present also in other bacterial RNase P-substrate
      complexes and is not limited to a particular bacterial species.

PMID- 8665414
TI  - Role of the three consecutive G:C base pairs conserved in the anticodon stem of
      initiator tRNAs in initiation of protein synthesis in Escherichia coli.
AB  - The three consecutive G:C base pairs, G29:C41, G30:C40, and G31:C39, are
      conserved in the anticodon stem of virtually all initiator tRNAs from eubacteria,
      eukaryotes, and archaebacteria. We show that these G:C base pairs are important
      for function of the tRNA in initiation of protein synthesis in vivo. We changed
      these base pairs individually and in combinations and analyzed the activities of
      the mutant Escherichia coli initiator tRNAs in initiation in vivo. For assessment
      of activity of the mutant tRNAs in vivo, mutations in the G:C base pairs were
      coupled to mutation in the anticodon sequence from CAU to CUA. Mutations in each
      of the G:C base pairs reduced activity of the mutant tRNA in initiation, with
      mutation in the second G:C base pair having the most severe effect. The greatly
      reduced activity of this C30:G40 mutant tRNA is not due to defects in
      aminoacylation or formulation of the tRNA or defects in base modification of the
      A37, next to the anticodon, which we had previously shown to be important for
      activity of the mutant tRNAs in initiation. The anticodon stem mutants are most
      likely affected specifically at the step of binding to the ribosomal P site. The
      pattern of cleavages in the anticodon loop of mutant tRNAs by S1 nuclease
      indicate that the G:C base pairs may be involved directly in interactions of the
      tRNA with components of the P site on the ribosome rather than indirectly by
      inducing a particular conformation of the anticodon loop critical for function of
      the tRNA in initiation.

PMID- 8665415
TI  - Kinetic characterization of two I/II format hammerhead ribozymes.
AB  - Five new hammerhead ribozymes were designed that assemble through the formation
      of helices I and II (I/II format) instead of the more standard assembly through
      helices I and III (I/III format). The substrate binding and cleavage properties
      of such hammerheads could potentially be different due to the absence of loop II
      and the requirement for the entire catalytic core to assemble. Two I/II format
      hammerheads, HHalpha1 and HHalpha5, which show structural homogeneity on native
      gels, were characterized kinetically. The association rate constants of both I/II
      hammerheads are unusually slow compared to the rate of RNA duplex formation. The
      dissociation rate constants indicate that the hammerhead core destabilizes an
      uninterrupted RNA helix somewhat less than was observed for I/III hammerheads.
      Whereas the cleavage rate constant of HHalpha5 is similar to that observed for
      I/III hammerheads, HHalpha1 cleaves 10-fold faster than any hammerhead previously
      reported. The temperature and pH dependence of the cleavage rate constant of
      HHalpha1 are similar to those reported for I/III hammerheads, suggesting a
      similar mechanism of cleavage.

PMID- 8665416
TI  - RNA sequences upstream of the 3' splice site repress splicing of mutantyeast ACT1
      introns.
AB  - A yeast ACT1 intron in which both the first and last intron nucleotides are
      mutated, the /a-c/ intron, splices 10% as well as wild type. We selected for
      additional cis-acting mutations that improve the splicing of /a-c/ introns and
      recovered small deletions upstream of the 3' splice site. For example, deletion
      of nucleotides -9 and -10 upstream of the 3' splice site increased the splicing
      activity of the /a-c/ intron to 30% that of the wild-type ACT1 intron. To
      determine if the increased /a-c/ splicing was due to changes in intron spacing or
      sequence, we made mutations that mimicked the local sequence of the delta-9, -10
      deletion without deleting any nucleotides. These mutants also increased /a-c/
      splicing, indicating that the increased splicing activity was due to changes in
      intron sequence. The delta-9, -10 deletion was not allele specific to the /a-c/
      intron, and improved the splicing efficiency of many mutant introns with step II
      splicing defects. To further define the sequences required for improved splicing
      of mutant introns, we randomized the region upstream of the ACT1 3' splice site.
      We found that almost all sequence alterations improved the splicing of the /a-c/
      intron. We postulate that this sequence near the 3' end of the intron represses
      the splicing of mutant introns, perhaps by serving as the binding site for a
      negative splicing factor.

PMID- 8665417
TI  - Wilfred Gordon Bigelow.

PMID- 8665418
TI  - Coronary artery disease among South Asians: identification of a high risk
      population.

PMID- 8665419
TI  - Survey of cardiac pacing in Canada (1993).
AB  - INTRODUCTION: The status of cardiac pacing in Canada in 1993 was determined from
      data provided by 33 of 128 physicians surveyed (25% response) and four major
      manufacturer/distributors. DEMOGRAPHICS: There were 268 new implants per million
      population, similar to the 1989 data, 279 per million. INDICATIONS: Sinus node
      disorders accounted for 38.2% of implants, atrial fibrillation with slow
      ventricular response for 18.1% and atrioventricular node dysfunction for 33.1% of
      patients. Implants for tachyarrhythmias accounted for only 3.5%. TECHNOLOGY:
      Single chamber units were implanted in 76% of patients and dual chamber in 23%,
      with rate modulation used in 35% of primary implants. There was an increase in
      the use of single chamber rate adaptive units from 1989 (from 15.9% to 25%). The
      per venous sheath introducer technique was used in 55% of lead insertions.
      Bipolar leads were used in 78% of atrial and 63% of ventricular leads; passive
      steroid leads were used in 50% of atrial and 55% of ventricular lead implants;
      40% of atrial leads and 7.5% of ventricular leads had active fixation. FOLLOW-UP:
      Most pulse generators were reprogrammed peri-operatively or within three months
      (97.4%). Most patients with new implants (92%) required hospital admission for
      2.5 days, while 75% of replacements were out-patient procedures. CONCLUSIONS:
      Comparison with previous surveys and other countries revealed little growth in
      pacemaker sales or new implant rates per million population; conservative
      indications and relatively constant use of dual chamber devices; and an increase
      in single chamber rate responsive units. The authors express concern regarding
      budget constraints and resource availability as factors limiting growth in
      pacemaker therapy.

PMID- 8665420
TI  - Maintaining physiological pacing in AV block using a new generation single lead
      VDD pacemaker.
AB  - OBJECTIVE: A prospective evaluation of patients with AV block using a single pass
      lead, VDD pacing system. DESIGN: Fifteen patients with AV block, eight males,
      seven females, average age 68.1 years (range 22.3 to 86.5) were implanted with
      the THERA VDD 8948 pacemaker and 5032 single pass steroid eluting lead
      (Medtronic, Inc). P wave sensing and ventricular thresholds were done
      predischarge and at one, three, and six months and subsequent six-month periods
      postimplant. P wave sensing was evaluated with exercise testing and other
      provocative tests. Twenty-four hour Holter monitoring was done before discharge.
      Patients were given a quality of life questionnaire pre- and postimplant.
      SETTING: Tertiary care hospital. RESULTS: Average follow-up was 6.4 months (1.5
      to 18). Ventricular thresholds remained stable. P wave amplitude at implant
      (average 2.2 mV; 1.6 to 3.6) showed a significant decrease at the initial visit
      (average 1.1 mV, 0.5 to 2.4), however, it remained stable at subsequent visits.
      This initial decrease had no clinical significance as the maximum atrial
      sensitivity of the device is 0.18 mV. The 24 hr Holter monitoring confirmed
      reliable AV synchronous pacing in 14 of 15 patient pacemakers programmed in the
      VDD mode. The sleep function maintained AV synchrony during nocturnal
      bradycardia; atrial rate histograms available at follow-up imply appropriate
      intrinsic rate variation and provocative sensing tests and exercise protocol
      demonstrated reliable atrial sensing. There was a significant improvement in
      overall patient well-being score using a quality of life questionnaire.
      CONCLUSIONS: During the follow-up period, this new generation VDD pacemaker,
      using a single pass lead, provided reliable AV synchronous pacing for patients
      diagnosed with AV block and normal sinus node function, as well as improved
      patient well-being.

PMID- 8665421
TI  - Noninvasive assessment of cardiac function during exercise in patients with CHF
      or COPD: measurement of aortic bloodflow indices by continuous wave Doppler.
AB  - OBJECTIVE: To test whether continuous-wave Doppler measurements of aortic
      bloodflow indices would reliably distinguish patients with congestive heart
      failure (CHF) from those with chronic obstructive pulmonary disease (COPD) and a
      similar degree of exertional dyspnea. DESIGN. Parallel group comparison. SETTING:
      University teaching hospital. PARTICIPANTS: Eighteen out-patients with clinically
      distinct syndromes of CHF or COPD but of similar age and functional limitation.
      INTERVENTION: Participants were observed during graded treadmill exercise. The
      following indices were obtained: heart rate, systolic blood pressure (SBP),
      earlobe oxygen saturation, and continuous-wave Doppler measurements of aortic
      bloodflow from the suprasternal notch. MAIN RESULTS: Exercise duration (mean +/-
      SE): COPD 14.2 +/- 1.2 mins, CHF 14.0 +/- 1.2 mins, not significant. Maximum
      results during exercise: heart rate, CHF 143 +/- 7 beats/min, COPD 149 +/- 5
      beats/min, not significant; peak velocity, CHF 0.60 +/- 0.04 m/s, COPD 0.92 +/-
      0.07 m/s, P < 0.005; peak acceleration, CHF 17 +/- 1 m/s2, COPD 37 +/- 3 m/s2, P
      < 0.001; SBP: CHF 152 +/- 8 mmHg, COPD 207 +/- 5 mmHg, P < 0.001; minimum oxygen
      saturation: CHF 92 +/- 1%, COPD 88 +/- 2%, not significant. CONCLUSIONS: Aortic
      bloodflow indices can be measured during exercise in patients with exertional
      dyspnea due to CHF or COPD and, in CHF, these indices are significantly reduced
      compared with individuals with COPD measured at similar levels of exercise. These
      data suggest that measurement of aortic bloodflow indices may have a role as an
      adjunct to routine tests in the diagnosis of patients with dyspnea. Further
      studies are indicated in patients with clinical features of both COPD and CHF in
      whom the etiology of dyspnea is uncertain.

PMID- 8665422
TI  - Tree structure and branching characteristics of the right coronary artery in a
      right-dominant human heart.
AB  - The hierarchic branching tree structure of the right coronary artery in a right
      dominant human heart is examined in terms of detailed measurements of lengths and
      diameters of the individual vessel segments comprising the structure. The results
      show that, while the right coronary artery in this heart does not supply a large
      portion of the posterior left ventricular wall, it nevertheless serves the left
      side of the heart to a greater extent than it does the right side in terms of the
      number and volume of vessel segments involved. The results show further that on
      the right side of this heart the right coronary artery exhibits clear features of
      a "distributing' vessel, but these features change abruptly as the vessel reaches
      the small region of the posterior left ventricular wall which it serves.

PMID- 8665423
TI  - Referral of young adult patients with congenital heart disease to adult centres.
      The Canadian Adult Congenital Heart Network.
AB  - OBJECTIVE: To establish a process of referral for young adult patients with
      congenital heart disease from pediatric to adult centres. DESIGN: Directors of
      pediatric cardiology units across Canada were asked to complete a questionnaire
      detailing their process of referral of young adult patients with congenital heart
      disease to adult centres. They were also asked to respond to specific case
      scenarios. Adult cardiologist members of the Canadian Adult Congenital Heart
      Network were asked to respond to the same case scenarios. MAIN RESULTS: Most
      pediatric cardiology centres refer patients to adult cardiologists at 18 years of
      age. The process of referral generally involves a referral letter and relevant
      parts of the chart. Few centres arrange a booked appointment with the adult
      cardiologist, although this would be preferred by the majority of the responding
      adult cardiologists. Generally good agreement existed between pediatric and adult
      cardiologists with regard to the kind of patients who required specialized care
      at an adult congenital heart centre. CONCLUSION: Within Canada, a process is
      rapidly evolving to facilitate the transfer of care of young adults with
      congenital heart disease.

PMID- 8665425
TI  - Impact of the social environment on blood pressure in women.
AB  - A remarkable increase in life expectancy, a decrease in fertility and delayed
      first birth as well as increased literacy have all contributed to major changes
      in women's lifestyles and their social environment. Several factors such as level
      of education, unemployment and low income have been associated in epidemiological
      studies with elevations in blood pressure. Social support appears to be an
      important buffer modulating the cardiovascular effects of a variety of stressors.
      Studies to date suggest that there may be important gender differences in the way
      socioenvironmental factors affect blood pressure, thus warranting development of
      intervention strategies directed uniquely at women.

PMID- 8665424
TI  - Metabolic recovery after global myocardial ischemia: effects of blood
      cardioplegic solutions.
AB  - OBJECTIVE: To determine the effect of whole blood cardioplegia (WBC) and a mix of
      crystalloid in blood (CB) hyperkalemic cardioplegic solutions on recovery of the
      myocardium following global ischemia. DESIGN: Twenty-one dogs were placed on
      normothermic cardiopulmonary bypass, and a pH probe was inserted in the anterior
      wall of the left ventricle. Global myocardial ischemia was obtained by clamping
      the ascending aorta until a decrease in myocardial tissue pH of 0.4 units from
      baseline value was obtained, at which time cardioplegic solutions were perfused
      over 30 mins. The aorta was then unclamped and 30 mins of reperfusion was
      allowed. RESULTS: The aortic cross-clamping time necessary to decrease myocardial
      tissue pH 0.4 units from baseline averaged 13 +/- 8 mins. Whereas myocardial
      tissue pH returned to baseline value (6.9 +/- 0.1) after an average of 24 mins
      with cold (15 degrees C) and warm (35 degrees C) WBC, it took an average of 48
      mins to reach control levels when warm CB solutions were used. Moreover, tissue
      pH decreased temporarily from 6.97 +/- 0.35 to 6.77 +/- 0.37 (P < 0.05) at
      initiation of normothermic myocardial reperfusion in cold WBC protected animals,
      and myocardial pH remained normal in the warm WBC group but remained severely
      acidic in warm CB animals (6.6 +/- 0.3). CONCLUSIONS: Metabolic recovery after
      global ischemia was faster with WBC cardioplegic protection. Normothermic blood
      reperfusion in cold WBC protected animals caused a significant but temporary
      tissue acidosis.

PMID- 8665426
TI  - Hypertension in women.
AB  - Hypertension in women has received little attention in comparison to men. There
      are only a handful of studies focusing on women with hypertension. Nevertheless,
      the data provide some information on the prevalence of hypertension in women,
      complications and the effectiveness of treatment. The Framingham Study showed
      that blood pressure (BP) increased with age in both men and women. The
      Hypertension Detection and Follow-up Program study demonstrated that hypertension
      was much more prevalent in men than women. However, in the postmenopausal group
      more than half were hypertensive. High BP is prevalent in older women. In
      absolute values, the complication rate is lower in women than in men but
      increases with age. At all levels of BP, the morbidity and mortality associated
      with BP is lower in women than men. Nevertheless, there is a five- to sixfold
      increase in risk in hypertensive compared with normotensive women. Furthermore,
      hypertensive women with a myocardial infarction have a worse prognosis than men.
      No study data using newer agents such as calcium channel blockers and angiotensin
      converting enzyme inhibitors are available yet. Since antihypertensive treatment
      appears to be effective in smokers, cessation of smoking is a very important
      intervention. Studies such as the European Working Party on Hypertension in
      Elderly, Systolic Hypertension in Elderly, Swedish Trial of Old Patients with
      Hypertension, and Medical Research Council 1992 have recruited patients 60 years
      of age and older, mainly women. These trials have shown that in the elderly
      hypertensive all-cause mortality is reduced by 30%, stroke by 33%, congestive
      heart disease mortality by 20% and heart failure by 40% to 50% with treatment.
      However, even these newer trials have used the so-called "old medications'.
      Studies using "newer drugs' are in progress.

PMID- 8665427
TI  - Women, hormones and blood pressure.
AB  - Raised blood pressure is an important risk factor for both coronary artery
      disease and stroke in women. In terms of exogenous sex hormones, use of
      premenopausal oral contraceptives has been consistently associated with higher
      blood pressure levels; both estrogenic and progestogenic components have been
      implicated. In contrast, a randomized trial has shown no effect of post
      menopausal hormone use on blood pressure. Observational studies indicate a
      protective effect of postmenopausal estrogen use on coronary artery disease. This
      is probably largely mediated through effects on lipoproteins and not blood
      pressure; data on post-menopausal estrogen use and stroke risk are less
      consistent. Treatment trials have demonstrated beneficial effects of lowering
      blood pressure on cardiovascular disease, particularly regarding stroke in women.
      The women most likely to benefit from individually-based clinical preventive
      interventions for cardiovascular disease, such as hypertension treatment or
      estrogen replacement therapy, are women who have high absolute risk of
      cardiovascular disease, ie, older women with high risk factor levels with a
      family or existing history of cardiovascular disease. Nevertheless, the large
      international variation in rates of cardiovascular disease indicate the large
      potential for prevention and suggest that most women are likely to benefit from
      lifestyles conducive to cardiovascular health, that is increasing physical
      activity, not smoking and following diets low in sodium and saturated fat and
      high in fruits and vegetables.

PMID- 8665428
TI  - The Puritan physician from Dorset.

PMID- 8665429
TI  - A rose by any other name....

PMID- 8665430
TI  - Recent advances in cardiology.

PMID- 8665431
TI  - Advances in endocrinology and metabolism, 1990-1995.

PMID- 8665432
TI  - Update of HIV and AIDS in North America.
AB  - The second wave of the HIV epidemic, which increasingly affects injection drug
      users, women, and minorities, necessitates the development of primary care HIV
      services so that these individuals may benefit from new therapies. The ability to
      dramatically decrease vertical transmission of HIV from mother to child with
      antiretroviral therapy is encouraging. Better understanding of HIV pathogenesis,
      disease progression, antiviral therapy, and opportunistic infection prophylaxis
      are leading to more effective therapy and prevention. Clinical trials are ongoing
      to assess the efficacy of protease inhibitors in combination with nucleoside
      analog antiretroviral therapy to provide long term viral suppression and alter
      the natural history of HIV. Prophylaxis of pneumocystis, toxoplasma, MAC, TB, and
      invasive fungal infections is cost effective and leads to improved quality of
      life.

PMID- 8665433
TI  - Fibromyalgia.

PMID- 8665434
TI  - Physical activity and health.

PMID- 8665435
TI  - Workplace smoking policies of Rhode Island employers, 1995.

PMID- 8665436
TI  - Bioengineering in dermatology: general aspects and perspectives.

PMID- 8665437
TI  - Bioengineering and the skin: standardization.

PMID- 8665438
TI  - Measurement of skin pH and its significance in cutaneous diseases.

PMID- 8665439
TI  - Quantitative evaluation of skin surface lipids.
AB  - More than 50 years of noninvasive studies of epidermal and sebaceous lipids has
      revealed a vast amount of information concerning secretion and regulation of
      SSLs. The first techniques developed (solvent extraction and cigarette paper)
      required very long experimental procedures to obtain valuable parameters;
      however, a great part of the knowledge on SSL production and regulation was
      obtained by these pioneers. Because of the difficulties encountered in these
      multistep procedures, applicability was restricted to a limited number of
      research centers. The sampling procedures in the newly developed techniques are
      significantly reduced and are followed by a fast and accurate evaluation.
      Moreover, the new sampling procedures permit us to study other aspects of sebum
      secretion, as demonstrated with the Sebutape method. When using photometric
      techniques an estimate of the SSL can be obtained within minutes (casual level
      measurements). After such a screening procedure, more standardized parameters can
      be accurately determined. Whatever the parameter under investigation, strictly
      controlled experimental procedures are required. Control of temperature and
      relative humidity of the experimental room, of the acclimatization periods, and
      of the volunteers during the collection periods is of capital importance. The
      studies discussed in this article clearly demonstrate the applicability of the
      new techniques not only for research and cosmetic purposes but also for clinical
      use.

PMID- 8665440
TI  - Instrumental evaluation of cutaneous hydration.

PMID- 8665441
TI  - Thermography and the possibilities for its applications in clinical and
      experimental dermatology.
AB  - At the present state of knowledge, thermostimulation-assisted telethermography
      can be considered a valid diagnostic tool, very useful not only in diagnosis of
      skin tumors, particularly melanoma, but in more extensive applications concerning
      the physiopathology of the microcirculation.

PMID- 8665442
TI  - Evaluation of skin blood flow by laser Doppler flowmetry.
AB  - Laser Doppler flowmetry is an excellent noninvasive technique for the measurement
      of cutaneous microcirculation. The list of applications of laser Doppler
      flowmetry in dermatology is long. It can be applied to monitor inflammation
      caused by various drugs, chemicals, and allergens related to blood flow. To
      measure certain inflammatory reactions a combination of other bioengineering
      measurements is desirable. Flaps can be monitored, and burn depth measured by
      laser Doppler flowmetry. Through blood flow measurement, the pathophysiology of
      various skin diseases can be verified and certain treatments can be partially
      monitored. Although it is not as directly applicable to daily clinical practice,
      except in a few cases, laser Doppler flowmetry is a very useful technique in
      various kinds of dermatologic research.

PMID- 8665443
TI  - High-frequency sonography combined with image analysis: a noninvasive objective
      method for skin evaluation and description.

PMID- 8665444
TI  - The physical basis of skin color and its evaluation.

PMID- 8665445
TI  - Practical applications of cutaneous colorimetry.
AB  - Dermatologists have long tried to quantify skin color and had few results until
      the advent of tristimulus colorimetry. With the Minolta colorimeter,
      quantification of skin color has become a simple matter: skin color can be
      measured rapidly, noninvasively, and reproducibly. The instrument, which can be
      used by paramedical staff, provides data that lend themselves for comparison,
      irrespective of where they are collected. The instrument has enabled definition
      of the range of physiologic values of skin color, and has revealed marked
      variations between exposed and nonexposed skin. Constitutional skin color
      characterizes an individual's phenotype better than facultative skin color and is
      highly indicative of vulnerability to sunlight. It is therefore a parameter for
      predicting the immediate and delayed response to light stimulation. On the
      practical level, colorimetric skin color values can be used to study pigmentation
      capacity, to program photochemotherapy, and to predict the risk of, and prevent,
      actinic cancer. Colorimetry can be used to quantify the intensity of erythema of
      spontaneous and experimental lesions. It has been used to monitor the efficacy of
      anti-inflammatory treatment of psoriasis and atopic dermatitis. It has also been
      used in the study of reactions induced by physical and allergic stimuli. Finally,
      colorimetry is useful in cosmetology for choosing appropriate sunscreens, for
      studying the effect of depigmentation products, and for determining the delicacy
      of detergents, and in any other situation that requires the measurement of
      parameters correlated with skin color that cannot be appreciated by visual
      observation.

PMID- 8665446
TI  - Evaluation of biomechanical properties of human skin.
AB  - Measurement of the physical properties of skin may seem "esoteric" and of little
      relevance to clinical science; however, the noninvasive nature of available
      techniques provides unique opportunities for monitoring the effects of disease,
      drugs, or cosmetics over time on exactly the same area of skin. In vitro testing
      gives repeatable standardized methods that can supply basic elastic and
      viscoelastic moduli for skin, which for low strain are comparable to results
      obtained from in vivo tests. Interpretation of in vivo tests can be difficult, as
      no analytical model has been developed that can relate measurements from these
      tests directly to basic skin properties. Each method and each implementation of
      that method has subtle differences from every other method so that results
      between studies are difficult to compare; however, the alternative to the
      bioengineering tests is the hand and eye, which provide subjective (and often
      biased), nonlinear, and notoriously variable data between individuals. Judging
      the severity of involvement, the changes due to treatment or progress of disease,
      and the efficacy of competing treatments is very difficult, even for an
      experienced clinician. Objective, numerical information on the effects of
      different active compounds and their formulations is essential if new
      preparations are to be optimized. Measurement of mechanical properties is one
      aspect of this important field of endeavor.

PMID- 8665448
TI  - Magnetic resonance imaging for diagnosing skin tumors.
AB  - The depth and three-dimensional morphology of skin tumors were studied with MR
      imaging. This technology was found to be an effective tool not only for
      evaluating depth but also for determining the degree of invasion of malignant
      tumors in the skin and soft tissue. Of the various tumors examined, this method
      was particularly useful for visualizing malignant melanoma and malignant fibrous
      histiocytoma. Thus, it is likely that MR imaging has great potential as an
      auxiliary tool for the diagnosis of other types of malignant skin tumors. By
      means of three-dimensional displays, tumors were more clearly visualized with
      respect to their relationship to the surrounding tissue and the three-dimensional
      state of infiltration, which was particularly useful in deciding on an
      appropriate resection area prior to surgery. The authors expect further
      technologic improvements in MR imaging in the future which will serve to increase
      the benefits obtained in its clinical applications.

PMID- 8665447
TI  - Digital imaging in dermatology.

PMID- 8665449
TI  - Image processing in the study of wound healing.
AB  - All wound care products that are said to be suitable for wound cleaning should
      preferably be evaluated with an observer-blind, quantitative system, as described
      above.

PMID- 8665450
TI  - Equipment available for bioengineering of the skin.

PMID- 8665451
TI  - Landmarks in the understanding of lymphatic function and the management of edema.

PMID- 8665452
TI  - Lymph transport in the skin.

PMID- 8665453
TI  - Mechanical resilience of skin: a function of blood supply and lymphatic drainage.

PMID- 8665454
TI  - Pathology of lymphedema.

PMID- 8665455
TI  - Assessment of abnormal lymph drainage for the diagnosis of lymphedema by isotopic
      lymphangiography and by indirect lymphography.

PMID- 8665457
TI  - Causes and clinical manifestations of lymphatic failure.

PMID- 8665458
TI  - Immune cell traffic from blood through the normal human skin to lymphatics.

PMID- 8665456
TI  - The interstitium, the connective tissue environment of the lymphatic, and
      angiogenesis in human skin.

PMID- 8665459
TI  - Lymphatics and the processing of antigen.

PMID- 8665461
TI  - Managing lymphedema.

PMID- 8665460
TI  - Lymphatics and adipose tissue.

PMID- 8665462
TI  - Education proposals for the population at risk.

PMID- 8665463
TI  - Epilogue: beyond the sphere of knowledge in lymphology.

PMID- 8665464
TI  - Chlamydia pneumoniae (TWAR).
AB  - Chlamydia pneumoniae (TWAR) is a recently recognized third species of the genus
      Chlamydia that causes acute respiratory disease. It is distinct from the other
      two chlamydial species that infect humans, C. trachomatis and C. psittaci, in
      elementary body morphology and shares less than 10% of the DNA homology with
      those species. The organism has a global distribution, with infection most common
      among children between the ages of 5 and 14 years. In children, TWAR infection is
      usually mild or asymptomatic, but it may be more severe in adults. Pneumonia and
      bronchitis are the most common clinical manifestations of infection, and TWAR is
      responsible for approximately 10% of cases of pneumonia and 5% of cases of
      bronchitis in the United States. The microimmunofluorescence serologic assay is
      specific for TWAR and can distinguish between recent and past infections. The
      organism can be isolated in cell culture; however, PCR techniques have recently
      facilitated its detection in tissues and clinical specimens.

PMID- 8665465
TI  - New and emerging yeast pathogens.
AB  - The most common yeast species that act as agents of human disease are Candida
      albicans, Candida tropicalis, Candida glabrata, Candida parapsilosis, and
      Cryptococcus neoformans. The incidence of infections by other yeasts has
      increased during the past decade. The most evident emerging pathogens are
      Malassezia furfur, Trichosporon beigelii, Rhodotorula species, Hansenula anomala,
      Candida lusitaniae, and Candida krusei. Organisms once considered environmental
      contaminants or only industrially important, such as Candida utilis and Candida
      lipolytica, have now been implicated as agents of fungemia, onychomycosis, and
      systemic disease. The unusual yeasts primarily infect immunocompromised patients,
      newborns, and the elderly. The role of central venous catheter removal and
      antifungal therapy in patient management is controversial. The antibiograms of
      the unusual yeasts range from resistant to the most recent azoles and
      amphotericin B to highly susceptible to all antifungal agents. Current routine
      methods for yeast identification may be insufficient to identify the unusual
      yeasts within 2 days after isolation. The recognition of unusual yeasts as agents
      of sometimes life-threatening infection and their unpredictable antifungal
      susceptibilities increase the burden on the clinical mycology laboratory to
      pursue complete species identification and MIC determinations. Given the current
      and evolving medical practices for management of seriously ill patients, further
      evaluations of the clinically important data about these yeasts are needed.

PMID- 8665466
TI  - Identification, classification, and clinical relevance of catalase-negative, gram
      positive cocci, excluding the streptococci and enterococci.
AB  - Several new genera and species of gram-positive, catalase-negative cocci that can
      cause infections in humans have been described. Although these bacteria were
      isolated in the clinical laboratory, they were considered nonpathogenic culture
      contaminants and were not thought to be the cause of any diseases. Isolation of
      pure cultures of these bacteria from normally sterile sites has led to the
      conclusion that these bacteria can be an infrequent cause of infection. This
      review describes the new bacteria and the procedures useful for clinical
      laboratories to aid in their identification. The clinical relevance and our
      experience with the various genera and species are reviewed and discussed.

PMID- 8665467
TI  - Antimicrobial agent resistance in mycobacteria: molecular genetic insights.
AB  - The primary theme emerging from molecular genetic work conducted with
      Mycobacterium tuberculosis and several other mycobacterial species is that
      resistance is commonly associated with simple nucleotide alterations in target
      chromosomal genes rather than with acquisition of new genetic elements encoding
      antibiotic-altering enzymes. Mutations in an 81-bp region of the gene (rpoB)
      encoding the beta subunit of RNA polymerase account for rifampin resistance in
      96% of M. tuberculosis and many Mycobacterium leprae isolates. Streptomycin
      resistance in about one-half of M. tuberculosis isolates is associated with
      missense mutations in the rpsL gene coding for ribosomal protein S12 or
      nucleotide substitutions in the 16S rRNA gene (rrs). Mutations in the katG gene
      resulting in catalase-peroxidase amino acid alterations nad nucleotide
      substitutions in the presumed regulatory region of the inhA locus are repeatedly
      associated with isoniazid-resistant M. tuberculosis isolates. A majority of
      fluoroquinolone-resistant M. tuberculosis isolates have amino acid substitutions
      in a region of the DNA gyrase A subunit homologous to a conserved fluoroquinolone
      resistance-determining region. Multidrug-resistant isolates of M. tuberculosis
      arise as a consequence of sequential accumulation of mutations conferring
      resistance to single therapeutic agents. Molecular strategies show considerable
      promise for rapid detection of mutations associated with antimicrobial
      resistance. These approaches are now amenable to utilization in an appropriately
      equipped clinical microbiology laboratory.

PMID- 8665469
TI  - Cervical cancer: is herpes simplex virus type II a cofactor?
AB  - In many ways, cervical cancer behaves as a sexually transmitted disease. The
      major risk factors are multiple sexual partners and early onset of sexual
      activity. Although high-risk types of human papillomaviruses (HPV) play an
      important role in the development of nearly all cases of cervical cancer, other
      sexually transmitted infectious agents may be cofactors. Herpes simplex virus
      type 2 (HSV-2) is transmitted primarily by sexual contact and therefore has been
      implicated as a risk factor. Several independent studies suggest that HSV-2
      infections correlate with a higher than normal incidence of cervical cancer. In
      contrast, other epidemiological studies have concluded that infection with HSV-2
      is not a major risk factor. Two separate transforming domains have been
      identified within the HSV-2 genome, but continued viral gene expression
      apparently is not necessary for neoplastic transformation. HSV infections lead to
      unscheduled cellular DNA synthesis, chromosomal amplifications, and mutations.
      These observations suggest that HSV-2 is not a typical DNA tumor virus. It is
      hypothesized that persistent or abortive infections induce permanent genetic
      alterations that interfere with differentiation of cervical epithelium and
      subsequently induce abnormal proliferation. Thus, HSV-2 may be a cofactor in some
      but not all cases of cervical cancer.

PMID- 8665470
TI  - beta-Lactamases in laboratory and clinical resistance.
AB  - beta-Lactamases are the commonest single cause of bacterial resistance to beta
      lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and
      may be classified by their sequences or phenotypic properties. The ability of a
      beta-lactamase to cause resistance varies with its activity, quantity, and
      cellular location and, for gram-negative organisms, the permeability of the
      producer strain. beta-Lactamases sometimes cause obvious resistance to substrate
      drugs in routine tests; often, however, these enzymes reduce susceptibility
      without causing resistance at current, pharmacologically chosen breakpoints. This
      review considers the ability of the prevalent beta-lactamases to cause resistance
      to widely used beta-lactams, whether resistance is accurately reflected in
      routine tests, and the extent to which the antibiogram for an organism can be
      used to predict the type of beta-lactamase that it produces.

PMID- 8665472
TI  - Infections and antibiotic resistance in nursing homes.
AB  - Infections occur frequently in nursing home residents. The most common infections
      are pneumonia, urinary tract infection, and skin and soft tissue infection. Aging
      associated physiologic and pathologic changes, functional disability,
      institutionalization, and invasive devices all contribute to the high occurrence
      of infection. Antimicrobial agent use in nursing homes is intense and usually
      empiric. All of these factors contribute to the increasing frequency of
      antimicrobial agent-resistant organisms in nursing homes. Programs that will
      limit the emergence and impact of antimicrobial resistance and infections in
      nursing homes need to be developed.

PMID- 8665468
TI  - Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus
      neoformans.
AB  - Although Cryptococcus neoformans and cryptococcosis have existed for several
      millennia, a century has passed since the discovery of this encapsulated yeast
      and its devastating disease. With the advent of the AIDS pandemic, cryptococcal
      meningitis has emerged as a leading cause of infectious morbidity and mortality
      and a frequently life-threatening opportunistic mycosis among patients with AIDS.
      Both basic and clinical research have accelerated in the 1990s, and this review
      attempts to highlight some of these advances. The discussion covers recent
      findings, current concepts, controversies, and unresolved issues related to the
      ecology and genetics of C. neoformans; the surface structure of the yeast; and
      the mechanisms of host defense. Regarding cell-mediated immunity, CD4+ T cells
      are crucial for successful resistance, but CD8+ T cells may also participate
      significantly in the cytokine-mediated activation of anticryptococcal effector
      cells. In addition to cell-mediated immunity, monoclonal antibodies to the major
      capsular polysaccharide, the glucuronoxylomannan, offer some protection in murine
      models of cryptococcosis. Clinical concepts are presented that relate to the
      distinctive features of cryptococcosis in patients with AIDS and the diagnosis,
      treatment, and prevention of cryptococcosis in AIDS patients.

PMID- 8665473
TI  - Molecular biology and pathogenesis of animal lentivirus infections.
AB  - Lentiviruses are a subfamily of retroviruses that are characterized by long
      incubation periods between infection of the host and the manifestation of
      clinical disease. Human immunodeficiency virus type 1, the causative agent of
      AIDS, is the most widely studied lentivirus. However, the lentiviruses that
      infect sheep, goats, and horses were identified and studied prior to the
      emergence of human immunodeficiency virus type 1. These and other animal
      lentiviruses provide important systems in which to investigate the molecular
      pathogenesis of this family of viruses. This review will focus on two animal
      lentivirus models: the ovine lentivirus visna virus; and the simian lentivirus,
      simian immunodeficiency virus. These animal lentiviruses have been used to
      examine, in particular, the pathogenesis of lentivirus-induced central nervous
      system disease as models for humans with AIDS as well as other chronic diseases.

PMID- 8665474
TI  - Sequence-based identification of microbial pathogens: a reconsideration of Koch's
      postulates.
AB  - Over 100 years ago, Robert Koch introduced his ideas about how to prove a causal
      relationship between a microorganism and a disease. Koch's postulates created a
      scientific standard for causal evidence that established the credibility of
      microbes as pathogens and led to the development of modern microbiology. In more
      recent times, Koch's postulates have evolved to accommodate a broader
      understanding of the host-parasite relationship as well as experimental advances.
      Techniques such as in situ hybridization, PCR, and representational difference
      analysis reveal previously uncharacterized, fastidious or uncultivated, microbial
      pathogens that resist the application of Koch's original postulates, but they
      also provide new approaches for proving disease causation. In particular, the
      increasing reliance on sequence-based methods for microbial identification
      requires a reassessment of the original postulates and the rationale that guided
      Koch and later revisionists. Recent investigations of Whipple's disease, human
      ehrlichiosis, hepatitis C, hantavirus pulmonary syndrome, and Kaposi's sarcoma
      illustrate some of these issues. A set of molecular guidelines for establishing
      disease causation with sequence-based technology is proposed, and the importance
      of the scientific concordance of evidence in supporting causal associations is
      emphasized.

PMID- 8665475
TI  - Activation of the complement system by pathogenic fungi.
AB  - Fungi have been studied as prototype activators of the complement cascade since
      the early 1900s. More recently, attention has focused on the role of the
      complement system in the pathogenesis of fungal infections. The interactions of
      Cryptococcus neoformans and Candida albicans with the complement system are the
      most widely characterized; however, all pathogenic fungi examined to date have
      the ability to initiate the complement cascade. The molecular mechanisms for
      initiation and regulation of the complement cascade differ from one fungus to
      another, most likely reflecting differences in the structure of the outer layers
      of the cell wall. The molecular bases for such differences remain to be
      identified. Studies of mycoses in experimental animals with induced or congenital
      deficiencies in the complement system demonstrate that complement is an important
      innate system for control of fungal infection. Contributions to host resistance
      include opsonization and generation of inflammatory mediators. Inflammation
      induced by chemotactic products of the complement system may contribute to the
      pathogenesis of some fungal infections.

PMID- 8665476
TI  - Clinical aspects of infection with Trichinella spp.
AB  - Isolated cases and outbreaks of infection with Trichinella spp. occur frequently
      throughout the world, sometimes resulting in fatalities. The clinical
      presentations of signs and symptoms are remarkably constant for most of the
      species of Trichinella, but in infections with Trichinella nativa and Trichinella
      britovi, classical symptoms of trichinellosis may be absent. It is important to
      be able to correlate the clinical presentation of trichinellosis with the life
      cycle of these helminths in order to make an accurate diagnosis. Knowledge of the
      epidemiology of the disease enables the physician to identify other potential
      cases, since most epidemics can be traced back to a common source of raw or
      undercooked meat. A comprehensive summary relating the most important clinical
      variables is presented graphically for easy reference to the text. Symptoms and
      signs are considered in relation to severity of infection. Laboratory findings
      and diagnostic techniques, including new modalities (e.g., DNA and antigen
      detection), are discussed. A discussion of treatment and preventive measures
      concludes our review.

PMID- 8665471
TI  - Current perspectives on glycopeptide resistance.
AB  - In the last 5 years, clinical isolates of gram-positive bacteria with intrinsic
      or acquired resistance to glycopeptide antibiotics have been encountered
      increasingly. In many of these isolates, resistance arises from an alteration of
      the antibiotic target site, with the terminal D-alanyl-D-alanine moiety of
      peptidoglycan precursors being replaced by groups that do not bind glycopeptides.
      Although the criteria for defining resistance have been revised frequently, the
      reliable detection of low-level glycopeptide resistance remains problematic and
      is influenced by the method chosen. Glycopeptide-resistant enterococci have
      emerged as a particular problem in hospitals, where in addition to sporadic
      cases, clusters of infections with evidence of interpatient spread have occurred.
      Studies using molecular typing methods have implicated colonization of patients,
      staff carriage, and environmental contamination in the dissemination of these
      bacteria. Choice of antimicrobial therapy for infections caused by glycopeptide
      resistant bacteria may be complicated by resistance to other antibiotics. Severe
      therapeutic difficulties are being encountered among patients infected with
      enterococci, with some infections being untreatable with currently available
      antibiotics.

PMID- 8665479
TI  - Hyperinsulinemia in colon, stomach and breast cancer patients.
AB  - The objective of this study was to collect more information on the intricate
      relationship between the presence of a tumor, insulin status and blood lipids. We
      selected non-obese subjects suffering from colon, stomach and breast cancer and
      determined the concentration of fasting insulin, glucose, cholesterol, and
      triglycerides in blood before (BS) and after surgery (AS). Controls were healthy
      non-obese subjects. Insulin was also measured in tumors and non-cancerous tissues
      from the same organ. BS insulin and glucose (with the exception of glucose in
      colon patients) were significantly higher than the controls and fell to almost
      normal levels at AS. Serum cholesterol and triglycerides levels were reduced in
      stomach patients, BS and AS and cholesterol in colon patients BS. Tumors had 1.9
      3.0 times as much insulin, or insulin-like substances, as control tissues. These
      results are consistent with our previous studies showing hyperinsulinemia in the
      presence of a tumor.

PMID- 8665480
TI  - Inhibitory effect of caloric restriction on tumorigenicity induced by 4
      aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in the
      CD1 newborn mouse bioassay.
AB  - The tumorigenicity of 4-aminobiphenyl (4-ABP) and 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (PhIP) were studied in combination with caloric
      restriction in the male neonatal CD1 mouse bioassay. 4-ABP and PhIP exhibited
      moderate and weak tumorigenicity, respectively, in ad libitum fed mice; however,
      none of the caloric restricted mice developed tumors. These results indicate that
      caloric restriction, even when begun 3 months after the conclusion of compound
      treatment, markedly inhibited 4-ABP- and PhIP-induced tumors in the CD1 mouse.

PMID- 8665482
TI  - Interphase and M-phase oral KB carcinoma cells are targetted in staurosporine
      induced apoptosis.
AB  - The effect of staurosporine, an antimicrobial agent and inhibitor of protein
      kinase C (PKC) on programmed cell death/apoptosis (PCD) was investigated in the
      human oral cavity epidermoid carcinoma KB cell line. Staurosporine-treated oral
      KB carcinoma cells exhibited morphological features characteristic of apoptosis
      such as (a) cell shrinkage and increased nuclear fluorescence (quantitated by
      image analysis with laser scanning confocal microscopy), (b) nuclear condensation
      and fragmentation observed under fluorescence microscopy with propidium-iodide
      DNA staining and (c) chromatin condensation seen under transmission electron
      microscopy. Specific terminal deoxynucleotidyl transferase (TdT)-mediated
      labeling of 3'OH ends of DNA breaks in staurosporine-treated cells confirmed DNA
      fragmentation. In addition, we show the concomitant existence of M-phase PCD with
      interphase PCD in staurosporine-treated KB cells. It would appear that
      staurosporine induces apoptosis regardless of the cell cycle phase and that
      mitosis and apoptosis are not necessarily mutually exclusive events.

PMID- 8665481
TI  - Role of prostatic basal cells in the regulation and suppression of human prostate
      cancer cells.
AB  - Cytokeratin expression in normal and malignant prostatic tissue indicates a loss
      of basal epithelial cells in cancer. We investigated the ability of basal-like
      prostatic epithelial cells to inhibit the growth of prostatic cancer cells. Human
      prostate LNCaP cells were grown in medium with or without 10 nM
      dihydrotestosterone (DHT) on plastic culture dishes or on extracellular matrix
      derived from basal-like epithelial cells (primary cultures derived from normal
      peripheral zone of the prostate) that were grown with or without 10 nM DHT.
      Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)
      assays were used to assess the growth of LNCaP cells. On plastic dishes, growth
      of LNCaP cells was increased 5-10% by the presence of DHT in the medium. On
      matrix derived from basal-like cells that were grown in the absence of DHT,
      growth of LNCaP cells with or without DHT was similar to that on plastic.
      However, on matrix derived from basal-like cells that were grown with DHT, growth
      of LNCaP cells was suppressed when compared to all other culture conditions (P <
      0.01). To determine whether basal-like cells could alter the function of LNCaP
      cells, we measured prostate-specific antigen (PSA) mRNA expression with the use
      of comparative RT-PCR. We found a significant decrease in the mature PSA
      transcript in cells grown on matrix derived from basal-like cells that were grown
      with DHT. The expression of PSA transcript was not altered in LNCaP cells that
      were grown on matrix derived from basal-like cells that were grown in the absence
      of DHT. Furthermore, using differential display of mRNA, we demonstrated that
      there were induction and suppression of multiple unique transcripts in the LNCaP
      cells when grown on the various culture conditions. To determine a possible
      mechanism for these observations. We used a dot blot immunoassay for several
      known inhibitory factors. We determined that DHT can induce the basal-like cells
      to secrete transforming growth factor-beta (TGF-beta 1), and that TGF-beta 1 can
      inhibit the proliferation of LNCaP cells in a dose dependent manner. We conclude
      that basal-like epithelial cells, in the presence of DHT, secrete an
      extracellular matrix o matrix associated factor(s), e.g. TGF-beta 1, that
      suppresses proliferation and function of prostate cancer cells. Our data suggest
      that the disappearance of the basal cell layer may be a prerequisite for the
      progression of prostatic neoplasia.

PMID- 8665478
TI  - Human endogenous retroviruses: nature, occurrence, and clinical implications in
      human disease.
AB  - Retroviral diagnostics have become standard in human laboratory medicine. While
      current emphasis is placed on the human exogenous viruses (human immunodeficiency
      virus and human T-cell leukemia virus), evidence implicating human endogenous
      retroviruses (HERVs) in various human disease entities continues to mount.
      Literature on the occurrence of HERVs in human tissues and cells was analyzed.
      Substantial evidence documents that retrovirus particles were clearly
      demonstrable in various tissues and cells in both health and disease and were
      abundant in the placenta and that their occurrence could be implicated in some of
      the reproductive diseases. The characteristics of HERVs are summarized,
      mechanisms of replication and regulation are outlined, and the consistent
      hormonal responsiveness of HERVs is noted. Clear evidence implicating HERV gene
      products as participants in glomerulonephritis in some cases of systemic lupus
      erythematosus is adduced. Data implicating HERVs as etiologic factors in
      reproductive diseases, in some of the autoimmune diseases, in some forms of
      rheumatoid arthritis and connective tissue disease, in psoriasis, and in some of
      the inflammatory neurologic diseases are reviewed. The current major needs are to
      improve methods for HERV detection, to identify the most appropriate HERV
      prototypes, and to develop diagnostic reagents so that the putative biologic and
      pathologic roles of HERVs can be better evaluated.

PMID- 8665484
TI  - Hepatocyte growth factor induces activation of Nck and phospholipase C-gamma in
      lung carcinoma cells.
AB  - Hepatocyte growth factor (HGF), a mesenchyme derived growth factor, promotes cell
      growth, cell motility, and morphogenesis in a variety of epithelial cells. The
      diverse responses are transduced across the cell membrane by the met/HGF
      receptor, a product of c-met protooncogene. The met/HGF receptor recruits a
      variety of second messenger molecules which relay the diverse intracellular
      responses of HGF. In this study, we show that HGF autophosphorylates and
      activates met/HGF receptor. The activated met/HGF receptor then physically
      associates with and activates phospholipase C-gamma (PLC-gamma). Furthermore,
      upon ligand stimulation, tyrosine-autophosphorylated met/HGF receptor also
      activates Nck oncogene product. Taken together, our results suggest that the
      receptor activation leads to formation of a complex in which PLC-gamma and Nck
      oncogene product co-exist with the activated met/HGF receptor, and that the Nck
      oncogene product is an important component of HGF signaling in Calu-1 and A549
      cells.

PMID- 8665483
TI  - Vitamin D3 treatment of tumor bearers can stimulate immune competence and reduce
      tumor growth when treatment coincides with a heightened presence of natural
      suppressor cells.
AB  - By secreting granulocyte-macrophage colony-stimulating factor (GM-CSF), Lewis
      lung carcinoma tumors induce immune suppressive granulocyte-macrophage progenitor
      cells. Treating mice having established tumors and high levels of suppressor
      activity with vitamin D3 eliminated suppressor activity, increased anti-tumor
      immunity, induced an immune stimulatory cell population, and reduced tumor
      growth. When instead, the vitamin D3 treatment was initiated earlier, when
      implanted tumors first became detectable and when natural suppressor activity was
      less prominent, the treatment had no effect. Thus, vitamin D3 treatment can
      stimulate the immune competence of tumor bearers when treatment is targeted to
      coincide with a heightened presence of GM-CSF-induced suppressor cells.

PMID- 8665485
TI  - Native cellular fluorescence identifies terminal squamous differentiation of
      normal oral epithelial cells in culture: a potential chemoprevention biomarker.
AB  - Native cellular fluorescence (NCF) is being investigated as an intermediate
      endpoint biomarker for chemoprevention. Oral epithelial cells were cultured under
      three conditions to identify a spectral pattern for epithelial differentiation:
      cells maintained in serum-free keratinocyte growth medium were the least
      differentiated (KGM cells); cells switched to DMEM/F12 plus 10% FCS were
      intermediate in differentiation (DMEM/F12/FCS cells); DMEM/F12/FCS cells switched
      to serum-free DMEM/F12 plus 0.8 M NaCl to induce cornified envelopes were the
      most differentiated (DMEM/F12/NaCl cells). The differentiation status was
      characterized using immunohistochemistry and electron microscopy. NCF analysis
      was able to distinguish terminally differentiated epithelial cells
      (DMEM/F12/NaCl) from those less differentiated cells (KGM, DMEM/F12/FCS) in
      several emission (lambda ex 340 nm, lambda em 360-660 nm; lambda ex 365 nm,
      lambda em 400-700 nm; lambda ex 420 nm, lambda em 440-800 nm) and excitation
      scans (lambda ex 200-360 nm; lambda em 380 nm, lambda ex 240-430 nm; lambda em
      450 nm, lambda ex 250-460 nm, lambda em 480 nm; lambda ex 270-500 nm, lambda em
      520 nm). The ability to discriminate terminal differentiation in this in vitro
      model supports the concept of using NCF as an intermediate biomarker to monitor
      in vivo mucosal differentiation.

PMID- 8665486
TI  - The p16 and p18 tumor suppressor genes in neuroblastoma: implications for drug
      resistance.
AB  - The cyclin dependent kinase inhibitors p16 and p18 were investigated in
      neuroblastoma. Only one of 19 neuroblastoma cell lines, an adriamycin-resistant
      variant, and none of 5 primary neuroblastoma, was deleted for p16 while its
      parental drug sensitive cell line is p16 intact. The region of deletion minimally
      extended centromeric to include p15, and telomeric to interferon-beta. This is
      the first report of a p16 gene alteration in neuroblastoma. No p16 gene
      hypermethylation or mutations were found. No homozygous deletions of p18 in these
      samples were found, although several instances of loss of heterozygosity are
      suspected. No p18 point mutations were detected. We conclude that (1) neither p16
      nor p18 are likely involved in the pathogenesis of neuroblastoma; and (2) the
      role of p16, or another 9p21 gene, in the development of drug resistance warrants
      further investigation.

PMID- 8665487
TI  - Pro-oxidant activity of flavonoids: effects on glutathione and glutathione S
      transferase in isolated rat liver nuclei.
AB  - The effects of three representative flavonoids, quercetin, myricetin and
      kaempferol, on the nuclear antioxidant defense glutathione (GSH) and glutathione
      S-transferase (GST) were investigated in a model system of isolated rat liver
      nuclei. The three flavonoids induced a concentration-dependent decrease of both
      the nuclear GSH content and GST activity. Myricetin, which has the maximum number
      of hydroxyl groups, was the most active. The results demonstrate the pro-oxidant
      activity of these polyphenolic flavonoids. The impairment of the nuclear
      antioxidant defense GSH and GST by the polyphenolic flavonoids can lead to
      oxidative DNA damage, which may be responsible for their mutagenicity.

PMID- 8665477
TI  - Taxonomy, biology, and periodontal aspects of Fusobacterium nucleatum.
AB  - The pathogenic potential of Fusobacterium nucleatum and its significance in the
      development of periodontal diseases, as well as in infections in other organs,
      have gained new interest for several reasons. First, this bacterium has the
      potential to be pathogenic because of its number and frequency in periodontal
      lesions, its production of tissue irritants, its synergism with other bacteria in
      mixed infections, and its ability to form aggregates with other suspected
      pathogens in periodontal disease and thus act as a bridge between early and late
      colonizers on the tooth surface. Second, of the microbial species that are
      statistically associated with periodontal disease, F. nucleatum is the most
      common in clinical infections of other body sites. Third, during the past few
      years, new techniques have made it possible to obtain more information about F.
      nucleatum on the genetic level, thereby also gaining better knowledge of the
      structure and functions of the outer membrane proteins (OMPs). OMPs are of great
      interest with respect to coaggregation, cell nutrition, and antibiotic
      susceptibility. This review covers what is known to date about F. nucleatum in
      general, such as taxonomy and biology, with special emphasis on its pathogenic
      potential. Its possible relationship to other periodontal bacteria in the
      development of periodontal diseases and the possible roles played by OMPs are
      considered.

PMID- 8665488
TI  - Prolongation of survival period and improvement of cancer cachexia by long-term
      administration of UFT.
AB  - We assayed the antitumoral and anticachectic activity of an oral
      fluoropyrimidine, UFT using the Colon-26-bearing murine cachexia model in terms
      of the survival period and parameters corresponding to clinical symptoms. Tumor
      growth was inhibited by UFT dose-dependently at the dose range of 12.5-25.0 mg/kg
      per day. Although UFT did not show significant growth inhibition at 15.0 and 12.5
      mg/kg to which UFT gave little toxicity, the survival period was shown to be
      superior to the case of maximum tolerated dose (25.0 mg/kg per day). Next, we
      compared the maximum increase of life span (ILS) value for an administration
      schedule of continuous 9 days and 5 weeks which mimics the clinical schedule and
      found that the ILS value in the latter group was superior to the former and UFT
      improved cachexia, in the same manner. In the following experiments, we have
      clarified that UFT decreased the level of both plasma interleukin-6 (IL-6) and
      tumorous prostaglandin E2 (PGE2) and it highly accelerated IL-6 production from
      Colon-26. These findings suggest that UFT therapy, in low-toxic dose, could be
      useful to cachectic patients with poor performance status.

PMID- 8665489
TI  - Inhibition of mucosal lipid hyperoxidation by green tea extract in 1,2
      dimethylhydrazine-induced rat colonic carcinogenesis.
AB  - Phosphatidylcholine hydroperoxide (PCOOH) measured using a chemiluminescence
      detector to examine colonic mucosal lipid hyperoxidation increased after
      injection of 1,2-dimethylhydrazine and green tea extract (GTE), which we
      previously showed inhibited carcinogenesis and oxidative DNA damage in the
      gastrointestinal tract. Therefore, the hyperoxidation of membrane phospholipids
      reflected well the degree of DNA damage and carcinogenic alteration, and may be a
      useful intermediate biomarker for initiation of carcinogenesis.

PMID- 8665491
TI  - The field bean protease inhibitor can effectively suppress 7,12
      dimethylbenz[a]anthracene-induced skin tumorigenesis in mice.
AB  - Prolonged topical treatment with protease inhibitors (PIs) both synthetic and of
      bacterial origin have been shown to prevent carcinogen initiated and croton oil
      or phorbol acetate promoted skin carcinogenesis in mice. However, no one has yet
      examined the possibility of a purified PI of plant origin to block skin
      carcinogenesis by sustained local treatment. We therefore studied this aspect
      using a purified PI from field bean (FBPI) in Swiss albino mice. Groups of 8-week
      old mice were taken and treated differently. Group I mice were treated with 100
      microliters of acetone alone, while mice of Group II were treated with a single
      high (150 micrograms) dose of 7,12-dimethylbenz[a]anthracene in acetone and 2
      weeks later they were treated with a high concentration (125 micrograms) of
      croton oil thrice weekly. Mice of Groups III, IV and V were treated exactly as
      described for mice of Group II, but 4 h after croton oil treatment they were
      further treated with an aqueous solution of 1 mg, 2 mg of FBPI or 2 mg of heat
      inactivated [corrected] FBPI, respectively. Treatment of all groups was continued
      until the mice were 25 weeks old, the appearance of tumors being recorded during
      the period. Our findings showed that treatment of carcinogen and croton oil
      exposed mice of Groups III and IV with two different doses of FBPI not only
      brought about appreciable delay in the appearance of tumors but also significant
      (P < 0.025-0.001) suppression of tumor incidence at nearly all times of
      promotion. Additionally, it lowered significantly (P < 0.01-0.001) the tumor
      multiplicity and the tumor appearance rate compared to mice of Groups II and V.
      These effects of FBPI appeared to be dose related. Lack of response with heat
      inactivated FBPI indicated that these actions of FBPI were related to its PI
      activity. The study thus confirmed that topical treatment with a legume-derived
      PI can effectively suppress skin carcinogenesis.

PMID- 8665490
TI  - Inhibition of metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1
      butanone by limonene.
AB  - Previous work by others shows that d-limonene (LIM) inhibits carcinogen-induced
      lung tumorigenesis in mice and strongly suggests that LIM can inhibit the
      metabolic activation of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)
      1-butanone (NNK). Thus, in the current study, the ability of LIM and other
      monoterpenes to inhibit the activation of the tobacco-specific NNK was examined
      in murine pulmonary and hepatic microsomes after addition in vitro or
      administration in vivo. LIM inhibited the metabolic activation of NNK in both
      pulmonary and hepatic microsomes. Perillyl alcohol was a more potent inhibitor
      than LIM, while p-menth-1-ene was equipotent with LIM. After administration of
      LIM, limonene 1,2-oxide, or perillyl alcohol in vivo, significant inhibition of
      cytochrome P450-mediated metabolites (NNK N-oxide and HPB) was found at 1 and 4 h
      after administration of monoterpene. These results indicate that LIM and other
      monoterpenes are effective inhibitors of NNK metabolic activation, and that other
      monoterpenes such as perillyl alcohol may be effective chemopreventive agents
      against NNK-induced lung tumorigenesis.

PMID- 8665492
TI  - Studies of the p53 gene mutation in Saudi non-Hodgkin's lymphoma.
AB  - Tumor biopsies (paraffin embedded tissue) obtained from 45 Saudi patients with
      non-Hodgkin's lymphoma (NHL) were examined for the incidence of p53 mutations
      screened by polymerase chain reaction (PCR) and single strand conformation
      polymorphism (SSCP) analysis. DNA sequencing was carried out to confirm the
      occurrence of p53 mutation in PCR products showing abnormal migration by SSCP
      analysis. Only 1/45 samples showed the incidence of a homozygous mutation at
      codon 179 (exon 5) of the p53 gene that replaces histidine with tyrosine. The
      data showed that the frequency of p53 mutations was very low in Saudi NHL. Our
      results are consistent with the general observation that the p53 mutation is
      rather infrequent in hematopoietic malignancies like NHLs.

PMID- 8665493
TI  - N-acetyltransferase expression and metabolic activation of the food-derived
      heterocyclic amines in the human mammary gland.
AB  - The heterocyclic amines (HCAs) found in cooked meat are procarcinogens that are
      metabolically activated by N-hydroxylation followed by O-acetylation by the N
      acetyltransferases NAT1 and NAT2. Despite the importance of metabolic activation
      in HCA carcinogenicity and the finding that several HCAs are rodent mammary gland
      carcinogens, nothing was known about O-acetylation activity in the human mammary
      gland. The current study examines the expression and catalytic activity of NAT
      toward the N-hydroxy-HCAs 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine
      (N-hydroxy-PhIP) and 2-hydroxy-amino-3-methylimidazo[4,5-f]quinoline (N-hydroxy
      IQ) in the human mammary gland. Mammary gland cytosol from 10 women and lysates
      from a primary culture of human mammary epithelial cells metabolically activated
      2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-hydroxyamino-3
      methylimidazo[4,5-f]quinoline by NAT-mediated 0-acetyltransferase, as measured by
      the acetyl CoA-enhanced binding of the N-hydroxylamines to calf thymus DNA in
      vitro. N-acetylation of p-aminosalicylic, an activity specific to NAT1, but not N
      acetylation of sulfamethazine, an activity specific to NAT2, was detected in the
      mammary gland cytosols and human mammary epithelial cell lysates.
      Immunohistochemical analysis of human mammary gland sections showed positive
      staining for NAT1 protein in the epithelial cells lining the mammary gland ducts.
      Reverse transcription-PCR analysis showed that mRNA transcripts for both NAT1 and
      NAT2 were present in human mammary gland; however, no NAT2 catalytic activity was
      detectable. Our data demonstrate for the first time that the human mammary gland
      is catalytically active toward the metabolic activation of HCA food mutagens, and
      that this activity is most likely contributed by NAT1 expressed in the ductular
      epithelial cells of the mammary gland.

PMID- 8665494
TI  - An integrated microsatellite length analysis using an automated fluorescent DNA
      sequencer.
AB  - Analyzing microsatellite instability (MI) in malignant tumors is thought to be
      useful for screening cancer patients to identify those patients with a higher
      risk of developing second malignant tumors. In this paper, we report a new,
      accurate, and efficient method of detecting MI using an automated fluorescent DNA
      sequencer and a computer that automatically calculates the size, height, and area
      of each fluorescent product, making it possible to assess MI more accurately and
      more rapidly. The primers for amplification of each microsatellite locus are
      labeled by two different fluorescent dyes, rox (red) and fam (blue). The rox
      labeled primer was used for the tumor, whereas the fam-labeled primer was used
      for the corresponding normal tissue. Two amplified products from both the tumor
      and the normal tissue were co-loaded into a single lane of the sequencing gel and
      were analyzed. MI could be detected based on the presence of different waving
      patterns. Furthermore, several loci could also be analyzed simultaneously for MI
      in a single lane. Using this method, we examined the frequency of MI in gastric
      cancer. The results showed that 5 of 22 (22.7 %) gastric cancers were MI
      positive, which corresponds to the findings of previous reports that used the
      radioisotopic method. The improved method may open up the possibility of
      performing routine examination of MI in many cancer patients and offers hope for
      the potential clinical application of Ml analysis as a follow-up evaluation of
      cancer patients.

PMID- 8665495
TI  - Metabolic phenotypes of retinoic acid and the risk of lung cancer.
AB  - The metabolic activity of cytochrome P-450 enzymes has been associated with an
      increased risk of developing lung cancer. We found previously that all-trans
      retinoic acid is catabolized by these oxidative enzymes, and that an inhibitor of
      this system discriminated between two populations of lung cancer patients. We
      examined the association between this metabolic phenotype and the risk of lung
      cancer in 85 subjects. The area under the plasma concentration x time curve (AUC)
      was calculated after a single oral dose of all-trans retinoic acid (45 mg/m2).
      The mean AUC for patients who had either squamous or large cell carcinomas was
      significantly lower than that of patients with adenocarcinomas (P = 0.0001) or
      control subjects (P = 0.01). Individuals with an AUC < 250 ng x h/ml had a
      greater likelihood of having squamous or large cell carcinoma (odds ratio =
      5.93). This study suggests that the "rapid" catabolism of all-trans retinoic acid
      is linked to an increased risk of squamous or large cell cancers of the lung.

PMID- 8665496
TI  - Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of
      bystander cells.
AB  - An emerging strategy for cancer gene therapy involves the transfer of the herpes
      simplex virus thymidine kinase (HSV-tk) gene into tumor cells, rendering them
      susceptible to the cytotoxic effects of ganciclovir. The observation that HSV-tk
      expressing cells can also induce cell death in neighboring cells, which do not
      express HSV-tk, has been called the bystander effect. Gap junction-mediated
      transfer of cytotoxic molecules to bystander cells may be an important mechanism
      of bystander cell death, although others have suggested a role for phagocytosis.
      In this study, we evaluated the mode of cell death in bystander cells. We
      detected apoptosis in bystander cells and found that bystander cell death could
      be inhibited by BCL2 expression. We determined that ganciclovir incubations for
      10 h were sufficient to induce cell death in most bystander cells cocultured with
      HSV-tk-expressing cells. During this period, no phagocytosis was detected,
      although it was obvious at later stages.

PMID- 8665497
TI  - Increased angiogenin expression in pancreatic cancer is related to cancer
      aggressiveness.
AB  - We have investigated the expression of angiogenin (ANG) in pancreatic cancer and
      the relevance of ANG expression to the progression of pancreatic cancer. In
      comparison to normal pancreas, increased ANG mRNA expression was observed in
      80.0% of the cases of pancreatic cancer by in situ hybridization, and increased
      ANG protein expression was observed in 86.7% of the cases of pancreatic cancer
      using Western blot analysis. The mean serum ANG concentration of pancreatic
      cancer patients (566.6 +/- 191.9 ng/ml) was significantly higher (P < 2.0 x 10(
      8)) than that of healthy volunteers (359.0 +/-t 59.9 ng/ml). Increased ANG mRNA
      expression as well as elevated serum ANG concentration correlated with poor
      prognosis. These findings suggest that ANG expression is up-regulated in
      pancreatic cancer patients and that ANG contributes to the aggressiveness of
      pancreatic cancer.

PMID- 8665498
TI  - Membrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and is
      secreted in a complex with tissue inhibitor of metalloproteinases 2.
AB  - The processing mechanism and gelatinolytic activity of the membrane-type matrix
      metalloproteinase 1 (MT-MMP-1) were examined by expressing in COS-1 cells a
      deletion mutant of MT-MMP-1 lacking the trans-membrane domain (delta MT1) and its
      site-directed mutant with a furin-resistant sequence in the propeptide domain
      (mutant delta MT1). delta MT1, but not mutant delta MT1, was processed to an
      active form and exhibited gelatinolytic activity as seen using gelatin
      zymography. delta MT1 isolated in a complex form with tissue inhibitor of
      metalloproteinases 2 (TIMP-2) from the stable transfectants demonstrated the NH2
      terminal sequence of Ala113-IIe-Gln-Leu, indicating cleavage at one amino acid
      down-stream from the furin recognition sequence. The delta MT1/TIMP-2 complex
      formed a ternary complex with proMMP-2 through the COOH termini of TIMP-2 and
      proMMP-2. A human breast carcinoma cell line (MDA-MB-231 cells) also secreted MT
      MMP-1 into culture media, which was purified in a complex form with TIMP-2 and
      showed gelatinolytic activity as seen using zymography. These results demonstrate
      for the first time that MT-MMP-1 is a gelatinolytic enzyme and secreted from
      cells in a complex with TIMP-2, which can form a ternary complex of MT-MMP
      1/TIMP2/proMMP-2.

PMID- 8665499
TI  - Protein kinase C inhibition induces apoptosis and ceramide production through
      activation of a neutral sphingomyelinase.
AB  - We report that WEHI-231 undergo apoptosis following exposure to the protein
      kinase C inhibitors chelerythrine chloride and calphostin C. Following the
      addition of chelerythrine or calphostin C to WEHI-231 cells, ceramide production
      increased over baseline levels with a concurrent decrease in sphingomyelin. More
      detailed examinations determined that the ceramide accumulation resulted from
      activation of neutral, but not acidic, sphingomyelinase. These results suggest an
      antagonistic relationship between protein kinase C activity and ceramide in the
      signaling events preceding apoptosis.

PMID- 8665500
TI  - Trans-dominant inhibition of poly(ADP-ribosyl)ation potentiates carcinogen
      induced gene amplification in SV40-transformed Chinese hamster cells.
AB  - Poly(ADP-ribose) polymerase (PARP) is an evolutionally conserved nuclear protein
      present in most eukaryotic species and catalyzes the formation of ADP-ribose
      polymers covalently attached to proteins. PARP is strongly activated by DNA
      single- or double-strand breaks and is thought to be involved in cellular
      responses to DNA damage. Based on the SV40-transformed Chinese hamster cell line
      CO60, we had established stable transfectants that overexpress the PARP DNA
      binding domain conditionally. DNA-binding domain overexpression led to trans
      dominant inhibition of poly(ADP-ribosyl)ation and sensitized the cells to
      genotoxic agents. Using the amplification of chromosomally integrated SV40 DNA as
      an indicator system, we show here that trans-dominant PARP inhibition potentiates
      genetic instability induced by N-methyl-N'-nitro-N-nitrosoguanidine treatment of
      cells.

PMID- 8665501
TI  - Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers.
AB  - The chromosome region 18q21 has been shown to be frequently deleted in lung
      cancers. Recent identification at this locus of DPC4, a gene whose inactivation
      has been suggested to play a role in pancreatic carcinogenesis, prompted as to
      examine whether it might also be altered in lung cancers. Two missense and 2-bp
      frameshift somatic mutations in DPC4 were detected among 42 lung cancer specimens
      taken directly from patients. DPC4 mutations, however, were not present in all
      lung cancers carrying l8q21 deletions. These findings suggest that DPC4 may play
      a role in a limited fraction of lung cancers and that another tumor suppressor
      gene may also exist in this chromosome region.

PMID- 8665502
TI  - Hypermethylation of the p16 gene in nasopharyngeal carcinoma.
AB  - We have recently reported that inactivation of the p16 gene by mutation and
      deletion is common in nasopharyngeal carcinoma (NPC). The present study
      demonstrates that hypermethylation of the 5' CpG island can serve as an
      alternative mechanism for inactivation of the p16 gene in this tumor. Using
      Southern blotting analysis and multiplex PCR, aberrant methylation of the 5' CpG
      island of the p16 gene was found in a NPC xenograft (xeno-666) and 6 (22%) of 27
      primary tumors, but not in normal tissues of the nasopharynx. In the NPC
      xenograft (xeno-666) and its newly derived cell line (cell-666), both showing
      hypermethylation of the p16 gene, no p16 gene expression was found. After
      treatment with 5-aza-2'-deoxycytidine, reexpression of the p16 gene was detected
      in the cell line cell-666. These findings suggest that aberrant methylation of
      the 5' CpG island may participate in the transcriptional inactivation of the p16
      gene in NPC. The present results further support that the p16 gene is the
      critical target on chromosome 9p21 for inactivation during the development of
      this disease.

PMID- 8665503
TI  - The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors
      reveals no evidence for mutation.
AB  - Heterozygosity for ataxia-telangiectasia (A-T), a cancer-prone recessive
      syndrome, has been associated with an increased risk of breast cancer. The gene
      for A-T (ATM) is located at chromosomal region 11q22-q23, a region of frequent
      loss of constitutional heterozygosity in breast and other tumors. Loss of
      constitutional heterozygosity at 1lq22-q23 was found in 47% of informative cases
      in the series of primary tumors analyzed in this study. To investigate the role
      of ATM in breast cancer, we have determined the complete genomic organization of
      the gene, developed an exon-scanning PCR single-strand conformation polymorphism
      (PCR-SSCP) assay for mutation detection of ATM, and screened 38 consecutive
      breast tumors for mutations using both genomic DNA- and cDNA-based assays. In
      addition to common ATM polymorphisms detected both in the coding sequence and in
      flanking introns, seven unique SSCP alleles were identified in six tumor DNAs.
      Sequence analysis of these alleles revealed rive nucleotide substitutions that
      were predicted to change the encoded amino acid. However, PCR-SSCP and nucleotide
      sequencing analysis of the paired blood samples and of an extended sample size of
      a total of 224 chromosomes indicated that these SSCP patterns represent
      constitutional rare polymorphisms with a frequency between 0.005 and 0.023.
      Because the majority of A-T mutations are null mutations and none of the ATM
      alleles found in breast cancer samples would lead to the truncation of the
      translation product, we conclude that, in this initial sample of sporadic breast
      cancer patients, there was no evidence for an increased number of A-T carriers.
      In addition, because no somatic mutations were found, our study rules out the ATM
      gene as the frequently altered tumor suppressor gene at 11q23.

PMID- 8665504
TI  - Detection of a mutator phenotype in cancer cells by inter-Alu polymerase chain
      reaction.
AB  - A mutator phenotype due to a DNA mismatch repair deficiency is usually detected
      by typing a number of microsatellite markets. Here, eight hereditary nonpolyposis
      colon cancer patients with microsatellite instability were investigated by inter
      Alu PCR, known to amplify DNA segments that may represent preferential targets of
      replication errors. Among 40-60 bands revealed in a single PCR experiment, more
      than 20% were found altered in tumoral DNA samples compared to matched normal
      samples from the same patient. Shifts and changes in signal intensity accounted
      for most of the alterations, whereas gains or losses of bands were rare. Certain
      bands were affected only in a single patient, whereas the instabilities in others
      were common. These results suggest that some genomic regions are more susceptible
      than others to the expression of a mutator phenotype. Four such bands altered in
      at least five patients were characterized further and shown to be unstable
      because of contractions of the Alu poly(A) tails. Interestingly, none of the
      bands representing loci shown previously to be polymorphic in the population
      displayed instability in the tumoral samples. Inter-Alu PCR appears to be a
      robust, cost-effective, and sensitive technique for revealing the mutator
      phenotype in cancer cells.

PMID- 8665505
TI  - Mutations of the BRCA2 gene in ovarian carcinomas.
AB  - Inherited mutations in the recently discovered BRCA2 gene are believed to be
      responsible for a significant fraction of early-onset hereditary breast cancers.
      Unlike BRCA1, however, which confers a high risk to both breast and ovarian
      cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked
      families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian
      cancer. Numerous allelotype studies indicate that allelic deletions Including the
      BRCA2 locus on chromosome 13q are common in ovarian cancers in general,
      suggesting that somatic mutations of this gene may be involved in sporadic
      ovarian tumorigenesis. The purpose of this study was to test the hypothesis that
      germline or somatic mutations of BRCA2 are associated with hereditary and/or
      sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2
      was screened for mutations in 130 consecutive ovarian tumors, the only selection
      criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of
      heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four
      germline mutations and two somatic mutations were identified; two of the germline
      mutations are recurrent, having been previously described. Remarkably, the
      patients with germline mutations were late-onset cases with no medical or family
      histories suggestive of hereditary cancer. These data suggest that mutations of
      BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian
      cancers resulting from hereditary predisposition may be higher than previously
      suspected based on estimates derived from studies of highly penetrant genetic
      loci.

PMID- 8665506
TI  - IA-2, a transmembrane protein tyrosine phosphatase, is expressed in human lung
      cancer cell lines with neuroendocrine phenotype.
AB  - IA-2 is a transmembrane protein tyrosine phosphatase isolated recently from a
      human insulinoma subtraction library. Its expression in normal human tissues is
      restricted primarily to the pancreatic islets and brain. In this report, we
      describe the expression of IA-2 mRNA in a panel consisting of 20 lung tumor cell
      lines with neuroendocrine and non-neuroendocrine phenotype and 17 non-lung tumor
      cell lines. IA-2 mRNA was detected in 8 of 11 neuroendocrine small cell lung
      carcinomas, 4 of 4 non-small cell lung carcinomas with neuroendocrine phenotype,
      and 11 of 12 non-lung neuroendocrine tumor cell lines. In contrast, IA-2 mRNA was
      not detected in five non-neuroendocrine lung carcinomas, nor in a panel of other
      non-neuroendocrine tumor cell lines. The expression pattern of IA-2 mRNA suggests
      that IA-2 may represent a new marker for neuroendocrine differentiation In human
      lung cancer cells and perhaps other neuroendocrine tumors.

PMID- 8665507
TI  - Inhibition of fatty acid synthesis induces programmed cell death in human breast
      cancer cells.
AB  - One of the key limiting factors in the treatment of advanced stage human
      epithelial malignancies is the lack of new, selective molecular targets for
      antineoplastic therapy. A substantial subset of human breast, ovarian,
      endometrial, colorectal, and prostatic cancers express elevated levels of fatty
      acid synthase, the major enzyme required for endogenous fatty acid biosynthesis,
      and carcinoma lines are growth inhibited by cerulenin, a noncompetitive inhibitor
      of fatty acid synthase. We have shown previously that the difference in fatty
      acid biosynthesis between cancer and normal cells is an exploitable target for
      metabolic inhibitors in the in vitro setting and in vivo in a human ovarian
      carcinoma xenograft in nude mice. Here, we report that cerulenin treatment of
      human breast cancer cells inhibits fatty acid synthesis within 6 h after
      exposure, that loss of clonogenic capacity occurs within the same interval, and
      that DNA fragmentation and morphological changes characteristic of apoptosis
      ensue.

PMID- 8665508
TI  - Wild-type p53 renders mouse astrocytes resistant to 1,3-Bis(2-chloroethyl)-1
      nitrosourea despite the absence of a p53-dependent cell cycle arrest [corrected].
AB  - We examined the response of normal and p53-deficient mouse astrocytes to the
      alkylating agent 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), a clinically useful
      DNA-damaging drug to which some human astrocytomas are resistant and some are
      sensitive. Astrocyte cultures were isolated from the cerebrums of wild-type,
      heterozygous, and knockout p53 neonatal mice and treated with various
      concentrations of BCNU. Wild-type p53 astrocytes were significantly more
      resistant to BCNU than were knockout p53 astrocytes, with heterozygous astrocytes
      exhibiting an intermediate level of resistance, Cell cycle analysis showed that
      wild-type p53 astrocytes treated with BCNU demonstrated a decline in the
      percentage of cells in G1 and an increase in the percentage of cells in G2.
      Similar cell cycle responses to BCNU occurred in knockout p53 astrocytes,
      suggesting that this effect was p53 independent. In contrast, G1 arrest was
      observed in wild-type astrocytes exposed to ionizing radiation and was not
      observed in knockout astrocytes, indicating a p53-dependent response. Our
      findings point to an as yet uncharacterized p53-associated mechanism of
      resistance to BCNU in mouse astrocytes.

PMID- 8665509
TI  - Human colorectal carcinomas specifically accumulate Mr 42,000 ubiquitin
      conjugated cytokeratin 8 fragments.
AB  - Recent studies have shown that various tumor cells accumulate ubiquitin (Ub)
      conjugated proteins, the profiles of which differ from those of normal cells. To
      identify the Ub-conjugated proteins accumulated specifically by human carcinoma
      cells, a two-dimensional immunoblot analysis of 31 surgically resected human
      primary colorectal carcinoma tissues was performed using an anti-Ub monoclonal
      antibody, KM691. Two distinct Mr 42,000 and 45,000 proteins in the Triton X
      insoluble fractions of carcinoma tissues reacted with this antibody, whereas only
      one Mr 45,000 protein reacted in normal tissues. The Mr 42,000 Ub-conjugated
      proteins were specific to carcinoma tissues from 25 patients (80.6%). One of the
      purified Mr 42,000 proteins was digested with Achromobacter protease I. This
      protein was identified as a cytokeratin 8 (CK 8) fragment based on both molecular
      mass determination and molecular mass searching of Achromobacter protease I
      digested fragments of proteins registered in a protein sequence data base. Two
      dimensional immunoblot analysis with an anti-CK 8 antibody confirmed that all of
      the Mr 42,000 proteins were CK 8 degradation products. These results demonstrate
      that human colorectal carcinomas specifically accumulate Mr 42,000 Ub-conjugated
      CK 8 fragments. This accumulation was observed frequently not only in advanced
      (18/22, 81.8%), but also in early stage cases (7/9, 77.8%), suggesting that it
      occurs even in the early stages of colorectal carcinoma progression.

PMID- 8665510
TI  - Regulation of carbonyl-reducing enzymes in rat liver by chemoprotectors.
AB  - Feeding rats on diets containing the synthetic antioxidants ethoxyquin, butylated
      hydroxyanisole, and oltipraz results in 15-, 9-, and 6-fold increases,
      respectively, in the hepatic levels of aflatoxin B1-dialdehyde reductase (AFAR)
      protein. By contrast, treatment of rats with either of the inducing agents
      phenobarbital or 3-methylcholanthrene results in an approximate increase of only
      1.4-fold in the amount of AFAR in rat liver. Northern blotting has shown that
      these increases in levels of hepatic AFAR protein are accompanied by
      corresponding increases in AFAR mRNA. Immunodepletion of AFAR from rat liver
      extracts has revealed that AFAR makes a considerable contribution to carbonyl
      metabolism in livers from animals treated with synthetic antioxidants and that it
      is the major reductase that can utilize aflatoxin B1-dialdehyde as a substrate.
      The immunodepletion experiments also revealed the presence of at least one other
      inducible carbonyl-reducing enzyme that, like AFAR, can metabolize 9,10
      phenanthraquinone. Carbonyl-reducing activity from rat liver has been resolved
      into six enzyme-containing peaks by anion-exchange chromatography on Q-Sepharose.
      This method has been used to show that, in addition to AFAR, two other rat liver
      carbonyl-reducing enzymes are induced by ethoxyquin, and that these are distinct
      from NAD(P)H: quinone oxidoreductase. Collectively, these data show that
      synthetic antioxidants can influence substantially the capacity of rat liver to
      metabolize reactive carbonyl-containing compounds.

PMID- 8665511
TI  - Chemopreventive effects of 24R,25-dihydroxyvitamin D3, a vitamin D3 derivative,
      on glandular stomach carcinogenesis induced in rats by N-methyl-N'-nitro-N
      nitrosoguanidine and sodium chloride.
AB  - The modifying effects of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], a vitamin D3
      derivative, on glandular stomach carcinogenesis were investigated in male Wistar
      rats by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride exposure
      during the postinitiation phase. A total of 130 male 6-week-old rats was divided
      into five groups. Groups 1-3 (consisting of 30 rats/group) were given MNNG in
      drinking water at a concentration of 100 ppm and were simultaneously fed a diet
      supplemented with 10% NaCl for 8 weeks. They were fed a diet containing either
      5.0 ppm (group 1) or 2.5 ppm (group 2) 24R,25(OH)2D3 or were kept on the basal
      diet alone (group 3) for the following 57 weeks. Rats in groups 4 and 5 were
      given 24R,25(OH)2D3, as were animals in groups 1 and 3, but did not receive the
      MNNG + NaCl treatment. The total incidence of combined atypical hyperplasias and
      adenocarcinomas in the glandular stomachs was significantly lower in group 1
      (24%) than in group 3 (70%; P < 0.01). The mean numbers of atypical hyperplasias
      or adenocarcinomas of the glandular stomachs in groups 1 (0.31) and 2 (0.66) were
      also significantly decreased (P < 0.01 and P < 0.05, respectively) as compared to
      the group 3 value (1.21). Thus, the development of cancerous and precancerous
      lesions in the glandular stomach was decreased by exposure to 24R,25(OH)2D3 in a
      dose-dependent manner. Urinary calcium levels were increased by this vitamin D3
      derivative (in line with the applied dose) when assayed at 10, 30, and 62 weeks,
      regardless of the MNNG + NaCl treatment The present results clearly indicate that
      24,25(OH)2D3 exerts chemopreventive effects, possibly by influencing calcium
      pharmacodynamics, when given during the postinitiation phase of glandular stomach
      carcinogenesis in rats.

PMID- 8665512
TI  - Manganese superoxide dismutase expression correlates with p53 status and local
      recurrence of cervical carcinoma treated with radiation therapy.
AB  - Manganese superoxide dismutase (Mn-SOD) inactivates the radiation effect by
      removal of radiation-induced toxic superoxide radicals. The purpose of this study
      was to assess the correlation among Mn-SOD, radiation sensitivity, and prognosis
      following radiation therapy. The Mn-SOD, p53 oncoprotein, and c-erbB-2
      oncoprotein expressions in 52 specimens from patients with cervical cancer
      treated with radiation therapy were investigated immunohistochemically. The
      frozen sections were stained using antihuman Mn-SOD, anti-p53 monoclonal
      antibodies, and anti-c-erbB-2 oncoprotein polyclonal antibody followed by the
      avidin-biotin peroxidase complex method. Correlations among Mn-SOD expression,
      prognosis, and failure patterns were analyzed. Additionally, correlations between
      p53 and c-erbB-2 oncoproteins and Mn-SOD expression were investigated. Positive
      expression of Mn-SOD in cervical carcinoma was 48.1%. No significant difference
      in positivity of Mn-SOD expression was noted according to stage and histological
      subtypes. The 5-year survival rate of Mn-SOD-positive patients was 42.5 %,
      significantly poorer than the 77.0% of Mn-SOD-negative patients (P < 0.05).
      Analysis of the failure patterns revealed that patients with Mn-SOD expression
      showed a significantly higher incidence of local recurrence than those without.
      However, there was no difference in distant metastasis between them. Although
      both p53 and c-erbB-2 oncoprotein expressions were significantly associated with
      the prognosis of the same patients, Mn-SOD expression was associated with p53
      oncoprotein expression but not with that of c-erbB-2 oncoprotein. Our results
      demonstrate that the Mn-SOD level of cancer cells is correlated with local
      control and is an important prognostic factor in radiation therapy for cervical
      cancer. The Mn-SOD level may help explain the intrinsic radiosensitivity of
      cervical cancer cells.

PMID- 8665513
TI  - Relationship between serum levels of interleukin 6, various disease parameters
      and malnutrition in patients with esophageal squamous cell carcinoma.
AB  - Serum levels of interleukin 6 (IL-6) are correlated with the disease status and
      prognosis in cancer patients. IL-6 is also an important mediator of experimental
      cancer cachexia. We investigated the production of IL-6 and IL-6 receptors and
      expression of IL-6 mRNA by esophageal squamous carcinoma cells using
      immunohistochemical staining and in situ reverse transcription-PCR. We also
      measured levels of serum IL-6 using an ELISA in 50 patients with esophageal
      squamous cell carcinoma (ESCC) to determine the correlation between serum levels
      of IL-6 and clinicopathological factors IL-6 mRNA was expressed in the primary
      tumor. Esophageal squamous carcinoma cells produced both IL-6 and IL-6 receptor.
      IL-6 concentrations were significantly higher in the primary tumor than in the
      normal epithelium. The incidences of weight loss, tumor invasion to adjacent
      organs, and noncurative resection were significantly higher in ESCC patients with
      serum levels of IL-6 > or = 7 pg/ml (n = 13, group C) compared with patients with
      serum levels <7 pg/ml and > or = 3 pg/ml (n = 14, group B) and <3 pg/ml (n = 23,
      group A). Tumor size and C-reactive protein levels were significantly higher and
      albumin levels were significantly lower in group C. Results suggest that IL-6,
      which is produced by tumor cells, may be related to various disease parameters as
      well as to the nutritional status in patients with ESCC.

PMID- 8665514
TI  - Repression of the insulin receptor promoter by the tumor suppressor gene product
      p53: a possible mechanism for receptor overexpression in breast cancer.
AB  - There is strong evidence to suggest that insulin and insulin-like growth factor
      (IGF)-I may be important for tumor growth. Both the insulin and IGF-I receptors
      (IGF-IR) are overexpressed in breast cancer, and antibody blockade of the IGF-IR
      inhibits the growth of some breast cancer cell lines. Furthermore, expression of
      an insulin receptor (IR) in a normal mammary epithelia] cell line causes insulin
      dependent transformation. Functional inactivation of p53 is also very frequent in
      many tumors. In this paper, we investigated whether inactivation of p53 might be
      involved in the overexpression of the IR in malignancy, specifically breast
      cancer. We demonstrate a positive correlation between IR and IGF-IR levels and
      p53 overexpression in primary human breast malignancies. To examine possible
      mechanisms by which p53 may regulate IR gene expression, we show that p53 can
      repress the IR promoter and that a dominant-negative p53 (248Q) can de-repress
      the promoter in cells containing normal p53. The p53 effect was shown to be
      mediated by C/EBP and Sp1 transcription factors. We also documented that p53-null
      mice had elevated levels of Sp1, but not C/EBPalpha, and that insulin binding to
      liver extracts was increased compared to wild-type controls. These results
      suggest that p53 inactivation may lead to an up-regulation of genes, such as the
      IR, that are dependent on these transcription factors.

PMID- 8665515
TI  - Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in
      breast cancer cells.
AB  - [3H]thymidine incorporation and DNA content were used to investigate the
      antiproliferative effects of 1,25(OH)2D3 and four analogues [16-ene-1,25(OH)2D3
      (16-ene)]; 16-ene,23-yne-1,25(0H)2,D3; EB1089; and 22 oxa-1,25(OH)2D3] on MCF-7,
      BT-474, and MDA-MB-453 breast cancer cell lines. 1,25(OH)2D3 and the analogues
      elicited a biphasic response from MCF-7 and BT-474 estrogen receptor (ER)
      positive cells, in the presence of estradiol (E2), with lower doses (between 10(
      12) and 10(-10) M) tending to stimulate proliferation and higher doses (between
      10(-9) and 10(-6) M) inhibiting proliferation by as much as 65%. In the absence
      of E2, the stimulatory effect was abrogated. Proliferation of MDA-MB-453,
      estrogen receptor-negative (ER-) cells, was stimulated by these compounds only at
      10(-12) M, and inhibited by all higher doses, by as much as 83%. All three cell
      lines were shown to be vitamin D receptor (VDR) positive, and 1,25(OH)2D3 and all
      four analogues bound to the VDR with high affinities in each cell line. The
      antiestrogen ICI 164,384 inhibited the proliferation of all three cell lines. ICI
      164,384 at 10(-8) M in combination with 1,25(OH)2D, or EB1089 converted biphasic
      response of the ER+ cells to one resembling the response of the ER- cells, by
      eliminating the stimulatory response elicited by 1,25(OH)2D3 at low doses and
      enhancing the antiproliferative effects of higher doses by as much as 1000-fold.
      These data are consistent with the hypothesis that E2 in the ER+ cells blocks the
      antiproliferative effects of the analogues and suggest the potential usefulness
      of combined antiestrogen and 1,25(OH)2D3 analogues in ER+ breast tumors, whereas
      1,25(OH)2D3 analogues alone might suffice in ER- breast tumors.

PMID- 8665516
TI  - Identification of topoisomerase I as the cytotoxic target of the protoberberine
      alkaloid coralyne.
AB  - Protoberberine alkaloids (coralyne and its derivatives), which exhibit
      antileukemic activity in animal models, have been shown to be potent inducers of
      topoisomerase (topo) I-DNA cleavable complexes using purified recombinant human
      DNA topo I. Different from the structurally similar benzophenanthridine alkaloid
      nitidine (a dual poison of both topos I and II), coralyne and its derivatives
      have marginal poisoning activity against DNA topo II. Yeast cells expressing
      human DNA topo I are shown to be specifically sensitive to killing by coralyne
      derivatives and nitidine, suggesting that cellular DNA topo I is their cytotoxic
      target. Two human camptothecin-resistant cell lines, CPT-K5 and A2780/CPT-2000,
      which are known to express highly camptothecin-resistant topo I, are only
      marginally resistant to coralyne derivatives and nitidine. Purification of human
      topo I from Escherichia coli cells overexpressing CPT-K5 recombinant topo I has
      demonstrated similar marginal cross-resistance to nitidine. It seems possible to
      develop coralyne and nitidine derivatives as new topo I-targeted therapeutics to
      overcome aspects of camptothecin-related resistance.

PMID- 8665517
TI  - Reduction of tumor hypoxia and inhibition of DNA repair by nicotinamide after
      irradiation of SCCVII murine tumors and normal tissues.
AB  - The alkaline comet assay was used to measure both tumor hypoxic fraction and DNA
      strand break rejoining kinetics in individual cells from tumors and tissues of
      C3H/HeN mice exposed to ionizing radiation and nicotinamide. The percentage of
      hypoxic cells in SCCVII marine squamous cell carcinoma decreased from 18.4 to
      4.4% in mice injected with a clinically relevant dose of 200 mg/kg nicotinamide
      30 min before irradiation. At higher doses (500 and 800 mg/kg), nicotinamide also
      increased the half-time of strand break rejoining in tumor, thymus, spleen, bone
      marrow, and testis from 10-20 min to 40-80 min. Cells from the brain rejoined
      radiation-induced breaks 3-5 times more slowly than did cells from other tissues
      and showed no additional delay after nicotinamide. Cells with extensive numbers
      of strand breaks appeared 24 h after treatment with nicotinamide and radiation
      and 48 h after treatment with radiation alone. For most tissues, damage was more
      consistent with necrosis than with apoptosis. The percentage of heavily damaged
      cells was dependent on tissue type, time after irradiation, radiation dose,
      nicotinamide dose, and sequence of administration. In SCCVII tumors of air
      breathing mice, nicotinamide enhanced radiation-induced cell killing primarily in
      cells close to the vasculature, but in tumors clamped before irradiation, 500
      mg/kg nicotinamide did not increase cell kill. It appears that in addition to
      promoting tumor reoxygenation, nicotinamide inhibits DNA strand break rejoining
      in tumors and most normal tissues and promotes the earlier appearance of
      radiation-damaged cells, perhaps through inhibition of poly(ADP-ribose)
      polymerase.

PMID- 8665518
TI  - Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung
      cancer and lung metastatic cancer.
AB  - We synthesized a potent new antitumor podophyllotoxin derivative (4beta
      aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a
      drug that has strong activity against lung cancer and lung metastatic cancer. TOP
      53 exhibited twice the inhibitory activity of etoposide (VP-16) against
      topoisomerase II and induced DNA strand breaks but showed no inhibitory activity
      against tubulin polymerization. The in vitro cytotoxic activity of TOP-53
      assessed as IC50 was 0.016-0.37 microg/ml and 0.26-8.9 microg/ml against marine
      tumor and human non-small cell lung cancer (NSCLC) cell lines, respectively. TOP
      53 exerted significant efficacy equivalent to that of VP-16 on s.c.-implanted
      murine solid tumors (Colon 26, B16-BL6, and Lewis lung carcinoma) at doses 3-5
      times lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was
      active for four of five tumors, whereas VP-16 was active for two of five tumors.
      Potent inhibitory activity of TOP-53 was also found against a lung tumor (Lewis
      lung carcinoma) and four lung metastatic tumors (NL-22 and NL-17 colon cancer,
      UV2237M fibrosarcoma, and K1735M2 melanoma). TOP-53 appeared to be more active
      against four of them than VP-16. Thus, TOP-53 is not only active against s.c.
      implanted lung cancers but also strongly active against lung localized tumor and
      metastatic tumors in the lungs. The high selectivity of TOP-53 was attributed to
      its high distribution into the lung and its persistence. TOP-53 is expected to be
      highly effective against lung cancer including NSCLC and various lung metastatic
      tumors in the clinical field.

PMID- 8665519
TI  - Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by
      the matrix metalloproteinase inhibitor batimastat (BB-94).
AB  - We examined the effects of the synthetic matrix metalloproteinase inhibitor
      batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat
      mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of
      the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human
      breast cancer, is the most prominent. Administration of batimastat (6 x 30 mg/kg
      i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung
      colonies following i.v. inoculation of cells. This implies an effect both on
      seeding efficiency and subsequent tumor development. In spontaneous metastasis
      assays, limited treatment with batimastat (commencing when s.c. tumors were
      established and continuing until 5 or 14 days after their surgical removal)
      significantly inhibited lung metastasis but had little effect on lymphatic
      metastasis. However, when treatment was initiated 2 days prior to surgery and
      continued until day 70, 100% of animals survived to day 120 when there was no
      evidence of metastatic disease. All control animals (n = 25) in two separate
      experiments died before day 100 with lymphatic, lung, and extrapulmonary
      metastases. Taken together, these data suggest that lymphatic dissemination by
      HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular
      invasion, but that long-term treatment can effectively prevent the outgrowth of
      putative micrometastases in both lymph nodes and lungs, allowing sustained tumor
      free survival.

PMID- 8665520
TI  - DT-diaphorase as a critical determinant of sensitivity to mitomycin C in human
      colon and gastric carcinoma cell lines.
AB  - Mitomycin C (MMC), a known cytotoxic agent, requires cellular enzyme-mediated
      activation for effective antitumor activity. To study the bioreductive enzymes
      responsible for MMC activation in tumor cells, we examined the enzyme activities
      of DT-diaphorase (DTD) and NADPH:cytochrome P-450 reductase in 13 colon and
      gastric carcinoma cell lines and then compared these activities to the respective
      cellular MMC sensitivity. We found that cell lines with nonexistent or marginal
      DTD activity, such as St-4 and MKN7, showed resistance to MMC, in comparison to
      cell lines with DTD activity ranging from 210 to 1420 nmol/min/mg protein. No
      correlation was found between NADPH:cytochrome P-450 reductase activity and MMC
      sensitivity in these cell lines. To confirm the role of DTD in cellular MMC
      sensitivity, we constructed an expression vector containing NQO1, a gene that
      codes for DTD, and transfected the vector into St-4 cells expressing no DTD
      activity. Several transfectant clones with DTD activity from 144 to 2085
      nmol/min/mg protein were obtained. All of the transfectants showed 5-10-fold
      higher sensitivity to MMC compared to the parental St-4 cells. Consistent with
      the MMC sensitivity, we also found that MMC-DNA adduct was formed more
      extensively in the NQO1 transfectants than in the St-4 cells. These results
      indicate that DTD activity is required for effective cytotoxicity of MMC in colon
      and gastric carcinoma cells.

PMID- 8665521
TI  - Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in
      cancer patients.
AB  - Serum vitamin D3-binding protein (Gc protein) can be converted by beta
      galactosidase of B cells and sialidase of T cells to a potent macrophage
      activating factor, a protein with N-acetylgalactosamine as the remaining sugar
      moiety. Thus, Gc protein is the precursor of the macrophage activating factor
      (MAF). Treatment of Gc protein with immobilized beta-galactosidase and sialidase
      generates an extremely high titered MAF, Gc-MAF. When peripheral blood
      monocytes/macrophages of 52 patients bearing various types of cancer were
      incubated with 100 pg/ml of GcMAF, the monocytes/macrophages of all patients were
      efficiently activated. However, the MAF precursor activity of patient plasma Gc
      protein was found to be severely reduced in about 25% of this patient population.
      About 45% of the patients had moderately reduced MAF precursor activities. Loss
      of the precursor activity was found to be due to deglycosylation of plasma Gc
      protein by alpha-N-acetylgalactosaminidase detected in the patient's bloodstream.
      The source of the enzyme appeared to be cancerous cells. Radiation therapy
      decreased plasma alpha-N-acetylgalactosaminidase activity with concomitant
      increase of precursor activity. This implies that radiation therapy decreases the
      number of cancerous cells capable of secreting alpha-N-acetylgalactosaminidase.
      Both alpha-N-acetylgalactosaminidase activity and MAF precursor activity of Gc
      protein in patient bloodstream can serve as diagnostic and prognostic indices.

PMID- 8665522
TI  - Costimulation enhances the active immunotherapy effect of recombinant anticancer
      vaccines.
AB  - Activation of T lymphocytes in the absence of a costimulatory signal can result
      in anergy or apoptotic cell death. Two molecules capable of providing a
      costimulatory signal, B7-1 (CD80) and B7-2 (CD86), have been shown to augment the
      immunogenicity of whole-tumor cell vaccines. To explore a potential role for
      costimulation in the design of recombinant anticancer vaccines, we used lacZ
      transduced CT26 as an experimental tumor and beta-galactosidase (beta-gal) as the
      model tumor antigen. Attempts to augment the function of a recombinant vaccinia
      virus (rVV) expressing beta-gal by admixture with rVV expressing murine B7-1 were
      unsuccessful. However, a double recombinant vaccinia virus engineered to express
      both B7-1 and the model antigen beta-gal was capable of significantly reducing
      the number of pulmonary metastases when administered to mice bearing tumors
      established for 3 or 6 days. Most important, the double recombinant vaccinia
      virus prolonged the survival of tumor-bearing mice. These effects were antigen
      specific. The related costimulatory molecule B7-2 was found to have a similar,
      although less impressive enhancing effect on the function of a rVV expressing
      beta-gal. Thus, the addition of B7-1 and, to a lesser extent, B7-2 to a rVV
      encoding a model antigen significantly enhanced the therapeutic antitumor effects
      of these poxvirus-based, therapeutic anticancer vaccines.

PMID- 8665523
TI  - Presence of urokinase in serum-free primary rat hepatocyte cultures and its role
      in activating hepatocyte growth factor.
AB  - Serum-free rat hepatocyte cultures can be stimulated to divide by the inactive,
      single-chain form of hepatocyte growth factor (scHGF), suggesting that
      hepatocytes contain a protein that can cleave scHGF to its biologically active,
      two-chain (tcHGF) form. We added radiolabeled scHGF to serum-free cultures and
      confirmed that tcHGF was being generated. Because scHGF can be cleaved to tcHGF
      by plasminogen activators (PAs), we next tested the cultures for active PA.
      Although little PA activity was initially present, the majority was of the
      urokinase type (u-PA) as determined by neutralization studies using either a
      polyclonal antibody against u-PA or, since u-PA functions in the context of its
      receptor (u-PAR), a monoclonal antibody against u-PAR. Considerable PA activity
      developed within 24 h, which was also neutralizable with antibody. To test
      whether the active, receptor-bound u-PA from the cell cultures was cleaving
      scHGF, iodinated scHGF was added to intact cells in the presence of the antibody
      against u-PAR. Comparison to control cultures determined that the antibody
      prevented scHGF cleavage. Analysis of cultures treated with HGF, epidermal growth
      factor, and transforming growth factor alpha (TGF-alpha) alpha showed these
      growth factors increased the hepatocyte PA activity in parallel with the mRNA for
      u-PA. TGF-beta had the opposite effect, and when TGF-beta was added to the
      culture system, conversion of scHGF to tcHGF was prevented in concert with the
      production of the type 1 PA inhibitor. When liver remnants from hepatectomized
      animals were assayed for active TGF-beta, elevated protein was found just prior
      to the appearance of PA inhibitor 1 message and protein. Collectively, our data
      show that in culture, active u-PA is present and cleaves scHGF to tcHGF in the
      context of its receptor. It also suggests that modulation of u-PA activity by
      various growth factors is relevant for regulating cleavage of scHGF to tcHGF both
      in vitro and in vivo.

PMID- 8665525
TI  - Immunohistochemical analysis of in vivo patterns of Bak expression, a
      proapoptotic member of the Bcl-2 protein family.
AB  - The in vivo patterns of bak gene expression were determined in human tissues
      using an immunohistochemical approach. Polyclonal antisera were raised in rabbits
      against a synthetic peptide corresponding to amino acids 14-36 of the human Bak
      protein, and were shown to be specific by immunoblot analysis of various human
      tissues and cell lines. Bak immunoreactivity was detected in a wide variety of
      cell types and was typically present within the cytosol in a punctuate pattern
      suggestive of association with intracellular organelles. Consistent with a
      proapoptotic role for the Bak protein, gradients of Bak protein production were
      observed in the complex epithelia of the nasopharynx, esophagus, colon, and
      bladder, with Bak immunointensity being highest in the upper layers and
      relatively low in the basal portions of these epithelia. Similarly, in the
      myeloid series of hematopoietic cells, Bak immunoreactivity was strongest in the
      terminally differentiated granulocytes, with only weak immunostaining occurring
      in most progenitor cells in the bone marrow. Among the other cell types and
      tissues with prominent Bak immunostaining were: (a) cardiomyocytes; (b) vascular
      and visceral smooth muscle cells; (c) basal cells of the prostate glands; (d)
      myoepithelial cells of the mammary glands; (e) distal convoluted tubules of the
      kidney; (f) epidermal keratinocytes; (g) enterocytes of the small intestine; (h)
      Sertoli and Leidig cells of the testes; (i) theca interna cells in the ovary; and
      (j) adrenal cortex (but not adrenal medulla). Nearly all neurons and glial cells
      of the central nervous system did not contain immunodetectable Bak protein,
      whereas sympathetic neurons as well as neurons in dorsal root ganglia and their
      axons were Bak immunopositive. Most circulating peripheral blood lymphocytes were
      negative for Bak immunostaining, whereas strong Bak immunoreactivity was found
      frequently in lymphocytes in the nodes and spleen. Overall, these patterns of bak
      expression are unique compared to other members of the bcl-2 gene family, and
      suggest that bak regulates cell death at specific stages of cell differentiation
      through tissue-specific control of its expression.

PMID- 8665524
TI  - High expression of ganglioside alpha-2,8-sialyltransferase (GD3 synthase) gene in
      adult T-cell leukemia cells unrelated to the gene expression of human T
      lymphotropic virus type I.
AB  - Expression of ganglioside alpha-2,8-sialyltransferase (GD3 synthetase; EC
      2.4.99.8) gene and gangliosides in human leukemia cells were analyzed. Flow
      cytometric analysis of various types of leukemia cells using monoclonal
      antibodies revealed that GD3 was expressed at a moderate level on adult T-cell
      leukemia (ATL) cells and weakly on T-cell acute lymphocytic leukemia cells.
      Accordingly, high levels of GD3 synthase mRNA in ATL and low levels in T-cell
      acute lymphocytic leukemia were demonstrated by semiquantitative reverse
      transcription-PCR analysis. High-level expression of the GD3 synthase gene in ATL
      cells was detected in the uncultured state, and was not changed during short-term
      culture in vitro. This was in contrast with the rapid up-regulation of GM2/GD2
      synthase gene, which was observed within 24 h after start of culture after the
      emergence of human T-lymphotropic virus type I (HTLV-I) gene expression in
      cultured normal T lymphocytes with or without HTLV-I p40tax protein, GD3 synthase
      gene was almost equally expressed, whereas GM2/GD2 synthase gene was much more
      strongly expressed in the p40tax-positive T cells. These findings indicated that
      the GD3 synthase gene was highly expressed in ATL cells unrelated to HTLV-I
      genome expression.

PMID- 8665527
TI  - Manganese-containing superoxide dismutase overexpression causes phenotypic
      reversion in SV40-transformed human lung fibroblasts.
AB  - Manganese superoxide dismutase (MnSOD) has been found to be low in a wide range
      of tumor cells as well as in vitro-transformed cell lines and has been implicated
      as a new type of tumor suppressor gene. The relationship between MnSOD activity
      and the malignant phenotype was studied by transfection of MnSOD cDNA into the
      SV40-transformed human fibroblast cell line WI-38 VA13 subline 2RA. The
      integration and expression of the exogenous MnSOD cDNA was confirmed in three
      selected clones with a 2-3.5-fold increase in MnSOD activity. The effect of
      elevated expression of MnSOD on the cell phenotype was determined by observing
      growth characteristics. Compared with the parental and neo control cells, the
      MnSOD-overexpressing clones had a slower growth rate, lower plating efficiency,
      increased anchorage dependence, and morphological differences. These changes were
      correlated strongly with the level of MnSOD activity. The results suggest that an
      increase of MnSOD activity can reverse part of the malignant phenotype in SV40
      transformed human fibroblast cells. A possible mechanism is that overexpression
      of MnSOD might alter the intracellular redox state by modulation of the balance
      of reactive oxygen species.

PMID- 8665526
TI  - Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of
      heparanase activity and heparanase degradation of specific heparan sulfate
      subpopulations.
AB  - Heparanase is an endo-beta-D-glucuronidase, the enzymatic targets of which are
      the glycosaminoglycan chains of heparan sulfate proteoglycans. Elevated levels of
      heparanase are associated with the metastatic potential of melanoma cells.
      Treatment of murine and human melanoma cells with the prototypic neurotrophin
      nerve growth factor (NGF) increases the production of heparanase by melanoma
      cells. We reported previously that physiological concentrations of NGF increased
      in vitro Matrigel invasion of early-passage human brain-metastatic 70W melanoma
      cells but not melanoma cells metastatic to other sites or nonmetastatic melanoma
      cells. Here we found that treatment of 70W melanoma cells with neurotrophin NT-3
      increased Matrigel invasion, whereas treatment with neurotrophins other than NGF
      or NT-3 did not influence invasion. Mutants of NGF that do not bind to the
      neurotrophin receptor p75NTR or other nonneuronal growth factors were not able to
      enhance the invasion of 70W melanoma cells. When 70W cells were exposed to
      antisense oligonucleotides directed against p75NTR mRNA, there was a reduction in
      NGF and NT-3 binding, and the neurotrophins failed to enhance Matrigel invasion.
      To study the properties of heparanase in NT-regulated malignant melanoma invasive
      processes, we developed a sensitive heparanase assay consisting of purified
      [35S]heparan sulfate subpopulations separated by agarose gel electrophoresis.
      Incubation of 70W cells with NGF or NT-3, but not brain-derived NT factor, NT
      4/5, or mutant NGF, resulted in increased release of heparanase activity that was
      capable of degrading a subpopulation of heparan sulfate molecules.

PMID- 8665528
TI  - Suppression of a human colon cancer cell line by introduction of an exogenous NF1
      gene.
AB  - Human colon carcinoma cell line HCT116 harbors an oncogenic Ki-ras gene.
      Introduction of an exogenous full-length NF1 gene or its GTPase-activating
      protein (GAP)-related domain suppressed the tumor-forming ability of this cell
      line in nude mice. A GAP-related domain peptide carrying a K1423E mutation, which
      shows greatly diminished GAP activity but a normal binding affinity for p2lras
      GTP, was also tested. This construct was able to suppress tumor formation by the
      HCT116 cell line, thus ruling out the possibility that the observed tumor
      suppression is due to the GAP activity of NF1. Reduced Raf-1 kinase activity in
      cells which expressed these NF1 constructs suggested that neurofibromin may
      interfere with the interaction between Ras and Raf. Introduction of a
      mutationally activated Raf-1 kinase domain reversed tumor suppression by
      neurofibromin, implicating Raf-1 as the primary downstream transducer of the
      oncogenic Ras signal. An increase in apoptotic cell death, which could be delayed
      by activated Raf-1 kinase, was also seen in cells carrying the exogenous NF1
      gene.

PMID- 8665529
TI  - Interactions of valproic acid with carbamazepine and its metabolites'
      concentrations, concentrations ratios, and level/dose ratios in epileptic
      children.
AB  - In two groups of epileptic children receiving carbamazepine (CBZ) therapy with or
      without valproic acid (VPA) comedication, we investigate the drug interactions of
      VPA on serum CBZ and its metabolites' concentrations, concentration ratios, and
      level/dose ratios. Serum total and free CBZ-10, 11-epoxide (CBZ-E) concentrations
      are significantly increased in patients taking CBZ plus VPA, together with higher
      CBZ-E/CBZ concentration ratios and CBZ-E level/dose ratios. These results reflect
      the accumulation of CBZ-E. The decreased concentration ratios of trans-10, 11
      dihydroxy-10, 11-dihydro-CBZ (CBZ-H)/CBZ-E observed in patients taking CBZ plus
      VPA suggest an inhibition in the biotransformation from CBZ-E to CBZ-H.
      Significant negative correlations are found between serum VPA level and CBZ-H/CBZ
      E concentration ratios, indicating that the inhibition of CBZ-E hydrolysis by VPA
      may depend on the concentration of VPA (total or free CBZ-H/CBZ-E concentration
      ratio = [formula: see text], respectively). VPA concentration also shows
      significant positive correlations with CBZ-E and CBZ level/dose ratios. Patients
      taking CBZ plus VPA have significant higher free fractions of CBZ and CBZ-E than
      do patients on CBZ alone, suggesting a protein-binding displacement by VPA.

PMID- 8665530
TI  - Seizure control after chronic pharmacotherapy in epileptic disorders beginning
      after 40 years of age.
AB  - Few studies have been published on the pharmacologic response to treatment of
      patients whose seizures begin after 40 years of age. The purpose of this study
      was to assess the impact of chronic pharmacotherapy on the seizure control of
      such patients. We retrospectively studied the seizure frequency recorded during a
      12-month period in a group of 94 outpatients whose seizure disorders began after
      40 years of age (median age of seizure onset 56.5 years) and who had been treated
      with anticonvulsant medication for a median period of 6 years (range 18 months to
      12 years). We assessed the relationship between the patients' seizure frequency
      during the last 12 months of treatment using (a) the present and previously
      prescribed pharmacologic regimens, (b) anticonvulsant blood levels of present
      regimen, (c) etiology and duration of seizure disorder, (d) age at onset of
      seizures, and (e) presence of electrographic (EEG) and neuroradiologic
      abnormalities. We only identified side effects occurring at blood levels within
      or below the drug's therapeutic range. Seventy-eight patients (83%) were seizure
      free during the last 12 months of treatment, 11 (11%) had rare seizures, and five
      (6%) had more than four seizures per year. Seizure frequency was not affected by
      duration and etiology of seizure disorder, age at onset of seizures, seizure
      type, neuroradiologic or electroencephalographic abnormalities, and present or
      previously prescribed pharmacologic regimens. Persistent side effects were
      reported in seven of 76 (9%) monotherapy regimens and in two of 12 (17%)
      polytherapy regimens. Our data suggest that seizures beginning after the age of
      40 have a favorable prognosis after chronic pharmacotherapy.

PMID- 8665531
TI  - Weight loss in patients taking felbamate.
AB  - Felbamate is a new antiepileptic drug (AED) with a good safety profile. Anorexia
      has been reported in patients taking felbamate, but the incidence and severity of
      this side effect have not been adequately investigated. We studied 65 patients
      with intractable seizures who received adjunctive felbamate therapy as part of
      clinical research trials or in a compassionate-use program. Mean treatment time
      on felbamate was 23 weeks (+/- SD 16; range, 6-116 weeks). Forty-nine patients
      (75%) lost weight during the trials. For subjects older than 15 years, there was
      a mean weight loss of 3.17 kg or 4.11% of body weight (T = 191.5, z = 4.18, p <
      0.001). For subjects 15 years or younger there was a mean weight loss 0.20 kg or
      a loss of 1.77% of body weight (T = 52.5, NS). Twenty-two patients (34%) lost > 4
      kg, and seven patients (11%) lost > 8 kg. Adjunctive treatment of adults with
      severe epilepsy with felbamate may be associated with clinically significant
      weight loss.

PMID- 8665532
TI  - Cognitive and quantified electroencephalographic correlates of cycloserine
      treatment in Alzheimer's disease.
AB  - Cycloserine acts as a potent and selective modulator of the N-methyl-D- aspartate
      (NMDA) receptor-associated glycine recognition site, which may be a possible
      mechanism for this compound's positive effects on memory formation and retrieval
      processes in animals. Studies in normal human volunteers have shown that
      cycloserine can have significant positive effects on cognitive processing in the
      elderly and can ameliorate memory deficits induced by subcutaneously administered
      scopolamine. Based on this profile, a double-blind, placebo controlled, parallel
      group (three drug dosages) study was conducted as part of a larger study to
      assess the efficacy and safety, as well as the cognitive and central nervous
      system (CNS) impact, of 6 months of cycloserine treatment in patients (N = 40)
      with probable dementia of the Alzheimer type (DAT). The Cognitive Drug Research
      Computerize Assessment System (CDR System) served as the primary outcome measure
      of efficacy. CNS activity was assessed using quantified electroencephalography
      (QEEG). Safety measures included adverse effects documentation and analysis of
      blood chemistry/hematology. Cycloserine proved to be a safe agent in this
      population at the doses given but failed to show any statistically significant
      effects in the areas of cognition and global clinical ratings and did not
      indicate significant CNS activity on QEEG. These findings suggest that
      cycloserine has no measurable therapeutic effect on Alzheimer's disease at the
      doses given.

PMID- 8665533
TI  - Remoxipride in Parkinson's disease: differential response in patients with
      dyskinesias fluctuations versus psychosis.
AB  - Remoxipride is a novel substituted benzamide that more effectively blocks
      mesolimbic than striatal D2 dopamine receptors. We used remoxipride in the
      management of nine patients with Parkinson's disease (PD) who were experiencing
      visual hallucinations due to dopaminergic therapy. Remoxipride was begun in a
      dose of 25 mg three times daily and gradually increased to 75-225 mg/d (mean 161
      mg). The psychiatric status improved in eight patients. Little or no change in
      the severity of parkinsonism was noted in five, a mild increase in two, and a
      moderate increase in two. Because one patient with moderately severe levodopa
      induced dyskinesias experienced a reduction in the abnormal movements without a
      substantial increase in parkinsonism, we began a trial of remoxipride for
      disabling peak-dose dyskinesias. The trial was abandoned after every one of the
      first four patients entered experienced an immediate, severe, and prolonged
      increase in off periods with single 10- to 25-mg doses. This striking
      differential response to an atypical neuroleptic with weak striatal D2 antagonist
      properties indicates that different states of postsynaptic dopamine receptor
      sensitivity or synaptic dopamine levels may be associated with various disease-
      and treatment-related problems found in late-stage PD.

PMID- 8665534
TI  - Effect of entacapone, a COMT inhibitor, on the pharmacokinetics and metabolism of
      levodopa after administration of controlled-release levodopa-carbidopa in
      volunteers.
AB  - We studied the effect of entacapone, a catechol-O-methyltransferase (COMT)
      inhibitor, on the pharmacokinetics and metabolism of levodopa after
      administration of a controlled-release (CR) levodopa-carbidopa preparation
      (Sinemet CR) in an open, randomized trial in 12 healthy male volunteers. The
      inhibition of soluble COMT (S-COMT) in red blood cells (RBCs) was also measured.
      Single graded doses of entacapone (100-800 mg) were administered concomitant with
      a single oral dose of CR levodopa, or CR levodopa was given without entacapone
      (control treatment), at least 1 week apart. Plasma concentrations of levodopa, 3
      O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid
      (HVA), carbidopa, and entacapone were determined for pharmacokinetic
      calculations. Entacapone decreased dose-dependently the activity of S-COMT in
      RBCs with a maximal inhibition of 66% after the highest dose (800 mg). Entacapone
      increased the area under the plasma concentration-time curve (AUC) of levodopa;
      the increase was highest (33%) after the 400-mg dose. Entacapone did not
      influence time to maximal concentration (Tmax) of levodopa. Entacapone was
      absorbed faster than levodopa from the CR preparation. The AUCs of 3-OMD and HVA
      decreased and that of DOPAC increased dose-dependently after entacapone,
      maximally by 69, 38, and 74%, respectively. Higher doses of entacapone (400 mg
      and 800 mg) decreased the AUC, but not Tmax of carbidopa. Over the dose range
      studied, entacapone was well tolerated. Entacapone is an effective COMT
      inhibitor. It improves the pharmacokinetic profile of levodopa when used in
      combination with a CR levodopa preparation, as it does with a standard levodopa
      preparation. The results justify further clinical studies with entacapone in
      combination with CR preparations of levodopa.

PMID- 8665535
TI  - Cerebrospinal fluid homovanillic acid is reduced in untreated Huntington's
      disease.
AB  - We measured homovanillic acid (HVA), 5-hydroxy indole acetic acid (5-HIAA), and
      tryptophan (TP) in cerebrospinal fluid (CSF) of 20 neuroleptic-free patients with
      Huntington's disease (HD), and compared mean values with those from four control
      groups including 15 normal individuals, 38 patients with dystonia, 23 untreated
      patients with Parkinson's disease, and 61 patients with other neurological
      diseases (ONDs). The mean levels of HVA in the CSF of patients with HD were
      reduced compared with those from normal controls (p < 0.001), dystonic patients
      (p < 0.005), individuals with ONDs (p < 0.0001), and even from untreated
      parkinsonian patients (p < 0.05). 5-HIAA and TP levels in the CSF of patients
      with HD were not significantly different from those in the CSF of control
      patients. Our data suggest a reduced dopamine neurotransmission in HD and may
      account for the bradykinesia observed in our patients.

PMID- 8665537
TI  - Valproic acid in ultra-rapid cycling: a case report.
AB  - Valproic acid has been proven to be efficient in the treatment of bipolar
      affective disorders as an adjunctive agent to lithium and carbamazepine.
      Recently, its efficacy in rapid cycling states has attracted interest. We present
      the case of a male patient with bipolar affective disorder who developed an
      extreme state of ultra-rapid cycling (48-h cycles). Only the addition of valproic
      acid therapy to prior lithium treatment succeeded in curtailing the ultra-rapid
      cycling. Several issues regarding ultra-rapid cycling and valproate's efficacy in
      bipolar disorder are discussed.

PMID- 8665536
TI  - Involvement of dopamine D1 receptors in phencyclidine-induced behavioral
      stimulation in rats.
AB  - The effects of dopamine receptor antagonists on phencyclidine (PCP)-induced
      behaviors were examined in rats. Acute administration with PCP (7.5 mg/kg i.p.)
      produced various behavioral changes, such as increases of spontaneous activity,
      head-weaving, sniffing, rearing, back-pedaling, and ataxia. To determine which
      dopamine receptor subtypes were involved in mediating the PCP-induced behaviors,
      SCH 23390 (0.05 and 0.5 mg/kg), sulpiride (20 and 100 mg/kg), or haloperidol
      (0.05 and 0.5 mg/kg) were pretreated 30 min before PCP treatment (7.5 mg/kg). A
      higher dose of SCH 23390 significantly reduced the increase of spontaneous
      activity induced by PCP. Both doses of sulpiride did not affect the PCP-induced
      behaviors. A higher dose of haloperidol decreased the PCP-induced spontaneous
      activity, whereas a lower dose of haloperidol enhanced the activity. Ketanserin
      (0.5 and 5 mg/kg) did not alter any PCP-induced behaviors. These results suggest
      that the D1, but not D2, dopamine receptor subtype may be involved in the PCP
      induced behavioral abnormality.

PMID- 8665538
TI  - Aggravation of parkinsonian tremor by cisapride.
AB  - Cisapride, a substituted piperidinyl benzamide that is chemically related to
      metoclopramide, is a prokinetic agent that facilitates motility of the
      gastrointestinal tract (1). The mechanism by which cisapride exerts its actions
      is not clear. It enhances acetylcholine release in the myenteric plexus of the
      gut, and evidence exists that it has an agonistic action on a serotonin receptor,
      probably the 5-HT4 receptor (2). The drug is well tolerated, and no central
      nervous system side effects have been reported. We describe two patients with
      parkinsonism who experienced aggravation of tremor while on therapy with
      cisapride.

PMID- 8665539
TI  - An imidazopyridine anxiolytic alters glucose tolerance in patients: a pilot
      investigation.
AB  - We have recently shown that compounds with high affinity for peripheral-type
      benzodiazepine receptors inhibited glucose-induced insulin secretion in vitro. We
      therefore performed an oral glucose tolerance test in anxious inpatients treated
      with the imidazopyridine derivative alpidem, which has been shown to display high
      affinity for these binding sites. The test was performed before and after 1 week
      of daily administration of the drug. As compared with pretreatment values, a
      significant alteration of the insulin response to glucose was observed. It is
      suggested that daily administration of alpidem, at therapeutically effective
      doses for the treatment of anxiety, may alter glucose tolerance.

PMID- 8665540
TI  - Octreotide effects on orthostatic hypotension in patients with multiple system
      atrophy: a controlled study of acute administration.
AB  - In nine patients with orthostatic hypotension due to multiple system atrophy, the
      effects of octreotide (100 micrograms s.c.), a somatostatin analogue, on blood
      pressure (BP), heart rate (HR), and norepinephrine (NE) plasma levels after 60
      degrees head up tilt test were evaluated by a randomly controlled study.
      Octreotide increased supine BP, tilt-test duration (+28%), and delay to obtain
      minimal BP during the 60 degrees head up tilt (+50%). Octreotide changed neither
      HR nor NE plasma levels.

PMID- 8665541
TI  - Nightmares related to fluoxetine treatment.
AB  - Sleep disturbances are found in most depressive patients. Serotonin reuptake
      inhibitors, such as fluoxetine hydrochloride, seem to improve sleep by changing
      the depressive affect and the underlying biological mechanisms. Insomnia is an
      occasional adverse effect of the medication, but it was shown that only 2-3% of
      the patients with fluoxetine-induced insomnia discontinued the drug for this
      reason. We could not find any report of nightmares or night terrors under
      fluoxetine treatment. We report on four patients who experienced nightmares on
      fluoxetine monotherapy.

PMID- 8665542
TI  - Possible therapeutic application of GABAB receptor agonists and antagonists.
AB  - After their discovery within the mammalian periphery in 1981, gamma-aminobutyric
      acid-B (GABAB) receptors have been characterized also in the central nervous
      system (CNS). The highest concentrations of GABAB binding sites appear to be in
      the cerebellum, frontal cortex, and thalamic nuclei, where they are located on
      pre- and postsynaptic neurons. On activation, the primary effects appear to be
      membrane hyperpolarization, suppression of transmitter release, and changes in
      the levels of cyclic nucleotides. GABAB receptors have been implicated in a
      variety of neurological phenomena and, as a consequence, receptor agonists and
      antagonists may well have therapeutic potential. This article is an introduction
      to GABAB receptor pharmacology and reviews the future of the receptor ligands.
      Particular attention is given to the role of spinal cord GABAB receptors in
      chronic pain.

PMID- 8665543
TI  - Selegeline hydrochloride treatment in narcolepsy. A double-blind, placebo
      controlled study.
AB  - The relative benefits of selegeline hydrochloride (2 x 5 mg, 2 x 10 mg
      selegeline) were studied in 30 narcoleptic patients using a randomized, double
      blind, placebo-controlled design. Patients were randomly assigned to three groups
      (placebo and 2 x 5 mg and 2 x 10 mg selegeline). After a 2-week washout period
      for previous anticataplectic and stimulant medication, the study started with a 2
      day period of placebo intake for each group, continued by 14 days of medication,
      ending with a 2-day placebo period. Outcome was measured by comparison of four
      polysomnographies and four multiple sleep latency tests (MSLTs) performed during
      the initial and the final placebo and medication period. Each MSLT day included
      acoustic and visual vigilance tests. Blood pressure and pulse rate were monitored
      daily. Patients reported daily about mood, concentration, subjective sleep time,
      nocturnal awakenings, nocturnal wake times, number of naps, and occurrence of
      symptoms of the narcoleptic tetrad. Selegeline caused dose-dependent REM
      suppression during nighttime sleep and naps and increase of sleep and REM
      latency. Under selegeline, daytime sleepiness improved significantly and the
      number of sleep attacks and naps as well as the frequency of cataplexy were
      reduced. Selegeline at a dose of a least 20 mg/day is a potent drug for the
      treatment of all narcoleptic symptoms.

PMID- 8665544
TI  - Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake
      inhibitors.
AB  - Treatment of serotonin reuptake inhibitors (SRIs) is associated with sexual
      dysfunction. The cause of this dysfunction is unclear but may be related to
      stimulation of the serotonergic system. In the present article, we describe seven
      patients in whom iatrogenic sexual dysfunction induced by SRIs was treated with
      cyproheptadine, a 5HT-2 antagonist with antihistaminergic and adrenolytic
      properties. Seven obsessive-compulsive male patients, aged 29-54 years, who
      developed sexual dysfunction following treatment with SRIs (fluoxetine,
      fluvoxamine, and clomipramine) were instructed to take cyproheptadine (4-12 mg) 1
      2 h before commencing sexual activity. Five of the seven patients displayed
      improvement in sexual function, although the improvement was transitory in two.
      The two remaining patients did not respond. All patients exhibited sedation on
      the day following cyproheptadine administration. Our preliminary observation
      suggests that some patients with sexual dysfunction associated with SRI
      treatment, mainly decreased libido and anorgasmia, may benefit from
      cyproheptadine administration. The role of 5HT-2 antagonists in SRI-induced
      sexual dysfunction merits further investigation.

PMID- 8665545
TI  - A longitudinal study of the effects of an L-dopa drug holiday on the course of
      Parkinson's disease.
AB  - Drug holidays as treatment in Parkinson's disease (PD) to ameliorate the effects
      of chronic L-dopa use are a controversial method. They are used in an attempt to
      resensitize dopamine receptors in the striatum so that L-dopa therapy can be
      reinstated at lower doses with fewer of the side effects that normally accompany
      long-term use of the drug. In the present study, 15 patients with PD were
      submitted to a 7-day L-dopa drug holiday and then followed for 3 years. The
      effect of the holiday on parkinsonian symptoms and grade of severity of PD was
      determined using the Webster and the Hoehn and Yahr scales, administered at
      intervals over the 3-year period. We found that within the first 6 months post
      drug-holiday, there was a dramatic improvement in the rating of the symptoms of
      PD that was statistically significant (p < 0.005). At 12 months, Webster scale
      scores had risen, but they remained significantly improved (p < 0.05) in
      comparison with the first postholiday score. This level of improvement was
      maintained at 24 and 36 months. The grade of severity of the disease stabilized
      since Hoehn and Yahr scale scores improved for all patients, except one, for the
      length of the study. One patient left the study after 6 months for unknown
      reasons. Of the 14 patients that remained, three were given additional drug
      holidays: two patients at 12 months and one patient at 12, 24, and 36 months. All
      patients were able to be maintained on a reduced L-dopa dose regimen of 50-70% of
      their pre-drug-holiday level for the entire 3-year period. In the patients in
      whom the drug holiday was least beneficial overall, there was a notable reduction
      in rigidity and in the "on-off" phenomenon. We conclude that an L-dopa drug
      holiday is a valuable option in the treatment of PD.

PMID- 8665546
TI  - Acute effects of COMT inhibition on L-DOPA pharmacokinetics in patients treated
      with carbidopa and selegiline.
AB  - The effects of acute catechol-O-methyltransferase (COMT) inhibition on L-DOPA
      pharmacokinetics were studied in 10 parkinsonian subjects on stable doses of L
      DOPA/carbidopa and selegiline. Tolcapone, a reversible COMT inhibitor, was
      administered in four single ascending doses (50-800 mg) randomly paired with
      placebo. Serial plasma concentrations of L-DOPA and its metabolites were
      measured, and patient diaries and clinical ratings of dyskinesia were completed
      every 30 min for 6 h. Tolcapone increased the area under the curve of the plasma
      L-DOPA concentration versus time curve and decreased the accumulation of
      homovanillic acid. COMT inhibition increased "on" time and the duration of
      dyskinesia without affecting the maximal amplitude of dyskinesia. Tolcapone may
      be a useful adjunct to L-DOPA/carbidopa.

PMID- 8665547
TI  - Pramipexole in patients with early Parkinson's disease.
AB  - We evaluated the efficacy, safety, tolerability, and pharmacokinetics of
      pramipexole, a novel dopamine D2 receptor agonist, in early Parkinson's disease
      (PD). The study design was a parallel, placebo-controlled trial using an
      ascending dose of 4.5 mg/day pramipexole maximum. All subjects received
      selegiline (10 mg/day) but were not treated with levodopa. Of the 55 subjects who
      received at least one dose of the study medication, all but one, in the placebo
      group, completed the trial, which was 9 weeks in duration. The primary efficacy
      endpoints were changes in scores from baseline to final measurement on the
      Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. The
      pramipexole group had a significantly greater improvement (p = 0.002) than the
      placebo group on UPDRS Part II (Activities of Daily Living). The change in score
      from baseline to final measurement on UPDRS Part III (Motor Examination) was not
      significantly different (p = 0.10) between the pramipexole and placebo groups,
      although the trend favoured the pramipexole group. All subjects in both the
      pramipexole and the placebo groups experienced one or more episodes of
      asymptomatic orthostatic hypotension; there was no significant difference between
      the pramipexole and the placebo groups in the number of subjects experiencing
      symptomatic orthostatic hypotension. The adverse events profile of pramipexole
      was similar, in general, to that of other dopamine receptor agonists. Plasma
      pramipexole levels increased linearly with dose. Pramipexole appears to be
      promising agent in the treatment of early PD.

PMID- 8665548
TI  - Effects of selegiline (deprenyl) on cognition in early Parkinson's disease.
AB  - The influence of selegiline (5 mg b.i.d.) on cognition of 20 levodopanaive
      patients with early Parkinson's disease (PD) was examined in an 8-week,
      randomized, placebo-controlled, double-blind trial. Clinical evaluations and
      cognitive tests were administered at baseline and at 8 weeks; patients with PD
      who received placebo were also examined 8 weeks after subsequent selegiline
      treatment. By comparison with non-PD controls, patients with PD were impaired on
      the Wisconsin card sorting task and on the advanced progressive matrices test,
      but not in terms of their performance on the Rivermead behavioral memory test or
      on the rod (spatial) orientation test. Selegiline improved scores on the
      mentation/mood part and the activities of daily living part of the Unified
      Parkinson's Disease Rating Scale, but it did not improve motor scores on this
      test, nor did it have clear effects on the specific neuropsychological measures
      that were examined.

PMID- 8665549
TI  - Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic
      pain with allodynia: a double-blind comparison to alfentanil and placebo.
AB  - NMDA antagonists and opioids relieve experimentally produced hyperalgesia in
      animals and humans, presumably by attenuating a heightened central nervous system
      response to afferent input. A few small studies in patients have suggested that
      intravenous boluses or rapid infusions of the N-methyl-D-aspartate (NMDA)
      antagonist ketamine relieve some neuropathic pains but also produce disturbances
      of cognition and mood. In a randomized, double-blind, crossover trial, we treated
      eight patients with chronic posttraumatic pain and widespread mechanical
      allodynia with 2-h intravenous infusions of the NMDA antagonist ketamine (mean
      dose, 58 mg), the opioid mu-receptor agonist alfentanil (mean dose, 11 mg), and
      placebo. The patients were selected because extensive sensory testing suggested
      that altered central processing contributed to their symptoms. The slow rate of
      drug infusion was chosen to see if pain relief would precede dose-limiting side
      effects. Means of the peak effect scores achieved during the 2-h infusion were
      for pain relief: ketamine, 65%, alfentanil, 46%, and placebo, 22% (p < 0.01 for
      ketamine and p = 0.08 for alfentanil, each compared to placebo); and for relief
      of allodynia: ketamine, 71%, alfentanil, 57%, and placebo, 21% (p < 0.01 for both
      ketamine and alfentanil). Appreciable symptomatic relief developed only after the
      onset of unpleasant drug side effects. After the infusion was stopped, pain
      relief disappeared before the side effects resolved. We conclude that NMDA
      antagonists may have promise for the treatment of neuropathic pain, but
      strategies are needed to improve their therapeutic ratio, such as intrathecal
      administration or systemic treatment with more selective drugs.

PMID- 8665550
TI  - Famotidine adjunctive pharmacotherapy of schizophrenia: a case report.
AB  - Recent reports suggest some utility for famotidine, a histamine type 2 (H2)
      antagonist, in the treatment of schizophrenia. The current report describes a
      treatment-resistant patient with chronic undifferentiated schizophrenia whose
      most dramatic symptomatic improvements were temporarily related to the open-label
      addition of famotidine (40-100 mg/day) to conventional neuroleptic treatment
      (molindone 150-200 mg/day) over the course of approximately 10 months. During one
      2-week interval, his symptoms were controlled with famotidine (40 mg/day) alone.
      The case suggests that some adjuvant efficacy exists for famotidine in at least
      some patients with schizophrenia. Placebo-controlled trials are needed to more
      fully evaluate the utility of famotidine in the treatment of schizophrenia.

PMID- 8665551
TI  - Can smoking be detected from cerebrospinal fluid?

PMID- 8665552
TI  - A comparison between IVIg and plasma exchange in Guillain-Barre syndrome: a
      review and decision analysis of the two treatment modalities.
AB  - Plasma exchange (PE) has been established as an effective treatment for Guillain
      Barre syndrome (GBS), and until recently, was the only treatment significantly to
      modify the disease course. Data from a recently published Dutch study suggest
      that intravenous immunoglobulin (IVIg) is as effective as PE in improving the
      speed of recovery and lessening disability. Recent small case series in the
      United States have shown unexpectedly high relapse rates in patients with GBS
      treated with IVIg. At present, clinicians face a dilemma in choosing between the
      two options, because there is uncertainty about the efficacy and relapse rate
      associated with IVIg. In this article, we perform a decision analysis that takes
      into account the efficacy of therapy, relapse rates, and patient preferences with
      respect to particular outcomes. Although both modalities are quite costly, an
      economic analysis shows a slight cost advantage for IVIg. Plasma exchange remains
      to preferred treatment, based on a decision analysis and currently available
      data. Results of future IVIg trials can be compared to the PE data using the
      decision-analysis model.

PMID- 8665553
TI  - Pharmacology of neuropathic pain.
AB  - The development of new animal models now allows the pharmacological study of the
      neuropathic pain. Our results concern mainly antidepressants and opiates;
      although the results are incomplete, they show that the different components of
      the pain syndrome depend on various mechanisms and require adapted treatments and
      that the treatment must begin as soon as possible, before plastic processes
      sustain a vicious circle of pain. In the future, pharmacological studies will
      permit better specification of indications for drugs already used, as well as the
      associations that improve their efficacy; studies will also encourage development
      of new treatments more adapted to the physiopathology of the pain syndrome.

PMID- 8665554
TI  - Triazolam and melatonin effects on cardiac autonomic function during sleep.
AB  - After benzodiazepine (BDZ) administration, a decrease in cardiac vagal tone has
      been described during wakefulness, but data on cardiac autonomic function during
      sleep are lacking. Melatonin (MLT), reported to have hypnotic properties, caused
      an increase in vagal tone in animals. The aim of this study was to evaluate heart
      rate (HR) variability during sleep after a single bedtime dose of triazolam (TRI,
      0.125 mg) and MLT (100 mg) in six healthy young subjects. We evaluated tonic
      (vagal activity) HR modifications in relation to sleep as well as phasic
      (sympathetic activity) HR modifications in relation to spontaneous body movements
      during rapid-eye-movement (REM) and non-REM (NREM) sleep. No significant change
      in sympathetic activity was observed after TRI and MLT in comparison with
      placebo, whereas TRI caused a significant decrease in vagal tone during sleep.
      Our nocturnal study seems to confirm previous diurnal findings about a decrease
      in vagal tone by BDZs.

PMID- 8665555
TI  - Effects of calcium antagonists on the dopamine system.
AB  - Calcium channel antagonists are drugs currently used in the treatment of
      neurological and cardiovascular disorders and occasionally produce parkinsonism
      and movement disorders as a side effect. We investigated the effects of calcium
      channel antagonists on the pharmacology of dopamine systems in vivo and in vitro.
      Flunarizine, cinnarizine, and diltiazem reduce the viability of dopamine-rich
      human neuroblastoma cells in vitro. These compounds plus verapamil, nifedipine,
      and nicardipine reduce 3H-spiperone binding to bovine striatal membranes, 3H
      dopamine uptake, K(+)-induced 3H-dopamine release, and apomorphine-induced
      rotation, but not amphetamine-induced rotation, in 6-OH-dopamine-lesioned rats.
      Therefore, all calcium channel antagonists tested reduce dopamine
      neurotransmission in vitro and in vivo, whereas the evidence of toxicity for
      dopamine cells in vitro is restricted to flunarizine, cinnarizine, and diltiazem.
      The clinical relevance of these toxic effects may depend on several factors,
      including age, penetration across the blood-brain barrier, and types of calcium
      channels present in the different neuronal subtypes. On the other hand, the
      finding of dopamine-regulating properties not associated to neurotoxic effects in
      the dihydropyridines and verapamil provides new putative therapeutics tools for
      the treatment of neurologic disorders associated with dopamine hyperactivity.

PMID- 8665557
TI  - Levodopa does not aggravate postural tremor in Parkinson's disease.
AB  - Characterization of postural tremor in Parkinson's disease (PD) is incomplete. It
      was suggested to be an exaggerated physiological tremor and to be enhanced by the
      action of levodopa. We compared the magnitude of postural tremor to the magnitude
      of rest tremor and to plasma levodopa levels in 20 PD patients, 10 with stable
      motor response to oral levodopa, and 10 with the wearing-off phenomenon. Tremor
      assessment included motor scores of the Unified Parkinson's Disease Rating Scale
      and accelerometric measurements. Accelerometric data showed that the absolute
      power of both rest and postural basal dominant tremor frequencies significantly
      diminished with the increase in plasma levodopa levels and increased with their
      decrease. Tremor frequencies were also significantly changed by levodopa, which
      slowed rest tremor and increased postural tremor dominant frequency. This latter,
      however, did not reach the 8- to 12-Hz frequency band said to be typical of
      exaggerated physiological tremor. No significant differences between groups were
      found in their tremor response to levodopa. This study shows that the net
      postural tremor exhibited by PD patients is improved by levodopa, that levodopa
      does not augment tremor in the 8- to 12-Hz range, and that this effect is
      independent of the patient's motor response pattern of oral levodopa.

PMID- 8665556
TI  - Acute challenge with apomorphine in Huntington's disease: a double-blind study.
AB  - Apomorphine (1.5 or 3 mg) or placebo was acutely administered to choreic patients
      affected by Huntington's disease in a double-blind fashion. The patients were
      evaluated before the administration, and at 15-min intervals for 2 h afterward,
      by means of a rating scale for Huntington's disease. As compared to baseline, the
      total score improved by 38.54% after 1.5 mg and by 30.41% after 3 mg; no
      variations were observed after placebo. Several items of the scale improved after
      the administration of 1.5 mg. An average 35.25% improvement was observed in items
      measuring the intensity of chorea (at rest, with arms outstretched, during
      conversation, and voluntary movements of the limbs); in addition, motor
      impersistence (as measured by tongue protrusion) and the capability to suppress
      associated movements (as measured by head movements during saccades) improved by
      an average of 31.46 and 61%, respectively. Some items of the scale improved after
      the administration of 3 mg. Items measuring the intensity of chorea improved by
      an average of 30.41%; in addition, the extent of vertical gaze improved by
      63.77%. These data indicate that apomorphine brings about a transient symptomatic
      improvement of chorea and of other associated clinical features in Huntington's
      disease. The time course observed for the antichoreic activity is only partially
      consistent with the antiparkinsonian action of apomorphine.

PMID- 8665558
TI  - Leuprolide treatment of sexual aggression in a patient with Dementia and the
      Kluver-Bucy syndrome.
AB  - A patient with dementia and features of the Kluver-Bucy syndrome was treated for
      verbal, physical, and sexually aggressive behavior disturbances. Propranolol was
      effective in controlling verbal and physical aggression but not sexually
      aggressive and inappropriate behaviors. The latter responded completely to
      treatment with leuprolide. The differential response to these treatments suggests
      that two basic forms of aggressive behavior in demented men can be identified and
      treated with relative specificity.

PMID- 8665559
TI  - Computerized measurement of MK-801-elicited popping and hyperactivity in mice.
AB  - MK-801, a high-affinity phencyclidine (PCP) analogue, is a noncompetitive
      antagonist of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptor that
      elicits hyperactivity, stereotypic behaviors, and "popping," an explosive
      episodic jumping behavior, in mice. The schizophreniform psychosis precipitated
      by PCP in humans has stimulated interest in studying MK-801-elicited mouse
      behaviors for their potential development as animal models of idiopathic
      psychosis. We describe a computerized method for measuring popping and
      hyperactivity elicited by MK-801 in mice, based on vertical displacements of a
      platform. This computerized procedure allows for the automatic measurement of
      discrete "pops" per individual episode of popping behavior, the force of each one
      of the explosive jumps, and the duration of discrete episodes of popping; these
      latter measures could not be easily ascertained by visual inspection alone.
      Moreover, the computerized measurements facilitate quantitative evaluation of the
      effects of pharmacological manipulations on MK-801-elicited popping. For example,
      the antipsychotic haloperidol was shown to reduce significantly both MK-801
      induced popping and hyperactivity. Ideally, MK-801-elicited mouse popping and
      hyperactivity will serve as a useful preclinical screening paradigm for potential
      antipsychotic medications. Additionally, it is hoped that the use of this
      automated system will contribute to a greater understanding of the mechanisms of
      MK-801-induced popping and hyperactivity.

PMID- 8665560
TI  - Color vision in Parkinson's disease: missing influence of amantadine sulphate.
AB  - In recent studies, disorders of chromatic and achromatic vision in parkinsonian
      patients have been demonstrated; these could be partially restored after
      application of L-Dopa. In this study, the effect of a 3-day infusion therapy with
      amantadine sulphate on color vision was evaluated in 19 parkinsonian patients by
      use of the Farnsworth-Munsell 100-Hue test. Under this treatment, the motor
      symptoms of parkinsonism improved significantly as assessed by the part "motor
      examination" of the Unified Parkinson's Disease Rating Scale (UPDRS). However,
      the total error scores of the Farnsworth-Munsell 100-Hue test before and after
      amantadine sulphate infusions were unchanged [before therapy, 94.53 (SD = 52.09);
      after therapy, 99.5 (SD = 58.81)]. From these results, it can be concluded that
      the pathophysiology of dopaminergic pathways in the visual system differs from
      that of the basal ganglia.

PMID- 8665561
TI  - Transient elevations in pancreatic enzymes in response to a cholinesterase
      inhibitor.

PMID- 8665562
TI  - Amantadine, livedo reticularis, and antiphospholipid antibodies.

PMID- 8665563
TI  - Treatment approaches for metastatic cancer of the prostate based on recent
      molecular evidence.

PMID- 8665564
TI  - Haematopoietic stem-cell transplantation in multiple myeloma.

PMID- 8665565
TI  - Vinorelbine: an overview.

PMID- 8665566
TI  - Medical treatment of advanced renal cell carcinoma: present options and future
      directions.
AB  - The treatment of patients with metastatic renal cell carcinoma (MRCC) continues
      to be disappointing. A large number of hormones, chemotherapeutic agents and
      combinations have been tested with poor and non-reproducible results. Among the
      immunological treatments investigated in MRCC, the best results have been claimed
      with interferons (IFNs) and interleukin-2 (IL-2) and, although no randomized
      studies have shown higher activity than cytotoxic drugs, hormones or even no
      treatment, many oncologists feel it justified to consider these biologic agents
      the treatment of choice for this disease. Of patients treated with alpha-IFN, 15
      20% achieve an objective remission and 3-5% achieve a long-lasting complete
      response. No substantial increase of the therapeutic activity of alpha-IFN was
      produced by combination with chemotherapeutic agents and gamma-IFN or tumour
      necrosis factor. High doses of IL-2 with or without lymphokine-activated killer
      cells led to successful results in about 20-30% of patients with 5-10% complete
      responses. More recently, less toxic regimens with lower doses of IL-2 alone or
      combined with alpha-IFN produce similar response rates. Many studies have
      clarified the importance of prognostic factors in patient selection for response
      and survival during treatments with IFNs and IL-2. Good performance status, a
      long interval from diagnosis to treatment, and only one site of disease seem to
      be the most important predictors for survival. Both IFNs and IL-2 appear to
      possess encouraging antitumour activity in patients with favourable prognostic
      factors, but further studies are needed to identify the treatment of choice, the
      optimal dose regimen and route of administration in this subgroup of patients.
      Patients with poor prognosis should be encouraged to enter controlled studies
      aimed to evaluate investigational drugs and new therapeutic methods.

PMID- 8665567
TI  - Differential modulation by interferon gamma of the sensitivity of human melanoma
      cells to cytolytic T cell clones that recognize differentiation or progression
      antigens.
AB  - Human melanoma is a highly immunogenic tumor capable of inducing a specific
      immune response. A number of melanoma-associated antigens have been characterized
      during the past several years and can be classified into two groups:
      differentiation antigens-present also in normal melanocytes-and tumor-specific
      antigens, which, with the exception of testis, are present only in tumor cells.
      In a previous publication [Kirkin A. F., Petersen T. R., Olsen A. C., Li L., thor
      Straten P., Zeuthen J. (1995) Cancer Immunol Immunother 41:71] we have described
      the production of clones of cytotoxic T lymphocytes (CTL) against the highly
      immunogenic human melanoma cell line FM3. Using these clones we have defined four
      previously unknown melanoma-associated antigens, which could be subdivided into
      differentiation and progression antigens. In the experiments reported in this
      paper, we have further compared CTL clones from different groups and shown that
      the sensitivity of melanoma cells to CTL that recognize differentiation or
      progression antigens is differentially modulated during tumor progression as well
      as by the lymphokines interferon gamma (IFN gamma) and interleukin-10 (IL-10).
      The interaction of CTL clones recognizing progression antigens was strongly
      increased after treatment of melanoma cells with IFN gamma, while the recognition
      by CTL clones specific for differentiation antigens either was unchanged or
      significantly decreased. IL-10 treatment of melanoma cells induced up-regulation
      with respect to recognition by CTL clones specific for differentiation antigens
      without affecting the recognition of melanoma cells by CTL clones specific for
      progression antigens. Using cellular systems at different stages of tumor
      progression, we demonstrated that the progressed state of melanoma cells is
      associated with increased sensitivity to recognition by CTL clones detecting
      progression antigens, and with decreased sensitivity to CTL clones recognizing
      differentiation antigens. Mimicking tumor progression, treatment with IFN-gamma
      induced apparent down-regulation of differentiation antigens. A hypothesis is
      suggested in which IFN-gamma plays different roles in the immune response against
      poorly immunogenic and highly immunogenic melanoma cells, increasing the
      progression of poorly immunogenic tumor cells or promoting a strong immune
      response and regression of highly immunogenic melanoma cells.

PMID- 8665568
TI  - Immune modulation by interleukin-12 in tumor-bearing mice receiving vitamin D3
      treatments to block induction of immunosuppressive granulocyte/macrophage
      progenitor cells.
AB  - Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the
      presence of granulocyte/macrophage (GM) progenitor cells having natural
      suppressor activity. Treatment of these tumor-bearing mice with interleukin-12
      (IL-12) resulted in minimal immune modulation. The objective of this study was to
      determine whether eliminating natural suppressor activity would allow for immune
      stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D3
      eliminated natural suppressor activity. In mice that were first treated with
      vitamin D3 and then also with IL-12, there was stimulation of splenic T cell
      proliferation in response to immobilized anti-CD3 plus IL-2. In addition, spleen
      and lymph node cells from vitamin-D3/IL-12-treated tumor-bearing mice became
      stimulated in response to autologous tumor to produce interferon gamma (IFN
      gamma), although IL-2 production was not stimulated. A prominent effect of the
      combined vitamin-D3/IL-12 treatment regimen was the synergistic augmentation of
      autologous tumor-specific cytolytic activity within the regional lymph nodes. The
      generation of these tumor-specific effector cells required the presence of the
      tumor mass since such activity was not elicited in the lymph nodes of mice from
      which the tumors had been surgically excised. The results of this study show
      that, after treatment of tumor bearers with vitamin D3 to eliminate GM-suppressor
      cells, IL-12 can induce select regional antitumor immune responses, particularly
      IFN gamma production and cytolysis by regional lymph node cells of autologous
      tumor.

PMID- 8665569
TI  - Specific anti-EL4-lymphoma immunity in mice cured 2 years earlier with
      doxorubicin and interleukin-2.
AB  - This laboratory has reported the conditions for an effective, non-toxic,
      chemoimmunotherapy utilizing doxorubicin in combination with prolonged
      administration of interleukin-2 and the identification of the critical role of
      activated CD8+ T cells in the therapeutic effect. Mice (C57BL/6) cured in those
      studies have been followed for the remainder of their life spans. These mice,
      approximately 2 months of age when initially inoculated with syngeneic EL4
      lymphoma, survived for more than 2 years, the normal life span of C57BL/6 mice.
      Mice 4 months old reinoculated with the EL4 cells all survived. At about 1 year
      of age mice were sacrificed and the ability of their thymocytes and splenocytes
      to develop specific CD8+ anti-EL4 activity was as high as it had been at the time
      of tumor rejection. At about 2 years of age EL4 was reimplanted into mice; all of
      them survived. These surviving mice, at 2 years 2 months of age, as well as a
      group of 2-year-old mice not rechallenged, were killed and functional antitumor
      activity and phenotype characteristics of various lymphocyte populations were
      determined in comparison to those of young and age-matched control mice. The
      phenotyping of the lymphocytes from the cured mice indicated very notable
      differences in subset distribution and increased CD44 expression. Functionally
      they developed high levels of anti-EL4 activity, which was ablated by combined
      treatment with monoclonal antibodies against CD8 and CD44, indicating the role of
      memory cells. Consistent with cells from aged mice, these same cell populations
      had a very reduced allogeneic responsiveness. It appears that cured mice have
      developed an immune memory specific for EL4.

PMID- 8665570
TI  - Involvement of tumor necrosis factor alpha and very late activation antigen
      4/vascular cell adhesion molecule 1 interaction in surgical-stress-enhanced
      experimental metastasis.
AB  - We examined the influence of surgical stress on hematogenous metastasis of
      malignant tumor cells. The study was performed by focusing on the involvement of
      inflammatory cytokines in the serum, raised acutely after surgery, and
      endothelial adhesion molecules in the metastatic process. Surgical stress, given
      to C57BL/6 mice before B16-BL6 melanoma inoculation, significantly enhanced the
      pulmonary metastasis. This enhancement was seen when the surgery lasted for more
      than 2 h. After the 2-h surgery, the enhancement of pulmonary metastasis was seen
      most remarkably when B16-BL6 was inoculated 24 h after surgery. The serum level
      of tumor necrosis factor alpha (TNF alpha) in the mice that underwent the 2-h
      surgery peaked 12 h after the surgery. In contrast, serum interferon gamma was
      not detectable. Administration of an anti-TNF alpha mAb before the surgery
      inhibited the enhanced metastasis by inhibiting the increased expression of
      vascular cell adhesion molecule 1 (VCAM-1) on lung vascular endothelium after the
      surgery. Pretreatment of B16-BL6 cells with an anti-very late activation antigen
      4 (anti-VLA-4) mAb completely inhibited the enhanced metastasis after surgery.
      Administration of an anti-VCAM-1 mAb before surgery also inhibited the
      enhancement. These results indicate that serum TNF alpha, raised by surgical
      stress, is critically involved in the enhanced pulmonary metastasis of mouse
      melanoma by inducing VCAM-1 expression on lung vascular endothelium.

PMID- 8665571
TI  - Diverse manifestations of tumorigenicity and immunogenicity displayed by the
      poorly immunogenic B16-BL6 melanoma transduced with cytokine genes.
AB  - We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine
      melanoma genetically altered to secrete interleukin-2 (IL-2), IL-4, interferon
      gamma (IFN gamma) and granulocyte/macrophage-colony-stimulating factor (GM-CSF).
      Three parameters were evaluated: (1) tumorigenicity, (2) vaccination of naive
      animals, and (3) assessment of antitumor reactivity of T cells derived from tumor
      draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of
      BL6, while IFN gamma and IL-4 partially reduced tumorigenicity, and GM-CSF had no
      effect. Protective immunity to wild-type tumor challenge could not be achieved by
      vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4
      secretion appeared to retard the growth of the challenge inoculum significantly.
      An alternative method to evaluate the immunogenicity of the cytokine-secreting
      tumors was to measure the ability of T cells obtained from TDLN to mediate
      regression of wild-type tumor in adoptive immunotherapy. Neither IL-2 nor IFN
      gamma secretion resulted in the induction of immune T cells. By contrast, GM-CSF
      and IL-4 secretion were found to induce immune T cells in the TDLN with GM-CSF
      being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not lead to
      enhanced induction of immune T cells. GM-CSF secretion was found to upregulate B7
      1 expression in TDLN, consistent with an increase in the population of antigen
      presenting cells. These studies demonstrated that reduced tumorigenicity by
      cytokine secretion did not correlate with increased immunogenicity. With the
      cytokines examined, there was limited capability of developing protective
      immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion
      significantly enhanced T cell immune reactivity to the poorly immunogenic BL6
      tumor.

PMID- 8665572
TI  - Identification of peptide epitopes of MAGE-1, -2, -3 that demonstrate HLA-A3
      specific binding.
AB  - The MAGE gene family of tumour antigens are expressed in a wide variety of human
      cancers. We have identified 43 nonamer peptide sequences, from MAGE-1, -2 and -3
      proteins that contain binding motifs for HLA-A3 MHC class I molecules. The T2
      cell line, transfected with the cDNA for the HLA-A3 gene, was used in a MHC class
      I stabilisation assay performed at 37 degrees C and 26 degrees C. At 37 degrees
      C, 2 peptides were identified that stabilised HLA-A3 with high affinity
      (fluorescence ratio, FR > 1.5), 4 peptides with low affinity (FR 1.11-1.49) and
      31 peptides that did not stabilise this HLA haplotype (FR < 1.1). At 26 degrees
      C, 12 peptides were identified that stabilised HLA-A3 with high affinity, 8
      peptides with low affinity and 17 peptides that did not stabilise this HLA
      haplotype. Two peptides stabilised HLA-A3 at both temperatures. Small changes in
      one to three amino acids at positions distinct from the anchor residues altered
      peptide affinity. Data were compared to a similar study in which a peptide
      competition assay was used to investigate MAGE-1 peptide binding to several HLA
      haplotypes. This study demonstrates that anchor residues do not accurately
      predict peptide binding to specific HLA haplotypes, changes in one to three amino
      acids at positions distinct from anchor residues influence peptide binding and
      alternative methods of determining peptide binding yield different results. We
      are currently investigating the ability of these peptides to induce antitumour
      cytotoxic T lymphocyte activity as they may be of potential therapeutic value.

PMID- 8665573
TI  - Effects of ifosfamide on immunocompetent effector cells.
AB  - We analyzed the effects of ifosfamide, a chemotherapeutic agent that is broadly
      used within anticancer therapy, on immunocompetent effector cell subpopulations.
      For our in vitro studies we used 4-hydroperoxyifosfamide (4-OOH-IF), which
      rapidly gives rise to 4-OH-IF, the activated form of ifosfamide. Activated
      cytotoxic T lymphocytes and natural killer (NK) cells were used because of their
      antitumor activity and their antiviral or antibacterial activity. Our study
      demonstrated three major findings. (1) The capacity of cytotoxic T cells to lyse
      their specific target cells was substantially reduced by 4-OH-IF treatment. This
      inhibition of the lytic activity could be correlated with a substantial depletion
      of the intracellular glutathione (GSH) levels. A rapid reconstitution of the
      depleted GSH levels and of the cytotoxic activity was achieved by incubation of
      the T cells with thiols such as mercaptoethanesulfonate (mesna). (2) In contrast
      to T cells the lytic activity of NK cells was not substantially affected by 4-OH
      IF treatment; this increased resistance of NK cells against 4-OH-IF treatment
      could be explained by their higher initial GSH levels and by their higher rate of
      GSH synthesis. Furthermore, we demonstrated that (3) NK cells, but not T cells,
      have the capacity to take up cystine, the oxidized form of cysteine, from the
      medium. In conclusion we can state that NK cells are much more resistant to
      ifosfamide treatment compared to T cells with respect to intracellular GSH levels
      and cytotoxic activity.

PMID- 8665574
TI  - Intradermal administration of lipopolysaccharide in treatment of human cancer.
AB  - Lipopolysaccharide (LPS) has been recognized as a potent antitumor agent in
      animal tumor models; however, its use in human cancer therapy has been limited to
      only one trial, in which LPS from Salmonella was given intravenously. It was not
      very successful because of poor tumor response and was also toxic. We originally
      developed LPS prepared from Pantoea agglomerans (LPSp), and this was a well
      purified, small-molecular-mass (5 kDa) agent. We chose intradermal rather than
      intravenous administration in the hope that the former would release LPS slowly
      into the bloodstream, and thus be less toxic while preserving antitumor activity.
      In our animal tumor models, intradermal administration was indeed less toxic and
      more beneficial for tumor regression than intravenous administration. We made a
      pilot study with intradermal administration of LPSp on the treatment of ten
      advanced cancer patients. Five of them had evaluable tumor, which had failed
      earlier to respond to conventional chemotherapy. Cyclophosphamide was also
      administered in this trial, in anticipation of its synergistic effect with LPSp.
      In this study LPSp was injected intradermally into each patient twice a week,
      starting with an initial dose of 0.4 ng/kg, and raising it to 600 or 1800 ng/kg.
      A 400-mg/m2 dose of cyclophosphamide was given intravenously every 2 weeks. After
      completion of the dose escalation, the treatment was continued for at least 4
      months, and it was found that 1800 ng/kg LPSp was well tolerated. A significant
      level of cytokines was observed in the sera for at least 8 h. These results
      indicate higher tolerable doses and remarkably more continuous induction of the
      cytokines than were reported in a previous study by others using intravenous
      administration. Three of the five evaluable tumors showed a significant response
      to our combined therapy. Intradermally administered, LPS was less toxic and
      elicited a tumor response in combination with cyclophosphamide; it can thus can
      be applied to cancer treatment even in humans.

PMID- 8665575
TI  - Pattern reversal visual evoked potentials in children with migraine or tension
      type headache.
AB  - Pattern reversal visual evoked potentials were recorded in 71 children with
      different types of migraine (e.g. migraine with aura, migraine without aura) or
      tension-type headache and in 19 controls (mean age of both groups 9 years). P100
      latencies were comparable in all three groups.

PMID- 8665576
TI  - IHS criteria and gender: a study on migraine and tension-type headache in
      children and adolescents.
AB  - The aim of this study was to investigate whether the IHS criteria for migraine
      and tension-type headache depend on gender. Among 409 children and adolescents
      with recurrent idiopathic headache seen at a university outpatient clinic, girls
      had significantly more often migraine with aura. Also, there was a trend towards
      a higher frequency of tension-type headache in girls. In migraine, aggravation of
      headache by physical activity and occurrence of aura symptoms were more common in
      females, whereas vomiting and phonophobia occurred more often in males. In
      tension-type headache, females more often reported mild intensity of headache.
      All other criteria were similar in both sexes. Age influenced the expression of
      some of the accompanying symptoms in the various types of migraine, but had only
      minimal influence on other diagnostic criteria of migraine and tension-type
      headache in females as well as in males. Our study suggests that the frequency of
      migraine (except that of migraine with aura) is similar among girls and boys,
      that tension-type headache may occur more often in girls, and that gender has
      some influence on the IHS criteria for migraine, but almost no influence on those
      of tension-type headache.

PMID- 8665577
TI  - Pilot study of MK-462 in migraine.
AB  - MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in
      treating acute migraine. We conducted a double-blind placebo-controlled inpatient
      study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg
      (n = 8) and 40 mg (n = 36) vs placebo (n = 21), administered to 65 male and post
      menopausal female migraine patients aged 22-51 with moderate or severe migraine
      headache. Headache severity and functional disability were measured at 0.5, 1,
      1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients
      obtained relief in headache severity at the 2 h time point. The 40 mg dose was
      well tolerated and was significantly (p < 0.05) superior to placebo at the 1.5
      and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21
      or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462,
      72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most
      common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg
      44%; placebo 24%), dry mouth (40 mg 36%; placebo 19%), and
      lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary
      results, MK-462 appears worthy of continued study for the treatment of acute
      migraine.

PMID- 8665578
TI  - Ketoprofen, paracetamol and placebo in the treatment of episodic tension-type
      headache.
AB  - The aim of the study was to assess the efficacy and tolerability of a single oral
      dose of ketoprofen 25 mg in comparison with single doses of ketoprofen 2 x 25 mg,
      paracetamol 500 mg and 1,000 mg, and placebo in the treatment of episodic tension
      type headache. The study was conducted as a single centre, double-blind,
      randomized, placebo-controlled, five-period, within-patient comparative trial in
      outpatients with episodic tension-type headache according to the International
      Headache Society's diagnostic criteria. Each patient had to treat five attacks of
      episodic tension-type headache with a single dose of each of the tested
      medications with a minimum interval of 72 h between two attacks. Details of the
      attack and response to treatment were recorded on a diary card. Altogether 30
      patients treated 5 attacks and 2, 3, 1 and 4 patients treated 4, 3, 2 and 1
      attack, respectively. The primary variable was decrease in headache pain
      intensity from baseline to 2 h after intake, evaluated by means of a 100 mm
      visual analogue scale. Ketoprofen 50 mg was significantly better than placebo and
      paracetamol for this main criterion. Neither of the paracetamol groups differed
      from the placebo group. Only a few adverse events were reported, usually of mild
      or moderate severity, with no difference between the treatments. Ketoprofen 50 mg
      may be considered an effective and well tolerated analgesic in the treatment of
      episodic tension-type headache of moderate or severe intensity.

PMID- 8665579
TI  - Primary low cerebrospinal fluid pressure syndrome with galactorrhea: findings at
      MR imaging.
AB  - A case of primary low cerebrospinal fluid (CSF) pressure syndrome with
      galactorrhea is reported. Magnetic resonance imaging demonstrated diffusely
      enhanced meninges, edematous brain, and enlarged pituitary gland. Coincidental
      enlargement of pituitary gland and edematous brain due to low CSF pressure
      compressed the pituitary portal system. The low-perfused anterior lobe of
      pituitary gland would be the mechanism of galactorrhea.

PMID- 8665580
TI  - Pressure-controlled palpation.

PMID- 8665581
TI  - Idiopathic stabbing headache.

PMID- 8665582
TI  - Spreading depression.

PMID- 8665583
TI  - Tension headache.

PMID- 8665584
TI  - Migraine and tension-type headache in children and adolescents.

PMID- 8665585
TI  - Pattern-reversal VEP.

PMID- 8665586
TI  - Headache as an occupational illness in the treatise "De morbis artificum
      diatriba" of Bernardino Ramazzini.
AB  - The treatise "De morbis artificum diatriba" (Modena, 1700) is considered to be
      the first text to specifically deal with occupational illnesses. It was also the
      last for over 150 years. Written by Bernardino Ramazzini (Carpi, 1633-Padua,
      1714), a professor at the University of Padua from 1700 to 1714, the book
      highlights the importance given at the time to headache as an occupational
      symptom. Among the 69 professions described, accounting for the majority of the
      occupations of the period, 12 were found to lead to headache as an important
      symptom caused by work. Ramazzini appears to have paid more attention to this
      than we do today. Ramazzini's work opens up a wide view on social conditions in
      the 18th century, as his sensitivity for occupational hazards was exceptional.
      His remarks on headache are typical of his way of collecting first-hand
      experience of working conditions, and they underline the importance of
      occupational hazards in the assessment of headache, today just as in 1710.

PMID- 8665587
TI  - Inhalational anesthetics inhibit spreading depression: relevance to migraine.
AB  - Cortical spreading depression (SD) has not been shown in the human neocortex by
      direct cortical recordings. However, animal studies suggest that cortical injury,
      such as that occurring during neurosurgical procedures, should result in the
      initiation of SD. It is possible that inhibition of SD by volatile anesthetic
      agents may partially explain the failure to observe SD in the human neocortex
      during surgery. This study examines the effect of the anesthetic agents alpha
      chloralose, halothane, nitrous oxide and isoflurane on the initiation of cortical
      SD in the cat neocortex. SD was seen in 100% of cats anesthetized with alpha
      chloralose (n = 15), in 3 of 7 (42%) animals anesthetized with isoflurane (p <
      0.05, chi 2 with Yates correction) and none of the animals (n = 4, 6 hemispheric
      preparations) anesthetized with halothane (p < 0.005, chi 2 with Yates
      correction, halothane vs alpha-chloralose group). In all cases this inhibitory
      effect was reversible. In four animals the administration of nitrous oxide (66%)
      reduced the inspired concentration of isoflurane required to inhibit SD by 0.75%.
      This study suggests that halothane, and to a lesser extent isoflurane and nitrous
      oxide, protect against the initiation of cortical SD. This observation may
      partially explain why SD has not been demonstrated in human neocortex during
      surgery. Further studies are needed to determine if SD may occur under
      pathological conditions, such as during migraine with aura, where the cortex may
      be predisposed to SD.

PMID- 8665588
TI  - Idiopathic stabbing headache (jabs and jolts syndrome)
AB  - The clinical features of idiopathic stabbing headache ("jabs and jolts syndrome")
      were studied in 38 patients who were diagnosed throughout a 1-year period. Mean
      age at the onset of symptoms was 47.1 years +/- 14.5 (SD), and a clear female
      preponderance was demonstrated (female/male ratio = 6.6). Painful attacks were
      ultrashort, i.e. virtually all attacks in more than two thirds of cases lasted
      only one second. The frequency of attacks varied immensely, ranging from 1 attack
      per year to 50 attacks daily. The pain paroxysms usually occurred with an
      irregular or sporadic temporal pattern. The localization of painful attacks was
      reported frequently as unifocal, usually in the orbital area, but also multifocal
      patterns were observed, the attacks frequently changing location from one area to
      the next. The majority of attacks occurred spontaneously, and accompanying
      phenomena were reported only rarely. Indomethacin treatment (75 mg daily) seemed
      to have a complete or partial effect in most patients treated as such (n = 17).

PMID- 8665589
TI  - Muscular disorders in tension-type headache.
AB  - In order to evaluate the diagnostic criteria for muscular disorders in tension
      type headache, pericranial muscle tenderness and pressure pain thresholds were
      studied in a random sample population of 735 adults aged 25-64. In addition,
      quantitative EMGs were recorded in 547 of these subjects. The correlation between
      the three diagnostic tests was assessed and the discriminality and cut-off points
      were analysed using Receiver Operating Characteristics analysis. Local tenderness
      from the temporal muscles was closely related to the total tenderness scores from
      14 pairs of muscles. In chronic tension-type headache, tenderness was positively
      related to EMG and inversely related to pain thresholds. In the episodic from the
      total tenderness score was inversely related to pain thresholds, whereas no
      significant relation to EMG was noted. The Receiver Operating Characteristics
      curves indicated that tenderness recorded by manual palpation was the most
      specific and sensitive test, whereas EMG and pain thresholds were of limited
      diagnostic value. Eighty-seven percent of subjects with the chronic, and 66% of
      subjects with the episodic form were found to have a "muscular disorder" defined
      as increased tenderness recorded by either manual palpation or pressure algometry
      and/or increased EMG levels. However, muscle tenderness increased significantly
      during pain, so the headache state should be considered in future studies.
      Suggestions for revision of the present diagnostic criteria for muscular
      disorders are given.

PMID- 8665590
TI  - Dendritic cells in antitumor immune responses. I. Defective antigen presentation
      in tumor-bearing hosts.
AB  - Induction of specific antitumor cytotoxic T cell responses was studied in BALB/c
      mice bearing tumors transfected with a mutant human p53 minigene. We observed
      that mice were resistant to the induction of peptide-specific CTL as early as 5
      days after challenge with a minimal lethal dose of tumor cells, and the cell
      types responsible for this effect were further characterized. The contribution of
      CD4+ and CD8+ T cells in this response was studied after peptide-pulsed dendritic
      cell (DC) immunization. In vitro depletion of CD4+ cells during peptide
      restimulation reduced the level of specific lysis in control mice, and depletion
      of CD8+ T cells completely abrogated it. Substitution of CD8+ cells from
      immunized control mice during restimulation of cells from immunized tumor-bearing
      mice did not change the level of specific lysis. Substitution of the CD4+ from
      tumor-bearing mice by CD4+ cells from control mice improved CTL response,
      although this response did not reach control values. Peptide-pulsed dendritic
      cells isolated from tumor-bearing mice showed a significantly reduced ability to
      induce specific CTL in control animals and reduced ability to restimulate immune
      T cells from control mice in vitro. DC from tumor-bearing mice also had a reduced
      ability to stimulate control allogeneic T cells. Restimulation of T cells from
      immunized tumor-bearing mice with DC from control animals, but not from tumor
      bearing mice, dramatically increased specific CTL responses to control levels.
      Macrophages at the same concentration were not able to improve CTL function.
      Thus, defective antigen presentation by DC appears to be a major determinant for
      CTL nonresponsiveness to peptide antigens in tumor-bearing mice, and addition of
      control DC can restore specific lysis. These data provide a basis for new
      approaches to peptide-based cancer immunotherapy.

PMID- 8665592
TI  - [Nomenclature and classification of membrane receptors and the subtypes].
AB  - Present rapid growth of information about receptors for endogenous ligands and
      drugs requires changes in definitions, nomenclature and classifications of
      receptors and their subtypes. Receptors are defined as such membrane structures
      for which we have sufficiently reliable characterization of their structure,
      transducing mechanisms (mediation of intracellular effects), and selectively
      acting drugs (operational criterion). This characterization is based on the
      integrated approach to classification that relies on all three essential
      criteria. The current classification of membrane receptors is organized by
      International Union of Pharmacology Committee on Receptor Nomenclature and Drug
      Classification (NC-IUPHAR). Their conclusions about receptor classification are
      regularly published in pharmacological journals and in special publications. List
      of presently known membrane receptors and their subtypes is provided in this
      review.

PMID- 8665591
TI  - Dendritic cells in antitumor immune responses. II. Dendritic cells grown from
      bone marrow precursors, but not mature DC from tumor-bearing mice, are effective
      antigen carriers in the therapy of established tumors.
AB  - Antitumor CTL responses were studied in a model tumor hearing a mutant human p53
      gene. We found ineffective induction of antitumor CTL in mice bearing these
      tumors associated with measurable defects in the function of dendritic cells (DC)
      from these animals. In this study we investigate the mechanism of this defect in
      mature DC and find that functional DC can be generated by growth from the bone
      marrow of tumor-hearing animals. Tumor cell supernatants did not affect the
      function of mature DC obtained from the spleen of tumor-bearing animals, but
      significantly suppressed the ability to generate functional DC from the bone
      marrow of control mice in vitro. This suggests that tumor cells may release
      factors which block early stages of DC maturation from precursors. DC generated
      from the bone marrow of tumor-bearing mice showed normal potential to stimulate
      allogeneic T cells, to stimulate anti-mutant p53 peptide-specific cytotoxic T
      cells, and to induce anti-p53 CTL responses in vivo in control mice. Repeated
      immunization with peptide-pulsed DC generated from the bone marrow of control
      mice (every 4-5 days) blocked progression of established tumors. Immunization of
      mice with peptide-pulsed DC obtained from the spleen of tumor-bearing mice (4
      weeks after tumor injection) did not affect the tumor growth, whereas
      immunization with peptide-pulsed DC generated from bone marrow of tumor-bearing
      mice resulted in significantly prolonged survival and delayed tumor growth. Tumor
      progression was associated with change of the balance Th1/Th2 cells in favor of
      the Th2-like cytokine profile, while effective immunization was associated with a
      shift to the Th1 phenotype. Thus, frequent immunization of mice with mutant p53
      peptide-pulsed DC generated from stem cells of tumor-bearing hosts can induce
      effective antitumor CTL responses associated with production of Th1 cells and
      lead to significant antitumor effects.

PMID- 8665593
TI  - [Adrenergic receptors--nomenclature and classification of types and subtypes].
AB  - The purpose of this review is to present current knowledge regarding adrenergic
      receptors and their subtypes. These receptors belong to the superfamily of
      structures with seven transmembrane domains. They are coupled with G-regulatory
      proteins. Similarly to other membrane receptors, their division is based on three
      criteria: structural, transductional, and operational. At present, adrenergic
      receptors are divided into three main groups, depicted as alpha 1, alpha 2 a beta
      receptors. Receptors alpha 1 and alpha 2 are further divided into additional 4
      subtypes, which are marked with upper case subscripts A-D. Receptors beta are
      subdivided into three types, marked with subscripts 1-3. Classification of
      adrenergic receptors can be considered as a prototype for classification of other
      membrane receptors. The significance of all known receptor subtypes is not yet
      known. Multiple subtypes of adrenergic and also other receptor types exist
      simultaneously not only in one tissue but also frequently in a single cell where
      they can exert both synergistic as well as antagonistic effects. The discovery of
      functions and interactions of individual receptor subtypes represents a big
      challenge for future studies. Introduction of new selective agonists and
      antagonists not only helps to classify various receptor subtypes but it also has
      a big therapeutic potential.

PMID- 8665594
TI  - [Do the kidneys have a significant role in the pathogenesis of "essential"
      hypertension?].
AB  - The Prague Hypertensive Rat (PHR) is a model of genetic hypertension derived from
      the Wistar strain, in which a normotensive parallel, the Prague Normotensive Rat
      (PNR), was also bred from the same parent pair. Thus, it is possible to transfer
      organs between both parallels without signs of rejection and without the use of
      immunosuppressive drugs. Unilateral nephrectomy and transplantation of one kidney
      within the PHR and PNR groups did not affect the systolic blood pressure (SBP).
      Transplantation of one kidney from PNR to a bilateral nephrectomized (BNX) PHR
      normalized the high SBP; and transplantation of one kidney from PHR to BNX PNR
      led to an elevation of SBP: hypertension "travels" with the kidney. When the
      development of high SBP in PHR was prevented for 2 months after weaning by
      antihypertensive drugs, transplantation of one kidney from these rats to BNX PNR
      always induced a sustained hypertension in the recipient. If a PHR was left with
      one original kidney in situ after transplantation of a "normotensive" kidney, the
      high blood pressure persisted until the original "hypertensive" kidney was
      removed. These results support the view that the kidney of PHR produces a
      "hypertensinogenic" substance, the secretion of which is genetically determined
      and is not influenced by the magnitude of the SBP.

PMID- 8665595
TI  - [The carotid bodies--mechanisms of hypoxia detection].
AB  - The carotid body is a peripheral chemoreceptor monitoring arterial blood gas
      tension and pH and contributing to the regulation of breathing. The molecular
      mechanism of oxygen sensing is unknown. However, it is hypothesised that lowering
      of arterial oxygen tension detected by O2 sensitive K+ channels, evokes a
      selective inhibition of K+ current of glomus cells, with an increase of cellular
      excitability. Hydrogen peroxide production within the glomus cells may serve as a
      messenger which regulates potassium channels or gene expression.

PMID- 8665596
TI  - [Non-reflex activity of the CNS].
AB  - Recent studies of biological rhythms have modified Sherrington's concept of
      nervous system as exclusively reflexive to include the fact that some neural
      activity is also endogenously rhythmic. Reflexes are undoubtedly the most
      important components of animal's and human behavior. But are reflexes the basic
      units of all complex movements and acts? Rhythmical movements such as
      respiration, walking and running and other forms of locomotion, as well as
      rhythmical alimentary processes such as respiration, walking and running and
      other forms of locomotion, as well as rhythmical alimentary processes such as
      licking, mastication, and the peristaltic propulsion of nutrients and waste are
      examples of acts controlled by intrinsic oscillators, so called central pattern
      generators. Information from the periphery is, however, essential for controlling
      the extent and rate of movements. Between reflex and non-reflex activity it is
      possible to place complex species-specific responses called by ethologists fixed
      action patterns. Recent investigators have shown that many complex sequences of
      behavior like speech or piano playing are determined by an internal plan, rather
      than being generated by a "chain" of reflexes. Non-reflexive activity appears
      earlier in ontogeny, and is probably phylogenetically older than reflexes.

PMID- 8665597
TI  - [Reactive oxygen species and homeostasis].
AB  - Oxygen represents an important reactant which plays both positive and negative
      role in the metabolism. The deleterious effects are caused by the reactivity of
      substances originating in the partial reductions of their molecules. Therefore in
      the course of evolution many antioxidant systems have been developed, both
      enzymic and non-enzymic. The present review describes individual reactive oxygen
      species and the way of their detoxication in the organism. An important feature
      of antioxidant defence is its compartmentalization and cooperation between
      individual antioxidant systems which are described also with respect to their
      genetic encoding. For comparison properties of some artificial widely-used
      antioxidants are shown and their biological effects are discussed.

PMID- 8665598
TI  - [New findings on the pathogenesis of atherosclerosis].
AB  - The initial step in the process of atherosclerosis is supposed to be an increased
      penetration of lipoprotein particles (especially LDL or Lp(a)) into the
      subendothelial space. It occurs predominantly in regions with endothelial damage.
      After penetration into intima, LDL particles are oxidized. In endothelial cells,
      the incompletely oxidized LDL can induce expression of chemotactic factors which
      attract monocytes from circulation. Formation of adhesive molecules which enable
      immunocompetent cells to enter the subendothelial space can be simultaneously
      induced. As a response to stimulation induced by partially oxidized LDL,
      secretion of colony-forming factors is launched in endothelial cells. These
      factors induce monocyte to differentiate into macrophages. In subsequent
      oxidation, strongly oxidized LDL is formed. It is changed not only in the lipoid
      component but also in the structure of apolipoprotein B100 which brings about
      additional atherogenic properties. Another form of LDL particle modification is
      glycation. Absorption of large amounts of modified LDL particles by means of
      scavenger receptors or by phagocytosis of the lipoprotein complexes with antibody
      or proteoglycans, macrophages transform into foam cells which are typical for
      atherosclerotic lesions. In addition, activated macrophages secern various growth
      factors and cytokins stimulating vascular smooth muscle cells to migrate,
      proliferate and form extracellular matrix.

PMID- 8665608
TI  - [The basis for the variable effects of thyroid hormones].
AB  - Among physiological reactions of the organism, the multiplicity of action of
      thyroid hormones is a well known phenomenon. Thyroid hormones (TH) regulate
      activity of other hormones, receptors for bioactive signals, enzymes, and the
      function of ion channels. Until triiodothyronine has been identified as a ligand
      for oncoprotein c-erbA, this broad potency of actions has been mysterious. C-erbA
      has been recognized to be a transcription factor and an authentic thyroid hormone
      receptor. Important evidence comes from molecular studies, which have described
      isoforms of c-erbA and other members of intranuclear receptor family, their
      heterodimerization, thyroid hormone responsive elements in the target genes, and
      the existence of the cross-talk mechanism. Till present, much has been learned
      about TH transcription regulations in vitro. An open question remains whether
      this regulations are operative also in the intact organism.

PMID- 8665609
TI  - [Mechanisms of neuroplasticity].
AB  - Primary organization of the neuronal circuits is based on the genetic program. In
      addition, individual elements of these circuits are able to adjust their function
      and structure to the changes in external and internal conditions. In a given
      moment, formation and rearrangement of the neuronal circuits are based on the
      mutual cooperation between mechanisms assuring plasticity and rigidity.
      Plasticity is related not only to the development of the organism or to changes
      in the internal or external conditions, it may also reflect the progress of some
      pathological states or the recovery of an injured nervous structure.
      Intensification of the natural neuroplastic mechanisms or the introduction of an
      active (or activated) neuronal tissue into the impaired circuits might improve
      the process of recovery in the central nervous system.

PMID- 8665610
TI  - [Adhesive substances in medicine--history, present status and perspectives].
AB  - In the introduction to this study, present state of the progress of tissue
      adhesives and their use in medicine is discussed. Synthetic adhesives and the
      fibrin system are described. The advantages and disadvantages of both types of
      adhesive are compared. The bioadhesive systems used in medicine must meet certain
      requirements necessary for their application. The composition and preparation of
      the fibrin adhesives are analyzed in detail. Their effect on the regeneration of
      tissue cells and the level of histotoxicity are very important. The
      characteristics of the fibrin adhesive system result from its physiological
      origin. The filling of the wound with these adhesives improves the natural
      processes of healing.

PMID- 8665611
TI  - [The Tissucol Kit and the USOL fibrin preparation--comparison of qualitative and
      quantitative parameters].
AB  - The tissue adhesives used in medicine have to achieve certain requirements
      necessary for their application. The composition and preparation of the fibrin
      adhesives are analyzed in details. Our experience with our own modified
      application system is described. In the experimental section, the quantitative
      indicators of the foreign product Tissucol Kit are compared with samples of the
      fibrin product developed by USOL Olomouc and manufactured from the locally
      produced components. The samples of the USOL adhesive were similar to Tissucol in
      their composition and concentration.

PMID- 8665612
TI  - [Free radicals in the central nervous system].
AB  - Central nervous system has a low antioxidative capacity, which is formed mainly
      by ascorbic acid. Therefore the cerebral tissue is threatened by the increased
      formation of free radicals and their metabolites (ROS--reactive oxygen species).
      ROS are formed such as in reperfusion phase after ischemia and in catecholamine
      metabolism, in oxidative stress due to hyperglycaemia. Polyunsaturated fatty
      acids (PUFA) are peroxidased by ROS; proteins and DNK are damaged as well. Free
      radicals are involved in etiology and pathogenesis of many CNS diseases, such as
      neuritis, Alzheimer disease, Parkinson disease, Huntington disease, aging and
      atherosclerosis of the brain, epilepsy, etc. During the antioxidant therapy it is
      necessary to consider the types of ROS, their origin and their mode of action,
      whether to administer hydrophilic or lipophilic antioxidants, eventually chelate
      agents, etc. Hydrophylic antioxidants are acting very soon after the
      administration, whereas the lipophilic ones reach their target tissues with a
      great delay. Therefore it is better to apply them preferentially like a
      prevention, if possible. Enzymatic antioxidants (SOD, GSPHx and catalase and
      others) are usually acting only for a short time. The methods of estimation of
      free radicals attacks are discussed as well their possible pathophysiological
      effects.

PMID- 8665613
TI  - [Biocybernetics and physiology yesterday and today].
AB  - In the first part of the article authors characterize briefly the biocybernetics
      as a branch of science and substantiate why it should be considered as an
      integral constituent of biological sciences, and consequently of the physiology,
      too. In the second part they are paying attention to the reasons and policies for
      embodying selected biocybernetical subjects into the course of physiology.

PMID- 8665614
TI  - [History of physiology journals].
AB  - Two physiological journals were founded in Czechoslovakia in 1952, namely
      Ceskoslovenska fyziologie and an international version which was then named
      Cechoslovackaja fiziologija, later renamed Physiologia Bohemoslovaca. The first
      three volumes of the latter journal were published exclusively in Russian with
      German summaries. It was not until 1956 that most reports began to be published
      in English, with Russian summaries. In 1958, the content of both journals at last
      became separated. Cs. fyziol. started to publish review articles in Czech or
      Slovak, abstracts of communications reported at various scientific meetings, news
      from international symposia, etc. Physiol. Bohemoslov. continued to print the
      results of original experimental work. The major personality standing at the
      cradle of the two journals was Ernest Gutmann. Both journals were published by
      the Institute of Physiology of the Czechoslovak Academy of Sciences in Prague. In
      an attempt to make the latter journal more attractive to perspective authors from
      abroad, the international journal was renamed Physiological Research (formerly
      Physiologia Bohemoslovaca) in 1991 and still is being published by the same
      institution. It is indexed and abstracted by Current Contents, Excerpta
      Medica/Medline, Biological Abstracts, Chemical Abstracts, Current Awareness in
      Biological Sciences and Science Citation Index. A major change also occurred with
      the journal Ceskoslovenska fyziologie. This is now (since 1992) being published
      by the Czech Medical Society J.E. Purkyne. Besides publishing reviews intended as
      pregraduate and postdoctoral training for physiologists, physicians,
      pharmacologists and others working in allied fields of science, the journal
      informs members of the Czech and Slovak Physiological Societies about domestic
      and world news in physiology.

PMID- 8665615
TI  - Studies on the mechanism of hepatotoxicity of 4-methylphenol (p-cresol): effects
      of deuterium labeling and ring substitution.
AB  - We recently observed that 4-methylphenol (p-cresol) is toxic to rat liver tissue
      slices. A possible mechanism involves biotransformation of 4-methylphenol to a
      reactive quinone methide intermediate which covalently binds to cellular
      macromolecules and elicits cytotoxicity. In order to obtain further evidence for
      this proposed mechanism, we studied the effects of deuterium-labeled 4
      methylphenol (4-[alpha, alpha, alpha-d3]-methylphenol), and the presence of
      various ring substituents, on the metabolism and toxicity of 4-methylphenol in
      precision cut liver slices prepared from male Sprague-Dawley rats. Deuterium
      labeled 4-methylphenol was significantly less toxic than the parent compound in
      rat liver slices (LC50 = 3.36 vs. 1.31 mM, respectively). In addition, the
      deuterium-labeled compound was metabolized to a reactive intermediate (measured
      as glutathione conjugate formation) at a slower rate than that of 4-methylphenol
      in both liver slices and liver microsomal incubations. The presence of electron
      withdrawing substituents (2-chloro or 2-bromo) markedly enhanced both metabolism
      and toxicity, with the exception of 2,6-dibromocresol, which was similar to
      cresol in terms of rate of metabolism and toxicity. Conversely, the presence of
      electron donating substituents (2-methoxy, 2-methyl or 2,6-dimethyl) diminished
      metabolism and toxicity. In addition, methylation of the hydroxyl group to form 4
      methylanisole, greatly reduced toxicity. These results support the hypothesis
      that the toxicity of 4-methylphenol is dependent on the formation of a reactive
      quinone methide intermediate.

PMID- 8665616
TI  - A pharmacokinetic model of anaerobic in vitro carbon tetrachloride metabolism.
AB  - Carbon tetrachloride (CCl4) is a potent hepatotoxic agent whose toxicity is
      mediated through cytochome P450-dependent metabolism. Results from anaerobic in
      vitro experiments with hepatic microsomes isolated from male F-344 rats indicate
      that chlorofom (CHCl3) formation from CCl4 is nonlinear with dose. Dose is
      traditionally expressed as the amount of CCl4 added to the vial. In this study, a
      pharmacokinetic model has been developed to calculate the concentration of CCl4
      in the microsomal suspension. Hepatic microsomes prepared from fed and fasted
      animals were incubated with CCl4 under anaerobic conditions and formation of
      CHCl3 over a 5-min incubation period was monitored by headspace gas
      chromatography. Dose-response curves, based on total amount of CCl4 added to the
      microsomes, revealed a nonlinear, biphasic appearance of CHCl3, with fasting
      slightly increasing CHCl3 production in microsomes prepared from fasted rats.
      Microsomes were also pretreated with the CYP2E1 inhibitor, diallyl sulfone (DAS),
      before addition of CCl4. In uninhibited microsomes, there appeared to be a high
      affinity saturable phase of metabolism occurring at lower concentrations followed
      by a linear phase at higher CCl4 concentrations. Following DAS pretreatment, the
      saturable portion of the dose-response curve was inhibited more than the linear
      phase with the biphasic CHCl3 production becoming more linear. DAS inhibition
      eliminated the effect of fasting on CHCl3 formation. The best fit kinetic
      constants for the saturable phase resulted in an estimate of V(max) of 0.017
      mg/h/mg protein (V(maxc) = 7.61 mg/h/kg) and Km of 2.3 mg/l (15 microM). The
      linear phase rate constant (kf) was determined to be 0.046 h-1) (kfc = 0.03 h-1).
      In conclusion, a pharmacokinetic model has been developed for anaerobic in vitro
      metabolism of CCl4 to CHCl3 that estimates metabolic rates based on CHCl3
      formation and actual CCl4 concentration in the microsomal suspension.

PMID- 8665617
TI  - Organ-specific and transplacental DNA damage and its repair in rats treated with
      1,2-dibromo-3-chloropropane.
AB  - An in vivo genotoxicity assay system based on alkaline elution has been used to
      study the formation and removal of DNA damage induced by 1,2-dibromo-3
      chloropropane (DBCP). Cells/nuclei from different tissues and organs of Wistar
      rats were prepared by a rapid mincing/homogenization technique. Thirty-six
      samples of which up to 11 were from different organs of the same animal, were
      then assayed in parallel for DNA damage (DNA single-strand breaks plus alkali
      labile sites = SSBs) with a semi-automated alkaline elution system. A single i.p.
      injection of DBCP gave dose-(5 and 10 mg/kg) and time-(20 min-4 h) dependent SSBs
      in kidney and liver DNA from male rats. At 10 mg/kg DBCP, SSBs were formed in all
      organs examined except the bone marrow and colon; however, an increased dose of
      40 mg/kg produced SSBs also in the latter two organs. The relative
      susceptibilities to DBCP-induced DNA damage were: kidney approximately duodenum >
      liver > lung approximately brain approximately urinary bladder approximately
      glandular stomach > spleen approximately testis > bone marrow approximately
      colon. These relative levels correlate with previous data on tissue distribution
      and organ necrosis in liver, kidney and testis of rats given a single i.p. dose
      of DBCP. When female rats were injected i.p. with 5, 10 or 20 mg/kg
      (nonhepatotoxic doses) at day 20 of pregnancy, similar levels of SSBs were
      detected in the livers of the dam and the fetuses. In adult male rats, time
      dependent changes in SSBs were followed in the liver and kidney after DBCP
      exposure. In both organs SSBs peaked around 4 h post-exposure, 50% had been
      removed by 12-24 h, whereas at day 2-3 SSB frequencies had returned to control
      levels. Pretreatment of rats with phenobarbital prior to DBCP exposure reduced
      the maximum level of DNA damage as well as its persistence. In cultured primary
      hepatocytes from male rats exposed in vitro to DBCP (2-20 microM. 1 h), 50% of
      the initial DNA damage had been repaired within approximately 100 min. In
      conclusion, the experiments indicate that the distribution characteristics of
      DBCP are of major importance for DNA damage and its persistence in various organs
      of rats. The data are also in accordance with glutathione-S-transferase, rather
      than P450, being the most important pathway for metabolic activation of DBCP in
      rat extrahepatic tissues including the fetal liver. It appears that alkaline
      elution of cells/nuclei prepared from exposed animals constitutes a sensitive,
      rapid and versatile technique to study organ- and cell-specific genotoxicity in
      vivo.

PMID- 8665618
TI  - Spectral shape modifications of anthracyclines bound to cell nuclei: a
      microspectrofluorometric study.
AB  - Anthracyclines remain today the medications of choice against a wide spectrum of
      human cancers. Anthracyclines are fluorescent molecules and microfluorimetric
      methods are often used to determine their cellular distribution. The use of
      microspectrofluorometric techniques yields additional information because not
      only the fluorescence intensity but also the spectral modifications of the
      chromophore can be used to assess the intracellular drug concentration, its
      localisation and also eventually its metabolisation. It is well-documented that
      the shape of the fluorescence spectrum of anthracyclines changes markedly with
      the hydrophobicity of their environment. This change can be quantitatively
      measured by the ratio rho of the fluorescence emission intensities at 560 and 590
      nm. We have observed that the shape of the fluorescent spectrum of adriamycin,
      daunorubicin and 4'-O-tetrahydropyranyladriamycin recorded from a small volume
      inside the cell nucleus was strongly dependent on the drug concentration and that
      the rho value decreases as the drug concentration increases. These data were
      compared with the rho variations when the drugs were either dissolved in
      different solvents or intercalated between the base pairs of DNA. We arrived at
      the conclusion that the shape variation of the drug spectra was not due to a
      change in their hydrophobicity environment but to an excitonic coupling of the
      electric dipolar transition moments of the pi --> pi* transition.

PMID- 8665619
TI  - Radiation-induced neoplastic transformation of stationary phase C3H/10T1/2 cells
      in response to different dose rates and to post-irradiation treatment with tumor
      promoter.
AB  - The induction of neoplastic transformation by exposure to high (HDR, 0.66 Gy/min)
      or very low (LDR, 4.8 x 10(-4) Gy/min) dose rates of 137Cs gamma-rays was studied
      in C3H/10T1/2 mouse embryo fibroblasts. Cells in stationary phase were exposed in
      the dose range 1-6 Gy in combination with a post-irradiation treatment with the
      tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). The post-irradiation
      treatment with TPA during 6 weeks of transformation assay did not induce any
      notable increase in the slope of the dose response curves for transformation
      frequency, compared to the conditions without TPA treatment. The lack of an
      enhancing TPA effect at both dose rates applied in this study may be related to
      the fact that the cells were irradiated in the stationary growth phase. Thus, the
      results differ from those generally obtained when exponentially growing cells are
      exposed to gamma-rays and afterwards treated with TPA in the transformation
      assay. Earlier studies of exponentially growing C3H/10T1/2 cells exposed to
      different dose rates show a significantly higher transformation frequency for
      high dose rate. This study, using stationary phase cells, also shows that the
      slopes of dose response curves for transformed foci were somewhat higher (about
      1.5-fold) for HDR exposure compared with LDR exposure. However, the difference
      was not statistically significant.

PMID- 8665620
TI  - [Semantic history: interdependence in the land of dementia].

PMID- 8665621
TI  - [Resistance to chemotherapy: current therapeutic approach].

PMID- 8665623
TI  - [Drug monitoring].

PMID- 8665622
TI  - [Biochemistry and medical value of NO. Physiology and physiopathology of nitric
      oxide].
AB  - The metabolism of nitric oxide (NO) and its derivatives has the advantage of
      ubiquitarian distribution and these compounds have multiple biological effects.
      The way of synthesis is simple and this biochemistry produces many variable
      products in normal physiological conditions. The way of synthesis is simple and
      this biochemistry produces many variable products in normal physiological
      conditions. The way of transportation and the pH (giving a particular redox
      condition) determine its half-life, the function of the molecule and its
      transmitted message. The advantage of the general distribution of this synthesis
      is probably a disadvantage in pharmacological approaches. Drugs which will
      increase or decrease the NO production have to act in a very precise location in
      a complex physiology so as not to produce more adverse side-effects in another
      location than benefit effects on the target. This review is a synthesis of the
      physiology and pathology of this biological information transmitting system.

PMID- 8665624
TI  - [Importance and value of drug monitoring in medical practice].

PMID- 8665625
TI  - [Tendinopathies and fluoroquinolones: a public health problem? Value of drug
      monitoring studies].

PMID- 8665626
TI  - [The practice of drug monitoring in the Lorraine Regional Center of Drug
      Monitoring (CRPV)].

PMID- 8665627
TI  - [Drug monitoring in the Grand Duchy of Luxembourg and in the European Community
      in 1995].

PMID- 8665628
TI  - [Perversion and psychiatry].

PMID- 8665629
TI  - Continuous epidural infusion of ropivacaine for the prevention of postoperative
      pain after major orthopaedic surgery: a dose-finding study.
AB  - PURPOSE: A dose-finding study to investigate the use of epidural infusions of
      ropivacaine for postoperative analgesia following orthopaedic surgery. METHODS:
      This was a randomized, double-blind study. Surgery was performed using a
      combination of a lumbar epidural block utilizing ropivacaine 0.5% and a
      standardized general anaesthetic. Postoperatively, an epidural infusion of the
      study solution (saline, ropivacaine 0.1%, 0.2% or 0.3%) was started at the rate
      of 10 ml.hr-1 and continued for 21 hr after arrival in the PACU. Analgesia was
      supplemented with PCA morphine (dose = 1.0 mg, lock-out = 5 min). RESULTS: Forty
      four patients completed the study. The ropivacaine 0.1%, 0.2%, 0.3% groups
      required less morphine over the 21 hr than the saline group (P < 0.01). The VAS
      pain scores were also lower in the three ropivacaine groups (P < 0.001). The
      ropivacaine groups maintained sensory anaesthesia to pinprick when compared with
      saline (P < 0.05). The motor block in the 0.3% group was significantly higher
      than the saline group at all times (P < 0.05), and higher than the 0.1% group at
      eight hours (P < 0.01), while the 0.2% group had higher Bromage scores than
      saline at 4 and 21 hr (P < 0.05). CONCLUSIONS: The use of continuous epidural
      infusions of ropivacaine 0.1%, 0.2% and 0.3% at 10 ml.hr-1 improved postoperative
      pain relief and decreased PCA morphine requirements in patients undergoing major
      orthopaedic surgery. The 0.1% and 0.2% concentrations produced similar sensory
      anaesthesia with less motor blockade than the 0.3% concentration.

PMID- 8665631
TI  - The incidence of airway problems depends on the definition used.
AB  - PURPOSE: Definitions currently used to describe airway difficulties are
      confusing, inconsistent, and may be misleading. To understand the "extent of the
      problem" better using three different definitions we examined the corresponding
      rates of airway difficulty in 3,325 consecutive adult patients who had direct
      laryngoscopy with tracheal intubation following induction of general anaesthesia.
      METHODS: Definitions were (i) poor view at laryngoscopy (GRADE 3-4) documented on
      modified diagrams of Cormack and Lehane; (ii) > or = 3 laryngoscopy attempts; and
      (iii) failure of direct laryngoscopy. The incidences of airway difficulty
      attributable to each definition were compared. RESULTS: For the three definitions
      rates varied, 10.1% for poor view, 1.9% > or = 3 laryngoscopies, and failure
      0.1%. For patients with a GRADE 3-4 view, 15.8% required > or = 3 laryngoscopies,
      but for those with > or = 3 laryngoscopies, 84.1% had GRADE 3-4 view. All
      patients with failed laryngoscopy had > or = 3 laryngoscopies and a GRADE 4 view.
      CONCLUSION: This wide variation in defining the "extent of the problem"
      emphasizes the need for agreement of definitions and improved methods to document
      airway difficulties.

PMID- 8665630
TI  - A comparison of the haemodynamic effects of intrathecal meperidine, meperidine
      bupivacaine mixture and hyperbaric bupivacaine.
AB  - PURPOSE: To study the haemodynamic effects of intrathecal meperidine,
      administered either alone or mixed with bupivacaine. METHODS: We studied 42
      Chinese patients, aged 59-87 yr, scheduled for transurethral bladder or prostate
      surgery, randomized into three equals groups, that received either meperidine 0.8
      mg.kg-1, meperidine 0.4 mg.kg-1 plus 1.5 ml of 0.5% heavy bupivacaine or 3 ml of
      heavy bupivacaine 0.5%. Non-invasive systolic (SAP) and mean (MAP) arterial
      pressures, central venous pressure and cardiac index, stroke index and heart rate
      (HR) measured by the BoMed NCCOM3-R7S bioimpedance device, were recorded over the
      first 25 min. Systemic vascular resistance index (SVRI) was derived. Onset of
      sensory and motor block was also measured. Decreases in MAP of 25% were treated
      with colloid and metaraminol. RESULTS: The onset of block was slower in the
      meperidine group (P < 0.05). Decreases in SAP, MAP and SVRI (all; P < 0.001)
      occurred within five minutes in all three groups. The HR was increased in the
      bupivacaine group (P = 0.03), but bradycardias treated with atropine occurred in
      six patients receiving meperidine and four patients receiving the mixture. Six
      patients receiving meperidine and two patients receiving the mixture required
      general anaesthesia for inadequate block. The incidence of nausea and vomiting
      was higher in the patients receiving meperidine (P < 0.05). No other
      complications were encountered. CONCLUSIONS: Intrathecal meperidine used alone or
      mixed with bupivacaine has no intra-operative advantage over heavy bupivacaine
      0.5%.

PMID- 8665632
TI  - Granisetron reduces vomiting after strabismus surgery and tonsillectomy in
      children.
AB  - PURPOSE: To evaluate the antiemetic efficacy of granisetron, a selective 5
      hydroxytryptamine type 3 receptor antagonist, on postoperative vomiting in
      children undergoing general anaesthesia for strabismus repair and tonsillectomy
      with or without adenoidectomy. METHODS: In a randomized, placebo-controlled,
      double-blind study, fifty patients, 4-10 yr of age, were given a single dose of
      either placebo (saline, n = 25) or granisetron (40 micrograms.kg-1, n = 25) iv
      over 2-5 min after the induction of anaesthesia and prior to the surgical
      procedure. Postoperatively, during the first 24 hr after anaesthesia, the
      frequencies of retching and vomiting were recorded. RESULTS: There were no
      differences between the two groups with regard to patient characteristics,
      surgical procedures and anaesthetic or postoperative management. The incidence of
      retching was 36% and 12% after administration of placebo or granisetron,
      respectively (P < 0.05); the corresponding frequencies of vomiting were 32% and
      8% (P < 0.05). Four children who had received placebo required another rescue
      antiemetic drug, whereas none who had received granisetron needed this agent.
      CONCLUSION: Granisetron is effective in the prevention of retching and vomiting
      after strabismus repair and tonsillectomy in paediatric patients.

PMID- 8665633
TI  - Differential effects of propofol, thiamylal and ketamine on the cricothyroid and
      posterior cricoarytenoid muscles of the canine larynx.
AB  - PURPOSE: To measure the electromyographic (EMG) responses of the phasic discharge
      in the cricothyroid (CT; a tensor muscle of the vocal folds) and the posterior
      cricoarytenoid (PCA; sole abductor muscle of the vocal folds) following
      intravenous infusion of propofol 1.0 mg.kg-1.min-1, thiamylal 1.0 mg.kg-1.min-1,
      or ketamine 0.5 mg.kg-1.min-1 for five minutes. DESIGN: Prospective,
      nonrandomized, controlled animal study. SETTING: University research laboratory.
      SUBJECTS: Fifteen mongrel dogs, including three groups of five animals in each
      group. INTERVENTIONS: Under 0.2-0.3% halothane and oxygen anesthesia with
      spontaneous ventilation, phasic EMG activities of the CT and PCA muscles were
      recorded in an identical manner after the administration of each drug.
      MEASUREMENTS AND MAIN RESULTS: Propofol infusion produced almost equal
      suppression of EMG activity of the CT and the PCA with time and three minutes
      after the start of infusion of propofol there was a significant depression of the
      phasic activities in the both muscles; EMG activity of the CT and the PCA was
      33.8 +/- 21.2 and 36.6 +/- 22.9% (% of control, mean +/- SD) respectively P <
      0.05). Thiamylal selectively reduced rhythmic discharges in the CT muscle during
      spontaneous breathing and significant depression of discharge in the CT muscle
      was observed three minutes after the drug (47.3 +/- 24.9%, P < 0.05). In
      contrast, both phasic EMG activities of the CT and the PCA were rhythmically
      active and the differential sensitivity between the CT and the PCA muscles was
      not observed after ketamine, even after ten minutes of administration.
      CONCLUSIONS: This study confirms a difference in sensitivity between the CT and
      the PCA muscles, demonstrating that the intrinsic laryngeal muscles do not behave
      similarly after the administration of conventional intravenous anaesthetic
      agents.

PMID- 8665634
TI  - Anaesthesia drug costs and utilization--time for a critical re-appraisal.

PMID- 8665635
TI  - Distribution of diaphragm blood flow during sevoflurane anaesthesia in dogs.
AB  - PURPOSE: The purpose of this study was to determine the effect of increasing the
      concentrations of sevoflurane anaesthesia on the distribution of diaphragm blood
      flow (Qdi) in ten dogs during mechanical ventilation. METHODS: Animals were
      divided into two groups, sevoflurane (n = 6) and time control (n = 4) groups.
      Blood flow to the crural and the costal diaphragm (Qcru, Qcost) was determined by
      the hydrogen clearance technique at 0, 0.5, 1.0 and 1.5 minimum alveolar
      concentration (MAC) of sevoflurane after a 30 min period of steady-state
      conditions. Cardiac output (CO) and the mean arterial blood pressure (MBP) were
      also measured. RESULTS: Sevoflurane anaesthesia caused a reduction in CO (L.min
      1) from a control value of 1.51 +/- 0.21 to 1.38 +/- 0.1 (0.5 MAC), 1.09 +/- 0.15
      (1.0 MAC) and 0.98 +/- 0.12 (1.5 MAC) (Mean +/- SD). Mean blood pressure, Qcru
      and Qcost also decreased with increasing depth of anaesthesia. In addition, the
      decrease of Qcru was greater than that of Qcost at all levels of MBP and CO. No
      change occurred in these variables in the time control group. CONCLUSION:
      Sevoflurane anaesthesia changes the distribution of Qdi with a greater reduction
      occurring in Qcru than in Qcost.

PMID- 8665636
TI  - Cardiac implications of amlodipine-dantrolene combinations.
AB  - PURPOSE: Cardiac disorders, cardiac arrest and ventricular fibrillation in the
      most severe cases, have been observed after the administration of dantrolene to
      patients treated by verapamil for coronary artery disease. This study was
      designed to examine the interaction of dantrolene with amlodipine, a
      dihydropyridine. METHODS: In 12 anaesthetized, open-chest pigs, the effects of
      the interaction have been studied on heart rate, atrioventricular conduction,
      monophasic action potential duration, intraventricular conduction time, left
      ventricular dP/dt max and mean blood pressure. The study was performed with
      normal coronary circulation and ischaemia of a large area of the left ventricule,
      obtained by complete occlusion of the left anterior descending coronary artery
      near its origin, under pacing at a constant high rate, 180 beats.min-1. The drugs
      were injected iv, amlodipine 0.4 mg.kg-1 first and dantrolene 3.0 mg.kg-1 20 min
      later in six animals and the order was reversed in the other animals. RESULTS:
      Sinus rate and atrioventricular conduction were not affected by amlodipine, but
      were slowed by dantrolene added (145 +/- 9 to 131 +/- 7 beats.min-1, P < 0.01 and
      150 +/- 15 to 180 +/- 20 msec, P < 0.01). In contrast, amlodipine or amlodipine
      plus dantrolene did not change MAP duration or conduction time in the normal
      heart. Similarly, they did not alter the maximal variations due to ischaemia, but
      delayed them, while prolonging the time to onset of fibrillation (111 +/- 8 to
      343 +/- 33 sec. P < 0.001 with amlodipine alone, 289 +/- 11 to 323 +/- 16 sec, P
      < 0.05 with dantrolene). Left ventricular dP/dt max was lowered from 1670 +/- 86
      to 1532 +/- 50 mmHg.sec-1 (P < 0.001) and mean blood pressure from 79 +/- 4 to 70
      +/- 3 mmHg (P < 0.01) by amlodipine, but dantrolene did not enhance and even
      counteracted these effects. Finally, potassium plasma concentration did not
      increase above 5.1 +/- 0.2 mmol.L-1 under the dual influence of amlodipine and
      dantrolene. CONCLUSION: In usual clinical doses, dantrolene may be safely
      administered concurrently with amlodipine.

PMID- 8665638
TI  - Ankylosing spondylitis and neuraxial anaesthesia--a 10 year review.
AB  - PURPOSE: Ankylosing Spondylitis (AS) patients present specific challenges to the
      anaesthetist. Both airway management and neuraxial access may prove to be
      difficult. The trend has been to deal with the airway challenge, and avoid
      neuraxial anaesthesia. In many cases this may lead to unnecessarily denying the
      patient neuraxial anesthesia (NA). We retrospectively reviewed the operative
      anaesthetic management of 51 consecutive AS patients who underwent 82 perineal or
      lower limb procedures and concurrent anaesthetic management at the Vancouver
      Hospital and Health Sciences Center from 1984 through 1994 (inclusive). SOURCE:
      Anaesthetic records were used to document the type of anaesthetic used, i.e.,
      general or regional, and the degree of difficulty experienced with each.
      PRINCIPAL FINDINGS: Of the 82 procedures performed on AS patients 16 (19.5%) were
      planned as NA. General anaesthesia (GA) was planned for 65 (79.3%) of the
      procedures. One procedure involved monitored anaesthetic care (MAC). Neuraxial
      access consisted of 13 spinal and three epidural attempts. Spinal anaesthesia was
      possible in 10 (76.2%) of cases and failed in 3 (23.8%). Epidural anaesthesia was
      unsuccessful in each attempt. There was no difference in demographics or duration
      of disease between the successes and failures. CONCLUSIONS: These data suggest
      that spinal anaesthesia can be used as an alternative to general anaesthesia in
      AS patients undergoing perineal or lower limb surgery. There were no factors
      identified in this review that were predictive of success or failure in gaining
      neuraxial access.

PMID- 8665637
TI  - Hysteroscopy and anaesthesia.
AB  - PURPOSE AND SOURCE: Hysteroscopy has become a widely accepted technique in the
      diagnosis and treatment of various gynaecological conditions. The advent of the
      fibreoptic endoscope and distending media has largely been responsible for the
      increasing use of hysteroscopy. It is our aim in this article to review the
      literature on the frequently used distending media such as carbon dioxide,
      glycine, dextran, dextrose, sorbitol and mannitol and their anaesthetic
      implications. PRINCIPAL FINDINGS: The endoscopist chooses the particular medium.
      Complications due to the distending media occur in < 4% of cases. Dilutional
      hyponatraemia and hypothermia are commonly encountered complications and, in
      addition, hyperglycaemia and volume expansion can occur. Less commonly
      encountered complications are embolism with carbon dioxide and pulmonary oedema,
      renal failure and in rare cases anaphylaxis and encephalopathy. Regional
      anaesthesia may offer an advantage over general anaesthesia in early recognition
      of fluid accumulation. Apropriate monitoring should include fluid balance,
      routine monitoring as well as temperature, electrolytes and blood sugar
      measurements. Precordial Doppler measurement, central venous and/or pulmonary
      artery pressure measurement may be of help in detecting as well as treating
      carbon dioxide and/or air embolism and fluid balance in high risk patients.
      CONCLUSIONS: There is no one commonly used medium and no one medium is devoid of
      complications. There have been no controlled studies comparing different
      anaesthetic techniques. Positioning of the patient can give rise to complications
      such as peripheral neuropathy. Hysteroscopy is a non invasive procedure which
      entails a short hospital course with minimal postoperative sequelae and may be
      cost saving.

PMID- 8665639
TI  - Continuous caudal anaesthesia with chloroprocaine as an adjunct to general
      anaesthesia in neonates.
AB  - PURPOSE: The authors prospectively evaluated the use of a continuous caudal
      epidural infusion of chloroprocaine as an adjunct to general anaesthesia during
      intra-abdominal surgery in neonates. CLINICAL FEATURES: The technique was used in
      25 neonates ranging in age from 1 to 28 days and in weight from 2.2 to 4.9 kg.
      Following anaesthetic induction and tracheal intubation, an initial bolus dose of
      chloroprocaine 3% (1 or 1.5 ml.kg-1) was followed by a continuous infusion of 1
      or 1.5 ml.kg-1.hr-1 administered through a caudal epidural catheter. No
      parenteral opioids were administered. The duration of the surgical procedures
      varied from one hour five minutes to three hours 15 min. The first three neonates
      received a bolus dose of 1.0 ml.kg-1 followed by an infusion of 1.0 ml.kg-1.hr-1
      chloroprocaine 3%. These three neonates required an additional bolus dose
      followed by an increase in the infusion to 1.5 ml.kg-1.hr-1 to provide surgical
      anaesthesia. Adequate intraoperative anaesthesia was achieved in all 25 neonates
      with an infusion of 1.5 ml.kg-1.hr-1 of chloroprocaine 3%. This was evidenced by
      a lack of haemodynamic response to surgical manipulation. No neonate required
      more than 0.2% isoflurane or 70% nitrous oxide in oxygen. No episodes of
      haemodynamic instability (decreased blood pressure/bradycardia) related to the
      caudal epidural anaesthesia were noted. Twenty-three of 25 of the neonates'
      tracheas were extubated immediately (within 10 minutes) following the surgical
      procedure. CONCLUSIONS: Caudal anaesthesia with a continuous infusion of
      chloroprocaine can be used as an adjunct to general anaesthesia during abdominal
      surgery in neonates. Our initial experience suggests that the combined technique
      may eliminate the need for parenteral opioids and limit the intraoperative
      requirements for inhalational anaesthetic agents.

PMID- 8665640
TI  - Bronchoscopic findings in post-obstructive pulmonary oedema.
AB  - PURPOSE: To present the first photographed bronchoscopic findings associated with
      negative pressure pulmonary oedema (NPPE). CLINICAL FEATURES: A previously
      healthy patient underwent anterior C3-C4 disc removal and arthrodesis. Following
      tracheal extubation he developed acute respiratory distress manifested as
      stridor, tachypnoea, restlessness, and desaturation. Once the trachea was
      reintubated, he displayed the classic findings of pulmonary oedema. Bronchoscopy
      was performed to confirm tracheal tube position and to rule out tracheal injury
      secondary to surgical manipulation. Diffuse punctate haemorrhages were noted
      throughout the visualised tracheobronchial tree. CONCLUSION: We believe that
      these haemorrhages represent disruption of the bronchial vasculature and may
      contribute to the clinical presentation of NPPE.

PMID- 8665641
TI  - Acute ventilatory complications during laparoscopic upper abdominal surgery.
AB  - PURPOSE: This article examines and summarizes the published reports dealing with
      subcutaneous emphysema, pneumothorax and carbon dioxide (CO2) embolism during
      laparoscopic upper abdominal surgery. The purpose is to describe the expected
      clinical picture, the differential diagnosis and the management of these
      complications. SOURCE: The information was obtained from a Medline literature
      search and the annual meeting supplements of Anesthesiology, Anesth Analg, Br J
      Anaesth and Can J Anaesth. PRINCIPAL FINDINGS: An abrupt increase in PETCO2 is
      the first sign of subcutaneous emphysema and of pneumothorax. Desaturation and
      increased airway pressure occur with pneumothorax, but not with subcutaneous
      emphysema alone. Desaturation and increased airway pressure also occur with
      bronchial intubation. The preliminary diagnosis is made by verifying the position
      of the tube, examination of the patient for swelling and crepitus and
      auscultation for air entry. Chest radiography and paracentesis confirm the
      diagnosis of pneumothorax, which frequently occurs with subcutaneous emphysema
      but is rarely of the tension type. Pulmonary embolism due to CO2 during LUAS has
      not been reported, but the available data suggest that small, haemodynamically
      inconsequential CO2 embolism occurs without change in PETCO2. Massive embolism is
      possible and will markedly decrease PETCO2, arterial O2 saturation (SpO2) and
      blood pressure. CONCLUSION: The immediate recognition of the three complications
      requires continuous monitoring of PETCO2, arterial saturation, airway pressure,
      and an index of pulmonary compliance.

PMID- 8665642
TI  - Anaesthetic management of a patient with myasthenia gravis and tracheal stenosis.
AB  - PURPOSE: The combination of myasthenia gravis and tracheal obstruction presents a
      number of difficulties for anaesthetic management. This case illustrates the
      advantages of careful planning. CLINICAL FEATURES: A 66-yr-old man with
      myasthenia gravis required resection of a stenosis at the site of an old
      tracheostomy. The primary goal was to accomplish safe management of the airway, a
      task made more difficult because the airway was shared with the surgeon. Awake
      fibreoptic examination of the tracheal stenosis performed in the operating room
      provided useful information in planning the subsequent anaesthetic. From this
      examination, it was found that the trachea could be intubated by a normal
      endotracheal tube passed through the stenosis over the fibreoptic bronchoscope.
      Intraoperatively, the orotracheal tube was withdrawn temporarily and replaced
      with an endotracheal tube placed by the surgeon into the distal trachea.
      Extubation was carried out judiciously and a plan for reintubation prepared in
      advance. The anaesthetic plan was modified because of the myasthenia gravis.
      Following careful investigation of the extent of the patient's disease and its
      treatment, an assessment was made of the patient's need for postoperative
      ventilation. The anaesthetic plan included maintenance of anticholinergic
      medications until the time of surgery and their early resumption postoperatively,
      avoidance of neuromuscular blocking agents, and careful monitoring of
      neuromuscular function during the anaesthetic. CONCLUSION: Careful examination of
      the area of tracheal stenosis and a carefully considered plan for reintubation
      are prerequisites for this type of surgery. Clinically well controlled myasthenia
      gravis was managed successfully using familiar principles.

PMID- 8665643
TI  - Anaesthesia drug cost, control and utilization in Canada.
AB  - PURPOSE: To investigate the attitudes of senior anaesthetists toward issues of
      anaesthesia drug cost control, utilization, and education, and to determine
      patterns of drug use of common clinical scenarios. METHODS: A questionnaire
      mailed to heads of anaesthesia departments in all large (> 200 beds) Canadian
      hospitals (n = 187). Data were analyzed with chi-square and t tests; P < 0.05 was
      considered significant. RESULTS: Sixty-eight per cent responded to the
      questionnaire. Ninety-four per cent considered cost when choosing anaesthetic
      agents, 63.7% indicated cheaper drugs could be used without decreasing quality of
      care, and 46.3% that restricted access to expensive agents was justified. Only
      32.8% of hospitals currently imposed restrictions. Departmental practice
      guidelines were favoured by 82.1% of respondents. Fifty-three per cent considered
      resident education about drug cost to be inadequate, and 57.4% indicated that
      resident teaching justified the use of expensive agents. Most respondents (69.8
      96.8%) felt they knew the cost of commonly used agents, many made considerable
      use of cheaper agents such as halothane, curare and morphine, and 61% re-used
      syringes containing residual drug. A few differences between teaching and non
      teaching hospitals anaesthetists were identified. CONCLUSIONS: These
      anaesthetists demonstrated awareness of pharmacoeconomic issues, believed that
      cheaper anaesthetic agents could be used without compromising quality of care,
      identified few hospitals with policies that restricted drug use, and indicated
      drug cost education could be improved. Control and responsibility of drug
      utilization were shared within their hospitals. Many approved the idea of
      practice guidelines. In common clinical scenarios cheaper agents were preferred
      and syringe re-use was surprisingly common.

PMID- 8665644
TI  - The use of an endotracheal ventilation catheter in the management of difficult
      extubations.
AB  - PURPOSE: To describe the clinical experience with a new device, designed to
      maintain airway access following tracheal extubation. FEATURES: The endotracheal
      ventilation catheter (ETVC) is a semi-rigid polyurethane catheter with a distal
      hole and side-holes. A proximal connector permits attachment to a high pressure
      gas source for jet ventilation. Such a device can be introduced through an
      existing endotracheal tube, prior to its removal, and then used as stylet to
      facilitate reintubation. In 202 consecutive patients, the main use was to
      maintain airway access for up to 72 hr. It was well tolerated and associated with
      a high probability of successful reintubation even when the glottis cannot be
      visualised. CONCLUSION: The ETVC is a safe and effective means of maintaining
      airway access after tracheal extubation, even when the glottis cannot be
      visualized.

PMID- 8665645
TI  - Anterior epidural haematoma following subarachnoid block.

PMID- 8665646
TI  - Acute transient unilateral macroglossia following use of a LMA.

PMID- 8665647
TI  - A combination of low dose spinal and general anaesthesia for laparoscopic
      cholecystectomy.

PMID- 8665648
TI  - An ounce of prevention...

PMID- 8665649
TI  - Physician job satisfaction: reversing the decline.

PMID- 8665650
TI  - Cardiovascular disease in renal failure: risk assessment, screening, treatment.

PMID- 8665651
TI  - Commentary on the new Guide to Clinical Preventive Services.

PMID- 8665652
TI  - A 59-year-old man with mouth pain.

PMID- 8665653
TI  - Individualizing the treatment of gout.
AB  - Treatment for gouty arthritis should be individualized to address the patient's
      other medical problems and the likelihood that gout will become chronic. We
      present a typical case and review the options, explaining their utility for this
      and other patients.

PMID- 8665654
TI  - Idiopathic hypoparathyroidism in a blind, deaf, elderly woman with dementia.

PMID- 8665655
TI  - The injured worker: assessing "return-to-work" status.
AB  - In workers injured on the job, the physical findings tell only part of the story.
      Physicians must also consider psychologic, economic, social, and legal factors
      when performing a return-to-work assessment.

PMID- 8665656
TI  - Recognizing and treating new and emerging infections encountered in everyday
      practice.
AB  - Although infectious diseases were once considered a diminishing threat, new
      pathogens are constantly challenging the health care system. This article reviews
      the clinical presentation, diagnosis, and treatment of seven emerging infections
      that primary care physicians are likely to encounter.

PMID- 8665657
TI  - Shark cartilage: the Laetrile of the 1990s.

PMID- 8665658
TI  - The clinical role of platelet glycoprotein IIb/IIIa receptor inhibitors in
      ischemic heart disease.
AB  - The platelet glycoprotein (GP) IIb/IIIa receptor antagonists are powerful new
      antiplatelet drugs that show promise in reducing complications of coronary
      angioplasty and acute coronary syndromes.

PMID- 8665659
TI  - Maternal hormonal manipulations in rats cause obesity and increase medial
      hypothalamic norepinephrine release in male offspring.
AB  - In previous work it has been shown that adult male, but not female, offspring of
      rats that have either been injected with Protamine Zinc Insulin on days 15-20
      gestation, or undernourished during the first 2 weeks of gestation, develop
      significant obesity commencing at about 50 days of age. The present experiment
      examines the question of whether rats with these two forms of obesity display
      neurochemical abnormalities in areas of the brain known to influence food intake
      and body weight. Twenty-one gauge stainless steel guide shafts were surgically
      implanted using standard stereotaxic procedures. One week later 26 ga
      microdialysis probes were lowered into the medial hypothalamus. Dialysates
      collected from male offspring in the two experimental conditions contain
      significantly higher norepinephrine (NE) levels than did controls. It would
      appear that in addition to sharing a similar time course of onset and a sex
      dependent expression of obesity, both of these models are also characterized by
      elevated medial hypothalamic NE. Since this obesity appears only in males, and at
      a time when testosterone levels are rapidly rising in males, and since
      testosterone has been shown to elevate food intake and body weights in rats, we
      also investigated whether gonadal weights or circulating testosterone levels were
      differentially elevated by our manipulations.

PMID- 8665660
TI  - Late loss of connections during callosal development in Siamese cats.
AB  - Siamese cats are hypopigmented mutants which have abnormal retino-geniculo
      cortical pathways. The callosal pathway between areas 17 and 18 of the two
      cortical hemispheres also exhibits abnormalities: projections arising from the
      supragranular layers are more widely distributed but greatly reduced in number
      compared to normally pigmented (NP) cats, whereas those from the infragranular
      layers are more widespread and more numerous than normal (Berman and Grant,
      Visual Sci., 9 (1992). Here we examine the development of these abnormalities,
      using pathway tracing combined with quantitative analyses of the projection in
      normal and Siamese kittens at different postnatal ages. In neonatal kittens of
      both strains studied prior to natural eye-opening supragranular layer callosal
      projections arose throughout areas 17 and 18, with those from the infragranular
      layers restricted more to the region of the area 17/18 border. Between postnatal
      days 10 and 30 there was a similar, major (approximately 50%) reduction in the
      number and distribution of supragranular layer callosal projections from the two
      areas. The reductions in the normal kittens largely established the adult pattern
      of projection, but in the Siamese kittens twice as many callosal neurons were
      present than in adults of the mutant genotype and this situation persisted at the
      end of the second postnatal month. There was also a major (> or = 50%) reduction
      in the number and distribution of infragranular layer callosal projections in the
      NP kittens after eye-opening, but in the mutants such reductions did not occur.
      Thus the sequence of callosal development in the Siamese cat differs markedly for
      its two laminar components and by comparison with normal animals: an abnormally
      late loss of the main source of callosal projections occurs from the upper
      cortical layers, while the lower layers maintain an early exuberancy. We conclude
      that abnormal callosal connectivity in these mutants does not result from a
      misrouting of growing callosal axons, but from subsequent alterations to
      different mechanisms of cortical pathway development.

PMID- 8665661
TI  - Migrating luteinizing hormone-releasing hormone (LHRH) neurons and processes are
      associated with a substrate that expresses S100.
AB  - Luteinizing hormone-releasing hormone (LHRH) containing neurons arise in the
      region of the medial olfactory placode and migrate into the developing olfactory
      bulbs and basal forebrain along branches of the terminal and vomeronasal nerves.
      The neurons ultimately come to reside in olfactory and septo-preoptic areas and
      project extensively to several brain regions, including the preoptic area and
      median eminence. The present study examined the expression of a glial-associated
      guidance molecule, S100, as a possible substrate for this migration. Monodelphis
      domestica (the Brazilian grey, short-tailed opossum) was studied since this
      species gives birth to very immature, young, allowing access to early periods of
      mammalian forebrain development. Immunoreactivity for both S100 and LHRH
      containing neurons and fibers were observed to be closely associated along the
      entire LHRH migratory route from the vomeronasal organ to the septo-preoptic
      areas as early as the day of birth (PO). By P10, S100-immunoreactivity was also
      seen in areas containing LHRH-immunoreactive fibers such as the preoptic area and
      median eminence. We suggest that S100, a protein with neurotrophic properties in
      vitro, acts as a guidance molecule for migrating LHRH-immunoreactive neurons and
      elongating processes.

PMID- 8665662
TI  - The effects of cocaine on cerebral metabolic function in periweanling rats: the
      roles of serotonergic and dopaminergic uptake blockade.
AB  - This report examines the short-term effects of cocaine exposure during postnatal
      (PoN) days 11-21 on the metabolic function of major central neuronal systems in
      the rat. It also examines the effects of inhibition of serotonin and dopamine
      uptake during this period of development. By comparing the effects of fluoxetine,
      a serotonin uptake inhibitor, and GBR12909, a dopamine uptake inhibitor, to the
      effects of cocaine, the contributions of these pharmacologic actions to the
      neurochemical effects of cocaine were determined. Four groups of rats were
      injected subcutaneously: cocaine 25 (mg/kg), fluoxetine (25/kg), GBR12909 (25
      mg/kg) and vehicle-injected. On day 21 all received their final dose of drug or
      vehicle 20 minutes prior to the deoxyglucose procedure. Glucose utilization in 43
      of 56 brain regions selected for analysis showed a main effect of treatment (P <
      or = 0.05, ANOVA) and 7 showed significant treatment X gender interactions.
      Females demonstrated a markedly greater sensitivity to the effects of cocaine
      than did the males. Both males and females showed a negligible response to
      fluoxetine treatment. In the female cocaine-treated group, 10 of 13 motor
      structures, 7 of 12 sensory structures, 10 of 24 limbic structures, 2 of 2
      association areas, and 3 of 5 hypothalamic structures demonstrated significantly
      increased rates of glucose utilization compared to the vehicle-injected group (P
      < or = 1 =0.05, Dunnett test). In the cocaine-treated males, only 3 of 56 regions
      were affected. The gender differences in response to RBR12909 were less apparent.
      In the females, 11 regions showed increased rates of glucose utilization, while
      in the males 7 regions were stimulated. Fluoxetine produced the smallest overall
      effect with 2 structures showing increases in metabolism in the females and 2
      structures showing decreases in metabolism in the males. The present study
      therefore suggests at 21 days of age, that inhibition of dopamine uptake makes a
      more significant contribution to the metabolic effects of cocaine than inhibition
      of serotonin uptake and that females are more sensitive to the effects of cocaine
      than males. Furthermore, the sexual dichotomy seen in the long-term effects of
      cocaine; females show the greater effect; is also seen at the time of drug
      administration.

PMID- 8665663
TI  - GABAA receptor subunit mRNA expression in the weaver cerebellum: modulation by
      cell-cell interactions.
AB  - Recent studies have suggested that the developmental expression of GABA(A)
      receptor subunit mRNAs in cerebellar Purkinje neurons is modulated by cell--cell
      interactions [correction of interacactions]. In this population, the levels of
      mRNAs encoding the alpha1, beta2, and gamma2 subunits increase simultaneously
      during the second week of postnatal ontogeny, a period temporally coincident with
      cerebellar maturation and synapse formation. To determine the importance of cell-
      cell interactions in modulating receptor gene expression, the levels of GABA(A)
      receptor subunit mRNAs in Purkinje neurons of weaver mice and littermate controls
      were examined by quantitative in situ hybridization histochemistry. In the weaver
      mutant most granule neurons die early in postnatal development, thus eliminating
      the major source of excitatory input to Purkinje cells. Despite this loss, the
      three subunit mRNAs were expressed in all Purkinje neurons. However, the levels
      of expression were generally lower in the mutants than in the littermate
      controls. These results suggest that the onset of GABA(A) receptor gene
      expression in cerebellar Purkinje neurons occurs in the absence of extensive
      synapse formation by mechanisms which may be intrinsic to the neurons. In
      contrast, the absolute level of transcript expression attained appears to be
      modulated by cell-cell interactions or by other extrinsic cues present in the
      cerebellar environment.

PMID- 8665664
TI  - Developmental rearrangements of cortical glutamate-NMDA receptor binding sites in
      late human gestation.
AB  - NMDA-preferring glutamate receptor biding sites were characterized using the site
      selective ligand [3H]MK801, in synaptic membranes prepared from cerebral cortex
      tissue obtained postmortem from human infants who had died with minimal
      neurological and neuropathological impairment between 22 and 42 weeks' gestation.
      It proved necessary to modify the assay protocol used with adult tissue before
      reliable data could be obtained. In the four cortical region studied (prefrontal,
      motor, occipital, temporal), [3H]MK801 bound to a single class of sites which
      showed significant variations in affinity only in motor cortex. The density of
      [3H]MK801 binding sites (calculated at constant affinity) showed marked increases
      in all cortical regions over this period. The extent to which glutamate could
      enhance [3H]MK801 binding became significantly lower in prefrontal and motor
      cortex as gestation progressed, so that at term, little activation was apparent.
      In occipital and temporal cortex, this parameter was low throughout late
      gestation. The evidence suggests that Glutamate-NMDA binding sites may undergo
      structural rearrangements which alter their ability to interact with ligands
      during the later stages of human gestation, and that such changes are regionally
      variable.

PMID- 8665665
TI  - Stabilisation of neuromuscular junctions by leupeptin increases motor unit size
      in partially denervated rat muscles.
AB  - The effect on inhibiting the calcium activated neutral protease (CANP) by
      leupeptin on force output and motor unit size of the partially denervated rat EDL
      muscle was studied. Partial denervation was performed under anaesthesia by
      section of the L4 ventral ramus in 3- and 18-day-old Wistar rats. Two days after
      the operation a silicon strip containing the inhibitor of CANP leupeptin was
      implanted alongside the partially denervated EDL. Two to 3 months later the
      animals were anaesthetized and the EDL muscles on both sides prepared for tension
      recording. The results from these recordings show dramatic reduction in force
      output and muscle weight in animals operated at 3 days and this reduction was
      less pronounced in muscles treated with leupeptin. The mean force output of
      individual motor units increases in the leupeptin-treated partially denervated
      muscle compared to the untreated muscle. The increased fatigue resistance typical
      of muscles partially denervated at 3 days [37] is less pronounced in the treated
      muscle. In animals operated at 18 days the individual motor units actually
      increased in size and the leupeptin treatment had no effect on the partially
      denervated EDL muscles. The difference between the response to leupeptin of the 3
      day and 18 day operated animals could be due to the different patterns of
      innervation of the muscles at the time of the application of the inhibitor of
      CANP.

PMID- 8665667
TI  - Hydroxyindole-O-methyltransferase gene expression in the pineal gland of chicken
      embryo: development of messenger RNA levels and regulation by serum.
AB  - Hydroxyindole-O-methyltransferase (HIOMT), the enzyme which catalyzes the final
      step of melatonin biosynthesis, constitutes a marker of the functional
      differentiation of pineal cells. In addition, a day/night rhythm of HIOMT mRNA
      concentration, previously described in the chicken pineal gland [6], would
      suggest that HIOMT gene transcription is one output of the circadian system that
      controls pineal function. The study sought to monitor the developmental
      expression of HIOMT mRNA in the chick pineal gland and to investigate a possible
      role of instructive signals in this differentiation process. RT-PCR analysis
      indicated that HIOMT mRNA is expressed at embryonic day 8 (E8). At E12, HIOMT
      mRNA became detectable on northern blots and traces of HIOMT activity could be
      measured. HIOMT mRNA concentration increased 100-fold between E14 and day 10 post
      hatch, then levelled off. A day/night rhythm of HIOMT mRNA concentration was
      readily observed in the pineal gland of 2-day-old chicks. Pineal glands isolated
      on minimum culture medium at E11 stopped developing HIOMT gene expression.
      However, the addition of serum to the culture medium restored HIOMT mRNA
      concentration to the levels observed in vivo. The data suggest that the
      functional differentiation of melatoninergic cells observed during the second
      week of embryonic life may be controlled [correction of controled] by serum
      factors.

PMID- 8665666
TI  - Na+ channel changes in the growth cone and developing nerve terminal.
AB  - Previous saxitoxin binding studies indicated two forms of the sodium channel in
      the fetal rat brain; a low-affinity precursor located in an internal membrane
      compartment, present exclusively in growth cones and a high-affinity mature form
      present in the plasmalemma of growth cones and characteristic of synapses. This
      raises the questions (1) of the presence or absence of the beta2 subunit in these
      channel forms and (2) of the developmental regulation of the the beta2 subunit.
      Antibodies against the alpha and beta2 channel subunits were used to probe
      Western blots of subcellular fractions from rat brains at embryonic day 18 (E18),
      pups at postnatal (P) days 7-25, and adults, as well as purified sodium channels
      from adult brain. In both synaptosomes and the purified sodium channel the beta2
      antibody recognized the expected band at 38 kDa under reducing conditions.
      However, in contrast to the alpha subunit, this band was absent at E18 and became
      apparent only from P7 onwards. At the earlier time intervals a very prominent
      immunoreactive band of unknown identity was evident at 260--300kDa, which
      declined in intensity concomitant with the appearance of the 38 kDa beta2 band.
      These data indicate that beta2 subunits are regulated independently from alpha
      subunits, are absent in differentiating neurons, and hence are not necessary for
      insertion of the sodium channel into the plasmalemma, at least during early
      development of the neuron.

PMID- 8665668
TI  - The influence of target and non-target brain regions on the development of mid
      brain dopaminergic neurons in organotypic slice culture.
AB  - The development and regeneration of rat dopaminergic neurons of the ventral
      mesencephalon was studied in organotypic slice cultures. Single ventral
      mesencephalon cultures and co-cultures of ventral mesencephalon with striatum (a
      target region) or cerebellum (a non-target region) were prepared from postnatal
      day 1 Wistar rats. Cultures were processed for tyrosine hydroxylase and glial
      fibrillary acidic protein immunoreactivity, at two day intervals, for an overall
      incubation period of 20 days. Analysis of these cultures revealed that the
      striatal target tissue, exerted neither a trophic nor a tropic influence on the
      tyrosine hydroxylase immunoreactive neurons. In both single and co-cultures,
      tyrosine hydroxylase immunoreactive neurites projected radially from the ventral
      mesencephalon slice. However, in striatal co-cultures, tyrosine hydroxylase
      immunoreactive neurites were seen penetrating the striatal slice, whereas in
      cerebellar co-cultures no tyrosine hydroxylase immunoreactive neurites entered
      the cerebellar tissue. Glial fibrillary acidic protein positive cells actively
      migrated from the tissue sections, however tyrosine hydroxylase immunoreactive
      neurite outgrowth was not guided by these glial cells. Tyrosine hydroxylase
      immunoreactive neurites terminated once they had penetrated the striatal slice.
      This retardation of neurite growth by a target region could be important in
      establishing and reinforcing synaptic connections in the developing nigro
      striatal pathway.

PMID- 8665669
TI  - Glycogenolytic response of primary chick and mouse cultures of astrocytes to
      noradrenaline across development.
AB  - Glycogen is the brain's largest energy store and it is mainly localised in
      astrocytes. Glycogen turnover is extremely rapid in the brain, especially during
      sudden increased demand when glucose supplies are insufficient. Previous culture
      studies have reported on the glycogenolytic effect of noradrenaline on 3--4 week
      old primary mouse astrocyte cultures. This effect is believed to be mediated by
      the beta-adrenergic-cAMP signal transduction system. Recent evidence has shown a
      drop in forebrain glycogen levels at a specific time point during memory
      formation for a passive avoidance task in the day-old chick. This 'memory
      related' glycogenolysis may be initiated by noradrenaline-induced rises in cAMP
      occurring around this point, but it is unknown whether astrocytic glycogenolysis
      is is stimulated by noradrenaline in day-old chicks. This question was approached
      in the present study and it was shown that noradrenaline is capable of
      stimulating both cAMP formation and glycogen breakdown in chick primary astrocyte
      cultures at developmental age (10-14 days in culture) comparable to the newborn
      chick. In contrast, noradrenaline did not have a corresponding glycogenolytic
      effect on 10-day-old mouse astrocyte cultures (equivalent to the 1-week mouse),
      although it induced a considerable amount of glycogen breakdown in older cultures
      (18 and 24-26 days).

PMID- 8665670
TI  - Chronic postnatal phencyclidine treatment on [3H](+) pentazocine binding in
      juvenile rat brain.
AB  - Chronic phencyclidine (PCP) administrations in postnatal rats produce long-term
      behavioral changes. Here we report the effects of repeated postnatal PCP
      treatment on [3H](+)pentazocine binding in juvenile rats. Saturation analyses of
      the binding data showed no significant difference in any of the binding
      characteristics between chronic PCP-related rats and saline-treated controls
      suggesting that mechanisms other than alterations in sigma1 binding underlie the
      behavioral effects of repeated postnatal PCP administration in immature rats.

PMID- 8665671
TI  - Phytoestrogens in breast milk--another advantage of breast-feeding?

PMID- 8665672
TI  - Leptin in humans: current progress and future directions.

PMID- 8665673
TI  - Errors in measurement of total bilirubin: a perennial problem.

PMID- 8665674
TI  - Lower limits of detection, biological detection limits, functional sensitivity,
      or residual cancer detection limit? Sensitivity reports on prostate-specific
      antigen assays mislead clinicians.

PMID- 8665675
TI  - Ultrasensitive prostate-specific antigen assays and their clinical application.

PMID- 8665676
TI  - Biological and clinical importance of the p53 tumor suppressor gene.
AB  - The p53 tumor suppressor gene controls cellular growth after DNA damage through
      mechanisms involving growth arrest and apoptosis. Mutations that inactivate p53
      occur commonly in virtually all human malignancies and can be detected by
      sequencing of the p53 gene, immunohistochemical staining of tumor tissue with
      anti-p53 antibodies, single-strand conformation polymorphisms, or other
      biological assays. Identification of p53 mutation in the germ line is diagnostic
      of the cancer-prone Li-Fraumeni syndrome. Alterations of the p53 gene result in
      defective cellular responses after DNA damage and predispose cells to
      dysregulated growth, tumor formation and progression, and potential resistance
      (of tumor cells) to certain chemotherapeutic agents or ionizing radiation. A
      variety of tumors involving mutant p53 have a worse prognosis than tumors of the
      same type containing no p53 mutations. New diagnostic and therapeutic strategies
      are evolving as the p53 pathways of cell-cycle arrest and apoptosis become
      elucidated.

PMID- 8665677
TI  - Interlaboratory variability of bilirubin measurements.
AB  - During an 8-month study, 14 laboratories used automated analytical systems to
      measure total bilirubin concentrations in lyophilized bovine specimens containing
      38, 169, and 253 micromol/L bilirubin (2.2, 9.9, and 14.8 mg/dL, respectively).
      The measured mean +/- SD (n, range) were: 39 +/- 7 micromol/L (n = 90, 31-53)
      [2.3 +/- 0.4 mg/dL (1.8-3.1)]; 176 +/- 29 micromol/L (n = 89, 146-222) [10.3 +/-
      1.7 mg/dL (8.5-13.0)]; and 260 +/- 43 micromol/L (n = 103, 208-316) [15.2 +/- 2.5
      mg/dL (12.1-18.5)]. In comparison with target values, measurements were
      consistently lower at 4, higher at 6, and within +/- 4% at 4 laboratories for
      each of the three concentrations. The measured values for each concentration
      remained fairly constant during the study at each laboratory. We conclude that
      bilirubin measurements differed significantly from the established target values
      at most of the participating laboratories.

PMID- 8665678
TI  - Novel homogeneous liposomal immunoassay for colorimetric estimation of serum IgG
      anticardiolipin antibodies.
AB  - Liposomes entrapping the dye sulforhodamine B were used to develop an assay for
      anticardiolipin antibodies (ACAs). In the presence of magnesium ions, IgG ACAs
      induced liposomal lysis and the resulting absorbance changes were dependent on
      the amount of ACAs present. The liposomal assay (y) showed similar intraassay
      imprecision and detection limit to an ELISA for IgG ACAs (x), with a correlation
      coefficient of 0.90 (y = 1.05x - 1.61). No correlation with ELISA IgM ACA
      measurements was observed. Although ELISA remains the method of choice,
      particularly in examining different ACA classes, the liposomal assay offers
      advantages of speed and potential for processing large numbers of samples for IgG
      ACAs. This may facilitate study of the significance of increased IgG ACAs in the
      groups of conditions with which they are associated, and perhaps enable more
      laboratories to perform the test.

PMID- 8665679
TI  - Linearity and stability of the AVL and Nova magnesium and calcium ion-selective
      electrodes.
AB  - We studied the stability and linearity of the AVL and Nova Mg and Ca ion
      selective electrodes and the relation between the ionized Ca and ionized Mg
      results reported by each analyzer. The response of the electrodes to different
      concentrations of Mg and Ca was determined for saline solutions, aqueous
      solutions, and serum samples. The electrodes from both manufacturers demonstrated
      acceptable stability for the time of the study. The response of the electrodes
      was linear within the range specified by each manufacturer, but relative
      nonlinearity and the values for the linear limits differed between the AVL and
      Nova analyzers. The ionized Mg results varied with the concentration of Ca. The
      relation between ionized Ca and ionized Mg results was nonlinear and differed
      between the AVL and Nova electrodes. Intermethod comparison between the
      electrodes showed poor agreement for ionized Mg results, especially at low and
      high concentrations of total Ca and total Mg.

PMID- 8665680
TI  - Use of medians and "average of normals" of patients' data for assessment of long
      term analytical stability.
AB  - Using results from patients, we studied several methods for long-term (years)
      monitoring of the analytical stability of various chemistry tests. For each test,
      we obtained on a bimonthly basis histograms of > or = 200 to approximately 2000
      data points and determined the median, mean, and mean of those data points in the
      reference range ("average of normal" or AON). Examining approximately 4 years'
      data, we found that the medians and AON are extremely stable for most tests, and
      that all observed shifts in the medians or in the AON could be explained by
      expected or unexpected changes in the laboratory. The means and peak values of
      the Erlang (gamma) distribution were less useful, owing to shifts caused by
      extreme outliers, especially for enzymes in serum. We assumed that the underlying
      patient population and testing patterns were stable. We recommend the use of
      medians or the AON of patients' data under defined conditions for monitoring the
      long-term analytical stability of certain tests involving serum or whole blood.

PMID- 8665681
TI  - Defining the smallest analyte concentration an immunoassay can measure.
AB  - An immunoassay's minimal detectable concentration (MDC), the smallest analyte
      concentration the assay can reliably measure, is one of its most important
      properties. Bayes' theorem is used to unify the five current mathematical MDC
      definitions. The unified definition has significant implications for defining
      positive results for screening and diagnostic tests, setting criteria for
      immunoassay quality control and optimal design, reliably measuring biological
      substances at low concentrations, and, in general, measuring small analyte
      concentrations with calibrated analytic methods. As an illustration, we apply the
      unified definition to the microparticle capture enzyme immunoassay for prostate
      specific antigen (PSA) developed for the Abbott IMx automated immunoassay system.
      The MDC of this assay as estimated by our unifying approach is shown to be 4.1
      7.1 times greater than currently reported. As a consequence, the ability of the
      assay to measure reliably small concentrations of PSA to detect early recurrences
      of prostate cancer is probably overstated.

PMID- 8665682
TI  - Greater frequency of K-ras Val-12 mutation in colorectal cancer as detected with
      sensitive methods.
AB  - Assays for tumor mutations need to be sufficiently sensitive that a mutation can
      be readily detected in a high background of wild-type sequence. We have evaluated
      competitive allele-specific oligonucleotide (cASO) hybridization, the
      amplification refractory mutation system (ARMS), and a combination of cASO with
      mutant-enriched polymerase chain reaction (ME-PCR) for their respective
      sensitivities in detecting the K-ras Val-12 mutation. cASO hybridization detected
      1 mutant allele in 100 wild-type alleles and identified 6 of 74 (8%) colorectal
      tumors as having the Val-12 mutation. ARMS detected 1 mutant in 1000 and 12 of 74
      (16%) tumor samples, and the ME-PCR with cASO hybridization detected 1 in 5000
      and 20 of 74 (27%) tumor samples. The mutation was not detected in normal bowel
      mucosa from selected Val-12 tumor-positive patients. ME-PCR combined with cASO
      resulted in a threefold higher detection rate than has previously been reported
      and suggests that other studies may have underestimated the frequency of K-ras
      mutations.

PMID- 8665683
TI  - Methylmalonic acid quantification by stable isotope dilution gas chromatography
      mass spectrometry from filter paper urine samples.
AB  - A specific method for quantification of methylmalonic acid (MMA) from urine
      samples dried onto filter paper is described. The method involves stable isotope
      dilution gas chromatography-mass spectrometry with [methyl-2H3]-MMA as the
      internal standard. MMA is stable in dry paper samples stored at room temperature
      for at least 2 weeks. The extraction efficiency of MMA from paper was 56-58%. The
      concentration of urinary MMA in dried filter paper specimens from 190 normal
      controls was 1.21 +/- 1.34 (mean +/- SD) mmol/mol of urinary creatinine. Age
      related reference values are also reported. The concentrations, normalized to the
      urinary creatinine concentration, decrease with age. The applicability of this
      method to rapid screening for cobalamin (vitamin B12)-related disorders and
      methylmalonic aciduria is demonstrated.

PMID- 8665684
TI  - Sequential microenzymatic assay of cholesterol, triglycerides, and phospholipids
      in a single aliquot.
AB  - The assay of multiple analytes in a single aliquot can be advantageous from both
      measurement and economic standpoints. The objective of this study was to develop
      a simple and sensitive microenzymatic method for the determination of three
      biologically important lipids. Triglycerides (as glycerol), phospholipids (as
      choline), and total cholesterol (as unesterified cholesterol) were assayed, in
      that order, by sequential addition of sample, reagents, and microbial enzymes
      directly into a single microtiter plate well, accompanied by continuous
      monitoring of a common reporter reaction in which hydrogen peroxide is quantified
      either by colorimetry with 4-aminoantipyrine and 3-hydroxy-2,4,6-triiodobenzoic
      acid or by ultraviolet fluorometry with p-hydroxyphenylacetic acid. The detection
      limit of the method is in the subnanomole mass range for all three lipids.
      Results obtained with either fluorescence or colored endpoints were in excellent
      agreement with alternative individual chemical and enzymatic procedures.

PMID- 8665685
TI  - Apolipoprotein B 3' hypervariable repeat genotype: association with plasma lipid
      concentration, coronary artery disease, and other restriction fragment
      polymorphisms.
AB  - Apolipoprotein B gene 3' variable number tandem repeat (VNTR) and related regions
      were amplified by PCR and analyzed by agarose gel electrophoresis. Eighteen VNTR
      alleles (VNTR25, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 58,
      60) and 45 genotypes were observed in 477 Taiwanese subjects. The VNTR35 allele
      and genotype VNTR35/35 were observed most frequently in this population. The
      polymorphism information content was 0.62. Some minor alleles, such as VNTR25 and
      60, were found only in coronary artery disease (CAD) and stroke patients in our
      sampling, and no statistically significant difference was observed in VNTR
      allelic frequency between control and CAD or stroke patients. Significant
      differences in allelic distribution of some VNTR alleles were observed between
      our normal Taiwanese population and a Caucasian group studied by others. VNTR43
      47 and AluI+ (coding Ala591) restriction fragment length polymorphism (RFLP) as
      well as VNTR49-60 and EcoRI- (coding Lys4154) RFLP were found to be highly
      coinherited. No apparent association between the VNTR genotype and plasma lipid
      concentration was observed; however, for the same genotype, the CAD and stroke
      patients frequently showed higher lipoprotein(a) and lower HDL cholesterol
      concentrations than the control group.

PMID- 8665686
TI  - Clinical comparison of three labeled-antibody immunoassays of free
      triiodothyronine.
AB  - Three labeled-antibody immunoassays of free triiodothyronine (FT3) were studied
      in hyperthyroid patients, patients with nonthyroidal illness, and patients being
      treated with amiodarone; we also studied sera presenting known interferences (n
      for all groups = 465). The results were compared with those of a one-step labeled
      analog assay. The precision of the two automated assays were similar to that of
      the manual assays. The three labeled-antibody FT3 assays demonstrated a
      satisfactory diagnostic performance for confirming hyperthyroidism and robustness
      to interference; nevertheless, two assays displayed unusual behavior in some
      patients with nonthyroidal illness, with chronic renal failure, or after
      amiodarone therapy.

PMID- 8665687
TI  - Radioimmunoassay of leptin in human plasma.
AB  - Recent studies suggest that leptin, the ob gene product absent in ob/ob mice, is
      a negative regulator of adiposity. We developed an RIA to measure human leptin in
      plasma or serum. The minimum detectable concentration by the assay is 0.5
      microg/L leptin and the limit of linearity is 100 microg/L. Recovery of leptin
      added to serum was 99-104% over by the linear range of the assay. The RIA agreed
      reasonably well with rough quantification by Western blot (RIA = 0.90 blot + 3.7
      microg/L, Sy/x = 10.9 microg/L). CVs within- and between-run ranged from 3.4% to
      8.3% and from 3.6% to 6.2%, respectively. Variation in plasma leptin
      concentrations in specimens collected on consecutive mornings was large (CVs of
      10.9% and 22.5%). After an overnight fast, leptin concentrations were similar to
      those 1-2 h after 1-2 meals. Plasma leptin concentrations in specimens from 83
      lean and obese adults correlated directly with body mass index (BMI; kg/m2): r =
      0.72, P <0.001. Correlations were significantly improved by separating results by
      gender (men r = 0.84, women r = 0.87; p <0.001). The increase in leptin
      concentrations with increasing BMI was greater in women than in men (slope 2.53
      vs 0.97 microg/L per unit BMI, respectively). Leptin concentrations determined in
      lean subjects (BMI between 18 and 25) were higher in women (7.36 +/- 3.73
      microg/L) than in men (3.84 +/- 1.79 microg/L) (P <0.001). Plasma leptin varied
      little with age and no significant difference was observed between whites and
      blacks. We conclude that: (a) plasma leptin concentrations are accurately and
      precisely measured by this new RIA; (b) leptin concentrations vary little due to
      short-term fasting, age, or race; but (c) plasma leptin concentrations are gender
      specific.

PMID- 8665688
TI  - Immunoassay for intact amino-terminal propeptide of human type I procollagen.
AB  - We have developed quantitative immunoassays for the intact, trimeric amino
      terminal propeptide of human type I procollagen (PINP) and its Col1 domain.
      Intact PINP was isolated from the pleural fluids of cancer patients by a
      combination of ion-exchange, gel-filtration, and reversed-phase chromatographies.
      The amino-terminal Col1 domain of PINP was isolated after bacterial collagenase
      treatment of the heat-denatured trimeric propeptide. For the intact PINP assay we
      used a polyclonal antibody with only 1.2% cross-reaction with the monomeric Col1
      domain. In human serum, this assay detects only one peak of PINP antigenicity
      that has the size of known intact PINP. Under similar conditions, an assay for
      the Coll domain of PINP recognized two circulating antigens. The biological
      relevance was further verified in wound fluid. Interassay and intraassay CVs were
      3.1-9.3% for values within the reference intervals (mean +/- 2SD) for intact PINP
      in serum, which were 19-84 microg/L for women and 20-76 microg/L for men.

PMID- 8665689
TI  - Daidzein and genistein concentrations in human milk after soy consumption.
AB  - Soy isoflavones were quantified from human milk by a fast, precise, and selective
      HPLC method after enzymatic hydrolysis of conjugated isoflavones and extraction
      with ethyl acetate. Isoflavone aglycones and their mammalian metabolites equol
      and O-desmethylangolensin were separated selectively and identified by absorbance
      patterns, fluorometric and electrochemical detection, gas chromatography-mass
      spectrometric analysis after trimethylsilylation, and with internal and external
      authentic standards. HPLC injections of 20 microL of human milk showed detection
      limits of 1-3 pmol for all analytes by using diode-array detection. The detection
      limit could be improved by as much as 1000-fold by extended concentration through
      partitioning with ethyl acetate, by using electrochemical detection, by
      increasing the injection volumes, or by combining these techniques. We used the
      proposed method to monitor isoflavone concentrations in human milk and in human
      urine after challenge with 5, 10, and 20 g of roasted soybeans in the diet.
      Implications of the results for the potential of isoflavones to prevent cancer in
      newborn infants exposed to these agents are discussed.

PMID- 8665690
TI  - Ultrafiltration discrepancies in recovery of myoglobin from urine.
AB  - We investigated the efficiency, accuracy, and reliability of the
      ultrafiltration/dipstick methodology commonly used to diagnose myoglobinuria.
      Twenty-five myoglobin-containing urine specimens were filtered by centrifugation
      for 15 min at 1500g through a Centricon-30 membrane filter. Both the original
      specimen and filtrate were assayed for myoglobin. The amount of myoglobin
      recovered subsequent to filtration varied from <1-38%. This poor and variable
      recovery was independent of sample matrix or precentrifugation of the specimens.
      This was most critical for urine specimens with myoglobin concentrations <60 000
      microg/L. Fourteen of 18 such filtrates had concentrations <350 microg/L, a
      concentration below which a negative result would be obtained by using
      conventional dipstick methods. Thus, the use of this procedure has the potential
      to misdiagnose patients with myoglobin concentrations associated with increased
      risk of subsequent renal dysfunction, in particular when urine myoglobin
      concentrations are <60 000 microg/L.

PMID- 8665691
TI  - Evolution of serum lipids in two male bodybuilders using anabolic steroids.
AB  - We followed weekly the evolution of serum lipid concentrations in two
      bodybuilders undergoing a cycle of treatment with anabolic steroids. These drugs
      caused maximum depression of high-density lipoprotein cholesterol concentrations
      by 69.1% in the fifth week after the beginning of the cycle for subject 1, and by
      72.4% in the fourth week for subject 2. Maximum increases in low-density
      lipoprotein cholesterol concentrations were 144% and 156%, respectively. Total
      cholesterol and apolipoprotein (apo) B were highly increased with anabolic
      steroid use. We also saw depression of apo A-I by 84% and 91%, and lipoprotein(a)
      decreased to undetectable amounts in both cases. These effects were reversed 10
      weeks after the end of the steroid cycle in subject 1, but subject 2 still
      presented abnormal concentrations of serum lipids 13 weeks after drug cessation.
      The periods until reversibility of anabolic steroid effects on lipids were longer
      than those reported in previous studies.

PMID- 8665692
TI  - Evaluation of a new commercial IRMA for bone-specific alkaline phosphatase during
      treatment with hormone replacement therapy and calcitonin.

PMID- 8665693
TI  - Syva Emit 2000 and Roche "on line" subject to less interference by digoxin-like
      factors than Abbott TDx FPIA in newborns and pregnant women.

PMID- 8665694
TI  - Comparison of von Willebrand factor and tissue plasminogen activator
      concentrations in plasma and serum.

PMID- 8665695
TI  - Simple, sensitive microplate IRMAs for intact and des-31,32-proinsulin compared
      with HPLC and cellulose IRMAs.

PMID- 8665696
TI  - Improved HPLC method for simultaneous analysis of cortisol, 11-deoxycortisol,
      prednisolone, methylprednisolone, and dexamethasone in serum and urine.

PMID- 8665697
TI  - Quantitative measurement of c-erbB-2 p185 and mutant p53 expression in ovarian
      neoplasms by enzyme immunoassay.

PMID- 8665698
TI  - Blood collection for screening children for exposure to lead.

PMID- 8665699
TI  - Marked hypouricemia in purine nucleoside phosphorylase deficiency--serendipitous
      finding on screen.

PMID- 8665700
TI  - Salivary reagent stick measures serum ethanol concentrations.

PMID- 8665701
TI  - Presentation of receiver-operating characteristics (ROC) plots.

PMID- 8665702
TI  - Interference from lipemia in cell count by hematology analyzers.

PMID- 8665703
TI  - Bilirubin interference with determination of creatinine, lactate, phosphorus, and
      uric acid on Beckman Synchron CX7.

PMID- 8665704
TI  - Genetic hearing loss. Past and future.

PMID- 8665706
TI  - Life-satisfaction in patients with head and neck cancer.
AB  - Life-satisfaction is a measure of a patient's perception of the difference
      between his reality and his needs, or wants. This study reports the results of a
      longitudinal survey of patients' self-reported life-satisfaction following
      treatment for head and neck cancer. Life-satisfaction scores improved with time,
      and were related to pain, speech difficulty, and dysphagia. Lack of adequate
      family support was also important, although an uncommon problem. Treatment
      modality did not emerge as a significant determinant of life-satisfaction; speech
      difficulties were more likely to be due to articulation problems than voicing
      difficulty.

PMID- 8665705
TI  - Objective measurement of the results of uvulopalatopharyngoplasty.
AB  - Thirty-two patients undergoing uvulopalatopharyngoplasty (UPPP) for snoring have
      been studied prospectively using objective measurement of snoring levels. A
      significant reduction was found, especially in the supine posture. The
      quantitative reduction was small and correlations between subjective and
      objective changes in snoring volume were weak.

PMID- 8665707
TI  - Heat and moisture exchangers as a treatment option in the post-operative
      rehabilitation of laryngectomized patients.
AB  - A multi-institutional, prospective clinical study was undertaken to investigate
      whether the use of a heat and moisture exchanger (HME) in the period following
      total laryngectomy could prevent the development or reduce the severity of
      respiratory symptoms. Fifty-nine patients from three hospitals were provided with
      HMEs, either immediately post-surgery or, in the case of post-surgical
      radiotherapy, upon completion of the radiotherapy. For the total sample (n = 59)
      statistically significant improvements over time (between 3 and 6 months) could
      be found in forced expectoration (P < 0.05), in the perceived voice quality (P <
      0.001), social anxiety (P < 0.001), social interactions (P < 0.001) and in
      feelings of anxiety and depression (P < 0.05). Repeated measures analysis of
      variance indicated statistically significant group differences over time in
      forced expectoration and stoma cleaning (P < 0.05). No statistically significant
      differences over time were noted between the regular and non(regular) HME user
      groups in voice quality or in various aspects of daily living.

PMID- 8665708
TI  - Audiovestibular complications of non-otological surgery.
AB  - Post-operative dizziness or imbalance is often regarded as 'trivial' and self
      limiting and vaguely ascribed to the drugs used in anaesthesia or to haemodynamic
      changes. While hearing loss after anaesthesia has been documented in several
      studies, very little attention has been paid to a possible vestibular cause for
      post-operative dizziness. Twelve patients with post-operative vestibular
      disorders, with or without concomitant hearing loss, and one patient with
      tinnitus are described. As effective management for vestibular dysfunction
      exists, the importance of identifying this potential cause of dizziness is
      emphasized.

PMID- 8665709
TI  - A histopathological comparison of the uvula between snorers and non-snorers.
AB  - Snoring is a very common problem but there are few publications on the
      histological findings of the soft palate/uvula and these lack consistency. The
      relative proportions of tissue types in the base of the uvula removed from 17
      adults who underwent uvulopalatopharyngoplasty for heavy snoring were therefore
      compared with 14 cadaveric specimens. The mean percentage of muscle from the
      snoring group was 12.1% compared with 7.2% in the control group (P < 0.05). The
      percentage of fibrous tissue was greater in the cadavers (52.8% vs 45.5% in the
      snorers, P < 0.05). The percentage of muscle was inversely related to the
      percentage of fibrous tissue in the snoring group (P < 0.02). We hypothesize that
      these changes are a consequence of the repetitive forces on the soft palate
      during snoring rather than being related to the pathogenesis of snoring.

PMID- 8665710
TI  - Hearing results in tympanic membrane footplate and malleus-footplate assemblies.
AB  - Ears with loss of the stapes arch present the otologist with a greater
      reconstructive challenge than those in which the arch is intact. A comparison has
      been made between the results of reconstructions in which a link was made between
      the malleus handle and stapes footplate and those in which a tympanic membrane to
      footplate assembly was used. In all 34 operations were studied, 17 in each group.
      Cases in which a malleus-footplate assembly was used had significantly smaller
      mean air-bone gaps (P = < 0.002) and larger mean hearing gains (P = < 0.03) 1
      year after surgery.

PMID- 8665711
TI  - Should ENT out-patients be seen in hospital or General Practitioners' surgeries?
AB  - This was a prospective trial involving 1000 consecutive patients attending an ENT
      out-patient department to assess the degree of investigation and procedures
      undertaken in routine practice. Results demonstrate that the majority of patients
      (both new and old) require a procedure which would necessitate either additional
      staff or equipment if the consultation occurred in a General Practitioner's
      (GP's) surgery. The results argue against out-patient clinics taking place in a
      GP's surgery.

PMID- 8665712
TI  - Tragal cartilage in the primary reconstruction of defects resulting from a nasal
      septal abscess.
AB  - Immediate reconstruction of nasal septal sequestration following a septal abscess
      with autologous tragal cartilage graft is the method of choice in children and
      adolescents. On one hand autologous tissue is used, thus foreign body reaction
      with rejection or irregular resorption does not occur. On the other hand further
      defects in the posterior septal segment with additional damage to growth zones do
      not arise. Furthermore local tissue is saved, thus it will be available later, in
      case revision surgery will be necessary. But in contrast to costal cartilage
      tragal cartilage is easy to obtain in reconstruction of the nasal septum. No
      visible or functional defect arise at the donor site.

PMID- 8665713
TI  - Measurement of nasal mucociliary transport rates on the isolated human inferior
      turbinate.
AB  - The mucociliary transport rate was measured using sequential images of graphite
      particles moving on 17 isolated human inferior turbinates. These had been removed
      from 13 patients who had normal saccharin clearance tests on the day of surgery.
      The initial mean mucociliary transport rate was found to be 4.1 mm/min rising to
      5.0 mm/min 2 h after harvesting. After 4 h it fell to 3.7 mm/min. Where the rate
      was measured at two different sites on the same turbinate (n = 4), there was a
      close correlation over 6 h (r = 0.95, P < 0.001). When the turbinates were
      exposed to an aqueous solution of adrenaline (1:10,000) or a 2.5% cocaine
      solution, the rate increased or decreased respectively by 100% and 58% but
      returned to within 10% of the initial level within 2 h. We believe that the
      isolated inferior turbinate can be considered a useful model for the study of
      mucociliary clearance and agents that may influence it.

PMID- 8665715
TI  - The prevalence of IgG1 and IgG4 autoantibodies to IgE in patients with allergic
      and non-allergic rhinitis.
AB  - In this study we have compared the levels of IgG1 and IgG4 autoantibodies to IgE
      in the sera of patients with allergic rhinitis and non-allergic rhinitis. A group
      of patients undergoing cosmetic nasal surgery, but who did not have rhinitis or
      any history of atopy, acted as control. The frequency of positive titres of IgG1
      and/or IgG4 anti-IgE was 70% (14/20) in patients with allergic rhinitis, 50%
      (10/20) in patients with non-allergic rhinitis and 20% (4/20) in the control
      group. The mean titres of IgG1 anti-IgE and IgG4 anti-IgE were in the order
      allergic rhinitis > non-allergic rhinitis > controls. In the allergic rhinitis
      group levels of IgG1 anti-IgE (P = 0.0055) and IgG4 anti-IgE (P = 0.0028) were
      significantly higher than those found in the control group. The non-allergic
      rhinitis group also showed significantly higher levels of IgG1 anti-IgE (P =
      0.0182) and IgG4 and anti-IgE (P = 0.0359) than the control group. The existence
      of IgG autoantibodies to IgE in both allergic and non-allergic rhinitis suggests
      a possible role for these antibodies in the disease process, particularly in
      patients whose symptoms are not due to an allergic trigger.

PMID- 8665714
TI  - The Bradford and Airedale baby hearing project. An assessment of the impact of
      screening on the earlier detection of infant hearing loss.
AB  - An infant screening programme based on auditory brain stem response testing (ABR)
      to detect hearing loss in high-risk babies has been introduced in West Yorkshire.
      In the 3 year period prior to the introduction of the screen hearing loss was
      diagnosed by the age of 9 months in only 12%. This increased to 85% for children
      screened by a high-risk register and ABR.

PMID- 8665716
TI  - Inner ear barotrauma: computed tomographic evaluation.
AB  - Eight patients with inner ear barotrauma were evaluated by computed tomography.
      The causes of the inner ear barotrauma were diving in four, flying in an airplane
      in three, and climbing in one. Regarding the width of the cochlear aqueduct, no
      significant difference was observed between the affected side (3.28 +/- 0.49 mm)
      and non-affected side (3.63 +/- 0.79 mm) at the base of the infundibulum. The
      jugular fossa could not be identified on the affected side in three patients.
      Some relationship may exist between inner ear barotrauma and poor development of
      the jugular fossa.

PMID- 8665717
TI  - Long-term pulmonary function after total laryngectomy.
AB  - In 58 laryngectomized patients pulmonary function tests were performed during a
      routine visit to the outpatient clinic. The assessment of pulmonary function with
      an extratracheal device could easily and reliably be accomplished in all
      instances. The results show that in long-term follow-up post-laryngectomy
      expiratory lung function values are significantly lower than predicted. Of the
      various subjective respiratory complaints, only a higher frequency of coughing
      was statistically significantly associated with decreased lung function values (P
      < 0.01). Neither time since surgery (> 1 year vs < 1 year), nor radiation therapy
      seemed to be correlated with the pulmonary function outcomes. In contrast, the
      age of the patient did have a significant influence. Although an age-related
      decline in pulmonary function is a well documented phenomenon, an additional
      adverse effect was suggested by the present series in the group who was over 65
      years of age. Bronchodilator treatment was found to significantly ameliorate
      several pulmonary function parameters in a sub-group of 18 patients. It may be
      concluded, that after total laryngectomy significant abnormalities in pulmonary
      function have to be anticipated. We have found that these disturbances seem to be
      more pronounced with increasing age.

PMID- 8665718
TI  - A prospective study of acid reflux and globus pharyngeus using a modified symptom
      index.
AB  - Previous authors have demonstrated an association between gastro-oesophageal
      reflux and globus pharyngeus. With the advent of 24-h pH monitoring the strength
      of this association has been questioned. A prospective study was performed using
      a 'Symptom Index' of acid reflux. A positive result was recorded when one out of
      two globus sensations occurred with acid reflux. The symptom index was assessed
      prospectively in 21 patients with a history of globus pharyngeus. In eight
      patients with significant acid reflux as defined by standard pH criteria the
      symptom index was positive in all cases. The remaining 13 patients had no
      objective evidence of significant reflux and the symptom index was negative. The
      symptom index is a useful additional marker to determine the significance of acid
      reflux in the pathogenesis of globus pharyngeus.

PMID- 8665719
TI  - Microbial colonization of the Groningen speaking valve and its relationship to
      valve failure.
AB  - Speaking valve failure may be related to biofilm development. An inter-observer
      validated method of assessing microbial overgrowth in defective prostheses was
      developed. Two independent observers recorded colonisation of the valves on a 100
      mm linear analogue scale in several defined areas. Inter-observer agreement was
      high in all areas. In vitro opening pressure and derived forward resistances were
      measured. The relationship between colonization of the valves and the in vitro
      measurements was investigated. Significant correlations for a two-tailed
      Spearman's test were recorded between the resistance and microbial colonization
      of the hinge and oesophageal areas (rs 0.22: P < 0.05, rs 0.25: P < 0.05, n =
      80). There was no significant association for resistance and colonization of the
      tracheal surface, and no significant association between the opening pressure and
      the colonization. This work suggests that microbial colonization of the
      prosthesis in the oesophageal and hinge areas is associated with valve failure.

PMID- 8665720
TI  - External facial dimensions and minimum nasal cross-sectional area.
AB  - The relationship of the total minimum nasal cross-sectional area of the
      decongested nasal cavity to specific, easily measured, facial dimensions was
      examined. The nasal cavities of 51 healthy volunteers were examined using
      acoustic rhinometry following nasal decongestant and their minimum nasal cross
      sectional area was estimated. This was compared with several personal
      characteristics, including height and weight, facial width and height, inter
      canthal width, and nasal height, alar breadth and the nasal triangular area (half
      the product of nasal height and alar breadth). The total minimum nasal cross
      sectional area showed a good correlation with both the alar breadth, 0.55 (P <
      0.0001) and the nasal triangular area, 0.62 (P < 0.0001). No significant
      correlation was seen with the remaining personal characteristics. The results
      suggest that it may be possible to produce a clinically useful formula that would
      be able to predict the expected normal total minimum cross-sectional area of the
      nasal cavity from these external dimensions. This predicted cross-sectional area
      could be compared with that measured by acoustic rhinometry. This may prove of
      value to a clinician wishing to establish if a given patient has a pathologically
      narrow nasal cavity.

PMID- 8665722
TI  - Microscopic tonsillectomy.

PMID- 8665721
TI  - Intranasal lysine aspirin in recurrent nasal polyposis.
AB  - Twenty patients with recurrent nasal polyposis but without any history of aspirin
      sensitivity were given 2000 micrograms of intranasal lysine aspirin to one
      nostril and saline to the other once a week for periods of up to 15 months. Two
      patients had increased nasal obstruction following the initial test doses of
      lysine aspirin and were excluded from the trial proper. In the remainder
      symptomatic polyp recurrence was delayed compared with the previous experience
      while on intranasal steroids, with eight patients remaining symptom free at 15
      months compared with an expected number of three (P = < 0.05, chi 2 test). Polyp
      recurrence was bilateral but there was a tendency for the lysine aspirin treated
      side to have less polyp tissue as assessed by nasendoscopy and by acoustic
      rhinometry.

PMID- 8665723
TI  - [Ischemic white matter lesions may be caused by the baroreceptor reflex are
      dysfunction].
AB  - Muscle sympathetic nerve activity (MSNA, bursts/min) was recorded
      microneurographically from the tibial nerve in the control group (8 males and 8
      females) and the cerebral infarction group (12 males and 12 females) with
      ischemic white matter lesions (WMLs) diagnosed on T2-weighted MR imaging.
      Subjects in the latter group were more hypertensive. A significant positive
      correlation between age and the MSNA at rest was detected in the control group,
      but not in the cerebral infarction group. The MSNA at rest was significantly low
      exclusively in infarcted females. Although the blood pressure did not decrease in
      either group during a 30 degrees head-up tilt, the MSNA was enhanced in the
      control group alone. On the cold pressor test, the control group demonstrated a
      significant pressor response, but not an increase in MSNA. In contrast, the
      cerebral infarction group showed a significant increase in MSNA, and, within the
      group, only infarcted females lacked a clear pressor response. These results
      indicated the existence of an insensitivity in the baroreceptor reflex arc on the
      part of infarcted males, as already indicated in hypertensive patients. On the
      other hand, on infarcted females, there were both a hypofunction of the
      baroreceptor reflex arc and a decline of the vascular reactivity, possibly due to
      an inadequate development of the sympathetic nervous system and a low level of
      estrogen. Interestingly mean WMLs%, which was calculated as total WMLs areas x
      100/total subdural areas on four horizontal T2-weighted MR images, 10, 20, 30, 40
      mm above the bicommisural plane, was significantly larger in infarcted females
      (8.7 +/- 0.7%, mean +/- S.E.) than males (5.1 +/- 0.7%). This discrepancy may be
      caused by the above-mentioned difference on the results between them. WMLs are
      mostly distributed in the watershed zone supplied by the long penetrating
      arteries. Therefore, the lesions may be produced by wide fluctuations in blood
      pressure as the result of a dysfunction of the baroreceptor reflex arc and a
      decrease of the vascular reactivity.

PMID- 8665724
TI  - [A family of X-linked motor and sensory neuropathy with a new type of connexin32
      mutation].
AB  - A 28-year-old man had complaints of muscle weakness in both his legs and fingers.
      Moderate degrees of symmetrical atrophy adn weakness of the bilateral lower
      limbs, moderate degree of muscle atrophy was also noticed distal to the lower one
      third of the upper thigh. A moderate degree of weakness of the anterior tibial,
      extensor digitorum and peroneus muscles was also noted. Pes cavus deformity was
      evident bilaterally. Knee jerk was normal, and Achilles tendon reflex was absent
      without pathologic reflexes. He could not walk on his heels. Vibratory sensation
      was severely decreased in the toes, and both touch and pain sensations were
      slightly decreased on the dorsum of the feet. The median motor nerve conduction
      velocity was 28.9 m/sec with a prolonged distal latency. An amplitude of M-wave
      evoked by electrical stimulation of the median nerve 1 mV. No M-wave was obtained
      from stimulation of the tibial nerve, and no sensory nerve action potentials were
      elicited from electrical stimulation of the median and sural nerves. Histologic
      studies of the biopsied sural nerve revealed the occasional presence of
      internodes with a thin myelin sheath and a decrease in the density of large
      myelinated fibers. Small and atypical onion-bulbs were occasionally observed by
      electron microscopy. Based on the neurological examination and nerve conduction
      study of the family members, a sister, mother and grandmother of the proband were
      found to be mildly affected without any disability in their daily activities.
      However, the father and an uncle on the mother's side of the proband were normal.
      Therefore, we concluded clinically that this family had HMSN type I with
      autosomal dominant inheritance or X-linked HMSN. In the studies of fluorescence
      in situ hybridization and restriction fragment length polymorphism of the genomic
      DNA of the proband, a DNA duplication in chromosome 17p11.2-12 was not observed.
      A single-strand conformational polymorphism analysis of the genomic DNA encoding
      connexin32 (Cx32) revealed the abnormal band different from that of the control.
      A sequence analysis of the genomic DNA obtained by use of the polymerase chain
      reaction was also performed. It revealed that there was a mutant allele, a
      cytosine to thymine substitution of the nucleotide position 140, which caused a
      substitution of leucine for serine at amino acid position 26. The proband's
      mother was heterozygous for the mutant allele and the normal allele. This type of
      Cx32 mutation was different from any type of Cx32 mutation reported in the
      literature. The mutation in this family is located in the first transmembrane
      portion of Cx32, and may alter the function of Cx32 protein, as well as lead to
      the functional and structural abnormalities of the myelin sheath at the nodes of
      Ranvier and Schmidt-Lanterman's incisures, where Cx32 is present. This is the
      first Japanese X-linked HMSN family showing a new type of mutation of Cx32 gene
      with clinical findings and a histologic evaluation of the sural nerve.

PMID- 8665725
TI  - [Cognitive dysfunction following anterior communicating artery aneurysm rupture.
      Comparison with alcoholic Korsakoff syndrome on neuropsychological performance].
AB  - The present study aims to compare neuropsychological performance of patients
      following anterior communicating artery aneurysm rupture (ACoA) with that of
      patients with alcoholic Korsakoff syndrome (AKS). Fifteen ACoA patients and ten
      age-and education-matched AKS patients were included in the study. All the
      patients were tested at least one year post onset of their illness at a stable
      condition. The WAIS and forward digit span scores of AKS were also matched to
      ACoA, and simple attention and general intelligence were well preserved both in
      ACoA and AKS. Frontal function as measured by the Wisconsin card sorting test
      (Keio version) (KWCST) was equivalently impaired in the two groups. Anterograde
      memory as measured by Wechsler memory scale subtests, serial seven word learning
      test, Rey auditory verbal learning test, and logical memorizing test (Luria's
      paired word-picture association), was more severely impaired in AKS than ACoA in
      contrast to the comparable attention, intelligence, and frontal function: (1)
      memory tasks with low correlations to KWCST (serial word learning tasks and
      paired verbal associates), reflecting primary simple serial memorizing, and (2)
      memory tasks with high correlations to KWCST (logical memory and logical
      memorizing), reflecting higher and complicated strategic mnemonic activities.
      However, the correlations between these anterograde memory subtests and KWCST
      were substantially equivalent in ACoA and AKS. This suggests that the differences
      in anterograde amnesia demonstrated in ACoA and AKS may be of quantitative, not
      of qualitative property. The extent of deficits in semantic encoding as measured
      by Wickens' release from proactive interference paradigm (PI release) was also
      milder in ACoA than AKS. Both AKS and ACoA failed to show PI release in contrast
      to normal PI release demonstrated in age-matched ten healthy subjects. PI release
      in ACoA, however, was in between AKS and healthy subjects. The results were
      interpreted in the light of a recently postulated hypothesis that a combination
      of frontal lobe damage and memory impairment is crucial for causing a deficit in
      semantic encoding. The extent of damage in the memory circuit in ACoA may be
      variable, which may result in milder degree of anterograde amnesia and semantic
      encoding than AKS in the present study.

PMID- 8665726
TI  - [Word fluency in spinocerebellar degeneration].
AB  - Two types of verbal fluency task-initial letter fluency and category (semantic)
      fluency--were examined in eleven patients with spinocerebellar degeneration
      (SCD), twenty four patients with Parkinson disease (PD), and twenty control
      subjects without neurological signs and symptoms. All patients and subjects
      showed normal results from the screening test for dementia. The numbers of
      initial letter fluency were less than those of category fluency in all groups.
      For category fluency, patients with SCD or PD had significantly lower scores than
      controls. For initial letter fluency, patients with SCD produced significantly
      lower scores than controls, but patients with PD did not produce significantly
      lower scores than controls. It is considered that the poor performance on both
      initial letter and category fluency in patients with SCD or Pd was related to
      disturbance of semantic memory associated with subcortical impairment, and the
      poor performance on initial letter fluency in patients with SCD was caused by the
      initiation and retrieval problems based on disturbance of frontostriatal circuits
      and linguistic systems. Therefore, we suggested cerebellar hemisphere played a
      role on the order and timing of rule-based generation of letters.

PMID- 8665727
TI  - [Intellectual impairment and brain MRI findings in myotonic dystrophy: with a
      special reference to hippocampal atrophy and white matter lesions].
AB  - We performed a correlative study between intellectual impairment, CTG repeat
      expansion and magnetic resonance imaging (MRI) abnormalities, including
      hippocampal atrophy, white matter lesions and ventricular dilatation in 15
      patients with myotonic dystrophy (MD). They included 4 males and 11 females aged
      from 20 to 66 years, averaging 43 years of age and 15 years of duration of
      illness. Nine patients had intellectual impairment (WAIS-R<80). Negative
      correlations were found between full scale IQ (FSIQ), duration of illness
      (p<0.05) and CTG repeat expansion (p<0.05). Compared with normal controls, the
      patients with MD showed a significant reduction in size of the hippocampal head
      (p<0.01), which was positively correlated to FSIQ, verbal IQ and performance IQ
      levels (p<0.05). Ten patients had white matter lesions. Severer white matter
      lesions tended to be recognized in patients with longer duration of illness and
      with decreased FSIQ level. These results suggest that hippocampal atrophy and
      white matter lesions are related to intellectual impairment in patients with MD.

PMID- 8665728
TI  - [Changes in regional cerebral blood flow in nondominant hemisphere during speech
      task in aphasics.: a PET activation study].
AB  - To investigate the patients with language disorder and to detect the activated
      areas in language processing, we measured the changes in the regional cerebral
      blood flow (CBF) during speech task (?counting? task) using O-15 water PET
      activation technique in six normal subjects (age 58.3 +/- 8.1), mean +/- SD), ten
      fluent aphasics (age 60.3 +/- 12.5) and six nonfluent aphasics (age 50.5 +/-
      8.3). In ?counting? task, the subjects were instructed to count the number aloud
      from 1 to 10 and repeat the sequence over and over in the native language
      (Japanese) at the rate of one number per 2.5 sec. The data were analyzed with
      stereotactic intersubject averaging analysis for the normal subjects. Apart from
      it, the regions of interest (ROI) analysis (a circular ROI of 12 mm diameter) was
      performed in the language-related areas: posteroinferofrontal areas (PIF),
      posterosuperotemporal area (PST), and Rolandic areas (related to the mouth and
      lips) were significantly activated bilaterally in the ?counting? task. PIF were
      activated with a dominance in the left side. In the resting state, rCBF in the
      left PIF and left PST were activated with a dominance in the left side. In the
      resting state, rCBF in the left PIF and left PST was reduced in both fluent and
      nonfluent aphasics. In nonfluent aphasics, the magnitude of activation in the
      right PIF by ?counting? task was significantly greater than normal subjects and
      patients with fluent aphasia (ANOVA). It suggests the importance of the right PIF
      in the simple language processing in the nonfluent aphasia. In the sixteen
      aphasic patients, the increase in rCBF in the right PST during the ?counting?
      task was negatively correlated with the score of comprehension (WAB) in the
      Spearman ranked correlation (p < 0.05). It suggests that, while the activity of
      the right PST is minimal for the ?counting? in normal subjects, it plays an
      important and compensatory role in aphasic patients.

PMID- 8665729
TI  - [A case of variant Gerstmann-Straussler-Scheinker disease with the mutation of
      codon P105L].
AB  - Here we present a case of variant GSS disease with mutations in codons 1055 and
      129 in a prion protein. The patient was a 54-year-old male, who developed
      weakness in the lower limbs and spastic, wide-based gait at the age of 46 years.
      Subsequently he developed dementia and spastic quadriplegia at the age of 49. He
      had marked pseudobulbar palsy at the age of 50 and became bed-ridden in
      decorticated posture at teh age of 53. CT and MRI examinations revealed marked
      atrophy of the frontal and temporal lobes, but the occipital lobes and the
      cerebellum were spared. His sister had been reported by Amano, et al. in 1992 as
      a case of variant GSS syndrome, who had very similar clinical features, and had
      numerous prion protein positive plaques in her cerebral cortex at the time of
      autopsy. His sister was confirmed to have the same mutations in a prion protein
      as the present case in later genetic studies.

PMID- 8665730
TI  - [An unusual case of peroneal muscular atrophy with rigidity, polyneuropathy,
      mental retardation, and diabetes mellitus developed in familial Parkinson's
      disease].
AB  - Familial polyneuropathy mimicking Charcot-Marie-Tooth disease associated with
      parkinsonism and dementia has been reported in literature. We present with
      similar peroneal muscular atrophy, rigidity of upper extremities, severe
      peripheral neuropathy, mental retardation and diabetes mellitus. The patient, a
      42-year-old man, developed progressive muscle weakness, mental retardation and
      difficulty in walking in childhood. Because of his pes cavus, he had three
      surgical operations. At the age of 20 years, he developed distal muscular atrophy
      of lower limbs. On neurological examination, all limb muscles were atrophic,
      especially in lower one third of the thigh. Rigidity was noted in the upper
      extremities. Deep tendon reflexes were hyperactive in the upper and diminished in
      the lower extremities. Muscle CT revealed low density areas in all the muscles
      examined, specially in the gastrocnemius and anterior tibial muscles. Needle EMG
      showed neurogenic change in the forearm, but not in the lower limbs, because of
      no voluntary contractions obtained due to severe muscle atrophy. Marked slowing
      of motor conduction velocity with muscle action potentials of very low amplitude
      was found in the ulnar nerve. Muscle action potentials were not elicited in the
      median and peroneal nerves. Sensory action potentials were not elicited from the
      median, ulnar and sural nerves. These findings were consistent with axonal
      polyneuropathy. In the sural nerve biopsy, the densities of myelinated fibers
      were markedly decreased. However, unmyelinated fiber densities were relatively
      preserved. Onion bulb formation was not found. This patient may be classified
      into hereditary motor-sensory neuropathy (HMSN) type II based on the clinical
      findings delayed nerve conduction velocities and axonal degeneration in the sural
      nerve. He has also diabetes mellitus. CT of the brain revealed nothing
      particular. He is one of members with familial Parkinson's disease (PD) developed
      in Sagamihara. Peroneal muscular atrophies are not necessarily associated with
      PD, though it has been occasionally complicated in various neuro-degenerative
      diseases including parkinsonism. We are now following the patient to detect the
      symptom of Parkinson's disease for early treatment.

PMID- 8665731
TI  - [Immunoadsorption therapy on Fisher's syndrome--removal ability of anti
      ganglioside antibodies by tryptophan-linked immunoadsorbent].
AB  - There have been several reports describing that immunoadsorption therapy improves
      the neurologic involvement in Fisher's syndrome (FS). However, few studies have
      assessed the usefulness of immunoadsorption therapy in view of the removal
      ability of anti-GQ(1b) antibody, which may function the development of FS. We
      examined the ability of immunoadsorbents for the anti-GQ(1b) antibody in a
      patient with FS. A 28-year-old woman developed diplopia and giddiness following a
      cough, fever and diarrhea. On admission (day 22), neurologic examination showed
      bilateral moderate oculomotor paralysis and bilateral complete abducens
      paralysis. She had areflexia, numbness of middle and ring fingers on the left and
      mild ataxic gait. Her serum had IgG anti-GQ(1b) and anti-GD(1b) antibodies. We
      examined the absorption of anti-ganglioside antibodies onto a polyvinyl alcohol
      gel (PVA), a phenylalanine-linked PVA (PH-350) and a tryptophan-linked PVA (TR
      350) by the batchwise adsorption method. TR-350 absorbed the autoantibodies, but
      the removal ability of autoantibody by PVA and PH-350 was not proved. The FS
      patient was treated with TR-350 (days 29, 34 and 43) and PH-350 (day 39). Anti
      GQ(1b) and anti-GD(1b) antibodies were significantly removed by the TR-350, in
      accordance with the results of the in vivo study. There was little loss of
      albumin as compared with the immunoglobulins and complements. The numbness and
      ataxia disappeared on day 44. The diplopia disappeared on day 106. TR-350 would
      be better than PH-350 in the treatment of FS by immunoadsorption therapy.

PMID- 8665732
TI  - [A case of portal-systemic encephalopathy with slowly progressive, non-flapping
      tremor].
AB  - A 52-year-old man has slowly developed a non-flapping tremor during 30 years. He
      also had suffered from poor concentration for two years. He had, however, no
      history of episodic disturbance of consciousness. He had no other neurological
      symptoms except for tremor and hyperreflexia. The tremor was postural and
      intentional, and extremely increased at the end point. The factor of intentional
      tremor and hyperkinesia volitionnelle seems to be present in the tremor.
      Laboratory examination disclosed a hyperammonemia, reduction in Fisher ratio, and
      poor excretion of ICG. Selective abdominal angiography visualized a large shunt
      vessel between the left gastric vein and the left renal vein. The normal liver
      scintigram with 99mTc excluded the dysfunction of liver, and we conclude that the
      shunt vessel might be congenital. Tremor markedly improved after normalizing
      blood ammonia level by resection of the shunt vessel. The present case suggests
      that tremor, even without episodic disturbance of consciousness, could be based
      on the portal-systemic encephalopathy.

PMID- 8665733
TI  - [A Japanese family with paramyotonia congenita which has a mutation in the muscle
      sodium channel gene].
AB  - We report here a Japanese family with paramyotonia congenita. The proband was a
      42-year-old woman (case 1), who noticed muscle stiffness and weakness in the cold
      since the age of 7 years. These symptoms were alleviated by warming. Her eldest
      son (case 2) also experienced similar symptoms, while her younger son and
      daughter were healthy. Neurological examination in case 1 revealed mild weakness
      in facial and neck muscles. Cold-induced muscle stiffness and weakness were
      present. Electromyography showed myotonic discharges, intensified by cooling or
      repetitive exercise. The amplitude of the compound muscle action potentials was
      also reduced by the repetitive exercise and cooling. Serum chemistry including
      potassium and CK was normal. Molecular analysis of SCN4A (exon22-24) by SSCP and
      nucleotide sequencing revealed a C-to-T transition at nucleotide 3,938, causing a
      substitution of 1313methionine of threonine in case 1. This mutation was
      confirmed by PCR-RFLP with a mismatched primer; the proband (case 1) and her
      eldest son (case 2) had a heterozygous mutation, while the other family members
      did not. This is the first report that a mutation in SCN4A was identified in a
      Japanese family with paramyotonia congenita.

PMID- 8665734
TI  - [Marked clinical improvement by plasmapheresis in a patient with stiff-man
      syndrome: a case with a negative anti-GAD antibody].
AB  - We described a 56-year-old man with stiff-man syndrome, who was markedly improved
      after plasmapheresis therapy. He had a 12-year history of progressive painful
      stiffness of his back and limbs, muscle cramps and difficulty in walking. He had
      been taking oral diazepam and prednisolone. On examination the abdominal and
      paraspinal muscles and limbs were continuously contracting, confirmed by surface
      and needle electromyography. Antibodies against glutamic acid decarboxylase (GAD)
      and pancreatic islet cells in the serum were negative, but antinuclear antibody
      and anti-smooth-muscle antibody were present. The patient underwent a course of 4
      double filtration plasma exchanges of 3,000 ml each in an 8-day period.
      Plasmapheresis resulted in marked clinical improvement. The disappearance of
      muscular cramps and a reduction of stiffness occurred within 24 hours after the
      first plasmapheresis, and he was able to walk unassisted. The patient's
      subjective improvement continued over 4 months after the plasma exchange. This
      case provides additional evidence of the autoimmune mechanism of stiff-man
      syndrome. Plasmapheresis is one choice in the management for stiff-man syndrome.

PMID- 8665735
TI  - [Axonal Guillain-Barre syndrome associated with anti-GalNAc-GD1a antibody
      subsequent to Campylobacter jejuni (PEN 43) enteritis].
AB  - We reported a 16-year-old boy who had Guillain-Barre syndrome (GBS) after
      suffering diarrhea. Campylobacter jejuni was isolated from his stool, and the
      serotype belonged to PEN 43. Neurologic examination revealed distal-dominant
      muscle weakness atrophy, and mild sensory disturbance. Motor and sensory nerve
      conduction velocities were normal, but compound muscle action potentials were
      markedly reduced. Serum from the patient had high titers of anti-FalNAc-GD1a
      antibodies. He had HLA-A24, B51, DRB1*04 and DRB1*09. His elder sister showed
      diarrhea and serum anti-C. jejuni antibody, but did not showed GBS and serum anti
      ganglioside antibody. Her HLA types were A24, B51, DRB1*09 and DRB1*14.

PMID- 8665736
TI  - [A case of Lissauer's general paresis with left hemisphere dominant brain atrophy
      and leuko-araiosis in the deep white matter on MRI].
AB  - A 38-year-old man presented with personality change, postural tremor of the right
      arm and leg, and right hemidysesthesia. MR imaging (MRI) revealed left hemisphere
      dominant brain atrophy and leuko-araiosis in the deep white matter. Serological
      test of serum and cerebrospinal fluid demonstrated high titers of antibodies to
      Treponema pallidum. He was diagnosed as Lissauer's general paresis based on the
      clinical symptoms and signs, and MRI findings. This disorder is characterized by
      focal cerebral atrophy, corresponding to focal neurologic signs.
      Neuropathological features in Lissauer's general paresis are spongiform atrophy
      of the cerebral cortex and demyelination of the white matter. Leuko-araiosis on
      MRI in our case may represent demyelination of the white matter. Although MRI
      findings in general paresis are usually nonspecific, this is, as far as we know
      the first case report of general paresis with MRI showing focal cerebral atrophy
      and leuko-araiosis.

PMID- 8665737
TI  - [Clinical analysis of the complex repetitive discharge following M wave].
AB  - In the nerve conduction study (NCS), the complex repetitive discharge (CRD) which
      follows M wave is occasionally observed. To understand the origin of CRD, we
      clinically analyzed the cases with CRD. Among the 1,580 cases examined by NCS, 13
      (0.82%) cases including 6 of myotonic dystrophies (MyD), 2 of carpal tunnel
      syndrome and a case of multiple sclerosis, chronic inflammatory demyelinating
      polyradiculoneuropathy, compression fracture of a lumbar vertebra, myasthenia
      gravis (MG) or Isaacs' syndrome had CRD. CRD was divided into forms; one
      consisted of an attenuating train of the complex of muscle potentials (muscular
      form) and the other one formed a simple repetition of single motor unit action
      potential (neural form). MyD, MG, and Isaacs' syndrome showed muscular form, and
      the others neural form. The pathophysiology of CRD was considered from the sites
      of lesions of nerve terminals, neuromuscular junctions, or muscle fibers and that
      the neural form might result from the axonal regeneration of peripheral motor
      nerve fibers.

PMID- 8665738
TI  - [A case of rhabdomyolysis with administration of intravenous vasopressin].
AB  - A 73-year-old man with alcoholic liver cirrhosis was admitted to our hospital
      because of massive hematemesis. He was treated with continuous intravenous
      infusion of vasopressin of 0.2 U/min. 22 hours after the infusion, he complained
      of myalgia, muscle weakness and skin mottling in the extremities. The skin lesion
      extended to the back. The serum CK and myoglobin levels were elevated to 52,280
      IU/L and 84,400 ng/ml respectively. The urinary myoglobin level was elevated to
      732,000 ng/ml. On the fifth hospital, he died of bleeding from the esophageal
      varices. Autopsy examination demonstrated necrosis of the skeletal muscle cells
      and myoglobin casts in the renal tubules. Our patient was probably hypersensitive
      to vasopressin because of underlying liver dysfunction. The massive myonecrosis
      might be induced from the following conditions; overreactive vasopressin-induced
      vasoconstriction resulted in ischemic muscle damage, and hypersensitive
      sarcoplasmic reticulum released excessive Ca2+ followed by muscle
      hypercontraction as seen in malignant syndrome or malignant hyperthermia.

PMID- 8665739
TI  - [Acute disseminated encephalomyelitis (ADEM)-like exacerbation in the patients
      with cryptococcus meningitis treated successfully by steroid pulse therapy].
AB  - A 58-year-old man was admitted to our hospital with suspicion of aseptic
      meningitis. He had been well until the day before admission, when he became
      suffering from headache and nausea. Cerebral spinal fluid (CSF) analysis on
      admission revealed Cryptococcus neoformans. Neurological examination and brain CT
      scan showed no abnormality. On the 5th hospital day, he noticed ataxia and
      weakness in his right extremities and soon fell into drowsy to comatose state.
      CSF study revealed marked elevation of pleocytosis and oligoclonal IgG bands. The
      T2 weighted image of brain MRI showed multiple high intensity areas, mainly in
      the white matter, in cerebellar hemisphere, vermis, left medulla oblongata, left
      occipital lobe and parieto-occipital lobe. Steroid pulse therapy remarkably
      improved neurological deficit as well as MRI abnormalities. He became alert at
      the next day. Ataxia and motor weakness disappeared in a week. Laboratory
      examination before the pulse therapy revealed impairment of T cell response to
      mitogens and reduced number of CD8-positive cells. These abnormalities in the
      cell-mediated immunity were completely corrected by the steroid pulse therapy. It
      was hypothesized that cryptococcus infection induced the autoimmune mechanism
      which resulted in the ADEM-like exacerbation.

PMID- 8665740
TI  - A critical review of studies of newborn discharge timing.
AB  - The duration of hospitalization for newborns has declined dramatically, driven by
      efforts to control health-care costs as well as by efforts to demedicalize
      childbirth. In order to determine the clinical basis for this practice, the
      quality of the published literature on discharge timing was analyzed. Thirteen
      experimental or quasi-experimental studies were retrieved through a computer
      search. Seven characteristics that influenced the quality of these studies were
      reviewed: research design; measures of effect; sample descriptions; statistical
      methods; reliability measures; sample size; and the definition of early
      discharge, including the use of any related interventions. Although all 13
      studies suggest that there are no differences between infants discharged early
      and their compeers, these studies have three limitations. First, with one
      exception, these reports are from hospitals where well-defined assessment and
      follow-up protocols have been established, potentially limiting their wide
      applicability. Second, these studies lack statistical power to assess the
      likelihood of rare events such as readmission. Third, few studies report outcomes
      other than readmission and medical conditions diagnosed within 1 to 6 weeks.
      Early discharge as the standard of care for well newborns has not been well
      established by empirical studies. Pediatricians and local public health officials
      have a responsibility to assure that the health objectives of hospitalization are
      met whether this occurs in the hospital or through other mechanisms, such as
      routine home visiting.

PMID- 8665741
TI  - High-risk children referred to an early-intervention developmental program.
AB  - Early-intervention programs for infants with developmental disabilities or with
      high-risk factors for such problems were first established in the United States
      more than 20 years ago. The benefits of such programs are generally recognized.
      This study describes the presenting problems of 698 children referred to an early
      intervention program over a 15-year period (1975-1989). Medical condition groups
      rather than specific diagnoses are considered. The developmental progress of 464
      children who attended the program for at least 6 months was determined by
      comparing their admission and discharge developmental quotients (DQ). Admission
      trends over time are noted and the value of intervention programs for young
      children with disabilities is discussed.

PMID- 8665742
TI  - Weaning ages in a sample of American women who practice extended breastfeeding.
AB  - This research examined age and method of weaning in a sample of 179 women who
      practiced extended breastfeeding. The average age for weaning was between 2 years
      6 months and 3 years 0 months and ranged from 1 month to 7 years 4 months.
      Fourteen women had each weaned at least three children, and the youngest children
      were significantly older at the time of weaning than were their older siblings.
      Weaning was described as being "gradual" and "child-led" by the majority of
      women. A smaller, but substantial, percentage of women cited reasons for weaning
      related to a subsequent pregnancy. Weaning ages for women who practice extended
      nursing were substantially older than were those of more typical North American
      mothers and were similar to those in traditional cultures with similar parenting
      practices.

PMID- 8665743
TI  - Extended breastfeeding in the United States.

PMID- 8665744
TI  - Occult spinal dysraphism in the infant.
AB  - The progressive neurologic dysfunction caused by occult spinal dysraphism can be
      prevented with early clinical recognition, radiographic diagnosis, and
      neurosurgical treatment. However, detection of occult spinal dysraphism in the
      infant is difficult because neurologic symptoms often are not apparent until the
      child becomes ambulatory. Occult spinal dysraphism, however, can be suspected in
      the asymptomatic neonate when cutaneous stigmata, such as hemangiomas, hairy
      patches, deep and/or eccentric dimples, or subcutaneous masses are seen over the
      lumbosacral spine. Because of the serious, often irreversible, sequelae of a
      delayed diagnosis, spinal sonography of high-risk infants with midline,
      lumbosacral, cutaneous stigmata should be considered as an effective, noninvasive
      screening method.

PMID- 8665745
TI  - Standard of care: the blind leading the blind?

PMID- 8665747
TI  - Acute respiratory failure in the hemolytic uremic syndrome.

PMID- 8665746
TI  - Nontuberculous Mycobacteria subcarinal lymphadenitis and severe airway
      obstruction.
AB  - This report has emphasized the importance of a careful evaluation of the chest
      roentgenogram for lymphadenopathy in children with wheezing, cough, or other
      symptoms of lower airway disease. This patient report also illustrates that
      intrathoracic lymphadenitis caused by nontuberculous mycobacteria should be
      considered in children with unexplained airway obstruction.

PMID- 8665748
TI  - Transient hypothyroidism in a child treated with alpha-interferon for chronic
      hepatitis B infection.

PMID- 8665749
TI  - Syringomyelia with hypotension.

PMID- 8665750
TI  - Helicobacter pylori disease in childhood.
AB  - Helicobacter pylori (H. pylori) is responsible for one of the most frequently
      encountered infectious diseases worldwide. H. pylori infection can lead to the
      development of gastritis and peptic ulcer disease. The presence of H. pylori in
      the human stomach also represents an increased risk for gastric cancer and
      gastric lymphoma. Epidemiologic data obtained in adults suggest that the actual
      colonization with H. pylori is in fact determined by childhood factors.
      Therefore, the pediatric age group represents the ideal target population for
      studies concerning the pathogenesis and epidemiology of H. pylori infection.

PMID- 8665751
TI  - Effects of heredity, age, weight, puberty, activity, and calcium intake on bone
      mineral density in children.
AB  - Osteoporosis is a disease that plagues older individuals, particularly women. At
      the usual age of diagnosis, limited therapy is available. By further delineating
      the factors that influence bone mineral acquisition before peak bone density is
      achieved, individuals at risk may be identified at an earlier age when therapies
      may be more effective. This was a study of 16 family units, 16 mothers, eight
      fathers, and their 28 children between the ages of 5 and 20 years. The evaluation
      consisted of a focused history, Tanner staging of adolescents, anthropometric
      data (height, weight), and spinal bone mineral density (BMD) by DEXA (dual-energy
      x-ray absorptiometry). Bone mineral density in the children was compared with
      multiple environmental factors. Bone mineral density Z-scores were then compared
      between children and their parents. Variables found to be positively correlated
      with children's BMDs were: age (r = 0.94, P < 0.001), Tanner stage (r = 0.90, P <
      0.001), weight (r = 0.88, P < 0.001), height (r = 0.81, P < 0.001), and body mass
      index (r = 0.77, P < 0.001). No association was found between calcium intake and
      BMD, owing possibly to increased calcium intake among children with a family
      history of osteoporosis. Activity was not significantly associated with BMD.
      Significant correlations were noted between the children's BMD and that of their
      father's (r = 0.83, P = 0.01), premenopausal mother's (r = 0.58, P = 0.03), and
      midparental (the mean value of both parents' BMDs) (r = 0.86, P = 0.01). These
      data suggest that children who have parents affected by low BMD may be at risk
      for low BMD themselves.

PMID- 8665752
TI  - Accuracy of injection site identification among children with insulin dependent
      diabetes mellitus: a comparison of traditional and new visual aids.
AB  - Children with insulin-dependent diabetes mellitus (IDDM) typically self-inject
      insulin twice daily. Injection sites must be rotated with each insulin
      administration to avoid lipohypertrophy. Lipohypertrophy results in erratic
      insulin release and threatens metabolic stability. To aid rotation, children are
      usually provided with a picture of a human figure with injection sites identified
      within a grid. Children often have difficulty using the charts or lack the skills
      necessary to identify injection sites. An alternative three-dimensional visual
      aid, a pair of "injection bears", simplifies injection site identification. Fifty
      eight 6- to 11-year-old children with IDDM identified 10 injection sites using
      both the injection chart and the injection bears. Accuracy of injection site
      identification was compared on five subcomponents. Forty-four percent of
      informants recalled that their doctors recommended using injection charts. Of
      those recalling the recommendation, 81% never or rarely used charts at home.
      Thirty-nine percent of the informants reported a history of lipohypertrophy.
      Matched sample t-tests demonstrated that children committed significantly fewer
      identification errors on all subcomponents (P < or = .05) when using the
      injection bears. Chi square analyses indicated a significant preference (P < or =
      .05) for the injection bears, which may be a useful tool for insulin injection
      rotation with younger children.

PMID- 8665753
TI  - Outcome of respiratory failure: a case-control study.
AB  - Despite the availability of ECMO (extracorporeal membrane oxygenation) services
      for nearly a decade, the criteria for the institution of ECMO for pediatric
      respiratory failure are still not clearly defined. Therefore, a chart review was
      performed on children who were mechanically ventilated more than 48 hours in 1989
      1990 in order to evaluate possible predictors of death from pediatric respiratory
      failure. Twenty-three children died as a consequence of respiratory failure.
      Nonsurvivors in both years were compared with the 78 survivors in 1990, and
      potential predictors were subjected to multivariate analysis. After 4 days of
      mechanical ventilation, an alveolar-arterial oxygen gradient (AaDO2) greater than
      400 torr (53.3 kPa) was a weak predictor of death due to respiratory failure, and
      yet an AaDO2 less than 400 torr (53.3 kPa) was a stronger predictor of
      survivability. Combination of variables did not yield a better predictor than any
      single variable. Early prediction of mortality from respiratory failure in this
      population was not found.

PMID- 8665754
TI  - Addition of rifampin to cephalexin therapy for recalcitrant staphylococcal skin
      infections--an observation.
AB  - We report two pediatric patients with recalcitrant staphylococcal infections
      whose infections resolved when rifampin was added to standard antistaphylococcal
      therapy. One patient had a post-varicella staphylococcal ulcerative lesion and
      did not respond to cephalexin alone but did respond when rifampin was added. A
      second patient had staphylococcal bullous impetigo and did not respond to
      dicloxacillin or cephalexin but did respond when rifampin was added to the
      cephalexin. If a patient fails to respond to traditional antistaphylococcal
      therapy, the addition of rifampin may be beneficial.

PMID- 8665756
TI  - Acute isoniazid overdose in a compliant adolescent patient.

PMID- 8665757
TI  - Adolescent presentation of congenital radioulnar synostosis.

PMID- 8665755
TI  - Multiple sclerosis with onset at 35 months of age.

PMID- 8665758
TI  - Ocular injury from a rooster attack.

PMID- 8665760
TI  - A novel method for neonatal endotracheal suctioning.

PMID- 8665759
TI  - Recommended Childhood Immunization Schedule--United States, January-June 1996.
AB  - In January 1995, the Recommended Childhood Immunization Schedule, developed by
      the Advisory Committee on Immunization Practices (ACIP) the American Academy of
      Pediatrics (AAP), and the American Academy of Family Physicians (AAFP), was
      published. This unified schedule represented the first such schedule developed
      through a collaborative process among the recommending groups, the pharmaceutical
      manufacturing industry, and the Food and Drug Administration. This process is
      intended to maintain a common childhood immunization schedule and to work toward
      further simplification of the schedule. The Recommended Childhood Immunization
      Schedule--United States, January-June 1996 (Figure 1) has been updated by these
      groups to incorporate newly licensed and/or recommended vaccines and to clarify
      specific issues. Since publication of the schedule in 1995, Varicella Zoster
      Virus Vaccine (Var) has been licensed, and recommendations for adolescent
      hepatitis B vaccination have been developed. The following changes are
      incorporated into the Recommended Childhood Immunization Schedule.

PMID- 8665761
TI  - Pediatric considerations in atherosclerosis.

PMID- 8665762
TI  - Medicolegal ramifications of electronic fetal monitoring during labor.
AB  - Fetal heart rate patterns play a significant role in the modern day obstetric
      care. They also play a significant role in medicolegal allegations of negligence
      when the fetus suffers injury. Proper interpretation of the fetal monitor tracing
      is only one factor in the evaluation of the reasonableness of obstetric care.
      Appropriate care and optimal defense both derive from reasonable interpretation
      of pertinent clinical data, including the monitor strip, along with timely
      pursuit of a thoughtful, properly annotated, plan of care.

PMID- 8665763
TI  - Using and archiving the labor curves.
AB  - Optimal interpretation of the events of labor requires integration of information
      about cervical changes, fetal descent, uterine contractions, fetal position and
      attitude, as well as fetal heart rate monitoring and maternal condition. The use
      and understanding of labor curves is a vital part of this process. The complexity
      and diversity of labor data lend itself to computer storage and analysis.

PMID- 8665764
TI  - Intrapartum use of fetal heart rate monitoring, contraction monitoring, and
      amnioinfusion.
AB  - Fetal heart rate monitoring, uterine contraction monitoring, and amnioinfusion
      are procedures used commonly during labor that have also improved our
      understanding of intrapartum physiology, although there are limitations to the
      ability of these procedures to improve pregnancy outcome. The current status of
      intrapartum fetal heart rate monitoring, uterine contraction monitoring, and
      amnioinfusion is reviewed.

PMID- 8665765
TI  - The use of oxytocin.
AB  - Synthetic oxytocin offers a safe and effective means of producing regular uterine
      activity and has a fairly large therapeutic index; however, the mild antidiuretic
      and vasoactive properties of oxytocin increase the risk of water intoxication and
      hypotension. The issue of reduction in cesarean section rates through the use of
      an active management protocol is being studied actively in the United States and
      Canada at this time. The authors recommend infusion protocols for the
      augmentation and induction of labor that use low doses of dilute oxytocin,
      increased at intervals no more than 40 minutes. Pharmacokinetic and clinical
      studies support the use of oxytocin in the physiologic range as efficacious and
      prudent. The longer induction to delivery time demonstrated by some, but not all
      authors, in our opinion, is a reasonable alternative to avoidable uterine
      hyperstimulation with the potential for fetal and maternal injury. We advocate
      the use of the lowest dose necessary to produce adequate uterine contractility
      and cervical change.

PMID- 8665766
TI  - Vacuum-assisted delivery.
AB  - The literature seems to allow certain general conclusions regarding the choice of
      instrument for assisted vaginal delivery. Both forceps and vacuum extraction
      offer certain advantages and drawbacks. Forceps are more difficult to apply, more
      prone to potentially significant facial injuries, require generally better
      maternal analgesia, and are associated with increased maternal soft tissue
      trauma. Vacuum extractors in general are easier to apply, are more likely to
      result in scalp trauma, and may be associated with increased rates of
      intracranial trauma. It seems likely that factors particular to each patient may
      play a significant role in the genesis of delivery associated with maternal and
      neonatal morbidity. Because of the ease of application, vacuum extractors may be
      used potentially in circumstances in which forceps assistance would not be
      attempted, allowing an operator of average experience to perform rotational
      deliveries. The use of vacuum extraction does appear to decrease the incidence of
      cesarean section in delivery populations. Given the apparent association between
      difficult assisted deliveries and increased neonatal morbidity, it is incumbent
      on the operator to attempt delivery only when vaginal delivery seems to be a safe
      option. Furthermore, the operator in such circumstances must be willing to
      reassess the attempt if initial attempts are not met with success. The minimal
      rates of significant intracranial injury associated with vacuum extraction in
      randomized studies of the method demonstrate the relative safety of the vacuum
      extraction when used judiciously. The ultimate choice of the route of delivery
      and method of assisted delivery should reflect a consideration of the fetal
      station, presentation, and maternal and fetal circumstances. It is hoped that
      further investigations in this area may clarify some of the issues discussed in
      this article.

PMID- 8665767
TI  - Forcep deliveries.
AB  - A historical review of the development of forceps and the refinements made that
      lend them to different clinical situations are presented. The proper settings for
      their use and the choice of instruments and methods of application for traction
      and rotation are discussed. The risks to mother and infant are considered.
      Following these general precepts should allow for continued safe usage in modern
      day obstetrics.

PMID- 8665768
TI  - The role of prostaglandins in labor and delivery.
AB  - The use of prostaglandins in obstetrics has undergone a rapid evolution since
      their discovery in the early 1970s. It appears certain now that, at least in some
      cases, prostaglandins are important mediators of uterine activity. Indeed, a much
      stronger case can be made for the role of prostaglandins in labor than can be
      made for oxytocin. The pivotal role of prostaglandins in contraction of the
      smooth muscle of the uterus and the biophysical changes associated with cervical
      ripening, however, point to a major problem with their clinical use.
      Prostaglandins are produced by almost every tissue in the body and serve as
      important messengers or effectors in a wide variety of functions. Attempts to
      inhibit the production of prostaglandins to produce a reduction in myometrial
      contractility are limited by the important role of prostaglandins in maintenance
      of fetal ductal flow and renal blood flow. Similarly, administration of
      prostaglandins for the purpose of inducing labor or ripening an unfavorable
      cervix is tempered by the effects of these agents in other systems, including the
      gut and brain. Significant advances, however, have been made in the application
      of prostaglandins to common clinical problems in obstetrics. Of the multitude of
      products derived from the actions of cyclooxygenase on arachidonic acid, the most
      important for labor, delivery, and the postpartum period are the F and E series
      prostaglandins. Unlike oxytocin which requires an induction of receptors that
      does not usually occur until the later part of pregnancy, prostaglandins
      receptors always are present in myometrial tissue. This allows for the use of
      prostaglandins in usual doses throughout pregnancy. Although both F and E series
      prostaglandins result in uterine contractions, E series prostaglandins are
      relatively more uteroselective and are clearly superior to F series
      prostaglandins in producing cervical ripening. Modification of the naturally
      occurring prostaglandins by blocking the sites that are affected during their
      usual rapid metabolism, results in products with much longer durations of action,
      efficacy at much lower concentrations, and a potential for significant savings in
      cost. We are now able to manage efficiently problems such as intrauterine fetal
      death and intractable hemorrhage from postpartum uterine atony that often
      resulted in a surgical procedure prior to the availability of prostaglandin. We
      can continue to explore the potential of these agents in helping to solve the
      most difficult problems faced by the obstetrician.

PMID- 8665769
TI  - Getting rid of carbon dioxide during exercise.

PMID- 8665770
TI  - Differential effects of low- and high-intensity lower body negative pressure on
      noradrenaline and adrenaline kinetics in humans.
AB  - 1. Lower body negative pressure provides a means to examine neurocirculatory
      reflexive responses to decreases in venous return to the heart. We assessed
      whether the pattern of catecholaminergic responses to lower body negative
      pressure depends on the intensity of the stimulus (-15 versus -40 mmHg). 2. In 14
      healthy subjects, responses of forearm blood flow and noradrenaline spillover and
      of total body noradrenaline and adrenaline spillover were assessed during
      infusion of [3H]noradrenaline and [3H]adrenaline during -15 and -40 mmHg of lower
      body negative pressure. 3. During lower body negative pressure at -15 mmHg, heart
      rate and pulse pressure did not change, but forearm vascular resistance increased
      by 25-50%. Forearm noradrenaline spillover increased by about 50%, from 0.63 +/-
      0.16 to 0.94 +/- 0.23 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline
      spillover did not change, and total body adrenaline spillover increased
      significantly by about 30%. Clearances of noradrenaline and adrenaline were
      unchanged. 4. During lower body negative pressure at -40 mmHg, heart rate
      increased and pulse pressure decreased. Forearm vascular resistance increased by
      about 100%, and forearm noradrenaline spillover increased by 80%, from 0.73 +/-
      0.19 to 1.32 +/- 0.36 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline
      spillover increased by 30%, and total body adrenaline spillover increased by
      about 50%. Clearances of both noradrenaline and adrenaline decreased. 5. The
      results are consistent with the view that selective deactivation of
      cardiopulmonary baroreceptors during low-intensity lower body negative pressure
      increases sympathoneural traffic to forearm skeletal muscle and increases
      adrenomedullary secretion without a concomitant generalized increase in
      sympathoneural outflows. Concurrent deactivation of cardiopulmonary and arterial
      baroreceptors during high-intensity lower body negative pressure evokes a more
      generalized increase in sympathoneural activity, accompanied by further increased
      adrenomedullary secretion and decreased plasma clearances of noradrenaline and
      adrenaline. The findings support differential increases in skeletal
      sympathoneural and adrenomedullary outflows during orthostasis, with more
      generalized sympathoneural responses to systemic hypotension.

PMID- 8665771
TI  - Autonomic control of skin microvessels: assessment by power spectrum of
      photoplethysmographic waves.
AB  - 1. Although it is well known that the microvessels of the skin constantly undergo
      spontaneous variations in volume, the significance of these rhythmic changes
      remains uncertain. 2. In 10 healthy males and in 15 patients in intensive care,
      we assessed the origin of the autonomic influences on spontaneous fluctuations in
      the microcirculation of the skin, obtained by an infra-red photoplethysmographic
      device; we used spectral analysis techniques to compare these fluctuations (which
      were recorded simultaneously in two sites) with those of blood pressure, in order
      to test the presence of autonomic control of any synchronous fluctuations in
      these different measurements from the cardiovascular system. In order to minimize
      mechanical fluctuations caused by occasional slow breaths, rather than nervously
      mediated fluctuations in skin blood flow, respiration was controlled at 15
      breaths/min (0.25 Hz). 3. Spontaneous infra-red photoplethysmographic
      fluctuations were observed in different body areas (left index finger and left
      ear lobe, right and left index finger), and all were evident at 0.1 Hz, as well
      as respiration-related components at 0.25 Hz. Active standing increased the power
      of the 0.1 Hz fluctuations (sympathetic activity) in both blood pressure (from
      62.7 +/- 7.1 to 79.2 +/- 3.7 normalized units, P < 0.05) and IRP (finger: from
      68.5 +/- 6.4 to 86.9 +/- 3.4 normalized units, P < 0.05; ear: from 59.0 +/- 5.9
      to 88.1 +/- 2.0, P < 0.01). There was a high (> 0.5) coherence between the
      fluctuations obtained in blood pressure, in IRP signals obtained simultaneously
      at the finger and at the ear, and in R-R interval. This synchronization between
      the oscillations in all these signals, which were unrelated to the respiratory
      frequency or to the pulse rate, suggests a common neural, non-local origin. The
      phase between IRP and blood pressure was positive in the 0.1 Hz region (+1.65 +/-
      0.41 radians, i.e. IRP was leading blood pressure, showing that 0.1 Hz
      fluctuations were not passively transmitted to the skin microvessels from large
      arteries) and negative in the 0.25 Hz region (-0.74 +/- 0.19 radians, P < 0.01
      compared with phase in the 0.1 Hz region, i.e. IRP was lagging behind blood
      pressure, suggesting possible passive transmission to the skin microvessels of
      blood pressure fluctuations caused by respiration). Fluctuations at lower
      frequency were observed in all IRP recordings, suggesting a local origin for
      these. Intra-arterial and IRP fluctuations were compared in the 15 intensive care
      patients and gave similar results. 4. The skin microcirculation is thus not only
      under local control, but also reflects changes in sympathetic activity; the
      effect of these changes on the skin microcirculation can be easily evaluated by
      the spectral analysis of the IRP signal obtained simultaneously in multiple
      areas, in conjunction with the spectra of R-R interval and blood pressure.

PMID- 8665772
TI  - Role for the endogenous natriuretic peptide system in the control of basal
      coronary vascular tone in dogs.
AB  - 1. While the natriuretic peptides (atrial, brain and C-type) mediate potent
      endothelium-independent vasorelaxing actions in vitro, the role of the endogenous
      natriuretic peptide system in vascular regulation in vivo remains unclear. 2. HS
      142-1 is a novel natriuretic peptide receptor antagonist derived from a fungus
      named Aureobasidium sp. which selectively blocks particulate guanylate cyclase
      linked natriuretic peptide A and B receptors that bind atrial, brain and C-type
      natriuretic peptide, and thus attenuates the generation of cGMP. 3. To
      characterize the vascular actions of the endogenous natriuretic peptide system in
      the control of basal coronary and systemic haemodynamics, six normal male mongrel
      anaesthetized dogs were studied while a second group of five dogs served as a
      control. HS-142-1 was given as an intravenous bolus at 3 mg/kg and was studied
      over five 20 min periods. 4. No significant difference after HS-142-1 was
      observed in mean arterial pressure, heart rate, cardiac output, right atrial
      pressure, pulmonary capillary wedge pressure or systemic vascular resistance
      compared with control. In contrast, a significant increase in coronary vascular
      resistance and decrease in coronary blood flow were observed which were different
      from the baseline values and the responses of the control group. 5. These studies
      demonstrate that HS-142-1 produces vasoconstriction in the coronary circulation.
      We conclude that the endogenous natriuretic peptide system, which is of cardiac
      and endothelial cell origin, is an important regulator of basal coronary vascular
      tone.

PMID- 8665773
TI  - Failure of thrombin inhibition to prevent intracoronary thrombosis in the dog.
AB  - 1. Recurrent occlusion after thrombolysis may be caused by thrombin receptor
      mediated platelet thrombosis occurring in a residual stenosis. To test the
      relative importance of the platelet thrombin receptor under conditions of high
      shear and endothelial damage (the Folts model of intracoronary thrombosis) we
      used the specific thrombin inhibitor recombinant hirudin. 2. A critical coronary
      artery stenosis overlying an area of crushed endothelium was used in a repeated
      measures study of eight open-chest anaesthetized dogs. In the control period,
      recurrent thrombosis occurred at an average rate (+/- SD) of 4.4 +/- 1.4 ml/min2.
      Infusion of recombinant hirudin at 1.6 mg h-1 kg-1 abolished recurrent thrombosis
      in three dogs, but the thrombosis rate averaged 4.7 +/- 2.9 ml/min2 in the
      remaining five animals. 3. Haematological measurements demonstrated the activity
      of recombinant hirudin: thrombin time rose from 13 +/- 3 s to > 165 s universally
      (P < 0.01), partial thromboplastin time rose from 14 +/- 2 s to 29 +/- 10 s (P <
      0.01). Bleeding time rose from 2.3 +/- 0.8 min to 4.7 +/- 1.8 min (P < 0.05). 4.
      It is concluded that specific thrombin inhibition, despite affecting coagulation,
      is relatively ineffective in preventing intracoronary thrombosis under conditions
      of high shear.

PMID- 8665774
TI  - Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric
      oxide synthase, during rodent endotoxaemia.
AB  - 1. The cardiovascular failure in sepsis may result from increased nitric oxide
      biosynthesis, through the diffuse expression of an inducible nitric oxide
      synthase. In such conditions, nitric oxide synthase inhibitors might be of
      therapeutic value, but detrimental side effects have been reported with their
      use, possibly related to the blockade of constitutive nitric oxide synthase.
      Therefore, the use of selective inhibitors of inducible nitric oxide synthase
      might be more suitable. The aim of this study was to evaluate the effects of L
      canavanine, a potentially selective inhibitor of inducible nitric oxide synthase,
      in an animal model of septic shock. 2. Anaesthetized rats were challenged with 10
      mg/kg lipopolysaccharide intravenously. One hour later, they randomly received a
      5 h infusion of either L-canavanine (20 mg h-1 kg-1, n = 15), nitro-L-arginine
      methyl ester (5 mg h-1 kg-1, n = 13) or 0.9% NaCl (2 ml h-1 kg-1, n = 21).
      Lipopolysaccharide induced a progressive fall in blood pressure and cardiac
      index, accompanied by a significant lactic acidosis and a marked rise in plasma
      nitrate. All these changes were significantly attenuated by L-canavanine, which
      also improved the tolerance of endotoxaemic animals to acute episodes of
      hypovolaemia. In addition, L-canavanine significantly increased survival of mice
      challenged with a lethal dose of lipopolysaccharide. In contrast to L-canavanine,
      nitro-L-arginine methyl ester increased blood pressure at the expense of a severe
      fall in cardiac index, while largely enhancing lactic acidosis. This agent did
      not improve survival of endotoxaemic mice. In additional experiments, we found
      that the pressor effect of L-canavanine in advanced endotoxaemia (4 h) was
      reversed by L-arginine, confirming that it was related to nitric oxide synthase
      inhibition. In contrast, L-canavanine did not exert any influence on blood
      pressure in the very early stage (first hour) of endotoxaemia or in the absence
      of lipopolysaccharide exposure, indicating a lack of constitutive nitric oxide
      synthase inhibition by this agent. 3. In conclusion, L-canavanine produced
      beneficial haemodynamic and metabolic effects and improved survival in rodent
      endotoxic shock. The actions of L-canavanine were associated with a selective
      inhibition of inducible nitric oxide synthase and were in marked contrast to the
      deleterious consequences of nitro-L-arginine methyl ester, a non-selective nitric
      oxide synthase inhibitor, in similar conditions.

PMID- 8665775
TI  - Nitric oxide in streptozotocin-induced diabetes mellitus in rats.
AB  - 1. The present study was performed to determine the relationship between diabetic
      glomerular hyperfiltration and nitric oxide as modulated by the chronic
      administration of L-arginine and/or N-omega-nitro-L-arginine, a known nitric
      oxide synthase inhibitor in streptozotocin-induced diabetic rats. 2. Normal rats
      and rats drinking hypertonic glucose (10%) were used as time-controlled groups.
      Six weeks after administration of streptozotocin the diabetic rats had
      significantly higher creatinine clearance (667 +/- 53 microliters min-1 100 g-1
      body weight) than before and streptozotocin (456 +/- 38 microliters min-1 100 g-1
      body weight, P < 0.005) and very high plasma (37.8 +/- 10.9 mumol/l) and urinary
      (3.492 +/- 0.179 nmol min-1 100 g-1 body weight) nitrite+nitrate (stable
      metabolites of nitric oxide) values compared with before streptozotocin
      administration [19.3 +/- 2.8 mumol/l (P < 0.001) and 0.420 +/- 0.051 nmol min-1
      100 g-1 body weight (P < 0.001) respectively]. The 6-week diabetic rats had
      higher systolic blood pressure (124.2 +/- 2.9 mmHg, P < 0.05) than before
      streptozotocin (108 +/- 8 mmHg), but had a value similar to that of the
      hypertonic-glucose-drinking rats. 3. The diabetic rats supplemented with L
      arginine did not show an increase in creatinine clearance and had a lower urinary
      excretion of nitrite+nitrate (0.999 +/- 0.27 nmol min-1 100 g-1 body weight, P <
      0.005) than the respective untreated streptozotocin-induced diabetic rats.
      Creatinine clearance increased in the normal and glucose-drinking rats that
      received L-arginine. The administration of L-arginine resulted in significant
      reduction in blood pressure in all groups studied. The chronic nitric oxide
      synthase inhibitor resulted in high blood pressure, and in a significant decrease
      in creatinine clearance and urinary nitrite+nitrate excretion in all groups
      studied. In both diabetic and glucose-drinking rats, the L-arginine therapy
      resulted in significantly lower plasma and urinary glucose levels than in their
      respective untreated control groups. 4. The nitric oxide synthase inhibitor
      increased the plasma and urinary glucose concentration in both diabetic and
      glucose-drinking rats. 5. Our results indicate that diabetic rats are
      characterized by high plasma concentrations and elevated urinary excretion of
      nitrite+nitrate, suggesting a state of high nitric oxide production. The vascular
      response to nitric oxide in diabetic rats may be different at the glomerular and
      peripheral vascular bed.

PMID- 8665777
TI  - Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme
      inhibition in rats with established adriamycin nephrosis.
AB  - 1. The mechanism of renal protection by angiotensin-converting enzyme inhibition
      is still the subject of debate. Inhibition of proteinuria might play a role. If
      so, a good antiproteinuric response to angiotensin-converting enzyme inhibition
      should predict subsequent protection against renal structural damage. This
      hypothesis has not been tested in models where treatment is started after the
      renal disease is well established, i.e. models that mimic the clinical situation.
      2. We therefore investigated this hypothesis in 96 male Wistar rats with
      established adriamycin nephrosis. Reduction of proteinuria was achieved by
      lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and
      0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and
      was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and
      proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks.
      Considerable interindividual differences in antiproteinuric response was found.
      Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin
      converting enzyme inhibitors were enhanced by sodium depletion, but sodium
      depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria
      (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the
      more proteinuria was reduced initially in an individual rat, the less sclerosis
      was found in the long term in that rat. 4. In conclusion, angiotensin-converting
      enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in
      established adriamycin nephrosis. These effects are enhanced by sodium depletion.
      The individual short-term antiproteinuric effect predicts the protection against
      ultimate glomerular damage. This is consistent with the hypothesis that reduction
      of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors
      exert renoprotection.

PMID- 8665776
TI  - Action of endothelin-1 on glomerular haemodynamics in the dog: lack of direct
      effects on glomerular ultrafiltration coefficient.
AB  - 1. Although numerous studies have demonstrated the potent vasoconstrictor effect
      of endothelin-1 on the renal vasculature, it is difficult to differentiate in
      vivo between indirect and direct actions of endothelin. 2. In the present study
      we therefore performed micropuncture experiments in 14 anaesthetized dogs after
      the administration of endothelin-1 into the renal artery (i.r.a.) for 15 min at a
      dose of 2.78 ng min-1 kg-1 which did not affect blood pressure or contralateral
      kidney function. 3. In seven dogs on a 'normal' sodium diet (3.5 mmol of NaCl day
      1 kg-1) endothelin-1 resulted in decreases in renal blood flow and glomerular
      filtration rate with a rise in filtration fraction from 0.24 +/- 0.01 to 0.35 +/-
      0.01. Similar changes were seen at the single-nephron level. An increase from
      0.11 +/- 0.01 to 0.23 +/- 0.02 (+109 +/- 11%) in efferent, and from 0.15 +/- 0.01
      to 0.24 +/- 0.02 mmHg min-1 microliter-1 (+58 +/- 4%) in afferent arteriolar
      resistance was observed. The ultrafiltration coefficient, Kf, decreased from 4.75
      +/- 0.14 to 3.67 +/- 0.14 microliter min-1 mmHg-1 (P < 0.01). 4. In another group
      of seven dogs, the same endothelin-1 infusion was given after an administration
      into the renal artery of a 'cocktail' designed to block the receptors of alpha-
      and beta-adrenergic agonists, thromboxane A2, leukotrienes and angiotensin II
      together with intravenous cyclo-oxygenase inhibition. Under these conditions, the
      vasoconstrictor action of endothelin-1 was reduced by more than 30%. The increase
      in vascular resistance was now relatively similar in both arterioles, i.e. +44 +/
      5% in the afferent and 66 +/- 6% in the efferent arterioles (no significant
      difference). No change in Kf was seen after the 'cocktail'-blockade (9.4 +/- 0.4
      versus 10.1 +/- 0.1 microliter min-1 mmHg-1). 5. In conclusion, in anaesthetized
      dogs on a 'normal' salt diet, the vasoconstrictor effect of endothelin-1 is more
      pronounced on the efferent than on the afferent arteriole. This is accompanied by
      decreases in glomerular filtration rate and water, urea and electrolyte
      excretion. Part of the vasoconstrictor action of endothelin seems to be mediated
      by other autacoids. Endothelin-1 itself contributes only partly to pre- and post
      glomerular vasoconstriction and has no direct effect on the glomerular
      ultrafiltration coefficient Kf.

PMID- 8665778
TI  - Enhanced phospholipase A2 activity in cultured cardiomyocytes from newborn
      spontaneously hypertensive rat.
AB  - 1. Changes in membrane lipid composition and metabolism could participate in
      myocardial membrane dysfunction in essential or experimental hypertension.
      Phospholipid-bound fatty acid profile and metabolism are altered in cultured
      heart myocytes of newborn genetically hypertensive rats. The present study was
      designed to investigate the participation of phospholipase A2 in these
      modifications. 2. Phospholipase A2 activity of cultured cardiomyocytes of neonate
      spontaneously hypertensive rats and normotensive control Wistar-Kyoto rats was
      compared. The enzyme activity was measured using 2-[1-14C]arachidonyl
      phosphatidylethanolamine as substrate. In both strains, Ca(2+)-dependent and
      independent phospholipase A2 activities were present. Only the Ca(2+)-dependent
      enzyme activity was altered in spontaneously hypertensive rat cardiomyocytes.
      With 0.2 mmol/l substrate and 5 mmol/l Ca2+, the phospholipase A2 activities were
      79.0 +/- 13.4 and 26.0 +/- 3.6 nmol h-1 mg-1 of protein in spontaneously
      hypertensive and Wistar-Kyoto rat cardiomyocytes respectively (n = 10 in both
      cases, P = 0.001). The maximum velocity of the enzyme was three times higher in
      spontaneously hypertensive rat than in Wistar-Kyoto rat, without changes in the
      apparent affinity of the enzyme for its substrate. 3. The present results
      demonstrate an enhanced phospholipase A2 activity in cultured heart muscle cells
      of spontaneously hypertensive rats, which could be genetically determined.

PMID- 8665779
TI  - Carbohydrate metabolism in insulin resistance: glucose uptake and lactate
      production by adipose and forearm tissues in vivo before and after a mixed meal.
AB  - 1. To examine whether insulin resistance in vivo is manifest equally in both
      muscle and adipose tissues, we measured arteriovenous glucose and lactate fluxes
      across forearm (muscle) and abdominal subcutaneous (adipose) tissue in nine
      obese, glucose-intolerant subjects and 13 non-obese subjects of similar age and
      sex. 2. Compared with non-obese subjects, the forearm of the obese subjects was
      resistant to insulin stimulation of glucose uptake after a mixed meal. In
      contrast, adipose tissue showed little evidence of insulin stimulation of glucose
      uptake, and adipose tissue in subjects in both normal and obese groups behaved
      very similarly (assessed per 100 g of tissue). 3. For lactate flux, adipose
      tissue behaved very similarly (per 100 g of tissue) in obese and non-obese
      subjects, and was a consistent lactate exporter. 4. We conclude that insulin
      resistance of glucose uptake observed in the forearm of obese subjects is not
      evident in adipose tissue. Adipose tissue glucose uptake in obese, insulin
      resistant subjects is similar to that in lean control subjects, although it
      occurs at elevated circulating insulin and glucose concentrations.

PMID- 8665780
TI  - Chemical characterization and quantification of proteoglycans in human post-burn
      hypertrophic and mature scars.
AB  - 1. Samples of normal skin from four patients, post-burn hypertrophic scar from
      five patients and post-burn mature scar from six patients were analysed for
      hydroxyproline, water and uronic acid and extracted with guanidinium chloride to
      yield the proteoglycan pool. A large chondroitin sulphate proteoglycan and
      biglycan were purified from one hypertrophic scar biopsy and decorin from a
      normal skin biopsy, by ion-exchange chromatography, gel-filtration and
      hydrophobic interaction chromatography. These purified proteoglycans were used in
      an inhibition ELISA assay to estimate the quantities of each in the tissue
      samples. 2. Samples of post-burn hypertrophic scar had on average 30% less
      hydroxyproline, 12% more water and 2.4 times as much uronic acid as normal skin.
      These differences were all statistically significant, whereas the small
      differences between mature scars and normal skin were not. The content of decorin
      in hypertrophic scars was only 25% of that in normal skin whereas the large
      chondroitin sulphate proteoglycan and biglycan were each about 6-fold higher. The
      mature scars had slightly elevated levels of large chondroitin sulphate
      proteoglycan and biglycan and a reduced content of decorin compared with normal
      skin but these differences were not statistically significant. 3. The results
      suggest that aberrant proteoglycan metabolism is a significant factor
      contributing to the altered physical properties of hypertrophic scars and that
      maturation of post-burn scars is dependent on a return of the relative
      proportions and concentrations of proteoglycans to those characteristic of normal
      dermis.

PMID- 8665781
TI  - Luminal epidermal growth factor preserves mucosal mass of small bowel in fasting
      rats.
AB  - 1. Fasting causes atrophy of small bowel mucosa which rapidly resolves with
      luminal feeding. This effect of enteral nutrient may be mediated by stimulation
      of growth factor secretion. We therefore evaluated whether luminal administration
      of epidermal growth factor, a peptide hormone found in gastro-intestinal contents
      and trophic for small bowel mucosa, would prevent the mucosal atrophy associated
      with starvation. 2. Adult rats were: (i) fasted for 3 days, (ii) fasted and then
      refed for 1 day or (iii) fasted and then refed for 2 days. During the 2 days
      before study, animals in each group received infusions of epidermal growth factor
      (2.5 micrograms/day) or diluent alone into distal jejunum. 3. Epidermal growth
      factor treatment of fasted animals resulted in a tripling of mucosal ornithine
      decarboxylase activity (P < 0.001) and a doubling of mucosal DNA content (P <
      0.001) in the jejunum, values similar to those of refed animals. Epidermal growth
      factor infusion in refed rats resulted in a further doubling of mucosal ornithine
      decarboxylase activity (P < 0.001), but no additional increase in DNA content.
      Effects of epidermal growth factor infusion were generally greater in jejunum
      than ileum. 4. In conclusion, luminal exposure to epidermal growth factor
      prevents starvation-induced mucosal atrophy in the small bowel, but does not
      enhance the mucosal growth associated with refeeding. Effects are greatest at the
      site of administration. Luminal epidermal growth factor is a potential mediator
      of the indirect effects of nutrient on mucosal growth in the small bowel. Enteral
      administration of epidermal growth factor holds promise for preventing atrophy
      and maintaining mucosal integrity in starved and post-operative patients.

PMID- 8665782
TI  - Multiple definitions of 'compliance'.

PMID- 8665783
TI  - Structural and pathologic changes in the lung vasculature in chronic liver
      disease.
AB  - The hepatopulmonary syndrome results from erythrocytes bypassing the lung without
      oxygenation. In addition to ventilation-perfusion mismatching, the hypoxemia may
      result from portapulmonary shunting, passage around alveoli through pleural and
      hilar blood vessels, and intrapulmonary vascular dilatations. Dilated vascular
      channels between arteries and veins on the pleural surface are seen more often
      than dilated intrapulmonary capillaries in chronic liver disease. These
      anastomoses appear grossly as vascular "spider nevi" on the pleura. Portal vein
      to-pulmonary vein anastomoses could produce arterial hypoxemia because the
      deoxygenated portal venous blood can mix with oxygenated pulmonary venous blood.
      There is an association of esophageal varices with the hepatopulmonary syndrome
      and anastomoses between the portal veins and pulmonary veins have been found in
      both animals and humans. As portal pressures increase, the mediastinal veins
      enlarge, enhancing the chance that they may penetrate the pleura and drain into
      pulmonary veins. Direct splenic injections in patients, however, suggest that
      this shunt pathway is uncommon and small. Pulmonary artery injection studies have
      demonstrated dilated intrapulmonary vascular segments in humans and animals.
      Dilation of capillaries may allow a more rapid flow through the lung and the
      greater distance between the erythrocyte and alveolar wall may make it more
      difficult to oxygenate rapidly passing erythrocytes. Pulmonary capillary dilation
      can explain the abnormalities of the perfusion lung scan and contrast
      echocardiogram that portapulmonary shunting cannot. Pulmonary hypertension may
      occur in chronic liver disease even without arterial hypoxemia, but it is rare.
      The prevalence of hypertensive pulmonary vascular disease in patients with
      cirrhosis of the liver is less than 1%, although a higher percentage (2%) has
      been found when patients with portal hypertension were studied by cardiac
      catheterization. The hypertensive pulmonary vascular disease (pulmonary
      arteriopathy with plexiform lesions) that occurs in patients with liver disease
      appears identical to that encountered in patients with congenital cardiac shunts
      and unexplained (primary) pulmonary hypertension.

PMID- 8665784
TI  - The hepatopulmonary syndrome. Effect of liver transplantation.
AB  - The role of liver transplantation as a treatment for the hepatopulmonary syndrome
      (HPS) has had an evolving and controversial history. Although early experience
      was disappointing, more recent experience has documented resolution of HPS
      associated hypoxemia after liver transplantation. This article reviews the
      history of liver transplantation for patients with the hepatopulmonary syndrome.
      In addition, we discuss the clinical features that have been considered to
      predict successful reversibility and the time frame over which reversal occurs.
      Despite this evolution of thought, many basic questions still remain.

PMID- 8665785
TI  - Pulmonary intravascular macrophages. Role in acute lung injury.
AB  - PIMs, although present only in selected animal species, may provide a clue to the
      potential role of mononuclear phagocytes on the vascular side of the air-blood
      barrier in lung inflammation and injury. We know PIMs localize circulating
      pathogens to the lungs in animals and concentrate the inflammatory response in
      the lung parenchyma. In certain disease states-e.g., biliary cirrhosis-pulmonary
      phagocytes may develop in the pulmonary capillaries, placing the lungs at risk
      for pathogen localization and subsequent inflammation. The two experimental
      approaches described last in this article-induction of intravascular macrophages
      in the lungs of rodents or rabbits and the selective inhibition or destruction of
      PIMs-offer models to study the role of mononuclear phagocytes in lung injury. The
      cirrhotic rat, especially, offers a model to investigate the interaction between
      pulmonary phagocytes and liver disease, including the adhesive molecules
      necessary for monocytes to adhere and differentiate in pulmonary capillaries. We
      then can investigate whether such factors arise in human lungs. We now can
      determine selectively whether macrophages can cause lung injury and what
      mediators they may contribute to the complex interactions among inflammatory
      cells, cytokines, proteases, oxygen radicals, and lipid mediators that
      participate in early sepsis-induced lung injury.

PMID- 8665786
TI  - Pulmonary intravascular phagocytosis in liver disease.
AB  - Pulmonary intravascular phagocytosis, the uptake of circulating particles by lung
      cells, has been detected in rats with chronic biliary cirrhosis and in humans
      with malignancy and liver diseases. Clinical and experimental evidence supporting
      the association of pulmonary intravascular phagocytosis with liver cirrhosis is
      reviewed, and its relationship to pulmonary intravascular macrophage is
      discussed. A hypothesis is asserted that the induction of pulmonary intravascular
      macrophage in liver cirrhosis leads to increased susceptibility to adult
      respiratory distress syndrome in these patients.

PMID- 8665787
TI  - Mediators, cytokines, and growth factors in liver-lung interactions.
AB  - Multiple mediators have been implicated in the interactions between the liver and
      the lungs in various disease states. The best characterized mediator of liver
      lung interaction is alpha 1-antitrypsin. Several cytokines and mediators may be
      involved in the pathogenesis of the hepatopulmonary syndrome and in the cytokine
      cascades that are activated in systemic inflammatory states such as acute
      respiratory distress syndrome. Hepatocyte growth factor or scatter factor is a
      recently described peptide with a broad range of biologic effects that may
      mediate lung-liver interactions.

PMID- 8665788
TI  - Pulmonary hypertension in chronic liver disease.
AB  - Pulmonary hypertension develops in approximately 2% of patients with portal
      hypertension. Diagnosis is often difficult and requires a high degree of clinical
      suspicion. Treatment of patients with portal and pulmonary hypertension is
      limited, and mean survival following diagnosis is approximately 15 months. The
      effect of liver transplantation on the natural history of disease is discussed.

PMID- 8665789
TI  - Hepatopulmonary syndrome. A pulmonary vascular complication of liver disease.
AB  - Hepatopulmonary syndrome is part of the spectrum of pulmonary vascular disorders
      seen in advanced liver disease. The pathophysiology of these entities likely is
      dependent on the degree of pulmonary vasoconstriction or vasodilation that
      occurs. Our understanding of hepatopulmonary syndrome has helped further our
      knowledge of the interaction of the liver and the lung. Advances in the
      management of this disorder, especially liver transplantation, finally have
      allowed us to offer some hope to patients with this disease.

PMID- 8665790
TI  - Mechanisms of gas exchange impairment in patients with liver cirrhosis.
AB  - This article reviews the basic pathophysiologic mechanisms underlying the
      abnormal pulmonary gas exchange often seen in patients with cirrhosis. To
      summarize, the following keypoints seem appropriate: (1) Patients with cirrhosis
      have a low pulmonary vascular tone characterized by a poor or absent hypoxic
      pressor response. This results in a marked dilation of the pulmonary vasculature.
      (2) This abnormal pulmonary vascular tone, independently of airway disease,
      causes VA/Q mismatch and mild to moderate hypoxemia. Yet, as liver disease
      progresses and hepatocellular function deteriorates, more severe degrees of
      intrapulmonary shunt emerge and, probably, O2 diffusion limitation ensues,
      causing severe respiratory failure (see Table 1). (3) At rest, the high cardiac
      output and minute ventilation of cirrhosis minimize the degree of arterial
      hypoxemia that otherwise would be expected from the observed degree of both VA/Q
      inequality and intrapulmonary shunt. During exercise, the relative
      "normalization' (with respect to metabolic demands) of the hemodynamic and
      ventilatory status of the patient explains the fall in PaO2. (4) A clear
      pathogenic mechanism of these pathophysiologic abnormalities is still lacking,
      although available evidence suggests that both the liver and the endothelial
      cells may play a pivotal role in the regulation of the pulmonary vascular tone in
      these patients. (5) To date, no pharmacologic intervention has been effective in
      treating hypoxemia in these patients. Yet liver transplantation helps in most of
      them. This observation reinforces the functional nature of the gas exchange
      abnormalities of cirrhosis.

PMID- 8665791
TI  - Recent pulmonary observations in alpha 1-antitrypsin deficiency, primary biliary
      cirrhosis, chronic hepatitis C, and other hepatic problems.
AB  - Patients with metabolic, immunologic, viral, and other types of hepatic disorders
      can have a spectrum of complicating pulmonary abnormalities. The natural history
      of these associations is poorly understood. Significant reversibility in hepatic
      and pulmonary dysfunction, however, has been well documented in the era of organ
      transplantation. The continued relationship among pulmonologists, hepatologists,
      and transplant surgeons hopefully will provide enlightening data on these
      interesting clinical associations, their natural histories, and their response to
      evolving therapeutic approaches.

PMID- 8665792
TI  - Lung-liver interactions in sepsis and multiple organ failure syndrome.

PMID- 8665794
TI  - New algorithmic-based digital filter processing system for real-time continuous
      blood pressure measurement and analysis in conscious rats.
AB  - A new algorithmic-based digital filter processing system for real-time continuous
      blood pressure (BP) measurement and analysis in freely-moving conscious rats has
      been developed. Real-time recognition of BP waveforms, real-time noise rejection
      and determination of representative waveform indexes (WIs) at indicated time
      points using digital filters and Smirnov's rejection test were realized with this
      system. Digital filters were applied for two different purposes: waveform
      segmentation and smoothing the calculations of representative WIs. Smirnov's
      rejection test was used for real-time noise rejection and yielded an accurate
      rejection rate of 99.99%. The result was that the digital filter processing and
      Smirnov's rejection test realized accurate real-time BP measurement and analysis
      in freely-moving conscious rats using a personal computer.

PMID- 8665793
TI  - Pulmonary complications of liver transplantation.
AB  - The preoperative pulmonary evaluation of organ transplant candidates involves the
      diagnosis of unexplained pulmonary infiltrates or symptoms, interpretation of
      pulmonary function abnormalities, and an assessment of surgical risk.
      Pretransplant pulmonary considerations in patients with end-stage hepatic
      diseases relate primarily to hypoxemia from poorly understood intrapulmonary
      vascular dilatations, mechanical dysfunction, and states of increased
      extravascular lung water. Except in severe cases, however, these generally do not
      prohibit liver transplantation, and even are likely to improve after transplant
      surgery. Early postoperative complications may be categorized as those expected
      from extensive intra-abdominal surgery that requires significant volume
      resuscitation, which typically are managed in the usual manner for those clinical
      situations. As immunosuppression begins to have an effect, the LTx recipient
      becomes susceptible to the same opportunistic infectious organisms (with their
      frequent pulmonary involvement) that cause significant morbidity and mortality in
      recipients of other solid organ transplants. Because many of the
      immunosuppressive agents also are the same, noninfectious side effects such as
      pulmonary edema and malignancy also are similar. As with all immunocompromised
      patients, prophylaxis, when possible, persistent infection surveillance, and an
      aggressive diagnostic and therapeutic approach help decrease the impact of
      pulmonary dysfunction in LTx recipients.

PMID- 8665795
TI  - Computer implementation in the reconstruction of 2-D flow velocity fields in
      ultrasound Doppler color imaging.
AB  - Doppler color imaging can easily render flow information within the vessels and
      simultaneously provide anatomic information for diagnostic purposes. However, the
      angle dependence problem of the Doppler velocity measurement is a significant
      barrier for continuing progress toward quantitative clinical applications of this
      technology. This paper presents a method and the computer implementation for
      reconstruction of the 2-D flow velocity field (angle independent) in ultrasound
      Doppler color imaging. Formulae for deriving angle independent velocity amplitude
      and angle direction from the color images acquired with a linear array transducer
      are given. The hardware configuration of the data acquiring and processing system
      is described. Major considerations in the development of algorithms, especially
      the strategies for reducing the computation time are presented.

PMID- 8665797
TI  - Simulation of stochastic micropopulation models--IV. SNAPPERS: model
      implementation for genetic traits.
AB  - The current paper concerning stochastic micropopulation simulations describes
      SNAPPERS, which serves as a framework for simulation models of the genetic
      transmission of disease. The versions described are implemented using the
      simulation shell, SUMMERS, which includes the generic commonalities of several
      micropopulation models. Population members in SNAPPERS move through states
      related to the individual's status relative to the genotype (phenotype). Features
      of the model include one or two major loci, polygenic and common familial
      contribution to the phenotype, assortative mating, and flexibility in defining
      gene action. The user can select from multiple ascertainment strategies for
      analysis of simulated families.

PMID- 8665796
TI  - Analytic solution of the Variable-Volume Double-Pool urea kinetics model applied
      to parameter estimation in hemodialysis.
AB  - An analytic solution of the Variable-Volume Double-Pool urea kinetics model and
      its application to the estimation of clinically relevant parameters of the
      patient-machine system, are presented. These include the urea distribution volume
      and generation rate and the mean dialyzer clearance. The estimation of these
      parameters is based on the assumption of constant values for the diffusion
      coefficient between the two pools and the intra-extracellular volume ratio.
      Results obtained by computer simulations show that the effect of a +/- 50%
      variation of these parameters influences the estimates less than standard
      measurement errors. Starting from these results, four methods to in vivo estimate
      the urea distribution volume and generation rate from blood samples are compared.
      Two methods are based on the analytic solution of the double-pool model using
      seven samples (reference method) or three samples (new clinical method). The
      remaining methods are based on urea mass-balance and are largely used in the
      clinical practice. These last techniques differ from each other for the blood
      sample taken at the end of the treatment or 30 min later. The results obtained
      from hemofiltration sessions show that the urea generation rate is accurately
      estimated by all methods. The total distribution volume is still accurately
      estimated by the new clinical method while it is systematically underestimated by
      the urea mass-balance when the blood sample at the end of dialysis is used.
      Instead, a high overcompensation results using the blood sample taken 30 min
      after the end of dialysis. Finally, the new clinical method also provides
      reliable estimates for the dialyzer clearance starting from only three blood
      samples all taken during dialysis.

PMID- 8665798
TI  - Automated exploration of two-level interrelations of differently-scaled
      variables.
AB  - The SAS macro EXPLORE is conceived as an exploratory data analysis tool. Its
      output is an extension to the traditional correlation matrix, allowing the
      assessment of both categorical and numerical data 'at one look'. Depending on the
      type of data, appropriate statistics and graphs are produced. An overview of the
      features of the program and their implementation is given. Program invocation and
      execution are explained. Potential misuses are discussed.

PMID- 8665799
TI  - Definition and application of a fourier domain texture measure: applications to
      histological image segmentation.
AB  - A texture measure is defined for the purpose of two-dimensional histological
      image classification, based upon a novel exploitation of the modulus of the
      Fourier transform. Its implementation in the form of an algorithm is presented
      and discussed, and employed to classify a set of histological images. The
      results, which were obtained by the analysis and classification of different
      mammalian tissue types, compare favourably with established texture recognition
      techniques. Furthermore, the results suggest that the method has a comparable
      performance to other techniques at reduced storage and time costs for images of a
      high grey level resolution.

PMID- 8665800
TI  - Extrinsic regulation of domestic animal-derived satellite cells.
AB  - Satellite cells are the postnatal myogenic cells, as they provide myonuclei to
      support skeletal muscle hypertrophy and are principal cells responsible for
      myofiber repair and regeneration. Even though research with satellite cells from
      meat animals is new, considerable data exist to suggest that these cells are
      regulated through both intrinsic and extrinsic mechanisms. This review covers the
      present status of the extrinsic factors known or postulated to modulate meat
      animal satellite cell growth and development.

PMID- 8665801
TI  - Purification and properties of porcine allantoic fluid retinol-binding protein.
AB  - Retinol-binding protein (RBP) was purified from Day 60 porcine allantoic fluid by
      a combination of diethylaminoethyl cellulose, G-100 Sephadex, G-50 Sephadex,
      Phenyl-Sepharose, and Reactive Green 19-dye-agarose chromatography. the yield was
      1 to 2 mg of RBP, which generated a single M(r) approximately 20,000 band after
      sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and up to
      four isoelectric variants (isoelectric variants 1 to 4) after two-dimensional
      PAGE (2D-PAGE). The protein cross-reacted with antiserum raised against human
      RBP. When incubated with [3H]retinol and subjected to G-100 Sephadex
      chromatography, [3H]retinol coeluted with the protein. These results indicate
      that the purified protein is an RBP. When purified RBP was subjected to native 2D
      PAGE, six forms of RBP were observed. Three native forms were fluorescent, and
      three were not fluorescent, suggesting that these forms were RBP with and without
      retinol, respectively. Denaturing 2D-PAGE analysis of each native form of RBP
      suggested that two of the nonfluorescent and two of the fluorescent native forms
      of RBP corresponded to isoelectric variant 1 on denaturing 2D-PAGE, whereas the
      other fluorescent and nonfluorescent forms corresponded to isoelectric variant 2.
      The incubation of RBP with 50 microM retinol enhanced the amount of both
      isoelectric variants present as fluorescent RBP, but uptake by isoelectric
      variant 1 was greater than that by isoelectric variant 2. These data indicate
      that RBP can be purified from porcine allantoic fluid and suggest that the
      isoelectric variants may differ in their affinity for retinol.

PMID- 8665802
TI  - Hormonal regulation of peripheral blood mononuclear cells in sheep.
AB  - The presence of growth hormone receptors (GHR) on sheep peripheral blood
      mononuclear (PBMN) cells was studied in two ways. The first was to directly
      measure specific GH-binding sites on PBMN cells drawn from lambs from birth to 5
      months of age. The second was to measure the effect of GH on resting and
      interleukin-2 (IL-2)-activated PBMN cells in vitro and also the effect of other
      hormones such as prolactin (PRL), insulin-like growth factor-1 (IGF-1), and
      glucocorticoid. The specific binding of [125I]human GH (hGH) was low on PBMN
      cells but increased (P < 0.05) with age up to 5 months. Interestingly, serum
      concentrations of GH-binding protein also increased (P < 0.01) with age and were
      highly correlated (r = 0.89; P < 0.05) with the specific binding of GH to PBMN
      cells. The addition of ovine GH (oGH) to PBMN cells in vitro resulted in
      increased (P < 0.01) proliferation (at a dose of 100 ng/ml). Higher doses of oGH
      (2 micrograms/ml) also increased PBMN cell proliferation. When PBMN cells were
      previously stimulated with IL-2, the dose of 100 ng/ml) oGH was no longer able to
      stimulate proliferation. IGF-1 inhibited (P < 0.04) resting PBMN cell
      proliferation at 100 ng/ml but had no effect on IL-2-activated PBMN cells. Other
      hormones such as PRL caused a stimulation of PBMN cell proliferation (P < 0.01)
      at 100 ng/ml, whereas dexamethasone (dex) inhibited PBMN cell proliferation at
      doses as low as 63 ng/ml. These studies show that GH, PRL, IGF-1, and
      glucocorticoids are effective in modulating the proliferation of PBMN cells from
      sheep and therefore suggest that a modulation of immune system function in vitro
      by these hormones is consistent with a purpose in vivo.

PMID- 8665803
TI  - Ontogenies of messenger RNA encoding tissue inhibitor of metalloproteinases 1 and
      2 within bovine periovulatory follicles and luteal tissue.
AB  - Tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) are important
      regulators of extracellular matrix remodeling and also possess growth factor
      activity. The objective of these studies was to characterize TIMP-1 and TIMP-2
      mRNA expression by bovine periovulatory follicles/ corpora hemorrhagica
      (Experiment 1) and luteal tissue (Experiment 2). In Experiment 1, beef heifers (n
      = 27) were ovariectomized at-16 (n = 6), 0 (n = 5), 8 (n = 3), 16 (n = 4), 24 (n
      = 4), or 48 (n = 5) hr relative to a gonadotropin-releasing hormone induced
      gonadotropin surge (40 hr after prostaglandin F2 alpha-induced luteolysis). Total
      cellular RNA was isolated from the large steroidogenically active follicle or
      corpus hemorrhagicum obtained from each animal, and the expression of TIMP-1 and
      TIMP-2 mRNA was subsequently examined by northern and dot blot analysis. The
      expression of TIMP-1 or TIMP-2 mRNa did not differ in preovulatory follicles
      collected at -16 vs. 0 hr. Concentrations of both TIMP-1 and TIMP-2 mRNA
      (picograms per microgram of tissue DNA) were increased (P < 0.05) at 8 hr
      postgonadotropin surge, had declined to presurge levels by 24 hr (P < 0.05), and
      were increased (P < 0.05) in corpora hemorrhagica collected at 48 hr after a
      gonadotropin surge. In Experiment 2, corpora lutea were collected from beef
      heifers on Days 4, 10, 15 (n = 4 each), or 19 (n = 3) postestrus (Day 0 =
      estrus). Concentrations of TIMP-1 mRNA (picograms per microgram of tissue DNA)
      were greater in corpora lutea collected on Day 4 (P < 0.05) vs. Day 10, 15, or
      19. Concentrations of TIMP-2 mRNA increased (P < 0.05) from Day 4 to 15 and
      decreased (P < 0.05) by Day 19. We conclude that: 1) during the periovulatory
      period, the ontogenies of TIMP-1 and TIMP-2 mRNA expression are similar, whereas
      2) during luteal phase, TIMP-1 mRNA expression is maximal during the early luteal
      phase, whereas concentrations of TIMP-2 mRNA peak during the midluteal phase.
      TIMP-1 and TIMP-2 may play important roles in the regulation of extracellular
      matrix remodeling during the periovulatory period and the subsequent luteal
      phase.

PMID- 8665804
TI  - Assessment of a combined anterior pituitary function test in beagle dogs: rapid
      sequential intravenous administration of four hypothalamic releasing hormones.
AB  - A combined anterior pituitary (CAP) function test was assessed in eight healthy
      male beagle dogs. The CAP test consisted of sequential 30-second intravenous
      administrations of four hypothalamic releasing hormones in the following order
      and doses: 1 microgram of corticotropin-releasing hormone (CRH)/kg, 1 microgram
      of growth hormone-releasing hormone (GHRH)/kg, 10 micrograms of gonadotropin
      releasing hormone (GnRH)/kg, and 10 micrograms of thyrotropin-releasing hormone
      (TRH)/kg. Plasma samples were assayed for adrenocorticotropin, cortisol, GH,
      luteinizing hormone (LH), and prolactin (PRL) at multiple times for 120 min after
      injection. Each releasing hormone was also administered separately in the same
      dose to the same eight dogs in order to investigate any interactions between the
      releasing hormones in the combined function test. Compared with separate
      administration, the combined administration of these four hypothalamic releasing
      hormones caused no apparent inhibition or synergism with respect to the responses
      to CRH, GHRH, and TRH. The combined administration of these four hypothalamic
      releasing hormones caused a 50% attenuation in LH response compared with the LH
      response to single GnRH administration. The side effects of the combined test
      were confined to restlessness and nausea in three dogs, which disappeared within
      minutes after the administration of the releasing hormones. It is concluded that
      with the rapid sequential administration of four hypothalamic releasing hormones
      (CRH, GHRH, GnRH, and TRH), the adenohypophyseal responses are similar to those
      occurring with the single administration of these secretagogues, with the
      exception of the LH response, which is lower in the CAP test than after single
      GnRH administration.

PMID- 8665805
TI  - The insulin status of sheep with genetic differences in glucose clearance.
AB  - Lines of sheep have been selected for Slow or Fast glucose clearance after a
      glucose tolerance test. The aim of this work was to establish what
      characteristics of the insulin status were altered by the breeding program. Six
      animals from each line with consistently Slow (T-half > 70 min) or Fast (T-half <
      60 min) decreases in plasma glucose concentration were studied in three different
      experiments. After the injection of [125I]insulin, blood was sampled for 300 min.
      The change in radioactivity with time was used in a three-compartment series
      model to estimate theoretical insulin pool sizes and flow rates between pools.
      All three pools were significantly (P < 0.05) larger in the Slow (61, 115, and
      191 mU) than in the Fast glucose clearance animals (45, 82, and 112 mU). Flow
      rates between the pools were not significantly different. A euglycemic clamp
      experiment was performed at two insulin infusion rates, each for 4 hr. A
      significantly higher glucose infusion rate was required to maintain blood glucose
      at basal levels in the Slow (3 and 9 mg of glucose/kg liveweight [lwt]0.75 per
      min) than in the Fast glucose clearance animals (1 and 5 mg/kg lwt0.75 per min).
      The increase in glucose infusion rate when the insulin infusion rate was
      increased from 0.63 to 3.46 mU/kg lwt0.75 per min (insulin sensitivity index) was
      significantly greater in Slow than in Fast glucose clearance animals (0.68 vs.
      0.35 mU of insulin/kg lwt0.75 per min). There was no difference between the lines
      in insulin binding to membranes isolated from muscle or adipose tissue. It is
      concluded that selection for Slow or Fast glucose clearance has altered several
      aspects of insulin status, but further work is required to identify the primary
      difference between the lines.

PMID- 8665806
TI  - Mechanics of the arterial wall: review and directions.
AB  - The goals of this article are threefold: to briefly review the theory of finite
      elasticity and its application to arterial mechanics; to review what is known
      about the mechanical behavior of arteries in health and disease; and to review
      several clinically relevant aspects of arterial mechanics, as for example, aging,
      aneurysms, angioplasty, embolectomy, heat therapies, hypertension, trauma, and
      the disruption of atherosclerotic plaques. It is shown that, despite a huge
      literature on arterial mechanics, much remains unknown. In particular, a pressing
      need exists for detailed nonlinear three-dimensional constitutive relations for
      the passive and active arterial wall as a function of position along the arterial
      tree and disease. Arterial mechanics has, therefore, yet to reach its full
      potential as an important and consistent contributor to vascular medicine and
      surgery, but the possibilities remain great.

PMID- 8665807
TI  - Hirschsprung's disease.

PMID- 8665808
TI  - [Robert Judet].

PMID- 8665809
TI  - [Computer-assisted surgery: assessment and perspectives].
AB  - The hospital in the future will be faced with the major problem of managing and
      optimizing the use of images provided from numerous sources examining both
      anatomy (MRI, CT-scan...) and function (gamma-camera, PET-scan...). One of the
      first to benefit from such rationalization will be the surgeon. After studying
      the results of the physical examination, the laboratory reports and the medical
      imaging, the surgeon will decide on the best curative measured and the best
      surgical route before operating. He thus needs a computer to assist him in
      integrating the multi-modal information available for his patient, in particular
      the imaging with automatic integration and visualisation in synoptic mode
      (perception step), showing the trajectory of possible access routes to the target
      organ, memorization of the chosen route (decision step) and real operation either
      using laser or a manuel tool, or with robot assistance under human control
      (action step). This close cooperation between surgery and computers is called
      computer-assisted surgery. A few examples of current uses an future perspectives
      of this new field of surgery are presented.

PMID- 8665810
TI  - [Neurologic complications of surgery of the spine in children].
AB  - Neurological deficiency can occur during or after spinal surgery. The most severe
      complications are seen after instrumental correction for scoliosis or kyphosis.
      Regression of paraplegia, paraparesia and Brown-Sequard syndrome is never a
      certainty and usually incomplete. Preoperative manoeuvres and evoked potentials
      do not provide absolute security and metal instrumentation should always be used
      prudently. The main risk factors are vertebral malformation, major kyphosis,
      preoperative signs of neurological deficit, excessive correction and double
      anterior and posterior access. Finally, the canal is poorly vascularized from T4
      to T8 or T9 which can raise further problems. Cordal deficiency during or
      following almost always requires removal of the metal implant, and exploration of
      the canal possibly with MRI. Injury include direct contusion of the spinal cord,
      devascularization and compressive haematomas. The frequency of neurological
      complications is currently about 1% and only extreme prudence and knowledge of
      causes can reduce this rate.

PMID- 8665811
TI  - [Ocular complications of surgery of the spine. Proposal for a new head-rest].
AB  - Although severe ocular complications after spinal surgery are rarely reported in
      the orthopaedic literature, they are not uncommon. We studied 10 cases observed
      in 4 orthopaedic units to determine the types of complications and their
      mechanisms. It appears that the classic head-rest used to stabilise the position
      of the head and protection of the ocular globes during the operation have not
      fulfilled their functions correctly. An original head-rest is proposed together
      with preventive pre- and intraoperative measures which should be used in all
      procedures involving spinal surgery.

PMID- 8665812
TI  - [Neurologic complications of surgery for spinal deformities].
AB  - Most of the neurological complications subsequent to surgery for spinal
      deformations involve medullar damage, which may be irreversible and sometimes
      dramatic. We reviewed 667 surgical cases of spinal deformations treated over a 10
      year period (1980-1990) and found 33 complications including 19 directly related
      to the material. There were 7 peripheral complications due to radiculalgia, 3
      meningeal complications and 17 medullary complications including 11 paraplegias.
      Factors influencing the rate of medullary complications (2.5%) and their course
      were the secondary aetiology of the curvature, a kyphosis component of the spinal
      deformation and especially the notion of a spinal cord at risk. Emphasis is
      placed on the delay to development of medullary complications which are
      particularly severe when they occur late and the relationship between the
      severity of the neurology syndrome and its course. The problem of material
      ablation in emergency situations is discussed. Since this series was analyzed,
      systematic surveillance with PES, the fact that several dangerous techniques such
      as sublaminal wiring have been abandoned, and more experience with CD implants
      have considerably reduced the rate of these complications.

PMID- 8665813
TI  - [Neurologic complications of surgery of the spine in adults].
AB  - Spine surgery exposes to neurological complications. There were 170 immediate
      complications of spine surgery at Pitie-Salpetriere Hospital out of 2,855
      reviewed (5.95%) during 9 years. The nature of the complication (radicular or
      medullar), severity and evolution were quite different but less than 2.76% where
      permanent. Among them, 1.43% were major neurological complications. The "high
      risk" etiologies were cervical stenosis and primitive malignant tumors. The major
      cause for these complications was due to surgical procedure in 60% of the cases.

PMID- 8665814
TI  - [Thoughts on the treatment of diverticular sigmoiditis. Apropos of 191 cases].
AB  - Between January 1, 1984 and December 31, 1993, we treated 191 patients with
      diverticular sigmoiditis. Three groups of patients were distinguished in this
      retrospective study. In group 1, there were 108 patients (56.5%) who were
      referred by gastroenterologists after one or two episodes of sigmoiditis and who
      underwent planned exeresis. In group 2, there were 42 patients (21.9%) in whom
      the sigmoiditis was revealed by a complication and who underwent and emergency
      procedure. In group 3, there were 41 patients (21.6%) over 70 years of age with
      major risk for anesthesia and/or surgery who were treated medically. Mortality,
      morbidity and duration of hospital stay were analyzed by group. Operative
      mortality was 0.92, 19 and 7.3% respectively. Operative morbidity among the
      survivors was 21 and 35% in groups 1 and 2 respectively. Mean hospital stay
      varied from 15 days for planned procedures up to 20 days for emergency surgery.
      It was 9 days in group III. These findings recall the need for radical preventive
      exeresis for diverticular sigmoiditis.

PMID- 8665815
TI  - [Late and multiple endocrine metastases of an adenocarcinoma of the kidney].
AB  - Ten years after nephrectomy a renal cell carcinoma of the felt kidney, the
      patient presented successively pancreatic, adrenal gland, thyroid gland and
      contralateral renal metastases. Surgical exeresis was performed for the different
      metastases with a survival period of 7 years. No similar observation (non
      necropsic discovery, surgical treatment, prolonged survival) of multiple
      metastasis of renal cell carcinoma to endocrine glands was found in the
      literature. The important role of modern imaging techniques are emphasized
      together with the need for long-term follow-up of operated renal cell cancer
      since the clinical course can be unpredictable. Long-term remission has been
      reported and surgical exeresis of metastasis should always be proposed when
      possible.

PMID- 8665816
TI  - Comparison of resistance in three breeds of cattle against African ixodid ticks.
AB  - Tick resistance in three breeds of cattle, two indigenous breeds (Arssi and
      Boran) and one Boran x Friesian cross-bread, were compared following natural tick
      infestations at Abernossa ranch in Ethiopia. The local Arssi breed was found to
      have the highest tick resistance, followed by the Boran breed, whereas the Boran
      x Friesian was the least resistant. Over a period of 12 months, from October 1991
      to September 1992, a total of 32,897 ticks composed of four genera were collected
      from the animals. The four most abundant tick species were Amblyomma variegatum
      (61.7%), Boophilus decoloratus (16%); Rhipicephalus evertsi evertsi (16.3%) and
      Hyalomma marginatum rufipes (3.7%). Furthermore, 63.5% of all ticks were
      collected from cross-breed cattle, and 26.2% from the Boran, whereas the local
      Arssi breed carried only 10.3%. The results indicated that cattle resistant to
      one species of tick were also resistant to other tick species.

PMID- 8665817
TI  - [Bilateral surgical lung volume reduction in severe emphysema].
AB  - OBJECTIVE: To report preliminary results with a new surgical method of treating
      terminal emphysema by bilateral reduction of lung volume. PATIENTS AND METHODS:
      In a prospective study, the results obtained with the first 20 consecutive
      patients (mean FEV1: 590 +/- 180 ml) who underwent operative reduction of lung
      volume were recorded. 19 of the 20 patients had required continuous oxygen
      supply. RESULTS: The patients were extubated 8.5 +/- 6 h postoperatively;
      thoracic drainage was removed after 9 +/- 6 days. The degree of dyspnoea was
      decreased in all patients (3.5 +/- 0.5 vs 0.5 +/- 0.1). Significant reduction of
      overinflation occurred soon after the operation (residual volume 273 +/- 125 to
      201 +/- 107% of normal; total capacity from 142 +/- 18 to 109 +/- 22% of normal),
      as well as reduction in the degree of obstruction (FEV1 from 18 +/- 6 to 24 +/-
      7% of normal; for each, P < 0.05). One patient died 3 weeks post-operatively of
      Candida infection. CONCLUSION: The method looks promising for the treatment of
      selected patients and may thus provide an alternative to lung transplantation.

PMID- 8665818
TI  - [Comparison of kidney transplantation with and without regard to HLA typing].
AB  - OBJECTIVE: To compare the functional results after transplantation of locally
      obtained and assigned kidneys (without taking into account HLA typing) with those
      after transplantation of kidneys obtained via Eurotransplant (with HLA typing as
      principal criterion for assignment). PATIENTS AND METHODS: Between December 1983
      and December 1993 a total of 236 kidneys were transplanted into 234 patients, 40
      kidneys having been obtained via Eurotransplant and 196 removed locally and
      transplanted directly into patients on the local waiting list according to strict
      criteria: same blood group; waiting time since decision on transplantation;
      negative current crossmatch between recipient's serum and donor lymphocytes.
      Transplantation results were analysed retrospectively according to: ischaemia
      time, HLA mismatch, postoperative renal failure, postoperative renal function,
      rejection rate and transplant survival. Mean observation period was 55 months for
      the local and 50 months for the Eurotransplant kidneys. RESULTS: The number of
      HLA matches was higher in Eurotransplant group (P < 0.001). However, the cold
      ischaemia time was greater for this group (20.2 vs 15.7 hours; P < 0.01). Acute
      renal failure was less common with locally assigned kidneys (33 vs 53%: P <
      0.02). There were no significant differences with regard to one-year and five
      year renal function (serum creatinine; percentage of normal): 90.2% local vs
      88.3% Eurotransplant and 81.8% vs 62.3%, respectively). Survival rates were also
      similar (96.9% local vs 95% Eurotransplant after one year, 94.4% vs 90% after 5
      years). CONCLUSION: Local assignment by waiting time and blood group gave results
      that were similar to those via Eurotransplant based on HLA typing criteria.

PMID- 8665819
TI  - [Ultra-high dosage streptokinase lysis in dysfunction of a St. Jude aortic
      prosthesis].
AB  - HISTORY AND CLINICAL FINDINGS: A 64-year-old man was hospitalised because of
      progressively worsening dyspnoea over the preceding few months. Three years
      previously he had undergone aortic valve replacement (St. Jude Medical bileaflet
      valve) for severe aortic stenosis and some regurgitation. He was much improved
      postoperatively and one year after the operation echocardiography demonstrated a
      well functioning prosthetic valve and a transvalvar pressure gradient (by Doppler
      echocardiography) of 28 mm Hg. On admission the patient reported to have stopped
      phenprocoumon 9 months before admission. The patient was in cardiac failure,
      grade III (NYHA classification). On auscultation there was a 4/6 crescendo
      decrescendo systolic murmur and a 2/6 early diastolic decrescendo murmur maximal
      over the second right ICS. INVESTIGATIONS: Echocardiography confirmed the
      suspected diagnosis of dysfunction of the prosthetic valve, one leaflet being
      immobile, with severe outflow obstruction (peak transvalvar pressure gradient 101
      mm Hg) combined with severe regurgitation. At fluoroscopy one leaflet moved
      normally, the other one being fixed between opening and closing positions.
      TREATMENT AND COURSE: As thrombosis was the most likely cause of the prosthetic
      valve dysfunction, thrombolysis treatment was started. After administration of 9
      mill. IU streptokinase both leaflets showed normal movement. The peak transvalvar
      gradient (by echocardiography) was now 40 mm Hg and there was only slight
      regurgitation. No complications were noted. After oral anticoagulation for 6
      months the prosthetic valve was functioning normally with unchanged movement
      pattern of both leaflets. CONCLUSION: Thrombolysis may be successful in
      thrombotic dysfunction of a prosthetic valve. If there are no contraindications,
      this form of treatment should be tried before reoperation is undertaken.

PMID- 8665820
TI  - [Reflux associated respiratory tract diseases].

PMID- 8665821
TI  - [Intraoperative cardiac risk and preoperative examinations from the anesthetic
      viewpoint].

PMID- 8665822
TI  - [Infectivity of hepatitis B].

PMID- 8665823
TI  - [Diphtheria immunity in adults in Berlin].

PMID- 8665824
TI  - [Therapy of lung abscess].

PMID- 8665825
TI  - [HIV therapy with drug combinations].

PMID- 8665826
TI  - [Inguinal hernia operation: still or after all an open one?].

PMID- 8665827
TI  - [The diagnostic value of the rate-corrected QT interval in long-term type-1
      diabetes mellitus].
AB  - OBJECTIVE: To assess the relationship between rate-corrected QT interval (QTc
      interval) and cardiac reflex tests in order to determine the value of QTc
      interval measurements in the diagnosis of diabetic cardiac autonomic neuropathy.
      INVESTIGATIONS: The QTc interval was measured in the resting ECG of 97 type 1
      diabetics (58 women, 39 men; mean age 35 +/- 12 years; duration of diabetes 18 +/
      10 years; HbA1c 7.8 +/- 1.8%). Age-related results were compared with five
      cardiac function tests (heart rate variation at rest and on forced breathing;
      30/15 ratio of heart rate; Valsalva manoeuvre; orthostasis). RESULTS: The QTc
      interval was not prolonged ( < or = 440 ms) in 68 patients (70%), while in 29
      (30%) it was prolonged ( > 440 ms). No significant differences regarding QTc
      interval were found between patients with autonomic cardiac neuropathy ( > or = 2
      abnormal function tests) and those without ( < 2 abnormal function tests) (QTc
      interval 436 +/- 25 vs 426 +/- 19 ms). QTc intervals correlated with the
      coefficients of variation for heart rate variation at rest and on forced
      breathing and the 30/15 ratio of heart rate (p = 0.001; p = 0.001; p = 0.03), but
      not with the results of the Valsalva manoeuvre and the orthostasis test.
      CONCLUSION: Prolongation of the QTc interval in longstanding type 1 diabetes does
      not provide a reliable indication of cardiac autonomic neuropathy and this
      measure cannot replace conventional reflex tests for its diagnosis.

PMID- 8665828
TI  - [The latency period between exposure and the symptoms in allergy to natural
      latex. Suggestions for prevention].
AB  - BASIC PROBLEM AND OBJECTIVE OF STUDY: Among persons working in the health care
      system allergies caused by natural rubber latex (NRL) are more common than among
      the general population, because the frequent use of latex gloves and other latex
      articles may cause sensitisation. A retrospective study was undertaken to
      determine the period before such an allergy occurs. PATIENTS AND METHODS: 63
      patients (53 women and 10 men; mean age 31.3 +/- 8.3 years) with symptoms of type
      1 (immediate response; IgE-mediated) allergy to NRL filled in a special
      questionnaire asking, among other items, about occupational history, duration and
      frequency of contact with latex gloves, as well as the course of occupational or
      other symptoms. All but five of the group had been in their job for less than 15
      years. A prick test with 21 ubiquitous environmental allergens was performed on
      62 of the patients. RESULTS: Two thirds of the patients had atopy. First symptoms
      of an allergy to latex developed at an average of 5 years (58.7 +/- 59.3 months)
      after starting work involving contact with latex products. In 59 persons the
      first symptoms were contact urticaria, in some together with rhinitis or dyspnea.
      The interval until onset of symptoms relating to the lower respiratory tract
      averaged a further 25.3 +/- 34.6 months. Symptoms developed earlier in patients
      with atopy than in those without (51.9 +/- 54.3 vs 76 +/- 69 months).
      CONCLUSIONS: The use of powdered natural rubber latex gloves should be
      discontinued to prevent the increasing incidence of sensitization to aerogenic
      latex and to protect those already sensitized from developing allergic bronchial
      asthma.

PMID- 8665830
TI  - [Meralgia paresthetica. A rare differential diagnosis of circumscribed alopecia].
AB  - HISTORY AND CLINICAL FINDINGS: Two patients with circumscribed alopecia on the
      lateral aspect of the thigh underwent a neurological investigation after medical
      and dermatological examinations had failed to establish the cause. Patient 1 also
      had neuralgia of the genitofemoral nerve after osteotomy of the iliac crest;
      patient 2 had insulin-dependent diabetes mellitus. Within the affected part of
      the skin both patients had sensory dysfunctions over the area of distribution of
      the cutaneous lateral femoral nerve. Patient 2 additionally had sensory
      dysfunctions in other areas of innervation. INVESTIGATIONS: Neurogram and
      recordings of sensory evoked potentials revealed decreased amplitudes on the
      affected side, establishing the diagnosis of meralgia paresthetica. TREATMENT AND
      COURSE: The painful neuropathy was successfully treated in both patients with
      carbamazepine (patient 1: 1.600 mg daily; patient 2: 900 mg daily). CONCLUSION:
      Circumscribed alopecia can be caused by peripheral nerve lesions. It should be
      considered in the differential diagnosis, particularly as the cause can be easily
      established.

PMID- 8665829
TI  - [Intensive medical monitoring with transesophageal echocardiography in fulminant
      pulmonary embolism].
AB  - HISTORY AND FINDINGS: A 60-year-old man underwent a continence-preserving
      anterior rectal resection for a high rectal carcinoma. After mobilisation on the
      5th postoperative day dyspnoea and cyanosis suddenly developed requiring
      emergency intubation and mechanical ventilation. INVESTIGATIONS: His heart rate
      was 160/min, blood pressure 80/50 mmHg, mean pulmonary artery pressure by
      indwelling catheter was 70 mmHg. The electrocardiogram had the classical signs of
      acute right-heart overload. Transoesophageal echocardiography (TOE) demonstrated
      marked right-heart and pulmonary artery dilatation. TREATMENT AND COURSE: Despite
      thrombolytic treatment (bolus of 50 mg r-TPA; one day later bolus of 1 million IU
      urokinase followed by 100,000 IU/h) a new thromboembolus was seen by TOE to
      straddle the pulmonary artery bifurcation. After the urokinase dosage had been
      raised to 200,000 IU/h TOE on the 6th day no longer showed the embolus and
      documented a reduction in right-heart dilatation associated with improved
      haemodynamics. CONCLUSION: TOE is an ideal method for the rapid diagnosis and for
      monitoring the response to treatment of fulminant pulmonary arterial embolism. As
      it can also diagnose thromboembolism without significant haemodynamic
      consequences it is possible to adjust fibrinolytic treatment accordingly.

PMID- 8665831
TI  - [The diagnosis and therapy of hypoparathyroidism].

PMID- 8665832
TI  - [Leukotriene blockade in asthma--a new anti-inflammatory therapeutic principle].

PMID- 8665833
TI  - [Opium drops in Crohn disease-induced diarrhea].

PMID- 8665834
TI  - [Angiotensin-converting enzyme as a follow-up parameter in sarcoidosis].

PMID- 8665836
TI  - Melting profile and temperature dependent binding constant of an anticancer drug
      daunomycin-DNA complex.
AB  - We calculate thermal fluctuational base pair opening probability and the drug
      binding constant of a daunomycin-bound Poly d(CGTA).Poly d(TACG) at temperatures
      from room temperature to its melting temperature. For comparison we also carry
      out a calculation on a drug-free DNA with the same sequence. Our calculations are
      carried out by means of a statistical approach using microscopic structures and
      established force fields and with cooperative effects incorporated into the
      algorithm. Both hydrogen bond disruption probabilities and drug unstacking
      probability are determined self-consistently. These probabilities are then used
      to determine temperature dependent base pair opening probabilities and the drug
      binding constant. The calculated base pair opening probabilities and drug binding
      constant are found to be in fair agreement with experiments carried out at room
      temperature. Our calculation shows cooperative base pair disruption and drug
      dissociation at certain critical temperatures close to the observed melting
      temperatures for similar helices. We find that the temperature dependence of the
      drug binding constant fits well to the van't Hoff relation, in agreement with
      observations. Our calculation indicates the occurrence of a premelting transition
      in the drug-bound DNA helix. Some comments are made about this premelting
      transition.

PMID- 8665835
TI  - Comparative analysis of the amino- and carboxy-terminal domains of calmodulin by
      Fourier transform infrared spectroscopy.
AB  - Fourier transform infrared spectra were obtained for mammalian calmodulin and two
      of its fragments produced by limited proteolysis with trypsin TR1C (1-77) and
      TR2C (78-148). Experiments were done in H2O, D2O and D2O/trifluoroethanol (TFE)
      mixtures. Information about secondary structure was obtained from analysis of the
      amide I and II bands; while characteristic absorbances for tyrosine,
      phenylalanine and carboxylate groups were analyzed for changes in tertiary
      structure. Our data indicate that the secondary and tertiary structure is
      preserved in the two half molecules of CaM, both in the apo- and Ca(2+)-saturated
      state. Addition of the structure-inducing solvent TFE causes marked changes only
      in the apo-TR1C domain. The maximum wavenumber for the amide I band of the two
      domains of CaM in D2O was markedly different (1642 cm-1 for TR1C versus 1646/1648
      cm-1 for Ca2+ and apo-TR2C). This renders the amide I band for the intact protein
      very broad in comparison to that in other proteins and is indicative of a
      distribution of alpha-helices with slightly different hydrogen bonding patterns.

PMID- 8665837
TI  - EXAFS investigation of the active site of iron superoxide dismutase of
      Escherichia coli and Propionibacterium shermanii.
AB  - The local structure of the iron site in ferric superoxide dismutase from P.
      shermanii was analyzed by X-ray absorption spectroscopy. The metal-ligand cluster
      of the enzyme is found to be similar to the crystallographically investigated
      ferric superoxide dismutase from E. coli. At pH 6.4 the enzyme is five-fold
      coordinated with three histidines, an aspartate and a water molecule. The average
      bond lengths between the metal and the histidines are about 2.10 A, between metal
      and aspartate they are about 1.86 A and between metal and water 1.96 A. With an
      increase in pH a change in the coordination number from five to six is observed
      both in pre-edge peak and EXAFS spectra analysis. However, the bond lengths of
      the ligands do not change dramatically, they are conserved for the aspartate and
      increase slightly to 2.13 A for the average metal-histidine distance at pH 9.3.
      The observation of the increase in coordination number is correlated with a
      decrease in enzymatic activity which occurs in the high pH range. The zinc EXAFS
      spectra of P. shermanii superoxide dismutase have shown that zinc can be
      incorporated in the active center instead of the iron.

PMID- 8665838
TI  - Spin label and 2H-NMR studies on the interaction of melanotropic peptides with
      lipid bilayers.
AB  - The interaction of the cationic tridecapeptide alpha-melanocyte stimulating
      hormone (alpha-MSH) and the biologically more active analog [Nle4, DPhe7]-alpha
      MSH with lipid membranes was investigated by means of ESR of spin probes
      incorporated in the bilayer, and NMR of deuterated lipids. All spin labels used
      here, stearic acid and phospholipid derivatives labeled at the 5th and 12th
      position of the hydrocarbon chain, and the cholestane label, incorporated into
      anionic vesicles of DMPG (1,2-dimyristoyl-sn-glycero-3-phosphoglycerol) in the
      liquid-crystalline phase, indicated that both peptides decrease the motional
      freedom of the acyl chains. No peptide effect was detected with neutral lipid
      bilayers. Changes in the alpha-deuteron quadrupolar splittings and spin lattice
      relaxation time of DMPG deuterated at the glycerol headgroup paralleled the
      results obtained with ESR, showing that the peptides cause a better packing both
      at the headgroup and at the acyl chain bilayer regions. The stronger effect
      caused by the more potent analog in the membrane structure, when compared to the
      native hormone, is discussed in terms of its larger lipid association constant
      and/or its deeper penetration into the bilayer.

PMID- 8665839
TI  - A left-hand beta-helix revealed by the crystal structure of a carbonic anhydrase
      from the archaeon Methanosarcina thermophila.
AB  - A carbonic anhydrase from the thermophilic archaeon Methanosarcina thermophila
      that exhibits no significant sequence similarity to known carbonic anhydrases has
      recently been characterized. Here we present the structure of this enzyme, which
      adopts a left-handed parallel beta-helix fold. This fold is of particular
      interest since it contains only left-handed crossover connections between the
      parallel beta-strands, which so far have been observed very infrequently. The
      active form of the enzyme is a trimer with three zinc-containing active sites,
      each located at the interface between two monomers. While the arrangement of
      active site groups differs between this enzyme and the carbonic anhydrases from
      higher vertebrates, there are structural similarities in the zinc coordination
      environment, suggestive of convergent evolution dictated by the chemical
      requirements for catalysis of the same reaction. Based on sequence similarities,
      the structure of this enzyme is the prototype of a new class of carbonic
      anhydrases with representatives in all three phylogenetic domains of life.

PMID- 8665840
TI  - Molecular identification of zeaxanthin epoxidase of Nicotiana plumbaginifolia, a
      gene involved in abscisic acid biosynthesis and corresponding to the ABA locus of
      Arabidopsis thaliana.
AB  - Abscisic acid (ABA) is a plant hormone which plays an important role in seed
      development and dormancy and in plant response to environmental stresses. An ABA
      deficient mutant of Nicotiana plumbaginifolia, aba2, was isolated by transposon
      tagging using the maize Activator transposon. The aba2 mutant exhibits precocious
      seed germination and a severe wilty phenotype. The mutant is impaired in the
      first step of the ABA biosynthesis pathway, the zeaxanthin epoxidation reaction.
      ABA2 cDNA is able to complement N.plumbaginifolia aba2 and Arabidopsis thaliana
      aba mutations indicating that these mutants are homologous. ABA2 cDNA encodes a
      chloroplast-imported protein of 72.5 kDa, sharing similarities with different
      mono-oxigenases and oxidases of bacterial origin and having an ADP-binding fold
      and an FAD-binding domain. ABA2 protein, produced in Escherichia coli, exhibits
      in vitro zeaxanthin epoxidase activity. This is the first report of the isolation
      of a gene of the ABA biosynthetic pathway. The molecular identification of ABA2
      opens the possibility to study the regulation of ABA biosynthesis and its
      cellular location.

PMID- 8665841
TI  - A novel immunogold cryoelectron microscopic approach to investigate the structure
      of the intracellular and extracellular forms of vaccinia virus.
AB  - We introduce a novel approach for combining immunogold labelling with
      cryoelectron microscopy of thin vitrified specimens. The method takes advantage
      of the observation that particles in suspension are concentrated at the air-water
      interface and remain there during the subsequent immunogold labelling procedure.
      Subsequently, a thin aqueous film can be formed that is vitrified and observed by
      cryoelectron microscopy. In our view, a key early step in the assembly of
      vaccinia virus, the formation of the spherical immature virus, involves the
      formation of a specialized cisternal domain of the intermediate compartment
      between the endoplasmic reticulum and the Golgi. Using this novel cryoelectron
      microscopy approach, we show that in the intracellular mature virus (IMV) the
      core remains surrounded by a membrane cisterna that comes off the viral core upon
      treatment with dithiothreitol, exposing an antigen on the surface of the viral
      core. Complementary protease studies suggest that the IMV may be sealed not by
      membrane fusion but by a proteinaceous structure that interrupts the outer
      membrane. We also describe the structure and membrane topology of the second
      infectious form of vaccinia, the extracellular enveloped virus, and confirm that
      this form possesses an extra membrane overlying the IMV.

PMID- 8665842
TI  - The channel domain of colicin A is inhibited by its immunity protein through
      direct interaction in the Escherichia coli inner membrane.
AB  - A bacterial signal sequence was fused to the colicin A pore-forming domain: the
      exported pore-forming domain was highly cytotoxic. We thus introduced a cysteine
      residue pair in the fusion protein which has been shown to form a disulfide bond
      in the natural colicin A pore-forming domain between alpha-helices 5 and 6.
      Formation of the disulfide bond prevented the cytotoxic activity of the fusion
      protein, presumably by preventing the membrane insertion of helices 5 and 6.
      However, the cytotoxicity of the disulfide-linked pore-forming domain was
      reactivated by adding dithiothreitol into the culture medium. We were then able
      to co-produce the immunity protein with the disulfide linked pore-forming domain,
      by using a co-immunoprecipitation procedure, in order to show that they interact.
      We showed both proteins to be co-localized in the Escherichia coli inner membrane
      and subsequently co-immunoprecipitated them. The interaction required a
      functional immunity protein. The immunity protein also interacted with a mutant
      form of the pore-forming domain carrying a mutation located in the voltage-gated
      region: this mutant was devoid of pore-forming activity but still inserted into
      the membrane. Our results indicate that the immunity protein interacts with the
      membrane-anchored channel domain; the interaction requires a functional membrane
      inserted immunity protein but does not require the channel to be in the open
      state.

PMID- 8665843
TI  - The IVS6 segment of the L-type calcium channel is critical for the action of
      dihydropyridines and phenylalkylamines.
AB  - The current through the L-type calcium channel is inhibited and stimulated by
      distinct dihydropyridines at very low concentrations. The molecular determinants
      for the high affinity block and stimulation were investigated using chimeras
      between the class C and E calcium channels. Mutation of three amino acids in the
      last putative transmembrane segment (IVS6) of the alpha1C subunit decreased the
      affinity for (+)isradipine 100-fold without significantly affecting the basic
      properties of the expressed channel. Mutation of two of these three amino acids
      completely abolished the stimulatory effect of the calcium channel agonist Bay K
      8644. These mutations only slightly affected the blocking efficacy of mibefradil
      and the phenylalkylamine devapamil. Three distinct but adjacently located amino
      acids mediated the high affinity block by devapamil. These results suggest that
      the IVS6 segment of the alpha1C subunit is critical for the high affinity
      interaction between the L-type calcium channel and the calcium channel agonist
      Bay K 8644 and the two antagonists isradipine and devapamil.

PMID- 8665845
TI  - Identification of a PY motif in the epithelial Na channel subunits as a target
      sequence for mutations causing channel activation found in Liddle syndrome.
AB  - Liddle syndrome is an autosomal dominant form of hypertension, resulting from
      mutations in the cytoplasmic C-terminus of either the beta or gamma subunits of
      the amiloride-sensitive epithelial Na channel (ENaC) which lead to constitutively
      increased channel activity. Most mutations reported to date result in the
      elimination of 45-75 normal amino acids from these segments, leaving open the
      question of the identity of the precise amino acids in which mutation can lead to
      an enhanced channel activity. To address this question, we have performed a
      systematic mutagenesis study of the C-termini of the alpha, beta and gamma ENaC
      subunits of the rat channel and have analyzed their function by expression in
      Xenopus oocytes. The results demonstrate that a short proline-rich segment
      present in the cytoplasmic C-terminus of each subunit is required for the normal
      regulation of channel activity. Missense mutations altering a consensus PPPXY
      sequence of the alpha, beta or gamma subunits reproduced the increase in channel
      activity found in mutants in which the entire cytoplasmic C-termini are deleted.
      This proline-rich sequence, referred to as the PY motif, is known to be a site of
      binding by proteins bearing a WW domain. These findings show that the three PY
      motifs in the C-termini of ENaC are involved in the regulation of channel
      activity, probably via protein-protein interactions. This new regulatory
      mechanism of channel function is critical for the maintenance of normal Na
      reabsorption in the kidney and of Na+ balance and blood pressure.

PMID- 8665844
TI  - WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+
      channel deleted in Liddle's syndrome.
AB  - The amiloride-sensitive epithelial sodium channel (ENaC) plays a major role in
      sodium transport in kidney and other epithelia, and in regulating blood pressure.
      The channel is composed of three subunits (alphabetagamma) each containing two
      proline-rich sequences (P1 and P2) at its C-terminus. The P2 regions in human
      beta and gammaENaC, identical to the rat betagammarENaC, were recently shown to
      be deleted in patients with Liddle's syndrome (a hereditary form of
      hypertension), leading to hyperactivation of the channel. Using a yeast two
      hybrid screen, we have now identified the rat homologue of Nedd4 (rNedd4) as the
      binding partner for the P2 regions of beta and gammarENaC. rNedd4 contains a Ca2+
      lipid binding (CaLB or C2) domain, three WW domains and a ubiquitin ligase (Hect)
      domain. Our yeast two-hybrid and in vitro binding studies revealed that the
      rNedd4-WW domains mediate this association by binding to the P2 regions, which
      include the PY motifs (XPPXY) of either betarENaC (PPPNY) or gammarENaC (PPPRY).
      SH3 domains were unable to bind these sequences. Moreover, mutations to Ala of
      Pro616 or Tyr618 within the betarENaC P2 sequence (to PPANY or PPPNA,
      respectively), recently described in Liddle's patients, led to abrogation of
      rNedd4-WW binding. Nedd4-WW domains also bound to the proline-rich C-terminus
      (containing the sequence PPPAY) of alpharENaC, and endogenous Nedd4 co
      immunoprecipitated with alpharENaC expressed in MDCK cells. These results
      demonstrate that the WW domains of rNedd4 bind to the PY motifs deleted from beta
      or gammaENaC in Liddle's syndrome patients, and suggest that Nedd4 may be a
      regulator (suppressor) of the epithelial Na+ channel.

PMID- 8665846
TI  - Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action
      through a specific cell surface receptor.
AB  - Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid implicated in
      mitogenesis and cytoskeletal remodelling, but its mechanism of action is poorly
      understood. We report here that in N1E-115 neuronal cells, S1P mimics the G
      protein-coupled receptor agonist lysophosphatidic acid (LPA) in rapidly inducing
      neurite retraction and soma rounding, a process driven by Rho-dependent
      contraction of the actin cytoskeleton. S1P is approximately 100-fold more potent
      than LPA in evoking these shape changes, with an EC50 as low as 1.5 nM.
      Microinjection of S1P has no effect, neither has addition of sphingosine or
      ceramide. As with LPA, S1P action is inhibited by suramin and subject to
      homologous desensitization; however, the responses to S1P and LPA do not show
      cross-desensitization. We conclude that S1P activates its own high affinity
      receptor to trigger Rho-regutated cytoskeletal events. Thus, S1P and LPA may
      belong to an emerging family of bioactive lysophospholipids that act through
      distinct G protein-coupled receptors to mediate similar actions.

PMID- 8665847
TI  - Cell cycle-controlled proteolysis of a flagellar motor protein that is
      asymmetrically distributed in the Caulobacter predivisional cell.
AB  - Flagellar biogenesis and release are developmental events tightly coupled to the
      cell cycle of Caulobacter crescentus. A single flagellum is assembled at the
      swarmer pole of the predivisional cell and is released later in the cell cycle.
      Here we show that the MS-ring monomer FliF, a central motor component that
      anchors the flagellum in the cell membrane, is synthesized only in the
      predivisional cell and is integrated into the membrane at the incipient swarmer
      cell pole, where it initiates flagellar assembly. FliF is proteolytically turned
      over during swarmer-to-stalked cell differentiation, coinciding with the loss of
      the flagellum, suggesting that its degradation is coupled to flagellar release.
      The membrane topology of FliF was determined and a region of the cytoplasmic C
      terminal domain was shown to be required for the interaction with a component of
      the motor switch. The very C-terminal end of FliF contains a turnover
      determinant, required for the cell cycle-dependent degradation of the MS-ring.
      The cell cycle-dependent proteolysis of FliF and the targeting of FliF to the
      swarmer pole together contribute to the asymmetric localization of the MS-ring in
      the predivisional cell.

PMID- 8665848
TI  - The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system
      by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32,
      via a novel two-step mechanism.
AB  - The major mechanism of cytotoxic lymphocyte killing involves the directed release
      of granules containing perforin and a number of proteases onto the target cell
      membrane. One of these proteases, granzyme B, has an unusual substrate site
      preference for Asp residues, a property that it shares with members of the
      emerging interleukin-1beta-converting enzyme (ICE)/CED-3 family of proteases.
      Here we show that granzyme B is sufficient to reproduce rapidly all of the key
      features of apoptosis, including the degradation of several protein substrates,
      when introduced into Jurkat cell-free extracts. Granzyme B-induced apoptosis was
      neutralized by a tetrapeptide inhibitor of the ICE/CED-3 family protease, CPP32,
      whereas a similar inhibitor of ICE had no effect. Granzyme B was found to convert
      CPP32, but not ICE, to its active form by cleaving between the large and small
      subunits of the CPP32 proenzyme, resulting in removal of the prodomain via an
      autocatalytic step. The cowpox virus protein CrmA, a known inhibitor of ICE
      family proteases as well as granzyme B, inhibited granzyme B-mediated CPP32
      processing and apoptosis. These data demonstrate that CPP32 activation is a key
      event during apoptosis initiated by granzyme B.

PMID- 8665849
TI  - Daunorubicin-induced apoptosis: triggering of ceramide generation through
      sphingomyelin hydrolysis.
AB  - The nature of the signaling pathway(s) which initiate drug-triggered apoptosis
      remains largely unknown and is of fundamental importance in understanding cell
      death induced by chemotherapeutic agents. Here we show that in the leukemic cell
      lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis,
      stimulated two distinct cycles of sphingomyelin hydrolysis (approximately 20%
      decrease at 1 microM) within 4-10 min and 60-75 min with concomitant ceramide
      generation. We demonstrate that the increase in ceramide levels, which precedes
      apoptosis, is mediated by a neutral sphingomyelinase and not by ceramide
      synthase. Indeed, potent ceramide synthase inhibitors such as fumonisin B1 did
      not affect daunorubicin-triggered sphingomyelin hydrolysis, ceramide generation
      or apoptosis. In conclusion, we provide evidence that daunorubicin-triggered
      apoptosis is mediated by a signaling pathway which is initiated by an early
      sphingomyelin-derived ceramide production.

PMID- 8665850
TI  - Suppression of interleukin-3-induced gene expression by a C-terminal truncated
      Stat5: role of Stat5 in proliferation.
AB  - Interleukin-3 (IL3) was shown recently to utilize the transcription factor Stat5,
      but the genes regulated by this pathway and the biological consequence of Stat5
      activation remained to be determined. In order to study the role of Stat5 in IL3
      signalling, we constructed a dominant-negative Stat5 protein by C-terminal
      truncation, and inducibly expressed it in an IL3-dependent cell line. The effect
      of dominant-negative Stat5 induction on expression of IL3 early response genes
      was examined, and expression of several genes, including cis, osm and pim-1 was
      inhibited profoundly. The expression of c-fos was also reduced, but to a lesser
      extent. While activated Ras alone (though not Stat5 alone) could induce c-fos,
      maximal expression required the action of both Ras and Stat5. Interestingly,
      although the membrane-proximal region of the IL3 receptor beta-chain is
      responsible for both Jak2-Stat5 activation and c-myc induction, c-myc levels were
      not affected by the dominant-negative Stat5. Thus, the signals directed by this
      membrane-proximal domain, which is essential for transducing a DNA synthesis
      signal, can be separated further into Stat5 or c-myc pathways. The net effect of
      dominant-negative Stat5 expression was partial inhibition of IL3-dependent
      growth. This provides the first direct evidence that Stat5 is involved in
      regulation of cell proliferation.

PMID- 8665851
TI  - Identification of tyrosine residues within the intracellular domain of the
      erythropoietin receptor crucial for STAT5 activation.
AB  - FDCP-1 cells are hematopoietic progenitor cells which require interleukin-3 for
      survival and proliferation. FDCP-1 cells stably transfected with the murine
      erythropoietin receptor cDNA survive and proliferate in the presence of
      erythropoietin. Erythropoietin induces the activation of the short forms (80 kDa)
      of STAT5 in the cells. Erythropoietin-induced activation of STAT5 was strongly
      reduced in cells expressing mutated variants of the erythropoietin receptors in
      which tyrosine residues in their intracellular domain have been eliminated. We
      determined that the erythropoietin receptor tyrosine residues 343 and 401 are
      independently necessary for STAT5 activation. The amino acid sequences
      surrounding these two tyrosine residues are very similar. Peptides comprising
      either phosphorylated Tyr343 or phosphorylated Tyr401, but not their
      unphosphorylated counterparts, inhibited the STAT5 activation. We propose that
      these two tyrosine residues of the erythropoietin receptor constitute docking
      sites for the STAT5 SH2 domain. The growth stimulus mediated by erythropoietin
      was decreased in cells expressing erythropoietin receptors lacking both Tyr343
      and Tyr401. This suggests that STAT5 activation could be involved in the growth
      control of FDCP-1 cells.

PMID- 8665852
TI  - Activation of phosphoinositide 3-kinase by interaction with Ras and by point
      mutation.
AB  - We have reported previously that Ras interacts with the catalytic subunit of
      phosphoinositide 3-kinase (PI 3-kinase) in a GTP-dependent manner. The affinity
      of the interaction of Ras-GTP with p85alpha/p110alpha is shown here to be
      approximately 150 nM. The site of interaction on the p110alpha and beta isoforms
      of PI 3-kinase lies between amino acid residues 133 and 314. A point mutation in
      this region, K227E, blocks the GTP-dependent interaction of PI 3-kinase p110alpha
      with Ras in vitro and the ability of Ras to activate PI 3-kinase in intact cells.
      In addition, this mutation elevates the basal activity of PI 3-kinase in intact
      cells, suggesting a direct influence of the Ras binding site on the catalytic
      activity of PI 3-kinase. Using an in vitro reconstitution assay, it is shown that
      the interaction of Ras-GTP, but not Ras-GDP, with PI 3-kinase leads to an
      increase in its enzymatic activity. This stimulation is synergistic with the
      effect of tyrosine phosphopeptide binding to p85, particularly at suboptimal
      peptide concentrations. These data show that PI 3-kinase is regulated by a number
      of mechanisms, and that Ras contributes to the activation of this lipid kinase
      synergistically with tyrosine kinases.

PMID- 8665854
TI  - Negative transactivation of cAMP response element by familial Alzheimer's mutants
      of APP.
AB  - In familial Alzheimer's disease (FAD), missense point mutations V642I/F/G, which
      co-segregate with the disease phenotype, have been discovered in amyloid
      precursor APP695. Here, we report that three FAD mutants (FAD-APPs) negatively
      regulated the transcriptional activity of cAMP response element (CRE) by a G(o)
      dependent mechanism, but expression of wildtype APP695 had no effect on CRE.
      Experiments with various Galpha(s) chimeras demonstrated that Phe-APP coupled
      selectively to the C-terminus of Galpha(0). Again, wild-type APP695 had no effect
      on its C-terminus. These data indicate that FAD-APPs are gain-of-function mutants
      of APP695 that negatively regulate the CRE activity through G(o). This negative
      transactivation of CRE is the first biochemically analyzed signal evoked by the
      three FAD-APPs, but not by wild-type APP695, in a whole-cell system. We discuss
      the significance of constitutive CRE suppression by FAD-APPs, which is
      potentially relevant to synaptic malplasticity or memory disorders.

PMID- 8665853
TI  - Diversification of Neu differentiation factor and epidermal growth factor
      signaling by combinatorial receptor interactions.
AB  - The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind
      to epidermal growth factor and Neu differentiation factor, and an orphan
      receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB
      3 is catalytically impaired. By using interleukin-3-dependent cells that
      ectopically express the three ErbB proteins or their combinations, we found that
      ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can
      reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3
      correlates with heterodimer formation and is reflected in receptor
      phosphorylation and the transregulation of ligand affinity. Inter-receptor
      interactions enable graded proliferative and survival signals: heterodimers are
      more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB
      2/ErbB-3 heterodimer, are more active than ErbB-1 complexes. Nevertheless, ErbB-1
      signaling displays dominance over ErbB-3 when the two receptors are coexpressed.
      Although all receptor combinations activate the mitogen-activated protein kinases
      ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to
      intervening signaling proteins. It is conceivable that combinatorial receptor
      interactions diversify signal transduction and confer double regulation, in cis
      and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.

PMID- 8665856
TI  - A sigma factor that modifies the circadian expression of a subset of genes in
      cyanobacteria.
AB  - We isolated mutants affected in the circadian expression of the psbAI gene in
      Synechococcus sp. strain PCC 7942 using a strategy that tags the genomic locus
      responsible for the mutant phenotype. The search identified one short period (22
      h) mutant (M2) and two low amplitude mutants, one of which showed apparent
      arhythmia (M11) and one that was still clearly rhythmic (M16). We characterized
      the disrupted locus of the low amplitude but still rhythmic mutant (M16) as the
      rpoD2 gene, a member of a gene family that encodes sigma70-like transcription
      factors in Synechococcus. We also inactivated rpoD2 in a number of reporter
      strains and showed that the circadian expression of some genes is not modified by
      the loss of this sigma factor. Therefore, we conclude that rpoD2 is a component
      of an output pathway of the biological clock that affects the circadian
      expression of a subset of genes in Synechococcus. This work demonstrates a direct
      link between a transcription factor and the manifestation of circadian gene
      expression.

PMID- 8665855
TI  - An extradenticle-induced conformational change in a HOX protein overcomes an
      inhibitory function of the conserved hexapeptide motif.
AB  - HOX homeoproteins control cell identities during animal development by
      differentially regulating target genes. The homeoprotein encoded by the
      extradenticle (exd) gene can selectively modify HOX DNA binding, suggesting that
      it contributes to HOX specificity in vivo. HOX-EXD interactions are in part
      mediated by a conserved stretch of amino acids termed the hexapeptide found in
      many HOX proteins. Here, we demonstrate that a 20 bp oligonucleotide from the 5'
      region of the mouse Hoxb-1 gene, a homolog of Drosophila labial (lab), is
      sufficient to direct an expression pattern in Drosophila that is very similar to
      endogenous lab. In vivo, this expression requires lab and exd and, in vitro, LAB
      requires EXD to bind this oligonucleotide. In contrast, LAB proteins with
      mutations in the hexapeptide bind DNA even in the absence of EXD. Moreover, a
      hexapeptide mutant of LAB has an increased ability to activate transcription in
      vivo. Partial proteolysis experiments suggest that EXD can induce a
      conformational change in LAB. These data are consistent with a mechanism whereby
      the LAB hexapeptide inhibits LAB function by inhibiting DNA binding and that an
      EXD-induced conformational change in LAB relieves this inhibition, promoting
      highly specific interactions with biologically relevant binding sites.

PMID- 8665857
TI  - Tissue-specific factors additively increase the probability of the all-or-none
      formation of a hypersensitive site.
AB  - DNase I-hypersensitive sites lack a canonical nucleosome and have binding sites
      for various transcription factors. To understand how the hypersensitivity is
      generated and maintained, we studied the chicken erythroid-specific
      beta(A)/epsilon globin gene enhancer, a region where both tissue-specific and
      ubiquitous transcription factors can bind. Constructions containing mutations of
      this enhancer were stably introduced into a chicken erythroid cell line. We found
      that the hypersensitivity was determined primarily by the erythroid factors and
      that their binding additively increased the accessibility. The fraction of
      accessible sites in clonal cell lines was quantitated using restriction
      endonucleases; these data implied that the formation of each hypersensitive site
      was an all-or-none phenomenon. Use of DNase I and micrococcal nuclease probes
      further indicated that the size of the hypersensitive site was influenced by the
      binding of transcription factors which then determined the length of the
      nucleosome-free gap. Our data are consistent with a model in which hypersensitive
      sites are generated stochastically: mutations that reduce the number of bound
      factors reduce the probability that these factors will prevail over a nucleosome;
      thus, the fraction of sites in the population that are accessible is also
      diminished.

PMID- 8665858
TI  - Acetylation of histone H4 plays a primary role in enhancing transcription factor
      binding to nucleosomal DNA in vitro.
AB  - Core histones isolated from normal and butyrate-treated HeLa cells have been
      reconstituted into nucleosome cores in order to analyze the role of histone
      acetylation in enhancing transcription factor binding to recognition sites in
      nucleosomal DNA. Moderate stimulation of nucleosome binding was observed for the
      basic helix-loop-helix factor USF and the Zn cluster DNA binding domain factor
      GAL4-AH using heterogeneously acetylated histones. However, by coupling novel
      immunoblotting techniques to a gel retardation assay, we observed that nucleosome
      cores containing the most highly acetylated forms of histone H4 have the highest
      affinity for these two transcription factors. Western analysis of gel-purified
      USF-nucleosome and GAL4-AH-nucleosome complexes demonstrated the predominant
      presence of acetylated histone H4 relative to acetylated histone H3.
      Immunoprecipitation of USF-nucleosome complexes with anti-USF antibodies also
      demonstrated that these complexes were enriched preferentially in acetylated
      histone H4. These data show that USF and GAL4-AH preferentially interact with
      nucleosome cores containing highly acetylated histone H4. Acetylation of histone
      H4 thus appears to play a primary role in the structural changes that mediate
      enhanced binding of transcription factors to their recognition sites within
      nucleosomes.

PMID- 8665859
TI  - A heteromeric complex containing the centromere binding factor 1 and two basic
      leucine zipper factors, Met4 and Met28, mediates the transcription activation of
      yeast sulfur metabolism.
AB  - Transcription activation of sulfur metabolism in yeast is dependent on two DNA
      binding factors, the centromere binding factor 1 (Cbf1) and Met4. While the role
      of Met4 was clearly established by showing that it acts as a transcription
      activator, the precise function in transcription of the multi-functional factor
      Cbf1 remains more elusive. We report here the identification of a new
      transcription factor Met28 which participates in the regulation of sulfur
      metabolism. Cloning and sequencing of MET28 revealed that it encodes a new member
      of the basic leucine zipper DNA binding factor family. We also demonstrate that
      Met28 possesses no intrinsic transcription activation capabilities. Studies of
      the DNA binding characteristics of Met28 led us to identify in gel mobility
      assays a heteromeric complex containing Cbf1, Met4 and Met28. We further
      demonstrated that the presence of Cbf1 and Met4 stimulates the binding of Met28
      to DNA. 'Two-hybrid' studies allowed us to carry out preliminary investigations
      on the binary protein-protein interactions involved in the formation of the Cbf1
      Met4-Met28 complex. Our results give evidence that the leucine zippers of Met4
      and Met28, along with the basic helix-loop-helix domain of Cbf1, provide the
      protein surfaces mediating these interactions. All these results suggest that the
      multi-functional factor Cbf1 functions in transcription activation by tethering
      specific activating factors to the DNA.

PMID- 8665860
TI  - The relationship between sequence-specific termination of DNA replication and
      transcription.
AB  - In Escherichia coli and Bacillus subtilis replication fork arrest occurs in the
      terminus at sequence-specific sites by the binding of replication terminator
      proteins to the fork arrest sites. The protein-DNA complex causes polar arrest of
      the replication forks by inhibiting the activity of the replicative helicases in
      only one orientation of the terminus with respect to the replication origin. This
      activity has been named as polar contrahelicase. In this paper we report on a
      second novel activity of the terminator proteins of E.coli and B.subtilis, namely
      the ability of the proteins to block RNA chain elongation by several prokaryotic
      RNA polymerases in a polar mode. The replication terminator proteins ter and RTP
      of E.coli and B.subtilis respectively, impeded RNA chain elongation catalyzed by
      T7, SP6 and E.coli RNA polymerases in a polar mode at the replication arrest
      sites. The RNA chain anti-elongation and the contrahelicase activities were
      isopolar. Whereas one monomer of ter was necessary and sufficient to block RNA
      chain elongation, two interacting dimers of RTP were needed to effect the same
      blockage. The biological significance of the RNA chain anti-elongation activity
      is manifested in the functional inactivation of a replication arrest site by
      invasion of RNA chains from outside, and the consequent need to preserve
      replication arrest activity by restricting the passage of transcription through
      the terminus-terminator protein complex.

PMID- 8665861
TI  - Immunoglobulin gene hyperconversion ongoing in chicken splenic germinal centers.
AB  - It has been believed that the peripheral lymphocytes in chickens proliferate by
      self-renewing amplification of the preimmune repertoire generated in bursa. We
      amplified rearranged immunoglobulin variable (V) region genes from the single
      germinal centers induced by immunization. The sequence analysis of these genes
      revealed that most were derived from distinct B-cell clones which expanded
      locally, generating somatic antibody mutants at a high rate. Somatic
      hypermutations included unlinked base changes and the linked base modifications
      interpreted as unidirectional transfer of sequences from V region pseudogenes.
      This finding demonstrates the ongoing post-bursal diversification of B-cells in
      splenic germinal centers by templated gene conversion as well as untemplated
      point mutations.

PMID- 8665862
TI  - Multiple roles for divalent metal ions in DNA transposition: distinct stages of
      Tn10 transposition have different Mg2+ requirements.
AB  - Tn10 transposition takes place by a non-replicative mechanism in which the
      transposon is excised from donor DNA and integrated into a target site. Mg2+ is
      an essential cofactor in this reaction. We have examined the Mg2+ requirements at
      various steps in Tn10 transposition. Results presented here demonstrate that Tn10
      excision can occur efficiently at a 16-fold lower Mg2+ concentration than strand
      transfer and that, at Mg2+ concentrations in the range of 60-fold below the wildt
      ype optimum, double strand cleavage events at the two transposon ends are
      completely uncoupled. These experiments identify specific breakpoints in Tn10
      transposition which are sensitive to Mg2+ concentration. Whereas the uncoupling
      of double strand cleavage events at the two transposon ends most likely reflects
      the inability of two separate IS10 transposase monomers in the synaptic complex
      to bind Mg2+, the uncoupling of transposon excision from strand transfer is
      expected to reflect either a conformational change in the active site or the
      existence of an Mg2+ binding site which functions specifically in target
      interactions. We also show that Mn2+ relaxes target specificity in Tn10
      transposition and suppresses a class of mutants which are blocked specifically
      for integration. These observations can be explained by a model in which sequence
      specific target site binding is tightly coupled to a conformational change in the
      synaptic complex which is required for catalysis of strand transfer.

PMID- 8665863
TI  - The environment of two metal ions surrounding the splice site of a group I
      intron.
AB  - Several divalent metal ions (Ca2+, Sr2+ and Pb2+) do not promote splicing, but
      instead induce cleavage at a single site in the conserved group I intron core in
      the absence of the guanosine cofactor at elevated pH, generating products with 5'
      OH and 3'-phosphate ends. The reaction is competed by Mg2+, which does not cleave
      at this position, but hydrolyses the splice sites producing 3'-OH and 5'
      phosphate ends. Mn2+ promotes both core cleavage and splice site hydrolysis under
      identical conditions, suggesting that two different metal atoms are involved,
      each responsible for one type of cleavage, and with different chemical and
      geometric requirements. Based on the core cleavage position and on the previously
      proposed coordination sites for Mg2+, we propose a structural location for two
      metal ions surrounding the splice site in the Michel-Westhof three-dimensional
      model of the group I intron core. The proposed location was strengthened by a
      first mutational analysis which supported the suggested interaction between one
      of the metal ions and the bulged residue in P7.

PMID- 8665864
TI  - A splice hepadnavirus RNA that is essential for virus replication.
AB  - According to the current model of hepadnavirus gene expression, the viral
      envelope proteins are produced from unspliced subgenomic RNAs, in contrast to the
      retroviral mechanism, where the subgenomic env RNA is generated by RNA splicing.
      We now describe and characterize a novel duck hepatitis B virus RNA species which
      is derived from the RNA pregenome by loss of a 1.15 kb intron. This RNA (termed
      spliced L RNA) codes for the large surface protein (L protein), as does the
      previously described unspliced mRNA (the preS RNA); however, it differs in 5'
      leader sequence and promoter control. Mutational analysis indicates that the
      spliced L RNA is functionally important for virus replication in infected
      hepatocytes and ducks, but not for virus formation from transfected DNA genomes.
      This suggests that the newly discovered second pathway for L protein synthesis
      plays a distinct role in an early step in the viral life cycle.

PMID- 8665865
TI  - Herpes simplex virus VP16 rescues viral mRNA from destruction by the virion host
      shutoff function.
AB  - Herpes simplex virus (HSV) virions contain two regulatory proteins that
      facilitate the onset of the lytic cycle: VP16 activates transcription of the
      viral immediate-early genes, and vhs triggers shutoff of host protein synthesis
      and accelerated turnover of cellular and viral mRNAs. VP16 and vhs form a complex
      in infected cells, raising the possibility of a regulatory link between them.
      Here we show that viral protein synthesis and mRNA levels undergo a severe
      decline at intermediate times after infection with a VP16 null mutant,
      culminating in virtually complete translational arrest. This phenotype was
      rescued by a transcriptionally incompetent derivative of VP16 that retains vhs
      binding activity, and was eliminated by inactivating the vhs gene. These results
      indicate that VP16 dampens vhs activity, allowing HSV mRNAs to persist in
      infected cells. Further evidence supporting this hypothesis came from the
      demonstration that a stably transfected cell line expressing VP16 was resistant
      to host shutoff induced by superinfecting HSV virions. Thus, in addition to its
      well known function as a transcriptional activator, VP16 stimulates viral gene
      expression at a post-transcriptional level, by sparing viral mRNAs from
      degradation by one of the virus-induced host shutoff mechanisms.

PMID- 8665866
TI  - CPEB controls the cytoplasmic polyadenylation of cyclin, Cdk2 and c-mos mRNAs and
      is necessary for oocyte maturation in Xenopus.
AB  - Cytoplasmic polyadenylation is a key mechanism controlling maternal mRNA
      translation in early development. In most cases, mRNAs that undergo poly(A)
      elongation are translationally activated; those that undergo poly(A) shortening
      are deactivated. Poly(A) elongation is regulated by two cis-acting sequences in
      the 3'-untranslated region (UTR) of responding mRNAs, the polyadenylation
      hexanucleotide AAUAAA and the U-rich cytoplasmic polyadenylation element (CPE).
      Previously, we cloned and characterized the Xenopus oocyte CPE binding protein
      (CPEB), showing that it was essential for the cytoplasmic polyadenylation of B4
      RNA. Here, we show that CPEB also binds the CPEs of G10, c-mos, cdk2, cyclins A1,
      B1 and B2 mRNAs. We find that CPEB is necessary for polyadenylation of these RNAs
      in egg extracts, suggesting that this protein is required for polyadenylation of
      most RNAs during oocyte maturation. Our data demonstrate that the complex timing
      and extent of polyadenylation are partially controlled by CPEB binding to
      multiple target sites in the 3' UTRs of responsive mRNAs. Finally, injection of
      CPEB antibody into oocytes not only inhibits polyadenylation in vivo, but also
      blocks progesterone-induced maturation. This is due to inhibition of
      polyadenylation and translation of c-mos mRNA, suggesting that CPEB is critical
      for early development.

PMID- 8665868
TI  - Enacyloxin IIa, an inhibitor of protein biosynthesis that acts on elongation
      factor Tu and the ribosome.
AB  - This work analyzes the action of enacyloxin Ila, an inhibitor of bacterial
      protein biosynthesis. Enacyloxin IIa [IC50 on poly(Phe) synthesis approximately
      70 nM] is shown to affect the interaction between elongation factor (EF) Tu and
      GTP or GDP; in particular, the dissociation of EF-Tu-GTP is strongly retarded,
      causing the Kd of EF- Tu-GTP to decrease from 500 to 0.7 nM. In its presence, the
      migration velocity of both GTP- and GDP-bound EF-Tu on native PAGE is increased.
      The stimulation of EF-Tu-GDP dissociation by EF-Ts is inhibited. EF- Tu-GTP can
      still form a stable complex with aminoacyl-tRNA (aa-tRNA), but it no longer
      protects aa-tRNA against spontaneous deacylation, showing that the EF-Tu-GTP
      orientation with respect to the 3' end of aa-tRNA is modified. However, the EF-Tu
      dependent binding of aa-tRNA to the ribosomal A-site is impaired only slightly by
      the antibiotic and the activity of the peptidyl-transferase center, as determined
      by puromycin reactivity, is not affected. In contrast, the C-terminal
      incorporation of Phe into poly(Phe)-tRNA bound to the P-site is inhibited, an
      effect that is observed if Phe-tRNA is bound to the A-site nonenzymatically as
      well. Thus, enacyloxin IIa can affect both EF-Tu and the ribosomal A-site
      directly, inducing an anomalous positioning of aa-tRNA, that inhibits the
      incorporation of the amino acid into the polypeptide chain. Therefore, it is the
      first antibiotic found to have a dual specificity targeted to EF-Tu and the
      ribosome.

PMID- 8665869
TI  - Fluorescence in situ hybridization: a brief review.
AB  - Fluorescence in situ hybridization (FISH) is used for many purposes, including
      analysis of chromosomal damage, gene mapping, clinical diagnostics, molecular
      toxicology and cross-species chromosome homology. FISH allows an investigator to
      identify the presence and location of a region of cellular DNA or RNA within
      morphologically preserved chromosome preparations, fixed cells or tissue
      sections. This report describes in situ hybridization, and discusses the past,
      present and future applications of this method for genetic analysis and molecular
      toxicology.

PMID- 8665867
TI  - Mutational analysis of mammalian poly(A) polymerase identifies a region for
      primer binding and catalytic domain, homologous to the family X polymerases, and
      to other nucleotidyltransferases.
AB  - We have tested deletion and substitution mutants of bovine poly(A) polymerase,
      and have identified a small region that overlaps with a nuclear localization
      signal and binds to the RNA primer. Systematic mutagenesis of carboxylic amino
      acids led to the identification of three aspartates that are essential for
      catalysis. Sequence and secondary structure comparisons of regions surrounding
      these aspartates with sequences of other polymerases revealed a significant
      homology to the palm structure of DNA polymerase beta, terminal
      deoxynucleotidyltransferase and DNA polymerase IV of Saccharomyces cerevisiae,
      all members of the family X of polymerases. This homology extends as far as cca:
      tRNA nucleotidyltransferase and streptomycin adenylyltransferase, an antibiotic
      resistance factor.

PMID- 8665870
TI  - Application of fluorescence in situ hybridisation to study the relationship
      between cytotoxicity, chromosome aberrations, and changes in chromosome number
      after treatment with the topoisomerase II inhibitor amsacrine.
AB  - Amsacrine (4'-(9-acridinylamino)methanesulphon-m-anisidide) is an antileukemic
      drug which inhibits topoisomerase II (topo II) enzymes. We studied effects of two
      concentrations of amsacrine on the GM10115A cell line. This is a Chinese hamster
      line containing a single human chromosome 4, which can be readily visualised
      using fluorescence in situ hybridisation (FISH). The low amsacrine concentration
      slowed cell growth but did not cause significant arrest in the G2 phase of the
      cell cycle, while a higher concentration caused more long-term effects on the
      growth of the cells and caused G2 arrest. Either concentration led to chromosomal
      fragments which were lost with increasing time after treatment, and chromosomal
      translocations which appeared stable for at least 8 days after treatment. At the
      low concentration, the loss or gain of a single chromosome was a common event.
      The higher concentration led to polyploid cells, usually containing an uneven
      number of chromosome 4. We propose two mechanisms for aneuploidy by amsacrine (or
      related topo II poisons), either of which can be readily detected using FISH. At
      low drug concentrations, aneuploidy may occur directly through, for example, a
      failure to resolve catenated chromatids prior to anaphase. However, there has
      been considerable interest in the role of the cell division control (cdc) kinase
      and cyclins in regulating the mammalian cell cycle, and these may also be
      involved in the response of cells to high concentrations of topo II poisons. Cdc2
      proteins and cyclins are involved in coordinating diverse activities during the M
      phase of the cell cycle, including catalysis of chromosome condensation and
      reorganisation of microtubules to allow chromosome separation during mitosis.
      Chromosome damage by topo II poisons will lead to G2 arrest, which allows the
      cells time to repair the damage. During this time, cyclin A and cdc2 levels will
      fall, preventing the cell from entering mitosis and effectively resetting the
      clock to G1 and the ploidy to tetraploid. Aneuploid cells will derive from
      polyploid cells through loss of extra chromosomes.

PMID- 8665871
TI  - Cytogenetic monitoring of occupational exposure to pesticides: characterization
      of GSTM1, GSTT1, and NAT2 genotypes.
AB  - Occupational exposure of floriculturists is characterized by alternating periods
      of intense pesticide spraying and reduced or no activity. Induction of sister
      chromatid exchanges (SCE), structural chromosome aberrations (CA) and micronuclei
      (MN) was investigated in peripheral lymphocytes of a group of 23 Italian
      floriculturists and 22 matched controls. Blood sampling was performed during and
      one month after the end of intensive pesticide treatments, in order to cover a
      period of high and low exposure, respectively. Each donor was genotyped for
      glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and N-acetyltransferase 2
      (NAT2), three polymorphic genes involved in xenobiotic metabolism, to assess
      their potential role in individual genotoxic response to the pesticide exposure.
      No effect of the pesticide exposure on the cytogenetic parameters were detected.
      Smoking, however, was found to increase SCE levels. The only significant
      influence of phenotype composition on cytogenetic response was an increase in SCE
      levels in the GSTT1 positive individuals compared with the GSTT1 nulls (P=0.02).
      This finding was, however, based on only four GSTT1 null donors (n=41 for GSTT1
      positive donors). In addition, a possible interaction was observed between
      smoking and GSTM1 genotype in the CA assay, GSTM1 null smokers, earlier reported
      to have an elevated risk for lung cancer, showing higher CA frequencies than
      GSTM1 positive smokers.

PMID- 8665872
TI  - SOS chromotest results in a broader context: empirical relationships between
      genotoxic potency, mutagenic potency, and carcinogenic potency.
AB  - Environmental monitoring requires that large numbers of samples be processed in a
      relatively short period of time. While microbioassays facilitate rapid testing,
      the results are often difficult to interpret in the broader context of human or
      animal health. Determining the consequences of exposure to genotoxic substances
      will ultimately require in situ monitoring of exposed organisms. However, it is
      immediately possible to construct a broad empirical framework within which
      available microbioassay results can be interpreted. To do this for SOS Chromotest
      results, we investigated the empirical relationships between SOS genotoxic
      potency and mutagenic potency (as measured with the Salmonella/microsome assay),
      as well as between genotoxic potency and carcinogenic potency (as measured using
      standard, chronic animal bioassays). Strong relationships were identified
      between; 1) genotoxic potency and mutagenic potency for 268 direct-acting
      substances (r2=0.76) and 2) genotoxic potency and mutagenic potency for 126 S9
      activated substances (r2=0.65). Ordinary least squares regression analyses of the
      SOS genotoxicity-Salmonella mutagenicity relationship revealed a significant
      effect of SOS genotoxicity as well as differences in mutagenic potency that can
      be attributed to the Salmonella strain used to measure mutagenic potency.
      Analyses of S9-activated substances revealed a significant interaction between
      the SOS genotoxic potency (SOSIP) effect and the Salmonella strain effect. Two
      regression models relating SOS genotoxicity and Salmonella mutagenicity were used
      to predict the mutagenic potency of several industrial effluent extracts
      previously analyzed for SOS genotoxicity by White et al. [(1996): Environ Mol
      Mutagen 27:116-139]. Predictions are consistent with published mutagenic potency
      values for similar industrial waste materials. A consistent relationship was also
      identified between genotoxic potency and carcinogenic potency for 51 substances.
      Linear regression analyses revealed an effect of SOS genotoxic potency as well as
      differences in carcinogenic potency that may be attributable to experimental
      animal and route of exposure. The correlation between genotoxicity and
      carcinogenicity was fairly weak (maximum r value = 0.51). Previous studies
      revealed similar strength of association between Ames mutagenicity and
      carcinogenicity. Predicted carcinogenic potencies of previously examined
      genotoxic, industrial effluent extracts are generally low compared to the pure
      substances included in the data set.

PMID- 8665873
TI  - Breakthrough of ultraviolet light from various brands of fluorescent lamps:
      lethal effects on DNA repair-defective bacteria.
AB  - In a comparative study of 17 pairs of 15 W fluorescent lamps intended for use in
      homes and purchased in local stores, we detect over 10-fold differences in UVB +
      UVC emissions between various lamps. This breakthrough of ultraviolet (UV) light
      is in part correlated with ability of lamps to kill DNA repair-defective recA
      uvrB- Salmonella. Relative proficiency of lamps in eliciting photoreactivation of
      UV-induced DNA lesions also plays a prominent role in the relative rates of
      bacterial inactivation by emissions from different lamps. Lamps made in Chile,
      such as Philips brand lamps and one type of General Electric lamp, produce far
      less UVB + UVC and fail to kill recA-uvrB- bacteria. In contrast, all tested
      lamps manufactured in the USA, Hungary, and Japan exhibit readily observed
      deleterious biological effects. When an E. coli recA-uvrB-phr- (photolyase
      negative) triple mutant is used for assay, lethal radiations are detected from
      all lamps, and single-hit exponential inactivation rates rather closely correlate
      to amount of directly measured UVB + UVC output of each pair of lamps. Although
      all lamps tested may meet international and United States standards for radiation
      safety, optimal practices in lamp manufacture are clearly capable of decreasing
      human exposure to indoor UV light.

PMID- 8665874
TI  - Structural and quantum chemical factors affecting mutagenic potency of
      aminoimidazo-azaarenes.
AB  - A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been
      isolated from cooked foods and identified as bacterial mutagens and rodent
      carcinogens, was selected from a larger series previously published [Hatch et al.
      (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study
      using computational methods. Structural features believed to affect mutagenic
      potency were tabulated. Molecular orbital energies and other electronic
      properties of these compounds were calculated using Huckel, semiempirical AM1,
      and ab initio quantum mechanical methods. Factor interrelationships were studied
      by multiple linear regression and canonical correlation analyses. Our goal was an
      improved understanding of the chemical basis of mutagenicity for this class of
      heterocyclic amines. The major findings were as follows: 1) mutagenic potency is
      related to the size of the aromatic ring system; 2) potency is enhanced by the
      presence and location of an N-methyl group; 3) potency is enhanced by addition of
      ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4)
      potency is inversely related to the energy of the LUMO (lowest unoccupied
      molecular orbital) of the parent amines; 5) potency is directly, though weakly,
      related to the LUMO energy of the derived nitrenium ions; and 6) the calculated
      thermodynamic stability of the nitrenium ions (relative to the parent amine) is
      directly correlated with nitrenium LUMO energy and with the negative charge on
      the exocyclic nitrogen atom. Although this study raises several intriguing issues
      relating mutagenicity to chemical properties, further study will be required to
      determine the plausibility of the nitrenium ion as the ultimate mutagen for
      binding to DNA.

PMID- 8665875
TI  - Pneumoperitoneum for laparoscopic surgery does not increase venous admixture.
AB  - Venous admixture as a measure of pulmonary gas exchange was studied before and
      during laparascopic cholecystectomy in 12 patients with normal healthy cardio
      pulmonary function. After induction of anaesthesia the patients were studied by
      radial and pulmonary arterial catheterization and simultaneous arterial and mixed
      venous blood gas sampling in the horizontal, 15-20 degrees head-down and 15-20
      degrees head-up tilt positions. After establishing the pneumoperitoneum (PP) by
      insufflation of carbon dioxide to an intraabdominal pressure level of 11-12 mmHg,
      the measurements were repeated in the same positions. The laparoscopic
      cholecystectomy then started and measurements were repeated every 30 min during
      surgery. The venous admixture was 4 +/- 0.6% (range 2-6%) in the horizontal
      position and was not influenced by altered body position. Immediately after
      establishment of PP, there was a 31 +/- 5% (P < 0.05) reduction of venous
      admixture and a 15 +/- 3% (P < 0.01) elevation of PaO2 compared with the control
      situation without PP. These changes were maintained during pneumoperitoneum and
      were not influenced by posture. It is suggested that alterations in the
      distribution of ventilation and/or lung perfusion results in a reduced venous
      admixture during PP without surgery. In addition, there was no indication that
      venous admixture is elevated as a result of laparoscopic surgery in the reversed
      Trendelenburg position.

PMID- 8665876
TI  - Pre-emptive versus post-surgical administration of ketorolac for hysterectomy.
AB  - Seventy-seven women who underwent routine vaginal or abdominal hysterectomy were
      randomly allocated to receive intravenous ketorolac 30 mg either 30 min before
      surgical incision (pre-emptive group, n = 37), or at the end of the surgical
      procedure (post-surgical group, n = 40). The patients received routine post
      operative care, which included morphine by patient-controlled analgesia, 1 mg per
      demand with a lockout of 6 min and a background infusion of 1 mg h-1. In
      addition, pain was assessed at 12 and 24 h using a 100 mm visual analogue scale
      (VAS), both at rest and on coughing. At 24 h, the median VAS at rest was 24 mm
      (range 0-80) in the pre-emptive group and 28 mm (range 0-100) in the post
      surgical group. The average morphine consumption rate over the first 24 h was 1.9
      mg h-1 (SD +/- 0.6) in the pre-emptive group, and 2.2 mg hr-1 (SD +/- 1.1) in the
      post-surgical group. There were no significant differences on univariate testing.
      Subsidiary stepwise multiple regression modelling identified age, weight, type of
      hysterectomy, and the timing of ketorolac administration as significant
      explanators of post-operative morphine consumption. A statistically significant
      pre-emptive analgesic effect was therefore identifiable, but the clinical
      significance is uncertain in relation to the other influences on post-operative
      analgesic requirements.

PMID- 8665877
TI  - Continuous non-invasive blood pressure monitoring by brachial artery displacement
      method in high-risk surgical patients.
AB  - Continuous non-invasive blood pressure (CNBP) measurements were compared to
      invasive radial artery pressure recordings in 26 patients with cardiac, vascular
      and/or pulmonary disease. Patients were studied during general anaesthesia (n =
      6), regional anaesthesia (n = 10), or combined technique (n = 10) for abdominal
      or transurethral surgery. CNBP was obtained from a cuff placed around the upper
      arm and simultaneously compared to invasive pressure from the ipsilateral radial
      artery. A CNBP device (7001 Cortronic) used intermittent oscillometric
      measurement for calibration. Through a cuff continuously inflated to a pressure
      of 20 mmHg, a microprocessor-controlled electro-pneumatic acquisition system
      sensed displacements of the brachial artery wall. Amplified, digitally converted,
      filtered and transformed data were displayed as a continuous pulse pressure
      waveform and digital pressure values on the screen. The CNBP method functioned
      without disturbances before surgery in all patients. Intra-operative use of
      electrocautery or a spontaneous occurrence of warning on the screen repeatedly
      triggered oscillometric recalibration, hence CNBP measurements were discontinued
      in nine patients. Coefficients of correlation (r) of all invasive and CNBP pairs
      (n = 1111) were 0.68, 0.58 and 0.70 for systolic, diastolic, and mean blood
      pressures, respectively. Prediction errors (bias, mean +/- SD) were -13.6 +/-
      22.5 mmHg (on average CNBP < invasive pressure) for systolic, +13.0 +/- 12.4 mmHg
      (CNBP > invasive pressure) for diastolic and +5.0 +/- 13.9 mmHg (CNBP > invasive
      pressure) for mean CNBP, as compared to radial artery pressure values. Absolute
      errors (precision) were 25.3 +/- 9.4 mmHg for systolic, 17.4 +/- 4.5 mmHg for
      diastolic, and 13.9 +/- 4.6 mmHg for mean CNBP. During anaesthesia induction (n =
      672) the difference between consecutive measurements (trend of pressure changes)
      with invasive and CNBP method exceeded 20 mmHg in 90 (13.3%) instances for
      systolic, in 33 (4.9%) instances for diastolic, and in 45 (6.6%) instances for
      mean blood pressure. In conclusion, the CNBP method by brachial artery wall
      displacement failed to measure the blood pressure reliably and to display the
      trend of pressure changes correctly during anaesthesia induction. In its present
      form this CNBP method should not replace invasive blood pressure monitoring in
      high-risk patients neither for anaesthesia induction nor during non-thoracic
      surgical procedures.

PMID- 8665878
TI  - Effect of a radiant heater on post-operative hypothermia: comparison with a
      reflective blanket.
AB  - Thirty patients with post-operative hypothermia following major surgery
      (thoracic, abdominal, orthopaedic) were allocated randomly to either active
      warming with a radiant heater (500 W) or passive rewarming with a reflective
      blanket. Rectal temperature, mean skin temperature (at four measuring sites),
      continuous haemoglobin saturation and shivering were measured for 2 h post
      operatively. Although post-operative heat supply with a radiant heater resulted
      in faster rewarming, there were no differences between the two groups with
      respect to haemoglobin saturation and shivering.

PMID- 8665879
TI  - Post-operative analgesia for craniotomy patients: current attitudes among
      neuroanaesthetists.
AB  - As part of an evaluation of post-operative analgesia for craniotomy patients, a
      postal questionnaire was sent to 183 consultant members of the Neuroanaesthesia
      Society of Great Britain and Ireland, inquiring about their current practices for
      post-operative neurosurgical analgesia. Replies were received from 110
      neuroanaesthetists in 37 different neurosurgical centres. Intramuscular codeine
      phosphate or dihydrocodeine was the mainstay of post-operative analgesia for 97%
      of neuroanaesthetists despite the fact that over half of them thought that
      analgesia was inadequate. Only four neuroanaesthetists would ever consider using
      opioids post-operatively because of fears about respiratory depression and
      sedation, yet all except one used opioids per-operatively. Post-operative
      analgesia for craniotomy patients is perceived as inadequate by most
      neuroanaesthetists, yet traditional prejudice against opioid use prevents this
      being remedied. We suggest that patient-controlled analgesia with morphine could
      be a safe alternative to codeine phosphate.

PMID- 8665880
TI  - The effects of midazolam followed by administration of either vecuronium or
      atracurium on the QT interval in humans.
AB  - Prolongation of the QT interval may produce potentially hazardous dysrhythmias.
      The effects on the QT interval of midazolam followed by administration of either
      vecuronium or atracurium have been investigated. Thirty patients, ASA I or II,
      without cardiovascular problems, electrolyte abnormalities or receiving any
      medication were studied. All patients were premedicated with midazolam 0.08 mg kg
      1 i.m. 30-60 min before surgery. Anaesthesia was induced with midazolam 0.4 mg kg
      1. ECG recordings as well as heart rate and arterial pressure measurements were
      obtained before induction of anaesthesia and 1, 3 and 5 min after midazolam
      administration. Further recordings were obtained at 1, 3 and 5 min after either
      vecuronium 0.1 mg kg-1 (15 patients) or atracurium 0.5 mg kg-1 (15 patients).
      Further recordings were obtained immediately after tracheal intubation and at 1,
      3 and 5 min later. Midazolam followed by administration of either vecuronium or
      atracurium did not produce any significant change in QTc interval (QT interval
      corrected for heart rate). Statistically significant prolongation of QTc was
      observed in both groups after intubation, although the mean QTc values did not
      exceed the upper limits of normal. Heart rate and arterial pressure were also
      increased significantly in both groups after intubation.

PMID- 8665881
TI  - Optimum time for neostigmine administration to antagonize vecuronium-induced
      neuromuscular blockade.
AB  - We followed the recovery time course in 46 patients antagonized by neostigmine
      (0.036 mg kg-1) at different levels of vecuronium-induced neuromuscular blockade
      ranging from post-tetanic count 1 to train-of-four ratio 0.4 and in 15 patients
      during spontaneous recovery. Non-linear regression curve fit analyses showed that
      the optimal time for neostigmine administration was when the first twitch in the
      train of four (T1) was between 1% and 10%. Visual analyses of the scattergram in
      which the level of block, when neostigmine was given, was plotted against total
      recovery time (the time elapsed from administration of the last dose of
      vecuronium to train-of-four ratio 0.7) gave the same result. The reduction in
      total recovery time achieved by neostigmine was 32.6 min (SE diff. 6.0 min). To
      achieve the optimum effect, neostigmine must therefore be given 32.6 min plus the
      required time for peak effect of neostigmine (5.3-7.1 min), i.e. 37.9-39.7 min,
      before train-of-four ratio 0.7 is reached. During spontaneous recovery this
      corresponds to a T1 between 1% and 15%.

PMID- 8665882
TI  - The effect of reversal of myoneural blockade on cerebrospinal fluid pressure
      following cerebral aneurysm surgery.
AB  - Drugs with a depolarizing action at the myoneural junction may cause a rise in
      intracranial pressure. Neostigmine, which is commonly used to reverse residual
      myoneural blockade, has a depolarizing action, and yet its effect on intracranial
      pressure is unknown. Lumbar cerebrospinal fluid pressure, which mirrors
      intracranial pressure, was determined in 12 patients undergoing cerebral aneurysm
      surgery. Cerebrospinal fluid pressure was measured during dense myoneural
      blockade and after its reversal with neostigmine. These effects on cerebrospinal
      fluid pressure were compared with those produced when the arterial partial
      pressure of carbon dioxide (PaCO2) rose from 4 to 5 kPa. After reversal of
      myoneural block, there was a small (non-significant) change in cerebrospinal
      fluid pressure from 3.6 to 4.3 kPa and a larger (significant) rise in
      cerebrospinal fluid pressure to 9.7 kPa when the PaCO2 was allowed to rise. In
      this group of patients, reversal of myoneural blockade with neostigmine causes no
      significant change in cerebrospinal fluid pressure.

PMID- 8665883
TI  - A comparison between ketorolac and diclofenac in laparoscopic sterilization.
AB  - We compared ketorolac and diclofenac for the prevention and treatment of post
      operative pain in patients undergoing laparoscopic sterilization. Fifty ASA I or
      II women were allocated randomly to receive either diclofenac 75 mg or ketorolac
      30 mg intramuscularly 30-90 min before general anaesthesia. Pain scores were
      assessed half-hourly in the recovery room and then at 2 h and 4 h in the ward. In
      the recovery room, pain was treated with a second dose of the study drug,
      followed by parenteral pethidine if necessary. Four patients in the diclofenac
      group and five patients in the ketorolac group requested no analgesics after
      surgery. Fifteen patients from each group had satisfactory analgesia after the
      second dose of study drug. Pain scores were similar between groups at all times.
      The median (range) initial pain score in the recovery room was 5 (0-9.5) in the
      diclofenac group and 5 (1-9) in the ketorolac group. Pain at the injection site
      was more common after diclofenac than ketorolac (12 vs. 3, P < 0.05). In
      conclusion, both intramuscular diclofenac and ketorolac were relatively
      ineffective in controlling the pain after laparoscopic sterilization. The drugs
      were equally well tolerated, but more patients complained of pain at the
      injection site after diclofenac.

PMID- 8665884
TI  - Peribulbar anaesthesia: the role of local anaesthetic volumes and Thiomucase in
      motor block and intraocular pressure.
AB  - Peribulbar anaesthesia is a useful regional anaesthesia and akinesia technique
      for eye surgery. We studied changes in muscular akinesia and intraocular pressure
      under peribulbar anaesthesia caused by different volumes of 0.75% bupivacaine
      with or without the addition of Thiomucase (chondroitin sulphatase) in patients
      undergoing cataract surgery. A total of 120 patients were randomly allocated into
      four groups: group 1, bupivacaine 5 mL; group 2, bupivacaine 5 mL plus Thiomucase
      10 U mL-1; group 3, bupivacaine 9 mL; group 4, bupivacaine 9 mL plus Thiomucase
      10 U mL-1. We assessed: (1) akinesia according to mobility in the four quadrants
      of the eyeball and the palpebral opening using a scoring system between 0 (total
      akinesia) and 10 (full movement); and (2) intraocular pressure before,
      immediately after and 15 min after peribulbar anaesthesia. A significantly better
      motor blockade was observed in groups 2, 3 and 4 than in group 1 (P < 0.05).
      Thiomucase increased the quality of motor blockade in group 2, but not in group
      4. Intraocular pressure increased by 5-10 mmHg in comparison with baseline values
      and, after 15 min application of Honan's balloon, decreased by 8-10 mmHg in
      comparison with baseline values, with no significant differences between groups.
      Thiomucase can improve the motor block if a lower volume of local anaesthetic is
      used. The administration of 5 or 9 mL volumes or the addition of Thiomucase
      decreases the the intraocular pressure in a similar way.

PMID- 8665885
TI  - Coronary artery spasm induced under lumbar epidural anaesthesia.
AB  - A case of coronary artery spasm during lumbar epidural anaesthesia prior to
      surgery is presented. Three paroxysmal episodes of ST segment elevation in lead
      II without changes in V5 developed concomitantly when the patient complained of
      chest discomfort. A denervation of the cardiac sympathetic nerve seems to be the
      primary genesis of the attack in a patient prone to such events.

PMID- 8665886
TI  - Use of a laryngeal mask airway in an adult patient with the Hunter syndrome.
AB  - The mucopolysaccharidoses are a rare group of diseases. The Hunter Syndrome
      (mucopolysaccharidosis II) has been classified into severe and mild forms with
      presentation between the years 2 and 4. Enzyme assays provide the definitive
      diagnosis. An outstanding concern for the anaesthetist is airway management. The
      management of a patient with this condition is illustrated with a case report.

PMID- 8665887
TI  - The pulmonary vascular response to propofol in the isolated perfused rat lung.
AB  - This study investigated the effect of propofol on the pulmonary vascular bed of
      the rat. Propofol (5 x 10(-6) to 5 x 10(-4) M) did not alter the basal perfusion
      pressure in isolated rat lungs perfused at a constant flow (0.03 mL g body wt-1
      min-1) with Krebs-Henseleit solution. When perfusion pressure was elevated by
      raising the K+ concentration to 30 mM (depolarizing Krebs-Henseleit solution),
      propofol decreased it in a concentration-dependent manner. Indomethacin (3 x 10(
      6) M) and NG-nitro-L-arginine methyl ester (10(-4) M) did not affect the response
      to propofol, which excluded the role of cyclo-oxygenase metabolites and nitric
      oxide, respectively. The ATP-sensitive K+ (K+ATP) channel blocker glibenclamide
      (3 x 10(-6) and 10(-5) M) inhibited the vasodilator effect of propofol. When
      lungs were perfused with Ca(2+)-free depolarizing Krebs-Henseleit solution, 0.1
      2.5 mM Ca+2 produced a concentration-dependent pressor response. Propofol (5 x
      10(-5) M) attenuated the vasopressor response to Ca2+ significantly. In
      conclusion, the activation of K+ATP channels is probably the major mechanism of
      the vasodilator effect of propofol, at clinically relevant concentrations, in the
      rat lung. The Ca2+ antagonistic property of propofol is evident only at higher
      concentrations.

PMID- 8665888
TI  - Chemotactic 5-oxo-icosatetraenoic acids activate a unique pattern of neutrophil
      responses. Analysis of phospholipid metabolism, intracellular Ca2+ transients,
      actin reorganization, superoxide-anion production and receptor up-regulation.
AB  - Neutrophil cell responses and signal pathways elicited by the chemotactic
      arachidonic acid metabolites (6E, 8Z, 11Z, 14Z)-5-oxo-icosatetraenoic acid and
      (6E, 8Z, 11Z, 13E)-5-oxo-15-hydroxy-icosatetraenoic acid were studied and
      compared with those of other chemotaxins. Polyphosphoinositol lipid analysis
      revealed activation of phosphatidylinositol-biphosphate 3-kinase by both
      agonists. Experiments with Fura-2 in the presence of EGTA indicated Ca2+
      mobilization from intracellular stores by both 5-oxo-icosanoids. A transient
      actin response and production of small amounts of superoxide anions upon
      stimulation with both agents was detected. The changes induced by 5-oxo
      icosanoids were more moderate and transient than those obtained by other
      chemotaxins. Desensitization studies indicated cross-desensitization between both
      5-oxo-icosanoids, but no interference with the response of other chemotaxins. All
      cell responses elicited by 5-oxo-icosanoids at concentrations 500-fold higher
      than the ED50 of other functions did not induce up-regulation of CD11b and N
      formyl-peptide receptors at the cell surface, and failed to potentiate N-formyl
      peptide-induced superoxide anion production. These results indicate that 5-oxo
      icosanoids trigger a unique pattern of neutrophil responses.

PMID- 8665889
TI  - Isolation, characterization and electron microscopy analysis of a hemidiscoidal
      phycobilisome type from the cyanobacterium Anabaena sp. PCC 7120.
AB  - In this work we present the characterization of a hemidiscoidal phycobilisome
      type of the heterocyst-forming cyanobacterium Anabaena sp. PCC 7120. The
      phycobilisome of this organism contains allophycocyanin, phycocyanin and
      phycoerythrocyanin, similar to the closely related thermophilic cyanobacterium
      Mastigocladus laminosus. Intact phycobilisomes exhibit an absorption maximum at
      619 nm and two fluorescence maxima at 664 nm and 680 nm, corroborating the
      presence of a complete energy pathyway along the antenna. Upon dissociation, the
      phycobiliproteins were released from the phycobilisome. One phycoerythrocyanin,
      one phycocyanin and three allophycocyanin complexes were isolated by ion-exchange
      chromatography and characterized by absorption and fluorescence spectroscopy and
      by SDS/PAGE. The amino-terminal sequences of the polypeptides belonging to the
      phycoerythrocyanin and phycocyanin families were identical with the derived
      sequences of their corresponding genes. Partial amino-terminal sequences of the
      polypeptides belonging to the allophycocyanin family are presented here. Our
      results show that the phycobiliproteins and linker polypeptides from Anabaena sp.
      PCC 7120 are similar to the phycobilisome components characterized in other
      cyanobacteria. The phycobilisome of Anabaena sp. PCC 7120 was extensively
      analyzed by electron microscopy. It differs from the common hemidiscoidal
      tricylindrical, six-rod phycobilisome type by a core domain consisting of five
      core cylinders surrounded by up to eight rods radiating in a hemidiscoidal
      manner. One rod is linked to each basal core cylinder, whereas the remaining core
      cylinders bind two rods each. On the basis of the data presented in this work, a
      revised model for the hemidiscoidal pentacylindrical phycobilisome of Anabaena
      sp. PCC 7120, M. laminosus and Anabaena variabilis is proposed. This model
      accounts more accurately for the 'grape' pattern typically exhibited by these
      phycobilisomes in electron micrographs.

PMID- 8665890
TI  - Crystal structures and solution studies of oxime adducts of mitochondrial
      aspartate aminotransferase.
AB  - The interaction of mitochondrial aspartate aminotransferase with hydroxylamine
      and five derivatives (in which the hydroxyl hydrogen is replaced by the side
      chain of naturally occurring amino acids) was investigated by X-ray diffraction
      as well as by kinetic and spectral measurements with the enzyme in solution. The
      inhibitors react with pyridoxal 5'-phosphate in the enzyme active site, both in
      solution and in the crystalline state, in a reversible single-step reaction
      forming spectrally distinct oxime adducts. Dissociation constants determined in
      solution range from 10(-8) M to 10(-6) M depending on the nature of the side
      chain group. The crystal structures of the adducts of mitochondrial aspartate
      aminotransferase with the monocarboxylic analogue of L-aspartate in the open and
      closed enzyme conformation were determined at 0.23-nm and 0.25-nm resolution,
      respectively. This inhibitor binds to both the open and closed crystal forms of
      the enzyme without disturbing the crystalline order. Small differences in the
      conformation of the cofactor pyridoxal phosphate were detected between the omega
      carboxylate of the inhibitor and Arg292 of the neighbouring subunit is mainly
      responsible for the attainment of near-coplanarity of the aldimine bond with the
      pyridine ring in the oxime adducts. Studies with a fluorescent probe aimed to
      detect shifts in the open/closed conformational equilibrium of the enzyme in
      oxime complexes showed that the hydroxylamine-derived inhibitors, even those
      containing a carboxylate group, do not induce the 'domain closure' in solution.
      This is probably due to the absence of the alpha-carboxylate group in the
      monocarboxylic hydroxylamine-derived inhibitors, emphasizing that both
      carboxylates of the substrates L-Asp and L-Glu are essential for stabilizing the
      closed form of aspartate aminotransferase.

PMID- 8665891
TI  - Insulin-induced GLUT4 recycling in rat adipose cells by a pathway insensitive to
      brefeldin A.

PMID- 8665892
TI  - Structure of sea-urchin arylsufatransferase.

PMID- 8665893
TI  - Initiation of protein synthesis in eukaryotic cells.
AB  - It is becoming increasingly apparent that translational control plays an
      important role in the regulation of gene expression in eukaryotic cells. Most of
      the known physiological effects on translation are exerted at the level of
      polypeptide chain initiation. Research on initiation of translation over the past
      five years has yielded much new information, which can be divided into three main
      areas: (a) structure and function of initiation factors (including identification
      by sequencing studies of consensus domains and motifs) and investigation of
      protein-protein and protein-RNA interactions during initiation; (b) physiological
      regulation of initiation factor activities and (c) identification of features in
      the 5' and 3' untranslated regions of messenger RNA molecules that regulate the
      selection of these mRNAs for translation. This review aims to assess recent
      progress in these three areas and to explore their interrelationships.

PMID- 8665894
TI  - Direct activating effects of dexamethasone on glycogen metabolizing enzymes in
      primary cultured rat hepatocytes.
AB  - The direct effects of dexamethasone on glycogen synthase and phosphorylase and
      glycogen content have been investigated in primary cultured rat hepatocytes.
      Dexamethasone induced the transient translocation of glycogen synthase from the
      soluble to the 10000xg pelletable fraction and the activation of this enzyme,
      although more significant, longer-standing activation was achieved in the
      pelletable fraction. Neither total glycogen synthase content nor glycogen
      synthase mRNA levels were modified. Dexamethasone also caused the sustained
      activation (up to 6h) of glycogen phosphorylase, which was not accompanied by an
      increase in its mRNA level. Glycogen cell content and the incorporation of (14C)
      glucose into glycogen decreased after dexamethasone treatment. The data show that
      dexamethasone, unlike other glycogenolytic hormones, at concentrations of 10 nM
      or higher, stimulate hepatocyte glycogenolysis without inducing the inverse
      coupling of synthase and phosphorylase. The co-existence of active forms of both
      glycogen synthase and phosphorylase promoted by dexamethasone leads to a
      situation that is analogous to that of the fasted liver.

PMID- 8665895
TI  - cis-Acting elements and transcription factors involved in the intestinal specific
      expression of the rat calbindin-D9K gene: binding of the intestine-specific
      transcription factor Cdx-2 to the TATA box.
AB  - The calbindin-D9K (CaBP9k) gene is mainly expressed in differentiated duodenal
      epithelial cells and is used as a model for studying the molecular mechanisms of
      intestine-specific transcription. The gene has been cloned, two major DNase-I
      hypersensitive sites in the duodenum have been described, and a vitamin-D
      response element has been identified. We have now analysed the transcription
      factors and regulatory sequences involved in the transcription of the CaBP9k gene
      in the intestine in ex vivo and in vitro experiments. Transfection experiments in
      intestinal (CaCo-2) and non-intestinal (HeLa) cell lines defined two regions in
      the 5'-flanking sequences of the rat CaBP9k gene. A minimal proximal region (-117
      to +20) promoted transcription in both intestinal expressing and non-expressing
      cell lines. Tissue specificity was conferred by the sequences situated further
      upstream, which are responsible for complete repression in the non-intestinal
      cells. Intestinal transcription was specified by the proximal region, containing
      a specialized TATA box, and a distal region, which contains a previously
      described intestinal DNase-I-hypersensitive site. In vitro DNase I footprinting,
      electrophoretic mobility shift assays and antibody supershift assays were used to
      examine the factors bound to the proximal promoter region (-800 to +80 bp). Rat
      duodenal nuclear extracts protected 12 sites. Some of them appear to be binding
      sites for ubiquitous (nuclear factor 1) or hepatic-enriched sites (hepatocyte
      nuclear factors 1 and 4, enhancer binding protein alpha and beta factors. DNA
      binding studies and transfection experiments indicated that an intestine-specific
      transcription factor, caudal homeobox-2, binds to the TATA box of the rat CaBP9k
      gene. These data contribute to our understanding of the control of the intestinal
      transcription of the CaBP9k gene and demonstrate that several trans-acting
      factors, other than the vitamin D receptor, may be factors for intestine-specific
      CaBP9k gene expression.

PMID- 8665896
TI  - Maturation of human intestinal lactase-phlorizin hydrolase: generation of the
      brush border form of the enzyme involves at least two proteolytic cleavage steps.
AB  - Human lactase-phlorizin hydrolase (LPH), a brush border membrane hydrolase of the
      small intestine, is synthesized as a precursor molecule that undergoes
      proteolytic cleavage to yield mature LPH (LPHbeta) by a trypsin-like protease
      (Naim et al., 1987, 1991). Arg868-Ala869 has been previously proposed to be the
      putative cleavage site for this processing step. Site-directed mutagenesis of
      this monobasic site does not lead to the generation of an uncleaved proLPH
      species, which strongly suggests the existence of an additional cleavage site.
      Further analyses of LPH synthesized in different cell lines lend support to this
      hypothesis. Biosynthetic labeling of human intestinal biopsy samples in the
      presence of trypsin reveals an LPHbeta species that is slightly smaller than the
      intracellularly cleaved molecule. When the proLPH molecule is screened for
      potential cleavage sites, two dibasic pairs are revealed upstream of the N
      terminal end of brush border LPH at Lys851-Arg852 and Arg830-Lys831. Treatment of
      proLPH with trypsin for different periods of time supports the idea of at least
      two cleavage steps, whereby Arg868-Ala869 represents the final cleavage site that
      generates LPHbeta. We propose that the initial cleavage of proLPH takes place
      intracellularly at a site further away from Arg868-Ala869, to generate LPHbeta
      initial; LPHbeta is subsequently cleaved extracellularly in the gut lumen,
      presumably by trypsin, at Arg868-Ala869 to mature brush border LPH (LPHbeta
      initial).

PMID- 8665897
TI  - Cellular stresses and cytokines activate multiple mitogen-activated-protein
      kinase kinase homologues in PC12 and KB cells.
AB  - The identities of the upstream activators of the mitogen-activated protein (MAP)
      kinase homologues termed stress-activated-protein (SAP) kinase-1 (also known as
      JNK or SAPK) and SAP kinase-2 (also known as p38, RK and CSBP) were investigated
      in rat PC12 cells and human KB cells after exposure to cellular stresses and
      cytokines. In PC12 cells, the same two upstream activators, SAP kinase kinase-1
      (SAPKK-1) and SAPKK-2 were activated after exposure to osmotic shock, ultraviolet
      irradiation or the protein synthesis inhibitor anisomycin, and more weakly in
      response to sodium arsenite. SAPKK-1 was capable of activating both SAP kinase-1
      and SAP kinase-2 and was similar, if not identical, to the previously described
      MAP kinase kinase homologue MKK4, as judged by immunological criteria and by its
      ability to be activated by MEK kinase in vitro. In contrast, SAPKK-2 activated
      SAP kinase-2, but not SAP kinase-1 in vitro. In KB cells, five distinct upstream
      activators of SAP kinase-1 and SAP kinase-2 were induced, namely SAPKK-1, SAPKK
      2, SAPKK-3, SAPKK-4 and SAPKK-5, whose appearance depended on the nature of the
      stimulus. SAPKK-3, which was strongly induced by every stimulus tested (osmotic
      shock, ultraviolet irradiation, anisomycin or IL-1), accounted for about 95% of
      the SAP kinase-2 activator activity in these cells, did not activate SAP kinase-1
      and eluted from Mono S at a lower salt concentration than SAPKK-2. SAPKK-4 and
      SAPKK-5 were also eluted from Mono S at higher NaC1 concentrations than SAPKK-3
      and these enzymes activated SAP kinase-1 but not SAP kinase-2. SAPKK-4 was the
      only SAP kinase-1 activator induced by interleukin-1 or ultraviolet irradiation,
      while two SAP kinase-1 activators, SAPKK-1 and SAPKK-5, were induced by osmotic
      shock or anisomycin. SAPKK-2, SAPKK-3, SAPKK-4 and SAPKK-5, were not activated by
      MEK kinase in vitro, were separable from the major activator(s) of p42 MAP
      kinase, and were not recognised by anti-MKK4 antibodies. At least two of these
      enzymes are likely to be novel MAP kinase kinase homologues. Our results
      demonstrate unexpected complexity in the upstream regulation of stress and
      cytokine-stimulated kinase cascades and indicate that the selection of the
      appropriate SAPKK varies with both the stimulus and the cell type.

PMID- 8665898
TI  - Purification of a 60-kDa protein from chicken liver associated with the internal
      nuclear matrix and closely related to carboxylesterases.
AB  - A 60-kDa protein was purified from chicken liver internal nuclear matrix and its
      nuclear localization was confirmed by immunofluorescence analysis. Structural
      information acquired from sequence analysis of the intact protein and of
      fragments obtained from enzymatic and chemical cleavages strongly suggests that
      it belongs to the carboxylesterases family, even if with some very peculiar
      features. The N-terminal sequence of the 60-kDa protein is completely different
      from the other carboxylesterases, but is similar to a region that is normally
      internal to all mammalian esterase sequences and localized after the serine
      residue at the active site. This suggests that the protein may be derived from a
      gene duplication and/or rearrangement. Since the 60-kDa protein shows a low
      esterase activity of about 0.2 micromol x min(-1) x mg(-1) using either p
      nitrophenyl acetate or p-nitrophenyl butyrate as substrates, it is not possible
      to rule out that the protein shares only a sequence similarity with
      carboxylesterases and is not a true esterase. Otherwise it could be an esterase
      which has developed different properties, i.e. a special substrate specificity,
      the requirement of additional factors or a different stability in solution. In
      the latter case, this protein could be related to the physiological control of
      hydrolysis of exogenous and endogenous esters which can act on nuclear functions
      and/or metabolism.

PMID- 8665899
TI  - Dynamics of parvalbumin expression in low-frequency-stimulated fast-twitch rat
      muscle.
AB  - Similar to previous observations in rabbit muscle, chronic low-frequency
      stimulation suppressed parvalbumin expression in fast-twitch muscles of the rat.
      In extensor digitorum longus and tibialis anterior muscles, parvalbumin mRNA
      levels steeply declined with apparent half-lives of approximately 26 h and 45 h,
      respectively. Measurements of parvalbumin synthesis indicated that the reduction
      in mRNA was immediately transmitted to the level of translation. Relative
      parvalbumin synthesis rates decayed with an apparent half-life of approximately
      60 h. Both the decrease in parvalbumin mRNA and synthesis considerably preceded
      the decay of parvalbumin protein. Although parvalbumin synthesis had approached
      zero in 14-day-stimulated muscles, parvalbumin content started to decrease only
      after some delay (28-day-stimulated muscles still contained 40-50% of their
      normal parvalbumin content). The lag time between fully suppressed synthesis and
      the onset of parvalbumin decay, as well as the stability of parvalbumin against
      tryptic cleavage in the presence of Ca2+ and Mg2+, indicated proteolysis as an
      important post-translational control of parvalbumin levels. The decrease in
      parvalbumin mRNA followed a similar time course as that of the mRNA specific to
      the fast myosin heavy chain HCIIb. After complete suppression, parvalbumin mRNA
      reached control levels 4 days after cessation of stimulation, which demonstrates
      the complete reversibility of the stimulation-induced parvalbumin suppression.
      These results show that a slow motoneuron-like impulse pattern rapidly silences
      the parvalbumin gene, thus overriding fast-fiber-type-specific programs of gene
      expression. Due to posttranscriptional regulation and the stability of
      parvalbumin, this high responsiveness of adult skeletal muscle to altered
      neuromuscular activity is more conspicuous at the mRNA level than at the protein
      level.

PMID- 8665900
TI  - Selective up-regulation of alpha 1-chimaerin mRNA in SK-N-SH neuroblastoma cells
      by K+/-induced depolarisation.
AB  - The expression of alpha 1-chimaerin, which encodes a neuron-specific GTPase
      activating protein for p21rac, is spatially and temporally regulated in vivo. In
      vitro, expression of the mRNA of both alpha 1-chimaerin and its alternative
      spliced form, alpha 2-chimaerin, was up-regulated when human neuroblastoma SK-N
      SH cells underwent neuronal-type differentiation in a serum-free medium. KCl
      induced membrane depolarisation also specifically up-regulated alpha 1-chimaerin
      mRNA expression in SK-N-SH cells at the transcriptional level. The up-regulation
      of alpha 1-chimaerin expression by membrane depolarisation is not an immediate
      early event, and occurs 3 h after KCl treatment. It does not require de novo
      protein synthesis. The increase in calcium influx via the L-type voltage
      sensitive calcium channel as the result of depolarisation is a key event leading
      to the up-regulation of alpha 1-chimaerin mRNA. alpha 1-Chimaerin expression was
      also found to respond positively to the hypertonic osmolarity changes. These
      results suggest that in vivo expression of alpha 1-chimaerin, a potential signal
      transduction molecule, may be regulated by neuronal/synaptic activity.

PMID- 8665901
TI  - The human cysteine-rich secretory protein (CRISP) family. Primary structure and
      tissue distribution of CRISP-1, CRISP-2 and CRISP-3.
AB  - We report the isolation and characterisation of cDNAs encoding three different,
      human members of the cysteine-rich secretory protein (CRISP) family. The novel
      CRISP-1 exists in five cDNA subtypes differing by the presence or absence of a
      stretch coding for a C-terminal cysteine-rich domain so far found in all members
      of the family, and by the length of their 3'-untranslated region. CRISP-2 cDNA
      corresponds to the previously described TPX1 form, with so far unreported 5'
      untranslated sequence heterogeneities while CRISP-3 cDNA codes for a new, unique
      protein. Northern blot analysis of various human organs indicates that CRISP-1
      transcripts are epididymis-specific whereas CRISP-2/TPX1 transcripts are detected
      mainly in the testis and also in the epididymis. CRISP-3 transcripts are more
      widely distributed and found predominantly in the salivary gland, pancreas and
      prostate, and in less abundance in the epididymis, ovary, thymus and colon. A
      protein reacting with an anti-mouse CRISP-1 antibody was isolated from human
      epididymal extracts and N-terminal sequencing revealed that it corresponded to
      the CRISP-1 cDNA we have isolated. In contrast to findings on its rat counterpart
      epididymal protein DE/acidic epididymal glycoprotein (AEG), no significant
      association of CRISP-1 with human spermatozoa was observed.

PMID- 8665902
TI  - Purification and characterization of the soluble interleukin-6 receptor from
      human plasma and identification of an isoform generated through alternative
      splicing.
AB  - The soluble human interleukin-6 receptor (shIL6R) was purified from human plasma.
      In a single immunoaffinity purification step a 140000-fold enrichment with a
      yield of 95% was achieved. A subsequent IL-6 affinity chromatography resulted in
      a homogeneous receptor preparation but only in a yield of less than 5%. The
      biological activity of the soluble receptor was clearly demonstrated by its
      ability to induce the synthesis of the acute-phase protein 1-antichymotrypsin in
      HepG2 cells stably transfected with IL-6. Upon gel filtration, the native shIL6R
      showed an apparent molecular mass of 93 kDa. Analysis by SDS/PAGE revealed an
      apparent molecular mass of 65 kDa for the soluble receptor. Deglycosylation with
      peptide N-glycosidase F led to a shift in molecular mass from 65 kDa to 45 kDa.
      It has previously been shown that the shIL6R can be generated by shedding the
      membrane-bound form or by expression of an alternatively spliced mRNA. Here we
      show that the shIL6R isolated from human plasma is recognized by an affinity
      purified peptide antibody raised against an amino acid sequence unique for the
      alternatively spliced isoform. Thus, the shIL6R isoform generated through
      alternative splicing which has been previously detected in supernatants of
      cultured cell lines is also an in vivo product circulating in human plasma.

PMID- 8665903
TI  - Aminopeptidase from Streptomyces griseus: primary structure and comparison with
      other zinc-containing aminopeptidases.
AB  - The aminopeptidase from Streptomyces griseus is a calcium-activated
      metalloenzyme, which contains 2 mol tightly bound zinc/mol protein. This
      aminopeptidase rapidly hydrolyzes peptide bonds formed by N-terminal hydrophobic
      amino acids, such as leucine, methionine and phenylalanine. We have determined
      the complete primary structure of the protein, which contains 284 amino acid
      residues, yielding a molecular mass of 29723 Da. A search in the Swiss-Prot
      database for sequence similarities revealed a low degree of identity (26-34%) to
      Saccharomyces cerevisiae aminopeptidase Y, Aeromonas proteolytica aminopeptidase,
      and a hypothetical 49.5-kDa protein from Bacillus subtilis, which is supposed to
      belong to the aminopeptidase Y family. In all these proteins, the residues that
      are known to be involved in zinc coordination are conserved.

PMID- 8665904
TI  - Enzymic characterization of fission yeast farnesyl transferase: recognition of
      the -CAAL motif at the C-terminus.
AB  - The enzyme farnesyl transferase (FTase) catalyzes the posttranslational
      modification of Ras and other Ras family proteins with a C15 farnesyl group. The
      target proteins have a consensus -CAAX motif (X, any amino acid except leucine)
      at the C-terminus. Since proteins that have leucine as the C-terminal amino acid
      X are modified with a C20 geranylgeranyl group, it is thought that the C-terminal
      leucine is the signal (-CAAL motif) for selection of isoprenoid molecules. Here,
      we report the presence of multiple FTase activities in the fission yeast
      Schizosaccharomyces pombe, each seeming to correspond to a particular protein
      known to be modified by the farnesyl group in vivo. Using enzymic activities
      specific to S. pombe Ras1, we found similar affinities for FTases in the wild
      type (EVSTKCCVIC) and mutant Ras1 peptide, in which the C-terminal amino acid is
      replaced by leucine (EVSTKCCVIL). These results suggest that recognition and
      selection of the correct isoprenoid group by the FTases require other amino acid
      sequences of the target protein in addition to the C-terminal -CAAX motif.

PMID- 8665905
TI  - Substrate specificity of rainbow trout testis CMP-3-deoxy-D-glycero-D-galacto
      nonulosonic acid (CMP-Kdn) synthetase: kinetic studies of the reaction of natural
      and synthetic analogues of nonulosonic acid catalyzed by CMP-Kdn synthetase.
AB  - In this report we present kinetic data of the activation reaction of several
      synthetic 3-deoxy-D-glycero-D-galacto-nonulosonic acid (Kdn) and N
      acetylneuraminic acid (Neu5Ac) analogues catalyzed by the rainbow trout testis
      CMP-Kdn synthetase. This enzyme showed broad substrate specificity in terms of
      substitutions at C4 or C5 position of Kdn and Neu5Ac. In contrast, calf brain CMP
      N-acylneuraminic acid synthetase had narrow substrate specificity, being active
      only on various N-acyl analogues of Neu5Ac and only slightly active on Kdn
      derivatives. Usefulness of the trout testis enzyme for synthesis of various CMP
      sialate analogues, which could be donor substrates for sialyltransferases, was
      demonstrated.

PMID- 8665906
TI  - Determinants in the presequence of cytochrome b2 for import into mitochondria and
      for proteolytic processing.
AB  - Determinants in a mitochondrial targeting signal for import and processing were
      analyzed by introducing deletions into the presequence of cytochrome b2. The
      matrix targeting signal and the signal recognized by the mitochondrial processing
      peptidase were found to be separate. The signal for import into the matrix is
      located at the N-terminus within a stretch of 20 amino acid residues that has the
      potential to form a positively charged, amphipathic alpha-helix. The
      mitochondrial processing peptidase cleaves after residue 31 and recognizes a
      short sequence motif around the scissile bond. In the context of a presequence,
      the cleavage site is accessible for the processing peptidase. At a different
      location or in a different context, the cleavage site motif is still specifically
      recognized but processed with lower efficiency. The matrix targeting signal may
      help to present the cleavage site motif to the mitochondrial processing
      peptidase.

PMID- 8665907
TI  - Platelet activation by 2-(4-bromo-2,3-dioxobutylthio)adenosine 5'-diphosphate is
      mediated by its binding to a putative ADP receptor, aggregin.
AB  - Platelet responses induced by ADP are mediated by a unique P21-purinergic
      receptor. Although a variety of ADP analogs, substituted at C2, have been used to
      delineate pharmacological properties of the ADP-binding site(s), the identity of
      the receptor protein has not been firmly established. 2-(4-Bromo-2,3
      dioxobutylthio)- ADP [2-BrCH2(CO)2CH2-S-ADP], a well-characterized ADP analog,
      has been previously used as an affinity label to examine the structure/function
      relationship of ADP-requiring enzymes [Kapetanovic, E., Bailey, J.B. & Colman,
      R.F. (1985) Biochemistry 24, 7586-7593]. We found that it induced platelet shape
      change, aggregation, exposure of fibrinogen binding sites, secretion and
      mobilization of intracellular calcium, but was less potent than ADP. Under non
      stirring conditions, incubation of platelets with this analog for longer time
      periods blocked ADP-induced shape change, aggregation, and the ability to ADP to
      antagonize the rise in intracellular levels of cAMP induced by iloprost (a
      prostaglandin I2 analog). Of a variety of agonists examined, only ADP-induced
      aggregation was almost completely inhibited in platelets irreversibly modified by
      the analog. An autoradiogram of the gel obtained by SDS/PAGE of solubilized
      platelets modified by the ADP analog followed by reduction of the dioxo group by
      NaB[3H], showed the presence of a single radiolabeled protein band at 100 kDa.
      Platelets incubated first with either ADP, ATP, or 2-methylthio-ADP were not
      labeled by 2-BrCH2(CO)2CH2S-ADP and NaB[3H]4-8-BrCH2(CO)2CH2-S-ADP was previously
      shown by us to irreversibly antagonize ADP-induced platelet responses by
      selectively modifying aggregin. Incubation of platelets with 2-BrCH2(CO)2CH2S-ADP
      completely blocked labeling of aggregin in platelets by 8-BrCH2(CO)2CH2S
      [32P]ADP. These results show that 2-BrCH2(CO)2CH2S-ADP initially interacts
      reversibly with aggregin (100kDa), a putative ADP receptor, and induces platelet
      shape change and aggregation, and at longer periods of incubation reacts
      irreversibly to block the ability of ADP to antagonize stimulated adenylate
      cyclase activity. In contrast, 6-BrCH2(CO)2CH2S-ADP was found to be a weak and
      reversible inhibitor of ADP-induced platelet aggregation. Prior incubation of
      platelets with the latter analog reduced labeling of aggregin by 8-BrCH2(CO)2CH2S
      [32P]ADP. Taken together, the results further show that substitution by the
      BrCH2(CO)2CH2 group at the C2 and C8 positions is tolerated, while the presence
      of a free amino function at the C6 position is essential for its interaction with
      aggregin.

PMID- 8665909
TI  - Distinct exocytotic responses of intact and permeabilised chromaffin cells after
      cleavage of the 25-kDa synaptosomal-associated protein (SNAP-25) or synaptobrevin
      by botulinum toxin A or B.
AB  - Botulinum neurotoxin (BoNT) types A and B are Zn2+-requiring endoproteases which
      potently block neurotransmitter release by cleavage of a 25-kDa synaptosomal
      associated protein (SNAP-25) and synaptobrevin, respectively. Synaptobrevin is
      important for the exocystosis of catecholamines from dense-core granules and
      evidence is presented here for the involvement of SNAP-25 in this process in
      neuroendocrine cells. The effects of BoNT/A and BoNT/B on regulated secretion
      were compared in intact bovine chromaffin cells to investigate the consequences
      of cleavage of the different targets. Catecholamine secretion elicited by Ba2+,
      by elevated K+ concentrations or by nicotine was prevented by each toxin. A very
      good correlation was observed between the extents of SNAP-25 cleavage or
      synaptobrevin cleavage and inhibition of secretion by BoNT/A or BoNT/B,
      respectively, which indicates the importance of SNAP-25 and synaptobrevin in
      regulated exocytosis. Despite truncation of almost the entire SNAP-25 pool by
      exposure of the cells to BoNT/A, a residual fraction of secretion persisted that
      was induced by 20microM Ca2+ (and to a lesser extent by 1 mM Ba2+) following
      permeabilisation. Addition of more BoNT/A failed to reduce this level of
      secretion. Inclusion of Mg.ATP, which greatly enhanced secretion from
      permeabilised cells, was required for Ca2+-stimulated or Ba2+-stimulated BoNT/A
      resistant secretion. Furthermore, synaptobrevin is essential for this response
      because the response was not observed in BoNT/B treated cells. In view of the
      ability of BoNT/E to abolish secretion from permeabilised cells and to delete 26
      amino acids from the C-terminus of SNAP-25, it can be deduced that cleavage of
      only nine residues by BoNT/A does not prevent the resultant truncated form
      exhibiting attenuated activity under the conditions created by permeabilisation.
      This identification of a novel component of secretion from permeabilised cells
      should facilitate investigation of the functional interaction of SNAP-25 with
      other proteins involved in regulated exocytosis.

PMID- 8665908
TI  - Surface-associated material from the bacterium Actinobacillus
      actinomycetemcomitans contains a peptide which, in contrast to
      lipopolysaccharide, directly stimulates fibroblast interleukin-6 gene
      transcription.
AB  - The oral commensal Gram-negative bacterium Actinobacillus actinomycetemcomitans
      is believed to be the causative organism of localized juvenile periodontitis, a
      disease in which there is rapid loss of alveolar bone supporting the teeth.
      Previously, we have reported that gentle saline extraction of this bacterium
      removed a loosely adherent proteinaceous fraction from the cell surface of the
      bacterium, which we have termed surface-associated material. This material
      contained potent bone-resorbing activity. We now report that surface-associated
      material is also a potent stimulator of cytokines, and in particular, interleukin
      6 (IL-6) synthesis, while the lipopolysaccharide from this bacterium is only a
      weak stimulator of IL-6 synthesis by fibroblasts and monocytes. In contrast to
      enteric lipopolysaccharide (LPS), which induces fibroblast IL-1, IL-6 and tumour
      necrosis factor (TNF) alpha synthesis, surface-associated material stimulated
      gingival fibroblasts to synthesize only IL-6, with no induction of IL-1 or TNF
      (the normal inducers of IL-6 synthesis). Reverse transcriptase PCR also failed to
      detect mRNA for IL-1 or TNF in surface-associated-material-stimulated
      fibroblasts, although both mRNAs were present in Escherichia coli LPS-stimulated
      cells. Neutralizing antibodies to IL-1 and/or TNF or the natural IL-1 receptor
      antagonist (IL-1ra) inhibited enteric LPS-induced IL-6 synthesis, but did not
      inhibit surface-associated-material-induced synthesis. In addition,
      dexamethasone, which completely suppressed LPS-induced IL-6 synthesis, only
      inhibited surface-associated-material-induced IL-6 synthesis by 50%. This
      suggests that the active constituent in the surface-associated material
      stimulates IL-6 gene transcription by a transcriptional control mechanism
      distinct to that of E. coli LPS. The IL-6 stimulating activity of the surface
      associated material is inhibited by both heat and trypsin, suggesting that it is
      proteinaceous. The activity has been isolated using anion-exchange, reverse-phase
      and size-exclusion HPLC. The active moiety is a peptide of molecular mass 2kDa
      which may be the product of a bacterial short open reading frame.

PMID- 8665910
TI  - The characterisation of the 5' regulatory region of a temperature-induced myosin
      heavy-chain gene associated with myotomal muscle growth in the carp.
AB  - We have isolated and characterised the 5' region of a member of the carp myosin
      heavy chain gene family. Expression of this gene has previously been shown to be
      induced by an increase in environmental temperature and is restricted to the
      small-diameter white myotomal muscle fibres which are associated with growth. The
      whole isoform gene, including potential regulatory sequence 5' to the
      transcription start site and the 3' untranslated region was cloned in a
      lambda2001 bacteriophage vector. Studies of the structure of the 5'-end of the
      gene revealed high amino acid sequence similarity with translated exons 3-7 of
      mammalian myosin heavy chain genes indicating identical exon/intron boundaries.
      The overall length of the gene was however only about one half of that in mammals
      and birds due to shorter introns. The region 5' to the transcription unit was
      sequenced and revealed the presence of putative TATA and CCAAAT boxes. In order
      to study the regulation of expression, a series of endonuclease-generated
      fragments from the 5' flanking sequence were spliced to chloramphenicol
      acetyltransferase reporter vectors and used in cell transfection assays or direct
      gene injection into carp skeletal muscle. The 5' flanking region, which contains
      a consensus sequence known as an E-box (CANNTG) and a MEF2 binding site, was
      shown to improve the expression of the reporter gene in fish acclimated at 18
      degrees C or 28 degrees C. Unlike the coding region, there was little similarity
      between the 5'-upstream sequence (promoter region) when compared with sequences
      flanking the 5'-end of the other myosin heavy chain genes in mammals or chicken.

PMID- 8665911
TI  - A regulatory domain within the virus-response element of the interferon alpha 1
      gene acts as a transcriptional repressor sequence and determinant of cell
      specific gene expression.
AB  - Type-I interferons are encoded by a multigene family, the major members of which
      are at least 13 IFN A subtypes and a single IFN B gene. IFNs A and B are induced
      in response to similar stimuli, such as virus infection and double-stranded RNA,
      but in different cell types: the induction of IFN A is almost exclusively
      restricted to cells of lymphoid origin, while IFN B has been found to be induced
      in a variety of cell types including fibroblasts. The virus-responsive enhancer
      element in the promoter region of IFN A family members is largely responsible for
      the differential expression of individual subtypes in responsive cells. In this
      paper we describe experiments which address the issue of the differential
      expression of IFN A and IFN B in different cell types. We show that IFN-beta is
      induced in a variety of cells of different origin, while not all of these are
      able to secrete IFN-alpha. By transfection of reporter gene constructs comprising
      the virus-responsive enhancer from the IFN A1 and IFN B genes, we show that this
      differential response is mediated at the level of transcription via these control
      elements. More detailed analysis of the function of these regions identifies
      specific sequences within the IFN A1 virus response element that has an
      inhibitory effect on expression in cells that are normally inducible, and is also
      implicated in the overall suppression of IFN A induction in non-inducible cells.

PMID- 8665912
TI  - Purification and characterisation of a plasmin-sensitive surface protein of
      Staphylococcus aureus.
AB  - Certain methicillin-resistant Staphylococcus aureus strains contain a 230-kDa
      cell-wall protein which is not present on the surface of other staphylococci. The
      presence of this 230-kDa protein is associated with a negative test result in
      commercial assays designed to detect fibrinogen-binding proteins and/or protein A
      on the staphylococcal surface. We have purified and partially characterised the
      230-kDa protein from a lysostaphin digest of a non-agglutinating methicillin
      resistant S. aureus strain. Partial amino acid sequence data obtained from the
      purified protein did not reveal any significant similarities to known proteins
      which indicates that the protein is novel. The 230-kDa protein was very sensitive
      to proteolysis; soluble plasmin, or plasmin formed on the bacterial-cell surface,
      rapidly degraded the 230-kDa protein to a 175-kDa form. The finding that the 230
      kDa protein bound to lectins allowed its purification by affinity chromatography
      on immobilised wheat germ agglutinin. Furthermore, the degradation of the 230-kDa
      protein was associated with an increased adherence of non-agglutinating
      methicillin-resistant S. aureus cells to solid-phase fibronectin, fibrinogen or
      IgG.

PMID- 8665913
TI  - Solution structure of the DNA-binding domain of the tomato heat-stress
      transcription factor HSF24.
AB  - Two-dimensional-NMR and three-dimensional-NMR experiments were performed to
      determine the solution structure of the DNA-binding domain of the tomato heat
      stress transcription factor HSF24. Samples of uniformly 15N-labeled and 15N, 13C
      labeled recombinant proteins were used in the investigation. A near-complete
      assignment of the backbone 1H, 15N, and 13C resonances was obtained by three
      dimensional triple-resonance experiments, whereas three-dimensional 15N-TOCSY
      heteronuclear-single-quantum-correlation-spectroscopy, HCCH-COSY and HCCH-TOCSY
      spectra were recorded for side-chain assignments, 885 non-redundant distance
      constraints from two-dimensional-homonuclear and three-dimensional-15N-edited and
      13C-edited NOESY spectra and 40 hydrogen-bond constraints from exchange
      experiments were used for structure calculations. The resulting three-dimensional
      structure contains a three-helix bundle and a small four-stranded antiparallel
      beta-sheet that forms a hydrophobic core. The two C-terminal helices are parts of
      a highly conserved helix-turn-helix motif that is probably involved in DNA
      recognition and binding. In contrast to heat-stress factors from yeast and
      animals, the plant heat-stress factors lack a loop of 11 amino acid residues
      inserted between beta3 and beta4. This leads to a tight turn between these beta
      strands.

PMID- 8665914
TI  - A mechanism for iron uptake by transferrin.
AB  - Iron uptake by transferrin from iron nitrilotriacetate (FeNAc3) in the presence
      of bicarbonate has been investigated in the pH range 6.5-8. Apotransferrin, in
      interaction with bicarbonate, extracts iron from FeNAc3, without the formation of
      an intermediate protein-iron-ligand mixed complex (iron-exchange-equilibrium
      constant, K1=1 +/- 0.05; direct second-order-rate constant, k1=8.0x10(4) +/-
      0.5x10(4)M(-1)s(-1)., reverse second-order-rate constant, k-1=7.5x10(4) +/-
      0.5x10(4)M(-1)s(-1). The newly formed iron-protein complex loses a single proton
      (proton-dissociation constant, Ka=16 +/- 1.5nM) and then undergoes a modification
      of its conformation followed by loss of two or three protons (first-order-rate
      constant, K2=2.80 +/- 0.10s-1). This includes a new modification in the
      conformation (first-order-rate constant, K2=6.2x10(2) +/- 0.3x10(-2)s(-1). This
      second modification in conformation controls the rate of iron uptake by the N
      site of the protein and is followed by loss of one proton (K3a=6.80 nM). Finally,
      the holoprotein or the monoferric transferrin in its final equilibrated state is
      produced by a third modification in the conformation that occurs after
      approximately 3000 s. Iron uptake by the N-site does not occur when the
      apotransferrin interacts with bicarbonate. Nevertheless, it occurs with the
      monoferric transferrin, in which iron is bound to the C-site, in its final state
      of equilibrium by a mechanism similar to that of iron uptake by the C-site of
      apotransferrin. These modifications in the conformation of the protein occur
      after iron uptake by the C-site and may be important for the recognition of the
      protein by its receptor prior to iron delivery by endocytosis.

PMID- 8665915
TI  - Immunological detection of proteins similar to bacterial proteases in higher
      plant chloroplasts.
AB  - Despite numerous demonstrations of protein degradation in chloroplasts of higher
      plants, little is known about the identity of the proteases involved in these
      reactions. To identify chloroplast proteases by immunological means, we
      investigated two proteins: ClpP, a protein similar to the proteolytic subunit of
      the bacterial ATP-dependent Clp protease, for which a gene is found in the
      chloroplast genome [Maurizi, M.R., Clark, W.P., Kim, S. H. & Gottesman, S. (1990)
      J. Biol. Chem. 265, 12546-12552] and PrcA, a cyanobacterial Ca2+-stimulated
      protease [Maldener, I., Lockau, W., Cai, Y. & Wolk, P. (1991) Mol. & Gen. Genet.
      225, 113-120]. We expressed the clpP gene from rice in Escherichia coli, purified
      its product, and generated antibodies against the product. Western blot analysis
      revealed the ClpP protein in different leaf extracts. Analysis of fractionated
      barley chloroplasts revealed that the protein was associated with the stromal
      fraction. The expression of ClpP is light independent and tissue specific, as it
      was found in green and etiolated barley leaves, but not in roots. A second
      protein, similar to the cyanobacterial protease PrcA, was also detected in
      chloroplasts. Antibody against this protease recognized proteins in various leaf
      extracts. When pea chloroplasts were fractionated, the antibody only recognized a
      stromal protein. The expression of this protein is regulated by light, as it was
      found in green leaves, but not in etiolated leaves. The tissue specificity of
      PrcA was similar to that of ClpP in that it could not be detected in root
      extracts.

PMID- 8665916
TI  - Properties of the recombinant beta subunit of glutamate synthase.
AB  - Glutamate synthase is a complex iron-sulfur flavoprotein containing one molecule
      each of FAD and FMN and three distinct iron-sulfur centers/alpha beta protomer.
      Production of the beta subunit was observed in total extracts of Escherichia coli
      BL21 (DE) cells harbouring a pT7-7 derivative carrying gltD, the gene encoding
      the Azospirillum brasilense glutamate synthase beta subunit. The protein was
      soluble, and the identity of the purified protein with the Azospirillum glutamate
      synthase beta subunit was confirmed by N-terminal sequence analysis. The kinetic
      and spectroscopic characterization of the glutamate synthase beta subunit
      confirmed that it contains the NADPH binding site, but, in contrast with earlier
      proposals that assigned both FAD and FMN binding sites to the alpha subunit of
      glutamate synthase, the beta subunit was shown to contain stoichiometric amounts
      of FAD. No iron-sulfur centers were detected by EPR spectroscopy measurements of
      the recombinant beta subunit. Under steady-state conditions, the glutamate
      synthase beta subunit can catalyze the NADPH-dependent reduction of several
      synthetic electron acceptors but no glutamate synthase or glutamate dehydrogenase
      reactions in either direction. The results are in agreement with previous data
      from our laboratory and, together with the absence of amino acid sequence
      similarity between glutamate synthase beta subunit and glutamate dehydrogenases,
      are against the hypothesis that glutamate synthase is evolutionarily derived from
      the association of an ancestral glutamate dehydrogenase (the beta subunit) and an
      amidotransferase (the alpha subunit). The protein-bound FAD is reduced by NADPH
      at a rate much faster than turnover with synthetic electron acceptors, leading to
      formation of a stable reduced flavin-NADP+ charge-transfer complex. The rate of
      reduction of the bound FAD by NADPH is also similar to the rate at which one of
      the flavins is reduced in the native glutamate synthase, as measured in a stopped
      flow spectrophotometer under pre-steady-state conditions. The ability of FAD
      bound to the beta subunit of glutamate synthase to react with NADPH and the lack
      of reactivity with sulfite lead us to conclude that FAD is Flavin 1 of glutamate
      synthase [Vanoni, M.A., Edmondson, D.E., Zanetti, G. & Curti, B. (1992)
      Biochemistry 31, 4613-4623].

PMID- 8665917
TI  - The catalytic site of chloroplastic NADP-dependent malate dehydrogenase contains
      a His/Asp pair.
AB  - Plant chloroplastic NADP-malate dehydrogenase is unique among malate
      dehydrogenases because of its reductive activation in the light and cofactor
      specificity. In this paper, the role of His229 in sorghum leaf protein has been
      investigated by site-directed mutagenesis. His229 was replaced by Asn and Gln,
      both mutations yielding an inactive protein. The role of a conserved Asp (Asp201)
      as a possible partner of His229 in catalysis has been studied by the same
      approach. Both Asp mutants (D201A, D201N) were only slightly active and were
      essentially characterized by a dramatically increased Km for oxaloacetate (45-80
      fold). pH dependence of catalytic rates revealed differences between the two Asp
      mutants. These results demonstrate that, in sorghum leaf NADP-dependent malate
      dehydrogenase, His229 is involved in catalysis in interaction with Asp201.

PMID- 8665918
TI  - Bradykinin induces tyrosine phosphorylation in human foreskin fibroblasts and 293
      cells transfected with rat B2 kinin receptor.
AB  - The intracellular effects of bradykinin are mediated through the recently cloned
      B2 kinin receptor which belongs to the superfamily of receptors with seven
      transmembrane domains. The molecular events which transduce the bradykinin signal
      on the post-receptor level are not understood in detail. We studied whether in
      human foreskin fibroblasts bradykinin treatment induces tyrosine phosphorylation
      of cellular proteins. Using phosphotyrosine antibodies we detected a bradykinin
      dependent phosphorylation of a group of proteins of about 130 kDa and an
      additional signal around 70kDa after starvation of cells. The effect evoked by 10
      nM bradykinin was rapid (2 min) and it was partially reduced by the B2-kinin
      receptor antagonist Hoe 140 which was shown to be a weak inducer of tyrosine
      phosphorylation. The bradykinin-mediated tyrosine phosphorylation events were
      reproduced in human embryonal kidney 293 fibroblasts which were transiently
      transfected with the rat B2 kinin receptor, but they were not observed in
      untransfected 293 control cells. These data suggest that the B2 kinin-receptor
      subtype is involved. Upon fractionation of cells the 130kDa protein group was
      recovered both in the membrane and the cytosolic protein fraction. To assess the
      specificity of this bradykinin effect we stimulated human foreskin fibroblasts
      with epidermal growth factor (EGF), platelet-derived growth factor (PDGF),
      insulin-like growth factor (IGF-I) and insulin. While IGF-I, insulin and EGF were
      almost ineffective, PDGF stimulated the tyrosine phosphorylation of 130-kDa bands
      with a similar pattern to that produced by bradykinin. Immunoprecipitation
      experiments with specific antibodies against potential candidate proteins in the
      molecular-mass range around 130kDa revealed positive results for the focal
      adhesion kinase FAK and the p130 Src substrate while negative results were
      obtained for the GTPase-activating protein GAP, the phospholipase C-gamma1, the
      Janus kinase JAK-1 and vinculin. The data suggest that the tyrosine
      phosphorylation of FAK and the pl30 Src substrate might be involved in the B2
      kinin-receptor signalling cascade.

PMID- 8665919
TI  - Similar conformations of hairpins with TTT and TTTT sequences: NMR and molecular
      modeling evidence for T.T base pairs in the TTTT hairpin.
AB  - The conformations of the d[G(1)C(2)G(3)C(4)-T(a)T(b)T(c)T(d)-G(5)C(6)G(7)C(8)]
      (T4) and d[G(1)C(2)G(3)C(4)-T(a)T(b)T(c)-G(5)C(6)G(7)C(8)] (T3) DNA hairpins have
      been studied. The 1H and 31P signals of the two hairpins have been nearly
      completely assigned by means of two-dimensional NMR spectroscopy in D2O (NOESY
      (two-dimensional nuclear Overhauser effect and exchange spectroscopy) at mixing
      times of 5, 50, 100, 300 and 500 ms, double-quantum-filtered correlation
      spectroscopy (DQF-COSY) and 1H-31P reverse chemical shift correlation (RCSC), and
      one-dimensional NOE spectra in 90% H2O. Conformational analysis using distance
      geometry (DG), molecular mechanics (MM) and molecular dynamics (MD) gave model
      conformations, which were evaluated by comparison of experimental and simulated
      2D NOESY spectra. For the T4 sequence in T4, both NMR data and modeling indicated
      a T(a).T(d) wobble base pair. Although two types of T(a).T(d) base pairs are
      possible, the one with T(a)NH-T(d)O4 and T(a)O2-T(d)NH H-bonds was calculated to
      be more stable. Because the T(a).T(d) base pair of T4 extends the stem, there are
      only two residues (T(b) and T(c) in the loop. Although there are three residues
      in the T3 loop, the T(c) base projects into the solvent. The resulting
      conformational models have very similar loop folding patterns (FP): the bases of
      the two adjacent residues that begin the loop [T(b)T(c) of T4 and T(a)T(b) or T3]
      have a minor groove/major groove orientation with the first residue each having a
      trans alpha torsion angle; and the phosphodiester group that links the residues
      at the 3' end of the loop and the 5' top of the stem [T(c)pT(d) of T4 and
      T(c)pG(5) of T3] has a gauche+, gauche+ zeta,alpha conformation with a trans
      gamma angle for the second residue in both. These or similar features appear to
      be present in most of the few other hairpins studied previously by conformational
      methods. Thus, we believe that the conformations of the loops in T3 and T4
      hairpins have greater similarities than previously recognized.

PMID- 8665921
TI  - Influence of expression system on chromophore binding and preservation of
      spectral properties in recombinant phytochrome A.
AB  - N-Terminal deletion mutants of the plant photoreceptor phytochrome, additionally
      truncated at two different positions at their C-terminal ends, were expressed
      both in Escherichia coli and in yeast (Pichia pastoris) and converted into
      chromoproteins upon chromophore incorporation. The start and end positions of the
      cDNA employed (phyA from oat) mimic the positions of tryptic cleavage (deletion
      of the first 64 amino acids, and stop codons after amino acid positions 425 or
      595, generating 39-kDa and 59-kDa peptides, respectively. The absorption
      properties and photochromicity upon red/far-red irradiation of these mutants were
      compared with their tryptic counterparts derived from native oat phytochrome and
      with recombinant products possessing intact N-termini, but C-terminal positions
      identical to those of the corresponding tryptic fragments (45-kDa and 65-kDa
      peptides). All recombinant 65-kDa and 59kDa peptides bound the chromophore after
      expression and showed the appropriate absorption spectra of the Pr and the Pfr
      forms. The smaller chromopeptides (45-kDa and 39-kDa) behaved differently
      depending on the expression system employed. E. coli-derived peptides exhibited a
      phytochrome-like difference spectrum only when the intact N-terminus was present
      (45-kDa product). The recombinant 39-kDa peptide from E. coli was incapable of
      chromophore binding whereas the identical peptide sequence expressed by P.
      pastoris formed a chromoprotein with phycocyanobilin. This recombinant
      phytochrome fragment exhibited a difference spectrum (Pr-Pfr) with an even larger
      Pfr absorption band than the comparable tryptic 39-kDa fragment. Selectivity of
      chromophore incorporation and spectral properties suggest that interactions
      between protein domains of phytochrome control the protein folding and the Pr/Pfr
      absorption characteristics. Evidently, trypsin digestion down to the 39-kDa
      fragment affects protein conformation also in terms of Pfr conservation.

PMID- 8665920
TI  - Cloning, sequencing and expression analysis of mouse cartilage matrix protein
      cDNA.
AB  - A cDNA encoding the mouse cartilage matrix protein (CMP) was cloned following the
      reverse-transcription polymerase chain reaction and rapid amplification of cDNA
      ends procedures using mRNA isolated from trachea. The open reading frame encodes
      a product of 500 amino acids. Large parts of the protein have been completely
      conserved when compared to chicken and human sequences, including all 12 cysteine
      residues of the mature CMP. In situ hybridization reveals an even distribution of
      the CMP mRNA in the developing skeleton, which is followed by a zonal
      distribution paralleling hypertrophy and calcification. From early cartilage
      differentiation and onwards, CMP transcript is absent in the forming articular
      surfaces and intervertebral discs. Extraskeletal expression of CMP mRNA was
      detected in the adult eye.

PMID- 8665922
TI  - Identification of uronic-acid-rich protein as urinary bikunin, the light chain of
      inter-alpha-inhibitor.
AB  - Uronic-acid-rich protein (UAP) is a urinary glycoprotein that inhibits calcium
      oxalate crystallization in vitro. It shows a structural similarity to bikunin, a
      component of inter-alpha-inhibitor (IalphaI) known for its inhibition of the
      action of many serine proteinases like trypsin and chymotrypsin. To clarify the
      relationship between these macromolecules, UAP, IalphaI, urinary bikunin, and
      plasma bikunin were purified and studied. Their calcium oxalate crystallization
      inhibitory activity was assayed before and after treatment with chondroitinase AC
      and pronase. Their molecular mass was determined by using SDS/PAGE before and
      after these treatments. Polyclonal bikunin antibody was used on Western blots for
      immunological identification. The partial amino acid sequence of UAP before and
      after chondroitinase treatment was determined. Also, the antitryptic activity of
      UAP was measured and compared to that of bikunin, which is responsible for the
      antiprotease activity of IalphaI. UAP exhibited a strong calcium oxalate
      crystallization inhibitory activity. IalphaI and both bikunins were less
      inhibitory. Chondroitinase AC had no effect on inhibitory activity of these
      proteins even when their molecular mass changed. However, after pronase
      treatment, the inhibitory activity of both bikunins and UAP was completely
      destroyed. The antitryptic activity of UAP was found to be 0.78 U/mg which is
      lower than that of bikunin which is about 1.9 U/mg. On Western blotting, bikunin
      antibody immunoreacted with UAP and both urinary and plasma bikunins. Partial
      amino acid sequence confirmed the identity of UAP as urinary bikunin.

PMID- 8665923
TI  - Identification, nuclear localization, and binding activities of OZF, a human
      protein solely composed of zinc-finger motifs.
AB  - The OZF cDNA was identified in a human mammary cell line and encodes a
      polypeptide solely composed of ten zinc-finger motifs which belongs to the
      Kruppel family of zinc-finger proteins. The OZF protein produced in Escherichia
      coli binds zinc ions, DNA and heparin. These binding activities are
      characteristic of zinc-finger proteins. Immunochemical analysis using antibodies
      produced against the recombinant protein detected its expression in human mammary
      epithelial cells but not in stroma cells, which is consistent with the pattern of
      expression observed at the RNA level in cell cultures. Western blot analysis
      demonstrated the expression of a 33-kDa nuclear protein similar in size to the
      predicted protein and therefore excluded the presence of an additional trans
      acting domain. These data establish the unique structure of the OZF protein which
      is distinct from previously identified zinc-finger proteins. In addition, OZF
      protein overexpression was found in a tumor cell line, which suggests a possible
      involvement in carcinogenesis.

PMID- 8665924
TI  - Investigation on the structure of the active site of monoamine oxidase-B by
      affinity labeling with the selective inhibitor lazabemide and by site-directed
      mutagenesis.
AB  - The structural features of the active site of human monoamine oxidase B (MAO-B)
      were investigated by affinity labeling and site-directed mutagenesis. The
      pseudosubstrate inhibitor N-[2-aminoethyl]-5-chloro-2-pyridine carboxamide HCl
      (lazabemide) can be irreversibly linked to MAO-B by reduction of the enzyme
      inhibitor complex with NaBH(3)CN. Analysis of the flavin spectrum of
      [(3)H]lazabemide-labeled human MAO-B indicated that insertion of the inhibitor
      did not occur into the isoalloxazine ring of FAD. After trypsin digestion and
      HPLC peptide mapping of the radiolabeled enzyme, two labeled peptides were
      observed. Sequence analysis showed that both peptides started at Val371 of human
      MAO-B. These results indicate that [(3)H]lazabemide is incorporated into the MAO
      B peptide stretch containing the FAD-modified Cys397. The function of putative
      active-site residues contained in this region was investigated by site-directed
      mutagenesis and expression of the mutant proteins in HEK-293 cells. Substitution
      of His382 of MAO-B with an Arg greatly reduced the enzymic activity, suggesting
      that this residue may represent a nucleophile relevant for the MAO-B catalytic
      mechanism. Whereas it has been shown that mutation of Cys389 with a Ser residue
      does not markedly affect the activity of the enzyme [Wu, H.-F., Chen, K. and
      Shih, J.C. (1993) Mol. Pharmacol. 43, 888-893] the mutant carrying an Ala at this
      position was virtually inactive. Conversely, substitution of Lys386 (to Met) and
      Ser394 (to Ala) did not markedly modify the kinetic properties of the enzyme. We
      also report that mutation of MAO-B Thr158 (to Ala) resulted in a dramatic loss of
      enzymic activity.

PMID- 8665925
TI  - Connections with connexins: the molecular basis of direct intercellular
      signaling.
AB  - Adjacent cells share ions, second messengers and small metabolites through
      intercellular channels which are present in gap junctions. This type of
      intercellular communication permits coordinated cellular activity, a critical
      feature for organ homeostasis during development and adult life of multicellular
      organisms. Intercellular channels are structurally more complex than other ion
      channels, because a complete cell-to-cell channel spans two plasma membranes and
      results from the association of two half channels, or connexons, contributed
      separately by each of the two participating cells. Each connexon, in turn, is a
      multimeric assembly of protein subunits. The structural proteins comprising these
      channels, collectively called connexins, are members of a highly related
      multigene family consisting of at least 13 members. Since the cloning of the
      first connexin in 1986, considerable progress has been made in our understanding
      of the complex molecular switches that control the formation and permeability of
      intercellular channels. Analysis of the mechanisms of channel assembly has
      revealed the selectivity of inter-connexin interactions and uncovered novel
      characteristics of the channel permeability and gating behavior.
      Structure/function studies have begun to provide a molecular understanding of the
      significance of connexin diversity and demonstrated the unique regulation of
      connexins by tyrosine kinases and oncogenes. Finally, mutations in two connexin
      genes have been linked to human diseases. The development of more specific
      approaches (dominant negative mutants, knockouts, transgenes) to study the
      functional role of connexins in organ homeostasis is providing a new perception
      about the significance of connexin diversity and the regulation of intercellular
      communication.

PMID- 8665926
TI  - Two distinct long-chain-acyl-CoA synthetases in guinea pig Harderian gland.
AB  - Two distinct long-chain-acyl-CoA synthetases which have different kinetic
      properties were identified in the guinea pig Harderian gland. One was localized
      in the microsomes and the other in the mitochondria. The relative V(max) values
      of the microsomal enzyme were 8.1, 1.7 and 1 and the apparent Km values were
      66.7, 12.0 and 30.0 microM for palmitic, linoleic and arachidonic acids,
      respectively. The relative V(max) values of the mitochondrial enzyme were 2.7,
      3.5 and 1 and the apparent Km values were 33.3, 29.9 and 30.0 microM for
      palmitic, linoleic and arachidonic acids, respectively. The relative V(max)
      values for the liver microsomal enzyme were 2.0, 2.5 and 1, while those of the
      liver mitochondrial enzyme were 4.1, 3.9 and 1 with palmitic, linoleic and
      arachidonic acids, respectively. There were no difference between the microsomal
      and the mitochondrial enzymes in the liver, regarding apparent Km values; these
      were 38.4, 29.9 and 22.0 microM for palmitic, linoleic and arachidonic acids,
      respectively. Thus, the substrate specificity and catalytic rate of the
      mitochondrial enzyme in Harderian gland for palmitic, linoleic and arachidonic
      acids were similar to the liver enzyme, but not to the microsomal enzyme in
      Harderian gland. On the other hand, the antiserum raised against the rat liver
      enzyme immune-titrated and immuno-blotted the enzymes from Harderian gland
      microsomes and liver, but not so the enzyme from Harderian gland mitochondria.
      Thus, the microsomal enzyme in Harderian gland had a common immunogenic
      epitope(s) with the liver enzyme, but the mitochondrial enzyme did not. The
      Harderian gland mitochondrial enzyme was a distinct protein from liver enzymes.
      The catalytic and immunogenic characteristics suggest that the enzyme proteins in
      the Harderian gland are unique, that is, different from that in the liver. The
      large V(max) value of the Harderian gland microsomal enzyme for palmitic acid
      suggests that it contributes to the synthesis of a large amount of the secretory
      lipid and the high Km value to maintenance of cellular lipid in this organ. The
      evidence that long-chain-acyl-CoA synthetase in the mitochondria is distinct from
      that in the microsomes was first found in guinea pig Harderian gland.

PMID- 8665927
TI  - Reconstitution and pigment-binding properties of recombinant CP29.
AB  - The minor light-harvesting chlorophyll-a/b-binding protein CP29 (Lhcb4),
      overexpressed in Escherichia coli, has been reconstituted in vitro with pigments.
      The recombinant pigment-protein complexes show biochemical and spectral
      properties identical to the native CP29 purified from maize thylakoids. The
      xanthophyll lutein is the only carotenoid necessary for reconstitution, a finding
      consistent with the structural role of two lutein molecules/polypeptide suggested
      by the crystallographic data for the homologous protein light-harvesting
      chlorophyll-a/b-binding protein of photosystem II (LHCII). The CP29 protein
      scaffold can accommodate different chromophores. This conclusion was deduced by
      the observation that the pigment composition of the reconstituted protein depends
      on the pigments present in the reconstitution mixture. Thus, in addition to a
      recombinant CP29 identical to the native one, two additional forms of the complex
      could be obtained by increasing chlorophyll b content. This finding is typical of
      CP29 because the major LHCII complex shows an absolute selectivity for
      chromophore binding [Plumley, F. G. & Schmidt, G. W. (1987) Proc. Natl Acad. Sci.
      USA 84, 146-150; Paulsen, H., Rumler, U. & Rudiger, W. (1990) Planta (Heidelb.)
      181, 204-211], and it is consistent with the higher stability of CP29 during
      greening and in chlorophyll b mutants compared with LHCII.

PMID- 8665929
TI  - Nucleocapsid protein 10 activates dimerization of the RNA of Moloney murine
      leukaemia virus in vitro.
AB  - Short RNA species that encompass the psi domain of the retroviral genome
      spontaneously form dimers in vitro, and the retroviral nucleocapsid protein
      activates this dimerization in vitro. Addition of gag RNA sequences downstream of
      the 3' end of the psi domain decreases the level of spontaneous dimerization.
      Here, we report the effects of RNA length on dimerization in vitro, studied with
      RNA fragments from Moloney murine leukaemia virus that contain the psi domain and
      all or part of the gag sequence. Extension of the RNA leads to progressive
      inhibition of the in vitro dimerization process. Sequences located downstream of
      the 3' end of the psi domain seem to stabilize the monomeric structures. This
      stabilization participates in dimerization of the RNA sequences involved in the
      recognition of two RNA molecules. We studied the ability of nucleocapsid protein
      10 to promote dimerization of such long RNA fragments, and found that the protein
      greatly enhances their dimerization in vitro. We propose that nucleocapsid
      protein 10 stimulates the overall dimerization process by reduction of the energy
      barrier that must be overcome to allow dimer formation. Our results show that
      dimerization of RNA form Moloney murine leukaemia virus in vitro is enhanced by
      nucleocapsid protein 10. This finding is in agreement with the involvement of the
      nucleocapsid protein in RNA dimerization in vivo.

PMID- 8665928
TI  - Characterization of centrin genes in Paramecium.
AB  - Centrins are highly conserved, ubiquitous cytoskeletal components which belong to
      the EF-hand superfamily of Ca2+-modulated proteins. We report here the molecular
      characterization of new members of the centrin family, Paramecium centrins.
      Previous studies described the organization of the infraciliary lattice (ICL),
      the innermost cortical cytoskeletal network of Paramecium, and showed that it was
      composed of a set of low-molecular-mass, Ca2+-binding polypeptides [Garreau de
      Loubresse, N., Klotz, C., Vigues, B., Rutin, J & Beisson, J. (1991) Biol. Cell
      71, 217-225]. In this paper we show that these polypeptides are recognized by
      specific anti-centrin polyclonal antibodies. Their microsequences revealed four
      distinct N-termini. For one of them, ICL1, N-terminal and internal peptide
      sequences were used for PCR amplification and cloning of a DNA fragment
      containing a complete centrin coding sequence. The deduced amino acid sequence
      presents about 50% identify with those of centrins from other species. Further
      molecular analysis allowed us to identify two additional closely related, co
      expressed ICL1 genes, providing the first example of a centrin multigenic family
      in a microorganism.

PMID- 8665930
TI  - A characterization of transcriptional regulatory elements in chicken ribosomal
      protein L37a gene.
AB  - Transcriptional control elements of chicken ribosomal protein L37a gene were
      characterized in terms of their activities to promote transcription and their
      protein binding activities. The region -120 to +168 was necessary for the maximal
      expression of the promoter-less CAT gene in a transfected chicken cell line.
      Using the DNase I protection assay, we identified nine protein binding regions
      distributed in a wide range of -122 to +195. The sequences of most of the
      elements are conserved among many vertebrate ribosomal protein genes at similar
      positions of the promoters. These common control elements and their binding
      proteins may coordinate the expression of ribosomal protein genes.

PMID- 8665931
TI  - Guanine-rich oligonucleotides targeted to a critical R . Y site located in the Ki
      ras promoter. The effect of competing self-structures on triplex formation.
AB  - The promoter of the murine Ki-ras proto-oncogene contains a (C+G)-rich homopurine
      . homopyrimidine (R . Y) sequence that is essential for transcription activity.
      We have designed two G-rich oligonucleotides, d(TGGGTGGGTGGTTGGGTGGG) (20GT) and
      d(AGGGAGGGAGGAAGGGAGGG) (20AG), that have the potential to bind the critical Ki
      ras sequence via triplex-helix formation. Band-shift experiments have shown that
      20GT binds the Ki-ras R . Y duplex with a delta G value of -40 +/- 5 kJ/mol,
      while 20AG appeared to have a lower affinity under the experimental conditions
      adopted: 50 mM Tris/HCl, pH 7.4, 50 mM NaCl, 5 mM MgCl2, 25 degrees C. In the
      absence of Mg2+, 20GT did not bind to the Ki-ras R . Y target, while 20AG
      exhibited the same affinity observed in the magnesium-containing buffer. To gain
      insight into the solution properties of 20GT and 20AG, we have performed several
      experiments including polyacrylamide gel electrophoresis (PAGE), hydroxyapatite
      chromatography, ultraviolet absorption melting and circular dichroism (CD). We
      found that 20AG rapidly self-associates into presumably a duplex, even at low
      concentration (< 1 microM), while 20GT forms aggregates slowly, a process
      favoured by high oligonucleotide concentrations (> 25 microM). The critical Ki
      ras sequence was inserted in Bluescript KS+, downstream from the T7 promoter, to
      investigate to what extent 20AG and 20GT, which are directed against the R . Y
      target, are able to inhibit T7 RNA polymerase transcription, under near
      physiological conditions. Transcription experiments conducted in vitro at pH 7.4
      have shown that oligonucleotide 20GT produced a remarkable repression of T7 RNA
      polymerase activity in the concentration range (10-25 microM), whereas 20AG had
      little effect on transcription. In conclusion, the results of this work together
      with other data reported in the literature [Olivas, W. M. & Maher, L. J. III
      (1995) Biochemistry 34, 278-284; Noonberg, S. B., Francois, J.-C., Garestier, T.
      & Helene, C. (1995) Nucleic Acids Res. 23, 1956-1963], demonstrate that G-rich
      oligonucleotides, in particular (G,A)-sequences, may raise problems for in vivo
      application due to self-aggregation.

PMID- 8665932
TI  - Purification and characterization of a p13suc1-bound serine/threonine kinase that
      is expressed in mature rat brain.
AB  - We previously reported that the histone-H1 kinase activity bound to p13suc1
      increased dramatically during development of the rat brain. In the present work,
      an in situ kinase assay in an SDS/polyacrylamide gel that contained substrate
      proteins was employed to characterize the enzyme. Two major proteins of 45 kDa
      and 100 kDa were found to have p13suc1-bound histone-H1 kinase activity. The
      former (p45) exhibited strong activity towards histone H1 and had weak
      autophosphorylation activity, whereas the latter (p100) acted on myelin basic
      protein or histone H1, and underwent autophosphorylation. p45 was further
      purified from the nuclear-enriched fraction of rat brain to near homogeneity
      through sequential column chromatographies. The purified enzyme retained its
      ability to bind specifically to p13suc1, which suggests that this binding does
      not require a cofactor. The immunochemical and enzymatic properties of p45
      revealed that it differs from Cdk that are known to bind to p13suc1 with high
      affinity. However, in vitro p45 acted on the peptide motif that is conserved
      among substrates for cyclin-dependent kinases (Cdk) and mitogen-activated protein
      kinases, which implies that this protein might belong to the large family of
      proline-directed kinases. The evidence obtained in this study suggest that p45 is
      a nuclear p13suc1-bound kinase that has unique functions in the mature brain.

PMID- 8665933
TI  - Structure of the O-specific polysaccharide of an Aeromonas trota strain cross
      reactive with Vibrio cholerae O139 Bengal.
AB  - The O-specific polysaccharide of an Aeromonas trota strain was isolated by
      hydrolysis of the lipopolysaccharide at pH 4.5 followed by gel-permeation
      chromatography and found to consist of hexasaccharide repeating units containing
      D-galactose, L-rhamnose, 3,6-dideoxy-L-xylo-hexose (colitose, Col), 2-acetamido-2
      deoxy-D-glucose and 2-acetamido-2-deoxy-D-galactose in the ratios 1:1:2:1:1.
      Partial hydrolysis of the polysaccharide with 48% hydrofluoric acid resulted in
      selective removal of colitose to give a modified polysaccharide containing the
      other four sugar constituents. On the basis of methylation analysis and NMR
      spectroscopic studies of the initial and modified, colitose-free polysaccharide,
      it was concluded that the repeating unit of the O-specific polysaccharide has the
      following structure [sequence: see text] The known cross-reactivity between the
      strain studied and Vibrio cholerae O139 Bengal is substantiated by the presence
      of a common colitose-containing epitope shared by the O-specific polysaccharide
      of A. trota and the capsular polysaccharide of V. cholerae, which is thought to
      carry determinants of O-specificity.

PMID- 8665934
TI  - Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+
      and oxidant stress.
AB  - Heart and liver mitochondria contain a structure that is able to form a large non
      selective pore in the inner membrane under conditions of high matrix Ca2+ and
      oxidant stress. The pore is blocked by cyclosporin A (CSA). In this study, rat
      liver mitochondria were covalently labelled with a photoactive CSA derivative in
      the presence and absence of the pore ligands Ca2+ and ADP. Photolabelling of a 21
      kDa protein was selectively depressed by Ca2+ in a manner reversed by ADP. The
      protein exhibited peptidyl-prolyl cis-trans isomerase (PPIase) activity and was
      inhibited by CSA (Ki, 8 nM). The PPIase was associated with the outside of
      sonicated submitochondrial particles but dissociated in 0.5 M NaCl. When
      mitochondria were treated with increasing concentrations of digitonin, the 21-kDa
      PPIase fractionated with the matrix marker enzyme, malate dehydrogenase. A second
      PPIase of 18 kDa fractionated with the intermembrane-space marker, adenylate
      kinase. Photolabelling of the 18-kDa PPIase was unaffected by Ca2+ or ADP. The 21
      kDa PPIase was digested with endoproteinase Asp-N and 11 of the peptides were N
      terminally sequenced. The sequences were most similar to those of human
      cyclophilin-D, and it is concluded that this protein is probably the CSA receptor
      during pore blockade by CSA. The implications of these findings are discussed.

PMID- 8665935
TI  - Association of the cytoplasmic domain of intercellular-adhesion molecule-1 with
      glyceraldehyde-3-phosphate dehydrogenase and beta-tubulin.
AB  - To elucidate the molecular mechanisms of the transendothelial migration of
      leukocytes, we attempted to identify the cellular proteins capable of interaction
      with the cytoplasmic domain of the intercellular adhesion molecule-1 (ICAM-1) in
      a rat brain microvessel endothelial cell line (RBE4 cells). A 27-amino-acid
      synthetic peptide, corresponding to the cytoplasmic domain of rat ICAM-1, was
      covalently linked to a Sepharose matrix. Upon affinity chromatography of RBE4
      cell cytosol, several ICAM-1-interacting proteins were specifically eluted by the
      soluble peptide. Two of these proteins have been identified by microsequencing as
      the cytoskeletal protein beta-tubulin and the glycolytic enzyme glyceraldehyde-3
      phosphate dehydrogenase (GraP-DH). Experiments carried out with purified GraP-DH
      or CNBr fragments of GraP-DH indicated that binding to the ICAM-1 matrix was
      mediated by the C-terminal domain of GraP-DH, containing the binding site of the
      cofactor NAD+, and that NAD+ could compete with this binding. Using a series of
      ICAM-1 C-terminal truncated peptides, we could demonstrate that (a) the nitric
      oxide-induced covalent linkage of NAD+ to GraP-DH was impaired by these peptides,
      (b) the glycolytic activity of GraP-DH was drastically inhibited by a truncated
      peptide containing the 15 C-terminal residues, (c) nitric oxide appeared to
      prevent this inhibition. Together, our results demonstrate that GraP-DH
      specifically associates with the isolated ICAM-1 cytoplasmic domain. Since GraP
      DH is known as a microtubule bundling protein, these findings suggest that, in a
      cellular environment, GraP-DH may behave as an adaptor molecule by linking ICAM-1
      to the microtubule network. The role of nitric oxide in the modulation of this
      interaction deserves further investigation.

PMID- 8665936
TI  - Conserved regulation of the Hansenula polymorpha MOX promoter in Saccharomyces
      cerevisiae reveals insights in the transcriptional activation by Adr1p.
AB  - The Hansenula polymorpha MOX gene encodes a peroxisomal enzyme that catalyzes the
      first step of the highly specialized methanol metabolism. MOX is strongly
      transcribed in cells growing in methanol and completely repressed in glucose. We
      show here that the MOX promoter confers a glucose-repressible expression upon a
      lacZ reporter gene in Saccharomyces cerevisiae, an unrelated yeast species that
      lacks the methanol metabolism. Repression was mediated by a 200-bp region of the
      MOX promoter, termed MOX-B, and was counteracted by Adr1p, a transcription factor
      involved in the derepression of S. cerevisiae genes encoding peroxisomal
      proteins, the class to which MOX belongs. Binding of Adr1p to MOX-B was
      demonstrated by gel retardation and DNaseI-footprinting, and Adr1p was shown to
      interact with a DNA region containing only a half of the putative Adr1p consensus
      binding site. Our findings suggest that Adr1p is a conserved regulator for genes
      encoding peroxisomal proteins at least in other yeast species, and that its
      interaction with the DNA is dependent on the promoter context.

PMID- 8665937
TI  - Conformational requirements of a recombinant ferredoxin-NADP+ reductase precursor
      for efficient binding to and import into isolated chloroplasts.
AB  - The cytosolic precursor of the chloroplast flavoprotein ferredoxin-NADP+
      reductase was expressed in Escherichia coli rendering a soluble protein that
      contained bound FAD and could be imported by isolated chloroplasts. The mechanism
      of plastid translocation was studied under defined conditions using this
      recombinant precursor holoprotein and intact pea chloroplasts. The first step in
      the import pathway, namely, binding of the reductase precursor to isolated
      chloroplasts, was saturable at about 2000 molecules/plastid, and showed a high
      affinity interaction with a dissociation constant Kd of approximately 5 nM.
      Binding was not affected by the addition of soluble leaf extracts or by prior
      denaturation of the precursor with urea. Analysis of the initial import rates at
      different precursor concentrations indicated the existence of a single
      translocation system for this protein. Inclusion of leaf extracts in the assay
      resulted in a three-fold increase of the maximal import rates to 14,000 molecules
      . min-(1).chloroplast-(1), with a concomitant decrease in the apparent Km for the
      recombinant precursor, from 1 microM to 100-150 nM. Comparison of Km and Kd
      values under various conditions indicated that the binding step of the
      translocation process is largely irreversible, favouring import and processing.
      In the absence of extract, a denatured precursor obtained by incubation with urea
      was a better substrate for plastid import than the holoprotein. Treatment of the
      precursor with either extract or urea resulted in similar increases in import
      efficiency (V/Km), suggesting that stimulation by leaf extracts is probably
      related to unfolding of the precursor prior to translocation.

PMID- 8665938
TI  - Cathepsin L is an intracellular and extracellular protease in Paramecium
      tetraurelia. Purification, cloning, sequencing and specific inhibition by its
      expressed propeptide.
AB  - The ciliate Paramecium tetraurelia secretes large amounts of a cysteine protease
      into the growth medium, presumably for extracellular food digestion. Two
      endoprotease isozymes (30 and 33 kDa on SDS/PAGE, respectively), both present in
      cell homogenates and in spent growth medium, were purified to homogeneity.
      Peptide sequence analysis revealed that these isozymes share identities at the
      amino acid level but are probably differently processed. Enzymatic
      characterization of the isolated proteases and sequencing of the cloned cDNA
      demonstrated that the enzymes belong to the cathepsin-L protease subfamily.
      Although the identity with mammalian and other protozoan L cathepsins was only
      around 30%, all important signature sequences for cathepsin L in the preproregion
      as well as in the catalyst of the enzyme were fully retained. The cDNA of this
      cysteine protease codes for a preproregion of 108 amino acids. The putative
      proregion of 86 amino acids which contained the characteristic conserved ERFNIN
      motif, was fused with a His6 tag, expressed in Escherichia coli, and purified.
      Both cathepsin L isozymes of Paramecium tetraurelia were inhibited by their
      cognate propeptide in the nanomolar concentration range. All other cysteine
      proteases tested (papain and mammalian cathepsin B, G and H) were unaffected by
      the propeptide up to 10 microM.

PMID- 8665939
TI  - The inhibition of phosphoenolpyruvate carboxykinase following in vivo chronic
      phenobarbital treatment in the rat is due to a post-translational event.
AB  - Chronic treatment of rats with phenobarbital has been reported to decrease
      gluconeogenesis in rat hepatocytes by a 50% inhibition of phosphoenolpyruvate (P
      pyruvate) carboxykinase activity [Argaud, D., Halimi, S., Catelloni, F. &
      Leverve, X. (1991) Biochem. J. 280, 663-669]. Contrary to the current knowledge
      of P-pyruvate carboxykinase regulation, we failed to find a diminution of either
      P-pyruvate carboxykinase protein (by using a polyclonal antibody) or P-pyruvate
      carboxykinase mRNA, in the liver of rats treated with phenobarbital for 2 weeks.
      Kinetic studies of P-pyruvate carboxykinase activity, measured by either
      carboxylation of P-pyruvate or decarboxylation of oxaloacetate, revealed a
      decrease in both V(max) and Km after phenobarbital treatment, whereas the
      nutritional state affected only the V(max), as expected. Assessment of P-pyruvate
      carboxykinase specificity was confirmed by the full inhibition of the enzyme with
      its specific inhibitor 3-mercaptopicolinate in the micromolar range. P-Pyruvate
      carboxykinase, purified either by ammonium sulfate fractionation or by
      immunoprecipitation, exhibited a similar decrease in affinity after phenobarbital
      treatment. Although the molecular mass does not appear to be altered, the pH
      sensitivity to 3-mercaptopicolinate inhibition and the enzyme recovery after
      immunoprecipitation both seemed to be affected. This leads us to propose that the
      effect of chronic phenobarbital treatment on P-pyruvate carboxykinase activity is
      not the result of transcriptional regulation but is exerted at the post
      translational level.

PMID- 8665940
TI  - Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated
      protein kinase cascade in cultured rat skeletal muscle cells.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a proposed mediator of insulin
      resistance in obese/diabetic animals through its effects on tyrosine
      phosphorylation of the insulin receptor and its substrate, insulin receptor
      substrate-1. In this study, the acute effects of TNF-alpha on the mitogen
      activated protein kinase (MAPK) signalling cascade were examined in cultured rat
      skeletal muscle cell line, L6. Insulin treatment of L6 cells resulted in a rapid
      increase in MAPK activity (> twofold in 5 min with 10 nM insulin). Prior
      treatment with TNF-alpha for 60 min blocked subsequent insulin-induced activation
      of MAPK in a dose- and time-dependent manner. Metabolic labelling studies with
      inorganic [32P]phosphate followed by immuno-precipitation of MAPK and its
      upstream activator, mitogen-activated protein kinase kinase, indicated decreased
      phosphorylation of MAPK and its kinase in response to insulin in cells exposed to
      TNF-alpha. This effect of TNF-alpha was not due to inhibition of insulin
      stimulated p21ras-GTP loading or Raf-1 phosphorylation. Low concentrations (2 nM)
      of okadaic acid, a serine/threonine phosphatase inhibitor, prevented TNF-alpha
      induced inhibition of MAPK and restored insulin's effect on MAPK activity, while
      orthovanadate (a tyrosine phosphatase inhibitor), inhibitor 2 (phosphatase-1
      inhibitor) and FK506 (phosphatase-2B inhibitor) were ineffective. These results
      suggested an involvement of an okadaic-acid-sensitive serine/threonine
      phosphatase in TNF-alpha-induced blockade of insulin's effect on MAPK and/or its
      kinase. Therefore, we examined the effect of TNF-alpha on protein phosphatase-1
      (PP-1) and protein phosphatase-2A (PP-2A) activities. As reported by us earlier,
      insulin rapidly stimulated PP-1 and concomitantly inhibited PP-2A activities in
      control cells. TNF-alpha treatment blocked insulin-induced activation of PP-1. In
      contrast to PP-1, TNF-alpha caused a 60% increase in PP-2A activity and insulin
      failed to prevent this TNF-alpha effect. The time course of PP-2A activation by
      TNF-alpha preceded the kinetics of inhibition of MAPK. Cell-permeable ceramide
      analogs mimicked the TNF-alpha effect on MAPK inhibition and PP-2A activation. We
      conclude that TNF-alpha abrogates the insulin effect on MAPK activation by
      increasing dephosphorylation of MAPK kinase via an activated phosphatase.

PMID- 8665941
TI  - Translation is enhanced after silent nucleotide substitutions in A+T- rich
      sequences of the coding region of CD46 cDNA.
AB  - Specific sequences in the coding region of CD46 (membrane cofactor protein)
      transcripts have been shown to have a marked effect on translation. Two A+T-rich
      regions of CD46 cDNA were altered by mutation without changing the CD46 amino
      acid sequence (silent nucleotide substitution). In one region, the A+T content
      was reduced from 78% to 55% and in the other a putative polyadenylation addition
      sequence was disrupted. In each example, mutated sequences transfected into COS-7
      cells produced significantly more soluble or cell surface protein (up to a 20
      fold increase) than wild-type sequences. The amount of cellular plasmid DNA and
      CD46 mRNA was not increased, suggesting that the effect was not due to increased
      transfection efficiency, or transcript synthesis or stability. Biosynthetically
      labelled transfected cells showed an increase in translation rate but cell-free
      in vitro translation studies demonstrated that wild-type and mutated transcripts
      were translated with similar efficiency. The data show that translation of CD46
      is affected by specific mRNA coding sequences, 400-540 bases from the initiation
      codon, and suggest that these sequences require the structural integrity of the
      cell to exert their effect.

PMID- 8665942
TI  - Characterization of alpha-neurotoxin and phospholipase A2 activities from
      Micrurus venoms. Determination of the amino acid sequence and receptor-binding
      ability of the major alpha-neurotoxin from Micrurus nigrocinctus nigrocinctus.
AB  - New World elapids are coral snakes that belong to the genus Micrurus, and for
      which the venom biochemistry is mostly unknown. Analysis has been difficult
      because the coral snakes produce small quantities of venom. Clinical observations
      following bites show mainly neurotoxic effects. Experimentally, cardiotoxic,
      haemolytic and myotoxic activities are also reported. An experimental approach,
      using reverse-phase high-performance liquid chromatography and specific assays
      for alpha-neurotoxin and phospholipase A2 activities, was conducted on milligram
      quantities of venoms from three Micrurus species from Costa Rica; M. nigrocinctus
      nigrocinctus, M. alleni yatesi and M. multifasciatus. Neurotoxicity was
      determined by competition binding experiments with the Torpedo marmorata
      acetylcholine receptor. Phospholipase A2 activity was measured by fluorimetry
      using a pyrene lipid substrate. In this way, we purified and characterized seven
      alpha-neurotoxins, five phospholipases A2 and four toxin homologs. The amino acid
      sequence of the major alpha-neurotoxin from M. nigrocinctus nigrocinctus venom
      was fully determined and compared to Old Word representatives. Distance matrix
      data were generated to set up phylogeny relationships among elapid short-chain
      alpha-neurotoxins, which proved to be in accordance with the taxonomic
      classification and geographical distribution of snake species.

PMID- 8665943
TI  - Structure/function analysis of human factor XII using recombinant deletion
      mutants. Evidence for an additional region involved in the binding to negatively
      charged surfaces.
AB  - The binding site of human factor XII (FXII) for negatively charged surfaces has
      been proposed to be localized in the N-terminal region of factor XII. We have
      generated two recombinant factor XII proteins that lack this region: one protein
      consisting of the second growth-factor-like domain, the kringle domain, the
      proline-rich region and the catalytic domain of FXII (rFXII-U-like), and another
      consisting of only 16 amino acids of the proline-rich region of the heavy-chain
      region and the catalytic domain (rFXII-1pc). Each recombinant truncated protein,
      as well as recombinant full-length FXII (rFXII), were produced in HepG2 cells and
      purified by immunoaffinity chromatography. The capability of these recombinant
      proteins to bind to negatively charged surfaces and to initiate contact
      activation was studied. Radiolabeled rFXII-U-like and, to a lesser extent, rFXII
      lpc bound to glass in a concentration-dependent manner, yet with lower efficiency
      than rFXII. The binding of the recombinant proteins was inhibited by a 100-fold
      molar excess of non-labeled native factor XII. On native polyacrylamide gel
      electrophoresis, both truncated proteins appeared to bind also to dextran
      sulfate, a soluble negatively charged compound. Glass-bound rFXII-U-like was able
      to activate prekallikrein in FXII-deficient plasma (assessed by measuring the
      generation of kallikrein-C1-inhibitor complexes), but less efficiently than
      rFXII, rFXII-U-like and rFXII-lpc exhibited coagulant activity, but this activity
      was significantly lower than that of rFXII. These data confirm that the N
      terminal part of the heavy-chain region of factor XII contains a binding site for
      negatively charged activating surfaces, and indicate that other sequences,
      possibly located on the second epidermal-growth-factor-like domain and/or the
      kringle domain, contribute to the binding of factor XII to these surfaces.

PMID- 8665944
TI  - Colocalization of cytosolic phospholipase A2, 5-lipoxygenase, and 5-lipoxygenase
      activating protein at the nuclear membrane of A23187-stimulated human
      neutrophils.
AB  - The distribution of cytosolic phospholipase A2 (cPLA2), arachidonate 5
      lipoxygenase, and 5-lipoxygenase-activating protein (5-LAP) was investigated in
      subcellular fractions of human neutrophils disrupted by three techniques. As
      determined by immunoblot analysis, the bulk of cPLA2 and 5-lipoxygenase was
      detected in cytosolic fractions of unstimulated neutrophils disrupted by
      sonication or cavitation. After cell stimulation with the calcium ionophore
      A23187, both proteins accumulated primarily in nuclei-containing fractions; this
      accumulation was accompanied by a loss of these enzymes from cytosolic fractions.
      Further resolution of nuclear fractions revealed that 5-lipoxygenase and cPLA2
      were localized in a fraction that contained nuclear membranes. In comparison, 5
      LAP was localized to the nuclear-membrane fraction of resting and activated
      neutrophils, as determined by immunoblotting and photoaffinity labeling. In
      agreement with the immunoblot data, A23187 stimulation markedly enhanced 5
      lipoxygenase enzymatic activity in the nuclear-membrane fraction, which was
      accompanied by decreased cytosolic 5-lipoxygenase activity. Similarly, neutrophil
      activation caused increased phosphorylation of cPLA2, a process that is known to
      result in enhanced catalytic activity. Our data demonstrate that in activated
      human neutrophils, the key proteins involved in leukotriene synthesis colocalize
      at the nuclear membrane, in a catalytically active state.

PMID- 8665945
TI  - Microheterogeneity of the hydrophobic and hydrophilic part of the
      glycosylphosphatidylinositol anchor of alkaline phosphatase from calf intestine.
AB  - Digestion of calf intestine alkaline phosphatase with pronase and subsequent
      dephosphorylation of the released peptidyl-(Etn-P)2-glycosyl-PtdIns with HF
      generated 8 glycosyl-Ins species the largest of which (G1 and G2) have the
      following proposed structures: [sequence: see text] G3 and G5 are lower
      homologues of G1 and G2, respectively, being one alpha 1-2 linked mannopyranosyl
      residue shorter. G4 is analogous to G2 lacking the N-acetylgalactosaminyl residue
      and G6 is the next lower homologue of G4. Most of G4 and G6 occur substituted
      with a palmitoyl (G4, G6) or a myristoyl residue (G6) probably attached to the
      inositol moiety. Thus, the basic ManxGlc-Ins species are either substituted with
      an N-acetylgalactosaminyl residue or a fatty acid ester. The structures were
      deduced from compositional analysis, molecular-mass determination by matrix
      assisted laser desorption MS, sequential hydrolysis with appropriate
      exoglycosidases and treatment with CrO3. Purification of the glycosylinositol
      species was achieved by a novel reverse-phase HPLC technique using fluorescent
      fluoren-9-yl-methoxy-carbonyl (Fmoc) derivatives. These stable derivatives were
      susceptible to hydrolysis with exoglycosidases which allowed sequential cleavages
      to be carried out and kinetics to be followed at the picomole level. We observed
      recently that native alkaline phosphatase separates on octyl-Sepharose into four
      distinct fractions of increasing hydrophobicity (F1-F4). Here we show that all
      four fractions contain G1-G6. The acylated species G4 and G6 were restricted to
      F2 and F4 which had been shown earlier to contain, on average, 2.5 and 3 fatty
      acid residues/subunit, respectively. In all four fractions the diradylglycerol
      moiety was predominantly diacylglycerol, alkylacylglycerol being less than 10%
      which is in contrast to most glycosyl-PtdIns--anchored proteins of mammalian
      origin.

PMID- 8665946
TI  - Structures of the glycolipid antigens of members of the third biovariant complex
      of Mycobacterium fortuitum.
AB  - Among the fast-growing mycobacteria, members of the Mycobacterium fortuitum
      complex are the most-commonly cited opportunistic human pathogens, notably in
      post-surgical infections. Previous studies showed that this complex was composed
      of four well-identified species and a group of isolates that did not correspond
      to recognized species, which has been referred to as the third biovariant
      complex. The occurrence and chemical structure of the glycolipid antigens of six
      strains that belong to this latter group were examined in the present study.
      Based on the TLC profiles, resistance to alkali and seroreactivities of their
      glycolipids, the examined strains were classified into three groups: one group
      was devoid of species-specific glycolipid and the two other groups contained
      alkali-stable or alkali-labile glycoconjugates. The structures of the major
      glycolipid antigens of the latter two groups were elucidated by fast-atom
      bombardment MS, one-dimensional and two-dimensional NMR spectroscopy and
      conventional chemical analyses. The alkali-stable glycolipids were structurally
      identical to the C-mycoside-type glycopeptidolipids characterized in the
      taxonomically related species Mycobacterium peregrinum. The major alkali-labile
      glycolipid was identified as beta-Glcp-1 --> 6)-alpha-Glcp2Acyl-(1 --> 1)-alpha
      GLcp3,4,6Acyl3. The acyl substituents consisted on one acetyl group and three
      fatty acyl residues composed mainly of tetradecanoyl residues, but significant
      amounts of 2-methylhexadecanoyl and 2-methyloctadecanoyl substituents were also
      present. The heterogeneity of the glycolipid content of members of the third
      biovariant complex of M. fortuitum demonstrated in the present study confirms the
      heterogeneity of the complex. In addition, the occurrence of a species-specific
      glycolipid in some strains supports the hypothesis that some strains of this
      complex of M. fortuitum may belong to a new mycobacterial species.

PMID- 8665947
TI  - Overexpression, solubilization and purification of rat and human olfactory
      receptors.
AB  - The superfamily of olfactory receptor genes, whose products are thought to be
      activated by odorant ligands, is critical for odor recognition. Two olfactory
      receptors, olp4 from rat and OR17-4 from human, were overexpressed in Sf9 insect
      cells. The presence of the proteins in cell membranes was monitored by
      immunoblotting with peptide-specific polyclonal antibodies directed against the C
      terminal sequences of these receptors and with a mAb against an N-terminal
      octapeptide epitope tag. A DNA sequence that codes for a His6 tag, which binds
      tightly to a Ni2+-chelate-affinity column, was incorporated into the N-termini of
      both genes. The expressed olfactory receptors were found mainly in the cell
      membrane fraction. The proteins were difficult to solubilize by many detergents
      and only lysophosphatidylcholine was found to be both suitable for efficient
      solubilization of the overexpressed olfactory receptors and compatible with the
      purification system used. After solubilization, the olfactory receptors were
      purified to near homogeneity by affinity chromatography on nickel
      nitrilotriacetic acid resin and by cation-exchange chromatography.
      Electrophoresis of the purified proteins and visualization with Coomassie Blue
      staining or by immunoblotting with specific antibodies, revealed bands of 32, 69
      and 94 kDa, which were identified as the monomeric, dimeric and trimeric forms of
      the receptor proteins. The oligomeric forms were resistant to reduction and
      alkylation, and are therefore thought to be held together by non-covalent
      hydrophobic interactions that are resistant to SDS. This finding is similar to
      previous observations for other guanine-nucleotide-binding-regulatory-protein
      coupled receptors. Reconstitution in phospholipid vesicles showed that the
      purified olfactory receptors insert specifically into the lipid bilayer. This
      provides a means to study functional reconstitution with putative transduction
      components such as olfactory guanine-nucleotide-binding-regulatory protein.

PMID- 8665948
TI  - Stereoselectivity of pigment exchange with 13(2)-hydroxylated tetrapyrroles in
      reaction centers of Rhodobacter sphaeroides R26.
AB  - Bacteriochlorophyll a and bacteriopheophytin a carry a stereochemically labile
      asymmetric carbon at position C13(2). The steric requirements of photosynthetic
      reaction centers from Rhodobacter sphaeroides R26 have been probed by exchange
      experiments with the respective epimeric 13(2)-hydroxylated pigments, in which
      epimerisation is blocked. (13(2)S)-13(2)-Hydroxy-bacteriochlorophyll a is
      accepted at both monomeric binding sites, BA,B, (13(2)S)-13(2)-hydroxy
      bacteriopheophytin a exclusively at the inactive site HB. The orientation of the
      13(2)-COOCH3 substituents in these pigments is the same as in the native (13(2)R)
      bacteriochlorophylls and (13(2)R)-bacteriopheophytins. In no cases are the
      unnaturally configured 13(2)-hydroxylated (13(2)R)-epimers accepted, even if a
      large excess (> 95%) is offered. It is concluded that the three binding sites
      always require the 13(2)-COOCH3 group on the opposite side of the macrocycle
      (down) than the 17-propionic ester side chain (up).

PMID- 8665949
TI  - Low-spin heme A in the heme A biosynthetic protein CtaA from Bacillus subtilis.
AB  - Synthesis of heme A from heme B (protoheme IX) most likely occurs in two steps
      with heme O as an intermediate. Bacillus subtilis CtaB, an integral membrane
      protein, functions in farnesylation of heme B to form heme O. CtaA, also a
      membrane protein, is required for heme A synthesis from heme O and appears to be
      a monooxygenase and/or a dehydrogenase. Wild-type ctaA and ctaB expressed
      together from plasmids in B. subtilis resulted in CtaA containing equimolar
      amounts of low-spin heme B and heme A; this form of CtaA was named cyt ba-CTA. A
      mutant ctaB gene was identified and characterised. It encodes a truncated CtaB
      polypeptide. Wild-type ctaA and the mutant ctaB gene on plasmids resulted in CtaA
      containing mainly low-spin heme B; this variant was named cyt b-CTA. The heme B
      component in cyt ba-CTA and cyt b-CTA showed identical properties; a mid-point
      redox potential of +85 mV, an EPR g(max) signal at 3.7, and a split alpha-band
      light absorption peak. The heme A component in cyt ba-CTA showed a mid-point
      potential of +242 mV, an EPR g(max) signal at 3.5, and the alpha-band light
      absorption peak at 585 nm. It is suggested that the CtaA protein contains two
      heme binding sites, one for heme B and one for substrate heme. The heme B would
      play a role in electron transfer, i.e. function as a cytochrome, in the
      monooxygenase and/or dehydrogenase reaction catalysed by CtaA whereas heme O/heme
      A would be substrate/product.

PMID- 8665950
TI  - CTBP1/RBP1, a Saccharomyces cerevisiae protein which binds to T-rich single
      stranded DNA containing the 11-bp core sequence of autonomously replicating
      sequence, is a poly(deoxypyrimidine)-binding protein.
AB  - South-Western screening of a glutathione-S-transferase fusion protein library
      constructed from the yeast Saccharomyces cerevisiae genomic DNA lead to isolation
      of core T-rich-strand-binding protein (CTBP) clones that bound to single-stranded
      DNA containing the T-rich-strand of the 11-bp core sequence of autonomously
      replicating sequences. One of these clones, CTBP1, contains a portion of
      previously described RBP1 which is an RNA-binding and single-stranded DNA-binding
      protein of S. cerevisiae. GST-CTBP1 as well as the full-length fusion protein
      with RBP1 (GST-RBP1) bind exclusively to the T-rich strand of the core sequence
      with an apparent dissociation constant of 5 nM, but not to the A-rich strand or
      double strand of the same sequence. Mutations within the core which reduce the
      number of T or C residues decrease the affinity of this protein. In keeping with
      this, binding of GST-CTBP1 to the core sequence is efficiently completed by
      poly(dT), poly(dT-dC) or poly(dC), but not by poly(dA) or poly(dG) to significant
      extents. Among polyribonucleic acids, GST-CTBP1 binds to poly(U) and poly(I) with
      greatest affinity, whereas GST-RBP1 binds to RNA in a rather non-specific manner.
      In no cases was affinity for RNA greater than that for DNA. Our results indicate
      that CTBP1/RBP1 is a polydeoxypyrimidine-binding protein of S. cerevisiae. CTBP1
      contains two sets of an RNA-recognition motif (RRM) and a glutamine stretch. The
      binding affinity of the N-terminal or C-terminal set containing one RRM and one
      glutamine stretch is nearly two orders of magnitude lower than that of the wild
      type CTBP1 containing both sets. The isolated N-terminal or C-terminal RRM alone
      (RRM1 and RRM2, respectively) is sufficient for binding nucleic acids with the
      binding specificity similar to that of the wild-type RRM, although the binding
      affinity of the isolated RRM2 is nearly two orders of magnitude lower than that
      of RRM1. Our results indicate that the two RRMs present in CTBP1/RBP1 have
      differential binding affinities and that the high affinity of RRM for
      polydeoxypyrimidine results from synergy between two lower-affinity RRMs.

PMID- 8665951
TI  - Isolation and characterization of the major gel proteins in human semen,
      semenogelin I and semenogelin II.
AB  - Semenogelin I and semenogelin II constitute the major gel-forming proteins in
      human semen. The gel proteins were rapidly solubilized and separated from
      spermatozoa in ejaculates collected at pH 9.7 in buffer containing 4 mol/l urea
      and dithiothreitol. This protected the semenogelins from proteolytic degradation
      by prostate-specific antigen, and allowed their isolation by affinity
      chromatography on heparin-Sepharose. Semenogelins I and II were almost
      selectively retained and eluted partially separated in 0.25 mol/l NaCl. Further
      purification was achieved by chromatography on Superose. Approximately 10-20 mg
      semenogelin I and 2-5 mg semenogelin II were recovered from each sample with a
      purity exceeding 95% as judged by SDS/PAGE. The molecular mass of semenogelin I
      (49 958 Da) and the major form of semenogelin II (63 539 Da) measured by mass
      spectrometry was consistent with the reported cDNA data. The occurrence of a
      second, larger form of semenogelin II was due to asparagine-linked glycosylation.
      The amino-termini of the purified proteins were blocked, but digestion with
      pyroglutamate amino-peptidase enabled the identification of amino-terminal
      sequences consistent with the reported cDNA data. The amino acid compositions of
      the purified proteins were also consistent with those derived from cDNA data. The
      absorption coefficients (280 nm, 1%, 1 cm) for semenogelins I and II were 5.5 and
      5.4, respectively, and the isoelectric point was above pH 9.5 for both proteins.

PMID- 8665952
TI  - Purification and characterization of a DNA helicase from pea chloroplast that
      translocates in the 3'-to-5' direction.
AB  - An ATP-dependent DNA helicase has been purified to near homogeneity from pea
      chloroplasts. The enzyme is a homodimer of 68-kDa subunits. The purified enzyme
      shows DNA-dependent ATPase activity and is devoid of DNA polymerase, DNA
      topoisomerase, DNA ligase or nuclease activities. The enzyme requires Mg2+ or
      Mn2+ for its maximum activity. ATP is the most favoured cofactor for this enzyme
      while other NTP or dNTP are poorly utilized. Pea chloroplast DNA helicase can
      unwind a 17-bp duplex whether it has unpaired single-stranded tails at both the
      5' end and 3' end, at the 5' end or at the 3' end only, or at neither end.
      However, it fails to act on a blunt-ended 17-bp duplex DNA. The enzyme moves
      unidirectionally from 3' to 5' along the bound strand. The unwinding activity is
      inhibited by the intercalating drugs nogalamycin and daunorubicine.

PMID- 8665953
TI  - Enlarged scale chemical synthesis and range of activity of drosocin, an O
      glycosylated antibacterial peptide of Drosophila.
AB  - Insects respond to a bacterial challenge by rapidly synthesizing a diverse range
      of antibacterial and antifungal peptides. One of them, drosocin, a 19-residue
      proline-rich antibacterial peptide, was isolated from Drosophila. This peptide
      carries a disaccharide moiety attached to a threonine residue in mid-chain
      position. The present report describes the enlarged-scale chemical synthesis of
      drosocin, glycosylated with Gal (beta 1 --> 3)GalNAc(alpha 1 --> O). We have
      studied the range of activity of the synthetic glycopeptide, of two truncated
      glycosylated isoforms, and of the unglycosylated L and D enantiomers. Both
      isolated and chemically synthesized drosocins carrying the disaccharide display
      the same antibacterial activity. Using circular dichroic spectroscopy we
      demonstrated that the O-linked disaccharidic motif did not affect the backbone
      conformation of drosocin. The antibacterial activity of the synthetic
      glycopeptide was directed against gram-negative strains with the exception of the
      gram-positive bacteria Micrococcus luteus. Deletion of the first five N-terminal
      residues completely abolished the activity of drosocin. As a first approach to
      the study of the mode of action of drosocin, we have synthesized a non
      glycosylated D enantiomer and, using this molecule, we have shown that drosocin
      may act on the gram-negative bacteria through a stereospecific target.

PMID- 8665954
TI  - Targeting of porcine pancreatic phospholipase A2 to human platelets. Introduction
      of an RGD sequence and acyl-group by chemical modification.
AB  - In the present study we prepared by chemical modification a series of porcine
      pancreatic phospholipase A2 (PLA) derivatives, that bind to the activated
      glycoprotein (GP) IIb/IIIa complex and hydrolyse phospholipids in the outer
      leaflet of the platelet membrane. To the native enzyme, an RGD-containing peptide
      was coupled to introduce affinity for GPIIb/IIIa in combination with lauric acid
      to improve binding to the membrane. As controls, derivatives containing only one
      of these modifications were prepared. Acylation of the enzyme improved the
      affinity for densely packed phospholipids, as deduced by kinetic analyses. After
      stimulation of platelets, the RGD-containing PLAs bound to GPIIb/IIIa since GRGDS
      peptide and a monoclonal antibody against the complex interfered with binding. No
      binding was found with native PLA. The binding seen with lauric acid PLA was not
      mediated by GPIIb/IIIa. All modified PLAs induced 1-3% hydrolysis of
      [3H]arachidonic-acid-labelled phospholipids in resting platelets. After
      activation with alpha-thrombin, hydrolysis increased to 17%, corresponding to
      about 90% of [3H]arachidonate-labelled phospholipids in the outer leaflet of the
      plasma membrane. RGD-containing PLAs were more active than lauroyl PLA, and their
      activity was mediated via GPIIb/IIIa since GRGDS inhibited release of
      [3H]arachidonic acid. Acylation of the RGD-containing PLAs did not further
      improve the hydrolytic properties. We conclude that chemical modification of PLA
      leads to a targetted hydrolytic action and could be a basis for the design of
      enzymes that specifically destroy activated platelets.

PMID- 8665955
TI  - Reactions of mitochondrial cruciform cutting endonuclease 1 (CCE1) of yeast
      Saccharomyces cerevisiae with branched DNAs in vitro.
AB  - Cruciform-cutting endonuclease 1 (CCE1) is an X-solvase from yeast Saccharomyces
      cerevisiae [Kleff, S., Kemper, B. & Sternglanz, R. (1992) EMBO J. 11, 699-704].
      We report here the purification of the cloned enzyme CCE1 to near homogeneity
      from over-expressing Escherichia coli cells. The purified protein has a globular
      shape and an apparent molecular mass of 38 kDa. CCE1 reacts specifically with
      branched DNAs, preferably with four-armed cruciforms. The enzyme linearizes
      native supercoiled DNA by cutting at the base of cruciform structures as they
      occur in derivatives of phage M13. Supercoiling was not required for cleavage per
      se and a relaxed circular DNA hybrid with a stable cruciform was linearized with
      the same relative cleavage efficiency. Fully synthetic cruciforms (four-armed X
      junctions) were also good substrates for CCE1, provided a symmetric 6-bp sequence
      (in our case an EcoRI restriction site) was maintained at the junction.
      Consequently, a synthetic cruciform made from fully randomized oligonucleotide
      sequences was not a substrate for CCE1. In general, cleavage sites were found
      clustered in a characteristic pattern in each arm of a cruciform structure. A
      synthetic three-armed Y-junction was also cleaved by CCE1, but with a lower
      efficiency than the related four-armed construct. CCE1 resolves efficiently
      branched synthetic DNAs in vitro. The function is consistent with the idea that
      CCE1 is responsible for a timely reversal of branched recombination intermediates
      preceding petite formation in mitochondrial DNA.

PMID- 8665956
TI  - Characterization of semenogelin II and its molecular interaction with prostate
      specific antigen and protein C inhibitor.
AB  - The serine protease, prostate-specific antigen (PSA), its protein substrates,
      semenogelin (Sg) I and II, and protein C inhibitor (PCI) have been described as
      components of human seminal plasma. PCI was found to inhibit the PSA-catalyzed
      degradation of insoluble coagula Sg I + II by forming a PSA-PCI complex.
      Digestion of seminal coagula with PSA released PCI and PSA-PCI complex from the
      coagula into a soluble phase, suggesting the presence of active PCI binding to
      the coagula. To investigate the molecular interaction of Sg with PSA and PCI, we
      purified Sg II from seminal coagula as a soluble form and found that Sg II is
      glycosylated with heterogeneous carbohydrate moieties. Sg II bound to the solid
      phase complex of diisopropylfluorophosphate (iPr2FP) and PSA with an apparent
      dissociation constant (kd) of 41 nM and to PCI with a Kd of 28 nM. The binding of
      Sg II to iPr2P-PSA was not affected by PCI and that of Sg II to PCI was not
      affected by iPr2P-PSA, suggesting that Sg II forms a ternary complex with PSA and
      PCI. The bindings of Sg II to both iPr2P-PSA and PCI were influenced by pH, ionic
      strength, heparin, dextran sulfate, and divalent cations, particularly by Zn2+.
      Treatment of Sg II with heparinase, heparitinase, N-glycanase, or with O
      glycanase following sialidase did not affect the binding of Sg II to iPr2P-PSA
      and PCI. These findings suggested that PCI bound to Sg in seminal vesicles
      regulates the PSA-catalyzed degradation of Sg in seminal plasma, and that the
      binding of PCI and PSA to Sg is modulated by several factors such as pH, ionic
      strength, divalent cations, and heparin-like substances in seminal plasma.

PMID- 8665957
TI  - Synthetic 20-epi analogs of calcitriol are potent inducers of target-gene
      activation in osteoblastic cells.
AB  - We have compared the actions of calcitriol and its three synthetic analogs, 20
      epi-22-oxa-24a,26a,27a-trihomo-1 alpha,25-dihydroxyvitamin D3 (KH 1060), 1
      alpha,24S-(OH)2-22-ene-26,27-cyclopropyl vitamin D3 (MC 903) and 20-epi-1
      alpha,25-dihydroxyvitamin D3 (MC 1288), on the expression of two marker genes of
      differentiated osteoblasts, namely alkaline phosphatase and osteocalcin, using
      human MG-63 osteosarcoma cells. Calcitriol and the analogs had qualitatively
      similar stimulatory effects on target-gene activation. Quantitatively, MC 903
      behaved in most experiments essentially as the parent compound calcitriol. In
      vitamin D receptor/DNA complex formation MC 903, however, was more potent than
      calcitriol. In contrast, the 20-epi analogs, KH 1060 and MC 1288, were much more
      potent even at lower concentrations, than calcitriol and MC 903 in stimulating
      alkaline phosphatase activity, osteocalcin mRNA synthesis and osteocalcin
      secretion. The stimulation occurred to a greater degree and for a longer period
      than with calcitriol. This effect was apparently mediated by stronger and longer
      lasting binding of the vitamin D receptor to the osteocalcin vitamin D responsive
      element by the 20-epi analogs. After a 6-h treatment and during subsequent
      culture without hormone, the effects of the 20-epi analogs were also stronger and
      lasted longer than those with calcitriol or MC 903. Collectively, at comparable
      and lower concentrations, the 20-epi analogs, KH 1060 and MC 1288, mediate much
      stronger and longer lasting stimulatory effects than calcitriol or its analog MC
      903 on target-gene expression associated with the differentiated phenotype of the
      MG-63 human osteosarcoma cells.

PMID- 8665958
TI  - Platelet reactivity, exercise, and stable coronary artery disease.

PMID- 8665959
TI  - Microvascular incompetence and the failure of hearts to recover contractile
      function after cardioplegia.

PMID- 8665960
TI  - Further evidence for beneficial effects of comprehensive cardiac rehabilitation
      in men with coronary artery disease.

PMID- 8665961
TI  - Balloon or blade for calcified mitral stenosis.

PMID- 8665962
TI  - Progress culminating from ten years of clinical trials on thrombolysis for acute
      myocardial infarction. GUSTO-I Steering Committee. Global Utilization of
      Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

PMID- 8665963
TI  - Ventricular tachycardia in ischaemic heart disease: insights into the mechanisms
      from cardiac mapping and implications for patient management.
AB  - Ventricular tachycardia following myocardial infarction in man is thought to be
      due to a reentrant mechanism, with a zone of slow conduction forming the critical
      element of the return pathway. Cardiac mapping has helped characterize the
      anatomical and functional nature of reentrant pathways, and is used to direct
      antiarrhythmic surgery and catheter ablation. This review will explore how
      cardiac mapping has contributed to our understanding of reentrant ventricular
      tachycardia. The role of diastolic mapping will be emphasised, and the
      implications for future management of ventricular tachycardia discussed.

PMID- 8665964
TI  - Platelet aggregability to platelet activating factor at rest and after exercise
      in patients with coronary artery disease.
AB  - The platelet response to the aggregatory effect of platelet-activating factor
      (PAF) in relation to blood PAF levels, serum PAF-acetylhydrolase (PAF-AH)
      activity and to their lipidaemic profile, was studied in 44 patients with
      coronary artery disease undergoing exercise tests. The PAF EC50 values in 21
      patients with positive exercise test results were found to be significantly
      decreased at rest compared with 21 normal subjects (12.6 +/- 3.9 nM and 24.9 +/-
      11.7 nM respectively) (P<0.0001). Moreover, the maximal percentage of aggregation
      to 50 nM PAF was found to be significantly increased (20.0 +/- 4.3% vs 13.5 +/-
      3.6%, respectively) (P<0.0001). By contrast, the PAF EC50 values and the maximal
      percentage of aggregation in 23 patients with negative exercise test results were
      not statistically significantly different from the control group (25.2 +/- 11.4
      nM and 14.1 +/- 4.7%, respectively). At the end of exercise, the PAF EC50 values
      and the maximal percentage of aggregation did not change in any group, and there
      were no significant differences in the whole-blood PAF levels either at rest or
      at the end of exercise. In patients with positive exercise test results, the PAF
      AH activity at rest was significantly higher compared with the control group
      (37.2 +/- 8.0 nmol.ml(-1).min(-1) vs 32.4 nmol.ml(-1).min(-1), (P<0.03), whereas
      the enzyme activity did not differ in patients with negative exercise test
      results compared to controls (33.6 +/- 6.1 nmol.ml(-1).min(-1)). There was no
      change in PAF-AH activity during exercise in any group. The enzyme activity was
      positively correlated to the serum total and low density lipoprotein (LDL)
      cholesterol levels in the control group and in patients with negative exercise
      test results, whereas no correlation was found between PAF-AH activity and total
      or LDL cholesterol levels in patients with positive exercise test results.

PMID- 8665965
TI  - Renin-angiotensin-aldosterone system, RR-interval and blood pressure variability
      during postural changes after myocardial infarction.
AB  - Low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz) components
      of heart rate variability have been used to evaluate the autonomic nervous
      system. The sympathico-vagal balance as well as the renin-angiotensin-aldosterone
      (RAA) axis are disturbed in the post-acute phase of acute myocardial infarction
      (AMI). This study examined the relationship between the RAA-axis and spectral
      indices of the RR-interval and blood pressure (BP) variabilities during postural
      manoeuvres in the post-AMI period. Power spectral analysis of the RR-interval and
      BP variability was computed from non-invasive beat-to-beat BP measurements 10-12
      days post-AMI, using Fast-Fourier transforms. Concomitantly, hormonal changes of
      the RAA-axis were determined and data were further correlated with the left
      ventricular ejection fraction. When the patient moved from the lying to the
      supine position all RAA-axis parameters significantly increased. Both LF and HF
      components of total RR-interval variability decreased upon standing, while the LF
      component of systolic and diastolic BP variability increased and HF components
      remained constant. In the upright position, plasma renin activity (P<0.01) and
      angiotensin II (borderline) were inversely related with the LF component of
      systolic BP. The aldosterone level was dissociated from plasma renin activity and
      angiotensin II. The left ventricular ejection fraction was inversely correlated
      (P<0.05) with systolic and diastolic BP variabilities and their LF and HF powers.
      These results suggest that the renin-angiotensin II system in the post-acute
      phase of AMI patients treated with aspirin and beta-blocking agents is correlated
      with cardiovascular autoregulation during postural manoeuvres.

PMID- 8665966
TI  - Preservation of myocardial blood flow by calcium antagonists does not prevent
      attenuation of regional myocardial function after repetitive brief periods of
      myocardial ischaemia in the rat heart.
AB  - The aim of this study was to assess the effect of two different calcium channel
      blockers on myocardial blood flow and function in a rat model of myocardial
      'stunning' by repeated short episodes of ischaemia ('repetitive ischaemia'). In
      an open chest rat model, the left anterior descending coronary artery was ligated
      for 10 min followed by 15 min reperfusion. In total, five periods of ischaemia
      and reperfusion were performed. Myocardial blood flow was assessed by the
      hydrogen clearance technique and systolic thickening fraction by pulsed Doppler.
      After five episodes of ischaemia, myocardial blood flow adn myocardial thickening
      in the ischaemic area were reduced by 60 +/- 8% and 52 +/- 7% (n=9),
      respectively, as compared to baseline. Continuous intravenous infusion of the
      calcium channel blockers nifedipine (n=6) and gallopamil (n=6), started 20 min
      prior to onset of ischaemia, attenuated the ischaemia-induced decrease of
      myocardial perfusion. Nifedipine was the most effective with only 5 +/- 2%
      reduction in blood flow after five ischaemic episodes, whereas reduction of
      myocardial blood flow was 30 +/- 4% in the presence of gallopamil. However,
      neither nifedipine nor gallopamil were able to prevent regional ventricular
      dysfunction induced by repetitive ischaemia. Despite the preservation of
      myocardial blood flow following repetitive ischaemia, calcium channel blockers do
      not prevent ischaemia-induced reduction of myocardial function in the ischaemic
      area.

PMID- 8665967
TI  - Evolution of electrocardiographic and echocardiographic abnormalities during the
      4 years following first acute myocardial infarction.
AB  - Therapies aimed at salvaging jeopardized myocardium in patients with acute
      myocardial infarction (MI) are now routine. The success of these therapies must
      often be estimated by non-invasive tests, such as the 12-lead electrocardiogram
      (ECG) or two-dimensional echocardiography. To monitor QRS changes and left
      ventricular (LV) function over time in patients who have received therapies aimed
      at myocardial salvage, it is important to know the 'spontaneous' evolution of
      these estimates. Consecutive MI survivors admitted in the pre-thrombolytic era
      with their first MI were re-studied at 4 years. Patients were excluded if they
      had experienced reinfarction, coronary revascularization or bundle branch block
      in the acute or follow-up period. A standard ECG and a two-dimensional
      echocardiogram were obtained prior to discharge and at follow-up. The
      quantitative ECG analysis was performed according to the Selvester QRS scoring
      method. During the two-dimensional echocardiogram each of the 20 segments of the
      LV were assessed to provide a wall motion score. Eighty patients with a median
      age of 64 years (range 40-79) were included in the study. Thirty-two had anterior
      and 48 inferior MI. A significant decrement in median QRS score-estimated AMI
      size occurred between pre-discharge and follow-up ECGs in the entire group (18.3%
      vs 10.5%; P<0.0001). This difference occurred in both anterior (21.6% vs 10.5%;
      P<0.0001) and inferior-posterior (16.5 vs 10.5%; P<0.0001) MI locations. In the
      anterior MI group ther was a trend towards a greater total decrease of QRS points
      than in the inferior-posterior MI group (42% vs 27%; P=0.10). Within the anterior
      MI group, more QRS points awarded in the anteroseptal leads (V1-V3) remained
      follow-up than in the anterosuperior and apical leads (I, aVL and V4-V6), (80% vs
      49%; P=0,03).

PMID- 8665968
TI  - Enhancing emotional well-being by comprehensive rehabilitation in patients with
      coronary heart disease.
AB  - Since emotional distress is linked to poor prognosis in coronary patients, there
      is urgent need for research into interventions that may enhance emotional well
      being in these patients. Cardiac rehabilitation aims to return the individual to
      optimal emotional function, but the psychological effect of this therapy still
      needs to be demonstrated. Hence, we examined the role of cardiac rehabilitation
      in enhancing emotional health. We examined 170 male patients with coronary heart
      disease, of whom 85 had participated in the outpatient rehabilitation programme
      of the University Hospital of Antwerp and 85 had received standard medical care
      only in two other hospitals. Rehabilitation and control patients were matched by
      medical category and tendency to experience distress. The Global Mood Scale, the
      Health Complaints Scale, and the Heart Patients Psychological Questionnaire were
      used to assess changes in emotional well-being over a 3-month period. These
      changes were significantly different as a function of cardiac rehabilitation
      (P<0.0001). Rehabilitation patients, but not control patients, reported a
      significant improvement in negative affect, positive affect, well-being , health
      and disability (P<0.001). At follow-up, differences in depression, tranquillizer
      use (P<0.05), and activity profile (P<0.01) confirmed that rehabilitation
      patients displayed more healthy behaviour than control patients. Patients not
      only improved more, but also deteriorated less as a function of rehabilitation.
      This therapy also had a positive effect on patients suffering minimal distress,
      which is at variance with previous research. These findings suggest that
      comprehensive rehabilitation may be an effective therapy for enhancing emotional
      well-being in patients with coronary heart disease.

PMID- 8665969
TI  - Balloon aortic valvuloplasty in elderly patients at high risk for surgery, or
      inoperable. Immediate and mid-term results.
AB  - Although aortic valve replacement is undoubtedly the treatment of choice for
      aortic valve stenosis, balloon aortic valvuloplasty may represent the only
      possible treatment for some frail elderly patients who may have additional
      medical problems. We evaluated immediate and 1-year results of balloon aortic
      valvuloplasty in 86 patients > or = 80 years with severe aortic stenosis. Mean
      age was 84 +/- 3 years. Forty-four % were 85 years or older. Mean gradient
      decreased from 68 to 26 mm Hg and valve area increased from 0.53 to 0.96 cm2
      (P<0.05). There were two per-procedural deaths. No local vascular complication
      was observed. During the follow-up (13 +/- 9 months), 27 patients died, four had
      repeat balloon aortic valvuloplasty and eight underwent aortic valve replacement.
      Persistent clinical improvement was observed in 78% of the surviving patients.
      One-year actuarial survival rate was 73%. Balloon aortic valvuloplasty appears to
      be a safe and valuable technique in cases where surgery cannot be performed or
      carries a very high risk.

PMID- 8665970
TI  - Aggressive pattern of angina after successful coronary angioplasty: the role of
      clinical and angiographic factors.
AB  - To assess possible clinical and angiographic factors associated with acute
      coronary events following PTCA, we performed quantitative angiography in 168
      consecutive patients who had undergone successful angioplasty in a native vessel
      (94 for stable angina, 74 for unstable angina), and who were restudied (24 +/- 15
      weeks; range 4 to 52) because of recurrent anginal symptoms. Of the 168 patients,
      38 (Group 1) were restudied because the pattern of angina was aggressive
      (unstable angina in 31, myocardial infarction in 7) and 130 because of effort
      related angina (Group 2). the two patient groups were well matched for extent of
      initial disease but patients in Group 1 were younger (P=0.03). PTCA for unstable
      angina was originally performed more frequently in Group 1 than in Group 2 (27 of
      38 patients (71% vs 47 of 130 patients (36%), P=0.0004). Disease progression in
      non-dilated segments occurred in 10 patients (26%) in Group 1 compared with eight
      (6%) in Group 2 (P=0.0004). Disease progression in non-dilated segments occurred
      in nine patients (24%) in Group 1 and in Group 2 (P=0.0004). Disease progression
      in non-dilated segments occurred in nine patients (24%) in Group 1 and in 10 (8%)
      in Group 2 (P=0.0006). Our conclusion is that patients who require re
      investigation as a result of angina which has become aggressive following PTCA
      are usually those who originally underwent PTCA for unstable angina. These
      patients have a higher incidence of occlusive restenosis or disease progression.

PMID- 8665971
TI  - Percutaneous mitral commissurotomy in the elderly.
AB  - Immediate and mid-term results of percutaneous mitral commissurotomy (PMC) were
      assessed in 75 patients aged > or = 70 years (mean 75 +/- 4 (70 to 86)). Co
      morbidities were present in 30 patients (40%), and 58 patients had calcified
      valves (77%). Technical failure occurred in two patients. PMC was performed in 73
      patients, using a single balloon in five, two balloons in 28, and the Inoue
      balloon in 42. After PMC, valve area increased from 1.0 +/- 0.2 to 1.6 +/- 0.3
      cm2 as assessed by 2D echo (P<0.001). Three procedural deaths occurred (4%). Good
      initial results (valve area > or = 1.5 cm2 with mitral regurgitation < or = 214)
      were obtained in 48 patients (66%). In multivariate analysis, predictors of poor
      initial results were previous commissurotomy (P=0.01) and valve calcification
      (P=0.04). Mean follow-up was 24 +/- 18 months. The 4-year actuarial results were:
      survival in 59 +/- 18%; no need for operation in 59 +/- 18%; and persistent good
      functional results (NYHA class I or II) in 34 +/- 16%. The only predictor of mid
      term good functional results was the quality of initial results (P<0.002). In
      conclusion, PMC in the elderly results in moderate but significant improvement in
      valve function at an acceptable risk; although subsequent functional
      deterioration is frequent. PMC is a useful although only palliative treatment in
      these patients.

PMID- 8665972
TI  - Sympathetic predominance followed by functional denervation in the progression of
      chronic heart failure.
AB  - Using spectral analysis of heart rate and systolic arterial pressure
      variabilities, the study was set up to evaluate cardiovascular efferent autonomic
      modulation in patients with different degrees of chronic heart failure. We
      studied 30 patients with stable chronic heart failure and 15 controls of similar
      age. ECG, arterial blood pressure and respiratory signal were recorded at rest,
      during controlled respiration and during passive head-up tilting. R-R interval
      periods of 256-512 were analysed. Routine 2D echocardiogram and Doppler studies
      were also carried out. As expected, we found a decrease in the mean and variance
      of R-R intervals in patients with sever heart failure. In New York Heart
      Association (NYHA) class II patients, the power spectral pattern of R-R
      variability was characterized by the predominance of the low frequency component
      (72 +/- 3 nu), considered a marker of sympathetic activity, and by its
      unresponsiveness to tilting. Patients in NYHA class III also presented blunted
      changes in spectral components during tilting. A drastic decrease in the variance
      of R-R intervals (191 +/- 58 vs 1056 +/- 149 ms2 in controls) and an almost
      complete absence of the low frequency spectral component (8 +/- 3 nu) were
      present in patients in NYHA class IV. Controlled respiration, which in normal
      subjects decreased the low frequency component, induced changes that blunted
      progressively as heart failure increased. These data suggest that autonomic
      neural modulation and cardiovascular response to neural activity differ at
      different stages of the disease.

PMID- 8665973
TI  - Correlations of antimyosin accumulation and histological manifestation of myocyte
      necrosis at different stages of idiopathic cardiomyopathy.
AB  - Although antimyosin uptake has been demonstrated in idiopathic cardiomyopathy,
      discrepancies between antimyosin positivity and histological examinations using
      biopsy speciments have been found. In order to investigate the correlations
      between antimyosin localization and histopathological alterations, the magnitude
      and distribution of antimyosin uptake were quantitatively assessed in aged
      matched control (F1b) and hereditary idiopathic cardiomyopathy (Bio 14.6)
      hamsters at three different ages. In these studies, gamma counting and
      macroautoradiography were compared with histological alterations. Myocardial
      activities and percent areas of antimyosin uptake were significantly (P<0.05)
      greater in 10-, 20-, and 30-week old Bio groups than in their respective control
      groups. Autoradiograms showed that antimyosin antibody was relatively localized,
      massive, and scattered in 10-week-old, 20-week-old and 30-week-old Bio hamsters,
      respectively. Histopathology demonstrated antimyosin positivity not only in
      necrotic myocytes and accompanying calcium deposits but also in tissues showing
      inflammatory reactions but no histologically identifiable myocyte necrosis. In
      conclusion, antimyosin uptake seen in tissues with age-related disease processes
      did not necessarily correspond to histologically verified myocyte necrosis in the
      cardiomyopathy hearts, suggesting that antimyosin positivity reflects myocytes
      which show impaired sarcolemmal integrity but have not yet undergone myolysis.

PMID- 8665974
TI  - Objective features of the surface electrocardiogram during ventricular
      tachyarrhythmias.
AB  - The aim of this study was to quantify the electrocardiographic signal
      characteristics of three types of ventricular arrhythmia; monomorphic ventricular
      tachycardia, polymorphic ventricular tachycardia and ventricular fibrillation.
      Patients in a coronary care unit were monitored using a single bipolar ECG lead.
      Thirty episodes of ventricular tachyarrhythmia (ten from each group) were
      recorded automatically by computer. Frequency analysis of ten consecutive 1 s
      epochs from each recording gave 100 spectra for each tachyarrhythmia group. Each
      spectrum was characterised by the frequency, there were significant differences
      in all characteristics between the tachyarrhythmia groups (P<0.025). Ventricular
      fibrillation had a higher mean dominant frequency (4.8 Hz) than polymorphic
      ventricular tachycardia (3.7 Hz) and monomorphic ventricular tachycardia (3.8
      Hz). The dominant frequency of ventricular fibrillation was also more variable
      than that of monomorphic ventricular tachycardia (P<0.01). Mean peak size was
      largest for monomorphic ventricular tachycardia (0.78) and smallest for
      ventricular fibrillation (0.64). The single spectral peaks seen throughout this
      study indicate that all three tachyarrhythmias have an underlying periodic
      mechanism. The differences in spectral characteristics show that varying degrees
      of myocardial electrical organisation can be quantified from surface ECG
      features.

PMID- 8665975
TI  - Effects of lisinopril vs hydralazine on left ventricular hypertrophy and
      ambulatory blood pressure monitoring in essential hypertension.
AB  - In order to compare the long-term effects on ambulatory blood pressure and left
      ventricular hypertrophy of hydralazine and lisinopril we studied 30 patients, all
      males, still hypertensive (diastolic blood pressure > or = 95 mm Hg) despite
      combined beta-blocker/diuretic therapy and with echocardiographic evidence of
      left ventricular hypertrophy (left ventricular mass index > or = 1.31 g.m(-1)).
      They wer randomized to receive hydralazine slow release 50 mg/ chlorthalidone
      12.5 mg) for 6 months. Casual blood pressure, non-invasive ambulatory blood
      pressure monitoring (ABPM), M-mode echocardiogram, plasma renin activity and
      plasma catecholamines were evaluated before the randomization and after 6 months
      of treatment. Both drugs significantly reduced casual as well as daytime systolic
      and diastolic blood pressure, without statistical differences between the two
      treatments. Lisinopril was significantly more effective than hydralazine in
      reducing night-time systolic and diastolic blood pressure. Plasma norepinephrine
      was significantly reduced by lisinopril and increased by hydralazine. Left
      ventricular mass was significantly reduced by lisinopril but not by hydralazine.
      The results of linear regression and multiple regression analysis suggested that
      the lisinopril-induced decrease in both day- and night-time blood pressure might
      account for the regression of left ventricular hypertrophy, whereas the lack of
      left ventricular hypertrophy regression during hydralazine treatment could be due
      mainly to the reflex sympathetic activation induced by the drug.

PMID- 8665976
TI  - The diagnostic and prognostic value of adenosine deaminase in tuberculous
      pericarditis.
AB  - Because of the difficulty in isolating the causative organism, pericardial
      tuberculosis is rarely diagnosed. Adenosine deaminase activity measured in the
      pericardial fluid of 108 patients was initially of undetermined origin.
      Subsequently, we classified five sources: (1) tuberculosis (20 cases); (2)
      idiopathy (82 cases); (3) neoplasia (three cases); (4) purulent bacterial
      infection (two cases); and (5) radiotherapy (one case). The highest mean
      adenosine deaminase value (126 +/- 16.68 U.l(-1) was found in group 1; other
      values were 29.4 +/- 8.9, 27 +/- 7.21, 29.5 +/- 13.4, 26 U.l(-1) in the
      idiopathy, neoplasia, purulent bacterial infection and radiotherapy groups,
      respectively. there was a statistically significant difference between group 1
      and the other groups (P less than 0.001), indicating that the adenosine deaminase
      value has 100% sensitivity and 91% specificity. In addition, there was a positive
      correlation between high adenosine deaminase values and the development of
      constrictive pericarditis. In this study, two patients required pericardectomy.
      Therefore, the adenosine deaminase value is a significant prognostic indicator
      for the development of constrictive pericarditis in tuberculous pericarditis.

PMID- 8665977
TI  - Effects of systolic anterior motion of the mitral valve on haemodynamics.
      Evaluation by a direct method.
AB  - We evaluated the effects of systolic anterior motion systolic anterior motion of
      the mitral valve on cardiac haemodynamics. Seven adult mongrel dogs in which
      systolic anterior motion-septal contact was observed after dobutamine
      administration were used. To exclude the effects of left ventricular function and
      morphology, a stone removal basket catheter was placed in the left ventricular
      outflow tract, and haemodynamics were compared with the basket closed and opened.
      The basket was opened five times in three dogs not showing systolic anterior
      motion-septal contact, but the basket itself did not effect the haemodynamics. In
      the seven dogs that showed systolic anterior motion-septal contact without left
      ventricular hypertrophy, the basket was opened a total of 33 times in the
      presence of various degrees of systolic anterior motion-septal contact. After
      opening the basket, systolic anterior motion was reduced echocardiographically,
      and significant (P<0.01) changes were observed in the left ventricle-aorta
      pressure gradient (from 68 +/- 22 to 25 +/- 15 mm Hg), the systolic ejection
      period (from 146 +/- 19 to 135 +/- 16 ms), and the stroke volume (SV; from 9.4 +/
      2.9 to 10.1 +/- 3.3 ml). After basket inflation, aortic pressure and aortic flow
      waveforms changed but the peak pressure and flow velocity did not. The temporal
      distribution of left ventricular ejection also definitely changed after the
      basket was opened. No changes were observed in the peak dp/dt, peak negative
      dp/dt, time constant, left ventricular end-diastolic pressure, or left atrial
      pressure. These observations in this animal model of systolic anterior motion
      without left ventricular hypertrophy suggest that: (1) there is no potential for
      generation of an intra-cavity gradient in the absence of systolic anterior motion
      of the mitral valve, so that (2) systolic anterior motion narrowed the left
      ventricular outflow tract and, consequently, produced the systolic ejection
      period, and affected the left ventricular ejection dynamics, and that (3) the
      basket catheter is useful because it allows these assessments in the same heart
      with a nearly fixed left ventricular contractility, at least in our animal model.

PMID- 8665978
TI  - Microvascular incompetence and the failure of hearts to recover contractile
      function after cardioplegia.
AB  - The relationship between the development of microvascular incompetence and the
      loss of potential for functional recovery following cardioplegia was investigated
      using St. Thomas' Hospital No. 2 solution (STH) in isolated working rat hearts.
      Cardiac function was measured prior to cardioplegia and again after 30 min of
      reperfusion at 37 degrees C following 1, 2 or 4 h arrest at 30 degrees C (n=5).
      The hearts were then fixed by perfusion with 2.5% glutaraldehyde and then nuclear
      track emulsion was perfused as an intravascular marker of competent capillaries.
      Following cardioplegia for 1 h hearts showed 95.4% recovery of aortic flow in the
      working mode, and a high proportion of the capillaries in the subendocardial
      (84.6 +/- 2.3%), middle (94.6 +/- 3.0%) and subepicardial (89.1 +/- 4.9%) thirds
      of the left ventricular myocardium transmitted perfusate. Two hours arrest
      resulted in significantly diminished recovery of left ventricular function
      (aortic flow: 56.6 +/- 7.6% and aortic pressure: 64.4 +/- 2.5% and heart rate
      56.0 +/- 23.1%). This loss of the remaining two thirds of the potential for
      functional recovery was associated with significant (P<0.02) reductions in the
      proportions of competent capillaries (subendocardial, middle and subepicardial
      thirds to 10.9%, 19.2% and 14.2%, respectively). These non-functional capillaries
      had open lumina and showed no sign of structural alteration, obstruction or
      compression, although some focal collections of myocytes (<30%) showed evidence
      of reperfusion damage including contraction band necrosis. Despite reductions in
      microvascular competence overall, coronary flow rates (non-working) did not
      decline, suggesting shunting via large arterio-venous channels. It seems likely
      that the loss of the first third of the potential for rapid functional recovery
      following cardioplegia is due to loss of high energy phosphates, whereas the loss
      of the remaining two-thirds is associated with endothelial cell mediated
      constriction of small arterial vessels which produces the capillary incompetence
      demonstrated in this study.

PMID- 8665979
TI  - Coil embolization of a coronary fistula in a post-transplant patient.
AB  - A 23-year-old man 6 months after post-orthotopic heart transplant was troubled by
      fatigue and breathlessness and noted to have a continuous murmur. Coronary
      angiography revealed five fistulae from the left anterior descending artery
      draining into the right ventricle. The left-to-right shunt was obliterated by
      coil embolization and this was associated with improvement in the patient's
      symptoms and a reduction in the murmur.

PMID- 8665980
TI  - Silent healing of spontaneous plaque disruption demonstrated by intracoronary
      ultrasound.
AB  - Intracoronary ultrasound was performed at diagnostic coronary angiography and 10
      days later in a 45-year-old patient with a 3-day history of acute inferior
      myocardial infarction. Coronary angiography showed considerable stenosis (80%) in
      the distal right coronary artery (RCA) (pre the crux) and what appeared to be a
      dissection in the middle RCA. Intracoronary ultrasound identified this as plaque
      disruption. Coronary balloon angioplasty was then performed in the distal
      stenotic segment. Follow-up angiography 10 days after coronary intervention
      revealed that the flap in the lumen had disappeared. Intracoronary ultrasound
      imaging showed that the ruptured plaque had resealed and had the appearance of
      layering in the atheroma similar to thrombus formation. In summary, plaque
      disruption and subsequent thrombus formation can be demonstrated in vivo by
      intracoronary ultrasound. Monitoring this process may have important clinical
      significance in patient management and in assessing clinical prognosis.

PMID- 8665981
TI  - Acute aortic regurgitation caused by non-bacterial thrombotic endocarditis.
AB  - A case of non-bacterial thrombotic endocarditis, which caused acute aortic
      regurgitation in a middle-aged, otherwise healthy woman, is presented. The
      diagnosis was confirmed with echocardiography and documented by a
      histopathological study of the excised aortic valve after operation for valve
      replacement.

PMID- 8665982
TI  - Adult onset Kawasaki disease diagnosed by the echocardiographic demonstration of
      coronary aneurysms.
AB  - A 17-year-old boy presented with fever, bilateral conjunctival infection, angina
      and extensive cervical adenopathy. Amoxycillin was started. Ten days later he was
      admitted to hospital because of persistent high fever, cervical adenopathy,
      erythema of the pharynx and tongue and lip fissuration. The most important
      interventions of his first hospitalization were endotracheal intubation because
      of increasing dyspnoea due to adult respiratory distress syndrome and
      haemodialysis for renal insufficiency. His admission to our hospital was marked
      by the echocardiographic discovery of giant coronary aneurysms in the first few
      centimeters of both right and left coronary arteries. Coronary angiography
      confirmed giant aneurysm formation of the right and left coronary arteries.
      Similarly, medium sized arteries (cerebral, hepatic, mesenteric, iliac) presented
      abnormalities and laboratory findings. This is the first description of adult
      onset Kawasaki disease with giant coronary aneurysm formation and more
      generalized arterial involvement. The severity of the clinical symptoms and the
      severity of the coronary disease indicates that Kawasaki disease of the adult
      does not always have a benign course.

PMID- 8665983
TI  - Disappearing left atrial vegetation in an intravenous drug abuser.
AB  - Isolated left atrial mural endocarditis is rare. We report a case where the
      diagnosis was made clinically and supported by blood cultures and
      transoesophageal echocardiography. Appropriate intravenous antibiotics were
      administered and serial transoesophageal echocardiograms helped in monitoring the
      decrease in size and final disappearance of the vegetation, thus avoiding the
      need for surgical intervention.

PMID- 8665984
TI  - Modifications with aging in the role played by vision and proprioception for
      movement control.
AB  - Young and older adults performed manual aiming movements to a visible target for
      either 40 or 200 trials. Under each level of practice, half of the subjects
      practiced the task under normal visual conditions (proprioception + vision [PV]
      condition), whereas the other half were not permitted to see their ongoing
      movement toward the target (proprioception-only [P] condition). Each acquisition
      trial was followed with knowledge of results (KR). After the last acquisition
      trial, all subjects were transferred to a common task in which only the target to
      be reached was visually available, with no KR. During acquisition, the younger
      subjects were found to be spatially more accurate than their older counterparts,
      and this was so regardless of the number of acquisition trials. Withdrawing KR
      during the transfer test did not modify the spatial accuracy of the subjects who
      had trained under the P condition. This indicates that the subjects had a
      reliable reference of the movement to be realized. Withdrawing vision of the
      moving hand and KR in the transfer test caused a significant increase in spatial
      error for both the older and the younger subjects. However, the increase in error
      was less pronounced for the older than for the younger subjects. In fact, the
      older subjects performed as well in the transfer test as the subjects who had
      trained in the P condition. This pattern of results suggests that in the transfer
      test, the older subjects could still guide their movements with the
      proprioceptive information that was available during both acquisition and
      transfer. However, such was not the case for the younger subjects. This suggests
      that, unlike the younger subjects, the older subjects could still rely on the
      proprioceptive cues available during acquisition in the PV condition. These
      results are taken to indicate that practicing with numerous sources of afferent
      information, as was the case in the PV condition, resulted in an integrated
      reference store for the younger subjects. In contrast, while practicing the task
      in the PV condition, the older subjects appeared to process independently from
      each other the different sources of sensory information available.

PMID- 8665985
TI  - Food identification, taste complaints, and depression in younger and older
      adults.
AB  - The relationships among the ability to identify food stimuli, self-assessed taste
      complaints and taste acuity, and depression were examined in younger and older
      adults. Subjects smelled, tasted, and subsequently identified 10 pureed foods
      while blindfolded. Subjects also completed a demographic questionnaire, the Beck
      Depression Inventory, and the Wechsler Adult Intelligence Scale-Revised
      Vocabulary subtest. Although an age difference in taste complaints was not found,
      older adults were poorer at identifying food items, rated their taste acuity as
      lower, and had higher depression scores than the younger adults. However, the age
      difference in identifying food items was not due to the age difference in
      depression, because depression was unrelated to food identification scores for
      both age groups.

PMID- 8665986
TI  - Approaches to the nonparametric analysis of limited longitudinal data sets.
AB  - The traditional goals of longitudinal studies are many: consideration of
      stability and change; description of patterns of development and behavior; and
      understanding of the processes involved in disease, including disease onset,
      recovery, response to treatment, natural history of the aging process, and
      identification of factors that predict age-related outcomes. Researchers in aging
      seek to unravel the impact and interaction of physical and psychological
      processes on human development, health, and disease. From the point of view of
      statistical analysis, the critical aspect of data obtained from longitudinal
      studies is the inherent correlational structure of multiple measurements made on
      a single subject or other experimental unit, which must be appropriately treated
      in the analysis of the data. We discuss a series of nonparametric approaches that
      are both analytically accessible and particularly well suited to the analysis of
      sparse or otherwise limited longitudinal data.

PMID- 8665987
TI  - Memory performance in relation to age, verbal ability, and activity.
AB  - Young and old adults completed a vocabulary test, the Activities Frequency
      Inventory (AFI), the Activity Preference Scale (APS), and memory tests that
      sampled six domains of everyday memory. The young adults' memory performance was
      significantly higher than the old adults'. Memory was better for the high-APS
      young than for the low-APS young and for the high-AFI old than for the low-AFI
      old. However, the age gap in memory performance was not closed when a subsample
      of active elderly was compared with a subsample of inactive young. Also, in
      regression analyses, neither activity measure added significantly to the
      vocabulary measure in predicting memory performance for either age group.

PMID- 8665988
TI  - Age-related impairment in instrumental conditioning is restricted to initial
      acquisition.
AB  - Performance on a variety of cognitive tasks has been reported to decline across
      the life span. The present research evaluated appetitive instrumental learning in
      young and mature rats. In Experiment 1, subjects were trained to criterion,
      placed on extinction training to criterion, and subsequently retrained for a
      total of three cycles. Results indicated that mature animals were impaired in the
      initial acquisition of the bar-press response but reacquired the response as
      quickly as young animals. Resistance to extinction was not significantly impaired
      in the mature group, both groups increased resistance by the third extinction
      period, despite the brevity of reinforcement. In Experiment 2, young and mature
      subjects underwent appetitive instrumental training that continued beyond the
      acquisition criterion for the first experiment. After the response had been
      established (to criterion), performance levels were equivalent for young and
      mature subjects. The number of responses were not significantly different between
      young and mature groups on the day criterion was met; comparison of number of
      responses for 4 days after criterion also indicated no significant differences
      over days of training or between age groups. Examination of the number of
      responses occurring early in training indicated no significant group difference;
      hence, the earlier acquisition by young animals in Experiment 1 does not appear
      to reflect greater activity level in younger animals resulting in earlier and
      greater exposure to reinforced responses. Results may reflect the contribution of
      use-induced plasticity, such as long-term potentiation, within brain systems
      involved in learning and memory. These findings are consistent with evidence of
      the effects of use and disuse on neurobiological and cognitive function.

PMID- 8665989
TI  - Factors that influence metaphor comprehension skills in adulthood.
AB  - We investigated differences between older and younger adults in interpreting
      metaphors describing emotions (e.g., "Joe was crashing thunder," meaning that he
      was angry). Subjects selected emotional interpretations and explained the basis
      of their selection for 12 metaphors. Twenty-four older and 24 younger adults read
      metaphors that described emotions. The group performed identically when selecting
      interpretations, but older adults were more likely to make up stories about the
      person named in the metaphor to explain the metaphor than were younger adults,
      who focused on attributes of the metaphoric terms. These findings suggest that
      observed adult age differences in metaphor comprehension reflect methodological
      factors and may reflect cognitive style differences.

PMID- 8665990
TI  - The effects of age on guided conjunction search.
AB  - The effect of age on top-down guidance in visual search for conjunctions of form
      and motion was examined with a task developed by Driver et al. (1992). Young
      (mean age = 19.2 years) and old (mean age = 77.3 years) adults searched for a
      vertically oscillating X among varying numbers of vertically oscillating Os and
      horizontally oscillating Xs. The ease with which subjects could use top-down
      guidance to improve search efficiency was manipulated by varying the motion
      coherence of display items. Overall, older adults produced steeper response-time
      display-size slopes than did young adults, and both age groups showed significant
      reductions in slopes when distractors oscillated coherently. Older adults,
      however, produced proportionally smaller reductions in slope than did younger
      adults, suggesting that age affects the efficiency of top-down guidance in
      conjunction search for form and motion.

PMID- 8665991
TI  - Clinical equivalence of two tablet formulations of felodipine. A placebo
      controlled study of 24-hour blood pressure control and tolerability.
AB  - OBJECTIVE: This study was performed to assess whether a new formulation of
      felodipine extended release (FER) tablets with a 9 mm diameter is similar to the
      presently used 11 mm diameter FER formulation with respect to antihypertensive
      effect and tolerability in patients with essential hypertension. A randomised,
      double-blind, placebo controlled, three-way cross-over study design was used.
      PATIENTS: Twenty-four patients with a supine diastolic blood pressure (DBP) of 95
      115 mmHg after a 4-week placebo run-in period were given FER 5 mg 9 mm tablets,
      FER 5 mg 11 mm tablets and placebo in randomised order. The tablets were given
      once daily and each double-blind treatment period lasted for two weeks. METHODS:
      Twenty-four hour ambulatory blood pressure monitoring was performed at the end of
      each treatment period. The primary effect variable was mean DBP over 24 hours.
      Nineteen patients had 24-hour blood pressure data valid for analysis using an
      analysis of variance with patient, treatment, period and carry-over as factors.
      RESULTS: Both formulations of FER 5 mg tablets significantly reduced the mean 24
      hour DBP compared to placebo. The 9 and 11 mm tablets resulted in, on average,
      4.7 and 3.4 mmHg lower mean 24-hour DBP than placebo. There was, however, no
      significant difference between the two different FER formulations. Both FER
      formulations were well tolerated and similar to placebo in this respect.
      CONCLUSION: Both FER 5 mg tablet formulations (9 and 11 mm diameter), given once
      daily, were clinically equivalent with respect to antihypertensive effect and
      tolerability in patients with mild to moderate essential hypertension.

PMID- 8665992
TI  - Polymorphic inhibition of human angiotensin I-converting enzyme by enalaprilat.
AB  - Many individuals possess an allele of the angiotensin I-converting enzyme (ACE)
      gene, which contains an extra 287-kb fragment in intron 16 (Rigat et al. 1992).
      Although the functionality of this fragment is at present unclear, the absence
      (deletion, D) or presence (insertion, I) of this fragment appears to be related
      to both the amount and activity of circulating ACE. This paper reports the
      possible polymorphic response of ACE to the ACE inhibitor enalaprilat in 54
      normal Chinese subjects that is independent of the I/D polymorphism. The kinetics
      of ACE inhibition with enalaprilat was studied in serum from 54 normal Chinese
      subjects. Enalaprilat appKi ranged between 0.46 and 2.16 nM. An antimode was
      observed at 1.4 nM. Four subjects could be characterized as being poor responders
      to enalaprilat.

PMID- 8665993
TI  - The dihydropyridine calcium channel blocker BAY t 7207 attenuates the exercise
      induced increase in plasma ANF and cyclic GMP in patients with mildly impaired
      left ventricular function.
AB  - In man, chronic antihypertensive calcium antagonist treatment improves cardiac
      function and reduces plasma ANF concentrations. Physical exercise increases
      cardiac workload and plasma ANF levels. In the present study, we investigated the
      effects of acute administration of the dihydropyridine calcium antagonist BAY t
      7207 (BAY) during bicycle exercise on plasma ANF and plasma cyclic GMP levels, on
      mean arterial pressure (MAP), heart rate (HR), and on natriuresis and urinary
      urodilatin excretion. In a randomized, double-blind placebo controlled cross-over
      trial, 8 patients (age 56.8 +/- 2.5 y) with documented coronary artery disease
      and mildly impaired left ventricular function (EF 50.0 +/- 1.3%), received oral
      BAY (20 mg) or placebo. Forty-five minutes after medication, patients underwent a
      standardised exercise bicycle test in the supine position (6 min 25 W, 6 min 50
      W). Before exercise, MAP was lower after BAY (88.8 +/- 4.1 mmHg) than after
      placebo (95.7 +/- 3.5 mmHg; p = 0.024), and HR was higher after BAY (76.8 +/- 3.5
      bpm) than after placebo (69.5 +/- 3.6 bpm; p = 0.049). Plasma ANF tended to be
      higher after BAY (31.2 +/- 5.6 pg/ml) than after placebo (26.7 +/- 5.0 pg/ml),
      and plasma cGMP was not different (BAY 3.4 +/- 0.3, placebo 3.8 +/- 0.3 pmol/ml).
      During exercise, the relative increases in HR (+43%) and MAP (+17%) were
      identical after BAY and placebo. In contrast, ANF levels during exercise
      increased by 130 +/- 28% after placebo but only by 36 +/- 11% after BAY (p =
      0.011). In parallel, plasma cyclic GMP increased by 61 +/- 13% after placebo and
      by 20 +/- 8% after BAY (p = 0.013). At the end of exercise, the BAY-induced
      reduction in plasma cyclic GMP reflected the reduction in diastolic arterial
      pressure (r = 0.717; p = 0.045). Compared to placebo, BAY treatment increased the
      fractional excretion rate of sodium from 0.46 +/- 0.11 to 0.90 +/- 0.22% (p =
      0.016), without relation to urinary urodilatin excretion. Thus, the calcium
      antagonist BAY t 7207 attenuated the exercise-induced increase in plasma ANF and
      cyclic GMP probably due to its vasodilator effect. The relationship between blood
      pressure and the ANF system during exercise, which parallels findings during
      chronic antihypertensive treatment, may open a perspective for early evaluation
      of long-term therapy with calcium channel blockers.

PMID- 8665995
TI  - Renal and endocrine effects of flosulide, after single and repeated
      administration to healthy volunteers.
AB  - Two double-blind, placebo-controlled, balanced cross-over studies were carried
      out successively in 8 male normotensive volunteers to investigate the acute and
      chronic effects of two doses of a novel non-steroidal anti-inflammatory drug
      flosulide (5 mg b.d. and 25 mg b.d.), on the renin-angiotensin-aldosterone
      system, linking this to changes in the urinary excretion of prostaglandins.
      Plasma renin and aldosterone were determined on Days 2 and 9, with the subject
      supine, after 1 h of rest in the sitting position following 1 h of walking, and 3
      h after oral intake of 40 mg furosemide, also in the sitting position. Twenty
      four hour urine samples were collected on Days 1 and 8 for the measurement of the
      electrolytes, aldosterone pH1 and the urinary prostaglandins PGE2, PGF2 alpha, 6
      keto-PGF1 alpha and TxB2. RESULTS: After the first day of treatment with 25 mg
      b.d. flosulide, the increase in body weight was close to significance (0.86 vs 
      0.08 kg with placebo). A dose- and time-dependent decrease in both active and
      inactive plasma renin were observed, whereas the fall in plasma and urinary
      aldosterone was statistically significant only after the higher dose of
      flosulide. These changes in the renin-angiotensin-aldosterone system were
      observed in the absence of oedema. Two out of eight volunteers experienced a
      strong and immediate reduction in the excretion of prostaglandins but overall the
      two doses tested did not produce a statistically significant inhibition in renal
      prostaglandins, especially following repeated dosing. The inhibitory effect of
      flosulide on renal prostaglandin synthesis was found to be less pronounced after
      repeated treatment, as documented on Day 9 by the lower inhibition of 6-keto-PGF1
      alpha and TxB2. CONCLUSION: These two studies in normal volunteers, in spite of
      some methodological limitations, were helpful in order to select doses of
      flosulide which should be effective and safe in patients during Phase II trials,
      by examining the inhibitory effect of the drug on renin synthesis and renal
      prostaglandin synthesis.

PMID- 8665994
TI  - Acute effects of the anxiolytics suriclone and alprazolam on cognitive
      information processing utilizing topographic mapping of event-related brain
      potentials (P300) in healthy subjects.
AB  - In a double-blind, placebo-controlled, cross-over study, acute effects of
      suriclone--a cyclopyrrolone derivative--were investigated by means of topographic
      mapping of event-related potentials (ERPs). Fifteen normal volunteers, aged 22-35
      years, received randomized, oral single doses of placebo, 0.1 mg, 0.2 mg and 0.4
      mg suriclone and 1 mg alprazolam as a reference compound. ERPs were investigated
      in an auditory oddball paradigm before and 3 h after intake of each drug. In
      addition to 17 EEG leads, vertical and horizontal electro-oculograms (EOGs) were
      recorded. After EOG minimization and artifact identification, the peak latencies
      of the spatial average were determined by an automatic procedure. Compared to
      placebo, no significant effects of the low and middle doses of suriclone on N1
      amplitude were observed; the highest dosage reduced N1 amplitude, as did 1 mg
      alprazolam to an even greater extent. While no consistent effects on P2 amplitude
      were observed after suriclone, alprazolam reduced P2 amplitude. P300 amplitude
      was reduced only after the highest dosage of suriclone, but much more so after
      alprazolam. P300 latency was not affected significantly by suriclone, but a
      marked prolongation of P300 latency was observed after 1 mg alprazolam.
      Concerning N1 and P2 effects, alprazolam, but not suriclone, may have an
      inhibitory influence on stimulus-induced cortical arousal. Concerning P300
      effects, the used doses of suriclone were superior to 1 mg alprazolam, which
      seemed to have reduced cognitive information processing capacity and prolonged
      stimulus evaluation time. Self-rated well-being (adjective checklist) showed
      subtle beneficial effects after 0.1 mg and 0.2 mg, but marked sedative effects
      after both 0.4 mg suriclone and 1 mg alprazolam.

PMID- 8665996
TI  - Relationship of changes in felodipine pharmacokinetics to haemodynamics during
      chronic oral treatment of congestive heart failure patients.
AB  - In congestive heart failure patients the kinetics of felodipine, a
      dihydropyridine calcium antagonist, show interpatient differences after acute
      i.v. administration that disappear after 8 weeks oral treatment with a change in
      kinetics in the patients with the largest clearances (CL) and the smallest
      volumes of distribution (Vss). Pharmacokinetic and haemodynamic data were
      combined to construct a haemodynamic-pharmacokinetic model. This model shows that
      the differences between the patients in i.v. pharmacokinetics are consistent with
      a difference in plasma flow distribution between liver and poorly perfused
      tissues. In patients in whom kinetics changed, felodipine treatment is supposed
      to cause a redistribution of flow from liver to peripheral tissues, accompanied
      by a decreased work load of the heart and a larger increase in VO2max during
      therapy than in the other patients, whose workload increased. This suggests a
      better therapeutic response in the patients whose kinetics changed. As change in
      kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL
      or even indocyanine CL might be predictive for the therapeutic effect of
      felodipine.

PMID- 8665997
TI  - 4-methylpyrazole monitoring during haemodialysis of ethylene glycol intoxicated
      patients.
AB  - 4-methylpyrazole (4-MP) was administered IV during haemodialysis of two ethylene
      glycol-intoxicated patients with anuric renal failure. The plasma 4-MP
      concentration decreased after each pass through the dialyser, indicating its
      dialysability in humans. In these two cases, the extraction coefficient was 0.78
      and 0.71, and the mean dialysance was calculated to be 137 and 117 ml.min-1,
      corresponding to a 4-MP removal rate of 83 and 50 mg.h-1, respectively. The
      results imply that a higher rate of 4-MP infusion would be needed to replace 4-MP
      lost due to metabolism and to haemodialysis. The treatment of two ethylene glycol
      poisoned patients who were haemodialysed raised the problem of the dialysance of
      4-MP. A recent study in pigs indicated that the amount of 4-MP removed by
      haemodialysis was significant [8]. No data were available for man. The aim of the
      study was to evaluate the dialysability of 4-MP in the two intoxicated patients,
      and to estimate how to compensate for 4-MP elimination during haemodialysis.

PMID- 8665998
TI  - Disposition and uric acid lowering effect of oxipurinol: comparison of different
      oxipurinol formulations and allopurinol in healthy individuals.
AB  - We have investigated the disposition and plasma uric acid lowering effect of
      oxipurinol in ten healthy individuals following oral administration of three
      different formulations of oxipurinol and of allopurinol in equimolar doses. The
      reduction of plasma uric acid was clearcut up to 48 h. As estimated from plasma
      AUC0-infinity, Cmax, tmax, tlag, and urinary drug excretion, a conventional rapid
      release preparation of oxipurinol sodium was clearly superior to oxipurinol as
      free acid and to enteric coated microtablets of oxipurinol sodium. Plasma
      oxipurinol concentrations following a single dose of the conventional formulation
      of oxipurinol sodium were approximately 25% lower than those observed after an
      equimolar dose (300 mg) of allopurinol, but mean Cmax reached the value reported
      to be necessary for 90% inhibition of xanthine oxidase. Since prolonged
      administration will result in accumulation of oxipurinol because of its slow
      elimination, this type of oxipurinol formulation can be expected to meet the
      therapeutic requirements for a drug to lower plasma uric acid.

PMID- 8665999
TI  - Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects
      and in subjects with renal or hepatic impairment.
AB  - The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites
      hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in
      12 healthy younger subjects < or = 55 years of age (YNG), 12 elderly subjects >
      or = 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis
      (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20-60 ml.min-1.
      The study was of parallel group design, with each of the four subject groups
      receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1
      week intervals. Serial blood samples for pharmacokinetic analysis were collected
      for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and
      mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone
      were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were
      generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP
      plasma levels were about 1/3 and < 1/10 those of NEF, respectively. There were no
      apparent gender-related pharmacokinetic differences in any group of subjects. NEF
      and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a
      superproportional increase in AUC and an increase in t1/2 with increasing dose
      was obtained, indicative of nonlinear pharmacokinetics. Relative to normal
      subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to
      NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with
      moderate renal impairment did not. Elderly and cirrhotic patients may require
      lower doses of NEF to achieve and maintain therapeutic effectiveness.

PMID- 8666001
TI  - Pharmacokinetic characteristics and tolerability of a novel intravenous
      immunoglobulin preparation.
AB  - In two independent trials 10 and 12 healthy volunteers received the novel
      intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively.
      BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are
      immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody
      against hepatitis B surface antigen (anti-HBs).ml-1. In trial I volunteers
      received 4.0 ml/kg (n = 4) and 8.0 ml.kg-1 (n = 6) BT 511 to study the
      tolerability and the magnitude of the increase in immunoglobulins in plasma as
      well as their decline over 1 month. After administration of the lower dose,
      plasma IgG increased from 10.7 to 14.7 g.l-1 directly after the infusion.
      Following the 8.0 ml.kg-1 dose a more pronounced increase from 12.4 to 21.2 g.l-1
      was observed. No adverse events occurred. After 1 month IgG concentrations had
      almost reached baseline values at 12.2 g.l-1 in the 4.0 ml.kg-1 group, but were
      still significantly increased at 15.2 g.l-1 after the high dose. There was a
      linear correlation between the maximal IgG plasma concentration and the
      subsequent decline of IgG during the 29-day observation period. After
      administration of BT 507 maximal anti-HBs concentrations of 1778 mU.ml-1 occurred
      1.4 h after termination of the infusion. The terminal elimination half-life was
      22.4 days, and total clearance and volume of distribution were determined to be
      0.122 ml.min-1 and 5.41, respectively. The pharmacokinetic parameters calculated
      for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic
      behaviour of native IgG.

PMID- 8666000
TI  - Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired
      renal function.
AB  - The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites
      hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in
      subjects with normal and impaired renal function. PATIENTS: The Study was of
      parallel group design which included 7 subjects with normal (NOR) renal function,
      CLCR > or = 72 ml.min-1 x 1.73 m-2, 6 with moderate (MOD) renal impairment, CLCR
      31-60 ml.min-1 x 1.73 m-2 and 9 with severe (SEV) renal impairment, CLCR < or =
      30 ml.min-1 x 1.73 m-2. Subjects in each renal function group received a 100-mg
      oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on
      day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered
      on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR,
      MOD and SEV, respectively). Single trough blood samples just prior to each
      morning dose (Cmin) and serial samples after the dose on day 8 were obtained at
      each dose level for pharmacokinetic analysis. Plasma samples were assayed by a
      specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that
      steady state was attained by the third day of BID administration of both the 100-
      and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF
      and HO-NEF attained steady-state Cmax within 2 h after administration of
      nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP
      plasma levels were about 1/3 and < 1/10 those of NEF, respectively, regardless of
      the status of renal function. Steady-state systemic exposure of NEF and HO-NEF,
      as reflected by AUC and Cmax, and elimination t1/2 values did not differ
      significantly among renal function groups. CONCLUSION: The study results suggest
      that dose adjustments may not be necessary, but nefazodone should be used with
      caution in the presence of severe renal impairment.

PMID- 8666002
TI  - The tolerability, pharmacokinetics and lack of effect on plasma cholesterol of
      447C88, an AcylCoA: Cholesterol Acyl Transferase (ACAT) inhibitor with low
      bioavailability, in healthy volunteers.
AB  - 447C88 (N-Heptyl-N'-(2,4 difluoro-4-6-(2(-4-(2,2
      dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal
      AcylCoA: Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng.ml-1 (23 nM).
      It is poorly absorbed but 5 mg.kg-1.day-1 completely abolishes the rise in plasma
      cholesterol in cholesterol-fed rats. In this study, twelve healthy, male
      volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of
      447C88 (n = 8) or placebo (n = 4) with food in a double-blind study with at least
      a week between occasions. The 400 mg dose was repeated after an overnight fast.
      Subsequently, fourteen different volunteers received a single 200 mg dose of
      447C88 (n = 8) or placebo (n = 6) with food and, a week later, the same dose
      twice daily for 10 days; all doses were given with food. All doses were well
      tolerated with no significant changes in vital signs, full blood counts or plasma
      biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after
      the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng.ml
      1 and 9.0 ng.ml-1.h after 200 mg rising to 5.4 ng.ml-1 and 23.8 ng.ml-1.h
      respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma
      447C88 concentrations were higher in the evening than the morning probably due to
      administration of the evening dose with more food. There were no significant
      changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing
      with 447C88.

PMID- 8666003
TI  - beta-Amyloid-(1-40) increases long-term potentiation in rat hippocampus in vitro.
AB  - The effect of beta-amyloid-(1-40) was investigated on long-term potentiation of
      glutamatergic excitatory postsynaptic field potentials recorded in the inner
      molecular layer in the rat dentate gyrus in vitro. In the presence of 200 nM beta
      amyloid-(1-40) there was an increase in long-term potentiation of 51%. Basal
      synaptic transmission was not affected. These results provide direct evidence
      that a relatively low concentration of beta-amyloid-(1-40) increases synaptic
      plasticity.

PMID- 8666004
TI  - Role of nitric oxide in the actions of substance P and other mediators of
      inflammation in rat skin microvasculature.
AB  - The role of nitric oxide in inflammatory responses to substance P and other
      mediators of inflammation was examined in rat skin microvasculature in a blister
      base raised on the hind footpad. Superfusion of substance P (1 microM) over the
      blister base caused an increase in plasma extravasation and a vasodilator
      response which was not maintained. N(G)-Nitro-L-arginine (100 microM), an
      inhibitor of nitric oxide biosynthesis, attenuated vasodilatation and plasma
      extravasation due to substance P. The inactive isomer N(G)-nitro-D-arginine was
      without effect. Neurokinin A (1 microM), 5-hydroxytryptamine (1 microM), ATP (50
      microM) and vasoactive intestinal polypeptide (1 microM) elicited vasodilation,
      which for vasoactive intestinal polypeptide was maintained even after washout. 5
      Hydroxytryptamine and neurokinin A, but not ATP or vasoactive intestinal
      polypeptide, significantly increased plasma extravasation. Vasodilatation to
      neurokinin A, 5-hydroxytryptamine and ATP, and the increase in plasma
      extravasation due to neurokinin A and 5-hydroxytryptamine were unaffected by N(G)
      nitro-L-arginine (100 microM), whereas vasodilation due to vasoactive intestinal
      polypeptide was significantly attenuated. These findings suggest that in rat skin
      microvasculature in vivo, nitric oxide is involved in vasodilator responses due
      to substance P and vasoactive intestinal polypeptide, and plasma extravasation
      due to substance P, but does not contribute significantly to vasodilatation
      induced by neurokinin A, 5-hydroxytryptamine or ATP, or the plasma extravasation
      induced by neurokinin A or 5-hydroxytryptamine.

PMID- 8666006
TI  - Presynaptic 5-HT1A receptors mediate the effect of ipsapirone on punished
      responding in rats.
AB  - The effect of ipsapirone, a partial agonist at 5-HT1A receptors, and of diazepam
      on punished operant responding was studied in rats injected
      intracerebroventricularly with 150 microg 5,7-dihydroxytryptamine to deplete
      brain serotonin or pretreated with (S)-WAY 100135 (N-tert-butyl) 3-4-(2
      methoxyphenyl)piperazin-1-yl-2-phenylpropanamide dihydrochloride), an antagonist
      at 5-HT1A receptors. 5,7-Dihydroxytryptamine markedly depleted brain serotonin
      and caused a sustained increase in punished responding with no effect on rates of
      unpunished responding in sham-operated rats but had no effect in animals which
      had received 5,7-dihydroxytryptamine. At 5 and 10 mg/kg ipsapirone reduced
      unpunished responding similarly in sham-operated and 5,7-dihydroxytryptamine
      treated rats. Diazepam 2.5 mg/kg i.p.significantly increased punished responding
      and reduced rates of unpunished responding similarly in sham-operated and in 5,7
      dihydroxytryptamine-treated animals. At 3 and 10 mg/kg (S)-WAY 100135 did not
      modify punished or unpunished responding but at 10 mg/kg it completely
      antagonized the effect of 5 mg/kg/s.c. ipsapirone on unpunished and punished
      responding. The results suggest that ipsapirone releases behaviour that is
      suppressed by punishment by stimulating presynaptic 5-HT1A receptors.

PMID- 8666005
TI  - Pharmacological characterization of three novel cannabinoid receptor agonists in
      the mouse isolated vas deferens.
AB  - The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1
      naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoy)indole, produced a dose-related
      inhibition of electrically evoked contractions of the mouse vas deferens, with
      IC50 values of 2.56 nM, 3.38 nM and 639 nM respectively. Kd values of the
      selective CB1 cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4
      chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide
      hydrochloride], determined in the vas deferens from experiments with these
      compounds are 1.34 nM, 3.86 nM and 8.06 nM respectively, indicating their
      susceptibility to antagonism by SR141716A is similar to that of their parent
      compound, the CB1 cannabinoid receptor agonist WIN 55,212-2 ?(R)-(+)-[2,3-dihydro
      5-methyl-3-[4-methylino)methyl]pyrrolo-[1,2, 3-de]-1,4-benzoxazin-6-yl](1
      naphthyl)methanone}. SR141716A (100 nM) had no effect on the actions of two non
      cannabinoid receptor agonists, morphine and clonidine. These results provide
      strong support for the hypothesis that 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1
      pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole are cannabinoid
      receptor agonists and confirm that the WIN 55,212-2 molecule can be modified
      considerably without detectable loss of cannabinoid activity.

PMID- 8666007
TI  - Dexamethasone inhibits the production of macrophage inflammatory protein 2 in the
      leukocytes in rat allergic inflammation.
AB  - In the air pouch-type allergic inflammation model in rats, when the infiltrated
      leukocytes in the pouch fluid collected 4 h after antigen challenge were
      incubated, neutrophil chemotactic activity in the conditioned medium increased
      time-dependently. They produced neutrophil chemotactic factors, viz. leukocyte
      derived neutrophil chemotactic factor (LDNCF)-2, a major component, and LDNCF-1,
      a minor component. When the infiltrated leukocytes were incubated in the presence
      of dexamethasone, neutrophil chemotactic activity in the conditioned medium
      decreased in a concentration-dependent manner, and production of LDNCF-2 and
      LDNCF-1 was inhibited. Because purified LDNCF-2 had been found to be identical
      with rat macrophage inflammatory protein 2 (MIP-2), effects of dexamethasone on
      the level of MIP-2 mRNA in the leukocytes were investigated. Using the reverse
      transcription-polymerase chain reaction technique, it was demonstrated that
      dexamethasone suppressed the level of MIP-2 mRNA in the leukocytes. These results
      indicate that dexamethasone inhibits MIP-2 production at the transcription level.

PMID- 8666008
TI  - Rat duodenum nitrergic-induced relaxations are cGMP-independent and apamin
      sensitive.
AB  - The effects of the K+ channel blockers, apamin, tetraethylammonium and 4
      aminopyridine, upon the relaxations of the isolated rat proximal duodenum induced
      by nitregic nerve activation, nitric oxide (NO), the NO donor 3
      morpholinosydnonimine (SIN-1) and Br-cyclic GMP were determined. The effects of
      the guanylate cyclase inhibitors, cystamine and N-methylhydroxylamine, on NO-,
      SIN-1- and nitrergic nerve-induced responses were also investigated. Apamin
      inhibited nitrergic nerve-, NO-and SIN-1-induced relaxations but did not affect
      those induced by Br-cGMP. Tetraethylammonium and 4-aminopyridine as well as
      cystamine and N-methylhydroxylamine failed to affect the relaxations caused by
      any of the agents tested. These findings indicate that, in the rat proximal
      duodenum, nitrergic nerve activation as well as exogenous nitric oxide cause
      relaxation through a cGMP-independent, apamin sensitive mechanism.

PMID- 8666009
TI  - Identification of drugs subtype-selective for alpha 2A-, alpha 2B-, and alpha 2C
      adrenoceptors in the pig cerebellum and kidney cortex.
AB  - The radioligands [3H]MK912 and [3H]RX821002 were used to label alpha2A-, alpha2B
      , and alpha2C-adrenoceptors of the pig cerebellum and kidney cortex. By inclusion
      of the alpha2A-adrenoceptor-selective drug, BRL44408, and using a 'multi-curve'
      experimental design all the three porcine alpha2-adrenoceptor subtypes could be
      characterized pharmacologically. The data indicate that the pig alpha2
      adrenoceptor subtypes are pharmacologically more related to human alpha2
      adrenoceptor subtypes than to the rodent alpha2-adrenoceptors. We suggest a set
      of drugs that are useful for the delineation of the pig alpha2-adrenoceptor
      subtypes.

PMID- 8666010
TI  - Angiotensin II-mediated renal vasoconstriction amenable to alpha 1-adrenoceptor
      blockade.
AB  - Renal adrenergic interactions of intravenously and intrarenal arterially
      administered angiotensin II were studied in the anesthetized rabbit. Systemic
      arterial blood pressure and left renal blood flow were monitored. Bolus doses of
      angiotensin II, 50 and 100 ng/kg given intravenously, caused an immediate
      reduction in renal blood flow followed by a more sustained vasoconstrictor
      response. Prazosin, 5 micrograms/kg/min, infused intrarenal arterially, decreased
      both components of the reduced renal blood flow, suggesting adrenergic
      contribution to the response. Renal denervation reduced significantly the
      immediate response to angiotensin II without affecting the sustained response;
      administration of prazosin after denervation caused a further decrease in the
      response. Left adrenalectomy had no significant effect on the angiotensin II
      induced renal blood flow response, ruling out the possible contribution of
      adrenal catecholamine release via the adrenal rete. In animals that had undergone
      renal denervation and left adrenalectomy, the renal blood flow response to
      intrarenal arterial injection of subpressor doses of angiotensin II (5 and 10
      ng/kg) was reduced by the infusion of prazosin. It is concluded that angiotensin
      II-induced renal vasoconstriction is contributed to by adrenergic actions
      dependent in part on intact renal nerves, but also by a component not requiring
      an intact nerve supply.

PMID- 8666011
TI  - Regulation of Na(+)-pump activity by dopamine in rat tail arteries.
AB  - We investigated the effect of dopamine on the vascular Na+-pump activity in
      isolated rat tail artery sections. Effect of dopamine on vascular tone was also
      assessed using a perfused tail artery preparation. Dopamine inhibited the Na+
      pump activity in isolated rat tail arteries in a dose-dependent manner. Both SKF
      38393 HCl, a selective dopamine D1 receptor agonist, and quinpirole HCl, a
      selective dopamine D2 receptor agonist inhibited the Na+-pump activity. The
      inhibition of the Na+-pump activity. The inhibition of the Na+-pump by dopamine
      was accompanied with a transient increase in the vascular tone. SKF-38393, but
      not quinpirole produced a sustained increase in the vascular tone. Tissues
      preincubated simultaneously with SCH-23390 HCl, a selective dopamine D1 receptor
      antagonist, and sulpiride, a selective dopamine D2 receptor antagonist, prevented
      the dopamine inhibition of the Na+-pump activity. Pertussis toxin blocked the Na+
      pump inhibition produced by the dopamine D1 receptor agonist but not by the
      dopamine D2 agonist. Similarly, the dopamine D1 receptor but not dopamine D2
      agonist increased the rate of phosphoinositide hydrolysis in rat tail artery
      sections. Our results indicate that dopamine inhibition of the Na+-pump is
      mediated by a pertussis toxin-sensitive mechanism and may be coupled to the
      activation of the phospholipase C system in rat tail arteries. The modulation of
      the Na+-pump by dopamine may contribute to the vascular tone.

PMID- 8666012
TI  - Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study.
AB  - Previous studies have shown that riluzole (2-amino-6-trifluoromethoxy
      benzothiazole), a drug which interferes with glutamate neurotransmission, has a
      neuroprotective action in rodent models of global and focal cerebral ischemia. In
      this pilot study, the protective and palliative effects of riluzole have been
      examined using an animal model of Parkinson's disease. Two monkeys were rendered
      hemiparkinsonian by one intracarotid injection of 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP), and motor signs were evaluated using clinical
      examination and electromyographic recordings. When riluzole (4 mg/kg) was
      administered before the injection of MPTP, parkinsonian motor symptoms, in
      particular bradykinesia and rigidity, were absent. When injected daily in one
      monkey which presented stable motor symptoms, bradykinesia and rigidity were
      significantly reduce d. Riluzole pretreatment induced a persistent increase in
      dopamine turnover when compared to MPTP alone. Thus, a possible neuroprotection
      and a facilitation of dopamine release may explain the behavioural effects
      reported with riluzole treatment. These preliminary results suggest that riluzole
      could possess neuroprotective and palliative effects in a primate model of
      Parkinson's disease.

PMID- 8666013
TI  - (-)-beta-cyclazocine is an antagonist of NMDA receptor-mediated responses and a
      potent neuroprotectant in rat cortical neurons.
AB  - Microspectrofluorimetry and excitotoxicity experiments were performed to study
      the NMDA receptor-blocking and neuroprotective actions of (-)- and (+)-beta
      cyclazocine in cultured rat cortical neurons. (-)-beta-Cyclazocine potently
      antagonized NMDA-induced[Ca2+]i increases (IC50 = 220 nM) in neurons loaded with
      the Ca2+ fluorophore, fura-2. (-)-beta-Cyclazocine was specific for NMDA receptor
      mediated responses versus those mediated through non-NMDA receptors or voltage
      activated Ca2+ channels. The agent was active against NMDA-induced neurotoxicity,
      even at 1 microM. In all experiments, the (+)-enantiomer was found to be
      considerably less potent than the (-)-enantiomer. These results indicate that (-)
      beta-cyclazocine is a specific NMDA receptor antagonist with potent
      neuroprotective properties in rat cortical neurons.

PMID- 8666014
TI  - The new NO donor SPM3672 increases cGMP and improves contraction in rat
      cardiomyocytes and isolated heart.
AB  - Recent evidence indicates that organic nitrate esters may directly affect heart
      muscle. In the present study we investigated the effects of the new organic
      nitrate ester, N-(3-nitratopivaloyl)-1-cysteineethylester (SPM3672), on isolated
      adult rat ventricular myocytes and on Langendorff preparations of spontaneously
      beating rat hearts perfused in a volume-constant manner. In cardiomyocytes
      SPM3672 (100 microM) induced a significant increase in the basal level of cGMP to
      232 +/- 44% (n=8) indicating its metabolism to nitric oxide. This was associated
      with an enhanced contractile response to electrical field stimulation (to 174 +/-
      9%, n=108). In isolated hearts SPM3672 elicited a slight reduction of coronary
      perfusion pressure (-15 +/- 8%) and a significant increase in maximal left
      ventricular pressure (LVPmax), dp/dtmax and dp/dtmin amounting to 18 +/- 7%, 18
      +/- 6% and 21 +/- 7% (n=7), respectively. Oxygen consumption and heart rate
      remained constant. Thus, SPM3672 improved the contractile response of
      cardiomyocytes and of isolated heart. This is probably due to the metabolism of
      SPM3672 to nitric oxide in ventricular cardiomyocytes.

PMID- 8666015
TI  - Glutamate participates in the peripheral modulation of thermal hyperalgesia in
      rats.
AB  - While the effects of excitatory amino acids have been well characterized in the
      central nervous system, relatively little is known about their possible
      modulation of elements responsible for hyperalgesia within peripheral tissue. The
      presented experiments demonstrate that the intraplantar (i.pl.) injection of L
      glutamate (30 nmol) evokes a thermal hyperalgesic response in the paw withdrawal
      latencies of normal rats which is stereospecific. In addition, the i.pl.
      injection of either the non-competitive N-methyl-D-aspartate (NMDA) receptor
      antagonist MK-801 (10 nmol) or the competitive alpha-amino-3-hydroxy-4-methyl-5
      isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7
      nitroquinoxaline-2,3-dione (CNQX)(100 nmol) into hindpaws inflamed with
      carrageenan significantly reduced the thermal hyperalgesic response in rats.
      Collectively, these results suggest that excitatory amino acids activate a
      peripheral target which facilitates a hyperalgesic behavioural response to
      thermal stimulation via a receptor mediated process.

PMID- 8666016
TI  - Prolyl-leucyl-glycinamide, thyrotropin-releasing hormone and beta-endorphin-(10
      16), like antidepressants, antagonize melatonin-induced behavioural changes in
      rats.
AB  - beta-Endorphin-(10-16), as well as a variety of antidepressants, has been
      reported to block the behavioural changes induced by injecting melatonin into the
      nucleus accumbens. In the present study the influence of subcutaneously
      administered prolyl-leucyl-glycinamide (PLG) and thyrotropin-releasing hormone
      (TRH) on the behavioural changes induced by melatonin administration in the
      nucleus accumbens were investigated and compared with that of beta-endorphin-(10
      16). PLG and TRH were found to be as effective as beta-endorphin-(10-16) in
      counteracting the melatonin-induced behavioural changes. The data suggest that
      these peptides may serve as a starting point for the development of a new class
      of antidepressants.

PMID- 8666017
TI  - Is alpha-adrenoceptor blockade responsible for atropine flush?
AB  - Toxic amounts of atropine usually, and therapeutic doses occasionally, dilate
      cutaneous blood vessels, especially those in the blush area (atropine flush).
      However, the mechanism of this anomalous vascular response is unknown. We,
      therefore, investigated this action of atropine not only in functional but also
      in binding studies with isolated rat aorta and brain, respectively. Endothelium
      denuded rat thoracic aortic rings were contracted with norepinephrine, U46619
      (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha, thromboxane A2
      receptor agonist) and KCl, and the relaxation in response to atropine was
      recorded. The norepinephrine-, but not the U46619- or KCL-mediated contraction
      was relaxed by atropine. Atropine caused a rightward parallel shift of the
      phenylephrine concentration-contraction curve with a pA2 value of 6.57 (slope
      0.58), but did not affect the concentration-contraction curve for U46619. In rat
      cerebral cortex homogenates, atropine displaced [3H]prazosin with Ki values of
      3.33 nM and 0.19 microM, respectively. These results suggest that even though
      atropine has low affinity for the alpha-adrenoceptor, it possesses
      characteristics similar to those of a competitive ligand for the alpha
      adrenoceptor. Thus, atropine, especially at high concentrations, has direct alpha
      adrenoceptor blocking activity, which may account, at least in part, for atropine
      flush.

PMID- 8666018
TI  - Identification of alpha 1-adrenoceptor subtypes involved in the antinatriuretic
      response to intrarenal infusion of phenylephrine.
AB  - It is reported that alpha 1-adrenoceptors located in the renal vasculature and
      renal tubules play a major role in mediating antinatriuretic response to renal
      nerve stimulation as well as to the infusion of alpha 1-adrenoceptor agonist. In
      the present study intrarenal infusion of alpha 1-adrenoceptor agonist
      phenylephrine (0.25 microgram/kg/min) to Inactin-anesthetized Sprague-Dawley rats
      produced approximately 50% reduction in urine output, Na+ excretion and
      glomerular filtration rate without causing significant alterations in mean blood
      pressure, heart rate and fractional Na+ excretion. These changes were completely
      abolished by prior intrarenal infusion of prazosin (0.5 microgram/kg/min for 30
      min). In separate groups of experiments, the animals received either a selective
      irreversible alpha 1A-adrenoceptor antagonist, SZL-49 [1-(4-amino-6,7-dimethoxy-2
      quinazolinyl)-4-(2-bicyclo[2,2,2]octa-2,5- diene-2-carbonyl)piperazine], or an
      alpha 1B-adrenoceptor antagonist, chloroethylclonidine, intrarenally prior to
      phenylephrine infusion. Neither SZL-49 nor chloroethylclonidine alone
      significantly altered glomerular filtration rate and renal electrolyte excretion.
      However, SZL-49 (0.15 microgram/kg/min), but not chloroethylclonidine (50
      micrograms/kg/min), completely abolished phenylephrine-induced changes in urine
      output, Na+ excretion and glomerular filtration rate. These results demonstrate
      that phenylephrine decreases urine output and Na+ excretion, mainly due to a
      reduction in glomerular filtration rate resulting from activation of alpha 1A
      adrenoceptors, and that proximal tubular alpha 1A- or alpha 1B-adrenoceptors do
      not appear to contribute to this response.

PMID- 8666019
TI  - Effect of bradykinin on NaCl transport in the medullary thick ascending limb of
      the rat.
AB  - The aim of the present study was to determine whether bradykinin affects NaCl
      reabsorption in the medullary thick ascending limb of the loop of Henle. At 10(
      8) M, bradykinin significantly inhibited Cl- transport in the in vitro
      microperfused rat medullary thick ascending limb by 67% (P < 0.01). This
      inhibitory effect could be totally prevented by preincubating tubules with the
      bradykinin B2 receptor antagonist N alpha-adamantaneacetyl-D-Arg-[Hyp3,Thi5,8,D
      Phe7]brady kinin (10(-6) M). In contrast, the bradykinin B1 receptor agonist des
      Arg9 bradykinin (10(-6) M) had no effect on Cl- transport. Bradykinin caused
      transient increases in intracellular Ca2+ concentration, which could be blocked
      by the bradykinin B2 receptor antagonist, but could not be reproduced with the
      bradykinin B1 receptor agonist. These data suggest that the natriuretic and
      diuretic effect of bradykinin in vivo is due, at least in part, to a bradykinin
      B2 receptor-mediated inhibition of NaCl reabsorption in the medullary thick
      ascending limb of the loop of Henle.

PMID- 8666020
TI  - Receptor binding profile of cyclazosin, a new alpha 1B-adrenoceptor antagonist.
AB  - The binding profile of cyclazosin, a new prazosin-related alpha 1-adrenoceptor
      antagonist, at alpha 1-, alpha 2-adrenoceptors, dopamine D2 and 5-HT1A receptors
      was compared to that of 5-methylurapidil, spiperone, risperidone and other
      prazosin-related ligands. In addition, cyclazosin was investigated at native and
      cloned alpha 1-adrenoceptor subtypes. Cyclazosin showed high specificity for
      alpha 1-adrenoceptors and a 10-15-fold selectivity for alpha 1B (alpha 1b)
      adrenoceptors with respect to the alpha 1A (alpha 1a) subtype (pKi values of 9.23
      9.57 and 8.18-8.41, respectively). However, it failed to discriminate between
      cloned alpha 1b and alpha 1d-adrenoceptors (pKi values of 9.23 and 9.28,
      respectively).

PMID- 8666021
TI  - Effects of high energy phosphates and L-arginine on the electrical parameters of
      ischemic-reperfused rat skeletal muscle fibers.
AB  - In skeletal muscle, 4 h of ischemia followed by 30 min of reperfusion depolarizes
      the fibers, markedly increases the Cl- and glibenclamide-sensitive K+
      conductances and reduces the excitability of the fibers. The ischemia-reperfusion
      also significantly decreases the ATP content of the muscles. In the present work,
      the electrical parameters of reperfused extensor digitorum longus muscle of rats
      were measured in vitro at 30 degrees C, by a computerized two-intracellular
      microelectrode technique, before and after in vivo pretreatment with equimolar
      doses of phosphocreatine disodium salt tetrahydrate, phosphocreatine di-L
      arginine salt and L-arginine hydrochloride. In the same experimental situations
      the ATP content of the muscles was also measured. Both phosphocreatine salts
      prevented the increase of membrane ion conductance due to muscle reperfusion by
      preloading the muscle fibers with extra ATP. Phosphocreatine disodium salt also
      prevented the depolarization and restored the normal excitability of the
      reperfused fibers. In contrast, phosphocreatine di-L-arginine salt did not
      restore the resting potential nor the excitability of the fibers, but it
      decreased the amplitude of the action potential by reducing the overshoot. The
      pretreatment with L-arginine also failed to protect the electrical parameters of
      the fibers from the ischemic-reperfusion insult. Furthermore, the L-amino acid
      produced a more pronounced reduction of the excitability of the fibers by
      increasing the threshold current needed to elicit an action potential and
      reducing it overshoot. The in vitro application of L-arginine to the muscle also
      reduced the overshoot of the action potential, suggesting a direct interaction of
      the L-amino acid with Na+ channels.

PMID- 8666022
TI  - Beneficial effects of a novel anti-hypoxemic agent, TEI-7322, on bleomycin
      induced experimental hypoxemia in rats.
AB  - Almitrine bismesylate is known to be an anti-hypoxemic agent that acts via the
      enhancement of hypoxic pulmonary vasoconstriction. However, screening for this
      class of compounds has been minimal, owing, in part, to a lack of convenient
      hypoxemic models in small animals. The present study was designed to establish a
      convenient model of hypoxemia induced by bleomycin and to evaluate anti-hypoxemic
      agents including a newly synthesized compound. TEI-7322, 2-allylamino-4-tert
      butyl-amino-7-methyl-7H-pyrrolo[2,3- d]pyrimidine hydrochloride by using this
      model. Bleomycin was intratracheally instilled into rats. After 3 weeks, the
      arterial blood gas pressures were monitored in the animals in the conscious
      state. Then, prednisolone, doxapram, almitrine or TEI-7322 was administered to
      the bleomycin-treated rats to monitor changes in arterial blood gas pressures.
      Bleomycin-treated rats showed a decrease in the arterial blood O2 pressure
      (PaO2). The blood CO2 pressure (PaCO2) increased, along with an increase in the
      alveolar-arterial oxygen difference (AaDO2). These blood gas pressures in
      bleomycin-treated rats were not affected by treatment with prednisolone. Doxapram
      decreased the PaCO2 but did not change the PaO2. However, administration of
      almitrine or TEI-7322 significantly improved the PaO2 of bleomycin-treated rats
      with a decrease in the PaCO2. In conclusion, (1) bleomycin-induced lung injury
      causes hypoxemia in rats, probably resulting from ventilation-perfusion
      inequality; thus this model may be useful for evaluating anti-hypoxemic agents;
      and (2) TEI-7322, as well as almitrine, showed anti-hypoxemic effects in this
      model with different properties from those of doxapram, possibly due to
      improvement of ventilation-perfusion inequality, indicating that TEI-7322 may be
      a potent candidate for the treatment of hypoxemia.

PMID- 8666023
TI  - Brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 maintain
      functional tolerance to ethanol.
AB  - Neurotrophins and growth factors not only affect neuronal development, but also
      maintain neuronal survival and influence neuronal function in the adult brain,
      and affect various cognitive processes related to learning and memory. Functional
      tolerance to ethanol represents an adaptive change in the central nervous system
      that has been hypothesized to have mechanisms in common with those underlying
      learning or memory. In the present work, the effects of neurotrophins on ethanol
      tolerance were compared to the effect of the neuropeptide, arginine vasopressin,
      which maintains (reduces the rate of dissipation of) both ethanol tolerance and
      memory. Functional tolerance to ethanol was induced in C57BL/6J mice by feeding
      them an ethanol-containing liquid diet, and the effect of neurotrophins on the
      rate of dissipation of tolerance to the hypnotic effect of ethanol was assessed.
      Human recombinant brain-derived neutrophic factor, neurotrophin-3 and
      neurotrophin-4/5, injected intracerebroventricularly once daily following ethanol
      withdrawal, maintained ethanol tolerance, while tolerance dissipated in ethanol
      fed mice injected with vehicle (artificial cerebrospinal fluid) or with basic
      fibroblast growth factor. The results demonstrate that some neurotrophins can
      modulate neuroadaptation to ethanol, supporting the hypothesis that these factors
      can influence the function of postmitotic neurons in the adult brain.

PMID- 8666024
TI  - Hypothalamic alpha 2A-adrenoceptors stimulate growth hormone release in the rat.
AB  - Oxymetazoline, the relatively selective alpha 2A-adrenoceptor agonist (with more
      than 60-fold selectivity over the alpha 2B-adrenoceptor subtype), was
      administered into the lateral ventricle (i.c.v.) of rats and plasma growth
      hormone (GH) levels were measured. Oxymetazoline was more potent to release GH
      after i.c.v. administration than was clonidine; 0.01 microgram i.c.v.
      oxymetazoline already caused a significant release of GH, while at least 0.1
      microgram clonidine had to be administered to cause a similar response. The dose
      response curve was of an inverted U shape since with 10 micrograms of
      oxymetazoline the plasma GH did not rise. When oxymetazoline was injected i.c.v.
      to rats with somatostatin fibres to the median eminence transected by an
      anterolateral cut in the hypothalamus there was a significant rise in plasma GH,
      suggesting that oxymetazoline stimulated GHRH rather than inhibited somatostatin
      release. Pretreatment with CH-38083 (7,8-(methylenedioxy)-14-alpha-hydroxy
      alloberban HCl, selective for alpha 2-adrenoceptors but not differentiating
      between alpha 2A and alpha 2B subtypes), prevented the plasma GH rise normally
      elicited by 1 microgram i.c.v. oxymetazoline. The alpha 2A- and alpha 1-selective
      adrenoceptor antagonist, WB-4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4
      benzodioxane hydrochloride), prevented the GH rise normally induced by
      oxymetazoline while prazosin, the alpha 2B- and alpha 1-selective adrenoceptor
      antagonist, prolonged the elevation occurring in the control rats between 30 and
      60 min after oxymetazoline injection. Since both prazosin and WB-4101 are alpha 1
      adrenoceptor antagonists but differ in their action on alpha 2A and alpha 2B
      subtypes as well as in their action on oxymetazoline-induced GH secretion, the
      antagonist studies suggest that oxymetazoline stimulates GH release through
      activation of alpha 2A-adrenoceptors stimulatory to GHRH release, and not by an
      action through alpha 2B- or alpha 2C- or alpha 1-adrenoceptors. Since WB-4101
      also antagonized clonidine action on GH release we also suggest that the major
      component may be the stimulation of the alpha 2A-adrenoceptors in the clonidine
      action on GH release.

PMID- 8666025
TI  - Involvement of neurohumoral factors in the pressor mechanism of NG-nitro-L
      arginine.
AB  - The mechanism of the NG-nitro-L-arginine (L-NNA)-induced pressor response was
      examined in pentobarbital-anesthetized dogs. The pressor effect of L-NNA (50
      mg/kg, i.v.) was significantly and equally diminished by pretreatment with either
      hexamethonium (25 mg/kg, i.v.) or phentolamine (5 mg/kg, i.v.). The
      intracisternal administration of L-NNA (1 mg/kg), which did not cause changes in
      cardiovascular parameters when administered systemically, produced a significant
      pressor response and tachycardia. Furthermore, significant suppression of L-NNA
      induced pressor responses was observed after treatment of dogs with captopril (5
      mg/kg, i.v.) or a non-peptide angiotensin II receptor antagonist, losartan (10
      mg/kg, i.v.), or bilateral occlusion of renal veins. The inhibitory effects of
      hexamethonium and losartan were additive. These results suggest that, in addition
      to vasoconstriction due to the inhibition of endothelial nitric oxide production,
      increased activity of the sympathetic nervous and renin-angiotensin systems
      contributes significantly to the development of pressor responses produced by the
      intravenous injection of L-NNA in anesthetized dogs.

PMID- 8666026
TI  - alpha 1-Adrenoceptor stimulation inhibits the isoproterenol-induced effects on
      myocardial contractility and protein phosphorylation.
AB  - In the present study the influence of alpha 1-adrenoceptor stimulation on the
      beta-adrenoceptor agonist-induced increases in contractile parameters and protein
      phosphorylation was determined in isolated perfused hearts and isolated cardiac
      myocytes, respectively. Methoxamine inhibited the isoproterenol-induced increases
      in left ventricular pressure and heart rate dose dependently up to 90% and 75%,
      respectively; the EC50 of this antiadrenergic effect was 4.4 microM. The alpha 1
      adrenoceptor antagonist, prazosin (1 microM), greatly diminished methoxamine's
      inhibitory action, confirming the alpha 1-adrenoceptor-mediated mechanism. The
      inotropic effect of glucagon was inhibited by methoxamine in a similar manner.
      Radioligand binding assays with [3H]dihydroalprenolol demonstrated that the
      antiadrenergic action of methoxamine is not due to an unspecific beta
      adrenoceptor blocking property. In an additional experimental series the effects
      of methoxamine and isoproterenol on the protein phosphorylation pattern of
      isolated cardiac myocytes were investigated. Isoproterenol increased the
      phosphorylation state of five proteins (6-kDa, phospholamban; 15-kDa; 28-kDa,
      troponin I; 97-kDa; 140-kDa) while in the experiments with methoxamine the 15-kDa
      protein was the only phosphorylated substrate. In the presence of methoxamine the
      isoproterenol-induced phosphorylation of phospholamban, troponin I and the 97-kDa
      and 140-kDa protein was markedly inhibited while the phosphorylation state of the
      15-kDa protein remained unaltered. The present study clearly demonstrated that
      alpha 1-adrenoceptor stimulation potently inhibits the beta-adrenoceptor-mediated
      changes in contractile force and phosphorylation of key regulatory proteins, most
      likely through modulation of cAMP metabolism.

PMID- 8666027
TI  - Brain enzyme activities after intracerebroventricular injection of streptozotocin
      in rats receiving acetyl-L-carnitine.
AB  - Intracerebroventricular (i.c.v.) injection of streptozotocin has been introduced
      as a means to inhibit glucose utilization in the rat brain, and to induce changes
      in neurotransmitter systems and behavior which resemble those seen in Alzheimer's
      disease. In this study, enzyme activities previously investigated in Alzheimer's
      disease (peptidases, dehydrogenases and acetyltransferases) were measured in the
      septum and hippocampus of control and streptozotocin-treated rats. Streptozotocin
      treated rats receiving acetyl-L-carnitine were also included in the experiments,
      to assess possible neuroprotective effects of this substance. All enzyme
      activities in the septum were affected by streptozotocin, with the exception of
      choline acetyltransferase activity. By contrast, choline acetyltransferase
      activity was the only enzyme activity affected in the hippocampus. The weight of
      the septum was reduced in streptozotocin-treated animals. These findings indicate
      that i.c.v. injection of streptozotocin causes septal damage and enzymatic
      changes that do not closely resemble those seen in Alzheimer's disease, which are
      more specific. Acetyl-L-carnitine partly prevented this damage, as reflected by
      an attenuation of the streptozotocin-induced decrease in hippocampal choline
      acetyltransferase activity. This finding indicates that streptozotocin-treated
      rats may be valuable to test possible neuroprotective effects of drugs.

PMID- 8666028
TI  - Fragments of pituitary adenylate cyclase activating polypeptide discriminate
      between type I and II recombinant receptors.
AB  - Pituitary adenylate cyclase activating polypeptide (PACAP) analogues were tested
      for their ability to occupy the recombinant selective PACAP receptors (PACAP type
      I receptor) or the non-selective PACAP-vasoactive intestinal polypeptide (VIP)
      receptors (PACAP type II, VIP1 and VIP2 receptors) stably transfected and
      expressed in Chinese hamster ovary (CHO) cells. The synthetic analogues consisted
      of N- and/or C-terminally shortened peptides. Thus, peptides starting at amino
      acid 1, 2, 3 or 6 and terminating at amino acid 27, 29, 30, 32 or 38 were
      compared on the three receptors studied. The shortening of PACAP-(1-38) to PACAP
      (1-27) was of little influence. However, in N-terminally deleted peptides the
      PACAP-38 derivatives were of higher affinity than the PACAP-27 fragments on PACAP
      type I and PACAP type II, VIP2 receptors but not on PACAP type II, VIP1
      receptors. The presence of the sequence 28-32 was in all cases sufficient to
      reproduce the data obtained with the PACAP-38 analogues. PACAP-(3-32) is able to
      discriminate the PACAP type II, VIP2 subtype from the other two subtypes, and
      PACAP-(6-30), PACAP-(6-32) and PACAP-(6-38) can discriminate the PACAP type II,
      VIP1 receptors from the other two subtypes. These molecules may help in the
      quantitative detection of receptor subclasses in complex systems when two or more
      receptor subtypes are found.

PMID- 8666030
TI  - The activity of 5-HT1D receptor ligands at cloned human 5-HT1D alpha and 5-HT1D
      beta receptors.
AB  - The present study has examined the functional activity of the 5-HT1D receptor
      agonist, sumatriptan, and antagonists, GR127935 (2'-methyl-4'-(5-methyl
      [1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyl ic acid [4-methoxy-3-(4-methyl
      piperazin-1-yl)-phenyl]-amide), GR55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-N
      [4-(4-pyridinyl)phenyl] benzamide), metergoline and methiothepin in HeLa cells,
      stably transfected with either 5-HT1D alpha or 5-HT1D beta receptor subtypes.
      Sumatriptan, GR127935 and metergoline (each 0.01-1 microM) behaved as agonists,
      producing a concentration-dependent inhibition of forskolin-stimulated adenosine
      3',5'-cyclic monophosphate (cAMP) production at both 5-HT1D alpha and 5-HT1D beta
      receptor subtypes (mean pIC50 values of 8.4 and 8.3 for sumatriptan, 7.9 and 8.0
      for GR127935, and 7.9 and 8.3 for metergoline, respectively). In contrast,
      GR55562 and methiothepin behaved as competitive 5-HT1D receptor antagonists and
      were devoid of any agonist activity. GR55562 (10 microM) caused a rightward
      displacement of the GR127935 and metergoline concentration-response curves. The
      agonist activity of GR127935 and metergoline, observed in the present study,
      contrasts with their recognised 5-HT1D receptor antagonist profiles in animal
      isolated tissue and behavioural models. Unlike GR127935, GR55562 behaved as a
      silent antagonist at the cloned human 5-HT1D alpha and 5-HT1D beta receptors in
      the study.

PMID- 8666029
TI  - Interactions between NMDA and AMPA/kainate receptors in the control of
      micturition in the rat.
AB  - In unanesthetized decerebrate rats, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8
      methylenedioxy-5H-2,3-benzodiazepine hydrochloride), an AMPA/kainate receptor
      antagonist, and MK-801 (dizocilpine), an NMDA receptor antagonist, acted
      synergistically to depress the micturition reflex. MK-801 (1 mg/kg i.v.) and GYKI
      52466 (4 mg/kg i.v.) administered separately had no or only a small depressant
      effect on reflex bladder contractions but markedly depressed external urethral
      sphincter activity. However, in MK-801-treated rats, GYKI 52466 decreased the
      amplitude, frequency and duration of reflex bladder contractions. These results
      suggest that both AMPA/kainate and NMDA glutamate receptors are important in the
      micturition reflex pathway and that these receptors may be activated in parallel
      at some site in the pathway so that excitatory transmission via only one receptor
      type is sufficient to mediate reflex activation of the bladder.

PMID- 8666031
TI  - Salbutamol-induced airway hyperreactivity in guinea pigs is not due to a loss of
      its bronchodilator effect.
AB  - Guinea pigs were treated for 10 days with (+/-)-salbutamol (0.2 mg/kg/day,
      delivered from subcutaneously implanted osmotic minipumps). Airway reactivity to
      intravenously administered histamine, methacholine and bombesin was substantially
      increased in salbutamol-treated guinea pigs relative to controls. In the same
      animals, the potency of intravenously administered salbutamol to reverse bombesin
      induced bronchoconstriction remained unchanged thus exactly reflecting effects in
      man. In conclusion, subchronic administration of salbutamol at low doses to
      guinea pigs increases airway reactivity. Since the bronchorelaxant effect of
      salbutamol remained unchanged, desensitisation of beta-adrenoceptors on airway
      smooth muscle is unlikely to account for this effect.

PMID- 8666032
TI  - Alkalinisation does not modify the effect of verapamil on myocardial Ca2+
      current.
AB  - The effect of verapamil on L-type Ca2+ current (ICa) was compared at external pH
      7.4 and 8.5 in rat ventricular myocytes. Alkalinisation increases the fraction of
      uncharged molecules of verapamil (pK 8.75) and thereby facilitates membrane
      permeation of the drug. Verapamil (1 microM) reduced the amplitude of ICa
      (ICa(peak)) by 36 +/- 4% at pH 7.4 and by 40 +/- 6% at pH 8.5, whereas
      alkalinisation from pH 7.4 to 8.5, without drug, increased ICa(peak) by 12 +/-
      3%. It is suggested that the efficiency of verapamil is not influenced by the
      amount of protonation or membrane permeation.

PMID- 8666033
TI  - Enalapril does not prevent the myocardial ischemia caused by the chronic
      inhibition of nitric oxide synthesis.
AB  - In rats, chronic administration of the nitric oxide (NO) inhibitor N omega-nitro
      L-arginine methyl ester (L-NAME) causes arterial hypertension, cardiac
      hypertrophy and myocardial ischemic alterations such as necrosis and fibrosis. In
      this study, we evaluated the effect of 8 weeks of treatment with enalapril
      maleate on cardiac weight and on the development of the histological alterations
      induced by L-NAME. Enalapril significantly inhibited the development of both
      arterial hypertension (117.2 +/- 5.8, 161.8 +/- 8.8 and 122.0 +/- 10.6 mm Hg, for
      control, L-NAME- and L-NAME + enalapril-treated animals, respectively) and left
      ventricular hypertrophy (1.36 +/- 0.13, 1.60 +/- 0.04 and 1.48 +/- 0.05 mg/g, for
      control, L-NAME- and L-NAME + enalapril-treated animals, respectively), but had
      no effect on the myocardial lesions. These findings demonstrate that although the
      renin-angiotensin system plays a major role in the development of arterial
      hypertension and cardiac hypertrophy, it does not modulate the ischemia-induced
      myocardial alterations observed in this model.

PMID- 8666034
TI  - Galantide distinguishes putative subtypes of galanin receptors in mudpuppy
      parasympathetic neurons.
AB  - The effect of the chimeric ligand galantide on the galanin-induced activation of
      membrane K+ conductance and inhibition of voltage-dependent Ca2+ conductance has
      been studied using voltage-clamped dissociated mudpuppy parasympathetic neurons.
      Galantide did not activate the K+ conductance but produced a concentration
      dependent antagonism (IC50 = 4 nM) of the galanin-induced increase in K+
      conductance. Galantide acted like galanin and inhibited the voltage-dependent
      Ba2+ current (IBa). The inhibition of IBa also was concentration dependent (IC50
      = 16 nM) and the maximum inhibition produced by galantide was approximately 40%.
      We also demonstrate that the galanin-(1-16) fragment increased the membrane K+
      conductance and decreased IBa, suggesting that the NH2 portion of the galanin
      molecule is sufficient to mediate both actions. One interpretation of these
      observations is that different galanin receptors mediate the different effects of
      galanin on the mudpuppy parasympathetic neurons.

PMID- 8666035
TI  - Stable expression of human cytochrome P450 3A4 in V79 cells and its application
      for metabolic profiling of ergot derivatives.
AB  - Expression of human cytochrome (CYP) in heterologous cells is a means of
      specifically studying the role of these enzymes in drug metabolism. The complete
      cDNA encoding CYP3A4 (PCN1) was inserted into an expression vector containing the
      strong myeloproliferative sarcoma virus promoter in combination with the enhancer
      of the cytomegalovirus and stably expressed in V79 Chinese hamster cells. The
      presence of genomically integrated CYP3A4 cDNA cell clones was confirmed by
      polymerase chain reaction analysis. Transcription was detected by reverse
      transcribed polymerase chain reaction analysis. Functional expression could be
      demonstrated by conversion of testosterone to the specific 6beta-hydroxylated
      product. In recombinant V79 cells expressing CYP3A4 about 6% of the substrate was
      converted to 6beta-hydroxytestosterone. The metabolism of two dopaminergic ergot
      derivatives was investigated in live recombinant V79 cells. Both lisuride and
      terguride were monodeethylated.

PMID- 8666037
TI  - Toxocara canis-induced airway eosinophilia and tracheal hyporeactivity in guinea
      pigs and mice.
AB  - Guinea pigs and mice infected with the parasitic worms Toxocara canis developed
      airway inflammation and tracheal hyporesponsiveness. Preceding inflammatory cell
      infiltration a brief hyperreactive response occurred in guinea pigs to
      histaminergic receptor stimulation at 3 days post infection (p.i.) and in mice to
      acetylcholine receptor stimulation at 1 day p.i. Few but large eosinophilic
      inflammatory foci developed in guinea pigs at 14 days p.i. Mice demonstrated
      progressive multifocal inflammation from 7 days p.i. In addition to eosinophils
      mouse airways were infiltrated by lymphocytes, forming perivascular and (partial)
      peribronchial infiltrates in an oedematous submucosa. The inflammation persisted
      in mice for > or = 3 months and likewise persisted tracheal hyporeactivity.
      Incubation of tracheae of non-infected mice with pulmonary inflammatory cells
      caused a significant decrease in cholinergic receptor responsiveness. This
      downward shift was prevented by 60% when a cyclooxygenase inhibitor was added to
      the incubation medium but not when inhibitors of lipoxygenase and superoxide
      formation were added, suggesting the involvement of prostaglandin E2. This
      suggestion was supported by the finding of significantly increased prostaglandin
      E2 concentrations in the bronchoalveolar lavage fluid at 14 and 28 days p.i. It
      was concluded that tracheal hyporeactivity coincided with the presence of large
      numbers of eosinophils in the airways of both, guinea pigs and mice and that
      prostaglandin E2 involvement was conceivable.

PMID- 8666036
TI  - Comparative properties of the nuclear aryl hydrocarbon (Ah) receptor complex from
      several human cell lines.
AB  - The aryl hydrocarbon (Ah) responsiveness of the T-47D, Hep G2, LS180, MCF-7,
      A431, C-4II and MDA-MB-231 human cancer cell lines was determined by the
      induction of CYP1A1 mRNA levels and ethoxyresorufin O-deethylase activity. With
      the exception of teh MDA-MB-231 breast cancer cell line, 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) significantly induced CYP1A1 mRNA levels and
      ethoxyresorufin O-deethylase activity in the remaining six cell lines and, based
      on their EC50 values, for ethoxyresorufin O-deethylase induction, their Ah
      responsiveness followed the order T-47D > C-4II > MCF-7 > LS180 > HEP G2 > A431.
      In contrast, all the cell lines expressed the nuclear Ah receptor complex (167.1
      24.5 fmol/mg protein) which bound to a 32P-labeled consensus dioxin responsive
      element (DRE) in a gel mobility shift assay. The results of gel permeation
      chromatography a sucrose density gradient centrifugation studies showed that the
      calculated Mr values for the nuclear Ah receptor complex varied from 175 kDa (MDA
      MB-231 cells) to 221 kDa and the apparent molecular weight of the nuclear Ah
      receptor complex cross-linked to a bromodeoxyuridine-substituted DRE was 200 kDa.
      The data show that the molecular properties and levels of the nuclear Ah receptor
      complex from seven different human cancer cell lines do not predict Ah
      responsiveness.

PMID- 8666038
TI  - Evidence for potential application of zinc as an antidote to acetaminophen
      induced hepatotoxicity.
AB  - The therapeutic application of zinc sulphate as an antidote to acetaminophen
      overdose was examined in ICR mice. Hepatotoxicity was induced by a single oral
      dose of acetaminophen (750 mg/kg). Various treatments (normal saline, 15 or 30
      mg/kg zinc sulphate, 150 mg/kg N-acetylcysteine, 15 mg/kg zinc sulphate + 150
      mg/kg N-acetylcysteine) were given i.p. 1 h after acetaminophen overdose. Serum
      alanine aminotransferase, hepatic glutathione and malondialdehyde levels were
      measured before experiments and at various intervals after the administration of
      acetaminophen. Serum acetaminophen levels were also measured at different
      different intervals. Zinc sulphate showed protection by dose-dependently reducing
      alanine aminotransferase and malondialdehyde levels. The drug also partially
      prevented the depletion of hepatic glutathione. These effects were not as good as
      those of N-acetylcysteine. However, the combination of zinc sulphate with N
      acetylcysteine produced even better protective effects. Furthermore, drug
      treatments did not affect serum acetaminophen levels. It is concluded that both
      drugs attenuate acetaminophen-induced hepatic toxicity, and the action is likely
      to be mediated through replenishment of hepatic glutathione levels. The use of
      zinc sulphate alone or in combination with N-acetylcysteine could be another
      alternative for the treatment of acetaminophen overdose in view of possible side
      effects produced by N-acetylcysteine.

PMID- 8666039
TI  - Mitochondrial ATPase: a target for paracetamol-induced hepatotoxicity.
AB  - We examined the effect of paracetamol treatment (650 mg/kg) on the function of
      ATPase from rat hepatic mitochondria. The drug treatment caused an overall 35%
      decrease in ATPase activity, with a complete loss of the high affinity component
      as determined by substrate kinetic studies. The Km for the intermediate and low
      affinity components decreased by about 30% without change in Vmax, which may
      represent a compensatory mechanism. The drug treatment also resulted in a
      dramatic decrease in the phase transition temperature by about 19 degrees C
      without affecting the energies of activation of the enzyme. Mitochondrial total
      phospholipid content increased significantly with a reciprocal decrease in the
      cholesterol content. The total phospholipid/cholesterol molar ration increased by
      50% after paracetamol treatment. However, phospholipid composition (as % of
      total) of the mitochondria was unaltered.

PMID- 8666040
TI  - Subanesthetic concentrations of drugs inhibit cytochrome P450-mediated metabolism
      of aniline.
AB  - We reported previously that 18 compounds varying in general anesthetic potency by
      up to 66 000-fold inhibited, at anesthetic concentrations, the metabolism of
      arachidonic acid and aminopyrine by cytochrome P450 monooxygenases in rat liver
      microsomes. Now, we report that P450-mediated para-hydroxylation of aniline is
      more sensitive to the anesthetics. The Ki values for enzyme inhibition for seven
      compounds were close to and for seven compounds 5-40 times less than their
      respective anesthetic potencies. Endogenous substrates with an aniline-like
      binding mode to P450 include histamine and related imidazoles. Acetone and each
      of the halogenated compounds, halothane, enflurane, and chloroform, stimulated
      aniline hydroxylase activity at concentrations well below and above their EC50
      values. These potent actions on the universal P450 isoenzymes may contribute to
      pharmacological effects of the anesthetics associated with levels of drug well
      below concentrations that effect general anesthesia.

PMID- 8666042
TI  - Depolarization and hypoxia-induced cell damage in serum-free cultures of the rat
      cortex, and related extracellular glutamate changes.
AB  - Experiments were carried out to clarify the influence of K+-induced chronic
      membrane depolarization on cytotoxicity and changes in extracellular glutamate,
      as induced by hypoxia in serum-free cortical cultures. Excitotoxic cell death was
      examined by measuring lactic dehydrogenase (LDH) activity released into the
      culture medium. In culture grown in the presence of 25 mM K+, morphological
      injury occurred during a 4 h exposure to hypoxia, together with a substantial
      efflux of LDH. In hypoxic cultures, extracellular glutamate concentrations were
      elevated and these responses were absent in cultures grown in physiological
      medium (K+ = 5.4 mM), even with 16 h of hypoxia. In cultures at 25 mM K+, the
      cytotoxicity induced by hypoxia was attenuated by NMDA receptor antagonists, in a
      concentration dependent manner. We also examined the effects of excitatory amino
      acids, agonists of the main glutamate receptor classes (glutamate, NMDA, kainate,
      and AMPA). In both 5.4 nM and 25 mM K+ cultures, a dose dependent release of LDH
      was induced by a long exposure to glutamate receptor agonists, although the
      release of LDH in the 5.4 mM K+ was less than that in the 25 mM K+ cultures.
      Despite of the expression of the glutamate receptor in the 5.4 mM K+ cultures,
      hypoxic neuronal damage did not occur. These results suggest that when cultures
      grown in a chronically depolarizing environment are exposed to hypoxia, they are
      damaged by an excitotoxic mechanism in which the main cause seems to be the
      glutamate released into the medium at high extracellular levels.

PMID- 8666041
TI  - Urethane directly inhibits chemoreflex excitation of medullary vasomotor neurons
      in rats.
AB  - In anesthetized rats, stimulation of the arterial chemoreceptors excites
      reticulospinal vasomotor neurons of the nucleus rostroventrolateral reticularis
      of the medulla oblongata, via activating the neuronal NMDA receptors. Excitation
      of these neurons is responsible for reflex increases in sympathetic neuronal
      activity and arterial pressure. Additional doses (0.12-0.24 g/kg i.v.) of
      urethane dose-dependently reduced the elevations in the discharge rate of
      reticulospinal vasomotor and sympathetic neurons and of arterial pressure,
      elicited by stimulating the carotid chemoreceptors with intra-carotid injections
      of sodium cyanide (100 nmol/10 microl), without affecting discharges of the
      carotid chemoafferents. Microiontophoresis of urethane onto the reticulospinal
      vasomotor neurons reversibly inhibited the excitation elicited by stimulation of
      the chemoreceptors and by iontophoretically applied L-glutamate. The results
      indicate that the suppression of chemoreflexes by excessive amount of urethane is
      central and one of its blocking excitatory amino acid transmission onto these
      vasomotor neurons.

PMID- 8666043
TI  - The effects of an inhaled corticosteroid on oxygen radical production by
      bronchoalveolar cells after allergen or ozone in dogs.
AB  - Both ozone and allergen inhalation increase the capacity to produce oxygen
      radicals by bronchoalveolar lavage cells in dogs. The purpose of these studies
      was to determine whether inhaled corticosteroids inhibits these increases in
      oxygen radical production from bronchoalveolar lavage cells. Six random source
      dogs were studied after dry air or ozone inhalation (3 ppm, 30 min). Seven random
      source dogs were studied after diluent or allergen inhalation. The dogs inhaled
      budesonide (2.74 mg/day) or lactose powder, twice daily for 7 days before ozone
      and allergen. 90 min after ozone or dry air, and 24 h after Ascaris suum or
      diluent a bronchoalveolar lavage was carried out. Spontaneous luminol-enhanced
      chemiluminescence was measured from bronchoalveolar lavage cells (4 x 10(6)
      cells) for 10 min, followed by a measurement of phorbol myristate acetate (PMA
      2.4 micromol/l) stimulated chemiluminescence for 10 min. Both ozone and allergen
      inhalation caused an increase in PMA stimulated chemiluminescence (P<0.05).
      Budesonide pretreatment inhibited ozone-induced (P<0.008), but not allergen
      induced PMA stimulated chemiluminescence (P>0.90). Both ozone and allergen
      inhalation caused an increase in the bronchoalveolar lavage neutrophils.
      Budesonide pretreatment significantly inhibited the ozone-induced (P=0.007), but
      not the ascaris-induced neutrophil influx (P=0.93). These results demonstrate
      that ozone, but not allergen, stimulated oxygen radical release and neutrophil
      influx are attenuated by inhaled corticosteroids. This suggests that luminol
      enhanced chemiluminescence from bronchoalveolar lavage cells measures oxygen
      radicals derived from neutrophils, and that ozone-and allergen-induced
      bronchoalveolar lavage neutrophilia are caused by different mechanisms.

PMID- 8666044
TI  - Ca(2+)-mediated damage to rabbit gastric mucosal cells: modulation by nitric
      oxide.
AB  - Pertubations in cellular Ca2+ homeostasis can lead to oxidative stress whereas
      nitric oxide has been shown to inactivate oxygen radicals. Therefore the effects
      of inhibition of nitric oxide (NO) synthase activity on Ca2+-mediated disruption
      to rabbit dispersed gastric mucosal cells have been examined. Addition of the
      Ca2+ ionophore A23187 (3-25 microM) to the incubation medium induced a
      concentration-dependent increase in cell damage is assessed by trypan blue dye
      uptake and decreased cellular metabolic activity as estimated by alamar blue
      absorbance. These responses were exacerbated by inhibition of NO synthase
      activity with NG-monomethyl-L-arginine (300 microM). The deleterious effects of
      ionophore A23187 and NG-monomethyl-L-arginine were ameliorated by addition of the
      NO donor S-nitroso-acetyl-penicillamine to the cell suspension. An increase in
      cellular Ca2+ in response to ionophore A23187 (12.5 microM) resulted in enhanced
      2'7'-dichlorofluorescein fluorescence suggesting an elevation in oxidative
      stress. Ca2+-mediated cell injury was abolished by the oxygen radical scavengers,
      catalase and 2',2'-dipyridyl. However, the cytotoxic effect of combined treatment
      with A23187 and NG-monomethyl-L-arginine was not reduced by administration of
      oxygen radical scavengers. NG-monomethyl-L-arginine treatment exacerbated the
      increase in cytosolic Ca2+ in response to ionophore A23187 as assessed by indo-1
      fluorescence. Furthermore this increase in cytosolic Ca2+ was reduced by addition
      of S-nitroso-acetyl-penicillamine to the incubation medium. These data suggest
      that NO synthase inhibition in gastric mucosal cells exacerbates the damaging
      actions of the Ca2+ ionophore A23187. The increase in cell damage in response to
      the NO synthase inhibitor NG-monomethyl-L-arginine does not appear to be mediated
      by an increase in oxidative stress and may be associated in part with changes in
      cellular Ca2+ flux.

PMID- 8666045
TI  - MK-801, memantine and amantadine show neuroprotective activity in the nucleus
      basalis magnocellularis.
AB  - The activation of glutamate receptors by endogenuous glutamate has been
      implicated in the processes that underlie cell loss associated with ischemia and
      trauma and in the development of some neurodegenerative diseases. The antagonism
      of NMDA-sensitive glutamate receptors may therefore have therapeutic
      applications. The present study compared the side effects and neuroprotective
      potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5
      dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H
      debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly
      into the nucleus basalis magnocellularis of rats. Each drug significantly
      attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The
      ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and
      amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50
      for the side effects observed, including ataxia, myorelaxation and stereotypy,
      and the ED50 for neuroprotective ability, was highest for memantine and the
      lowest for (+)-MK-801. The results suggest that a potential neuroprotective
      action of NMDA receptor antagonists, memantine and amantadine in particular, can
      be seen at low doses lacking side effects.

PMID- 8666046
TI  - Effect of environmental temperature on tissue lead accumulation in mice
      repeatedly treated with lead acetate.
AB  - The effect of environmental temperature on lead accumulation in tissues of mice
      repeatedly treated with lead acetate (2 mg/kg per day and 5 mg/kg per day) for 3
      or 6 weeks was studied. In blood, kidney and liver, the amount of lead
      accumulated after 3 weeks of treatment was markedly higher in animals exposed to
      22 degrees C than those maintained at 35 degrees C. Conversely, when the
      treatment was extended to 6 weeks, lead concentrations in the liver and kidney
      were equal or higher respectively, in the mice exposed to 35 degrees C. In the
      brain, lead concentration was lower than that found in kidney and liver and it
      was independent of dose and ambient temperature of lead being higher at 35
      degrees C than at 22 degrees C. These results demonstrate that environmental
      temperature influences the amount of lead accumulated in some rodent tissues, and
      that the duration of the treatment modifies the effect produced by temperature,
      suggesting that the changes elicited during the period of acclimation to the hot
      environment could be responsible for these findings.

PMID- 8666048
TI  - Circadian rhythm of embryotoxicity induced by sodium valproate in mice.
AB  - The influence of dosing time on embryotoxicity of valproate was investigated in
      ICR (Institute of Cancer Research, USA) mice under light-dark (12:12) cycle. A
      significant circadian rhythm was shown for embryotoxicity, with the highest value
      at 17:00 and the lowest at 01:00. No significant difference between injection at
      17:00 and 01:00 was demonstrated for valproate concentrations in the embryo. The
      rhythm in the embryotoxicity seems to be related to the rhythm in the sensitivity
      to the drug. Embryotoxicity and valproate concentrations were significantly
      higher on gestational day 13 than day 7. The timing of drug administration (i.e.,
      gestational stage and circadian phase) appears to be essential in the study of
      embryotoxicity of valproate in mice.

PMID- 8666047
TI  - Lack of neuroprotective effect of sigma receptor ligands in the neurotoxicity of
      p-chloroamphetamine in rat brain.
AB  - We studied the mechanism of antagonism of p-chloroamphetamine-induced
      neurotoxicity by dextromethorphan. The pretreatment with potent and selective
      sigma receptor ligands, 4-phenyl-4-(1-phenylbutyl)piperidine (4-PPBP) and N,N
      dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE
      100), did not alter the reduction of 5-hydroxytryptamine and 5-hydroxytryptamine
      and 5-hydroxyindoleacetic acid in the cerebral cortex by repeated administration
      of p-chloroamphetamine. These results suggest that sigma receptors might not play
      a significant role in the antagonism of p-chloroamphetamine-induced neurotoxicity
      by dextromethorphan.

PMID- 8666049
TI  - Expression of inducible nitric oxide synthase mRNA in Brown Norway rats exposed
      to ozone: effect of dexamethasone.
AB  - We studied the effects of ozone exposure and dexamethasone on inducible nitric
      synthase (iNOS) gene expression in Brown Norway rats in vivo. Using a murine iNOS
      cDNA probe, we detected a 4.4 kb iNOS mRNA by Northern analysis in rat lung. The
      iNOS signal was weak in control lungs, but increased in lungs exposed to ozone (3
      ppm, 6 h). Ozone-induced iNOS mRNA expression was time-dependent, with maximal
      expression at 2 h, declining by 8 h and increasing again at 24 h postexposure.
      Dexamethasone significantly reduced the iNOS mRNA expression in the lungs of both
      controls and ozone-exposed rats. These results demonstrate that ozone inhalation
      induces iNOS expression in vivo, thus providing evidence at the molecular level
      for the possible involvement of nitric oxide generation in ozone-induced
      pulmonary inflammation or lung damage.

PMID- 8666050
TI  - Action of beta-phenylethylamine and related amines on nigrostriatal dopamine
      neurotransmission.
AB  - The present paper describes the effect of beta-phenylethylamine and its
      metabolites phenylethanolamine, tyramine, acetyl-phenylethylamine and
      phenylacetaldehyde on the dopaminergic nigrostriatal system. The rotational
      behavioural response to the i.v. injection of these drugs was quantified in
      animals with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine
      system. Only beta-phenylethylamine and acetyl-phenylethylamine induced rotations
      ipsilateral to the side of the brain lesion. None of the compounds under study
      stimulated contralateral rotations. Acetyl-phenylethylamine was 90% less active
      than beta-phenylethylamine. After beta-phenylethylamine injection all animals
      (16/16) showed ipsilateral rotations. The dose-response curve showed that at
      doses as low as 1.75 mg/kg ipsilateral turns increase, with a dose-related
      rotational response between 1.75 mg/kg and 11.66 mg/kg, no differences being
      found at doses between 11.66 and 29.16 mg/kg. Rotations began a few seconds after
      beta-phenylethylamine injection. The highest response was found 30-60 s after the
      injection. The duration of the response was dose-related (4 min for the 3.5 mg/kg
      doses). The inhibition of dopamine-beta-hydroxylase activity with [1-3,5
      difluorobenzyl)imidazole-2-thiol (SKF102698) did not modify the rotational
      response to beta-phenylethylamine. The inhibition of type B monoamine oxidase
      activity with l-deprenyl induced a slight increase in the ipsilateral rotational
      response to beta-phenylethylamine. The inhibition of tyrosine hydroxylase
      activity with alpha-methyl-p-tyrosine decreased the rotational response to beta
      phenylethylamine. The dopamine receptor antagonist, haloperidol, completely
      blocked the ipsilateral rotational response to beta-phenylethylamine. The
      blocking of dopamine uptake into storage vesicles with reserpine increased the
      rotational action of beta-phenylethylamine. Taken together, the data suggest
      that, at low doses, beta-phenylethylamine stimulates the release of dopamine from
      the cytoplasmic pool and behaves as a dopamine receptor agonist with a very rapid
      and brief action.

PMID- 8666051
TI  - Potential anxiolytic properties of R-(+)-8-OSO2CF3-PAT, a 5-HT 1A receptor
      agonist.
AB  - The anxiolytic property of R-(+)-8-OSO2CF3-PAT(R-(+)-8-
      [[(trifluoromethyl)sulfonyl]oxy]-2-(n-propyl-amino)tetralin), a 5-HT1A receptor
      agonist, was evaluated in Wistar rats by means of animal models of anxiety, the
      conditioned defensive burying model and the conditioned stress-induced freezing
      response followed by the elevated plus-maze test, respectively. In addition, the
      5-HIAA/5-HT ratio (5-hydroxy-indole acetic acid/5-hydroxytryptamine) of rat brain
      homogenates was studied. Acute drug administration resulted in abolition of the
      burying behaviour (3 mg/kg i.p.), a dose-dependent decrease of rearing and
      induction of hyperphagia. R-(+)-8-OSO2CF3-PAT had no effect on conditioned
      footshock-induced freezing behaviour but increased open-arm activity in the rats
      on the plus-maze. The 5-HIAA/5-HT ratio was decreased in the lateral septum (1
      and 3 mg/kg), dorsal hippocampus (3 mg/kg) and somatosensory cortex (3 mg/kg),
      implying that R-(+)-8-OSO2CF3-PAT affects particularly the limbic system in
      anxiety-inducing situations.

PMID- 8666052
TI  - Failure of carbamazepine to prevent behavioural and histopathological sequels of
      experimentally induced status epilepticus.
AB  - Sustained electrical stimulation of the perforant pathway was used to induce long
      lasting hippocampal seizures in conscious rats. One hour prior to stimulation,
      rats were given i.p. injections of either saline or a commonly used antiepileptic
      drug, carbamazepine (5H-dibenz[b, f]azepine-5-carboxamide; CBZ; 20 mg/kg). When
      tested 2 weeks later in a water maze, both the saline- and the carbamazepine
      pretreated rats showed similarly a severe impairment in spatial learning compared
      to non-stimulated controls. Histological evaluation revealed that the pyramidal
      cell damage was (P < 0.05) milder in the carbamazepine-pretreated group in the
      CA1, but not the CA3c subfield. However, the number of somatostatin
      immunoreactive neurons in both stimulated groups was reduced equally. Thus, at
      the dose of 20 mg/kg, which is a usual anticonvulsive dose in humans,
      carbamazepine seems to offer only partial protection against pyramidal cell
      damage, but no protection against the hilar somatostatin-immunoreactive neuron
      loss or the spatial learning deficit after perforant pathway stimulation in rats.
      The result clearly differs from that obtained either with a GABA (gamma
      aminobutyric acid)-enhancing drug and a novel antiepileptic, vigabatrin (4-amino
      hex-5-enoic acid) or with a competitive NMDA (N-methyl-D-aspartate) receptor
      antagonist, CGP 39551 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid
      carboxyethylester) in the same test situation.

PMID- 8666053
TI  - Antimyoclonic effect of gabapentin in a posthypoxic animal model of myoclonus.
AB  - The antimyoclonic property of the novel antiepileptic drug, gabapentin (1
      (aminomethyl) cyclohexane acetic acid), was tested in cardiac arrest-and p,p'
      DDT(1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane)-induced animal models of
      myoclonus. Gabapentin dose-dependently attenuated myoclonus in posthypoxic rats
      for more than 3 h. The drug was also found to be effective in controlling the
      early stages of seizures following the anoxic insult. In contrast, the drug was
      ineffective in controlling either myoclonus or seizures in p,p'-DDT-treated
      animals. These results suggest that gabapentin can be used used as an effective
      therapeutic agent in an acute hypoxia/ischemia-induced neurological disorder. The
      data further indicate that distinct neurological mechanisms may be operating in
      the expression of myoclonus among posthypoxic and p,p'-DDT-induced animal models.

PMID- 8666054
TI  - Effect of KBT-3022, a new cyclooxygenase inhibitor, on experimental brain edema
      in vitro and in vivo.
AB  - The effect of KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1
      ylacetate), a new cyclooxygenase inhibitor, on experimental brain edema was
      studied. In vitro, KBT-3022 (100 microM) and its metabolite desethyl KBT-3022 (10
      and 100 microM), but neither acetylsalicylic acid nor indomethacin, inhibited
      arachidonic acid-induced swelling of guinea pig cortical slices. KBT-3022 (3-100
      microM) and desethyl KBT-3022 (3-30 microM), but neither acetylsalicylic acid nor
      indomethacin, inhibited lipid peroxidation in guinea pig brain homogenate. In
      vivo, oral administration of KBT-3022 (1, 3 and 10 mg/kg) and indomethacin (10
      and 30 mg/kg), but not acetylsalicylic acid, prevented brain edema induced by
      bilateral carotid occlusion and recirculation in gerbils. Indomethacin then
      prevented postischemic hyperthermia, but not KBT-3022. KBT-3022 (10 mg/kg) and
      indomethacin (30 mg/kg) inhibited lactate accumulation in gerbil brain after
      ischemia and recirculation. These results suggest that KBT-3022 prevents
      development of both cytotoxic edema in vitro and vasogenic edema in vivo.

PMID- 8666055
TI  - Negative chronotropic and dromotropic effects of E-4031, an IKr blocker, on the
      atrioventricular node in anesthetized dog hearts.
AB  - To investigate the effect of the delayed rectifier K+ current (IK) on the
      atrioventricular (AV) node of the heart in situ, we studied the direct effects of
      (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(methylsulfonyl-aminobenzoyl)piperidi ne (E
      4031), an IKr (a rapid type of IK) blocker, on the AV junctional rate, atrio-His
      interval (AH interval), and right ventricular pressure, and the cardiac responses
      to sympathetic nerve stimulation in the anesthetized dog heart. AV junctional
      rhythm was induced by clamping the sinoatrial (SA) pacemaker area. E-4031 (0.01-3
      mumol/kg, i.v.) attenuated the AV junctional rate dose dependently. The
      junctional negative chronotropic effect was less than the decrease in sinus rate
      induced by E-4031 in the same doses. E-4031 did not affect the junctional rate
      increased by sympathetic stimulation. In the paced heart, E-4031 slightly
      increased the AH interval but did not change right ventricular pressure
      responses. E-4031 attenuated neither positive dromotropic nor positive
      ventricular pressure responses to sympathetic stimulation. After E-4031
      treatment, zatebradine (a hyperpolarization-activated current blocker) additively
      decreased the junctional rate and the junctional positive chronotropic responses
      to sympathetic stimulation. These results suggest that IKr has much less effect
      on AV nodal pacemaker activity than on SA nodal pacemaker activity, and an IKr
      blocker, E-4031, unlike zatebradine, does not antagonize the junctional positive
      chronotropic responses to sympathetic activation in anesthetized dog heart.

PMID- 8666056
TI  - Alpha 1-adrenoceptor-induced contractility in rat aorta is mediated by the alpha
      1D subtype.
AB  - Adrenoceptor agonists were used to characterize the alpha 1-adrenoceptor subtype
      responsible for mediating tension (phasic and tonic combined) in the denuded rat
      aorta and compared with radioligand binding at alpha 1-adrenoceptor subtypes. The
      rank order of potency at the rat aorta was the same as that obtained for binding
      affinity at the rat clonal alpha 1d-adrenoceptor: norepinephrine > epinephrine >
      cirazoline > phenylephrine > oxymetazoline > A-61603 > methoxamine. Correlation
      coefficients comparing rat aortic contraction (pD2) to binding (pKi) were 0.09
      0.21 for alpha 1A/a receptors, 0.66 for clonal alpha 1b and 0.94 for clonal alpha
      1d-adrenoceptors. Correlation coefficients comparing the clonal alpha 1d
      adrenoceptor binding affinity to in vitro contractile responses were 0.03 and
      0.10 for the rat vas deferens and canine prostate alpha 1A-adrenoceptor
      responses, respectively, 0.09 for the rat spleen alpha 1B and as noted, 0.94 for
      the rat aorta. The agreement observed between agonist potency at the rat aorta
      and affinity for the alpha 1d binding site provide new evidence that the alpha 1D
      adrenoceptor subtype is responsible for mediating contractions in the rat aorta.

PMID- 8666057
TI  - Comparative effects of K+ channel modulating agents on contractions of rat
      intestinal smooth muscle.
AB  - The effects of six K+ channel openers were investigated on contractions of the
      rat ileum longitudinal muscle-myenteric plexus preparation elicited by electrical
      field stimulation and by K+. Levcromakalim, pinacidil, RP 49356 (N-methyl-2-(3
      pyridyl)-tetrahydrothiopyran-2-carbothioamide-1-oxide) and SDZ PCO 400 ((3S,4R)
      3, 4-dihydro-3-hydroxy-2, 2-dimethyl-4-[(3-oxo-1-cyclopenten-1-yl)oxy]-2H-1
      benzopyran-6-car bonitrile) completely abolished contractions elicited by
      electrical stimulation and caused complete relaxation of contractions elicited by
      K+ with comparable IC50 values. Minoxidil sulphate was much less potent and
      diazoxide was without effect in either protocol. The relaxant effects of these
      agents were antagonized by glibenclamide, tetraethylammonium and yohimbine in a
      manner which was not surmountable. The present study indicates that the relaxant
      effect of these compounds in intestinal smooth muscle is mediated through
      glibenclamide-sensitive ATP-dependent K+ channels. These compounds did not
      preferentially inhibit either direct smooth muscle- or nerve-mediated responses.
      The present data may point to differences in the channels or their regulatory
      sites, in intestinal, compared with vascular, smooth muscle.

PMID- 8666058
TI  - Role of nitric oxide and prostaglandins in lipopolysaccharide-induced increase in
      vascular permeability in mouse skin.
AB  - To examine the possible role of increased vascular permeability in the
      circulatory shock induced by endotoxin (lipopolysaccharide), we examined whether
      lipopolysaccharide elicits plasma extravasation in the skin of ddY strain mice.
      We also studied whether nitric oxide (NO) and prostaglandins may mediate the
      lipopolysaccharide-induced increase in vascular permeability. Subcutaneous
      injection of lipopolysaccharide (100-400 micrograms/site) induced a dose-related
      and delayed increase in vascular permeability at the injection site as determined
      by the leakage of pontamine sky blue. Concurrent administration of aminoguanidine
      (a putative inducible NO synthase inhibitor) (10 mg/kg, i.v.) inhibited the
      lipopolysaccharide (400 micrograms/site)-induced dye leakage by 71%. N(G)-Nitro-L
      arginine methyl ester (an inhibitor for both constitutive and inducible NO
      synthase) (10 and 20 mg/kg, i.v.) inhibited the lipopolysaccharide-induced dye
      leakage by 36% and 54%, respectively, whereas the inactive enantiomer, N(G)-nitro
      D-arginine methyl ester (10 mg/kg, i.v.), had no effect. Pretreatment with an
      intraperitoneal injection of dexamethasone (500 micrograms/kg) or indomethacin (a
      cyclooxygenase-1 and -2 inhibitor) (5 mg/kg) almost completely inhibited the
      response induced by lipopolysaccharide, by 96% and 84%, respectively. [N-(2
      Cyclohexyloxy-4-nitrophenyl) methanesulphonamide (a cyclooxygenase-2-specific
      inhibitor) (0.01-1 mg/kg, i.p.) also induced a dose-related inhibition of dye
      leakage elicited by lipopolysaccharide: 38% and 80% suppression at the doses of
      0.1 and 1 mg/kg, respectively. Cycloheximide (a protein biosynthesis inhibitor)
      (35 mg/kg, s.c.) suppressed the effect of lipopolysaccharide by 74%. These
      results suggest that the increase in vascular permeability induced by
      lipopolysaccharide is mediated by both NO and prostaglandins and that synthesis
      of inducible NO synthase and cyclooxygenase-2 may be involved in this effect of
      lipopolysaccharide.

PMID- 8666059
TI  - Acetylcholine as a mitogen: muscarinic receptor-mediated proliferation of rat
      astrocytes and human astrocytoma cells.
AB  - The mitogenic effect of muscarinic receptor agonists in glial cells has been
      characterized in rat cortical astrocytes and human 132 1N1 astrocytoma cells. The
      muscarinic receptor agonist carbachol caused a dose- and time-dependent increase
      in proliferation, as measured by [3H]thymidine incorporation. The mitogenic
      effect was mimicked by several muscarinic, but not nicotinic receptor agonists,
      and was blocked by muscarinic receptor antagonists. Reverse transcription
      polymerase chain reaction (RT-PCR) experiments indicated the presence of m2, m3
      and to a lesser degree, m5 muscarinic receptor mRNA in both astrocytes and
      astrocytoma cells. Proliferation experiments with subtype-specific muscarinic
      receptor antagonists suggest that carbachol-induced proliferation is due to
      activation of muscarinic M3 receptors. The phorbol ester 12-O-tetradecanoyl
      phorbol 13-acetate (TPA) also stimulated glial cell proliferation. Down
      regulation of protein kinase C, or the protein kinase C antagonist 1,5
      (isoquinolynsulfanyl)-2-methylpiperazine dihydrochloride (H7) blocked
      proliferation induced by either TPA or carbachol. Of other neurotransmitters
      tested, histamine caused glial cell proliferation, norepinephrine and gamma
      aminobutyric acid were ineffective, while serotonin and glutamate inhibited basal
      or serum-stimulated proliferation.

PMID- 8666060
TI  - Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP
      responses in the rat hippocampus.
AB  - The effects of group 2- versus group 3-selective metabotropic glutamate (mGlu)
      receptor agonists were examined against forskolin (10 microM)-, vasoactive
      intestinal peptide (VIP; 1 microM)- and 5'-N-ethylcarboxamidoadenosine (NECA; 10
      microM)-stimulated cAMP accumulations in adult rat hippocampal slices (in the
      presence of adenosine deaminase). Group 2 mGlu receptor-selective ((1S,3R)-1
      aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4S)-alpha
      (carboxycyclopropyl)-glycine (L-CCG I)) and group 3 mGlu receptor-selective (L-2
      amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphate) agonists greatly
      inhibited forskolin-stimulated cAMP formation ( > 80% at maximally effective
      concentrations). In contrast, stimulation of cAMP by VIP or NECA was inhibited by
      group 3, but not by group 2, mGlu receptor agonists. In fact, group 2 mGlu
      receptor agonists greatly potentiated cAMP accumulation evoked by NECA. Both the
      inhibitory effects of 1S,3R-ACPD on forskolin-stimulated cAMP and the
      potentiating effects on NECA-stimulated cAMP accumulation were reversed by the
      competitive group 1/2 mGlu receptor antagonist (+)-alpha-methyl-4
      carboxyphenylglycine ((+)-MCPG). However, (+)-MCPG had no effects on L-AP4
      inhibition of cAMP. Thus, the effects of group 2 versus group 3 mGlu receptor
      agonists on cAMP coupling can be pharmacologically as well as functionally
      differentiated in the rat hippocampus.

PMID- 8666061
TI  - Pharmacological basis for functional selectivity of partial muscarinic receptor
      agonists.
AB  - Muscarinic receptor agonists activate phosphoinositide hydrolysis and adenylate
      cyclase in Chinese hamster ovary cells transfected with cDNAs encoding the human
      muscarinic ml and m3 receptors. Whereas carbachol activates similarly both
      receptor subtypes, 4-[3-chlorophenyl-carbamoyloxy]-2-butynyltrimethyl ammonium
      chloride (McN-A-343) preferentially activates the m1 subtype over m3, in regard
      to both phosphoinositide hydrolysis and adenylate cyclase activity. On the other
      hand, oxotremorine activates phosphoinositide hydrolysis to a similar extent in
      both cell lines, but it activates preferentially adenylate cyclase in m1 versus
      m3 receptor expressing cells. Relative to carbachol, both McN-A-343 and
      oxotremorine activate preferentially phosphoinositide hydrolysis over adenylate
      cyclase in both cell lines. Prolonged incubation of cells with either carbachol,
      McN-A-343, or oxotremorine down-regulated the m1 receptors. This was accompanied
      by a parallel decrease in adenylate cyclase activity, whereas phosphoinositide
      hydrolysis remained relatively high. Inactivation of the receptors by alkylation
      with acetylethylcholine mustard, or by blocking with atropine, reduced carbachol
      stimulated adenylate cyclase activity more effectively than carbachol-induced
      phosphoinositide hydrolysis in both m1 and m3 receptor expressing cells. These
      findings imply that the receptor reserve in these cell lines is greater for
      phosphoinositide hydrolysis response than for adenylate cyclase response. Yet,
      the receptor reserve for each of these responses is similar in both m1 and m3
      receptor expressing cells. Since the binding affinities of McN-A-343 and of
      oxotremorine to m1 and m3 receptors are very similar, and since both cell lines
      contain similar amounts of spare receptors, we propose that the preferential
      activation of muscarinic m1 over m3 receptor by partial agonists is related to
      differences in the abilities of the two receptor subtypes to undergo
      conformational changes following agonist binding. This hypothesis is supported by
      results showing that the muscarinic m1 but not m3 receptor exhibits two affinity
      states in a competition binding assay.

PMID- 8666062
TI  - Na(+)-permeable channels induced by maitotoxin in guinea-pig single ventricular
      cells.
AB  - The characteristics of maitotoxin-induced single channel currents were studied in
      guinea-pig single ventricular cells using the cell-attached or inside-out
      configuration of the patch clamp. When the patch electrode was filled with normal
      Tyrode solution containing 10 nM maitotoxin, elementary currents flowing through
      the single channel were observed in the cell-attached patch. The amplitude of the
      single channel current at the resting potential was 1.6 +/- 0.1 pA. The current
      voltage relation of the current was linear and the single channel conductance was
      16.0 +/- 0.9 pS. The distribution of open times was fitted by a single
      exponential function (decay time constant: 27 ms), while that of closed times was
      fitted by the sum of two exponential functions (decay time constants: 1.6 and 34
      ms). When the electrode solution was filled with the Ca(2+)-free Tyrode solution,
      maitotoxin also induced single channel currents with parameters similar to those
      in the normal Tyrode solution. Under inside-out patch clamp conditions and in 150
      mM Na+ solution on both sides of the patch membrane, maitotoxin also induced
      single channel currents. Choline+ could not substitute for Na+. These results
      indicate that maitotoxin induces single ionic channels irrespective of the
      presence or absence of Ca2+ and that the charge carrier of the single channel
      current is Na+ rather than Ca2+. The increase in Na+ permeability through
      maitotoxin-induced channels may be possibly responsible for its biological
      actions.

PMID- 8666063
TI  - Alterations in angiotensin AT1 and AT2 receptor subtype levels in brain regions
      from patients with neurodegenerative disorders.
AB  - The present studies assessed the levels of [125I][Sar1,ILE8]angiotensin II
      labelled angiotensin AT1 and AT2 receptor recognition sites in homogenates of
      various brain areas (including caudate nucleus, putamen, substantia nigra,
      hippocampus, frontal cortex, temporal cortex and cerebellum) from patients with
      clinically diagnosed Parkinson's disease, Huntington's disease and Alzheimer's
      disease and those from age-, sex- and post-mortem delay-matched neurologically
      and psychiatrically normal patients. Radiolabelled angiotensin AT1 receptor
      recognition site levels were significantly decreased by approximately 70%, 70%
      and 90% in the caudate nucleus, putamen and substantia nigra, respectively, from
      patients with Parkinson's disease relative to matched controls. Furthermore,
      radiolabelled angiotensin AT2 receptor levels were decreased by some 60% in the
      caudate nucleus of patients with Parkinson's disease relative to control
      patients. In brain tissue homogenates from patients with Huntington's disease,
      the angiotensin AT1 receptor recognition site levels were decreased by
      approximately 30% in putamen relative to the control patients whilst angiotensin
      AT2 receptor levels were increased by some 90% in the caudate nucleus relative to
      the control patients. In brain tissue homogenates from patients with Alzheimer
      disease, the angiotensin AT2 receptor recognition site levels were significantly
      increased by approximately 200% in the temporal cortex relative to the control
      patients. The present results indicate that the reduction of angiotensin AT1
      and/or AT2 receptor recognition site levels in the caudate nucleus, putamen and
      substantia nigra correlates with the principal neuropathology associated with
      Parkinson's disease and as such indicates that at least a significant population
      of angiotensin AT1 and AT2 receptors are located on the human dopaminergic
      nigrostriatal pathway. In addition, the marked increase in the levels of
      angiotensin AT2 receptor recognition sites in temporal cortex from patients with
      Alzheimer's disease correlates with some other markers associated with the renin
      angiotensin system previously investigated in tissue from patients with this
      neurological disease.

PMID- 8666064
TI  - Regulation of angiotensin AT1 receptor gene expression during cell growth of
      vascular smooth muscle cells.
AB  - Cell proliferation influences the expression of numerous tissue-specific genes.
      The angiotensin AT1 receptor is highly expressed on vascular smooth muscle cells
      where it mediates cell contraction upon activation with angiotensin II. Since
      vascular smooth muscle cell de-differentiation leads to differential expression
      of several genes, we investigated the effects of cell growth on angiotensin AT1
      receptor gene expression in vascular smooth muscle cells in culture. Northern
      hybridization analysis revealed a decrease of angiotensin AT1 receptor mRNA
      levels to approximately 20% in proliferating cells in comparison to growth
      arrested cells. There is a correlative loss of membrane-associated angiotensin
      AT1 receptor protein in growing cells versus non-growing cells, as assessed by
      saturation radioligand binding assays. In addition, the BB-isoform of platelet
      derived growth factor (PDGF-BB), which induces proliferation of quiescent
      vascular smooth muscle cells, causes a marked down-regulation of angiotensin AT1
      receptor mRNA. These data suggest that proliferation of vascular smooth muscle
      cells leads to reduced angiotensin AT1 receptor gene expression. The mechanisms
      underlying this process and its physiological implications remain to be defined.

PMID- 8666065
TI  - The Jenner bicentenary; still uses for smallpox vaccine.

PMID- 8666066
TI  - The development and use of a vaccinia-rabies recombinant oral vaccine for the
      control of wildlife rabies; a link between Jenner and Pasteur.
AB  - To improve both safety and stability of the oral vaccines used in the field to
      vaccinate foxes against rabies, a recombinant vaccinia virus, which expresses the
      immunizing G protein of rabies virus has been developed by inserting the cDNA
      which codes for the immunogenic glycoprotein of rabies virus into the thymidine
      kinase (TK) gene of the Copenhagen strain of vaccinia virus. The efficacy of this
      vaccine was tested by the oral route, primarily in foxes. The immunity conferred,
      a minimum of 12 months in cubs and 18 months in adult animals, corresponds to the
      duration of the protection required for vaccination of foxes in the field.
      Innocuity was tested in foxes, domestic animals, and in numerous European wild
      animal species that could compete with the red fox for the vaccine bait. No
      clinical signs or lesions were observed in any of the vaccinated animals during a
      minimum of 28 days post vaccination. Moreover, no transmission of immunizing
      doses of the recombinant occurred between foxes or other species tested. To study
      the stability of the vaccine strain, baits containing the vaccine were placed in
      the field. Despite considerable variations of environmental temperatures, the
      vaccine remained stable for at least one month. Because bait is taken within one
      month, it can be assumed that most animals taking the baits are effectively
      vaccinated. To test the field efficacy of the recombinant vaccine, large-scale
      campaigns of fox vaccination were set up in a 2200 km2 region of southern
      Belgium, were rabies was prevalent. A dramatic decrease in the incidence of
      rabies was noted after the campaigns. The recombinant is presently used to
      control wildlife rabies in the field both in several European countries and in
      the United States.

PMID- 8666068
TI  - Foodborne outbreaks caused by Salmonella in Italy, 1991-4.
AB  - This report summarizes studies on 1699 foodborne outbreaks, in Italy, reported to
      the Istituto Superior di Sanita (ISS) (the National Institute of Health of Italy,
      Rome) during the period 1991-4. The most frequently reported foodborne outbreaks
      were caused by salmonellae (81%), in particular by Salmonella enteritidis and non
      serotyped group D salmonella (34% and 33% of the total salmonella outbreaks,
      respectively). A vehicle was implicated in 69% of the salmonella outbreaks; eggs
      were implicated in 77% of the outbreaks for which a vehicle was identified or
      suspected. Salmonella strains isolated in 54 outbreaks were studied for
      phenotypic and genotypic characteristics. The isolates belonged to S. enteritidis
      (50 outbreaks), S. typhimurium (three outbreaks) and S. hadar (one outbreak). In
      the S. enteritidis outbreaks, phage type 4 was most frequently isolated (64.8%),
      followed by phage type 1 (14.8%). The virulence plasmid of 38 megadaltons was
      found in many different phage types of S. enteritidis.

PMID- 8666069
TI  - Virulence and genotype stability of Salmonella enterica serovar Berta during a
      natural outbreak.
AB  - Strains of Salmonella enterica serotype Berta, collected over a period of 6 years
      from a well documented natural outbreak in Denmark, have been characterized in
      order to assess the stability of chromosomal typing systems and virulence
      properties. Outbreak strains were identical in Pvu II and PSTI IS200 profiles,
      all but two strains showed the same Sma I ribotype, and all but one strain showed
      the same Not I pulsed field gel electrophoretic pattern, indicating that these
      molecular markers remained almost constant during the outbreak. In general,
      strains of S. Berta were found to be of moderate to low virulence; log VC10
      values were found to vary between 3.0 and 4.4 after i.p. challenge of mice, and
      maximum CFU in internal organs of day-old chicks varied between 2 and 4 log10
      units following oral challenge. The minor differences observed between strains in
      vivo did not correlate with differences in in vitro invasion into cultured MDCK
      cells, nor with in vitro growth characteristics. A succession of different
      plasmid profile types was observed during the outbreak but a hierarchical
      selection of clones based on differences in virulence was unlikely to have caused
      the succession of types of S. Berta during this outbreak.

PMID- 8666067
TI  - Non-replicating expression vectors: applications in vaccine development and gene
      therapy.

PMID- 8666070
TI  - Changing epidemiology of cholera due to Vibrio cholerae O1 and O139 Bengal in
      Dhaka, Bangladesh.
AB  - At the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,
      B) Dhaka we studied the trends in cholera for the period January 1992 to May
      1995. Vibrio cholerae O139 Bengal emerged as a second aetiologic agent of cholera
      in Dhaka in January 1993. In 1993, the majority of cholera cases was due to V.
      cholerae O139, with V. cholerae O1 accounting for a small proportion of cases.
      During the latter part of the study period (Jan 1994-May 1995), V. cholerae O1 re
      emerged as the predominant cholera strain. The predominant age group affected in
      endemic cholera due to V. cholerae O1 was children 2-9 years old, and the
      organism was isolated from more females than from males at all ages. In contrast,
      cholera due to V. cholerae O139 caused disease mostly in adults 15 years and
      older, which indicated that this organism was new in this population. As with V.
      cholerae O1, V. cholerae O139 was isolated from more females than males. The
      initial rapid emergence and predominance of V. cholerae O139 was considered
      possibly to herald the start of the eighth pandemic of cholera. However, just
      after a year, the prevalence of V. cholerae O139 decreased dramatically with V.
      cholerae O1 resuming the role of the dominant cholera strain. The factor(s)
      contributing to the dramatic decline in prevalence of V. cholerae O139 is not
      well understood.

PMID- 8666071
TI  - Epidemiology of infection due to Escherichia coli O157: a 3-year prospective
      study.
AB  - A 3-year study of Escherichia coli infections in Grampian Region was conducted to
      ascertain the incidence, document clinical sequelae and identify at-risk groups.
      Approximately 30,000 stools from patients with acute diarrhoea were screened for
      E. coli O157, and an epidemiological questionnaire filled in for each patient
      whose stool was positive. Eighty-three patients were studied. The annual
      incidence was 6 per 100, 000. Proportionately more infections occurred in people
      involved in agriculture. Evidence was seen of case-to-case transmission, and
      contamination of a water supply. Eight cases developed haemolytic uraemic
      syndrome (HUS). There were 2 deaths due to HUS and 2 due to haemorrhagic colitis
      (HC). Symptomatic E. coli infection is relatively common in the Grampian Region,
      more common in the agricultural community, and is the main cause of HUS in this
      Region.

PMID- 8666072
TI  - Estimating the economic benefits of avoiding food-borne risk: is 'willingness to
      pay' feasible?
AB  - In this paper, the results of a pilot study of willingness to pay (WTP) to avoid
      poultry-borne illness are reported. Through this, the problems of devising an
      economic measure of the 'intangible' benefits of prevention of food-borne risk
      are explored. The study is the first to allow those against a prevention policy
      (irradiation of poultry-meat) to register their WTP not to have the policy
      implemented. The study demonstrates that it is feasible to obtain answers to WTP
      questions from a self-selected sample. Future studies should ensure greater
      representativeness of respondents, that better information about benefits is
      provided to respondents and that an appropriate method of aggregation of benefits
      is used.

PMID- 8666073
TI  - Phage typing and drug resistance of Shigella sonnei isolated in England and
      Wales.
AB  - Phage typing of Shigella sonnei has been used to examine isolates from the 1991-2
      sonnei dysentery outbreak in England and Wales and compare them with strains
      isolated during and following a widespread foodborne outbreak in 1994 which was
      associated with consumption of imported lettuce. The distribution of phage types
      was different in the three periods studied with PT 3 predominating during 1991-2,
      PT 2 during the 'lettuce' outbreak in the summer months and PT 6 during the
      subsequent months. PT 6 was frequently associated with travel outside the UK.
      Variation was also seen in the distribution of drug resistance patterns.

PMID- 8666074
TI  - A mixed outbreak of cryptosporidium and campylobacter infection associated with a
      private water supply.
AB  - In an outbreak of gastroenteritis affecting 43 people, cryptosporidium and
      campylobacter were isolated from stool specimens and in two cases dual infection
      was found. All the cases had drunk unboiled water from a private untreated water
      supply. Investigations revealed the carcasses of three lambs in a collection
      chamber connected with the water supply, and these, or run-off of slurry from
      surrounding fields, were the presumed source of contamination. Issues relating to
      the maintenance and monitoring of private water supplies are discussed. Problems
      with such supplies include old piping, proximity of livestock, inadequate
      knowledge of the layout and limited resources for monitoring and maintenance.

PMID- 8666075
TI  - Burkholderia cepacia respiratory tract acquisition: epidemiology and molecular
      characterization of a large nosocomial outbreak.
AB  - In 1994 we investigated a large outbreak of Burkholderia (formerly Pseudomonas)
      cepacia respiratory tract acquisition. A case patient was defined as any patient
      with at least one sputum culture from which B. cepacia was isolated from 1
      January to 31 December 1994. Seventy cases were identified. Most (40 [61%])
      occurred between 1 February and 31 March 1994; of these, 35 (86%) were
      mechanically ventilated patients, 30 of whom were in an intensive-care unit (ICU)
      when B. cepacia was first isolated. Compared with control patients who were
      mechanically ventilated in an ICU, these 30 case-patients were significantly more
      likely to have been ventilated for 2 or more days (30/30 v. 15/30; P < 0.001) or
      to have been intubated more than once (12/30 v. 2/30; OR = 9.3, 95% CI 1.6-68.8;
      P = 0.002) before the first isolation of B. cepacia. By multivariate analysis,
      the 35 mechanically ventilated case-patients were significantly more likely to
      have received a nebulized medication (OR = 11.9, 95% CI = 1.6-553.1; P < 0.001)
      and a cephalosporin antimicrobial (OR = 11.9, 95% CI = 1.6-553.1) in the 10 days
      before the first isolation of B. cepacia, compared with B. cepacia-negative
      control-patients matched by date and duration of most recent mechanical
      ventilation. Although B. cepacia was not cultured from medications or the
      hospital environment, all outbreak strains tested had an identical DNA
      restriction endonuclease digestion pattern by pulsed-field gel electrophoresis.
      Review of respiratory therapy procedures revealed opportunities for contamination
      of nebulizer reservoirs. This investigation suggests that careful adherence to
      standard procedures for administration of nebulized medications is essential to
      prevent nosocomial respiratory infections.

PMID- 8666076
TI  - Nasal carriage of enterotoxin-producing Staphylococcus aureus among restaurant
      workers in Kuwait City.
AB  - Enterotoxin-producing Staphylococcus aureus is a common cause of staphylococcal
      food poisoning. To determine the incidence of carriage of enterotoxin-producing
      S. aureus in a sample of the healthy population in Kuwait city, restaurant
      workers in the city were screened for nasal carriage of S. aureus. 26.6% of 500
      workers studied carried S. aureus and 86.6% of the S. aureus produced
      staphylococcal enterotoxins. 28% produced enterotoxin A, 28.5% produced
      enterotoxin B, 16.4% produced enterotoxin C and 3.5% produced enterotoxin D. Ten
      isolates produced both enterotoxins A and B or A and C. 73% of the isolates were
      untypeable with standard phages. However, 17.1%, 3% and 6% belonged to phage
      groups I, II and III respectively. The results demonstrated a high level of
      enterotoxigenic S. aureus carriage among restaurant workers which although lower
      than that reported for the general population and hospital workers may be
      important in the restaurant industry.

PMID- 8666077
TI  - Do intestinal parasites interfere with the seroepidemiologic surveillance of
      Schistosoma mansoni infection?
AB  - In view of the known cross-reactivity of sera from patients with intestinal
      parasites to some Schistosoma mansoni antigens, field work was conducted in an
      area of Venezuela non-endemic for schistosomiasis using the routine
      immunoenzymatic assay (ELISA) with soluble egg antigen (SEA). False positive
      reactions represented 15.3% of the total population as determined by SEA-ELISA.
      SEA-immunoblotting of the false positive sera indicated that protein fractions of
      91 and 80 kDa appear to be responsible for cross-reactivity. Sera from hookworm
      infected individuals produced a higher frequency and intensity of cross-reaction
      than other sera. SEA-fractions of 105, 54, 46, 42, 32, 25 and 15 kDa were the
      most specific.

PMID- 8666078
TI  - A school outbreak of parvovirus B19 infection investigated using salivary
      antibody assays.
AB  - An outbreak of parvovirus B19 infection at a primary school was investigated
      using saliva samples. Antibody capture immunoassays for salivary B19 IgG and IgM
      were developed using a recombinant B19 antigen and monoclonal antibody to B19
      virus. Evaluation of the salivary IgG assay using paired serum and saliva samples
      from 43 staff at St Thomas' Hospital showed that it had a sensitivity of 100% and
      a specificity of 95%. Evaluation of the salivary B19 IgM assay using 87 paired
      blood and saliva samples from a study of general practitioner rubella
      notifications showed it had a sensitivity of 60% and a specificity of 98%. Using
      the salivary assay the level of B19 IgG within 2 weeks of the start of the
      outbreak ranged from 5-33% in children and 29% in staff. By detecting salivary
      B19 IgM and/or B19 IgG seroconversions, attack rates of 8-50% in children in
      different classes and 47% in staff were observed. Household transmission was also
      studied and an attack rate of 45% was recorded in 11 susceptibles. After the
      outbreak, the level of B19 IgG in children with the highest attack rates was 60
      70%, similar to that seen in adults in the UK. This study highlights the risk of
      B19 infection in an institutional setting and shows that saliva samples are a
      useful alternative to blood.

PMID- 8666079
TI  - Outbreaks of Norwalk-like virus-associated gastroenteritis traced to shellfish:
      coexistence of two genotypes in one specimen.
AB  - We determined the nucleotide sequences of Norwalk-like viruses in 10 PCR products
      from stool or oyster specimens obtained from four outbreaks of gastroenteritis in
      which shellfish was suspected as the cause in Shizuoka prefecture in Japan
      between 1987-94. The sequences were determined from nucleotide positions 4561
      4852 (292 bp) in the polymerase region. Two types of sequences were detected. One
      (genotype 1) had 87% sequence homology with the prototype Norwalk virus, and the
      other (genotype 2) had 59% sequence homology. The sequences from isolates
      belonging to the same genotype were almost the same regardless of the year of
      isolation. Because sequences of 2 genotypes were detected in 2 of the 4
      outbreaks, nested PCR was performed with genotype-specific primers to detect the
      presence of 2 genotypes in the same specimen. In 5 of 10 specimens, PCR bands
      were detected with both genotype-specific primers, indicating the coexistence of
      2 genotypes in 1 specimen. We also detected two genotypes of Norwalk-like virus
      in an oyster from a sample implicated in one of the outbreaks which may provide
      direct evidence of oysters as the cause of the gastroenteritis.

PMID- 8666080
TI  - Risk factors for recent toxoplasma infection in pregnant women in Naples.
AB  - Effective primary prevention of congenital toxoplasmosis requires up to date
      information on locally relevant risk factors for infection in pregnant women. In
      Naples, risk factors for toxoplasma infection were compared in recently infected
      women (as assessed by detection of specific IgM in serum) and susceptible, IgG
      negative women. Recent infection was strongly associated with frequency of
      consumption of cured pork and raw meat. Eating cured pork or raw meat at least
      once a month increased the risk of toxoplasma infection threefold. This simple
      study design for determining locally relevant sources of toxoplasma infection is
      the first report of cured pork as a risk factor for infection. Further research
      is required to determine cyst viability in cured pork products. Our findings
      suggest that in southern Italy, cured pork and raw meat should be avoided by
      susceptible pregnant women.

PMID- 8666081
TI  - Investigation of tick-borne viruses as pathogens of humans in South Africa and
      evidence of Dugbe virus infection in a patient with prolonged thrombocytopenia.
AB  - In the course of investigating suspected cases of viral haemorrhagic fever in
      South Africa patients were encountered who had been bitten by ticks, but who
      lacked evidence of infection with Crimean-Congo haemorrhagic fever (CCHF) virus
      or non-viral tick-borne agents. Cattle sera were tested by enzyme-linked
      immunoassay to determine whether tick-borne viruses other than CCHF occur in the
      country. The prevalence of antibody in cattle sera was 905/2116 (42.8%) for CCHF
      virus, 70/1358 (5.2%) for Dugbe, 21/1358 (1.5%) for louping ill, 6/450 (1.3%) for
      West Nile, 7/1358 (0.5%) for Nairobi sheep disease, 3/625 (0.5%) for Kadam and
      2/450 (0.4%) for Chenuda. No reactions were recorded with Hazara, Bahig, Bhanja,
      Thogoto and Dhori viruses. The CCHF findings confirmed previous observations that
      the virus is widely prevalent within the distribution range of ticks of the genus
      Hyalomma, while antibody activity to Dugbe antigen was detected only within the
      distribution range of the tick Amblyomma hebraeum. Cross-reactivity for the
      nairoviruses, Hazara, Nairobi sheep disease and Dugbe, was detected in serum
      samples from 3/72 human patients with confirmed CCHF infection, and serum from
      1/162 other patients reacted monospecifically with Dugbe antigen. The latter
      patient suffered from febrile illness with prolonged thrombocytopenia.

PMID- 8666082
TI  - Failure of vaccination to prevent outbreaks of foot-and-mouth disease.
AB  - Outbreaks of foot-and-mouth disease persist in dairy cattle herds in Saudi Arabia
      despite revaccination at intervals of 4-6 months. Vaccine trials provide data on
      antibody responses following vaccination. Using this information we developed a
      mathematical model of the decay of protective antibodies with which we estimated
      the fraction of susceptible animals at a given time after vaccination. The model
      describes the data well, suggesting over 95% take with an antibody half-life of
      43 days. Farm records provided data on the time course of five outbreaks. We
      applied a 'SLIR' epidemiological model to these data, fitting a single parameter
      representing disease transmission rate. The analysis provides estimates of the
      basic reproduction number R(0), which may exceed 70 in some cases. We conclude
      that the critical intervaccination interval which would provide herd immunity
      against FMDV is unrealistically short, especially for heterologous challenge. We
      suggest that it may not be possible to prevent foot-and-mouth disease outbreaks
      on these farms using currently available vaccines.

PMID- 8666084
TI  - How many children with HIV?

PMID- 8666083
TI  - An abattoir-based study of the prevalence of subclinical Johne's disease in adult
      cattle in south west England.
AB  - The prevalance of subclinical Johne's disease was estimated in adult cattle
      slaughtered at three major abattoirs in south west England. A polymerase chain
      reaction (PCR) based on IS900 was used to detect Mycobacterium paratuberculosis
      in intestinal lymph nodes of 1553 cattle. Culture was also carried out on all PCR
      positive and inconclusive samples. The prevalence of subclinical disease in adult
      cattle was 3.5% (95% confidence intervals (CI) 2.6-4.7) by PCR and 2.6% (CI 1.8
      3.6) by culture. The proportion of the disease in each month ranged from 1.6% (CI
      0.2-5.5) in April to 4.6% (CI 2.8-6.9) in November, but the difference was not
      significant (P > 0.05). The proportion of PCR positive lymph nodes in each
      abattoir ranged from 2.8% (CI 1.6-4.6) to 4.9% (CI 2.9-7.6), this difference was
      not significant either (P > 0.05). The prevalence in young cattle was 2.0% (CI
      0.6-4.5). The difference between age groups was not statistically significant (P
      > 0.05).

PMID- 8666085
TI  - Women, hiv and condom use.

PMID- 8666086
TI  - Consequences for children of their birth planning status.
AB  - Of 1,327 children younger than two in 1986 whose mothers were participants in the
      National Longitudinal Survey of Youth, 61% were wanted, 34% were mistimed and 5%
      were unwanted. Planning status is associated with the level of developmental
      resources the child receives at home: At ages one and older, mistimed and
      unwanted children score significantly lower on a scale measuring opportunity for
      skill development and on a scale measuring nonauthoritarian parenting style than
      their wanted peers; by preschool age, they also have significantly less-positive
      relationships with their mothers. Measures of the direct effects of planning
      status on development also indicate that mistimed and unwanted children are at a
      disadvantage: Those younger than two have higher mean scores for fearfulness than
      wanted infants and lower scores for positive affect; unintended preschoolers
      score lower on a measure of receptive vocabulary.

PMID- 8666087
TI  - Parent and peer communication effects on AIDS-related behavior among U.S. high
      school students.
AB  - Data from a 1989 national probability sample of 8,098 high school students in the
      United States indicate that young people's discussions about the human
      immunodeficiency virus (HIV) with parents and with peers are highly correlated
      and have opposite effects on behavior. Students who discussed HIV with their
      parents were less likely than those who did not to have had multiple sex
      partners, to have had unprotected sexual intercourse and to have ever injected
      drugs; on the other hand, students who discussed HIV with their peers were more
      likely than those who did not to have had multiple partners and to have had
      unprotected sexual intercourse. Subgroup analyses show that young women were
      influenced more by HIV discussions with parents, while young men were influenced
      more by discussions with peers; some communication effects differed by race and
      ethnicity. Students who received HIV instruction in school were more likely to
      have talked about HIV with both parents and peers.

PMID- 8666088
TI  - Multiple partners, risky partners and HIV risk among low-income urban women.
AB  - A sample of 671 predominantly single, young black women living in 10 low-income
      housing developments in five cities completed an anonymous questionnaire
      assessing factors related to their risk of contracting the human immunodeficiency
      virus, including their sexual behavior and condom use, and their partners' risk
      related behaviors. In the two months before the 1994 survey, 17% of the women had
      sex with multiple partners and 22% had an exclusive partner who either had had
      other sexual partners in the past year or had a history of injection drug use;
      40% had an exclusive partner who they believed had not engaged in these risky
      behaviors. During the same interval, 26% of women who had multiple partners
      received treatment for a sexually transmitted disease, compared with 9-11% of
      those who had an exclusive relationship. Condom use at last intercourse and
      communications about condom use were less frequent among women with an exclusive,
      risky partner than among those with multiple partners; attitudinal barriers to
      condom use did not vary, however, by the characteristics of women's
      relationships.

PMID- 8666089
TI  - Still waiting for the contraceptive revolution.

PMID- 8666090
TI  - The women's conference: where aspirations and realities met.

PMID- 8666091
TI  - Impairment of gas exchange in liver cirrhosis.

PMID- 8666092
TI  - Empirical treatment of nonsevere community-acquired pneumonia: still a difficult
      issue.

PMID- 8666093
TI  - Treatment of community-acquired pneumonia: a randomized comparison of
      sparfloxacin, amoxycillin-clavulanic acid and erythromycin.
AB  - The treatment of community-acquired pneumonia is empirical in most cases and must
      cover a wide range of potential pathogens, such as Streptococcus pneumoniae,
      including penicillin-resistant strains, Haemophilus influenzae and intracellular
      microorganisms. The objective of this double-blind, randomized, parallel group
      study was to compare the efficacy and safety of sparfloxacin (400 mg loading
      dose, followed by 200 mg o.d.) with that of oral amoxycillin-clavulanic acid
      (500/125 mg t.i.d.) or oral erythromycin (1 g b.i.d.), during 7-14 days in 808
      patients with confirmed community-acquired pneumonia. The overall success rates
      for sparfloxacin (87%), amoxycillin-clavulanic acid (80%) and erythromycin (85%)
      were similar in evaluable patients, and the equivalence hypothesis used for the
      statistical analysis showed at least an equivalent efficacy for the three
      antibiotics tested. The analysis of microbiologically documented infections (40%
      of the patients) showed that overall success rates were similar for S. pneumoniae
      and H. influenzae infections. Treatment withdrawal was necessary in 3.5, 2.5 and
      7.7% of the patients treated with sparfloxacin, amoxycillin-clavulanic acid and
      erythromycin, respectively. This study indicates that sparfloxacin was at least
      as effective as amoxycillin-clavulanic acid or erythromycin in the treatment of
      mild-to-moderate community-acquired pneumonia and that the adverse effects were
      similar in the three groups.

PMID- 8666094
TI  - Evaluation of a novel tuberculosis complex-specific 34 kDa protein in the
      serological diagnosis of tuberculosis.
AB  - Tuberculosis (TB) serological testing with antigen complexes, although very
      sensitive, is not always as specific due to reactive serum antibodies in patients
      with inactive TB or nontuberculous infections. Since the use of recombinant M.
      tuberculosis proteins may enhance specificity, this study was designed to
      evaluate a novel 34 kDa tuberculosis complex-specific protein as a component of
      an antigen panel of recombinant proteins. Seventy patients with active TB (41
      positive and 29 negative for acid-fast bacilli (AFB) in sputum) were evaluated,
      in comparison with 30 tuberculin purified protein derivative skin test positive
      (PPD+) and 30 PPD- normals, 20 subjects with inactive TB and 20 PPD+ subjects
      with nontuberculous pneumonia as controls. Serum antibody levels were quantified
      using enzyme linked immunosorbent assay (ELISA) tests with MS2-34, a fusion
      protein comprising the NH2-terminal 16 kDa of the 34 kDa protein, a recombinant
      38 kDa protein (p38), and PPD. Using MS2-34 and p38 as an antigen panel in active
      TB patients yielded higher sensitivity and negative predictive value (sensitivity
      86%; negative predictive value 91%) than using PPD (sensitivity 66%; negative
      predictive value 81%). Importantly, the MS2-34+p38 panel yielded a higher
      sensitivity (83%) than PPD (66%) in the subset of AFB- active TB patients. Thus,
      this novel protein increases sensitivity and specificity of serological testing
      for TB when used in panels of recombinant proteins.

PMID- 8666095
TI  - Pulmonary vascular dilatation and diffusion-dependent impairment of gas exchange
      in liver cirrhosis.
AB  - To test the hypothesis that diffusion-limitation for oxygen is due to abnormal
      vascular dilatation and significantly contributes to the arterial hypoxaemia of
      liver cirrhosis requires an experimental approach that detects both diffusion
      limitation for oxygen and the presence of abnormal dilatation of pulmonary
      vessels exposed to alveolar gas. We therefore studied the gas exchange of a 64
      year old man with alcoholic liver cirrhosis and severe resting arterial
      hypoxaemia (arterial oxygen tension (Pa,O2) 7.5 kPa) whilst breathing air and
      100% O2 using conventional blood gas (CBG) analysis, the multiple inert gas
      elimination technique (MIGET) and whole body scintigraphy (WBS) following the
      i.v. administration of radiolabelled boli of macroaggregates with a minimum
      diameter of 15 microM. During air breathing, there was a consistently positive
      difference between the arterial oxygen tension predicted by MIGET and that
      actually measured (P-M Pa,O2, average 0.9 kPa). During O2 breathing, P-M Pa,O2
      became negative, (average -12.2 kPa), and shunt estimated by the O2 method (% of
      Q') was consistently less than that measured by MIGET. Whereas both O2 method and
      MIGET estimates of shunt never exceeded 25%, the WBS shunt was 40%, indicating
      that a substantial fraction of cardiac output flowed through abnormally dilated
      pulmonary vessels, some of which were exposed to alveolar gas and, hence,
      participated in gas exchange. Although our observations pertain to one subject,
      we believe they provide the most convincing in vivo evidence to date that
      abnormal dilatation of interalveolar vessels may, per se, result in a significant
      diffusion impairment for O2. Furthermore, in view of the consistently negative P
      M Pa,O2 observed during oxygen breathing, we speculate that such abnormal
      vascular dilatation may also have produced a significant diffusive impairment of
      one or more of the less soluble inert gases used in the MIGET analysis.

PMID- 8666096
TI  - Ventilatory and gas exchange abnormalities on exercise in chronic heart failure.
AB  - The mechanism of breathlessness on exertion in patients with chronic heart
      failure are still not fully understood. We therefore investigated the effects of
      ventilatory and gas exchange abnormalities on exercise capacity in chronic heart
      failure. Exercise testing was performed in 30 patients with exertional
      breathlessness due to chronic heart failure and in 30 controls, using continuous
      transcutaneous blood gas monitoring. Maximal symptom-limited oxygen consumption
      as (V'O2) as a percentage predicted was reduced in patients (45 +/- 10%; mean +/-
      SD) compared to controls (87 +/- 7). The ventilatory response (minute
      ventilation/carbon dioxide production (V'E/V'CO2)) was significantly increased in
      patients compared to controls (39.9 +/- 7.7 and 25.9 +/- 3.6, respectively). The
      dead space to tidal volume ratio (VD/VT) was raised in patients compared to
      controls at rest (0.45 +/- 0.04 vs 0.35 +/- 0.02, respectively) and this
      persisted on exertion (0.40 +/- 0.05 in patients and 0.20 +/- 0.05 in controls).
      At maximal symptom-limited exercise, V'E/V'CO2 was inversely related to the %
      predicted V'O2 in patients, but not in controls (r = -0.62 and r = -0.24,
      respectively). In patients, V'E/V'CO2 was significantly correlated with VD/VT at
      maximum exercise (r = 0.82). Patients with chronic heart failure have a
      significant degree of "wasted ventilation" on exertion, which is associated with
      increased ventilatory response. The increased ventilatory response on exertion
      appears to contribute to exercise limitation in these patients.

PMID- 8666097
TI  - Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene
      related peptide in hypoxic rats contrasts with increased binding sites.
AB  - Levels of calcitonin gene-related peptide (CGRP), a vasodilator peptide present
      in nerves and airway endocrine cells of the rat respiratory tract, are increased
      in hypoxic lung and decreased in plasma, suggesting impaired CGRP release. We
      wanted to determine whether there was an adaptive functional response to reduced
      CGRP levels in hypoxia. Density of binding sites for CGRP were compared with its
      vascular actions following hypoxia, and with binding following administration of
      the sensory neurotoxin capsaicin to deplete neural CGRP. Autoradiography of lung
      sections incubated with 125I-labelled CGRP and other vasoactive peptides was used
      to quantify their binding sites, in male Wistar rats exposed to periods of
      hypoxia (inspiratory oxygen fraction (FI,O2) = 0.1) ranging 0-10 days (n = 5
      each), in controls, and in rats treated neonatally with capsaicin. Relaxation to
      CGRP was compared in pulmonary artery of control and hypoxic rats. CGRP binding
      was seen in the vascular endothelium and was significantly elevated after 5 days
      of hypoxia (mean +/- SEM: control 4.6 +/- 0.4 versus hypoxic 16.6 +/- 2.4 amol.mm
      2). CGRP-induced (5 x 10(-7)M) relaxation of pulmonary artery was reduced,
      compared with controls, following 8 and 21 days of hypoxia (mean +/- SEM)
      percentage of relaxation to phenylephrine: 78 +/- 3, 36 +/- 5 and 32 +/- 3,
      respectively) and was abolished by removal of endothelium. Capsaicin treatment
      also significantly elevated vascular CGRP binding. Atrial natriuretic peptide
      (ANP) binding levels were decreased in smooth muscle of all blood vessels after 7
      days of hypoxia, but endothelin-1 (ET-1) and vasoactive intestinal peptide (VIP)
      binding was unchanged. We conclude that the vasodilator effects of CGRP are
      endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not
      due to reduction in receptors, thereby implicating alterations in the nitric
      oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide
      binding sites occur in hypoxia, which may be due to changes in endogenous peptide
      levels.

PMID- 8666098
TI  - Inhibition of factor Xa-mediated procoagulant activity of human lung fibroblasts
      and pleural mesothelial cells.
AB  - Extravascular fibrin deposition characterizes diverse forms of lung and pleural
      injury. Fibrin formation in these compartments is locally potentiated by the
      assembly and expression of the prothrombinase procoagulant complex (factors Xa,
      Va and II) at the surface of human lung fibroblasts and pleural mesothelial
      cells. We sought to identify structural domains on factor Xa that mediate
      expression of prothrombinase activity by these cells. In order to accomplish this
      objective, we used panels of monoclonal antibodies (MoAbs) to factor X to block
      prothrombinase assembly and function on the surface of cultured human lung
      fibroblasts and pleural mesothelial cells. Of 30 factor X MoAbs that recognized
      native factors X and Xa, 10 completely inhibited factor Xa function (prothrombin
      activation), and five others neutralized Xa function without affecting cell
      binding, presumably by blocking the prothrombin binding site. Western blots
      showed that these inhibitory MoAbs reacted with the Xa heavy-chain. One MoAb that
      recognized the factor Xa light-chain blocked prothrombin activation at the factor
      Va binding site. Our results indicate that prothrombinase activity at the surface
      of lung parachymal or pleural cells can be blocked by MoAbs that interact with
      either the heavy- or light-chain of factors X. Antibodies that neutralize cell
      surface-expressed prothrombin activation offer a potential means to arrest
      pericellular fibrin formation in the lung and pleural space.

PMID- 8666099
TI  - Cross-sectional assessment of workers with repeated exposure to chlorine over a
      three year period.
AB  - Airflow obstruction has been described in workers who experienced symptoms after
      acute exposure to chlorine. Persistent bronchial hyperresponsiveness has also
      been assessed, but mainly in case studies. In this cross-sectional study, we have
      assessed the relationship between inhalational accidents ("puffs") involving
      chlorine and persistent symptoms as well as hyperresponsiveness in 239 out of 255
      at-risk workers (94%). No relationship was found between persistent symptoms and
      the exposure variables studied. Forced vital capacity (FVC) was higher in
      subjects who had had no symptoms after a "puff", compared with those who had
      experienced mild symptoms. Forced expiratory volume in one second (FEV1) and FVC
      were significantly lower in subjects who experienced more than 10 puffs with mild
      symptoms than in subjects who reported no symptomatic puff. The presence of
      bronchial hyperresponsiveness was not related to exposure, but the methacholine
      dose-response slope showed a tendency to increased bronchial responsiveness with
      increased exposure. A significant difference was shown in subjects who
      experienced more than 10 puffs with mild symptoms. In this group of workers,
      repeated exposure to chlorine with acute respiratory symptoms was associated with
      a slight but significant reduction in expiratory flow rates, together with an
      increase in bronchial responsiveness, without long-term symptoms.

PMID- 8666100
TI  - Respiratory symptoms in elderly Chinese living in Hong Kong.
AB  - Respiratory diseases can cause considerable disability in the elderly because of
      their limited respiratory reserve as a result of ageing. We have investigated the
      prevalence of respiratory symptoms and diseases in elderly Chinese in Hong Kong
      and compared these data with those in elderly Caucasian populations. Two thousand
      and thirty two (999 male and 1,033 female) subjects, selected by age-stratified
      random sampling from a register of Hong Kong residents aged 70 yrs and over were
      interviewed to complete a respiratory questionnaire. Total serum immunoglobulin E
      (IgE) was measured in 195 subjects. At least one respiratory symptom was reported
      by 56% of subjects. The most frequently reported symptoms were morning phlegm
      (26%), chronic cough with phlegm (10%) and wheeze in the past 12 months (8%). Of
      the self-reported diseases, the commonest was chronic bronchitis (7%), followed
      by asthma (5%), pulmonary tuberculosis (3%) and emphysema (2%). Of the 218
      subjects with obstructive airway diseases, 128 (59%) had sought medical advice in
      the past 12 months. The most important determinants for respiratory symptoms and
      diseases were smoking and social class. Total serum IgE was significantly higher
      in current smokers than nonsmokers and also in those with chronic cough and
      phlegm than those without these complaints. Our study shows that respiratory
      ailments in Hong Kong elderly are as common as those reported in Sweden and the
      USA but less than those in England.

PMID- 8666101
TI  - Home treatment for chronic respiratory failure in children: a prospective study.
AB  - Home treatment for children with chronic respiratory failure (CRF) is increasing.
      However, the causes of CRF in children and the details of their home treatment
      are not well-known. The aim of this study was to describe the causes of CRF in
      the paediatric population and the treatments that the patients received at home.
      We surveyed all children (aged < or = 18 yrs) entering the Association Nationale
      pour le Traitement a Domicile de l'Insuffisance Respiratoire chronique (ANTADIR)
      for home treatment of CRF between March 1992 and March 1993. Two hundred and
      eighty seven children (178 boys, 62%) started home treatment for CRF during the
      year. One hundred and eleven patients had obstructive respiratory disease: cystic
      fibrosis (CF) (n = 24); bronchopulmonary dysplasia (BPD) (n = 79); other
      obstructive respiratory disease (n = 8). One hundred and seventy six patients had
      restrictive lung disease: neuromuscular disease (n = 87); kyphoscoliosis (n =
      21); pulmonary fibrosis (n = 6); cardiac disease (n = 14); stomatological disease
      (n = 10); other restrictive respiratory disease (n = 9); and 29 miscellaneous
      causes. One hundred and thirteen patients received oxygen therapy, with a mean
      daily use of 17.7 h (20 h.day-1 for BPD patients and 12.3 h.day-1 for CF
      patients). Oxygen was delivered by a concentrator in 88% of cases. One hundred
      and fifty eight children received mechanical ventilation (MV). Five children
      received nasal continuous positive airway pressure ventilation for sleep apnoea,
      four had pneumatic belt ventilation, and 12 had a tracheostomy without MV.
      Treatment was stopped in 21 children, because of death in nine and improvement in
      the other 12. Home treatment for children with CRF is well developed in France
      via the ANTADIR network. Causes of CRF in children are heterogeneous, with a
      relatively good prognosis.

PMID- 8666102
TI  - Lung function measurement in awake young children.
AB  - The aim of the study was to evaluate methods applicable in a clinical setting for
      monitoring of changes in lung function in awake young children. Impedance
      measurements by the impulse oscillation technique (ZIOS), respiratory resistance
      measurements by the interrupter technique (Rint) and transcutaneous measurements
      of oxygen tension (Ptc,O2) were compared with concomitant measurements of
      specific airway resistance (sRaw) and forced expiratory volume in one second
      (FEV1) by whole body plethysmography and spirometry, respectively, during
      methacholine challenge in 21 young children aged 4-6 yrs, with suspected asthma.
      Measurements with each technique were repeated after each challenge step. A
      special face-mask was developed with an integrated mouthpiece which ensured mouth
      breathing during the measurements. The order of sensitivity of the techniques to
      assess methacholine-induced changes in lung function was ZIOS > sRaw > Ptc,O2 >
      FEV1 > Rint. ZIOS was significantly more sensitive than all subsequent methods,
      and Ptc,O2 was significantly more sensitive than FEV1. ZIOS, sRaw and Rint, but
      not Ptc,O2 and FEV1, detected the subclinical increase in bronchial muscle tone
      in the children during baseline, which was revealed by the significantly reduced
      airway obstruction after inhalation of a beta 2-agonist as compared to baseline.
      It is concluded that ZIOS, Rint and Ptc,O2 change in parallel with sRaw and FEV1
      and with a comparable sensitivity during simultanoeous measurements of the
      response to methacholine in young children aged 4-6 yrs. This implies that ZIOS,
      Rint and Ptc,O2 provide convenient indices of changes in lung function. Their
      combined use will be useful for monitoring airway diseases of young children.

PMID- 8666103
TI  - Frequency of nocturnal symptoms in asthmatic children attending a hospital out
      patient clinic.
AB  - Since nocturnal symptoms indicate more severe asthma, we investigated their
      frequency in a hospital-based population of asthmatic children. Recognition of
      these symptoms offers the possibility to introduce appropriate treatment. We
      studied 796 consecutive children with asthma (mean (SD) age 9 (4) yrs) attending
      a hospital clinic, to determine whether these nocturnal symptoms predicted that
      daytime activities would be affected, and also the patients' perception of
      disease severity. At the end of a regular out-patient clinic visit, the answers
      to seven different questions concerning nocturnal symptoms in the previous 3
      weeks were recorded. The forced expiratory volume in one second (FEV1) was > or =
      90% predicted in 98% of the population that was able to perform lung function
      measurements (72% of the total population). In 38% of the patients with nocturnal
      symptoms, these symptoms were reported spontaneously. When asked for, nocturnal
      symptoms were reported by 47% of the children; 6% every night and 34% at least
      once a week. Cough was the most frequently reported symptom (31%). Children with
      nocturnal symptoms had a lower FEV1, scored their perception of asthma as more
      severe, and had their daytime activities affected more than those without
      nocturnal symptoms. Doctors should specifically ask about nocturnal symptoms, as
      not all patients with nocturnal symptoms report them spontaneously and they
      predict more severe disease.

PMID- 8666104
TI  - Outcome of wheeze in childhood: the influence of atopy.
AB  - We have previously demonstrated that the adult outcome of childhood asthma
      differs from that of wheeze occurring only in the presence of infection. This
      paper examines the role of atopy in relation to outcome. We investigated the
      atopic status, current symptoms and bronchial reactivity to methacholine of 235
      subjects aged 34-40 yrs, originally classified at age 10-15 yrs as having asthma
      (asthma group), wheeze only in the presence of infection (wheezy group), or no
      respiratory symptoms (comparison group). Subjects from the original asthma group
      were more likely to be atopic as defined by skin test reactivity, total serum
      immunoglobulin E (IgE) measurement or specific IgE radio allergosorbent test
      (RAST) measurement than those from the wheezy group. The wheezy group differed
      significantly from the reference group only in RAST results, when other variables
      were taken into account. In a logistic regression model, the important
      independent predictors for adult wheezing symptoms were original group, atopy and
      current smoking. Methacholine responsiveness was independently associated with
      original group (the asthma group were more likely to respond positively), atopy
      and female gender. The results suggest that atopy is an important predictor for
      wheeze and bronchial hyperreactivity in middle age. However, the difference in
      outcome for children who had asthma compared to those who had wheeze only in the
      presence of infection cannot be explained by atopy alone.

PMID- 8666105
TI  - Facial cooling, but not nasal breathing of cold air, induces bronchoconstriction:
      a study in asthmatic and healthy subjects.
AB  - Reflex-mediated bronchoconstriction in cold climates may be more important than
      it has previously been thought. This issue has seldom been studied using
      physiological methods. We wanted to investigate, using physiological methods,
      what triggers the bronchoconstriction occurring at cold ambient temperature
      during resting nasal ventilation: cooling of the skin of the face or cooling of
      the nasal cavity. Three experiments were carried out in 15 stable asthmatics and
      10 healthy volunteers: 1) a whole-body exposure to subfreezing temperature in an
      environmental chamber, during which the subjects breathed cold air through the
      nose; 2) a similar exposure to subfreezing temperature except that the subjects
      now breathed warm air through the mouth from outside the chamber; and 3) nasal
      breathing of subfreezing air from a heat exchanger whilst the subjects sat at
      room temperature. Spirometric values and facial skin temperature were measured
      both during and after the exposures. Maximal decrements (means +/- standard
      errors) of forced expiratory volume in one second (FEV1) in experiments 1, 2 and
      3 were: 5.8 +/- 0.8, 5.1 +/- 0.7 and 2.1 +/- 0.5%, respectively (p < 0.001). Only
      the two experiments in the environmental chamber induced significant
      bronchoconstriction. All responses were of similar magnitude in the asthmatic and
      the healthy subjects. The cooling of the skin of the face seems to be the trigger
      for the bronchoconstriction during resting nasal ventilation at cold ambient
      temperature both in asthmatic and nonasthmatic subjects.

PMID- 8666106
TI  - Histamine-induced end-tidal inspiratory activity and lung receptors in cats.
AB  - Hyperinflation in acute asthma has been associated with inspiratory muscle
      activity, which persist during expiration. The main objective of the present
      study was to evaluate the role of rapidly adapting receptors (RARs), slowly
      adapting receptors (SARs) and C-fibre endings in generating end-tidal inspiratory
      activity (ETIA). ETIA was induced by intravenous administration of histamine and
      continuous negative airway pressure (CNAP) in anaesthetized, spontaneously
      breathing cats. To differentiate between reflex activities from the three types
      of lung receptors, both vagus nerves were cooled to eight different temperatures
      (Tvg) between 4 and 37 degrees C. It is known that CNAP stimulates RARs and
      inhibits SARs. Histamine was used to stimulate RARs, and this was combined with
      continuous positive airway pressure (CPAP) to further stimulate SARs. ETIA was
      evoked in the diaphragm and in parasternal intercostal muscles by both stimuli
      (histamine and CNAP) in 8 out of 18 cats. After vagotomy, neither histamine nor
      CNAP evoked ETIA any more. At Tvg = 37 degrees C, CPAP suppressed histamine
      induced ETIA; whereas, this suppression was diminished at Tvg between 14 and 8
      degrees C. ETIA sharply declined for Tvg between 8 degrees and 4 degrees C, and
      at Tvg = 4 degrees C ETIA had virtually disappeared. At Tvg = 37 degrees and 22
      degrees C values of ETIA during CNAP were larger than those in response to
      histamine; whereas, at Tvg = 10 degrees C comparable ETIA values were obtained.
      It was shown that ETIA is a vagal reflex activity in which C-fibre endings are
      not involved. Histamine-induced ETIA originates from stimulation of RARs, and is
      inhibited by stimulation of SARs. Mechanical stimulation of RARs is a forceful
      stimulus to induce ETIA. This suggests that hyperinflation in acute asthma might
      be due, at least in part, to ETIA resulting from an imbalance between SAR and RAR
      activity.

PMID- 8666107
TI  - Time-course of antigen-induced airway inflammation in the guinea-pig and its
      relationship to airway hyperresponsiveness.
AB  - The causative relationship between airway inflammation and hyperreactivity is
      unclear, since inflammatory changes have been examined at one or, at most, a few
      time-points after antigen challenge in both human asthma and animal models. We
      have made a detailed investigation of inflammatory and functional changes in the
      airways up to 8 days after antigen challenge in guinea-pigs. In particular, we
      examined the hypothesis that eosinophil-derived mediators contribute to tissue
      damage and the development of airway hyperresponsiveness. Following antigen
      challenge, the influx of inflammatory cells and mediator release in airway tissue
      and bronchoalveolar lavage fluid were correlated temporally with
      histopathological changes in airway tissue and airway responsiveness. Eosinophil
      influx was demonstrable at 4 h. Eosinophilia peaked after 24 h and persisted for
      at least 8 days. Parallel increases in the concentrations of major basic protein
      and eosinophil cationic protein in bronchoalveolar lavage fluid indicated that
      the eosinophils were activated. Eosinophilia was accompanied by subepithelial
      oedema and epithelial damage co-localized with major basic protein
      immunoreactivity. A transient neutrophilia (< 48 h duration) and an increase in
      neutrophil elastase in bronchoalveolar lavage fluid peaked at 14 h. The
      proportion of airway macrophages with an activated morphology increased at 8 h
      and remained markedly elevated until 72 h. Airways were hyperresponsive to
      histamine at 4 h and for at least 8 days. The antigen-induced airway inflammation
      resemble in time-course and histopathology that seen in antigen-challenged
      asthmatics, and indicate that the eosinophil and its cytotoxic proteins may be
      major mediators of airway mucosal damage and airway hyperresponsiveness.

PMID- 8666108
TI  - Xanthine derivatives inhibit the increase in intracellular Ca2+ concentration
      induced by acetylcholine in nasal gland acinar cells of the guinea-pig.
AB  - Intracellular calcium is considered to play a major role in secretory responses
      of various exocrine cell types. We examined whether xanthine derivatives can
      inhibit Ca2+ mobilization and entry in secretory cells in the airways. Therefore,
      the inhibitory effect of xanthines in the intracellular Ca2+ concentration
      ([Ca2+]i) in the isolated submucosal acinar cells of the guinea-pig nasal septum
      was investigated by means of fluorescence ratio microscopy. The inhibitory
      effects on Ca2+ release from stores was examined in Ca(2+)-free conditions.
      Effects on Ca2+ entry were estimated by two different protocols; 1) the sustained
      phase in a long-term application of acetylcholine (ACh) and 2) the [Ca2+]i
      overshoot following removal of ACh in Ca(2+)-free conditions. Xanthine
      derivatives, 3-isobutyl-1-methyl-xanthine (IBMX), caffeine, and theophylline,
      significantly inhibited the increase in [Ca2+]i evoked by ACh; both mobilization
      from internal Ca2+ stores and Ca2+ entry from the external space. The rank order
      of potency of these xanthine derivatives was IBMX > theophylline > caffeine. The
      addition of dibutyryl-cyclic adenosine monophosphate (cAMP) and forskolin to
      nasal gland acinar cells failed to inhibit the ACh-evoked increase in [Ca2+]i.
      Furthermore, a protein kinase A inhibitor, H-89, did not affect the inhibitory
      effect of the xanthine derivatives. The action of xanthines on the present acinar
      cells did not involve Ca(2+)-induced Ca2+ release (CICR) or an interaction with
      purinergic receptors. Thus, xanthines have a direct inhibitory effect both on
      Ca2+ release and entry in nasal gland acinar cells, and might thereby have
      antisecretory activity within the airways.

PMID- 8666109
TI  - The acoustic properties of snores.
AB  - This study was undertaken in an attempt to characterize the acoustic properties
      of snoring sounds in the time and frequency domains, and to correlate between
      these properties and the mechanical events underlying their production. Three
      experimental set-ups were used: 1) Dog model--six mongrel dogs, in which partial
      upper airway obstruction was created by an implanted supraglottic balloon. Flow,
      supraglottic pressure, and snoring sounds were recorded during different degrees
      of obstruction. Fifteen to 20 snores from each dog (total 100 snores) were
      analysed. 2) Simulated human snores--Six simulated snores from each of four
      subjects were recorded in two locations (trachea and ambient) with simultaneous
      airflow, and their correlations examined. 3) Snoring patients--snores were
      recorded with an ambient microphone from nine subjects with "heavy" snoring and
      no obstructive sleep apnoea (OSA). Forty to 50 snores from each subject were
      analysed (total of 400 snores). The snoring sound was analysed in the time (time
      expanded waveform) and frequency (power spectrum) domains. After analysing these
      snores, we were able to identify two dominant patterns which are distinctly
      different from each other: the "simple-waveform" and the "complex-waveform". The
      complex-waveform snore is characterized by repetitive, equally-spaced, train of
      sound structures, starting with a large deflection followed by a decaying
      amplitude wave. In the frequency domain, it is characterized by multiple, equally
      spaced peaks of power (comb-like spectrum). Simple-waveform snores have a quasi
      sinusoidal waveform, with a range of variants, and almost no secondary internal
      oscillations. Their power spectrum contains only 1-3 peaks, of which the first is
      the most prominent. We developed a mathematical representation of these
      waveforms, which is presented along with its implications. The complex-waveform
      snores result from colliding of the airway walls and represent actual brief
      airway closure. Simple-waveform snores are of higher frequency and probably
      result from oscillation around a neutral position without actual closure of the
      lumen.

PMID- 8666110
TI  - Cellular and molecular mechanisms in the pathogenesis of severe pulmonary
      hypertension.
AB  - Chronic pulmonary hypertension leads to structural alterations of the lung
      vessels. The pathophysiology of this remodelling process is still poorly
      understood. Furthermore, the structural damage of the lung vessels limits the
      clinical success of vasodilator treatment. Given a genetic susceptibility, shear
      stress and inflammation are the principal pathogenetic factors involved in lung
      vessel remodelling. In this overview, we compared the lung vascular histology of
      patients with unexplained pulmonary hypertension, scleroderma, or acquired immune
      deficiency syndrome (AIDS)-associated pulmonary hypertension. We demonstrate the
      presence of inflammatory cells (T- and B-lymphocytes and macrophages) in
      plexiform lesions and discuss the potential role of growth factors (platelet
      derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and
      vascular endothelial growth factor (VEGF) in pulmonary hypertensive remodelling.
      Ultimately, we need to develop an in-depth understanding of the key mechanisms of
      gene expression and signalling pathways, which transduce signals generated from
      increased chronic shear stress (or from chronic hypoxia) and lead to vascular
      injury and repair.

PMID- 8666111
TI  - Crackles: recording, analysis and clinical significance.
AB  - Crackles are short interrupted breath sounds usually associated with pulmonary
      disorders. According to present opinion, a crackle is generated when an
      abnormally closed airway opens during inspiration or closes at the end of
      expiration. The timing of crackles in breathing cycles can be assessed with
      phonopneumography, their duration with time-expanded waveform analysis, and their
      pitch with analysis of frequency spectra. The timing, pitch and waveform of
      crackles are different in pulmonary disorders reflecting different pulmonary
      pathophysiology. This review deals with the genesis, auscultation, recording and
      analysis of crackles, with an emphasis on modern signal-processing methods.

PMID- 8666112
TI  - Respiratory health effects of man-made vitreous (mineral) fibres.
AB  - The group of man-made mineral or vitreous fibres (MMMFs or MMVFs) includes glass
      wool, rock wool, slag wool, glass filaments and microfibres, and refractory
      ceramic fibres (RCFs). Experimental observations have provided evidence that some
      types of MMVF are bioactive under certain conditions. The critical role of size
      parameters has been demonstrated in cellular and animal experiments, when intact
      fibres are in direct contact with the target cells. It is, however, difficult to
      extrapolate the results from these studies to humans since they bypass
      inhalation, deposition, clearance and translocation mechanisms. Inhalation
      studies are more realistic, but show differences between animal species regarding
      their sensibility to tumour induction by fibres. Fibre biopersistence is an
      important factor, as suggested by recent inhalation studies, which demonstrate
      positive results with RCF for fibrosis, lung tumours and mesothelioma. There is
      no firm evidence that exposure to glass-, rock- and slag wool is associated with
      lung fibrosis, pleural lesions, or nonspecific respiratory disease in humans.
      Exposure to RCF could enhance the effects of smoking in causing airways
      obstruction. An elevated standard mortality ratio for lung cancer has been
      demonstrated in cohorts of workers exposed to MMVF, especially in the early
      technological phase of mineral (rock slag) wool production. During that period,
      several carcinogenic agents (arsenic, asbestos, polycyclic aromatic hydrocarbons
      (PAH)) were also present at the workplace and quantitative data about smoking and
      fibre levels are lacking. It is not possible from these data to determine whether
      the risk of lung cancer is due to the MMVFs themselves. No increased risk of
      mesothelioma has been demonstrated in the cohorts of workers exposed to glass-,
      slag- or rock wool. There are in fact insufficient epidemiological data available
      concerning neoplastic diseases in RCF production workers because of the small
      size of the workforce and the relatively recent industrial production.

PMID- 8666113
TI  - Corynebacterium parvum versus tetracycline as pleural sclerosing agents in
      rabbits.
AB  - Tetracycline has been one of the most commonly used agents for producing a
      pleurodesis. However, it is no longer available due to more stringent
      requirements on the manufacturing process. The objective of this project was to
      determine whether Corynebacterium parvum is an effective sclerosant in an
      experimental model in rabbits. The following medications were instilled
      intrapleurally in anaesthetized male rabbits: tetracycline 35 mg.kg-1 or C.
      parvum 4 or 8 mg, all diluted with bacteriostatic saline solution. Twenty eight
      days after the instillation, the animals were sacrificed and the pleural spaces
      assessed macroscopically for evidence of pleurodesis and microscopically for
      evidence of fibrosis and inflammation. The intrapleural injection of C. parvum
      was ineffective in creating pleural fibrosis. The mean degree of pleurodesis in
      the 10 rabbits who received tetracycline was 3.5 +/- 0.7 (scale 0-4) whilst in
      the 10 rabbits that received 4 mg C. parvum it was 0.0 +/- 0.0, and in the 10
      rabbits that received 8 mg C. parvum it was 0.5 +/- 0.8. Based on this study, we
      recommend that C. parvum should not be used as a pleural sclerosant in patients
      with normal pleura.

PMID- 8666114
TI  - Actual pentamidine dose delivered by Respigard II nebulizer.
AB  - The Respigard II nebulizer system is the approved method to deliver pentamidine
      aerosols in the USA. Although continuous operation of the nebulizer until dryness
      is a designated regimen, the actual pentamidine dose delivered under the
      operating condition has not been thoroughly studied. Pentamidine solutions (300
      mg in 6 mL water) were nebulized continuously with the Respigard II nebulizer
      system until dryness (40 min operation). Aerosols were delivered to the lower
      airways via an oropharyngeal model and sampled on a filter with a standard
      breathing mode of 20 breaths.min-1 frequency and 750 mL tidal volume.
      Intermediate samples were also obtained for the initial 20 min delivery. The
      pentamidine dose delivered to the mouth was 1.6% of the dose placed in the
      nebulizer. Of the dose delivered to the mouth, 92% was delivered during the
      initial 20 min period. Aerosol loss in the oropharyngeal model was 15% of the
      dose delivered to the mouth or 0.24% of the dose initially placed in the
      nebulizer. Pentamidine dose delivered to the lower airways was a very small
      fraction of the initial dose in the nebulizer. A partial delivery for the initial
      20 min was nearly comparable to complete delivery.

PMID- 8666115
TI  - Fatal haemorrhage from mesenchymal cystic hamartoma of the lung.
AB  - A 34 year old women was admitted to the hospital with a 9 year history of
      intermittent haemoptysis associated with increasing breathlessness. A working
      diagnosis of lymphangioleiomyomatosis was made, based on clinical, radiological
      and histological findings. Three years later, the patient was admitted to
      hospital with worsening haemoptysis, which rapidly progressed and resulted in
      death from massive pulmonary haemorrhage. Postmortem examination and histology
      revealed findings consistent with multiple mesenchymal cystic hamartomas of the
      lungs. This is a rare condition which has previously been described as having a
      good prognosis. This case is the first fatality resulting directly from the
      disease to be reported.

PMID- 8666116
TI  - Bronchogenic cyst presenting as mediastinal mass with pleural effusion.
AB  - Mediastinal bronchogenic cysts are usually identified on computed tomography (CT)
      as well-defined masses of variable density that may contain rim calcifications.
      Pleural effusion has never been described in association with these cysts. We
      report two cases of bronchogenic cysts with unusual presentation because of an
      association with a pleural effusion not explained by pulmonary infection. The
      patients were studied with CT scan (n = 2) and magnetic resonance imaging (MRI)
      of the chest (n = 1). In the first case, the pleural effusion directed diagnosis
      towards lung tumour; and the diagnosis of bronchogenic cyst was made on
      thoracotomy. In the second case, bronchogenic cyst was suspected on MRI findings.
      Inflammatory reaction was also suspected on the CT scan, which showed enhancement
      of the cyst edge. In both cases, surgical excision of the cyst was difficult
      because of pericystic adhesions to adjacent organs. Therefore, solely on the
      finding of a pleural effusion, pericystic inflammation had to be suspected.

PMID- 8666117
TI  - Spontaneous cervical subcutaneous and mediastinal emphysema secondary to occult
      sigmoid diverticulitis.
AB  - We present a case of spontaneous mediastinal and subcutaneous cervical emphysema
      due to perforation of an occult sigmoid diverticulitis. Mediastinal emphysema
      should alert the physician to the possibility of retroperitoneal gastrointestinal
      perforation, even in patients without signs of distinct peritoneal irritation.

PMID- 8666118
TI  - Constrictive bronchiolitis obliterans following gold therapy for psoriatic
      arthritis.
AB  - A 41 year old male with psoriatic arthritis developed progressive dyspnoea and
      airflow obstruction following 4 months of intramuscular gold therapy. Open lung
      biopsy revealed bronchiolitis obliterans of the constrictive type. This case
      suggests a possible aetiological role for gold in the pathogenesis of
      constrictive bronchiolitis obliterans, or alternatively an association between
      psoriatic arthritis and this inflammatory airway condition.

PMID- 8666119
TI  - Lung deposition of budesonide from Turbuhaler is twice that from a pressurized
      metered-dose inhaler (P-MDI)

PMID- 8666120
TI  - Todays issues in HRT with a focus on Menorest. Introduction.

PMID- 8666121
TI  - HRT: the woman's perspective.
AB  - Questionnaire studies in Europe show that women's concerns at the menopause are
      more related to their self-image and sexual identity than to medical consequences
      such as osteoporosis or coronary heart disease. Women long for help with
      menopausal problems, yet are concerned about the potential side effects of HRT
      and often perceive the information they receive from their doctors to be
      inadequate. Adverse effects of menopausal estrogen deprivation on sexual and
      psychological function occur via two main mechanisms. Firstly, the physical
      changes that occur at the menopause affect body image, sexual function and
      women's relationships with their partners. Lack of estrogens worsens the effects
      of ageing on the female body and psyche. Secondly, there are changes in
      neuroendocrine and psychological function (e.g. effects on mood, memory and sleep
      patterns), affecting ego and self-perception. Estrogen replacement in hormone
      replacement therapy (HRT) improves both sexual and psychological self-image and
      function.

PMID- 8666122
TI  - New trends in transdermal technologies: development of the skin patch, Menorest.
AB  - Menorest is a transdermal patch, in which 17 beta-estradiol is dispersed as a
      microfine suspension in an adhesive matrix. This system reduces the size and
      thickness of the patch making it more cosmetically acceptable than older
      reservoir patches. Pharmacokinetic studies indicate that, at doses from 25-100
      micrograms/day, Menorest releases estradiol at a constant and reproducible rate.
      There is a linear relationship between the dose of estradiol administered (which
      is determined by the surface area of the patch) and the plasma concentration of
      estradiol. Unlike the standard reference reservoir patch, Estraderm, or another
      matrix patch, Systen/Evorel, Menorest maintains plasma estradiol concentrations
      at or above the target level of 40 pg/ml throughout the 80-h dosing interval.

PMID- 8666123
TI  - HRT and long-term compliance: the efficacy and safety of Menorest.
AB  - Hormone replacement therapy (HRT) is perhaps the most important development in
      preventive medicine in the Western world for half a century, yet long-term
      compliance is notoriously poor. Up to 75% of women who start on HRT are reported
      to drop out within the first 6 months. Poor compliance may arise from a lack of
      awareness of the benefits of HRT, or from a number of common misconceptions,
      particularly the idea that HRT is ?unnatural', and will cause weight gain,
      cancer, or unpleasant side effects. While side effects (usually progestogenic)
      may of course occur on HRT, they can usually be managed by a change in the
      regimen. Studies of the efficacy and safety of Menorest, an adhesive matrix
      transdermal system, used in combination with dydrogesterone for 12 days in each
      cycle, show it to be effective in relieving menopausal symptoms and increasing
      lumbar and spinal bone mass. Menorest was as effective and well-tolerated as a
      reference oral treatment (conjugated estrogens), and its twice weekly application
      may be considered to promote compliance.

PMID- 8666124
TI  - Menorest: a clinical overview.
AB  - Menorest is an adhesive matrix patch containing 17 beta-estradiol at various
      doses. Menorest 50 micrograms/day has been compared with oral equine estrogens
      (Premarin 0.625 mg/day) and with a reservoir patch, Estraderm at 50
      micrograms/day. Menorest was as effective as either of the two comparison
      treatments in controlling vasovagal and urinogenital symptoms of the menopause.
      None of the treatments produced any significant effects on blood pressure or the
      lipid profile. All three treatments were well-tolerated, but there appeared to be
      slightly more side effects with Estraderm than with Menorest, particularly with
      regard to local erythema and itching.

PMID- 8666125
TI  - HRT prescribing guidelines: dream or reality?
AB  - An international round-table meeting was held in the UK in June 1995, with the
      aim of developing simple, practical guidelines for hormone replacement therapy
      (HRT). Great emphasis was placed on initial and on-going counselling as a means
      of promoting compliance. The choice of preparation will depend on whether the
      patient has an intact uterus, and, if so, whether she is willing to accept
      regular bleeding. Hysterectomized women should receive continuous estrogen alone,
      while, for non-hysterectomized women, the first choice of treatment is continuous
      estrogen with sequential progesterone for at least 10 days in each month.
      Continuous combined treatment may be given as an alternative. Symptomatic side
      effects are most likely to occur at the beginning of treatment and can usually be
      easily managed by a change in the preparations. Despite misleading information in
      package inserts, there are few absolute contra-indications to HRT.

PMID- 8666126
TI  - Control of epitheliomesenchymal transformation. II. Cross-modulation of cell
      adhesion and cytoskeletal systems in embryonic neural cells.
AB  - Protein kinase (PK) inhibitors like staurosporine induce precocious
      epitheliomesenchymal transformation (EMT) of quail embryo neural anlagen cultured
      on the extracellular matrix (ECM) molecule fibronectin (Newgreen and Minichiello,
      Dev. Biol. 170, 91-101; 1995). We show here that this also occurs on laminin,
      vitronectin, and collagen type I and type IV, but not on polylysine or BSA. In
      the absence of cell-ECM adhesion, staurosporine produced a rapid increase in,
      rather than a loss of, cohesion in isolated neural anlagen and increased the rate
      of reaggregation of dissociated neural cells. In the absence of cell-cell
      adhesions (i.e., with dissociated cells), almost all neural cells rapidly adhered
      to fibronectin in vitro and staurosporine made only a marginal difference to
      this. Almost no neural cells spread on fibronectin in control conditions but
      staurosporine stimulated spreading by almost all cells. When cell-cell adhesions
      were present, neural anlage explants were more difficult to dislodge by
      controlled shear from fibronectin substrates in the presence of staurosporine
      than under control conditions, but in both experiments and controls dislodgment
      was due to the cell bodies breaking proximal to the cell-fibronectin adhesion
      sites. EMT in neural cells in culture, both spontaneous and induced by
      staurosporine, involved rapid reduction in circumferential F-actin fibers and an
      increase in pancytoplasmic G-actin, as shown by fluorescent phalloidin and DNase
      I labeling. Loss of immunoreactivity for N-cadherin at cell-cell junctions also
      occurred in both spontaneous and induced EMT. However, in spontaneous EMT the
      cadherin changes preceded the actin changes, whereas in induced EMT, the reverse
      occurred. The results suggest that the molecules involved in EMT which are
      affected by PK inhibitors are cytoskeletal and link elements. These results also
      suggest that balanced cross-modulation among cell-cell adhesion molecules, cell
      ECM adhesion molecules, and cytoskeletal molecules can trigger and orchestrate
      EMT, without direct genetic supervision.

PMID- 8666127
TI  - Fetal behavior in developmental psychobiology.

PMID- 8666128
TI  - Stress reactivity and attachment security.
AB  - Seventy-three 18-month-olds were tested in the Ainsworth Strange Situation. These
      children were a subset of 83 infants tested at 2, 4, 6, and 15 months during
      their well-baby examinations with inoculations. Salivary cortisol, behavioral
      distress, and maternal responsiveness measures obtained during these clinic
      visits were examined in relation to attachment classifications. In addition,
      parental report measures of the children's social fearfulness in the 2nd year of
      life were used to classify the children into high-fearful versus average- to low
      fearful groups. In the 2nd year, the combination of high fearfulness and insecure
      versus secure attachment was associated with higher cortisol responses to both
      the clinic exam-inoculation situation and the Strange Situation. Thus, attachment
      security moderates the physiological consequences of fearful, inhibited
      temperament. Regarding the 2-, 4-, and 6-month data, later attachment security
      was related to greater maternal responsiveness and lower cortisol baselines.
      Neither cortisol nor behavioral reactivity to the inoculations predicted later
      attachment classifications. There was some suggestion, however, that at their 2
      month checkup, infants who would later be classified as insecurely attached
      exhibited larger dissociations between the magnitude of their behavioral and
      hormonal response to the inoculations. Greater differences between internal
      (hormonal) and external (crying) responses were also negatively correlated with
      maternal responsiveness and positively correlated with pretest cortisol levels
      during these early months of life.

PMID- 8666129
TI  - Asymmetric headturning to speech and nonspeech in human newborns.
AB  - Functional asymmetries were examined in 59 newborns by recording headturns from
      midline to binaurally equivalent sounds. Results showed that robust, asymmetric
      pattern of headturning occurred in most newborns' responses to binaurally
      presented unfiltered female speech sounds, with increased rightward orientation
      demonstrated in five replications. Female speech that was modified by attenuation
      of frequencies above 500 Hz, as well as speech attenuated below 1500 Hz and above
      3000 Hz, resulted in a significant rightward bias in headturning. In contrast,
      female speech attenuated below 3500 Hz, and continuous, repetitive stimuli such
      as heartbeat sounds and phrases of speech repeated at the rate of heartbeat
      (termed heartspeech), failed to generate the rightward orientation bias. These
      results suggest that female speech sounds, particularly low-frequency sounds
      related to the naturally occurring prosodic characteristics of speech, are a
      salient class of stimuli for the organization of lateral biases in orienting in
      newborns.

PMID- 8666130
TI  - Ontogenetic differences in variability on simple measures of learning:
      theoretical and practical implications.
AB  - Data from a variety of sources, including a number of tasks and dependent
      measures, suggests that a systematic inverse relationship exists between age and
      the amount of variability observed on simple measures of learning. Implications
      for general theoretical perspectives concerning ontogenetic differences in
      stimulus and response selection, acquired knowledge or experience, and general
      speed of information processing are discussed. It is argued that such a
      regularity offers possibilities for both methodological and theoretical
      explorations.

PMID- 8666131
TI  - Diet selection by chicks.
AB  - Seven experiments with 324 chicks tested their ability to select a nutritionally
      adequate diet from separate sources of purified casein and various supplements,
      including gelatin (a source of two amino acids), a gelatin-creatine mixture (a
      source of three amino acids), and fiber (nonnutritive bulk). Nonselecting
      controls consumed the basal purified-casein diet or a supplemented purified
      casein diet. Chicks in all selection conditions composed diets that yielded
      normal intake, normal body temperature, normal activity, and the maximum growth
      possible for their intake. They also selected components in the same percentages
      as in premixed diets. In all instances, their selection was nonrandom and
      regulated. What chicks included in their diet depended on what else was
      available. Although the specific percentage taken from each dietary component
      varied across different selection alternatives, these differences affected
      neither intake nor growth. Selection, per se, incurred a caloric cost. Chicks
      selecting from fractions of a corn-and-soy diet offset this cost by increasing
      intake compensatorily, but chicks with a purified-casein fraction did not,
      suggesting that some unspecified property of casein placed a ceiling on its
      intake. These findings unequivocally demonstrate that immature chicks not only
      can self-select nutritionally adequate diets, but can do so with unexpected
      precision by exploiting different but equally successful strategies.

PMID- 8666132
TI  - K+ channels: generating excitement in pancreatic beta-cells.
AB  - K+ channels play a key role in cellular physiology by regulating the efflux of K+
      ions. They are the most diverse group of ion channel proteins; more than 30 K+
      channel genes have been characterized. Regulated by ATP, voltage, and calcium,
      multiple K+ channels coexist in the beta-cell to regulate membrane potential,
      cell excitability, and insulin secretion. Recent developments at the molecular
      level have greatly expanded our understanding of beta-cell K+ channel structure
      and function, especially in regard to the ATP-sensitive K+ channel, the target
      for sulfonylurea drugs. Mutations in K+ channel genes underlie diseases as
      diverse as persistent hyperinsulinemia of infancy, cardiac long QT syndrome,
      cerebellar degeneration, and certain ataxias. These discoveries have identified
      new pharmacological targets for possible therapeutic intervention in the
      treatment of diabetes.

PMID- 8666133
TI  - Wortmannin inhibits insulin secretion in pancreatic islets and beta-TC3 cells
      independent of its inhibition of phosphatidylinositol 3-kinase.
AB  - Glucose is the primary stimulus for insulin secretion by pancreatic beta-cells,
      and it triggers membrane depolarization and influx of extracellular Ca2+.
      Cholinergic agonists amplify insulin release by several pathways, including
      activation of phospholipase C, which hydrolyzes membrane polyphosphoinositides. A
      novel phospholipid, phosphatidylinositol 3,4,5- trisphosphate [PtdIns(3,4,5)P3],
      a product of phosphatidylinositol 3-kinase (PI 3-kinase), has recently been found
      in various cell types. We demonstrate by immunoblotting that PI 3-kinase is
      present in both cytosolic and membrane fractions of insulin-secreting beta-TC3
      cells and in rat islets. The catalytic activity of PI 3-kinase in
      immunoprecipitates of islets and beta-TC3 cells was measured by the production of
      radioactive phosphatidylinositol 3-monophosphate from phosphatidylinositol
      (PtdIns) in the presence of [gamma-32P]ATP. Wortmannin, a fungal metabolite, dose
      dependently inhibited PI 3-kinase activity of both islets and beta-TC3 cells,
      with an IC50 of 1 nmol/l and a maximally effective concentration of 100 nmol/l,
      when it was added directly to the kinase assay. However, if intact islets were
      incubated with wortmannin and PI 3-kinase subsequently was determined in islet
      immunoprecipitates, approximately 50% inhibition of PI 3-kinase activity (but no
      inhibition of glucose- and carbachol-stimulated insulin secretion) from intact
      islets was obtained at wortmannin concentrations of 100 nmol/l. Wortmannin, at
      higher concentrations (1 and 10 micromol/l), inhibited glucose- and carbachol
      induced insulin secretion of Intact rat islets by 58 and 92%, respectively.
      Wortmannin had no effect on the basal insulin release from rat islets. A similar
      dose curve of inhibition of glucose- and carbachol-induced insulin secretion by
      wortmannin was obtained when beta-TC3 cells were used. Cellular metabolism was,
      not changed by any wortmannin concentrations tested (0.01-10 micromol/l). Both
      basal cytosolic [Ca2+]i and carbamyl choline-induced increases of [Ca2]i were
      unaffected by wortmannin in the presence of 2.5 mmol/l Ca2+, while Ca2+
      mobilization from intracellular stores was partially decreased by wortmannin.
      Together, these data suggest that wortmannin at concentrations that inhibit PI 3
      kinase does not affect insulin secretion. PI 3-kinase is unlikely to have a major
      role in insulin secretion induced by glucose and carbachol.

PMID- 8666134
TI  - Glutamine and alanine metabolism in NIDDM.
AB  - Gluconeogenesis is increased in NIDDM. We therefore examined the metabolism of
      glutamine and alanine, the most important gluconeogenic amino acids, in 14
      postabsorptive NIDDM subjects and 18 nondiabetic volunteers using a combination
      of isotopic ([6-3H]glucose (20 microCi, 0.2 microCi/min), [U-14C]glutamine (20
      microCi, 0.2 microCi/min), [3-13C]alanine (99% 13C, 2 mmol, 20 micromol/min),
      [ring-2H5]phenylalanine (99% 2H, 2 micromol/kg, 0.03 micromol x kg(-1) x min(
      1)), and limb balance techniques. Alanine turnover (4.54 +/- 0.24 vs. 5.64 +/-
      0.33 micromol x kg(-1) x min(-1)), de novo synthesis (3.00 +/- 0.25 vs. 4.01 +/-
      0.33 micromol x kg(-1) x min(-1)), and conversion to glucose (1.02 +/- 0.09 vs.
      1.56 +/- 0.17 micromol x kg(-1) x min(-1)) were increased in NIDDM subjects (all
      P < 0.01), while its forearm release (0.45 +/- 0.04 vs. 0.39 +/- 0.04 micromol x
      kg(-1) x min(-1)) was unaltered. Although glutamine turnover (4.81 +/- 0.23 vs.
      4.40 +/- 0.31 micromol x kg(-1) x min(-1)) was unaltered in NIDDM, its conversion
      to glucose (0.57 +/- 0.04 vs. 1.08 +/- 0.10 micromol x kg(-1) x min(-1)) and to
      alanine (0.10 +/- 0.01 vs. 0.34 +/- 0.04 micromol x kg(-1) x min(-1)) (both P =
      0.001) was increased while its oxidation (2.84 +/- 0.27 vs. 1.84 +/- 0.15
      micromol x kg(-1) x min(-1), P = 0.03) and forearm release (0.77 +/- 0.05 vs.
      0.62 +/- 0.09 micromol x kg(-1) x min(-1), P < 0.008) were both reduced. Our
      results thus demonstrate that there are substantial alterations of glutamine and
      alanine metabolism in NIDDM. Conversion of both amino acids to glucose and the
      proportion of their turnover used for gluconeogenesis are increased; release of
      both amino acids from tissues other than skeletal muscle seems to be increased.
      Finally, the reduction in glutamine oxidation, possibly the result of competition
      with glucose and free fatty acids as fuels, makes more glutamine available for
      gluconeogenesis without a change in its turnover.

PMID- 8666135
TI  - Effect of IGF-I on phosphatidylinositol 3-kinase in soleus muscle of lean and
      insulin-resistant obese mice.
AB  - Insulin and IGF-I induced a similar stimulation of glucose transport in isolated
      soleus muscle. These actions require phosphatidylinositol (PI) 3-kinase
      activation since the PI 3-kinase inhibitor, wortmannin, blocked the stimulation
      by both peptides. We compared IGF-I with insulin in the ability to activate PI 3
      kinase in the isolated soleus muscle from lean and gold thioglucose-induced obese
      insulin-resistant mice. In muscles from lean mice, IGF-I and insulin were able to
      activate PI 3-kinase with a similar time course, the effects being maximal within
      3-5 min of stimulation. However, the IGF-I concentrations required to obtain
      similar effects on PI 3-kinase were about 10 times higher than the corresponding
      insulin doses. To determine through which receptor IGF-I was activating PI 3
      kinase, the ability of IGF-I to activate both its own receptor and insulin
      receptor was simultaneously measured. Whatever the dose used (100 or 500 nmol/l),
      IGF-I activated to a nearly similar extent both the tyrosine kinase activity of
      its own receptor and that of the insulin receptor, suggesting that IGF-I was not
      only activating its receptor but was also able to stimulate the insulin receptor
      kinase. In muscles of obese insulin-resistant mice, although the defect of PI 3
      kinase activation in response to IGF-I was relatively less pronounced (45%) than
      in response to insulin (70%) when compared with lean mice, PI 3-kinase
      stimulation was still markedly altered in response to IGF-I.

PMID- 8666136
TI  - Effects of a physiological insulin concentration on the endothelin-sensitive Ca2+
      store in porcine coronary artery smooth muscle.
AB  - The effect of insulin to attenuate the Ca2+ and contractile response of vascular
      smooth muscle to a number of agonists has been described previously, but the Ca2+
      regulatory mechanisms of insulin action remain unclear. We determined the effect
      of a physiological insulin concentration (300 pmol/l) on the Ca2+ response of
      vascular smooth muscle cells of the porcine right coronary artery to endothelin 1
      (ET-1); furthermore, we examined the cellular Ca2+ stores affected by insulin
      (i.e., Ca2+ stores releasable by inositol 1,4,5-trisphosphate, caffeine, and
      ionomycin). We measured the Ca2+ responses of acutely isolated single smooth
      muscle cells with the fluorescent Ca2+ indicator Fura-2. Acute insulin exposure
      (20 min) significantly attenuated the Ca2+ response of single smooth muscle cells
      to 10 nmol/l ET-1. This inhibitory effect of insulin was observed both in the
      presence and absence of extracellular Ca2+. In contrast with the effects on ET-1
      induced Ca2+ responses, insulin did not inhibit the Ca2+ response to 5 mmol/l
      caffeine, an agent that directly releases sarcoplasmic reticulum Ca2+ stores.
      Insulin was also without effect on the total cellular Ca2+ store released by 1
      micromol/l ionomycin, a Ca2+-transporting ionophore. When ET-1 and caffeine were
      given in succession, a sizable caffeine-sensitive Ca2+ store could be released
      from insulin-treated cells but not control cells, indicating that the
      sarcoplasmic reticulum Ca2+ store of insulin-treated cells was not depleted by ET
      1. Generalized depletion of the sarcoplasmic reticulum Ca2+ store is not one of
      the cellular mechanisms involved in the effect of insulin on coronary smooth
      muscle; instead, the effect may be due to an inhibitory influence on
      transmembrane signal transduction, such as diminished ET-1-induced inositol 1,4,5
      trisphosphate production or reduced ability of this phosphoinositol to release
      stored Ca2+.

PMID- 8666137
TI  - Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin
      sensitivity and glycemic control in patients with NIDDM.
AB  - Inhibition of tumor necrosis factor (TNF)-alpha action has recently been shown to
      reverse insulin resistance dramatically and to improve glycemic control in obese
      rodents. This double-blind study was designed to assess the effects of a
      recombinant-engineered human TNF-alpha-neutralizing antibody (CDP571) on glucose
      homeostasis in obese NIDDM patients. Glycemic control and insulin sensitivity
      were monitored in 21 NIDDM subjects for a 2-week run-in and then for 6 weeks
      after treatment in a randomized fashion with a single intravenous dose of either
      CDP571 (5 mg/kg) or an equivalent volume of normal saline. The prolonged half
      life of the antibody ensured adequate plasma levels as measured throughout the
      study. Concentrations of fasting glucose (CDP571: 10.0 +/- 0.8, 10.1 +/- 0.8,
      10.0 +/- 1.0; placebo: 8.5 +/- 0.6, 8.1 +/- 0.5, 8.7 +/- 0.8 mmol/l at baseline,
      day 1, and week 4, respectively), fasting serum insulin (CDP571: 21.2 +/- 2.8,
      21.0 +/- 2.8, 24.8 +/- 3.3; placebo: 19.0 +/- 2.8, 20.8 +/- 2.9, 17.5 +/- 2.2
      pmol/l, respectively), and C-peptide remained unaffected by the type of treatment
      throughout the study. The percentage rate of glucose clearance per minute (KITT)
      during intravenous insulin sensitivity tests was identical in the CDP571 and
      placebo groups at baseline and also at 1 and 4 weeks after treatment (mean +/-
      SE; CDP571: 1.33 +/- 0.21, 1.44 +/- 0.25, 1.26 +/- 0.18; placebo: 1.38 +/- 0.15,
      1.47 +/- 0.20, 1.52 +/- 0.20; P = 0.85, 0.93, and 0.36, respectively). TNF-alpha
      neutralization over a period of 4 weeks had no effect on insulin sensitivity in
      obese NIDDM subjects.

PMID- 8666138
TI  - Normalization by insulin treatment of low mitochondrial glycerol phosphate
      dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat.
AB  - The enzyme activity of the mitochondrial glycerol phosphate dehydrogenase (mGPD)
      in the pancreatic islet has been reported to be less than one-half of normal in
      the Goto-Kakizaki (GK) rat, a genetic model of NIDDM. In the current study, mGPD
      enzyme activity and the amount of mGPD protein, as judged by Western analysis,
      were 35-40% of normal in the islets of these animals. With the exception of
      pyruvate carboxylase, the activities of other enzymes were not abnormal. The
      assayable activity and amount of pyruvate carboxylase protein were decreased
      approximately 50% in the islets of the GK rats. Because mGPD, which is the key
      enzyme of the glycerol phosphate shuttle, and pyruvate carboxylase, which is the
      key component of the pyruvate malate shuttle, have been proposed to be essential
      for stimulus-secretion coupling in the pancreatic beta-cell, an important
      question is whether the decreases in these enzymes have a causal role in the
      hyperglycemia or whether the diabetic syndrome caused the decreases. To attempt
      to differentiate between these two possibilities, GK rats were treated with
      insulin to normalize their blood sugars. The activities of both mGPD and pyruvate
      carboxylase were also normalized by insulin treatment. An incidental discovery of
      this study was the identification of a high level of propionyl-CoA carboxylase
      activity and a lesser amount of methylcrotonyl-CoA carboxylase activity in
      pancreatic islets. These enzymes were normal in the islets of the GK rats. This
      is the first report on the presence of these two carboxylases in the islet and of
      low pyruvate carboxylase activity in the islet in NIDDM. We conclude that the
      decreased mGPD and pyruvate carboxylase in the pancreatic islet of the GK rat
      result from the diabetic syndrome.

PMID- 8666139
TI  - Glucose-6-phosphatase mRNA and activity are increased to the same extent in
      kidney and liver of diabetic rats.
AB  - Using Northern blot with a specific glucose-6-phosphatase (Glc6Pase) cDNA probe
      and enzymatic activity determination, we studied the effect of streptozotocin
      induced diabetes on Glc6Pase in rat gluconeogenic tissues. The Glc6Pase mRNA
      abundance was increased four to five times in both the liver and kidney of
      diabetic rats. This was correlated with a concomitant 130% increase in Glc6Pase
      catalytic subunit in both tissues. The elevated level of Glc6Pase mRNA was
      significantly corrected in both the liver and kidney of diabetic rats after a 12
      h insulin treatment. We also studied Glc6Pase mRNA and activity in gluconeogenic
      tissues during the fed-fasted and fasted-refed transitions in normal rats. In the
      liver, the abundance of Glc6Pase mRNA was sharply increased about four times
      after 24 or 48 h of fasting. In the kidney, the Glc6Pase mRNA level was gradually
      increased some three and five times after 24 and 48 h of fasting, respectively.
      The increase of Glc6Pase mRNA in both organs was matched with a doubling of the
      activity of Glc6Pase catalytic subunit: rapid in the liver and gradual in the
      kidney. The liver Glc6Pase mRNA abundance in 48-h fasted rats was acutely and
      importantly decreased upon refeeding. The kidney Glc6Pase mRNA level was also
      significantly lowered under these conditions, albeit less rapidly. These data
      demonstrate that efficient control of Glc6Pase takes place in both gluconeogenic
      organs at the pretranslational level and suggest that insulin might play an
      important role in this control. In addition, using reverse transcription
      polymerase chain reaction and Northern blot, we report that Glc6Pase mRNA is not
      detectable in several other tissues previously assumed to express the enzyme.

PMID- 8666140
TI  - Human prohormone convertase 3 gene: exon-intron organization and molecular
      scanning for mutations in Japanese subjects with NIDDM.
AB  - Proinsulin is converted to insulin by the concerted action of two sequence
      specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and
      prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that
      initiates the sequential processing of proinsulin to insulin by cleaving the
      proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31
      Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in
      regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are
      coordinately regulated by glucose, consistent with the important role of PC3 in
      regulating proinsulin processing. NIDDM is associated with increased secretion of
      proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3
      gene may be involved in the development of this disorder. To examine this
      hypothesis, we have isolated and characterized the human PC3 gene and screened it
      for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists
      of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3
      genes are conserved, consistent with a common evolutionary origin for the
      prohormone convertase gene family. Single-strand conformational analysis and
      nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese
      subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14
      (Gln/Glu638), neither of which was associated with NIDDM in this population.
      These data suggest that genetic variation in the PC3 gene is unlikely to be a
      major contributor to NIDDM susceptibility in Japanese.

PMID- 8666141
TI  - MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell
      responses in autoimmune diabetes-prone NOD mice.
AB  - The common class I alleles (e.g., Kd and Db) within the H2g7 major
      histocompatibility complex (MHC) clearly contribute to autoimmune IDDM in NOD
      mice, but the mechanism by which this occurs has been controversial. One
      laboratory has reported that the peptide transporter encoded by the Tap1 gene
      within H2g7 is defective, and this contributes to IDDM by impairing MHC class I
      mediated antigen presentation. If true, defective MHC class I-mediated antigen
      presentation should segregate with the H2g7 haplotype. NOD mice, related congenic
      stocks, and other control strains were used to test this hypothesis. H2g7
      positive strains did not differ from those expressing other MHC haplotypes in
      ability to present MHC class I-restricted H3aa or H3ab minor histocompatibility
      (H) antigens to cytotoxic T-lymphocytes (CTL). The H2g7 haplotype was found to
      have a reduced capacity to mediate MHC class I-restricted presentation of the
      H47a minor H antigen. However, MHC class I-restricted presentation of H47a was
      found to be Tap independent. NOD mice and control strains also did not differ in
      ability to activate adenovirus-specific MHC class I restricted CTL. Thus, the
      H2g7 haplotype is not characterized by a Tap gene defect that only impairs the
      inductive phase of the immune response. In addition, MHC class I-restricted
      presentation of either minor H or adenoviral antigens was equivalent in male and
      female NOD mice. Therefore, while the class I alleles of the H2g7 haplotype exert
      diabetogenic functions in NOD mice, this is not elicited through a Tap gene
      defect. The absence of female-specific Tap gene defects also indicates this
      cannot account for the reduced male incidence of IDDM in some NOD mouse colonies.

PMID- 8666142
TI  - Activation of beta(3) adrenergic receptors suppresses leptin expression and
      mediates a leptin-independent inhibition of food intake in mice.
AB  - To examine potential interactions between leptin and the beta3 adrenergic system
      in the regulation of food intake, we determined the effects of treatment with a
      selective beta3 adrenergic receptor (AR) agonist (CL 316,243 [1 mg/kg]) on body
      weight, food intake, and leptin expression. Studies were carried out in C57Bl/6J
      and FVB male control mice as well as in mice with targeted disruption of the
      beta3 AR gene. These findings were correlated with measurement of the expression
      in hypothalamus of neuropeptide Y (NPY) and melanin concentrating hormone (MCH),
      two neuropeptides that may be involved in the central regulation of food intake.
      Treatment with CL 316,243 (1 mg/kg) for 12 or 24 h decreased leptin mRNA
      abundance and circulating levels to 20% of baseline in normal animals. No effect
      of the CL 316,243 compound was seen in mice with targeted disruption of the beta3
      AR gene. Despite the failing leptin levels, beta3 agonist administration acutely
      suppressed food intake. Finally, the induced suppression of food intake and
      leptin levels occurred despite unchanged or increased hypothalamic expression of
      the orexigenic neuropeptides NPY and MCH. Thus, beta3 AR agonists via beta3 ARs
      suppress leptin levels acutely and simultaneously suppress food intake via a
      mechanism that operates downstream of leptin and two of its putative central
      targets.

PMID- 8666143
TI  - Roles of glucose transport and glucose phosphorylation in muscle insulin
      resistance of NIDDM.
AB  - Insulin resistance for glucose metabolism in skeletal muscle is a key feature in
      NIDDM. The quantitative role of the cellular effectors of glucose metabolism in
      determining this insulin resistance is still imperfectly known. We assessed
      transmembrane glucose transport and intracellular glucose phosphorylation in vivo
      in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin
      clamp studies in combination with the forearm balance technique (brachial artery
      and deep forearm vein catheterization) in five nonobese NIDDM patients and seven
      age- and weight-matched control subjects (study 1). D-Mannitol (a
      nontransportable molecule), 3-O-[14C]methyl-D-glucose (transportable, but not
      metabolizable) and D[3-3H]glucose (transportable and metabolizable) were
      simultaneously injected into the brachial artery, and the washout curves were
      measured in the deep venous effluent blood. In vivo rates of transmembrane
      transport and intracellular phosphorylation of D-glucose in forearm muscle were
      determined by analyzing the washout curves with the aid of a multicompartmental
      model of glucose kinetics in forearm tissues. At similar steady-state
      concentrations of plasma insulin (approximately 500 pmol/l) and glucose
      (approximately 5.0 mmol/l), the rates of transmembrane influx (34.3 +/- 9.1 vs.
      58.5 +/- 6.5 micromol x min(-1) x kg(-1), P < 0.05) and intracellular
      phosphorylation (5.4 +/- 1.6 vs. 38.8 +/- 5.1 micromol x min(-1) x kg(-1), P <
      0.01) in skeletal muscle were markedly lower in the NIDDM patients than in the
      control subjects. In the NIDDM patients (study 2), the insulin clamp was repeated
      at hyperglycemia, (approximately 13 mmol/l) trying to match the rates of
      transmembrane glucose influx measured during the clamp in the controls. The rate
      of transmembrane glucose influx (62 +/- 15 micromol x min(-1) x kg(-1)) in the
      NIDDM patients was similar to the control subjects, but the rate of intracellular
      glucose phosphorylation (16.6 +/- 7.5 micromol x min(-1) x kg(-1)), although
      threefold higher than in the patients during study 1 (P < 0.05), was still
      approximately 60% lower than in the control subjects (P < 0.05). These data
      suggest that when assessed in vivo, both transmembrane transport and
      intracellular phosphorylation of glucose are refractory to insulin action and add
      to each other in determining insulin resistance in skeletal muscle of NIDDM
      patients. It will be of interest to compare the present results with the in vivo
      quantitation of the initial rate of muscle glucose transport when methodology to
      perform this measurement becomes available.

PMID- 8666145
TI  - Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK
      rats: a defect ameliorated by cAMP.
AB  - The GK rat is a spontaneous model of NIDDM. The insulin response to 16.7 mmol/l
      glucose was markedly impaired in both isolated perfused pancreas and isolated
      islets from GK rats compared with control Wistar rats. Depolarization with 30
      mmol/l KCl in the presence of 3.3 mmol/l glucose and 250 micromol/l diazoxide
      induced similar insulin responses in perfused pancreases of GK and control rats.
      In contrast, the glucose-stimulated insulin release was also severely impaired in
      GK pancreases in the depolarized state. Forskolin (1 micromol/l) markedly
      enhanced insulin release at 3.3 mmol/l glucose in GK but not control pancreases
      (54 +/- 15 vs. 3 +/- 1 pmol/10 min, P < 0.001). Dibutyryl cAMP (1 mmol/l) exerted
      effects similar to forskolin on insulin release in the perfused pancreas. In
      depolarized pancreases of GK but not control rats, forskolin also induced a
      marked insulin response at 3.3 mmol/l glucose (163 +/- 48 vs. 16 +/- 1 pmol/20
      min, P < 0.03). Similarly, in studies on isolated islets from GK rats cultured in
      5.5 or 16.7 mmol/l glucose for 48 h, forskolin (5 pmol/l) restored insulin
      release in response to 16.7 mmol/l glucose but had no effect on islet glucose
      utilization at 3.3 or 16.7 mmol/l glucose. Forskolin markedly stimulated insulin
      release at 3.3 mmol/l glucose in GK but not control rat islets cultured for 48 h
      in 5.5 mmol/l glucose, whereas 20 mmol/l arginine had an almost identical effect
      in both islet varieties. However, in islets cultured in 16.7 mmol/l glucose,
      forskolin stimulated insulin release similarly both in control and GK islets at
      3.3 mmol/l glucose. In conclusion, this study suggests that the insulinotropic
      effects of glucose are coupled to a direct regulation of the exocytotic machinery
      in the pancreatic beta-cell. This pathway is markedly impaired in GK rats,
      contributing to defective insulin response to glucose. In this model, cAMP
      generation restores the insulin response to 16.7 mmol/l glucose and exerts a
      marked insulin release even at 3.3 mmol/l glucose.

PMID- 8666144
TI  - Prediction of type I diabetes in first-degree relatives using a combination of
      insulin, GAD, and ICA512bdc/IA-2 autoantibodies.
AB  - Islet cell antibodies (ICAs) are predictive of type I diabetes in first-degree
      relatives, but this immunohistochemical assay has proven difficult to
      standardize. As an alternative, we assessed the use of radioassays for antibodies
      against three molecularly characterized islet autoantigens, including ICA512bdc
      (amino acid residues 256-979 of the IA-2 molecule, incorporating the
      intracellular domain). We measured insulin autoantibodies (IAAs), GAD
      autoantibodies (GAAs), and ICA512bdc autoantibodies (ICA512bdcAAs) by radioassay,
      in addition to ICAs, in 882 first-degree relatives of patients with type I
      diabetes, 50 of whom later developed diabetes with a median follow-up of 2.0
      years (maximum 11.3 years). The cutoff for each radioassay was determined by
      testing >200 control subjects. When autoantibody frequencies among the relatives
      were analyzed according to relationship to the proband, the offspring of diabetic
      fathers had a higher frequency of ICA5I2bdcAAs (P = 0.008), IAAs (P = 0.0001) and
      GAAs (P = 0.0001) than the offspring of diabetic mothers. ICA512bdcAAs and IAAs
      both showed a significant association with HLA-DR4-DQ8 (P = 0.0005). Among
      relatives developing diabetes, 98% had one or more of IAAs, GAAs, or
      ICA512bdcAAs, and 80% had two or more of these autoantibodies, compared with none
      of the control subjects. Using survival analysis to allow for different lengths
      of follow-up, there was a significant increase in the risk of diabetes with the
      number of these autoantibodies present, comparing zero, one, two, and three
      autoantibodies (P < 0.0001, log-rank test), and by Cox regression analysis, this
      was independent of ICAs and age. For relatives with two or more of these
      autoantibodies, the risk of diabetes within 3 years was 39% (95% CI, 27-52) and
      the risk within 5 years was 68% (95% CI, 52-84). Relatives with all three
      autoantibodies had a risk within 5 years estimated to be 100%. The presence of
      low first-phase insulin release further increased the risk for relatives with one
      or two autoantibodies. We conclude that the presence of two or more
      autoantibodies (out of IAAs, GAAs, and ICA512bdcAAs) is highly predictive of the
      development of type I diabetes among relatives.

PMID- 8666146
TI  - Poor capacity for proliferation of pancreatic beta-cells in Otsuka-Long-Evans
      Tokushima Fatty rat: a model of spontaneous NIDDM.
AB  - Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a genetic model of spontaneous
      development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and
      insulin resistance similar to that in humans. It is still unclear whether a
      defect in the beta-cell proliferation per se is the primary pathogenetic event in
      OLETF rat. To determine whether it is, we used partially pancreatectomized rats
      as a model, with administration of phlorizin to control blood glucose level, to
      examine whether the capacity for proliferation of beta-cells during hyperglycemia
      or normoglycemia differs between OLETF and their diabetes-resistant counterparts,
      Long-Evans-Tokushima-Otsuka (LETO) rats. We also examined whether such a defect,
      if present, could be improved by nicotinamide. Male rats, 6 weeks of age, were
      allocated at random to two groups: 70% pancreatectomy (Px) and sham
      pancreatectomy (sham). Each group was divided into four subgroups by date of
      killing after surgery: 3-day, 7-day, 28-day (treated with phlorizin,
      nicotinamide, or saline), and 91-day. A sustained hyperglycemia was evident in
      the Px OLETF rats after surgery, which was associated with insufficient
      proliferation of beta-cells, characterized by decrease in beta-cell labeling
      index in proportion to decrease in beta-cell mass and reduction in insulin
      content in the remnant pancreas. This defect was unaffected by restoration of
      normoglycemia induced by phlorizin injection. Administration of nicotinamide,
      however, ameliorated the sustained hyperglycemia by increasing beta-cell
      proliferation. These findings suggest that OLETF rats have poor capacity for
      proliferation of pancreatic beta-cells and that this change may be the critical
      pathogenetic event before the onset of overt diabetes.

PMID- 8666147
TI  - Insulin action and age. European Group for the Study of Insulin Resistance
      (EGIR).
AB  - Evidence that age is associated with insulin resistance is discordant. We
      analyzed euglycemic insulin clamp (1 mU x min(-1) x kg(-1)) data collected at 20
      centers throughout Europe from 1,146 men and women with normal glucose tolerance,
      ranging in age from 18 to 85 years. In the whole group, insulin action (as the M
      value) declined slightly with age (at a rate of 0.9 micromol x min(-1)-kg(-1) per
      decade of life, 95% CI = 0.4-1.3, P = 0.0002). When adjusted for BMI, this
      relationship was no longer statistically significant. The same result was
      obtained whether insulin action was expressed per kilogram of body weight or per
      kilogram of fat-free mass, expressed as the M:I ratio, or estimated from fasting
      plasma insulin concentrations. Subgroup analysis showed that a significant BMI
      adjusted decrease in insulin action with age was present only in lean (BMI <25
      kg/m2) women (a rate of 1.6 micromol x min(-1) x kg(-1) per decade, 95% CI = 0.6
      2.5, P = 0.001), in whom percentage fat mass also increased with age (by 0.38%
      body weight per decade, P = 0.0007). Insulin action was positively associated
      with insulin suppression of circulating free fatty acids (FFAs) (+1.5 micromol x
      min(-1) x kg(-1) for each 10% increase in FFA suppression, P < 0.0001) in a
      multivariate model accounting for sex, BMI, age, and fasting FFA levels.
      Furthermore, insulin suppression of FFAs improved with age in men (2% per decade,
      P < 0.0001) but not in women. In the subgroup of lean women in whom insulin
      action declined with age, adding FFA suppression to a multiple regression
      equation canceled the association between age and insulin action. Thus, the small
      effect of age on insulin action could be adequately explained on the basis of age
      related changes in body composition and substrate competition. We conclude that
      in healthy Europeans, age per se is not a significant cause of insulin resistance
      of glucose metabolism or lipolysis.

PMID- 8666148
TI  - Glucose-dependent interleukin 6 and tumor necrosis factor production by human
      peripheral blood monocytes in vitro.
AB  - To clarify the mechanisms that cause elevation of plasma fibrinogen levels in
      diabetes, we first examined the effect of hyperglycemia on the production of
      interleukin 6 (IL-6) and tumor necrosis factor (TNF) by cultured human peripheral
      blood monocytes. Monocyte-enriched fractions isolated from 20 healthy volunteers
      were incubated with 11 mmol/l glucose, 33 mmol/l glucose, or mannitol as an
      osmolar control for 6 or 24 h. After 6 h of incubation, IL-6 and TNF-alpha mRNA
      levels were analyzed by reverse transcription and polymerase chain reaction. In
      addition, after 24 h of incubation, IL-6 and TNF-alpha immunoreactivity in the
      culture medium was measured by enzyme-linked immunoassay. Both IL-6 and TNF-alpha
      mRNA levels and immunoreactivity were significantly increased by treatment with
      33 mmol/l glucose compared with treatment with 11 mmol/l glucose or 11 mmol/l
      glucose with 22 mmol/l mannitol. In addition, preincubation of the cells with an
      anti-TNF monoclonal antibody (mAb) blocked the stimulatory effect of 33 mmol/l
      glucose on IL-6 synthesis and secretion. Second, we examined the ability of
      conditioned media from human peripheral blood monocytes to stimulate beta
      fibrinogen mRNA synthesis in HepG2 cells. The conditioned medium from monocytes
      treated with 33 mmol/l glucose increased beta-fibrinogen mRNA levels. The results
      of this study demonstrate that hyperglycemia stimulated IL-6 and TNF synthesis
      and secretion by human peripheral monocytes in vitro and that the IL-6 response
      to hyperglycemia may be mediated by TNF. Furthermore, hyperglycemia may increase
      fibrinogen levels through stimulation of peripheral monocytes. These results
      suggest that hyperglycemia may cause hyperfibrinogenemia in diabetic patients
      through an IL-6-dependent and TNF-dependent mechanism.

PMID- 8666149
TI  - Autonomic mediation of glucagon secretion during insulin-induced hypoglycemia in
      rhesus monkeys.
AB  - Autonomic activation mediates the majority of the increase of glucagon secretion
      during insulin-induced hypoglycemia in several species including dogs, mice, and
      rats. However, the role of the autonomic nervous system to increase glucagon
      during hypoglycemia in humans remains controversial, and investigations in
      nonhuman primates have not been previously conducted. The autonomic contribution
      to glucagon secretion during hypoglycemia in a nonhuman primate was examined by
      two independent pharmacological approaches. Glucagon responses to clamped insulin
      induced hypoglycemia were compared in conscious rhesus monkeys in the presence or
      absence of ganglionic blockade with trimethaphan, or during combined muscarinic
      and adrenergic receptor blockade with atropine, propranolol, and tolazoline.
      Insulin-induced hypoglycemia (plasma glucose = 1.9 +/- 0.1 mmol/l) activated
      parasympathetic nerves to the pancreas as assessed by increased plasma pancreatic
      polypeptide (PP) levels (delta = 135.0 +/- 36.8 pmol/l, P < 0.01), produced
      sympathoadrenal activation as assessed by elevations of plasma epinephrine (EPI)
      (delta = 22.3 +/- 2.95 nmol/l, P < 0.0005) and norepinephrine (NE) (delta = 3.72
      +/- 0.77 mmol/l, P < 0.0025) and increased plasma immunoreactive glucagon (IRG)
      (delta = 920 +/- 294 ng/l, P < 0.025). Nicotinic ganglionic blockade with
      trimethaphan prevented parasympathetic (deltaPP = 16.5 +/- 16.3 pmol/l, P < 0.01
      vs. control) and sympathoadrenal (deltaEPI = 1.52 +/- 0.98 nmol/l; deltaNE = 
      0.62 +/- 0.24 mmol/l, both P < 0.0025 vs. control) activation during hypoglycemia
      and inhibited the IRG response by 70% (delta = 278 +/- 67 ng/l, P < 0.025 vs.
      control). Combined muscarinic and adrenergic receptor blockade reduced
      parasympathetic activation (deltaPP = 48.3 +/- 16.3 pmol/l, P < 0.01 vs. control)
      and inhibited the IRG response by a similar degree to ganglionic blockade
      (deltaIRG = 284 +/- 60 ng/l, P < 0.025 vs. control). These results demonstrate by
      two independent pharmacological approaches that autonomic activation makes a
      substantial contribution to increased glucagon secretion during hypoglycemia of
      approximately 2.0 mmol/l in a species of nonhuman primate.

PMID- 8666151
TI  - Multiple lipoprotein abnormalities in type I diabetic patients with renal
      disease.
AB  - The aim of this study was to characterize abnormalities of triglyceride-rich
      apolipoprotein (apo) B-containing lipoproteins in type I diabetic patients with
      elevated albumin excretion rates (AERs). Sixty-four patients (31 men, 33 women)
      with normoalbuminuria (AER <20 microg/min), 52 (35 men, 17 women) with
      microalbuminuria (AER 20-200 microg/min), and 37 (17 men, 20 women) with
      albuminuria (AER >200 microg/min) and 56 healthy control subjects matched for age
      and body weight were studied. The major finding was increased mass concentrations
      of the highly atherogenic intermediate-density lipoprotein fraction in patients
      with microalbuminuria (P < 0.05) and albuminuria (P < 0.05), compared with those
      with normoalbuminuria. Triglyceride, free cholesterol, cholesterol ester, and
      phospholipid concentrations in the VLDL, intermediate-density lipoprotein, and
      LDL (P < 0.05-0.01), as well as total cholesterol, total triglyceride, and apoB
      concentrations were higher in patients with renal disease than in those without.
      Notably, there were no differences between patients with microalbuminuria and
      albuminuria. Only minor compositional changes could be detected. Postheparin
      plasma lipoprotein lipase (LPL) activities were identical, but hepatic lipase
      activities were higher in microalbuminuric and albuminuric patients than in
      normoalbuminuric patients (P < 0.01). LPL activity and VLDL1, (Sf 60-400) (r = 
      0.528; P < 0.001) and VLDL2 (Sf 20-60) mass concentrations (r = -0.471; P <
      0.001) were negatively related. In conclusion, in type I diabetic patients with
      early renal disease, there are multiple lipoprotein changes, which are
      potentially atherogenic and may contribute to the excess of macrovascular
      complications seen in such patients.

PMID- 8666150
TI  - Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter
      BABY-DIAB study: detection of humoral immune responses to islet antigens in early
      childhood.
AB  - IDDM results from immune-mediated destruction of insulin-producing pancreatic
      beta-cells in individuals genetically susceptible for the disease. There is
      evidence that the 65-kDa isoform of GAD plays a critical role in the induction of
      autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what
      beta-cell antigens autoreactive lymphocytes become activated during early
      disease. We conducted a prospective study from birth, BABY-DIAB, among children
      of mothers with IDDM or gestational diabetes or fathers with IDDM, and we
      investigated the temporal sequence of antibody responses to islet cells (ICA),
      insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA
      2A). Of 1,019 children included at birth, we have currently followed 513 to the
      age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At
      birth, all antibody specificities were frequent in newborns of diabetic mothers
      but not fathers and are suggested to be transplacentally acquired because they
      are strongly correlated with antibody levels in their diabetic mothers. In early
      childhood, antibody levels were <99th percentile of control subjects in the
      majority of children. However, 37 children exhibited elevated antibody levels;
      these were most frequently detected at the age of 2 years. The antibody
      prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8%
      for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers
      were positive for at least one antibody more frequently than were children of
      diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%).
      There was no specific sequence in the appearance of positive autoantibodies, but
      13 (35%) antibody-positive cases already had more than one ICA before the age of
      2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5
      years. The presence of multiple antibodies confers high risk for the future
      development of diabetes; three of six children who exhibited positive antibody
      responses to all four antibodies tested and another child with two positive
      antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5
      years. We conclude that loss of tolerance to beta-cell autoantigens and
      appearance of autoimmune phenomena occur very early in life in individuals with
      genetic susceptibility for IDDM. Screening programs to identify candidates for
      disease-prevention therapies can therefore be focused on this young age-group, in
      whom the disease process may be less advanced and who may therefore be best
      suited to such therapies.

PMID- 8666152
TI  - The inhibition of the insulin receptor by the receptor protein PC-1 is not
      specific and results from the hydrolysis of ATP.
AB  - The membrane protein plasma cell differentiation antigen 1 (PC-1) has been
      purified as an inhibitor of insulin receptor tyrosine kinase activity and has
      been implicated in the pathogenesis of NIDDM. However, we show here that PC-1 is
      a general protein kinase inhibitor in vitro and that this inhibition results from
      the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC
      1. Thus, the inhibition diminished with increasing ATP concentrations, and it was
      nullified when the ATP concentration was kept constant with a regenerating system
      or when ATP was added repetitively. When care was taken to avoid ATP depletion,
      PC-1 did not affect the insulin sensitivity of insulin receptor
      autophosphorylation. We conclude that the reported inhibition of insulin
      signaling by PC-1 does not result from a direct inhibition of the insulin
      receptor kinase activity.

PMID- 8666153
TI  - Adipose tissue leptin production and plasma leptin kinetics in humans.
AB  - Abdominal adipose tissue leptin production was determined in vivo by
      arteriovenous balance in 14 lean and obese men (mean BMI 27.0 +/- 1.9, range 21.4
      45.2). Blood samples were taken simultaneously from an abdominal vein that drains
      subcutaneous adipose tissue and from a radial artery. Adipose tissue blood flow
      was measured by xenon washout. Abdominal vein leptin concentrations (mean 8.9 +/-
      2.4 ng/ml, range 2.1-36.5 ng/ml) were consistently greater than arterial values
      (mean 6.6 +/- 1.9 ng/ml, range 1.7-28.2 ng/ml) (P < 0.001). The net rate of
      abdominal adipose tissue leptin production (mean 3.2 +/- 0.5 ng x 100 g(-1) x
      min(-1)) correlated directly with percentage body fat (rs = 0.59, P = 0.016).
      Estimated whole-body leptin production rate (797 +/- 283 ng x person(-1) x min(
      1)) correlated directly with percent body fat (rs = 0.93, P < 0.0001) and with
      regional leptin production (rs = 0.81, P < 0.001). In contrast, the rate of
      leptin clearance from plasma (mean 1.50 +/- 0.23 ml x kg(-1) x min(-1)) and
      plasma leptin half-life (mean 24.9 +/- 4.4 min) was unrelated to adiposity (rs =
      0.06, P = 0.30; rs = 0.16, P = 0.30, respectively). These results provide direct
      evidence that leptin is produced by adipose tissue in humans and that the rate of
      production is directly related to adiposity. A combination of greater leptin
      production per unit of body fat and increased production from expanded total body
      fat mass, rather than alterations in leptin clearance, account for the increase
      in plasma leptin concentrations observed in obese humans.

PMID- 8666154
TI  - Relationship between insulin sensitivity and plasma leptin concentration in lean
      and obese men.
AB  - Alterations in the production of or the sensitivity to leptin, the protein
      encoded by the ob gene, cause obesity and diabetes in rodents. We evaluated the
      isolated relationship between leptin and insulin sensitivity in lean and obese
      humans. Three groups of subjects who were carefully matched for either insulin
      sensitivity (determined by the modified intravenous glucose tolerance test and
      minimal model analysis) or adiposity (determined by hydrodensitometry) were
      studied: 1) lean insulin-sensitive men (percentage body fat, 15 +/- 1%); 2) lean
      insulin-resistant men (percentage body fat, 16 +/- 1%), matched on percentage
      body fat and fat mass with the lean insulin-sensitive group; and 3) obese insulin
      resistant men (percentage body fat, 31 +/- 3), matched on insulin sensitivity
      with the lean insulin-resistant group. Basal plasma leptin concentrations were
      significantly lower in the lean insulin-sensitive than in the lean insulin
      resistant men (1.90 +/- 0.4 vs. 4.35 +/- 1.21 ng/ml, P < 0.05) despite identical
      body composition. Plasma leptin in the obese men (9.27 +/- 1.4 ng/ml) was
      significantly higher than values in the two lean groups (P < 0.01). Marked
      alterations in plasma glucose and insulin concentrations induced by glucose and
      tolbutamide injection did not cause any change in plasma leptin levels. These
      results demonstrate that insulin resistance is associated with elevated plasma
      leptin levels independent of body fat mass. However, plasma insulin itself does
      not acutely regulate leptin production.

PMID- 8666155
TI  - The hypothalamic leptin receptor in humans: identification of incidental sequence
      polymorphisms and absence of the db/db mouse and fa/fa rat mutations.
AB  - Leptin-receptor gene expression in hypothalamic tissue from lean and obese humans
      was examined. The full-length leptin receptor, that is believed to transmit the
      leptin signal, is expressed in human hypothalamus. There was no difference in the
      amount of leptin-receptor mRNA In seven lean (BMI 23.3 +/- 0.9 kg/m2) and eight
      obese (BMI 36.9 +/- 1.5) subjects as determined by reverse transcription
      polymerase chain reaction. A sequence polymorphism (A-->G) was detected at
      position 668 of the leptin receptor cDNA. This second base substitution changed a
      glutamine to an arginine at position 223 of the leptin receptor protein. Of 15
      subjects analyzed, 11 were heterozygous for this base change and 3 were
      homozygous. The occurrence [correction of occurance] of the polymorphic allele(s)
      did not correlate with BMI in the population studied. The mutation responsible
      for the defect in the leptin receptor in db/db mice was not detected in any obese
      human, nor was the fa/fa rat mutation. These results provide evidence that the
      leptin resistance observed in obese humans is not due to a defect in the leptin
      receptor.

PMID- 8666156
TI  - Introduction: basal and inducible expression of cytochromes P450 and related
      enzymes.

PMID- 8666157
TI  - Cytochromes P450 5: induction of cytochrome P4501A1: a model for analyzing
      mammalian gene transcription.
AB  - The induction of microsomal cytochrome P4501A1 by polycyclic aromatic
      hydrocarbons represents an interesting response by which mammalian cells adapt to
      xenobiotic exposure. Enzyme induction reflects increased transcription of the
      corresponding CYP1A1 gene. Analyses of the induction mechanism using genetic,
      biochemical, and molecular biological approaches have revealed a novel
      transcriptional regulatory pathway that involves ligand-dependent
      heterodimerization between two basic helix-loop-helix proteins (the Ah receptor
      and Arnt), interaction of the heterodimer with a xenobiotic-responsive enhancer,
      transmission of the induction signal from the enhancer to the CYP1A1 promoter,
      and alterations in chromatin structure. Current techniques permit examination of
      the induction mechanism in intact cells and analyses of the CYP1A1 gene in its
      native chromosomal configuration. Such experiments generate new insights into the
      control of mammalian transcription that are of relatively broad interest.

PMID- 8666158
TI  - Liver regeneration 7. Prometheus' myth revisited: transgenic mice as a powerful
      tool to study liver regeneration.
AB  - In this review, we present examples of the contribution of transgenic mice to our
      knowledge concerning the type of cells that are able to repopulate a damaged
      liver and information on the factors and mechanisms involved in postnatal liver
      growth and regeneration. The transgenic technology offers the opportunity to
      evaluate the physiological consequences of perturbating expression of a given
      gene in vivo. It has provided insights into the concerted action of extracellular
      (HGF/SF, TGF-alpha, EGF, TGF-beta) and intracellular factors (c-myc, c-fos, c
      jun, p53, c-met, and others) in liver regeneration. Transgenic mice can also
      contribute to the dissection of the molecular mechanisms responsible for the
      regulated expression of these factors, both at the transcriptional and the
      posttranscriptional level. An illustration of such a strategy is given by the
      study of the sequences involved in the posttranscriptional regulation of the c
      myc proto-oncogene. The recent improvement of gene targeting, in which endogenous
      genes are inactivated by homologous recombination, represents a further step
      toward the study of the function of a particular gene. Inactivation of most of
      the factors described in this review has been undertaken. However, further
      studies of their role in liver growth control are impeded by the fact that the
      corresponding knockout mice die prematurely. This problem could be overcome by
      the advent of new techniques, which will be briefly presented, aimed at turning
      genes on and off at will and in a tissue-specific manner.

PMID- 8666159
TI  - Glutamine nutrition and metabolism: where do we go from here ?
AB  - Glutamine, a "nonessential" amino acid, is attracting widespread attention
      because of its relevance to numerous metabolic processes and its potential role
      in the treatment and prevention of critical illness. In this paper we review some
      key concepts of glutamine biochemistry, metabolism, and nutrition. We then
      discuss several studies in the area of glutamine metabolism and nutrition that
      are primed for further investigation.

PMID- 8666161
TI  - Biochemistry, molecular biology, and genetics of the oligosaccharyltransferase.
AB  - Asparagine-linked glycosylation is a highly conserved protein modification
      reaction that occurs in all eukaryotes. The initial stage in the biosynthesis of
      N-linked glycoproteins, catalyzed by the enzyme oligosaccharyltransferase (OST),
      involves the transfer of a preassembled high-mannose oligosaccharide from a
      dolichol-linked oligosaccharide donor onto asparagine acceptor sites in nascent
      proteins in the lumen of the rough endoplasmic reticulum. Biochemical, molecular
      biological, and genetic studies conducted during the past 5 years have resulted
      in an explosive growth in our knowledge concerning the OST. Although the basic
      biochemical properties of the enzyme were determined more than a decade ago using
      intact microsomal membranes, recent studies provide novel insight into the
      catalytic mechanism of the enzyme. The OST was recently purified as a large
      heteroligomeric membrane protein complex; the sequences of many of the subunits
      have been determined from both fungal and vertebrate sources. Consistent with the
      evolutionary conservation of N-linked glycosylation, protein sequence comparisons
      reveal significant homologies between vertebrate, invertebrate, plant, and fungal
      OST subunits. Yeast molecular genetic methods have been instrumental in the
      functional characterization of the OST subunits, and have proven to be powerful
      tools for the identification of novel gene products that influence
      oligosaccharide transfer in vivo.

PMID- 8666160
TI  - Glycobiology of schistosomiasis.
AB  - Schistosomiasis is a helminthic parasitic disease that results in a wide-ranging
      pathology in the approximately 200 million infected people worldwide. Much of the
      immunity to the parasite is directed against carbohydrate determinants in both
      glycoproteins and glycolipids from the adult worms and their eggs. Circulating
      glycoproteins derived from the parasite may be diagnostic for the disease. Recent
      studies of the structures of schistosome-derived glycoconjugates reveal that they
      exhibit several interesting and novel motifs. Many schistosome glycans are rich
      in fucose and devoid of sialic acid. It is surprising that some of the
      fucosylated schistosome glycans contain the Lewis x (Le(x)) antigen that is also
      found on human leukocytes and other tissues. These Le(x)-containing glycans
      elicit autoantibodies, and the glycans may affect lymphocyte functions. This
      review highlights recent progress in schistosome research in terms of structure,
      function, and biosynthesis of glycoconjugates. It is hoped that the deeper
      understanding being gained about glycoconjugates will foster innovative new
      strategies for lessening the mortality and morbidity caused by these parasites.

PMID- 8666163
TI  - A polygenic model of inherited predisposition to cancer.
AB  - Polygenic inheritance of predisposition to cancer is demonstrated in experimental
      animals for different tumor types. Genetic susceptibility to
      hepatocarcinogenesis, lung tumorigenesis, skin and intestine carcinogenesis, and
      plasmacytomagenesis is determined by inheritance of multiple cancer
      predisposition and resistance alleles, whose chromosomal locations have been
      found by genetic linkage analysis. In some of these experimental models, genetic
      heterogeneity has also been reported. In humans, increased risk of lung cancer
      associated with multiple genes coding for drug metabolizing enzymes, increased
      risk of cancer in relatives of cancer patients, and genetic heterogeneity are
      compatible with polygenic inheritance of cancer predisposition. Polygenic
      inheritance based on the combination of multiple alleles that give predisposition
      and resistance to cancer would predict a very high risk of cancer in carrier
      individuals and a marginal increase in the relative risk of cancer in the progeny
      of the cancer patients. Therefore, predisposition to cancer may be genetically
      determined even in the absence of familial clustering of cases.

PMID- 8666162
TI  - Basic concepts in RNA virus evolution.
AB  - A hallmark of RNA genomes is the error-prone nature of their replication and
      retrotranscription. The major biochemical basis of the limited replication
      fidelity is the absence of proofreading/repair and postreplicative error
      correction mechanisms that normally operate during replication of cellular DNA.
      In spite of this unique feature of RNA replicons, the dynamics of viral
      populations seems to follow the same basic principles that classical population
      genetics has established for higher organisms. Here we review recent evidence of
      the profound effects that genetic bottlenecks have in enhancing the deleterious
      effects of Muller's ratchet during RNA virus evolution. The validity of the Red
      Queen hypothesis and of the competitive exclusion principle for RNA viruses are
      viewed as the expected result of the highly variable and adaptable nature of
      viral quasispecies. Viral fitness, or ability to replicate infectious progeny,
      can vary a million-fold within short time intervals. Paradoxically, functional
      and structural studies suggest extreme limitations to virus variation.
      Adaptability of RNA viruses appears to be based on the occupation of very narrow
      portions of sequence space at any given time.

PMID- 8666164
TI  - Desmosomes and hemidesmosomes: structure and function of molecular components.
AB  - Desmosomes and hemidesmosomes are the major cell surface attachment sites for
      intermediate filaments at cell-cell and cell-substrate contacts, respectively.
      The transmembrane molecules of the desmosome belong to the cadherin family of
      calcium-dependent adhesion molecules, whereas those in the hemidesmosome include
      the integrin class of cell matrix receptors. In each junction, the cytoplasmic
      domains of certain transmembrane junction components contain unusually long
      carboxy-terminal tails not found in those family members involved in linkage of
      actin to the cell surface. These domains are thought to be important for the
      regulation of junction assembly and specific attachment of intermediate filaments
      via associated adapter proteins. Recent developments have suggested the exciting
      possibility that these junctions, in addition to playing an important structural
      function in tissue integrity, are both acceptors and affectors of cell signaling
      pathways. Many desmosomal and hemidesmosomal constituents are phosphoproteins and
      in certain cases the function of specific phosphorylation sites in regulating
      protein-protein interactions is being uncovered. In addition, a more active role
      in transmitting signals that control morphogenesis during development and
      possibly even regulate cell growth and differentiation are being defined for
      cytoplasmic and membrane components of these junctions.

PMID- 8666165
TI  - Neurohormone melatonin prevents cell damage: effect on gene expression for
      antioxidant enzymes.
AB  - It is well known that porphyrins cause a toxic light-mediated effect due to their
      capability to generate free radicals. Several reports have proved that melatonin
      is a potent free radical scavenger. The aim of this work has been to study the
      ability of melatonin to prevent the cell damage caused by porphyrins in the
      Harderian gland of female Syrian hamsters. Cell injury was evaluated estimating
      the percentage of damaged cells found in the gland and analyzing the degree of
      this damage at ultrastructural level. To explain the mechanism by which this
      hormone could prevent the cell damage caused by porphyrins, its capability to
      both decrease porphyrin synthesis and increase the mRNA levels for antioxidant
      enzymes was evaluated. Our results demonstrate that melatonin administration
      decreases the percentage of damaged cells, porphyrin synthesis, and
      aminolevulinate synthase (ALA-S) mRNA levels and increases the mRNA levels for
      manganese superoxide-dismutase and copper-zinc superoxide dismutase. When
      observed under an electron microscope, the lesions in the clear cells of the
      treated females were much less severe than in the corresponding cells of the
      control animals. Melatonin exerts a cytoprotective effect by inhibiting the ALA-S
      gene expression (and so porphyrin synthesis) and by raising the mRNA levels for
      several antioxidant enzymes.

PMID- 8666166
TI  - Neuroprotection by melatonin from kainate-induced excitotoxicity in rats.
AB  - In this study, we injected 10 mg/kg kainate i.p. into rats. This resulted in a
      brain injury, which we quantified in the hippocampus, the amygdala, and the
      pyriform cortex. Neuronal damage was preceded by a set of typical behavioral
      signs and by biochemical changes (noradrenaline decrease and 5
      hydroxyindoleacetic acid increase) in the affected brain areas. Melatonin (2.5
      mg/kg) was injected i.p. four times: 20 min before kainate, immediately after,
      and 1 and 2 h after the kainate. The cumulative dose of 10 mg/kg melatonin
      prevented kainate-induced neuronal death as well as behavioral and biochemical
      disturbances. A possible mechanism of melatonin-provided neuroprotection lies in
      its antioxidant action. Our results suggest that melatonin holds potential for
      the treatment of pathologies such as epilepsy-associated brain damage, stroke,
      and brain trauma.

PMID- 8666167
TI  - Upper airway collapsibility, and contractile and metabolic characteristics of
      musculus uvulae.
AB  - Physiologic, metabolic, and histochemical characteristics of one upper airway
      (UA) dilator muscle (musculus uvulae; MU) differ between sleep apnea hypopnea
      syndrome (SAHS) and nonapneic snorers. We hypothesized that these differences in
      MU characteristics could result from the cumulative effects of the diurnal and
      nocturnal intermittent contractions of UA muscles in order to compensate for a
      permanent increase in UA collapsibility. The aim of this study was to determine
      the influence of UA collapsibility on MU characteristics. Seventeen SAHS and
      three nonapneic snorers, who underwent an uvulo-palato-pharyngoplasty as a
      treatment for snoring or SAHS, participated in the study. Awake and sleeping UA
      critical pressure (Pcrit) was measured during continuous positive or negative
      airway pressure trials by analysis of the relationship between maximal
      inspiratory flow and the upstream pressure of flow-limited breathing cycles.
      Maximum isometric twitch (Pt) and tetanic tension (Po), fatigability
      measurements, activities of marker enzymes for anaerobic and aerobic-oxidative
      profile, and fiber type proportions and areas of MU were determined. There was a
      significant positive relationship between Pt, Po, and Pcrit measured during
      wakefulness and sleep. The fatigability index was negatively correlated with
      awake Pcrit values (r = -0.79). Activity level of the anaerobic enzymes as well
      as the percentage of surface occupied by type I and type IIA muscle fibers as
      correlated witb awake Pcrit. We conclude that the differences in awake UA
      collapsibility help to determine the contractile properties and metabolic and
      histochemical characteristics of MU.

PMID- 8666168
TI  - Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and
      nonreproductive tissues in ovariectomized rats.
AB  - For the first time, four well-characterized compounds from four distinct chemical
      classes were directly compared for efficacy and potency in hone, uteri, lipids,
      and adipose tissues in an ovariectomized model with 6 month old rats. Five weeks
      of oral dosing confirmed that ethynyl estradiol, tamoxifen, and raloxifene are
      potent inhibitors of the loss in volumetric bone mineral density (BMD, mg/cc)
      induced by ovariectomy, as measured by computed tomography. In the metaphysis of
      distal femora from ovariectomized rats, analysis showed a significant 12-20%
      decrease (P< 0.01) in the BMD. Linear regression analysis was used to calculate
      half-maximal efficacious doses for ethynyl estradiol ED(50) =0.04mg /kg, which
      was threefold more potent than tamoxifen, which in turn was threefold more potent
      than raloxifene, which was more efficacious than nafoxidine. In the uterus,
      raloxifene had minimal effects on the endometrium and smaller effects on uterine
      eosinophil peroxidase activity than nafoxidine, tamoxifen, or estrogen,
      respectively. Estrogen was the most potent in reducing cholesterol levels in
      ovariectomized rats, whereas tamoxifen and nafoxidine were more effective than
      raloxifene in blocking gain in body weight. Distinct compounds had advantages in
      the management of bone, uterine, serum cholesterol, and adipose tissues after
      ovariectomy. The distinct pattern of pharmacological effects may be best
      understood in terms of their respective chemical structure, specifically
      estrogens, benzothiophenes (raloxifene), dihydronapthylenes (nafoxidine), and
      triphenylethylenes (tamoxifen). These data point to advantages of separate
      compounds in the management of bone, uterine, serum cholesterol, and adipose
      tissues after estrogen deficiency, and show that the benzothiophene raloxifene
      has potentially important advantages over estrogen, tamoxifen, or nafoxidine in
      the uterus.

PMID- 8666169
TI  - Effect of isothermal radiofrequency radiation on cytolytic T lymphocytes.
AB  - Previous in vitro studies provide evidence that RF electromagnetic radiation
      modulates proliferation of human glioma, lymphocytes, and other cell types. The
      mechanism of RF radiation cell proliferation modulation, as well as mechanisms
      for effects on other cell physiologic endpoints, are not well understood. To
      obtain insight regarding interaction mechanisms, we investigated effects of RF
      radiation exposure on interleukin 2 (IL-2) -dependent proliferation of cytolytic
      T lymphocytes (CTLL-2). After exposure to RF radiation in the presence or absence
      of IL-2 cells were cultured at various physiological concentrations of IL-2.
      Treatment effects on CTLL-2 proliferation were determined by tritiated thymidine
      incorporation immediately or 24 h after exposure. Exposure to 2450 MHz RIF
      radiation at specific absorption rates (SARs) of greater than 25 W/kg (induced E
      field strength 98.4 V/m) induced a consistent, statistically significant
      reduction in CTLL-2 proliferation, especially at low IL-2 concentrations. At
      lower SARs, 2450 MHz exposure increased CTLL-2 proliferation immediately after
      exposure but reduced 24 h postexposure proliferation. RF radiation effects
      depended on the mitotic state of the cells at the time of exposure. Comparison of
      the effects of temperature elevation and RF radiation indicated significant
      qualitative and quantitative differences.

PMID- 8666170
TI  - The stimulation of Na,K,Cl cotransport and of system A for neutral amino acid
      transport is a mechanism for cell volume increase during the cell cycle.
AB  - It has been known for several years that the triggering of cell proliferation is
      associated with an increase of the activity of Na,K,Cl cotransport and of
      transport system A for neutral amino acids. These systems are also enhanced
      during the volume recovery of hypertonically shrunk cells. We demonstrate here
      that during the cell cycle of NIH3T3 cells, an increase in cell volume is
      associated with an enhanced cell content of potassium and amino acids. Bumetanide
      delays cell cycle progression and hampers volume increase. The nonmetabolizable
      analog 2-methylamino-isobutyric acid, a specific substrate of system A, can
      partially substitute natural amino acids accumulated during the cell cycle as
      intracellular osmolytes. It is therefore proposed that the stimulation of Na,K,Cl
      cotransport and of system A, observed in proliferating cells, causes an expansion
      of cell volume through an enhanced intracellular accumulation of both inorganic
      and organic osmolytes and the concurrent, osmotically obliged uptake of water.

PMID- 8666171
TI  - Collagen/collagenase interaction: does the enzyme mimic the conformation of its
      own substrate?
AB  - In this report, we present a hypothesis on the mechanism used by interstitial
      collagenases to cleave their natural substrate, interstitial collagens. The
      hypothesis is based on the assumption that the proline hinge domain of
      interstitial collagenase adopts a collagen-like conformation. With a collagen
      like domain, the enzyme is able to disturb the quaternary organization of the
      triple helix in the collagenase-susceptible site. A modeling analysis suggests
      that interaction between prolines of both collagen and collagenase forming a kind
      of "proline zipper" is involved in the destabilization step. This destabilization
      makes the three-collagen helix susceptible to the catalytic cleft of the
      catalytic core.

PMID- 8666172
TI  - How I got my start in lipids, and where it led me.

PMID- 8666173
TI  - [Prevention of coronary disease in clinical practice. Guidelines of the Task
      Force of the European Society of Cardiology, European Atherosclerosis Society and
      European Society of Hypertension].

PMID- 8666174
TI  - [Lipid peroxidation and LDL modifications in nondiabetic patients with ischemic
      heart disease: the role of insulin action].
AB  - BACKGROUND: Nondiabetic patients with advanced coronary artery disease (CAD) were
      assessed for lipid peroxidation, LDL modifications and insulin action. Twenty
      four patients and 10 normal controls were studied. METHODS: Insulin tolerance
      test (Kitt), glucose, insulin lipoproteins, electronegatively charged, modified,
      low density lipoproteins (LDL-) and the thiobarbituric acid reactivity (TBARS),
      as an index of lipid peroxidation, were determined. RESULTS: No difference was
      observed in insulin action (determined by insulin tolerance test) between
      patients with CAD (3.31 +/- 0.28%/min; range 0.73-6.13) and normal controls (3.59
      +/- 0.42; range 1.76-6.06). The percentage of modified, electronegative LDL (LDL 
      ) was higher in patients with CAD (0.5 +/- 0.48%; range 1.3-9.2) than that of
      controls (2.80 +/- 0.33; range 1.00-4.00; p = 0.013). TBARS were significantly (P
      = 0.043) higher in CAD patients (3.49 +/- 0.17 nmol/ml; range 2.4-5.5) than
      normal controls (1.47 +/- 0.12; range 1.07-2.10). A significantly negative
      correlation was observed between Kitt and TBARS (r= - 0.48; p = 0.016), and a
      significant (r = 0.46; p = 0.022) positive correlation was observed between
      plasma glucose and TBARS. On the contrary no correlation has been observed
      between LDL- and TBARS. CONCLUSIONS: We conclude that in patients with advanced
      coronary artery disease: A) there are increased circulating levels of modified
      low density lipoprotein; B) there is evidence of increased lipid peroxidation.
      This latter process is significantly influenced by the degree of insulin action.

PMID- 8666175
TI  - [Postischemic dysfunction and persistent ischemia in the early postinfarction
      period. Evaluation by echo-dobutamine-atropine test].
AB  - AIM: To study post-ischemic dysfunction and persistent ischemia in early post
      infarction, by means of Echo-dobutamine-Atropine stress test (ECHO-DOB). Methods.
      We studied 138 patients (pts) aged < or = 75 yrs (mean 59.2 +/- 9.8) at their
      first uncomplicated myocardial infarction (AMI), treated with systemic
      thrombolysis. All pts underwent the test within 2 weeks since the onset of the
      attack and they were reevaluated in follow-up 3 months later. Under Echo and ECG
      monitoring, ECHO-DOB was performed according to EDICS protocol. Low doses was
      infused (5-10 mcg/Kg/min every 3') to assess the viability and high doses (20 >
      or = 40 mg/Kg/min + Atropine) to assess a possible persistent ischemia. The Wall
      Motion Score Index (WMSI) was used for the semiquantitative analysis of kinesis
      in a model of left ventricle divided into 16 segments. coronary angiography was
      performed within 30 days from the AMI, in 82.3% of pts. Results. Low dose of
      Dobutamine (DOB) induced in 92/136 (67.6%) pts an improvement in the contractile
      dysfunction in the region of necrosis; in 31.5% (29/92) it remained until the end
      of the test, suggesting the presence of viable myocardium, In absence of
      myocardium "at risk". High doses DOB induced worsening of contractile dysfunction
      in 64 pts (47%); in 40 (62.5%) viability had been previously detected (viable but
      ischemic myocardium); In 30 (75%) it was homozone or adjacent (viable but
      ischemic myocardium in the region of the coronary artery or in the tributary
      vessels correlated to the necrosis). In 24/64 (37.5%) pts the absence of
      modification of WMSI (no improvement and no worsening), suggested the presence of
      necrotic tissue in the tributary region of the vessel of necrosis. The
      significant improvement in kinesis revealed in 92 pts, by the follow-up control
      was confirmed in 64 (p < 0.001) (69.5%). Forty-four pts without hyperkinesia
      showed no significant improvement compared with the base line (stunned or
      hibernating myocardium). The sensitivity of low doses for viable myocardium (gold
      standard follow-up) was 69%; specificity was 77%. The sensitivity of high doses
      for ischemia (gold standard coronary arteriography) was 78%; specificity was
      100%. No major side effects during the Dobutamine Atropine test were observed.
      CONCLUSIONS: The ECHO-DOB test in the post-infarction period allow the assessment
      of the functional significance of what is the objectified by coronary angiography
      and identifies pts at risk of more serious events. An integration of the test
      with the angiographic data can direct towards more suitable therapeutical or
      surgical choices.

PMID- 8666176
TI  - [Prognostic value of echo-dobutamine test in patients with ischemic heart
      disease: comparison with exercise test].
AB  - BACKGROUNDS: The aim of the study was to assess the relative prognostic accuracy
      of dobutamine echocardiography (TED) vs maximal bicycle exercise
      electrocardiography (TE) in patients with proven coronary artery disease.
      METHODS: One hundred and thirty consecutive patients (70 patients with
      uncomplicated recent myocardial infarction, 19 asymptomatic patients with
      previous myocardial infarction and 41 patients with stable angina pectoris and
      previous myocardial infarction or previous myocardial revascularization
      procedure) underwent TED (incremental dobutamine infusion: 5 to 40 ncg/kg/min,
      continued with atropine 0.25 to 1 mg iv if necessary) and TE on different days
      and in random order. Criteria for positivity were: new or worsening regional
      dyssynergy for TED; ST segment shift > or = 1 mm from baseline for TE. End points
      were defined as spontaneous events (cardiac death, myocardial infarction and
      unstable angina) and total events (spontaneous events plus myocardial
      revascularization procedures). RESULTS: During 15.4 +/- 7.9 (range 1-33) months
      of follow-up, 33 events occurred: cardiac death (1), myocardial infarction (4)
      unstable angina (21) myocardial revascularization (7). Sensitivity, specificity,
      positive and negative predictive value, prognostic accuracy were similar for TED
      and TE (P = NS). Cumulative event-free survival curves as a function of TED and
      TE results were both statistically significant. A Cox stepwise regression
      analysis identified TED positivity obtained without atropine administration as
      the best predictor of spontaneous and total events (Odds ratio 5.33 and 4.38,
      respectively). Cumulative survival curves obtained by the combination of TED and
      TE results were statistically different (P < 0.05 and P < 0.001 for spontaneous
      and total events, respectively) and showed a poor clinical outcome in patients
      with both tests or only TED positive. TED correctly predicted clinical outcome in
      24/39 patients in whom there was disagreement between the two tests. CONCLUSIONS:
      In patients with proven coronary artery disease, TED and TE have a similar
      accuracy for predicting clinical outcome. Where a discrepancy is seen between the
      two tests, TED appears to have a slightly higher prognostic value.

PMID- 8666177
TI  - [Intraoperative stent implantation in congenital stenosis of pulmonary veins].
AB  - Congenital stenosis and/or hypoplasia of the pulmonary veins(s) is a rare cardiac
      malformation, whose treatment is difficult and not well defined, so conditioning
      an extremely poor prognosis. In fact, balloon angioplasty and surgery proved to
      be ineffective during a mid-term follow-up, thus not significantly modifying the
      natural history of this cardiovascular malformation. Although heart-lung
      transplantation is thought by someone to be the sole reliable treatment for
      congenital stenosis of the pulmonary vein(s), a recently available therapeutic
      option, the endovascular "stent" implantation during cardiac catheterization
      prompted to hope for a better outlook for these patients. However, this procedure
      is far from being an easy approach, due to technical problems that cause a high
      rate of failure and major complications. We report on two cases of pulmonary vein
      stenosis successfully treated by endoluminal "stent" implantation during open
      heart surgery, and suggest, and suggest that this safe and effective approach
      might be an alternative therapeutic option in the definitive or palliative
      treatment of this congenital cardiovascular malformation.

PMID- 8666178
TI  - [Acute myocardial infarction in bacterial endocarditis].
AB  - The authors report on a 47-years old woman with bacterial endocarditis involving
      both the mitral and aortic valves. At first echocardiographic examination, the
      mitral vegetation was small, while the aortic one was large highly mobile.
      Despite adequate antibiotic therapy, the aortic vegetation had become bigger and
      the valve regurgitation, initially mild to moderate, resulted severe and was
      associated with left heart failure. While awaiting surgery, the patient sustained
      an acute non Q wave myocardial infarction with ST segment elevation in inferior
      and anterolateral leads, complicated by ventricular arrhythmias. Thirty-six hours
      later, the patient received mitral and aortic valve replacement: at surgical
      view, the aortic vegetations was found to be very close to the right coronary
      orifice. After a period of further antibiotic therapy, the woman discharged and
      at a six months follow-up, she was fairly well. The authors review the mechanisms
      of acute coronary insufficiency in infective endocarditis and suggest an embolic
      pathogenesis in the case reported. Taking into account the possible life
      threatening embolic complications, it seems reasonable not to delay surgery when
      antibiotic therapy fails to reduce the size and mobility of valve vegetations.

PMID- 8666179
TI  - [Treatment of supraventricular tachyarrhythmias: drugs or ablation?].

PMID- 8666180
TI  - [Documentation and communication in cardiovascular prevention. A proposal of the
      regional project of cardiovascular prevention of Friuli Venezia Giulia].

PMID- 8666181
TI  - [Hemoglobin oxygen-transport activity in lymphosarcomas].
AB  - To evaluate oxygen transport function of Hb in lymphoid sarcomas, 15 patients
      aged 16-63 were examined for Hb oxygen capacity, concentrations of fetal Hb and
      creatinin, basic ligands H+, CO2, 2,3-diphosphoglycerate (2,3-DPG). Oxy-Hb
      dissociation curves were plotted. The patients' blood contained HbF in elevated
      quantities, whereas red cells had high creatinin. This emphasizes the role of
      hemolysis in genesis of anemia in lymphosarcomas. 70% of the examinees retained
      normal Hb affinity to oxygen in vivo, in 30% this affinity exceeded the standard.
      Compensatory mechanism responsible for low Hb affinity to oxygen in this disease
      fails. Therefore lymphosarcoma patients with anemia need early replacement
      hemotransfusions.

PMID- 8666182
TI  - [The thrombocyte count and potassium concentration of the blood in acute
      nonlymphoblastic leukemia (towards an understanding of the regulatory mechanisms
      of hemopoiesis)].
AB  - The authors show that when platelet count and potassium concentrations in ANLL
      patients correlate positively or do not correlate, there is a positive and
      negative correlation between survival and hemoglobin level (number of red cells),
      respectively. Clinically, it means that in certain conditions hemotransfusion of
      red cell mass may be useless or even harmful. In groups with different
      relationships between platelet count and blood potassium levels, other indicators
      also vary in interrelations. Thus, in the groups compared cholesterol
      concentration correlated differently with platelet number, hemoglobin and
      potassium concentrations. It is suggested that in certain conditions group
      correlation may be similar to individual (physiological) correlation of the
      signs. In situation when it is true, great methodological prospects are opened
      for quantitative description and investigation of physiological regularities.

PMID- 8666183
TI  - [The role of splenectomy in treating severe aplastic anemia].
AB  - Efficacy of splenectomy at initial stage of multimodality treatment of severe
      aplastic anemia was assessed in 25 patients aged 15-42. None of the patients
      achieved remission though there was a relief of hemorrhagic syndrome, diminished
      requirement in transfusion of donor platelets, a persistent rise in the counts of
      reticulocytes, leukocytes, absolute number of granulocytes in peripheral blood on
      postoperative days 14-21 and 60. All the patients were subsequently treated with
      immunodepressants.

PMID- 8666184
TI  - [The role of shifts in blood rheology in the genesis of thrombosis in patients
      with arthrosis deformans of the hip joint].
AB  - Blood rheology was studied in 83 patients with deforming coxarthrosis and 32
      healthy controls. The following parameters were measured: blood viscosity,
      hematocrit, yield point, red cell aggregation and deformability, suspension
      stability. It is shown that blood rheology in coxarthrosis undergoes changes
      early in the disease course which progress with worsening of the patient's
      condition. High blood density in coxarthrosis is one of the factors responsible
      for postoperative thrombotic and thromboembolic complications.

PMID- 8666185
TI  - [The clinico-instrumental characteristics of the kidneys in hemophilia patients].
AB  - Urinary system was examined in 35 hemophiliacs. 25 of them had in the past 2 to 6
      episodes of hematuria. The examinees had also depressed cellular immunity. Their
      humoral immunity, on the contrary, was activated. In the absence of clinical and
      x-ray evidence of urinary abnormalities, renal affections were registered in
      88.6% of the examinees. According to the data obtained all hemophiliacs suffer
      from unbalance of cellular and humoral immunity, abnormal clearance of immune
      complexes, probable renal damage. Therefore, it is desirable to make ultrasonic
      investigation of the kidneys in all hemophiliacs to check latent renal affection
      and take therapeutic measures.

PMID- 8666186
TI  - [The cell cycle patterns of the hemopoietic cells under the action of ionizing
      radiation].
AB  - The analysis of changes in bone marrow cell cycle induced by ionising radiation
      in animals and humans in comparison with myelogram evidence on postradiation
      death of myelocaryocytes shows that radiation is responsible for pronounced dose
      dependent shifts in cell cycle early after radiation prior to postradiation cell
      death. These phenomena are considered in light of new hypophysis on the existence
      of cell cycle regulation system and initiation of apoptosis at the cell level.

PMID- 8666187
TI  - [The influence of the blood microcirculatory bed on the cellular immune response
      in the regional lymph nodes of a cancerous tumor (an immunohistochemical and
      ultrastructural study)].
AB  - Immunohistochemical, ultrastructural, morphological and morphometric techniques
      as well as monoclonal antibodies to F VIII R:Ag endotheliocytes, CD2 and CD3 T
      lymphocytes, CD1 and CD10 T-lymphoblasts, CD4 T helpers, CD8 and CD30 T-killers
      and activated lymphocytes were used to study blood microcirculation relationship
      to cellular immunity in lymph nodes regional to malignant tumor. It was
      established that on the one hand there was early activation of cellular immune
      reactions with high level of cytotoxic T-cells and enhanced lymphocyte
      recirculation via postcapillary venules, on the other side at later stages
      changes in the vascular wall and circulatory disorders develop in line with
      deposition of intra- and extravascular fibrin. This impedes lymphocyte
      recirculation and leads to a cut in the number of T-effectors enabling prevention
      of metastatic spread to the lymph nodes.

PMID- 8666189
TI  - [The Fas/APO-1 antigen--a molecule mediating apoptosis].

PMID- 8666188
TI  - [Results of screening hematological and cytochemical blood studies of 906
      children living in Bryansk Province at places with different intensities of soil
      contamination with cesium-137 and strontium-90].
AB  - Populations of children living in the Bryansk territory (radionuclide
      contamination 0.2-63.9 Cu/km2) are characterized by heterogeneous blood counts,
      though relevant mean values are close to control. Mean cytochemical indices
      indicated a significant reduction in activity of point nonspecific esterase
      (NSEP), a marker of mature T-cells, in children from all the contaminated
      districts. Shifts in cytochemical blood lymphocytogram by NSEP test evidencing
      rejuvenascence of T-lymphocyte pool were recorded in 12-33% of children from
      different villages. A 10% decrease in NSEP suggested poor adaptation and
      feasibility of immunodeficiency. In one-third of children with low NSEP the
      number of lymphocytes with large-granular PAS reaction may reflect uneffective B
      lymphopoiesis in these children. In two villages significantly contaminated with
      137Cs and 90Sr half of the children had blood hemoglobin above 150 milligrams.
      Children from three villages exhibited a sharp rise in the number of lymphocytes
      with intensive-granular PAS reaction. These changes may be related to thyroid
      abnormalities. The number of children at risk of health deterioration grows with
      growing environmental contamination with 137Cs.

PMID- 8666190
TI  - [Determination of the rhesus classification of human blood].

PMID- 8666191
TI  - [The comparative results of determining the rhesus classification of donors using
      anti-D monoclonal antibodies on the plate and a universal reagent in the test
      tube without heating].

PMID- 8666193
TI  - [A case of CD30 (Ki-1)-positive acute leukemia in a 2-year-old child].

PMID- 8666194
TI  - [The potentials of a new approach to solving the current problems in the care of
      patients with blood diseases today. The Health and Nutrition Association
      program].

PMID- 8666192
TI  - [The clinical picture and morphocytochemical characteristics of the cells in an
      idiopathic myelodysplastic syndrome].

PMID- 8666195
TI  - [An analysis of the associational connections of immunogenetic blood markers with
      lymphogranulomatosis in Armenians].
AB  - A study of 11 immunogenetical blood systems (HLA-A, B C, DR; ABO; Rh-Hr; MNSs;
      Kidd; Kell-Chellano; Duffy; Lewis; Diego; Gm; Inv) involving 59 antigens was
      performed in patients of Armenian nationality with lymphogranulomatosis (LGM).
      Pathogenic associations of HLA, MNSs and Duffy systems with LGM were established.
      Positive correlations were found (p < 0.001) with HLA phenotypes DR-8, B-14, B
      21, SS, Fy(a+b-). These phenotypes have significant correlation with LGM (RR =
      4.7-2.1) and can be considered as genetic markers of LGM in the Armenian
      population.

PMID- 8666196
TI  - Induction of phenazine biosynthesis in cultures of Pseudomonas aeruginosa by L-N
      (3-oxohexanoyl)homoserine lactone.
AB  - A range of Pseudomonas spp. and other Gram-negative bacteria were screened for
      induction of antimicrobial activity in response to the autoregulatory factor L-N
      (3-oxohexanoyl)homoserine lactone. In one of these, P. aeruginosa ATCC 10145, the
      production of phenazine metabolites was shown to be inducible in a dose-dependent
      manner. The production of phenazine-1-carboxamide increased over 50-fold compared
      to control cultures when supplemented with 200 micrograms/ml of the
      autoregulator. In addition, the production of an unidentified polar antibacterial
      substance by this strain increased with autoregulator concentration.

PMID- 8666197
TI  - Analysis of the catalytic domain of the lysin of the lactococcal bacteriophage
      Tuc2009 by chimeric gene assembling.
AB  - An active chimeric cell wall lytic enzyme (Tsl) has been constructed by fusing
      the region coding for the N-terminal half of the lactococcal phage Tuc2009 lysin
      and the region coding for the C-terminal domain of the major pneumococcal
      autolysin. The chimeric enzyme exhibited a glycosidase activity capable of
      hydrolysing choline-containing pneumococcal cell walls. This experimental
      approach demonstrated that the Tuc2009 lysin possesses a modular structure and
      further supports the hypothesis that many cell wall lytic enzymes have evolved by
      the fusion of preexisting catalytic and peptidoglycan-binding domains.

PMID- 8666198
TI  - Cell wall changes in nisin-resistant variants of Listeria innocua grown in the
      presence of high nisin concentrations.
AB  - Two nisin-resistant variants of a strain of Listeria innocua were isolated after
      growth in the presence of 500 and 4000 IU ml-1 of nisin A showed increased cell
      wall hydrophobicity, resistance to phage attack and three different cell wall
      acting antibiotics, as well as to the peptidoglycan hydrolytic enzymes lysozyme
      and mutanolysin, as compared to the parental strain. Transmission electron
      microscopy revealed marked thickening of the wall of nisin-resistant cells with
      an irregular surface. Differences in thickness were lost after cell wall
      purification and no significant difference in gross wall composition was observed
      between the parental and resistant variants. Cell wall changes in nisin-resistant
      listeriae are attributed to abnormal cell wall synthesis and autolysin
      inhibition, the latter possibly associated with subtle changes in cell wall
      structures and function.

PMID- 8666199
TI  - Characterisation of carbon dioxide-inducible genes of the marine bacterium,
      Pseudomonas sp. S91.
AB  - Characterisation of two genes in Pseudomonas sp. S91 that are responsive to
      carbon dioxide is reported. These were identified by random transposon
      mutagenesis leading to fusion of the Escherichia coli lacZ reporter gene to the
      genes of interest. Expression of the genes' promoters was quantified by measuring
      the reporter gene product, beta-galactosidase. beta-Galactosidase synthesis was
      induced when cells were exposed to 10% CO2 on solid media or during growth in
      aqueous phase when the culture density was greater than 1 at 610 nm, in either
      rich or minimal media. Induction of beta-galactosidase synthesis was not due to:
      increased alkalinity, onset of stationary phase, build up of soluble metabolites
      in the culture supernatant, or cell density-dependent signalling. The CO2
      inducible gene fusions were not induced by other environmental conditions that
      are known to stimulate global regulators of environmental gene expression.
      Benzoic acid (2 mM) induced beta-galactosidase synthesis in one of the mutants
      indicating the Co2 response may involve the intracellular CO2 partial
      pressure/bicarbonate ion concentration/pH equilibrium.

PMID- 8666200
TI  - The pel1 mutant of Saccharomyces cerevisiae is deficient in cardiolipin and does
      not survive the disruption of the CHO1 gene encoding phosphatidylserine synthase.
AB  - Cells of the pel1 mutant of Saccharomyces cerevisiae were found to contain an
      extremely low content of cardiolipin, a decreased level of phosphatidylcholine
      and an increased level of phosphatidylinositol. Disruption of the PEL1 gene in
      cells containing a null mutation in the CHO1 gene was lethal. Despite its
      putative functional homology with CHO1, the overexpression of the PEL1 gene in
      the cho1 null mutant did not restore the wild-type properties of the transformed
      cells and failed to stimulate the incorporation of L-[3-3H]serine into total
      lipids of the intact yeast cells.

PMID- 8666201
TI  - Identification of the Streptococcus mutans frp gene as a potential regulator of
      fructosyltransferase expression.
AB  - Four putative open reading frames (ORFs) were previously identified in the
      regions flanking the Streptococcus mutans GS-5 fructosyltransferase (FTF) gene.
      One of these, ORF 3, appeared to code for a low-molecular-mass protein containing
      amino acid sequences sharing homology with several Gram-positive bacterial DNA
      binding proteins and it was suggested that the ORF 3 gene product might be an FTF
      regulatory protein (FRP). In order to characterize this protein, we have purified
      the biotinylated tag-FRP fusion protein using the PinPoint protein purification
      system and this fusion protein was used in gel shift assays with DNA fragments
      containing the ftf promoter region. FRP bound specifically to the upstream region
      of the ftf promoter containing the inverted repeat structure that is present
      upstream of the -35 sequence. In contrast, FRP did not bind to DNA fragments
      lacking the inverted repeat structure. The results of these experiments suggest
      that FRP interacts with the inverted repeat region upstream of the ftf promoter
      and such interactions may regulate FTF expression.

PMID- 8666202
TI  - TonB-dependent iron supply in Salmonella by alpha-ketoacids and alpha
      hydroxyacids.
AB  - A range of structurally diverse alpha-ketoacids and alpha-hydroxyacids promoted
      the growth of isolates of Salmonella serovars S. typhimurium, S. enteritidis, S.
      agona, S. paratyphi and S. stanleyville in iron restricted conditions in the
      absence of functional siderophores. Growth stimulation, observed both in cross
      feeding tests on solid medium and in liquid cultures, and uptake of 55Fe in the
      presence of alpha-ketoisocaproic acid, were TonB dependent in S. typhimurium. In
      this respect the mechanism is distinct from a previously described Serratia
      marcescens system (sfuABC); the presence of the cloned sfuABC genes mediated tonB
      independent uptake by S. typhimurium of iron complexed with alpha-ketoacids.

PMID- 8666203
TI  - Analysis of the shut-off of ribosomal RNA promoters in Escherichia coli upon
      entering the stationary phase of growth.
AB  - Most bacterial RNA consists of stable RNA which is composed of rRNA and tRNA. We
      have followed by primer extension analysis the level of ribosomal RNA synthesis
      along the growth phases of a cell culture. A sharp drop in rRNA synthesis was
      observed upon the transition from the exponential to the stationary phase of
      growth. Our results demonstrate that an effective shut-off of rRNA synthesis
      occurs also in the absence of ppGpp. Mutations in the host factors Fis and H-NS,
      which are known to regulate rrn P1 promoters, did not affect the shut-off process
      of ribosomal RNA promoters. We also tested the effect of RpoS, the sigma factor
      known to induce a number of genes in the stationary phase. It was shown that the
      host factors Fis, H-NS and RpoS do not play a major role in the regulation of the
      shut-off process of rRNA synthesis. The results presented demonstrate that the
      rate of rRNA synthesis provides a sensitive measure of the growth phase of the
      bacterial culture.

PMID- 8666204
TI  - Trehalose-6-phosphate synthase A affects citrate accumulation by Aspergillus
      niger under conditions of high glycolytic flux.
AB  - Accumulation of citric acid by Aspergillus niger depends on a high flux through
      glycolysis. We have investigated the possibility of control of this flux by
      trehalose 6-phosphate, an inhibitor of hexokinase of Saccharomyces cerevisiae and
      other eukaryotes (Blasquez et al., FEBS Lett. (1993) 329, 51-54). Hexokinase of
      A. niger was shown in vitro to be only weakly inhibited by trehalose 6-phosphate
      (KI 1.5-2 mM). To investigate the in vivo relevance of this inhibition, we used
      isogenic strains of A. niger, carrying either a disruption or an amplification of
      the trehalose-6-phosphate synthase A (T6PSA)-encoding gene (ggsA) and exhibiting
      corresponding differences in T6PSA activity. These strains produced citric acid
      at comparable rates and with similar yields on 1 or 2.5% (w/v) sucrose. At 5-14%
      (w/v) sucrose, the ggsA disrupted strain initiated citric acid accumulation
      earlier, whereas the multicopy strain showed the reverse effect. When sucrose was
      replaced by lactose, which enabled only low rates of catabolism irrespective of
      its concentration (1-8%), no differences in the initiation or rate of citric acid
      accumulation were observed between the three strains. The possible mechanisms by
      which ggsA controls glycolytic flux in A. niger in the presence of high sugar
      concentrations are discussed.

PMID- 8666205
TI  - Isolation and characterization of pLS1 plasmid mutants with increased copy
      numbers.
AB  - Streptococcus pneumoniae genetic systems designed for isolation of plasmid
      mutants with copy-up phenotypes have been developed. The target plasmids have the
      pLS1 replicon, and two different strategies have been followed: (i) selection of
      clones exhibiting augmented resistance to antibiotics, or (ii) obligatory co
      existence of incompatible plasmids. We have isolated 23 plasmid mutants
      exhibiting increased number of copies. All the mutations corresponded to four
      different alleles of the copG gene of plasmid pLS1. These strategies could be
      used with other plasmids.

PMID- 8666207
TI  - Practice variation in rural mental health care delivery systems.

PMID- 8666206
TI  - Expression of genes involved in phycocyanin biosynthesis following recovery of
      Synechococcus PCC 6301 from nitrogen starvation, and the effect of gabaculine on
      cpcBa transcript levels.
AB  - The effect of the tetrapyrrole biosynthesis inhibitor gabaculine on the
      expression of specific genes involved in phycocyanin biosynthesis was
      investigated in cultures of Synechococcus PCC6301 in nitrogen chlorosis, and
      during recovery to nitrogen sufficiency. Patterns of transcription of the cpcBA
      (phycocyanin subunits), hemL (glutamate semialdehyde aminotransferase) and hemB
      (aminolaevulinate dehydratase) genes were visualised by Northern blotting and
      gene product formation for cpcBA, hemL and the gene for glu tRNA synthetase were
      monitored by Western blotting. Inhibition of phycobilin biosynthesis by
      gabaculine greatly decreased production of phycocyanin protein and of cpcBA
      transcript, indicating a tight coordination of apoprotein biosynthesis with
      chromophore supply at the level of transcription. Different patterns of response
      were observed with the other genes at the level of transcript formation or gene
      product synthesis.

PMID- 8666208
TI  - Patterns of rural mental health care. An exploratory study.
AB  - In rural areas, it is important to clarify our understanding of how primary care
      and specialty mental health professionals organize care for those with mental
      disorders, and the role that linkages between specialty mental health and primary
      health care providers can play in the effectiveness of such care. Although these
      are issues that must be generally addressed, in rural areas fewer institutional
      and individual providers per capita accentuate problems of health care
      organization and delivery. This paper reports findings from an exploratory study
      of service use in two primary care sites in a rural, group-model HMO (Site A
      enrollment = 2,625; Site B = 6,019). We found that patients in the primary care
      site who had weaker mental health consultative linkages, higher rurality, and
      less availability of mental health specialty care used more mental health
      services by primary care providers (RR = 5.19 (3.78,6.61)), received more
      ambulatory care from joint mental health/ primary care providers (RR = 1.68
      (1.02,2.78)), and had more mental health hospital utilization (adjusted OR = 1.84
      (0.54,6.23)). These findings point to the need for further study of primary care
      providers and their linkage relationships in rural areas, in this large and
      currently often underserved population.

PMID- 8666209
TI  - Do primary care patients accept psychological treatments?
AB  - Most individuals seeking care for psychological distress go to primary care
      physicians rather than to mental health professionals. Many have symptoms of
      distress that do not meet criteria for psychiatric disorders; pharmacotherapies
      are generally not available for these subsyndromal problems. Preliminary studies
      suggest that psychosocial therapies may be useful. The aim of this paper was to
      learn whether medical patients would accept psychological treatments for 1)
      depression, an explicit psychopathology; 2) stress, a nonpathological, but
      psychological, problem; and 3) medical problems, a nonpsychological issue.
      Respondents were 131 primary care patients at San Francisco General Hospital, a
      public sector hospital. The results show that most of the patients (107 of 131)
      found psychological interventions acceptable. In addition, the vast majority were
      willing to have the treatments focus on psychological issues such as depression
      and stress. This study demonstrates that primary care patients find psychological
      interventions acceptable.

PMID- 8666210
TI  - Overdiagnosis of depression in the general hospital.
AB  - To test the hypothesis that depression is often inaccurately detected in medical
      settings, we examined the psychiatric consultations performed at two medical
      surgical teaching hospitals. All records for the 4396 consultations seen in a 3
      year period were retrospectively reviewed. Consultations were categorized by the
      reason for referral. These reasons were compared with the consulting
      psychiatrist's diagnosis. Diagnoses were grouped into "Depressed" and "Not
      Depressed" categories, depending on whether the psychiatric diagnoses implied any
      form of depressive illness (alone or in combination with other diagnoses). The
      majority of the referrals for psychiatric consultation (about 25% and 30% at the
      respective sites) were for presumed depression. Of these referrals for
      depression, approximately 40% were judged by the consultant to have no depressive
      diagnosis. Of the referrals for depression judged not to be depressed, the
      majority had other undiagnosed illnesses, particularly delirium, dementia, and
      anxiety disorders. The authors conclude that although numerous studies report
      that depression is unrecognized in medical patients, it may also be
      inappropriately suspected. This is of most concern when the presumption of
      depression delays other medical, neurological, or psychiatric evaluation.

PMID- 8666211
TI  - Functioning and well-being of patients in a consultation-liaison psychiatry
      clinic.
AB  - Outpatient consultation-liaison (C-L) psychiatry clinics are valuable settings
      for research and teaching endeavors. However, little is known about psychiatric
      symptoms and health status of persons treated in such settings. In this study, 80
      persons seen in an outpatient C-L psychiatry clinic were compared with 100
      persons seen in a mood disorder clinic on a variety of self-report instruments.
      Outpatient C-L clinic patients were found to have significantly poorer health
      status than mood clinic patients on the following domains as measured by the RAND
      instrument: general health perception, pain, physical functioning, and role
      functioning due to physical problems. Both groups had poor role functioning due
      to emotional problems and poor social functioning. The groups did not differ in
      depressive symptoms but C-L patients were significantly less anxious. Thus, it
      appears that patients in an outpatient C-L setting not only have significant
      medical comorbidity, as expected, but have levels of psychiatric distress
      comparable to that seen in a traditional psychiatry outpatient setting. These
      findings indicate that such a clinic is a fertile area for research and training
      in the diagnosis and treatment of persons with comorbid physical and mental
      disorders.

PMID- 8666212
TI  - Pathogenesis of cognitive complaints in patients on hemodialysis.
AB  - Memory-concentration complaints are a common symptom among end-stage renal
      disease patients receiving hemodialysis. However, assuming an organic basis for
      these complaints might lead to unnecessary and expensive testing. To further
      explore the etiology of cognitive complaints, this study examined the
      contribution of demographic, neuropsychological, medical, affective, and
      personality variables to memory-concentration complaints in 426 hemodialysis
      patients. Following stepwise multiple regression to identify the best predictor
      variables within each domain, hierarchical multiple-regression analysis
      determined the significant predictors of memory-concentration complaints.
      Education, digit symbol score, and hemoglobin jointly accounted for approximately
      7% of the variance. Cognitive (psychological) symptoms of depression explained an
      additional 9% of variance. Somatic symptoms of depression did not significantly
      contribute, whereas state anxiety did. Finally, personality variables
      collectively accounted for another 9% of variance. Overall, the model accounted
      for 28% of explained variance in memory-concentration complaints. These findings
      demonstrate that affect and personality factors are more predictive of memory
      concentration complaints in hemodialysis patients than are neuropsychological or
      medical factors. The clinical implication is that the initial response to memory
      concentration complaints in these patients should be evaluations of psychological
      condition.

PMID- 8666213
TI  - The European Consultation-Liaison Workgroup (ECLW) Collaborative Study. I.
      General outline.
AB  - Previous C-L psychiatric service research is seriously limited by its parochial
      nature; very few results can be generalized outside of the hospital in which the
      original study was performed because of differences in the nature of the hospital
      and the type of C-L service. This article presents the general outline and
      methodology of a European multicentered C-L service delivery study effected by
      the European Consultation-Liaison Workgroup for General Hospital Psychiatry and
      Psychosomatics (ECLW). The study is unique in its kind as it allows the
      comparison of very different C-L services; for example, some services are run by
      C-L psychiatrists, others are run by C-L psychosomaticists and the study
      encompasses a large variety of different settings. As a result, both common
      factors in C-L service delivery and specific local patterns can be explored. The
      overall hypothesis tested in this study was that the most developed services
      would see (as well as more patients) a wider variety of clinical problems than
      small services. The implication is that the absence of well-developed C-L
      services in a general hospital may mean that there are patients with unmet mental
      health needs. In separate articles the training and reliability testing of the
      new Patient Registration Form (PRF) and the Institutional and Provider
      characteristics will be described. The former includes the use of ICD-10 in the
      general hospital setting. This study is a collaborative effort made by 226
      consultants from 56 psychiatric C-L services in 11 countries. Each consultant
      recorded details of 1 year's caseload leading to a thorough description of 14,717
      patients collected between 1991 and 1993. The advanced methodology included a
      multicentered international approach, rigid training for all participating
      consultants, and the development and testing of new instruments. This will allow
      us to assess the impact of important structural and process variables on the
      outcome of C-L service delivery in several European countries. These results will
      be reported in papers both in the international and national literature of the
      participating countries.

PMID- 8666214
TI  - Childhood abuse and suicidality in obstetrics patients in a hospital-based urban
      prenatal clinic.
AB  - This study reports findings from a chart review examining the relationship
      between self-report of a history of childhood abuse and the emergence of suicidal
      ideation in pregnancy in a group of patients referred for psychiatric evaluation.
      The relationship between history of childhood abuse and actual suicide attempts
      prior to the current pregnancy was also investigated. Results revealed that women
      reporting a history of childhood sexual abuse, physical abuse, or both were
      significantly more likely than those not reporting a history of abuse to evidence
      suicidal ideation during the pregnancy. Additionally, those reporting a history
      of sexual abuse or both physical and sexual abuse were more likely than those not
      reporting such a history to have made a suicide attempt in the past at some point
      prior to the current pregnancy. Interpretations and potential implications of
      these findings for clinical work with psychiatrically at-risk pregnant women are
      discussed.

PMID- 8666215
TI  - Depression in patients with coronary heart disease. A 12-month follow-up.
AB  - Little is known about the course and outcome of depression in patients with
      coronary heart disease, despite its prevalence and effect on medical prognosis. A
      series of 200 patients undergoing diagnostic cardiac catheterization and coronary
      angiography were administered a psychiatric diagnostic interview. Seventeen
      percent were diagnosed with a current major depressive episode, and another 17%
      with a current minor depressive episode. Ninety percent of those patients who
      consented to follow-up completed the study. Half of the patients with major
      depression either remained depressed or relapsed within 12 months. Nearly half of
      the patients with minor depression remitted, but 42% subsequently developed major
      depression. These results suggest that major depression, if left untreated, is
      persistent in patients with coronary heart disease. Furthermore, minor depression
      is nearly as likely to progress to major depression as to remit over the course
      of the 12 months following diagnostic angiography.

PMID- 8666217
TI  - [A new mechanism of mutation in man: expansion of trinucleotide repeats].
AB  - An analysis of a novel, recently discovered class of mutations in man - an
      expansion, i.e., an increase of the copy number of intragenic unstable
      trinucleotide repeats - is presented. The expansion of trinucleotide repeats
      causes the development of at least seven hereditary diseases which damage the
      nervous system: the fragile X chromosome syndrome (two separate variants of the
      disease - FRAXA and FRAXE), myotonic dystrophy, spinal and bulbar Kennedy's
      amyotrophy, Huntington's chorea, type 1 spinocerebellar ataxia, and dentatorubral
      pallidolyusian atrophy. The discovery of triplet expansion allows a satisfactory
      explanation on the molecular level of a series of unusual clinical genetic
      phenomena, such as anticipation, the ?paternal transmission? effect, the ?Sherman
      paradox?, and others. The common properties and the distinctions of unstable
      trinucleotide mutations in the above-mentioned nosologic forms are analyzed
      comprehensively among for the mechanism by which these mutations cause disease,
      the time of their appearance in ontogenesis, and various clinical genetic
      correlations. The evolutionary origin of this class of mutations and, in
      particular, the role of alleles with an ?intermediate? triplet number, which are
      the persistent reservoir of mutations arising de novo in a population, are also
      discussed. The possible implication of unstable trinucleotide repeats for a
      series of other hereditary diseases, such as spinocerebellar ataxia of type 2,
      Machado-Joseph disease, hereditary spastic paraplegia, essential tremor,
      schizophrenia and others, is also suggested.

PMID- 8666216
TI  - Fluoxetine in depressed patients with renal failure and in depressed patients
      with normal kidney function.
AB  - Nine depressed patients with normal kidney function and seven depressed patients
      with renal failure undergoing hemodialysis were treated with open-label
      fluoxetine 20 mg/day in an 8-week study. The study was designed to evaluate the
      pharmacokinetics of fluoxetine during repeated administration and to acquire
      preliminary data regarding the effectiveness of this antidepressant in a
      population undergoing hemodialysis. Six patients in each group completed the
      study. Of these, five patients undergoing hemodialysis and five patients with
      normal renal function experienced moderate to marked improvement in their
      depression. Side effects were equal and minor in both groups, indicating that
      fluoxetine is safe in patients with renal impairment. The mean +/- standard
      deviation steady-state plasma concentrations of the sum of fluoxetine plus its
      metabolite norfluoxetine for patients completing 8 weeks (N = 6, both groups)
      were comparable for the patients undergoing hemodialysis (253 +/- 61 ng/ml) and
      those with normal kidney function (218 +/- 122 ng/ml; t = 1.5, df = 70, p >
      0.13). These data suggest that the efficacy of fluoxetine in patients with renal
      failure undergoing hemodialysis is comparable to that in patients with normal
      kidney function. These data further suggest that renal failure and the process of
      hemodialysis do not materially alter the pharmacokinetics of fluoxetine or its
      major metabolite norfluoxetine.

PMID- 8666218
TI  - [Effect of internal sequences in the Moloney murine leukemia virus genome on
      replication].
AB  - Construction and using of retrovirus vectors derived from the Moloney murine
      leukemia virus (MoMuLV) are described. These vectors, designated minimal vectors,
      contain the left and right long terminal repeats (LTRs), a binding site for
      proline tRNA, a polypurine tract (PPT), and a dominant marker for selective
      introduction of vectors into a packaging cell line, but lack the internal
      sequences of the virus genome. The experiments showed that the minimal vectors
      can be replicated and that their titer was approximately 1500-fold lower than
      that of wild-type vectors. The minimal vectors were shown to contain all the cis
      acting sequences necessary for correct reverse transcription. One infectious
      virion. like wild-type viruses, produced only one provirus. Unlike the avian
      reticuloendotheliosis virus (REV), psi+ and psi(-)-genomes of MoMuLV did not
      compete for virion proteins in the psi2 packaging cell line. When an insert was
      introduced into a central part of the lTR U5 region, the titer of the minimal
      vector remained the same, while the titer of the wild-type vector decreased
      approximately 40-fold.

PMID- 8666219
TI  - [Comparison of repeat DNA sequences in the Erinaceidae mammal family by
      restriction analysis].
AB  - Hedgehog (Erinaceidae) DNA was digested with teh Sau 96 I, Bsp 143 I, Csp 6 I,
      Taq I, Hinf I, Msp I, Eco 130I, Bcn I, BsuR I restriction endonucleases. The
      obtained products were end-labeled and electrophoretically separated in
      polyacrylamide gel. DNA fragments consisting of highly repetitive genomic
      sequences were detected as a set of bands corresponding to fragments between 30
      and 500 bp in length. Comparison of DNA restriction patterns of the species
      analyzed revealed the presence of species-specific bands as well as common bands.
      Phylogenetic trees were constructed by means of the maximum parsimony method and
      the bootstrap procedure. Our data suggest that hedgehog species from arid areas
      are clearly distinguished from forest species.

PMID- 8666220
TI  - [Cryptic transposable phages of Pseudomonas aeruginosa].
AB  - Frequencies of nucleotide sequences homologous to phage transposons (PT) of two
      species, D3112 and B3, were assessed in genomes of natural Pseudomonas aeruginosa
      strains by the dot-blot hybridization method. These strains were incapable of
      liberating viable phages on a lawn of the PA01 standard indicator strain of P.
      aeruginosa. It was shown that the homologies detected belong to two groups, high
      and intermediate, with respect to homology level. Homology patterns were
      classified as high when they provided signals comparable to those for
      hybridization in a positive control; they were classified as intermediate when
      the hybridization level higher than the background level, but lower than in the
      positive control. Homologous PT sequences were designated as cryptic PT. Intact
      cryptic PT prophages were shown to exist in genomes of particular natural strains
      manifesting a high level of hybridization. However, the growth of these phages
      was limited by the restriction system of strain PA01. It is possible to isolate
      strains maintaining the growth of a portion of cryptic PT. These strains differed
      from P. aeruginosa with respect to the specificity of the restriction and
      modification system. Nevertheless, in most cases, the attempt to identify a novel
      host capable of maintaining growth of a cryptic PT failed. Natural strains often
      carry cryptic PT related to both known PT species, D3112 and B3. The frequency of
      cryptic PT is extremely high, reaching 30% in only strains with a high level of
      homology and up to 50% in all strains exhibiting homology. This high PT frequency
      is assumed to be associated with the considerable variation of P. aeruginosa.

PMID- 8666221
TI  - [Crossing over in rearranged Drosophila chromosomes: the role of delayed
      pairing].
AB  - A Df(2R)MS2-10 deletion of pericentromeric heterochromatin, an Is(Y;2L)419
      insertion of Y material in the region 34A, as well as nondisjunction of
      chromosomes 2 in 2/F(2L); F(2R) females did not directly prevent chromosome arms
      in chromosome 2 of Drosophila from pairing. However, these events resulted in (1)
      two- to four-fold decrease in the rate of crossing-over in chromosome 2;(2) a
      decreased proportion of exchange tetrads two to three times greater for multiple
      exchange tetrads than for single-exchange ones; (3) and a decreased rate of
      crossing-over throughout the entire chromosome arm enhanced in a proximal
      direction, An In(l)dl-49+BMl inversion in the X chromosome cancelled the
      suppression of crossing-over. Crossing-over increased due to an increasing
      proportion of single-exchange tetrads. The changes in crossing-over found cannot
      be explained by asynapsis in the chromosomes with rearrangements. According to
      the authors, these changes are probably accounted for by a delayed pairing of
      these chromosomes. The delayed pairing of individual chromosome regions or the
      whole chromosome is considered the most common type of pairing disturbances. Its
      effect on meiosis are discussed.

PMID- 8666222
TI  - [Clinico-genetic aspects of cutaneous melanoma. I. Incidence, familial study,
      genetic heterogeneity].
AB  - Epidemiologic and clinical genetic data on cutaneous malignant melanoma (CMM) are
      presented. The incidence of CMM in Moscow from 1983 to 1987 was analyzed.
      Cumulative incidence (cumulative risk) was calculated for various life periods on
      the basis of estimates for various age groups, which were used as population
      frequencies. By the age of 85, these frequencies were 0.35% for males and 0.38%
      for females. Among relatives of patients, the incidence of CMM was 1.420 +/-
      0.498% for males and 1.110 +/- 0.348% for females; i.e., the incidence exceeded
      the population frequency by a factor of 3 or 4. As a whole, the familial
      frequency of cancer was equal to 13.3% for male probands and 14.2% for female
      probands, i.e., more than three times higher than the population frequency. The
      data obtained formed the basis for the development of CMM classification.
      hereditary and nonhereditary variants of cutaneous melanoma were identified.
      Familial cases and CMM that occurred against the background of inherited disease
      or syndromes were classified as hereditary variants of CMM; taken together, they
      accounted for 38.8%. The data provided grounds for identification of families at
      increased risk for the development of CMM.

PMID- 8666223
TI  - [Clinico-genetic aspects of cutaneous melanoma. II. Interconnection and
      pathogenetic commonality with dysplastic nevus syndrome].
AB  - Evidence for the role of dysplastic nevi (DN) in the development of cutaneous
      malignant melanoma (CMM) is presented. Primary multiple foci of CMM were found
      considerably more frequently in individuals with DN. The frequency of primary
      multiple CMM was found to be 3.1% in males with DN and 0.9% in males without DN;
      in females, 6.8 and 0.6%, respectively. Genetic correlation analysis was
      performed to determine the genetic interrelation between DN and CMM. In general,
      the genetic correlation coefficient was 0.9; i.e., predisposition to DN and CMM
      is determined by common genes for 90%. The frequency and distribution of
      constitutive fragile sites in chromosomes of peripheral lymphocytes was studied
      by the method of principal components for discrete variables. The site 1p22 is
      responsible for variability of the traits CMM and DN for 98.5%. On the one hand,
      this suggests that one of the supposed genes for CMM can be located at 1p22; on
      the other hand, CMM and DN are likely to have a common genetic determination or
      to be very tightly linked. Estimates of risk for the development of CMM in
      patients' relatives are given with reference to the variants of CMM manifestation
      and presence of DN.

PMID- 8666224
TI  - [A comparative computer analysis of thermodynamic parameters of transport RNA
      secondary structure].
AB  - Thermodynamic parameters of the cloverleaf secondary structure of tRNAs of
      several major taxons (archaebacteria, eubacteria, eukaryotes, chloroplasts, and
      mitochondria) were subjected to computer analysis. The distribution of free
      energy values was close to normal in all groups (except for the mitochondrial
      tRNA). In the organisms existing under extreme environmental conditions, the
      stability of the tRNA secondary structure was higher. Comparative analysis of teh
      frequency of ?quasi-complementary? GU pairs in stems of randomly generated and
      real sequences demonstrated preferential fixation of such pairs in the contexts
      with the most favorable thermodynamics parameters. Noncanonic pairs in tRNA stems
      set limits on the presence of highly mutable CG dinucleotides. Moreover, the
      effect of noncanonic pairs other than GU on the frequency of such dinucleotides
      is far more pronounced than that of GU pairs.

PMID- 8666225
TI  - [The effect of acute hypoxia on the cytogenetic effect of cyclophosphamide in rat
      bone marrow cells, differing in resistance to oxygen deficiency].
AB  - The frequency of chromosomal aberrations in rat bone marrow cells injected with
      intraperitoneal cyclophosphamide (CF) during the 24 h after acute hypoxia was
      studied. We used two groups of rats: a group with low resistance (LR) to acute
      hypoxia that was unable to endure more than 5 min in a vacuum chamber at the
      altitude of 11,000 m, and a group of highly resistant (HR) rats able to endure 25
      min or longer under the above conditions in vacuum chamber. Acute hypoxia was
      shown to enhance the cytogenetic activity of cyclophosphamide, and the number of
      chromosomal aberrations was higher in HR rats than in LR animals.

PMID- 8666226
TI  - [Inter-tissue differences in the C-polymorphic regions of human embryo
      chromosomes: possible role of DNA methylation].
AB  - Sizes of C-band heterochromatin regions were estimated in embryonic and
      extraembryonic lineages. These regions in chromosomes 1 and 16, containing mainly
      satellite 2 DNA, were significantly longer in extraembryonic tissues than in
      embryonic tissues. The differences in length between chromosome 9 C-band
      heterochromatin, which contained satellite 3 DNA, and Y chromosome C-band, which
      contained all four classical satellite types, were not significant between the
      two tissues. Our data, together with other findings on the correlation between
      chromosome compactization and DNA methylation, indicated that the observed
      variations in C-band length reflected a tissue-specific pattern of
      heterochromatin methylation. Satellite 2 DNA probably was the most sensitive
      target for the decondensation effect of DNA methylation compared with other
      satellite types.

PMID- 8666227
TI  - [Analysis of linkage between beta-lactoglobulin and J blood group system loci in
      cattle].
AB  - Linkage between loci controlling variants of beta-lactoglobulin and blood groups
      of the J system in cattle was studied by means of stochastic genetic methods
      reported earlier. The studies were conducted on a herd of Black Pied cattle
      improved with Holstein sires; population genetic data were analyzed. A plot for
      lod score was constructed, and point (r - 0.28) and interval estimations of the
      coefficient of recombination were obtained. The results are in good agreement
      with earlier reported data on other subjects.

PMID- 8666228
TI  - Biochemistry and genetics of eukaryotic mismatch repair.

PMID- 8666229
TI  - The axis-inducing activity, stability, and subcellular distribution of beta
      catenin is regulated in Xenopus embryos by glycogen synthase kinase 3.
AB  - The serine/threonine kinase Xgsk-3 and the intracellular protein beta-catenin are
      necessary for the establishment of the dorsal-ventral axis in Xenopus. Although
      genetic evidence from Drosophila indicates that Xgsk-3 is upstream of beta
      catenin, direct interactions between these proteins have not been demonstrated.
      We demonstrate that phosphorylation of beta-catenin in vivo requires an in vitro
      amino-terminal Xgsk-3 phosphorylation site, which is conserved in the Drosophila
      protein armadillo. beta-catenin mutants lacking this site are more active in
      inducing an ectopic axis in Xenopus embryos and are more stable than wild-type
      beta-catenin in the presence of Xgsk-3 activity, supporting the hypothesis that
      Xgsk-3 is a negative regulator of beta-catenin that acts through the amino
      terminal site. Inhibition of endogenous Xgsk-3 function with a dominant-negative
      mutant leads to an increase in the steady-state levels of ectopic beta-catenin,
      indicating that Xgsk-3 functions to destabilize beta-catenin and thus decrease
      the amount of beta-catenin available for signaling. The levels of endogenous beta
      catenin in the nucleus increases in the presence of the dominant-negative Xgsk-3
      mutant, suggesting that a role of Xgsk-3 is to regulate the steady-state levels
      of beta-catenin within specific subcellular compartments. These studies provide a
      basis for understanding the interaction between Xgsk-3 and beta-catenin in the
      establishment of the dorsal-ventral axis in early Xenopus embryos.

PMID- 8666230
TI  - Protein kinase C-zeta reverts v-raf transformation of NIH-3T3 cells.
AB  - We have identified protein kinase C-zeta (PKC-zeta) as a novel suppressor of
      neoplastic transformation caused by the v-raf oncogene. PKC-zeta overexpression
      drastically retards proliferation, abolishes anchorage-independent growth, and
      reverts the morphological transformation of v-raf-transformed NIH-3T3 cells. The
      molecular basis for this effect appears to be a specific induction of junB and
      egr-1 expression, triggered synergistically by PKC-zeta via a Raf/Mek/MAPK
      independent mechanism and v-raf. junB-promoter/CAT assays revealed that PKC-zeta
      directly targets the junB promoter. The induction of junB and egr-1 is linked to
      the v-raf transformation-suppressing effect of PKC-zeta as constitutive
      expression of junB and egr-1 but not of c-jun also abolishes anchorage
      independent growth of v-raf-transformed NIH-3T3 cells. Moreover, junB
      overexpression leads to a retardation of proliferation in these cells. PKC-zeta
      interferes with the serum inducibility of an AP-1 reporter plasmid in v-raf
      transformed NIH-3T3 cells, indicating that PKC-zeta antagonizes transformation
      and proliferation by down-modulating AP-1 function via induction of junB. In
      summary, our data suggest that PKC-zeta counteracts v-raf transformation by
      modulating the expression of the transcription factors junB and egr-1.

PMID- 8666231
TI  - Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted
      disruption of Winged Helix transcription factor BF-2.
AB  - Metanephric mesenchyme gives rise to both the epithelial cells of the nephron and
      the stromal cells of the mature kidney. The function of the stroma. in kidney
      morphogenesis is poorly understood. We have generated mice with a null mutation
      in the Winged Helix (WH) transcription factor BF-2 to examine its function during
      development. BF-2 expression within the developing kidney is restricted to the
      stromal cell lineage. Homozygotes die within the first 24 hr after birth with
      abnormal kidneys. Mutant kidneys are small, fused longitudinally, and rotated 90
      degrees ventrally. Histological examination reveals a smaller collecting system,
      numerous large condensations of mesenchyme, and a decrease in the number of
      nephrons. Using molecular markers we show that induction and condensation of the
      nephrogenic mesenchyme occurs normally in mutant. The disruption of BF-2 reduces
      the rate of differentiation of the condensed mesenchyme into tubular epithelium,
      as well as the rate of growth and branching of the ureter and collecting system.
      Our findings demonstrate that BF-2 and stromal cells have essential functions
      during kidney morphogenesis. Furthermore, they suggest that BF-2 controls the
      production, by the stroma, of signals or factors that are required for the normal
      transition of induced mesenchyme into tubular epithelium and full growth and
      branching of the collecting system.

PMID- 8666232
TI  - Activator-dependent regulation of transcriptional pausing on nucleosomal
      templates.
AB  - Promoter-proximal pausing during transcriptional elongation is an important way
      of regulating many diverse genes, including human c-myc and c-fos, some HIV
      genes, and the Drosophila heat shock loci. To characterize the mechanisms that
      regulate pausing, we have established an in vitro system using the human hsp7O
      gene. We demonstrate that nucleosome formation increases by >100-fold the
      duration of a transcriptional pause on the human hsp7O gene in vitro at the same
      location as pausing is observed in vivo. Readthrough of this pause is increased
      by an activator that contains the human heat shock factor 1 (HSF1)
      transcriptional activation domains. Maximal effect of the activator requires that
      the system be supplemented with fractions that have hSWI/SNF activity, which has
      been shown previously to alter nucleosome structure. No significant readthrough
      is observed in the absence of activator, and neither the activator nor the
      hSWI/SNF fraction affected elongation on naked DNA; therefore, these results
      suggest that an activator can cause increased readthrough of promoter-proximal
      pausing by decreasing the inhibitory effect of nucleosomes on transcriptional
      elongation.

PMID- 8666233
TI  - Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and
      stabilizes Cdk4.
AB  - CDC37, an essential gene in Saccharomyces cerevisiae, interacts genetically with
      multiple protein kinases and is required for production of Cdc28p/cyclin
      complexes through an unknown mechanism. We have identified mammalian p50Cdc37 as
      a protein kinase-targeting subunit of the molecular chaperone Hsp90. Previously,
      p50 was observed in complexes with pp60v-src and Raf-1, but its identity and
      function have remained elusive. In mouse fibroblasts, a primary target of Cdc37
      is Cdk4. This kinase is activated by D-type cyclins and functions in passage
      through G1. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 and both
      in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of
      Cdk4 not bound to D-type cyclins. Cdc37 is coexpressed with cyclin Dl in cells
      undergoing programmed proliferation in vivo, consistent with a positive role in
      cell cycle progression. Pharmacological inactivation of Cdc37/Hsp90 function
      decreases the half-life of newly synthesized Cdk4, indicating a role for
      Cdc37/Hsp90 in Cdk4 stabilization. This study suggests a general role for
      p50Cdc37 in signaling pathways dependent on intrinsically unstable protein
      kinases and reveals a previously unrecognized chaperone-dependent step in the
      production of Cdk4/cyclin D complexes.

PMID- 8666234
TI  - Xe-p9, a Xenopus Suc1/Cks homolog, has multiple essential roles in cell cycle
      control.
AB  - The small Suc1/Cks protein is a ubiquitous subunit of Cdk/cyclin complexes, but
      its precise function has remained unclear. We have isolated a Xenopus homolog, Xe
      p9, of the Suc1/Cks protein by virtue of its ability to rescue a fission yeast
      mutant that enters mitosis prematurely. To assess its functional role in cell
      cycle control, we have both overexpressed p9 in Xenopus egg extracts and
      immunodepleted the protein from these extracts. We found that addition of
      recombinant His6-p9 to egg extracts results in a pronounced delay of mitosis that
      can be attributed to an inhibition of the tyrosine dephosphorylation of the
      inactive Cdc2/cyclin B complex. In immunodepletion studies, we observed that the
      consequences of removing p9 from egg extracts depend on the stage of the cell
      cycle. Specifically, in the case of interphase extracts, the removal of p9
      abolishes the entry into mitosis as a result of a failure in the activation of
      the Cdc2/cyclin B complex by tyrosine dephosphorylation. Furthermore, mitotic
      extracts lacking p9 fail to exit mitosis because of a defect in the destruction
      of cyclin B. Collectively, these results indicate that p9 has multiple essential
      roles in the cell cycle by governing the interaction of the Cdc2/cyclin B complex
      with both positive and negative regulators.

PMID- 8666235
TI  - Activation of S-phase-promoting CDKs in late G1 defines a "point of no return"
      after which Cdc6 synthesis cannot promote DNA replication in yeast.
AB  - In eukaryotic cells, DNA replication is confined to a discrete period of the cell
      cycle and does not usually recur until after anaphase. In the budding yeast
      Saccharomyces cerevisiae, assembly of pre-replication complexes (pre-RCs) at
      future origins as cells exit mitosis (or later during G1 is necessary for
      subsequent initiation of DNA replication triggered by activation in late G1 of
      Cdc28/Cdk1 kinases associated with B-type cyclins Clb1-Clb6. The absence of pre
      RCs during G2 and M phases could explain why origins of DNA replication fire only
      once during the cell cycle, even though S-phase-promoting Cdks remain active from
      the beginning of S phase through the end of M phase. Formation of pre-RCs and
      their maintenance during G1 depend on the synthesis and activity of an unstable
      protein encoded by CDC6. We find that Cdc6 synthesis can only promote DNA
      replication in a restricted window of the cell cycle: between destruction of Clbs
      after anaphase and activation of Clb5/ and Clb6/Cdk1 in late G1. The latter
      corresponds to a "point of no return," after which Cdc6 synthesis can no longer
      promote DNA replication. Cdc6 protein can be made throughout the cell cycle and,
      in certain circumstances, can accumulate within the nuclei of G2 and M phase
      cells without inducing re-replication. Thus, control over Cdc6 degradation and/or
      nuclear localization is not crucial for preventing origin re-firing. Our data are
      consistent with the notion that cells can no longer incorporate de novo
      synthesized Cdc6 into pre-RCs once C1b/Cdk1 kinases have been activated. We show
      that Cdc6p associates with Clb/Cdk1 kinases from late G1 until late anaphase,
      which might be important for inhibiting pre-RC assembly during S, G2, and M
      phases. Inhibition of pre-RC assembly by the same kinases that trigger initiation
      explains how origins are prevented from re-firing until Clb kinases are destroyed
      after anaphase.

PMID- 8666236
TI  - Caulobacter Lon protease has a critical role in cell-cycle control of DNA
      methylation.
AB  - CcrM, an adenine DNA methyltransferase, is essential for viability in Caulobacter
      crescentus. The CcrM protein is present only in the predivisional stage of the
      cell cycle, resulting in cell-cycle-dependent variation of the DNA methylation
      state of the chromosome. The availability of CcrM is controlled in two ways: (1)
      the ccrM gene is transcribed only in the predivisional. cell, and (2) the CcrM
      protein is rapidly degraded prior to cell division. We demonstrate here that CcrM
      is an important target of the Lon protease pathway in C. crescentus. In a lon
      null mutant, ccrM transcription is still temporally regulated, but the CcrM
      protein is present throughout the cell cycle because of a dramatic increase in
      its stability that results in a fully methylated chromosome throughout the cell
      cycle. Because the Lon protease is present throughout the cell cycle, it is
      likely that the level of CcrM in the cell is controlled by a dynamic balance
      between temporally varied transcription and constitutive degradation. We have
      shown previously that restriction of CcrM to the C. crescentus predivisional cell
      is essential for normal morphogenesis and progression through the cell cycle.
      Comparison of the lon null mutant strain with a strain whose DNA remains fully
      methylated as a result of constitutive expression of ccrM suggests that the
      effect of Lon on DNA methylation contributes to several developmental defects
      observed in the lon mutant. These defects include a frequent failure to complete
      cell division and loss of precise cell-cycle control of initiation of DNA
      replication. Other developmental abnormalities exhibited by the lon null mutant,
      such as the formation of abnormally long stalks, appear to be unrelated to
      altered chromosome methylation state. The Lon protease thus exhibits pleiotropic
      effects in C. crescentus growth and development.

PMID- 8666237
TI  - The SL1 trans-spliced leader RNA performs an essential embryonic function in
      Caenorhabditis elegans that can also be supplied by SL2 RNA.
AB  - Covalent joining of leader RNA exons to pre-mRNAs by trans-splicing has been
      observed in protists and invertebrates, and can occur in cultured mammalian
      cells. In the nematode Caenorhabditis elegans, approximately 60% of mRNA species
      are trans-spliced to the 22-nucleotide SL1 leader, and another approximately 10%
      of mRNAs receive the 22-nucleotide SL2 leader. We have isolated deletions that
      remove the rrs-1 cluster, a gene complex that contains approximately 110 tandem
      copies of a repeat encoding both SL1 RNA and 5S rRNA. An SL1-encoding gene alone
      rescues the embryonic lethality caused by these deletions. Mutations within the
      Sm-binding site of SL1 RNA, which is required for trans-splicing, eliminate
      rescue, suggesting that the ability of the SL1 leader to be trans-spliced is
      required for its essential activity. We observe pleiotropic defects in embryos
      lacking SL1 RNA, suggesting that multiple mRNAs may be affected by the absence of
      an SL1 leader. We found, however, that SL1-receiving messages are expressed
      without an SL1 leader. Surprisingly, when overexpressed, SL2 RNA, which performs
      a distinct function from that of SL1 RNA in wild-type animals, can rescue the
      lethality of embryos lacking SL1 RNA. Moreover, in these mutant embryos, we
      detect SL2 instead of SL1 leaders on normally SL1-trans-spliced messages; this
      result suggests that the mechanism that discriminates between SL1 and SL2-trans
      splicing may involve competition between SL1 and SL2-specific trans-splicing. Our
      findings demonstrate that SL1 RNA is essential for embryogenesis in C. elegans
      and that SL2 RNA can substitute for SL1 RNA in vivo.

PMID- 8666238
TI  - Selective translation initiation by ribosome jumping in adenovirus-infected and
      heat-shocked cells.
AB  - Translation initiation on eukaryotic mRNAs usually occurs by 5'-processive
      scanning of 40S ribosome subunits from the m7GTP-cap to the initiating AUG. In
      contrast, picornavirus and some specialized mRNAS initiate translation by
      internally binding ribosomes. A poorly described third mechanism of initiation,
      referred to as ribosome shunting or jumping, involves discontinuous scanning by
      40S ribosome subunits, in which large segments of the 5' noncoding region are
      bypassed. Ribosome shunting has only been observed to date on a cauliflower
      mosaic virus mRNA. In this report we show that the family of adenovirus late
      mRNAs, which are preferentially translated during infection, use a ribosome
      jumping mechanism to initiate protein synthesis. Late adenovirus mRNAs contain a
      common 5'-noncoding region known as the tripartite leader, which confers
      preferential translation by reducing the requirement for the rate-limiting
      initiation factor eIF-4F (cap-binding protein complex). Adenovirus inhibits cell
      protein synthesis largely by inactivating eIF-4F. We show that the tripartite
      leader directs both 5' linear ribosome scanning and ribosome jumping when eIF-4F
      is abundant but exclusively uses a ribosome jumping mechanism during late
      adenovirus infection or heat shock (stress) of mammalian cells, when eIF-4F is
      altered or inactivated. Shunting is directed by a complex group of secondary
      structures in the tripartite leader and is facilitated by one or more
      unidentified viral late gene products. We propose that shunting may represent a
      widespread mechanism to facilitate selective translation of specialized classes
      of capped mRNAs, including some stress and developmentally regulated mRNAs, which
      possess little requirement for eIF-4F but do not initiate by internal ribosome
      binding.

PMID- 8666239
TI  - The intron-containing ribosomal protein-encoding genes L5, L7a and L37a are
      unlinked in chicken.
AB  - Chicken ribosomal protein (rp)-encoding genes are currently being studied at the
      nucleotide level and three independent recombinant phages have been isolated from
      chicken genomic libraries using cloned cDNA probes. Each of these was shown to
      include an intron-containing rp gene of chicken (L5, L7a, L37a). In this study
      the chromosomal location of these three intron-containing rp from the large
      subunit of the chicken ribosome was determined by fluorescence in situ
      hybridization. L7a mapped to a microchromosome, whereas L5 and L37a mapped to
      macrochromosomes 8 and 7, respectively. The results demonstrate that these
      functionally related genes are widely dispersed in the genome. Furthermore, as in
      the case of many other evolutionarily advanced eukaryotes, there is no apparent
      linkage of rp and rRNA genes.

PMID- 8666240
TI  - Structure and chromosomal location of the mouse medium-chain acyl-CoA
      dehydrogenase-encoding gene and its promoter.
AB  - Medium-chain acyl-coenzyme A dehydrogenase (MCAD; mouse gene Acadm; human gene
      ACADM) catalyzes the initial step of fatty acid beta-oxidation in mitochondria.
      Inherited MCAD deficiency is an autosomal recessive disorder that occurs at high
      frequency in humans and is associated with considerable morbidity and mortality.
      We have cloned and characterized mouse Acadm which spans approximately 25 kb and
      contains 12 exons. The promoter region does not contain TATA or CAAT boxes and is
      G + C-rich (60%) within 200 bp of the cap site. A CpG island extends from 5' of
      the transcription start point into intron 1. The 5' regulatory region and a
      portion of intron 1 contain several Sp1 consensus sites and three regions
      containing hexamer DNA sequences that match the binding consensus for
      steroid/thyroid nuclear receptors. These putative nuclear receptor response
      elements (NRRE) share DNA sequence homology and electrophoretic mobility shift
      characteristics with known NRRE in the human ACADM promoter [Carter et al., J.
      Biol. Chem. 268 (1993) 13805-13810]. We have mapped mouse Acadm to the distal end
      of chromosome 3. Sequences previously localized to chromosome 8 are shown to be a
      pseudogene, and an additional pseudogene was identified on chromosome 11.

PMID- 8666241
TI  - An apparent autocrine mechanism amplifies the dexamethasone- and retinoic acid
      induced expression of mouse lipocalin-encoding gene 24p3.
AB  - We have isolated, sequenced and characterized the mouse 24p3 gene. The 24p3
      protein is a member of the lipocalin family comprising secreted transporters of
      hydrophobic ligands. The 24p3 cDNA had been initially isolated during a search
      for genes overexpressed during a SV40-induced mitotic reaction [Hraba-Renevey et
      al., Oncogene 4 (1989) 601-608]. 24p3 comprises six exons, five introns and 793
      bp of 5' regulatory region. The transcription start point (tsp) was identified by
      primer extension. Putative regulatory elements, including a TATA-like box and two
      glucocorticoid responsive core elements (GRE), have been mapped in the 5'
      flanking region. Based on this observation, we examined the effect of a
      glucocorticoid (dexamethasone, Dex) on 24p3 expression. Dex induced the
      expression of 24p3 dramatically in the absence of de novo protein synthesis. This
      activation was further amplified by an apparent autocrine mechanism. Similar
      results were obtained with retinoic acid. Using the cat reporter gene system, we
      have shown that the 5'-flanking region of 24p3 confers Dex inducibility.
      Furthermore, we have identified a 43-bp region of the 24p3 promoter required for
      the Dex responsiveness. The biological implications are discussed in light of
      these results.

PMID- 8666242
TI  - Cloning, expression, and cellular localization of the oncogenic 58-kDa inhibitor
      of the RNA-activated human and mouse protein kinase.
AB  - The 58-kDa inhibitor of the interferon-induced double-stranded RNA-activated
      protein kinase (PKR) is a cellular protein that is activated during influenza
      virus infection to down-regulate the activity of PKR. This study was initiated to
      further our understanding of the inhibitor which, when overproduced, has the
      capacity to malignantly transform cells. We report here the isolation and
      characterization of cDNA clones encoding the inhibitor, designated p58, from
      human HeLa and mouse NIH 3T3 cells. The human and mouse p58 cDNAs were 6.5 and
      1.6 kb in length, respectively. Surprisingly, the deduced amino acid sequences of
      the human and mouse p58 were 96% identical, indicating a remarkably high degree
      of conservation between species. An examination of p58 mRNA expression in human
      tissues revealed a 6.5-kb transcript in all tissues examined, with a particularly
      high level of expression present in the pancreas and liver, and also in certain
      leukemic cell lines. Similarly, p58 expression was detected in all mouse tissues
      examined, with the highest level of expression found in liver. In contrast to
      human tissues, three p58 transcripts of approximately 1.7, 3.3 and 5.4 kb were
      observed in mouse tissues, suggesting that p58 expression may be regulated
      differently in human and mouse cells. Western blot analysis of subcellular
      fractions and indirect immunofluorescence analysis of intact cells revealed that
      p58 was found predominantly in the cytoplasm, consistent with its function as an
      inhibitor of PKR, which is also a predominantly cytoplasmic protein.

PMID- 8666243
TI  - cDNA cloning and structural analysis of the human limbic-system-associated
      membrane protein (LAMP).
AB  - The limbic-system-associated membrane protein (LAMP) is a 64-68-kDa neuronal
      surface glycoprotein distributed in cortical and subcortical regions of the
      limbic system. The human LAMP gene was cloned by RT-PCR using human cerebral
      cortex mRNA and oligodeoxyribonucleotide (oligo) primers derived from the rat
      lamp cDNA sequence. The human and rat LAMP cDNAs showed 94% identity at the
      nucleotide (nt) level, and the encoded 338-amino-acid (aa) polypeptides shared
      99% sequence identity. All the important features of LAMP were conserved: (i) the
      deduced aa sequence reflecting a glycosyl-phosphatidylinositol (GPI)-anchor, (ii)
      eight putative N-linked glycosylation sites, and (iii) conserved pairs of Cys
      forming three internal repeats characteristic of the immunoglobulin superfamily
      (IgSF). Northern blot analysis indicated the presence of two mRNA transcripts in
      the human brain of a size identical to those identified in adult rat brain. These
      data indicate that LAMP is a highly conserved new member of the IgSF which,
      together with the opioid-binding cell adhesion molecule (OBCAM) and neurotrimin,
      comprises a new subfamily that has been designated as IgLONs. With a unique
      distribution in limbic structures, LAMP may play an important role in limbic
      system development and function, as suggested by previous in vitro and in vivo
      functional studies.

PMID- 8666244
TI  - Structure of the gene encoding nitrilase 1 from Arabidopsis thaliana.
AB  - The nitrilases of Arabidopsis thaliana (At) catalyze the conversion of indole-3
      acetonitrile (IAN) to indole-3-acetic acid (IAA), thus controlling the last step
      of auxin biosynthesis. A full-length genomic clone encoding the complete cluster
      of the At nitrilases 1 to 3 (NIT1-3), including the respective promoter regions,
      has been isolated and the NIT1 isoform has been sequenced. The coding region
      (nit1) spans about 2.3 kb and is composed of five exons separated by four
      introns. The exon-intron splice junctions agree with the consensus sequences
      typical for plant genes. In agreement with the known cDNA sequence, the exons
      encode a protein of 346 amino acids (aa) with a deduced molecular mass of 38.2
      kDa. The transcription start point (tsp) of nit1 was determined by primer
      extension experiments. This tsp defines a 5' untranslated region of 36 bp and is
      located 32 bp downstream from a TATA box. The promoter region of nit1 is located
      within the approx. 1.5-kb intergenic part that separates the nit2 and nit1 coding
      sections.

PMID- 8666245
TI  - The first intron of the Arabidopsis thaliana gene coding for elongation factor 1
      beta contains an enhancer-like element.
AB  - Genomic and cDNA clones coding for elongation factor-1 beta (eEF-1 beta) from
      Arabidopsis thaliana (At) were isolated and characterized. eEF-1 beta was found
      to be encoded by a single-copy At gene. Chimeric genes fusing the promoter and
      the 5' untranslated region of the At eEF-1 beta gene to the gus reporter gene
      were constructed and used to study the expression of this gene in transgenic
      tobacco plants. Interestingly, it was found that the first intron of this gene is
      required for high levels of expression. Experiments using chimeric promoters
      showed that an enhancer-like element is present in the first intron of At eEF-1
      beta. Gel-shift assays were used to demonstrate that this intron is specifically
      bound by putative transcription factors present in nuclear protein extracts.

PMID- 8666246
TI  - Clustered genes within the genome of Arabidopsis thaliana encoding pectin
      methylesterase-like enzymes.
AB  - We focused our attention on the isolation and regulation of genes encoding for
      pectin methylesterase (PME) isoenzymes in Arabidopsis thaliana (At). The present
      data reports the identification of two PME-like genes, named AtPME1 and AtPME2,
      that are closely linked in the At genome. These genes possess different
      structural organisations. While all higher plant PME characterised so far possess
      an intron at a similar location relative to their coding sequence, AtPME2 shows
      an additional intron whose presence within other higher plant PME-like genes has
      not been previously reported. Sequence comparison of the N-terminal region
      suggests that the secretory pathways of the putative AtPME1 and AtPME2 isoforms
      are different, and that this region may contribute to specify a biological
      function to each isoform. Moreover, phylogenetic analysis reflects the possible
      existence of functional groups of PME isoforms in higher plant species that seem
      to have been conserved during evolution.

PMID- 8666247
TI  - Nucleotide sequences of four pathogen-induced alfalfa peroxidase-encoding cDNAs.
AB  - We constructed an alfalfa cDNA library from mRNA extracted from leaves after
      infection with Pseudomonas syringae (incompatible interaction). Screening with
      oligodeoxyribonucleotides designed from regions conserved in all known
      peroxidases allowed the isolation of four cDNAs (Msprx1A, 1B, 1C and 2). Sequence
      analysis revealed the presence of open reading frames of 351, 355, 358 and 323
      amino acids, respectively, with the characteristic consensus sequences of plant
      peroxidases. Sequence comparison showed that the Msprx2 product is significantly
      different from the others and, particularly, lacks a C-terminal propeptide which
      might be required for vacuolar targeting.

PMID- 8666248
TI  - Characterization of a rice sucrose-phosphate synthase-encoding gene.
AB  - A rice genomic clone (sps1) coding for sucrose phosphate synthase (SPS) was
      isolated and sequenced. Rice sps1 contains 13 exons and 12 introns, an unusually
      long 366-bp leader region with a highly organized primary structure and a
      promoter region with no obvious homology with eukaryotic promoter consensus
      sequences. Southern blot analysis showed that SPS is encoded by a single-copy
      gene in the rice genome. Comparison of the rice, maize, potato and spinach SPS
      deduced amino acid (aa) sequences showed that these enzymes have a well conserved
      region comprising their first 700 aa, and a variable C-terminal region. Analysis
      of rice sps1 expression showed that mRNA levels change during leaf development.
      SPS activity and mRNA were undetectable in roots.

PMID- 8666249
TI  - Cloning of the rice seed alpha-globulin-encoding gene: sequence similarity of the
      5'-flanking region to those of the genes encoding wheat high-molecular-weight
      glutenin and barley D hordein.
AB  - A genomic clone encoding the rice endosperm major globulin (alpha-globulin) with
      an apparent molecular mass of 26 kDa was isolated, and its nucleotide (nt)
      sequence and transcription start point (tsp) were determined. The tsp was
      identical to that of the gene encoding the wheat high-molecular-weight (HMW)
      glutenin subunit. The consensus '-300 element' and an A + T-rich sequence exist
      upstream from the TATA box in the 5'-flanking region. A nt sequence of about 130
      bp in the 5'-flanking region was found to be markedly homologous to those of the
      genes encoding the wheat HMW glutenin subunit and barley D hordein.

PMID- 8666250
TI  - Cloning and characterization of several cDNAs for UDP-glucose pyrophosphorylase
      from barley (Hordeum vulgare) tissues.
AB  - Eleven cDNA clones encoding UDP-glucose pyrophosphorylase (UGPase) have been
      isolated from cDNA libraries prepared from seed embryo, seed endosperm and leaves
      of barley (Hordeum vulgare L.). The sequences were identical, with the exception
      of positioning of the poly(A) tail; at least five clones with different
      polyadenylation sites were found. For a putative full-length cDNA [1775
      nucleotides (nt) plus polyadenylation tail], isolated from an embryo cDNA
      library, an open reading frame of 1419 nt encodes a protein of 473 amino acids
      (aa) of 51.6 kDa. An alignment of the derived aa sequence with other UGPases has
      revealed high identity to UGPases from eukaryotic tissues, but not from bacteria.
      Within the aa sequence, no homology was found to a UDP-glucose-binding motif that
      has been postulated for a family of glucosyl transferases. The derived aa
      sequence of UGPase contains three putative N-glycosylation sites and has a highly
      conserved positioning of five Lys residues, previously shown to be critical for
      catalysis and substrate binding of potato tuber UGPase. A possible role for N
      glycosylation in the intracellular targeting of UGPase is discussed.

PMID- 8666251
TI  - Cloning of a cDNA encoding a new ribosome-inactivating protein from Beta vulgaris
      vulgaris (mangold).
AB  - By means of a lambda ZAP II cDNA library constructed from seedings of Beta
      vulgaris vulgaris and immunoscreening, a cDNA clone containing a partial sequence
      of a new ribosome-inactivating protein (RIP) was obtained. As confirmed by
      Western blot analysis, this clone produced a RIP upon induction with IPTG. We
      called it betavulgin (Bvg). The recombinant protein (re-Bvg) was somewhat smaller
      than plant-derived RIP (28 versus 30 and 32 kDa), but showed the specific N
      glycosidase activity on tobacco ribosomes, confirming its RIP character. The cDNA
      was sequenced and the missing 5'-end was established by RACE using bvg-specific
      primers. The entire cDNA was 1080 nucleotides in length and encoded a protein of
      272 amino acids with a sequence identity of 26-40% with other RIP.

PMID- 8666252
TI  - The structure and expression of an hsc70 gene from Lycopersicon esculentum.
AB  - A tomato hsc70 genomic clone (Lehsc70-3; Lycopersicon esculentum heat-shock
      cognate 70-3) was obtained by screening a genomic library with the tomato Lehsc70
      2 cDNA. Two restriction fragments of 2.6 and 5 kb, which compose the Lehsc70-3
      gene, were subcloned into pBluescriptIIKS+ and analyzed. Transcript mapping
      reveals that the mature Lehsc70-3 mRNA contains a 122-nt 5' untranslated region
      (UTR), a coding region of 1956 nt corresponding to a polypeptide of 651 amino
      acids, an intron of 717 nt and a 3' UTR. Analysis of genomic DNA indicates that
      Lehsc70-3 is present as a low-copy-number gene. We note that the sequence
      upstream from the coding region of Lehsc70-3 shares common features with a number
      of hsc/hsp genes. High-temperature treatment (37 degrees C) caused a twofold
      increase in the level of the Lehsc70-3 mRNA. However, Lehsc70-3 has also been
      expressed at substantial levels in tomato vegetative tissues, suggesting a
      general function of this hsc70 gene in L. esculentum.

PMID- 8666253
TI  - A lea-class gene of tomato confers salt and freezing tolerance when expressed in
      Saccharomyces cerevisiae.
AB  - During periods of water deficit, plants accumulate late embryogenesis-abundant
      (LEA) proteins which are thought to protect cells from stresses associated with
      dehydration. One of these genes, le25, is expressed in tomato leaves and roots in
      response to water deficit and abscisic acid accumulation. To study the function
      of this protein and to test the effect of overproduction of the LE25 protein in
      Saccharomyces cerevisiae (Sc), a recombinant plasmid in which le25 is expressed
      under the control of the GAL1 promoter was constructed. The content of LE25 was
      high in Sc cells transformed with the recombinant plasmid. The transformant
      exhibited several stress-tolerant phenotypes. Growth of the transformant in a
      medium with 1.2 M NaCl was improved, as compared to a control strain. While the
      control strain showed a long lag phase of 40 h, le25-expressing cells showed a
      shortened lag phase of 10 h. However, no growth improvement was observed in a
      medium with 2 M sorbitol. In addition, the transformant had an increased survival
      rate after freezing stress, but not after high-temperature stress. These results,
      together with its predicted secondary structure, may indicate that LE25 functions
      as an ion scavenger.

PMID- 8666254
TI  - Sequence of the immunoregulatory early region 3 and flanking sequences of
      adenovirus type 35.
AB  - Adenovirus type 35 (Ad35) is an important pathogen in immunosuppressed
      individuals such as AIDS patients and bone marrow transplant recipients. Ad35, a
      member of Ad subgroup B, differs with respect to pathogenic properties from the
      more fully characterized subgroup C Ad, such as Ad2 and Ad5. One region of human
      Ad which varies between subgroups and which may influence Ad pathogenesis is
      early region 3 (E3), a region which appears to modulate the immune response to Ad
      infection. In order to begin to characterize the differences between the Ad35 E3
      and the E3 of other Ad, the complete DNA sequence of the Ad35 E3 promoter and
      coding sequence along with two flanking structural proteins, pVIII and fiber, has
      been determined. Ad35 contains open reading frames which are unique to the
      subgroup B Ad in addition to the four characterized immunoregulatory proteins
      encoded by the subgroup C Ad. Further evaluation of the sequence of one of these
      proteins, 18.5K, which is the class-I major histocompatibility complex (MHC)
      binding protein of 18.5 kDa, demonstrates that the amino acid sequence of this
      Ad2 gp19K homologue fits a proposed model of gp19K-MHC interaction. Analysis of
      promoter sequences demonstrates that an NF-kappa B site found in the subgroup C
      E3 promoter is absent from the Ad35 E3 promoter. In addition, the fiber genes of
      Ad35 and other subgroup B Ad have been shown to diverge in an unexpected way,
      yielding three clusters of fiber homology.

PMID- 8666256
TI  - A silent trans-splicing signal in the cuticlin-encoding gene of the plant
      parasitic nematode Meloidogyne artiellia.
AB  - A gene (cut-1) coding for a cuticular protein, cuticlin-1, has been isolated and
      sequenced in the plant parasitic nematode, Meloidogyne artiellia. The nucleotide
      sequence revealed a typical eukaryotic-like organization, exons and introns
      bordered by canonical sequences. The 5' flanking region presents nematode
      specific sequence motifis, including a trans-splicing signal. Studies on the
      expression of this gene demonstrated that, while in the adult females cut-1 is
      not expressed, the removal of the introns occurs in the eggs. These experiments
      also indicate that cis-splicing precedes the processing of the 5' untranslated
      region. In no case has a trans-spliced transcript been detected.

PMID- 8666257
TI  - The lobster shaw gene: cloning, sequence analysis and comparison to fly shaw.
AB  - We cloned and sequenced the cDNA for the shaw gene, encoding a voltage-dependent
      potassium (K+) channel, from the spiny lobster, Panulirus interruptus. The
      deduced amino acid sequence has a high degree of homology to the Drosophila
      melanogaster Shaw protein. In addition, lobster Shaw has several putative sites
      for post-translational modifications.

PMID- 8666255
TI  - Infection of human cells by murine ecotropic viruses: retroviral vectors carrying
      the hygromycin resistance-encoding gene.
AB  - The construction of a new retroviral vector, pSKV, is described. This vector
      carries two unique cloning sites, located between two Moloney leukemia virus
      derived LTR, into which genes of interest may be introduced. The gene encoding
      hygromycin resistance (HyR) was subsequently introduced into one of the two
      sites, producing a second vector (pSKV/HyR) containing a unique SfiI site for the
      introduction of cDNA clones under the control of the cytomegalovirus (CMV)
      promoter (P-CMV). The cDNA (mH13), encoding a protein that has been shown to
      serve as a murine ecotropic retroviral receptor in transient assays, was cloned
      into the SfiI site (pSKV/HyR/mH13). Both constructs can be packaged into
      retroviral particles following transfection into an appropriate packaging cell
      line. Stable transfectants of the human glioblastoma cell line (U118MG) carrying
      each of these two constructs were generated by transfection and subsequent Hy
      selection. Clones expressing both the selectable marker and the mH13 gene, but
      not those expressing only the selectable marker, are shown to be susceptible to
      infection with murine ecotropic retroviral particles. These cells (HyR and mH13
      positive) were then exposed to CRE/Xtk culture supernatant, a packaging cell line
      producing ecotropic retroviral particles carrying the HSV-TK (Herpes simplex
      virus-thymidine kinase) and neoR (neomycin-resistance) genes. Selection was in
      the presence of G418. In vitro growth of the U118MG/HyR/mH13/TK cells, but not
      that of the U118MG/HyR/mH13 cells, was inhibited by ganciclovir (GCV), indicating
      the successful transfer of HSV-TK by infection of human cells with murine
      retroviruses via the mH13 product.

PMID- 8666258
TI  - Cloning and transcription factor-binding sites of the human c-rel proto-oncogene
      promoter.
AB  - We report here the cloning, sequencing, functional analysis and DNase I
      footprinting of the human c-rel promoter region. The results revealed an 824-bp
      BsaAI-StuI minimal promoter region with a large number of NF-kappa B, Ap2 and Sp1
      binding sites, some of them variants of known consensus sequences. This is the
      first promoter in the Rel/NF-kappa B/I kappa B family to be subjected to a
      detailed footprinting analysis for the binding of transcription activator
      proteins. Our finding of 14 Ap2-binding sites may indicate why the human c-rel
      promoter, unlike the chicken c-rel promoter, has a strong function and is highly
      responsive to phorbol esters. The presence of five NF-kappa B and six Sp1-binding
      sites in turn adds to growing evidence that, in mammals, the promoter of the
      Rel/NF-kappa B/I kappa B family may utilize multiple NF-kappa B- and Sp1-binding
      sites for their interactive regulation. Furthermore, there are putative binding
      sites for the PU.1 and Oct 1/2 transcription activator proteins, also present in
      the mouse c-rel promoter, which may help explain the preferential transcription
      of the c-rel gene in B- and T-lymphoid cells.

PMID- 8666259
TI  - The gene encoding the ovine gonadotropin-releasing hormone (GnRH) receptor:
      cloning and initial characterization.
AB  - We have isolated four lambda clones, which, in their aggregate, contain the
      entire coding sequence of the ovine gene encoding the gonadotropin-releasing
      hormone (GnRH) receptor (GnRHR). Like its human and murine counterparts, ovine
      GnRHR exists as a single-copy gene and is comprised of three exons and two
      introns. Furthermore, the locations of all exon-intron boundaries are perfectly
      conserved among the human, ovine and murine genes. The most striking difference
      among these genes is the location of the transcription start points (tsp) and,
      thus, the length of 5' untranslated region (UTR). This variation in size of the
      5' UTR between the murine, human and ovine genes raises the possibility that
      different mechanisms have evolved for cell-specific expression of this gene.
      Isolation of the ovine GnRHR and its associated 5' flanking region is the
      essential first step in defining the molecular mechanisms underlying cell
      specific and hormonal regulation of its expression in ruminants.

PMID- 8666260
TI  - Sequence analysis of the 5'-flanking region of the gene encoding human N
      acetylglucosaminyltransferase III.
AB  - We have isolated and characterized the immediate (1651 bP) 5'-flanking region of
      the gene (GnT-III) encoding N-acetylglucosaminyltransferase III (GnT-III) from a
      human placental genomic library. Analysis of promoter elements shows a similarity
      to the 5'-flanking region of murine 1,4-galactosyltransferase. The sequence lacks
      obvious TATA elements and CCAAT boxes; however, putative regulatory sites,
      including 2 potential cAMP-response regulatory elements (CRE), 11 insulin
      response element consensus sequences (IRE), 7 potential AP-2 binding sites, 2 SP1
      consensus sequences (GC boxes) and 2 sequences similar to the half-palindromic
      glucocorticoid-responsive element (GRE), are present.

PMID- 8666261
TI  - Cloning of the cDNA encoding the sodium channel beta 1 subunit from rabbit.
AB  - Here, we report the nucleotide (nt) sequence of the cDNA encoding the sodium
      channel beta 1 subunit from rabbit (o beta 1). Cloning of the o beta 1 cDNA was
      accomplished by reverse transcription-polymerase chain reaction using rabbit
      brain RNA as a template for cDNA synthesis. The nt sequence of the o beta 1 cDNA
      predicts a 218-amino-acid polypeptide which is 96.3 and 97.3% identical to the
      beta 1 from human (h beta 1) and rat (r beta 1), respectively.

PMID- 8666262
TI  - Cloning and partial structure of the gene encoding human tissue inhibitor of
      metalloproteinases-3.
AB  - Using a cDNA probe, two genomic clones were obtained encoding the human tissue
      inhibitor of metalloproteinases-3 (TIMP-3). Analysis of these clones showed that
      they contained four distal exons and three introns of the gene. Although the
      intron-exon structure is similar to that of the timp1 gene, the first intron of
      the timp3 gene is much longer, being at least 17.5 kb in size.

PMID- 8666263
TI  - Two human valyl-tRNA synthetase-encoding cDNA sequences deposited in GenBank
      display extensive differences.
AB  - Five blocks of significant differences exist between two published sequences of
      the cDNA encoding human valyl-tRNA synthetase (GenBank X59303 and M98326). By
      comparison with the partial sequence of rat valyl-tRNA synthetase (GenBank
      M98327) the correct sequence can be deduced for two such blocks. The possible
      origin of the diversity for the two sequences is discussed.

PMID- 8666264
TI  - Cloning and characterization of the nitrate reductase-encoding gene from
      Chlorella vulgaris: structure and identification of transcription start points
      and initiator sequences.
AB  - The reduction of nitrate to nitrite catalyzed by nitrate reductase (NR) is
      considered to be the rate-limiting and regulated step of nitrate assimilation, a
      major metabolic pathway occurring in a wide range of organisms which in turn
      supply the nutritional nitrogen requirements for other forms of life. Chlorella
      vulgaris NR mRNA levels are very responsive to changes in nitrogen source. In the
      presence of ammonia as the sole nitrogen source, under repressed conditions, NR
      mRNA is undetectable. Under inducing conditions, the removal of ammonia and
      addition of nitrate, rapid NR mRNA synthesis occurs. We are studying the elements
      involved in regulating the expression of this important gene. Two overlapping
      genomic clones (NRS1 and NR5') were isolated from a cosmid library. The two
      clones were sequenced and their sequences were aligned with that of a full-length
      NR cDNA. The gene is approximately 8 kb long and consists of 19 exons and 18
      introns. Unlike NR isolated from other species, the exons which code for the
      functional domains of C. vulgaris are separated by introns. Two transcription
      start points (tsp) were identified and each is surrounded by potential initiator
      sequences. No TATA, CAAT or GC-rich promoter elements were located. A time course
      of NR induction revealed that while transcription initiation from one tsp remains
      at a constant level from the point of induction through steady state, the level
      of initiation from another tsp is high upon induction, but decreases as steady
      state is attained.

PMID- 8666265
TI  - Nonautonomous inverted repeat Alien transposable elements are associated with
      genes of both monocotyledonous and dicotyledonous plants.
AB  - Alien are highly repeated plant transposable elements characterized by their
      small size (approx. 400 bp), high A + T content, target site specificity,
      potential to form stable secondary structures and possession of a conserved 28-bp
      terminal inverted repeat (TIR). Besides the TIR, they contain subterminal
      inverted repeat motifs (SIRM), as well as the 5'-CATGCAT domain which has been
      reported to be a cis-acting regulatory element of gene expression in some plant
      species. Although they were first identified in the intron of the bell pepper
      (Capsicum annuum) Sn-2 gene and in the promoter region of the potato starch
      phosphorylase-encoding gene, Alien arranged in tandem are present in the promoter
      of patatin class-II genes. PCR on the bell pepper genomic DNA using the Alien TIR
      consensus sequence as primer yielded DNA fragments of nearly 400 bp. These
      fragments have characteristics of transposable elements and contain numerous
      motifs reminiscent of Alien elements. Importantly, PCR on genomic DNA extracts
      from various monocotyledonous and dicotyledonous plants using the TIR consensus
      sequence as primer and subsequent hybridization with different Alien probes
      revealed that these elements are ubiquitously present and highly repeated in the
      genomes of higher plants.

PMID- 8666266
TI  - The complete sequence of a Singapore isolate of odontoglossum ringspot virus and
      comparison with other tobamoviruses.
AB  - The complete sequence of a Singapore isolate of odontoglossum ringspot virus
      (ORSV-S1) comprises 6609 nucleotides (nt) and four open reading frames (ORFs 1 to
      4). The 126/183-kDa RNA-dependent RNA polymerase (RdRp), 33-kDa movement protein
      (MP) and 18-kDa coat protein (CP) cistrons are located at nt 63-3401/4901, 4807
      5718, and 5721-6197 on the genome, respectively. The 5' UTR contains three copies
      of an 8-base direct repeat and (CAA)n motifs. Characteristic tRNA-like structure
      and three consecutive homologous regions were present in the 3' UTR. The genomic
      RNA and MP of ORSV-S1 are one of the longest among all members of the TOV group.
      Phylogenetic analysis of all four genes indicates evolutionary divergence, but
      within each gene there are some degrees of evolutionary convergence. The
      conserved amino acid sequences in the MP can be used for the classification of
      tobamoviruses.

PMID- 8666267
TI  - Identification of a novel Drosophila melanogaster heat-shock gene,
      lethal(2)denticleless [l(2)dtl], coding for an 83-kDa protein.
AB  - In this study, we describe the identification of a novel Drosophila melanogaster
      (Dm) gene, l(2)dtl, characterized by elevated expression under heat-shock (HS)
      conditions. It encodes a protein of 83 kDa with no homology to known members of
      the HSP90 family and other proteins. Gene l(2)dtl is located on the right arm of
      the second chromosome at locus 59F5, close to the tumor suppressor gene l(2)tid,
      a homolog of the dnaJ encoding a chaperone strongly conserved in evolution. In
      the following, we present the sequence of l(2)dtl, the putative protein it
      encodes, and its molecular localization in a closely interspaced gene cluster
      consisting of at least four nested genes spanning an approximately 10-kb genomic
      interval. Furthermore, we present the temporal expression of l(2)dtl in the wild
      type under normal and HS conditions, and describe the isolation and the phenotype
      of eight embryonic lethal l(2)dtl mutants.

PMID- 8666268
TI  - DNA from Drosophila melanogaster beta-heterochromatin binds specifically to
      nuclear lamins in vitro and the nuclear envelope in situ.
AB  - A DNA fragment designated lambda 20p1.4 binds in vitro to polymerized Drosophila
      melanogaster lamin. In situ hybridization of lambda 20p1.4 to isolated polytene
      chromosomes revealed localization at the chromocenter and to the 49 CD region on
      the right arm of chromosome 2. About 120 copies of sequences homologous to lambda
      20p1.4 were detected per haploid genome. Nucleotide (nt) sequence analysis
      demonstrates that lambda 20p1.4 is an A + T-rich, 1327-bp fragment containing
      four repeated units between nt 595 and 919. Results suggest that lamin interacts
      with a region of lambda 20p1.4 between nt 300 and 1000. Confocal
      immunofluorescence co-localization demonstrates that in situ, the major locus of
      lambda 20p1.4 hybridization, the chromocenter, is found juxtaposed to the nuclear
      envelope (lamina). This is the first demonstration that a DNA sequence that binds
      specifically to nuclear lamins in vitro, is located at or near the nuclear
      envelope in situ and, presumably, in vivo.

PMID- 8666269
TI  - Actin-encoding cDNAs and gene expression during the intermolt cycle of the
      Bermuda land crab Gecarcinus lateralis.
AB  - Two actin-encoding cDNAs (act1 and act2) from Gecarcinus lateralis have been
      sequenced or partially sequenced and the corresponding proteins deduced. The act1
      cDNA has a complete ORF; the act2 cDNA lacks most of the 5' end of the coding
      region. The nucleotide (nt) sequences of both clones are very similar to act
      sequences of many organisms, the most closely related being from another
      arthropod, the silkmoth Bombyx mori. The proteins Act1 and Act2 are more similar
      to vertebrate cytoplasmic actin isoforms (beta-actins) than to vertebrate muscle
      actins (alpha-actins); they are also more similar to animal actins than to those
      of fungi or plants. Codon usage is strongly biased toward C or G in the third
      position. The deduced number of amino acid (aa) residues and calculated Mr for
      Act1 are 376 aa and 41.94 kDa, respectively. The deduced aa sequence of Act1 is
      very similar to those of muscle actins of B. mori and Drosophila melanogaster.
      Southern blots indicated seven to eleven act genes in the crab genome. Northern
      blots probed with a segment from the 3' UTR of act1 showed a single band of
      approx. 1.6 kb in poly(A)+ mRNAs from epidermis, limb bud or claw muscle and in
      total RNAs from ovary and gill, and two bands of approx. 1.6 and 1.8 kb in total
      RNA from midgut gland. Western blots of one-dimensional gels of proteins from the
      four layers of the exoskeleton, epidermis, limb buds and claw muscle were probed
      with a monoclonal Ab against chicken gizzard actin; tissue- and stage-specific
      changes in actin content were observed. The presence of several isoforms, and
      differences in their number and occurrence at various stages of the intermolt
      cycle, were detected on Western blots of two-dimensional gels.

PMID- 8666270
TI  - Multiple lobster tubulin isoforms are encoded by a simple gene family.
AB  - Microtubule proteins isolated from pleopod tegumental gland (PTG) tissue of the
      American lobster, Homarus americanus, reveal a complex tubulin (Tub) profile. To
      determine whether Tub heterogeneity in PTG is due to expression of a large tub
      gene family or the result of post-translational modification, a PTG cDNA library
      was constructed. Clones coding for both alpha- and beta-Tub were isolated,
      sequenced and found to contain open reading frames (ORFs) of 451 amino acids
      (aa). Alignments reveal phylogenetic clustering with other arthropods and
      identify unique changes in primary structure which may have functional
      significance. These clones, when used to probe restriction enzyme-digested
      lobster genomic DNA in transfer-hybridization experiments, revealed a simple
      banding pattern indicating a lobster tub gene family of limited complexity.
      Lobsters appear to make use of a small tub gene family and fulfill the varied
      functional requirements imposed upon cellular microtubules through post
      translational modifications of relatively few gene products.

PMID- 8666271
TI  - Identification of a maize endosperm-specific cDNA encoding farnesyl pyrophosphate
      synthetase.
AB  - Farnesyl pyrophosphate synthetase (FPS; EC 2.5.1.10) produces the 15-carbon
      farnesyl pyrophosphate which is utilized in the synthesis of sterols,
      carotenoids, dolichols, coenzyme Q, heme a and farnesylated proteins. We have
      cloned this mRNA sequence from a maize endosperm cDNA library and determined the
      1378-nucleotide (nt) sequence of the DNA fragment. This sequence specifies an
      open reading frame of 1050 nt encoding FPS. The deduced amino acid sequence shows
      a high degree of similarity to FPS from a wide range of organisms. Southern blot
      analysis indicated that there are at least two FPS gene copies in the maize
      genome. The cloned FPS is expressed preferentially in maize endosperm and is up
      regulated in the endosperm mutants, o2 and fl2.

PMID- 8666272
TI  - A modular set of Flp, FRT and lacZ fusion vectors for manipulating genes by site
      specific recombination.
AB  - Site-specific recombinases can serve as powerful tools to target genetic
      manipulations to specific cell populations in culture and in the organism. A
      series of vectors for engineering gene activation, deletion and integration in
      mammalian cells using Flp recombinase is described here. The vectors are modular
      in design so that specific cassettes can be linked depending on the application.
      Using these vectors, efficient Flp-mediated lacZ activation and beta
      galactosidase (beta Gal) detection has been demonstrated in mammalian cell
      culture. These vectors should facilitate using Flp to mark cell populations, as
      well as to activate, remove or mutate genes in culture and in the mouse.

PMID- 8666273
TI  - Retroviral vectors designed for targeted expression of RNA polymerase III-driven
      transcripts: a comparative study.
AB  - Retroviral gene delivery systems for RNA polymerase II (RNA pol II)-based
      promoters have been developed and are widely used in gene transfer studies. In
      contrast, gene delivery systems with RNA pol III-based expression cassettes have
      not been studied comprehensively, although therapeutic applications (e.g.,
      ribozymes, antisense, triplex RNA and RNA decoys) have been proposed. In this
      report, we describe retroviral vectors designed to optimize expression of short
      chimeric RNAs transcribed from a number of RNA pol III promoters. Our results
      show that all analysed RNA pol III expression cassettes (tRNA, U6, Ad VA1),
      regardless of orientation, do not transcribe efficiently when located between the
      retroviral long terminal repeats (LTRs). In contrast, high steady-state
      expression levels can be achieved by inserting the RNA pol III expression
      cassette into the U3 region of the LTR (double-copy design). Compared to human
      tRNA gene promoters (tRNA(Met), tRNA(Val)), the human small nuclear RNA U6 gene
      (U6) and the adenovirus virus-associated RNA 1 (Ad VA1) gene promoters yielded
      higher expression levels. The majority of the chimeric U6-derived transcripts
      were detected in the nuclear RNA fraction, and the VA1 and tRNA-driven
      transcripts were predominantly detected in the cytoplasmic compartments. This
      report is the first comparative study of RNA pol III-driven promoters expressing
      short chimeric transcripts leading to an optimized retroviral-vector design.

PMID- 8666274
TI  - A recombination-efficient baculovirus vector for simultaneous expression of
      multiple genes.
AB  - The baculovirus system is an extremely powerful tool for expression of
      heterologous genes in eukaryotic environment. A multiple expression vector,
      pBacUCmP3, was constructed which harbored two copies of the Autographa
      californica nuclear polyhedrosis virus very late gene promoter and the Drosophila
      melanogaster 70-kDa heat-shock protein (hsp70) promoter with downstream unique
      restriction sites for cloning of three independent foreign genes. Co-transfection
      of pBacUCmP3 with Bsu36I-linearized viral DNA yields recombinant progeny viruses
      at very high frequencies. The utility of this multiple expression transfer vector
      was demonstrated using three heterologous reporter genes encoding the beta
      subunit of the human chorionic gonadotropin hormone, firefly luciferase and the
      bacterial beta-galactosidase (beta Gal) enzyme. The expression of reporter genes,
      monitored at various times post-infection, confirmed that while beta-Gal
      synthesis was under the transcriptional control of the hsp70 promoter, the beta
      hCG and Luc proteins were synthesized as a function of polyhedrin promoter
      activation profile. This vector will be useful for multiple synthesis of proteins
      at different time points.

PMID- 8666275
TI  - Characterization of a flatworm ribosomal RNA-encoding gene: promoter sequence and
      small subunit rRNA secondary structure.
AB  - The transcription start point (tsp) of a ribosomal RNA (rRNA)-encoding gene
      (rDNA) from Echinococcus granulosus has been mapped at a position located 1.1 kb
      upstream from the small subunit (SSU) rRNA coding sequence. As expected from the
      analysis of the putative promoter sequence (-200 to +50), no homology was found
      with rDNA promoters from other organisms. Nevertheless, some interesting motifs
      were found. There is a d(T)11 track flanked by an inverted repeat (IR) centered
      at position -32, which is analogous to the position of the TATA box in promoters
      transcribed by RNA polymerase II. Two other IR were observed that are also
      present in the Trypanosoma cruzi rDNA promoter. We have also determined the SSU
      rDNA sequence and established a secondary structure model. The analysis of the
      secondary structure strongly suggests that this gene encodes a functional SSU
      rRNA. The fact that both the promoter and the rRNA coding sequence are derived
      from the same rDNA repeat indicates that the promoter is also functional.

PMID- 8666276
TI  - Drosophila melanogaster P1 genomic clone DS05563 contains the chaperonin-encoding
      gene Cctg.
AB  - We report the sequence analysis of a Drosophila melanogaster (Dm) P1 genomic
      clone (DS05563) which contains the gamma-chaperonin-encoding gene, Cctg. The (Hs)
      Cctg orthologue was found to share strong sequence identity with a 1603-bp region
      of DS05563, suggesting that Dm Cctg is located within this region. Detailed
      analysis has shown that Dm Cctg comprises four exons and is interrupted by three
      introns of 55, 85 and 66 bp. Dm Cctg encodes a predicted peptide of 545 amino
      acids (aa) (approx. 60 kDa). The predicted Dm CCT gamma aa sequence shares a high
      degree of sequence identity with gamma-orthologues from human (70%), mouse (70%),
      protozoa (60%) and yeast (60%), and also contains domains found in other
      chaperonins including bacterial GroEL, mitochondrial Hsp60 and plant Rubisco
      large subunit-binding protein. These data support the conclusion that the DS05563
      clone contains the Dm Cctg gene.

PMID- 8666277
TI  - A Drosophila melanogaster homologue of the human DEAD-box gene DDX1.
AB  - DEAD-box genes are found throughout evolution and encode RNA-binding proteins.
      Such proteins include eukaryotic initiation factor-4A, which is essential for
      protein translation, Vasa, which is essential for germ line development, and a
      number of nuclear and mitochondrial RNA splicing factors. Transcription of a
      human DEAD-box gene, DDX1, is elevated in two retinoblastoma cell lines as a
      result of amplification of the immediate chromosomal region surrounding it,
      suggesting an important role for this gene in control of cell growth and
      division. We have isolated a Drosophila melanogaster (Dm) homologue (Ddx1) of
      DDX1 which is strikingly similar to the human gene. The similarity (58.3% amino
      acid (aa) identity over 720 aa) extends beyond regions conserved in all DEAD-box
      proteins and covers the entire lengths of the proteins. The 2.7-kb Dm Ddx1 RNA is
      expressed throughout development, but its levels are elevated in early embryos.
      Ddx1 maps to polytene chromosome band 79D4 on the left arm of Dm chromosome 3.

PMID- 8666278
TI  - Duplication of an amphioxus myogenic bHLH gene is independent of vertebrate
      myogenic bHLH gene duplication.
AB  - Gene duplication is thought to be a major genetic change that may have permitted
      the evolution of vertebrates from invertebrates. The myogenic genes encode basic
      helix-loop-helix (bHLH) transcriptional factors essential for the formation of
      skeletal muscle. The invertebrate genome contains only a single myogenic bHLH
      gene, whereas the vertebrate genome contains four (MyoD, Myf-5, myogenin and
      MRF4). Since the tunicate genome contains a single myogenic bHLH gene, its
      duplication might have occurred some time during chordate evolution. To determine
      whether the duplication of the myogenic bHLH gene occurred prior to, or after the
      divergence of vertebrates from the cephalochordate lineage, we amplified target
      fragments from the amphioxus, Branchiostoma floridae, by means of PCR. Sequence
      analysis and genomic Southern analysis revealed that the amphioxus genome
      contains two myogenic bHLH genes (BMD1 and BMD2). A comparison of the amino acid
      sequences in the bHLH domain between BMD1, BMD2 and four vertebrate myogenic bHLH
      gene products, however, showed that neither BMD1 nor BMD2 resembled any of the
      four genes. These results suggested that the duplication of amphioxus myogenic
      bHLH gene occurred independently of that leading to the four myogenic bHLH genes
      in vertebrates.

PMID- 8666279
TI  - Expression of the genes encoding the ecdysteroid and retinoid receptors in
      regenerating limb tissues from the fiddler crab, Uca pugilator.
AB  - Using sequence information derived from the Drosophila melanogaster (Dm)
      ecdysteroid receptor (EcR)- and retinoid X receptor (RXR)-encoding gene homologs,
      we have isolated cDNA clones corresponding to the DNA-binding domains (DBD) for
      these two nuclear receptors from the fiddler crab, Uca pugilator (Up). Both genes
      appear to be represented in 1-2 copies in the Up genome, and unlike Dm, contain
      an intron within the DBD-encoding region. Sequence comparisons to the Dm EcR and
      RXR homologs indicate 76 and 82% nucleotide identity, respectively, corresponding
      to 6 and 4 single-amino acid substitutions which primarily cluster in the region
      of the molecule involved in dimerization. RT-PCR analysis indicates that both the
      EcR and RXR homologs are expressed during the initial stages of limb
      regeneration, temporally concomitant with early blastema formation and the
      secretion of a flexible sac cuticle at the site of limb loss.

PMID- 8666280
TI  - Isolation and characterization of xnov, a Xenopus laevis ortholog of the chicken
      nov gene.
AB  - We have isolated an ortholog (xnov) of the chicken nov gene (for nephroblastoma
      overexpressed; encoding a putative avian proto-oncogene) from Xenopus laevis (Xl)
      by screening an Xl ovary cDNA library and genomic library using the entire coding
      region of human CTGF (encoding connective tissue growth factor) as a probe and by
      5'RACE (rapid amplification of cDNA ends). xnov has the same genomic organization
      as chicken nov, mouse fisp12 and cyr61, but has a unique promoter sequence. The
      Xl open reading frame (ORF) encodes a 343-amino-acid (aa) polypeptide of 37.9
      kDa. Xnov shows 62.9, 60.5, 52.2, 52.1, 47.6 and 45.8% identity with the chicken
      Nov, human NovH, human CTGF, mouse Fisp12, chicken Cef10 and mouse Cyr61
      proteins, respectively. Xnov contains four aa domains which characterize the CTGF
      family. RT-PCR (reverse transcription-polymerase chain reaction) analysis shows
      that the xnov mRNA is very low in abundance and appears to be present throughout
      early Xl development. Our results also indicate that xnov and nov are not
      orthologs of human CTGF.

PMID- 8666281
TI  - The gene encoding mouse intestinal trefoil factor: structural organization,
      partial sequence analysis and mapping to murine chromosome 17q.
AB  - Trefoil peptides, a growing family of secretory molecules, have been identified
      mainly in the gastrointestinal tract of humans, rodents and amphibians. In the
      present study, the nucleotide sequence of a large portion (81%) of the gene
      encoding murine intestinal trefoil factor (mITF) and its whole genomic
      organization were determined. The mITF gene contains three exons distributed over
      5 kb of genomic DNA. The genomic sequence is highly conserved, as compared with
      that of the rat and human ITF, and contains several AP-1-binding sites, the
      consensus binding site for the transcription factor Sp1, and a sequence
      homologous to a heat-shock element. Fluorescence in situ hybridization was used
      to assign ITF to chromosome 17 of the murine genome, a region syntenic with the
      trefoil gene cluster on human chromosome 21q22.3.

PMID- 8666282
TI  - Structure and characterization of the gene encoding a mouse kappa3-related opioid
      receptor.
AB  - A genomic clone comprising the entire cDNA sequence encoding a mouse kappa3
      related opioid receptor (KOR-3) was isolated by screening a mouse genomic library
      with a radiolabeled mouse KOR-3 cDNA probe. Sequence analysis of the genomic
      clone indicates that the KOR-3 gene contains five exons separated by four
      introns. The transcription start point (tsp) of KOR-3 was mapped by primer
      extension analysis of RNAs synthesized either in vivo or in vitro. A TATA-box and
      several potential regulatory elements, including five GRE sites, four NF-E1
      binding sites and one MRE site, are present in the 2 kb of 5'-flanking region. A
      putative poly(A) signal (AATAAA) is found in the 3'-flanking region.

PMID- 8666283
TI  - The murine gene encoding apolipoprotein D exhibits a unique expression pattern as
      compared to other species.
AB  - The ApoD cDNA coding for murine apolipoprotein D (ApoD) was cloned from a mammary
      gland library and sequenced. The nucleotide sequence and encoded mature protein
      are highly homologous to those of rabbit and human. Interestingly, unlike in
      other species, ApoD RNA is not found in spleen, liver, pancreas or kidney.

PMID- 8666284
TI  - Cloning and expression of the murine Elf-1 cDNA.
AB  - The Ets family of transcription factors has been implicated in the etiology of
      several types of cancer. We cloned and characterized the gene encoding the murine
      homologue of one Ets family member, Elf-1 (mElf-1), in order to gain insight into
      its cellular physiology. We examined mElf-1 mRNA expression in normal mouse
      tissues and in several murine and human cell lines. Expression of mElf-1,
      although highest in lymphocytes, was observed in a number of hematopoietic cell
      lineages, including the myeloid, macrophages and erythroid lineages, and was
      lowest in the murine fibroblast cell line, NIH3T3. Analysis of human and fetal
      tissue mRNAs confirmed that mElf-1 is expressed in a variety of cell lineages,
      principally in hematopoietic cells. Western blot analysis using antiserum
      generated to a synthetic C-terminal peptide of mElf-1, and extracts prepared from
      cell lines that expressed the mElf-1 mRNA identified multiple mElf-1 species that
      migrated near the 97-kDa molecular weight marker. Site selection analysis
      indicated that the binding site preferred by mElf-1 is very similar to that of
      the Drosophila melanogaster homologue, E74, and to that of Fli-1, another Ets
      family member. We conclude that the expression of mElf-1 is not restricted to the
      lymphoid lineage, and suggest that Elf-1 may regulate the transcription of a
      broad spectrum of genes.

PMID- 8666285
TI  - The complete cDNA sequence encoding plasminogen from the European hedgehog
      (Erinaceus europaeus).
AB  - Using a PCR-based strategy, we have determined the complete cDNA sequence
      encoding hedgehog plasminogen (Plg). The 2700-nucleotide cDNA (corresponding to a
      2.9-kb liver-derived transcript) encodes an open reading frame of 811 amino acids
      which shares 74-76% identity with Plg characterized from mouse, human and rhesus
      monkey. Residues corresponding to the catalytic triad, tPA-cleavage site, as well
      as seven of the eight lysine-binding residues in kringle IV are conserved in the
      hedgehog. However, potential N-linked glycosylation sites which have been
      reported in human and rhesus Plg are not present in analogous positions in the
      hedgehog Plg sequence.

PMID- 8666286
TI  - Cloning of a cDNA encoding bovine erythropoietin and analysis of its
      transcription in selected tissues.
AB  - A bovine cDNA encoding erythropoietin (Epo) was isolated by polymerase chain
      reaction (PCR) amplification and screening of a bovine kidney cDNA library. The
      sequenced cDNA has a length of 1312 bp and an open reading frame that encodes a
      predicted 192-amino-acid (aa) protein, including a putative signal sequence of 25
      aa. A mature protein of 167 aa (18.4 kDa) results upon cleavage of the putative
      signal peptide. The deduced bovine mature Epo peptide exhibits 96, 88, 83, 82 and
      79% sequence identity to that of sheep, swine, human, monkey and rat,
      respectively. The expression of the bovine Epo gene in tissues from a severely
      anemic calf, bovine fetus and a healthy steer was analysed by a competitive RT
      PCR method. In kidneys of the severely anemic calf, Epo mRNA levels increased 60
      fold relative to that from the kidneys of the healthy steer. Epo mRNA levels were
      threefold higher in the liver of the bovine fetus than that in its kidneys. Low
      levels of Epo transcripts were detected in RNA from spleen of the severely anemic
      calf and the bovine fetus. No Epo transcripts were detectable in spleen from the
      healthy steer.

PMID- 8666287
TI  - A novel expression vector for transfection of bovine MHC class I genes.
AB  - A vector is described for the expression of genomic or cDNA copies of bovine
      major histocompatibility complex (MHC) class I genes in transfected mouse Ltk-
      cells. Class I gene fragments are amplified by the polymerase chain reaction,
      using primers in conserved parts of exon 2 and the 3'-untranslated region of the
      gene. Amplified class I gene fragments can then be subcloned into the expression
      vector, pBoLA-21, which contains the necessary 5'- and 3'-sequences for correct
      expression. The vector was tested by subcloning and expressing genomic and cDNA
      clones.

PMID- 8666288
TI  - Cloning, sequencing and functional studies of the gene encoding human GTP
      cyclohydrolase I.
AB  - We have identified a genomic clone containing the 5' regulatory region of the
      gene GTP-CH encoding human GTP cyclohydrolase I. The transcription start point
      (tsp) was mapped by 5'-rapid amplification of cDNA ends (5'-RACE). The 2.6-kb
      region upstream from the tsp showed promoter activity when ligated upstream from
      a reporter gene. The truncation of approximately 2 kb of the promoter did not
      change expression activity, while a further removal of 243 bp halved the
      activity. The promoter contains CCAAT and TATA boxes. The GC-rich region close to
      the tsp, which contains several putative Sp1-responsive elements, is required for
      maximum promoter activity. Interferon-gamma treatment of B-cells transfected with
      reporter constructs had no influence on the expression activity.

PMID- 8666289
TI  - Cloning and chromosomal localization of a novel gene-encoding a human beta 2
      integrin alpha subunit.
AB  - We isolated a partial genomic clone encoding ITGAD, a novel beta 2-integrin alpha
      subunit. The ITGAD gene is highly homologous to the three previously known alpha
      subunit-encoding genes, that compose the beta 2 integrin family, in deduced amino
      acid sequence, intron/exon structure and mapping location (chromosome 16p11).

PMID- 8666290
TI  - Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor.
AB  - We have cloned and sequenced a 3055-bp human placenta cDNA encoding a P2
      purinoceptor. An identical receptor has also been found in human saphenous vein
      endothelial cells. Comparison of the deduced amino acid (aa) sequence to those of
      previously described P2Y1 purinoceptors revealed greater than 95% aa identity
      with the rat and mouse counterparts, and 83% with the chick P2Y1 purinoceptor.
      Northern blot experiments revealed two mRNAs of 7.5 and 4.6 kb whose expression
      varies according to the tissue examined.

PMID- 8666291
TI  - The cDNA sequence and infectious transcripts of peanut stripe virus.
AB  - A full-length cDNA clone of the blotch isolate of the peanut stripe potyvirus
      (PStV) RNA genome was constructed downstream from the bacteriophage SP6 RNA
      polymerase promoter. The full-length PStV cDNA clone (PStVSF9) was sequenced and
      compared to the previously published sequence of PStV-B. In vitro-synthesized
      PStV transcripts capped with m7GpppG were infectious in Nicotiana benthamiana
      plants, and the progeny virus was aphid transmissible. To confirm the origin of
      infection, a mutant PStV (PStVDAE), with a Gly14 to Glu mutation in the coat
      protein-encoding gene, was constructed. Transcripts from PStVDAE produced
      symptoms indistinguishable from native or PStVSF9 virus, but was not transmitted
      by aphids.

PMID- 8666292
TI  - An alanine tRNA gene cluster from Nephila clavipes.
AB  - We report the sequence of a 2.3-kb genomic DNA fragment from the orb-web spider,
      Nephila clavipes (Nc). The fragment contains four regions of high homology to
      tRNA(Ala). The members of this irregularly spaced cluster of genes are oriented
      in the same direction and have the same anticodon (GCA), but their sequence
      differs at several positions. Initiation and termination signals, as well as
      consensus intragenic promoter sequences characteristic of tRNA genes, have been
      identified in all genes. tRNA(Ala) are involved in the regulation of the fibroin
      synthesis in the large ampullate Nc glands.

PMID- 8666293
TI  - Sequences of the lizard cDNAs encoding lactate dehydrogenase (LDH) isozymes A
      (muscle) and B (heart).
AB  - The nucleotide and deduced amino acid sequences of cDNAs encoding L-lactate
      dehydrogenase (LDH) isozymes A (muscle) and B (heart) from the lizard, Sceloporus
      undulatus, were determined. The evolutionary relationships among LDH isozymes
      from animals, plants and bacteria are presented.

PMID- 8666294
TI  - Probable exclusion of the cortexin-encoding gene as a candidate for mouse
      neurological mutants: nervous, tottering and motor neuron degeneration.
AB  - We have tested the gene encoding cortexin, Ctxn, which maps to chromosome 8, as a
      candidate for the mouse neurological mutants: nervous (nr), tottering (tg) plus
      tottering-leaner (tgla), and motor neuron degeneration (mnd) by Northern blot
      analysis of brain poly(A)+ RNA and direct polymerase chain reaction (PCR)
      sequencing. No difference from wild-type was seen in any of these mutants. Based
      upon these observations, we conclude that Ctxn is not involved in the genetic
      defects found in nr, tg or mnd mice.

PMID- 8666296
TI  - Sequence analysis of the 5'-untranslated region of the human H1 histamine
      receptor-encoding gene.
AB  - A clone containing the H1 histamine receptor (H1HR)-encoding gene was isolated
      from a human genomic DNA library. The 5'-UTR of the H1HR gene reported here
      differs upstream from bp -142 from that reported previously [Fukui et al.,
      Biochem. Biophys. Res. Comm. 201 (1994) 894-901]. PCR amplification utilizing
      primer pairs derived from the 5'-UTR reported herein amplified a DNA fragment of
      the expected size from human genomic DNA whereas 5'-UTR primers derived from the
      Fukui et al. sequence did not yield a PCR product. The 5'-UTR of H1HR contains
      potential TATA and CCAAT boxes, a CACCC sequence, potential GREs and other DNA
      binding motifs.

PMID- 8666295
TI  - Isolation and sequencing of the 5' end of the rat microtubule-associated protein
      (MAP1B)-encoding cDNA.
AB  - We have isolated and sequenced the 5' end of the cDNA encoding the rat
      microtubule-associated protein 1B (MAP1B). We found that this region is highly
      homologous to the corresponding regions of the human [Lien et al., 22 (1994) 273
      280] and mouse [Noble et al., J. Cell Biol. 109 (1989) 3367-3376] MAP1B genes.
      The combination of the sequence that we are presenting with the previously
      published sequence [Zauner et al., Eur. J. Cell Biol. 57 (1992) 66-74],
      represents the complete rat MAP1B cDNA coding sequence.

PMID- 8666297
TI  - Sequence of the cDNA encoding human GP-2, the major membrane protein in the
      secretory granule of the exocrine pancreas.
AB  - GP-2 is the major membrane protein in the pancreatic secretory granule of the
      exocrine pancreas. The nucleotide sequence of the human GP-2 gene was determined
      from cDNA clones isolated from a lambda gt11 pancreatic library.

PMID- 8666299
TI  - [The combined action of styrene vapors and total vibration in a chronic
      toxicological experiment].

PMID- 8666298
TI  - [The effect of soil extracts with different heavy metal levels on the viability
      of isolated blood system cells].
AB  - Short-term incubation of rat thymocytes, bone marrow cells, and macrophages with
      aqueous extracts of soil demonstrated positive correlations between damage to the
      cells and increased levels of copper, chromium, and manganese in the soil, while
      increased levels of zinc and lanthanum were associated with less pronounced
      changes in the cells.

PMID- 8666300
TI  - [The forecasting of hygienic regulations for industrial substances possessing
      irritant action].
AB  - Computer analysis of hygienic standards in Russia and the USA and of the
      toxicometric parameters of chemicals characterized by predominantly irritating
      effects helped create a prognostic model for the calculation of maximum allowable
      concentrations of chemicals in the air of working zones.

PMID- 8666301
TI  - [The morphological characteristics of the lung lesions in straighteners working
      with brass-bronze alloys].
AB  - Morphologic study of lung specimens obtained during diagnostic thoractomy in 6
      workers engaged in smelting brass-bronze alloys showed changes typical of
      exogenous fibrosing alveolitis, namely, terminal bronchiolitis with
      pseudopolypous growth in the submucous layer, vasculitis (predominantly
      arteritis) paralleled by secondary recalibration of vessels, arteriolar and
      venular shunting, and microcirculatory disorders.

PMID- 8666302
TI  - [The problem in assessing the health status of children and adolescents in
      hygienic research].

PMID- 8666303
TI  - [The characteristics of their free time and the physical work capacity of
      adolescents].
AB  - Discusses the problems in the search for the simplest and most effective methods
      for improving the performance capacity of adolescents. This parameter is
      determined by biological and social factors, and, hence, rational organization of
      free-time activity can appreciably improve the energy potential of the organism.

PMID- 8666304
TI  - [Changes in the lipid spectrum of the lungs in poisoning by nitrogen oxides or
      adrenaline].
AB  - The content of lipids and fatty acids was measured in lung tissue of intact rats
      and animals with lung edema caused by nitrogen oxide or adrenaline. Lung edema
      was found to involve disagreement between the phospholipid and fatty acid spectra
      and to increase the permeability of membranes. The toxic and adrenaline-induced
      edemas were found identical as regards the type of changes in the ratio of
      fractions of neutral lipids, phospholipids, and fatty acid spectrum, that is,
      these shifts represent a nonspecific reaction of lung tissue to aggression.

PMID- 8666305
TI  - [An improvement in the prevention of anthropozoonoses in Moscow and on the Moscow
      railroad junction].

PMID- 8666307
TI  - [The medico-ecological concept of the rehabilitation of territory and the health
      of the population in the Altai Territory].

PMID- 8666306
TI  - [The experimental validation of new methods for disinfecting railroad transtation
      installations].

PMID- 8666308
TI  - [The hygienic and toxicological characteristics of the new cotton defoliants
      zied, morel and nazhot].

PMID- 8666310
TI  - [The organizational status of laboratory control in the State Epidemiological
      Health Service system of the Russian Federation].

PMID- 8666309
TI  - [The biomedical aspects of mercury neurotoxicity (a review)].

PMID- 8666311
TI  - [The concept of the organization and development of laboratory support in the
      State Epidemiological Health Service system of the Russian Federation].

PMID- 8666312
TI  - [The hygienic standardization of 3-phenoxybenzyl alcohol in the atmospheric air
      of populated places].
AB  - The threshold level of 3-phenoxybenzyl alcohol (3-PBA) in ambient air was set up
      at 0.48 mg/m3. Inhalation of 3-PBA in concentrations of 4.86 and 0.518 mg/m3
      caused changes in the central nervous system, metabolic processes, liver
      function, reduced the nonspecific resistance of the organism, and had a
      gonadotoxic effect. The concentration of 0.518 m3 was the threshold one, causing
      changes in only few of the general toxic parameters, and the 0.059 mg/m3
      concentration was noneffective. The maximum permissible concentration (MPC) for 3
      PBA upon a single exposure is recommended to be set up at the level of 0.2 mg/m3,
      the mean daily MPC at 0.06 mg/m3. By its reflex and resorptive effects the agent
      was referred to hazard class IV.

PMID- 8666313
TI  - [The disinfection and preservation of drinking water with low-voltage pulsed
      electrical discharges].
AB  - Two-hour exposure to low-voltage (2.8 to 3 kV) pulsed electric discharges (PED)
      effectively (by 99.9999%) disinfected drinking water. Preservation of water with
      IED had a pronounced bactericidal effect in respect of numerous pathogenic and
      opportunistic microorganisms. The aftereffect of PED persists for at least 2
      months.

PMID- 8666314
TI  - Adenine arabinoside monophosphate coupled to lactosaminated human albumin
      administered for 4 weeks in patients with chronic type B hepatitis decreased
      viremia without producing significant side effects.
AB  - A conjugate of adenine arabinoside monophosphate (ara-AMP) with the liver
      targeting molecule lactosaminated human serum albumin (L-HSA) was administered by
      intravenous infusion for 28 days to eight patients with chronic type B hepatitis.
      The daily dose varied among the patients, ranging from 34 mg/kg to 53 mg/kg
      (equal to 1.5 and 2.3 mg/kg ara-AMP, respectively). Pharmacokinetic analysis
      indicated that, at every dose tested, the conjugate was disposed of without
      accumulation. Viral DNA serum levels fell markedly during treatment; values rose
      again when treatment was ceased. The L-HSA-ara-AMP conjugate did not cause either
      the neurotoxic side effects of free ara-AMP or other adverse clinical reactions.
      It produced a significant increase both in serum alkaline phosphatase activity
      and platelet number, and a small but significant decrease in erythrocyte number.
      These laboratory parameters returned to normal levels within 2 months after
      treatment. The conjugate induced the production of small amounts of antibodies
      (approximately 20 pmol of conjugate bound by 1 mL of serum) in one patient only.
      In conclusion, the present results indicate that the L-HSA-ara-AMP conjugate can
      exert the antiviral activity of ara-AMP in chronic type B hepatitis patients
      without producing the neurotoxic side effects which hamper a 4-week period of
      treatment with the free drug.

PMID- 8666315
TI  - Overexpression of a p-glycoprotein in hepatocellular carcinomas from woodchuck
      hepatitis virus-infected woodchucks (Marmota monax).
AB  - The leading cause of human hepatocellular carcinomas (HCCs) is hepatitis B virus
      (HBV) infection. Woodchucks infected with a closely related hepadnavirus,
      woodchuck hepatitis virus (WHV), serve as a model for HBV because woodchucks
      chronically infected with WHV also develop hepatocellular carcinomas. Increased
      expression of p-glycoprotein (pgp) in human HCCs is a common obstacle in
      successful cancer chemotherapy. Pgps are encoded by a family of multidrug
      resistance (MDR) genes. Livers from uninfected and WHV-infected woodchucks were
      examined to determine if pgp was expressed in HCCs and if there was a difference
      in expression between HCCs and nonneoplastic liver. A 170-kd protein was
      identified by Western blot in HCCs, whereas, constitutive pgp was not detected in
      normal liver taken from the same animals in 3 of 3 cases. Immunolocalization of
      the pgp with a panel of monoclonal antibodies revealed intensification of
      staining in 7 of 20 foci and 12 of 22 HCCs from six animals. Using primers for
      the human MDR1 gene, a single product was detected by reverse-transcribed
      polymerase chain reaction (RT-PCR) from HCCs. We have shown an increase in pgp in
      HCCs compared with normal liver from WHV-infected woodchucks. This is the first
      example of the induction of a pgp in a naturally hepadnavirus infected rodent
      system. It suggests the woodchuck can be a useful model for the study of the
      acquisition of resistance to chemotherapeutic agents in virally induced HCCs.

PMID- 8666317
TI  - Intrahepatic hepatitis C RNA levels do not correlate with degree of liver injury
      in patients with chronic hepatitis C.
AB  - The balance between a direct cytopathic effect by hepatitis C virus (HCV) and
      immune-mediated injury remains unclear. This report aims to test the following
      hypotheses: (1) that intrahepatic HCV load would correlate with the degree of
      liver injury; (2) that interferon alfa (IFN-alpha) would decrease intrahepatic
      HCV-RNA levels. Liver tissues (n = 56) were obtained from 47 patients with
      chronic HCV (9 before and after IFN-alpha therapy). Total RNA was isolated and
      quantitated for specific HCV RNA by dot-blot polymerase chain reaction (DB-PCR)
      using a standard curve created from synthetic HCV RNA of known titer to calculate
      actual RNA levels. A multivariate analysis was undertaken to determine the
      relationship of intrahepatic HCV-RNA levels with risk factors, length of HCV
      exposure, and histological injury scores. The confounding effect of HCV genotype
      was examined by direct sequencing of the NS5b region. Liver HCV RNA ranged from
      10(2) to 3.1 x 10(7) molecules per microgram total liver RNA. The multiple
      regression analysis showed no effect of length of HCV exposure, risk factors,
      degree of bile duct damage, steatosis, or total Scheuer or Knodell score on RNA
      levels. No significant confounding effect of HCV genotype on the degree of liver
      injury was observed. However, genotype 1b had a significantly higher mean
      intrahepatic HCV-RNA load compared with the other genotypes detected. In the 9
      patients who received IFN-alpha, treatment, 7 had no detectable HCV after
      treatment. This was associated with a significant decrease in intrahepatic HCV
      RNA levels (7.57 +/- 2.53 X 10(5) to 1.82 +/- 1.80 x 10(3) molecules per
      microgram total liver RNA +/- SEM, n = 9, P = .0005). These results do not
      directly support our hypothesis that increased intrahepatic HCV load is
      associated with more severe liver injury. Intrahepatic viral load appears to be
      significantly increased in patients with genotype lb. IFN-alpha treatment does
      significantly lower intrahepatic HCV load.

PMID- 8666316
TI  - Induction of interleukin-6 by interferon alfa and its abrogation by a serine
      protease inhibitor in patients with chronic hepatitis C.
AB  - We investigated short-term alterations in plasma interleukin-6 (IL-6),
      interleukin-1beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha) levels
      induced by interferon alfa (IFN-alpha) injection in 18 patients with chronic
      hepatitis C. A single intramuscular injection of human recombinant IFN-alpha 2a
      (6 million units [MU]) significantly increased the plasma IL-6 level 6 hours
      after the injection (P < .05). On the other hand, the IFN-alpha injection did not
      affect the plasma TNF-alpha and IL-lbeta levels. Polymerase chain reaction (PCR)
      analysis showed accumulation of IL-6 gene transcripts in peripheral blood
      mononuclear cells (PBMC) after IFN-alpha injection, indicating that IFN-alpha
      enhances IL-6 production at the messenger RNA level. The induction of IL-6 by IFN
      alpha was completely suppressed by the intravenous administration of gabexate
      mesilate (GM), a serine protease inhibitor. The mechanism whereby GM suppresses
      the elevation in circulating IL-6 levels seems to be the inhibition of IL-6
      production at the messenger RNA level. Elevations of both serum C-reactive
      protein (CRP) levels and body temperature after GM-suppressed IFN-alpha injection
      suggest that the administration of GM by suppressing IL-6 production, may
      attenuate the IL-6-related responses induced by IFN-alpha injection. In
      conclusion, we found that IL-6 was induced by IFN-alpha in vivo, and that this
      induction was completely abrogated by the administration of GM. Our results
      indicate that serine protease inhibitors may be useful for inhibiting IL-6
      relating responses.

PMID- 8666318
TI  - Hepatitis C in human immunodeficiency virus-coinfected patients: increased
      variability in the hypervariable envelope coding domain.
AB  - Patients coinfected with the hepatitis C virus (HCV) and the human
      immunodeficiency virus (HIV) were studied with regard to nucleotide sequence
      variability in the E2/NS1 first hypervariable region of the HCV genome. The
      nucleotide variability within individual patients was compared to patients
      infected only with HCV. The proportion of predicted synonymous and nonsynonymous
      amino acid changes, and the relationship to putative high-antigenicity sites,
      were evaluated in the hypervariable envelope domain. Ninety-one clones from 10
      patients with HCV/HIV coinfection were sequenced, following polymerase chain
      reaction (PCR) amplification of the hypervariable region. The control HCV group
      included 53 clones from 7 patients. Sequence analysis encompassed the region
      coding for amino acids 384 to 414. Consensus sequences from each patient were
      used as the internal standard for nonsynonymous amino acid codon variability.
      Cumulative proportional comparison at each amino acid site revealed increased
      variability in HCV RNA from patients with HCV/HIV coinfection versus HCV alone (P
      < .05). The greatest variability was observed at amino acids 386, 397, 400, 402,
      405, 407, and 414, with >l0 percent clonal variation at these sites. Jameson-Wolf
      plots were used to predict putative high-antigenicity domains. Nonsynonymous
      clonal variation resulted in alteration of putative antigenic sites within the
      hypervariable region. All clones had at least one high-probability site. Clones
      with unique predicted antigenic domains were observed more frequently in HIV/HCV
      coinfected patients, and, independent of viral titer, were consistent with
      increased sequence variability. These data suggest an accumulation of envelope
      variants in the HCV/HIV coinfected patients, which could be related to
      ineffective viral clearance, and may help explain prior reports of interferon
      (IFN) resistance in this patient group.

PMID- 8666319
TI  - The natural course of chronic hepatitis C: a comparison between patients with
      genotypes 1 and 2 hepatitis C viruses.
AB  - This study was conducted to clarify if the long-term histological outcome among
      patients with chronic hepatitis C differs according to whether they are infected
      with genotype 1 or 2 hepatitis C virus (HCV). We examined 140 patients with
      chronic hepatitis C. The HCV genotype was determined by the enzyme-linked
      immunosorbent assay (ELISA) based on genotypes 1 and 2 specific recombinant
      proteins; genotype 1 was found in 100 patients (96 were 1b and 4 were
      indeterminate) and genotype 2 in 36. The two groups showed no significant
      difference for any clinical background features. Deterioration of the grade of
      liver histology during the follow-up period was seen in 68.0 percent of the
      patients with genotype 1 as compared with 41.7 percent of those with genotype 2
      (P < .01). Similarly, the deterioration of the stage of liver histology was more
      common in the former group than in the latter (63.0 percent and 38.9 percent
      respectively; P < .05). The mean serum HCV-RNA titer was significantly higher in
      the patients with genotype 1 than in those with genotype 2 (P < .001), and
      multivariate analysis showed the titer was one of the independent factors of the
      deterioration of the stage (P = .0044). This phenomenon may be related in part to
      the difference in pathogenicity between the two HCV genotypes. In conclusion, our
      results suggest that more severe progression of chronic hepatitis C is seen in
      patients showing genotype 1b compared with those with genotype 2.

PMID- 8666320
TI  - Lymphoblastoid interferon alfa with or without steroid pretreatment in children
      with chronic hepatitis B: a multicenter controlled trial.
AB  - The comparative efficacy of prednisolone followed by interferon alfa (IFN-alpha)
      versus IFN-alpha alone in enhancing the rate of antibody to hepatitis B e antigen
      (anti-HBe) seroconversion has not been evaluated in a large cohort of white
      children. To determine this, a multicenter-controlled trial was conducted in 95
      hepatitis B virus (HBV)-DNA/hepatitis B e antigen (HBeAg)-positive children
      (median age, 9 years [range, 2-16 years]; 56 boys; 84 [89 percent] white), all
      having inflammatory changes on liver biopsy. Patients were randomized to receive
      either prednisolone followed by IFN-alpha (n = 34); placebo followed by IFN-alpha
      (n = 30); or no treatment (n = 31). The prednisolone/placebo was given on a
      double-blind basis. Lymphoblastoid IFN-alpha was given at 5 MU/m(2) three times a
      week for 12 weeks. Baseline clinical, biochemical, and histological features were
      similar for the three groups. The majority (85 percent) had a baseline aspartate
      aminotransferase (AST) level < or = 100 IU/L. On follow-up between 12 and 18
      months (median, 15 months) after treatment, the loss of HBeAg with anti-HBe
      seroconversion was more common in patients pretreated with steroids (12 of 34 [35
      percent]) or placebo [12 of 30 (40 percent)] as against controls (4 of 31 [13
      percent], P< .05). Factors predictive of anti-HBe seroconversion were baseline
      HBV-DNA concentration of < or = 1,000 pg/mL and a greater degree of portal tract
      inflammation on pretrial biopsy. Our results show that in white children
      treatment with IFN-alpha, at the dose and duration used in this study, improves
      the rate of anti-HBe seroconversion. Steroid priming does not potentiate the
      effect of IFN-alpha.

PMID- 8666322
TI  - Admission levels of serum Gc-globulin: predictive value in fulminant hepatic
      failure.
AB  - Gc-globulin scavenges actin released from necrotic hepatocytes to the
      extracellular space. In 77 patients with fulminant hepatic failure (FHF)
      (excluding patients treated with liver transplantation), admission levels of
      serum Gc-globulin and degree of complexing with monomeric actin (complex ratio)
      were determined to evaluate their predictive values in relation to
      survival/nonsurvival. Gc-globulin levels were significantly reduced in 47
      nonsurvivors, compared with 30 survivors (96 +/- 71 mg/L vs. 169 +/- 101 mg/L, P
      < .001), whereas the complex ratio in nonsurvivors did not differ significantly
      from that of survivors. Gc-globulin levels were significantly lower in 59
      patients with non-acetaminophen-induced FHF, compared with 18 patients with
      acetaminophen-induced FHF (P < .01). Using a cutoff level of serum Gc-globulin of
      100 mg/L, a lesser value correctly predicted nonsurvival in 79 percent of
      patients with non-acetaminophen-induced FHF, whereas a higher value predicted
      survival in 60 percent. In patients with acetaminophen-induced FHF, nonsurvival
      was correctly predicted in 100 percent of patients and survival in 53 percent. In
      comparison, the King's College Hospital (KCH) criteria correctly predicted
      nonsurvival and survival in 69 percent and 57 percent, respectively, of the same
      non-acetaminophen-induced FHF patients and in 60 percent and 38 percent,
      respectively, of the acetaminophen-induced FHF patients. Thus, in our study
      population, the predictive properties of Gc-globulin were in the same range as
      the KCH criteria. An advantage of Gc-globulin is that it gives an estimate of the
      outcome already on admission. Acute liver transplantation should be considered in
      FHF patients with Gc-globulin less than 100 mg/L.

PMID- 8666321
TI  - Prospective assessment of donor blood screening for antibody to hepatitis C virus
      by first- and second-generation assays as a means of preventing posttransfusion
      hepatitis.
AB  - In November 1989, the Japanese Red Cross began screening blood donors for the
      hepatitis C virus antibody (anti-HCV) by first-generation assay and high-titer
      hepatitis B virus core antigen antibody. A significant reduction in the incidence
      of acute posttransfusion hepatitis was reported; however, the incidence still
      ranged from 2 percent to 4 percent. The Red Cross changed to the second
      generation assay in February 1992, the objective being the complete elimination
      of potential posttransfusion hepatitis. The aim was to elucidate the advantage of
      second-generation assay as a blood-donor screening test. The incidence of
      posttransfusion hepatitis after the introduction of second-generation assay was
      compared with that before the introduction of the first-generation assay and with
      that during its use. The incidence of posttransfusion hepatitis was 9.6 percent
      (216/2,240) before anti-HCV-s donor screening. It was 3.7 percent (24/655) and
      0.9 percent (3/326) after the introductions of the first- and second-generation
      hepatitis C virus (HCV) assays, respectively (chi (2) = 50.0, P < .01). Blood
      donor screening by second-generation anti-HCV provided a significant benefit
      compared with the first-generation assay.

PMID- 8666324
TI  - Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical
      consequences among homozygous siblings.
AB  - The relationship between alcoholism and hereditary hemochromatosis remains
      controversial. Previous studies have included patients with alcoholic siderosis
      rather than hereditary hemochromatosis. In this retrospective study, the clinical
      features, iron status, alcohol history, liver histology, and long-term survival
      were reviewed in 105 homozygotes for hemochromatosis using rigid diagnostic
      criteria including an HLA identical sibling with iron overload. Heavy alcohol
      consumption (>80 g ethanol/day) was found in 15 percent of hemochromatosis
      patients. Histological features of alcoholic liver disease (Mallory's hyaline
      bodies, pericentral fibrosis, polymorphonuclear infiltrate, and fatty
      infiltration) were uncommon in hemochromatosis. Hemochromatosis patients with
      heavy alcohol consumption had a higher prevalence of cirrhosis than
      hemochromatosis patients without heavy alcohol consumption. Hepatic iron
      concentration and hepatic iron index did not significantly differ between these
      two hemochromatosis groups. Long-term survival was significantly reduced in
      patients with heavy alcohol consumption (mean follow-up, 9.22 years). This
      suggests that chronic alcohol consumption has an additive hepatotoxic effect
      despite the paucity of histological features of alcoholic liver disease.

PMID- 8666323
TI  - Spontaneous bacterial empyema in cirrhotic patients: a prospective study.
AB  - Spontaneous bacterial empyema (SBEM) is an infection of a preexisting hydrothorax
      in cirrhotic patients and has seldom been reported. To determine its incidence
      and primary characteristics, all cirrhotic patients with pleural effusion
      underwent thoracentesis at our hospital either on admission or when an infection
      was suspected. Pleural fluid (PF) study included biochemical analysis,
      polymorphonuclear (PMN) leukocyte count, and culture by two methods: conventional
      and modified (inoculation of 10 mL of PF into a blood culture bottle at the
      bedside). SBEM was defined according to previously reported criteria: PF culture
      positive or PMN count greater than 500 cells/micro L, and exclusion of
      parapneumonic effusions. Sixteen of the 120 (13 percent) cirrhotic patients
      admitted with hydrothorax had 24 episodes of SBEM. In 10 of the 24 episodes (43
      percent), SBEM was not associated with spontaneous bacterial peritonitis (SBP).
      PF culture was positive by the conventional method in 8 episodes (33 percent) and
      by the modified method (blood culture inoculation) in 18 (75 percent) (P = .004,
      McNemar). The microorganisms identified in PF were Escherichia coli in 8
      episodes, Streptococcus species in 4, Enterococcus species in 3, Klebsiella
      pneumoniae in 2, and Pseudomonas stutzeri in 1. All episodes were treated with
      antibiotics without inserting a chest tube in any case. Mortality during
      treatment was 20 percent. We conclude that SBEM is a common complication of
      cirrhotic patients with hydrothorax. Almost half of the episodes were not
      associated with SBP; thus, thoracentesis should be performed in patients with
      cirrhosis, pleural effusion, and suspected infection. Culture of PF should be
      performed by inoculating 10 mL into a blood culture bottle at the bedside.

PMID- 8666325
TI  - Etiology, evaluation, and outcome of jaundice in patients with acquired
      immunodeficiency syndrome.
AB  - Although liver test abnormalities are frequently identified in patients with
      acquired immunodeficiency syndrome (AIDS), the causes, evaluation, and outcome of
      jaundice in these patients have not been systematically evaluated. From August 1,
      1990 through September 1, 1994, all human immunodeficiency virus (HIV)-infected
      patients with liver test abnormalities seen by the gastroenterology service at a
      large, inner-city hospital were prospectively identified. Jaundice was defined as
      a serum bilirubin concentration > or = 3 mg/dL. The etiology of jaundice was
      determined by the pattern of liver biochemistry test abnormalities, radiographic
      studies, liver biopsy, clinical follow-up, and autopsy. During the study period,
      541 HIV-infected patients (511 with AIDS) were evaluated for liver disease by our
      service; 36 of these patients had jaundice (7 percent). The most common causes of
      jaundice were drug-induced hepatitis, occurring in 11 patients (31 percent), and
      alcoholic liver disease, occurring in 5 (13 percent). Opportunistic infections or
      neoplasms were identified as the cause of jaundice in 11 patients (30 percent),
      with 4 having intrahepatic disease and 7 having extrahepatic disease. Multiple
      potential causes were seen in 3 patients. Abdominal ultrasonography (US) and
      computed tomography (CT) were helpful in suggesting the underlying cause of
      disease. The short-term mortality was high, with 9 patients dying during the
      hospitalization (25 percent) and 7 patients dying within 6 months of evaluation.
      Liver disease was the cause of death in 7 of these patients. In conclusion,
      jaundice is uncommon in AIDS and may result from a variety of both opportunistic
      and non-opportunistic etiologies. Drug-induced hepatitis is the most common cause
      and may be fatal. Long-term survival was poor.

PMID- 8666326
TI  - Comparison of glyceraldehyde-3-phosphate dehydrogenase and 28s-ribosomal RNA gene
      expression in human hepatocellular carcinoma.
AB  - The gene responsible for transcribing glyceraldehyde-3-phosphate dehydrogenase
      (GAPDH) is commonly used as a reporter gene to estimate the amount of RNA present
      in Northern analyses. However, recent data suggest that GAPDH gene expression may
      vary with the extent of cell proliferation and differentiation. 28S-ribosomal RNA
      (28S-rRNA) has also been employed to normalize Northern blots prepared with total
      RNA. In the present study, we compared the expression of GAPDH messenger RNA
      (mRNA) with 28S-rRNA by Northern blot analyses in human hepatocellular carcinoma
      tissues (HCC) and adjacent non-HCC tissues from eight patients with chronic viral
      hepatitis-induced cirrhosis and normal liver tissue from eight healthy control
      subjects. The results of the study revealed that GAPDH mRNA levels in HCC were
      significantly higher (14X-16x) than those in adjacent non-HCC and normal liver
      tissues. Conversely, 28S-rRNA levels did not vary among HCC, adjacent non-HCC,
      and normal liver tissues. We also demonstrated that the 28S-RNA signal was
      proportional to the amount of RNA loaded. These findings indicate that 28S-rRNA,
      rather than GAPDH mRNA, should be used as RNA loading controls for Northern blot
      analyses involving HCC and nontumor tissues. The findings also raise the
      possibility that GAPDH mRNA gene expression might serve as a diagnostic indicator
      for human HCC.

PMID- 8666327
TI  - Behavior of various cholesterol crystals in bile from patients with gallstones.
AB  - Besides classical plate-like cholesterol monohydrate crystals, a variety of
      crystal shapes have recently been described in model biles but their relevance
      for human gallstone formation is unknown. We therefore studied crystallization
      behavior in gallbladder bile from cholesterol stone patients (54 untreated, 13
      ursodeoxycholate-treated) and 6 pigment stone patients. Bile preparation by
      ultrafiltration or ultracentrifugation left biliary lipid composition unchanged
      but plates and their aggregates, and arcs and needles crystallized more
      extensively while spirals and tubules crystallized less extensively in ultra
      centrifuged bile than in ultrafiltered bile. Plates, aggregates, and arcs/needles
      were seen in 90 percent, 36 percent, and 18 percent of the cases respectively of
      fresh unfiltered biles of untreated cholesterol stone patients, while spirals and
      tubules were always absent. In ultrafiltered biles arcs/needles, plates and
      aggregates progressively developed as persistent forms. Spirals and tubules
      occurred transiently and were associated with increased deoxycholic acid (+41
      percent, P = .039) and with more extensive cholesterol crystallization.
      Rate/extent of crystallization of all crystal forms was higher (P < .0001) for
      multiple than solitary cholesterol stone patients. Ursodeoxycholate-treated
      patients had atypical platelike cholesterol crystals in fresh unfiltered biles
      that decreased in size at prolonged observation and in 2 cases even dissolved
      after 15 and 20 days. No crystals ever developed in ultra-filtered bile of
      ursodeoxycholic acid (UDCA)-treated patients during 21 days. Pigment stone
      patients seldom developed crystals. Thus, plates, aggregates and arcs/needles are
      persistent forms with high crystallization rate in multiple cholesterol stone
      patients. Tubules and spirals are transient forms that are associated with more
      extensive crystallization. Patients treated with ursodeoxycholate often have
      atypical crystals in their fresh bile.

PMID- 8666328
TI  - Inhibition of Kupffer cell functions as an explanation for the hepatoprotective
      properties of silibinin.
AB  - The flavonoid silibinin, the main compound extracted from the milk thistle
      Silybum marianum, displays hepatoprotective properties in acute and chronic liver
      injury. To further elucidate the mechanisms by which it acts, we studied the
      effects of silibinin on different functions of isolated rat Kupffer cells, namely
      the formation of superoxide anion radical (02-), nitric oxide (NO), tumor
      necrosis factor alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), and leukotriene
      B(4) (LTB(4)). Production of 02- and NO were inhibited in a dose-dependent
      manner, with an 50 percent inhibitory concentration (IC(50)) value around 80
      micro mol/L. No effect on TNF-alpha formation was detected. Opposite effects were
      found on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid
      metabolism. Whereas no influence on PGE(2) formation was observed with silibinin
      concentrations up to 100 micro mol/L, a strong inhibitory effect on LTB(4)
      formation became evident. The IC(50)-value for inhibiting the formation of this
      eicosanoid was determined to be 15 micro mol/L silibinin. The strong inhibition
      of LTB(4), formation by silibinin was confirmed in experiments with phagocytic
      cells isolated from human liver. Hence, while rather high concentrations of
      silibinin are necessary to diminish free radical formation by activated Kupffer
      cells, significant inhibition of the 5-lipoxygenase pathway already occurs at
      silibinin concentrations which are achieved in vivo. Selective inhibition of
      leukotriene formation by Kupffer cells can at least partly account for the
      hepatoprotective properties of silibinin.

PMID- 8666329
TI  - The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells,
      reducing procollagen gene expression in rat liver fibrosis induced by choline
      deficient L-amino acid-defined diet.
AB  - No effective therapy has yet developed for liver fibrosis by directory inhibiting
      the accumulation of extracellular matrix. The effect of a newly synthesized
      prolyl4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2, 4-di-carboxylic-di(2
      methoxyethyl)amide), was examined using the model of choline-deficient L-amino
      acid (CDAA) defined diet-induced liver fibrosis in 16-week-old male Wistar rats.
      HOE 077 at doses up to 200 ppm prevented fibrosis in a dose-dependent manner, as
      indicated by reduced hydroxyproline content in liver as well as inhibition of
      increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm
      reduced expression of type III procollagen alpha 1, messenger RNA (mRNA) in the
      liver, with a good correlation with serum PIIIP and hydroxyproline content of the
      liver. Histologically, HOE 077 at 200 ppm also reduced proliferation of
      myofibroblastlike cells (activated Ito cells). These results indicate that a PH
      inhibitor can prevent fibrosis by inhibiting not only the hydroxylation of
      proline but also the activation of Ito cells, which are considered the main
      collagen-producing cells, resulting in reduced expression of procollagen mRNA.

PMID- 8666330
TI  - Inhibition of hereditary hepatitis and liver tumor development in Long-Evans
      cinnamon rats by the copper-chelating agent trientine dihydrochloride.
AB  - Trientine dihydrochloride (trientine) is an alternative medicinal copper
      chelating agent for patients with Wilson's disease of penicillamine intolerance.
      We examined the effects of trientine on the spontaneous development of hepatitis
      and hepatic tumors, by its short-term and long-term administration to Long-Evans
      cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models
      of Wilson's disease. Male rats were given trientine in their drinking water at
      1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment,
      and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in
      the long-term experiment. Development of hepatitis was observed in the control
      LEC rats at 18 weeks of age. They had high levels of plasma transaminases
      (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]),
      and on pathological examination, hepatocyte destruction was observed.
      Histological findings revealed that short-term administration of trientine
      inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels
      of treated animals were only slightly higher than those of normal LEA (Long-Evans
      with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the
      liver were decreased by a maximum of 50 percent. In the long-term administration
      of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats
      was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in
      the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7
      +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis
      in LEC rats was completely prevented by long-term administration of the agent.
      The copper level in the liver of treated rats was reduced by 33 percent at 87
      weeks of age. Development of HCC in LEC rats might be partly, but not totally,
      because of copper accumulation. No effects on the levels of copper, iron, or zinc
      in the liver of LEA rats was detected, and no adverse effects were detected in
      either LEC or LEA rats after both short- and long-term administration of
      trientine in drinking water.

PMID- 8666331
TI  - Hepatobiliary disposition of valproic acid and valproate glucuronide: use of a
      pharmacokinetic model to examine the rate-limiting steps and potential sites of
      drug interactions.
AB  - Previous work in this laboratory has suggested that the nonlinear disposition of
      valproic acid (VPA) in the rat may be due to nonlinear distribution of VPA into
      the liver. The present study was undertaken to elucidate further the
      hepatobiliary disposition of VPA. VPA (0.1-2 mmol/L) was incubated with isolated
      rat hepatocytes in vitro. Uptake of [(3)H]-VPA was linear from 10 to 50 seconds,
      with minimal (<7 percent) biotransformation. The initial velocity of VPA uptake
      varied in proportion with the extracellular concentration and was temperature
      independent, suggesting that VPA traverses the hepatocyte membrane predominantly
      by passive diffusion. In separate studies, the hepatobiliary disposition of VPA
      (20mg) was examined in the isolated perfused rat liver (IPL). A pharmacokinetic
      model was developed to describe the influence of phenobarbital on the
      hepatobiliary disposition of VPA and valproate glucuronide (V-G) in the IPL; all
      processes governing VPA and V-G disposition appeared to be linear. Acute
      administration of phenobarbital to the liver (1.12 mg) decreased the rate
      constant for canalicular egress of V-G (0.0489 +/- 0.0266 vs. 0.164 +/- 0.075
      min(-1)). In vivo pretreatment with phenobarbital (75 mg/kg/d x 5 d) before liver
      isolation decreased the biliary excretion of both VPA (1.06E-04 +/- 0.27E-04 vs.
      2.76E-04 +/- 0.45E-04 min(-1)) and V-G (5.63E- 03 +/- 1.98E-03 vs. 1.74E-02 +/-
      0.5E-02 min(-1)), and increased the apparent volume of distribution of VPA (84.6
      +/- 2.2 vs. 72.3 +/- 2.1 mL). In vivo phenobarbital pretreatment a changed V-G
      excretion from a formation to an elimination rate-limited process. These results
      are consistent with phenobarbital-associated impairment of canalicular egress of
      some organic anions. This work further supports the utility of pharmacokinetic
      modeling in: (1) determining the rate-limiting steps in hepatobiliary drug
      disposition and (2) identifying sites of drug interactions within the
      hepatobiliary system that may not be evident based on conventional mass-balance
      analysis.

PMID- 8666332
TI  - Selective intestinal decontamination with norfloxacin reduces bacterial
      translocation in ascitic cirrhotic rats exposed to hemorrhagic shock.
AB  - Bacterial translocation (BT) can be involved in the pathogenesis of severe
      infections due to bacteria of enteric origin that complicates bleeding cirrhotic
      patients. To assess the effect of hemorrhagic shock (HS) on the incidence of BT
      and if selective intestinal decontamination (SID) reduces this incidence, we
      studied six groups of Sprague-Dawley rats: ascitic rats, ascitic rats exposed to
      HS with and without previous norfloxacin prophylaxis, healthy rats, and healthy
      shocked rats with and without previous norfloxacin prophylaxis. BT tended to be
      higher in ascitic rats with shock than without shock (69% vs. 41%, P = .15) and
      was significantly higher in healthy rats with than without shock (50 percent vs.
      0 percent, P = .01). Norfloxacin significantly reduced translocation in ascitic
      shocked rats in comparison with nondecontaminated ascitic shocked rats (31
      percent vs. 69 percent, P = .038). This effect was due mainly to a reduction of
      gram-negative BT (O percent vs. 37 percent, P = .008). In addition, norfloxacin
      prevented translocation in healthy shocked rats. Accordingly, aerobic gram
      negative bacteria disappeared from fecal flora in all rats administered
      norfloxacin, except for Klebsiella species in one control rat. Cecal severe
      submucosal edema, chronic inflammatory infiltrate, and intestinal
      lymphangiectasia were significantly more frequent in ascitic rats than in control
      rats. Intestinal mucosal injury related with HS, particularly subepithelial cecal
      edema, was observed only in ascitic shocked rats. In conclusion, HS increases the
      incidence of BT both in ascitic cirrhotic and healthy rats. Norfloxacin reduces
      significantly the incidence of translocation after shock, especially in those
      cases caused by aerobic gram-negative bacilli.

PMID- 8666333
TI  - Kupffer cell inactivation prevents lipopolysaccharide-induced structural changes
      in the rat liver sinusoid: an electron-microscopic study.
AB  - Scanning and transmission electron-microscopic examination of the rat liver
      sinusoid was performed in this study after in vivo treatment of rats with gram
      negative bacterial lipopolysaccharide (LPS, 1 mg/Kg(-1) body weight), with or
      without pretreatment with gadolinium chloride (GdCl3 10 mg(Kg(-1) body weight).
      Twenty-seven and 48 hours after GdCl3 administration, to inactivate/eliminate
      part of the Kupffer cell population, a decrease in the number of visualized
      Kupffer cells was observed, without evident effects on the sinusoidal endothelial
      cell or on the hepatocyte. Three and 24 hours after its administration, LPS
      produced ultrastructural changes in the sinusoid characterized by morphological
      evidence of Kupffer cell activation (i.e., swelling and expanded philopodia
      anchoring the Kupffer cell to the luminal surface of the sinusoidal wall), and a
      marked decrease in the population of endothelial cell fenestration. The reduction
      in the number of fenestrae was associated with a change in the diameter of
      fenestrae and can be interpreted as a component of the "capillarization" process
      of the hepatic sinusoid. Such ultrastructural changes were prevented by the
      administration of GdCl3 24 hours before LPS injection. Hence, these findings
      suggest that LPS-induced structural changes in the liver sinusoid are mediated by
      an LPS-induced Kupffer cell activation. Coupled with previous experimental data,
      showing similar effects of GdCl3 on one of the hepatic sinusoidal endothelial
      cell (SEC) functions, i.e., hyaluronan scavenging, the data presented in this
      study strongly support the view that Kupffer cells modulate both the hepatic
      SEC's functional as well as ultrastructural properties.

PMID- 8666334
TI  - Interleukin 1 beta markedly stimulates nitric oxide formation in the absence of
      other cytokines or lipopolysaccharide in primary cultured rat hepatocytes but not
      in Kupffer cells.
AB  - To investigate whether a single inflammatory cytokine could stimulate nitric
      oxide formation in the absence of other cytokines or lipopolysaccharide (LPS), NO
      was measured by the redox chemiluminescence method in primary cultured rat
      hepatocytes and in rat Kupffer cells. Interleukin (IL) 1 beta, but neither IL-6,
      tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), nor LPS
      stimulated NO formation in a dose-dependent manner and induced half-maximal
      effects at 30 pmol/L. Maximal stimulation was achieved at 12 to 16 hours after
      the addition of 1I nmol/L of IL-1 beta, and was 50- to 60-fold above basal levels
      in rat hepatocytes. The combined effect of these cytokines with LPS or IFN-gamma
      on NO formation was also examined. Neither LPS nor IFN-gamma affected the IL-1
      beta-induced NO formation. TNF-alpha, however, stimulated IL-1 beta-induced NO
      formation, while IL-6 inhibited it, although independently these cytokines had no
      effect on NO formation. None of the cytokines tested stimulated NO formation in
      cultured rat Kupffer cells. In hepatocytes, the NO formation induced by IL-l beta
      was blocked by both the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L
      NMMA) and by IL-1 receptor antagonist (IL-1ra). Furthermore, IL-1 beta markedly
      increased NOS activity, and this increase in activity was accompanied by the
      expression of inducible NOS (iNOS) messenger RNA (mRNA). This study clearly
      demonstrated that IL-1 beta markedly stimulates NO formation in hepatocytes, in
      the absence of other cytokines or LPS.

PMID- 8666335
TI  - Nitric oxide is not involved in hepatocyte killing by neutrophils activated by N
      formyl-methionyl-leucylphenylalanine or phorbol myristate acetate in vitro.
AB  - Polymorphonuclear leukocytes (PMNS) have been implicated as cellular mediators of
      hepatic injury in models of inflammation in vivo. In vitro, hepatocyte killing by
      activated PMNs is mediated in part by proteases, but the role of nitric oxide is
      unknown. NO is produced by PMNs and hepatocytes and can act either to damage or
      protect in various models of toxicity. Therefore, we tested the hypothesis that
      NO is important in PMN-mediated hepatocyte killing in vitro. Freshly isolated
      hepatocytes from rat liver and PMNs elicited from rat peritoneum were cultured
      together or alone for 16 hours. Both cell types spontaneously released NO,
      estimated as its stable breakdown product, nitrite. Accumulation of nitrite in
      medium from hepatocyte cultures was augmented threefold by incubation with L
      arginine and was completely inhibited by treatment with the nitric oxide synthase
      (NOS) inhibitor NG-methyl-L-arginine (NMA). Nitrite release in PMN cultures was
      unaffected by L-arginine addition and only partially inhibited by NMA. In
      PMN:hepatocyte cocultures (10:1), accumulation of nitrite was additive relative
      to cells cultured separately. Incubation with NMA blocked nitrite production
      completely in cocultures, whereas L-arginine caused a two-fold increase in
      nitrite. Addition of PMN stimulants, N-formyl-methionyl-leucyl-phenylalanine
      (FMLP), or phorbol myristate acetate (PMA), caused increased release of alanine
      aminotransferase (ALT) activity into medium from hepatocytes cultured with PMNs
      but not from hepatocytes cultured alone; this indicated that injury to
      hepatocytes was due to activated PMNS. However, neither FMLP nor PMA
      significantly altered nitrite release from cocultures. Despite the alterations in
      NO production induced by addition of NMA or L-arginine, neither agent altered the
      release of ALT from hepatocytes in coculture with activated PMNs. Thus, PMNs and
      hepatocytes provided NO in vitro, but neither suppression nor elevation of NO
      production affected PMN-mediated hepatocyte killing. Accordingly, NO is not
      involved in the mechanisms by which FMLP-or PMA-stimulated PMNs mediate
      hepatocyte injury in vitro.

PMID- 8666336
TI  - Contribution of immune response to the hepatic fibrosis induced by porcine serum.
AB  - To investigate whether hepatic fibrosis induced by porcine serum in rats is
      caused by an immune reaction to porcine serum, rats that were immunologically
      tolerant exclusively to porcine serum were subjected to the repeated injection of
      porcine serum over a long period. This porcine serum-tolerant group consisted of
      15 Wistar rats that had been injected intraperitoneally with porcine serum twice
      a week from the first postnatal day for 18 weeks. The control group consisted of
      16 Wistar rats, aged 8 weeks, that were injected intraperitoneally with porcine
      serum twice a week for 10 weeks. Livers were fixed and examined by light
      microscopy. The serum of each rat was subjected to indirect enzyme-linked
      immunosorbent assay (ELISA) to measure the level of antibody to porcine albumin.
      In addition, immunohistochemical staining for ED1 was performed on untreated
      normal and porcine serum-induced fibrotic rat livers to examine the distribution
      of macrophages and their precursors, the monocytes. All rats in the tolerant
      group showed an extremely low antibody level (x = 68.27 +/- 4.53), and none
      (0/15) developed hepatic fibrosis. The majority of rats in the control group
      showed a very high antibody level (x = 1242.19 +/- 201.15); 75 percent (12/16)
      developed hepatic fibrosis. Data indicate that, despite the prolonged, repeated
      injections of porcine serum, if an immune response to porcine serum does not
      occur, the rats do not develop hepatic fibrosis. The porcine serum-tolerant rats
      developed hepatic fibrosis after 4 weeks of CCl4 treatment, indicating that
      injection of porcine serum into neonatal rats did not cause anergy of
      fibrogenesis, thereby preventing the animal from developing hepatic fibrosis. In
      normal rat liver, ED1-positive cells, which include nearly all Kupffer cells,
      were located pre-dominantly in the periportal area. In fibrotic rat liver, ED1
      positive cells aggregated prominently in the newly formed and advanced connective
      tissue septa developed mainly between the neighboring central veins, and in
      fibrotic parts of the liver capsule. Aggregation of ED1-positive cells was rarely
      observed in nonfibrotic parts of the liver capsule. The difference between normal
      and fibrotic rat liver in distribution of EDl-positive cells suggests an
      involvement of macrophages in fibrogenesis and septum formation. In conclusion,
      our study showed a significant contribution by the immune response to porcine
      serum antigens leading to porcine serum-induced rat hepatic fibrosis--processes
      in which macrophages may be important. This study may lead to an understanding of
      the mechanism responsible for this form of experimental hepatic fibrosis.

PMID- 8666337
TI  - Synthesis of insulinlike growth factor binding proteins and of the acid-labile
      subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in
      cocultures: regulation by insulin, insulinlike growth factor, and growth hormone.
AB  - The adult liver is the main source of circulating insulinlike growth factors
      (IGFs) and their serum binding proteins (IGFBPs) including the acid-labile
      subunit (ALS), a component of the ternary binding protein complex. Within the
      liver, the biosynthesis of individual proteins has been attributed to different
      cell populations, e.g., that of ALS to hepatocytes and that of IGFBP-3 to
      nonparenchymal cells. Ligand and immunoblotting as well as Northern blotting
      analyses were used to study synthesis of IGFBPs and their hormonal regulation in
      cultured adult rat hepatocytes, Kupffer cells (KCs), and cocultures. In
      hepatocytes, synthesis of IGFBP-1, -2, and -4 was observed; insulin and IGF-I
      decreased that of IGFBP-1, and -2 while increasing that of IGFBP-4. KCs
      synthesized IGFBP-2, and -3, insulin and IGF-I showing no effect. In cocultures,
      however, synthesis of IGFBP-3 was stimulated by insulin and IGF-I. By
      immunocytochemistry IGFBP-3 biosynthesis was localized to KCs exclusively. When
      pore membranes were used for separation of hepatocytes and KCs in coculture, this
      insulin-stimulatory action on IGFBP-3 synthesis was preserved. Growth hormone
      (GH) did not affect biosynthesis of IGFBPs. Expression of ALS was localized in
      hepatocytes only. Insulin, IGF-I, and GH increased ALS expression. It can be
      concluded that biosynthesis of individual IGFBPs and of ALS are compartmentalized
      in adult rat liver and are distinctly regulated by insulin, IGF-I, and GH. The
      insulin-dependent stimulation of IGFBP-3 synthesis in KCs appears to require a
      diffusable mediator derived from hepatocytes.

PMID- 8666338
TI  - Assessment of microchimerism in rat liver transplantation by polymerase chain
      reaction.
AB  - Mixed chimerism has been demonstrated in organ transplant recipients surviving
      over a long period. However, little is known about the fate and movements of
      donor cells following liver transplantation. In this study, using rat male-to
      female liver transplantation, we assessed microchimerism by semiquantitative
      polymerase chain reaction (PCR). A PCR specific for the Y-chromosome (sex
      determining region Y [Sry]) allowed the distinction of small amounts of male
      cells in a large excess of female cells. Nonimmunosuppressed Lewis recipients of
      Lewis liver grafts survived >60 days, and donor cells were detected in peripheral
      blood up to day 60 in four of six recipients. All immunosuppressed Lewis
      recipients survived for 60 days, and the donor cells were detected up to day 60.
      Semiquantitative PCR demonstrated that in immunosuppressed Lewis recipients
      surviving >60 days with no acute rejection episode, the donor-to-recipient cell
      ratio remained >1:1,000. In nonimmunosuppressed Lewis recipients of ACI liver
      allografts, donor cells in peripheral blood decreased rapidly by day 7. In
      immunosuppressed Lewis recipients of ACI liver allografts, donor cells were
      detected for longer periods, in proportion to the amount and duration of FK506
      (Fujisawa Pharmaceutical Co., Osaka, Japan) administered. However, in recipients
      with deteriorating function due to ongoing rejection, small amounts (0.01
      percent) of donor cells were detected. Our results indicate that the Sry-specific
      PCR is useful for assessing microchimerism following rat liver transplantation,
      and demonstrate correlation between microchimerism and graft outcome; high-level
      microchimerism (>O.l percent) correlated well with graft acceptance, whereas low
      level microchimerism (<O.01 percent) did not.

PMID- 8666339
TI  - Persistent sex differences in growth control of early rat liver lesions are
      programmed during promotion in the resistant hepatocyte model.
AB  - The effects of gonadal hormones on several parameters associated with sex
      differentiated promotion in the resistant hepatocyte (RH) model were studied.
      Male and female rats were initiated with diethylnitrosamine and promoted with 2
      acetylaminofluorene (2-AAF) and partial hepatectomy [correction of hepatecomy]
      (PH). Before promotion, some female rats were ovariectomized, with or without
      receiving subcutaneous testosterone implants. Rats were killed either at the time
      of cessation of 2-AAF treatment or 2 weeks later. Ovariectomy decreased the
      messenger RNA (mRNA) expression of the female-specific cytochrome P450 2C12
      (CYP2C12) at the time of PH, but did not increase the male-specific CYP2C11.
      Testosterone treatment further decreased CYP2C12 and induced CYP2C11 to the level
      in male liver. Hepatic foci positive for the placental form of glutathione-S
      transferase (GST-P) were larger in male than in female rats. Ovariectomy did not
      affect the size of foci, whereas testosterone treatment increased the size to the
      male level. At the time of cessation of 2-AAF treatment, the labeling index,
      determined as cells staining for proliferating cell nuclear antigen, was higher
      in foci of males and testosterone-treated females than in foci from females with
      or without ovariectomy, whereas the labeling index in the surrounding hepatocytes
      was lower in males and testosterone-treated females. Two weeks later, the sex
      differences in labeling index were still present in foci, but no differences were
      observed in the surrounding hepatocytes. An elevated c-myc expression was
      observed in nodules isolated 3 weeks after PH from males and testosterone-treated
      females, but not in nodules from intact females. In conclusion, ovarian hormones
      did not affect promotion in the RH-model, whereas testosterone administration to
      ovariectomized females masculinized growth hormone-regulated hepatic parameters
      and response to promotion.

PMID- 8666340
TI  - Transforming growth factor beta 1-induced cell death in preneoplastic foci of rat
      liver and sensitization by the antiestrogen tamoxifen.
AB  - Previous studies have shown 5- to 10-fold higher rates of apoptosis in prestages
      of liver cancer (putative preneoplastic cell foci [PPF]) than in unaltered liver;
      fasting or withdrawal of tumor promoters enhanced apoptosis even further. We
      studied whether transforming growth factor beta 1 (TGF-beta 1), an inducer of
      apoptosis in normal liver, might be involved in induction of apoptosis in PPF.
      PPF were produced in 7-week-old female Sprague-Dawley rats with a single oral
      dose of the genotoxic carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). At 24
      weeks of age, TGF-beta 1 was injected into animals (40 micro g/kg intravenously)
      either once and they were killed 4 hours later (single-dose experiment) or eight
      times at 24-hour intervals and they were killed 24 hours after the last
      administration (multiple-dose experiment). Further subgroups received daily
      subcutaneous injections of tamoxifen (TAM) (8 mg/kg) for 4 consecutive weeks
      before TGF-beta 1 treatment. In normal liver, the apoptosis incidence was low in
      solvent- and TAM-only-treated animals, in the single- as well as the multiple
      dose experiment. TGF-beta 1, increased the apoptosis incidence severalfold, and
      the combined administration of TGF-beta 1 with TAM caused a further strong
      increase. The already-elevated basal apoptotic incidence in PPF was further
      increased by TGF-beta 1, and particularly by TGF-beta 1 plus TAM treatments,
      which resulted in a reduction of foci number and size. In summary, these results
      show that TGF-beta 1 can induce apoptosis in PPF. This apoptosis-inducing
      activity is strongly enhanced by the additional treatment with the antiestrogen
      TAM, which by itself does not have any cell death-inducing effect in the liver or
      PPF. The elevated apoptotic activity of PPF in response to TGF-beta 1 can lead to
      a selective reduction of the liver load with preneoplastic cells.

PMID- 8666341
TI  - Impact of essential fatty acid deficiency on hepatic sterol metabolism in rats.
AB  - The major aim of the current investigation was to define whether essential fatty
      acid (EFA) deficiency modifies the intrahepatic metabolism and biliary output of
      sterols in rats. EFA-deficient diet caused an impoverishment in linoleic,
      arachidonic, and docosahexaenoic acids, and a marked enrichment in the
      eicosatrienoic acid of the plasma, liver, and hepatic microsomes. During a short
      term of biliary drainage, a significant decline of the pool size of biliary
      sterols was noted in EFA-deficient rats compared with control rats. To assess the
      biosynthesis of biliary components, the common bile duct was cannulated and the
      pool size depleted (24 hours). Subsequently, a 6-hour bile collection disclosed a
      significant decrease (nmoles/min/g liver) in bile acids (4.8 +/- 0.3 vs. 8.4 +/-
      0.7, P < .005), cholesterol (0.26 +/- 0.01 vs. 0.34 +/- 0.02, P < .05), and
      phospholipids (1.49 +/- 0.11 vs. 2.82 +/- 0.32, P < .005) in EFA-deficient rats
      compared with controls (n = 6/group). When cholesterogenesis was measured by the
      incorporation of [14C]acetate and 3H20 into cholesterol, using liver slices, it
      was also found to be significantly (P < .001) reduced in EFA-deficient rats. The
      activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate
      limiting enzyme in cholesterol biosynthesis, was consistently lower (80 percent,
      P < .001) in EFA-deficient rats. In parallel experiments, the direct measurement
      of microsomal acyl-CoA:cholesterol acyl-transferase (ACAT) showed a decrease
      averaging 52 percent (P < .001). This is in striking contrast to the elevated
      activity (157 percent, P < .005) of cholesterol 7 alpha-hydroxylase, the rate
      limiting enzyme in bile acid biosynthesis. Current experiments also suggest that
      the enzyme regulation involving phosphorylation and dephosphorylation is modified
      by EFA deficiency. Among the structural alterations observed in the morphology of
      hepatocytes in EFA-deficient rats, the lumen of bile canaliculi was reduced in
      size. These results underline the importance of EFA in the major mechanisms
      involved in the maintenance of hepatocyte sterol balance.

PMID- 8666342
TI  - The role of a purinergic P2z receptor in calcium-dependent cell killing of
      isolated rat hepatocytes by extracellular adenosine triphosphate.
AB  - Extracellular adenosine triphosphate (ATP o) (0.4 mmol/L), a P2-purinergic
      receptor agonist, induces cytolysis in several cell types including isolated rat
      hepatocytes. In this study, we investigated the P2-receptor involved in ATP o
      induced, Ca2+-dependent cytotoxicity in hepatocytes. Pretreatment of hepatocytes
      with oxidized ATP, a P2z-receptor antagonist, or complexation of ATP(4-) (the
      agonist for the P2z-receptor) with an excess of Mg2+, prevented ATP o-induced
      cell death. Both protective treatments also prevented the development of a
      sustained high intracellular Ca2+ concentration as well as the subsequent
      accumulation of inorganic phosphate (Pi). The P2Z-receptor agonist 3'-O-'(4
      benzoylbenzoyl)-ATP (BzATP) was twofold more potent than ATP in eliciting
      cytolysis, which was preceded by a sustained high intracellular Ca2+
      concentration; pretreatment with oxidized ATP prevented both the increase in the
      intracellular Ca2+ concentration and cell death. Prevention of ATP o-induced cell
      death, as well as the increases in the intracellular Ca2+ concentration and
      inorganic phosphate (Pi) was also achieved by decreasing the pH o to 6.9.
      Together the findings indicate that Ca2+-dependent cell killing by extracellular
      ATP in hepatocytes is mediated by a P2Z-receptor. The cytolytic effects
      correlated specifically with a secondary "late" increase in the intracellular
      Ca2+ concentration.

PMID- 8666343
TI  - n-Butyrate induces plasminogen activator inhibitor type 1 messenger RNA in
      cultured Hep G2 cells.
AB  - n-Butyrate, a short-chain aliphatic carboxylic acid with pleiotropic actions, is
      present at high concentrations in the portal circulation and thus may play an
      important role in the regulation of specific gene expression in the mammalian
      liver. We report here that n-butyrate can increase substantially the level of
      plasminogen activator inhibitor type 1 (PAI-1) messenger RNA (mRNA) in Hep G2
      cells, up to eightfold above control cultures. Maximal effects occurred at a
      concentration of 3 mmol/L n-butyrate and with a treatment period of 8 to 12
      hours. Increases in PAI-1 mRNA were accompanied by modest increases (twofold) in
      the encoded protein as assessed by specific enzyme-linked immunosorbent assay and
      by [35S]methionine incorporation into immunoprecipitable PAI-1 in the culture
      medium. Nuclear run-on studies showed that the rate of transcription of the PAI-1
      gene did not appear altered by treatment with 3 mmol/L n-butyrate for 6 hours.
      The increases in steady-state PAI-1 mRNA caused by exposure to n-butyrate can be
      blocked by cycloheximide. Enhanced stability of mature PAI-1 transcript could not
      be demonstrated in Hep G2 cells treated with the carboxylic acid. We have
      reported previously that n-butyrate can reduce the level of beta-galactoside
      alpha 2,6-sialyltransferase expression in Hep G2 cells. That effect was
      attenuated with inhibitors of protein and RNA synthesis and was mediated at the
      post-transcriptional level. Thus, n-butyrate can influence the expression of
      multiple genes in this hepatoblastoma cell through its actions on events that
      appear to be posttranscriptional. These observations may be relevant to the
      normal physiology of the mammalian liver because of the high concentrations of n
      butyrate and related compounds to which the organ is ordinarily exposed.

PMID- 8666345
TI  - A comparison of the effect of inducers on the expression of glutathione-S
      transferases in the liver of the intact rat and in hepatocytes in primary
      culture.
AB  - Recently, we used human hepatocytes in primary culture to study the effects of
      inducers of glutathione-S-transferases (GSTs) in the expectation that information
      obtained can be used to predict the value of particular inducers for use in the
      chemoprevention of cancer and other toxicities. However, in vitro human studies
      cannot readily be confirmed by studies in vivo. This problem does not arise in
      experimental animals. In the current studies, the response of male rat
      hepatocytes in primary culture to the following inducers of GST isoenzymes has
      been determined: 3-methylcholanthrene (MC); phenobarbital (PB); 1,2-dithiole-3
      thione and its 5-(2-pyrazinyl)-4-methyl derivative, oltipraz (OPZ), and the
      results have been compared with induction obtained in livers of MC- and OPZ
      treated rats. Each type of inducer was found to elicit a different response. In
      vitro, phenobarbital increased messenger RNA (mRNA) levels of subunits 1b and 3
      after 12 and 72 hours, respectively; MC had a rapid effect on GST alpha class
      mRNAs (bringing about increase after only 2 hours of treatment), increased
      subunit 7 mRNA slightly, and had no effect on mu class mRNAs; dithiolethiones
      induced both subunit lb and 7 mRNAs after 4 hours and, to a much lower extent,
      subunit 3 mRNA after 72 hours. In vivo, MC induced significantly both subunit lb
      and 7 mRNAs whereas OPZ increased significantly subunits lb, 3 and 7 mRNA levels,
      and to a lower extent those of subunit 2, after 3 days and beyond to at least 5
      days of treatment. Results obtained in mRNA studies were confirmed by high
      pressure liquid chromatography (HPLC) analysis of GST subunits. HPLC also showed
      an induction of subunit 10 at the protein level of which the mRNA was not
      analyzed. Our results show that rat hepatocytes in primary culture prove to be a
      good model for the effect of inducers on both the expression of GST mRNA and
      protein levels in the rat liver in vivo. The demonstration of this good
      correlation in the rat with respect to increases gives support for the use of
      human hepatocytes for predictive studies of chemoprotection in human
      pharmacology.

PMID- 8666344
TI  - Acetaldehyde and malondialdehyde react together to generate distinct protein
      adducts in the liver during long-term ethanol administration.
AB  - Acetaldehyde and the lipid peroxidation-derived aldehyde malondialdehyde (MDA),
      are reactive compounds that are generated during ethanol metabolism in the liver,
      and both aldehydes have been shown to be capable of binding to proteins and
      forming stable adducts. Because similar concentrations of MDA and acetaldehyde
      can coexist in the liver during ethanol oxidation, protein adduct formation in
      the presence of both of these aldehydes was studied under both in vitro and in
      vivo conditions. When proteins were incubated in the presence of both MDA and
      acetaldehyde, MDA caused a marked and concentration-dependent increase in the
      stable binding of acetaldehyde to proteins. Maximum stimulation of binding
      occurred at approximately a fourfold molar excess of MDA relative to acetaldehyde
      when concentrations of 1.0 mmol/L and 0.1 mmol/L were tested. The formation of
      highly fluorescent product or products was associated with the MDA stimulation of
      acetaldehyde binding, indicating that new and distinct products were being
      generated. These hybrid adducts of MDA and acetaldehyde have been designated as
      MAA adducts. An affinity-purified polyclonal antibody was produced that
      specifically recognized MAA epitopes on proteins and did not cross-react with
      carrier proteins or proteins modified with either acetaldehyde or MDA alone. A
      quantitative competitive enzyme-linked immunosorbent assay (ELISA) was developed
      and detected the presence of MAA-modified proteins in liver cytosol from ethanol
      fed rats but not in pair-fed controls. Quantification of the data from the
      competitive ELISA indicated the presence of approximately 75 pmoles protein-bound
      MAA per milligram liver cytosol proteins of the ethanol-fed animals. These
      results indicate that acetaldehyde and MDA can react together in a synergistic
      manner and generate hybrid adducts (MAA-adducts) and further suggest that MAA
      adducts may represent a major species of adducts formed in the liver during
      ethanol metabolism in vivo.

PMID- 8666346
TI  - Hepatic mucosal mast cell hyperplasia in rats with secondary biliary cirrhosis.
AB  - Mast cells have been shown to play a role in many chronic inflammatory and
      fibrotic disorders. However, their possible contribution to the pathological
      changes that occur in liver cirrhosis is unknown. To explore this, we examined
      whether changes in hepatic mast cell number and mediator content were associated
      with fibrotic changes in experimental biliary cirrhosis. Rats were studied 7, 14,
      or 21 days after bile duct resection (BDR). Hepatic mast cells were identified by
      histochemical and immunohistochemical stains. Rat mast cell protease II (RMCP
      II), a marker of mast cell degranulation, was measured in liver by enzyme-linked
      immunosorbent assay. Hepatic collagen deposition was assessed by Sirius Red F3BA
      staining. In day 21 BDR rats, there was a one- to twofold increase (P < .001) in
      the number of hepatic mast cells, but this was not observed in day 7 or 14 BDR
      rats. Mild fibrotic changes were noted in BDR rat livers as early as 7 days after
      induction of cholestasis. Significant expansion and organization of fibrous
      tissue had occurred in day 14 BDR rats which progressed to bridging fibrosis by
      day 21. Liver RMCP-II levels were decreased by 50 percent (P < .05) and mast cell
      degranulation was apparent as shown by histamine immunostaining. These results
      suggest that hepatic mast cell hyperplasia and degranulation occur during
      prolonged cholestasis in the rat. Although these changes do not correlate with
      the onset of hepatic fibrosis, they do occur at a time during which there is
      significant deposition and organization extracellular matrix elements. Hepatic
      mast cells, by releasing profibrogenic mediators, may contribute to fibrotic
      changes in biliary cirrhosis.

PMID- 8666347
TI  - Ultracentrifugation systematically overestimates vesicular cholesterol levels in
      bile.
AB  - To accurately determine the cholesterol (Ch) distribution between mixed micelles
      and vesicles in lithogenic bile, both ultracentrifugation and gel chromatography
      with the correct intermixed micellar/vesicular bile salt concentration (IMC) have
      been proposed. We have systematically compared both separation techniques with
      physiological model biles to ascertain their quantitative separation ability.
      After determination of optimal ultra-centrifugation conditions in systems
      containing only micelles or vesicles, Ch-supersaturated model biles [3-10 g/dL,
      10 mol percent Ch, taurocholate (TC)]/([TC + egg yolk phosphatidylcholine (EYPC)]
      = 0.6 and 0.7) were adjusted to a density of 1.03 g/mL, and ultracentrifuged at
      42,000 rpm and 37 degrees C for 13 hours. Identical model biles were subjected to
      gel chromatography with the correct IMC, either directly or after remixing and
      incubation at 37 degrees C after ultracentrifugation. By ultracentrifugation, 31
      percent +/- 2 percent (TC/(TC + EYPC) = 0.6) and 40 percent +/- 5 percent (TC/(TC
      + EYPC) = 0.7) of total Ch were found in vesicles (Ch/EYPC molar ratios = 1.0 and
      1.3, respectively). However, by gel chromatography, only 19 percent +/- 2 percent
      (Ch/EYPC = 1.0) and 22 percent +/- 2 percent (Ch/EYPC = 1.5) of total Ch were
      found in the corresponding biles. Gel chromatography of biles (TC/(TC + EYPC) =
      0.7) ultracentrifuged for various durations showed a progressive increase in
      vesicular Ch to 41 percent after 13 hours. On incubation for 11.5 hours after
      ultracentrifugation, vesicular Ch decreased to 31 percent, thus approaching the
      initial (gel chromatography) value. Quasielastic light scattering also
      demonstrated formation of vesicles in ultracentrifuged Ch-unsaturated model bile
      (cholesterol saturation index (CSI) approximately 0.97). As compared with gel
      chromatography, ultracentrifugation systematically elevates vesicular Ch,
      possibly because of induced shifts in lipids between lipid aggregates caused by
      variation in local bile salt concentration. Because ultracentrifugation can alter
      the phases present in bile, gel chromatography with the correct IMC more
      accurately represents the distribution of Ch in biliary lipid aggregates.

PMID- 8666348
TI  - Defect of multidrug-resistance 3 gene expression in a subtype of progressive
      familial intrahepatic cholestasis.
AB  - Disruption of the murine mdr2 (multidrug-resistance) gene, which encodes a
      phosphatidylcholine flippase, leads to a hepatic disorder because of loss of
      biliary phospholipid secretion. Among the hereditary human cholestasis, a subtype
      of progressive familial intrahepatic cholestasis with high gamma
      glutamyltranspeptidase (GGT) serum activity shares histological, biochemical, and
      genetic features with mice lacking mdr2 gene expression (mdr2 -/- mice). No MDR3
      (human mdr2 homolog) messenger RNA (mRNA) was detected by Northern blotting in
      the liver of a patient suffering from this form of PFIC, and the biliary
      phospholipid level in a second patient was substantially decreased. Thus, the
      absence of the MDR3 P-glycoprotein may be responsible for this type of PFIC,
      which, as in the murine model, may be due to a toxic effect of bile acids on the
      biliary epithelium in absence of biliary phospholipids.

PMID- 8666349
TI  - Actions of cytokines on the immune response and viral interactions: an overview.

PMID- 8666350
TI  - Meta-analysis: an introduction and point of view.

PMID- 8666351
TI  - A scavenger that really scavenges is better in the liver than in the artery.

PMID- 8666352
TI  - Can interferon alfa treatment prevent hepatocellular carcinoma in patients with
      chronic hepatitis C infection and compensated cirrhosis?

PMID- 8666353
TI  - How to diagnose autoimmune hepatitis in systemic lupus erythematosus?

PMID- 8666354
TI  - Subcutaneous octreotide for the prevention of early variceal rebleeding.

PMID- 8666355
TI  - Donor selection for liver transplantation.

PMID- 8666356
TI  - Cefotaxime in the treatment of spontaneous bacterial peritonitis.

PMID- 8666357
TI  - Low malignant potential tumors of the ovary: does microinvasion matter?

PMID- 8666358
TI  - Use of human tissue blocks for research. Association of Directors of Anatomic and
      Surgical Pathology.

PMID- 8666359
TI  - Microinvasion in low malignant potential tumors of the ovary.
AB  - The presence of microinvasion (Mi) has not previously been investigated in
      nonserous low malignant potential (LMP) tumors of the ovary. In serous LMP tumors
      (SLMP), Mi has not worsened the prognosis compared with usual SLMP in previous
      reports. In a retrospective clinicopathologic review of 126 cases of serous and
      mucinous LMP (MLMP) tumors of the ovary, the authors identified 14 cases with Mi:
      seven of 72 SLMP, four of 44 mucinous intestinal LMP (MILMP), and three of 10
      mucinous mullerian LMP (MMLMP). Tumors with Mi resembled usual LMP histologically
      except for small foci (up to 0.2 cm) in the stroma consisting predominantly of
      single cells or small clusters of cells, sometimes in a cribriform pattern. In
      SLMP-Mi, the cells had eosinophilic cytoplasm, and the stromal reaction was
      minimal/absent. In MILMP-Mi and MMLMP-Mi, nuclear staining was paler; the stroma
      often showed a fibrous reaction or edema, especially in MILMP-Mi. All 14 patients
      had follow-up (2.2 to 18.6 years) and were without evidence of disease. Careful
      screening of both mucinous and serous ovarian LMP can show Mi. Mi foci should be
      distinguished from true stromal invasion, pseudoinvasion, endothelial cells,
      decidual cells and histiocytes, and pseudomyxoma in mucinous LMP. Mi does not
      seem to worsen prognosis in MLMP and SLMP tumors of the ovary.

PMID- 8666360
TI  - Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi
      between expert pathologists.
AB  - The reliability of a diagnostic test depends on the reproducibility of the
      result. Many clinical diagnostic tests can be quantified with established ranges
      and standard deviations. Other tests are more subjective, such as those that
      depend on analysis of a visual image with an increased possibility of variance in
      the result. To study this variance, the authors analyzed the performance of
      expert pathologists in the interpretation of cutaneous melanocytic tumors. A
      panel of expert pathologists was convened to review anatomic pathology specimens
      from melanocytic tumors. Each pathologist submitted five specimens, from which 37
      were selected for review. Only one slide was used for each case. All specimens
      were interpreted by each pathologist without consultation with each other. In
      addition to standard diagnostic terms, each specimen was designated as benign,
      malignant, or indeterminate. Statistical analysis was used to determine the
      degree of concordance. The combined kappa statistic for the eight observers and
      three possible outcomes (benign, malignant, or indeterminate) was 0.50. A kappa
      statistic of this magnitude, is defined as being moderate. In 62% of the
      specimens, there was unanimous agreement or only one discordant designation.
      Thirty-eight percent had two or more discordant interpretations. No single
      pathologist had a disproportionate number of discordant designations. This study
      mimics the consultation practice of anatomic pathology and shows the variability
      and discordance in diagnostic language and designation of biological behavior.
      The results suggest the criteria for the diagnosis of melanomas and melanocytic
      nevi need to be refined and more consistently applied.

PMID- 8666361
TI  - Defects of the respiratory chain in oxyphil and chief cells of the normal
      parathyroid and in hyperfunction.
AB  - Immunohistochemical detection of complex HIII (ubiquinone- cytochrome-c
      oxidoreductase) and complex IV (cytochrome-c-oxidase) of the respiratory chain
      was performed in parathyroids of 164 humans with normal renal function (group I)
      and in 55 patients with chronic renal insufficiency (group II) obtained at
      autopsy. In group I, 33 of the 164 cases showed defects of the respiratory chain
      (20%). Eighty-five percent of the defects occurred in advanced age (> 50 years).
      In group II, 39 of 55 cases (70%) had defects, and about 70% of the defects
      occurred after age 50. In both groups, more than 80% of the defects were
      localized in oxyphil cell nodules. However, not every oxyphil nodule was
      involved. In group I, selective defects of complex IV predominated and were found
      in 47 of 86 defects (55%). Combined defects of complexes III and IV were present
      in 25 of 86 defects (29%). In contrast, in group II combined defects predominated
      and were found in 45% (107 of 240 defects), whereas single defects of complex IV
      existed in 38% (93 of 240 defects). The frequency of selective defects of complex
      III was about 16% to 17% in both groups. In situ hybridization and PCR studies
      for the detection of the common deletion (4.977 base pairs) and of various point
      mutations of mitochondrial of (m)DNA revealed no consistent molecular genetic
      abnormalities. A point mutation in the tRNALeu(UUR) at nucleotide (nt) 3.260 was
      found in only one probe. The results show that defects of the respiratory chain
      occur already in normal parathyroids, most probably during cell aging, especially
      in oxyphil cells and at a higher rate in hyperfunction. The high predominance of
      respiratory chain defects in oxyphil cells and their random distribution favors
      mutations of mtDNA as a possible cause of oxyphilic cell transformation and of
      the respiratory chain defects. However, the mutations of mtDNA in the
      parathyroids are apparently different from those in other ageing tissues.

PMID- 8666362
TI  - p53 and MDM2 immunostaining in pulmonary blastomas and bronchogenic carcinomas.
AB  - Pulmonary blastomas (PBs) are rare primary malignancies that include adult types:
      biphasic pulmonary blastoma (BPB) and well-differentiated fetal adenocarcinoma
      (WDFA); and childhood type: pleuropulmonary blastoma (PPB). Their pathogenesis
      and relationship to bronchogenic carcinoma (BCA) are controversial. To determine
      whether or not PB share molecular pathological features with BCA, the authors
      immunostained three BPB, three WDFA, three PPB, and 80 standard BCA for p53
      protein and MDM2 protein, gene products believed to be significant in the
      pathogenesis of BCA. Paraffin-embedded tissue sections were immunostained with
      monoclonal antibody to p53 and MDM2 proteins. Strong intranuclear staining in
      greater than 10% of cells was considered positive. Three (50%) BPB and WDFA
      stained for p53 and five (83%) for MDM2. None of the PPB stained for p53, and one
      PPB did not stain for either p53 or MDM2. Five of six adult type PB occurred in
      smokers, whereas none of the PPB was associated with smoking. Seventy-five (94%)
      of the BCA stained for MDM2 and 46 (61%) for p53. Immunostaining patterns for p53
      and MDM2 in adult types of PB, and not PPB, appear similar to those for BCA. This
      may suggest that adult type PB, but not childhood PB, have a similar pathogenesis
      to BCA.

PMID- 8666363
TI  - Immunolocalization of glycoprotein A-80 in prostatic carcinoma and prostatic
      intraepithelial neoplasia.
AB  - A-80 is a mucin-like glycoprotein associated with exocrine differentiation that
      shows little or no expression in normal exocrine cells and typical adenomas, but
      is upregulated in dysplasia and adenocarcinoma of certain organs. Its expression
      has not been systematically examined in prostatic adenocarcinoma and its putative
      precursor, prostatic intraepithelial neoplasia (PIN). The authors applied a mouse
      monoclonal antibody against A-80 in paraffin-embedded sections from 103 cases of
      prostatic carcinoma, 26 cases of nodular hyperplasia, 7 autopsy samples from
      normal young adult prostates, and 12 fetal prostates. All but one cancer reacted,
      although expression was heterogeneous; 75 of 103 stained extensively (> 3+ on a 0
      to 5+ scale) and strongly. Staining extent and intensity were independent of
      tumor grade, and tended to be strong even when focal. Seventy-seven of 84 foci
      (92%) of high-grade PIN and 38 of 52 foci (73%) of low-grade PIN stained for A
      80; reactions were most extensive and intense in high grade PIN. Only 5 of 26
      cases (19%) of hyperplasia reacted, and this consisted of weak to moderate
      staining in sporadic cells; the remainder were negative. Normal adult prostatic
      epithelium did not express A-80 except for weak and inconsistent staining in foci
      of inflammation and infarction; atrophic glands were negative. Fetal prostate
      showed focally strong reactivity. These results indicate that A-80 is selectively
      expressed in most cases of intraepithelial neoplasia and prostate cancer, but is
      usually absent in benign and hyperplastic epithelium. The upregulation of
      glycoprotein A-80 in PIN and adenocarcinoma parallels observations in other
      organs, such as the breast and colon, suggesting that this is a significant
      oncodevelopmental molecule with potential clinical applications.

PMID- 8666364
TI  - Interlaboratory reproducibility of semiautomated cell cycle analysis of flow
      cytometry DNA-histograms obtained from fresh material of 1,295 breast cancer
      cases.
AB  - Conflicting prognostic results have been published as to the DNA variables, such
      as DNA ploidy, DNA index, and % S-phase cells for breast cancer patients. These
      variables can be obtained by interpreting DNA histograms by cell cycle analysis.
      Explanations for these conflicting results might be found on the level of the
      interpretation of the DNA histograms. In a previous study, the semi automated
      cell cycle analysis computer program MultiCycle (Phoenix Flow Systems, San Diego,
      CA) showed high intralaboratory reproducibility. However, what types of DNA
      histograms may cause disagreements was still unclear. The aim of this study was
      to determine the interlaboratory reproducibility of MultiCycle-based cell cycle
      analysis of 1,295 flow cytometric DNA histograms derived from fresh frozen breast
      cancer material and to clarify potential sources of interobserver variation when
      analyzing DNA histograms. DNA ploidy classification into diploid, hyperdiploid,
      tetraploid, hypertetraploid, and multiploid showed an interlaboratory agreement
      of 94% (kappa value = 0.92). The 6% discrepancies (n = 74) were caused by
      tetraploid peaks, as established in one laboratory, which shifted outside the
      tetraploid region on reanalysis by the other laboratory (37%), shoulders
      sometimes interpreted as peaks (24%), small peaks not always recognized as such
      (24%), fitting failures (10%), and overlooking of tetraploid peaks (5%).
      Furthermore, the cell cycle analysis variables showed variable reproducibility.
      The % S-phase cells of the first, second, and third cell cycle showed overall a
      moderate reproducibility (0.62 < or = R < or = 0.79), but the average % S-phase
      cells and the average aneuploid % S-phase cells were more reproducible with
      correlation coefficients of 0.89 and 0.81, respectively. The coefficient of
      variation of the G0/G1 peak of the first cell cycle, the DNA indices and the %
      diploid cells were highly reproducible (R > or = 0.94), and the % G2/M-phase
      cells of the first, second, and third cell cycle were poorly reproducible (0.22 <
      or = R < or = 0.68). When a cut-point was used at the mean value of 7% for the
      average % S-phase cells, the number of "threshold discrepancy cases" was 6%.
      Sources of variation for cell cycle analysis were variations in the debris
      correction procedures, disagreement about the modes of the aneuploid peaks,
      disagreement about small peaks, shoulders sometimes interpreted as peaks, and
      overlooking of tetraploid peaks.

PMID- 8666365
TI  - Prognostic significance of biomarkers (c-erbB-2, p53, proliferating cell nuclear
      antigen, and DNA content) in salivary duct carcinoma.
AB  - Salivary duct carcinoma (SDC), a rare neoplasm of the major salivary glands, is a
      high-grade carcinoma with a predilection for elderly men. The authors
      investigated the prognostic role of p53, c-erbB2, proliferating cell nuclear
      antigen (PCNA), and DNA flow cytometry in a pathobiological evaluation of a
      cohort of 30 patients with these neoplasms. The patient group comprised 24 men
      and 6 women, with ages ranging from 22 to 87 years (mean = 61 years). Twenty
      eight tumors were located in the parotid gland and two in the submandibular
      gland. Tumor size ranged from 1.0 to 8.0 cm (mean = 3.48 cm). Regional metastases
      were found in 73.3% (22 patients), systemic metastases in 43.3% (13 patients),
      and recurrences in 8 (26.6%) patients. DNA aneuploidy was found in 18 tumors
      (58.0%) and DNA diploidy in 12 (42%), with proliferative fractions ranging from
      8.60% to 15.5 (mean = 10.6%). p53 protein nuclear immunostaining was positive in
      56.6% and c-erbB2 overexpression was observed in 63% of the tumors. PCNA
      positivity ranged from 16.5% to 91.0%, with a mean of 49.5%. p53
      immunopositivity, DNA aneuploidy, high growth, and proliferative fractions by
      PCNA and flow cytometry did not correlate with patient outcome. These results
      indicate that tumor size (P = .05), distant metastasis (P = .006), and C-erbB2
      amplification (P = .04) are independent prognostic parameters in patients with
      salivary duct carcinoma.

PMID- 8666366
TI  - The role of p53 mutation and protein expression in primary and recurrent adenoid
      cystic carcinoma.
AB  - Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin
      having a propensity for spread by direct extension or perineural invasion with
      frequent recurrences. Previous reports have shown that tumor behavior is not
      always predicted by histological pattern or stage. Little is known of the role of
      p53 tumor suppressor gene mutation and altered protein expression with respect to
      ACC pathobiology and recurrence. The authors analyzed a group of 14 ACC specimens
      (seven primary; seven recurrent) from 13 patients treated between 1987 to 1993.
      Formalin-fixed, paraffin-embedded specimens were reviewed and subjected to,
      immunohistochemistry (p53, DO-7, DAKO, Nutley, NJ; and WAF-I, Ab-1, Oncogene
      Sciences, Uniondale, NY) on 4-microm-thick histological sections as a prelude to
      p53 genotyping. In one case, sequential material representing primary and
      recurrent tumor was analyzed. Each tumor specimen was topographically genotyped
      for p53 point mutational change. Minute tissue samples were removed from
      unstained sections, polymerase chain reaction (PCR) amplified for p53 exons 5 to
      8, and then underwent direct DNA sequencing. Six of seven primary ACCs were p53
      immunostain negative. Four of seven recurrent (57%) ACCs were p53 immunopositive.
      These tumors showed varying degrees of p53 immunopositivity ranging from diffuse,
      intense staining of most tumor cells (n = 1) to interspersed, strongly positive
      cells mixed with predominantly p53 immunonegative cells (n = 4). All tumors were
      WAF-I immunostain negative. Two of the most immunopositive recurrent tumors each
      manifested a single type of p53 point mutation detected by p53 DNA genotyping
      (p53 exon 5:codon 175 and p53 exon 6:codon 199). In the case in which both
      primary and recurrent tumor was available, only the recurrent tumor contained
      point mutational damage. Negative immunostaining for p53 in primary ACC suggests
      that p53 mutation is not important in early events involving development of this
      tumor. In contrast, the frequent presence of p53-positive cells and the detection
      of point mutations in recurrent ACC suggests that p53 alterations are involved in
      later stages of tumor progression, important in the phenomenon of ACC recurrence.

PMID- 8666367
TI  - Correlation of genetic and immunodetection of TP53 mutations in malignant and
      benign prostate tissues.
AB  - The prognostic value of the p53 gene (TP53), the most commonly mutated gene in
      human cancers, has been well established for several cancer types. However,
      because varying frequencies of TP53 mutations have been identified in prostatic
      adenocarcinoma (CaP) by genetic and immunohistochemical (IHC) studies, the role
      of TP53 in CaP tumorigenesis is currently unresolved. These experimental
      discrepancies could be caused by tissue heterogeneity within prostatic neoplasms,
      variations in experimental protocols, or other factors. Thus, the goal of this
      study was to develop a reliable IHC approach for the detection of p53 in archival
      prostate tissue. The authors evaluated four p53 antibodies, CM-1, 1801, DO-1, and
      DO-7, for their ability to reveal p53. They chose two reference CaP cell lines,
      26 patient specimens (including eight benign prostatic hyperplasias (BPHs), 16
      CaPs, and two lymph node metastases), one prostate and nine kidney cell lines for
      p53 analysis. The TP53 status of these samples was characterized using single
      strand conformational polymorphism (SSCP) analysis of RNA/PCR products and
      sequencing. IHC detection of p53 was markedly enhanced by using the combination
      of microwave heat-induced antigen unmasking and a cocktail of the DO-1 and DO-7
      antibodies. This approach identified 14 of 15 (93%) cell lines and patient
      samples having TP53 missense mutations in the exons 5 to 8 region. Of the 21
      patient samples and cell lines that were either normal by SSCP or expressed p53
      mutations that are not expected to stain, 18 (86%) were immunonegative. Because
      of this good correlation between molecular and IHC analysis, this approach may
      help to resolve the uncertainty about TP53 in CaP tumorigenesis.

PMID- 8666368
TI  - Bethesda classification of cervicovaginal smears: reproducibility and viral
      correlates.
AB  - Fifty-five cervicovaginal smears from women with squamous intraepithelial lesions
      (SILs) were independently evaluated on two separate occasions by four
      cytopathologists using a binary classification system (the Bethesda system).
      Smears were categorized as low-grade (LSIL) or high-grade (HSIL) using previously
      published criteria. All women had subsequent cervical biopsies containing human
      papillomavirus (HPV) DNA amplified with the polymerase chain reaction and typed
      by restriction fragment polymorphism analysis. Three or more observers agreed on
      classification in 49 of 55 cases (87%); unanimous diagnoses were rendered in 31
      cases (56%). Interobserver and intraobserver reproducibility ranged from fair to
      near-excellent (kappa values 0.40 to 0.63; 0.63 to 0.74, respectively). HPV types
      included HPV 16 (27%), 18 (7%), 31 (9%), 35 (4%), 39 (4%), 6 (10%), 11 (2%),
      novel types (30%), and multiple types (4%). High-risk HPV types (16, 18, 31, 35,
      and 39) were significantly associated (P = .03) with consensus HSIL diagnoses
      (agreement of three or more observers). This was primarily because of the strong
      association of HPV 16 with HSIL (P = .001). After excluding HPV 16, the other
      high-risk HPV types (18, 31, 35, and 39) were no longer significantly associated
      with consensus HSIL diagnoses (P > .5). Conversely, LSIL diagnoses were
      significantly associated with non-high-risk HPV types (all HPV types except 16,
      18, 31, 35, and 39; P = .006). Binary cytological classification of
      cervicovaginal SILs is reproducible among cytopathologists. Such classification
      correlates well with most low-risk HPV types and with the prototypic high-risk
      HPV 16 but not with other high-risk HPV types.

PMID- 8666369
TI  - p53 gene mutations in human astrocytic brain tumors including pilocytic
      astrocytomas.
AB  - Recent molecular biological studies have shown evidence for a distinct
      pathogenesis of pilocytic astrocytomas based on alterations other than mutations
      of the tumor suppressor gene p53. To prove these data, the authors screened a
      series of 42 astrocytic human brain tumors with a relatively high proportion
      (16.6%) of the pilocytic variant for the presence of p53 mutations, using the
      polymerase chain reaction (PCR) and single-strand conformation polymorphism
      (SSCP) analysis, followed by DNA sequencing. Mutations were found in one of seven
      (14.3%) pilocytic astrocytomas, in one of 18 (5.6%) low grade astrocytomas, and
      in one of four (25%) anaplastic astrocytomas, but in none of 13 glioblastomas.
      Sites of missense mutations were in exon 8 (codons 281 and 282), and exon 5
      (codon 151). Silent mutation was found in exon 9 (codon 324), which was related
      to pilocytic astrocytoma. This is, to the authors' knowledge, the first report
      that shows a p53 mutation in pilocytic astrocytomas. However, the p53 mutation
      was only found in one of seven tumors of this entity and was a silent mutation,
      which does not lead to change of amino acids. Thus, the significance of this
      alteration for the development of this special tumor type seems to be low.
      Nevertheless, it may be a sign of genetic instability and is thus suggested to be
      of certain pathogenetic relevance. The p53 findings concerning the other tumors
      are in accordance with the view of p53 gene mutations to be early events in
      astrocytoma formation.

PMID- 8666370
TI  - Detection of the t(2;5)(p23;q35) chromosomal translocation in large B-cell
      lymphomas other than anaplastic large cell lymphoma.
AB  - In general, the large cell lymphomas are a cytogenetically heterogeneous group of
      diseases, and the cytogenetic findings do not correlate with morphological
      findings in this group of malignant lymphomas. The CD30-positive anaplastic large
      cell lymphomas, however, are thought to be an exception, with the t(2;5) reported
      to correlate with the morphological changes of this disease entity. A subgroup of
      Hodgkin's disease cases have been reported by some investigators to have the
      t(2;5) translocation, leading to speculation that these two diseases are related.
      In the current study, the authors used a sensitive reverse transcriptase
      polymerase chain reaction (RT-PCR) methodology to evaluate the frequency of
      t(2;5) in 33 cases of large cell lymphoma, of B lineage, other than anaplastic
      large cell lymphoma. The authors detected evidence of t(2;5) in four of the cases
      (12%), a frequency similar to that of the authors' previous study of cases of
      CD30 positive anaplastic large cell lymphoma. Three of the positive large B-cell
      lymphoma cases were CD30 negative and were morphologically indistinguishable from
      the cases without evidence of t(2;5). The fourth case had a subpopulation of CD30
      positive cells but also did not have morphological features of anaplastic large
      cell lymphoma. These results would suggest that t(2;5) is not restricted to cases
      of malignant lymphomas with anaplastic morphology or to CD30 expression.

PMID- 8666371
TI  - Adrenal 4-binding protein in common epithelial and metastatic tumors of the
      ovary.
AB  - Adrenal 4-binding protein (Ad4BP) is a transcription factor that regulates the
      expression of steroidogenic enzymes. Ovarian tumors other than sex cord stromal
      tumors are occasionally associated with functioning stroma or hormonal
      abnormalities. To determine the steroidogenic potential of these tumors, the
      authors determined the immunohistochemical distribution of Ad4BP in 75 patients
      with primary common epithelial tumors (20 cystadenomas, 15 carcinomas of low
      malignant potential, and 40 carcinomas), and seven patients with metastatic
      carcinoma of the ovary. Ad4BP immunoreactivity was observed in intratumoral
      stromal cells in 3 of 15 (20%) carcinomas of low malignant potential, 26 of 40
      (65%) carcinomas, and three of seven (43%) metastatic carcinomas. Ad4BP
      immunoreactivity was not observed in the stroma of cystadenomas. Among the
      positive cases, Ad4BP-positive stromal cells were particularly distributed
      adjacent to invasive carcinomatous glands. Among ovarian carcinomas, mucinous
      carcinoma showed a significantly higher number of Ad4BP-positive intratumoral
      stromal cells than did other histological types. Results suggest that invasion of
      primary or metastatic carcinoma into the ovarian stroma, especially in the case
      of mucinous carcinoma, may render the stromal cells to acquire the potential of
      metabolizing and synthesizing steroid hormones.

PMID- 8666372
TI  - Histogenesis of primary liver carcinomas: strengths and weaknesses of cytokeratin
      profile and albumin mRNA detection.
AB  - To assess the utility of cytokeratin (CK) profile and albumin mRNA detection (as
      revealed by in situ hybridization) in the differential diagnosis of primary liver
      carcinomas (PLCs) we evaluated a series of surgically resected PLCs, comprising
      20 "pure" hepatocellular carcinomas (HCCs) (10 well-differentiated, 10 poorly
      differentiated), 15 cholangiocarcinomas (CCs) (6 peripheral, 5 hilar, and 4 major
      duct ones) and 10 hepatocholangio-carcinomas (HCC-CCs). 11 of 20 (55%) of the
      pure HCCs expressed CKs of pure hepatocytic lineage (CK 8 and CK 18); 2 of 10
      (20%) of the HCC-CCs displayed only hepatocytic profile, whereas 12 of 15 (80%)
      of the CCs evidenced mature bile duct cell phenotype (CK 8, CK 18, CK 7, CK 19).
      All HCCs expressed varying distributions of albumin mRNA, whereas 4 of 6 (67%)
      peripheral CCs showed cells with focal positivity for albumin mRNA. This suggests
      that the phenotypic expression of PLC cells are often not fixed, and in
      particular: (1) peripheral CCs have a different phenotype from hilar and large
      duct ones; (2) the CK profile and albumin mRNA expression in peripheral CCs show
      many similarities with those of some HCCs. Furthermore, the results show that a
      mixed biological phenotype (ie, CK 8, CK 18 and CK 7 and/or CK 19) can be found
      both among morphologically pure HCCs and peripheral CCs, suggesting that these
      two forms could share a common histogenesis. We think that special attention
      should be given to cases in which CK profile and albumin mRNA reveal mixed
      phenotype, as these tumors could have different biological behavior and respond
      differently to therapy.

PMID- 8666373
TI  - Pituitary adenoma presenting as sinonasal tumor: pitfalls in diagnosis.
AB  - Pituitary adenomas may cause significant difficulties in histological diagnosis
      when presenting in unusual sites either as extension from an intrasellar lesion
      or as ectopic tumor. Three such cases, involving the sinonasal tract are
      described herein, and the differential diagnoses are discussed. Two of them were
      invasive intrasellar macroadenomas that presented as unilateral nasal polyp, and
      one was an ectopic pituitary adenoma involving the sphenoid sinus. There was
      notable cellular atypia in two cases, with nuclear pleomorphism, giant cells,
      chromatin clumping, and distinct nucleoli, leading to serious consideration of
      the possibility of poorly differentiated carcinoma. In none of the cases was the
      diagnosis of pituitary adenoma suspected clinically. The clues to diagnosis were
      an endocrine growth pattern comprising tumor cells arranged in packets, ribbons,
      or rosettes, with prominent delicate vascularized stroma; a high index of
      suspicion; and immunohistochemical showing of neuroendocrine markers and
      pituitary hormones in the tumor cells. A correct diagnosis is important because
      in contrast to neuroendocrine carcinoma as a whole or to poorly differentiated
      carcinoma, pituitary neoplasms have a much more favorable prognosis and a low
      metastatic potential.

PMID- 8666374
TI  - Gliofibroma: a distinct entity or a subtype of desmoplastic astrocytoma?
AB  - Gliofibromas are rarely encountered astrocytic neoplasms characterized by an
      admixture of astrocytic and fibroblastic cell components. The exact nature of
      these rare tumors are still a matter of considerable debate. This article reports
      a case of gliofibroma occurring in a 3-month-old boy. The astrocytic component of
      the tumor stained diffusely positive for glial fibrillary acidic protein (GFAP)
      and S-100 protein. Prominent reticulin staining was observed within the
      fibroblastic component of the tumor. The MIB1 labeling index (positive number of
      tumor cells divided by total tumor cells counted X 100) was low (0.9), supporting
      the general slow growth of these tumors. Immunohistochemical staining with
      antibody against p53 protein was negative. Gliofibromas seem to be a low-grade
      variant of an astrocytoma that shares many features with other desmoplastic
      astrocytic neoplasms (desmoplastic infantile astrocytoma, desmoplastic infantile
      ganglioglioma) including a generally favorable prognosis.

PMID- 8666375
TI  - In situ amplification and detection of HIV-1 DNA in fixed pediatric AIDS brain
      tissue.
AB  - To examine whether latent infection by HIV-1 occurs in the central nervous
      system, we optimized a procedure for amplification and detection of HIV-1 DNA in
      situ, in formalin-fixed brain tissue from a child with severe HIV-1-associated
      progressive encephalopathy and severe HIV-1 encephalitis. By the use of a two
      step technique, which involved polymerase chain reaction with incorporation of
      digoxigenin-labeled nucleotides followed by in situ hybridization with
      biotinylated probes, we found infection of numerous mononuclear cells and
      astrocytes in the cerebral white matter as well as of perineuronal satellite
      cells in basal ganglia, but not of neurons. Following PCR amplification, nuclear
      signal was found in 10 to 20 times as many cells as in parallel, control
      experiments using conventional, unamplified in situ hybridization.

PMID- 8666376
TI  - Adaptation of mitotic scoring of breast carcinomas.

PMID- 8666377
TI  - A comparison of linkage disequilibrium measures for fine-scale mapping.
AB  - Linkage mapping generally localizes disease genes to 1- to 2-cM regions of
      chromosomes. In theory, further refinement of location can be achieved by
      population-based studies of linkage disequilibrium between disease locus alleles
      and alleles at adjacent markers. One approach to localization, dubbed simple
      disequilibrium mapping, is to determine the relative location of the disease
      locus by plotting disequilibrium values against marker locations. We investigate
      the simple mapping properties of five disequilibrium measures, the correlation
      coefficient delta, Lewontin's D', the robust formulation of the population
      attributable risk delta, Yule's Q, and Kaplan and Weir's proportional difference
      d under the assumption of initial complete disequilibrium between disease and
      marker loci. The studies indicate that delta is a superior measure for fine
      mapping because it is directly related to the recombination fraction between the
      disease and the marker loci, and it is invariant when disease haplotypes are
      sampled at a rate higher than their population frequencies, as in a case-control
      study. D' yields results comparable to those of delta in many realistic settings.
      Of the remaining three measures, Q, delta, and d, Q yields the best results. From
      simulations of short-term evolution, all measures show some sensitivity to marker
      allele frequencies; however, as predicted by analytic results, Q, delta, and d
      exhibit the greatest sensitivity to variation in marker allele frequencies across
      loci.

PMID- 8666378
TI  - Gene conversion between red and defective green opsin gene in blue cone
      monochromacy.
AB  - Blue cone monochromacy is an X-linked condition in which the function of both the
      red pigment gene (RCP) and the green pigment gene (GCP) is impaired. Blue cone
      monochromacy can be due to a red/green gene array rearrangement existing of a
      single red/green hybrid gene and an inactivating C203R point mutation in GCP. We
      describe here a family with blue cone monochromacy due to the presence of the
      C203R mutation in both RCP and GCP. The flanking sequences of the C203R mutation
      in exon 4 of RCP were characteristic for GCP, indicating that this mutation was
      transferred from GCP into RCP by gene conversion.

PMID- 8666379
TI  - Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and a novel
      overlapping gene.
AB  - The PMS2 gene encodes a protein that is involved in DNA mismatch repair and is
      mutated in a subset of patients with hereditary nonpolyposis colon cancer
      (HNPCC). The previously published PMS2 cDNA sequence lacks an upstream in-frame
      stop codon preceding the presumptive initiating methionine. To evaluate the 5'
      terminus of the PMS2 coding region further, we isolated additional cDNA clones,
      RT-PCR products, and the corresponding 5' genomic segment of the PMS2 locus. The
      PMS2 gene transcripts were found to have heterogeneous but colinear 5' termini,
      one of which contained an in-frame termination codon preceding the initiating
      methionine. In addition, a novel gene encoding a 34.5-kDa polypeptide was found
      to initiate transcriptionally within PMS2 from the opposite strand.

PMID- 8666381
TI  - Structure of the human myelin/oligodendrocyte glycoprotein gene and multiple
      alternative spliced isoforms.
AB  - Myelin/oligodendrocyte glycoprotein (MOG), a specific component of the central
      nervous system localized on the outermost lamellae of mature myelin, is a member
      of the immunoglobulin superfamily. We report here the organization of the human
      MOG gene, which spans approximately 17 kb, and the characterization of six MOG
      mRNA splicing variants. The intron/exon structure of the human MOG gene confirmed
      the splicing pattern, supporting the hypothesis that mRNA isoforms could arise by
      alternative splicing of a single gene. In addition to the eight exons coding for
      the major. MOG isoform, the human MOG gene also contains, in the 3' region, a
      previously unknown alternatively spliced coding exon, VIA. Alternative
      utilization of two acceptor splicing sites for exon VIII could produce two
      different C-termini. The nucleotide sequences presented here may be a useful tool
      to study further possible involvement of the MOG gene in hereditary neurological
      disorders.

PMID- 8666380
TI  - Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14,
      encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin
      receptors.
AB  - We employed the polymerase chain reaction and genomic DNA library screening to
      clone novel human genes, GPR9 and GPR10, and a rat gene, GPR14. GPR9, GPR10, and
      GPR14 each encode G protein-coupled receptors. GPR10 and GPR14 are intronless
      within their coding regions, while GPR9 contains at least one intron. The
      receptor encoded by GPR9 shares the highest identity with human IL-8 receptor
      type B (38% overall and 53% in the transmembrane regions), followed by IL-8
      receptor type A (36% overall and 51% in the transmembrane domains). GPR10 encodes
      a receptor that shares highest identity with the neuropeptide Y receptor (31%
      overall and 46% in the transmembrane domains). The receptor encoded by GPR14
      shares highest identity with the somatostatin receptor SSTR 4 (27% overall and
      41% in the transmembrane domains). Fluorescence in situ hybridization analysis
      localized GPR9 to chromosome 8p11.2-p12 and GPR10 to chromosome 10q25.3-q26.

PMID- 8666382
TI  - CpG islands in human ZFX and ZFY and mouse Zfx genes: sequence similarities and
      methylation differences.
AB  - The human ZFX, human ZFY, and mouse Zfx genes have CpG islands near their 5;
      ends. These islands are typical in that they span about 1.5 kb, contain
      transcription initiation sites, and encompass some 5' untranslated exons and
      introns. However, comparitive nucleotide sequencing of these human and mouse
      islands provided evidence of evolutionary conservation to a degree unprecedented
      among mammalian 5' CpG islands. In one stretch of 165 nucleotides containing 19
      CpGs, mouse Zfx and human ZFX are identical to each other and differ from human
      ZFY at only 9 nucleotides. In contrast, we found no evidence of homologous CpG
      islands in the mouse Zfy genes, whose transcription is more circumscribed than
      that of human ZFX, human ZFY, and mouse Zfx. Using the isoschizomers HpaII and
      MspI to examine a highly conserved segment of the ZFX CpG island, we detected
      methylation on inactive mouse X chromosomes but not on inactive human X
      chromosomes. These observations parallel the previous findings that mouse Zfx
      undergoes X inactivation while human ZFX escapes it.

PMID- 8666383
TI  - Toward a cDNA map of the human genome.
AB  - Advances in the Human Genome Project are shaping the strategies for identifying
      the 50,000-100,000 human genes. High-resolution genetic maps of the human genome
      combined with sequencing herald an era of rapid regional definition of disease
      genes. However, only once their chromosome band location is known will the
      systematic partial sequencing of thousands of random cDNA clones provide the
      reagents for teh rapid assessment of the genes responsible for the inherited
      disorders. We now present an approach to the rapid determination of map position
      and therefore to the creation of a transcribed map of the human genome. Sensitive
      fluorescence in situ hybridization has been combined with high-resolution
      chromosome banding and random cDNA sequencing to map 41 cDNAs with an average
      insert size of <2 kb to single human chromosome bands. The result provide 15 new
      genes, with database and functional information, as candidates for human disease.
      These include the large extracellular signal-related kinase (HUMERK), the ERK
      activator kinase (PRKMK1), a new member of the RAS oncogene family, protein
      phosphatase 2 regulatory subunit B alpha isoform (PPP2R2A), and a novel human
      gene with very high homology to a plant membrane transport family. Further, an
      analysis of expressed genes associated with pseudogenes showed that by using
      these techniques, it is possible to detect accurately the transcribed locus
      within a multigene or processed pseudogene family in most cases. These findings
      suggest that direct cDNA mapping using fluorescence in situ hybridization
      provides an accurate and rapid approach to the definition of a transcribed map of
      the human genome. This low-cost, high-resolution (2-5 Mb) mapping greatly
      enhances the speed with which these genes can be subsequently assigned to
      contigs. This assignment provides a necessary first step in understanding the
      relationship of the genes to both acquired and inherited human diseases.

PMID- 8666384
TI  - The IL-9 receptor gene (IL9R): genomic structure, chromosomal localization in the
      pseudoautosomal region of the long arm of the sex chromosomes, and identification
      of IL9R pseudogenes at 9qter, 10pter, 16pter, and 18pter.
AB  - Cosmids containing the human IL-9 receptor (R) gene (IL9R) have been isolated
      from a genomic library using the IL9R cDNA as a probe. We have shown that the
      human IL9R cDNA as a probe. We have shown that hte human IL9R gene is composed of
      11 exons and 10 introns, stretching over approximately 17 kb, and is located
      within the pseudoautosomal region of the Xq and Yq chromosome, in the vicinity of
      the telomere. Analysis f the 5' flanking region revealed multiple transcription
      initiation sites as well as potential binding motifs for AP1, AP2, AP3, Sp1, and
      NF-kB, although this region lacks a TATA box. Using the human IL9R cosmid as a
      probe to perform fluorescence in situ hybridization, additional signals were
      identified in the subtelomeric regions of chromosomes 9q, 10p, 16p, and 18p. IL9R
      homologs located on chromosomes 16 and 10 were completely sequenced. Although
      they are similar to the IL9R gene (approximately 90% identity), none of these
      copies encodes a functional receptor: none of them contains sequences homologous
      to the 5' flanking region or exon 1 of the IL9R gene, and the remaining ORFs have
      been inactivated by various point mutations and deletions. Taken together, our
      results indicate that the IL9R gene is located at Xq28 and Yq12, in the long arm
      pseudoautosomal region, and that four IL9R pseudogenes are located on 9q34,
      10p15, 16p13.3, and 18p11.3, probably dispersed as the result of translocations
      during evolution.

PMID- 8666385
TI  - Expressed sequence tags from the long arm of human chromosome 21.
AB  - We isolated expressed sequence tags (ESTs) on the long arm of chromosome 21. The
      ESTs were mapped by PCR using a monochromosomal somatic-cell mapping panel. Of a
      total of 55 cDNAs, 30 mapped back uniquely to chromosome 21, 7 mapped back to
      other chromosomes including chromosome 21, 8 mapped back to chromosomes other
      than 21, and 10 could not be assigned using this methodology. The 30 chromosome
      21-specific markers so isolated represent useful EST markers. A rapid PCR-based
      method was used to delineate the expression pattern of these 30 pairs in
      different tissues.

PMID- 8666386
TI  - Sequence of human tryptophan 2,3-dioxygenase (TDO2): presence of a glucocorticoid
      response-like element composed of a GTT repeat and an intronic CCCCT repeat.
AB  - Abnormalities in serotonin levels have been implicated in a wide range of
      psychiatric disorders. Tryptophan 2,3-dioxygenase is the rate-limiting enzyme in
      the catabolism of tryptophan, the precursor of serotonin. As such it is a
      potential major candidate gene in psychiatric genetics. The regulatory, intron,
      and exon regions of the human TDO2 gene have been sequenced. Twelve exons were
      identified. The amino acid sequence of the enzyme was 88% homologous to that of
      the rat. Compared to the rat, the regulatory region of the human TDO2 gene had an
      insertion of approximately 1064 bp of random DNA beginning at -293 bp and
      extending to -1357 bp. This displaced the glucocorticoid response element (GRE)
      occurring at -1174 bp in the rat to -1500 in the human. The proximal GRE at -419
      in the rat was missing in the human. However, within the DNA insert there was a
      GRE-like microsatellite region containing multiple GTT repeats plus additional
      GT(n) sequences. This could produce several staggered regions of the sequence
      TGTTGTnnnTGTTGT similar to a GRE consensus sequence of TGTTCAnnnTGTTCT. The
      intron regions 5' and 3' to each exon were sequenced This showed a HIS --> Val
      mutation polymorphism in exon 7. Three introns, 1,5, and 6, were completely
      sequenced and examined for polymorphism. This identified two polymorphisms
      consisting of G -- >T and G --> A mutations 2 bp apart in intron 6. The 3' end of
      intron 5 showed an extensive CCCT pentanucleotide repeat that was markedly
      polymorphic. These polymorphisms allow the TDO2 gene to be examined for a
      possible role in psychiatric disorders.

PMID- 8666387
TI  - Human genomic characterization of a novel locus-specific repetitive sequence.
AB  - A novel human chromosome locus-specific repetitive sequence was identified and
      characterized using arbitrary PCR. The repeat monomer consensus sequence is 100
      bp long, and there are a minimum of 140 to 160 copies of the repetitive sequence
      per haploid human genome. The repetitive sequence is highly clustered on 20q12
      within a 200- to 400-kb region. The highly polymorphic repeat array is inherited
      in a stable Mendelian fashion. Hybridization analysis revealed detectable
      conservation of the repeated element only among hominoids and Old World monkeys,
      where repeat arrangements are also polymorphic.

PMID- 8666388
TI  - A novel PCR technique using Alu-specific primers to identify unknown flanking
      sequences from the human genome.
AB  - The rapid and reproducible identification of new cellular DNA sequences adjacent
      to known sequences is difficult to achieve with the currently available
      procedures. Here we describe a novel approach based on the polymerase chain
      reaction (PCR) using a primer specific to the known sequence and another directed
      to a human Alu repeat. To avoid undesirable amplifications between Alu sequences,
      primers are constructed with dUTPs and destroyed by uracil DNA glycosylase
      treatment after 10 initial cycles of amplification. Only desirable fragments are
      then further amplified with specific primers to the known region and to a tag
      sequence introduced in the Alu-specific primer. Using this protocol, we have
      successfully identified cellular sequences flanking integrated hepatitis B virus
      DNA from the human genome of three hepatoma tissues. The method enables a direct
      specific amplification without any ligation or nonspecific annealing steps as
      required by previous PCR-based protocols. This rapid and straightforward approach
      will be a powerful tool for the study of viral integration sites, but is also
      widely applicable to other studies of the human genome.

PMID- 8666389
TI  - A locus for axonal motor-sensory neuropathy with deafness and mental retardation
      maps to Xq24-q26.
AB  - DNA markers on the X chromosome were used to map the locus for an unusual form of
      X-linked recessive hereditary motor and sensory neuropathy with associated
      deafness and mental retardation in a three-generation family that was originally
      reported by Cowchock et al. (Am, J. Hum. Genet. 35: 85A, 1993; Am. J. Med. Genet.
      20: 307-315, 1985). This family included seven affected males, three obligate
      carrier females, and four unaffected males. The patients were severely affected
      within the first few years of life with distal weakness, muscle atrophy, sensory
      loss, areflexia, pes cavus, and hammer toes. Five of the seven affected males
      showed associated deafness, and three of these five individuals also presented
      with mental retardation or social developmental delay. Motor nerve conduction
      velocities in affected males were normal to mildly delayed, and sensory
      conduction was markedly abnormal. Heterozygous females were asymptomatic. Close
      linkage to the Xg blood group locus (Xp22) and the PGK locus (Xq13) was
      previously excluded in this family, while weak linkage of the disease gene to
      DXYS1 (XQ21.3) was suggested. Our current linkage studies and haplotype analysis
      of 19 microsatellite markers on the long arm of the X chromosome demonstrate that
      DXS425 (Xq24) and HPRT (Xq26.1) are flanking markers and that the disease gene is
      closely linked to the markers DXS1122, DXS994, DXS737, DXS1206, and DXS1047.

PMID- 8666390
TI  - Construction and characterization of a bovine bacterial artificial chromosome
      library.
AB  - A bacterial artificial chromosome (BAC) library has been constructed for use in
      bovine genome mapping using constructed for use in bovine genome mapping using
      the pBeloBAC11 vector. Currently, the library consists of 23,040 clones, which
      achieves a 70% probability (P=0.70) of the library containing a specific unique
      DNA sequence. Sixty thousand clones, or about three haploid bovine genomes, will
      be required to achieve a 95% probability (P=0.95) of containing a unique
      sequence. An average insert size of 146 kb was estimated from the analysis of 77
      randomly selected BAC clones produced by one or two rounds of size selection. The
      bovine DNA inserts proved to be very stable for at least 100 cell generations. No
      chimeric clones were detected among 11 large, size-selected BAC clones using
      fluorescence in situ hybridization (FISH) on metaphase bovine chromosomes. Thirty
      three of 46 (72%) sequences were present in the library in at least one copy,
      which is consistent with the estimated 70% probability of this library containing
      a unique DNA sequence. A BAC clone as sequence-tagged sites for genetic mapping.
      These markers cosegregated, and no recombinants were detected in 193 informative
      meioses. Plasmid end rescue and the inverse polymerase chain reaction methods
      were used to rescue both ends of this BAC clone, and chromosome walking was
      performed using PCR primers designed within the end region sequences. Based on
      our experimental results, the BAC system provides a very useful tool for complex
      genome analysis.

PMID- 8666391
TI  - cDNA cloning, molecular characterization, and chromosomal localization of
      NET(EPHT2), a human EPH-related receptor protein-tyrosine kinase gene
      preferentially expressed in brain.
AB  - By screening a human fetal brain cDNA expression library using a monoclonal anti
      phosphotyrosine antibody, we have isolated a cDNA clone encoding a receptor type
      protein-tyrosine kinase belonging to the EPH family, NET (neuronally expressed
      EPH-related tyrosine kinase). NET shows 87% homology in nucleotide sequence and
      99% homology in the deduced amino acid sequence to rat elk, suggesting that NET
      is the human homologue of elk. The NET gene is mapped to human chromosome 3q21
      q23 by PCR screening of a human-rodent somatic cell hybrid panel and by
      fluorescence in situ hybridization. Examination of NET mRNA expression in several
      human tissues has shown that the NET gene is expressed preferentially in brain as
      a 5-kb transcript. Steady-state levels of NET mRNA in human brain are greater in
      the midterm fetus than in the adult. Lower levels of NET mRNA are found in fetal
      kidney and adult skeletal muscle. The expression pattern of NET mRNA thus differs
      from that of elk, suggesting that these two gene products may perform distinct
      roles in human and rat. NET transcripts are detected in human NTera-2
      teratocarcinoma cells after retinoic acid-induced neuronal differentiation.
      Several human tumor cell lines derived from neuroectoderm including primitive
      neuroectodermal tumor, small cell lung carcinoma, and neuroblastoma also express
      NET transcripts. Since the NET mRNA expression in human brain is developmentally
      regulated and is induced during neuronal differentiation, NET potentially plays
      important roles in human neurogenesis.

PMID- 8666392
TI  - Different susceptibility to lung tumorigenesis in mice with an identical Kras2
      intron 2.
AB  - The A/J mouse strain is genetically susceptible to pulmonary tumorigenesis. We
      have performed a genetic linkage analysis to map pulmonary adenoma susceptibility
      (Pas) loci in an urethane-treated (A/J x Mus spretus) x C57BL/6J (ASB)
      interspecific testcross. In this interspecific cross we have confirmed our
      previous results in AC3F2 mice on the mapping of the Pas1 locus to the distal
      region of chromosome 6, near Kras2 (Nature Genetics 3: 132-136, 1993). The A/J
      and M. spretus strains differed at the Pas1 locus, with the M. spretus providing
      the resistant allele. In the latter strain, we studied the nucleotide sequence of
      a portion of the second intron of Kras2 that contains polymorphisms associated
      with lung tumor susceptibility in several inbred strains. The lung tumor
      resistant M. spretus strain had the same specific nucleotide sequence of
      susceptible strains. Mutations in codon 61 of Kras2 in urethane-induced lung
      tumors from ASF1 hybrids involved the A/J allele in all cases, while the M.
      spretus allele was never affected. Our results indicate that the M. spretus and
      A/J mice have an identical structure of the second intron of the Kras2 gene, but
      they differ in genetic susceptibility to pulmonary tumorigenesis and in
      mutability of their Kras2 allele.

PMID- 8666393
TI  - Mapping of four mouse genes encoding eye lens-specific structural, gap junction,
      and integral membrane proteins: Cryba1 (crystallin beta A3/A1), Crybb2
      (crystallin beta B2), Gja8 (MP70), and Lim2 (MP19).
AB  - Four genes encoding eye lens-specific proteins, potential candidate genes for
      congenital cataract (CC) mutations, were mapped in the mouse genome using a panel
      of somatic cell hybrids and DNAs from the EU-CIB (European Collaborative
      Interspecific Backcross). Two of them are lens fiber cell structural proteins:
      the Cryba1 locus encoding crystallinbetaA3/A1 maps to chromosome 11, 2.5 +/- 2.5
      cM distal to D11Mit31, and the Crybb2 locus encoding crystallinbetaB2 maps to
      chromosome 5, 9.1 +/- 4.3 cM distal to D5Mit88. The other two genes encode lens
      specific gap junction and integral membrane proteins, respectively: The Gja8
      locus encoding gap juction membrane channel protein alpha8, also called
      connexin50 or MP70, maps to chromosome 3, 11.9 +/- 5.0 cM distal to D3Mit22, and
      the Lim2 locus encoding lens intrinsic membrane protein 2, also called MP19, maps
      to chromosome 7, 2.5 +/- 2.5 cM proximal to Ngfg. All four map positions, when
      compared with the corresponding positions in human, lie within known regions of
      conserved synteny between mouse and human chromosomes.

PMID- 8666394
TI  - Localization of the human mitochondrial citrate transporter protein gene to
      chromosome 22Q11 in the DiGeorge syndrome critical region.
AB  - A high percentage of patients with DiGeorge syndrome and velo-cardio-facial
      syndrome have interstitial deletions on chromosome 22q11. The shortest region of
      overlap is currently estimated to be around 55 kb. Two segments of DNA from
      chromosome 22q11, located 160 kb apart, were cloned because they contained NotI
      restriction enzyme sites. In the current study we demonstrate that these segments
      are absent from chromosomes 22 carrying microdeletions of two different DiGeorge
      patients. Fluorescence in situ and Southern blot hybridization was further used
      to show that this locus is within the DiGeorge critical region. Phylogenetically
      conserved sequences adjacent to one human cell lines. cDNAs isolated with a probe
      from this segment showed it to contain the gene for teh human mitochondrial
      citrate transporter protein. Deletion of this gene in DiGeorge syndrome and
      velocardio-facial syndrome may contribute to the mental deficiency seen in the
      patients.

PMID- 8666395
TI  - Mapping the mouse dactylaplasia mutation, Dac, and a gene that controls its
      expression, mdac.
AB  - Dactylaplasia is an inherited mouse limb malformation whose manifestation is
      clearly dependent on the interaction of two genes and thus represents an
      excellent model system for studying such gene interactions in vivo. The Dac
      mutation is inherited as a semidominant trait and may be a model for some forms
      of human ectrodactyly. Heterozygotes show absence of digits on each foot; the
      long bones are normal. On the SM/Ckc background on which the mutation occurred,
      Dac homozygotes die around birth. We mapped Dac to the distal end of Chr 19 by
      backcross segregation analysis A closely linked marker was then used to
      distinguish +/+, Dac/+, and Dac/Dac genotypes of embryos and adults. When
      intercrossed with the NZB/BINJ strain, Dac homozygotes were shown to be viable
      and fertile, but had a more severe limb malformation (only a single remaining
      digit) than heterozygotes. Expression of the abnormal limb phenotypes of Dac/+
      and Dac/Dac mice also depends on homozygosity for a recessive allele of another
      unlinked gene, mdac, that is polymorphic among inbred mouse strains. We mapped
      mdac to the middle of Chr 13 by segregation analysis of both recombinant inbred
      strains and backcross progeny.

PMID- 8666396
TI  - Cloning of a new member of the insulin gene superfamily (INSL4) expressed in
      human placenta.
AB  - A new member of the insulin gene superfamily was identified by screening a
      subtracted cDNA library of first-trimester human placenta and, hence, was
      tentatively named early placenta insulin-like peptide (EPIL). In this paper, we
      report the cloning and sequencing of the EPIL cDNA and the EPIL gene (INSL4).
      Comparison of the deduced amino acid sequence of the early placenta insulin-like
      peptide revealed significant overall and structural homologies with members of
      the insulin-like hormone superfamily. Moreover, the organization of the early
      placenta insulin-like gene, which is composed of two exons and one intron, is
      similar to that of insulin and relaxin. By in situ hybridization, the INSL4 gene
      was assigned to band p24 of the short arm of chromosome 9. RT-PCR analysis of
      EPIL tissue distribution revealed that its transcripts are expressed in the
      placenta and uterus.

PMID- 8666397
TI  - The mouse homolog of the Wiskott-Aldrich syndrome protein (WASP) gene is highly
      conserved and maps near the scurfy (sf) mutation on the X chromosome.
AB  - The mouse WASP gene, the homolog of the gene mutated in Wiskott-Aldrich syndrome,
      has been isolated and sequenced. the predicted amino acid sequence is 86%
      identical to the human WASP sequence. A distinct feature of the mouse gene is an
      expanded polymorphic GGA trinucleotide repeat that codes for polyglycine and
      varies from 15 to 17 triplets in different Mus musculus strains. The genomic
      structure of the mouse WASP gene is expressed as an approximately 2.4-kb mRNA in
      thymus and spleen. Chromosomal mapping in an interspecific M. Musculus/M. spretus
      backcross placed the Wasp locus near the centromere of the mouse X chromosome,
      inseparable from Gata1, Tcfe3, and scurfy (sf). This localization makes Wasp a
      candidate for involvement in scurfy, a T cell-mediated fatal lymphoreticular
      disease of mice that has previously been proposed as a mouse homolog of Wiskott
      Aldrich syndrome. Northern analysis of sf tissue samples indicated the presence
      of WASP mRNA in liver and skin, presumably as a consequence of lymphocytic
      infiltration, but non abnormalities in the amount or size of mRNA present.

PMID- 8666398
TI  - YAC and cosmid contigs spanning the Batten disease (CLN3) region at 16p12.1
      p11.2.
AB  - A yeast artificial chromosome (YAC) contig has been constructed in 16p12.1-p11.2
      that encompasses three loci (D16S288, D16S299, and D16S298) closely linked to the
      gene causing Batten disease or juvenile-onset neuronal ceroid lipofuscinosis
      (CLN3). The physical map has been ordered using 42 sequence tagged sites. Four
      genes, interleukin-4 receptor (IL4R), phenol-preferring phenol sulfotransferase
      (STP), monoamine-preferring phenol sulfotransferase (STM), and sialophorin (SPN),
      have been mapped to the YAC contig. A partial genomic restriction map has been
      constructed to confirm the order and distances between D16S298, predicted to be
      the locus closest to CLN3. The overlapping genomic clones are a valuable resource
      for cloning the Batten gene (CLN3) and other genes in the region.

PMID- 8666399
TI  - Structure and evolution of the human IKBA gene.
AB  - IkappaBalpha belongs to a gene family whose members are characterized by their 6
      7 Ankyrin repeats, which allow them to interact with members of the Rel family of
      transcription factors. We have sequenced a human IkappaBalpha genomic clone to
      determine its gene structure. The human IkappaBalpha gene (IKBA) has six exons
      and five introns that span approximately 3.5 kb. This genomic organization is
      similar to that of other members of the Ankyrin gene family. The human IKBA gene
      shares similar intron/exon boundaries with the human BCL3 and NFKB2 genes, which
      is consistent with their conserved Ankyrin repeats. To examine further the
      evolutionary relationship between human IkappaBalpha and other members of its
      gene family, we performed a phylogenetic analysis. Although the resulting
      phylogenetic tree does not identify a common ancestor of the IkappaBalpha and
      other members of its gene family, it indicates that this family diverges into two
      groups based on structure and function.

PMID- 8666400
TI  - Construction of two YAC contigs in human Xp11.23-p11.22, one encompassing the
      loci OATL1, GATA, TFE3, and SYP, the other linking DXS255 to DXS146.
AB  - We have constructed two YAC contigs in the Xp11.23-p11.22 interval of the human X
      chromosome, a region that was previously poorly characterized. One contig, of at
      least 1.4 Mb, links the pseudogene OATL1 to the genes GATA1, TFE3, and SYP and
      also contains loci implicated in Wiskott-Aldrich syndrome and synovial sarcoma. A
      second contig, mapping proximal to the first, is estimated to be over 2.1 Mb and
      links the hypervariable locus DXS255 to DXS146, and also contains a chloride
      channel gene that is responsible for hereditary nephrolithiasis. We have used
      plasmid rescue, inverse PCR, and Alu-PCR to generate 20 novel markers from this
      region, 1 of which is polymorphic, and have positioned these relative to one
      another on the basis of YAC analysis. The order of previously known markers
      within our contigs, Xpter-OATL1-GATA-TFE3-SYP-DXS255146- Xcen, agrees with
      genomic pulsed-field maps of the region. In addition, we have constructed a rare
      cutter restriction map for a 710-kb region of the DXS255-DXS146 contig and have
      identified three CPG islands. These contigs and new markers will provide a useful
      resource for more detailed analysis of Xp11.23-p11.22, a region implicated in
      several genetic diseases.

PMID- 8666401
TI  - Integration of transcript and genetic maps of chromosome 16 at near-1-Mb
      resolution: demonstration of a "hot spot" for recombination at 16p12.
AB  - A single mapping resource, a mouse/human somatic cell panel with average distance
      between breakpoints of 1.2 Mb and a potential resolution of 1 Mb, has been
      utilized to integrate the genetic map and a transcript map of human chromosome
      16. This map includes 141 genetic markers and 200 genes and transcripts. The
      localization of four genes (CHEL3, TK2, TRG1, and MMP9) reported to map to
      chromosome 16 could not be confirmed, and for three of these localizations to
      other human chromosomes are reported. A correlation between genetic and physical
      distance over a region estimated to be 23 Mb on the short arm of chromosome 16
      identified an interval demonstrating a greatly increased rate of recombination
      where, in females, 1 cM is equivalent to a physical distance of 100 kb.

PMID- 8666402
TI  - An STS content map of human chromosome 11: localization of 910 YAC clones and 109
      islands.
AB  - Physical mapping of human chromosomes at a resolution of 100 kb to 1 Mb will
      provide important reagents for gene identification and framework templates for
      ultimately determining the complete DNA sequence. Sequence-tagged site (STS)
      content mapping, coupled with large fragment cloning in yeast artificial
      chromosomes, provides an efficient mechanism for producing first-generation, low
      resolution maps of human chromosomes. Previously, we produced a set of
      standardized STSs for human chromosome 11 regionally localized by fluorescence in
      situ hybridization or somatic cell hybrid analysis. In this paper, we used these
      as well as other STS content, and identify 109 islands spanning an estimated 218
      Mb on the 126-Mb chromosome. Since about 62% of the islands contain markers
      ordered on chromosome 11 by genetic or radiation hybrid analysis, this data set
      represents a first-order approximation of a physical map of human chromosome 11.
      This set of clones, contigs, and associated STSs will provide the material for
      the production of a continuous overlapping set of YACs as well for high
      resolution physical mapping based upon sampled and complete DNA sequencing.

PMID- 8666403
TI  - cDNA sequence, genomic organization, and evolutionary conservation of a novel
      gene from the WAGR region.
AB  - A new gene (239FB) with predominant and differential expression in fetal brain
      has recently been isolated from a chromosome 11p13-p14 boundary area near FSHB.
      The corresponding mRNA has an open reading frame of 294 amino acids, a 3'
      untranslated region of 1247 nucleotides, and a highly GC-rich 5' untranslated
      region. The coding and 3' UT sequence is specified by 6 exons within nearly 87 kb
      of isolated genomic locus. The 5' end region of the transcript maps adjacent to
      the only genomically defined CpG island in a chromosomal subregion that may be
      associated with part of the mental retardation of some WAGR (Wilms tumor,
      aniridia, genitourinary anomalies, and mental retardation) syndrome patients. In
      addition to nucleotide and amino acid similarity to an EST from a normalized
      infant brain cDNA library, the predicted protein has extensive similarity to two
      Caenorhabditis elegans polypeptides of, as yet, unknown function. The 239FB locus
      is, therefore, likely part of a family of genes with two members expressed in
      human brain. The extensive conservation of the predicted protein suggests a
      fundamental function of the gene product and will enable evaluation of the role
      of the 239FB gene in neurogenesis in model organisms.

PMID- 8666404
TI  - Cloning of a highly conserved human protein serine-threonine phosphatase gene
      from the glioma candidate region on chromosome 19q13.3.
AB  - Allelic loss studies have suggested that a glioma tumor suppressor gene resides
      in a 425-kb region of chromosome 19q, telomeric to D19S219 and centromeric to
      D19S112. Exon amplification of a cosmid contig spanning this region yielded four
      exons with high homology to a rat protein serine-threonine phosphatase from a
      cosmid approximately 100 kb telomeric to D19S219. Isolation of a near full-length
      cDNA from a human fetal brain cDNA library revealed a protein serine-threonine
      phosphatase with a tetratricopeptide motif, almost identical to human PPP5C (PP5)
      and highly homologous to rat PPT. Northern blotting demonstrated expression in
      most tissues, including brain. Primary and cultured gliomas were studied for
      genetic alterations in this gene using pulsed-field gel electrophoresis, routine
      Southern blots, and genomic DNA-and RNA-based single-strand conformation
      polymorphism analysis. Genomic alterations were were not detected in any of the
      gliomas, and all studied gliomas expressed the gene, suggesting that this
      phosphatase is not the putative chromosome 19q glioma tumor suppressor gene.

PMID- 8666405
TI  - Palmoplantar keratoderma in association with carcinoma of the esophagus maps to
      chromosome 17q distal to the keratin gene cluster.
AB  - Palmoplantar keratoderma is a group of hereditary disorders of keratinization
      involving hyperkeratosis of palms and soles. Two different forms of palmoplantar
      keratoderma have recently been shown to be caused by mutations in the body site
      specific keratin 9 gene and in the keratin 1 gene, respectively. Now we have
      analyzed a large German family with autosomal dominantly inherited palmoplantar
      keratoderma in association with carcinoma of the esophagus. Linkage to both the
      type I keratin gene cluster on chromosome 17q distal to the type I keratin genes.
      Two-point linkage data at D17S801 gave a lod score Zmax - 5.1 at theta = 0.00.
      Therefore, palmoplantar keratoderma is shown to be heterogeneous clinically as
      well as genetically and may be caused by mutations in keratins as well as in
      nonkeratins.

PMID- 8666406
TI  - The human SOX11 gene: cloning, chromosomal assignment and tissue expression.
AB  - The mammalian testis determining gene SRY contains an HMG box-related DNA binding
      motif. By analogy a family of genes related to SRY in the HMG domain have been
      called SOX (SRY box-related genes). We have cloned and characterized the human
      SOX11 gene using the partial cloning of both human and mouse SOX11 genes and
      mapped it to chromosome 1p25. The SOX11 sequence is strongly conserved with the
      chicken homologue and is related to SOX4. It contains several putative
      transcriptional either activator or repressor domains. SOX11 expression pattern
      is consistent with the hypothesis that this gene is important in the developing
      nervous system.

PMID- 8666407
TI  - Cloning and chromosomal localization of a mouse cDNA with homology to the
      Saccharomyces cerevisiae gene zuotin.
AB  - The eukaryotic DnaJ homologs form a family of proteins with diverse functions.
      One member of the family, the Saccharomyces cerevisiae gene zuotin, was isolated
      for its ability to bind Z-DNA. Here, we have isolated a mouse cDNA called ZRF1
      (for zuotin-related factor1) with significant homology to zuotin. The DnaJ domain
      and candidate phosphorylation sites of zuotin and ZRF1 are highly conserved. ZRF1
      gene is localized on chromosome 5. The structural similarity of zuotin and ZRF1
      suggests conservation of function of this DnaJ subfamily.

PMID- 8666408
TI  - The toxic milk mutation, tx, which results in a condition resembling Wilson
      disease in humans, is linked to mouse chromosome 8.

PMID- 8666409
TI  - Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3
      q23.1.

PMID- 8666411
TI  - Premarital screening of hemoglobinopathies: a pilot study in Turkey.
AB  - To identify premarital couples who are carriers for hemoglobinopathies, a
      screening study was conducted in one of the southern cities of Turkey. For 2,113
      couples, total blood count, Hb A2 and Hb F levels were determined and hemoglobin
      electrophoresis was performed. The frequency of Hb S was 4.6% and beta
      thalassemia 2.3%. In 35 of 2,113 prospective families, both partners were found
      to be carriers. During the 4-year follow-up period, prenatal diagnosis was sought
      in 10 pregnancies of these at-risk families. This study indicated that premarital
      screening is a very useful tool for detecting carrier couples. The immediate
      beneficial effect of this study was the application of prenatal hemoglobinopathy
      diagnosis from the first pregnancy.

PMID- 8666410
TI  - A noninvasive 'swish and spit' method for collecting nucleated cells for HLA
      typing by PCR in population studies.
AB  - Buccal-cell-derived DNA collected by a 'swish and spit' technique and blood
      derived DNA were compared for ease of collection, participant acceptance, utility
      and accuracy for HLA class II DR typing by the polymerase chain reaction with
      sequence-specific primers (PCR-SSP). The HLA class II DR typing results
      determined from DNA extracted by proteinase K digestion followed by
      phenol/chloroform extraction and ethanol precipitation from buccal cells and
      blood cells were identical for all subjects we studied (n = 10). Class II typing
      by PCR-SSP using DNA extracted from buccal cells stored at -20, 4, 25 or 37
      degrees C for 1 week was successful. The samples can be collected without medical
      supervision and are not affected by exposure to a variety of temperature
      conditions for up to 1 week. The stability of the buccal cell specimens to these
      extreme conditions demonstrates the utility of this 'swish and spit' technique
      for collecting nucleated cells for geographically dispersed large-scale
      population studies. Buccal-cell-derived DNA collected by a simple 'swish and
      spit' mouthwash technique is an excellent and practical substitute for blood
      derived DNA.

PMID- 8666412
TI  - Low frequency of PIM3 gene in patients with monoclonal gammopathies.
AB  - The distribution of PI (protease inhibitor) phenotypes and PI M subtypes was
      studied in 200 patients with monoclonal gammopathies and 320 healthy blood donors
      by isoelectric focusing in thin-layer polyacrylamide gels, pH range 4-5. The
      distribution of PI phenotypes and gene frequencies in the patients differed
      significantly from the corresponding values found in the blood donors, as shown
      by the chi 2 test (chi 2 = 16.5, p = 0.02 and chi 2 = 17.6, p = 0.0014,
      respectively). A lower frequency of the M3 variant was observed in patients, both
      in homozygous (PI M3) and heterozygous forms (PI M1M3 and PI M2M3). No
      significant difference between PIz allele frequencies in patients and healthy
      controls was found.

PMID- 8666414
TI  - Variation in genetic identity among relatives.
AB  - Genetic identity, or genetic relatedness, among relatives, is a key concept in
      kin recognition, which in turn is important in models for inclusive fitness and
      inbreeding avoidance. A mathematical definition is presented for the genetic
      identity based on the proportion of genome shared identical by descent by two
      relatives. The method of Guo [Am J Hum Genet 1995;56:1468-1476] is used to
      compute the variance of the genetic identity for various types of relationships.
      The method is versatile and can handle any kind of relationship. To illustrate
      the method, the standard errors of the genetic identity using published human
      genetic maps are computed.

PMID- 8666413
TI  - A previously unknown polymorphism located within the RB1 locus only present in
      Asian individuals.
AB  - Although the retinoblastoma susceptibility locus (RB1) spans some 180 kb in the
      human and has been fully sequenced, few polymorphisms within the locus have been
      identified and none have been shown to vary in allelic frequency in different
      populations. We have identified a previously unknown polymorphism within intron
      18 of the retinoblastoma susceptibility gene that is present in Asians but not in
      the other ethnic groups examined. This polymorphism eliminates a Tsp5091
      restriction enzyme site, making it easily detectable for use in linkage analysis
      and genetic population studies.

PMID- 8666415
TI  - HLA-DQ alpha genotype and allele frequencies in an Austrian population.
AB  - The HLA-DQ alpha system is used to an increasing degree in forensic serology, for
      stain investigations, and paternity cases. Therefore samples which were taken
      from 85 unrelated persons living in Austria were examined. DNA was analyzed by
      polymerase chain reaction (PCR) amplification followed by hybridization to allele
      specific oligonucleotide probes in a reversed dot-blot technique after extraction
      with phenol/chloroform. HLA-DQ alpha allele frequencies of German, Finnish,
      Dutch, British, Italian, Caucasian/USA and of Austrian populations were compared.
      Six common HLA-DQ alpha alleles are detectable. These alleles determine 21
      possible genotypes. In our study 20 genotypes were obtained; the genotype 3/3 was
      not observed. The HLA-DQ alpha typing system using PCR-amplified DNA is a simple
      and rapid method for typing very small amounts of DNA and very old and/or
      degraded DNA. Therefore it is a helpful method in forensic casework.

PMID- 8666416
TI  - Familial aggregation studies with matched proband sampling.
AB  - A method is proposed for the analysis of clustered, continuous data arising from
      matched familial aggregation studies. The problem is suggested by a study
      designed to estimate the familial aggregation of obstructive sleep apnea (OSA).
      The study design uses 'proband' sampling, in which individuals identified at
      sleep clinics as having a high degree of OSA ('cases') are matched to
      neighborhood 'controls', individuals with normal levels of OSA. The resulting
      data are used to develop estimates of familial correlations for indices of
      hypopnea/apnea derived from the sleep monitoring of individual family members.
      The properties of conditional multivariate normal distributions and random
      effects models are used to accommodate proband sampling and matching effects.
      Examples and simulations are used to demonstrate the importance of applying the
      proposed procedures.

PMID- 8666417
TI  - Suballeles of the ABO blood group system in a Japanese population.
AB  - The nucleotides (nt) at positions 467 and 646 of the ABO blood group system were
      analyzed in a Japanese population by means of the polymerase chain reaction (PCR)
      and restriction fragment length polymorphism (RFLP) methods. Two types at nt467,
      tentatively designated 'Pro' and 'Leu', were found in the common A (= A1)
      alleles, and two types at nt646 named 'T' and 'A' were found in O alleles. The
      types at nt467 of B and O alleles were Pro and those at nt646 of A and B alleles
      were T. Therefore, A alleles were divided into A(Leu) and A(Pro) suballeles and O
      alleles were divided into O(T) and O(A). The allele frequencies in the present
      survey were calculated as ABO*A(Pro) = 0.0712, ABO*A(Leu) = 0.2163, ABO*B =
      0.1779, ABO*O(T) = 0.2731 and ABO*O(A) = 0.2615. No O2 (or O(3)) allele was
      observed in the population samples. At least five alleles with polymorphic
      frequencies and 15 genotypes are present in the Japanese sample.

PMID- 8666419
TI  - Linkage analyses in tibial muscular dystrophy.
AB  - Tibial muscular dystrophy (TMD) is a recently described muscular disease first
      discovered in a highly consanguineous family in Finland. The pedigree also
      included patients whose symptoms resembled another phenotype, classical limb
      girdle muscular dystrophy. Extensive linkage analysis was carried out in this
      complex pedigree using 157 highly polymorphic DNA markers. Because of the
      presence of two phenotypes, several inheritance models were used in linkage
      analysis studies to allow for the possibility of intrafamilial heterogeneity. The
      results summarize information from over 10,000 genotypings and exclude several
      known loci for muscular dystrophies. The findings suggest that TMD may be caused
      by a mutation in a previously unknown locus for muscular dystrophy.

PMID- 8666418
TI  - Alpha-1-antitrypsin deficiency in aneurysmal disease.
AB  - alpha 1-Antitrypsin (alpha 1-AT) deficiency may play a role in arterial
      aneurysmal disease by allowing increased proteolysis of arterial structural
      proteins. Alpha 1-AT levels are influenced by variation at the PI (protease
      inhibitor) locus. PI phenotypes were determined in 173 patients with abdominal
      aortic aneurysms (77 from Pittsburgh, 96 from London) and in 72 patients with
      intracranial aneurysms (26 from Pittsburgh, 46 from London). No excess of PI
      deficiency alleles was observed in either of the aortic aneurysm data sets or in
      the Pittsburgh intracranial aneurysm data. The PI*Z deficiency allele frequency
      in the London intracranial aneurysm data was 8-fold higher than in controls;
      however, this was not significant after correcting for multiple comparisons. PI
      phenotype had no effect on aneurysm age-at-diagnosis within any of the data sets.
      Smoking history had an effect on aneurysm age-at-diagnosis only within the
      Pittsburgh intracranial-aneurysm data.

PMID- 8666420
TI  - The molecular mechanism of T-cell control of Chlamydia in mice: role of nitric
      oxide.
AB  - T-cell mediated immunity (CMI) is crucial for protection against genital
      chlamydial infection in mice. To define the underlying molecular mechanism for
      this protection, several T-cell clones generated against the Chlamydia
      trachomatis agent of mouse pneumonitis (MoPn) were analysed in an in vitro model
      of the mucosal epithelium, the polarized epithelial-lymphocyte co-culture (PELC)
      system, for immunobiological functions that correlated with chlamydial
      inhibition. The six clones analysed were classified as protective or non
      protective on the basis of their ability to cure genital chlamydial infection in
      syngeneic mice. The results revealed a direct relationship between the ability of
      a clone to protect in vivo and to inhibit the multiplication of MoPn in vitro.
      Also, the protective ability of a clone correlated with its capacity to elaborate
      relatively high levels of interferon-gamma (IFN-gamma) and to induce nitric oxide
      (NO) production. Moreover, neutralizing anti-IFN-gamma antibodies used alone at
      50 micrograms/ml or in combination with anti-tumour necrosis-factor (TNF-alpha),
      and the L-arginine analogue and NO synthase inhibitor, NG-monomethyl-L-arginine
      monoacetate (MLA), could significantly suppress the ability of protective clones
      to inhibit MoPn in epithelial cells. The results suggested that the IFN-gamma
      inducible NO synthease pathway is important for chlamydial control in mice.
      Furthermore, IFN-gamma could stimulate infected murine epithelial cells (line
      TM3) to secrete NO, resulting in inhibition of MoPn growth. However, the degree
      of MoPn inhibition obtained with IFN-gamma alone was less than that observed when
      T cells were co-cultured with infected epithelial cells. T-cell-derived NO could
      partly explain the enhanced chlamydial inhibition when T cells were co-cultured
      with infected epithelial cells. These results are consistent with the hypothesis
      that, besides T-cell-derived IFN-gamma, other factors associated with
      lymphoepithelial interactions are likely to contribute an important role in
      chlamydial control by T cells in mice.

PMID- 8666421
TI  - Analysis of lymphoproliferative cytokines produced by thymic myoid cells.
AB  - Lymphoproliferative activities produced by cloned thymic myoid cell 871207B were
      analysed by immunological and biochemical methods. The lymphoproliferative
      activities were separated into two fractions by DEAE-Sepharose CL-6B
      chromatography: one is in the fraction passed through the column and the other in
      the fraction eluated from the column with a low concentration of NaCl. The
      eluated fraction induced the proliferation of interleukin-1 (IL-1)-dependent
      D10N4 M cells. This activity was abrogated by an anti-IL-1 alpha antibody, but
      not an anti-IL-1 beta antibody. Expression of IL-1 alpha mRNA was also detected
      in 871207B cells. The thymocyte proliferative activity found in the fraction
      passed through the DEAE-Sepharose column was further separated into three
      fractions by heparin-Sepharose column chromatography: (1) the fraction passed
      through the column, (2) the fraction weakly bound to the column, and (3) the
      fraction firmly bound to the heparin column. The fraction passed through the
      heparin column sustained the growth of IL-6-dependent MH60.BSF-2 cells. IL-6
      specific mRNA was found in 871207B cells. The thymocyte proliferative activity of
      the fraction firmly bound to the heparin column was neutralized with an anti-IL-7
      antibody. The biological activity of the fraction weakly bound to the column
      remained to be elucidated. These results suggest that thymic myoid cells produce
      IL-1 alpha, IL-6, IL-7 and unidentified lympho-stimulatory factors, all of which
      play significant roles in many steps of T-cell development in the thymus.

PMID- 8666422
TI  - Type-1 and type-2 CD8+ T-cell subsets isolated from chronic adult periodontitis
      tissue differ in surface phenotype and biological functions.
AB  - Cloning of CD8+ T cells expressing the alpha beta T-cell receptor from inflamed
      human gingiva revealed that at least two different subsets were found within the
      tissue and that these subsets were able to interact with each other. One subset
      produced high levels of interferon-gamma (IFN-gamma) and no interleukin-4 (IL-4)
      or IL-5, exhibited phytohaemagglutinin (PHA)- or anti-CD3-mediated cytolytic
      activity, and were CD28+. The other subset produced high levels of IL-4 in
      combination with IL-5, displayed no cytotoxicity and were CD28-. From the latter
      subset CD8+ T-cell clones were able to suppress the proliferative response of
      cytotoxic CD8+ T-cell clones. This suppression could be abolished by anti-IL-4
      monoclonal antibodies. However, IL-4 alone was not able to induce the
      suppression. Our results indicate that CD8+ T cells might participate in local
      immune responses by the suppression of IFN-gamma-producing cells and by favouring
      humoral responses via the production of IL-4 and IL-5.

PMID- 8666423
TI  - Limiting dilution analysis of CD4 T-cell cytokine production in mice administered
      native versus polymerized ovalbumin: directed induction of T-helper type-1-like
      activation.
AB  - Polarized expression of T-helper type-1 (Th1)- or Th2-like patterns of cytokine
      production frequently correlates with disease outcome. Previously, we have
      described the long-lived reciprocal regulation of ovalbumin (OVA)-specific IgE (>
      95% inhibition) and IgG2a (300-800-fold increased) production following
      administration of high MW OVA polymers (OVA-POL), in both de novo and ongoing OVA
      (alum)-induced responses. Here, limiting dilution analysis (LDA) was used to
      compare precursor frequencies of CD4 T cells producing interferon-gamma (IFN
      gamma), interleukin-4 (IL-4) or IL-10 following OVA versus OVA-POL exposure in
      vivo. Adjuvants were not used, so as to circumvent their impact on measurement of
      precursor frequencies. We found that the two forms of antigen elicited T-cell
      activation of comparable intensity, as indicated by equivalent precursor
      frequencies of clonogenic antigen-specific CD4 T cells. However, they elicited
      qualitatively different cytokine responses. OVA-POL treatment led to 10-fold
      higher (mean of six independent LDA experiments) frequencies of IFN-gamma
      producing cells, and a mean fivefold lower frequency of IL-10-producing cells,
      than was observed following in vivo administration of unmodified OVA. Thus, the
      high MW polymerized form of antigen acted to steer commitment of naive (for this
      antigen) CD4 T-cell activation from a situation in which IL-10 producers
      outnumbered IFN-gamma-producing cells by a factor of 4:1 (found in mice
      administered OVA), to one where IFN-gamma producers dominated by a factor of 11:1
      (in mice given OVA-POL), i.e. a qualitative shift in the nature of the OVA
      specific response induced from Th2-like to Th1-like. In vivo co-administration of
      anti-IFN-gamma monoclonal antibody (mAb) abolished the capacity of OVA-POL to
      preferentially elicit Th1-like dominance. Interestingly, although the ratios of
      IFN-gamma:IL-4 and IFN-gamma:IL-10 OVA-specific precursor frequencies were
      strongly increased following OVA-POL exposure (mean 18- and 47-fold higher), the
      frequency of IL-4-producing CD4 T cells did not differ significantly. The data
      suggest that this modified antigen promotes in vivo commitment of naive T cells
      towards a Th1-like response, with consequent inhibition of IgE and enhancement of
      IgG2a responses, not through direct effects on IL-4 production, but via decreased
      frequencies of IL-10 and increased frequencies of IFN-gamma-producing OVA
      specific CD4 cells. Collectively, the data (1) demonstrate the ability to
      manipulate commitment of antigen-driven CD4 T-cell populations in naive mice to
      specific patterns of cytokine gene expression, and (2) provide in vivo evidence
      of the regulatory role played by IFN-gamma in limiting induction and/or expansion
      of IL-4- and IL-10-producing CD4 cells to protein allergens.

PMID- 8666424
TI  - Effect of human cytokines (IFN-gamma, TNF-alpha, IL-1 beta, IL-4) on porcine
      endothelial cells: induction of MHC and adhesion molecules and functional
      significance of these changes.
AB  - Previous studies using cultured human endothelial cells have demonstrated the
      role of inflammatory cytokines [interferon-gamma (IFN-gamma), tumour necrosis
      factor-gamma (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-4] in the
      regulation of major histocompatibility complex (MHC) and adhesion molecule
      expression. These cytokines are therefore implicated in the amplification of
      allograft, and more recently xenograft, rejection. In view of the likely event of
      grafted porcine tissues being exposed to human cytokines, we have investigated
      the effect of IFN-gamma, TNF-alpha, IL-1 beta, IL-4 and recombinant porcine IFN
      gamma (rpoIFN-gamma) on cultured porcine aortic endothelial cells (PAEC) with
      respect to induction/up-regulation of porcine MHC and adhesion molecules and B7
      receptors. Expression was detected using monoclonal antibodies (mAb) against
      porcine ligands and human CTLA-4-immunoglobulin; binding was analysed by flow
      microfluorimetry. TNF-alpha but not the other human cytokines unregulated swine
      leucocyte antigens (SLA) class I, class II and B7 receptor expression and induced
      vascular cell adhesion molecule (VCAM) and E-selectin expression. Porcine IFN
      gamma also up-regulated SLA class I and class II, the ligand for CTLA-4
      immunoglobulin and VCAM expression; the magnitude and kinetics of this response
      differed to that produced by recombinant human TNF-alpha (rhTNF-alpha). The
      ability of untreated, rpoIFN-gamma- and rhTNF-alpha-treated PAEC to stimulate
      CD4+ T cell was compared. CD4+ T-cell proliferation and IL-2 production were
      significantly enhanced by rhTNF-alpha and rpoIFN-gamma, rpoIFN-gamma being more
      effective than rhTNF-alpha. Use of blocking antibodies and CTLA-4-immunoglobulin
      demonstrated that the enhanced proliferative response, but not apparently IL-2
      production, was dependent on cytokine-mediated up-regulation of SLA class II and
      B7 receptors. In conclusion, human TNF-alpha acts as a proinflammatory cytokine
      on PAEC and is likely to enhance the cellular response to xenogeneic organs in
      vivo.

PMID- 8666425
TI  - Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha
      and neutrophils: in vivo and in vitro studies.
AB  - Inflammatory cytokines decrease the expression of thrombomodulin (TM) on the
      endothelial cell surface by suppression of TM transcription and translation or
      internalization with subsequent degradation. Nevertheless, elevated serum TM
      levels are found in diseases associated with systemical or locally increased
      levels of inflammatory cytokines. To study directly the in vivo effects of tumour
      necrosis factor-alpha (TNF-alpha) we determined the course of serum TM after
      systemic recombinant human (rh)TNF-alpha therapy. The TM levels were determined
      by enzyme-linked immunosorbent assay (ELISA). Systemic rhTNF-alpha therapy
      resulted in a marked and significant increase of serum TM. Using a mouse model we
      studied whether increased serum TM is associated with a decreased expression of
      TM on the endothelial surface in vivo. The immunohistochemical staining of the
      vasculature of meth-A sarcoma transplanted in mice showed a loss of TM
      immunoreactivity 4 hr after intravenous TNF-alpha application. To study the
      mechanism of TNF-alpha mediated release of TM, cultured endothelial cells were
      incubated with neutrophils and TNF-alpha. Incubation with TNF-alpha alone did not
      lead to an increase of TM in vitro. However TM was released into the culture
      supernatant when endothelial cells pretreated with TNF-alpha were exposed to
      neutrophils. This was associated with morphological evidence of endothelial cell
      damage. Therefore, the concerted action of cytokine-stimulated endothelial cells
      and neutrophils results in release of TM from cultured endothelial cells after
      rhTNF-alpha therapy. This might explain the increased serum TM levels observed in
      diseases associated with increased systemic or local levels of inflammatory
      cytokines despite the induced internalization and the direct inhibitory effects
      of TNF-alpha on TM transcription and translation.

PMID- 8666426
TI  - Thy-1-mediated activation of rat mast cells: the role of Thy-1 membrane
      microdomains.
AB  - The glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein Thy-1 is one of the
      most abundant molecules expressed on the surface of rat mast cells and rat
      basophilic leukemia (RBL) cells. The finding that Thy-1 from detergent
      solubilized RBL-2H3 cells forms complexes with src-related protein-tyrosine
      kinase p56/p53lyn suggested that this kinase may play a key role in Thy-1
      mediated mast-cell activation. The molecular mechanism of this activation is,
      however, unknown. Here we show that in RBL-2H3-derived cells extracted by the
      standard procedure with several non-ionic detergents, the majority of Thy-1 and
      p56/p53lyn were not released into postnuclear supernatant but remained associated
      with the detergent-resistant cytoskeletal/nuclear fraction. Pretreatment of the
      cells with the cholesterol-complexing agents, saponin or digitonin, resulted in
      complete solubilization of Thy-1 and p56/p53lyn in non-ionic detergents and
      dissociation of the complexes; this implies that cholesterol plays a crucial role
      in stabilization of the complexes. This conclusion was supported by double
      immunofluorescence colocalization experiments which also allowed us to estimate
      the size of the insoluble complexes to be about 0.1 micron. Sequential treatment
      with saponin and Nonidet P-40 was used to fractionate tyrosine-phosphorylated
      proteins during Thy-1-mediated activation of RBL-2H3 cells. Among the soluble
      cytoplasmic proteins the most dramatic change in tyrosine phosphorylation was
      found in pp72, whereas pp40 and pp33 were found mainly in the membrane fraction.
      Our data suggest that surface aggregation of GPI-anchored Thy-1 molecules leads
      to aggregation of p56/p53lyn kinase located in the same membrane microdomain,
      followed by transphosphorylation of both soluble and membrane-bound substrates.

PMID- 8666427
TI  - Gene expression of interleukin-2 in purified human peripheral blood eosinophils.
AB  - To verify the hypothesis that eosinophils produce interleukin-2 (IL-2), a
      cytokine essential for lymphocyte activation, the expression of IL-2 was examined
      in peripheral blood eosinophils obtained from normal, atopic, asthmatic and
      hypereosinophilic subjects. Purified blood cell preparations were > 95%
      eosinophils, the remaining cells being neutrophils. Based on morphological
      observations and on CD3 expression, no lymphocytes were detected in these
      eosinophil preparations. The expression of IL-2 mRNA was detected by reverse
      transcriptase polymerase chain reaction (RT-PCR) in total RNA extracted from
      purified eosinophils stimulated with granulocyte-macrophage colony-stimulating
      factor (GM-CSF), with or without calcium ionophore (A23187). In-cell RT-PCR
      combined with in situ hybridization further confirmed that it was the eosinophils
      that expressed IL-2 mRNA. Moreover, in this experiment IL-2 mRNA expression
      increased upon costimulation with A23187 and GM-CSF suggesting that a steady
      state level of IL-2 mRNA was inducible. Finally, IL-2 was detected in purified
      eosinophils by immunochemistry. These data, obtained by different techniques,
      demonstrate that eosinophils can express IL-2. An IL-2-mediated eosinophil
      lymphocyte interaction could contribute to the chronic state of cell activation
      in inflamed tissues where these cells are implicated.

PMID- 8666428
TI  - Suppression of T-helper type-1 immune response against Listeria monocytogenes by
      treatment of mice with goat antibodies to mouse IgD.
AB  - Injection of goat anti-mouse IgD antibodies (GAM IgD) to mice has been shown to
      induce polyclonal IgG1 and IgE production by B cells and interleukin-4 (IL-4)
      production by goat Ig-specific T cells. Surface IgD cross-linking also activates
      B cells to function as antigen-presenting cells (APC). Although the GAM IgD
      treatment is a well-established system for analysis of B-cell dependent antigen
      presentation, the influence of GAM IgD treatment on the immune response to
      irrelevant antigens is not known. To address this issue, we analysed effects of
      GAM IgD treatment on (1) the mitogen response of freshly isolated T cells, and
      (2) the listerial antigen-specific response after immunization with viable
      Listeria monocytogenes, which induces CD4+ interferon-gamma (IFN-gamma) producing
      protective T cells in normal mice. Spleen CD4+ T cells from the GAM IgD-treated
      mice produced higher levels of IL-4 but lower levels of IFN-gamma and IL-2 than
      those from the control mice when they were stimulated with concanavalin A (Con A)
      in vitro. When spleen T cells were stimulated with listerial antigen 10 days
      after a low dose (1/20 LD50) of L. monocytogenes infection, CD4+ T cells from the
      GAM IgD-treated mice showed increased IL-4 production and decreased IFN-gamma and
      IL-2 production compared with those from the control L. monocytogenes-infected
      mice. Furthermore, the GAM IgD treatment resulted in a reduction of the survival
      rate after a high dose (1/2 LD50) of L. monocytogenes infection. These results
      suggest that treatment of mice with GAM IgD suppresses the T-helper type-1 (Th1)
      type T-cell response and induces a Th2-type response against irrelevant antigens,
      even when they are injected after GAM IgD treatment.

PMID- 8666429
TI  - Identification of interleukin-2 in human peripheral blood eosinophils.
AB  - Interleukin-2 (IL-2) is an essential growth factor for T cells. Previous studies
      have shown that human peripheral eosinophils respond to IL-2 in chemotaxis and
      express the IL-2 receptor (CD25). In addition, eosinophils have been shown to
      transcribe messenger RNA for IL-2. The aim of the present study was to determine
      whether eosinophils translate mRNA for IL-2 and to determine the site of
      intracellular localization. By immunocytochemistry, an average of 9% of cells
      showed cytoplasmic staining for IL-2 in freshly isolated unstimulated blood
      eosinophils obtained from asthmatic subjects who were not receiving oral
      corticosteroid treatment (n = 5). Freshly isolated, disrupted, highly purified
      eosinophils (> 99%, by CD16- immunomagnetic selection) contained an average of 6
      pg/10(6) cells of IL-2 measured by a specific enzyme linked immunosorbent assay
      (ELISA) (n = 7). Purified eosinophil incubated with serum-coated Sephadex beads
      showed an increase in the amount of intracellularly-retained IL-2 (26.2 +/- 7.2
      pg/10(6) cells) with some evidence for release of this cytokine but only in three
      out of six eosinophil preparations (range 1.3-5.8 pg/10(6) cells). The
      intracellular localization of IL-2 was determined by fractionation of the cells
      on a linear (0-45%) Nycodenz gradient in sucrose buffer followed by detection of
      IL-2 in the fractions using an IL-2-specific ELISA and dot blotting. The majority
      of the IL-2 detected co-eluted with known eosinophil granule markers (i.e. major
      basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase
      (EPO) and beta-hexosaminidase) but small quantities were also detected in the
      cytosolic (lactate dehydrogenase-(LDH) associated) and membrane (CD9+) fractions.
      Immunogold labelling of intact eosinophils using an anti-IL-2 monoclonal antibody
      confirmed IL-2 immunoreactivity in association with the eosinophil crystalline
      granule cores. These data are consistent with the hypothesis that eosinophils
      synthesize, release and store IL-2 largely within cystalloid granules. This
      stored IL-2 may serve as a reservoir for rapid release of IL-2 in inflammatory
      reactions associated with eosinophilia.

PMID- 8666430
TI  - Granulocyte-macrophage colony-stimulating factor antagonizes the transforming
      growth factor-beta-induced expression of Fc gamma RIII (CD16) on human monocytes.
AB  - Fc-gamma receptor III (Fc gamma RIII, CD16) type A is expressed on natural killer
      cells, on a small subset of peripheral blood monocytes and on mature macrophages.
      Along with differentiation into macrophages, monocytes will express Fc gamma RIII
      when cultured with transforming growth factor-beta (TGF-beta). In view of the
      involvement of granulocyte-macrophage colony-stimulating factor (GM-CSF) in
      myeloid cell differentiation, we investigated the effect of this cytokine on Fc
      gamma RIII expression in cultures of peripheral blood monocytes. GM-CSF
      antagonized TGF-beta-induced expression of Fc gamma RIII on monocytes in vitro in
      a dose-dependent way. The effect of GM-CSF persisted in cultures until at least
      day 7. The suppression was at the mRNA level, as shown by Northern analyses with
      a CD16 specific probe, and the signalling pathway involved tyrosine kinase
      activity. Interferon-gamma and interleukin-2 had no effect on the induced
      expression of Fc gamma RIII by TGF-beta, while interleukin-4, similar to GM-CSF,
      antagonized this induction. Our findings suggest that regulatory cytokine
      networks can drive monocytes into different effector functions and
      differentiation pathways.

PMID- 8666431
TI  - Evidence for the early recruitment of T-cell receptor gamma delta+ T cells during
      rat listeriosis.
AB  - We have previously reported that heat-shock protein (hsp) 60-reactive T-cell
      receptor (TCR)gamma delta+ T cells appear in the peritoneal cavity during the
      early stage of infection with Listeria monocytogenes in mice. In this study, we
      examined the kinetics of TCR gamma delta+ T cells during listeriosis in F344 rats
      by flow cytometry using a V65 monoclonal antibody (mAb) directed to a constant
      determinant of rat TCR gamma delta chains. TCR gamma delta+ T cells significantly
      increased in the peritoneal cavity on day 6 and then decreased by day 10 after
      infection, in parallel with the kinetics of hsp60 expression in the peritoneal
      macrophages during listeriosis in F344 rats. Most of the early appearing TCR
      gamma delta+ T cells were of the CD4- CD8 alpha beta+ CD5+ lymphocyte function
      associated antigen (LFA)-1 alpha high CD45RC- interleukin-2 receptor (IL-2R)
      alpha- phenotype, although a significant fraction of the TCR gamma delta+ T cells
      expressed CD8 alpha only. The increase in TCR gamma delta+ T cells during
      listeriosis was prominent in F1 (F344 x Lewis) rats but only marginal in Lewis
      rats, which was correlated with the expression level of hsp 60 in the peritoneal
      macrophages. The peritoneal TCR gamma delta+ T cells in naive F344 rats appeared
      to proliferate significantly in response to recombinant hsp 60 (rhsp 60) derived
      from Mycobacterium bovis bacillus Calmette-Guerin (BCG). These results imply that
      the early appearance of hsp 60-reactive TCR gamma delta+ T cells during listerial
      infection can be generalized across species.

PMID- 8666432
TI  - Exacerbation of Plasmodium chabaudi malaria in mice by depletion of TCR alpha
      beta+ T cells, but not TCR gamma delta+ T cells.
AB  - Although gamma delta T cells are found in increased numbers in the spleens of
      humans and mice infected with malaria, it is not known if these cells are
      necessary components of an effective immune response. The surface phenotype of
      spleen cells obtained from mice infected with avirulent Plasmodium chabaudi adami
      or virulent Plasmodium chabaudi chabaudi were examined using anti-delta or anti
      alpha beta T-cell-specific reagents and flow cytometry. Levels of parasitaemia,
      red blood cell (RBC) counts, and survival times were followed in mice depleted of
      tumour necrosis factor (TCR)gamma delta+ or TCR alpha beta+ T cells. Numbers of
      gamma delta T cells increased in the spleens of control antibody-treated infected
      mice, but not in mice depleted of TCR gamma delta+ or TCR alpha beta+ T cells.
      Mice depleted of gamma delta T cells had levels of parasitaemia, RBCs, and
      survival rates similar to control antibody-treated mice. However, mice depleted
      of TCR alpha beta+ T cells had higher levels of parasitaemia, lower RBC counts,
      and decreased survival rates. These results indicate that TCR alpha beta+ but not
      TCR gamma delta+ T cells play an essential role in host defense against P.
      chabaudi infection in mice.

PMID- 8666433
TI  - Role of virus-specific CD4+ cytotoxic T cells in recovery from mouse hepatitis
      virus infection.
AB  - Macrophages and T lymphocytes play an important role in recovery from viral
      infections. During mouse hepatitis virus (MHV-A59) infection, a clear virus
      specific class II-restricted cytotoxic T-cell response is generated. Transfer of
      these CD4+ cytotoxic T cells (CTL) into naive mice protects against a lethal
      challenge with MHV. However, their in vivo antiviral effector mechanism is not
      yet clear. To further investigate a possible effector mechanism, we studied the
      effect of adoptive transfer of CD4+ CTL on virus localization in spleen and
      liver. We showed that adoptive transfer of virus-specific T cells does not affect
      localization of MHV-A59 in different macrophage subsets. Interestingly, a rapid
      and large infiltrate of CD4+ T cells in and around MHV-A59-infected foci in the
      liver was observed early in infection, whereas no CD8+ T cells were detectable.
      Moreover, transfer of virus-specific T cells resulted in significantly decreased
      viral titres in the liver and spleen and a marginally increased anti-MHV-A59 IgM
      production. These results imply an important role for virus-specific CD4+ CTL in
      elimination of infectious MHV-A59 and induction of an effective immune response
      in the absence of CD8+ CTL.

PMID- 8666434
TI  - Both H-2- and non-H-2-linked genes influence influenza nucleoprotein epitope
      recognition by CD4+ T cells.
AB  - The specificity of the influenza nucleoprotein-induced T-cell proliferative
      response by mouse strains differing in either H-2- or non-H-2-linked background
      genes was compared by using a panel of synthetic peptides covering 90% of the
      nucleoprotein molecule. The results showed, as expected, that H-2 genes strongly
      influenced the major regions of the molecules recognized by T cells, as the
      response was focused on different peptides in mice of different H-2 haplotypes.
      However, some regions of the molecule (e.g. 260-283) were recognized by several
      different haplotypes, with overlapping but distinct minimal determinants. The
      lymph node proliferative response appeared to be predominantly restricted by the
      I-A molecule, as expression of I-E in mice did not result in any detectable
      recognition of additional epitopes. In the majority of cases the same T-cell
      epitopes were recognized by mouse strains sharing the same H-2 haplotype but
      differing in many background genes. Low responsiveness was however observed to
      p55-77 by DBA/2 and p127-141 by AKR mice to which other H-2d or H-2k strains were
      high responders. Low responsiveness is therefore unlikely to be a consequence of
      failure of these peptides to bind to the relevant major histocompatibility
      complex class II molecule. In addition antigen-presenting cells from the DBA/2
      low responder strain was able to process and present whole influenza virus or
      nucleoprotein as well as antigen-presenting cells from the high responder BALB/c
      strain. It is therefore suggested that low responsiveness to the peptide p55-77
      may be due to a 'hole in the T-cell repertoire', caused perhaps by expression of
      Mls-1a in the DBA/2 strain. This is supported by the observation that low
      responsiveness to this epitope appears to be dominant in F1 (low x high) mice.

PMID- 8666435
TI  - The superantigen Staphylococcus enterotoxin B induces a strong and accelerated
      secondary T-cell response rather than anergy.
AB  - The primary and secondary immune response of V beta 8+ T cells to the bacterial
      superantigen Staphylococcus enterotoxin B was compared in BALB/c mice. Secondary
      responder T cells were found to up-regulate the expression of the adhesion
      molecule LFA-1 faster, and to enter the cell cycle earlier than primary responder
      T cells. Both, primary and secondary responder T cells upregulate the expression
      of CD2 and CD25 and turn into blast cells with superimposable time kinetics.
      Secondary responder T cells terminate DNA synthesis, blast formation and the
      upregulation of CD25 and CD2 expression earlier than primary responder T cells
      and become more rapidly deleted. Two days after superantigen challenge, when
      primary responder T cells reach peak activity in terms of DNA synthesis and blast
      formation, secondary responder T cells have returned to the size of microblasts
      and ceased to replicate their DNA. Whereas our results are consistent with the
      observations leading to the concept of superantigen-induced T-cell anergy, they
      demonstrate, by revealing the accelerated vigorous secondary T-cell response to
      the superantigen, that this concept requires reconsideration.

PMID- 8666436
TI  - Induction of immune responses to functional determinants of a cell surface
      streptococcal antigen.
AB  - Antibodies directed against the cell surface adhesin, termed streptococcal
      antigen I/II of Streptococcus mutans can protect against dental caries.
      Streptococcal antigen I/II (SA I/II) interacts with salivary glycoproteins and
      promotes adhesion to the tooth surface. Topical application of monoclonal
      antibodies which recognize a domain within residues 816-1213 (fragment 3)
      prevents colonization by S. mutans in primates. In this study the immunogenicity
      and antigenicity of fragment 3 was investigated in five strains of mice. Fragment
      3 induced an immune response following immunization with whole cells of S. mutans
      in all strains of mice. Immunization with recombinant fragment 3 also induced T
      cell proliferative and antibody responses both to fragment 3 and to the SA I/II.
      Antibody responses to the previously defined adhesion determinants (residues 1005
      1044) were weak or undetectable. Immunization of three representative strains of
      mice with a recombinant polypeptide (residues 975-1044) comprising this adhesion
      epitope and an adjacent T-cell epitope (residues 975-1004) elicited both T- and B
      cell responses to the polypeptide and to native SA I/II. The B-cell epitopes
      overlapped with the adhesion determinant. These findings provide a means of
      directing immune responses to functional determinants of SA I/II.

PMID- 8666437
TI  - Identification of a molecule uniquely expressed on a gamma/delta TCR+ subset
      within bovine intestinal intraepithelial lymphocytes.
AB  - An antigen has been identified, recognized by a novel monoclonal antibody CC45,
      which is expressed by a subpopulation of bovine gamma/delta T-cell receptor
      positive (gamma/delta TCR+) T cells restricted in their distribution to the
      intestinal epithelium. This subset of intestinal intraepithelial lymphocytes
      (iIEL) which represented 8-29% of gamma/delta TCR+ T cells in the gut epithelium
      expressed CD45, CD3 and L-selectin; most of these cells were CD2- and CD8-.
      Electron microscopic studies of CC45+ cells revealed that they were large
      mononuclear leucocytes containing numerous mitochondria and smooth vesicles; a
      proportion of these contained membrane-bound dense granules. Immunoprecipitation
      of 125I-labelled iIEL analysed by sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis under reducing and non-reducing conditions revealed polypeptides
      of 60,000 and 200,000 molecular weights, respectively indicating that the
      antigen, which appears distinct from molecules described in other species, is
      expressed on the cell surface as a complex.

PMID- 8666438
TI  - Bovine gamma/delta T-cell proliferation is associated with self-derived molecules
      constitutively expressed in vivo on mononuclear phagocytes.
AB  - Bovine gamma/delta T cells have been shown previously to proliferate when
      cocultured with gamma-irradiated bovine monocytes in the 'autologous mixed
      leucocyte reaction' (AMLR). It was suggested that the response may be to culture
      derived or culture-induced antigenic epitopes. Data presented here indicate that
      the gamma/delta T-cell stimulatory activity is attributable to a self-derived
      cell-surface molecule of mononuclear phagocytes that is constitutively expressed
      in vivo. The ability to induce an AMLR did not require in vitro culture or stress
      associated with in vitro isolation of cells or increased temperature since it
      could be induced by monocytes fixed by paraformaldehyde during blood collection
      from normal animals. Furthermore, stimulation by monocytes did not depend upon
      secreted molecules since fixed monocytes that had been incubated overnight at 37
      degrees to allow secretion of preformed molecules, or subjected to hypotonic
      shock in H2O for 10 min before addition to the cultures, induced an AMLR as did
      plasma membranes prepared from ex vivo monocytes. In contrast, enzymatic
      treatment of monocytes to digest surface molecules followed by fixation destroyed
      their ability to stimulate an AMLR. The ability of monocytes to stimulate
      proliferation of gamma/delta T cells was distinguishable from their ability to
      stimulate alpha/beta T cells, since the former was destroyed by glutaraldehyde
      fixation whereas stimulation of alpha/beta T cells by major histocompatibility
      complex (MHC)-presented antigenic epitopes is not. Moreover, induction of
      proliferation of bovine gamma/delta T cells was not MHC-restricted. Finally,
      bovine alveolar macrophages, sheep monocytes and transformed bovine monocytes
      stimulated proliferation of bovine gamma/delta T cells whereas none of the
      following did so: human monocytes, murine macrophages, bovine myeloid cells other
      than mononuclear phagocytes, other nucleated cells found in bovine blood
      including activated MHC class II-bearing B cells, and a variety of species of
      bacteria. Thus, the stimulatory epitope is unique to and conserved among
      mononuclear phagocytes of ruminants. Demonstration of stimulation of bovine
      gamma/delta T cells by self-derived molecules is consistent with reports for
      murine gamma/delta T cells.

PMID- 8666439
TI  - The immunosuppressive compound 2-acetyl-4-tetrahydroxybutyl imidazole inhibits
      the allogeneic mixed lymphocyte reaction by sequestration of a recirculating
      subpopulation of T cells.
AB  - 2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI) is an immunosuppressive
      component of caramel food colouring that causes lymphopenia in mice and rats by
      an unknown mechanism. In this study we investigated some of the affects of THI on
      the murine immune system. Initially we showed that splenic T lymphocytes from
      mice treated with 50 mg/l THI in their drinking water were unable to launch a
      mixed lymphocyte reaction (MLR) against allogeneic stimulator cells, and had
      decreased and delayed interleukin-2 (IL-2) production. However, these T cells
      exhibited a normal proliferative response to concanavalin A (Con A), immobilized
      anti-CD3 monoclonal antibody (mAb) and anti-CD3 plus anti-CD28 mAb. Furthermore,
      the MLR response could be restored by the addition of IL-2 to the MLR culture.
      Homing studies using intravenous injection of fluorescence-labelled splenocytes
      showed that THI treatment decreased absolute numbers of labelled T and B
      lymphocytes in the blood and the spleen. Furthermore, these labelled cells
      reappeared in the blood and the spleen when mice were taken off THI, indicating
      that lymphocyte recirculation and splenic homing were modified reversibly by THI
      treatment. Cessation of THI treatment also resulted in a rapid reappearance of
      MLR responsiveness in the spleen, indicating that THI treatment does not
      functionally impair recirculating T cells. Collectively these data are compatible
      with the concept that a rapidly recirculating population of T cells, which
      produce IL-2 in an allogeneic MLR, are lost from the blood and spleen following
      THI treatment, and are sequestered in other, yet to be identified, tissues.

PMID- 8666440
TI  - Reduced expression of the interleukin-2-receptor gamma chain on cord blood
      lymphocytes: relationship to functional immaturity of the neonatal immune
      response.
AB  - Mutation of the interleukin-2 (IL-2) receptor gamma chain, which also serves as a
      component of the receptor complexes for IL-4, 7, 9 and 15, results in severe
      immune deficiency. We hypothesized that the immunological immaturity of healthy
      neonates might be associated with low levels of expression of this receptor
      molecule. Using monoclonal antibody and a highly sensitive immunofluorescence
      method, we showed that IL-2 receptor gamma chain is expressed at significantly
      lower levels on cord blood cells compared with adult cells. IL-2-dependent T-cell
      activation in vitro was reduced in cord blood cells compared with adult cells,
      but B-cell responses to IL-4 were not obviously impaired. The lower level of
      expression of the gamma chain and some other cytokine receptor chains may
      contribute to the immunological immaturity of the newborn, by selectively
      depressing particular immunological mechanisms.

PMID- 8666441
TI  - A sequential study of the bovine tuberculin reaction.
AB  - The sequential histopathological and immunocytochemical changes that characterize
      the tuberculin reaction were studied in 13 cattle experimentally sensitized to
      Mycobacterium bovis, and 14 cattle naturally infected with M. bovis. There were
      two distinct, temporally related patterns of morphological change that were
      similar for both groups of cattle. The first phase, between 6 hr and 24 hr after
      the intradermal injection of purified protein derivative (PPD), was characterized
      by a perivascular aggregation of WC1+ gamma delta T cells and neutrophils and the
      presence of leucocytoclastic vasculitis within the papillary dermis. The second
      phase of the reaction was characterized by increased numbers of infiltrating
      BoCD4+ cells, BoCD8+ cells and macrophages, as well as an increase in expression
      of the interleukin-2 (IL-2) receptor and the ACT2 antigen. Macrophages were the
      most numerous infiltrating leucocytes between 24 hr and 72 hr after the
      intradermal injection of PPD. At 72 hr, the reaction was characterized by intense
      perivascular cuffing with BoCD4+ cells, BoCD8+ cells and macrophages; gamma delta
      T cells and neutrophils were a minor component of the reaction and
      leucocytoclastic vasculitis was no longer observed. No B cells were detected in
      the dermis throughout the period of study. The increase in skin thickness was
      primarily because of inflammatory oedema that was contained within the area by a
      meshwork of fibrin deposited around the collagen bundles of the reticular dermis.

PMID- 8666443
TI  - Differential usage of T-cell receptor V beta gene families by CD4+ and CD8+ T
      cells in patients with CD8hi common variable immunodeficiency: evidence of a post
      thymic effect.
AB  - In this study, we report that differences between T-cell receptor (TCR) V beta
      gene family usage in CD4+ and CD8+ T cells are significantly greater in a
      subgroup of patients with common variable immunodeficiency (CVI) and high levels
      of activated CD8+ T cells (CD8hi CVI) than in controls (P < 0.001). In CD8hi CVI
      patients, such differences were also significantly greater for V beta 12 than for
      other V beta families. As the causes of the differential usage of V beta gene
      families by CD4+ and CD8+ T cells are under investigation, it was interesting
      that the combined differences between V beta gene family usage in the CD4+ and
      CD8+ T-cell subpopulations as a whole were significantly lower than the combined
      differences between individual V beta gene family usage in either CD4+ or CD8+ T
      cell subpopulations (P < 0.001 in both control and CD8hi CVI patients). Further,
      the pattern of V beta gene family usage in CD4+ T cells was remarkably similar to
      that in CD8+ T cells in both groups. These data strongly suggest that differences
      in V beta gene family usage arising from coselection by major histocompatibility
      complex (MHC) class I versus MHC class II restriction elements do not
      fundamentally distort 'basic' V beta gene family usage patterns. They also
      support the concept that differences in CD4+ and CD8+ T-cell V beta gene family
      usage, which were increased in CD8hi CVI, can arise from high-affinity
      interactions between disease-associated antigens or superantigens and T cells in
      the post-thymic T-cell compartment.

PMID- 8666444
TI  - About those abstract translations.

PMID- 8666442
TI  - Soluble mediators and cytokines produced by human CD3- leucocyte clones from
      decidualized endometrium.
AB  - CD3- granulated leucocyte clones have been generated from human first-trimester
      decidualized endometrial tissue following culture in interleukin-2 (IL-2).
      Supernatants from both CD3- decidual granulated leucocyte (dGL) and CD3-
      peripheral blood natural killer (PBNK) cell clones inhibited the proliferation of
      choriocarcinoma cell lines. A panel of CD3- dGL clones, with or without
      phytohaemagglutinin stimulation, was assayed for cytokine secretion compared with
      CD3- PBNK clones and fresh tissue extracts. Levels of interferon-gamma,
      granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor
      alpha (TNF-alpha) and IL-10 produced by stimulated CD3-CD8- dGL clones were
      greater than those produced by stimulated CD3-CD8+ dGL clones. In contrast, CD8+
      dGL clones were more effective in production of IL-6 than CD8- dGL clones.
      Immunoreactive transforming growth factor-beta 2 (TGF-beta 2) was undetectable in
      supernatants from CD3- dGL and PBNK clones. CD3- dGL clones generally produced
      higher levels of all cytokines than PBNK clones. Some unstimulated CD3- dGL and
      PBNK clones spontaneously produced these cytokines, but usually at a reduced
      level. Fresh extracts of first-trimester decidual tissue contained detectable GM
      CSF, TNF-alpha, IL-10,IL-6 and TGF-beta 2. Cytokine production by fresh CD3- dGL
      and CD3- dGL clones indicates that these cells could play an important role in
      the regulation of placental growth.

PMID- 8666445
TI  - In vivo measurements of precision of fit involving implant-supported prostheses
      in the edentulous jaw.
AB  - The objective of this study was to measure and compare the precision of fit of
      implant-supported prostheses in the edentulous jaw by using both the master cast
      replicas and the intraoral implants as references. Seven maxillary and 10
      mandibular prostheses were randomly selected and measured by means of a three
      dimensional (3-D) photogrammetric technique. The results indicated that
      prostheses routinely connected to osseointegrated implants could demonstrate
      distortion between the framework and individual implants of up to several hundred
      microns. When master casts were used as a reference, the mean 3-D distortion of
      the center point of gold cylinders was 37 microns (SD 18) and 75 microns (SD 40)
      for mandibular and maxillary prostheses, respectively. The corresponding mean
      displacement was 90 microns (SD 51) and 111 microns (SD 59), respectively, when
      the intraoral implants were used as references. The mean 3-D distortion was
      significantly higher for the intraoral measurements in both arches (P < .001 and
      P < .05). Furthermore, the overall distortion was significantly higher for the
      maxillary prostheses when the master casts were used as the reference (P < .05).
      However, for the intraoral measurements, no statistically significant difference
      of fit between the arches was possible to observe (P < .05). This could possibly
      be explained by the finding that intraoral measurements of the mandibular
      prostheses indicated a deformation and rotation of the mandible that was not
      observed in the maxillary prostheses. A further factor in the lack of statistical
      significance could be the relatively small sample size.

PMID- 8666446
TI  - Bone-anchored craniofacial prosthesis study.
AB  - A prospective study involving 24 centers and 145 patients was conducted to
      evaluate the long-term osseointegration survival rate for titanium implants
      anchoring a craniofacial prosthesis (auricular, orbital, or nasal) and to
      evaluate the long-term retention and stability of the prosthesis. Of 452 implants
      placed, 19 were lost (overall survival rate of 96%). Of the 145 patients, 115
      were evaluated (remained active) throughout the study period and were followed-up
      for at least 30 months. The results of the study suggest that the bone-anchored
      craniofacial prosthesis system is a viable alternative to conventional
      reconstructive surgery and offers significant improvement in the quality of life
      when compared with the support systems previously available for these types of
      prostheses.

PMID- 8666447
TI  - The influence of titanium abutment surface roughness on plaque accumulation and
      gingivitis: short-term observations.
AB  - The roughness of intraoral hard surfaces plays an important role in bacterial
      adhesion and colonization. Earlier studies have shown that rough surfaces
      accumulate up to 25 times more subgingival plaque than do smooth sites. In the
      present study, the influence of surface smoothing was studied. In six partially
      edentulous patients waiting for a fixed prosthesis supported by endosseous
      titanium implants, four titanium abutments with different surface roughness were
      randomly placed. After 1 month of intraoral exposure, subgingival plaque samples
      from each abutment were compared within each patient by means of differential
      phase-contrast microscopy. After 3 months, supragingival and subgingival plaque
      samples were taken from all abutments for differential phase-contrast microscopy
      and culturing. Probing depth, recession, and bleeding upon probing were scored at
      the same visit. Differential phase-contrast microscopy showed that subgingivally,
      only the two roughest abutments harbored spirochetes after 1 month. After 3
      months, subgingivally, the composition of the flora showed little variation on
      the different abutment types, although spirochetes were only noticed around the
      roughest abutments. Anaerobic culturing resulted in comparable amounts of colony
      forming units for all abutment types, both supragingivally and subgingivally.
      Subgingivally, the microbiologic composition did not show major interabutment
      differences. Clinically, small differences in probing depth were observed. The
      roughest abutment showed some attachment gain (0.2 mm) during 3 months, whereas
      all other abutments had an attachment loss ranging from 0.8 to greater than 1 mm.
      The results indicate that a reduction in surface roughness (less than a roughness
      of 0.2 micron) had no major effect on the microbiologic composition,
      supragingivally or subgingivally. These observations indicate the existence of a
      threshold roughness below which no further impact on the bacterial adhesion
      and/or colonization should be expected. However, clinical evaluation seems to
      indicate that a certain surface roughness is necessary for increased resistance
      to clinical probing.

PMID- 8666448
TI  - The reverse-torque test: a clinical report.
AB  - Reverse torque to failure on implants has been studied in animals. Three implants
      were reverse torqued to failure in a human volunteer, with failure rates between
      45 and 58 Ncm. Clinical data are presented on 404 implants examined after reverse
      torque testing and loading, with no increase in failure rates. Reverse-torque
      testing at 20 Ncm appears to be a safe, reliable method for verifying
      osseointegration with pure titanium screw-shaped implants.

PMID- 8666449
TI  - Mandibular lengthening by intraoral distraction using osseointegrated implants.
AB  - Mandibular lengthening by distraction osteogenesis is a new method for use in
      treating congenital deformities or postsurgical bone defects. However, the use of
      extraoral transcutaneous pins in the mandible has disadvantages, such as facial
      scars and facial nerve or inferior alveolar nerve injury. The purpose of this
      study was to establish a new approach to distraction osteogenesis in the mandible
      by using osseointegrated implants and an intraoral device. Ten adult canines were
      used for this experiment. After extraction of the teeth and placement of two
      titanium implants in the left mandible, connection of the intraoral distraction
      device to the abutments, and corticotomy in the medial portion between implants
      were performed. Distraction was done at the rate of 1 mm per day to elongate 10
      mm in length. Radiographic and histologic examinations showed that successful
      mandibular lengthening was achieved. New bone was primarily formed by
      intramembranous ossification and partial endochondral ossification. Titanium
      implants placed for anchorage of the device remained stable during the course of
      mandibular lengthening. Study results suggest that the intraoral device using
      osseointegrated dental implants can be used as a mechanism for distraction
      osteogenesis in the mandible.

PMID- 8666451
TI  - Copy-milled all-ceramic Celay-InCeram crowns for modified CeraOne abutments: a
      technical report.
AB  - With single-tooth implant restorations, a divergence between implant and crown
      axes, a lack of interocclusal space, and supracrestal implant placement may
      result in fabrication problems for the prosthetic crown. It was found that the
      CeraOne abutment can be modified in three ways: (1) height reduction is possible;
      (2) a 15-degree taper can be applied; and (3) the cervical shoulder can be
      reduced in height with a chamfer remaining. For these modified abutments, the
      Celay-InCeram system was used to create individual, all-ceramic crowns for these
      modified abutments with improved esthetics.

PMID- 8666450
TI  - Denture satisfaction in a comparative study of implant-retained mandibular
      overdentures: a randomized clinical trial.
AB  - This study compared the experiences with surgical procedures and treatment
      effects of a mainly implant-supported overdenture retained by a transmandibular
      implant with those of an implant tissue-supported overdenture retained by two
      cylindrical endosseous implants. Treatment had been assigned according to a
      balanced allocation method to 95 patients, including a control group who received
      only conventional complete dentures. Since some of the patients refused the
      allocated treatment, the "intention to treat" analysis was applied. The results
      show that the experiences with surgical procedures were significantly more
      positive for the transmandibular implant group than the endosseous implant group.
      The differences with respect to satisfaction, complaints, and subjective chewing
      ability were not statistically significant. These results were unexpected because
      the overdentures retained by the transmandibular implants were, to a much larger
      extent, supported by the implant than were the overdentures retained by two
      endosseous implants.

PMID- 8666452
TI  - Immediate placement of implants into extraction sockets: implant survival.
AB  - In 51 patients (21 males and 30 females) aged 16 to 72 years, a total of 109
      Nobelpharma implants were placed into extraction sockets immediately following
      extraction. The follow-up period varied between 1 and 67 months with a mean of
      30.5 months. Osseointegration was determined by clinical stability, lack of
      symptoms, and lack of peri-implant pathology based on radiographic examination.
      The implant survival rate was 93.6%. Six implants were mobile at the abutment
      connection stage, and one was lost when function commenced. The success rate was
      92.0% for implants replacing teeth extracted because of periodontitis and 95.8%
      for implants replacing teeth extracted for other reasons. Two other complications
      occurred: 12 cover screws perforated the gingiva during healing; and infection
      developed in five cases. The incidence of infection was higher in the
      periodontitis group. It was found that immediate placement of implants into
      extraction sockets is a safe and predictable procedure if certain guidelines are
      followed.

PMID- 8666453
TI  - Resistance to bacterial aggression involving exposed nonresorbable membranes in
      the oral cavity.
AB  - Bacterial colonies split implanted membranes that are exposed to oral biologic
      fluids as a consequence of dehiscence. The clinical and histologic behavior of 14
      implanted polyurethane membranes was observed during the period of exposure to
      oral fluids for 2, 3, 4, and 6 weeks and without dehiscence (after 8 weeks).
      Statistical analysis indicated that the decrease in the number of neutrophils
      after 5 weeks, associated with the increase in the number of activated
      fibroblasts, cellular debris, giant cells, and aggression of bacteria, was
      statistically significant (from P < .05 and P < .01 for activated fibroblasts to
      P <.005 and P < .001 for neutrophilic cells). The increase in bacterial passage
      through the polyurethane membranes and in the number of giant cells and cellular
      debris after 8 weeks represents late dissolution of the membranes; the
      progressive increase of activated fibroblasts is significant because the longer
      the membrane resists, the better the cells can grow and give way to the process
      of tissue regeneration.

PMID- 8666454
TI  - Accuracy of implant impression techniques.
AB  - Three impression techniques were assessed for accuracy in a laboratory cast that
      simulated clinical practice. The first technique used autopolymerizing acrylic
      resin to splint the transfer copings. The second involved splinting of the
      transfer copings directly to an acrylic resin custom tray. In the third, only
      impression material was used to orient the transfer copings. The accuracy of
      stone casts with implant analogs was measured against a master framework. The fit
      of the framework on the casts was tested using strain gauges. The technique using
      acrylic resin to splint transfer copings in the impression material was
      significantly more accurate than the two other techniques. Stresses observed in
      the framework are described and discussed with suggestions to improve clinical
      and laboratory techniques.

PMID- 8666455
TI  - Marginal bone levels around maxillary implants supporting overdentures or fixed
      prostheses: a comparative study using detailed narrow-beam radiographs.
AB  - The issue of changes in marginal bone levels around maxillary implants supporting
      overdentures has been studied very little because of radiographic difficulties
      when using conventional intraoral techniques. The present study used detailed
      narrow-beam radiography, which offers excellent opportunities to depict implants
      and the surrounding bone in severely resorbed maxillae. Marginal bone levels
      around implants in patients with overdentures were compared to corresponding bone
      levels in a group of matched control patients with fixed prostheses supported by
      osseointegrated implants. No statistically significant difference in marginal
      bone height was noted between the groups. This finding is not in accordance with
      an earlier report on continuous loss of marginal bone around many maxillary
      implants supporting overdentures.

PMID- 8666456
TI  - Peri-implant tissue reaction in bone irradiated the fifth day after implantation
      in rabbits: histologic and histomorphometric measurements.
AB  - To evaluate tissue reaction to cobalt 60 irradiation around implant materials
      used in maxillofacial surgery, 2.0-mm titanium alloy bone screws and 2.0-mm
      cylindrical solid hydroxyapatite implants were placed in mandibular bone of
      rabbits and irradiated with a single 15-Gy dose on the fifth postoperative day.
      Tissue reaction around the implants was examined histologically and
      histomorphometrically at 7, 14, 28 and 56 days after irradiation. Mature bone was
      relatively radioresistant, but newly formed bone around both implants was damaged
      by irradiation in several places. After irradiation, the beginning of bone
      formation was delayed and the amount of new bone formed was less. Bone-implant
      contact measured histomorphometrically was less in the irradiated group than in
      the nonirradiated group. All titanium alloy screws showed bone contact, but two
      of eight hydroxyapatite implants failed after irradiation, probably the result of
      loss of primary stability of the cylindrical implants caused by radiation damage
      to newly formed bone.

PMID- 8666457
TI  - The use of demineralized laminar bone sheets in guided bone regeneration
      procedures: report of three cases.
AB  - Demineralized laminar bone sheets were utilized as membranes to affect guided
      bone regeneration around five implants in two patients and to perform a ridge
      augmentation procedure in one patient. In all cases, significant regeneration of
      hard tissues occurred, and no complications were encountered. The regenerated
      hard tissues have been in function for up to 32 months with no clinical signs of
      breakdown.

PMID- 8666459
TI  - Hypoallergenic gloves.
AB  - Hypoallergenic gloves have been introduced in response to the growing problems of
      occupationally acquired hand dermatitis. Such labelling can, however, be
      misleading and some gloves contain measurable allergen levels. Hypoallergenic
      gloves containing natural rubber latex will not address the problem of
      individuals suffering from latex allergy and their inappropriate use may provoke
      a potentially life threatening reaction. Regulatory authorities must ensure that
      manufacturers provide adequate labelling for gloves, with the appropriate warning
      about their allergen content. Dental health care workers must become more
      knowledgeable about gloves and staff should be given appropriate advice about the
      risks of latex sensitisation.

PMID- 8666460
TI  - Anxiety and heart rate correlation prior to dental checkup.
AB  - The aim of this study was to investigate the possible relationship between dental
      anxiety and heart rate prior to a dental checkup. Anxiety was determined in 44
      patients using the Dental Anxiety Scale (DAS). Heart rate was measured 24 hours
      before, and immediately prior to, a dental checkup. The mean heart rate was
      higher immediately prior to the checkup than it had been 24 hours previously. The
      DAS score showed no relation to the heart rate immediately prior to the dental
      checkup, but showed a significant relation to the heart rate of women 24 hours
      before the checkup. In men, this relation did not reach significance. It is
      concluded that anticipation of a dental checkup increases heart rate. The average
      increase in heart rate is higher in patients with a low DAS score.

PMID- 8666458
TI  - Histologic study of failed hollow implants.
AB  - Nine hollow dental implants that were removed from patients were examined
      histologically to determine whether there was a common mechanism of failure with
      this implant design. When a hollow implant showed saucerized bone loss at the
      neck portion radiologically, the hollow portion was divided histologically into
      soft tissue and bone tissue. In advanced cases, stratified flattened epithelium
      that had invaded the hollow and the dead space at the top was observed. The
      condition of bone tissue located in the bottom of the basket can be adversely
      affected by an unfavorable crown-root ratio. The presence of an empty basket may
      cause fracture of the basket portion. The hollow portion can foster the growth of
      pathogenic bacteria. The hollow-type implant may not be suitable for immediate
      placement because surrounding soft tissues can invade the basket immediately.

PMID- 8666461
TI  - Environmental microbial contamination. Pilot study in a dental surgery.
AB  - Environmental contamination by bacterial aerosols occurs every day in the dental
      surgery. The aim of this study was to determine bacterial levels in five
      different areas of a dental surgery during ultrasonic scaling procedures using
      bacterial cultures. Two areas with markedly different amounts of infective
      aerosols were identified. The role of the air conditioning system was also
      assessed. There was evidence that the air conditioning system could act as a
      vehicle for the transmission of microorganisms.

PMID- 8666463
TI  - Does resin based dentine bonding work?
AB  - Since Buonocore, in the mid 1950s, introduced enamel etching to be used to bond
      resinous restorations to enamel, different resin based bonding procedures have
      continuously found their way into dental practise. Today, dentists bond materials
      not only to enamel, but also to dentine. Up until recently, the clinical success
      with dentine bonding agents had been unreliable at best, and many clinicians had
      become sceptical as to whether it would ever be possible to bond to dentine. In
      this paper, some of the important break-throughs in the field of dentinal
      adhesives are reviewed in an attempt to throw some light on the question, does
      resin based dentine bonding work? The technical procedure used to optimise
      dentine bonding is reviewed, emphasising the significance of etching dentine,
      placing the primer on a slightly moist dentine surface, avoiding oxygen
      inhibition of the bonding resin, and maximising the degree of cure. In addition,
      emphasis is also placed on the significance of variations in dentine structure,
      and how sclerotic dentine may make dentine bonding less efficient. The conclusion
      of the entire review is that although significant improvements have been made in
      the field of dentine bonding during the last few years, it is still too early to
      conclude that dentine bonding will survive several years of clinical service.

PMID- 8666462
TI  - Measuring oral health: an historical view and details of a contemporary oral
      health index (OHX).
AB  - The paper describes a new index for measuring oral health, the Oral Health Index
      (OHX). In reviewing the indices so far developed, the paper discusses the
      relative merits and disadvantages of these, especially in relation to their
      specificity to individual disease processes. The component parts of the OHX are
      described, together with pilot studies of its use and suggested future areas for
      its implementation.

PMID- 8666464
TI  - The periodontal status of Jordanian adolescents measured by CPITN.
AB  - The prevalence and severity of periodontal disease were assessed in 2039, 15-16
      year old Jordanian adolescents using the Community Periodontal Index of Treatment
      Needs (CPITN). The findings revealed that around 37 per cent of the subjects had
      a healthy periodontium (score 0), whilst 40 per cent had bleeding on probing
      (score 1). Calculus deposits (score 2) were found in 17.4 per cent of the
      subjects. Both shallow and deep pockets (scores 3 and 4) were present in only a
      small percentage of the sample (5.32 per cent and 0.29 per cent, respectively).
      When the severity of the periodontal condition was assessed, it was found that
      bleeding on probing was present in 2.4 sextants per person and calculus deposits
      in 1.04 sextants per person. The sextants which were affected by shallow and deep
      pockets were minimal (0.32 and 0.02 sextant per person respectively). The mean
      number of healthy sextants per person was found to be 2.22. These findings
      indicate that gingival rather than periodontal disease is more common in
      Jordanian adolescents.

PMID- 8666466
TI  - Correlates of war-induced stress responses among late middle-aged and elderly
      Israelis.
AB  - Over a period of six weeks in the winter of 1991, Israel was exposed to hostile
      enemy actions unlike any others in its history. In the Gulf War, civilians were
      front-line targets for Scud missiles which fell in the heart of the country's
      most heavily populated areas. One hundred and sixty-four late middle-aged and
      elderly Israelis were interviewed with respect to their emotional and behavioral
      reactions. Subjective health, gender, and attribution of meaning were the most
      significant variables, explaining most of the variance in the two measures of
      response. Satisfaction with informal network effectiveness was a relatively
      strong predictor of change in the affective distress variable. Degree of
      religious commitment and chronological age were weak but significant predictors
      of affective distress and social interaction distress respectively. Location of
      residence in relation to the missile impact zone was of no significance in
      explaining variance in the dependent measures. The findings are discussed in
      light of the uniquely subjective, interpretive context of stress phenomena, and
      the need to identify those variables that explain individual differences among
      older adults in their responses to stress.

PMID- 8666465
TI  - Caregiving and dementia: predicting negative and positive outcomes for
      caregivers.
AB  - A sample of 118 caregivers, maintaining relatives with dementia at home, were
      interviewed and completed questionnaires at initial and follow-up assessment six
      months later. All dependents received a cognitive assessment. The results of
      LISREL analysis of the data supported a model of caregiving in which negative
      outcomes of burden and impaired health reduced positive outcomes of enjoyment of
      aspects of caregiving. Caregivers with larger social support networks were more
      satisfied with their support, reducing feelings of impaired health, although as
      caregiving became more difficult, satisfaction with support decreased. The
      retrospective perception of the premorbid relationship as more difficult lead to
      the appraisal of the patient's symptoms as presently being more extensive and
      increased burden. Women caregivers reported both greater feelings of burden and
      more aspects of caregiving as enjoyable.

PMID- 8666467
TI  - Motivation in later life: theory and assessment.
AB  - A framework that has been found useful in research on young adults, Deci and
      Ryan's self-determination theory [1, 2], is suggested as a promising direction
      for research on motivation in later life. The theory proposes the existence of
      four types of motivation (intrinsic, self-determined extrinsic, nonself
      determined extrinsic, and amotivation) which are assumed to have varying
      consequences for adaptation and well-being. A previously published French measure
      of motivational styles which is known to be reliable and valid was translated
      into English and was tested on seventy-seven nursing home residents (aged 60 to
      98 years). It was found that the four motivational styles can be reliably
      measured; that the intercorrelations between the motivational styles are
      consistent with theoretical predictions; and that the four types of motivation
      are related to other important aspects of the lives of elderly people in a
      theoretically meaningful manner. Suggestions are made for further research using
      self-determination theory and the present scales.

PMID- 8666468
TI  - Successful aging, life satisfaction, and generativity in later life.
AB  - This article explores the meanings older people attach to successful aging and
      life satisfaction and how these concepts can be differentiated. Forty elderly
      employees of the Ozarks Area Foster Grandparent Program (ages 61-92) were
      randomly selected and interviewed using an open-ended survey questionnaire. These
      questions explored understandings of successful aging and life satisfaction, the
      factors essential for each, and the differences perceived between these concepts.
      Qualitative data were coded by two independent reviewers. Respondents'
      understandings of successful aging involved attitudinal or coping orientations
      nearly twice as often as those for life satisfaction. Descriptions of life
      satisfaction emphasized the fulfillment of basic needs and was viewed as a
      precursor to successful aging. Content analysis confirmed five features of
      successful aging: interactions with others, a sense of purpose, self-acceptance,
      personal growth, and autonomy. The findings suggest that generativity contributes
      to successful aging and remains a vital developmental task in later life.

PMID- 8666469
TI  - The effects of a life review program on disorientation, social interaction and
      self-esteem of nursing home residents.
AB  - This study examined the effects on veteran and novice participants of a life
      review program designed for nursing home residents with Alzheimer's disease or
      severe cognitive disfunction. Using a pre-post test experimental design,
      veterans, novices and the control group were tested for changes in
      disorientation, social interaction, and self-esteem. The results confirm the
      findings of an earlier study [1] that there is an impact of the Life Review
      Program on level of disorientation, social interaction and life review. There is
      some evidence to suggest that the improvements may be somehow stored in memory
      and triggered when the program is repeated.

PMID- 8666470
TI  - Revealing the distinction between perception and cognition through intra
      individual variability of visual evoked responses.
AB  - Searching for a method to objectively detect the cognitive activity of the brain,
      the variability of visual evoked responses (ER) was analysed in 75 human subjects
      and 10 animals. The individual ERs of a normal subject were found typically very
      scattered in the first approx. 120 ms after stimulation, converging at 160-220 ms
      and then diverging again progressively. This variability pattern (VP) is event
      related and is not attributable to background noise. On the other hand,
      statistically significant correlation showed that in most patients, with
      anatomically intact visual structures but with pronounced mental troubles, the VP
      is absent and the ERs are randomly scattered. Based on these results we consider
      that the event-related variability reflects the cognition function of the
      subjects and that it is instrumental in evidencing the distinction between
      cognitive and perceptive processes. The results are further consistent with the
      idea that cognition implies the chaotic activity of certain neural populations
      and that the VP reflects this chaotic, non-repetitive, non-linear and
      impredictable but effective neural activity.

PMID- 8666471
TI  - A new approach to differential diagnosis of diseases.
AB  - The main goal of this paper is to show the usefulness of the logic-combinatory
      approach in pattern recognition theory for developing auxiliary criteria for
      differential medical diagnosis, based on the methodology presented by Heathfield
      et al. (J Biomed Eng 13 (1991) 51-57). Firstly, we propose a change in the
      characterization base, from disease characterization to patient characterization
      then, we suggest a k-valued treatment for variables which allows us to assign
      them values in a wider range in order to represent different degrees in symptom
      manifestations. Secondly, the methodology proposed is based on Testor Theory.
      This theory allows us to obtain the minimum combination of features (symptoms)
      and the set of features combination equally discriminant (typical testors) among
      the diseases considered. Then, applying some classification algorithm that uses
      typical testors, physicians will have more making differential flexibility
      diagnosis.

PMID- 8666473
TI  - An integrated rule- and case-based approach to AIDS initial assessment.
AB  - The traditional approach to the development of knowledge-based systems (KBS) has
      been rule-based, where heuristic knowledge is encoded in a set of production
      rules. A rule-based reasoning (RBR) system needs a well constructed domain theory
      as its reasoning basis, and it does not make substantial use of the knowledge
      embedded in previous cases. An RBR system performs relatively well in a knowledge
      rich application environment. Although its capability may be limited when
      previous experiences are not a good representation of the whole population, a
      case-based reasoning (CBR) system is capable of using past experiences as problem
      solving tools, therefore, it is appropriate for an experience-rich domain. In
      recent years, both RBR and CBR have emerged as important and complementary
      reasoning methodologies in artificial intelligence. For problem solving in AIDS
      intervention and prevention, it is useful to integrate RBR and CBR. In this
      paper, a hybrid KBS which integrates a deductive RBR system and an inductive CBR
      system is proposed to assess AIDS-risky behaviors.

PMID- 8666472
TI  - Nursing information management and processing: a framework and definition for
      systems analysis, design and evaluation.
AB  - This paper discusses a new framework and definition for the development of
      nursing information systems. Graves and Corcoran presented a framework for
      nursing informatics and defined the science. In this article their framework is
      expanded to include nursing practice as domain of study and to better integrate
      the fact that nursing informatics finds its foundation in both the nursing and
      the informatics disciplines. The expansion is based on both the review of
      definitions of medical and nursing informatics and of models and descriptions
      from the informatics discipline. For research purposes, the domain of nursing
      informatics is defined, and methods for conducting investigations in the area of
      analysis, modeling and development of nursing information systems are described.

PMID- 8666474
TI  - Object-free adaptive meshing in highly heterogeneous 3-D domains.
AB  - Traditional approaches to the generation of finite element meshes are well suited
      for modeling the homogeneous or mildly heterogeneous domains presented by man
      made objects, but are difficult to apply to the complex 3-D domains encountered
      in some biomedical applications. In this paper, we describe an adaptive algorithm
      that automates the modeling of these domains. The method differs from traditional
      approaches in that no explicit description is required of the boundaries between
      objects with dissimilar material properties. The algorithm uses images of the
      tissue class to build irregular meshes, and continuity is enforced by
      constraining the solution at irregular nodes. Local estimates of the error in the
      flux solution are used to refine the mesh. For an analytic problem with a rapid
      change along a spherical boundary, the adaptive method converges to a 1% voltage
      error using 25% of the degrees of freedom required by a uniform refinement, and
      to a 5% voltage gradient error using 11% of the degrees of freedom. For a
      defibrillation model in a pig thorax, the voltage gradient solution in the
      ventricles of the heart converges to within 5% of a uniform mesh solution using
      less than 8% of the memory and processing resources required by a uniform mesh,
      which has been the only practical alternative for subject-specific modeling.

PMID- 8666475
TI  - Comparison of different neural network algorithms in the diagnosis of acute
      appendicitis.
AB  - Four different neural network algorithms, binary adaptive resonance theory
      (ART1), self-organizing map, learning vector quantization and back-propagation,
      were compared in the diagnosis of acute appendicitis with different parameter
      groups. The results show that supervised learning algorithms learning vector
      quantization and back-propagation were better than unsupervised algorithms in
      this medical decision making problem. The best results were obtained with the
      learning vector quantization. The self-organizing map algorithm showed good
      specificity, but this was in conjunction with lower sensitivity. The best
      parameter group was found to be the clinical signs. It seems beneficial to design
      a decision support system which uses these methods in the decision making
      process.

PMID- 8666476
TI  - Within-centre evaluation of hypercalcaemia discriminant functions 5 years after
      their development.
AB  - Diagnostic hypercalcaemia discriminant functions, discriminating between
      clinically significant and non-significant hypercalcaemia, were tested 5 years
      after their development in order to evaluate the impact of time on their
      diagnostic capacity. Two populations, consisting of 257 and 129 patients with
      hypercalcaemia, were consecutively recorded, during six and three months
      respectively, 5 years apart under similar circumstances. The prevalence of
      hypercalcaemia was comparable in both populations, being 2.57 and 2.38%
      respectively (non-significant) (NS). The female/male ratio was 1.9 and 1.7 (NS).
      The discriminant functions correctly classified 81 and 80% of the women,
      respectively (NS) and respectively 75% and 64% of the men (NS) in the first and
      second recorded populations.

PMID- 8666477
TI  - Feeding practices and growth among low-income Peruvian infants: a comparison of
      internationally-recommended definitions.
AB  - BACKGROUND: Data from a longitudinal study of 153 low-income Peruvian infants
      were used to assess the relationship between internationally-recommended
      definitions of feeding practices and infants' monthly weight gain and weight
      status at 12 months. METHODS: Infants were classified into feeding categories
      using monthly reported data. Analysis of variance was used to assess the
      relationship between reported usual feeding practices and growth. Reported
      breastfeeding practices were compared to observed breastfeeding practices and to
      weighted breast milk intakes to determine the validity of recommended
      breastfeeding definitions. RESULTS: Breastfed infants who consumed non-human
      milks during the first month of life gained less weight during that month (P <
      0.002) than exclusively and predominantly breastfed infants. Reported daily
      nursing frequency was associated with observed nursing frequency and breast milk
      energy intake (P < 0.05) for infants < 9 months old. Patterns of growth varied
      according to early diets. Infants who consumed breast milk and non-human milks
      and those who were fully weaned by 4 months were more likely to be underweight at
      12 months than other infants. Infants classified as token breastfeeders ( < or =
      3 times/24 hours) from 0 to 120 days had monthly gains that were similar to those
      of fully weaned infants. CONCLUSIONS: Infants feeding definitions should 1)
      continue to differentiate exclusively breastfed infants from other infants who
      are almost exclusively or predominantly breastfed; 2) distinguish partially
      breastfed infants who consume only non-breastfeeding frequency or the % of their
      total daily energy that comes from breast milk.

PMID- 8666478
TI  - Reason for termination of breastfeeding and the length of breastfeeding.
AB  - BACKGROUND: In third world countries the length of breastfeeding often has a
      major influence on child mortality, morbidity and nutritional status. When
      evaluating the impact of length of breastfeeding the reason why a mother
      terminates breastfeeding is usually not taken into consideration. METHODS: Risk
      factors for termination of breastfeeding were studied in a prospective community
      study following 1678 children in Guinea Bissau, West Africa from birth to
      cessation of breastfeeding, migration or death. RESULTS: The median weaning age
      was 22.6 months. Illness of the child, new pregnancy of the mother and illness of
      the mother were associated with significantly shorter lactation period compared
      with children weaned because they were 'healthy' or 'old enough'. These
      explanations had an impact independent of other determinants for weaning,
      including ethnic group, mother's age, mother's education, birth order and number
      of dead siblings. Weaning before 12 months of age was only associated with
      illness of the mother or child and new pregnancy and not with any socioeconomic
      or cultural factors. CONCLUSIONS: Health workers should pay special attention to
      the encouragement of breastfeeding in connection with illness of the mother or
      child; these considerations may also be important in the planning of
      breastfeeding promotion campaigns. Since premature termination of breastfeeding
      is associated with new pregnancy, family planning should be part of any
      breastfeeding promotion programme.

PMID- 8666479
TI  - Self-reported birthweight and history of having been breastfed among younger
      women: an assessment of validity.
AB  - BACKGROUND: Recent evidence suggests potential associations between birthweight
      and infant feeding history and risk of a variety of health outcomes during
      adulthood. Because studies may rely on self-reported birthweight and infant
      feeding history, it is important to assess the validity of this information.
      METHODS: The authors compared birthweights reported by a sample of 538 women, 27
      44 years of age, participating in the Nurses' Healthy Study II (NHSII) cohort,
      with birthweights recalled by their mothers and with those from state birth
      records. In addition, we compared participants' self-reported history of having
      breastfed with their breastfeeding history reported by their mothers. RESULTS:
      For birthweight, the correlation between reports by the cohort participants and
      by their mothers was high (Spearman r = 0.75). Compared with weights recorded on
      state birth records, correlations were 0.74 for reports by cohort participants
      and 0.85 for reports by their mothers. When comparing NHSII participants' self
      report of ever having been breastfed with their mothers' report, sensitivity was
      82% and specificity was 86%. For duration of breastfeeding, the Spearman
      correlation between mother and daughter reports was 0.74. In analyses stratified
      by four ethnic groups (African-American, Asian, Caucasian, and Hispanic) we
      observed substantial differences in distribution of birthweight and breastfeeding
      patterns; however, the degree of validity in reporting them was similar.
      CONCLUSION: The validity of self-reported birthweight and breastfeeding history
      by these middle-aged women appears to be high.

PMID- 8666480
TI  - Mental health of the mothers of malnourished children.
AB  - BACKGROUND: The objective of this study is to measure the association between
      protein-energy malnutrition (PEM) in children and their mothers' mental health,
      in a low income area in the city of Embu, Sao Paulo, Brazil. METHODS: A case
      control study was performed. Cases were 60 moderately and severely malnourished
      children (Gomez criteria) selected from two primary health care units. Controls
      consisted of 45 eutrophic children attending the same units. The main outcome
      measure was for the mothers to present a mental health score > 6 according with
      the 'Adult Psychiatric Morbidity Questionnaire' (QMPA), a psychiatric screening
      instrument. RESULTS: Of mothers of children with PEM, 63% and 38% of mothers in
      the control group were QMPA positive: odds ratio (OR) = 2.8 (95% confidence
      interval [CI]: 1.2-6.9). Of PEM children, 27% had low birthweight (LBW = < 2500
      g) and 6% of the control group had LBW. Interactions were found between: mothers'
      mental health and number of children (with > or = 4 children: OR = 20.0 [95% CI:
      2.1-274.2], with < or = 3 children: OR = 1.6 [95% CI: 0.6-4.5), as well as
      mothers' mental health and maternal age (in women > 30: OR = 12.5 [95% CI: 2.0
      93.4], in women < or = 30: OR = 1.5 [95% CI: 0.5-4.4]. CONCLUSIONS: Mothers of
      children with PEM showed a higher rate of mental disturbances than mothers of
      eutrophic children. Unlike LBW, maternal age and number of children interact with
      mothers' mental health, increasing the association. Management of poor mental
      health may lead to mothers being better caretakers of their children and this may
      have a positive impact on PEM.

PMID- 8666481
TI  - Serum respiratory virus antibodies: predictor of reduced one-second forced
      expiratory volume (FEV1) in Norwegian adults.
AB  - BACKGROUND: The purpose of this cross-sectional study was to investigate whether
      the presence of serum complement antibodies was associated with reduced one
      second forced expiratory volume (FEV1) in adults. METHODS: From a stratified
      random sample of 18-73 year old adults, we performed measurements of serum
      complement fixing virus antibodies against influenza type A and B, parainfluenza
      type 1, 2, and 3, respiratory syncytial virus and adenovirus on 82% (n = 1239).
      RESULTS: In the crude data, subjects having five of the seven virus antibodies
      had significantly lower lung function, given as sex-, age- and height
      standardized residuals of FEV1 (SFEV1), compared with those without. After
      adjusting in addition for smoking habits, lifetime smoking consumption and
      season, the lung function levels were significantly lower in subjects with
      influenza type B and respiratory syncytial virus antibodies compared to those
      without (P < 0.01). Increasing influenza and respiratory syncytial virus antibody
      titres and increasing numbers of virus antibodies, respectively, were related to
      progressively lower lung function. Subjects with respiratory symptoms but without
      obstructive lung disease had lower antibody levels than subjects with obstructive
      lung disease, but higher levels than asymptomatic subjects. In a final multiple
      linear regression analysis adjusting in addition for respiratory symptom and
      disease status as well as for the other respiratory virus antibodies, the
      presence of respiratory syncytial virus antibodies was a significant predictor
      for reduced SFEV1 (regression coefficient: -0.226; SE = 0.112; P = 0.04). The
      magnitude of the effect on lung function remained after excluding subjects
      reporting symptoms of respiratory infection within 3 weeks prior to the
      examination (regression coefficient: -0.252; SE = -0.218; P = 0.25). CONCLUSIONS:
      This cross-sectional community study indicates that respiratory syncytial virus
      infection or re-infection is an independent predictor for reduced lung function
      in adults of a wide age range.

PMID- 8666482
TI  - Male cancer incidence by occupation: New Zealand, 1972-1984.
AB  - BACKGROUND: This study was carried out to identify male occupational groups with
      increased incidence of cancer for the period 1972-1984 in New Zealand. No data on
      cancer incidence by occupation have been reported previously for New Zealand.
      METHODS: Age (SIR1) and age and socioeconomic level (SIR2) standardized incidence
      ratios were calculated for males 15-64 years for all cancers combined and for
      site-specific cancers by occupational group. Directly age standardized rates were
      also calculated by socioeconomic level. RESULTS: In general, occupations in
      higher socioeconomic levels had lower all-cancer incidence ratios and lower
      socioeconomic levels had higher ratios. However, the highest socioeconomic level
      (level 1) had a higher all-cancer incidence rate than levels 2-6. After
      socioeconomic adjustment in increased incidence ratio for lung cancer was found
      for jewellery and precious metal workers (SIR2 = 241; 95% confidence interval
      [CI]: 116-146), and bricklayers and carpenters (SIR2 = 130; 95% CI: 120-433),
      Woodworkers had increased ratios for stomach (SIR2 = 144; 95% CI: 110-186) and
      rectal cancer (SIR2 = 146; 95% CI: 116-181). Firefighters had an increase for
      laryngeal cancer (SIR2 = 1074; 95% CI: 279-2776). CONCLUSIONS: Research appears
      to be warranted to further investigate associations of laryngeal cancer in
      firefighters, lung cancer in jewellery and precious metal workers and bricklayers
      and carpenters, and digestive cancers in woodworkers.

PMID- 8666483
TI  - Influence of gender on susceptibility to multiple sclerosis and age of onset in
      concordant sibships.
AB  - BACKGROUND: Research has produced conflicting findings about whether there is an
      excess of like-sexed pairs among concordant multiple sclerosis (MS) sibships.
      Although a positive correlation in onset age among sibling pairs overall has been
      reported, no data have been published describing age at onset correlations for
      like-sexed versus unlike-sexed pairs. The purpose of this study was to provide
      additional information on both issues. METHODS: Patients with an MS sibling were
      sought through the files of the University of Alberta MS clinic (Edmonton,
      Canada). The clinic neurologist either reviewed clinical/autopsy material or
      assessed relatives of index cases prior to accepting the relative as having MS.
      Pairs of siblings (excluding twins) were divided into (1) male-male pairs, (2)
      female-female pairs, and (3) female-male pairs. RESULTS: A total of 62 concordant
      sibling pairs were identified. There were 33 like-sexed pairs (6 male-male/27
      female-female) and 29 unlike-sexed pairs. The observed number of like-sexed pairs
      was not significantly different from the expected frequency using 2 x 2 chi2
      analysis, where expected values represent the binomial distribution predicted
      from the frequency of each sex as determined by total number of males and
      females. The age at onset intraclass correlation coefficient was -0.09 for
      sibling pairs overall, -0.22 for like-sexed pairs and +0.02 for unlike-sexed
      pairs. CONCLUSIONS: This study does not provide evidence for an association
      between disease susceptibility and gender in siblings concordant for MS; nor does
      it suggest that genetics plays a role in onset age.

PMID- 8666484
TI  - Screening for stereopsis without the use of technical equipment: scale
      development and cross-validation.
AB  - BACKGROUND: Although adequate stereopsis is important for many common sensory
      motor activities, large-scale normative samples of the relationship between
      stereopsis and other individual difference variables are relatively scarce, and
      stereopsis is often not routinely tested even in settings where it might play an
      important role. This is, in part, due to the fact that data collection requires
      individual testing, the use of costly technical equipment and trained personnel.
      METHOD: Beginning with a pool of 161 items and an initial sample of 542
      individuals, we developed a self-report inventory-suitable for group testing,
      survey administration or rapid individual screening--possessing a high
      correlation with laboratory measures of stereopsis. The inventory was then cross
      validated against laboratory measures of stereo-acuity in a separate sample of
      573 subjects. RESULTS: For the combined samples, the resulting 10-item Stereopsis
      Screening Inventory (SSI) correlated with laboratory measures of per cent
      stereopsis (r = 0.80). The inventory's reliability was assessed with a resulting
      internal consistency coefficient (alpha) of 0.88. CONCLUSIONS: The SSI provides a
      fast, valid and inexpensive measure of uncorrected stereopsis which can be used
      for rapid screening or epidemiological surveys. The correct classification rate
      for the SSI was 84% for a low fence requiring 65% stereopsis or better, and 81%
      for a high fence of residual stereopsis of 25% or less. A conversion equation,
      with inventory and scoring procedure is given in the Appendix.

PMID- 8666485
TI  - Retest reliability of recall measures of leisure-time physical activity in
      Australian adults.
AB  - BACKGROUND: Several studies have reported that short-term recall measures of
      physical activity participation have acceptable repeatability, but in most cases
      employed convenience samples and did not use optimal statistics. In this
      Australian study repeatability was assessed on participants recall of activity
      over two different time periods and over the same time period. METHODS: Two 14
      day recall measures of physical activity participation were administered in two
      studies to randomly selected population samples of adults in Adelaide, South
      Australia. Intraclass correlation coefficients (ICC), 80% and 95% limits of
      agreement and the kappa statistic were calculated. RESULTS: For a continuous
      measure of energy expenditure the ICC was 0.86 using recall of the same 2-week
      period (N = 115), and was 0.58 for activity recalled over different 2-week period
      (N = 116). For categorized energy expenditure (inactive, low, Moderate and
      Vigorous categories), kappa was 0.76 for recall of the same period and was 0.36
      for different recall periods. Similar results were observed for continuous and
      categorical forms of a measure of physical activity that recorded frequency of
      participation in vigorous and moderate activities and walking. The 80% limits of
      agreement were markedly smaller than 95% limits of agreement, but were still
      large. CONCLUSIONS: These data suggest that the variation in repeatability
      coefficients between recall of the same 2-week time period and activity recalled
      over different 2-week periods was due to actual variation in physical activity
      participation over different time periods, and not to poor recall or to poor
      measurement characteristics. The recall measures appear to have good
      repeatability for most respondents, but repeatability is poor for a substantial
      minority of the population.

PMID- 8666486
TI  - Predictors of life satisfaction amongst retired people in Paris.
AB  - BACKGROUND: The objective of the present study was to examine predictors of life
      satisfaction in a survey of retired men and women living in the Paris
      Metropolitan area. METHODS: In all 627 subjects took part in the first phase of
      the survey (1982-1983, T1), and 464 in the follow-up phase (1987-1988, T2) during
      which life satisfaction was evaluated, using the Life Satisfaction Index A
      (LSIA). Possible predictors were explored among the factors characterizing
      subjects at T1 and among those related to their occupational history. RESULTS: In
      the multivariate analyses, significant relationships were found between life
      satisfaction and the number of physical impairments and leisure activities,
      marital and mental health status and family relations. Taking into account the
      changes in these factors between the two phases of the survey increased the
      predictiveness of the regression models. CONCLUSIONS: These results confirm the
      links between life satisfaction and the factors generally recognized as its
      determinants. On the other hand, no effect of past occupational characteristics
      on life satisfaction long after retirement was shown.

PMID- 8666488
TI  - Statistical choropleth cartography in epidemiology.
AB  - BACKGROUND: The potential of maps in the study of regional variation and
      similarity in health and in understanding the underlying processes is being
      increasingly realized. It has thus become important that more care is exercised
      in drawing health maps and the subjective elements are minimized. Conventional
      choropleth maps based on qualitative data are mostly arbitrary with regard to the
      number of categories and the cutoff points. This can lead to substantially
      different pictures based on the same data set. METHODS: We suggest use of cluster
      methods to discover 'natural' groups of data points which to a large extent are
      suggested by the data themselves. These methods can determine not only the cutoff
      points but also the number of categories required to depict the variability in
      the data. The methods have natural extension to the multivariate set-up and thus
      can provide the strategy to construct integrated maps based on the simultaneous
      consideration of several variables. Since different cluster methods can yield
      different grouping we propose a simple method to identify cutoffs common to a
      majority of the methods. RESULTS: The details of the methods are explained on two
      real data sets. One is the indicators of mortality before one year of age in
      India and the other is years of life lost due to premature mortality in different
      countries. The maps obtained are compared with the conventional maps. CONCLUSION:
      The cutoff points obtained by a majority of cluster methods deserve attention for
      obtaining natural groups for choroplethic depiction. Maps based on such cutoffs
      seem to have promise for increasing the accuracy in perception and cognition of
      regional variation.

PMID- 8666487
TI  - An interview technique for recording work postures in epidemiological studies.
      Music-Norrtalje Study Group.
AB  - BACKGROUND: The aim of the study was to present and evaluate a work-task-oriented
      interview technique focusing on the placement of the hands relative to the body
      and assessing per cent time spent in five standard work postures during a working
      day. METHODS: The reproducibility of estimated time spent in each work posture
      was tested by the test-retest method in 32 subjects; 16 were interviewed by the
      same interviewer and 16 were interviewed by another one at the retest. The
      validity concerning estimated time spent in th five standard work postures was
      tested in relation to observations in 58 male blue-collar workers. The mean
      registration (assessment) time was 6 hours and 15 minutes. RESULTS: No evident
      differences in the reproducibility depending on same or different interviewers at
      test and retest could be observed. The linear relationship between times
      estimated by the interview and by observations was high for four of the work
      postures: 'sitting' (r = 0.86), 'standing with hands above shoulder level' (r =
      0.87), 'between shoulder and knuckle level' (r = 0.75), and 'below knuckle level'
      (r = 0.93). When the work posture 'standing with hands between shoulder and
      knuckle level' was divided into 'hands fixed' (r = 0.62) and 'hands not fixed' (r
      = 0.50) the correlations were weak. Current musculoskeletal complaints did not
      influence the accuracy of the estimations. CONCLUSIONS: The present task-oriented
      interview technique may be the best available method to estimate these work
      postures in a way that requires few resources compared to observations and
      technical measurements.

PMID- 8666489
TI  - AIDS-related conditions: study of a representative sample of 1203 patients
      deceased in 1992 in France.
AB  - BACKGROUND: Little representative information exists on the frequency of human
      immunodeficiency virus (HIV)-related diseases among the overall AIDS population.
      The objective of this research is to assess the nature, frequency and
      characteristics of these diseases among AIDS patients during their last year of
      life and to analyse these frequencies according to the mode of transmission and
      other socio-demographic and medical characteristics. METHODS: To obtain
      comprehensive data, we conducted an investigation based on retrospective
      collection of clinical information on a representative sample (1203 deaths) of
      all AIDS deaths that occurred in France during 1992. RESULTS: The frequency of
      the diseases was markedly higher than the one described in the AIDS surveillance
      registers and varied between homosexuals and intravenous drug users (IVDU). After
      controlling for other variables (age, CD4 counts, survival times) by means of
      logistic regression, homosexuality remained a significant explaining factor for
      Kaposi's sarcoma, cytomegalovirus infections, herpes simplex and
      cryptosporidiosis. In contrast, HIV encephalopathy, hepatitis, mental disorders,
      invasive candidiasis and cachexia were more frequent in male IVDU. Few
      differences were observed by sex. CONCLUSIONS: Several factors may explain the
      differences: variation in exposure to infectious agents, general health status,
      use of medical care and direct influence of the mode of HIV transmission. These
      data are of particular value for medical services in planning the magnitude of
      health care needs among the AIDS population overall, for clinicians and
      researchers for advancing the understanding of the natural history of AIDS and in
      the definition of prophylactic strategies against opportunistic infections.

PMID- 8666490
TI  - A not quite as quick but much cleaner alternative to the Expanded Programme on
      Immunization (EPI) Cluster Survey design.
AB  - BACKGROUND: Although the Expanded Programme on Immunization (EPI) cluster survey
      methodology has been successfully used for assessing levels of immunization
      programme coverage in developing country settings, certain features of the
      methodology, as it is usually carried out, make it less-than-optimal choice for
      large, national surveys and/or surveys with multiple measurement objectives. What
      is needed is a 'middle ground' between rigorous cluster sampling methods, which
      are seen as unfeasible for routine use in many developing country settings, and
      the EPI cluster survey approach. METHODS: This article suggests some fairly
      straightforward modifications to the basic EPI cluster survey design that put it
      on a solid probability footing and render it easily adaptable to differing and/or
      multiple measurement objectives, without incurring prohibitive costs or adding
      appreciably to the complexity of survey operations. The proposed modifications
      concern primarily the manner in which households are chosen at the second stage
      of sample selection. CONCLUSIONS: Because the modified sampling strategy
      maintains the scientific rigor of conventional cluster sampling methods while
      retaining many of the desirable features of the EPI survey methodology, the
      methodology is likely to be a preferred 'middle ground' survey design, relevant
      for many applications, particularly surveys designed to monitor multiple health
      indicators over time. The fieldwork burden in the modified design is only
      marginally higher than in EPI cluster surveys, and considerably lower than in
      conventional cluster surveys.

PMID- 8666491
TI  - Prevalence of antibiotics to hepatitis C in a population of intravenous drug
      users in Valencia, Spain, 1990-1992.
AB  - BACKGROUND: Hepatitis C has been related to other viral diseases such as the
      human immunodeficiency virus infection (HIV) or hepatitis B (HBV). The objective
      of this study was to estimate the prevalence and determinants of antibodies to
      hepatitis C virus (HCV) in intravenous drug users (IVDU) in Valencia (Spain) and
      to compare the seroprevalence between the HCV, HIV and HBV in this high risk
      group. METHODS: A cross-sectional study was conducted in a sample of 1056 current
      IVDU from the Valencia area who attended the city's AIDS Information Centre
      between January 1990 and December 1992. Information on sociodemographic, sexual
      behaviour, and drug use variables was collected by means of a structured
      questionnaire. Antibodies to HCV, HIV and HBV were assayed by ELISA test.
      RESULTS: The seroprevalence of HCV for the whole period was 85.5% (95% confidence
      interval [CI]: 83.2-87.5%), ranging from 76.5% in 1990 (95% CI: 71.9-81.1%) to
      87.8% in 1992 (95% CI: 82.5-93.1%). Year of testing and prevalence of HBV markers
      showed an independent association with HCV seroprevalence. When only IVDU aged <
      25 years were analysed, sharing of needles also appeared as an independent
      dominant. Of those IVDU with less than one year of addiction, 69% were HCV
      seropositive compared with 41% for HBV and 14% for HIV. CONCLUSIONS: Intravenous
      drug users in Valencia showed one of the highest reported hepatitis C
      seroprevalences (85.5%). A more efficient parenteral transmission of hepatitis C
      virus than HBV or HIV is suggested.

PMID- 8666492
TI  - Increased risk of Helicobacter pylori associated with birth in wartime and post
      war Japan.
AB  - BACKGROUND: Helicobacter pylori infection is now widely recognized as a cause of
      stomach cancer. We assessed trends in H. pylori infection in Japan, a population
      with high rates of gastric malignancy. METHODS: Using an enzyme-linked
      immunosorbent assay (ELISA), we tested sera collected between 1980 and 1993 from
      Tokyo University Hospital patients for anti-H. pylori IgG. Patients ranged in age
      from 0 to 94 years. Helicobacter pylori prevalence was then assessed for age
      and/or birth cohort effects. RESULTS: Of 1207 sera, 470 (38.9%) were positive for
      H. pylori IgG. By univariate analysis, both older age and birth in an earlier
      decade were associated with an increased risk of infection. Age-specific
      prevalence of H. pylori by birth cohort suggested increases in infection during
      the decades from 1900 to 1959, and age-specific decreases since 1960. In
      multivariate analysis, H. pylori infection increased with age and was most
      prevalent among those born in the 1940s and 1950s. CONCLUSION: Relative to other
      birth cohorts, people born in the 1940s and 1950s have a higher prevalence of H.
      pylori. This increased prevalence of infection among those born in wartime Japan
      likely attests to the impact of compromised living conditions on acquisition of
      H. pylori, and may portend continued high rates of gastric cancer in forthcoming
      years.

PMID- 8666493
TI  - Alcohol and all-cause mortality.

PMID- 8666494
TI  - Alcohol and all-cause mortality.

PMID- 8666495
TI  - Blood pressure and cancer in middle-aged British men.
AB  - BACKGROUND: This paper examines the relationship between blood pressure and
      cancer mortality. METHODS: A prospective study of 7735 middle-aged men drawn at
      random from one general practice in each of 24 British towns. RESULTS: During a
      mean follow-up period of 12.75 years there were 351 deaths from cancers. The
      relationship between blood pressure and cancer differed with respect to follow-up
      period. In the first 5 years of follow-up, a significant inverse relationship was
      seen between systolic (SBP) and diastolic blood pressure (DBP) and cancer
      mortality even after adjustment for age, smoking, social class, physical
      activity, alcohol intake, body mass index, diabetes, pre-existing ischaemic heart
      disease, use of antihypertensive drugs, cholesterol, heart rate and serum
      albumin. In the subsequent follow-up period (5.1-12.75 years) a significant
      positive association was seen between SBP (but not DBP) and risk of cancer
      mortality, even after adjustment for the other risk factors. Men in the top fifth
      of SBP ( > or = 161 mmHg) showed over a 50% increase in risk of cancer mortality
      compared to men in the bottom quintile (RR = 1.56 95% CI 95% CI: 1.04-2.38). This
      positive relationship between SBP and cancer was seen only in current cigarette
      smokers. Use of antihypertensive drugs was not associated with cancer mortality.
      CONCLUSION: The association of elevated SBP with increased risk of cancer
      mortality seen only in current smokers warrants the search for factors which
      affect SBP, interact with smoking and are potentially carcinogenic.

PMID- 8666496
TI  - Infant feeding and development.

PMID- 8666497
TI  - Social desirability bias in dietary self-report may compromise the validity of
      dietary intake measures. Implications for diet disease relationships.

PMID- 8666498
TI  - Ethanol intake and body weight among smokers.

PMID- 8666499
TI  - Aromatic amine exposure and oesophageal cancer.

PMID- 8666500
TI  - A census of European health surveys.

PMID- 8666501
TI  - Dietary factors and lung cancer among men in west Sweden.
AB  - BACKGROUND: Previous studies have reported an association between tea drinking
      and lung cancer. In view of these data, the relationship between tea drinking as
      well as other dietary factors and lung cancer was investigated in a case-control
      study in the west of Sweden. METHODS: Patients with suspected lung cancer were
      collected from pulmonary units at central hospitals in the area investigated, and
      population controls were matched for age. The material reported here comprises
      308 male cases with a confirmed diagnosis of lung cancer and 504 controls. The
      participants were interviewed by specially trained nurses, using a questionnaire
      to assess smoking, dietary habits, occupational exposures and conditions in the
      residential area (local air pollution). This paper reports the results from
      dietary factors studied with a food frequency technique. RESULTS: The results
      demonstrated a strong protective effect of vegetables (odds ratio [OR] = 0.69,
      95% confidence interval [CI]: 0.46-1.05, and OR = 0.37, 95% CI: 0.23-0.61 for
      intermediate and high consumption classes respectively). A low OR was consistent
      for all histological types of lung cancer. High consumption of fruits did not
      show any similar protective effect. Drinking milk was associated with a dose
      response related risk increase after adjustment for smoking and vegetable
      consumption (P for trend = 0.07). Odds ratio was 1.73, 95% CI: 1.00-3.01 for high
      consumption of milk. CONCLUSIONS: High intake of vegetables had a strong
      protective effect among males. Diet is thus a potential confounding factor in
      studies on lung cancer and environmental factors and should thus be taken into
      consideration in the planning of such studies.

PMID- 8666503
TI  - Surveillance for equity in cervical cytology screening.
AB  - BACKGROUND: The opportunistic basis on which screening has been conducted in
      South Africa has resulted in multiple rescreening of a small proportion of the
      population (which excludes most women at high risk) and low population coverage.
      There has consequently been a failure of screening to impact on the incidence of
      cervical cancer in most of the population. AIM: To propose the use of the ratio
      of smears showing cervical intra-epithelial neoplasia (CIN)III: smears showing
      signs of malignancy as an indicator for the surveillance of equity in cervical
      cytology screening, and to apply this indicator to an area of the Western Cape of
      South Africa. RESULTS: Marked inequity in screening is demonstrated between
      metropolitan and non-metropolitan area, and between different non-metropolitan
      districts. Inequity in screening between different age groups of women is also
      found, and this is associated with an inappropriately young age distribution of
      screening activity. CONCLUSIONS: The application of this indicator in the routine
      surveillance of screening activity may be useful in monitoring progress towards
      the implementation of more equitable screening programmes, and the validity of
      the indicator should be tested in other settings.

PMID- 8666502
TI  - Breast cancer in Singapore: trends in incidence 1968-1992.
AB  - BACKGROUND: Breast cancer is the most commonly occurring cancer among women in
      Singapore, a country which has experienced significant changes in lifestyle over
      the past three decades. The increase in incidence of the disease is a matter of
      some concern. METHODS: Data from the population-based Singapore Cancer Registry
      for 1968-1992 were used to determine time trends, inter-ethnic differences and
      the contributions of age, period and cohort effects to the incidence of the
      disease. RESULTS: Our results revealed an average annual increase of 3.6% over
      the 25-year period for all women, form 20.2 per 100,000 women in the period 1968
      1972 to 38.8 per 100,000 in 1988-1992. There was a statistically significant
      difference between the three major ethnic groups, the rate of increase being
      highest in Malays (4.4%) and lowest in Indians (1.4%). The overall increase was
      attributable to a strong cohort effect that remained significant when adjusted
      for time period for Chinese women and for all ethnic groups combined. The risk
      was observed to increase in successive birth cohorts from the 1890s to 1960s.
      CONCLUSIONS: Our results suggest that breast cancer incidence rates are likely to
      continue to increase more sharply in the future as women born after the mid-20th
      century reach the high-risk age groups. They also suggest the pattern by which
      important aetiological factors for the disease in our population have exerted
      their effects, and provide support for the role of demographic and lifestyle
      changes as possible risk factors.

PMID- 8666505
TI  - Cervical neoplasia in pap smears: risk of cervical intra-epithelial neoplasia
      (CIN) after negative or no prior smears in a population without a mass screening
      programme.
AB  - BACKGROUND: The aim of this study was to examine, in a population not submitted
      to mass screening, the risk of cancer and cervical intra-epithelial neoplasia
      (CIN) in Pap smears from women without previously reported positive smears.
      METHODS: In a logistic regression model consisting of 58,271 smears from 40,536
      Norwegian women the risk of cytologically indicated CIN was studied according to
      age and time elapsed since last smear. RESULTS: The risk of CIN was highest in
      smears from women with no previously registered smears and in smears taken after
      an interval of > or = 5 years. Odds ratio for CIN I-II adjusted for age was
      highest in first time smears and in smears taken after an interval of 5 years.
      Odds ratio for CIN III was highest in first registered smears. No difference in
      risk of CIN III was found in smears taken within one year or 2-3 years after the
      last smear. The increased risk of CIN III in first smears was most pronounced in
      postmenopausal women ( > 50 years). Nine of 16 cases with cytological indication
      of cancer were found in women having a smear taken for the first time. All cases
      with malignancy in smears were > 50 years. CONCLUSIONS: The risk of cytologically
      diagnosed premalignant cervical conditions increases with time since the previous
      smear, but more than 5 years have to elapse before the risk is comparable with
      that in first smears taken. Postmenopausal women without previous smears run the
      highest risk of serious cervical premalignancies and cancer.

PMID- 8666504
TI  - Cancer mortality among north African migrants in France.
AB  - BACKGROUND: Data on cancer mortality in North African migrants to France (the
      largest foreign-born community in the country) are presented, providing useful
      insights both into cancer patterns in North Africa and their changes following
      migration. METHODS: The cancer mortality in migrants from North Africa (Algeria,
      Morocco, Tunisia and Egypt) resident in France relative to that of the local-born
      population, is estimated from mortality data for the period 1979-1985, and
      population data from the 1982 French census. Risks of death from different
      cancers were adjusted for important confounding factors such as social status and
      area of residence. RESULTS: The risks are quite similar for Algerian, Tunisian
      and Moroccan migrants. Compared to the local-born, those Maghrebian migrants of
      one or both sexes have higher risks of death from cancer of the nasopharynx,
      gallbladder and bladder (in Algerians only). Conversely, Maghrebian migrants have
      lower risks of death from cancer of the oral cavity, other pharynx, oesophagus,
      stomach, colon, rectum, lung, larynx, melanoma (in Algerians only), kidney and
      nervous system (except in Tunisians), breast, ovary, and cervix uteri (except in
      Moroccans). For Egyptian migrants, because of small numbers, few of the estimates
      are statistically significant. They are at lower risk of death from lung cancer
      and at higher risk for lymphoma and leukaemia. CONCLUSION: The findings provide
      confirmatory evidence of the unusual cancer patterns among North African
      populations, who have low risks for most cancer sites, and high risks for certain
      cancers, such as of the nasopharynx and bladder.

PMID- 8666506
TI  - High mortality from cardiovascular disease and analysis of risk factors in Indian
      and Melanesian Fijians.
AB  - BACKGROUND: In recent years, developing populations such as the Pacific island
      nation of Fiji, have seen decreases in infectious diseases and increasing
      frequency of cardiovascular diseases (CVD), diabetes and cancer. However, cohort
      studies of mortality in these populations are scarce. Here we report 11-year all
      cause and cause-specific mortality rates and risk factors for total, CVD and
      coronary heart disease (CHD) for indigenous Melanesian and Asian Indian people of
      Fiji. METHODS: Following a baseline risk factor survey in 1980, mortality
      surveillance continue until 1991 in a representative cohort of 1325 Melanesians
      and 1221 Indians from urban and rural areas of Fiji. Date and cause of death were
      recorded and total, CVD and CHD mortality rates calculated. Baseline predictors
      of mortality were assessed using Cox regression. RESULTS: Total mortality rates
      in Melanesians were 15.9 and 9.2/1000 person-years, and in Indians were 13.5 and
      6.8/1000 person-years, in men and women respectively. Death due to CHD was more
      common in men than women, and in Indian than Melanesian men, although total CVD
      deaths were more common in Melanesian men. Deaths due to CHD were more common in
      the urban than the rural area. After adjusting for other risk factors Indian
      ethnicity was associated with a significantly reduced risk of total and CVD
      mortality in men, and total mortality in women. Age and systolic blood pressure
      were consistently and independently associated with mortality from all causes, as
      well as CVD and CHD (except in Indian women). In men associations were also
      identified for total cholesterol with CVD and CHD mortality in Melanesians, and 2
      hour plasma glucose with total and CVD mortality in Indians. In women, 2-hour
      glucose was important for total, CVD and CHD mortality in both ethnic groups as
      was smoking in Indians. Obesity had inconsistent associations with mortality.
      CONCLUSION: Cardiovascular disease is now responsible for a large proportion of
      total mortality in both Indian and Melanesian Fijians. The major risk factors
      identified in Fijians are similar to those observed in developed populations.

PMID- 8666507
TI  - Do dietary and supplementary intakes of antioxidants differ with smoking status?
AB  - BACKGROUND: Differences in dietary and supplementary intake of antioxidants were
      determine between different categories of smokers and never-smokers. METHODS:
      Data from a large, cross-sectional, population-based study were used. Subjects (n
      = 4244) were divided into five smoking categories according to the number of
      cigarettes smoked per day. Differences in intake of antioxidants or frequency of
      supplement use were assessed using multiple linear regression analysis and
      multiple logistic regression analysis, adjusting for potential confounders such
      as age, body mass index, education level, alcohol intake, and total energy
      intake. RESULTS: Men who smoked > 20 cigarettes/day had significantly lower
      intakes of beta-carotene and especially ascorbic acid compared to those who never
      smoked, resulting from an almost 60% lower fruit intake. Moderate and heavy
      smoking women also had lower ascorbic acid and fruit intake but differences were
      not as large as in men. A higher percentage of female heavy smokers compared with
      never-smokers consumed vitamin C (21.1% versus 14.1%), vitamin E (5.6% versus
      1.8%), and multivitamin supplements (18.5% versus 12.2%). Among men only the
      moderate smokers differed significantly from never-smokers in supplement intake,
      in the sense that male moderate smokers had a higher percentage of multivitamin
      use (15.3% versus 12.2%) compared to never-smokers. CONCLUSIONS: Male heavy
      smokers not only have a lower dietary antioxidant intake than never-smokers, but
      additionally seem to use supplementation relatively infrequently.

PMID- 8666508
TI  - Body mass index and disability pension in middle-aged men--non-linear relations.
AB  - BACKGROUND: Obesity has, in a number of studies, been found to correlate to
      disability and mortality, primarily due to diseases of the circulatory and
      musculoskeletal systems. In addition, an excess mortality among underweight
      subjects has been observed in previous studies. METHODS: Five complete birth-year
      cohorts (1926-1930) of male residents in Malmo (n = 7697) were invited to the
      survey at the Department of Preventive Medicine, Malmo General Hospital, and 5926
      (77%) attended with complete data. Each subject was followed from inclusion,
      defined by the date of examination, until the end of the calendar year when he
      turned 58, a total study period of approximately 11 years. Data on about 300
      questionnaire items and laboratory tests were determined at the health survey
      visit. Nationwide Swedish data registers were used for surveillance. RESULTS: Of
      the participants, 4.7% were underweight, 37.7% overweight, 7.3% obese and 50.3%
      normal weight; 849 (14.3%) had been granted disability pension at the end of
      follow-up, 717 after screening. After adjustment for smoking there was a J-shaped
      relation between body mass index (BMI) and incidence of disability pension, the
      relative risk ( with the normal group as reference) among underweight men being
      1.9. For the overweight subjects it was 1.3 and for the obese 2.8, all
      differences were significant. Disease of the musculoskeletal and circulatory
      systems and mental disorders accounted for 67.2% of all main diagnoses resulting
      in disability pensions during follow-up. A total of 377 (6.4%) men died during
      follow-up. Diseases of the circulatory system, neoplasms, injury/poisoning and
      diseases of the respiratory system accounted for 91.8% of the deaths.
      CONCLUSIONS: Both underweight, overweight and obesity were related to risk of
      disability pension, with a J-shaped risk relationship.

PMID- 8666509
TI  - Conditioning leisure time physical activity and cardiorespiratory fitness in
      sociodemographic groups of middle-ages men in eastern Finland.
AB  - BACKGROUND: Physical inactivity and poor cardiorespiratory fitness have been
      found to be associated with an increased risk of coronary heart disease,
      hypertension, stroke, non-insulin-dependent diabetes mellitus and cancer METHODS:
      To characterize the least active and the least fit sociodemographic groups of
      middle-aged males, we investigated conditioning leisure time physical activity
      and maximal oxygen uptake (VO2max) in a population sample of 2589 men aged 42-60
      years in Eastern Finland. RESULTS: In covariate models, younger (P = 0.004),
      rural (P < 0.001), married or engaged (P = 0.04), lower income (P = 0.009), and
      employed men (P < 0.001), as well as farmers (P < 0.001) had a shorter duration
      of physical activity, whereas older (P < 0.001), urban (P = 0.05), single (P <
      0.001), less educated (P < 0.0001), lower income (P < 0.001), and unemployed or
      retired men (P < 0.001), as well as blue-collar workers (P < 0.001) had a lower
      mean intensity of physical activity than others. Older (P < 0.001), single (P <
      0.001), less educated (P < 0.001), lower income (P < 0.001), and unemployed or
      retired men (P < 0.001), as well as blue-collar workers and farmers (P < 0.001)
      had lower VO2max than others. CONCLUSION: On the basis of our data, for health
      promotion regarding physical activity, special attention should be paid to people
      in a lower socioeconomic position.

PMID- 8666510
TI  - The effect of changes in population characteristics on breastfeeding trends in
      fifteen developing countries.
AB  - BACKGROUND: Extended breastfeeding is known to benefit the health of children in
      developing countries and despite widespread expectations of a decline in
      breastfeeding in these countries, it has been demonstrated that the incidence and
      duration of breastfeeding are in fact increasing many countries. METHODS: In this
      paper, trends in breastfeeding duration are examined in 15 developing countries,
      using data from two comparable surveys for each country, the World Fertility
      Survey (conducted in the late 1970s) and the Demographic and Health Survey
      (conducted in the late 1980s). Multivariate regression models are used to examine
      differentials in breastfeeding behaviour across population subgroups in these
      countries for each time period, and these differentials are used to determine the
      extent to which the observed trends are due to changes in population
      characteristics and to what extent behaviour has changed within population
      subgroups. RESULTS: Results show that changes in the characteristics of the
      population have almost universally pushed breastfeeding durations in the downward
      direction. On the other hand, trends within population subgroups have been
      positive in all but two of the 15 countries examined. CONCLUSIONS: Changes in
      population characteristics can be expected to continue for most developing
      countries, exerting a downward pressure on breastfeeding. Policies that promote
      breastfeeding are needed to counter these changes, especially in the most
      vulnerable population subgroups.

PMID- 8666511
TI  - [Epidemics and causal evidence].

PMID- 8666512
TI  - [Agreement between information supplied by the patient and a family member on
      medical history, consumption of tobacco, alcohol and coffee and diet in cancer of
      the exocrine pancreas and extrahepatic biliary tract].
AB  - OBJECTIVE: No study on mutations in the K-ras oncogene and cancer of the exocrine
      pancreas or cancer of the biliary system has analyzed the reliability of clinical
      and epidemiological information. METHODS: Agreement between patient and surrogate
      on factors potentially related to both tumours was evaluated within a multicentre
      prospective study. Interviews were personally administered to both patient and
      surrogate (N = 110 pairs). Agreement was examined via the simple kappa index (k),
      the weighted kappa index (kw), the percentage of simple agreement, and the
      percentages of positive and negative agreement. RESULTS: Agreement for medical
      history was excellent (k between 0.89 and 0.76), as it was for tobacco
      consumption (k = 0.98). Agreement was moderate for coffee consumption (k = 0.68),
      frequencies of food groups (kw from 0.66 to 0.38), and consumption of alcoholic
      drinks (k from 0.66 to 0.32). Surrogates indicated a higher consumption of
      alcohol than patients. CONCLUSION: Surrogates can be an alternative source of
      information when patients cannot be interviewed, but information on alcohol
      consumption should be treated with caution.

PMID- 8666513
TI  - [Influence of age and sex on various types of utilization of the primary health
      care].
AB  - OBJECTIVE: To find out the influence of gender and age on various types of
      utilization of primary care services. METHOD: A random sample group containing
      2662 patients over 14 years of age was observed over a continuous period of a
      year. Having already excluded the losses subjects, health service utilization was
      measured using patients whose clinical records had previously been validated.
      RESULTS: A small number of patients (15%) use a disproportionate amount of the
      total number of visits. A numerical breakdown shows: 43% of global visits (GV),
      45% of acute clinical visits (ACV), 68% administrative visits (AV) and 94%
      programmed visits (PV). The ACV, PV and GV were significantly higher in woman (p
      = 0.000), though in the AV was not the case. These remained a significant
      difference when age was controlling factor. The coefficients of correlation
      between age and the logarithm of the ACV, AV, PV and GV were respectively 0.27,
      0.23, 0.40 and 0.41. Gender is not a consideration with regard to use of health
      services below 35 and above 75 years of age. In multiple lineal regression
      equations age stands out as the most predictive variable, followed by gender,
      excluding the AV where the doctor comes before gender. CONCLUSION: A small group
      of highusers use a desproportionate amount of the total number of visits,
      particularly the AV and PV. The positive correlation between age and utilization
      is more clear by the PV and GV. The female is more user than the male, specially
      among 35 and 75 years old; although the gender is not determinant by the AV.
      There is not much explained variability with the age and gender, but the age is
      more important than the gender on utilization.

PMID- 8666514
TI  - [How much and how are we using the Hospital Morbidity Survey?].
AB  - OBJECTIVE: The Hospital Morbidity Survey (HMS) is the only national level
      systematic statistic of morbidity attended in Spanish hospitals. The aim of this
      work is to describe publications related with HMS. METHODS: A review was carried
      out of Spanish scientific literature by means of an automatic literature search
      with the Spanish Medical Index (1971-1993), completed manually. RESULTS: 31
      publications were found related to the HMS of which 10 are applied works directly
      using its results, other 13 publications deal with the quality (compliance
      diagnosis agreement between sources or others) of the HMS and 8 are reflections
      on the utility and limitations of the survey. CONCLUSIONS: Despite de number of
      scientific articles that use the HMS represents an underestimation of the real
      use of HMS, we conclude that the scientific utilization of HMS is very low.

PMID- 8666515
TI  - [Search strategies for retrieval of articles in Spanish journals. A case study:
      evaluation of the quality of information systems].
AB  - OBJECTIVES: To describe a systematic procedure for exhaustive retrieval of
      Spanish articles about evaluation or health information systems (1983-1992); to
      analyze the useful terms, the item contribution and the retrieval failures of the
      sources. METHODS: As sources for identification of articles, data base Indice
      Medico Espanol (IME), contents of journals and references of the retrieved items
      have been used. As analysis variables, coincidence of terms in search profile,
      item's titles and key words; item contribution, specific contribution and overlap
      indexes; hindsight analysis of failures. RESULTS: 94 items have been retrieved,
      83 of them have, at least one term related with the subject. Referred to sources
      contribution, IME gives 74 items; journal contents 75 and references 33. Specific
      contribution of IME was 16 items, contents 12 and references 2. Overlap between
      sources was 25.5%. CONCLUSION: The three sources are complementary. Complete
      retrieval of the literature requires systematic use of the abstracts and
      references of the papers, where the perception of its contents are less dependent
      of the terms used in the titles.

PMID- 8666516
TI  - [Causality in occupational health: the Ardystil case].
AB  - Establishing causal relationships has been and is today a matter of debate in
      epidemiology. The observational nature of epidemiological research rends
      difficult the proving of these relationships. Related to this, different models
      and causal criteria have been proposed in order to explain health and disease
      determinants, from pure determinism in Koch postulates, accepting unicausal
      explanation for diseases, to more realistic multicausal models. In occupational
      health it is necessary to formulate causal models and criteria to assess
      causality, and frequently causal assessment in this field has important social,
      economic and juridical relevance. This paper deal with evaluation of causal
      relationships in epidemiology and this evaluation is illustrated with a recent
      example of an occupational health problem in our milieu: the Ardystil case.

PMID- 8666517
TI  - [Spanish presence in Internet discussion lists on epidemiology].

PMID- 8666518
TI  - The woodchuck: an animal model for hepatitis B virus infection in man.
AB  - Since the discovery of woodchuck hepatitis virus (WHV) in 1978, the virus and its
      host, the American woodchuck, have been studied and used as the most suitable
      model for human hepatitis B virus infection. WHV is closely related to the human
      virus, having strong similarities in morphology, genome structure and gene
      products, replication, epidemiology, the course of infection and in the
      development of illness and hepatocellular carcinoma. Because of this high
      homology, the woodchuck model is used for many studies for the development of new
      vaccines, therapeutic vaccination and antiviral agents. In addition, the
      woodchuck system is used for investigation of molecular mechanisms of the viral
      life cycle, the mechanisms of carcinogenesis and cell infection.

PMID- 8666519
TI  - Therapy of hepadnavirus infection using antisense oligonucleotides.
AB  - Chronic infection with the hepatitis B virus (HBV) is a major health problem
      worldwide. The only established therapy is alpha-interferon with an efficacy of
      only 30-40% in highly selected patients. Major theoretical problems of
      therapeutical strategies against hepadnaviral infections are the limited immune
      response and the presence of covalently closed HBV DNA in the nucleus. Many
      nucleoside analogues and inhibitors of viral reverse transcriptases were tested
      in vitro and in vivo with transient effects and often severe side effects.
      Molecular therapeutic strategies include antisense DNA/RNA and ribozymes. In
      vitro antisense oligodeoxynucleotides could be shown to inhibit viral replication
      and gene expression in human hepatoma cell lines. In vivo an antisense
      oligodeoxynucleotide directed against the 5'-region of the preS gene of the duck
      hepatitis B virus inhibited the viral replication and gene expression in ducks.
      These results demonstrate the potential clinical use of antisense DNA/RNA as
      antiviral therapeutics.

PMID- 8666520
TI  - Mutational analysis of HBsAg assembly.
AB  - The 20-nm noninfectious empty envelope particles carrying the hepatitis B surface
      antigen are secreted in large excess from hepatocytes during a hepatitis B
      infection. Similar particles produced in cell lines or yeast are an efficient
      vaccine against hepatitis B virus. We have analyzed the assembly of 20-nm
      particles using a mutagenesis approach. Specific mutations were introduced into
      the S gene and the preS region encoding the viral envelope proteins using
      recombinant DNA techniques. The mutant genes were expressed in cell lines to
      identify the amino acid residues that are critical for the assembly and the
      secretion of the 20-nm particles.

PMID- 8666521
TI  - Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as
      reflected by sequence variability of the S-gene.
AB  - The serologic heterogeneity of the hepatitis B virus (HBV) has been established
      from immunodiffusion experiments for a long time. Four serotypes called subtypes
      of the hepatitis B surface antigen (HBsAg) have been defined by two mutually
      exclusive determinant pairs, d/y and w/r, and a common determinant a. These
      subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in
      the mid-70s, nine different subtypes were identified. Sequencing of viral genomes
      has now become a major goal of descriptive virology, and sequence data is now
      used to trace routes of infection, to reconstruct the phylogenetic history of
      viruses and two delimit genetic subtypes. A genetic classification based on the
      comparison of complete genomes has defined four genomic groups of HBV, later
      referred upon as genotypes, which were designated with A-D. However, the
      interrelation of the nine subtypes to the genotypes, the possible presence of
      more than four human HBV genotypes as well as their global geographical
      prevalence remained to be determined. By sequencing the S-gene of HBV the
      molecular basis was assessed for the serological variations of HBsAg within the
      major four subtypes. Thereby, also two new genotypes of HBV designated with E and
      F were identified. Complete genomic sequencing of E and F strains confirmed their
      status as new genotypes. The F genotype was found to diverge from other HBV
      genomes sequenced by 14%, thus being the most divergent HBV genome so far
      characterized. When the worldwide molecular epidemiology of HBV based on the
      variability of the S-gene was defined, the E and F strains seemed to originate in
      aboriginal populations of Africa and the New World, respectively. They shared a
      unique substitution at residue 140 in the second immunodominant loop of their
      encoded surface antigen when compared to the vaccine strain. Future research will
      establish whether this substitution may predispose to a vaccine escape mutant at
      residue 141, that now has been reported to occur in conjunction with the 140
      substitution.

PMID- 8666522
TI  - Hepatitis B surface antigen variation and protective immunity.
AB  - Hepatitis B surface antigen (HBsAg) particles consist predominantly of a
      glycoprotein of 226 amino acids which bears the B-cell epitopes important for the
      induction of protective antibody responses in humans. It has been clearly shown
      that the region between residues 120 and 150 of the S protein represents the a
      determinants common to all hepatitis B virus (HBV) isolates and is exposed on the
      surface of the HBV particle. Anti-a antibodies protect adults against the
      majority of infections irrespective of the subtype of the wild-type virus.
      Occasional examples of infection positive for anti-HBs antibodies have been
      associated with the emergence of HBV variants. In particular, asymptomatic
      infections have been described in vaccinated children, an observation which is
      associated with an amino acid change in a domain critical for anti-HBs binding.
      Variation in amino acid sequence is also found within the preS amino terminal
      extensions of the S protein, although these do not correlate with subtypic
      variations among the S-antigenic domains. There is no direct evidence that preS
      determinants per se may stimulate a protective immune response in humans,
      although the hepatocyte attachment domain is located in the preS1 region which is
      conserved between HBV isolates. The inclusion of preS specificities augments anti
      HBs responses in an experimental animal; however, at the present time it is
      unclear as to how this may best be exploited in improving hepatitis B vaccines
      for human use. Variability in HBV envelope proteins has implications for the
      design of vaccination programmes and the diagnosis of HBV infections; however,
      the low frequency of HBV variants emerging in the face of increasing levels of
      herd immunity to hepatitis B at the present time means that the extension of
      immunization programmes using existing vaccines remains a priority.

PMID- 8666523
TI  - Immunization against hepatitis B through adoptive transfer of immunity.
AB  - Clearance of hepatitis B virus (HBV) infection requires an effective T-cell
      dependent humoral response that is often defective in HBV carriers and in
      immunosuppressed patients. We have shown in mice and humans that bone marrow (BM)
      derived memory cells, capable of producing antibodies to the HBV envelope and
      nucleocapsid antigens, are transferable from BM donors (BMD) to their recipients.
      BMD BALB/c mice were immunized with recombinant HBV surface antigen (HBsAg), and
      BM from anti-HBs-positive donors was transplanted to irradiated recipient mice,
      who seroconverted to anti-HBs within 30 days of bone marrow transplantation
      (BMT), and responded to booster vaccination. In a similar manner, 19/26 human BM
      recipients, who received their HLA-matched BM from BMDs immunized once with
      HBsAg, seroconverted within several weeks after BMT. Antibodies to HBsAg were
      also observed in 3 recipients of peripheral blood lymphocytes (PBL) obtained from
      HLA-matched immunized human donors. Finally, clearance of HBsAg and HBV DNA was
      observed in an HBsAg carrier with leukemia who received BMT from his HLA-matched
      anti-HBc+/anti-HBs+ brother. These results indicate that adoptive transfer of
      immunity to HBV may be achieved through immunization of BM or PBL donors against
      HBV.

PMID- 8666524
TI  - Assembly and antigenicity of hepatitis B virus core particles.
AB  - Recent studies in Xenopus oocytes and other systems have led to an understanding
      of the HBV capsid, or core particle, assembly process. Nascent HBV core
      polypeptides rapidly dimerize. Accumulation of free dimers to a signature
      concentration (approximately 0.8 microM) then triggers a highly cooperative
      capsid assembly reaction. This dimer-to-capsid transition is accompanied by a
      switch from HBe to HBc antigenicity and appears to be nucleated by interaction
      between core protein and RNA: deletion of a protamine-like RNA binding domain at
      the C-terminus of the core protein markedly increases the concentration of dimers
      needed to drive capsid assembly. The simple assembly pathway seen for HBV capsids
      mirrors that of R17 bacteriophage.

PMID- 8666527
TI  - Computer-aided studies on the spatial structure of the small hepatitis B surface
      protein.
AB  - Hepatitis B surface proteins play a central role in the assembly of the virus and
      in the infection of the host cells. Whereas some functional aspects of the
      proteins have been studied in detail, little is known about their structure.
      Since X-ray analysis of these proteins appear unlikely in the near future, we
      chose to use a variety of computer-aided methods to improve the model for the
      major surface protein (SHBs). We here describe the model, discuss it in light of
      current results in the literature and discuss new functional implications of
      SHBs.

PMID- 8666526
TI  - Variation in the core and X genes of hepatitis B virus.
AB  - Variation in viral genomes is dependent upon rates of polymerase error and the
      relative influence of selection pressures. For HBV, it appears that there is
      substantial immune pressure in keeping with the immunopathogenesis; the ability
      of the virus to persist is probably linked with this process. As the viral genome
      is small, mutants may have multiple effects, particularly apparent within regions
      that have overlapping functions, such as the encapsidation signal and the X gene.
      Here, an attempt has been made to correlate variation within the pre-core/core
      gene with clinical progression and response to interferon and to put forward
      hypotheses to show the relationship of these mutations to the immune response.
      Their effects on overlapping regions are also discussed. Little is currently
      known about the functional importance of mutations within and around the X gene,
      but it is likely that this will prove a fruitful area of research.

PMID- 8666525
TI  - Hepatitis B virus core particles as epitope carriers.
AB  - HBV core (HBc) particle is one of the most intensively studied particulate
      carriers for the insertion of foreign peptide sequences. Recombinant HBc protein
      expressed from the cloned gene undergoes the correct folding in a large variety
      of bacterial, yeast, insect and mammalian cells. Unique assembly properties and
      shape of 30/34-nm HBc particles allow substantial insertions into their primary
      structure without loss of their capsid-forming ability. N- and C-terminal
      regions, as well as the immunodominant loop in the middle of the molecule are
      widely accepted as targets for the introduction of foreign epitopes, ensuring
      retention and even enhancement of the original immunological activity of inserted
      sequences. Special sets of display vectors have been constructed on the basis of
      the cloned HBc gene. Epitope sequences of viral (BLV, FeLV, FMDV, HBV, HCV, HIV
      1, HRV2, MCMV, PV-1, SIV) and nonviral (human chorionic gonadotropin) origin have
      been studied as model display moieties.

PMID- 8666528
TI  - Biochemistry and functions of hepatitis B virus X protein.
AB  - Hepatitis B virus X gene codes for a small basic cytoplasmic protein and is able
      to transactivate viral and cellular genes, although X protein exhibits no DNA
      binding activity. The mechanism of transactivation by X protein has been
      suggested to be via protein-protein interaction(s). X protein had amino acid
      sequences homologous to the functionally essential domain of Kunitz-type serine
      protease inhibitors, and these sequences were indispensable for transactivation
      function. X protein activated X-gene transcription itself and an X-responsive
      element were localized in their minimal promoter. Furthermore, tumor suppressor
      gene product p53, but not mutant p53, repressed X-gene transcription from the
      minimal promoter, indicating that X protein disrupts the function of normal p53,
      which represses transcription of X gene or cellular gene. Data suggest that
      inhibition of a hepatic serine protease by X protein leads to eliminate the
      suppressor effect of p53 on the basic transcription machinery in nucleus.

PMID- 8666529
TI  - Headache in patients with neurofibromatosis type 1.
AB  - A study of headache in a homogeneously ascertained population of 181 subjects
      suffering from neurofibromatosis type 1 is described. All subjects underwent a
      diagnostic protocol including imaging studies (for subjects over 5 years old up
      until 1992). Headache data were collected by means of a questionnaire. Headache
      was present in 55 of 181 subjects (25 males). Overall headache frequency was 30%,
      which is not significantly different from the frequency of headache reported in
      the general population. Headache was primary in 52 cases (5 migraine and 47
      tension-type) and secondary to obstructive hydrocephalus with brain tumor-induced
      intracranial hypertension in 3 with a tension-type pattern. It was concluded that
      headache is not a specific feature of neurofibromatosis type 1, it is not
      significantly related to central nervous system abnormalities, and in itself, it
      is not an indication for neuroradiological examination.

PMID- 8666530
TI  - Analgesic rebound headache in clinical practice: data from a physician survey.
AB  - BACKGROUND: Frequent, excessive use of over-the-counter or prescription
      analgesics may lead to analgesic rebound headache. Little is known about the
      magnitude of the health problem posed by analgesic rebound headache, its
      epidemiology, the characteristics of analgesic rebound headache sufferers, or
      about physicians' approaches to treatment. METHODS: Four hundred seventy-three
      practitioners, who had previously expressed an interest in the treatment of
      headache, were mailed a questionnaire designed to capture information about the
      frequency and management of analgesic rebound headache and about the
      characteristics of analgesic rebound headache sufferers. RESULTS: Completed
      questionnaires were returned by 174 practitioners (37%) from 40 states, the
      District of Columbia, and Puerto Rico. More than 40% of respondents indicated
      that analgesic rebound headache was present in at least 20% of their patients. On
      average, the physicians reported that 73% of patients with analgesic rebound
      headache were women. Analgesic rebound headache was most likely to occur in
      patients aged 31 to 40 years. No one analgesic was consistently identified as
      causative, although acetaminophen, butalbital + aspirin + caffeine, and aspirin
      were commonly used by patients. Eighty percent of respondents indicated that
      depression was commonly observed in analgesic rebound headache sufferers; 77%
      indicated that physical conditions (especially gastrointestinal symptoms) were
      commonly observed. A variety of therapeutic strategies, including
      pharmacotherapy, were used in the management of analgesic rebound headache.
      CONCLUSION: Analgesic rebound headache was recognized as a distinct entity and a
      substantive component in more than 40% of the practices of 174 surveyed
      practitioners. General practitioners, who see a wide variety of patient types
      with a spectrum of complaints, need to be able to diagnose analgesic rebound
      headache by taking a good history.

PMID- 8666531
TI  - Chronic paroxysmal hemicrania and hemicrania continua. Interval between
      indomethacin administration and response.
AB  - The interval between indomethacin dosage and clinical response was assessed in
      hemicrania continua (n = 12) and chronic paroxysmal hemicrania (n = 11)
      sufferers. The number of trials per patient ranged from 1 to 30. At the time of
      testing, the patients had "considerable" pain after discontinuation of the drug.
      The dosage used was the usual one for that patient at the given pain level; ie,
      25 or 50 mg tid. All the patients had a complete, long-term response to
      treatment. Nevertheless, the average interval between drug intake and pain relief
      during the present study ranged between 30 minutes and 48 hours in both
      disorders. In most patients (10 in both groups), the indomethacin effect was
      complete within 24 hours, and frequently within 8 hours. It is suggested that
      interindividual differences in dosage and timing to abolish the headaches may be
      due to different bioavailability or individual sensitivity. Recommendations on
      indomethacin testing in unilateral headaches are given.

PMID- 8666532
TI  - Migraine as a cause of sudden hearing loss.
AB  - Sudden hearing loss is common, but unexplained in many cases. Although usually
      attributed to a viral infection of the inner ear in most patients, the abrupt
      onset of the hearing loss in many patients argues against a viral etiology. We
      present 13 cases of unexplained sudden hearing loss who meet the diagnostic
      criteria for migraine. All had the sudden onset of hearing loss and other
      neurologic phenomena that could be attributed to vasospasm, including vertigo,
      amaurosis fugax, hemiplegia, facial pain, chest pain, and visual aura. We suggest
      that vasospasm of the cochlear vasculature was the cause of the sudden hearing
      loss in these patients. A personal and family history of migraine should be
      sought in patients with sudden hearing loss and when found, a trial of
      antispasmodic agents should be considered.

PMID- 8666533
TI  - The effect of sumatriptan on brain monoamines in rats.
AB  - Clinical data suggests that sumatriptan is effective in the acute treatment of
      migraine. The vascular effects of the drug have been invoked to explain this
      antimigraine efficacy. However, the effect of sumatriptan on brain monoamines has
      not previously been investigated. In order to study these hypothetical effects,
      we administered the drug to 24 male rats, subcutaneously, at three doses (0.3,
      0.6, and 0.9 mg/kg of body weight), and 30 minutes later, all animals were
      decapitated. Dopamine, serotonin, and their metabolites 3,4 dihydroxyphenylacetic
      acid, 5-hydroxyindoleacetic acid, and homovanillic acid concentrations were
      measured in the frontal cortex, hypothalamus, striatum, and hippocampus, by high
      performance liquid chromatography. Plasma concentrations of the drug were also
      determined. The control group was treated with NaCl 0.9%, given subcutaneously.
      Sumatriptan, at the dose of 0.3 mg/kg did not alter the brain monoamine
      concentrations; however, at the dose of 0.6 mg/kg, sumatriptan decreased
      serotonin concentration in the hypothalamus and increased the turnover of
      dopamine and serotonin in the hypothalamus and striatum, while at the dose of 0.9
      mg/kg, it augmented only the turnover of serotonin in the hypothalamus. No dose
      dependent effect of the drug was found. This subcortical antidopaminergic and
      antiserotoninergic effect of sumatriptan may be involved in its antimigraine
      action.

PMID- 8666534
TI  - The site of sympathetic deficit in cluster headache.
AB  - The pattern of autonomic deficit in the face of cluster headache patients
      resembles the deficit in patients with a postganglionic sympathetic lesion from
      some other cause; however, the presence of abnormal cardiac rhythms and bilateral
      pupillary reflex deficit in some patients with cluster headache suggests that the
      lesion might compromise central sympathetic drive. To investigate this
      possibility, the vasomotor and sudomotor startle reflex was investigated in the
      hands of six cluster headache patients with ocular and thermoregulatory signs of
      postganglionic sympathetic deficit in the face; for comparison, responses were
      also investigated in 15 patients with a lesion in the cervical sympathetic
      pathway from some other cause. The startle reflex was intact in the hands of the
      six cluster headache patients, but was diminished ipsilaterally in patients with
      a central or preganglionic sympathetic lesion and also, surprisingly, in patients
      with a postganglionic lesion caused by an aneurysm of the internal carotid
      artery. Ocular sympathetic deficit was greater in patients with an aneurysm of
      the internal carotid artery than in cluster headache patients or in patients with
      a postganglionic sympathetic lesion from some other cause; the aneurysm may have
      compromised neurons with projections to the face and hand, or could have induced
      transsynaptic degeneration of preganglionic fibers supplying both regions. The
      findings indicate that central sympathetic drive is not impaired in cluster
      headache patients; thus, a peripheral lesion probably induces sympathetic deficit
      on the symptomatic side of the face.

PMID- 8666535
TI  - Occipital nerve release in patients with whiplash trauma and occipital neuralgia.
AB  - The results of 18 greater occipital nerve release operations in 13 patients were
      analyzed. All patients had deep aching pain in the occipital area due to a
      whiplash trauma, and in all cases the pain was relieved temporarily by local
      anesthesia of the occipital nerve. The time from accident to operation was 6 to
      96 months. The results of 13 (72.2%) operations were reported as good or
      excellent, although complete pain relief was not attained in any patient. It is
      concluded that neurolysis of the greater occipital nerve after whiplash injury
      can give meaningful pain relief in selected patients.

PMID- 8666536
TI  - Cerebrovascular reactivity in migraine with and without aura.
AB  - Abnormal cerebrovascular regulation has been implicated in the pathogenesis of
      migraine. Our aim in this study was to evaluate cerebrovascular reactivity to
      different stimulations in migraine with and without aura. Using bilateral
      transcranial Doppler, the changes of flow velocity during hypercapnia and mental
      and motor activity were measured in the middle cerebral arteries of 15 controls
      and 30 patients with migraine with aura (n = 15) or without aura (n = 15) in an
      attack-free period. Vascular response to all tests was similar in controls and
      patients. In patients with unilateral headache, no side-to-side difference was
      found. These findings suggest that no alteration of cerebrovascular reactivity
      exists outside attacks in migraine with and without aura. Further studies with
      transcranial Doppler considering all intracranial vessels and the comparison with
      other techniques of flow investigation with better regional resolution are needed
      to confirm these data.

PMID- 8666537
TI  - Familial cluster headache: report of three families.
AB  - We report on three families in which cluster headache is present in more than one
      member. In one of these families a boy, his father, and paternal grandfather were
      affected. In the other two families, a father and son and mother and daughter
      were the affected members. Diagnoses were based on IHS criteria, after examining
      and taking the history directly from the patient in all but one of the seven
      cases; the seventh patient was deceased and the diagnosis was based on reports
      from the affected son. Considered in the light of other recent reports of
      familial cluster headache, these cases suggest that cluster headache can have a
      genetic component.

PMID- 8666538
TI  - Repeat CT or MRI in posttraumatic headache.
AB  - Repeat CT or MRI of the brain should be considered in posttraumatic headache. We
      describe two patients with posttraumatic headache who had negative CT scans on
      initial presentation. One patient later had bilateral subdural hematomas on CT,
      and the other had temporal lobe hemorrhage on MRI. We recommend considering
      repeat CT or MRI for persisting posttraumatic headache and mental status change.

PMID- 8666539
TI  - Reduction of migrainous headaches during the use of acenocoumarol.
AB  - Disappearance of migraine during the use of warfarin and of phenprocoumon has
      been described in sporadic case reports. Treatment with heparin has also been
      associated with a reduction of migranous headaches. Recently, the Netherlands
      Pharmacovigilance Foundation LAREB received a case report concerning the
      diminution of migrainous headaches associated with the use of the vitamin K
      antagonist, acenocoumarol.

PMID- 8666540
TI  - Occipital lobe tumor presenting as migraine with typical aura.
AB  - We report the case of a 60-year-old woman in whom migraine with typical aura
      heralded the presence of an occipital lobe tumor. Her headache was characterized
      by recurrent episodes of visual aura confined to the left visual field followed
      by right hemicranial throbbing headaches accompanied by nausea, photophobia, and
      phonophobia. Interictal neurologic and ophthalmologic examinations were negative,
      as was an unenhanced brain CT scan. The headaches increased in frequency over 4
      months despite a number of medications known to prevent attacks of migraine. A
      low-grade right occipital lobe tumor was eventually discovered on MR scan. This
      case illustrates that headache fulfilling the International Headache Society
      (IHS) criteria for migraine with typical aura can occur in association with an
      occipital lobe tumor.

PMID- 8666541
TI  - Meningeal hyperperfusion visualized by MRI in a patient with visual
      hallucinations and migraine.
AB  - A 41-year-old patient with a history of migraine but with no history of seizures
      had intermittent prolonged and variable complex visual hallucinations and
      illusions lasting 9 days, accompanied by unilateral headache.
      Electroencephalography during these visual symptoms revealed occipital epileptic
      discharges. Distinction between focal migrainous attacks and ictal phenomena was
      difficult. Magnetic resonance imaging showed a lesion in the right visual cortex
      probably related to low perfusion and hyperemia of meningeal vessels,
      representing the rarely described transient MRI changes associated with migraine.
      Continued treatment with antiepileptic drugs and calcium-channel blocking agents
      completely resolved the headache and visual symptoms, while minor EEG changes
      persisted. After discontinuation of treatment, a second attack occurred with a
      similar and reversible pattern on EEG.

PMID- 8666542
TI  - Abdominal pain and migraine.

PMID- 8666543
TI  - Reaction norms of Arabidopsis IV. Relationships between plasticity and fitness.
AB  - The study of the association between fitness and reaction norms is of primary
      importance given the hypothesized role for phenotypic plasticity in shaping
      evolutionary patterns: in microevolution, as one of mechanism for maintaining
      genetic variation, and in macroevolution, as a means of generating phenotypic
      novelties. In a glasshouse experiment, we investigated variation in reaction
      norms to nutrient availability in populations of Arabidopsis thaliana, and the
      relationship between this variation and reproductive fitness. We found evidence
      for across-treatment directional selection on the means for leaf number,
      flowering time, plant height, branching and growth rate; across-treatment
      stabilizing selection was detected for growth rate; and across-treatment
      disruptive selection was significant for leaf number. We also uncovered selection
      on the plasticity of some traits: directional for the plasticity of branching,
      and stabilizing for the plasticity of both branching and growth rate. When the
      two environments were considered separately, directional selection for height was
      detected under low nutrients; under high nutrients, we found evidence for
      directional selection on leaf number and height, and for disruptive selection on
      flowering time. The genetic correlation between a trait's expression in one
      environment and its expression in the alternate environment was positive and
      highly significant only for flowering time and growth rate. A principle
      components analysis revealed possible constraints on future selection responses,
      because of correlations among character means and among character plasticities.

PMID- 8666544
TI  - Extreme genetic differences among populations of Gazella granti, Grant's gazelle
      in Kenya.
AB  - Mitochondrial DNA (mtDNA) control region sequences from six Kenyan Grant's
      gazelle (Gazella granti) populations were highly divergent among locations.
      Neighbouring populations not separated by geographical or vegetational barriers
      exhibited and nucleotide sequence divergence about 14 per cent. A similar level
      of divergence separates Grant's gazelles from a closely related species, the
      Soemmering's gazelle (G. soemmeringii). Nuclear microsatellite repeat number
      variation at two loci also indicated substantial population genetic
      differentiation. Despite high levels of sequence divergence populations of
      Grant's gazelles were more closely related to each other than to Soemmering's and
      Thompson's gazelles (G. thomsoni) as measured by nucleotide sequence divergence
      at the mtDNA protein coding cytochrome b gene and the nuclear alpha-lactalbumin
      gene. This pattern of extensive differentiation is hypothesized to have resulted
      from recently established contacts between formerly allopatric populations.

PMID- 8666545
TI  - Evidence for sibling species in Cryptocercus punctulatus, the wood roach, from
      variation in mitochondrial DNA and karyotype.
AB  - The wood-feeding genus Cryptocercus is considered the basal lineage among extant
      cockroaches. Cryptocercus is the sole representative of the family Cryptocercidae
      and at present three species are recognized within the genus worldwide:
      Cryptocercus punctulatus in the United States, C. relictus in Eurasia and C.
      primarius in the Orient. The geological distribution of C. punctulatus in the USA
      is disjunct, with populations occurring along the Appalachian Mountains and in
      the Pacific North-west. In samples collected from several locations of the
      eastern and western USA, we investigated variation in DNA sequence of portions of
      the two mitochondrial rRNA genes and in chromosome number. The overall sequence
      divergence among 30 individuals assayed from 17 locations was 17.3 percent. A
      phylogenetic analysis revealed that in the east, individuals in Virginia had
      diverged significantly in their haplotype from those in North Carolina, Georgia
      and Alabama; individuals in the west (Oregon) had diverged in their haplotype
      from individuals in the east. The diploid chromosome number for 52 male C.
      punctulatus sampled from 15 locations varied from 37 (18(II) + X) to 47 (23(II) +
      X). In the eastern samples, the diploid chromosome number ranged from 37 to 45,
      whereas in Oregon all individuals had 2n = 47. No polymorphism in DNA sequence or
      chromosome number among individuals collected within a locality was detected. The
      DNA sequence and chromosome number variation data, together with preliminary
      studies on mating incompatibility, strongly suggest that C. punctulatus in the
      USA is comprised of at least two probably three sibling species, with one species
      occurring in western USA and one or more species in eastern USA.

PMID- 8666546
TI  - S-allele diversity in a natural population of Physalis crassifolia (Solanaceae)
      (ground cherry) assessed by RT-PCR.
AB  - Allelic diversity at the self-incompatibility (S-) locus in the ground cherry,
      Physalis crassifolia (Solanaceae), was surveyed in a natural population occurring
      in Deep Canyon, CA, using a molecular assay to determine the genotype of
      individual plants. A total of 28 different S-alleles were identified and
      sequenced from a sample of 22 plants. All plants examined were heterozygous, as
      expected under gametophytic self-incompatibility (GSI). The estimated number of
      alleles in this population is 43-44, comparable to allelic diversity reported for
      other species, as determined by the standard diallel crossing method. Allele
      frequencies in the sample deviated from the expectation of equal frequency under
      GSI; it is suggested that this deviation may result from sampling of related
      individuals. Molecular analysis of genotypes within single pollen donor families
      indicates that, for all alleles examined, segregation is consistent with
      predictions for single-locus GSI. The implications of a reliable and efficient
      molecular assay for determining the S-genotype of plants are discussed.

PMID- 8666547
TI  - Mitochondrial DNA differentiation among geographical populations of Pronolagus
      rupestris, Smith's red rock rabbit (Mammalia: Lagomorpha).
AB  - Geographical genetic population structure was determined for an endemic African
      leporid, Smith's red rock rabbit, Pronolagus rupestris. Restriction fragment
      length polymorphism analysis of mitochondrial DNA from 55 specimens revealed 32
      distinct material lineages for the population sampled. The data show two major
      genetic assemblages separated by a mean sequence divergence of 7.94 per cent (+/-
      1.40 per cent) and provide little support for the continued recognition of most
      of the described subspecies. The south-eastern assemblage is confined to the
      mountain ranges comprising the Great Escarpment of South Africa, while the north
      western assemblage is not so tightly constrained. With the possible exception of
      elevation, no readily apparent ecological or topographical barrier could be
      identified which delimits the two mitochondrial clades. The sequence divergence
      separating the south-eastern and north western P. rupestris clades is high, and
      approximates the interspecific sequence divergences detected between P. rupestris
      and other Pronolagus species. The two P. rupestris clades are parapatric for part
      of their distribution, and the absence of shared mtDNA lineages is consistent
      with the hypothesis that the two populations are reproductively isolated from
      each other. We provisionally interpret this to reflect the presence of two
      hitherto undetected biological species in what has conventionally been recognized
      as a single taxon, P. rupestris.

PMID- 8666548
TI  - Binding of peptides of the human acetylcholine receptor alpha-subunit to HLA
      class II of patients with myasthenia gravis.
AB  - MG is an autoimmune disease in which T cells specific to T-cell epitopes of the
      human acetylcholine receptor play a role. We have identified two peptides, p195
      212 and p259-271, of the human acetylcholine receptor alpha-subunit, to which
      PBLs of MG patients responded by proliferation. Nevertheless, proliferation
      assays are relatively complicated to perform and might be affected by medications
      taken by the patients. Therefore, we tested the possibility of using a different
      assay to determine recognition of these peptides by MG patients. Thus, we
      performed a direct binding assay using biotinylated peptides and APCs from
      peripheral blood of MG patients and healthy controls. With this assay we detected
      the binding of the two peptides to the surface of intact APCs of both MG patients
      and control donors. Moreover, the presentation of peptide p259-271 by individuals
      with MG was significantly higher than that observed in healthy subjects. The
      peptides were specifically bound to HLA class II determinants on the APCs, as
      shown by inhibition with antibodies to the HLA class II haplotypes of the
      individuals investigated. Moreover, the binding of these peptides was in
      correlation with their ability to induce specific proliferative responses of
      peripheral blood T cells of these patients. The ability to screen for potentially
      pathogenic epitopes in each patient is of importance for the future design of
      specific inhibitory analogues that might be used to treat MG.

PMID- 8666549
TI  - Association of the HLA-DQA1*0501 allele in multiple racial groups with juvenile
      dermatomyositis.
AB  - We wanted to determine if HLA-DQA1*0501 is as strongly associated with JDMS in
      Hispanic and African Americans as it is Caucasians. Using DNA sequencing and
      oligonucleotide typing, the DNA of 70 JDMS subjects was studied. The HLA-DQA1
      allelle DQA1*0501 was present in 13 out of 15 (87%) of the African-American JDMS
      subjects vs 9 out of 27 (33%) of the African-American controls (p < 0.0009), 12
      out of 13 (92%) of the Hispanic JDMS subjects vs 5 out of 18 (28%) of the
      Hispanic controls (p < 0.0004), and 36 out of 42 (86%) of the Caucasian JDMS
      subjects vs 36 out of 78 (46%) of the Caucasian controls (p < 0.0009).

PMID- 8666550
TI  - Lymphocytes induce enhanced expression of HLA class I antigens on cytomegalovirus
      infected syngeneic human endothelial cells.
AB  - Human cytomegalovirus (HCMV) infection has been associated with enhanced
      expression of HLA antigens on the endothelium and with cellular infiltrates
      within the graft following human organ transplantation. We investigated the
      interactions between human cytomegalovirus-infected cultured endothelial cells
      and cocultured syngeneic as well as allogeneic lymphocytes. Our objective was to
      find out whether cocultured lymphocytes elicit HCMV-mediated immune responses. In
      this report we focus on the modified expression of HLA antigens on the surface
      membrane of human umbilical vein endothelial cells (HUVECs). Endothelial
      expression of HLA class I and II antigens was measured by means of flow
      cytometry. Cocultures of HCMV-infected HUVECs with unprimed autologous PBLs led
      to virus-specific lymphocyte response, resulting in enhanced expression of HLA
      class I on HUVECs. This effect was only observed when lymphocytes were added to
      HUVECs during the very early phase after virus inoculation and was due to the
      stimulation of the CD8+ T-cell subpopulation. The modification of endothelial HLA
      expression was not observed in transwell cocultures, indicating the importance of
      cellular contact between endothelial cells and lymphocytes to elicit this effect.
      We conclude that HCMV-infected endothelial cells may induce virus-specific
      responses of unprimed syngeneic lymphocytes that lead to upregulated HLA class I
      expression on the endothelium. This pathway might be of important relevance for
      graft rejection crises after transplantation.

PMID- 8666551
TI  - Interleukin 12 unmasks HLA class I differences during mixed lymphocyte reaction
      induced interferon gamma production.
AB  - We investigated the genetic control of IFN-gamma release during MLR and its
      relationship with TNF-alpha and IL-12. Blocking experiments demonstrated the IFN
      gamma dependence of TNF-alpha production and the significant contribution of IL
      12 to IFN-gamma secretion. We studied informative pairs allowing the evaluation
      of the relative importance of HLA class I and class II antigens. Maximal IFN
      gamma secretion allowing discrimination between fully HLA different and identical
      subjects required 5 days. In class I different but DRB1 identical pairs, a
      moderate but discriminant IFN-gamma release was found. Exogenous IL-12 addition
      after 24 hours of preactivation by MLR resulted in a marked enhancement of IFN
      gamma production at day 2. In pairs differing only by class I antigens, the
      discriminating capacity was significantly increased as compared to values
      obtained in absence of IL-12 at day 2 (p < 0.004) and at day 5 (p < 0.004). The
      crucial role of class I antigens on IFN-gamma release was further substantiated
      by the blocking action of the W6/32 mAb directed against a monomorphic epitope
      common to all HLA-A, -B, and -C antigens. We conclude that IFN-gamma production
      during MLR is under the control of class I antigens. Furthermore, exogenous IL-12
      strongly amplifies their influence.

PMID- 8666552
TI  - Genetic predisposition to HIV-1 infection and acquired immune deficiency virus
      syndrome: a review of the literature examining associations with HLA [corrected].
AB  - Researchers have been studying the relationship between host HLA type and the
      immune response to HIV-1 since early in the AIDS epidemic. Although the
      literature is replete with suggestions of an association, the exact locus and
      nature is unclear. This article reviews the current HLA-HIV/AIDS literature,
      providing a complete summary of all significant associations reported in journal
      articles (N = 30) between 1982 and 1993. Consistent associations with alleles
      comprising the haplotype DQ2-DR3-B8-Cw7-A1 and AIDS progression support a genetic
      component in AIDS progression. DQ1-DR1-B35-Cw4-A11 and DR5 also show consistent
      associations with HIV/AIDS outcomes, although it is unclear whether they are
      measuring susceptibility to HIV-1 infection, AIDS progression, or both. The
      question of whether HLA influences susceptibility to HIV-1 infection remains
      unanswered, as well-designed studies addressing this topic are lacking.
      Similarly, further studies are needed to clarify if HLA type is associated with
      KS. Several issues that complicate across-study comparisons are discussed
      including heterogeneity of both HLA and AIDS, potential confounding by race or
      risk group, and other biases which may influence results. In addition, several
      proposed biologic mechanisms are explored.

PMID- 8666553
TI  - In vitro impairment of interleukin-5 production in HLA-B8, DR3-positive
      individuals implications for immunoglobulin A synthesis dysfunction.
AB  - Healthy subjects carrying the HLA-B8,DR3 haplotype may show a large number of
      immune dysfunctions. Concerning T-cell dysfunctions, the most intriguing is a
      defect of the early phases of T-cell activation, responsible for the impairment
      of in vitro mitogen-stimulated cytokine production. Regarding B-cell
      dysfunctions, one the most fascinating topics is the association between this
      haplotype and IgA deficiency in healthy blood donors. Accordingly, HLA-B8,DR3
      positive healthy subjects show significantly lower values of serum IgA than HLA
      B8,DR3-negative ones. Because IL-5 is a stimulating factor for the secretion of
      IgA by committed B cells, we have analyzed the in vitro mitogen-stimulated IL-5
      production by MNCs from healthy HLA-B8,DR3-positive individuals to study whether
      they display an impaired production of IL-5. The results clearly demonstrate that
      MNCs from HLA-B8,DR3-positive individuals display significant reduction of IL-5
      production, suggesting that IgA synthesis dysregulation observed in HLA-B8,DR3
      positive subjects could be due to an impairment of IL-5 production.

PMID- 8666555
TI  - Analysis of dendritic-cell-induced primary T-cell responses between HLA
      genotypically identical individuals.
AB  - DCs are known for their superior antigen-processing and antigen-presenting
      capacities. They are capable of processing intact protein: either endocytosed
      exogenous proteins or newly synthesized endogenous viral and bacterial proteins.
      They are potent inducers of primary T-cell immune responses such as in allogeneic
      MLRs. It is also known that DCs can provide a strong stimulus for autologous T
      cell proliferation. So far no information exists on the capacity of DCs to induce
      primary mH antigen-specific T-cell responses. Therefore, we investigated whether
      human DCs, isolated from peripheral blood, were able to generate specific T-cell
      responses between MLR-negative HLA genotypically identical individuals in vitro.
      To this end, unfractionated cells, monocytes, and B cells were assayed in
      parallel with DCs to compare their capacity to activate unprimed T cells in a
      primary MLR. DCs indeed induced significant proliferation between HLA
      genotypically identical siblings, whereas the other APCs were unable to evoke any
      T-cell response at all. As expected, besides these allogeneic T-cell responses,
      autologous T-cell responses were initiated by the DCs as well. Nonetheless,
      despite further detailed analyses of the responding T cells, neither
      proliferative nor cytotoxic mH antigen-specific reactivities could yet be
      detected using the stimulation protocols described herein.

PMID- 8666554
TI  - Influence of gender and age at onset on the HLA associations in Chinese with
      insulin-dependent diabetes mellitus.
AB  - IDDM in Singaporean Chinese was associated with HLA B58, DRB1*0301, DQB1*0201,
      and joint occurrences of DRB1*0301/*0901 and DRB1*0301/*04. Of the DR4s the
      frequencies of DRB1*0401, *0404, and *0405 were higher and *0406 was lower in
      patients compared to controls. DRB1*0301/*0901 was observed mainly in female
      patients and the frequency showed an inverse relationship with age at onset,
      whereas DRB1*0301/*04 was observed mainly in male patients and also showed an
      inverse relationship with age at onset. DRB1*1202 showed an increasing frequency
      with age at onset. IDDM patients had a higher frequency of homozygous NAsp57 DQ
      beta chains and a lower frequency of homozygous Asp57 DQ beta chains compared to
      controls, especially in younger onset patients.

PMID- 8666556
TI  - Desire and the female analyst.
AB  - The literature on erotic transference and countertransference between female
      analyst and male patient is reviewed and discussed. It is known that female
      analysts are less likely than their male colleagues to act out sexually with
      their patients. It has been claimed that a) male patients do not experience
      sustained erotic transferences, and b) female analysts do not experience erotic
      countertransferences with female or male patients. These views are challenged and
      it is argued that, if there is less sexual acting out by female analysts, it is
      not because of an absence of eros in the therapeutic relationship. The literature
      review covers material drawn from psychoanalysis, feminist psychotherapy, Jungian
      analysis, as well as some sociological and cultural sources. It is organized
      under the following headings: the gender of the analyst, sexual acting out,
      erotic transference, maternal and paternal transference, gender and power,
      countertransference, incest taboo--mothers and sons and sexual themes in the
      transference.

PMID- 8666557
TI  - Assessment of therapeutic efficacy versus sedation with antipsychotic agents.

PMID- 8666558
TI  - Naltrexone as a treatment for repetitive self-injurious behaviour:an open-label
      trial.
AB  - BACKGROUND: Repetitive self-injurious behavior (SIB) is a dangerous and often
      treatment-refractory syndrome encountered frequently in clinical practice. The
      authors sought to determine if oral naltrexone could decrease SIB in a sample of
      adult psychiatric patients. METHOD: Seven female patients with SIB accompanied by
      analgesia and dysphoria reduction were administered oral naltrexone (50 mg/day)
      in an open-label trial. All patients demonstrated persistent and clinically
      significant SIB prior to receiving the drug. Mean follow-up period was 10.7
      weeks. RESULTS: SIB in six of seven patients ceased entirely during naltrexone
      treatment. Two patients who discontinued naltrexone briefly experienced the rapid
      resumption of SIB, which again ceased after resumption of naltrexone therapy. One
      patient exhibited superficial cutting on two occasions while receiving
      naltrexone, a rate that reflected a significant reduction of SIB. CONCLUSION:
      These preliminary observations are consistent with the hypothesis that the
      endogenous opioid system is involved in cases of SIB that are accompanied by
      analgesia and dysphoria reduction. Additional placebo-controlled studies that
      explore the effectiveness of naltrexone in treating patients with this syndrome
      are warranted.

PMID- 8666559
TI  - The use of valproate in an elderly population with affective symptoms.
AB  - BACKGROUND: Little is known about the efficacy and tolerability of valproate in
      the elderly population with affective disorders. This pharmacoepidemiologic study
      was undertaken to determine the side effect profile and efficacy of valproate in
      an elderly population with psychiatric symptomatology. METHOD: This was a
      retrospective chart review of all elderly inpatients at McLean Hospital who
      received valproate between May 8, 1989, and May 8, 1992. Charts were reviewed to
      determine gender, discharge diagnosis, indication for the agent, and length of
      time on each medication. Charts were also reviewed for abnormalities in liver
      function tests, blood cell dyscrasias, sedation, nausea and vomiting, weight
      gain, impairment of cognition, tremor, and hair loss. The efficacy of the
      medication was also determined. RESULTS: Thirty-five elderly subjects who
      suffered from an affective disorder and who had received valproate were
      identified. The mean age was 71.3 years. The mean length of time the patient
      received valproate was 32.7 days. The mean dose was 743 mg/day, and the mean
      blood drug level was 52.9 mg/L. The valproate was rated as efficacious in 18
      (62%) of the 29 patients who had had an adequate drug trial at discharge. Overall
      the medication was well tolerated. There were no reports of liver function test
      abnormalities. One patient experienced transient leukopenia. Other adverse events
      included two reports of nausea, two reports of sedation, and one complaint of
      confusion. None of the variables examined were found to be statistically
      significant in regard to efficacy. CONCLUSION: Valproate was well tolerated and
      efficacious in this elderly population with affective disorders. Further
      controlled studies are needed to confirm our results.

PMID- 8666560
TI  - Structural brain scanning in psychiatric patients: a further look.
AB  - BACKGROUND: Indications for computed tomographic (CT) and magnetic resonance (MR)
      scans of the brain in psychiatric patients are not clearly defined. This survey
      attempted to refine indications suggested by an earlier survey. METHOD: All brain
      scans ordered in a psychiatric teaching hospital were surveyed over a period of
      approximately 23 months. A revised order sheet provided information about the
      assumed need for scanning as well as indicated those factors from the previous
      survey most likely to reveal pertinent information. Scan results were later
      correlated with this information. RESULTS: Of 68 scans reviewed, 40 were normal,
      16 equivocal, and 12 were abnormal. Cognitive decline and/or confusion were
      indications for 30 scans; 7 were abnormal, all meriting a clinical diagnosis of
      Alzheimer dementia. Only 1 of 12 scans to investigate a history of head injury
      was abnormal. Only 2 of 11 scans based on a history of seizures were abnormal;
      all had other possible indications. In one patient a prior stroke was confirmed,
      and in another, active multiple sclerosis. Ten of the group of 12 abnormal scans
      were found in patients over the age of 40 years, emphasizing the influence of
      age. CONCLUSION: Revised indications based on this second survey were as follow:
      (1) The importance of new or unexplained focal neurologic signs was confirmed;
      (2) Scans are useful for bolstering a clinical diagnosis of Alzheimer disease;
      (3) A first psychotic break or personality change after the age of 50 years will
      require investigation; (4) Cognitive decline in a patient with a prior history of
      functional psychosis is most likely part of the psychosis rather than a
      confounding organic disorder; (5) Isolated seizures of long duration or abnormal
      EEG without other clinical findings are seldom associated with abnormal scans.

PMID- 8666561
TI  - An open-label trial of nefazodone in high comorbidity panic disorder.
AB  - BACKGROUND: Nefazodone is a recently marketed compound with demonstrated efficacy
      in major depression. This study was undertaken to assess the efficacy and safety
      of nefazodone in a sample of panic disorder patients with a high degree of
      depressive comorbidity. METHOD: Fourteen patients were screened for entry into an
      open 8-week trial of nefazodone clinically titrated between 200-600 mg. Patients
      fulfilled DSM-III-R criteria for panic disorder and were allowed to enter with
      concurrent diagnoses of major depression, dysthymia, generalized anxiety
      disorder, and depression NOS. Primary outcome measures included panic attack
      frequency and severity and the Clinical Global Impression scale. RESULTS: At Week
      8 of treatment, 10/14 patients (71%) were judged to be much or very much improved
      with study treatment. Panic attack frequency decreased from a mean of 5.4 at
      baseline to 2.1 at Week 8, reaching significance by Week 8 (p < .05) as did
      decreases in phobic anxiety. Improvement in panic attack severity, phobic
      avoidance, HAM-D, HAM-A, CGI-Severity, and Sheehan Disability Scale scores was
      significant by Week 4. Five of the 8 patients with comorbid major depression were
      responders, as were 3/5 patients with generalized anxiety disorder comorbidity.
      Five of 6 patients with pure panic or minor depressive symptoms responded to the
      study treatment. None of the patients withdrew because of side effects of
      nefazodone. CONCLUSION: This report presents preliminary evidence for the
      efficacy and tolerability of nefazodone in panic disorder and panic with comorbid
      depression or depressive symptoms.

PMID- 8666562
TI  - Risperidone in the treatment of mania.
AB  - BACKGROUND: Risperidone, a 5-HT2 and D2 antagonist, has been shown to be an
      effective antipsychotic in the treatment of schizophrenia but has unclear
      efficacy in the treatment of psychotic affective disorders. The purpose of the
      study was to assess the efficacy of risperidone in the treatment of acute mania
      with psychotic features. METHOD: We conducted an open-label pilot study of
      risperidone and concurrent mood-stabilizing drugs in the treatment of acute mania
      with psychotic features. Patients were diagnosed with the Structured Clinical
      Interview for DSM-III-R (SCID). Efficacy was measured weekly with the use of the
      Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).
      RESULTS: Ten women and 5 men (mean age = 38 years) were included in the study. Of
      the 13 patients who completed 2 weeks of treatment, 8 of these 13 had a 50%
      improvement of the BPRS, and all 13 had at least a 25% improvement (p = .002, 95%
      confidence interval [CI] = 46.0 to 57.8). Of the 8 patients who completed 6 weeks
      of treatment, 7 of the 8 had a 50% improvement, and all 8 had a 25% improvement
      (p = .012, 95% CI = 52.4 to 69.3). Similar results were obtained with the YMRS.
      By the second week of treatment, 10 of the 13 patients remaining in treatment had
      at least a 50% improvement, and 12 of these 13 had a 25% improvement (p = .002,
      95% CI = 55.1 to 89.9). By the sixth week, all of the 8 patients remaining in
      treatment had a 75% improvement (p = .012, 95% CI = 90.5 to 102.8). The
      medication was well tolerated, and no case worsened. CONCLUSION: When used with
      concomitant mood-stabilizing drugs, risperidone may be effective and well
      tolerated in patients with acute mania with psychotic features. Considering the
      open design, small sample size, and limited period of observation, further
      studies need to be conducted.

PMID- 8666563
TI  - Fluoxetine treatment of dysthymia in the elderly.
AB  - BACKGROUND: Despite their prevalence, little is known about the treatment of mild
      depressive syndromes in older patients. The purpose of this study was to evaluate
      the efficacy of fluoxetine in dysthymic disorder in the elderly. METHOD: Twenty
      three elderly outpatients with dysthymic disorder (DSM-III-R criteria) entered a
      13-week study of fluoxetine (2-week placebo run-in period and 11 weeks of
      fluoxetine treatment with a dose range of 20-60 mg/day). Ratings to assess
      clinical response included the Hamilton Rating Scale for Depression (HAM-D), the
      Clinic Global Impression (CGI), and the Cornell Dysthymia Rating Scale (CDRS).
      RESULTS: Nine patients (39%) had never received psychiatric treatment during the
      index episode, despite a long duration of illness (mean +/- SD = 18.5 +/- 17.1
      years). Twenty of the 23 patients completed the entire study. The mean +/- SD HAM
      D (24-item) score decreased from 14.6 +/- 3.7 to 7.9 +/- 5.0 during the trial,
      and the CDRS score decreased from 28.1 +/- 9.1 to 15.7 +/- 10.0. When response
      criteria of a 50% reduction from baseline in the HAM-D score, final HAM-D score <
      or = 8, and a CGI score of 1 or 2 (very much or much improved) were used, 12
      (60%) of the completers were responders. Side effects were uncommon, and the
      fluoxetine was generally well tolerated. CONCLUSION: These preliminary findings
      suggest that fluoxetine is an effective treatment in elderly patients with
      dysthymic disorder. Double-blind, placebo-controlled studies are warranted.

PMID- 8666564
TI  - Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety,
      and tolerability data.
AB  - BACKGROUND: Combination treatment with tricyclic antidepressants (TCAs) and
      serotonin selective reuptake inhibitors (SSRIs) is an increasingly employed
      strategy especially in depressed patients unresponsive to monotherapy.
      Comedications with SSRIs, however, may be hazardous owing to pharmacokinetic
      interactions that can result in elevated serum TCA levels. For the combinations,
      safety and tolerability data are lacking. METHOD: We report tolerability and
      safety of combined treatment with fluvoxamine and clomipramine (CMI) in 22
      patients. Most patients suffered from depression and obsessive-compulsive
      symptoms. Diagnoses were made according to DSM-III-R criteria. Serum levels of
      CMI, N-desmethylclomipramine (DCMI), and 8-hydroxylated metabolites were
      determined. EEG, ECG, and laboratory parameters and adverse effects reported by
      the patients, as well as global clinical improvement, were assessed. RESULTS:
      Generally, fluvoxamine/clomipramine comedication was well tolerated. Serum CMI
      levels reached 500 to 1200 ng/mL in half of the patients, while corresponding
      levels for DCMI and 8-hydroxylated metabolites were low. Moreover, the ratios of
      N-demethylation DCMI:CMI calculated from the ratios of drug concentrations in
      serum were markedly lower under comedication than under CMI monotherapy.
      Alterations in EEG, ECG, and laboratory parameters that had clinical relevance
      were rarely observed and were reversible after dose reduction of CMI. However, 2
      patients developed myoclonic jerks. A majority of patients improved clinically
      during combination treatment. Clinically relevant side effects were absent in
      patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N
      demethylation below 0.3. CONCLUSION: Our results suggest that comedication of
      fluvoxamine and clomipramine will result in markedly elevated serum clomipramine
      levels. Therefore, combination treatment with fluvoxamine and clomipramine should
      be carefully monitored by determination of serum levels of the TCA. Clinically,
      the pharmacokinetic interactions between fluvoxamine and clomipramine may be well
      tolerated in a majority of patients. However, in a few patients, higher serum
      levels may be associated with an increased risk of EEG changes and changes of
      intracardiac conductance. EEG and ECG should be used regularly to monitor
      comedicated patients.

PMID- 8666565
TI  - Incentive bias?

PMID- 8666566
TI  - Incentive bias?

PMID- 8666567
TI  - Panic disorder in completed suicide.
AB  - BACKGROUND: Patients with panic disorder are reportedly at increased risk of
      suicidal behavior, but in psychological autopsy studies of completed suicides, a
      current diagnosis of panic disorder has been rare or absent. The comorbidity and
      other clinical characteristics of panic disorder among suicides are not known.
      METHOD: On the basis of data from a psychological autopsy study of all suicides
      (N = 1397) in Finland occurring during 1 year, all victims with current DSM-III-R
      panic disorder were retrospectively identified and examined in terms of
      comorbidity, suicide methods, history of suicide attempts, treatment setting, and
      duration of panic disorder. RESULTS: Seventeen victims with current panic
      disorder, 1.2% of all suicides, were identified. The prevalence of panic disorder
      was higher among female (2.8%, 9 of 320) than male suicides (0.7%, 8 of 1077; p =
      .007). All victims with panic disorder suffered concurrent Axis I disorders, and
      8 (47%) Axis II disorders. Major depression was diagnosed in 10 (59%), and
      substance dependence or abuse in 8 (47%) of the cases. The mean duration of panic
      disorder before suicide was 8 years. In most cases, the onset of panic disorder
      preceded comorbid Axis I disorders and previous suicide attempts. Most victims
      with panic disorder had a history of psychiatric treatment. CONCLUSION: Current
      panic disorder, and noncomorbid panic disorder in particular, seem to be rare
      among completed suicides. Suicide in persons with panic disorder is associated
      with superimposed major depression and substance abuse, and with personality
      disorders. For recognizing panic disorder patients at risk of suicide, the
      assessment and monitoring of the overall psychopathology are essential.

PMID- 8666568
TI  - Memory functioning in Lyme borreliosis.
AB  - BACKGROUND: To objectively measure memory functioning in patients with Lyme
      borreliosis and examine the relationship between subjective reports of memory
      dysfunction and actual impairment. METHOD: A prospective pretreatment study of
      patients with Lyme borreliosis (N = 21), a patient control group (osteomyelitis,
      N = 21), and healthy controls (N = 21) was conducted by using tests of verbal
      memory functioning (California Verbal Learning Test) and self-reported depression
      (Beck Depression Inventory-Cognitive Index), fatigue (Fatigue Severity Scale),
      and subjective ratings of memory abilities (Self-Rating Scale of Memory
      Functions). RESULTS: Patients with Lyme borreliosis performed worse than healthy
      controls on verbal memory testing, but did not perform significantly differently
      from patient controls. Lyme borreliosis patients reported increased fatigue,
      which was correlated with poorer memory performance. Although the Lyme
      borreliosis patients rated their memory as more impaired, subjective complaints
      were not correlated with objective memory scores. CONCLUSION: These findings
      suggest impaired memory performance is not specific to Lyme borreliosis and may
      be a result of evaluating cognitive functioning in patients with physical illness
      and somatic complaints. Fatigue is a prominent presenting complaint in patients
      with Lyme borreliosis and needs to be controlled for since it is known to
      influence neuropsychological performance. Subjective complaints are not
      correlated with objective memory assessment, so self-report of memory impairment
      should not be the criterion for inclusion in studies investigating cognitive
      manifestations of Lyme borreliosis.

PMID- 8666569
TI  - Efficacy of buspirone in generalized anxiety disorder with coexisting mild
      depressive symptoms.
AB  - BACKGROUND: This study was designed to evaluate the anxiolytic efficacy of
      buspirone in patients with a diagnosis of generalized anxiety disorder (GAD) with
      coexisting mild depressive symptoms. METHOD: Patients who participated in this
      multicenter study scored >/= 18 on the Hamilton Rating Scale for Anxiety (HAM-A)
      and between 12 and 17 on the Hamilton Rating Scale for Depression (HAM-D).
      Following a 7- to 10-day placebo lead-in phase, patients who continued to qualify
      were randomly assigned to receive either buspirone titrated from 15 to 45 mg/day
      (N = 80) or placebo (N = 82) for the next 6 weeks. 121 patients completed 6 weeks
      of treatment. The primary efficacy measure was the HAM-A, taken weekly during the
      study. RESULTS: Buspirone-treated patients averaged a 12.4-point reduction from
      their baseline total HAM-A score of 24.9, while their counterparts on placebo
      averaged a 9.5-point reduction from their mean baseline total HAM-A score of
      25.6. This 2.9-point difference in HAM-A reductions between treatment groups was
      significantly different (p < .03). Buspirone patients decreased their HAM-D
      scores by an average 5.7 points from their mean baseline total HAM-D score of
      15.8, while placebo patients decreased their HAM-D scores by an average 3.5
      points from their mean baseline score of 16.3 (p < .05). Overall, the incidence
      of adverse events was similar for both treatment groups, but buspirone-treated
      patients reported significantly more nausea, dizziness, somnolence, and sweating
      than placebo patients. CONCLUSION: Buspirone is superior to placebo in improving
      anxiety and depressive symptoms in GAD patients who have coexisting depressive
      symptoms.

PMID- 8666570
TI  - Factors associated with pharmacologic noncompliance in patients with mania.
AB  - BACKGROUND: Studies of noncompliance with pharmacotherapy in bipolar disorder
      have primarily involved outpatients receiving lithium. There are limited data to
      date regarding the rates of noncompliance in patients with bipolar disorder and
      schizoaffective disorder hospitalized for recurrent mania. Similarly, the
      influence of race, illness phenomenology, and comorbid psychiatric and medical
      disorders and the treatment with antipsychotics, antidepressants, and mood
      stabilizing agents other than lithium on noncompliance in this population have
      not been systematically examined. METHOD: Patients hospitalized for acute mania
      (N = 101) were evaluated by the Structured Clinical Interview for DSM-III-R to
      establish diagnosis and comorbidity and the Young Mania Rating Scale and Hamilton
      Rating Scale for Depression to assess severity of manic and depressive symptoms,
      respectively. Compliance was assessed by responses to a clinician-administered
      questionnaire administered to the patient, treaters, and significant others and
      by admission plasma concentrations of mood-stabilizing agents. RESULTS: Sixty
      five patients (64%) were noncompliant with their pharmacologic regimen in the
      month prior to admission as defined by criteria for full compliance and partial
      or total noncompliance. Noncompliance was significantly associated with greater
      severity of mania upon admission (p = .02) and treatment with combinations of
      mood stabilizers (p = .01). CONCLUSION: Noncompliance with pharmacotherapy was
      present in the majority of patients admitted for acute mania and was associated
      with greater severity of mania upon admission and treatment with combinations of
      mood stabilizers.

PMID- 8666571
TI  - A practical loading dose method for converting schizophrenic patients from oral
      to depot haloperidol therapy.
AB  - BACKGROUND: Haloperidol decanoate is a long-acting depot antipsychotic agent used
      for the treatment of schizophrenic patients. The decanoate formulation was
      developed to treat schizophrenics who have a history of noncompliance with oral
      medication. Studies of techniques to convert from oral to depot therapy have not
      utilized the pharmacokinetics of the decanoate formulation. This study is a
      prospective evaluation for converting patients from oral to depot treatment.
      METHOD: Twenty-one patients meeting DSM-III-R criteria for schizophrenia
      participated in the study. Patients were treated with oral haloperidol for 6
      weeks and then were switched to decanoate. Haloperidol decanoate 100 mg was
      administered on a weekly basis for the first 4 weeks. Afterward, injection
      intervals were increased to every 2 weeks and then to every 4 weeks. Plasma
      haloperidol concentrations were obtained prior to the next injection and assayed
      by HPLC with electrochemical detection. Patients were monitored by the
      psychiatrists and nursing staff for symptoms of clinical deterioration. RESULTS:
      All patients completed the conversion trial during the first 4 weeks without any
      problems or adverse side effects. By the third week, mean plasma haloperidol
      concentrations from the decanoate injections were comparable with those of the 10
      mg oral haloperidol treatment (7.95 +/- 4.94 ng/mL vs. 7.79 +/- 4.79 ng/mL).
      Steady-state conditions for the decanoate therapy were achieved by the fourth
      week. CONCLUSION: These findings suggest that schizophrenic patients can be
      easily converted from oral to depot therapy without problems. Further studies
      with haloperidol decanoate and its conversion from oral treatment utilizing
      plasma concentrations are needed.

PMID- 8666572
TI  - Risperidone augmentation of SRI treatment for refractory obsessive-compulsive
      disorder.
AB  - BACKGROUND: Although serotonin reuptake inhibitors (SRIs) are the mainstay of
      pharmacologic treatment for obsessive-compulsive disorder (OCD), many patients do
      not have an adequate response to these medications. One approach to treating SRI
      refractory OCD patients has been to add other classes of medications to the SRI.
      We predicted that augmentation with risperidone would alleviate symptoms in SRI
      refractory OCD patients. METHOD: 21 patients were treated openly with the
      combination of an SRI and adjunctive risperidone (mean dose = 2.75 mg/day). All
      met DSM-IV criteria for obsessive-compulsive disorder and had a variety of
      comorbid disorders. Prior to addition of risperidone, all patients had failed to
      respond to at least one adequate trial of an SRI. Response was determined by
      clinical judgment and standardized rating scales. RESULTS: 5 (24%) of the 21
      patients experienced side effects (most commonly, akathisia), which forced
      discontinuation of risperidone. Of the 16 patients who tolerated combined
      treatment, 14 (87%) had substantial reductions in obsessive-compulsive symptoms
      within 3 weeks. Patients with horrific mental imagery had the strongest and
      fastest response, often within a few days. Patients with comorbid psychotic
      disorders improved gradually over 2 to 3 weeks. Patients with comorbid tic
      disorders had the poorest rate of response and highest rate of akathisia.
      CONCLUSION: These results suggest that risperidone augmentation is effective and
      well tolerated in patients with SRI-refractory obsessive-compulsive disorder.
      Response to risperidone augmentation appears to be influenced by symptom subtypes
      and comorbid conditions. Controlled trials are required to confirm the efficacy
      of risperidone augmentation for refractory OCD.

PMID- 8666573
TI  - Nefazodone relief of alprazolam interdose dysphoria: a potential therapeutic
      benefit of 3A3/4 inhibition.

PMID- 8666575
TI  - Treatment of a 4-year-old boy with ADHD with the dopamine releaser phentermine.

PMID- 8666574
TI  - Medication optimization during clozapine treatment.

PMID- 8666576
TI  - Clozapine in elderly psychotic patients.

PMID- 8666577
TI  - SSRI withdrawal.

PMID- 8666578
TI  - Spectrum models.

PMID- 8666579
TI  - MAOI-carbamazepine combination and statistical power.

PMID- 8666580
TI  - Advances in CNS Drugs. Recent advances and considerations in the treatment of
      schizophrenia.

PMID- 8666581
TI  - Human osteoblasts from younger normal and osteoporotic donors show differences in
      proliferation and TGF beta-release in response to cyclic strain.
AB  - Mechanical stimulation of bone tissue by physical activity stimulates bone
      formation in normal bone and may attenuate bone loss of osteoporotic patients.
      However, altered responsiveness of osteoblasts in osteoporotic bone to mechanical
      stimuli may contribute to osteoporotic bone involution. The purpose of the
      present study was to investigate whether osteoblasts from osteoporotic patients
      and normal donors show differences in proliferation and TGF beta production in
      responses to cyclic strain. Human osteoblasts isolated from collagenase-treated
      bone explants of 10 osteoporotic patients (average age 70 +/- 6 yr) and 8 normal
      donors (average age 54 +/- 10 yr) were plated into elastic rectangular silicone
      dishes. Subconfluent cultures were stimulated by cyclic strain (1%, 1 Hz) in
      electromechanical cell stretching apparatus at three consecutive days for each 30
      min. The cultures were assayed for proliferation, alkaline phosphatase activity
      and TGF beta release in each three parallel cultures. In all experiments,
      osteoblasts grown in the same elastic dishes but without mechanical stimulation
      served as controls. Significant differences between stimulated cultures and
      unstimulated controls were determined by a paired two-tailed Wilcoxon test. In
      comparison to the unstimulated controls, osteoblasts from normal donors
      significantly increased proliferation (p = 0.025) and TGF beta secretion (p =
      0.009) into the conditioned culture medium. In contrast, osteoblasts from
      osteoporotic donors failed to increase both proliferation (p > 0.05) and TGF beta
      release (p > 0.05) in response to cyclic strain. Alkaline phosphatase activity
      was not significantly affected (p > 0.05) in normal as well as osteoporotic bone
      derived osteoblasts. These findings suggest a different responsiveness to 1%
      cyclic strain of osteoblasts isolated from normal and osteoporotic bone that
      could be influenced by both the disease of osteoporosis and the higher average
      age of the osteoporotic patient group. While osteoblasts from osteoporotic donors
      failed to increase proliferation and TGF beta release under the chosen mechanical
      strain regimen that stimulated both parameters in normal osteoblasts, it is
      possible that some other strain regimen would provide more effective stimulation
      of osteoporotic cells.

PMID- 8666582
TI  - Cellular deformation reversibly depresses RT-PCR detectable levels of bone
      related mRNA.
AB  - Osteoblastic cells respond to mechanical stimuli with alterations in
      proliferation and/or phenotypic expression. In some cases, these responses occur
      within only a few applications of stimuli (i.e. 'cycle-dependent trigger
      response') rather than in a dose-dependent manner. To explore potential
      mechanisms of the cycle dependent trigger response, we raised the following
      questions: (1) Does strain of bone cells alter gene expression; if so, how
      quickly does it occur and how long does it last? (2) Are alterations in message
      level strain magnitude dependent? (3) Are alterations in steady-state message
      levels cycle dependent? Cultures were evaluated for osteocalcin mRNA one week
      following a daily stretch application at four stretch magnitudes and four cycle
      numbers and compared to nonstretched controls. Steady state mRNA message was
      ascertained prior to and at 10, 20, 30, 60, 120, 180, and 240 min following
      initiation of stretch. Following mRNA isolation, first strand cDNA synthesis was
      performed and fluorometrically quantitated. A reverse transcriptase based PCR (RT
      PCR) approach allowed assessment of osteocalcin mRNA levels from microcultures
      (50,000 cells per 10 microliters culture or 5000 cells mm2) of rat calvarial
      osteoblasts. Optimized PCR was performed using primers to the bone specific
      protein, osteocalcin (OC) and two 'housekeeping' genes, beta-actin and GAP-DH.
      PCR products were separated on 4% agarose gels and band intensities digitized
      with relative quantitation based on internal standards in each gel. The lowest
      magnitude of stretch (- 1 KPa) at 1800 cycles per day reproducibly depressed
      message for osteocalcin, but not beta-actin when assayed immediately following
      the cessation of strain application. By three hours following the initiation of
      stretch, message levels returned to control values. At the time of stretch
      cessation, the 1800 cycle stretch regimen diminished (p < 0.0001) steady-state
      osteocalcin message independently of the four stretch magnitudes. Stretch for 300
      cycles failed to depress (p = 0.05) osteocalcin message cultures at any time, but
      600 cycles depressed message by 30 min. By one and two hours, cultures stretch
      600, 900, and 1800 cycles showed similar levels of message depression. Four hours
      following the initiation of stretch, message levels returning to nonstrained
      levels in all groups. We conclude that alterations in cell response to strain are
      in part mediated by gene expression, that alterations last 3-4 h in this system,
      and that the message mechanism itself exhibits a trigger-response dependency to
      cycle number.

PMID- 8666583
TI  - Osmotic dilution stimulates axonal outgrowth by making axons more sensitive to
      tension.
AB  - Mechanical tension is a potent stimulator of axonal growth rate, which is also
      stimulated by osmotic dilution. We wished to determine the relationship, if any,
      between osmotic stimulation and tensile regulation of axonal growth. We used
      calibrated glass needles to apply constant force to elongate axons of cultured
      chick sensory neurons. We find that a neurite being pulled at a constant force
      will grow 50-300% faster following a 50% dilution of inorganic ions in the
      culture medium. That is, osmotic dilution appears to cause axons to increase
      their sensitivity to applied tensions. Experimental interventions suggest that
      this effect is not mediated by dilution of extracellular calcium, or to osmotic
      stimulation of adenylate cyclase, or to osmotic stimulation of mechanosensitive
      ion channels. Rather, experiments measuring the static tension normally borne by
      neurites suggest a direct mechanical effect on the cytoskeletal proteins of the
      neurite shaft. Our results are consistent with a formal thermodynamic model for
      axonal growth in which removing a compressive load on axonal microtubules
      promotes their assembly, thus promoting axonal elongation.

PMID- 8666584
TI  - Protein kinases as mediators of fluid shear stress stimulated signal transduction
      in endothelial cells: a hypothesis for calcium-dependent and calcium-independent
      events activated by flow.
AB  - Fluid shear stress regulates endothelial cell function, but the signal
      transduction mechanisms involved in mechanotransduction remain unclear. Recent
      findings demonstrate that several intracellular kinases are activated by
      mechanical forces. In particular, members of the mitogen-activated protein (MAP)
      kinase family are stimulated by hyperosmolarity, stretch, and stress such as heat
      shock. We propose a model for mechanotransduction in endothelial cells involving
      calcium-dependent and calcium-independent protein kinase pathways. The calcium
      dependent pathway involves activation of phospholipase C, hydrolysis of
      phosphatidylinositol 4,5-bisphosphate (PIP2), increases in intracellular calcium
      and stimulation of kinases such as calcium-calmodulin and C kinases (PKC). The
      calcium-independent pathway involves activation of a small GTP-binding protein
      and stimulation of calcium-independent PKC and MAP kinases. The calcium-dependent
      pathway mediates the rapid, transient response to fluid shear stress including
      activation of nitric oxide synthase (NOS) and ion transport. In contrast, the
      calcium-independent pathway mediates a slower response including the sustained
      activation of NOS and changes in cell morphology and gene expression. We propose
      that focal adhesion complexes link the calcium-dependent and calcium-independent
      pathways by regulating activity of phosphatidylinositol 4-phosphate (PIP) 5
      kinase (which regulates PIP2 levels) and p125 focal adhesion kinase (FAK, which
      phosphorylates paxillin and interacts with cytoskeletal proteins). This model
      predicts that dynamic interactions between integrin molecules present in focal
      adhesion complexes and membrane events involved in mechanotransduction will be
      integrated by calcium-dependent and calcium-independent kinases to generate
      intracellular signals involved in the endothelial cell response to flow.

PMID- 8666585
TI  - Multiple cis-elements mediate shear stress-induced gene expression.
AB  - Fluid shear stress activates the expression of immediate early (IE) genes in
      vascular endothelial cells. The transcriptional regulation can be mediated
      through the shear stress-sensitive cis-acting elements at the 5' promoter regions
      of various IE genes such as the monocyte chemotactic protein-1 (MCP-1) gene. We
      linked wild-type and mutated MCP-1 promoters to the reporter gene luciferase and
      used such constructs to investigate the role of the phorbol ester TPA responsive
      element (TRE) in the shear-induced MCP-1 gene expression in vascular endothelial
      cells. Functional analysis showed that TGACTCC (a divergent TRE) located at nt 
      54 to -60 is necessary for shear-inducibility in bovine aortic endothelial cells
      (BAEC). The induction of the wild-type MCP-1 promoter construct by shear stress
      was attenuated by pretreating the cells with 1 microM dexamethasone or 1 microM
      retinoic acid 12 h before the shear stress experiments. The induction by shear
      stress reduced from 13-fold in the untreated cells to 7- and 3-folds in the
      dexamethasone- and retinoic acid-treated cells, respectively. These results
      demonstrate that the glucocorticoid receptor and retinoic acid receptor may
      interfere with the shear stress-activated AP-1/TRE. The reporter activity of
      HIV(LTR), which is a plasmid construct of the long terminal repeats of the human
      immunodeficiency virus and contains a kappa B enhancer element, was also
      activated by shear stress. The results of our investigations indicate that the
      shear stress-induced IE gene expression can be mediated through multiple cis
      elements.

PMID- 8666586
TI  - Effects of wall shear stress and fluid recirculation on the localization of
      circulating monocytes in a three-dimensional flow model.
AB  - There is a correlation between the location of early atherosclerotic lesions and
      the hemodynamic characteristics at those sites. Circulating monocytes are key
      cells in the pathogenesis of atherosclerotic plaques and localize at sites of
      atherogenesis. The hypothesis that the distribution of monocyte adhesion to the
      vascular wall is determined in part by hemodynamic factors was addressed by
      studying monocyte adhesion in an in vitro flow model in the absence of any
      biological activity in the model wall. Suspensions of U937 cells were perfused
      (Re = 200) through an axisymmetric silicone flow model with a stenosis followed
      by a reverse step. The model provided spatially varying wall shear stress, flow
      separation and reattachment, and a three-dimensional flow pattern. The cell
      rolling velocity and adhesion rates were determined by analysis of
      videomicrographs. Wall shear stress was obtained by numerical solution of the
      equations of fluid motion. Cell adhesion patterns were also studied in the
      presence of chemotactic peptide gradients. The cell rolling velocity varied
      linearly with wall shear stress. The adhesion rate tended to decrease with
      increasing local wall shear stress, but was also affected by the radial component
      of velocity and the dynamics of the recirculation region and flow reattachment.
      Adhesion was increased in the vicinity of chemotactic peptide sources downstream
      of the expansion site. Results with human monocytes were qualitatively similar to
      the U937 experiments. Differences in the adhesion rates of U937 cells occurring
      solely as a function of the fluid dynamic properties of the flow field were
      clearly demonstrated in the absence of any biological activity in the model wall.

PMID- 8666587
TI  - Cell shape, cytoskeletal mechanics, and cell cycle control in angiogenesis.
AB  - Capillary endothelial cells can be switched between growth and differentiation by
      altering cell-extracellular matrix interactions and thereby, modulating cell
      shape. Studies were carried out to determine when cell shape exerts its growth
      regulatory influence during cell cycle progression and to explore the role of
      cytoskeletal structure and mechanics in this control mechanism. When G0
      synchronized cells were cultured in basic fibroblast growth factor (FGF)
      containing defined medium on dishes coated with increasing densities of
      fibronectin or a synthetic integrin ligand (RGD-containing peptide), cell
      spreading, nuclear extension, and DNA synthesis all increased in parallel. To
      determine the minimum time cells must be adherent and spread on extracellular
      matrix (ECM) to gain entry into S phase, cells were removed with trypsin or
      induced to retract using cytochalasin D at different times after plating. Both
      approaches revealed that cells must remain extended for approximately 12-15 h and
      hence, most of G1, in order to enter S phase. After this restriction point was
      passed, normally 'anchorage-dependent' endothelial cells turned on DNA synthesis
      even when round and in suspension. The importance of actin-containing
      microfilaments in shape-dependent growth control was confirmed by culturing cells
      in the presence of cytochalasin D (25-1000 ng ml-1): dose-dependent inhibition of
      cell spreading, nuclear extension, and DNA synthesis resulted. In contrast,
      induction of microtubule disassembly using nocodazole had little effect on cell
      or nuclear spreading and only partially inhibited DNA synthesis. Interestingly,
      combination of nocodazole with a suboptimal dose of cytochalasin D (100 ng ml-1)
      resulted in potent inhibition of both spreading and growth, suggesting that
      microtubules are redundant structural elements which can provide critical load
      bearing functions when microfilaments are partially compromised. Similar
      synergism between nocodazole and cytochalasin D was observed when cytoskeletal
      stiffness was measured directly in living cells using magnetic twisting
      cytometry. These results emphasize the importance of matrix-dependent changes in
      cell and nuclear shape as well as higher order structural interactions between
      different cytoskeletal filament systems for control of capillary cell growth
      during angiogenesis.

PMID- 8666588
TI  - Cyclic strain causes heterogeneous induction of transcription factors, AP-1, CRE
      binding protein and NF-kB, in endothelial cells: species and vascular bed
      diversity.
AB  - Recent studies demonstrate that cyclic strain stimulates protein kinase C in
      bovine aortic endothelial cells (BAEC) as well as the induction of immediate
      early genes and the transcription factor activator protein-1 (AP-1) in human
      umbilical vein endothelial cells (HUVEC). The objective of this study was to
      determine whether transcriptional factor induction in endothelial cells (EC)
      exposed to strain is the same with regard to the species and vascular bed they
      are derived from. Evidence for a heterogeneous response for growth, orientation
      and prostacyclin secretion has been obtained for a variety of EC exposed to
      cyclic strain. In this study, we investigated cyclic strain mediated induction of
      transcription factors, AP-1, cAMP response element binding protein (CRE) and
      nuclear factor kB (NF-kB) in cultured EC from HUVEC, human aorta (HAEC), and
      BAEC. EC were exposed to 10% average strain at 60 cpm for up to 24 h. At varying
      time points, nuclear protein was extracted and analyzed for production of AP-1,
      CRE and NF-kB by electromobility shift assay. The results demonstrate that EC
      exposure to cyclic strain leads to a significant induction of AP-1, CRE and NF-kB
      in HAEC and HUVEC, but not in BAEC. Furthermore, these findings are in marked
      contrast to the previously described shear stress induced activation of AP-1 and
      NF-kB in BAEC. There was also a temporal difference in their response such that
      stretch-induced activation of AP-1 and NF-kB peaked at 4 h, whereas CRE increased
      in a biphasic manner at 15 min and 24 h. These results may partially explain the
      divergent effects of cyclic strain on EC gene expression and phenotype in EC from
      different vascular beds and species and underscore the difference in EC response
      to cyclic strain and shear stress.

PMID- 8666589
TI  - Mechanical stimulation by intermittent hydrostatic compression promotes bone
      specific gene expression in vitro.
AB  - In a previous study of the cellular mechanism underlaying Wolff's law we showed
      that mechanical stimulation by intermittent hydrostatic compression (IHC)
      increases bone formation in cultured fetal mouse calvariae compared to non
      stimulated cultures. To test whether mechanical stimuli may modulate bone
      specific gene expression, we studied the effect of IHC on alkaline phosphatase
      (AP) expression and enzyme activity as well as collagen and actin mRNA levels in
      neonatal mouse calvariae and calvarial bone cells. Two cell populations, one
      resembling osteoprogenitor (OPR) cells and another resembling osteoblasts (OB)
      were obtained from calvariae by sequential digestion. IHC was applied by
      intermittently (0.3 Hz) compressing the gas- phase of a closed culture chamber
      (peak stress 13kPa, peak stress rate 32.5 kPas-1). In control cultures of
      calvariae as well as OB and OPR cells, AP activity and AP-, collagen-, and actin
      mRNA levels all decreased after one or more days, with the exception of OPR cell
      collagen expression which increased during culture. IHC treatment upregulated AP,
      collagen and actin expression and AP activity in calvariae and OB cells, but
      decreased collagen expression in OPR cells. These results suggest that treatment
      with IHC promotes the osteoblastic phenotype in bone organ cultures and in
      osteoblasts. Osteoprogenitor cells seem to react somewhat differently to
      mechanical stress than osteoblasts. The loss of bone-specific gene expression
      under control culture conditions, in the absence of mechanical stimuli, suggests
      that the mechanical environment is important in maintaining the differentiated
      phenotype of bone cells, and that IHC treatment partially restores this
      environment in bone cell- and organ cultures.

PMID- 8666590
TI  - PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon
      fibroblasts in vitro.
AB  - Resident cells in the surface epitenon and internal compartment of flexor tendons
      are subjected to cyclic mechanical load as muscle contracts to move limbs or
      digits. Tendons are largely tensile load bearing tissues and are highly matrix
      intensive with nondividing cells providing maintenance functions. However, when
      an injury occurs, tendon cells are stimulated to divide by activated endogenous
      growth factors and those from platelets and plasma. We hypothesize that tendon
      cells detect mechanical load signals but do not interpret such signals as
      mitogenic unless an active growth factor is present. We have used an in vitro
      mechanical load model, application of cyclic strain to cells cultured on flexible
      bottomed culture plates, to test the hypothesis that tendon cells require
      platelet-derived growth factor (PDGF-BB) and insulin-like growth factor-I (IGF-I)
      in addition to mechanical load to stimulate DNA synthesis. In addition, we
      demonstrate that in avian tendon cells, load and growth factors stimulate
      phosphorylation of tyrosine residues in multiple proteins, including pp60src, a
      protein kinase that phosphorylates receptor protein tyrosine kinases. A lack of
      mitogenic responsiveness to mechanical load alone by tendon cells may be a
      characteristic of a regulatory pathway that modulates cell division.

PMID- 8666591
TI  - Control of endothelial cell gene expression by flow.
AB  - The vessel wall is constantly subjected to, and affected by, the stresses
      resulting from the hemodynamic stimuli of transmural pressure and flow. At the
      interface between blood and the vessel wall, the endothelial cell plays a crucial
      role in controlling vessel structure and function in response to changes in
      hemodynamic conditions. Using bovine aortic endothelium monolayers, we show that
      fluid shear stress causes simultaneous differential regulation of endothelial
      derived products. We also report that the downregulation of endothelin-1 mRNA by
      flow is a reversible process, and through the use of uncharged dextran
      supplementation demonstrate it to be shear stress- rather than shear rate
      dependent. Recent work on the effect of fluid shear stress on endothelial cell
      gene expression of a number of potent endothelial products is reviewed, including
      vasoactive substances, autocrine and paracrine growth factors,
      thrombosis/fibrinolysis modulators, chemotactic factors, surface receptors and
      immediate-early genes. The encountered patterns of gene expression responses are
      classified into three categories: a transient increase with return to baseline
      (type I), a sustained increase (type II) and a biphasic response consisting of an
      early transient increase of varying extent followed by a pronounced and sustained
      decrease (type III). The importance of the dynamic character of the flow stimulus
      and the magnitude dependence of the response are presented. Potential molecular
      mechanisms of shear-induced gene regulation, including putative shear stress
      response elements (SSRE), are discussed. These results suggest exquisite
      modulation of endothelial cell phenotype by local fluid shear stress and may
      offer insight into the mechanism of flow-dependent vascular remodeling and the
      observed propensity of atherosclerosis formation around bifurcations and areas of
      low shear stress.

PMID- 8666592
TI  - Compression-induced changes in the shape and volume of the chondrocyte nucleus.
AB  - Changes in cell shape and volume are believed to play a role in the process of
      mechanical signal transduction by chondrocytes in articular cartilage. One
      proposed pathway through which chondrocyte deformation may be transduced to an
      intracellular signal is through cytoskeletally mediated deformation of
      intracellular organelles, and more specifically, of the cell nucleus. In this
      study, confocal scanning laser microscopy was used to perform in situ three
      dimensional morphometric analyses of the nuclei of viable chondrocytes during
      controlled compression of articular cartilage explants from the canine
      patellofemoral groove. Unconfined compression of the tissue to a 15% surface-to
      surface strain resulted in a significant decrease of chondrocyte height and
      volume by 14.7 +/- 6.4 and 11.4 +/- 8.4%, respectively, and of nuclear height and
      volume by 8.8 +/- 6.2% and 9.8 +/- 8.8%, respectively. Disruption of the actin
      cytoskeleton using cytochalasin D altered the relationship between matrix
      deformation and changes in nuclear height and shape, but not volume. The
      morphology and deformation behavior of the chondrocytes were not affected by
      cytochalasin treatment. These results suggest that the actin cytoskeleton plays
      an important role in the link between compression of the extracellular matrix and
      deformation of the chondrocyte nuclei and imply that chondrocytes and their
      nuclei undergo significant changes in shape and volume in vivo.

PMID- 8666593
TI  - Cell orientation response to cyclically deformed substrates: experimental
      validation of a cell model.
AB  - We have developed a stochastic model that describes the orientation response of
      bipolar cells grown on a cyclically deformed substrate. The model was based on
      the following hypotheses regarding the behavior of individual cells: (a) the
      mechanical signal responsible for cell reorientation is the peak to peak surface
      strain along the cell's major axis (p-p axial strain); (b) each cell has an axial
      strain threshold and the threshold is normally distributed in the cell
      population; (c) the cell will avoid any direction where the p-p axial strain is
      above its threshold; and (d) the cell will randomly orient within the range of
      directions where the p-p axial strains are less than the cell's threshold. These
      hypotheses were tested by comparing model predictions with experimental
      observations from stretch experiments conducted with human melanocytes. The cells
      were grown on elastic rectangular culture dishes subjected to unidirectional
      cyclic (1 Hz) stretching with amplitudes of 0, 4, 8, and 12%. After 24 h of
      stimulation, the distribution of cell orientations was determined by measuring
      the orientations of 300-400 randomly selected cells. The 12% stretch experiment
      was used to determine the mean, 3.5%, and the standard deviation, 1.0% of the
      strain threshold for the cell population. The Kolmogorov-Smirnov test was then
      used to determine if the orientation distributions predicted by the model were
      different from experimentally measured distributions for the 4 and 8% stretches.
      No significant differences were found between the predicted and experimental
      distributions (4%: p = 0.70; and 8%: p = 0.71). These results support the
      hypothesis that cells randomly orient, but avoid directions where the p-p axial
      strains are above their thresholds.

PMID- 8666594
TI  - A mechanism for heterogeneous endothelial responses to flow in vivo and in vitro.
AB  - Exposure of endothelium to a nominally uniform flow field in vivo and in vitro
      frequently results in a heterogeneous distribution of individual cell responses.
      Extremes in response levels are often noted in neighboring cells. Such variations
      are important for the spatial interpretation of vascular responses to flow and
      for an understanding of mechanotransduction mechanisms at the level of single
      cells. We propose that variations of local forces defined by the cell surface
      geometry contribute to these differences. Atomic force microscopy measurements of
      cell surface topography in living endothelium both in vitro and in situ combined
      with computational fluid dynamics demonstrated large cell-to-cell variations in
      the distribution of flow-generated shear stresses at the endothelial luminal
      surface. The distribution of forces throughout the surface of individual cells of
      the monolayer was also found to vary considerably and to be defined by the
      surface geometry. We conclude that the endothelial three-dimensional surface
      geometry defines the detailed distribution of shear stresses and gradients at the
      single cell level, and that there are large variations in force magnitude and
      distribution between neighboring cells. The measurements support a topographic
      basis for differential endothelial responses to flow observed in vivo and in
      vitro. Included in these studies are the first preliminary measurements of the
      living endothelial cell surface in an intact artery.

PMID- 8666595
TI  - Changes in proteoglycan synthesis of chondrocytes in articular cartilage are
      associated with the time-dependent changes in their mechanical environment.
AB  - Explant loading experiments were conducted to investigate the effect of load
      duration on proteoglycan synthesis. A compressive load of 0.1 MPa applied for 10
      min was found to stimulate proteoglycan synthesis, while the same load applied
      for 20 h suppressed synthesis. This bimodal response suggests that the cells are
      responding to different mechanical stimuli as time progresses. A theoretical
      model has therefore been developed to describe the mechanical environment
      perceived by cells within soft hydrated tissues (e.g. articular cartilage) while
      the tissue is being loaded. The cells are modeled, using the biphasic theory, as
      fluid-solid inclusions embedded in and attached to a biphasic extracellular
      matrix of distinct material properties. A method of solution is developed which
      is valid for any axisymmetric loading configuration, provided that the cell
      radius, a, is small relative to the tissue height, h (i.e. h/a >> 1). A closed
      form analytical solution for this inclusion problem is then presented for the
      confined compression configuration. Results from this model show that the
      mechanical environment in and around the cells is time dependent and
      inhomogeneous, and can be significantly influenced by differences in properties
      between the cell and the extracellular matrix.

PMID- 8666596
TI  - There are things that we can do.

PMID- 8666597
TI  - Arthroscopically assisted reconstruction of the anterior cruciate ligament. A
      prospective randomized analysis of three techniques.
AB  - One hundred and twenty-seven patients who had a rupture of the anterior cruciate
      ligament agreed to participate in a prospective, randomized study of three
      arthroscopically assisted reconstruction techniques. One hundred and twenty-five
      patients (125 reconstructions) were evaluated after a mean duration of follow-up
      of forty-two months (range, two to five years). Group I included forty patients
      who had a two-incision reconstruction with use of an autogenous semitendinosus
      gracilis graft, group II consisted of forty patients who had a two-incision
      reconstruction with use of an autogenous patellar-ligament graft, and group III
      included forty-five patients who had a single-incision reconstruction (endoscopic
      technique) with use of an autogenous patellar-ligament graft. The male-female
      ratio, age range, level of athletic activity, interval between the injury and the
      reconstruction, previous operative procedures, and associated injuries were
      similar in all three groups. The same postoperative rehabilitation protocol was
      followed for all patients. Testing with a KT-2000 arthrometer at maximum manual
      force was done at the follow-up evaluation; the difference in laxity between the
      involved knee and the contralateral knee was three millimeters or less in thirty
      three patients (83 per cent) in group I, thirty-seven patients (93 per cent) in
      group II, and thirty-nine patients (87 per cent) in group III. A difference of
      two millimeters or less was found in thirty patients (75 per cent) in group I,
      thirty-one patients (78 per cent) in group II, and thirty-five patients (78 per
      cent) in group III. Thirty-five patients (88 per cent) in group I, thirty-eight
      patients (95 per cent) in group II, and forty patients (89 per cent) in group III
      returned to at least the same level of athletic activity. Four grafts (two in
      group I and two in group II) failed as a result of trauma. There was one
      additional failure in groups I and III, as evidenced by a difference of nine and
      seven millimeters, respectively, on instrumented testing of laxity. The
      significant findings were that no knee was rated D according to the system of the
      International Knee Documentation Committee (p < 0.002, 94 per cent confidence
      level) and that fewer additional operative procedures were done on patients in
      group III (p < 0.08). Also, it was found that the patients in group II returned
      to a greater level of athletic activity (p < 0.02) and that a higher percentage
      of the patients in this group had a difference of three millimeters or less on
      testing with the KT-2000 arthrometer than in the other two groups (p < 0.08).
      However, with the numbers available, there were no significant differences in the
      over-all outcome among the three groups (p > 0.1). Importantly, the rate of
      failure was not greater and the outcomes were not less satisfactory for the late
      reconstructions than they were for the acute reconstructions (those performed
      less than three weeks after the injury), including those done with an autogenous
      semitendinosus-gracilis graft in a chronically unstable knee.

PMID- 8666598
TI  - Brace-free rehabilitation, with early return to activity, for knees reconstructed
      with a double-looped semitendinosus and gracilis graft.
AB  - Forty-one patients in whom operative reconstruction of a torn anterior cruciate
      ligament had been performed by one surgeon with use of a double-looped
      semitendinosus and gracilis hamstring graft were studied to determine (1) if a
      brace-free rehabilitation program compromised the early stability of the knee;
      (2) if the stability of the knee deteriorated between four months, when the
      patient returned to unrestricted activities, and two years; and (3) if the
      function of the treated knee was completely restored by four months after the
      operation. The graft was placed arthroscopically, without impingement by the
      intercondylar roof, and was fixed within the tibial tunnel to conserve the length
      of the graft. The stability and function of thirty-seven of the knees were
      assessed at four months as part of a larger prospective study. Four patients
      chose not to return for the four-month evaluation. The patients returned to
      unrestricted sports and work activities after the four-month evaluation. At two
      years, all forty-one patients were evaluated. At four months, after completion of
      the brace-free rehabilitation program, thirty-three (82 per cent) of the thirty
      seven patients had an absent pivot shift and a normal Lachman test. Twenty-eight
      (88 per cent) of thirty-four knees had less than three millimeters of difference
      in laxity compared with the contralateral knee, as determined by testing at the
      maximum manual force with use of a KT-1000 arthrometer. Stability remained
      unchanged at two years, justifying the early return to vigorous activities at
      four months. The girth of the thigh, the extension of the knee, and the Lysholm
      and Gillquist score were the same at four months as at two years, verifying the
      success of the brace-free intensive rehabilitation program in the restoration of
      early function to the treated knee. However, some continued improvement was
      observed in the performance of the one-leg-hop for distance test between four
      months and two years.

PMID- 8666599
TI  - Prophylaxis against deep venous thrombosis after total knee arthroplasty.
      Pneumatic plantar compression and aspirin compared with aspirin alone.
AB  - A prospective, randomized study was conducted to assess the efficacy of pulsatile
      pneumatic plantar compression for prophylaxis against deep venous thrombosis
      after total knee arthroplasty performed with use of regional anesthesia. One
      hundred and twenty-two patients (164 knees) who were scheduled to have a
      unilateral or a one-stage bilateral total knee arthroplasty were separately
      randomized to be managed with either aspirin alone or the pulsatile pneumatic
      plantar-compression device and aspirin. The prevalence of deep venous thrombosis
      was 27 per cent (twenty-two of eighty-one knees) in the group treated with
      pneumatic plantar compression compared with 59 per cent (forty-nine of eighty
      three knees) in the patients managed with aspirin alone (the control group) (p <
      0.001). A significant difference was also noted in the group that had had a
      unilateral arthroplasty (a prevalence of 27 per cent [eleven of forty-one knees]
      in the group treated with pneumatic plantar compression, compared with 67 per
      cent [twenty-six of thirty-nine knees] in that treated with aspirin alone; p <
      0.006) and in the group that had had a one-stage bilateral procedure (a
      prevalence of 28 per cent [eleven of forty knees] in the group treated with
      pneumatic plantar compression, compared with 52 per cent [twenty-three of forty
      four knees] in that treated with aspirin alone; p < 0.03). No proximal thrombi
      were noted in any patient who used the pulsatile pneumatic plantar-compression
      device, while the prevalence of proximal thrombosis in the popliteal or femoral
      veins was 14 per cent (twelve of eighty-three knees) in the group treated with
      aspirin alone (p < 0.0003). In the group treated with a unilateral procedure and
      aspirin alone the prevalence of proximal thrombosis was 13 per cent (five of
      thirty-nine knees; p < 0.02), while in the group treated with a bilateral
      procedure and aspirin alone it was 16 per cent (seven of forty-four knees; p <
      0.01). Only in the patients who had had a unilateral procedure was use of the
      compression device associated with significantly less edema postoperatively than
      was use of aspirin alone. The change between the preoperative and postoperative
      circumferences of the thigh and leg was significantly less (9 +/- 4.1 millimeters
      [mean and standard deviation] less for the thigh [p < 0.01] and 6 +/- 3.9
      millimeters less for the leg [p < 0.049]) with the compression device than with
      aspirin alone. In addition, there was significantly less mean drainage (98 +/-
      61.1 milliliters) in the group treated with a unilateral procedure and pneumatic
      compression, compared with that treated with a unilateral procedure and aspirin
      alone (p < 0.041). An internal timer of the compression device was used to assess
      the compliance of the patient with use of the device, and a relationship between
      deep venous thrombosis and the total duration of treatment with the device was
      found. The patients in whom deep venous thrombosis did not develop used the
      device for a mean of 96 +/- 23.4 hours (range, sixty to 164 hours)
      postoperatively, or 19.2 +/- 5.1 hours a day, while those in whom thrombosis
      developed used it for a mean of 67 +/- 21.1 hours (range, twenty-six to 101
      hours), or 13.4 +/- 4.3 hours a day (p < 0.001). No untoward effects were noted
      in any patient who used the device. This study confirms the safety and efficacy
      of pulsatile pneumatic plantar compression and aspirin compared with aspirin
      alone and supports the use of mechanical compression for prophylaxis against deep
      venous thrombosis and for reduction of edema in patients who have had a total
      knee arthroplasty. In addition, we found a direct relationship between compliance
      with the use of this device and its efficacy in reducing deep venous thrombosis.

PMID- 8666600
TI  - Differences between patients' and physicians' evaluations of outcome after total
      hip arthroplasty.
AB  - The purpose of this study was to compare patients' and physicians' evaluations of
      the results of 147 total hip arthroplasties. The patients and physicians
      independently evaluated pain and over-all satisfaction with the outcome of the
      procedure using a 10.0-centimeter visual-analog scale. They also answered a
      questionnaire with which they assessed general health, functional ability, and
      pain. The mean (and standard deviation) analog rating for pain (with 0.0
      centimeters indicating no pain and 10.0 centimeters, severe pain) was 1.7 +/- 2.6
      centimeters as assessed by the patients and 1.1 +/- 1.8 centimeters as assessed
      by the physicians (p < 0.001, paired t test). The mean analog rating for over-all
      satisfaction (with 0.0 centimeters indicating poor and 10.0 centimeters,
      excellent) was 8.6 +/- 2.1 centimeters as assessed by the patients and 8.8 +/-
      1.7 centimeters as assessed by the physicians (p = 0.07, paired t test). There
      was a marked disparity between the patients' and the physicians' scores when the
      patients assigned a low score to a particular area. For the thirty patients who
      rated the pain as more than 4.0 centimeters, the mean analog rating was 6.8 +/-
      2.1 centimeters according to the patients, while it was 3.6 +/- 2.7 centimeters
      according to the physicians (p < 0.001, linear regression). The mean analog
      rating for over-all satisfaction according to the nineteen patients who rated
      this parameter as less than 7.0 centimeters was 3.8 +/- 2.0 centimeters, while
      the mean rating according to the physicians 6.5 +/- 2.8 centimeters (p < 0.001,
      linear regression). The patients' and physicians' evaluations were similar
      regarding the results of the total hip arthroplasty when the patients had little
      or no pain and were satisfied with the result. However, the disparity increased
      as the patients' ratings for pain increased and their ratings for over-all
      satisfaction decreased. This study highlights a discrepancy between patients' and
      physicians' evaluations of the results of total hip arthroplasty. This
      discrepancy increased when the patient was not satisfied with the outcome. The
      use of patients' self-administered questionnaires as well as traditional
      physician-generated assessments may provide a more complete evaluation of the
      results of total hip arthroplasty.

PMID- 8666601
TI  - Perioperative complications of anterior procedures on the spine.
AB  - We reviewed the operative and hospital records of 447 patients in order to
      determine the rates of perioperative complications associated with an anterior
      procedure on the thoracic, thoracolumbar, or lumbar spine. The anterior
      procedures were performed to treat spinal deformity or for debridement or
      decompression of the spinal canal. The diagnostic groups that we studied included
      idiopathic scoliosis in adolescents or young adults (100 patients), scoliosis in
      mature adults (sixty-three patients), kyphosis (sixty-one patients),
      neuromuscular scoliosis (sixty patients), fracture (forty-seven patients), a
      revision procedure (thirty-nine patients), congenital scoliosis (thirty-six
      patients), tumor (nineteen patients), vertebral osteomyelitis or discitis (eight
      patients), and miscellaneous (fourteen patients). Complications occurred in 140
      (31 per cent) of the 447 patients and were classified as major or minor. Forty
      seven patients (11 per cent) had at least one major complication and 109 (24 per
      cent) had at least one minor complication. Two patients died, both from pulmonary
      complications after the operation. The most common type of major complication was
      pulmonary; the most common type of minor complication was genito-urinary. The
      adolescent or young adult patients who had idiopathic scoliosis had the lowest
      rate of complications, and the patients who had neuromuscular scoliosis had the
      highest. An age of more than sixty years at the time of the operation was
      associated with a higher risk of complications. The duration of the procedures
      involving a thoracic approach was shorter than that of those involving a
      thoracolumbar or lumbar approach; however, the rate of complications was not
      significantly different among the three approaches. Vertebrectomies took longer
      to perform and were associated with a greater estimated blood loss than
      discectomies; however, there was no significant difference in the rate of
      complications between the two types of procedures. The patients who had a
      fracture or a tumor lost more blood than those from the other diagnostic groups.
      Blood loss increased as the duration of the operation increased for all
      procedures. Combined anterior and posterior procedures performed during the same
      anesthesia session were associated with a higher rate of major complications than
      were procedures that were staged. A logistical regression analysis showed that
      the variables that increased the risk of a major complication were an estimated
      blood loss of more than 520 milliliters and an anterior and posterior procedure
      performed sequentially under the same anesthesia session. This analysis also
      demonstrated that the diagnosis of idiopathic scoliosis in adolescents or young
      adults was associated with a reduced risk of major complications. Compared with
      other major operations, an anterior procedure on the thoracic, thoracolumbar, or
      lumbar spine performed for the indications mentioned in this study is relatively
      safe.

PMID- 8666602
TI  - Local control of extra-abdominal desmoid tumors.
AB  - We analyzed the records and histopathological specimens of fifty patients who had
      had a previously untreated desmoid tumor. The patients were followed for at least
      two years (average, forty-eight months). Three patients had a biopsy and were
      managed with observation only, and three patients had radiation therapy only. Of
      the remaining forty-four patients, thirty-four were managed with an operation and
      ten, with an operation and radiation therapy. In the group that was managed
      operatively without radiation therapy, the resection was wide in thirteen
      patients, marginal in nineteen, and intralesional in two. At the most recent
      follow-up examination, there had been no local recurrence in eleven of the
      patients who had had a wide resection, ten of the patients who had had a marginal
      resection, and one of the patients who had had an intralesional resection. Thus,
      twenty-two (65 per cent) of the thirty-four patients had no local recurrence at
      the time of the latest follow-up. In the group of ten patients who had been
      managed with an operation and radiation therapy, eight had no local recurrence:
      the two who had had a wide resection, three of the four who had had a marginal
      resection, and three of the four who had had an intralesional resection. None of
      the fifty patients died of the disease.

PMID- 8666603
TI  - Evaluation of the biomechanics of the hip following a triple osteotomy of the
      innominate bone.
AB  - The biomechanics of the hip joint were evaluated in seventeen patients (twenty
      two hips), twelve to forty-one years old (mean, twenty-four years old), who had a
      triple osteotomy of the innominate bone for treatment of symptomatic dysplasia of
      the hip. The duration of follow-up ranged from 2.2 to 13.8 years (mean, 6.8
      years). Hip load, the area of the weight-bearing surface, and stress were
      determined from measurements on pelvic radiographs that were made preoperatively,
      postoperatively, and at the time of the latest follow-up; the values were
      compared with those in twenty-one hips from control subjects. The Harris hip
      rating system was used for clinical assessment. According to the biomechanical
      analysis, there was significantly less relative stress on the hip after the
      triple osteotomy and at the time of the latest follow-up (p < 0.001 for both)
      than there had been preoperatively. The decrease in stress was a direct result of
      a significant increase in the area of the weight-bearing surface of the hip (p <
      0.001). The load on the hip was not altered significantly, with the numbers
      available. The functional outcome was improved substantially when the
      biomechanical goals were achieved. Through the application of basic biomechanical
      principles, we were able to demonstrate the biomechanical efficacy of a triple
      osteotomy of the innominate bone. We recommend the use of biomechanical analysis
      as an adjunct to the clinical decision-making process in the treatment of a
      dysplastic hip.

PMID- 8666604
TI  - The operative treatment of peroneal nerve palsy.
AB  - We retrospectively reviewed the results of operative decompression for peroneal
      nerve palsy in thirty-one patients who had been managed between 1980 and 1990.
      All patients had been managed non-operatively for at least two months after they
      had initially been seen. Intraoperatively, we found epineurial fibrosis and bands
      of fibrous tissue constricting the peroneal nerve at the level of the fibular
      head and at the proximal origin of the peroneus longus muscle. At a mean of
      thirty-six months (range, twelve to seventy-two months) postoperatively, thirty
      (97 per cent) of the thirty-one patients reported subjective and functional
      improvement and were able to discontinue the use of the ankle-foot orthosis. In
      contrast, only three of nine patients who had been managed non-operatively
      reported subjective and functional improvement (p < 0.01). Peroneal nerve palsy
      does not always resolve spontaneously; if it is left untreated, the loss of
      dorsiflexion of the ankle and persistent paresthesias can result in severe
      functional disability. Therefore, if non-operative measures do not lead to
      improvement within two months, we believe that operative decompression should be
      considered.

PMID- 8666605
TI  - Preoperative irradiation for prevention of heterotopic ossification following
      total hip arthroplasty.
AB  - Eighty-six hips in eighty-five patients who were considered to be at risk for
      heterotopic ossification following a total hip arthroplasty were prospectively
      randomized or assigned to one of two treatment groups that received a single 800
      centigray dose of limited-field radiation either preoperatively (Group I) or
      postoperatively (Group II). The risk factors for postoperative heterotopic
      ossification included previous heterotopic ossification following an operation
      about the hip, hypertrophic osteoarthrosis or post-traumatic osteoarthrosis
      characterized by the presence of extensive osteophytes, radiographic evidence of
      diffuse idiopathic skeletal hyperostosis, and ankylosing spondylitis. The hips in
      Group I were irradiated within 6.1 hours before the operation and those in Group
      II, within 51.3 hours after the operation. Either extra-field ossification or
      heterotopic ossification was observed in forty-one (48 per cent) of the eighty
      six hips, thereby confirming the high risk for the population in this study.
      After a minimum duration of follow-up of six months, thirty-seven (76 per cent)
      of the forty-nine hips that had been treated with preoperative irradiation
      exhibited no new heterotopic ossification and eleven, progression to grade-I or
      II ossification. The remaining hip in that group was in a woman who had Paget
      disease as well as previous grade-IV (ankylosing) heterotopic ossification about
      the ipsilateral hip; heterotopic ossification progressed from grade II on the
      radiographs made immediately after the index revision procedure to grade III at
      the most recent follow-up assessment. Of the thirty-seven hips that had been
      treated with postoperative irradiation, twenty-seven (73 per cent) exhibited no
      new heterotopic ossification and nine had progression from grade-0 to grade-I
      ossification. The remaining hip in that group was in a man who had Parkinson
      disease and previous grade-III ossification about the ipsilateral hip;
      heterotopic ossification progressed from grade III immediately post-operatively
      to grade IV at the time of the most recent evaluation. Extra-field ossification
      was identified in twelve (24 per cent) of the forty-nine hips that had been
      irradiated preoperatively compared with three (8 per cent) of the thirty-seven
      hips that had been irradiated postoperatively (p = 0.05). Extra-field
      ossification was not associated with clinical symptoms of bursitis of the greater
      trochanter in any hip. Three of the ten hips that had a revision operation
      subsequently had a non-union of the greater trochanter; all three had been
      treated with preoperative irradiation. The findings of the present study suggest
      that pre-operative irradiation is effective for the prevention of heterotopic
      ossification following total hip arthroplasty and that it eliminates the
      discomfort and morbidity that are associated with conventional postoperative
      treatment. Furthermore, the efficacy of preoperative irradiation suggests that
      osteogenic precursor cells that are active in this process are derived from the
      local tissues within the operative field rather than from distant blood-borne
      cell lines.

PMID- 8666606
TI  - Measuring function of the shoulder. A cross-sectional comparison of five
      questionnaires.
AB  - Measures of both generic and disease-specific health status are being developed
      and used with increasing frequency for the appraisal of musculoskeletal
      conditions. The purpose of this study was to compare prospectively the validity
      of five questionnaires in the assessment of function of the shoulder. Ninety
      subjects who had various problems related to the shoulder agreed to enter the
      study. All of the subjects completed a questionnaire package that included the
      Shoulder Pain and Disability Index, the Simple Shoulder Test, the Subjective
      Shoulder Rating Scale, the Modified American Shoulder and Elbow Surgeons Shoulder
      Patient Self-Evaluation Form, and the Shoulder Severity Index as well as a
      measure of generic health status (the acute version of the Short Form 36 [SF-36])
      and two questions that asked the patient to rate the severity of the problem and
      his or her over-all health. Frequency distributions were created and compared
      among questionnaires. Spearman rank correlations were calculated to compare the
      questionnaires with each other and with other assessments. One-way analysis of
      variance was used to determine the ability of the questionnaires to discriminate
      between self-rated severity of the problem and over-all health. The frequency
      distributions were similar among the five shoulder questionnaires, but those of
      the five shoulder questionnaires differed from that of the SF-36. The
      correlations were good (0.73 < or = r < or = 0.80) among all of the five shoulder
      questionnaires except the Subjective Shoulder Rating Scale; they were lower with
      the Subjective Shoulder Rating Scale and the physical function dimension of the
      SF-36 (0.12 < or = r < or = 0.60). The shoulder questionnaires discriminated
      between levels of severity (p < 0.0001) but not between levels of over-all health
      (0.10 < or = p < or = 0.86). In this concurrent comparison of measures of
      shoulder-specific outcome in the same subjects, the shoulder questionnaires
      performed similarly, both in describing function of the shoulder and in
      discriminating between levels of severity. The shoulder questionnaires performed
      differently than the SF-36, which confirms the need to use both disease-specific
      and generic health-status measures to evaluate patients who have a problem
      related to the shoulder.

PMID- 8666607
TI  - Interlocking intramedullary nailing of pathological fractures of the shaft of the
      humerus.
AB  - We performed a retrospective study of thirteen patients who had had sixteen
      pathological fractures of the shaft of the humerus secondary to metastatic
      disease. All but one fracture was stabilized with interlocking intramedullary
      nailing with use of a closed technique. The mean operative time for the sixteen
      procedures was ninety-two minutes (range, fifty to 180 minutes), the mean blood
      loss was 116 milliliters (range, fifty to 200 milliliters), and the mean duration
      of hospitalization was five days (range, two to ten days). Fourteen extremities
      had a return to nearly normal function within three weeks after nailing. Relief
      of pain was rated as good or excellent in all but one patient. Eleven patients
      (fourteen humeri) received radiation therapy at a mean of seven days (range,
      three to fourteen days) after the operation. Nine patients died at a mean of four
      months (range, one to twelve months) postoperatively; the remaining four patients
      were still alive at a mean of ten months (range, nine to fifteen months). There
      were no problems related to the wound, deep infections, nerve palsies, or
      failures of the implant. The fracture was united in all seven of the eleven
      extremities in patients who survived for at least three months and had
      radiographs available. Interlocking intramedullary nailing of the humerus for
      pathological fractures provides immediate stability and can be accomplished with
      a closed technique, brief operative time, and minimum morbidity, with a resultant
      early return of function to the extremity.

PMID- 8666608
TI  - Arthrodesis of the wrist for post-traumatic disorders.
AB  - We retrospectively reviewed the records of eighty-nine consecutive patients
      (ninety wrists) who had had a total arthrodesis of the wrist for the treatment of
      a post-traumatic disorder at one center. Fifty-six patients (fifty-seven wrists)
      had the arthrodesis with plate fixation, and thirty-three patients (thirty-three
      wrists) had the arthrodesis with a variety of other techniques. The average age
      of the patients at the time of the arthrodesis was forty-two years, and the
      dominant wrist was treated in forty-two patients. Fifty-six (98 per cent) of the
      fifty-seven wrists that had been fixed with a plate had a successful union at an
      average of 10.3 weeks postoperatively. Twenty-seven (82 per cent) of the thirty
      three wrists that had been treated with other methods had a successful union at
      an average of 12.2 weeks postoperatively. The difference in the rates of union
      between the wrists fixed with a plate and those treated with alternative
      techniques was significant (p = 0.009; Fisher exact test). A total of thirty-nine
      complications were associated with twenty-nine (51 per cent) of the fifty-seven
      arthrodeses with plate fixation. Sixteen (41 per cent) of the complications
      (thirteen wrists) resolved with non-operative treatment. Twenty-six (79 per cent)
      of the thirty-three arthrodeses with alternative methods of fixation were
      associated with a total of twenty-nine complications. Twenty-three (79 per cent)
      of those complications (twenty wrists) resolved with non-operative treatment. The
      difference between the rate of complications associated with the arthrodeses with
      plate fixation and that associated with the arthrodeses with alternative methods
      of fixation was significant (p = 0.03; Fisher exact test).

PMID- 8666609
TI  - Toxic shock syndrome complicating orthopaedic manipulation of bone. A report of
      two cases.

PMID- 8666610
TI  - Late lateral displacement of the humeral head after closed reduction of
      glenohumeral dislocation: a sign of vascular injury. Report of a case.

PMID- 8666611
TI  - Solitary bone cyst with epiphyseal involvement: confirmation with magnetic
      resonance imaging. A case report and review of the literature.

PMID- 8666612
TI  - Chronic disorders of the forearm.

PMID- 8666613
TI  - Hallux valgus.

PMID- 8666614
TI  - Effect of ketorolac tromethamine on bleeding and on requirements for analgesia
      after total knee arthroplasty.

PMID- 8666616
TI  - Non-union of the scaphoid. Revascularization of the proximal pole with
      implantation of a vascular bundle and bone grafting.

PMID- 8666615
TI  - Effect of ketorolac tromethamine on bleeding and on requirements for analgesia
      after total knee arthroplasty.

PMID- 8666617
TI  - Current concepts in the treatment of fractures of the radial head, the olecranon
      and the coronoid.

PMID- 8666618
TI  - Magnetic resonance imaging of meniscal tears of the knee.

PMID- 8666619
TI  - Prospects for the treatment of spinal cord and peripheral nerve injury.

PMID- 8666620
TI  - Stanmore compared with Charnley total hip replacement. A prospective study of 413
      arthroplasties.
AB  - From 1982 to 1987, we randomised prospectively 413 patients requiring primary
      total hip replacements to receive either a Stanmore or Charnley prosthesis. They
      were reviewed by an independent observer in an attempt to correlate a number of
      factors including femoral head size with longevity. There were 213 Stanmore hips
      and 200 Charnley prostheses. At five to ten years (mean 6.5) 76 patients had died
      and 16 arthroplasties had required revision. Seven were radiologically loose in
      asymptomatic patients. There was only one case of deep infection. We found no
      difference statistically in the clinical outcome or in the revision rate of 4% in
      the two types of prosthesis. The revision rate was greater for trainees than for
      senior operating surgeons, and there were recognisable technical errors in seven
      of the nine Stanmore, and four of the seven Charnley replacements which required
      revision. Retrospective radiological analysis of a random subset of 51 Charnely
      and 57 Stanmore femoral components showed no difference in femoral subsidence,
      but in 14 patients who had had bilateral replacements with one femoral component
      of each type, there was greater early subsidence of the Stanmore prosthesis. Our
      results confirm that conventional cemented total hip replacements give acceptable
      results in a general teaching unit, and we found no evidence of any effect of the
      size of the femoral head on wear or loosening at five to ten years.

PMID- 8666621
TI  - Questionnaire on the perceptions of patients about total hip replacement.
AB  - We developed a 12-item questionnaire for completion by patients having total hip
      replacement (THR). A prospective study of 220 patients was undertaken before
      operation and at follow-up six months later. Each completed the new questionnaire
      as well as the SF36, and some the Arthritis Impact Measurement Scales (AIMS). An
      orthopaedic surgeon assessed the Charnley hip score. The single score derived
      from the questionnaire had a high internal consistency. Reproducibility was
      examined by test-retest reliability and was found to be satisfactory. The
      validity of the questionnaire was established by obtaining significant
      correlation in the expected direction with the Charnley scores and relevant
      scales of the SF36 and the AIMS. Sensitivity to change was assessed by analysing
      the differences between the preoperative scores and those at the follow-up. The
      standardised effect size for the new questionnaire compared favourably with that
      for the SF36 and the AIMS. The new questionnaire provides a measure of outcome
      for THR which is short, practical, reliable, valid and sensitive to clinically
      important changes.

PMID- 8666622
TI  - Radiological evaluation of the interfaces after cemented total hip replacement.
      Interobserver and intraobserver agreement.
AB  - Three radiological methods are commonly used to assess the outcome of total hip
      replacement (THR). They aim to record the appearance of lucent areas and
      migration of the prosthesis in a reproducible manner. Two of them were designed
      to monitor the implant through time and one to grade the quality of cementing. We
      have measured the level of inter- and intraobserver agreement in all three
      systems. We randomised 30 patients to receive either finger packing or retrograde
      gun cementing during Charnley hip replacements. The postoperative departmental
      radiographs were evaluated in a blinded study by two orthopaedic trainees, two
      consultants and two experts in THR. The trainees and consultants repeated the
      exercise at least two weeks later. We used the unweighted kappa statistic to
      establish the levels of agreement. In general, intraobserver agreement was
      moderate but interobserver agreement was poor, with levels similar to or less
      than those expected by chance. Our results indicate that such systems cannot
      provide reliable data from centres in different parts of the world, with various
      levels of surgeon evaluating radiographs at differing time intervals. We discuss
      the problem and suggest some methods of improvement.

PMID- 8666623
TI  - The cementless PM hip arthroplasty. Four-to-seven-year results.
AB  - We implanted 300 uncoated cementless PM prostheses into 271 patients and followed
      251 (92.6%) of them for four to seven years. By then 37 had already been revised
      for aseptic and three for septic loosening. The survival rate with implant
      failure as the endpoint was 88.8% for the cup and 85.3% for the stem after six
      years. There was a higher risk of implant loosening in congenital dysplasia,
      unilateral hip arthroplasty and obesity. The results of 225 unrevised hip
      replacements were assessed by questionnaire. Only 27.4% of the patients were
      completely free from pain and 17.9% had pain on walking any distance or at all
      times. The walking distance was for less than 30 minutes in 40%. Because of the
      poor results in comparison with other prostheses we do not recommend further use
      of the uncoated PM prosthesis.

PMID- 8666624
TI  - Hydroxyapatite coating of an acetabular prosthesis. Effect on stability.
AB  - We report the radiological and clinical outcome of a press-fit (SLF) acetabular
      component at two to three years in two groups of patients having primary total
      hip replacement. In 69 the implant was coated with hydroxyapatite (HA) and in 40
      it was uncoated. The stability of the cup was assessed by measurement of proximal
      migration and change in the angle of inclination. The clinical results in the two
      groups did not differ significantly, and the mean proximal linear wear was
      similar in both. Fewer radiolucent lines (RLLs) were seen on the radiographs of
      cups coated with HA. The mean proximal migration was studied by calculating
      regression lines for each patient using migration measurements: for the SLF+HA
      group the mean slope was 0.06 mm/year and for the SLF-HA group 0.20 mm/year (p =
      0.22). The change in the angle of inclination during follow-up was also
      consistently smaller in HA-coated cups. Using regression methods the SLF+HA group
      had a mean slope of 0.08 degrees/year and the SLF-HA group 0.44 degrees/year and
      the SLF-HA group 0.44 degrees/year (p = 0.023). Partial HA coating appeared to
      have no effect on the clinical outcome or on the rate of wear of polyethylene,
      but there was a trend towards a reduced rate of proximal migration, and a
      significant reduction in rotational migration and the number of radiolucent
      lines. This suggests that HA coating enhances the stability of this acetabular
      component.

PMID- 8666625
TI  - Surgical experience related to dislocations after total hip arthroplasty.
AB  - We studied the effect of surgical experience on the dislocation rate after 4230
      primary total hip arthroplasties (THAs) all performed using the posterior
      approach at three orthopaedic centres at major county hospitals. There were 129
      postoperative (3%) dislocations. Twice the number of dislocations were registered
      for inexperienced surgeons as for their more experienced colleagues. This
      frequency of dislocation levelled off with increasing numbers of operations and
      remained constant after approximately 30. For every ten primary THAs performed
      annually, the risk of dislocation decreased by 50%.

PMID- 8666626
TI  - The frequency of venous thrombosis in cemented and non-cemented hip arthroplasty.
AB  - We randomised 250 patients undergoing unilateral, elective hip arthroplasty for
      osteoarthritis to receive either a cemented or a non-cemented Mallory Head
      prosthesis. Aspirin was used as prophylaxis against thromboembolism during the
      first half of the study and adjusted-dose warfarin during the second half.
      Postoperatively, all patients were asked to have bilateral venography and 80%
      agreed. All were evaluated clinically for pulmonary embolism. There was no
      difference in the frequency of deep-venous thrombosis between the two groups (50%
      cemented nu 47% non-cemented, p = 0.73; 95% CI of the difference -13.6% to
      19.3%). Three of the 64 patients (5%) in whom venography had demonstrated
      isolated distal thrombi developed pulmonary emboli.

PMID- 8666627
TI  - Structural allograft in two-stage revisions for failed septic hip arthroplasty.
AB  - We report 11 patients having revision of total hip arthroplasty using massive
      structural allografts for failure due to sepsis and associated bone loss. All
      patients had a two-stage reconstruction and the mean follow-up was 47.8 months
      (24 to 72). Positive cultures were obtained at the first stage in nine of the 11
      patients, with Staphylococcus epidermidis being the most common organism. The
      other two patients had draining sinuses with negative cultures. There was no
      recurrence of infection in any patient. The mean increase in the modified Harris
      hip score was 45 and all the grafts appeared to have united to host bone. Two
      patients required additional procedures, but only one was related to the
      allograft. Complications included an incomplete sciatic nerve palsy and one case
      of graft resorption. Our results support the use of massive allografts in failed
      septic hip arthroplasty in which there is associated bone loss.

PMID- 8666628
TI  - Articular debridement versus washout for degeneration of the medial femoral
      condyle. A five-year study.
AB  - In a prospective randomised trial 76 knees with isolated degenerative changes in
      the medial femoral condyle of grades 3 or 4 were treated by either arthroscopic
      debridement (40) or washout (36). All knees were followed up for at least one
      year and 58 for five years. The mean follow-up time was 4.5 years in the
      debridement group and 4.3 years in the washout group. At one year 32 of the
      debridement group and five of the washout group were painfree and at five years
      19 of a total of 32 survivors in the debridement group and three of the 26 in the
      washout group were also free from pain. The mean improvement in a modified
      Lysholm score was 28 for the debridement group at one year and 21 at five years.
      In the washout group it was only 5 at one year and 4 at five years. For knees
      with lesions of the medial femoral condyle of grades 3 or 4, arthroscopic
      debridement appears to be the treatment of choice with over half the patients
      free from pain after five years.

PMID- 8666629
TI  - Fracture of the metal tibial tray after Kinematic total knee replacement. A
      common cause of early aseptic failure.
AB  - We reviewed 1567 elective knee replacements performed between 1980 and 1990,
      using either the Total Condylar prosthesis with an all-plastic tibial component,
      or the Kinematic prosthesis which has a metal tibial tray. The ten-year
      probability of survival was 92.1% for the Total Condylar design and 87.9% for the
      Kinematic. The difference was mainly due to 16 revisions required in the
      Kinematic series for fracture of the metal base-plate. This was the most common
      cause of aseptic failure in this group. These fractures were strongly associated
      with a preoperative varus deformity (hazard ratio (HR) 8.8) and there was a
      slightly increased risk in males (HR 1.9) and in osteoarthritic knees (HR 1.8).
      In the nine fractures which occurred within four years of primary implantation
      (group 1), failure to correct adequately a preoperative varus deformity and the
      use of a bone graft to correct such a deformity were both strongly associated
      with fracture (HR 13.9 and 15.8, respectively). In eight fractures which occurred
      more than five years after primary replacement (group 2) we could detect no
      significant risk factors. Early complications occurred in two patients after the
      16 revision procedures for tray fracture. One had a deep infection and the other
      refracture of the tray.

PMID- 8666630
TI  - Patellar resurfacing versus retention in total knee arthroplasty.
AB  - We studied 40 patients in whom the patella was not severely deformed and who were
      undergoing primary total knee arthroplasty (TKA) for osteoarthritis by one
      surgeon using one type of prosthesis. They were randomly allocated either to have
      the patella retained or resurfaced with a cemented, all-polyethylene component
      regardless of the state of the patellar articular cartilage. Apart from removal
      of osteophytes, no surgery was undertaken on the retained patellae. All 38
      surviving patients were evaluated at three years using the HSS knee score and a
      new, specifically designed Patellar score (maximum score of 30). No TKA was
      revised, but two patients in the resurfacing group had a further unrelated
      procedure. The mean HSS and Patellar scores at follow-up were 89 and 28 in the
      patellar retention group and 83 and 26 in the patellar resurfacing group.
      Statistically significant lower scores for both were recorded in women and in
      heavier patients. Stair-climbing ability was significantly better in the
      retention group. Although there were no complications related to patellar
      resurfacing, in the medium term we did not find any significant benefit from
      resurfacing the patella during TKA for osteoarthritis if it was not severely
      deformed.

PMID- 8666631
TI  - An evaluation of the Constant-Murley shoulder assessment.
AB  - We have analysed the Constant-Murley (1987) assessment for 25 patients with
      shoulder pathology. We found the score easy to use, with low inter- and
      intraobserver errors, but sufficiently imprecise in repeated measurements to give
      concern in its use for clinical follow-up of patients. We have calculated 95%
      confidence limits for a single assessment to be within 16 to 20 points in most
      cases. In addition, we found that all our subjects with instability as their main
      problem scored within five points of the maximum; this suggests that the scoring
      method may need to be revised for use on these patients.

PMID- 8666633
TI  - Anterior interosseous nerve lesions. Clinical and electrophysiological features.
AB  - Lesions of the anterior interosseous nerve in the forearm are rare and often
      misdiagnosed as tendon injuries. A consecutive series of 13 patients with this
      condition referred for electrodiagnosis is reviewed. Only three had originally a
      correct clinical diagnosis and three were initially considered to have tendon
      ruptures. Five cases were of mechanical origin and seven due to 'neuritis'. All
      showed electrophysiological abnormalities, most commonly involving the pronator
      quadratus. Late spontaneous recovery was common, and only one case had surgical
      exploration.

PMID- 8666632
TI  - Analgesic effect of extracorporeal shock-wave therapy on chronic tennis elbow.
AB  - We report a controlled, prospective study to investigate the effect of treatment
      by low-energy extracorporeal shock waves on pain in tennis elbow. We assigned at
      random 100 patients who had had symptoms for more than 12 months to two groups to
      receive low-energy shock-wave therapy. Group I received a total of 3000 impulses
      of 0.08 mJ/mm2 and group II, the control group, 30 impulses. The patients were
      reviewed after 3, 6 and 24 weeks. There was significant alleviation of pain and
      improvement of function after treatment in group I in which there was a good or
      excellent outcome in 48% and an acceptable result in 42% at the final review,
      compared with 6% and 24%, respectively, in group II.

PMID- 8666634
TI  - Patterns of degenerative change in the acromioclavicular joint.
AB  - A distinctive and consistent pattern of degenerative change was seen in 560
      acromioclavicular joints from dry bone skeletons of subjects over 40 years of
      age. An appreciation of this characteristic configuration is helpful at operation
      or when introducing a needle into the joint.

PMID- 8666635
TI  - A floating prosthesis for radial-head fractures.
AB  - We report our experience over seven years with a floating radial-head prosthesis
      for acute fractures of the radial head and the complications which may result
      from such injury. The prosthesis has an integrated articulation which allows
      change of position during movement of the elbow. We present the results in 12
      patients with a minimum follow-up of two years. Five prostheses had been
      implanted shortly after injury with an average follow-up of 49 months and seven
      for the treatment of sequelae with an average follow-up of 43 months. All
      prostheses have performed well with an improved functional score (modified from
      Broberg and Morrey 1986). We have not experienced any of the complications
      previously reported with silicone radial-head replacement. Our initial results
      suggest that the prosthesis may be suitable for the early or delayed treatment of
      Mason type-III fractures and more complex injuries involving the radial head.

PMID- 8666636
TI  - Distal tibiofibular synostosis after ankle fracture. A 14-year follow-up study.
AB  - Over an eight-year period up to 1983, a total of 322 consecutive patients had
      operations for ankle fractures; 176 were Weber type B and 128 type C. We were
      able to review 230 of these patients after a mean follow-up of six years (1 to
      11) including 128 with Weber B and 102 with Weber C fractures. We used an ankle
      score which combined symptoms and clinical and radiological findings, with a
      maximum score of 100 points. The mean score for all 230 was 92 (68 to 100).
      Fifteen of these patients had developed a distal synostosis between the tibia and
      fibula, three after a Weber B and 12 after a Weber C fracture. In 13 of these 15
      ankles the synostosis had been visible radiologically within three months of the
      operation. In the other two there had been radiologically visible calcification
      at the three-month follow-up. In 1993, we were able to review nine of the 15
      patients with synostosis using the same scoring system. At a mean follow-up of 14
      years (12 to 18) the mean score for those with synostosis was 91 (71 to 100),
      much the same as this group's previous score and the mean score of the whole
      group of operated patients. We conclude that distal tibiofibular synostosis after
      ankle fracture usually causes few symptoms and does not generally require any
      treatment.

PMID- 8666637
TI  - MRI of early osteonecrosis of the femoral head after transcervical fracture.
AB  - We have carried out a prospective study of 17 patients (14 women, 3 men) of mean
      age 48 years (21 to 76) with transcervical fractures of the femur using MRI to
      detect early evidence of avascular necrosis of the head. Two fractures were
      Garden stage I, 12 stage II, and three stage III. We performed internal fixation
      under radiological control at a mean of five days (2 to 15) after injury using a
      titanium cannulated cancellous screw or a titanium compression hip screw. MRI was
      performed at one, six and 12 months and then yearly after operation. T1- and T2
      weighted images were obtained by a spin-echo technique. The duration of follow-up
      of patients who did not subsequently require replacement of the head of the femur
      was from 2 to 5 years (mean 3.2). One month after operation eight of the 17 hips
      showed a band of low signal intensity on T1-weighted images and high signal
      intensity on T2-weighted images indicating lesions in the femoral head away from
      the fracture line. These were of three types: type I was a small infarct at the
      superolateral region of the femoral head and was seen in three hips; type II was
      a shallow lesion from the superolateral region to the fovea of the femoral head
      (three hips); and type III was a large lesion occupying most of the femoral head
      (two hips). No further changes were seen in the MRI after six months from
      operation. Collapse of the femoral head did not occur in the three hips with type
      I lesions, but two of the three type-II hips and both type-III hips subsequently
      collapsed. At the final follow-up the three hips with a type-I lesion and one
      with a type-II were still asymptomatic but radiography showed sclerosis in the
      femoral head corresponding to the MRI lesions. The nine hips which showed no
      changes on MRI at one month had no abnormal findings on physical examination,
      radiography or MRI at final follow-up.

PMID- 8666638
TI  - Cytological diagnosis of bone tumours.
AB  - We evaluated the diagnostic accuracy of fine-needle aspiration biopsy in a
      prospective study of 300 patients with previously undiagnosed bone lesions.
      Patients with suspected local recurrence of a primary bone tumour or a metastatic
      lesion of a previously diagnosed malignancy were excluded. Fine-needle aspiration
      biopsy was performed under radiological control as an outpatient procedure. The
      series was grouped into three major categories: 1) benign bone lesions including
      infections; 2) primary malignant bone tumours; and 3) metastases including
      lymphomas and myelomas. We compared the cytological diagnosis with the final
      diagnosis as assessed by histological examination and/or the clinical and
      radiological features. Material considered conclusive for cytological diagnosis
      was obtained from 251 of the 300 patients. Of the 49 failures, there were 24
      aspirates with insufficient cellular yield and 25 in which a diagnosis could not
      be made although the cytological material was adequate in quantity. Most of the
      inconclusive aspirates (36/49) were obtained from benign bone lesions. The
      diagnosis was correct in 239 (95%) of the 251 cases providing adequate
      cytological material. There were eight (3%) falsely benign diagnoses, one (0.3%)
      falsely malignant, and three cases in which we were unable to differentiate
      between sarcoma and a metastasis. Chondrosarcoma (2/12) gave the greatest
      diagnostic difficulty and Ewing's sarcoma the least (0/9). There were no decisive
      errors of treatment. All falsely benign or malignant diagnoses were questioned,
      and led to open biopsy since they did not correlate with the clinical and
      radiological features. Our study suggests that fine-needle aspiration biopsy is a
      valid option for the diagnosis of bone tumours. It is a simple outpatient
      procedure which gives sufficient cytological material for the correct diagnosis
      in 80% of cases. As with histological analysis of material from open biopsy, the
      cytological assessment must agree with the clinical and radiological findings.

PMID- 8666639
TI  - The Ilizarov method in the management of giant-cell tumours of the proximal
      tibia.
AB  - We have used the Ilizarov technique for the management of subarticular defects
      after the excision of giant-cell tumours in the proximal tibia in five patients.
      The defect was reconstructed with a segment of 5 to 6 cm obtained from the
      diaphysis of the affected tibia and by autogenous bone graft from the iliac
      crest. The newly developed defect in the diaphysis was reconstructed by
      distraction using the Ilizarov apparatus. Bone grafting at the docking site was
      performed soon after positioning the bone segments. The mean length of the bone
      defect was 5.7 cm and the mean duration of external fixation was 233 days. The
      relative blood flow in the leg measured by 99mTc angiography increased by 1.7 to
      2.3 times that of the control level during distraction and consolidation. When
      seen at a mean of 43 months all patients showed a normal range of motion in the
      knee and ankle with no collapse of the articular surfaces.

PMID- 8666640
TI  - Structural bulk allografts in acetabular reconstruction. Analysis of two grafts
      retrieved at post-mortem.
AB  - Two acetabula which contained large bone allografts introduced at revision
      arthroplasty were obtained at post-mortem. The allografts had been placed in
      superior defects to support cementless acetabular components, and both hips were
      functioning well at the time of death. Clinical radiographs demonstrated apparent
      healing of graft to host bone, no graft collapse and stability of the acetabular
      components. Microscopic examination of sections through these specimens showed
      that the bulk allografts were encapsulated in fibrous tissue. Vascularity was
      increased at the host-graft interface, but there was limited evidence of bone
      union between the graft and the host. In the few areas where union had occurred,
      revascularisation extended no more than 2 mm beyond the graft-host interface.
      Within the body of the graft, the acellular matrix of trabecular bone maintained
      structural integrity up to 48 months after surgery. In areas where the allograft
      was adjacent to an implant, there was fibrous tissue orientated parallel to the
      implant surface. The acetabulum which contained a porous-coated component showed
      evidence of bone growth into the porous surface where it was in contact with
      viable host bone. No ingrowth occurred in areas where the porous coating was in
      contact with the graft. Although the grafts were functioning well, allograft
      revascularisation and remodelling were minimal, and the radiological appearance
      of healing did not correlate with histological findings.

PMID- 8666641
TI  - The significance of an absent ankle reflex.
AB  - We assessed the prevalence of abnormal ankle reflexes in 1074 adult patients
      attending orthopaedic clinics and related it to age. Those with possible
      pathological causes of reflex loss were excluded. The absence of one or both
      reflexes was significantly related to increasing age; all patients under 30 years
      had both reflexes. Few had absent reflexes between 30 and 40 years, but over 40
      years, the proportion with both reflexes absent increased rapidly from 5% (40 to
      50 years) to 80% (90 to 100 years). Unilateral absence did not show the same
      pattern of increase being 3% to 5% at 40 to 60 years and 7% to 10% at over 60
      years. Our results suggest that a significant number of 'normal' adults have
      unilateral absence of an ankle reflex, but this finding is rare enough to be a
      definite clinical sign, irrespective of age.

PMID- 8666642
TI  - Prospective clinical and joint simulator studies of a new total hip arthroplasty
      using alumina ceramic heads and cross-linked polyethylene cups.
AB  - We report the findings from independent prospective clinical and laboratory-based
      joint-simulator studies of the performance of ceramic femoral heads of 22.225 mm
      diameter in cross-linked polyethylene (XLP) acetabular cups. We found remarkable
      qualitative and quantitative agreement between the clinical and simulator results
      for the wear characteristics with time, and confirmed that ceramic femoral heads
      penetrate the XLP cups at only about half the rate of otherwise comparable metal
      heads. In the clinical study, 19 hips in 17 patients were followed for an average
      of 77 months. In the hip-joint simulator a similar prosthesis was tested for 7.3
      million cycles. Both clinical and simulator results showed relatively high rates
      of penetration over the first 18 months or 1.5 million cycles, followed by a very
      much lower wear thereafter. Once an initial bedding-in of 0.2 mm to 0.4 mm had
      taken place the subsequent rates of penetration were very small. The initial
      clinical wear during bedding-in averaged 0.29 mm/year; subsequent progression was
      an order of magnitude lower at about 0.022 mm/year, lower than the 0.07 mm/year
      in metal-to-UHMWP Charnley LFAs. Our results show the excellent tribological
      features of alumina-ceramic-to-XLP implants, and also confirm the value of well
      designed joint simulators for the evaluation of total joint replacements.

PMID- 8666643
TI  - Stiffness measurements to assess healing during leg lengthening. A preliminary
      report.
AB  - We describe a technique for measuring the stiffness of regenerate bone after leg
      lengthening. This allows early identification of slow healing by reference to
      normal patterns. We determined the time of removal of the fixator from clinical
      and radiological information independent of the stiffness result. In a series of
      30 leg lengthenings there were no refractures when the tibial stiffness had
      reached 15 Nm/degree or the femoral stiffness 20 Nm/degree. Three refractures
      occurred at lower stiffness values. The technique is simple to perform, will
      allow a reduction in plain radiography and is recommended for routine
      postoperative management.

PMID- 8666644
TI  - Leg lengthening in Turner dwarfism.
AB  - We have reviewed 16 patients treated by leg lengthening for various forms of
      Turner dwarfism with regard to the long period of healing and the complications.
      We consider that Turner dwarfism is a suitable indication for leg lengthening
      because of the moderate length deficit and the morphological appearance of the
      patients, and have introduced an improved programme of management to deal with
      the problems encountered.

PMID- 8666645
TI  - Function of dislocated hips in children with lower level spina bifida.
AB  - We reviewed 52 children, born between 1974 and 1985 with spina bifida affecting
      L3 and L4, who had dislocated hips. Their motor function was stable and they were
      able to walk at the time of dislocation. They were interviewed and examined
      physically and radiologically. Physical function was measured by the Rand Health
      Insurance Study questionnaire (HIS), the Childhood Health Assessment
      questionnaire (CHAQ), and by determining the functional level of ambulation
      according to Hoffer et al (1973). In a subgroup of 12 patients with L4 level of
      involvement from both treatment groups we measured the metabolic energy
      consumption while walking. Thirty patient (49 hips) had been treated by operative
      relocation and 22 conservatively. Ten of the hips treated by operation subluxated
      or redislocated. The function in the two groups (conservative nu operated) was
      similar (HIS score 7.8 v 8.0, p = 0.45; CHAQ 14 v 13, p = 0.2; level of mobility
      0.61 v 0.63, p = 0.5). Patients in whom operation had failed had worse function
      than did those with successful surgery (HIS score 8.8 v 6.1, p = 0.025) and those
      with successful surgery had better function than patients treated conservatively
      (HIS score 8.8 v 8.0, p = 0.15). Function in patients with failed operations,
      however, was worse than in those who did not have surgical treatment (HIS score
      6.6 v 7.8, p = 0.07). In the 12 so examined the operated group had a 30% more
      energy-efficient gait (0.271 v 0.361 ml O2 kg/m, p = 0.05). Patients with failed
      operations had worse function than those who were not operated on. The benefit of
      surgical relocation of the dislocated hips was marginal.

PMID- 8666646
TI  - Anterior release for fixed flexion deformity of the hip in spina bifida.
AB  - We reviewed the results of anterior hip release for fixed flexion deformity in 57
      hips in 38 children with spina bifida at an average follow-up of 8.9 years (2 to
      22). The indication for this operation was a fixed flexion deformity of more then
      30 degrees which interfered with function. In 43 hips there was a good outcome in
      that the fixed flexion deformity remained less than 30 degrees at follow-up. Four
      hips had a good initial result but deteriorated after an average of five years,
      and ten had a poor outcome with deformity of over 30 degrees. Six hips required a
      repeated anterior hip release and two of these were successful. The success of
      anterior hip release could not be related to the neurological level or the age at
      operation. Successful surgery correlated with the walking ability of the child at
      the latest follow-up.

PMID- 8666647
TI  - Obstetric brachial plexus palsy associated with breech delivery. A different
      pattern of injury.
AB  - Most obstetric brachial plexus palsies are due to rupture of the upper roots in
      babies whose delivery was complicated by shoulder dystocia. If treated by early
      exploration and grafting, they have a favourable prognosis. We reviewed 36 babies
      who had had an obstetric brachial plexus palsy after a breech delivery and found
      that they had a different pattern of injury; 81% had avulsion of the upper roots.
      This injury cannot be treated satisfactorily by exploration and microsurgical
      grafting and carries a considerably worse prognosis for shoulder function.

PMID- 8666648
TI  - Occipito-atlanto-axial fusion in Morquio-Brailsford syndrome. A ten-year
      experience.
AB  - In 17 patients (eleven males, six females) with Morquio-Brailsford syndrome
      (mucopolysaccharidosis IV) we have used onlay femoral and tibial autografts
      placed posteriorly and secured to the laminae of C1 and C2 to obtain satisfactory
      occipito-C1/C2 posterior fusion. They were immobilised postoperatively in a halo
      plaster body jacket for four months. The age at operation varied between three
      and 28 years. Those with myelopathic symptoms of recent onset made some recovery,
      but severely myelopathic patients showed little or no recovery. We advise
      prophylactic occipitocervical fusion in these patients since the cartilaginous
      dens is not strong enough to ensure atlanto-axial mechanical stability.

PMID- 8666650
TI  - Myositis ossificans: calcification of the entire tibialis anterior after
      ischaemic injury (compartment syndrome).

PMID- 8666649
TI  - MRI of 'idiopathic' juvenile scoliosis. A prospective study.
AB  - In a prospective trial we performed MRI of the spine and hind brain in 31
      patients with scoliosis of onset between the ages of four and 12 years. In eight
      patients (26%) there was a significant neuroanatomical abnormality; there were
      six cases of Chiari-1 malformation associated with a syrinx, one isolated Chiari
      1 malformation and one astrocytoma of the cervical spine. Four of these patients
      had left-sided curves. There were no clinical features which could reliably
      identify those patients with abnormalities on MRI. In particular, the unilateral
      absence of abdominal reflexes was found to be non-specific (1 of 8 of patients
      with neuroanatomical abnormalities (12.5%) v 2 of 23 with normal scans (8.7%). In
      view of the established risks of surgical correction of scoliosis in the presence
      of undecompressed syringomyelia and the possible improvement that may follow
      decompression of the foramen magnum, we feel that MRI of all patients with
      scoliosis of juvenile onset should be obligatory.

PMID- 8666651
TI  - Radiological screening for congenital hip dislocation in the infant 'at risk'.

PMID- 8666652
TI  - The centre-edge angle of Wiberg in the adult Indian population.

PMID- 8666653
TI  - Persistent synovial fistula after arthroscopy: is titanium synovitis a risk
      factor?

PMID- 8666654
TI  - Aneurysmal bone cyst in monozygotic twins: a case report.

PMID- 8666655
TI  - Closed vascular injury of the finger.

PMID- 8666656
TI  - Congenital vertical talus with a talocalcaneal coalition.

PMID- 8666657
TI  - Chronic patellofemoral instability.

PMID- 8666658
TI  - Variability in Cobb angle measurements.

PMID- 8666659
TI  - Intron-dependent recruitment of pre-mRNA splicing factors to sites of
      transcription.
AB  - We have examined the nuclear localization of transiently and stably expressed
      nascent RNA transcripts containing or lacking introns in order to determine if
      the spatial association of RNA transcripts and pre-mRNA splicing factors in
      nuclei is random or functionally significant. Our findings show that the
      association between nascent RNA and splicing factors in the nucleus is intron
      dependent when the RNAs are either transiently or stably expressed. Furthermore,
      our data indicate that splicing factors are recruited to the transcription sites.
      The presence of both pre-and mRNA at these locations suggest that pre-mRNA
      splicing occurs at these sites of transcription. In addition, electron
      microscopic examination of the highly active transcription sites has revealed a
      granular appearance which closely resembles, but is functionally different from,
      interchromatin granule clusters. Our findings demonstrate that the nucleus is
      highly organized and dynamic with regard to the functions of the transcription
      and pre-mRNA splicing.

PMID- 8666661
TI  - A novel adaptor-related protein complex.
AB  - Coat proteins are required for the budding of the transport vesicles that mediate
      membrane traffic pathways, but for many pathways such proteins pathways, but for
      many pathways such proteins have not yet been identified. We have raised
      antibodies against p47, a homologue of the medium chains of the adaptor complexes
      of clathrin-coated vesicles (Pevsner, J., W. Volknandt, B.R. Wong, and R.H.
      Scheller. 1994. Gene (Amst.). 146:279-283), to determine whether this protein
      might be a component of a new type of coat. p47 coimmunoprecipitates with three
      other proteins: two unknown proteins of 160 and 25 kD, and beta-NAP, a homologue
      of the beta/beta'-adaptins, indicating that it is a subunit of an adaptor-like
      heterotetrameric complex. However, p47 is not enriched in preparations of
      clathrin-coated vesicles. Recruitment of the p47-containing complex onto cell
      membranes is stimulated by GTP gamma S and blocked by brefeldin A, indicating
      that, like other coat proteins, its membrane association is regulated by an ARF.
      The newly recruited complex is localized to non-clathrin-coated buds and vesicles
      associated with the TGN. Endogenous complex in primary cultures of neuronal cells
      is also localized to the TGN, and in addition, some complex is associated with
      the plasma membrane. These results indicate that the complex is a component of a
      novel type of coat that facilitates the budding of vesicles from the TGN,
      possibly for transporting newly synthesized proteins to the plasma membrane.

PMID- 8666660
TI  - The ion channel activity of the influenza virus M2 protein affects transport
      through the Golgi apparatus.
AB  - High level expression of the M2 ion channel protein of influenza virus inhibits
      the rate of intracellular transport of the influenza virus hemagglutinin (HA) and
      that of other integral membrane glycoproteins. HA coexpressed with M2 is properly
      folded, is not associated with GRP78-BiP, and trimerizes with the same kinetics
      as when HA is expressed alone. Analysis of the rate of transport of HA from the
      ER to the cis and medial golgi compartments and the TGN indicated that transport
      through the Golgi apparatus is delayed. Uncleaved HA0 was not expressed at the
      cell surface, and accumulation HA at the plasma membrane was reduced to 75-80% of
      control cells. The delay in intracellular transport of HA on coexpression of M2
      was not observed in the presence of the M2-specific ion channel blocker,
      amantadine, indicating that the Golgi transport delay is due to the M2 protein
      ion channel activity equilibrating pH between the Golgi lumen and the cytoplasm,
      and not due to saturation of the intracellular transport machinery. The Na+/H+
      ionophore, monensin, which also equilibrates pH between the Golgi lumen and the
      cytoplasm, caused a similar inhibition of intracellular transport as M2 protein
      expression did for HA and other integral membrane glycoproteins. EM data showed a
      dilation of Golgi cisternae in cells expressing the M2 ion channel protein. Taken
      together, the data suggest a similarity of effects of M2 ion channel activity and
      monensin on intracellular transport through the Golgi apparatus.

PMID- 8666663
TI  - Transport of an external Lys-Asp-Glu-Leu (KDEL) protein from the plasma membrane
      to the endoplasmic reticulum: studies with cholera toxin in Vero cells.
AB  - The A2 chain of cholera toxin (CTX) contains a COOH-terminal Lys-Asp-Glu-Leu
      (KDEL) sequence. We have, therefore, analyzed by immunofluorescence and by
      subcellular fractionation in Vero cells whether CTX can used to demonstrate a
      retrograde transport of KDEL proteins from the Golgi to the ER.
      Immunofluorescence studies reveal that after a pulse treatment with CTX, the CTX
      A and B subunits (CTX-A and CTX-B) reach Golgi-like structures after 15-20 min
      (maximum after 30 min). Between 30 and 90 min, CTX-A (but not CTX-B) appear in
      the intermediate compartment and in the ER, whereas the CTX-B are translocated to
      the lysosomes. Subcellular fractionation studies confirm these results: after CTX
      uptake for 15 min, CTX-A is associated only with endosomal and Golgi
      compartments. After 30 min, a small amount of CTX-A appears in the ER in a
      trypsin-resistant form, and after 60 min, a significant amount appears. CTX-A
      seems to be transported mainly in its oxidized form (CTX-A1-S-S-CTX-A2) from the
      Golgi to the ER, where it becomes slowly reduced to form free CTX A1 and CTX-A2,
      as indicated by experiments in which cells were homogenized 30 and 90 min after
      the onset of CTX uptake in the presence of N-ethylmaleimide. Nocodazol applied
      after accumulation of CTX in Golgi inhibits the appearance of CTX-A in the ER and
      delays the increase of 3',5'cAMP, indicating the participation of microtubules in
      the retrograde Golgi-ER transport.

PMID- 8666662
TI  - Association of a dynamin-like protein with the Golgi apparatus in mammalian
      cells.
AB  - Dynamins are a family of 100-kD GTPases comprised of at least three distinct gene
      products and multiple alternatively spliced variants. Homologies with the shibire
      gene product in Drosophila melanogaster and with Vps1p and Dnm1p in Saccharomyces
      cerevisiae suggest that dynamins play an important role in vesicular transport.
      Morphological studies have localized brain dynamin to coated pits and tubular
      invaginations at the plasma membrane, where it is believed to facilitate the
      formation of endocytic vesicles. Because similar membrane-budding events occur at
      the Golgi apparatus and multiple dynamin isoforms exist, we have studied the
      distribution of dynamins in mammalian cells. To this end, we generated and
      characterized peptide-specific antibodies directed against conserved regions of
      the dynamin family. By immunoblot analysis, these antibodies reacted specifically
      with a 100-kD protein in fibroblasts that sedimented with membranes and
      microtubules in vitro in a manner similar to brain dynamin. By immunofluorescence
      microscopy, these antibodies strongly labeled the Golgi complex in cultured
      fibroblasts and melanocytes, as confirmed by double labeling with a Golgi
      specific antibody. Furthermore, Western blot analysis showed significant
      enrichment of a 100-kD dynamin band in Golgi fractions isolated from the liver.
      To substantiate these findings, we use a specific antidynamin antibody to
      immunoisolate Golgi membranes from subcellular Golgi fractions, as determined by
      EM and immunoblot analysis. This study provides the first morphological and
      biochemical evidence that a dynamin-like protein associates with the Golgi
      apparatus in mammalian cells, and suggests that dynamin-related proteins may have
      multiple cytoplasmic distributions. The potential contributions of dynamin to the
      secretory and endocytic pathways are discussed.

PMID- 8666665
TI  - Oligomeric and subunit structure of the Helicobacter pylori vacuolating
      cytotoxin.
AB  - Disease-associated strains of Helicobacter pylori produce a potent toxin that is
      believed to play a key role in peptic ulcer disease in man. In vitro the toxin
      causes severe vacuolar degeneration in target cells and has thus been termed VacA
      (for vacuolating cytotoxin A). Cytotoxic activity is associated with a > 600-kD
      protein consisting of several copies of a 95-kD polypeptide that undergoes
      specific proteolytic cleavage after release from the bacteria to produce 37- and
      58-kD fragments. Quick freeze, deep etch electron microscopy has revealed that
      the native cytotoxin is formed as regular oligomers with either six- or seven
      fold radial symmetry. Within each monomer, two domains can clearly be
      distinguished, suggesting that the 37- and 58-kD fragments derive from
      proteolytic cleavage between discrete subunits of the monomer. Analysis of
      preparations of the toxin that had undergone extensive cleavage into the 37- and
      58-kD subunits supports this interpretation and reveals that after cleavage the
      subunits remain associated in the oligomeric structure. The data suggest a
      structural similarity with AB-type toxins.

PMID- 8666664
TI  - Endocytosis of GPI-anchored proteins in human lymphocytes: role of glycolipid
      based domains, actin cytoskeleton, and protein kinases.
AB  - GPI-anchored surface proteins mediate many important functions, including
      transport, signal transduction, adhesion, and protection against complement. They
      cluster into glycolipid-based membrane domains and caveolae, plasmalemmal
      vesicles involved in the transcytosis and endocytosis of these surface proteins.
      However, in lymphocytes, neither the characteristic flask shaped caveolae nor
      caveolin, a transmembrane protein typical of caveolae, have been observed. Here,
      we show that the GPI-anchored CD59 molecule on Jurkat T cells is internalized
      after cross-linking, a process inhibited by nystatin, a sterol chelating agent.
      Clustered CD59 molecules mostly accumulate in non-coated invaginations of the
      lymphocyte membrane before endocytosis, in marked contrast with the pattern of
      CD3-TCR internalization. Cytochalasin H blocked CD59 internalization in
      lymphocytes, but neither CD3 internalization nor transferrin uptake. Confocal
      microscopy analysis of F-actin distribution within lymphocytes showed that CD59
      clusters were associated with patches of polymerized actin. Also, we found that
      internalization of CD59 was prevented by the protein kinase C inhibitor
      staurosporine and by the protein kinase A activator forskolin. Thus, in
      lymphocytes, as in other cell types, glycolipid-based domains provide sites of
      integration of signaling pathways involved in GPI-anchored protein endocytosis.
      This process, which is regulated by both protein kinase C and A activity, is
      tightly controlled by the dynamic organization of actin cytoskeleton, and may be
      critical for polarized contacts of circulating cells.

PMID- 8666666
TI  - The sea urchin sperm receptor for egg jelly is a modular protein with extensive
      homology to the human polycystic kidney disease protein, PKD1.
AB  - During fertilization, the sea urchin sperm acrosome reaction (AR), an ion channel
      regulated event, is triggered by glycoproteins in egg jelly (EJ). A 210-kD sperm
      membrane glycoprotein is the receptor for EJ (REJ). This conclusion is based on
      the following data: purified REJ binds species specifically to EJ dotted onto
      nitrocellulose, an mAb to REJ induces the sperm AR, antibody induction is blocked
      by purified REJ, and purified REJ absorbs the AR-inducing activity of EJ.
      Overlapping fragments of REJ cDNA were cloned (total length, 5,596 bp). The
      sequence was confirmed by microsequencing six peptides of mature REJ and by
      Western blotting with antibody to a synthetic peptide designed from the sequence.
      Complete deglycosylation of REJ followed by Western blotting yielded a size
      estimate in agreement with that of the mature amino acid sequence. REJ is modular
      in design; it contains one EGF module and two C-type lectin carbohydrate
      recognition modules. Most importantly, it contains a novel module, herein named
      the REJ module (700 residues), which shares extensive homology with the human
      polycystic kidney disease protein (PKD1). Mutations in PKD1 cause autosomal
      dominant polycystic kidney disease, one of the most frequent genetic disease of
      humans. The lesion in cellular physiology resulting from mutations in the PKD1
      protein remains unknown. The homology between REJ modules of the sea urchin REJ
      and human PKD1 suggests that PKD1 could be involved in ionic regulation.

PMID- 8666668
TI  - Mammalian cells express three distinct dynein heavy chains that are localized to
      different cytoplasmic organelles.
AB  - We describe two dynein heavy chain (DHC)-like polypeptides (DHCs 2 and 3) that
      are distinct from the heavy chain of conventional cytoplasmic dynein (DHC1) but
      are expressed in a variety of mammalian cells that lack axonemes. DHC2 is a
      distant member of the "cytoplasmic" branch of the dynein phylogenetic tree, while
      DHC3 shares more sequence similarity with dynein-like polypeptides that have been
      thought to be axonemal. Each cytoplasmic dynein is associated with distinct
      cellular organelles. DHC2 is localized predominantly to the Golgi apparatus.
      Moreover, the Golgi disperses upon microinjection of antibodies to DHC2,
      suggesting that this motor is involved in establishing proper Golgi organization.
      DCH3 is associated with as yet unidentified structures that may represent
      transport intermediates between two or more cytoplasmic compartments. Apparently,
      specific cytoplasmic dyneins, like individual members of the kinesin superfamily,
      play unique roles in the traffic of cytomembranes.

PMID- 8666667
TI  - Identification of a small cytoplasmic ankyrin (AnkG119) in the kidney and muscle
      that binds beta I sigma spectrin and associates with the Golgi apparatus.
AB  - Ankyrins are a family of large, membrane-associated proteins that mediate the
      linkage of the cytoskeleton to a variety of membrane transport and receptor
      proteins. A repetitive 33-residue motif characteristic of domain I of ankyrin has
      also been identified in proteins involved with cell cycle control and
      development. We have cloned and characterized a novel ankyrin isoform, AnkG119
      (GenBank accession No. U43965), from the human kidney which lacks part of this
      repetitive domain and associates in MDCK cells with beta I sigma spectrin and the
      Golgi apparatus, but not the plasma membrane. Sequence comparison reveals this
      ankyrin to be an alternative transcript of AnkG, a much larger ankyrin recently
      cloned from brain. AnkG119 has a predicted size of 119,201 D, and contains a 47
      kD domain I consisting of 13 ankyrin repeat units, a 67-kD domain II with a
      highly conserved spectrin-binding motif, and a truncated 5-kD putative regulatory
      domain. An AnkG119 cDNA probe hybridized to a 6.0-kb message in human and rat
      kidney, placenta, and skeletal muscle. An antibody raised to AnkG119 recognized
      an apparent 116-kD peptide in rat kidney cortical tissue and MDCK cell lysates,
      and did not react with larger isoforms of ankyrin at 190 and 210 kD in these
      tissues, nor in bovine brain, nor with ankyrin from human erythrocytes. AnkG119
      remains extractable in 0.5% Triton X-100, and assumes a punctuate cytoplasmic
      distribution in mature MDCK cells, in contrast to the Triton-stable plasma
      membrane localization of all previously described renal ankyrins. AnkG119
      immunocreativity in subconfluent MDCK cells distributes with the Golgi complex in
      a pattern coincident with beta -COP and beta I sigma spectrin immunoreactivity. A
      fusion peptide containing residues 669-860 of AnkG119 interacts with beta I sigma
      1 spectrin in vitro with a Kd = 4.2 +/- 4.0 ( +/- 2 SD) nM, and avidly binds the
      beta spectrin in MDCK cell lysates. Collectively, these data identify AnkG119 as
      a novel small ankyrin that binds and colocalizes with beta I sigma spectrin in
      the ER and Golgi apparatus, and possible on a subset of endosomes during the
      early stages of polarity development. We hypothesize that AnkG119 and beta I
      spectrin form a vesicular Golgi-associated membrane skeleton, promote the
      organization of protein microdomains within the Golgi and trans-Golgi networks,
      and contribute to polarized vesicle transport.

PMID- 8666669
TI  - Distinct cellular and subcellular patterns of expression imply distinct functions
      for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor
      suppressor, merlin.
AB  - Interest in members of the protein 4.1 super-family, which includes the ezrin
      radixin-moesin (ERM) group, has been stimulated recently by the discovery that
      the human neurofibromatosis 2 (NF2) tumor suppressor gene encodes an ERM-like
      protein, merlin. Although many proteins in this family are thought to act by
      linking the actin-based cytoskeleton to transmembrane proteins, the cellular
      functions of merlin have not been defined. To investigate the cellular and
      developmental functions of these proteins, we have identified and characterized
      Drosophila homologues of moesin (Dmoesin) and of the NF2 tumor suppressor merlin
      (Dmerlin). Using specific antibodies, we show that although these proteins are
      frequently coexpressed in developing tissues, they display distinct subcellular
      localizations. While Dmoesin is observed in continuous association with the
      plasma membrane, as is typical for an ERM family protein, Dmerlin is found in
      punctuate structures at the membrane and in the cytoplasm. Investigation of
      Dmerlin cultured cells demonstrates that it is associated with endocytic
      compartments. As a result of these studies, we propose that the merlin protein
      has unique functions in the cell which differ from those of other ERM family
      members.

PMID- 8666670
TI  - Disrupted glial fibrillary acidic protein network in astrocytes from vimentin
      knockout mice.
AB  - Glial fibrillary acidic protein (GFAP) is an intermediate filament protein
      expressed predominantly in astrocytes. The study of its expression in the
      astrocyte lineage during development and in reactive astrocytes has revealed an
      intricate relationship with the expression of vimentin, another intermediate
      filament protein widely expressed in embryonic development. these findings
      suggested that vimentin could be implicated in the organization of the GFAP
      network. To address this question, we have examined GFAP expression and network
      formation in the recently generated vimentin knockout (Vim-) mice. We show that
      the GFAP network is disrupted in astrocytes that normally coexpress vimentin and
      GFAP, e.g., those of the corpus callosum or the Bergmann glia of cerebellum.
      Furthermore, Western blot analysis of GFAP protein content in the cerebellum
      suggests that posttranslational mechanisms are implicated in the disturbance of
      GFAP network formation. The role of vimentin in this process was further
      suggested by transfection of Vim-cultured astrocytes with a vimentin cDNA, which
      resulted in the normal assembly of the GFAP network. Finally, we examined GFAP
      expression after stab wound-induced astrogliosis. We demonstrate that in Vim-
      mice, reactive astrocytes that normally express both GFAP and vimentin do not
      exhibit GFAP immunoreactivity, whereas those that normally express GFAP only
      retain GFAP immunoreactivity. Taken together, these results show that in
      astrocytes, where vimentin is normally expressed with GFAP fails to assemble into
      a filamentous network in the absence of vimentin. In these cells, therefore,
      vimentin appears necessary to stabilize GFAP filaments and consequently the
      network formation.

PMID- 8666672
TI  - Associations among PH and SH3 domain-containing proteins and Rho-type GTPases in
      Yeast.
AB  - The src homology region 3 (SH3) domain-bearing protein Bem1p and the Rho-type
      GTPase Cdc42p are important for bud emergence in Saccharomyces cervisiae. Here,
      we present evidence that through its second SH3 domain, Bem1p binds to the
      structurally and functionally similar proteins Boi1p and Boi2p, each of which
      contain an SH3 and pleckstrin homology (PH) domain. Deletion of BOI1 and BO12
      together leads to impaired morphogenesis and poor ability. A PH domain-bearing
      segment of Boi1p that lacks the Bem1p-binding site is necessary and sufficient
      for function. This segment of Boi1p displays a two-hybrid interaction with
      Cdc42p, suggesting that Boi1p either binds directly to or is part of a larger
      complex that contains Cdc42p. Consistent with these possibilities, overexpression
      of Boi1p inhibits bud emergence, but this inhibition is counteracted by
      cooverexpression of Cdc42p. Increased expression of the Rho-type GTPase Rho3p,
      which is implicated in bud growth defects of boil boi2 mutants, suggesting that
      Boi1p and Boi2p may also play roles in the activation or function of Rho3p. These
      findings provide an example of a tight coupling in function between PH domain
      bearing proteins and both Rho-type GTPases and SH3 domain-containing proteins,
      and they raise the possibility that Boi1p and Boi2 play a role in linking the
      actions of Cdc42p and Rho3p.

PMID- 8666671
TI  - Yeast src homology region 3 domain-binding proteins involved in bud formation.
AB  - The yeast protein Bem1p, which bears two src homology region 3 (SH3) domains, is
      involved in cell polarization. A Rho-type GTPase, Rho3p, is involved in the
      maintenance of cell polarity for bud formation, and the rho3 defect is suppressed
      by a high dose of BEM1. Mutational analysis revealed that the second SH3 domain
      from the NH2 terminus (SH3-2) of Bem1p is important for the functions of Bem1p in
      bud formation and in the suppression of the rho3 defect. Boi2p, which bound to
      SH3-2 Bem1p, was identified using the two-hybrid system. Boi2p has a proline-rich
      sequence that is critical for displaying the Boi2p-Bem1p two-hybrid interaction,
      an SH3 domain in its NH2-terminal half, and a pleckstrin homology domain in its
      COOH-terminal half. A BOI2 homologue, BOI1, was identified as a gene whose
      overexpression inhibited cell growth. Cells overexpressing either BOI1 or BOI2
      were arrested as large, round, and unbudded cells, indicating that the Boi
      proteins affect cell polarization. Genetic analysis revealed that BOI1 and BOI2
      are functionally redundant and important for cell growth. delta boi1 delta boi2
      cells became large round cells or lysed with buds, displaying defects in bud
      formation and in the maintenance of cell polarity. Analysis using several
      truncated versions of BOI2 revealed that the COOH-terminal half, which contains
      the pleckstrin homology domain is essential for the function of Boi2p in cell
      growth, while the NH2-terminal half is not, and the NH2-terminal half might be
      required for modulating the function of Bem1p. Overproduction of either Rho3p or
      the Rho3p-related GTPase Rho4p suppressed the boi defect. These results
      demonstrate that Rho3p GTPases and Boi proteins function in the maintenance of
      cell polarity for bud formation.

PMID- 8666676
TI  - Confidentiality, death and the doctor.

PMID- 8666673
TI  - Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective
      adhesion-dependent neutrophil functions.
AB  - Cross-linking of the neutrophil-beta 2- or beta 3-related leukocyte response
      integrins by extracellular matrix (ECM) proteins or monoclonal antibodies (mAb)
      stimulates cytoskeletal rearrangement leading to cell spreading and respiratory
      burst. Tyrosin phosphorylation of a variety of proteins and activation of the Src
      family kinases within polymorphonuclear leukocytes (PMN) have recently been
      implicated in the intracellular signaling pathways generated by leukocyte
      integrins (Yan, S.R., L. Fumagalli, and G Berton. 1995. J. Inflammation. 45:217
      311.) To directly test whether these functional responses are dependent on the
      Src family kinases p59/61hck and p58c-fgr, we examined adhesion-dependent
      respiratory burst in PMNs isolated from hck -/-, fgr -/-, and hck -/- fgr -/-
      knockout mice. Purified bone marrow PMNS from wild-type mice released significant
      amounts of O2- when adherent to fibrinogen-, fibronectin-, or collagen-coated
      surfaces, in the presence of activating agents such as tumor necrosis factor
      (TNF) or formyl-methionyl-leucyl-phenylalanine, as described for human PMNs. PMNs
      from hck-/-fgr-/- double-mutant mic, however, failed to respond. This defect was
      specific for integrin signaling, since respiratory burst was normal in hck-/-fgr
      /-PMNs stimulated by immune complexes or PMA. Stimulation of respiratory burst
      was observed in TNF-primed wild-type PMN plated on surfaces coated with murine
      intracellular adhesion molecule-1 (ICAM-1), while hck-/-fgr-/- PMNs, failed to
      respond. Direct cross-linking of the subunits of beta 2 and beta 2 integrins by
      surface-bound mAbs was elicited O2- production by wild-type PMNs, while the
      double-mutant hck-/-fgr-/- cells failed to respond. Photomicroscopy and cell
      adhesion assays revealed that the impaired functional responses of hck-/-fgr-/-
      PMNs were caused by defective spreading and tight adhesion on either ECM protein-
      or mAb-coated surfaces. In contrast, hck-/-or fgr-/-single mutant cells produced
      O2- at levels equivalent to wild-type cells on ECM protein, murine ICAM-1, and
      antiintegrin mAb-coated surfaces. Hence, either p59/61 hck and p 58c-fgr is
      required for signaling through leukocyte beta 2 and beta 3 integrins leading to
      PMN spreading and respiratory burst. This is the first direct genetic evidence of
      the importance of Src family kinases in integrin signaling within leukocytes, and
      it is also the best example of overlapping function between members of this gene
      family within a defined signal transduction pathway.

PMID- 8666675
TI  - Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial
      integrins in regulating inflammation in the lung and skin.
AB  - The integrin alpha v beta 6 is only expressed in epithelial cells. In healthy
      adult epithelia, this receptor is barely detectable, but expression is rapidly
      induced following epithelial injury. Mice homozygous for a null mutation in the
      gene encoding the beta 6 subunit had juvenile baldness associated with
      infiltration of macrophages into the skin, and accumulated activated lymphocytes
      around conducting airways in the lungs. Beta 6-/- mice also demonstrated airway
      hyperresponsiveness to acetylcholine, a hallmark feature of asthma. These results
      suggest that the epithelial integrin alpha v beta 6 participates in the
      modulation of epithelial inflammation. Genetic or acquired alterations in this
      integrin could thus contribute to the development of inflammatory diseases of
      epithelial organs, such as the lungs and skin.

PMID- 8666674
TI  - The fucosyltransferase FucT-VII regulates E-selectin ligand synthesis in human T
      cells.
AB  - Selectin-ligands on T cells contribute to the recruitment of circulating cells
      into chronic inflammatory lesions in the skin and elsewhere. This report provides
      the first evidence that a single fucosyltransferase, termed FucT-VII, controls
      the synthesis of E-selectin ligands in human T-lymphoblasts. The FucT-IV
      transferase (the ELFT enzyme), in contrast constructs lower avidity E-selectin
      ligands and requires enzyme levels found only in myeloid cells. Treatment of
      Jurkat cells with phorbol myristate acetate increased the expression of
      sialylated Lewis(x)-related sLe(x)related epitopes and induced the synthesis of E
      selectin ligands functional at physiologic levels of linear shear-stress.
      Northern analysis revealed a parallel increase in the steady-state levels FucT
      VII mRNA, but there were no increases in the two other leukocyte-associated
      fucosyltransferases (FucT-IV and VI). The stable transfection of the FucT-VII
      gene into Jurkat cells induced high levels of the sLe(x)-related epitopes and the
      synthesis of E-selectin ligands which equal or exceeded the avidity of those on
      circulating lymphocytes. The growth of T-lymphoblasts under conditions which
      induced expression of the sLe(x,a) epitopes increased the level of FucT-VII mRNA,
      the synthesis of sialylated-Lewis(x) structures by cell-free extracts and the
      synthesis of E-selectin ligands equal in avidity to those on FucT-VII
      transfectants. In contrast, neither the mRNA levels nor activities of the FucT-IV
      and VI enzymes increased in association with E-selectin ligand synthesis in T
      lymphoblasts. Myeloid cell lines, unlike lymphoblasts, expressed high levels of
      both the FucT-VII and IV enzymes in conjunction with E-selectin ligands raising
      the possibility that both enzymes contributed to ligand synthesis. FucT-IV
      transfected Jurkat cells synthesized low avidity ligands for E-selectin but only
      in association with CDw65 (VIM-2) carbohydrate epitope. Only blood neutrophils
      and myeloid cell lines expressed this epitope at the levels associated with E
      ligand synthesis in the transfectants. In contrast, native Jurkat cells, blood
      monocytes, blood lymphocytes, and cultured T-lymphoblasts expressed low levels or
      none. We conclude that FucT-VII is a principal regulator of E-selectin ligand
      synthesis in human T-lymphoblasts while both FucT-VII and FucT-IV may direct
      ligand synthesis in some myeloid cells.

PMID- 8666677
TI  - Wide variability in the sensitivity of APTT reagents for monitoring of heparin
      dosage.
AB  - AIM: To assess the sensitivity of activated partial thromboplastin time (APTT)
      reagents for monitoring heparin dosage using data from the UK National External
      Quality Assessment Scheme (NEQAS) for blood coagulation. METHODS: Data were
      reviewed from four surveys using samples prepared by addition of heparin to
      normal plasma in vitro and from two surveys in which samples were prepared using
      plasma from patients receiving heparin therapy (ex vivo samples). RESULTS: For
      both in vitro and ex vivo samples, notable differences between APTT reagents with
      respect to heparin sensitivity were noted. This indicates that a uniform
      therapeutic range of 1.5-2.5 calculated by the APTT ratio may not be appropriate
      for all reagents. Reagent sensitivity in ex vivo samples was substantially
      different to that in in vitro samples. CONCLUSIONS: The results of this large
      series of laboratories clearly indicate that reagent specific therapeutic ranges
      may be necessary, and that samples prepared by the addition of heparin to normal
      plasma in vitro can be misleading and should not be used.

PMID- 8666678
TI  - Phenotypic changes in acute myeloid leukaemia: implications in the detection of
      minimal residual disease.
AB  - AIM: To explore the role of phenotypic changes as possible limiting factors in
      the immunological detection of minimal residual disease in patients with acute
      myeloid leukaemia (AML). METHODS: 20 relapses were evaluated, with special
      attention to changes in the criteria used for the definition of a phenotype as
      "aberrant". In all cases the same monoclonal antibody and fluorochrome were used
      at diagnosis and in relapse. RESULTS: Six out of the 16 patients showed aberrant
      phenotypes at diagnosis. At relapse, no changes in the aberrant phenotypes were
      detected in most of the patients; nevertheless, in two of the four patients with
      asynchronous antigen expression this aberration disappeared at relapse. At
      diagnosis in both cases there were already small blast cell subpopulations
      showing the phenotype of leukaemic cells at relapse. Ten out of the 16 cases
      analysed showed significant changes in the expression of at least one of the
      markers analysed. CONCLUSIONS: At relapse in AML the "leukaemic phenotypes"
      usually remained unaltered, while other phenotypic features--not relevant for
      distinguishing leukaemic blast cells among normal progenitors--changed
      frequently; however, they were not a major limitation in the immunological
      detection of minimal residual disease.

PMID- 8666679
TI  - Prevalence of microalbuminuria, lipoprotein (a) and coronary artery disease in
      the lipid clinic.
AB  - AIMS: To assess the prevalence of microalbuminuria (MA) and elevated serum
      lipoprotein (a) (Lp (a)) concentration, and their association with coronary
      artery disease (CAD) and other conventional cardiovascular risk factors in non
      diabetic patients attending a lipid clinic. METHODS: Clinical details were
      obtained from 96 consecutive non-diabetic patients from whom a fasting blood
      sample was taken to measure serum lipid, lipoprotein, apolipoprotein and plasma
      glucose, urea, and electrolyte concentrations. The urine albumin/creatinine ratio
      (Ua/Uc) was estimated from a random clinic sample. RESULTS: Of the patients, 26%
      had MA (defined as a Ua/Uc > 2.2 mg/mumol), 38% had an elevated Lp (a)
      concentration (defined as > 0.4 g/l), 36% were hypertensive (blood pressure >
      160/95) or were taking antihypertensive medication, and 25% had established CAD
      defined on clinical criteria. In men the Ua/Uc ratio was highly associated with
      age, plasma low density lipoprotein cholesterol, and triglyceride concentrations.
      In women there was no association between the Ua/Uc ratio and variables examined.
      Lp (a) concentration was not associated with variables examined in either sex. In
      multiple logistic regression analysis adjusted for age and sex, serum Lp (a)
      concentration, diastolic blood pressure and treatment of hyperlipidaemia were
      highly associated with CAD. MA was not, however, associated with CAD.
      CONCLUSIONS: MA is common in a lipid clinic and is more likely to be found among
      older male patients with hyperlipidaemia. However, in contrast with Lp (a)
      concentrations, MA is not a risk factor for CAD in this high risk population. Lp
      (a) concentration may be a useful tool in the lipid clinic, but there does not
      seem to be a justification for measuring the Ua/Uc ratio, at least in non
      diabetic subjects.

PMID- 8666680
TI  - Evaluation of formulae for CSF IgG synthesis using data obtained from two
      methods: importance of receiver operator characteristic curve analysis.
AB  - AIMS: To determine the clinical performance of three cerebrospinal fluid (CSF)
      IgG synthesis formulae using data obtained from two quantitation methods.
      METHODS: Receiver operator characteristic (ROC) analysis and decision index plots
      were used to compare a rate nephelometric (RN) and a rocket immunoelectrophoretic
      (RIEP) method for quantitating albumin and IgG for use in CSF IgG synthesis
      formulae. Further analysis was used to determine the most clinically accurate of
      these formulae for a diagnosis of multiple sclerosis with regard to technical
      accuracy and cost effectiveness. RESULTS: Values for albumin and IgG determined
      by RN gave better sensitivities and specificities than the RIEP method when
      applied to all three formulae; however, when the 95% confidence limits were
      considered, the difference was not significant. Using the RN method with an
      agreed "rule in" threshold value of 90% specificity, the IgG index gave the best
      clinical performance. CONCLUSION: ROC curve analysis and decision index plots
      provide valuable tools in assessing and comparing the clinical performance of new
      and existing laboratory assays.

PMID- 8666681
TI  - Analysis of necropsy request behaviour of clinicians.
AB  - AIM: To develop a necropsy related audit system to record accurate information in
      relation to necropsy requests, necropsy rates and coronial referrals. METHODS: A
      simple audit form was used to record detailed necropsy related data via an
      integrated questionnaire design and data entry system based on available optical
      image scanning technology. The system recorded the numbers and locations of
      deaths, referrals to the coroner, clinical necropsy requests, hospital and
      medicolegal necropsies, the grade of clinician involved in these processes, and
      the identity of the consultant in charge of the case. The overall, hospital and
      medicolegal necropsy rates were calculated by individual consultant, specialty
      and for the whole hospital. Necropsy request rates and coronial referral rates
      were also calculated and these data were related to the grade of clinician. All
      data were available on a monthly or an accumulative basis. RESULTS: Of 1398
      deaths, 534 (38%) were discussed with the local coroner's office and 167 of these
      were accepted for further investigation. House officers and senior house officers
      referred over 80% of all cases, whereas consultants referred only 2%. There were
      no significant differences in case acceptance rates by grade of clinician.
      Clinicians made 307 hospital necropsy requests (overall hospital necropsy request
      rate 22%). House officers made 65% of all necropsy requests. Consultant necropsy
      requests represented 13% of all requests. There were no significant differences
      in necropsy request success rates by grade of clinician. CONCLUSIONS: The
      referral of cases to coroners and clinical necropsy requests are still being
      inappropriately delegated to the most junior clinicians. This study illustrates
      the type of useful information which can be produced for individual clinicians,
      specialty audit groups and pathology departments using a simple necropsy related
      audit system.

PMID- 8666682
TI  - Detection of myocardial infarction by immunohistological staining for C9 on
      formalin fixed, paraffin wax embedded sections.
AB  - AIMS: To evaluate an immunohistological stain for complement component C9 as a
      method of detecting early myocardial infarction and to compare this with (1) an
      enzyme histochemical method and (2) conventional histological staining. METHODS:
      (1) Eight hearts taken at necropsy were stained using the nitroblue
      tetrazolium/phenazine methosulphate method and an immunohistological stain for
      C9. (2) Twenty five hearts from cases of suspected or confirmed myocardial
      infarction and 25 from cases without conventional evidence of infarction were
      stained for C9 and by haematoxylin and eosin. RESULTS: (1) The histochemical
      method indicated myocardial necrosis in five hearts and the C9 method in seven,
      all of which had clinical evidence of myocardial damage or a reason for it. The
      histochemical method required fresh myocardium, was difficult to use and was
      difficult to interpret. (2) Of 25 hearts with suspected or confirmed infarction,
      24 were stained by the C9 method. Staining with haematoxylin and eosin showed
      infarction in 16 of these, all with infarcts at least 24 hours old; the other
      eight had clinical evidence of infarction less than 24 hours old. The heart not
      stained by C9 was from a patient who, on review, had no evidence of infarction.
      Of the 25 control hearts, none had infarction on staining with haematoxylin and
      eosin, but three were stained by the C9 method. These three were from patients
      with septicaemia or another reason for myocardial damage. CONCLUSIONS: The
      immunohistological method for C9 is a simple, reliable and sensitive method for
      the detection of early myocardial necrosis that could be used on formalin fixed,
      paraffin wax embedded necropsy material. This had advantages over a histochemical
      method and conventional staining with haematoxylin and eosin.

PMID- 8666684
TI  - CD45RO and CD45RA positive cell populations in idiopathic membranous and IgA
      glomerulopathy.
AB  - AIMS: To immunophenotype and quantitate glomerular and interstitial inflammatory
      cells in cases of idiopathic membranous and IgA glomerulopathy; to correlate cell
      numbers with aspects of clinical data and renal function. METHODS: Routine
      indirect immunoperoxidase staining was performed on frozen section renal biopsy
      specimens for T and B lymphocyte related antigens, macrophages and MHC class II
      antigens. Double immunohistochemical staining was performed to identify CD45RO+
      and CD45RA+ cells. RESULTS: In IgA glomerulopathy correlations were found
      relating interstitial cell numbers to creatinine concentration at biopsy (CD45RO+
      and CD45RA+ cells) and follow up creatinine concentration (CD3+, CD4+, CD8+,
      CD45RO+, and CD45RA+ cells). Also in IgA glomerulopathy mean arterial pressure at
      biopsy correlated with interstitial cell numbers and most recent follow up
      creatinine concentration. There were no correlations between glomerular
      inflammatory cells and renal function in either disease. Double staining showed
      that although most glomerular CD45RO+ and CD45RA+ cells were macrophages,
      positive cells in the interstitium were lymphocytes. The interstitial CD45RO+:RA+
      ratio in normal renal biopsy specimens was approximately 5:1; for IgA
      glomerulopathy it was 1.5 and was 1.0 in idiopathic membranous glomerulopathy.
      CONCLUSIONS: This study demonstrates that interstitial, and not glomerular,
      inflammatory cell numbers correlate with renal function in primary glomerular
      disease and that double staining is necessary to interpret positive
      immunostaining for antigens located on more than one type of inflammatory cell.
      Detailed investigation of the interstitial CD45RO+ and CD45RA+ cells may give an
      insight into the pathogenesis of glomerular disease.

PMID- 8666683
TI  - Increased dimeric IgA producing B cells in the bone marrow in IgA nephropathy
      determined by in situ hybridisation for J chain mRNA.
AB  - AIM: To investigate the possible role of the systemic IgA immune system in the
      pathogenesis of IgA nephropathy METHODS: J chain mRNA expression in the IgA cells
      of the bone marrow was studied. Bone marrow trephine biopsy specimens from seven
      patients with IgA nephropathy and seven matched controls were examined by (1) non
      isotopic in situ hybridisation (ISH) and (2) combined immunofluorescence and non
      isotopic ISH to identify the plasma cell type. Serum polymeric IgA was also
      determined using standard high pressure liquid chromatography and sandwich enzyme
      linked immunosorbent assay. RESULTS: Non-isotopic ISH revealed a similar number
      of J chain mRNA positive cells/unit length in biopsy specimens from patients
      (16.5 +/- 2.7 cells/mm) and controls (17.7 +/- 2.4 cells/mm). Combined
      immunofluorescence and ISH revealed a greater proportion of J chain mRNA positive
      IgA cells in patients (7.6 +/- 1.45%) compared with controls (3 +/- 0.8%). Serum
      polymeric IgA was similar in both patients (91 +/- 22 mg/l) and controls (77 +/-
      24 mg/l). CONCLUSION: These data suggest that excess production of dimeric IgA
      occurs in the bone marrow in IgA nephropathy.

PMID- 8666685
TI  - Three dimensional anatomy of complete duct systems in human breast: pathological
      and developmental implications.
AB  - AIMS: To reconstruct the arrangement in space of all major ducts and their
      branches from nipple to periphery of a human breast obtained at necropsy.
      METHODS: Duct tracing through cleared haematoxylin stained 2 mm sub-gross coronal
      slices of a complete necropsy breast and computer modelling of duct territories.
      RESULTS: All branches were traced for 10 complete duct systems of a single breast
      from a 19 year old girl. Their complexity prevented comprehensive modelling of
      individual ducts and rami using available computer software, but the territories
      (catchments) drained by individual duct systems did not overlap and could be
      reconstructed. Catchment volume and length of the central unbranched duct
      draining each catchment varied greatly. Duct spacing showed non-random uniformity
      which is also seen in rodent mammary glands. CONCLUSIONS: These spatial relations
      are consistent with mutual growth inhibition between duct systems during mammary
      development. Although there is no clear morphological distinction between mammary
      duct end buds and lateral buds in women, the present study does suggest that
      processes of branching morphogenesis occurring during development of the breasts
      in women do show some analogies with the growth of end buds/lateral
      branches/alveoli during rodent mammary gland development. Rodent models of
      mammary development may usefully suggest hypotheses about human breast biology.
      Less laborious methods of three dimensional reconstruction of mammary ducts and
      their branches from sub-gross slices, allowing more specimens to be studied,
      would be valuable for the study of normal human breast development and mammary
      intraepithelial neoplasia. Increasing power and decreasing costs of high
      definition image processing hardware and software may make such endeavours
      practicable.

PMID- 8666686
TI  - Audit of anticoagulant therapy.

PMID- 8666687
TI  - Biliary expression of heat shock protein: a non-specific feature of chronic
      cholestatic liver diseases.
AB  - AIM: To analyse the expression of heat shock protein (HSP) 60 in biliary
      epithelium in auto-immune liver conditions and also in chronic cholestatic and
      other liver diseases. METHODS: Hepatic expression of HSP-60 in frozen liver
      biopsy specimens from patients with primary sclerosing cholangitis (PSC), primary
      biliary cirrhosis (PBC), auto-immune hepatitis (AIH), obstructive jaundice (LDO),
      alcoholic liver disease (ALD), and from normal controls was studied by
      immunohistochemistry using the APAAP technique and confocal laser scanning
      microscopy. RESULTS: Increased expression of HSP-60 was demonstrated in the
      biliary epithelium of patients with PBC, LDO and, to a lesser extent, with PSC.
      Focal, weaker, biliary epithelial expression of HSP-60 was observed in AIH, ALD
      and normal liver tissue. Increased expression was also seen on Kupffer cells in
      LDO and in hepatocytes in areas of piecemeal necrosis in AIH. CONCLUSION:
      Enhanced biliary expression of HSP-60 is a common feature of chronic biliary
      disease irrespective of aetiology and is not specific to auto-immune diseases.

PMID- 8666688
TI  - Prognostic value of cathepsin D in breast cancer: comparison of
      immunohistochemical and immunoradiometric detection methods.
AB  - AIM: To test whether immunoradiometric or immunohistochemical detection of
      lysosomal protease cathepsin D in breast cancer is more predictive of outcome.
      METHODS: Tumour tissues from 270 primary breast cancer patients were evaluated
      for the expression of cathepsin D using immunohistochemistry (IH; paraffin
      embedded tissues) and an immunoradiometric assay (IRMA; cytosol from frozen
      tissues). Immunohistochemical scores were based on immunoreaction in tumour cells
      and tumour associated macrophages. RESULTS: IRMA values (cut off 40 fmol/mg cell
      protein) correlated significantly with IH values. Recorded incidences of positive
      immunoreaction in tumour cells using two different cut off values were 52% and
      35%, respectively. Macrophages stained positive in 31% of tissues. Combined
      evaluation of tumour cells and macrophages resulted in positivity rates of 59%
      and 48%, respectively. Node status was the only variable found to correlate with
      cathepsin D expression. IH results correlated significantly with clinical outcome
      (median observation time 68 months) in node negative patients (n = 120) but not
      in node positive patients (n = 145). Cathepsin D positivity as measured by IRMA
      was not related to clinical outcome in either group. On multivariate analysis in
      the node negative group, IH detection of cathepsin D appeared to be the only
      independent factor indicating prognosis. For node positive patients, tumour
      grade, size, and receptor status were of prognostic relevance. CONCLUSIONS:
      Because of the simple methodology and the minimal amount of tissue used for
      analysis, immunohistochemistry was preferred to immunoradiometry for cathepsin D
      measurement; it also provided more predictive data with respect to prognosis.

PMID- 8666689
TI  - Inverse correlation between Helicobacter pylori infection and inflammatory bowel
      disease.
AB  - AIMS: To determine the seroprevalence of Helicobacter pylori in patients with
      Crohn's disease or ulcerative colitis and in controls without inflammatory bowel
      disease (IBD). METHODS: One hundred consecutive patients with Crohn's disease,
      100 consecutive patients with ulcerative colitis, and 100 age and sex matched
      controls were studied. Serum H pylori IgG and IgA antibody titres were measured
      by enzyme immunoassay. RESULTS: The seroprevalence of H pylori was 15% in
      patients with IBD (13% in patients with Crohn's disease and 18% in patients with
      ulcerative colitis), whereas the corresponding figure for the controls was 43%.
      When compared with controls, the seroprevalence of H pylori in patients with IBD
      was considerably lower in all age groups tested. There was no important
      difference in treatment with sulphasalazine or in any other medical therapy
      administered to H pylori positive and negative patients. At the time of blood
      sampling there was no difference in the level of education or in the employment
      status between the patients and the controls. CONCLUSIONS: Patients with IBD were
      less likely to be infected with H pylori than their age and sex matched controls.
      Neither medical treatment nor socioeconomic factors could explain the difference.

PMID- 8666690
TI  - Increased gastric epithelial cell proliferation in Helicobacter pylori associated
      follicular gastritis.
AB  - AIMS: An increase in the proliferative state of the gastric epithelium has been
      attributed to infection with Helicobacter pylori. In order to obtain a more
      precise estimate of the magnitude of this change, the proliferative state of 17
      cases of florid H pylori associated follicular gastritis was examined using the
      antibody MIB-1. METHODS: Comparable results were produced from control and
      gastritis cases by using a combination of two reproducible measures of the
      labelled cells. Dividing cells in the gastric mucosa are concentrated within a
      proliferating compartment, situated at the base of the crypts. This compartment
      was measured and expressed as a proportion of the total crypt length. The
      proportion of positively labelled cells within the compartment was also counted.
      RESULTS: The proliferation compartment in the gastritis cases occupied 45.6% of
      the gastric crypt compared with 15.4% in the control group. Of the cells in the
      proliferating compartment, 79.5% were positively labelled in the gastritis cases
      and 33.4% in the control group. CONCLUSIONS: The convoluted nature of the gastric
      crypt does not make it a forgiving experimental model. The use of long lengths of
      mucosa obtained from gastrectomy specimens permitted the production of consistent
      results, using a morphometric method. The greater than 100% difference in the
      proportion of proliferating cells between the two groups suggests that further
      investigation is warranted.

PMID- 8666691
TI  - Expression of Epstein-Barr virus encoded latent genes in nasal T cell lymphomas.
AB  - AIMS: To determine the expression of Epstein-Barr (EB) virus encoded latent genes
      in nasal T-cell lymphomas in The Netherlands. METHODS: Seven europid (Dutch)
      cases of nasal T cell lymphoma were investigated for the presence of EB virus by
      RNA in situ hybridisation (EBER). The expression of the EB virus encoded genes
      BARF0, EBNA1, EBNA2, LMP1, LMP2A, LMP2B, and ZEBRA was studied at the mRNA level
      using reverse transcriptase polymerase chain reaction. At the protein level the
      expression was investigated of EBNA2 and LMP1 by immunohistochemistry. RESULTS:
      In all seven nasal T cell lymphomas EBER was detected in the nuclei of virtually
      all tumour cells. BARF0 mRNA was detected in all samples. EBNA1 mRNA was found in
      six cases, LMP1 mRNA in five, LMP2A mRNA in three, LMP2B mRNA in one, and ZEBRA
      mRNA in one. EBNA2 mRNA was not found in any case. At the protein level
      occasional LMP1 positive tumour cells were seen in only one case. The EBNA2
      protein was not detected. CONCLUSIONS: Nasal T cell lymphomas in The Netherlands
      are strongly associated with EB virus. The virus shows a type II latency pattern
      (EBNA1+, LMP1+, EBNA2-) that seems to be similar to the EB virus associated nasal
      T cell lymphomas in oriental countries.

PMID- 8666693
TI  - Tumour related cutaneous elastophagocytosis.
AB  - Dermal granulomatous inflammation was identified immediately adjacent to seven
      (77%) of nine atypical fibroxanthomas arising in sun damaged skin. Concomitant
      elastophagocytosis was observed in five (56%) of these seven patients. Similar
      inflammation with elastophagocytosis was found in association with only two (6%)
      of 36 epithelial tumours arising on the same background (10 basal and 10 squamous
      cell carcinomas, 10 nodular malignant melanomas, and six keratocanthomas).
      Granulomatous inflammation is an unusual dermal reaction to tumour and
      elastophagocytosis is rare. The fact that both of these features occur with
      inordinate frequency in association with atypical fibroxanthomas, when compared
      with other, more common skin tumours, suggests that atypical fibroxanthomas might
      modulate the inflammatory response, either passively, by its dermal location, or
      actively, by secreting locally effective cytokines.

PMID- 8666692
TI  - Phraseology in pathology reports. A comparative study of interpretation among
      pathologists and surgeons.
AB  - This questionnaire based study compared the interpretation, use and preferences,
      among pathologists and surgeons, of descriptive phrases found in surgical
      reports. The results show that there is a wide variation in individual
      interpretation of phrases in both groups. The frequency of usage of phrases by
      pathologists and preference for phrases by surgeons were also diverse. The
      adoption of a limited number of descriptive phrases that are mutually understood
      and acceptable for use by both pathologists and clinicians is recommended to
      avoid interpretive ambiguity in pathology reports.

PMID- 8666694
TI  - Gallstones split at laparoscopic cholecystectomy: a new cause of intraperitoneal
      granulomas.
AB  - A case of a 32 year old woman with a foreign body-type granulomatous reaction to
      gallstones split at previous laparoscopic cholecystectomy is reported. The
      patient presented with hard nodules within the omentum at a subsequent Caesarean
      section, raising the possibility of metastatic tumour. Histological examination
      showed gallstones with an associated foreign body-type granulomatous reaction.
      With increasingly widespread use of laparoscopic surgery and relatively common
      spillage of gallstones at surgery, it is likely that histopathologists will
      encounter this condition more frequently in the future, both in surgical biopsy
      specimens and at necropsy.

PMID- 8666695
TI  - Ulcerating rheumatoid nodule of the vulva.
AB  - A case of an ulcerating rheumatoid nodule of the vulva in a 76 year old woman
      with rheumatoid arthritis complicated by Felty's syndrome is reported. The
      patient presented with a mass in the vulval region. On clinical examination, she
      had an ulcerated mass associated with inguinal lymphadenopathy. These findings
      resulted in a clinical diagnosis of invasive carcinoma of the vulva and an
      excision biopsy was carried out. On microscopic examination, the lesion showed
      the characteristic features of a rheumatoid nodule with ulceration of overlying
      epidermis. Adjacent vessels showed inflammation and fibrinoid necrosis of their
      walls suggestive of a vasculitis. Awareness of the possibility of ulceration in
      rheumatoid nodules may facilitate diagnosis and avert unduly aggressive
      treatment.

PMID- 8666696
TI  - Pleomorphic adenoma of the bronchus.
AB  - An example of pleomorphic adenoma of the bronchus is described in a 27 year old
      male student who was referred for evaluation of a coin lesion identified
      incidentally on chest x ray. The tumour exhibited the classic histological,
      immunohistochemical and ultrastructural features of this rare entity but, in
      addition, contained mature and immature adipose tissue in the stroma and showed
      transition, in its superficial portion, between ostensibly normal bronchial mucus
      glands and tumour tubules. Neither of these features has been commented upon
      previously.

PMID- 8666697
TI  - Detection by PCR of Toxoplasma gondii in blood in the diagnosis of cerebral
      toxoplasmosis in patients with AIDS.
AB  - The polymerase chain reaction (PCR) for amplification of Toxoplasma gondii DNA
      was performed prospectively in the blood of 19 patients with AIDS and cerebral
      toxoplasmosis. The B1 gene and TGR1E sequence were used as targets and results
      were confirmed by hybridisation. Controls consisted of 24 HIV infected patients
      with tissue culture proven T gondii parasitaemia and 57 HIV infected patients
      without toxoplasmosis. PCR was positive with both targets in 20 of 24 samples
      (84%) from patients with parasitaemia. Three of 57 samples (5%) from patients
      without toxoplasmosis were PCR positive with either target, but none was positive
      with both targets. Only three of the 19 patients (16%) with cerebral
      toxoplasmosis had a positive PCR with both targets before the start of specific
      treatment. PCR performed in blood is of little diagnostic value in cases of
      cerebral toxoplasmosis but could be useful in patients with disseminated
      infection.

PMID- 8666698
TI  - Amphotericin B responsive Scedosporium apiospermum infection in a patient with
      acute myeloid leukaemia.
AB  - A 71 year old man with newly diagnosed acute myelomonocytic leukaemia developed a
      soft tissue infection of his foot during his first course of chemotherapy.
      Scedosporium apiospermum was isolated from the lesion, which resolved rapidly on
      treatment with intravenous amphotericin B despite being resistant in vitro to
      this agent. This observation suggests that sensitivity testing of S apiospermum
      should be interpreted with caution and that clinical response may be a better
      indicator of outcome.

PMID- 8666699
TI  - Self-discrepancies and persecutory delusions: evidence for a model of paranoid
      ideation.
AB  - The self-discrepancies of paranoid patients, depressed patients, and nonpatients
      were examined using a modified version of Higgins's Selves Questionnaire (E. T.
      Higgins, 1987). Nonpatients showed high consistencies between all domains of the
      self-concept, whereas depressed patients showed marked self-discrepancies.
      Paranoid patients alone displayed a high degree of consistency between self
      perceptions and self-guides together with discrepancies between self-perceptions
      and the believed perceptions of parents about the self. Paranoid patients also
      believed that their parents had more negative views of them than did other
      participants. These findings are consistent with R. P. Bentall, P. Kinderman, and
      S. Kaney's (1994) model, which assumes that persecutory delusions are a product
      of attributional processes serving to maintain a positive explicit self-concept.

PMID- 8666700
TI  - A longitudinal study of drug and alcohol use by psychosis-prone and impulsive
      nonconforming individuals.
AB  - The rates of substance use and abuse are higher among psychotic patients and
      antisocial individuals than in the general population. In a 10-year longitudinal
      study, psychosis-prone individuals identified by the Perceptual Aberration (L. J.
      Chapman, J. P. Chapman, M. L. Raulin, 1976) and Magical Ideation (Per-Mag) scales
      (M. Eckblad & L. J. Chapman, 1983), and individuals with antisocial traits,
      identified by the Impulsive Nonconformity (Noncon) scale (L. J. Chapman et al.,
      1984), exceeded a control group on rates of substance use disorders. As
      hypothesized, the Per-Mag group demonstrated preferential patterns of substance
      use similar to those reported for schizophrenic patients. Participants who scored
      deviantly on both the Per-Mag and Noncon scales were at especially heightened
      risk for substance use disorders. Psychosis proneness at the initial screening
      predicted substance abuse at the follow-up evaluation, but substance abuse at the
      initial interview did not predict later clinical psychosis or psychoticlike
      experiences.

PMID- 8666701
TI  - Unacknowledged versus acknowledged rape victims: situational factors and
      posttraumatic stress.
AB  - Investigators of sexual assault have found that a substantial number of women who
      have been raped do not conceptualize their experiences as such. The present
      investigation examined differences between 40 unacknowledged rape victims and 20
      women who acknowledged their experience as rape in a sample of college women, as
      well as a control group of 23 nonvictims. Groups were compared in terms of
      situational factors, postassault symptomatology, defense mechanisms, dissociative
      disorders, and sexual revictimization. In comparison to unacknowledged victims,
      acknowledged victims reported more forceful assaults and indicated more
      resistance and clearer refusal. Acknowledged victims exhibited more posttraumatic
      stress disorder symptoms than unacknowledged victims, who exhibited more symptoms
      than nonvictims, as measured by clinical interview. Implications of these
      findings are discussed.

PMID- 8666702
TI  - Anxiety and the use of strategies in the performance of a sentence-picture
      verification task.
AB  - An experiment was conducted to examine processing strategy differences in
      anxiety. The sentence-picture verification task was modified to incorporate a
      block of threat-related trials (involving a knife and a rifle) and a block of
      neutral trials (involving a truck and a chair). It was predicted that the high
      trait, relative to low-trait, anxious individuals would prefer to use a
      linguistic strategy for threat-related as compared to neutral trials. In
      addition, the idea that an image-based strategy is more important for processing
      emotional material was examined. There was some support for both of these
      hypotheses.

PMID- 8666703
TI  - Effect of psychological stress on airway impedance in individuals with asthma and
      panic disorder.
AB  - The authors assessed airway impedance responses to psychological stressors among
      113 individuals: 61 with asthma only (AS), 10 with asthma and panic disorder
      (ASPD), 24 with panic disorder only (PD), and 18 controls with neither condition
      (CON). Individuals with either AS or PD were affected by psychological stressors
      as measured by the forced oscillation technique. Individuals with PD (with or
      without AS) displayed lower airway impedance than those without PD. These data
      suggest that the airways of individuals with PD are in a chronic state of
      preparedness, which may promote hyperventilation.

PMID- 8666705
TI  - Anxiety sensitivity, suffocation fear, and breath-holding duration as predictors
      of response to carbon dioxide challenge.
AB  - Predictors of response to carbon dioxide challenge (i.e., breathing deeply and
      rapidly into a paper bag for 5 min) were evaluated in 78 college students. Zero
      order correlations revealed that scores on the Suffocation Fear Scale (SFS; S.
      Rachman & S. Taylor, 1994) and the Anxiety Sensitivity Index (S. Reiss, R. A.
      Peterson, D. M. Gursky, & R. J. McNally, 1986) predicted anxiety and self
      reported bodily sensations, whereas a behavioral measure of carbon dioxide
      sensitivity (i.e., maximum breath-holding duration) did not. Multiple regression
      analyses revealed that the SFS was the only significant predictor of anxiety and
      bodily sensations. Just as anxiety sensitivity is a better predictor than trait
      anxiety of the response to biological challenges in general, suffocation fear is
      a better predictor than anxiety sensitivity for challenges that increase carbon
      dioxide.

PMID- 8666706
TI  - Display visual angle and attentional scanpaths on the span of apprehension task
      in schizophrenia.
AB  - The effect of display visual angle on span of apprehension (SOA) task performance
      was investigated in patients with schizophrenia and nonpsychiatric individuals.
      Narrow and wide visual-angle presentations of 3- and 10-letter arrays were
      compared. Detection rates were significantly higher with narrow than wide visual
      angle for nonpsychiatric individuals; the performance of those with schizophrenia
      was stable across visual-angle conditions. Patients with schizophrenia were best
      discriminated from nonpsychiatric individuals in the narrow-angle, 10-letter
      condition. Scanpath analyses, which were based on the pattern of detection rates
      across different target quadrant locations, suggested that the patients with
      schizophrenia used a similar number and path of covert scan moves as did the
      controls. Hypotheses are discussed regarding which of the multiple cognitive
      processes tapped by the SOA task may be impaired in schizophrenia.

PMID- 8666704
TI  - Reporting biases in hypnosis: suggestion or compliance?
AB  - The tendency of highly hypnotizable participants to bias their retrospective
      perceptual reports in response to instructional demands was reexamined with the
      addition of low-hypnotizable control participants instructed to simulate
      hypnosis. Mean scores of high-hypnotizable participants and simulators did not
      differ, but the responses of simulators to the demand instruction was less
      variable than those of high-hypnotizable participants, and the shape of the
      response distribution was different. Unlike simulators, some high-hypnotizable
      participants who had reported changes in perception that were consistent with a
      hypnotic suggestion subsequently reported changes opposite to those suggested by
      a demand instruction. These data were interpreted as suggesting that the
      responses of high-hypnotizable participants to both the demand instruction and
      the preceding hypnotic suggestion were not entirely due to compliance.

PMID- 8666707
TI  - Sociotropy, autonomy, and dysphoric emotional responses to specific classes of
      stress: a psychophysiological evaluation.
AB  - The aim of this study was to assess the ability of trait measures of sociotropy
      and autonomy to predict immediate emotional responses to imagery conditions
      depicting social rejection and achievement failure. Emotional responses were
      assessed by self-report techniques and by 2 putative psychophysiological measures
      of dysphoric mood: heart rate and facial muscle activity. Undergraduate
      volunteers (N = 100) were assessed for sociotropic and autonomous traits, general
      levels of depression, and sensory imagery ability, before performing a series of
      imagery trials depicting neutral and stressful (social rejection and achievement
      failure) scenes. Results provided support for the role of sociotropy as a
      vulnerability factor to dysphoric response to social rejection and to a lesser
      degree for achievement failure, but there was no support for autonomy as a
      vulnerability factor for either type of stressful script.

PMID- 8666709
TI  - Unconscious mood-congruent memory bias in depression.
AB  - The purpose of this study was to investigate an unconscious or implicit mood
      congruent memory (MCM) bias in clinical depression. Many studies have shown an
      explicit memory bias, but no study has yet found an implicit MCM bias in clinical
      depression. The authors compared depressed and control group participants on a
      conceptually driven implicit memory test. After studying words of positive,
      neutral, and negative affective valences, participants produced free associations
      to various cues. Implicit memory or priming was demonstrated by the production of
      more studied than unstudied words to the association cues. Depressed participants
      showed more priming of negative words, whereas controls showed more priming of
      positive words, thus supporting the MCM pattern. Also, no implicit memory deficit
      was found in depressed participants. These findings are discussed in the context
      of several prominent theories of cognition and depression.

PMID- 8666708
TI  - DSM-IV antisocial personality disorder field trial.
AB  - The development of the 4th edition of the Diagnostic and Statistical Manual of
      Mental Disorders (American Psychiatric Association, 1994) included 12 field
      trials to assess proposed revisions. This article provides results from the
      antisocial personality disorder (APD) field trial that was conducted to obtain
      data of relevance to the proposals for simplification and for the inclusion of
      more traditional traits of psychopathy. Provided herein are the results from 4
      sites that had sampled from populations of particular relevance to the diagnosis
      of APD (i.e., prison inmates, psychiatric inpatients, outpatients with substance
      use disorders, and homeless persons). The results indicated that some items from
      the 3rd revised Diagnostic and Statistical Manual of Mental Disorders (American
      Psychiatric Association, 1987) could be deleted without affecting the diagnosis.
      The field trial provided mixed support for the proposal to include more
      traditional traits of psychopathy.

PMID- 8666710
TI  - Goal-relevant dimensions of hypochondriacal tendencies and their relation to
      symptom manifestation and psychological distress.
AB  - A national sample of 60 male and 61 female adults completed a telephone interview
      that included measures of hypochondriacal tendencies, psychological distress, and
      symptom manifestation. They also provided cognitive evaluations for their most
      important health goal on scales measuring self-efficacy, value, planning, self
      reward, self-criticism, self-monitoring, social comparison, and positive and
      negative goal-based arousal. Health goal cognition significantly predicted
      hypochondriacal tendencies measured 15 to 30 days after the goal assessment, even
      after controlling for chronic illness diagnosis. Correlations between goal
      cognition and hypochondriacal tendencies differed from those observed for
      psychological distress, and no significant correlations emerged with symptom
      manifestation. Results support a motivational account of hypochondriacal
      tendencies and extend previous goals research.

PMID- 8666711
TI  - Schizotypy and maternal exposure to influenza and to cold temperature: the
      Mauritius study.
AB  - A topic of current controversy is that maternal exposure to influenza in the 2nd
      trimester of pregnancy may place the offspring at increased risk for
      schizophrenia. However, exposure to cold and to influenza may be confounded in
      existing studies, and case finding and identification may introduce error. Use of
      measures of schizotypy that are dimensional may be used to overcome some of the
      difficulties of case identification. Data are derived from the longitudinal study
      in Mauritius, an island in the southern hemisphere, where, in the case of the
      1968-1972 Hong Kong/A2 influenza virus epidemic, influenza and low temperature
      were not confounded. The results suggest that women's exposure to influenza in
      pregnancy is associated with an elevation of positive schizotypy scores, whereas
      exposure to low environmental temperatures is associated with an elevation of
      anhedonia scores in their offspring.

PMID- 8666712
TI  - Effects of focus of attention on anxiety levels and social performance of
      individuals with social phobia.
AB  - Self-focused attention has been linked to social anxiety and poor social
      performance, but the causal direction of this relationship has not been
      established. For this study, focus of attention was manipulated during a speech
      task, conducted in pairs for 38 individuals with generalized social phobia.
      Results indicated that intensifying self-focused attention increased anticipated
      anxiety and anxious appearance, regardless of whether the individual was giving a
      speech or passively standing before the audience. The self-focus manipulation
      also increased self-reported anxiety during the task, but only for individuals
      assigned to a passive role. Contrary to expectation, self-focused attention did
      not affect any measure of social performance. These results indicate that self
      focused attention may play a causal role in exacerbating social anxiety.

PMID- 8666713
TI  - The relation of parent alcoholism to adolescent substance use: a longitudinal
      follow-up study.
AB  - The current study tested parent alcoholism effects on growth curves of adolescent
      substance use and examined whether parent and peer influences, temperamental
      emotionality and sociability, and stress and negative affect could explain parent
      alcoholism effects. Longitudinal latent growth curve modeling showed that
      adolescents with alcoholic fathers, boys, and adolescents with drug-using peers
      had steeper growth in substance use over time than did adolescents without
      alcoholic fathers, girls, and adolescents without drug-using peers. Data were
      consistent with father's monitoring and stress as possible mediators of paternal
      alcoholism effects. However, the direct effects of paternal alcoholism on
      substance use growth remained significant even after including the hypothesized
      mediators in the model. This suggests that other (unmeasured) mediators are
      necessary to fully explain paternal alcoholism risk for adolescents' escalating
      substance use over time.

PMID- 8666714
TI  - Language production and thought disorder in schizophrenia.
AB  - The authors examined the relationship between language production (LP) processes
      and thought disorder. Thirty-nine schizophrenic or schizoaffective participants
      completed tasks measuring discourse planning, monitoring, and grammatical
      phonological encoding, as well as an interview used to rate thought disorder. The
      authors found that different LP processes were differentially related to
      different thought disorder subtypes. Incompetent references were strongly and
      selectively related to discourse planning performance. In addition, word
      approximations-neologisms were strongly and specifically associated with
      grammatical-phonological encoding performance. The article concludes with a
      discussion of the implications of these results for understanding the
      multifaceted nature and etiology of thought disorder.

PMID- 8666715
TI  - Diazepam blocks fear-potentiated startle in humans.
AB  - The effects of an anxiolytic drug (diazepam) on emotional responses to aversive
      stimuli were investigated using physiological measures, including the startle
      probe reflex. Participants were 54 university students assigned to either a
      placebo group or a 10 mg or 15 mg diazepam group in a double-blind design. Blink
      responses to intermittent noise probes were recorded during viewing of neutral
      and unpleasant slides. Consistent with prior animal work, diazepam blocked
      startle potentiation during aversive stimulus processing without decreasing the
      overall magnitude of startle responses. These findings suggest that a common
      defensive state mediates startle reflex potentiation in animals and humans and
      that this index of fear can be used to assess the emotional effects of different
      drugs.

PMID- 8666716
TI  - The influence of depressive symptomatology on episodic memory functioning among
      clinically nondepressed older adults.
AB  - The authors examined a community-based sample of 303 clinically nondepressed
      individuals aged 75 through 96 years on 4 recall tasks: free recall of rapidly
      presented random words, free recall of slowly presented random words, free recall
      of organizable words, and cued recall of organizable words. Using a
      classification taxonomy that identified mood- and motivation-related symptoms of
      depression, it was found that motivation-related symptoms had a negative effect
      on performance across all tasks, whereas mood-related symptoms had no effects. In
      addition, motivation-related symptoms negatively influenced the ability to
      benefit from more study time but had no effect on the ability to make use of item
      organization or category cues. An analysis of the specific motivation-related
      symptoms suggested that symptoms that may affect the ability to focus and sustain
      attention (e.g., concentration difficulties, lack of interest) were most strongly
      associated with performance deficits.

PMID- 8666717
TI  - Toxicological evaluation of mu-agonists. Part II: Assessment of toxicity
      following 30 days of repeated oral dosing of male and female rats with levo-alpha
      noracetylmethadol HCl (NorLAAM).
AB  - This study evaluated levo-alpha-noracetylmethadol (NorLAAM), the first N
      demethylated metabolite of levo-alpha-acetylmethadol (LAAM), a long-acting
      morphine-like (mu) agonist, approved in 1993 to treat opiate dependence. After
      acute and 7-day pilot studies to define dose levels appropriate for use in longer
      term evaluations, Sprague-Dawley rats (20 of each sex per group) were gavaged
      with doses of 4.4-25.9 mg kg(-1) day(-1) for 30 days followed by a 14-day
      recovery period. Treatment-related effects included dose-dependent CNS depression
      paralleled by changes in food consumption, body weight gain and fecal output, as
      well as reddish urine and abdominal staining. Tolerance developed by day 7. The
      spectrum of activity observed differed from the parent compound primarily in its
      time course. Cage-biting and gnawing behavior were observed only with NorLAAM.
      Mortality was dose-dependent, with deaths occurring predominantly during the
      first week. At day 30, all male-treated groups exhibited statistically
      significant, dose-dependent decreases in body weight gain and increases in serum
      cholesterol that returned to the control range following recovery. Increases in
      brain/body weight and testes/body weight ratios and decreases in kidney/brain,
      liver/brain, spleen/brain and heart/brain ratios, as well as decreases in kidney,
      liver, spleen and heart absolute weights, achieved statistical significance only
      for males. At terminal sacrifice, histological findings in the kidneys included
      increased incidences of tubular mineral deposition in mid- and high-dose groups
      of both sexes and of corticomedullary mineral deposition in females. Hepatic
      centrilobular hypertrophy was evident in male and female mid- and high-dose
      groups. Histopathological changes abated following the recovery period. In
      summary, acute and repeated administration of NorLAAM produced a pharmacodynamic
      profile commensurate with its role as the primary N-demethylated metabolite of
      LAAM, which is more potent and less lipophilic than the parent compound; this was
      reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall
      pattern of activity is consistent with its activity as a mu-agonist, which
      stimulates hepatic microsomal enzymes in rodents.

PMID- 8666718
TI  - Exposures to carbon monoxide, hydrogen cyanide and their mixtures:
      interrelationship between gas exposure concentration, time to incapacitation,
      carboxyhemoglobin and blood cyanide in rats.
AB  - Carbon monoxide (CO) and hydrogen cyanide (HCN) are generated during aircraft
      interior fires in sufficient amounts to incapacitate cabin occupants. For typical
      post-crash and in-flight fires, minimum protection periods of 5 and 35 min,
      respectively, have been suggested for breathing devices to protect the occupants
      from smoke. Relationships of blood carboxyhemoglobin (COHb) and cyanide (CN-)
      levels to incapacitation have not been well defined for these gases. Therefore,
      time to incapacitation (ti) and blood COHb and CN- at incapacitation were
      examined in rats exposed to CO (5706 ppm for 5-min ti; 1902 ppm for 35-min ti),
      HCN (184 ppm for 5-min ti; 64 ppm for 35-min ti) and their mixtures (equipotent
      concentrations of each gas that produced 5- and 35-min ti). Blood CO and HCN
      uptakes were evaluated at the two concentrations of each gas. With either gas,
      variation in ti was higher for the 35-min ti than the 5-min ti The COHb level
      reached a plateau prior to incapacitation at both CO concentrations, and COHb
      levels at the 5- and 35-min ti were different from each other. Blood CN-
      increased as a function of both HCN concentration and exposure time, but CN- at
      the 5-min ti was half of the 35-min ti CN- level. The HCN uptake at the high
      concentration was about three times that at the low concentration. In the high
      concentration CO-HCN mixture, ti was shortened from 5 to 2.6 min; COHb dropped
      from 81 to 55% and blood CN- from 2.3 to 1.1 microgram ml(-1). At the low
      concentration CO-HCN mixture, where ti was reduced from 35 to 11.1 min, COHb
      decreased from 71 to 61% and blood CN- from 4.2 to 1.1 microgram ml(-1). Any
      alteration in the uptake of either gas by the presence of the other was minimal.
      Our findings suggest that specific levels of blood COHb and CN- cannot be
      correlated directly with the incapacitation onset and that postmortem blood COHb
      and CN- levels should be evaluated carefully in fire victims.

PMID- 8666719
TI  - Semiautomated quantification of cytotoxic damage induced in cultured insect cells
      exposed to commercial Bacillus thuringiensis biopesticides.
AB  - A convenient in vitro bioassay based on semiautomated quantification of live-cell
      reduction of tetrazolium dyes--3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
      tetrazolium bromide (MTT) and 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-2H
      tetrazolium-5-corb  oxanilide sodium salt (XTT)--to formazan was developed and
      used to evaluate cytotoxic effects of two commercial insecticides (BT) derived
      from Bacillus thuringiensis subsp. kurstaki (Btk). Comparison of two target
      insect cell lines MG1 (Trichoplusia ni, cabbage looper midgut) and Sf9
      (Spodoptera frugiperda, fall army worm oocyte) revealed similar cell-dependent
      responses in mitochondrial-associated electron transport activity. The 50%
      inhibition of formazan production (ID50) obtained by exposing these cells to 20
      microM 2,4-dinitrophenol or 5 mM sodium azide occurred in the range 10(-7)-10(-6)
      International Units (IU) of BT cell(-1) 24 h(-1). Damage to cell adhesion and
      cytoarchitecture, revealed by light and electron microscopic analysis, increased
      with BT exposure and dose. MTT was superior to XTT as a cytotoxic indicator in
      kinetic studies related to spores, a major component of BT. Unless blocked by
      antibiotic (gentamicin), vegetative growth resulting from spore germination was
      the major cause of toxicity. The ID50 exposure time using vegetative Btk cells
      was approximately 0.1-0.2 times that required for BT spores, with or without
      intact parasporal proteins present. This difference in exposure is an indirect
      measure of the time required for spores to germinate and produce vegetative
      cells. The assay methodology developed here, if linked with suitable target and
      non-target animal cell types, should have broad application for conducting
      standardizable estimates of cytotoxic potential of any microbe-based
      biotechnology product.

PMID- 8666720
TI  - Effects of short-term occupational exposure to lead on erythrocyte glucose-6
      phosphate dehydrogenase activity and serum cholesterol.
AB  - The effect of short-term occupational exposure to lead on erythrocyte glucose-6
      phosphate dehydrogenase (G6PD) activity and serum cholesterol was studied in 40
      male workers of a lead and zinc foundry. All parameters were measured just before
      employment and after 172 +/- 21.3 days of work. Genetic deficiency of erythrocyte
      G6PD was observed in 5/40 subjects. Among G6PD normal subjects, increases in
      enzyme activity followed any change (increase or decrease) in blood lead. At the
      pre-employment test, serum cholesterol parameters did not show any correlation
      with GOD activity or blood lead, and they were not affected by exposure.
      Cholesterol values observed among all the GOD-deficient subjects were within the
      range of the rest of the study population.

PMID- 8666721
TI  - Mechanism of testicular atrophy induced by di-n-butyl phthalate in rats. Part 5.
      Testicular iron depletion and levels of ferritin, haemoglobin and transferrin in
      the bone marrow, liver and spleen.
AB  - This study reports changes in levels of ferritin, haemoglobin and transferrin in
      the bone marrow, liver and spleen as an attempt to determine the causes of
      testicular iron depletion. A single oral dose of di-n-butyl phthalate (DBP) to
      male rats caused a sloughing of the germ cells (at 6 h) prior to testicular
      atrophy. Before the sloughing it was observed that DBP induced decreases both in
      the iron levels in the blood, bone marrow and testis and in haemoglobin (Hb)
      levels in the blood, bone marrow and spleen. Decrease in transferrin (Tf) levels
      was observed in the liver. Significant increases in ferritin and haemosiderin
      (Hs) levels were observed in the spleen and in the liver and spleen,
      respectively. In vitro studies where mono-n-butyl phthalate (MBP) was incubated
      with liver homogenates, MBP caused both the decreases in Hb and Tf-bound iron
      levels and increases in Hs and Hs-iron levels. The present study proposes that
      the mechanism of testicular atrophy by DBP might be associated with both the iron
      release from Hb and/or Tf in the liver and spleen and the subsequent depletion of
      iron in the blood and testes.

PMID- 8666722
TI  - Effect of metformin on glutathione and magnesium in normal and streptozotocin
      induced diabetic rats.
AB  - Recently there has been growing interest in magnesium deficiency and its
      correlation with coronary artery disease, chronic complications of diabetes
      mellitus and antioxidant enzyme activity. Hypomagnesemia is a common association
      of diabetes mellitus, and the blood glutathione (GSH) level is significantly
      lower in both conditions. Metformin (Met), 'an oral antihyperglycemic drug'
      frequently used in the management of diabetes mellitus outside the USA, has been
      shown to have an insulin-like action. The purpose of this study was to
      investigate the effect of oral administration of Met (60 mg kg(-1)) for 14 days
      on GSH and magnesium levels in blood, liver and heart of normal and
      streptozotocin-induced diabetic Wistar rats. Diabetes was induced by an i.p.
      injection of streptozotocin (60 mg kg(-1)). Our results showed that Met did not
      affect fasting serum glucose concentration in non-diabetic animals but reduced it
      significantly in diabetic animals. Serum and liver magnesium levels were
      significantly decreased in the untreated diabetic group compared with the normal
      group. Treatment with Met improved liver magnesium concentration in the diabetic
      group only. It has no effect on serum magnesium in diabetic or non-diabetic rats.
      Heart magnesium levels showed non-significant changes in all groups. In diabetic
      animals a significant decrease of GSH in both blood and liver was observed.
      Treatment with Met increased these levels significantly, with a similar effect on
      GSH levels in non-diabetic rats. There were no significant changes in heart GSH
      levels in any of the groups. This study demonstrates that oral Met therapy
      improves the altered levels of magnesium and GSH in diabetic rats.

PMID- 8666723
TI  - Effects of copper on gill structure and transport function in the rainbow trout,
      Oncorhynchus mykiss.
AB  - Effects of copper were studied in freshwater adapted rainbow trout using the
      perfused head preparation. In its monovalent chemical form, copper at millimolar
      concentrations had no significant effects on Na+ and water transport. By
      contrast, the divalent form produced an increase in gill perfusion pressure, a
      significant reduction in Na+ influx and water fluxes and reversed Na+ net flux.
      Observations by light microscopy showed important cell damage (oedema, mucus
      production, cellular desquamation). By electron microscopy there was smoothing of
      apical membranes, swelling of the tubular system and destruction of mitochondria.
      The Na, K-ATPase activity was totally suppressed and residual ATPase activity
      largely inhibited by 1 mM Cu2+. There was inhibition of the Na,K-ATPase activity
      with an IC50 of approximately 10 microM of total copper (free and bound cupric
      fractions). As active sodium transport is located on the secondary lamellae, our
      results show that its entry mechanism is inhibited at that level by cupric ions
      only. Results are discussed in relation to hydromineral balance of the trout.

PMID- 8666724
TI  - Nephrotoxicity of ifosfamide in rats.
AB  - Renal proximal tubule cell injury is an important side effect of the
      chemotherapeutic agent ifosfamide in humans. We investigated the effect of this
      medication on kidney function in rats. Animals received either 40 or 80 mg kg(-1)
      ifosfamide intraperitoneally daily for 3 days every 3 weeks for a total of four
      treatment courses. Ifosfamide-treated rats had significantly lower body weight
      and hematocrit than sterile water-treated control rats. Animals receiving 40 mg
      kg(-1) ifosfamide developed isolated phosphaturia after their fourth and final
      treatment course. Rats receiving 80 mg kg(-1) ifosfamide had low-grade
      glucosuria, phosphaturia and proteinuria throughout the study. Urine flow rate,
      creatinine clearance, urinary sodium and potassium excretion and kidney
      glutathione and malondialdehyde content were not affected by ifosfamide at either
      dose. These findings indicate that ifosfamide produces abnormalities in rat renal
      function resembling subclinical Fanconi syndrome.

PMID- 8666725
TI  - Oxidative modifications produced in HL-60 cells on exposure to benzene
      metabolites.
AB  - We have studied the effects of the benzene metabolites hydroquinone, p
      benzoquinone or 1,2,4-benzenetriol on cytotoxicity, active oxygen formation,
      hydrogen peroxide (i.e. hydroperoxide) production and nitric oxide formation in
      HL-60 cells. We also examined the effects of these compounds on antioxidant
      enzymes and intracellular antioxidants in these cells. The cytotoxicity of
      benzene metabolites to HL-60 cells was found to be of the order of p
      benzoquinone>hydroquinone>benzenetriol. No appreciable changes in the basal
      levels of either superoxide anion production or nitric oxide formation were
      observed following exposures to the benzene metabolites, but significant
      increases in superoxide were seen on stimulation with TPA for each metabolite,
      whereas hydroquinone and p-benzoquinone, but not 1,2,4-benzenetriol, increased
      nitric oxide production under these conditions. Following exposure to the benzene
      metabolites, HL-60 cells showed significant rises in hydrogen peroxide formation
      compared to controls. The study of antioxidant enzymes and intracellular
      antioxidants suggested that the benzene metabolites inhibit or reduce the levels
      of different antioxidant mechanisms and, thereby, cause the accumulation of free
      radicals in these cells predisposing them for oxidative damage.

PMID- 8666727
TI  - Harry D. Krause: scholar for all seasons.

PMID- 8666726
TI  - Effect of dosing vehicle on the toxicity and metabolism of unsaturated aliphatic
      nitriles.
AB  - The effect of dosing vehicle on toxicity and metabolism of unsaturated aliphatic
      nitriles was investigated in male Sprague-Dawley rats. Five unsaturated aliphatic
      nitriles--acrylonitrile, methacrylonitrile, allylnitrile, crotononitrile and
      fumaronitrile--were prepared in five different dosing vehicles--saline, corn oil,
      safflower oil, mineral oil, olive oil and Tween-20. Groups of six male rats were
      given 0.5 LD50 doses of the nitriles by gavage and they were observed for 12 It
      for cholinomimetic and central nervous system effects. Cyanide and glutathione
      levels were determined in blood and various organs at 1, 3 and 6 h after nitrile
      administration and thiocyanate levels were determined at 6 h after nitrile
      administration. The results indicate that all the vehicles studied potentiated
      the toxicity of all the nitriles compared to nitriles administered in saline and
      significantly increased their metabolism to cyanide and thiocyanate and nitrile
      induced depletion of glutathione in rats. This behavior of vehicles illustrates
      the difficulty of identifying suitable vehicles for administration of lipophilic
      compounds in toxicology studies.

PMID- 8666728
TI  - Questing for grails: duplicity, betrayal and self-deception in postmodern medical
      research.

PMID- 8666729
TI  - Irreversible error: the power and prejudice of female genital mutilation.

PMID- 8666730
TI  - Drug use and human rights: privacy, vulnerability, disability, and human rights
      infringements.
AB  - Drug use is a complex social phenomenon involving the drugs which are used, the
      people using them, the context in which they are acquired and used, and the
      social construction of drug use by society and by governments. It is a popular
      yet controversial behavior which elicits extreme public opinion. Discourse about
      drug use is often polarized, emotional, and divisive. This is most evident in the
      approaches used or proposed to control drug use and the risks and harms
      associated with its use and control. Despite this, there is almost no discourse
      about the human rights of drug users. This Article addresses this issue by
      examining the privacy rights of drug users, their vulnerability to use drugs and
      to be harmed by using them, and the deprivation of opportunities for drug users
      to exercise their rights. This Article will also analyze disabilities
      attributable to drug use, as well as situations in which the human rights of drug
      users are likely to be infringed.

PMID- 8666731
TI  - Consent to medical treatment by older children in English & Scottish law.

PMID- 8666733
TI  - Legal recognition of transsexuals in Australia.

PMID- 8666732
TI  - Teenage abortion in Germany: with reference to the legal system in the United
      States.

PMID- 8666734
TI  - Accreditation of those who arrange adoptions under the Hague Convention on
      intercountry adoption as a means of protecting, through private international
      law, the rights of children.

PMID- 8666735
TI  - Absolving a deadly sin: a medical and legal argument for including obesity as a
      disability under the Americans with Disabilities Act.

PMID- 8666736
TI  - The North American Free Trade Agreement's effect on pharmaceutical patents: a
      bitter pill to swallow or a therapeutic solution?

PMID- 8666737
TI  - The maternal-fetal rights dilemma: honoring a woman's choice of medical care
      during pregnancy.

PMID- 8666738
TI  - The False Memory Syndrome debate--will the victim please stand up?

PMID- 8666739
TI  - NLRB v. Health Care and Retirement Corp. of America: analysis and disapproval of
      the National Labor Relations Board's determination of supervisory status of
      nurses.

PMID- 8666740
TI  - DNA inclusions within autolytic cytoplasmic vacuoles of hemopoietic stem cell
      line FDCP-Mix.
AB  - FDCP-Mix, a pluripotent routine hemopoietic stem cell line undergoes
      internucleosomal cleavage of DNA when induced to apoptosis either by drugs or by
      withdrawal of growth factor (IL-3), and also displays a pattern of nuclear
      morphology that is typical for apoptosis. However, increased autolytic activity
      in the cytoplasm precedes the nuclear changes. For etoposide-treated FDCP-Mix
      cells, mitochondria were identified as a target for autolytic digestion in large
      autolytic vacuoles, but during this period an increase in the number of
      mitochondria was observed. The autolytic vacuoles displayed variations in their
      content. Large, electron-dense inclusions resembling "condensed chromatin" could
      regularly be found in FDCP-Mix cells treated with low concentrations of etoposide
      (<4 microM). Confocal fluorescence microscopy and DNAse-gold labeling were
      employed to demonstrate the presence of DNA in the formation of the electron
      dense inclusions within autolytic vacuoles. The identification of mitochondrial
      macroautophagy, the evidence for an etoposide-induced proliferation of
      mitochondria, and the fact that electron-dense inclusions are formed at a stage
      when the morphology of the nucleus is still not effected, suggests that the DNA
      within the autolytic vacuoles may be of mitochondrial origin.

PMID- 8666741
TI  - Semi-automated positional analysis using laser scanning microscopy of cells
      transfected in a regenerating newt limb.
AB  - Limb regeneration in urodele amphibians such as the newt is a key system for
      investigating the positional identity of cells. The regenerate arises locally
      from blastemal cells, mesenchymal progenitors that normally give rise to
      structures distal to the amputation plane but which can be respecified
      (proximalized) by treatment with retinoic acid (RA) such that proximal structures
      are formed. To establish an assay for positional identity, cells of distal and RA
      treated distal blastemas are labeled by transfection with an alkaline phosphatase
      marker gene using particle bombardment (biolistics). After grafting the distal
      blastema to a proximal stump, a context known as intercalary regeneration, the
      proximodistal distribution of labeled cells in the resulting regenerate is an
      index of positional identity. We use enzyme-labeled fluorescence (ELF) in
      conjunction with laser scanning microscopy to detect transfected cells within a
      section of the entire regenerate. A semi-automated analysis of the positional
      distribution of marked cells along the proximal-distal axis demonstrates that
      cells from both distal and RA-treated blastemas contribute to the regenerate.
      This procedure provides an efficient and accurate tool for positional analysis of
      transfected cells, and should be applicable for studying genes that play a role
      in specifying cell position during morphogenesis.

PMID- 8666742
TI  - Dihydrorhodamine 123 identifies impaired mitochondrial respiratory chain function
      in cultured cells harboring mitochondrial DNA mutations.
AB  - Several human diseases have been found to be caused by mitochondrial DNA (mtDNA)
      mutations. Pathogenic mutated (mut) mtDNAs are usually "heteroplasmic,"
      coexisting intracellularly with wild-type (wt) mtDNAs. For some mtDNA mutations,
      cells have normal levels of respiratory chain function unless the percentage of
      mut-mtDNA is very high. Although progress in understanding the molecular basis of
      mitochondrial diseases has been remarkable, the heterogeneity of mut-mtDNA
      distribution, even among cells of the same tissue, makes it difficult to clearly
      delineate the relationships between mtDNA mutations, gene dosage, and clinical
      phenotypes. In a search for screening methods for identifying cultured cells with
      deficient mitochondrial function, we incubated living cells harboring mut-mtDNAs
      with dihydrorhodamine 123 (DHR123), an uncharged, nonfluorescent agent that can
      be converted by oxidation to the fluorescent laser dye rhodamine 123 (R123).
      Bright mitochondrial staining was observed in cells that respired normally.
      Fluorescence was significantly reduced in cells with mitochondrial respiratory
      chain dysfunction resulting from very high levels of mut-mtDNAs. The data show
      that DHR123 is useful for assessing mitochondrial function in single cells, and
      can be used for isolating viable, respiratory chain-deficient cells from
      heterogeneous cultures.

PMID- 8666744
TI  - Detection of plasma proteins in CNS neurons: conspicuous influence of tissue
      processing parameters and the utilization of serum for blocking nonspecific
      reactions.
AB  - Despite the presence of a blood-brain barrier (BBB), plasma proteins have been
      detected intraneuronally in regions with axonal projections confined to the CNS.
      This finding raises the question of whether plasma proteins are taken up from the
      brain interstitium or whether the results are due to experimental artifact. We
      examined the effect of various protocols for tissue processing on the
      intraneuronal distribution of plasma proteins using immunohistochemistry. The
      detection level of plasma proteins decreased after prolonged fixation,
      irrespective of the fixative and embedding method employed. In cryostat sections,
      attempts to block nonspecific staining by serum protein caused considerable
      nonspecific staining in itself. When nonspecific staining was blocked with a
      serum-free buffer, specifically labeled neuronal perikarya were found in cryostat
      sections of brains fixed by perfusion with paraformaldehyde without postfixation.
      Albumin and IgG occurred predominantly in neurons having projections beyond the
      BBB but also sparsely in neurons having projections confined to the CNS.
      Transferrin was evenly distributed within neuronal somata, irrespective of the
      orientation of projections. The immunoreaction product of the three plasma
      proteins exhibited a specific intraneuronal localization in the differently
      projecting neurons. In circumventricular organs, plasma proteins were observed
      extracellularly and in projecting fibers. In conclusion, plasma proteins are
      present in neurons with projections confined to the CNS and are probably taken up
      from the brain interstitium.

PMID- 8666743
TI  - Labeling of peroxisomes with green fluorescent protein in living P. pastoris
      cells.
AB  - We exploited the light-activated fluorescent properties of the green fluorescent
      protein (GFP) of the jellyfish Aequorea victoria for studies on the peroxisomal
      sorting of polypeptides. GFP and GFP-SKL (containing a C-terminal, tripeptide
      peroxisomal targeting signal, SKL) were expressed from a methanol-inducible,
      alcohol oxidase (AOX1) promoter in the methylotrophic yeast Pichia pastoris. GFP
      was cytosolic, whereas the GFP-SKL fusion protein was targeted to peroxisomes, as
      demonstrated by biochemical fractionation of organelles on Nycodenz gradients.
      Neither GFP nor GFP-SKL affected the viability of yeast cells but both were
      fluorescent on excitation with 395-nm UV light. The subcellular locations of GFP
      and GFP-SKL in living yeast cells were monitored by fluorescence microscopy and
      their fluorescence was coupled to photo-oxidation of diaminobenzidine (DAB),
      resulting in the deposition of electron-dense oxidized DAB at intracellular
      locations of GFP derivatives. This photooxidation procedure permitted facile
      ultrastructural localization of GFP in cells by electron microscopy, and provided
      further evidence that GFP produced in P. pastoris is cytosolic, whereas GFP-SKL
      is peroxisomal. The GFP-SKL fusion protein is therefore a versatile reporter for
      the peroxisomal compartment, with many applications for studies involving
      peroxisomal import and biogenesis.

PMID- 8666745
TI  - Detection and spatial distribution of IL-2 receptors on mouse T-lymphocytes by
      immunogold-labeled ligands.
AB  - To identify the plasma membrane (PM) structures implicated in T-cell activation,
      we studied the distribution of interleukin-2 receptors (IL-2R) and the surface
      topography of lymphocytes by affinity labeling in electron microscopy (EM). In
      particular, we analyzed the distribution of the IL-2R alpha-chain on CTLL-2 cells
      (a murine cytotoxic T-cell lymphoma line). Some of our experiments were extended
      to the functionally and morphologically distinct cell line EL4 (a routine helper
      T-cell lymphoma line). As affinity ligands we used a rat monoclonal antibody
      (clone 7D4) reactive with the routine alpha-chain of IL-2R and recombinant mouse
      IL-2 (rIL-2). The distribution of IL-2R was visualized on the cell surface by
      ligands coupled to colloidal gold particles of different sizes. Unfixed cells
      were labeled with gold probes and attached to concanavalin A (ConA)-pretreated
      coverslips. Subsequently, the cells were prepared for EM. Examination of
      ultrathin sections and large surface replicas revealed a high degree of
      variability in cell morphology and in the density of the randomly distributed
      gold-labeled ligands among CTLL cells. According to their typical appearance,
      lymphocytes with strong receptor expression can be easily identified within the
      cell population. In contrast, the label on many mitogen-activated EL4 cells
      showed a cap-like polar distribution. The results suggest the existence of
      diverse distribution patterns of IL-2R on CTLL and EL4 cells. These differences
      are believed to reflect the different physiological roles played by T-cell
      subsets in the immune system.

PMID- 8666746
TI  - Use of serial semithin frozen sections to evaluate the co-localization of
      estrogen receptors and progesterone receptors in cells of breast cancer tissues.
AB  - The extent of co-expression of estrogen receptors (ER) and progesterone receptors
      (PgR) in breast cancer cells was examined immunocytochemically. Eight surgical
      cases of infiltrating ductal carcinoma designated as ER-positive and PgR-positive
      (ER+/PgR+) by enzyme immunoassay (EIA) were used. They were fixed with 4%
      formaldehyde and cut into serial frozen semithin sections. Using sections stained
      with either anti-ER or anti-PgR antibody, we ascertained the co-localization of
      ER and PgR in a single cell and estimated the ratio of the number of cells co
      expressing ER and PgR. Twenty-six to 95% of the cells were immunopositive for
      both ER and PgR, 2-25% of them, varying in cases, were positive for ER but not
      for PgR, and <3% of the cells were positive for PgR but not for ER. The remaining
      5-60% cells were positive for neither ER nor PgR. A significant percentage of
      breast cancer cells in tissues designated as ER+/PgR+ by EIA showed the phenotype
      of ER-positive but PgR-negative. The co-expression ratio of ER and PgR in
      biochemically detected ER+/PgR+ breast cancer may reflect a particular clinical
      parameter, such as the heterogeneous responsiveness of ER+/PgR+ breast cancers to
      hormonal treatment. Immunostaining of serial semithin frozen sections for two or
      more different antigens is a useful method to assess the correlation of
      localization of antigens.

PMID- 8666747
TI  - Expression of the pituitary transcription factor GHF-1/PIT-1 in cell types of the
      adult porcine adenohypophysis.
AB  - We describe the expression of the transcription factor GHF-1/PIT-1 in adult
      porcine adenohypophysis by a nonradioactive in situ hybridization (ISH) method
      using a digoxigenin-labeled cDNA probe corresponding to the entire coding region
      of rat GHF-1. GHF-1 transcripts were found in 71.7% of adenohypophyseal cells. We
      also report the simultaneous detection of GHF-1 mRNA and pituitary hormones by
      combined ISH and immunocytochemistry (IC) in dispersed adenohypophyseal cells,
      detected with an alkaline phosphatase-NBT/BCIP technique and with an
      immunoperoxidase-3-amino-9-ethylcarbazole (AEC) method, respectively. The
      combination of the two techniques neither abolished nor diminished their
      sensitivity or specificity. GHF-1 is expressed in all five of the cell types in
      the adult porcine adenohypophysis, showing that this method is suitable for
      simultaneous detection of transcripts and proteins at the single-cell level.

PMID- 8666748
TI  - High-efficiency expression gene cloning by flow cytometry.
AB  - Our goal was to develop a convenient and widely applicable procedure for gene
      cloning based on flow cytometry. To this purpose, we have developed an efficient
      protocol for DNA transfection and selection of rare transfectants. Transfection
      by calcium phosphate co-precipitation was extensively investigated. The use of
      specific batches of calcium chloride, of carrier DNA purified in guanidinium
      thiocyanate, and of plasmid DNA banded in cesium chloride proved crucial for high
      efficiency of transfection. Several tissue culture parameters were also found
      critical. With the optimized procedure we can transfect almost 100% of the COS-7
      cells with cDNA encoding cell surface antigens or green fluorescent protein.
      Moreover, we routinely obtain high average levels of expression. Efficient cell
      sorting in flow cytometry was achieved by subtracting the cell autofluorescence
      background, by displacing stained cells in the red dimension, and by combining
      fluorescein-conjugated primary and secondary antibodies. Efficient recovery of
      the transfected DNA constructs was obtained from 2500-3000 cells directly sorted
      in Hirt lysis buffer. Using the above protocol we have cloned by expression the
      gene encoding Trop-2, a cell surface glycoprotein expressed by human carcinomas.

PMID- 8666749
TI  - Bifunctional protein cross-linking reagents improve labeling of cytoskeletal
      proteins for qualitative and quantitative fluorescence microscopy.
AB  - Because permeabilization of the cell membrane is necessary to label intracellular
      proteins with most fluorescent probes, it is important to optimize the
      preservation and labeling of the proteins under study. We used qualitative and
      quantitative fluorescence microscopy to evaluate the effects of six different
      bifunctional protein cross-linking reagents and several extraction conditions on
      the labeling of filamentous actin with phalloidin and the immunolabeling of
      tubulin and gelsolin. The labeling of cytoskeletal and associated proteins can be
      significantly enhanced by the appropriate combination of bifunctional protein
      cross-linking reagents and extraction conditions. However, the conditions that
      give the most intense labeling vary depending on the label used. The greatest
      intensity of labeling with either phalloidin or antibodies was obtained with the
      intermediate-length cross-linker DSP. The two-step procedure of cross-linking
      with DSP and extracting in Triton X-100 in microtubule-stabilizing buffer
      containing DSP gives maximal labeling with phalloidin. Maximal labeling of
      gelsolin and tubulin with antibodies is obtained by extracting DSP-cross-linked
      cells with Triton in Hank's saline containing DSP. Therefore, DSP reproducibly
      improves preservation of both soluble and filamentous proteins for quantitative
      and qualitative studies by fluorescence microscopy.

PMID- 8666750
TI  - A quantitative luminescence assay for nonradioactive nucleic acid probes.
AB  - In histochemical work with digoxigenin- or biotin-labeled nucleic acid probes,
      reproducibility of in situ hybridization depends on accurate measurement of the
      amount of non-radioactive label being used. We describe a rapid and sensitive
      assay for nonradioactive label incorporated into nucleic acids employing a
      luminogenic substrate for alkaline phosphatase, CSPD (disodium 3-(4
      methoxyspirol?1,2-dioxetane-3,2'-(5'-chloro)tricyclo [3.3.1.1(3,7)]decan?-4
      yl)phenyl phosphate). An alkaline phosphatase-antibody conjugate was bound to
      digoxigenin-labeled nucleic acids spotted on nylon membranes. Light emission from
      the reaction of the bound alkaline phosphatase with CSPD was measured with a
      luminometer. This method allows an accurate determination of digoxigenin
      incorporated into nucleic acid probes in the range of 0.5-500 fmol of
      nonradioactive label.

PMID- 8666751
TI  - Leftist sexual politics and homosexuality: a historical overview.
AB  - For almost a full century now, the revolutionary prospect of socialism has
      fuelled opening forays first of the homosexual emancipation and later of the gay
      liberation movements, both in Europe and in North America. It inspired Edward
      Carpenter and Magnus Hirschfeld at the turn of the century; Andre Gide and
      Richard Linsert in the post-World War I years; Harry Hay and Jim Kepner in the
      post-World War II era; and the British and American Gay Liberation Front, the
      Italian Fuori!, the French FHAR, the German "Rotzschwule," and the Dutch Red
      Faggots following the Stonewall rebellion. While the official socialist parties
      of Northwestern Europe may have made only limited contributions to homosexual
      emancipation, they certainly have a better record than conservative and Christian
      parties and even the liberals, who have consistently, if contradictorily,
      underlined the freedom of private life. Even so, parties across the entire
      political spectrum have gradually come to endorse at least some of the movement's
      goals. As it has advanced, the gay movement has changed as well, and it now finds
      itself pulled in divergent directions. Gay leftists who still subscribe to the
      ideals expressed in Marxist and utopian socialist writings now find themselves at
      demonstrations shoulder-to-shoulder with members of ACT UP and Queer Nation, to
      say nothing of gay conservatives and gay Christians. The successes achieved by
      the contemporary gay movement despite or precisely because of its diversity
      support Foucault's argument that "there is no single locus of great Refusal, no
      soul of revolt, source of all rebellions, or pure law of the revolutionary.
      Instead there is a plurality of resistances, each of them a special case...." At
      the close of the twentieth century, the welfare state has reached its apogee in
      Northwestern Europe. As blue-collar workers historically committed to class
      struggle have become relatively well-to-do and minoritarian, socialist parties
      have increasingly lost their traditional base of support and been forced into the
      defensive. Depending only on the socialists would mean relying on an ineffectual
      partner, for nowhere are they in a stable position of power. Long before the
      collapse of "really existing socialism" in Eastern Europe and the former Soviet
      Union, gay and lesbian movements began developing their own autonomous politics
      independent of parties. They moved in this direction in part because the
      coalition with leftism so frequently led to disappointment, particularly when
      gays and lesbians working within socialist parties were called upon to
      subordinate or abandon their own goals in favor of party platforms. In other
      cases the gay-left coalition failed to yield results because a single-minded
      reliance on one party placed limits on lobbying other parties and entering
      compromises. We have reached a time when inherited ideologies are no longer
      capable of laying claim to the undivided loyalty of the gay movement, if indeed
      they ever were. As it has developed autonomous theories and practices, the gay
      movement's choice of coalition partners has increasingly come to be based on
      pragmatism and success in advancing the gay agenda. Indeed, the roles of the gay
      movement and political parties have undergone a notable switch in recent years,
      with parties currying the support of the gay movement rather than vice versa.
      This signals a shift from the desire for politics to a politics of desire, going
      far beyond traditional socialist ideologies.

PMID- 8666752
TI  - Anarchism and homosexuality in Wilhelmine Germany: Senna Hoy, Erich Muhsam, John
      Henry Mackay.
AB  - Homosexuality and its social and legal suppression were heatedly discussed in
      early twentieth-century Germany, including on the left. Among the anarchists,
      positions with markedly diverse forms of argument were espoused by such prominent
      advocates of individualist anarchism as John Henry Mackay and by others coming
      from the Bakuninist tradition, such as Senna Hoy and Erich Muhsam. Their writings
      evidence that prior to World War I and into the 1920s, German anarchists-
      especially when compared with the Social Democrats--intervened consistently on
      behalf of individual self-determination extending into the sexual sphere, even
      though an undercurrent of hostility toward homosexuals persisted within the
      leftist movement as a whole.

PMID- 8666753
TI  - Soviet policy toward male homosexuality: its origins and historical roots.
AB  - Sodomy was a crime under tsarist criminal law. Having abrogated the tsarist legal
      codes in the name of socialist justice, the new Soviet regime did not at first
      impose criminal sanctions on sodomy. It was only in 1934, after Stalin had
      consolidated power, that an anti-sodomy statute was added to the Soviet criminal
      code. Although Russian radicals had never been friendly to variant sexual
      practices, which they viewed as the product of capitalist decadence, Soviet
      sexologists in the 1920s participated in the international movement for sexual
      reform and criminologists deplored the use of penal sanctions to censor private
      sexual conduct. The 1934 return to legal prosecution represented the recovery of
      two traditions: the radicals' disregard for issues of sexual freedom and tsarist
      legal custom. It was not, however, a clear reversal of the seemingly enlightened
      legal practice of the 1920s. This essay examines the trial of a group of
      homosexual men and the investigation of a lesbian couple, both from 1922, which
      show that Soviet courts tried to repress sexual variation even when homosexuality
      was not a crime. These cases and the status of homosexuality in general reflect
      on the murky status of the law and on the ambiguities of Soviet politics in the
      early years of the new regime.

PMID- 8666754
TI  - Gide in the U.S.S.R.: some observations on Comradeship.
AB  - After 1914-18, Gide emphasized the value of the Comradeship of Mankind rather
      than the essentially individualistic ethos to which he had been previously
      committed. However, while believing in the social benefits of tolerating
      pederasty, he still saw a person's difference from the norm as the guarantee of
      authenticity. Political idealism and curiosity took him to the U.S.S.R. in 1936,
      and on his return he criticized the inertia, ignorance, and conformism which he
      considered were encouraged by the Soviet state's promotion of the family unit.
      This essay examines how his attitude towards sexuality led him to question
      alleged political freedoms and to see in the Soviet oppression of minorities,
      including homosexuals, the denial of the revolutionary spirit.

PMID- 8666755
TI  - Communists, Social Democrats, and the homosexual movement in the Weimar Republic.
AB  - Two cliches of gay historiography concerning the relationship between homosexuals
      and the political parties of the Weimar Republic are here subjected to critical
      examination. The notion that the political left of that era was similar in its
      homophobia to the right-wing and centrist parties is challenged with a number of
      particulars showing that the goals of the homosexual movement were supported
      almost exclusively by the left, especially the Communist Party, and that leftist
      homophobia was an atypical exception. Attention is also devoted to the active
      involvement of homosexual men in the Nazi movement and the destruction of the
      Weimar Republic, which casts doubt on the notion that homosexuals were merely
      passive victims of Nazi homophobia and persecution. The possibility of a special
      affinity between homosexual men and the Nazi movement is explored using the
      example of the Nazi leader Ernst Rohm.

PMID- 8666756
TI  - The "Jews" of the antifascist left: homosexuality and socialist resistance to
      Nazism.
AB  - In the early 1930s, German Social Democrats and Communists seized upon the
      homosexual orientation of some Nazi leaders, especially Ernst Rohm, with the aim
      of discrediting the entire National Socialist movement. In Western Europe as well
      as the Soviet Union, there was a general tendency among socialists in the 1930s
      to identify homosexuality with Nazism. Antifascist leftists created the
      impression that homosexuality was widespread in Nazi organizations. Such
      socialist theorists as Wilhelm Reich tended to view homosexuality sociologically
      and psychologically as a typical rightist, nationalist, and above all fascist
      aberration. Leftist aversion to homosexuality was not only an expression of
      political opportunism. Prejudices against homosexuality were part and parcel of
      socialist thinking and became even more deep-rooted among leftists as a
      consequence of the ideological and moral confrontation with National Socialism.
      Against the presumed immortality and perversion of the Nazis, the antifascists
      stressed their own rationality and purity.

PMID- 8666757
TI  - Male inverts and homosexuals: sex discourse in the anarchist Revista Blanca.
AB  - Historically, the anarchist movement has placed great emphasis on the personal
      and the political and the desire to liberate sexual expression. This was no less
      the case in the Spanish anarchist movement during the first decades of this
      century. By analyzing one influential anarchist journal of the time, the Revista
      Blanca, this essay examines the treatment of same-sex eroticism by some Spanish
      anarchists and attempts to place their understanding and treatment of this in the
      context of the time. This essay can be viewed as a point of departure for further
      necessary work on Spanish anarchist views of same-sex sexuality.

PMID- 8666758
TI  - Theories about sex and sexuality in utopian socialism.
AB  - It was the utopian socialists of the period 1800-50 (Fourier, Saint-Simon, and
      the Saint-Simonians in France, as well as the Owenites in Great Britain) who not
      only challenged the imperialism of reason but sought to rehabilitate the flesh by
      valuing its pleasure and incentives. Sex and sexuality were central issues for
      the first socialists, who were scorned as "utopian" by Marx and Engels for
      seeking to improve the status of all members of society through peaceful means.
      Because Marxism has played a greater role in the history of socialism, the
      utopian socialist discussions have been largely disregarded. This essay analyzes
      the works of the utopian socialists Fourier, Saint-Simon, and the Saint
      Simonians, arguing that resurgences of the utopian socialist tradition can be
      discerned around 1900 and again circa 1970.

PMID- 8666759
TI  - Johann Baptist von Schweitzer: the queer Marx loved to hate.
AB  - Despite his conviction on a morals charge involving a boy, the early German
      Social Democrat Johann Baptist von Schweitzer went on to have a successful
      political career. His life furnishes the context to present remarks by his
      political opponents Marx and Engels, which reveal their deep-seated homophobia.
      It is pointed out that this has been glossed over by the translations of the
      recently published Marx/Engels Collected Works. Some remarks on boy-love and
      anarchism are appended.

PMID- 8666760
TI  - Homosexuality and the Left in the Netherlands: 1890-1911.
AB  - The attitudes of the Dutch socialist left toward homosexuality are examined,
      drawing upon a wide range of sources. At the end of the nineteenth century, a
      political debate on prostitution heightened social interest in sexuality in its
      diverse forms. Medical literature on sexual perversion was another starting point
      for the growing discussion of homosexuality. These debates were joined by Dutch
      socialists of divergent opinions. Whereas some of them wanted to acknowledge the
      right of homosexuals who were born that way to express themselves, only one
      exceptional author defended the right to homosexual sex. But most socialists were
      prejudiced against homosexuality and generally endorsed Frank van der Goes's
      proposal to eliminate homosexual behavior while accepting the notion of an inborn
      homosexual orientation.

PMID- 8666761
TI  - Examination of biofilm formation and risk of infection associated with the use of
      urinary catheters with leg bags.
AB  - Urinary catheters and legs bags were simultaneously colonized by Escherichia coli
      and Proteus vulgaris using a model urinary drainage system. the system was
      continuously supplied with filter-sterilized artificial urine using a diurnal
      flow pattern. The extent of colonization was determined by assessment of both
      planktonic and biofilm formation over time. Contamination of the catheters
      resulted in rapid colonization of the whole system within a 24 h period.
      Contamination of the leg bags resulted in an ascending biofilm formation over a
      four-day period. Results indicated that infection risk could be minimized by
      changing the catheter and leg bags at least once a week. The design of the leg
      bags was not found to influence the rate or extent of biofilm formation.

PMID- 8666762
TI  - Prospective survey of the incidence, risk factors and outcome of hospital
      acquired infections in the elderly.
AB  - Four hundred and thirty-six patient admissions to either an acute assessment or a
      rehabilitation ward for the care of the elderly were studied. A total of 113
      episodes fitting the definition of a hospital-acquired infection (HAI) occurred
      in 81 (18.5%) of admissions. The global infection rate was 10.8 per 1000 patient
      bed days and did not differ between the wards. The chest and urinary tract were
      the commonest sites of infection, and 26 patients appeared to be infected at more
      than one site. The majority of first infections occurred within 14 days of
      admission. Median length of stay for patients with one or more infective episodes
      was significantly longer than for those who did not develop an HAI. The presence
      of an HAI, multiple-site infections and chest infections were significantly
      associated with fatal outcome. HAI occurs commonly in elderly patients and is
      associated with prolonged hospital stay and increased mortality.

PMID- 8666763
TI  - Bacterial colonization of nursing home residents on admission to an acute care
      hospital.
AB  - Very little data obtained in a prospective, controlled fashion examines the
      prevalence of colonization with antibiotic-resistant bacteria and yeast in
      nursing home residents on admission to acute-care hospitals. We cultured swabs
      taken from all nursing home patients admitted to a medical center on selected
      days of the week. Age-matched control patients were also enrolled. Nasal,
      pharyngeal, and rectal or perineal swabs were done within 24 h of admission.
      Susceptibility to gentamicin was used as a marker for antibiotic resistance. Most
      nursing home patients (45/56) were colonized with gentamicin-resistant isolates
      of coagulase-negative staphylococci; in the control group, 24 patients only
      carried these organisms (P = 0.0001 chi square). The only resistant Gram-negative
      bacteria were recovered from control patients (3/56 vs. 0/56 nursing home
      residents; P = 0.12, Fisher's exact test). Yeast were common colonizers of both
      nursing home residents and controls but were more frequently recovered from
      nursing home patients (P = 0.03, chi square). Although colonization by antibiotic
      resistant staphylococci of nursing home residents on admission to an acute-care
      hospital was common, resistant Gram-negative bacilli were not found in this
      study. Additional investigations are needed to determine the risk of infection/
      colonization with resistant organisms in this population.

PMID- 8666764
TI  - Discriminatory power and usefulness of pulsed-field gel electrophoresis in
      epidemiological studies of Pseudomonas aeruginosa.
AB  - We assessed the discriminatory power of pulsed-field gel electrophoresis (PFGE)
      for the analysis of DNA restriction fragment length polymorphism (RFLP) in
      Pseudomonas aeruginosa. We determined DraI PFGE-RFLP of DNA of unrelated clinical
      and environmental strains, and clinical strains isolated from two intensive care
      units of the Besancon University Hospital. The typeability and reproducibility
      was 100%. The discriminatory index was 0.998, and the DNA patterns were stable in
      vitro and in vivo. There was a very low correlation between PFGE-RFLP and
      traditional typing methods. The typeability, reproducibility, the high
      discriminatory power and the stability of PFGE-RFLP make this a valuable method
      to be used in conjunction with serotyping. Further standardization and
      quantitative interpretation are possible and should lead to this technique
      becoming a library typing system.

PMID- 8666765
TI  - Efficacy of hospital infection control in Thailand 1988-1992.
AB  - Hospital infection control in Thailand was initiated in 1971, but it was not
      until 1987 that active infection control activities actually started. To evaluate
      the efficacy of the infection control programme, two national prevalence studies
      of hospital acquired infection (HAI) were undertaken. The HAI prevalence rate in
      1988 was 11.7%; this was reduced to 7.3% four years later. The reduction of HAI
      was found in hospitals of all sizes, in all types of infection and almost all
      services. This reduction happened despite a shortage of infection control
      personnel. Co-operation of administrators, doctors and nurses is essential for
      success in HAI control. Such co-operation has been successfully created by the
      Nosocomial Infection Control Group of Thailand.

PMID- 8666766
TI  - Low incidence of quinolone resistance in gram-negative bacteria after five-years
      use of ofloxacin in prophylaxis during afebrile neutropenia.

PMID- 8666767
TI  - Comparison of chlorine and chlorine dioxide disinfection for control of
      Legionella in a hospital potable water supply.

PMID- 8666768
TI  - Creative infection control.
AB  - In spite of the widespread use of educational programmes, there still remains a
      low staff knowledge and non-compliance of infection control policies. In order to
      overcome these problems we have attempted to increase interest and raise
      awareness of infection control by introducing a motivational programme termed
      Creative Infection Control. Some of the activities are illustrated and are
      loosely structured, and rely largely on humour and intergroup competition. These
      methods are based on sound psychological principles with an emphasis on adult
      learning theory. Objective measures indicate that such programmes can
      significantly influence infection control outcomes.

PMID- 8666769
TI  - Contamination of central venous catheters. The skin insertion wound is a major
      source of contamination.
AB  - In a prospective controlled trial we compared the rates of catheter-tip
      contamination in central venous catheters inserted with or without skin contact.
      The study was designed so that each patient was their own control. All patients
      had a single-lumen central venous catheter and a Swan-Gantz sheet inserted
      through the skin. A Swan-Gantz catheter was inserted and retracted through the
      sheet thus avoiding contact with skin or subcutaneous tissue. Catheter-tip
      cultures were performed on removal of catheters. Thirty-three Swan-Gantz
      catheters were cultured and all were sterile. In the corresponding 33 sheets 16
      (48.6%) yielded bacterial growth. Four of the sheets showed growth of more than
      15 cfu. In the 26 single-lumen catheters, eight (30.8%) catheter-tips grew
      bacteria, and four of them had more than 15 colonies. The study supports the
      theory that the skin-insertion wound is a major source of catheter-contamination.

PMID- 8666770
TI  - Signaling through CD28/CTLA-4 family receptors: puzzling participation of
      phosphatidylinositol-3 kinase.

PMID- 8666771
TI  - TCR-mediated death of mature T lymphocytes occurs in the absence of p53.
AB  - The p53 protein plays an important role in various forms of thymocyte apoptosis,
      however its role in mature T lymphocyte death caused by TCR stimulation has not
      been examined. We demonstrate here that T cell blasts derived from mice
      containing a germ-line deficiency of the p53 tumor suppressor gene are
      susceptible to TCR-induced apoptosis to the same degree as wild-type T cells. TCR
      stimulation of both resting and proliferatingT cells results in up-regulated
      expression of the p53-induced genes Bax and p21, and the induction of these genes
      appears reduced in T cells that are deficient in p53. Thus, while activation of
      p53-dependent genes following TCR stimulation is defective in p53-/- T cells,
      there is no impairment in their ability to undergo apoptosis. These results
      suggest that TCR-mediated apoptosis of mature T cells takes place via a pathway
      that is independent of p53.

PMID- 8666772
TI  - Epicutaneous exposure of protein antigen induces a predominant Th2-like response
      with high IgE production in mice.
AB  - Hapten-induced contact hypersensitivity has been well-characterized in humans as
      well as in animal models. However, it is not clear whether or not protein Ag can
      directly sensitize epicutaneously and induce a primary immune response. We
      demonstrated in this study, for the first time, that through epicutaneous
      exposure protein Ag in the absence of adjuvant sensitizes animals and induces a
      predominant Th2-like response. Furthermore, mice receiving repeated protein Ag
      sustained elevated levels of specific IgE. This animal model can be used to
      investigate the molecular mechanism controlling the differential Th1/Th2
      development in skin diseases.

PMID- 8666773
TI  - Intracellular signaling pathways involved in the induction of apoptosis in
      immature thymic T lymphocytes.
AB  - We describe a novel technique for studying the signaling pathways that control
      thymocyte negative selection which maintains the essential interactions between
      thymocytes and thymic stromal cells. Bisected lobes from newborn mouse thymus are
      maintained in organ culture for up to 36 h, and the thymocytes analyzed by flow
      cytometry. Inclusion of [3H]inositol during culture allows measurements of
      phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) hydrolysis and inositol
      phosphate accumulation. Using this technique we have compared the thymocyte
      responses induced by anti-CD3, anti-Fas, Con A, and beta-adrenergic stimulation.
      We show that PtdIns(4,5)P2 hydrolysis precedes anti-CD3-induced thymocyte
      apoptosis, but not the apoptosis induced by anti-Fas. In contrast, Con A
      stimulates PtdIns(4,5)P2 hydrolysis, but does not induce thymocyte apoptosis.
      Anti-CD3, anti-Fas, and Con A all fail to change thymic cAMP levels, but beta
      adrenergic stimulation causes a large increase in intracellular cAMP, and agents
      that elevate cAMP induce thymocyte apoptosis. Inhibition of protein synthesis
      (with cycloheximide or emetine) prevents the apoptosis induced by anti-CD3 and
      elevated cAMP, but not that induced by anti-Fas, whereas protease inhibition
      (with 3,4-dichloroisocoumarin or N(alpha)-tosyl-phenylalanine chloromethyl
      ketone) prevents the apoptosis caused by all of the effective stimuli. These
      results offer three important conclusions. First, activation of a variety of
      different signaling pathways can bring about thymocyte apoptosis. Second,
      ligation of the thymocyte TCR/CD3 complex provokes PtdIns(4,5)P2 hydrolysis, but
      signaling through this pathway alone does not necessarily lead to apoptosis.
      Third, by whichever signaling pathway the response is initiated, the activity of
      one or more protease enzymes appears to form an essential component in the final
      common pathway leading to apoptosis.

PMID- 8666774
TI  - CD95 (Fas/Apo-1)-induced apoptosis results in loss of glucose transporter
      function.
AB  - Treatment of activated human T cells with CD95 (Fas/Apo-1) ligand or Abs against
      CD95 results in apoptotic cell death. Although cellular responses to CD95
      ligation have been described in some detail, the early molecular events that
      result in T cell death are only now beginning to be elucidated. Using Jurkat
      cells as a model of activated human T cells, we have investigated the effects of
      CD95 ligation on glucose transport and on glucose transporter function. We show
      that within minutes of CD95 activation, the ability to transport glucose across
      the plasma membrane is compromised and that transient exposure to Abs against
      CD95 for as little as 3 min results in reduced glucose transport and 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) responses measured at
      16 h. The effects of CD95 ligation on glucose transport are shown to be
      associated with loss of affinity of glucose transporters for glucose without
      altered maximum velocity and without changes in the cell surface expression of
      Glut 1, the predominant glucose transporter isotype on Jurkat cells. These
      results support a model of CD95 induced cell death that, at least in its early
      stages, does not depend on signaling to the nucleus or on macromolecular
      synthesis. Acute regulation of glucose transport is proposed to be an early
      effector mechanism in CD95-induced apoptotic cell death.

PMID- 8666775
TI  - TCR-independent activation of human CD4+ 45RO- T cells by anti-CD28 plus IL-2:
      Induction of clonal expansion and priming for a Th2 phenotype.
AB  - In this study we show that uncommitted human CD4+ CD45RA+ RO- CD25- CD71- HLA-DR-
      T cells can be primed for a Th2 phenotype before they encounter TCR signals and
      before they are exposed to IL-4. We found that >99% of uncommitted T cells
      proliferated upon costimulation by immobilized anti-CD3 plus anti-CD28 mAbs and
      differentiated into pure Th1 cells. In contrast, uncommitted T cells did not
      respond to stimulation by either anti-CD3 or anti-CD28, or by IL-2 alone.
      Interestingly, 5% of uncommitted T cells proliferated efficiently in response to
      stimulation by immobilized anti-CD28 plus IL-2 (in the absence of TCR/CD3
      signals) and differentiated into pure Th2 "precursor" cells. Like murine CD4+
      NK1.1+ T cells, human Th2 precursors promptly expressed mRNA for Th2 cytokines
      upon stimulation via the TCR/CD3 complex by anti-CD3 mAb or staphylococcal
      enterotoxin B, and secreted up to 50 ng of IL-4, IL-5, and IL-13 per 10(6) cells.
      Th2 "precursors" developed only in the complete absence of IL-4, as addition of
      0.1 U (5 pg) of exogenous IL-4 suppressed their clonal expansion by >90%, whereas
      addition of neutralizing anti-IL-4 mAb had no effect. Together these results
      suggest that, in vivo, a significant fraction of uncommitted T cells may be
      primed for a Th2 phenotype independent of Ag and IL-4 if they are exposed to Th1
      cell-derived IL-2 and simultaneously interact with accessory cells bearing the
      natural CD28 ligands B7-1 and B7-2. When stimulated by specific Ag, such primed
      Th2 precursor cells may provide a source of IL-4 to promote Th2 immunity.

PMID- 8666776
TI  - Inability to produce IL-6 is a functional feature of human germinal center B
      lymphocytes.
AB  - In response to Ag encounter, B lymphocytes undergo a complex maturation process
      yielding phenotypically distinct subpopulations that are located in highly
      organized compartments of secondary lymphoid organs. This study describes the
      patterns of cytokine secretion of naive, memory, and germinal center (GC) human
      tonsillar B lymphocytes, activated either through CD40 or B cell receptor or with
      Staphylococcus aureus Cowan I particles. The three B cell subpopulations produced
      comparable levels of IL-10 and TNF-alpha, regardless of the stimulation pathway.
      Interestingly, activated GC B lymphocytes fail to express IL-6, as determined
      both at mRNA and at protein levels, whereas both naive and memory B cells can be
      induced to secrete IL-6. Likewise, naive B lymphocytes undergoing dual ligation
      of CD40 and B cell receptor fail to express IL-6, since they acquire a GC-like
      phenotype. IL-6 receptors are up-regulated on both ex vivo-purified GC B
      lymphocytes and in vitro generated GC-like B cells, following CD40 activation.
      Consistent with this, addition of exogenous IL-6 sustains growth of CD40
      stimulated GC B lymphocytes. Taken together, these results demonstrate that loss
      of IL-6 secretion is a functional characteristic of human GC B lymphocytes. The
      swap from an autocrine to a paracrine IL-6 response may permit a better control
      of B cell growth and differentiation during the germinal center reaction.

PMID- 8666777
TI  - Adoptively transferred CD4+ lymphocytes from CD8 -/- mice are sufficient to
      mediate the rejection of MHC class II or class I disparate skin grafts.
AB  - Recent studies revealed that CD4+ cells initiate allograft rejection through
      direct recognition of allogeneic MHC class II Ags and indirect recognition of MHC
      peptides processed by self APCs. Both pathways were shown to help CD8+ cells that
      eventually lysed allogeneic MHC class I-presenting targets. There was little
      evidence, however, that CD4+ cells are sufficient for graft rejection. We studied
      skin graft rejection by CD8-deficient (CD8 -/-) mice. We showed that BALB/cJ(H
      2d) CD8 -/- mice could reject allogeneic skin from C57BL/6J(H-2b) mice deficient
      in MHC class I or in MHC class II Ags. To understand the role of CD4+ cells in
      this process, we isolated them from CD8 -/- mice and transferred them to BALB/cJ
      nude mice that had been grafted with allogeneic skin (H-2b) from animals
      deficient in MHC class I or MHC class II. Nude mice injected with CD4+ cells
      rejected MHC class II and, albeit more slowly, MHC class I disparate skins. We
      showed in vitro evidence that CD4+ cells were not cytotoxic toward MHC class I or
      MHC class II disparate targets and that they recognized MHC class I allogeneic
      targets through indirect recognition. CD4+ cells produced Th1 cytokines, but not
      IL-4, following stimulation with allogeneic cells. Furthermore, intragraft TNF
      alpha was elevated in skin grafted onto nude mice reconstituted with CD4+ cells
      compared with nonreconstituted mice. This suggests that MHC class II- or MHC
      class I-guided CD4+ cells alone are sufficient to induce rejection by the
      generation of cytokine-induced lesions.

PMID- 8666778
TI  - Complete TCR-delta rearrangements and partial (D-J) recombination of the TCR-beta
      locus in CD34+7+ precursors from human cord blood.
AB  - In the neonatal human thymus, early immature precursors co-express CD34 and CD7
      cell surface Ags, and we have recently shown that its most primitive CD34+7+1-
      fraction includes TCR-beta-rearranging cells. Bone marrow and cord blood also
      contain a CD34+7+ population. Although this population is heterogeneous in terms
      of both phenotype and differentiation capacities, it may include T cell-committed
      thymus colonizing precursors (prothymocytes). Recently, it has been shown in the
      mouse that initiation of TCR-beta rearrangements is not restricted to early
      thymocytes. In the present study, we examined the TCR-beta and TCR-delta
      rearrangement and transcription status of cord blood CD34+7- and CD34+7+
      subpopulations. RNA and DNA were isolated from these cell subsets purified by two
      consecutive rounds of fluorescence-activated cell sorting from CD3-depleted cord
      blood cells. Using D-J(beta) or V-J(beta) primer sets and genomic DNA PCR
      amplification, we showed that CD34+7+, but not CD34+7-, contained D-J(beta)
      rearrangements without concomitant V-D(beta) recombination. These partial TCR
      beta rearrangements within CD34+7+ progenitors were also confirmed at the
      transcriptional level. Furthermore, whereas none of the CD34+ cord blood cell
      fraction expressed TCR-alpha transcripts, mature V(delta)1-C(delta) mRNA could be
      amplified from the CD34+7+ subset. The TdT gene was also transcriptionally active
      in CD34+7+ cells, thus confirming their lymphoid progenitor content. These data
      indicate that cord blood CD34+7+ cells, like CD34+7+1- neonatal thymocytes, can
      initiate TCR-beta gene recombination, reinforcing the idea that T cell commitment
      may occur before prothymocyte migration to the thymus.

PMID- 8666779
TI  - Vasoactive intestinal peptide and pituitary adenylate cyclase-activating
      polypeptide-38 inhibit IL-10 production in murine T lymphocytes.
AB  - Vasoactive intestinal peptide (VIP), a neuropeptide present in the peptidergic
      innervation of lymphoid organs and expressed in thymocytes and peripheral
      lymphocytes has been previously reported to modulate cytokine expression in T
      lymphocytes. In this study, we investigated the effects of VIP and of the
      structurally related neuropeptide PACAP-38 on the expression of IL-10 in murine
      lymphocyte cultures. Both neuropeptides inhibit IL-10 production by spleen cells
      or thymocytes activated via the TCR-associated CD3 complex in a similar dose
      response manner. The inhibition is specific, presumably mediated through the VIP
      R1, and maximum inhibitory levels are achieved within the first 5 to 15 min of
      exposure to VIP or PACAP-38. CD4+ T cells function as direct cellular targets for
      the two neuropeptides. The fact that VIP, PACAP-38, and forskolin, all known cAMP
      inducers, also inhibit IL-10 production, suggests the participation of cAMP in
      signal transduction. VIP and PACAP-38 regulate transcriptional expression of IL
      10, since IL-10 steady state mRNA levels are significantly reduced by treatment
      with the two neuropeptides. These results expand the range of neuroendocrine
      regulated cytokines and support the idea that neuropeptides such as VIP and
      PACAP, which are released or produced in the local lymphoid microenvironment and
      specifically modulate the expression of various cytokines, may participate in the
      intricate cytokine network controlling local immune responses.

PMID- 8666780
TI  - Distinct effects of recombinant cholera toxin B subunit and holotoxin on
      different stages of class II MHC antigen processing and presentation by
      macrophages.
AB  - Cholera toxin (CT) is a potent mucosal adjuvant with enhancing effects on Ag
      presentation, although the mechanisms of its adjuvanticity remain poorly
      understood. Using an in vitro Ag presentation assay, we found CT and recombinant
      B subunit (rCTB) to have distinct effects on different stages of processing and
      class II MHC (MHC-II)-restricted presentation of hen egg lysozyme (HEL). CT
      treatment of macrophages resulted in enhanced presentation of soluble HEL(48-61)
      peptide to3A9 hybridoma cells. However, CT had inhibitory effects on
      intracellular processing of soluble native Ag. Thus, CT inhibited presentation
      when added prior to HEL, whereas presentation was enhanced when CT was added
      after HEL exposure and the generation of peptide-MHC-II complexes. Pretreatment
      of macrophages with CT also markedly inhibited phagocytic processing of a Crl-HEL
      fusion protein (containing the HEL(48-61) epitope) expressed in intact bacteria
      (Escherichia coli HB101.Crl-HEL or Salmonella typhimurium 14028s.Crl-HEL),
      whereas addition of CT to macrophages after a 2-h incubation with the bacteria
      again enhanced presentation. CT produced little effect on overall uptake and
      catabolism of radiolabeled HEL or HB101.Crl-HEL. In contrast to the holotoxin,
      purified rCTB subunit did not inhibit intracellular processing of soluble or
      bacterial Ag, although it similarly enhanced the presentation of surface HEL-(48
      61)-I-Ak complexes to 3A9 cells. These data suggest that the inhibitory effects
      of CT on Ag processing are mediated by the A subunit.

PMID- 8666781
TI  - Inactivation of the small GTP binding protein Rho induces multinucleate cell
      formation and apoptosis in murine T lymphoma EL4.
AB  - The small G-protein Rho regulates the actin microfilament-dependent cytoskeleton.
      Exoenzyme C3 of Clostridium botulinum ADP-ribosylates Rho at Asn41, a
      modification that functionally inactivates Rho. Using a Sindbis virus-based
      transient gene expression system, we studied the role of Rho in murine EL4 T
      lymphoma cells. We generated a double subgenomic infectious Sindbis virus
      (dsSIN:C3) recombinant which expressed C3 in >95% of EL4 cells. This
      intracellular C3 resulted in modification and inactivation of virtually all
      endogenous Rho. dsSIN:C3 infection led to the formation of multinucleate cells,
      likely by inhibiting the actin microfilament-dependent step of cytokinesis.
      Intriguingly, in spite of the inhibition of cytokinesis, karyokinesis continued,
      with the result that cells containing a nuclear DNA content as high as 16N (eight
      nuclei) were observed. In addition, dsSIN:C3-mediated inactivation of Rho was a
      potent activator of apoptosis in EL4 cells. To discern whether the formation of
      multinucleate cells was responsible for the activation of apoptosis, 5
      fluorouracil (5-FUra) was used to induce cell cycle arrest. As expected, EL4
      cells treated with 5-FUra were prevented from forming multinucleate cells upon
      infection with dsSIN:C3. dsSIN:C3 infection, however, still caused marked
      apoptosis in 5-FUra-treated cells, indicating that this activation of apoptosis
      was independent of multinucleate cell formation.

PMID- 8666782
TI  - Regulation of CTLA-4 expression during T cell activation.
AB  - T cell activation requires at least two distinct signals, including signaling via
      the Ag-specific TCR and a costimulatory pathway. The best characterized
      costimulatory pathway involves the CD28 molecule, which is expressed
      constitutively on T cells and binds the family of B7 counter-receptors on APCs.
      Inhibition of this costimulatory pathway prevents T cell activation and can lead
      to long-term T cell unresponsiveness or anergy. In contrast, CTLA4, which is
      homologous to CD28, has been shown to be a negative regulator of T cell
      activation. The CTLA4 molecule is not expressed on resting T cells, but is
      induced after the initial steps of T cell activation. To address the regulation
      of CTLA4 expression, we have analyzed CTLA4 at the level of cell surface
      expression, mRNA, rate of transcription, and rate of decay of message. Nuclear
      runoff results show an increase in the rate of transcription following T cell
      activation. Our analyses of non-T cells, including B cells, mastocytoma, and
      fibroblasts, by Northern blot analysis detect only T cell expression of CTLA4.
      Reporter gene analysis indicates that 335 bp of upstream CTLA4 sequence are
      sufficient to control inducibility. We have identified important regulatory
      regions that control inducible and cell-specific CTLA4 expression. These results
      also suggest that both positive and negative response elements modulate the
      transcriptional regulation of CTLA4 gene expression. Understanding the regulation
      of CTLA4 should provide insight into the regulation of T cell activation at the
      molecular level.

PMID- 8666783
TI  - Modulation of the expression of the IFN-gamma receptor beta-chain controls
      responsiveness to IFN-gamma in human peripheral blood T cells.
AB  - IFN-gamma has potent antiproliferative and apoptotic effects in T cells that are
      important in determining T cell development and polarized differentiation.
      Therefore, any event that enables T cells to become less responsive to IFN- gamma
      may potentially alter immune responsiveness to Ag. In this work, we show that
      human peripheral blood T cells that are stimulated through the TCR and expanded
      with IL-2 are unresponsive to IFN-gamma, as determined by a lack of activation of
      jak kinases and the transcription factor, STAT1(alpha), a signal transducer and
      activator of transcription. This nonresponsiveness occurs because of a lack of
      expression of the beta- chain (accessory factor) of the IFN-gamma receptor, while
      at the same time maintaining IFN-gamma receptor alpha-chain expression.
      Expression of the beta-chain can be restored by secondary TCR ligation or PMA
      treatment. T cell blasts treated with PMA are now responsive to IFN-gamma. When
      freshly isolated, highly enriched (>98%) T cells are examined for IFN-gamma
      responsiveness; these cells can respond to IFN-gamma and express beta-chain.
      Therefore, as T cells progress from primary TCR activation through IL-2-dependent
      proliferation, followed by secondary TCR stimulation, their responsiveness to IFN
      gamma varies, and this may affect their ability to participate in an ongoing
      immune response.

PMID- 8666785
TI  - A novel substrate-binding pocket interaction restricts the specificity of the
      human NK cell-specific serine protease, Met-ase-1.
AB  - Human Met-ase-1 is a NK cell-specific member of a family of serine proteases
      (granzymes) that participate in target cell death inflicted by cytotoxic
      lymphocytes. This granzyme is predicted to cleave to the carboxyl side of long
      narrow hydrophobic amino acids (such as methionine), but not large, bulky
      hydrophobic amino acids (such as phenylalanine). To study the key structural
      features that confer this unusual serine protease specificity, active recombinant
      human Met-ase-1 was expressed in COS-7 cells. Protease assays of transfected COS
      7 cell lysates provided evidence that an activation prohexapeptide normally
      regulates processing of this granzyme in NK cells. Recombinant human Met-ase-1
      cleaved thiobenzylester substrates specifically after methionine, norleucine, or
      leucine residues in the primary substrate site (P1). Two key residues of human
      Met-ase-1, Lys179 Met (approximately chymotrypsin CHA192) and Ser201Gly
      (approximately CHA216), were mutated based upon a model structure derived from
      the crystal structure of chymotrypsin A. These mutants had reduced activity for
      substrate containing methionine at P1, but acquired chymase activity for
      phenylalanine at P1. Lys179 Met and Ser201Gly in the substrate-binding pocket of
      human Met-ase-1 restrict the preference of this granzyme for long narrow
      hydrophobic amino acids in the P1. A potential hydrogen-bonding interaction
      between these two residues on opposing sides of the substrate-binding pocket
      represents a novel molecular mechanism by which lymphocyte serine proteases might
      provide greater substrate specificity.

PMID- 8666784
TI  - Inhibition of constitutive serine phosphatase activity in T lymphoma cells
      results in phosphorylation of pp19/cofilin and induces apoptosis.
AB  - In untransformed T lymphocytes, pp19/cofilin, a cytoplasmic actin-binding
      protein, undergoes dephosphorylation and nuclear translocation in response to
      costimulation through accessory receptors (e.g., CD2), but not following TCR/CD3
      triggering. In malignant T lymphoma cells, dephosphorylation and nuclear
      translocation of pp19/cofilin occur spontaneously through constitutive activation
      of a serine phosphatase. Blockade of these processes by the serine phosphatase
      inhibitor okadaic acid leads to apoptosis. Moreover, lowering the intracellular
      pp19/cofilin concentrations by antisense-cofilin transfection results in reduced
      cloning efficiencies. These findings provide support for the view that
      pp19/cofilin plays a critical role in the growth and survival of both
      untransformed and malignant T lymphocytes.

PMID- 8666787
TI  - pH dependence of MHC class I-restricted peptide presentation.
AB  - The function of MHC class I molecules is to bind and present antigenic peptides
      to cytotoxic T cells. Here, we report that class I-restricted peptide
      presentation is strongly pH dependent. The presentation of some peptides was
      enhanced at acidic pH, whereas the presentation of others was inhibited.
      Biochemical peptide-MHC class I binding assays demonstrated that peptide-MHC
      class I complexes are more stable at neutral pH than at acidic pH. We suggest
      that acid-dependent peptide dissociation can generate empty class I molecules and
      that the resulting binding potential can be exploited by a subset of peptide-MHC
      class I combinations, in some cases leading to considerable peptide exchange. We
      further speculate that the relative instability of peptide-class I complexes
      under acidic conditions may affect the outcome of class I-restricted Ag
      presentation, as less stably associated peptides may dissociate from class I
      during passage of the acidic trans-Golgi network, and therefore may not be
      presented. Finally, our results may in part explain how endocytosed proteins can
      be presented by MHC class I molecules to cytotoxic T cells.

PMID- 8666786
TI  - Roles of proteasomes, transporter for antigen presentation (TAP), and beta 2
      microglobulin in the processing of bacterial or particulate antigens via an
      alternate class I MHC processing pathway.
AB  - Latex-OVA and bacteria expressing an OVA fusion protein were processed by
      macrophages via an alternate class I MHC (MHC-I) processing pathway to present
      OVA(257-264):Kb. This pathway was resistant to dipeptide aldehyde proteasome
      inhibitors and brefeldin A, unlike the cytosolic MHC-I pathway. TAP1-/-
      macrophages exhibited decreases in cell surface peptide-receptive MHC-I and
      binding of extracellular peptide during transient incubations. This may explain
      an apparent influence of TAP on alternate MHC-I processing. Alternate MHC-I
      processing by TAP1-/- cells was enhanced by preincubation at 26 degrees C or with
      beta 2-microglobulin to increase peptide-receptive MHC-I. Thus, peptides may bind
      to MHC-I within post-Golgi vacuolar organelles accessible to exogenous beta 2
      microglobulin or on the cell surface (following peptide regurgitation).

PMID- 8666789
TI  - TAP-independent selection of CD8+ intestinal intraepithelial lymphocytes.
AB  - Intestinal intraepithelial lymphocytes (IEL) are mostly CD8 single positive T
      cells. IEL with a TCR-alpha(beta) that are CD8 single positive are absent from
      beta(2)-microglobulin (beta(2)m)-deficient mice, consistent with the idea that
      these IEL, like other TCR-alpha(beta)+, CD8+ T cells, require class I molecules
      for positive selection. In contrast, here we show that substantial numbers of TCR
      alpha(beta)+, CD8 single positive IEL are present in mice deficient for the
      transporter associated with Ag processing 1 (TAP 1) gene, although T cells with
      this phenotype are absent from thymus, spleen, and lymph nodes of these same
      mice. The majority of TCR-alpha(beta)+, CD8 single positive IEL in TAP-deficient
      mice expresses CD8 molecules composed of alpha(alpha) homodimers and they express
      a diverse set of V(beta) gene segments. In addition, the number of TCR
      alpha(beta)+, CD4/CD8 double positive IEL is decreased in beta(2)m-deficient mice
      but not in TAP-deficient mice. The dependence of the two TCR-alpha(beta)+ IEL
      populations that express CD8alpha(alpha) homodimers on beta(2)m as opposed to TAP
      molecules is striking. It suggests that TAP-independent but beta(2)m-requiring
      nonclassical class I molecules expressed by cells in the intestine, such as the
      thymus leukemia Ag and CD1, could play a pivotal role in the development and/or
      the accumulation of major subpopulations of TCR-alpha(beta)+ IEL.

PMID- 8666790
TI  - EBV induces proliferation of immature human thymocytes in an IL-2-mediated
      response.
AB  - The receptor for EBV, CD21 is expressed on a population of immature human
      thymocytes and facilitates infection of these cells by EBV. Thymocytes infected
      by EBV become responsive to exogenous rIL-2- or CD2-mediated stimulation in
      vitro. To address whether such costimulation may be provided by thymic presenting
      cells and to study the cellular effects of EBV infection, the present work
      utilizes thymocyte cultures containing autologous thymic presenting cells. In the
      presence of these presenting cells, EBV induces proliferation of thymocytes. EBV
      infection promotes the formation of adhesions between two populations of cells in
      an APC responder fashion, and separation of these two populations abrogates the
      proliferative response to EBV. The response is mediated by IL-2 because Ab
      blocking of the IL-2R inhibits proliferation as does cyclosporin A. EBV promotes
      an expansion in the number of CD4+8+ thymocytes, and the proliferating population
      is vulnerable to TCR/CD3-generated signals, indicating that the responding cells
      are phenotypically and functionally immature. Finally, addition of exogenous IL-2
      to EBV-exposed thymocytes promotes a second wave of proliferation. Phenotypic
      characterization of the EBV-induced, IL-2-responding cells shows them to express
      reduced levels of CD1 and a transitional CD4(high)8(low) phenotype. These data
      characterize the cellular response to EBV infection in thymocytes and may offer
      insight into EBV-associated T lineage malignancies and autoimmune disorders.

PMID- 8666788
TI  - Hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice exhibit
      T cell apoptosis defect.
AB  - We previously demonstrated that hematopoietic cell protein-tyrosine phosphatase
      is one of the molecules that can transduce Fas-mediated apoptosis signals in
      lymphoid cells. The present study analyzed the effect of defective Fas signaling
      on the T cell phenotype and apoptosis function in hematopoietic cell protein
      tyrosine phosphatase-deficient motheaten mice. Viable motheaten (me(v)/me(v))
      mice exhibited increased T cell proliferation and defective activation-induced
      apoptosis of Fas+ T cells in the lymph node, which was not ascribed to defective
      Fas ligand function. Furthermore, the Fas-mediated apoptosis defect in activated
      T cells from me(v)/me(v) mice was confirmed by their resistance to anti-Fas
      induced apoptosis. No protein tyrosine dephosphorylation signal was delivered
      after anti-Fas cross-linking in the lymph node cells of me(v)/me(v) mice as
      revealed by 32Pi labeling of protein phosphatase substrates. The defective
      activation-induced apoptosis of Fas+ T cells in me(v)/me(v) mice led to
      lymphadenopathy with an accumulation of CD4- CD8- B220+ CD3+ T cells. Pneumonitis
      in me(v)/me(v) mice was associated with infiltration of cycling T cells detected
      by bromodeoxyuridine uptake in vivo. Thus, T cells from me(v)/me(v) mice are
      resistant to Fas-mediated apoptosis which results in lymphoproliferative disease
      and tissue infiltration.

PMID- 8666791
TI  - Expression of HLA-G in human mononuclear phagocytes and selective induction by
      IFN-gamma.
AB  - In situ hybridization studies have shown that at early but not late stages of
      gestation, human placental stromal cells, many of which are macrophages (Hofbauer
      cells), contain HLA-G message. In this study, the HLA-G protein was identified in
      the macrophage-like stromal cells by immunohistochemistry using the anti-HLA-G
      mAb, 87G. Expression of the HLA-G gene was then analyzed in macrophage cell lines
      (U937, HL-60, THP-1) and blood monocytes. HLA-G mRNA identified by using reverse
      transcriptase PCR was consistent with production of a transcript containing
      intron 4, which codes for a soluble form of HLA-G. Low levels of HLA-G mRNA were
      identified in mononuclear phagocytes by Northern blot hybridization, and little
      if any HLA-G Ag was detectable. By contrast, essentially all of the cells
      displayed high levels of HLA-B/C H chains detected by the mAb, 4E, and B2m.
      Treatment of macrophage cell lines and monocytes with IFN-gamma increased steady
      state levels of HLA-G mRNA, stimulated higher levels of cell surface and
      intracellular HLA-G Ag in a dose-dependent manner, and increased the proportions
      of HLA-G relative to HLA-B/C. INF-alpha and IFN-beta enhanced steady-state levels
      of HLA-G mRNA and in some lines modestly increased the numbers of weakly positive
      cells but were poor inducers of cell-surface and intracellular HLA-G and did not
      increase HLA-G relative to HLA-B/C. Thus, mononuclear phagocytes express low
      levels of HLA-G mRNA and protein, and IFN-gamma selectively enhances expression
      of this HLA class Ib gene relative to HLA class Ia, which could influence the
      repertoire of peptides presented during embryogenesis as well as during
      inflammatory situations in adults. Soluble HLA-G might influence both fetal and
      maternal immune responses.

PMID- 8666792
TI  - Modulation of antigen presentation and class II expression by a class II
      associated invariant chain peptide.
AB  - During the process of MHC class II assembly, the class II-associated invariant
      chain peptide (CLIP) remains bound within the peptide binding groove until its
      subsequent removal, which is mediated by H-2 M. We have defined the functional
      role of CLIP, through saturation of the endosomal compartment with exogenous CLIP
      (85-101), resulting in reduced class II MHC on the surface of APCs and an impeded
      T cell response. Conversely, incubation of the same cells with immunogenic
      peptides or proteins resulted in an up-regulation of surface class II MHC. T
      cells from CLIP- plus Ag-immunized mice showed a marked decrease in Ag-specific
      response over that in mice primed with Ag alone. A B cell hybridoma, TA3 (H-2d,k)
      incubated with CLIP in vitro showed dramatically reduced MHC class II I-A surface
      expression. APCs derived from CLIP-immunized mice exhibited down-regulation of
      surface class II MHC, but not of CD45 (B220). Electrophoretic studies showed that
      the addition of exogenous CLIP resulted in a relative decrease in SDS-stable MHC
      class II heterodimers in TA3 cells. Studies with FITC-CLIP and FITC-OVA-(323-339)
      peptides demonstrated that exogenously added CLIP peptide does not bind to
      surface class II molecules via the endogenous route, whereas OVA peptide does.
      This suggests that exogenously added CLIP acts intracellularly, perhaps in the
      compartment where H-2 M intersects with class II molecules. These findings
      demonstrate the functional role of CLIP to regulate MHC class II-mediated Ag
      presentation in CD4+ T cell responses.

PMID- 8666793
TI  - The J chain gene is transcribed during B and T lymphopoiesis in humans.
AB  - In mice and chickens, J chain appears to be expressed only in activated B cells
      and plasma cells. In humans, studies based mainly on transformed cells suggest
      that J chain expression may initiate during earlier stages in B lineage
      differentiation. In the present study, we isolated a series of hematopoietic
      subpopulations from human fetal and adult tissues by immunofluorescence cell
      sorting and examined each subpopulation for J chain expression by reverse
      transcriptase-PCR. In fetal and adult bone marrow, J chain transcripts were
      detected at all stages of B lineage differentiation, including the progenitor
      (CD34+/CD19-) and pro-B (CD34+/CD19+) cell subpopulations. J chain mRNA was also
      detected during fetal thymocyte development: double negative (CD4-/CD8-) through
      single positive (CD4+ or CD8+) cell subpopulations. The J chain message was not
      detected in peripheral CD3+ T cells, CD14+ monocytes, and CD56+ NK cells from
      either fetal or adult samples. The nucleotide sequence of J chain PCR products
      from CD34+/CD19- bone marrow progenitors and CD4+/CD8- thymocytes proved
      identical to the previously reported sequence of functionally spliced J chain
      mRNA. These results suggest that the J chain gene is transcriptionally active
      during early stages of both B cell and T cell differentiation, before the
      expression of their respective Ag receptors.

PMID- 8666794
TI  - Isolation of low molecular mass polypeptide complementary DNA clones from
      primitive vertebrates. Implications for the origin of MHC class I-restricted
      antigen presentation.
AB  - Proteasomes are the multisubunit proteases thought to be involved in the
      generation of peptides presented by MHC class I molecules. When cells are
      stimulated with IFN-gamma, two MHC encoded subunits, LMP2 and LMP7, are
      incorporated into the proteasomal complex, presumably by displacing the
      housekeeping subunits, designated Y and X, respectively. These changes in the
      subunit composition appear to facilitate class I-mediated Ag presentation,
      presumably bu altering the cleavage specificities of the proteasome. Here we show
      that the cartilaginous fish, the most primitive class of vertebrates in which the
      MHC has been identified, have both LMP7 and X genes. Interestingly, nurse sharks,
      a member of the cartilaginous fish, appear to have two LMP7 genes, one encoding a
      typical LMP7 subunit and the other encoding a less typical one. In contrast, only
      cDNA clones with residues characteristic of X were identified in hagfishes and
      lampreys, the two extant members of the jawless fish in which no MHC has been
      identified. Pairwise amino acid sequence comparison and phylogenetic tree
      analysis showed that the subunits encoded by these clones were nearly equidistant
      from LMP7 and X, suggesting that the LMP7 gene might have emerged after the
      appearance of the jawless fish. Sequence comparison of the LMP7 and X/X-like
      subunits isolated from various vertebrate species showed that, unlike the X/X
      like subunit, the LMP7 subunit displays a striking interspecies sequence
      variability in the vicinity of its catalytic site.

PMID- 8666795
TI  - Induction of CIITA and modification of in vivo HLA-DR promoter occupancy in
      normal thymic epithelial cells treated with IFN-gamma: similarities and
      distinctions with respect to HLA-DR-constitutive B cells.
AB  - In this study, the IFN-gamma induction of MHC class II gene expression in primary
      cultures of thymic epithelial cells (TEC) was analyzed. This cellular system
      offers the advantage that MHC class II induction is studied in a "physiologic"
      cell lineage that, as a result of this expression within the thymus, is thought
      to participate to the selection and maturation of the T cells. It was found that
      the MHC class II gene expression was associated with the de novo transcription of
      the gene encoding the CIITA trans-activator, a crucial MHC class II gene
      regulatory factor. Furthermore, the anatomy of interaction between the MHC class
      II DRA promoter and corresponding binding factors was analyzed by in vivo DNAse I
      footprint. It was found that treatment with IFN-gamma induces changes in the
      occupancy of the DRA gene regulatory sequences by nuclear factors. The resulting
      occupancy displays strong similarities with the one observed in the MHC class II
      constitutive B cells, represented by both the Burkitt lymphoma line Raji and
      normal tonsil- derived B cells. However, some peculiar differences were observed
      between the TEC, either IFN-gamma-induced or not, and the constitutive B cells.
      These results suggest that both common mechanisms, such as the one mediated by
      the CIITA trans-activator, and distinct tissue-specific constraints contribute to
      the transcriptional control of constitutive and IFN-gamma-induced MHC class II
      gene expression.

PMID- 8666797
TI  - Studies of tum- peptide analogs define an alternative anchor that can be utilized
      by Ld ligands lacking the consensus P2 anchor.
AB  - To determine how peptides that lack a consensus binding motif interact with class
      I molecules, we have studied the binding of the tumor-associated tum- P91A 14-22
      (tum-) peptide to Ld. Previously, a proline at position 2 (P2) and a hydrophobic
      residue at P9 had been defined as anchors for Ld ligands. However, the tum-
      peptide lacks the P2 proline anchor. To compare how peptides with and without the
      P2 proline anchor bind to Ld, we analyzed the binding of monosubstituted
      analogues of the murine cytomegalovirus (MCMV) pp89 168-176 and the tum- peptides
      to Ld. As expected, the binding of both peptides was inhibited by substitutions
      at P9, the carboxyl-terminal anchor. As also predicted, the MCMV peptide was
      found to be dependent upon its P2 proline for binding to Ld. By contrast, the
      binding of the tum- peptide to Ld is dependent primarily on a P8 aspartate
      residue. Interestingly, the p2Ca peptide that is immunodominant in
      allorecognition of Ld also lacks the P2 proline anchor and has been shown to
      depend on residues near the carboxyl terminus for binding to Ld. Furthermore,
      both the p2Ca and the tum- peptides can bind to Ld as octamers. These combined
      studies suggest that there are at least two alternative manners by which peptides
      can bind to Ld. Although most Ld ligands bind using a P2 proline anchor, the tum-
      and p2Ca peptides bind using alternative anchors in the carboxyl-terminal region.

PMID- 8666796
TI  - Rat RT6.2 and mouse Rt6 locus 1 are NAD+: arginine ADP ribosyltransferases with
      auto-ADP ribosylation activity.
AB  - RT6 is a glycosylphosphatidylinositol-linked protein found on the surface of
      mature rat T lymphocytes. Cells that express RT6 have an immunoregulatory
      function and modulate the expression of autoimmune diabetes mellitus in the
      BioBreeding rat. A homologue of the rat RT6 gene, designated Rt6, has been
      identified in the mouse, but expression of mouse Rt6 protein has not been
      documented. Rat RT6 is known to be a nicotinamide adenine dinucleotide (NAD+)
      glycohydrolase. We now report that rat RT6.2 and recombinant mouse Rt6 locus 1
      proteins possess auto-ADP ribosylation activity. In addition, mouse Rt6 but not
      rat RT6, catalyzes the ADP ribosylation of exogenous acceptors such as histones.
      The ADP-ribosyl-protein bonds in auto-ADP-ribosylated rat RT6.2, auto-ADP
      ribosylated mouse Rt6, and ADP-ribosylhistone synthesized by Rt6 were stable to
      HgCl2 and HCl, but labile to NH2OH, consistent with ADP ribosylarginine linkages.
      To determine if these enzymatic activities could affect the function of rat T
      cells, the effect of substrate availability on lymphocyte proliferation was
      examined. An inverse correlation was observed between NAD+ concentration in the
      medium and the ability of rat T cells to respond to anti-CD3, ConA, and PMA plus
      ionomycin. The data suggest that lymphocyte surface ADP ribosyltransferases could
      be involved in signaling and immunoregulatory processes.

PMID- 8666799
TI  - Bias in the gamma delta T cell response to Listeria monocytogenes. V delta 6.3+
      cells are a major component of the gamma delta T cell response to Listeria
      monocytogenes.
AB  - Despite extensive research, the role that gamma delta T cells play in the immune
      response to infectious disease has yet to be established. Here we report the
      generation of a mAb specific for the V delta 6.3 TCR and investigate the gamma
      delta+ and V delta 6.3+ T cell responses to the intracellular bacterium Listeria
      monocytogenes in BALB/c mice. By infecting animals with various doses of Listeria
      and analyzing the components of the cellular immune response at the two primary
      sites of infection, the liver and spleen, we have shown that the kinetics,
      composition, and magnitude of the gamma delta and V delta 6.3 T cell responses
      are dependent upon the injected dose of bacteria and the organ in which the
      infection is established. At low doses of infection, the gamma delta T cell
      response occurs late in the disease course, while at high doses, the response is
      earlier and of greater magnitude, particularly in the liver. At all infectious
      doses and in both tissues, the V delta 6.3+ population predominates and together
      with V delta 4+ cells composes the bulk of the gamma delta T cell response.
      Changes in the morphology of gamma delta+ and V delta 6.3+ cells at the site of
      infection are consistent with cellular activation and suggest that these cells
      are active participants in the Listeria-induced immune response. The results of
      our study suggest that many features of the gamma delta T cell response to
      Listeria are dose and tissue related.

PMID- 8666798
TI  - Cloning of the cDNA for human IFN-gamma-inducing factor, expression in
      Escherichia coli, and studies on the biologic activities of the protein.
AB  - We have recently reported that a novel molecule, murine IFN-gamma-inducing factor
      (IGIF) produced by mouse liver cells, possesses potent biologic activities,
      including the induction of IFN-gamma production by spleen cells and the
      enhancement of NK cell cytotoxicity. In this paper, we report on the isolation of
      human IGIF cDNA clones from normal human liver cDNA libraries using murine IGIF
      cDNA as a probe. The amino acid sequence deduced from the human cDNA clones
      indicated a 193-amino acid precursor peptide and revealed 65% homology with that
      of murine IGIF. The amino acid sequence of IGIF also included an IL-1 signature
      like sequence. Subsequently, the cloned cDNA was expressed in Escherichia coli,
      and preliminary studies on the biologic activities of the recombinant protein
      were performed. The recombinant human IGIF induced IFN-gamma production by
      mitogen-stimulated PBMC and enhanced NK cell cytotoxicity, in a manner similar to
      murine IGIF. In addition, recombinant human IGIF also augmented granulocyte
      macrophage-CSF production and decreased IL-10 production, but had no effect on IL
      4 production by Con A-stimulated PBMC. Based on these pleiotropic effects of
      IGIF, we propose that this novel cytokine be designated as IL-18.

PMID- 8666800
TI  - IL-6-deficient mice exhibit normal mucosal IgA responses to local immunizations
      and Helicobacter felis infection.
AB  - Using IL-6-deficient (IL-6 -/-) or wild-type mice, we investigated whether IL-6
      is involved in the intestinal adjuvant activity of cholera toxin (CT) and to what
      extent IL-6 is required for mucosal IgA responses against soluble protein Ags or
      live Helicobacter felis infection. In naive IL-6 -/- mice we found normal total
      IgA levels in serum, bronchial and intestinal lavage and unaltered frequencies of
      IgA plasma cells in intestinal lamina propria. In Peyer's patches (PP) and
      mesenteric lymph nodes (MLN) IgA-producing cells were as frequent in IL-6 -/- as
      in wild-type mice. Immunohistochemical analysis of PP revealed germinal centers
      that co-localized IgA+ cells, indicating B cell activation and isotype switching
      in situ in the intestinal immune inductive site. Phenotypic analysis of the
      distribution of conventional B-2 cells (B220+CD5-/Mac-1-) and B-1 cells (B220+,
      CD5+/Mac-1+) in intestine-associated tissues gave comparable results in IL-6 -/-
      and wild-type mice. The ability to respond with mucosal IgA following oral and
      intranasal immunization with specific Ag, KLH or OVA, in the presence of CT
      adjuvant or to live H. felis infection was similar in IL-6 -/- and wild-type
      mice. CT exerted strong and comparable adjuvant functions in IL-6 -/- and wild
      type mice. Repeated oral immunizations with CT alone stimulated immune protection
      against CT-induced diarrhea in ligated loops that was of similar magnitude in IL
      6 -/- and wild-type mice. We conclude that, although IL-6 has been ascribed a
      crucial role in terminal differentiation of IgA B cells in vitro, we found no
      evidence to support the notion that IL-6 is critically required for IgA B cell
      development or specific mucosal IgA responses in vivo.

PMID- 8666801
TI  - Insight into the mechanism(s) through which TNF promotes the generation of T cell
      mediated antitumor cytotoxicity by tumor bearer splenic cells.
AB  - We have shown previously that addition of TNF to stimulation cultures of MOPC-315
      tumor bearer splenic cell suspensions containing metastatic tumor cells capable
      of secreting TGF-beta greatly enhances the generation of anti-MOPC-315 lytic
      activity by their CD8+ T cells. The current studies were undertaken to gain some
      insight into the mechanism(s) through which TNF potentiates the in vitro
      generation of anti-MOPC-315 cytotoxicity by such tumor bearer splenic cells. Here
      we show that TNF is capable of 1) preventing completely the inhibitory activity
      of TGF-beta for CTL generation when both cytokines are added at the time of
      initiation of a 5-day stimulation culture and 2) reversing at least part of the
      inhibitory activity of TGF-beta when TNF is added as late as 3 days after TGF
      beta addition. The costimulatory molecule B7-2 is shown here to be important for
      the realization of the potentiating activity of TNF for CTL generation by tumor
      bearer splenic cells. However, despite the importance of the B7-2 molecule, TNF
      does not mediate its immunopotentiating activity for CTL generation through up
      regulation in IL-2 production. In addition, we show here that GM-CSF, but not IL
      12, is important for the potentiating effect of TNF for CTL generation by tumor
      bearer splenic cells. Taken together, these studies identify several factors that
      are important for the realization of the potentiating effect of TNF for the in
      vitro generation of antitumor cytotoxicity by tumor-infiltrated splenic cells. It
      is not known at present, however, whether these factors utilize distinct and/or
      overlapping mechanisms in realizing the TNF effect.

PMID- 8666802
TI  - Neutralizing antibody responses elicited in mice immunized with recombinant
      bacillus Calmette-Guerin producing the Schistosoma mansoni glutathione S
      transferase.
AB  - Schistosomiasis is a group of severe parasitic diseases, in humans and domestic
      animals, that are especially of importance in the developing world. No
      efficacious vaccine is currently available. However, Ab-mediated immune responses
      against the 28-kDa glutathione S-transferase of Schistosoma mansoni (Sm28GST)
      appear to be involved in protection. This Ag was produced in recombinant
      Mycobacterium bovis bacillus Calmette-Guerin (BCG). The recombinant protein bound
      glutathione and expressed enzymatic activity, indicating that the active site of
      Sm28GST was folded properly. Single i.v., i.p., s.c., or intranasal immunizations
      with rBCG in BALB/c mice resulted in significant anti-SM28GST Ab responses, which
      were enhanced by a booster dose. The Ab responses remained high for at least 1 yr
      after immunization. Analyses of the isotype profiles indicated that i.v.
      immunized mice produced high titers of anti-Sm28GST IgG2a, and less IgG2b and
      IgG1. Mice immunized by the s.c. route initially also produced high levels of
      IgG2a and low titers of IgG1 and IgG2b, but the titers of the latter two isotypes
      increased gradually thereafter, tending toward a mixed profile. Intraperitoneal
      immunization provided a mixed profile directly after the first administration.
      High titers of anti-Sm28GST Abs also corresponded to high levels of
      neutralization of the enzymatic activity. These results indicate that rBCG
      induces strong IgG1, IgG2a, and IgG2b, and neutralizing Ab responses against
      Sm28GST, which has been found to correlate with protection against S. mansoni in
      humans.

PMID- 8666803
TI  - Presentation of the protective parasite antigen LACK by Leishmania-infected
      macrophages.
AB  - Macrophages are apparently the only cells that in vivo allow the growth of the
      intracellular pathogen Leishmania. They are thus generally considered as likely
      candidates for the presentation of parasite Ag to CD4+ T lymphocytes known to be
      involved in protective and counterprotective immune responses. In the present
      study, we examined whether mouse macrophages infected with Leishmania were
      capable of stimulating T cell hybrids and a T cell clone reacting with the
      previously identified protective Ag LACK (Leishmania homologue of receptors for
      Activated C Kinase). This parasite protein is expressed in both promastigote and
      amastigote stages of Leishmania. We found that IFN-gamma-treated macrophages
      recently infected with live Leishmania promastigotes were fully competent to
      activate LACK-reactive T cells. However, at later times of infection, permissive
      macrophages infected with promastigotes were no longer able to present LACK, in
      spite of the presence of numerous intracellular parasites. This punctual
      presentation of LACK was apparently linked with the destruction, at least
      partial, of the intracellular parasites. In contrast, macrophages infected with
      live Leishmania amastigotes were always unable to stimulate the LACK-specific T
      cells. Amastigote-infected macrophages could, however, reactivate the T cells if
      LACK-delta(1), a recombinant form of LACK, was added as an exogenous protein in
      the culture medium. Similar results were obtained with all combinations tested
      involving macrophages from various origins, different activating cytokines (IFN
      gamma, granulocyte-macrophage CSF, IL-4), several Leishmania species (L.
      amazonensis, L. major, L. donovani), and 15 different LACK-reactive T cell
      hybrids and clones. From these data, it is tempting to propose that the
      differentiation of promastigotes into amastigotes, which leads to a better
      survival of the parasites within macrophages, also allows them to go unnoticed by
      the immune system.

PMID- 8666804
TI  - Local intestinal immune responses to infections with Trichinella spiralis. Real
      time, continuous assay of cytokines in the intestinal (afferent) and efferent
      thoracic duct lymph of rats.
AB  - Levels of IL-4, IL-5, TNF-alpha, and IFN-gamma were quantitated in the intestinal
      (afferent) and efferent thoracic duct lymph of rats during the course (0 to 289
      h) of an infection with Trichinella spiralis. Intestinal lymph was collected by
      cannulating thoracic ducts of mesenteric lymphadenectomized animals. These
      studies showed that cytokines typical of a Th2 type (IL-4 and IL-5) and a Th1
      type (IFN-gamma) were simultaneously detected in the intestinal lymph during the
      first 8 days after infection. Worm expulsion (day 11 to 12) was associated with
      increased levels of IL-4 and IL-5 in the intestinal lymph. IL-5 levels rose as
      early as 15 to 20 h and remained elevated throughout the infection. IL-4 activity
      appeared in intestinal lymph 60 h after infection and reached peak levels during
      worm expulsion. Despite the predominantly Th2 nature of cytokine response, IFN
      gamma levels showed several cycles of high and low production during the course
      of infection. A comparison of cytokine levels between intestinal and efferent
      lymph values showed no significant differences in IL-4 or IL-5 levels suggesting
      no contribution by the mesenteric node to efferent lymph. However, IFN-gamma and
      TNF-alpha levels were lower in efferent lymph compared with intestinal lymph
      suggesting mesenteric node consumption. Adoptive transfer experiments showed that
      protective CD4+CD45RC- cells primed the gut for a more rapid TH2-type response
      that was faster than in a primary infection. In contrast, adoptive transfer of
      CD4+CD45RC+ cells primed the gut for a more rapid Th1-type(IFN-gamma) response.
      These studies demonstrate a novel method for measuring real-time changes in
      cytokine levels in the gut during the course of an active infection.

PMID- 8666805
TI  - Genetically determined differences in IL-10 and IFN-gamma responses correlate
      with clearance of Chlamydia trachomatis mouse pneumonitis infection.
AB  - Cytokine patterns elicited by infection are critical in the regulation of the
      adaptive immune response and in the resolution of infection. Using a murine model
      of pneumonia induced by intranasal inoculation with the Chlamydia trachomatis
      mouse pneumonitis (MoPn) biovar, we found that the patterns of immune responses
      and cytokine production by spleen cells were correlated with quantitative growth
      of MoPn in the lungs of C57BL/6 and BALB/c mice. Specifically, BALB/c (H-2d) mice
      had a significantly higher mortality rate and a slower clearance of the organism
      from the lungs than did C57BL/6 mice (H-2b). BALB/c mice exhibited higher IL-10
      production, higher IgG1 Ab responses, and less IFN-gamma production than C57BL/6
      mice, which showed higher IFN-gamma production, stronger delayed-type
      hypersensitivity (DTH) responses, and significantly less IL-10 production. In
      vivo neutralization of IL-10 in BALB/c mice with an anti-IL-10 mAB during MoPn
      infection significantly increased the DTH response and enhanced clearance of
      MoPn. These findings support the hypothesis that excessive IL-10 production in
      BALB/c mice inhibits Th1-like responses, including IFN-gamma expression and the
      DTH response following chlamydial infection and consequently delay infection
      resolution.

PMID- 8666806
TI  - Autocrine activation of hemopoietic progenitor-derived myelo-monocytic cells by
      IFN-gamma gene transfer.
AB  - Immunomodulatory cytokines have been used with success as adjunctive therapy in
      genetic disorders such as chronic granulomatous disease and infectious diseases
      such as leishmaniasis and leprosy. As the first step toward developing novel
      methods to deliver immunomodulatory cytokines, we used retrovirus-mediated
      somatic gene transfer techniques to produce IFN-gamma from human peripheral blood
      CD34+ hemopoietic progenitor (PBHP) cells. After transduction, the PBHP cells
      were made to differentiate toward myelo-monocytic lineages. Only the PBHP-derived
      myelo-monocytic cells that were transduced with the IFN-gamma cDNA produced IFN
      gamma(4 +/- 1.3 ng of IFN-gamma/10(6) PBHP cells.) Despite a reduction in the
      proliferation of IFN-gamma-transduced PBHP cells as well as a decrease in
      erythroid colony formation, there was an enhancement of monocyte differentiation
      and activation. Monocytes differentiated from the IFN-gamma-transduced PBHP cells
      demonstrated 1) up-regulation of MHC class I and II Ag expression, 2) increased
      Fc(gamma)RI expression, and 3) enhanced superoxide production in response to both
      opsonized zymosan (25-fold) and phorbol ester (3-fold). Furthermore, a functional
      response to a monocyte-specific chemokine, monocyte chemotactic protein-1
      (mobilization of intracellular Ca2+) was seen only in the IFN-gamma-transduced
      cells. Thus, PBHP cells transduced with IFN-gamma cDNA produce not only
      biologically active IFN-gamma, but also enhanced monocyte differentiation,
      resulting in an activated state that includes unique functions, such as
      responsiveness to monocyte chemotactic protein-1. These transduced activated
      monocytes may be specifically suited to cellular therapy requiring homing to
      sites of inflammation where their anti- microbicidal, cytotoxic and APC functions
      play an important role in host defense against foreign pathogens.

PMID- 8666807
TI  - TNF-alpha inactivation of collagen receptors: implications for fibroblast
      function and fibrosis.
AB  - TNF-alpha inhibits collagen synthesis and at high concentrations stimulates
      collagenase synthesis in fibroblasts. As fluid from chronic inflammatory lesions
      contains significant levels of TNF-alpha, it is puzzling why these lesions
      exhibit dense accumulations of disorganized collagen. In this study we determined
      if low concentrations of TNF-alpha may inhibit the collagen phagocytic pathway in
      fibroblasts and thereby contribute to fibrosis. Collagen phagocytosis was
      measured by flow cytometric assessment of internalized, fluorescent collagen
      beads. TNF-alpha induced a dose-dependent reduction (optimal dose: 40% at 10
      ng/ml; p<0.001) in the proportion of phagocytic cells and a twofold reduction of
      the number of internalized beads per cell but did not alter the total number of
      vital cells. TNF-alpha reduced by twofold the degradation of collagen films.
      Fluid flow shear-force assays demonstrated that TNF-alpha caused a 72% reduction
      (p < 0.05) in strong binding of collagen-coated beads to cells indicating that
      TNF-alpha may inactivate receptors and inhibit collagen binding. Furthermore, TNF
      alpha reduced cell contact area with collagen substrates by threefold and
      inhibited reattachment of trypsinized cells by fourfold. Although levels of
      collagen receptors were increased by TNF-alpha (53% increase in alpha(2) (beta)1
      integrin; p<0.001, 20% increase in alpha(1)beta(1)), the receptors were
      inactivated by the cytokine. The reduced phagocytic activity of TNF-alpha-treated
      cells was restored to control levels by treatment with the integrin-activating
      Abs A16G6 and JBS2. TNF-alpha inhibited focal adhesion formation and
      phosphotyrosine staining in focal adhesions. These effects were replicated by the
      tyrosine kinase inhibitor genistein, which also inhibited phagocytosis.
      Collectively, these data indicate that TNF-alpha inhibits adherence and
      phagocytosis of collagen. These effects are mediated by a reduction in the
      strength of alpha(2)beta(1) integrin binding to collagen, possibly through
      tyrosine kinases in focal adhesions. At low concentrations of TNF-alpha (10
      ng/ml) that are found in the periphery of chronic inflammatory lesions, we
      suggest that inhibition of the collagen phagocytic pathway may contribute to
      fibrosis.

PMID- 8666808
TI  - Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after
      mechanical injury to the brain.
AB  - By 24 h after mechanical trauma to the cerebral cortex, astroglial reaction
      begins and injury sites are infiltrated by activated mononuclear phagocytes
      derived from blood-borne monocytes and endogenous microglia. There is little
      information about cellular interactions between astrocytes and leukocytes during
      this process. We previously showed that murine astrocytes produce chemokines
      including monocyte chemoattractant protein-1 (MCP-1) during experimental
      autoimmune encephalomyelitis. In this study, we asked whether astrocytes produce
      MCP-1 in the absence of immune mediated inflammation. To address this question,
      we analyzed the time course and cellular source of MCP-1 in mouse brain after
      penetrating mechanical injury, with particular focus on early time points before
      histologic detection of infiltrating mononuclear phagocytes. We observed sharply
      increased steady state levels of MCP-1 mRNA within 3 h after nitrocellulose
      membrane stab or implant injury to the adult mouse brain, and MCP-1 protein
      elevations were documented at 12 h postinjury. In situ hybridization combined
      with immunohistochemistry for the glial fibrillary acidic protein astrocyte
      marker showed that astrocytes were the cellular source of MCP-1 mRNA at these
      early time points after mechanical brain injury. Stab injury to the neonatal
      brain evoked neither MCP-1 expression nor astrogliosis. These results demonstrate
      that chemokine gene expression comprises one component of the astrocyte
      activation program. The data are consistent with a role for MCP-1 in the central
      nervous system inflammatory response to trauma.

PMID- 8666809
TI  - Stimulation of Fc(alpha) receptors induces tyrosine phosphorylation of
      phospholipase C-gamma(1), phosphatidylinositol phosphate hydrolysis, and Ca2+
      mobilization in rat and human mesangial cells.
AB  - Although knowledge of IgA Fc receptor (Fc(alpha)R) structure and gene
      organization has progressed in the past few years, signal transduction pathways
      elicited by its activation have hardly been studied. Previously, we have
      demonstrated that mesangial cells (MC) possess Fc(alpha)R stimulation triggers
      several biologic responses. In this work, we studied the early biochemical
      signals triggered by Fc(alpha)R stimulation in MC. MC incubation with aggregated
      IgA (AIgA) elicited a dose-dependent increase in cytosolic Ca2+ ([Ca2+]i). The
      response was rapid and transient, and slowly fell to the original baseline. Ca2+
      mobilization was dependent on the Fc region of the IgA, because Fc, but neither
      Fab fragment nor carbohydrates, inhibited the [Ca2+] rise. The initial induction
      of [Ca2+]i rise was due to Ca2+ mobilization from inositol trisphosphate (IP3)
      sensitive intracellular stores, while sustained levels were maintained through
      extracellular Ca2+ influx. Stimulation of Fc(alpha)R also resulted in production
      of IP3, temporally correlated with Ca2+ mobilization. Protein tyrosine kinase
      inhibitors abolished [Ca2+]i rise, indicating that tyrosine phosphorylation of
      some substrates is required for Ca2+ mobilization. Stimulation through Fc(alpha)R
      gave rise to a marked increase in tyrosine phosphorylation of several proteins,
      including the 147-kDa band, similar in size to phospholipase C-gamma(1) (PLC
      gamma(1)). Tyrosine phosphorylation of PLC-gamma(1) reached a maximum 30 s after
      stimulation, as determined by immunoprecipitation and Western blot. Collectively,
      these results indicate that the Fc(alpha)R signaling pathway in MC involves PLC
      (gamma(1) activation, IP3 formation, and Ca2+ mobilization, and is linked to
      activation of tyrosine kinases.

PMID- 8666810
TI  - Characterization and subcellular localization of target membrane soluble NSF
      attachment protein receptors (t-SNAREs) in macrophages. Syntaxins 2, 3, and 4 are
      present on phagosomal membranes.
AB  - Phagosomes formed during ingestion of microorganisms by leukocytes undergo a
      rapid maturation, generating an acidic, microbicidal organelle. Maturation
      requires interactions with intracellular vesicles that dock and fuse
      preferentially with the phagosomal membrane. The basis of specificity of vesiculo
      phagosomal interaction has not been elucidated. By contrast, the molecular basis
      of vesicular fusion in other systems is better understood. At neural synapses,
      vesicular docking and fusion to the plasma membrane are mediated by a protein
      complex including syntaxin 1. We explored whether macrophages contain syntaxins,
      and whether selective fusion of vesicles with the phagosome results from the
      accumulation of syntaxins in the phagosomal membrane. Isoform-specific Abs were
      utilized to demonstrate utilized to demonstrate that syntaxins 2, 3, and 4, but
      not syntaxin 1, are present in murine and human macrophages. Biochemical
      characterization demonstrated the presence of these syntaxins on microsomes,
      where they are integral membrane proteins. Subcellular localization using
      confocal immunofluorescence microscopy demonstrated that syntaxins 3 and 4 are
      present on the plasma membrane as well as on intracellular vesicles. Importantly,
      phagosomes isolated by fractionation were shown by immunoblotting to contain
      syntaxins 2, 3, and 4, suggesting that they may participate in phagosomal
      maturation. The density of the syntaxins on the phagosomal membrane was found to
      be comparable with that on the surface membrane. This suggests that preferential
      fusion of vesicles with the phagosomal membrane is not the result of segregation
      of the syntaxins to this organelle. Instead, local generation of second
      messengers in the vicinity of the phagosomal membrane may trigger focal fusion.

PMID- 8666811
TI  - Stimulation of macrophages and neutrophils by complexes of lipopolysaccharide and
      soluble CD14.
AB  - Sensitive responses of monocytes, macrophages, and neutrophils to bacterial LPS
      require membrane-bound CD14 (mCD14) and a plasma protein called LPS-binding
      protein (LBP). Cells lacking mCD14 respond to complexes of LPS and soluble CD14
      (sCD14); these responses do not require LBP. To determine whether LBP is
      necessary for responses of mCD14-bearing cells to LPS, we measured responses of
      macrophages and neutrophils to complexes of LPS and sCD14 formed in the absence
      of LBP. We found that the amount of LPS needed to induce adhesive responses of
      neutrophils or cytokine production by macrophages was the same whether LPS was
      added with LBP or as LPS-sCD14 complexes, and was >100-fold less than when LPS
      was added alone. This result supports the view that LBP transfers LPS to CD14,
      but is not directly involved in responses of CD14-bearing cells to LPS. Responses
      of neutrophils to LPS-sCD14 complexes could be inhibited partially by blocking
      mCD14, suggesting that LPS may move rapidly from sCD14 to mCD14. Additionally, we
      found that responses of neutrophils to LBP and smooth LPS were made 30 to 100
      times more sensitive when sCD14 was added. Our findings show that LBP is not
      necessary for the activation of CD14-bearing cells with LPS, and suggest that LPS
      sCD14 complexes are an important intermediate in the inflammatory responses of
      leukocytes to LPS.

PMID- 8666813
TI  - Release of leukemia inhibitory factor in primate sepsis. Analysis of the role of
      TNF-alpha.
AB  - Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic
      effects overlapping with those of IL-6, has been implicated in the pathogenesis
      of sepsis. We here analyzed the kinetics of LIF in 13 baboons challenged with a
      lethal (n=6) or sublethal (n=7) dose of Escherichia coli. In addition, to assess
      the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied
      that had either received a bolus injection of recombinant human TNF-alpha (100
      micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E. coli
      challenge was administered (n=4). LIF levels increased 2 h after E coli
      challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6
      ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively. TNF-alpha injection
      induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46
      pg/ml). Circulating LIF correlated with plasma levels of IL-6, both after E. coli
      challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as
      well as upon TNF-alpha injection (r=0.863, p<0.001). Moreover, the E. coli
      induced release of either cytokine was reduced 6- to 10-fold after pretreatment
      with anti-TNF mAb, except in one nonsurviving animal, which exhibited a
      progressive increase of LIF and IL-6 levels despite the absence of TNF
      immunoreactivity. These results show that TNF-alpha is an intermediate factor in
      concerted release of LIF and IL-6 in vivo, and indicate that the enhanced
      elaboration of these cytokines may predict disease outcome in severe sepsis.

PMID- 8666812
TI  - Antisense inhibition of vitamin D receptor expression induces apoptosis in
      monoblastoid U937 cells.
AB  - The active vitamin D3 metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D3) acts
      as an antiproliferative and differentiating agent for the monoblastoid cell line
      U937 and as an important immunologic mediator implicated particularly in the
      function of cells belonging to the monocyte/macrophage lineage. These effects are
      controlled by the vitamin D receptor (VDR), a member of the steroid hormone
      receptor family. The objective of this study was to develop U937 transfectants
      expressing antisense VDR mRNA, and to use these to examine the role of
      1,25(OH)2D3-VDR interaction in this lineage. A 2-kb VDR cDNA insert (including
      the complete VDR coding region) was cloned in an antisense orientation into the
      EBV episomal vector pMEP4 under the control of an inducible promoter and
      transfected into U937. The resultant cell line, DH42, was hygromycin resistant,
      contained VDR cDNA, expressed fewer VDRs than controls, and showed a substantial
      decrease in antiproliferative response to 1,25(OH)2D3. However, 1,25(OH)2D3
      increased the number of cells expressing macrophage cell surface Ags, including
      CD14 and CD11b. A subpopulation of smaller cells did not express the
      differentiation markers after cadmium stimulation. Cell cycle analysis showed
      shifts in the distribution of cells from G1 to S phase, which were more
      pronounced after cadmium treatment. A considerable proportion of cells were
      outside the cycle and DNA fragmentation confirmed apoptosis. Thus, the functional
      outcome of the VDR antisense transfection suggests that in the myelomonocytic
      lineage, VDR expression may act as a protective mechanism against programmed cell
      death.

PMID- 8666814
TI  - Adenosine enhances IL-10 secretion by human monocytes.
AB  - Adenosine is a potent endogenous antiinflammatory agent released by cells under
      metabolically unfavorable conditions. Its effects on the production of IL-10 by
      human monocytes were presently investigated. Pre-incubation with adenosine dose
      dependently enhanced IL-10 release by TNF stimulated human monocytes (+29, +58,
      and +116% at 1, 10, and 100 muM, respectively.) Adenosine also significantly
      enhanced IL-10 production after hydrogen peroxide and LPS stimulation and dose
      dependently inhibited TNF secretion. Pre-incubation was not mandatory to achieve
      these effects, since addition of adenosine at the time of or 30 min after the
      stimulus led to the same results. Blocking IL-10 with anti-IL-10 mAbs partially
      restored adenosine-induced TNF inhibition. The enhanced IL-10 production was not
      observed when cells were preincubated with adenosine A1 or A2 receptor agonists
      (R-phenylisopropyladenosine, 5'-N-ethylcarboxamido-adenosine, and 2
      chloroadenosine) and was not affected by pretreatment with theophyllin, an
      antagonist of both A1 and A2 receptors, or with dipyridamole, an inhibitor of
      adenosine cellular uptake. In conclusion, adenosine, in the submillimolar
      concentration range, increases IL-10 secretion by stimulated monocytes. This
      phenomenon participates in TNF inhibition, a known property of adenosine, but is
      not mediated through the occupancy of A1 or A2 receptors. This may represent a
      novel antiinflammatory property of adenosine by which it could modulate
      inflammation and limit ischemia-reperfusion injury.

PMID- 8666815
TI  - Membrane cofactor protein (MCP; CD46). Isoforms differ in protection against the
      classical pathway of complement.
AB  - Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding
      glycoprotein that inhibits complement activation on host cells. MCP is expressed
      primarily as four isoforms that arise by alternative splicing of a single gene.
      The differences reside in the domains for O-glycosylation and cytoplasmic tails.
      Tissue-specific expression of isoforms and the differential processing of
      precursors mediated by the cytoplasmic tails suggest that isoform variations are
      biologically significant. The goal of these experiments was to characterize the
      complement inhibitory profile of the four commonly expressed isoforms. The MCP
      isoforms (BC) with a larger O-glycosylation domain bound C4b more efficiently
      than the C isoforms, which are smaller and less glycosylated in this region.
      Additionally, cytoprotection assays of individual clones of transfected isoforms
      bearing equivalent copy numbers demonstrated that the BC isoforms also provided
      enhanced protection in a classical pathway-mediated system and cleaved cell-bound
      C4b more efficiently than the C isoforms. Taken together, these data demonstrate
      that BC isoforms preferentially protect against the classical pathway of
      complement. Such findings indicate a physiologic role for isoform variation and
      have therapeutic implications for use of MCP isoforms as complement inhibitors in
      such areas as xenotransplantation.

PMID- 8666816
TI  - Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and
      eosinophilic granulocytes.
AB  - Eosinophils and neutrophils are closely related, terminally differentiated cells
      that in vitro undergo constitutive cell death by apoptosis. The onset of
      apoptosis in both cell types can be delayed by hemopoietins and inflammatory
      mediators. Although there have been a number of reports demonstrating that
      glucocorticoids (in particular dexamethasone) antagonize the eosinophil life
      prolonging effects of hemopoietins, direct effects of dexamethasone on eosinophil
      apoptosis have not been documented. In this study we examined the direct effects
      of glucocorticoids on eosinophil and neutrophil apoptosis in light of their
      common therapeutic use as anti-inflammatory and anti-allergic/hypereosinophilic
      agents. We found that treatment with dexamethasone induced eosinophil apoptosis.
      In contrast, dexamethasone was a potent inhibitor of neutrophil apoptosis. The
      effect of dexamethasone on both cell types was mediated through the
      glucocorticoid receptor, i.e., it was abolished by the glucocorticoid receptor
      antagonist RU38486. This is the first description of an agent that promotes
      eosinophil apoptosis while inhibiting neutrophil apoptosis, and thus presents a
      novel approach to the study of control of apoptosis in these closely related cell
      types as well as increases our understanding of the clinical action of
      glucocorticoids in inflammation.

PMID- 8666817
TI  - IFN-gamma up-regulates expression of the complement components C3 and C4 by
      stabilization of mRNA.
AB  - We investigated the mechanisms underlying the regulation of complement genes C3
      and C4 by IFN-gamma. IFN-gamma (500 U/ml, 24 h incubation) increased steady state
      mRNA levels for both C3 and C4 in three different cell types (Hep G2, U937, and
      primary fibroblasts). The response to IFN-gamma in Hep G2 cells was time and dose
      dependent. At all doses of IFN-gamma and at all incubation times, the
      transcription rate for these two genes, determined by nuclear run-on assays, was
      reduced (0.3 +/- 0.1; unstimulated rate = 1.00). The t1/2 of mRNA for C3 and C4
      in unstimulated cells was 1.8 +/- 0.3 and 2.2 +/- 0.2 h, respectively. After high
      dose IFN-gamma stimulation, both C3 and C4 mRNA levels remained at 100% with
      respect to baseline at 5 h, but after 12 h, levels fell to 13 +/- 2% (C3) and 8
      +/- 3% (C4) of baseline values, giving a half-life for these mRNA species of
      between 5 and 12 h. IFN-gamma stimulation increased C3 and C4 protein synthesis
      measured at 24 h. We suggest that it is the increase in mRNA stability that is
      the major effector mechanism by which IFN-gamma regulates C3 and C4 gene
      expression.

PMID- 8666818
TI  - Binding of model soluble immune complexes to modified C-reactive protein.
AB  - We have identified a binding interaction between a modified form of C-reactive
      protein (mCRP) and model immune complexes. We have characterized these
      interactions in terms of their relative affinity, specificity, pH dependence, and
      recognition site on mCRP. First, binding isotherms were generated for the
      reaction of immobilized mCRP with heat-aggregated IgG (HAG) which gave an
      estimate for the value of the dissociation constant, Kd, of 1.6 nM. Second,
      competitive binding assays were performed using immobilized HAG to determine the
      relative affinity (IC50) for the interaction between HAG or monomeric IgG and
      mCRP in the fluid phase. While the binding of HAG to mCRP occurred with high
      affinity (IC50=0.72 nM), the binding of monomeric IgG to mCRP occurred with >2000
      fold lower affinity (IC50>1.66 muM). Third, immune complex binding to immobilized
      mCRP was studied using defined ratios of horseradish peroxidase and rabbit anti
      peroxidase Ab. The binding of these complexes to mCRP was strongly pH dependent,
      with a maximum at pH 5.5. At this optimal pH, preformed peroxidase-antiperoxidase
      immune complexes (approximately 2:3 Ab:Ag molar ratio) were shown to bind
      immobilized mCRP with a Kd of 111 nM. Fourth, using mCRP-specific mAbs, HAG and
      peroxidase- antiperoxidase binding sites were localized to CRP sequences to 130
      to 138 and 200 to 206. Since inflammatory processes often cause microenvironments
      to become acidic, and since mCRP selectively binds immune complexes at acidic pH,
      we propose that mCRP mediates the specific binding of immune complexes in vivo
      and potentiates effector reactions for immune complex removal.

PMID- 8666819
TI  - Identification of Fc alpha receptor (CD89) isoforms generated by alternative
      splicing that are differentially expressed between blood monocytes and alveolar
      macrophages.
AB  - One of the hallmarks of mucosal-host defense is the clearance of inhaled Ags by
      alveolar macrophages (AM) through interactions of IgA Abs and IgA Fc receptors
      (Fc alpha R). AM constitutively expressed Fc alpha R at lower levels than freshly
      isolated and in vitro-differentiated monocytes as determined by
      immunofluorescence using four anti-Fc alpha R mAb. SDS-PAGE analysis of iodinated
      cell surface proteins revealed that Fc alpha R on AM has an Mr of 50 to 65 kDa,
      slightly lower than that on monocytes (55-75 kDa). Treatment of AM Fc alpha R by
      N-glycanase gave rise to a protein core of 28 KDa, smaller than the 32-kDa
      backbone of blood monocytes. AM Fc alpha R molecules were unaffected by
      phosphatidylinositol-phospholipase C treatment. Fc alpha R transcripts were
      analyzed by reverse transcription-PCR using primers in the 5' and 3' regions of a
      U937 Fc alpha R cDNA. Three transcripts were amplified, cloned, and sequenced
      from AM and/or monocyte mRNA, the full length Fc alpha R and two alternatively
      spliced products corresponding to deletions of 66 and 288 nucleotides in the
      portion coding for the extracellular domain; they were named Fc alpha R a.1, a.2,
      and a.3, respectively. These PCR products were transcribed and translated in
      vitro into three proteins (Mr 32, 30, and 22 kDa, respectively), in which the 32-
      and 30-kDa species were immunoprecipitated by an anti-Fc alpha R mAb. The
      predicted size of the protein encoded by the Fc alpha R a.2 transcript without
      the leader peptide is Mr approximately 27,400, a value that is consistent with
      the Mr of AM Fc alpha R backbone. These results indicate that AM express at their
      surfaces a protein product of an alternatively spliced Fc alpha R transcript, the
      Fc alpha R a.2 isoform, that might have physiologic relevance in IgA-mediated
      host defense at mucosal sites.

PMID- 8666820
TI  - Eosinophil-fibroblast interactions. Granule major basic protein interacts with IL
      1 and transforming growth factor-beta in the stimulation of lung fibroblast IL-6
      type cytokine production.
AB  - To test the hypothesis that eosinophil major basic protein (MBP) is an important
      regulator of fibroblast effector function, we characterized the effects of MBP on
      human lung fibroblast production of the IL-6-type cytokines, IL-6, IL-11, and
      leukemia inhibitory factor. Unstimulated fibroblasts did not produce substantial
      quantities of these cytokines, while IL-1 and TGF-beta(1) stimulated these
      cytokines in a potent fashion. MBP at doses < or = 44 micrograms/ml did not
      stimulate IL-6-type cytokine production. It did, however, interact in a
      synergistic, dose- and time-dependent fashion with rIL-1-alpha and TGF-beta(1) to
      further increase IL-6-type cytokine elaboration. These MBP-induced increases in
      cytokine production were associated with proportionate alterations in mRNA
      accumulation. In contrast, eosinophil-derived neurotoxin did not regulate
      fibroblast cytokine production, and MBP did not augment fibroblast granulocyte
      macrophage-CSF, or type I collagen production, or fibroblast proliferation in
      this culture system. The effects of MBP could not be attributed to cell
      cytotoxicity or contaminants in the MBP preparations. They were, however, at
      least partially charge mediated, since heparin abolished the effects of MBP on IL
      1-stimulated cells, and the surrogate cationic molecule poly-L-arginine mimicked
      the stimulatory effects of MBP on fibroblast IL-6-type cytokine elaboration.
      These studies demonstrate that MBP interacts in a synergistic fashion with rIL-1
      alpha or TGF-beta(1) to further augment fibroblast IL-6-type cytokine production.
      They also demonstrate that this stimulation is pretranslationally mediated and
      due, in part, to the cationic nature of the MBP molecule. MBP regulation of
      fibroblast cytokine production may play an important role in the pathogenesis of
      eosinophilic disorders of the airway or other organs.

PMID- 8666821
TI  - Activation of multiple proline-directed kinases by bacterial lipopolysaccharide
      in murine macrophages.
AB  - Bacterial LPS stimulation of murine macrophages leads to increased tyrosine
      phosphorylation and activation of the 42- and 44-kDa mitogen-activated protein
      kinases (MAPK) and the activation of stress-activated protein kinases (SAPK)/c
      Jun N-terminal kinase (JNK) and p38, related to the high osmolarity glycerol
      protein kinase in Saccharomyces cerevisiae (HOG1). LPS caused a rapid increase
      (10 min) in phosphotransferase activity toward myelin basic protein (MBP), a
      polypeptide that encompassed the first 169 residues of c-Jun fused to
      gluthathione S-transferase (GST-c-Jun (1-169)) and 27-kDa heat shock protein
      (hsp27). MonoQ fractionation of cell extracts resolved phosphotransferase
      activity peaks toward MBP, GST-c-Jun (1-169), and hsp27, which contained MAPK,
      SAPK/JNK, and MAPKAPK2, respectively, as indicated by immunoblotting data. In RAW
      264.7 macrophages, LPS stimulation of MAPKAPK2, a substrate of p38 HOG1 and MAPK,
      appeared to occur predominantly via p38 HOG1 and not the MAPK. PMA, which
      activated the MAPK as potently as LPS, did not strongly activate MAPKAPK2, as
      assessed by hsp27 phosphorylation. Consistent with p38 HOG1-mediating LPS
      activation of MAPKAPK2, treatment with LPS, but not PMA, increased the tyrosine
      phosphorylation of p38 HOG1, a modification known to elevate the enzymatic
      capacity of this kinase. In LPS-treated cells, the activity of SAPK/JNK was
      increased 5- to 10-fold, as measured by precipitating SAPK/JNK with Abs or
      immobilized GST-c-Jun and performing an in vitro kinase assay. In addition, the
      kinases thought to be upstream of SAPK/JNK, SAPK/ERK kinase 1 (SEK1), and
      MAPK/ERK kinase kinase 1 (MEKK1), were activated following LPS, but not PMA,
      exposure (5-fold and 2.5-fold, respectively.

PMID- 8666822
TI  - Inhibition of the hemolytic activity of the first component of complement C1 by
      an Escherichia coli C1q binding protein.
AB  - Molecular mimicry is a well established mechanism via which bacteria protect
      themselves from complement-mediated killing. We have previously demonstrated that
      a number of human cells express receptors for C1q (C1qR) and that the soluble
      form of this receptor inhibits activation of the classical pathway of complement.
      We now investigated whether Escherichia coli possesses a C1qR-like protein that
      protects these bacteria from complement-mediated injury. By FACS analysis it was
      shown that approximately 60% of the bacteria bound C1q directly in the absence of
      Abs. With ELISA we confirmed that the bacterial cell envelope was able to bind
      C1q in a dose-dependent fashion. We isolated a cell envelope associated C1q
      binding protein (C1qBP) by C1q affinity chromatography, then by anion exchange
      chromatography and gel filtration chromatography. On SDS-PAGE, the m.w. of C1qBP
      appeared to be 57 kDa and 51 kDa under reducing and nonreducing conditions,
      respectively. It was demonstrated that C1qBP specifically binds C1q and inhibits
      the hemolytic activity of C1q in both a dose- and time-dependent fashion. The
      binding of C1qBP to C1q is inhibited by C1q itself and also by the collagen-like
      stalks and the globular heads of C1q. In this respect, bacterial C1qBP is
      different from human C1qR because the binding of C1q to C1qR is only inhibited by
      the collagen-like stalks of C1q and not by the globular heads of C1q. C1qBP, when
      bound to C1q, prevents the assembly with C1r and C1s to form a functional C1
      complex. The occurrence of C1qBP is not limited to certain E. coli strains, but
      is also found on Staphylococcus aureus, Citrobacter freundii, and Pseudomonas
      aeruginosa. Also, the binding of 125(I)-labeled C1q to these bacteria is specific
      because the binding of C1q to these bacteria is inhibitable with isolated soluble
      C1qBP. These findings provide evidence for the existence of a C1qR-like protein
      on bacteria that might protect them from complement-mediated damage.

PMID- 8666823
TI  - Identification of multiple and distinct CD8+ T cell suppressor activities:
      dichotomy between infected and uninfected individuals, evolution with progression
      of disease, and sensitivity to gamma irradiation.
AB  - Using an in vitro model system that reflects the cellular interactions occurring
      in the microenvironment of lymphoid organs (i.e., the interaction between
      dendritic cells (DC) and CD4+ T lymphocytes), the ability of CD8+ T cells to
      inhibit HIV replication was investigated. DC, the most potent APC in the
      paracortical region of lymphoid organs, were cocultured with autologous,
      unstimulated CD4+ T cells resulting in viral replication in the absence of
      exogenous stimulation. Using two variations of DC cocultures, one an acute
      infection system and the other an endogenous infection system, two sets of
      activities were identified. One activity was expressed in both HIV-infected and 
      uninfected individuals, and a second was found only in HIV-infected individuals.
      These activities can be differentiated further by their evolution or lack thereof
      with disease progression in infected individuals and their sensitivity to gamma
      irradiation. Furthermore, the results indicate that CD8+ T cell modulation of HIV
      replication in CD4+ T cells is a multifactorial phenomenon involving both
      inhibitory and stimulatory effects on HIV replication.

PMID- 8666824
TI  - Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A
      ribonucleoprotein autoantigen.
AB  - Calreticulin (CR) is a multifunctional, calcium-binding protein that has recently
      been shown to bind to and promote the replication of the rubella virus genome in
      mammalian cells. While CR is now widely recognized as a new human autoantigen,
      the relationship between CR and the Ro/SS-A ribonucleo-protein (RNP) autoantigen
      has been somewhat controversial. In this work, we demonstrate that
      unphosphorylated human rCR binds specifically and distinctly to in vitro
      transcribed forms of hYRNA, the RNA backbone of the Ro/SS-A RNP particle. This
      interaction appears to be mediated by binding through the N- and C-terminal
      domains of CR, but not by the central proline-rich domain. Furthermore, our
      studies indicate that CR can facilitate the binding of the 60-kDa polypeptide
      component of the Ro/SS-A RNP (Ro60) to hYRNA. In addition, CR and the 52-kDa
      Ro/SS-A polypeptide (Ro52) appear to be capable of interacting through direct
      protein-protein binding. These studies confirm that CR is an hYRNA-binding
      protein, and provide for the first time a molecular mechanism by which Ro52 can
      be linked physically to hYRNA. Through these molecular interactions and its known
      functional role as a chaperone, it is suggested that CR plays a supportive role
      in the formation of the Ro/SS-A RNP complex. The capacity of CR to interact with
      RNA viruses such as rubella provides an additional argument for an infectious
      trigger for autoantibody production against self RNP particles such as Ro/SS-A.

PMID- 8666825
TI  - Role of IL-12 in peripheral blood mononuclear cell responses to fungi in persons
      with and without HIV infection.
AB  - Clinical trials of IL-12 in persons infected with HIV have been proposed based on
      recent evidence suggesting IL-12 plays a critical role in the development of
      protective immune responses, and the HIV infection is associated with a
      deficiency of IL-12. As fungal infections are among the most common opportunistic
      infections associated with AIDS, we examined whether IL-12 p40 gene expression
      and p70 release in response to Cryptococcus neoformans and Candida albicans were
      deficient in monocyte-enriched PBMC from HIV-seropositive donors and whether rIL
      12 could augment the proliferation of PBMC from HIV-seropositive donors in
      response to these fungi and to Pneumocystis carinii. PBMC from HIV-seronegative
      donors expressed IL-12 p40 mRNA in response to C. neoformans, C. albicans, and
      the positive control Staphylococcus aureus Cowan strain 1 (SAC), although the
      induction of IL-12 p40 mRNA was later and more prolonged with C. neoformans as
      the stimulus. Expression of IL-12 p40 mRNA in response to the three stimuli was
      similar in cells from HIV-seropositive and HIV-seronegative donors. However, when
      stimulated with SAC, cells from HIV-seropositive donors released significantly
      less IL-12, suggesting HIV infection induces a post-transcriptional defect in IL
      12 release in response to SAC. While PBMC from HIV-seropositive donors had
      impaired proliferative responses to the three fungi tested, addition of rIL-12
      did not enhance proliferation. These studies do not lend further support for the
      therapeutic use of IL-12 to prevent or treat fungal infections in persons
      infected with HIV.

PMID- 8666826
TI  - Resting B cells from New Zealand Black mice demonstrate a defect in apoptosis
      induction following surface IgM ligation.
AB  - New Zealand Black (NZB) mice spontaneously develop autoimmune disease, usually
      characterized by an autoimmune hemolytic anemia, and NZB genes are essential for
      a severe systemic lupus-like disease in (NZB x NZW)F1 mice. We have found that
      resting B cells from NZB mice demonstrate a pronounced defect, compared with five
      normal strains, in apoptosis induction after cross-linking with anti-IgM Abs. In
      contrast, spontaneous apoptosis of NZB B cells in culture was similar to normal
      strains. B cells from young (NZB x SM/J)F1 and (NZB x NZW)F1 mice underwent
      apoptosis normally, indicating that the NZB defect in apoptosis is a recessive
      trait. However, older (8-32 wk) predisease (NZB x NZW)F1 mice manifested a
      similar defect in apoptosis induction. The analysis of NXSM recombinant inbred
      mice derived from NZB and SM/J, in addition to backcross mice, suggested that the
      NZB apoptosis defect is a multigenic trait. Interestingly, resting B cells form
      B6.lpr and B6gld mice underwent apoptosis following anti-IgM treatment at a level
      similar to that of the C57BL/6 parental strain. Thus, the induced apoptosis of
      resting B cells and the NZB defect are likely not related to either Fas or Fas
      ligand. We propose that this phenotypic defect in apoptosis induction, or the
      biochemical alteration that underlies the defect, may be casually related to
      autoimmune disease in NZB mice and its contribution to lupus-like disease in (NZB
      x NZW)F1 mice.

PMID- 8666827
TI  - Selection of antigenic and immunogenic mimics of hepatitis C virus using sera
      from patients.
AB  - Using sera from hepatitis C virus (HCV)-infected patients and noninfected
      subjects to screen random peptide libraries displayed on phage, we selected
      peptides specifically reacting with sera from infected patients. These phage-
      borne peptides were shown to mimic distinct HCV determinants. They detected in
      all cases the presence of anti-HCV Abs in a large panel of patients' sera, thus
      demonstrating the high sensitivity of the selected peptides as diagnostic
      markers. In addition, this diagnostic approach allowed a detailed
      characterization of the individual humoral response to viral infection. Phage
      displayed HCV mimics were substitutes for the authentic HCV epitopes in inducing
      a strong specific response against HCV when used as immunogens in mice. These
      results support the search for HCV mimics with the potential to elicit a
      protective immune response as leads for the development of a mimotope-based
      vaccine against viral infection.

PMID- 8666828
TI  - Anti-psoriatic drug anthralin activates transcription factor NF-kappa B in murine
      keratinocytes.
AB  - Anthralin is one of the most effective and safest therapeutic agents for the
      treatment of psoriasis, a skin disease characterized by epidermal
      hyperproliferation and hyperkeratosis. The drug induces and inflammatory response
      in the skin involving the expression of cytokine and cell adhesion molecule genes
      that is thought to be essential for its therapeutic efficacy. Reactive oxygen
      intermediates (ROIs) generated in vivo during the auto-oxidation of anthralin
      were discussed as mediators of the inflammatory response, but it is not yet
      understood how this is translated into novel inflammatory gene expression. In
      this study, we show that at little as 10 microM anthralin can activate a
      prototypic form of transcription factor NF-(kappa)B, a central transcriptional
      regulator of inflammatory and immune responses. Two different lines of evidence
      show that ROIs, in particular H2O2, are second messengers for the anthralin
      induced NF-(kappa)B activation. Firstly, the activation could be inhibited by the
      structurally unrelated antioxidants N-acetyl-L-cysteine and
      pyrrolidinedithiocarbamate. Secondly, keratinocytes stably overexpressing
      catalase showed a significant reduction of NF-(kappa)B activation, while stable
      overexpression of Cu/Zn-superoxide dismutase augmented the anthralin effect. Our
      data suggest that ROI-induced NF-(kappa)B plays a role in the anti-psoriatic
      activity of the drug anthralin.

PMID- 8666829
TI  - Collagen-induced arthritis in CD4- or CD8-deficient mice: CD8+ T cells play a
      role in initiation and regulate recovery phase of collagen-induced arthritis.
AB  - Collagen-induced arthritis (CIA) is an experimental autoimmune disease induced by
      immunization with collagen type II (CII). We studied CIA in CD4- or CD8-deficient
      DBA/1 mice to further define the roles of CD4+ and CD8+ T cells in the disease.
      CD4-deficient mice developed severe arthritis, and no differences in incidence,
      clinical course, and severity were observed between CD4 -/- and CD4 +/- mice.
      Proliferative responses of lymph node T cells to CII was, however, reduced in CD4
      -/- mice, and inflamed joints revealed relative accumulation of CD4-CD8
      TCR(alpha)(beta)+ cells. A CII-specific T cell line generated from CD4-deficient
      mice responded to CII in a MHC-restricted fashion and had a CD4-CD8
      TCR(alpha)(beta)+ phenotype. Disease incidence in CD8 -/- mice was significantly
      decreased compared with CD8 +/- mice, even though the severity of arthritis in
      arthritic mice was not different. These results suggests a role for CD8+ T cells
      in initiating CIA. Interestingly, CD8-deficient mice were more susceptible to a
      second induction of arthritis after remission of initial disease, pointing
      towards an immunoregulatory role for CD8+ T cells. CD8-deficient mice did not,
      however, show any defect in oral tolerance induction using CII. Taken together,
      our findings demonstrate that CD4-CD8-TCR(alpha)(beta) cells can trigger systemic
      arthritis in CD4-deficient mice and that CD8+ T cells can play dual and opposing
      roles, important both in initiation of CIA and in providing resistance to
      reinduction of CIA after recovery from initial disease.

PMID- 8666830
TI  - Antibody production in rabbits and chickens immunized with human IgG. A
      comparison of titre and avidity development in rabbit serum, chicken serum and
      egg yolk using three different adjuvants.
AB  - The antibody response in rabbits and chickens (serum and egg yolk) immunized with
      human immunoglobulin G was studied during a 1-year immunisation period comparing
      the efficacy of three adjuvants: Freund's complete adjuvant (FCA), Freund's
      incomplete adjuvant (FIA) and Hunter's TiterMax adjuvant (HTM). Monthly boosters
      of the antigen in saline were administered. Adjuvants were used in the initial
      immunisation and in a booster at week 26. FCA was found to result in the highest
      titre in both species. FIA was more efficient than HTM in mediating an antibody
      response in rabbits. In chickens, FIA resulted in similar antibody titres in
      serum and egg yolk. The effect of HTM was similar to FIA in chicken serum but
      lower in egg yolk. The titres obtained in rabbits were approximately a factor 1.5
      2.0 higher than in the corresponding chicken groups. However, the antibody
      productivity of the chicken, when using the egg yolk as the antibody source, was
      a factor 5-10 higher than that of the rabbit depending on the adjuvant used. FCA
      and FIA resulted in similar antibody avidity in rabbits whereas HTM had a lesser
      effect. In chickens FCA initially resulted in the highest antibody avidity in
      both serum and egg yolk, but after the booster with adjuvant the antibody avidity
      became similar for all three adjuvants.

PMID- 8666831
TI  - Development of a flow cytometric assay to quantify lymphocyte adhesion to
      cytokine-stimulated human endothelial and biliary epithelial cells.
AB  - The adhesive interaction between T lymphocytes and parenchymal cells is of
      importance for many processes of the cellular immune response. This adhesion is
      regulated by the activation status of the T cell and by cytokines in the
      microenvironment which can alter adhesion molecule expression by endothelial and
      epithelial cells. In this study results from an isotopic adhesion assay were
      compared with those from a flow cytometric assay in order to determine which was
      most appropriate for the investigation of lymphocyte adhesion to human umbilical
      vein endothelial cells (HUVEC) and intrahepatic biliary epithelial cells (HIBEC).
      Treatment of both these cell types with the proinflammatory cytokines interferon
      gamma (IFN-gamma) or tumour necrosis factor-alpha (TNF-alpha) significantly
      upregulated expression of intercellular adhesion molecule-1 (ICAM-1). Treatment
      with TNF-alpha also induced endothelial cells to express vascular cell adhesion
      molecule-1 (VCAM-1). The isotopic assay demonstrated increased adhesion of
      lymphoblasts to HUVEC which had been stimulated with cytokines for 15 h but
      failed to detect major changes in adhesion following 72 h of cytokine treatment
      of HUVEC or HIBEC. However, the flow cytometric assay reproducibly demonstrated
      increased adhesion following cytokine treatment for both these time periods;
      these increases corresponded with the changes in adhesion molecule expression by
      cytokine-stimulated HUVEC and HIBEC targets. The differences in apparent adhesion
      measured by the two assays after cytokine stimulation for 72 h may be explained
      by cytokine-induced changes in the morphology and confluency of cultured cells.
      Results of the isotopic assay are proportional to the total number of lymphoid
      cells bound by the cultured target cells and will be distorted by changes in
      effective target cell area. The flow cytometric assay measures the mean number of
      lymphoid cells bound by each target cell and is independent of the total binding
      area. It is concluded that the flow cytometric assay is more suitable than the
      isotopic technique for following time-dependent changes in the adhesion of
      leukocytes to cytokine-stimulated target cells.

PMID- 8666832
TI  - Detection and quantification of blood-derived CD8+ T lymphocytes secreting tumor
      necrosis factor alpha in response to HLA-A2.1-binding melanoma and viral peptide
      antigens.
AB  - We applied an enzyme-linked immunospot (ELISPOT) assay for the detection and
      quantification of blood-derived CD8+ T cells recognizing peptide antigens
      presented by HLA-A2.1. CD8+ T lymphocytes were isolated from peripheral blood and
      were stimulated for 40 h with peptide-loaded A2.1-positive 0.174 x CEM.T2 cells.
      Tumor necrosis factor alpha (TNF-alpha) secreted by single T cells in response to
      antigen contact was trapped on nitrocellulose membranes precoated with anti-TNF
      alpha antibodies and was then immunochemically visualized as spots. With this
      assay, up to 25% of cloned cytolytic T lymphocytes (CTL) were detected during the
      test period that recognized defined melanoma antigens in association with HLA
      A2.1. CD8+ lymphocytes responsive to a known immunogenic HLA-A2.1-binding peptide
      from reverse transcriptase of the human immunodeficiency virus (HIV) were only
      detectable in HIV-infected patients, but not in anti-HIV-negative donors. T cells
      reacting with a peptide derived from a mutated cyclin-dependent kinase 4 (CDK4
      R24C) were exclusively detected among CD8+ lymphocytes isolated from blood of the
      patient, whose melanoma had previously been found to carry the CDK4-R24C allele.
      T cells responding to HLA-A2.1-associated peptides of normal melanocyte
      differentiation antigens tyrosinase and Melan-A/MART-1 were found at low
      frequencies in almost all donors tested, which might reflect a natural
      autoimmunity to these antigens. However, in a melanoma patient we found a few
      days after surgery of melanoma metastases high frequencies of T cells against
      Melan-A/MART-1 and tyrosinase peptides (up to 38 per 10(5) CD8+ T cells), which
      gradually decreased during the following months. In an HIV-infected patient with
      progressive disease we observed a loss of T cells reactive with the HIV reverse
      transcriptase peptide. These observations provide evidence that peptide-dependent
      TNF-alpha spot formation in vitro resulted from previous antigen exposure in
      vivo. Therefore, the TNF-alpha ELISPOT assay might be useful in monitoring
      antigen-specific T lymphocyte responses during the natural course of diseases as
      well as during therapeutic interventions aiming at the induction of protective T
      cell immunity. In addition, it might help to identify immunodominant T cell
      epitopes.

PMID- 8666833
TI  - Introduction of the cell survival gene bcl-xL improves the viability of CTLL-2
      cells without affecting their IL-2 proliferative response. Implications for the
      development of bioassays.
AB  - A standard method for the quantitation of cytokines is to perform a bioassay in
      which aliquots of samples are compared to known concentrations of a cytokine in
      supporting the proliferation of a cytokine-dependent cell line. In most instances
      however, these cell lines are dependent on the cytokine not only for
      proliferation but also for survival. For example, a cell line that is commonly
      utilized for interleukin-2 (IL-2) bioassays is the IL-2-dependent line, CTLL-2.
      CTLL-2 cells will die rapidly by apoptosis if withdrawn from IL-2, thus these
      cells can be difficult to maintain in culture for extended periods.
      Overexpression of the anti-apoptotic protein Bcl-x(L) can enhance CTLL-2 survival
      in the absence of IL-2. However, while overexpression of Bcl-x(L) can prevent
      CTLL-2 cells from dying in the absence of IL-2, overexpression of Bcl-x(L) does
      not impair the ability of CTLL-2 cells to be used for proliferation-based IL-2
      bioassays. Thus the bcl-x(L)-transfected CTLL-2 cells are equivalent to the
      parental cell line for determination of IL-2 levels in a culture supernatant, yet
      are easier to maintain in culture. Introduction of Bcl-x(L) or Bcl-2 into other
      factor-dependent cell lines may also simplify their maintenance without
      significantly affecting their utility in bioassays.

PMID- 8666834
TI  - A putative enzyme from various secretions specifically inhibits antibody-antigen
      interactions.
AB  - Various human secretions (intestinal secretion, saliva, nasal mucus, lacrimal
      fluid) have been found to inhibit the binding of antibodies to their antigens.
      Various characteristics (e.g. time, pH, temperature dependence, affinity and size
      exclusion chromatography) suggested that the inhibitory activity was attributable
      to an enzyme. Further investigations revealed that this enzyme reacted with the
      Fab portion of immunoglobulin G, specifically with the heavy chain. It is assumed
      that it represents a novel immunoglobulin-specific protease since similar results
      were not obtained with proteolytic enzymes from human digestive organs e.g.
      pepsin, trypsin and chymotrypsin. Finally, investigating saliva it was
      demonstrated that the putative protease was not identical to enzymes from
      periodontal bacteria which are proteolytic for the Fc portion of immunoglobulins.
      The findings could be of general importance in the design of immunoassays which
      are to be applied to human (and possibly animal) secretions.

PMID- 8666835
TI  - Water-soluble conductive polymer homogeneous immunoassay (SOPHIA). A novel
      immunoassay capable of automation.
AB  - Conductive polymers are extensively conjugated macromolecules able to conduct
      electricity in their doped state and having a UV-visible spectrum which undergoes
      important chromatic modifications when subjected to pH changes or to oxido
      reductive processes. This article describes a novel homogeneous immunoassay in
      which a water-soluble conductive polymer is used as the label. When antigen
      antibody binding occurs, the local pH near the complex is modified. Such a pH
      change is in turn able to induce modifications in the absorbance at a
      characteristic wavelength of a conductive polymer covalently linked to either the
      antigen or the antibody. Consequently, the extent of tracer binding can be
      directly monitored by photometry during incubation. We present examples which
      validate the concept and exemplify its applicability in quantitative competitive
      immunoassays for human C-reactive protein and human serum albumin, as performed
      in a Cobas-Mira automated analyzer.

PMID- 8666836
TI  - An improved cell-ELISA for the differential screening of antibodies against cell
      surface molecules of viable adherent Schwann cells.
AB  - In this report we describe a highly sensitive large-scale screening assay that
      uses viable adherent cells. The newly developed test design combines the
      advantages of live cell immunocytochemistry with the versatility of a
      conventional ELISA technique. Culturing of target cells as well as incubation
      with antibodies is done in the same microtiter plate. No processing of cells
      prior to incubation with the antibodies, such as fixation or enzymatic detachment
      of the cells, is performed. This eliminates possible factors that might interfere
      with antibody-antigen recognition and results in a dramatically increased
      sensitivity that is comparable to cell-free ELISA procedures with an assay
      detection limit reproducibly between 0.004 and 0.002 micrograms/ml. Furthermore,
      this test design is convenient for the rapid identification of antibodies against
      differentiation-dependent antigens. Incubation in parallel with the same antibody
      of different cell types (forskolin-stimulated Schwann cells or fibroblasts) or
      cells grown under different conditions (forskolin-stimulated and non-stimulated
      Schwann cells) facilitates the selection of antibodies displaying genotypic or
      phenotypic specificity. Since culture of target cells and the detection of
      antibodies is done on one microtiter plate, it is not only possible to detect
      cell surface molecules but also secreted molecules that remain bound to the cell
      surface or the culture substrate. Compared to other previously introduced cell
      ELISAs, our protocol offers the following advantages: (i) increased sensitivity,
      (ii) convenience for large-scale screening, (iii) optimal identification of
      antibodies reacting with native molecules, and (iv) identification of
      differentiation-dependent antigens. Since this assay could also be used in
      studies examining the regulation of cell surface molecules at a semiquantitative
      level it may be of general relevance.

PMID- 8666837
TI  - Antibodies to p24 antigen do not specifically detect HIV-infected lymphocytes in
      AIDS patients.
AB  - A flow cytometric assay (FCA), which detects the p24 antigen in HIV-infected cell
      lines and in peripheral blood mononuclear cells (PBMC) of AIDS patients, has been
      described in several studies. However, the results presented here clearly show
      that this p24-FCA, although useful for the analysis of HIV infection of cells in
      vitro, does not specifically detect HIV-infected PBMC from patients. Isotype
      control antibodies also stained PBMC from HIV-infected patients to a greater
      degree than the PBMC from healthy controls. Furthermore, the CD4-negative
      lymphocytes, which are generally not infected with HIV, were also found to stain
      with anti-p24. Finally, no enrichment of HIV-infected cells was found in the FACS
      purified CD4+p24+ lymphocytes, compared to the CD4+p24- cell fraction. The p24
      FCA, therefore, was not useful for determining the percentage of infected PBMCs
      from HIV-infected individuals.

PMID- 8666838
TI  - Limitations on the use of dihydrorhodamine 123 for flow cytometric analysis of
      the neutrophil respiratory burst.
AB  - Intracellular oxidation of dihydrorhodamine 123 (DHR) to the fluorescent compound
      rhodamine 123 (Rho123) was used to detect the production of oxygen metabolites in
      activated neutrophils. Total leukocyte preparations can be used in this assay,
      which is a great advantage when priming of the respiratory burst is studied. We
      have defined the conditions that should be taken into account when priming is
      studied with this assay. We found that neither the extent nor the kinetics of DHR
      oxidation match those of NADPH oxidase activity. In addition, DHR oxidation is
      influenced by the absolute and relative number of neutrophils in the leukocyte
      suspension, by the DHR concentration and by myeloperoxidase availability. The
      results presented in this study emphasize the need for carefully designed
      experiments when DHR is used to study the respiratory burst in neutrophils.

PMID- 8666839
TI  - Assays for measuring soluble cellular adhesion molecules and soluble cytokine
      receptors.

PMID- 8666840
TI  - Phaeohyphomycosis caused by Dactylaria (human dactylariosis): report of a case
      with review of the literature.
AB  - Phaeohyphomycosis due to Dactylaria (Ochroconis) spp. is a rare infection of man.
      It was first reported in 1986. All patients have had significant
      immunosuppression. To our knowledge, this is the second case of phaeohyphomycosis
      caused by Dactylaria constricta var. gallopava in a liver transplant patient and
      it developed even though he had been receiving fungal prophylaxis with
      fluconazole. Moreover, this case may represent nosocomial acquisition. In
      addition, we have reviewed the English language literature of previously reported
      patients with phaeohyphomycosis caused by Dactylaria spp.

PMID- 8666841
TI  - Acute meningitis of unknown aetiology: analysis of 219 cases admitted to hospital
      between 1977 and 1990.
AB  - Clinical and biochemical parameters in 219 patients with meningitis of unknown
      aetiology were analyzed according to their initial CSF leucocyte count. The
      male/female ratio was 1.1 and the median age 30 years,(males = 22 years/females =
      42 years). Pre-admission antibiotic, which may inhibit bacterial growth, was
      given to 28% patients. On admission symptoms of meningitis were predominant: 96%
      had fever, 91% neck rigidity and 19% a severely affected mental state. In
      addition, 10% had a petechial rash. A bacterial aetiology was likely, as 91% had
      a predominance of polymorphonuclear leucocytes in the CSF and in 50% it was
      frankly purulent. The CSF leucocyte count correlated positively with age, the
      period of fever and the length of hospitalization, but did not relate to the
      10.1% in-patient mortality rate. Mortality was related to advancing age, but not
      to the antibiotic regimen chosen. Patients admitted directly from their homes had
      the least complicated disease course and all survived. A low CSF leucocyte count,
      mainly found in young patients so admitted, could indicate either a non-bacterial
      self-limiting aetiology or diagnosis at an early stage of the disease. We found,
      however, that bacterial meningitis cannot be excluded on the basis of the CSF
      leucocyte count in combination with any clinical and biochemical parameters.
      Rapid hospital admission, regardless of age, is of major importance for
      prognosis. Improvement of non-cultural diagnostics tests and adjunctive therapy
      regimens are essential.

PMID- 8666842
TI  - The impact of bacteraemia on HIV infection. Nine years experience in a large
      Italian university hospital.
AB  - The object of this case control study was to evaluate the frequency, the risk
      factors, the microbiological spectrum and the outcome of 249 cases of bacteraemia
      observed in 209 HIV-infected patients, most them affected by AIDS. The rate of
      bacteraemia in the total yearly HIV-related admissions increased from 4% in 1985
      to 13% in 1993. The more common aetiological agents of bacteraemia were:
      Staphylococcus aureus (29.7%), non-typhoidal species of Salmonella (14.1%),
      Staphylococcus epidermidis (10.9%), Streptococcus pneumoniae (8.4%) and
      Pseudomonas aeruginosa (7.6%). A mixed flora was found in 14% of the episodes.
      Multivariate analysis of predisposing factors indicated that a low CD4+T-cell
      count (<0.2 x 10(9)/l) (P=0.01), use of central venous catheters (CVC) (P=0.01)
      and neutropenia (polymorphonuclear neutrophils <1.0 x 10(9)/l) (P=0.04) were
      independent risk factors for the development of bacteraemia. Logistic regression
      did not reveal any association of bacteraemia with intravenous drug abuse (on
      univariate analysis P=0.04). The response (31.8%). Recurrences to specific
      therapy was favourable in 170 episodes (68.2%); death occurred in 79 (31.8%).
      Recurrences arose in 40 patients, 17 (42.5%) of them died. The outcome of
      bacteraemia was influenced by a low number of CD4+T-cells (P<0.001) but not of
      polymorphonuclear cells. Our findings suggest that bacteraemia is a relatively
      common event in HIV-infected patients, especially under particular conditions
      (e.g. intravenous drug abuse, use of CVC, neutropenia and a low CD4-T-cell
      count). It requires special attention from physicians who must recognise and
      treat the condition promptly at an early stage.

PMID- 8666843
TI  - Migration and Helicobacter pylori seroprevalence: Bangladeshi migrants in the
      U.K.
AB  - Helicobacter pylori, an infectious agent of worldwide public health importance,
      has higher seroprevalence in developing countries than in developed countries. We
      investigated whether Bangladeshi women, born in Bangladesh, have a greater H.
      pylori seroprevalence than Bangladeshi women born in the U.K. and, in addition,
      whether there is an association between H. pylori seropositivity and age of
      migration to the U.K. amongst Bangladeshi women. Women attending antenatal
      clinics at the Royal London Hospital were screened using ELISA for anti-H. pylori
      IgG. In Bangladeshi individuals born in the U.K., 13/16 (81%, 95% confidence
      interval (CI) 54%-96%) and, in Bangladeshi individuals born in Bangladesh 91/137
      (66%, 95% CI 59%-74%) had antibodies to H. pylori. No significant association was
      found between H. pylori seropositivity and country of birth, or age at migration
      to the U.K. Public health strategies concerning H. pylori should consider migrant
      populations with high seroprevalence of H. pylori.

PMID- 8666844
TI  - An outbreak of Campylobacter jejuni enteritis associated with failed milk
      pasteurisation.
AB  - This paper describes an outbreak of gastrointestinal illness affecting at least
      110 people, of whom 41 had microbiological confirmation of Campylobacter jejuni
      infection. The outbreak of infection was found to have been associated with
      consumption of inadequately pasteurised milk from a local dairy. The problem of
      enforcement of food and safety regulations when milk from dairies fails the
      phosphatase test is discussed. The prevalence of seroconversion to campylobacter
      in the community is estimated from a sample of cases and controls involved in
      this outbreak.

PMID- 8666845
TI  - Circulating levels of mannose binding protein in human immunodeficiency virus
      infection.
AB  - Mannose binding protein (MBP) is a serum lectin which, upon binding to a
      carbohydrate extremity, acquires the ability to activate the classical complement
      pathway. MBP binds human immunodeficiency virus (HIV) in vitro via glycans on
      gp120 and thus, it may play a defensive role in HIV infection and contribute to
      virus clearance through the activation of complement associated with this
      condition. We measured serum MBP and activation indices of the classical
      complement pathway (plasma C4d and C3d) in HIV-seropositive patients at different
      stages of disease severity, and in normal subjects. MBP was higher in HIV
      patients as a whole and in each Centers for Disease Control (CDC) group than
      controls (P<0.01). MBP was not significantly different between CDC groups and and
      did not significantly correlate either with CD4-positive lymphocytes, neopterin
      or beta2-microglobulin or with C4d and C3d. The possibility that MBP plays a
      defensive role in HIV infection cannot be excluded, but, it it is, it does not
      appear to act by recruiting complement for vital elimination.

PMID- 8666846
TI  - Specificity of Widal test in healthy blood donors and patients with meningitis.

PMID- 8666847
TI  - A case of Fusobacterium necrophorum sepsis.

PMID- 8666848
TI  - Epidemiology and molecular characterisation of toxigenic Corynebacterium
      diphtheriae var mitis from a case of cutaneous diphtheria in Manchester.
AB  - Diphtheria is now an uncommon disease in Britain. We describe an imported case of
      cutaneous diphtheria in a previously immunised adult cause by C. diphtheriae var
      mitis. The control measures adopted to deal with the index case and two secondary
      cases so as to limit further spread among household and school contacts are
      outlined. Molecular typing was used to study the mode of spread of the organism
      among contacts.

PMID- 8666849
TI  - The presence of Epstein-Barr virus in multiple organs in a fatal case of virus
      associated haemophagocytic syndrome.
AB  - We describe a case report of a 21-year-old male with fatal Epstein-Barr virus
      associated haemophagocytic syndrome. Virus is detected in multiple organs by
      polymerase chain reaction and in the tissue-specific cells of those organs by in
      situ hybridisation. It is suggested that organ failure may be a direct response
      to infection.

PMID- 8666850
TI  - Meningitis in infancy caused by Pasteurella multocida.
AB  - A high proportion of household pets are colonised by Pasteurella multocida. The
      organism can be transmitted to humans by contact with animal saliva and is a
      recognised, although rare, cause of meningitis in infancy. Intimate contact
      between infants and family pets should be discouraged.

PMID- 8666851
TI  - HIV-2 infection with a long asymptomatic period.
AB  - We give details of a patient infected with HIV-2 which had what we believe to be
      the longest asymptomatic period so far reported. The infection was probably
      acquired though a blood transfusion in Africa 27 years ago. At present the
      patient remains asymptomatic and her cellular defence mechanisms, evaluated by
      CD+4 lymphocyte counts and hypersensitivity skin tests, are not severely
      compromised. HIV-2 has come distinct epidemiological, clinical and biological
      features which are different from the related HIV-1 and deserve investigation in
      order for its natural history to be better understood.

PMID- 8666852
TI  - Pulmonary actinomycosis--a master of disguise.
AB  - Three cases of pulmonary actinomycosis are described. In all three cases, an
      initial diagnosis of pulmonary malignant neoplasia was made. The correct
      diagnosis was made histologically after the three patients underwent either
      lobectomy or pneumonectomy. All patients recovered after appropriate therapy.
      Pulmonary actinomycosis should always be considered in the differential diagnosis
      of pulmonary neoplasia, especially in young adults.

PMID- 8666853
TI  - Reactive arthritis as a complication of Campylobacter lari enteritis.

PMID- 8666854
TI  - Haemagglutination is not correlated with pathogenicity in Helicobacter.

PMID- 8666855
TI  - Fever in the returned traveller. Remember murine typhus!

PMID- 8666856
TI  - Parapharyngeal abscess from Pseudomonas aeruginosa infection in an HIV positive
      patient.

PMID- 8666857
TI  - Pasteurella multocida septicaemia in Milroy's disease.

PMID- 8666858
TI  - Xanthomonas maltophilia and Pseudomonas cepacia in lower respiratory tracts of
      patients in critical care units.
AB  - Xanthomonas maltophilia and Pseudomonas cepacia are Gram-negative bacilli that
      are considered to opportunistic pathogens. These bacteria may cause colonization
      and infection, especially in acutely ill patients. Between 1 July 1990 and 30
      June 1992 sputum [correction of suptum] culture results from patients in the
      critical care units were surveyed daily. During the 2 year period, sputum from 27
      patients grew X. maltophilia. It was hospital-acquired in 26 patients. A total of
      26 patients were mechanically ventilated for between 1 day and 8 months (median
      19 days) before sputum cultures grew X. maltophilia. Various antimicrobial agents
      were prescribed for 25 of the 27 patients before they acquired X. maltophilia
      infection. The case fatality was 44.4%. Sputum from 79 patients grew P. cepacia.
      It was hospital-acquired in all who were ventilated for between 1 day and 50 days
      (median 9 days) before sputum cultures grew P. cepacia. Several antimicrobial
      agents were given to 77 patients before P. cepacia was isolated from them. The
      case fatality rate was 51.9%. In the majority of cases, the positive cultures
      indicated colonization. Patients with APACHE II scores >15 experienced a higher
      fatality (55.6% vs. 22.2%, P<0.05 for X. maltophilia and 56.9% vs.28.6%, P<0.05
      for P. cepacia).

PMID- 8666859
TI  - Diagnostic challenge of tuberculosis of the elderly in hospital: experience at a
      university hospital in Saudi Arabia.
AB  - We studied retrospectively 80 elderly patients who had been admitted to hospital
      with tuberculosis (TB) between January 1988 and June 1993. There were 64 with
      pulmonary TB and 16 with miliary tuberculosis (MTB). The mean age was 70+/-7.5
      years (range 60-88 years) with 56% over 70 years of age. Underlying disease
      preceding TB was present in 86.3% patients. In the majority of patients clinical
      manifestations were subtle. Chest X-ray showed involvement of lower lung fields
      and miliary shadowing in 71.2% (33/80) and 20% (16/80) patients, respectively.
      The organism was detected in expectorated sputum specimens in 62.5% (50/80). Of
      the specimens obtained by flexible fibreoptic bronchoscopy (FOB), 61% were
      positive for acid-fast bacilli (AFB) by films and culture. Drug-induced adverse
      effects were observed in 17.6% (6/34). In 18 patients (22.5%), the diagnosis of
      TB was delayed or missed. The overall mortality of 21% (9/43) included seven
      patients with MTB and two with pulmonary TB. TB was the direct cause of death in
      the former and a significant contributory cause in the latter.

PMID- 8666860
TI  - Better efficacy of twice-monthly than monthly aerosolised pentamidine for
      secondary prophylaxis of Pneumocystis carinii pneumonia in patients with AIDS. An
      Italian multicentric randomised controlled trial. The Italian PCP Study Group.
AB  - The aim of this multicentric randomised controlled trial was to evaluate long
      term efficacy and safety of once-monthly versus twice-monthly 300 mg aerosolized
      pentamidine (AP) as secondary prophylaxis of Pneumocystis carinii pneumonia
      (PCP). We randomised 205 patients with a previous confirmed episode of PCP (107
      treated with 300 mg once-monthly AP, and 98 with 300 mg twice monthly AP); the
      median review period was 232 days. Kaplan-Meier method and Cox's hazard
      regression model were used for analysis. The main outcome assessments were PCP
      recurrence, survival and incidence of drug toxicity. The two groups were balanced
      for prognostic predictors. In the once-monthly AP group, 14 relapses of confirmed
      PCP were observed, while five occurred in the twice-monthly AP group; the crude
      relative risk (RR) was 2.69 (95% CI 1.002-7.236, P=0.0496) and the adjusted RR
      accounting for prognostic predictors was 2.62 (95% CI 0.92-7.5, P=0.071). Death
      occurred in 36 of 26 patients respectively (adjusted RR 1.32, 95% CI 0.8-2.18,
      P=0.28). Two patients interrupted the study because of intolerance to AP (one in
      each group), and severe coughing occurred in two patients (one in each group). At
      the end of the study, pulmonary function tests were not changed compared with
      baseline and were the same between the two groups. Our study suggests that 300 mg
      twice-monthly AP is more effective than 300 mg once-monthly AP as secondary
      prophylaxis of PCP.

PMID- 8666861
TI  - [Valvular surgery in the patients more than 70 years old].
AB  - One hundred twenty-eight valvular surgeries in patients over 70-year-old were
      reviewed (AVR:58, MVR:38, AVR and MVR: 11, mitral valvuloplasty (MVP): 11, AVR +
      MVP:11, mitral valvuloplasty (MVP): 11, AVR + MVP: 8, others: 2). Concomitant
      CABG was performed in 7, Maze in 6, TVR in 5 and Bentall in 3 cases. Early deaths
      occurred in 17 patients (13%). The early mortality was 5% in AVR, 21% MVR, 18% in
      AVR and MVR, 0% in MVP and 38% in AVR and MVP. Late death occurred in 16
      patients. Forty-three percent of the late deaths were cardiac death. The
      actuarial survival at 10 years was around 50% in all groups. In the aortic
      position, a mechanical valve was implanted in 47 cases and a bioprosthetic valve
      was implanted in 33 cases. In the mitral position, the mechanical valve was
      implanted in 37 cases and the bioprosthetic valve was implanted in 12 cases. The
      event free rate after AVR at 10 years was 37% in patients with the mechanical
      valve (3 cerebral hemorrhage, 2 PVE, 1 thromboembolism and 1 sudden death) and
      46% in patients with the bioprosthetic valve (2 PVE and 1 primary tissue
      failure). The event free rate after MVR at 10 years was 84% in patients with
      mechanical valves (1 perivalvular leak, 1 PVE and 1 sudden death) and 75% in
      patients with bioprosthetic valves (1 PVE and 1 sudden death). Between mechanical
      valve group and bioprosthesis group, no statistically significance was found in
      the event free curve after AVR nor MVR. There was no valve related event after
      MVP. Considering the better durability of bioprostheses in the aortic position
      than in the mitral position, the presence of atrial fibrillation and necessity of
      warfarin anticoagulation, we conclude that a choice of a bioprosthetic valve
      could be acceptable in the aortic position, but may not be recommended in the
      mitral position.

PMID- 8666862
TI  - [Efficacy of coronary artery reconstruction in maintaining myocardial viability:
      quantitative determination of local myocardial circulation with 13NH3 myocardial
      positron emission tomography].
AB  - Thirty patients (280 areas) whose bypass grafts remained patent after surgical
      reconstruction of the coronary artery were examined. Before and after
      reconstruction, local myocardial blood circulation in infarcted regions and post
      stenotic regions was measured by 13 NH(3) myocardial positron emission computed
      tomography (PET) at rest of during physical exercise in order to evaluate the
      efficacy of coronary artery reconstruction. Before operation, mean blood flow in
      post-stenotic regions (n = 198) was 65 +/- 15 ml/min/100 g at rest and 85 +/- 23
      ml/min/100 g during exercise. After coronary artery bypass grafting (CABG), mean
      blood flow was increased to 78 +/ 21 ml/min/100 g at rest (p, 0.01) and 105 +/-
      32 ml/min/100 g during exercise (p < 0.01). In infarcted regions (n = 82), mean
      blood flow before operation was 51 +/- 23 ml/min/100 g at rest and 69 +/- 23
      ml/min/100 g during exercise. After CABG, it increased to 62 +/- 19 ml/min/100 g
      at rest (p < 0.01) and 81 +/- 29 ml/min/100 g during exercise (p < 0.01). Thus,
      significant increases in blood flow were observed in both post-stenotic and
      infarcted regions at rest and physical exercise after operation. The regions of
      infarction were divided into three groups based on local myocardial blood flow at
      rest before operation: Group I: greater than 45 ml/min/100 g (n = 35); Group II:
      less than 45 ml/min/100 g (n = 30) but greater than 30 ml/min/100 g; and Group
      III: less than 30 ml/min/100 g (n = 30). The efficacy of reconstruction was
      compared among these groups. The group with preoperative myocardial blood flow
      greater than 30 ml/min/100 g had increased blood flow after operation, indicating
      myocardial viability.

PMID- 8666863
TI  - [Comparison between intermittent retrograde cold blood cardioplegia and
      retrograde crystalloid cardioplegia].
AB  - Intermittent retrograde cold blood cardioplegia was compared with retrograde
      crystalloid cardioplegia. Twenty-two adult patients underwent open heart surgery
      divided into two groups. Group BCP (n = 10) was protected with 15 degrees C blood
      containing potassium 15 mEq/l; Group CCP (n = 12) was protected with 4 degrees C
      St. Thomas' Hospital cardioplegic solution. Lactate, pyruvate, and CK-MB levels
      in coronary sinus blood were measured at 5 and 15 minutes after aortic unclamping
      and 5 minutes after weaning from cardiopulmonary bypass (CPB) in both groups. CPB
      time, cross-cross clamp time, incidence of postoperative low output syndrome and
      spontaneous return to sinus rhythm after aortic unclamping were not different
      between two groups. Cardiac index and pulmonary capillary wedge pressure measured
      immediately after weaning from CPB, were not different in both groups. Lactate
      level was significantly low in group BCP. Lactate uptaking ratio of myocardium
      was significantly high in group BCP. CK-MB levels were not different between two
      groups. Cold blood cardioplegia was seemed to provide better aerobic myocardial
      metabolism during aortic cross clamp. However, CK-MB levels and hemodynamic
      studies were not different.

PMID- 8666864
TI  - [Analysis of specificity of resected esophageal cancer patients with a history of
      apoplexy].
AB  - We studied 15 resected cases with a history of apoplexy (2.5%) among 599 cases of
      esophageal cancer admitted between 1972 and 1993. Fourteen were male, and female,
      aged 48 to 77 years. Twelve had suffered from cerebral infarction, 2
      intracerebral hemorrhage, and one subarachnoid hemorrhage. Duration from apoplexy
      to operation was between 2 months and 19 years in the cerebral infarction cases,
      between 8 and 10 years in the intracerebral hemorrhage cases and 4 years in the
      subarachnoid hemorrhage case. Preoperative neurological disturbance was found in
      7 of the 12 cerebral infarction cases, and in both intracerebral hemorrhage
      cases. Four cases showed hemiplegia, and the other 5 cases showed partial
      paralysis of limbs. Preoperative complications were found in 7 of the 15 cases,
      and consisted of diabetes mellitus in 5, hypertension in 4, bronchial asthma in
      one, and renal dysfunction in one case. Intra- and postoperative complications
      were found in 11 of the 15 cases, and consisted of anastomotic leakage in 5,
      delirium in 3, apoplexy in 2, peritonitis in one, ARDS in one, intraoperative
      cardiac arrest in one, and wound infection in one. Postoperative disorders of
      consciousness were found in 5 cases, consisting of delirium in 3, and excitation
      at awakening of anethesia in 2 cases. Rate of direct operative death was 6.7% in
      preoperative apoplectic patients, and 8.5% in non-apoplectic patients, and there
      was no significant difference between the 2 groups. On the other hand, rate of
      postoperative apoplexy was 13.3% in the preoperative apoplectic patients, and
      0.4% in non-apoplectic patients. There was a significant difference between them
      (p < 0.01). But they were cured of it, and left our hospital. It is concluded
      that active surgical treatment can be indicated for esophageal cancer patients
      with a history of apoplexy, if more attention is given to the management of
      diabetes mellitus or hypertension.

PMID- 8666865
TI  - [Carotid screening with duplex scanning before coronary artery bypass].
AB  - Seventy-one patients undergoing scheduled coronary artery bypass were
      preoperatively evaluated for the presence of carotid stenosis by duplex scanning.
      Prevalence of a moderate degree of stenosis (peak systolic flow velocity of
      internal carotid artery > 130 cm/sec) or a high degree of stenosis (peak systolic
      flow velocity > 250 or < 25 cm/sec) was 12.7% (nine patients). Predictive risk
      factors for carotid stenosis were diabetes mellitus and history of stroke.
      Compared with carotid angiogram, hemodynamically critical stenosis greater than
      90% was found in three patients, severe stenosis (75-90%) in four, moderate
      stenosis (50-75%) in two. Bilateral carotid occlusion, complete occlusion of an
      internal carotid artery with contralateral 99% stenosis, was found in one
      patient. In the critical stenosis group (n = 3), simultaneous carotid
      endarterectomy and coronary artery bypass were performed in two and coronary
      artery bypass alone in one patient with unilateral complete occlusion of the
      internal carotid artery. There was neither operative death nor postoperative
      stroke in this series of patients. In conclusion, carotid screening with a duplex
      scan is very helpful to evaluate the presence of carotid occlusive disease in
      coronary artery bypass candidates. When significant carotid stenosis is detected,
      further examination should be done to clarify the carotid hemodynamics and brain
      protection during the operation should be employed.

PMID- 8666866
TI  - [Prognosis of the surgical treatment for non-Hodgkin lymphoma originating from
      chronic tuberculous empyema--analysis of 11 cases with pleuropneumonectomy].
AB  - In total 19 cases of non-Hodgkin lymphoma originating from the wall of chronic
      tuberculous empyema, pleuropneumonectomeic were performed since 1979, with the
      aim of total cures for not only lymphoma but empyema in 11 cases. Of these cases
      extraresections (5 of thoracic cages, 4 of diaphragms, 2 of axillar lymph nodes,
      each of adventitia of descending aorta and esophagus, of the liver, of the left
      adrenal grand) were added to extirpate tumors completely. The mean operating time
      was 6 degrees 55', the mean blood loss during operations was 3090 ml, but in the
      3 most recent cases it was less than under 1000 ml using electrocartesy-cutting
      technique under direct observation. Although preoperative radiations were done to
      4 cases to decrease invasive area of tumors and postoperative radiation was done
      to 1 case, there were no adjuvant chemotherapies. The indicative limitation for
      resections from the point of ventilatory functions was the same as that of
      pleuropneumonectomy for ordinary chronic tuberculous empyema. There were 2 cases
      with serious postoperative complications. One suffered from ARDS and died on the
      14th postoperative day, and another developed acute respiratory failure and MOF.
      But the other 9 cases kept good postoperative courses with a few recurrences of
      minor empyema. The prognoses for 10 remaining cases is excellent. Only one case
      died from local recurrence in of lymphoma 27 months later, but all other 9 cases
      have revealed no recurrence in any places, and the 5 year survival rate based on
      Kaplan-Meier method of 10 cases is 85.7%. By the way no cases could survive one
      year later in unresected group. So under the poor prognosis of treatment with
      radiation or chemotherapy for non-Hodgkin lymphoma originating from chronic
      tuberculous empyema, we conclude that the complete resection of tumor and
      empyema, so called pleuropneumonectomy, is the best way to cure this disease.

PMID- 8666867
TI  - [Open heart surgery in patients with systemic diseases requiring steroid
      treatment].
AB  - Our surgical experiences in 9 patients who required steroid treatment for
      systemic diseases before, during and after the open heart surgery were reviewed.
      Subjects included 3 patients with systemic lupus erythematodes, 3 with aortitis
      syndrome, 1 with Behcet disease and 1 with rheumatoid arthritis. Cardiovascular
      lesion was aortic valve regurgitation in 2, Stanford A aortic dissection in 1 and
      ischemic heart disease in 3 patients. Duration of morbidity for systemic diseases
      before the surgery ranged between 0 nd 102 months, with a mean of 36 months.
      Steroid treatment was continued for 4 to 216 months (mean 70+/-76 months) before
      the surgery at a dose of 5-40 mg per day for conversion into prednisolone. In
      principal, methylprednisolone was given during the surgery, and the prednisolone
      was given at a dose of 20-140 mg per day on the day of operation or on the first
      postoperative day. Surgical procedures included a aortic valve prosthesis with
      Dacron cloth skirt implantation in 1 patient, surgical angioplasty of the left
      main coronary ostium in 1 and internal thoracic arteries grafting in 2 patients.
      Hospital mortality was 1 patient due to low cardiac output syndrome. Acute renal
      failure occurred in 2 patients with systemic lupus erythematodes, and wound
      complication was observed in 2 patients. In our experience, appropriate treatment
      for systemic diseases, timing of surgery and continuation of steroid treatment at
      an appropriate dose during and after the surgery seemed very important such as
      surgical procedure in order to prevent postoperative complications such as
      periprosthetic leakage and failure of anastomosis.

PMID- 8666868
TI  - [Acute aortic dissection with leg ischemia].
AB  - From January of 1987 to July of 1994, 83 patients with acute aortic dissection
      were treated at our institution. Of these, 7 patients (8%) sustained acute leg
      ischemia. Angiography showed that one patient had arterial occlusion at the
      abdominal aorta, three had occlusion at the right common iliac artery, and one
      had severe right common iliac artery stenosis. Four patients with acute type A
      dissection underwent emergency replacement of the aortic arch and/or ascending
      aorta. Three of them were discharged, but one patient died due to renal failure
      and multiple organ failure. In three patients with acute type B dissection, one
      with aortic rupture was successfully treated by replacement of the descending
      thoracic aorta; of the other two who received bypass operations for leg ischemia,
      one died due to myonephropathic metabolic syndrome and sepsis which were caused
      by a delay in surgery. In conclusion, emergency thoracic aortic repair should be
      performed in acute type A dissection with leg ischemia, whereas bypass operation
      for ischemic leg should be considered in patients of acute type B dissection with
      leg ischemia when they are not complicated with rupture or visceral ischemia.

PMID- 8666869
TI  - [Review of results after surgery for pulmonary embolism].
AB  - The results of direct pulmonary embolectomy in 20 cases of pulmonary embolism
      treated in our facility from 1982 to May, 1995 was analyzed. The ages of the
      patients ranged from 25 to 72 years (mean: 46 years). The male-to-female ratio
      was 12:8. The 20 cases were divided into three groups based on the type of
      pulmonary embolism: Group I (4 cases of acute massive pulmonary thrombo
      embolism). Group II (12 cases of chronic pulmonary thrombo-embolism) and Group
      III (4 cases of tumor embolism). In Group I, 2 patients developed shock and 2
      developed severe right heart failure. Emergency thrombectomy using
      cardiopulmonary bypass succeeded in saving the lives of 3 patients in this group.
      In Group II, the preoperative NYHA grade was II in 1 case, III in 9 cases, and IV
      in 2 cases. The preoperative systolic pressure of the pulmonary artery ranged
      from 24 to 90 mmHg (mean: 74 mmHg). Surgery through a thoracotomy was carried out
      on 7 cases (on the right side in 4 cases on the left in 3 cases). Of these 7
      patients, 2 died of heart failure and respiratory failure because
      thromboendarterectomy was inadequate. In another 2 patients, symptoms improved
      enough to allow them to resume their previous lives. The other three patients
      showed no change in their symptoms after surgery, but they could be discharged.
      The remaining 5 patients in Group II underwent surgery through the median
      approach. Deep hypothermia with circulatory arrest was used in the latter 4 of
      these 5 patients during surgery. 3 patients died during the perioperative period
      because adequate thromboendarterectomy was not possible and because their
      preoperative condition was very poor. 2 patients who were able to be performed
      adequate thromboendarterectomy showed good postoperative courses. Of the 4
      patients in Group III, one patient survived 11 months after surgery, but the
      other 3 died during the preoperative period because very little embolus could be
      removed. These results allow us to conclude that the lives of patients with acute
      pulmonary thromboembolism can be saved by early detection and prompt surgery, but
      that management of chronic pulmonary thromboembolism involves difficulties in
      selecting surgical cases and in performing thromboendarterectomy.

PMID- 8666871
TI  - [A report of surgical treatment for atherosclerotic aneurysm in the aortic arch
      associated with type III acute aortic dissection].
AB  - A 75-year-old man was admitted to our hospital because of severe chest pain. A
      chest CT scan demonstrated an atherosclerotic true aneurysm measuring 50 mm in
      diameter located just distal to the aortic arch as well as a DeBakey type III
      dissection. Although the patient received medical therapy, the size of the true
      aortic aneurysm increased to 71 mm and the false lumen of the descending aorta
      was also enlarged after three weeks. At 11 weeks after admission, the aortic arch
      and the proximal portion of the descending aorta were replaced with a 32 mm
      Hemashield graft using moderate hypothermic selective cerebral perfusion. The
      postoperative course was uneventful, and there were no neurological
      complications. Coexistence of atherosclerotic true aneurysm and acute aortic
      dissection appears to increase the risk of aortic rupture, early surgical
      treatment should be considered.

PMID- 8666870
TI  - [Left free wall rupture complicating acute myocardial infarction--a case report
      of surgical success by a new modified method].
AB  - The success rate of surgical treatment for blowout type free wall rupture of the
      left ventricle following myocardial infarction has been reported as 4 to 24%. A
      64-year-old woman was admitted to our hospital for inferior acute myocardial
      infarction with cardiogenic shock. In the catheter laboratory, her hemodynamics
      disclosed electro-mechanical dissociation, and we had to perform an emergent
      operation there. In order to preserve left ventricular volume and reduce the risk
      of bleeding, we adopted a modified method using both patch and felt strip
      sandwich methods which obtained favorable result. The patient was sent to a
      rehabilitation hospital on the 43rd post operative day because of a mild cerebral
      complication and she is now doing well with only a slight speaking disturbance at
      a follow-up period of 10 months.

PMID- 8666872
TI  - [A case of dumbbell-shaped chondrosarcoma of the rib in the posterior
      mediastinum].
AB  - A 43-year-old man was pointed out an abnormal shadow in the left hilar lesion
      with no symptom. Chest CT and MRI showed that the mass might be a dumbbell-shaped
      neurogenic mediastinal tumor next to the 8th thoracic intervertebral foramen. The
      resection of the chest wall and the thoracic vertebrae including the tumor was
      carried out, so it was revealed chondrosarcoma arising from the 8th rib by the
      operative findings and histological examination. The dumbbell-shaped
      chondrosarcoma of the rib in the posterior mediastinum is very rare, and a brief
      review was made from the literature.

PMID- 8666873
TI  - [A case of resected lung cancer associated with bullous pemphigoid].
AB  - The relationship between bullous pemphigoid and malignancies of visceral organs
      is still controversial. A case of lung cancer associated with bullous pemphigoid
      is reported. A 63-year-old man admitted hospital because of multiple bullae of
      the whole body skin and continuous fever. The skin lesions were diagnosed as
      bullous pemphigoid by the skin biopsy. However, the chest x-ray on admission
      revealed a large tumor in the left upper lung field. The tumor was diagnosed as a
      lung cancer by trans-bronchial lung biopsy. The fever withdrew with the
      administration of prednisolone. The left upper lobectomy of the lung and
      mediastinal lymph node dissection were performed. The skin lesion disappeared 5
      days after the surgery. This clinical course is thought to indicate the
      relationship of both diseases. Bullous pemphigoid is thought to have many
      problems during perioperative period, such as hypoproteinemia and delayed wound
      healing due to administration of the steroid, therefore intensive care is
      necessary in the perioperative care.

PMID- 8666874
TI  - [A successful surgical case of descending necrotizing mediastinitis with fistula
      formation to the right main bronchus].
AB  - Descending necrotizing mediastinitis (DNM) is extremely rare and one of the most
      lethal forms of mediastinitis, even in the era of antibiotics. We have recently
      treated a 65-year-old man who was diagnosed as having a fistula to the right main
      bronchus caused by DNM secondary to a peritonsillar abscess. Surgical treatment
      consisted in closing the right bronchial fistula and covering it with the
      latissimus dorsi muscle flap and mediastinal drainage through thoracotomy.
      Postoperative course was uneventful. This is the second known reported case of a
      successful operation for DNM with bronchial fistula.

PMID- 8666875
TI  - [Dissection of the interventricular septum with aorto-left ventricular
      communication due to infective endocarditis--report of a rare case].
AB  - Dissection of the interventricular septum is an uncommon manifestation, which is
      rarely associated with infective endocarditis, aneurysm of sinus of Valsalva and
      thoracic trauma. We report a 34-year-old male case with aorto-left ventricular
      communication due to infective endocarditis. The patient had chief complaints of
      dyspnea on exertion and precordial discomfort. Preoperative laboratory data
      showed normal white blood cell counts, a slightly elevated CRP, and negative
      blood culture in bacterial examinations. Echocardiogram revealed progressive
      dissection of the interventricular septum and stenosis of the left ventricular
      outflow tract. Disturbance of conduction including progressive atrioventricular
      block and bundle branch block were found in the electrocardiogram. The dissection
      extended over 2 x 2 x 2.5 cm in diameter, with an entry located at the basis of
      the right coronary cusp and reentry communicated to the left ventricle. Operative
      procedures included the aortic valve replacement with prosthetic valve due to
      severe inflammation, in addition to resection of the dissecting cavity.
      Pathological examination of the resected tissue accorded with infective
      endocarditis in active phase, showing necrosis, small cell infiltration and
      microabscess. However, a bacterial colony was not found in the surgical specimen.
      Postoperative course was uneventful and the patient was discharged in
      satisfactory conditions.

PMID- 8666876
TI  - [A case report of a left atrial ball thrombus at 16 years after mitral valve
      replacement].
AB  - A free floating ball thrombus in left atrium is very rare, only 2 cases that
      develop ball thrombus after mitral valve replacement (MVR) have been reported.
      This case was a 55-year-old female who underwent MVR and tricuspid annuloplasty
      (TAP) in 1978. After 16 years, she developed replaced mitral valve stenosis due
      to pannus formation and tricuspid regurgitation (TR), with a free floating ball
      thrombus in the giant left atrium. A ball thrombus was taken out, and Re-MVR and
      tricuspid valve replacement (TVR) was carried out. Post operative course was
      uneventful. Because a free floating ball thrombus easily causes "Hole-in-one"
      sudden death, early surgical treatment must be considered.

PMID- 8666877
TI  - [Report of a case with re-mitral valve replacement for Bjork-Shiley Delrin disc
      valve prosthesis--disc wear of the Delrin disc 20 years after implantation].
AB  - We reported a patient in whom slight congestive heart failure gradually developed
      20 years after mitral valve replacement with a Delrin disc Bjork-Shiley valve
      prosthesis. Although no evident cause of prosthetic valve malfunction could be
      detected preoperatively, the mitral prosthesis was excised and replaced
      uneventfully with a 29 mm St. Jude Medical valve prosthesis. At gross inspection,
      marked wears of the Delrin disc surface and strut shaped indentations were
      present. These disc variance, occurred much earlier than initially predicted by
      Dr. Bjork, allowed prosthetic valve malfunction. The patient with this specific
      model should be carefully followed-up, if necessary, performed reoperation.

PMID- 8666878
TI  - [Isolated rupture of the ventricular septum caused by nonpenetrating trauma--a
      case report of operation in acute stage].
AB  - We experienced a case of the isolated ventricular septal defect due to
      nonpenetrating chest trauma. The patient was 22-year-old male who hit his chest
      with a steering wheel on car accident. The echocardiogram examined on the next
      day revealed a ventricular septal defect. Four days after the injury,
      intracardiac repair was performed. On cardiopulmonary bypass the ventricular
      perforation (35 x 35 mm size) located in the muscular portion near the apex was
      closed with a PTFE and equestrian pericardial patch. Postoperative
      cardiopulmonary function could improve enough to wean from IABP and respiratory
      support. However, the patient died on the fifth postoperative day of severe
      hepatic failure due to profound shock persisted after the accident.

PMID- 8666879
TI  - [Tricuspid valve replacement by right thoracotomy with minimal dissection in
      reoperations].
AB  - We report two cases of tricuspid valve replacement for tricuspid valve
      insufficiency as reoperations following mitral valve replacement through midline
      sternotomy. A right thoracotomy was used to approach the tricuspid valve. To
      avoid the risk of cardiac laceration, cardiopulmonary bypass was instituted after
      cannulation of the femoral artery and of superior vena cava through right atrium
      with balloon caval occlusion and inferior vena cava through the femoral vein with
      balloon caval occlusion. Without aortic cross clamping under mild hypothermia,
      right atriotomy was performed through adherent parietal pleura, pericardium, and
      right atrial wall without dissection. Tricuspid valve was replaced utilizing the
      bioprosthetic valve with good clinical results. These new measures were
      expeditiously carried out without dissection of the heart, which has been deemed
      to be the risk of reoperations.

PMID- 8666880
TI  - [Surgical repair of atrial septal defect in patients over 70 years of age].
AB  - Three patients over 70 years of age underwent surgical repair of secundum atrial
      septal defect (ASD). All patients had preoperative symptoms such as heart
      failure, atrial fibrillation and cardiomegaly. According to the New York Heart
      Association (NYHA) functional classification, two patients belonged to class II
      and one class III. Cardiac catheterization data revealed mild pulmonary
      hypertension and mild to moderate tricuspid regurgitation in all the patients. An
      ASD was directly closed in all the patients, and two of them required tricuspid
      anuloplasty. The use of catecholamine continued for two or three weeks in two
      patients because of postoperative cardiac dysfunction. Postoperative physical
      activity has improved in all the patients. Surgical repair of an ASD is
      recommended even for patients over 70 years of age unless they have major risks
      and severe pulmonary hypertension.

PMID- 8666881
TI  - [Extralobar sequestration presenting increased serum CA19-9 and associated with
      lung aspergillosis--an unusual case].
AB  - In a thirty-four-year old man, an asymptomatic abnormal mass shadow was detected
      in S10 of the left lower lobe on chest X-ray film. The serum CA19-9 was
      abnormally elevated 395 U/ml). The definitive histological diagnosis was not
      obtained by both transbronchial and percutaneous lung biopsy preoperatively.
      Surgery demonstrated that an abnormal mass was separated from S10 of the left
      lower lobe by a fibrous tissue, and it contained severe inflammatory changes and
      abscess. Extralobar pulmonary sequestration was diagnosed, but aberrant arteries
      were not conformed. Sequestered lung and a part of the lower lobe were resected
      en bloc. The serum CA19-9 level returned to normal postoperatively. Aspergillus
      was only detected in the sequestered lung by postoperative cultre. Moreover, CA19
      9 level in the fluid of this sequestered lung was markedly high, 50,000 U/ml.
      Production of CA19-9 was demonstrated in bronchial epithelium of the sequestered
      lung immunohistochemically. Extralobar pulmonary sequestration associated with
      aspergillosis and high serum CA19-9 is very rare. To our knowledge, this is the
      first reported case in the literatures.

PMID- 8666882
TI  - [Successful aorto-coronary bypass grafting and concomitant left ventricular
      myotomy-myectomy in a patient with coronary artery disease associated with
      hypertrophic obstructive cardiomyopathy].
AB  - A 65-year-old man complained chest oppression at rest and dizziness.
      Echocardiography showed subaortic stenosis with outflow gradient of 100 mmHg,
      although interventricular septal thickness was only 12 mm and left ventricular
      posterior wall thickness was 11 mm, and mild mitral regurgitation. Selective
      coronary angiography demonstrated 90% stenosis in left main truncus, 50% stenosis
      in first diagonal branch, and hypoplastic right coronary artery. Emergent
      coronary artery revasculization concomitant with left ventricular myotomy
      myectomy was performed. Immediately after weaning off the cardiopulmonary pump,
      IABP was employed for cardiac assistance, because of residual left ventricular
      outflow pressure gradient, which was provoked by cathecholamine and amyl nitrite.
      He was discharged in 1 month in NYHA class I. Echocardiography 3 months after
      operation showed no residual outflow pressure gradient, no systolic anterior
      motion of mitral anterior leaflet, and mild approximately mitral regurgitation.
      Careful operative management, including myocardial protection and avoiding
      perforation of ventricular septum and postoperative medical care are mandatory to
      this group of patients. This case is the first successful coronary artery bypass
      grafting and concomitant left ventricular myotomy-myectomy reported in Japan.

PMID- 8666883
TI  - [Single-stage surgery for annulo aortic ectasia, Stanford type-A aortic
      dissection and pectus excavatum in a patient with Marfan's syndrome].
AB  - A 43-year-old female was hospitalized on October 25, 1993, due to severe back
      pain. She was diagnosed with annulo aortic ectasis, Stanford type-A acute aortic
      dissection and pectus excavatum caused by Marfan's syndrome. On November 30,
      1993, single-stage surgery was performed, including modified Bentall procedure,
      aortic arch replacement, elephant trunk method and sternoplasty. Concerning the
      procedure for pectus excavatum, sternoplasty was selected because we thought that
      sternoplasty could endure the long procedure which would cause infection compared
      with sternal turnover. Postoperative course was satisfactory, and she is well 18
      months after surgery.

PMID- 8666884
TI  - [Mid mediastinal lipoma--a case report].
AB  - Mediastinal lipomas are relatively rare neoplasm in Japan. They are generally
      asymptomatic tumors because they often arise from anterior mediastinum especially
      nearby diaphragma. We experienced a 67-year-old man who presented with transient
      edema on the face and upper limbs. The phlebography showed compression of left
      brachiocephalic vein, superior vena cava and right pulmonary artery by the tumor.
      The sagittal view of the chest MRI gave precise and useful anatomical
      informations. The complete resection of the tumor was performed uneventfully. The
      tumor was 15 x 12 x 5 cm in size, and there was no secondary change at the
      superior vena cava. Postoperative chest CT showed the complete decompression of
      the superior vena cava. The pathological diagnosis of the tumor was benign mature
      lipoma. Postoperative course was uneventful and the patient is now being well.
      There is no evidence of recurrence 6 months after the operation. This is the
      first report of the mediastinal lipoma which arised from the mediastinum in
      Japanese literature as far as we have reviewed.

PMID- 8666885
TI  - New insights into the mobilization and phagocytic activity of dendritic cells.

PMID- 8666886
TI  - Apoptosis: mitochondria resurrected?

PMID- 8666887
TI  - Primary allergic sensitization to environmental antigens: perinatal T cell
      priming as a determinant of responder phenotype in adulthood.

PMID- 8666888
TI  - Central role of immunoglobulin (Ig) E in the induction of lung eosinophil
      infiltration and T helper 2 cell cytokine production: inhibition by a non
      anaphylactogenic anti-IgE antibody.
AB  - Elevated levels of immunoglobulin (Ig) E are associated with bronchial asthma, a
      disease characterized by eosinophilic inflammation of the airways. Activation of
      antigen-specific T helper (Th) 2 cells in the lung with the subsequent release of
      interleukin (IL) 4 and IL-5 is believed to play an important role in the
      pathogenesis of this disease. In this study, we have used a non-anaphylactogenic
      anti-mouse-IgE antibody to investigate the relationship between IgE, airway
      eosinophil infiltration, and the production of Th2 cytokines. Immunization of
      mice with house dust mite antigen increased serum levels of IgE and IgG. Antigen
      challenge of immunized but not control mice induced an infiltration of
      eosinophils in the bronchoalveolar lavage associated with the production of IL-4
      and IL-5 from lung purified Thy1.2+ cells activated through the CD3-T cell
      receptor complex. Administration of the anti-IgE monoclonal antibody (mAb) 6h
      before antigen challenge neutralized serum IgE but not IgG and inhibited the
      recruitment of eosinophils into the lungs and the production of IL-4 and IL-5 but
      not interferon gamma. Studies performed using an anti-CD23 mAb, CD23 deficient
      and mast cell deficient mice suggest that anti-IgE mAb suppresses eosinophil
      infiltration and Th2 cytokine production by inhibiting IgE-CD23-facilitated
      antigen presentation to T cells. Our results demonstrate that IgE-dependent
      mechanisms are important in the induction of a Th2 immune response and the
      subsequent infiltration of eosinophils into the airways. Neutralization of IgE,
      for example, non-anaphylactogenic anti-IgE mAbs may provide a novel therapeutic
      approach to the treatment of allergic airway disease.

PMID- 8666889
TI  - Endogenous altered peptide ligands can affect peripheral T cell responses.
AB  - T cells potentially encounter a large number of endogenous self-peptide/MHC
      ligands in the thymus and the periphery. These endogenous ligands are critical to
      both positive and negative selection in the thymus; however, their effect on
      peripheral T cells has not been directly ascertained. Using the murine allelic
      Hbd (64-76)/I-Ek self-antigen model, we have previously identified altered
      peptide ligands (APLs) which are able to stimulate some but not all TCR-mediated
      effector functions. To determine directly the effect of endogenously synthesized
      APL/MHC complexes on peripheral T cells, we used a TCR transgenic mouse which had
      reversed our normal antigen system, with Ser69 peptide now being the agonist and
      Hbd(64-76) being the APL. In this report, we show that the constitutive level of
      endogenous Hbd(64-76)/I-Ek complexes presented by APCs in vivo is too low to
      affect the response of Ser69 reactive T cells. However, by increasing the number
      of Hbd(64-76)/I-Ek complexes expressed by the APCs, TCR antagonism is observed
      for both primary T cells and T cell hybridomas. In addition, the level of the CD4
      coreceptor expressed on T cells and T cell hybridomas. In addition, the level of
      the CD4 coreceptor expressed on T cells changes the response pattern to
      endogenously presented Hbd(64-76)/I-Ek ligand. These findings demonstrate that T
      cells are selected to ignore the constitutive levels of endogenous complexes they
      encounter in the periphery. T cell responses can be affected by endogenous APLs
      in the periphery under limited but attainable circumstances which change the
      efficacy of the TCR/ligand interaction. Thus, endogenous APLs play a role in both
      the selection of T cells in the thymus and the responses of peripheral T cells.

PMID- 8666890
TI  - The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice
      is related to reduce expression of the inducible nitric oxide synthase gene.
AB  - Nitric oxide (NO) is a major effector molecule in the destruction of tumor cells
      by activated macrophages. However, in many cases, developing neoplasms appear to
      be capable of impairing steps in the complex process leading to NO production as
      a means of avoiding immune destruction. After activation with lipopolysaccharide
      (LPS), peritoneal-elicited macrophages (PEM) from mice bearing mammary tumors
      display alterations in their ability to lyse tumor cells due to reduced
      production of NO. In contrast, when these same cells are stimulated with LPS in
      combination with interferon gamma (IFN-gamma), they are able to produce NO and
      lyse targets at normal levels. Since tumor-associated macrophages are intimately
      associated with the cells of the developing tumor, their ability to produce NO
      and lyse tumor targets is likely to be more relevant to controlling tumor growth.
      This population of macrophages exhibited a more profound inability to produce NO
      and lyse targets and, unlike the PEM, was not able to upregulate these functions
      even when treated with combinations of LPS and IFN-gamma. Northern and Western
      blots revealed that inducible nitric oxide synthase (iNOS) mRNA and protein
      levels correlated directly with the ability of each macrophage population to
      produce NO, and the levels of these macromolecules were altered sufficiently in
      tumor bearers' macrophages to account for the diminished NO production described.
      These results indicate that a spatial gradient of suppression of macrophage
      cytolytic activity and iNOS expression exists in mammary tumor-bearing mice,
      whereby macrophages from within the tumor exhibit a more pronounced suppression
      than the more distally located PEM. This suppression may be due to proximity of
      the macrophages to the developing tumor, macrophage maturational state, or both.

PMID- 8666891
TI  - Major histocompatibility complex class II-associated p41 invariant chain fragment
      is a strong inhibitor of lysosomal cathepsin L.
AB  - The invariant chain (Ii) is associated with major histocompatibility complex
      class II molecules during early stages of their intracellular transport. In an
      acidic endosomal/lysosomal compartment, it is proteolytically cleaved and removed
      from class II heterodimers. Participation of aspartic and cysteine proteases has
      been observed in in vitro degradation of Ii, but the specific enzymes responsible
      for its in vivo processing are as yet undefined. We have previously isolated a
      noncovalent complex of the lysosomal cysteine protease cathepsin L with a peptide
      fragment derived from the p41 form of Ii from human kidney. Here we show that
      this Ii fragment, which is identical to the alternatively spliced segment of p41,
      is a very potent competitive inhibitor of cathepsin L (equilibrium inhibition
      constant Ki = 1.7 X 10(-12) M). It inhibits two other cysteine proteases,
      cathepsin H and papain, but to much lesser extent. Cysteine proteases cathepsins
      B, C, and S, as well as representatives of serine, aspartic, and
      metalloproteases, are not inhibited at all. These findings suggest a novel role
      for p41 in the regulation of various proteolytic activities during antigen
      processing and presentation. The Ii inhibitory fragment shows no sequence
      homology with the known cysteine protease inhibitors, and may, therefore,
      represent a new class.

PMID- 8666892
TI  - CD4+ T cell activation and tolerance induction in B cell knockout mice.
AB  - B cell knockout mice microMT/microMT were used to examine the requirement for B
      cell antigen (Ag) presentation in the establishment of CD4+ T cell tolerance.
      CD4+T cells from microMT mice injected with exogenous protein Ag in adjuvant
      responded to in vitro challenge by transcription of cytokine mRNA, cytokine
      secretion, and proliferation. Peripheral tolerance could be established in
      microMT mice with a single dose of deaggragated protein. This tolerance was
      manifested by a loss of T cell proliferation and cytokine production (including
      both T helper cell type 1 [Th1]- and Th2-related cytokines), indicating that B
      cells are not required for the induction of peripheral T cell tolerance and
      suggesting that the dual zone tolerance theory is not applicable to all protein
      Ags and is not mediated through Ag presentation by B cells.

PMID- 8666893
TI  - Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin
      6-deficient mice infected with Candida albicans.
AB  - To define the role of interleukin (IL)6 in Candida albicans infection, IL-6
      deficient mice were assessed for susceptibility to systemic or gastrointestinal
      infection, as well as for parameters of elicited T helper cell (Th) immunity. IL
      6-deficient mice were more susceptible than wild-type mice to either type of
      infection caused by virulent C. albicans. In response to systemic challenge with
      a live vaccine strain of yeast, IL-6-deficient mice failed to mount Th1
      associated protective immunity, but the resulting Th2-biased response could be
      redirected to the Th1 phenotype by IL-10 neutralization. Severe impairment of the
      macrophage and neutrophil response to infection was observed in IL-6-deficient
      mice, but administration of IL-6 would increase both neutrophil response and
      resistance to infection. IL-6 seems to oppose the Th2-promoting role of IL-10 in
      candidiasis, its early regulatory activity involving effects on neutrophil
      function.

PMID- 8666894
TI  - Therapy of murine tumors with p53 wild-type and mutant sequence peptide-based
      vaccines.
AB  - The BALB/c Meth A sarcoma carries a p53 missense mutation at codon 234, which
      occurs in a peptide, termed 234CM, capable of being presented to cytotoxic T
      lymphocytes (CTL) by H-2Kd molecules (Noguchi, Y., E.C. Richards, Y.-T. Chen, and
      L.J. Old. 1994. Proc. Natl. Acad. Sci. USA. 91:3171-3175). Immunization of BALB/c
      mice with bone marrow-derived dendritic cells (DC), generated in the presence of
      granulocyte macrophage colony-stimulating factor and interleukin 4, and prepulsed
      with the Meth A p53 mutant peptide, induced CTL that specifically recognized
      peptide-pulsed P815 cells, as well as Meth A cells naturally expressing this
      epitope. Immunization with this vaccine also protected naive mice from a
      subsequent tumor challenge, and it inhibited tumor growth in mice bearing day 7
      subcutaneous Meth A tumors. We additionally determined that immunization of
      BALB/c mice with DC pulsed with the p53 peptide containing the wild-type residue
      at position 234, 234CW, induced peptide-specific CTL that reacted against several
      methylcholanthrene-induced BALB/c sarcomas, including CMS4 sarcoma, and rejection
      of CMS4 sarcoma in vaccination and therapy (day 7) protocols. These results
      support the efficacy of DC-based, p53-derived peptide vaccines for the
      immunotherapy of cancer. The translational potential of this strategy is enhanced
      by previous reports showing that DC can readily be generated from human
      peripheral blood lymphocytes.

PMID- 8666895
TI  - Visualization, characterization, and turnover of CD8+ memory T cells in virus
      infected hosts.
AB  - The cellular basis of T cell memory is a controversial issue and progress has
      been hampered by the inability to induce and to trace long-term memory T cells
      specific for a defined antigen in vivo. By using the murine model of lymphocytic
      choriomeningitis virus (LCMV) infection and an adoptive transfer system with CD8+
      T cells from transgenic mice expressing an LCMV-specific T cell receptor, a
      population of authentic memory T cells specific for LCMV was generated and
      analyzed in vivo. The transgenic T cells that have expanded (1,000-fold) and then
      decreased (10-fold) in LCMV-infected C57BL/6 recipient mice exhibited the
      following characteristics: they were (a) of larger average cell size than their
      naive counterparts but smaller than day 8 effector cells; (b) heterogeneous with
      respect to expression of cell surface "memory" markers; and (c) directly
      cytolytic when isolated from recipient spleens. The time-dependent proliferative
      activity of these LCMV-specific memory T cells was analyzed in the recipients by
      bromodeoxyuridine labeling experiments in vivo. The experiments revealed that
      LCMV-specific CD8+ memory T cells can persist in LCMV-immune mice for extended
      periods of time (>2 mo) in the absence of cell division; the memory population as
      a whole survived beyond 11 mo.

PMID- 8666896
TI  - Concurrent engagement of CD40 and the antigen receptor protects naive and memory
      human B cells from APO-1/Fas-mediated apoptosis.
AB  - Naive and memory B cells were isolated from human tonsils and examined for
      expression of APO-1/Fas and for their sensitivity to the APO-1-dependent
      apoptosis. APO-1 was found to be constitutively expressed on memory but not on
      naive B cells. The susceptibility of both cell types to the APO-1 apoptotic
      pathway was acquired upon CD40 triggering and was correlated with increased
      expression of the APO-1 receptor. Both naive and memory B cells were protected
      from the APO-1-mediated death signal after dual ligation of the Ag receptor adn
      CD40. Our findings suggest that the APO-1 pathway controls the specificity of B
      cell responses to T-dependent Ags and that occupancy of the Ag receptor dictates
      the outcome of APO-1-ligation on B cell survival.

PMID- 8666897
TI  - Modulation of renal disease in autoimmune NZB/NZW mice by immunization with
      bacterial DNA.
AB  - Preautoimmune New Zealand Black/White (NZB/NZW) mice immunized with Escherichia
      coli (EC) double standard (ds) DNA produce antibodies that bind mammalian dsDNA
      and display specificities similar to spontaneous lupus anti-DNA. Since calf
      thymus (CT) dsDNA fails to induce these antibodies, these results suggest a
      special potency of foreign DNA in inducing serological manifestations of lupus in
      a susceptible host. To assess the effects of DNA immunization on clinical
      manifestations in NZB/NZW mice, we measured renal disease and survival of mice
      immunized with either (a) EC dsDNA as complexes with methylated bovine serum
      albumin (mBSA) in adjuvant; (b) CT dsDNA with mBSA in adjuvant; (c)mBSA alone in
      adjuvant; or (d) unimmunized. After immunization with EC dsDNA, NZB/NZW mice
      developed significant levels of anti-dsDNA antibodies. Nevertheless, these mice
      had less proteinuria, nitrate/nitrite excretion, and glomerular pathology than
      mice immunized with either mBSA alone, CT dsDNA/mBSA complexes, or unimmunized
      mice. Survival of the EC dsDNA immunized mice was significantly increased
      compared with the other mice. Furthermore, immunization of mice after the onset
      of anti-DNA production and proteinuria stabilized nephritis and prolonged
      survival. The improvement in renal disease occurred despite the expression of
      autoantibodies that bound mammalian dsDNA as well as glomerular antigens. These
      results suggest that bacterial DNA has immunological properties that attenuate
      murine lupus despite the induction of pathogenic antibodies.

PMID- 8666898
TI  - The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization
      of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of
      the plasma half-life of IL-6.
AB  - Interleukin 6 (IL-6) is considered an important mediator of acute inflammatory
      responses. Moreover, IL-6 functions as a differentiation and growth factor of
      hematopoietic precursor cells, B cells, T cells, keratinocytes, neuronal cells,
      osteoclasts, and endothelial cells. IL-6 exhibits its action via a receptor
      complex consisting of a specific IL-6 receptor (IL-6R) and a signal transducing
      subunit (gp130). Soluble forms of both receptor components are generated by
      shedding and are found in patients with various diseases such as acquired immune
      deficiency syndrome, rheumatoid arthritis, and others. The function of the
      soluble (s)IL-6R in vivo is unknown. Since human (h)IL-6 acts on human and murine
      target cells, but murine IL-6 on murine cells only, we constructed transgenic
      mice expressing the hsIL-6R. We report here that in the presence of hsIL-6R, mice
      are hypersensitized towards hIL-6, mounting an acute phase protein gene induction
      at significantly lower IL-6 dosages compared to control animals. Furthermore, in
      hsIL-6R transgenic mice, the detected acute phase response persists for a longer
      period of time. The IL-6/IL-6R complex prolongs markedly the Il-6 plasma half
      life. Our results reinforce the role of the hsIL-6R as an agonistic protein, help
      to understand the function of the hsIL-6R in vivo, and highlight the significance
      of the receptor in the induction of the acute phase response.

PMID- 8666899
TI  - Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by
      cytokines in human eosinophils.
AB  - In allergic diseases, the cytokines interleukin (IL)5 and granulocyte/macrophage
      colony-stimulating factor (GM-CSF) are upregulated and have been proposed to
      cause blood and tissue eosinophilia by inhibition of eosinophil apoptosis. We
      demonstrate herein, in freshly isolated human eosinophils, that the IL-3/IL-5/GM
      CSF receptor beta subunit interacts with cytoplasmic tyrosine kinases to induce
      phosphorylation of several cellular substrates, including the beta subunit
      itself. The Lyn and Syk intracellular tyrosine kinases constitutively associate
      at a low level with the IL-3/IL-5/GM-CSF receptor beta subunit in human
      eosinophils. Stimulation with GM-CSF or IL-5 results in a rapid and transient
      increase in the amount of Lyn and Syk associated with the IL-3/IL-5/GM-CSF
      receptor beta subunit. Lyn is required for optimal tyrosine phosphorylation and
      activation of Syk. In contrast, Syk is not required for optimal tyrosine
      phosphorylation and activation of Lyn. These data suggest that Lyn is proximal to
      Syk in a tyrosine kinase cascade that transduces IL-3, IL-5, or GM-CSF signals.
      Compatible with this model, both Lyn and Syk are essential for the activation of
      the antiapoptotic pathway(s) induced through the IL-3/IL-5/GM-CSF receptor beta
      subunit in human eosinophils.

PMID- 8666900
TI  - LFA-1-deficient mice show normal CTL responses to virus but fail to reject
      immunogenic tumor.
AB  - The leukocyte integrin LFA-1 (CD11a/CD18) plays an important role in lymphocyte
      recirculation and homotypic interactions. Leukocytes from mice lacking CD11a
      displayed defects in in vitro homotypic aggregation, in proliferation in mixed
      lymphocyte reactions, and in response to mitogen. Mutant mice mounted normal
      cytotoxic T cell (CTL) responses against systemic LCMV and VSV infections and
      showed normal ex vivo CTL function. However, LFA-1-deficient mice did not reject
      immunogenic tumors grafted into footpads and did not demonstrate priming response
      against tumor-specific antigen. Thus CD11a deficiency causes a selective defect
      in induction of peripheral immune responses whereas responses to systemic
      infection are normal.

PMID- 8666901
TI  - Mice deficient in IL-1beta manifest impaired contact hypersensitivity to
      trinitrochlorobenzone.
AB  - Mice rendered deficient in IL-1 beta by gene targeting in embryonic stem cells
      develop and grow normally in a protected laboratory environment. Endotoxin
      stimulated peritoneal macrophages from IL-1beta-deficient mice showed normal
      synthesis and cellular release of IL-1alpha after treatment with 5 mM ATP
      demonstrating that IL-1beta is not necessary for expression and release of the IL
      1alpha isoform. Mice deficient in IL-1beta showed unaltered sensitivity to
      endotoxic shock, with or without pretreatment with D-galactosamine. In contrast,
      IL-1beta-deficient mice showed defective contact hypersensitivity responses to
      topically applied trinitrochlorobenzene (TNCB). This defect could be overcome
      either by application of very high doses of sensitizing antigen, or by local
      intradermal injection of recombinant IL-1beta immediately before antigen
      application. These data demonstrate an essential role for IL-1beta in contact
      hypersensitivity and suggest that IL-1beta acts early during the sensitization
      phase of response. They suggest an important role for IL-1beta in initiation of
      the host of response at the epidermal barrier.

PMID- 8666902
TI  - Different superantigens interact with distinct sites in the Vbeta domain of a
      single T cell receptor.
AB  - CD4 T cell receptors (TCRs) recognize antigenic peptides presented by self major
      histocompatibility complex (MHC) class II molecules as well as non-self MHC class
      II molecules. The TCRs can also recognize endogenous retroviral gene products and
      bacterial toxins known collectively as superantigens (SAGs) that act mainly on
      the Vbeta gene segment-encoded portion of the Vbeta domain; most SAGs also
      require MHC II class for presentation. We have studied the interaction of the TCR
      from a well-characterized CD4 T cell line with SAGs by mutational analysis of its
      Vbeta domain. This appears to separate viral (v)SAG from bacterial (b)SAG
      recognition. T cells having a TCR with glycine to valine mutation in amino acid
      residue 51 (G51V) in complementarity determining region 2 of the TCR Vbeta domain
      fail to respond the bSAGs staphylococcal enterotoxin B (SEB), SEC1, SEC2, and
      SEC3, whereas they retain the ability to respond to non-self MHC class II
      molecules and to foreign peptides presented by self MHC class II molecules. It is
      interesting to note that T cells expressing mutations of both G51V and G53D of V
      beta regain the response to SEB and partially that to SEC1, but do not respond to
      SEC2, and SEC3, suggesting that different bacterial SAGs are viewed differently
      by the same TCR. These results are surprising, because it has been generally
      believed that SAG recognition by T cells is mediated exclusively by hypervariable
      region 4 on the exposed, lateral face of the TCR Vbeta domain. Response to the
      vSAG Mtv-7 was generated by mutation in Vbeta residue 24 (N24H), confirming
      previously published data. These data show that the vSAG Mtv-7 and bSAGs are
      recognized by different regions of the TCR Vbeta domain. In addition, various
      bSAGs are recognized differently by the same TCR. Thus, these mutational data,
      combined with the crystal structure of the TCR beta chain, provide evidence for
      distinct recognition sites for vSAG and bSAG.

PMID- 8666903
TI  - The role of interleukin 12 and nitric oxide in the development of spontaneous
      autoimmune disease in MRL/MP-lpr/lpr mice.
AB  - MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum
      from these mice contained significantly higher concentrations of nitrite/nitrate
      than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice.
      Spleen and peritoneal cells from MRL/lpr mice also produced significantly more
      nitric oxide (NO) than those from the control mice when cultured with interferon
      (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that
      peritoneal cells from MRL/lpr mice also produced markedly higher concentrations
      of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with
      same stimuli. It is striking that cells from MRL/lpr mice produced high
      concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced
      NO synthesis induced by IFN-gamma/LPS was substantially inhibited by anti-IL-12
      antibody. In addition, IL-12-induced NO production can also be markedly inhibited
      by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis
      factor alpha antibody. The effect of IL-12 on NO production was dependent on the
      presence of natural killer and possibly T cells. Serum from MRL/lpr mice
      contained significantly higher concentrations of IL-12 compared with those of
      MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to
      increased serum levels of IFN-gamma and NO metabolites, and accelerated
      glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared
      with controls injected with phosphate-buffered saline alone. These data, together
      with previous finding that NO synthase inhibitors can ameliorate autoimmune
      disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12
      and their greater responsiveness to IL-12, leading to the production of high
      concentrations of NO, are important factors in this spontaneous model of
      autoimmune disease.

PMID- 8666904
TI  - Chronic inflammation caused by lymphotoxin is lymphoid neogenesis.
AB  - In presenting a unifying concept for chronic inflammation and lymphoid
      organogenesis, we suggest that lymphotoxin's (LT, LT-alpha, TNF-beta) crucial
      role in these processes is pivotal and similar. Chronic inflammatory lesions that
      developed in the kidney and pancreas at the sites of transgene expression in rat
      insulin promoter-LT (RIP-LT) mice resembled lymph nodes with regard to cellular
      composition (T cells, B cells, plasma cells, and antigen-presenting cells),
      delineated T and B cell areas, primary and secondary follicles, characteristic
      morphologic and antigenic (ICAM-1, VCAM-1, MAdCAM-1, and PNAd) features of high
      endothelial venules, and ability to respond to antigen and undergo Ig class
      switching when obtained from mice immunized with SRBC. The vascular changes, with
      the exception of PNAd, appear to be the direct consequence of transgene derived
      LT expression, as they were also observed in RIP-LT mice lacking mature T and B
      cells. These data show that LT-induced chronic inflammation has the
      characteristics of organized lymphoid tissue.

PMID- 8666906
TI  - Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor
      delta gene-mutant mice.
AB  - The function of murine dendritic epidermal cells (dEC) remains largely
      speculative, probably because of the lack of a suitable in vivo model, although
      previous studies suggest that gamma/delta+ dEC may have originally evolved to
      serve as a self-protection mechanism(s). Our previous study demonstrated that the
      epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host
      disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained
      unexpectedly large numbers of dEC and became resistant to subsequent attempts to
      induce GVHD in a site-restricted manner, suggesting that the resistance is
      mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC
      were greatly increased in number in the epidermis, it was unclear whether
      gamma/delta+ dEC are indeed responsible for this protection. The availability of
      this murine model and mice selectively lacking gamma/delta T cells as a result of
      disruption of the T cell receptor C delta gene segment allowed us to investigate
      the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient
      mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by
      alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal
      injection of the autoreactive T cells, delta-/- mice developed significantly
      enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which
      persisted longer than in heterozygous littermate controls (delta+/-).
      Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis
      of delta-/- mice after spontaneous recovery from the GVHD, whereas the
      "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta
      dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of
      day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the
      appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution
      with gamma/delta+ dEC restored the protective immune response of the epidermis
      against the GVHD to nearly normal levels. These results indicate that
      gamma/delta+ dEC are responsible for the site-restricted protection against
      cutaneous GVHD.

PMID- 8666905
TI  - Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type-2
      mediated autoimmune disease.
AB  - We assessed the role of CD40-CD40L, cytotoxic T lymphocyte (CTL)A4/CD28-B7s, and
      CD2-CD48/CD58 lymphocyte costimulatory pathways in the development of mercury
      chloride (HgCl2)-induced autoimmune disease in mice, which is believed to be
      mediated by T helper (Th) subset Th2. Inhibition of CD40-CD40-L and CTLA4/CD28
      B7s interactions by anti-CD40-L antibody and soluble CTLA4-immunoglobulin (Ig)
      fusion protein, respectively, abrogated the autoimmune disease without affecting
      interleukin 4 (IL-4) production, showing the importance of physical contact
      between T and B lymphocytes in the Th2-mediated process. In contrast, two anti
      CD2 antibodies that have been shown to induce immunosuppression of Th1-mediated
      events exacerbated the autoantibody response and augmented IgG1, IgE, and IL-4
      production, transforming a mild mesangial glomerulopathy into a severe systemic
      immune complex disease. These observations demonstrate that manipulation of
      lymphocyte accessory counterreceptor interactions may affect the course of Th2
      associated autoimmune disease and suggest that signals resulting from CD2
      engagement play an essential role in the regulation of the Th1-Th2 effector
      equilibrium.

PMID- 8666907
TI  - Localization of DNA damage and its role in altered antigen-presenting cell
      function in ultraviolet-irradiated mice.
AB  - Prior ultraviolet (UV) irradiation of the site of application of hapten on murine
      skin reduces contact sensitization, impairs the ability of dendritic cells in the
      draining lymph nodes (DLN) to present antigen, and leads to development of hapten
      specific suppressor T lymphocytes. We tested the hypothesis that UV-induced DNA
      damage plays a role in the impaired antigen-presenting activity of DLN cells.
      First, we assessed the location and persistence of cells containing DNA damage. A
      monoclonal antibody specific for cyclobutyl pyrimidine dimers (CPD) was used to
      identify UV-damaged cells in the skin and DLN of C3H mice exposed to UV
      radiation. Cells containing CPD were present in the epidermis, dermis, and DLN
      and persisted, particularly in the dermis, for at least 4 d after UV irradiation.
      When fluorescein isothiocyanate (FITC) was applied to UV-exposed skin, the DLN
      contained cells that were Ia+, FITC+, and CPD+; such cells from mice sensitized 3
      d after UV irradiation exhibited reduced antigen-presenting function in vivo. We
      then assessed the role of DNA damage in UV-induced modulation of antigen
      presenting cell (APC) function by using a novel method of increasing DNA repair
      in mouse skin in vivo. Liposomes containing T4 endonuclease V (T4N5) were applied
      to the site of UV exposure immediately after irradiation. This treatment
      prevented the impairment in APC function and reduced the number of CPD+ cells in
      the DLN of UV-irradiated mice. Treatment of unirradiated skin with T4N5 in
      liposomes or treatment of UV-irradiated skin with liposomes containing heat
      inactivated T4N5 did not restore immune function. These studies demonstrate that
      cutaneous immune cells sustain DNA damage in vivo that persists for several days,
      and that FITC sensitization causes the migration of these to the DLN, which
      exhibits impaired APC function. Further, they support the hypothesis that DNA
      damage is an essential initiator of one or more of the steps involved in impaired
      APC function after UV irradiation.

PMID- 8666908
TI  - Reactivation of latent leishmaniasis by inhibition of inducible nitric oxide
      synthase.
AB  - Nitric oxide (NO) synthase (iNOS) is required for the resolution of acute
      cutaneous leishmaniasis in resistant C57BL/6 mice. As is the case in several
      other infections, the clinically cured host organism still harbors small amounts
      of live Leishmania major parasites. Here, we demonstrate lifelong expression of
      iNOS at the site of the original skin lesion and in the draining lymph node of
      long-term-infected C57BL/6 mice. iNOS activity in the lymph node was dependent on
      CD4+, but not on the CD8+ T cells. By double labeling techniques, iNOS and L.
      major were each found in macrophages (F4/80+, BM-8+, and/or MOMA-2+) and
      dendritic cells (NLDC-145+), but not in granulocytes or endothelial cells. In
      situ triple labeling of lymph node sections revealed that approximately 30-40% of
      the L. major foci were associated with iNOS-positive macrophages or dendritic
      cells. The majority of the L. major foci (60-70%), however, was located in areas
      that were negative for both iNOS and the macrophage and dendritic cell markers.
      In L. major-infected C57BL/6 mice, which had cured their cutaneous lesions,
      administration of L-N6-iminoethyl-lysine (L-NIL), a potent inhibitor of iNOS, led
      to a 10(4)-10(5)-fold increase of the parasite burden in the cutaneous and
      lymphoid tissue and caused clinical recrudescence of the disease. Persistent
      expression of iNOS and resumption of parasite replication after application of L
      NIL was also observed in resistant C3H/HeN and CBA/J mice. We conclude that iNOS
      activity is crucial for the control of Leishmania persisting in immunocompetent
      hosts after resolution of the primary infection. Failure to maintain iNOS
      activity might be the mechanism underlying endogenous reactivation of latent
      infections with NO-sensitive microbes during phases of immunosuppression.

PMID- 8666909
TI  - Mechanisms of platelet-activating factor-induced lipid body formation: requisite
      roles for 5-lipoxygenase and de novo protein synthesis in the
      compartmentalization of neutrophil lipids.
AB  - Lipid bodies, lipid rich cytoplasmic inclusions, are characteristically abundant
      in vivo in leukocytes associated with inflammation. Because lipid bodies are
      potential reservoirs of esterified arachidonate and sites at which eicosanoid
      forming enzymes may localize, we evaluated mechanisms of lipid body formation in
      neutrophils (PMN). Among receptor-mediated agonists, platelet activating factor
      (PAF), but not C5a, formyl-methyl-phenylalanine, interleukin 8, or leukotriene
      (LT) B4, induced the rapid formation of lipid bodies in PMN. This action of PAF
      was receptor mediated, as it was dose dependently inhibited by the PAF receptor
      antagonist WEB 2086 and blocked by pertussis toxin. Lipid body induction by PAF
      required 5-lipoxygenase (LO) activity and was inhibited by the 5-lipoxygenase
      activating protein antagonist MK 886 and the 5-LO inhibitor zileuton, but not by
      cyclooxygenase inhibitors. Corroborating the dependency of PAF-induced lipid body
      formation on 5-LO, PMN and macrophages from wild-type mice, but not from 5-LO
      genetically deficient mice, formed lipid bodies on exposure to PAF both in vitro
      and in vivo within the pleural cavity. The 5-LO product inducing lipid body
      formation was not LTB4 but was 5(S)-hydroxyeicosatetraenoic acid [5(S)-HETE],
      which was active at 10-fold lower concentrations than PAF and was also inhibited
      by pertussis toxin but not by zileuton or WEB 2086. Furthermore, 5-HETE was
      equally effective in inducing lipid body formation in both wild-type and 5-LO
      genetically deficient mice. Both PAF- and 5(S)-HETE-induced lipid body formation
      were inhibited by protein kinase C (PKC) inhibitors staurosporine and
      chelerythrine, the phospholipase C (PLC) inhibitors D609 and U-73122, and by
      actinomycin D and cycloheximide. Prior stimulation of human PMN with PAF to form
      lipid bodies enhanced eicosanoid production in response to submaximal stimulation
      with the calcium ionophore A23187; and the levels of both prostaglandin (PG) E2
      and LTB4 correlated with the number of lipid bodies. Furthermore, pretreatment of
      cells with actinomycin D or cycloheximide inhibited not only the induction of
      lipid body formation by PAF, but also the PAF-induced "priming" for enhanced PGE2
      and LTB4 in PMN. Thus, the compartmentalization of lipids to form lipid bodies in
      PMN is dependent on specific cellular responses that can be PAF receptor
      mediated, involves signaling through 5-LO to form 5-HETE and then through PKC and
      PLC, and requires new protein synthesis. Since increases in lipid body numbers
      correlated with priming for enhanced PGE2 and LTB4 production in PMN, the
      induction of lipid bodies may have a role in the formation of eicosanoid
      mediators by leukocytes involved in inflammation.

PMID- 8666910
TI  - Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding
      proteins and donate iron to mycobactins in the M. tuberculosis cell wall.
AB  - To multiply and cause disease in the host, Mycobacterium tuberculosis must
      acquire iron from the extracellular environment at sites of replication. To do
      so, the bacterium releases high-affinity iron-binding siderophores called
      exochelins. In previous studies, we have described the purification and
      characterization of the exochelin family of molecules. These molecules share a
      common core structure with another type of high-affinity iron-binding molecule
      located in the cell wall of M. tuberculosis: the mycobactins. The water-soluble
      exochelins differ from each other and from water insoluble mycobactins in
      polarity, which is dependent primarily upon the length and modifications of an
      alkyl side chain. In this study, we have investigated the capacity of purified
      exochelins to remove iron from host high-affinity iron-binding molecules, and to
      transfer iron to mycobactins. Purified desferri-exochelins rapidly removed iron
      from human transferrin, whether it was 95 or 40% iron saturated, its approximate
      percent saturation in human serum, and from human lactoferrin. Desferri
      exochelins also removed iron, but at a slower rate, from the iron storage protein
      ferritin. Purified ferri-exochelins, but not iron transferrin, transferred iron
      to desferri-mycobactins in the cell wall of live bacteria. To explore the
      possibility that the transfer iron from exochelins to mycobactins was influenced
      by their polarity, we investigated the influence of polarity on the iron affinity
      of exochelins. Exochelins of different polarity exchanged iron equally with each
      other. This study supports the concept that exochelins acquire iron for M.
      tuberculosis by removing this element from host iron-binding proteins and
      transferring it to desferri-mycobactins in the cell wall of the bacterium. The
      finding that ferri-exochelins but not iron transferrin transfer iron to
      mycobactins in the cell wall underscores the importance of exochelins in iron
      acquisition. This study also shows that the variable alkyl side chain on the core
      structure of exochelins and mycobactins, the principal determinant of their
      polarity, has little or no influence on their iron affinity.

PMID- 8666911
TI  - Mitochondrial control of nuclear apoptosis.
AB  - Anucleate cells can be induced to undergo programmed cell death (PCD), indicating
      the existence of a cytoplasmic PCD pathway that functions independently from the
      nucleus. Cytoplasmic structures including mitochondria have been shown to
      participate in the control of apoptotic nuclear disintegration. Before cells
      exhibit common signs of nuclear apoptosis (chromatin condensation and
      endonuclease-mediated DNA fragmentation), they undergo a reduction of the
      mitochondrial transmembrane potential (delta psi m) that may be due to the
      opening of mitochondrial permeability transition (PT) pores. Here, we present
      direct evidence indicating that mitochondrial PT constitutes a critical early
      event of the apoptotic process. In a cell-free system combining purified
      mitochondria and nuclei, mitochondria undergoing PT suffice to induce chromatin
      condensation and DNA fragmentation. Induction of PT by pharmacological agents
      augments the apoptosis-inducing potential of mitochondria. In contrast,
      prevention of PT by pharmacological agents impedes nuclear apoptosis, both in
      vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing
      apoptosis, but not those from normal cells, induce disintegration of isolated
      Hela nuclei. A specific ligand of the mitochondrial adenine nucleotide
      translocator (ANT), bongkreik acid, inhibits PT and reduces apoptosis induction
      by mitochondria in a cell-free system. Moreover, it inhibits the induction of
      apoptosis in intact cells. Several pieces of evidence suggest that the proto
      oncogene product Bcl-2 inhibits apoptosis by preventing mitochondrial PT. First,
      to inhibit nuclear apoptosis, Bcl-2 must be localized in mitochondrial but not
      nuclear membranes. Second, transfection-enforced hyperexpression of Bcl-2
      directly abolishes the induction of mitochondrial PT in response to a
      protonophore, a pro-oxidant, as well as to the ANT ligand atractyloside,
      correlating with its apoptosis-inhibitory effect. In conclusion, mitochondrial PT
      appears to be a critical step of the apoptotic cascade.

PMID- 8666912
TI  - The requirement for proteasome activity class I major histocompatibility complex
      antigen presentation is dictated by the length of preprocessed antigen.
AB  - Accumulating evidence has implicated the proteasome in the processing of protein
      along the major histocompatibility complex (MHC) class I presentation pathway.
      The availability of potent proteasome inhibitors provides an opportunity to
      examine the role of proteasome function in antigen presentation by MHC class I
      molecules to CD8+ cytotoxic T lymphocytes (CTLs). We have investigated the
      processing and presenting of antigenic epitopes from influenza hemagglutinin in
      target cells treated with the inhibitor of proteasome activity MG132. In the
      absence of proteasome activity, the processing and presentation of the full
      length hemagglutinin was abolished, suggesting the requirement for proteasome
      function in the processing and presentation of the hemagglutinin glycoprotein.
      Epitope-containing translation products as short as 21 amino acids when expressed
      in target cells required proteasome activity for processing and presentation of
      the hemagglutin epitope to CTLs. However, when endogenous peptides of 17 amino
      acids or shorter were expressed in target cells, the processing and presentation
      of epitopes contained in these peptides were insensitive to the proteasome
      inhibitor. Our results support the hypothesis that proteasome activity is
      required for the generation of peptides presented by MHC class I molecules and
      that the requirement for proteasome activity is dependent on the size of the
      translation product expressed in the target cell. The implications of these
      findings are discussed.

PMID- 8666913
TI  - Recognition of class I major histocompatibility complex molecules by Ly-49:
      specificities and domain interactions.
AB  - Ly-49 is a family type II transmembrane proteins encoded by a gene cluster on
      murine chromosome 6. One member of this family, Ly-49A, is expressed by a natural
      killer (NK) cell subset, binds to class I major histocompatibility complex (MHC)
      molecules, and blocks the killing of target cells bearing the appropriate H-2
      antigens. Here we show that another member of this family which is expressed by
      an NK cell subset, Ly-49C, recognizes H-2b and H-2d structures which are distinct
      from and overlapping with those recognized by Ly-49A. Interactions between Ly-49A
      and C and their class I ligands are entirely blocked by the antibodies 5E6,
      YE1/48, YE1/32, and A1, all of which were found to recognize epitopes contained
      within the carbohydrate recognition domain (CRD). However, cell-cell binding
      assays revealed that class I binding specificity is conferred by a combination of
      sequences within both the CRD and a 19-amino acid adjacent region. We also
      investigated the question of whether Ly-49A and C form dimers on cells which
      express both receptors. When coexpressed on COS cells, sequential
      immunoprecipitation demonstrated that these receptors pair exclusively as
      homodimers, with no evidence for heterodimeric structures. These observations
      provide insight into both the biochemical nature of the Ly-49 family as well as
      the receptor functions of Ly-49C on NK cells.

PMID- 8666914
TI  - Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2
      responses and prevents murine insulin-dependent diabetes.
AB  - We previously demonstrated that a spontaneous Th1 response against glutamate
      decarboxylase (GAD65) arises in NOD mice at four weeks in age and subsequently T
      cell autoimmunity spreads both intramolecularly and intermolecularly. Induction
      of passive tolerance to GAD65, through inactivation of reactive T cells before
      the onset of autoimmunity, prevented determinant spreading and the development of
      insulin-dependent diabetes mellitus (IDDM). Here, we examined whether an
      alternative strategy, designed to induce active tolerance via the engagement of
      Th2 immune responses to GAD65, before the spontaneous onset of autoimmunity,
      could inhibit the cascade of Th1 responses that lead to IDDM. We observed that a
      single intranasal administration of GAD65 peptides to 2-3-wk-old NOD mice induced
      high levels of IgG1 antibodies to GAD65. GAD65 peptide treated mice displayed
      greatly reduced IFN gamma responses and increased IL-5 responses to GAD65,
      confirming the diversion of the spontaneous GAD65 Th1 response toward a Th2
      phenotype. Consistent with the induction of an active tolerance mechanism,
      splenic CD4+ (but not CD8+) T cells from GAD65 peptide-treated mice, inhibited
      the adoptive transfer of IDDM to NOD-scid/scid mice. This active mechanism not
      only inhibited the development of proliferative T cell responses to GAD65, it
      also limited the expansion of autoreactive T cell responses to other beta cell
      antigens (i.e., determinant spreading). Finally, GAD65 peptide treatment reduced
      insulitis and long-term IDDM incidence. Collectively, these data suggest that the
      nasal administration of GAD65 peptides induces a Th2 cell response that inhibits
      the spontaneous development of autoreactive Th1 responses and the progression of
      beta cell autoimmunity in NOD mice.

PMID- 8666915
TI  - The protease inhibitor, N-acetyl-L-leucyl-L-leucyl-leucyl-L-norleucinal,
      decreases the pool of major histocompatibility complex class I-binding peptides
      and inhibits peptide trimming in the endoplasmic reticulum.
AB  - N-acetyl-L-leucyl-L-leucyl-L-norleucinal, (LLnL), which inhibits proteasomes in
      addition to other proteases, was found to prolong the association of major
      histocompatibility complex class I molecules with the transporters associated
      with antigen processing (TAP), and to slow their transport out of the endoplasmic
      reticulum (ER). LLnL induced a reversible accumulation of ubiquitinated proteins
      and changed the spectrum of peptides bound by class I molecules. These effects
      can probably be attributed to proteasome inhibition. Unexpectedly, in the TAP
      deficient cell line .174, the rate of intracellular transport of human
      histocompatibility leukocyte antigen (HLA) A2 was also reduced by LLnL, and the
      generation of most HLA-A2-associated signal sequence peptides was inhibited. The
      inhibition of HLA-A2 transport in .174 cells was found to be less sensitive to
      LLnL than in wild-type cells, and a similar difference was found for a second
      protease inhibitor, benzyloxycarbonyl-L-leucyl-L-leucyl-L-phenylalanilal. These
      data suggest that under some conditions such inhibitors can block trimming of
      peptides by an ER peptidase in addition to inhibiting cytosolic peptide
      generation.

PMID- 8666916
TI  - Localization of the binding site for the monocyte immunoglobulin (Ig) A-Fc
      receptor (CD89) to the domain boundary between Calpha2 and Calpha3 in human IgA1.
AB  - Immunoglobulin (Ig) A serves as the first line of humoral defense at all mucosal
      surfaces and is present in large quantities of blood. In playing its role in
      humoral immunity, IgA interacts with a variety of effector molecules present both
      in serum and on the surfaces of immune and inflammatory cells. To study these
      interactions, we previously established expression of human IgA1 in insect cells
      using recombinant baculoviruses and showed that the expressed antibody is a
      structurally and functionally intact polypeptide useful for examining the
      molecular properties of IgA. Indeed, since the C alpha 2 N-linked glycosylation
      site lies near the Fab-distal pole of C alpha 2, the inability of a mutant IgA1
      lacking C alpha 2 N-glycosylation to bind its cognate receptor suggested that the
      monocyte Fc alpha receptor (mFcalphaR) recognizes IgA at a hinge-distal site
      encompassing the boundary between the C alpha 2 and C alpha 3 domains. In this
      report, we utilize both domain-swapped IgA/IgG and point-mutated IgA chimeras to
      verify the above hypothesis. Using an antigen-specific rosetting assay and a mFc
      alpha R-expressing cell line, we show that (a) C alpha 2 and C alpha 3 together
      are necessary and sufficient for binding; (b) neither the IgA hinge nor the
      tailpiece is necessary for binding; (c) mutations away from the interdomain
      boundary do not affect binding; and (d) mutations located near the three
      dimensional boundary between C alpha 2 and C alpha 3 completely disrupt binding.
      Taken together, these results localize the mFc alpha R recognition site on IgA to
      the boundary region between the second and third constant domains--a site
      analogous to that recognized by Staphylococcus aureus protein A on IgG. The use
      of this hinge-distal site is, to date, unique among Fc receptors of the Ig
      superfamily.

PMID- 8666917
TI  - Metabolism of Tac (IL2Ralpha): physiology of cell surface shedding and renal
      catabolism, and suppression of catabolism by antibody binding.
AB  - The interleukin 2 receptor alpha (IL2Ralpha; CD25; Tac) is the prototypic model
      for soluble receptor studies. It exists in vivo as a transmembrane complete
      molecule (TM-Tac) on cell surfaces and as a truncated soluble form (sTac; sIL2R
      alpha). sTac has been used as a serum marker of T cell activation in immune
      disorders and of tumor burden in Tac-expressing malignancies. In vivo, serum
      levels of all soluble proteins depend on the balance between production and
      catabolism, but little is known about the metabolic features of this class of
      molecules. We have developed a model for Tac metabolism that incorporates new
      insights in its production and catabolism. Tac was shed from the surface of
      malignant and activated human T cells with a model half-life (t1/2) of 2-6h, but
      which was prolonged under certain circumstances. The rate of shedding is first
      order overall and nonsaturable over a two order of magnitude range of substrate
      (TM-Tac) expression. Once shed from cells Tac is subject to catabolic activities
      in the host. In vivo studies in mice showed that 90% of Tac was catabolized by
      the kidney with a t1/2 of 1 h and a filtration fraction of 0.11 relative to
      creatinine. The remaining 10% of catabolism was mediated by other tissues with a
      t1/2 of 10 h. Approximately 1-3% of sTac is excreted intact as proteinuria with
      the remaining 97-99% catabolized to amino acids. Antibody to the receptor induced
      a marked delay in sTac catabolism by preventing filtration of the smaller protein
      through the renal glomerulus and additionally suppressing other nonrenal
      catabolic mechanisms. A discrepancy between the catabolic rats for Tac and anti
      Tac in the same complex was interpreted as a previously unrecognized differential
      catabolic mechanism, suggesting features of the Brambell hypothesis and
      immunoglobulin G transport and catabolism, in which the antigen-in-complex in
      intracellular vesicles is relatively less protected from catabolism than the
      associated antibody. In light of the pivotal role played by the kidney in sTac
      catabolism and the impact of administered antibody, the serum concentration of
      Tac in the settings of renal dysfunction or antibody therapy is not a suitable
      surrogate of activated T cells or of the body burden of tumor. These results
      provide parameters for assessing soluble receptor-ligand interactions generally.

PMID- 8666918
TI  - Major histocompatibility complex class II-expressing endothelial cells induce
      allospecific nonresponsiveness in naive T cells.
AB  - The role of endothelial cells (EC) in initiating a primary T cell response is of
      importance in clinical transplantation and autoimmunity since EC are the first
      allogeneic target encountered by the recipient's immune system and may display
      tissue-specific autoantigens in the context of an inflammatory response. In this
      study, we have investigated the antigen-presenting cell function of human
      umbilical vein-derived EC (HUVEC), depleted of constitutively major
      histocompatibility complex class II+ cells and induced to express class II
      molecules by interferon-gamma. The results show that HUVEC do not express B7 but
      can support proliferation by antigen-specific T cell clones. In contrast, they
      were unable to initiate a primary alloresponse using three independent HUVEC
      cultures and MHC class II-mismatched CD4+ T cells from eight donors. The response
      to HUVEC was reconstituted by trans-costimulation provided by DAP.3 transfectants
      expressing human B7.1. Coculture of peripheral blood T cells with EC expressing
      allogeneic DR molecules had markedly different effects on CD45RO+ and RA+
      subsets. Subsequent reactivity of the RO+ T cells was unaffected by exposure to
      EC, indicating a neutral encounter. In contrast, culture with DR+ EC induced
      allospecific nonresponsiveness in RA+ T cells.

PMID- 8666919
TI  - Neonatal peptide exposure can prime T cells and, upon subsequent immunization,
      induce their immune deviation: implications for antibody vs. T cell-mediated
      autoimmunity.
AB  - Neonatal exposure to antigen is believed to result in T cell clonal inactivation
      or deletion. Here we report that, contrary to this notion, neonatal injection of
      BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic"
      doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab)
      response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2
      dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete
      Freund's adjuvant in adult life, although this neonatal regimen suppressed
      proliferation and the production of Th1 cytokines (interleukin[IL]-2 and
      interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased,
      and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab
      remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could
      be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment
      with a peptide antigen induces T cell priming including production of IgG Abs of
      both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the
      peptide-specific T cell responses undergo an effective class switch in the
      direction of Th2, resulting in T cell proliferative unresponsiveness.
      Accordingly, this shift towards increased Ab production to autoantigen could be
      deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal
      treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H
      58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in
      lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell
      proliferation. This adverse clinical response is in sharp contrast to the
      beneficial outcome of neonatal treatment with autoantigens in Th1-mediated
      autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others.
      A Th1 to Th2 immune deviation can explain the discordant biological responses
      after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1
      mediated autoimmune diseases.

PMID- 8666920
TI  - Rabies superantigen as a Vbeta T-dependent adjuvant.
AB  - Recently we reported evidence that nucleocapsid (NC) of rabies virus is a Vbeta8
      specific exogenous superantigen (SAg) in humans and a Vbeta6-specific SAg in
      BALB/c mice. NC was also found to stimulate rabies vaccination by enhancing the
      rabies neutralizing antibody response. In this study, we tested the hypothesis
      that the stimulating effect of NC and its SAg properties are linked. To do this,
      we studied the effect of rabies SAg on the immune response to an unrelated
      antigen, the influenza virus, and compared the response in two congenic strains
      of mice, BALB/c and BALB/D2. BALB/c mice are rabies SAg responsive, whereas
      BALB/D2 mice are not responsive to SAg activation by rabies NC because they lack
      the SAg recognition element, the Vbeta6 T cell receptor. In BALB/c mice,
      coinjection of rabies SAg with inactivated influenza virus resulted in a rapid
      and long-term increase in (a) the titres of influenza virus-specific antibodies
      (IgG and IgM), including protective hemagglutination-inhibiting antibodies, (b)
      antigen-specific proliferation and, (c) IL-2 and IL-4 secretion by lymph node
      lymphocytes, when compared to mice that received influenza virus only. In
      contrast, in BALB/D2 mice, neither antibody nor lymphocyte responses were
      stimulated. Moreover, during establishment of the primary response, the increase
      in influenza-primed T cells was mainly restricted to those bearing a Vbeta6 TCR.
      These data establish that rabies SAg can stimulate both T and B cell-specific
      responses to an unrelated antigen, depending on expression of the SAg target
      (Vbeta6 T lymphocytes). This is the first report linking NC adjuvant properties
      with its SAg mechanism.

PMID- 8666921
TI  - 5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human
      polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous
      and exogenous precursors.
AB  - 5-Lipoxygenase activation of human blood polymorphonuclear cells (PMN) from
      asthmatic patients (asthmatics) was studied to investigate whether differences
      may exist with healthy subjects (controls). The respective cell capacities to
      produce lipoxins (LXs), leukotrienes, and 5(S), 15(S)-dihydroxyeicosatetraenoic
      acid [5(S),15(S)-diHETE] were compared under in vitro stimulation by ionophore
      A23187, with or without exogenous 15(S)-hydroxyeicosatetraenoic acid [15(S)
      diHETE]. Eicosanoids were analyzed by elution with an isocratic reverse-phase
      high performance liquid chromatography system, and their profiles, detected by
      simultaneous monitoring at 302, 280, and 246 nm, were evaluated on the basis of
      chromatographic behavior: UV spectral characteristics and coelution with
      synthetic standards. In the presence of exogenous 15(S)-HETE, human PMN were able
      to produce LXs and 5(S),15(S)-diHETE, PMN from asthmatics were able to produce
      5(S), 5(S),15(S)-diHETE, and LXs from endogenous sources, whereas in the same
      experimental conditions, no detectable amounts of these compounds were released
      by PMN from controls. The levels of 5(S),15(S)-diHETE, and LXs biosynthesized
      from endogenous arachidonic acid were highly correlated. Two different LX
      patterns were observed involving two possible metabolic pathways: (a) via the
      intermediate 5,6-epoxytetraene alone for LXs generation from exogenous 15(S)
      HETE; and (b) via 5,6- and/or 14,15-epoxytetraenes leading to the formation of an
      enzyme-bound delocalized carbocation for LXs generation from endogenous
      arachidonate, respectively. The enhanced 5-lipoxygenase activation of blood PMN
      from asthmatics and the metabolism of exogenous 15(S)-HETE may reflect a priming
      induced by various mediators released from environmental cells, and could be
      considered as a model of transcellular signalization between PMN and endothelial
      cells.

PMID- 8666922
TI  - Infection of human immunodeficiency virus 1 transgenic mice with Toxoplasma
      gondii stimulates proviral transcription in macrophages in vivo.
AB  - Human immunodeficiency virus (HIV) 1 transgenic mice expressing low or
      undetectable levels of viral mRNA in lymphoid tissue were infected with the
      intracellular protozoan Toxoplasma gondii. Exposure to this parasite resulted in
      an increase in HIV-1 transcript in lymph nodes, spleens, and lungs during the
      acute phase of infection and in the central nervous system during the chronic
      stage of disease. In vivo and ex vivo experiments identified macrophages as a
      major source of the induced HIV-1 transcripts. In contrast, T. gondii infection
      failed to stimulate HIV-1 transcription in tissues of two HIV-1 transgenic mouse
      strains harboring a HIV-1 proviral DNA in which the nuclear factor (NF) kappa B
      binding motifs from the viral long terminal repeats had been replaced with a
      duplicated Moloney murine leukemia virus core enhancer. A role for NF-kappaB in
      the activation of the HIV-1 by T. gondii was also suggested by the simultaneous
      induction of NF-kappaB binding activity and tumor necrosis factor alpha synthesis
      in transgenic mouse macrophages stimulated by exposure to parasite extracts.
      These results demonstrate the potential of an opportunistic pathogen to induce
      HIV-1 transcription in vivo and suggest a mechanism for the in vivo dissemination
      of HIV-1 by macrophages.

PMID- 8666923
TI  - Breaking self-tolerance in nonobese diabetic mice.
AB  - Unresponsiveness to self is maintained through two mechanisms of immune
      regulation: thymic-negative selection and peripheral tolerance. Although thymic
      negative selection is a major mechanism to eliminate self-reactive T cells,
      normal mice have readily detectable populations of T cells reactive to self
      proteins but do not exhibit autoimmune responses. It has been postulated that
      autoimmune disease results from breakdown or loss of peripheral tolerance. We
      present data that demonstrate that peripheral tolerance or unresponsiveness to
      self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but
      not of conventional mice) with self-peptides caused an immune response to self
      peptide with resultant autoproliferation of peripheral lymphocytes.
      Autoproliferation of self-reactive T cells in NOD mice resulted from the
      recognition and proliferation of the activated T cells to endogenously processed
      and presented self-antigens. This loss of self-tolerance demonstrated in vitro
      may well be the basis of NOD autoimmune disease in vivo.

PMID- 8666924
TI  - Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and
      cyclin B1 expression.
AB  - The hyaluronan (HA) receptor RHAMM is an important regulator of cell growth.
      Overexpression of RHAMM is transforming and is required for H-ras transformation.
      The molecular mechanism underlying growth control by RHAMM and other
      extracellular matrix receptors remains largely unknown. We report that soluble
      RHAMM induces G2/M arrest by suppressing the expression of Cdc2/Cyclin B1, a
      protein kinase complex essential for mitosis. Down-regulation of RHAMM by use of
      dominant negative mutants or antisense of mRNA also decreases Cdc2 protein
      levels. Suppression of Cdc2 occurs as a result of an increased rate of cdc2 mRNA
      degradation. Moreover, tumor cells treated with soluble RHAMM are unable to form
      lung metastases. Thus, we show that mitosis is directly linked to RHAMM through
      control of Cdc2 and Cyclin B1 expression. Failure to sustain levels of Cdc2 and
      Cyclin B1 proteins leads to cell cycle arrest.

PMID- 8666925
TI  - T cell receptor usage and fine specificity of human immunodeficiency virus 1
      specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition
      reveals a dominant response directed against a minor in vivo variant.
AB  - Numerous virus-specific, class I-restricted cytotoxic T lymphocyte (CTL) epitopes
      have been identified, yet little information is available regarding the
      specificity of the CTL response in persons of the same human histocompatibility
      leukocyte antigen (HLA) type. In this study, the human immunodeficiency virus
      (HIV) 1 envelope-specific CTL response was evaluated in five HLA-B14-positive
      persons. CTL responses specific for a previously described nine-amino acid
      epitope in gp41 (aa 584-592, ERYLKDQQL) could be identified in all subjects, and
      CTL clones specific for this epitope could be isolated from four persons. Despite
      heterogeneous T cell receptor usage, the fine specificity of the clones was
      similar, as defined by recognition of alanine-substituted peptides as well as
      peptides representing natural HIV-1 sequence variants. Correlation with in vivo
      virus sequences revealed that the dominant species in two of the subjects
      represented poorly recognized variants, with a K-->Q substitution at amino acid
      588, whereas no variants were observed in the other two subjects. Although clonal
      type-specific responses to these dominant variants could be identified, the
      magnitude of these responses remained small, and the dominant CTL response was
      directed at the minor in vivo variant. These studies indicate that despite
      similar epitope-specific immunologic pressure in persons of the same HLA type,
      the in vivo quasispecies may differ, and that the major in vivo immune response
      to a given CTL epitope can be directed at a minor variant.

PMID- 8666926
TI  - Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin.
AB  - gammadelta T cells can be grouped into discrete subsets based upon their
      expression of T cell receptor (TCR) variable (V) region families, their tissue
      distribution, and their specificity. Vdelta2+ T cells constitute the majority of
      gammadelta T cells in peripheral blood whereas Vdelta1+T cells reside
      preferentially in skin epithelium and in the intestine. gammadelta T cells are
      envisioned as first line host defense mechanisms capable of providing a source of
      immune effector T cells and immunomodulating cytokines such as interleukin (IL) 4
      or interferon (IFN) gamma. We describe here the fine specificity of three
      distinct gammadelta+ tumor-infiltrating lymphocytes (TIL) obtained from patients
      with primary or metastatic colorectal cancer, that could be readily expanded in
      vitro in the presence of IL-1beta and IL-7. Irrespective of donor, these
      individual gammadelta T cells exhibited a similar pattern of reactivity defined
      by recognition of autologous and allogeneic colorectal cancer cells, renal cell
      cancer, pancreatic cancer, and a freshly isolated explant from human intestine as
      measured by cytolytic T cell responses and by IFN-gamma release. In contrast,
      tumors of alternate histologies were not lysed, including lung cancer, squamous
      cell cancer, as well as the natural/lymphocyte-activated killer cell-sensitive
      hematopoietic cell lines T2, C1R, or Daudi. The cell line K562 was only poorly
      lysed when compared with colorectal cancer targets. Target cell reactivity
      mediated by Vdelta1+ T cells was partially blocked with Abs directed against the
      TCR, the beta2 or beta7 integrin chains, or fibronectin receptor. Marker analysis
      using flow cytometry revealed that all three gammadelta T cell lines exhibit a
      similar phenotype. Analysis of the gammadelta TCR junctional suggested exclusive
      usage of the Vdelta1/Ddelta3/Jdelta1 TCR segments with extensive (< or = 29 bp)
      N/P region diversity. T cell recognition of target cells did not appear to be a
      major histocompatibility complex restricted or to be correlated with target cell
      expression of heat-shock proteins. Based on the ability of some epithelial
      tumors, including colorectal, pancreatic, and renal cell cancers to effectively
      cold target inhibit the lysis of colorectal cancer cell lines by these Vdelta1+ T
      cell lines, we suggest that intestinal Vdelta1+ T cell lines, we suggest that
      intestinal Vdelta1+ T cells are capable of recognizing cell surface Ag(s) shared
      by tumors of epithelial origin.

PMID- 8666927
TI  - Distinct T cell receptor signaling requirements for perforin- or FasL-mediated
      cytotoxicity.
AB  - A diverse array of signals are generated in a cytotoxic T lymphocyte (CTL) after
      the T cell receptor (TCR) engages the class I major histocompatibility complex
      (MHC) peptide complex. These signals result in a multitude of CTL effector
      functions, including cellular cytotoxicity, cell surface receptor expression, and
      cytokine secretion. We have examined signaling through the TCR in a wild type
      CD8+, MHC-restricted, antigen-specific CTL clone, 14-7, and its interleukin 2
      dependent variant clone 14-7FD. We report here that 14-7FD is unable to kill via
      the perforin mechanism of killing, yet is able to kill via the Fas ligand/Fas
      mechanism and secrete interferon-gamma in an antigen-specific manner. 14-7FD has
      cytolytic granules that contain perforin and serine esterases, which are secreted
      after phorbol ester and Ca2+ ionophore treatment. Lastly, to investigate which
      TCR signaling requirements were operational in 14-7FD, we examined TCR-triggered
      intracellular Ca2+ mobilization in the two clones. After TCR engagement, 14-7FD
      failed to mobilize intracellular Ca2+, which may be the cause for its inability
      to trigger the perforin/granule exocytosis mechanism of killing. These results
      indicate that the signal transduction events that trigger perforin killing and
      the signaling requirements to induce FasL expression are distinct. We hypothesize
      that these two distinct TCR signal transduction requirements allow for separate
      activation of these two mechanisms of killing relating to their role in
      eradication of infected cells or regulation of immune responses.

PMID- 8666929
TI  - Requirement for CD8+ T cells in the development of airway hyperresponsiveness in
      a marine model of airway sensitization.
AB  - To study the role of CD8+ T cells in allergic sensitization, we examined the
      effects of in vivo depletion of CD8+ T cells prior to sensitization on IgE
      production, immediate type cutaneous hypersensitivity and development of altered
      airway responsiveness. BALB/c mice were thymectomized and treated with anti-CD8
      antibody resulting in depletion of CD8+ T cells (<1%) in spleen and lymphoid
      tissues. In these mice, sensitization to ovalbumin (OVA) via the airways still
      resulted in IgE anti-OVA responses and immediate cutaneous reactions to OVA, but
      the animals were unable to develop airway hyperresponsiveness, eosinophil
      infiltration of the lung parenchyma, or IL-5 production in the local lymph nodes
      of the airway. Transfer of CD8+ T cells from naive animals during sensitization
      (on day 8 of the 10-d protocol) fully restored the ability to develop airway
      hyperresponsiveness and this was accompanied by IL-5 production and eosinophil
      accumulation in the lung. These data indicate a critical role for CD8+ T cells in
      the production of IL-5 and the development of altered airway responsiveness after
      antigen sensitization through the airways.

PMID- 8666928
TI  - CD45-null transgenic mice reveal a positive regulatory role for CD45 in early
      thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell
      maturation.
AB  - The CD45 transmembrane glycoprotein has been shown to be a protein
      phosphotyrosine phosphatase and to be important in signal transduction in T and B
      lymphocytes. We have employed gene targeting to create a strain of transgenic
      mice that completely lacks expression of all isoforms of CD45. The spleens from
      CD45-null mice contain approximately twice the number of B cells and one fifth
      the number of T cells found in normal controls. The increase in B cell numbers is
      due to the specific expansion of two B cell subpopulations that express high
      levels of immunoglobulin (IgM) staining. T cell development is significantly
      inhibited in CD45-null animals at two distinct stages. The efficiency of the
      development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by
      twofold, subsequently the frequency of successful maturation of the double
      positive population into mature, single positive thymocytes is reduced by a
      further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes
      are severely impaired in their apoptotic response to cross-linking signals via T
      cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be
      induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both
      positive and negative selection require signals through the TCR complex, these
      findings suggest that CD45 is an important regulator of signal transduction via
      the TCR complex at multiple stages of T cell development. CD45 is absolutely
      required for the transmission of mitogenic signals via IgM and IgD. By contrast,
      CD45-null B cells proliferate as well as wild-type cells to CD40-mediated
      signals. The proliferation of B cells in response to CD38 cross-linking is
      significantly reduced but not abolished by the CD45-null mutation. We conclude
      that CD45 is not required at any stage during the generation of mature peripheral
      B cells, however its loss reveals a previously unrecognized role for CD45 in the
      regulation of certain subpopulations of B cells.

PMID- 8666930
TI  - The half-life of RAG-1 protein in precursor B cells is increased in the absence
      of RAG-2 expression.
AB  - Site-specific recombination of immunoglobulin and T cell receptor gene segments
      in B and T lymphocytes is dependent on the expression of two recombinant
      activation genes, Rag-1 and Rag-2. Here, we show that RAG-1 protein turnover in
      pre-B cells depends on the expression of RAG-2. The apparent half-life of RAG-1
      protein is increased when RAG-2 is not expressed in differentiating pre-B cells.

PMID- 8666931
TI  - Circumventing genetic restriction of protection against malaria with multigene
      DNA immunization: CD8+ cell-, interferon gamma-, and nitric oxide-dependent
      immunity.
AB  - Despite efforts to develop vaccines that protect against malaria by inducing CD8+
      T cells that kill infected hepatocytes, no subunit vaccine has been shown to
      circumvent the genetic restriction inherent in this approach, and little is known
      about the interaction of subunit vaccine-induced immune effectors and infected
      hepatocytes. We now report that immunization with plasmid DNA encoding the
      plasmodium yoelii circumsporozoite protein protected one of five strains of mice
      against malaria (H-2d, 75%); a PyHEP17 DNA vaccine protected three of the five
      strains (H-2a, 71%; H-2k, 54%; H-2d, 26%); and the combination protected 82% of H
      2a, 90% of H-2k, and 88% of H-2d mice. Protection was absolutely dependent on
      CD8+ T cells, INF-gamma, or nitric oxide. These data introduce a new target of
      protective preerythrocytic immune responses, PyHEP 17 and its P. falciparum
      homologue, and provide a realistic perspective on the opportunities and
      challenges inherent in developing malaria vaccines that target the infected
      hepatocyte.

PMID- 8666932
TI  - Transcriptional regulation of the Icam-1 gene in antigen receptor- and phorbol
      ester-stimulated B lymphocytes: role for transcription factor EGR1.
AB  - Intercellular adhesion molecule (ICAM) 1/CD54 plays an important role in T cell
      dependent B cell activation and for function of B lymphocytes as antigen
      presenting cells. ICAM-1 expression is upregulated as a consequence of B
      lymphocyte antigen receptor (BCR) signaling, thereby serving to render antigen
      stimulated B cells more receptive to T cell-mediated costimulatory signals. We
      have investigated BCR-induced expression of the Icam-1 gene in primary B cells
      and B cell lines and have found it to be dependent on BCR-induced expression of
      the transcription factor EGR1. Icam-1 transcription, induced by BCR cross-linking
      or bypassing the BCR with phorbol ester, is absent in a B cell line in which the
      EGR1-encoding gene (egr-1) is methylated and not expressed. A potential EGR1
      binding site was located at -701 bp upstream of the murine Icam-1 gene
      transcription start site and shown by electrophoretic mobility shift assay to
      bind to murine EGR1. Mutation of this site in the context of 1.1 kb of the Icam-1
      promoter significantly abrogated transcriptional induction by phorbol ester and
      anti-mu stimulation in primary B cells. A direct effect of EGR1 on the Icam-1
      promoter is suggested by the ability of EGR1 expressed from an SV40-driven
      expression vector transactivate the wild-type Icam-1 promoter, whereas mutation
      of the EGR1 mutation of the EGR1 binding motif at -701 bp markedly compromises
      this induction. These data identify EGR1 as a signaling intermediate in BCR
      stimulated B cell functional responses, specifically linking BCR signal
      transduction to induction of the Icam-1 gene. Furthermore, similar findings for
      BCR-induced CD44 gene induction (Maltzman, J.S., J.A. Carman, and J.G. Monroe.
      1996. Role of EGR1 in regulation of stimulus-dependent CD44 transcription in B
      lymphocytes. Mol. Cell. Biol. In press) suggest that EGR1 may be an important
      signaling molecule for regulating levels of migration and adhesion molecules
      during humoral immune responses.

PMID- 8666934
TI  - A predictable sequential determinant spreading cascade invariably accompanies
      progression of experimental autoimmune encephalomyelitis: a basis for peptide
      specific therapy after onset of clinical disease.
AB  - The development of autoimmune disease is accompanied by the acquired recognition
      of new self-determinants, a process commonly referred to as determinant
      spreading. In this study, we addressed the question of whether determinant
      spreading is pathogenic for progression of chronic-relapsing experimental
      autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple
      sclerosis (MS). Our approach involved a systematic epitope mapping of responses
      to myelin proteolipid protein (PLP) as well as assaying responses to known
      encephalitogenic determinants of myelin basic protein (MBP 87-89) and myelin
      oligodendrocyte glycoprotein (MOG 92-106) at various times after induction of EAE
      in (SWR X SJL)F1 mice immunized with PLP 139-151. We found that the order in
      which new determinants are recognized during the course of disease follows a
      predictable sequential pattern. At monthly intervals after immunization with p139
      151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially
      accumulated in al mice examined. Three lines of evidence showed that determinant
      spreading is pathogenic for disease progression: (a) spreading determinants
      mediate passive transfer of acute EAE in naive (SWR X SJL)F1 recipients; (b) an
      invariant relationship exists between the development of relapse/progression and
      the spreading of recognition to new immunodominant encephalitogenic determinants;
      and (c) after EAE onset, the induction of peptide-specific tolerance to spreading
      but not to nonspreading encephalitogenic determinants prevents subsequent
      progression of EAE. Thus, the predictability of acquired self-determinant
      recognition provides a basis for sequential determinant-specific therapeutic
      intervention after onset of the autoimmune disease process.

PMID- 8666933
TI  - Patr-A and B, the orthologues of HLA-A and B, present hepatitis C virus epitopes
      to CD8+ cytotoxic T cells from two chronically infected chimpanzees.
AB  - Common chimpanzees (Pan troglodytes) infected with hepatitis C virus (HCV) show a
      disease progression similar to that observed for human patients. Although most
      infected animals develop a chronic hepatitis, virus persistence is associated
      with an ongoing immune response, for which the beneficial or detrimental effects
      are uncertain. Lines of virus-specific cytotoxic CD8+ T lymphocytes (CTL) have
      been previously established from liver biopsies of two common chimpanzees
      chronically infected with HCV-1. The viral epitopes recognized by six lines of
      CTL have been defined using synthetic peptides and shown to consist of 8 to 9
      residue peptides derived from various viral proteins. Five of the epitopes derive
      from sequences that vary among strains of HCV. The majority of the corresponding
      variant epitopes from different HCV strains were either recognized less
      efficiently or not at all by the CTL, suggesting their response may have limited
      potential for controlling replication of HCV variants. Complementary DNAs
      encoding class I alleles of the two common chimpanzees, Patr-A, -B, and -C were
      cloned, sequenced, and transfected individually into a class I-deficient human
      cell line. Analysis of peptide presentation by the class I transfectants to CTL
      identified the Patr class I allotypes that present the six epitopes defined here
      and an additional epitope defined previously. The assignment of epitopes to class
      I allotypes based upon analysis of the transfected cells correlates precisely
      with the segregation of antigen-presenting function within a panel of common
      chimpanzee cell lines and the expression of class I heavy chains as defined by
      isoelectric focusing. Five of the HCV-1 epitopes are presented by Patr-B
      allotypes, two epitopes are presented by a Patr-A allotype, and none is presented
      by Patr-C allotypes.

PMID- 8666935
TI  - A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced
      apoptosis.
AB  - Dendritic cells (DC), the most efficient antigen-presenting cells, are well
      equipped for activation of naive CD4+ T cells by their expression of high levels
      of major histocompatibility complex and costimulator molecules. We now
      demonstrate that some DC are equally well equipped for killing these same T
      cells. Murine splenic DC consist of both conventional CD8alpha- DC and a major
      population of CD8alpha+ DC. Whereas CD8- DC induce a vigorous proliferative
      response in CD4 T cells, CD8+ DC induce a lesser response that is associated with
      marked T cell apoptosis. By using various mixtures of T cells and DC from Fas
      mutant lpr/lpr mice and Fas-ligand (FasL) mutant gld/gld mice, we show this death
      is due to interaction of Fas on activated T cells with FasL on CD8+ DC.
      Furthermore, we show by direct surface staining that CD8+ DC, but not CD8- DC,
      express FasL at high levels. These findings indicate that FasL+ CD8+ DC are a
      specialized subgroup of DC with a role in the regulation of the response of
      primary peripheral T cells.

PMID- 8666936
TI  - Isolation and functional properties of murine hematopoietic stem cells that are
      replicating in vivo.
AB  - Hematopoietic stem cells (HSC) are multipotent cells that reside in the bone
      marrow and replenish all adult hematopoietic lineages throughout the lifetime of
      the animal. While experimenting with staining of murine bone marrow cells with
      the vital dye, Hoechst 33342, we discovered that display of Hoechst fluorescence
      simultaneously at two emission wavelengths revealed a small and distinct subset
      of whole bone marrow cells that had phenotypic markers of multipotential HSC.
      These cells were shown in competitive repopulation experiments to contain the
      vast majority of HSC activity from murine bone marrow and to be enriched at least
      1,000-fold for in vivo reconstitution activity. Further, these Hoechst-stained
      side population (SP) cells were shown to protect recipients from lethal
      irradiation at low cell doses, and to contribute to both lymphoid and myeloid
      lineages. The formation of the Hoechst SP profile was blocked when staining was
      performed in the presence of verapamil, indicating that the distinctly low
      staining pattern of the SP cells is due to a multidrug resistance protein (mdr)
      or mdr-like mediated efflux of the dye from HSC. The ability to block the Hoechst
      efflux activity also allowed us to use Hoechst to determine the DNA content of
      the SP cells. Between 1 and 3% of the HSC were shown to be in S-G2M. This also
      enabled the purification of the G0-G1 and S-G2M HSC had a reconstitution capacity
      equivalent to quiescent stem cells. These findings have implications for models
      of hematopoietic cell development and for the development of genetic therapies
      for diseases involving hematopoietic cells.

PMID- 8666937
TI  - Newly identified pair of proteasomal subunits regulated reciprocally by
      interferon gamma.
AB  - Interferon (IFN) gamma induces replacements of the proteasomal subunits X and Y
      by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic
      specificity. We found a third pair of proteasome subunits expressed reciprocally
      in response to IFN-gamma. Molecular cloning of a cDNA encoding one subunit
      designated as Z, downregulated by IFN-gamma, showed that it is a novel
      proteasomal subunit with high homology to MECL1, which is markedly induced by IFN
      gamma. Thus, IFN-gamma induces subunit replacements of not only X and Y by LMP7
      and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible
      for immunological processing of endogenous antigens. When processed from their
      precursors, three pairs of the 10 homologous, but distinct, beta-type subunits of
      eukaryotic proteasomes, that is, X/LMP7, Y/LMP2, and Z/MECL1, have an NH2
      terminal threonine residue, assumed to be part of a catalytic center. These
      findings suggest that the altered molecular organization of the proteasome
      induced by IFN-gamma may be responsible for acquisition of its functional change.

PMID- 8666938
TI  - Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I
      receptor among individuals of different human histocompatibility leukocyte
      antigens types appear genetically regulated, but not linked to major
      histocompatibililty complex haplotype.
AB  - Natural killer (NK) cells that express the NKB1 receptor are inhibited from
      killing target cells that possess human histocompatibility leukocyte antigen
      (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether
      NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA
      typed donors were examined. Most donors had a single population of NKB1+ cells,
      but some had two populations expressing different cell surface levels of NKB1,
      and others had no detectable NKB1+ cells. Among the donors expressing NKB1, both
      the relative abundance of NKB1+ NK cells and their level of cell surface
      expression varied substantially. The percentage of NKB1+ NK cells ranged from 0
      to >75% (mean 14.7%), and the mean fluorescence of the positive population varied
      over three orders of magnitude. For each donor, the small percentage of T cells
      expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the
      NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period
      that five donors were tested. Patterns of NKB1 expression were not associated
      with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA
      A or -B antigens. Cells expressing NKB1 are often found in donors who do not
      possess an appropriate class I ligand, and can be absent in those who express
      Bw4+ HLA-B antigens. Family studies further suggested that the phenotype of NKB1
      expression is inherited but not HLA linked. Whereas identical twins show matching
      patterns of NKB1 expression, HLA-identical siblings can differ in NKB1
      expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1
      expression phenotypes are tightly regulated and extremely heterogeneous, but not
      correlated with HLA type.

PMID- 8666939
TI  - The immunosuppressive fungal metabolite gliotoxin specifically inhibits
      transcription factor NF-kappaB.
AB  - Opportunistic infections, such as aspergillosis, are among the most serious
      complications suffered by immunocompromised patients. Aspergillus fumigatus and
      other pathogenic fungi synthesize a toxic epipolythiodioxopiperazine metabolite
      called gliotoxin. Gliotoxin exhibits profound immunosuppressive activity in vivo.
      It induces apoptosis in thymocytes, splenocytes, and mesenteric lymph node cells
      and can selectively deplete bone marrow of mature lymphocytes. The molecular
      mechanism by which gliotoxin exerts these effects remains unknown. Here, we
      report that nanomolar concentrations of gliotoxin inhibited the activation of
      transcription factor NF-kappaB in response to a variety of stimuli in T and B
      cells. The effect of gliotoxin was specific because, at the same concentrations,
      the toxin did not affect activation of the transcription factor NF-AT or of
      interferon-responsive signal transducers and activators of transcription.
      Likewise, the activity of the constitutively DNA-binding transcription factors
      Oct-1 and cyclic AMP response element binding protein (CREB), as well as the
      activation of protein tyrosine kinases p56lck and p59fyn, was not altered by
      gliotoxin. Very high concentrations of gliotoxin prevented NF-kappaB DNA binding
      in vitro. However, in intact cells, inhibition of NF-kappaB did not occur at the
      level of DNA binding; rather, the toxin appeared to prevent degradation of
      IkappaB-alpha, NF-kappaB's inhibitory subunit. Our data raise the possibility
      that the immunosuppression observed during aspergillosis results in part from
      gliotoxin-mediated NF-kappaB inhibition.

PMID- 8666940
TI  - Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a
      surface "receptor" with anti-interleukin-1 function.
AB  - The hypothesis that the type II receptor (RII) acts as a decoy for interleukin-1
      (IL-1) was tested by gene transfer in cells expressing only the type I receptor
      (8387 fibroblasts). RII-transfected cells showed defective responsiveness to IL-1
      in terms of NFkappaB activation, cytokine gene expression and production.
      Blocking monoclonal antibodies against RII restored the capacity of RII
      transfected cells to respond to IL-1 beta. Hence defective IL-1 responsiveness of
      RII-transfected cells requires surface expression of the molecule. RII
      transfected cells showed normal responsiveness to TNF, which shares functional
      properties and elements in the signal transduction pathway with IL-1. Cells
      transfected with a deletion mutant of RII missing 26 of 29 amino acids of the
      cytoplasmic portion of the molecule showed impaired responsiveness to IL-2. Cells
      transfected with full-length or the cytoplasmic deletion mutant of RII released
      copious amounts of RII in the supernatant. However, transfected cells showed
      defective responsiveness to brief exposure to IL-1, in the absence of measurable
      released RII. These results indicate that impairment of the responsiveness to IL
      1 following RII gene transfer was dependent upon surface expression of the
      molecule, specific for IL-1 and unaffected by truncation of the cytoplasmic
      portion. Thus, the type II "receptor" is a decoy surface molecule, regulated by
      antiinflammatory signals, whose only known function is to capture and block IL-1.

PMID- 8666941
TI  - The interaction of macrophage and non-macrophage tropic isolates of HIV-1 with
      thymic and tonsillar dendritic cells in vitro.
AB  - Dendritic cells isolated from thymus and tonsil were tested for susceptibility to
      HIV-1 strains that are tropic for macrophages or for T cell lines. DCs were
      purified by cell sorting and before infection expressed high levels of CD4 and
      HLA-DR and lacked markers for T, B, NK cells, or macrophages. Viral entry and
      reverse transcription was found after pulsing with strains of HIV-1 that could
      infect macrophages. During the first 36 h the PCR signals for gag sequences
      increased in DCs and macrophages. In contrast little if any viral DNA was found
      after pulsing macrophages or DCs with HIV-1 that was able to infect T cell lines.
      DCs pulsed with HIV-1 were able to transmit infection to responding T cells
      during an allogeneic or superantigen response. Selection for virus able to infect
      lymphoid DCs and other DCs expressing CD4 and its transfer to T cells during
      subsequent immune responses may provide a mechanism for the observed predominance
      of macrophage-tropic HIV-1 after in vivo transmission.

PMID- 8666943
TI  - A life stage of particle-laden rat dendritic cells in vivo: their terminal
      division, active phagocytosis, and translocation from the liver to the draining
      lymph.
AB  - Initiation of an adoptive immune response against pathogenic organisms, such as
      bacteria and fungi, may involve phagocytic activity of dendritic cells (DC) or
      their immature precursors as a prelude to antigen processing and presentation.
      After intravenous injection of rats with particulate matter, particle-laden cells
      were detected in the peripheral hepatic lymph. Since it has been known there is a
      constant efflux of DC from nonlymphoid organs into the draining peripheral lymph,
      we examined whether these particle-laden cells belonged to the DC or macrophage
      lineage. The majority of particle-laden cells in lymph showed immature monocyte
      like cytology, and the amount of ingested particles was small relative to typical
      macrophages. We identified these particle-laden cells as DC based on a number of
      established criteria: (a) they had a phenotype characteristic of rat DC, that is,
      major histocompatibility complex class Ihigh+ and IIhigh+, intercellular adhesion
      molecule 1+ and 80% positive with the rat DC-specific mAb OX62; (b) they showed
      strong stimulating capacity in primary allogeneic mixed leukocyte reaction; (c)
      in vitro, they had little phagocytic activity; and (d) the kinetics of
      translocation was similar to that of lymph DC in that they migrated to the thymus
      dependent area of the regional nodes. Furthermore, bromodeoxyuridine feeding
      studies revealed that most of the particle-laden DC were recently produced by the
      terminal division of precursor cells, at least 45% of them being <5.5 d old. The
      particle-laden DC, defined as OX62+ latex-laden cells, were first found in the
      sinusoidal area of the liver, in the liver perfusate, and in spleen cell
      suspensions, suggesting that the site of particle capture was mainly in the blood
      marginating pool. It is concluded that the particle-laden cells in the hepatic
      lymph are recently produced immature DC that manifest a temporary phagocytic
      activity for intravascular particles during or after the terminal division and
      that the phagocytic activity is downregulated at a migratory stage when they
      translocate from the sinusoidal area to the hepatic lymph.

PMID- 8666942
TI  - Antibody response to a T-dependent antigen requires B cell expression of
      complement receptors.
AB  - Several lines of evidence indicate that antibody responses to T-dependent
      antigens require complement receptors expressed on either B lymphocytes or
      follicular dendritic cells. We have used RAG-2 deficient blastocyst
      complementation to create mice specifically lacking B cell complement receptors.
      Despite normal expression of complement receptor 1 (CR1[CD35]) and CR2 (CD21) on
      follicular dendritic cells, these mice have a profound defect in their capacity
      to mount a T-dependent antibody response. This is the first direct demonstration
      in vivo that B cell expression of complement receptors is required for a humoral
      immune response. This is the first direct demonstration in vivo that B cell
      expression of complement receptors is required for a humoral immune response.
      This suggests that CD21 and/or CD35 on B lymphocytes may be required for cellular
      activation, adsorptive endocytosis of antigen, recruitment to germinal centers,
      and/or protection from apoptosis during the humoral response to T-dependent
      antigens.

PMID- 8666945
TI  - Inhibition of leukotriene B4-receptor interaction suppresses eosinophil
      infiltration and disease pathology in a murine model of experimental allergic
      encephalomyelitis.
AB  - Leukotriene B4 (LTB4) is a chemotactic and cell-activating factor present at
      inflammatory sites in a variety of autoimmune diseases including multiple
      sclerosis (MS). In this study, we used a murine model of MS, experimental
      allergic encephalomyelitis (EAE), to assess the potential role of LTB4 on cell
      infiltration and paralysis. Injection of encephalogenic T cells into naive
      animals induced paralysis and weight loss that was completely inhibited by
      treatment with the selective LTB4 receptor antagonist CP-105,696 (ED50= 8.6 mg/kg
      orally). Although migration of lymphocytes into the central nervous system was
      unaffected, the efficacious effects of CP-105,696 correlated with up to a 97%
      decrease in eosinophil infiltration into the lower spinal cord as determined by
      light and electron microscopy and quantitated by levels of the specific enzyme
      marker eosinophil peroxidase. These results demonstrate that eosinophil
      recruitment in EAE is dependent on LTB4 receptor ligation and further reveal a
      previously unrecognized role for eosinophils in the pathogenesis of this disease.

PMID- 8666944
TI  - Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T
      cells.
AB  - The Nur77/Nurr1 family of DNA binding proteins has been reported to be required
      for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T
      cell hybridomas. To determine the role of this family of DNA-binding proteins in
      thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation
      were produced. The transgene consisted of a truncated Nur77 (deltaNur77) gene
      encoding the DNA-binding domain of Nur77 ligated to a TCR-beta enhancer resulting
      in early expression in thymocytes. Apoptosis of CD4+CD8+ thymocytes mediated by
      CD3/TCR signaling was greatly inhibited in the deltaNur77 Tg mice, compared with
      non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo
      and in vitro. Clonal deletion of self-reactive T cells was investigated in
      deltaNur77-Db/HY TCR-alpha/beta double Tg mice. There was a five-fold increase in
      the total number of thymocytes expressing self-reactive Db/HY TCR-alpha/beta in
      the deltaNur77-TCR-alpha/beta double Tg male mice. Deficient clonal deletion of
      self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8+
      thymocytes that expressed Tg TCR-alpha/beta. There was an eightfold increase in
      the CD8+, Db/HY TCR-alpha/beta T cells in the lymph nodes (LN) of delta Nur77
      Db/HY TCR-alpha/beta double Tg compared with Db/HY TCR-alpha/beta Tg male mice.
      In spite of defective clonal deletion, the T cells expressing the Tg TCR were
      functionally anergic. In vivo analysis revealed increased activation and
      apoptosis of T cells associated with increased expression of Fas and Fas ligand
      in LN of deltaNur77-Db/HY TCR-alpha/beta double male mice. These results indicate
      that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic
      clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal
      deletion in LN and spleen.

PMID- 8666946
TI  - Association of mitogen-activated protein kinases with microtubules in mouse
      macrophages.
AB  - Taxol, a microtubule-binding diterpene, mimics many effects of lipopolysaccharide
      (LPS) on mouse macrophages. The LPS-mimetic effects of taxol appear to be under
      the same genetic control as responses to LPS itself. Thus we have postulated a
      role for microtubule-associated proteins (MAP) in the response of macrophages to
      LPS. Stimulation of macrophages by LPS quickly induces the activation of mitogen
      activated protein kinases (MAPK). MAPK are generally considered cytosolic
      enzymes. Herein we report that much of the LPS-activatable pool of MAPK in
      primary mouse peritoneal macrophages is microtubule associated. By
      immunofluorescence, MAPK were localized to colchicine- and nocodazole-disruptible
      filaments. From both mouse brain and RAW 264.7 macrophages, MAPK could be
      coisolated with polymerized tubulin. Fractionation of primary macrophages into
      cytosol-, microfilament-, microtubule-, and intermediated filament-rich extracts
      revealed that approximately 10% of MAPK but none of MAPK kinase (MEK1A and MEK2)
      was microtubule bound. Exposure of macrophages to LPS did not change the
      proportion of MAPK bound to microtubules, but preferentially activated the
      microtubule-associated pool. These findings confirm the prediction that LPS
      activates a kinase bound to microtubules. Together with LPS-mimetic actions of
      taxol and the shared genetic control of responses to LPS and taxol, these results
      support the hypothesis that a major LPS-signaling pathway in mouse macrophages
      may involve activation of one or more microtubule-associated kinases.

PMID- 8666947
TI  - Immunoglobulin G3 blocking antibodies to the fungal pathogen Cryptococcus
      neoformans.
AB  - Vaccination and infection can elicit protective and nonprotective antibodies to
      the fungus Cryptococcus neoformans in mice. The effect of nonprotective
      antibodies on host defense is unknown. In this study we used mixtures of
      protective and nonprotective monoclonal antibodies (mAbs) to determine if
      nonprotective mAbs blocked the activity of the protective mAbs. Antibody isotype
      and epitope specificity are important in determining the ability to prolong
      survival in mice given a lethal C. neoformans infection. Three different
      nonprotective immunoglobulin (Ig) G23 mAbs to cryptococcal capsular
      polysaccharide were used to study the interaction between the IgG3 isotype and
      protective IgG1 and IgG2a mAbs in murine cryptococcal infection. One IgG3 mAb
      reduced the protective efficacy of an IgG1 with identical epitope specificity. A
      second IgG3 mAb with different epitope specificity also reduced the protection
      provided by the IgG1 mAb. The protective efficacy of an IgG2a mAb was also
      dramatically decreased by still another IgG3 mAb. To our knowledge this is the
      first report of blocking antibodies to a fungal pathogen. The results have
      important implications for the development of vaccines and passive antibody
      therapy against C. neoformans.

PMID- 8666948
TI  - The beta subunit of human granulocyte-macrophage colony-stimulating factor
      receptor forms a homodimer and is activated via association with the alpha
      subunit.
AB  - Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) receptor (hGMR)
      consists of alpha and beta subunits, and the precise stoichiometry of these
      subunits has remained to be determined. In this work, oligomerization of the beta
      subunit was studied using a chemical cross-linker. In Ba/F3, a mouse interleukin
      3-dependent cell line expressing both subunits of hGMR (Ba/F3-alpha,beta), a
      protein with a molecular mass corresponding to that of a homodimer of the beta
      subunit (beta homodimer) was detected only when cells were treated with the cross
      linker. Dimerization of the beta subunit was confirmed by coimmunoprecipitation
      of a tagged beta subunit with the wild type beta subunit COS7 cells. The beta
      homodimer had already formed in the absence of hGM-CSF, whereas stimulation with
      the ligand brought both alpha and beta subunits into a complex, the result being
      tyrosine phosphorylation of the beta homodimer. Tyrosine phosphorylation of the
      subunit was impaired by deletion of the cytoplasmic domain of the alpha subunit
      without interfering with the association of both subunits. These results indicate
      that the beta homodimer, which alone is insufficient for signaling, forms the
      functional hGMR with the alpha subunit in response to hGM-CSF.

PMID- 8666949
TI  - Different responses are elicited in cytotoxic T lymphocytes by different levels
      of T cell receptor occupancy.
AB  - We have investigated the level of TCR occupancy required to elicit different
      biological responses in human CTL clones specific for an influenza matrix
      peptide. Specific cytotoxicity could be detected at extremely low peptide
      concentrations (10(-12) to 10(-15) M). However, IFN-gamma production,
      responsiveness to IL-2 and Ca++ fluxes were observed only at peptide
      concentrations > 10(-9) M, while autonomous proliferation required even higher
      peptide concentrations. In parallel experiments we measured TCR downregulation to
      estimate the number of TCRs triggered. We observed that at low peptide
      concentrations, where only cytotoxicity is triggered, TCR downregulation was
      hardly detectable. Conversely, induction of IFN-gamma production and
      proliferation required triggering of at least 20-50% of TCRs. Taken together
      these results indicate that a single CTL can graduate different biological
      responses as a function of antigen concentration and that killing of the specific
      target does not necessarily result in full activation.

PMID- 8666950
TI  - p53 prevents maturation to the CD4+CD8+ stage of thymocyte differentiation in the
      absence of T cell receptor rearrangement.
AB  - Rearrangement of the immunoglobulin (Ig) and T cell receptor (TCR) gene loci
      allows for the generation of B and T lymphocytes with antigen-specific receptors.
      Complete rearrangement and expression of the TCR-beta chain enables immature
      thymocytes to differentiate from the CD4-CD8- to the CD4+CD8+ stage mice in which
      rearrangement is impaired, such as severe combined immunodeficient (SCID) mice or
      recombinase activating gene-deficient (RAG-/-) mice, lack mature B and T
      lymphocytes. Thymocytes from these mice are arrested at the CD4-CD8- stage of T
      cell development. We previously observed that thymocytes from RAG-2-/- mice
      exposed to gamma radiation differentiate from CD4-CD8- into CD4+CD8+ without TCR
      beta chain rearrangement. We now report that irradiated RAG-2-/- thymocytes
      undergo direct somatic mutations at the p53 gene locus, and that p53 inactivation
      is associated with maturation of RAG2-/- thymocytes to the CD4+CD8+ stage.
      Generation of RAG2-/- and p53-/- double-deficient mice revealed that, in the
      absence of TCR-beta chain rearrangement, loss of p53 function is sufficient for
      CD4-CD8- thymocytes to differentiate into the CD4+CD8+ stage of T cell
      development. Our data provide evidence for a novel p53 mediated checkpoint in
      early thymocyte development that regulates the transition of CD4-CD8- into
      CD4+CD8+ thymocytes.

PMID- 8666951
TI  - gamma/delta T cell-deficient mice have impaired mucosal immunoglobulin A
      responses.
AB  - Mucosal tissues of mice are enriched in T cells that express the gamma/delta T
      cell receptor. Since the function of these cells remains unclear, we have
      compared mucosal immune responses in gamma/delta T cell receptor-deficient
      (TCRdelta-/-) mice versus control mice of the same genetic background. The
      frequency of intestinal immunoglobulin (Ig) A plasma cells as well as IgA levels
      in serum, bile, saliva, and fecal samples were markedly reduced in TCRdelta-/-
      mice. The TCRdelta-/- mice produced much lower levels of IgA antibodies when
      immunized orally with a vaccine of tetanus toxoid plus cholera toxin as adjuvant.
      Conversely, the antigen-specific IgM and IgG antibody responses were comparable
      to orally immunized control mice. Direct assessment of the cells forming
      antibodies against the tetanus toxoid and cholera toxin antigens indicated that
      significantly lower numbers of IgA antibody-producing cells were present in the
      intestinal lamina propria and Peyer's patches of TCRdelta-/- mice compared with
      the orally immunized control mice. The selective reduction of IgA responses to
      ingested antigens in the absence of gamma/delta T cells suggests a specialized
      role for gamma/delta cells in mucosal immunity.

PMID- 8666952
TI  - Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor
      mediated interleukin 2 production.
AB  - Recently we described the molecular cloning of SLP-76, a hematopoietic cell
      specific 76-kD protein that was first identified through its association with
      GST/Grb2 fusion proteins. The primary sequence of SLP-76 predicts a protein of
      533 amino acids comprising an amino-terminal region with numerous potential
      tyrosine phosphorylation sites, a central region rich in proline residues, and a
      single carboxy-terminal SH2 domain. Here we demonstrate formally that Grb2
      associates with unphosphorylated SLP-76 and map the Grb2 binding site on SLP-76
      undergoes rapid tyrosine phosphorylation and associates with tyrosine
      phosphoproteins of 36, 62, and 130 kD. In vitro experiments show that the SH2
      domain of SLP-76 associates with the 62- and 130-kD proteins and additionally
      with a serine/threonine kinase. Finally, we demonstrate that transient
      overexpression of SLP-76 results in dramatically enhanced TCR-mediated induction
      of nuclear factor of activated T cells (NFAT) and interleukin (IL) 2 promoter
      activity; and we provide evidence that a functional SLP-76 SH2 domain is required
      for this effect. Our data document the in vivo associations of SLP-76 with
      several proteins that potentially participate in T cell activation and implicate
      SLP-76 itself as an important molecule in TCR-mediated IL-2 production.

PMID- 8666953
TI  - Visual stability across saccades while viewing complex pictures.
AB  - As people examine their world, the proximal stimulus changes position on their
      retinae with every saccade, but they perceive the world as being stable. This
      phenomenon of visual stability was explored by making changes in natural, full
      color pictures during selected saccades as observers examined them in preparation
      for a recognition test. In Experiment 1, the pictures were displaced up, down,
      left, or right by 0.3, 0.4, or 1.2 degrees. In Experiment 2, the pictures were
      expanded or contracted by 10% or 20%. As a secondary task, subjects pressed a
      button when a change was detected. Three results from previous studies with
      simpler stimuli did not generalize. Evidence suggests that subjects' detection of
      image changes primarily involves the use of local information in the region of
      the eyes' landing position. A saccade target theory of visual stability is
      proposed.

PMID- 8666954
TI  - Grasping a fruit: selection for action.
AB  - This study used a natural task, with no emphasis placed on speeded responses, to
      investigate unconscious information processing. Using the ELITE system, a
      kinematic analysis was performed of the upper limb reach-to-grasp movement. Nine
      experiments explored how the presence of distractors affects the transport and
      grasp component of this movement. Experiment 1 showed that the kinematics for
      grasping apples, mandarins, cherries, and bananas were measurably different.
      Experiments 2A-D, 3, and 4 showed that these kinematics were not affected by the
      presence of nearby distractor fruits of either the same or a different kind. In
      Experiment 5, interference effects became evident when participants were required
      to perform a subsidiary task involving the distractor (counting the number of
      times a laterally placed fruit was illuminated). Experiment 6, requiring both
      grasping a target fruit and counting the number of times that this fruit was
      illuminated, revealed no interference effects. Taken together, these results
      suggest that selection for action does not involve substantial passive processing
      of distractors. However, dual-action processing of simultaneously presented
      objects does appear to involve automatic processing of even the task-irrelevant
      properties of the distractor.

PMID- 8666955
TI  - Spectral regularity as a factor distinct from harmonic relations in auditory
      grouping.
AB  - When the regular spectral pattern formed by an odd-harmonic complex (the base) is
      disrupted by an added even harmonic, the added component is judged as more
      salient than its neighbors. This study considered whether the effects of spectral
      pattern on perceptual segregation are restricted to harmonic stimuli.
      Participants either rated the clarity or judged the relative pitch of a cued
      component in a series of complex tones. The difference in clarity between added
      and base components found for the harmonic complexes was not reduced when the
      complexes were made inharmonic either by a frequency shift or by spectral stretch
      or compression. However, the added-base difference could be abolished for an
      inharmonic complex when the distribution of components across frequency was made
      uniform. These findings suggest that spectral regularity is a factor distinct
      from harmonic relations in auditory grouping.

PMID- 8666956
TI  - Testing models of decision making using confidence ratings in classification.
AB  - Classification implies decision making (or response selection) of some kind.
      Studying the decision process using a traditional signal detection theory
      analysis is difficult for two reasons: (a) The model makes a strong assumption
      about the encoding process (normal noise), and (b) the two most popular decision
      models, optimal and distance-from-criterion models, can mimic each other's
      predictions about performance level. In this article, the authors show that by
      analyzing certain distributional properties of confidence ratings, a researcher
      can determine whether the decision process is optimal, without knowing the form
      of the encoding distributions. Empirical results are reported for three types of
      experiments: recognition memory, perceptual discrimination, and perceptual
      categorization. In each case, the data strongly favored the distance-from
      criterion model over the optimal model.

PMID- 8666957
TI  - A constructive-associative model of the contextual dependence of unidimensional
      similarity.
AB  - Conditions under which pairwise dissimilarity ratings should reflect
      manipulations of the stimulus distribution were outlined by a model that proposed
      these effects. These conditions arise from either a context dependent process for
      constructing implicit scale values or a process that uses previously established
      stimulus-response associates. Consistent with the model, results from 3
      experiments using unidimensional psychophysical stimuli demonstrated disordinal
      context effects on pairwise dissimilarity ratings when (a) there was a 3-s delay
      between presentation of pair members or (b) a unidimensional rating task preceded
      the pairwise dissimilarity ratings. Global effects of density were fit well by a
      model that extended A. Parducci's (1983) range-frequency theory to dissimilarity
      ratings. Local density effects were generally consistent with predictions from
      C.L.Krumhansl's (1978) distance-density theory.

PMID- 8666958
TI  - Facial asymmetry and attractiveness judgment in developmental perspective.
AB  - This study examined the role of facial symmetry in the judgment of physical
      attractiveness. Four experiments investigated people's preference for either
      somewhat asymmetrical portraits or their symmetrical chimeric composites when
      presented simultaneously. Experiment 1 found a higher selection rate for
      symmetrical faces with neutral expression for portraits of old people, and
      Experiment 2 indicated this may be because symmetry serves as cue for youth in
      old age. In Experiments 3 and 4 participants examined portraits with emotional
      expressions. Experiment 3 found a higher selection rate for asymmetrical faces,
      and Experiment 4 indicated this may be because observers perceived them as more
      genuine and natural. This study suggests that the low degree of facial asymmetry
      found in normal people does not affect attractiveness ratings (except for old
      age), probably because observers are not tuned to perceive it.

PMID- 8666959
TI  - Effects of changing viewing conditions on the perceived structure of smoothly
      curved surfaces.
AB  - Observers' perceptions of a male and a female torso were investigated using
      monocular and stereoscopic images under varying conditions of illumination.
      Observers judged the shapes of these torsos by adjusting a gauge figure to
      estimate the local slant and tilt at numerous probe points arranged in a lattice
      over the torso's surface. The results revealed that the judged surfaces in the
      monocular and stereoscopic conditions were related by an affine stretching
      transformation in depth that accounted for approximately 95% of the between
      condition variance. There was also a strong affine component between the
      judgments obtained for the different illumination directions, although a further
      analysis of the residuals indicated that changing the direction of illumination
      influenced perceived structure in a piecewise manner.

PMID- 8666960
TI  - Mechanisms of visual-spatial attention: resource allocation or uncertainty
      reduction?
AB  - Many studies have found that stimuli can be discriminated more accurately at
      attended locations than at unattended locations, and such results have typically
      been taken as evidence for the hypothesis that attention operates by allocating
      limited perceptual processing resources to attended locations. An alternative
      proposal, however, is that attention acts to reduce uncertainty about target
      location, thereby increasing accuracy by decreasing the number of noise sources.
      To distinguish between these alternatives, we conducted 6 spatial cuing
      experiments in which target location uncertainty was eliminated. Despite the
      absence of uncertainty, target discriminations were more accurate at the attended
      location, consistent with resource allocation models. These cue validity effects
      were observed under a broad range of conditions, including central and peripheral
      cuing, but were absent at very short cue-target delay intervals.

PMID- 8666961
TI  - Texture segmentation along the horizontal meridian: nonmonotonic changes in
      performance with eccentricity.
AB  - In 3 experiments, subjects were required to detect the presence of a small region
      of disparate texture embedded in a larger background at a range of
      eccentricities. Detection performance always peaked several degrees from
      fixation. Experiment 1 showed that the location of the peak was not retinally
      specific; scaling the display changed the location of the performance peak.
      Experiment 2 showed that poor foveal performance could not be explained by cross
      frequency interference; filtering out high spatial frequencies did not lead to
      improved foveal performance. Experiment 3 showed that the effect is not unique to
      textures comprising left and right oblique line segments. A parsimonious account
      of these data is that, at the fovea, there is a mismatch between the scale of the
      texture and the scale of the mechanisms responsible for encoding texture
      differences. This mismatch diminishes as the textures are moved further into the
      periphery.

PMID- 8666962
TI  - Is there feature-based attentional selection in visual search?
AB  - A new paradigm combines attentional cuing and rapid serial visual presentation to
      disentangle the effects of perceptual filtering and location selection. Observers
      search successive, superimposed arrays, in which feature values are alternated
      for a target numeral among letters. Two dimensions, size (small, large) and color
      (red, green) are tested. Selective attention to feature values is jointly
      manipulated by instructions, presentation probabilities, and payoffs. In
      Experiment 1, the attended feature provides temporal, not spatial, information;
      observers show no attentional costs or benefits in response accuracy. In
      Experiment 2, the attended feature indicates a unique location; observers show
      consistent attentional costs and benefits. Selective attention to a particular
      size or color does not cause perceptual exclusion or admission of items
      containing that feature; it acts by guiding search processes to spatial locations
      that contain the to-be-attended feature.

PMID- 8666964
TI  - Medicine and public health initiative.

PMID- 8666965
TI  - Who are we? We are one big family with big problems.

PMID- 8666963
TI  - Spatial precues affect target discrimination in the absence of visual noise.
AB  - In 2 earlier sets of experiments, the author reported that shape discrimination
      in an otherwise empty visual field is facilitated when the target shape is
      preceded by a valid spatial precue (J. M. Henderson, 1991; J. M. Henderson & A.
      D. Macquistan, 1993). L. Shiu and H. Pashler (1994) recently suggested that these
      earlier results were due to the presence of multiple posttarget pattern masks.
      They concluded that precue effects are observed only when visual noise is
      present. The author reviews the existing evidence and presents new data
      supporting the view that spatial precues influence shape discrimination in the
      absence of visual noise, consistent with a limited capacity conception of visual
      spatial attention.

PMID- 8666966
TI  - The Human Genome Project and the clinician.
AB  - The Florida Supreme Court's decision in Pate v Threlkel is an early warning sing
      of the massive impact human genome research will have on medical practice.
      Genetic screening is a scientific tool whose widespread use in clinical medicine
      will expand due to the combined influences of the federally funded Human Genome
      Project, biotechnology market forces, and corporate and societal pressures to
      both use and further develop the technique. Once testing becomes cost-effective,
      clinicians, by virtue of their position as "knowledgeable professionals" and as
      the primary source of health information for patients with genetic disorders,
      will be required to act as gatekeepers to the genetic heritage of their patients.
      This will seriously impact the legal definitions of reasonable care, a
      physician's duty to warn, the concept of informed consent, and the
      confidentiality of medical records.

PMID- 8666968
TI  - Attitudes of Florida Academic Physicians toward the Florida Medical Association.
AB  - An Ad Hoc Committee on Academic Physicians was given the charge in 1992 of
      studying Florida academic physician's participation in the Florida Medical
      Association. It was postulated that academic physicians may participate less in
      organized medicine than community physicians and, therefore, may be a group that
      should be selectively targeted during membership campaigns. Data was obtained
      from the American Medical Association Masterfiles about Florida academic and
      community physician membership in the FMA and AMA. Academic physicians at the
      four academic medical centers in Florida were surveyed about their attitudes
      toward organized medicine, especially the Florida Medical Association. Unlike any
      other state in the Federation, more academic physicians than community physicians
      were members of the state society (46.9% v 43.5%) p < 0.05, which was accounted
      for mainly women academic physicians. There were substantial differences across
      the academic medical centers with the University of Florida at Gainesville and
      Jacksonville being overrepresented, the University of South Florida having
      average membership, and the University of Miami being underrepresented. Florida
      academic and community physician membership in the AMA was 34.6% and 38.5%
      respectively, which was consistent with national trends. Academic physicians at
      the University of Florida campuses rated their relationship and communication
      with the FMA as being better than academic physicians at the University of South
      Florida and Miami. Academic physicians at all four medical centers rated
      membership dues as being too high relative to the benefits derived, but there was
      indirect evidence to suggest that this was an apparent and not real barrier.
      Also, academic physicians thought that the FMA represented community physicians
      more effectively than academic physicians. The state of Florida is unique in that
      more academic physicians than community physicians are members of the state
      medical society. The differences by academic medical centers may be accounted for
      by variations in leadership at the different medical centers. Decreasing the
      membership dues for academic physicians probably will not have a significant
      effect on membership of academic physicians. The FMA should direct efforts at
      informing academic physicians about how the FMA is representing their interest in
      forums such as governmental and other regulatory agencies, and third party payers
      like the insurance industry.

PMID- 8666967
TI  - Meperidine associated mental status changes in a patient with chronic renal
      failure.
AB  - Meperidine is widely used for pain control in the hospital setting. It is also
      known for its propensity to cause mental status changes in renally and
      hepatically impaired patients. A case is reported of a 37-year-old man with
      chronic renal failure maintained on peritoneal dialysis in whom delirium
      developed when he was treated with meperidine not only on one occasion but also
      on two subsequent admissions. The pharmacology of meperidine is reviewed and the
      implications of using the medication in patients with renal impairment are
      discussed.

PMID- 8666969
TI  - Physician's duty to warn expanded.

PMID- 8666970
TI  - Patenting of pure surgical and other medical procedures. Medical community's
      response and need for a legislative solution.

PMID- 8666971
TI  - Physician liability for health-care fraud.

PMID- 8666972
TI  - Free radical damage and oxidative stress in Huntington's disease.
AB  - Bioenergetic defects and oxidative stress may be critical links in an excitotoxic
      mechanism of neuronal death. Oxidative stress, a condition describing the
      production of oxygen radicals beyond a threshold for proper antioxidant
      neutralization, has been implicated as a pathologic condition in several
      neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.
      In addition, oxygen radicals are known to be important mediators in acute
      pathologies, in the theory of senescence, cancer, as well as our healthy immune
      system. Although free radicals may have a special chemical nature which allows
      them to perform important cellular functions, they are a damaging entity whose
      reactivity may play a part in the development of cellular compromises that can
      kill a neuron. In this review, the free radicals in biological systems, the
      defense systems against them, and the damaging interactions, i.e., oxidative
      stress, which they confer are discussed. The descriptions provided raise the
      hypothesis that an imbalance between the production and removal of radicals would
      be abrasive on a neuron. Accordingly, the neurodegeneration initially caused by
      gene mutation in Huntington's disease may be further worsened by free radical
      damage underlied by oxidative stress. This article reviews existing data on the
      free radical damage and the oxidative stress, which are primarily directed
      towards Parkinson's disease and Alzheimer's disease, and whenever possible
      relates such mechanisms to Huntington's disease.

PMID- 8666974
TI  - Individual responsibility.

PMID- 8666973
TI  - Tobacco.

PMID- 8666976
TI  - Medical jive.

PMID- 8666977
TI  - We are members of one another.

PMID- 8666975
TI  - Personal decision.

PMID- 8666978
TI  - Gp130, a shared signal transducing receptor component for hematopoietic and
      neuropoietic cytokines.
AB  - Most of the receptors for soluble factors functioning in the hematopoietic system
      belong to the class I cytokine receptor family. These receptors often share
      common signal transducing receptor components in the same family, which explains
      the functional redundancy of cytokines. One typical example is a group of
      receptor systems for interleukin-6 (IL-6) and related cytokines that share gp130
      as a signal transducer. This subset of cytokines, i.e., IL-6, IL-11, leukemia
      inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin
      1, are all pleiotropic, exhibiting overlapping biological activities, and are
      known to function also in the neuronal system. In their receptor complexes, gp130
      and ligand-specific chains possess no intrinsic tyrosine kinase domain but are
      associated with members of the Jak family of cytoplasmic tyrosine kinases. The
      Jak kinases become activated after ligand-induced homo- or heterodimerization of
      gp130. This activation appears to link the cell surface receptors to the nuclear
      genes through a series of biochemical changes, including tyrosine phosphorylation
      and activation of a latent cytoplasmic transcription factor called signal
      transducer and activator of transcription 3 (STAT3).

PMID- 8666979
TI  - Recoverin in cultured human retinoblastoma cells: enhanced expression during
      morphological differentiation.
AB  - Recoverin is a calcium-binding protein expressed in retinal photoreceptors. It
      appears to delay the termination of the phototransduction cascade by blocking the
      phosphorylation of photoexcited rhodopsin. The goal of this study was to
      determine if recoverin mRNA and protein are expressed in cultured human Y79
      retinoblastoma cells, so that this cell line could be used as a model to study
      the mechanism of recoverin gene expression in the retina. A cDNA encoding human
      recoverin was PCR cloned and used for prokaryotic expression of recoverin
      protein. Polyclonal antibodies raised against pure recombinant recoverin were
      used for western blotting and immunocytochemistry of Y79 cells grown as
      attachment cultures in the presence of the differentiating agents dibutyryl
      cyclic AMP (dbcAMP) or butyrate. Northern blot analysis was performed on mRNA
      extracted from Y79 cells that were also treated with the differentiating agents.
      In Y79 cell monolayer cultures, recoverin was immunolocalized to the cell
      cytoplasm, and immunoreactivity was increased dramatically by the addition of 2
      mM butyrate to the culture medium. Butyrate treatment also caused an increase in
      the development of neurite-like cellular processes. Addition of 4 mM dbcAMP
      resulted in a moderate increase in both recoverin immunoreactivity and number of
      cellular processes. Western and northern blots of butyrate and dbcAMP-treated Y79
      cell cultures demonstrated an increase in recoverin protein and RNA expression,
      respectively, comparable with that observed with immunocytochemistry. These data
      suggest that, under the influence of the differentiating agent butyrate, Y79
      cells exhibit an increase in expression of the photoreceptor protein recoverin
      and a concomitant morphological differentiation toward a neuronal phenotype.

PMID- 8666981
TI  - Acetylcholinesterase and nicotinic acetylcholine receptor expression diverge in
      muscular dysgenic mice lacking the L-type calcium channel.
AB  - L-type Ca2+ channels play critical roles in achieving stabilization of
      acetylcholinesterase (AChe) mRNA during myogenesis in C2-C12 skeletal muscle
      cells. To ascertain the importance of this signaling pathway in AChE expression
      during skeletal muscle development in the animal, we examined AChE mRNA levels in
      skeletal muscle and heart from control (+/+) and muscular dysgenic (mdg/mdg) mice
      that lack the skeletal, but not the cardiac, muscle L-type Ca2+ channels. RNase
      protection analysis showed 40-60% reductions in content of AChE mRNA in leg
      muscle, but not heart, from newborn and day 18 embryonic dysgenic mice. AChE
      activity was also reduced uniquely in skeletal muscle. In contrast to AChE
      transcripts, mRNA levels of the alpha-subunit of the nicotinic acetylcholine
      receptors (nAChRs) were increased in dysgenic skeletal muscle. Similar
      alterations in activity and mRNA levels of AChE were also observed form skeletal
      muscle cell lines derived from mdg mice. Because run-on transcription revealed no
      corresponding decrease in transcription rate, the decrease in mRNA content is
      likely a consequence of the inability of the dysgenic muscle cells to stabilize
      AChE mRNA during differentiation. These findings indicate that L-type Ca2+
      channels play an important role in regulation of AChE expression during skeletal
      muscle development in vivo. The differential influence of muscle dysgenesis on
      mRNA levels of AChE and nAChRs provides additional evidence for distinct
      mechanisms of regulation of these two proteins.

PMID- 8666980
TI  - A transgenic mouse model to study transsynaptic regulation of tyrosine
      hydroxylase gene expression.
AB  - Previous studies demonstrated that 9 kb of the rat tyrosine hydroxylase (TH) 5'
      flanking sequence directed appropriate spatiotemporal expression of a lacZ
      reporter gene to catecholaminergic cells in the CNS of transgenic mice. In the
      present study, specificity of transgene expression was further extended to
      demonstrate cell type-specific functional regulation of lacZ expression using
      manipulations known to alter endogenous TH expression. Alterations in lacZ
      reporter expression should parallel changes in endogenous TH levels if the DNA
      elements mediating these functional changes of TH expression in vivo reside
      within the 9 kb of the TH promoter region. Naris closure induced an activity
      dependent decrease of TH expression in dopaminergic periglomerular cells in the
      olfactory bulb that was paralleled by down-regulation of lacZ expression in the
      transgenic mice. Densitometry and image analysis were used to quantify lacZ
      expression following acute reserpine administration (5 mg/kg s.c.), which up
      regulates endogenous TH. At 48 h postinjection, analysis of OD values indicated a
      significant increase of X-gal staining in the locus coeruleus and ventral
      tegmental area but not in the substantia nigra or olfactory bulb of reserpine
      treated transgenic animals. These data showed that the 9-kb sequence also
      mediates cell type-specific transsynaptic regulation of reporter gene expression.
      Analysis of this transgenic animal offers a useful model system to study in vivo
      regulation of TH gene expression.

PMID- 8666982
TI  - Thrombin causes cell spreading and redistribution of beta-amyloid
      immunoreactivity in cultured hippocampal neurons.
AB  - Culture of rat embryonic hippocampal neurons in serum-free B27/Neurobasal for 4
      days enabled tests of the effect of added thrombin on differentiated cell
      morphology and processing of the amyloid precursor protein (APP). By fluorescence
      microscopy of neurons labeled with dil and by scanning electron microscopy, an
      increase in spreading of the neuron soma was clearly seen in cells treated with 1
      microg/ml (27 nM) of thrombin for 24 h. This treatment also caused a dose
      dependent increase in immunoreactive area/cell, detected with antibody 4G8
      binding to the beta-amyloid region of APP. Thrombin treatment also produced a
      dose-dependent increase in immunoreactive brightness detected with the Alz-50
      antibody. Thrombin did not affect viability or cause neurite retraction. The
      thrombin effect on 4G8 immunoreactivity required 24 h for full effect and could
      be blocked by the thrombin inhibitor antithrombin III or hirudin. A thrombin
      receptor appeared to be activated because a full immunoreactive response was
      observed by treatment of neurons with the thrombin receptor-activating peptide
      SFL-LRNPNNKYEPF. When cytoplasmic extracts were analyzed by western immunoblots
      or by pulse-chase radiolabeling, no thrombin-dependent changes in processing of
      127- and 120-kDa bands were seen. Material migrating in the region of synthetic
      betaA4 was not found. Together, these results suggest that thrombin acts on
      neurons through a thrombin receptor to stimulate cell spreading and
      redistribution of APP without amyloidogenic changes. The adhesion responsible for
      this spreading could be important in altering synaptic connections in the brain.

PMID- 8666983
TI  - Regulation of Bcl-2 protein expression in human neuroblastoma SH-SY5Y cells:
      positive and negative effects of protein kinases C and A, respectively.
AB  - The regulatory mechanism of Bcl-2 protein expression was investigated in SH-SY5Y
      cells, the human neuroblastoma cell line that expresses natively Bcl-2 proteins.
      WHen the cells were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or
      retinoic acid, the level of Bcl-2 protein was increased compared with the
      control. These effects were inhibited by pretreatment with a protein kinase C
      (PKC) inhibitor, staurosporine or calphostin C. The level of Bcl-2 protein was
      also increased by treatment with carbachol, a muscarinic acetylcholine receptor
      (mAChR) agonist, and the effect were also inhibited by pretreatment with
      staurosporine or calphostin C. An addition, a carbachol-induced increase in Bcl-2
      protein levels and a transient elevation of [Ca2+]i were inhibited by
      pretreatment with 4-DAMP (4-diphenylacetoxy-N-methylpiperidine), an m3 mAChR
      antagonist. In contrast, the level of Bcl-2 protein was decreased by treatment
      with dibutyryl cAMP (diBu-cAMP), forskolin, or cholera toxin, and the effects of
      diBu-cAMP were inhibited by pretreatment with a protein kinase A (PKA) inhibitor,
      H-89. From these results, we suggest that the expression of Bcl-2 proteins is
      regulated by PKC and PKA in positive and negative manners, respectively, in SH
      SY5Y cells. Furthermore, the nucleosomal DNA fragmentation induced by serum
      depletion for 4 h was observed in SH-SY5Y cells when the level of Bcl-2 protein
      was down-regulated by treatment with 1 mM diBu-cAMP for 3 days, although the DNA
      fragmentation by serum depletion for 4 h was not observed in nontreatment cells,
      indicating that Bcl-2 proteins whose expression is regulated by PKC and PKA play
      important roles in serum depletion-induced apoptosis.

PMID- 8666984
TI  - Biochemical evidence of functional interaction between mu- and delta-opioid
      receptors in SK-N-BE neuroblastoma cell line.
AB  - Radioligand binding assays and functional experiments revealed that the SK-N-BE
      neuroblastoma cell line expresses a similar ratio of mu- and delta-opioid
      receptors, both negatively coupled to adenylyl cyclase through pertussis toxin
      sensitive G proteins. Our findings also indicate that some functional interaction
      occurred between the two opioid subtypes; in fact, long-term exposure to [D-Ala2
      N-methyl-Phe4-Gly-ol5]enkephalin (DAMGO), a mu-selective agonist, sensitized the
      functional response of the delta-selective agonist but not vice versa. It is
      interesting that in acute interaction experiments, we observed a shift to the
      right of the concentration-effect curve of either DAMGO or [D-Pen2,5]enkephalin
      (DPDPE), a delta-selective agonist, as a result of DPDPE or DAMGO administration,
      respectively. In addition, low doses of naloxone, an antagonist selective for mu
      receptors, increased the inhibitory effect [D-Ala2-D-Met5]enkephalinamide (DAME),
      a mixed mu/delta agonist, on adenylyl cyclase activity. Taken overall, these data
      support the hypothesis of the existence of a cross talk between mu and delta
      receptors in the SK-N-BE cell line.

PMID- 8666986
TI  - Exocytosis coupled to mobilization of intracellular calcium by muscarine and
      caffeine in rat chromaffin cells.
AB  - We used cultured rat chromaffin cells to test the hypothesis that Ca2+ entry but
      not release from internal stores is utilized for exocytosis. Two protocols were
      used to identify internal versus external Ca2+ sources: (a) Ca2+ surrounding
      single cells was transiently displaced by applying agonist with or without Ca2+
      from an ejection pipette. (b) Intracellular stores of Ca2+ were depleted by
      soaking cells in Ca2+ -free plus 1 mM EGTA solution before transient exposure to
      agonist plus Ca2+. Exocytosis from individual cells was measured by
      microelectrochemical detection, and the intracellular Ca2+ concentration
      ([Ca2+]i) was measured by indo-1 fluorescence. KCl (35 mM) and nicotine (10
      microM) caused an immediate increase in [Ca2+]i and secretion in cells with or
      without internal Ca2+ stores, but only when applied with Ca2+ in the ejection
      pipette. Caffeine (10 mM) and muscarine (30 microM) evoked exocytosis whether or
      not Ca2+ was included in the pipette, but neither produced responses in cells
      depleted of internal Ca2+ stores. Pretreatment with ryanodine (0.1 microM)
      inhibited caffeine- but not muscarine-stimulated responses. Elevated [Ca2+]i and
      exocytosis exhibited long latency to onset after stimulation by caffeine (2.9 +/-
      0.38 s) or muscarine (2.2 +/- 0.25 s). However, the duration of caffeine-evoked
      exocytosis (7.1 +/- 0.8 s) was significantly shorter than that evoked by
      muscarine (33.1 +/- 3.5 s). The duration of caffeine-evoked exocytosis was not
      affected by changing the application period between 0.5 and 30 s. An
      approximately 20-s refractory period was found between repeated caffeine-evoked
      exocytosis bursts even though [Ca2+]i continued to be elevated. However,
      muscarine or nicotine could evoke exocytosis during the caffeine refractory
      period. We conclude that muscarine and caffeine mobilize different internal Ca2+
      stores and that both are coupled to exocytosis in rat chromaffin cells. The
      nicotinic component of acetylcholine action depends primarily on influx of
      external Ca2+. These results and conclusions are consistent with our original
      observations in the perfused adrenal gland.

PMID- 8666985
TI  - Similarity between rat brain nicotinic alpha-bungarotoxin receptors and stably
      expressed alpha-bungarotoxin binding sites.
AB  - The present results demonstrate stable expression of alpha-bungarotoxin (alpha
      BGT) binding sites by cells of the GH4C1 rat pituitary clonal line. Wild-type
      GH4C1 cells do not express alpha-BGT binding sites, nor do they contain
      detectable mRNA for nicotinic receptor alpha2, alpha3, alpha4, alpha5, alpha7,
      beta2, or beta3 subunits. However, GH4C1 cells stably transfected with rat
      nicotinic receptor alpha7 cDNA (alpha7/GH4C1 cells) express the transgene
      abundantly as mRNA, and northern analysis showed that the message is of teh
      predicted size. The alpha7/GH4C1 cells also express saturable, high-affinity
      binding sites for 125I-labeled alpha-BGT, with a KD of 0.4 nM and Bmax of 3.2
      fmol/10(6) intact cells. 125I-alpha-BGT binding affinities and pharmacological
      profiles are not significantly different for sites in membranes prepared either
      from rat brain or alpha7/GH4C1 cells. Furthermore, KD and Ki values for 125I
      alpha-BGT binding sites on intact alpha7/GH4C1 cells are essentially similar to
      those for hippocampal neurons in culture. Sucrose density gradient analysis
      showed that the size of the alpha-BGT binding sites expressed in alpha7/GH4C1
      cells was similar to that of the native brain alpha-BGT receptor. Chronic
      exposure of alpha7/GH4C1 cells in culture to nicotine or an elevated
      extracellular potassium concentration induces changes in the number of alpha-BGT
      binding sites comparable to those observed in cultured neurons. Collectively, the
      present results show that the properties of alpha-BGT binding sites in
      transfected alpha7/GH4C1 cells resemble those for brain nicotinic alpha-BGT
      receptors. If the heterologously expressed alpha-BGT binding sites in the present
      study are composed solely of alpha7 subunits, the results could suggest that the
      rat brain alpha-BGT receptor has a similar homooligomeric structure.
      Alternatively, if alpha-BGT binding sites exist as heterooligomers of alpha7 plus
      some other previously identified or novel subunit(s), the data would indicate
      that the alpha7 subunits play a major role in determining properties of the alpha
      BGT receptor.

PMID- 8666987
TI  - Voltage-sensitive Ca2+ channels involved in nicotinic receptor-mediated
      [3H]dopamine release from rat striatal synaptosomes.
AB  - The potent nicotinic agonist anatoxin-a elicits mecamylamine-sensitive
      [3H]dopamine release from striatal synaptosomes, and this action is both Na+ and
      Ca2+ dependent and is blocked by Cd2+. This suggests that stimulation of
      presynaptic nicotinic receptors results in Na+ influx and local depolarisation
      that activates voltage-sensitive Ca2+ channels, which in turn provide the Ca2+
      for exocytosis. Here we have investigated the subtypes of Ca2+ channels
      implicated in this mechanism. [3H]-Dopamine release evoked by anatoxin-a (1
      microM) was partially blocked by 20 microM nifedipine, whereas KCl-evoked release
      was insensitive to the dihydropyridine. However, a 86Rb+ efflux assay of
      nicotinic receptor function suggested that nifedipine has a direct effect on the
      receptor, discrediting the involvement of L-type channels. The N-type Ca2+
      channel blocker omega-conotoxin GVIA (1 microM) blocked anatoxin-a-evoked
      [3H]dopamine release by 60% but had no significant effect on 86Rb+ efflux;
      release evoked by both 15 and 25 mM KCl was inhibited by only 30%. The P-type
      channel blocker omega-agatoxin IVA (90 nM) also inhibited KCl-evoked release by
      approximately 30%, whereas anatoxin-a-evoked release was insensitive. The Q-type
      channel blocker omega-conotoxin MVIIC (1 microM) had no effect on either
      stimulus. These results suggest that presynaptic nicotinic receptors on striatal
      nerve terminals promote [3H]dopamine release by activation of N-type Ca2+
      channels. In contrast, KCl-evoked [3H]dopamine release appears to involve both N
      type and P-type channels.

PMID- 8666988
TI  - Endogenous GABA modulates histamine release from the anterior hypothalamus of the
      rat.
AB  - Using a microdialysis method, we investigated the effects of the nipecotic acid
      induced increase in content of endogenous GABA on in vivo release of histamine
      from the anterior hypothalamus (AHy) of urethane-anesthetized rats. Nipecotic
      acid (0.5 mM), an inhibitor of GABA uptake, decreased histamine release to
      approximately 60% of the basal level. This effect was partially antagonized by
      picrotoxin (0.1 mM), an antagonist of GABAA receptors, or phaclofen (0.1 mM), an
      antagonist of GABAB receptors. These results suggest that histamine release is
      modulated by endogenous GABA through both GABAA and GABAB receptors. When the
      tuberomammillary nucleus, where the cell bodies of the histaminergic neurons are
      localized, was stimulated electrically, the evoked release of histamine from the
      nerve terminals in the AHy was significantly enhanced by phaclofen, suggesting
      that GABAB receptors may be located on the histaminergic nerve terminals and
      modulate histamine release presynaptically. On the other hand, picrotoxin caused
      an increase in histamine release to approximately 170% of the basal level, and
      this increase was diminished by coinfusion with D(-)-2-amino-5-phosphonopentanoic
      acid (0.1 mM), an antagonist of NMDA receptors. Previously, we demonstrated tonic
      control of histamine release by glutamate mediated through NMDA receptors located
      on the histaminergic terminals in the AHy. These results suggest the possible
      localization of GABAA receptors on glutamatergic nerve terminals and that the
      receptors may regulate the basal release of histamine indirectly.

PMID- 8666989
TI  - Adenylyl cyclases: mRNA and characteristics of enzyme activity in three areas of
      brain.
AB  - RNase protection assays were used in a comparative analysis of the quantities of
      mRNA for five "calcium-sensitive" (types I, III, V, VI, and VIII) adenylyl
      cyclases and one "calcium-insensitive" (type II) adenylyl cyclase in mouse
      cerebral cortex, cerebellum, and nucleus accumbens. The mRNA levels for type V
      adenylyl cyclase were dominant in the nucleus accumbens. Type V adenylyl cyclase
      mRNA was also found in the cerebral cortex and at low levels in the cerebellum.
      Type I adenylyl cyclase mRNA was the major form in the cerebellum with 15-50-fold
      higher levels compared with other adenylyl cyclase mRNAs. Type I adenylyl cyclase
      mRNA was also the most prominent adenylyl cyclase mRNA in the cerebral cortex,
      although the mRNA levels of other adenylyl cyclase forms were more comparable to
      those of the type I enzyme in this brain area. The mRNA levels for adenylyl
      cyclase types II, III, VI, and VIII were intermediate to low depending on the
      brain area. Cell membranes from the nucleus accumbens demonstrated adenylyl
      cyclase activity that was synergistically activated by concomitant addition of
      GTP and forskolin to assay mixtures, reflecting a characteristic of type V
      adenylyl cyclase protein. Calcium/calmodulin stimulated adenylyl cyclase activity
      in membranes from all three brain areas. However, synergistic activation of
      adenylyl cyclase activity by GTP and calcium/calmodulin was noted only with
      cortical membranes, and this characteristic may reflect the presence of type VIII
      adenylyl cyclase mRNA in the cortex. Although mRNA for type VIII adenylyl cyclase
      was almost equivalent in the cortex and cerebellum, the lack of a synergistic
      effect of GTP plus calcium/calmodulin on the cerebellar enzyme activity may be a
      result of the significant dominance of type I adenylyl cyclase mRNA (and protein)
      in the cerebellum. In general, the mRNA levels for the various adenylyl cyclases
      were predictive of the regulatory characteristics of adenylyl cyclase activity in
      membranes of the brain areas studied.

PMID- 8666990
TI  - Release of adenosine from rat hippocampal slices by nitric oxide donors.
AB  - In the present study we have used perfused hippocampal slices to examine the
      hypothesis that nitric oxide (NO) can evoke the release of adenosine from nervous
      tissue. ATP stores were labeled by incubation with [3H]adenine. Electrical field
      stimulation at 5 Hz for 5 min evoked the release of 3H-purines, and this was
      enhanced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Stimulation at
      10 Hz for 15 min evoked a larger release of 3H-purines, which was enhanced in a
      concentration-dependent manner by both SNAP and sodium nitroprusside (SNP), with
      SNP being 100-fold less potent than SNAP. N-Acetylpenicillamine (N-AP) was
      without effect. SNAP had a markedly reduced, although significant, effect when
      given in the absence of field stimulation. Using HPLC it was found that SNAP
      enhanced the release of both endogenous and labeled adenosine in a concentration
      dependent manner. At the highest concentration used (1 mM), SNAP increased
      electrically evoked release of endogenous adenosine 100-fold and unstimulated
      adenosine release eightfold. The ability of SNAP to enhance adenosine release was
      eliminated in the added presence of hemoglobin (10 microM), further supporting
      the proposal that the effects of SNAP were due to the liberation of NO. These
      data provide direct evidence that NO evokes a concentration-dependent release of
      adenosine from both stimulated and unstimulated nerves of the hippocampus. It is
      suggested that such NO-stimulated adenosine release may contribute to some of the
      reported effects of NO donors in the nervous system.

PMID- 8666991
TI  - New species of human tyrosine hydroxylase mRNA are produced in variable amounts
      in adrenal medulla and are overexpressed in progressive supranuclear palsy.
AB  - Alternative splicing of human tyrosine hydroxylase (TH) pre-mRNA produces four
      mRNAs leading to four different TH isoforms and is thought to have important
      regulatory functions. We show that the diversity of TH mRNAs is greater than
      previously described in the autonomous nervous system: New splice junctions
      corresponding to the skipping of exon 3 were identified by amplification of cDNA
      synthesized from pheochromocytoma RNA. In all cases the reading frame was
      maintained. These species were assayed by RNase protection experiments; their
      abundance (4-6%) was comparable to that of the previously identified human TH-3
      and -4 species in normal adrenal medulla. However, higher levels (11-34%) of
      these species were found in adrenal medullas of patients suffering from
      progressive supranuclear palsy. Whether such changes are specific to the disease
      or the consequences of the stress associated with this severe neurodegeneration
      remains to be established.

PMID- 8666992
TI  - Protein tyrosine kinase-mediated potentiation of currents from cloned NMDA
      receptors.
AB  - Although serine/threonine phosphorylation has been more commonly recognized as a
      mechanism to modulate the function of ion channels and receptors, tyrosine
      phosphorylation is under increasing scrutiny. An important subtype of glutamate
      receptor, the NMDA receptor, is shown to be regulated by insulin via protein
      tyrosine kinase (PTK). NMDA currents through cloned receptors are potentiated by
      insulin in a subunit-specific manner. The insulin-mediated potentiation of NMDA
      current is diminished by inhibitors of PTKs. At least one exogenous cytosolic
      PTK, pp60c-src, is also able to potentiate NMDA current. Because later
      application of PTK inhibitors can reverse the seemingly stable insulin-mediated
      potentiation of NMDA current, it appears that tyrosine residues responsible for
      potentiation are continually rephosphorylated by some long-term PTK activity that
      was induced via insulin treatment.

PMID- 8666994
TI  - Chimeric D2/D3 dopamine receptors efficiently inhibit adenylyl cyclase in HEK 293
      cells.
AB  - Despite a high degree of sequence homology, the dopamine D2 and D3 receptors have
      substantially different second messenger coupling properties. We have used
      chimeric D2/D3 receptors to investigate the contribution of the intracellular
      loops to the signaling properties of these receptors. In HEK 293 cells, D2
      receptors inhibit prostaglandin E1-stimulated cyclic AMP levels by >90%, whereas
      D3 receptors inhibit cyclic AMP accumulation by only 20%. In chimeras that have
      the second or third intracellular loop, or both loops simultaneously, switched
      between the D2 and D3 receptors, the maximal inhibition of adenylyl cyclase is 60
      90%. In addition, the potency of quinpirole to inhibit adenylyl cyclase activity
      at some of the chimeras is altered compared with the wild-type receptors. It
      appears that the intracellular loops of the D3 receptor are capable of
      interacting with G proteins, as when these loops are expressed in the D2
      receptor, the chimeras inhibit adenylyl cyclase similarly to the wild-type D2
      receptor. Our data suggest that the overall conformation of the D3 receptor may
      be such that it interacts with G proteins only weakly, but when the intracellular
      loops are expressed in another context or the D3 receptor structure is altered by
      the introduction of D2 receptor sequence, this constraint may be lifted.

PMID- 8666993
TI  - Ethanol-induced inhibition of [3H]thienylcyclohexylpiperidine (TCP) binding to
      NMDA receptors in brain synaptic membranes and to a purified protein complex.
AB  - N-Methyl-D-aspartate receptors (NMDARs) are a major target of ethanol effects in
      the nervous system. Haloperidol-insensitive, but dizocilpine (MK-801)-sensitive,
      binding of N-[1-(2-[3H]thienyl)cyclohexyl]piperidine ([3H]TCP) to synaptic
      membranes has the characteristics of ligand interaction with the ion channel of
      NMDARs. In the present studies, ethanol produced a concentration-dependent
      decrease in the maximal activation of [3H]TCP binding to synaptic membranes by
      NMDA and Gly, but a moderate change in the activation by L-Glu when L-Glu was
      present at concentrations < 100 microM. However, ethanol (100 mM) inhibited
      completely the activation of [3H]TCP binding produced by high concentrations of L
      Glu (200-400 microM). It also inhibited strongly the activation of [3H]TCP
      binding by spermidine or spermidine plus Gly. In a purified complex of proteins
      that has L-Glu-, Gly-, and [3H]TCP-binding sites, ethanol (100 mM) decreased
      significantly the maximal activation of [3H]TCP binding produced by either L-Glu
      or Gly. Activation constants (Kact) for L-Glu and Gly acting on the purified
      complex were 12 and 28 microM, respectively. Ethanol had no significant effect on
      the Kact of L-Glu but caused an increase in Kact of Gly. These studies have
      identified at least one protein complex in neuronal membranes whose response to
      both L-Glu and Gly is inhibited by ethanol. These findings may explain some of
      the effects of acute and chronic ethanol treatment on the function and expression
      of the subunits of this complex in brain neurons.

PMID- 8666995
TI  - Stimulation of an insulin receptor activates and down-regulates the Ca2+
      independent protein kinase C, Apl II, through a Wortmannin-sensitive signaling
      pathway in Aplysia.
AB  - Activation of tyrosine kinase-linked receptors has been shown to stimulate Ca2+
      independent protein kinase C isoforms in nonneuronal cells. We have examined this
      signaling pathway in the nervous system. Incubating bag cell neurons from the
      marine mollusk Aplysia californica with concentrations of insulin known to
      stimulate a tyrosine kinase-linked receptor in these cells persistently activated
      and down-regulated the Ca2+-independent protein kinase C (Apl II), whereas
      insulin only transiently activated and did not down-regulate the Ca2+-activated
      protein kinase C (Apl I). The effects of insulin may be mediated by activation of
      phosphoinositide 3-kinase because (a) diC16phosphatidylinositol 3,4,5
      trisphosphate, a synthetic phosphoinositide 3-kinase product, stimulated
      autophosphorylation of baculovirus-expressed Apl II, but not of Apl I, and (b)
      wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked the activation and
      down-regulation of Apl II by insulin but not the transient activation of Apl I.
      These results suggest that activators of tyrosine kinase-linked receptors may
      mediate some of their effects in neurons through activation of Ca2+-independent
      protein kinase C isoforms.

PMID- 8666996
TI  - Dopaminergic regulation of secretory granule-associated proteins in rat
      intermediate pituitary.
AB  - The biosynthesis of peptides requires the synthesis of the prohormone, several
      biosynthetic processing enzymes, and other granule constituents. We have
      investigated the regulated expression of proopiomelanocortin (POMC) and five
      enzymes essential for the processing of POMC to smaller, bioactive peptides in
      intermediate pituitary melanotropes. Rats were treated with a dopaminergic
      agonist (bromocriptine) or antagonist (haloperidol) for periods ranging from 1 h
      to 5 days, followed by analyses of mRNA levels and protein biosynthetic rates.
      Multiplex RNase protection assays showed that bromocriptine treatment caused a
      striking decrease in POMC mRNA levels, and significant decreases in mRNA levels
      for prohormone convertase 2 (PC2), carboxypeptidase H (CPH), and peptidylglycine
      alpha-amidating monooxygenase (PAM). Smaller increases in mRNA levels were seen
      after haloperidol stimulation. Protein biosynthetic rates changed more profoundly
      than mRNA levels at short drug treatment times, indicating a role for
      translational effects after treatment with bromocriptine and with haloperidol.
      The homogeneous population of melanotropes in the intermediate lobe of the
      pituitary allows a quantitative analysis of transcript levels and biosynthetic
      rates. POMC mRNA levels are 200-1,000-fold higher than levels of any of the
      processing enzyme mRNAs, and POMC biosynthetic rates exceed those of PC2, PC1,
      and PAM by 1,000-10,000-fold.

PMID- 8666997
TI  - Regulation of tryptophan hydroxylase by cyclic AMP, calcium, norepinephrine, and
      light in cultured chick pineal cells.
AB  - The level of 35S incorporation into tryptophan hydroxylase (TPH) shows a
      circadian rhythm in cultured chick pineal cells. The TPH oscillation peaks in the
      early subjective night, persists in constant darkness, and can be phase shifted
      by light, in parallel to the effect of these treatments on melatonin synthesis.
      Using quantitative two-dimensional polyacrylamide gel electrophoresis, we have
      examined the regulation of TPH by agents known to affect melatonin synthesis in
      the chick pineal. We report here that 35S incorporation into TPH is induced by
      cyclic AMP and calcium, and partially inhibited by acute exposure to light.
      Cyclic AMP also causes a proportional increase in the radiolabeling of one of the
      TPH isoforms and a concomitant decrease in another isoform, possibly reflecting a
      change in the phosphorylation state of TPH. This effect is reversed by treatments
      known to reduce intracellular cyclic AMP levels in the chick pineal. Cyclic AMP
      thus appears to be involved in both translational and posttranslational processes
      regulating the expression of TPH in chick pineal cells.

PMID- 8666998
TI  - Matrix metalloproteinases in the neocortex and spinal cord of amyotrophic lateral
      sclerosis patients.
AB  - Matrix metalloproteinases (MMPs) were analyzed by immunohistochemistry and
      zymography in amyotrophic lateral sclerosis (ALS) and control brain and spinal
      cord specimens. Three major bands of enzyme activity (70, 100, and 130 kDa) were
      consistently observed and were subsequently identified as MMP-2 (70 kDa; also
      known as EC 3.4.24.24 or gelatinase A) and MMP-9 (100 and 130 kDa; also known as
      EC 3.4.24.35 or gelatinase B). Immunohistochemical studies established the
      presence of MMP-2 in astrocytes and MMP-9 in pyramidal neurons in the motor
      cortex and motor neurons in the spinal cord of ALS patients. Although a
      significant decrease in MMP-2 activity was noticed in the ALS motor cortex,
      statistically significant increases in MMP-9 (100-kDa) activity were observed in
      ALS frontal and occipital cortices (BA10 and 17) and all three spinal cord
      regions when compared with control specimens. The highest MMP-9 (100-kDa)
      activities in ALS were found in the motor cortex and thoracic and lumbar cord
      specimens. The abnormally high amount of MMP-9 and its possible release at the
      synapse may destroy the structural integrity of the surrounding matrix, thereby
      contributing to the pathogenesis of ALS.

PMID- 8667000
TI  - High levels of glycine and serine as a cause of the seizure symptoms of cavernous
      angiomas?
AB  - Cavernous angiomas are vascular malformations that cause neurodegeneration and
      symptoms including epileptiform seizures, headache, and motor deficits. Following
      neurosurgical removal of the angiomas, patients mostly recover well and become
      seizure-free. This study reports on the levels of certain amino acids in
      angiomas, obtained from 13 patients. Distinct zones of the angiomas were
      analyzed, from the thrombotic core, via gliotic, hemosiderin-infiltrated
      intermediate zones, to a periphery without macroscopic abnormalities. The
      neurotransmitter amino acids glutamate, aspartate, and GABA as well as
      phosphoethanolamine displayed decreasing levels from the periphery to the core,
      reflecting the gradual neuronal loss. Compared with normal brain tissue, there
      was a marked increase in the levels of serine (fivefold), glycine (10-fold), and
      ethanolamine (20-fold) in the peripheral zone of the cavernous angiomas. The
      results are discussed in relation to seizures and NMDA receptor activation,
      neuron-glia interactions, membrane phospholipids, and blood-brain barrier
      function.

PMID- 8666999
TI  - The roles of CRE, TRE, and TRE-adjacent S1 nuclease sensitive element in the
      regulation of tyrosine hydroxylase gene promoter activity by angiotensin II.
AB  - The cis elements mediating activation of the tyrosine hydroxylase gene by
      angiotensin II were examined by transfecting tyrosine hydroxylase promoter
      luciferase constructs into cultured bone adrenal medullary cells. Angiotensin II
      responsive elements are located within -54/+25-bp and -269/-55-bp promoter
      regions and were identified, respectively, as cyclic AMP (CRE)- and 12-O
      tetradecanoylphorbol 13-acetate responsive element (TRE)-like sequences. Unlike
      CRE, TRE also supports basal promoter activity. Mutations of TRE or CRE that
      reduced angiotensin II stimulation abolished in vitro binding of nuclear proteins
      to those elements, suggesting that proteins forming CRE- and TRE-inducible
      complexes may mediate angiotensin II stimulation. The TRE is adjacent to a dyad
      symmetry element. Those two sites form a common regulatory unit in which the dyad
      symmetry element acts as a repressor of the TRE site. Isolated dyad symmetry
      element did not bind nuclear proteins in vitro. In supercoiled DNA it exhibited
      S1 nuclease sensitivity and was recognized by a DNA cruciform-specific antibody
      consistent with the extrusion of a cruciform structure that overlaps with the
      TRE. A mutation that abolished formation of the cruciform correlated with a loss
      of repressor activity. We propose a novel model of tyrosine hydroxylase gene
      regulation in which functions of the TRE are modulated via structural transition
      in the adjacent DNA.

PMID- 8667001
TI  - Expression of glucose transporters in rat brain following transient focal
      ischemic injury.
AB  - We have investigated the serial changes in the transcription and translation of
      the rat glucose transporter (GLUT) 1 and 3 genes after 3 h of middle cerebral
      artery (MCA) occlusion followed by reperfusion. Northern blot analysis and in
      situ hybridization study were performed to determine the chronological change and
      regional expression. In the ipsilateral anterior cerebral artery (ACA) cortex,
      GLUT1 mRNA expression was increased at 12 h (11.6-fold) of reperfusion, and its
      expression was detected not only in vascular endothelial cells but also in
      neurons. At 48 h of reperfusion, GLUT3 mRNA expression was increased in the
      ipsilateral ACA (8.6-fold) and in the contralateral MCA cortex (9.1-fold).
      Immunohistochemical study failed to show GLUT1 protein synthesis in neurons in
      the ipsilateral ACA cortex. The immunoreactivity of GLUT3 protein was increased
      in neurons in ipsilateral ACA cortex and contralateral MCA cortex. Our results
      suggest that the expression of GLUT1 and GLUT3 is controlled differently after
      transient focal ischemic conditions. Furthermore, the postischemic localizations
      of both GLUT1 and GLUT3 expressions may be altered from the normal physiological
      expression pattern, which may be of importance in investigating postischemic cell
      function.

PMID- 8667002
TI  - Beta-amyloid-induced cell toxicity: enhancement of 3-(4,5-dimethylthiazol-2-yl)
      2,5-diphenyltetrazolium bromide-dependent cell death.
AB  - In an attempt to understand the cause of neurodegeneration in Alzheimer's
      disease, the toxic effects of beta-amyloid (Abeta) peptides have been widely
      studied. At high micromolar concentrations Abeta peptides have been demonstrated
      to be acutely toxic to various cell types. At submicromolar concentrations, Abeta
      peptides have been suggested to inhibit cellular metabolic activity, due to their
      inhibition of the ability of cells to metabolize the oxidoreductase substrate 3
      (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Here we show,
      first, that MTT reduction surprisingly leads to a breakdown in PC12 cell membrane
      integrity and cell death, presumably through the formation of a crystalline
      formazan product, and, second, that pretreatment of PC12 cells with nanomolar
      concentrations of Abeta peptide, rather than inhibiting their metabolic activity,
      increases the susceptibility of these cells to the secondary toxic effect of
      formazan crystal formation. These results suggest that low nanomolar
      concentrations of Abeta render membranes more susceptible to damage by a
      secondary insult, in this case, MTT reduction. It is plausible that such an
      effect, when combined with additional risk factors, could contribute to the
      neurodegeneration that occurs in Alzheimer's disease.

PMID- 8667003
TI  - Amyloid beta peptide (25-35) inhibits Na+-dependent glutamate uptake in rat
      hippocampal astrocyte cultures.
AB  - Large numbers of neuritic plaques surrounded by reactive astrocytes are
      characteristic of Alzheimer's disease (AD). There is a large body of research
      supporting a causal role for the amyloid beta peptide (Abeta), a main constituent
      of these plaques, in the neuropathology of AD. Several hypotheses have been
      proposed to explain the toxicity of Abeta including free radical injury and
      excitotoxicity. It has been reported that treatment of neuronal/astrocytic
      cultures with Abeta increases the vulnerability of neurons to glutamate-induced
      cell death. One mechanism that may explain this finding is inhibition of the
      astrocyte glutamate transporter by Abeta. The aim of the current study was to
      determine if Abetas inhibit astrocyte glutamate uptake and if this inhibition
      involves free radical damage to the transporter/astrocytes. We have previously
      reported that Abeta can generate free radicals, and this radical production was
      correlated with the oxidation of neurons in culture and inhibition of astrocyte
      glutamate uptake. In the present study, Abeta (25-35) significantly inhibited L
      glutamate uptake in rat hippocampal astrocyte cultures and this inhibition was
      prevented by the antioxidant Trolox. Decreases in astrocyte function, in
      particular L-glutamate uptake, may contribute to neuronal degeneration such as
      that seen in AD. These results lead to a revised excitotoxicity/free radical
      hypothesis of Abeta toxicity involving astrocytes.

PMID- 8667004
TI  - Sigma receptor modulation of noradrenergic-stimulated pineal melatonin
      biosynthesis in rats.
AB  - Because sigma receptors are richly concentrated in the rat pineal gland, the
      present study was performed to investigate their possible role in the modulation
      of melatonin production. To this purpose, we assessed in vivo the effects of the
      sigma-receptor ligands 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine on
      the rat pineal gland activity during either the daytime or the nighttime.
      Compared with vehicle, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine
      potentiated the enhancement of N-acetyltransferase activity and pineal melatonin
      content induced by isoproterenol administration during the daytime, whereas they
      did not affect the diurnal basal biosynthetic activity of the gland. Conversely,
      at night, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine enhanced
      significantly the physiological increases in both pineal N-acetyltransferase
      activity and melatonin levels. This enhancement was prevented by pretreatment
      with rimcazole, a specific sigma-receptor antagonist. These findings suggest
      that, in rats, the activation of pineal sigma-receptor sites does not affect the
      biosynthetic activity of the pineal gland during daytime, whereas it potentiates
      the production of melatonin when the gland is noradrenergically stimulated either
      by isoproterenol administration or by the endogenously released norepinephrine at
      nighttime.

PMID- 8667005
TI  - High-resolution separation of amyloid beta-peptides: structural variants present
      in Alzheimer's disease amyloid.
AB  - In Alzheimer's disease (AD), one of the cardinal neuropathological signs is
      deposition of amyloid, primarily consisting of the amyloid beta-peptide (Abeta).
      Structural variants of AD-associated Abeta peptides have been difficult to purify
      by high-resolution chromatographic techniques. We therefore developed a novel
      chromatographic protocol, enabling high-resolution reverse-phase liquid
      chromatography (RPLC) purification of Abeta variants displaying very small
      structural differences. By using a combination of size-exclusion chromatography
      and the novel RPLC protocol, Abeta peptides extracted from AD amyloid were
      purified and subsequently characterized. Structural analysis by microsequencing
      and electrospray-ionization mass spectrometry revealed that the RPLC system
      resolved a complex mixture of Abeta variants terminating at either residue 40 or
      42. Abeta variants differing by as little as one amino acid residue could be
      purified rapidly to apparent homogeneity. The resolution of the system was
      further illustrated by its ability to separate the structural isomers of Abeta1
      40. The present chromatography system might provide further insight into the role
      of N-terminally and posttranslationally modified Abeta variants, because each
      variant can now be studied individually.

PMID- 8667006
TI  - Interaction between A1 adenosine and class II metabotropic glutamate receptors in
      the regulation of purine and glutamate release from rat hippocampal slices.
AB  - Electrical stimulation of rat hippocampal slices evoked the release of excitatory
      amino acids and purines, as reflected by a time-dependent increase in the
      extracellular levels of glutamate and adenosine, as well as by the increased
      efflux of radioactivity in slices preloaded with both [14C]glutamate and
      [3H]adenosine. The evoked release of excitatory amino acids and purines was
      amplified when slices were exposed to 8-cyclopentyl-1,3-dipropylxanthine (a
      selective A1 adenosine receptor antagonist), (+)-alpha-methyl-4
      carboxyphenylglycine [a mixed antagonist of metabotropic glutamate receptors
      (mGluRs)], or (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (a selective
      antagonist of class II mGluRs). In contrast, 2-chloro-N6-cyclopentyladenosine
      (CCPA; a selective A1 receptor agonist) or (2S,1R,2R,3R)-(2,3
      dicarboxycyclopropyl)glycine (DCG-IV; a selective agonist of class II mGluRs)
      reduced the evoked release of excitatory amino acids and purines. CCPA and DCG-IV
      also reduced the increase in cyclic AMP formation induced by either forskolin or
      electrical stimulation in hippocampal slices. The inhibitory effect of CCPA and
      DCG-IV on release or cyclic AMP formation was less than additive. We conclude
      that the evoked release of excitatory amino acids and purines is under an
      inhibitory control by A1 receptors and class II mGluRs, i.e., mGluR2 or 3, which
      appear to operate through a common transduction pathway. In addition, although
      these receptors are activated by endogenous adenosine and glutamate, they can
      still respond to pharmacological agonists. This provides a rationale for the use
      of A1 or class II mGluR agonists as neuroprotective agents in experimental models
      of excitotoxic neuronal degeneration.

PMID- 8667007
TI  - Septal and hippocampal glutamate receptors modulate the output of acetylcholine
      in hippocampus: a microdialysis study.
AB  - In the present study, glutamate receptor agonists and antagonists were
      administered by retrograde microdialysis into either the medial septum/vertical
      limb of the diagonal band (MS/vDB), or hippocampus, and the output of
      acetylcholine (ACh) was measured in the hippocampus by using intracerebral
      microdialysis. Perfusion with N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3
      hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the MS/vDB caused an incrase
      in ACh output in the hippocampus. This increase was completely blocked by
      coadministration of their respective antagonists D(-)-2-amino-5
      phosphonopentanoic acid (D-AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX).
      Perfusion in the MS/vDB with kainic acid also caused an increase in ACh output,
      but coadministration of CNQX attenuated the increase only partially. Perfusion
      with D-AP5 and CNQX alone in the septal probe did not affect ACh output from the
      hippocampus. In contrast to the results of septal administration of NMDA and
      AMPA, local perfusion with the same drugs in the hippocampus caused a decrease in
      ACh output. Whereas the results of septal administration of drugs indicate that
      septal cholinergic neurons probably receive excitatory glutamatergic innervation,
      the decrease in ACh output caused by administration of NMDA and AMPA in the
      hippocampus is poorly understood.

PMID- 8667008
TI  - Ca2+-dependent and Ca2+-independent protein kinase C changes in the brain of
      patients with Alzheimer's disease.
AB  - We examined protein kinase C (PKC) activity in Ca2+-dependent PKC (Ca2+-dependent
      PKC activities) and Ca2+-independent PKC (Ca2+-independent PKC activities) assay
      conditions in brains from Alzheimer's disease (AD) patients and age-matched
      controls. In cytosolic and membranous fractions, Ca2+-dependent and Ca2+
      independent PKC activities were significantly lower in AD brain than in control
      brain. In particular, reduction of Ca2+-independent PKC activity in the
      membranous fraction of AD brain was most enhanced when cardiolipin, the optimal
      stimulator of PKC-epsilon, was used in the assay; whereas Ca2+-independent PKC
      activity stimulated by phosphatidylinositol, the optimal stimulator of PKC-delta,
      was not significantly reduced in AD. Further studies on the protein levels of
      Ca2+-independent PKC-delta, PKC-epsilon and PKC-zeta in AD brain revealed
      reduction of the PKC-epsilon level in both cytosolic and membranous fractions,
      although PKC-delta and PKC-zeta levels were not changed. These findings indicated
      that Ca2+-dependent and Ca2+-independent PKC are changed in AD, and that among
      Ca2+-independent PKC isozymes, the alteration of PKC-epsilon is a specific event
      in AD brain, suggesting its crucial role in AD pathophysiology.

PMID- 8667009
TI  - Tetanus toxin-induced effects on extracellular amino acid levels in rat
      hippocampus: an in vivo microdialysis study.
AB  - Tetanus toxin is a potent neurotoxin that is widely considered to produce its
      effect through impairment of inhibitory neurotransmission. We report the effect
      of a single unilateral intrahippocampal injection of tetanus toxin on
      extracellular levels of neuroactive amino acids in freely moving rats, at times
      ranging between 1 and 7 days posttreatment. Tetanus toxin treatment did not alter
      extracellular levels of aspartate, glutamate, and taurine at any time during the
      study. However, although extracellular GABA levels were unaffected by toxin
      injection 1, 2, and 3 days after treatment, they were reduced (45 +/- 8% of
      contralateral vehicle-injected level) at day 7. Challenge with a high K+
      concentration, 7 days after treatment, produced elevations in extracellular
      levels of taurine and GABA in both vehicle- and toxin-injected hippocampi, with
      evoked levels of GABA being lower in the toxin-treated side (39 +/- 16% of
      contralateral vehicle-injected level). Aspartate and glutamate levels were not
      increased by high-K+ infusion. These findings are discussed in relation to the
      possible role that an imbalance in excitatory/inhibitory tone may play in the
      production of tetanus toxin-induced neurodegeneration.

PMID- 8667010
TI  - Sodium and chloride ion-dependent transport of beta-alanine across the blood
      brain barrier.
AB  - The characteristics of beta-alanine transport at the blood-brain barrier were
      studied by using primary cultured bovine brain capillary endothelial cells.
      Kinetic analysis of the beta-[3H]alanine transport indicated that the transporter
      for beta-alanine functions with Kt of 25.3 +/- 2.5 microM and Jmax of 6.90 +/-
      0.48 nmol/30 min/mg of protein in the brain capillary endothelial cells. Beta
      [3H]Alanine uptake is mediated by an active transporter, because metabolic
      inhibitors (2,4-dinitrophenol and NaN3) and low temperature reduced the uptake
      significantly. Furthermore, the uptake of beta-[3H]alanine required Na+ and Cl-
      in the external medium. Stoichiometric analysis of the transport demonstrated
      that two sodium ions and one chloride ion are associated with one beta-alanine
      molecule. The Na+ and Cl--dependent uptake of beta-[3H]alanine was stimulated by
      a valinomycin-induced inside-negative K+-diffusion potential. beta-Amino acids
      (beta-alanine, taurine, and hypotaurine) inhibited strongly the uptake of beta
      [3H]-alanine, whereas alpha- and gamma-amino acids had little or no inhibitory
      effect. In ATP-depleted cells, the uptake of beta-[3H]alanine was stimulated by
      preloading of beta-alanine or taurine but not L-leucine. These results show that
      beta-alanine is taken up by brain capillary endothelial cells, via the secondary
      active transport mechanism that is common to beta-amino acids.

PMID- 8667011
TI  - Developmental expression of the glycine transporters GLYT1 and GLYT2 in mouse
      brain.
AB  - Using immunocytochemical localization, the distribution of the glycine
      transporters GLYT1 and GLYT2 in the developing mouse brain was studied. GLYT1 and
      GLYT2 immunoreactivity begins during the period of fiber outgrow and
      synaptogenesis. GLYT2 is first expressed in spinal and spinothalamic white matter
      and is followed by the expression of synaptophysin. In the postnatal stages,
      GLYT2 staining in the white matter disappears, and a punctuated pattern in the
      gray matter emerges. In contrast, in the fetal brain GLYT1 immunoreactivity
      coincides with gray matter neuropil and processes of radial glia. GLYT1 is
      distributed over a much wider area of the brain than GLYT2. However, the
      distribution of these two GLYTs implies that GLYT1 and GLYT2 operate in concert
      within the area where both are present. At the day 12 embryo stage, GLYT1
      antibodies stain the liver, and later they also react with the pancreas and the
      gastroduodenal junction. No other organs exhibit significant GLYT1
      immunoreactivity. We additionally observed the presence of GLYT1 in rat fetal
      cerebral cortex and hippocampus, which was not detected in fetal mouse brain.
      Moreover, GLYT1 immunoreactivity was found in the mouse floor plate and the
      ventral commissure but was not present in the same regions in rats. These
      findings suggest possible differences in the expression of GLYT1 between these
      two species.

PMID- 8667012
TI  - K252a modulates the expression of nerve growth factor-dependent capsaicin
      sensitivity and substance P levels in cultured adult rat dorsal root ganglion
      neurones.
AB  - K252a, an inhibitor of trk phosphorylation and nerve growth factor signal
      transduction in PC12 cells, blocked nerve growth factor-induced responses in
      cultured adult rat dorsal root ganglion sensory neurones. The nerve growth factor
      dependent appearance of capsaicin sensitivity and accumulation of the
      neuropeptide substance P were inhibited when dorsal root ganglion neurones were
      grown in the presence of low concentrations (100 nM) of K252a. At higher
      concentrations (3 microM), however, K252a stimulated the development of capsaicin
      sensitivity and the accumulation of substance P even in the absence of nerve
      growth factor. By using a wide dose range, therefore, we showed that K252a could
      either inhibit or mimic nerve growth factor's actions on sensory neurones. These
      results may explain the apparent paradox in the literature that some groups show
      a blocking effect of K252a on nerve growth factor-dependent survival of dorsal
      root ganglion sensory neurones, whereas other report that K252a can substitute
      for nerve growth factor or other trophic factors and promote neuronal survival.

PMID- 8667013
TI  - Acute and repeated systemic amphetamine administration: effects on extracellular
      glutamate, aspartate, and serine levels in rat ventral tegmental area and nucleus
      accumbens.
AB  - Recent work indicates an important role for excitatory amino acids in behavioral
      sensitization to amphetamine. We therefore examined, using in vivo microdialysis
      in awake rats, the effects of amphetamine on efflux of glutamate, aspartate, and
      serine in the ventral tegmental area and nucleus accumbens, brain regions
      important for the initiation and expression of amphetamine sensitization,
      respectively. Water-pretreated and amphetamine-pretreated rats were compared to
      determine if sensitization altered such effects. In both brain regions, Ca2+
      dependent efflux of glutamate accounted for approximately 20% of basal glutamate
      efflux. A challenge injection of water or 2.5 mg/kg of amphetamine did not
      significantly alter glutamate, aspartate, or serine efflux in the ventral
      tegmental area or nucleus accumbens of water- or amphetamine-pretreated rats.
      However, 5 mg/kg of amphetamine produced a gradual increase in glutamate efflux
      in both regions that did not reverse, was observed in both water- and amphetamine
      pretreated rats, and was prevented by haloperidol. Although increased glutamate
      efflux occurred with too great a delay to mediate acute behavioral responses to
      amphetamine, it is possible that repeated augmentation of glutamate efflux during
      repeated amphetamine administration results in compensatory changes in levels of
      excitatory amino acid receptors in the ventral tegmental area and nucleus
      accumbens that contribute to development of expression of amphetamine
      sensitization.

PMID- 8667014
TI  - Agonist-evoked Ca2+ mobilization from stores expressing inositol 1,4,5
      trisphosphate receptors and ryanodine receptors in cerebellar granule neurones.
AB  - The mechanisms involved in Ca2+ mobilization evoked by the muscarinic
      cholinoceptor (mAChR) agonist carbachol (CCh) and N-methyl-D-aspartate (NMDA) in
      cerebellar granule cells have been investigated. An initial challenge with
      caffeine greatly reduced the subsequent intracellular Ca2+ concentration
      ([Ca2+]i) response to CCh (to 45 +/- 19% of the control), and, similarly, a much
      reduced caffeine response was detectable after prior stimulation with CCh (to 27
      +/- 6% of the control). CCh-evoked [Ca2+]i responses were inhibited by
      preincubation with thapsigargin (10 microM), 2,5-di(tert-butyl)-1,4
      benzohydroquinone (BHQ; 25 microM), ryanodine (10 microM), or dantrolene (25
      microM). BHQ pretreatment was found to have no effect on the sustained phase of
      the NMDA-evoked [Ca2+]i response. Both CCh (1 mM) and 1-aminocyclopentane-1S,3R
      dicarboxylic acid (ACPD; 200 microM) evoked a much diminished increase in [Ca2+]i
      in granule cells pretreated with CCh for 24 h compared with vehicle-treated
      control cells (CCh, 23 +/- 14%; ACPD, 27 +/- 1% of respective control values). In
      contrast, a 24-h CCh pretreatment decreased the subsequent inositol 1,4,5
      trisphosphate (InsP3) response to CCh to a much greater extent compared with
      responses evoked by metabotropic glutamate receptor (mGluR) agonists; this
      suggests that the former effect on Ca2+ mobilization represents a heterologous
      desensitization of the mGluR-mediated response distal to the pathway second
      messenger. Furthermore, [Ca2+]i responses to caffeine and NMDA were unaffected by
      a 24-h pretreatment with CCh. This study indicates that ryanodine receptors, as
      well as InsP3 receptors, appear to be crucial to the mAChR-mediated [Ca2+]i
      response in granule cells. As BHQ apparently differentiates between the CCh- and
      NMDA-evoked responses, it is possible that the directly InsP3-sensitive pool is
      physically different from the ryanodine receptor pool. Also, activation of InsP3
      receptors may not contribute significantly to NMDA-evoked elevation of [Ca2+]i in
      cerebellar granule cells. A model for the topographic organization of cerebellar
      granule cell Ca2+ stores is proposed.

PMID- 8667015
TI  - Calcium channel subunits in the mouse cochlea.
AB  - Messages for subunits of voltage-gated calcium channels were examined in the
      cochlea of the CBAJ mouse by PCR analysis. Total RNA was extracted from the
      auditory organs of 16-18-day-old animals. After reverse transcription, resulting
      cDNA was amplified by PCR with primers targeted to nucleotide sequences
      corresponding to 12 different calcium channel subunits. PCR products representing
      subunit gene expression were strongly and consistently amplified for alpha1C,
      alpha1D, alpha1E, alpha2delta, beta1, beta3, and beta4 but not for alph1A,
      alpha1B, alpha1S, beta2, or gamma. The chosen primers amplified cochlear cDNA to
      yield an overall pattern of bands different from that of any tissue studied thus
      far, in particular with respect to the alpha2delta and beta1 subunits; the
      alpha2delata product was found to be significantly shorter than the corresponding
      brain and skeletal muscle isoforms. Nucleotide sequencing confirmed the identity
      of mouse cochlear subunit cDNAs. The results suggest that L-type and presumptive
      R-type calcium channels are expressed in the mammalian cochlea and that the
      alpha2delta subunits may be coded by a characteristic splice-variant mRNA.

PMID- 8667017
TI  - N-acetylsuccinimidylglutamate, a cyclic imide form of the peptide N
      acetylaspartylglutamate, is present in low micromolar concentrations in murine
      and bovine CNS.
AB  - N-Acetylsuccinimidylglutamate [(asu)NAAG], a cyclic form of the peptide N
      acetylaspartylglutamate (NAAG) in which the aspartyl residue is linked to
      glutamate via the alpha- and beta-carboxylates, was identified and quantified by
      HPLC in the murine and bovine CNS. In the rat, the highest concentrations of
      (asu)NAAG were detected in the spinal cord (1.83 +/- 0.15 pmol/mg of wet tissue
      weight) and brainstem (1.16 +/- 0.08 pmol/mg wet weight), whereas the levels were
      below the limit of detection in cerebellum, hippocampus, and cerebral cortex.
      (Asu)NAAG was also detected in significant amount in the superior colliculus and
      lateral geniculate nucleus (1.17 +/- 0.05 and 0.82 +/- 0.13 pmol/mg we weight,
      respectively). Although the tissue content of (asu)NAAG was about three orders of
      magnitude lower than that of NAAG, levels of both peptides were positively
      correlated among different CNS regions (r=0.74, p<0.003). In the rat spinal cord,
      (asu)NAAG levels progressively increased from week 2 to month 12 after birth. In
      bovine spinal cord, the contents of (asu)NAAG and NAAG were comparable in gray
      and white matter as well as in the dorsal and ventral horns. These results
      suggest that NAAG and (asu)-NAAG are closely related metabolically and raise the
      question of the physiological significance of such a cyclic peptide.

PMID- 8667016
TI  - Dual signalling by the adenosine A2a receptor involves activation of both N- and
      P-type calcium channels by different G proteins and protein kinases in the same
      striatal nerve terminals.
AB  - Many Gs-linked receptors have been reported to use multiple signalling pathways
      in transfected cels but few in their normal cell environment. We show that the
      adenosine A2a receptor uses two signalling pathways to increase the release of
      acetylcholine from striatal nerve terminals. One pathway involves activation of
      Gs, adenylyl acylase, protein kinase A, and P-type calcium channels; the other is
      mediated by a cholera toxin-insensitive G protein, protein kinase C, and N-type
      calcium channels. The effects of these two pathways are not additive, the second
      pathway being inhibited by the first; but they are equally sensitive to the A2a
      receptor antagonist KF17837. This demonstrates that the A2a receptor activates
      two signalling systems in striatal cholinergic neurons.

PMID- 8667019
TI  - ATP-activated nonselective cation current in NG108-15 cells.
AB  - ATP (1 mM) induced a biphasic increase in intracellular Ca2+ concentration
      ([Ca2+]i), i.e., an initial transient increase decayed to a level of sustained
      increase, in NG108-15 cells. The transient increase was inhibited by a
      phospholipase C inhibitor, 1-[6[[17beta-3-methoxyestra-1,3,5(10)-trien-17
      yl]amino]hexyl]-1H- pyrrole-2,5-dione (U73122), whereas the sustained increase
      was abolished by removal of external Ca2+. We examined the mechanism of the ATP
      elicited sustained [Ca2+]i increase using the fura-2 fluorescent method and the
      whole-cell patch clamp technique. ATP (1 mM) induced a membrane current with the
      reversal potential of 12.5 +/- 0.8 mV (n = 10) in Tyrode external solution. The
      EC50 of ATP was approximately 0.75 mM. The permeability ratio of various cations
      carrying this current was Na+ (defined as 1) > Li+ (0.92 +/- 0.01; n = 5) > K+
      (0.89 +/- 0.03; n = 6) > Rb+ (0.55 +/- 0.02; n = 6) > Cs+ (0.51 +/- 0.01; n = 5)
      > Ca2+ (0.22 +/- 0.03; n = 3) > N-methyl-D-glucamine (0.13 +/- 0.01; n = 5),
      suggesting that ATP activated a nonselective cation current. The ATP-induced
      current was larger at lower concentrations of external Mg2+. ATP analogues that
      induced the current were 2-methylthio-ATP (2MeSATP), benzoylbenzoic-ATP,
      adenosine 5'-thiotriphosphate (ATPgammaS), and adenosine 5'-O-(2
      thiodiphosphate), but not adenosine, ADP, alpha,beta-methylene-ATP (AMPCPP),
      beta,gamma-methylene-ATP (AMPPCP), or UTP. Concomitant with the current data,
      2MeSATP and ATPgammaS, but not AMPCPP or AMPPCP, increased the sustained [Ca2+]i
      increase. We conclude that ATP activates a class of Ca2+-permeable nonselective
      cation channels via the P2z receptor in NG108-15 cells.

PMID- 8667018
TI  - Evidence for the induction of repetitive action potentials in synaptosomes by K+
      channel inhibitors: an analysis of plasma membrane ion fluxes.
AB  - The effects of four K+-channel inhibitors on synaptosomal free Ca2+
      concentrations and 86Rb+ fluxes are analysed. 4-Aminopyridine, alpha-dendrotoxin,
      charybdotoxin, and tetraethylammonium all increase the free Ca2+ concentration,
      although their potencies differ widely. In each case, the elevation in free Ca2+
      concentration is reversed by the subsequent addition of tetrodotoxin. The
      transient 86Rb+ efflux from preequilibrated synaptosomes induced with high
      concentrations of veratridine is partially inhibited by 4-aminopyridine and alpha
      dendrotoxin. In contrast, when 4-aminopyridine or alpha-dendrotoxin is added to
      polarized synaptosomes, and enhanced 86Rb+ flux is seen, both for uptake and for
      efflux with no change in the total 86Rb+/K+ content of the synaptosomes and with
      only a slight time-averaged plasma membrane depolarization (6.4 and 3.3 mV,
      respectively). The enhancements of flux by 4-aminopyridine or alpha-dendrotoxin
      are sensitive to ouabain and/or to tetrodotoxin. Furthermore, these flux changes
      show the same concentration dependencies as the blocked component of veratridine
      stimulated 86Rb+ efflux, the elevation of free Ca2+ concentration, and the
      facilitation of glutamate exocytosis that are elicited by 4-aminopyridine or
      alpha-dendrotoxin. It is concluded that these findings support the proposal of
      spontaneous, repetitive firing of synaptosomes evoked by K+-channel inhibitors
      and that the enhanced 86Rb+ flux is a consequence of the activity of 4
      aminopyridine- and alpha-dendrotoxin-insensitive K+ channels during these action
      potentials.

PMID- 8667020
TI  - Distinct thermodynamic parameters of serotonin 5-HT3 agonists and antagonists to
      displace [3H]granisetron binding.
AB  - Specific binding of [3H]granisetron was examined to serotonin 5-HT3 receptors in
      synaptosomal membranes of rat cerebral cortex between 1 and 37 degrees C.
      Displacing potencies were determined for 5-HT3 antagonists (granisetron,
      ondansetron, tropisetron, and d-tubocurarine) and agonists (5-hydroxytryptamine,
      2-methyl-5-hydroxytryptamine, phenylbiguanide, m-chlorophenylbiguanide, and SR
      57227A). Displacing potencies of the agonists decreased with decreasing
      temperature. In contrast, displacing potencies of all antagonists increased with
      decreasing temperature, whereas those of tropisetron and d-tubocurarine passed a
      maximum. Scatchard analysis of [3H]granisetron binding resulted in KD values
      lower than the IC50 values of granisetron and a decreasing number of binding
      sites at higher temperatures. It can be reconciled with temperature-dependent
      agonist and antagonist states of 5-HT3 receptors. A semiquantitative
      thermodynamic analysis was based on displacing potencies. The distinct patterns
      for the signs of entropy, enthalpy, and heat capacity changes on binding can be
      reconciled with ionic interactions for agonists and hydrophobic interactions for
      antagonists. The distinctive differences in these thermodynamic parameters exceed
      those for GABAA and glycine receptor-ionophore complexes.

PMID- 8667021
TI  - In vivo and in vitro evidence for the biosynthesis of testosterone in the
      telencephalon of the female frog.
AB  - Neurons and glial cells are capable of synthesizing various steroid hormones, but
      biosynthesis of testosterone in the CNS has never been reported. The aim of the
      present study was to demonstrate the synthesis of testosterone in the frog brain.
      The presence of 17beta-hydroxysteroid dehydrogenase (17beta-HSD)-like
      immunoreactivity was detected in a population of glial cells located in the
      telencephalon. Reversed-phase HPLC analysis of brain tissue extracts combined
      with radioimmunoassay detection revealed the presence of substantial amounts of
      testosterone and 5alpha-dihydrotestosterone (5alpha-DHT) in the telencephalon
      where 17beta-HSD-positive cells were visualized. In male frogs, castration
      totally suppressed testosterone and 5alpha-DHT in the blood and in the
      rhombencephalon but did not affect the concentration of these two steroids in the
      telencephalon. Chemical characterization of testosterone in female frog
      telencephalon extracts was performed by coupling HPLC analysis with gas
      chromatography-mass spectrometry. Using the pulse-chase technique with
      [3H]pregnenolone as a precursor, the formation of a series of metabolites was
      observed, including dehydroepiandrosterone, androstenedione, testosterone, 5alpha
      DHT, and estradiol. These data demonstrate the existence of an active form of
      17beta-HSD in the frog telencephalon, which is likely involved in testosterone
      biosynthesis within the brain.

PMID- 8667022
TI  - Kinetics of tert-[35S]butylbicyclophosphorothionate binding in the cerebral
      cortex of newborn and adult rats: effects of GABA and receptor desensitization.
AB  - The effects of GABA on the kinetics of tert-[35S]butylbicyclophosphorothionate
      ([35S]TBPS) binding to the convulsant site of GABAA receptors were studied in
      membrane suspensions from the cerebral cortex of newborn (1-day-old) and adult
      (90-day-old) rats. TBPS dissociation was biphasic in neonates and adults,
      indicating that more than one interconvertible state of [35S]TBPS binding sites
      may be present in the cerebral cortex. In the absence of GABA, the fast (t1/2, 11
      min) and slow (t1/2, 77 min) components of TBPS dissociation in newborn rats were
      approximately fourfold slower than in adults. The acceleration of the
      dissociation rates caused by 2 microM GABA, however, was more robust in neonates
      than in adults (six- to ninefold vs. twofold increase, respectively). Moreover,
      the dissociation rates of TBPS in membranes preincubated with 2 microM GABA
      (dissociation started by adding 40 microM picrotoxin) were two- to fourfold
      slower than in membranes preincubated without GABA (dissociation started by
      adding 40 microM picrotoxin plus 2 microM GABA). Taken together, these results
      suggest that (1) the closed state of GABAA receptors is associated with a more
      effective steric barrier for the binding of TBPS in neonates compared with
      adults, (2) GABA produces a larger acceleration of the binding kinetics of TBPS
      in neonates than in adults, and (3) long incubations with GABA may cause receptor
      desensitization, which in turn slows down the dissociation rates of TBPS.

PMID- 8667023
TI  - Striatal malonate lesions are attenuated in neuronal nitric oxide synthase
      knockout mice.
AB  - Intrastriatal administration of the reversible succinate dehydrogenase inhibitor
      malonate produces both energy depletion and striatal lesions by a secondary
      excitotoxic mechanism. To investigate the role of nitric oxide (NO.) in the
      pathogenesis of the lesions we examined malonate toxicity in mice in which the
      genes for neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide
      synthase (eNOS) were disrupted. Malonate striatal lesions were significantly
      attenuated in the nNOS mutant mice, and they were significantly increased in the
      eNOS mutant mice. Malonate-induced increases in levels of 2,3- and 2,5
      dihydroxybenzoic acid/salicylate, markers of hydroxyl radical generation, were
      significantly attenuated in the nNOS knockout mice. Malonate-induced increases in
      3-nitrotyrosine, a marker for peroxynitrite-mediated damage, were blocked in the
      nNOS mice, whereas a significant increase occurred in the eNOS mice. These
      findings show that NO. produced by nNOS results in generation of peroxynitrite,
      which plays a role in malonate neurotoxicity.

PMID- 8667024
TI  - Bidirectional regulation of GABAA receptor alpha1 and alpha6 subunit expression
      by a cyclic AMP-mediated signalling mechanism in cerebellar granule cells in
      primary culture.
AB  - Forskolin treatment of cerebellar granule cells in culture resulted in
      bidirectional regulation of the expression of GABAA receptor alpha1 and alpha6
      subunits. Thus, forskolin applied at 2 days in vitro (DIV) increased expression
      of the alpha1 subunit but decreased the expression of the alpha6 subunit. Values
      with respect to control cultures, both assayed at 9 DIV by immunoblotting, were
      310 +/- 48% for alpha1 and 25 +/- 16% for the alpha6 subunit. Similar effects
      were evoked following chronic treatment with both dibutyryl cyclic AMP and 3
      isobutyl-1-methylxanthine. Dideoxyforskolin had no effect on the level of
      expression of either the alpha1 or the alpha6 GABAA receptor subunits. The
      changes in subunit expression were accompanied by a 1.7-fold increase in number
      of total specific [3H]Ro 15-4513 binding sites expressed by intact cerebellar
      granule cells. This increase in total binding sites was accommodated by a 2.7
      fold increase in number of diazepam-sensitive Ro 15-4513 binding sites in
      accordance with the observed increase in alpha1 subunit expression. The number of
      diazepam-insensitive subtype of binding sites were not significantly changed.
      These results suggest that GABAA receptor subtype expression can be
      differentially regulated by intracellular cyclic AMP concentration.

PMID- 8667025
TI  - The Caenorhabditis elegans behavioral gene unc-24 encodes a novel bipartite
      protein similar to both erythrocyte band 7.2 (stomatin) and nonspecific lipid
      transfer protein.
AB  - We report here the positional cloning and molecular characterization of the unc
      24 gene of Caenorhabditis elegans. This gene is required for normal locomotion
      and interacts with genes that affect the worm's response to volatile anesthetics.
      The predicted gene product contains a domain similar to part of two ion channel
      regulators (the erythrocyte integral membrane protein stomatin and the C. elegans
      neuronal protein MEC-2) juxtaposed to a domain similar to nonspecific lipid
      transfer protein (nsLTP; also called sterol carrier protein 2). Sequence analysis
      suggests that the nsLTP-like domain of UNC-24 provides lipid carrier function and
      is tethered to the plasma membrane by the stomatin-like domain which may be
      regulatory. We postulate that UNC-24 may be involved in lipid transfer between
      closely apposed membranes.

PMID- 8667026
TI  - The C-terminal domain of the mGluR1 metabotropic glutamate receptor affects
      sensitivity to agonists.
AB  - The metabotropic glutamate receptor (mGluR) subtype 1 exists as at least three
      variants (-1a, -1b, and -1c) generated by alternative splicing at the C-terminal
      domain. Fluorometric Ca2+ measurements were used to compare the concentration
      dependency of agonist-induced rises in intracellular free Ca2+ concentration
      ([Ca2+]i) in human embryonic HEK 293 cells transiently expressing rat mGluR1a,
      mGluR1b, or mGluR1c. The rank order of agonist potencies was quisqualate >>
      (2S,1'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) > (1S,3R)-1-aminocyclopentane
      1,3-dicarboxylic acid [(1S,3R)-ACPD] and did not differ among the splice
      variants. However, agonists were consistently more potent at mGluR1a than at
      mGluR1c and mGluR1b. In the same system, we characterized the agonist
      pharmacology of two chimeric rat mGluR3/1 receptors where the first and/or the
      second intracellular loop(s) and the C-terminal domain were exchanged with the
      corresponding mGluR1a or mGluR1c sequences and that were previously shown to
      mediate elevations in [Ca2+]i in response to agonists. The potency of agonists
      was higher at the chimera having the C-terminus of mGluR1a as compared with those
      having the mGluR1c C-terminus. Both chimeric mGluR3/1 receptors had the same rank
      order of agonist potencies: L-CCG-I >> (1S,3R)-ACPD approximately quisqualate.
      These data support the hypothesis that the C-terminal domain of mGluRs plays a
      role in determining the potency of agonists for inducing mGluR-mediated
      functional responses.

PMID- 8667027
TI  - Expression of the apoptosis-effector gene, Bax, is up-regulated in vulnerable
      hippocampal CA1 neurons following global ischemia.
AB  - The observation that delayed death of CA1 neurons after global ischemia is
      inhibited by protein synthesis inhibitors suggests that the delayed death of
      these neurons is an active process that requires new gene expression. Delayed
      death in CA1 has some of the characteristics of apoptotic death; however,
      candidate proapoptotic proteins have not been identified in the CA1 after
      ischemia. We studied the expression of Bax protein and mRNA, a member of the bcl
      2 family that is an effector of apoptotic cell death, after global ischemia in
      the four-vessel global ischemia model in the rat and compared these results with
      the expression of the antiapoptotic gene bcl-2. Bax mRNA and protein are both
      expressed in CA1 before delayed death, whereas bcl-2 protein is not expressed.
      Bcl-2 protein expression, but not that of Bax, is increased in CA3, a region that
      is ischemic but less susceptible to ischemic injury. In the dentate gyrus, both
      Bax and bcl-2 proteins are expressed. The selective expression of Bax in Ca1
      supports the hypothesis that Bax could contribute to delayed neuronal death in
      these vulnerable neurons by an independent mechanism or by forming heterodimers
      with gene family members other than bcl-2.

PMID- 8667028
TI  - Activation of protein kinase C augments peptide release from rat sensory neurons.
AB  - To determine whether protein kinase C (PKC) mediates release of peptides from
      sensory neurons, we examined the effects of altering PKC activity on resting and
      evoked release of substance P (SP) and calcitonin gene-related peptide (CGRP).
      Exposing rat sensory neurons in culture to 10 or 50 nM phorbol 12,13-dibutyrate
      (PDBu) significantly increased SP and CGRP release at least 10-fold above resting
      levels, whereas the inactive 4alpha-PDBu analogue at 100 nM had no effect on
      release. Furthermore, 100 nM bradykinin increased peptide release approximately
      fivefold. Down-regulation of PKC significantly attenuated the release of peptides
      evoked by either PDBu or bradykinin. PDBu at 1 nM or 1-oleoyl-2-acetyl-sn
      glycerol at 50 microM did not alter resting release of peptides, but augmented
      potassium- and capsaicin-stimulated release of both SP and CGRP approximately
      twofold. This sensitizing action of PKC activators on peptide release was
      significantly reduced by PKC down-regulation or by pretreating cultures with 10
      nM staurosporine. These results establish that activation of PKC is important in
      the regulation of peptide release from sensory neurons. The PKC-induced
      enhancement of peptide release may be a mechanism underlying the neuronal
      sensitization that produces hyperalgesia.

PMID- 8667029
TI  - Adenosine release and uptake in cerebellar granule neurons both occur via an
      equilibrative nucleoside carrier that is modulated by G proteins.
AB  - These is debate about the mechanisms mediating adenosine release from neurons. In
      this study, the release of adenosine evoked by depolarizing cultured cerebellar
      granule neurons with 50 mM K+ was inhibited by 49 +/- 7% in Ca2+-free medium. The
      remaining release was blocked by dipyridamole (IC50 = 6.4 x 10(-8) M) and
      nitrobenzylthioinosine (IC50 = 3.6 x 10(-8) M), inhibitors of adenosine uptake.
      Ca2+-dependent release was reduced by 78 +/- 9% following a 21-h pretreatment of
      the cells with pertussis toxin, which ADP-ribosylates Gi/Go G proteins, thereby
      preventing their dissociation. The nucleoside transporter-mediated component of
      K+-induced adenosine release also was inhibited by 62 +/- 8% by pertussis toxin
      and was potentiated by 78 +/- 11% following cholera toxin treatment, which
      permanently activates Gs. Uptake of [3H]adenosine into cultured cerebellar
      granule neurons over a 10-min period was not dependent on extracellular Na+ but
      was reduced by dipyridamole (IC50 = 3.2 x 10(-8) M) and nitrobenzylthioinosine
      (IC50 = 2.6 x 10(-8) M). Thus, adenosine uptake likely occurs via the same
      transporter mediating Ca2+-independent adenosine release. Adenosine uptake was
      potentiated by cholera toxin pretreatment (152 +/- 15% of control), but pertussis
      toxin had no statistically significant effect. It is possible that Gs, Gi/Go, or
      free Gbetagamma dimer modulate the equilibrative, inhibitor-sensitive nucleoside
      carrier to enhance adenosine transport.

PMID- 8667030
TI  - Molecular cloning and characterization of annexin V-binding proteins with highly
      hydrophilic peptide structure.
AB  - We previously reported that annexin V promoted the survival of cultured rat
      neocortical neurons. In an effort to elucidate the mechanism underlying this
      neurotrophic activity of annexin V, we have attempted to identify the target or
      binding proteins of annexin V in neuronal cells. Herein, we screened an embryonic
      day 17 rat brain cDNA library by western blot using glutathione S-transferase
      annexin V fusion protein as a probe and then isolated four clones showing binding
      to annexin V in a Ca2+ - and phospholipid-dependent manner. Although these cDNAs
      encoded different polypeptides, all four polypeptides shared the unique feature
      of containing highly hydrophilic stretches with high Lys, Glu, and Ser contents.
      Deduced amino acid sequences of two clones showed high homology with human X
      linked Helicase2 (XH2) and DNA (cytosine-5) methyltransferase (DMTase) sequences,
      whereas the other two were not related to any known peptide sequence. These
      results suggest that XH2 and DMTase are candidates for annexin V-binding proteins
      and thus may mediate the biological activity of annexin V.

PMID- 8667031
TI  - Nerve growth factor and ras regulate beta-amyloid precursor protein gene
      expression in PC12 cells.
AB  - The beta-amyloid protein, the major component of the vascular and plaque amyloid
      deposits that characterize Alzheimer's disease, derives from a larger beta
      amyloid precursor protein (APP) that is expressed in both neural and nonneural
      cells. An increased expression of APP might actively contribute to the
      development of the pathology; however, the mechanisms involved in the regulation
      of APP gene expression are not yet well understood. In PC12 cells, a rat
      pheochromocytoma cell line, we have demonstrated that nerve growth factor (NGF)
      induces the APP gene expression and increases APP mRNA levels in the presence of
      0.5 or 15% serum. Expression of activated ras in the PC12 cell subline UR61 also
      leads to a significant increase in content of APP transcripts, and a dominant
      negative mutant of ras blocks the NGF-induced response. Other ligands of tyrosine
      kinase receptors, such as fibroblast growth factor, which causes morphological
      differentiation, or epidermal growth factor, which induces cell growth, also
      increase APP mRNA levels in PC12 cells. These results suggest that ras mediates
      the induction of APP gene expression by NGF and other ligands of tyrosine kinase
      receptors.

PMID- 8667032
TI  - Survival and therapy of burn patients at the threshold of the twenty-first
      century: a review.
AB  - This review summarizes the progress achieved in care of burned patients over the
      last half century by analyzing the most significant results published between
      1949 and 1995. Improved survival has paralleled the development of new
      antibiotics as well as major advances in resuscitation, nutritional support,
      immunomodulating agents, surgical techniques and wound care. Today the average
      burn size associated with a 50% mortality breakpoint is about 70% of the total
      body surface area--a notable increase over figures from the past.

PMID- 8667033
TI  - Determination of the in vitro susceptibility of 220 Mycobacterium fortuitum
      isolates to ten antimicrobial agents.
AB  - The authors investigated the in vitro susceptibility to antimicrobial agents of
      220 Mycobacterium fortuitum isolates originating from clinical samples (14) of
      patients attending the Hospital Universitario de Canarias and Hospital del Torax,
      and from environmental sources (206): 3 from sea water, 10 from the water supply
      and 193 from sewage. The Minimum Inhibitory Concentration (MIC) was calculated
      using the broth microdilution method with Mueller-Hinton Broth without
      supplement. Amikacin was the most efficacious antimicrobial agent against all the
      isolates of M. fortuitum with an MIC which was considerably lower than its
      critical concentration. The good results achieved with amikacin in vitro are
      confirmed by those obtained in vivo, with patients infected with M. fortuitum. No
      significant difference was found in the efficacy of amikacin and ofloxacin
      against all the isolates assayed.

PMID- 8667034
TI  - Antimicrobial resistance and prevalence of extended spectrum beta-lactamase among
      clinical isolates of gram-negative bacteria in Riyadh.
AB  - The activity of ciprofloxacin, imipenem and 12 other commonly used antibiotics
      was evaluated against 106 documented clinical isolates from a medical Intensive
      Care Unit (ICU). The resistance rates to ceftriaxone, cefotaxime, aztreonam and
      ceftazidime were 42, 25, 24 and 21%, respectively. Apart from Pseudomonas
      aeruginosa, all isolates were sensitive to ciprofloxacin and imipenem. Complete
      cross resistance among tested beta-lactam groups was uniformly evident in
      Enterobacter cloacae, Citrobacter freundii and P. aeruginosa. On the other hand,
      penicillins and second generation cephalosporins showed cross resistance among
      Escherichia coli and Klebseilla pneumoniae isolates. Induction experiments
      indicate that 70 and 62% of P. aeruginosa and E. cloacae or C. freundii produce
      class I cephalosporinase, respectively. Among all tested isolates, plasmid
      mediated extended spectrum beta-lactamase (ESBL) was detected in one isolate of
      K. pneumoniae. The plasmid mediated beta-lactamase is transferable and inhibited
      by beta-lactamase inhibitors. The transconjugates not only expressed resistance
      to extended spectrum beta-lactams and aztreonam but also toward tested
      aminoglycoside antibiotics, with the exception of gentamicin. The obtained
      transconjugates conferred high level resistance to ceftazidime and aztreonam but
      considerably low resistance to ceftriaxone and cefotaxime. The isoelectric point
      for the extended-spectrum beta-lactamase is 8.2.

PMID- 8667035
TI  - The in vitro activity of trospectomycin against anaerobic bacteria.
AB  - The authors evaluated the activity of trospectomycin, a new aminocyclitol which
      is characterized by good antibacterial and broad spectrum activity, in comparison
      with clindamycin and ampicillin on a sample of recent isolates: Bacteroides
      fragilis (15 strains), Bacteroides urealyticus (5 strains), Bacteroides vulgatus
      (5 strains), Bacteroides spp. (15 strains), Prevotella melaninogenica (6
      strains), Porphyromonas asaccharolytica (7 strains), Mobiluncus spp. (3 strains),
      Peptococcus niger (3 strains), Peptococcus variabilis (9 strains), Peptococcus
      spp (30 strains), Peptostreptococcus anaerobius (5 strains), Peptostreptococcus
      asaccharolyticus (3 strains), Peptostreptococcus spp. (25 strains) and
      Propionibacterium spp. (7 strains). The minimum inhibitory concentration (MIC)
      and minimum bactericidal concentration (MBC) were determined for all strains by
      microtiter serial dilutions in Wilkins-Chalgren broth in an anaerobic chamber in
      an atmosphere of 10% H2, 10% CO2, 80% N2. All the drugs tested exert their
      activity against Gram-positive and Gram-negative anaerobic isolates. In
      particular, trospectomycin is quite active against Gram-positive cocci (MIC 90 =
      4 - 8 mg/l), Gram-negative rods (MIC 90 = 8 - 16 mg/l), Gram-positive rods (MIC
      90 = 4 mg/l) and Mobiluncus spp. (MIC 90 = 0.5 mg/l).

PMID- 8667036
TI  - Alterations in surface morphology of Candida albicans produced by rilopirox: a
      scanning electron microscopy study.
AB  - The topological changes produced in Candida albicans cells by incubation in vitro
      with rilopirox have been investigated by scanning electron microscopy. Rilopirox
      is a new hydroxypyridone compound with fungicidal activity and the effects of 1x
      MIC (2.9 micrograms/ml) and 4 x MIC (11.6 micrograms/ml) after 1, 12, 24 hours of
      incubation were evaluated. The morphological alterations produced by rilopirox
      are round shapes, collapsed cells, surface folds, clusters, holes and thorn-like
      extrusion. The effects of rilopirox are already evident at 1 x MIC and after 1 h
      but their frequency and severity are correlated with the time of incubation and
      the MIC.

PMID- 8667037
TI  - In-vitro activity of commonly used antifungal agents in the presence of rifampin,
      polymyxin B and norfloxacin against Candida albicans.
AB  - This study assessed the in-vitro antifungal activity against Candida albicans of
      amphotericin B, ketoconazole and miconazole, each in the presence of rifampin,
      polymyxin B and norfloxacin. Evaluation of drug interactions was estimated by the
      checkerboard pattern broth dilution method and by time-kill studies. Rifampin
      reduced the activity of the three antifungal agents used, with the reduction
      being more pronounced with amphotericin B. Synergy was observed when polymyxin B
      was combined with any of the antifungal agents used. The addition of norfloxacin
      resulted in minimal, if any, change in the activity.

PMID- 8667038
TI  - Bactericidal kinetics and postantibiotic effect of sparfloxacin against selected
      species of respiratory pathogens.
AB  - We determined the bactericidal kinetics and postantibiotic effect (PAE) of
      sparfloxacin against Haemophilus influenzae, Moraxella (Branhamella) catarrhalis,
      Klebsiella pneumonia, Streptococcus pneumoniae, and Staphylococcus aureus. Time
      kill studies were performed by using 1 x and 4 x the minimum inhibitory
      concentrations (MICs) of sparfloxacin, ciprofloxacin, co-trimoxazole,
      amoxicillin/clavulanic acid and erythromycin (inoculum 10(5) and 10(7) CFU/ml).
      The PAE was induced by exposing the strains to 1xMIC and 4xMIC of sparfloxacin
      and ciprofloxacin for 1 h. Sparfloxacin was the most bactericidal of all the
      antibiotics tested, being active against Gram-positive and Gram-negative isolates
      with a 99.9% reduction within 3 to 6 h of exposure, depending upon strain,
      inoculum and concentration. The PAE of sparfloxacin against all species tested
      ranged from 1.1 to 2.6 hours; the most notable PAE occurring with M. catarrhalis.

PMID- 8667039
TI  - Open, controlled, randomized study on the efficacy and safety of cefodizime
      single daily dose versus two daily doses and versus ceftriaxone single daily dose
      in patients with acute purulent bronchitis and acute purulent exacerbation of
      chronic bronchitis.
AB  - Two hundred and thirty-eight in-patients with signs and symptoms of acute
      purulent bronchitis or purulent exacerbation of chronic bronchitis at stage 1 and
      2 of Anthonisen's classification were enrolled in 11 Centers and randomly
      assigned to one of the following 3 treatment groups: group A, cefodizime 1 g i.m.
      qD; group B, cefodizime 1 g i.m. BID; group C, ceftriaxone 1 g i.m. qD.
      Bacteriological results after treatment were satisfactory in 64 patients (91.4%)
      of group A, 64 (92.8%) of group B and 74 (94.9%) of group C. Global clinical
      results after treatment showed satisfactory efficacy in 57 patients (79.2%) of
      group A, 59 (85.5%) of group B and 63 (80.8%) of group C. There was no
      statistically significant difference in improvement in single symptoms, global
      bacteriological or clinical results between the 3 groups. Mild adverse events
      occurred in only 3 patients (one per group).

PMID- 8667040
TI  - Tiazofurine uptake by the isolated guinea pig heart.
AB  - Tiazofurine is a selective inhibitor of the enzyme inosine monophosphate
      dehydrogenase, and exhibits potent antitumor activity. Considering the potential
      side effects on the heart, [3H] tiazofurine uptake into the cardiomyocytes, as
      well as the mechanism of transport, were studied in the isolated perfused guinea
      pig heart, using the rapid single circulation, paired-tracer technique. The
      maximal cellular uptake (Umax) of [3H] tiazofurine ranged from 19% to 25% of the
      injected dose, with total cellular uptake (Utot) ranging 12.1-15.6%. The addition
      of unlabeled tiazofurine caused inhibition of [3H] tiazofurine uptake, with a
      Umax value of 9.06 +/- 4.6%. Therefore, the uptake of tiazofurine into
      cardiomyocytes could be considered a saturable process. The inhibition of [3H]
      tiazofurine uptake caused by adenosine and dipyridamole was of the same degree as
      the inhibition by unlabeled tiazofurine. Thus, it can be assumed that
      nucleosides' transport system(s) are involved in transport of tiazofurine into
      myocardial cells.

PMID- 8667041
TI  - Concurrent carboplatin and radiotherapy in the treatment of squamous cell
      carcinoma of the head and neck, stage IV. Preliminary data of a phase II study.
AB  - About two-thirds of the patients with squamous cell carcinoma of the head and
      neck (SCCHN) are diagnosed when the disease is in a locoregionally advanced
      stage. If surgery is not advisable, radiotherapy is the only treatment presently
      available to obtain radicality. In order to improve the therapeutic efficacy of
      radiotherapy (RT), chemotherapy has been associated with it with the aim of
      eradicating possible micrometastatic foci outside the radiotherapic fields and to
      enhance the cytotoxic effects of radiation. Results with concomitant
      chemoradiotherapy have been encouraging. We carried out a phase II study with the
      combination of carboplatin 300 mg/m2 every 21 days and RT at conventional doses
      in SCCHN stage IV (non M1). We obtained an overall response of 85.7% with an 18
      month survival of 70%. The toxicity was moderate. These results encourage us to
      continue the accural of patients.

PMID- 8667043
TI  - Research in nuclear medicine: plans for the future.

PMID- 8667042
TI  - Communicating risk: nuclear physicians as patient advocate.

PMID- 8667044
TI  - Use of neural networks in brain SPECT to diagnose Alzheimer's disease.
AB  - The usefulness of artificial neural networks in the classification of 99mTc-HMPAO
      SPECT axial brain scans was investigated in a study group of Alzheimer's disease
      patients and age-matched normal subjects. METHODS: The cortical circumferential
      profiling (CCP) technique was used to extract information regarding patterns of
      cortical perfusion. Traditional analysis of the CCP data, taken from slices at
      the level of the basal ganglia, indicated significant perfusion deficits for
      Alzheimer's disease patients relative to normals, particularly in the left
      temporo-parietal and left posterior frontal areas of the cortex. The compressed
      profiles were then used to train a neural-network classifier, the performance of
      which was compared with that of a number of more traditional statistical
      (discriminant function) techniques and that of two expert viewers. RESULTS: The
      optimal classification performance of the neural network (ROC area = 0.91) was
      better than that of the alternative statistical techniques (max. ROC area = 0.85)
      and that of the expert viewers (max. ROC area = 0.79). CONCLUSION: The CCP
      produces perfusion profiles which are well suited to automated classification
      methods, particularly those employing neural networks. The technique has the
      potential for wide application.

PMID- 8667045
TI  - Diminished glucose transport and phosphorylation in Alzheimer's disease
      determined by dynamic FDG-PET.
AB  - Using dynamic [18F]fluorodeoxyglucose (FDG) and PET, kinetic rate constants that
      describe influx (K1) and efflux (k2) of FDG as well as phosphorylation (k3) and
      dephosphorylation (k4) were determined in patients with probable Alzheimer's
      disease and similarly aged normal controls. METHODS: The regional cerebral
      metabolic rate for glucose (CMRglu) was calculated from individually fitted rate
      constants in frontal, temporal, parietal and occipital cerebral cortex, caudate
      nucleus, putamen, thalamus and cerebellar cortex. Dynamic PET scans were obtained
      in normal controls (n = 10, mean age = 67) and Alzheimer's disease patients (n =
      8, mean age = 67) for 60 min following injection of 10 mCi of FDG. RESULTS: The
      Alzheimer's disease group was characterized by decreases of the CMRglu ranging
      from 13.3% in the frontal to 40.9% in the parietal cortex, which achieved
      significance in all regions except the thalamus. K1 was significantly reduced in
      the parietal (p < 0.01) and temporal cortices (p < 0.05). Significant declines in
      k3 were found in the parietal (p < 0.005), temporal and occipital cortex, and in
      the putamen and cerebellum (p < 0.05). The rate constants k2 and k4 were
      unchanged in the Alzheimer's disease group. CONCLUSION: These data suggest that
      hypometabolism in Alzheimer's disease is related to reduced glucose
      phosphorylation activity as well as diminished glucose transport, particularly in
      the most metabolically affected areas of the brain, the parietal and temporal
      cortex.

PMID- 8667046
TI  - Combined FDOPA and 3OMFD PET studies in Parkinson's disease.
AB  - PET has been used to quantify striatal 6-[18F]fluoro-L-dopa (FDOPA) uptake as a
      measure of presynaptic dopaminergic function. It has been suggested that the
      estimation of dopa-decarboxylation (DDC) rate, kD3, using a compartmental
      approach to dynamic FDOPA/PET data, can provide a better objective marker of
      parkinsonism. This modeling process, however, requires many assumptions to
      estimate DDC activity with acceptable errors. METHODS: We combined FDOPA 3-O
      methyl-fluorodopa PET studies on three normal subjects and five Parkinson's
      disease patients. RESULTS: The contradicted modeling assumptions are: (a) the
      rate constants across the blood-brain barrier, KD1 and kD2, for 3OMFD and FDOPA
      were in similar range (ratio approximately equal to 1) and thus not equal to
      assumed values of KM1/KD1 of 2.3 derived from rat studies and applied to human
      FDOPA studies and (b) the KD1/kD2 ratio for frontal cortex was not equal to that
      for the striatum (0.70 +/- 0.15 versus 1.07 +/- 0.3; p < 0.002). Discriminant
      analyses indicate that simple estimates like the striatum-to-occipital ratio, or
      the graphically derived unidirectional transport rate constant (KiFD) separate
      normals from Parkinson's disease patients at least as accurately as estimates of
      striatal DDC activity (kD3). CONCLUSION: Measurements of striatal DDC activity
      with dynamic FDOPA/PET and compartmental modeling may be based on incorrect
      assumptions. Even though such complex models yield microparameters that may be
      applicable to certain clinical research demands, they may produce misleading
      results in other experimental settings.

PMID- 8667047
TI  - Clinical significance of striatal DOPA decarboxylase activity in Parkinson's
      disease.
AB  - We performed dynamic PET studies with fluorodopa (FDOPA) in 9 normal volunteers
      and 16 patients with Parkinson's disease to investigate the applicability of dopa
      decarboxylase (DDC) activity measurements as useful markers of the parkinsonian
      disease process. METHODS: From the 3-O-methyl-FDOPA (3OMFD)/PET studies, we
      obtained mean population values of the kinetic rate constants for 3OMFD (K1M =
      0.0400 and k2M = 0.0420). We applied these values to calculate striatal DDC
      activity using the FDOPA compartmental model. We estimated k3D in this group
      using dynamic FDOPA-PET and population mean K1M and k2M values. We then applied
      the mean population K1M and k2M values to estimate k3D(pop) to a new group (6
      normal volunteers and 11 patients) studied only with dynamic FDOPA-PET. In all
      FDOPA/PET studies, we calculated striatal uptake rate constants (KiFD) using a
      graphical method and also measured the striato-occipital ratio (SOR). RESULTS:
      Although DDC activity has been postulated as a precise indicator of presynaptic
      nigrostriatal dopaminergic function, KiFD and SOR provided better between-group
      discrimination than did estimates of striatal DDC activity. KiFD and k3D(pop)
      both correlated significantly with quantitative disease severity ratings, with a
      similar degree of accuracy (r = 0.69 and 0.63 for k3D(pop) and KiFD,
      respectively; p < 0.01). CONCLUSION: Although estimated striatal DDC activity
      correlates with clinical disability, this measure is comparably less effective
      for early diagnosis. We conclude that a simple estimate such as striatal KiFD is
      superior to k3D measurements for most clinical and research applications.

PMID- 8667048
TI  - Reproducibility of iodine-123-beta-CIT SPECT brain measurement of dopamine
      transporters.
AB  - Iodine-123-beta-CIT has been used as a probe of monoamine transporters in human
      and nonhuman primates utilizing SPECT. To assess the utility of this tracer for
      measurement of striatal dopamine (DA) transporters in human disease, we studied
      the test/retest variability and reliability of SPECT measures obtained after
      bolus injection of [123I]beta-CIT 0-7 hr (Day 1) and 18-24 hr (Day 2) after
      administration. METHODS: For the Day 2 study, seven healthy humans (4 men, 3
      women; aged 19-74 yr) participated in two [123I]beta-CIT SPECT scans separated by
      7-14 days. Subjects were imaged at 18, 21 and 24 hr postinjection of 370 MBq (10
      mCi) [123I]beta-CIT. Two outcome measures were evaluated: (a) the ratio of
      specific striatal (activity associated with DA transporter binding) to
      nondisplaceable uptake, also designated V"3 and (b) the total, specific striatal
      uptake (%SSU) expressed as a percentage of injected radiotracer dose. Test/retest
      variability associated with V"3 and total specific striatal uptakes were compared
      for scans acquired at 18, 21 and 24 hr with 24 hr only postinjection scans. For
      the Day 1 study, three of the subjects participated in two kinetic studies of
      [123I]beta-CIT uptake. A three-compartment model was used for determination of
      konBmax and binding potential (BP = Bmax/Kd) and the reproducibility of the
      measures assessed. RESULTS: In the Day 2 study, both outcome measures
      demonstrated excellent test/retest reproducibility with variability of V"3 = 6.8
      +/- 6.8% and percent striatal uptake = 6.6 +/- 4.3% using data acquired from all
      time points. There were no significant differences in variability for the two
      outcome measures obtained. The intraclass correlation coefficient rho was 0.96
      and 0.98 for V"3 and %SSU, respectively. Considering the 24 hr postinjection
      scans only, there was a nonsignificant trend toward lower test/retest variability
      for %SSU compared to V"3 (6.6 +/- 4.2% and 12.8 +/- 9.0%, respectively). The
      test/retest variability for the Day 1 kinetic modeling data showed marked
      differences depending on the fitting strategy and assumptions about the
      reversibility of [123I]beta-CIT in striatum. Using a model that assumed a low,
      fixed value for reversible striatal binding (k4) produced low variability (12 +/-
      9%). CONCLUSION: These data suggest that SPECT imaging performed at either 0-7 hr
      or 18-24 hr after [123I]beta-CIT injection permits calculation of reliable and
      reproducible measures of dopamine transporters and supports the feasibility of
      using [123I]beta-CIT in serial evaluation of human neuropsychiatric disease.

PMID- 8667049
TI  - Iodine-131 treatment of hyperthyroidism: significance of effective half-life
      measurements.
AB  - Our goals were to evaluate the effect of half-life determination and differences
      in the half-life of 131I between patients with Graves' disease and toxic nodular
      goiter, and the influence of antithyroid drugs on iodine uptake. METHODS: We
      reviewed the records of 555 patients who had received radioiodine treatment for
      Graves' disease and toxic nodular goiter to analyze iodine uptake, half-life
      values and pretreatment with antithyroid drugs. Two different methods of dose
      calculation were compared: one using repeated uptake measurements at 24 and 48 hr
      and 4 or 6 days to define the effective half-life. The other method assumed a
      half-life of 5 days and uptake at 24 hr only. All patients were treated according
      to the first method. A follow-up questionnaire was sent to 327 patients (238
      responders) to assess the treatment outcome. RESULTS: After comparing the results
      of the two methods, we found that repeat uptake measurements and determination of
      effective half-life results in administered activities that differ considerably
      from those calculated when an assumed, fixed half-life and a single uptake
      measurement are used. The simpler method would lead to over- as well as
      undertreatment of the patient. There was a functional difference between patients
      with Graves' disease and toxic nodular goiter, as reflected by the shorter 131I
      half-life in Graves' disease (mean 5.0 days) than toxic nodular goiter (mean 6.0
      days) and a skewed distribution in toxic nodular goiter. Patients pretreated with
      antithyroid drugs had shorter 131I half-lives in both categories. Ten percent of
      the patients required more than one treatment; 94% of the patients with Graves'
      disease and 45% with toxic nodular goiter had thyroxine substitution 1-5 yr after
      treatment. CONCLUSION: A dose calculation method that uses three uptake
      measurements provides sufficient data about the effective half-life of 131I in
      the thyroid. There is considerable difference in the half-life based on the
      disease being treated (Graves' disease or toxic nodular goiter). The 131I half
      life also is shorter after pretreatment with anti-thyroid drugs. Thus, the
      simpler method leads to significant uncertainty, leading to over- as well
      undertreatment of the patient.

PMID- 8667050
TI  - Institute of Medicine study supports state regulation of medical isotopes over
      NRC.

PMID- 8667051
TI  - Technetium-99m-MIBI scintigraphy in pulmonary tuberculosis.
AB  - We investigated the usefulness of 99mTc-methoxyisobutylisonitrile scintigraphy in
      patients with known or suspected pulmonary tuberculosis (PTB) in comparison with
      radiological and bacteriological findings. METHODS: Thirty-six patients aged 13
      59 yr were scanned 15 and 60 min after intravenous injection of 370 MBq (10 mCi)
      99mTc-methoxyisobutylisonitrile. Twenty-four patients had active PTB proven by
      chest radiograph and sputum examinations, two had miliary tuberculosis and ten
      were suspected of having relapsed PTB with negative sputum examinations and
      indeterminate chest radiographs. In 12 patients 99mTc-MIBI imaging was repeated 1
      3 mo after chemotherapy. RESULTS: Of 24 patients with active localized PTB, 22
      (92%) showed increased focal uptake of 99mTc-MIBI, but two patients with minimal
      infiltration on chest radiographs had no accumulation of 99mTc-MIBI. Both
      patients with miliary PTB showed diffuse 99mTc-MIBI uptake in the lungs. Among 10
      patients with suspicion of relapse, 99mTc-MIBI scans were true-positive in 4 of 5
      patients (80%) with culture-proven tuberculosis and false-positive in 2 of 5
      (40%) patients with negative sputum cultures. For repeat imaging, 6 of 10
      patients with active localized PTB showed reduced MIBI uptake, which correlated
      with chest radiograph findings, and one patient had increased MIBI uptake again
      concordant with clinical and radiological findings which were suggestive of
      resistance to first line chemotherapy of tuberculosis. The other three patients
      showed no significant scintigraphic changes despite clinical and partial
      radiological regression. CONCLUSION: Active PTB granulomas generally present
      considerable 99mTc-MIBI uptake that is most probably related to disease activity.
      Therefore, 99mTc-MIBI scanning could be used in the detection and follow-up of
      active PTB as a complement to routine techniques.

PMID- 8667052
TI  - Utility of technetium-99m-DTPA in determining regional ventilation.
AB  - The goal of this study was to determine the usefulness of radiolabeled aerosols
      in the assessment of regional ventilation in tracheotomized patients maintained
      on mechanical ventilation. METHODS: Three commercially available radioaerosol
      nebulizer kits were studied on the bench to determine nebulizer efficiency and
      particle distribution of 99mTc-DTPA aerosols. We studied ventilated
      tracheotomized human subjects with a gamma camera and simultaneously measured
      regional ventilation with 81mKr gas and 99mTc-DTPA aerosol. Images were compared
      by analysis of radioactivity distributions in computer-generated regions of
      interest. RESULTS: The UltraVent nebulizing system produced the smallest
      particles with a mass median aerodynamic diameter of 0.9 micron compared to the
      AeroTech I and Venti-Scan II systems, which both produced aerosols of 1.3
      microns. Despite relatively small particle sizes, 99mTc-DTPA deposition images
      with the UltraVent nebulizer did not accurately represent regional ventilation as
      measured by 81mKr equilibrium. Visual inspection of images revealed significant
      amounts of particle deposition in the region of the trachea which was diminished
      but not eliminated following replacement of the tracheotomy tube inner cannula.
      Based on regional analysis, correlation between radioactivity distributions of
      both isotopes was poor (r = 0.262, p = 0.162) with segmental analysis suggesting
      that the upper and middle lung regions were significantly affected by residual
      tracheal activity. CONCLUSION: The lungs of patients maintained on mechanical
      ventilation can be imaged after the inhalation of 99mTc-DTPA from commercially
      available delivery kits, but the correlation between aerosol deposition and
      regional ventilation is poor. Better definition of ventilated lung segments is
      obtained when using a gas such as 81mKr because tracheal activity with the
      radiolabeled gas is minimized.

PMID- 8667053
TI  - Phase 1 study of rhenium-186-HEDP in patients with bone metastases originating
      from breast cancer.
AB  - Rhenium-186-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) has been used for
      the palliative treatment of metastatic bone pain. A Phase 1 dosage escalation
      study was performed using 186Re-HEDP in patients with metastatic breast cancer.
      METHODS: Twelve patients with metastatic breast cancer were studied. Each patient
      had at least four bone metastases and adequate hematological function. Groups of
      three consecutive patients were treated with dosages starting at 1295 MBq (35
      mCi) and increasing to 2960 MBq (80 mCi) (escalated in increments of 555 MBq).
      RESULTS: A transient increase in pain ("flare" reaction) was observed in six
      patients. Two patients who received 2960 MBq 186Re-HEDP showed Grades 3
      (platelets 25-50 x 10(9)/l) and 4 (platelets < 25 x 10(9)/l) platelet toxicity,
      which was defined as unacceptable. Prior to treatment, alkaline phosphatase
      levels were elevated in seven cases. These patients showed a transient decline in
      alkaline phosphatase levels during the first 4 wk. CONCLUSION: The maximum
      tolerated administered activity of 186Re-HEDP in patients with metastatic breast
      cancer is 2405 MBq (65 mCi). Thrombocytopenia proved to be the dose-limiting
      toxicity, which could not be predicted adequately by the administered activity.
      Changes of alkaline phosphatase levels suggest anti-tumor effects of 186Re-HEDP.

PMID- 8667054
TI  - Dosage and response in radiopharmaceutical therapy of painful osseous metastases.

PMID- 8667055
TI  - Radioimmunoscintigraphy in patients with early stage cutaneous malignant
      melanoma.
AB  - CT and MRI examinations remain relatively insensitive for the detection of
      metastatic melanoma lesions, especially those of regional lymph nodes. Imaging
      cutaneous malignant melanoma patients with the Fab fragment of monoclonal
      antibody (MAb) NR-ML-05 labeled with 99mTc has been reported to increase the
      accuracy of staging. Our purpose in this study was to assess the sensitivity of
      99mTc-labeled NR-ML-05 in detecting the spread of melanoma. METHODS: Twenty-six
      adult cutaneous malignant melanoma patients were enrolled in this study and were
      followed for 6 to 60 mo after radioimmunoscintigraphy. At the time of imaging, 20
      patients had their primary lesions resected, whereas the remaining 6 patients had
      their primary lesions intact. RESULTS: Radioimmunoscintigraphy correctly detected
      8 of 18 suspicious lesions as malignant, as well as 4 additional malignant
      lesions which had not been suspected previously. Radioimmunoscintigraphy also
      correctly identified 8 of the 18 suspicious lesions as benign. Two of the 18
      suspicious lesions were found to be false negatives. The overall lesion
      sensitivity of radioimmunoscintigraphy was 86%. CONCLUSION: Twenty-four of the 26
      patients were correctly staged by radioimmunoscintigraphy. The accuracy of
      staging of cutaneous malignant melanoma patients by clinical and or radiologic
      examinations (73%) was greatly improved with the use of radioimmunoscintigraphy
      (93%). These results suggest that radioimmunoscintigraphy may be a clinically
      useful adjunct to the current armamentarium for guidance of medical, and
      particularly surgical, therapy of cutaneous malignant melanoma patients.

PMID- 8667056
TI  - Fluorine-18-fluorodeoxyglucose PET imaging of soft-tissue sarcoma.
AB  - PET with 18F-fluoro-2-deoxy-D-glucose (FDG) was used to study soft-tissue
      lesions. The goals of the study were to establish FDG uptake in soft-tissue
      sarcoma, to determine the sensitivity of this technique, to investigate the
      correlation between histologic grade and glucose consumption and to determine
      whether FDG-PET can discriminate between benign and malignant lesions. METHODS:
      PET imaging was performed in 18 patients with soft-tissue sarcoma and 4 patients
      with a benign soft-tissue lesion. Glucose consumption in the tumors was
      calculated using Patlak's graphical analysis with an assumption made for the
      lumped constant. Standardized uptake values also were calculated. RESULTS: All
      soft-tissue sarcomas were clearly depicted. The median glucose consumption was
      13.0 mumole/100 g/min (range 2.9-41.8 mumole/100 g/min). A correlation was found
      between glucose metabolism and the histopathologic malignancy grade. Such a
      correlation was not demonstrated for the standardized uptake values. One benign
      lesion was also visualized. Benign lesions were not visualized in two patients
      and in the remaining patient an equivocal scan was obtained. Benign lesions could
      be distinguished from high-grade malignant lesions but not consistently from
      lesions with low or intermediate malignancy grades. CONCLUSION: PET with FDG is
      an effective technique to visualize soft-tissue sarcomas. We found a sensitivity
      of 100%. There is a correlation between glucose metabolic rate and tumor
      malignancy grade. FDG appears to be unsuitable for discriminating benign lesions
      from soft-tissue sarcomas with low or intermediate malignancy grades.

PMID- 8667057
TI  - Dynamic cholescintigraphy: induction and description of gallbladder emptying.
AB  - The main purposes of this study were to investigate the best parameter for
      describing gallbladder emptying and whether gallbladder bile emptying should be
      induced with a bolus injection or continuous infusion of cholecystokinin
      octapeptide (CCK-8). METHODS: Gallbladder emptying was measured by dynamic
      cholescintigraphy. Twelve healthy subjects and six patients with gallstones were
      examined twice with CCK-8 infusion cholescintigraphy, 0.3 ng CCK-8 kg per min for
      60 min under identical circumstances. Another six healthy subjects randomly
      received bolus injection (0.04 microgram/kg) and infusion of CCK-8 (0.3 ng/kg per
      min for 60 min), respectively, during cholescintigraphy on two separate
      occasions. The choice of bolus dose was based on recommendations from the CCK-8
      manufacturer. The infusion dose was chosen to produce plasma CCK concentrations
      similar to postprandial plasma CCK levels. RESULTS: A parameter of gallbladder
      emptying, mean ejection fraction (EF), was defined as 100% minus the area under
      the time-activity curve normalized to 100% and divided by the time interval from
      maximum to minimum counts per minute. This parameter proved superior to the well
      known parameters, EFmax. and EF30, in regard to reproducibility in healthy
      subjects. The slope of the regression line for the mean EF was 0.998 and the
      intercept value approximately 0% (p = 0.0001). The mean coefficient of variation
      was 4%. Apart from a higher mean coefficient of variation, similar
      reproducibility results were seen in the six patients. The measurements of EF30
      in healthy subjects scattered more widely around the mean compared to the mean EF
      and EFmax, which indicates poorer ability to separate normal from abnormal
      gallbladder emptying. Intravenous bolus injection of CCK-8 resulted in incomplete
      gallbladder emptying with a mean EF value of 16% (s.d. 9%; range 7%-32%) compared
      to 49% (s.d. 7%; range 37%-57%) following CCK-8 infusion (p = 0.004). Abdominal
      discomfort was observed in all subjects after administration of the bolus
      injection, whereas no complaints were reported during infusion. CONCLUSION: Mean
      EF is the best parameter for describing gallbladder emptying. Moreover, slow
      infusion of a physiological dose of CCK-8 is preferable to induce gallbladder
      emptying because it results in more complete emptying and has no side effects.

PMID- 8667058
TI  - Gallbladder nonvisualization with pericholecystic rim sign: morphine-augmentation
      optimizes diagnosis of acute cholecystitis.
AB  - This study investigated the value of morphine-augmentation in patients who
      demonstrated gallbladder nonvisualization with a pericholecystic rim sign at 1
      hr, a cholescintigraphic pattern considered highly predictive of acute
      cholecystitis. METHODS: Retrospectively, 170 consecutive morphine-augmented
      cholescintigrams were analyzed for the presence of a pericholecystic rim sign,
      marked or mild, associated with gallbladder nonvisualization at 1 hr (before
      morphine); those with a pericholecystic rim sign were further evaluated for
      persistent gallbladder nonvisualization versus gallbladder visualization after
      morphine. Scintigraphic interpretations were correlated with surgical pathology
      or clinical diagnosis. RESULTS: Before morphine, 43/170 (25%) patients
      demonstrated gallbladder nonvisualization with a pericholecystic rim sign. Since
      only 31 had acute cholecystitis, a diagnosis based solely on that scintigraphic
      pattern would have resulted in 12 false-positives. After morphine, gallbladder
      visualization correctly excluded acute cholecystitis in seven; a single false
      negative was encountered; five false-positives remained. Morphine-augmentation
      improved the positive predictive value from 72% (gallbladder nonvisualization
      with pericholecystic rim sign before morphine) to 86% (gallbladder
      nonvisualization after morphine). Of 24 patients with marked pericholecystic rim
      signs, 21 had acute cholecystitis. Of 31 with acute cholecystitis, however, 10
      (32%) had a mild pericholecystic rim sign. CONCLUSION: Morphine-augmented
      cholescintigraphy optimizes the diagnosis of acute cholecystitis in patients with
      the suggestive, but not pathognomonic, cholescintigraphic pattern at 1 hr of
      gallbladder nonvisualization with a pericholecystic rim sign, regardless of its
      intensity.

PMID- 8667059
TI  - Carcinoid tumor of the jugulo-tympanic region.
AB  - Increased levels of 5-hydroxyindole acetic acid (5-HIAA) were found in a patient
      with a tumor arising in the middle ear. Iodine-123-metaiodobenzylguanidine
      ([123I]MIBG) scintigraphy and biochemical analysis showed evidence of serotonin
      production by the tumor. Immunohistochemistry of the tumor showed reactivity with
      antibodies directed against serotonin, chromogranin, leu-7 and neuron-specific
      enolase; S-100, met-enkephalin, leu-enkephalin and glial fibrillary acid protein
      were negative. This case suggests a close relationship between functioning
      paragangliomas and carcinoid tumors because a strong clinical and
      endocrinological resemblance exists. The hormonal activity found is discussed in
      relation to extra-adrenal paragangliomas. We recommend urinary screening not only
      for detection of increased levels of catecholamines, but also of 5-HIAA in all
      patients with paragangliomas of the head and neck. When elevated levels are
      found, [123I]MIBG scintigraphy should be performed to localize the areas of
      increased uptake in or outside the head and neck region.

PMID- 8667060
TI  - Grade II astrocytoma visualized by technetium-99m-ECD SPECT.
AB  - We present a case of primary brain tumor demonstrating increased uptake of 99mTc
      ECD. Astrocytoma (Grade II) showed significantly increased cerebral blood
      perfusion on dynamic images and homogeneously increased uptake on static images
      with 99mTc-ECD brain SPECT. There seems to be some difference in perfusion and
      mechanism of tumor uptake among the cerebral blood flow imaging agents (99mTc
      ECD, 99mTc-HMPAO and [123I]-IMP) and 201TI-chloride.

PMID- 8667062
TI  - A feasibility study on L-[1-carbon-11]tyrosine and L-[methyl-carbon-11]methionine
      to assess liver protein synthesis by PET.
AB  - We studied the potential of L-[1-11C]tyrosine ([1-11C]Tyr) and L-[methyl
      11C]methionine ([Me-11C]Met) as tracers for measuring protein synthesis rate
      (PSR) in the liver by PET and proposed their metabolic models. METHODS: In the
      liver and plasma of control and cycloheximide-treated mice injected with [1
      14C]Tyr and [Me-3H]Met, incorporation of the radioactivity into the acid-soluble
      fraction and chloroform/methanol-extract (CM), RNA and protein fractions were
      measured. Data were compared with those from rat studies with 11C-labeled analogs
      and PET. RESULTS: In mice, liver uptake of [Me-3H]Met was over twice as large as
      that of [1-14C]Tyr. Similar uptake patterns of the 11C-labeled analogs were found
      in rats by PET. In the mouse liver at 1 to 6 hr after injection, approximately
      69%-73% of the 14C was detected in the protein fraction, whereas approximately
      65%-70% of the 3H was in the CM fraction, which reflected phospholipid synthesis.
      In plasma, the percentages of the protein fractions were approximately 73%-76%
      for 14C and approximately 36%-46% for 3H. Gel-filtration analysis suggested that
      80% of the 14C-labeled plasma proteins was albumin originating from the liver,
      which corresponds to approximately 25% of the total labeled proteins synthesized
      in the liver at 6 hr. When protein synthesis was inhibited by cycloheximide, the
      liver uptake of the [1-14C]Tyr and the protein-incorporation of 14C in the liver
      and in plasma were decreased dose-dependently. On the other hand, uptake of [Me
      3H]Met was significantly enhanced in the liver due to increased incorporation
      into the CM fraction. CONCLUSION: [1-Carbon-11]Tyr can be used for measuring the
      PSR in the liver by PET. Liver uptake of [Me-11C]Met mainly reflects phospholipid
      synthesis through the transmethylation process.

PMID- 8667061
TI  - Left ventricular myocardial uptake of a labeled somatostatin analog in carcinoid
      syndrome.
AB  - We report a case of left ventricular (LV) myocardial uptake of a labeled
      somatostatin analog in a patient with a carcinoid tumor of the small bowel. The
      patient developed liver metastases and a carcinoid syndrome, including right
      carcinoid heart disease, without right-to-left shunt on contrast ultrasonography
      or left ventricular myocardial metastases. The basis for visualization of the LV
      myocardium is probable somatostatin receptor upregulation.

PMID- 8667063
TI  - Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells:
      correlation with mdr gene expression.
AB  - Early diagnosis of multidrug-resistance (MDR) development is extremely important
      for the judicious choice of treatment protocols in breast cancer chemotherapy. In
      this study, the mechanism of 99mTc-sestamibi uptake by nine human breast tumor
      cell lines was analyzed as a function of P-glycoprotein (PgP) expression.
      METHODS: Technetium-99m-sestamibi radioactivity incorporation into the cells was
      determined after different times of incubation at 37 degrees C. We analyzed the
      mechanism of 99mTc-sestamibi uptake as follows: (a) effect of temperature (4
      degrees C); (b) influence of extracellular 99mTc-sestamibi concentration; and (c)
      competitive inhibition of cell uptake with cold 99mTc-sestamibi. Technetium-99m
      sestamibi uptake was compared to the level of PgP determined by Western blotting.
      The PgP reversing effect of verapamil was evaluated at different drug
      concentrations (50, 200, 500 microM). RESULTS: Technetium-99m-sestamibi uptake
      plateaued at 60 min, which was 14 times lower at 4 degrees C than at 37 degrees C
      and was directly proportional to the extracellular concentration between 0.3 and
      10 nM. Technetium-99m-sestamibi percentage uptake by cells expressing
      nonimmunodetectable levels of PgP was significantly higher (7.3% +/- 0.6% (s.d.)
      to 14.9% +/- 1.9%) than that by cells expressing high PgP levels (0.7% +/- 0.4%,
      p < 0.001). In the presence of verapamil, a known reverser of PgP functions,
      99mTc-sestamibi uptake was increased by a factor of 2 in cells expressing no
      detectable levels of PgP and by a factor of 12 in cells with high PgP levels.
      CONCLUSION: Technetium-99m-sestamibi uptake by these breast tumor cells is energy
      dependent but not specific. These data suggest that 99mTc-sestamibi imaging may
      be used as a noninvasive technique to diagnose the presence of MDR in breast
      tumors in vivo.

PMID- 8667064
TI  - Analysis of 2-carbon-11-thymidine blood metabolites in PET imaging.
AB  - Carbon-11-thymidine labeled in the ring-2 position was used with PET to image
      tumor and tissue proliferation. Since thymidine is rapidly degraded in the body,
      one must consider the generation of metabolites to fully interpret the PET data.
      METHODS: We have measured the blood time-activity curves of thymidine and its
      metabolites in arterial blood samples. Blood was processed to obtain three input
      curves, including the total activity, the activity with CO2 removed and the
      fraction of CO2-free activity in intact thymidine (% Tdr). RESULTS: We found that
      CO2 reached a plateau of 65% (+/- 12%) of total blood activity by 11 min after
      injection. When a 1-min infusion of labeled thymidine is used, the time to 50%
      degradation to thymine and metabolites other than CO2 (measured in acidified
      samples by HPLC) was 2.9 +/- 0.6 min. We fit the results of the blood metabolism
      with a compartmental model. We found that we could accurately determine the % Tdr
      curve with as few as three measured points with an root mean square (RMS) error
      of 2% in the integrated curve, compared to the curve using all blood samples
      (mean of seven samples per patient). The integral of thymidine blood activity
      serves as the input to thymidine models, so similar errors could be expected in
      calculations of DNA synthetic rates. We found that the determination of CO2 could
      be accomplished with as few as five samples, with an RMS error of 4% in plateau
      %CO2 value. CONCLUSION: While it is essential to take metabolites into account
      when interpreting results obtained with 11C-thymidine, the reproducibility of
      these degradation curves may allow the use of a limited number of samples to
      measure the catabolic products of thymidine. These data from the blood, along
      with tissue kinetic models, are needed to calculate DNA synthetic rates.

PMID- 8667065
TI  - FDG-PET evaluation of therapeutic effects on VX2 liver tumor.
AB  - Transplanted VX2 liver tumor in the rabbit is an experimental liver tumor model
      in which 18F-2-fluoro-2-deoxy-D-glucose (FDG) accumulates to a 3.5-fold level
      that surrounds normal liver tissue. In this study, changes in FDG uptake were
      assessed in this liver tumor model after transcatheter arterial embolization
      (TAE) and radiotherapy. METHODS: Fifteen rabbits bearing VX2 liver tumors were
      treated with TAE with gelatin sponges 1 day before the FDG study, and 18 rabbits
      received local irradiation with electron beams at a dose of 12-36 Gy 1-10 days
      before the FDG study. In the FDG study, serial arterial blood sampling was
      performed to determine arterial input (AI), and 1 hr after tracer injection,
      normal liver tissue and tumor tissue were excised to measure radioactivity. The
      tumor FDG level per AI and the tumor-to-normal liver ratio were assessed. Dynamic
      PET images were obtained in 20 of the 46 rabbits. RESULTS: Tumor FDG uptake was
      significantly decreased 1 day after TAE (from 3.54 to 0.83 in the tumor-to-normal
      liver ratio) and 5 days after 30 Gy of irradiation (from 3.54 to 1.28). The
      decrease in tumor FDG uptake was dose-dependent, especially in the relatively low
      dose range (12-24 Gy). The untreated tumors could be clearly distinguished from
      the surrounding normal liver tissue, while the embolized tumors or the irradiated
      tumors were not clearly delineated. Histological analysis showed that the
      decrease in tumor FDG after treatment agreed well with the decrease in number of
      viable tumor cells. CONCLUSION: The VX2 liver tumor is an appropriate
      experimental tumor model for evaluating the change in FDG uptake in various
      therapeutic modalities. Moreover, the therapeutic effects can be assessed 1 day
      after TAE and 5 days after irradiation. Further clinical trials for the early
      evaluation of therapeutic effects on liver tumors using FDG-PET are warranted.

PMID- 8667066
TI  - Accurate measurement of copper-67 in the presence of copper-64 contaminant using
      a dose calibrator.
AB  - The use of 67Cu-labeled antibodies for the treatment of cancer has advanced to
      the clinical trial phase. Quantitation of 67Cu radiopharmaceuticals is
      complicated by the presence of the radioimpurity of 64Cu in 67Cu supplies. Here
      we report a method to assay 67Cu and 64Cu in a mixed sample with a commonly
      available instrument, the ionization chamber dose calibrator. METHODS: The
      activities of 67Cu and 64Cu in a mixed sample can be calculated from a single
      dose calibrator measurement. The calculation requires (1) instrument-specific
      response coefficients D67 and D64, generated by gauging the instrument for the
      efficiency of measurement of 67Cu and 64Cu, and (2) a value for the ratio of 67Cu
      to 64Cu in the sample, routinely provided by major suppliers of 67Cu. D67 and D64
      were empirically determined by measuring samples containing known amounts of 67Cu
      and 64Cu. The samples were also assayed by gamma ray spectroscopy to verify the
      isotope ratios given by the suppliers. RESULTS: This method generated accurate
      response coefficients. At the recommended dose calibrator setting for the
      measurement of 67Cu, at which D67 = 1.0, the measurement for D67 with this method
      was 1.02 (+/- 0.04). Isotope ratios provided by the radionuclide suppliers were
      corroborated by gamma ray spectroscopy. CONCLUSION: A method is presented by
      which 67Cu and 64Cu in a mixed sample can be assayed using a dose calibrator.
      Although the derived numeric constants are only correct for a specific dose
      calibrator and setting, the method can be adapted for use with any dose
      calibrator.

PMID- 8667068
TI  - Evaluation of carbon-14-colchicine biodistribution with whole-body quantitative
      autoradiography in colchicine-sensitive and -resistant xenografts.
AB  - Quantitative autoradiography (QAR) with radiolabeled monoclonal antibodies in
      xenografted animals has been extensively described in the past, either on
      individual tissues or on the whole body. We applied whole-body QAR to identify
      multidrug resistant tumors using 14C-colchicine (14C-CHC). METHODS: Two groups of
      five animals each were xenografted with CHC-sensitive and CHC-resistant human
      neuroblastoma cells. Animals were injected intravenously with 4 microCi/0.11
      mumole 14C-CHC per gram of body weight and sacrificed after 60 min. Whole-body
      QAR was carried out using 25-microns thick sections. RESULTS: Fusion images
      allowed direct comparison of 14C-CHC uptake in tumor and nontumor tissues. Mean
      14C-CHC distribution in sensitive and resistant tumors was 882.0 +/- 43.6 and
      399.6 +/- 157.7 nCi/g corresponding to 24.5 +/- 1.21 and 11.1 +/- 4.38 nmole/g,
      respectively (p < 0.001), with normal tissue distribution in both groups being
      similar. Three-dimensional QAR showed that the uptake of 14C-CHC was in the
      cellular zones of the tumor. This method has potential in biodistribution studies
      of novel radiopharmaceuticals such as 14C-CHC. CONCLUSION: These studies further
      suggest that PET imaging of 11C-CHC is feasible to distinguish between sensitive
      and resistant tumor deposits in vivo.

PMID- 8667067
TI  - In vivo labeling of angiotensin II receptors with a carbon-11-labeled selective
      nonpeptide antagonist.
AB  - Angiotensin II (ANG II) initiates a variety of physiological effects by binding
      to high affinity receptors. Two ANG II receptor subtypes, AT1 and AT2, have
      recently been identified. This study was undertaken to evaluate [11C]L-159,884,
      an AT1 subtype selective nonpeptide antagonist, as a potential PET tracer.
      METHODS: Carbon-11-L-159,884 was prepared by alkylation of the nor precursor with
      [11C]methyliodide and was studied for its in vivo binding characteristics,
      biodistribution and kinetics in mice. The effects of PD-123319, an AT2-selective
      ANGII antagonist, as well as those of alpha- and beta-adrenergic drugs on [11C]L
      159,884 binding were investigated also. RESULTS: Administration of the AT1
      antagonists resulted in dose-dependent inhibition of [11C]L-159,884 binding in
      the kidneys, the organ with the highest density of AT1 receptors. Inhibition was
      also observed in the lungs and the heart. Adrenergic drugs did not influence
      [11C]L-159,884 binding to AT1 receptors. Kinetic studies showed rapid tracer
      uptake in the liver, kidneys, lungs and heart. Excretion of the radioactivity
      occurred primarily through the intestinal tract (> 20% in 90 min), with less than
      8% excreted through the urine. CONCLUSION: The results suggest that [11C]L
      159,884 binds in vivo to AT1 receptors in mouse kidneys, lungs and heart. This
      radiotracer appears to be a promising candidate for studying ANG II receptors in
      vivo by PET.

PMID- 8667069
TI  - Tumor-targeting potential of radioiodinated iododeoxyuridine in bladder cancer.
AB  - Since bladder cancer arises in the superficial lining of the urothelium, it is a
      likely candidate for site-directed administration of 5-iodo-2'-deoxyuridine
      radiolabeled with the Auger electron emitter 123I or 125I (*IUdR). METHODS: We
      instilled *IUdR for 2 hr directly within the bladder lumen of rats bearing N
      methyl-N-nitrosourea (NMU)-induced bladder cancer and conducted scintigraphic,
      biodistribution and autoradiography (ARG) studies 48 hr and 1 wk later. Control
      animals were not subjected to the carcinogen but were instilled with *IUdR.
      RESULTS: Two groups of animals were identified after instillation of MNU: Group A
      consisted of rats with hyperplasia and Group B of rats with papillary carcinoma
      (stages Ta and T1). Scintigraphic detection of carcinomas was achieved with high
      sensitivity and specificity, and increased tumor-to-normal tissue ratios were
      obtained in both groups. Moreover, ARG demonstrated that (1) the uptake of *IUdR
      was observed in the hyperplastic and carcinomatous urothelium but not in the
      normal urothelium; (2) uptake was detected at a very early stage of tumor
      development (hyperplasia stage); (3) *IUdR was able to penetrate deep within the
      bladder wall; and (4) other normal dividing tissues, such as the bone marrow, the
      small intestine and the large intestine, were free of silver grains (i.e., no DNA
      incorporated *IUdR). CONCLUSION: Since this carrier of Auger electron emitters
      has antineoplastic effects ([123I]IUdR and [125I]IUdR) in addition to its
      scintigraphic potential ([123I]IUdR and [131I]IUdR), it holds promise for therapy
      and early diagnosis of bladder cancer.

PMID- 8667070
TI  - Feasibility of fluorine-18-fluorophenylalanine for tumor imaging compared with
      carbon-11-L-methionine.
AB  - L-[methyl-11C]methionine (11C-Met) is a useful tracer for tumor imaging with PET.
      The drawbacks include a short half-life and high physiological accumulation in
      abdominal organs. To overcome these shortfalls, the feasible use of
      [18F]fluorophenylalanine (18F-Phe), which shares the same amino acid transport
      system with Met, for tumor imaging was examined. METHODS: The time course of
      tissue distribution of 18F-Phe and the tumor uptake response to radiotherapy were
      compared with 14C-Met and [3H] thymidine (3H-Thd) in the rat AH109A tumor model.
      Intratumoral distribution of 18F-Phe was compared with 14C-Met and 14C-Thd using
      double-tracer macroautoradiography (ARG). We also evaluated whole-body ARG.
      RESULTS: Tumor uptake of 18F-Phe peaked at 60 min postinjection and was higher
      than that of the liver, intestine and kidney but lower than the pancreas. Tumor
      uptake of 18F-Phe was similar to that of 14C-Met. Tumor-to-blood and tumor-to
      muscle ratios were higher in 14C-Met compared with that of 18F-Phe because of the
      rapid blood clearance of 14C-Met. With whole-body ARG, the tumor was clearly
      visualized with high contrast. Radiotherapeutic response of tumor uptake of 18F
      Phe was as rapid as that with 14C-Met and with 3H-Thd. Intratumoral distribution
      of 18F-Phe and 14C-Met were identical, and 18F-Phe and 14C-Thd were similar.
      CONCLUSION: Fluorine-18-Phe seems to be a potentially useful amino acid tracer
      for tumor imaging with a longer half-life than 11C, with higher tumor contrast in
      the abdomen than Met and a similar sensitive response to radiotherapy.

PMID- 8667071
TI  - Optimal radiolabeled liposomes for tumor imaging.
AB  - We conducted a systematic study of the effects of liposome formulation and
      encapsulated radionuclides on imaging ability. METHODS: Various types of
      liposomes were prepared and labeled with 67Ga, 111In or 99mTc. Their tumor
      imaging potential was evaluated in terms of tumor accumulation and tumor-to-blood
      ratios of radioactivity delivered by the liposomes. Mouse sarcoma 180 and Ehrlich
      solid tumor were the tumor models. RESULTS: Liposomes could be labeled rapidly
      and with high efficiency, which was sufficient for clinical application. Tumor
      accumulation of liposome-encapsulated radionuclides that have intrinsic tumor
      affinity, such as 67Ga-NTA or 111In-NTA, was larger than that of the other
      nuclides. Liposomes that were fairly small, cholesterol-rich and composed of so
      called rigid phospholipids, could deliver large amounts of encapsulated
      radionuclides to the tumor. We also found that tumor uptake of such liposomes was
      large and their blood retention was prolonged. Liposomal lipid dose also
      influenced tumor delivery and blood retention. The results suggest that these
      factors extended liposomal blood retention and, consequently, increased tumor
      uptake of the liposomes and tumor delivery of encapsulated radionuclides. Not all
      liposomes with long blood retention, however, are suitable for tumor imaging.
      Incorporation of monosialo-ganglioside in the liposomal membrane greatly extended
      blood retention but increased tumor uptake only slightly and, consequently, made
      the tumor-to-blood value worse. One of the 67Ga-labeled liposome formulations
      resulted in high tumor uptake and tumor-to-blood ratios in various tumor models
      as well as clearly visualized tumors clearly in sarcoma 180-bearing mice.
      CONCLUSION: For tumor imaging with radiolabeled liposomes, we should choose
      liposomal formulations and dose to give prolonged blood retention for large tumor
      delivery. We must then select liposomes that give good tumor-to-blood values. For
      the best results, the radionuclide should have intrinsic tumor affinity. Labeled
      liposomes that meet these criteria result in excellent tumor images.

PMID- 8667072
TI  - Hepatic artery injection of Yttrium-90-lipiodol: biodistribution in rats with
      hepatoma.
AB  - In this study, we analyzed the biodistribution of 90Y-lipiodol in rats with liver
      tumors (hepatoma) following hepatic arterial injection. METHODS: Sixteen male
      Sprague-Dawley rats with liver tumors were killed at 1, 24, 48 and 72 hr (four
      rats at each time) after injection of approximately 0.1 mCi 90Y-lipiodol through
      the hepatic artery, respectively. Samples of tumor, liver, spleen, skeletal
      muscle, lung, kidney, bone, whole blood and testis were obtained and counted to
      calculate the tissue concentrations (%ID/g). RESULTS: We found that the
      radioactivity in the liver tumor was high at 1 and 24 hr and then declined
      slowly. The biological half-time was 84.1 hr. The radioactivity in normal liver
      tissue was also high at 1 hr but was significantly lower than that in the tumor.
      The biological half-time was 38.5 hr. The ratio of tissue concentration between
      liver tumor and normal liver tissue (T/N ratio) was 3.03 at 1 hr and rose to 6.45
      at 72 hr. The radioactivity in the lung was almost as high as in normal liver
      tissue at 1 hr and declined rapidly with a biological half-time of 25.6 hr. The
      activity levels of the kidney were moderate at 1 hr and remained at almost the
      same level throughout the study. A moderate concentration of radioactivity in
      bone was noted within the first 24 hr. The concentration, however, rose over the
      ensuing time. The concentration of radioactivity in skeletal muscle, spleen,
      testis and whole blood was quite low. CONCLUSION: Following hepatic arterial
      injection of 90Y-lipiodol, tracer uptake in liver tumor was high and tumor
      retention was lengthy. Consequently, large radiation doses could be delivered to
      the tumor. We suggest that 90Y-lipiodol is a potential agent in the treatment of
      liver malignancy.

PMID- 8667073
TI  - Transferrin-mediated uptake of radionuclides by the testis.
AB  - In an attempt to explain the deleterious effects of gonadal radionuclide
      localization, we examined the role of transferrin in testicular radionuclide
      uptake. METHODS: In vivo testicular uptake and retention of the transferrin
      binding radionuclides 114mIn-citrate and 59Fe-citrate were compared with that of
      the nontransferrin binding isotopes 137Cs-citrate and Na125I for 63 days
      postinjection. Isotope uptake mechanisms were investigated in vitro using
      isolated seminiferous tubules and Sertoli cell monolayers grown in bicameral
      culture chambers. RESULTS: Indium-114m, 59Fe and 137Cs were localized in the
      testis by 24 hr postinjection, but accumulation of 125I was minimal. Although
      testicular 114mIn remained constant, 59Fe declined slowly over the following 63
      days and 137Cs fell very rapidly. When 114mIn- or 59Fe-loaded testes were
      fractionated, and markedly more 114mIn was associated with the seminiferous
      tubules than 59Fe, suggesting that 114mIn may be retained. In vitro uptake of
      59Fe, 67Ga and 114mIn by isolated seminiferous tubules was inhibited by
      transferrin, but uptake of 137Cs and 125I was unaffected. Iron-59, 67Ga and
      114mIn were retained by isolated tubules in contrast to 137Cs and 125I. Whereas
      137Cs, 59Fe and 114mIn all crossed Sertoli cell monolayers, the rate of
      transcellular transport of 137Cs was faster than that of 59Fe or 114mIn,
      suggesting differences in the intracellular processing of transferrin binding and
      nontransferrin binding radionuclides. CONCLUSION: These data suggest that some
      radionuclides may access the seminiferous epithelium through receptor-mediated
      endocytosis of transferrin. Such radionuclide localization could lead to
      continuous irradiation of the testes, resulting in mutagenic damage to
      spermatogenic cells.

PMID- 8667074
TI  - Simple production of [1-carbon-11]acetate.
AB  - We report an attractive approach for the preparation of [1-11C]acetate. METHODS:
      The procedure involved the instantaneous hydrolysis of [1-11C]acetyl chloride
      back to [1-11C]acetic acid by simply trapping the volatile acid chloride in
      physiological saline. This delivered [1-11C]acetate immediately in pharmaceutical
      quality. RESULTS: An easy and quantitative gas phase separation of the
      radiopharmaceutical from any inorganic residue and organic contamination could be
      achieved. The preparation required a minimum of automation and afforded only 5
      min for an amount of 15 GBq of [1-11C]acetate which was yet ready for injection.
      Multiple preparations could be performed within 1 day. CONCLUSION: The use of [1
      11C]acetyl chloride as a precursor to [1-11C]acetate is of considerable practical
      importance lending itself to automation with ease and giving the target compound
      directly in sterile solution without the need for further care and purification.

PMID- 8667075
TI  - Antibody-dependent signal amplification in tumor xenografts after pretreatment
      with biotinylated monoclonal antibody and avidin or streptavidin.
AB  - Due to their high affinity for biotin, avidin (Av) and streptavidin (SAv) are
      used to bridge pretargeted antibody molecules and radiolabeled biotin derivatives
      in vivo. METHODS: We compared uptake of 125I-labeled Av or SAv (approximately 10
      500 micrograms) in tumor and normal tissues 3 days after a biotinylated B72.3
      monoclonal antibody (100 micrograms) injection in nude mice. The animals were
      killed 24 hr later and the biodistribution of 125I was determined. RESULTS: The
      percent injected dose per gram of tumor remained constant over the range of
      injected doses for Av while that for SAv varied. As larger amounts of Av/SAv were
      injected, the number of moles of each trapped within tumor increased, with the
      values for SAv being much higher. While the injection of larger doses of Av led
      to an increase in tumor-to-normal tissue ratios, that of SAv did not. CONCLUSION:
      SAv (2.5 mg/kg) is the preferred "second-step" reagent. At this dose, the number
      of receptors available for targeting by radiolabeled biotin derivatives is
      approximately 1.8 times the number of antigen-binding sites accessible for
      targeting by radiolabeled antibody. Additional targeted-signal amplification
      should be possible by the successive and repeated administration of such
      polymeric reagents, each exhibiting high affinity to and forming a specific
      binding pair with the last-targeted molecule.

PMID- 8667076
TI  - Monoclonal antibodies labeled with rhenium-186 using the MAG3 chelate:
      relationship between the number of chelated groups and biodistribution
      characteristics.
AB  - Our previous studies on the preparation of 186Re-MAb conjugates for clinical
      radioimmunotherapy (RIT) were extended with the aim to derive conjugates which
      have a high Re:MAb molar ratio, are stable in vitro and in vivo, have favorable
      biodistribution characteristics and can be used together with 99mTc-MAb
      conjugates as a matched pair in combined radioimmunoscintigraphy/RIT studies.
      METHODS: Rhenium and 99mTc-conjugates of intact MAb E48 were prepared according
      to our previously described multistep procedure using the MAG3 chelate and
      analyzed by protein mass spectrometry for the number of chelate molecules coupled
      to the MAb. For biodistribution analysis, tumor-free nude mice were
      simultaneously injected with 186Re-, 99mTc/99Tc- and/or 125I-labeled E48 IgG and
      dissected 1-48 hr postinjection. RESULTS: Rhenium-186-MAb conjugates with up to
      20 Re-MAG3 groups per MAb molecule were prepared with an overall radiochemical
      yield of 40%-60%. The conjugates did not contain empty MAG3 groups and no
      aggregates were formed. Only conjugates with a 186Re-MAG3:MAb molar ratio higher
      than 12 demonstrated slightly impaired immunoreactivity to a maximum of 15%
      decrease at the 20:1 molar ratio. Biodistribution experiments revealed that a
      proportion of the conjugate became rapidly eliminated from the blood for
      conjugates with a Re-MAG3:MAb molar ratio higher than 8. In this case, an
      increased uptake of activity was observed in the liver and intestines. The
      99mTc/99Tc-MAb conjugates showed a similar enhanced blood clearance when
      containing more than eight Tc-MAG3 groups, while dual labeling of MAbs revealed
      that the in vivo stability of the conjugated Re-MAG3 complex itself does not
      differ from the corresponding Tc-MAG3 complex. CONCLUSION: With the method
      described in this study, it is possible to prepare 186Re-MAG3-MAb conjugates that
      fulfil all the aforementioned criteria for use in clinical RIT. Coupling of too
      many metal-MAG3 groups to MAbs results in rapid blood clearance. At the same
      metal-MAG3:MAb molar ratio, 99mTc/99Tc-MAb conjugates show a similar
      pharmacokinetic behavior as 186Re-MAb conjugates and can thus be used to predict
      the localization of 186Re-labeled MAbs and make dosimetric predictions in
      individual patients.

PMID- 8667077
TI  - Bifunctional NHS-BAT ester for antibody conjugation and stable technetium-99m
      labeling: conjugation chemistry, immunoreactivity and kit formulation.
AB  - Conjugation chemistry and kit formulated binding of the NHS ester of 6-(4'-(4"
      carboxyphenoxy)butyl)-2, 10-dimercapto-2,10-dimethyl-4,8-diazaundecane (NHS-BAT
      ester) to monoclonal antibodies (MAbs) was investigated. The functionalities of
      the resulting BAT conjugated and 99mTc-labeled MAbs BW 431/26, MAb 425 and
      bispecific MDX210 (fragment construct) were tested by immunoreactivity and
      immunoscintigraphy. METHODS: The kinetics and chemistry of the conjugation
      reaction were monitored by high-performance liquid chromatography, size-exclusion
      chromatography and positive fast-atom-bombardment mass spectra (FAB-MS). The
      99mTc BAT-MAbs were tested with various immunoreactivity assays. The
      biodistribution of 99mTc-BAT-BW 431/26 in rats was compared with directly labeled
      BW 431/26. RESULTS: At pH 8.5 and 25 degrees C, the reactivity of the NHS-BAT
      ester was high with 90% completion after 30 min. The conjugation yield of 19
      microM MAb and 228 microM NHS-BAT ester amounted to 30%. Higher NHS-BAT ester
      concentrations afforded higher BAT-to-MAb ratios. According to FAB-MS, the
      conjugation competing hydrolysis surprisingly occurred at the NHS ring. Almost
      quantitative 99mTc labeling was achieved after 5 min at 25 degrees C.
      Immunoreactivity of the 99mTc-BAT antibodies showed > 90% recovery and proved to
      be insensitive to BAT-to-MAb ratios of up to 10. The 99mTc-BAT-BW 431/26 showed
      similar organ distribution but revealed less urinary excretion compared with the
      directly labeled BW 431/26. Immunoscintigraphy with 99mTc-labeled and BAT-BW
      431/26 and BAT-MAb 425 showed the respective biological function in vivo.
      CONCLUSION: According to straightforward conjugation chemistry, the ease of 99mTc
      labeling and the application of a simple ultrafiltration technique, the NHS-BAT
      ester represents a nondestructive, universally applicable biofunctional ligand to
      introduce stable 99mTc protein binding sites. Kit formulated conjugation/labeling
      can be performed with little time requirements and laboratory experience.

PMID- 8667078
TI  - Enhanced FDG-PET tumor imaging with correlation-coefficient filtered influx
      constant images.
AB  - Although FDG is an excellent PET tumor imaging agent, residual tracer activity in
      normal structures such as blood vessels and the liver can impair the detection of
      small or modestly tracer-avid tumors. Since tumors generally have a continuous
      influx of FDG over time while normal tissues generally show tracer efflux, we
      produced and optimized correlation-coefficient constrained influx-constant
      "parametric" images to maximize tumor visualization but minimize background and
      artifacts for FDG-PET cancer imaging. METHODS: Influx-constant image sets were
      generated in 17 patients with various cancers for a range of correlation
      coefficient constraint values. Quantitative evaluation of the parametric PET
      images was performed. RESULTS: Image noise was reduced 70% (mean) with no loss of
      tumor signal for r > or = 0.90 constraint versus no constraint. Higher (0.95
      0.99) constraints improved tumor-to-normal ratios but resulted in some loss of
      tumor signal. Mild constraints (0-0.85) produced more background artifacts than
      higher constraints, though all correlation constraints improved tumor-to-normal
      ratios over the single 50-60-min acquisition frame. CONCLUSION: Correlation
      coefficient filtered parametric imaging, especially with an r-value constraint of
      > or = 0.90, enhances tumor-to-normal contrast for FDG-PET and appears promising
      for improving lesion detectability.

PMID- 8667079
TI  - Noninvasive quantification of iodine-123-iomazenil SPECT.
AB  - The feasibility of a noninvasive method for quantification of [123I]iomazenil
      binding using a standardized arterial input function and a single venous blood
      sample was assessed in normal volunteers. METHODS: Serial SPECT images and blood
      data from six healthy male volunteers after intravenous injection of
      [123I]iomazenil were used. The standardized input function was derived by
      averaging the six subjects' arterial curves. Individual input functions were
      estimated by calibrating the standardized input function with one-point venous
      blood radioactivity concentration. Ligand transport (K1) and receptor binding
      were computed from the estimated input functions and two separate SPECT scans
      using a table look-up procedure based on a three-compartment, two-parameter
      model. Reference values for K1 and receptor binding were determined from the
      serial SPECT data and individual arterial curves using a three-compartment, three
      parameter model and curve fitting. RESULTS: Analyses of the error caused by the
      calibration in relation to the time postinjection revealed that the optimal
      calibration time was 30 min postinjection. Receptor binding obtained by this
      simplified method correlated well with the reference values (r = 0.941) and was
      estimated within an error of 10% in the cerebral cortical regions. Although the
      estimated K1 showed relatively poor correlation (r = 0.699) with the reference
      value, it was an excellent relative measure in each subject. CONCLUSION: Our
      method provided an absolute measure of the benzodiazepine receptor binding and a
      relative measure of ligand transport from two SPECT scans and a venous blood
      sample. This method would be useful for quantitative assessment of benzodiazepine
      receptors in clinical settings.

PMID- 8667080
TI  - Metal ion speciation in blood plasma: gallium-67-citrate and MRI contrast agents.
AB  - Metal chelate ions are commonly used in medical diagnostic imaging as MRI
      contrast or imaging agents. The efficacy of these metals depends on their in vivo
      behavior, which in turn depends on their in vivo speciation. METHODS: A computer
      model has been used to simulate the speciation of Ga3+ and Gd3+ in blood plasma.
      The model has been tested against known clinical data and then used to
      investigate Ga3+ uptake by tumor cells. The iatrogenic effect of a gadopentetic
      acid enhanced MRI scan upon the biodistribution of 67Ga citrate has also been
      calculated. RESULTS: The speciation of Ga3+ calculated using the computer model
      is concordant with clinical data. The results support transferrin mediated uptake
      of Ga3+ by tumor cells but also account for Ga(III) biodistribution observed in
      hypotransferrinemic subjects. In a study of the effect of gadopentetic acid upon
      67Ga gallium citrate, neither residual DTPA nor [Gd(DTPA)]2- cause significant
      changes in the speciation of Ga(III). The calculations show that dissociation of
      4% of the administered gadopentetic acid results in the formation of a mixed,
      Gd(III) and Ga(III), metal transferrin complex and a 100-fold increase in the
      concentration of [Ga(OH)4]-. CONCLUSION: Computer simulation is a valuable tool
      which can be used to explain/understand in vivo behavior of radioactive metal
      ions.

PMID- 8667081
TI  - Estimated radiation dose to the newborn in FDG-PET studies.
AB  - The aim of this study was to estimate the radiation dose due to intravenous
      injection of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) for infants studied with PET.
      METHODS: The radioactivity concentration in the brain and bladder content was
      measured with PET to determine the cumulated activity in these organs in 21
      infant FDG studies. The individual organ masses were estimated according to the
      whole-body and brain masses, and they were used to calculate the absorbed dose
      per unit cumulated activity (S values). For organs other than brain and bladder,
      the cumulated activity was defined from adult studies. For each individual
      patient, the absorbed dose to the brain, bladder wall and selected organs were
      calculated. An estimation of the effective dose was determined. RESULTS: Whole
      body distribution of FDG in the infants differed from adults: a greater
      proportion of the injected activity accumulated into the brain (9% versus 7%) and
      less was excreted to urine (7% versus 20% respectively). The measured cumulated
      activity in the brain was 0.25 MBq.h/MBq and in the bladder content 0.04
      MBq.h/MBq with a large individual variation in latter. The calculated absorbed
      dose was 0.24 mGy/MBq to the brain and 1.03 mGy/MBq to the bladder wall. The
      estimated effective dose was 0.43 mSv/MBq. CONCLUSION: The dose to the bladder
      wall was lower in infants as compared to adults with ordinary amounts of injected
      activity. The greater amount of activity remaining in the body may increase the
      dose to other organs. The effective dose was lower compared to adults and
      conventional nuclear medicine studies of infants. PET can be a valuable tool in
      pediatric nuclear medicine because of good resolution images, sensitive radiation
      measurement and a variety of tracers labeled with short-lived isotopes.

PMID- 8667082
TI  - Fluorine-18-fluorodeoxyglucose PET to determine regional cerebral glucose
      utilization: a re-examination.

PMID- 8667083
TI  - Leukocyte scintigraphy to assess disease activity in inflammatory bowel disease.

PMID- 8667084
TI  - Strontium-89 injected through implanted ports.

PMID- 8667085
TI  - Bisphosphonate effect on bone scintigraphy.

PMID- 8667086
TI  - Disseminated intravascular coagulation in metastatic prostate cancer.

PMID- 8667087
TI  - Radioiodine therapy of the autonomous thyroid nodule in patients with or without
      visible extranodular activity.

PMID- 8667088
TI  - Is renography suitable for deconvolution analysis?

PMID- 8667089
TI  - Discriminant value of semiquantitative SPECT data in mild Alzheimer's disease.

PMID- 8667090
TI  - Implementation of local guidelines for cost-effective management of hypertension.
      A trial of the firm system.
AB  - OBJECTIVE: To evaluate the effects of an intensive intervention to implement
      guidelines for cost-effective management of hypertension on medication use and
      cost, blood pressure control, and other resource use. DESIGN: Retrospective
      cohort trial based on the Cleveland Veterans' Affairs Medical Center Firm System.
      SETTING: General internal medicine teaching clinic in a large university
      affiliated Department of Veterans Affairs Medical Center. PARTICIPANTS: All
      patients seen in the intervention firm (n = 1273) and control firm (n = 884)
      clinics in the 3-month period following the introduction of the guidelines.
      INTERVENTIONS: The control firm received guidelines and usual education for the
      cost-effective outpatient management of hypertension. The intervention firm
      received guidelines plus intensive guideline-based education and supervision.
      MEASUREMENTS AND MAIN RESULTS: The use of guideline medications was greater in
      the intervention firm as compared with the control. The intervention firm
      initiated more hydrochlorothiazide (HCTZ), 17.4% (95% confidence interval [CI]
      14.8, 20.1) of patients versus 11.9% (CI 9.3, 14.8) in the control firm (p =
      .002). Atenolol was initiated in 7.2% (CI 5.6, 9.0) in intervention firm versus
      4.7% (CI 3.2, 6.6) in the control (p = .03). In addition, the use of nonguideline
      medications was less in the intervention firm. The intervention firm initiated
      less long-acting nifedipine, 7.8% (CI 6.0, 9.8) versus 10.6% (CI 8.2, 13.5) in
      the control (p = .04). Blood pressure control demonstrated greater improvement in
      the intervention firm (p = .02). Use of guidelines was associated with decreased
      costs for antihypertensive medications in the intervention firm as a whole as
      compared with the control firm. There was no increased use in other measured
      resources in the intervention firm including the number of outpatient laboratory
      services obtained, clinic visits, emergency room visits, or hospitalizations.
      CONCLUSIONS: Intensive implementation of guideline-based education and
      supervision was associated with an increased use of guideline medications,
      decreased use of costly alternative agents, and no decrement in the measured
      outcomes of care.

PMID- 8667092
TI  - Ambulatory health services provided to low-income and homeless adult patients in
      a major community health center.
AB  - OBJECTIVE: The homeless are more likely than other poor and vulnerable
      populations to manifest serious health problems. Early research focused on needs
      assessments of this population; current work has shifted to examine issues of
      access, use of health services, and barriers to care. However, current research
      has not examined whether model clinics designed for the homeless have created
      parity with their low-income domiciled peers in terms of provision of ambulatory
      services. Such data are increasingly in demand as managed care looms just over
      the political horizon as a means of providing services to low-income patients.
      SETTING: A major community ambulatory health center in West Los Angeles.
      PATIENTS: Homeless (N = 210) and low-income domiciled (N = 250) patients. DESIGN:
      A medical record review of care provided over a one-year period to homeless and
      low-income domiciled adult patients in a major community ambulatory health center
      in West Lost Angeles was conducted. Data were collected on length of visits,
      laboratory tests, procedures, and services, immunizations, specialty clinic
      referrals, medications, and travel vouchers. RESULTS: On average, homeless
      patients were provided with as many outside laboratory tests per patient as low
      income domiciled patients (1.1 vs 1.3). Further, they returned for more visits
      (3.4 vs 2.9), were more likely to have had longer visits (88% vs 61%), and were
      provided with more laboratory tests (2.3 vs 1.7), procedures and services (3.1 vs
      1.1), referrals (1.3 vs 0.7), medications (4.4 vs 3.3), and travel vouchers (0.6
      vs 0.2) (all p < .01). Many of the procedures and services received by the
      homeless were for nonmedical assistance. Preventive health services such as
      tuberculosis skin tests, sexually transmitted disease (STD) screening, and Pap
      tests were provided to both homeless and domiciled patients at low rates.
      CONCLUSIONS: Findings from this study on the provision of care in a major West
      Los Angeles community health center indicate that homeless patients receiving
      care from a model program designed to address their special needs will return for
      follow-up visits and will utilize services at least as much as low-income
      domiciled patients.

PMID- 8667091
TI  - Effects of a physician communication intervention on patient care outcomes.
AB  - OBJECTIVE: To determine whether an intervention designed to improve patient
      physician communication increases the frequency with which physicians elicit
      patients' concerns, changes other communication behaviors, and improves health
      care outcomes. DESIGN: Pretest-posttest design with random assignment of
      physicians to intervention or control groups. SETTING: General medicine clinics
      of a university-affiliated Veterans Affairs Hospital. PATIENTS/PARTICIPANTS:
      Forty-two physicians and 348 continuity care patients taking prescription
      medications for chronic medical conditions. INTERVENTIONS: Intervention group
      physicians received 4.5 hours of training on eliciting and responding to
      patients' concerns and requests, and their patients filled out the Patient
      Requests for Services Questionnaire prior to a subsequent clinic visit. Control
      group physicians received 4.5 hours of training in medical decision-making.
      MEASUREMENTS AND MAIN RESULTS: The frequency with which physicians elicited all
      of a patient's concerns increased in the intervention group as compared with the
      control group (p = .032). Patients perceptions of the amount of information
      received from the physician did increase significantly (p < .05), but the actual
      magnitude of change was small. A measure of patient satisfaction with the
      physicians was high at baseline and also showed no significant change after the
      intervention. Likewise, the intervention was not associated with changes in
      patient compliance with medications or appointments, nor were there any effects
      on outpatient utilization. CONCLUSIONS: A low-intensity intervention changed
      physician behavior but had no effect on patient outcomes such as satisfaction,
      compliance, or utilization. Interventions may need to focus on physicians and
      patients to have the greatest effect.

PMID- 8667093
TI  - Late-life depression in primary care. How well are we doing?
AB  - OBJECTIVE: To discover primary care physicians' attitudes toward their abilities
      to detect and treat depression in the elderly. DESIGN: A self-administered
      questionnaire sent to 1,000 primary care physicians in the state of Michigan.
      SETTING: The survey was sent to physicians who practice general internal medicine
      or family medicine. PARTICIPANTS: The questionnaire was sent to 500 MD and 500 DO
      physicians; equal representation was given to general internal medicine and
      family medicine. Of all 1,000 physicians, 60% (n = 604) responded, 51% (n = 309)
      were MD's, 48% (n = 295) were DO's, 41% (n = 245) were general internists, and
      59% (n = 359) were family medicine physicians. MEASUREMENTS AND MAIN RESULTS:
      Despite positive attitudes about their skills for detecting and treating
      depression in the elderly, only one quarter of the respondents routinely used a
      screening tool in practice. Forty-one percent of all physicians were not aware of
      depression practice guidelines. Family physicians were more confident about their
      treatment skills than were general internists (85% vs 50%; chi 2 = 11.42, p < or
      = .003). Male physicians more often endorsed pharmacologic treatment, while
      female physicians more frequently used counseling and exercise techniques to
      treat depressed older patients. Half of all physicians felt knowledgeable about
      community resources to treat older depressed patients. CONCLUSIONS: This survey
      identified several perceived needs for future targeted interventions: (1)
      additional Agency for Health Care Policy and Research guideline exposure for all
      primary care physicians, (2) targeted counseling skill intervention for male
      physicians and medication management for female physicians, and (3) additional
      continuing medical education intervention for practicing general internists.
      Further research is needed to correlate physician attitudes with ensuing
      behaviors to fully appreciate the nature of late-life depression treatment within
      the primary care arena.

PMID- 8667095
TI  - Beyond Guidelines. Can general internists show the (critical) paths?

PMID- 8667094
TI  - New method to predict patients' intravenous heparin dose requirements.
AB  - OBJECTIVE: To predict intravenous heparin dose requirements of patients treated
      for thromboembolic disorders. DESIGN: A retrospective cohort study in which we
      used simple linear regression to predict patients' effective maintenance dose
      (EMD) of heparin (units/kg/hour needed to achieve and maintain APTT therapeutic
      range) from patients' "heparin responsiveness" (the APTT increase after the
      initial 6 hours of heparin treatment per units/kg/hour received).
      SETTING/PATIENTS: The model was derived from 46 patients treated at one hospital
      (Hospital A) and then tested in 42 patients treated at another hospital (Hospital
      B). MEASUREMENTS AND MAIN RESULTS: Among Hospital A patients, there was a strong
      linear correlation (r = -.880; p < .001) between EMD (mean 16.02 units/kg/hour;
      95% CI 14.9, 17.15) and "heparin responsiveness" (HR): EMD = 25.651 - [95.118 x
      HR]. This model accurately predicted Hospital B patients' EMD: 97% (37/38) fell
      within the model's 95% prediction interval; the mean absolute difference between
      predicted and actual EMD was 1.73 units/kg/hour (95% CI 1.39, 2.08); and only 16%
      of patients had EMD's more than 3 units/kg/hour different from that predicted by
      the regression model. The model's accuracy was comparable to that of our gold
      standard, the weight-based heparin dosing nomogram. CONCLUSION: The infusion dose
      of intravenous heparin effective for an individual patient can be predicted
      accurately from the patient's body weight and APTT response to the initial 6
      hours of treatment. Especially in hospitals where validated heparin dosing
      nomograms are not used, clinicians may find this simple technique useful in
      achieving timely therapeutic anticoagulation.

PMID- 8667096
TI  - Practice guidelines. What are internists looking for?
AB  - To determine features of the presentation of clinical practice guidelines that
      may enhance their use by internists, we conducted a cross-sectional survey to
      which 1,513 (60%) of 2,513 eligible internists responded. Endorsements by
      respected colleagues and by major organizations were identified as very important
      by 72% and 69% of respondents, respectively. Respondents preferred short
      pamphlets and manuals summarizing a number of guidelines and felt that concise
      recommendations (86%), synopsis of supporting evidence (85%), and quantification
      of benefit (77%) were important in guideline presentation. We conclude that
      guideline developers should gain the endorsement of major organizations and
      present key aspects in brief, easily assimilated formats.

PMID- 8667097
TI  - Effects of a postdischarge clinic on housestaff satisfaction and utilization of
      hospital services.
AB  - This randomized, controlled clinical trial evaluated the effect of a
      postdischarge clinic on housestaff education and patient utilization of hospital
      services. Medicine housestaff were randomized either to attend a clinic once a
      week in which they saw all eligible patients they had recently discharged from
      the hospital, or to continue with usual discharge practices. We enrolled 751
      patients, 312 on intervention teams and 439 on control teams. Intervention
      housestaff did not feel that the clinic took too much time and felt that they
      better knew how patients did after discharge. Fewer intervention patients had
      emergency room visits (28.0% to 20.8%, p = .03) in the 30 days after discharge.
      Length of stay, readmission rates, and mortality were similar for the two groups.
      We conclude that a postdischarge clinic can improve resident education and reduce
      postdischarge emergency room utilization.

PMID- 8667098
TI  - Improving outpatient clinic staffing and scheduling with computer simulation.
AB  - Patient flow in an appointment-based, outpatient internal medicine clinic
      involving multiple, sequential providers-registrar, triage nurse, physician, and
      discharger-was studied using computer simulation. Provider task time
      distributions were obtained through a time-motion study and then input into the
      computer program, which simulated the clinic situation well. Time interval and
      sensitivity analyses yielded insights into staffing levels, appointment times,
      and clinic dynamics. A bottleneck provider was shown, and patient time in the
      clinic was related to the time of appointment and was slowed by having too many
      doctors in the clinic. Subsequent operational changes significantly decreased the
      average observed patient total time in clinic from 75.4 (SD 34.2) minutes to 57.1
      (SD 30.2) minutes (p < .001, t test).

PMID- 8667099
TI  - Reconnoitering critical pathways and guidelines.

PMID- 8667100
TI  - Maximizing the quality of the physician-patient encounter.

PMID- 8667101
TI  - A study of cross-coverage calls.

PMID- 8667102
TI  - Balanced experiential curriculum for internal medicine residents of a municipal
      hospital.

PMID- 8667103
TI  - Guidelines: the next generation.

PMID- 8667104
TI  - Contemporary American medicine: a view from the trenches.

PMID- 8667105
TI  - Fatal group A streptococcal infection with toxic shock syndrome: complicating
      minor orthopedic trauma.
AB  - Since 1987, reports have appeared of a streptococcal toxic shock syndrome in
      various clinical settings. None have appeared in the orthopaedic literature.
      Between 1989 and 1991 at our institution three patients with relatively minor
      orthopaedic injuries or procedures died of group A streptococcal infections
      complicated by toxic shock syndrome. The manifestations of this syndrome included
      rapid progression of systemic sepsis, necrotizing soft-tissue infections, acute
      renal failure, adult respiratory distress syndrome, and coagulopathy. All three
      patients died despite aggressive resuscitative measures and surgical debridement.
      Optimal treatment of this life-threatening process requires early recognition,
      aggressive surgical debridement, appropriate antibiotic management, and intensive
      care unit support.

PMID- 8667106
TI  - Retropubic vascular hazards of the ilioinguinal exposure: a cadaveric and
      clinical study.
AB  - In the course of ilioinguinal exposure, significant bleeding can occur from
      anastomotic vascular channels along the posterior aspect of the superior public
      ramus. A cadaveric study was undertaken to quantify and qualify these
      communicating vascular systems. We made bilateral ilioinguinal exposures on 40
      cadavers. All vessels > 2 mm in diameter, connecting the obturator system with a
      more superficial system, were singled out and their courses recorded. Fifty-eight
      of 79 sides (73%) had at least one large-diameter communicating vascular channel
      along the posterior aspect of the superior pubic ramus. In 47 of the 79 exposures
      (59%) communicating veins were noted. Arterial channels were identified in 34
      exposures (43%). A prospective clinical study was also performed. Thirty-eight
      consecutive patients with displaced acetabular fractures were treated surgically
      using ilioinguinal exposures. Fourteen of the patients (37%) had anastomotic
      vessels. This study confirms the variability of the retropubic vascular system.

PMID- 8667107
TI  - Optimal technique of screw placement in the ischial tuberosity for posterior
      acetabular fractures.
AB  - Thirty dry adult bony specimens and eight embalmed cadavers were used to report
      on the morphological data of the ischial tuberosity and to determine the most
      optimal technique for ischial tuberosity screw placement for open reduction and
      internal fixation of posterior acetabular fractures. The average width, height,
      and depth of the ischial tuberosity were 27.0 mm, 32.2 mm, and 32.4 mm,
      respectively. The average angles between the posterior and medial aspects and
      between the posterior and lateral aspects of the ischial tuberosities were 79.5
      degrees, and 111.5 degrees, respectively. The risk to the internal pudendal
      neurovascular bundle increases with either a more medially placed screw or a
      laterally placed screw that is angled medially. The tendinous origin of the
      hamstrings becomes quite substantial (7-10 mm thick) at a point 2 cm distal to
      the inferior acetabular margin. The exposure of the ischial tuberosity should
      therefore be restricted to this level. The entry point of the screws should be 5
      mm or 10 mm medial to the lateral margin of the ischial tuberosity, and the
      screws should be directed 35-40 degrees, 45-50 degrees, and 50-55 degrees
      caudally at the level of the inferior acetabular margin and 1 cm and 2 cm below
      it, respectively, to obtain the most favorable bony purchase.

PMID- 8667108
TI  - The crescent fracture: a posterior fracture dislocation of the sacroiliac joint.
AB  - Between October 1987 and August 1992, 22 patients with crescent fractures, a
      posterior fracture-dislocation of the sacroiliac joint, were admitted, treated,
      and available for review at Tampa General Hospital and The Hospital for Special
      Surgery. The purpose of the study was twofold: (a) to evaluate the incidence,
      severity, and pattern of associated injuries, and (b) to determine the efficacy
      of a treatment protocol using a posterior extrapelvic approach and extraarticular
      internal fixation. The study population was composed of 13 females and nine
      males; the average age was 25 years (range 10-52). Despite the fracture pattern
      resulting in a rotationally unstable hemipelvis, all patients were
      hemodynamically stable at the time of presentation. Fourteen patients (64%) had
      other associated injuries, including five (23%) with closed head injury. In all
      cases a posterior extrapelvic approach was used with an anatomic reduction of the
      fractured iliac wing and the sacroiliac joint dislocation. Stable extraarticular
      internal fixation was obtained using intertable lag screws and outer-table
      neutralization plates. All the fractures were clinically and radiographically
      healed within 8-10 weeks postoperatively, and there were no acute wound,
      neurologic, or vascular complications. One patient developed osteomyelitis of the
      iliac crest 6 months postoperatively.

PMID- 8667109
TI  - Radiographic recognition of the sacral alar slope for optimal placement of
      iliosacral screws: a cadaveric and clinical study.
AB  - Malpositioning of iliosacral screws happens more often when common variations in
      the morphology of the upper sacral segments are unrecognized. Radiological
      anatomic correlations of sacral anatomy were studied in 10 fresh-frozen cadaveric
      pelvises without evidence of skeletal disease, obtained from six male and four
      female donors. Eighty consecutive patients with complicated pelvic fractures
      treated operatively by the same surgeon using percutaneously placed iliosacral
      screws were evaluated. Variations in the sacral alar anatomy and slope found in
      upper sacral segmentation anomalies are common. Surgically important and
      predictable abnormal morphological patterns can be easily identified using pelvic
      outlet and lateral sacral plain radiographs along with computed tomographic
      scans. On the true lateral projections, the iliac cortical density adjacent to
      the sacroiliac joint parallels the sacral alar slope and is almost always caudal
      and posterior to it; it delineates the anterior extent of the "safe zone" for
      iliosacral screw insertion. Thus, the lateral sacral image provides the surgeon
      with a better understanding of the sacral alar slope and can help prevent
      iliosacral screw placement errors. The lateral sacral image should always be used
      intraoperatively with the inlet and outlet images to guide iliosacral screw
      placement.

PMID- 8667110
TI  - Bone regeneration with resorbable polymeric membranes: treatment of diaphyseal
      bone defects in the rabbit radius with poly(L-lactide) membrane. A pilot study.
AB  - Tubular poly(L-lactide) membranes with a pore size of 5-15 microns and a
      molecular weight of 70,000 Daltons were implanted into 24 New Zealand skeletally
      mature rabbits to cover 10-mm mid-diaphyseal defects of the radius of the
      forelimb. An identical defect on the contralateral limb was not treated with the
      membrane and served as a control. The animals were killed at 1, 2, 4, 8, 12, 24,
      36, and 64 weeks after implantation, and radiographic and microscopic studies
      were conducted. The canals of the polymeric tubes were initially filled with
      blood. At 2 weeks, there was direct woven bone formation within the polymeric
      tube in continuity with the fragment cortices and its medullary canal. The
      formation of woven bone across the defect progressed until reconstruction of the
      defect had occurred at 6-8 weeks. The bone continued to remodel throughout the
      observation period of 64 weeks. By 12 weeks, bone within the lumen of the implant
      consisted of cancellous bone and cortical bone lining the membrane walls. At 24,
      36, and 64 weeks, the implants were filled with cancellous bone and cortical bone
      in direct apposition to the polymer membrane. For one implant, the newly formed
      woven bone had only incompletely filled the defect at 8 weeks. This resulted in a
      nonunion with a residual gap of 0.5 mm and the appearance of mature bone. There
      was extensive bone formation along the intraosseous membrane in both control and
      implanted defects, although the untreated defects were rapidly filled with
      overlying muscle and soft tissues. The osseous activity of the untreated defects
      appeared confined to the bone ends by the interposed muscle and fibrous soft
      tissue margins. The untreated defects resulted in radial-ulnar synostosis along
      the intraosseous membrane with cortical bone caps at the bone ends. The poly(L
      lactide) membrane remained intact throughout the 64-week period without evidence
      of significant degradation. The membranes were encapsulated in a thin fibrous
      tissue. There was no histological evidence of acute or chronic inflammation
      associated with the implants.

PMID- 8667112
TI  - Posterior plating of displaced Weber B fibula fractures.
AB  - This is a prospective study that examines 32 patients who were treated with
      posterior plating of a displaced Weber B fibula fracture and had a minimum of 1
      year follow-up. The surgical technique included application of an unbent one
      third tubular plate to the posterior aspect of the fibula using the antiglide
      technique. Twenty-seven fractures were classified as supination-eversion IV: 13
      with deltoid disruption and 14 with a medial malleolar fracture. Three were
      classified as pronation-abduction and two as low pronation-eversion fractures at
      the level of the plafond. A six-hole plate was used most often (18 cases), and 23
      patients had a lag screw placed through the plate. There were no nonunions or
      malunions. No wound complications, screw loosening, loss of fixation,
      intraarticular screws, or palpable screws were found. Four patients had transient
      peroneal tendinitis that resolved in 4-8 weeks. Two patients had later plate
      removal caused by poor technique because of a symptomatic lag screw. Twenty of
      the 21 patients who returned a questionnaire were satisfied with their result
      (95%). Posterior fibular plating offers many advantages over lateral plating,
      including the possibility of no intraarticular or palpable screws and an improved
      and stronger distal fixation construct. Our favorable results suggest that this
      technique should be given consideration as a treatment of choice for displaced
      Weber B fibula fractures.

PMID- 8667111
TI  - Early complications with external fixation of pediatric femoral shaft fractures.
AB  - A retrospective study of 27 pediatric patients with femoral shaft fractures
      treated by external fixation was made to identify complications and evaluate
      outcomes. The average age at the time of injury was 8 years, 9 months (range 5
      years, 6 months to 13 years, 2 months). Sixteen fractures were isolated, and nine
      were associated with polytrauma. There was only one open fracture. Data obtained
      from chart review (n = 27), radiographs (n = 27), physical exam (n = 16), and
      questionnaire (n = 21) identified eight major complications (30%) in six patients
      and 29 minor complications (107%) in 20 patients. The major complications
      included two refractures, two fractures through pin sites, one postimmobilization
      supracondylar femoral fracture, one persistent pin-tract infection requiring
      early fixator removal, one malreduction, and one loss of reduction. Both the
      patient with malreduction and the one who lost reduction had > 10 degrees of
      varus deformity before adjustment of their frames. Five of the eight major
      complications (64%) were secondary to errors in operative technique or
      postoperative treatment. Only one major complication was noted among the 16
      patients with isolated injuries. Of the patients with minor complications, 14 had
      pin-tract infections requiring oral antibiotics, five refused to go to school
      with the fixator in place, five were dissatisfied with scar appearance, and five
      had clinically insignificant malunions. A clinically insignificant malunion was
      considered to be angulation > or = 5 degrees varus or valgus or > or = 10 degrees
      procurvatum or recurvatum deformity that did not affect the patient's function.
      The minor complications were considered intrinsic to the procedure and difficult
      to avoid. Despite these problems, all patients with isolated injuries, except one
      with a slipped capital femoral epiphysis, had excellent function at the time of
      final review. If external fixation is chosen as the method of treatment for a
      pediatric femur fracture, careful attention must be paid to operative technique
      and postoperative treatment in order to minimize complications.

PMID- 8667113
TI  - The strength of plate fixation in relation to the number and spacing of bone
      screws.
AB  - Our purpose was to study the relationship between the number of plate holes
      filled and the spacing between the screws and the resultant strength of plated
      constructs. Broad regular DC plates were anchored with 4.5-mm cortical screws to
      blocks of polyurethane foam. Six constructs were tested: (a) screws in holes 1,
      2, and 3; (b) screws in holes 1 and 3; (c) screws in holes 1 and 4; (d) screws in
      holes 1 and 5; (e) screws in holes 1 and 6; (f) screws in holes 1, 3, and 5. The
      strength was quantified using a material-testing system. In cantilever and four
      point bending, the constructs were loaded in both gap-closing and gap-opening
      modes. Screws in holes 1, 2, and 3 were tested against other constructs. For
      cantilever bending (gap opening and gap closing), construct (a) was stronger than
      construct (b), as strong as construct (c), but weaker than the constructs with
      more widely spaced screws (p < 0.0001). In terms of four-point bending, for gap
      opening, the standard fixation (construct (a) was stronger than construct (b) but
      weaker than the more widely spaced constructs. For gap closing, construct (a) was
      stronger than constructs (b) and (c) but weaker than the rest. Regardless of the
      spacing of screws and the plate length, strength in torsion was dependent on the
      number of screws securing the plate. In a laboratory fracture model of plate-bone
      constructs tested to failure by screw pullout, wider spacing of bone screws
      increases the bending strength of screw-plate fixation and can be more effective
      than increasing the number of screws. Torsional strength is independent of screw
      placement in plates of a given width and depends on the number of screws used.

PMID- 8667114
TI  - Greenstick fractures of the radius in adults: a report of two cases.
AB  - To our knowledge, greenstick fractures, which are common in children, have not
      been found to occur in adults. We report on two cases of greenstick fracture of
      the radial shaft in an adult. Treatment principles, which differ from those for
      children's fractures, are discussed.

PMID- 8667115
TI  - Traumatic plastic deformity of an adult forearm: case report and literature
      review.
AB  - We report a case of plastic deformity involving both the radius and the ulna in
      an adult treated with osteotomy of both bones.

PMID- 8667116
TI  - Unrecognized foreign body in the hip joint.
AB  - A 40-year-old woman involved in a motor vehicle accident sustained a left
      acetabular fracture and a dislocated left hip with a large ipsilateral traumatic
      hip wound. Multiple plain radiographic films of the pelvis and a pelvic computed
      tomographic scan were obtained. None of these images showed a 25 x 20 x 12-mm
      piece of the gearshift that was found in the hip joint at the time of the
      surgery. Hence, we present this case highlighting an unusual phenomenon in which
      a large foreign body was not recognized on preoperative radiographic studies.

PMID- 8667117
TI  - In response to article by Ostrum and Geel.

PMID- 8667118
TI  - Four year clinical study of glass-infiltrated, sintered alumina crowns.
AB  - The clinical outcome of 95 consecutively placed In-Ceram complete coverage
      crowns, 68 posterior and 28 anterior, all luted with conventional cements, was
      studied. In the 56 month observation period no total failure requiring
      replacement of a restoration occurred. The veneer of a molar single crown
      fractured, while its ceramic core remained intact. With four crowns, marginal
      caries was observed after 2-4.5 years. It was concluded from this clinical study
      that In-Ceram complete coverage all-ceramic crowns are indicated for anterior and
      posterior teeth.

PMID- 8667119
TI  - The acquisition and validation of removable partial denture design knowledge. I.
      Methodology and overview.
AB  - The authors report on the eliciting of the partial denture design expertise of
      teachers of prosthetic dentistry. Their approach was to identify 125 design rules
      and then to sample expert reaction by surveying 10 experts individually and by
      surveying the prosthetic departments in all 17 dental schools in the British
      Isles. The surveys achieved a return of 100% and revealed an unsuspected
      consensus concerning the rules. A majority of schools were in agreement on
      whether or not 111 (89%) of the rules could be supported. This design expertise
      will be disseminated through RaPiD, a knowledge-based assistant for the design of
      removable partial dentures. It is expected that by incorporating into this design
      assistant rules which have been shown to be widely supported, the acceptability
      and usefulness of RaPiD for clinical education and practice will be increased.

PMID- 8667120
TI  - Synthesis of fluorinated Bis-GMA and its use with other fluorinated monomers to
      formulate hydrophobic composites.
AB  - Fluorinated Bis-GMA was synthesized and used with other commercially available
      fluorinated monomers and diluents to prepare hydrophobic composites. The
      composites were formulated as one-paste systems and were polymerized using blue
      light. Mechanical properties and water-related qualities were determined.
      Fluorination generally improved the hydrophobicity of the composites, but there
      was no clear-cut effect on mechanical properties.

PMID- 8667121
TI  - Long-term observations of extensive fixed partial dentures on mandibular canine
      teeth.
AB  - Twelve patients were followed for 15 years after treatment with a 12-unit
      cantilever fixed partial denture on the mandibular canines opposite to a complete
      maxillary denture. Four constructions failed and had to be removed but four were
      still in function after 15 years. Four patients died during the observation
      period still wearing their constructions. Endodontic complications, pulpal
      necrosis and loss of retention of posts were the most frequent, while caries and
      periodontal lesions were rare. The maintenance costs over the years were fairly
      low even compared to maintenance costs for patients treated with implants.
      Extensive mandibular cantilever fixed partial dentures may be used in the
      rehabilitation of patients with a very reduced dentition and a history of
      difficulties adapting to removable dentures.

PMID- 8667122
TI  - Influence of layer and stain firing on the fracture strength of heat-pressed
      ceramics.
AB  - Fracture strength (T = torque to initiate fracture; K(IC) = fracture toughness)
      and the fractography of heat-pressed leucite reinforced ceramic (IPS Empress,
      Ivoclar AG-Schaan, Liechtenstein) were analysed by the notched disc test
      technique and scanning electron microscopy methodologies. To determine the
      effects of additional firing schedules on the heat-pressed core ceramic, three
      groups of specimens were prepared. These groups were heat-pressed core, heat
      pressed core and simulated stain firing, and heat-pressed core and simulated
      layer firing. Statistical analysis of both T and K(IC) values showed that there
      was no statistically significant difference between these three groups (P >
      0.05). Scanning electron microscopy analysis of the fractured surfaces revealed
      that crack propagation occurred around some of the leucite particles and also
      partly and directly through other leucite particles.

PMID- 8667123
TI  - Oral conditions and aptitude to receive implants in patients with removable
      partial denture: a cross-sectional study. Part II Aptitude.
AB  - The aim of this study was to evaluate the possibility of replacing removable
      partial denture (RPD) with fixed partial dentures on osseointegrated implants in
      a selective group of patients with partially edentulous lower jaws. Forty
      patients were evaluated to receive implants. Twenty-three patients showed a
      precarious oral hygiene, five patients refused the treatment (being satisfied
      with their RPD), six refused for economic reasons, three patients refused for
      fear and scepticism, one for long duration of therapy, and one was not treated
      because of a very marked atrophy of the alveolar crest. Finally, one patient was
      treated with implants. For these reasons, at the present time implants are not an
      appropriate treatment for introduction into large-scale public health programmes
      and RPD must still be considered a valid therapeutic procedure.

PMID- 8667124
TI  - The evaluation of post-retained crowns using a custom-designed fatigue machine.
AB  - There are many published reports of static tests on dental materials that are
      required to perform clinically under a range of load amplitudes and cyclic
      frequencies. There are fewer reports in the dental literature of fatigue tests on
      dental structures and materials, and these are reviewed in this paper along with
      a description of the design, manufacture and commissioning of a machine which can
      apply chosen cyclic load/time characteristics up to a maximum amplitude of 700 N
      and frequency of 5 Hz. The machine design is not specific to particular test
      specimens but is widely applicable within dental materials testing. The machine
      is being used for a continuing study of post-retained crowns, cemented with glass
      ionomer cement. The planning of fatigue tests and the interpretation of results
      is discussed with reference to the experience of previous authors, and it is
      concluded that a survival analysis approach offers a means of understanding
      materials' performances. The initial results from a random, blocked comparison of
      three glass-ionomer luting cements indicated that cyclic loads can be identified
      to give a 50% survival probability for specimens. It is expected that loads
      experienced in vivo have lower amplitude than those applied in this study,
      however, such loading cycles have been chosen to facilitate material comparisons.
      It is concluded that gaining significant results under laboratory fatigue
      conditions is difficult, but that they may usefully complement clinical trials.

PMID- 8667125
TI  - Long-term follow-up of cross-arch fixed partial dentures in patients with
      advanced periodontal destruction: evaluation of occlusion and subjective
      function.
AB  - The study aimed to investigate occlusal factors in fixed partial dentures (FPDs)
      still in service for more than 10 years, and to assess the patients' opinions
      regarding oral function with these constructions. Thirty-four patients with 43
      FPDs were examined clinically concerning occlusion and by means of a
      questionnaire on functional aspects. The most common occlusal contact pattern was
      group function (51% on both sides, 7% on one side) while canine protected
      occlusion was recorded in 16% on both sides, 7% on one side. Balanced occlusion
      (19%) was mainly found when the FPD occluded against a complete denture and when
      there were few abutments and a small amount of abutment supporting tissue. The
      number and intensity of the occlusal contacts were assessed by means of thin
      occlusal sheets (50 microns). On average, one occlusal contact was observed on
      each dental unit with antagonist. The average number of sheets that could be
      introduced between the antagonists when the patient bit hard in the intercuspal
      position was two without significant differences between different areas
      (anterior/posterior) or type of dental unit (abutment, pontics, cantilever
      section). In the cantilever sections there were looser contacts (more
      interocclusal sheets) more distally. The great majority of patients were
      satisfied with the function of their FPDs (mastication, phonetics, aesthetics,
      comfort, and hygiene). Subjective function was not significantly influenced by
      FPD design, occlusal factors or number of FPD units. The only significant
      difference observed was that patients with a small amount of supporting tissues
      said they had more difficulties with hard foods than the others had. Although a
      stable occlusion was found in all FPDs, none of the other occlusal parameters
      examined were related to the long-term results.

PMID- 8667127
TI  - A new technique for determining the denture tooth bond.
AB  - Defective bonds between resin teeth and denture base material remain a continuing
      source of failure. Findings from the limited number of studies on this topic are
      diminished by the numerous experimental approaches adopted. National and
      international standard specifications also adopt different methods of specimen
      preparation and physical straining. A critical appraisal of the various standards
      is carried out and a new procedure for determining the denture tooth to acrylic
      resin bond is described. A study using this technique found that physical
      modification and alginate contamination of the tooth had no significant effect on
      the bond strength. Ineffectual wax elimination was the main cause of failure.

PMID- 8667126
TI  - Determination of fluoride release from light-cured glass-ionomers and a
      fluoridated composite resin from the viewpoint of curing time.
AB  - The purpose of this study was to investigate the fluoride releasing pattern of
      several visible light-curing glass-ionomers and one fluoride-containing filling
      material, from the viewpoint of curing time. Standardized blocks of Time Line
      (Caulk-USA), XR-Ionomer (Kerr-USA), Vitrebond (3M-USA) and Heliomolar-Ro
      (Vivadent-Lichtenstein) were light cured for 20, 40 and 60 s, and then stored in
      deionized distilled water at 37 degrees C for 24, 48, 72 h and 7 days. The water
      was changed every day and measurements of the fluoride released from the
      materials were made daily. The results were compared statistically with the
      results obtained from Ketac-Bond (Espe-Germany) prepared in the same manner. The
      levels were highest for the first 24 h; in the following days they decreased
      rapidly. The fluoride-releasing patterns of all these materials were similar to
      each other. The fluoride release was the highest from XR-Ionomer, and the lowest
      from Heliomolar-RO. For Time Line glass-ionomer, the fluoride release from 20 s
      cured blocks was significantly higher than the fluoride release from 40 and 60 s
      cured blocks at the end of 1 week. It was observed that the fluoride release from
      Ketac-Bond was significantly lower than XR-Ionomer and Vitre-Bond and higher than
      Time Line and Heliomolar-Ro.

PMID- 8667128
TI  - Light-activated restorative materials: a method of determining effective
      radiation times.
AB  - The aim of this investigation was to develop a test method that allows an
      operator to determine the appropriate radiation time for any light-activated
      material, irrespective of the characteristics of the light-activation unit or
      material to be cured. A computer-based radiometer was used to monitor the
      radiation energy transmitted through a number of light-activated materials during
      irradiation, and a method was devised to determine the predicted radiation time
      for any given material/shade/light unit combination based upon the change in
      transmission against time that occurred as the material polymerized. Additional
      test samples were cured for the predicted radiation times and upper and lower
      surface microhardness measurements were taken to verify the validity of the test
      method. Predicted times varied from 16 to 44 s for 2 mm thick samples of the
      materials/shade/light-activation units used. This method may allow operators to
      determine appropriate radiation times for any new light-activated restorative
      they decide to use with their own light-activation unit.

PMID- 8667129
TI  - Long-term evaluation of periodontal therapy: II. Incidence of sites breaking
      down.
AB  - Eighty-two patients were treated in a split mouth design with coronal scaling
      (CS), root planing (RP), modified Widman surgery (MW), and flap with osseous
      surgery (FO) which were randomly assigned to the various quadrants in the
      dentition. Following phase I and phase II therapy, the patients received
      supportive periodontal treatment (SPT) at 3-month intervals for up to 7 years.
      Clinical attachment level (CAL) was determined initially, post-phase I, post
      phase II and prior to each SPT appointment. If a site lost > or = 3 mm of CAL
      from its baseline, it was classified as a breakdown site. Baselines were the
      initial exam for sites treated by CS and 10 weeks post-phase II for sites treated
      by RP, MW, and FO. Data were grouped by probing depth (PD) severity at the
      initial exam and at post-phase II. The breakdown for CS sites was assessed
      separately from RP, MW, and FO sites because of different baselines and
      retreatment protocols. Sites treated by CS had a higher incidence of breakdown
      than the other therapies through year 1 of SPT. The breakdown incidences/year for
      RP and MW sites were similar and greater than for FO sites in 1 to 4 mm and 5 to
      6 mm PD categories. Breakdown incidence of RP sites was greater than MW sites
      which was greater than FO sites initially > or = 7 mm. Differences in incidence
      of breakdown between therapies after recategorizing data by post-phase II PD were
      the same as above, except no difference was present between RP and MW sites > or
      = 7 mm. Breakdown incidences were greater in increasing PD severities regardless
      of when they were categorized. There was no further loss of CAL one year after
      retreatment in 88% of sites. Patients with higher breakdown incidences tended to
      be smokers at the initial exam.

PMID- 8667130
TI  - Periodontal status and detection frequency of bacteria at sites of periodontal
      health and gingivitis.
AB  - It is generally recognized that bacteria in dental plaque at sites of periodontal
      diseases are not commonly found at sites of periodontal health. One hypothesis to
      explain the etiology of periodontitis is that pathogenic bacteria from diseased
      sites infect healthy sites. It has been suggested that gingival inflammation may
      predispose sites to colonization by bacteria associated with periodontal
      diseases. The purpose of this cross-sectional study was to determine whether the
      detection frequency of selected bacteria at sites of periodontal health or
      gingivitis differed between subjects who were in good periodontal health,
      subjects who had gingivitis, or subjects with periodontitis. The clinical status
      of every tooth (except third molars) from 106 subjects was characterized by means
      of clinical attachment level, probing depth and by signs of inflammation.
      Subgingival plaque was collected from mesio-facial and disto-lingual surfaces.
      Specific monoclonal antibodies were used in an immunocytochemical assay to
      identify Campylobacter rectus, Eikenella corrodens, Porphyromonas gingivalis,
      pathogen-related oral spirochetes (PROS, using Treponema pallidum subspecies
      pallidum monoclonal antibodies), T. denticola (serotypes A-D), T. socranskii
      subspecies buccale and T. socranskii subspecies socranskii. Differences in
      detection of bacteria between groups of subjects were measured using odds ratios
      (OR). Results of this study indicate that PROS was the only identified bacterium
      at sites of both health and gingivitis that demonstrated a significant positive
      relationship with the presence of periodontitis. These findings do not prove that
      bacteria spread from periodontitis sites, nor do they imply that disease
      necessarily results from infection. However, these data do suggest that some
      bacteria associated with periodontitis are more likely than others to tolerate
      conditions at healthy sites and that the presence of periodontitis increases risk
      of infection at healthy sites.

PMID- 8667131
TI  - Effect of smokeless tobacco extract on human gingival keratinocyte levels of
      prostaglandin E2 and interleukin-1.
AB  - Gingival recession and white mucosal lesions frequently occur at sites of
      smokeless tobacco (ST) placement. The etiology of these alterations is presumably
      related to the irritating effects of tobacco components. The purpose of this
      study was to examine the effect of an aqueous ST extract (STE) on gingival
      keratinocyte production of prostaglandin E2 (PGE2) and interleukin-1 (IL-1),
      mediators involved in periodontal destruction and keratinocyte proliferation.
      Keratinocyte cultures were established from healthy tissues discarded from 8
      subjects undergoing crown lengthening procedures. Cells (passage 2-3) were seeded
      at 2.5 x 10(4) cells/well into 48 well tissue culture plates and maintained in
      serum-free media at 37 degrees C. On day 4 or 5, the wells were divided into 4
      groups receiving either 10%, 5%, 2.5%, or 0% STE for time periods ranging from 30
      to 240 minutes. PGE2 levels (pg/10(4) cells), as measured by enzyme immunoassay,
      were significantly (P < 0.05) increased in the 10% (215.66 +/- 34.58) and 5% STE
      (151.82 +/- 27.97) treated cultures compared to untreated cells (46.16 +/- 9.58).
      IL-1 alpha and IL-1 beta proteins were elevated (P < 0.05) in cell lysates
      (299.45 +/- 38.69 and 28.45 +/- 5.18, respectively) from 5% STE exposed cultures
      compared to control wells. At 10% STE, secreted IL-1 alpha was decreased (P <
      0.05) relative to 2.5% STE. This may reflect a toxic effect, as 10% STE
      significantly (P < 0.05) depressed cell numbers and viability. Lower tobacco
      concentrations did not affect cell numbers or viability, but significantly (P <
      0.05) increased PGE2 and IL-1 levels. Tobacco-induced synthesis of these
      mediators may play a role in the development of tobacco-related oral disease.

PMID- 8667132
TI  - A comparison of 2 analgesic regimens for the control of postoperative periodontal
      discomfort.
AB  - A single blind study of 24 patients compared the postoperative periodontal pain
      relief and adverse effects associated with a pretreatment regimen with etodolac,
      a nonsteroidal anti-inflammatory drug (NSAID), to a typical pro re nada (prn)
      regimen with a combination of acetaminophen with hydrocodone. Patients selected
      required one or more periodontal osseous surgeries that were judged to involve
      relatively similar degrees of surgical manipulation. Patients in the etodolac
      group received two 300 mg capsules 30 minutes prior to surgery and then redosed
      themselves prn. Patients who received the combination drug were not premedicated
      and followed a prn regimen. The subjects used a verbal analogue scale to report
      levels of pain hourly for the first 8 hours (starting 30 minutes prior to
      surgery) and also indicated any side effects experienced during the first week
      after surgery. Specific parameters monitored were the mean sum of hourly pain
      scores, mean hourly pain scores, time to first medication, number of
      postoperative doses, and adverse effects. Of the parameters studied, the only one
      that showed a statistically significant difference was the time to first
      medication. The time span from 30 minutes prior to the beginning of surgery to
      the first postsurgical dose was greater for etodolac than for the combination
      drug. However, the total number of medications taken under both regimens was
      similar. The side effects were minimal for both of the drugs studied. It was
      concluded that the analgesic regimens tested under clinical practice conditions
      were comparable in providing analgesia with minimum side effects in uncomplicated
      periodontal osseous surgery. Studies with larger numbers of patients are needed
      to definitively address whether these regimens are truly equivalent.

PMID- 8667134
TI  - Healing response to anorganic bone implantation in periodontal intrabony defects
      in dogs. Part I. Bone regeneration. A microradiographic study.
AB  - The purpose of the present study was to explore the regenerative potential of
      anorganic bone plus collagen (AB-C) in experimental intrabony defects. Eight
      healthy female beagle dogs, 3 to 4 years old and weighing 15 to 16 kilos, were
      used. After extraction of the mandibular third premolars (P3), surgical defects
      were created and inflammation induced by placement of cotton and steel braids.
      Eight weeks later, the braids were removed. The experimental lesions thus
      obtained were either treated by plain flap curettage (group 1: control) or were,
      in addition, implanted with AB-C (group 2: experimental). Blocks of AB-C alone
      were observed by scanning electron microscopy (SEM). The results show that the
      surface of the particles have the characteristics of a bone tissue. These
      particles are gathered together with a fibrillar network. Six, 18, and 36 weeks
      postoperative (PO), non-decalcified specimens from both groups were examined
      histologically by contact microradiography. In group 1, no significant bone
      regeneration was observed at 6, 18, or 36 weeks PO. In group 2, trabeculae
      undergoing mineralization and circumscribing dense particles above the reference
      notch were seen at 6 weeks PO; 18 and 36 week specimens showed significant bone
      regeneration with more or less dense remaining particles. The periodontal
      ligament space was always clear and the only signs of ankylosis noticed were deep
      in the notch on one 18 week group 2 specimen and on one 36 week group 1 specimen.

PMID- 8667133
TI  - Repopulation of periodontal pockets by microbial pathogens in the absence of
      supportive therapy.
AB  - This clinical study evaluated the reinfection incidence by Actinobacillus
      actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), and Prevotella
      intermedia (Pi) in periodontal pockets following scaling and root planing (SRP)
      and intra-pocket irrigation with antimicrobial agents in a patient population who
      did not receive supportive maintenance therapy. The number of target organisms
      was determined utilizing DNA probes. Forty-one (41) inflamed pockets > or = 5 mm
      with attachment loss and containing at least one target species were selected in
      6 adult patients. Following a baseline clinical and bacterial examination, all
      patients received thorough SRP. In addition, 1 to 2 teeth in each patient were
      randomly assigned to each of the following 4 treatment modalities: 1) control
      group, no irrigation; 2) saline group, irrigation with 2 cc of 0.85% saline; 3)
      tetracycline group, irrigation with 2 cc of aqueous tetracycline HCl, 50 mg/ml
      (5%); and 4) chlorhexidine group, irrigation with 2 cc, respectively. All
      selected sites were non-adjacent. No additional therapy was rendered during the
      entire 1-year observation period. Clinical parameters and microbial analyses were
      recorded again at 1 week, and 1, 3, 6, 9, and 12 months post-treatment. The
      effect of antimicrobial irrigation on the reinfection rate of sites by Aa, Pg,
      and Pi was compared with that of the control groups (1 and 2) by ANOVA. No
      statistically significant differences were observed among the irrigation
      treatment groups with regard to any of the clinical or bacterial parameters
      studied. Therefore, the 4 treatment groups were combined into a single group
      whereby the rate of bacterial repopulation following extensive scaling and root
      planing could be ascertained. The infection incidence of sites at baseline (of
      total sites), 1 week and 12 months (of sites originally infected at baseline) was
      14/41, 3/14, and 7/14 for Aa; 33/41, 6/33, and 12/33 for Pg; and 37/41, 3/37, and
      12/37 for Pi, respectively. Thus, half or fewer of the originally infected sites
      became reinfected at 12 months despite lack of maintenance therapy. The results
      suggest that 1) a single episode of pocket irrigation with antimicrobial agents
      following thorough scaling and root planing did not affect the rate of
      repopulation of periodontal pockets by the tested pathogens; 2) thorough scaling
      and root planing has a lasting suppressive effect on selected periodontal
      pathogens for the majority of sites in patients with adult periodontitis; 3) pre
      operative probing depth, the amount of gingival fluid flow and the composition of
      the subgingival microflora may serve as predictors for reinfection in the absence
      of maintenance care; and 4) reinfection of the treated sites by Aa, Pg, and/or Pi
      may constitute a risk factor that diminishes the effect of therapy in the absence
      of supportive maintenance care.

PMID- 8667135
TI  - Fate of demineralized freeze-dried bone allografts in human intrabony defects.
AB  - Demineralized freeze-dried bone (DFDBA) is the most widely used allograft in
      periodontics. Little information exists, however, on the fate of DFDBA matrix or
      on the effects of residual particles within grafted defects. The purpose of this
      study was to histologically examine the fate of DFDBA used for regeneration in
      intrabony defects. A secondary objective was to compare the amount of new
      attachment apparatus formation, including component tissues, in relation to the
      presence or absence of residual graft material. Histologic data were obtained
      from earlier studies in which intrabony defects grafted with DFDBA were removed
      at 6 months en bloc and submitted for histologic examination. Histologic sections
      (1,120) from 12 patients with 32 grafted defects revealed that 72% of the grafted
      defects exhibited residual DFDBA particles. When present, DFDBA appeared
      amalgamated within the new viable bone. Data from 5 patients with 14 grafted
      sites permitted a within-subject comparison of the amount of regeneration in
      relation to the presence or absence of residual graft material. Defects harboring
      residual graft particles exhibited significantly greater amounts of new
      attachment apparatus formation (1.72 mm vs. 0.20 mm), including new bone (2.33 mm
      vs. 0.23 mm), cementum (1.74 mm vs. 0.23 mm), and associated periodontal ligament
      than sites without evidence of graft matrix (P < or = 0.05). No apparent
      differences were seen in the nature of the new attachment apparatus or component
      tissues, other than in amount of formation. Inflammation and graft containment
      appear to be important factors influencing the fate of DFDBA and the regenerative
      response.

PMID- 8667136
TI  - Vertical ridge augmentation using a resorbable membrane: a case report.
AB  - The vertical dimension may be very important clinically where anatomic structures
      may limit the bone height available for implant insertion. Moreover, lack of bone
      tissue may result in exposure of implant threads, soft tissue recession, less
      than-optimal implant stability, and esthetic problems in the prosthetic
      reconstruction. Attempts have been made to increase the bone height with the
      placement of autografts and allografts on top of the ridge, but long-term results
      have been unsatisfactory. Recently an increase of bone in a vertical direction
      has been obtained in rats, rabbits, and man using expanded
      polytetrafluoroethylene (ePTFE) membranes. The authors present a case in which an
      increase of the vertical dimension of the alveolar ridge was obtained using a
      resorbable freeze-dried dura mater membrane in association with demineralized
      freeze-dried bone. After a 6-month uneventful healing period the space under the
      membrane was filled by a tissue with the macroscopic features of bone, and the
      two implants were almost covered by the newly-formed tissue. An histological
      examination of a retrieved sample of the newly formed tissue demonstrated the
      presence of mature bone. It can be concluded that a localized vertical increase
      of the alveolar ridge may be obtained with the use of a resorbable freeze-dried
      dura mater membrane.

PMID- 8667137
TI  - Verruciform xanthoma. Case report and literature review.
AB  - Verruciform xanthoma is a relatively uncommon lesion. Half of the reported cases
      occurred in the gingiva or alveolar ridge. In most cases, the clinical
      impressions are papilloma or verrucous carcinoma, which demonstrates the
      importance of the clinical and pathological recognition of this lesion. The cause
      of pathogenesis is still unknown since the first report in 1971. There are some
      cases reported in conjunction with leukoplakia, carcinoma in situ, pemphigus, and
      discoid lupus erythematosus (DLE), which merits close evaluation of this disease.
      This article reports two cases of verruciform xanthoma and reviews the evidence
      of its pathogenesis from the available literature.

PMID- 8667138
TI  - Diabetes and periodontal diseases.
AB  - This position paper on diabetes mellitus was prepared by the Research, Science
      and Therapy Committee of The American Academy of Periodontology. It is intended
      to: 1) update members of the dental profession on the diagnosis and medical
      management of patients with diabetes mellitus; 2) summarize current knowledge on
      the relation between diabetes mellitus and periodontal diseases; 3) provide an
      overview of factors in diabetic patients relevant to understanding the
      pathogenesis of periodontal diseases in these subjects; 4) outline special
      considerations associated with treatment of periodontal diseases in diabetic
      patients; and 5) discuss possible approaches to the management of diabetic
      emergencies in the dental office. Reliance on this position paper in patient
      management will not guarantee a successful outcome. Periodontal diseases often
      involve numerous and complex causes and symptoms. Ultimately, decisions regarding
      the diagnosis and treatment of disease in an individual patient must be made by
      the treating practitioner in light of the specific facts presented by that
      patient.

PMID- 8667139
TI  - The American Academy of Periodontology.

PMID- 8667140
TI  - Periodontal and microbiological changes associated with the placement of
      orthodontic appliances. A review.
AB  - This review examines specific aspects of orthodontic treatment and periodontal
      health, namely the effects of orthodontic banded attachments on periodontal
      disease and more specifically the microflora found around the gingival margins.
      This review highlights critical developments in orthodontic techniques and
      microbiological advances which have helped clarify the interrelationships between
      orthodontic appliances and periodontal disease. Suggestions as to how these may
      be modified are made, as well as targeting specific areas for research.

PMID- 8667141
TI  - Fractures of hydroxyapatite-coated blade implants connected with natural teeth. A
      histological study using SEM, light microscopy, and an image processing system.
AB  - A clinical study was conducted of 59 patients treated with 78 hydroxyapatite (HA)
      coated blade implants from August 1986. Five implants in 5 patients were broken
      at the neck portion, and one implant in one patient was removed from the jaw
      bone. The histological findings around a broken implant which was removed from
      the mandible are presented. These sections showed good adaptation of the bone to
      the implant without a fibrous layer. Histomorphometric evaluation of bone-to
      implant contact showed 73.5%. The scanning electron microscopy image of the
      fractured surface revealed a fatigue fracture. The suspected cause of the
      fracture was stress concentration at the cervix portion, because of excessive
      mobility or deleterious change of abutment teeth. Consequently, the
      osseointegration/biointegration implants should not be connected with natural
      teeth.

PMID- 8667142
TI  - Long-term evaluation of periodontal therapy: I. Response to 4 therapeutic
      modalities.
AB  - Eighty-two periodontal patients were treated in a split mouth design with coronal
      scaling (CS), root planing (RP), modified Widman surgery (MW), and flap with
      osseous resection surgery (FO) which were randomly assigned to various quadrants
      in the dentition. Therapy was performed in 3 phases: non-surgical, surgical, and
      supportive periodontal treatment (SPT) < or = 7 years. Clinical data consisted of
      probing depth (PD), clinical attachment level (CAL), gingival recession (REC),
      bleeding on probing (BOP), suppuration (SUP), and supragingival plaque (PL).
      Because of the necessity to exit many CS treated sites due to breakdown, data for
      CS were reported only up to 2 years. All therapies produced mean PD reduction
      with FO > MW > RP > CS following the surgical phase for all probing depth
      severities. By the end of year 2 there were no differences between the therapies
      in the 1 to 4 mm sites. There were no differences in PD reduction between MW and
      RP treated sites by the end of year 3 in the 5 to 6 mm sites and by the end of
      year 5 in the > or = 7 mm sites. FO produced greater PD reduction in > or = 5 mm
      sites through year 7 of SPT. Following the surgical phase, FO produced a mean CAL
      loss and CS and RP produced a slight gain in 1-4 mm sites. RP and MW produced a
      greater gain of CAL than CS and FO following the surgical phase in 5 to 6 mm
      sites, but the magnitude of difference decreased during SPT. Similar CAL gains
      were produced by RP, MW, and FO in sites > or = 7 mm. These gains were greater
      than that produced by CS and were sustained during SPT. Recession was produced
      with FO > MW > RP > CS. This relationship was maintained throughout SPT. The
      prevalences of BOP, SUP, and PL were greatly reduced throughout the study and
      were comparable between sites treated by RP, MW, and FO while the CS sites had
      more BOP and SUP.

PMID- 8667143
TI  - The Big-Five factor structure as an integrative framework: an analysis of
      Clarke's AVA model.
AB  - Using a large (N = 3,629) sample of participants selected to be representative of
      U.S. working adults in the year 2,000, we provide links between the constructs in
      2 personality models that have been derived from quite different rationales. We
      demonstrate the use of a novel procedure for providing orthogonal Big-Five factor
      scores and use those scores to analyze the scales of the Activity Vector Analysis
      (AVA). We discuss the implications of our many findings both for the science of
      personality assessment and for future research using the AVA model.

PMID- 8667144
TI  - Development and preliminary validation of a self-report measure of psychopathic
      personality traits in noncriminal populations.
AB  - Research on psychopathology has been hindered by persisting difficulties and
      controversies regarding its assessment. The primary goals of this set of studies
      were to (a) develop, and initiate the construct validation of, a self-report
      measure that assesses the major personality traits of psychopathy in noncriminal
      populations and (b) clarify the nature of these traits via an exploratory
      approach to test construction. This measure, the Psychopathic Personality
      Inventory (PPI), was developed by writing items to assess a large number of
      personality domains relevant to psychopathy and performing successive item-level
      factor analyses and revisions on three undergraduate samples. The PPI total score
      and its eight subscales were found to possess satisfactory internal consistency
      and test-retest reliability. In four studies with undergraduates, the PPI and its
      subscales exhibited a promising pattern of convergent and discriminant validity
      with self-report, psychiatric interview, observer rating, and family history
      data. In addition, the PPI total score demonstrated incremental validity relative
      to several commonly used self-report psychopathy-related measures. Future
      construct validation studies, unresolved conceptual issues regarding the
      assessment of psychopathy, and potential research uses of the PPI are outlined.

PMID- 8667145
TI  - Dissociative trance disorder: clinical and Rorschach findings in ten persons
      reporting demon possession and treated by exorcism.
AB  - Although dissociative trance disorders, especially possession disorder, are
      probably more common than is usually though, precise clinical data are lacking.
      Ten persons undergoing exorcisms for devil trance possession state were studied
      with the Dissociative Disorders Diagnostic Schedule and the Rorschach test. These
      persons had many traits in common with dissociative identity disorder patients.
      They were overwhelmed by paranormal experiences. Despite claiming possession by a
      demon, most of them managed to maintain normal social functioning. Rorschach
      findings showed that these persons had a complex personality organization: Some
      of them displayed a tendency to oversimplify stimulus perception whereas others
      seemed more committed to psychological complexity. Most had severe impairment of
      reality testing, and 6 of the participants had an extratensive coping stile. In
      this group of persons reporting demon possession, dissociative trance disorder
      seems to be a distinct clinical manifestation of a dissociative continuum,
      sharing some features with dissociative identity disorder.

PMID- 8667146
TI  - A comparison of Culture-Free Self-Esteem Scale means from different child and
      adolescent groups.
AB  - The Culture-Free Self-Esteem Inventory (CFSEI-2) was administered to 7 groups of
      children: 84 White Catholic school students from a New Orleans suburb, 78 White
      rural public school students from Virginia, 62 Hispanic Migrant student from
      Florida, 90 Aboriginal and White students from an isolated Canadian community,
      199 African American students attending an inner city school, 60 Hispanic and
      White international students from Venezuela, and 61 Innuit students from isolated
      community in Labrador. The four elder groups also wrote three words to describe
      themselves (the Adjective Generation Technique [AGT]). Significant differences in
      responding between groups were found on all CFSEI-2 scales and for AGT
      favorability means. Although several possible reasons for these results are
      discussed, we conclude that the CFSEI-2 is not culture-free. Recommendations are:
      change the title of the test to avoid misrepresentation, limit test usage to
      elementary school children, develop an adolescent version with age appropriate
      language, and construct local norms before using the CFSEI-2 to make decisions
      about a child's self-esteem. To determine relevance of scores, a team of
      professionals and lay persons should review items from this or any test given to
      children who may be different from the normative or standardization group.

PMID- 8667147
TI  - Relationships of objective and projective dependency scores to sex role
      orientation in college student participants.
AB  - Research on the dependency-sex role orientation relationship indicates that when
      objective dependency measures are used, participants show positive correlations
      between dependency and femininity scores, and negative correlations between
      dependency and masculinity scores. In this study, a mixed-sex sample of 87
      undergraduates (47 women and 40 men) completed widely used objective and
      projective measures of dependency, and a self-report measure of sex role
      orientation. Consistent with previous studies in this area, high objective
      dependency scores were associated with high femininity scores and low masculinity
      scores in participants of both sexes. There were no relationships between
      projective dependency scores and sex role orientation scores in participants of
      either sex. Findings are discussed in the context of theoretical frameworks that
      distinguish "implicit" dependency needs from "self-attributed" dependency needs.
      The role that sex role socialization experiences play in determining
      participants' willingness to acknowledge dependency-related traits and behaviors
      on self-report tests is also discussed.

PMID- 8667148
TI  - Comparative validity of MMPI-2 and MCMI-II personality disorder classifications.
AB  - Minnesota Multiphasic Personality Inventory-2 (MMPI-2) overlapping and
      nonoverlapping scales were demonstrated to perform comparably to their original
      MMPI forms. They were then evaluated for convergent and discriminant validity
      with the Million Clinical Multiaxial Inventory-II (MCMI-II) personality disorder
      scales. The MMPI-2 and MCMI-II personality disorder scales demonstrated
      convergent and discriminant coefficients similar to their original forms.
      However, the MMPI-2 personality scales classified significantly more of the
      sample as Dramatic, whereas the MCMI-II diagnosed more of the sample as Anxious.
      Furthermore, single-scale and 2-point code type classification rates were quite
      low, indicating that at the level of the individual, the personality disorder
      scales are not measuring comparable constructs. Hence, each instrument is
      providing similar and unique information, justifying their continued use together
      for the purpose of diagnosing personality disorders.

PMID- 8667149
TI  - Personality styles and dynamics of Alaska Native and nonnative incarcerated men.
AB  - The Rorschach and Million Clinical Multiaxial Inventory-II (MCMI-II) were used to
      examine personality styles and dynamics of 73 incarcerated Alaska Native and
      nonnative men. There were clear differences between native and nonnative inmates
      on both the MCMI-II and the Rorschach. Also, when the participants were separated
      into bicultural, assimilated, and traditional groups, the bicultural group had
      the most difficulties in coping and in interpersonal relationships. The results
      of this study suggest that the profile for offenders is not the same for Alaska
      natives and nonnatives. Culture and cultural styles may contribute to create a
      significantly different type of "criminal personality" seen in forensic settings.

PMID- 8667150
TI  - The community connection.

PMID- 8667151
TI  - Infants with bronchopulmonary dysplasia: a developmental perspective.
AB  - Infants with bronchopulmonary dysplasia (BPD) are medically fragile and
      developmentally at risk for neuromotor and sensory delays. long-term
      neurodevelopmental outcomes can be positively impacted by an organized and
      purposeful program of developmental follow-up and early intervention. Nurses play
      an integral role in provision and coordination of the multifaceted health care
      required by these medically fragile infants.

PMID- 8667152
TI  - Factors influencing parent decision making about pediatric cardiac
      transplantation.
AB  - The purpose of this prospective qualitative study was to investigate factors that
      influenced 15 parental decision-making situations regarding pediatric heart
      transplantation for children with end-stage heart disease. Twenty-four parents of
      15 children, ranging in age from 1 day to 16 years, who had been given the heart
      transplantation option were inducted into the study as a convenience sample. All
      24 parents were either interviewed (n = 18) or observed at some point during the
      decision-making process. Data collection strategies included participant
      observation and in-depth interviews. Data were coded into relevant themes and
      then clustered into categories; concurrent coding and analysis continued until
      new categories were no longer found. Predominant factors identified that
      influenced parental decision making were (a) psychological/emotional, (b)
      familial, and (c) social factors, and (d) physician endorsement of a treatment
      option. In 10 of the 15 situations, family beliefs and values were the main
      parental decision-making factors. Ten families chose transplantation for their
      child; 5 decided against the procedure. Pediatric nurses have central roles in
      facilitating parent-health professional communication in complex decision making
      concerning treatment alternatives of children.

PMID- 8667153
TI  - Pain responses of hospitalized infants and children to venipuncture and
      intravenous cannulation.
AB  - The purpose of this study was to describe the experience of pain in infants and
      children in response to venipuncture and intravenous cannulation. Data on
      physiological, behavioral, and subjective responses were collected from 90
      infants and children, in subgroups of 1 to 12 months, 1 to 3 years, 4 to 6 years,
      and 7 to 12 years. Changes in behavior were significant in all four groups,
      although the toddler group was the only group that showed a significant
      physiological change. The subjective measures showed that the children were able
      to identify their pain sites and intensity.

PMID- 8667154
TI  - Use of occlusive dressings on central venous catheter sites in hospitalized
      children.
AB  - Although the use of occlusive dressings in adults has been criticized in the
      literature, there has been little written on their use in the pediatric
      population. Management of dressing sites requires nursing judgement unique to
      this population. This study focused on the progression of microbial colonization
      and signs of inflammation occurring beneath repeated occlusive dressings applied
      to central venous catheter (CVC) insertion sites among 104 hospitalized children
      (neonate to 18 years). A noninvasive skin culture was obtained within 24 hours of
      CVC placement, 3 to 7 days later before the next routine dressing change, and at
      the time the CVC was discontinued or the child was discharged, whichever occurred
      first. Results showed a significant increase in microbial growth (p < or = .001)
      at the second dressing change, when serosanguinous drainage was heaviest, and
      continued significant growth (p < or = .001) when the dressing was discontinued.
      This microbial growth pattern was curious in the face of a 0.3% systemic sepsis
      rate. When neonates under 1,800 g were excluded from calculation, the pattern was
      not notable (p = .2119). Findings suggest the use of occlusive dressings during
      prolonged hospitalization for tunnelled CVCs does not lead to increased site
      infections in children over 1,800 g.

PMID- 8667155
TI  - The adolescent with slipped capital femoral epiphysis.
AB  - Slipped capital femoral epiphysis (SCFE) is an orthopedic disorder that occurs
      primarily in individuals in their early teen years. The disorder is one that
      requires immediate hospitalization for treatment purposes. This article discusses
      the symptoms of the disorder and the various treatments that are available for
      preventing future disability for the early adolescent. Because the adolescent has
      special needs and a long recovery period, nursing interventions must not only
      help in the resolution of the immediate orthopedic problems, but also be directed
      toward promotion of normal adolescent growth and development.

PMID- 8667156
TI  - Having a future: sexual decision making in early adolescence.
AB  - There is meager information about how adolescents decide to become sexually
      active and use protection against pregnancy and disease. The purpose of this
      project was to explore the thinking of adolescents, ages 12 to 14, about becoming
      sexually active and using protection during sexual encounters. In a health class,
      45 adolescents responded to questions about influences on having sex and using
      protection. Short-answer, written responses were analyzed using Heideggerian
      hermeneutic interpretation. The reflections of youth faced with sexual decision
      making focused on self-protection against pregnancy and disease. Postponing
      sexuality or using protection meant having a future, one that could hold the
      promise of love, marriage, and desired children.

PMID- 8667157
TI  - The use of Medicaid managed care: a case study of two states.

PMID- 8667158
TI  - Maintaining the creative edge during health care reform.

PMID- 8667159
TI  - International cooperation for improving pediatric nursing.

PMID- 8667160
TI  - Enhancing self-esteem by directed-thinking tasks: cognitive and affective
      positivity asymmetries.
AB  - Insofar as people organize information about and evaluations of important topics
      in connected and coherent systems, attitudes may be changed from within by
      enhancing the salience of information already present virtually within the
      person's belief system without communicating new information from outside
      sources. A cognitive positivity bias is predicted such that stimulus evaluation
      (e.g., self-esteem) is affected more by characteristics that the stimulus
      possesses than by ones it lacks. Experiment 1 tested relations between
      participants' momentary self-esteem and concurrently salient desirable (vs.
      undesirable) self-characteristics possessed (vs. lacked). Experiments 2 and 3
      changed participants' self-esteem by using directed-thinking tasks to manipulate
      the salience of desirable (vs. undesirable) self-characteristics possessed (and,
      to a lesser extent, lacked).

PMID- 8667161
TI  - Development and mental representation of stereotypes.
AB  - A mixed model of stereotype representation was tested. Experiment 1 examined the
      development of stereotypes about novel groups. Results showed that, at low levels
      of experience, stereotypic group knowledge is derived from information about
      particular group exemplars. However, as experience increases, an abstract group
      stereotype is formed that is stored and retrieved independently of the exemplars
      on which it was based. Results of Experiment 2 suggest that preexisting
      stereotypes about well-known groups are represented as abstract structures in
      memory. These results indicate that stereotypical knowledge is most likely to be
      exemplar-based in the absence of abstract stereotypes. The implications of these
      findings for other aspects of stereotyping and social perception are discussed.

PMID- 8667162
TI  - Strategic self-promotion and competitor derogation: sex and context effects on
      the perceived effectiveness of mate attraction tactics.
AB  - In this article, 7 evolutionary hypotheses about the context-specific nature of
      mate attraction effectiveness were empirically tested and supported. In the
      context of short-term mating, for example, men have faced the adaptive problem of
      finding sexually accessible women. As a result, men express a preference for
      sexually availability in short-term mates. In Studies 1 and 2, separate groups of
      undergraduate participants judged sexual availability tactics as most effective
      when used by women seeking short-term mates, confirming the hypothesized link
      between the judged effectiveness of mate attraction tactics used by one sex and
      the expressed mate preferences of the other. Showing resource potential was
      judged most effective for men seeking a long-term mate, whereas giving resources
      immediately was judged most effective for men seeking short-term mates,
      confirming the hypothesized importance of temporal context in mate attraction
      effectiveness. Discussion focuses on the context-specificity of human mating
      psychology and on linking evolutionary and traditional approaches to romantic
      attraction.

PMID- 8667163
TI  - A nonverbal signal in voices of interview partners effectively predicts
      communication accommodation and social status perceptions.
AB  - Derivations from nonverbal communications accommodation theory are tested, and
      this knowledge is extended both theoretically and methodologically. Fast fourier
      transform and statistical analysis of a low-frequency nonverbal signal-in voices
      from 25 dyadic interviews between a talk show host and his guests revealed voice
      convergence between partners. Correlation coefficients from comparisons of
      partners' voice spectra and factor analysis of the correlation matrix showed that
      lower status partners accommodated their voices to higher status partners via the
      nonverbal signal. Student ratings of the social status of the same talk show host
      and guests were correlated with factor loadings, thereby providing convergent
      validity of the nonverbal signal as a predictor of social status perceptions and
      accommodation.

PMID- 8667164
TI  - The role of loneliness and social support in adjustment to loss: a test of
      attachment versus stress theory.
AB  - A longitudinal study of a matched sample of 60 recently widowed and 60 married
      men and women tested predictions from stress and attachment theory regarding the
      role of social support in adjustment to bereavement. Stress theory predicts a
      buffering effect, attributing the impact of bereavement on well-being to
      stressful deficits caused by the loss and assuming that these deficits can be
      compensated through social support. In contrast, attachment theory denies that
      supportive friends can compensate the loss of an attachment figure and predicts
      main effects of marital status and social support. Attachment theory further
      suggests that marital status and social support influence well-being by different
      pathways, with the impact of marital status mediated by emotional loneliness and
      the impact of social support mediated by social loneliness. Results clearly
      supported attachment theory.

PMID- 8667165
TI  - The relation between overly positive self-evaluation and adjustment: a comment on
      Colvin, Block, and Funder (1995)
AB  - C.R. Colvin, J. Block, and D.C. Funder (1995) calculated a self-enhancement index
      the discrepancy between favorability of participants' self-ratings and
      favorability of others' ratings of the participants. They found that the index
      was negatively correlated with psychological adjustment. However, the discrepancy
      between self- and other-ratings cannot add to the variance accounted for once
      self-ratings and other-ratings are controlled for. Consequently, the index cannot
      properly be used to examine how self-enhancement influences adjustment. An
      appropriate test for the self-enhancement effect is the interaction between
      favorability of self- and other-ratings.

PMID- 8667167
TI  - Environmental and personal determinants of support perceptions: three
      generalizability studies.
AB  - The extent to which perceived social support reflects characteristics of the
      environment, the personality of the perceiver, and their interaction is unknown.
      This article shows how the methods of generalizability theory can be used to
      address these questions. When participants rate the same targets on the targets'
      supportiveness, generalizability theory provides methods for determining the
      extent to which support judgments are determined by effects due to targets
      (supporters), perceivers, and their interaction. In 3 studies, each source of
      variance made significant contributions to support judgments, with the Perceivers
      x Supporters interaction, characteristics of supporters, and biases of perceivers
      making the largest contributions, respectively. The implications for theoretical
      models of perceived support are discussed.

PMID- 8667166
TI  - Are shame, guilt, and embarrassment distinct emotions?
AB  - 182 undergraduates described personal embarrassment, shame, and guilt experiences
      and rated these experiences on structural and phenomenological dimensions.
      Contrary to popular belief, shame was no more likely than guilt to be experienced
      in "public" situations; all 3 emotions typically occurred in social contexts, but
      a significant proportion of shame and guilt events occurred when respondents were
      alone. Analyses of participants' phenomenological ratings clearly demonstrated
      that shame, guilt, and embarrassment are not merely different terms for the same
      affective experience. In particular, embarrassment was a relatively distant
      neighbor of shame and guilt, and the differences among the 3 could not be
      explained simply by intensity of affect or by degree of moral transgression.
      Finally, participants generally were their own harshest critics in each type of
      event, evaluating themselves more negatively than they believed others did.

PMID- 8667168
TI  - Assessing the MMPI-based Cook-Medley Hostility Scale: the implications of
      dimensionality.
AB  - The Minnesota Multiphasic Personality Inventory- (MMPI-) based Cook-Medley
      Hostility scale (Cook & Medley, 1954) historically has been used to investigate
      links between personality factors and health outcomes. We assessed the
      dimensionality of 27 Cook-Medley items previously found to predict mortality
      using full-information maximum likelihood factor analysis. The factor analyses
      revealed that these items serve as indicators for several constructs, with some
      factors apparently reflecting word usage rather than a meaningful psychological
      dimension. Our analyses indicate that the psychological meaning of these
      (sub)scales is ambiguous and differs according to the respondent's gender. The
      findings are discussed in the context of evidence to support the construct
      validity of the scale and the implications of dimensionality for making
      inferences concerning the link among scale scores, personality factors, and
      health outcomes.

PMID- 8667170
TI  - On fighting versus accepting stressful circumstances: primary and secondary
      control among HIV-positive men in prison.
AB  - The primacy of primary control over secondary control and ethnic differences in
      control processes were tested in HIV-positive male state prison inmates. They
      rated their perceptions of control and psychological distress at an initial
      interview (N = 95) and 3 months later (N = 78). Regression analyses revealed that
      primary control had primacy as it had greater adaptive value. However, secondary
      control did not function as a backup to primary control, and temporal differences
      in control were not found. No mean differences due to ethnicity (African American
      vs. White) were found, but there was a strong ethnic difference in the effects of
      primary control. White participants showed the expected negative relationship
      between distress and primary control, but African American participants did not.
      The idea that the benefits of primary control would be the same across various
      subcultures was not supported.

PMID- 8667169
TI  - Female and male personality styles: a typological and developmental analysis.
AB  - The personality styles of 137 women and 138 men aged 27 years were examined in an
      ongoing Finnish longitudinal study in which the participants were first assessed
      at age 8. Data were collected by means of a mailed questionnaire, personality
      inventories, and a semistructured interview. Variables covered personality
      characteristics, life orientation, and behavioral activities. Both women and men
      fell into two major clusters, the adjusted (3/4) and the conflicted (1/4). Both
      clusters divided into subclusters; altogether, 7 were extracted for women and men
      replicating the personality types obtained by J. Block (1971) despite the use of
      a different methodology in a different culture. The clusters had roots in
      individuals' emotional and behavioral regulation from the early school years
      onward, and they also predicted personality characteristics over a period of 6
      years when the Big Five personality factors were used as criteria.

PMID- 8667171
TI  - Repressive emotional discreteness after failure.
AB  - The relationship between coping dispositions and emotional responses after
      failure in an anagram task was examined. Previous research indicated that only
      repressers' nondominant emotions were less intense compared to nonrepressers',
      whereas the dominant emotion was of equal intensity. Using an experimental design
      in which emotions were measured as they were actually felt, the authors were able
      to demonstrate that this effect, called repressive emotional discreteness, also
      is apparent during an emotional event. Compared to nonrepressers, repressers
      reported roughly the same amount of guilt, which was the dominant emotion after
      failure, but they showed lower self-rated fear, sadness, and hostility. No
      differential effects were observed regarding positive emotions after success,
      indicating that repressive discreteness is restricted to negative emotions. The
      implications of these findings for explaining the mechanism underlying repression
      are discussed.

PMID- 8667172
TI  - Implications of rejection sensitivity for intimate relationships.
AB  - People who are sensitive to social rejection tend to anxiously expect, readily
      perceive, and overreact to it. This article shows that this cognitive-affective
      processing disposition undermines intimate relationships. Study 1 describes a
      measure that operationalizes the anxious-expectations component of rejection
      sensitivity. Study 2 provides experimental evidence that people who anxiously
      expect rejection readily perceive intentional rejection in the ambiguous behavior
      of others. Study 3 shows that people who enter romantic relationships with
      anxious expectations of rejection readily perceive intentional rejection in the
      insensitive behavior of their new partners. Study 4 demonstrates that rejection
      sensitive people and their romantic partners are dissatisfied with their
      relationships. Rejection-sensitive men's jealousy and rejection-sensitive women's
      hostility and diminished supportiveness help explain their partners'
      dissatisfaction.

PMID- 8667173
TI  - Development of silastic polyurethane (Angioflex) materials with antibacterial
      agent.
AB  - Bioimplants incorporated with antimicrobial agents are needed to control Foreign
      Body Associated Infection (FBAI) in clinical settings. Attempts are made here to
      develop five different types of polyurethane (Angioflex), viz., (1) bare polymer,
      (2) bare polymer glow discharged, (3) bare polymer coated with chlorhexidine, (4)
      chlorhexidine coated polymer glow discharged, and (5) material (4) recoated with
      another layer of chlorhexidine digluconate. These materials are tested for their
      in vitro antibacterial effects using disc diffusion technique against five
      different standard clinical staphylococcus strains, viz., Wood 46 (Staph.
      aureus), A 182 (Staph. epidermidis), A 313 (Staph. epidermidis), A 61 (Staph.
      epidermidis), and A 72 (Staph. epidermidis). Maximum antibacterial effects (zone
      of inhibition) are observed with polyurethanes incorporated with chlorhexidine
      digluconate (3) and chlorhexidine incorporated and glow discharged (4). Findings
      of this study indicate that glow discharge does not seem to produce either
      additive 8r synergistic antibacterial effects with chlorhexidine digluconate
      coated Angioflex material.

PMID- 8667174
TI  - The effect of modification of acrylic resins on controlled release and
      bioadhesion.
AB  - The effect of various treatments on the properties of an acrylic matrix was
      studied, in terms of its swelling properties in buffer solution. The release of
      two types of drugs from those matrices and their bioadhesive character were also
      considered. Calcium stearate and sodium lauryl sulfate were used as additives for
      the matrix treatment. 2-Hydroxyethyl methacrylate was also used as a reactive
      agent for the acrylic resin treatment. The main function of the above chemicals
      is the modification of the hydrophilic/hydrophobic character of the matrix. This
      investigation showed that controlled release systems can be designed by adjusting
      the matrix properties via additives or chemical reaction.

PMID- 8667176
TI  - The creep behavior of acrylic denture base resins.
AB  - The creep behavior of acrylic dental base resins, at room temperature and at
      different loading conditions, has been examined. The behaviors of these resins
      are similar to that of "commercial perspex" at room temperature over a period of
      1000 seconds. The pseudo-elastic moduli of the blends of PMMA VC show a
      significant increase compared with PMMA alone. The addition of the PVC powder to
      the heat-cured acrylic resin increased the time-dependent elastic modulus. This
      increase in elastic modulus is advantageous in the production of denture based
      resins of improv mechanical properties.

PMID- 8667175
TI  - Enhancement of neovascularization in regenerating skeletal muscle by the
      sustained release of erucamide from a polymer matrix.
AB  - The angiogenic agent erucamide (cis-13-docosenamide), incorporated into a
      polymeric biomaterial (Elvax 40P, a copolymer of ethylene and vinyl acetate), was
      used to determine whether angiogenesis can be increased in the regenerating
      skeletal muscle, and whether the enhanced revascularization improves the new
      muscle formation. The angiogenic nature of this lipid was confirmed in a rat
      cornea-micropocket assay, prior to insertion of small strips of the polymer
      containing either 3 micrograms, 300 micrograms erucamide or only polymer as a
      control into the mid-region of crush-injured tibialis anterior (TA) muscles of
      forty-five adult male BALB/c mice. All TA muscles were sampled ten days after
      injury and analyzed morphometrically. Statistical analyses of the mean blood
      vessel area density in lesions from twelve perfused TA muscles (three from each
      of the erucamide-treated or control group), revealed a dose-dependent angiogenic
      effect of erucamide: a dosage of 3 micrograms increased mean blood vessel area
      density to 5.1% compared to 2.0% in controls, due to numerous large caliber, thin
      walled vessels, whereas the mean vessel area density in both the 30-micrograms
      (3.5%) and 300-micrograms (1.5%) doses were similar to controls. However, at all
      three doses tested, erucamide did not significantly alter the degree of new
      muscle formation, connective tissue deposition, or removal of necrotic debris.

PMID- 8667177
TI  - Use of digitalis glycosides to identify the mechanisms of amantadine transport by
      renal tubules.
AB  - The mechanism(s) for uptake of organic cations by renal cortical tubules was
      (were) examined further. Renal cortical tubules were purified from rat kidneys by
      a Percoll gradient centrifugation technique. Bicarbonate buffer (Krebs-Henseleit,
      KHS) conditions were altered, and chemical modulators were used which affect the
      activity of the basolateral Na+/K+-ATPase. Renal tubule uptake of the achiral
      organic cation amantadine was determined. The cardiac glycosides digoxin and
      acetylstrophanthidin and ouabagenin did not alter amantadine uptake by either
      proximal or distal tubule fragments in KHS. However, ouabain inhibited proximal
      tubule amantadine uptake in a dose-dependent manner with lower potency than
      distal tubule amantadine uptake in KHS. Ouabain did not inhibit amantadine tubule
      uptake in phosphate buffer. However, inhibition of amantadine uptake by ouabain
      returned in a time-dependent manner upon addition of bicarbonate to the phosphate
      buffer. Low extracellular sodium or potassium did not alter amantadine uptake by
      proximal tubules. Hypokalemic and hypokalemic/ hyponatremic conditions decreased
      the inhibitory potency of ouabain for amantadine uptake by proximal tubules. For
      distal tubules, both hyponatremic and hypokalemic conditions, alone and together,
      decreased the inhibitory potency of ouabain, but did not affect amantadine uptake
      in the absence of ouabain. Hypochloremic conditions decreased affinity for
      amantadine uptake by distal, but not proximal tubules. No change in maximal
      transport capacity for amantadine uptake was observed under hypochloremic
      conditions for either tubule fragment. These studies challenge the widely
      accepted concept of Na+/ K+-adenosine triphosphatase activity and maintenance of
      the basolateral membrane potential as rate-limiting steps for the energy
      dependent renal tubule uptake of organic cations. Furthermore, these studies
      suggest a mechanism for ouabain inhibition of organic cation renal tubule uptake
      that may not involve the Na+/K+-adenosine triphosphatase and may be possibly
      bicarbonate-dependent.

PMID- 8667178
TI  - Possible contribution of platelet cyclooxygenase to the renal vascular action of
      5,6-epoxyeicosatrienoic acid.
AB  - 5,6-Epoxyeicosatrienoic acid (5,6-EET), a cytochrome P450-dependent arachidonate
      product, is a substrate for cyclooxygenase (COX) and, in some vascular
      preparations, elicits COX-dependent vasodilation. In the blood perfused rat
      kidney, 5,6-EET causes COX-dependent renal vasoconstriction, whereas in the rat
      isolated kidney perfused with a physiological buffer, 5,6-EET produces dose
      dependent vasodilation that is unaffected by indomethacin. We examined the
      possible contribution of platelet COX to the vasoconstrictor action of 5,6-EET.
      Incubation of labeled 5,6-EET with rat washed platelets yields additional
      products that elute between 14 to 17 min on high-performance liquid
      chromatography (HPLC) and cause constriction of the perfused kidney. Indomethacin
      decreased the formation of these products and reduced the vasoconstrictor
      capacity of the corresponding HPLC fractions. Thus, platelet COX can metabolize
      5,6-EET to vasoconstrictor products that may contribute to the in vivo
      vasoconstrictor effect of this eicosanoid.

PMID- 8667179
TI  - The zinc pool is involved in the immune-reconstituting effect of melatonin in
      pinealectomized mice.
AB  - Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An
      involvement of the zinc pool in the immune-reconstituting effect of MEL in old
      mice has recently been documented. An altered zinc turnover and impaired immune
      functions are also evident in pinealectomized (px) mice. The present work
      investigates further the effect of "physiological" doses of MEL on the zinc pool
      and on thymic and peripheral immune functions in px mice. Daily injections of MEL
      (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance
      from negative to positive values. Thymic and peripheral immune functions,
      including plasma levels of interleukin-2, also recovered. The nontoxic effect of
      MEL on immune functions was observed in sham-operated mice. Because the half-life
      of MEL is very short (12 min), interruption of MEL treatment in px mice resulted,
      after 1 month, in a renewed negative crude zinc balance and a regression of
      immune functions. Both the zinc pool and immunological parameters were restored
      by 30 further days of MEL treatment. The existence of a significant correlation
      between zinc and thymic hormone after both cycles of MEL treatment clearly shows
      an involvement of the zinc pool in the immunoenhancing effects of MEL and thus
      suggests an inter-relationship between zinc and MEL in px mice. Moreover, the
      existence of significant positive correlations between zinc or thymulin and
      interleukin-2 suggests that interleukin-2 may participate in the action of MEL,
      via zinc, on thymic functions in px MEL-treated mice.

PMID- 8667180
TI  - Catecholamine secretion induced by nicotine is due to Ca++ channel but not Na+
      channel activation in porcine adrenal chromaffin cells.
AB  - Secretion induced by nicotinic agonists in adrenal chromaffin cells depends on
      membrane depolarization produced by the opening of nicotinic receptor channels.
      It is generally believed that membrane depolarization activates voltage-gated Na+
      channels, leading to the generation of action potentials and the subsequent
      activation of voltage-gated Ca++ channels. However, our results indicate that, in
      cultured porcine chromaffin cells, Na+ channels and action potentials play little
      role in nicotine-induced secretion. Although removal of extracellular Na+ blocked
      secretion produced by nicotine, tetrodotoxin, which abolished voltage-activated
      Na+ currents, had no effect on nicotine-induced secretion, even at low nicotine
      concentrations. The blocking effect of Na+ removal on nicotine-induced secretion
      could be reversed by adding excess extracellular Ca++ (20 mM), a reversal which
      was inhibited by the dihydropyridine Ca++ channel blocker, nimodipine (2 microM).
      Nimodipine also blocked nicotine-induced secretion under normal ionic conditions,
      but had little effect on nicotine-induced depolarization. When measured using a
      perforated patch (nystatin), current clamp technique, nicotine produced a rapid
      and sustained depolarization which included an initial volley of 1 to 15 action
      potentials. In contrast, when measured using a standard whole-cell, current clamp
      configuration, nicotine produced a slower depolarization and numerous action
      potentials. These results suggest that voltage-gated Ca++ channels in porcine
      chromaffin cells are activated directly by persistent depolarization produced by
      Na+ entry through the nicotinic receptor channel under normal ionic conditions,
      and by Ca++ entry through the nicotinic receptor channel in the absence of Na+,
      but the presence of high extracellular Ca++.

PMID- 8667181
TI  - ATP-sensitive potassium channel modulators: both pinacidil and glibenclamide
      produce antiarrhythmic activity during acute myocardial infarction in conscious
      rats.
AB  - We investigated the effects of pinacidil, an ATP-sensitive potassium channel
      opener, and of glibenclamide, an ATP-sensitive potassium channel inhibitor, on
      the incidence of arrhythmias and sudden cardiac death after coronary artery
      ligation in conscious rats. Occlusion of the left main coronary artery was
      produced by tightening a previously placed loose silk ligature. In the control
      group (n = 25) only 40% and 24% of the animals survived for 15 min and 16 hr
      after coronary artery ligation, respectively. Intravenous pretreatment with 0.1,
      0.3 or 1 mg/kg pinacidil increased the survival rate to 67% (n = 15), 70% (n =
      20) and 67% (n = 12) in the first 15 min and to 60%, 55% and 67% in the first 16
      hr, respectively. Glibenclamide pretreatment (5.0 mg/kg i.p.) improved the
      survival rate at both time-points to 87% (n = 16). Both types of pretreatment
      significantly decreased the incidence of life-threatening arrhythmias and
      increased the number of animals that survived without developing any arrhythmia.
      In conclusion, the present findings demonstrate that in conscious rats,
      pretreatment with pinacidil and pretreatment with glibenclamide, although they
      obviously have different mechanisms of action, may result in a very similar final
      outcome with respect to arrhythmias and sudden cardiac death during the acute
      phase of experimental myocardial infarction.

PMID- 8667182
TI  - Zwitterionic phospholipids enhance aspirin's therapeutic activity, as
      demonstrated in rodent model systems.
AB  - We have recently reported that the Gl toxicity of aspirin is markedly reduced
      when the drug is preassociated with the zwitterionic phospholipid
      dipalmitoylphosphatidycholine (DPPC) before intragastric administration. The
      present study was designed to determine whether the biological availability and
      therapeutic activity of aspirin were affected by chemically associating the drug
      with DPPC. To evaluate this, we compared the kinetics of entry of labeled aspirin
      into the blood, after intragastric administration of the drug in the free and
      lipid-associated states; we also tested the ability of the above formulations to
      inhibit fever, inflammation and pain in appropriate rodent model systems. We
      found that although the Gl absorption of free aspirin and that of the
      aspirin/DPPC complex were similar, in all three rodent models the complex had
      significantly greater antipyretic, anti-inflammatory and analgesic efficacy than
      aspirin alone. Dose-response analyses employing the fever model demonstrated that
      potency of aspirin to reduce fever was increased 5 to 10-fold when the aspirin
      was intragastrically administered in the lipid-associated state. We conclude that
      the therapeutic activity of aspirin to inhibit fever, inflammation and pain is
      remarkably enhanced when the drug is intragastrically administered in chemical
      association with the zwitterionic phospholipid DPPC. A number of molecular
      mechanisms have been proposed to explain the observed phospholipid-dependent
      increase in aspirin's therapeutic activity.

PMID- 8667183
TI  - Comparative clinical pharmacology of short-acting mu opioids in drug abusers.
AB  - The clinical pharmacology of fentanyl and alfentanil was examined in opioid
      experienced volunteers with agonist and antagonist sensitivity measures. Two
      studies used within-subject, placebo-controlled, crossover designs. In study 1,
      fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by
      naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control;
      simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared.
      Fentanyl rapidly constricted pupils, depressed respiration and produced
      subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the
      measure. Naloxone precipitated withdrawal symptoms of comparable intensity at
      each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.),
      alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by
      naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge
      sessions. The two drugs produced a comparable range of effects with similar peak
      magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25
      mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was
      brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg
      fentanyl. These findings support typical mu opioid characteristics (pleasurable
      subjective effects, physical dependence) for both drugs, differential duration of
      action (fentanyl > alfentanil) and peak effects consistent with a 1:8
      (fentanyl/alfentanil) potency ratio.

PMID- 8667184
TI  - Functional antagonistic activity of Rec 15/2739, a novel alpha-1 antagonist
      selective for the lower urinary tract, on noradrenaline-induced contraction of
      human prostate and mesenteric artery.
AB  - The aim of this study was to compare with known reference standards the
      functional in vitro alpha-1 antagonistic activity of Rec 15/2739 on noradrenaline
      induced contractions of human prostate and mesenteric artery. We also
      characterized these tissues with regard to the alpha-1 adrenoceptor subtypes
      present. Comparing the apparent pKB values revealed Rec 15/2739 to be one of the
      most potent compounds action on the prostate. Its potency was slightly lower than
      that of tamsulosin and was higher than the potencies of prazosin, terazosin and 5
      methylurapidil. On the mesenteric artery, tamsulosin was the most potent
      compound. Comparing the results from the functional studies with those obtained
      from radioreceptor binding studies, we found that the potency (pKB value) in
      inhibiting the contraction of prostatic tissue showed a close and significant
      correlation with the affinity for native and recombinant alpha-1A adrenoceptors.
      No significant correlation was found with affinity for either the native or the
      recombinant alpha-1B adrenoceptor subtype, or for recombinant alpha-1d receptors.
      Similar results were obtained for mesenteric artery. In order to characterize
      further the alpha-1 adrenoceptor subtypes present in the examined tissues, we
      investigated the functional effects of chloroethylclonidine, an alpha-1B-D
      subtypes selective alpha-1 adrenoceptor irreversible antagonist, and those of
      nifedipine, which antagonizes the extracellular calcium influx primarily mediated
      by alpha-1A adrenoceptor stimulation. The results indicate the presence of both
      chloroethylclonidine-sensitive and -insensitive alpha-1 adrenoceptor subtypes in
      the human prostate, whereas in mesenteric artery the alpha-1A subtype seems to be
      present exclusively. The possibility that the functionally relevant alpha-1
      adrenoceptor subtype could be classified as alpha-1L in both tissues shoul also
      be considered.

PMID- 8667185
TI  - The effects of eticlopride and naltrexone on responding maintained by food,
      cocaine, heroin and cocaine/heroin combinations in rats.
AB  - In the first experiment, responding was maintained for food under a fixed ratio
      (FR) 10 with a 6-min timeout reinforcement schedule. Eticlopride (0.1-1.0 mg/kg
      i.p.) dose-dependently decreased the number of food pellets obtained, whereas
      naltrexone (3-30 mg/kg i.p.) did not significantly alter responding. In the
      second experiment, intravenous self-administration of cocaine (vehicle, 125, 250
      and 500 micrograms/infusion), heroin (vehicle, 5.4, 9 and 18 micrograms/infusion)
      and cocaine/heroin combinations were maintained under a FR10 reinforcement
      schedule. Cocaine/heroin combinations included the aforementioned cocaine doses
      combined with 5.4 micrograms/infusion heroin (CH5.4) or 18 micrograms/infusion
      heroin (CH18). Cocaine/heroin combinations dose-dependently decreased the number
      of infusions compared with cocaine alone. Eticlopride (0.03-0.3 mg/kg i.p.)
      decreased self-administration of 125 micrograms/infusion cocaine and increased
      self-administration of 500 micrograms/infusion cocaine. Self-administration of
      250 micrograms/infusion cocaine was increased after 0.03 and 0.1 mg/kg and
      decreased after 0.3 mg/kg eticlopride. Eticlopride decreased heroin self
      administration, an effect which may be attributable to its rate-decreasing
      effects. Eticlopride partially reversed the downward shift of the CH5.4 group but
      did not reverse the effect in the CH18 group. Naltrexone (1.0-10.0 mg/kg i.p.)
      decreased self-administration of 5.4 micrograms/infusion heroin and increased
      self-administration of 18 micrograms/infusion heroin. Self-administration of 9
      micrograms/infusion heroin was increased by 1.0 mg/kg, not affected by 3.0 mg/kg
      and decreased by 10.0 mg/kg naltrexone. For the CH5.4 and CH18 groups, naltrexone
      dose-dependently shifted the dose-effect curves toward the cocaine dose-effect
      curve. Therefore, self-administration of cocaine/heroine combinations can be
      maintained in the rat and downward shifts in the cocaine dose-effect curve after
      combination with heroin are mediated through a naltrexone-sensitive mechanism.

PMID- 8667186
TI  - Lack of 5-hydroxytryptamine1A-mediated inhibition of adenylyl cyclase in dorsal
      raphe of male and female rats.
AB  - In the rat hippocampus, 5-hydroxytryptamine (5-HT)1A receptors couple to two
      independent effector mechanisms, the inhibition of adenylyl cyclase activity and
      the opening of a K+ channel. In the dorsal raphe, 5-HT1A receptors also open K+
      channels; however, coupling to adenylyl cyclase has not been demonstrated. In
      this study, the selective 5-HT1A agonists (+/-)- 8-hydroxy-2-(di-n
      propylamino)tetralin, (R+)-8-hydroxy-2-(di-n-propylamino)tetralin and dipropyl-5
      carboxamidotryptamine, did not inhibit forskolin-stimulated adenylyl cyclase
      (FSAC) activity in raphe region homogenates, although these drugs were
      efficacious in hippocampal homogenates. Other 5-HT1A agonists, NAN-190, BMY-7378,
      buspirone and gepirone, were also ineffective in raphe region homogenates.
      Estrogen-treatment of ovariectomized female rats, which is known to enhance 5
      HT1A-mediated inhibition of FSAC in the hippocampus, did not promote the action
      of 5-HT1A agonists. Nor did activation of 5-HT1A receptors stimulate basal
      adenylyl cyclase activity in raphe homogenates as it does in the hippocampus.
      FSAC activity was inhibited in raphe region homogenates by activation of
      adenosine A1 or gamma-aminobutyric acidB receptors or by direct activation of the
      inhibitor G-protein, Gi, with guanyl-5'-6'-imidodiphosphate, indicating that the
      raphe homogenates have the biochemical machinery for inhibition of FSAC. High
      affinity binding studies showed that, in raphe homogenates, 5-HT1A receptors were
      expressed at a density comparable to that of adenosine A1 receptors and that they
      were coupled to G-proteins. It should be noted that our failure to observe 5-HT1A
      mediated inhibition of adenylyl cyclase in the raphe does not prove that such
      coupling does not exist. However, a lack of 5-HT1A receptor coupling to adenylyl
      cyclase in the raphe would support contentions that coupling of the 5-HT1A
      receptor to adenylyl cyclase may be independent of its coupling to the K+ channel
      and that there may be distinct differences between pre- and postsynaptic 5-HT1A
      receptor systems.

PMID- 8667187
TI  - Effect of nicotine and nicotinic receptor agonists on latent inhibition in the
      rat.
AB  - The present experiments assessed the influence of nicotinic cholinergic receptors
      on latent inhibition (LI), which is the decrement in Pavlovian conditioning
      resulting from extensive preexposure to a conditioned stimulus (CS). LI was
      assessed within a conditioned emotional response paradigm involving three phases:
      preexposure [either 0 (nonpreexposed) or 60 (preexposed) presentations of a 60
      sec tone], conditioning (two-tone, 0.6 mA; 0.5-sec footshock pairings) and test
      (assessment of CS-induced suppression of lever press responding). LI was obtained
      in that untreated preexposed-animals displayed less conditioned suppression
      compared to nonpreexposed controls. Administration of nicotine (0.4 mg/kg i.p.)
      augmented LI when administered during conditioning. In addition, nicotine
      enhanced LI when administered during preexposure, suggesting that nicotine can
      enhance the ability of an animal to filter irrelevant stimuli. The nicotinic
      agonists cytisine (5 mg/kg) and lobeline (10 mg/kg) also augmented LI. Nicotine
      did not influence the behavior of nonpreexposed animals, suggesting that
      nicotine's effect was specific to mechanisms mediating LI. The nicotinic
      antagonists hexamethonium (10 mg/kg) and mecamylamine (5 mg/kg) reversed
      nicotine's enhancement of LI. Finally, nicotine's effect on LI was found to
      depend upon CS preexposure parameters; nicotine attenuated, rather than enhanced,
      the LI observed after 40 presentations of a 5-sec CS. These results suggest that
      stimulation of nicotine receptors can either amplify or curtail the efficacy of
      mechanisms involved in filtering irrelevant stimuli from further cognitive
      processing and that the direction of this modulation depends on the CS
      preexposure parameters.

PMID- 8667188
TI  - Inogatran, a novel direct low molecular weight thrombin inhibitor, given with,
      but not after, tissue-plasminogen activator, improves thrombolysis.
AB  - Coronary artery often reoccludes after therapy of acute myocardial infarction
      with recombinant tissue plasminogen activator rt-PA, most likely due to in situ
      thrombin generation during thrombolysis. Previous studies with high molecular
      weight thrombin inhibitors, such as hirudin, have shown variable improvement in
      the frequency of sustained thrombolysis. This study was conducted to examine the
      modulation of thrombolysis, indices of thrombin generation and activated partial
      thromboplastin time (APTT) by a novel low molecular weight direct thrombin
      inhibitor, inogatran. A stable occlusive intracoronary thrombus was created in 19
      dogs. Nine dogs were given an intravenous bolus of saline (group A), and 5 dogs
      were given inogatran (group B) followed by rapid infusion of rt-PA (1 mg/kg over
      20 min), whereas saline or inogatran was continuously infused for 2 hr. Five
      other dogs were given inogatran (bolus and continuous infusion) only after
      thrombolysis by rt-PA was obtained (group C). Time to reflow was similar in all
      dogs. None of the reperfused coronary arteries reoccluded in group B dogs (vs.
      75% and 40% reocclusion rates in groups A and C, respectively, P < .02).
      Accordingly, the mean duration of reflow was > 120 min in group B dogs (vs. 39 +/
      7 and 44 +/- 14 min in group A and C dogs, respectively, P < .05). After
      infusion of inogatran, APTT was increased to 1.6 to 1.9 times the base-line
      value, and the changes in APTT were similar in group B and C dogs. Thrombin
      generation and activity, assessed by thrombin-antithrombin complex and
      fibrinopeptide A levels, increased in all dogs during thrombus formation. The
      increase in thrombin-antithrombin complex and fibrinopeptide A levels during
      thrombolysis was not evident in group B dogs. These data show that direct
      thrombin inhibition with inogatran, when initiated before rt-PA, results in
      sustained thrombolysis and only a modest increase in APTT. However, inogatran
      given after thrombolysis only partially prevents reocclusion because large
      amounts of thrombin generation occur during the early stages of thrombolysis.

PMID- 8667189
TI  - Structure-activity relationships for SNC80 and related compounds at cloned human
      delta and mu opioid receptors.
AB  - The racemic compound (+/-)-BW373U86 ?(+/-)-4-((alpha R*)- alpha-((2S*,5R*)-4
      allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy- benzyl)-N,N-diethylbenzamide
      dihydrochloride} is a potent delta opioid receptor agonist in the mouse vas
      deferens assay with little mu or kappa opioid receptor activity in the guinea pig
      ileum tissue preparation. In contrast, radioligand binding studies show that (+/
      )-BW373U86 is only about 10-fold selective for delta over mu opioid receptors.
      Studies of the enantiomeric forms of (+/-)-BW373U86 and derivatives (SNC80 and
      related compounds) show that some of these isomers are significantly better in
      both receptor binding and pharmacological selectivity than (+/-)-BW373U86. In
      this study we have determined the binding affinities of 10 different SNC80
      related compounds at cloned human delta and mu opioid receptors and measured the
      potency of SNC80 for the inhibition of forskolin-stimulated adenylyl cyclase. The
      most selective delta receptor ligand (SNC162) differed from SNC80 by the absence
      of the 3-methoxy substitution of the benzyl ring. The Ki for SNC162 at the delta
      receptor (0.625 nM) was over 8700-fold lower than that at the mu receptor (5500
      nM), making this the most selective delta receptor ligand available. Reduction of
      the allyl side chain of SNC80 to produce radiolabeled [3H]SNC121 allowed direct
      measurement of the association and dissociation rate constants. SNC80 was 26-fold
      less potent than [D-Pen2, pCI-Phe4, D-Pen5]enkephalin in the delta receptor
      adenylyl cyclase inhibition assay, but showed full agonist activity with an EC50
      value of 9.2 nM. The regulation of SNC80 binding affinity to the delta receptor
      by GTP analogs is undetectable in [3H]naltrindole binding inhibition studies, but
      direct binding studies with [3H]SNC121 in the presence of 100 microM 5'
      guanylylimidotriphosphate show a 55% reduction in maximum binding site density
      consistent with a lower affinity for a part of the receptor population. Addition
      of 120 mM sodium chloride reduces SNC80 affinity nearly 40-fold in
      [3H]naltrindole binding inhibition studies. The results of these studies define
      specific structural features of these compounds responsible for opioid receptor
      interactions and suggest a possibly novel mechanism for delta receptor
      activation.

PMID- 8667190
TI  - Effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1 -H-1
      benzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase
      inhibitor, on impaired learning and memory in animal models.
AB  - We examined the effects of p.o. administered 3-[1-(phenylmethyl)-4-piperidinyl]-1
      (2,3,4,5-tetrahydro-1H-1-b enzazepin-8- yl)-1-propanone fumarate (TAK-147), a
      novel AChE inhibitor, on impaired learning and memory in animal models. At 1 to 3
      mg/kg, TAK-147 ameliorated the passive avoidance deficit induced by diazepam. TAK
      147 did not affect delayed-matching-to-position (DMTP) performance of normal rats
      at doses of 1 to 30 mg/kg assessed by using a three-lever operant chamber, but 9
      amino-tetrahydroacridine disrupted the DMTP response at 5 to 20 mg/kg.
      Scopolamine (0.02-0.1 mg/kg s.c.) impaired DMTP performance, whereas
      methylscopolamine did not affect the DMTP task. TAK-147 ameliorated the
      impairment of DMTP performance induced by scopolamine without affecting the
      general behavior of the rats; however, 9-amino-tetrahydroacridine produced no
      significant amelioration of the impairment. The intraventricular injection of
      AF64A disrupted differential-reinforcement-of-low-rate 10-sec performance in
      rats, as demonstrated by marked decreases in reinforcement rate and response
      efficiency. TAK-147 slightly increased the reinforcement rate in AF64A-treated
      rats at a low dose of 1 mg/kg, but the effect was not significant statistically.
      TAK-147 had no significant effect on the duration of immobility in rats in a
      forced swimming test at doses of 2 to 10 mg/kg. 9-Amino-tetrahydroacridine
      prolonged the duration of immobility at 5 to 20 mg/kg. Furthermore, TAK-147
      reversed reserpine-induced hypothermia and ptosis in mice at doses of 3 to 10
      mg/kg, a result that implies an antidepressant-like action. These results
      indicate that TAK-147 ameliorates learning and memory impairment in animal models
      without affecting the general behavior or causing behavioral depression and
      suggest that TAK-147 may be useful for the treatment of Alzheimer's disease.

PMID- 8667191
TI  - A comparison of the effects of valproate and its major active metabolite E-2-en
      valproate on single unit activity of substantia nigra pars reticulata neurons in
      rats.
AB  - Numerous findings suggest that the substantia nigra pars reticulata (SNR) acts as
      a seizure-gating mechanism and constitutes a site where protection against a
      broad spectrum of seizures can be obtained by inhibiting the activity of
      GABAergic output neurons to SNR target regions, particularly the superior
      colliculus. Most pharmacological studies on SNR neurons have been conducted with
      local microinjection of drugs, whereas studies with systemic administration of
      anticonvulsant drugs, e.g., the antiepileptic drug valproic acid (VPA), have
      yielded inconsistent data. In the present study, we examined the dose response
      and time course of the effects of anticonvulsant doses of VPA and its major
      active metabolite E-2-en-VPA on extracellularly recorded spontaneous single unit
      activity of nondopaminergic SNR neurons in a large group of chloral hydrate
      anesthetized rats. The activity of each neuron was recorded over a period of at
      least 30 min after intravenous drug or vehicle administration. Both drugs rapidly
      decreased the firing rate of SNR neurons. Compared with predrug base-line values
      of neuronal firing of SNR neurons, the average peak inhibition of neuronal
      activity was approximately 16% at the lowest dose (50 mg/kg), approximately 20%
      (VPA) or 30% (E-2-en-VPA) at 100 mg/kg and approximately 50% (VPA) or 60% (E-2-en
      VPA) at the highest dose (200 mg/kg) tested. ED50 values calculated from these
      data were 240 mg/kg for VPA and 159 mg/kg for E-2-en-VPA, respectively.
      Determination of drug levels in SN at time of peak effect after administration of
      100 mg/kg VPA or E-2-en-VPA indicated that E-2-en-VPA exhibited its inhibitory
      effect on SNR firing at significantly lower concentration than VPA, suggesting
      that E-2-en-VPA is more potent than VPA in this regard. Except one SNR neuron,
      all neurons recorded in 52 rats reacted with a reduction in firing rate to
      administration of VPA or E-2-en-VPA, demonstrating a rather homogeneous
      susceptibility of SNR neurons to these drugs. The inhibition of SNR neurons by
      these drugs could be a result of increased GABA turnover, which has previously
      been reported to be induced in this region by systemic administration of VPA. We
      conclude that the ability of VPA and E-2-en-VPA to reduce firing of SNR neurons
      could be critically involved in their effectiveness in inhibiting seizures in
      various experimental models.

PMID- 8667192
TI  - delta 9-Tetrahydrocannabinol selectively inhibits macrophage costimulatory
      activity and down-regulates heat-stable antigen expression.
AB  - delta 9-Tetrahydrocannabinol (THC) exposure inhibits numerous immunologic
      functions of macrophages. The ability of THC-exposed macrophages to provide
      costimulatory signals to helper T cell hybridomas was investigated by induction
      of interleukin-2 secretion by T cells in response to immobilized monoclonal anti
      CD3 antibody. Exogenous interleukin-1 did not deliver a costimulatory signal to
      these T cells, suggesting that macrophage costimulatory activity was mediated
      through cell surface molecules. Modulation of the T cell responses by THC
      depended on the source of costimulation. THC did not suppress costimulatory
      activity provided by peritoneal macrophages or immobilized fibronectin. THC at
      low concentrations markedly diminished the costimulatory activity of a macrophage
      hybridoma to activate one T cell but not another. Inhibition of costimulation by
      THC inversely correlated with the loss of activity caused by paraformaldehyde
      fixation of macrophages. THC at 10(-8) M significantly decreased expression of
      costimulatory heat-stable antigen, which is resistant to fixation, on the
      macrophage hybridoma. However, expression of costimulatory B7-1 and B7-2
      molecules, which are sensitive to fixation, was not affected by THC. Therefore,
      THC selectively suppresses a fixation-resistant costimulatory signal to helper T
      cells in part by diminishing expression of heat-stable antigen.

PMID- 8667194
TI  - Regional vascular effects of MPC-1304, a novel dihydropyridine derivative, in
      conscious normotensive and spontaneously hypertensive rats.
AB  - The purpose of this study was to compare the regional vascular effect of a novel
      dihydropyridine derivative, MPC-1304 [(+/-)- methyl-2-oxopropyl-1,4-dihydro-2,6
      dimethyl-4-(2-nitrophenyl)-3, 5-pyridinedicarboxylate], with that of nifedipine
      and manidipine in conscious spontaneously hypertensive rats (SHR) and Wistar
      Kyoto rats (WKY). The radioactive microsphere technique was used to measure
      systemic and regional hemodynamic parameters before and 1 hr after p.o.
      administration of drugs. In SHR, MPC-1304 at a dose of 1 mg/kg reduced the mean
      blood pressure and systemic vascular resistance and increased cardiac output, as
      did nifedipine (10 mg/kg) and manidipine (3 mg/kg). MPC-1304, as well as
      nifedipine, significantly increased the blood flow in pulmonary, gastric, small
      intestinal and skeletal muscular beds and reduced their vascular resistance.
      Manidipine increased regional blood flow only in small intestinal and skeletal
      muscular beds. Only MPC-1304 increased the renal blood flow. In WKY, MPC-1304 and
      nifedipine reduced the mean blood pressure and systemic vascular resistance to
      lesser degrees than in SHR. Both drugs significantly increased coronary and
      skeletal muscular blood flow. MPC-1304 significantly reduced the renal blood flow
      without altering renal vascular resistance, in striking contrast to its renal
      effect in SHR. These findings suggest that MPC-1304 possesses a genetic
      hypertension-dependent renal vasodilating action, unlike nifedipine and
      manidipine. One possible mechanism for this difference in the effect on renal
      circulation between SHR and WKY may involve the potent antagonizing effects of
      MPC-1304 on alpha-2 adrenoceptor-mediated vasoconstriction.

PMID- 8667193
TI  - Buprenorphine differentially alters opioid receptor adaptation in rat brain
      regions.
AB  - Previous in vivo studies revealed that the mixed agonist-antagonist buprenorphine
      can down-regulate mu and up-regulate delta 2 and kappa 1 opioid receptors in rat
      brain. In this report brain regional differences in opioid receptor adaptation
      were addressed. Rats received i.p. injections with buprenorphine (0.5-2.5 mg/kg)
      and were killed 20 h later. Membranes from 7 brain regions were analyzed for mu
      (3H-[D-Ala2,N-mephe4,Gly-ol5] enkephalin), kappa 1 (3H-U-69593), delta 1 (3H-[D
      Pen2, D-Pen5] enkephalin) and delta 2 (3H-deltorphin II) receptor binding
      parameters. Buprenorphine induced down-regulation of mu receptors in frontal
      cortex, occipital cortex, thalamus, hippocampus, striatum and brain stem. Kd
      values for 3H-[D-Ala2,N-mephe4,Gly-ol5] enkephalin were unchanged from controls.
      Up-regulation of kappa 1 receptors was observed in frontal, parietal, occipital
      cortexes and striatum. Binding to delta 2 sites was elevated in frontal and
      parietal cortexes. Buprenorphine did not alter delta 1 binding in any of the
      regions examined. Changes in opioid receptor adaptation induced by buprenorphine
      were further supported by data from cross-linking of 125I-beta-endorphin to
      cortical membrane preparations. A reduction in a 60- to 65-kDa band was detected
      in frontal and occipital cortices in which binding assays revealed down
      regulation of mu receptors. In parietal cortex neither the 60- to 65-kDa product
      nor Bmax changes were observed. These results indicate that buprenorphine is a
      useful tool to study brain opioid receptor adaptation in vivo and the information
      accrued may be relevant to the mode of action of this drug in the treatment of
      heroin and cocaine abuse.

PMID- 8667195
TI  - Evidence of a bradykinin B1 receptor in human ileum: pharmacological comparison
      to the rabbit aorta B1 receptor.
AB  - Bradykinin B1 receptors have been identified in a limited number of human tissues
      and may have implications in pathological states of chronic inflammation. In the
      present study, longitudinal strips of postmortem human ileum displayed a strong
      contractile response to the B2 receptor agonist, bradykinin (EC50 = 7.0 nM).
      Noninduced ileum strips contracted only to high concentrations (1 and 10 microM)
      of the B1 receptor agonists, des-Arg9-BK and Lys0des-Arg9-BK. After incubation
      overnight at 37 degrees C the potency of des-Arg9-BK and Lys0des-Arg9-BK
      dramatically increased (EC50 = 183 and 13.2 nM, respectively). The increase in B1
      agonist potency was inhibited by the protein synthesis inhibitor, puromycin.
      Similarly, rabbit aorta strips displayed a protein synthesis-dependent induction
      of the B1 agonist response. Incubated human ileum and rabbit aorta exhibited a
      reproducible response to des-Arg9-BK over time, whereas responses to Lys0des-Arg9
      BK were not reproducible, having reduced potency and magnitude over time.
      Lys0[Leu8]des-Arg9-BK was a more potent antagonist at the B1 receptor in both
      tissues compared with [Leu8]des-Arg9-BK. The B2 antagonist, HOE-140, was a very
      weak inhibitor of the B1 response in human ileum and inactive in rabbit aorta. In
      conclusion, incubation of isolated human ileum overnight induces expression of a
      B1 receptor through a mechanism that depends on de novo protein synthesis. The
      potency profile of selected B1 agonists and antagonists indicates pharmacological
      similarities between the inducible B1 receptor in both the human ileum and rabbit
      aorta.

PMID- 8667196
TI  - Perinatal methadone exposure produces physical dependence and altered behavioral
      development in the rat.
AB  - Pregnant rats were implanted with osmotic minipumps containing either methadone
      hydrochloride (9 mg/kg/day) or sterile water. Their offspring were cross-fostered
      so that the following prenatal/postnatal exposure groups were obtained:
      water/water, methadone/water, water/methadone and methadone/methadone. Methadone
      slightly reduced litter size, particularly the number of male offspring, and
      reduced litter birth weight. The induction or maintenance of physical dependence
      in the postnatal methadone exposure groups was confirmed by an experiment in
      which PD19 pups were challenged with naloxone (1 mg/kg, s.c.). Methadone
      concentrations were assayed in pup brain on postnatal days 4, 10 and 22.
      Postnatal exposure to methadone via maternal milk produced measurable levels of
      methadone which decreased with age. Neuromuscular and physical development were
      assessed. Exposure to methadone accelerated acquisition of the righting reflex,
      but tended to delay the acquisition of the negative geotaxic response. Postnatal
      exposure to methadone was associated with decreased somatic growth as measured
      through postnatal day 21. The older pups (postnatal day 21) exposed to methadone
      exhibited variations in activity levels: pups exposed to methadone both
      prenatally and postnatally exhibited the least amount of spontaneous locomotor
      activity and pups exposed only postnatally exhibited the most activity.
      Therefore, it is possible to induce and/or maintain physical dependence via
      lactation in rat pups fostered to methadone-treated dams. Perinatal exposure to
      methadone by this route produces several subtle disruptions of pup development in
      the absence of gross maternal or fetal toxicity.

PMID- 8667197
TI  - A-4, a tertiary amine analog of HC-3, lowers arterial pressure in spontaneously
      hypertensive rats.
AB  - The 4-methyl piperidine analog (A-4) of hemicholinium-3 is a tertiary amine. A-4,
      like hemicholinium-3, inhibits sodium-dependent, high-affinity choline transport.
      The present study examined whether central cholinergic systems are involved in
      the expression of genetic hypertension. We examined the effects of i.v. and
      i.c.v. administration of A-4 in spontaneously hypertensive rats (SHR) and
      normotensive Wistar-Kyoto rats (WKY; control). Basal mean arterial pressure and
      heart rate values were 108 +/- 4 mm Hg and 370 +/- 5 bpm in WKY and 167 +/- 5 mm
      Hg and 337 +/- 13 bpm in SHR. The i.v. injection of A-4 (5, 10 and 20 mumol/kg)
      evoked a dose-dependent decrease in MAP in SHR, but not in WKY. The maximal
      decrease in MAP was 18 +/- 6 mm Hg (P < .01) in SHR. Depressor responses appeared
      within 1 min and reached maximum within 10 min. The reductions in MAP were not
      associated with reductions in peripheral vascular resistances, suggesting that
      the hypotension was due to a reduction in cardiac output. The i.c.v. injection of
      A-4 (100 nmol/rat) significantly decreased MAP in SHR (-23.8 +/- 2.4 mm Hg, P <
      .01), but not in WKY. The maximal decrease in MAP appeared within 1 min and
      reached maximum 10 min later. These falls in MAP were associated with falls in
      vascular resistances, suggesting that the hypotension was due to peripheral
      vasodilation. This dose was ineffective when given i.v. in either strain. A-4
      induced decreases in MAP were accompanied by significant tachycardia, which was
      maximal within 3 min of injection. These studies demonstrate that A-4 lowers MAP
      in SHR, but not in WKY. The rapid onset of hypotension in SHR after A-4
      administration suggests that there is rapid turnover of brain acetylcholine which
      may be directly involved in maintaining elevated arterial pressure in SHR.

PMID- 8667198
TI  - Mechanisms by which octreotide ameliorates symptoms in the dumping syndrome.
AB  - Octreotide reduces abdominal and vasomotor symptoms in dumping syndrome by
      unknown mechanisms. Effects of octreotide (50 microgram) on symptoms, hemodynamic
      parameters and plasma glucose and insulin levels after glucose meals were tested
      in double-blind, placebo-controlled, crossover fashion in eight patients with
      dumping syndrome. Gastric scintigraphy tested whether octreotide reduces symptoms
      by slowing gastric emptying. Octreotide reduced diarrhea, lightheadedness and
      palpitations after 75 g of glucose, compared with placebo (P < .001). Orthostatic
      pulse increases after glucose decreased from 36 +/- 6 beats/min after placebo to
      9 +/- 5 beats/min after octreotide (P < .05), and standing blood pressure
      decreases after glucose were abolished (P < .05), but octreotide had no effect on
      increase in hematocrit or plasma osmolarity after glucose. Late hypoglycemia was
      prevented by octreotide, and peak fed insulin levels were reduced from 87 +/- 15
      to 26 +/- 9 microU/ml after octreotide (P < .05). Times to maximal plasma glucose
      levels after meals were prolonged from 28 +/- 4 to 78 +/- 6 min after octreotide
      (P < .05). Octreotide had no effect on gastric emptying of liquids or solids. In
      conclusion, amelioration of dumping symptoms by octreotide is associated with
      reduced orthostasis, which is not a consequence of prevention of
      hemoconcentration. Prevention of late hypoglycemia may be due to blunted insulin
      release. Octreotide does not reverse rapid gastric emptying, indicating a limited
      role for this purported mechanism of action.

PMID- 8667200
TI  - Heme oxygenase inhibitor zinc protoporphyrin IX causes an activation of nitric
      oxide synthase in the rabbit internal anal sphincter.
AB  - The studies were performed in the rabbit internal anal sphincter (IAS) smooth
      muscle strips to examine the influence of the heme oxygenase inhibitor, [zinc
      protporphyrin (ZnPP IX)], on basal tone. ZnPP IX produced a concentration
      dependent fall in the basal tone and was the focus of our investigation. To
      examine the mechanism of the fall in IAS tone by ZnPP IX, the effect of different
      concentrations of ZnPP IX on basal IAS tone and the release of nitric oxide were
      examined before and after the neurotoxin tetrodotoxin and various nitric oxide
      synthase (NOS) inhibitors. The inhibitory effect of ZnPP IX was blocked by the
      NOS inhibitors L-NG-nitroarginine, NG-monomethyl-L- arginine and L-N5-(1
      iminoethyl)ornithine and the neurotoxin TTX. The fall in IAS tension by ZnPP IX
      was accompanied by a release of NO. ZnPP IX(1 x 10(-3)M) caused a fall in IAS
      tension of 43.7% which was reduced to 16.5% in the presence of L-NG-nitroarginine
      (1 x 10(-4)M). Furthermore, the fall in IAS tone in the presence of ZnPP IX was
      restored both by the NOS inhibitors and tetrodotoxin. The basal release of nitric
      oxide in these experiments was 0.50 +/- 0.07 nmol and in the presence of ZnPP IX
      (1 x 10(-3)M), it increased to 1.72 +/- 0.28 nmol (more than a 3-fold increase).
      Thus the fall in the basal IAS tone by ZnPP IX was associated with a release of
      NO from the myenteric neurons as these effects were significantly blocked by the
      NOS inhibitors and tetrodotoxin. We conclude that in the rabbit IAS, ZnPP IX
      causes a fall in the basal IAS tension by the activation of NOS in myenteric
      neurons. We speculate that in the resting state, the heme oxygenase pathway
      exerts important counter-regulatory effects on the NOS pathway and when blocked
      (e.g., by ZnPP IX), the underlying NOS pathway is unmasked leading to a massive
      and prolonged release of NO. The exact significance of this mechanism remains to
      be determined.

PMID- 8667199
TI  - Enkephalin analog prodrugs: assessment of in vitro conversion, enzyme cleavage
      characterization and blood-brain barrier permeability.
AB  - To improve the blood-brain barrier penetration of the delta-opioid receptor
      peptides [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Pen2, L-Cys5]enkephalin
      (DPLCE), various prodrug forms were synthesized to increase lipophilicity and
      drug delivery to the brain. The aims of this study were 3-fold, 1) to assess the
      metabolic conversion of various DPDPE and DPLCE prodrugs in vitro using mouse
      brain homogenate and mouse serum, 2)to characterize the proteolytic enzymes
      responsible for cleaving prodrugs to the parent compounds using select peptidase
      inhibitors and 3)to assess the blood-brain barrier permeability of prodrugs,
      compared with their parent compounds, using the in vitro bovine brain microvessel
      endothelial cell culture model. The prodrugs with carboxyl-terminal phenylalanine
      residues (DPDPE-Phe and DPLCE-Phe) had significantly longer metabolic conversion
      times in both mouse serum and brain homogenates than did the prodrugs with amino
      terminal phenylalanine residues. Inhibition of leucine aminopeptidase with
      bestatin in the serum increased the conversion time of Phe0-DPDPE from 6.8 min to
      92.2 min. Inhibition of aminopeptidase M with amastatin in the brain homogenate
      increased the conversion time of Phe0-DPDPE from 3.9 min to > 450 min. The long
      half-life of DPLCE-Arg-Pro-Ala in serum (317 min) vs. brain (9.2 min) can be
      explained by the high levels of the degradative endopeptidase 24.15 (EC
      3.4.24.15) in the central nervous system but not in plasma. The data also showed
      that, for specific prodrugs of DPDPE such as Phe0-DPDPE and DPDPE-Arg-Gly, the
      prodrug shows a significant improvement in permeability, compared with the parent
      compound. Therefore, these data provide evidence that prodrugs or prodrug-enzyme
      inhibitor combinations may optimize the delivery of peptide and/or protein drugs
      to the central nervous system.

PMID- 8667201
TI  - Nicotinic agonists differ in activation and desensitization of 86Rb+ efflux from
      mouse thalamic synaptosomes.
AB  - The effects of the nicotinic agonists acetylcholine, (+)-anatox in-a, carbachol,
      cytisine, dimethylphenylpiperazinum, (+)-epibatidine, (-)-epibatidine,
      methylcarbachol, D-nicotine, L-nicotine, and tetramethylammonium on 86Rb+ efflux
      from mouse thalamic synaptosomes were investigated. All 11 agonists evoked a
      concentration-dependent stimulation of 86Rb+ efflux as well as a time- and
      concentration-dependent reduction of response (desensitization). The agonists
      varied widely in potency, efficacy and rate of desensitization. (+)-Epibatidine
      was the most potent agonist (EC50 = 10 nM), whereas tetramethylammonium was the
      least potent (EC50 = 65 microM). The agonists containing a quaternary ammonium
      group were generally more efficacious than the other agonists, except for both of
      the enantiomers of epibatidine, which stimulated 86Rb+ efflux at least as well as
      acetylcholine. Cytisine was the least efficacious compound tested with a maximal
      response approximately 10% that of (-)-epibatidine. Exposure of the thalamic
      synaptosomes to agonist concentrations that generally stimulated little or no
      efflux reduced in a concentration-dependent manner a subsequent response to 10
      microM nicotine. The IC50 values for this functional blockade (desensitization)
      were highly correlated with the Ki values for the inhibition of [3H]nicotine
      binding. Furthermore, exposure of the thalamic synaptosomes to 300 nM L-nicotine
      reduced the responses evoked by a subsequent exposure to a stimulating
      concentration of all 11 agonists. The observation of desensitization by both
      stimulating and substimulating concentrations of each agonist is consistent with
      the predictions of the two-state model of Katz and Thesleff.

PMID- 8667202
TI  - Effects of iodotubercidin on adenosine kinase activity and nucleoside transport
      in DDT1 MF-2 smooth muscle cells.
AB  - Iodotubercidin is an adenosine kinase inhibitor that through its ability to
      increase levels of endogenous adenosine can enhance adenosine's receptor-mediated
      effects. We investigated whether iodotubercidin can inhibit [3H]adenosine
      accumulation by inhibiting transport processes in addition to inhibition of
      intracellular trapping of labeled adenine nucleotides. Under conditions in which
      extensive metabolism of intracellular adenosine was present, [3H]adenosine
      accumulation by DDT1 MF-2 cells was almost completely inhibited by iodotubercidin
      and the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine or by
      the nucleoside transport inhibitor nitrobenzylthioinosine. By using similar
      conditions, [3H]adenosine accumulation was significantly greater in Na+ buffer
      than in buffer containing N-methyl-D-glucamine in place of Na+; however, this
      effect may be explained by an observed 40% inhibition of adenosine kinase
      activity by N-methyl-D-glucamine. By using uptake intervals of 14 sec to
      represent the transport component of uptake, iodotubercidin decreased the
      affinity for adenosine, by about 3-fold, but had no effect on maximum velocity of
      transport. That these effects of iodotubercidin were due to direct interactions
      with nucleoside transporters was supported by findings that iodotubercidin
      inhibited [3H]nitrobenzylthioinosine binding to nucleoside transporters with a Ki
      value of 4 microM and inhibited [3H]uridine and [3H]formycin B uptake with IC50
      values of 7 and 15 microM, respectively. These data suggest that iodotubercidin,
      at pharmacologically relevant concentrations, inhibits nucleoside transport
      independently of its well characterized inhibition of adenosine kinase and that N
      methyl-D-glucamine must be used with caution in experiments to determine the
      possible presence of Na+ gradient-dependent concentrative nucleoside
      transporters.

PMID- 8667203
TI  - Rates of glutathione synthesis in lung subcompartments of mice and monkeys:
      possible role in species and site selective injury.
AB  - Injury to pulmonary epithelial cells from chemicals that undergo P450-dependent
      metabolic activation and from gases such as ozone is highly focal. These studies
      examined the rates of glutathione resynthesis in pulmonary subcompartments
      (trachea, minor daughter/respiratory bronchiole and parenchyma) of mice and
      monkeys to determine whether differences in glutathione synthesis are partly
      responsible for wide regional/species variations in susceptibility of the lung to
      insult. Glutathione levels remained unchanged in lung subcompartments incubated
      for up to 4 hr in Waymouth's medium. Glutathione levels decreased less than 30%
      in 4-hr incubations of monkey airways in medium devoid of sulfur amino acids
      although in mouse airways decreases of 40 to 60% were observed. Diethyl maleate
      depleted glutathione in lung subcompartments in vitro by varying amounts
      depending on the species and subcompartment examined. Airways incubated in the
      presence of cysteine but not methionine or glutathione regenerated glutathione
      rapidly after diethyl maleate depletion. The rates of regeneration differed
      significantly with species and airway level. In all airways of the monkey,
      glutathione levels returned to the initial level within 2 to 4 hr after addition
      of cysteine containing medium although in mice recovery of glutathione required
      only 1 (minor daughter and parenchyma) or 2 hr (trachea) incubation with cysteine
      supplemented medium. These studies show striking species and airway level
      differences in the rates of glutathione resynthesis and suggest that focal injury
      to respiratory epithelium may, in part, be mediated by regional differences in
      the ability to supply glutathione for protection against electrophiles and
      reactive oxygen species.

PMID- 8667204
TI  - L-deprenyl (selegiline) exerts anticonvulsant effects against different seizure
      types in mice.
AB  - L-Deprenyl (selegiline), a selective inhibitor of monoamine oxidase type B, has
      recently been shown to exert anticonvulsant and antiepileptogenic effects in the
      kindling model of partial (focal) epilepsy. In the present study, we examined if
      L-deprenyl exerts anticonvulsant effects in standard rodent models of generalized
      seizures. In addition to anticonvulsant activity, behavioral effects induced by L
      deprenyl were monitored closely. To assess the stereoselectivity of
      anticonvulsant and behavioral effects of deprenyl, the D-enantiomer was included
      in the studies. Furthermore, the antiepileptic drug phenobarbital was used for
      comparison. The following tests were performed in mice: 1) the threshold for
      tonic electroconvulsions; 2) the maximal electroshock seizure test with fixed
      supramaximal (suprathreshold) stimulation; 3) the threshold for myoclonic, clonic
      and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ); 4)
      the s.c. PTZ seizure test, with a fixed dose of PTZ (80 microgram/kg) for seizure
      induction; 5) the rotarod and chimney tests for determination of motor
      impairment. Furthermore, animals were observed in cage and open field for
      stereotyped behavior and other behavioral abnormalities. L-Deprenyl, tested at
      doses of 1 to 40 microgram/kg i.p., significantly increased myoclonic and clonic
      PTZ thresholds and the threshold for tonic electroconvulsions, whereas D-deprenyl
      was either ineffective or exhibited a lower anticonvulsant potency than L
      deprenyl. Both drugs were ineffective in the maximal electroshock seizure and
      s.c. PTZ seizure tests. In contrast to the higher anticonvulsant potency of L
      deprenyl in seizure threshold tests, D-deprenyl was more potent than L-deprenyl
      to induce behavioral abnormalities, such as hyperlocomotion. The data indicate
      that L-deprenyl exerts anticonvulsant activity against different seizure types.
      This anticonvulsant activity and the previously reported neuroprotective and
      cognition-enhancing action of L-deprenyl offer a unique combination of drug
      effects which might be of clinical benefit in patients with epilepsy.

PMID- 8667205
TI  - Effect of endotoxin on permeability of bovine cerebral endothelial cell layers in
      vitro.
AB  - The effect of lipopolysaccharide (LPS) on cultured cerebral endothelial cells was
      investigated to assess the changes in the trans endothelial electrical resistance
      (TEER) across the blood-brain barrier that may occur during inflammatory diseases
      of the central nervous system. Primary cultures of bovine cerebral endothelial
      cells were cultured to tight monolayers with a TEER of 250 to 300 omega.cm2 on
      polycarbonate Transwell filters. LPS induced a time- and dose-dependent decline
      in TEER. Transport of the hydrophilic model compounds sodium fluorescein and
      fluorescein dextran (MR, 4 kDa) across monolayers of bovine cerebral endothelial
      cells increased more than 3-fold after treatment of the cells with LPS (50
      ng/ml). Treatment of the monolayers with various concentrations of LPS caused a 3
      to 4-fold increase in the permeability of bovine cerebral endothelial cells for
      [125I]bovine serum albumin, which was also preceded by a decrease in TEER. The
      reduction of TEER by LPS could be inhibited completely by indomethacin (10(-6)M
      for 30 min), a cyclooxygenase inhibitor, but not by dexamethasone, a
      glucocorticoid (10(-7) M for 16 hr). In conclusion, LPS administration to blood
      brain barrier endothelial cells causes a decrease in TEER which leads to enhanced
      transport of low and high molecular weight molecules. During this process the
      production of eicosanoids by the endothelial cells seem to play a key role.

PMID- 8667206
TI  - NG-nitro-L-arginine methyl ester attenuates the maintenance and expression of
      methamphetamine-induced behavioral sensitization and enhancement of striatal
      dopamine release.
AB  - We examined the roles of nitric oxide (NO) in methamphetamine (MAP)-induced
      behavioral sensitization and enhancement of striatal dopamine (DA) release using
      both in vivo and in vitro methods. Repeated administration of MAP produced
      augmentation of MAP-induced locomotor activity after 3-day withdrawal of MAP and
      an enhancement of MAP-evoked DA release from striatal slices after 6-day
      withdrawal. When the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester
      (L- NAME) was administered only during the period of MAP withdrawal, the
      behavioral sensitization and enhancement of DA release were attenuated
      significantly. In contrast, NG-nitro-D- arginine methyl ester, an inactive isomer
      of L-NAME, exhibited no such effect. When L-NAME was administered acutely before
      the challenge injection of MAP, behavioral sensitization was also attenuated only
      when the dose of L-NAME was high. Coadministration of L-NAME with MAP did not
      block the development of sensitization to MAP. We also examined whether MAP
      induced behavioral sensitization and enhancement of DA release could be observed
      in vivo in a microdialysis experiment. Challenge injection of MAP caused marked
      enhancement of DA release in MAP-sensitized rats compared with saline-treated
      controls corresponding to robust augmentation of locomotor activity. When L-NAME
      was injected during the MAP withdrawal period, the enhancement of DA release and
      locomotor activity induced by challenge injection of MAP were attenuated. These
      results suggest that NO production plays a role in the maintenance (expression)
      of MAP-induced behavioral sensitization and enhancement of DA release but not in
      the development of these effects.

PMID- 8667207
TI  - Electrically evoked acetylcholine release from hippocampal slices is inhibited by
      the cannabinoid receptor agonist, WIN 55212-2, and is potentiated by the
      cannabinoid antagonist, SR 141716A.
AB  - This study examined the effect of the cannabinoid receptor agonist, WIN 55212-2,
      on the electrically evoked release of [14C]acetylcholine (ACh) from superfused
      brain slices from the hippocampus, a region with a high density of cannabinoid
      receptors. A comparison was also made with [14C]ACh release from the nucleus
      accumbens, which has relatively fewer cannabinoid receptors. In the hippocampal
      slices, WIN 55212-2 produced a dose-dependent inhibition of [14C]ACh release,
      with an EC50 of 0.03 microM and a maximal inhibition of 81% at 1 microM. In the
      nucleus accumbens slices, WIN 55212-2 produced a weak inhibition of [14C]ACh
      release, which did not quite reach statistical significance. The inhibition of
      electrically evoked hippocampal [14C]ACh release by WIN 55212-2 could be
      prevented by the cannabinoid receptor antagonist, SR 141716A (EC50, 0.3-1.0
      microM). In addition to antagonizing the effects of WIN 55212-2, SR 141716A alone
      produced a 2-fold potentiation of the electrically stimulated [14C]ACh release in
      this region (EC50, 0.1-0.3 microM). By contrast, in nucleus accumbens slices, no
      potentiation of the stimulated release of [14C]ACh release by SR 141716A was
      observed. Basal [14C]ACh release was unaffected by WIN 55212-2 or SR 141716A in
      either area. These results suggest that cannabinoid receptor activation can
      produce a strong inhibition of ACh release in the hippocampus. Furthermore, the
      potentiation of ACh release in the hippocampus by SR 141716A alone suggests
      either that this compound is an inverse agonist at cannabinoid receptors or it is
      antagonizing the actions of an endogenous ligand acting on these receptors.

PMID- 8667208
TI  - Catecholamine transporters and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      neurotoxicity: studies comparing the cloned human noradrenaline and human
      dopamine transporter.
AB  - The uptake and cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic
      metabolite of the parkinsonism inducing agent 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP), were studied in COS-7 cells transiently transfected
      with the cloned human noradrenaline and dopamine transporters and in permanently
      transfected SK-N-MC neuroblastoma cells. MPP+ had a 10- to 20-fold lower K(m)
      value for the noradrenaline than for the dopamine transporter. In dopamine
      transporter expressing cells, the maximal transport rate (Vmax) of MPP+, dopamine
      and noradrenaline was the same, but in noradrenaline transporter expressing cells
      the Vmax of MPP+ and dopamine was only one-half of the Vmax of noradrenaline. The
      turnover numbers (Vmax of uptake/maximal binding sites of binding) were 5 times
      higher for the dopamine transporter (as measured with [3H]dopamine and [3H]-2
      beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane than for the noradrenaline
      transporter (as measured with [3H]noradrenaline and [3H]nisoxetine). In SK-N-MC
      cells with similar Vmax values for both catecholamines, noradrenaline transporter
      expressing cells were killed by lower concentrations of MPP+ in the medium than
      dopamine transporter expressing cells. Desipramine blocked the toxicity of MPP+
      toward the noradrenaline transporter, but not the dopamine transporter expressing
      cells. We conclude that the toxic effect of MPTP at the striatal dopamine system
      in the MPTP primate model of Parkinson's disease is not correlated with the
      affinity profile of MPP+ for catecholamine transporters, but rather with the
      higher turnover number of MPP+ at the dopamine transporter. In contradistinction,
      the toxicity of MPTP at the noradrenaline neurons in the primate cerebral cortex
      (Pifl et al., 1991) may involve the higher affinity of MPP+ for the noradrenaline
      transporter.

PMID- 8667209
TI  - Tamoxifen (estrogen antagonist) inhibits voltage-gated calcium current and
      contractility in vascular smooth muscle from rats.
AB  - Tamoxifen (Tx) has been used in breast cancer treatment and prophylaxis because
      of its antiestrogenic activity; however, Tx may also have beneficial
      cardiovascular effects and other actions mediated by mechanisms other than
      estrogen receptors. Previous studies showing interactions of Tx with Ca+(+)
      channel blockers suggested that Tx may affect Ca++ channels, an hypothesis that
      was investigated using whole cell patch clamp techniques in vascular smooth
      muscle cells (cell line A7r5 and freshly dissociated cells) and by determining
      effects on contractions of isolated blood vessels. Tx reduced current through L
      type Ca+2 channels, with an ID50 of 2 x 10(-6) M when applied by cumulative
      addition to A7r5 cells. With acute application, 10(-6) M Tx significantly reduced
      L-type current in A7r5 cells within 2 min to 88% of control (vehicle, 0.1%
      ethanol) in A7r5 cells, 67% of control in aortic vascular smooth muscle cells,
      and 60% of control in tail artery vascular smooth muscle cells. Tx also decreased
      the rate of inactivation of L-type current. Inhibition of T-type current by Tx
      was less than for L-type current but was significant at 10(-5) M Tx. Treatment of
      tail artery rings with Tx (10(-5) M, 15 min; 10(-6) M, 4 hr) reduced K+-elicited
      contractions. Since therapeutic concentrations of Tx during treatment may exceed
      10(-6) M, these effects of Tx on vascular smooth muscle Ca++ channels and vessel
      contractions may have a role in the efficacy and side-effects of Tx treatment.

PMID- 8667210
TI  - Electrophysiological effects of a novel, short-acting and potent ester derivative
      of amiodarone, ATI-2001, in guinea pig isolated heart.
AB  - In this study the acute effects of ATI-2001, a recently developed ester
      derivative of amiodarone, on heart rate, atrioventricular conduction and
      frequency-dependent prolongation of ventricular conduction, repolarization and
      refractoriness were investigated in guinea pig isolated heart. Compared with
      amiodarone, an equimolar concentration of ATI-2001 (1 microM) caused
      significantly greater slowing of heart rate, depression of atrioventricular and
      intraventricular conduction and prolongation of ventricular repolarization.
      Unlike amiodarone, the effects of ATI-2001 were significantly reversed during
      washout of the drug. ATI-2001 exhibited frequency-independent effects on
      ventricular repolarization and refractoriness. It prolonged base-line ventricular
      monophasic action potential duration by 10%, 8%, 9% and 9% and ventricular
      effective refractory period by 24%, 20%, 22% and 26% at cycle lengths of 350,
      300, 250 and 200 msec, respectively. Thus, ATI-2001 (1 microM) increased the
      ventricular effective refractory period/action potential duration ratio,
      suggesting both time- and voltage-dependent prolongation of ventricular
      refractoriness. In addition, ATI-2001 lengthened ventricular conduction times
      (QRS interval and basic conduction time) significantly more at shorter cycle
      lengths. Conversely, d-sotalol, a pure class III antiarrhythmic agent, had no
      effect on ventricular conduction times and exhibited a reverse frequency
      dependent effect on ventricular repolarization. In summary, the
      electrophysiological effects of ATI-2001 were greater and more rapidly reversible
      than those of amiodarone. The lack of reverse frequency-dependent effects on
      ventricular repolarization and refractoriness suggests that ATI-2001 may be more
      efficacious than d-sotalol or other pure class III drugs in treating ventricular
      tachycardias and less likely to become proarrhythmic at normal or slow heart
      rates.

PMID- 8667211
TI  - Nonsteroidal anti-inflammatory drugs activate carbonic anhydrase by a direct
      mechanism of action.
AB  - Previous studies by this research team proved that vasodilating prostaglandins
      (PGs) E1, E2 and I2 inhibit carbonic anhydrase (CA) in vitro and in vivo, which
      suggested involvement of CA in gastric acid secretion inhibition and the increase
      of gastric mucosa blood flow produced by this group of PGs. Relying on these
      findings, as well as on our clinical observations, we studied in vitro and in
      vivo the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on CA I and CA
      II. We also followed in vitro the effects on these isozymes of NSAIDs associated
      to histamine, Ca, PGE2 and acetazolamide. The results show that the NSAIDs used
      here, which reduce the activity of cyclooxygenase and PG production, activated CA
      I and CA II in a dose-dependent manner by a mechanism of the noncompetitive type.
      Histamine and Ca added to NSAIDs amplified the activating effect of the latter on
      CA II. Association of PGE2 or acetazolamide to NSAIDs reduced NSAID-induced
      activation of CA I and CA II. Indomethacin abolished the inhibitory effect of
      acetazolamide on CA I and CA II. Our data imply that between CA and
      cyclooxygenase there is an inverse relationship, CA activation being accompanied
      by reduction of cyclooxygenase activity, a reduction achieved by the pH
      modifications induced by CA activation. In this way, cyclooxygenase, inhibition
      occurs "via CA," with the pH variations it brings about.

PMID- 8667212
TI  - Alterations in locomotor activity after microinjections of GBR-12909, selective
      dopamine antagonists or neurotensin into the medial prefrontal cortex.
AB  - It has been postulated that increased dopamine (DA) activity in the medial
      prefrontal cortex (mPFC) exerts an inhibitory influence over DA release in the
      nucleus accumbens and, thus, also over locomotor activity. Experiments were
      designed to examine the role of mPFC DA and neurotensin (NT), a neuropeptide
      which interacts with DA, in spontaneous locomotor activity. LS/IBG mice were
      injected bilaterally with either GBR-12909, a selective DA uptake blocker, the DA
      D1 receptor antagonist R-(+)-SCH-23390, the DA D2 receptor antagonist epidepride,
      NT or a combination of drugs. GBR-12909 produced a U-shaped dose-response curve
      with a maximum inhibition of 47% of control. Postmortem tissue levels of DA, 5
      hydroxytryptamine, norepinephrine and their major metabolites were determined
      after microinjections of GBR-12909. Tissue levels of these compounds were not
      significantly affected by GBR-12909. However, the ratios of homovanilic acid/DA
      and homovanilic acid + 3,4-dihyroxyphenylacetic acid/DA were significantly
      decreased, whereas the 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio was
      not affected by GBR-12909, suggesting a selective effect on DAergic processes. By
      itself, R-(+)-SCH-23390 had no effect on locomotor activity except at a very high
      dose which caused locomotor inhibition (49% of control). Epidepride caused a dose
      dependent inhibition of locomotor activity with a maximum inhibition of 49% of
      control. When coinjected with an inhibitory dose of GBR-12909, both epidepride
      and R-(+)-SCH-23390 attenuated the GBR-12909 effect in a dose-dependent manner. A
      broad range of doses of NT was found to have no consistent effect on locomotor
      activity. However, when coinjected with an inhibitory dose of GBR-12909, NT
      attenuated the GBR-12909-induced inhibition in a dose-dependent manner. The
      results suggest that stimulation of DA receptors in the mPFC, both DA D1 and DA
      D2 receptors mediates locomotor inhibition. Furthermore, stimulation of NT
      receptors appears to antagonize the effects of DA.

PMID- 8667213
TI  - Alternations in splenocyte and thymocyte subpopulations in B6C3F1 mice exposed to
      cocaine plus diazinon.
AB  - Our laboratory has proposed a working model which asserts that cocaine's effects
      on immunity are mediated by reactive metabolites generated by the cytochrome P
      450 system. This metabolic pathway is normally a minor one in humans, but takes
      on significance when metabolism of cocaine by the P-450 system is increased, as
      may occur with excessive alcohol consumption (enzyme induction) or after exposure
      to organophosphate pesticides (esterase inhibition). Results from our laboratory
      demonstrate that cocaine exerts its most dramatic effects on immunocompetence
      when administered to mice that have been pretreated with diazinon, an
      organophosphate esterase inhibitor. Most notably, we observed decreases in both
      the splenic T-dependent antibody response to sheep erythrocytes and the splenic T
      independent antibody response to DNP-ficoll and a dramatic thymic atrophy in mice
      exposed to cocaine + diazinon, which were not seen in mice exposed to cocaine
      alone. The primary objective of the present investigation was to determine
      whether the exposure conditions used to produce the changes noted above are also
      capable of causing changes in lymphocyte cell types by use of flow cytometric
      analysis. Administration of cocaine after pretreatment with diazinon only
      modestly affected splenic lymphocyte subsets, which caused a slight decrease in
      the number of B cells. No effect was observed in the macrophage, T-helper or T
      suppressor subpopulations in the spleen. These results suggest that changes in
      splenocyte subpopulations induced by cocaine + diazinon cannot account for the
      suppression of the antibody response. In contrast, all T-cell subsets in the
      thymus were decreased significantly, with immature double-positive thymocytes
      suffering the greatest loss in cell number. These results indicate that T cells,
      especially immature thymocytes located in the thymus, are sensitive to effects
      associated with the combined treatment of cocaine + diazinon.

PMID- 8667215
TI  - Regional hemodynamic effects of purinergic P2 receptor subtype agonists in rats.
AB  - ATP produces significant cardiovascular effects by activation of P2
      purinoceptors. In the present study, we examined the regional hemodynamic
      profiles produced by intravenous administration of a P2X and a P2Y purinergic
      receptor agonist. Sprague-Dawley rats were anesthetized with Inactin, catheters
      were placed in the femoral artery and vein and the rats were instrumented to
      measure renal, mesenteric, hindquarter, coronary and cerebral blood flow using
      Doppler flow probes. Administration of bolus doses (1-1000 nmol kg-1) of the P2X
      agonist beta, gama-methylene-ATP dose-dependently increased arterial pressure at
      doses greater than 100 nmol kg-1. This increase in mean arterial pressure was
      mediated by increases in coronary, mesenteric and renal vascular resistance after
      administration of 300 nmol kg-1. Cerebral and hindquarter vascular resistances
      were increased significantly only after 1000 nmol kg-1. This P2X agonist had the
      greatest efficacy in elevating resistance in the renal and mesenteric vascular
      beds. In a separate group of animals, the pressor response to administration of
      100 nmol kg-1 was demonstrated to be reproducible when bolus doses of the agonist
      were administered at 10-min intervals. In contrast to P2X receptor stimulation,
      administration of bolus doses (1-1000 nmol kg-1) of the P2Y agonist 2-methylthio
      ATP (2MeSATP) dose-dependently reduced mean arterial pressure. This decrease in
      arterial pressure was mediated by significant reductions in cerebral, coronary
      and mesenteric vascular resistance at doses greater than 30 nmol kg-1.
      Hindquarter vascular resistance was decreased significantly after administration
      of 100 nmol kg-1. The P2Y agonist 2MeSATP had the greatest efficacy in reducing
      resistance in the cerebral and hindquarter vascular beds. Renal vascular
      resistance was not altered significantly at any dose of 2MeSATP. Administration
      of the A1/A2 antagonist CGS15943 (1 mg kg-1) minimally affected these responses,
      demonstrating that these vasoconstrictor/vasodilator effects were not mediated by
      adenosine A1 or A2 receptors. Although the pressor and depressor responses to
      bolus administration were robust and reproducible, these responses were not
      maintained with intravenous infusion of these two agonists at rates from 2 to 200
      nmol kg-1 min-1. Thus, we have established time courses and distinct regional
      hemodynamic profiles for agonists selectively activating P2X and P2Y receptor
      subtypes in the rat.

PMID- 8667214
TI  - Nitric oxide mediates the inhibitory action of platelet-activating factor on
      angiotensin II-induced renal vasoconstriction, in vivo.
AB  - The objective of our study was to determine the mechanism(s) involved in the
      inhibitory effect of platelet-activating factor on renal vascular reactivity, in
      vivo. Bolus injections of vasoconstrictor agonists were administered into the
      renal circulation of pentobarbital anesthetized male Wistar rats at a dose to
      cause a transient 45 to 50% decrease in renal blood flow. Intrarenal infusion of
      platelet-activating factor (PAF) at 2.5 ng/min/kg attenuated the vasoconstrictor
      response to angiotensin II by 66%, a significantly smaller reduction of 35% for
      norepinephrine-mediated vasoconstriction, 22% for vasopressin-mediated
      vasoconstriction and no alteration of KCl-mediated vasoconstriction. The
      preferential inhibitory effect of platelet-activating factor on angiotensin II
      mediated renal vasoconstriction was mimicked by the intrarenal infusion of either
      0.2 to 5 micrograms/min/kg methacholine (endothelium-dependent vasodilator) or 2
      micrograms/min/kg sodium nitroprusside (nitric oxide donor). After inhibition of
      nitric oxide synthesis with NG-monomethyl-L-arginine, intrarenal infusion of PAF
      or methacholine reduced angiotensin II-mediated renal vasoconstriction
      significantly less than that observed in the absence of NG-monomethyl-L-arginine.
      Therefore, this study provides evidence that the shared ability of platelet
      activating factor and methacholine to selectively reduce angiotensin II-mediated
      renal vasoconstriction involves endothelium-derived nitric oxide.

PMID- 8667216
TI  - Mechanisms of [Ca++]i elevation induced by erythrocyte components in endothelial
      cells.
AB  - Erythrocyte components released from blood clot after subarachnoid hemorrhage are
      thought to be involved in the pathogenesis of cerebral vasospasm. The effect of
      erythrocyte components on smooth muscle has been investigated extensively;
      however, their action on endothelium remains unclear. We studied the effects of
      different erythrocyte components and bloody cerebrospinal fluid (CSF) on [CA++]i
      in cultured bovine pulmonary and cerebral arterial endothelial cells using fura-2
      [Ca++]i microfluorimetry. Erythrocyte lysate and bloody CSF produced a biphasic
      [Ca++]i response, a peak and a plateau, and the effect of erythrocyte lysate on
      [Ca++]i was attenuated by the endoplasmic reticulum Ca++ pump inhibitors
      thapsigargin and cyclopiazonic acid, by the voltage-independent Ca++ channel
      blocker SK&F96365, by the P450 cytochrome inhibitors econazole and miconazole and
      by the inorganic Ca++ pathway blockers lanthanum, nickel and cobalt. This
      suggests that erythrocyte lysate releases Ca++ from internal stores and promotes
      Ca++ influx from voltage from voltage-independent Ca++ channel. Erythrocyte
      lysate was then fractionated into different molecular weight fractions with
      different pore-size membranes and each fraction was tested separately. The
      component that increased [Ca++]i had a molecular weight < 1 kdalton. Fractions
      that contained oxyhemoglobin did not affect [Ca++]i. Adenosine nucleotides
      mimicked the effect of erythrocyte lysate and bloody CSF on [Ca++]i. The P2
      purinoceptor antagonist suramin attenuated the effect of ATP, erythrocyte lysate,
      the fraction < 1 kdalton and bloody CSF. We concluded that adenosine nucleotides
      are the component of erythrocyte lysate and bloody CSF that increase [Ca+2]i in
      endothelial cells and that the effect involves P2-purinoceptors. However, no
      evidence is presented that this increase in endothelial [Ca+2]i by erythrocyte
      lysate causes cerebral vasospasm.

PMID- 8667217
TI  - Neural and endocrine circuits mediating inhibition of bradykinin-induced plasma
      extravasation by subcutaneous and spinal-intrathecal nicotine.
AB  - In this study we evaluated the mechanisms underlying s.c. and spinal intrathecal
      (i.t.) nicotine inhibition of bradykinin-induced plasma extravasation in the knee
      joint of the rat (J. Pharmacol. Exp. Ther. 262: 889-895, 1992; ibid., 264: 839
      844, 1993). The dose-response curve for the inhibitory action of s.c. nicotine on
      bradykinin-induced plasma extravasation was attenuated by adrenal medullectomy
      and by intra-articular perfusion of ICI-118,551 (a beta-2 adrenoceptor
      antagonist). In addition, the dose-response curve of s.c. nicotine was attenuated
      by acute surgical lumbar sympathectomy and by intra-articular phentolamine (an
      alpha adrenoceptor antagonist). The dose-response curve for i.t. nicotine (up to
      1 mg/kg) was not attenuated by intra-articular ICI-118,551 and was potentiated by
      adrenal medullectomy. The action of i.t. nicotine was also not affected by intra
      articular phentolamine or by acute surgical lumbar sympathectomy. These results
      suggest that the inhibition of bradykinin-induced plasma extravasation in the
      knee joint of the rat by s.c., but not i.t., nicotine is mediated through the
      sympathoadrenal and sympathetic systems.

PMID- 8667218
TI  - The effects of mibefradil, a novel calcium channel antagonist on ventricular
      arrhythmias induced by myocardial ischemia and programmed electrical stimulation.
AB  - Calcium channel antagonists can reduce calcium overload induced by myocardial
      ischemia and thereby protect against malignant arrhythmias. However, these drugs
      may also adversely affect cardiac contractile function. Mibefradil is a new
      calcium antagonist that can inhibit cardiac calcium current without reducing
      myocardial force development. The effects of mibefradil on the inducibility of
      arrhythmias both before and during ischemia were therefore evaluated in animals
      with healed infarctions. First, a 2-min coronary occlusion was made during the
      last minute of exercise (n = 48): 25 animals had ventricular fibrillation
      (susceptible), whereas 23 did not (resistant). On a subsequent day, programmed
      electrical stimulation (PES, 8 paced beats followed by two extrastimuli) induced
      ventricular tachycardia in 19 of 25 susceptible animals but in none of the
      resistant animals (chi square = 24.6, P < .001). Verapamil (n = 14), diltiazem (n
      = 13) and mibefradil (n = 14) elicited significant dose-dependent decreases in
      refractory period and in the Q-Tc interval (except mibefradil) yet failed to
      prevent PES-induced arrhythmias. Diltiazem and verapamil also increased P-R
      interval and reduced the maximum rate of change of left ventricular pressure,
      whereas mibefradil did not. However, all three drugs abolished arrhythmias
      induced by PES during ischemia. In contrast, lidocaine suppressed PES-induced
      arrhythmias but failed to prevent ischemically induced arrhythmias. Thus
      mibefradil can prevent ischemically induced ventricular fibrillation without
      adverse actions on either A-V nodal conduction or contractile function. These
      data further suggest that calcium entry may play a critical role in the
      initiation of ventricular fibrillation during ischemia, whereas other factors
      must be responsible for the extrasystoles induced by PES.

PMID- 8667219
TI  - Protein kinase C activators decrease dopamine uptake into striatal synaptosomes.
AB  - Incubation with either of the protein kinase C activators phorbol 12-myristate 13
      acetate (PMA) and sn-1,2 dioctanoylglycerol (DiC8) decreased the uptake of
      dopamine into striatal synaptosomes, whereas the inactive phorbol ester 4 alpha
      PMA had no effect. Washout of PMA and DiC8 failed to reverse the decrease in
      uptake. Kinetic analysis showed a decrease in the apparent V(max) for the
      transporter without changes in the K(m). Neither PMA nor DiC8 affected mazindol
      binding to the dopamine transporter. Preincubation with the protein kinase
      inhibitor staurosporine prevented the DiC8-induced decrease of dopamine uptake.
      Furthermore, the protein phosphatase inhibitor okadaic acid decreased dopamine
      uptake by itself and enhanced the DiC8-induced reduction of uptake. These
      findings support a role for protein kinase C in modulating dopamine transporter
      activity.

PMID- 8667220
TI  - Evidence for the involvement of the caudal region of the periaqueductal gray in a
      subset of morphine-induced alterations of immune status.
AB  - This study was directed at determining whether morphine's immunomodulatory
      effects are mediated through the periaqueductal gray (PAG). The initial study
      showed that microinjection of morphine (0.0, 0.4, 4.0, or 40.0 micrograms/rat)
      into the lateral ventricle induces pronounced dose-dependent reductions in
      lymphocyte proliferation to T- and B-cell mitogens, natural killer cell
      cytotoxicity, and the production of interleukin-2 and interferon-gamma. In
      contrast, microinjection of morphine (0.0, 0.004, 0.04, 0.4, or 4.0
      micrograms/rat) into the caudal aspect of the PAG induced dose-dependent
      alterations in natural killer cell cytotoxicity, but had no effect on lymphocyte
      proliferation or cytokine production. These results indicate that opioid
      receptors in the PAG are involved in the regulation of natural killer cell
      activity, but are not associated with morphine's effects on proliferation or
      cytokine production. A subsequent study showed that the effect of morphine in the
      PAG is restricted to the more caudal aspects of the PAG because microinjections
      of morphine into the rostral aspects do not result in any alteration of immune
      status. To determine that the activation of opioid receptors in the PAG is not
      only sufficient, but is required for morphine's effects on natural killer cell
      activity, N-methylnaltrexone was administered into the PAG (0, 0.0001, 0.001, or
      0.01 micrograms/rat) before the systemic administration of morphine (15 mg/kg), a
      dose that induces pronounced alterations of natural killer cell activity. The
      results showed that the administration of N-methylnaltrexone directly into the
      PAG antagonized morphine's effects on natural killer cell activity, which
      indicate that activation of opioid receptors within the PAG are required for
      morphine to alter natural killer cell activity. Collectively, this study showed
      that activation of opioid receptors within the more caudal aspects of the PAG are
      required for morphine to induce alterations in splenic natural killer cell
      activity. The results also suggest that other brain regions are responsible for
      morphine's effect on lymphocyte proliferation and cytokine production.

PMID- 8667221
TI  - Regional effects of MK-801 on dopamine release: effects of competitive NMDA or 5
      HT2A receptor blockade.
AB  - The open channel N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine (MK
      801) and phencyclidine (PCP) increase the firing rate of both A9 and A10
      dopaminergic neurons in the rat. In the A10 nucleus, this effect of MK-801 is
      reportedly prevented by either competitive NMDA antagonists or serotonin2 (5-HT2)
      antagonists. The present study examined the neurochemical correlates of these
      effects using the technique of in vivo microdialysis in conscious rats. In
      contrast to its reported electrophysiological effects at the cell body level, MK
      801 (2 mg/kg, i.p.) has divergent effects on dopamine release in the terminal
      fields of the A9 and A10 systems. MK-801 stimulated dopamine release in both the
      medial prefrontal cortex and the nucleus accumbens but tended to decrease release
      in the striatum. Stimulated dopamine release in the nucleus accumbens was
      selectively blocked by either the competitive NMDA receptor antagonist, MDL
      100,453 or the 5-HT2A receptor antagonist, MDL 100,907. Neither MDL 100,453 nor
      MDL 100,907 affected MK-801-induced release in the medial prefrontal cortex. The
      results illustrate the complex regulation of the forebrain dopaminergic systems
      by glutamate and indicate that the serotonergic system, via the 5-HT2A receptor,
      may play an important role in this regulation.

PMID- 8667222
TI  - Brain efflux index as a novel method of analyzing efflux transport at the blood
      brain barrier.
AB  - A brain efflux index method has been developed to characterize an efflux
      transport system for substrates from the cerebrum to the circulating blood across
      the blood-brain barrier. The brain efflux index value is defined as the relative
      amount of test drug effluxed from cerebrum compared with that of a reference
      compound, [14C]carboxylinulin, which has limited blood-brain barrier
      permeability. Microinjection of 0.2, 0.5 or 1.0 microliter into the parietal
      cortex area 2 region was found to be an appropriate procedure for obtaining a
      high recovery and for restricting the test drug and reference compound to the
      ipsilateral cerebrum. No significant increase in influx clearance of
      [14C]carboxylinulin into the brain was observed for the ipsilateral cerebrum
      after the sham microinjection compared with the contralateral cerebrum, which
      demonstrated that only limited physical damage is caused. Microinjection of
      [3H]H2O into the cerebrum devoid of cerebral blood flow yielded no elimination
      from the brain. Analysis based on a pharmacokinetic model demonstrated that the
      elimination of a highly permeable compound [3H]H2O from the brain was governed by
      cerebral blood flow. The apparent elimination rate constant (Kel) of [3H]3-O
      methyl-D-glucose from the brain was determined as 0.129 +/- 0.014 (min-1) and was
      reduced significantly by a preinjection of excess cold 3-O-methyl-D-glucose and
      phloridzin, whereas no significant elimination was observed for L[3H]glucose. The
      efflux clearance of 3-O-methyl-D-glucose was calculated from the Kel value and
      the compound's distribution volume, the value being close to that of the influx
      clearance. These results demonstrate that the brain efflux index method is a
      useful technique for analyzing an efflux process from the brain across the blood
      brain barrier involving a carrier-mediated transport system.

PMID- 8667223
TI  - LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced
      relaxation in canine coronary artery.
AB  - The canine coronary artery possesses a smooth muscle relaxant serotonin (5-HT)
      receptor distinct from previously characterized 5-HT receptors. On the basis of
      the ability of LY53857 to block weakly coronary smooth muscle relaxation to 5-HT,
      we examined several structurally related ergolines in endothelium denuded rings
      of canine coronary artery precontracted with PGF2 alpha (10 microM). 5-HT (10 nM
      100 microM)-induced relaxation was antagonized competitively by the ergoline
      esters LY53857 (-log KB = 6.5) and sergolexole (-log KB = 6.4) and by the
      ergoline amide amersergide, (-log KB = 6.7). In contrast to the relatively low
      affinity of these ergolines, LY215840, another ergoline amide, antagonized 5-HT
      induced relaxation in a competitive manner with the highest affinity (-log KB =
      8.3). This effect was independent of the 5-HT2 receptor affinity of these
      ergolines, because LY215840, LY53857, sergolexole and amesergide all possessed
      similar 5-HT2 receptor affinity. Further, all four ergolines possessed affinity
      for the human 5-HT7 receptor, and LY215840 had the highest 5-HT7 receptor
      affinity (Ki = 14.7 nM). Finally, in vascular smooth muscle under basal tone,
      LY215840 (1 microM) blocked the relaxant response to high concentrations of 5-HT
      and 5-MeOT without altering their contractile potency. LY215840 (1 microM) did
      not alter contraction to sumatriptan, an agent that lacks relaxant activity. In
      contrast, LY215840 (1 microM) markedly potentiated contraction to 5
      carboxamidotryptamine, the most potent coronary relaxant agonist and the agonist
      with the highest 5-HT7 receptor affinity. The ability of LY215840 to block the
      relaxant 5-HT receptor in canine coronary artery may reflect its 5-HT7 receptor
      antagonist activity and make it a useful tool to probe the relationship between
      the 5-HT7 receptor and the coronary vasoactive properties of 5-HT.

PMID- 8667225
TI  - Positive inotropic effects of the calcium sensitizer CGP 48506 in guinea pig
      myocardium.
AB  - In isolated papillary muscles from reserpinized guinea pigs, CGP 48506 increased
      force of contraction in a concentration-dependent and reversible manner, starting
      at 10 mumol/l and reaching 364.14 +/- 46.10% of predrug values at 100 mumol/l.
      The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l
      carbachol. The positive inotropic effect of CGP 48506 was accompanied by
      increases in time to peak tension and in time of relaxation amounting to 223.37
      +/- 6.87% and 247.10 +/- 9.34% of control, respectively, at 100 mumol/l (n = 10).
      CGP 48506 sensitized trabeculae from guinea pig hearts to calcium with an EC50
      value of 22 mumol/l. However, CGP 48506 (up to 300 mumol/l) did not affect the
      activity of cardiac PDE isoenzymes I to IV. Likewise, CGP 48506 (up to 100
      mumol/l) did not increase phosphorylation of select cardiac regulatory proteins
      or cyclic AMP content in guinea pig ventricular cardiomyocytes and did not affect
      cardiac phosphorylase phosphatase activity. CGP 48506 is the first
      pharmacological agent with noteworthy calcium-sensitizing properties that has
      been found to be devoid of inhibitory activity on cardiac PDE.

PMID- 8667224
TI  - Nonpeptide endothelin receptor antagonists. VII: Binding characteristics of
      [3H]SB 209670, a novel nonpeptide antagonist of endothelin receptors.
AB  - The data presented in this manuscript describes the binding characteristics of
      [3H]SB 209670, a potent nonpeptide tritium-labeled endothelin (ET) receptor
      antagonist. The binding of this antagonist to cloned human ETA and ETB receptors
      was specific, saturable and of high affinity. The apparent dissociation constants
      were 0.20 and 1.0 nM for ETA and ETB receptors, respectively. The maximum binding
      was 4.7 and 22.5 pmol/mg protein for ETA and ETB receptors, respectively. Unlike
      [125]ET-1, the binding of [3H]SB 209670 was reversible. The half-times (T1/2) for
      dissociation of this ligand from ETA and ETB receptors were approximately 60 and
      10 min, respectively. Competition binding studies using [3H]SB 209670 and
      unlabeled agonists ET-1, ET-3 and S6c indicated that these agonists displayed
      similar affinities for human ETB receptors, whereas with ETA receptors, ET-1 was
      approximately 50-fold and 1500-fold more potent than ET-3 and S6c, respectively.
      Of the peptide antagonists tested, BQ123 (ETA-selective peptide antagonist),
      displayed Ki values of 40 and > 2300 nM for ETA and ETB, whereas RES701 (ETB
      selective antagonist) displayed Ki values of > 1600 and 81 nM for ETA and ETB
      receptors, respectively. The nonselective peptide antagonist, PD 142893, was
      approximately 2-fold more potent for ETA compared with ETB receptors. Similar
      observations were made with nonselective nonpeptide antagonists, Bosentan, (+/-)
      SB 209670, SB 209670, and (-) SB 209670. All these compounds were 2 to 10 times
      more potent for ETA than ETB receptors.

PMID- 8667226
TI  - Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human
      myocardium.
AB  - In trabeculae carneae from failing human myocardium, CGP 48506 increased the
      force of contraction, which reached 310 +/- 41% of predrug values at 100 mumol/l.
      Its stereoisomer CGP 48508 did not affect the force of contraction (100 mumol/l).
      The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l
      carbachol. The positive inotropic effect of CGP 48506 was accompanied by
      increases in time to peak tension and time of relaxation amounting to 175 +/- 4%
      and 205 +/- 15% of control, respectively, at 100 mumol/l. CGP 48506 but not CGP
      48508 sensitized skinned trabeculae from failing human myocardium to calcium with
      an EC50 value of 10 mumol/l. However, CGP 48506 and CGP 48508 (up to 300 mumol/l)
      did not affect the activity of PDE isoenzymes I to IV from failing human
      myocardium. CGP 48506 is the first inotropic agent with calcium-sensitizing
      properties in the human heart that has been found to be devoid of inhibitory
      activity on human cardiac PDE isoenzymes.

PMID- 8667227
TI  - Differential effects of unique profile antipsychotic drugs on extracellular amino
      acids in the ventral pallidum and globus pallidus of rats.
AB  - The effects of antipsychotic drugs (APDs) on brain dopamine receptors in the
      striatum are ultimately expressed through efferent projections which primarily
      use amino acid transmitters, including gamma-aminobutyric acid and glutamate. The
      present study examined the effects of APDs on extracellular amino acid levels in
      the rat ventral pallidum (VP) and globus pallidus (GP), areas that receive
      projections from distinct striatal subregions. Clozapine, an APD with low motor
      side effect liability, and metoclopramide, a low-potency APD with high motor side
      effect liability, were compared with haloperidol, a widely used APD with high
      motor side effect liability. Drugs were administered subcutaneously and amino
      acid levels were monitored concurrently in the VP and GP by intracranial
      microdialysis. High doses of haloperidol and metoclopramide increased and
      clozapine decreased extracellular gamma-aminobutyric acid levels in the GP but
      not the VP. Low, but not high, doses of the three drugs tended to increase
      extracellular glutamate levels in both pallidal regions. Clozapine, but not the
      other two drugs, decreased extracellular threonine in the GP and glycine and
      threonine in the VP. Results indicate a correlation between increased gamma
      aminobutyric acid levels in the GP and the propensity of the APDs tested to
      induce motor side effects. The novel effects of clozapine on extracellular
      glycine and threonine further distinguish this drug as a unique antipsychotic
      compound.

PMID- 8667228
TI  - Properties of ABT-299, a prodrug of A-85783, a highly potent platelet activating
      factor receptor antagonist.
AB  - ABT-299 is an aqueous soluble prodrug that is converted rapidly in vivo to A
      85783, a novel, highly potent, specific platelet activating factor (PAF)
      antagonist. The K, for inhibiting PAF binding to rabbit platelet membranes is 3.9
      and 0.3 nM for human platelets. Inhibition is selective and reversible and is
      correlated with functional antagonism of PAF-mediated cellular responses (calcium
      mobilization, priming of superoxide generation, aggregation and degranulation).
      The in vivo generation of A-85783 from ABT-299 leads to potent inhibition of PAF
      induced inflammatory responses (increased vascular permeability, hypotension and
      edema) and PAF-induced lethality. When administered i.v., the potency (ED50) of
      ABT-299 for inhibiting PAF responses was between 6 to 10 micrograms/kg in the rat
      and mouse and 100 micrograms/kg in the guinea pig. A dose of 100 micrograms/kg in
      the rat provided greater than 60% protection for 8 to 16 hr against cutaneous and
      systemic PAF challenge. This duration was also evidenced by ex vivo inhibition of
      platelet aggregation in guinea pig and sheep. In addition to being active
      parenterally, ABT-299 exhibited p.o. activity in the rat and mouse (ED50 = 100
      micrograms/kg in both species). Pharmacokinetic studies in the rat revealed that
      ABT-299 was converted rapidly to A-85783 and, in turn, metabolized to the
      corresponding pyridine-N-oxide and sulfoxide metabolites. These metabolites
      exhibited significant potency in vitro and in vivo and thus may contribute to the
      activity observed after administration of ABT-299.

PMID- 8667229
TI  - Platelet-activating factor production in stimulated macrophages is down-regulated
      by concurrently produced prostaglandin E2.
AB  - When rat peritoneal macrophages were incubated in medium containing 12-O
      tetradecanoylphorbol 13-acetate (TPA), a protein kinase C activator, production
      of cell-associated platelet-activating factor (PAF) and extracellular
      prostaglandin E2 (PGE2) increased. In the presence of the cyclooxygenase
      inhibitor indomethacin, TPA-induced PAF production was further enhanced dose
      dependently in accordance with decrease of PGE2 levels. In addition, indomethacin
      further enhanced PAF production that was stimulated by the protein kinase C
      activators, aplysiatoxin and teleocidin. Other cyclooxygenase inhibitors such as
      naproxen and ibuprofen also enhanced TPA-stimulated PAF production in accordance
      with inhibition of PGE2 production. Cyclooxygenase inhibitor-induced enhancement
      of PAF production was markedly prevented by exogenous PGE2. Exogenous arachidonic
      acid also inhibited TPA-induced PAF production in parallel with increase in PGE2
      levels. Inhibition of PAF production by exogenous arachidonic acid was abolished
      by indomethacin. Furthermore, PAF production stimulated by the endomembrane Ca+2
      ATPase inhibitors thapsigargin or thapsigargicin, or by the Ca+2 ionophore
      A23187, was also enhanced by indomethacin in compensation for the decrease in
      PGE2 production. In addition, the adenylate cyclase activator forskolin, or the
      cyclic adenosine monophosphate (cAMP) analogues 8-bromo cAMP and dibutyryl cAMP
      inhibited thapsigargin-induced PAF production. TPA-induced accumulation of
      intracellular cAMP was inhibited by indomethacin, and indomethacin-induced
      decrease of cAMP level was reversed by exogenous PGE2. These results suggested
      that concurrently produced PGE2 in stimulated macrophages down-regulates PAF
      production via adenylate cyclase and cAMP pathway.

PMID- 8667230
TI  - Active transport of cimetidine and ranitidine into the milk of Sprague Dawley
      rats.
AB  - Diffusion determines the extent of accumulation into milk for most xenobiotics.
      However, cimetidine (CM) and ranitidine (RN) have been reported to accumulate to
      an extent greater than expected in rat and human milk, suggesting an active
      transport mechanism. In the present study, lactating Sprague Dawley rats were
      used in a random crossover design to characterize CM and RN active transport. Rat
      milk-to-serum ratios (M/S) (29.3 +/- 3.2 vs. 13.0 +/- 6.0; P < .05) and systemic
      clearance, Cls (12.9 +/- 1.2 vs. 4.6 +/- 1.0 ml/min, P < .05), were significantly
      reduced when exposed to a higher steady state infusion regimen of CM (0.4 and 30
      mg/hr, respectively). By contrast, a infusion regimen of RN (0.4 and 30 mg/hr,
      respectively) produced modest, but not statistically significant, reductions in
      M/S (12.7 +/- 3.8 vs. 9.0 +/- 2.6; P > .05) and Cls (12.2 +/- 1.5 vs. 9.9 +/- 2.7
      ml/min; P > .05). In a third set of rats, CM M/S (30.4 +/- 2.7 vs. 27.5 +/- 4.6;
      P > .05) and Cls (12.5 +/- 2.8 vs. 10.7 +/- 4.8 ml/min; P > .05), were marginally
      reduced by a concomitant RN infusion regimen (30 mg/hr) when compared with CM
      steady state infusions alone (0.4 mg/hr). By contrast, RN M/S (16.1 +/- 2.0 vs.
      10.5 +/- 2.0; P < .05) and Cls (11.0 +/- 1.3 vs. 7.1 +/- 0.9 ml/min, P < .05),
      were significantly reduced by a concomitant CM infusion regimen (30 mg/hr) when
      compared with RN steady state infusions alone (0.4 mg/hr). Models for M/S and Cls
      as a function of CM steady state serum concentration were proposed and fitted to
      the data. Values for the maximum transport velocity of the transport system
      (Tmax') and the apparent dissociation constant (Km) for the M/S relationship were
      326 and 55 micrograms/ml, respectively. For the Cls relationship, estimates of
      the nonsaturable clearance component (Clns), the maximum velocity of the
      saturable elimination process (Vmax), and Km were 3.6 ml/min, 135 micrograms/min,
      and 16 micrograms/ml, respectively. These observations provide evidence that CM
      and RN milk transfer can be saturated and inhibited, which would be consistent
      with the hypothesis that these compounds are actively transported across mammary
      epithelial cells into rat milk.

PMID- 8667231
TI  - Involvement of endothelins in immediate and late asthmatic responses of guinea
      pigs.
AB  - To explore the pathophysiological roles of endothelin isopeptides and receptor
      subtypes in asthmatic responses, a guinea pig model for asthma was used to test
      the effects of antiendothelin (ET) serum and selective ET receptor antagonists
      for antigen-induced specific airway conductance changes as measured by whole-body
      plethysmography. In this model, all of the animals so far tested demonstrated
      both the immediate and late asthmatic responses. Although preimmune serum had no
      apparent effects, anti-ET antiserum suppressed the maximal reduction of specific
      airway conductance in both the immediate and late asthmatic responses, which
      suggested that ET(s) are involved in the pathophysiology of both the immediate
      and late asthmatic responses. The ETB selective antagonists, BQ788 and RES701-1,
      blocked the immediate asthmatic response but not the late asthmatic response,
      whereas the ETA antagonists, BQ123 and (Shionogi) 97-139, suppressed only the
      late asthmatic response without influencing the immediate asthmatic response. In
      vitro constrictive responses of isolated tracheas and bronchi to ET1 were
      inhibited mainly by BQ123 and BQ788, respectively, which suggested that
      distribution of ETA and ETB receptors for bronchoconstriction are topographically
      distinct along airways. Furthermore, thromboxane A2 and platelet activating
      factor (PAF) antagonists were effective in suppressing the late asthmatic
      response but not the immediate asthmatic response. Taken together, our present
      observations suggest that ET(s) influences pulmonary functions by constricting
      airway smooth muscle via ETB receptors during the immediate asthmatic response
      and by modulating pulmonary inflammation via ETA receptors during the late
      asthmatic response, respectively.

PMID- 8667232
TI  - Prediction of the human pharmacokinetics of troglitazone, a new and extensively
      metabolized antidiabetic agent, after oral administration, with an animal scale
      up approach.
AB  - We have attempted to predict the human pharmacokinetics of troglitazone after
      oral administration based on animal data. Troglitazone is a new antidiabetic
      agent that exhibits a high-metabolic clearance and is metabolized mainly in the
      liver to sulfate and glucuronide conjugates. The prediction of the area under the
      plasma concentration-time curve (AUCp.o.) and bio-availability (F) in humans
      after oral administration was initially attempted by use of allometric equations
      involving the oral plasma clearance of total (CLp.o.) or unbound drug
      (CLp.o.,fu), or the hepatic intrinsic clearance of unbound drug (CLuint) and
      animal body weight. The exponents in the allometric equations between the
      clearances and body weights were 0.63 to 0.82 with high correlation coefficients
      (r > .98), and there was no marked difference in predictability by the three
      methods. Next, the prediction of the range of plasma profiles after oral
      administration to humans was attempted by the following series of steps: (1)
      calculation of the exponent and coefficients in the allometric relationships
      between body weight and parameters, such as total body plasma clearance (CLi.v.)
      and various distribution volumes (Vss, V beta and Vc) based on animal data; (2)
      estimation of the absorption rate constant (ka) from allometric relationship to
      body weight, and estimation of F value from the predicted AUCp.o. (3) description
      of the plasma concentration-time profiles after oral administration by an
      equation involving the allometric exponents and coefficients, ka, F and body
      weight. The observed and simulated plasma profiles were similar and the predicted
      AUCp.o. values were 60 to 120% of those observed. These methodologies will be
      useful for predicting the human pharmacokinetics after oral dosing from animal
      data.

PMID- 8667233
TI  - Pharmacology of the spinal adenosine receptor which mediates the antiallodynic
      action of intrathecal adenosine agonists.
AB  - The effects of intrathecally delivered adenosine agonists on allodynia induced by
      L5/L6 spinal nerve ligation in rats with lumbar intrathecal catheters were
      examined. Tactile allodynia was assessed by measuring the threshold for evoking
      withdrawal of the lesioned hind paw with calibrated von Frey hairs. Intrathecal
      administration of the A1 adenosine selective agonist, N6-(2-phenylisopropyl)
      adenosine R-(-)isomer (R-PIA), produced a dose-dependent (0.3-3 nmol; ED50 = 0.6
      nmol) antiallodynic action and evoked a delayed motor weakness at a dosage of 30
      nmol. Intrathecal administration of the A2 adenosine selective agonist, CGS 21680
      {2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine
      hydrochloride}, also produced a dose-dependent reduction in allodynia (2-40 nmol;
      ED50 = 15 nmol), but this effect was associated at 40 nmol after a short interval
      with prominent hind limb weakness. Intrathecal pretreatment with A1/A2 adenosine
      antagonists, caffeine (20 mumol) and 8-sulfophenyltheophylline (60 nmol), blocked
      antiallodynic actions of R-PIA (1 nmol) and CGS 21680 (40 nmol). Intrathecal
      pretreatment with the A1 adenosine-selective antagonist, 8-cyclopentyl-1,3
      dimethylxanthine (3 nmol), blocked the antiallodynic effect of R-PIA (1 nmol),
      but even a dose as high as 10 nmol did not block the effect of CGS 21680 (40
      nmol). The A2 adenosine-selective antagonist, 3, 7-dimethyl-1-propargylxanthine
      (3 nmol), prevented the antiallodynic effects of R-PIA (1 nmol) and CGS 21680 (40
      nmol). Pretreatment with caffeine (20 mumol), 8-sulfophenyltheophylline (60 nmol)
      and 3,7-dimethyl-1-propargylxanthine (3 nmol) prevented the motor dysfunction
      induced by R-PIA (30 nmol) and CGS 21680 (40 nmol), but 8-cyclopentyl-1,3
      dimethylxanthine (3 or 10 nmol) did not. Based on these effects, we hypothesize
      that the antiallodynic effects are mediated through the activation of spinal A1
      adenosine receptors and motor dysfunction effects are mediated through A2
      adenosine receptors.

PMID- 8667234
TI  - Inhibition of thalidomide teratogenicity by acetylsalicylic acid: evidence for
      prostaglandin H synthase-catalyzed bioactivation of thalidomide to a teratogenic
      reactive intermediate.
AB  - Thalidomide is a teratogenic sedative-hypnotic drug that is structurally similar
      to phenytoin, which is thought to be bioactivated by prostaglandin H synthase
      (PHS) and other peroxidases to a teratogenic reactive intermediate. The relevance
      of this mechanism to thalidomide teratogenicity was evaluated in pregnant New
      Zealand White rabbits treated with thalidomide at 11:00 A.M. on gestational days
      8 to 11, with day 0 indicating the time when sperm were observed in the vaginal
      fluid. Thalidomide (7.5 mg/kg i.v.) produced mainly fetal limb anomalies
      analogous to those observed in humans. Thalidomide (25-200 mg/kg i.p.), produced
      a dose-related increase in a spectrum of fetal anomalies, and in postpartum
      lethality, but did not produce a reliable incidence of limb anomalies. In
      subsequent studies, pregnant does received the irreversible PHS inhibitor
      acetylsalicylic acid (ASA), 75 mg/kg i.p., or its vehicle, followed 2 hr later by
      thalidomide, 7.5 mg/kg i.v., or its vehicle. ASA pretreatment was remarkably
      embryoprotective, resulting in respective 61.2 and 61.4% decreases in thalidomide
      initiated fetal limb anomalies (P = .002) and postpartum fetal lethality (P <
      .02), and a small but significant reduction in thalidomide-initiated fetal weight
      loss. ASA alone did not produce significant embryopathy. These results show that
      ASA can protect the embryo from thalidomide teratogenicity, suggesting that
      thalidomide may be bioactivated by PHS to a teratogenic reactive intermediate.

PMID- 8667235
TI  - The biotransformation of clomipramine in vitro, identification of the cytochrome
      P450s responsible for the separate metabolic pathways.
AB  - The aim of the study was to identify the cytochrome P450s (CYPs) that catalyze
      the biotransformation of clomipramine in vitro. A high-performance liquid
      chromatography method was developed to assay N-desmethylclomipramine, 8
      hydroxyclomipramine, 2-hydroxyclomipramine, 8-hydroxydesmethhylclomipramine,
      didesmethylclomipramine and 2-hydroxydesmethylclomipramine formed by microsomes
      prepared from human liver and yeast expressing human CYP1A1, 1A2, 2C8, 2C9, 2C18,
      2C19, 2D6 and 3A4. There was a statistically significant correlation between the
      formation rate of desmethylclomipramine and the immunoquantified concentration of
      CYP3A4 in 12 human liver microsome preparations (rs = 0.664, P = .028).
      Ketoconazole was a very potent inhibitor of desmethylclomipramine formation (Ki =
      0.054 microM) and microsomes from yeast expressing CYP3A4 were also active in
      forming the metabolite (formation rate: 25.6 nmol/nmol of CYP per hr). Thus, the
      results are consistent with the assumption that the N-demethylation of
      clomipramine is catalyzed by CYP3A4. As expected from in vivo panel studies,
      CYP2C19 in yeast was also very active in the N-demethylation (formation rate, 145
      nmol/nmol of CYP per hr). Fluvoxamine was a potent inhibitor of
      desmethylclomipramine formation (Ki, 0.15 microM), suggesting that CYP1A2 is a
      third CYP involved in the N-demethylation. CYP2D6 in yeast microsomes catalyzed
      the 8-hydroxylation of clomipramine and desmethylclomipramine (formation rates,
      65 and 75 nmol/nmol of CYP per hr) and quinidine was a very potent inhibitor (Ki,
      0.10 and 0.16 microM). Both results confirm that CYP2D6 catalyzes the 8
      hydroxylation in agreement with the results obtained in previous in vivo studies.
      Besides quinidine, paroxetine, fluoxetine and norfluoxetine, all were potent
      inhibitors of the 8-hydroxylations (Ki, 0.24-1.5 microM) and sertraline was a
      less potent inhibitor (Ki, 16 and 27 microM, respectively).

PMID- 8667236
TI  - Protection from 1,1-dichloroethylene-induced Clara cell injury by diallyl
      sulfone, a derivative of garlic.
AB  - Bronchiolar Clara cell damage ensues after treatment of mice with 1,1
      dichloroethylene (DCE). The cytotoxicity is mediated by CYP2E1, a cytochrome P450
      isozyme that is highly localized in the Clara cells. Bioactivation of DCE
      produces the primary metabolites 2,2-dichloroacetaldehyde, which hydrolyzes to
      the acetal, and DCE epoxide, which reacts with glutathione to form the conjugates
      2-(S-glutathionyl) acetyl glutathione [B] and 2-S-glutathionyl acetate [C]. In
      this study, we investigated the potential of diallyl sulfone (DASO2) to inhibit
      CYP2E1, to suppress the bioactivation of DCE to reactive intermediates and to
      abrogate DCE-induced Clara cell cytotoxicity. Our results showed that treatment
      of mice with DASO2 (100 mg/kg p.o.) produced decreases in CYP2E1-dependent p
      nitrophenol hydroxylation that were apparent at 1 h. Enzyme activity plummeted to
      about 20% of the control by 2 h and remained at this low level from 3 to 8 h.
      Recovery of activity was evident at 16 h and returned to the control level by 24
      h. Immunoreactivity of the CYP2E1 protein was decreased in immunoblots of lung
      microsomes from DASO2-treated mice. Treatment with DASO2 did not cause any
      structural alterations in lung tissue; in contrast, treatment with DCE (75 mg/kg)
      produced Clara cell damage. This lesion was not manifested in mice treated with
      DASO2 in conjunction with DCE. The lack of cytotoxicity observed in vivo
      correlated with a reduction of about 45% in the levels of both the acetal and the
      DCE epoxide-derived conjugates [B] and [C] in vitro. These results demonstrated
      that DASO2 significantly inhibited the CYP2E1 enzyme, decreased the production of
      DCE metabolites and protected Clara cells from DCE-induced cytotoxicity.

PMID- 8667237
TI  - Hyaluronic acid increases proteoglycan synthesis in bovine articular cartilage in
      the presence of interleukin-1.
AB  - Osteoarthritis is a common joint disorder in humans. Although intra-articular
      injection of hyaluronic acid (HA) is in widespread clinical use, there are
      limited data on the effect of HA on degenerated cartilage. When bovine articular
      cartilage is degraded with interleukin-1, HA penetrates the cartilage and
      accumulates in the pericellular matrix of chondrocytes. HA also enhances
      proteoglycan synthesis that has been reduced by interleukin-1. Thus HA seems to
      have anabolic effects on degraded cartilage.

PMID- 8667238
TI  - Suppressed expression of phenobarbital-inducible hepatic cytochrome P-450s in
      Eisai-hyperbilirubinuria rats (EHBR/Eis).
AB  - The differential induction of hepatic cytochrome P-450 (P450) was studied in
      Eisai-hyperbilirubinuria rats (EHBR/Eis). This rat is a mutant that has as high a
      concentration of bilirubin in the urine as in the plasma. A single administration
      of trans-stilbene oxide (TSO, 2 mmol/kg), a phenobarbital (PB)-type P450 inducer,
      did not increase total P450, the CYP2B1/2 or the CYP2C6 in EHBR/Eis liver. TSO
      was able to induce delta-aminolevulinic acid synthetase and heme oxygenase, rate
      limiting enzymes in heme biosynthesis and degradation, respectively, in both
      EHBR/Eis and Sprague-Dawley rat (SDR), the strain from which EHBR/Eis is derived.
      TSO also produced similar effects on glutathione depletion and on the activities
      of other drug-metabolizing enzymes in both strains. A 23-fold increase in
      CYP2B1/2 mRNA in the SDR liver was observed 24 hr after TSO treatment. In the
      EHBR/Eis strain, however, TSO increased CYP2B1/2 mRNA only 2-fold. In addition,
      repeated injection of TSO failed to induce P450 isozymes, CYP2B1/2, CYP2C6 or
      CYP3A2 in EHBR/Eis. On the other hand, there was essentially no difference in the
      induced levels of CYP1A1/2 apoprotein and mRNA between twins of SDR and EHBR/Eis
      livers treated with 3-methylcholanthrene or 1-benzylimidazole. The increased
      levels of both CYP2B1/2 apoprotein and mRNA from EHBR/Eis liver treated with TSO
      and 1-benzylimidazole were much smaller (2.5- and 5-fold increases, respectively)
      than from the SDR liver (17.5- and 15-fold increases, respectively). Although PB
      expressed CYP2B1/2 apoprotein and mRNA to a similar extent in both homozygous and
      heterozygous EHBR/Eis livers, CYP3A2 and CYP2C6 were less responsive to PB in
      homozygous EHBR/Eis. Repeated treatment with TSO induced these isozymes in
      heterozygote but not in homozygote. These findings suggest that the suppressed
      expression of PB-inducible P450 isozyme genes in the EHBR/Eis liver may be a
      general phenomenon associated with PB-type inducers. Therefore, EHBR/Eis may be
      experimentally useful for studying the mechanism of P450 induction by PB and PB
      type inducers.

PMID- 8667239
TI  - Effects of nicotine on dopaminergic nigrostriatal axons requires stimulation of
      presynaptic glutamatergic receptors.
AB  - An electrophysiological method for evaluating changes in axonal excitability was
      used to examine presynaptic effects of the local striatal administration of
      nicotine on nigrostriatal dopaminergic terminal axons in the rat. To eliminate
      postsynaptic interactions, intrinsic striatal neurons were destroyed with a
      unilateral kainate lesion performed 10 to 15 days before the recording
      experiments. Excitability was assessed by determining the striatal stimulus
      current just sufficient to elicit an antidromic response from the striatal
      terminal field of a dopaminergic nigral neuron on 95% of the stimulus
      presentations. Local nicotine infusion (1-100 microM/0.3 microliter) produced a
      dose-dependent increase in excitability. Previous intrastriatal administration of
      the nicotine receptor antagonists mecamylamine or chlorisondamine blocked the
      nicotine effect and subsequent administration reversed the nicotine response.
      Increased dopamine autoreceptor stimulation, presumably resulting from nicotine
      induced dopamine release, appeared to oppose the nicotine-induced increase in
      excitability. Accordingly, in animals in which dopamine synthesis was blocked
      with alpha-methyl-p-tyrosine (250 mg/kg, 12 and 2 h before recording), the
      nicotine-induced increase in terminal excitability was larger than in untreated
      rats. Simultaneous intrastriatal administration of the glutamate receptor
      antagonists, 6,7-dinitro-quinoxaline-2,3-dione and 2-amino-7-phosphonoheptanoate,
      prevented the nicotine-induced increase in excitability in animals with or
      without alpha-methyl-p-tyrosine pretreatment. We conclude that the nicotine
      induced increase in nigrostriatal terminal excitability is an indirect effect
      resulting from a nicotine-evoked increase in glutamate release and a subsequent
      increase in the stimulation of presynaptic glutamate heteroreceptors on the
      dopamine-containing terminals.

PMID- 8667240
TI  - Medium chain triglycerides and vitamin E reduce the severity of established
      experimental alcoholic liver disease.
AB  - Lipid peroxidation may be important in the pathogenesis of alcoholic liver
      injury. We investigated the potential of medium chain triglycerides and vitamin E
      to decrease lipid peroxidation and reverse established alcoholic liver injury.
      Four groups (five rats/group) of male Wistar rats were studied. Rats in group 1
      were fed a fish oil-ethanol diet for 6 weeks. Rats in groups 2, 3 and 4 were fed
      the fish oil-ethanol diet for 6 weeks before being switched to fish oil-dextrose
      (group 2), fish oil-dextrose plus vitamin E (group 3) or medium chain
      triglycerides-dextrose (group 4) diets for 2 weeks. Liver samples were analyzed
      for histopathology, lipid peroxidation, fatty acid composition and cytochrome
      P450 2E1 activity. By 6 weeks, all rats developed fatty liver, inflammation and
      necrosis. After switching to the dextrose-containing diets, there was minimal
      histologic improvement in group 2, moderate improvement in group 3 and near
      normalization of the histology in group 4. Histologic improvement was associated
      with decreased lipid peroxidation and cytochrome P450 2E1 activity. Higher levels
      of polyunsaturated fatty acids were seen in groups 2 and 3 than in group 4. Our
      results indicate that a diet enriched in saturated (group 4) but not
      polyunsaturated (group 2) fatty acids effectively reverses alcoholic liver
      injury. Treatment with vitamin E also led to histologic improvement. These
      effects may be explained, at least in part, by down-regulation of lipid
      peroxidation. Other effects of medium chain triglycerides, such as their
      propensity for oxidation rather than esterification, may also be important.

PMID- 8667241
TI  - Angiotensin-converting enzyme inhibition attenuates arterial constrictor
      responses in experimental hypertension.
AB  - Angiotensin-converting enzyme inhibition has been shown to attenuate arterial
      contractions, but the underlying mechanisms have not been clarified in detail.
      Therefore, we investigated the effects of 10-week-long quinapril therapy (10 mg
      kg-1 day-1) on responses of mesenteric arterial rings in vitro in spontaneously
      hypertensive rats (SHR) and normotensive Wistar-Kyoto rats. The hypertrophy of
      cardiac muscle and mesenteric arterial smooth muscle was effectively reduced in
      SHR by quinapril treatment. Maximal contractile force generation to 5-hydroxy
      tryptamine was reduced in endothelium-intact and -denuded rings of quinapril
      treated SHR when compared with untreated SHR. Contractile sensitivity of
      endothelium-intact rings to 5-hydroxytryptamine was also attenuated in SHR by
      quinapril, whereas no differences were found between the study groups in
      sensitivity of endothelium-denuded rings. Inhibition of NO synthesis by NG-nitro
      L-arginine methyl ester increased the sensitivity and contractile force
      generation of endothelium-intact rings to 5-hydroxytryptamine more effectively in
      quinapril-treated than in untreated SHR, whereas indomethacin had only minor
      effects on the responses in the study groups. Maximal responses and sensitivity
      to norepinephrine were also reduced in SHR by quinapril and were more effectively
      increased by NG-nitro-L-arginine in quinapril-treated than in untreated SHR. In
      addition, KCI-induced maximal contractions of endothelium-denuded rings were
      attenuated in quinapril-treated SHR. However, when the release of norepinephrine
      from vascular adrenergic nerve endings was eliminated by sympathectomy, no
      differences were found in maximal KCI-induced contractions between the study
      groups; this suggests that diminished contractions to KCI in quinapril-treated
      SHR resulted from reduced release of endogenous norepinephrine from vascular
      nerve endings during depolarization. The inhibitory effects of the calcium
      channel blocker nifedipine on arterial contractions in the Wistar-Kyoto rat
      groups and the quinapril-treated SHR were similar and were lower than in
      untreated SHR. In conclusion, the present findings suggest that effective
      reversal of cardiovascular hypertrophy, normalization of the function of voltage
      dependent calcium channels, sympathoinhibitory action and enhanced endothelium
      derived NO release can explain the attenuated arterial constrictor responses that
      occur after the long-term inhibition of angiotensin-converting enzyme.

PMID- 8667242
TI  - Selective suppression of rat hepatic microsomal activity during chronic
      cyclosporine nephrotoxicity.
AB  - Cyclosporine is an immunosuppressant that undergoes extensive hepatic
      biotransformation to hydroxylated and demethylated metabolites. At present, the
      CYP3A gene family is thought to be the primary enzyme system responsible for
      cyclosporine metabolism. The effect of chronic cyclosporine therapy on the
      suppression of drug metabolism was studied in male and female rats maintained on
      a low-salt diet. After 28 days of subcutaneous cyclosporine dosing 15 mg/kg,
      cyclosporine-treated rats had significant renal dysfunction as compared with
      gender-matched control rats. Creatinine clearance in male cyclosporine-treated
      rats was reduced by 47% (P < .01) as compared with male controls. Female rats
      demonstrated a 38% (P < .01) decrease in creatinine clearance as a result of
      chronic cyclosporine therapy. Despite similar nephrotoxicity, female rats had
      whole blood cyclosporine levels 48% (P < .01) less than male rats. Immunoblot
      analysis of hepatic microsomal proteins indicated that chronic cyclosporine
      treatment decreased the protein levels of P450 3A2 in male rats. This loss was
      paralleled by reduced production of 6 beta-hydroxytestosterone, the primary
      product of P450 3A activity, by hepatic microsomes from cyclosporine-treated male
      rats by 76% (P < .001). In addition, cyclosporine treatment of male rats also
      reduced the formation of 2 alpha-hydroxytestosterone and 16 alpha
      hydroxytestosterone by 81% (P < .01) and 84% (P < .001), respectively. At the end
      of the study period, steroid 5 alpha-reductase activity in control male rats was
      only 4% (P < .001) of female counter-parts; however, cyclosporine treatment
      increased steroid 5 alpha-reductase activity in male rats to 79% (P < .001) of
      female values. These alterations in testosterone metabolism are consistent with
      the suppression of the predominately male-associated P450 3A2, P450 2C11 and P450
      2C13 isoforms. Levels of 6 alpha-hydroxytestosterone and 7 alpha
      hydroxytestosterone were not statistically different between rat groups. Taken
      together, the steady-state blood levels and metabolism studies suggest that,
      after chronic cyclosporine treatment, isoforms other than those from the CYP3A
      family or unidentified members of the CYP3A family are likely responsible for
      cyclosporine metabolism.

PMID- 8667243
TI  - Hydrogen peroxide mediates the killing of U937 tumor cells elicited by
      pharmacologically attainable concentrations of ascorbic acid: cell death
      prevention by extracellular catalase or catalase from cocultured erythrocytes or
      fibroblasts.
AB  - Pharmacologically attainable concentrations of ascorbic acid are highly toxic for
      U937 cells (a human promyelocytic cell line), and this response appears to be
      mediated by H2O2. This inference finds experimental support in the following
      observations: 1) toxic levels of H2O2 are readily generated upon dissolution of
      survival-range concentrations of ascorbic acid in the culture medium; 2) the
      lethal effects elicited by ascorbic acid or reagent H2O2 are prevented by the
      addition of either catalase or the intracellular iron chelator o-phenanthroline
      and are characterized by similar temporal dependence; 3) U937 cells resistant to
      hydrogen peroxide are cross-resistant to ascorbic acid; 4) under the conditions
      utilized in this study, H2O2 and ascorbate promote similar modes of cell death
      (i.e., necrosis); and 5) cell killing provoked by H2O2 or ascorbate is an inverse
      function of cell density and is suppressed by coculturing U937 target cells with
      human erythrocytes (at a density far below that present in the blood) and human
      fibroblasts. Cytoprotection was not observed using catalase-depleted
      erythrocytes. Taken together, these results strongly suggest that H2O2 is
      entirely responsible for the ascorbate-induced U937 cell killing. We therefore
      propose that it is unlikely that the vitamin damages or kills tumor cells of
      normal tissues in vivo via the H2O2 based mechanism, because the oxidant would be
      removed promptly by the neighboring cells.

PMID- 8667244
TI  - Inorganic mercury chloride-induced apoptosis in the cultured porcine renal cell
      line LLC-PK1.
AB  - HgCl2 is known to be a renal toxin, but its mechanisms of toxicity are not well
      understood. The cell line LLC-PK1 was used as a model for renal proximal tubule
      cells, and the effects of different concentrations of HgCl2 were studied.
      Apoptosis in response to 35 microM HgCl2 was confirmed by observation of
      morphological features characteristic of apoptotic cells as well as cleavage of
      chromosomal DNA into fragments of multiples of 200 base pairs. Ten percent of LLC
      PK1 cells in a monolayer underwent apoptosis. These cells detached from the
      culture flask before apoptosis. Measurement of transepithelial resistance (TER)
      was used as a functional assay of junctional complex integrity in a novel
      approach to characterize preapoptotic events in this cell line. Monolayers of LLC
      PK1 cells that contained apoptotic cells showed a transient decrease in TER
      followed by a recovery of TER to the initial levels. The decrease in TER was
      accompanied by a loss of hemicysts within the monolayer. These data indicate a
      temporary loss of junctional complexes within the monolayer during apoptosis. One
      hundred micromolar HgCl2 caused all cells to become necrotic within 3 hr. HgCl2
      (10 microM) caused some changes in cell morphology, but no cell death.

PMID- 8667245
TI  - The membrane hyperpolarization of rat dorsolateral septal nucleus neurons is
      mediated by a novel nicotinic receptor.
AB  - The pharmacology, calcium dependence and G protein mediation of the membrane
      hyperpolarization of rat dorsolateral septal nucleus (DLSN) neurons in response
      to nicotinic agonists was examined to classify the nicotinic receptor mediating
      the response. Intracellular recording from DSLN neurons in a brain slice
      preparation was used to determine whether chlorisondamine, trimethaphan, cytisine
      or strychnine inhibited the membrane hyperpolarization in response to application
      of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP).
      Chlorisondamine was found to block the response only at a high concentration (500
      microM) although strychnine (100 microM) was without effect. Cytisine was neither
      an effective agonist nor an antagonist (500 microM). Surprisingly, trimethaphan
      appeared to act as an agonist, rather than an antagonist, with a potency and
      efficacy similar to that reported for nicotine at this receptor. The response was
      dependent on intracellular calcium stores because it persisted in the absence of
      extracellular calcium but was blocked by intracellular injection of 1,2-bis(2
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Injection of GTP gamma S
      into the neurons blocked the nicotinic response. Apamin, iberiotoxin and
      charybdotoxin reduced but did not block the response at concentrations that
      selectively block calcium-dependent potassium channels. These results indicate
      that the nicotinic response in DLSN neurons may be mediated by a metabotropic
      nicotinic receptor coupled to a calcium-dependent potassium channel through the
      activation of a G-protein and release of intracellular calcium stores. The
      unusual pharmacology of the nicotinic receptor on DLSN neurons indicates that it
      may be a novel receptor which has yet to be cloned.

PMID- 8667246
TI  - In vivo effects of angiotensin II on vascular smooth muscle contraction and blood
      pressure are mediated through a protein tyrosine-kinase-dependent mechanism.
AB  - The effects of in vivo angiotensin II (AII) treatment on protein tyrosine kinase
      (PTK) levels were examined. It was found that administration of AII to
      normotensive Wistar-Kyoto rats induced tyrosine phosphorylation in aorta in a
      time-dependent manner. There was a rapid increase in phosphotyrosine content as
      early as 1 min, with peak phosphorylation occurring between 5 and 10 min. The
      response was also dose dependent, with increases in phosphorylation levels from 1
      to 1000 micrograms/kg AII. Tyrosine phosphorylation was blocked using the
      angiotensin type 1 receptor antagonist losartan (10 mg/kg), suggesting that the
      effects are receptor mediated. Tyrphostin-25 (100 microM), a selective inhibitor
      of PTKs, when given in vivo was also able to attenuate phosphorylation by AII,
      further suggesting a PTK-mediated event. To couple these biochemical changes with
      physiological events, we also examined the ability of AII to induce
      vasoconstriction and raise systolic blood pressure through a PTK-mediated
      mechanism. In addition to increasing phosphorylation levels, AII caused a rise in
      systolic pressure in vivo and induced contraction in vitro. Both of these
      responses could be attenuated by pretreatment with losartan or tyrphostin-25.
      This is the first demonstration of the effects of AII on tyrosine phosphorylation
      in vivo. The data suggest that AII may induce a pressor response at least in part
      through activation of PTKs and subsequent phosphorylation of smooth muscle
      contractile proteins or activation of other protein kinases.

PMID- 8667247
TI  - Adrenergic regulation of the heat shock response in brown adipose tissue.
AB  - One of several ways that cells respond to damage or stress is by the expression
      of a set of highly conserved proteins termed, heat shock proteins (HSP).
      Induction of the heat shock response has been positively correlated with
      adaptation or protection of cells and tissues from the destructive effects of
      various types of stressors. Although heat can induce a generalized HSP response
      in most cells, the selective induction of HSP in specific cell populations by
      pharmacological agents may prove therapeutically useful for the protection of
      organs or tissues at risk for damage. Results from our studies suggest that the
      HSP response is integrated with fundamental physiological stress responses and
      demonstrate that distinct regulatory events couple neurotransmitter/hormone
      receptor interactions with HSP expression in mammalian tissues. We demonstrate
      that the adrenergic receptor agonist, phenylephrine, induces HSP expression in
      brown adipose tissue (BAT). Apparently, this response is mediated by alpha
      adrenergic receptors in BAT because prazosin, but not propranolol, blocks HSP
      induction and hexamethonium is without effect. Based on the transcripts induced
      and the magnitude of heat shock element-binding activity, phenylephrine appears
      to induce HSP expression through unique transcriptional regulatory mechanisms.
      The phenylephrine-induced HSP response is not unique to BAT as we have found that
      HSP are induced in other tissues as well. In BAT, HSP may facilitate the
      thermogenic function of this tissue, however, their function in other tissues
      remains unclear. The results of this study characterize a model system where the
      heat shock response is differentially evoked by a specific pharmacological agent
      and may aide in the development of treatment strategies to selectively target HSP
      expression in vivo.

PMID- 8667249
TI  - Characterization and localization of [125I]RTI-55-labeled cocaine binding sites
      in fetal and adult rat brain.
AB  - The present studies examined the characteristics of fetal (gestational day 20)
      and adult rat brain cocaine recognition sites labeled with the potent cocaine
      congener [125I]RTI-55 [3 beta-(4-iodophenyl)-tropane-2 beta-carboxylic acid
      methyl ester]. Saturation analyses of [125I]RTI-55 binding to membrane fractions
      from both fetal and adult whole-brain yielded curvilinear Scatchard plots that
      were resolved by nonlinear curve-fitting into high- and low-affinity components.
      Mean Kd values were 0.13 nM and 12 nM for fetal brain high- and low-affinity
      sites, respectively, compared to 0.26 and 18 nM for adult brain. The Kd for high
      affinity binding was significantly different between the groups, suggesting a
      possible developmental change in the properties of [125I]RTI-55 binding sites.
      Drug displacement studies with various monoamine uptake inhibitors indicated that
      at a 10 pM concentration of [125I]RTI-55, almost all binding to fetal brain
      membranes could be accounted for by interaction with the serotonin (5-HT) and (to
      a lesser extent) dopamine (DA) transporters. This conclusion was supported by
      autoradiographic studies of both adult and fetal brain, demonstrating a
      predominance of [125I]RTI-55 binding in areas with high densities of 5-HT and/or
      DA uptake sites. The present results are in accordance with our previous
      demonstration of [3H]cocaine binding sites in fetal brain (Meyer et al., 1993)
      and further suggest that [125I]RTI-55 should be a useful ligand for assessing the
      effects of prenatal cocaine exposure on the subsequent development of cocaine
      recognition sites on the DA and 5-HT transporters.

PMID- 8667248
TI  - Effects of felbamate on muscarinic and metabotropic-glutamate agonist-mediated
      responses and magnesium-free or 4-aminopyridine-induced epileptiform activity in
      guinea pig olfactory cortex neurons in vitro.
AB  - The effects of the anticonvulsant agent felbamate (FBM) were examined on
      muscarinic and metabotropic-glutamate receptor agonist-induced responses and
      chemically induced epilepti-form activity, in guinea pig olfactory cortex slices
      in vitro. FBM (100-500 microM) had little effect on neuronal membrane properties
      and on postsynaptic potentials evoked by electrical stimulation of lateral
      olfactory tract terminals, whereas it reduced the duration of presumed Ca++
      spikes induced by intracellular Cs+ loading. In contrast, the muscarinic receptor
      agonist oxotremorine-M (10 microM) or the metabotropic glutamate receptor agonist
      1-aminocyclopentane-1S-3R-dicarboxylic acid (10 microM) induced a sustained
      membrane depolarization with repetitive firing, an increase in input resistance
      and the appearance of a slow poststimulus afterdepolarizing potential. These
      effects were reversibly reduced in the presence of FBM (100-500 microM). After
      preincubation of slices with Mg+(+)-free solution or 200 microM 4-aminopyridine,
      neurons exhibited spontaneous and stimulus-evoked epileptiform potentials that
      were suppressed by FBM (1 mM). We conclude that FBM can interfere with muscarinic
      and metabotropic-glutamate response generation and slow after-depolarization
      induction in olfactory cortical neurons, most likely by blocking Ca++ influx
      through voltage-sensitive Ca++ channels. A possible interaction of FBM with other
      voltage-insensitive Ca++ conductances is also considered. We also suggest that
      FBM can suppress epileptiform activity induced by Mg+(+)-free or 4-aminopyridine
      exposure primarily through inhibition of N-methyl-D-aspartate-gated ion channels,
      although additional actions on non-N-methyl-D-aspartate receptor sites and/or
      presynaptic transmitter release mechanisms cannot be excluded.

PMID- 8667251
TI  - Prostaglandin E2 induces apoptosis in resting immature and mature human
      lymphocytes: a c-Myc-dependent and Bcl-2-independent associated pathway.
AB  - Prostaglandin E2 (PGE2) is a known negative regulator of T lymphocyte
      proliferation. Previously we have indirectly evidentiated the involvement of PGE2
      in apoptosis of lymphocytes both in vitro and in vivo. We have evaluated a
      possible direct effect of PGE2 on apoptosis. To this end we have investigated the
      in vitro effects of PGE2 on cell death, and its possible correlation with c-Myc
      and Bcl-2 proteins. We used freshly isolated unstimulated human lymphocytes from
      neonatal thymus, cord blood and adult peripheral blood. PGE2 induced DNA
      fragmentation in both peripheral and cord blood at 10(-7) to 10(-5) M
      concentrations, even though this induction was delayed in peripheral blood with
      respect to cord blood. Apoptosis induced by PGE2 was always associated with a
      dose-dependent increase of cellular steady state c-Myc protein levels, whereas
      Bcl-2 protein levels were not substantially affected. Unstimulated thymocytes
      showed spontaneous DNA fragmentation that occurred earlier and at higher levels
      in PGE2-(10(-5) M) treated cells with respect to untreated controls. Also in
      these cells, PGE2 produced an early increase of c-Myc protein expression,
      although Bcl-2 protein levels remained unchanged. In conclusion, PGE2 induces
      apoptosis with different kinetics on immature and mature T cells: this induction
      is associated with the increase of c-Myc protein expression and seems to be
      independent from Bcl-2 regulation.

PMID- 8667250
TI  - Felbamate inhibits [3H]t-butylbicycloorthobenzoate (TBOB) binding and enhances Cl
      current at the gamma-aminobutyric AcidA (GABAA) receptor.
AB  - We investigated the interaction of felbamate (FBM) with gamma-aminobutyric acid
      type A receptors using receptor autoradiography with [3H]t
      butylbicycloorthobenzoate (TBOB) and whole-cell patch-clamp recordings of
      cultured mouse cortical neurons. FBM produced dose-dependent inhibition of [3H]T
      BOB binding with IC50 values of approximately 250 microM. Saturation analysis in
      the presence of FBM revealed increased Kd and decreased Bmax. Dissociation
      initiated by picrotoxin (PTX) was accelerated by FBM. The regional pattern of
      [3H]TBOB binding inhibition by FBM was different from the regional modulation of
      [3H]TBOB binding produced by gamma-aminobutyric acid (GABA) agonists,
      bicuculline, zinc or neurosteroids. With electrophysiological recordings, FBM
      enhanced GABA-elicited Cl- currents at GABA concentrations of 10 microM but not 3
      microM or 100 microM. FBM enhancement was not blocked by the benzodiazepine
      antagonist flumazenil, and FBM did not affect pentobarbital potentiation of GABA
      elicited currents. FBM also had no effect on PTX inhibition of GABA-elicited Cl-
      currents. These results suggest that FBM potentiates gamma-aminobutyric acid type
      A receptor function, at least in part, by acting at a site that interacts with
      the PTX site but is distinct from the PTX, barbiturate, GABA, benzodiazepine,
      zinc and neurosteroid sites.

PMID- 8667252
TI  - Type II collagen-induced arthritis in the diabetic-resistant biobreeding rat:
      inflammatory and histopathological features of joint pathology and effects of
      antiinflammatory and antirheumatic drugs on this chronic arthritic process.
AB  - Diabetic-resistant (DR) BioBreeding (BB) rats developed an erosive hind paw
      arthritis when immunized with an emulsion of bovine type II collagen (CII) and
      incomplete Freund's adjuvant. Macroscopic clinical evidence of type II collagen
      induced arthritis (CIA) first appeared as periarticular erythema and edema in the
      hind paws between days 9 and 10 postimmunization with CII. The incidence of CIA
      was 100% by day 11 in the CII-challenged rats; and CIA severity progressed over a
      28-day period with radiographic evaluation revealing focal resorption of bone
      together with osteophyte formation in the tibiotarsal joint and soft tissue
      swelling. The histopathology of CIA included an hyperplastic synovium that
      invaded and eroded articular cartilage at the joint margins, and subchondral bone
      resorption associated with bone-derived, multinucleated cell-containing
      granulomatous lesions in the rat hind paw. The corticosteroid, methylprednisolone
      (medrol), and the nonsteroidal antiinflammatory drug, flurbiprofen (Ansaid),
      administered at 2 mg/kg (p.o.), suppressed the clinical signs of CIA, and caused
      79 to 83% inhibition of hind paw inflammation. However, methylprednisolone, but
      not flurbiprofen, inhibited the joint pathology in CIA. The antirheumatic drugs,
      cyclophosphamide (cytoxan, 5 mg/kg, p.o.) and cyclosporin A (CsA, 25 mg/kg, p.o.)
      suppressed the cartilage erosion in inflamed rat joints, and exerted marked
      inhibition (89-100%) of hind paw swelling. Methotrexate (0.15 mg/kg, p.o.)
      treatment reduced hind paw swelling (48%), whereas azathioprine, D-penicillamine
      (DP) and the oral gold preparation, auranofin, were inactive. Anti-CII antibody
      titers were completely suppressed by cyclosporin A and cytoxan. Radiographic
      evidence of protection from bone resorption, osteophyte formation and soft tissue
      swelling was apparent in the tibiotarsal joints of cytoxan, cyclosporin A,
      methylprednisolone and methotrexate-treated rat.

PMID- 8667253
TI  - Renal ischemia/reperfusion up-regulates heme oxygenase-1 (HSP32) expression and
      increases cGMP in rat heart.
AB  - For the first time, the authors report an intimate link between kidney and heart
      functions as it pertains to the regulation of stress protein gene expression in
      the heart. They show that the stress on the target organ, the kidney, is
      translated into a response in the cardiovascular system, as reflected by the
      induction of heme oxygenase (HO)-1 gene expression, which, in turn, may be a
      cellular defense response as suggested by an increase in cGMP level in the heart,
      and an increase in the rate of bilirubin formation by the kidney and the heart.
      HO-1 is a stress protein (HSP32) and, together with HO-2, catalyzes oxidation of
      the heme molecule to generate CO, a likely signal molecule for the generation of
      cGMP, and bilirubin, an antioxidant. Specifically, bilateral renal ischemia for
      30 min caused a 3-fold increase in the approximately 1.8-kb HO-1 mRNA in the
      heart within 4 h after reperfusion and remained essentially at this level for 24
      h, at which point, a 2.6-fold increase in HO-1 mRNA in the descending aorta was
      also detected. Heart HO-1 mRNA remained elevated for more than 48 h; in contrast,
      at the 48-h time point, the transcript level in the kidney, which had increased
      by 10-fold 24 h after reperfusion, had returned to the control level. Neither in
      the heart nor in the kidney did HO-2 transcripts (approximately 1.3 and 1.9 kb)
      respond to renal ischemia/ reperfusion. The increase in heart HO-1 transcript
      level was accompanied by an increase in HO-1 protein, as judged by Western blot
      and immunohistochemical analysis, and in enzyme activity, as judged by bilirubin
      formation. In addition, cGMP concentration in the heart was elevated when
      measured at 24 h and 48 h after reperfusion of the kidney, in the absence of an
      increase in the activity of NO. Data suggest that hemodynamic stress caused by
      the occlusion of the renal artery is responsible for activation of HO-1 gene
      expression in the heart. An argument is made for the role of HO-1 in the defense
      mechanisms of the heart pertaining to the enzyme's function in a hemoprotein
      regulatory capacity, along with the biological activity of its products.

PMID- 8667254
TI  - Regional distribution and characterization of [3H]dextrorphan binding sites in
      rat brain determined by quantitative autoradiography.
AB  - The pharmacologic specificity and anatomic distribution of [3H]dextrorphan
      recognition sites in the rat brain was characterized by quantitative
      autoradiography. Equilibrium saturation analysis indicated that [3H]dextrorphan
      labeled a single population of high affinity binding sites. These sites are
      heterogeneously distributed throughout rat forebrain with the following order of
      binding densities: hippocampal formation > cerebral cortex > thalamic nuclei >
      striatum. The association rate of [3H]dextrorphan with its binding site in area
      stratum radiatum of CA1 is accelerated by the addition of glycine and glutamate.
      [3H]Dextrorphan binding is, however, relatively insensitive to glycine and
      glutamate under equilibrium conditions, despite extensive prewashing procedures
      to deplete endogenous levels of these substances. The competitive N-methyl-D
      aspartate (NMDA) antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and
      the glycine site antagonist 7-chlorokynurenic acid completely inhibit specific
      [3H]dextrorphan binding. D-AP5 suppresses [3H]dextrorphan binding in a regionally
      distinctive manner; a population of binding sites is weakly inhibited by D-AP5 in
      the lateral thalamic regions, whereas D-AP5 potently inhibits [3H]dextrorphan
      binding in the cerebral cortex. The rank order of potencies of an array of
      noncompetitive antagonists to inhibit [3H]dextrorphan binding unambiguously
      displays the pharmacologic profile of the noncompetitive antagonist domain of the
      NMDA receptor-channel complex. Furthermore, the distribution of [3H]dextrorphan
      binding sites in slide-mounted tissue appears qualitatively similar to the
      distribution of NMDA receptors previously reported using NMDA-displacement of
      [3H]glutamate, [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi
      ne (MK-801) and [3H]1-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) in most brain
      areas examined except the cerebellum. The molecular layer of the cerebellum
      displays a particularly high density of [3H]dextrorphan binding sites. The
      regional distribution of [3H]dextrorphan binding sites in rat brain does not
      correspond to the reported distributions of [3H]dextromethorphan or sigma binding
      sites.

PMID- 8667255
TI  - Oral white lesions with special reference to precancerous and tobacco- related
      lesions: conclusions of an international symposium held in Uppsala, Sweden, May
      18-21 1994. International Collaborative Group on Oral White Lesions.
AB  - An international group of epidemiologists, clinicians and pathologists with a
      special interest in oral white lesions and their precancerous significance has
      reviewed earlier work on this topic and identified some of the problems
      associated with previous definitions, descriptions and classifications.
      Modifications to these definitions, descriptions and classifications have been
      proposed, accompanied by explanations of the reasons for identifying the need for
      changes to be made. Leukoplakia may be a provisional or definitive diagnosis
      dependent upon the circumstances of oral examination and the availability of
      other information. Guidelines are provided to assist in the application of the
      definitions of oral leukoplakia and illustrations depict the homogeneous and non
      homogeneous clinical variants. Consideration is also given to the importance of a
      red component in a white lesion, or a lesion that is entirely red
      (erythroplakia). A new clinical staging procedure for oral leukoplakia is also
      proposed.

PMID- 8667256
TI  - Overexpression of p53 protein in squamous cell carcinoma of buccal mucosa and
      tongue in Taiwan: an immunohistochemical and clinicopathological study.
AB  - Sixty squamous cell carcinomas of tongue and buccal mucosa were examined for
      expression of p53 protein by using an immunohistochemical technique improved by
      an antigen retrieval method. Twenty-seven (45%) tumors demonstrated strongly
      positive staining. Thirteen of p53-positive tumors (48%) also exhibited
      overexpression of p53 in immediately adjoining hyperplastic or pre-malignant
      epithelium. All 22 metastatic lymph nodes and 18 local recurrent lesions (except
      two) had an identical p53 immunophenotype to their corresponding primary sites.
      Mitotic indices were significantly higher in p53-positive tumors (P < 0.01);
      however, no association of PCNA scores with p53 expression was found (P > 0.1).
      There was no correlation between p53 overexpression and tumor grade, size and
      staging, vascular invasion, lymph node metastasis, and early local recurrence.
      Overexpression of p53 was found to be relatively higher, although not
      statistically significant, in nonsmokers than in heavy smokers (66.7% vs. 42.9%),
      and in nonbetel-quid chewers than in heavy chewers (62.5% vs. 34.2%). These data
      are consistent with the hypothesis that inactivation of p53 protein may occur in
      the early phases of oral tumorigenesis. It may not be a useful prognostic marker
      but could possibly be used for risk assessment and surveillance of local
      recurrence.

PMID- 8667257
TI  - The use of antigen retrieval for immunohistochemical detection of p53 over
      expression in malignant and benign oral mucosa: a cautionary note.
AB  - The tumour suppressor gene p53 is frequently mutated in neoplasia. Since mutant
      p53 protein is often over-expressed, mutation can be indirectly detected by
      immunocytochemical techniques. As microwave antigen retrieval is becoming a
      widespread method for increasing the antigenicity of paraffin sections, we
      investigated the application of this technique to p53 immunohistochemical
      staining of oral mucosa specimens. Paraffin sections of 22 squamous cell
      carcinomas (SCC) and 36 benign lesions were immunohistochemically stained with
      and without antigen retrieval. Without antigen retrieval p53 over-expression was
      observed in 6/22 SCC and 1/36 benign lesions. Following antigen retrieval
      positive staining was observed in 15/22 SCC and 35/36 benign lesions. Staining in
      benign lesions was confined to basal and parabasal cells and could reflect normal
      functioning of wild-type p53. We conclude that antigen retrieval increases the
      sensitivity of p53 immunoreactivity, but such staining is not specific for
      malignancy and should be interpreted with caution.

PMID- 8667258
TI  - Minimal arecaidine concentrations showing a promotion effect during DMBA-induced
      hamster cheek pouch carcinogenesis.
AB  - The purpose of the present study was to determine the minimal arecaidine
      concentrations showing a synergistic effect on DMBA-induced hamster cheek pouch
      carcinogenesis. One hundred and twelve male adult Syrian golden hamsters were
      divided into 16 groups, each containing seven animals. After eight weeks of DMBA
      initiation and then four weeks of arecaidine promotion, 100% tumor incidence was
      found with arecaidine concentrations of 400 micrograms/ml and 500 micrograms/ml;
      average tumor numbers were 1.86 +/- 0.63 and 1.86 +/- 0.93 respectively (P <
      0.05). After four weeks of DMBA and a subsequent eight weeks of arecaidine
      painting, all hamsters developed visible tumors with arecaidine concentrations of
      900 micrograms/ml and 1000 micrograms/ml; average tumor numbers were 1.86 +/-
      0.82 and 2.14 +/- 1.09 respectively (P < 0.05). The tumor dimensions varied
      little and differences were not statistically significant. Without DMBA
      pretreatment, regardless of the high arecaidine concentrations (1000
      micrograms/ml, 2000 micrograms/ml and 3000 micrograms/ml) applied, no visible
      tumor growth was observed; only hyperkeratosis and inflammation could be
      discerned histologically. Thus, the minimal concentrations of arecaidine
      displaying a synergistic effect in the DMBA-induced hamster cheek pouch of
      carcinogenesis were found to be 400 micrograms/ ml applied for four weeks after
      eight weeks of DMBA application, and 900 micrograms/ml applied for eight weeks
      after four weeks of DMBA painting. These findings may be useful for other studies
      concerning the tumorgenicity of arecaidine.

PMID- 8667259
TI  - Prevalence and related risk factors of betel quid chewing by adolescent students
      in southern Taiwan.
AB  - The prevalence and related risk factors of betel quid chewing among adolescent
      students were studied in a junior high school (group 1) and in a vocational
      school (group 2) in southern Taiwan. Group 1 consisted of 3548 participants
      (89.7% response rate) and group 2 of 1358 (97.6% response rate). The students
      were asked to complete a questionnaire anonymously. In the junior high school
      1.9% of students including all grades (13-15 years old) and both sexes was found
      to be a current betel quid chewer and 14% was an ex-chewer, whereas 10.2% of
      vocational school students (16-18 years old) was a current chewer and 31% was an
      ex-chewer. The prevalence of betel chewing was significantly higher among boys
      than girls. A high proportion of chewers was also a smoker and alcohol drinker. A
      statistical analysis of sociodemographic factors showed that male students who
      smoked tobacco, consumed alcohol and were friends or classmates of students who
      were betel quid chewers, were the likeliest adolescents to chew betel quid.

PMID- 8667260
TI  - Scanning electron microscopic and immunocytochemical studies of contraction
      during secondary CO2 laser wound healing in rat tongue mucosa.
AB  - An experimental model was established in which the decrease in surface area of
      CO2 laser wounds on rat tongues was measured during the healing process. Scanning
      electron microscopy was used to measure and delineate the outlines of the initial
      wounds and those of the residual wounds. A 50% decrease in the surface area of
      the wounds was observed 10 days after surgery during the healing process. At day
      30, the scar surface area was less than 10% (7.4%) of the wound surface area at
      day 2. This contrasts with studies reported elsewhere where only minimal
      contraction was observed during the healing of CO2 laser wounds. Immunoperoxidase
      techniques revealed that three different phenotypes of myofibroblasts were
      present inside the healing area, expressing vimentin, actin and desmin. These
      persisted until day 30 after CO2 irradiation.

PMID- 8667261
TI  - An immunohistochemical study of collagen types III, VI and IX in rabbit
      craniomandibular joint tissues following surgical induction of anterior disk
      displacement.
AB  - The purpose of this study was to determine the effect of surgical induction of
      anterior disk displacement (ADD) on type-III, VI and IX collagens of the rabbit
      craniomandibular joint (CMJ) tissues using an immunohistochemical technique. The
      right joint was exposed surgically, all discal attachments were severed except
      for the posterior discal attachment (bilaminar zone). The disk was then
      repositioned anteriorly and sutured to the zygomatic arch. The left joint served
      as a sham-operated control. Ten additional joints were used as non-operated
      controls. Deeply anesthetized rabbits were perfused with 2% buffered formalin 2
      weeks (10 rabbits) or 6 weeks (10 rabbits) following surgery. The articular disk,
      bilaminar zone, mandibular condyle and articular eminence were excised. The last
      two were decalcified in EDTA. All tissues were then sectioned at 10 microns in a
      cryostat. Sections were incubated with monoclonal antibodies directed against
      type-III, VI or IX collagens. Following incubation in the appropriate FITC
      labelled secondary antibodies, all sections were studied under the fluorescence
      microscope. The results showed a reduction in immunostaining for type-VI and IX
      collagens in the condylar cartilage, disk and articular eminence at 2 weeks,
      followed by an increase in their immunostaining at 6 weeks and the appearance of
      a de novo type-III collagen in the condylar cartilage and the articular eminence.
      It is concluded that surgical induction of ADD in the rabbit CMJ leads to
      alterations in its type-III, VI and IX collagens.

PMID- 8667262
TI  - Anomalies in the permanent dentition and other oral findings in 29 individuals
      with Laurence-Moon-Bardet-Biedl syndrome.
AB  - This paper reports a clinical and roentgenological examination of the teeth, jaws
      and saliva of 29 Scandinavian individuals with Laurence-Moon-Bardet-Biedl (LMBB)
      syndrome, whose cardinal signs are retinal dystrophy, polydactyly, obesity,
      hypogenitalism and mental retardation. All subjects had at least three of these
      signs, including retinal dystrophy. Compared with normal subjects, the group had
      statistically significantly higher frequencies of hypodontia, small teeth and
      short roots. In addition, the saliva showed a buffering capacity higher than
      normal. In conclusion, there seem to exist disturbances of both dental and
      skeletal formation in the LMBB syndrome.

PMID- 8667263
TI  - Polypoid carcinoma of the tongue.
AB  - An unusual case of polypoid carcinoma in a 72-year-old woman is reported. The
      tumor showed a pedunculated growth on the lateral border of the tongue and was
      composed of a malignant basaloid component in intimate association with definable
      foci of epithelial dysplasia of the surface mucosa. It was considered that
      histologic features of the present case corresponded with those of basaloid
      squamous carcinoma.

PMID- 8667264
TI  - Immunohistochemical observations on a possible ameloblastic fibro-odontoma.
AB  - An ameloblastic fibro-odontoma which occurred in the mandible of a 3-year-old
      Japanese boy is reported together with immunohistochemical findings.
      Histologically, the tumor consisted of an ameloblastic fibroma-like area and some
      typical complex odontoma-like areas. The epithelial islands in the ameloblastic
      fibroma-like area showed different developmental stages of the epithelial
      connective tissue interface. Immunohistochemical examination revealed that all
      epithelial components in the ameloblastic fibroma-like area showed expression of
      CK 8, CKs 13, 16, CK 14, CK 18 and CK 19, and coexpression of these cytokeratins
      and vimentin. These findings suggest that even the epithelial component without
      obvious epithelial-mesenchymal induction showed the final cell differentiation of
      the enamel organ with the potential for epithelial-mesenchymal induction.

PMID- 8667265
TI  - Combination syndrome associated with a mandibular implant-supported overdenture:
      a clinical report.

PMID- 8667266
TI  - Acrylic resin labial flange for a Kennedy Class I partial denture: a clinical
      report.
AB  - Traditionally the distal extension mandibular RPD is designed with the use of
      major connectors in cobalt chromium alloy with its associated clasping systems.
      However when few teeth remain, especially in the mandible, it may be helpful to
      use an alternative method of treatment, such as this acrylic resin labial denture
      design to provide as inexpensive interim alternative. The design allows easy
      additions of artificial teeth to the denture. Patients on whom this design is
      used should pursue an intense course of oral hygiene to maintain the condition of
      the periodontium and ridge.

PMID- 8667267
TI  - Use of a modified ear face-bow for surgical stent location during ear implant
      placement: a clinical report.

PMID- 8667268
TI  - Surface roughness of dentin after tooth preparation with different rotary
      instrumentation.
AB  - Although surface finish can be a critical variable in clinical performance, there
      is a dearth of information regarding surface characteristics of teeth prepared
      for artificial crowns. This study characterized teeth prepared for complete cast
      restorations using three representative types of rotary instruments. One hundred
      and five standardized tooth preparations for complete crowns were performed using
      a modified milling machine on extracted human teeth with diamond, tungsten
      carbide, and tungsten carbide finishing burs of similar shape (n = 35). The
      prepared dentin was analyzed with a surface profilometer and a scanning electron
      microscope (SEM). Differences between rotary instrument groups were determined
      with parametric ANOVA and Tukey's Studentized Range (HSD). Statistically
      significant differences in the surface topography of prepared teeth were open.
      Mean surface roughnesses (Ra) were 8.6 and 6.8 mum for teeth prepared with
      diamond and tungsten carbide burs. Teeth completed with finishing burs appeared
      to result in a smoother surface (1.2 mum).

PMID- 8667269
TI  - Effect of two dentinal desensitizing agents on retention of complete cast coping
      using four cements.
AB  - The cementation of artificial crowns is commonly accompanied by sensitivity, so
      the clinical application of desensitizing agents has become prevalent. This study
      investigated the effects of Imperva bonding agent and All-Bond desensitizing
      agent on the retention of artificial crowns. The cements selected for this study
      were: zinc phosphate, polycarboxylate, glass ionomer, and resin luting agents.
      Extracted, intact, human molars were mounted in autopolymerizing acrylic resin
      and prepared for complete cast copings. Thirty-two teeth were treated with All
      Bond desensitizing agent, 32 teeth with Imperva bonding agent, and 32 remained
      untreated. Castings were cemented and tested on an Instron testing machine. The
      results demonstrated a significant reduction in retention when All-Bond
      desensitizing agent was used with polycarboxylate cement and some reduction with
      zinc phosphate cement. Imperva bonding agent demonstrated less retention with
      glass ionomer cement.

PMID- 8667270
TI  - Practical considerations and technical procedures for post-retained restorations.
AB  - Post-retained restorations are a practical and dependable treatment option for
      restoring teeth with insufficient coronal tooth structure. Manufactured post
      patterns combined with an effective clinical procedure will provide a simple,
      reliable, and economic method to produce restorations with a cast tapered post.
      The cast tapered post can be used for all clinical applications in which a post
      retained restoration is indicated.

PMID- 8667271
TI  - Influence of post dimension on stress distribution in dentin.
AB  - Stress distribution studies can be helpful in determining the appropriate
      diameter and length of endodontic posts for specific teeth in select occlusal
      relationships. This study selected the finite element method to predict
      distribution of stresses in dentin of an endodontically treated tooth restored
      with cast post and cores with various post dimensions. Peak dentinal shear
      stresses occurred adjacent to the post at mid-root. Peak shear stresses were
      elevated as the length of the post decreased. Peak dentinal tensile stresses
      occurred in the gingival third of the facial root surface, whereas peak dentinal
      compressive stresses were evident in the gingival third of the lingual root
      surface. The distribution of tensile and compressive stresses was not affected
      with variation in the dimensions of the posts.

PMID- 8667272
TI  - Comparison of fatigue for three prefabricated threaded post systems.
AB  - Post designs may have a direct effect on fracture resistance of endodontically
      treated teeth. This in vitro study compared the resistance of three prefabricated
      threaded post systems with lateral shearing forces. After endodontics were
      completed, prefabricated posts were inserted according to the manufacturer's
      instructions. A silver amalgam core was placed, and extracted human teeth were
      prepared to a standard size with a 1 mm gingival chamfer finished on sound
      dentino A cast was fabricated and cemented, and the specimens were thermocycled.
      The test samples were secured to an Instron testing machine and loaded until
      failure. Fracture patterns were recorded, fractured surface areas were measured,
      and compressive stresses were calculated. However, there were no statistically
      significant differences among threaded posts in each test group.

PMID- 8667273
TI  - Shear bond strength of several new core materials.
AB  - This study compared the shear bond strengths of three core materials: a light
      activated glass-ionomer cement (VariGlass VLC), a fluoride-release dual cure
      composite resin (Fluoro Core), and a conventional silver-reinforced glass-ionomer
      cement (Miracle Mix) when cured to dentin. Fifty-four noncarious molar teeth were
      extracted, cleaned, mounted in acrylic resin, and sectioned horizontally to
      expose the dentin surface. Each material was mixed according to manufacturer's
      instructions, applied in a premade mold to the exposed dentin, and then cured.
      The specimens were randomized into three group (six teeth from each material) and
      stored (37 degrees C, 100% humidity) for 15 minutes, 24 hours, and 24 hours and
      were then thermocycled (5 degrees to 55 degrees C) for 125 cycles. The specimens
      were tested for shear bond strength with the Instron universal testing machine.
      The differences among time groups were not statistically significant except for
      Miracle Mix and VariGlass VLC cements, which showed a greater improvement with
      thermocycling. This study indicated that the FluoroCore resin exhibited the
      greatest shear bond strength of the core materials and that VariGlass VLC cement
      had greater bond strength than Miracle Mix cement except after thermocycling,
      when VariGlass VLC cement and FluoroCore resin were not significantly different.

PMID- 8667274
TI  - Clinical comparison of postoperative sensitivity for a glass ionomer and a zinc
      phosphate luting cement.
AB  - In 60 patients, 120 partial and full-coverage restorations were cemented on vital
      abutment teeth with either a glass ionomer or a zinc phosphate luting cement. A
      split-mouth design and a patient blind data acquisition protocol were used.
      During an average observation period of 17.3 months there were no differences
      between the two types of luting cements in regard to subjective and clinical
      parameters. A high incidence of postoperative hypersensitivity, which is often
      said to accompany the use of glass ionomer luting cements, was not observed. With
      the cementation method used in this study, the glass ionomer cement Ketac-Cem
      Maxicap was an acceptable alternative to conventional zinc phosphate cement.
      Capsule systems make the clinical handling of glass ionomer luting cements safe
      and easy and should be used routinely in dental practice.

PMID- 8667276
TI  - Perspective of facial esthetics in dental treatment planning.
AB  - Enhancement of facial beauty is one of the primary elective goals of patients
      seeking dental care. The lower one third of the face has a major impact on the
      perception of facial esthetics. Frequently improvements in natural beauty can be
      expected to follow restoration of ideal relationships between the denture and the
      facial soft tissues. By improving deficient facial proportion and integumental
      form, surgeons, orthodontists, and restorative dentists have the unique
      opportunity to address these esthetic needs. Comprehensive evaluation that
      relates the facial soft tissues to underlying skeletal form provides this
      possibility. Fundamental relationships exist that allow correlation of
      deficiencies in facial form to existing dentoalveolar anatomy. Classical
      evaluation of mounted casts and occlusal analysis does not offer this insight.

PMID- 8667275
TI  - Bond strength and durability of porcelain bonding systems.
AB  - Because the most effective bonding system for ceramic restorations has not been
      documented, this study examined bond strength and durability of bonding systems
      joined to a feldspathic porcelain. Disks of porcelain specimens were fired on
      refractory investment materials and were air-abraded with alumina. The disks were
      then bonded with six combinations of five silane primers and six luting agents.
      Durability of the bond was evaluated by means of a thermocycling machine. Shear
      bond strengths were determined before and after thermocycling. The results showed
      that reduction in bond strengths after thermocycling was remarkable for five
      systems (p < 0.05). However, three systems exhibited shear bond strength greater
      than 20 MPa after 20,000 cycles.

PMID- 8667277
TI  - A cephalometric study comparing the occlusal plane in dentulous and edentulous
      subjects in relation to the maxillomandibular space.
AB  - This study examines the validity of Camper's plane as a guide to determine the
      occlusal plane in edentulous subjects. Based on the data collected from the
      cephalometric tracings of 40 dentulous and edentulous patients and with the use
      of the significant correlations of the variables of the maxillomandibular space
      established from the dentulous group, the dentulous and edentulous groups were
      classified into four subdivisions based on length and maxillomandibular angle.
      The occlusal plane/maxillary plane angles and the occlusal plane/mandibular plane
      angles were then compared to check for similarities in the two groups.

PMID- 8667279
TI  - Indicators of masticatory performance among elderly complete denture wearers.
AB  - The literature on current techniques for evaluating the masticatory capacity
      leads to categorizing them into two groups: objective masticatory tests and
      questionnaires that evaluate the subject masticatory capacity. This study
      examines how a simple questionnaire on the reported capacity to chew certain food
      can predict the masticatory performance of edentulous elderly patients. The
      masticatory performance of 367 completely edentulous elderly persons was measured
      with the Swallowing Threshold Test Index and compared with their reported
      masticatory capacity previously measured with a questionnaire on the capacity of
      the individual to chew nine food items. A total of 47.4% of the individuals had a
      low masticatory performance. This problem was more frequent in women (51.7%) than
      in men (41.8%). In measuring the reported masticatory performance with seven of
      the nine food items listed in the questionnaire, this indicator predicted the
      masticatory performance with a sensitivity of 65.5% and a specificity of 81.9%.
      However, even though the measure of prosthesis retention/stability is related to
      the masticatory performance, it was not a good predictor.

PMID- 8667278
TI  - Effect of light-exposure duration on the amount of leachable monomers from light
      activated reline material.
AB  - Leaching of monomers from light-activated direct intraoral reline material
      (Lebaron LC) was determined by means of high-pressure liquid chromatography
      analysis. This study evaluated the effects of exposure duration and thickness to
      determine appropriate curing conditions that reduce the levels of unreacted
      monomeric components. Prolonged duration of exposure (30 minutes) reduced the
      amount of leached monomer. However, the results of this study indicated that the
      amount of leached monomeric components increased with an increasing reline
      material thickness. The results suggest that the light-activated reline material
      should be cured for sufficient prolonged exposure duration.

PMID- 8667281
TI  - Pterygoid hamulus bursitis: one cause of craniofacial pain.
AB  - Craniofacial pain disorders are frustrating to the doctor and the patient.
      Diagnosis is often difficult because the anatomy of the head and neck region is
      complex, grossly and neurologically. Frequently, several pain syndromes exhibit
      similar symptoms. One such disorder is bursitis of the pterygoid hamulus. This
      type of bursitis may produce symptoms of soft palatal, ear, and throat pain,
      maxillary pain, and difficulty and pain on swallowing. This disorder is often
      misdiagnosed as otitis media. Treatment may be conservative or surgical. This
      article discusses the anatomy, symptoms, diagnosis, and treatment of bursitis of
      the hamular process.

PMID- 8667280
TI  - Clinical aspects of a multicenter clinical trial of implant-retained mandibular
      overdentures in patients with severely resorbed mandibles.
AB  - In a multicenter clinical trial treatment, the effects of overdentures on
      different implant systems in patients with severely resorbed mandibles were
      compared 1 year after the insertion of new dentures. The implant systems used
      were the transmandibular implant (TMI), the IMZ (IMZ), and the Branemark system
      (BRA). Treatment was randomly assigned to 88 patients according to a balanced
      allocation method. Evaluation included peri-implant and radiographic parameters.
      According to the Delphi method a Clinical Implant Performance scale (CIP) was
      constructed based on all conceivable complications of the different implant
      systems. During the healing period, one IMZ and one BRA implant were lost, and
      one TMI implant was removed after functional loading. The results of the peri
      implant and radiographic parameters and the CIP scale revealed no significant
      differences between the three implant systems.

PMID- 8667282
TI  - Effect of selected physical properties of waxes on investments and casting
      shrinkage.
AB  - This study evaluated the relationship between flow characteristics, bending
      strength, and softening temperature of paraffin and dental inlay waxes to casting
      shrinkage when patterns were invested with a phosphate-bonded investment. This
      study found that the casting shrinkage decreased as the flow of the wax pattern
      increased. If a low flow wax is used or if there is a need for a thick pattern,
      the size of the casting ring should be increased. When wax patterns are formed
      for cast restorations, it is important to select the type of wax with the most
      desirable properties for the margin and the occlusal portions. Moreover, to
      accurately fabricate castings, it is necessary to understand the physical
      properties of the chosen waxes.

PMID- 8667284
TI  - Time-management training: effects on time behaviors, attitudes, and job
      performance.
AB  - This quasi-experimental field study examined the effects of a time-management
      training program on 44 employees' self-reports of time-management behavior
      control over their time, job satisfaction, and stress responses, and on
      supervisor's ratings of these employees' job performance. Contrary to
      expectations, respondents did not report more frequent use of time-management
      behaviors, more job satisfaction, or less job-induced tension after training,
      compared with those not receiving training. Job performance did not significantly
      change after training. The training-group participants' perceptions of control
      over time, however, increased 4 to 5 months after training, approaching the level
      maintained by the no-training group. Thus, in general, the assertions made about
      time management were not supported.

PMID- 8667283
TI  - Porphyromonas gingivalis endotoxin affinity for dental ceramics.
AB  - This study evaluated the effects of chemical composition, surface treatment, and
      initial exposure dose on Porphyromonas gingivalis lipopolysaccharide adherence to
      and elution from dental ceramics. Lipopolysaccharide, commonly known as
      endotoxin, can initiate a variety of biologic responses. Opaque, body, and Dicor
      ceramic disks were individually exposed to 250, 1000, or 2500 EU/ml 3H
      lipopolysaccharide and incubated for 24 hours at 37 degrees C. Disks were then
      transferred to fresh lipopolysaccharide-free water and incubated for up to 96
      hours to evaluate elution. Mean initial lipopolysaccharide adherence ranged from
      0.397 +/- 0.048 EU/mm2 to 5.056 +/- 0.117 EU/mm2. Greater initial exposure levels
      resulted in greater adherence, and at higher lipopolysaccharide exposure levels,
      lipopolysaccharide adherence differences were based on ceramic type. Mean
      lipopolysaccharide elution levels ranged from 0.063 +/- 0.02 EU/mm2 to 0.00
      EU/mm2 at 96 hours for all groups. Greater initial adherence resulted in greater
      elution. Ceramic type did not affect elution. Surface finish affected elution at
      the 2500 EU exposure level. The affinity of lipopolysaccharide for dental
      ceramics could contribute to a periodontal inflammatory process.

PMID- 8667286
TI  - Olfactory memory: a case study in cognitive psychology.
AB  - Over the last decade, interest in the general applicability of psychological
      research has increased significantly, leading to doubts among some critics of
      cognitive psychology regarding the usefulness of the modern information
      processing approach. In particular, current cognitive models of memory address
      mainly visual and verbal information processing, with little acknowledgement of
      the existence of other sensory modalities. However, since the mid-1970's, the
      literature on olfactory memory has expanded rapidly, and it has remained
      relatively independent of mainstream memory research. This article outlines the
      olfactory literature, which has focused principally on examination of the
      Proustian characteristics of smell. The relationship between olfactory and other
      types of memory is also examined. The author notes that there is evidence that
      models of memory intended to be general have taken insufficient account of
      findings from olfaction and other sensory modalities, an approach that could be
      considered symptomatic of dangerous tendency to base purportedly general theories
      on databases that are too narrow.

PMID- 8667285
TI  - Predicting dyadic adjustment from general and relationship-specific beliefs.
AB  - The cognitive mediation model of human psychological functioning has received
      increasing attention by researchers studying the role of cognitive variables in
      relationship distress. This study is an examination of the role of general
      irrational beliefs, as measured by the Irrational Beliefs Test (IBT; Jones,
      1968), and relationship-specific irrational beliefs, as measured by the
      Relationship Belief Questionnaire (RBQ; Romans & DeBord, 1994), in predicting the
      perceived quality of relationships by married or cohabiting couples. Results
      indicated that respondents who reported higher levels of relationship-specific
      irrational beliefs also reported higher levels of dyadic adjustment; but contrary
      to expectation, higher levels of general irrational beliefs correlated with lower
      levels of dyadic adjustment. Implications of these findings are discussed in
      relation to the depressive realism hypothesis.

PMID- 8667287
TI  - The effects of researcher precautions on perceptions of the ethicality of
      unobtrusive field experiments.
AB  - The effects of stating researchers' precautions on perceptions about the
      ethicality of questionable studies were examined. The studies used were by West,
      Gunn, and Chernicky (1975) and by Middlemist, Knowles, and Matter (1976). The
      first study was generally evaluated more favorably than the second study. Women
      viewed the West et al. study more negatively than did men, regardless of
      precautionary information. Most important, precautionary information enhanced
      men's, but not women's evaluations of the Middlemist et al. study. Implications
      of these results for ethical decision making, publication policy, and the image
      of the profession are noted.

PMID- 8667288
TI  - Presentation format in analogue studies: effects on participants' evaluation.
AB  - Whether presentation format (video, audio, written transcript, or written
      transcript with photograph) affects participants' responses to counseling
      scenarios in an analogue study was examined. After watching a brief counseling
      session presented in one of four formats, 131 participants completed three
      instruments measuring counselor credibility and expectations. Results revealed
      significant differences among the formats on teh COunselor Rating Form (CRF-S;
      Corrigan & Schmidt, 1983) Trustworthiness and Expertness Scales, with transcripts
      with pictures rated the highest (higher than videotape and audiotape) and
      transcripts without pictures rated second highest (higher than video). No
      significant differences between the presentation formats were revealed on the
      Expectations about Counseling Questionnaire (EAC; Tinsley, Workman, & Kass, 1980)
      or 15 Personal Problem Inventory (15PPI; Cash, Begley, McCown, & Weise, 1975).
      Results suggest that studies using differing formats with the CRF-S are not
      necessarily comparable and that the four types of analogue approaches may not be
      interchangeable.

PMID- 8667289
TI  - The central connections and actions during walking of tibial campaniform sensilla
      in the locust.
AB  - Strain acting on the exoskeleton of insects is monitored by campaniform sensilla.
      On the tibia of a mesothoracic leg of the locust (Schistocerca gregaria) there
      are three groups of campaniform sensilla on the proximo-dorsal surface. This
      study analyses the responses of the afferents from one group, their connections
      with central neurones and their actions during walking. The afferents of the
      campaniform sensilla make direct excitatory connections with flexor tibiae motor
      neurones. They also make direct connections with particular spiking local
      interneurones that make direct inhibitory output connections with the slow
      extensor tibiae motor neurone. During walking extension movements of the tibiae
      during stance produce longitudinal tensile forces on the dorsal tibia that peak
      during mid stance before returning to zero prior to swing. This decline in
      tension can activate the campaniform sensilla. In turn this would lead to an
      inhibition of the extensor tibiae motor neurone and an excitation of the flexor
      tibiae motor neurones. This, therefore, aids the transition from stance to swing.
      During turning movements, the tibia is flexed and the dorsal surface is put under
      compression. This can also activate some of campaniform sensilla whose effect on
      the flexor motor neurones will reinforce the flexion of the tibia.

PMID- 8667290
TI  - Patch-clamp study on membrane properties and transmitter activated currents of
      rabbit area postrema neurons.
AB  - Using the patch-clamp technique in combination wit sliced tissue preparation the
      membrane properties of newborn rabbit area postrema neurons were investigated.
      The neurons responded upon depolarization with a fast Na+-current followed by an
      inactivating and non-inactivating K+-current. GABA-activated currents were
      investigated resulting in a large C1-(-)conductance, indicating the expression of
      GABAA-receptors. The expression of glutamate receptor mRNA was studied by in situ
      hybridization and electrophysiological measurements of these receptors by means
      of the patch-clamp technique. As a main result it was found that ionotropic
      glutamate receptors in the area postrema are composed of "flop" variants of the
      GluA-, GluB- and GluC-subunits.

PMID- 8667291
TI  - Hearing in the FM-bat Phyllostomus discolor: a behavioral audiogram.
AB  - Absolute auditory thresholds of six adult lesser spear-nosed bats Phyllostomus
      discolor (Chiroptera, Phyllostomidae) were determined in a two-alternative forced
      choice procedure. Behavioral response to pure tone stimuli could be elicited
      throughout the tested frequency range of 5-142 kHz. The shape of the average
      audiogram is characterized by two sensitivity peaks and a pronounced increase of
      thresholds around 55 kHz, and towards the limits of the tested frequency range.
      The spectral extent of both sensitivity peaks shows a close relation to the
      bandwidth of two types of species-specific vocalizations. The first low threshold
      area (> 10 and < 55 kHz) of the audiogram seems perfectly adapted to the
      directive call used for intraspecifc communication, whereas the second
      sensitivity peak, centered around 85 kHz, covers most of the bandwidth of the
      species' echolocation calls.

PMID- 8667292
TI  - Detection of frequency modulation in the FM-bat Phyllostomus discolor.
AB  - In a two-alternative forced-choice procedure lesser spear-nosed bats,
      Phyllostomus discolor, had to discriminate between a pure tone stimulus and a
      sinusoidally frequency-modulated signal generated at the same carrier frequency
      as the tone. Modulation depths of the SFM stimuli were reduced until the animals'
      performance dropped below the 75%-correct level which was used to determine
      difference limens for detection of frequency modulation (FMDL). The dependence of
      FMDLs on modulation and carrier frequency was systematically investigated. For a
      carrier frequency of 18.5 kHz, average FMDLs increased from 95 Hz at a modulation
      frequency of 10 Hz to 820 Hz at a modulation frequency of 2000 Hz which
      corresponds to Weber ratios (2 delta f/f) of 0.005 and 0.044 respectively.
      Further, difference limens were found to increase linearly in proportion to
      carrier frequency throughout a major part (9-74 kHz) of the species' hearing
      range. In comparison to other mammals, P. discolor has a pronounced capability
      for frequency discrimination which might be related to the extensive use of
      individually distinct frequency-modulated communication calls and audio-vocal
      learning.

PMID- 8667293
TI  - Spectral sensitivity of photoreceptors mediating phase-shifts of circadian
      rhythms in retinally degenerate CBA/J (rd/rd) and normal CBA/N (+/+)mice.
AB  - Light-dark cycles are the most important time cue for the circadian system to
      entrain the endogenous circadian clock to the environmental 24 h cycle. Although
      photic entrainment of circadian rhythms is mediated by the eye in mammals,
      photoreceptors implicated in circadian photoreception remain unknown. In our
      previous study, retinally degenerate CBA/J (rd/rd) mice were found to have lower
      circadian photosensitivity for phase-shifting the locomotor activity rhythms than
      normal CBA/N(+/+) mice. In the present study, the spectral sensitivity for phase
      shifting the rhythms was examined in order to characterize the photopigments
      involved in circadian photoreception of these mice. The spectral sensitivity of
      CBA/J-rd/rd mice clearly fitted to the Dartnall nomogram for a retinal(1)-based
      pigment with a maximum at 480 nm, while the best fitted nomogram had a maximum at
      500 nm in CBA/N- +/+ mice. These results suggest that circadian photopigments
      involved in CBA/J-rd/rd and CBA/N- +/+ mice may be different.

PMID- 8667294
TI  - The control of wing kinematics by two steering muscles of the blowfly (Calliphora
      vicina).
AB  - We used a combination of high speed video and electrophysiological recordings to
      investigate the relationship between wing kinematics and the firing patterns of
      the first (b1) and second (b2) basalar muscles of tethered flying blowflies
      (Calliphora vicina). The b1 typically fires once during every wing stroke near
      the time of the dorsal stroke reversal. The b2 fires either intermittenly or in
      bursts that may be elicited by a visual turning stimulus. Sustained activation of
      the b1 at rates near wing beat frequency appears necessary for tonic maintenance
      of stroke amplitude. In addition, advances in the phase of b1 activation were
      correlated with both increased wing protraction during the down-stroke and
      increased stroke amplitude. Similar kinematic alterations was correlated with b2
      spikes, and consequently, both muscles may function in the control of turns
      toward the contralateral side. The effects of the two muscles were evident within
      a single stroke period and decayed quickly. Kinematic changes correlated with b1
      phase shifts were graded, suggesting a role in compensatory course stabilization.
      In contrast, b2 spikes were correlated with all-or-none changes in the wing
      stroke, a characteristic consistent with a role in mediating rapid turns towards
      or away from objects.

PMID- 8667295
TI  - Quantitative assessment of song-selectivity in the zebra finch "high vocal
      center".
AB  - 1. Auditory responses in the zebra finch (Taenopygia guttata) song-system nucleus
      HVc were assessed at 54 recording sites by 3 different methods: discriminated
      action potentials; excitatory summed responses; and excitatory minus inhibitory
      summed responses. Four standard stimuli were presented at each site: the bird's
      own song; this song reversed; a conspecific song; and a noise burst. Responses
      were quantified by calculating a relative response index that partitoned the
      response, to provide a response profile, across the stimuli. 2. Regardless of
      analysis method, the strongest response was most often to the bird's own song (78
      82%, depending on method). The predominant rank order of response strength across
      the remaining three stimuli was conspecific song > reversed song > noise. 3. The
      distribution of relative response magnitude was sensitive to analysis method.
      Discriminated spikes captured the heterogeneity of HVc neurons, whereas the
      excitatory summed responses reflected. the overall trends more consistently. When
      inhibition was subtracted from excitation in the summed responses, the variance
      of the relative responses increased, but this method presented some problems for
      statistical analysis. 4. A small sample of neurons in other forebrain auditory
      areas was used for comparative analyses. At these recording sites, the bird's own
      song did not consistently elicit the best response and there were generally
      smaller differences in the relative responses to the four stimuli. The smaller
      degree of stimulus selectivity among these cells resulted in less sensitivity to
      differences in the assessment methods.

PMID- 8667296
TI  - What can prosody tell a parser?
AB  - In this paper, I consider how a sentence processor might use specific prosodic
      cues at various points in the processing of particular sentences containing (at
      least temporary) syntactic ambiguity. In principle, the usefulness of prosodic
      information depends on what a given cluster of prosodic cues typically signifies,
      and on which syntactic options exist for a given string: in only some instances
      can prosodic information provide useful disambiguating information.

PMID- 8667297
TI  - A prosody tutorial for investigators of auditory sentence processing.
AB  - In this tutorial we present evidence that, because syntax does not fully predict
      the way that spoken utterances are organized, prosody is a significant issue for
      studies of auditory sentence processing. We describe the basic elements and
      principles of current prosodic theory, review the psycholinguistic evidence that
      supports an active role for prosodic structure in sentence representation, and
      provide a road map of references that contain more complete arguments about
      prosodic structure and prominence. Because current theories do not predict the
      precise prosodic shape that a particular utterance will take, it is important to
      determine the prosodic choices that a speaker has made for utterances that are
      used in an auditory sentence processing study. To this end, we provide
      information about practical tools such as systems for signal display and prosodic
      transcription, and several caveats which we have found useful to keep in mind.

PMID- 8667298
TI  - The influence of prosodic structure on the resolution of temporary syntactic
      closure ambiguities.
AB  - This paper investigates the influence of prosodic structure on the process of
      sentence comprehension, with a specific focus on the relative contributions of
      syntactic and prosodic information to the resolution of temporary syntactic
      closure ambiguities. We argue that prosodic structure provides an initial memory
      representation for spoken sentences, and that information from this prosodic
      representation is available to inform syntactic parsing decisions. This view
      makes three predictions for the processing of temporary syntactic ambiguity: 1.
      When prosodic and syntactic boundaries coincide, syntactic processing should be
      facilitated. 2. When prosodic boundaries are placed at misleading points in
      syntactic structure, syntactic processing should show interference effects. 3.
      The processing difficulties that have been reliably demonstrated in reading
      experiments for syntactically complex sentences should disappear when those
      sentences are presented with a felicitous prosodic structure in listening
      experiments. These predictions were confirmed by series of experiments measuring
      end-of-sentence comprehension time and cross-modal naming time for sentences with
      temporary syntactic closure ambiguities. Sentences with coinciding or conflicting
      prosodic and syntactic boundaries were compared to a prosodic baseline condition.

PMID- 8667299
TI  - Exploring the use of prosody during language comprehension using the auditory
      moving window technique.
AB  - Researchers in psycholinguistics have speculated about the possible role of
      prosody in resolving syntactic ambiguities. We argue in this paper that the issue
      is complicated by the following considerations: first, prosody may be even more
      effective at conveying semantic information than syntactic structure, yet the
      question how prosody signals meaning is essentially unstudied. Second, the one-to
      many relation between syntactic and prosodic structure leads to a great deal of
      variability across speakers and contexts in the way a given sentence will be
      produced. The parser must somehow deal with this variability. Third, resolution
      of architectural debates in the parsing literature requires the use of sensitive,
      online techniques for measuring processing load during comprehension. In the
      auditory domain, no optimal technique is presently available. We discuss the
      strengths and weaknesses of a technique we introduced in previous work, which is
      an analogue of the visual moving window. We present the results of an experiment
      demonstrating that the technique preserves some aspects of the prosody of a
      spoken sentence but disrupts others, and we discuss ways of dealing with this
      problem. We conclude that the technique is useful for studying language
      processing, including the use of prosody during parsing. However, we also argue
      that researchers should study not just the role of prosody in parsing, but also
      its role in establishing sentence meaning.

PMID- 8667300
TI  - Prosodic form and parsing commitments.
AB  - This paper examines the question of whether there are effects of prosody on the
      syntactic parsing of temporarily ambiguous sentences containing complement verbs.
      It reports the results of five experiments employing cross-modal response tasks
      where the visually presented target word was either an ?appropriate' or an
      ?inappropriate' continuation in terms of the prosodic form of the preceeding
      auditory sentence fragment. Two experiments employing cross-modal naming only
      showed indications of sensitivity to syntactic and appropriateness manipulations
      when coupled with a simultaneous appropriateness judgment task. In contrast, the
      experiments employing cross-modal lexical decision showed greater sensitivity to
      syntactic and appropriateness effects. However, while the results from these
      studies replicated our earlier auditory parsing results and provided support for
      the suggestion that there are differences in visual and auditory parsing
      processes and for a ?constituent-based, ' ?minimal commitment' type auditory
      parser, none of the studies demonstrated an effect of prosodic form on the
      parsing process.

PMID- 8667301
TI  - Prosodic influences on the resolution of temporary ambiguity during on-line
      sentence processing.
AB  - We present three experiments designed to investigate the role of prosody during
      sentence processing. The first investigated the question of whether an
      utterance's prosodic contour influences its comprehension on-line. We spliced the
      beginning and end portions of direct object and embedded clause sentences and
      observed the consequent effects on comprehension using a dual-task procedure to
      measure processing load. Our second experiment sought to determine whether the
      constituent structure of these sentences could be reliably predicted using
      prosodic information. We found that the duration and F0 contour associated with
      the main-clause verb and the following NP reliably distinguished between the
      direct object and embedded clause constructions. In the final experiment, we
      manipulated the duration of the main-clause verb and found that subjects used
      this information to guide their initial parse during on-line sentence
      comprehension. The need for a model of sentence processing that addresses the use
      of prosodic information is discussed.

PMID- 8667302
TI  - Prosody's role in language acquisition and adult parsing.
AB  - There has been recent interest in the role of prosody in language acquisition as
      well as in adult sentence processing. Although the specific questions about
      prosody asked in these two domains may appear to differ, there are at least three
      basic issues that they have in common. These include the role of prosody in
      segmentation (i.e., deciding whether two adjacent sections of speech belong to
      the same or to different linguistic units), structural bracketing (i.e.,
      discerning structural relations among linguistic units), and the reliability of
      prosodic cues. Data from both language acquisition and adult parsing research
      suggest that, although prosody almost certainly plays a role in segmentation, it
      probably does not aid in bracketing. Research on the reliability of prosodic cues
      suggest that these are probably more reliable and robust in child-directed than
      in adult-directed speech registers, raising questions about how child and adult
      listeners interpret the presence vs. absence of prosodic cues.

PMID- 8667303
TI  - Prosodic planning while reading aloud: on-line examination of Japanese sentences.
AB  - In this paper, we discuss the process of generating prosody on-line while reading
      a sentence orally. We report results from two studies in which eye-voice span was
      measured while subjects read aloud. In study one, the average eye-voice span for
      simple texts was only about 2.5 characters. In study two, the eye-voice span was
      also about 2.5 characters even when the subjects read garden-path sentences which
      required reanalysis during processing. That the readers looked only a few
      characters ahead before reading aloud suggests that the prosody which they
      generate is not based on a global syntactic analysis, but instead reflects only
      limited, local syntactic information. The subjects, therefore, make errors and
      repairs when this locally determined prosody obviously contradicts the meaning of
      the sentence.

PMID- 8667304
TI  - Soaring beyond the cuckoo's nest: health care reform and ECT.

PMID- 8667305
TI  - Electroconvulsive therapy: what nurses need to know.

PMID- 8667306
TI  - Everything I learned, I learned from patients: radical positive reframing.

PMID- 8667307
TI  - The 'stably unstable' borderline personality disorder: history, theory, and
      nursing intervention.

PMID- 8667308
TI  - The role of the consultation-liaison nurse. Caring for patients with AIDS
      dementia complex.

PMID- 8667310
TI  - Mystery series character is a role model for those who struggle with mental
      illness.

PMID- 8667309
TI  - A discharge check list for psychiatric patients.

PMID- 8667311
TI  - Spiritual caregiving in nursing practice.

PMID- 8667312
TI  - The use of dental sealants by Ohio dentists.
AB  - OBJECTIVES: To assess the extent to which Ohio dentists report using pit and
      fissure sealants and factors associated with sealant use. METHODS: A mail survey
      of a random sample of Ohio dentists was conducted in 1989 and repeated in 1992
      with a newly drawn sample. Only responses from general dentists were analyzed
      using univariate analyses and multiple regression. RESULTS: Dentists who reported
      using sealants increased from 79.4 percent in 1989 to 91.8 percent in 1992. In
      1992, 42.9 percent were low-level users (< 15% of school-aged patients), 41.7
      percent were moderate-level users (15-39%), and 15.3 percent were high-level
      users (> 39%). Over three-fourths of sealant-using dentists expressed some degree
      of willingness to seal incipient caries. The level of sealant use was associated
      with dentists' knowledge about sealants, conservative management of dental
      caries, number of children seen in the practice, and influence of insurance
      coverage for sealants. The regression model explained 22.0 percent of the
      variance. Clinical factors associated with the level of use were: dentists'
      willingness to seal premolars; caries-free teeth; teeth with deep, narrow pits
      and fissures; teeth with small, frank occlusal caries; and patients 18 years of
      age or older. This regression model explained only 15.1 percent of the variance.
      CONCLUSIONS: The grate majority of Ohio dentists report using sealants. The
      percent of reported sealant users increased between 1989 and 1992. Ohio dentists
      are not consistent with regard to the percent of their child patients for whom
      they apply sealants or their willingness to seal incipient caries. Dentists
      continue to identify lack of insurance coverage for sealant application as a
      major barrier to patients receiving the service.

PMID- 8667313
TI  - The risk of fluorosis in students exposed to a higher than optimal concentration
      of fluoride in well water.
AB  - OBJECTIVES: In December 1991 the residents of the community of Rigolet, Labrador,
      Canada, discovered that they were exposed to higher than 2.0 ppm fluoride in the
      drinking water from the new town well, which became operational in December 1983.
      In 1993 an investigation of the occurrence of fluorosis in children exposed to
      the high-fluoride water during different ages of life was carried out. METHODS: A
      dental examination for fluorosis was conducted using Pendrys' Fluorosis Risk
      Index. Out of 84 students in Rigolet, 74 were examined and the parents of 60
      students agreed to be interviewed. Out of the 60 students, 48 lived all of their
      first six years of life in Rigolet. RESULTS: Of the 48 children with life-long
      residence, the odds ratio of fluorosis on enamel zones that began forming during
      the first year of life was 8.31 (95% CI = 1.84, 38.59) for children exposed since
      birth or during the first year of life relative to those exposed after 1 year of
      age. The odds that a child had a maxillary central incisor with fluorosis were
      5.69 (95% CI = 1.34, 24.15) times higher if exposure occurred during the first
      yea of life compared with exposure after 1 year of age. Only those exposed to the
      high-fluoride water during the first year of life developed fluorosis on the
      mandibular central incisors. CONCLUSIONS: Within the limitations of this small
      population study, age relative to the date when the new water well became
      operational was a significant risk factor in development of fluorosis. The first
      year of life was a significant period for developing fluorosis on the mandibular
      and maxillary central incisors.

PMID- 8667314
TI  - The RCI revisited after 15 years: used, reinvented, modified, debated, and
      natural logged.
AB  - OBJECTIVES: The purpose of this article is to review the status of the Root
      Caries Index (RCI) 15 years after it was first introduced in the dental
      literature as a method for the reporting of supragingival root lesions. This
      review focuses on the extent to which the RCI has been used by epidemiologic
      researchers, as well as on the issues concerning the RCI as a useful index that
      have been raised and debated in the literature by those epidemiologic
      researchers. METHODS: The debated points are categorized into six issues,
      including whether: (1) the RCI underestimates the prevalence of root caries by
      omitting subgingival root caries lesions; (2) the RCI overestimates the
      prevalence of root caries by using too rigid a definition of when recession can
      be visualized; (3) the RCI makes the assumption that there is a linear
      relationship between root caries lesions and the occurrence of at-risk surfaces,
      i.e., surfaces with recession; (4) the RCI, by ignoring missing teeth, distorts
      the descriptive epidemiologic picture of root caries; (5) recession is a
      predictor of root caries versus merely being an antecedent state; and (6) the
      imprecision of diagnosing gingival recession renders the RCI useless. RESULTS:
      Given both the evidence from recent studies and the professional interest in
      subgingival root caries, as addressed in the first debated point, it seems
      reasonable to modify the RCI to include a separate reporting of subgingival root
      caries. Of the remaining debated points over the past 15 years, three of these
      (points #2, #4, and #5 above) seemingly serve to clarify specific aspects of the
      RCI that were intended as inherent elements of the RCI as originally presented.
      The question as to whether there is an assumption of a linear relationship
      between root caries lesions and the occurrence of at-risk surfaces (point #3) is
      answered in the negative. The final debated point (#6), while addressing a
      fundamental periodontal tissue measurement issue--namely the reliability of
      identifying gingival recession--and while theoretically interesting, should not
      undermine the current use, or utility, of the RCI, but rather suggests the need
      for improved periodontal diagnostic techniques for the condition of recession.
      CONCLUSIONS: After 15 years, the RCI appears to be one of the two most common
      methods of reporting root caries in the epidemiologic literature (along with DFS
      counts). In fact, the best overall descriptive picture of root caries is achieved
      when those two reporting methods are presented in the same study accompanied by
      descriptive presentations of missing teeth and at-risk surfaces. Of all the
      debated points in the literature, the suggested modification of including
      subgingival lesions in the RCI leads now to the recommendation to collect
      subgingival data, but to do so in a manner that allows for separate presentation
      of supra- and subgingival root caries findings.

PMID- 8667315
TI  - Diversity, dental public health practice, and the public's health.

PMID- 8667316
TI  - Oral health for all: the HRSA perspective.

PMID- 8667317
TI  - Description and epidemiology of nursing caries.
AB  - Nursing caries is a virulent form of tooth decay that affects the primary
      dentition of infants and preschool children. The purpose of this paper is to
      review the scientific literature to describe the clinical characteristics of this
      disease and to report on its prevalence in various locations and populations
      around the world. A Medline search was completed using the key words below. All
      English-language articles that reported on the prevalence of caries involving the
      primary maxillary incisors in preschool children in association with feeding
      habits were included in the review. Nursing caries is associated with ad libitum
      bottle feeding, particularly at naptime or nighttime, and has been reported in
      children who engage in demand breastfeeding. A substantial body of literature
      from numerous countries now exists that documents the prevalence of nursing
      caries. In developed countries the prevalence is reported to vary between 1
      percent and 12 percent. However, in developing countries and within disadvantaged
      populations in developed countries, the prevalence has been reported to be as
      high as 70 percent in the preschool population. A universally accepted definition
      for nursing caries does not exist and methods used to define the condition,
      establish study populations, and collect prevalence data vary widely among
      studies. This review provides a detailed clinical description of nursing caries,
      reviews the characteristics of children who may be at risk for nursing caries,
      and reviews the prevalence data for nursing caries for countries that have
      reported it, and suggests directions for research into nursing caries etiology
      and prevalence.

PMID- 8667318
TI  - "Where is Waldo?": the timing of fluorosis.

PMID- 8667319
TI  - Etiology of nursing caries: a microbiologic perspective.
AB  - A compelling body of scientific evidence supports the concept that nursing caries
      is an infectious and transmissible disease. This evidence makes a strong case to
      support the tenet that infants who are colonized by mutans streptococci, and who
      have feeding habits characterized by frequent and prolonged oral exposure to
      cariogenic substrates, are likely to have a drastic increase in their oral mutans
      streptococci populations. Such an increase is associated with a high risk for
      rampant dental caries. This evidence strongly suggests that the first step in the
      etiology of nursing caries is primary infection by mutans streptococci; the
      second step is accumulation of these organisms to pathogenic levels as a
      consequence of frequent and prolonged oral exposure to cariogenic substrates; and
      the third step is rapid demineralization and cavitation of enamel resulting in
      rampant dental caries. This three-step model might provide an important framework
      for the design of clinical trials targeted at prevention of nursing caries.

PMID- 8667320
TI  - Research recommendations: pleas for enhanced research efforts to impact the
      epidemic of dental disease in infants.
AB  - Infant caries is an infectious disease with microbiological, dietary, and host
      risk factors. The disease is of epidemic proportions in immigrant and Native
      American populations studied. This paper reviews progress in current research and
      suggests a number of new approaches focusing on behavioral and chemotherapeutic
      methods.

PMID- 8667321
TI  - Frustrating patient visits.
AB  - OBJECTIVES: This study, part of a national mail survey of dentist malpractice
      liability claims, reports the reliability and validity of a new 22-item
      instrument measuring frustrating patient visits. METHODS: The items were
      subjected to factor analysis and subscales constructed. Reliability was assessed
      using Cronbach's alpha. Validity was assessed by comparing subscale scores to
      self-reports of satisfaction and liability claims. RESULTS: Factor analysis
      revealed four subscales representing unpleasant feelings, lack of communication,
      compliance, and practice organization (alpha = 0.60-0.86). Compliance was the
      most important factor. Subscale scores were related to satisfaction with practice
      and the proportion of patient visits in the practice that were frustrating to the
      dentist. Dentists who reported frustrating patient visits as quite typical of
      their practices were more likely to have had a malpractice liability claim within
      the last five years. CONCLUSION: This instrument may be of value in detecting
      patient-dentist communication difficulties that are the precursor to liability
      claims.

PMID- 8667323
TI  - The laryngeal mask airway (its potential for the military).
AB  - The introduction of the laryngeal mask airway (LMA) in the early 1980s has
      revolutionised airway management. Clinicians have shown the ease of LMA insertion
      compared to endotracheal intubation by unskilled personnel. Despite the lack of
      protection against aspiration of gastric contents, the LMA's ability to maintain
      the airway and oxygenation warrants its incorporation into military life support
      protocols and into an integrated respiratory support concept for conventional and
      NBC operations.

PMID- 8667322
TI  - Guidelines for dietary supplementation of pregnant women in a Rwandan refugee
      camp.
AB  - Units deployed on humanitarian aid may have little experience of the most
      appropriate interventions which can be expected to produce the most favourable
      population outcomes. Guidelines produced by UNICEF and the International
      Dispensary Association (IDA) can be used as a basis for planning. These
      guidelines were previously untested in Rwanda. This report focuses on iron and
      folate supplementation for pregnant women suggested by the IDA. The high levels
      of anaemia in pregnancy would suggest that supplementation is appropriate.
      However, before fully embracing the full set of recommendations, further field
      testing would be sensible.

PMID- 8667324
TI  - An assessment of a proposed method for adjusting and focusing ANVIS night vision
      goggles.
AB  - Night vision goggles are becoming an increasingly important tool in military
      aviation. They provide superior visual capability over unaided night vision, but
      any reduction in goggle performance can have a serious effect on flight safety
      and operational effectiveness. This study shows that the use of a standard
      adjustment procedure in a night vision goggle (NVG) test lane, with a resolution
      chart, provides an effective method for aircrew to obtain better visual
      capability than is currently obtained by focusing on distant features of the
      landscape. Visual acuity (VA) was measured for 20 aircrew representing all crew
      positions, after using both the current adjustment method and the proposed method
      for adjusting ANVIS NVGs. The average visual acuity showed an improvement from
      6/19 (s.d. = 3.9) with the current method to 6/13 (s.d. = 2.8) with the proposed
      method. However, NVG test lanes cannot be used with goggles which have fixed
      infinity objective lenses eg Nite.

PMID- 8667326
TI  - Defence Costs Study 15.

PMID- 8667325
TI  - Pilot study of the introduction of the J95 health data collection system.
AB  - J95 is a health data collection system aimed at gathering information on the
      weight of health problems facing the Army in order to allow rational and
      effective prioritization. Before implementing the system Army-wide, a pilot study
      has been undertaken to validate the J95 ICD 9-based classification system, to
      test the practical problems encountered with operating the system and its
      practical value to decision-makers. Both internal and external coding validity
      were tested in terms of agreement with a "gold standard' and in terms of
      repeatability and they scored highly. A number of problems were identified
      analysing discordances and using the comments raised by the participants. A final
      shortened version of the classification was developed accordingly. The report
      also contains a number of examples of the potential of the system which is due to
      be implemented by 1 January 1996.

PMID- 8667327
TI  - Malignant hyperpyrexia in a serving officer.

PMID- 8667328
TI  - Dysphagia--a presenting symptom of forestier disease.
AB  - We describe the case of a 48-year-old lady who developed dysphagia to solids.
      Barium swallow and lateral spine radiographs confirmed Forestier disease.

PMID- 8667329
TI  - Heat illness--a review of military experience (Part 2).
AB  - This is the second part of a two part review of the military experience of heat
      illness. It presents a synopsis of the literature from the end of the Second
      World War to the present day. The epidemiological evidence for the factors
      causing heat injuries are summarised as well as the international developments of
      preventive measures. Finally the current areas of uncertainty are identified and
      some proposals for future research will be made.

PMID- 8667330
TI  - Some account of the British military hospitals of World War I at Etaples, in the
      orbit of Sir Almroth Wright.
AB  - A group of British Military Hospitals was established between 1915 and 1918 along
      the estuary of the River Canche on the northern French coast. Their positions,
      now obliterated, can be identified from a plan of the time. With the growing
      realisation of the importance of bacteriology in the treatment of wound
      infection, the laboratory of Sir Almroth Wright in neighbouring Boulogne-sur-mer
      had a strong local influence.

PMID- 8667331
TI  - Defence Costs Study 15.

PMID- 8667332
TI  - The establishment of follicular dominance in co-cultured mouse ovarian follicles.
AB  - An in vitro model of dominant and subordinate ovarian follicles was developed to
      allow a closer investigation of the phenomenon of follicular dominance. Preantral
      mouse ovarian follicles were cultured either alone or in pairs. Pairs of
      follicles were either in direct contact or in shared medium, but without physical
      contact. The experiments showed that where contact was allowed to develop between
      follicles one follicle invariably became dominant, while the other would grow and
      develop little during the culture period. In contrast, there was no effect of co
      culture on follicle development in the absence of contact between the follicles.
      There was, therefore, no evidence of secretion of a diffusible factor by a
      dominant follicle that could affect the development of neighbouring follicles.
      After 6 days of co-culture with contact, histological examination of the
      subordinate follicle showed that it was healthy, in spite of remarkably little
      growth during culture. In a further experiment, the subordinate follicle was
      separated from the dominant one after 2 days of co-culture (when a significant
      difference in size had already developed), and cultured alone. These 'released'
      follicles exhibited a spurt of growth during the remaining culture period,
      attaining a size and appearance indistinguishable from those of controls by the
      end of culture. This confirms that the dominant follicle, while depressing the
      growth of its neighbour, is not inducing irreversible atresia in the subordinate
      follicle in this model. The in vitro model will allow a more detailed study of
      direct influences of dominant-subordinate follicle interactions, and should
      increase our knowledge of a poorly understood phenomenon.

PMID- 8667333
TI  - Insulin-like growth factor I (IGF-I), IGF-II and type-I IGF receptor gene
      expression in the ovary of the laying hen.
AB  - Expression of genes encoding insulin-like growth factor I (IGF-I), insulin-like
      growth factor II (IGF-II) and type I insulin-like growth factor receptor (IGFr)
      was measured in theca and granulosa cells from the ovary of the laying hen, using
      an RNase protection assay. Expression of genes encoding IGF-I and -II was
      confined to theca tissue and expression was not detected in granulosa cells. In
      contrast, expression of genes encoding IGFr in granulosa cells was significantly
      greater than that in theca tissue. The 98 base IGF-II probe was similar to a
      region of the second coding exon of chicken IGF-II and produced multiple RNase
      protected RNA hybrids. Theca RNA from follicles at all stages of development
      produced RNase-protected hybrids of size 98, 96 and 90 bases; however, an
      additional band (66 bases) was also observed in theca RNA from small yellow
      follicles. The stage of follicular development during which maximum amounts of
      the 66 base RNase-protected fragment was detected correlates with the stage at
      which small follicles are selected for recruitment into the follicular hierarchy.
      The results provide evidence for the involvement of IGFs in the intraovarian
      control of ovarian function in a non-mammalian species, and highlight the
      importance of IGF-II in this process.

PMID- 8667334
TI  - Lack of effect of sex on pig embryonic development in vivo.
AB  - The effect of sex on pig conceptus development to day 12 of gestation was
      investigated. On day 2 of gestation, reciprocal embryo transfers were performed
      resulting in four groups (Yorkshire-Yorkshire, Yorkshire-Meishan, Meishan
      Yorkshire and Meishan-Meishan). Conceptuses at day 12 were recovered from each
      recipient and diameter, as well as DNA, protein and oestradiol content were
      determined for individual conceptuses. The sex of individual conceptuses at day
      12 was determined by amplification of a fragment of the pig SRY gene, using the
      polymerase chain reaction. Embryos developed more rapidly to day 12 in Yorkshire
      recipients, but there was no detectable effect of sex on the diameter, DNA,
      protein or oestradiol content of conceptuses from any transfer group. Thus, no
      sex effect was apparent under conditions either promoting or retarding the rate
      of early pig blastocyst growth. These results provide strong evidence that pig
      embryonic development occurs at a rate determined by uterine environment and not
      by sex of the conceptus.

PMID- 8667335
TI  - A comparison of the number of inner cell mass and trophectoderm cells of
      preimplantation Meishan and Yorkshire pig embryos at similar developmental
      stages.
AB  - Day 12 blastocysts from Meishan gilts contain fewer cells than do day 12
      blastocysts from Yorkshire gilts. The purpose of this study was to evaluate the
      effect of breed on the relative numbers of inner cell mass and trophectoderm
      cells in Meishan and Yorkshire embryos at similar stages. Embryos were collected
      on days 5.5-6.5 of gestation and were subjected to image analysis and
      differential cell staining. No breed differences were detected in the thickness
      of zona pellucida or in the areas of the perivitelline space, embryo proper,
      blastocoel and inner cell mass at any of the developmental stages examined
      (compact morula, early blastocyst or blastocyst). However, differences were
      observed in the pattern of growth of embryos from Meishan versus Yorkshire gilts.
      The total number of cells of Meishan embryos from Meishan gilts increased
      progressively from the compact morula through the blastocyst stage, whereas the
      total number of cells of embryos from Yorkshire gilts remained constant from
      compact morula through to early blastocyst, and then increased markedly from the
      early blastocyst to the blastocyst stage. At the blastocyst stage, Meishan
      embryos contained fewer (P < 0.05) cells than did Yorkshire embryos, and this
      lower number of cells was due entirely to fewer (P < 0.05) trophectoderm cells.
      As the number of inner cell mass cells increased during embryonic growth, Meishan
      embryos exhibited a slower (P < 0.02) increase in the number of trophectoderm
      cells than did Yorkshire embryos. These results demonstrate that the reduced
      number of cells present in Meishan embryos results from a selective reduction in
      the number of trophectoderm, but not inner cell mass, cells.

PMID- 8667336
TI  - Epidermal growth factor and epidermal growth factor receptor in the ovary of the
      domestic cat (Felis catus).
AB  - Identification of epidermal growth factor (EGF) and its distribution in the ovary
      were examined with an immunohistochemical technique using a polyclonal rabbit
      antibody against mouse EGF. A combination of HPLC and enzymeimmunoassay was
      elaborated to quantify EGF in different compartments of the feline ovary. In
      addition, EGF receptors were localized in ovarian cryostat sections with a new
      ligand-histochemical technique using biotinylated EGF for labelling. Epidermal
      growth factor was present in theca interna cells, in specific aggregations of
      interstitial gland cells located next to tertiary follicles, in smaller, single
      cells of the ovarian cortex, and in the corpus luteum. The strongest EGF-positive
      reaction was found in vacuolized cells of the interstitium and in theca interna
      cells of large tertiary follicles rich in cytoplasm. The strictly cellular
      localization of the EGF-antibody reaction suggests the synthesis of EGF in these
      cells. Specific binding sites of EGF were present on granulosa cells of secondary
      and tertiary follicles and on interstitial gland cells. The EGF-binding capacity
      of granulosa cells of the cumulus oophorus was greater than that of the mural
      granulosa cells. Granulosa cells of atretic follicles showed a lower or no
      affinity for staining. In conclusion, we suggest that EGF plays an important role
      in ovarian folliculogenesis in cats.

PMID- 8667337
TI  - The penetration of chromium-EDTA from blood plasma into various compartments of
      rat testes as an indicator of function of the blood-testis barrier after exposure
      of the testes to heat.
AB  - The concentration of chromium51-EDTA in blood plasma after an intravenous
      infusion was found to be about 40 times that present in rete testis fluid and 20
      times that in the additional seminiferous tubular fluid resulting from ligation
      of the efferent ducts. These values indicate the effectiveness of the blood
      testis barrier to small water-soluble molecules, like Cr-EDTA. The volume of
      distribution in microlitres of Cr-EDTA in the parenchyma was about 60% of the
      volume of the interstitial tissue as determined on frozen sections by
      morphometry, and was similar, or slightly less, in the ligated testes, compared
      with the unligated testes. Heating the testes to 43 degrees C for 30 min led to
      the expected reduction several days later in testis mass, but the volume of
      distribution of Cr-EDTA was no greater than that in the testes of control rats,
      and the ratio of Cr-EDTA space to interstitial tissue was not different, while
      the concentration of Cr-EDTA in the additional seminiferous tubular fluid
      increased only slightly as testis mass fell. These results indicate that the
      blood-testis barrier was only slightly less effective, if changed at all, during
      the period of spermatogenic disruption following local heating of the testis.

PMID- 8667338
TI  - Development to blastocysts of domestic cat oocytes matured and fertilized in
      vitro after prolonged cold storage.
AB  - Four experiments determined the kinetics of in vitro maturation and fertilization
      of cat oocytes and the effects of prolonged cold storage of ovaries before oocyte
      recovery on in vitro maturation/in vitro fertilization (IVM/IVF) success.
      Domestic cat ovaries were collected at ovariohysterectomy and stored at 4 degrees
      C in PBS until oocyte recovery and culture in Eagle's minimal essential medium
      (EMEM) containing FSH, LH, oestradiol and BSA for maturation. In Expt 1, meiotic
      maturation was assessed at 0, 12, 24, 38 and 48 h of culture. After 24 h, > 61%
      of oocytes were in telophase I or metaphase II. In Expt 2, oocytes were recovered
      from ovaries stored for 24, 48 or 72 h and cultured in EMEM for 24 h. There was
      no difference among groups (P > 0.05) in the ability to achieve nuclear
      maturation (mean +/- SEM, 57.1 +/- 5.3%, 60.4 +/- 5.4%, 55.4 +/- 15.1% for 24, 48
      and 72 h, respectively). Fertilization and embryo development after insemination
      at 16, 24, 32, 40 and 48 h of culture were examined in Expt 3. Of 98 oocytes
      inseminated at 32 h, 69% cleaved, 59% developed into morulae and 13% into
      blastocysts, more (P < 0.05) than those oocytes inseminated at earlier and later
      times. Development to blastocysts occurred after insemination at 16 (1.2%), 24
      (9.1%) and 32 (13.3%) h of culture, but not after insemination at 40 or 48 h.
      Expt 4 involved cold storage of ovaries for 24, 48 or 72 h before oocyte recovery
      and insemination at 32 h of culture (the optimal time measured in Expt 3).
      Compared with storage for 24 h, fertilization success was lower (P < 0.05) in the
      48 and 72 h groups, and, although 9.1% of inseminated oocytes from the 24 h
      storage group developed to blastocysts, none (P < 0.05) achieved this stage after
      48 or 72 h of storage. These results indicate that domestic cat oocytes reach
      nuclear maturity by 24 h in culture and can be fertilized and develop to
      blastocysts optimally after insemination at 32 h. Oocytes recovered from ovaries
      stored at 4 degrees C for up to 72 h are capable of reaching telophase I or
      metaphase II in vitro. However, only oocytes stored within the ovary for 24 h
      produce blastocysts, indicating that the ability to achieve nuclear maturation is
      an inadequate indicator of fertilization and developmental competence.

PMID- 8667339
TI  - Regulation of leukocyte interleukin 2 and interleukin 2 receptor gene expression
      by rabbit blastocoelic fluid.
AB  - The mechanisms underlying the inhibition of lymphocyte proliferative response by
      rabbit blastocoelic fluid collected on day 12 of embryonic development were
      investigated. Treatment with blastocoelic fluid, even in the presence of
      concanavalin A, maintains lymphocytes in a quiescent state by preventing cell
      entry into the S phase of the cell cycle. Gene expression of interleukin 2
      receptor is completely blocked by treatment with blastocoelic fluid as are the
      secretion and gene expression of interleukin 2. Addition of interleukin 2 to
      prestimulated interleukin 2 receptor positive lymphocytes failed to downregulate
      the expression of high-affinity interleukin 2 receptor and completely abolished
      the embryonic fluid-mediated inhibitory effect on [3H]thymidine incorporation.
      Taken together, these results suggest that embryonic fluid has differential
      inhibitory effects, depending on the activation state of the lymphocytes.
      Nevertheless, inhibition of interleukin 2 and interleukin 2 receptor expression
      by embryonic fluid restrains immune cell activity and therefore can be implicated
      in the survival of the fetal semi-allograft.

PMID- 8667340
TI  - Autonomous testicular hormonal control of fetal gubernaculum development in
      rabbits: a re-examination of histological slides in the legacy of the late
      Professor Alfred Jost.
AB  - The present study investigated whether the male differentiation of the
      gubernacular primordia depends on fetal pituitary control. Therefore,
      gubernaculum development was analysed in the same histological preparations that
      the late Professor Alfred Jost had used to examine the effects of fetal
      decapitation on the other parts of the developing genitalia. Decapitation had
      taken place at the onset of sexual differentiation (day 19 after conception) and
      the results examined just before the expected birth (day 28 after conception).
      Fetal decapitation had no noticeable effect on the development of these large and
      complex male-specific structures. It was concluded (1) that fetal control of male
      gubernaculum development operates through a mechanism different from that
      involved in male differentiation of the other component parts of the genitalia
      and (2) that this mechanism is not under fetal pituitary control. The results
      thus provide further support for the existence of a separate fetal hormone to
      bring about male differentiation of the gubernacular primordia.

PMID- 8667341
TI  - 5-Hydroxytryptamine--a local regulator of testicular blood flow and vasomotion in
      rats.
AB  - The effects of 5-hydroxytryptamine (5-HT), 5-HT2 receptor antagonists (ritanserin
      and ketanserin), histamine and substance 48/80 on testicular blood flow and
      microcirculation were studied in adult rats. The substances were administered by
      topical application on the testicular surface and by intratesticular injections,
      and blood flow was measured by radioactive microspheres and with a laser Doppler
      flowmeter. Blood flow was decreased by 5-HT in a dose-dependent manner and
      vasomotion in the testis was inhibited, suggesting that it could be involved in
      the physiological regulation of the testicular vasculature. The 5-HT antagonists
      did not significantly influence flow or vasomotion in intact testes. Histamine
      did not cause any major effects on testicular blood flow. Substance 48/80 caused
      degranulation of testicular mast cells, and reduced testicular blood flow and
      vasomotion suggesting that testicular mast cells, possibly by releasing 5-HT,
      could be involved in the local control of the testicular vasculature.

PMID- 8667342
TI  - Oxytocin receptor development in ovine uterus and cervix throughout pregnancy and
      at parturition as determined by in situ hybridization analysis.
AB  - The development of uterine oxytocin receptors is an important regulatory step in
      the initiation of labour. Paracrine production of oxytocin by uterine and
      placental tissues may also be involved in some species. Placentome,
      intercotyledonary endometrium, myometrium and fetal membranes were collected from
      3-5 ewes each, at regular intervals throughout pregnancy and from eight ewes
      during labour. Localization of mRNA encoding oxytocin and its receptor was by in
      situ hybridization; oxytocin peptide concentrations were measured by
      radioimmunoassay and oxytocin receptor concentrations were measured by
      autoradiography and radioreceptor assay. In the intercotyledonary endometrium,
      mRNA encoding the oxytocin receptor was located in the luminal epithelium only.
      Both the epithelial and myometrial receptors were detected at low concentrations
      from the fourth week of gestation onwards, with a major increase associated with
      the onset of labour. In the placentomes, oxytocin receptors were localized to a
      stromal capsule surrounding the placental villi. Expression in this region was
      maximal in mid-gestation, declining in the second half of pregnancy and remaining
      low during labour. Cervical oxytocin receptors were detected at low
      concentrations in the epithelium and the muscular/connective tissue layers from
      day 22 of pregnancy onwards. There was no evidence for the local uterine
      production of oxytocin in the ewe; mRNA encoding oxytocin was undetectable and
      oxytocin concentrations were always < 23 pg g-1 wet mass of tissue. These results
      suggest that regulation of the timing of oxytocin receptor development varies
      between the different tissue types, despite a similar steroidal background. The
      receptors in the luminal epithelium are probably associated with the ability of
      exogenous oxytocin to induce the release of PGF2 alpha throughout most of
      pregnancy. The increase in receptors in both the intercotyledonary endometrium
      and myometrium at term suggest an involvement in labour, whereas their role in
      caruncular stroma in mid-pregnancy is unknown.

PMID- 8667344
TI  - Prolonged dominance of follicles and reduced viability of bovine oocytes.
AB  - Prolonging the lifespan of bovine follicles is known to result in reduced
      fertility after ovulation and insemination. In this study, the effect of
      prolonged development of follicles on oocyte viability was examined. In Expt 1,
      six cows in the aspirated-prolonged-follicle group received a vaginal
      progesterone releasing device on day 4 of the oestrous cycle (day 1 = ovulation)
      and prostaglandin F2 alpha (40 mg) on day 6. Ultrasound-guided follicular
      aspiration was performed on day 13. Six cows in the aspirated-growing-follicle
      group received prostaglandin F2 alpha on day 6, and follicular aspiration on day
      7. In Expt 2, all cows were stimulated with 36 mg FSH-P to develop multiple large
      follicles for study. Three cows in the prolonged-multiple-follicle group received
      the same treatment as did cows in Expt 1, but were ovariectomized on day 13.
      Three cows in the growing-multiple-follicle group received prostaglandin F2 alpha
      on day 6 and were ovariectomized on day 7. Oocytes recovered in both experiments
      were stained to reveal the stage of nuclear development. All oocytes from
      aspirated-prolonged and prolonged-multiple follicles showed expanded cumulus
      cells and condensed chromatin dispersed in the ooplasm, with possible germinal
      vesicle breakdown. Oocytes from aspirated-growing and growing-multiple follicles
      showed compact cumulus cells and an intact germinal vesicle. Plasma
      concentrations of oestradiol in both growing follicle groups increased until
      oocyte recovery. Oestradiol in the aspirated-prolonged-follicle group increased
      after luteolysis on day 6 and remained high until follicular aspiration. In
      contrast, in the FSH-stimulated prolonged-multiple-follicle group, oestradiol
      fell to trace amounts on day 8 and remained low. Oestradiol concentrations in
      follicular fluid were consistent with plasma concentrations for all groups.
      Bovine oocytes from prolonged dominant follicles undergo premature maturation in
      vivo, which perhaps accounts for the poor fertility observed in other studies
      when oestrous synchronization with progestins prolongs follicle lifespan.

PMID- 8667343
TI  - Endometrial progesterone receptor expression during the human menstrual cycle.
AB  - The human endometrium undergoes regular cyclical changes under the endocrine
      control of oestrogens and progesterone acting via specific nuclear receptors. The
      molecular and cellular events mediating these changes are not understood. The
      present study examined the changes in the endometrial progesterone receptor and
      its mRNA during the menstrual cycle. Forty-four endometrial samples obtained from
      women with normal menstrual cycles were divided into four categories: early
      proliferative (days 6-9), late proliferative (days 10-14), early secretory (days
      15-21) and late secretory (days 22-28). The progesterone receptor protein was
      determined using a human progesterone receptor enzyme-linked immunoassay kit.
      Total RNA was extracted using RNAzol and the abundance of mRNA encoding the
      progesterone receptor was determined by reverse transcriptase-polymerase chain
      reaction and by northern blot analysis. The concentration of the progesterone
      receptor in the endometrium was highest during the late proliferative phase and
      was lowest in the late secretory phase. Significant differences were observed
      between the menstrual cycle phases (P < 0.003). No cyclical variation was
      observed in the concentration of mRNA encoding for the progesterone receptor in
      the endometrium when analysed by reverse transcriptase polymerase chain reaction
      or by northern analysis. There appears to be no association between the amounts
      of mRNA encoding the progesterone receptor and progesterone receptor protein
      during the menstrual cycle suggesting that the control of the expression of the
      progesterone receptor may not occur solely at the transcriptional level.

PMID- 8667345
TI  - Antifertility potential of 2-[piperdinoethoxyphenyl]-3-[4- methoxyphenyl]-2H
      benzopyran: a potent anti-oestrogenic compound in rats.
AB  - The present study was carried out to investigate the artifertility potential of 2
      [piperdinoethoxyphenyl]-3-[4-methoxyphenyl]-2H benzopyran (K-7) in rats. A single
      oral administration of 250 micrograms K-7 kg-1 body mass after coitus prevented
      pregnancy in rats. The minimum effective dose in rats given K-7 orally for 1-4
      days after coitus was 100 micrograms kg-1 body mass. K-7 had weak oestrogenicity
      in ovariectomized immature rats but had no androgenic or anti-gonadotrophic
      activity. Studies in vivo showed that K-7 was a potent anti-oestrogenic compound
      and that at 100 micrograms kg-1 it could mitigate the effect of 1.0 microgram
      oestradiol. On the basis of the above results, K-7 appeared to exert its
      antifertility action(s) by its weak oestrogenic and its strong anti-oestrogenic
      activity. The anti-oestrogenic activity of K-7 was substantiated further by
      performing studies on the competition of K-7 for binding of [3H]oestradiol to rat
      uterine oestrogen receptors. A high affinity for binding to oestrogen receptors
      was displayed by K-7, with a relative binding affinity of 71%. These findings
      show that K-7 is an effective anti-oestrogenic compound and is a potent
      antifertility agent.

PMID- 8667346
TI  - Effects of exogenous oxytocin and progesterone on GnRH-induced short luteal
      phases in anoestrous ewes.
AB  - Two experiments investigate the effects of oxytocin and progesterone on premature
      luteolysis in ewes. In Expt 1, 20 anoestrous ewes were induced to ovulate by
      multiple injections of GnRH (250 ng i.v. every 2 h for 24 h) followed by a bolus
      injection of GnRH (125 micrograms, i.v.). Ten ewes received a continuous infusion
      of oxytocin from the day after the GnRH bolus injection and the other ten ewes
      were infused with saline. Oxytocin infusion had no significant effect on the
      proportion of ewes with short luteal phases (P > 0.05). All ewes that had luteal
      phases of normal duration from either group (n = 9) exhibited a transient
      increase in plasma concentrations of progesterone 2 h after insertion of the
      pump. In Expt 2, 25 anoestrous ewes were treated with GnRH as in Expt 1. Five
      ewes were pretreated with progestagen for 11 days and ten ewes received
      progesterone (12 mg, i.m.) 24 h after the bolus injection of GnRH. All animals
      received an oxytocin injection (1 microgram, i.v.) on day 4 after the GnRH bolus.
      All five ewes that were pretreated with progestagen had normal luteal function
      and none exhibited a 13, 14-dihydro-15-keto PGF2 alpha (PGFM) response to
      oxytocin. None of the ten ewes injected with progesterone had a normal luteal
      phase and six ewes exhibited a PGFM response to oxytocin. Four ewes in the
      control group had normal luteal function and three had short luteal phases. It is
      concluded that (1) administration of oxytocin from about the time of ovulation
      does not prevent premature luteal regression; (2) a transient increase in
      progesterone at about the time of ovulation is associated with luteal phases of
      normal duration; (3) a more extended exposure to progesterone at about the time
      of ovulation prevents normal luteal function and may inhibit luteinization and
      (4) pretreatment with progesterone prevents luteolysis by reducing the uterine
      response to oxytocin early in the luteal phase.

PMID- 8667347
TI  - Abnormal sperm morphology and function in the fathers of hypospadiacs.
AB  - A lower motility of spermatozoa and a higher incidence of abnormal sperm
      morphology were found in 25 fathers of hypospadiacs compared with those of 50
      fathers who produced children who were not hypospadiacs. Subfertility of fathers
      may result in a higher risk of hypospadias in offspring and as subfertile males
      now represent a higher proportion among fathers, owing to the improved efficacy
      of infertility treatment, this may explain the increased occurrence of
      hypospadias. Our relaxed-selection hypothesis, which states that there is a
      redistribution in the number of children born to fertile and infertile
      (subfertile) couples, may account for the increasing number of other defects and
      cancers of male genitalia observed today and the fall in sperm counts.

PMID- 8667348
TI  - The association between basal body temperature, plasma progesterone and the
      oestrous cycle in a marsupial, the Tasmanian bettong (Bettongia gaimardi).
AB  - Basal body temperature, quantitative changes in vaginal smears and plasma
      concentrations of progesterone were measured during a number of oestrous cycles
      in Tasmanian bettongs (Bettongia gaimardi). These methods of monitoring the
      reproductive cycle were compared in an attempt to find a technique that allowed
      non-stressful assessment of the reproductive condition of the bettongs.
      Telemetric measurement of basal body temperature showed that there was a diurnal
      variation of 1.3 degrees C, typical of a nocturnal animal. During the oestrous
      cycle, there was a small, but not significant, peak in basal body temperature at
      oestrus (day 0) followed by a significant trough on day 2. There was a
      significant increase on day 3 and the temperature remained raised until day 10,
      during which time plasma progesterone concentrations are also high; the
      temperature then fell 2 days before oestrus. This fall corresponds to a decrease
      in concentration of plasma progesterone and in the numbers of leucocytes in
      vaginal smears. Telemetric measurement of body temperature may be useful as a non
      stressful method of monitoring the oestrous cycle in bettongs.

PMID- 8667349
TI  - Induction and maintenance of oestradiol and immunoreactive inhibin production
      with FSH by ovine granulosa cells cultured in serum-free media.
AB  - A serum-free ovine granulosa cell culture system is described that allows the
      induction of FSH-responsive oestradiol production by undifferentiated cells from
      small (< 3.5 mm) follicles (P < 0.001) and the maintenance of oestradiol
      production by differentiated cells from large (> or = 3.5 mm) follicles.
      Physiological doses of FSH stimulated (P < 0.01) proliferation of cultured
      granulosa cells from both small and large follicles. The synthesis of
      immunoreactive inhibin and progesterone by granulosa cells from small and large
      follicles increased (P < 0.01) with time of culture, and was not dependent on
      FSH. Inhibin secretion expressed on a per cell basis was not FSH responsive.
      Insulin and insulin-like growth factor I (IGF-I), in the presence of FSH,
      stimulated (P < 0.001) cell proliferation and oestradiol and inhibin production
      by granulosa cells from small and large follicles. There was a significant (P <
      0.001) interaction between insulin and IGF-I in the stimulation of granulosa cell
      proliferation and differentiation. Both epidermal growth factor (EGF) and
      transforming growth factor alpha (TGF-alpha) in the presence of FSH stimulated
      cellular proliferation (P < 0.001) in a dose-responsive manner and concomitantly
      inhibited (P < 0.001) oestradiol and inhibin secretion. The development of this
      granulosa cell culture system will make it possible to study, in vitro, the
      cascade of events that controls granulosa cell differentiation and ultimately
      follicle selection in sheep.

PMID- 8667350
TI  - Relationship between the number of immunostaining gonadotropes and the plasma
      concentrations of gonadotrophins in ewes with and without the FecBB gene.
AB  - Booroola ewes possess a major gene, FecBB, that influences their ovulation rate
      (number of ovulations per oestrous cycle). Homozygous (BB) carriers of the FecBB
      gene have higher plasma concentrations of FSH and sometimes LH relative to the
      non-carriers (++). The aim of this study was to determine whether the plasma
      concentration differences in FSH or LH between the genotypes were due to a
      greater number of FSH beta- or LH beta-immunostaining cells in the anterior
      pituitary gland of BB ewes during the luteal phase of the oestrous cycle. No
      differences were found between the BB (n = 7) ewes and ++ (n = 8) ewes in total
      number of pituitary cells, pituitary volume, numbers or diameters of FSH beta- or
      LH beta-immunostaining cells, notwithstanding significantly higher concentrations
      of immunoreactive plasma FSH (P < 0.001) but not LH in BB compared with ++
      animals. Significant linear relationships were found within each genotype between
      plasma FSH and number of FSH beta-immunostaining cells. No such relationship was
      found for plasma LH and number of LH beta cells. For the FSH relationship, the
      slopes of the regression lines were the same. It is hypothesized that the
      differences in plasma concentration of FSH between the genotypes is due to a
      greater output of FSH per pituitary cell in the BB animals.

PMID- 8667351
TI  - Dissociation of increases in plasma insulin-like growth factor I and testosterone
      during the onset of puberty in bulls.
AB  - The present study was conducted to examine the relationship between plasma
      concentrations of testosterone, insulin-like growth factor I (IGF-I) and IGF
      binding proteins (IGFBPs) during puberty, in male calves treated with GnRH or
      testosterone propionate. Twelve male Holstein calves (10 weeks old) were assigned
      to the control group (n = 6), the GnRH-treated group (n = 3) or the testosterone
      treated group (n = 3). For 8 weeks, the GnRH-treated group received a single i.v.
      injection of GnRH (0.5 microgram kg-1 body mass) each day while the testosterone
      treated group received an i.m. injection of testosterone propionate (0.5 mg kg-1
      body mass) twice a day. The calves were studied until they were 200 days old.
      Hormone treatments were stopped one month after puberty was reached in the
      control group. Blood samples were collected every 30 min for 8 h every third day.
      Hormone concentrations were determined by radioimmunoassay. Western ligand
      blotting and immunoblotting, using monoclonal antibodies against IGFBP-2 and
      IGFBP-3, were used to characterize the IGF-binding proteins. In the control
      group, puberty occurred at about 120 days of age and was associated with an
      increase in concentrations of testosterone, IGF-I and IGFBP-3 and a decrease in
      concentration of IGFBP-2. In the GnRH-treated group, plasma testosterone remained
      low until 8 weeks after establishment of puberty in the control group (4 weeks
      after the end of treatment). In the testosterone-treated group, testosterone was
      high during the treatment period and then decreased to prepubertal values when
      treatment was stopped. Testosterone values increased again to reach postpubertal
      values 5 weeks after the end of hormone treatment. Nevertheless, independent of
      testosterone status, the profile of IGF-I and the IGFBPs in the GnRH- and
      testosterone-treated groups were parallel to that reported for the control group
      with the transition from prepubertal to adult values at about 120 days of age. In
      conclusion, concentrations of testosterone, IGF-I and IGFBP-3 increase together,
      but probably independently, during the onset of puberty in male calves.

PMID- 8667352
TI  - Responsiveness of ovaries to exogenous gonadotrophins and laparoscopic artificial
      insemination with frozen-thawed spermatozoa in ocelots (Felis pardalis).
AB  - Adult female ocelots (Felis pardalis) were treated with one of four dosages of
      equine chorionic gonadotrophin (eCG) and human chorionic gonadotrophin (hCG) (100
      iu eCG/75 iu hCG, n = 3; 200 iu eCG/150 iu hCG, n = 4; 400 iu eCG/150 iu hCG, n =
      5; 500 iu eCG/225 iu hCG, n = 5); hCG was administered 80 h after eCG. Ovaries of
      each animal were evaluated by laparoscopy 39-43 h after hCG, and blood was
      collected for progesterone and oestradiol analysis. With progressive increases in
      gonadotrophin dosage, female ocelots produced more (P < 0.05) unovulated
      follicles (> or = 2 mm in diameter), ranging from 1.3 +/- 0.7 (mean +/- SEM)
      follicles per female at the lowest dosage to 8.8 +/- 2.8 follicles per female at
      the highest dosage. Similarly, ocelots produced more (P < 0.05) corpora lutea
      with increasing gonadotrophin dosages, with mean values ranging from 0-5.0 +/-
      1.2 corpora lutea. However, across treatment groups, a similar proportion (P >
      0.05) of females ovulated in response to each dosage. At laparoscopy, serum
      concentrations of oestradiol (overall mean, 330.2 +/- 62.2 pg ml-1) and serum
      concentrations of progesterone (overall mean, 18.5 +/- 6.4 ng ml-1) in ovulating
      females did not differ (P > 0.05) across treatment groups. Ten ovulating ocelots
      were laparoscopically inseminated with fresh (4.7 +/- 0.2 x 10(6); n = 2 females)
      or frozen-thawed (10.7 +/- 1.8 x 10(6); n = 8 females), motile spermatozoa. One
      female treated with 500 iu eCG/225 iu hCG and inseminated with 7.5 x 10(6)
      motile, frozen-thawed spermatozoa conceived and gave birth to a healthy male
      kitten after a gestation of 78 days. We conclude that ocelots are relatively
      insensitive to exogenous gonadotrophins, requiring much higher dosages (on a per
      body mass basis) to elicit an appropriate ovarian response than do any other
      felid species studied to date. Nonetheless, the gonadotrophin-treated female can
      become pregnant and carry offspring to term after laparoscopic intrauterine
      insemination with frozen-thawed spermatozoa.

PMID- 8667353
TI  - The use of prostaglandins and oxytocin for transcervical recovery of bovine
      fetuses at days 33-58 of gestation.
AB  - The study of bovine germ cells of known developmental stage calls for
      alternatives to the recovery of fetuses by surgery or slaughter. Fetuses were
      therefore obtained during the second month of pregnancy by aborting 49 animals
      using a progressively modified treatment regimen of cloprostenol, prostaglandin
      E2 (PGE2) and oxytocin. The viability of fetuses was monitored by ultrasonography
      throughout treatment. Intracervical treatment with PGE2 led to cervical dilation
      in all treated animals. However, retrieval of the fetuses by subsequent flushing
      of the uterus was successful in only two of six animals. When i.m. injections of
      cloprostenol were given 20-40 h before PGE2 treatment, fetuses < or = 40 days of
      gestation were expelled spontaneously, while the majority of fetuses > or = 50
      days of gestation were retained. When i.m. injections of oxytocin were given in
      relation to clinical signs of impending fetal expulsion after cloprostenol and
      PGE2 treatment, 20 of 22 fetuses were expelled 42-53 h after the cloprostenol
      injection. Of these 20 fetuses, 19 were expelled 0-7 h after the cessation of
      fetal heartbeat. The subsequent fertility of animals was not affected. Thus, the
      final protocol allowed bovine fetuses to be retrieved at predictable times,
      within a few hours of death, with little maternal trauma and without affecting
      subsequent fertility.

PMID- 8667354
TI  - The enediyne antibiotics.

PMID- 8667356
TI  - Discovery and optimization of a novel class of orally active nonpeptidic
      endothelin-A receptor antagonists.
AB  - A novel class of endothelin-A receptor ligands was discovered by high-throughput
      screening. Lead structure optimization led to highly potent antagonists which can
      be synthesized in a short sequence. The compounds are endothelin-A-selective, are
      orally available, and show a long duration of action.

PMID- 8667355
TI  - Discovery of an orally active non-peptide fibrinogen receptor antagonist.

PMID- 8667357
TI  - Comparative molecular moment analysis (CoMMA): 3D-QSAR without molecular
      superposition.
AB  - 3d-QSAR procedures utilize descriptors that characterize molecular shape and
      charge distributions responsible for the steric and electrostatic nonbonding
      interactions intimately involved in ligand-receptor binding. Comparative
      molecular moment analysis (CoMMA) utilizes moments of the molecular mass and
      charge distributions up to and including second order in the development of
      molecular similarity descriptors. As a consequence, two Cartesian reference
      frames are then defined with respect to each molecular structure. One frame is
      the principal inertial axes calculated with respect to the center-of-mass. For
      neutrally charged molecular species, the other reference frame is the principal
      quadrupolar axes calculated with respect to the molecular "center-of-dipole."
      QSAR descriptors include quantities that characterize shape and charge
      independently as well as quantities that characterize their relationship. 3D-QSAR
      partial least squares (PLS) cross-validation procedures are utilized to predict
      the activity of several training sets of molecules previously investigated. This
      is the first time that molecular electrostatic quadrupolar moments have been
      utilized in a 3D-QSAR analysis, and it is shown that descriptors involving the
      quadrupolar moments and related quantities are required for the significant cross
      validated predictive r2's obtained. CoMMA requires no superposition step, i.e.,
      no step requiring a comparison between two molecules at any stage of the 3D-QSAR
      calculation.

PMID- 8667358
TI  - Molecular structure, conformational analysis, and structure-activity studies of
      Dendrotoxin and its homologues using molecular mechanics and molecular dynamics
      techniques.
AB  - Three-dimensional structures of Dendrotoxin (DtX), Toxin-I (DpI), and Toxin-K
      (DpK) were determined using molecular mechanics and molecular dynamics
      techniques. The overall molecular conformation and protein folding of the three
      dendrotoxins are very similar to the published crystal structures of bovine
      pancreatic trypsin inhibitor (BPTI) and alpha-DtX. Major secondary structural
      regions of the dendrotoxins are stable without much fluctuation during the
      dynamics simulation; the regions corresponding to the turns and bends (rich in
      lysines and arginines) exhibit more fluctuations. The conformational angles and
      the C alpha...C alpha' distances of the three disulfides (in each of the
      dendrotoxins) are different from each other. Comparative model building studies,
      involving the dendrotoxins and the proteinases, reveal that the key interactions
      (observed in BPTI-trypsin complex) needed for anti-protease activity are absent
      due to structural differences between the dendrotoxins and BPTI at the anti
      protease loop; this explains the inability of the dendrotoxins to inhibit
      proteinases. The model also suggests that the solvent-exposed beta-turn region,
      rich in lysines (residues 26-28), might bind directly to the extracellular
      anionic sites of the receptors (K+ channels) by ionic interactions. The
      strikingly homologous cysteine distribution (Cys-x-x-x-Cys) in DtX, DpI, and DpK,
      at the C-terminus, induces the occurrence of a characteristic conformational
      motif, consisting of an alpha-helix (in an amphiphilic environment) stabilized by
      two disulfides, one involving a cysteine at the beta-strand, and the other at the
      N-terminus. This amphiphilic secondary structural element seems to provide the
      rigid frame work needed for exposing the proposed active site region of the
      dendrotoxins to the anionic sites of the K+ channel receptors.

PMID- 8667359
TI  - Preparation and structure-activity relationship of novel P1/P1'-substituted
      cyclic urea-based human immunodeficiency virus type-1 protease inhibitors.
AB  - A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors
      was prepared. Three different synthetic schemes were used to assemble these
      compounds. The first approach uses amino acid-based starting materials and was
      originally used to prepare DMP 323. The other two approaches use L-tartaric acid
      or L-mannitol as the starting material. The required four contiguous R,S,S,R
      centers of the cyclic urea scaffold are introduced using substrate control
      methodology. Each approach has specific advantages based on the desired P1/P1'
      substituent. Designing analogs based on the enzyme's natural substrates provided
      compounds with reduced activity. Attempts at exploiting hydrogen bond sites in
      the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful.
      Several analogs had better binding affinity compared to our initial leads.
      Modulating the compound's physical properties led to a 10-fold improvement in
      translation resulting in better overall antiviral activity.

PMID- 8667360
TI  - Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor
      tyrosine kinase: structure-activity relationships in quinoxalines, quinolines,
      and indole tyrphostins.
AB  - A series of 3-indoleacrylonitrile tyrphostins, 2-chloro-3-phenylquinolines, and 3
      arylquinoxalines were prepared and tested for inhibition of platelet-derived
      growth factor receptor tyrosine kinase (PDGF-RTK) activity. The potency of the
      inhibitors was found to be quinoxalines > quinolines > indoles. Lipophilic groups
      (methyl, methoxy) in the 6 and 7 positions and phenyl at the 3 position of
      quinoxalines and quinolines were essential for potency, in contrast to the
      hydrophilic catechol group in tyrphostins active against EGFR kinase inhibition
      at different sites. The inhibitors showed selectivity for PDGF and were not
      active against EGF receptor and HER-2/c-ErbB-2 receptor.

PMID- 8667361
TI  - Ureido-based peptidomimetic inhibitor of herpes simplex virus ribonucleotide
      reductase: an investigation of inhibitor bioactive conformation.
AB  - We have been investigating peptidomimetic inhibitors of herpes simplex virus
      (HSV) ribonucleotide reductase (RR). These inhibitors bind to the HSV RR large
      subunit and consequently prevent subunit association and subsequent enzymatic
      activity. This report introduces a new series of compounds that contain an extra
      nitrogen (a ureido function) at the inhibitor N-terminus. This nitrogen improves
      inhibitor binding potency 50-fold over our first published inhibitor series.
      Evidence supports that this improvement in potency results from a new hydrogen
      bonding contact between the inhibitor and the RR large subunit. This report also
      provides evidence for the bioactive conformation around two important amino acid
      residues contained in our inhibitors. A tert-butyl group, which contributes 100
      fold to inhibitor potency but does not directly bind to the large subunit, favors
      an extended beta-strand conformation that is prevalent in solution and in the
      bound state. More significantly, the bioactive conformation around a pyrrolidine
      modified asparagine residue, which contributes over 30 000-fold to inhibitor
      potency, is elucidated through a series of conformationally restricted analogues.

PMID- 8667362
TI  - Inhibition of DNA topoisomerase II by azaelliptitoxins functionalized in the
      variable substituent domain.
AB  - A series of novel C11-substituted derivatives of azaelliptitoxin (azatoxin) have
      been synthesized and tested for their inhibitory activity against human DNA
      topoisomerase II. Incorporation of a C11 polyamine or amine resulted in an
      increase in the intercalation properties of the drug and a decrease of
      topoisomerase II activity. The structure-activity relationship (SAR) profile of
      the nonintercalating C11 anilino azatoxin class follows the SAR of the
      (anilino)acridine family. 11-(4-Cyanoanilino)azatoxin (14) was found to be the
      most active analog in this series, exhibiting approximately 10-fold higher
      activity than azatoxin 12 and etoposide.

PMID- 8667364
TI  - Modeling study on a hydrolytic mechanism of class A beta-lactamases.
AB  - Comparison of the hydrogen-bond networks at the active site in the
      crystallographic structures reported for class A beta-lactamases revealed an
      importance of a switch of the hydrogen-bond network for the catalytic process.
      Taking account of the conformational mobility of the Lys73 residue, we have
      constructed putative complex models for beta-lactam antibiotics and the enzymes
      in the multistep hydrolysis which consists of a Michaelis complex, an acyl
      enzyme, and a tetrahedral oxyanion for deacylation. In the acylation, the C3
      carboxylate of penicillin derivatives would participate in activation of the
      Ser130 hydroxyl group and then the oxyanion of the Ser130 residue would
      deprotonate the ammonium group of the Lys73 residue which will act as a general
      base for activation of the Ser70 residue. In the deacylation, the deacylating
      water molecule would be accommodated during a conformational change of the acyl
      moiety without a structural change of the active-site residues and the
      unprotonated N4 atom of the penicillins would act as a general base to activate
      the water molecule. This catalytic process provided a new account for the
      stability of the acyl-enzyme complexes. This substrate-assisted mechanism would
      also be extended to a hydrolytic mechanism of class C enzymes.

PMID- 8667363
TI  - Diphenylpropionic acids as new AT1 selective angiotensin II antagonists.
AB  - The synthesis and pharmacological evaluation of a new series of potent AT1
      selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists
      are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and
      AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of
      angiotensin II-induced increase in mean arterial blood pressure in pithed rats.
      Unsaturation of the diphenylpropionic acids as well as substitution or
      replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of
      potency. On the other hand, the presence of small alkyl groups in the alpha
      position to the carboxylic acid was important for activity, with one of the
      resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other
      (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated
      sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood
      pressure dose dependently. This compound showed in vitro and iv potencies similar
      to that of the reference compound losartan but faster onset of action and
      somewhat greater oral activity, presumably due to its improved bioavailability.

PMID- 8667365
TI  - Structure-activity studies of 6-(tetrazolylalkyl)-substituted
      decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 1. Effects of
      stereochemistry, chain length, and chain substitution.
AB  - A series of 6-substituted decahydroisoquinoline-3-carboxylic acids were prepared
      as excitatory amino acid (EAA) receptor antagonists. These compounds are
      antagonists at the N-methyl-D-aspartate (NMDA) and 2-amino-3-(5-methyl-3
      hydroxyisoxazol-4-yl) propanoic acid (AMPA) subclasses of ligand gated ion
      channel (ionotropic) EAA receptors. (3S,4aR, 6R,8aR)-6-(2-(1H-tetrazol-5
      yl)ethyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (9) is a
      potent, selective and systemically active AMPA antagonist. Other analogs from
      this series, including (3S,4aR,6S,8aR)-6-((1H-tetrazol-5-yl)methyl)-
      1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32) and
      (3S,4aR,6S,8aR)-6- (phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline
      3-ca rboxylic acid (61) are potent, selective, and systemically active NMDA
      antagonists. This and the subsequent publication look at the AMPA antagonist
      aspects of this SAR. Herein we report the effects of varying stereochemistry
      around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of
      having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon
      chain connecting a tetrazole to the bicyclic nucleus; and of holding the
      connecting chain constant at two atoms, the effect of heteroatom substitution in
      the position adjacent to the bicyclic nucleus and substitution with methyl or
      phenyl on the chain. Compounds were evaluated on rat cortical tissue for their
      ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA),
      NMDA ([3H]CGS 19755), and kainic acid ([3H]-kainic acid) receptors and for their
      ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM),
      and kainic acid (10 microM). Our findings revealed that the optimal
      stereochemical array was the same for both NMDA (32 and 61) and AMPA (9)
      antagonists identified in this series and that the tetrahydroisoquinoline (25)
      and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the
      distal acid position, an ethylene spacer (9) is optimal; substitution with oxygen
      or nitrogen on the chain in the position adjacent to the bicyclic nucleus
      significantly reduced activity, while substitution with a methyl or phenyl group
      on the chain was well tolerated.

PMID- 8667366
TI  - Structure-activity studies of 6-substituted decahydroisoquinoline-3-carboxylic
      acid AMPA receptor antagonists. 2. Effects of distal acid bioisosteric
      substitution, absolute stereochemical preferences, and in vivo activity.
AB  - We have explored the excitatory amino acid antagonist activity in a series of
      decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent
      and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl)
      decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we
      looked at the structure-activity relationships for AMPA antagonist activity in
      this series of compounds. We have already shown that 1 had the optimal
      stereochemical array and that AMPA antagonist activity was maximized for a two
      carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we
      explored the effects of varying the distal acid and the absolute stereochemical
      preferences of many of these analogs. We looked at a variety of different acid
      bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4
      triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl
      sulfonamides. Compounds were evaluated in rat cortical tissue for their ability
      to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA
      ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their
      ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM),
      and kainic acid (10 microM). A number of compounds from this and the preceding
      paper were also evaluated in mice for their ability to block maximal electroshock
      induced convulsions and ATPA-induced rigidity in mice.

PMID- 8667367
TI  - Synthesis and structure-activity relationships of 6-substituted androst-4-ene
      analogs as aromatase inhibitors.
AB  - Series of 6 alpha- and 6 beta-alkyl-substituted androst-4-en-17-ones (18 and 19)
      and their 17 beta-reduced derivatives (14 and 15)(alkyl: methyl, ethyl, n-propyl,
      n-pentyl, n-octyl) were synthesized and evaluated as aromatase inhibitors.
      Androst-4-en-17-ones having an oxygen function (hydroxy, acetoxy, or methoxy
      group) at C-6 alpha and C-6 beta (4 and 5) were also tested for their abilities
      to inhibit aromatase. All of the steroids studied inhibited human placental
      aromatase in a competitive manner. The inhibitory activities of the 6 alpha- and
      6 beta-methyl-17-keto steroids 18a and 19a (Ki = 3.1 and 5.3 nM, respectively) as
      well as the 6 beta- alcohol 5a (Ki = 6.0 nM) were high, and their apparent Ki
      values were lower than that of the parent 6-unsubstituted 3-deoxy steroid 1 (Ki =
      6.8 nM). Elongation of the methyl group decreased affinity for aromatase in
      relation to carbon number of the alkyl chain in each series, in which the 6 alpha
      alkyl steroids 18 essentially had higher affinity for the enzyme than the
      corresponding 6 beta- isomers 19. The inhibitory activities of the 17 beta
      hydroxy analogs 14 and 15 were less potent than those of the corresponding 17
      keto steroids. The 6 alpha-ethyl compound 18b, the 6 alpha-oxygenated derivatives
      4, and the 6 beta-acetoxy and 6 beta-methoxy analogs 5b and 5c were powerful
      inhibitors (Ki = 12-24 nM). The methyl steroids (18a and 19a) produced "type I"
      difference spectra upon interaction with aromatase. These results along with
      molecular modeling with the PM3 method suggest that compounds 18a and 19a may
      produce a thermodynamically stable enzyme-inhibitor complex in the hydrophobic
      binding pocket with a limited accessible volume. A carbonyl group at C-17 of the
      6-alkylandrost-4-enes is essential for the tight binding. Moreover, the binding
      pocket also tolerates a polar hydroxy group at the 6 beta-position rather than at
      the 6 alpha-position.

PMID- 8667368
TI  - Synthesis, absolute configuration, and biological profile of the enantiomers of
      trans-[2-(2,6-dimethoxyphenoxy)ethyl] [(3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2
      yl)methyl]amine (mephendioxan), a potent competitive alpha 1A-adrenoreceptor
      antagonist.
AB  - The enantiomers of trans-[2-(2,6-dimethoxyphenoxy)ethyl] [(3-p-tolyl-2,3-dihydro
      1,4-benzodioxin-2-yl) methyl]amine (mephendioxan, 2) were synthesized from the
      chiral trans-3-p-tolyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acids [(+)-3 and
      (-)-3] which in turn were obtained through the resolution of the racemic acid
      with (R)- and (S)-alpha-methylbenzylamine. Comparison of CD spectra of the
      enantiomers of 2 with that of (2S,3S)-3-methyl-2-phenyl-1,4-benzodioxane allowed
      the assignment of the 2S,3S configuration to the (-)-enantiomer of 2 and of the
      2R,3R configuration to the other enantiomer. The binding profile of the
      enantiomers of 2 was assessed at alpha 1, alpha 2, D2, and 5-HT1A receptors, in
      comparison to WB 4101 (1), 5-methylurapidil, and (+)-niguldipine. In addition,
      the two enantiomers were investigated at native and cloned alpha 1-adrenoreceptor
      subtypes. (-)-2 was 10-30 times as potent as the (+)-enantiomer at alpha 1
      adrenoreceptor subtypes in both functional and binding assays. It was 36-fold
      selective for the alpha 1A- versus alpha 1B-adrenoreceptor and 60- and 20-fold
      selective in binding to the alpha 1a-adrenoreceptor relative to alpha 1b and
      alpha 1d subtypes, respectively. Furthermore, the enantiomer (-)-2 displayed
      selectivities of 12000-, 2500-, and 250-fold in binding to alpha 1a
      adrenoreceptors relative to alpha 2-adrenoreceptors and 5-HT1A and D2 receptors.
      These results indicate that (-)-2 may be a valuable tool in the characterization
      of alpha 1-adrenoreceptor subtypes.

PMID- 8667369
TI  - Synthesis and pharmacological characterization of all sixteen stereoisomers of 2
      (2'-carboxy-3'-phenylcyclopropyl)glycine. Focus on (2S,1'S,2'S,3'R)-2-(2'-carboxy
      3'-phenylcyclopropyl)glycine, a novel and selective group II metabotropic
      glutamate receptors antagonist.
AB  - All 16 2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCGs) stereoisomers 32-47
      have been prepared from the corresponding racemic aldehydes 12-15 following an
      enantiodivergent synthetic protocol. Compounds 32-47 were evaluated by a number
      of binding and functional experiments as potential ligands for several classes of
      excitatory amino acid receptors, including metabotropic glutamate receptors
      (mGluR1a, mGluR2, mGluR4) and ionotropic glutamate receptors (NMDA, KA, AMPA) as
      well as sodium-dependent and calcium/ chloride-dependent glutamate transport
      systems. The stereolibrary of compounds 32-47 appears to be endowed with a
      peculiar pharmacological profile. PCCG-2 (33) and PCCG-3 (34) displaced labeled
      kainate at low micromolar concentration; PCCG-9 (40) and PCCG-11 (42) weakly
      interacted with the NMDA site; PCCG-5 (36), PCCG-10 (41), and PCCG-12 (43) showed
      to be potent inhibitors of Ca2+/Cl(-)-dependent glutamate transport system. Most
      interestingly, PCCG-4 (35) has been shown to be able to antagonize (IC50 = 8
      microM) the effects of glutamate on forskolin-stimulated cAMP formation in BHK
      cells expressing mGluR2. Uneffective at mGluR1, 35 is a weak mGluR4 agonist (EC50
      = 156 microM) and has no effect on either ionotropic receptors or glutamate
      transport systems, thus demonstrating to be a novel selective mGluR2 antagonist
      with a 6-fold increase in potency over previously reported antagonists.

PMID- 8667370
TI  - Synthesis and physicochemical, biological, and pharmacological properties of new
      bile acids amidated with cyclic amino acids.
AB  - New analogs of cyclic amino acid-conjugated bile acids were synthesized, and
      their physicochemical and biological properties were compared with those of
      natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4
      hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids
      were amidated with L-proline. The physicochemical properties were similar to
      those of the natural analogs. All of them were highly stable toward enzymatic C
      24 amide bond hydrolysis and 7-dehydroxylation. Their transport, metabolism, and
      effect on biliary lipid secretion were evaluated in bile fistula rat after
      intravenous infusion. All the analogs were secreted in bile unmodified. The 4
      methoxy-L-proline derivative produced the highest secretion rate, much higher
      than those of all the other natural and synthetic analogs. This was associated
      with a selective reduction of cholesterol secretion with normal phospholipid
      secretion and choleresis. When coinfused, all the analogs were able to prevent
      the hepatotoxicity induced by intravenous taurochenodeoxycholic acid, as revealed
      by normal choleresis, alkaline phosphatase, and lactate dehydrogenase values in
      bile. Considering the overall data, 4-methoxy-L-proline, 4-hydroxy-L-proline, and
      L-proline derivatives of ursodeoxycholic acid were more potent than the natural
      analogs.

PMID- 8667371
TI  - Handling small arbovirus vectors safely during biosafety level 3 containment:
      Culicoides variipennis sonorensis (Diptera:Ceratopogonidae) and exotic bluetongue
      viruses.
AB  - Equipment and procedures are described for biosafety level 3 (BL-3) containment
      work with small, zoophilic arthropods. BL-3 classified pathogens always must be
      manipulated in biological safety cabinets. Procedures, including physical
      barriers and handling methods, that prevent the escape of potentially virus
      infected insects are discussed, and the use of a monitoring system for insect
      security is explained. The inability to recover escaped minute, flying insects
      poses a major difference from similar work with larger insects, such as
      mosquitoes. Methods were developed for the safe and secure handling of Culicoides
      variipennis sonorensis Wirth & Jones infected with exotic bluetongue viruses
      during BL-3 containment.

PMID- 8667372
TI  - Bionomics of Lutzomyia evansi (Diptera: Psychodidae) vector of visceral
      leishmaniasis in northern Columbia.
AB  - The feeding behavior, seasonality, and natural infection rate of Lutzomyia evansi
      (Nunez-Tovar) with Leishmania chagasi (Cuna & Chagas) was studied during a 12-mo
      period at 2 hamlets, El Contento and Vidales. Sand fly abundance in extra-, peri
      , and intradomestic habitats was evaluated with sticky traps and CDC light traps,
      whereas human bait and Shannon trap collections were made only in peridomestic
      habitats. All trapping methods showed a clear predominance of L. evansi
      throughout the year. Sand flies were present during most of the year, with the
      exception of the driest months (February and March). Although the total number of
      sand flies was higher in El Contento than in Vidales, a larger proportion of L.
      evansi was found in intradomestic habitat than in the peri- and extradomestic
      habitats at Vidales. Also, sand flies from Vidales had a higher infection rate
      with L. chagasi than did those from El Contento. Although 2 of 9 promastigote
      infections detected in L. evansi were identified as L. chagasi, the difficulty of
      isolating and propagating leishmania strains from this visceral leishmaniasis
      focus precluded characterization of most parasite samples. Parous and infected
      sand flies were most abundant toward the end of the rainy season (October
      December). For this reason, control strategies based on reducing sand fly
      populations or avoiding human-vector contact should be concentrated during the
      October-December period.

PMID- 8667373
TI  - Improvement of techniques for age grading hematophagous insects: ovarian oil
      injection and ovariolar separation techniques.
AB  - After injection of oil into the oviduct of hematophagous Diptera, the ovarioles
      become completely separated from each other, allowing examination of a large
      number of undamaged ovarioles, an important advantage over other techniques for
      accurately determining the physiological age of mosquitoes. The technique has
      been simplified and improved, especially by using a sodium chloride-glycerol
      formaldehyde mixture for mounting preparations, which are more convenient and
      permanent for examination of the ovarioles. The difficulties of using the
      technique, their possible causes, and possibilities for overcoming them are
      described. Similar results can be obtained with an alternative technique, the
      ovariolar separation technique, using strongly diluted Carnoy's solution, which
      leaves ovaries in a fixed condition. Both techniques can be used for several
      hematophagous dipteran groups.

PMID- 8667374
TI  - Application of the ovarian oil injection and ovariolar separation techniques for
      age grading hematophagous Diptera.
AB  - The ovarian oil injection and ovariolar separation techniques were applied to
      determine the physiological age of species of the 3 dipteran families Culicidae,
      Simuliidae, and Tabanidae. The presence of a granular basal body (a granular area
      in the calyx wall within the ovariolar sheath) indicates at least 1 egg laying;
      that is, it can be used to separate parous from nulliparous females, which
      possess no granular basal body. In parous females, the number of ovipositions can
      be determined accurately by counting the number of dilatations in the diagnostic
      ovarioles. An egg sac, when present, indicates only the current egg laying. A
      diagram for age grading using the technique is presented and discussed.

PMID- 8667375
TI  - Ixodes (Ixodes) scapularis (Acari:Ixodidae): redescription of all active stages,
      distribution, hosts, geographical variation, and medical and veterinary
      importance.
AB  - The blacklegged tick, Ixodes (Ixodes) scapularis Say, 1821, is redescribed, based
      on laboratory reared specimens originating in Bulloch County, Georgia.
      Information on distribution, host associations, morphological variation, and
      medical/veterinary importance is also presented. A great deal of recent work has
      focused on this species because it is the principal vector of the agent of Lyme
      disease (Borrelia burgdorferi Johnson, Schmidt, Hyde, Steigerwaldt & Brenner) in
      eastern North America. Its distribution appears to be expanding, and includes the
      state of Florida in the southeastern United States north to the provinces of Nova
      Scotia and Prince Edward Island, Canada, west to North and South Dakota, United
      States, and south to the state of Coahuila, Mexico. Although I. scapularis feeds
      on at least 125 species of North American vertebrates (54 mammalian, 57 avian,
      and 14 lizard species), analysis of the U.S. National Tick Collection holdings
      show that white-tailed deer, Odocoileus virginianus (Zimmermann), cattle, Bos
      taurus L., dogs, Canis lupus L., and other medium-to-large sized mammals are
      important hosts for adults as are native mice and other small mammals, certain
      ground-frequenting birds, skinks, and glass lizards for nymphs and larvae. This
      tick is a polytypic species exhibiting north-south and east-west morphological
      clines. Analysis of variance and Student-Newman-Keuls multiple comparisons
      revealed significant interpopulational variation that is expressed most
      significantly in the nymphal stage. Nymphs from northern (Minnesota,
      Massachusetts, Maryland) populations had relatively larger basis capituli with
      shorter cornua (except Maryland) than southern (North Carolina, Georgia)
      populations. Midwestern populations (Minnesota, Missouri) differed from eastern
      populations (Massachusetts, Maryland, North Carolina, Georgia) in idiosomal
      characters (broader scuta, larger coxae III, and IV). In addition to Lyme
      disease, this tick is also a primary vector of the agent of human and rodent
      babesiosis, Babesia microti Franca. Under laboratory conditions it has
      transmitted the agents of deer babesiosis, Babesia odocoilei Emerson & Wright,
      tularemia, Francisella tularensis McCoy & Chapin, and anaplasmosis, Anaplasma
      marginale Theiler. Moreover, I. scapularis can reach pest proportions on
      livestock, and females can cause tick paralysis in dogs.

PMID- 8667376
TI  - Ixodes (Ixodes) jellisoni and I. (I.) neotomae (Acari:Ixodidae): descriptions of
      the immature stages from California.
AB  - Nymphal and larval stages of Ixodes (Ixodes) jellisoni Cooley & Kohls and I. (I.)
      neotomae Cooley are described for the first time. These 2 tick species occur only
      in the western United States, predominantly in California. The primary host for
      I. jellisoni is the California kangaroo rat, Dipodomys californicus (Merriam);
      that for I. neotomae is the dusky-footed woodrat, Neotoma fuscipes Baird. The
      etiologic agent of Lyme disease Borrelia burgdorferi Johnson, Schmidt, Hyde,
      Steigerwalt & Brenner has recently been isolated from both tick species, and I.
      neotomae was proven a competent enzootic vector of the Lyme disease spirochete.

PMID- 8667377
TI  - Simulation studies of African horse sickness and Culicoides imicola
      (Diptera:Ceratopogonidae).
AB  - A simulation model of African horse sickness in Spain was developed to
      investigate what factors affect the likelihood of an epidemic after the
      introduction of the virus. The model included 2 host species (horses and donkeys)
      and 1 vector species (Culicoides imicola Kieffer). Latin hypercube sampling was
      used for sensitivity analysis of the model, to include uncertainty in parameter
      estimates. In general, if an epidemic occurred most hosts were infected. The peak
      prevalence in midges was low, and never exceeded 3%. Midge population size, the
      recovery rate in horses, and the time of year when the virus was introduced were
      the most significant factors in determining whether or not an epidemic occurred.
      The uncertainty in interbloodmeal interval, removal rate (mortality and recovery)
      of infectious horses, midge population size, and transmission rates were
      significant factors in the size of the epidemic. These factors should be
      priorities for empirical research, and should be considered in the design of
      control strategies in areas at risk of virus introduction.

PMID- 8667378
TI  - Lyme borreliosis spirochetes in Ixodes ricinus (Acari:Ixodidae) and the varying
      hare on isolated islands in the Baltic, Sea.
AB  - We investigated isolated ecosystems to determine if Lyme borreliosis is
      maintained in the absence of reservoir-competent small mammals. Human cases of
      Lyme disease have been reported on the isolated islands of Gotska Sandon and
      Stora Karlso in the Baltic Sea. The varying hare, Lepus timidus, is the only
      terrestrial vertebrate species capable of serving as a host for all stages of
      Ixodes ricinus (L.) on these islands. In August, mean larval infestation on 5
      hares from each island was 548 with a maximum of 2,276 larvae on 1 hare. Smaller
      numbers of nymphal and female ticks were also engorging on the hares. During
      August-September, B. burgdorferi s.l. was detected in 11-24% of nymphal I.
      ricinus fed as larvae on hares and in 8-19% of host-seeking nymphal I. ricinus
      collected from the vegetation. We conclude that L. timidus serves as a
      maintenance host for B. burgdorferi s.l. and its vector, I. ricinus, on both
      islands.

PMID- 8667379
TI  - Spatial distribution of adult mosquitoes (Diptera:Culicidae) in habitats
      associated with the rice agroecosystem of northern California.
AB  - The objective of this study was to determine whether abundance, blood feeding
      rates, and sex ratios of adult Anopheles freeborni Aitken and Culex tarsalis
      Coquillett were associated significantly with either rice field, pasture,
      riparian, or mixed habitats found within the rice culture agroecosystem of
      northern California. Significantly higher numbers of adult An. freeborni occurred
      in riparian and mixed habitats compared with rice and pasture habitats. Such a
      pattern was not evident for Cx. tarsalis. Riparian and pasture habitats contained
      significantly higher proportions of blood fed An. freeborni females than did rice
      and mixed habitats; however, the proportions of blood fed Cx. tarsalis females
      did not vary significantly among habitat types. The proportions of blood fed An.
      freeborni and Cx. tarsalis females in riparian habitats decreased with increasing
      abundance. There was no correlation between blood feeding rates and abundance for
      An. freeborni and Cx. tarsalis females in the other habitat types. The sex ratio
      of An. freeborni in pasture and riparian habitats was significantly female
      biased, unlike the other habitats which did not differ significantly from unity
      (1:1). Overall, riparian and mixed habitats contained greater numbers of adults
      mosquitoes; therefore, surveillance and control efforts of these mosquito species
      should be focused on such habitats.

PMID- 8667380
TI  - Exchange of Borrelia burgdorferi between Ixodes persulcatus (Ixodidae:Acarina)
      sexual partners.
AB  - Borrelia burgdorferi sensu lato infection rate in Ixodes persulcatus Schulze
      maintained at different relative humidity gradients in male and females pairs,
      separated by sex, and in ticks of both sexes having either normal or abnormal
      exoskeleton were compared. Ticks were collected in the St. Petersburg Region of
      Russia during 1992 and 1994. We observed that the infection rate among the ticks
      maintained as sexual pairs was 1.75-2.00 times higher than that among ticks
      maintained singles, indicating a borreliae interchange between sexual partners.
      This pathogen interchange was thought to result from a venereal or omovampiric
      (cannibalistic) mode of borreliae transmission. Borrelia burgdorferi s.l. was
      determined to be present in 22.9% (112 infected specimens of 489 total), whereas
      infection occurred in 17.4% of single females and 16.5% of single males. The data
      indicate the importance of isolating ticks sexually during quantitative disease
      investigations with borreliae as well as tick-borne encephalitis virus and other
      tick-borne pathogens.

PMID- 8667381
TI  - Evaluation of permethrin-impregnated cotton balls as potential nesting material
      to control ectoparasites of woodrats in California.
AB  - The dusky-footed woodrat, Neotoma fuscipes Baird is a natural reservoir of the
      Lyme disease spirochete, Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt
      & Brenner, in California. To investigate the potential of host-targeted
      insecticide to control the tick vectors of B. burgdorferi, permethrin-impregnated
      or untreated cotton balls were distributed in metal cylinders as potential
      nesting material adjacent to 95 woodrat houses in chaparral-covered rangeland.
      Laboratory experiments demonstrated that adult woodrats would enter the cylinders
      and construct nests from permethrin-treated or untreated cotton. The residual
      concentration of permethrin did not vary significantly during an 11-mo period and
      remained > 60% of the registered insecticidal formulation (7.5% [AI] by cotton
      weight). The abundance of 4 species of ticks (Ixodes neotomae Cooley; the western
      blacklegged tick I. pacificus Cooley & Kohls; I. woodi Bishopp; and the Pacific
      Coast tick, Dermacentor occidentalis Marx) infesting woodrats was similar in the
      treatment and control areas. Although > 90% of the cotton disappeared from the
      metal cylinders in both areas, examination of 8 active woodrat houses revealed
      that small amounts of cotton had been incorporated into the nest cups of only
      25%. In contrast, the abundance of the flea Orchopeas sexdentatus (Baker)
      decreased significantly in the treatment area only. Spirochetes were not detected
      in 168 adult O. sexdentatus fleas that had fed on spirochetemic woodrats, which
      demonstrates that this flea is an inefficient host of B. burgdorferi. We conclude
      that the use of permethrin-impregnated cotton as potential nesting material is
      ineffective for controlling ticks associated with the dusky-footed woodrat in
      brushlands, but this methodology may be useful for reducing populations of
      sylvatic fleas.

PMID- 8667382
TI  - Model stimulations to estimate malaria risk under climate change.
AB  - The current geographic range of malaria is much smaller than its potential range.
      In many regions there exists a phenomena characterized as "Anophelism without
      malaria." The vectors are present but malaria transmission does not occur.
      Vectorial capacity often has been used as a parameter to estimate the
      susceptibility of an area to malaria. Model computations with global
      climatological data show that a dynamic concept of vectorial capacity can be used
      as a comparative risk indicator to predict the current extent and distribution of
      malarious regions in the world. A sensitivity analysis done in 3 distinct
      geographic areas shows that the areas of largest change of epidemic potential
      caused by a temperature increase are those where mosquitoes already occur but
      where development of the parasite is limited by temperature. Computations with
      the model presented here predict, with different climate scenarios, an increased
      malaria risk in areas bordering malaria endemic regions and at higher altitudes
      within malarious regions under a temperature increase of 2-4 degrees C.

PMID- 8667383
TI  - Distention and sugar feeding induce autogenous egg development by the Asian tiger
      mosquito (Diptera:Culicidae).
AB  - Mechanisms initiating autogenous egg development were studied using a selected
      strain of Asian tiger mosquito, Aedes albopictus (Skuse), that required a sugar
      meal to develop eggs autogenously. Caloric intake and the abdominal distention
      produced by ingesting sucrose solutions were interrelated in their effects on
      autogeny. Distention of the abdomen with 2 microliters of saline, with no caloric
      intake, induced autogenous egg maturation in 66% of the females. Abdominal
      distention produced by 2 microliters of saline did not induce egg development if
      the ventral nerve cord was transected. However, eggs were produced when females
      ingested 200 micrograms of sucrose in 2 microliters of water following ventral
      nerve cord transection. A meal containing at least 100 micrograms of sucrose was
      required for egg development if abdominal distention was < 1 microliter. Mating
      influenced autogeny in only 10% of the population. Neither distention, caloric
      intake nor mating affected the number of eggs that matured.

PMID- 8667384
TI  - Lyme disease spirochetes in ticks collected from birds in midwestern United
      States.
AB  - In a tick-spirochete survey conducted from all 1989 through fall 1992 in north
      western Wisconsin, 4,256 birds (composed of 91 species) were examined for ticks.
      Infestations were recorded for 400 birds (composed of 30 species). Of 1,184 ticks
      taken from 335 birds (composed of 26 species), 60 (5%) Haemaphysalis
      leporispalustris (Packard) from 8 species of birds were infected with the Lyme
      disease spirochete. Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt &
      Brenner. Similar surveys conducted in 1990 and 1991 in Minnesota and Michigan
      yielded 223 H. leporispalustris from 61 birds (composed of 23 species), all free
      of spirochetes. However, 1 B. burgdorferi-infected Ixodes scapularis (Say) was
      found on 1 bird species in Minnesota. Most ticks were collected in fall from
      ground-foraging birds such as thrushes and sparrows. These results confirm that
      tick-infested birds are important in disseminating Lyme disease spirochetes and
      may also play a role as sources for infecting ticks.

PMID- 8667385
TI  - Systemic treatment of white-tailed deer with ivermectin-medicated bait to control
      free-living populations of lone star ticks (Acari:Ixodidae).
AB  - Whole-kernel corn was treated with 10 mg ivermectin per 0.45 kg corn and fed at
      rate of approximately .45 kg/deer per day to white-tailed deer confined in the
      treatment pasture, whereas deer in an adjacent control pasture received a similar
      ration of untreated corn. Treatments were dispensed from February through
      September of 1992 and 1993, and free-living populations of lone star ticks.
      Amblyomma americanum (L.), were monitored in both pastures using dry-ice traps to
      quantify nymphs and adults and flip-cloths to assay the relative abundance of
      larval masses. Control values that were calculated for all ticks collected in
      both pastures during 1993 showed 83.4% fewer adults, 92.4% fewer nymphs and
      100.0% fewer larval masses in the treatment versus control pasture. Serum
      ivermectin concentrations in treated deer averaged 21.7 and 28.3 ppb during 1992
      and 1993, respectively. These values compared favorably with the goal
      concentration of 30.0 ppb which was anticipated under ideal conditions. This
      study demonstrates that a freely consumed, systemically active acaricidal bait
      ingested by white-tailed deer under nearly wild conditions can significantly
      reduce the abundance of all stages of free-living long star ticks.

PMID- 8667386
TI  - Reproductive strategies of the cat flea (Siphonaptera:Pulicidae): parthenogenesis
      and autogeny?
AB  - The objective of this study was to determine if there is evidence of
      parthenogenesis or autogenous reproduction in the cat flea, Ctenocephalides felis
      (Bouche). To examine parthenogenesis, 400 newly eclosed virgin female fleas were
      collected from a laboratory colony and 100 were placed into each of 4 feeding
      cages and fed bovine blood through a Parafilm membrane. Three of the feeding
      cages were monitored for egg production for 7 d and each group of 100 virgin
      female fleas produced an average 1,119 eggs per cage, but none was viable. Fifty
      male fleas were added to those 3 feeding cages on day 7, and within 24 h the
      female fleas began ovipositing fertile eggs and nearly quadrupled their egg
      output. The other cage in which no males were introduced served as a control and
      did not produce a single viable egg in the 14-d experimental period. A similar
      experiment examined the continuance of virgin females to lay nonviable eggs and
      it was found that they continued to lay nonviable eggs for at least 58 d. Egg
      production was also studied in unfed fleas and it was found that unfed fleas did
      not produce eggs. These results suggest that neither parthenogenetic reproduction
      nor autogeny are exhibited by the cat flea.

PMID- 8667387
TI  - Experimental evidence against replication or dissemination of hepatitis C virus
      in mosquitoes (Diptera:Culicidae) using detection by reverse transcriptase
      polymerase chain reaction.
AB  - In 3 laboratory experiments, mosquitoes were fed hepatitis C virus (HCV)-RNA
      positive blood by using membrane feeders, separated into head, thorax, and
      abdomen, and tested by a reverse transcriptase polymerase chain reaction for HCV
      RNA. HCV did not replicate or disseminate in mosquitoes that had ingested blood
      from patients that were HCV-viremic positive. When yellow fever mosquitoes, Aedes
      aegypti (L.), were held for 1, 3, 7, 14, and 21 d after feeding, HCV-RNA was
      detected in the abdomens of 5/5 mosquitoes at 1 d after feeding; remaining
      tissues were negative with the exception of a single positive head at 7 d. In
      agreement, HCV-RNA was detected in Asian tiger mosquito, Aedes albopictus Skuse,
      and Anopheles stephensi Liston abdomens at 1 d, but not 3 d after feeding no HCV
      RNA was detected in heads or thoraces. In addition, HCV-RNA was detected in heads
      of Ae. aegypti at 10 and 20 min, but not at 30 min, after feeding. The latter
      results raise the possibility of HCV contamination of mouthparts and,
      theoretically, mechanical transmission of this virus.

PMID- 8667388
TI  - Parity diagnosis and ovulation in Culiseta inornata (Diptera:Culicidae).
AB  - The hypothesis that ovulation in mosquitoes results in the formation of a single
      basal dilatation per ovariole, regardless of previous history of the ovariole,
      was supported for known 1- and 2-parous Culiseta inornata (Williston). The
      examination of histological sections of whole ovaries of Cs. inornata, before and
      after ovulation in the 1st gonotrophic cycle, indicated that the pedicel is
      destroyed during ovulation. Dissections revealed that 88% of 1- dilated ovarioles
      in 1-pars lacked a pedicel, and 90% of 2-pars had a mean of only 12.5 2-dilated
      ovarioles (10% had none). Criteria are proposed for the separation of
      nulliparous, 1-parous and 2-parous (anautogenous) Cs. inornata. Fifty percent of
      nullipars and 42% of 1-pars had a mean of 2.6 and 2.0 rogue ovarioles,
      respectively. The criteria account for rogue ovarioles in nullipars, but
      misdiagnose 2-pars as 1-pars when the former have few (or lack) diagnostic
      ovarioles. This diagnostic error can be reduced using structural differences in
      rogue versus diagnostic ovarioles.

PMID- 8667389
TI  - Population genetics and gene variation of stable fly populations
      (Diptera:Muscidae) in Nebraska.
AB  - Genetic variation in stable fly, Stomoxys calcitrans (L.), populations from
      Nebraska, Canada, and Texas was sampled. Four of 12 allozyme loci were
      polymorphic, with an average of 1.7 alleles per locus. Observed and expected
      heterozygosities were 0.086 and 0.070, respectively. Nei's genetic distance
      between populations averaged 0.001 and ranged from 0.000 to 0.005. Wright's F
      statistics revealed greater variation within than among populations. Allele
      frequencies were homogeneous among temporal samples from a single population.
      Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)
      analysis of 6.4 kb of the mitochondrial DNA genome with 16 restriction enzymes
      revealed no variation in stable fly populations from Canada, Nebraska, and Texas.
      PCR-RFLP analysis of a 2.0-kb fragment of the nuclear ribosomal DNA internally
      transcribed spacer region also revealed no variation. The lack of genetic
      differentiation among stable fly populations indicates high levels of gene flow
      among populations. The low levels of variation observed with biochemical and
      molecular techniques are consistent with a genetic bottleneck during stable fly
      colonization of North America.

PMID- 8667390
TI  - Evidence for multiple foci of eastern equine encephalitis virus
      (Togaviridae:Alphavirus) in central New York State.
AB  - A regional surveillance system for eastern equine encephalitis (EEE) virus was
      established in central New York in 1984 after the 2nd human EEE fatality occurred
      in 1983. Extensive mosquito surveillance activities were coordinated with the
      rapid laboratory processing of mosquito specimens for EEE virus. Active
      surveillance for EEE infections in humans and equines also was initiated. Results
      of long-term surveillance detected the presence of multiple Culiseta breeding
      swamps. A 6-yr interepizootic period (1984-1989) was followed by 2 yr of equine
      EEE. In 1990, there were 7 equine cases and a record number of EEE virus
      isolations from mosquitoes (n = 86), wild birds (n = 27), and sentinel pheasants
      (n = 7). In 1991, 7 equine cases also occurred, although there were fewer
      isolations from mosquitoes (n = 40). The sequence to the appearance of EEE virus
      at swamps and upland sites and at individual swam complexes, and the spatial and
      temporal distribution of equine cases provide evidence for multiple foci of EEE
      virus in central New York. The role of infected Culiseta melanura (Coquillett) in
      the transfer of EEE virus between swamp and upland areas and among swamp
      complexes is advanced.

PMID- 8667391
TI  - Seasonal variation in the vector competence of Culex tarsalis (Diptera:Culicidae)
      from the Coachella Valley of California for western equine encephalomyelitis and
      St. Louis encephalitis viruses.
AB  - The vector competence of Culex tarsalis Coquillett from the Coachella Valley of
      California for western equine encephalomyelitis (WEE) and St. Louis encephalitis
      (SLE) viruses was monitored monthly from February to November 1993. The
      concentration of WEE virus required to infect 50% of the females increased during
      summer coincidentally with ambient temperature and was highest during July.
      Transmission rates of WEE virus were high during March, low during May-June, and
      high again during July-September. Females expressed both mesenteronal escape and
      salivary gland barriers limiting WEE virus dissemination and transmission rates,
      respectively. SLE virus infection and dissemination rates did not vary among
      months, but transmission rates, were highest during July-September. Although
      infection rates with SLE virus were moderate, most infected females developed
      disseminated infections. Salivary gland infection or escape barriers prevented
      SLE virus transmission in 16-100% of infected females.

PMID- 8667392
TI  - Overwintering strategies of mosquitoes (Diptera:Culicidae) on warmer islands may
      predict impact of global warming on Kyushu, Japan.
AB  - Mosquito overwintering was studied on Tanegashima and Yakushima, islands south of
      Kyushu, to predict the impact of global warming on northern Kyushu where
      mosquitoes overwinter in diapause. On Tanegashima and Yakushima, the following 5
      types of overwintering strategies were recognized: (1) continued reproduction
      without diapause (2 Anopheles spp., 2 Culex spp., 2 Aedes spp.); (2) diapausing
      female adults but a few adults from late-developing larvae may emerge in
      midwinter (2 Anopheles spp. and 9 culex spp.); (3) diapausing eggs but a few
      adults may emerge in midwinter (5 Aedes spp.); (4) diapausing larvae (1
      Orthopodomyia sp., 1 Aedes sp., 1 Armigeres sp., 1 Uranotaenia sp., 1
      Toxorhynchites sp.); and (5) diapausing eggs and larvae (1 Tripteroides sp.). Few
      females of 4 aedine species were collected while seeking hosts in midwinter, but
      neither larvae nor adults of Culex tritaeniorhynchus Giles or southern house
      mosquito, Culex quinquefasciatus Say, were found during this survey. The 5
      degrees C increase in the midwinter mean temperature in northern Kyushu probably
      will not produce serious mosquito problems directly, but the proximity of the
      subtropical regions may have significant effects through dispersal of adult
      mosquitoes.

PMID- 8667393
TI  - Colonization and bionomics of Forcipomyia taiwana (Diptera:Ceratopogonidae) in
      the laboratory.
AB  - An improvement in colonizing the biting midge Forcipomyia taiwana (Shiraki) was
      achieved by a new technique that facilitated the rearing of the midges and
      induced them to mate in the laboratory. At temperature of 15, 20, 25, and 30
      degrees C, the development duration of the egg, 4 larval instars, and pupa
      decreased as temperature increased. Among 7 different diets, the blue green
      algae, Anabaena sp.Ch3, was the best food for rearing the midges. When the larvae
      were fed on the blue green algae at 25 degrees C, they needed 12 d to pupate, the
      pupation rate was 71.4%, the emergence rate was 80.2%, and the average longevity
      of the male and the female 38.3 and 22.6 d, respectively. When 120 paris were
      kept in a plastic cage (60 by 60 by 60 cm), swarming and copulation occurred
      during 0700-0900 and 1700-1800 hours. Swarm occurred throughout the cage and
      consisted of 10 males. The copulation was performed on the wall and the bottom of
      the cage, and the average duration was 290 s.

PMID- 8667394
TI  - Evaluation of reverse transcriptase polymerase chain reaction for the detection
      of eastern equine encephalomyelitis virus during vector surveillance.
AB  - A reverse transcriptase polymerase chain reaction (RT-PCR) assay was evaluated
      for the detection of eastern equine encephalomyelitis virus (EEEV). EEEV was
      detected by amplification of a 416-bp PCR product from within the E2 gene.
      Internal restriction endonuclease digestion and hybridizations to EEEV RNA
      demonstrated that the PCR product was amplified from EEEV. PCR amplifications
      from serial dilutions of an EEEV isolate identified by a neutralization test and
      titered by an infectious assay in cell culture indicated that this RT-PCR assay
      detected viral RNA at concentrations below 1 plaque forming unit(PFU) per
      reaction. The performance of the PCR assay in detection of EEEV was compared with
      an infectious assay detection procedure (IA/IFA) as part of the New Jersey 1993
      vector surveillance program. During 1993, 7,007 field-collected Culiseta melanura
      (Coquillett) were assayed in 522 pools by both RT-PCR and IA/IFA. EEEV was
      detected in 95 pools by RT-PCR and 17 pools by IA/IFA; all IA/IFA positive pools
      were also positive by RT-PCR. During the 1993 field season, RT-PCR consistently
      detected virus at enzootic foci earlier that IA/IFA and in greater numbers of
      mosquito pools. The data indicated that viral RNA may be present earlier and in
      more mosquitoes than indicated by IA/IFA.

PMID- 8667395
TI  - Immunotherapy trial for horses in British Columbia with Culicoides
      (Diptera:Ceratopogonidae) hypersensitivity.
AB  - Immunotherapy was used to treat horses in British Columbia for Culicoides
      hypersensitivity. This is a severe, chronic, recurrent allergic disease of horses
      that results in severe irritation, large lesions, hair loss and secondary
      infection in the ventral midline, mane, and proximal region of the tail. A crude
      Culicoides extract was injected subcutaneously, in increasing doses, into 10
      horses that were affected severely by the disease. Weekly doses reduced the
      clinical signs in 9 of the 10 horses in the 1st yr. Eight horses were treated
      with a maintenance dose during a 2nd yr. After the 2nd yr, 3 horses were
      completely free of clinical signs, 3 showed much less severe clinical signs than
      in untreated years, and 2 showed moderate reduction in clinical signs. Dosage,
      frequency of injections, and possible future applications of this technique are
      discussed.

PMID- 8667396
TI  - Thalassornectes dendrocygnae new species (Acari:Hypoderatidae) from the black
      bellied whistling-duck (Aves:Anseriformes; Dendrocygnidae).
AB  - A new species of hypoderatid deutonymph is described from the subcutaneous
      adipose tissues of the black-bellied whistling-duck, Dendrocygna autumnalis (L.),
      from Texas. Thalassornectes dendrocygnae n. sp. is most similar to
      thalassornectes rwandae Fain from the white-backed duck, Thalassornis leuconotos
      Eyton, in Africa. The new species is distinguished by a complete genital apodeme,
      the interrupted pattern of midventral cuticular sclerotization between coxal
      fields II and III, the dense cuticular sclerotization of the posterior idiosoma,
      and the long filiform seta d5, which is longer than the other idiosomal setae. In
      T. rwandae, the anterior and posterior parts of the genital sclerite are
      separated in the middle, the pattern of midventral cuticular sclerotization is
      continuous in the midventer, there is no dense sclerotization in the posterior
      idiosoma, and seta d5 is not figured (broken or absent?). There also are minor
      differences in chaetotaxy and solenidiotaxy of legs I and III of these 2 species.
      T. dendrocygnae is only the 2nd species of hypoderatid described from the host
      order Anseriformes. The 2 Thalassornectes spp. are described exclusively from
      each of the 2 genera in the host family Dendrocygnidae, respectively.
      Reevaluation of the suite of characters used to differentiate subgenera in the
      genus Thalassornectes indicates that Thalassornectes Fain, Rallidectes Fain, and
      Alcidectes Pence & Hoberg should be considered invalid.

PMID- 8667397
TI  - Localization of myosuppressinlike peptides in the hypocerebral ganglion of two
      blood-feeding flies: horn fly and stable fly (Diptera:Muscidae).
AB  - The insect peptides leucomyosuppressin (pEDVDHVFLRFamide) and dromyosuppressin
      (TDVDHVFLRFamide) have identical chemical sequences with the exception of the N
      terminal amino acid; both inhibit spontaneous contraction of insect visceral
      muscles. Neurons in the hypocerebral ganglion of horn fly, Hematobia irritans
      (L.), and stable fly, Stomoxys calcitrans (L.), were found to contain material
      immunoreactive to antiserum produced against the C-terminal of
      leucomyosuppressin, but not to the N-terminal of dromyossuppressin. Two large
      lateral clusters containing 8 cells, linked dorsally and ventrally by 2 chains of
      6 cells, encircled the anterior surface of the proventriculus and were
      immunoreactive of leucomyosuppressin and FMRFamide antisera. Axons from these
      cells were traced to the wall of the aorta and over the surface of the
      proventriculus. Ultrastructural analysis revealed these cells contained a
      singular type of elementary secretory granule that contained material of
      relatively low electron density, both in the cell body and at the axon terminals.

PMID- 8667398
TI  - Presence of calreticulin in vector fleas (Siphonaptera).
AB  - Calreticulin has been defined in the cat flea, Ctenophalides felis (Bouche), and
      oriental rat flea, Xenopsylla cheopis (Rothschild). Calreticulin, a major
      endoplasmic reticulum protein, was previously identified as a component of ixodid
      tick saliva. Using a riboprobe generated from tick calreticulin complementary DNA
      (cDNA), we distinguished 2 transcripts for calreticulin in cat fleas by Northern
      blot analysis. Increased expression of calreticulin was not evident in fed versus
      unfed adult fleas. We were able to amplify a calreticulin flea product from fed
      female messenger RNa (mRNA) using primers designed from the tick calreticulin
      gene. One of these products hybridized to the tick riboprobe. Localization of
      specific antibody to cat flea tissues showed calreticulin in the midgut with no
      detection in the salivary glands. We also observed specific labeling of
      calreticulin with antibody in the ovaries of fed females. Several cat flea
      polypeptides appear to crossreact with anticalreticulin antibody in Western
      blots. We did not detect a calreticulin using antibody to the tick-secreted
      protein in cat flea salivary glands. This antibody did recognize a protein in the
      rate flea salivary glands. Our results show that fleas have calreticulin and,
      possibly, several isoforms. It appears that the salivary glands of the cat and
      oriental rat flea differ in detectable levels of calreticulin. The specific
      antibody labeling of the ovaries is interesting and remains to be understood.
      Calreticulin's appearance in the midgut suggests a possible source of
      calreticulin as a flea secretion. Further studies are in progress to complete the
      sequencing of the flea polymerase chain reaction (PCR) product to compare to tick
      secreted calreticulin. Comparisons to other blood-feeding arthropods at the
      protein and gene level are also being done. We hope to define further the
      expression of calreticulin in fleas, and in general, blood-feeding arthropods,
      with respect to its role in feeding and pathogen transmission.

PMID- 8667399
TI  - Acquisition of the cat scratch disease agent Bartonella henselae by cat fleas
      (Siphonaptera:Pulicidae).
AB  - We assayed the ability of cat fleas to become infected with Bartonella henselae,
      using an artificial feeding device. Fleas fed a concentration of 1 x 10(5) cfu/ml
      in blood were examined using immunofluorescent antibody assay and polymerase
      chain reaction. Bacteria were present in the gut at 3 h, and persisted up to 9 d
      after infection. Qualitatively, the density of B. henselae was greater in the
      flea gut at 9 d, indicating that replication was occurring in the gut. B.
      henselae also was detected in the feces of infected fleas 9 d after infection,
      and produced viable colonies upon inoculation onto heart infusion agar/rabbit
      blood plates. Our results indicate that fleas can maintain infection with B.
      henselae, and may play a role in the transmission of this bacterium from infected
      cats to humans.

PMID- 8667400
TI  - Structural characterization of peripheral nerve cells and nerve-muscle junctions
      of the oviduct of stable fly (Diptera:Muscidae).
AB  - Fine structure of both peripheral nerve cells and neuromuscular junctions
      associated with the oviduct of stable fly. Stomoxys calcitrans (L.), was
      described. Twelve or more multipolar peripheral neurons were found along major
      branch nerves that enter the ovipositor. Several were suspended in the haemacoel
      and others were in close proximity to the surface of the oviduct. Some peripheral
      neurons contained an abundance of neurosecretory granules that ranged in size
      from 32 to 180 nm in diameter. No glial elements enveloped the perikarya of such
      cells. Neurosecretory axons were usually found in the boundary region of large
      nerves just beneath the stroma. Peripheral nerve cells in close apposition to
      oviduct muscles were generally non-neurosecretory and were ensheathed in a glial
      perineurium. Peripheral neurons were surrounded occasionally by an extensive
      network of extracellular spaces in the glial perineurium. Other smaller neurons
      were found within large nerve trunks. Nerve-muscle junctions contained large
      clusters of synaptic vesicles and occasionally included small groups of neuro
      secretory granules. Many nerve terminals on the surface of the oviduct contained
      a complex postsynaptic folding of sarcolemma. Active transmission sites were
      indicated by increased densities along the neurolemma. Some neurohemal release
      sites were also evident.

PMID- 8667401
TI  - Methods for enhancing the blood feeding response of field-collected Culicoides
      impunctatus (Diptera:Ceratopogonidae).
AB  - Handling methods were found to be lengthen the time after capture that Culicoides
      impunctatus Goetghebuer could be blood fed successfully in the laboratory using
      an artificial membrane technique. By maintaining high levels of humidity in
      holding cages kept in a cool, dark environment, > 30% feeding success was
      achieved 72 h after capture, when feeding was carried out at low light
      conditions.

PMID- 8667402
TI  - Culicoides (Diptera:Ceratopogonidae) collected during epizootics of hemorrhagic
      disease among captive white-tailed deer.
AB  - To help determine specific vectors of epizootic hemorrhagic disease (EHD) and
      bluetongue (BT) viruses for white-tailed deer, Odocoileus virginianus Zimmermann,
      in the southeastern United States, Culicoides sp. midges were collected during
      epizootics of hemorrhagic disease among captive white-tailed deer in Georgia,
      Mississippi, and North Carolina. Culicoides variipennis (Coquillett), a confirmed
      vector of EHD and BT viruses, was present in low numbers in light-trap
      collections made at all sites. Collections from deer made in Georgia and North
      Carolina yielded only a single specimen of C. variipennis. Other Culicoides
      species present in far greater numbers during the epizootics included C. lahillei
      Lutz, C. paraensis (Goeldi), and C. stellifer (Coquillett) C. lahillei warrants
      particular attention as a potential vector because its readily feeds on white
      tailed deer and was by far the predominant species collected from deer during the
      epizootics.

PMID- 8667403
TI  - Immunity to Chlamydia trachomatis: lessons from a Gambian village.

PMID- 8667404
TI  - Replication of IFDO on a chemically defined medium.
AB  - An agar or liquid medium containing haemoglobin, high density horse lipoprotein,
      trypsin, Tween 80, phosphate buffer, CaCl(2), glucose, glutamic acid and NaCl
      supported growth of ileal fluid dependent organism (IFDO). Glucose, glutamic acid
      and NaCl were not essential but enhanced growth. Trace amounts of lipoprotein
      were sufficient to support growth, and some human sera and serum fractions rich
      in low density lipoprotein could be substituted for horse lipoprotein. Addition
      of lipase enhanced the growth rate, and reduced the requirement for lipoprotein.
      No nucleic acid precursors were identified as essential for growth. However,
      nucleosides, especially cytidine, accelerated the growth rate. The growth rate
      was also increased by DNAase and RNAase. These observations indicate that the
      organisation of the IFDO particle is more complex than that of a crystal. They
      are consistent with the hypothesis that IFDO is a replicating agent that utilises
      specific preformed protein to assemble a proteinaceous particle, and support the
      postulated relationship of IFDO to transmissible spongiform encephalopathy
      agents.

PMID- 8667405
TI  - Prognostic indicators of the outcome of meningococcal disease: a study of 562
      patients.
AB  - To assess prognostic indicators of a fatal outcome in patients with meningococcal
      disease, data from 562 patients with culture-proven meningococcal disease,
      reported in the Netherlands between 1 April 1989 and 30 April 1990, were
      collected prospectively by means of a questionnaire completed by the specialist
      in attendance. Analysis was done by the chi2 test and multiple logistic
      regression. During the study period 43 patients (7.7%) died. The risk of a fatal
      outcome was increased in patients aged 0-5 months, 10-19 years, and > or = 50
      years, in female patients and in patients presenting with coma, temperature < or
      = 38.0 degrees C, mean arterial pressure < or = 70 mmHg, white blood cell count <
      or = 10 x 10(9)/L and platelet count < or = 100 x 10(9)/L. Predisposing factors
      and duration of disease before admission were significantly associated with
      outcome, but these associations disappeared in the multivariate analysis. Race,
      the administration of antibiotics prior to admission, seizures and haemorrhagic
      skin lesions were not associated with outcome. In conclusion age, gender, coma,
      temperature, mean arterial pressure, white blood cell count and platelet count
      were independent prognostic indicators of the outcome of meningococcal disease.
      The assessment of these characteristics may be helpful for the identification of
      high risk patients, whose prognosis might be improved by prompt transfer to an
      intensive care unit.

PMID- 8667406
TI  - Isolation of non-sporing anaerobic rods from infections in children.
AB  - From 1974 to 1994, 2033 microbiological specimens from children were submitted
      for cultures for anaerobic bacteria. Fifty-seven isolates of Bifidobacterium spp.
      were obtained from 55 (3%) children, 67 isolates of Eubacterium spp. from 65 (3%)
      children and 41 isolates of Lactobacillus spp. from 40 (2%) children. Most
      Bifidobacterium isolates were from chronic otitis media, abscesses, peritonitis,
      aspiration pneumonia and paronychia. Most Eubacterium isolates were from
      abscesses, peritonitis, decubitus ulcers and bites. Lactobacillus spp. were
      mainly isolated from abscesses, aspiration pneumonia, bacteraemia and
      conjunctivitis. Most (> 90%) infections from which these species were isolated
      were polymicrobial and yielded a mixture of aerobic and anaerobic bacteria. The
      organisms most commonly isolated with the non-sporing anaerobic gram-positive
      rods were Peptostreptococcus spp., Bacteroides spp., pigmented Prevotella and
      Porphyromonas spp., Fusobacterium spp., Staphylococcus aureus and Escherichia
      coli. Most Bacteroides spp. and E. coli were isolated from intra-abdominal
      infection and skin and soft tissue infection around the rectal area, whereas most
      Prevotella, Porphyromonas and Fusobacterium isolates were from oropharyngeal,
      pulmonary and head and neck sites. The predisposing conditions associated with
      the isolation of non-sporing anaerobic gram-positive rods were previous surgery,
      malignancy, steroid therapy and immunodeficiency. Antimicrobial therapy was given
      to 149 (83%) of the 160 patients, in conjunction with surgical drainage or
      correction of pathology in 89 (56%).

PMID- 8667407
TI  - Comparison of culture with the polymerase chain reaction for detection of
      Ureaplasma urealyticum in endotracheal aspirates of preterm infants.
AB  - Polymerase chain reaction (PCR) amplification of the urease genes of Ureaplasma
      urealyticum was compared with culture for detection of the organism in 100
      endotracheal aspirates from 54 ventilated preterm infants. Ninety specimens gave
      negative results by both culture and PCR and three specimens gave positive
      results by both culture and PCR. Six specimens were negative by culture but
      positive by PCR. The one specimen positive by culture and negative by PCR was
      interpreted as a false-positive culture result. Overall agreement between results
      obtained by culture and PCR was 93%. PCR is a sensitive and reliable method for
      the detection of U. urealyticum in neonatal endotracheal secretions. Detection by
      PCR (1-2 days) is more rapid than culture (2-5 days) and this will be important
      if early therapeutic intervention is shown to be effective.

PMID- 8667408
TI  - Herpes simplex keratitis.

PMID- 8667409
TI  - Production of the new cholera toxin by environmental isolates of Vibrio cholerae
      non-O1.
AB  - One of five strains of Vibrio cholerae non-O1 isolated from environmental sources
      caused fluid accumulation in an initial rabbit ileal loop (RIL) test. The four
      strains that caused little or no accumulation of fluid gave a positive response
      after one-to-three consecutive passages through RILs. The amount of fluid
      produced increased after each passage. Filtrates of cultures of all five
      environmental isolates caused fluid accumulation similar to that produced by live
      cells. The enterotoxin showed a precipitin band with new cholera antitoxin and
      was neutralised completely by new cholera antitoxin diluted 1 in 32, indicating
      its close immunobiological relationship to the new cholera toxin. The present
      study indicates that V. cholerae non-O1 strains produce an enterotoxin that is
      similar to the new cholera toxin.

PMID- 8667410
TI  - Haemolysin produced by Vibrio cholerae non-O1 is not enterotoxic.
AB  - Of 28 isolates of Vibrio cholerae non-O1 (10 from diarrhoeal patients and 18 from
      environmental sources) examined for haemolytic activity and its correlation, if
      any, with enterotoxic activity, 24 showed haemolysis. The four non-haemolytic
      isolates showed haemolysis after consecutive passages through rabbit ileal loops
      (RILs). The titres of haemolytic activity were 4-64 HU/ml irrespective of their
      source. Eight (28.5%) of the non-O1 isolates caused fluid accumulation; six (25%)
      were haemolytic and two (50%) non-haemolytic. The remaining isolates showed
      enterotoxic activity after one-to-three consecutive passages through RILs
      irrespective of their haemolytic character and source. Environmental isolates
      caused significantly more fluid accumulation than the diarrhoeal isolates. All
      these isolates reverted to their original non-toxigenic character on repeated
      subculture or on storage in the laboratory, but continued to show haemolytic
      activity. The results of the present study indicate that V. cholerae non-O1
      strains are potentially enterotoxigenic independent of their haemolytic character
      and source, and enterotoxin, not haemolysin, is the factor most likely to be
      responsible for their enterotoxic activity.

PMID- 8667411
TI  - Growth hormone modulates IL-alpha and IFN-gamma release by murine splenocytes
      activated by LPS or porins of Salmonella typhimurium.
AB  - The effect of growth hormone (GH) on the release of IL-1alpha and IFN-gamma from
      murine splenocytes was investigated. Their release from splenocytes activated by
      Salmonella enterica serovar Typhimurium lipopolysaccharide (LPS) 0.5 microg/ml
      was increased by c. 65% in the presence of GH 100 pg/ml. With splenocytes
      activated by S. Typhimurium porins 5 microg/ml, GH increased the production of
      both IL-1alpha and IFN-gamma by c. 56%. Polymyxin treatment abolished the
      cytokine-releasing activity of LPS but had no effect on the activity of the porin
      preparation.

PMID- 8667412
TI  - Comparison of three molecular methods for typing and subtyping pathogenic
      Yersinia enterocolitica strains.
AB  - The efficiency of pulsed-field gel electrophoresis (PFGE), ribotyping and
      restriction enzyme analysis of the virulence plasmid (REAP) for typing and
      subtyping strains of Yersinia enterocolitica was compared. All three techniques
      gave concordant results, and the strains studied could be separated into three
      distinct clusters: (1) heterogeneous strains of biotype 1A and serotype O5
      (1A/O5); (2) one 3/O3 strain and all 2/O9 strains; and (3) all 4/O3, 2/O5 and two
      3/O3 strains. Within cluster 3, the 2/O5 and 3/O3 strains were related more
      closely to each other than to the 4/O3 isolates. With ribotyping, PFGE and phage
      typing, the 4/O3 isolates were subdivided into two homogeneous groups,
      corresponding to strains of phage type IXb and strains of other phage types,
      respectively. Similarly, ribotyping and PFGE subdivided the 2/O9 strains into two
      conserved groups (I and II), but REAP gave a different subdivision and identified
      a new REAP pattern (P3). The three techniques confirmed the clear distinction
      between the heterogeneous group of non-pathogenic 1A/O5 strains and the well
      conserved group of pathogenic 2/O5 strains. Additional plasmids were identified
      in some 3/O3 strains. Combined, the results indicated that REAP (with EcoRI) and
      ribotyping (with EcoRV) are valuable alternatives to bioserotype determination,
      and PFGE is the most suitable technique for epidemiological tracing.

PMID- 8667413
TI  - A novel plasmid from Staphylococcus epidermidis specifying resistance to
      kanamycin, neomycin and tetracycline.
AB  - The naturally occurring plasmid pSTS7 from Staphylococcus epidermidis mediated
      resistance to tetracycline via a tetL gene and to kanamycin and neomycin via an
      aadD gene. Plasmid pSTS7 showed partial restriction map and sequence homology to
      the previously described tetracycline resistance plasmid pNS1981 from Bacillus
      subtilis and to the kanamycin/neomycin/bleomycin resistance plasmid pUB110 from
      S. aureus. Sequence analysis of the regions flanking the two resistance genes in
      pSTS7 led to the identification of a novel site for interplasmid recombination
      which could explain the derivation of pSTS7 from the incompatible pNS1981- and
      pUB110-like parental plasmids under tetracycline-selective pressure.

PMID- 8667414
TI  - Heterogeneity of human intestinal spirochaetes demonstrated by one-dimensional
      polyacrylamide gel electrophoresis of proteins visualised by (35)S-methionine
      labelling and Coomassie blue staining.
AB  - The relatedness of strains of a human intestinal spirochaete was investigated by
      comparison of electrophoretic protein profiles produced by Coomassie Blue
      staining of proteins separated by polyacrylamide gel electrophoresis (PAGE) of
      lysed organisms and by examination of autoradiographs following PAGE of lysed
      (35)S-methionine-labelled organisms. A wide diversity of strains was revealed by
      both techniques but clustering of strains was different by the two methods. These
      findings support the view that the human intestinal spirochaetes comprise a group
      of bacteria of considerable heterogeneity.

PMID- 8667415
TI  - A spontaneous 99-kb chromosomal deletion results in multi-antibiotic
      susceptibility and an attenuation of contact haemolysis in Shigella flexneri 2a.
AB  - A Tn5-generated mutant (strain S2430) of Shigella flexneri 2a (strain YSH6000)
      exhibited attenuated virulence and, in addition to the Tn5 insertion in the SalI
      K fragment of its virulence plasmid, had a 99-kb deletion within its chromosome.
      Unlike its wild-type parent, strain S2430 was susceptible to ampicillin,
      streptomycin, tetracycline and chloramphenicol. An independent multi-antibiotic
      susceptible variant of strain YSH6000 had a similar deletion. Southern blot
      analysis of pulsed field electrophoresis gels enabled the sizing of this deletion
      and its mapping to a region of the chromosome on NotI fragment D bounded by the
      S. flexneri homologues of ompA and pyrC. Hybridisation experiments with a probe
      specific to the multi-antibiotic resistance region indicated that this large
      deletion was responsible for antibiotic susceptibility. Both strain S2430 and a
      derivative of the antibiotic-susceptible variant, with a Tn5 insertion in its
      SalI K fragment, exhibited an equal reduction in contact haemolysis compared with
      the Tn5-bearing derivative of strain YSH6000. However, strain S2430 alone clearly
      displayed delayed plaque forming ability in LLC-MK2 monolayers, suggesting that
      the two examples of this deletion may not be identical.

PMID- 8667416
TI  - A rapid immunoassay method for the direct detection of PCR products: application
      to detection of TEM beta-lactamase genes.
AB  - A rapid immunoassay for the detection of specific PCR products is described in
      which a positive PCR amplification result is detected, usually in less than 5
      min, by applying a few drops of the diluted PCR end-product to a small
      immunoassay sample device. The method was evaluated in comparison with
      conventional susceptibility tests and isoelectric focusing (IEF) for the
      detection of TEM-family beta-lactamase genes in 477 Escherichia coli isolates
      from urine samples. Of 187 isolates identified as presumptive TEM beta-lactamase
      producers by conventional methods, 185 generated a positive signal in the PCR
      immunoassay system. Two further signal-positive isolates were recognised when the
      PCR was repeated. In addition, one of the 276 ampicillin-susceptible isolates
      gave a positive signal in repeated PCR-immunoassay experiments despite being
      ampicillin susceptible and failing to give a TEM-type enzyme band in iso-electric
      focusing experiments.

PMID- 8667417
TI  - Re: Helicobacter pylori and atrophic gastritis: importance of the cagA status.

PMID- 8667418
TI  - Paclitaxel-induced severe neuropathy in patients with previous radiotherapy to
      the head and neck region.

PMID- 8667419
TI  - No additive impact on patient survival of the double alteration of p53 and c-erbB
      2 in breast carcinomas.

PMID- 8667421
TI  - Peritoneal cytology in gynecologic cancer: an essential adjunct.

PMID- 8667420
TI  - Re: Risk factors for breast cancer according to family history of breast cancer.

PMID- 8667422
TI  - Aspirin and breast cancer: no surprises yet.

PMID- 8667423
TI  - Is chemoprevention overrated or underfunded?

PMID- 8667424
TI  - Mismatch repair genes matched to several new roles in cancer.

PMID- 8667425
TI  - Search for prostate cancer gene sites may succeed in 1996.

PMID- 8667426
TI  - UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with
      disrupted p53.
AB  - BACKGROUND: Arrest of the cell cycle in G2 phase following DNA damage helps
      protect cell viability by allowing time for DNA repair before entry into mitosis
      (M phase). Abrogation of G2 arrest sensitizes cells to the effects of DNA
      damaging agents. UCN-01 (7-hydroxystaurosporine), a protein kinase C inhibitor
      that may block G2 checkpoint regulation, has been reported to enhance the
      cytotoxicity of mitomycin C, a known DNA-damaging agent. PURPOSE: We studied the
      effect of UCN-01 on G2 checkpoint control in human lymphoma CA46 cells, whose
      sensitivity to various DNA-damaging agents and G2 response to DNA damage have
      been characterized. We also assessed the ability of UCN-01 to enhance the
      cytotoxicity of gamma irradiation in CA46 cells and human colon carcinoma HT-29
      cells, both of which are mutant for p53 function. The influence of p53 function
      on UCN-01-mediated abrogation of the G2 checkpoint and enhancement of DNA
      damaging agent cytotoxicity was studied in transfected human breast carcinoma MCF
      7 cells that either expressed or did not express the human papillomavirus type-16
      E6 protein. MCF-7 cells have normal p53 function, and the E6 protein binds p53
      protein and promotes its destruction. METHODS: The effect of UCN-01 on cell cycle
      arrest induced by gamma irradiation was studied in CA46 cells and in transfected
      MCF-7 cells by use of flow cytometry. A histone H1 phosphorylation assay was
      employed to measure cyclin B1/Cdc2 kinase activity in extracts derived from
      irradiated and nonirradiated CA46 cells that had been either treated or not
      treated with UCN-01; the phosphorylation status of Cdc2 kinase protein in the
      same extracts was determined by use of western blotting. The effect of UCN-01 on
      the cytotoxicity of gamma irradiation in CA46 and HT-29 cells was determined by
      use of MTT (thiazolyl blue) and clonogenic (colony-forming) assays, respectively;
      a clonogenic assay was also used to measure the effect of UCN-01 on the
      cytotoxicity of cisplatin in transfected and nontransfected MCF-7 cells. RESULTS:
      G2 arrest induced in CA46 cells by gamma irradiation was minibited by treatment
      with UCN-01 in a dose-dependent manner; arrest in G2 was completely abrogated by
      exposure to 300 nM UCN-01. Biochemical markers indicative of the G2/M transition,
      including the activation of cyclin B1/Cdc2 kinase and the suppression of Cdc2
      threonine-14 and tyrosine-15 phosphorylation, were detected in irradiated cells
      treated with UCN-01. UCN-01 enhanced the cytotoxicity of gamma irradiation in
      CA46 and HT-29 cells. MCF-7 cells with functional p53 protein were more resistant
      to G2 checkpoint abrogation by UCN-01 than MCF-7 cells with disrupted p53
      function. UCN-01 markedly enhanced the cell-killing activity of cisplatin in MCF
      7 cells defective for p53 function. CONCLUSIONS AND IMPLICATIONS: UCN-01 is a
      potent abrogator of G2 checkpoint control in cancer cells with disrupted p53
      function. UCN-01 might be capable of enhancing the effectiveness of DNA-damaging
      agents in the treatment of tumors with cells lacking normal p53 function.

PMID- 8667427
TI  - Indoor radon exposure and risk of lung cancer: a nested case-control study in
      Finland.
AB  - BACKGROUND: Inhaled radon has been shown to cause lung cancer among underground
      miners exposed to very high radon concentrations, but the results regarding the
      effects of residential radon have been conflicting. PURPOSE: Our aim was to
      assess the effect of indoor radon exposure on the risk of lung cancer. METHODS:
      To investigate this effect, a nested case-control study was conducted in Finland.
      The subjects of the study were the 1973 lung cancer case patients (excluding
      patients with cancers of the pleura) diagnosed from January 1, 1986, until March
      31, 1992, within a cohort of Finns residing in the same one-family house from
      January 1, 1967, or earlier, until the end of 1985 and 2885 control subjects
      identified from the same cohort and matched by age and sex. In September 1992, a
      letter was sent to all study subjects or proxy respondents explaining the purpose
      and methods of the study. After giving informed consent, the study participants
      were asked to fill out a questionnaire on smoking habits, occupational exposures,
      and other determinants of lung cancer risk and radon exposure. The odds ratio
      (OR) of lung cancer was estimated from matched and unmatched logistic regression
      analyses relative to indoor radon concentration assessed by use of a 12-month
      measurement with a passive alpha track detector. RESULTS. Five hundred seventeen
      case-control pairs were used in the matched analysis, and 1055 case subjects and
      1544 control subjects were used in the unmatched analysis. The OR of lung cancer
      for indoor radon exposure obtained from matched analysis was 1.01 (95% confidence
      interval [CI] = 0.94-1.08) per 2.7 pCi/L (100 Bq m-3) after adjustment for the
      cigarette smoking status, intensity, duration, and age at commencement of smoking
      by subjects. For indoor radon concentrations 1.4-2.6, 2.7-5.3, 5.4-10.7, and 10.8
      34.5 pCi/L (50-99, 100-199, 200-399, and 400-1277 Bq m-3, respectively), the
      matched ORs were 1.03 (95% CI = 0.84-1.26), 1.00 (95% CI = 0.78-1.29), 0.91 (95%
      CI = 0.61-1.35), and 1.15 (95% CI = 0.69-1.93), respectively, relative to the
      concentration below 1.4 pCi/L (0-49 Bq m-3). The unmatched analysis yielded
      similar results with somewhat smaller CIs. In the analyses stratified by age,
      sex, smoking status, or histologic type of lung cancer, no statistically
      significant indications of increased risk of lung cancer related to indoor radon
      concentration were observed for any of the subgroups. CONCLUSIONS: Our results do
      not indicate increased risk of lung cancer from indoor radon exposure.
      IMPLICATION: Indoor radon exposure does not appear to be an important cause of
      lung cancer.

PMID- 8667428
TI  - B-cell non-Hodgkin's lymphoma: evidence for the t (14;18) translocation in all
      hematopoietic cell lineages.
AB  - BACKGROUND: B cells of patients with non-Hodgkin's lymphoma (B-NHL) harbor
      specific chromosomal translocations, including t(14;18), the most common
      aberration found in this disease. The translocation involves the immunoglobulin
      (Ig) heavy-chain joining (JH) region gene on chromosome 14 and the BCL2 gene on
      chromosome 18, resulting in dysregulated expression of the BCL2 gene. The
      t(14;18) translocation has been thought to occur in the pre-B-cell stage, during
      the first event of Ig gene rearrangement. PURPOSE: This study was conducted to
      investigate the potential involvement of nonlymphoid lineages in B-NHL. METHODS:
      We studied the t(14;18) translocation and other frequently occurring
      translocations in total bone marrow aspirates of 10 patients with B-NHL, with the
      use of the fluorescence in situ hybridization (FISH) technique. We also performed
      cytogenetic analyses on representative bone marrow aspirates from the patients.
      Moreover, to define which of the major cell lineages present in the bone marrow
      carry the t(14;18) translocation, we used a series of monoclonal antibodies
      together with fluorescence-activated cell sorter (FACS) analyses to purify cells
      positive for CD3 (T cells), CD19 (B cells), CD10 (CALLA-positive cells), CD41a
      (megakaryocytic cells), CD13 (myeloid cells), and glycophorin A (erythroid
      cells). The cells of each subgroup underwent FISH analysis with the use of JH and
      BCL2 probes to detect the t(14;18) translocation. Bone marrow samples obtained
      from five healthy donors served as controls. RESULTS: Bone marrow cells from
      eight of the 10 patients studied carried the t(14;18) translocation. When
      present, the translocation was observed in many or even all of the cell lineages
      (lymphoid, myeloid, megakaryocytic, and erythroid) present in the bone marrow,
      including peripheral blood progenitor stem cells; for seven of the eight patients
      carrying the translocation, it was found in 96%-100% of the unfractionated bone
      marrow cells as well as in all of the FACS-purified cell fractions in which it
      could be detected or studied. Conventional cytogenetic analyses performed on
      representative bone marrow aspirates confirmed the results obtained by FISH
      analysis. Cells in control bone marrow samples obtained from the five healthy
      donors were negative for the t(14;18) translocation by FISH analysis.
      CONCLUSIONS: Our findings indicate that the t(14;18) translocation most probably
      occurs in a very early multilineage progenitor stem cell. IMPLICATIONS: Given
      that the t(14;18) chromosomal translocation was found in all types of bone marrow
      cells when only the B cells were malignant, our results suggest that this
      translocation is not sufficient to induce neoplastic transformation. This finding
      underscores the need for the development of new approaches for the detection and
      surveillance of B-NHL.

PMID- 8667429
TI  - Peritoneal washing cytology in gynecologic cancers: long-term follow-up of 355
      patients.
AB  - BACKGROUND: Microscopic evaluation of cells washed from the peritoneal cavity
      during surgery for gynecologic tumors is used to detect subclinical
      intraperitoneal metastases from these tumors. The prognostic significance of this
      test, however, has been questioned. PURPOSE: Stressing histologic correlation and
      pitfalls in interpretation, we previously reported that the sensitivity of
      intraoperative peritoneal washing cytology was lower than was suggested earlier.
      This study evaluates the clinical utility of this test in the long-term follow-up
      of our patients. METHODS: Staging (International Federation of Gynecology and
      Obstetrics [FIGO], 1971) and follow-up information was available for 355
      unselected patients with primary tumors who had peritoneal washings performed
      during initial surgery at University Hospital-Stony Brook, NY, during the period
      from 1980 through 1989. There were 135 patients with endometrial carcinomas, 112
      with ovarian carcinomas, 92 with cervical carcinomas, and 16 with borderline
      (i.e., of low malignant potential) ovarian tumors. The median follow-up of the
      patients was 57 months (range, 0-154 months). Follow-up data were obtained from
      the Tumor Registry at University Hospital-Stony Brook. Survival differences were
      determined by Kaplan-Meier analysis and were evaluated by two-tailed logrank
      test. RESULTS. Peritoneal washing cytology was positive at initial surgery for
      120 (33.8%) of 355 patients, including 90 (80.4%) of 112 patients with ovarian
      carcinomas, five (31.2%) of 16 patients with borderline ovarian tumors, 17
      (12.6%) of 135 patients with endometrial carcinomas, and eight (8.7%) of 92
      patients with cervical cancers. For 203 patients with stage I tumors, the
      peritoneal cytology was positive in 29.4% of the patients with ovarian
      carcinomas, 18.2% with borderline ovarian tumors, 6.1% with endometrial
      carcinomas, and 5.2% with cervical carcinomas. By use of peritoneal histology as
      the standard, peritoneal cytology was highly specific (98.1%) but less sensitive
      (82.9%) in detecting intraperitoneal involvement. For patients with stage I
      tumors, 80.0% with ovarian carcinomas, 83.3% with endometrial carcinomas, and
      100% with cervical carcinomas who showed positive cytology died of their cancer,
      compared with 25.0% with ovarian carcinomas, 13.0% with endometrial carcinomas,
      and 21.9% with cervical carcinomas who showed negative peritoneal cytology. Four
      (2.0%) patients with stage I tumors had positive peritoneal cytology but negative
      peritoneal histology. Of these patients, three (two with ovarian carcinoma and
      one with cervical carcinoma) died of their cancer, whereas one patient with a
      borderline ovarian tumor was free of disease at the last follow-up. Survival
      analysis indicated that peritoneal washing cytology stratified for stage provides
      better prognostic information for each primary cancer site studied than does
      stage alone. All patients with borderline ovarian tumors were alive at last
      follow-up, regardless of disease stage or peritoneal status. CONCLUSIONS:
      Regardless of FIGO stage, positive peritoneal washing cytology predicted poor
      prognosis for women with epithelial tumors of the genital tract, except for
      patients with borderline ovarian tumors. Patients in whom peritoneal cytology was
      the only evidence of intraperitoneal spread were few, but the disease in such
      patients was associated with poor outcome. IMPLICATIONS: Strict adherence to
      specialized cytologic criteria in peritoneal washing cytology allows for results
      that are highly predictive of survival. This information may be useful in
      stratifying women in therapeutic trials for treatment of genital tract
      carcinomas.

PMID- 8667430
TI  - Prospective study of regular aspirin use and the risk of breast cancer.
AB  - BACKGROUND: Evidence suggests that aspirin and other nonsteroidal anti
      inflammatory drugs (NSAIDs) can inhibit tumor development in the large bowel. An
      inverse association between the use of NSAIDs and the incidence of breast cancer
      has been observed, but this association has not been statistically significant in
      all studies. PURPOSE: We analyzed data from the prospective Nurses' Health Study
      to evaluate the influence of aspirin use on breast cancer risk. METHODS: We
      studied a population of 89,528 female registered nurses who reported no history
      of breast or other cancers (excluding nonmelanoma skin cancer) and who returned a
      mailed questionnaire in 1980 that elicited information concerning breast cancer
      risk factors and current and past aspirin use. Follow-up questionnaires were
      mailed to the participants every 2 years; the women were followed through 1992.
      Information concerning current aspirin use was obtained from each biennial
      questionnaire, except in 1986. Cases of breast cancer were identified through
      questionnaire responses, and permission was sought for a review of medical
      records to confirm the diagnoses. Our analysis was based on 2414 cases of
      invasive breast cancer, which included 2303 cases confirmed with medical records
      and 111 cases for which no records were obtained. Relative risks (RRs) with 95%
      confidence intervals (CIs), adjusted for age or age plus other known or potential
      breast cancer risk factors (i.e., multivariate), were calculated. RESULTS:
      Regular aspirin use (two or more tablets per week) in 1980 was unrelated to
      breast cancer incidence during the succeeding 12-year period (with no regular
      aspirin use as the referent, multivariate RR = 1.03; 95% CI = 0.95-1.12). The
      corresponding risk estimate for consistent regular aspirin use during the period
      from 1980 through 1988 was 1.01 (95% CI = 0.80-1.27). The risks were similar for
      heavy aspirin use (for more than two tablets per day [i.e., > 14 per week] in
      1980 and in 1980 through 1988, the multivariate RRs [95% CIs] were 1.05 [0.89
      1.23] and 1.09 [0.75-1.60], respectively) and for extended durations of regular
      use (e.g., for 20 years or more of regular use, multivariate RR = 1.00; 95% CI =
      0.71-1.41). CONCLUSION: Our results indicate that regular aspirin use does not
      reduce the risk of breast cancer.

PMID- 8667431
TI  - Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient Mice.
AB  - BACKGROUND: P-glycoprotein (Pgp) is a membrane protein that acts as an extrusion
      pump for many cytotoxic drugs. Pgp is expressed in normal tissues, and its
      (over)expression in tumor cells contributes to their drug resistance. Human Pgp
      is encoded by the MDR1 gene, In mice, two Pgps (encoded by the mdr1a and mdr1b
      genes) appear to perform the same function as the single human protein. The
      simultaneous use of cytotoxic drugs and agents that block Pgp function has raised
      questions of safety, since a blockade of Pgp in normal tissues could alter drug
      pharmacokinetics and change the spectrum of toxic side effects. Analysis of the
      consequences of Pgp blockade has been facilitated by the generation of mice with
      disrupted mdr1a genes [mdr1a(-/-)]. PURPOSE: We studied the plasma pharmaco
      kinetics, tissue distribution, and excretion of the cytotoxic drug vinblastine
      (VBL) and its metabolites in mdr1a (-/-) mice and in wild-type [mdr1a(+/+)] mice.
      METHODS: VBL was administered to mice in bolus doses of either 1 or 6 mg/kg body
      weight by intravenous injection. VBL and its metabolites were quantified in
      tissue specimens, plasma, feces, and urine by use of high-performance liquid
      chromatography. Liquid scintillation counting was used to measure radioactivity
      in specimens from animals that had received [3H]VBL. Pharmacokinetic parameters
      were calculated by use of noncompartmental methods. Only two-sided P values are
      reported. RESULTS: The half-life (t1/2) of VBL during its terminal phase of
      elimination was longer in mdr1a (-/-) mice than in wild-type mice. The t1/2
      values with a 1-mg/kg dose were 3.6 hours +/- 0.3 hour (mean +/- standard error)
      and 2.1 hours +/- 0.3 hour, respectively (P < .05); with a 6-mg/kg dose, the
      values were 8.6 hours +/- 1.8 hours and 4.2 hours +/- 0.2 hour, respectively (P =
      .058). Fecal excretion of nonmetabolized VBL was reduced from 20%-25% of the
      administered dose (either 1 or 6 mg/kg) in wild-type mice to 9.3% (1-mg/kg dose)
      or 3.4% (6-mg/kg dose) in mdr1a(-/-) mice (both P < .05); the cumulative urinary
      excretion of VBL was low (< 6% of the administered dose) and not substantially
      different in the two types of mice. The metabolism of VBL to hydrophilic
      compounds, a primary mechanism involved in its elimination, was not altered in
      mdr1a(-/-) mice. The brains of mdr1a(-/-) mice accumulated substantially more VBL
      than the brains of wild-type mice. In mdr1a(-/-) mice, a few other tissues, such
      as the heart and the liver, accumulated increased amounts of VBL, but the
      relative levels of accumulation were lower than those found in the brain.
      CONCLUSIONS: Mice lacking the Pgp encoded by the mdr1a gene exhibit reduced fecal
      excretion of VBL, leading to a prolonged elimination t1/2 for this drug. Intact
      mdr1a function appears to protect the brain against high plasma levels of VBL,
      but most other tissues are not similarly protected. IMPLICATIONS: Enhanced drug
      accumulation in nonmalignant tissues after Pgp blockade should be carefully
      considered in future clinical trials of Pgp modulation.

PMID- 8667432
TI  - Hypercalcemia associated with adult cell leukemia/lymphoma.

PMID- 8667433
TI  - Health care in the African-American community. A chronology of successes, an
      examination of realities, and a hope for remedies.

PMID- 8667434
TI  - The governors' medical and welfare reform.

PMID- 8667435
TI  - Young black males and trauma: predisposing factors to presentation in an urban
      trauma unit.
AB  - Young black males are disproportionately represented as patients in trauma units.
      Unemployment, low educational level, and family composition may predispose young
      black males to trauma unit admission. To test this hypothesis, 300 males between
      the ages of 18 and 40 admitted to the Cook County Hospital Trauma Unit were
      surveyed with respect to demographic data, family composition, educational level,
      and employment background. The majority of patients were black (87%) and
      unemployed (68%). The most common diagnoses were penetrating trauma (53.2%) and
      assault (33.5%). Highest unemployment and lowest educational levels were found
      among patients who were victims of penetrating trauma or assault. Sixty-six
      percent reported the presence of an adult male in the household while growing up,
      and 93% reported the consistent presence of their biological mother. There was a
      significant correlation between race, trauma mechanism, unemployment, low
      educational level, and family composition. Recognition and amelioration of the
      economic and educational inequities that may exist in this population might
      reduce the incidence of trauma significantly.

PMID- 8667436
TI  - Emergency medicine and the laboratory.
AB  - The laboratory is an extremely important and necessary resource for the emergency
      department. This article discusses the uniqueness of the relationship and
      discusses various principles and procedures crucial to the successful operation
      of an emergency department in a large inner-city hospital. Special consideration
      is given to the requirements for a stat laboratory, which provides mandatory
      service for any large general hospital emergency department. A major problem
      experienced by teaching hospitals relates to the inappropriate use of the
      laboratory, and this issue is discussed as well as the dynamics that leads to
      laboratory overuse by emergency department housestaff.

PMID- 8667437
TI  - Subchorionic placental cyst: a cause of fetal growth retardation--ultrasound and
      color-flow Doppler diagnosis and follow-up.
AB  - Subchorionic placental cysts are ominous findings. When attached near the
      umbilical cord insertion, the risk of umbilical cord constriction is increased.
      This may cause fetal growth retardation and intrauterine asphyxia. This article
      reports a case of subchorionic placental cyst diagnosed in the first trimester by
      transvaginal ultrasound. Color Doppler ultrasound demonstrated a reduction of the
      umbilical cord bloodstream as the cyst increased in size. Fetal growth
      retardation was evident in the third trimester.

PMID- 8667438
TI  - Knowledge, beliefs, and use of prescribed antibiotic medications among low
      socioeconomic African Americans.
AB  - This study examined knowledge, beliefs, and use of prescribed oral antibiotics of
      163 low-socioeconomic African-American adults in a large midwestern city. The
      effects of age, education, and gender on knowledge and use of antibiotics were
      examined. Slightly more than 65% of the subjects in this study preferred using
      brand-name antibiotics. Females were more likely to report using all of their
      prescribed antibiotics, while males and those in the older age category were more
      likely to report using antibiotics only until the problem stopped. Twenty-three
      percent of the males and 18% of the females reported sharing their antibiotics
      with someone. Less than half of the respondents reported using physicians (and
      other health professionals) as a major source of information on prescribed
      antibiotics. Respondents often incorrectly identified painkillers and other
      medications as antibiotics. Based on these results, it appears that more
      education is needed to improve patients' understanding of antibiotic regimens.

PMID- 8667439
TI  - How patients stress, con, and intimidate physicians to file dubious disability
      reports.
AB  - This study was undertaken to determine the association between health providers'
      stress and performances, and patients who presented with disability forms that
      the providers did not feel were justified. Two questionnaires were given to
      health-care providers at the Family Practice Clinic, Martin Luther King/Drew
      Medical Center, Los Angeles, California. One questionnaire assessed the level of
      stress they suffered from, and a second questionnaire assessed how these types of
      patients may affect their general performance. The data suggested that the
      performance of providers was definitely affected by hostile, demanding,
      threatening, and malingering patients. The students, residents, nurses, and
      clinic administrative staff were all affected. Third-year medical students and
      foreign-trained doctors appeared not to be affected as much, probably because of
      a lack of knowledge about the "system" or because they preferred not to "rock the
      boat".

PMID- 8667440
TI  - Deceptive prothrombin and activated partial thromboplastin times in alcoholic
      cirrhosis.
AB  - It is believed that perioperative hemorrhage, in the hepatoportal area, results
      from a coagulopathy. This study determined if this could be quantitated by a
      modified recalcification time (MRT) test developed in our laboratory. Unlike
      prothrombin (PT) and activated partial thromboplastin times (APTT), the MRT is
      performed with whole blood to ensure the role of blood cells and chemicals
      (particularly tissue factor, a potent procoagulant) in the coagulation process.
      Candidates for liver transplantation (n = 11) were studied. Samples (5 mL) of
      citrated venous blood were obtained from the patients. Aliquots (1 mL) from these
      samples were divided into groups of vials labeled C, S, and E. Groups C and S
      received 20 microL saline and group E, 20 microL of saline containing 10
      micrograms of Escherichia coli endotoxin (055: B5W). Vial C was incubated for 10
      minutes and vials S and E for 120 minutes, all at 37 degrees C. Then, the MRT was
      determined on 300 microL of blood from each vial after adding 40 microL of 0.1M
      calcium chloride. Mean MRT values (minutes +/- standard deviation) for C (MRTC),
      for S (MRTS), and for E (MRTE) were compared with like values from healthy
      controls (n = 29). Despite prolonged PT and APTT values, MRT values were
      shortened in patients with cirrhosis. This hypercoagulability detected by the MRT
      exonerates a hemorrhagic coagulopathy and possibly implicates widened and thinned
      gaps in the walls of the portal venous tributaries as the cause of perioperative
      hemorrhage.

PMID- 8667441
TI  - Increased incidence of second primary malignancy in patients with carcinoid
      tumors: case report and literature review.
AB  - There is an increased incidence of second noncarcinoid neoplasms in patients with
      carcinoid tumors. This article reports a case of a synchronous malignant ileal
      carcinoid tumor in a patient with an adenocarcinoma of the sigmoid colon. This
      report illustrates the increased association of carcinoid tumors with other
      gastrointestinal malignancies.

PMID- 8667442
TI  - Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism.
AB  - Milk-alkali syndrome was first described 70 years ago in the context of the
      treatment of peptic ulcer disease with large amounts of calcium and alkali.
      Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate),
      the frequency of milk-alkali syndrome has decreased significantly, the classic
      triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of
      the syndrome. Milk-alkali syndrome can present serious and occasionally life
      threatening illness unless diagnosed and treated appropriately. This article
      presents a patient with hypoparathyroidism who was treated with calcium carbonate
      and calcitriol resulting in two admissions to the hospital for milk-alkali
      syndrome. The patient was successfully treated with intravenous pamidronate on
      his first admission and with hydrocortisone on the second. This illustrates
      intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome
      presents as hypercalcemic emergency.

PMID- 8667443
TI  - The Julius Rosenwald Fund syphilis seroprevalence studies.
AB  - In 1929 the Julius Rosenwald Fund, in conjunction with the Public Health Service
      (PHS), sponsored a syphilis seroprevalence study in the South characterized as a
      humanitarian effort to benefit the health of rural African Americans. The study
      reported extraordinarily high rates of positive Wassermann tests, even among
      children. Despite the unreliability and nonspecificity of this test, modern
      authors continue to indict these subjects as syphilitic. However, there was no
      consistent relationship between syphilis and a positive Wassermann test.
      Additional treponemal pathogens that potentially caused false-positive tests
      could explain the results. After public outcry to the Tuskegee Syphilis
      Experiment, the Rosenwald study acquired new significance. It was used as
      evidence to bolster the argument that Tuskegee was a consequence of humanitarian
      motives that became captive to misguided methods of researchers at the Venereal
      Disease Division of the PHS. Humanitarianism implies the acknowledgement of a
      right invested in the recipient; health is an end in itself. However, African
      Americans were necessary as a source of cheap labor for competition in the world
      cotton markets and as a restraint on the market value of white labor in
      manufacturing. The administrative structure of the PHS, not zealous individuals,
      adopted utilitarianism as its paradigm for human research. Syphilis
      seroprevalence was a calculated use of public health as a means to economic
      development.

PMID- 8667444
TI  - Studies on the optimal treatment period and parameters for detection of male
      fertility disorder in rats--introductory summary.

PMID- 8667445
TI  - Effects of adriamycin, an anticancer drug showing testicular toxicity, on
      fertility in male rats.
AB  - Adriamycin (ADR), an anticancer drug,was intravenously administered to Slc:SD
      male rats at doses of 0, 1 and 2 mg/kg once a week for 4 or 9 weeks before
      pairing, and the treatment period and parameters suitable for detection of male
      fertility disorder were examined. No adverse effects were observed on the
      copulation index, fertility index and spermatozoa, but testicular weights were
      low in the 1 and 2 mg/kg groups after 4-week treatment. In the 2 mg/kg group
      after 9-week treatment, 11 of 12 males had died or became moribund, and no
      successful pregnancies were observed. The males in the 1 and 2 mg/kg groups after
      9-week treatment had decreased weights of the genital organs, an extremely
      decreased number of sperm and low sperm motility as well as a low implantation
      rate and a decreased number of live fetuses. Microscopically, the numbers of
      spermatogonia were decreased in the 1 and 2 mg/kg groups after 4-week treatment,
      whereas the numbers of even spermatozoa were diminished and genital organs showed
      atrophy after 9-week treatment. These results indicate that 4-week treatment
      before pairing is sufficient to detect effects of ADR on the testis, especially
      on spermatogonia, and that microscopic findings and testis weight are appropriate
      parameters for detection of male fertility disorders.

PMID- 8667446
TI  - Effects of short-term administration of alpha-chlorohydrin on reproductive
      toxicity parameters in male Sprague-Dawley rats.
AB  - alpha-Chlorohydrin (alpha-CH) was administered orally at doses of 0, 2 or 8
      mg/kg/day for 2 weeks to Sprague-Dawley male rats. At the end of the
      administration period or 2 weeks after withdrawal (one group also treated with 8
      mg/kg for 4 weeks), males were mated (treatment with alpha-CH was continued
      throughout the mating period of 2 weeks) with untreated females, and underwent
      examination, including assessment of sperm, to determine fertility. No
      significant treatment-associated changes were observed in terms of body weight,
      food consumption, or weights of the testes, epididymides or prostate in either
      the 2 or the 8 mg/kg group. Although there were no significant differences in
      sperm number, viability or maturation rate between either of the treated groups
      and the control group, sperm motility in the 8 mg/kg group observed after 2 hours
      incubation and sperm activity in groups treated with 8 mg/kg observed immediately
      after collection or after 2 hours incubation, as well as in the 2 mg/kg observed
      after 2 hours of incubation were significantly decreased. Two weeks after
      withdrawal (8 mg/kg group only), sperm motility and activity were no longer
      decreased. Histopathological examination of the testes after 4 weeks of alpha-CH
      administration disclosed no abnormalities on staining with Hematoxylin-Eosin
      after fixation in Bouin's solution. All treated male rats copulated with
      untreated females, but no pregnancy resulted from mating in the 8 mg/kg
      continuous administration case. There were no significant differences between the
      control and 2 mg/kg groups in numbers of corpora lutea and implantations in
      animals becoming pregnant. Two weeks after withdrawal, male rats treated with 8
      mg/kg copulated and impregnated females. These findings suggest that evaluation
      of male fertility is possible within or following a 2-week treatment period for
      compounds like alpha-CH which have no toxicological, histopathological or sperm
      morphological effects, and that the use of several parameters for sperm
      examination is important in determining male fertility.

PMID- 8667447
TI  - Effects of a new platinum complex on male fertility in rats--collaborative work
      to determine the optimal period and optimal parameters to detect effects on male
      fertility in rats.
AB  - To assess the testicular toxicity induced by compound C, a new platinum complex
      being developed as an anti-cancer drug, the substance was intravenously
      administered to male rats at doses of 1, 3 and 10 mg/kg/day for 4 weeks and at
      doses of 0.3, 1 and 3 mg/kg/day for 9 weeks. Males were cohabited with non
      treated females after these treatment periods and at sacrifice the genital organ
      weights and number of sperm in the testis were recorded and a histopathological
      examination performed. The females were sacrificed on day 13 of gestation and the
      numbers of corpora lutea, implantations and resorptions were counted. In the 4
      weeks treatment 10 mg/kg/day group, the testis weight increased while the weights
      of the epididymides, seminal vesicles and prostate decreased significantly, and
      the number of sperm was significantly decreased. Extension of seminiferous
      tubules, vacuolization of spermatocytes, spermatids and Sertoli cells, and
      degeneration of spermatocytes and spermatids were observed by histopathological
      examination. Copulation and impregnation were not affected by treatment but the
      implantation rate was significantly decreased in the 10 mg/kg/day group. These
      results show that compound C has testicular toxicity like other platinum
      complexes and that organ weight, number of sperm, number of implantation and
      histopathological examination are useful for detection purposes. Treatment with
      compound C for 9 weeks did not affect male reproductive function in spite of
      severe general toxicity. This suggests that testicular toxicity should be
      detected after 4 weeks rather than 9 weeks treatment.

PMID- 8667448
TI  - Effects of repeated doses of compound E for 4 and 9 weeks on the male
      reproductive organs.
AB  - Results of two toxicity studies of Compound E, which is an anticancer drug, on
      male reproductive organs and fertility by oral repeated dosing at dose levels of
      12.5, 25 and 50 mg/kg/day for 4 and 9 weeks in rats were compared. After repeated
      dosing, the male fertility was studied by mating with untreated female animals.
      At the dose of 50 mg/kg/day in the 4-week study, Compound E significantly
      decreased testes weight and number of epididymal sperm, caused histopathological
      changes in the testis and epididymis characterized by decreased germ cells, but
      did not affect fertility. The dose of 25 mg/kg/day in the 9-week study caused
      reduction in epididymal weight and number of epididymal sperm and
      histopathological changes in the testis. The dose of 50 mg/kg/day in the 9-week
      study was lethal and caused more prominent toxic effects in the reproductive
      organs and loss of fertility. The present studies suggest that the order of
      sensitivity of parameters on male reproductive organs is as follows;
      histopathological examination = organ weight > number of sperm in epididymis >
      pregnancy index> copulation index. Further, 4-weeks repeated dosing is of
      sufficient duration to predict adverse effects of test compounds.

PMID- 8667449
TI  - Collaborative project to establish the optimal period and parameters for
      detection of reproductive toxicity in male rats--effects of compound T on male
      fertility.
AB  - To assess the optimal dosing period and parameters for measurement of effects on
      male fertility, Compound T was administered to male Jcl:Wistar rats at dosage
      levels of 0, 2, 10 and/or 50 mg/kg/day for 4 weeks (Experiment 1) or for 9 weeks
      (Experiment 2). Experiment 1: In the 50 mg/kg group, the ventral prostate weight
      was low when compared to the control value, and desquamation of round spermatids
      was observed in the testes. Experiment 2: When treated males were mated with
      untreated females after dosing for 9 weeks (the first mating), the fertility
      index was slightly lowered and preimplantation loss was significantly elevated in
      the 50 mg/kg group as compared to the control values. In this treatment group,
      serum testosterone level at 2.5 hours after dosing was significantly decreased
      after dosing for 12 weeks, and degeneration of spermatids/spermatocytes in the
      testis and epididymis was observed after dosing for 13 weeks. After a recovery
      period of for 6 weeks, remating resulted in copulatory and fertility indices and
      cesarean section data which were comparable in all groups. In conclusion, there
      were no differences in toxicity relevant to male fertility between 4 and 9 weeks
      of dosing, and it is considered that the observed changes resulted from decreased
      function of Sertoli cells due to depressed production/secretion of testosterone.

PMID- 8667450
TI  - Collaborative assessment of optimal administration period and parameters to
      detect effects on male fertility in the rat: effects of cyclophosphamide on the
      male reproductive system.
AB  - As part of a collaborative project to determine optimal administration period and
      parameters to detect compound effects on male fertility in the rat, adult male
      rats were administered cyclophosphamide daily at 5, 10, 20 and 40 mg/kg for 2
      weeks, or at 2.5, 5 and 10 mg/kg for 4 or 9 weeks. After the pre-pairing
      administration period, each male was paired with an untreated female. After
      mating, testes and epididymides were removed and examined for organ weights,
      sperm head counts, sperm morphology and histopathology. Mated females were
      caesarean-sectioned on Day 13 of gestation. Although atrophy of epithelia in the
      cauda epididymides and decreases of spermatogenic cells in the testes were
      observed in the higher dose groups in the 2w study, no other effects on the male
      reproductive system were noted in any of the studies. There were clear effects on
      pregnancy outcome; implantation efficiency was decreased in the highest dosage
      groups and postimplantation losses increased in all the dosage groups in all
      studies. These results suggest that a fertility study with females is needed
      particularly in the case of mutagenic agents, together with a detailed
      histopathological evaluation for reliable detection of toxicity on the male
      reproductive system.

PMID- 8667451
TI  - Collaborative work to determine the optimal administration period and parameters
      to detect drug effects on male rat fertility--study on estradiol benzoate
      effects.
AB  - In order to examine the optimal administration period and parameters for male
      fertility assessment, male rats were subcutaneously administered 0.2, 2 or 20
      micrograms/kg of estradiol benzoate (E2B), a known testicular toxicant, for 4
      weeks or 9 weeks before mating. After 4 weeks administration, suppression of body
      weight gain and food consumption, decreases in prostate and seminal vesicle
      weights, atrophy of Leydig cells, and mature spermatid retention at stages IX, X
      and XI were observed in the 2 and 20 micrograms/kg groups. In the 20,
      micrograms/kg group, decreases in epididymides weight and copulation index were
      also found but the number of sperm and sperm motility were not affected. In the
      0.2 micrograms/kg group, no changes were noted in any parameters. After 9 weeks
      administration, decreases in testis weight and the number and motility of sperm
      were observed in the 20, micrograms/kg group, in addition to the changes found
      after 4 weeks administration. These results suggest that detailed
      histopathological evaluation and determination of accessory sex organ weights are
      sensitive for evaluating the effects of E2B on male fertility. Results with the 4
      weeks treatment were comparable to those with the 9-weeks treatment in terms of
      these parameters.

PMID- 8667452
TI  - Male reproductive toxicity of ethinylestradiol associated with 4 weeks daily
      dosing prior to mating in rats.
AB  - Parameters of male reproductive toxicity of ethinylestradiol were assessed by
      conducting a mating test, sperm assay, organ weight determination and
      histopathological examination. Male Sprague Dawley rats were orally administered
      0.1, 0.3, 3 or 10 mg/kg/day ethinylestradiol for 4 weeks prior to mating. Body
      weight gain and food consumption were suppressed in all treated groups.
      Reproductive ability of the 3 and 10 mg/kg/day males disappeared. Slightly low
      copulation indices were observed in the 0.1 and 0.3 mg/kg/day groups, although
      fertility indices were not affected. Sperm could hardly be found in the
      epididymis of 3 and 10 mg/kg/day males. Sperm counts were also decreased in the
      other treated groups, but sperm motility was not affected. Decreased absolute
      and/or relative weights of testes, epididymides, prostate and seminal vesicles
      were observed in all treated groups along with testis, epididymis, seminal
      vesicle and prostate atrophy, and degenerative changes of spermatocytes,
      spermatids, Sertoli cells and Leydig cells. These results suggest that sperm
      quantification and histopathological assessment are more appropriate for
      assessing male reproductive toxicity of ethinylestradiol than performance of
      copulation and fertility tests.

PMID- 8667453
TI  - Male fertility in rats treated with etretinate for 4 weeks.
AB  - The toxicity of Etretinate, a retinoid compound, on the male reproductive system
      was studied in male rats. The drug was administered for four weeks at the dose
      levels of 0 (control: Vehicle, Peanut oil), 5 and 25 mg/kg/day. The animals were
      then allowed to mate, and their male reproductive functions and organs were
      examined in detail. No significant changes due to toxicity were observed in male
      reproductive functions and organs in the 5 mg/kg/day group after the 4-week
      treatment. In contrast, males in the 25 mg/kg/day group showed drug-related
      changes in their reproductive performance (decrease of mating ability and
      fertility rate), testosterone blood level, sperm head counts, sperm viability and
      number in the caudal epididymis, organ weight and in the histopathology of their
      reproductive organs (atrophy of seminiferous tubules, necrosis of spermatocytes
      and spermatids, vacuolation of nuclei of spermatocytes and spermatids). Even
      though Etretinate belong to the retinoid group of compounds, the changes seen in
      the 25 mg/kg/day group were almost the same as those observed in Vitamin A
      deficient animals. In conclusion, there is a correlation between changes due to
      toxicity observed for parameters of male fertility and for histopathological
      evaluation of the testis of rats that receiving high dose, treatment with
      Etretinate for 4 weeks.

PMID- 8667454
TI  - Collaborative work to determine an optimal administration period and optimal
      parameters for detection of effects on male fertility in rats--male reproductive
      toxicity study of haloperidol.
AB  - Haloperidol, a neuroleptic, was orally administered at 0, 3, 10, 30 and 60
      mg/kg/day in a 4-week dosing study, and 0, 3, 10 and 30 mg/kg/day in a 9-week
      dosing study, to Sprague-Dawley male rats which were then sacrificed for
      histopathological examination or mated with untreated females. The males in the
      mating groups were continuously treated during the mating period. Sperm positive
      females were sacrificed on day 20 of gestation. The males in the histopathology
      groups were sacrificed after 4- or 9-week dosing and their testes were fixed in
      Bouin's fluid and sections stained with HE or PAS. The mated males were
      sacrificed and reproductive organ weights were determined. At 3 mg/kg or more,
      reduced spontaneous motor activity was observed and body weights were lowered.
      The absolute weight of testes was decreased with 60 mg/kg in the 4-week dosing
      study, and was decreased with 10 and 30 mg/kg in the 9-week dosing study.
      However, the relative weight was increased or showed a tendency to increase. In
      the 4-week dosing study, decrease in the fertility index with 60 mg/kg and
      increase in pre-implantation loss with 30 mg/kg or more were noted. However,
      there were no adverse effects on the copulation index in any of the treated
      groups. The males given 60 mg/kg showed slight changes in the testes (necrosis of
      pachytene spermatocytes in seminiferous tubules of stage VII, exfoliation of
      round spermatids in the lumina and atrophy of Leydig cells) and seminal vesicles
      (atrophy of epithelial cells). Atrophy of Leydig cells was also observed at 30
      mg/kg in the 4-week dosing study. In the 9-week dosing study, neither male
      reproductive ability nor histopathological parameters were affected by
      haloperidol up to 30 mg/kg. From the results detailed above, it may be concluded
      that 4-weeks dosing before mating is suitable for detection of effects of
      haloperidol on male reproductive ability, and that histopathological changes
      together provide an optimal parameter for predicting male reproductive disorders.

PMID- 8667455
TI  - Male reproductive toxicity study of nefiracetam in rats.
AB  - Sprague-Dawley male rats were administered nefiracetam orally at daily doses of
      500 and 1500 mg/kg/day for 4 or 9 weeks. Although the copulation index was not
      affected by nefiracetam treatment, the fertility index was extremely low in the
      1500 mg/kg/day group for both treatment periods. This high dose group
      consistently exhibited decreased testicular weights. Epididymal and prostate
      weights were also reduced in the 1500 mg/kg/day group after both 4- and 9-week
      treatments and in the 500 mg/kg/day group after the 9-week treatment. Severe
      degenerative changes such as degeneration of germ cells, loss of germ cells and
      atrophy of seminiferous tubules were observed in all rats of the 1500 mg/kg/day
      groups after both 4 and 9 weeks of treatment. Retention of spermatids in stage
      IX, X and XI seminiferous tubules was also noted after the 4- and 9-week
      treatments at 500 mg/kg/day. The testicular sperm head counts were markedly
      decreased following the 4- and 9-week treatments at 1500 mg/kg/day, and mildly
      reduced after the 4-weeks treatment at 500 mg/kg/day. From these results it is
      concluded that histopathological examination and the testicular sperm head count
      method are highly useful for detecting testicular toxicity and that testicular
      lesions caused by nefiracetam can be detected after 4 weeks of exposure.

PMID- 8667456
TI  - Male reproductive toxicity study of nitrazepam in rats.
AB  - The main focus of this study is the optimal administration period concerning
      toxic effects on male fertility in rats. To assess functional and morphological
      changes induced in the testis by nitrazepam, male rats were administered the drug
      at doses of 0, 20, 40 or 80 mg/kg during pre-mating periods of 2, 4 or 9 weeks
      and then the 2 weeks of mating. At the end of the administration period the
      animals were sacrificed and sperm number, motility, abnormalities and
      histopathological changes in the testis were examined. Decreases in testis
      weight, epididymis weight, number of sperm in the testis and sperm motility were
      observed in the 40 and 80 mg/kg sections of the 2, 4 and 9 week pre-mating
      treated groups. Mating with untreated females revealed no adverse effects on
      copulation rate in any group; however, a remarkable decrease in pregnancy rate
      was noted in the 80 mg/kg section of the 2, 4 and 9 week treated groups. On
      histological examination, various degrees of localized necrosis in the
      seminiferous epithelium and Leydig cell hyperplasia were observed in the testis.
      No clear changes were observed in the 20 mg/kg section of the 2 week pre-mating
      administration group, but at the 4 week time point, necrosis of spermatogenic
      cells began to appear. The primary morphological event was evident in
      spermatocytes with necrosis of the cytoplasm observed from 4 weeks after
      administration of nitrazepam, although sperm motility and sperm head counts were
      unaffected. From these findings, examination of sperm characteristics and
      histopathological changes in the testis are important parameters for evaluation
      of drugs inducing testicular damage. We conclude that a 4 week administration
      period is sufficient to detect effects of nitrazepam on male fertility.

PMID- 8667457
TI  - Potential parameters of male reproductive toxicity: reproductive performance,
      histopathology and sperm evaluation in SD rats given nitrazepam.
AB  - The present study was designed to elucidate the correlation between findings from
      reproductive performance testing and those from histopathological examination of
      the testis and sperm analysis in rats given a benzodiazepine derivative,
      nitrazepam, for 2 and 4 weeks. The mechanisms of toxicological action of
      nitrazepam on the male reproductive organs were also investigated. Nitrazepam was
      given orally to Sprague-Dawley male rats (6-week-old) at a daily dose of 80 mg/kg
      for 2 weeks or at daily doses of 20, 40 or 80 mg/kg for 4 weeks. Treated males
      were mated to examine reproductive performance with untreated females after each
      dosing period, and after 4 and 9 week of recovery periods. Necropsy was performed
      for histopathological examination of the testis and epididymis and for sperm
      analysis after each dosing period and the final mating trial (total of 11 weeks
      recovery). In the findings from reproductive performance testing, significant
      decrease in the fertility index was observed in the 80 mg/kg group even after 2
      weeks dosing and thereafter until 4 weeks recovery, though the mating index did
      not significantly differ from that of controls through the experiment. In the
      histopathological examination and sperm analysis, testicular signs of toxicity,
      decrease in number of sperm heads in the testis and increase in number of sperm
      with abnormal heads in the seminiferous tubules were noted in the 80 mg/kg group
      after 2 weeks dosing and in the 40 and 80 mg/kg groups after 4 weeks dosing.
      Concentrations of plasma testosterone and content of testis testosterone in
      nitrazepam-treated groups were not significantly different from those of
      controls. Plasma FSH concentration was significantly elevated in the 80 mg/kg
      group through the experiment, although significant elevation of plasma LH was
      observed only after 2 weeks dosing. These results indicate that histopathological
      examination is the most reliable approach to detect male reproductive adverse
      effects induced by nitrazepam rather than using parameters from mating trials.
      The four-week-dosing period is appropriate for their detection.
      Hypospermatogenesis induced by nitrazepam is suggested to be caused by direct
      action of nitrazepam on germ cells and/or Sertoli cells rather than by indirect
      action through inhibition of testosterone secretion.

PMID- 8667458
TI  - Effects of nitrofurazone on spermatogenesis and reproductive toxicity in male
      rats--part of a collaborative work to determine optimal administration period and
      endpoints.
AB  - To determine an appropriate administration period and sensitive end-points for
      the evaluation of effects on male fertility, male Sprague-Dawley rats were orally
      given nitrofurazone, a model compound, at doses of 12.5, 25, or 50 mg/kg/day for
      4 weeks, or at doses of 12.5 or 25 mg/kg/day for 9 weeks before mating with
      untreated females. Copulation and fertility indices were decreased, and pregnancy
      did not result at doses of 25 mg/kg/day and over with both dosing periods. An
      increase in preimplantation loss, and decreases in implants and live fetuses were
      observed with 12.5 mg/kg/day after 9-weeks dosing. However, no reproductive
      endpoints were affected by the same dose level for 4-weeks. Sperm head count was
      reduced at doses of 25 mg/kg/day and over with both dosing periods.
      Histopathology revealed tubular degeneration and interstitial cell hyperplasia at
      doses of 25 mg/kg/day and over after both periods of dosing. Moreover, failure of
      spermiation in tubular epithelia was also detected in the 12.5 mg/kg groups.
      These results suggest that 4-weeks premating exposure is sufficient for
      evaluation of the effects of nitrofurazone on mate fertility, and the most
      sensitive endpoint in this 4-week premating-dose study is a histopathological
      change.

PMID- 8667459
TI  - Effects of pyridoxine on male fertility.
AB  - Pyridoxine (PN) was intraperitoneally given at 250 and 500 mg/kg to male rats for
      2, 4, or 6 weeks, and its effects on male fertility evaluated in terms of the
      optimal treatment period and detection parameters. Animals of all PN groups
      showed depression of body weight gains from week I of treatment onwards,
      significant at all but the 250 mg/kg 2 week administration I week time point.
      After 2 weeks treatment, the testes demonstrated only very slight
      histopathological changes. The 4- and 6-week treatments caused decreased
      spermatozoal motility and some histopathological changes in the testes including
      degeneration of germinal epithelial cells with both doses and also decreases in
      the fertility index and mean velocity of sperm, reduction in the testes and
      epididymides weights, and changes in testicular proteins. In the animals
      undergoing a 4-week recovery period following 4 or 6 weeks exposure, changes
      disappeared with the 250 mg/kg dose, but still remained with 500 mg/kg. From
      these findings, it is concluded that a treatment period of 4 weeks is sufficient
      for evaluation of drug effects on male fertility and that histopathology can
      detect the slightest toxic effects on the testis.

PMID- 8667460
TI  - Influence of daily subcutaneous administration of reserpine for 4 weeks or 9
      weeks before mating on testis, sperm and male fertility in rats.
AB  - To determine the optimum period of drug treatment and assessment parameters to
      evaluate male fertility in rats, different methods of examination and periods of
      treatment before mating were investigated in Sprague-Dawley (Crj:CD) male rats
      treated with a testicular oxicity-inducing agent, reserpine. The rats were given
      reserpine subcutaneously at daily doses of 0.05, 0.1 and 0.2 mg/kg for 4 and 9
      weeks (4-week test and 9-week test). Reproductive performance was tested and
      after mating, the testes, epididymides, prostate and pituitary weights were
      measured. Sperm analysis and histopathological examinations of the genital organs
      were also performed in the 4-week test case. After 4 weeks, prostate weight was
      decreased and the implantation rate showed a tendency for decrease.
      Histopathological examination of the testes revealed changes such as retention of
      step 19 spermatids in the seminiferous tubules of stages IX to XII, although
      sperm analysis showed no abnormal findings. In the 9-week test, testes and
      prostate weights were decreased along with the implantation rate was decreased.
      In conclusion, of the approaches used to evaluate the effects of reserpine on
      male fertility, histopathological examination and measurement of genital organ
      weights proved more sensitive than reproductive performance testing and sperm
      analysis. Regarding the optimum treatment period, 4 weeks was found to be
      sufficient for detection of histopathological and genital organ weight changes.

PMID- 8667461
TI  - Administration of purified human plasma cholinesterase protects against cocaine
      toxicity in mice.
AB  - BACKGROUND: Cocaine is metabolized in part by plasma cholinesterase to form
      ecgonine methyl ester. Decreased plasma cholinesterase activity is associated
      with enhanced cocaine toxicity in both humans and animals. This study was
      designed to determine whether the administration of exogenous plasma
      cholinesterase is protective against cocaine toxicity. METHODS: Using a blinded
      protocol, female Swiss albino mice were randomized to receive an intraperitoneal
      injection of either 13.7 mg/kg of purified human plasma cholinesterase dissolved
      in phosphate buffered saline, or an equal volume of phosphate buffered saline as
      a control. One hour later, all animals received an intraperitoneal injection of
      either 100 or 125 mg/kg of cocaine, and the incidence of seizures and death was
      recorded. In a similar fashion, another group of animals was randomized to
      receive a human plasma cholinesterase dose of either 13.7 or 27.4 mg/kg, followed
      by 150 mg/kg of cocaine. RESULTS: Administration of 13.7 mg/kg of human plasma
      cholinesterase increased plasma cholinesterase activity by a mean of 63 +/- 13
      fold, with a Tmax of 90 minutes and a Vd of 85 +/- 13 mL/kg. Cocaine's effects on
      seizures and death were attenuated by human plasma cholinesterase. A cocaine dose
      of 150 mg/kg represents an ED100 for seizures and an LD100. At this dose,
      lethality was reduced to 30% (p < 0.001) and seizures were reduced to 40% (p <
      0.001) by administration of 27.4 mg/kg of human plasma cholinesterase.
      CONCLUSIONS: Pretreatment with purified human plasma cholinesterase protects mice
      against the convulsive and lethal effects of cocaine.

PMID- 8667462
TI  - Five year retrospective evaluation of sulfonylurea ingestion in children.
AB  - BACKGROUND: Oral hypoglycemic medications are frequently used for Type II
      diabetes and accidental ingestions by children may occur. There are no
      comprehensive pediatric studies documenting poison center experiences. STUDY
      OBJECTIVE: To evaluate the toxicity of oral sulfonylurea ingestion in children
      and the efficacy of treatments instituted in these cases. METHOD: Retrospective
      review of all ingestions of oral sulfonylureas reported to a single regional
      poison control center 1987-1991. RESULTS: Ninety-three cases were identified, one
      to 16 years old (mean of 3.5 years). Eighty cases (86%) were less than six years
      of age. Of the six medications used, three, chlorpropamide, glipizide and
      glyburide made up 88 (95%) cases. Twenty-five patients (27%) became hypoglycemic
      (glucose < 60 mg/dL). The mean minimum blood glucose in these patients was 46.5
      mg/dL (minimum 20 mg/dL). Time of onset of hypoglycemia ranged from 0.5 to 16 h
      (mean 4.3 h; median 2 h). Only four patients had the onset of chemical
      hypoglycemia more than four hours postexposure. Persistent hypoglycemia occurred
      in nine children (10%) despite intravenous glucose therapy. There were no
      seizures. Mean time to decontamination of patients with and without hypoglycemia
      was 1.4 and 1.2 h respectively. Intravenous glucose of the following
      concentrations was administered: 5% (40), 10% (15), 20% (1), and 50% (3).
      Accidental ingestion of a single tablet of chlorpropamide (250 mg), glipizide (5
      mg). and glyburide (2.5 mg) each produced hypoglycemia in children ages one to
      four years. Accidental ingestion of 5-10 mg glyburide produced a blood glucose of
      57 mg/dL in an 11-year-old child. All patients recovered fully. There were no
      neurological sequelae noted. CONCLUSION: Children ingesting oral hypoglycemics
      should be admitted to a health care facility for 24 h observation. In this series
      a single tablet produced hypoglycemia.

PMID- 8667463
TI  - Oral hypoglycemics: ACMTnet concurs.

PMID- 8667464
TI  - Relative toxicity of beta blockers in overdose.
AB  - OBJECTIVE: To compare the toxicity of beta blockers in overdose and to identify
      clinical features predictive of serious toxicity. DESIGN: Comparison of clinical
      data collected prospectively on a relational database of subjects presenting to
      hospital with self-poisoning, coroner's data and prescription data. SETTING:
      Newcastle and Lake Macquarie, Australia, 1987-1995. MAIN OUTCOME MEASURES: Death,
      seizure, cardiovascular collapse, hypoglycemia, coma and respiratory depression.
      SUBJECTS: Fifty-eight self-poisonings with beta blockers and two deaths
      investigated by the coroner with evidence of propranolol poisoning. RESULTS: All
      patients who developed toxicity did so within six hours of ingestion. The use of
      ipecac was temporally associated with cardiorespiratory arrest in one patient.
      Propranolol was the only beta blocker associated with seizure; of those who
      ingested more than 2 g of propranolol, two thirds had a seizure. There was a
      significant association between a QRS duration of > 100 ms and risk of seizures.
      Propranolol was over represented in beta blocker poisoning when prescription data
      were also examined. Propranolol was the only beta blocker associated with death.
      Propranolol was taken by a younger age group. CONCLUSIONS: Propranolol should be
      avoided in patients at risk of self-poisoning. Propranolol poisonings should be
      observed closely for the first six hours post ingestion. Syrup of ipecac should
      not be used to decontaminate the gastrointestinal tract after beta blocker
      overdose.

PMID- 8667465
TI  - Efficacy of deferiprone in the treatment of acute iron intoxication in rats.
AB  - BACKGROUND: Deferiprone [(1,2-dimethyl-3-hydroxypyrid-4-one) (L1)], is the first
      orally active iron chelating agent to reach clinical trials in patients with
      chronic iron overload. Its efficacy in preventing morbidity and mortality in
      acute iron poisoning has not been tested. OBJECTIVE: To determine whether
      deferiprone can reduce the mortality of rats following toxic oral doses of iron.
      METHODS: Rats were administered 612 mg/kg elemental iron by gavage, corresponding
      to the LD58. A parallel group received the same oral dose of iron followed by
      deferiprone intraperitoneally at 400 mg/kg (loading dose), followed by additional
      intraperitoneal injections of 200 mg/kg, 100 mg/kg and 100 mg/kg of deferiprone
      at one hour intervals. RESULTS: Coadministering deferiprone with the iron
      decreased mortality from 58% (11/19) to 15% (3/20) (p = 0.013). The
      administration of deferiprone was associated with urinary excretion of iron
      (which did not occur with iron alone) and the production of the red deferiprone
      iron complex. On histological examination there appeared to be less iron in the
      liver and gastrointestinal tract. CONCLUSION: The coadministration of deferiprone
      can decrease morbidity and mortality caused by acute iron overdose. Deferiprone
      holds promise for the treatment of iron poisoning but additional study is
      required.

PMID- 8667466
TI  - Pharmacokinetics following a loading plus a continuous infusion of pralidoxime
      compared with the traditional short infusion regimen in human volunteers.
AB  - BACKGROUND: Many authors currently recommend infusing the adult dose (1 g) of
      pralidoxime over a 15-30 minute period. When administered in this manner,
      computer simulations predict that plasma pralidoxime concentrations will fall
      below 4 mg/L as early as one and one half hours after administration. The
      objective of this study was to assess whether a loading dose followed by a
      continuous infusion would maintain therapeutic levels longer than the traditional
      short infusion regimen of pralidoxime if the same total dose was administered.
      METHODS: Utilizing a randomized, crossover design, healthy volunteers were
      administered either 16 mg/kg of pralidoxime intravenous over 30 minutes or 4
      mg/kg of pralidoxime intravenous over 15 minutes followed by 3.2 mg/kg/h for 3.75
      h (for a total dose of 16 mg/kg). Pralidoxime levels were obtained at 0, 10, 20,
      30, 60, 120, 180, 240, 300, and 390 minutes and patients were observed for vital
      sign changes and adverse effects. RESULTS: Seven subjects completed both arms of
      the study. One subject's data were excluded from pharmacokinetic analysis due to
      aberrant plasma pralidoxime analysis. The loading dose followed by the continuous
      infusion maintained therapeutic levels for 257.3 +/- 50.5 minutes whereas the
      short infusion maintained therapeutic levels for 118.1 +/- 52.1 (p < 0.001).
      Adverse effects were encountered during the short infusion regimen which did not
      occur during the continuous infusion. Dizziness or blurred vision occurred in all
      subjects during the short infusion regimen. Additionally, statistically
      significant increases in diastolic blood pressure occurred during the short
      infusion regimen. CONCLUSIONS: The results of this study indicate that a loading
      dose followed by a continuous infusion of pralidoxime maintains therapeutic
      concentrations for a longer period of time than the currently recommended short
      infusion regimen in healthy volunteers.

PMID- 8667467
TI  - Carbohydrate-deficient transferrin for identification of drug overdose patients
      at risk of an alcohol withdrawal syndrome.
AB  - BACKGROUND: Chronic alcohol abuse is frequent in patients admitted to the
      intensive care unit with acute drug overdose. During detoxification, an alcohol
      withdrawal syndrome may develop in patients with a history of chronic alcohol
      abuse. Withdrawal or delirium is associated with serious risks, necessitating
      early identification of patients at risk. Since the information obtained from the
      patients or their relatives on alcohol consumption is often unreliable,
      biochemical markers may be helpful. Carbohydrate deficient transferrin is
      considered a highly specific marker (reported maximum specificity 97%,
      sensitivity 40-85%) for identifying alcohol abuse. METHODS: In 20 patients with
      acute drug overdose and suspected alcohol abuse, carbohydrate deficient
      transferrin was determined by an immunoturbidimetric assay on admission to the
      intensive care unit. Eight of the patients had carbohydrate deficient transferrin
      levels above the "positive" threshold and nine in a suspicious range. A "false"
      negative carbohydrate deficient transferrin was found in three patients who were
      thought to have changed their drinking habits prior to hospitalization. A
      "positive" carbohydrate deficient transferrin test is assumed to be associated
      with ingestion of more than 60-80 g ethanol/d for a period of more than seven
      days. RESULTS: In all patients, clonidine (30-210 micrograms/h i.v.) was started.
      None developed delirium. Since alcohol addiction is frequently denied,
      determination of carbohydrate deficient transferrin may be useful for its early
      diagnosis but the sensitivity of this parameter requires further evaluation.

PMID- 8667468
TI  - Increased matrix proteins, collagen and transforming growth factor are early
      markers of hepatotoxicity in patients on long-term methotrexate therapy.
AB  - BACKGROUND: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often
      limits the use of long-term low dose methotrexate for psoriasis and autoimmune
      diseases. Standard light microscopy lacks sensitivity for early fibrosis. DESIGN:
      This is a retrospective study of immunohistochemical markers of early fibrosis
      including laminin and fibronectin, collagen deposition and lipocyte activation in
      hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to
      five years, at an average dose of 20 mg/week. Biopsies before initiation of
      methotrexate (n = 36) showed minimal immunohistochemical expression of desmin,
      transforming growth factor alpha, matrix proteins, and collagen. Expression of
      laminin, fibronectin, collagens III and IV increased significantly and
      progressively over baseline values after cumulative doses of 1.5 +/- 0.25 g (n =
      20) and 3 +/- 0.5 g methotrexate, respectively. Increases in desmin, smooth
      muscle actin and collagen type I also occurred but the changes were less
      consistent. Light microscopic abnormalities of hepatotoxicity were not detectable
      in any of these biopsies. CONCLUSIONS: Immunohistochemical quantification of
      matrix proteins and collagens type III and IV may be early, sensitive and dose
      responsive markers of methotrexate hepatotoxicity which progress with increasing
      cumulative doses of methotrexate.

PMID- 8667469
TI  - The effect of polyethylene glycol on the charcoal adsorption of chlorpromazine
      studied by ion selective electrode potentiometry.
AB  - BACKGROUND: This investigation was undertaken to study: a) the adsorption
      characteristics of chlorpromazine to activated charcoal and its formulations
      Carbomix powder and Ultracarbon tablets at gastric pH; b) the effect on
      chlorpromazine adsorption of polyethylene glycol and its combination with
      electrolyte lavage solution; c) the effect of the order of addition of
      polyethylene glycol-electrolyte lavage solution. METHOD: Ion selective electrode
      potentiometry, based on the selective, direct and continuous response of a
      chlorpromazine-ion selective electrode to the concentration of the free drug, was
      used. Successive additions of microvolumes of a chlorpromazine solution were made
      into a charcoal slurry in acidic medium of pH 1.2 with measurement of the
      chlorpromazine-ion selective electrode potential at equilibrium. RESULTS: The
      maximum adsorption capacity values of activated charcoal, Carbomix and
      Ultracarbon, were 297, 563, and 382 mg/g respectively, while the affinity
      constant values were 40.2, 70.4, and 40.5 L/g, respectively. The adsorption of
      chlorpromazine to each of the Ultracarbon and Carbomix components was compared to
      the total adsorption of the formulations. The addition of polyethylene glycol
      electrolyte lavage solution causes a slight desorption of chlorpromazine from
      activated charcoal at gastric pH, more pronounced when polyethylene glycol
      electrolyte lavage solution follows the addition of activated charcoal,
      suggesting the possibility of a nonspecific binding of chlorpromazine to
      polyethylene glycol. The amount of chlorpromazine absorbed to Carbomix and
      Ultracarbon was not significantly affected at gastric pH by the presence of
      polyethylene glycol or polyethylene glycol-electrolyte lavage solution added
      either concurrently or sequentially to these formulations.

PMID- 8667470
TI  - A comparative clinico-pathological study of oral submucous fibrosis in habitual
      chewers of pan masala and betelquid.
AB  - BACKGROUND: Oral submucous fibrosis associated with chewing of betel nut products
      has an estimated prevalence of 0.2-1.2% in India. The increasing use of pan
      masala/gutkha, a mix of tobacco and a less moist form of betelquid lacking the
      betel leaf, seems associated with an earlier age of onset of oral submucous
      fibrosis. METHOD: A prospective study examined the in vivo effects of pan
      masala/gutkha and betelquid chewing on buccal mucosal cytology in 50 patients
      with oral submucous fibrosis and 40 controls. RESULTS: The percentage of
      nucleolated intermediate cells or proliferative fraction of buccal mucosa cells
      was significantly higher in all habitual chewers than controls. Pan masala/gutkha
      chewers presented with oral submucous fibrosis after 2.7 +/- 0.6 y of use whereas
      the betelquid users presented with oral submucous fibrosis reported 8.6 +/- 2.3 y
      of use (p < 0.05). CONCLUSIONS: Habitual chewing of pan masala/gutkha is
      associated with earlier presentation of oral submucous fibrosis than betelquid
      use. Factors which may be responsible for these differences are the tobacco
      content, the absence of the betel leaf and its carotenes and the much higher dry
      weight of pan masala/gutkha.

PMID- 8667471
TI  - Hydrogen peroxide 3% exposures.
AB  - OBJECTIVE: To present a child who developed gastric ulcers and duodenal erosions
      after ingestion of hydrogen peroxide 3% and delineate the epidemiology, medical
      outcomes, and toxicity of exposures to this agent managed by a poison control
      center. METHODS: A retrospective chart review of exposures to hydrogen peroxide
      3% reported to the Long Island Regional Poison Control Center from January 1992
      to April 1995 was conducted. Data extracted included age, route of exposure,
      amount of agent, symptoms, therapy, and medical outcome. RESULTS: There were 670
      exposures to hydrogen peroxide 3% of 81,126 total exposures reported during the
      40 months. Most exposures were by oral route (77%), occurred in children < 17
      years old (67%), and were asymptomatic (85.6%). All but one exposure resulted in
      a benign outcome. One child, who presented with bloody emesis, developed multiple
      gastric ulcers and duodenal erosions after ingestion of hydrogen peroxide 2-4 oz.
      CONCLUSIONS: Exposure to hydrogen peroxide 3% is usually benign, however, severe
      gastric injury may occur following small ingestions in children. Patients who
      report persistent vomiting or bloody emesis require medical evaluation and
      consideration of endoscopy to evaluate gastrointestinal injury.

PMID- 8667472
TI  - Severe lead poisoning from an imported clothing accessory: "watch" out for lead.
AB  - CASE REPORT: A case of severe lead poisoning following ingestion of an imported
      clothing accessory is reported. The child presented with abdominal pain,
      vomiting, and anemia but did not develop encephalopathy. RESULTS: Prompt removal
      of the object in conjunction with whole bowel irrigation and chelation therapy
      led to a favorable outcome.

PMID- 8667473
TI  - Delayed peak serum valproic acid in massive divalproex overdose--treatment with
      charcoal hemoperfusion.
AB  - BACKGROUND: Increased clearance and apparent clinical improvement in valproic
      acid overdose has been reported following in-series hemodialysis/hemoperfusion
      therapy. We report a case of divalproex sodium and chlorpheniramine overdose
      treated with charcoal hemoperfusion and multiple-dose activated charcoal. CASE
      REPORT: A 32-year-old female presented alert three hours postingestion of her own
      medication. Serum valproic acid was 105 micrograms/mL. No anticholinergic
      toxicity was seen. Despite three doses of activated charcoal over 14 hours, serum
      valproic acid continued to rise. Whole bowel irrigation and multiple-dose
      activated charcoal were commenced 17 h postingestion when serum valproic acid was
      1380 micrograms/mL. Charcoal hemoperfusion was instituted three hours later when
      serum valproic acid had not fallen and the patient remained obtunded. RESULTS:
      Initial extraction ratio of the hemoperfusion cartridge was 0.54 with plasma
      clearance of 54.5 mL/min. Valproic acid elimination half-life was 3 h during the
      190 min hemoperfusion cycle. Posthemoperfusion elimination half-life was 4.8 h
      with continued multiple-dose activated charcoal dosing. The clinical condition
      improved during hemoperfusion. CONCLUSION: Enteric coated valproic acid
      preparations may cause delayed toxicity in overdose, particularly with coingested
      anticholinergic medications. In our case, charcoal hemoperfusion appeared to
      increase valproic acid clearance.

PMID- 8667474
TI  - Acute pancreatitis following organophosphate intoxication.
AB  - BACKGROUND: Acute pancreatitis as a complication of organophosphate intoxication
      has been infrequently addressed. Previous reports have suggested that acute
      pancreatitis may follow the oral ingestion of several organophosphates, including
      parathion, malathion, difonate, coumaphos, and diazinon, or after cutaneous
      exposure to dimethoate. No cases of acute pancreatitis following mevinphos (CAS
      7786-34-71) poisoning have been reported to date. The possible pathogeneses of
      the pancreatic insult in organophosphate intoxication are excessive cholinergic
      stimulation of the pancreas and ductular hypertension. CASE REPORT: We describe a
      patient presenting with painless acute pancreatitis following an intentional
      ingestion of large amounts of mevinphos. Serum amylase and lipase values were
      increased and determination of amylase isoenzymes confirmed a pancreatic origin.
      A computerized tomograph of the abdomen showed diffuse swelling of the pancreas.
      The patient was discharged after a seven week clinical course, complicated by a
      delayed neuropathy. CONCLUSIONS: As acute pancreatitis in organophosphate
      intoxication may be more common than reported, serum pancreatic enzymes and
      appropriate imaging studies should be more liberally utilized. Early recognition
      and appropriate therapy for acute pancreatitis may lead to an improved prognosis.

PMID- 8667475
TI  - Low alcohol drinks and risk of high blood alcohol in children.

PMID- 8667476
TI  - Acute dystonia in a child associated with therapeutic ingestion of a
      dextromethorphan containing cough and cold syrup.

PMID- 8667477
TI  - Three-dimensional echocardiographic evaluation of fetal heart anatomy and
      function: acquisition, analysis, and display.
AB  - The purpose of this work was to assess the functional dynamics and anatomy of the
      cardiac chambers and great vessels in the fetus (18 to 36 weeks) using in utero
      three-dimensional ultrasonographic imaging. Fifteen patients were studied using
      conventional two-dimensional sonographic equipment incorporating a position
      sensor attached to the transducer and a graphics workstation. Sonographic image
      data were acquired at 30 images per second and required less than 30 seconds per
      data set. Fetal heart rate and time in the cardiac cycle were determined and used
      to synchronize image data for reprojection into a volume at the appropriate part
      of the cardiac cycle. Volume data were analyzed, rendered, and displayed
      interactively. Three-dimensional sonographic volume data demonstrated fetal
      cardiac anatomy from multiple orientations and showed the myocardium, valves,
      ventricles, and atria clearly. The images showed good correlation with currently
      available embryologic-anatomic-pathologic data. Dynamic and spatial relationships
      among chambers, valves, and great vessels were readily appreciated. Three
      dimensional sonographic imaging of the fetal heart provides both anatomic and
      functional information regarding the valves, myocardium, great vessels, and
      chamber dynamics. Interactive three-dimensional cinegraphic display enhances
      visualization of cardiac anatomy, which can be difficult to appreciate with two
      dimensional methods. The methods presented in this work demonstrate the
      feasibility of three-dimensional fetal echocardiography.

PMID- 8667478
TI  - Doppler sonography in the diagnosis of antepartum pyelonephritis: value of
      intrarenal resistive index measurements.
AB  - This study aims to define the effects of pyelonephritis on intrarenal resistive
      indices and to determine the role of Doppler sonography in the diagnosis of
      pyelonephritis in pregnant patients. Twenty pregnant women with pyelonephritis
      underwent renal Doppler sonography with calculation of intrarenal resistive
      indices. The resistive index was calculated for the upper, lower, and interpolar
      areas of each kidney in the patients with pyelonephritis (40 kidneys) and was
      compared to the resistive indices for a control group of 153 normal asymptomatic
      pregnant women (306 kidneys). Doppler findings were correlated with the location
      (sidedness) of flank pain in the pyelonephritis group. The mean resistive index
      values of patients with pyelonephritis were 0.04 higher than in the controls, and
      this difference was statistically significant (P < 0.001). Four patients with
      pyelonephritis had a mean resistive index > or = 0.70, whereas the remaining 16
      patients had resistive indices within the normal range of < or = 0.70. In
      patients with confirmed pyelonephritis and unilateral pain, the average resistive
      index in the kidney on the side of pain was 0.03 greater than that on the
      asymptomatic side (P = < 0.01). The mean renal resistive index is significantly
      greater in pregnant patients with pyelonephritis than in pregnant women without
      pyelonephritis. Even so, the magnitude of the differences in resistive index is
      too small and the overlap between the groups too large for this parameter to be
      of discriminating clinical value.

PMID- 8667479
TI  - Doppler color flow imaging surveillance of deep vein thrombosis in high-risk
      trauma patients.
AB  - To determine the prevalence of upper and lower extremity deep vein thrombosis in
      high-risk trauma patients, 136 consecutive high-risk trauma patients were
      prospectively evaluated with weekly Doppler color flow imaging. Incomplete
      compressibility and visualized intraluminal thrombus were considered diagnostic
      of deep vein thrombosis. Pulmonary embolus was documented by pulmonary
      arteriography. Deep vein thrombosis occurred at 27 non-contiguous sites in 19
      patients (14%). Eight of 27 cases of deep vein thrombosis (30%) involved the
      upper extremity and 19 (70%) occurred in the lower extremity. Twenty-one of 27
      deep vein thromboses (78%) were partially occlusive, whereas six (22%) were
      occlusive. Pulmonary embolus was documented in three patients (2.2%). Doppler
      color flow imaging detected occult deep vein thrombosis in 14% of high-risk
      trauma patients (30% occurring in the upper extremity).

PMID- 8667480
TI  - Selection and identification of standard cardiac views from three-dimensional
      volume scans of the fetal thorax.
AB  - The feasibility of fetal echocardiographic examination using three-dimensional
      ultrasonography was investigated in 54 healthy pregnant women with uncomplicated
      pregnancies between 17 and 37 weeks of gestation. In 46 cases (85.2%), good
      quality three-dimensional volumes of the fetal heart were obtained from both
      apical and lateral four-chamber views. By reslicing apical volumes, the
      reformatted sections of the long axis view of the left ventricle and the aortic
      crest were seen in 40 (87%) and 38 (83%) of 46 cases, respectively. The short
      axis was seen in 26 (57%) and ductal arch in 30 (65%) cases. The examination of
      lateral volumes was much less successful. The short axis was seen in 11 (24%)
      cases, and the aortic crest in 22 (48%), whereas the analysis of the longitudinal
      views was not possible. The best results were obtained at a gestational age
      between 22 and 27 weeks. Three-dimensional fetal echocardiography allowed the
      examination of the four chambers of the heart and left outflow tract during the
      late second trimester. The technique may become useful for the screening and
      diagnosis of congenital cardiac defects in the future.

PMID- 8667481
TI  - Papilla of Vater: normal sonographic appearance.
AB  - To ascertain the normal appearance of the papilla of Vater with transabdominal
      sonography, 37 subjects without biliary or pancreatic disease were examined with
      high resolution sonographic equipment. The normal appearance of the papilla and
      its frequency of visualization were evaluated. Characteristically the papilla of
      Vater appeared as a blind-ending cylindrical or oval structure projecting into
      the duodenal lumen at the distal end of the common bile duct. The diameter ranged
      from 3 mm to 6 mm (mean, 4.4 mm). Among the 37 subjects, the papilla was well
      demonstrated in 28 subjects (76%), fairly well demonstrated in five subjects
      (14%), and not demonstrated in four subjects (10%). Awareness of the normal
      sonographic appearance of the papilla of Vater on transabdominal sonography may
      be helpful in the evaluation of periampullary pathology.

PMID- 8667482
TI  - Malignant hepatic hilar tumors: can ultrasonography be used as an alternative to
      angiography with CT arterial portography for determination of resectability?
AB  - Nineteen consecutive patients with malignant hilar obstruction were imaged with
      angiography, CT portography, and ultrasonography with color and spectral Doppler
      technique; all had surgical pathologic correlation. At surgery, 12 of 19 patients
      (63%) were found to have portal vein involvement; 15 of 19 (79%) had parenchymal
      invasion; and 11 of 19 (58%) had lobar atrophy. Level of biliary obstruction was
      determined in seven of 19 patients (37%) without drainage catheters. No
      difference was found between ultrasonography and angiography with CT portography
      for diagnosis of atrophy, level of bile duct obstruction, hepatic involvement, or
      venous invasion. Extrahepatic metastases in nine of 19 patients (47%) were poorly
      predicted by both CT portography and ultrasonography.

PMID- 8667483
TI  - The clinical implications of early diastolic notch in third trimester Doppler
      waveform analysis of the uterine artery.
AB  - To evaluate the clinical utility of third trimester Doppler waveform analysis of
      the uterine artery in predicting complicated pregnancies and fetal well-being, we
      compared adverse pregnancy outcomes in 2321 women with the presence of an
      elevated systolic-diastolic ratio (greater than 2.6) with the persistence of an
      early diastolic notch and with the combination of an elevated systolic-diastolic
      ratio and an early diastolic notch. The positive predictive values are 47.5%,
      82.9%, and 92.6%, respectively. From these data we can conclude that
      determination of the presence or absence of an early diastolic notch is more
      valuable in predicting the perinatal outcome than is the presence of an elevated
      systolic-diastolic ratio alone. We also suggest that an assessment of the uterine
      artery systolic-diastolic ratio combined with the evaluation for persistent early
      diastolic notch would be a clinically useful test for fetal well-being.

PMID- 8667484
TI  - Assessment of luteal blood flow in normal early pregnancy.
AB  - A cross-sectional study was performed in 85 low-risk singleton first trimester
      pregnancies to assess corpus luteum blood flow during this period. Gestational
      age, established by measuring crown-rump length, ranged from 6 to 12 weeks. All
      cases were studied by transvaginal color velocity imaging and pulsed Doppler
      ultrasonography. After corpus luteum blood flow was identified by color velocity
      imaging, the resistive index and pulsatility index were calculated to assess
      vascular resistance. Overall, detection rate of corpus luteum blood flow was
      75.2%. No statistical differences were found in mean resistive index and
      pulsatility index among gestational weeks studied. Linear regression analysis
      showed that nonsignificant changes in resistive and pulsatility indices occur
      during the first weeks of normal early pregnancy (R2 = 0.0059 for resistive
      index, R2 = 0.0008 for pulsatility index). In conclusion, luteal blood flow is
      constant during normal early pregnancy.

PMID- 8667485
TI  - Transient arteriovenous fistulae after transrectal prostate biopsy: diagnosis
      with color Doppler ultrasonography.
AB  - To assess the prevalence and significance of arteriovenous fistulae after
      prostate biopsy, we performed color Doppler ultrasonography immediately after 136
      consecutive transrectal prostate needle biopsies. Pathologic results were
      correlated with color Doppler ultrasonographic findings. Arteriovenous fistulae
      developed after 17 biopsies (13%), all closed spontaneously within 18 minutes,
      and none were associated with unusual bleeding. Carcinoma was noted in 25 biopsy
      specimens (18%), 10 (40%) of which were followed by arteriovenous fistula. The
      correlation between malignancy and postbiopsy arteriovenous fistula was
      statistically significant (P < 0.0004), consistent with hypervascularity known to
      be present in many prostate cancers.

PMID- 8667486
TI  - Power Doppler imaging of focal lesions of the gastrointestinal tract: comparison
      with conventional color Doppler imaging.
AB  - To compare the usefulness of power Doppler imaging and color Doppler imaging in
      the vascular evaluation of gastrointestinal lesions, 21 patients with focal
      gastrointestinal tract lesions were examined with both power and color Doppler
      imaging. Two reviewers blinded to the diagnosis compared intramural vascularity
      detected by each of these methods. Power Doppler imaging detected flow in 16
      patients with nonischemic lesions, whereas color Doppler imaging detected flow in
      only 11 patients. Neither modality detected flow in three patients with
      transmural infarction, but only power Doppler imaging detected minimal flow in
      the two patients with reversible ischemia. Power Doppler imaging improves
      visualization of intramural gastrointestinal vascularity, increasing the level of
      confidence in differentiating ischemic from nonischemic lesions.

PMID- 8667488
TI  - Prenatal ultrasonographic detection of regression of an encephalocele.

PMID- 8667487
TI  - Recurrent bleeding from ileal varices treated by transjugular intrahepatic
      portosystemic shunt: value of Doppler ultrasonography in diagnosis and follow-up.

PMID- 8667489
TI  - Cystic carcinoma of the prostate.

PMID- 8667490
TI  - Sonographic and Doppler assessment of the inferior mesenteric artery.

PMID- 8667491
TI  - Prenatal diagnosis of frontonasal dysplasia (median cleft syndrome).

PMID- 8667492
TI  - Prenatal diagnosis of Seckel syndrome.

PMID- 8667493
TI  - Focal sparing of liver parenchyma.

PMID- 8667494
TI  - Overcoming our fear of flying--vascular surgery in the next decade.

PMID- 8667495
TI  - An outcome analysis of carotid endarterectomy: the incidence and natural history
      of recurrent stenosis.
AB  - PURPOSE: This report identifies the incidence of recurrent carotid stenosis after
      carotid endarterectomy (CEA) and records the natural history of the disease
      process to gain further insight into its proper management. METHODS: A
      prospective surveillance protocol with duplex imaging and velocity spectral
      analysis was used to detect recurrent stenosis ( > 50% diameter reduction) and to
      document the clinical outcomes of patients who underwent CEA. Between 1984 and
      1993, 619 consecutive CEAs were performed in 587 patients. RESULTS: Recurrent
      carotid stenosis developed in 48 CEA sites (7.8%) during a mean follow-up
      interval of 34 months (range, 2 to 118 months). Normal results on intraoperative
      assessment correlated with a 5.6% incidence of recurrent stenosis, compared with
      a 19% incidence when a residual hemodynamic abnormality was present (p < 0.0003).
      In the first year after surgery, there were no transient ischemic attacks,
      strokes, or carotid occlusions from recurrent stenosis, compared with a 27%
      morbidity rate in later follow-up (p < 0.01). Three patients with recurrent
      stenosis subsequently had occlusion at the CEA site, two of whom had severe
      ipsilateral strokes. CONCLUSIONS: The incidence of recurrent carotid stenosis is
      low. Patients are at significant risk for neurologic morbidity when a recurrent
      stenosis occludes. With a 0.3% incidence of late stroke resulting from carotid
      bifurcation disease, these data confirm that CEA does provide long-term
      protection from stroke.

PMID- 8667497
TI  - Platelet-derived growth factor is a cofactor in the induction of 1 alpha(I)
      procollagen expression by transforming growth factor-beta 1 in smooth muscle
      cells.
AB  - PURPOSE: Depending on the derivation of vascular smooth muscle cells (SMC),
      transforming growth factor-beta 1 (TGF-beta 1) has variable effects on
      proliferation and expression of extracellular matrix. Relatively little is known
      about TGF-beta 1's effects on human arterial SMC. Therefore, we sought to
      determine the effects of TGF-beta 1 on human arterial SMC proliferation and 1
      alpha(I) procollagen expression. The mechanisms by which TGF-beta 1 regulate type
      I procollagen expression were also investigated. METHODS: SMC cultures were
      established from the aorta of transplant donors. Serial doses of TGF-beta 1 were
      applied, and cellular proliferation assessed by cell counting and tritiated
      thymidine incorporation. Total cellular ribonucleic acid (RNA) was analyzed by
      reverse transcription-polymerase chain reaction and Northern blot for changes in
      1 alpha(I) procollagen and platelet-derived growth factor (PDGF)-A transcripts.
      RESULTS: In a dose-dependent manner, TGF-beta 1 inhibited SMC proliferation
      despite early induction of PDGF-A mRNA. After a delay of 24 hours, TGF-beta 1
      increased 1 alpha(I) procollagen expression by 36% compared with control. PDGF
      neutralizing antibodies blocked the TGF-beta 1-mediated upregulation of type I
      procollagen, although PDGF alone had no effect on matrix expression. CONCLUSION:
      The results indicate that TGF-beta 1 is a potent inhibitor of human arterial SMC
      proliferation that has a moderate effect on 1 alpha(I) procollagen transcripts.
      Despite inducing PDGF-A gene expression, TGF-beta 1 is not a mitogen in adult
      human arterial SMC. TGF-beta 1 regulates SMC type I procollagen expression partly
      by inducing PDGF-A as a co-factor.

PMID- 8667496
TI  - Atherosclerotic plaque rupture in symptomatic carotid artery stenosis.
AB  - PURPOSE: Plaque rupture is often the precipitating event in acute coronary
      syndromes. We hypothesized that a similar process occurs in stenotic carotid
      plaques in association with ischemic neurologic symptoms. Our purpose was to
      examine several morphologic features of stenotic carotid plaques and to determine
      which characteristics are more commonly associated with plaques obtained from
      patients with symptomatic carotid artery disease than with those from patients
      with asymptomatic carotid artery disease. METHODS: Forty-four carotid
      endarterectomy specimens (from 25 asymptomatic and 19 symptomatic patients) were
      analyzed with pentachrome staining and light microscopy. The asymptomatic
      patients and symptomatic patients had similar mean percent stenosis (77% vs 74%).
      Other risk factors, including hypertension, diabetes mellitus, coronary artery
      disease, smoking history, serum cholesterol, and triglyceride levels, were
      similar between groups. RESULTS: Patients with symptomatic carotid artery disease
      were found to have more frequent plaque rupture, fibrous cap thinning, and
      fibrous cap foam-cell infiltration when compared with the asymptomatic group.
      Plaque rupture was seen in 74% of symptomatic plaques and in only 32% of plaques
      from asymptomatic patients (p = 0.004). Fibrous cap thinning was noted in 95% of
      symptomatic plaques and in 48% of asymptomatic plaques (p = 0.003). Infiltration
      of the fibrous cap with foam cells was also significantly more common in the
      symptomatic plaques (84% vs 44% of asymptomatic plaques; p = 0.006). In addition,
      intraplaque fibrin was more common in symptomatic plaques than in asymptomatic
      (100% vs 68%; p = 0.008). No significant differences were found between the two
      groups with respect to plaque hemorrhage, the presence of a necrotic core,
      luminal thrombus, smooth muscle cell infiltration, eccentric shape, and plaque
      type (fibrous, necrotic, or calcified). CONCLUSIONS: As in the coronary artery
      system, rupture of the atherosclerotic plaque may play an important role in the
      pathogenesis of ischemic stroke caused by carotid artery stenosis. The process of
      inflammation, involving foam-cell infiltration of the fibrous cap, may contribute
      to rupture of the atherosclerotic plaque.

PMID- 8667498
TI  - Resection of the internal carotid artery and replacement with greater saphenous
      vein: a safe procedure for en bloc cancer resections with carotid involvement.
AB  - PURPOSE: Many patients who have advanced cancer of the neck will have involvement
      of the internal carotid artery. The management of this condition remains
      controversial, and a wide range of therapeutic options have been suggested
      including ligation, "shaving" the tumor off the carotid, or en bloc resection and
      replacement of the internal carotid artery by polytetrafluoroethylene, vein, or
      superficial femoral artery. We reviewed our experience with en bloc resections of
      the internal carotid artery in a consecutive series of patients who had
      malignancies involving the internal carotid artery at a single institution from
      1989 to 1995. METHODS: We used a retrospective chart review based on a list of 20
      patients generated by the Hospital Cancer Registry and our Vascular Surgery
      clinical database. RESULTS: All patients had their internal carotid artery
      removed and replaced with a greater saphenous vein while they were under general
      anesthesia. A resection of their cervical malignancy was also performed.
      Concomitant myocutaneous flaps were rotated over the carotid bypass in six (30%)
      patients. Eight (40%) of the bypass grafts were nonreversed, and 12(60%) were
      reversed, with a clear trend towards using nonreversed veins more recently.
      Shunts were used in 18(90%). Eighteen of the 20 patients had some form of
      intraoperative contamination including tracheostomies, pharyngostomies, or
      fistulas. Half of the patients had intraoperative radiation therapy, and 16(80%)
      patients underwent operation for recurrent cancer. During the follow-up period
      two (10%) patients had strokes (one minor and one major), and one patient had a
      graft blowout, which was treated by ligation without stroke. One patient had an
      asymptomatic occlusion of his graft. CONCLUSIONS: From these results we conclude
      that the use of the greater saphenous vein to replace the internal carotid artery
      after en bloc resection is not attended by a high rate of infectious
      complications or graft blowout even in the presence of intraoperative
      tracheopharyngeal contamination and that the greater saphenous vein is the
      conduit of choice for replacing an internal carotid artery after cancer
      resections.

PMID- 8667499
TI  - Inhibition of smooth muscle cell proliferation and migration in vitro by
      antisense oligonucleotide to c-myb.
AB  - PURPOSE: Smooth muscle cell (SMC) migration and proliferation are prominent
      features of intimal hyperplasia. Previous studies have shown that inhibition of c
      myb inhibits arterial SMC proliferation. Our goal was to evaluate the effect of
      an antisense oligonucleotide targeted to c-myb on the proliferation and migration
      of SMC explanted from synthetic vascular grafts. METHODS: SMCs were enzymatically
      removed from aortas and Dacron grafts explanted from dogs (n = 5). For
      proliferation studies, quiescent SMCs were incubated with either 0.0, 0.5, 5.0,
      or 10.0 microM antisense (GTGTCGGGGTCTCCGGGC) or sense (GCCCGGAGACCCCGACAC)
      oligonucleotides to c-myb. Proliferation was measured after 24 hours by
      incorporation of [3H]thymidine. Migration was assessed 24 hours after a razor
      injury. RESULTS: Antisense to c-myb consistently inhibited proliferation and
      migration of both native aortic and graft SMCs in a dose-dependent fashion. At a
      concentration of 10 microM antisense oligonucleotide, aortic and graft SMC
      proliferation rates were 32% +/- 20% and 56% +/- 9% of control samples,
      respectively. At 25 microM antisense, the number of migrating aortic and graft
      SMCs decreased to 41.9% +/- 26.8% and 51.9% +/- 34.1% of control samples,
      respectively. CONCLUSIONS: Our results suggest that antisense oligonucleotides to
      c-myb may be useful in the inhibition of SMC proliferation and migration
      associated with development of intimal hyperplasia.

PMID- 8667500
TI  - Use of magnetic resonance angiography for the preoperative evaluation of patients
      with infrainguinal arterial occlusive disease.
AB  - PURPOSE: This study was designed to determine whether magnetic resonance
      angiography (MRA) will allow preoperative management decisions without the need
      for contrast arteriography in patients with lower extremity ischemia caused by
      infrainguinal arterial occlusive disease. METHODS: Forty-five patients with lower
      extremity ischemia in 50 limbs were evaluated by both two-dimensional time-of
      flight MRA and intraarterial digital subtraction angiography (DSA) between
      February 1992 and June 1995. Independent management plans were based on clinical
      presentation, pulse volume recordings, and separate reviews of the MRA and DSA.
      RESULTS: Of 50 limbs, 23 required arterial bypass, 19 percutaneous transluminal
      angioplasty, 5 patch angioplasty, and 3 amputation. MRA and DSA correlated
      exactly in 89.5% of infrainguinal arterial segments, whereas interpretations
      disagreed in 10.5% of arterial segments. Mismatches that had an influence on
      patient treatment decisions occurred in only 8 (2.3%) of 352 arterial segments.
      Independent MRA- and DSA-based revascularization plans agreed in 45 (90%)
      extremities. MRA predicted the level of arterial reconstruction in all 23 limbs
      that required arterial bypass. MRA identified focal stenoses amenable to
      percutaneous transluminal angioplasty in 18 (94.7%) of the 19 limbs that
      ultimately underwent percutaneous transluminal angioplasty. A strategy of
      preoperative planning by MRA with confirmatory intraoperative arteriography would
      represent a 31% cost savings per patient at our institution while eliminating the
      morbidity of preoperative DSA. CONCLUSIONS: When used in combination with the
      patient's physical examination and segmental limb pressures with plethysmography,
      MRA is sufficient for planning infrainguinal arterial bypass procedures and
      selecting patients for percutaneous transluminal angioplasty.

PMID- 8667501
TI  - Selection of patients for cardiac evaluation before peripheral vascular
      operations.
AB  - PURPOSE: This study evaluated the value of preoperative cardiac screening with
      dipyridamole thallium scintigraphy and radionuclide ventriculography in vascular
      surgery patients. METHODS: From July 1, 1989, to Dec. 31, 1991, we routinely
      (irrespective of the patient's cardiac history or symptomatology) performed
      dipyridamole thallium scintigraphy (DTS) and radionuclide ventriculography (RVG)
      in 394 patients being considered for an elective vascular operation. Patients
      with reversible defects on DTS underwent coronary arteriography. RESULTS: DTS
      results were normal in 146 patients (37%), showed a fixed defect in 75 (19%), and
      showed a reversible defect in 173 (44%). Patients with and without a history of
      angina or myocardial infarction had identical rates of reversible defects. Normal
      left ventricular function (> 50%) was noted in 76% of the patients; 17% had
      moderate dysfunction (35% to 50%) and 7% had a low ejection fraction (< 35%). The
      finding of severe coronary artery disease led to cardiac revascularization in 17
      patients who had no prior history of cardiac disease and in 13 patients with a
      history of angina or myocardial infarction. Two deaths and nine major
      complications were associated with coronary arteriography and cardiac
      revascularization. Vascular procedures (144 aortic, 53 carotid, 146
      infrainguinal) were ultimately performed in 343 patients, with a mortality rate
      of 1.7% (3.5% aortic, 0% carotid, and 0.7% infrainguinal bypass). The nonfatal
      perioperative myocardial infarction rate was 2.0%. We monitored all 394 patients
      for cardiovascular events, with a mean follow-up of 40 months. Patients who
      underwent cardiac revascularization had a 4-year survival rate of 75%, which was
      similar to those with a normal DTS. Late cardiac events were significantly more
      frequent in patients who had either a reversible DTS or RVG < 35%. CONCLUSIONS:
      Routine cardiac screening of vascular surgery patients had similar impact on
      patients irrespective of their prior history or current symptoms suggesting
      coronary artery disease. Routine screening did not result in substantial benefit.
      Screening studies such as DTS or RVG may be most useful as part of an overall
      risk versus benefit assessment in patients without active symptoms of coronary
      artery disease who have less compelling indications for vascular intervention
      (claudication, moderate-sized aortic aneurysms, or asymptomatic carotid disease).

PMID- 8667503
TI  - Results of endoluminal grafting in an experimental aortic aneurysm model.
AB  - We studied the impact of an endoluminally placed stented aortic graft on the
      geometry of a surgically created abdominal aortic dilation (AAD) in
      nonatherosclerotic mongrel dogs. Patulous iliac vein patch infrarenal aortoplasty
      produced a fusiform AAD, doubling the aorta diameter. Lumbar and mesenteric
      aortic tributaries were preserved and no mural thrombus formed. AADs created in
      23 dogs were endoluminally excluded through transfemoral placement of a thin-wall
      Dacron graft 4 +/- 2 months later. Balloon-expandable stents were used to anchor
      each end of the graft to the aorta. The graft was crimped radially in its body
      and longitudinally at its ends to provide longitudinal and radial expandability
      in these respective zones. Serial color duplex, angiography, and direct caliper
      measurements were made. Before graft placement, a 19% +/- 11% diameter growth was
      observed. At graft placement, flow arrest immediately occurred in the space
      between the graft and the AAD intima in all cases. Although microscopic
      recanalization of the thrombus in this space was seen at sacrifice 6 and 12
      months later, no macroscopic duplex flow was imaged. A 10% +/- 11% reduction in
      AAD diameter was measured at 6 months (p < 0.001), with no further reduction at
      12 months. Graft dimensions remained stable. No anastomotic leaks developed. AAD
      growth stopped during the first year after effective endoluminal exclusion in
      normotensive dogs despite patent side branches (< 1.5 mm internal diameter) and
      no mural thrombus at the time of graft placement. Whether microscopic
      recanalization of the thrombus that forms outside the graft has an impact after 1
      year remains to be seen.

PMID- 8667502
TI  - Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic
      aorta.
AB  - PURPOSE: Plasminogen activator inhibitor type I (PAI-1) inhibits the plasminogen
      activators that convert plasminogen to plasmin. In addition to initiating
      fibrinolysis, plasmin activates tissue matrix metalloproteinases, which cause
      degradation of the extracellular matrix (ECM) in the arterial wall. Elevated
      levels of PAI-1 ultimately decrease plasmin formation and may lead to an
      accumulation of ECM and arteriosclerosis. METHODS: PAI-1 was studied by four
      methods in atherosclerotic (aneurysmal and occlusive) and normal (organ donor)
      aorta: (1) PAI-1 secretion by tissue explant supernatants, including time course
      and inhibition studies; (2) tissue PAI-1 by protein extraction; (3) PAI-1 mRNA
      was quantitated by Northern analysis using glyceraldehyde-3-phosphate
      dehydrogenase to normalize for RNA loading; and (4) in situ hybridization was
      used to localize the cells that produced PAI-1 mRNA. RESULTS: Supernatant PAI-1
      levels at 48 hours were 776 +/- 352, ng/ml in 11 atherosclerotic aortas and 248
      +/- 98 ng/ml in 8 normal aortas (p < 0.005). Tissue PAI-1 levels per 100 mg of
      tissue were 99 +/- 58 ng in 11 atherosclerotic aortas and 38 +/- 20 ng in 5
      normal aortas (p < 0.05). PAI-1 mRNA levels by Northern analysis were 0.91 +/-
      0.49 in seven atherosclerotic aortas and 0.44 +/- 0.27 in five normal aortas.
      Supernatant time-course experiments revealed that PAI-1 increased over time.
      Inhibitor studies revealed that PAI-1 decreased to approximately one third of
      control values when cycloheximide or actinomycin D were added to the media,
      indicating that active synthesis of PAI-1 had occurred. In-situ hybridization
      localized PAI-1 mRNA predominately to endothelial cells and a few scattered
      vascular smooth muscle and inflammatory cells. Subgroup analysis revealed no
      statistically significant differences between aneurysmal and occlusive PAI-1
      levels in any of the experiments. CONCLUSION: PAI-1 secretion, as measured by
      tissue explant supernatants, and total tissue PAI-1 in the protein extracts were
      significantly increased in atherosclerotic aorta. This elevation was also
      observed in the mRNA, which suggests that the increase is controlled at the level
      of transcription. PAI-1 mRNA was localized to endothelial, vascular smooth
      muscle, and inflammatory cells. We conclude that elevated levels of PAI-1 exist
      in diseased aorta. These elevated levels may lead to an accumulation of ECM,
      thereby contributing to the arteriosclerosis found in aortic occlusive and
      aneurysmal disease.

PMID- 8667504
TI  - Defining the critical limit of oxygen extraction in the human small intestine.
AB  - Although animal models have been used to characterize the relation between oxygen
      consumption and blood flow, reliable data have not been generated in the human
      small intestine. We perfused segments of human small intestine by using an ex
      vivo perfusion circuit that allowed precise manipulation of blood flow and
      perfusion pressure. Our goal was to define the critical level of intestinal blood
      flow necessary to maintain the metabolic needs of the tissue. Human small
      intestine (n = 5) tissue obtained at transplantation harvest was transported on
      ice to the laboratory. A 40-cm mid-jejunal segment was selected for perfusion,
      and appropriate inflow and outflow vessels were identified and cannulated.
      Perfusion with an autologous blood solution was initiated through an
      extracorporeal membrane oxygenation circuit. After a 30-minute equilibration
      period, arterial and venous blood gases were measured at varying flow rates while
      maintaining a constant hematocrit level. Arterial and venous oxygen content,
      arteriovenous oxygen difference (A-VO2 diff), and oxygen consumption (VO2) were
      then calculated. Our results demonstrated that at blood flows > 30 ml/min/100 g,
      VO2 is independent of blood flow (1.6 +/- 0.06 ml/min/100 g), and oxygen
      extraction is inversely related to flow. Below this blood flow rate of 30
      ml/min/100 g, oxygen extraction does not increase further (6.3 +/- 0.3 vol%), and
      VO2 becomes flow dependent. This ex vivo preparation defines for the first time a
      threshold value of blood flow for small intestine below which oxygen consumption
      decreases (30 ml/min/100 g). Previous animal studies have correlated such a
      decrease in oxygen consumption with functional and histologic evidence of tissue
      injury. This "critical" flow rate in human intestine is similar to that found
      previously in canine and feline intestine, but lower than that of rodent species.

PMID- 8667505
TI  - Use of enoxaparin in patients with heparin-induced thrombocytopenia syndrome.
AB  - PURPOSE: To determine whether low molecular weight heparin (LMWH) can be an
      alternative to unfractionated heparin (UH) for patients with heparin-induced
      thrombocytopenia syndrome (HIT). METHODS: The diagnosis of HIT was established in
      126 patients by platelet aggregometry with UH (1 U/ml). These plasma samples were
      also tested for the ability to aggregate platelets in the presence of the LMWH
      enoxaparin (1 U/ml). Two patients with the HIT syndrome, after negative platelet
      aggregometry testing with enoxaparin, were anticoagulated with enoxaparin.
      RESULTS: Fifteen plasma samples that tested negative to UH also tested negative
      to enoxaparin. Forty-three of 126 (34%) UH-positive plasma samples aggregated
      platelets in the presence of enoxaparin. Twenty-two of 102 (22%) plasma samples
      with limited positive aggregation responses (minimal or no change in optical
      density) aggregated platelets in the presence of enoxaparin. However, 21 of 24
      (88%) strongly positive plasma samples (30% to 60% change in optical density at 3
      to 27 minutes) also aggregated platelets in the presence of enoxaparin. Two
      patients with HIT who received enoxaparin after aggregation testing demonstrated
      no cross-reactivity to enoxaparin achieved adequate anticoagulation and did not
      develop HIT. CONCLUSIONS: Thirty-four percent of plasma samples from patients
      with HIT (88% of those strongly positive) aggregated platelets in the presence of
      enoxaparin. Patients with HIT may safely receive enoxaparin if their plasma does
      not aggregate platelets in the presence of enoxaparin.

PMID- 8667506
TI  - Surgical complications of transaxillary arteriography: a case-control study.
AB  - PURPOSE: The purpose of this study was to review the complications of
      transaxillary arteriography (TRAX), determine clinical factors associated with
      their occurrence, and define optimal treatment methods. METHODS: A retrospective
      review of 842 consecutive TRAX studies performed in a large, urban, tertiary
      care, academic medical center was undertaken. Patients with complications were
      compared with a concurrent randomized control group without complications with
      the use of a multivariate analysis model. Results of operative therapy for nerve
      injury were compared with those of nonoperative therapy. RESULTS: Nineteen (2.3%)
      complications were identified including 14 nerve injuries, four expanding
      hematomas/pseudoaneurysms without neurologic deficit, and one puncture site
      thrombosis. Several statistically significant or suggestive findings associated
      with the occurrence of complications were identified: female sex (odds ratio [OR]
      = 4.7), systolic blood pressure > or = 150 mm Hg at the conclusion of TRAX (OR =
      9.5), periprocedural systemic heparin anticoagulation (OR = 7.9), concomitant use
      of intraarterial thrombolysis or percutaneous angioplasty (OR = 12.0), and
      duration of procedure > or = 90 minutes (OR = 4.0). Patients who underwent prompt
      exploration (< or = 4 hours from symptom onset) for nerve injuries were more
      likely to have complete resolution of their neurologic deficits (five of six
      patients) than those who were observed or underwent delayed operation (three of
      eight patients) (OR = 8.3). CONCLUSIONS: Aggressive treatment of post-TRAX
      hypertension, limitation of TRAX duration, delay of postprocedure
      anticoagulation, and use of alternative sites for arterial puncture in female
      patients or patients undergoing catheter-based intervention may reduce the
      incidence of TRAX-related complications. In patients who have neurologic deficits
      prompt surgical exploration of the puncture site with decompression of the
      involved nerve(s) may reduce the incidence of prolonged deficits.

PMID- 8667507
TI  - Urokinase treatment preserves endothelial and smooth muscle function in
      experimental acute arterial thrombosis.
AB  - PURPOSE: Pharmacologic lysis or balloon thrombectomy are options to treat acute
      arterial thrombosis; however, little is known about their effects on functional
      changes in the arterial wall. The aim of this study was to determine function of
      the endothelium and smooth muscle in canine arteries revascularized after acute
      thrombosis with balloon thrombectomy or lytic therapy. METHODS: Acute thrombosis
      was obtained by bilateral proximal and distal ligation of 8-cm. segments of the
      femoral arteries in dogs. After 24 hours, the ties were removed and the arteries
      randomized to treatment groups: group 1, balloon thrombectomy (# 4 Fogarty
      balloon catheter at 60 grams linear shear x 1 pass, n = 7); group 2, untreated,
      tie removal only (n = 6); group 3, regional intra-arterial urokinase infusion
      (4000 U/min x 90 min, n = 6); group 4, regional intra-arterial carrier infusion
      (0.43 ml/min x 90 min, n = 6); group 5, unoperated normal vessels (n = 5). After
      treatment, the arteries were removed and endothelial and smooth muscle responses
      examined in organ chambers. Endothelial loss was graded with light microscopy of
      vessel rings from each animal by an observer blinded to the treatment group.
      Findings were confirmed with scanning electron microscopy. RESULTS: Treatment
      with urokinase did not alter endothelium-dependent relaxations or smooth muscle
      contractions compared with carrier infusion or untreated alone. Balloon catheter
      thrombectomy significantly reduced endothelium-dependent relaxations compared
      with all other groups in response to acetylcholine, bradykinin, and thrombin (p <
      0.001). Contractions of smooth muscle in response to potassium chloride (60
      mol/L) and phenylephrine (1 x 10-6 mol/L) were also reduced (p < 0.05). Rings
      from balloon thrombectomized arteries contracted in response to calcium ionophore
      A23187 (p < 0.001); these contractions were endothelium dependent and not reduced
      by indomethacin or blockade of endothelin A and B receptors. No significant
      differences in percentage of endothelial coverage between groups were assessed by
      light and electron microscopy. CONCLUSION: Thrombolysis with urokinase caused no
      or minimal abnormalities in endothelial and smooth muscle function. Endothelium
      present after balloon thrombectomy produces contractile factors. Although the
      duration and recovery of these abnormalities in function are unknown, these
      findings support preferential use of urokinase over balloon thrombectomy when
      possible in acute arterial thrombosis or embolism.

PMID- 8667508
TI  - Inflammatory abdominal aortic aneurysms: a case-control study.
AB  - PURPOSE: This study was designed to identify significant differences in the
      clinical and radiologic characteristics and outcome between patients with
      inflammatory and noninflammatory abdominal aortic aneurysms (AAAs). METHODS: We
      reviewed 29 consecutive patients who underwent repair of an inflammatory AAA
      between 1985 and 1994. This group was matched in a case-control fashion by date
      of surgery and by the performing surgeon to a group of 58 patients who underwent
      repair of noninflammatory AAAs. RESULTS: The two groups had comparable
      characteristics of age, gender, and cardiovascular risk factors. Patients with
      inflammatory AAAs were significantly more symptomatic than those with
      noninflammatory AAAs (93% vs 9%, p < 0.001), were more likely to have a family
      history of aneurysms (17% vs 1.5%, p = 0.007), and tended to be current smokers
      (45% vs 24%, p = 0.049). The most significant laboratory difference was an
      elevated sedimentation rate in patients with inflammatory AAAs (mean, 53 mm/hr vs
      12 mm/hr, p < 0.00001). Inflammatory AAAs also were significantly larger than
      noninflammatory AAAs at presentation (6.8 cm vs 5.9 cm, p < 0.05). Although
      operative mortality was low in both groups, patients with an inflammatory AAA
      tended to have higher morbidity, including sepsis (p < 0.01) and renal failure (p
      = 0.04). Five-year survival rates, however, were similar for the two groups (79%
      for inflammatory and 83% for noninflammatory AAAs). On follow-up computed
      tomographic scans, the retroperitoneal inflammatory process resolved completely
      in 53% of the patients, but 47% of patients had persistent inflammation that
      involved the ureters in 32% and resulted in long-term solitary or bilateral renal
      atrophy in 47%. CONCLUSIONS: This case-control study provides preliminary
      evidence that inflammatory AAAs may have a relatively strong familial connection
      and that current smoking may play an important role in the inflammatory response.
      The study also documents that persistent retroperitoneal inflammation may be more
      prevalent than has been previously reported, and stresses the need for an
      improved understanding of the pathogenesis and long-term management of
      inflammatory AAAs.

PMID- 8667509
TI  - Influence of gender on cardiac risk and survival in patients with infrarenal
      aortic aneurysms.
AB  - PURPOSE: To determine whether gender distinction influence the cardiac risk or
      survival rates associated with surgical treatment of infrarenal abdominal aortic
      aneurysms (AAAs). METHODS: From 1983 to 1988, graft replacement of intact AAAs
      was performed in 490 men (84%) and in 92 women (16%) who had no history of
      myocardial revascularization before the discovery of their AAAs. Patients of both
      genders were comparable with respect to mean age (68 years) and the prevalence of
      coronary artery disease (CAD) by standard clinical criteria (men, 73%; women,
      65%). Preoperative coronary angiography was obtained in 471 of the 582 patients
      (men, 81%; women, 80%) during this particular study period. Preliminary coronary
      bypass was warranted on the basis of existing indications in 111 (24%) of these
      471 patients (men, 25%; women, 18%), including 104 (31%) of the 337 who had
      clinical indications of CAD (men, 32%; women, 26%) but only 7 (5.2%) of the 134
      who did not (men, 6%; women, 4%). Follow-up data were collected during a mean
      interval of 53 months (men, 54 months; women, 48 months) and were analyzed by
      Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS:
      Twenty-nine perioperative deaths (5.0%) occurred in conjunction with AAA repair
      (men, 5.1%; women, 4.3%), and 126 early and late deaths have occurred (men, 22%;
      women, 22%). Survival rates for the series were found to correlate with age (p <
      0.001), the serum creatinine level (p < 0.001), and the coronary angiographic
      classification (p < 0.001). No significant differences were identified between
      the gender cohorts. The cardiac mortality rate for AAA resection was only 1.8% in
      the 111 patients who had preliminary coronary bypass, but five additional
      perioperative deaths (4.5%) related to renal failure or sepsis occurred in this
      group. However, 5-year survival rates for patients receiving preliminary bypass
      (men, 82%; women, 75%) were closely comparable with those for patients found to
      have only mild to moderate CAD by angiography (men, 86%; women, 82%). CONCLUSION:
      We conclude that men and women with AAAs have similar cardiac risks and survival
      rates associated with surgical treatment. Our results also illustrate that the
      potential benefit of coronary intervention for severe CAD in patients of either
      gender must be considered in the context of long-term outcome and the early
      mortality rate of AAA repair.

PMID- 8667510
TI  - Inappropriate use of venous duplex scans: an analysis of indications and results.
AB  - PURPOSE: The increasing demand for venous duplex scans despite the relative
      rarity of detecting acute deep venous thrombosis (DVT) prompted us to review our
      experience with this diagnostic method. METHODS: We retrospectively analyzed the
      results and indications of 2993 lower extremity venous duplex scans performed
      between July 1, 1992, and June 30, 1994, at our institution. The indication for
      the study and the results were prospectively recorded in a computerized data
      bank. The indications for these studies were leg pain (34%), leg swelling (24%),
      surveillance for DVT in a patient at high risk (23%), searching for a source of
      pulmonary embolism (14%), follow-up of previously diagnosed DVT (3%), and other
      indications (i.e., varicose veins, venous ulcer, 2%). RESULTS: Overall, 74.1% of
      all scans were completely normal, and only 13.1% detected acute proximal
      (popliteal vein or higher) DVT. Scans performed for surveillance (87.3% normal)
      or source of pulmonary embolism (79.6% normal) were significantly more likely to
      be normal than when performed for any other indication (p < 0.01). When leg edema
      or calf tenderness was present, the incidence of acute DVT was significantly
      greater for all indications (p < 0.0001). CONCLUSIONS: The high percentage of
      normal venous scans implies that this diagnostic method is being inappropriately
      used. In the current climate of cost containment our data suggest that
      indications for venous duplex scans must be better defined and that improved
      education for referring physicians is needed.

PMID- 8667511
TI  - Who we are, what we do, and where we are going.

PMID- 8667512
TI  - The E. Stanley Crawford Critical Issues Forum 1995: the future of vascular
      surgery in a changing world.

PMID- 8667513
TI  - Vision of the vascular surgeon as the vascular specialist of the future.

PMID- 8667514
TI  - Role of the national and regional vascular societies in shaping the future of
      vascular surgery.

PMID- 8667515
TI  - The vascular center: a model for multidisciplinary delivery of vascular care for
      the future.

PMID- 8667516
TI  - Adapting practice patterns to a managed care environment: carotid endarterectomy-
      a case example.
AB  - The way American medicine is practiced is changing rapidly. By the beginning of
      the next century, most Americans may be enrolled in for-profit managed care plans
      in which physicians are responsible for both a budget and a population of
      patients. As health care is revolutionized, the overriding issue is whether the
      mission of health care organizations will be simply to contain costs, or whether
      it will be to increase the value (i.e., the quality) that we get for the money we
      are willing to spend on health care. The purpose of this article is to illustrate
      for carotid endarterectomy how quality can remain on the health care reform
      agenda. Vascular surgeons must assume a leadership role, and they must be willing
      to alter their practice patterns. More specifically, they should: (1) support and
      facilitate the development of clinically-detailed multispecialty criteria that
      describe under what circumstances carotid endarterectomy is both appropriate and
      necessary; (2) support the development of a system for publicly reporting outcome
      data by physician and hospital; (3) support regionalization of carotid
      endarterectomy; (4) conduct a prospective assessment of appropriateness before
      the procedure is performed; (5) consider changing the system by which carotid
      angiographies are read to increase their reliability; and (6) help develop a
      system to ensure that people who need carotid endarterectomy are offered the
      procedure.

PMID- 8667517
TI  - Building a partnership between vascular medicine and vascular surgery: a
      coalition for the future of vascular care.

PMID- 8667518
TI  - Vision of optimal vascular surgical training in the next two decades: strategies
      for adapting to new technologies.

PMID- 8667519
TI  - The endarterectomy-produced common carotid artery step: a harbinger of early
      emboli and late restenosis.
AB  - PURPOSE: This study analyzes the role of the carotid endarterectomy (CEA)
      produced common carotid step or shelf on early and late CEA outcome. A simple
      method of reconstruction that covers the exposed media and intima of the step and
      smooths out the flow channel is presented. METHODS: Since 1984 intraoperative
      geometric measurements were made on 1019 CEA. Duplex scans were made after
      surgery on 968 (95%); 234 (23%) were monitored for at least 5 years. Of the first
      920 CEA, 261 (28%) had a step > or = 2 mm. Of the last 99 operations, the 27
      (27%) with a step > or = 2 mm had inversion plication reconstruction of the step.
      RESULTS: Three patients had early post-CEA neurologic events attributed to a
      common carotid step, two had transient ischemic attacks, and one had a mild
      stroke. All three had a CEA-produced step > or = 2 mm (1.2% of 261, p = 0.03 when
      compared with no unexplained early neurologic events in the 659 without a step).
      Duplex scans were normal in all three except for a common carotid artery step.
      Six patients had seven reoperations for common carotid artery restenosis at 23 to
      104 months (mean 73 months) after CEA. All had a step > or = 2 mm at the origin
      CEA (2.7% of 261, p = 0.001 when compared with no reoperations for common carotid
      artery stenosis in the 659 CEA without a step). All but one patient had > 75%
      restenosis. Four were asymptomatic. All seven with restenosis were within 2 mm of
      the original common carotid end point step. Four restenoses were concentric, two
      eccentric, and one ulcerated. Six of the seven arteries were originally
      reconstructed with a greater saphenous vein patch that extended 3 to 6 mm
      proximal to the step. Early postoperative duplex scans of the 27 recent CEA with
      step reconstruction demonstrated a tortuous but smooth common carotid artery flow
      channel. CONCLUSION: The CEA-produced common carotid artery step is a potential
      source of both early postoperative emboli and late restenosis. The incidence is
      approximately 4% in patients with a CEA step > or = 2 mm. CEA vein patch
      reconstruction does not prevent restenosis in the region of the step but may
      lower the incidence. Although not proven, reconstruction techniques directed at
      covering the exposed step media and intima and smoothing the flow channel may
      favorably alter outcome.

PMID- 8667521
TI  - The relative contributions of carotid duplex scanning, magnetic resonance
      angiography, and cerebral arteriography to clinical decisionmaking: a prospective
      study in patients with carotid occlusive disease.
AB  - PURPOSE: Recent reports suggest that 80% to 90% of patients can safely undergo
      carotid endarterectomy on the basis of duplex scanning alone without cerebral
      angiography. Other investigators have recommended that a complementary imaging
      study such as magnetic resonance angiography (MRA) also be obtained. METHODS: We
      prospectively evaluated 103 consecutive patients with carotid occlusive disease.
      Eighty percent of patients were symptomatic. All 103 patients underwent duplex
      scanning and arteriography. Additional noninvasive tests included computed
      tomography, magnetic resonance imaging, and MRA in 50%, 56%, and 48% of patients,
      respectively. At a multispecialty conference all studies except angiograms were
      reviewed, and a treatment decision was made by a panel of attending vascular
      surgeons, neurosurgeons, and neurologists. The cerebral angiograms then were
      reviewed and changes made to final treatment plans were noted. RESULTS: After
      review of noninvasive studies, 30 of 103 of patients (29%) were believed to
      require arteriography because of diagnostic uncertainty of carotid occlusion in
      three patients, suggestion of nonatherosclerotic disease in four, suggestion of
      proximal disease in two, suboptimal noninvasive studies in one, and uncertainty
      of therapy despite good-quality noninvasive studies in 20 patients primarily with
      borderline stenoses and unclear symptoms. In 10 of these 30 patients (33%)
      management decisions were changed on the basis of angiogram results. Of the
      remaining 73 patients (71%) in whom the panel felt comfortable proceeding with
      operative or medical therapy without angiography, only one patient (1.4%) would
      have had management altered by results of angiography. MRA results concurred with
      duplex findings in 92% of studies, but did not alter management in any patient.
      CONCLUSIONS: In patients with good-quality duplex images, focal atherosclerotic
      bifurcation disease, and clear clinical presentation, treatment decisions can be
      made without arteriography. In 30% of patients angiography is useful in
      clarifying decisionmaking. MRA is unlikely to influence management decisions and
      is thus rarely indicated.

PMID- 8667522
TI  - Health plan accountability still a long-term goal.

PMID- 8667520
TI  - Endothelial function and adrenergic reactivity in human type-II diabetic
      resistance arteries.
AB  - PURPOSE: This study was performed to examine the role of the vascular endothelium
      in modulating arterial reactivity to adrenergic vasoconstriction in subcutaneous
      arteries from patients with type II diabetes. METHODS: Small subcutaneous
      arteries (inner diameter = 90 to 180 microns) from control subjects (n = 22) and
      patients with diabetes (n = 18) were dissected from skin biopsies obtained at
      surgery and mounted on a specialized arteriograph that allowed for continuous
      measurement of lumen diameter under controlled pressure. The sensitivity to
      norepinephrine was compared in arteries that were either intact, denuded of
      endothelium, or intact and exposed to N omega-nitro-L-arginine (L-NNA), an
      inhibitor of nitric oxide synthesis. Stimulated release of nitric oxide by
      acetylcholine and smooth muscle cell responses to sodium nitroprusside were also
      evaluated in diabetic and control arteries. RESULTS: Sensitivity to
      norepinephrine was augmented in diabetic arteries and the amount of agonist
      necessary to contract the vessels 50% of maximum (EC50) decreased from 0.35 +/-
      0.05 mumol/L in the control arteries to 0.16 +/- 0.06 mumol/L in the diabetic
      arteries (p < 0.05). Both endothelial removal and blockade of nitric oxide
      synthesis increased sensitivity to norepinephrine in control arteries (EC50
      denuded = 0.14 +/- 0.03 mumol/L and EC50 L-NNA = 0.14 +/- 0.04 mumol/L; p < 0.01)
      but failed to augment sensitivity in diabetic arteries (EC50 denuded = 0.17 +/-
      0.05 mumol/L and EC50 L-NNA = 0.15 +/- 0.04 mumol/L; p > 0.05). Stimulated
      release of nitric oxide by acetylcholine was increased in the diabetic arteries:
      EC50 control = 0.04 +/- 0.01 mumol/L versus EC50 diabetic = 0.009 +/- 0.001
      mumol/L (p < 0.05). Sensitivity of vascular smooth muscle to sodium nitroprusside
      was similar in both nondiabetic and diabetic arteries. CONCLUSIONS: The
      endothelium mitigates adrenergic reactivity in control arteries, which is lacking
      in diabetic arteries and results in enhanced reactivity to norepinephrine;
      increased sensitivity of diabetic arteries to acetylcholine, however, indicates a
      possible alteration at the receptor level.

PMID- 8667523
TI  - Gerontology researchers look toward millennium.

PMID- 8667524
TI  - New drugs for the nail fungus prevalent in elderly.

PMID- 8667525
TI  - From the Food and Drug Administration.

PMID- 8667526
TI  - From the Centers for Disease Control and Prevention. Work-related injuries and
      illnesses associated with child labor--United States, 1993.

PMID- 8667527
TI  - From the Centers for Disease Control and Prevention. Mercury exposure among
      residents of a building formerly used for industrial purposes--New Jersey, 1995.

PMID- 8667528
TI  - The patient-physician relationship: time to reimburse what we preach.

PMID- 8667529
TI  - Preventive therapy for multidrug-resistant tuberculosis.

PMID- 8667530
TI  - Defining clinically insignificant prostate cancer.

PMID- 8667531
TI  - Probiotics: how microorganisms compete.

PMID- 8667532
TI  - Growth reduction vs budget cuts for Medicare: What's in a name?

PMID- 8667533
TI  - Pregnancy termination and risk of breast cancer.

PMID- 8667534
TI  - Pregnancy termination and risk of breast cancer.

PMID- 8667535
TI  - Rabies prevention: cost to an Indian laborer.

PMID- 8667536
TI  - Effect of age, breast density, and family history on the sensitivity of first
      screening mammography.
AB  - OBJECTIVE: To determine factors that influence the sensitivity of modern first
      screening mammography. DESIGN: Cross-sectional. SETTING: Nine counties in
      northern California. PARTICIPANTS: A total of 28 271 women aged 30 years and
      older referred for first screening mammography to the Mobile Mammography
      Screening Program of the University of California, San Francisco, from April 1985
      to March 1992, of whom 238 were subsequently diagnosed as having breast cancer.
      MEASUREMENTS: Breast cancer risk profile, 2 standard mammographic views per
      breast, breast density, and follow-up of abnormal and normal mammography by
      contacting women's physicians and by linkage to the regional Surveillance,
      Epidemiology, and End Results tumor registry to determine the occurrence of any
      invasive cancer or ductal carcinoma in situ. RESULTS: For women aged 50 years and
      older, the sensitivity of first screening mammography was relatively high and
      decreased slightly with increasing length of follow-up after mammography: 98.5%
      for 7 months of follow-up, 93.2% for 13 months, and 85.7% for 25 months.
      Sensitivity was higher among women aged 50 years and older when breast density
      was primarily fatty rather than primarily dense (98.4% vs 83.7%; P < .01). For
      women younger than 50 years, the sensitivity of first screening mammography also
      decreased with increasing length of follow-up but was significantly lower than
      for older women: 87.5% for 7 months of follow-up, 83.6% for 13 months, and 71.4%
      for 25 months. For women younger than 50 years, breast density did not affect the
      sensitivity of mammography (81.8% for those with primarily fatty breasts vs 85.4%
      for those with primarily dense breasts) and was lower among those with a family
      history of breast cancer (68.8%). CONCLUSIONS: The sensitivity of modern
      mammography is highest among women aged 50 years and older who have primarily
      fatty breast density. Sensitivity is lowest among women younger than 50 years and
      particularly low when the time between screenings is about 2 years or when women
      have a family history of breast cancer, possibly because of rapid tumor growth.

PMID- 8667537
TI  - Likelihood ratios for modern screening mammography. Risk of breast cancer based
      on age and mammographic interpretation.
AB  - OBJECTIVE: To determine the sensitivity, specificity, and likelihood ratios (LRs)
      for modern screening mammography by decade of age and mammographic
      interpretation. DESIGN: Cross-sectional. SETTING: Nine counties in northern
      California. PARTICIPANTS: A total of 26,057 women aged 30 years and older who
      underwent a total of 41,747 first and subsequent screening mammographic
      examinations at the Mobile Mammography Screening Program of the University of
      California, San Francisco, from April 1985 to September 1991. MEASUREMENTS:
      Breast cancer risk profile, 2 standard mammographic views per breast, and follow
      up of abnormal and normal mammograms of contacting women's physicians and by
      linkage to the regional Surveillance, Epidemiology, and End Results tumor
      registry. False-negative examinations were normal examinations that occurred
      within 13 months of a diagnosis of invasive breast cancer or ductal carcinoma in
      situ. RESULTS: The sensitivity of first screening mammography increased with age:
      77.3% for ages 30 to 39 years, 86.7% for ages 40 to 49 years, 93.6% for ages 50
      to 59 years, 94.1% for ages 60 to 69 years, and 91.2% for ages 70 years and older
      (P = .04). Specificity was similar for all ages, ranging from 92.6% to 95.2%. Of
      all abnormal first screening examinations, 92.9% were reported as "additional
      evaluation needed." The LRs for that category ranged from 5.2 to 8.8 and did not
      vary with age. Based on the risk of breast cancer before mammography, which
      increases with age, the risk of breast cancer after mammography associated with
      these LRs were 0.01 for ages 30 to 39 years, 0.02 for ages 40 to 49 years, 0.05
      for ages 50 to 59 years, 0.07 for ages 60 to 69 years, and 0.07 for ages 70 years
      and older. The LRs for mammography reported as "suspicious for malignancy" ranged
      from 88 to 144 and did not vary across age groups. These LRs were associated with
      a risk of breast cancer about 10 times greater than when mammography was reported
      as "additional evaluation needed." CONCLUSION: Most abnormal first screening
      mammography are interpreted as "additional evaluation needed" and are associated
      with LRs of about 7. Given this low LR, the risk of breast cancer after
      mammography is primarily influenced by a woman's age-specific risk of breast
      cancer before mammography. The LRs for screening mammography interpreted as
      "suspicious for malignancy" are high (about 124) and are associated with a
      substantial increase in the risk of breast cancer irrespective of age, but these
      interpretations comprise only a small proportion of abnormal mammography.

PMID- 8667538
TI  - Patient-initiated, twice-daily oral famciclovir for early recurrent genital
      herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study
      Group.
AB  - OBJECTIVE: To compare the efficacy and safety of episodic patient-initiated oral
      famciclovir with placebo in recurrent genital herpes. DESIGN: Randomized, double
      blind, frequent-observation, dose-ranging study comparing twice-daily 125-mg, 250
      mg, or 500-mg oral famciclovir with placebo. Patients initiated therapy after
      self-culturing, reported to the clinic within 12 hours, and were assessed twice
      daily for at least 5 days. SETTING: Fifteen Canadian university, private
      practice, or public outpatient clinics. PATIENTS: A total of 692 patients with
      culture-proven recurrent genital herpes were randomized; 467 patients experienced
      a symptomatic episode and commenced treatment. MAIN OUTCOME MEASURE: Time to
      complete healing of all lesions. RESULTS: Famciclovir (all doses) was
      significantly more effective than placebo in reducing time to healing, time to
      cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and
      crusts. Times to cessation of all symptoms and of moderate to severe lesion
      tenderness, pain, and burning were also reduced. Patients who initiated
      famciclovir prior to viral shedding were more likely to not shed virus
      throughout. All doses were equally effective, safe, and well tolerated.
      CONCLUSIONS: Oral famciclovir reduced the onset and duration of viral shedding,
      lesion persistence, and uncomfortable symptoms. Several individual symptoms and
      lesion stages were also reduced in duration by this episodic therapy.
      Additionally, our twice-daily observation trial design proved to be a helpful
      tool for studying recurrent disease. Episodic oral famciclovir provides a
      convenient and effective alternative for those patients with recurrent genital
      herpes whose frequency rates do not require continuous antiviral suppression.

PMID- 8667539
TI  - Evaluation of Medicaid managed care. Satisfaction, access, and use.
AB  - OBJECTIVE: To evaluate the effects of managed care on Medicaid beneficiaries'
      satisfaction with, access to, and use of medical care during early implementation
      of an enrollment initiative. DESIGN: Cross-sectional survey of a random sample of
      Medicaid beneficiaries in 5 managed care plans and in the conventional Medicaid
      program. SETTING: New York, NY. PARTICIPANTS: Adults aged 18 to 64 years who
      received Medicaid insurance benefits through Aid to Families With Dependent
      Children or State Home Relief and had been enrolled in a managed care plan or
      receiving benefits under conventional Medicaid for at least 6 months. Of the 2500
      enrollees in managed care plans and the 600 other beneficiaries in conventional
      Medicaid whom we surveyed, 1038 enrollees and 410 nonenrollees responded. OUTCOME
      MEASURES: Beneficiaries' ratings of overall satisfaction and 13 dimensions of
      satisfaction related to access, interpersonal and technical quality, and cost;
      reports of access, including regular source (location) of care, waiting time for
      appointment, waiting time in office, and ability to obtain care; and reports of
      use, including inpatient, emergency department, and ambulatory visits. RESULTS:
      Compared with beneficiaries in conventional Medicaid, managed care enrollees in
      general gave higher ratings of satisfaction. The results were not consistent,
      however, between the proportion who were extremely satisfied and the proportion
      who were extremely dissatisfied. Managed care enrollees had significantly greater
      odds of being extremely satisfied (excellent and very good ratings), but fewer
      differences were statistically significant for levels of extreme dissatisfaction
      (fair and poor ratings). With regard to access, managed care enrollees had
      significantly greater odds of having a usual source of care (odds ratio [OR],
      2.33) and seeing the same clinician there (OR, 2.72) and had significantly
      shorter appointment and office waiting times. Managed care and conventional
      Medicaid beneficiaries reported no significant differences in obtaining or delays
      in getting needed care and in inpatient or emergency department use. CONCLUSIONS:
      Medicaid managed care enrollees in New York City reported better access to care
      and higher levels of satisfaction compared with conventional Medicaid
      beneficiaries. Differences between these findings and those for privately insured
      populations highlight the pitfalls of generalizing from other groups to Medicaid
      for policy purposes. Given growing reliance on consumer satisfaction surveys for
      clinical and public policy, future research should focus on factors that explain
      extreme satisfaction vs extreme dissatisfaction. New York State's initiative,
      which has been associated with careful state and local monitoring, merits
      continuing evaluation as managed care enrollment grows and may become mandatory.

PMID- 8667540
TI  - The effect of epidemic measles on immunization rates.
AB  - OBJECTIVE: To evaluate whether immunization against a vaccine-preventable disease
      is sought to avoid the naturally occurring disease itself, we hypothesized that
      the rate of "on-time" measles immunization would increase during an epidemic of
      that disease. If such an effect occurred, we wondered whether it would have an
      impact on on-time administration of other recommended immunizations. DESIGN:
      Retrospective evaluation of immunization rates of children at their second
      birthday with the use of computerized health records of children entering
      kindergarten in an 8-year interval spanning the onset of epidemic measles in
      Chicago, Ill, in 1989 and 1990. SETTING: Children entering Chicago public
      schools. MAIN OUTCOME MEASURES: Rates of receipt of measles-containing vaccine
      (MCV), 1 to 4 doses of a diptheria toxoid-tetanus toxoid-pertussis (DTP) or
      diphtheria toxoid-tetanus toxoid (DT) vaccine, 1 to 3 doses of oral or
      inactivated polio vaccine (OPV/IPV), and the full series of these vaccines
      (4:3:1) that are required to be "up-to-date" by the second birthday. RESULTS: The
      rate of on-time MCV receipt increased from 56% to 58% in the years prior to 70%
      during the epidemic (1989 and 1990). A similar increase did not occur to DTP/DT 4
      or OPV/IPV 3. Moreover, among older children delayed in MCV receipt, evidence of
      catch-up immunization also occurred during the epidemic years; similar catch-up
      for delayed DTP/DT 4 or OPV/IPV 3 immunization did not occur. CONCLUSIONS:
      Dramatic increases in one-time and catch-up MCV receipt occurred during the
      Chicago measles epidemic of 1989 and 1990. The lack of similar increases in
      DTP/DT 4 and OPV/IPV 3 suggests MCV receipt was not associated with receipt of
      other recommended immunizations during that time.

PMID- 8667541
TI  - An 85-year-old woman with a history of falls.

PMID- 8667542
TI  - A 50-year-old woman with disabling spinal stenosis, 1 year later.

PMID- 8667543
TI  - Mentally disabled research subjects. The enduring policy issues.
AB  - Mentally disabled adults often serve as subjects in research on mental illness,
      developmental disabilities, dementia, and other conditions associated with mental
      impairment. Since US regulatory policy fails to resolve many ethical issues
      presented by such research, investigators and institutional review boards must
      determine the appropriate standards and procedures for studies involving adults
      with mental disabilities. Procedures for capacity assessment and information
      disclosure should enhance the autonomy of capable subjects and accurately
      identify subjects incapable of independent choice. Research teams should inform
      proxy decision makers of their ethical responsibities. Decisionally incapable
      adults objecting to research involvement should rarely be included in studies.
      Researchers, institutional review boards, advocacy groups, and federal officials
      should collaborate to improve evaluation of risks and potential benefits to
      decisionally incapable subjects. These groups should also seek consensus on
      appropriate risk limits in studies presenting no prospect of direct benefit to
      decisionally incapable subjects. Finally, subject populations should be
      represented in research planning and review activities.

PMID- 8667545
TI  - What does authorship mean in a peer-reviewed medical journal?

PMID- 8667544
TI  - Strategies for improving sensitivity of screening mammography for women aged 40
      to 49 years.

PMID- 8667546
TI  - 18th century medical institution renews its educational and scientific mission.

PMID- 8667547
TI  - A piece of my mind. Racing.

PMID- 8667548
TI  - Female Olympians' sex tests outmoded.

PMID- 8667549
TI  - Olympic athletes face heat, other health hurdles.

PMID- 8667550
TI  - Biological clock may be as crucial as stopwatch in deciding athletic contests.

PMID- 8667551
TI  - From the Centers for Disease Control and Prevention. Outbreaks of Cyclospora
      cayetanensis infection--United States, 1996.

PMID- 8667552
TI  - From the Centers for Disease Control and Prevention. Addition of prevalence of
      cigarette smoking as a nationally notifiable condition--June 1996.

PMID- 8667553
TI  - From the Centers for Disease Control and Prevention. Tobacco use and usual source
      of cigarettes among high school students--United States, 1995.

PMID- 8667554
TI  - Professional boxing, bleeding, and HIV testing.

PMID- 8667555
TI  - More exercise, less central fat distribution in women.

PMID- 8667556
TI  - Tympanic membrane vs rectal temperature measurement in marathon runners.

PMID- 8667557
TI  - Improving dietary patterns and physical activity levels among children and
      adolescents.

PMID- 8667558
TI  - Defining and assessing alternative medicine practices.

PMID- 8667559
TI  - Physician-assisted suicide and euthanasia.

PMID- 8667560
TI  - Laboratory testing in primary care.

PMID- 8667561
TI  - A global theme issue on emerging and reemerging global microbial threats.

PMID- 8667562
TI  - Clinicians' documentation of gunshot wounds.

PMID- 8667563
TI  - Sudden death in young competitive athletes. Clinical, demographic, and
      pathological profiles.
AB  - OBJECTIVE: To develop clinical, demographic, and pathological profiles of young
      competitive athletes who died suddenly. DESIGN: Systematic evaluation of clinical
      information and circumstances associated with sudden deaths; interviews with
      family members, witnesses, and coaches; and analyses of postmortem anatomic,
      microscopic, and toxicologic data. PARTICIPANTS AND SETTING: A total of 158
      sudden deaths that occurred in trained athletes throughout the United States from
      1985 through 1995 were analyzed. MAIN OUTCOME MEASURES--Characteristics and
      probable cause of death. RESULTS: Of 158 sudden deaths among athletes, 24 (15%)
      were explained by noncardiovascular causes. Among the 134 athletes who had
      cardiovascular causes of sudden death, the median age was 17 years (range, 12-40
      years), 120 (90%) were male, 70 (52%) were white, and 59 (44%) were black. The
      most common competitive sports involved were basketball (47 cases) and football
      (45 cases), together accounting for 68% of sudden deaths. A total of 121 athletes
      (90%) collapsed during or immediately after a training session (78 cases) or a
      formal athletic contest (43 cases), with 80 deaths (63%) occurring between 3 PM
      and 9 PM. The most common structural cardiovascular diseases identified at
      autopsy as the primary cause of death were hypertrophic cardiomyopathy (48
      athletes [36%]), which was disproportionately prevalent in black athletes
      compared with white athletes (48% vs 26% of deaths; P = .01), and malformations
      involving anomalous coronary artery origin (17 athletes [13%]). Of 115 athletes
      who had a standard preparticipation medical evaluation, only 4 (3%) were
      suspected of having cardiovascular disease, and the cardiovascular abnormality
      responsible for sudden death was correctly identified in only 1 athlete (0.9%).
      CONCLUSIONS: Sudden death in young competitive athletes usually is precipitated
      by physical activity and may be due to a heterogeneous spectrum of cardiovascular
      disease, most commonly hypertrophic cardiomyopathy. Preparticipation screening
      appeared to be of limited value in identification of underlying cardiovascular
      abnormalities.

PMID- 8667564
TI  - Influences of cardiorespiratory fitness and other precursors on cardiovascular
      disease and all-cause mortality in men and women.
AB  - OBJECTIVE: To quantify the relation of cardiorespiratory fitness to
      cardiovascular disease (CVD) mortality and to all-cause mortality within strata
      of other personal characteristics that predispose to early mortality. DESIGN-
      Observational cohort study. We calculated CVD and all-cause death rates for low
      (least fit 20%), moderate (next 40%), and high (most fit 40%) fitness categories
      by strata of smoking habit, cholesterol level, blood pressure, and health status.
      SETTING: Preventive medicine clinic. STUDY PARTICIPANTS: Participants were 25341
      men and 7080 women who completed preventive medical examinations, including a
      maximal exercise test. MAIN OUTCOME MEASURES: Cardiovascular disease and all
      cause mortality. RESULTS: There were 601 deaths during 211996 man-years of follow
      up, and 89 deaths during 52982 woman-years of follow-up. Independent predictors
      of mortality among men, with adjusted relative risks (RRs) and 95% confidence
      intervals (CIs), were low fitness (RR, 1.52;95% CI, 1.28-1.82), smoking (RR,
      1.65; 95% CI, 1.39-1.97), abnormal electrocardiogram (RR, 1.64;95% CI, 1.34
      2.01), chronic illness (RR, 1.63;95% CI, 1.37-1.95), increased cholesterol level
      (RR, 1.34; 95% CI, 1.13-1.59), and elevated systolic blood pressure (RR, 1.34;
      95% CI, 1.13-1.59). The only statistically significant independent predictors of
      mortality in women were low fitness (RR, 2.10; 95% Cl, 1.36-3.21) and smoking
      (RR, 1.99; 95% Cl, 1.25-3.17). Inverse gradients were seen for mortality across
      fitness categories within strata of other mortality predictors for both sexes.
      Fit persons with any combination of smoking, elevated blood pressure, or elevated
      cholesterol level had lower adjusted death rates than low-fit persons with none
      of these characteristics. CONCLUSIONS: Low fitness is an important precursor of
      mortality. The protective effect of fitness held for smokers and nonsmokers,
      those with and without elevated cholesterol levels or elevated blood pressure,
      and unhealthy and healthy persons. Moderate fitness seems to protect against the
      influence of these other predictors on mortality. Physicians should encourage
      sedentary patients to become physically active and thereby reduce the risk of
      premature mortality.

PMID- 8667565
TI  - Athlete's heart in women. Echocardiographic characterization of highly trained
      elite female athletes.
AB  - OBJECTIVES; To define the expression of "athlete's heart" in women by determining
      the alterations in cardiac dimensions associated with long-term intense
      conditioning in elite female athletes. DESIGN; Prospective cardiovascular
      assessment conducted from 1986 through 1993. Subjects were evaluated using 2
      dimensional, M-mode, and Doppler echo-cardiographic studies. SETTING: Institute
      of Sports Science, Italian National Olympic Committee, Rome, Italy. PARTICIPANTS:
      A total of 600 elite female athletes (mean age, 21 years; range, 12-49 years) who
      had participated in vigorous training (mean duration, 9 years; range, 2-32 years)
      and had competed in 27 sports, including 211 athletes at the international level
      and 389 at the national level. A control group consisted of 65 sedentary
      volunteer women (mean age, 23.7 years; range, 14-41 years) who were free of
      cardiovascular disease and who did not participate in regular athletic training.
      MAIN OUTCOME MEASURES: Left ventricular end-diastolic cavity dimension and wall
      thickness. RESULTS: Athletes demonstrated larger left ventricular end-diastolic
      cavity dimension (mean +/- SD) (49 +/- 4 mm) and greater maximal wall thickness
      (8.2 +/- 0.9 mm) than controls (46 +/- 3 mm and 7.2 +/- 0.6 mm; P < .001). These
      dimensions were 6% and 14% larger in athletes. Among athletes, left ventricular
      cavity dimension was 40 mm to 66 mm, exceeded normal limits ( > 54 mm) in 47
      women (8%), and was within the range consistent with primary dilated
      cardiomyopathy ( > or = 60 mm) in 4 athletes (1%). Training for endurance sports,
      such as cycling, cross-country skiing, and rowing had the greatest effect on
      cavity dimension. Left ventricular wall thickness was 6 mm to 12 mm in athletes
      and did not exceed normal limits or extend into the borderline gray zone with
      hypertrophic cardiomyopathy in any subject. Compared with data from 738
      previously studied male athletes, female athletes showed significantly smaller
      left ventricular cavity dimension (11% less; P < .001) and wall thickness (23%
      less; P < .001). CONCLUSIONS: Highly trained women athletes frequently
      demonstrate cardiac dimensional changes as an adaptation to physical training,
      although absolute left ventricular cavity size exceeding normal limits was
      evident in a minority (8%) of women athletes and was rarely (1% of athletes)
      within the range of dilated cardiomyopathy. Athletic training was not a stimulus
      for substantial increases in absolute left ventricular wall thickness, which was
      within normal limits for all women athletes. These findings suggest that the
      clinical differentiation of athlete's heart and hypertrophic cardiomyopathy
      appears to be a diagnostic dilemma that is limited to male athletes.

PMID- 8667566
TI  - Hospital care in later life among former world-class Finnish athletes.
AB  - OBJECTIVE: To investigate the use of hospital care from all causes among former
      top-level athletes from different vigorous sports to determine whether health
      benefits or adverse effects have the greater influence. DESIGN: National,
      population-based cohort study with a 21-year follow-up. SETTING: Finland.
      SUBJECTS: A total of 2049 male athletes who had represented Finland during 1920
      to 1965, and 1403 male controls classified healthy at 20 years of age. MAIN
      OUTCOME MEASURE: In-hospital care from all causes was extracted from the national
      hospital discharge registry for the period 1970 through 1990 expressed as
      hospital days per person-years of exposure. RESULTS: Compared with controls, the
      rate ratios (RRs) for all-cause hospital days per person-years of exposure were
      lower in athletes from endurance sports (RR, 0.71; 95% confidence interval [Cl],
      0.70-0.73), mixed sports (including endurance and weight training) (RR, 0.86; 95%
      Cl, 0.85-0.87), and power sports (RR, 0.95; 95% Cl, 0.94-0.96) (P < .001 for all
      comparisons) after adjustment for age and occupational group. The lower RR among
      athletes from endurance sports and other sports involving aerobic activity was
      largely explained by lower rates of hospital care for heart disease, respiratory
      disease, and neoplasms, but not for musculoskeletal disorders. CONCLUSIONS:
      Former elite athletes, particularly those in aerobic sports, use less hospital
      care. Other beneficial health habits are known to be associated with a physically
      active lifestyle.

PMID- 8667567
TI  - Effects of a single bout of ultraendurance exercise on lipid levels and
      susceptibility of lipids to peroxidation in triathletes.
AB  - OBJECTIVE: To determine the effects of a single bout of ultraendurance exercise,
      as a model for physiologic stress, on lipid and lipoprotein levels, and oxidative
      susceptibility of lipids in highly trained athletes. DESIGN: Observational trial.
      POPULATION AND SETTING: Thirty-nine volunteer subjects (26 mean, 13 women; mean
      age, 38 +/- 10 years) who competed in and completed the 1994 Hawaii Ironman World
      Championship Triathlon consisting of a consecutive 3.9-km (2.4-mi) swim, 180.2-km
      (112-mi) bike ride, and a 42.2-km (26.2-mi) run. Subjects answered questionnaires
      and had blood samples obtained 2 days prior to and within 15 minutes of
      completion of the triathlon. MAIN OUTCOME MEASURES: Prerace vs postrace changes
      in lipid and lipoprotein levels, and susceptibility of lipids to peroxidation.
      RESULTS: The mean duration of exercise was 753 +/- 128 minutes. With exercise,
      plasma volume-corrected levels of triglycerides decreased 39% from 1.58 +/- 0.83
      to 0.97 +/- 0.68 mmol/L (139.6 +/- 73.6 to 85.8 +/- 60.5 mg/dL) (P < .001).
      Levels of total cholesterol decreased 9% from 4.94 +/- 0.88 to 4.50 +/- 0.79
      mmol/L (190.8 +/- 33.8 to 173.8 +/- 30.6 mg/dL) (P < .001), low-density
      lipoprotein cholesterol decreased 11% from 2.59 +/- 0.77 to 2.30 +/- 0.86 mmol/L
      (100.1 +/- 29.9 to 88.7 +/- 33.3 mg/dL) (P = .02), and apolipoprotein B decreased
      10% from 0.91 +/- 0.20 to 0.82 +/- 0.18 g/L (90.7 +/- 20.0 to 82.0 +/- 17.9
      mg/dL) (P < .001). High-density lipoprotein cholesterol and apolipoprotein A-I
      increased with exercise but not significantly. The susceptibility of lipids to
      peroxidation decreased significantly (4.51 +/- 1.91 micromol/L, preexercise, vs
      2.42 +/- 2.27 micromol/L, postexercise, P < .001), an effect that was not related
      to antioxidant use or levels of vitamins A, C, or E. Serum iron, a potential pro
      oxidant, also decreased by 45% with exercise from 15.75 +/- 5.55 to 8.59 +/- 4.30
      micromol/L (88 +/- 31 to 48 +/- 24 micrograms/dL) (P < .001), an effect that was
      weakly correlated with changes in lipid peroxidation (P = .05). CONCLUSIONS:
      These data suggest that a single bout of prolonged exercise can reduce lipid and
      lipoprotein risk factors for developing cardiovascular disease. Moreover,
      susceptibility of lipids to peroxidation is reduced by exercise, thereby adding
      to the benefits of physical activity. This effect appears to be independent of
      antioxidant supplement use and may be mediated by induction of endogenous
      antioxidants. These observations may explain in part the reduced risk of
      developing vascular and other diseases in individuals who are physically active.

PMID- 8667568
TI  - Changes in bone mineral content in male athletes. Mechanisms of action and
      intervention effects.
AB  - OBJECTIVES: To determine changes in bone mineral content (BMC) in male athletes,
      to examine the mechanisms of changes, and to evaluate the effects of
      intervention. DESIGN: Dual-energy x-ray absorptiometry (DEXA) tests were
      administered over a 2-year period, and calcium loss during training was
      determined by analysis of sweat and urine. Calcium supplementation was
      administered during year 2. SETTING--A midsouth university. PARTICIPANTS: Eleven
      members of a college Division I-A basketball team. INTERVENTION: Based on
      observed calcium loss, athletes received differential levels of calcium
      supplementation. Intervention commenced the week prior to the fall training
      season and continued through postseason play. MAIN OUTCOME MEASURE--Changes in
      BMC. RESULTS: Total body BMC decreased 3.8% from preseason to midseason of year 1
      (mean decrease, 133.4 g, P = .02), increased nonsignificantly by 1.1% (mean
      increase, 35.3 g, P = .22) during the offseason, but decreased an additional 3.3%
      during summer months when practices resumed (mean decrease, 113.1 g, P = .01).
      Dermal calcium loss averaged 247 mg [corrected] per training session. From
      preseason to late summer, there was an overall decrease of 6.1% in total BMC and
      a 10.5% decrease in BMC of the legs. Calcium supplementation was associated with
      significant increases in BMC and lean body mass. CONCLUSIONS: Bone loss is
      calcium related and exercise is positively related to BMC provided that calcium
      intake is sufficient to offset dermal loss.

PMID- 8667569
TI  - Performance-enhancing drugs, fair competition, and Olympic sport.
AB  - Drug control has become an important component of Olympic sport. At the Atlanta
      Centennial Olympic Games, urine samples will be tested for prohibited substances,
      including stimulants, narcotics, anabolic agents, diuretics, peptides, and
      glycoprotein hormones as well as prohibited methods of enhancing performance,
      including blood doping and pharmacological, chemical, and physical manipulation
      of the urine. Drug testing programs must address short-acting stimulants, beta
      blockers, and diuretics; training drugs such as anabolic steroids; and drugs
      affecting the detectability of other drugs. Programs include short- or no-notice
      testing during training periods, testing at qualifying competitions, and testing
      at the Olympic Games. Procedures and disposition that occur when a prohibited
      substance is found in an athlete competing in an Olympic sport are discussed. An
      analysis of the ethics of the use of performance-enhancing drugs in sports and of
      drug control in terms of fair competition and the impact of enhancement
      technologies of the meaning of sports also is presented.

PMID- 8667570
TI  - Bone density at multiple skeletal sites in amenorrheic athletes.
AB  - OBJECTIVE: To determine if there is a generalized loss of bone mass at multiple
      skeletal sites in amenorrheic athletes compared with a group of eumenorrheic
      athletes. DESIGN: A case-control study examining the differences in bone mineral
      density (BMD) between amenorrheic and eumenorrheic athletes. SETTING: Seattle,
      Wash, and surrounding communities. PARTICIPANTS: Forty-nine athletes, aged 17 to
      39 years, were selected from those responding to advertisements in local sporting
      goods stores and a track-and-field newsletter. Athletes were defined as
      amenorrheic if they had had fewer than 2 menstrual cycles in the last 12 months
      or none in the past 6 months, or eumenorrheic if they had had 10 to 13 cycles in
      the previous year. Only women who met these criteria, confirmed by tests for
      estradiol and progesterone levels, were enrolled in the study. MAIN OUTCOME
      MEASURES: Bone mineral density measured by dual-energy x-ray absorptiometry.
      RESULTS: Amenorrheic athletes had significantly lower BMD (P < .01) at the lumbar
      spine, femoral neck, trochanter, Ward triangle, intertrochanteric region, femoral
      shaft, and tibia. No difference was noted at the fibula. Body weight combined
      with months of amenorrhea and age of menarche predicted the BMD of the lumbar
      spine for amenorrheic athletes. Duration of amenorrhea and body weight of
      amenorrheic athletes predicted BMD at the femoral neck, trochanter,
      intertrochanteric region, and tibia. Weight alone predicted BMD at the femoral
      shaft and tibia. Age plus weight predicted lumbar BMD of eumenorrheic women.
      CONCLUSION: Extended periods of amenorrhea may result in low bone density at
      multiple skeletal sites including those subjected to impact loading during
      exercise.

PMID- 8667571
TI  - Physical activity and cardiovascular health. NIH Consensus Development Panel on
      Physical Activity and Cardiovascular Health.
AB  - OBJECTIVE: To provide physicians and the general public with a responsible
      assessment of the relationship between physical activity and cardiovascular
      health. PARTICIPANTS: A nonfederal, nonadvocate, 13-member panel representing the
      fields of cardiology, psychology, exercise physiology, nutrition, pediatrics,
      public health, and epidemiology. In addition, 27 experts in cardiology,
      psychology, epidemiology, exercise physiology, geriatrics, nutrition, pediatrics,
      public health, and sports medicine presented data to the panel and a conference
      audience of 600 during a 2-day public session. Questions and statements from
      conference attendees were considered during the open session. Closed
      deliberations by the panel occurred during the remainder of the second day and
      the morning of the third day. EVIDENCE: The literature was searched through
      MEDLINE and an extensive bibliography of references was provided to the panel and
      the conference audience. Experts prepared abstracts with relevant citations from
      the literature. Scientific evidence was given precedence over clinical anecdotal
      experience. CONSENSUS PROCESS: The panel, answering predefined questions,
      developed their conclusions based on the scientific evidence presented in open
      forum and the scientific literature. CONSENSUS STATEMENT: The panel composed a
      draft statement that was read in its entirety and circulated to the experts and
      the audience for comment. There-after, the panel resolved conflicting
      recommendations and released a revised statement at the end of the conference.
      The panel finalized the revisions within a few weeks after the conference.
      CONCLUSIONS: All Americans should engage in regular physical activity at a level
      appropriate to their capacity, needs, and interest. Children and adults alike
      should set a goal of accumulating at least 30 minutes of moderate-intensity
      physical activity on most, and preferably all, days of the week. Most Americans
      have little or no physical activity in their daily lives, and accumulating
      evidence indicates that physical inactivity is a major risk factor for
      cardiovascular disease. However, moderate levels of physical activity confer
      significant health benefits. Even those who currently meet these daily standards
      may derive additional health and fitness benefits by becoming more physically
      active or including more vigorous activity. For those with known cardiovascular
      disease, cardiac rehabilitation programs that combine physical activity with
      reduction in other risk factors should be more widely used.

PMID- 8667572
TI  - Aspirations and ideals in the Olympic games.

PMID- 8667574
TI  - Adverse effects of anabolic steroids.

PMID- 8667575
TI  - [Bone and joint lesions in burns in childhood].
AB  - Bone and joint lesions as an underlying cause of disability require exact and
      emergency diagnosis and treatment. This is a report on the case material of the
      Pediatric Clinic of Burns and Plastic Surgery, with emphasis on the
      characteristic features of the children's population, having an essential bearing
      on the course of osteoarticular changes in the various stages of burn disease.
      The basic principles of treating osteoarticular lesions in each of the three
      groups, adopted in the clinic, are outlined, with special attention focused on
      the therapeutic approach to each of the groups, and on the emergency operative
      procedures aimed at maximally prompt removal of necrotic tissues and resurfacing
      of the osteoarticular lesions in early terms with a view to a varying degree
      preservation of function. Emphasis is also laid on the important practical
      implications of early rehabilitation as an element invariably present in the
      complex of functional recovery of the osteoarticular apparatus.

PMID- 8667573
TI  - An Olympic medical legacy.

PMID- 8667576
TI  - [The treatment of slowly healing wounds with collagen and growth factors].
AB  - Experience had with the local application of collagen and autologous growth
      factors, isolated from platelets, in 35 patients presenting chronic, slowly
      healing wounds, treated with conventional methods, is discussed. In 24 cases of
      the series reviewed the wounds undergo epithelization within six weeks, and in
      the remainder (11)-within 10 weeks. As shown by the results, the healing process
      is quicker in wounds of patients treated with growth factors in combination with
      collagen, as compared to the control group--p(t) > 0.05.

PMID- 8667578
TI  - [The use of expanders in soft-tissue plastic-reconstructive surgery].
AB  - Thirty-six years ago, Neumann was the first to practically implement skin
      expansion by means of subcutaneous rubber balloon inflation. After discovery of
      the silicone elastomer (1970), Padovan initiated the wide application of
      expanders in practice. Ever since then, the latter have conclusively demonstrated
      their contribution to plastic and reconstructive surgery in handling skin and
      soft-tissue defects in all parts of the body. The preparation and utilization of
      expanders are closely linked to the goals pursued, and evolve through several
      stages: 1) selection of the size and number of expanders, 2) choice of expander
      consistent with the valve type, 3) choice of the site and orientation of the
      incision for subcutaneous puch formation for the expander, 4) depth of expander
      insertion, 5) size of the punch for expander, valve and tube. After insertion of
      the silicone balloon (expander) subcutaneously, its inflation with serum is
      begun. Recently, early (for 24 hours) and quick (for 7-10 days) inflation of the
      expander is resorted to. The tolerance of both tissues involved, and patient is
      the basic criterion for practical implementation of the technique described. As
      any operative intervention and procedure, the use of expanders is associated with
      a number of complications. In general they are divided in: 1. minor--where
      discontinuation of the expansion process is unnecessary, but it is prolonged
      until the planned extension is attained, and 2. major--necessitating complete
      discontinuation of the process of expansion and performing additional procedures.

PMID- 8667577
TI  - [The restoration of the weight-bearing capacity of the lower extremities and the
      gait of patients with traumatic detachments].
AB  - The functional recovery terms are estimated in 65 patients presenting extensive
      traumatic detachments (decollement) and defects of the lower extremities. The
      series includes 40 children (61.5 per cent), and 25 adult individuals (38.5 per
      cent). The distribution of patients by gender, age, surface involved by the
      lesion, its location and concomitant damage to deep anatomical structures is
      studied. The patients are subjected to 2-8 years postoperative follow-up.
      According to type of intervention, they are distributed in three groups, as
      follows: group one--patients with reimplantation, group two--reimplantation with
      ensuing necrosis, and group three--cases presenting granulation wounds on
      admission. The results are evaluated by the static loadbearing test of Buglaev
      and ichnography, and subjected to statistical processing by variation analysis.
      As shown by the results, maximal functional recovery in group one is attained by
      the end of the first year, in group two--by the end of the second year, and in
      group three--by the end of the fourth year. Application of early exercise
      therapy, individually prescribed, contributes to the positive outcome.

PMID- 8667580
TI  - [Early results of our 1-year experience in using lipo-aspiration].
AB  - Lipoaspiration is a method of subcutaneous fatty tissue reduction by vacuum
      aspiration through a cannula or syringes, using one or more incisional openings.
      Lipoaspiration is indeed a revolution in the surgical modelling of a silhouette,
      and nowadays it is widely diffused and practically implemented worldwide. At the
      cost of a small scar any subcutaneous fatty accumulation lends itself
      successfully to correction. Virtually, this means that the whole body--form chin
      to ankle--may undergo remodelling. Liposaspiration is successful in correcting
      the deep. so-called "cold adipose tissue" (graisses froides) which is
      irresponsive to diet reduction.

PMID- 8667579
TI  - [The effect of an extract of sea buckthorn (Hippophae rhamnoides L.) on the
      healing of experimental skin wounds in rats].
AB  - The effect exerted by Hippophae rhamnoides L. extract on the healing of
      experimental wounds in rats is studied histomorphologically in dynamics. The
      animals are divided up in three groups, as follows: group one--controls, group
      two--controls treated with indifferent carrier (carbopol gel), and group three-
      experimental, treated with carbopol gel containing extract of Hippophae
      rhamnoides L. The wounds induced are standard, oval to elliptic with diameter
      about 3 cm. In groups I and II they are subjected to daily daubing over a 10-day
      period. The study of cytologic smears at 8, 24 and 48 hours, and biopsy performed
      on the 10th day show that in group three the epithelization is more intensive and
      occurs earlier, and granulation tissue differentiation (mature collagen fibers,
      profuse vascularity) is quicker, by comparison with groups one and two. The
      markedly expressed stimulating effect on the healing process is explained with
      the rich content of vitamins (A, C, E etc.) and microelements (sulfur, selenium,
      zinc, copper etc.) in the extract used.

PMID- 8667581
TI  - [The noninvasive intraoperative assessment of the skin blood circulation in
      children with burns].
AB  - To measure skin temperature two noninvasive methods--skin thermometry and digital
      volume rheography--are used in 42 children with burns. Two types of anesthesia
      are applied. In 21 children analgesia is attained by general inhalatory
      anesthesia with halothane, nitrous oxide and oxygen at controlled ventilation,
      and in the remainder--by intravenous anesthesia with fractionated ketamine at
      spontaneous respiration. For statistical reasons the duration of study is 120
      minutes. Comparative assessment of the two procedures is done, and correlative
      dependences between the respective indicators are found. For the purpose
      regression equations are suggested.

PMID- 8667582
TI  - [The prognostic and informative value of temperature differences in thermal
      shock].
AB  - In thermal shock patients thermoregulation impairment occurs through peripheral
      and central mechanisms. Rather significant temperature differences between the
      single parts of the body are produced. The study covers 25 patients in thermal
      shock phase, including 11 adults and 14 children. The ages of the patients range
      from 15 months to 50 years, with burnt surface from 15 to 50 percent. The dynamic
      patterns of the listed below indicators are followed up: oral, rectal, skin and
      roop temperatures, and relative humidity of the room. In patients with shock
      running a mild course the oral-skin and rectal-skin temperatures return to normal
      as early as within 24 hours. In extensive burns, irrespective of infusional and
      drug treatment, temperature differences within the limits 12 degrees-14 degrees C
      persist. Based on the study results an assessment is made of the prognostic
      relevance of the indicators proposed.

PMID- 8667583
TI  - [Postoperative necrotizing fasciitis of the anterior abdominal wall].
AB  - Postoperative necrotizing fasciitis of the anterior abdominal wall is a serious
      and life-endangering complication of an acute progressive synergistic infective
      process. There is an absolute increase in its incidence rate attributable to a
      number of situations in modern life. Morphological and clinical studies are
      carried out on personal case material of 28 patients, followed up over a 3-year
      period. The presence of aerobic-anaerobic mixed polyinfection, consisting of
      average 3.75 bacterial species of which 1.43 aerobes and 2.32 anaerobes, is
      demonstrated microbiologically. Of the latter non-spore-bearing obligate
      anaerobes predominate among which B fragillis is the most common. As shown by the
      study, the process is characterized by slow initial course with ensuring rapid
      spreading by neighbourhood. The process reveals all signs of a mixed aerobic
      anaerobic polyinfection, thereby necessitating subordination of both antibiotic
      therapy and surgical tactics to the latter.

PMID- 8667584
TI  - [Clostridial surgical infection].
AB  - An ever increasing attention of clinicists is being focused on nontraumatic
      clostridal surgical infections. Personal clinical case material consisting of 390
      patients with microbiologically proved clostridial infection are subjected to
      clinical and microbiological investigations aimed at establishing the nature of
      the infective process. In 377 patients (group one) signs of mixed aerobic
      anaerobic polyinfection are clinically documented, fully confirmed by the
      comprehensive microbiological examinations performed. In 120 patients of this
      group 162 Clostridida species are isolated, but none of them, including the
      severest cases, are suspected for gas gangrene presence. In 13 patients of group
      two presenting clinical picture of a typical gas gangrene, the latter is both
      demonstrative and impressive. Here the microbiological examinations are
      absolutely analogical to those in group one which warrants the assumption of the
      endogenous character of the infective process, leading in turn to
      inferenceshaving important practical implications and recommendation to modify
      the antiepidemiological measures with a special reference to the endogenous
      character of the infective process.

PMID- 8667585
TI  - [Medical first aid and the transportation of burn patients].
AB  - The new trends in delivering emergency medical aid and transportation of burnt
      patients are outlined. The successiveness of emergency measures on the site of
      accident is specified, namely: securing patency of the airways, spontaneous
      respiration, free venous return for maintaining circulation. No local treatment
      of wounds is done. The need of transportation to specialized centers for
      treatment of burns throughout the country (4 units available) is substantiated.
      It is emphasized that adequate treatment, both infusional and operative, may be
      effected only by the specialized teams in such centers, and provided the
      casualties are hospitalized within the first few hours of trauma. The
      contraindications for transportation of patients in the early post-accident hours
      include: respiratory insufficiency, intubation, multiply injured patients and
      severe hemorrhages, as well as cases with unspecified diagnosis. Transportation
      is mandatorily carried out with an accompanying doctor under the supervision and
      consent of the team on duty from the respective center and its consultant.

PMID- 8667586
TI  - [Anaerobic infection of the maxillary sinus complicated by phlegmon of the
      orbit].
AB  - A male patient presenting acute left-side purulent masillary sinus and orbital
      phlegmon is described. Anaerobic flora is demonstrated microbiologically.
      Emphasis is laid on the necessity of opportune operative treatment, adequate
      antibiotic therapy and team work with microbiologists and ophthalmologists.

PMID- 8667587
TI  - [Atypical (pleomorphic) lipoma].

PMID- 8667588
TI  - [The reconstruction of extensive exenterations with the aid of an absorbable
      prosthesis].

PMID- 8667589
TI  - [The basic principles of the antibiotic therapy of burn patients].
AB  - Proceeding from many years experience with antibiotic treatment of bacterial
      infections in burnt patients, accumulated in the Section of Burns and Plastic
      Surgery, and pertinent literature reports, the basic principles of antibacterial
      therapy in this contingency of patients are set forth. A detailed protocol is
      presented, based on: 1) presence of clinical and laboratory evidence of infection
      and its location, and the most likely causing agents involved, 2) bacteriological
      data on the commonest causing agents of local and systemic infection in burns,
      and their sensitivity to antibiotics, 3) duration and surface, deepness and
      location of the burn injury, and 4) spectrum of action, pharmacokinetics,
      pharmacodynamics and side effects of the various groups of antibiotics,
      consistent with the age and concomitant diseases of the patients. A number of
      antibiotic constellations in cases presenting sepsis where resorting to "blind"
      therapy is necessitated, are recommended. It is underscored that the protocol
      suggested is open for modifications, and also that antibiotic therapy efficiency
      may be anticipated only when combined with adequate infusional and operative
      management.

PMID- 8667591
TI  - Reliability of the probability effect on event-related potentials during repeated
      testing.
AB  - The reliability of event-related potentials (ERPs) was studied in 10 healthy
      adults who were tested 8 times over 7-10 day intervals using a standard auditory
      oddball paradigm. The difference waveforms, obtained by subtracting the averaged
      waveforms for frequent trials from those obtained in rare trials, were designed
      to analyze the components of the ERPs, such as the P300, and to focus on the
      reliability of the probability effect on the ERPs. The between-session
      reliability (8 sessions) and the within-session reliability (order of blocks or
      of different visual procedures) were computed for the obtained difference
      waveforms. The between-session reliabilities, expressed as the intraclass
      correlations (r') for the P300 amplitude, area and latency, were 0.70, 0.61 and
      0.65, respectively. The within-session reliability, presented as the Pearson
      correlation coefficients (r) for the three P300 measures were 0.43, 0.35 and 0.25
      for different eyes. The values were 0.45, 0.39, 0.42 between the first and the
      second blocks (eyes-open) and 0.58, 0.47 and 0.29 (eyes-closed). These findings
      indicate that the P300 amplitude calculated from the difference waveforms may be
      the most stable marker for the between-session reliabilities. There were no
      significant differences in the P300 measures over the 8 sessions, suggesting that
      habituation may not occur with the difference waveform reflecting the probability
      effect on ERPs. The difference waveform may be useful in research on repetitive
      group ERPs.

PMID- 8667590
TI  - Increased sensitivity of eosinophils for eosinophilopoietic cytokines in atopic
      dermatitis.
AB  - Despite normal concentrations of serum eosinophilopoietic cytokines, blood
      eosinophilia was noted in patients with atopic dermatitis (AD) (n = 32).
      Significant increase of EG2+ "activated" eosinophil numbers that are mirrored in
      serum eosinophil cationic protein (ECP) levels in vitro, though not always in
      synchrony with total eosinophil counts, was also demonstrated. Functionally, AD
      source eosinophils showed an enhanced MCLA-dependent chemiluminescence (MDCL)
      responsiveness to the eosinophilopoietic cytokines, with the characteristics that
      interleukin-5 (IL-5)-induced MDCL responses strongly correlated with EG2+
      eosinophil proportions, whereas both IL-3- and granulocyte-macrophage colony
      stimulating factor (GM-CSF)-induced MDCL responses rather significantly
      correlated with the degree of blood eosinophilia. Like other eosinophil
      associated parameters (total eosinophil counts, EG2+ eosinophil counts and serum
      ECP levels), those cytokine-induced eosinophil MDCL responses significantly
      increased in correlation to the AD severity. These results suggest that i)
      eosinophilopoiesis accompanying development of both IL-3- and GM-CSF-sensitive
      eosinophils within the bone marrow, and induction of IL-5-sensitive/EG2-reactive
      eosinophils in the periphery may be regulated through inflammatory events in AD
      lesional skin; ii) it is unlikely that these eosinophil in vivo differentiation
      may be due to direct effect of locally synthesized three eosinophilopoietic
      cytokines; and iii) enhanced sensitivity of EG2+ eosinophils for IL-5 may be
      responsible for elevated levels of serum ECP in vitro.

PMID- 8667592
TI  - Thy1(+) lymphocytes with LAK-like activity are present in rat liver sinusoids.
AB  - Lymphocytes with cytotoxic activity have been identified in sinusoids of rat
      liver. We investigated the effects of aging on the cytotoxicity of liver
      sinusoidal lymphocytes in the rat and attempted to identify the cells responsible
      for cytotoxicity using a Thy1 monoclonal antibody. Natural Killer (NK) activity
      against YAC1 peaked at the age of 8 weeks, while cytotoxicity against NK
      resistant Lymphokine Activated Killer (LAK)-sensitive P815 increased gradually
      with age. A cold target inhibition assay showed that lymphocytes cytotoxic for
      P815 and AH109 were also present in the liver sinusoids of aged rats. When these
      cells were fractionated by the Percoll discontinuous density gradient method,
      cytotoxic cells were found to comprise large granular lymphocytes (LGLs) rich in
      low- and middle-density fractions. Cytotoxicity against various targets increased
      when CD5(+) cells were removed using CD5-conjugated beads. Cytotoxicity against
      P815, AH109 and AH130 was decreased as compared with control lymphocytes when
      CD5(-) Thy1(+) lymphocytes were removed using CD5, Thy1-conjugated beads.
      Immunohistologic examination revealed Thy1(+) LGLs with rod-cored vesicles and
      electron-dense granules in the liver sinusoids. We consider that LAK-like cells
      with a Thy1 phenotype are present in the liver sinusoids and suggest that they
      have a broad range of cytotoxicity.

PMID- 8667593
TI  - Pancreatojejunal sutural insufficiency occurring after pancreatoduodenectomy and
      countermeasures.
AB  - Pancreatojejunal sutural insufficiency occurring after pancreatoduodenectomy and
      countermeasures are discussed. In the Department of Surgery at Kurume University
      School of Medicine, 318 patients underwent pancreatoduodenectomies. The present
      study includes 15 of these patients, all of whom had pancreatojejunal sutural
      insufficiency. The frequency of sutural insufficiency was 4.7%. Five patients had
      bile duct cancer, 5 had cancer of the papilla of Vater, 2 had a carcinoma of the
      pancreatic head, 1 each had gallbladder cancer, chronic pancreatitis, and
      papillitis. Six (40%) of the 15 patients died during hospitalization. The
      presence or absence of sutural insufficiency was confirmed mainly by radiography
      and determining the properties and amylase levels of the drainage fluid. There
      was no significant difference due to the method of anastomosis. End-to-side
      anastomosis had a rate of 5 (5.9%) of 85 patients, while end-to-end had 10 (4.3%)
      of 233 patients. The sutural insufficiency was manifested as a major leakage in 6
      patients and a minor leakage in 9. The degree of lymph node dissection was D0 in
      6.1%, D1 in 1.4%, D2 in 4.8% and D3 in 10.8%, with a high incidence of sutural
      insufficiency in D3 patients. The pancreatic duct diameter was smaller than 4 mm
      in 10, 5-7 mm in 4 and over 8 mm in 1 patient. The intraoperative pancreatic
      findings were a soft pancreas in 8, slightly hard in 3, and hard in 4 patients.
      Fibrosis of the pancreas was normal to slight in 11 and moderate in 4 patients.
      Drainage by relaparotomy was performed in 4 of the 6 patients with major leakages
      to control sutural insufficiency, and the other 2 underwent continuous aspiration
      with an intraperitoneal drain inserted during the operation. The 9 patients with
      minor leakage underwent conservative treatment including continuous aspiration
      via an intraperitoneal drain inserted during surgery, fasting, intravenous
      hyperalimentation, and antibiotic administration. All of the patients with major
      leakage died from an associated occurrence of hepatic insufficiency, renal
      insufficiency, intraperitoneal hemorrhage or diffuse peritonitis during
      hospitalization. However, 8 of the 9 patients with minor leakage had some
      healing, and the 1 remaining patient developed a pancreatic fistula. The
      frequency of pancreatojejunal sutural insufficiency was high in patients with
      minimal pancreatic fibrosis, with soft pancreatic tissue without dilatation of
      the pancreatic duct, and with relatively good pancreatic function.

PMID- 8667594
TI  - Morphological analysis by lateral cephalography of sleep apnea syndrome in 53
      patients.
AB  - To determine the morphologic characteristics of patients with sleep apnea
      syndrome (SAS), the facial skeleton, tongue area, soft palate area and upper
      airway area were examined on lateral cephalograms from 53 male patients with SAS.
      The SAS patients were divided into two groups according to their body mass index
      (BMI): Group N (BMI < 25, N = 23) and Group O (BMI > or = 25, N = 30). Fifty non
      snoring adult men were used as a control (Group C). The mean BMI of all 53
      patients with SAS was 26.2 +/- 3.1 kg/m2. The mean SNB was smaller in Group N
      (76.7 +/- 3.2 degrees) than in Group C (78.4 +/- 3.0 degrees). The mean airway
      area was markedly smaller in Groups N and O than in Group C. The tongue area was
      larger in Groups N (36.0 +/- 2.3 cm2) and O (39.3 +/- 2.7 cm2) than in Group C
      (33.3 +/- 3.4 cm2). There was a positive correlation (R2 = 0.670) in all subjects
      between tongue area and body weight. There was also a positive correlation (R2 =
      0.656) between tongue area and the distance between the ANS and the base of the
      epiglottis in the 103 subjects, the base of the epiglottis being shifted to a
      posteroinferior position as a result of the enlarged tongue. The findings suggest
      that micrognathia is a morphological characteristic of the Japanese patients with
      SAS. Micrognathia and enlargement of the tongue and soft palate due to obesity,
      were considered to be involved in the narrowing of the airway in SAS patients.

PMID- 8667596
TI  - Dental care works and work-related complaints of dentists.
AB  - To clarify the relationship between daily performed dental practices and work
      related physical complaints by dentists, we examined 16 male dentists who worked
      at their clinic in an urban district. Each subject answered a questionnaire
      concerning work-related complaints and was examined by a time study of daily
      actions. The electromyograms of back muscles were taken from ten different
      positions. Approximately 62% of the daily practice was occupied by the dental
      care work. The dental care postures were classified into 3 types according to the
      inclination of the body. The most common posture was a right-forward position.
      The prevalence of complaints including problems with eyes, hands and arms, neck
      and shoulders and low back differed among 3 types. The order of complaints was
      neck and shoulders, eyes, and low back. The amplitude of the electromyograms was
      increased by the extension of the muscles to lateral bending of 30 degrees and
      internal rotation of 15 degrees. These results suggest that the body positions of
      daily dental care practices cause an increase in work-related complaints in
      dentists.

PMID- 8667595
TI  - Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients.
AB  - Antineoplastons, which were firstly described by Burzynski, are naturally
      occurring peptides and amino acid derivatives which control neoplastic growth. We
      conducted a toxicological study of the Antineoplastons A-10 and AS2-1 in
      combination with other anticancer agents or radiation in 42 patients, 46 tumors
      with terminal stage cancer. Antineoplaston A-10 oral formulation and A-10
      injectable formulation was administered in 14 and 25 patients respectively. The
      maximum daily dose was 10 g and 40 g, respectively and the longest term of
      administration was 610 days and 67 days, respectively. Antineoplaston AS2-1 oral
      formulation and AS2-1 injectable formulation was administered in 33 and 10
      patients, respectively, the maximum daily dose was 12 g and 30 g, respectively,
      and the longest term was 1070 days and 25 days, respectively. The major adverse
      effects that may have been related to these agents as used in combination with
      other conventional chemotherapeutic agents or radiation were general weakness,
      myelosuppression, and liver dysfunction, but these effects were not seen when
      either Antineoplaston was administered alone. The minor adverse effects observed
      in single use of either Antineoplaston A-10 or AS2-1 were excess gas,
      maculopapullar rash, fingers rigidity, reduced cholesterol, reduced albumin,
      increased amylase, eosinophilia, increased alkaline phosphatase, headache,
      hypertension, palpitation, peripheral edema but these adverse effects did not
      limit to continuation of either agent. The evaluation of the usefulness of the
      Antineoplastons in combination therapy based on the imaging findings during the
      course of treatment revealed disappearance or measurable shrinkage of the tumor
      lasting more than one months as visualized by magnetic resonance imaging or
      computed tomography was seen in 15 tumors (32.6%). No increase in size of tumor
      for more than 3 months was observed in 8 (17.4%). The mean survival time of these
      patients was significantly longer than that in patients with tumors showing
      progressive increasing (17.52 + 3.31 months vs 4.80 + 0.65 months, p < 0.005).
      Antineoplaston A-10 and AS2-1 are less toxic than conventional chemotherapeutics
      and they were useful in maintenance therapy for cancer patients.

PMID- 8667597
TI  - A chemiluminescence procedure for determination of the release of myeloperoxidase
      from activated human neutrophils.
AB  - A chemiluminescence (CL) procedure was developed to determine the time course of
      the release of myeloperoxidase (MPO) from activated human neutrophils using two
      CL probes, luminol, and MCLA. Luminol-dependent CL (LDCL) and MCLA-dependent CL
      (MDCL) in a hypoxanthine (HX)/xanthine oxidase (XOD) system, both of which were
      completely inhibited by superoxide dismutase, were a linear function of the XOD
      concentration, with the relationship formula being LDCL = 0.003 x MDCL. Under the
      same conditions, MPO could enhance LDCL in a dose-dependent manner, without
      influencing MDCL. There was a linear correlation between the MPO concentrations
      and the values of (LDCL-0.003 x DCL) (coefficient of correlation = 0.004). This
      correlation made it possible to determine the release of MPO in the
      neutrophil/stimulus system by simultaneously monitoring the generation of LDCL
      and MDCL. By this CL procedure, it was revealed that there were variations in
      both neutrophil MPO releasing patterns and levels depending on the stimulating
      agent used.

PMID- 8667598
TI  - Health diary study on illness in rural northeast Thailand.
AB  - A health diary was used for measurement of illnesses in the northeast rural area
      of Thailand during the month of November, 1992. Target population were villagers
      residing in 12 villages which were randomly selected from 2 districts in Khon
      Kaen province. Three hundred forty-five households (1690 subjects) were selected
      for the study from all households in those 12 villages. The sample represented
      22.2% of all households. Each respondent was instructed how to record illness
      which may occur among family members during the observation period. Demonstration
      of recording was performed as well to ensure uniform reporting. Frequency of ill
      persons among the 1690 members of the selected 345 households was 299 persons
      (17.7%) in 333 episodes. The ratio of males to females for the reported illnesses
      was 1:1.18. The most common illnesses were common cold, fever, and abdominal
      pain, which occurred in 78, 59, and 47 episodes, respectively, followed by
      headache, and cough. According to the WHO international classification of
      diseases, diseases of the respiratory system were prevalent (26.1% of total
      episodes). Types of illness among age groups 0-1 years and 2-5 years were common
      cold followed by fever. The others two age groups; 16-45, 46-65 years were ill
      with abdominal pain as the first rank followed by common cold. Fever and common
      cold were the most frequent illness in age group 6-15 years and the elderly
      respectively.

PMID- 8667599
TI  - Epidemiological assessment of an intervention trial to increase calcium intake in
      female college students.
AB  - An educational intervention trial to increase calcium (Ca) intake was conducted
      on female college students taking a dietician course and the efficacy of the
      trial was assessed by a prospective cohort study. The one hundred and eight 18-
      or 19-year-old students were divided into two cohorts, i.e., a control group and
      an intervention group. The educational intervention was given to the intervention
      group only and both group received 3 surveys, before the intervention (baseline,
      BL), 1 week after the intervention (WAI), and 1 year after the intervention
      (YAI). The amount of Ca intake at BL did not differ significantly between the
      cohorts. The Ca intake of the control group did not change significantly in the 3
      surveys. The intervention group significantly increased Ca intake at WAI and
      maintained a higher level of Ca intake at the time of YAI. These results suggest
      some efficacy of the educational intervention to increase Ca intake in the female
      college students.

PMID- 8667600
TI  - Effect of low dosage inhaled nitric oxide on pulmonary hypertension in congenital
      heart disease.
AB  - An evaluation of the pulmonary vascular resistance and the reversibility of
      pulmonary vascular reaction in children with congenital heart disease is
      essential for determining the surgical indication and for assessing the long-term
      prognosis. We report the clinical efficacy of low dosage inhaled nitric oxide and
      investigate the relationship between its effect and hemodynamic parameters in 18
      patients with congenital heart disease. The patients were divided into 3 Groups;
      Group 1 consisting of 3 patients with Eisenmenger syndrome, Group 2 of 10
      patients whose mean pulmonary artery pressure was more than 30 mmHg, and Group 3
      consisting of 5 patients whose mean pulmonary artery pressure was less than 30
      mmHg. High concentration (90%) oxygen, and also normal oxygen (21%) containing 10
      parts per million nitric oxide were administered by cardiac catheterization. In
      Group 1, both the 90% oxygen and the normal oxygen with nitric oxide showed no
      affect on the hemodynamical variables. In Group 2, the pulmonary artery pressure
      and the pulmonary vascular resistance both significantly decreased with the 90%
      oxygen, and with the nitric oxide inhalation, but these decreases were not found
      in Group 3. In the 15 patients (of Groups 2 and 3 combined) who were considered
      to have reversible pulmonary vascular changes, significant correlations were
      found between the baseline pulmonary artery pressure and the magnitude of
      pulmonary vasodilation. No clinical evidence of toxicity was seen with the
      administration of the inhaled nitric oxide. These data suggested that inhaled
      nitric oxide, even in a low dosage, was a potent and selective pulmonary
      vasodilator in patients with congenital heart disease complicated with pulmonary
      hypertension. Since a positive correlation was found between the baseline
      pulmonary artery pressure and the magnitude of pulmonary vasodilation, this
      examination demonstrated potential efficacy for objective analysis in patients
      with pulmonary hypertension.

PMID- 8667601
TI  - Enhanced expression of bcl-2 inhibits apoptosis in cultured human keratinocytes.
AB  - The molecular mechanisms regulating epidermal differentiation and apoptosis have
      not been elucidated. Bcl-2, one of the candidate genes for suppressing apoptosis,
      was originally cloned from the breakpoint of at (14;18) translocation present in
      many human B cell lymphomas. In this study, the influence of bcl-2 on apoptosis
      was observed in transfected keratinocytes. After transfection of pEF-BOS vector
      with/without bcl-2, the expression of coded protein and the viability under
      starved conditions were examined. The bcl-2-transfected keratinocytes had
      cytoplasmic positive staining with anti-bcl-2 monoclonal antibodies, however the
      vector only transfected cells were devoid of the reaction products. The viability
      of transfected keratinocytes under starved conditions, with a lack of epidermal
      growth factor and bovine pituitary extract, was maintained in bcl-2 transfected
      cells; while the vector only transfected cells showed apoptotic cell death. The
      present result indicates that bcl-2 suppresses apoptotic cell death under starved
      conditions due to a lack of epidermal growth factor and bovine pituitary extract.

PMID- 8667602
TI  - Effect of a helium-neon laser on cutaneous inflammation.
AB  - A Helium-Neon (He-Ne) laser with a wavelength of 632.8 nm is known to have
      photobiological effects and is widely used for reducing the pain of herpes zoster
      and accelerating wound healing, however the cellular mechanism and effect of the
      He-Ne laser are poorly understood. The present study was designed to examine the
      influence of He-Ne laser irradiation on irritant and allergic contact dermatitis
      of the mouse ear and on histamine release from rat peritoneal mast cells.
      Irradiation was applied with a He-Ne laser (12.2 J/cm2) at 1 h, 10 min, 5 min and
      0 min before, and 5 min, 6 hs and 24 hs after a challenge of an irritated contact
      dermatitis (ICD) or allergic contact dermatitis (ACD) was made on the right ears
      of ICR-mice. Twenty-four hours after the challenge, the swelling of the ear was
      measured with a dial thickness gauge, and the anti-inflammatory effect of He-Ne
      laser irradiation was expressed as an ear thickness ratio (ETR). Although the
      laser did not decelerate the ETR from ICD, the allergic response was decelerated.
      Irradiation at 5 min after the challenge of contact dermatitis increased the
      thickness ratio. Next, the influence of the He-Ne laser on histamine release from
      Wistar-rat peritoneal mast cells was observed. The spontaneous histamine release
      was inhibited by laser irradiation, while substance P and compound 48/80-induced
      histamine release were not inhibited. From these results, it can be suggested
      that He-Ne laser irradiation has an anti-inflammatory effect on cutaneous
      inflammation.

PMID- 8667603
TI  - A case of acute exacerbation of chronic hepatitis B accompanied by antibody to
      HBeAg with remission of liver damage after long-term treatment with interferon.
AB  - The patient was a 47-year-old female with chronic hepatitis B having antibody to
      HBe antigen (HBeAg). She was admitted to our hospital in March, 1994, because of
      acute exacerbation of chronic hepatitis B. Laboratory data revealed the elevated
      serum transaminase and DNA-polymerase levels, and decreased prothrombin activity.
      The histological examination of the liver showed chronic active hepatitis with
      severe hepatic necrosis. Point mutation of the precore region of HBV-DNA (pre-C
      mutant) was observed in clones from this case by polymerase chain reaction
      method. The patient was treated with recombinant interferon alpha-2a 9 MU daily
      for 2 weeks and thereafter 3 times weekly for 6 months. After interferon therapy,
      the pre-C mutant disappeared with the improvement of transaminase levels and
      prothrombin activity. These findings suggest the possibility that long-term
      treatment with interferon therapy is effective for the acute exacerbation of
      chronic hepatitis B accompanied by antibody to HBeAg.

PMID- 8667604
TI  - Thyroid dysfunction induced by interferon therapy for the treatment of hepatitis
      type C. A report of 4 cases.
AB  - We describe 4 patients with onset or aggravation of thyroid dysfunction induced
      by interferon (IFN) treatment of hepatitis type C. All 4 patients were females; 2
      had hyperthyroidism and 2 had hypothyroidism during or after IFN therapy. The
      onset or aggravation of thyroid dysfunction occurred during administration of IFN
      in 1 patient and 4 weeks after the end of IFN therapy in the remaining 3
      patients. The 2 patients who demonstrated hyperthyroidism were euthyroid and
      negative for thyroid autoantibodies before receiving IFN therapy. The remaining 2
      patients who demonstrated hypothyroidism were positive for thyroid autoantibodies
      before IFN therapy. One of these patients had a slight decrease in thyroid
      function before IFN therapy. Anti-thyroid stimulating hormone (TSH) receptor
      antibodies became positive in all 4 patients. Since there may have been a causal
      relationship between IFN therapy and the onset or aggravation of thyroid
      dysfunction, IFN therapy should be administered with caution.

PMID- 8667605
TI  - Retention of p53val135 wild-type function in transgenic mice.
AB  - We targeted a mutant p53 gene (val135), previously shown to cause tumors in
      transgenic mice, to the kidney and eye using a gamma-glutamyltranspeptidase
      promoter. Although transgene RNA was expressed in both tissues, and mutant
      protein could be detected at high levels in the kidney and was appropriately
      localized to the nuclei of proximal tubules, no gross or microscopic lesions
      developed, even when mice were held as long as 75 weeks. When these mice were
      crossed with transgenic mice carrying HrasT24 (containing a codon 12 mutation)
      driven by the same promoter, the p53val135 transgene partially suppressed the
      mutant ras phenotype (proximal tubular hyperplasia and adenomas and carcinomas of
      the ciliary body and retinal pigment epithelium). The kidneys of double
      transgenic mice younger than 25 weeks showed less tubular hyperplasia and cystic
      change than littermates carrying gamma-glutamyltranspeptidase(I)rasT24 alone. By
      33 weeks, there was no difference in the severity of the kidney lesions. The eye
      lesions were less aggressive, and no malignant lesions were identified. Our
      findings are consistent with the work of others, indicating that p53val135 is not
      tumorigenic under all conditions; in fact, in some circumstances, it retains some
      of the suppressing activity of wild-type p53.

PMID- 8667606
TI  - Poly-D-glutamic acid induces an acute lysosomal thesaurismosis of proximal
      tubules and a marked proliferation of interstitium in rat kidney.
AB  - Renal damage caused by polycationic peptides is well documented, but renal damage
      caused by polyanionic peptides is not. During our attempts to inhibit the
      nephrotoxicity of aminoglycoside antibiotics by polyanionic peptides, we
      discovered that poly-D-glutamic acid (molecular weight, 20 kd; 250 mg/kg/day
      subcutaneously for 1 to 4 days) produces an acute thesaurismosis in the proximal
      tubular cells associated with a marked proliferation of peritubular interstitial
      cells in rat kidney. Thesaurismotic bodies were easily visualized by light
      microscopy at the basal pole of proximal tubular cells with the cationic stain
      Giemsa. By electron microscopy, these bodies appeared membrane-limited,
      frequently distorted, filled with heterogeneous granular material, accessible to
      injected peroxidase (a tracer of the endocytic pathway), and generally stainable
      for the lysosomal enzyme arylsulfatase. Specimens obtained 3 hours after
      injection of poly-D-glutamic acid and horseradish peroxidase suggested an
      impairment of endosome and/or lysosome fission, but not fusion. By
      histoautoradiographic examination after 3H-thymidine incorporation, global
      labeling indices of cortical cells were increased 11- to 18-fold in poly-D
      glutamic acid-treated rats as compared with controls, with > 80% of labeled cells
      localized in the interstitium. Distal tubular and glomerular cells also showed a
      moderate proliferation, but proximal tubular cells showed no significant necrosis
      or proliferation. Although tubular thesaurismosis persisted, interstitial cell
      proliferation resolved within 7 days after cessation of treatment. We suggest
      that poly-D-glutamic acid is a convenient tool to induce a rapid and sustained
      lysosomal storage disorder. It could also help clarify the relationship between
      insults to tubular cells and proliferation of peritubular cells, two features
      frequently associated in tubulointerstitial disorders. The mechanism of the
      thesaurismosis and of the interference with the dynamics of fusion-fission of the
      endocytic apparatus are addressed in the companion paper.

PMID- 8667607
TI  - Mechanism of the thesaurismosis and altered lysosomal dynamics induced by poly-D
      glutamic acid in kidney proximal tubular cells.
AB  - In the companion paper, we report that a single injection of poly-D-glutamic acid
      causes an acute lysosomal storage condition and apparently impairs the lysosomal
      fission dynamics. The present paper addresses the mechanisms of these two
      alterations using a combination of in vivo and in vitro biochemical approaches.
      After a single intravenous injection, 14C-poly-D-glutamic acid was rapidly
      cleared from the plasma and appeared in the urine. Yet, a small but sizable
      fraction of the injected polymer was taken up by the kidney cortex through a
      saturable process (Kuptake, 150 mg/kg body wt; uptakemax 96 micrograms/g cortex).
      Analytical subcellular fractionation of cortex homogenates demonstrated that at
      initial stages, the 14C label was predominantly associated with subcellular
      particles of intermediate size and low equilibrium density, and was therefore
      slowly transferred to larger particles equilibrating at high density, then
      codistributing with the lysosomal hydrolases. At a concentration of 10 mg/ml
      (equivalent to its estimated concentration in lysosomes), poly-D-glutamic acid
      formed micronic aggregates ( > or = 10 microns) when brought to solution at pH <
      or = 6 in relation to its decreased ionization (pKa of lateral chains
      approximately equal to 4.25). Finally, 1 day after the injection of poly-D
      glutamic acid, the activities of several lysosomal enzymes (hexosaminidase,
      cathepsin B, acid sphingomyelinase, and sulfatase B), but not of all of them (eg,
      acid phosphatase), were increased in the kidney cortex. We propose that poly-D
      glutamic acid reaches lysosomes by adsorptive endocytosis and becomes
      concentrated within these organelles because its withstands hydrolysis until it
      forms aggregates or precipitates, causing a decrease in the fluidity or the
      deformability ("gelling") of the lysosomal matrix. This should alter the dynamics
      of intercommunication of these organelles by impairing their fission without a
      proportionate effect on their fusion properties. In addition, the data suggest
      that the presence of poly-D-glutamic acid directly or indirectly slows down the
      degradation of several lysosomal enzymes.

PMID- 8667608
TI  - Expression of CD46, CD55, and CD59 on renal tumor cell lines and their role in
      preventing complement-mediated tumor cell lysis.
AB  - Nucleated cells are protected from complement-mediated injury by the expression
      of membrane-bound regulators of complement activation (mRCA) CD46, CD55, and
      CD59. Increased expression of these mRCA may be a mechanism by which tumor cells
      protect themselves from complement-mediated injury and prevent an inflammatory
      response. In the present study, we have investigated whether human renal tumor
      cell lines and cultured proximal tubular epithelial cells express CD46, CD55, and
      CD59 and whether these mRCA influence complement-mediated lysis of these cells.
      The expression of CD46, CD55, and CD59 was measured by flow cytometry. To
      determine the effect of mRCA on lysis, tumor cells were opsonized with complement
      activating anti-HLA class l mAb. Lysis was measured in the presence or absence of
      anti-CD46, anti-CD55 or anti-CD59 mAb and serum as a source of complement, using
      a 51Cr release assay. Flow cytometric analysis revealed that renal tumor cell
      lines and proximal tubular epithelial cells all express CD46, CD55, and CD59.
      Lysis of renal tumor cell lines in the presence of rabbit serum depended on the
      number of HLA class I molecules expressed by the tumor cells. Using human serum,
      complement-mediated lysis was decreased by at least one-third as compared with
      rabbit serum. The susceptibility of renal tumor cells for complement-mediated
      lysis could be increased up to the level observed with rabbit serum by inhibiting
      the function of CD59. Inhibition of the function of CD46 or CD55 with mAb
      directed against these mRCA had no substantial effect on lysis. We conclude from
      this work that renal tumor cells and proximal tubular epithelial cells express
      CD46, CD55, and CD59. Of these mRCA, CD59 is most efficient in preventing
      complement-mediated lysis of these cells. Expression of mRCA on tumor cells may
      influence the effectiveness of immunotherapy with tumor-associated mAb.

PMID- 8667609
TI  - A single-chain Fv reactive with the Goodpasture antigen.
AB  - Goodpasture's disease is defined by the presence of autoantibodies to the
      glomerular basement membrane and characterized clinically by rapidly progressive
      glomerulonephritis and pulmonary hemorrhage. P1, a murine monoclonal antibody to
      the Goodpasture antigen (the noncollagenous domain of the alpha 3 chain of type
      IV collagen, alpha 3(IV)NC1), has been a valuable reagent in investigating the
      pathogenesis of this disorder. The purpose of this study was to generate and
      characterize a recombinant form of P1 as a single-chain Fv (scFv). First strand
      cDNA was made from RNA extracted from the P1 hybridoma cell line, and DNA
      encoding the antibody light and heavy chain variable domains was amplified by
      polymerase chain reaction, using universal oligonucleotides. The purified
      products were ligated sequentially into an expression plasmid separated by a
      sequence encoding a 15 amino acid flexible oligopeptide linker. The resulting
      scFv was expressed in E. coli. Functional scFv, designated HBR-3, was obtained by
      denaturing and refolding the expressed product. HBR-3 was shown by ELISA,
      immunoblotting, and immunohistologic techniques, to have the same specificity for
      alpha 3(IV)NC1 as P1 and autoantibodies from patients with Goodpasture's disease.
      HBR-3 and P1 were shown to have similar affinity for their mutual ligand. On
      sections of normal human kidney, the scFv bound only to glomerular basement
      membrane and distal tubular basement membrane. It did not bind to the glomerular
      basement membrane of patients with Alport's syndrome, in whom the Goodpasture
      antigen is often not expressed in an antigenic form. We have, therefore,
      generated a scFv which reproduces the specific binding properties of the parent
      monoclonal antibody, P1. The potential of HBR-3 as a diagnostic reagent in
      Alport's syndrome has been demonstrated. The development of this recombinant
      molecule should permit new approaches to the investigation of Goodpasture's
      disease.

PMID- 8667610
TI  - Increased expression of direct gene transfer into skeletal muscles observed after
      acute ischemic injury in rats.
AB  - The direct injection of plasmid DNA into skeletal muscles represents a novel
      strategy that is potentially applicable to lower limb ischemic diseases. Most
      previous studies that involved skeletal muscle gene transfer have used only
      normal animals, however, and the efficiency of gene transfer into the ischemic
      muscles has not yet been well characterized. Accordingly, we sought to determine
      the extent to which gene expression is altered by performing skeletal muscle
      transfection under ischemic conditions. The femoral artery was ligated in one
      limb to induce limb ischemia in rats. The rectus femoris muscle of the
      ipsilateral limb was transfected 0 to 14 days later with the plasmid pRSVLUC,
      which contains the firefly luciferase coding sequence. Muscles of the
      contralateral nonischemic limb also were transfected in an identical fashion to
      serve as controls. At the end of the study, the rectus femoris muscle of the
      ischemic limb showed a significant reduction in weight compared with the controls
      (0.99 +/- 0.02 mg vs 1.07 +/- 0.03 mg, p < 0.0001), which demonstrates that the
      ligation of the femoral artery created significant limb ischemia in this animal
      model. Luciferase expression was readily detected in all 98 transfected limb
      muscles from 49 rats but not in nontransfected muscles or other organs. The
      relative luciferase activity (ischemic limb to nonischemic limb) calculated for
      each rat was 1.64 +/- 0.49 at Day 0. It significantly increased after Day 4 (3.76
      +/- 1.33), reached its peak at Day 7 (9.00 +/- 3.38, p < 0.05), and declined to
      the base-line levels by Day 14 (1.44 +/- 0.43). These in vivo results indicate
      that gene expression after skeletal muscle transfection is significantly
      augmented by transfecting genes under ischemic conditions, which may have
      potential implications to increase the efficacy of gene therapy for lower limb
      vascular occlusive disease.

PMID- 8667611
TI  - Oxidative modification of low-density lipoprotein enhances the murine mesangial
      cell cytokines associated with monocyte migration, differentiation, and
      proliferation.
AB  - The oxidative modification of atherogenic lipoproteins has been proposed to
      induce critical interactions between the monocytes and glomerular cells that are
      mediated by the expression of adhesion molecules and monocyte chemoattractants.
      Because increased localization of atherogenic lipoproteins, including oxidatively
      modified low-density lipoprotein (ox-LDL) and monocytes, has been seen in
      experimental glomerulosclerotic lesions, we examined the ability of ox-LDL to
      activate mesangial cells to express macrophage-colony stimulating factor (M-CSF)
      and the murine homologue of human monocyte chemotactic protein-1 (JE/MCP-1) and
      to induce monocyte migration and proliferation. Incubation of mesangial cells
      with ox-LDL markedly increased M-CSF and JE/MCP-1 gene expression dose
      dependently when compared with native LDL. The biologic activity of lipoprotein
      induced M-CSF secretion by mesangial cells was examined by adding aliquots of
      native or ox-LDL-activated mesangial cell-conditioned media to bone marrow cells
      in a methylcellulose semisolid culture dish. Conditioned media from ox-LDL
      activated mesangial cells enhanced the growth of bone marrow progenitor colonies
      when compared with either control or native LDL-activated cell media. The
      increase in progenitor colony formation in response to either LDL or ox-LDL could
      be attenuated by the addition of anti-M-CSF. The conditioned media obtained from
      lipoprotein-activated mesangial cells increased the incorporation of 3H-thymidine
      into monocyte DNA that could be attenuated by the addition of anti-M-CSF.
      Finally, the supernatant that was obtained from mesangial cells activated with ox
      LDL-stimulated monocyte migration dose-dependently when compared with media that
      were obtained from cells incubated with native LDL. Increased monocyte migration
      could also be blocked by the addition of anti-JE/MCP-1. The results of these
      studies indicate that oxidative modification of LDL further enhances its potency
      to induce renal injury by stimulating M-CSF and JE/MCP-1 expression. Thus, the
      data suggest that ox-LDL may play a critical role similar to that of systemic
      vascular cells in the pathobiologic cellular events associated with
      glomerulosclerosis by increasing monocyte recruitment, retention, and
      proliferation within the mesangium.

PMID- 8667612
TI  - Effect of poly(vinylsulfonate) on murine AA amyloid: a high-resolution
      ultrastructural study.
AB  - In experimental murine inflammation-associated amyloidosis (AA amyloidosis), an
      interaction between heparan sulfate and serum amyloid A (SAA), the AA precursor,
      has been demonstrated and is believed to play an important role in AA
      amyloidogenesis. Poly(vinylsulfonate) sodium salt (PVS) can arrest AA amyloid
      induction and cause established amyloid deposits to regress. PVS is thought to
      have this property by virtue of limited anionic structural similarities it has to
      heparan sulfate. In the present study, a comparison has been made of the in situ
      light microscopic and high-resolution ultrastructure of amyloid deposits before
      and after PVS treatment. As shown recently in situ, AA fibrils from untreated
      mice are composed of an outer layer of heparan sulfate proteoglycan and a 1- to 2
      nm filament network of AA protein. This layer encloses a microfibril-like
      structure composed of chondroitin sulfate proteoglycan wound around a core of
      amyloid P component. After treatment with PVS, both the heparan sulfate
      proteoglycan and the AA filament network are lost from the fibrils, and the more
      central portion disintegrates into the chondroitin sulfate proteoglycan with
      associated amyloid P subunits. These findings add further support to the concept
      that heparan sulfate proteoglycan is important in amyloid fibril structure, and
      interference with its binding interactions with the amyloid filament protein
      provides a point of therapeutic attack.

PMID- 8667613
TI  - Altered expression of basement membrane proteins and their integrin receptors in
      lichen planus: possible pathogenetic role of gelatinases A and B.
AB  - Lichenoid lesions of the skin are characterized by a band-like dermal
      inflammatory infiltrate and structural alterations of the basement membrane (BM).
      The etiopathogenesis of these lesions, of which lichen planus (LP) is perhaps the
      prototypic example, is unknown. Acute cases of LP are accompanied by the
      destruction of epidermal BM, degeneration of basal keratinocytes with loss of
      tonofilaments and hemidesmosomes, vesicular alterations, and even blister
      formation. Chronic LP is characterized by hyperkeratosis and acanthosis in the
      epidermis, fibrosis, and dense infiltrate in dermis. We found that acute LP
      lesions are characterized by uneven or absent immunostaining for laminin-5,
      laminin-1, and collagen type IV. Distribution and activity of gelatinases matrix
      metalloproteinase (MMP)-9 and MMP-2, and a specific inhibitor of MMP-2, tissue
      inhibitor of metalloprotein-2, were analyzed. The expression and activity of MMP
      2 were increased, whereas tissue inhibitor of metalloprotein-2 expression was
      weak in the involved areas during the acute phase of LP. Moreover, we
      demonstrated in vitro that MMP-2 is directly capable of digesting laminin-5 gamma
      2 chains to yield a 80-kd fragment. We also observed a weak or absent staining of
      all examined integrin receptors in the acute LP lesions. In chronic lesions, the
      staining of BM components was similar to normal controls. In these sections,
      normal expression of gelatinases and inhibitor was observed. There was, however,
      up-regulation and altered polarity of integrin receptors. These results indicate
      a link between overexpression of gelatinases, BM disruption, and altered integrin
      expression. In LP, the digestion of BM by MMP-2 may contribute to the
      pathogenesis by inducing altered integrin expression in basal keratinocytes and
      ultimately blister formation.

PMID- 8667615
TI  - The lethal hemolytic mutation in beta I sigma 2 spectrin Providence yields a null
      phenotype in neonatal skeletal muscle.
AB  - Point mutations in beta I sigma 1 spectrin that impair the self-association of
      spectrin alpha beta heterodimers cause mild to severe hemolytic disease and
      erythrocyte shape abnormalities. Most such mutations act in a dominant negative
      fashion. One mutation that is particularly devastating is found in beta spectrin
      Providence. The Providence mutation replaces serine2019 with proline.
      Heterozygotes display microcytic and fragile erythrocytes; homozygotes die in the
      neonatal period. It has recently been determined that an alternative transcript
      of the same beta I sigma 1 spectrin gene expressed in erythroid lineage cells is
      the major spectrin in skeletal and cardiac muscle and in some neurons. Because
      the site of the Providence mutation is common to both beta I sigma 1 and beta I
      sigma 2 spectrin, defective protein must also be expressed in these tissues. Yet
      the impact of this or any other beta I spectrin mutation outside of the red cell
      is unexplored. To address this question with respect to skeletal muscle, we have
      examined the effects of the Providence mutation in cultured muscle cells, after
      adoptive gene transfer to adult mice, and in two infants homozygous for spectrin
      Providence. Transfection of the FLAG epitope tagged wild-type beta I sigma 2 or
      Providence beta I sigma 2 cDNA constructs into C2C12 myoblasts demonstrated by
      sedimentation velocity analysis that spectrin beta I sigma 2 Providence formed
      alpha II/-beta I sigma 2 heterodimers in muscle cells but not heterotetramers.
      Correspondingly, wild-type beta I sigma 2 spectrin formed both alpha II/beta I
      sigma 1 dimers and heterotetramers, although the proportion of dimers was
      surprisingly high, which suggested some limitation on self-association in the
      muscle environment. After adoptive gene transfer into adult mouse skeletal muscle
      in vivo, both the wild-type and mutant beta I sigma 2 spectrins assembled into a
      subsarcolemmal complex in a pattern indistinguishable from the native spectrin
      skeleton. Skeletal muscle taken at autopsy from two infants homozygous for
      spectrin Providence was normal histologically, as was the intracellular
      distribution of beta I sigma 2 spectrin as measured by immunoperoxidase staining.
      These patients also revealed no clinical evidence of myopathy or muscle wasting.
      It is unknown if they would have experienced dystrophic or myopathic changes if
      they had lived longer, although we believe that this is unlikely based on the
      absence of clinical myopathies in patients with other (albeit less severe) beta I
      spectrin self-association defects. Collectively, these observations indicate that
      the spectrin mutations that impact tetramer and oligomer formation, even those
      with a severe hemolytic phenotype, do not impact skeletal muscle function
      primarily because skeletal muscle does not use the oligomerizing feature of the
      spectrin skeleton to the same degree as erythrocytes.

PMID- 8667614
TI  - Strong expression of vascular permeability factor (vascular endothelial growth
      factor) and its receptors in ovarian borderline and malignant neoplasms.
AB  - Angiogenesis is a critical factor in the growth, progression, and metastatic
      spread of solid tumors. Furthermore, angiogenesis has been correlated with
      prognosis in patients with ovarian cancer. The pathogenesis of the angiogenic
      events in ovarian cancer, however, are not well defined. Vascular permeability
      factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional
      cytokine that has been shown to be an important regulator of tumor angiogenesis.
      The purpose of the present study was to define the expression of VPF/VEGF and its
      receptors flt-1 and KDR in ovarian tumors. Four specimens of normal ovarian
      cortex and 41 specimens of benign (4), borderline (8), and malignant (29) ovarian
      tumors were studied by in situ hybridization, and in some cases by
      immunohistochemical analysis. VPF/VEGF protein was also determined by an
      immunofluorometric assay in cyst fluids obtained from 11 patients, including 7
      benign, 2 borderline, and 2 malignant tumors. VPF/VEGF mRNA and protein were
      expressed by the neoplastic cells in all of the malignant tumors evaluated, with
      the majority of tumors (28 of 29) showing strong expression of mRNA. Serous
      borderline tumors had variable VPF/VEGF mRNA expression, with two of six cases
      showing focal strong expression and four showing low-level expression. No
      definite expression of VPF/VEGF was seen in two cases of mucinous borderline
      tumors. No strong expression of VPF/VEGF mRNA was observed in normal ovarian
      cortex, including surface epithelium, or benign tumors. Substantially higher VPF
      protein concentrations were detected in cyst fluids of the two malignant (60, 440
      pM) and two borderline tumors (210, 590 pM) than in the seven benign serous cysts
      (mean, 10 +/- 3 pM). In addition, microvascular endothelial cells strongly
      expressed mRNA of the VPF/VEGF receptors flt-1 and KDR and immunostained for
      VPF/VEGF protein in the majority of malignant and borderline tumors examined.
      These findings suggest that VPF/VEGF plays an important role in the angiogenesis
      associated with ovarian neoplasms.

PMID- 8667616
TI  - Growth factors in the regenerating pancreas of gamma-interferon transgenic mice.
AB  - We examined the distribution of several relevant growth factors in gamma
      interferon transgenic mice, which undergo continual growth and differentiation in
      the pancreas. As a result, epidermal growth factor (EGF), TGF-alpha, and the EGF
      receptor were identified as potentially important in mediating some of these
      regenerative changes. Transient up-regulation of EGF, TGF-alpha, and the EGF
      receptor were observed in acini undergoing differentiation into duct-like
      structures. These ducts have been shown to proliferate and potentiate
      regeneration of the pancreatic islet mass.

PMID- 8667617
TI  - Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive
      renal disease.
AB  - Several lines of evidence suggest that local production of transforming growth
      factor-beta (TGF-beta) contributes to renal disease, particularly to the
      accumulation of the extracellular matrix protein that characterizes
      glomerulosclerosis and interstitial fibrosis. We have examined whether elevated
      levels of circulating TGF-beta adversely affect the kidney. We have studied mice
      that are transgenic for an active form of TGF-beta 1 under the control of murine
      albumin promoter and enhancer DNA sequences. These mice express the transgene
      exclusively in the liver and have elevated plasma concentrations of TGF-beta 1.
      Renal disease was seen in two of three lines of Alb/TGF-beta 1 transgenic mice;
      these two lines had the highest levels of hepatic transgene expression and the
      highest plasma TGF-beta 1 levels. Histologic abnormalities, which included
      mesangial expansion and thickened capillary loops, were noted in the glomeruli by
      3 weeks of age. Interstitial fibrosis and tubular atrophy appeared subsequently.
      Mice from Line 25, the line with highest levels of TGF-beta 1, developed
      proteinuria by 5 weeks of age. These mice subsequently manifested nephrotic
      syndrome with ascites and progressive azotemia; uremic death occurred in more
      than 25% of the mice by 15 weeks of age. The glomeruli contained immune deposits
      in subendothelial and mesangial locations, but complement deposition was
      infrequent. Ultrastructural examination revealed an increase in extracellular
      matrix material, including collagen fibrils, in subendothelial and mesangial
      locations. Increased levels of circulating TGF-beta 1 induced progressive renal
      disease that was characterized by mesangial expansion, accumulation of glomerular
      immune deposits and matrix proteins, and interstitial fibrosis in this transgenic
      mouse model. These data suggest that chronically elevated circulating levels of
      TGF-beta 1 induce progressive glomerulosclerosis.

PMID- 8667618
TI  - Apical and basolateral Ca(2) channels modulate cytosolic Ca(2)+ in gallbladder
      epithelia.
AB  - Gallstone formation is associated with altered gallbladder (GB) ion transport and
      increased concentration of GB bile Ca2+. Recent studies show that increased
      cytosolic Ca2+ ([Ca2+]i) stimulates GB Cl- secretion. However, the mechanism by
      which extracellular Ca2+ ([Ca2+]e) enters the cytosol remains unclear. We tested
      the hypothesis that entry of [Ca2+] into cytosol occurs via apical and
      basolateral membrane Ca2+ channels. Prairie dog GBs were mounted in Ussing
      chambers, standard electrophysiologic parameters were recorded, and
      unidirectional Cl- fluxes (J, microEq x cm(-2) x hr(-1) were measured using 36Cl
      at various mucosal Ca2+ in the absence or presence of mucosal lanthanum (La3+), a
      non-diffusible Ca2+ channel blocker. Serosal [Ca2+]e was maintained at trace
      levels. In the absence of mucosal La3+, short circuit current (Isc) showed a
      positive correlation with mucosal [Ca2+]e as represented by a second order
      polynomial equation (y = 4.1 + 2.5x - 0.73x(2), r = 0.68, P < 0.001). In
      contrast, unidirectional mucosa to serosa Cl flux (JCl/ms) was inversely
      correlated with [Ca2+] (y = 47.9 - 8.7x + 0.9x(2), r = 0.51, P <.05) Addition of
      1 mM mucosal La3+ blunted the effects of [Ca2+]e on electrophysiologic parameters
      and JCl/ms. However, basolateral repletion with 5 mM Ca2+ reverses the blocking
      effects of La3+ on JCl/ms. These data suggest that [Ca2+]e enters the cytosol via
      apical and basolateral Ca2+ channels. We conclude that GB apical Ca2+ channels
      may represent a pathway for biliary Ca2+ entry into the cell and therefore may
      represent an important regulatory pathway for GB ion transport during gallstone
      formation.

PMID- 8667619
TI  - A phase I trial of a synthetic mucin peptide vaccine. Induction of specific
      immune reactivity in patients with adenocarcinoma.
AB  - We tested a 105 amino acid synthetic mucin MUC-1 peptide that has 5 repeated
      immunodominant epitopes to evaluate toxicity and detect mucin-specific immune
      responses in patients with adenocarcinoma. We also studied the enhancement of
      these responses by vaccinating patients with the synthetic mucin peptide admixed
      with BCG. Mucins are glycoproteins present on the luminal surface of ductal
      epithelial cells and on tumors derived from them. The MUC-1 mucin is
      hypoglycosylated and nonpolarized on tumors and this exposes epitopes that can
      stimulate cytotoxic T-Cells (CTL). We vaccinated 63 patients with 100 micrograms
      of the 105aa mucin peptide mixed with BCG. Two additional vaccinations were given
      at 3-week intervals. All patients were able to tolerate vaccination, with most
      experiencing local ulceration at the vaccination site. All patients underwent
      hypersensitivity (DTH) testing with the 105aa and shorter mucin peptides, prior
      to vaccination. DTH responses were evaluated at 48 hr and the sites of highest
      peptide concentration were biopsied. Only 3 patients had a strong skin response
      to the long peptide. Examination of 55 biopsies showed intense T-Cell
      infiltration in 37 patients and lesser infiltration in 7. Seven of 22 patients
      tested had a 2- to 4-fold increase in mucin-specific CTLp. Serum levels of IL-6
      were measured sequentially using the B9 hybridoma bioassay. Increasing serum
      levels of IL-6 correlated with constitutional symptoms (significance 0.001) and
      hypoalbuminemia (significance 0.007) but not with the extent of skin breakdown at
      vaccination sites. We conclude that mucin vaccination is safe and might serve to
      enhance specific responses to tumor antigens. IL-6 may be responsible for the
      constitution symptoms and hypoalbuminemia in these patients.

PMID- 8667620
TI  - How do we apply genetic testing for breast cancer susceptibility to clinical
      practice?

PMID- 8667621
TI  - Interpectoral nodes in carcinoma of the breast: requiem or resurrection.
AB  - Fifty-eight consecutive patients undergoing a modified radical mastectomy were
      subjected to complete dissection and pathological assessment of the interpectoral
      fascia and the group of lymph nodes it contains. The dissection was carried out
      in all patients, irrespective of whether they were palpable or not. Interpectoral
      nodes (IPNs) were anatomically present in 28 patients (48%) and were completely
      absent in 30 patients (52%). Ten patients were Stage I, 18 were Stage II, and 30
      were Stage III. Of the 25% (15/58) of patients with microscopic metastasis, only
      12/15 had palpable nodes; 66% (10/15) of patients had axillary and apical nodes
      positive. Significantly, two patients with negative nodes in the axillary and
      apical group had metastatic Rotter's nodes. Of the 15 patients with positive
      IPNs, nine had primary tumors located within the upper quadrants of the breast,
      whereas only five had tumors in lower quadrants and one had a centrally located
      tumor. The neurovascular bundle to the pectoralis major could be safely preserved
      in 93% (54/58) of patients. The incidence of impalpable nodes with microscopic
      metastasis and the evidence of exclusively metastatic interpectoral nodes with
      uninvolved axillary and apical nodes prompt the following conclusions: (1)
      interpectoral fascia and nodes should be mandatorily dissected in all patients
      irrespective of the nodes being palpable or not; (2) the dissection is anatomic
      and is associated with almost no additional morbidity; (3) the group of patients
      with IPNs positive and the axillary group negative, would benefit maximally from
      the IPN dissection. Similarly, this dissection in all other groups of patients
      would enable a more accurate staging and selection of therapeutic strategies.

PMID- 8667622
TI  - Cis-diamminedichloroplatinum(II) augments expression of tumor-associated antigens
      on human gastric cancer cell line KATO-3 and increases susceptibility and binding
      of tumor cells to various cytotoxic effector cells.
AB  - Previous studies have demonstrated the immunomodulatory effects of cisplatin
      under certain conditions. The present study was designed to clarify whether
      cisplatin modulates the expression of surface antigens, especially human
      leukocyte antigen (HLA), on human tumor cell lines and/or augments the
      susceptibility and binding of tumor cells to cytotoxic effector cells. A human
      gastric cancer cell line, KATO-3, was employed. The expression of HLA and other
      tumor-associated antigens was analyzed by flow cytometry using FITC-conjugated
      monoclonal antibodies. The cytotoxicity of effector cells was determined by 51Cr
      release assay. The expression of HLA class I antigen, beta2-microglobulin,
      leukocyte function-associated antigen-1, and AC-81 adenocarcinoma-associated
      antigen on KATO-3 increased after exposure to cisplatin at 10 micrograms/ml for 3
      6 hr; augmentation of HLA class I subtypes -B2 and -B27 was particularly
      prominent. Furthermore, the susceptibility and binding of KATO-3 to both
      lymphokine-activated killer cells and KATO-3-specific cytotoxic T lymphocytes
      significantly increased after cisplatin treatment. Cisplatin may modulate the
      expression of tumor-associated antigens on some human tumor cells. Tumor
      regression by cisplatin administration may depend on its direct cytotoxicity as
      well as on its modulating effects on the expression of tumor-associated antigens,
      subsequently leading to the activation of the immune surveillance system against
      the tumor.

PMID- 8667623
TI  - Immunohistochemical expression of sialyl Tn, sialyl Lewis a, sialyl Lewis a-b-,
      and sialyl Lewis x in primary tumor and metastatic lymph nodes in human gastric
      cancer.
AB  - Sialyl Lewis Tn(STN), sialyl Lewis a(CA-9-9), sialyl Lewis a-b-(DU-PAN-2), and
      sialyl Lewis x(SLX) antigens were immunohistochemically examined in the primary
      tumor and metastatic lymph nodes in 35 patients with advanced gastric cancer.
      STN, CA-19-9, DU-PAN-2, and SLX were expressed in 91%, 60%, 31%, and 60% in the
      primary lesion, and 77%, 54%, 22%, and 51% in the metastatic lesion,
      respectively. In only four cases, (11%) were all four antigens expressed in both
      the primary and metastatic lesions. Three antigens were expressed in 49% of
      primary lesions and in 20% of metastatic lesions. Compared with expression in
      primary lesions, increased, unchanged and decreased expressions in metastatic
      lesions were noted in 23%, 37%, and 40% for STN, 20%, 40%, and 40% for CA-19-9,
      17%, 57%, and 26% for DU-PAN-2, and 26%, 31%, and 43% for SLX, respectively.
      These results indicate that the tumor in the primary and metastatic lesions has a
      heterogeneous expression of sialyl-related antigens. However, metastases cannot
      be predicted based upon the expression of these antigens.

PMID- 8667625
TI  - Malignant humeral bone tumors in children: excision and reconstruction with the
      use of rotated clavicle.
AB  - The application of intensive multimodality therapy has made possible salvage
      surgery in bone tumors. Reconstruction of the removed part of bone is the great
      problem, especially in fast-growing children. In three patients (two
      osteosarcomas and one Ewing's sarcoma), the tumor was confined to the proximal
      half part of humerus, without invasion of shoulder joint. After induction
      chemotherapy, reduction of tumor size was observed both clinically and
      radiologically. During the operation, wide resection of the tumor together with a
      12- to 14-cm-long fragment of humerus, was performed. Afterward, the clavicle was
      rotated in the place of the removed bone, with preservation of the coracoacromial
      ligament. The humeral stump and clavicle were fixed with the use of metal plate.
      Adjuvant chemotherapy was used a few days following surgery. After 3 months, the
      osteosynthesis had healed. The movements in shoulder joint are limited, but
      functions of elbow joint remained normal. All children are alive and disease
      free. Reconstruction of humerus with clavicle rotation is possible when the
      proximal bone loss is not longer than 10-14 cm. This method seems to be an
      alternative to allogeneic grafts and endoprostheses.

PMID- 8667624
TI  - Cytolysis of malignant glioma cells by lymphokine-activated killer cells combined
      with anti-CD3/antiglioma bifunctional antibody and tumor necrosis factor-alpha.
AB  - With the aim of developing an effective immunotherapy for malignant glioma,
      glioma cells were incubated with tumor necrosis factor-alpha (TNF-alpha) to
      increase their susceptibility to lysis by lymphokine-activated killer (LAK)
      cells. Treatment with exogenous TNF-alpha induced the expression of intercellular
      adhesion molecule-1 (ICAM-1) on the surface of glioma cells. In addition, the
      cytolytic activity of LAK cells toward exogenous TNF-alpha treated glioma cells
      was significantly greater than LAK cell activity toward untreated glioma cells.
      This increase in cytolytic activity was blocked by anti-ICAM-1 monoclonal
      antibodies (MAb). Furthermore, co-treatment with a bifunctional antibody (BFA)
      composed of anti-CD3 (UCHT1) and antiglioma (G-22) antibodies synergistically
      increased the cytolytic activity of LAK cells towards TNF-alpha-treated glioma
      cells. These results indicate that a combination of exogenous TNF-alpha and anti
      CD3/antiglioma BFA may provide an effective modified adoptive immunotherapy for
      patients with malignant glioma.

PMID- 8667626
TI  - Improvement of pharmacokinetics and antitumor activity against human hepatoma
      cell line by using adriamycin-entrapped stealth liposomes.
AB  - Preferential accumulation in the reticuloendothelial system is one of the major
      obstacles to the use of liposomes as a drug carrier for targeting therapy. To
      reduce their uptake, ganglioside GM1 was introduced into the components of
      conventional liposomes that had been used in our targeting experiments. Two types
      of such liposomes were prepared. Tissue distribution studies on Adriamycin
      entrapped in both types of liposomes clearly indicated that the uptake of
      Adriamycin by liver and spleen decreased to the level comparable to that of free
      Adriamycin administration. By contrast, the level of Adriamycin in the serum
      remains high, and some increase was observed in the accumulation to the tumor.
      Furthermore, Adriamycin in these liposomes, which were conjugated with anti-alpha
      fetoprotein (AFP) antibody, inhibited the growth of AFP-positive human hepatoma
      Li-7 more efficiently than free Adriamycin or Adriamycin in antibody-conjugated
      conventional liposomes.

PMID- 8667627
TI  - Antisense oligonucleotide intralesional therapy for human PC-3 prostate tumors
      carried in athymic nude mice.
AB  - Previously we reported hemorrhagic necrosis in human-derived PC-3 prostate
      tumors, in athymic nude mice, produced by the intralesional injection of
      antisense oligonucleotides (oligos) directed against mRNAs encoding transforming
      growth factor-alpha (TGF-alpha) and its target, the epidermal growth factor
      receptor (EGFR). We now describe our experience with these oligos in treating
      additional mice with various doses and modes of administration. During prolonged
      treatment, a dose-response effect was observed, with the optimal dosage
      consisting of the combination of 400 micrograms of each oligo. Although responses
      varied, based upon amount and how oligos were administered, we found that tumors
      were best treated when initially less than 156 mm3. Intralesional inoculations
      produced necrosis and yielded responses, ranging from complete response (CR) or
      cure to partial responses (PR) in 9 of 12 tumors treated with full dose (400
      micrograms of each oligo) and 1 of 1 treated with 800 micrograms of each oligo,
      against a large tumor. Included among the 9 positive responses with full-dose
      administration were 2 tumors that regressed (one completely). A single tumor
      treated with twice (2X) the normal dosage (800 micrograms of each oligo) also
      regressed. A single tumor treated with half (1/2) dose (200 micrograms of each)
      progressed similar to controls, as did 3 of 12 treated with the full dose.
      Limited experience with ALZET diffusion pumps gave CR (1 of 3) or PR (2 of 3) in
      100% of tumors treated (including one mouse cured of multiple tumors in a five
      day period). It appears that multiple inoculations consisting of 400 micrograms
      of each oligo is most effective against these tumors, particularly when
      administered against tumors of <156 mm3 in initial size.

PMID- 8667628
TI  - Are argyrophilic nucleolar organizer regions good prognostic indicators of
      survival of patients with esophageal cancer with lymph node metastasis?
AB  - Argyrophilic nucleolar organizer regions (AgNORs) were evaluated in 95 samples
      from primary esophageal squamous cell carcinomas and 75 samples from metastatic
      lymph nodes. The number of AgNORs per nucleus in primary tumors with positive
      nodes (n=53, 6.1+/-1.8) was greater than that in primary tumors with negative
      nodes (n=42, 3.8+/-1.1, P<0.001). In 39 of 53 patients with positive nodes, the
      numbers of AgNORs per nucleus in metastatic lymph nodes were lower than those in
      primary tumors. The 5-year survival rate of these patients was 23.7%. However,
      the numbers of AgNORs per nucleus in metastatic lymph nodes were greater than
      those of primary tumors in 14 of 53 patients with positive nodes, and 11 of these
      14 patients died from recurrence of cancer within 3 years after surgery. These
      observations suggest that the proliferative activity of cancer cells might be
      suppressed in the regional lymph nodes. However, cancer cells with higher
      proliferative activity in the regional lymph nodes than in the primary tumors
      might overcome immunological defenses and subsequent further metastasis might
      occur.

PMID- 8667629
TI  - Cancer of the low and middle rectum: local and distant recurrences, and survival
      in 350 radically resected patients.
AB  - The purpose of this study was to compare local recurrence, distant metastases,
      and survival rate in 350 patients with cancer of the middle and low rectum who
      underwent a radical abdominoperineal resection (APER) or a sphincter-saving
      resection (SSR) in our Institute. There were 257 APER patients and 93 SSR
      patients, with a median follow-up of 77 months. At 5 years, the estimates in APER
      and SSR patients were respectively 11% and 30% for the incidence of pelvic
      recurrence, 18% and 8% for the incidence of distant metastases, and 64% and 73%
      for overall survival. In the multivariate analysis it was found that Dukes' stage
      significantly affected pelvic recurrences, distant metastases rate and overall
      survival; histologic type affected only the pelvic recurrence rate. However, the
      final outcome of patients following APER or SSR was similar, suggesting that
      local failure per se does not affect long-term survival.

PMID- 8667630
TI  - Tumor bed implant brachytherapy for residual carcinoma after palliative
      esophagectomy.
AB  - Twenty-six patients with esophageal carcinoma at stage pT4 underwent
      esophagectomy with lymph node dissection leaving part of the tumor in adjacent
      organs. Several plastic catheters were fixed to the tumor bed and led to the
      outside of the thorax for postoperative brachytherapy. Using these catheters, the
      patients underwent brachytherapy followed by external beam irradiation. The
      operative mortality rate was 11.5%. No serious complications resulting directly
      from the brachytherapy occurred. Recurrent disease was found in 17 patients,
      among whom only six had local recurrence. The median survival of the patients was
      314 days, and the 5-year survival rate was 16.2%. Of the 10 patients at stage
      pT4N0, three survived more than three years after surgery. Tumor bed implant
      brachytherapy for residual tumor after esophagectomy is a safe and useful
      treatment strategy for patients with pT4 tumor, especially those without lymph
      node metastasis.

PMID- 8667631
TI  - Primary carcinoid tumor of the liver: report of four resected cases including one
      with gastrin production.
AB  - Four cases of primary hepatic carcinoid were identified during a retrospective
      study of liver resections for primary tumor. The cases included two adult males,
      one adult female, and a 9-year-old boy in whom gastrin levels were documented.
      The estimation of gastrin levels was prompted by symptoms suggestive of acid
      peptic disease. One patient died postoperatively. The other three are alive and
      well at 3 years, 2 years, and at 1 year, respectively, after surgery, outcomes
      distinctly different from hepatocellular carcinomas. Diagnostic difficulties may
      be experienced in histologic assessment, and this may require recourse to
      immunohistochemistry and electron microscopy. Long-term follow-up and careful
      exclusion of a possible primary elsewhere are necessary for establishing the
      primary nature of liver carcinoids.

PMID- 8667632
TI  - Catheter fracture: a rare complication of totally implantable subclavian venous
      access devices.
AB  - Catheter fracture represents a rare problem among non-infectious complications
      following the insertion of totally implantable long-term central venous access
      systems for the application of chemotherapeutic agents. A literature survey
      revealed a total incidence of catheter fractures of 0-2.1%. Imminent catheter
      fracture can be identified radiologically, using different degrees of catheter
      narrowing between the clavicle and the first rib, called pinch-off sign. Two
      cases of catheter fracture are described and potential causes are discussed.
      Recommendations to avoid the pinch-off sign with the subsequent risk of catheter
      fracture and migration include a more lateral and direct puncture of the
      subclavian vein. In case of catheter narrowing in the clavicular-first rib angle,
      patients should be followed carefully by chest X-rays every 4 weeks. Whenever
      possible, the system should be removed within 6 months following insertion.

PMID- 8667633
TI  - Percutaneous biliary stents for palliation of hilar malignancies.

PMID- 8667634
TI  - Breast-conserving treatment: controversies and consensus.
AB  - Although breast-conserving therapy (BCT) is an accepted alternative for the
      treatment of breast cancer, numerous controversies surround the selection
      criteria and the treatment details. A review of the literature revealed that
      patient selection is of critical importance. However, there is disagreement over
      the relative importance of some of the criteria for patient selection. A wide
      excision is preferable to a less complete excision (tumorectomy) or a more
      radical excision (quadrantectomy). Accurate assessment of surgical margins is
      important. The risk of local recurrence may be diminished if a re-excision is
      performed to obtain tumor-free margins. However, the suitability and practicality
      of the techniques used to assess the resection margins have been questioned.
      Radiotherapy is an integral part of BCT. Surgery alone remains an investigational
      approach. Axillary dissection remains a reliable method of assessing nodal status
      and treating regional disease.

PMID- 8667635
TI  - Characterization of cell surface-expressed proteochondroitin sulfate of pre-B
      Nalm-6 cells and its possible role in laminin adhesion.
AB  - Cell surface-expressed proteoglycans mediate contacts to extracellular matrix
      (ECM). Human B lymphocytes produce a species of a proteochondroitin sulfate
      (CSPG) with an approximate molecular mass of 135-150 kDa. Using a monoclonal
      antibody (mAb) against B cell CSPG in flow cytometry we found that this CSPG is
      expressed on tumor cells of patients with CD19+ common acute lymphoblastic
      leukemia and on the corresponding cell lines Nalm-6, Reh and KM3. The CSPG is
      also present on hairy cell leukemia JOK-1 cells and weakly on the myeloma line
      U266. Concomitant with CSPG expression, Nalm-6 cells express the integrins alpha
      5/beta 1 (CD49e/CD29) and alpha 6/beta 1 (CD49f/CD29), adhesion receptors for
      fibronectin and laminin, in contrast to the other two cell lines tested.
      Expression patterns of these adhesion receptors and CSPG were paralleled by
      strong adhesion of Nalm-6 to fibronectin and laminin. Adhesion of Nalm-6 to
      fibronectin was inhibited by the alpha 5-specific antibody SAM 1 by 80% whereas
      the alpha 6-specific antibody GoH3 reduced binding to laminin only by 20%. A
      possible involvement of surface-expressed CSPG in adhesion to ECM components was
      investigated by 24 h incubation of Nalm-6 cells with p-nitrophenyl-beta-D
      xyloside, an inhibitor of proteoglycan glycosylation. By this treatment, both
      adhesion of Nalm-6 to laminin and expression of CSPG were reduced by 40-50%.
      Furthermore, addition of chondroitin-6-sulfate, a structural element of Nalm-6
      CSPG, reduced adhesion of Nalm-6 to laminin by 60%. Chondroitin-4-sulfate,
      heparin and heparan sulfate did not effectively inhibit the adhesion process.
      These observations suggest that surface-expressed CSPG may be involved in binding
      of Nalm-6 cells to laminin and that the specific sulfation pattern of chondroitin
      6-sulfate may be essential in this regard.

PMID- 8667636
TI  - Flt3-ligand production by human bone marrow stromal cells.
AB  - Bone marrow stromal cells are important sources of cytokines and growth factors
      which participate in regulation of proliferation and differentiation of
      hematopoietic stem and progenitor cells. Recently flt3/flk-2-ligand (flt3-L), a
      new growth factor which uses a membrane tyrosine kinase receptor, was cloned. It
      is expressed in transmembrane and soluble forms and stimulates/co-stimulates
      proliferation and colony formation of hematopoietic stem/progenitor cells. It has
      not been reported whether flt3-L is produced by cells of the hematopoietic bone
      marrow microenvironment. We demonstrate the expression of flt3-L in bone marrow
      fibroblasts (BMF) and in stromal cells of adherent layers of long-term bone
      marrow cultures by RT-PCR, Northern blot, immunocytochemistry and FACS analysis.
      The latter two methods localized flt3-L intracellularly and on cell membranes.
      Treatment with interleukin-1 alpha increased the expression of flt3-L in BMF.
      This demonstrates production and modulation of flt3-L in stromal cells of human
      bone marrow.

PMID- 8667637
TI  - Induction of apoptosis by cordycepin in ADA-inhibited TdT-positive leukemia
      cells.
AB  - The nucleoside analogue cordycepin (3'-deoxyadenosine), when protected against
      ADA deamination, is specifically cytotoxic for TdT-positive leukemia cells.
      Cordycepin-treated, ADA-inhibited, TdT-positive cells undergo the classic changes
      associated with drug-induced apoptosis: reduction in cell volume, chromatin
      clumping, membrane blebbing, and 180-bp multimer DNA laddering on agarose gels.
      In common with the apoptosis seen in normal TdT-positive thymocytes, following
      exposure to various agents, apoptosis induced by cordycepin in TdT-positive
      leukemia cells was associated with increased protein kinase A (PK-A) activity.
      Unlike thymocyte apoptosis however, no elevation in cAMP levels was seen
      preceding the rise in PK-A activity. Ex vivo we show that cordycepin
      monophosphate can activate PK-A as efficiently as cAMP. On this basis we
      speculate that cordycepin monophosphate in TdT-positive cells may be able to
      activate PK-A in place of cAMP, and that PK-A may phosphorylate TdT, augmenting
      its activity as an endonuclease. In cell-free experiments, the activity of
      recombinant TdT as an endonuclease digesting supercoiled plasmid DNA into linear
      fragments was dramatically increased following phosphorylation of TdT by PK-A. A
      role for TdT as an apoptotic endonuclease in TdT-positive leukemia cells
      following cordycepin exposure is now the subject of on-going work.

PMID- 8667638
TI  - Establishment and characterization of two novel cytokine-responsive acute myeloid
      and monocytic leukemia cell lines, MUTZ-2 and MUTZ-3.
AB  - Human permanent leukemia cell lines represent powerful research tools in a
      multitude of investigations. The two new continuous leukemia cell lines MUTZ-2
      and MUTZ-3 were derived from the peripheral blood of patients with acute myeloid
      leukemia (AML) FAB M2 and AML FAB M4. MUTZ-2 and MUTZ-3 cells have morphological
      and immunophenotypical features of myeloid and monocytic cells, respectively.
      While MUTZ-2 is negative, MUTZ-3 cells express the monocytic surface marker CD14,
      albeit weakly. The monocytic nature of MUTZ-3 cells is underlined by the
      expression of the monocyte-specific esterase (MSE), myeloperoxidase (MPO) and
      tartrateresistant acid phosphatase (TRAP) enzymes; MUTZ-2 is negative for MSE and
      TRAP, but expresses MPO. For sustained cell growth, both cell lines require
      constitutively the addition of cytokines to the culture medium and retain an
      absolute dependence on conditioned medium or recombinant growth factors for
      proliferation and survival. Incubation with single recombinant cytokines from a
      broad spectrum of growth factors established that the strongest proliferation
      response of MUTZ-2 cells was elicited by FLT-3 ligand, granulocyte colony
      stimulating factor (G-CSF), macrophage CSF (M-CSF), interferon-gamma (IFN-gamma)
      and stem cell factor (SCF), whereas granulocyte-macrophage CSF (GM-CSF), M-CSF,
      interleukin-3 (IL-3) and SCF were the most effective growth factors in inducing
      proliferation of MUTZ-3. Both cell lines were proliferatively responsive to
      several further cytokines, however, to a lesser extent. Exposure to phorbol ester
      12-O-tetradecanoyl-phorbol-13-acetate (TPA) or the physiological all-trans
      retinoic acid (ATRA) had growth-inhibitory and differentiation-inducing effects
      on both cell lines. Using a clonogenic cell recovery assay, both cell lines were
      found to be sensitive to the chemotherapeutic drugs cytosine arabinoside (Ara-C)
      and daunorubicin (DNR), MUTZ-2 cells being more sensitive to both Ara-C and DNR
      treatment than MUTZ-3 cells. Chromosomal trisomies 8 and 10 were found in MUTZ-2
      cells without any additional structural abnormalities. MUTZ-3 carries the rare,
      but recurrent AML-associated translocation (12;22)(p13;q11-q12) reflecting the
      karyotype of the original tumor. The main characteristics of these cell lines
      remained the same during about 1 year of continuous culture as well as after
      freezing and thawing. In summary, we established and characterized two new
      leukemia cell lines with myeloid or monocytic features which are growth factor
      responsive, one of them carrying a unique chromosomal translocation. These cells
      will be of particular value for investigating the complex cytokine network and
      molecular events caused by chromosomal aberrations.

PMID- 8667640
TI  - Specificity of CD117 expression in the diagnosis of acute myeloid leukemia.

PMID- 8667639
TI  - Composition and function of the hemopoietic microenvironment in human myeloid
      leukemia.
AB  - In normal adult mammals, blood cell production, hemopoiesis, takes place within
      the medullary cavity. There, hemopoietic cell proliferation and differentiation
      are regulated by a network of stromal/accessory cells and their products (ie
      cytokines and extracellular matrix molecules), known as the hemopoietic
      microenvironment. Recent in vitro studies indicate that both cell composition and
      functional abnormalities of the hemopoletic microenvironment are present in a
      proportion of patients with myeloid leukemia, both chronic (CML) and acute (AML).
      Cell composition abnormalities have been primarily observed in a subset of
      patients with AML; these abnormalities include reduced numbers of fibroblast
      progenitors and, in some cases, reduced numbers of macrophages and adipocytes. In
      terms of function, it has been shown that the marrow stromal cells from a
      significant number of both CML and AML patients, possess a deficient hemopoletic
      supportive capacity in vitro. This seems to be related to the presence of
      functionally abnormal, malignant macrophages. The mechanisms by which these
      macrophages alter the hemopoietic function of the marrow stroma, as a whole, are
      still not fully understood. Whereas in AML, a macrophage-derived soluble
      inhibitory activity (containing tumor necrosis factor alpha) has been described;
      in CML, a direct, macrophage-mediated cell-to-cell contact mechanism for
      hemopoietic inhibition seems to be involved. To date, however, it is not clear
      whether the abnormalities in the hemopoietic microenvironment are secondary to
      myeloid leukemia or if they precede clinical CML/AML. Furthermore, it is not
      known to what extent the functional abnormalities observed in vitro contribute to
      the hematologic dysfunction that characterizes myeloid leukemia and to the in
      vivo progression of the disease.

PMID- 8667641
TI  - Forced over-expression of the myeloid zinc finger gene MZF-1 inhibits apoptosis
      and promotes oncogenesis in interleukin-3-dependent FDCP.1 cells.
AB  - The myeloid zinc finger protein MZF-1 is important in hematopoiesis. Previous
      studies have found that reducing expression of MZF-1 inhibited G-CSF-driven human
      marrow colony formation assays. In this study we found that retrovirally
      overexpressing MZF-1 in IL-3-dependent FDCP.1 cells inhibited their apoptosis
      when IL-3 was withdrawn. The MZF-1-transduced FDCP.1 cells also formed tumors
      when injected into congenic mice, whereas control FDCP.1 cells did not.

PMID- 8667642
TI  - Association of 6q deletions with AIDS-related diffuse large cell lymphoma.
AB  - Deletions of chromosome 6 at band q27 represent the site of a putative novel
      tumor suppressor gene in non-Hodgkin's lymphomas (NHL) of the immunocompetent
      host. Although several genetic lesions have been identified in AIDS-related NHL
      (AIDS-NHL), the involvement of 6q27 loss has not been investigated in this NHL
      category. In this report, we tested the presence of a 6q deletion at the
      molecular level in a panel of AIDS-NHL representative of the major histologic
      types, including AIDS-related small non-cleaved cell lymphoma (AIDS-SNCCL; n =
      10), AIDS-related diffuse large cell lymphoma (AIDS-DLCL; n = 13) and AIDS
      related anaplastic large cell lymphoma (AIDS-ALCL; n = 3). We report that 6q
      deletions occur in 5/26 AIDS-NHL tested (19.2%). Notably, 6q deletions do not
      randomly distribute throughout the spectrum of AIDS-NHL histologic types, but
      rather selectively cluster with AIDS-DLCL (5/13; 38.4%). Overall, these data add
      to the notion that the molecular pathogenesis of AIDS-NHL is heterogeneous and
      that distinct genetic pathways associate with specific histologic categories of
      AIDS-NHL.

PMID- 8667643
TI  - Investigating and improving the specificity of ribozymes directed against the bcr
      abl translocation.
AB  - Chronic myelogenous leukaemia (CML) is associated with a translocation between
      the ABL and BCR genes on chromosomes 9 and 22, t(9;22). The resulting
      transcription and translation products, bcr-abl mRNA and p210bcr-abl, are unique
      to the malignant cells and as such are ideal targets for specific chemicals or
      drugs. We have designed hammerhead ribozymes to cleave the two predominant forms
      of bcr-abl mRNA, b2a2 and b3a2. Synthetic bcr-abl RNA substrates were cleaved by
      the ribozymes in vitro, but so was a wild-type abl RNA sequence. bcr RNA was not
      cleaved in vitro and mutant ribozymes showed no cleavage activity. Ribozymes
      designed to cleave 9 nucleotides (nt) from either of the fusion points were non
      specific for the bcr-abl substrate, but a ribozyme designed to cleave 3 nt
      upstream of the b3a2 fusion point was specific for b3a2 RNA. However, this
      ribozyme was less efficient than the others. The shortening of one of the
      ribozymes arms from 10 nt to 4 nt resulted in a ribozyme that was more specific
      without losing any efficiency. We conclude that it is possible to specifically
      cleave bcr-abl RNA in vitro by using hammerhead ribozymes.

PMID- 8667644
TI  - Automated counting of in situ hybridization dots in interphase cells of leukemia
      samples.
AB  - Twenty-seven samples (cell cultures prepared for routine cytogenetics) of
      leukemia patients with known cytogenetic abnormalities were stained by in situ
      hybridization for interphase cytogenetics with centromere specific probes for
      chromosome Nos 4, 6, 7, 8, 9, 12, 17, 18, X and Y. The number of hybridization
      domains per nucleus was quantified using a semi-automated system developed in our
      laboratory. Results of this automated counting procedure (with and without
      verification of the counting results by the operator) were compared with
      conventional cytogenetic data and with visual scoring of the number of
      hybridization dots. The findings show that the system is capable of analysing
      1000 cell nuclei in less than 30 min, including the necessary verification of the
      results by the operator. Automated counting and visual scoring were in good
      agreement. Conventional cytogenetics and interphase cytogenetics agreed in only
      50% of the cases, confirming other studies showing that conventional cytogenetic
      results are not always representative for the majority of the cell population.

PMID- 8667645
TI  - Presentation of chronic myelogenous leukemia as a rheumatoid syndrome--MRT
      diagnosed chloroma.

PMID- 8667646
TI  - Control of apoptosis in hematopoiesis and leukemia by cytokines, tumor suppressor
      and oncogenes.
AB  - Hematopoietic cells require certain cytokines including colony-stimulating
      factors and interleukins to maintain viability. Without these cytokines the
      program of apoptotic cell death is activated. Cells from many myeloid leukemias
      require cytokines for viability, and apoptosis is also activated in these
      leukemic cells after cytokine withdrawal resulting in reduced leukemogenicity.
      The same cytokines protect normal and leukemic cells from induction of apoptosis
      by irradiation and cytotoxic chemotherapeutic compounds. This suggests that
      decreasing the levels of viability inducing cytokines may increase the
      effectiveness of cytotoxic anti-cancer therapy. The susceptibility of normal and
      cancer cells to induction of apoptosis is also regulated by the balance between
      apoptosis-inducing genes such as the tumor suppressor wild-type p53, and c-myc
      and bax, and apoptosis-suppressing genes such as the oncogene mutant p53, and bcl
      2 and bcl-XL. Cell susceptibility to induction of apoptosis in leukemic cells
      could be enhanced by increased expression of apoptosis-inducing genes and/or
      decreased expression of apoptosis-suppressing genes. Modulation of expression of
      apoptosis-regulating genes should thus also be useful for improvement of anti
      cancer therapy.

PMID- 8667647
TI  - Treatment of refractory AML.
AB  - Refractory AML is variously defined. MD Anderson data indicate that patients with
      AML that stayed in first remission for less than 2 years are incurable with
      standard chemotherapy regimens, hence meriting a definition of refractory; the
      prognosis of patients whose first remissions are longer is on average similar to
      that of untreated patients. Within the refractory group, Hiddeman et al' s
      definition (Leukemia 1990; 4: 184-188) is elaborated to account for the number of
      courses of initial therapy and for response to prior salvage regimens. If
      patients with refractory AML cannot receive an allogeneic transplant, the
      standard of therapy should be investigational chemotherapy regimens. A new
      Bayesian pre-phase II designed is described for use in testing such regimens.

PMID- 8667648
TI  - Role of multidrug resistance and its pharmacological modulation in acute myeloid
      leukemia.
AB  - Cellular expression of the multidrug transporter, P-glycoprotein (Pgp) is
      recognized as a biological mechanism possibly contributing to treatment failure
      in acute myeloid leukemia (AML). Correlative studies indicate its association
      with poor risk features including secondary AML, CD34+ surface phenotype,
      unfavorable karyotype and advanced age. Reported disparity in the prognostic
      impact of Pgp relates in part to variance in drug transport capacity. In Pgp
      expressing cells, capacity for drug extrusion is governed by maturation phenotype
      and is largely restricted to CD34+ populations lacking myeloid maturation
      antigens. Three competitive inhibitors of Pgp function showing promise in pilot
      studies, cyclosporin A (CsA), quinine and the cyclosporin D analogue PSC 833,
      have entered testing in phase III trials. The presence of non-Pgp-related
      mechanisms of multidrug resistance, relatively insensitive to Pgp modulators, may
      limit the success of such treatment strategies. Preliminary investigations
      indicate that overexpression of the gene encoding the multidrug resistance
      related protein (MRP) occurs infrequently in de novo AML, but relative increases
      in gene message are evident in relapsed specimens. Overexpression of lung
      resistance protein (LRP) is associated with adverse prognostic variables such as
      age, secondary disease and Pgp, and has demonstrated prognostic relevance.
      Because treatment with Pgp modulators may select for this drug resistance
      phenotype, LRP merits evaluation in randomized trials of Pgp antagonists. These
      observations indicate that multiple biological mechanisms contribute to
      anthracycline resistance in AML, thereby warranting development of
      multifunctional modulators or chemotherapeutic agents with novel mechanisms of
      action.

PMID- 8667649
TI  - Biological and clinical advances in stem cell expansion.
AB  - One of the most exciting areas of hematological research is the ex vivo expansion
      of peripheral blood progenitor cells (PBPC). Several groups clearly demonstrated
      that the ex vivo expansion of hematopoietic progenitor cells is possible in the
      presence of various cytokine combination and/or different feeder layer models.
      This minireview summarizes recent developments in ex vivo expansion systems as
      well as first clinical applications.

PMID- 8667650
TI  - De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic
      significance.
AB  - Dysplastic hematopoiesis is the morphological hallmark of myelodysplastic
      syndromes. Dysplastic features in one or more lineages are also found frequently
      in bone marrow aspirates from patients with de novo AML and have been associated
      with an unfavorable prognosis. We asked whether dyshematopoiesis is an
      independent prognostic factor or an indicator of unrecognized secondary leukemia,
      identified by characteristic chromosomal abnormalities. Bone marrow aspirates
      from 102 patients with newly diagnosed AML were analyzed. Morphological analysis
      was obtained in all patients, flow cytometric analysis in 96 and successful
      cytogenetic analysis in 65 bone marrow aspirates. Dysgranulopoiesis (DysG) was
      found in 55, dysmegakaryopoiesis (DysM) in 32 and dyserythropoiesis (DysE) in 23
      patients. Decreased side scatter signals of neutrophils in the flow cytometric
      analysis (DysS) were detected in 32 patients. DysG and DysS showed a highly
      significant correlation (P = 0.0005). DysG was an adverse negative prognostic
      factor for remission rate and event-free survival (P = 0.04, P = 0.02). An
      unfavorable karyotype was associated with a significantly lower chance for event
      free survival (P = 0.002). The incidence of an unfavorable karyotype was
      significantly higher in patients with DysG (P = 0.01), DysM (P = 0.02) and DysS
      (P = 0.01). In patients with an unfavorable karyotype, dysplasia had no
      additional prognostic influence, however, in patients with a normal, favorable or
      prognostically uncertain karyotype DysG remained a predictor of lower remission
      rate (P = 0.03). We conclude that dysgranulopoiesis, dysmegakaryopoiesis and
      decreased side scatter signals of neutrophils are indicators of secondary
      leukemias in bone marrow aspirates from patients with de novo AML.

PMID- 8667651
TI  - Prognostic factors in the acute lymphoid and myeloid leukemias of infants.
AB  - The age boundaries and prognostic factors that define the infant leukemias are
      still controversial. We therefore analyzed event-free survival according to age
      group in 96 children treated for acute lymphoblastic leukemia (ALL) and 51
      treated for acute myeloid leukemia (AML) before the age of 2 years. The study
      population was registered in consecutive institutional trials of multiagent
      chemotherapy conducted between 1980 and 1994. Among infants with ALL, event-free
      survival was significantly poorer in the 0- to 6-month-old group than in patients
      treated between 6 and 12 months of age (P = 0.03), whose outcome was in turn
      inferior to that in the 12- to 18-month and 18- to 24-month age groups (P =
      0.013). Leukemic cells from ALL patients younger than 12 months had a
      significantly higher frequency of 11q23/MLL abnormalities, as well as better
      growth in stromal cell culture, compared to lymphoblasts from the older groups (P
      < 0.01). The only independent predictor of adverse prognosis among infants
      diagnosed with ALL before age 12 months was the presence of an 11q23/MLL
      rearrangement (P = 0.03). These findings contrast sharply with results for the
      AML cohort, whose event-free survival did not vary significantly by age group (P
      = 0.58). Male sex (P = 0.01) and leukocyte count > or = 50 x 10(9/l) (P = 0.04),
      but not 11q23 abnormalities, were independently associated with a poorer outcome
      for children with AML younger than 12 months at diagnosis. Thus, in very young
      children with ALL (but not AML), the rearrangement status of the 11q23/MLL region
      supersedes age group as a determinant of treatment outcome.

PMID- 8667653
TI  - Factors predicting complete remission and subsequent disease-free survival after
      a second course of induction therapy in patients with acute myelogenous leukemia
      resistant to the first.
AB  - Patients with newly diagnosed acute myelogenous leukemia (AML) with persistent
      leukemia after their first course (CO1) of induction chemotherapy are generally
      given a second similar course, although their outcome is known to be worse than
      CO1 responders even when a complete remission (CR) is achieved. To identify
      specific patients who should or should not receive a second induction course
      identical to the first we analyzed outcome in 370 patients with persistent AML
      after CO1 who received a second identical course. One hundred and forty-two (38%)
      achieved CR on this course; median subsequent disease-free survival (DFS) in
      these 142 was 29 weeks and 10% were alive in CR at 5 years. The 5-year DFS of CO2
      responders was significantly lower than that of CO1 responders (10 vs 24%, P <
      0.001). Logistic regression identified pretreatment cytogenetic abnormalities
      (except inv 16, t(8;21), or t(15;17)), presence of an antecedent hematologic
      disorder or secondary AML as each having unfavorable prognostic import similar to
      the case in untreated patients. Treatment with "high-dose' rather than standard
      dose cytarabine increased the probability of 2nd course CR. The occurrence of
      pneumonia, sepsis, or major hemorrhage were prognostically unfavorable, primarily
      in the high-dose cytarabine group, and, once in CR, DFS was shorter in this
      group. Equations predicting probability of 2nd course CR were derived. If
      validated prospectively these could be used to assign patients to either receive
      a second course of initial induction therapy or to change to salvage or
      investigational therapy after the first course. Alternatively, they could be used
      to stratify patients entering a prospective randomized trial comparing these two
      strategies.

PMID- 8667652
TI  - Incidence and clinical outcome of children with BCR/ABL-positive acute
      lymphoblastic leukemia (ALL). A prospective RT-PCR study based on 673 patients
      enrolled in the German pediatric multicenter therapy trials ALL-BFM-90 and CoALL
      05-92.
AB  - A variety of oncogenes are activated by specific chromosomal translocations,
      which are associated with distinct subtypes of leukemia. The identification of
      these rearrangements provides critical diagnostic and prognostic information,
      which may contribute to the selection of specific anti-leukemic therapy. The
      translocation t(9;22), the equivalent of the BCR/ABL rearrangement, is associated
      with a poor prognosis. We therefore used RT-PCR to detect this molecular event in
      a prospective study including 890 children. 673 of them suffered from acute
      lymphoblastic leukemia (ALL) at primary diagnosis and a transcription of the
      chimeric gene was detected in 21 of 648 with a successful analysis (3.2%). All
      children were treated by one of the two German multicenter childhood ALL therapy
      studies ALL-BFM-90 or COALL-05-92, respectively. Comparison of clinical features
      between BCR/ABL-positive and -negative children showed no significant differences
      regarding WBC, percentage of blasts, splenomegaly, hepatomegaly and age.
      Immunophenotypic studies at diagnosis in 21 BCR/ABL-positive children identified
      common ALL in 16 patients (76.2%), pre-B-ALL in four (19.0%), and an early T
      lineage ALL in one (4.8%). Coexpression of myeloid antigens (CD13 and/or CD33)
      was observed in six of 16 common ALL patients as well as in the one child with
      early T-lineage ALL phenotype. The type of breakpoint (m-BCR/ABL: n = 14; M
      BCR/ABL: n = 7) showed no correlation with clinical parameters. A comparison of
      cytogenetic and molecular data was performed in 16 positive patients and was
      concordant in all of them. We analyzed the response to the prednisone
      pretreatment and found a higher incidence of poor responders among the BCR/ABL
      positive children. Regarding the event-free survival (EFS) of BCR/ABL-positive
      (0.53) and -negative patients (0.79) after a follow-up of 2 years, significant
      differences (P < 0.05) between both groups could be demonstrated.

PMID- 8667654
TI  - Rearrangement of the 5' cluster region of the BCL2 gene in lymphoid neoplasm: a
      summary of nine cases.
AB  - Rearrangement of the BCL2 gene with the immunoglobulin (IG) genes is the most
      frequent genetic abnormality in B cell lymphoid neoplasms. In the majority of
      cases, breakages occur at two breakpoint cluster regions; major breakpoint
      cluster (MBR) and minor cluster region (mcr). In a minority of cases with non
      Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), rearrangements
      involving the 5' flanking region of the BCL2 (5'-BCL2) have been reported. Here,
      we investigated 196 patients with NHL and 31 with CLL, with regard to
      rearrangement of the BCL2 gene. Hybridization analyses using probes representing
      the three cluster regions revealed that a total of 57 patients had a
      rearrangement of the BCL2; 42 (73.7%) were within the MBR, seven (12.2%) were
      within the mcr, and nine (15.8%) had a rearrangement at the 5'-BCL2. The nine
      patients with 5'BCL2 rearrangement included two with follicular lymphoma, four
      with diffuse large cell lymphoma and immunoblastic variant, two with leukemic
      phase of follicular lymphoma, and one with CLL. Comigration analysis with probes
      for the IG heavy chain gene (IGH), kappa-chain gene (IG kappa) and lambda-chain
      gene (IG lambda), demonstrated a 5'-BCL2/IGH junction at the JH region in four
      patients with NHL derived from follicular center B cell. Thus, the 5'flanking
      region is a third cluster for recombination between the BCL2 and IGH, which is
      closely associated with the development of follicular center cell lymphoma.
      Molecular cloning of a 5'-BCL2/IGH junction demonstrated recombination of the two
      affected genes in divergent orientation. A 5'-BCL2/IG kappa junction was observed
      in two patients with immunoblastic lymphoma, and one with CLL had a 5'-BCL2/IG
      lambda recombination. Two patients, including one with a BCL2-MBR/JH junction,
      lacked obvious recombination of the 5'-BCL2 with IG genes, suggesting the
      presence of a deletion at the 5'-BCL2. Our findings demonstrated heterogeneity
      not only in clinicopathological presentation of B cell disease with rearrangement
      of 5'-BCL2, but also in molecular lesions resulting from the rearrangement.

PMID- 8667655
TI  - Expression of receptor protein tyrosine kinase tif is regulated during leukemia
      cell differentiation.
AB  - tif is a recently cloned and characterized cDNA predicting a transmembrane
      protein with a putative tyrosine kinase structure in its cytoplasmic domain. By
      analysis of the purified tif cytoplasmic domain expressed in Escherichia coli, we
      have demonstrated that tif is an active protein tyrosine kinase capable of
      autophosphorylation on tyrosine residues and this phosphorylation is inhibited by
      a tyrosine-specific inhibitor genistein. Northern blot analyses of various
      leukemia cell lines have revealed that tif mRNA expression is primarily confined
      to those bearing erythroid and megakaryocytic phenotypes. Megakaryocytic
      differentiation of K562 and HEL cells induced by phorbol 12-myristate 13-acetate
      is accompanied by down-regulation of tif mRNA expression. In addition, treatment
      of K562 and HEL with hexamethylene bis-acetamide, but not with hemin, decreases
      the steady-state level of tif mRNA. These combined results suggest that the
      receptor tyrosine kinase tif is involved in hematopoietic development.

PMID- 8667656
TI  - DNA-binding domain of AML1, expressed in t(8;21) and t(3;21) myeloid leukemias,
      inhibits PEBP2/CBF DNA-binding but is not sufficient to transform 32D cl3 myeloid
      cells.
AB  - Truncated AML1 proteins are predicted to be expressed from out-of-frame AML1
      transcripts present in myeloid leukemia cells harboring t(8;21) and t(3;21). To
      test whether these proteins, consisting of almost exclusively an N-terminal AML1
      DNA-binding domain, interfere with myeloid differentiation we expressed a similar
      truncated AML1 protein in 32D cl3 myeloid cells. In all clones examined, the
      ectopically expressed truncated AML1 protein prevented binding of endogenous
      PEBP2/CBFs to DNA, possibly by interacting with all available CBF beta subunits.
      However, compared to control clones, the 32D cl3 clones expressing truncated AML1
      remained IL-3 dependent for survival, proliferated similarly in low and high
      concentrations of IL-3, and differentiated similarly upon transfer to G-CSF.
      Thus, truncated AML1 proteins may contribute to myeloid leukemogeneis by
      inhibiting PEBP2/CBF activities, although contributions from other oncoproteins
      are likely required as well.

PMID- 8667657
TI  - High incidence of TEL/AML1 fusion resulting from a cryptic t(12;21) in childhood
      B-lineage acute lymphoblastic leukemia in Taiwan.
AB  - Despite its rarity by routine karyotypic analysis, cryptic t(12;21)(p12-13;q22)
      translocation leading to TEL/AML1 fusion has been recognized as the most frequent
      genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) in two
      recent studies, one from France and the other from the United States. To estimate
      the frequency of this abnormality in the Chinese population, we studied 41
      children with ALL and 17 with acute myeloid leukemia (AML) in two medical centers
      in Taiwan, using the reverse transcriptase polymerase chain reaction (RT-PCR)
      assay. Results of this analysis demonstrated a 17% frequency of this
      translocation in the ALL population overall and 19% in patients with B-lineage
      ALL, similar to previous findings in Caucasian children. None of the patients
      with AML had TEL/AML1 fusion transcripts. In addition to its association with the
      B-lineage immunophenotype, TEL/AML1 was also correlated with a low presenting
      leukocyte count and favorable age (1-10 years). These findings, combined with
      earlier reports, indicate that TEL/AML1 fusion is the most frequent genetic
      abnormality in childhood ALL, regardless of race. Molecular diagnosis of t(12;21)
      positive ALL may identify a subgroup of patients who do not require intensive
      treatment for cure.

PMID- 8667658
TI  - Mechanisms of glucocorticoid resistance in human leukemic cells: implication of
      abnormal 90 and 70 kDa heat shock proteins.
AB  - The unliganded glucocorticoid receptor is a multi-oligomer complex consisting of
      a ligand-binding protein with which two 90 kDa heat shock proteins (hsp90s) are
      associated. Upon binding of glucocorticoid to the receptor, the ligand-binding
      protein, which dissociated from hsp90s, enters the nucleus, binds to a specific
      site in DNA, and thus transmits signal(s). The 70 kDa heat shock protein (hsp70)
      also works as a molecular chaperone when the ligand-binding protein enters the
      nucleus. Regarding the mechanisms of glucocorticoid resistance, a decreased
      expression of glucocorticoid receptor and a mutant protein with low ligand
      binding affinity have been reported. In the present study, to address other
      mechanisms of glucocorticoid resistance, we examined the expression of hsp90 and
      hsp70 in addition to the number of glucocorticoid-binding sites and their
      affinity using glucocorticoid-sensitive and -resistant human leukemic cell lines.
      We showed that two of nine resistant cell lines with normal glucocorticoid
      binding proteins express aberrant hsp90 and extremely low hsp70, while another
      seven resistant cell lines had decreased binding sites with normal hsps. These
      results suggest that there are at least two independent mechanisms of
      glucocorticoid resistance in human leukemic cell lines: the decreased ligand
      binding sites and the abnormal hsps expression.

PMID- 8667659
TI  - [Patterns of the use of electroconvulsive therapy in Barcelona].
AB  - BACKGROUND: To study the prevalence of use and the characteristics of current
      utilization of electroconvulsive therapy (ECT) in Barcelona. METHODS: A
      descriptive study was carried out in August of 1993. A structured interview
      designed by the authors was administered to psychiatrists in 20 hospitals,
      including general hospitals with Department of Psychiatry and psychiatric
      hospitals. RESULTS: In 12 hospitals of the sample (60%) ECT was practised. The
      most frequent indication was depression (83%) followed by schizophrenia (17%). In
      all these hospitals pharmacological treatment was simultaneously used and the
      application of electrodes was bilateral. Most of them used stimulation by
      sinusoidal wave, thiopental was used as anesthetic agent, the duration of
      seizures was not evaluated, EEG monitoring was not performed and treatment in a
      surgeon's room was not applied. In 10 hospitals written consent was obtained.
      CONCLUSIONS: ECT was used in general hospitals with psychiatric department of
      Barcelona, Spain, with high coincidence in indications but not in the technical
      aspects.

PMID- 8667660
TI  - [Study of the squamous cell carcinoma (SCC) antigen in benign diseases].
AB  - BACKGROUND: The values of the squamous cell carcinoma (SCC) antigen in benign
      diseases were studied with the aim of determining false positive values in the
      study of epidermoid carcinomas. METHODS: Serum determinations of the SCC antigen
      were performed by radioimmunoanalysis with the Abbott SCC-RIA kit. The control
      group was made up of a total of 719 subjects of whom 317 were healthy blood
      donors and 402 were healthy women with normal cervicovaginal cytology. The study
      group was made up of 693 women with benign diseases. RESULTS: Ninety-eight point
      two percent of the subjects from the control group presented values under 2.5
      ng/ml, therefore this value was chosen as the maximum limit of normality. Higher
      values than this threshold of normality were observed in 11.7% of the 34 patients
      with chronic disease (0.1-18.2 ng/ml) and in 57.5% of the 40 patients with
      chronic renal failure (0.5-6.0 ng/ml). CONCLUSIONS: In patients with chronic
      liver disease or chronic renal failure, the serum determination of the squamous
      cell carcinoma antigen loses its value as a tumor marker of epidermoid carcinomas
      given the risk of obtaining false positive values.

PMID- 8667662
TI  - [Electroconvulsive therapy: yesterday, today and tomorrow].

PMID- 8667661
TI  - [Helicobacter pylori, gastric ulcer and non-steroidal anti-inflammatory agents].
AB  - BACKGROUND: The aim of this study was to describe the prevalence of Helicobacter
      pylori infection in patients with gastric ulcer in addition to study its
      relationship with the ingestion of non steroid antiinflammatory drugs (NSAIDS).
      METHODS: One hundred sixty-one patients (mean age 54 years, 70% males) in whom
      gastric ulcer was endoscopically demonstrated were studied. Biopsies of the
      antrum and gastric body (hematoxillin-eosin, Gram staining and culture) were
      obtained during endoscopy. RESULTS: H. pylori was detected in 83% (CI = 78-89%)
      of the cases. In the patients not taking NSAIDS positivity was 87% (CI = 81-93%)
      while in those with NSAIDS this was only 63% (CI = 43-79%) (p = 0.008). The
      percentage of patients without H. pylori infection or NSAIDS intake represented
      11% (CI = 6-16%). On multivariant analysis the only variable correlated with H.
      pylori infection was NSAIDS intake (OR = 0.25; CI = 0.09-0.66; chi 2 model =
      7.27; p = 0.007) while the remaining variables (sex, age, smoking, alcohol and
      ulcer site) did not show a significant correlation. The percentage of chronic
      gastritis was higher (p < 0.001) in H. pylori positive patients in comparison
      with those who were uninfected (97% versus 67% in the antrum and 78% versus 41%
      in the gastric body). CONCLUSIONS: The prevalence of infection by Helicobacter
      pylori in patients with gastric ulcer is greater in those without non steroid
      antiinflammatory drug (NSAIDS) intake in comparison with those who have this
      history. The percentage of patients without H. pylori infection or NSAIDS
      ingestion was very low (11%), and thus it may be deduced that these elements
      represent pathogenic factors of major importance in gastric ulcer disease since
      the appearance of this entity in the absence of both is infrequent.

PMID- 8667663
TI  - [The newly deceased patients as a tool: legal and ethical considerations].

PMID- 8667664
TI  - [Identification of Arg-135-Leu mutation in the rhodopsin gene in a family with
      autosomal dominant retinitis pigmentosa].
AB  - Mutations in the rhodopsin gene have been sought in a family with autosomal
      dominant retinitis pigmentosa. Screening for mutations in the rhodopsin gene was
      carried out by polimerase chain reaction and denaturant gradient gel
      electrophoresis. Direct DNA sequencing was performed for the characterization of
      punctual mutations. A base substitution in the exon 2 of the rhodopsin gene was
      detected. Direct DNA sequencing revealed a CGC to CTG change in codon 135, that
      substitutes arginine for leucine residue in rhodopsin. The mutation segregates
      with the disease phenotype in the family. The mutation Arg-135-Leu causes the
      retinitis pigmentosa phenotype in the family, where the disease is inherited
      following an autosomal dominant pattern.

PMID- 8667665
TI  - [Specific problems of analgesic therapy in hospital environment].

PMID- 8667666
TI  - [Progressive dementia in a 76-year-old man].

PMID- 8667667
TI  - [Autochthonous problems concerning digoxin dosage in Spain?].

PMID- 8667668
TI  - [Thrombocytopenic purpura and nephrotic syndrome preceding the diagnosis of
      Hodgkin's disease].

PMID- 8667669
TI  - [New standardization of the measurement of serum proteins. New reference
      intervals].

PMID- 8667670
TI  - [Massive intestinal hemorrhage as presentation of Behcet's disease].

PMID- 8667671
TI  - [Sabbatical years].

PMID- 8667672
TI  - [Hepatita B and C virus infections in patients with hepatocellular carcinoma].
AB  - BACKGROUND: The prevalence of HBV and HCV infections in patients with
      hepatocellular carcinoma may be related to variations in the geographic area of
      study. For this reason, we have analized the relative prevalence of HBV and HCV
      infections in 94 patients with hepatocellular carcinoma from Cantabria (North of
      Spain). PATIENTS AND METHODS: We have studied 94 patients with hepatocellular
      carcinoma from January 1988 to December 1993. Commercially available
      radioimmunoassay or ELISA were used for detection of HBsAg, anti-HBs and anti
      HBc. The HBV DNA was analized by PCR. The HCV infection was assayed by ELISA-2
      and RT-PCR. RESULTS: The HBV infection was detected in 27 patients: 19 patients
      were HBsAg positive and 8 patients HBsAg negative, anti-HBc positive, DNA HBV
      positive by PCR. The HCV infection was found in 57 patients. Forty patients were
      infected with both viruses. Of the remain twenty-four, forty were alcoholics. We
      found in 61 patients more than one etiological factor. Hepatoma was the first
      manifestation of liver disease in 24 cases and these were more frequently in HCV
      than in those with HBV infection. Moreover, the first group were older and have
      lower alcohol intake. CONCLUSIONS: 1) In Cantabria, Spain, the majority of cases
      of hepatocellular carcinoma are related to HBV, HCV and alcohol. 2) Analysis of
      DNA HBV and RNA HCV by PCR allows the diagnosis of cryptic infections by both
      viruses, especially in the cases of HBV and HCV coinfection. 3) Hepatoma is the
      first manifestation of liver disease in a high percentage of cases.

PMID- 8667673
TI  - [The pattern of AIDS-indicative diseases in adults and adolescents in Spain, 1988
      1993].
AB  - BACKGROUND: The pattern of AIDS-defining diseases in adults and adolescents in
      Spain from 1988-1993 has been described. METHODS: Twenty-two thousand two hundred
      thirty-nine cases (CDC, 1987) diagnosed in patients over the age of 12 years from
      1988 to 1993 were taken from the National AIDS Registry. The percentage of cases
      which each of the indicative diseases on registry was evaluated and the
      differences based on the category of HIV transmission, sex and age were
      identified. RESULTS: The most frequent AIDS indicative diseases were
      extrapulmonary tuberculosis (29.7%), Pneumocystis carinii (28.2%) and invasive
      candidiasis (24.8%). The percentage of cases with extrapulmonary tuberculosis was
      higher among the intravenous drug users and Kaposi's sarcoma, non Hodgkin's
      lymphoma (NHL) and cytomegalovirus disease (CMV) among the homosexual males. The
      disease pattern has demonstrated some differences between sexes on adjustment by
      transmission category and age. Herpes simplex disease, retinitis by CMV and
      cerebral toxoplasmosis appeared were more frequent in women and extrapulmonary
      tuberculosis and NHL in males. On adjustment by transmission category and sex,
      extrapulmonary tuberculosis was observed with a higher frequency in patients
      under the age of 30 years while wasting syndrome and progressive multifocal
      leukoencephalopathy were more often observed in those over the age of 30 years.
      CONCLUSIONS: The category of HIV transmission plays and important role in the
      pattern of AIDS-defining diseases. Sex and age also play a role although to in a
      lesser degree.

PMID- 8667675
TI  - [Specialization of medical professionals].

PMID- 8667674
TI  - [Appropriate use and effectiveness of chronic domiciliary oxygen therapy in
      Catalonia].
AB  - BACKGROUND: The aim of this study was to study the pattern of the use of chronic
      domiciliary oxigenotherapy (CDO) in Catalonia, Spain. METHODS: A transversal
      study including 110 patients randomly selected from a list of all the subjects
      with CDO (n = 3,585) was made. A domiciliary survey on the characteristics of the
      indication for CDO and its fulfillment was carried out. Two pulsioximetries were
      also performed one breathing room air and another with oxigen. RESULTS: Of the 70
      eligible patients the following factors were simultaneously observed in only 14
      (20% of the total): adequate indication for CDO, use of oxigen at a flow which
      corrected the hypoxemia, and prescription fulfillment. The most important cause
      of inadequate usage of CDO was inappropriate indication since only 19 patients
      (27%) presented SaO2 less than or equal to 88%. Hypoxemia was not corrected in
      four of these 19 patients. Thirty-seven percent of the total admitted bad
      fulfillment, bot only one of the 15 patients with SaO2 less than or equal to 88%
      and in whom hypoxemia was corrected, recognized bad fulfillment. Sixty-nine
      percent of the patients had a document explaining the way and length of time they
      should receive the oxigen. CONCLUSIONS: The inappropriate indication of CDO is
      the main factor influencing the low effectiveness of chronic domiciliary
      oxigenotherapy in Catalonia.

PMID- 8667676
TI  - [How and why to prepare a protocol].

PMID- 8667677
TI  - [Splenomegalic pancytopenia of probable immune origin: cure after treatment with
      glucocorticoids].
AB  - Two female patients of 54 and 48 years, respectively, with pancytopenia and
      splenomegaly of probable immune origin are reported. The first presented anemic
      syndrome and fever, and the second bleeding. In both cases large sized
      splenomegaly was found on physical examination. Serologic and immunologic studies
      excluded chronic infection or systemic autoimmune disease. Bone marrow biopsy
      showed hematopoietic hyperplasia with lymphoid nodules and reticulin fibrosis.
      Treatment with glucocorticoids and splenectomy was performed in one case and only
      glucocorticoids were administered in the other case with the cytopenias
      disappearing and the bone marrow becoming normocellular. Reactive follicular
      hyperplasia was observed in the white pulp of the spleen in one of the patients,
      as were abundant macrophagic activity in the red pulp, and myeloid metaplasia.
      The patients remain asymptomatic at 4 and 12 years of follow up. The origin of
      the process was attributed probably to an immune etiology and differential
      diagnosis with idiopathic myelofibrosis and non tropical idiopathic splenomegaly
      must be considered.

PMID- 8667680
TI  - [Debate on general internal medicine].

PMID- 8667679
TI  - [Health care aspects of internal medicine in a 3d-level hospital].

PMID- 8667678
TI  - [Microbial resistance. What to do?].

PMID- 8667681
TI  - [Screening for HIV infection in prisons].

PMID- 8667682
TI  - [Clinical practice guidelines].

PMID- 8667683
TI  - [Multiple pseudocystic spondylodiscitis in oligoarthritis of unknown origin].

PMID- 8667684
TI  - [Fibrinolytic treatment in acute myocardial infarction: analysis of delay].
AB  - BACKGROUND: The delay time from the onset of symptoms to the initiation of
      intravenous fibrinolytic treatment in patients with acute myocardial infarction
      (AMI) is herein described. METHODS: A study was carried out of the consecutive
      AMI diagnosed in the Medical Area of the Emergency Department of the Hospital del
      Mar in Barcelona, Spain, with a 24-hour follow up from 15 May 1993 to 14 January,
      1994. All the patients under the age of 80 years with transmural AMI of any
      localization and evolution of under 6 hours were considered to receive
      fibrinolytic treatment. The following delay times were analyzed: total delay
      time, extrahospitalary delay time and intrahospitalary delay time, which included
      assistance delay time, delay in fibrinolytic treatment indication and delay time
      in performance of the same. RESULTS: During the study period 18,316 patients were
      attended in the Emergency Medical Area, of which 80 corresponded to AMI.
      Fibrinolytic treatment was initiated with intravenous streptokinase in 33
      patients (41.3%). The total delay time was 287.2 +/- 202.6 (mean +/- SD) minutes;
      the extrahospitalary and intrahospitalary delays were 159.8 +/- 151.7 and 126.8
      +/- 161.7 minutes, respectively. The delay time for assistance was 8.5 +/- 12.7
      minutes, the delay time in treatment indication was 78.8 +/- 101.8 minutes and in
      performance it was 39.5 +/- 52.6 minutes. This latter time was analyzed on the
      basis of the administration site, with statistically significant differences (p <
      0.005) if the fibrinolytic treatment was performed in the Emergency Medical Area
      (12.5 +/- 0.7 minutes), in the observation room (41.4 +/- 50.7 minutes) or in the
      Intensive Care Unit (61.4 +/- 75.8 minutes). CONCLUSIONS: Most of the
      intrahospitalary delay in the administration of fibrinolytic treatment is due to
      decision delay in regards to carrying out this therapy.

PMID- 8667685
TI  - [Socioeconomic differences in mortality in 8 Spanish provinces].
AB  - BACKGROUND: The scarce fulfillment of the job in the Bulletin on Death (BD) has
      limited the study of the socioeconomic differences in mortality in Spain.
      Nonetheless, the authors have studied the socioeconomic differences in mortality
      by different causes of death, using the Spanish geographical areas in which the
      information regarding the occupation of the deceased persons in the BD is of good
      quality. METHODS: Males between 30-64 years of age who died in eight Spanish
      provinces from 1988-1990 were included in the study. Overall mortality was
      compared by the relative risk of mortality adjusted for age and by the main
      causes of death among the professionals and managers, manual workers and farmers.
      The relative risk was calculated with the use of log-lineal models (Poisson
      regression) taking the group of professionals and managers as the reference
      group. RESULTS: The global relative risk of mortality in the group of manual
      workers was 1.72 and was 1.56 in the farmers. The highest mortality by different
      causes of death was observed in the manual workers while intermediate mortality
      was found in the farmers. The exceptions to this general pattern were colon and
      rectum cancer and leukemias with a higher mortality being found in the group of
      professionals and managers, although the differences were not statistically
      significant. Cerebrovascular diseases, suicide and cancer of the nervous system
      showed the highest relative risk of mortality in the farmers. Both the manual
      workers and the farmers demonstrated the highest relative risks of mortality in
      the youngest age groups although this difference attenuated with age.
      CONCLUSIONS: Except for colon and rectal cancer and leukemias, manual workers and
      farmers present higher mortality than professionals and managers. Furthermore,
      these differences may be underestimated since only the active economic population
      was studied, thereby excluding the individuals pertaining to the population
      groups with higher mortality rates.

PMID- 8667686
TI  - [A unique medical experience: the 1992 Barcelona Olympic Games].
AB  - BACKGROUND: The request for medical attention derived from Olympic Games is
      variable, with few previously published experiences and thus, the estimations
      made by the organizers are difficult. METHODS: The health care program
      established during the 1992 Olympic Games held in Barcelona is described and the
      clinical cases attended are reported. RESULTS: The number of persons accredited
      by the Barcelona Olympic Committee was 132,286. Health care attendance was
      provided in the sports installations, the olympic villages of the journalists and
      athletes, olympic family hotels, press centers and the International Youth Camp.
      A Polyclinic was in operation in the Olympic Village with a 24 hour Emergency
      Department. A total of 15,552 visits were made, 524 of which were sent to the
      Emergency Department of the Olympic Hospital (Hospital del Mar in Barcelona).
      Three hundred twenty visits were programed in the Out Patient Departments of the
      Hospital and a total of 81 patients were admitted to the hospital with a mean
      stay of 3.9 days. The most common medical problems encountered were those related
      with the locomotor system. CONCLUSIONS: The health care program designed for the
      Barcelona 1992 Olympic Games was adequate to attend the health care demand
      required.

PMID- 8667687
TI  - [Percutaneous therapy: a new specialty?].

PMID- 8667688
TI  - [Translation of titles into English in Medicina Clinica: quality and influence of
      the Spanish language].
AB  - BACKGROUND: Journals that are not published solely in English have the titles of
      papers translated into English, the international language of medicine. The aim
      of this paper is to analyse the accuracy and quality of such translations in
      Medicina Clinica and to assess the influence of the morphology and syntax of
      Spanish on the English versions of the titles. METHODS: Two professional medical
      translators, one Spanish and the other English, each with a knowledge of both
      languages, compared the original Spanish and the English translations of the
      titles of the 292 papers and communications published in the 20 issues of volume
      100 of Medicina Clinica. The discrepancies or "errors" were classified in five
      groups of increasing seriousness. RESULTS: Of the titles studied, 77% contained
      some sort of error (458 errors were detected). In 100 titles (34%) there were
      differences in meaning between the original Spanish and the English translations.
      Another 72 titles contained serious orthographical, lexical or grammatical
      mistakes, though the basic meaning was not distorted. Approximately a third of
      the lexical and grammatical errors were attributable to the direct influence of
      Spanish. CONCLUSIONS: The English translations of titles in Medicina Clinica
      contain numerous orthographical, lexical and gammatical mistakes. Serious errors
      of meaning in a number of translated titles could result in misinterpretation by
      readers who do not know Spanish. We recommend that the authors should play a part
      in the translation of the titles, as this should provide a simple and effective
      mean of improving the accuracy of the translations. Our comparison yielded much
      worse results than had been expected, which suggests that similar studies with
      other medical journals in Spanish and other languages would be justified.

PMID- 8667689
TI  - [Alpha interferon treatment in idiopathic hypereosinophilic syndrome resistant to
      conventional therapy].
AB  - The idiopathic hypereosinophilic syndrome (HES) is an infrequent entity defined
      by an eosinophil count > 1.5 x 10(9)/l and the specific infiltration of different
      organs not attributable to another disease. Its prognosis is marked by the
      complications derived from visceral, particularly cardiac, infiltration
      determining a median survival of less than one year if treatment is not
      administered. Although a notable prolongation in survival may be achieved in
      these patients with the administration of glucocorticoids and cytolytic drugs,
      mainly hydroxiurea, there remains a group of patients who do not respond to these
      therapeutic measures, thus leading to alpha interferon trials with promising
      results. A favourable experience with the use of alpha interferon in two patients
      with IHS resistant to conventional treatment is reported. The first patient
      presented a picture characterized by diarrhoea, palpitations and effort dyspnea
      demonstrating heart involvement suggestive of eosinophilic infiltration on
      echocardiographic study. The second patient presented dyspneic night cough and
      generalized pruritus in addition to anemia and thrombocytopenia. The
      administration of alpha interferon (3 x 10(6) U/3 days a week and 3 x 10(6)
      U/day, respectively) was followed in both cases by the rapid disappearance of the
      symptomatology, normalization of the hematologic parameters and a reduction of
      the eosinophilia to values of less than 1 x 10(9)/l. This response has maintained
      over the two years of control in which the patients have received alpha
      interferon as a maintenance treatment.

PMID- 8667690
TI  - [Aprotinin in the control of surgical hemorrhage].

PMID- 8667691
TI  - [Ticlopidine-induced lymphocytic colitis].

PMID- 8667692
TI  - [Acute gastric anisakiasis caused by insufficient microwave cooking].

PMID- 8667693
TI  - [Espartosis or plasterer's lung?].

PMID- 8667694
TI  - [Hemoptysis caused by aortobronchial fistula].

PMID- 8667695
TI  - [Desensitization to rifampicin. Apropos of a case].

PMID- 8667696
TI  - [Role of hepatitis C virus in porphyria cutanea tarda hepatopathy].
AB  - BACKGROUND: Porphyria cutanea tarda has been classically considered as an
      acquired disorder due to the exerted influence of several factors (such as viral
      infections) on its fenotipic expression. The aim of the present study has been
      focussed on the prevalence analysis and the hepatotoxic role of the hepatitis C
      virus (HCV). PATIENTS AND METHODS: By means of a second generation ELISA test,
      serum antibodies against hepatitis C virus was studied in 132 patients with
      porphyria cutanea tarda. The polymerase chain reaction (PCR) was assayed in 55
      cases to detect serum viral RNA. A liver biopsy was performed in 93 cases.
      RESULTS: The 64.4% of the studied patients were seropositive and PCR for HCV was
      positive in the 83% out of the 55 studied cases. The group of 19 patients
      suffering from familial porphyria cutanea tarda showed a similar prevalence to
      the group of 113 patients with sporadic porphyria (47.3% vs 67.2%). In 82% out of
      the total cases, risk factors for HCV infection were not found. In seropositive
      cases, both transaminases were more frequently altered than in seronegative ones.
      The univariant study was not able to demonstrate the relationship between
      seropositivity, and transaminases, urinary porphyrins alcohol consumption,
      frequency of antibodies against hepatitis B virus, relevance of the histological
      hepatic damage or incidence of porphyria relapses. Nevertheless, a multivariant
      analysis on 93 patients with liver biopsy showed that the risk to suffer from
      severe liver disease increases 2.8 times in seropositive patients, 3.13 times in
      those presenting high levels of serum ferritin and 9.25 times in patients up to
      65 years old. CONCLUSIONS: The frequent hepatitis C virus infection in patients
      with porphyria cutanea tarda must be considered as a precipitating factor for the
      disease and as an aggravating factor of its associated liver damage.

PMID- 8667697
TI  - [Helicobacter pylori infection and basal levels of serum gastrins in patients
      with duodenal ulcer and subjects with normal endoscopy].
AB  - BACKGROUND: To study basal gastrin levels in duodenal ulcer patients and in those
      with normal endoscopy, according to Helicobacter pylori infection. METHODS:
      Eighty-four duodenal ulcer patients and 164 with normal endoscopy were studied.
      Biopsy specimens were taken from gastric antrum and body, and investigated for
      microbiology (Gram stain and culture) and histology (hematoxilin-eosin stain).
      Basal gastrin levels were measured (RIA). RESULTS: In duodenal ulcer patients the
      percentage of chronic gastritis was higher (p < 0.001) than in patients with
      normal endoscopy without H. pylori infection, and similar to patients infected by
      H. pylori. In patients with normal endoscopy (n = 164), those infected with H.
      pylori (n = 115) had higher (p = 0.02) gastrin levels (mean +/- SD) than non
      infected (64 +/- 34 vs 51 +/- 14 pg/ml) and similar to duodenal ulcer patients
      (62 +/- 20 pg/ml). In the multiple regression model analysis H. pylori infection
      was the only variable which correlated with gastrin levels (regression
      coefficient 9.48 [SE = 4.59]; multiple correlation coefficient 0.22 [p = 0.008]).
      Additional variables (age, sex, duodenal ulcer) were not correlated with gastrin
      levels. Patients with chronic gastritis had higher gastrin levels (p < 0.01) than
      those with normal histologic mucosa. CONCLUSIONS: In patients with normal
      endoscopy, those infected with H. pylori had significantly higher basal gastrin
      levels than non-infected individuals, and similar to duodenal ulcer patients.
      Therefore, hypergastrinaemia seems to be associated with H. pylori infection, and
      is not a distinctive feature of duodenal ulcer disease.

PMID- 8667698
TI  - [Economic costs of autotransplantation of hematopoietic progenitors].
AB  - BACKGROUND: A comparative analysis of the economic costs of the different methods
      of autologous transplantation was carried out. METHODS: A series of 22 patients
      was retrospectively studied: 8 treated with autologous bone marrow
      transplantation (ABMT), 9 treated with peripheral blood stem cell (PBSC)
      transplantation and 5 in whom mixed transplantation of bone marrow and peripheral
      blood hematopoietic progenitors was performed. The expenses derived from
      pretransplant studies and from the collection of hematopoietic progenitors and
      from the autologous transplantation procedure itself were evaluated. RESULTS: The
      pretrasplant study and the collection of hemopoietic progenitors were
      significantly more expensive in the PBSC than in the ABMT (p = 0.04 and p =
      0.007, respectively). Nonetheless, the costs of the transplant procedure were
      lower in the PBSC than in the ABMT group although the differences were not
      statistically significant. The estimated costs of these procedures in the
      Hematology Unit of the General Hospital of the University of Murcia, Spain, is of
      3 million pesetas for the ABMT and 2.5 million for the PBSC. The greatest cost
      observed in the ABMT was due to these patients requiring longer hospitalization,
      greater transfusion support and longer antibiotic treatment. CONCLUSIONS:
      Although the collection of hematopoietic progenitors and pretransplant evaluation
      are less expensive in autologous bone marrow transplantation, the early morbidity
      is higher than that of peripheral blood stem cell transplantation or mixed
      autotrasplanted of bone marrow and circulating progenitors thus resulting in
      higher costs.

PMID- 8667699
TI  - [Lymphomatoid granulomatosis: 23 years of development].

PMID- 8667700
TI  - [Functional interdisciplinary geriatrics units in general hospitals. Functioning
      and analysis of effectiveness].

PMID- 8667701
TI  - [Black widow spider (Latrodectus tredecimguttatus) bite. Presentation of 12
      cases].
AB  - The most severe cases of arachnidism are those due to Latrodectus
      tredecimguttatus spider-bite. The Mediterranean area is the habitat of the L.
      tredecimguttatus species. In the last few years no series of patients with
      latrodectism has been reported in Spain. A retrospective study of the patients
      admitted for L. tredecimguttatus spider bite in the Torrecardenas Hospital in
      Almeria, Spain from 1984 to 1994 was performed. Twelve patients were diagnosed
      with latrodectism. Eleven were bitten while carrying out agricultural tasks, 8 of
      which were performed in greenhouses. The mean time between the bite and the
      appearance of the general symptoms was 40 minutes (20-120 minutes), with the most
      common signs and symptoms being: pain and abdominal stiffness (10 cases),
      erythema (10 cases) or pain (8 cases) at the site of the bite, thoracic pain,
      pain in extremities and contractures and psychomotor alterations (6 cases).
      Laboratory findings were limited to leukocytosis (4 cases), increase in
      creatinphosphokinase count (4 cases) and proteinuria (3 cases). All the patients
      received analgesics, 6 were administered myorelaxants and calcium gluconate was
      given in 6 cases. The evolution was good without complications in all of the
      patients. Latrodectism is a rare phenomenon Spain. The diagnosis is difficult
      when there is absence of a clear history of spider bite and due to the lack of
      knowledge as to its semiology. Antivenom serum is not usually required.

PMID- 8667702
TI  - [Pain, paresthesias and loss of strength in the lower limbs in a 45-year-old
      woman].

PMID- 8667703
TI  - [Local fibrinolysis in massive pulmonary thromboembolism].

PMID- 8667704
TI  - [Sweet's syndrome and multiple myeloma].

PMID- 8667705
TI  - [The area under the ROC curve].

PMID- 8667706
TI  - [Metrorrahgia induced by topical application of medroxyprogesterone. Is it worth
      it?].

PMID- 8667707
TI  - [Extrahospital nephrology understood as a good project].

PMID- 8667708
TI  - [Clinical management: the great forgotten in primary health care?].

PMID- 8667709
TI  - [Herpetic hepatitis in an immunocompetent patient with spontaneous resolution].

PMID- 8667710
TI  - [The booster effect].

PMID- 8667711
TI  - [Ten hospitals united in the most extended IT project so far].

PMID- 8667712
TI  - [A visit to the Princess Royal Hospital, Telford: English physicians are worried
      by tendencies towards shorter continuing education].

PMID- 8667713
TI  - [Who will direct the choice of drugs in the future? Independent drug information
      must be supported].

PMID- 8667714
TI  - [Alzheimer disease cannot be treated with Cognex].

PMID- 8667715
TI  - [Occupational medical tests in the past].

PMID- 8667716
TI  - [The government rules refugee policy].

PMID- 8667717
TI  - [What is the role of physicians employed by insurance companies?].

PMID- 8667719
TI  - [Insurance coverage difficulties].

PMID- 8667718
TI  - [Prescription rules for licensed drugs should not be simplified].

PMID- 8667720
TI  - [Ethical leadership, please!].

PMID- 8667721
TI  - [Amalgam sickness in a wrong perspective].

PMID- 8667722
TI  - [The art of getting many P-values].

PMID- 8667723
TI  - [What benefit for the patients are high-class physicians?].

PMID- 8667724
TI  - [Prevalence of whiplash injuries in records].

PMID- 8667725
TI  - [The laser man on color blindness].

PMID- 8667726
TI  - [The HSAN statement should be reconsidered].

PMID- 8667727
TI  - [Astra companies break the existing rules].

PMID- 8667728
TI  - [Comprehensive facts on narcotics are needed].

PMID- 8667729
TI  - [Colonoscopy after polypectomy. A valuable follow-up].

PMID- 8667730
TI  - [Relief of dyspnea, right-sided failure and hypoxemia].

PMID- 8667731
TI  - [Increasing trends of genital chlamydia].

PMID- 8667732
TI  - [Dercum's disease. Fatty tissue rheumatism caused by immune defense reaction?].

PMID- 8667734
TI  - [Are calcium channel blockers hazardous? Insufficient follow-up in spite of early
      warning].

PMID- 8667733
TI  - [Arm and leg weakness may by a symptom of spinal stenosis].

PMID- 8667735
TI  - [Tartaros phthisis. The first medical dissertation in Sweden 1628 by Johannes
      Raicus].

PMID- 8667736
TI  - [New medical technology generates new ethical problems].

PMID- 8667738
TI  - [Lists presented by eight drug committees compared. The number of preparations
      varies. Similar views on the most expensive drugs].

PMID- 8667737
TI  - [Life-long life style changes. A model of self care in coronary disease focused
      on behavior].

PMID- 8667739
TI  - [Jack Kevorkian was found not guilty for the second time. Physicians and jurists
      in the USA in a hard dispute over euthanasia].

PMID- 8667741
TI  - [Are physicians above the law?].

PMID- 8667740
TI  - [Physicians and pharmacists should cooperate more and more! It is beneficial for
      independent drug information].

PMID- 8667742
TI  - [The fear of hepatitis transmission should not be minimized].

PMID- 8667743
TI  - [Vaccination against hepatitis B should be offered to all children].

PMID- 8667744
TI  - [How to measure the pulse?].

PMID- 8667745
TI  - [Disclosure of the actual situation of interns!].

PMID- 8667747
TI  - [Orthopedics in primary health care].

PMID- 8667746
TI  - ["The best for the Children"--a paradoxical concept].

PMID- 8667748
TI  - [Why are so many drugs prescribed?].

PMID- 8667749
TI  - [Avoid unnecessary colonic radiography! Suspected cancer can be excluded by more
      stringent diagnostic methods].

PMID- 8667750
TI  - [Rupture of the Achilles tendon after ciproxine therapy].

PMID- 8667751
TI  - [MIBI-scintigraphy. A simple and reliable method for localization of pathological
      parathyroid glands].
AB  - 99Tcm-sestamibi scintigraphy was used to localise enlarged parathyroid glands in
      25 patients with primary hyperparathyroidism previously operated in the neck, 20
      of whom had recurrent disease and five had previously undergone surgery for
      thyroid disorders. Of the 18 patients for whom positive scans were obtained, nine
      were operated on the scan findings being confirmed. Crucial information was
      provided in two cases of intrathyroidal and one case of intramediastinal
      localisation of the pathological gland were not operated on as the hypercalcaemia
      was only marginal or the symptoms were vague. Though preoperative localisation of
      pathological parathyroid glands is a prerequisite for neck exploration in
      patients with persistent or recurrent hypercalcaemia due to primary (or
      secondary) hyperparathyroidism, the procedure is not cost-effective before the
      initial operation.

PMID- 8667752
TI  - [Signal changes in the cerebral white matter. Common findings by MRI examinations
      of the elderly].

PMID- 8667753
TI  - [More resources for the treatment of obesity!].

PMID- 8667754
TI  - [Knowledge of one's own behavior is better than dieting].

PMID- 8667755
TI  - [Are well-documented bad habits to be defended? Painful withdrawal from learnt
      "truths"].

PMID- 8667756
TI  - [What is the value of well-tried experience of general practitioners?].

PMID- 8667757
TI  - [Science watchers wink at the logic].

PMID- 8667758
TI  - [Growing pains in a scientific network. The Cochrane Collaboration works mostly
      for libraries so far].

PMID- 8667759
TI  - [Pseudotumor cerebri in children. Neuroborreliosis may be the cause].

PMID- 8667760
TI  - [Lumbar puncture must be performed immediately in suspected meningitis].

PMID- 8667761
TI  - [No to euthanasia, yes to good palliative care!].

PMID- 8667762
TI  - [Historical perspective of euthanasia. From Hippokrates to Nazi physicians].

PMID- 8667763
TI  - [There is no reason to substitute the Swedish scale for cranial injuries].

PMID- 8667764
TI  - [Dyspepsia and H pylori--in which patients should gastroscopy be performed?].

PMID- 8667765
TI  - [Choice of treatment of H pylori infection--what sources have been used?].

PMID- 8667766
TI  - [Directives for emergency care interns create problems].

PMID- 8667767
TI  - [Make the concepts on quality of health care clear!].

PMID- 8667768
TI  - [Childhood environment directs cognitive development. Check-ups of 4-year old
      children at child health care centers may be used as a tool in municipal
      planning].

PMID- 8667769
TI  - [Botulinum toxin--from threat to cure].

PMID- 8667771
TI  - [Chubby women absolutely do not sell].

PMID- 8667770
TI  - [Increased resistance after administration of antibiotics to animals].

PMID- 8667772
TI  - [Weight watchers. Profitable business and popular movement].

PMID- 8667773
TI  - [Doctor Aly has reconsidered fasting].

PMID- 8667774
TI  - [Children with poliomyelitis in Sweden 1996].

PMID- 8667775
TI  - [A registry of adverse effects of dental materials in Umea].

PMID- 8667776
TI  - [A man ate penicillin, died within an hour].

PMID- 8667777
TI  - [Esophageal cancer on the increase. Is Barrett esophagus the cause?].
AB  - At the Dept of Surgery, Lund University, during the 10-year period 1985-95, 54
      patients with adenocarcinoma of the gastro-oesophageal junction (17 with
      Barrett's epithelium, and 37 without) underwent oesophageal resection:
      oesophagectomy and gastric pull-up (n = 10), extended total gastrectomy (n = 37),
      or oesophageal resection and interposition of colon (n = 2) or jejunum (n = 5).
      Hospital mortality was 3.7% (2/54), and the mean duration of hospitalisation 13
      days (range, 9-42). Long-term survival was significantly better in the Barrett's
      oesophagus subgroup than in the carcinoma of the cardia (non-Barrett's
      oesophagus) subgroup, the respective rates being 50% vs. 10% (p = 0.0052; Log
      rank test). The better survival in the Barrett's oesophagus subgroup is probably
      to be explained by the earlier stage of disease among these patients, in turn due
      to a history of gastro-oesophageal reflux, whereas the predominant symptom in the
      cardia carcinoma subgroup was dysphagia.

PMID- 8667778
TI  - [Increasing claims to Patient Insurance. 3000 compensations go to injured
      patients in a single year].

PMID- 8667779
TI  - [Nerve injuries in rectal surgery].

PMID- 8667780
TI  - [Don't forget the men! A group of relatives of women surgically treated for
      breast cancer understands more and worries less].

PMID- 8667782
TI  - ["According to the patient" in the new certificates].

PMID- 8667781
TI  - [The physician and the computer].

PMID- 8667783
TI  - [Practical information on Angelman syndrome].

PMID- 8667784
TI  - [Risks of a calcium channel blocker concerns an old preparation].

PMID- 8667785
TI  - [Preventive work requires more engagement].

PMID- 8667786
TI  - [Pharmacological therapy in bleeding esophageal varices: good results with
      glypressin].

PMID- 8667787
TI  - [The 10 cases which shook England. Distinctive features of a new variant of
      Creutzfeldt-Jakob syndrome].

PMID- 8667788
TI  - [Good prognosis for very low birth weight infants].
AB  - A population-based multicentre study, comprising all very low birthweight (VLBW;
      < or = 1,500 g) infants born alive in the south-east region of Sweden during a 15
      month period, was performed in the late 1980s. Among the VLBW infants there were
      107 lifebirths (a rate of 0.72%), 86 (80.4%) neonatal survivors and no late
      deaths. Twenty (18.4%) had intracranial complications, two (2.3%) retinopathy of
      prematurity, grade 3, and six (5.6%) bronchopulmonary dysplasia. At follow-up at
      18 months of uncorrected age, the VLBW infants were still lighter in weight and
      of shorter stature than control group infants. Of the five (5.8%) of the
      surviving VLBW infants who had significant neurological disorder at 18 months of
      age, all had weighed less than 800 g at birth, and had manifested neurological
      symptoms at 6 months of age. The hospitalisation rate during the first 18 months
      of life was greater in the VLBW than the control group.

PMID- 8667789
TI  - [A proposal from the Ministry of Health and Social Affairs: prohibit genetic
      tests for insurance purposes].

PMID- 8667790
TI  - [Missing links in immunologic defense. Endogenous antibiotics are the primary
      protection].

PMID- 8667791
TI  - [A study of newborn infants with severe heart defects. Longer transportation did
      not increase the risks].

PMID- 8667792
TI  - [A study of spontaneous nosebleed. Pharmaceuticals contributed probably in every
      third case].

PMID- 8667793
TI  - [Hereditary spherocytosis is more common than expected. Hemolysis, anemia and
      splenomegaly are among the symptoms].

PMID- 8667794
TI  - [Difficult to assess suicide threats. Many reports received by the insurance
      companies]].

PMID- 8667795
TI  - [Compensation for delayed diagnosis of vitamin B 12 deficiency].

PMID- 8667796
TI  - [Successful treatment of "electricity hypersensitivity". The patient was assisted
      in curing himself].

PMID- 8667798
TI  - ["Repressed memories" don't prove sexual abuse].

PMID- 8667797
TI  - [Effect of a care program examined. Physicians interviewed on asthma therapy].

PMID- 8667799
TI  - [The health data committee wants law regulations on personal registries in health
      care].

PMID- 8667800
TI  - [A new model for more efficient planning of continuing education in the county of
      Varmland].

PMID- 8667801
TI  - [Psyk-Adel (Psychiatric care for the aged)].

PMID- 8667802
TI  - [Are child health services really efficient? Resources can be allocated to
      exposed children].

PMID- 8667804
TI  - [Statistical scientific scrutiny has not been done].

PMID- 8667803
TI  - [A society of professors emeriti: take advantages of the capacity among medical
      emeriti!].

PMID- 8667806
TI  - [A headband--dry and wet].

PMID- 8667805
TI  - [Aggressive diagnostic methods are needed in stroke].

PMID- 8667807
TI  - [New prescription forms counteract quality development].

PMID- 8667808
TI  - [Declaration on health status in Europe].

PMID- 8667809
TI  - [A meaningless dieting cure].

PMID- 8667810
TI  - [HSAN's over-confidence in radiography].

PMID- 8667811
TI  - [A significant difference between genetic testing and substance abuse testing at
      workplaces].

PMID- 8667812
TI  - [Intensify the diagnosis of myocardial infarction! Longer hospitalization should
      be beneficial].

PMID- 8667813
TI  - [Why was myocardial infarction missed? 5 years of reports to the HSAN give a
      hint].

PMID- 8667815
TI  - [A chest-pain-unit. A complement to the department of myocardial infarction].

PMID- 8667814
TI  - [Myocardial infarction is diagnosed in every 20th case of acute chest pain. Good
      consistency between 2 emergency admmission departments].

PMID- 8667816
TI  - [Urinary incontinence. A female curse covered by health services guaranteed by
      politicians].

PMID- 8667817
TI  - [Reintroduction of social security numbers gives better basis for evaluation. The
      patient registry is open for research].

PMID- 8667818
TI  - [Tores Theorell on the stress causing disease. "New" hormones protect during a
      crisis].

PMID- 8667819
TI  - [Art psychotherapy solves psychosomatic disorders].

PMID- 8667820
TI  - [Angiogenesis--a marker for metastases].

PMID- 8667821
TI  - [The man behind the Fanconi's anemia. A citizen of the world in pediatrics].

PMID- 8667822
TI  - [A milestone for cytogenetic research. Genes of the yeast cell surveyd].

PMID- 8667823
TI  - [Comment to Goran Sjonell: child health services are continuously revised].

PMID- 8667824
TI  - [Child health services are efficient--but more studies are necessary].

PMID- 8667825
TI  - [A new form for every fifth prescription!].

PMID- 8667827
TI  - [Does nitric oxide cause pulmonary hypertension? A new report with new
      questions].

PMID- 8667826
TI  - [Diagnosis of ascites--malignant or benign etiology?].

PMID- 8667828
TI  - [Pseudoaneurysm is most easily cured with ulrasound].

PMID- 8667829
TI  - [Unsatisfactory routines. Optimal treatment of postoperative pain needs
      cooperation and education].

PMID- 8667830
TI  - [Belching, flatus, breath. Measurements of airborne nitric oxide in the non
      invasive diagnosis of inflammation].
AB  - Enzymatic and non-enzymatic production of nitric oxide in humans: role in
      inflammation and host defence. Recent studies indicate that nitric oxide (NO) may
      play an important role in first line of defense in the airways and the stomach,
      since bacteriostatic concentrations of this gas has been found in the lumen of
      these organs. Airway NO synthesis is mostly carried out by a high producing
      "inducible like" NO synthase constantly present in the epithelium of the
      paranasal sinuses. Stomach NO synthesis, on the other hand, is non-enzymatic and
      results from acidification of salivary derived nitrite. Excess NO production has
      been implicated in the pathogenesis of inflammation although the exact role of NO
      is still unclear. NO production is enhanced in the mucosa of inflammatory
      diseases such as asthma and ulcerative colitis. Measurements of local NO
      production may be done in an easy way in the airways and the gastrointestinal
      tract by simply analyzing the concentrations of NO gas in luminal air of these
      hollow organs. Such non-invasive methods may be useful not only to explore what
      role NO plays in inflammation and host defence but possibly also in the diagnosis
      and monitoring of inflammatory mucosal diseases in the airways and
      gastrointestinal tract.

PMID- 8667831
TI  - [Immediate care in myocardial infarction is most important. Thrombolysis right at
      home or in the ambulance saves lives].

PMID- 8667833
TI  - [Optometrists in the USA want the right to surgically treat myopia].

PMID- 8667832
TI  - [Poisonings with analgesics. Paracetamol and dextropropoxyphene dominate and
      cause the most severe symptoms in a 3-year material].

PMID- 8667834
TI  - [Blood donors have a positive attitude towards donation of other organs. The
      donation card is most common among women].

PMID- 8667835
TI  - [The man behind the syndrome: William John Adie. He won an involuntary victory in
      an academic dispute].

PMID- 8667836
TI  - [Decisions made by insurance companies should be questioned. An offended patient
      should receive assistance to a legal trial].

PMID- 8667837
TI  - [Ten cases of poisoning with gamma hydroxybutyrate. An endogenous substance used
      by body builders].

PMID- 8667838
TI  - [Reduced transmission of HIV in several African countries].

PMID- 8667839
TI  - [Is the head of a clinic a common civil servant?].

PMID- 8667840
TI  - [Forensic psychiatry and special care are important!].

PMID- 8667841
TI  - [Total assessment must be done in bone density estimation].

PMID- 8667842
TI  - [Fibromyalgia--the explanatory mechanisms should be searched centrally, not
      peripherally].

PMID- 8667843
TI  - [A new study on hypercholesterolemia. Statin is effective against heart disease].

PMID- 8667845
TI  - [Biological aspects of sexual orientation: similar behavior in mice and men].

PMID- 8667844
TI  - [Hemorrhagic complications of anticoagulation therapy. Avoid underreporting!
      Check registries!].

PMID- 8667846
TI  - [Postpartum weight gain is not easy to explain].

PMID- 8667847
TI  - [The connection between obesity and chronic diseases. Hospital registries may be
      used for surveys].

PMID- 8667849
TI  - [Hearing loss in Turner syndrome].

PMID- 8667848
TI  - [Diagnosis of anal sphincter injuries caused by delivery. Intra-anal ultrasound
      is a well-functioning method].

PMID- 8667850
TI  - [Children with not confirmed diagnosis of brain diseases. "Anonymous"--a network
      for support and information].

PMID- 8667851
TI  - [Food, drugs or doping? Some branched-chain amino acids and an evening paper!].

PMID- 8667852
TI  - [Adverse effects of ergot alkaloids. An important differential diagnosis from
      asbestos-induced pleuritis].

PMID- 8667853
TI  - [Peroperative cholangiography is a good weapon against injuries. Surgery of
      gallstones is still done without access to radiography].

PMID- 8667854
TI  - [Patients received wrong treatment due to wrong diagnosis. They will receive
      compensation for adverse effects of psychopharmaceuticals].

PMID- 8667855
TI  - [Severe abdominal symptoms may be disguised by NSAID preparations].

PMID- 8667856
TI  - [New recommendations on treatment of acne].

PMID- 8667858
TI  - Climate-and-health debate warms up.

PMID- 8667857
TI  - Long-term comparative trial of glibenclamide and chlorpropamide in diet-failed,
      maturity-onset diabetics.
AB  - The long-term clinical effectiveness of glibenclamide was compared with
      chlorpropamide in highly comparable groups of three hundred and twenty-one diet
      failed, non-obese, maturity-onset, newly diagnosed diabetics. The overall primary
      failure-rate in the chlorpropamide-treated patients was significantly less
      (p<0.05), and more patients were on chlorpropamide at the end of two years than
      were on glibenclamide (p<0.01). Although there were fewer secondary failures with
      chlorpropamide treatment, this difference was not significant. The final blood
      glucose and change in body-weight were similar in patients from both treatment
      groups still taking the original sulphonylurea agent 2 years later. Hypoglycaemic
      episodes were more common and severe in the glibenclamide-treated patients.

PMID- 8667859
TI  - Raltitrexed, a new drug for advanced colorectal cancer.

PMID- 8667860
TI  - Age as a predictor of progression in HIV infection.

PMID- 8667861
TI  - Japanese encephalitis: a Chinese solution?

PMID- 8667862
TI  - Influence of physician perceptions on putting knowledge into practice.

PMID- 8667863
TI  - Confusion of levels in monitoring outcomes and/or process.

PMID- 8667864
TI  - Importance of age at infection with HIV-1 for survival and development of AIDS in
      UK haemophilia population. UK Haemophilia Centre Directors' Organisation.
AB  - BACKGROUND: Greater age at infection with HIV-1 is known to be associated with
      shorter time to development of AIDS, but the size of the differences between
      people infected in infancy and those infected in old age has not been examined in
      a single large population of patients with death as an endpoint. We, therefore,
      investigated the role of age at seroconversion in the entire UK population of
      haemophiliacs. METHODS: We studied 1216 HIV-1-infected haemophilia patients in
      the UK who were registered with the National Haemophilia Register and were alive
      on Jan 1, 1985. Their estimated ages at HIV-1 seroconversion ranged from 8 months
      to 79 years. FINDINGS: 10 years after seroconversion 67% (95% Cl 64-69) of the
      population were still alive. Survival was strongly related to age at
      seroconversion (86% [82-90], 72% [68-76], 45% [39-51], and 12% [5-21] at 10 years
      among those patients who seroconverted at ages < 15, 15-34, 35-54, and > or =
      55). This steep age-gradient in survival was not explained by deaths expected in
      the absence of HIV infection or by confounding with other factors such as
      haemophilia type or severity. The age-gradient was steeper for survival (ie, time
      from HIV-1 infection to death) than for time to diagnosis of AIDS, partly because
      survival after an AIDS diagnosis was poorer in older patients, and there was also
      a substantial increase in mortality among HIV-infected patients who did not
      satisfy the formal AIDS definition and this increase was greater in older
      patients. INTERPRETATION: Age at infection with HIV-1 is a more important
      determinant of survival than has previously been appreciated. Age should,
      therefore, be considered in future studies of disease progression, and studies
      that compare people infected at different ages should provide insight into the
      biology of the immune response to HIV-1.

PMID- 8667865
TI  - Critical illness myopathy and neuropathy.
AB  - BACKGROUND: Critically ill patients may develop muscle weakness or paralysis
      during the course of sepsis and multiple-organ failure. We studied peripheral
      nerve and muscle disorders (NMD) in comatose patients. METHOD: Comatose patients
      who developed paralysis associated with absent deep-tendon reflexes had
      electroneuromyography (ENMG) and muscle-nerve biopsy specimens taken. Onset and
      duration of sepsis, multiple-organ dysfunction and failure, biochemical
      alterations, and drugs potentially interfering with nerve-muscle function were
      recorded. FINDINGS: 24 patients became quadriparetic or quadriplegic; muscle
      changes were found in 23. Axonal neuropathy was found in eight of 22 patients
      examined. All patients had prolonged sepsis and multiple-organ dysfunction, but
      only 14 had multiple-organ failure. Drugs such as steroids, neuromuscular
      blocking agents, and aminoglycosides were not responsible for paresis, and the
      part played by hyperglycaemia and hypoalbuminaemia is uncertain. Attending
      physicians predicted a fatal outcome in all cases, although six of seven
      survivors fully recovered within 115-210 days from the onset of paralysis.
      INTERPRETATION: Comatose patients may become completely paralysed because of NMD.
      The diagnosis is important to avoid unnecessary investigations and unreasonably
      pessimistic prognosis. ENMG is essential for the diagnosis and for planning
      further clinical management. Biopsy needs to be done only when it is necessary to
      properly classify NMD.

PMID- 8667866
TI  - Effectiveness of live-attenuated Japanese encephalitis vaccine (SA14-14-2): a
      case-control study.
AB  - BACKGROUND: Japanese encephalitis is a major cause of death and disability
      throughout Asia, including the Indian subcontinent. Although an effective vaccine
      for Japanese encephalitis is available, hundreds of millions of susceptible
      individuals remain unimmunised because of the vaccine's cost. In 1988, an
      inexpensive live-attenuated vaccine (SA14-14-2) was licensed in China. We have
      measured the effectiveness of this vaccine. METHODS: In a case-control study in
      rural Sichuan Province, China, the 56 cases consisted of children admitted to
      hospital with acute Japanese encephalitis, and were confirmed serologically. 1299
      village-matched and age-matched controls were identified, and vaccination
      histories obtained from pre-existing written records. FINDINGS: The effectiveness
      of one dose was 80% (95% Cl 44 to 93%); that of two doses was 97.5% (86 to
      99.6%). Controlling for multiple potential confounders did not alter these
      results. INTERPRETATION: We conclude that a regimen of two doses of live
      attenuated Japanese encephalitis vaccine, administered 1 year apart, is effective
      in the prevention of clinically important disease. Subsequent study is needed to
      assure the safety of this vaccine.

PMID- 8667867
TI  - Functional activation of mutant human insulin receptor by monoclonal antibody.
AB  - BACKGROUND: A mutant insulin receptor, Ser323Leu, has been reported in two
      severely insulin-resistant patients with Rabson-Mendenhall syndrome. In both
      cases, extreme hyperglycaemia could not be controlled by conventional
      antidiabetic therapy. The SER323Leu mutant insulin receptor is inserted normally
      in the plasma membrane but has very low binding affinity for insulin. A
      monoclonal antibody directed against the extracellular domain of the insulin
      receptor (83.14) can mimic the natural ligand as far as the first step after
      ligand binding--autophosphorylation of the intracellular domain of the receptor.
      We have investigated whether antibody binding can imitate autophosphorylation of
      the Ser323Leu mutant receptor and lead to metabolic events within the cell.
      METHODS: The effects of insulin and the insulin-receptor monoclonal antibody on
      receptor autophosphorylation and glycogen synthesis were compared in Chinese
      hamster ovary cells expressing the wild-type human insulin receptor, mock
      transfected cells, cells expressing an insulin-receptor mutant without
      autophosphorylation capacity, and cells expressing the Ser323Leu mutant receptor.
      FINDINGS: Cells expressing the SER323Leu mutant receptor had very low specific
      insulin binding and, unlike cells expressing wild-type insulin receptors, did not
      show autophosphorylation or stimulation of glycogen synthesis in response to
      insulin. However, exposure of cells expressing the Ser323Leu mutant receptor to
      monoclonal antibody 83.14 resulted in autophosphorylation and stimulation of
      glycogen synthesis similar to that seen in cells expressing wild-type insulin
      receptors. INTERPRETATION: Although insulin does not bind to cells expressing the
      Ser323Leu mutation, insulin signalling can be mimicked by exposure of the cells
      to an antibody to the extracellular domain of the insulin receptor. Activation by
      monoclonal antibodies of mutant transmembrane receptors that show normal cell
      surface expression but defective ligand binding may provide an approach to the
      therapy of some subtypes of inherited hormone resistance for which little
      effective treatment is available.

PMID- 8667868
TI  - Endarterectomy for moderate symptomatic carotid stenosis: interim results from
      the MRC European Carotid Surgery Trial.
AB  - BACKGROUND: The objective of this study was to assess whether carotid
      endarterectomy is an appropriate treatment for patients with recent
      cerebrovascular events in the territory supplied by a moderately stenosed (30
      69%) internal carotid artery. Results have previously been reported for severe
      (70-99%) and mild (0-29%) stenosis. METHODS: A multicentre randomised controlled
      trial recruited 1599 patients with moderate stenosis treated in 97 hospitals from
      15 countries. 60% of patients were allocated to receive and 40% to avoid carotid
      endarterectomy. The analysis was by intention to treat. FINDINGS: Nine patients
      were omitted from the analysis because no follow-up data were received. Stroke
      free life expectancy (curtailed at 8 years) was shorter in the surgery patients
      than in the non-surgery control groups (patients with 30-49% stenosis, life
      expectancy = 6.16 years [controls: 6.63 years]; patients with 50-69% stenosis,
      life expectancy = 5.93 [6.14] years). It remains possible that patients might
      derive some benefit from surgery in the very long term; however, our data show
      that no benefit would be gained over a period of < 4-5 years in patients with 50
      69% stenosis and < 6-7 years in patients with 30-49% stenosis. INTERPRETATION:
      Previous interim results from this study showed that surgery is beneficial in
      patients with severe stenosis but harmful in those with mild stenosis. With more
      randomised patients and longer follow-up, the study now shows that endarterectomy
      is not indicated for most, possibly all, patients with moderate symptomatic
      carotid stenosis.

PMID- 8667869
TI  - Syringomyelia as a cause of body hypertrophy.
AB  - BACKGROUND: Among 26 patients with communicating syringomyelia who came to our
      out-patient clinic from April, 1989, to March, 1995, three (11.5%) had
      hypertrophy in limbs, hands, or feet. One had crossed hypertrophy. We considered
      the possibility that syringomyelia caused body hypertrophy. METHODS: We searched
      MEDLINE for articles which mention body asymmetry or hypertrophy, and examined
      the findings in our own patients. FINDINGS: The site of hypertrophy in our three
      patients coincided with the site of the neurological and magnetic resonance
      imaging findings. In addition, the horizontal and vertical location of the syrinx
      corresponded with the site of all four hypertrophic limbs. We located ten
      articles in which a diagnosis of syringomyelia was made, and five in which other
      diagnoses were made. INTERPRETATION: From studying our patients as well as those
      previously reported, we speculate that some types of body hypertrophy are due to
      damage, accompanied by stimulation, of the sympathetic neurons in the ipsilateral
      lateral horn of the spinal cord. Although there are many causes of hypertrophy,
      we suggest that the possibility of syringomyelia be investigated in patients with
      body hypertrophy, especially in those with any accompanying neurological
      abnormality.

PMID- 8667870
TI  - An unhappily married man with thick soles.

PMID- 8667871
TI  - Field trial of oxygen concentrators in upper Egypt.
AB  - Technical problems in developing countries often require more than just
      technological solutions. Many small hospitals in rural areas are without a
      reliable oxygen supply; small oxygen concentrators offer a solution, but simply
      sending out machines is ineffective. This account details the setting up and
      first year's operation of a project to test oxygen concentrations in a developing
      country. A co-ordinated strategy has been developed to include machines,
      supplies, education, training, and feedback. Initial results are encouraging, and
      support the idea that suitably installed and maintained concentrations can have a
      valuable role in bringing oxygen therapy to patients and hospitals in countries
      which have so far been denied it.

PMID- 8667872
TI  - An uneasy relationship: the tensions between medicine and the media.
AB  - The enduring tensions between medicine and the media are largely due to the
      different perspectives of biomedical scientists and journalists, as this final
      essay in the series on medicine and the media underscores. These tensions arise
      because of perceived differences in defining science news, conflicts over styles
      of science reporting, and most of all disagreement about the role of the media.
      In the 1990s, scientists are especially concerned by media messages that question
      their credibility. Since scientists and journalists depend on each other in the
      communication of science and the shaping of the public meaning of science and
      medicine, the tensions are likely to increase.

PMID- 8667873
TI  - A unifying purinergic hypothesis for the initiation of pain.
AB  - There have been hints over the years about the involvement of purines in pain,
      and we now have direct evidence with the cloning and characterisation of
      extracellular receptors for ATP (P2X-purinoceptors) on nociceptive sensory
      neurons. In this article, a hypothesis is put forward about the sources of ATP
      released to activate these receptors in three different pain conditions--as a
      cotransmitter from sympathetic nerves in causalgia and reflex sympathetic
      dystrophy; from endothelial cells in vascular pain, including migraine and
      angina; and from tumour cells in cancer. These findings are leading to an active
      search for selective P2-purinoceptor antagonists to alleviate pain.

PMID- 8667874
TI  - Caring effects.

PMID- 8667875
TI  - Malarial range set to spread in a warmer world.

PMID- 8667876
TI  - FDA approve bark-derived drug.

PMID- 8667878
TI  - Egypt's trade in hymen repair.

PMID- 8667877
TI  - Pumping iron in Parkinson's disease.

PMID- 8667879
TI  - Upjohn and FDA criticized over Halcion.

PMID- 8667880
TI  - Surprise twist to Canada's tainted-blood inquiry.

PMID- 8667881
TI  - Unproven breast-cancer therapy widely used in USA.

PMID- 8667882
TI  - Effect of smoking cessation on cervical lesion size.

PMID- 8667883
TI  - Effects of smoking cessation on cervical lesion size.

PMID- 8667884
TI  - Steatorrhoea: you cannot trust your eyes when it comes to diagnosis.

PMID- 8667885
TI  - Nitrous oxide and morphine in children with sickle cell crisis.

PMID- 8667886
TI  - Randomised trial of laparoscopic versus small-incision cholecystectomy.

PMID- 8667887
TI  - Randomised trial of laparoscopic versus small-incision cholecystectomy.

PMID- 8667888
TI  - Randomised trial of laparoscopic versus small-incision cholecystectomy.

PMID- 8667889
TI  - Randomised trial of laparoscopic versus small-incision cholecystectomy.

PMID- 8667890
TI  - Female athletes: their hormones, muscles, and bones.

PMID- 8667891
TI  - Randomised trial of laparoscopic versus small-incision cholecystectomy.

PMID- 8667892
TI  - Down's syndrome screening.

PMID- 8667893
TI  - Down's syndrome screening.

PMID- 8667894
TI  - Occlusion of central retinal vein after hepatitis B vaccination.

PMID- 8667895
TI  - Selection of the fittest in stroke research and audit.

PMID- 8667896
TI  - Breast cancer and radiotherapy in ataxia-telangiectasia heterozygote.

PMID- 8667897
TI  - Pharmaceutical company trials and the integrity of medical research.

PMID- 8667898
TI  - Pharmaceutical company trials and the integrity of medical research.

PMID- 8667899
TI  - Screening for early detection of prostate cancer.

PMID- 8667900
TI  - Thrombolytic therapy for acute myocardial infarction in rural Japan. The Kochi
      Acute Myocardial Infarction (KAMI) Study Group.

PMID- 8667901
TI  - Stress in hospital consultants.

PMID- 8667902
TI  - Safety of oral immunisation with recombinant urease in patients with Helicobacter
      pylori infection.

PMID- 8667903
TI  - Prostate-specific antigen in nipple aspirate.

PMID- 8667904
TI  - Role of gamma delta T cells in Behcet's disease.

PMID- 8667905
TI  - Hepatitis G virus in long-term survivors of haematological malignancy.

PMID- 8667906
TI  - Poliomyelitis outbreak in Zambia.

PMID- 8667907
TI  - Childhood cancer mortality in Italy.

PMID- 8667908
TI  - Manic-depressive illness and tyrosine hydroxylase markers. Bipolar Disorder
      Working Group.

PMID- 8667909
TI  - Maternal segregation distortion in sickle-cell trait.

PMID- 8667910
TI  - Beef safety and publication of scientific information.

PMID- 8667911
TI  - Beef safety and publication of scientific information.

PMID- 8667912
TI  - Prion protein released by platelets.

PMID- 8667913
TI  - Global transient amnesia and subclavian steal syndrome.

PMID- 8667914
TI  - Managing a comfortable death.

PMID- 8667915
TI  - Implications of genetic variability in HIV for epidemiology and public health.

PMID- 8667917
TI  - Familial Mediterranean fever: underlying defect clearer, but diagnostic problems
      persist.

PMID- 8667916
TI  - Sports for all or physical activity for all?

PMID- 8667918
TI  - 100 years of the endocrine battle against breast cancer.

PMID- 8667919
TI  - Glaucoma and nitric oxide.

PMID- 8667920
TI  - Playing with smoke, but not without fire.

PMID- 8667921
TI  - Duration and intensity of maintenance chemotherapy in acute lymphoblastic
      leukaemia: overview of 42 trials involving 12 000 randomised children.
AB  - BACKGROUND: The effects on long-term outcome in childhood acute lymphoblastic
      leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy
      need to be assessed reliably. With this objective the Childhood ALL Collaborative
      Group coordinated a worldwide overview of all randomised trials that began before
      1987. METHODS: Individual patient data were sought for about 3900 children in
      trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of
      intensive "reinduction" chemotherapy during maintenance, and 4400 in trials of
      various other questions, including 1300 in trials of pulses of vincristine and
      prednisone (VP) during maintenance. Analyses were of survival in first remission,
      overall survival, and cause-specific mortality. FINDINGS: Deaths during remission
      were increased by longer maintenance (2.7 percent vs 1.2 percent), VP pulses (4.0
      vs 3.2 percent), and intensive reinduction (4.8 percent vs 3.3 percent), but
      these increases were counterbalanced by reductions in relapses. Total events
      (relapse or death) were significantly reduced by longer maintenance (23.3 percent
      vs 27.6 percent), VP pulses (31.2 percent vs 40.4 percent) and intensive
      reinduction (27.8 percent vs 35.8 percent) (each 2p<0.001). Many of those who
      relapsed were successfully re-treated, however, and only for intensive
      reinduction was overall survival significantly improved (18.5 percent vs 22.3
      percent; 2p=0.01). INTERPRETATION: Intensive reinduction chemotherapy in these
      trials produced an absolute improvement of about 4 percent in long-term survival;
      if the extra deaths in remission had been avoided, this would have been a 5
      percent benefit. Further improvements in survival seem more likely to be obtained
      with intensive treatment than with longer low-level maintenance.

PMID- 8667922
TI  - Sports participation and emotional wellbeing in adolescents.
AB  - BACKGROUND: Regular physical activity may have psychological benefits. Our study
      assessed the association between extent of participation in regular sport or
      vigorous recreational activity and emotional wellbeing in adolescents aged 16
      years. METHODS: Data were collected from a cohort of adolescents, born between
      April 5 and April 11, 1970, in England, Scotland, and Wales, who took part in the
      follow-up assessment at age 16 years. Emotional wellbeing was assessed by the
      general health questionnaire (GHQ) and the malaise inventory (divided into
      psychological and somatic subscales). Information was obtained about
      participation in ten team and 25 individual sports and vigorous recreational
      activities during the previous year. Non-vigorous recreations, such as darts and
      snooker, were assessed separately. Social class and health status (recent illness
      and use of hospital services) were included in our analyses as possible
      confounding factors. 2223 boys and 2838 girls with a mean age of 16.3 years (SD
      0.38) were included in our analysis. Statistical analysis was by multiple linear
      and logistic regression. FINDINGS: The sport and vigorous recreational activity
      index was positively associated with emotional wellbeing independently of sex,
      social class, health status, and use of hospital services. These associations
      were significant for the psychological symptom subscale of the malaise inventory
      (regression coefficient -0.024, 95 percent Cl -0.036 to -0.011, p<0.001) and the
      GHQ (odds ratio of emotional distress per unit increase in vigorous physical
      activity 0.992, 95 percent Cl 0.985-0.998, p<O.O1). By contrast, participation in
      non-vigorous activities was associated with high psychological and somatic
      symptoms on the malaise inventory. INTERPRETATION: We conclude that emotional
      wellbeing is positively associated with extent of participation in sport and
      vigorous recreational activity among adolescents. Although causal associations
      cannot be assumed in this cross-sectional analysis, our results are consistent
      with experimental evidence that vigorous exercise has favourable effects on
      emotional state.

PMID- 8667923
TI  - Measles and atopy in Guinea-Bissau.
AB  - BACKGROUND: Epidemiological studies have led to speculation that infections in
      early childhood may prevent allergic sensitisation but evidence to support this
      hypothesis is lacking. We investigated whether measles infection protects against
      the development of atopy in children of Guinea-Bissau, West Africa. METHODS: We
      conducted a historical cohort study in Bandim, a semi-rural district of Bissau,
      the capital of Guinea-Bissau. 395 young adults, first surveyed in 1978-80 aged 0
      6 years, were followed up in 1994. Our analyses were restricted to 262
      individuals still living in Bandim for whom a measles history, documented in
      childhood, was judged to be reliable. We defined atopy as skin-prick test
      positivity (> or = 3 mm weal) to one or more of seven allergens. FINDINGS: 17
      (12.8 percent) of 133 participants who had had measles infection were atopic
      compared with 33 (25.6 percent) of 129 of those who had been vaccinated and not
      had measles (odds ratio, adjusted for potential confounding variables 0.36 [95
      percent CI 0.17-0.78], p=O.O1). Participants who had been breastfed for more than
      a year were less likely to have a positive skin test to housedust mite. After
      adjustment for breastfeeding and other variables, measles infection was
      associated with a large reduction in the risk of skin-prick test positivity to
      housedust mite (odds ratio for Dermatophagoides pteronyssinus 0.20 [0.05-0.81],
      p=0.02; D farinae 0.20 [0.06-0.71], p=0.01). INTERPRETATION: Measles infection
      may prevent the development of atopy in African children.

PMID- 8667924
TI  - Lethal infection by a previously unrecognised metazoan parasite.
AB  - BACKGROUND: New microbial pathogens or variant clinical manifestations of known
      organisms may be first found in immunodeficient patients. An HIV-infected man
      developed a rapidly-enlarging abdominal mass, suggestive of a neoplasm, that
      subsequently invaded his liver and caused death. Initial studies showed unusual
      tissue morphology that could not be matched with any known disease process.
      METHODS: Tissues obtained from biopsy at laparotomy and necropsy were studied by
      light microscopy, immunohistochemistry, electron microscopy, and broad-range
      ribosomal DNA-amplification and sequence analysis. FINDINGS: Tissue lesions were
      characterised by peculiar cytoplasmic sacs containing minute cells with very
      prominent nucleoli. The pathological process was recognised as a parasitic
      infection, although its features were different from those of any known
      eukaryotic pathogen. Phylogenetic analysis of a 357 bp 18S rDNA sequence
      amplified directly from the involved tissue indicated that the causative agent
      was a previously-uncharacterised cestode. INTERPRETATION: Fatal disease produced
      by this newly recognised cestode may not be limited to immunodeficient hosts.
      Awareness of this metazoan infection may allow early diagnosis-by morphology and
      DNA sequence analysis--and perhaps successful treatment of subsequent cases.

PMID- 8667925
TI  - Current results of intestinal transplantation. The International Intestinal
      Transplant Registry.
AB  - BACKGROUND: Intestinal transplantation is an alternative to total parenteral
      nutrition (TPN) for the treatment of chronic intestinal failure. To determine the
      current status of small-bowel transplantation, we have reviewed the world
      experience since 1985. METHODS: We built up an international registry by asking
      twenty-five intestinal transplantation programmes to submit standard data on
      their cases operated on between 1985 and June, 1995. FINDINGS: One centre (two
      transplantations) did not use our report form, and these cases were excluded. The
      remaining twenty-four programmes did 180 transplantations in 170 patients. Two
      thirds of the recipients were children. The main indication (64 percent) was
      short-gut syndrome, another 13 percent had a tumour. Of the grafts, 38 percent
      were small-bowel with or without colon, 46 percent were intestine plus liver, and
      16 percent were multivisceral. Graft/patients' survival (percent) at 1 and 3
      years under cyclosporin immunosuppression was, respectively: 17/57 and 11/50 for
      small bowel only; 44/44 and 28/28 for intestine plus liver; and 41/41 and 41/41
      for multiviscera. The corresponding figures under tacrolimus were: 65/83 and
      29/47; 64/66 and 38/40; and 51/59 and 37/43. 78 percent of the 86 survivors had
      stopped TPN and resumed oral nutrition. INTERPRETATION: Our approach cannot give
      data on long-term outcome. The short-term results of intestinal transplantation
      are similar to those of lung grafting. We conclude that small-bowel
      transplantation has become a life-saving option for patients who cannot be
      maintained on TPN and for those who require massive abdominal evisceration for
      locally aggressive tumours.

PMID- 8667926
TI  - A woman who took cod-liver oil and smoked.

PMID- 8667928
TI  - King George III's urine and indigo blue.

PMID- 8667927
TI  - Euthanasia and physician-assisted suicide: attitudes and experiences of oncology
      patients, oncologists, and the public.
AB  - BACKGROUND: Euthanasia and physician-assisted suicide are pressing public issues.
      We aimed to collect empirical data on these controversial interventions,
      particularly on the attitudes and experiences of oncology patients. METHODS: We
      interviewed, by telephone with vignette-style questions, 155 oncology patients,
      355 oncologists, and 193 members of the public to assess their attitudes and
      experiences in relation to euthanasia and physician-assisted suicide. FINDINGS:
      About two thirds of oncology patients and the public found euthanasia and
      physician-assisted suicide acceptable for patients with unremitting pain.
      Oncology patients and the public found euthanasia and physician-assisted suicide
      least acceptable in vignettes involving "burden on the family" and "life viewed
      as meaningless". In no vignette--even for patients with unremitting pain--did a
      majority of oncologists find euthanasia or physician-assisted suicide ethically
      acceptable. Patients actually experiencing pain were more likely to find
      euthanasia or physician-assisted suicide unacceptable. More than a quarter of
      oncology patients had seriously thought about euthanasia or physician-assisted
      suicide and nearly 12 percent had seriously discussed these interventions with
      physicians or others. Patients with depression and psychological distress were
      significantly more likely to have seriously discussed euthanasia, hoarded drugs,
      or read Final Exit. More than half of oncologists had received requests for
      euthanasia or physician-assisted suicide. Nearly one in seven oncologists had
      carried out euthanasia or physician-assisted suicide. INTERPRETATION: Euthanasia
      and physician-assisted suicide are important issues in the care of terminally ill
      patients and while oncology patients experiencing pain are unlikely to desire
      these interventions patients with depression are more likely to request
      assistance in committing suicide. Patients who request such an intervention
      should be evaluated and, where appropriate, treated for depression before
      euthanasia can be discussed seriously.

PMID- 8667929
TI  - Intelligence and the X chromosome.

PMID- 8667930
TI  - Timing of fetal membrane rupture predicts HIV risk.

PMID- 8667931
TI  - New ideas for restenosis research aired in Ohio.

PMID- 8667932
TI  - Relentless unravelling of New Zealand's health-care system.

PMID- 8667933
TI  - Leading council.

PMID- 8667934
TI  - Gastric anisakidosis due to Pseudoterranova decipiens larva.

PMID- 8667935
TI  - Dissociation between cerebral imaging and clinical picture.

PMID- 8667936
TI  - 5HT 2a receptor T102C polymorphism and schizophrenia.

PMID- 8667937
TI  - 5HT 2a receptor T102C polymorphism and schizophrenia.

PMID- 8667939
TI  - 5HT 2a receptor T102C polymorphism and schizophrenia.

PMID- 8667938
TI  - 5HT 2a receptor T102C polymorphism and schizophrenia.

PMID- 8667940
TI  - 5HT 2a receptor T102C polymorphism and schizophrenia.

PMID- 8667941
TI  - 5HT 2a receptor T102C polymorphism and schizophrenia.

PMID- 8667942
TI  - Hypothyroid nails and evolution.

PMID- 8667943
TI  - Clues to the death of an Olympic champion.

PMID- 8667944
TI  - Dysglycaemia and risk of cardiovascular disease.

PMID- 8667945
TI  - Dysglycaemia and risk of cardiovascular disease.

PMID- 8667946
TI  - Avoparcin and animal feedstuff.

PMID- 8667947
TI  - Dysglycaemia and risk of cardiovascular disease.

PMID- 8667948
TI  - Newly recognised hantavirus in Siberian lemmings.

PMID- 8667949
TI  - Blood-based PCR assay to detect pulmonary tuberculosis.

PMID- 8667950
TI  - HHV8 DNA in angiolymphoid hyperplasia of the skin.

PMID- 8667951
TI  - Multidrug resistant tuberculosis in South Africa.

PMID- 8667952
TI  - de Kooning's dementia.

PMID- 8667953
TI  - de Kooning's dementia.

PMID- 8667954
TI  - Medical transfer programmes for Bosnia and Herzegovina.

PMID- 8667955
TI  - Evidence-based medicine and compassion.

PMID- 8667956
TI  - Uninsured in the USA.

PMID- 8667957
TI  - Diphtheria immunity in health staff.

PMID- 8667958
TI  - Tobacco chewing, oral submucous fibrosis, and anaesthetic risk.

PMID- 8667959
TI  - 12 years on: coproxamol revisited.

PMID- 8667960
TI  - Activated protein C and pulmonary embolism.

PMID- 8667961
TI  - Activated protein C and pulmonary embolism.

PMID- 8667962
TI  - Activated protein C and pulmonary embolism.

PMID- 8667963
TI  - Amelioration of hepatorenal syndrome with selective endothelin-A antagonist.

PMID- 8667964
TI  - Outcome assessments and air ambulance services.

PMID- 8667965
TI  - Outcome assessments and air ambulance services.

PMID- 8667966
TI  - Semen quality among members of organic food associations in Zealand, Denmark.

PMID- 8667968
TI  - Ankle systolic blood pressure measurement and cuff application.

PMID- 8667967
TI  - Tight-fitting underwear and sperm quality.

PMID- 8667969
TI  - Diagnosing death.

PMID- 8667970
TI  - Two brothers with mediastinal tumours.

PMID- 8667971
TI  - Laryngology education at the turn of the century.

PMID- 8667972
TI  - The age of the medical education revolution.

PMID- 8667973
TI  - James R. Chandler: "Malignant external otitis." (Laryngoscope. 1968;78:1257
      1294).

PMID- 8667974
TI  - Nasofrontal duct reconstruction with silicone rubber sheeting for inflammatory
      frontal sinus disease: analysis of 164 cases.
AB  - The authors reviewed their experience in reconstructing the nasofrontal duct with
      thin silicone rubber sheeting in patients who had chronic inflammatory frontal
      sinus disease. The 164 patients were divided into four groups. The patients in
      group 1 had the traditional modified Lynch procedure, while those in group 2 had
      certain technical variations of the modified Lynch operation. The patients in the
      other two groups had major technical variations: those in group 3 had a primary
      osteoplastic flap approach and those in group 4 had revisions of failed
      osteoplastic flap with fat obliteration operations. Surgical indications included
      mucopyocele (87 patients), chronic frontal sinusitis (71 patients), osteomyelitis
      (2 patients), acute sinusitis (2 patients), and subacute sinusitis (2 patients).
      Follow-up averaged 47 months. At their last clinic visit, 157 patients (96%) were
      asymptomatic. Forty-six revision procedures were performed in 30 patients (18% of
      initial cases). There were no major complications. Nasofrontal duct
      reconstruction using thin silicone rubber sheeting is technically
      straightforward, safe, and effective.

PMID- 8667975
TI  - Cost utility of the multichannel cochlear implants in 258 profoundly deaf
      individuals.
AB  - Cost utility analysis is a method of cost-effectiveness analysis which provides
      results in terms of cost per quality-adjusted life-year (QALY). Cost utility for
      the multichannel cochlear implant was calculated using Ontario Health Utilities
      Index data from 229 Nucleus 22-channel implant users and 32 cochlear implant
      candidates awaiting surgery. The health utility of the implanted group was
      greater than that of the candidate group by 0.204 (P<.0001). Use of this figure
      in a cost utility calculation indicates that cochlear implantation costs
      approximately $15,928 per QALY provided. Sensitivity analysis, a technique which
      systematically varies the assumptions underlying the calculations, suggests a
      range for the true value of between $12,000 and $30,000. This compares very
      favorably with other medical interventions. It is concluded that profound hearing
      loss has a significant effect on quality of life, and measurement of the changes
      that result from cochlear implant use indicates that this technology provides
      significant improvements and is quite cost-effective.

PMID- 8667976
TI  - Distortion generated by the ear: its emergence and evolution during development.
AB  - Physiologically vulnerable active mechanics associated with the transduction of
      sounds in adults distort cochlear output. Specifically, frequencies not present
      in the incoming acoustic signal are represented in its output (ie., the spike
      trains of auditory nerve fibers). The purpose of this investigation was to study
      the appearance and evolution of intermodulation distortion during development.
      Established surgical and electrophysiologic techniques were used to record the
      extracellular electrical activity of individual auditory nerve fibers from
      developing kittens. Discharge-rate or synchrony-based responses to two tones (f1
      and f2) presented simultaneously at various ratios of f2/f1 were recorded. The
      cubic distortion product (CDP; 2f1-f2, where f1<f2) and the difference tone (f2
      f1) were the intermodulation distortion products (DPs) emphasized in the
      investigation. CDPs were first observed nearly 10 days after the earliest
      auditory nerve fiber responses to simple tone-burst stimuli could be elicited in
      neonatal cats. Furthermore, the spectrum of DPs generated in the cochlea changed
      dramatically during the second postnatal week and achieved adultlike
      characteristics after the first postnatal month. Findings reported here support
      the notion that cochlear transduction is initially linear in neonatal cats,
      possibly representing a critical period of auditory development, and that the
      content of distortion-related spectral information carried in auditory nerve
      fiber spike trains increases during development, in concert with other peripheral
      auditory attributes.

PMID- 8667978
TI  - Laser-assisted uvulopalatoplasty: postoperative complications.
AB  - Laser-assisted uvulopalatoplasty (LAUP) has become a widely used procedure for
      the treatment of snoring and mild sleep apnea in the United States. Between July
      1993 and December 1994, the authors of this study prospectively evaluated 541
      consecutive patients referred to their hospital for possible LAUP to treat loud
      disruptive snoring. Of the 541 patients, 275 patients had a total of 754 LAUP
      procedures. There were 26 complications (3.45%). These complications included
      postoperative hemorrhage in 16 patients (2.12%), local infection in 4 patients
      (0.53%), temporary palatal incompetence in 4 patients (0.53% , and temporary loss
      of taste in 2 patients (0.27%). None of the 16 patients with postoperative
      hemorrhage required a blood transfusion. Only 10 patients (1.3%) had hemorrhage
      that required medical attention; in the other patients, the bleeding stopped
      spontaneously. There were no cases of hypernasal speech, permanent palatal
      incompetence, nasopharyngeal stenosis, airway compromise, or death.

PMID- 8667977
TI  - Stapedectomy in profound cochlear loss.
AB  - Stapedectomy can be used in certain patients with profound sensorineural hearing
      loss and stapes fixation to improve hearing to a level at which a hearing aid may
      be effective. This study reviews the outcomes of 11 patients with profound
      cochlear loss secondary to otosclerosis who underwent stapes surgery performed by
      the senior author (M.E.G.) over a 25-year period. Postoperative hearing aid usage
      was effective in 9 of 11 patients. Preoperatively, these patients derived no
      benefits from hearing aids. Stapedectomy may be of immense value in patients with
      the proper history and profound cochlear loss.

PMID- 8667979
TI  - Acoustic reflexes, auditory brainstem response, and MRI in the evaluation of
      acoustic neuromas.
AB  - Patient records were reviewed to determine whether persons with absent acoustic
      reflexes have a higher incidence of abnormal auditory brainstem response (ABR)
      results in the absence of a cerebellopontine angle (CPA) tumor than those with
      normal acoustic reflexes. Results showed patients with absent reflexes to have
      borderline or abnormal ABR results in 45.2% of the cases. Patients with normal
      reflexes had borderline or abnormal ABR results in 14.2% of the cases. Results
      indicate that magnetic resonance imaging is a more appropriate test for patients
      with absent reflexes, since ABR was often nondiagnostic for a CPA tumor in this
      group.

PMID- 8667980
TI  - Evaluation of a new laser-resistant fabric and copper foil-wrapped endotracheal
      tube.
AB  - The risk of an endotracheal tube's combustion during laser airway surgery
      necessitates the use of special anesthetic techniques and equipment to prevent
      this complication. This study was designed to evaluate the Laser-Trach(TM), a new
      laser-resistant rubber endotracheal tube for use during laser airway surgery. The
      Laser-Trach endotracheal tubes that were evaluated were size 6.0 mm internal
      diameter (ID) red rubber endotracheal tubes which had been commercially wrapped
      by Kendall-Sheridan (Mansfield, Mass.) with copper foil tape and overwrapped with
      fabric. The fabric layer was saturated with water prior to our tests, as
      recommended by the manufacturer. The Laser-Trach endotracheal tubes were compared
      with plain (bare) size 6.0 mm ID Rusch red rubber endotracheal tubes. The tubes
      under study were positioned horizontally on wet towels in air and had 5 L x min(
      1) of oxygen flowing through them. They were subjected to continuous laser
      radiation at 40 W from either a CO2 or an Nd-YAG laser. The Nd-YAG laser was
      propagated via a 600-micron fiber bundle. Each laser was directed perpendicularly
      at the shaft of the endotracheal tube being studied, and its output was continued
      until a blowtorch fire occurred or 60 seconds had elapsed. Sixty seconds of CO2
      laser fire did not ignite any of the eight Laser-Trach endotracheal tubes tested.
      However, blowtorch ignition of all eight bare rubber tubes tested occurred after
      0.87 +/- 0.21 (mean +/- SD) seconds of CO2 laser fire. Nd-YAG laser contact with
      the Laser-Trach endotracheal tubes caused the perforation and blowtorch ignition
      of all eight tubes tested after 18.79 +/- 7.83 seconds. This was a significantly
      (P<.05) longer time than the 5.45 +/- 4.75 seconds required for the blowtorch
      ignition of all eight plain rubber endotracheal tubes tested with the Nd-YAG
      laser. Our results show that under the conditions of this study, the shafts of
      the Kendall-Sheridan Laser-Trach endotracheal tubes were resistant to the C02
      laser. However, this endotracheal tube is not recommended for use with the Nd-YAG
      laser.

PMID- 8667981
TI  - Thermal injury patterns and tensile strength of canine oral mucosa after carbon
      dioxide laser incisions.
AB  - The amount of collateral damage in laser surgery is affected by the precision of
      the beam delivery. To test a new control system, the authors of this study
      produced surgical incisions in the canine oral mucosa and then documented
      histologic and tensile strength changes during the wound healing process. The
      incisions were made by three different methods: scalpel, manually controlled
      carbon dioxide (CO2) laser, and computer-controlled C02 laser. Both types of
      laser incisions took longer to heal than the scalpel incisions. The laser
      incisions were accompanied by a zone of thermal damage lateral to the incision.
      With the computer-controlled laser incision, the area of thermal damage was
      reduced, the laser-induced delay in wound healing was less, and tensile strength
      was relatively greater. The data indicate that surgical performance is improved
      by critical beam control.

PMID- 8667982
TI  - Metastatic neoplasms to the larynx: report of three cases.
AB  - Metastatic involvement of the larynx by distant malignancies is a rare event that
      can occur by hematogenous or lymphogenous spread through a retrograde or
      anterograde route. Only 143 cases of secondary laryngeal tumors have been
      reported in the literature. Metastases from cutaneous melanoma and renal
      carcinoma are the most common, whereas only sporadic cases stemming from lung and
      colon adenocarcinoma have been documented. The authors report a case of lung
      adenocarcinoma and two cases of colonic adenocarcinoma metastatic to the larynx
      and discuss the problems related to the pathogenesis, diagnosis, and management
      of secondary laryngeal neoplasms.

PMID- 8667983
TI  - Neonatal mesenchyme temporal bone study: typical receding pattern versus increase
      in Potter's sequence.
AB  - The fate of mesenchyme, which lines the fetal and newborn bony middle ear, is not
      well understood. The authors wished to test previous observations that a greater
      amount of mesenchyme was found in Potter's sequence (renal anomalies, pulmonary
      hypoplasia, and oligohydramnios). Using celloidin-embedded neonatal temporal
      bones (68 cases, 123 ears), with clinical and autopsy information, middle ear
      volumes were compared among diagnostic groups using analysis of variance. In 16
      ears of Potter's sequence cases the volume of mesenchyme increased in proportion
      to the size of the middle ear. Conversely, in all other cases the volume of
      mesenchyme remained constant compared to increasing middle ear size. Both the
      volume of the bony middle ear and the volume of the air cavity increased at 15
      mm3/500 g of body weight (gbw). Mesenchyme percentage decreased by 2%/500 gbw.
      Middle ear mesenchyme appears to recede rather than reabsorb. However, in
      Potter's sequence cases the volume of mesenchyme increases, raising issues of a
      missing renal signal that inhibits mesenchymal growth under normal circumstances.

PMID- 8667984
TI  - Immunobiological peculiarities of cholesteatoma in children: quantification of
      epithelial proliferation by MIB1.
AB  - Cholesteatoma in children is characterized by a more extensive and rapid growth
      in the middle ear and mastoid cavities. The growth characteristics of the
      cholesteatoma in 20 children were studied using the monoclonal antibody MIB 1,
      which recognizes a nuclear antigen expressed by cells in the G1, S, and G2/M
      phases. Specimens of normal adult auditory meatal skin (n = 15) and adult
      cholesteatoma (n = 15) served as controls. The tissue specimens were prepared for
      immunohistochemical examination using the alkaline phosphatase-antialkaline
      phosphatase method and an automatic image analyzer. Specimens of normal skin
      revealed an average MIB 1 score of 9.2 +/- 3.10%. Child and adult cholesteatomas
      showed higher values. The average MIB 1 score was higher in child cholesteatoma
      (42 +/- 9.4%) than in adult cholesteatoma (28.2 +/- 6%). This difference was
      statistically significant (P<.01). Our results confirm a significant increase of
      the proliferative rate of cholesteatoma keratinocytes in children, giving an
      explanation for the more aggressive clinical behavior observed in these patients.

PMID- 8667985
TI  - Criteria for success in pediatric functional endonasal sinus surgery.
AB  - Functional endonasal sinus surgery (FESS) is widely used in the treatment of
      chronic sinusitis in adults and children. Although success rates of 80% to 93%
      have been reported, no criteria for success or improvement have been suggested.
      Standardized measures are needed to assess the outcome of FESS and to compare the
      results obtained by different surgical teams and for various patient groups.
      After reviewing the charts of 500 pediatric patients who underwent FESS between
      July 1987 and June 1992, the authors of this study formalized criteria for
      assessing the outcome of surgery.

PMID- 8667986
TI  - Pneumatized superior turbinate as a cause of referred migraine headache.
AB  - Three patients with typical (common) migraine unresponsive to conventional
      therapy were evaluated with complete otolaryngologic examination, diagnostic
      nasal endoscopy, and coronal sinus computed tomography (CT). Enlargement of the
      superior turbinate due to pneumatization, with accompanying mucosal contact, was
      found in each case. Application of topical or injected anesthetic to the superior
      turbinate lessened or relieved headache, and subsequent endoscopic sinonasal
      surgery succeeded in providing significant headache relief (follow-up of 6 to 14
      months). This is the first report of superior turbinate variations/abnormalities
      causing migraine, or indeed any type of headache. A discussion of the mechanism
      of referred pain from mucosal contact is offered after a discussion of each case.

PMID- 8667987
TI  - Postoperative irradiation of patients with malignant tumors of skull base.
AB  - To better understand how to irradiate patients after skull-base surgery, the
      authors of this study analyzed the tumor recurrence patterns in 22 patients with
      various malignancies. Of these patients, 13 underwent craniofacial resection, 6
      had infratemporal fossa resection, and 3 had temporal bone resection. The entire
      operative field was irradiated in 8 patients (total-field group), and part of the
      operative field was irradiated in 14 patients (partial-field group). Tumor regrew
      within the irradiated area in 25% of the total-field group and 14% of the partial
      field group. Tumor appeared outside the operative field in 13% of the total-field
      group and 57% of the partial-field group. Recurrences appeared in contiguous
      sites in 5 patients, in the unirradiated scar in 5 patients, and in the lymph
      nodes in 4 patients. Based on the study findings, the authors state that
      irradiation of the entire operative field, including scars and potential areas of
      contiguous spread, may be necessary to maximize local control after skull-base
      surgery.

PMID- 8667988
TI  - Prognostic value of EGFR and TGF-alpha in early laryngeal cancer treated with
      radiotherapy.
AB  - The purpose of this study was to determine the overexpression of both epidermal
      growth factor receptor (EGFR) and transforming growth factor-alpha (TGF-alpha) (a
      ligand of EGFR) in early laryngeal squamous cell carcinoma. In addition, we
      attempted to evaluate the prognostic values of our findings. Expression of EGFR
      and TGF-alpha in tumor tissue was examined immunohistochemically in 68 patients
      who had been treated with radiotherapy for early laryngeal cancer. Overexpression
      of the two factors was noted in 42.6% and 55.9%, respectively. No significant
      differences due to age, tumor size, and location or grade of cancer tissues were
      seen. Higher survival rates, found in patients with EGFR (-) and TGF-alpha (-)
      tumors as compared with those with EGFR (+) and TGF-alpha (+) (97.4%, 100% and
      86.2%, 86.8%, respectively), were not statistically significant. The recurrence
      rates were similar between EGFR (+) and EGFR (-) (37.9% and 35.9%, respectively).
      However, the recurrence rate in patients with TGF-alpha (+) was significantly
      higher (57.9%) than in those with TGF-alpha (-) (10%; P<.01). Therefore
      overexpression of TGF-alpha may be an important indicator for recurrence in
      patients with early laryngeal squamous cell carcinoma treated by irradiation.

PMID- 8667989
TI  - Regulation of transforming growth factor-beta 1-mediated apoptosis in head and
      neck squamous cell carcinoma.
AB  - The apoptotic cell death in Cal-27 cells induced by exposure to transforming
      growth factor-beta 1 was inhibited by the endonuclease inhibitor
      aurintricarboxylic acid (ATA) in a concentration-dependent fashion. In vitro
      studies of cytotoxicity, DNA fragmentation, and protein synthesis by Cal-27 cell
      lines were performed. Inhibition of cytotoxicity as well as endonucleolytic DNA
      cleavage was detected. ATA did not inhibit cytotoxicity either via transforming
      growth factor cell-surface-receptor alteration or by inhibition of macromolecular
      synthesis. ATA-sensitive events occurred late during treatment. These data
      suggest that endonucleolytic DNA cleavage is a mandatory event leading to cell
      death in this system.

PMID- 8667990
TI  - Genotype-phenotype correlations in type 1 Waardenburg syndrome.
AB  - Type 1 Waardenburg syndrome (WS1) is an autosomal dominant disorder characterized
      by dystopia canthorum, sensorineural deafness, and pigmentary disturbances.
      Previous work has linked the disease to PAX3, a transcription factor with two
      highly conserved DNA binding motifs: a paired box and a homeobox. Several
      mutations within the paired box of PAX3 have been reported. We have identified
      the first two mutations within the homeobox in two different families. Herein, we
      report the phenotypic expression of WS1 in these two families and explore the
      implications for possible genotype-phenotype correlations. The phenotypic
      expression was variable within and between the families. Sensorineural hearing
      loss was present in 71% of affected individuals. Spectrum of hearing loss
      included unilateral high frequency (>4000 Hz), profound unilateral hearing loss,
      and bilateral profound hearing loss. The severity of hearing impairment varied
      significantly within and among families. Phenotypically, these two WS1 families
      with mutations within the PAX3 homeobox could not be differentiated from those
      families with paired box mutations. More precise genotype/phenotype correlation
      may be possible when additional mutations are described throughout the PAX3 gene.

PMID- 8667991
TI  - The importance of mandibular position in microvascular mandibular reconstruction.
AB  - The challenge of mandibular reconstruction rests in the difficulty of re-creating
      the intricate three-dimensional relationship of the oral cavity, thereby ensuring
      occlusal relationships, oral competence, and facial contour. Recent advances in
      microvascular surgery have made reliable transfer of autologous tissue possible,
      hut successful reconstruction depends on accurate insetting of the bone flap. The
      authors reviewed their five years of experience with mandibular reconstruction
      and found six patients with a poor reconstructive result secondary to improper
      insetting of the bone flap. Anteromedially rotated and free-floating proximal
      mandibular segments appeared to be the most significant contributor to incorrect
      placement of the bone flap. Based on their findings, the authors devised a simple
      technique for stabilizing proximal mandibular segments.

PMID- 8667992
TI  - Tissue expander insertion through a mini incision.

PMID- 8667993
TI  - Microsurgical intranasal reconstruction of isolated blowout fractures of the
      medial orbital wall.

PMID- 8667994
TI  - Transnasal-transsphenoidal endoscopic surgery of the pituitary gland.

PMID- 8667995
TI  - Peripheral nerve monitoring in children undergoing neuromuscular blockade after
      single-stage laryngotracheoplasty.

PMID- 8667996
TI  - Involuntarily detained HIV-infected patients in Sweden: reasons for referral and
      psychiatric diagnoses.
AB  - The Swedish Communicable Diseases Act permits the isolation of an HIV-infected
      person if there is risk of disease transmission. The purpose is for the patient
      to receive the support needed to alter his or her attitude and behaviour so that
      the isolation can be terminated. This study describes the reasons for referral
      and the psychiatric diagnoses of 34 isolated HIV-infected patients. All patients
      who were isolated in Stockholm from 1986 to 1993 were included. Psychiatric data
      were collected from their psychiatric records. The most frequent reason for
      referral was unprotected sex with a partner who was not informed about the
      infection. The most common psychiatric diagnosis was amphetamine or opiate abuse.
      Drug users without delusions and immigrants with adjustment disorders or post
      traumatic stress disorder had the shortest treatment periods. All patients
      belonged to underprivileged groups, were drug users or refugees. More effort is
      needed to teach these groups about HIV.

PMID- 8667998
TI  - Religiosity, criminality and types of offences of Jewish male prisoners.
AB  - The study examined whether the percentage of religious criminals was lower than
      the percentage of religious people in the population and whether the types of
      crimes committed by religious prison inmates differed from those committed by non
      religious inmates. The 193 religious criminals studied consisted of all the
      religious male prisoners in the men's prisons in Israel. The percentage of
      religious criminals (3.7%) was found to be far below the percentage of religious
      people in the population (about 20%). In general both groups committed the same
      types of crimes. The exceptions were that religious criminals committed more sex
      and white-collar crimes and less security crimes than non-religious criminals.

PMID- 8667997
TI  - A study of parenting of IVF and DI children.
AB  - This article describes a study which provides data about the long-term issues
      experienced by parents rearing children from in vitro fertilization and donor
      insemination programmes. Fifty-four families bringing up a total of 101 children,
      74 of whom were the result of assisted conception interventions, were
      interviewed. The methodology was such as to secure a representative cross-section
      of participants. The findings presented in this article relevant to medicine and
      law relate to: (1) The consequences where 50% of the genetic history of a child
      created by the use of donated gametes is unknown to the parents and the child.
      (2) The impact of male infertility, as a largely taboo subject, on family
      relationships, and the consequent deception of the child. (3) The dilemmas of
      maintaining a secret for a lifetime from much loved children, all relatives and
      friends.

PMID- 8667999
TI  - Crime, disorder and legal pressure as a result of addiction problems in The
      Netherlands.
AB  - Coercing drug users into treatment might seem contrary to the philosophy of drug
      addiction care, which sets great store by the user's own motivation.
      Nevertheless, legal pressure and even force are increasingly being brought to
      bear in the Netherlands to persuade users to attend drug care programmes. The
      criminal justice system and the addiction care services have various means at
      their disposal to motivate addicts to come off drugs. This article discusses the
      relationship between addiction and crime. It begins with a brief description of
      how the addiction problem has evolved in the Netherlands over the years. This is
      followed by an explanation of how crime has developed during the same period and
      the effect this has had on social services for addicts. The article concludes
      with some recent policy proposals concerning diversion, coercion and
      pressurization strategies.

PMID- 8668000
TI  - Age and assisted reproduction.
AB  - Parenthood is conceptualized as a commitment. Responsible parents are reasonably
      certain that they will be able to meet their parental obligations and
      responsibilities. Two factors which may cause the failure to meet the commitment
      are discussed: (1) lack of time and (2) insufficient personal resources and
      capacities. Since these capacities are no longer present in most people in their
      seventies, the age limit for parenthood is placed around 50. The use of the
      average competent life span as a reference for decisions about the cut-off age
      limit is closely connected to an opinion about what constitutes a complete life.
      A complete life is a life in which (a) one's moral obligations and
      responsibilities have been discharged; and (b) one's life possibilities have on
      the whole been accomplished. Both conditions are fulfilled if procreation takes
      place before the age of 50.

PMID- 8668001
TI  - Natural law, human dignity and alcohol.

PMID- 8668002
TI  - Burning brides--a medicolegal study.
AB  - A 'burning' topic in India is the burn deaths of young females. Such a way of
      ending life is peculiarly common in our country. Many young newly married females
      die from burn injuries, the most common reasons given in post-mortem reports
      therefore being that she caught a light (a) while cooking; (b) after an oil
      explosion in a stove; or (c) when a chimney fell on her at night. These are the
      usual explanations given in post-mortem requisition documents furnished by the
      police, but on enquiry from relatives and neighbours many were found not to be
      true. The article discusses the methods to be used in medicolegal investigations
      of burn deaths, summarizes statistics gleaned from police records of deaths by
      burning, especially those of 16- to 25-year-old newly married women, criticizes
      the blind acceptance of dying declarations by the courts, and highlights the
      magnitude of these problems.

PMID- 8668003
TI  - The use of cost-value analysis to judge patients' right to treatment.
AB  - In deciding patients' right to treatment, there are trade-offs to be made between
      severity of illness, efficacy of treatment and treatment costs. These trade-offs
      can be expressed in numerical terms, using a multicategory scale to describe both
      severity of illness and treatment effect. Given the existence of this
      methodology, one may hypothesize that patients' right to treatment within
      specified time-limits can be enforced through formal legislation without
      necessarily damaging efforts at overall cost containment or imposing unreasonable
      administrative burdens on the health care system. Practical trials, for instance
      in selected geographical areas, are probably necessary to determine whether or
      not this hypothesis is true.

PMID- 8668004
TI  - Formal complaints and disciplinary proceedings involving medical practitioners:
      recent developments in New South Wales, Australia.
AB  - Complaints against medical practitioners are of interest to all the stakeholders
      in health care who are concerned with quality assurance and its definition,
      implementation and monitoring. New South Wales,Australia, has recently made
      statutory provision for independent structures of complaint investigation and
      resolution, including revised disciplinary proceedings to protect the public
      interest and regulate the conduct of the state's medical profession. This article
      discusses the new mechanisms and recent experience of them. They are intended to
      offer independence and an integrated and comprehensive system of grievance
      procedures but there remains a need for disciplinary procedures that afford lay
      control over the regulation of medical conduct.

PMID- 8668005
TI  - Comparative analysis of European legislation on doping.
AB  - The authors analyse legislation and regulations concerning doping in force in
      Belgium, Italy, Great Britain, Greece, Switzerland, France, Spain, Finland,
      Norway, Portugal, Luxemburg, Sweden, Germany, Austria and Denmark and examine the
      causes and the definition of doping as well as problems surrounding education and
      information, the tracing of forbidden substances, the determination of their use,
      and the controls and the sanctions provided. Prominence is given to those
      provisions which, according to the authors, have to be adopted from each law or
      regulation in order to form a homogeneous European regulation.

PMID- 8668006
TI  - New legislation on civil commitment in Hungary.
AB  - In Hungary the legal provisions concerning civil commitment of mentally ill
      patients recently changed. The new act became effective in February 1995. The
      main reason for the amendment was to fulfil the duty concerning harmonization of
      the legal system with the European Convention on the Protection of Human Rights
      and Liberties, which was ratified by Hungary in 1992. Both the substantive
      criteria and the procedural rules changed: The need for treatment no longer
      justifies civil commitment, the role of the court has become more important, and
      more emphasis is laid on the protection of the rights of patients in commitment
      proceeding. In spite of these advantageous changes some important provisions
      remained unchanged: a regulation on the rights of committed patients is absent,
      and informed consent issues are not addressed in the new act.

PMID- 8668007
TI  - Trends in health legislation and human rights.
AB  - For the past three or four decades many countries have ranked health as one of
      their social priorities and have embarked on comprehensive programmes to ensure
      universal access to health care. In the same period, mostly under the influence
      of the international community, the protection and promotion of human rights have
      become an integral part of modern legal theories and, in many countries or
      regions, these rights have been framed as constitutional norms or as rules
      paramount to local legislation. Trends observed in recent legislation may lead to
      infringements of human rights. At the core of these trends are measures, derived
      from express legislative sources or implemented by having recourse to the use of
      delegated powers, concerning the allocation of resources and the duty to render
      assistance. These measures often impact on the rights of an individual and are
      thus questionable under human rights theories. This article assesses the
      consequences of these legislative trends and questions the implicit proposal that
      the balance between individual rights and collective interests should be weighed
      in favour of the latter.

PMID- 8668008
TI  - Legal status of the mentally disabled person in South African law.
AB  - Mental illness or insanity has a dramatic influence on a person's legal status. A
      person's status determines his or her competencies such as legal capacity,
      capacity to act, accountability and capacity to litigate. A mentally ill person
      is incapable of performing juristic acts; he or she is not capable of becoming a
      party to legal proceedings; is virtually incapable of committing a crime or being
      liable for a delict; etc. However, not all mentally ill persons are precluded
      from performing legal acts or, for that matter, giving valid consent to medical
      treatment. The reason being that status is factually determined according to the
      degree to which the mental illness is present at the time when the mentally ill
      person participates in the legal traffic. The measure of capability depends on
      the patient's intellectual and volitional capacities that will decide whether the
      patient can validly contract, litigate or consent to medical treatment. More
      specifically medical research of a non-therapeutic nature can only be carried out
      on mental patients who are capable of consenting thereto. This article endeavours
      to touch upon the different aspects of the mentally ill person's legal status.

PMID- 8668009
TI  - Current challenges to the principles of medical law and their new interpretation.
AB  - The traditional function of the principles of medical law has been to protect the
      person of the patient against the use of power in health care. These principles
      have not generally been seen as factors which would also protect the patient
      economically. An analysis of the significance of the use of power in health care
      and a review of the field of damage sustained through erroneous procedures in the
      care relationship, make it possible to observe that the patient's need for legal
      protection is particularly great not only as regards factors related to the
      person, but also as regards the finances of the patient. On the other hand,
      evaluation of the relevant contents of the principles shows beyond doubt that
      they are to be conceived of generally as norms safeguarding the patient's rights.
      In Western countries in particular, where some years ago an economic recession
      set in, serious note should be taken of the wider interpretation of the
      principles of medical law as one potential means of furthering the well-being of
      the patient. In the application of legal rules affecting the legal position of
      the patient the principles of medical law may--like legal principles in general-
      be utilized both to guide the choice of a solution norm and to complement/
      specify the solution norm. In both these roles the principles yield criteria for
      application of the law which lead to the taking into consideration of aspects
      relating to the patient's financial interests and assessments.

PMID- 8668010
TI  - Multiple personality: perplexities about the law.
AB  - The challenges that multiple personality poses to legal concepts are discussed.
      They include issues such as consent, competency to stand trial and to testify,
      defence, criminal responsibility and capacity. The author concludes that the law
      is based on the idea of a person as a unity and that a person must take
      responsibility for his or her sub-personalities.

PMID- 8668011
TI  - Psychopathology of victims of aggression.

PMID- 8668012
TI  - Involuntary psychiatric hospitalization of minors.
AB  - Hospital records of the psychiatric hospitalization of minors living in the south
      of Israel were studied retrospectively for age, diagnosis and legal status on
      admission. The records of those minors who were involuntary hospitalized were
      investigated for behavioural symptomatology and justification for involuntary
      hospitalization. A range of psychiatric diagnoses was found, excluding diagnoses
      of schizophrenia and bipolar affective disorder. Explanations for these findings
      are offered.

PMID- 8668013
TI  - Battered woman syndrome: a conceptual analysis of its status vis-a-vis DSM IV
      mental disorders.
AB  - Literature on battered woman syndrome is examined with a view to validating the
      use of the word 'syndrome'. It is concluded that there is now sufficient
      information to justify its serious consideration as a form of post-traumatic
      stress disorder, as that diagnosis is defined in DSM IV: and that this has
      significance for the legal defence of battered women who react aggressively
      towards their abusers.

PMID- 8668014
TI  - Stigma, labelling and psychiatric misdiagnosis: origins and outcomes.
AB  - The sources and consequences of inaccurate psychiatric diagnosis are discussed.
      The philosophy of the DSM diagnosis system is described, and the hazards of the
      practice of labelling together with its resulting social stigma are explored. The
      dangers and complications of psychiatric misdiagnosis are illustrated with a case
      example. Recommendations are made for extreme caution to be exercised in the
      making of psychiatric diagnoses and the need to revise misdiagnoses is strongly
      emphasized.

PMID- 8668015
TI  - Law and psychology: a historical perspective (1).
AB  - In this first of a series of three articles, the relationship between law and
      psychology is discussed from a historical perspective. The article is divided
      into four sections: First, the early developments are described. Secondly, the
      use of medical knowledge and experts in Roman law is discussed. Thirdly,
      attention is devoted to the legal status of the mentally ill during the Middle
      Ages and how the thirteenth century appears to have been a turning-point in this
      regard. Lastly, important medicolegal developments during the Renaissance and the
      replacement of the belief in witchcraft by a more scientific approach are
      described.

PMID- 8668016
TI  - Expert evidence: the emergence of psychiatry and psychology (2).
AB  - In this second of a series of three articles, attention is devoted to the
      developing role of psychiatrists and psychologists as expert witnesses. As far as
      psychiatry is concerned, the first recorded use of psychiatric evidence in an
      English court dates back to the first half of the eighteenth century, but it was
      not until the nineteenth century that psychiatry was recognized as a field that
      could contribute significantly to the law. Developments in South Africa regarding
      forensic psychiatry followed a similar pattern. As for psychology, immediately
      after its emergence as an autonomous science late in the nineteenth century, it
      interacted with law. Developments from the stormy early years to the present in
      the United Kingdom are discussed.

PMID- 8668017
TI  - Law and psychology in South Africa: development and recommendations (3).
AB  - In this last article in a series, the historical development and present status
      of forensic psychology in South Africa are discussed. First, a critical
      comparison is made between the legal status of forensic psychologists and that of
      psychiatrists, and reasons for the present situation are given. Secondly, the
      reasons why psychologists may soon be expected to play a more important role in
      the forensic field, are discussed. Lastly, prerequisites for the development of
      forensic psychology in South Africa are listed: the need for a sound theoretical
      and clinical knowledge of the chosen field or fields of psychology, knowledge of
      the relevant legal principles in the specific legal field, the promotion of
      research and the address of ethical aspects of forensic psychology.

PMID- 8668018
TI  - Recordkeeping in psychiatry.

PMID- 8668019
TI  - [The possibilities for the transcranial monitoring of the blood flow in the
      circle of Willis arteries during operations on the brachiocephalic arteries and
      in heart operations].
AB  - The paper gives the results of arterial blood flow monitoring in the circle of
      Willis via transcranial Doppler during 81 reparative operations on
      brachiocephalic arteries (including carotid endarterectomy from the internal
      carotid artery in 32 patients). Transcranial monitoring of blood flow supports
      the fact that there is a collateral reflow along the cerebral arteries during
      removal of the common carotid artery and that there is a relationship between the
      status of great arteries and arteries of Willis' circle. The paper also summaries
      the results of a comprehensive ultrasound study of 9 patients who have undergone
      reparative and plastic operations on the cardiac valves during extracorporeal
      circulation and general hypothermia. Blood flow was intraoperatively monitored in
      the arteries of the basis cerebri by using transcranial duplex scanning with
      colour Doppler flow mapping to evaluate not only hemodynamics, but also the
      embolic situation, as well as to check up how air was removed from the cardiac
      cavities by transesophageal echocardiography.

PMID- 8668020
TI  - [The aberrant characteristics of the optical systems in medical endoscopes built
      on the basis of gradient optics. 1. The 3rd-order monochromatic aberrations].
AB  - Analytical descriptions of third-order monochromatic aberrations have been
      obtained in the optical systems based on gradient optics. Ways of minimizing
      monochromatic aberrations have been indicated.

PMID- 8668021
TI  - [A computerized informational-diagnostic package for performing
      electrocardiographic studies].

PMID- 8668022
TI  - [The RA6-02 rheoanalyzer for studying systemic hemodynamics by the methods of
      tetrapolar and focusing rheography].
AB  - The paper analyzes automatic rheographic (impedance) equipment, shows the
      prospects for using rheography to study systemic hemodynamics, as well as
      describes the potentialities of a new universal rheoanalyzer by employing
      tetrapolar and focusing rheography. The device uses an algorithm of automatic
      recording and processing rheosignals, which has been developed on 20-year
      worldwide experience in applying rheography. Specific volumetric and velocity
      parameters, as well as total amplitude-time parameters of rheosignals and their
      ratios, which virtually satisfy all users are identified in the procedures for
      examining hemodynamics in the heart, extremity, head, liver and lung.

PMID- 8668023
TI  - [The " Neoterm" incubator for neonatal life support].

PMID- 8668024
TI  - [Apparatus for medical electroroentgenography].
AB  - The paper provides a brief assessment of the development of electric X-ray as a
      tool for medical examinations and a detailed consideration of the new development
      - an (See Journal) automatic electric X-ray device.

PMID- 8668025
TI  - [Transcranial dopplerography in the optimization of the treatment procedure in
      cerebral arteriovenous malformations taking into account the functional cerebral
      hemodynamics].
AB  - The incidence of vascular abnormalities in the pattern of central nervous
      diseases is steadily increasing. Arterioventricular malformations (AVM) are of
      great significance among cerebrovascular diseases to be surgically treated. A
      comprehensive examination of 57 patients with AVM, which involved cerebral
      angiography, transcranial Doppler at the stages of surgical treatment led to the
      conclusion that the application of AVM morphological characteristics alone did
      not allow the development of specific complications, hyperemic ones in
      particular, to be accurately predicted in the early postoperative period after
      elimination of malformation. It was suggested that due to the naturally
      significant relationship of Doppler indices of blood flow in the nutrient
      arteries having structural malformations and showing cerebral circulatory
      disorders, the use of values of the linear velocity of blood flow in and the
      reactivity and resistance in the nutrient arteries enables one to predict a risk
      for hyperemic complications after AVM elimination to a high precision and to
      define a preferable surgical intervention. The priority employment of
      transcranial Doppler in the diagnostic examination of patients with AVM will
      optimize an instrumental preliminary study, make a correct treatment policy,
      improve the outcomes of surgical intervention, and reduce the length of hospital
      stay.

PMID- 8668026
TI  - [The "Kompomed" elbow joint endoprosthesis from the Central Research Institute of
      Traumatology and Orthopedics].
AB  - Elbow joint implants having a metallic and polymeric mobility center and
      flattened structurilized stems have been developed, patented and allowed for
      commercial production. The construction of the implant allows for its firm joint
      with appropriate bones. The metallic and polymeric mobility center makes friction
      efforts relatively small. These qualities significantly lower the shaking
      properties of the stem and the implant operates long without displaying any signs
      of instability.

PMID- 8668027
TI  - [A shock-absorber-damper endoprosthesis for the hip joint].
AB  - The paper deals with the construction of an implant for complete thigh joint
      removal. The implant works on a new principle, i.e. division of the major parts
      of the prosthesis into load-carrying and bearing parts which are isolated all the
      way with damping silicone gaskets. The implant has a fundamentally new
      construction. It is accessible for commercial production by advanced technologies
      and readily applicable in clinical practice. The estimated results of its
      application are positive as when used, the implant brings a considerably less
      pressure to bear on the bone than do the well-known Russian and foreign implant
      models.

PMID- 8668029
TI  - [An automated system for the management of a medical institution (a medical
      health unit)].

PMID- 8668028
TI  - [A knee joint endoprosthesis].
AB  - A knee joint implant is used to recover joint functions in patients with various
      sequelae of nonpurulent inflammatory diseases, degenerative and dystrophic
      processes, injuries, and tumorous and borderline processes in the knee joint. The
      study was undertaken to simplify the construction of the implant by preserving
      functional potentialities. The implant proposed by the authors is easy-to-use and
      shows reliability of the joining of the implant constituents due to the insertion
      of new parts. The implant exhibits its construction reliability and simplicity of
      making the implant in orthopedic, traumatological, and oncological institutions
      and patients' reduced rehabilitation stay.

PMID- 8668030
TI  - [A portable microcomputer analyzer of cardiac rhythm].
AB  - A portable and easy-to-use analyzer of cardiac rhythms is described. The device
      is based on an Elektronika MK-85M microcomputer and works on the principle of
      variational pulsometer which determines the status of the autonomic nervous
      system.

PMID- 8668031
TI  - [Experience in using kymographic pertubation in the diagnosis and treatment of
      infertility in a consultation office for women].
AB  - The paper describes the authors' experience in using a [symbol: see text]JITB-01
      hysterotubator in the diagnosis of amphora at a women's dispensary from 1991 to
      1995. All females who had complaints of being infertile for two years were
      examined with the hysterotubator. They included 290 females aged 21 to 43 years.
      Taking into account reexaminations, such studies were 317 altogether. Long-term
      outcomes could be followed up in 67% of the examinees undergone kymopertubation.
      Pregnancy occurred in 7% of cases within the first six months after
      kymoperturbation.

PMID- 8668033
TI  - [A drying cabinet for X-ray film].

PMID- 8668032
TI  - [Experience in using the DLTB-01 hysterotubator for the diagnosis and treatment
      of tubal infertility].
AB  - The paper presents some experience in applying a DLTB-01 hysterotubator to
      diagnose and treat tubal infertility in females. The patients underwent
      kymoperturbation from either diagnostic or therapeutical points of view. A
      hundred seventy eight sessions were performed in 151 females. Analysis of the
      results of examinations and treatment suggests that the DLTB-01 hysterotubator is
      beneficial.

PMID- 8668034
TI  - [Ultrasonic diagnosis of patients with circulatory encephalopathy].
AB  - The paper describes the results of examining intracerebral blood flow in patient
      with different stages of dyscirculatory encephalopathies. Transcranial Doppler
      was applied. Ultrasound examination of the great arteries of the head was made by
      determining the linear and volumetric velocities of blood flow. Progressive
      cerebral atherosclerosis was found to result in an earlier decrease in
      cerebrovascular blood flow.

PMID- 8668035
TI  - [The theory of a low-frequency emitter for ultrasonic therapy].
AB  - While performing ultrasonic therapy for some soft tissue diseases, a deep tissue
      ultrasound penetration should be prevented since there may be potential thermal
      effects on the borderline surfaces (the periostrium, articular menisci, etc.)
      with greatly varying acoustic properties. For this, a bimorphic low-wave emitter
      should be used. A emitter-generated pressure-distance relationship has been
      theoretically derived and experimentally tested. There is an abrupt pressure
      decline when the emitter is removed from the surface, which recommends that the
      emitter of this type should be applied to the physiotherapy for diseases needed
      only near-surface exposure.

PMID- 8668036
TI  - Organized medicine needs a tune-up.

PMID- 8668037
TI  - Private label insurance. Physician-run plans let doctors take the risk.

PMID- 8668038
TI  - Michigan medical schools face cadaver shortage.

PMID- 8668039
TI  - Young physicians: taking charge in an era of change. Interview by Karen Bouffard.

PMID- 8668040
TI  - A day in the life of Gregory L. Walker, MD. Interview by Karen Bouffard.

PMID- 8668041
TI  - Medicare: critical analysis.

PMID- 8668043
TI  - Lessons from Pogo.

PMID- 8668042
TI  - James K. Haveman, Jr. Building Michigan's public health care future. Interview by
      Karen Bouffard.

PMID- 8668044
TI  - Disinfection and the control of nosocomial infection.

PMID- 8668045
TI  - Bacterial contamination of hospital disinfectants.
AB  - A study to determine contamination of diluted disinfectants at different points
      in preparation and use in 6 Malaysian hospitals was done using the in-use test. A
      growth of > or = 250 organisms/ml was taken as an indication of contamination. A
      total of 342 (7.9%) of the 4316 freshly diluted samples collected from
      disinfectant bottles in the pharmacy were found to be contaminated. The bacterial
      isolates obtained were Pseudomonas spp. (42.4%), Moraxella spp. (22.0%),
      Flavobacterium spp. (11.6%) and Enterobacter spp. (4.2%). Three hundred and sixty
      seven out of 2278 ward stock were contaminated. The isolates were Pseudomonas
      spp. (48.6%), Moraxella spp. (17.8%), Acinetobacter spp. (8.9%) and
      Flavobacterium spp. (7.0%). Of the 9265 disinfectants in-use, 1519 (16.4%) were
      contaminated. Among the organisms isolated were Pseudomonas spp. (44.3%),
      Bacillus spp. (13.0%), Enterobacter spp. (9.5%) and Acinetobacter spp. (7.3%).
      The results indicated a high level of contamination of diluted disinfectants
      prepared in the pharmacy, stored and used in the wards. This gave a high index of
      suspicion that recommendations for cleaning of disinfectant containers before
      refilling, handling of diluted stock solutions and using of disinfectants were
      not closely adhered to. Standard disinfection procedures outlined in the
      disinfection and sterilization policy by the Ministry of Health should therefore
      be followed.

PMID- 8668046
TI  - HIV infection in Malaysia: a report of cases seen at the University Hospital,
      Kuala Lumpur.
AB  - The spread of HIV infection into Malaysia is estimated to have occurred in the
      early 1980's. The first case of AIDS was reported here in 1986. As of March 31,
      1994, the numbers have increased to 8049 HIV positive individuals detected in the
      country. The risk behaviours among those tested positive were intravenous drug
      use in 77.2%, sexual transmission in 4.5%, while the remainder are still under
      investigation. Pediatric AIDS constitutes 0.2% of positives. The high prevalence
      among intravenous drug users (IVDU) is likely to be due to mandatory testing for
      HIV upon entry to rehabilitation centres. The trend of HIV infection in this
      country seems to be highest amongst the intravenous drug users. The increasing
      number of HIV infected prostitutes and heterosexuals in our population is
      worrying. Since 1986, a total of 104 HIV positive individuals have been treated
      at the University Hospital, Kuala Lumpur, Malaysia. Of these, 25 have died and of
      those still alive, 5 have symptomatic disease. The most common AIDS-defining
      illness is Pneumocystis carinii pneumonia. Education programmes have been
      developed targeting the various high risk groups and the general population.

PMID- 8668047
TI  - The prevalence of anti-HCV antibody in risk groups and blood donors.
AB  - Anti-HCV antibody was detected in 1.9% of the blood donors in University
      Hospital. Among the risk groups, 33.3% of the patients with post-transfusion
      hepatitis were tested positive for anti-HCV antibody. The anti-HCV antibody was
      detected in 30% of the IDU. Haemodialysis patients, patients with acute and
      chronic hepatitis and patients with liver cirrhosis appeared to have increased
      risk of Hepatitis C virus infection. The results indicate that the frequency of
      HCV infection increases with the exposure to blood or blood products.

PMID- 8668048
TI  - A hospital based audit of tuberculosis deaths.
AB  - An audit was done on 54 tuberculosis patients presenting to Penang Hospital who
      died during 1993. Active tuberculosis was the cause of death in 29 (53.7%) and
      48.3% were aged under 50 years. Tuberculosis was a contributory cause of death in
      8 patients and in 17 patients tuberculosis was irrelevant to the cause of death.
      The diagnosis of tuberculosis was made after death in 17 patients (31.5%). Late
      diagnosis was the most important factor resulting in death. Only 41.4% of the
      deaths from active tuberculosis were correctly certified in government hospitals.
      Medically inspected and certified deaths from tuberculosis is an unreliable
      indicator of tuberculosis mortality because of inaccuracies in death
      certification, tuberculosis deaths occurring outside hospital and tuberculosis
      patients undiagnosed until after death.

PMID- 8668049
TI  - Hookworm infection and reinfection following treatment among Orang Asli children.
AB  - In hookworm endemic areas where sanitation is often wanting, reinfection of
      treated children is a problem. This study was conducted to enumerate the
      prevalence and the reinfection rate of hookworm in 193 Orang Asli children
      following treatment with stat dose of 400mg of albendazole at 2 and 4 months post
      treatment. All samples were examined using the Kato-Katz and Harada Mori
      techniques. The overall initial prevalence was 31.0%, with 27.0% in males and
      34.0% in females although there was no statistical difference. Only 7.0% of the
      children had moderate intensity of infection. The overall infection rate at 2 and
      4 months post-treatment was 11.0% and 8.0%. New cases were detected at 1.0% and
      5.0% at 2 and 4 months post-treatment period. Reinfection rate 2 months post
      treatment was 24.0%, and it was 30.0%, 4 months after treatment. All infection at
      2 and 4 months post-treatment were light. Long-term strategies incorporating
      health education on personal hygiene, provision of toilets and safe water supply
      need to be adopted in these Orang Asli villages to control rapid reinfection.

PMID- 8668051
TI  - Relationship of stress, experienced by rescue workers in the highland towers
      condominium collapse to probable risk factors--a preliminary report.
AB  - The aim of this study was to examine the relationship between the level of stress
      experienced by rescue workers after the collapse of a 13 story condominium in
      Kuala Lumpur, and other probable risk factors. Within a month of the incident,
      123 firefighters filled up the Impact of Life Event score (Horowitz) and the
      General Health Questionnaire (GHQ). The results indicated that 7 (6%) firemen
      could be classified as possible 'cases' on the GHQ, and significantly 5 from this
      group also scored highly on the impact of events score. No other risk factors
      were identified in the firemen. On conclusion, the GHQ can be used to screen
      those with high impact scores to pick up possible cases early enough, so that
      intervention can be successful.

PMID- 8668050
TI  - The HIV-associated risk behaviour among male drug abusers in Malaysia.
AB  - To examine the risk factors of HIV type-I infection among male drug addicts in
      Malaysia, a case-control study was conducted on inmates, aged 20-40 years, at a
      drug rehabilitation centre in January, 1994. Stratified random sampling was
      performed. A total of 87 cases and 261 controls, chosen by frequency matching for
      age and ethnicity, answered self-administered questionnaires. About 59.8% of the
      subjects administered drugs intravenously and of these, 71.2% shared needles.
      Practices significantly associated with HIV infection were needle-sharing (OR =
      8.53; 95% CI = 3.36-5.52), sexual relationship with prostitutes (OR = 3.70; 95%
      CI = 2.10-6.56), homosexuality (OR = 4.05; 95% CI = 1.49-11.11) and non-condom
      use while having sex with prostitutes (OR = 2.27; 95% CI = 1.05-4.97).

PMID- 8668052
TI  - Results of 50 consecutive aneurysmectomies for abdominal aortic aneurysms at a
      private specialist centre.
AB  - The management of abdominal aortic aneurysms (AAA) at a private medical centre
      was reviewed. The criteria for surgery were AAA more than or equal to five
      centimeters in diameter, symptomatic AAA even if less than five centimeters and
      ruptured AAA. A total of 67 patients were seen between October 1991 to September
      1994. The age range was 48 to 94 years, mean = 69.8. There were 58 males to nine
      females. Twelve patients presented with ruptured AAA. There were three suprarenal
      AAA and three mycotic AAA. Aneurysmectomies were performed on 50 patients. This
      include all patients with ruptured AAA. There was no mortality in the elective
      cases. One patient with ruptured AAA died, ie. an operative mortality of eight
      per cent. It was concluded that a very low operative mortality can be achieved in
      this group of high risk patients. Our results were comparable to those reported
      by other centres in the developed countries. Important factors contributing to
      these results include a team approach in a unit interested in this disease,
      careful pre-operative preparation and a rigid post-operative regime. For ruptured
      AAA, survival of the patient depended on a successful and timely operation. It
      was also concluded that no patient should be deemed unfit for surgery or denied
      an operation if they needed to have one and it was safe to transport patients
      with ruptured AAA to a centre where the operation can be performed.

PMID- 8668053
TI  - Video-assisted thoracoscopic surgery for pneumothorax.
AB  - Five cases of spontaneous pneumothorax were treated with video-assisted
      thoracoscopic surgery (VATS). These included four cases of recurrent pneumothorax
      and one case of persistent pneumothorax. The mean age was 33 years. The
      identified bullae were eliminated with either endoloop ligation (in one patient)
      or stapled excision (in four patients). There were no recurrences reported in a
      mean follow-up of 9.4 months. In conclusion, VATS offers an equally effective and
      less morbid alternative to open thoracotomy in the management of primary
      spontaneous pneumothorax.

PMID- 8668054
TI  - Endoscopic pneumatic balloon dilatation for achalasia of the cardia.
AB  - This study evaluated the efficacy and safety of endoscopic pneumatic balloon
      dilatation as the initial treatment for achalasia of the cardia. 15 patients with
      achalasia underwent a total of 19 dilatations using the new polyethylene dilator
      (Microvasive Rigiflex Balloon Dilator) over the last 6 years. An overall
      treatment success rate of 93% was achieved. 11 patients (73.3%) have not required
      a further dilatation and 3 patients (20%) required between 1 and 2 further
      dilatations. Elective surgery was necessary in 1 patient. The mean follow-up
      period was 31.5 months. There was no complication or death attributable to the
      procedure. Endoscopic pneumatic balloon dilation is a safe and effective
      treatment for achalasia and should be considered as the initial treatment of
      choice in most patients with achalasia.

PMID- 8668056
TI  - Insertion of Hickman catheters by the percutaneous technique.
AB  - Hickman catheters have previously been conventionally placed by surgical
      dissection. This usually performed by experienced surgeons and is carried out
      under general anaesthesia. We report our preliminary experience in Hickman
      catheter placement by percutaneous technique in twenty patients. We outline the
      implantation methods and complications encountered by this technique. The
      procedure is relatively simple provided the operator is skilled in central venous
      cannulation. The chief advantages are that the procedure can be done under local
      anaesthesia and results in less trauma compared with surgical dissection. Such an
      alternative in catheter insertion would promote wider usage of Hickman catheters
      in cancer patients.

PMID- 8668055
TI  - A preliminary study of possible prognostic factors of traumatic liver injury seen
      at University Hospital, 1984-1991.
AB  - A retrospective study was carried out on 42 patients (38 males, 4 females, mean
      age 25.9) with liver injury at the University Hospital, Kuala Lumpur from 1994
      through to 1991. Prognostic factors that might help to identify those patient
      survival was related to pulse rate on arrival ( < or = 120 beats per minute, p =
      0.027), systolic blood pressure at induction of anaesthesia ( > or = to 80 mmHg,
      p = 0.003) and intraoperative blood transfusion of < or = to 4 units (p = 0.05).
      This data were supported by the 95% confidence interval suggesting that these
      factors may be strong prognostic indicators individually. Increased mortality was
      also associated with increased total blood transfused (p = 0.002) and grade of
      liver injury (p = 0.02). Although the factors we have identified reflect both the
      severity of injury and resuscitative and surgical efforts, further studies using
      a prospective design are required to confirm these findings.

PMID- 8668057
TI  - Risk profile of pregnant mothers in Kelantan.
AB  - A demographic and obstetric profile of pregnant mothers attending antenatal
      clinics in kelantan over period of one year was determined by a retrospective
      study of 10,032 registered pregnant mothers. The prevalence of risk factors
      related to the age of the mother, parity, weight, haemoglobin level, bad
      obstetric history and pregnancy related diseases were determined. Prevalence of
      teenage pregnancy and primigravida accounted for 4.3 and 17.2 percent
      respectively. Nearly 3.9 percent of the mothers weighed less than 40 kg and 44.5
      percent of mothers were found to be anaemic (Hb less than 11g/d) at the first
      antenatal visit. Only 3.2 percent of the mothers did not have any designated risk
      factor. Previous bad obstetric history and pregnancy related disease accounted
      for 17.1 and 3.5 percent of mothers respectively.

PMID- 8668058
TI  - Recurrent headaches in children--an analysis of 47 cases.
AB  - In a retrospective analysis of paediatric referrals to a Neurology Outpatient
      Clinic, the largest single category of 47 patients (32%) presented with acute
      recurrent headache. There were 30 girls and 17 boys. Age of onset ranged from 4
      to 11 years (8.35 +/- 1.98) and duration of headache from half month to 42 months
      (19.2 +/- 11.9). Only 6 children were unable to describe the quality of their
      pain. Using conventional criteria, 43 of the children could be classified as
      classical migraine (10), common migraine (20), basilar migraine (3),
      ophthalmoplegic migraine (1) and tension tension headache (9). None had any
      positive physical signs, and all responded to simple measures.

PMID- 8668059
TI  - Comparison of two bolus doses of esmolol for attenuation of haemodynamic response
      to tracheal intubation.
AB  - This prospective study was designed to compare the effectiveness of esmolol
      (either 100 mg or 200 mg) with a placebo in blunting the haemodynamic response to
      laryngoscopy and intubation. Seventy-five patients of ASA I or II scheduled for
      routine-surgery were selected and entered into a placebo-controlled study.
      Patients were randomly allocated to receive placebo, 100 mg or 200 mg of esmolol
      IV as part of an anaesthetic induction technique. There were no significant
      differences in the demographic distribution of the patients in the study. There
      was no statistical difference in the baseline heart rate (HR) and systolic blood
      pressure (SBP) between the three groups. One minute after the administration of
      the drug (prior to intubation) the differences in HR between the placebo group
      and both the 100 mg and 200 mg groups were significant (p < 0.05), and also at 1
      min and 2 min following intubation for the 200 mg group (p < 0.05). In the 200 mg
      group there was a significant decrease, compared with placebo, in SBP at 1 min (p
      < 0.05) and at 2 min (p < 0.05) after intubation. In this study, adequate
      haemodynamic control following was obtained with the administration of 200 mg of
      esmolol.

PMID- 8668060
TI  - Upper eyelid and eyebrow dimensions in Malays.
AB  - The upper eyelid crease height pretarsal skin and eyebrow height were studied in
      305 Malay subjects (146 males and 159 females) varying in age from 2-80 years,
      who were randomly selected from the residents of Kota Bharu, Kelantan. In
      females, from the age of 11 years the mean pretarsal skin height increased
      progressively with age. In males, however, it decreased with age up to 60 years.
      In both sexes, subjects more than 60 years old showed highest values for
      pretarsal skin height. The mean eyelid crease height increased progressively with
      age from 11 years onwards in males but not in females. The mean eyebrow height
      increased with age in females but not in males. Eyebrow and eyelid measurements
      seem to show a definite racial variation. Besides establishing normal values for
      eyelid and eyebrow measurements in Malays, our findings indicate that age and sex
      should be taken into consideration to achieve satisfactory results in cosmetic
      eyelid surgery in Malays.

PMID- 8668062
TI  - Survey of availability of iodine-enriched salt in Sarawak.
AB  - Three hundred and forty five salt samples were randomly taken from 106 sources
      where iodised salts were supplied or put for sale in all areas gazetted as
      endemic goitre areas in Sarawak. The samples were analysed for the presence of
      iodine. In areas in Sibu, Sarikei and Kapit Divisions, 53-70% of salt put for
      sale were iodised while in the other 6 Divisions, it was less than 27%. As
      iodisation of salt is an interventive measure in addressing the goitre problem in
      the State, regular monitoring of iodisation facilities and iodine content of
      iodised salt in the affected areas is important to ensure the effectiveness of
      the programme.

PMID- 8668061
TI  - Nutrient intake and socio-economic status among children attending a health
      exhibition in Malaysian rural villages.
AB  - A dietary survey was carried out in 216 children (109 males, 107 females) aged 1
      7 years, living in rural villages in Selangor, Malaysia to assess their nutrient
      intake and to determine the association between nutrient consumption and socio
      economic background. All the children studied had inadequate intakes of energy,
      iron and niacin according to Recommended Daily Intake (RDI). Children aged of 4-9
      years showed inadequate intake of calcium, thiamine and riboflavin. However, the
      intake of protein, vitamin A and ascorbic acid were above the recommended value.
      The mean percentage requirements of protein, iron and niacin were significantly
      higher in children from small families compared with children from large
      families. However the employment status of mothers had a significantly effect on
      the mean percentage requirements of niacin. The results indicate that education
      level of the mothers, is strongly associated with the mean percentage nutrient
      requirements of children and we strongly feel that this is a strategy to be
      adopted for improvement in nutrition of children.

PMID- 8668063
TI  - A study of unclaimed prescriptions in Hospital Universiti Sains Malaysia (HUSM).
AB  - An analysis of 524 unclaimed prescriptions (which contributed 0.9% of the total
      prescriptions) showed that 23.8% were for vitamins, 17.7% for anti-inflammatory
      drugs, 16.4% medications for skin and mucous membrane and 9.9% for antibiotics.
      The unclaimed prescription rates varied inversely to the staff-strength working
      in the dispensary. Sixty-eight point nine per cent of the unclaimed drugs could
      be purchased at the pharmacy shops without doctor's prescription.

PMID- 8668064
TI  - Continuous spinal anaesthesia--early experience in University Hospital, Kuala
      Lumpur.
AB  - Continuous spinal anaesthesia using the incremental technique was used in
      nineteen high risk patients with multiple medical problems, seventeen of whom
      were elderly, for lower limb orthopaedic and pelvic surgery. An intrathecal
      catheter (18G/28G) was inserted under local anaesthesia via the lumbar
      interspinous space. Spinal anaesthesia was induced with small incremental doses
      of 0.5% bupivacaine hydrochloride through the intrathecal catheter to achieve the
      level of analgesia required for surgery. The duration of surgery ranged from 45
      to 300 minutes (mean + S.D 100 + 37 min). The initial volume of 0.5% bupivacaine
      required for surgery ranged from 0.8 ml-2.0 ml (1.2 + 0.7 ml) and the total
      volume ranged from 0.9 ml to 3.1 ml (mean + S.D 1.4 + 0.7 ml). Haemodynamic
      stability was well maintained perioperatively. Only two patients required 6 mg of
      ephedrine and 1 mg of aramine respectively for a greater than 25% reduction in
      systolic blood pressure with induction of spinal anaesthesia. Intrathecal
      morphine 0.1-0.3 mg was administered to 15 patients at the end of surgery for
      postoperative pain relief with good effect. One patient developed late
      respiratory depression from an inadvertent overdose of intrathecal morphine. No
      neurological sequelae were noted and no patient developed a postdural puncture
      headache. The use of the microcatheter was discontinued in the U.S.A and
      Australia following four case reports of cauda equina syndrome with this
      technique. Current opinion, however, is that the reported cauda equina syndrome
      was due to the neurotoxic effects of lignocaine 5% that was used and not due to
      the microcatheter per se. Continuous spinal anaesthesia is now used widely in
      Europe when cardiovascular stability is desired in poor risk patients undergoing
      lower limb and lower abdominal surgery.

PMID- 8668066
TI  - Knee arthrodesis with interlocking nail after excision of giant cell tumour of
      the distal femur.
AB  - Giant cell tumour of bone occurring around the knee is fairly common and can be
      difficult to manage. We report a case of such tumour involving the distal femur
      which was successfully treated with complete excision followed by arthrodesis of
      the knee with a long interlocking intramedullary nail.

PMID- 8668065
TI  - Acute gonococcal sacro-iliitis--a case report.
AB  - Acute infective sacro-iliitis is a rare condition. Though gonococcal arthritis is
      not uncommon, this organism does not appear to have been isolated from the sacro
      iliac joint. The first proven case of gonococcal sacro-iliitis is reported here.
      Difficulties in correct diagnosis of infective sacro-iliitis are highlighted.
      Management of gonococcal sacro-iliitis is described. With the increase in number
      of gonococcal infections, a case can be made for routine culture of joint
      material N. Gonorrhoeae in cases of septic arthritis in patients at high risk.

PMID- 8668067
TI  - Claw toes correction and factor XIII deficiency--a case report.
AB  - A 26-year-old male presented with claw toes and Factor XIII deficiency.
      Correction for his deformity was undertaken. Pre, intra and post-operative
      transfusions of plasma and blood prevented any haemorrhagic complications.

PMID- 8668068
TI  - Non-fatal strangulation: an uncommon parachute-related accident.
AB  - A case of non-fatal strangulation of the neck by rigging lines of a parachute
      during military training is presented. It is an unusual but potentially life
      threatening injury. Probable factors leading to such injury are discussed.

PMID- 8668069
TI  - Autosomal dominant thrombocytopenia with microthrombocytes: a family study.
AB  - A family demonstrating autosomal dominant thrombocytopenia is described. A 28
      year-old Malay housewife was found to have a platelet count of 40 x 10(9)/l with
      a low mean platelet volume (6.8 fl) while being investigated prior to ovarian
      cystectomy. The bone marrow was consistent with immune thrombocytopenia but she
      failed to respond to appropriate therapy. Five siblings, one parent and one
      nephew have easy bruising and platelet counts of 39-82 x 10(9)/l. Platelet
      aggregation studies excluded a major functional defect. Survival of homologous
      platelets in the circulation was normal. Familial thrombocytopenias are rare but
      important to differentiate from the common acquired thrombocytopenias in order to
      spare the patient unnecessary treatments.

PMID- 8668070
TI  - Recombinant factor VII.

PMID- 8668071
TI  - Chylothorax secondary to tuberculosis.

PMID- 8668072
TI  - Latex allergy: a real problem.

PMID- 8668073
TI  - "Grown-ups" with congenital heart disease.

PMID- 8668074
TI  - General practice--a rising phoenix.

PMID- 8668076
TI  - Age-specific HIV incidence among homosexually active men in Australia.
AB  - OBJECTIVE: To estimate age at HIV infection among homosexually active men in
      Australia. DESIGN: Age-specific back-projection estimates of HIV incidence.
      METHODS: Monthly counts of AIDS among homosexually active men diagnosed by 30
      June 1994 and reported by 31 March 1995 were obtained from the National AIDS
      Registry and were adjusted for reporting delays. The progression rate to AIDS was
      estimated from a large cohort study of HIV-infected homosexual men, with
      adjustment for the effect of age at HIV infection and the effect of
      antiretroviral and prophylactic treatments. RESULTS: The median age at HIV
      infection was estimated to have decreased from 31 years of age between 1982 and
      1984 to between 23 and 27 years in the periods 1987 to 1989 and 1990 to 1994.
      Despite the trend to a younger median age at HIV infection during the current
      epidemic, HIV incidence was estimated to have declined in all age groups from a
      peak in the mid-1980s. This decline was more pronounced in the older age groups,
      with more modest reductions in age groups under 30 years. CONCLUSION: Most HIV
      infections among homosexually active men since 1987 appear to have occurred in
      men aged under 30 years. This has implications for education programs aimed at
      preventing HIV infection among homosexually active men.

PMID- 8668075
TI  - Prevalence of latex allergy in a dental school.
AB  - OBJECTIVE: To determine the prevalence of latex allergy in dental workers.
      DESIGN: Questionnaire survey of staff of a dental school. SETTING: The Westmead
      Dental School, a large dental facility in western Sydney. PARTICIPANTS: 230 staff
      members of the Westmead Dental School (consisting of general and specialist
      dentists, chairside assistants and registered nurses, laboratory technicians,
      dental therapists and hygienists) received questionnaires. MAIN OUTCOME MEASURES:
      The prevalence of latex allergy, defined by prompt onset of hand urticaria with
      or without generalised symptoms, and the prevalence of hand dermatitis and other
      glove-related symptoms. Also, the relationship between latex allergy and
      associated atopic status. RESULTS: 177 staff (77%) responded by the set
      collection date; 33% reported symptoms related to wearing gloves and 22%
      satisfied the criteria for glove dermatitis. Sixteen respondents (9%) reported
      characteristics suggestive of latex-glove allergy. CONCLUSIONS: Confirmation of
      the 9% prevalence of latex allergy among dental workers will require further
      studies incorporating an objective measure of IgE-mediated hypersensitivity.

PMID- 8668077
TI  - Malignancy in chronic leg ulcers.
AB  - OBJECTIVE: To evaluate the frequency of malignant ulcers in patients presenting
      with leg ulcers. DESIGN: A descriptive study from data collected between July
      1988 and June 1995 from 981 patients (2448 ulcers) attending a leg ulcer clinic.
      SETTING: A specialised leg ulcer clinic at a tertiary teaching hospital.
      SUBJECTS: 43 patients with 55 malignant skin lesions. OUTCOME MEASURES: Tissue
      biopsies in ulcerated lesions that suggested malignancy or were not responding to
      appropriate treatment. RESULTS: Forty-three patients were found to have malignant
      lesions on the legs, giving a frequency of malignant ulcers of 4.4 per 100 leg
      ulcer patients, or 2.2 per 100 leg ulcers. Seventy-five per cent of the malignant
      ulcers were basal cell carcinoma and 25% were squamous cell carcinoma.
      CONCLUSIONS: Malignant skin changes are common in chronic leg ulcers. A biopsy
      should be taken from all suspicious ulcers or ulcers that do not respond to
      appropriate treatment.

PMID- 8668078
TI  - Emerging epidemic of community-acquired methicillin-resistant Staphylococcus
      aureus infection in the Northern Territory.
AB  - OBJECTIVE: To investigate the epidemiology of WA MRSA (the recently recognised
      Western Australian strains of methicillin-resistant Staphylococcus aureus) in the
      north of the Northern Territory (NT). DESIGN: Retrospective survey of data from
      hospital records. SETTING: Royal Darwin Hospital (a tertiary referral hospital
      that serves the north of the NT) between January 1991 and July 1995. SUBJECTS:
      All inpatients with clinical MRSA infection. OUTCOME MEASURES: Incidence of MRSA
      infection, classification of MRSA as WA or EA (Eastern Australian) based on
      antibiotic susceptibility, patient demographic details (age, sex, ethnicity,
      region of residence), source of infection (nosocomial or community-acquired).
      RESULTS: There were 125 WA MRSA and 93 EA MRSA infections, comprising 7% of all
      S. aureus infections. The incidence of WA MRSA infections consistently increased,
      while that of EA MRSA initially fell and then increased. All EA MRSA infections
      were nosocomial, while 50% of WA MRSA infections were community-acquired. Rates
      of WA MRSA infections were highest in patients from the west region of the NT,
      adjacent to the Kimberley region of Western Australia (WA). Community-acquired WA
      MRSA infections were more likely to affect Aboriginals than non-Aboriginals
      (relative risk [RR], 25.86; 95% confidence interval [CI], 12.51-53.47, based on
      population data; RR, 15.43; 95% CI, 7.85-30.32, based on admission data), as were
      nosocomial EA MRSA infections (RR, 2.54; 95% CI, 1.44-4.47, based on population
      data; RR, 2.30; 95% CI, 1.52-3.46, based on admission data). CONCLUSIONS: Changes
      in the epidemiology of MRSA infection in the north of the NT are consistent with
      the hypothesis that community-acquired WA MRSA spread into and across the NT from
      the Kimberley region of WA. Alternatively, crowded living conditions, hygiene
      difficulties and increasing use of broad spectrum antibiotics may have led to
      independent emergence of WA MRSA in both regions. Current infection control
      policies and their use in rural Aboriginal communities must be reassessed.

PMID- 8668079
TI  - Effective control of bone pain by octreotide in a patient with metastatic
      gastrinoma.

PMID- 8668080
TI  - Peak flow meter use in asthma management. Thoracic Society of Australia and New
      Zealand.
AB  - Peak flow monitoring is used to assist in establishing a diagnosis of asthma, to
      measure asthma severity, to assess the response to treatment and to recognise
      deteriorating asthma. This article describes the advantages and limitations of
      peak flow monitoring, practical aspects of peak flow meter use and the
      circumstances in which peak flow monitoring is most likely to ensure better
      patient outcomes. Recommendations are made for a written action plan, based on
      peak flow monitoring, for the effective management of asthma at home and
      treatment of asthma exacerbations.

PMID- 8668081
TI  - Investigating: is thoroughness always "good medicine"?

PMID- 8668082
TI  - Atopic dermatitis.

PMID- 8668083
TI  - Ionising radiation in diagnosis: do the risks outweigh the benefits?
AB  - Every diagnostic test in medicine has costs and potential benefits. Doctors must
      ensure that the benefits of each test performed outweigh the costs, which include
      financial considerations and risks to the health of the patient. The possible
      adverse effects of some invasive tests such as biopsies may be well understood,
      but for others the risks are not so obvious or immediate. Seemingly "non
      invasive" tests involve the use of ionising radiation and carry the risk of
      causing malignant tumours. This risk is widely underestimated in medical practice
      in Australia, and it is the responsibility of the radiological community to
      demonstrate that commonly performed investigations result in a net benefit to
      patients.

PMID- 8668085
TI  - General practice reform: the shared management model.

PMID- 8668084
TI  - Quality in Australian Health Care Study.

PMID- 8668086
TI  - Nedocromil sodium (Tilade) metered aerosol in the treatment of chronic cough.

PMID- 8668087
TI  - Human hydatidosis in New South Wales and the Australian Capital Territory.

PMID- 8668089
TI  - Workers' compensation--what role the doctor?

PMID- 8668088
TI  - Wildlife reservoir for human hydatidosis.

PMID- 8668090
TI  - Workers' compensation--what role the doctor?

PMID- 8668091
TI  - Great expectations: the coroner's report on the haemolytic-uraemic syndrome
      outbreak.

PMID- 8668092
TI  - When is hypospadias not hypospadias?

PMID- 8668093
TI  - The evolution of the intensivist: from health care provider to economic
      rationalist and ethicist.

PMID- 8668094
TI  - Public response to a smoke-free policy at a major sporting venue.

PMID- 8668095
TI  - Palliative care for the terminally ill.

PMID- 8668096
TI  - Physical, sexual and emotional violence against women: a general practice-based
      prevalence study.

PMID- 8668097
TI  - Hypnotic drugs.

PMID- 8668098
TI  - Anastrozole for metastatic breast cancer.

PMID- 8668099
TI  - Imaging characteristics of x-ray capillary optics in digital mammography.
AB  - Computed radiography (CR) has shown promise in digital mammographic screening due
      to its good low spatial frequency MTF and its relatively wide exposure latitude.
      The CR image format has not gained acceptance clinically because of reduced high
      spatial frequency resolution as compared to film-screen images. X-ray capillary
      optics, aligned between the breast and CR phosphor imaging plate, will capture
      primary x-ray photons almost exclusively. Due to the very small angle of
      acceptance, scattered photons angled more than about 1.6 x 10(-3) radians from
      primary trajectory will not be accepted at the capillary optic entrance. The
      virtual elimination of detected scatter means almost 100% of the possible primary
      contrast should be visible in the image. In addition, the image can be magnified
      without focal spot blurring. Effective resolution of CR images can be increased
      by a factor equal to that magnification. Clinical implementation of future
      capillary optics are expected to be either in the form of a large, stationary,
      post-patient optic that accepts primary from the entire breast or a fan-shaped
      optic that is scanned across the breast. Measurements of a test capillary optic
      showed a reduction of scatter fraction to 0.018. Images of a lucite contrast
      detail phantom revealed a corresponding increase in image contrast when compared
      to anti-scatter grid and no grid methods. Spectral transmission measurements
      using a high-purity germanium detector showed good primary transmission (45%-50%)
      in the mammographic energy range. The MTF measurements of both stationary and
      scanned capillary optics showed improvement at the 5% MTF level to 8.4 mm-1 for
      scanned optics and 9.2 mm-1 for stationary optics representing a 68% and 84%
      respective increase over the CR MTF without magnification or capillary optics.

PMID- 8668100
TI  - Three-dimensional reconstruction of vascular trees. Theory and methodology.
AB  - In this paper we examine the few-view reconstruction problem as it applies to
      imaging vascular trees. A fully automated reconstruction algorithm is described
      that circumvents the traditional "correspondence problem," using only notions of
      consistency and connectivity. It is assumed that the vascular tree is a connected
      structure and that its centerlines have been identified in three or more images.
      The first of three steps in the procedure involves generating a connected
      structure that represents the multiplicity of solutions that are consistent with
      any two (different) projections. The second step assigns to each branch in this
      structure a measure of agreement based on its relationship with one or more
      additional views of the vasculature. The problem then becomes one of propagating
      this information, via connectivity relationships and consistency checks,
      throughout the above structure to distinguish between the branches comprising the
      imaged structure and the accompanying artifacts. In this paper we present the
      theory and methodology of the technique, while in a companion paper we address
      the issue of validation via simulations and experiments. Together, these papers
      shed some light on why ambiguities arise and often lead to errors in the few-view
      reconstruction problem. Strategies to handle these errors are described and
      results are presented that demonstrate the ability to obtain adequate
      reconstructions with as few as three distinct views.

PMID- 8668101
TI  - Dual-slice spiral versus single-slice spiral scanning: comparison of the physical
      performance of two computed tomography scanners.
AB  - In this paper we deal with two types of spiral scanners; one is a single-slice
      spiral scanner, while the other employs dual-slice technology into spiral
      scanning. Physical performance parameters, including image noise, contrast
      resolution, spatial resolution (transversal and longitudinal), and radiation
      exposure are measured. Computer simulations based on two interpolation methods
      (180 degrees and 360 degrees linear interpolation) are also used in evaluating
      the slice-sensitivity profile (SSP) and noise. The results show that the noise
      behaves in the same way for both types of scanners. The noise change, relative to
      that of the standard scan with the same scanning parameters, depends solely on
      the interpolation algorithm. Table speed and scanner geometry (either single
      slice or dual slice) have no effect on the noise value. For the given table
      speed, as well as individual detector collimation (slice width) the dual-slice
      scan results in better longitudinal resolution (SSP) compared to a single-slice
      scan if the scan is obtained with nonoverlapping slices (pitch greater than 2).
      This is because the dual-slice scan obtains twice the number of nonoverlapped
      projections for the same length, which reduces the degradation of the slice
      profile by using more densely arranged projections (in the longitudinal
      direction) for the interpolation. In the dual-slice scanner the workable scan
      rate is extended up to pitch 4 compared to a pitch of 2 for the single-slice
      scanner. Therefore, the dual-slice spiral scanner is preferred in applications
      requiring an increased scan rate with comparative image quality.

PMID- 8668102
TI  - A general approach to the reconstruction of x-ray helical computed tomography.
AB  - Helical Computed Tomography (HCT) has become the method of choice for many
      routine clinical studies. The advantages of HCT include the capability of
      scanning a complete anatomical volume in a single breath hold, the capability of
      generating images at any desired location, and the improved patient throughput.
      However, these advantages come at the expense of some image quality compromises.
      This is mainly caused by the fact that the projection set is inherently
      incomplete and inconsistent, due to the constant patient translation during the
      data acquisition process. In this paper, we will briefly review the research work
      performed in this area and present a more general approach to the problem. We
      give two specific examples of the general approach and compare the performance of
      one of the examples with one of the best methods available today.

PMID- 8668104
TI  - Radiation dose and image quality of double-loaded cassettes.
AB  - Some U.S. hospitals double-load x-ray cassettes for certain procedures. Loading
      two films in the same cassette for portable emergency room (ER), intensive care
      unit (ICU), or operating room radiographs provides both the referring clinicians
      and the radiologists with immediate images. Our study demonstrates a cost
      increase of 15%, an increase in air kerma for a chest x ray from 0.12 to 0.35 mGy
      (12-35 mrad), slight differences in optical density, image contrast, and spatial
      resolution under double-loading conditions. Our study shows that double loading
      cassettes may improve patient care by economically expediting the communication
      of radiographic findings. The decision to double load portable ICU or ER
      cassettes must be based on a balance of factors.

PMID- 8668103
TI  - Measurement of quantum noise in fluoroscopic systems for portal imaging.
AB  - In fluoroscopic portal imaging systems, a metal plate is bonded to a phosphor
      screen and together these act as the primary x-ray sensor. The light from the
      screen is collected and imaged by a lens on the target of a video camera. The
      demagnification (M) between the large area of the phosphor being imaged and the
      small active area of the video camera results in poor optical coupling between
      the screen and the video camera. Consequently x-ray quantum noise is small
      compared to other noise sources. By reducing the demagnification, the light from
      the screen is collected more efficiently, so we were able to increase the x-ray
      quantum noise relative to other noise sources and thus unambiguously identify it.
      The noise power spectrum was measured as a function of M to determine the
      relationship between the x-ray quantum noise. shot noise, and amplifier noise. It
      was found by extrapolation to clinical demagnifications that the amplifier noise
      dominates x-ray quantum noise, at all spatial frequencies, but the shot noise was
      less than the x-ray quantum noise at low spatial frequencies. For low spatial
      frequencies, this implies that a secondary quantum sink can be avoided. If
      amplifier noise could be sufficiently reduced, x-ray quantum limited images could
      be obtained in clinical systems at low spatial frequencies.

PMID- 8668105
TI  - A mathematical spread sheet application for production of entrance skin exposure
      nomograms.

PMID- 8668107
TI  - Correction of motion artifacts in linogram and projection reconstruction MRI
      using geometry and consistency constraints.
AB  - Motion results in various artifacts such as blurring and streaks in clinical
      imaging of subjects based on reconstruction from projections. We model subject
      motion-induced artifacts due to scaling, translational and rotational motion. A
      correction algorithm based on the Ludwig-Helgason consistency conditions is
      derived here. These conditions are satisfied whenever the projection data are
      consistent. We apply the algorithm to simulated data collected on linogram (LR)
      and projection reconstruction (PR) geometries, and to real PR geometry data, in
      magnetic resonance imaging (MRI). The results show that motion-induced in-plane,
      interview artifacts can be reduced with application of the algorithm. The
      algorithm is general enough to be applied to certain other cases arising in
      tomographic imaging.

PMID- 8668106
TI  - Spatial mapping of the percentage cellularity in human bone marrow using magnetic
      resonance imaging.
AB  - A noninvasive assay for the spatial distribution of the percentage cellularity in
      human bone marrow is presented. Twelve individuals were studied using two
      magnetic resonance imaging techniques: (1) fast spin echo imaging with frequency
      selective presaturation, and (2) three-point chemical shift imaging. The data
      were compared to results obtained using a previously validated stimulated echo
      spectroscopic method. The results of this study demonstrate that a measure of the
      percentage cellularity in bone marrow is possible using magnetic resonance
      imaging techniques provided that high-quality water or lipid suppression is
      achieved across the region of interest. Since the method is applicable to bone
      marrow at any anatomic location, it may prove useful in dosimetric calculations
      during and after a course of internal or external beam radiotherapy.

PMID- 8668108
TI  - Transmission imaging of large attenuators using a slant hole collimator on a
      three-headed SPECT system.
AB  - By combining conjugate views, truncation-free attenuation profiles of patients
      can be obtained by using slant hole collimators on three-headed SPECT systems.
      The alterations in reconstruction algorithms necessary for use with slant hole
      collimators and potential image artifacts are discussed. Based on an evaluation
      of the size of objects that can be imaged without truncation and the size of the
      overlap region in the conjugate views, a 15 degrees slant angle was determined to
      be optimal. Studies with a 30 degrees slant hole collimator verified the ability
      of slant hole transmission imaging to provide accurate, truncation-free
      attenuation maps of a 56 cm lateral width phantom. The center of rotation was
      determined to be dependent on the slant angle and radius of rotation of the slant
      collimator. These studies also demonstrated that the spatial resolution in the
      transaxial plane of the attenuation maps depends on radius of rotation of the
      slant hole collimator, but does not depend on the radius of rotation of an
      uncollimated transmission source. A multiline transmission source was
      investigated for use with estimating the attenuation map in Tc-99m labeled
      sestamibi perfusion imaging.

PMID- 8668109
TI  - Calibration of the delayed-gamma neutron activation facility.
AB  - The delayed-gamma neutron activation facility at Brookhaven National Laboratory
      was originally calibrated using an anthropomorphic hollow phantom filled with
      solutions containing predetermined amounts of Ca. However, 99% of the total Ca in
      the human body is not homogeneously distributed but contained within the
      skeleton. Recently, an artificial skeleton was designed, constructed, and placed
      in a bottle phantom to better represent the Ca distribution in the human body.
      Neutron activation measurements of an anthropomorphic and a bottle (with no
      skeleton) phantom demonstrate that the difference in size and shape between the
      two phantoms changes the total body calcium results by less than 1%. To test the
      artificial skeleton, two small polyethylene jerry-can phantoms were made, one
      with a femur from a cadaver and one with an artificial bone in exactly the same
      geometry. The femur was ashed following the neutron activation measurements for
      chemical analysis of Ca. Results indicate that the artificial bone closely
      simulates the real bone in neutron activation analysis and provides accurate
      calibration for Ca measurements. Therefore, the calibration of the delayed-gamma
      neutron activation system is now based on the new bottle phantom containing an
      artificial skeleton. This change has improved the accuracy of measurement for
      total body calcium. Also, the simple geometry of this phantom and the artificial
      skeleton allows us to simulate the neutron activation process using a Monte Carlo
      code, which enables us to calibrate the system for human subjects larger and
      smaller than the phantoms used as standards.

PMID- 8668111
TI  - [Micromorphological aspects of dentin].
AB  - Samples of dentine of healthy teeth were analysed in this study with at the
      scanning electron microscope. In order to see the morphological changes in the
      structure of both the dentine and the dentinary tubules, the dentine was observed
      at different levels according to the distance from the pulp. After the removal of
      the odontoblasts the predentine appears to be composed only by collagen fibres
      and is about 15 microns thick. At this level, the dentinary tubules can reach a
      diameter of 4 microns. This measure decreases progressively in proportion to the
      distance from the pulp, reaching about 2 microns at a distance of 1 mm, and 1
      micron at 2 mm from the pulp. A decrease in the tubular lumina is observed when
      the peritubular dentine changes from 0.8 to 1 in thickness. The internal surface
      of the tubules appears smooth and shows the confluence of very thin lateral
      canaliculi. The dentinary tubules end forming forks which spread out until they
      enter into contact with the enamel.

PMID- 8668110
TI  - PbF2 compared to Al2O3 and AlF3 to produce an epithermal neutron beam for
      radiotherapy.

PMID- 8668112
TI  - [The role of autologous parietal bone graft in alveolar cleft].
AB  - Autologous bone grafting of alveolar clefts is a well recognized procedure.
      Calvarium represents an interesting donor site because of the absence of
      morbidity and the dimensional stability of this membranous bone compared with
      endochondral bone sources. The authors reponed their experiences with this type
      of grafting used in 17 patients. Referred to the parameters analized in an
      important Swedish study, the rate of success was about 80% agree with the results
      of other authors with the same type of graft. Aspects of general planning,
      timing, technique and failure are extensively discussed. Pre and post surgical
      orthodontic treatment is also very important for a good result. The pattern of
      maxillo-facial growth and the effect of the graft materials on facial development
      are mentioned. The study of literature indicates that the best grafting results
      are achieved when free autogenous mandibular symphyseal bone grafts were used.
      The only true disadvantage is the small quantity of bone tissue available. The
      authors conclude suggesting the use of chin bone grafting in situations where the
      technique provides sufficient bone and recommend the use of cranial vault as the
      alternative source of membranous bone graft, for example, in bilateral clefts,
      when anterior theeth are not erupted yet and in any other situation where the
      mandibular bone graft is not possible.

PMID- 8668113
TI  - [Immunochemical and immunohistochemical study of calpastatin, an endogenous
      calpain inhibitor, in the masseter muscle of the rabbit].
AB  - The calpains-calpastatin system (calcium-activated neutral proteases and
      endogenous inhibitor) seems to be, in the skeletal muscle, a fine enzymatic
      system of myofibrillar turnover regulation, in normal as well as pathological
      conditions (for ex., dystrophic muscle). The purpose of the research is to
      establish in qualitative and quantitative terms whether the level of calpastatin
      can evidence differences between a muscle in normal activity conditions and one
      having dysfunctional alterations experimentally induced. So the masseter muscle
      of rabbit in normal conditions and with experimentally modified occlusal plane
      has been used. Our results confirm the presence of the 68 KDa calpastatin in the
      masseter muscle. The presence of the inhibitor in the same subcellular structures
      in which the calpains have been detected (myofibrillars, sarcolemma, endomysial
      connective) has been confirmed. Finally, variations in calpastatin amount in the
      muscle of animals experimentally treated with respect to the controls have been
      found. Thus, calpastatin seems to act as a marker of muscle dysfunctions
      connected to occlusal plane alteration and to loss of vertical dimention.

PMID- 8668115
TI  - [Standard electromyographic and kinesiographic parameters in a sample of healthy
      population].
AB  - The authors have examined through the electromygraphic-kinesiographic system
      provided, the mandibolar movements and the electric activity of the masseter and
      temporal muscles of group of 25 subjects, aged 22-25 (15 women and 10 men), with
      complete natural dentition, whose history and clinical examination of cranio
      mandibular disorders were negative. The aim of the study is to analyse the values
      come out by these instrumental researches and to compare them with the already
      existing literature, trying to obtain standard data of "normality", to be used as
      comparative and diagnostic parameters for this age range and, on the other hand,
      as a further method of evaluation for electromyiografic-kinesiographic and
      electromyiographic analysis of subjects suffering from algic-dysfunctional
      pathology of the cranio-mandibular apparatus. The analysed champion of healthy
      subjects, with symmetrical electromyiographic normal values (temporan muscles 0.5
      2.5 microvolts, masseter muscles 0.5-2.0 microvolts), presents physiological
      mandibular movementes along the three space axes: furthermore the results
      outlined by the existing literature, according to which the female champion has a
      lower muscular electric potential and mandibular dinamic paths than the male
      champion, are confirmed. The authors point out the importance of computerised
      clinical research, not only to get data, but also to store them and to be able to
      compare them in long term.

PMID- 8668114
TI  - [Germectomy of the lower third molars. Follow up studies on 71 patients].
AB  - The clinical research was carried on in the department of Oral Surgery of the
      Maxillo-Facial Surgery Division of Turin University and concerned patients of an
      average age of 15 years. All the patients underwent the operation for orthodontic
      reasons. About two years after operation patients were called and underwent a
      check-up to see the surgical scar and to examine the health of lower second
      molars that could have been damaged during surgical operations for germectomy.
      Periodontal probings were effected around all lower second molars, therefore
      their mobility level an vitality were observed. Nervous alterations were
      researched and the authors effected a radiographic check-up to look for possible
      bone-loss after germectomy. According to the results obtained, the authors assert
      that the health of lower second molars isn't damaged by germectomy of lower third
      molars. So although not welcome by the young patients, the authors affirm that
      preventive germectomy of lower third molars compared to correct indications is a
      justified treatment.

PMID- 8668116
TI  - [Highlights in the subject of low frequency-high intensity TENS (review)].
AB  - Transcutaneous electrical neural stimulation (l.f.-h.i. TENS), employed in
      dentistry, allows masticatory muscles relaxation, temporary clearance of muscular
      and periodontal proprioceptive input and even oro-facial pain relief. The
      mechanisms involved in this type of stimulation are not entirely clarified.
      According to the most recent neurophysiological researches, the authors describe
      several l.f.-h.i. TENS. action modalities. Some of them are well known such as
      the gate control theory, the endogenous antinociceptive system activation, the
      metabolic recovery of the muscular tissue and the unloading reflex. Other
      mechanisms, instead, are less known such as hypnosis and stress analgesia,
      exteroceptive suppression and counterirritation (DNIC). Some hypothetical
      mechanisms are also considered such as endogenous inhibition and sympathetic
      activity reduction.

PMID- 8668117
TI  - [An unusual case of adenocarcinoma of the median parieto-occipital area of the
      scalp with brain involvement].
AB  - The authors describe an uncommon personally observed case of adenocarcinoma of
      the soft tissues in the medial parietoccipital region of the scalp, with the
      involvement of the brain. This case is very interesting for the localization of
      the cancer and its marked aggressiveness, which did not allow radical surgery.

PMID- 8668118
TI  - [Francesco Vichi].

PMID- 8668119
TI  - Prevention of varicella: Recommendations of the Advisory Committee on
      Immunization Practices (ACIP). Centers for Disease Control and Prevention.
AB  - These recommendations represent the first statement by the Advisory Committee on
      Immunization Practices (ACIP) on the use of live, attenuated varicella virus
      vaccine--VARIVAX--manufactured by Merck and Company, Inc. and licensed in March
      1995 for use in healthy persons > or = 12 months of age. In addition to
      presenting information regarding vaccine, this statement updates previous
      recommendations concerning the use of varicella zoster immune globulin (VZIG) as
      prophylaxis against varicella (MMWR 1984; 33:84-90, 95-100).

PMID- 8668121
TI  - Analysis of chimeric UmuC proteins: identification of regions in Salmonella
      typhimurium UmuC important for mutagenic activity.
AB  - Unlike Escherichia coli, the closely related bacterium Salmonella typhimurium is
      relatively unresponsive to the mutagenic effects of DNA-damaging agents. Previous
      experiments have suggested that these phenotypic differences might result from
      reduced activity of the S. typhimurium UmuC protein. To investigate this
      possibility, we have taken advantage of the high degree of homology between the
      UmuC proteins of E. coli and S. typhimurium and have constructed a series of
      plasmid-encoded chimeric proteins. The possibility that the phenotypic
      differences might be due to differential expression of the respective UmuC
      proteins was eliminated by constructing chimeric proteins that retained the first
      25 N-terminal amino acids of either of the UmuC proteins (and presumably the same
      translational signals), but substituting the remaining 397 C-terminal amino acids
      with the corresponding segments from the reciprocal operon. Constructs expressing
      mostly E. coli UmuC were moderately proficient for mutagenesis whereas those
      expressing mostly S. typhimurium UmuC exhibited much lower frequencies of
      mutation, indicating that the activity of the UmuC protein of S. typhimurium is
      indeed curtailed. The regions responsible for this phenotype were more precisely
      localized by introducing smaller segments of the S. typhimurium UmuC protein into
      the UmuC protein of E. coli. While some regions could be interchanged with few or
      no phenotypic effects, substitution of residues 212-395 and 396-422 of E. coli
      UmuC with those from S. typhimurium resulted in reduced mutability, while
      substitution of residues 26-59 caused a dramatic loss of activity. We suggest,
      therefore, that the primary cause for the poor mutability of S. typhimurium can
      be attributed to mutations located within residues 26-59 of the S. typhimurium
      UmuC protein.

PMID- 8668120
TI  - A gene cluster involved in nogalamycin biosynthesis from Streptomyces nogalater:
      sequence analysis and complementation of early-block mutations in the
      anthracycline pathway.
AB  - We have analyzed an anthracycline biosynthesis gene cluster from Streptomyces
      nogalater. Based on sequence analysis, a contiguous region of 11 kb is deduced to
      include genes for the early steps in anthracycline biosynthesis, a regulatory
      gene (snoA) promoting the expression of the biosynthetic genes, and at least one
      gene whose product might have a role in modification of the glycoside moiety. The
      three ORFs encoding a minimal polyketide synthase (PKS) are separated from the
      regulatory gene (snoA) by a comparatively AT-rich region (GC content 60%).
      Subfragments of the DNA region were transferred to Streptomyces galilaeus mutants
      blocked in aclacinomycin biosynthesis, and to a regulatory mutant of S.
      nogalater. The S. galilaeus mutants carrying the S. nogalater minimal PKS genes
      produced auramycinone glycosides, demonstrating replacement of the starter unit
      for polyketide biosynthesis. The product of snoA seems to be needed for
      expression of at least the genes for the minimal PKS.

PMID- 8668122
TI  - Rates of movement of transposable elements in Drosophila melanogaster.
AB  - Mobilization rates of nine families of transposable elements (P, hobo, FB, gypsy,
      412, copia, blood, 297, and jockey) were estimated by using 182 lines. Lines were
      started from a completely isogenic population of Drosophila melanogaster,
      carrying the marker sepia as an indicator of possible contamination, and have
      been accumulating spontaneous mutations independently for 80 generations of
      brother-sister (or two double-first-cousin) matings. Transposable element
      movements have been analyzed in complete genomes by the Southern technique.
      Mobilization was a rare event, with an average rate of 10(-5) per site per
      generation. The most active element was FB. In contrast, the retroelements gypsy
      and blood did not move at all. Most changes in restriction patterns were
      consistent with rearrangements rather than with true transposition. The
      euchromatic or heterochromatic location of elements was tested by comparing
      insertion patterns from adults and salivary glands. Certain putative
      rearrangements involved heterochromatic copies of the retroelements 412, copia or
      297. Clustering of movement across families was observed, suggesting that
      movement of different families may be non-independent. As association between
      modified insertion patterns and mutant effects on quantitative traits shows that
      spontaneous transposition events cause continuous variation.

PMID- 8668123
TI  - Copper ions and the regulation of Saccharomyces cerevisiae metallothionein genes
      under aerobic and anaerobic conditions.
AB  - We have previously reported that the Saccharomyces cerevisiae CRS5
      metallothionein gene is negatively regulated by oxygen. The mechanism of this
      repression was the focus of the current study. We observed that the aerobic
      repression of CRS5 is rapid and occurs within minutes of exposing anaerobic
      cultures to air. Furthermore, the CUP1 metallothionein gene of S. cerevisiae was
      found to be subject to a similar downregulation of gene expression. We provide
      evidence that the aerobic repression of yeast metallothioneins involves copper
      ions and Ace1, the copper trans-activator of CUP1 and CRS5 gene expression. A
      functional Ace1 binding site was found to be necessary for the aerobic repression
      of CRS5. Moreover, the aerobic down-regulation of the metallothioneins was
      abolished when cells were treated with elevated levels of copper. Our studies
      show that anaerobic cultures accumulate higher levels of copper than do aerobic
      cells and that this copper is rapidly lost when cells are exposed to air. In
      fact, the kinetics of this copper loss closely parallels the kinetics of CUP1 and
      CRS5 gene repression. The yeast metallothionein genes, therefore, serve as
      excellent markers for variations in copper accumulation and homeostasis that
      occur in response to changes in the oxidative status of the cell.

PMID- 8668124
TI  - A multicopy suppressor of nin1-1 of the yeast Saccharomyces cerevisiae is a
      counterpart of the Drosophila melanogaster diphenol oxidase A2 gene, Dox-A2.
AB  - NIN1 is an essential gene for growth of the yeast Saccharomyces cerevisiae and
      was recently found to encode a component of the regulatory subunit of the 26S
      proteasome. The nin1-1 mutant is temperature sensitive and its main defect is in
      G1/S progression and G2/M progression at non-permissive temperatures. One of the
      two multicopy suppressors of nin1-1, SUN2 (SUppressor of Nin1-1), was found to
      encode a protein of 523 amino acids whose sequence is similar to those of
      Drosophila melanogaster diphenol oxidase A2 and the mouse mast-cell Tum(-)
      transplantation antigen, P91A. The C-terminal half of Sun2p was found to be
      functional as Sun2p at 25 degrees C, 30 degrees C, and 34 degrees C but not at 37
      degrees C. The open reading frame (ORF) of the Drosophila diphenol oxidase A2
      gene (Dox-A2) was obtained from a lambda phage cDNA library using the polymerase
      chain reaction technique. The Dox-A2 ORF driven by the TDH3 promoter complemented
      the phenotype of a strain deleted for sun2. This Dox-A2-dependent strain was
      temperature sensitive and accumulated dumb-bell-shaped cells, with an undivided
      nucleus at the isthmus, after temperature upshift. This morphology is similar to
      that of nin1-1 cells kept at a restrictive temperature. These results suggest
      that SUN2 is a functional counterpart of Dox-A2 and that these genes play a
      pivotal role in the cell cycle in each organism.

PMID- 8668125
TI  - Two-hybrid interaction of a human UBC9 homolog with centromere proteins of
      Saccharomyces cerevisiae.
AB  - Using a two-hybrid system, we cloned a human cDNA encoding a ubiquitin
      conjugating enzyme (UBC), hUBC9, which interacts specifically with all three
      subunits of the Saccharomyces cerevisiae centromere DNA-binding core complex,
      CBF3. The hUBC9 protein shows highest homology to a new member of the UBC family:
      54% identity to S. cerevisiae Ubc9p and 64% identity to Schizosaccharomyces pombe
      (Sp) hus5. Overexpression of hUBC9 partially suppresses a S. cerevisiae ubc9
      temperature-sensitive mutation, indicating that the UBC9 gene family is also
      functionally conserved. Like hUBC9, Sphus5 also interacts specifically with all
      three subunits of the CBF3 complex. However, S. cerevisiae Ubc9p interacts only
      with the Cbf3p subunit (64 kDa) of the CBF3 complex, indicating the specificity
      of the interaction between S. cerevisiae Ubc9 and Cbf3p proteins. The function of
      Ubc9p in the G2/M phase of S. cerevisiae could be related to regulation of
      centromere proteins in chromosome segregation in mitosis. Therefore, the
      ubiquitination process and centromere function may be linked to chromosome
      segregation. We also provide further in vivo evidence that Mck1p, a protein
      kinase, is specifically associated with the centromere proteins Cbf2p and Cbf5p,
      which were previously shown to interact in vitro.

PMID- 8668126
TI  - An eye imaginal disc-specific transcriptional enhancer in the long terminal
      repeat of the tom retrotransposon is responsible for eye morphology mutations of
      Drosophila ananassae.
AB  - Optic morphology (Om) mutations of Drosophila ananassae are semidominant,
      neomorphic and nonpleiotropic, map to at least 22 loci scattered throughout the
      genome, and are associated with the insertion of the tom retrotransposon.
      Molecular and genetic analyses have revealed that eye morphology defects of Om
      mutants are caused by the ectopic or excessive expression of Om genes in the eye
      imaginal discs of third instar larvae. It is therefore assumed that the tom
      element carries tissue-specific gene regulatory sequences which enhance
      expression of the Om genes. In the present study, we examined whether or not the
      long terminal repeats (LTR) of the tom element contain such an eye imaginal disc
      specific enhancer, using D. melanogaster transformants containing a lacZ gene
      ligated to the tom LTR. Analyses of lacZ gene expression in the eye imaginal
      discs of third instar larvae of 18 independently established transformant lines
      showed that the tom LTR was capable of enhancing lacZ expression in all the
      transformant lines, but the degree of enhancement varied between lines. In
      addition, the effect of the tom LTR lacZ gene evidently changed when the tom LTR
      construct was relocated to different chromosomal positions. On the basis of these
      findings, it is hypothesized that ectopic and excessive expression of the Om
      genes in the eye imaginal discs is induced by an eye imaginal disc-specific
      enhancer present in the tom LTR, the effect of which may be subject to
      chromosomal position effects.

PMID- 8668127
TI  - Identification of the DNA damage-responsive elements of the rhp51+ gene, a recA
      and RAD51 homolog from the fission yeast Schizosaccharomyces pombe.
AB  - The Schizosaccharomyces pombe rhp51+ gene encodes a recombinational repair
      protein that shares significant sequence identities with the bacterial RecA and
      the Saccharomyces cerevisiae RAD51 protein. Levels of rhp51+ mRNA increase
      following several types of DNA damage or inhibition of DNA synthesis. An
      rhp51::ura4 fusion gene was used to identify the cis-acting promoter elements
      involved in regulating rhp51+ expression in response to DNA damage. Two elements,
      designated DRE1 and DRE2 (for damage-responsive element), match a decamer
      consensus URS (upstream repressing sequence) found in the promoters of many other
      DNA repair and metabolism genes from S. cerevisiae. However, our results show
      that DRE1 and DRE2 each function as a UAS (upstream activating sequence) rather
      than a URS and are also required for DNA-damage inducibility of the gene. A 20-bp
      fragment located downstream of both DRE1 and DRE2 is responsible for URS
      function. The DRE1 and DRE2 elements cross-competed for binding to two proteins
      of 45 and 59 kDa. DNase I footprint analysis suggests that DRE1 and DRE2 bind to
      the same DNA-binding proteins. These results suggest that the DRE-binding
      proteins may play an important role in the DNA-damage inducibility of rhp51+
      expression.

PMID- 8668128
TI  - Dominant mutant alleles of yeast protein kinase gene CDC15 suppress the lte1
      defect in termination of M phase and genetically interact with CDC14.
AB  - LTE1 encodes a homolog of GDP-GTP exchange factors for the Ras superfamily and is
      required at low temperatures for cell cycle progression at the stage of the
      termination of M phase in Saccharomyces cerevisiae. We isolated extragenic
      suppressors which suppress the cold sensitivity of lte1 cells and confer a
      temperature-sensitive phenotype on cells. Cells mutant for the suppressor alone
      were arrested at telophase at non-permissive temperatures and the terminal
      phenotype was almost identical to that of lte1 cells at non-permissive
      temperatures. Genetic analysis revealed that the suppressor is allelic to CDC15,
      which encodes a protein kinase. The cdc15 mutations thus isolated were recessive
      with regard to the temperature-sensitive phenotype and were dominant with respect
      to suppression of lte1. We isolated CDC14 as a low-copy-number suppressor of
      cdc15-rlt1. CDC14 encodes a phosphotyrosine phosphatase (PTPase) and is essential
      for termination of M phase. An extra copy of CDC14 suppressed the temperature
      sensitivity of cdc15-rlt1 cells, but not that of cdc15-1 cells. In addition, some
      residues that are essential for the CDC14 PTPase activity were found to be non
      essential for the suppression. These results strongly indicate that Cdc14
      possesses dual functions; PTPase activity is needed for one function but not for
      the other. We postulate that the cooperative action of Cdc14 and Cdc15 plays an
      essential role in the termination of M phase.

PMID- 8668130
TI  - The circadian clock gates expression of two Arabidopsis catalase genes to
      distinct and opposite circadian phases.
AB  - In Arabidopsis thaliana, catalase is encoded by a small gene family. We have
      characterized cDNA and genomic clones containing the Arabidopsis catalase gene
      CAT3, present as a single copy in the nuclear genome. Six introns were identified
      in the CAT3 coding region and two transcription start sites have been been mapped
      by primer extension. The deduced amino acid sequence of CAT3 is highly similar to
      other catalases. CAT3 expression is similar in seedlings germinated and grown
      either in continuous light or in continuous dark, suggesting that CAT3 expression
      in seedlings is not light responsive. CAT3 expression is controlled by the
      circadian clock; in 5-week-old plants grown on a light-dark cycle and then
      transferred to continuous light, robust oscillations in CAT3 mRNA abundance with
      circadian period persist for at least five circadian cycles. Interestingly, the
      peak in CAT3 mRNA abundance occurs in the subjective evening, which is out of
      phase with expression of the Arabidopsis CAT2 catalase gene, which shows clock
      regulated expression gated to the subjective early morning.

PMID- 8668129
TI  - The synthesis of the Streptomyces reticuli cellulase (avicelase) is regulated by
      both activation and repression mechanisms.
AB  - The Streptomyces reticuli cellulase (Cell, Avicelase) hydrolyzes crystalline
      cellulose (Avicel) efficiently to cellobiose. The synthesis of the enzyme is
      induced by Avicel and repressed by glucose. DNA-binding proteins were purified
      from induced S. reticuli mycelia by affinity chromatography using the upstream
      region of the cell gene linked to Sepharose. The enriched protein(s) provoked a
      gel electrophoresis mobility shift of the upstream region, irrespective of the
      presence or absence of a 14-bp palindromic sequence, and enhanced the
      transcription of the cell gene by the S. reticuli RNA polymerase in vitro. The
      binding site (GTGACTGAGCGCCG) for the protein(s) was located in the vicinity of a
      DNA bend upstream of the transcriptional start site. Results of physiological
      studies, deletion and gel-shift analyses lead to the conclusion that a 14-bp
      palindrome (TGGGAGCGCTCCCA)--situated between the transcriptional start site and
      the structure gene--is the operator for a repressor protein. The data presented
      suggest that the two identified cis-acting elements, in cooperation with an
      activator and a repressor, mediate regulation of cell transcription.

PMID- 8668131
TI  - Cloning by functional complementation, and inactivation, of the
      Schizosaccharomyces pombe homologue of the Saccharomyces cerevisiae gene ABC1.
AB  - The Saccharomyces cerevisiae gene ABC1 is required for the correct functioning of
      the bc1 complex of the mitochondrial respiratory chain. By functional
      complementation of a S. cerevisiae abc1(-) mutant, we have cloned a
      Schizosaccharomyces pombe cDNA, whose predicted product is 50% identical to the
      Abc1 protein. Significant homology is also observed with bacterial, nematode, and
      even human amino acid sequences of unknown function, suggesting that the Abc1
      protein is conserved through evolution. The cloned cDNA corresponds to a single
      S. pombe gene abc1Sp, located on chromosome II, expression of which is not
      regulated by the carbon source. Inactivation of the abc1Sp gene by homologous
      gene replacement causes a respiratory deficiency which is efficiently rescued by
      the expression of the S. cerevisiae ABC1 gene. The inactivated strain shows a
      drastic decrease in the bc1 complex activity. a decrease in cytochrome aa3 and a
      slow growth phenotype. To our knowledge, this is the first example of the
      inactivation of a respiratory gene in S. pombe. Our results highlight the fact
      that S. pombe growth is highly dependent upon respiration, and that S. pombe
      could represent a valuable model for studying nucleo-mitochondrial interactions
      in higher eukaryotes.

PMID- 8668133
TI  - A single amino acid change in acetolactate synthase confers resistance to valine
      in tobacco.
AB  - The metabolic control of branches chain amino acid (BCAA) biosynthesis involves
      allosteric regulation of acetolactate synthase (ALS) by the end-products of the
      pathway, valine, leucine and isoleucine. We describe here the molecular basis of
      valine resistance. We cloned and sequenced an ALS gene from the tobacco mutant
      Valr-1 and found a single basepair substitution relative to the wild-type allele.
      This mutation causes a serine to leucine change in the amino acid sequence of ALS
      at position 214. We then mutagenized the wild-type allele of the ALS gene of
      Arabidopsis and found that it confers valine resistance when introduced into
      tobacco plants. Taken together, these results suggest that the serine to leucine
      change at position 214 of ALS is responsible for valine resistance in tobacco.

PMID- 8668132
TI  - Genetic evidence for the functional redundancy of the calcineurin- and Mpk1
      mediated pathways in the regulation of cellular events important for growth in
      Saccharomyces cerevisiae.
AB  - Saccharomyces cerevisiae mutants which exhibit phenotypes (calcium resistance and
      vanadate sensitivity) similar to those of calcineurin-deficient mutants were
      isolated. The mutants were classified into four complementation groups (crv1,2,3
      and 4). Crv1 was allelic to cnb1, a mutation in the regulatory subunit of
      calcineurin. The nucleotide sequences of CRV2 and CRV3 genes which complemented
      the crv2 and crv3 mutations, respectively, are identical to those of
      BCK1/SLK1/SKC1/SSP31 and MPK1/SLT2, respectively, which are both involved in the
      MAP kinase cascade. A calcineurin-deletion mutation (delta cnb1), which by itself
      has no detectable effect on growth and morphology, enhanced some phenotypes (slow
      growth and morphological abnormality) of crv2 and crv3 mutants. These phenotypes
      of crv2 and crv3 mutants were partially suppressed by Ca2+ or by overproduction
      of the calcineurin subunits (Cmp2 and Cnb1). Like the calcineurin-deficient
      mutant, crv2 and crv3 mutants were defective in recovery from alpha-factor
      induced growth arrest. The defect in recovery of the delta cnb1 mutant was
      suppressed by overexpression of MPK1. These results indicated that the
      calcineurin-mediated and the Mpk1- (Bck1-) mediated signaling pathways act in
      parallel to regulate functionally redundant cellular events important for growth.

PMID- 8668134
TI  - Identification of cis-acting DNA sequences involved in the transcription of the
      virulence regulatory gene spvR in Salmonella typhimurium.
AB  - The SpvR protein is a DNA-binding protein of the LysR family, required for the
      transcription of the spvABCD virulence operon of Salmonella typhimurium. An
      alternative sigma factor, sigma S (RpoS), in conjunction with SpvR, controls the
      transcription of the spvR gene. In this study, we used a combination of primer
      extension experiments and deletion/fusion analyses of the spvR gene to identify
      sequences involved in spvR transcription in S. typhimurium. When induced in the
      stationary phase of growth in rich medium or during carbon starvation,
      transcription of spvR in S. typhimurium is driven by a single promoter (spvRp1)
      and initiates 17 nucleotides upstream of the spvR start codon. The level of spvR
      transcription originating at spvRp1 was 20-fold higher in the wild-type strain
      than in the rpoS mutant. In both strains, however, transcription at spvRp1
      requires the SpvR protein. 5' Deletions up to position -86, relative to the spvR
      start codon, did not inhibit inducibility by sigma S and/or SPVR. In contrast, 5'
      deletion up to -75 abolished the activation of spvRp1 by SpvR in both the wild
      type strain and rpoS mutant. Within the 11-bp sequence lying between position -86
      and position -75, a 10-bp consensus motif TNTNTGCANA, present in both the spvR
      and spvA promoter regions, was identified and may contain the DNA recognition
      site for SpvR. In addition, we detected initiation of transcription within the
      spvR coding region. This finding may have implications for comparative studies of
      regulation with spvR gene fusions.

PMID- 8668135
TI  - AUR1, a novel gene conferring aureobasidin resistance on Saccharomyces
      cerevisiae: a study of defective morphologies in Aur1p-depleted cells.
AB  - Aureobasidin A (AbA), a cyclic depsipeptide produced by Aureobasidium pullulans
      R106, is highly toxic to fungi including Saccharomyces cerevisiae. We isolated
      several dominant mutants of S. cerevisiae which are resistant to more than 25
      micrograms/ml of AbA. From a genomic library of one such AUR1 mutant, the AUR1R
      (for aureobasidin resistant) mutant gene was isolated as a gene that confers
      resistance to AbA on wild-type cells. Its nucleotide sequence showed that the
      predicted polypeptide is a hydrophobic protein composed of 401 amino acids, which
      contains several possible transmembrane domains and at least one predicted N
      linked glycosylation site. Comparison of the mutant gene with the wild-type aur1+
      gene revealed that the substitution of Phe at position 158 by Tyr is responsible
      for acquisition of AbA resistance. We suggest that the gene product of the wild
      type aur1+ is a target for AbA on the basis of following results. Firstly, cells
      that overexpress the wild-type aur1+ gene become resistant to AbA, just as cells
      with an AUR1R mutation do. Secondly, disruption of the aur1+ gene demonstrated
      that it is essential for growth. Thirdly, in the cells with a disrupted aur1
      locus, pleiotropic morphological changes including disappearance of microtubules,
      degradation of tubulin and abnormal deposition of chitin were observed. Some of
      these abnormalities are also observed when wild-type cells are treated with AbA.
      The abnormality in microtubules suggests that the Aur1 protein is involved in
      microtubule organization and stabilization.

PMID- 8668136
TI  - Implication of a repression system, homologous to those of other bacteria, in the
      control of arginine biosynthesis genes in Streptomyces coelicolor.
AB  - As with most amino acid biosynthetic pathways in streptomycetes, enzymes of
      arginine biosynthesis in Streptomyces coelicolor show only slight derepression in
      minimal medium without, as opposed to with, exogenous arginine. However, when an
      arginine auxotroph was cultured in limiting arginine, ornithine
      carbamoyltransferase (OCT) activities rose by as much as 100-fold. The response
      was not due to a general starvation effect. To elucidate the repression
      derepression mechanism, a DNA fragment containing the upstream region of the
      previously isolated S. coelicolor argCJB cluster was cloned into a multicopy
      vector and transformed into wild-type S. coelicolor; a slight transient
      derepression of OCT was observed in minimal medium without, though not with,
      added arginine, consistent with titration by the insert of a negatively acting
      macromolecule such as a repressor. A subfragment carrying the 5' end of argC and
      the region immediately upstream showed specific binding, in mobility shift
      assays, to purified AhrC, the repressor/activator of genes of arginine metabolism
      in Bacillus subtilis. It is therefore likely that in S. coelicolor, expression of
      arginine biosynthesis genes is controlled by a protein homologous to the well
      characterised B. subtilis and Escherichia coli repressors.

PMID- 8668137
TI  - Intron-specific stimulation of anaerobic gene expression and splicing efficiency
      in maize cells.
AB  - Most of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes characterized
      in plants and algae to date have one intron very close to the 5' end of the gene.
      To study the functional relevance of some of these introns for gene expression we
      have analysed the influence of three 5' introns on transient gene expression of
      the anaerobically inducible maize GapC4 promoter in maize cells. Under aerobic
      conditions, reporter gene expression is increased in the presence of the first
      introns of the GapC4 and GapC1 genes, and the first intron of the nuclear encoded
      chloroplast-specific GapA1 gene. In contrast, the GapC4 intron increases
      anaerobic gene expression above the level obtained for the intronless construct,
      while anaerobic expression of constructs harboring the GapA1 and GapC1 introns
      was similar to the anaerobic expression level of the intronless construct.
      Splicing analysis revealed that the GapC4 intron is processed more efficiently
      under anaerobic conditions, while no change in splicing efficiency is observed
      for the GapC1 and the GapA1 introns when subjected to anaerobic conditions. These
      results suggest that an increase in splicing efficiency contributes to the
      anaerobic induction of the maize GapC4 gene.

PMID- 8668138
TI  - Yeast pip3/mec3 mutants fail to delay entry into S phase and to slow DNA
      replication in response to DNA damage, and they define a functional link between
      Mec3 and DNA primase.
AB  - The catalytic DNA primase subunit of the DNA polymerase alpha-primase complex is
      encoded by the essential PRI1 gene in Saccharomyces cerevisiae. To identify
      factors that functionally interact with yeast DNA primase in living cells, we
      developed a genetic screen for mutants that are lethal at the permissive
      temperature in a cold-sensitive pril-2 genetic background. Twenty-four recessive
      mutations belonging to seven complementation groups were identified. Some mutants
      showed additional phenotypes, such as increased sensitivity to UV irradiation,
      methyl methanesulfonate, and hydroxyurea, that were suggestive of defects in DNA
      repair and/or checkpoint mechanisms. We have cloned and characterized the gene of
      one complementation group, PIP3, whose product is necessary both for delaying
      entry into S phase or mitosis when cells are UV irradiated in G1 or G2 phase and
      for lowering the rate of ongoing DNA synthesis in the presence of methyl
      methanesulfonate. PIP3 turned out to be the MEC3 gene, previously identified as a
      component of the G2 DNA damage checkpoint. The finding that Mec3 is also required
      for the G1- and S-phase DNA damage checkpoints, together with the analysis of
      genetic interactions between a mec3 null allele and several conditional DNA
      replication mutations at the permissive temperature, suggests that Mec3 could be
      part of a mechanism coupling DNA replication with repair of DNA damage, and DNA
      primase might be involved in this process.

PMID- 8668139
TI  - Site-specific methylation of the rat prolactin and growth hormone promoters
      correlates with gene expression.
AB  - The methylation patterns of the rat prolactin (rPRL) (positions -440 to -20) and
      growth hormone (rGH) (positions -360 to -110) promoters were analyzed by
      bisulfite genomic sequencing. Two normal tissues, the anterior pituitary and the
      liver, and three rat pituitary GH3 cell lines that differ considerably in their
      abilities to express both genes were tested. High levels of rPRL gene expression
      were correlated with hypomethylation of the CpG dinucleotides located at
      positions -277 and -97, near or within positive cis-acting regulatory elements.
      For the nine CpG sites analyzed in the rGH promoter, an overall hypomethylation
      expression coupling was also observed for the anterior pituitary, the liver, and
      two of the cell lines. The effect of DNA methylation was tested by measuring the
      transient expression of the chloramphenicol acetyltransferase reporter gene
      driven by a regionally methylated rPRL promoter. CpG methylation resulted in a
      decrease in the activity of the rPRL promoter which was proportional to the
      number of modified CpG sites. The extent of the inhibition was also found to be
      dependent on the position of methylated sites. Taken together, these data suggest
      that site-specific methylation may modulate the action of transcription factors
      that dictate the tissue-specific expression of the rPRL and rGH genes in vivo.

PMID- 8668140
TI  - Bul1, a new protein that binds to the Rsp5 ubiquitin ligase in Saccharomyces
      cerevisiae.
AB  - We characterized a temperature-sensitive mutant of Saccharomyces cerevisiae in
      which a mini-chromosome was unstable at a high temperature and cloned a new gene
      which encodes a basic and hydrophilic protein (110 kDa). The disruption of this
      gene caused the same temperature-sensitive growth as the original mutation. By
      using the two-hybrid system, we further isolated RSP5 (reverses Spt- phenotype),
      which encodes a hect (homologous to E6-AP C terminus) domain, as a gene encoding
      a ubiquitin ligase. Thus, we named our gene BUL1 (for a protein that binds to the
      ubiquitin ligase). BUL1 seems to be involved in the ubiquitination pathway, since
      a high dose of UBI1, encoding a ubiquitin, partially suppressed the temperature
      sensitivity of the bul1 disruptant as well as that of a rsp5 mutant. Coexpression
      of RSP5 and BUL1 on a multicopy plasmid was toxic for mitotic growth of the wild
      type cells. Pulse-chase experiments revealed that Bul1 in the wild-type cells
      remained stable, while the bands of Bul1 in the rsp5 cells were hardly detected.
      Since the steady-state levels of the protein were the same in the two strains as
      determined by immunoblotting analysis, Bul1 might be easily degraded during
      immunoprecipitation in the absence of intact Rsp5. Furthermore, both Bul1 and
      Rsp5 appeared to be associated with large complexes which were separated through
      a sucrose gradient centrifugation, and Rsp5 was coimmunoprecipitated with Bul1.
      We discuss the possibility that Bul1 functions together with Rsp5 in protein
      ubiquitination.

PMID- 8668141
TI  - EGT2 gene transcription is induced predominantly by Swi5 in early G1.
AB  - In a screen for cell cycle-regulated genes in the yeast Saccharomyces cerevisiae,
      we have identified a gene, EGT2, which is involved in cell separation in the G1
      stage of the cell cycle. Transcription of EGT2 is tightly regulated in a cell
      cycle-dependent manner. Transcriptional levels peak at the boundary of mitosis
      and early G1 The transcription factors responsible for EGT2 expression in early
      G1 are Swi5 and, to a lesser extent, Ace2. Swi5 is involved in the
      transcriptional activation of the HO gene during late G1 and early S phase, and
      Ace2 induces CTS1 transcription during early and late G1 We show that Swi5
      activates EGT2 transcription as soon as it enters the nucleus at the end of
      mitosis in a concentration-dependent manner. Since Swi5 is unstable in the
      nucleus, its level drops rapidly, causing termination of EGT2 transcription
      before cells are committed to the next cell cycle. However, Swi5 is still able to
      activate transcription of HO in late G1 in conjunction with additional activators
      such as Swi4 and Swi6.

PMID- 8668143
TI  - Terminal long tandem repeats in chromosomes form Chironomus pallidivittatus.
AB  - We provide evidence that a chromosome end in the dipteran Chironomus
      pallidivittatus contains 340-bp tandem repeats reaching the extreme terminus of
      the chromosome. After adding synthetic oligonucleotide tails to DNA extracted
      from the microdissected right end of the fourth chromosome, we could demonstrate
      that the blocks of repeats were tailed at only one end, the chromosome terminus,
      the interior of the arrays being unavailable for tailing. Using PCR, we
      furthermore showed that the added tails were connected to 340-bp repeat DNA
      directly, i.e., without intervening DNA of any other kind. The tailed repeats
      belong to a subfamily previously known to be the most peripheral one of the
      different types of 340-bp units. Using plasmid controls, we could also make
      certain that we did not amplify rare or nonrepresentative DNA termini.

PMID- 8668142
TI  - Human ARF4 expression rescues sec7 mutant yeast cells.
AB  - Vesicle-mediated traffic between compartments of the yeast secretory pathway
      involves recruitment of multiple cytosolic proteins for budding, targeting, and
      membrane fusion events. The SEC7 gene product (Sec7p) is a constituent of coat
      structures on transport vesicles en route to the Golgi complex in the yeast
      Saccharomyces cerevisiae. To identify mammalian homologs of Sec7p and its
      interacting proteins, we used a genetic selection strategy in which a human HepG2
      cDNA library was transformed into conditional-lethal yeast sec7 mutants. We
      isolated several clones capable of rescuing sec7 mutant growth at the restrictive
      temperature. The cDNA encoding the most effective suppressor was identified as
      human ADP ribosylation factor 4 (hARF4), a member of the GTPase family proposed
      to regulate recruitment of vesicle coat proteins in mammalian cells. Having
      identified a Sec7p-interacting protein rather than the mammalian Sec7p homolog,
      we provide evidence that hARF4 suppressed the sec7 mutation by restoring
      secretory pathway function. Shifting sec7 strains to the restrictive temperature
      results in the disappearance of the mutant Sec7p cytosolic pool without apparent
      changes in the membrane-associated fraction. The introduction of hARF4 to the
      cells maintained the balance between cytosolic and membrane-associated Sec7p
      pools. These results suggest a requirement for Sec7p cycling on and off of the
      membranes for cell growth and vesicular traffic. In addition, overexpression of
      the yeast GTPase-encoding genes ARF1 and ARF2, but not that of YPT1, suppressed
      the sec7 mutant growth phenotype in an allele-specific manner. This allele
      specificity indicates that individual ARFs are recruited to perform two different
      Sec7p-related functions in vesicle coat dynamics.

PMID- 8668144
TI  - TFIIH functions in regulating transcriptional elongation by RNA polymerase II in
      Xenopus oocytes.
AB  - We investigated the role of TFIIH in transcription by RNA polymerase II (pol II)
      in vivo by microinjection of antibodies against this factor into Xenopus oocytes.
      Five different antibodies directed against four subunits of TFIIH were tested for
      effects on transcription of coinjected human immunodeficiency virus type 2 and c
      myc templates. Each of these antibodies severely reduced the efficiency of
      elongation through human immunodeficiency virus type 2 and c-myc terminator
      elements. In contrast, an anti-TFIIB antibody did not inhibit elongation. Anti
      TFIIH antibodies also had a much smaller inhibitory effect on total transcription
      than did anti-TFIIB or anti-pol II large subunit. Three inhibitors of TFIIH
      kinase activity, H-7, H-8, and dichlororibofuranosylbenzimidazole (DRB),
      inhibited elongation similarly to anti-TFIIH antibodies. These results strongly
      suggest a role for TFIIH in the stimulation of transcriptional elongation in
      vivo.

PMID- 8668145
TI  - Interleukin-11 mRNA stabilization in phorbol ester-stimulated primate bone marrow
      stromal cells.
AB  - 12-O-Tetradecanoylphorbol-13-acetate (TPA) stimulation of PU-34 cells, a primate
      bone marrow stromal cell line, resulted in a prolonged elevation of interleukin
      11 (IL-11) mRNA, which can be inhibited by protein synthesis inhibitors. Nuclear
      run-on assays and actinomycin D experiments demonstrated that the up-regulation
      of IL-11 gene expression is mainly controlled at the posttranscriptional level
      through the protein kinase C (PKC) pathway. Inhibition of PKC activity by
      calphostin C generated an IL-11 mRNA degradation intermediate in TPA-stimulated
      PU-34 cells. This intermediate retains the 5' untranslated region (5'UTR) and
      coding region of the IL-11 mRNA but has lost the poly(A) tail and the 3'UTR. The
      mechanisms underlying IL-11 mRNA stabilization were further investigated by
      transfections with a variety of chimeric IL-11 constructs and deletion mutants.
      Two important observations were made from these transient expression experiments:
      (i) the same 3'UTR of IL-11 mRNA shown to confer instability in one chimeric
      transcript may not function as a destabilizer in another chimeric RNA, and (ii)
      the 5'UTR, coding region, and 3'UTR all contribute to IL-11 mRNA decay, and
      labile IL-11 deletion transcripts are not necessarily stabilized by TPA
      stimulation. Our study suggests that multiple regions within the IL-11 mRNA are
      involved in TPA-stimulated IL-11 mRNA stabilization, possibly through a unique
      RNA folding conformation involving interactions of various RNA sequences within
      the IL-11 mRNA molecule.

PMID- 8668146
TI  - TFG/TAF30/ANC1, a component of the yeast SWI/SNF complex that is similar to the
      leukemogenic proteins ENL and AF-9.
AB  - The SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 gene products are all required for
      proper transcriptional control of many genes in the yeast Saccharomyces
      cerevisiae. Genetic studies indicated that these gene products might form a
      multiprotein SWI/SNF complex important for chromatin transitions preceding
      transcription from RNA polymerase II promoters. Biochemical studies identified a
      SWI/SNF complex containing these and at least six additional polypeptides. Here
      we show that the 29-kDa component of the SWI/SNF complex is identical to
      TFG3/TAF30/ANC1. Thus, a component of the SWI/SNF complex is also a member of the
      TFIIF and TFIID transcription complexes. TFG3 interacted with the SNF5 component
      of the SWI/SNF complex in protein interaction blots. TFG3 is significantly
      similar to ENL and AF-9, two proteins implicated in human acute leukemia. These
      results suggest that ENL and AF-9 proteins interact with the SNF5 component of
      the human SWI/SNF complex and raise the possibility that the SWI/SNF complex is
      involved in acute leukemia.

PMID- 8668147
TI  - Identification of proteins that interact with exon sequences, splice sites, and
      the branchpoint sequence during each stage of spliceosome assembly.
AB  - We have carried out a systematic analysis of the proteins that interact with
      specific intron and exon sequences during each stage of mammalian spliceosome
      assembly. This was achieved by site-specifically labeling individual nucleotides
      within the 5' and 3' splice sites, the branchpoint sequence (BPS), or the exons
      with 32P and identifying UV-cross-linked proteins in the E, A, B, or C
      spliceosomal complex. Significantly, two members of the SR family of splicing
      factors, which are known to promote E-complex assembly, cross-link within exon
      sequences to a region approximately 25 nucleotides upstream from the 5' splice
      site. At the 5' splice site, cross-linking of the U5 small nuclear
      ribonucleoprotein particle protein, U5(200), was detected in both the B and C
      complexes. As observed in yeast cells, U5(200), also cross-links to intron/exon
      sequences at the 3' splice site in the C complex and may play a role in aligning
      the 5' and 3' exons for ligation. With label at the branch site, we detected
      three distinct proteins, designated BPS72,BpS70, and BPS56, which replace one
      another in the E, A, and C complexes. Another dynamic exchange was detected with
      pre-mRNA labeled at the AG dinucleotide of the 3' splice site. In this case, a
      protein, AG100,cross-links in the A complex and is replaced by another protein,
      AG75, in the C complex. The observation that these proteins are specifically
      associated with critical pre-mRNA sequence elements in functional complexes at
      different stages of spliceosome assembly implicates roles for these factors in
      key recognition events during the splicing pathway.

PMID- 8668148
TI  - Human enhancer of filamentation 1, a novel p130cas-like docking protein,
      associates with focal adhesion kinase and induces pseudohyphal growth in
      Saccharomyces cerevisiae.
AB  - Budding in Saccharomyces cerevisiae follows a genetically programmed pattern of
      cell division which can be regulated by external signals. On the basis of the
      known functional conservation between a number of mammalian oncogenes and
      antioncogenes with genes in the yeast budding pathway, we used enhancement of
      pseudohyphal budding in S. cerevisiae by human proteins expressed from a HeLa
      cDNA library as a morphological screen to identify candidate genes that
      coordinate cellular signaling and morphology. In this report, we describe the
      isolation and characterization of human enhancer of filamentation 1 (HEF1), an
      SH3-domain-containing protein that is similar in structure to pl30cas, a recently
      identified docking protein that is a substrate for phosphorylation by a number of
      oncogenic tyrosine kinases. In contrast to p130cas, the expression of HEF1
      appears to be tissue specific. Further, whereas p130cas is localized
      predominantly at focal adhesions, immunofluorescence indicates that HEF1
      localizes to both the cell periphery and the cell nucleus and is differently
      localized in fibroblasts and epithelial cells, suggesting a more complex role in
      cell signalling. Through immunoprecipitation and two-hybrid analysis, we
      demonstrate a direct physical interaction between HEF1 and p130cas, as well as an
      interaction of the SH3 domain of HEF1 with two discrete proline-rich regions of
      focal adhesion kinase. Finally, we demonstrate that as with p130cas,
      transformation with the oncogene v-abl results in an increase in tyrosine
      phosphorylation on HEF1, mediated by a direct association between HEF1 and v-Abl.
      We anticipate that HEF1 may prove to be an important linking element between
      extracellular signalling and regulation of the cytoskeleton.

PMID- 8668151
TI  - Identification of a binding site in c-Ab1 tyrosine kinase for the C-terminal
      repeated domain of RNA polymerase II.
AB  - The c-abl proto-oncogene encodes a nuclear tyrosine kinase that can phosphorylate
      the mammalian RNA polymerase II (RNAP II) on its C-terminal repeated domain (CTD)
      in vitro. Phosphorylation of the CTD has previously been shown to require the
      tyrosine kinase and the SH2 domain of Abl. We show here that a CTD-interacting
      domain (CTD-ID) at the C-terminal region of c-Abl is also required. Deletion of
      the CTD-ID causes the Km 0.4 microM to increase by 2 orders of magnitude. Direct
      binding of the CTD-ID to CTD and to RNAP II could be demonstrated in vitro.
      Phosphorylation of a recombinant glutathione S-transferase-CTD by c-Abl was
      observed in cotransfected COS cells. Mutant Abl proteins lacking the CTD-ID,
      while capable of autophosphorylation, neither phosphorylated nor associated with
      the glutathione S-transferase-CTD in vivo. Transient overexpression of c-Abl also
      led to a four- to fivefold increase in the phosphotyrosine content of the RNAP II
      large subunit. Moreover, the large subunit of RNAP II could be coprecipitated
      with c-Abl. Tyrosine phosphorylation of the coprecipitated RNAP II was again
      dependent on the presence of the CTD-ID in Abl. Finally, the ability of c-Abl to
      phosphorylate and associate with RNAP II could be correlated with the enhancement
      of transcription by c-Abl in transient cotransfection assays. Taken together,
      these observations demonstrate that c-Abl can function as a CTD kinase in vitro
      as well as in vivo.

PMID- 8668149
TI  - Determinants of DNA-binding specificity of ETS-domain transcription factors.
AB  - Several mechanisms are employed by members of transcription factor families to
      achieve sequence-specific DNA recognition. In this study, we have investigated
      how members of the ETS-domain transcription factor family achieve such
      specificity. We have used the ternary complex factor (TCF) subfamily as an
      example. ERK2 mitogen-activated protein kinase stimulates serum response factor
      dependent and autonomous DNA binding by the TCFs Elk-1 and SAP-la. Phosphorylated
      Elk-1 and SAP-la exhibit specificities of DNA binding similar to those of their
      isolated ETS domains. The ETS domains of Elk-1 and SAP-la and SAP-2 exhibit
      related but distinct DNA-binding specificities. A single residue, D-69 (Elk-1) or
      V-68 (SAP-1), has been identified as the critical determinant for the
      differential binding specificities of Elk-1 and SAP-1a, and an additional
      residue, D-38 (Elk-1) or Q-37 (SAP-1), further modulates their DNA binding.
      Creation of mutations D38Q and D69V is sufficient to confer SAP-la DNA-binding
      specificity upon Elk-1 and thereby allow it to bind to a greater spectrum of
      sites. Molecular modelling indicates that these two residues (D-38 and D-69) are
      located away from the DNA-binding interface of Elk-1. Our data suggest a
      mechanism in which these residues modulate DNA binding by influencing the
      interaction of other residues with DNA.

PMID- 8668152
TI  - Ras induces anchorage-independent growth by subverting multiple adhesion
      regulated cell cycle events.
AB  - Anchorage-independent growth is a hallmark of transformed cells, but little is
      known of the molecular mechanisms that underlie this phenomenon. We describe here
      studies of cell cycle control of anchorage-independent growth induced by the ras
      oncogene, with the use of a somatic cell mutant fibroblast line (ER-1-2) that is
      specifically defective in oncogene-mediated, anchorage-independent growth.
      Control, nontransformed PKC3-F4 cells and ER-1-2 cells cannot proliferate in
      semisolid medium. Three important cell cycle events are dependent on adhesion of
      these cells to a substratum: phosphorylation of the retinoblastoma protein, pRB;
      cyclin E-dependent kinase activity; and cyclin A expression. PKC3-F4 cells that
      express ras (PKC3-F4/ras cells) proliferate in nonadherent cultures, and each of
      these three events occurs in the absence of adhesion in PKC3-F4/ras cells. Thus,
      ras can override the adhesion requirement of cellular functions that are
      necessary for cell cycle progression. ER-1-2 cells that express ras (ER-1-2/ras
      cells) possess hyperphosphorylated forms of pRB and cyclin E-dependent kinase
      activity in the absence of adhesion but remain adhesion dependent for expression
      of cyclin A. The adhesion dependence of pRB phosphorylation and cyclin E
      dependent kinase activity is therefore dissociable from the adhesion dependence
      of cyclin A expression. Furthermore, ectopic expression of cyclin A is sufficient
      to rescue anchorage-independent growth of ER-1-2/ras cells but does not induce
      anchorage-independent growth of PKC3-F4 or ER-1-2 cells. However, like pRB
      phosphorylation and cyclin E-dependent kinase activity, the kinase activity
      associated with ectopically expressed cyclin A is dependent on cell adhesion, and
      this dependence is overcome by ras. Thus, the induction of anchorage-independent
      growth by ras may involve multiple signals that lead to both expression of cyclin
      A and activation of G1 cyclin-dependent kinase activities in the absence of cell
      adhesion.

PMID- 8668150
TI  - Retinoids increase human apolipoprotein A-11 expression through activation of the
      retinoid X receptor but not the retinoic acid receptor.
AB  - Considering the link between plasma high-density lipoprotein (HDL) cholesterol
      levels and a protective effect against coronary artery disease as well as the
      suggested beneficial effects of retinoids on the production of the major HDL
      apolipoprotein (apo), apo A-I, the goal of this study was to analyze the
      influence of retinoids on the expression of apo A-II, the other major HDL
      protein. Retinoic acid (RA) derivatives have a direct effect on hepatic apo A-II
      production, since all-trans (at) RA induces apo A-II mRNA levels and apo A-II
      secretion in primary cultures of human hepatocytes. In the HepG2 human
      hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X
      receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist
      ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]
      benzoic acid (TTNPB), induce apo A-II mRNA levels. Transient-transfection
      experiments with a reporter construct driven by the human apo A-II gene promoter
      indicated that 9-cis RA and at-RA, as well as the RXR agonists LGD 1069 and LG
      100268, induced apo A-II gene expression at the transcriptional level. Only
      minimal effects of the RAR agonist TTNPB were observed on the apo A-II promoter
      reporter construct. Unilateral deletions and site-directed mutagenesis identified
      the J site of the apo A-II promoter mediating the responsiveness to RA. This
      element contains two imperfect half-sites spaced by 1 oligonucleotide.
      Cotransfection assays in combination with the use of RXR or RAR agonists showed
      that RXR but not RAR transactivates the apo A-II promoter through this element.
      By contrast, RAR inhibits the inductive effects of RXR on the apo A-II J site in
      a dose-dependent fashion. Gel retardation assays demonstrated that RXR homodimers
      bind, although with a lower affinity than RAR-RXR heterodimers, to the AH-RXR
      response element. In conclusion, retinoids induce hepatic apo A-II production at
      the transcriptional level via the interaction of RXR with an element in the J
      site containing two imperfect half-sites spaced by 1 oligonucleotide, thereby
      demonstrating an important role of RXR in controlling human lipoprotein
      metabolism. Since the J site also confers responsiveness of the apo A-II gene to
      fibrates and fatty acids via the activation of peroxisome proliferator-activated
      receptor-RXR heterodimers, this site can be considered a plurimetabolic response
      element.

PMID- 8668153
TI  - The DNA-binding and enhancer-blocking domains of the Drosophila suppressor of
      Hairy-wing protein.
AB  - Mutations in the suppressor of Hairy-wing [su(Hw)] gene of Drosophila
      melanogaster can cause female sterility and suppress mutations that are
      insertions of the gypsy retrotransposon. Gypsy binds the protein (SUHW) encoded
      by su(Hw), and SUHW prevents enhancers promoter-distal to gypsy from activating
      gene transcription. SUHW contains 12 zinc fingers flanked by acidic N- and C
      terminal domains. We examined the roles of each of the 12 zinc fingers in binding
      gypsy DNA and classified them into four groups: essential (fingers 6 through 10);
      beneficial but nonessential (fingers 1, 2, 3, and 11); unimportant (fingers 5 and
      12); and inhibitory (finger 4). Because finger 10 is not required for female
      fertility but is essential for binding gypsy, these results imply that the SUHW
      binding sites required for oogenesis differ in sequence from the gypsy-binding
      sites. We also examined the functions of the N- and C-terminal domains of SUHW by
      determining the ability of various deletion mutants to support female fertility
      and to alter expression of gypsy insertion alleles of the yellow, cut, forked,
      and Ultrabithorax genes. No individual segment of the N- and C-terminal domains
      of SUHW is absolutely required to alter expression of gypsy insertion alleles.
      However, the most important domain lies between residues 737 and 880 in the C
      terminal domain. This region also contains the residues required for female
      fertility, and the fertility domain may be congruent with the enhancer-blocking
      domain. These results imply that SUHW blocks different enhancers and supports
      oogenesis by the same or closely related molecular mechanisms.

PMID- 8668154
TI  - Intron retention generates a novel isoform of the murine vitamin D receptor that
      acts in a dominant negative way on the vitamin D signaling pathway.
AB  - We identified and characterized a novel rat vitamin D receptor isoform (rVDR1),
      which retains intron 8 of the canonical VDR (rVDR0) during alternative splicing.
      In this isoform protein directed by the stop codon in this newly identified exon,
      a part of the ligand binding domain (86 amino acids) is truncated at the C
      terminal end but contains 19 extra amino acids. The rVDR1 transcript was
      expressed at a level 1/15 to 1/20 of that of rVDR0 in the kidney and intestine in
      adult rats but not in embryos. The recombinant rVDR1 protein showed no ligand
      binding activity. Homo- and heterodimers of the recombinant rVDR0 and rVDR1
      proteins bound to a consensus vitamin D response element (VDRE) but not to
      consensus response elements for thyroid hormone and retinoic acid. However,
      unlike rVDR0, rVDR1 did not form a heterodimeric complex with RXR on the VDRE. A
      transient expression assay showed that this isoform acted as a dominant negative
      receptor against rVDR0 transactivation. Interestingly, the dominant negative
      activities of rVDR1 differed among VDREs. Thus, the present study indicates that
      this new VDR isoform negatively modulates the vitamin D signaling pathway,
      through a particular set of target genes.

PMID- 8668155
TI  - Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site
      in the promoter.
AB  - Cyclin E controls progression through the G1 phase of the cell cycle in mammalian
      fibroblasts and potentially in many other cell types. Cyclin E is a rate-limiting
      activator of cdk2 kinase in late G1. The abundance of cyclin E is controlled by
      phase-specific fluctuations in the mRNA level; in mammalian fibroblasts, mRNA is
      not detected under conditions of serum starvation and is accumulated upon serum
      stimulation, with expression starting in mid-G1. Here, we report the cloning of
      the murine cyclin E promoter. We isolated a 3.8-kb genomic fragment that contains
      several transcriptional start sites and confers cell cycle regulation on a
      luciferase reporter gene. This fragment also supports transcriptional activation
      by adenovirus E1A, a known upstream regulator of cyclin E gene expression. An E2F
      binding site which is required for G1-specific activation of the cyclin E
      promoter in synchronized NIH 3T3 cells was identified in this fragment.

PMID- 8668156
TI  - Differentiation-dependent expression of the brown adipocyte uncoupling protein
      gene: regulation by peroxisome proliferator-activated receptor gamma.
AB  - Uncoupling protein (UCP) is expressed only in brown adipocytes and is responsible
      for the unique thermogenic properties of this cell type. The novel brown
      preadipocyte cell line, HIB-1B, expresses UCP in a strictly differentiation
      dependent manner. Transgenic mice studies have shown that a region from kb -2.8
      to -1.0 of the marine UCP gene is required for brown adipocyte-specific
      expression. Subsequent analysis identified a potent 220-bp enhancer from kb -2.5
      to -2.3. We show that this enhancer is active only in differentiated HIB-1B
      adipocytes, and we identify a peroxisome proliferator-activated receptor gamma
      (PPARgamma) response element, referred to as UCP regulatory element 1 (URE1),
      within the enhancer. URE1 has differentiation-dependent enhancing activity in HIB
      1B cells and is required for enhancer action, since mutations of URE1 that block
      protein binding abolish enhancer activity. We also show that PPAR gamma
      antibodies block binding to URE1 of nuclear extracts from cultured brown
      adipocytes and from the brown adipose tissue of cold-exposed mice. Protein
      binding to URE1 increases substantially during differentiation of HIB-1B
      preadipocytes, and PPAR-gamma mRNA levels increase correspondingly. Although
      forced expression of PPAR gamma and retinoid X receptor alpha activates the
      enhancer in HIB-1B preadipocytes, these receptors are not capable of activating
      the enhancer in NIH 3T3 fibroblasts. Our results show that PPAR gamma is a
      regulator of the differentiation-dependent expression of UCP and suggest that
      there are additional factors in HIB-1B cells required for brown adipocyte
      specific UCP expression.

PMID- 8668158
TI  - Yeast mitochondrial RNase P RNA synthesis is altered in an RNase P protein
      subunit mutant: insights into the biogenesis of a mitochondrial RNA-processing
      enzyme.
AB  - Rpm2p is a protein subunit of Saccharomyces cerevisiae yeast mitochondrial RNase
      P, an enzyme which removes 5' leader sequences from mitochondrial tRNA
      precursors. Precursor tRNAs accumulate in strains carrying a disrupted allele of
      RPM2. The resulting defect in mitochondrial protein synthesis causes petite
      mutants to form. We report here that alteration in the biogenesis of Rpm1r, the
      RNase P RNA subunit, is another consequence of disrupting RPM2. High-molecular
      weight transcripts accumulate, and no mature Rpm1r is produced. Transcript
      mapping reveals that the smallest RNA accumulated is extended on both the 5' and
      3' ends relative to mature Rpm1r. This intermediate and other longer transcripts
      which accumulate are also found as low-abundance RNAs in wild-type cells,
      allowing identification of processing events necessary for conversion of the
      primary transcript to final products. Our data demonstrate directly that Rpm1r is
      transcribed with its substrates, tRNA met f and tRNAPro, from a promoter located
      upstream of the tRNA met f gene and suggest that a portion also originates from a
      second promoter, located between the tRNA met f gene and RPM1. We tested the
      possibility that precursors accumulate because the RNase P deficiency prevents
      the removal of the downstream tRNAPro. Large RPM1 transcripts still accumulate in
      strains missing this tRNA. Thus, an inability to process cotranscribed tRNAs does
      not explain the precursor accumulation phenotype. Furthermore, strains with
      mutant RPM1 genes also accumulate precursor Rpm1r, suggesting that mutations in
      either gene can lead to similar biogenesis defects. Several models to explain
      precursor accumulation are presented.

PMID- 8668157
TI  - Schizosaccharomyces pombe map1+ encodes a MADS-box-family protein required for
      cell-type-specific gene expression.
AB  - We cloned the Schizosaccharomyces pombe map1 gene by virtue of its ability to
      stimulate transcription of the sxa2 gene, which encodes a carboxypeptidase
      expressed specifically in h- cells in response to mating-pheromone signaling. The
      cloned gene had a coding capacity of 398 amino acids split by two introns, and
      the deduced product was a protein of the MADS box family. This gene was most
      similar to Saccharomyces cerevisiae MCM1, which regulates cell-type-specific gene
      expression in budding yeast cells. Disruption of the S. pombe gene did not affect
      vegetative cell growth but conferred sterility. It blocked the mating ability of
      h+ cells completely and that of h- cells partially. Genetic and sequencing
      analysis indicated that the cloned gene is map1], which was originally defined by
      a mutation that caused h+-speciftic sterility. Northern (RNA) blot analysis
      showed that the function of map1 is absolutely essential for the expression of h+
      specific genes and is required for the full activation of h--specific gene
      expression. Overexpression of map1 resulted in enhanced transcription of cell
      type-specilic genes, but the range of genes affected by Map1 was restricted by
      the mating type of the cell. Results of yeast two-hybrid analysis suggested that
      Map1 may physically interact with Mat1-Pc, the product of the h(+)-specific
      mating-type gene mat1-Pc. On the basis of these observations, we speculate that
      Map1 may be a transcriptional regulator of cell-type-specific genes similar to S.
      cerevisiae MCM1, whose activity is modulated by the oil and alpha2 mating-type
      gene products.

PMID- 8668160
TI  - Molecular genetic analysis of volatile-anesthetic action.
AB  - The mechanism(s) and site(s) of action of volatile inhaled anesthetics are
      unknown in spite of the clinical use of these agents for more than 150 years. In
      the present study, the model eukaryote Saccharomyces cerevisiae was used to
      investigate the action of anesthetic agents because of its powerful molecular
      genetics. It was found that growth of yeast cells is inhibited by the five common
      volatile anesthetics tested (isoflurane, halothane, enflurane, sevoflurane, and
      methoxyflurane). Growth inhibition by the agents is relatively rapid and
      reversible. The potency of these compounds as yeast growth inhibitors directly
      correlates with their lipophilicity as is predicted by the Meyer-Overton
      relationship, which directly correlates anesthetic potency of agents and their
      lipophilicity. The effects of isoflurane on yeast cells were characterized in the
      most detail. Yeast cells survive at least 48 h in a concentration of isoflurane
      that inhibits colony formation. Mutants resistant to the growth-inhibitory
      effects of isoflurane are readily selected. The gene identified by one of these
      mutations, zzz4-1, has been cloned and characterized. The predicted ZZZ4 gene
      product has extensive homology to phospholipase A2-activating protein, a GO
      effector protein of mice. Both zzz4-1 and a deletion of ZZZ4 confer resistance to
      all five of the agents tested, suggesting that signal transduction may be
      involved in the response of these cells to volatile anesthetics.

PMID- 8668159
TI  - Processing of nontelomeric 3' ends by telomerase: default template alignment and
      endonucleolytic cleavage.
AB  - Telomerase is a specialized reverse transcriptase that maintains telomeres at
      chromosome ends by extending preexisting tracts of telomeric DNA and forming
      telomeres de novo on broken chromosomes. Whereas the interaction of telomerase
      with telomeric DNA has been studied in some detail, relatively little is known
      about how this enzyme processes nontelomeric DNA. In this study we recruited the
      Euplotes telomerase to nontelomeric 3' termini in vitro using chimeric DNA
      primers that carried one repeat of a telomeric sequence at various positions
      upstream of a nontelomeric 3' end. Such primers were processed in two distinct
      pathways. First, nontelomeric 3' ends could be elongated directly by positioning
      a primer terminus at a specific site on the RNA template. Delivery to this
      default site was precise, always resulting in the addition of 4 dG residues to
      the non-telomeric 3' ends. These same residues initiate new telomeres formed in
      vivo. Alternatively, 3' nontelomeric nucleotides were removed from primers prior
      to initiating the first elongation cycle. As with default positioning of
      nontelomeric 3' ends, the cleavage event was extremely precise and was followed
      by the addition of dG residues to the primer 3' ends. The specificity of the
      cleavage reaction was mediated by primer interaction with the RNA template and,
      remarkably, proceeded by an endonucleolytic mechanism. These observations suggest
      a mechanism for the precision of developmentally regulated de novo telomere
      formation and expand our understanding of the enzymatic properties of telomerase.

PMID- 8668161
TI  - Association of p300 and CBP with simian virus 40 large T antigen.
AB  - p300 and the CREB-binding protein CBP are two large nuclear phosphoproteins that
      are structurally highly related. Both function, in part, as transcriptional
      adapters and are targeted by the adenovirus E1A oncoprotein. We show here that
      p300 and CBP interact with another transforming protein, the simian virus 40
      large T antigen (T). This interaction depends on the integrity of a region of T
      which is critical for its transforming and mitogenic properties and includes its
      LXCXE Rb-binding motif. T interferes with normal p300 and CBP function on at
      least two different levels. The presence of T alters the phosphorylation states
      of both proteins and inhibits their transcriptional activities on certain
      promoters. Although E1A and T show little sequence similarity, they interact with
      the same domain of p300 and CBP, suggesting that this region exhibits
      considerable flexibility in accommodating diverse protein ligands.

PMID- 8668163
TI  - Identification of an autoinhibitory region in the activation loop of the Mos
      protein kinase.
AB  - The Mos protein is a serine/threonine protein kinase which acts to regulate
      progression through meiosis in vertebrate oocytes. Although Mos function is
      dependent on its ability to act as a protein kinase, little is known about the
      factors which regulate Mos kinase activity. To understand the mechanism by which
      Mos kinase activity is regulated, we have used molecular modeling to construct a
      three-dimensional model of Mos based on the crystallographic coordinates of
      cyclic AMP-dependent kinase (PKA). This model identified a loop in Mos which is
      positioned near the active site and appears capable of blocking substrate access
      to the active site. Mutagenesis was used to construct altered forms of the Mos
      protein with deletions of parts or all of the loop. In vitro kinase assays showed
      that Mos proteins with the loop removed had up to a fourfold increase in kinase
      activity compared with the wild-type protein, indicating that the loop acts in an
      autoinhibitory manner for Mos kinase activity. Point mutations were also made on
      individual residues of the loop which were determined from the molecular model to
      be capable of reaching the active site. Determination of the kinase activities of
      these mutants showed that individual mutations in the loop region are capable of
      either increasing or decreasing kinase activity with regard to the wild-type
      protein. These data suggest that the loop identified in Mos acts as an
      autoinhibitor of kinase activity.

PMID- 8668162
TI  - Regulation of Btk by Src family tyrosine kinases.
AB  - Loss of function of Bruton's tyrosine kinase (Btk) results in X-linked
      immunodeficiencies characterized by a broad spectrum of signaling defects,
      including those dependent on Src family kinase-linked cell surface receptors. A
      gain-of-function mutant, Btk*, induces the growth of fibroblasts in soft agar and
      relieves the interleukin-5 dependence of a pre-B-cell line. To genetically define
      Btk signaling pathways, we used a strategy to either activate or inactivate Src
      family kinases in fibroblasts that express Btk*. The transformation potential of
      Btk* was dramatically increased by coexpression with a partly activated c-Src
      mutant (E-378 --> G). This synergy was further potentiated by deletion of the Btk
      Src homology 3 domain. Downregulation of Src family kinases by the C-terminal Src
      kinase (Csk) suppressed Btk* activation and biological potency. In contrast,
      kinase-inactive Csk (K-222 --> R), which functioned as a dominant negative
      molecule, synergized with Btk* in biological transformation. Activation of Btk*
      correlated with increased phosphotyrosine on transphosphorylation and
      autophosphorylation sites. These findings suggest that the Src and Btk kinase
      families form specific signaling units in tissues in which both are expressed.

PMID- 8668164
TI  - A dominant inhibitory mutant of the type II transforming growth factor beta
      receptor in the malignant progression of a cutaneous T-cell lymphoma.
AB  - In many cancers, inactivating mutations in both alleles of the transforming
      growth factor beta (TGF-beta) type 11 receptor (TbetaRII) gene occur and
      correlate with loss of sensitivity to TGF-beta. Here we describe a novel
      mechanism for loss of sensitivity to growth inhibition by TGF-beta in tumor
      development. Mac-1 cells, isolated from the blood of a patient with an indolent
      form of cutaneous T-cell lymphoma, express wild-type TbetaRII and are sensitive
      to TGF-beta. Mac-2A cells, clonally related to Mac-1 and isolated from a skin
      nodule of the same patient at a later, clinically aggressive stage of lymphoma,
      are resistant to TGF-beta. They express both the wild-type TbetaRII and a
      receptor with a single point mutation (Asp-404-Gly [D404G]) in the kinase domain
      (D404G-->TbetaRII); no TbetaRI or TbetaRII is found on the plasma membrane,
      suggesting that D404G-TbetaRII dominantly inhibits the function of the wild-type
      receptor by inhibiting its appearance on the plasma membrane. Indeed, inducible
      expression, under control of a tetracycline-regulated promoter, of D404G-TbetaRII
      in TGF-beta- sensitive Mac-1 cells as well as in Hep3B hepatoma cells results in
      resistance to TGF-beta and disappearance of cell surface TbetaRI and TbetaRII.
      Overexpression of wild-type TbetaRII in Mac-2A cells restores cell surface
      TbetaRI and TbetaRH and sensitivity to TGF-beta. The ability of the D404G-TbetaRH
      to dominantly inhibit function of wild-type TGF-beta receptors represents a new
      mechanism for loss of sensitivity to the growth-inhibitory functions of TGF-beta
      in tumor development.

PMID- 8668165
TI  - The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein
      whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine
      inducible nuclear proteins.
AB  - Acute-phase reactants (APRs) are proteins synthesized in the liver following
      induction by interleukin-1 (IL-1), IL-6, and glucocorticoids, involving
      transcriptional gene activation. Lipopolysaccharide-binding protein (LBP) is a
      recently identified hepatic secretory protein potentially involved in the
      pathogenesis of sepsis, capable of binding the bacterial cell wall product
      endotoxin and directing it to its cellular receptor, CD14. In order to examine
      the transcriptional induction mechanisms by which the LBP gene is activated, we
      have investigated the regulation of expression of its mRNA in vitro and in vivo
      as well as the organization of 5' upstream regulatory DNA sequences. We show that
      induction of LBP expression is transcriptionally regulated and is dependent on
      stimulation with IL-1beta, IL-6, and dexamethasone. By definition, LBP thus has
      to be viewed as a class 1 acute-phase protein and represents the first APR
      identified which is capable of detecting pathogenic bacteria. Furthermore,
      cloning of the LBP promoter revealed the presence of regulatory elements,
      including the common APR promoter motif APRE/STAT-3 (acute-phase response
      element/signal transducer and activator of transcription 3). Luciferase reporter
      gene assays utilizing LBP promoter truncation and point mutation variants
      indicated that transcriptional activation of the LBP gene required a functional
      APRE/STAT-3 binding site downstream of the transcription start site, as well as
      an AP-1 and a C/EBP (CCAAT enhancer-binding protein) binding site. Gel
      retardation and supershift assays confirmed that upon cytokine stimulation
      APRF/STAT-3 binds to its recognition site, leading to strong activation of the
      LBP gene. Unraveling of the mechanism of transcriptional activation of the LBP
      gene, involving three known transcription factors, may contribute to our
      understanding of the acute-phase response and the pathophysiology of sepsis and
      septic shock.

PMID- 8668166
TI  - A single editing event is a prerequisite for efficient processing of potato
      mitochondrial phenylalanine tRNA.
AB  - In bean, potato, and Oenothera plants, the C encoded at position 4 (C4) in the
      mitochondrial tRNA Phe GAA gene is converted into a U in the mature tRNA. This
      nucleotide change corrects a mismatched C4-A69 base pair which appears when the
      gene sequence is folded into the cloverleaf structure. C-to-U conversions
      constitute the most common editing events occurring in plant mitochondrial mRNAs.
      While most of these conversions introduce changes in the amino acids specified by
      the mRNA and appear to be essential for the synthesis of functional proteins in
      plant mitochondria, the putative role of mitochondrial tRNA editing has not yet
      been defined. Since the edited form of the tRNA has the correct secondary and
      tertiary structures compared with the nonedited form, the two main processes
      which might be affected by a nucleotide conversion are aminoacylation and
      maturation. To test these possibilities, we determined the aminoacylation
      properties of unedited and edited potato mitochondrial tRNAPhe in vitro
      transcripts, as well as the processing efficiency of in vitro-synthesized potato
      mitochondrial tRNAPhe precursors. Reverse transcription-PCR amplification of
      natural precursors followed by cDNA sequencing was also used to investigate the
      influence of editing on processing. Our results show that C-to-U conversion at
      position 4 in the potato mitochondrial tRNA Phe GAA is not required for
      aminoacylation with phenylalanine but is likely to he essential for efficient
      processing of this tRNA.

PMID- 8668168
TI  - Evidence for involvement of trans-acting factors in selection of the AUG start
      codon during eukaryotic translational initiation.
AB  - The molecular mechanism with which an appropriate AUG codon is selected as the
      start site for translational initiation by eukaryotic ribosomes is not known. By
      using a cell-free translation system, small RNA molecules containing single AUG
      codons, surrounded by various nucleotide sequences, were tested for their
      abilities to interfere with the translation of a reporter mRNA. RNAs containing
      the AUG in an ACCAUGG context (Kozak consensus sequence) were able to inhibit
      translation of the reporter mRNA. In contrast, RNAs containing the AUG in a less
      favorable context for start site selection (for example, CAGAUGG) had no effect
      on the translation of the reporter mRNA. The effect mediated by the ACCAUGC
      containing RNAs was not due to sequestration of ribosomal subunits or to
      particular structural features in these RNAs. To identify potential trans-acting
      factors that might be preferentially bound by ACCAUGG-containing RNAs, ACCAUGG-
      and CAGAUGC-containing RNAs with a single 4-thiouridine residue at the AUG were
      incubated with partially fractionated extracts, and AUG-binding proteins were
      identified after irradiation of the complexes with UV light and subsequent
      analysis by gel electrophoresis. The analysis (of such complexes in competition
      experiments revealed that proteins, approximately 50 and 100 kDa in size, were
      found to bind directly at the AUG codon embedded in the ACCAUGG motif. One of
      these proteins has been identified as the La autoantigen. These findings indicate
      that trans-acting factors may play a role in AUG start site selection during
      translational initiation.

PMID- 8668167
TI  - Identification of sequences in c-myc mRNA that regulate its steady-state levels.
AB  - The level of cellular myc proto-oncogene expression is rapidly regulated in
      response to environmental signals and influences cell proliferation and
      differentiation. Regulation is dependent on the fast turnover of c-myc mRNA,
      which enables cells to rapidly alter c-myc mRNA levels. Efforts to identify
      elements in myc mRNA responsible for its instability have used a variety of
      approaches, all of which require manipulations that perturb normal cell
      metabolism. These various approaches have implicated different regions of the
      mRNA and have led to a lack of consensus over which regions actually dictate
      rapid turnover and low steady-state levels of c-myc mRNA. To identify these
      regions by an approach that does not perturb cell metabolism acutely and that
      directly assesses the effect of a c-myc mRNA region on the steady-state levels of
      c-myc mRNA, we developed an assay using reverse transcription and PCR to compare
      the steady-state levels of human myc mRNAs transcribed from two similarly
      constructed myc genes transiently cotransfected into proliferating C2C12
      myoblasts. Deletion mutations were introduced into myc genes, and the levels of
      their mRNAs were compared with that of a near-normal, reference myc mRNA.
      Deletion of most of the myc 3' untranslated region (UTR) raised myc mRNA levels,
      while deletion of sequences in the myc 5' UTR (most of exon 1), exon 2, or the
      protein-coding region of exon 3 did not, thus demonstrating that the 3' UTR is
      responsible for keeping myc mRNA levels low. Using a similar reverse
      transcription-PCR assay for comparing the steady-state levels of two beta-globin
      myc fusion mRNAs, we showed that fusion of the myc 3' UTR lowers globin mRNA
      levels by destabilizing beta-globin mRNA. Surprisingly, fusion of the protein
      coding region of myc exon 3 also lowered globin mRNA steady-state levels.
      Investigating the possibility that exon 3 coding sequences may play some other
      role in regulating c-myc mRNA turnover, we demonstrated that these sequences, but
      not myc 3' UTR sequences, are necessary for the normal posttranscriptional
      downregulation of c-myc mRNA during myoblast differentiation. We conclude that,
      while two elements within c-myc mRNA can act as instability determinants in a
      heterologous context, only the instability element in the 3' UTR regulates its
      steady-state levels in proliferating C2C12 cells.

PMID- 8668169
TI  - Comparison of targeted-gene replacement frequencies in Drosophila melanogaster at
      the forked and white loci.
AB  - P element-induced gene conversion has been previously used to modify the white
      gene of Drosophila melanogaster in a directed fashion. The applicability of this
      approach of gene targeting in Drosophila melanogaster, however, has not been
      analyzed quantitatively for other genes. We took advantage of the P element
      induced forked allele, f(hd), which was used as a target, and we constructed a
      vector containing a modified forked fragment for converting f(hd). Conversion
      frequencies were analyzed for this locus as well as for an alternative white
      allele, w(eh812). Combination of both P element-induced mutant genes allowed the
      simultaneous analysis of conversion frequencies under identical genetic,
      developmental, and environmental conditions. This paper demonstrates that gene
      conversion through P element-induced gap repair can be applied with similar
      success rates at the forked locus and in the white gene. The average conversion
      frequency at forked was 0.29%, and that at white was 0.17%. These frequencies
      indicate that in vivo gene targeting in Drosophila melanogaster should be
      applicable for other genes in this species at manageable rates. We also confirmed
      the homolog dependence of reversions at the forked locus, indicating that P
      elements transpose via a cut-and-paste mechanism. In a different experiment, we
      attempted conversion with a modified forked allele containing the su(Hw) binding
      site. Despite an increased sample size, there were no conversion events with this
      template. One interpretation (under investigation) is that the binding of the
      su(Hw) product prevents double-strand break repair.

PMID- 8668171
TI  - Constitutive phosphorylation of IkappaBalpha by casein kinase II occurs
      preferentially at serine 293: requirement for degradation of free IkappaBalpha.
AB  - IkappaBalpha is a phosphoprotein that sequesters the NF-kappaB/Rel transcription
      factors in the cytoplasm by physical association. Following induction by a wide
      variety of agents, IkappaBalpha is further phosphorylated and degraded, allowing
      NF-kappaB/Rel proteins to translocate to the nucleus and induce transcription. We
      have previously reported that the constitutive phosphorylation site resides in
      the C-terminal PEST region of IkappaBalpha and is phosphorylated by casein kinase
      II (CKII). Here we show that serine 293 is the preferred CKII phosphorylation
      site. Additionally, we show compensatory phosphorylation by CKII at neighboring
      serine and threonine residues. Thus, only when all five of the serine and
      threonine residues in the C-terminal region of IkappaBalpha are converted to
      alanine (MutF), is constitutive phosphorylation abolished. Finally, we show that
      constitutive phosphorylation is required for efficient degradation of free
      IkappaBalpha, in that unassociated Mutf has a half-life two times longer than
      wild-type IkappaBalpha. A serine residue alone at position 293, as well as
      aspartic acid at this position, can revert the Mutf phenotype. Therefore, the
      constitutive CKII phosphorylation site is an integral part of the PEST region of
      IkappaBalpha, and this phosphorylation is required for rapid proteolysis of the
      unassociated protein.

PMID- 8668170
TI  - NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and
      differentiative stimuli.
AB  - Previous work had identified a corepressor, NAB1, which represses transcriptional
      activation mediated by NGFI-A (also known as Egr-1, zif268, and Krox24) and
      Krox20. These zinc finger transcription factors are encoded by immediate-early
      genes and have been implicated in a wide variety of proliferative and
      differentiative processes. We have isolated and characterized another
      corepressor, NAB2, which is highly related to NAB1 within two discrete domains.
      The first conserved domain of NAB2 mediates an interaction with the R1 domain of
      NGFI-A. NAB2 represses the activity of both NGFI-A and Krox20, and its expression
      is regulated by some of the same stimuli that induce NGFI-A expression, including
      serum stimulation of fibroblasts and nerve growth factor stimulation of PC12
      cells. The human NAB2 gene has been localized to chromosome 12ql3.3-14.1, a
      region that is rearranged in several solid tumors, lipomas, uterine leiomyomata,
      and liposarcomas. Sequencing of the Caenorhabditis elegans genome has identified
      a gene that bears high homology to both NAB1 and NAB2, suggesting that NAB
      molecules fulfill an evolutionarily conserved role.

PMID- 8668172
TI  - Altered mRNA binding activity and decreased translational initiation in a nuclear
      mutant lacking translation of the chloroplast psbA mRNA.
AB  - Translational regulation has been identified as one of the key steps in
      chloroplast-encoded gene expression. Genetic and biochemical analysis with
      Chlamydomonas reinhardtii has implicated nucleus-encoded factors that interact
      specifically with the 5' untranslated region of chloroplast mRNAs to mediate
      light-activated translation. F35 is a nuclear mutation in C. reinhardtii that
      specifically affects translation of the psbA mRNA (encoding D1, a core
      polypeptide of photosystem II), causing a photosynthetic deficiency in the mutant
      strain. The F35 mutant has reduced ribosome association of the psbA mRNA as a
      result of decreased translation initiation. This reduction in ribosome
      association correlates with a decrease in the stability of the mRNA. Binding
      activity of the psbA specific protein complex to the 5' untranslated region of
      the mRNA is diminished in F35 cells, and two members of this binding complex
      (RB47 and RB55) are reduced compared with the wild type. These data suggest that
      alteration of members of the psbA mRNA binding complex in F35 cells results in a
      reduction in psbA mRNA-protein complex formation, thereby causing a decrease in
      translation initiation of this mRNA.

PMID- 8668173
TI  - Requirements for interleukin 2 promoter transactivation by the Tax protein of
      human T-cell leukemia virus type 1.
AB  - The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) upregulates the
      expression of several cellular genes by activating members of both the NF-kappaB
      and bZIP families of transcription factors. Recent studies demonstrate that the
      CD28 response element (CD28RE) of the interleukin 2 (IL-2) promoter is the site
      upregulated by Tax in stimulated T cells. Although some reports suggest that this
      site is transactivated by NF-kappaB family members, others disagree, leaving the
      identity of the transcription factor(s) binding the CD28RE unclear. The studies
      presented here further characterize the response of the IL-2 promoter and CD28RE
      to the HTLV-1 Tax protein and demonstrate that the TATA-proximal AP-1 binding
      site of the IL-2 promoter is also necessary for Tax transactivation in stimulated
      Jurkat cells. In contrast to its upregulation of the IL-2 promoter which requires
      T-cell stimulation, Tax transactivates the isolated CD28RE-AP-1 element without
      stimulation but is greatly synergized by calcium ionophore and phorbol ester.
      Additionally, transactivation of the IL-2 promoter requires the Tax activation
      domain involved in upregulation of bZIP-enhanced transcription while the NF
      kappaB-activating domain of Tax is dispensable. Interestingly, both domains
      appear to be necessary for the activation of the isolated CD28RE-AP-1 sequence in
      the context of a heterologous promoter construct. This strongly suggests that
      activation of NF-kappaB is insufficient to activate transcription via the CD28RE
      AP-1 element of the IL-2 promoter and that a different transcription factor,
      upregulated via the activation domain of the HTLV-1 Tax protein, may be involved.

PMID- 8668174
TI  - Identification of overlapping DNA-binding and centromere-targeting domains in the
      human kinetochore protein CENP-C.
AB  - The kinetochore in eukaryotes serves as the chromosomal site of attachment for
      microtubules of the mitotic spindle and directs the movements necessary for
      proper chromosome segregation. In mammalian cells, the kinetochore is a highly
      differentiated trilaminar structure situated at the surface of the centromeric
      heterochromatin. CENP-C is a basic, DNA-binding protein that localizes to the
      inner kinetochore plate, the region that abuts the heterochromatin.
      Microinjection experiments using antibodies specific for CENP-C have demonstrated
      that this protein is required for the assembly and/or stability of the
      kinetochore as well as for a timely transition through mitosis. From these
      observations, it has been suggested that CENP-C is a structural protein that is
      involved in the organization or the kinetochore. In this report, we wished to
      identify and map the functional domains of CENP-C. Analysis of CENP-C truncation
      mutants expressed in vivo demonstrated that CENP-C possesses an autonomous
      centromere-targeting domain situated at the central region of the CENP-C
      polypeptide. Similarly, in vitro assays revealed that a region of CENP-C with the
      ability to bind DNA is also located at the center of the CENP-C molecule, where
      it overlaps the centromere-targeting domain.

PMID- 8668175
TI  - Formation of extrachromosomal circular amplicons with direct or inverted
      duplications in drug-resistant Leishmania tarentolae.
AB  - Selection for methotrexate resistance in Leishmania spp. is often associated with
      amplification of the H locus short-chain dehydrogenase-reductase gene ptr1 as
      part of extrachromosomal elements. Extensive sequences are always coamplified and
      often contain inverted duplications, most likely formed by the annealing of
      inverted repeats present at the H locus. By gene targeting mediated by homologous
      recombination, several repeated sequences were introduced in the vicinity of
      ptr1. Selection for methotrexate resistance in these transfectants led to ptr1
      amplification as part of small circles with direct or inverted duplications
      whether the integrated sequences consisted of direct or inverted repeats. Hence,
      for a region to he amplified in L. tarentolae during drug selection, a drug
      resistance gene is required and must be flanked by (any) homologous repeated
      sequences. The distance between these repeats and their orientation will
      determine the length of the amplicon and whether it contains direct or inverted
      duplications.

PMID- 8668176
TI  - GATA factors are essential for activity of the neuron-specific enhancer of the
      gonadotropin-releasing hormone gene.
AB  - The multicomponent neuron-specific enhancer of the gonadotropin-releasing hormone
      (GnRH) gene specifically targets expression to the GnRH-secreting neurons of the
      hypothalamus, a small population of specialized cells which play a central role
      in regulating reproductive function. Utilizing the GnRH-secreting hypothalamic
      neuronal cell line, GT1, as a model system, we show that members of the GATA
      family of transcription factors regulate GnRH transcription through two GATA
      factor-binding motifs that occur in a tandem repeat within the GnRH neuron
      specific enhancer. Although GT1 cells contain GATA-2 and GATA-4 mRNAs, only GATA
      4 was detected in a GnRH enhancer GATA site-specific complex. Cotransfection
      experiments with wild-type and mutant GnRH enhancer reporter plasmids with wild
      type and dominant negative GATA factor expression vectors demonstrated that both
      GATA-binding elements are functional in the context of the enhancer. We conclude
      that GATA-binding proteins are important factors in regulating the neuron
      specific expression of the GnRH gene in hypothalamic cells. Although the presence
      of GATA-2 in a neuronal cell type is not unusual, the presence of GATA-4 in GT1
      cells is novel for a neuronal cell type. However, the presence of GATA-4 is
      consistent with the unique developmental origin of GnRH neurons and may provide
      insight into the transcriptional mechanisms mediating the differentiation of this
      limited population of GnRH-secreting neurons.

PMID- 8668177
TI  - Transcriptional repression and growth suppression by the p107 pocket protein.
AB  - p107 is a member of the pocket family of proteins that includes the
      retinoblastoma tumor suppressor. Overexpression of p107 arrests cells in G1,
      suggesting that it is important for cell cycle control. This growth suppression
      is mediated at least in part through the interaction of p107 with a member of the
      E2F family of cell cycle transcription factors, and this interaction can be
      disrupted by oncoproteins from DNA tumor viruses such as adenovirus E1a that bind
      p107. Not only does the binding of p107 to E2F inactivate E2F, but also we show
      that when p107 is tethered to the promoter through binding to E2F it functions as
      a general transcriptional repressor. This general repressor activity was also
      evident when p107 was fused to the DNA binding domain of Gal4 so that it could be
      directly targeted to the promoter in an E2F-independent fashion. Using p107
      mutants, we compared the regions of the protein required for transcriptional
      repression and cell growth suppression. We found that the pocket domain is
      sufficient for inactivation of E2F, general repressor activity, and most of the
      growth suppressor activity. Binding of conserved region 1 from Ela to p107
      blocked interaction with E2F, but it did not affect general repressor activity,
      demonstrating that binding and inactivation of E2F and general repressor activity
      are distinguishable properties of p107. Within the pocket, two conserved domains,
      A and B, were sufficient for growth suppression and transcriptional repressor
      activity. Surprisingly, we found that these two domains were fully functional
      when they were coexpressed as separate proteins, and we present results
      suggesting that the domains may interact at the promoter to form an active
      pocket.

PMID- 8668178
TI  - DNA rearrangements associated with multiple consecutive directed antigenic
      switches in Trypanosoma brucei.
AB  - Changes in variant surface glycoprotein (Vsg) expression allow Trypanosoma brucei
      to elude the immune response. The expressed vsg is always located at the
      telomeric end of a polycistronic transcription unit known as an expression site
      (ES). Although there are many ESs, only one is active at any particular time. The
      mechanisms regulating ES transcription and switching are unknown. Chromosome
      rearrangements within or upstream of the ES have been described to occur in
      occasional switch events, but no changes have been consistently associated with
      switching. We inserted the drug resistance genes neo and ble, conferring
      resistance to G418 and phleomycin, respectively, 1 kb downstream of "silent" ES
      promoters. This demonstrated that short-range transcription could be achieved
      from a silent ES promoter. From one initial transformant clone, panels of
      independent consecutive on-off-on switch clones were generated and analyzed. The
      first activation of the neo-targeted ES was always associated with deletion of
      the upstream tandem promoter in this ES, but no further rearrangements were
      detected in consecutive off-on switches of this ES. On the other hand, direct
      analysis of ES promoters showed that deletions and duplications occurred
      elsewhere. Activation of a ble-tagged 300-kb chromosome could not be achieved,
      but phleomycin-resistant clones could be obtained. One such clone arose from
      recombination between three ESs. Taken together, our experiments suggest that ES
      switching may occur after a period of chromosomal interactivity that may or may
      not leave tangible evidence in the form of detectable sequence changes.

PMID- 8668179
TI  - Hepatocyte nuclear factor 3 activates transcription of thyroid transcription
      factor 1 in respiratory epithelial cells.
AB  - Thyroid transcription factor 1 (TTF-1), hepatocyte nuclear factor 3alpha (HNF
      3alpha), and HNF-3beta regulate the transcription of genes expressed in the
      respiratory epithelium. To test whether members of the HNF-3/forkhead family
      influence TTF-1 gene expression, deletion constructs containing the 5' region of
      the human TTF-1 gene were transfected into immortalized mouse lung epithelial
      (MLE) cells. DNase I protection and electrophoretic mobility shift assays
      identified elements in the 5' region of the TTF-1 gene that bound MLE cell
      nuclear proteins consistent with the binding of HNF-3 to sites at positions -135
      to -124 and -14 to -3. In MLE cells, TTF-1-luciferase reporter constructs were
      activated by cotransfection with HNF-3beta, activated to a lesser extent by HNF
      3alpha, but not activated by HFH-8. HNF-3alpha. and HFH-8 inhibited the
      activation of TTF-1-luciferase by HNF-3beta. Site-specific mutagenesis of each of
      the HNF-3 binding sites in the human TTF-1 gene inhibited the binding of MLE cell
      nuclear proteins and inhibited transactivation of the TTF-1-luciferase constructs
      after cotransfection with HNF-3beta. Immunohistochemical staining demonstrated
      that both HNF-3beta and TTF-1 were detected in bronchiolar and alveolar type II
      cells in the human lung. Modulation of TTF-1 gene expression by members of the
      HNF-3/forkhead family members may provide a mechanism by which distinct HNF
      3/forkhead family members influence respiratory epithelial cell gene expression
      and cell differentiation.

PMID- 8668180
TI  - Signaling in the yeast pheromone response pathway: specific and high-affinity
      interaction of the mitogen-activated protein (MAP) kinases Kss1 and Fus3 with the
      upstream MAP kinase kinase Ste7.
AB  - Kss1 and Fus3 are mitogen-activated protein kinases (MAPKs or ERKs), and Ste7 is
      their activating MAPK/ERK kinase (MEK), in the pheromone response pathway of
      Saccharomyces cerevisiae. To investigate the potential role of specific
      interactions between these enzymes during signaling, their ability to associate
      with each other was examined both in solution and in vivo. When synthesized by in
      vitro translation, Kss1 and Fus3 could each form a tight complex (Kd of
      approximately 5 nM) with Ste7 in the absence of any additional yeast proteins.
      These complexes were specific because neither Hog1 nor Mpk1 (two other yeast
      MAPKs), nor mammalian Erk2, was able to associate detectably with Ste7. Neither
      the kinase catalytic core of Ste7 nor the phosphoacceptor regions of Ste7 and
      Kss1 were necessary for complex formation. Ste7-Kss1 (and Ste7-Fus3) complexes
      were present in yeast cell extracts and were undiminished in extracts prepared
      from a ste5delta-ste11delta double mutant strain. In Ste7-Kss1 (or Ste7-Fus3)
      complexes isolated from naive or pheromone-treated cells, Ste7 phosphorylated
      Kss1 (or Fus3), and Kss1 (or Fus3) phosphorylated Ste7, in a pheromone-stimulated
      manner; dissociation of the high-affinity complex was shown to be required for
      either phosphorylation event. Deletions of Ste7 in the region required for its
      stable association with Kss1 and Fus3 in vitro significantly decreased (but did
      not eliminate) signaling in vivo. These findings suggest that the high-affinity
      and active site-independent binding observed in vitro facilitates signal
      transduction in vivo and suggest further that MEK-MAPK interactions may utilize a
      double-selection mechanism to ensure fidelity in signal transmission and to
      insulate one signaling pathway from another.

PMID- 8668181
TI  - Identifying a species-specific region of yeast TF11B in vivo.
AB  - The general transcription factor IIB (TFIIB) is required for RNA polymerase II
      transcription in eukaryotes. It provides a physical link between the TATA-binding
      protein (TBP) and the RNA polymerase and is a component previously suggested to
      respond to transcriptional activators in vitro. In this report, we compare the
      yeast (Saccharomyces cerevisiae) and human forms of the protein in yeast cells to
      study their functional differences. We demonstrate that human TFIIB fails to
      functionally replace yeast TFIIB in yeast cells. By analyzing various human-yeast
      hybrid TFIIB molecules, we show that a 14-amino-acid region at the amino terminus
      of the first repeat of yeast TFIIB plays an important role in determining species
      specificity in vivo. In addition, we identify four amino acids in this region
      that are critical for an amphipathic helix unique to yeast TFIIB. By site
      directed mutagenesis analyses we demonstrate that these four amino acids are
      important for yeast TFIIB's activity in vivo. Finally, we show that mutations in
      the species-specific region of yeast TFIIB can differentially affect the
      expression of genes activated by different activators in vivo. These results
      provide strong evidence suggesting that yeast TFIIB is involved in the process of
      transcriptional activation in living cells.

PMID- 8668182
TI  - Non-Mendelian, heritable blocks to DNA rearrangement are induced by loading the
      somatic nucleus of Tetrahymena thermophila with germ line-limited DNA.
AB  - Site-specific DNA deletion occurs at thousands of sites within the genome during
      macronuclear development of Tetrahymena thermophila. These deletion elements are
      usually not detected in macronuclear chromosomes. We have interfered with the
      normal deletion of two of these elements, the adjacent M and R elements, by
      loading vegetative macronuclei with these elements prior to sexual conjugation.
      Transformed cell lines containing the exogenous M or R element, carried on high
      copy-number vectors containing genes encoding rRNA within parental (old)
      macronuclei, consistently failed to excise chromosomal copies of the M or R
      element during formation of new macronuclei. Little or no interference with the
      deletions of adjacent elements or of unlinked elements was observed. The
      micronucleus (germ line)-limited region of each element was sufficient to inhibit
      specific DNA deletion. This interference with DNA deletion usually is manifested
      as a cytoplasmic dominant trait: deletion elements present in the old
      macronucleus of one partner of a mating pair were sufficient to inhibit deletion
      occurring in the other partner. Remarkably, the failure to excise these elements
      became a non-Mendelian, inheritable trait in the next generation and did not
      require the high copy number of exogenously introduced elements. The introduction
      of exogenous deletion elements into parental macronuclei provides us with an
      epigenetic means to establish a heritable pattern of DNA rearrangement.

PMID- 8668183
TI  - A novel methyltransferase (Hmt1p) modifies poly(A)+-RNA-binding proteins.
AB  - RNA-binding proteins play many essential roles in the metabolism of nuclear pre
      mRNA. As such, they demonstrate a myriad of dynamic behaviors and modifications.
      In particular, heterogeneous nuclear ribonucleoproteins (hnRNPs) contain the bulk
      of methylated arginine residues in eukaryotic cells. We have identified the first
      eukaryotic hnRNP-specific methyltransferase via a genetic screen for proteins
      that interact with an abundant poly(A)+-RNA-binding protein termed Npl3p. We have
      previously shown that npl3-1 mutants are temperature sensitive for growth and
      defective for export of mRNA from the nucleus. New mutants in interacting genes
      were isolated by their failure to survive in the presence of the npl3-1 allele.
      Four alleles of the same gene were identified in this manner. Cloning of the
      cognate gene revealed an encoded protein with similarity to methyltransferases
      that was termed HMT1 for hnRNP methyltransferase. HMT1 is not required for normal
      cell viability except when NPL3 is also defective. The Hmt1 protein is located in
      the nucleus. We demonstrate that Npl3p is methylated by Hmt1p both in vivo and in
      vitro. These findings now allow further exploration of the function of this
      previously uncharacterized class of enzymes.

PMID- 8668184
TI  - The molecular chaperone Ydj1 is required for the p34CDC28-dependent
      phosphorylation of the cyclin Cln3 that signals its degradation.
AB  - The G1 cyclin Cln3 of the yeast Saccharomyces cerevisiae is rapidly degraded by
      the ubiquitin-proteasome pathway. This process is triggered by p34CDC28-dependent
      phosphorylation of Cln3. Here we demonstrate that the molecular chaperone Ydj1, a
      DnaJ homolog, is required for this phosphorylation. In a ydj1 mutant at the
      nonpermissive temperature, both phosphorylation and degradation of Cln3 were
      deficient. No change was seen upon inactivation of Sis1, another DnaJ homolog.
      The phosphorylation defect in the ydj1 mutant was specific to Cln3, because no
      reduction in the phosphorylation of Cln2 or histone H1, which also requires
      p34CDC28, was observed. Ydj1 was required for Cln3 phosphorylation and
      degradation rather than for the proper folding of this cyclin, since Cln3
      produced in the ydj1 mutant was fully active in the stimulation of p34CDC28
      histone kinase activity. Moreover, Ydj1 directly associates with Cln3 in close
      proximity to the segment that is phosphorylated and signals degradation. Thus,
      binding of Ydj1 to this domain of Cln3 seems to be essential for the
      phosphorylation and breakdown of this cyclin. In a cell-free system, purified
      Ydj1 stimulated the p34CDC28-dependent phosphorylation of the C-terminal segment
      of Cln3 and did not affect phosphorylation of Cln2 (as was found in vivo). The
      reconstitution of this process with pure components provides evidence of a direct
      role for the chaperone in the phosphorylation of Cln3.

PMID- 8668185
TI  - Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain
      containing tyrosine phosphatase SHPTP1.
AB  - SHPTP1 (PTP1C, HCP, SHP) is an SH2 domain-containing tyrosine phosphatase
      expressed predominantly in hematopoietic cells. A frameshift mutation in the
      SHPTP1 gene causes the motheaten (me/me) mouse. These mice are essentially SHPTP1
      null and display multiple hematopoietic abnormalities, most prominently
      hyperproliferation and inappropriate activation of granulocytes and macrophages.
      The me/me phenotype suggests that SHPTP1 negatively regulates macrophage
      proliferative pathways. Using primary bone marrow-derived macrophages from me/me
      mice and normal littermates, we examined the role of SHPTP1 in regulating
      signaling by the major macrophage mitogen colony-stimulating factor 1 (CSF-1)
      (also known as macrophage colony-stimulating factor). Macrophages from me/me mice
      hyperproliferate in response to CSF-1. In the absence of SHPTP1, the CSF-1
      receptor (CSF-1R) is hyperphosphorylated upon CSF-1 stimulation, suggesting that
      SHPTP1 dephosphorylates the CSF-1R. At least some CSF-1R-associated proteins also
      are hyperactivated. SHPTP1 is associated constitutively, via its SH2 domains,
      with an unidentified 130-kDa phosphotyrosyl protein (P130). P130 and SHPTP1 are
      further tyrosyl phosphorylated upon CSF-1 stimulation. Tyrosyl-phosphorylated
      SHPTP1 binds to Grb2 via the Grb2 SH2 domain. Moreover, in me/me macrophages,
      Grb2 is associated, via its SH3 domains, with several tyrosyl phosphoproteins.
      These proteins are hyperphosphorylated on tyrosyl residues in me/me macrophages,
      suggesting that Grb2 may recruit substrates for SHPTP1. Our results indicate that
      SHPTP1 is a critical negative regulator of CSF-1 signaling in vivo and suggest a
      potential new function for Grb2.

PMID- 8668186
TI  - Expression of dominant-negative mutant DP-1 blocks cell cycle progression in G1.
AB  - Unregulated expression of the transcription factor E2F promotes the G1-to-S phase
      transition in cultured mammalian cells. However, there has been no direct
      evidence for an E2F requirement in this process. To demonstrate that E2F is
      obligatory for cell cycle progression, we attempted to inactivate E2F by
      overexpressing dominant-negative forms of one of its heterodimeric partners, DP
      1. We dissected the functional domains of DP-1 and separated the region that
      facilitate heterodimer DNA binding from the E2F dimerization domain. Various DP-1
      mutants were introduced into cells via transfection, and the cell cycle profile
      of the transfected cells was analyzed by flow cytometry. Expression of wild-type
      DP-1 or DP-1 mutants that bind to both DNA and E2F drove cells into S phase. In
      contrast, DP-1 mutants that retained E2F binding but lost DNA binding arrested
      cells in the G1 phase of the cell cycle. The DP-1 mutants that were unable to
      bind DNA resulted in transcriptionally inactive E2F complexes, suggesting that
      the G1 arrest is caused by formation of defective E2F heterodimers. Furthermore,
      the G1 arrest instigated by these DP-1 mutants could be rescued by coexpression
      of wild-type E2F or DP protein. These experiments define functional domains of DP
      and demonstrate a requirement for active E2F complexes in cell cycle progression.

PMID- 8668188
TI  - Site-specific excision repair of 1-nitrosopyrene-induced DNA adducts at the
      nucleotide level in the HPRT gene of human fibroblasts: effect of adduct
      conformation on the pattern of site-specific repair.
AB  - Studies showing that different types of DNA adducts are repaired in human cells
      at different rates suggest that DNA adduct conformation is the major determinant
      of the rate of nucleotide excision repair. However, recent studies of repair of
      cyclobutane pyrimidine dimers or benzo[a]pyrene diol epoxide (BPDE)-induced
      adducts at the nucleotide level in DNA of normal human fibroblasts indicate that
      the rate of repair of the same adduct at different nucleotide positions can vary
      up to 10-fold, suggesting an important role for local DNA conformation. To see if
      site-specific DNA repair is a common phenomenon for bulky DNA adducts, we
      determined the rate of repair of 1-nitrosopyrene (1-NOP)-induced adducts in exon
      3 of the hypoxanthine phosphoribosyltransferase gene at the nucleotide level
      using ligation-mediated PCR. To distinguish between the contributions of adduct
      conformation and local DNA conformation to the rate of repair, we compared the
      results obtained with 1-NOP with those we obtained previously using BPDE. The
      principal DNA adduct formed by either agent involves guanine. We found that rates
      of repair of 1-NOP-induced adducts also varied significantly at the nucleotide
      level, but the pattern of site-specific repair differed from that of BPDE-induced
      adducts at the same guanine positions in the same region of DNA. The average rate
      of excision repair of 1-NOP adducts in exon 3 was two to three times faster than
      that of BPDE adducts, but at particular nucleotides the rate was slower or faster
      than that of BPDE adducts or, in some cases, equal to that of BPDE adducts. These
      results indicate that the contribution of the local DNA conformation to the rate
      of repair at a particular nucleotide position depends upon the specific DNA
      adduct involved. However, the data also indicate that the conformation of the DNA
      adduct is not the only factor contributing to the rate of repair at different
      nucleotide positions. Instead, the rate of repair at a particular nucleotide
      position depends on the interaction between the specific adduct conformation and
      the local DNA conformation at that nucleotide.

PMID- 8668187
TI  - Actions of Rho family small G proteins and p21-activated protein kinases on
      mitogen-activated protein kinase family members.
AB  - The mitogen-activated protein (MAP) kinases are a family of serine/threonine
      kinases that are regulated by distinct extracellular stimuli. The currently known
      members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the
      c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP
      kinases. We find that overexpression of the Ste20-related enzymes p21-activated
      kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a
      lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can
      stimulate the activity of each of these MAP kinases. Although neither activated
      Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant
      negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated
      activation of ERK2, suggesting a permissive role for Rac in the control of the
      ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize
      with an activated form of Raf to increase ERK2 activity. These findings reveal a
      previously unrecognized connection between Rho family small G proteins and the
      ERK pathway.

PMID- 8668190
TI  - The product of HUM1, a novel yeast gene, is required for vacuolar Ca2+/H+
      exchange and is related to mammalian Na+/Ca2+ exchangers.
AB  - Calcineurin, or PP2B, plays a critical role in mediating Ca2+-dependent signaling
      in many cell types. In yeast cells, this highly conserved protein phosphatase
      regulates aspects of ion homeostasis and cell wall synthesis. We show that
      calcineurin mutants are sensitive to high concentrations of Mn2+ and identify two
      genes, CCC1 and HUM1, that, at high dosages, increase the Mn2+ tolerance of
      calcineurin mutants. CCC1 was previously identified by complementation of a Ca2+
      sensitive (csg1) mutant. HUM1 (for "high copy number undoes manganese") is a
      novel gene whose predicted protein product shows similarity to mammalian Na+/Ca2+
      exchangers. hum1 mutations confer Mn2+ sensitivity in some genetic backgrounds
      and exacerbate the Mn2+ sensitivity of calcineurin mutants. Furthermore,
      disruption of HUM1 in a calcineurin mutant strain results in a Ca2+-sensitive
      phenotype. We investigated the effect of disrupting HUM1 in other strains with
      defects in Ca2+ homeostasis. The Ca2+ sensitivity of pmc1 mutants, which lack a P
      type ATPase presumed to transport Ca2+ into the vacuole, is exacerbated in a hum1
      mutant strain background. Also, the Ca2+ content of hum1 pmc1 cells is less than
      that of pmc1 cells. In contrast, the Ca2+ sensitivity of vph1 mutants, which are
      specifically defective in vacuolar acidification, is not significantly altered by
      disruption of Hum1p function. These genetic interactions suggest that Hum1p may
      participate in vacuolar Ca2+/H+ exchange. Therefore, we prepared vacuolar
      membrane vesicles from wild-type and hum1 cells and compared their Ca2+ transport
      properties. Vacuolar membrane vesicles from hum1 mutants lack all Ca2+/H+
      antiport activity, demonstrating that Hum1p catalyzes the exchange of Ca2+ for H+
      across the yeast vacuolar membrane.

PMID- 8668189
TI  - The testis-specific high-mobility-group protein, a phosphorylation-dependent DNA
      packaging factor of elongating and condensing spermatids.
AB  - Mammalian spermiogenesis is characterized by a striking restructuring of the
      spermatid chromatin caused by the replacement of nucleohistones with transition
      proteins and their subsequent replacement with nucleoprotamines. The onset of
      nuclear elongation and chromatin condensation in spermatids is accompanied by a
      general decrease in the transcriptional activity of the DNA. A recently
      identified testis-specific high-mobility-group (tsHMG) protein, similar to the
      human mitochondrial transcription factor I and to the linker-associated protein
      delta of Tetrahymena thermophila micronuclei, is thought to play a structural
      role in this process. We confirm by immunoblot analysis of fractionated germ
      cells that the presence of tsHMG is restricted to transcriptionally quiescent
      elongating and condensing spermatids. Purified recombinant tsHMG protein displays
      preferential binding to supercoiled plasmid DNA, which reversibly protects the
      DNA against the DNA-relaxing activity of eukaryotic topoisomerase I and also
      impairs the transcriptional activity of this template when assayed in vitro. The
      tsHMG protein can also introduce negative supercoils into a relaxed plasmid
      substrate in a topoisomerase I-dependent manner. We also show that the tsHMG
      protein is the substrate of a Ca2+-phospholipid-dependent protein kinase (protein
      kinase C) present in testis extracts of adult mice and demonstrate that
      phosphorylation by protein kinase C is required for both the DNA-binding and the
      topoisomerase I-dependent supercoiling activities of tsHMG. Our results support
      the hypothesis that the spermatid tsHMG protein is a topological factor
      (transition protein) that can modulate the activity of topoisomerase I. This
      activity could contribute to the important transition in chromatin structure
      which leads to the decrease in DNA metabolism observed at the early stages of
      spermatid elongation.

PMID- 8668191
TI  - Flanking sequences modulate the cell specificity of M-CAT elements.
AB  - M-CAT elements mediate both muscle-specific and non-muscle-specific
      transcription. We used artificial promoters to dissect M-CAT elements derived
      from the cardiac troponin T promoter, whose regulation is highly striated muscle
      specific. We show that muscle-specific M-CAT-dependent expression requires two
      distinct components: the core heptameric M-CAT motif (5'-CATTCCT-3'), which
      constitutes the canonical binding site for TEF-1-related proteins, and specific
      sequences immediately flanking the core motif that bind an additional factor(s).
      These factors are found in higher-order M-CAT DNA-protein complexes with TEF-1
      proteins. Non-muscle-specific promoters are produced when the sequences flanking
      the M-CAT motif are removed or modified to match those of non-muscle-specific
      promoters such as the simian virus 40 promoter. Moreover, a mutation of the 5'
      flanking region of the cardiac troponin T M-CAT-1 element upregulated expression
      in nonmuscle cells. That mutation also disrupts a potential E box that apparently
      does not bind myogenic basic helix-loop-helix proteins. We propose a model in
      which M-CAT motifs are potentially active in many cell types but are modulated
      through protein binding to specific flanking sequences. In nonmuscle cells, these
      flanking sequences bind a factor(s) that represses M-CAT-dependent activity. In
      muscle cells, on the other hand, the factor(s) binding to these flanking
      sequences contributes to both the cell specificity and the overall
      transcriptional strength of M-CAT-dependent promoters.

PMID- 8668192
TI  - The 3' ends of tRNA-derived short interspersed repetitive elements are derived
      from the 3' ends of long interspersed repetitive elements.
AB  - Short interspersed repetitive elements (SINEs) are a type of retroposon, being
      members of a class of informational molecules that are amplified via cDNA
      intermediates and flow back into the host genome. In contrast to retroviruses and
      retrotransposons, SINEs do not encode the enzymes required for their
      amplification, such as reverse transcriptases, so they are presumed to borrow
      these enzymes from other sources. In the present study, we isolated a family of
      long interspersed repetitive elements (LINEs) from the turtle genome. The
      sequence of this family was found to be very similar to those of the avian CR1
      family. To our surprise, the sequence at the 3' end of the LINE in the turtle
      genome was nearly identical to that of a family of tortoise SINEs. Since CR1-like
      LINEs are widespread in birds and in many other reptiles, including the turtle,
      and since the tortoise SINEs are only found in vertical-necked turtles, it seems
      possible that the sequence at the 3' end of the tortoise SINEs might have been
      generated by recombination with the CR1-like LINE in a common ancestor of
      vertical-necked turtles, after the divergence of side-necked turtles. We extended
      our observations to show that the 3'-end sequences of families of several tRNA
      derived SINEs, such as the salmonid HpaI family, the tobacco TS family, and the
      salmon SmaI family, might have originated from the respective LINEs. Since it
      appears reasonable that the recognition sites of LINEs for reverse transcriptase
      are located within their 3'-end sequences, these results provide the basis for a
      general scheme for the mechanism by which SINEs might acquire retropositional
      activity. We propose here that tRNA-derived SINEs might have been generated by a
      recombination event in which a strong-stop DNA with a primer tRNA, which is an
      intermediate in the replication of certain retroviruses and long terminal repeat
      retrotransposons, was directly integrated at the 3' end of a LINE.

PMID- 8668193
TI  - Telomerase activation in mouse mammary tumors: lack of detectable telomere
      shortening and evidence for regulation of telomerase RNA with cell proliferation.
AB  - Activation of telomerase in human cancers is thought to be necessary to overcome
      the progressive loss of telomeric DNA that accompanies proliferation of normal
      somatic cells. According to this model, telomerase provides a growth advantage to
      cells in which extensive terminal sequence loss threatens viability. To test
      these ideas, we have examined telomere dynamics and telomerase activation during
      mammary tumorigenesis in mice carrying a mouse mammary tumor virus long terminal
      repeat-driven Wnt-1 transgene. We also analyzed Wnt-1-induced mammary tumors in
      mice lacking p53 function. Normal mammary glands, hyperplastic mammary glands,
      and mammary carcinomas all had the long telomeres (20 to 50 kb) typical of Mus
      musculus and did not show telomere shortening during tumor development.
      Nevertheless, telomerase activity and the RNA component of the enzyme were
      consistently upregulated in Wnt-1-induced mammary tumors compared with normal and
      hyperplastic tissues. The upregulation of telomerase activity and RNA also
      occurred during tumorigenesis in p53-deficient mice. The expression of telomerase
      RNA correlated strongly with histone H4 mRNA in all normal tissues and tumors,
      indicating that the RNA component of telomerase is regulated with cell
      proliferation. Telomerase activity in the tumors was elevated to a greater extent
      than telomerase RNA, implying that the enzymatic activity of telomerase is
      regulated at additional levels. Our data suggest that the mechanism of telomerase
      activation in mouse mammary tumors is not linked to global loss of telomere
      function but involves multiple regulatory events including upregulation of
      telomerase RNA in proliferating cells.

PMID- 8668194
TI  - DNA sequence preferences of GAL4 and PPR1: how a subset of Zn2 Cys6 binuclear
      cluster proteins recognizes DNA.
AB  - Biophysical and genetic experiments have defined how the Saccharomyces cerevisiae
      protein GAL4 and a subset of related proteins recognize specific DNA sequences.
      We assessed DNA sequence preferences of GAL4 and a related protein, PPR1, in an
      in vitro DNA binding assay. For GAL4, the palindromic CGG triplets at the ends of
      the 17-bp recognition site are essential for tight binding, whereas the
      identities of the internal 11 bp are much less important, results consistent with
      the GAL4-DNA crystal structure. Small reductions in affinity due to mutations at
      the center-most 5 bp are consistent with the idea that an observed constriction
      in the minor groove in the crystalline GAL4-DNA complex is sequence dependent.
      The crystal structure suggests that this sequence dependence is due to phosphate
      contacts mediated by arginine 51, as part of a network of hydrogen bonds. Here we
      show that the mutant protein GAL4(1-100)R51A fails to discriminate sites with
      alterations in the center of the site from the wild-type site. PPR1, a relative
      of GAL4, also recognizes palindromic CGG triplets at the ends of its 12-bp
      recognition sequence. The identities of the internal 6 bp do not influence the
      binding of PPR1. We also show that the PPR1 site consists of a 12-bp duplex
      rather than 16 bp as reported previously: the two T residues immediately 5' to
      the CGG sequence in each half site, although highly conserved, are not important
      for binding by PPR1. Thus, GAL4 and PPR1 share common CGG half sites, but they
      prefer DNA sequences with the palindromic CGG separated by the appropriate number
      of base pairs, 11 for GAL4 and 6 for PPR1.

PMID- 8668195
TI  - Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by
      different pathways.
AB  - Several cellular mRNAs are regulated posttranscriptionally by iron-responsive
      elements (IREs) and the cytosolic IRE-binding proteins IRP-1 and IRP-2. Three
      different signals are known to elicit IRP-1 activity and thus regulate IRE
      containing mRNAs: iron deficiency, nitric oxide (NO), and the reactive oxygen
      intermediate hydrogen peroxide (H2O2). In this report, we characterize the
      pathways for IRP-1 regulation by NO and H2O2 and examine their effects on IRP-2.
      We show that the responses of IRP-1 and IRP-2 to NO remarkably resemble those
      elicited by iron deficiency: IRP-1 induction by NO and by iron deficiency is slow
      and posttranslational, while IRP-2 induction by these inductive signals is slow
      and requires de novo protein synthesis. In contrast, H2O2 induces a rapid
      posttranslational activation which is limited to IRP-1. Removal of the inductive
      signal H2O2 after < or = 15 min of treatment (induction phase) permits a complete
      IRP-1 activation within 60 min (execution phase) which is sustained for several
      hours. This contrasts with the IRP-1 activation pathway by NO and iron depletion,
      in which NO-releasing drugs or iron chelators need to be present during the
      entire activation phase. Finally, we demonstrate that biologically synthesized NO
      regulates the expression of IRE-containing mRNAs in target cells by passive
      diffusion and that oxidative stress endogenously generated by pharmacological
      modulation of the mitochondrial respiratory chain activates IRP-1, underscoring
      the physiological significance of NO and reactive oxygen intermediates as
      regulators of cellular iron metabolism. We discuss models to explain the
      activation pathways of IRP-1 and IRP-2. In particular, we suggest the possibility
      that NO affects iron availability rather than the iron-sulfur cluster of IRP-1.

PMID- 8668196
TI  - Cyclin A expression is under negative transcriptional control during the cell
      cycle.
AB  - Transcription of the gene coding for cyclin A, a protein required for S-phase
      transit, is cell cycle regulated and is restricted to proliferating cells. To
      further explore transcriptional regulation linked to cell division cycle control,
      a genomic clone containing 5' flanking sequences of the murine cyclin A gene was
      isolated. When it was fused to a luciferase reporter gene, it was shown to
      function as a proliferation-regulated promoter in NIH 3T3 cells. Transcription of
      the mouse cyclin A gene is negatively regulated by arrest of cell proliferation.
      A mutation of a GC-rich sequence conserved between mice and humans is sufficient
      to relieve transcriptional repression, resulting in a promoter with
      constitutively high activity. In agreement with this result, in vivo footprinting
      reveals a protection of the cell cycle-responsive element in G0/early G1 cells
      which is not observed at later stages of the cell cycle. Moreover, the footprint
      is present in dimethyl sulfoxide-induced differentiating and not in proliferating
      Friend erythroleukemia cells. Conversely, two other sites, which in vitro bind
      ATF-1 and NF-Y, respectively, are constitutively occupied throughout cell cycle
      progression.

PMID- 8668198
TI  - Activation and repression by nuclear hormone receptors: hormone modulates an
      equilibrium between active and repressive states.
AB  - Transactivation-defective retinoid X and thyroid hormone receptors have been used
      to examine mechanisms of hormonal activation. Activation and repression of
      transcription by retinoid X and thyroid hormone receptors are shown to be
      mediated by physically distinct and functionally independent regions of the
      hormone binding domain. Nevertheless, the ability of receptors to respond to
      hormone requires communication between both functional domains. Deletion of the
      hormone-dependent transactivation function of the retinoid X receptor, the common
      subunit of heterodimeric nuclear receptors, significantly impairs hormone
      dependent transcription by retinoic acid, thyroid hormone, and vitamin D
      receptors. The results indicate that receptors do not exist in static off and on
      conformations but that hormone alters an equilibrium between inactive and active
      states.

PMID- 8668197
TI  - Modulation of thermal induction of hsp70 expression by Ku autoantigen or its
      individual subunits.
AB  - Previously, we proposed a dual control mechanism for the regulation of the heat
      shock response in mammalian cells: a positive control mediated by the heat shock
      transcription factor HSF1 and a negative control mediated by the constitutive
      heat shock element-binding factor (CHBF). To study the physiological role of CHBF
      in the regulation of heat shock response, we purified CHBF to apparent
      homogeneity and showed it to be identical to the Ku autoantigen, a heterodimer
      consisting of 70-kDa (Ku-70) and 86-kDa (Ku-80) polypeptides. To study further
      the functional significance of Ku/CHBF in the cellular response to heat shock, we
      established rodent cell lines that stably and constitutively overexpressed one or
      both subunits of the human Ku protein, and examined the thermal induction of
      hsp70 and other heat shock proteins in these Ku-overexpressing ing cells. We show
      that expression of the human Ku-70 and Ku-80 subunits jointly or of the Ku-70
      subunit alone specifically inhibits heat-induced hsp70 expression. Conversely,
      expression of human Ku-80 alone does not have this effect. Thermal induction of
      other heat shock proteins in all of the Ku-overexpressing cell lines appears not
      to be significantly affected, nor is the state of phosphorylation or the DNA
      binding ability of HSF1 affected. These findings support a model in which hsp70
      expression is controlled by a second regulatory factor in addition to the
      positive activation of HSF1. The Ku protein, specifically the Ku-70 subunit, is
      involved in the regulation of hsp70 gene expression.

PMID- 8668199
TI  - MEF2B is a potent transactivator expressed in early myogenic lineages.
AB  - There are four members of the myocyte enhancer binding factor 2 (MEF2) family of
      transcription factors, MEF2A, -B, -C, and -D, that have homology within an amino
      terminal MADS box and an adjacent MEF2 domain that together mediate dimerization
      and DNA binding. MEF2A, -C, and -D have previously been shown to bind an A/T-rich
      DNA sequence in the control regions of numerous muscle-specific genes, whereas
      MEF2B was reported to be unable to bind this sequence unless the carboxyl
      terminus was deleted. To further define the functions of MEF2B, we analyzed its
      DNA binding and transcriptional activities. In contrast to previous studies, our
      results show that MEF2B binds the same DNA sequence as other members of the MEF2
      family and acts as a strong transactivator through that sequence. Transcriptional
      activation by MEF2B is dependent on the carboxyl terminus, which contains two
      conserved sequence motifs found in all vertebrate MEF2 factors. During mouse
      embryogenesis, MEF2B transcripts are expressed in the developing cardiac and
      skeletal muscle lineages in a temporospatial pattern distinct from but
      overlapping with those of the other Mef2 genes. The mouse Mef2b gene maps to
      chromosome 8 and is unlinked to other Mef2 genes; its intron-exon organization is
      similar to that of the other vertebrate Mef2 genes and the single Drosophila Mef2
      gene, consistent with the notion that these different Mef2 genes evolved from a
      common ancestral gene.

PMID- 8668200
TI  - Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins
      mediate their binding to 60S ribosomal subunits and the interactions among them.
AB  - Fragile X syndrome, the most common form of hereditary mental retardation,
      usually results from lack of expression of the FMR1 gene. The FMR1 protein is a
      cytoplasmic RNA-binding protein. The RNA-binding activity of FMR1 is an essential
      feature of FMR1, as fragile X syndrome can also result from the expression of
      mutant FMR1 protein that is impaired in RNA binding. Recently, we described two
      novel cytoplasmic proteins, FXR1 and FXR2, which are both very similar in amino
      acid sequence to FMR1 and which also interact strongly with FMR1 and with each
      other. To understand the function of FMR1 and the FXR proteins, we carried out
      cell fractionation and sedimentation experiments with monoclonal antibodies to
      these proteins to characterize the complexes they form. Here, we report that the
      FMR1 and FXR proteins are associated with ribosomes, predominantly with 60S large
      ribosomal subunits. The FXR proteins are associated with 60S ribosomal subunits
      even in cells that lack FMR1 and that are derived from a fragile X syndrome
      patient, indicating that FMR1 is not required for this association. We delineated
      the regions of FMR1 that mediate its binding to 60S ribosomal subunits and the
      interactions among the FMR1-FXR family members. Both regions contain sequences
      predicted to have a high propensity to form coiled coil interactions, and the
      sequences are highly evolutionarily conserved in this protein family. The
      association of the FMR1, FXR1, and FXR2 proteins with ribosomes suggests they
      have functions in translation or mRNA stability.

PMID- 8668201
TI  - Functional mapping of the translation-dependent instability element of yeast
      MATalpha1 mRNA.
AB  - The determinants of mRNA stability include specific cis-acting destabilizing
      sequences located within mRNA coding and noncoding regions. We have developed an
      approach for mapping coding-region instability sequences in unstable yeast mRNAs
      that exploits the link between mRNA translation and turnover and the dependence
      of nonsense-mediated mRNA decay on the activity of the UPF1 gene product. This
      approach, which involves the systematic insertion of in-frame translational
      termination codons into the coding sequence of a gene of interest in a upf1delta
      strain, differs significantly from conventional methods for mapping cis-acting
      elements in that it causes minimal perturbations to overall mRNA structure. Using
      the previously characterized MATalpha1 mRNA as a model, we have accurately
      localized its 65-nucleotide instability element (IE) within the protein coding
      region. Termination of translation 5' to this element stabilized the MATalpha1
      mRNA two- to threefold relative to wild-type transcripts. Translation through the
      element was sufficient to restore an unstable decay phenotype, while internal
      termination resulted in different extents of mRNA stabilization dependent on the
      precise location of ribosome stalling. Detailed mutagenesis of the element's rare
      codon/AU-rich sequence boundary revealed that the destabilizing activity of the
      MATalpha1 IE is observed when the terminal codon of the element's rare-codon
      interval is translated. This region of stability transition corresponds precisely
      to a MATalpha1 IE sequence previously shown to be complementary to 18S rRNA.
      Deletion of three nucleotides 3' to this sequence shifted the stability boundary
      one codon 5' to its wild-type location. Conversely, constructs containing an
      additional three nucleotides at this same location shifted the transition
      downstream by an equivalent sequence distance. Our results suggest a model in
      which the triggering of MATalpha1 mRNA destabilization results from establishment
      of an interaction between translating ribosomes and a downstream sequence
      element. Furthermore, our data provide direct molecular evidence for a
      relationship between mRNA turnover and mRNA translation.

PMID- 8668202
TI  - Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.
AB  - Altered expression or function of the p16CDKN2 tumor suppressor gene on
      chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene
      have been shown to segregate with familial predisposition to malignant melanoma.
      We have used a variety of assays to examine the functional properties of tumor
      associated alleles, including eight premature termination mutants, eight missense
      mutants, and three isoforms of p16 initiated at different amino-terminal
      methionine codons. The amino- and carboxy-terminal domains of the protein,
      outside the ankyrin-like repeats, appeared to be dispensable, but the majority of
      the premature termination mutations led to loss of function. Of the missense
      mutations tested, four displayed clear loss of function whereas two behaved like
      the wild type under all conditions tested. The remaining two mutations, a G-to-W
      mutation at position 101 (Gl01W) and V126D, both of which are associated with
      familial melanoma, were found to be temperature sensitive for binding to Cdk4 and
      Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay,
      and for increasing the proportion of G1-phase cells following transfection. These
      findings clarify previous disparities and argue strongly that p16CDKN2 is a bona
      fide tumor suppressor associated with familial melanoma.

PMID- 8668204
TI  - Analysis of functional domain organization in DNA topoisomerase II from humans
      and Saccharomyces cerevisiae.
AB  - The functional domain structure of human DNA topoisomerase IIalpha and
      Saccharomyces cerevisiae DNA topoisomerase II was studied by investigating the
      abilities of insertion and deletion mutant enzymes to support mitotic growth and
      catalyze transitions in DNA topology in vitro. Alignment of the human
      topoisomerase IIalpha and S. cerevisiae topoisomerase II sequences defined 13
      conserved regions separated by less conserved or differently spaced sequences.
      The spatial tolerance of the spacer regions was addressed by insertion of
      linkers. The importance of the conserved regions was assessed through deletion of
      individual domains. We found that the exact spacing between most of the conserved
      domains is noncritical, as insertions in the spacer regions were tolerated with
      no influence on complementation ability. All conserved domains, however, are
      essential for sustained mitotic growth of S. cerevisiae and for enzymatic
      activity in vitro. A series of topoisomerase II carboxy-terminal truncations were
      investigated with respect to the ability to support viability, cellular
      localization, and enzymatic properties. The analysis showed that the divergent
      carboxy-terminal region of human topoisomerase IIalpha is dispensable for
      catalytic activity but contains elements that specifically locate the protein to
      the nucleus.

PMID- 8668203
TI  - The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila
      FTZ-F1 family.
AB  - The alpha1-fetoprotein (AFP) gene is located between the albumin and alpha
      albumin genes and is activated by transcription factor FTF (fetoprotein
      transcription factor), presumed to transduce early developmental signals to the
      albumin gene cluster. We have identified FTF as an orphan nuclear receptor of the
      Drosophila FTZ-F1 family. FTF recognizes the DNA sequence 5'-TCAAGGTCA-3', the
      canonical recognition motif for FTZ-F1 receptors. cDNA sequence homologies
      indicate that rat FTF is the ortholog of mouse LRH-1 and Xenopus xFF1rA. Rodent
      FTF is encoded by a single-copy gene, related to the gene encoding steroidogenic
      factor 1 (SF-1). The 5.2-kb FTF transcript is translated from several in-frame
      initiator codons into FTF isoforms (54 to 64 kDa) which appear to bind DNA as
      monomers, with no need for a specific ligand, similar KdS (approximately equal 3
      x 10(-10) M), and similar transcriptional effects. FTF activates the AFP promoter
      without the use of an amino-terminal activation domain; carboxy-terminus
      truncated FTF exerts strong dominant negative effects. In the AFP promoter, FTF
      recruits an accessory trans-activator which imparts glucocorticoid reactivity
      upon the AFP gene. FTF binding sites are found in the promoters of other liver
      expressed genes, some encoding liver transcription factors; FTF, liver alpha1
      antitrypsin promoter factor LFB2, and HNF-3beta promoter factor UF2-H3beta are
      probably the same factor. FTF is also abundantly expressed in the pancreas and
      may exert differentiation functions in endodermal sublineages, similar to SF-1 in
      steroidogenic tissues. HepG2 hepatoma cells seem to express a mutated form of
      FTF.

PMID- 8668205
TI  - C/EBPalpha regulation of the growth-arrest-associated gene gadd45.
AB  - CCAAT/enhancer-binding protein alpha (C/EBPalpha) is expressed in postmitotic,
      differentiated adipocytes and is required for adipose conversion of 3T3-L1 cells
      in culture. Temporal misexpression of C/EBPalpha in undifferentiated adipoblasts
      leads to mitotic growth arrest. We report here that growth arrest- and DNA damage
      inducible gene 45 (gadd45) is preferentially expressed in differentiated 3T3-L1
      adipocytes similar to phenotype-associated genes. Furthermore, C/EBPalpha
      transactivates a reporter plasmid containing 1.5 kb of the gadd45 promoter
      region. The proto-oncogene myc, which inhibits adipocyte differentiation,
      abrogates C/EBPalpha activation of gadd45. gadd45 is known to be a target of the
      tumor suppressor p53 in a G1 checkpoint activated by DNA damage.
      Immunoprecipitation of radiolabeled proteins with conformation-specific
      antibodies revealed that wild-type p53 is expressed throughout 3T3-L1 adipocyte
      development, including the postmitotic period characterized by the accumulation
      of gadd45 and C/EBPalpha. A stable 3T3-L1 subline was engineered to express a
      dominant negative p53, human p53(143ala). The p53(143ala) subline differentiated
      to adipocytes and showed appropriate developmental expression of gadd45. These
      findings suggest that postmitotic growth arrest is coupled to adipocyte
      differentiation via C/EBPalpha stimulation of growth arrest-associated and
      phenotype-associated genes.

PMID- 8668206
TI  - The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle
      progression at G2/M.
AB  - Using the yeast two-hybrid system, we have isolated a cDNA (designated BBP, for
      Bcl2-binding protein) for a protein (Bbp) that interacts with Bcl2. Bbp is
      identical to 53BP2, a partial clone of which was previously isolated in a two
      hybrid screen for proteins that interact with p53. In this study, we show that
      specific interactions of Bbp/53BP2 with either Bcl2 or p53 require its ankyrin
      repeats and SH3 domain. These interactions can be reproduced in vitro with
      bacterially expressed fusion proteins, and competition experiments indicate that
      Bcl2 prevents p53 from binding to Bbp/53BP2. BBP/53BP2 mRNA is abundant in most
      cell lines examined, but the protein cannot be stably expressed in a variety of
      cell types by transfection. In transiently transfected cells, Bbp partially
      colocalizes with Bcl2 in the cytoplasm and results in an increased number of
      cells at G2/M, possibly accounting for the inability to obtain stable
      transfectants expressing the protein. These results demonstrate that a single
      protein can interact with either Bcl2 or p53 both in yeast cells and in vitro.
      The in vivo significance of these interactions and their potential consequences
      for cell cycle progression and cell death remain to be determined.

PMID- 8668208
TI  - Tumor cell complementation groups based on myogenic potential: evidence for
      inactivation of loci required for basic helix-loop-helix protein activity.
AB  - Basic helix-loop-helix (bHLH) proteins mediate terminal differentiation in many
      lineages. By using the bHLH protein MyoD, which can dominantly activate the
      myogenic differentiation program in numerous cell types, we demonstrated that
      recessive defects in bHLH protein function are present in human tumor lines. In
      contrast to prior work with primary cell cultures, MyoD did not activate the
      myogenic program in six of the eight tumor lines we tested. Cell fusions between
      the MyoD-defective lines and fibroblasts restored MyoD activity, indicating that
      the deficiency of a gene or factor prevents bHLH protein function in the tumor
      lines. Fusions between certain pairings of the MyoD-defective lines also restored
      MyoD activity, allowing the tumor lines to be assigned to complementation groups
      on the basis of their ability to execute the myogenic program and indicating that
      multiple mechanisms exist for abrogation of bHLH protein activity. These groups
      provide a basis for identifying genes critical for bHLH-mediated differentiation
      and tumor progression by using genetic complementation.

PMID- 8668207
TI  - Differences between MyoD DNA binding and activation site requirements revealed by
      functional random sequence selection.
AB  - A method has been developed for selecting functional enhancer/promoter sites from
      random DNA sequences in higher eukaryotic cells. Of sequences that were thus
      selected for transcriptional activation by the muscle-specific basic helix-loop
      helix protein MyoD, only a subset are similar to the preferred in vitro binding
      consensus, and in the same promoter context an optimal in vitro binding site was
      inactive. Other sequences with full transcriptional activity instead exhibit
      sequence preferences that, remarkably, are generally either identical or very
      similar to those found in naturally occurring muscle-specific promoters. This
      first systematic examination of the relation between DNA binding and
      transcriptional activation by basic helix-loop-helix proteins indicates that
      binding per se is necessary but not sufficient for transcriptional activation by
      MyoD and implies a requirement for other DNA sequence-dependent interactions or
      conformations at its binding site.

PMID- 8668209
TI  - Distinct regulatory elements control muscle-specific, fiber-type-selective, and
      axially graded expression of a myosin light-chain gene in transgenic mice.
AB  - The fast alkali myosin light chain 1f/3f (MLC1f/3f) gene is developmentally
      regulated, muscle specific, and preferentially expressed in fast-twitch fibers. A
      transgene containing an MLC1f promoter plus a downstream enhancer replicates this
      pattern of expression in transgenic mice. Unexpectedly, this transgene is also
      expressed in a striking (approximately 100-fold) rostrocaudal gradient in axial
      muscles (reviewed by J. R. Sanes, M. J. Donoghue, M. C. Wallace, and J. P.
      Merlie, Cold Spring Harbor Symp. Quant. Biol. 57:451-460, 1992). Here, we
      analyzed the expression of mutated transgenes to map sites necessary for muscle
      specific, fiber-type-selective, and axially graded expression. We show that two E
      boxes (myogenic factor binding sites), a homeodomain (hox) protein binding site,
      and an MEF2 site, which are clustered in an approximately 170-bp core enhancer,
      are all necessary for maximal transgene activity in muscle but not for fiber-type
      or position-dependent expression. A distinct region within the core enhancer
      promotes selective expression of the transgene in fast-twitch muscles. Sequences
      that flank the core enhancer are also necessary for high-level activity in
      transgenic mice but have little influence on activity in transfected cells,
      suggesting the presence of regions resembling matrix attachment sites.
      Truncations of the MLC1f promoter affected position-dependent expression of the
      transgene, revealing distinct regions that repress transgene activity in neck
      muscles and promote differential expression among intercostal muscles. Thus, the
      whole-body gradient of expression displayed by the complete transgene may reflect
      the integrated activities of discrete elements that regulate expression in
      subsets of muscles. Finally, we show that transgene activity is not significantly
      affected by deletion or overexpression of the myoD gene, suggesting that
      intermuscular differences in myogenic factor levels do not affect patterns of
      transgene expression. Together, our results provide evidence for at least nine
      distinct sites that exert major effects on the levels and patterns of MLC1f
      expression in adult muscles.

PMID- 8668210
TI  - Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent
      pathways is sufficient to cause tumorigenic transformation.
AB  - Substantial evidence supports a critical role for the activation of the Raf
      1/MEK/mitogen-activated protein kinase pathway in oncogenic Ras-mediated
      transformation. For example, dominant negative mutants of Raf-1, MEK, and mitogen
      activated protein kinase all inhibit Ras transformation. Furthermore, the
      observation that plasma membrane-localized Raf-1 exhibits the same transforming
      potency as oncogenic Ras suggests that Raf-1 activation alone is sufficient to
      mediate full Ras transforming activity. However, the recent identification of
      other candidate Ras effectors (e.g., RalGDS and phosphatidylinositol-3 kinase)
      suggests that activation of other downstream effector-mediated signaling pathways
      may also mediate Ras transforming activity. In support of this, two H-Ras
      effector domain mutants, H-Ras(12V, 37G) and H-Ras(12V, 40C), which are defective
      for Raf binding and activation, induced potent tumorigenic transformation of some
      strains of NIH 3T3 fibroblasts. These Raf-binding defective mutants of H-Ras
      induced a transformed morphology that was indistinguishable from that induced by
      activated members of Rho family proteins. Furthermore, the transforming
      activities of both of these mutants were synergistically enhanced by activated
      Raf-1 and inhibited by the dominant negative RhoA(19N) mutant, indicating that
      Ras may cause transformation that occurs via coordinate activation of Raf
      dependent and -independent pathways that involves Rho family proteins. Finally,
      cotransfection of H-Ras(12V, 37G) and H-Ras(12V, 40C) resulted in synergistic
      cooperation of their focus-forming activities, indicating that Ras activates at
      least two Raf-independent, Ras effector-mediated signaling events.

PMID- 8668211
TI  - Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a
      reversible G0-like arrest.
AB  - Alpha interferon is a potent growth inhibitor of Daudi Burkitt's lymphoma cells.
      We show here that alpha-interferon signaling interacted simultaneously with
      several components of the basic cell cycle machinery, causing cells to enter into
      a state that had many features characteristic of the G0 state. Within a few hours
      after alpha-interferon treatment, cyclin D3 mRNA and protein levels dropped to
      undetectable levels and, in parallel, the activities of cyclin A- and cyclin E
      associated kinases were significantly reduced. The latter resulted from the rapid
      alpha-interferon-mediated elimination of cdc25A, a phosphatase that is required
      for antagonism of negative tyrosine phosphorylation of cdk2 in cyclin-cdk
      complexes. This regulation represents a novel mechanism through which an external
      inhibitory cytokine interacts with the cell cycle machinery. At later time points
      after alpha-interferon treatment, the levels of the 55-kDa slowly migrating
      hyperphosphorylated form of cyclin E and of cyclin A were also reduced. The
      antiproliferative effects were reversible, and cultures from which alpha
      interferon was removed reentered S phase after a lag that typically corresponded
      to approximately two doubling times. During this lag period, the expression of
      cyclin D3 and cyclin A, as well as of the cdc25A phosphatase, continued to be
      switched off, in spite of the removal of alpha interferon from the cell surface.
      In contrast, c-myc, which represents another downstream target gene that is
      subjected to negative regulation by alpha interferon, was relieved from
      suppression much earlier, concomitant with the decay in early signaling of the
      cytokine. The delayed pattern of cyclin reexpression provides evidence that alpha
      interferon signaling imposes a G0-like state on this system.

PMID- 8668212
TI  - T-cell receptor stimulation elicits an early phase of activation and a later
      phase of deactivation of the transcription factor NFAT1.
AB  - We show here that NFAT1 is rapidly activated, then slowly deactivated, by
      stimulation of T cells through their antigen receptor. Within minutes of T-cell
      receptor stimulation, NFAT1 is dephosphorylated, translocates from the cytoplasm
      into the nucleus, and shows an increase in its ability to bind to DNA. These
      changes are dependent on calcium mobilization and calcineurin activation, since
      they are also elicited by ionomycin and are blocked by the immunosuppressive drug
      cyclosporin A. After several hours of T-cell receptor stimulation, the majority
      of the NFAT1 in the cell reverts to its original phosphorylated form, reappears
      in the cytoplasm, and again displays a low affinity for DNA. Deactivation of
      NFAT1 is facilitated by phorbol 12-myristate 13-acetate and inhibitors of
      capacitative calcium entry and most likely reflects the slow return of
      intracellular free calcium concentrations towards resting levels. Our results
      suggest that calcineurin-dependent signalling pathways mediate the early
      activation of NFAT1, while phorbol 12-myristate 13-acetate-dependent feedback
      pathways contribute to the late deactivation. Persistent NFAT-dependent cytokine
      gene transcription in activated T cells may be mediated by other NFAT family
      proteins in addition to NFAT1 during the immune response.

PMID- 8668215
TI  - Images in clinical medicine. Vitamin B12 deficiency.

PMID- 8668213
TI  - Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates
      transcription of several cytokine genes.
AB  - Transcription factors of the NFAT family play a key role in the transcription of
      cytokine genes and other genes during the immune response. We have identified two
      new isoforms of the transcription factor NFAT1 (previously termed NFATp) that are
      the predominant isoforms expressed in murine and human T cells. When expressed in
      Jurkat T cells, recombinant NFAT1 is regulated, as expected, by the calmodulin
      dependent phosphatase calcineurin, and its function is inhibited by the
      immunosuppressive agent cyclosporin A (CsA). Transactivation by recombinant NFAT1
      in Jurkat T cells requires dual stimulation with ionomycin and phorbol 12
      myristate 13-acetate; this activity is potentiated by coexpression of
      constitutively active calcineurin and is inhibited by CsA. Immunocytochemical
      analysis indicates that recombinant NFAT1 localizes in the cytoplasm of
      transiently transfected T cells and translocates into the nucleus in a CsA
      sensitive manner following ionomycin stimulation. When expressed in COS cells,
      however, NFAT1 is capable of transactivation, but it is not regulated correctly:
      its subcellular localization and transcriptional function are not affected by
      stimulation of the COS cells with ionomycin and phorbol 12-myristate 13-acetate.
      Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4,
      tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor
      promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive
      transcription of these genes during the immune response.

PMID- 8668216
TI  - Physicians' experience and survival in patients with AIDS.

PMID- 8668217
TI  - Physicians' experience and survival in patients with AIDS.

PMID- 8668214
TI  - The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute
      myeloid leukemia gene product, and potentially regulates its transactivation
      ability.
AB  - AML1 (also called PEBP2alphaB, CBFA2, or CBFalpha2) is one of the most frequently
      disrupted genes in chromosome abnormalities seen in human leukemias. It has been
      reported that AML1 plays several pivotal roles in myeloid hematopoietic
      differentiation and other biological phenomena, probably through the
      transcriptional regulation of various relevant genes. Here, we investigated the
      mechanism of regulation of AML1 functions through signal transduction pathways.
      The results showed that AML1 is phosphorylated in vivo on two serine residues
      within the proline-, serine-, and threonine-rich region, with dependence on the
      activation of extracellular signal-regulated kinase (ERK) and with interleukin-3
      stimulation in a hematopoietic cell line. These in vivo phosphorylation sites of
      AML1 were phosphorylated directly in vitro by ERK. Although differences between
      wild-type AML1 and phosphorylation site mutants in DNA-binding affinity were not
      observed, we have shown that ERK-dependent phosphorylation potentiates the
      transactivation ability of AML1. Furthermore the phosphorylation site mutations
      reduced the transforming capacity of AML1 in fibroblast cells. These data
      indicate that AML1 functions are potentially regulated by ERK, which is activated
      by cytokine and growth factor stimuli. This study provides some important clues
      for clarifying unidentified facets of the regulatory mechanism of AML1 function.

PMID- 8668218
TI  - Physicians' experience and survival in patients with AIDS.

PMID- 8668219
TI  - Physicians' experience and survival in patients with AIDS.

PMID- 8668220
TI  - Human herpesvirus 8 and interstitial pneumonitis in an HIV-negative patient.

PMID- 8668221
TI  - Late effects of treatment for childhood Hodgkin's disease.

PMID- 8668222
TI  - Late effects of treatment for childhood Hodgkin's disease.

PMID- 8668223
TI  - Late effects of treatment for childhood Hodgkin's disease.

PMID- 8668224
TI  - Cryoglobulinemia after hepatitis B vaccination.

PMID- 8668225
TI  - Traffic accidents and daylight saving time.

PMID- 8668226
TI  - Traffic accidents and daylight saving time.

PMID- 8668227
TI  - Traffic accidents and daylight saving time.

PMID- 8668228
TI  - Columbia/HCA and the resurgence of the for-profit hospital business. (1)

PMID- 8668229
TI  - [X-ray microscopy].
AB  - Owing to the short wavelengths of X-radiation X-ray microscopes allow higher
      resolution than optical microscopes. In contrast to electron microscopes, X
      radiation can be used to study relatively thick aqueous specimens in their
      natural environment. X-ray microscopes require intense X-radiation, which is best
      provided by electron storage rings, as well as efficient X-ray optics. X-ray
      microscopes with zone plate optics are installed at the storage ring BESSY in
      Berlin for studies in the fields of biology, medicine, biophysics, colloid
      chemistry, and soil sciences.

PMID- 8668230
TI  - A tectorial membrane fovea in the cochlea of the mustached bat.

PMID- 8668231
TI  - [Microsensory systems in cell biology basic research and medical diagnostics].
AB  - The development of an integrated sensor system, called the physiocontrol
      microsystem, is presented. It is suited for microscopy, and works with both
      adherent cell types and cultures growing in suspension, as well as with tissue
      biopsies. The central part, a miniaturized culture chamber equipped with
      differently constructed microsensors, allows continuous observation of important
      physiological parameters even in the course of long-lasting experiments. Besides
      a description of the physical components, the study provides a summary of
      selected applications of the physiocontrol microsystem in basic cellular research
      and biomedical diagnostics.

PMID- 8668233
TI  - Inverse relationship between brain size and callosal connectivity.

PMID- 8668234
TI  - [Chemotherapy, yes or no?].

PMID- 8668235
TI  - [Infections caused by Listeria monocytogenes].

PMID- 8668236
TI  - [Quality of life in the evaluation of cancer therapy].

PMID- 8668232
TI  - [Stress and the immune system].
AB  - Research in psychoneuroimmunology has demonstrated that biopsychosocial factors
      such as psychological stress can influence the immune system. Chronic stress has
      been associated with the suppression of the immune function. In contrast, acute
      psychological stressors and physical exercise have been shown to transiently
      enhance immune responses. These stress effects on immunity seem to be mediated
      via endocrine factors, since hormones, neurotransmitters, and neuropeptides can
      interact with cellular components of the immune system. In summary, experimental
      and clinical evidence suggests a functional relationship between stress,
      immunity, and diseases.

PMID- 8668237
TI  - [Ovarian carcinoma in the elderly; a diagnostic and therapeutic dilemma].

PMID- 8668238
TI  - [Problems in the use, cleaning and maintenance of nebulization equipment in the
      home situation].
AB  - OBJECTIVE: To determine whether jet nebulizers used at home for the treatment of
      children with asthma are used optimally. DESIGN: Descriptive. SETTING: Outpatient
      clinic for child pulmonary diseases of the Academic Hospital/Sophia Children's
      Hospital Rotterdam and outpatient clinic for child diseases of the Baronie
      Hospital Breda, the Netherlands. METHOD: Thirty-nine children aged 0-13 years and
      their parents were interviewed at home, and medication cup, saline and aerosol
      were cultured for bacterial analysis. The pressures of the compressor and
      nebulizer were measured with a manometer, and the particle size of the aerosol of
      10 jet nebulizers was measured by laser technique. RESULTS: The suppliers of the
      nebulizer did not provide clear instructions on user-related aspects and
      technical maintenance of the jet nebulizer. Many patients used damaged and poorly
      functioning, contaminated jet nebulizers. Contamination by potentially pathogenic
      micro-organisms was present in 50% of the saline, medication cups and aerosols
      (Klebsiella, Enterobacter, Pseudomonas, Serratia, Escherichia coli). The
      operating pressure of compressor and nebulizer was below the requirements in more
      than 50% of the jet nebulizers. In addition, we found that the aerodynamic mass
      median diameter increased considerably as the nebulizer became older. In 6/10
      nebulizers the particle size was below 5 microns. CONCLUSION: A periodical
      checkup of user-related aspects and technical quality of jet nebulizers is
      necessary. The quality of the instruction to users about the procedure for
      cleaning and maintenance of the jet nebulizer should be improved.

PMID- 8668239
TI  - [Transjugular placement of an intrahepatic portosystemic shunt as current
      treatment for complications of portal hypertension].
AB  - OBJECTIVE: To analyse the results in 31 patients who underwent transjugular
      intrahepatic portosystemic shunting (TIPS). DESIGN: Retrospective study. SETTING:
      University Hospital Rotterdam-Dijkzigt, Rotterdam, the Netherlands. METHOD: Data
      of all patients who underwent a TIPS procedure from February 1992 to September
      1994 were analysed. Indications for TIPS included recurrent variceal bleedings
      and refractory ascites. TIPS was performed under general anaesthesia. After TIPS
      heparin was given during one week. RESULTS: TIPS creation succeeded in 29 out of
      31 patients. The mean portosystemic pressure gradient after TIPS was 9.6 mmHg.
      After 1.5 years the cumulative percentage of recurrent variceal bleeding was 44.
      The quantity of ascites decreased in 73% of the patients. During
      recatheterisation shunt dysfunction was seen in 16 out of 21 patients. Mortality
      was 13% within 30 days. The actuarial percentage of patients who died was 43
      after 1.5 years. Mortality depended on Child-Pugh classification. CONCLUSION:
      TIPS is a new, safe and fast treatment for patients with complications of portal
      hypertension. The number of recurrent variceal bleedings was substantial.
      Intensive control examinations are imperative to discern shunt dysfunction. Long
      term survival rates and morbidity depend on the seriousness of the pre-existing
      liver disease.

PMID- 8668240
TI  - [Pregnancy in a hemodialysis patient].
AB  - A 22 year-old Turkish patient on haemodialysis experienced an unplanned, but
      wanted pregnancy and prematurely gave birth to a viable infant. The pregnancy of
      a patient on haemodialysis can be complicated by hypertension, anaemia, bleeding,
      intrauterine growth retardation and premature delivery and has to be followed
      closely, with a higher frequency of haemodialysis. Fertile women on haemodialysis
      should be informed about birth control. After renal transplantation the chances
      of becoming pregnant are much higher as well as the chances of a successful
      outcome. The women on haemodialysis should not be dissuaded from having a
      pregnancy because of obstetrical and foetal risk factors, but the risks should be
      balanced against the odds of having a renal transplantation.

PMID- 8668241
TI  - [Hepatitis attributed to the use of terbinafine].
AB  - A 71-year-old woman was admitted to our hospital with jaundice after she had been
      using terbinafine for a few weeks. The liver function tests showed a mixed
      cholestatic-hepatocellular pattern. A liver biopsy revealed large amounts of
      intracellular bile pigment. Causes of the liver disorder other than the use of
      the aforementioned antimycotic drug were excluded. Ten months after cessation of
      the drug the patient had recovered completely. The Netherlands Inspectorate for
      Health Care received 20 reports of liver enzyme elevations due to terbinafine in
      1991-1994.

PMID- 8668242
TI  - [Stimulation Program Health Research. VII. Evaluation of the program section
      'COPD Family Medicine'].

PMID- 8668243
TI  - [Regular vitamin A supplements are safe for pregnant women who consume few liver
      products].

PMID- 8668244
TI  - [Angina pectoris and myocardial infarct in infants].

PMID- 8668245
TI  - [Epileptic insults, cerebral infarct and rhabdomyolysis as as complications of
      amphetamine use].

PMID- 8668246
TI  - [Modern laser treatment of port-wine stains].

PMID- 8668247
TI  - [Laparoscopic inguinal hernia surgery: (for the time being) marking time].

PMID- 8668248
TI  - [Chemotherapy in brain tumors].

PMID- 8668249
TI  - [2 safety measures for diagnostic ultrasound: the mechanical and thermal index].

PMID- 8668250
TI  - [Dog bites: publications on risk factors, infections, antibiotics and primary
      wound closure].
AB  - OBJECTIVE: To determine, on the basis of published research on dog bites, risk
      groups and localisations, risk factors for wound infection, effectiveness of
      prophylactic antibiotics and indications and contraindications for primary
      closure of the bite wounds. DESIGN: Literature study. METHODS: Search in Medline
      (1975-October 1994) on "dog" and "bite(s)" and selection using methodological
      inclusion and exclusion criteria. RESULTS: Incidence of dog bites is highest in
      younger children and in hands/arms. The infection rate amounts to 3-17%. Risk
      factors for wound infection include hand/arms, puncture wounds, delay of
      presentation and possibly older age. The effectiveness of prophylactic
      antibiotics appears to be limited. There is no evidence that the infection rate
      after primary closure of wounds is higher. Cleaning and debridement are
      important. CONCLUSIONS: More attention should be paid to prevention of dog bites,
      especially in children. Most important is adequate cleaning of the wounds.
      Antibiotics should be given on indication only, such as hand wounds, puncture
      deep wounds and immune compromised patients. Primary closure is not
      contraindicated.

PMID- 8668251
TI  - [Urogenital symptoms and their resulting discomfort in non-institutionalized 50
      to-75-year-old Dutch women].
AB  - OBJECTIVE: To determine the prevalence of urogenital symptoms in non
      institutionalized Dutch women, aged 50 to 75 years, and the degree of discomfort.
      DESIGN: Cross-sectional study. SETTING: Nationwide investigation. METHOD: A
      questionnaire was sent to 2157 non-institutionalized Dutch women aged 50 to 75
      years. The survey sample was representative of the female population aged 50 to
      75 years with respect to age, marital status, level of education and menopausal
      age. RESULTS: The usable response was 81.6% (n = 1761). The overall prevalence of
      vaginal dryness, soreness and dyspareunia was 27%. The prevalence of micturition
      symptoms, urinary incontinence and recurrent urinary tract infections was 36%.
      The prevalence estimates for vaginal dryness and urinary incontinence showed a
      linear decrease with increasing age. Almost half of the symptomatic women
      reported moderate to severe discomfort. One-third of those affected received
      medical care. Previous hysterectomy had no effect on the reported prevalence
      estimates. Hysterectomized women reported moderate to severe complaints more
      often than non-hysterectomized ones. CONCLUSION: The prevalence of urogenital
      symptoms in non-institutionalized Dutch women aged 50 to 75 years, was high: 47%.
      Of these women, 40% to 60% experienced discomfort, but only one-third had sought
      medical advice. These urogenital problems will probably increase in the coming
      decades.

PMID- 8668253
TI  - [Progressive partial lipodystrophy; an external problem with internal anomalies].
AB  - Progressive partial lipodystrophy (PPL) was diagnosed in two girls aged 6 and 8
      years. PPL is characterized by loss of subcutaneous fat, starting in the face and
      progressing to trunk and arms. Diagnosis is based upon the cachectic appearance
      and the normal growth parameters. It is a rare disease of unknown aetiology,
      usually beginning in childhood and more frequent in females. An association with
      diabetes mellitus, hypertriglyceridaemia and glomerulonephritis has been
      described. Follow-up should be focused on these and on psychological effects. No
      causal therapy is available. The facial appearance can be restored by injection
      of liquid silicones. Life expectancy does not appear to be affected.

PMID- 8668252
TI  - [Increase in number of admissions and increased mortality due to malnutrition in
      children in Paramaribo].
AB  - OBJECTIVE: To determine the extent and severity of malnutrition in children in
      the last 10 years in 's Lands Hospitaal. SETTING: Paramaribo, Surinam. DESIGN:
      Retrospective descriptive study. METHOD: Data were collected from the medical
      files of children admitted because of malnutrition, by completing a standard
      questionnaire. RESULTS: The number of children hospitalized because of
      malnutrition increased markedly from fewer than 20 per year in the period 1985
      1990 to 142 in 1994. The increase involved both sexes, all age groups and all
      ethnic groups. The number of children who died from malnutrition increased from a
      maximum of two per year before 1993 to 18 in 1994. CONCLUSION: The increase of
      admissions because of malnutrition and the increase of the corresponding
      mortality are the consequences of the deteriorated socioeconomic situation in
      Surinam.

PMID- 8668254
TI  - [Controversial contraception: immunization against human chorionic gonadotrophin.
      Consultancy of Maternal Health and Family Planning of the Netherlands Association
      for Obstetrics and Gynecology].

PMID- 8668255
TI  - [Alarming increase in poisonings due to deptoprine].

PMID- 8668256
TI  - [Double vision as a result of diabetic neuropathy].

PMID- 8668257
TI  - [Preternatural anus?].

PMID- 8668258
TI  - [Standard 'low back pain' of the Dutch Society of Family Physicians; viewpoint
      from neurology].

PMID- 8668259
TI  - [Standard 'Low back pain' from the Dutch Society of Family Physicians; viewpoint
      from a center for back symptoms].

PMID- 8668260
TI  - [Long-term postmenopausal hormone substitution and incidence of breast cancer:
      the Nurses' Health Study].

PMID- 8668261
TI  - [Drug treatment of chronic obstructive pulmonary disease].

PMID- 8668262
TI  - [Clinical judgment and decision in practice. A patient with dyspnea].

PMID- 8668263
TI  - [Synopsis of the standard 'Low Back Pain' of the Dutch Society of Family
      Physicians].

PMID- 8668264
TI  - [Causes of death in Amsterdam children who died abroad, 1982-1993; potential for
      prevention].
AB  - OBJECTIVE: To determine the causes of death among Amsterdam children dying
      abroad. DESIGN: Retrospective study. SETTING: Department of Youth Health Care in
      Amsterdam, the Netherlands. METHOD: Analysis was based on the data bank of the
      Department of Youth Health Care, which contains the items sex, age and ethnic
      origin of decreased children as well as time, place and cause of death. RESULTS:
      A total of 791 Amsterdam children (1 week-14 years old) died during the period
      1982-1993. Of these children 98 (12.4%) died outside the Netherlands; of two the
      place of death was unknown. A relatively large proportion of decreased Turkish
      and Moroccan children died while abroad, 24.7% and 34.2% respectively. The
      distribution of causes of death among children dying in the Netherlands differed
      from children dying abroad. The most important causes abroad were accidents
      (especially car accidents), infections (especially gastrointestinal infections)
      and congenital disorders. Children who died of accidents were mainly between 1
      and 9 years old. Fatal infections were primarily seen in children 0 years old and
      of Moroccan origin, and in the period 1982-1985. Children who died of congenital
      abnormalities were mostly of Moroccan origin. CONCLUSION: Mortality among Turkish
      and Moroccan Amsterdam children often occurred outside the Netherlands. Mortality
      in children visiting foreign countries was mainly the result of preventable
      causes such as accidents and infections.

PMID- 8668265
TI  - [Registration of postoperative complications to improve the results of surgery].
AB  - OBJECTIVE: To analyse the consequences of postoperative complications in 1418
      surgical patients. DESIGN: Prospective descriptive study. SETTING: St. Elisabeth
      Hospital in Tilburg, The Netherlands. METHOD: In the period 1986-1992 all
      postoperative complications and their consequences occurring during or after the
      clinical treatment of surgical patients were registered. RESULTS: In 5% of the
      28,485 surgical procedures (= 1418 patients) postoperative complications were
      found. To treat these complications, 577 patients had to be reoperated on, 233
      patients several times, and generally because of postoperative infections.
      Readmission after discharge was necessary in 310 patients for treatment of their
      complications. Mean hospital stay for all patients was 10 days, as against 21
      days in patients with postoperative complications. On the basis of the figures
      recorded, quality enhancing measures were taken, e.g. regarding antibiotic
      prophylaxis and wound treatment. CONCLUSION: The consequences of postoperative
      complications are considerable. With respect to quality control in health care it
      is important to develop national registration and documentation of surgical
      complications.

PMID- 8668266
TI  - [An unusual cause of fever: chronic meningococcemia].
AB  - In a 14-year old boy admitted because of fever of unknown origin chronic
      meningococcaemia was diagnosed. He had suffered for the last four months from
      periods of high fever accompanied by skin rash and arthralgia. Blood culture
      showed the presence of Neisseria meningitidis. Cerebrospinal fluid culture
      remained negative. Following the administration of high-dose intravenous
      benzylpenicillin a prompt resolution of all signs and symptoms was observed. No
      immunological abnormalities were found. Chronic meningococcaemia can be a-
      nowadays uncommon--cause of fever of unknown origin.

PMID- 8668267
TI  - [Treatment of intermittent claudication; prospective randomized study in the
      BAESIC-Trial (bypass, angioplasty or endarterectomy patients with severe
      intermittent claudication)].

PMID- 8668268
TI  - [Quality policy of the Dutch Society for Surgery].

PMID- 8668269
TI  - [Stimulation Program Health Research. VIII. Evaluation of the program section
      'Medical Technology Assessment'].

PMID- 8668271
TI  - [Active euthanasia in newborn children with spina bifida?].

PMID- 8668270
TI  - [Active euthanasia in newborn infants with spina bifida?].

PMID- 8668272
TI  - [Active euthanasia in newborn infants with spina bifida?].

PMID- 8668273
TI  - [Stress electrocardiography and its consequences; the 'oculostenotic reflex'].

PMID- 8668274
TI  - [Treatment of Angina pectoris using nitrates].

PMID- 8668275
TI  - [Tumors outside of the central nervous system in Von Hippel-Lindau disease].

PMID- 8668276
TI  - [Results of kidney transplantation in Leiden, 1966-1994, and prognostic factors].
AB  - OBJECTIVE: Evaluating prognostic determinants and results of renal
      transplantation. DESIGN: Descriptive study. SETTING: Leiden University Hospital,
      The Netherlands. METHODS: Follow-up of all 1289 patients who had a kidney
      transplantation in Leiden University Hospital between March 1966 and December
      1994. The following determinants were investigated: age and sex of donors and
      recipients. HLA matching, type of immunosuppression, presensitization, presence
      of diabetes mellitus, and living or post-mortem donor. RESULTS: Renal
      transplantation was very successful during the first few years, one-year graft
      survival dropped to 50% during the second decade and gradually increased to
      almost 90% during the last years. 5-year and 10-year graft survival were 65% and
      50% respectively. The mean age of recipients increased from 32.8 years to 45.7
      years, that of donors from 24.9 to 37.9 years. Duration of dialysis before
      transplantation increased from 19.7 months to 35.7 months. The introduction of
      cyclosporine and matching on the HLA-DR locus were responsible for better
      transplantation results. Other favourable prognostic factors were absence of
      diabetes mellitus, absence of panel reactive antibodies, kidney from a living
      donor, male donor and donor age between 20 and 50 years. CONCLUSION: Both short
      term and long term results of renal transplantation improved in spite of a strong
      increase of mean donor age and mean recipient age and an increase of co-morbidity
      of the recipients. Introduction of HLA-DR matching and cyclosporine
      immunosuppression contributed to better graft survival.

PMID- 8668277
TI  - [Follow-up not according to guidelines after an abnormal cervix smear].
AB  - OBJECTIVE: To investigate whether the recommendations for the follow-up after a
      positive cervical smear test, made within the Dutch national screening programme
      on cervical cancer, are followed in practice. DESIGN: Descriptive. SETTING: The
      Rotterdam Municipal Health Services Area. METHOD: All cytological and clinical
      histological findings on women who had a Pap smear of at least Pap class IIIA in
      the period 1989-1991, were collected from the Pathological Anatomical National
      Automised Archives (PALGA). Per smear test result, the cervix-cytological and
      histological examinations that took place after the screening programme were
      arranged in order of occurrence. RESULTS: 61% of the women with Pap class IIIA
      had been followed according to the recommendations, in 12% no follow-up had been
      done. Repeat cytology was often done much later than after three months as
      recommended. After Pap class IIIB, IV or V smear test outcome the recommendations
      were followed in respectively over half, about three-quarters, and all cases. In
      9% of women with Pap class IIIB or IV, no follow-up was recorded in the PALGA
      data base. CONCLUSION: Often, the recommendations for follow-up after a positive
      smear were followed poorly. Further research into the problems in the follow-up
      route is necessary.

PMID- 8668278
TI  - [Variation in the diagnosis and treatment of benign prostatic hyperplasia in
      urological practice].
AB  - OBJECTIVE: To analyse practice variation among urologists and its determinants
      with respect to diagnostics and therapy choice in benign prostatic hyperplasia
      (BPH). DESIGN: Cross-sectional. SETTING: Stratified sample of 12 urological
      practices throughout the Netherlands. METHODS: On 670 consecutive, newly referred
      BPH patients > or = 50 years, data were collected about symptomatology,
      discomfort and sexual functioning (patient questionnaire), diagnostic procedures
      and outcomes (medical record), and (considerations for) therapy choice (urologist
      questionnaire). Characteristics of patients as well as of urologists were
      integrally studied to explain the variation. RESULTS: With respect to
      diagnostics, highest variation (interquartile ranges) was found for
      ultrasonography of the prostate (19-86%), kidneys (19-68%), and bladder (42-91%),
      and lowest variation for digital rectal examination (97-100%) and blood tests and
      urinalysis (88-100% and 86-99% respectively). For therapy choice, interquartile
      ranges were 24-42% (surgery), 32-49% (watchful waiting), 5-29% (alpha-blockers),
      and 0-17% (5-alpha-reductase-inhibitor). Variation in diagnostics was associated
      with characteristics of urologists and work setting as well as of patients. For
      differences in therapy choice, symptomatology, discomfort, sexual activity, peak
      flow, volume of residual urine, prostate volume, comorbidity, experience of the
      urologist, and the type of hospital were the most important explanatory
      variables. CONCLUSION: Variation in both diagnostics and therapy choice is
      considerable. This variation is associated with characteristics of patients as
      well as of urologists and work setting.

PMID- 8668280
TI  - [Clinically manifest liver lesions during use of simvastatin].
AB  - Symptomatic hepatic damage was diagnosed in six patients, three males and three
      females, during treatment with simvastatin. All patients recovered after
      discontinuation of the drug. One patient used the drug again, which led to
      another increase of serum liver enzyme activity. The period between the start of
      the treatment with simvastatin and the first symptoms of hepatic damage varied
      between 1 month and 3 years. If serum liver enzyme activities increase in
      patients using simvastatin, a causative relation should be considered.

PMID- 8668279
TI  - [Paroxysmal and bizarre motor agitation as manifestation of partial frontal lobe
      epileptic seizures].
AB  - Three patients, two men of 21 and 38 years and a woman of 20 years old, showed
      atypical seizures with motor agitation without tongue bite, incontinence or
      postictal confusion. After extensive video-EEG registration frontal lobe
      epilepsia was diagnosed. This is a relatively recently recognized disease entity.

PMID- 8668281
TI  - [Ibopamine: the message, the messenger and the need of pharmacoepidemiological
      research].

PMID- 8668282
TI  - [Acute poisoning in the work situation in The Netherlands].

PMID- 8668283
TI  - [Functional MRI: imaging of motor cortex functions].

PMID- 8668284
TI  - [Gout: current viewpoint on etiology, diagnosis and therapy].

PMID- 8668285
TI  - [Temporal arteritis associated with hyperthyroidism and complicated by angina
      pectoris. A case report].
AB  - A case of temporal arteritis is described in a woman of 67, affected by non
      insulin dependent diabetes mellitus, associated with polymyalgia rheumatica and
      complicated by angina pectoris. Angina, which appeared a few days after
      diagnosis, was coupled with electrocardiographic alterations, which did not seem
      sensitive to nitrates but went back when steroid at full dose was added. The
      patient was also affected by Basedow disease, which was present during the whole
      course of the vasculitis. Furthermore islet-cell antibodies (ICA) were present.
      HLA typing showed the presence of the B8, DR3 haplotype. The patient died after
      22 months from the diagnosis of digestive hemorrhage, probably favoured by
      extended cortisone therapy, while signs of arteritis were still evident.

PMID- 8668286
TI  - IgD multiple myeloma. A report of three cases.
AB  - Three patients suffering from IgD myeloma, which a rare variant of multiple
      myeloma which often has an aggressive course, were studied retrospectively in
      order to elucidate the existence of clinical or laboratory features in
      relationship to survival time. The patients were monitored in follow-up for a
      time variable for 8 to 52 months. All patients received courses of chemotherapy
      using an association of Melphalan and Prednisone (MP); one patient also received
      recombinant interferon alpha in association. Response to chemotherapy, with a >
      50% reduction of serum M component, disappearance of Bence Jones proteinuria and
      permanent control of the disease was achieved in all patients. The median
      duration of survival in IgD myeloma is shorter than that currently observed in
      patients with other myeloma types: in our series one patient died 8 months after
      diagnosis but other two patients are still alive 8 and 52 months after diagnosis,
      respectively. Great difficulty was encountered in analysis of unfavourable
      prognostic clinical and laboratory data: in our series, in spite of the small
      number of cases, the Authors observe that only the relief of increased serum
      levels of Lactate Dehydrogenase (LDH) seem to be in relationship with a trend of
      shorter survival. The authors, confirming the particular clinical and laboratory
      aspects of this myeloma, stress that there may coexist cases in which standard
      chemotherapy failed to control the diseases: these seem to indicate neoplasia
      with fast growth kinetics. Further studies are necessary in order to identify new
      prognostic index which allows the identification of selected groups of patients
      who can profit from a combination chemotherapy regimen other than the standard MP
      association.

PMID- 8668287
TI  - [Progressive paralysis. A case report].
AB  - STUDY OBJECTIVE: A fairly uncommon case of neurosyphilis is reported in a not
      immunocompromised patient. CASE REPORT: A case of general paresis in a 40 year
      old male with the recent onset of mania is described. Psychiatric anamnesis was
      negative. Neurologic examination was negative. Laboratory tests were performed
      and serologic tests for syphilis were positive. Cerebrospinal fluid (CSF)
      examination showed 80 leukocytes/mm3, a reactive Venereal Disease Research
      Laboratory (VDRL) and normal protein concentration. CSF gamma globulin with an
      oligoclonal pattern and abnormal IgG index were found. A test for antibodies to
      Human Immunodeficiency Virus (HIV) was negative. The patient underwent a high
      dose intravenous penicillin G regimen for two weeks. A follow-up six months later
      showed a normal CSF even though the IgG index was still abnormal and the mental
      status was unchanged. CONCLUDING REMARKS: The authors suggest that patients with
      neurologic and/or psychiatric symptoms with a recent onset and a reactive VDRL
      should undergo a CSF examination to exclude a possible neurosyphilis.

PMID- 8668288
TI  - [Clinical evaluation of cinnoxicam 30 mg in patients with osteoarthrosis. A
      double-blind controlled study].
AB  - We tested the therapeutic response of osteoarthrosis subjects to piroxicam
      cinnamate 30 mg tablets (Sinartrol). The double-blind study was conducted in 2
      homogeneous groups of 30 patients each treated with piroxicam cinnamate one 30 mg
      tablet twice daily for 2 days followed by 1 tablet daily for 13 more days and
      with piroxicam cinnamate 20 mg tablets (according to the same posologic scheme)
      respectively. The results obtained demonstrate the efficacy of this new piroxicam
      cinnamate formulation which led to a significant clinical improvement, already
      evident after 2 days of treatment and even more evident at the end of therapy.
      Patients' compliance to treatment was good and side effects were scarce and
      spontaneously subsiding.

PMID- 8668289
TI  - [Analytical evaluation of an automated hematologic analyzer: Cell Dyn 3500].
AB  - In this study we evaluated the analytical performances of the Cell Dyn 3500, an
      automated hematology analyzer that provides the electronic and optical detection
      of leukocyte count and the complete cell counts in samples of whole blood. The
      protocol included evaluation of complete blood count and differential leukocyte
      count parameters, using the ICSH and the NCCLS H20-A protocols. Technical
      performances with regards, to linearity, carry over, precision and stability were
      quite well acceptable; the accuracy showed a good agreement between Cell Dyn 3500
      and instruments used in our laboratory for the major hematologic indices and a
      good correlation for neutrophils, lymphocytes and eosinophils compared with the
      manual count.

PMID- 8668290
TI  - Long-term therapy with interferon in anti-HCV positive chronic hepatitis: is it
      conceivable?
AB  - HCV positive hepatitis possesses a relevant social impact as regards national
      health costs. On the other hand, interferon (IFN) therapy represents to date the
      best therapeutic approach to this problem. However, several clinical questions
      have arisen regarding the efficacy and safety of long-term treatments, and above
      all the management of those patients who did not respond to acute therapy.
      Nevertheless, it is well known there is a high rate of relapse after the
      cessation of treatment. The goal of the present paper has therefore been to
      verify both efficacy and safety of a weekly single dose of IFN in maintaining an
      adequate remission rate in 38 outpatients who obtained a good response (either
      type I or II according to Marcellin's classification) to a 12 months' IFN course.
      Our results evidenced that a maintenance therapy with a single a weekly dose of
      IFN (3MU) did not seem to lead to a lower rate of relapses when compared to
      patients who were not given any treatment.

PMID- 8668291
TI  - [Levels of different metabolites of arachidonic acid in synovial fluid of
      patients with arthrosis or rheumatoid arthritis].
AB  - OBJECTIVE: Clinical and experimental evidence suggests that arachidonic acid
      metabolism through lipoxygenase and cyclooxygenase pathways may play an important
      role in the pathogenesis of both inflammatory and degenerative joint diseases.
      The aim of the present paper was to measure the levels of different arachidonate
      metabolites in arthrosis or rheumatoid joint effusions. MATERIALS AND METHODS: We
      studied synovial fluids from 22 patients with arthrosis and 8 patients with
      rheumatoid arthritis. The levels of TxB2, 6-keto-PGF1 alpha LTB4 and LTC4 were
      measured by radioimmunoassay. RESULTS: The levels of the different arachidonate
      metabolites were higher in patients with rheumatoid arthritis than in those with
      arthrosis and the differences were always statistically significant, except for
      TxB2 values. Furthermore, in patients with arthrosis the levels of such
      metabolites were not significantly correlated with one another, with the
      exception of LTB4 and LTC4 values, while in patients with rheumatoid arthritis
      these levels were directly and significantly correlated. CONCLUSIONS: In
      inflammatory joint disease levels of arachidonate metabolites are higher and more
      directly correlated with one another than in degenerative joint disease. Our data
      may explain the better efficacy of non-steroidal anti-inflammatory drugs in
      patients with arthrosis than in those with rheumatoid arthritis and the frequent
      necessity for steroidal treatment in this last condition.

PMID- 8668293
TI  - [Decubitus ulcer in the calcaneus region: rapid development, difficult recovery].
AB  - Heel pressure sores frequently arise in patients kept in bed for a long time
      independently of their primary disease. In account of this event the authors
      completed a study concerning possible mutual relations between heel pressure
      sores and primary disease of the patients; to validate the pharmacological
      treatment in less severe sores and the surgical resolution in more serious
      cutaneous lesions. In the last 3 years (1992-1995) at the Rehabilitation Centre
      of Montescano the authors have treated 39 patients suffering from 63 different
      severe cutaneous lesions: from phlycten to deep necrosis. The therapeutic plane
      utilized pharmacological treatment for 1st, 2nd, 3rd degree pressure sores, and
      surgical treatment for 4th degree. Pharmacological treatment included: enzymatic
      drugs, bactericidal and bacteriostatic medicines and cicatrizing substances.
      Different healing times were related to different pressure sore severity.
      Surgical treatment consisted of transposition of flap into wound defect. This
      system caused considerable reduction in resolution times. The authors noticed how
      easily pressure sores arise in the heel region, and how difficultly they heal.
      This is probably connected with particular anatomical and vascular
      characteristics of this region.

PMID- 8668292
TI  - [Experimental osteoporosis caused by estrogen deficiency in rats. Role of a
      lactose, L-arginine and L-lysine combination in the prevention and therapy].
AB  - The role of a lactose, L-arginine and L-lysine association in the treatment of
      osteoporosis was evaluated in an in vivo model. Fifty Sprague Dawley female rats,
      10 months age, were divided into 5 groups: 10 non-ovariectomized animals
      sacrificed at the beginning of the study (I group); 10 ovariectomized animals
      (OVX) without treatment and sacrificed at three months (II group); 10 OVX animals
      without treatment sacrificed at 6 months; 10 OVX animals treated starting from
      the I post-operative day with the association for three months (IV group,
      prevention) and 10 OVX animals treated like those of the IV group starting three
      months after surgery (V group, therapy). Animals were sacrificed in general
      anesthesia according to the scheduled times for radiologic, densitometric,
      histologic and mineralogic investigations. Preliminary results, which will need
      further researches, seem to show a progressive reduction of bone mass after
      ovariectomy in 10 months female rat and that the pharmacological association
      given as therapy (V group) may be able to lessen the reduction of bone mineral
      content.

PMID- 8668295
TI  - [Report of a rare case of Langerhans-cell histiocytosis of the skull base].
AB  - INTRODUCTION: Langerhans cell histiocytosis, once called histiocytosis X, is a
      rare disease. Usually it can occur in children and is characterized by granulomas
      (eosinophilic granuloma and Hand-Schueller-Christian disease) or by a extensive
      involvement of various organs (Letterer-Siwe disease). The etiology remains
      uncertain and could be related to undefined immunologic disturbance. Lesions can
      involve bone marrow, skin, oral mucosa, retro-orbital tissue, central nervous
      system, lymph nodes, spleen, liver, lung, and gastroenteric tract. Surgery,
      radiotherapy and chemotherapy can be employed as treatment. Prognosis is
      different in relation to the extension of the disease. CASE REPORT: In our case
      (a 33 year old female) came to observation for swelling in temporal region. The
      patient underwent clinical and radiological examinations: the lesion involved the
      skull base in the right part of the sphenoid bone. CT and MRI showed a
      "clepsydra" lesion with wider extension to infratemporal fossa and to
      intracranial middle fossa and shrinking in the base of the skull; inside the
      lesion a lot of wider calcifications were present. A biopsy proved a diagnosis of
      Langerhans cell histiocytosis. No other localizations of disease were found. The
      patient was treated with chemotherapy followed by localized radiotherapy.
      Chemotherapy was performed with 3 cycles of etoposide 260 mg for 3 days every
      month. After this treatment a response of 25% was observed. Afterwards a
      radiotherapy with cobalt 60 was employed through two angled wedged fields for a
      total dose of 22 Gy and conventional fractionation. During the follow-up a slow,
      partial regression of the lesion with increase of the extension of the
      calcifications documented by CT and MRI was observed. After 5 years follow-up no
      progression of disease was observed. DISCUSSION: The usual treatment of
      Langerhans cell histiocytosis is surgery and eventually radiotherapy for
      localized disease and chemotherapy for extended disease. The prognosis is related
      to the number of involved organs: usually favorable with only one site of disease
      and unfavorable when more organs are involved. Other unfavorable prognostic
      factors are the age < 2 years, the presence of anemia, liver and spleen
      involvement and respiratory failure. In our case only one site of disease was
      evident and the clinical behavior has been quite favorable. The main
      peculiarities are the radiologic aspect and the slow, partial regression after
      the treatment; this fact could be related to the presence of wide calcifications
      inside the lesion. After 5 years follow-up it is possible to consider the absence
      of progression as a response to the treatment.

PMID- 8668296
TI  - Current issues in the management of hereditary nonpolyposis colorectal cancer.

PMID- 8668294
TI  - [Adrenal adenoma or hyperplasia? Problems of differential diagnosis in an unusual
      case of primary hyperaldosteronism].
AB  - Although primary hyperaldosteronism is an uncommon cause of hypertension, it is
      the most common form of renin-independent hypermineralocorticoidism. The plasma
      aldosterone concentration and PRA with orthostatic test and saline infusion test
      are very useful aids to make a diagnosis. In this case the inconsistency between
      hormonal data and morphologic images (TC and NMR) led us to a dilemma: it was a
      question of adrenal adenoma or hyperplasia? Because it was impossible to dose the
      18-OH-corticosterone, we had to perform a iodocholesterol scintigraphy NP 59. To
      distinguish an hyperplasia as cause of this kind of hyperaldosteronism made us
      able to define a therapeutic program useful to hypertension control.

PMID- 8668297
TI  - Do Polynesians still believe that big is beautiful? Comparison of body size
      perceptions and preferences of Cook Islands, Maori and Australians.
AB  - AIMS: To examine body size perceptions in a group of Polynesians from the Cook
      Islands and compare these with perceptions of Australians of European decent.
      METHODS: Residents of Tutakimoa village on the island of Rarotonga, Cook Islands
      completed a questionnaire on body size perception (83 females, 49 males, 80%
      response rate). The responses were compared with the same number of Australian
      subjects who were matched for sex, age and body mass index (BMI). Culturally
      appropriate, graded sets of photographs (one female and one male for each ethnic
      group) were used as the stimuli for questions on body perception. RESULTS: Cook
      Islands women were the most accurate in their perception of their current size;
      other groups overestimated. All groups preferred to be smaller, particularly
      women, with similar preferences (BMI 23-24) in women of both ethnic groups. Cook
      Islands subjects chose larger ideal sizes than Australians for both females (BMI
      24.4 vs 22.5) and males (BMI 27 vs 24.2). CONCLUSIONS: The traditional Polynesian
      concepts of very large body sizes being considered healthy and attractive are not
      evident in the modern day Cook Islanders. The excessive pursuit of western
      fashions for small female body size may have longer term detrimental effects in
      Polynesian women.

PMID- 8668298
TI  - Percutaneous rotational coronary atherectomy: initial Green Lane and Mercy
      hospitals' experience.
AB  - AIMS: Rotational atherectomy is a new interventional technique and can be used as
      an alternative percutaneous treatment for selected coronary atherosclerotic
      lesions. We report the initial Green Lane/Mercy hospitals experience with
      rotational atherectomy and review the published international experience with the
      device. METHODS: Patient case notes and prospectively recorded New Zealand
      national angioplasty data forms were reviewed for basic demographic data and
      angina symptoms, in-hospital complications and length of the hospital stay.
      Catheter laboratory worksheets were reviewed to obtain the duration of ablation,
      burr diameter and adjunctive PTCA balloon diameter. RESULTS: The main indications
      for rotational atherectomy were heavy lesion calcification, ostial location, or
      failure of an angioplasty balloon to cross or to dilate the lesion. Procedural
      success was achieved in 28 of 30 patients (93%). One patient suffered a Q wave
      myocardial infarction and in another the lesion could not be crossed with the
      guide wire. Two patients required repeat balloon angioplasty for early
      reocclusion without other sequelae and one patient had directional atherectomy 2
      weeks later for ongoing sumptoms. CONCLUSION: Rotational atherectomy is a useful
      adjunct to the percutaneous devices available to treat coronary disease.

PMID- 8668299
TI  - Soft cot mattresses and the sudden infant death syndrome.
AB  - AIMS: To investigate whether soft cot mattresses are a risk factor for the sudden
      infant death syndrome (SIDS). METHODS: A follow up postal questionnaire was sent
      to the subjects who were interviewed 3.8 years (range 2.2 to 5.2 years)
      previously as part of the New Zealand Cot Death Study, a large nationwide case
      control study. RESULTS: 105 European SIDS cases were compared with 828 European
      controls. Soft cot mattresses were associated with an increased risk of SIDS
      (adjusted OR = 2.36; 95% CI = 1.06, 5,25) compared with average or hard
      mattresses. The firmness of the mattress did not interact with the sleeping
      position of infant. CONCLUSIONS: Soft cot mattresses should be avoided.

PMID- 8668300
TI  - Trauma data collection using a customised trauma registry: a New Zealand
      experience.
AB  - AIM: To describe the process of selection and adaptation of a trauma registry and
      the initial experience with its use. METHOD: The decision-making processes
      involved in selection of a data set and computer software are described. The
      problems associated with collection of data, recording and analysis are outlined.
      RESULTS: In the 6 months from 1 January to 30 June 1995, 615 patients were
      entered on the Auckland Hospital trauma registry. 590 patients were discharged or
      transferred alive and 25 (4.1%) died in hospital. Median length of stay of
      survivors was 6 days (mean 9.03 days) with median ICU stay being 0 days (mean
      0.81 days). A range of difficulties including data collection, recording and
      analysis were experienced. CONCLUSION: Despite some teething problems,
      establishment of a trauma registry has proven to be an achievable task within the
      trauma service. Recording of data which allows assessment of the quality of care,
      resource use and outcome has been possible. Effectiveness of the trauma service
      has been enhanced by the availability of this data.

PMID- 8668301
TI  - New Zealand immunisation schedule history.
AB  - The first formal immunisation schedule for the delivery of triple (DTP) vaccine
      was drawn up in November 1960. Since 1960 there have been many changes to the
      immunisation schedule, with a further change proposed for 1996. These changes
      have been in response to new vaccine development and better understanding of
      vaccine immunology. Further changes are certain.

PMID- 8668302
TI  - Neurocysticercosis: a rare cause of epilepsy in New Zealand.

PMID- 8668303
TI  - Sir Lambert Ormsby--expatriate New Zealander.

PMID- 8668304
TI  - Breast cancer followup: how much is enough?

PMID- 8668305
TI  - Cot death in New Zealand and Hong Kong.

PMID- 8668306
TI  - Reference to abortion.

PMID- 8668307
TI  - Dentists to get green light on more creative advertising.

PMID- 8668308
TI  - Fanning the flames.

PMID- 8668309
TI  - Fanning the flames.

PMID- 8668310
TI  - Planning for a secure future.

PMID- 8668311
TI  - Meniscal disorders.
AB  - The classical concepts of internal derangement (ID) of the TMJ meniscus are being
      challenged by findings focused at the microscopic and even molecular level.
      Acceptance of these findings means the definition of ID must be modified
      somewhat, along with the objective(s) of treatment modalities. It no longer seems
      appropriate to direct treatment primarily at mechanical restoration of 'normal'
      anatomical relationships within the joint.

PMID- 8668312
TI  - Mobile dental unit brings services to the young and needy.

PMID- 8668313
TI  - Diagnosing and treating victims of domestic violence.
AB  - Domestic violence can be defined as any violent behavior directed against an
      individual within the home or family. Intrafamily violence occurs in all segments
      of society and is not limited to a single ethnic or socioeconomic group. Unless
      the assaults within the home are stopped, the violence tends to escalate and
      become more serious, sometimes resulting in serious injury or death. Since the
      greater half of all non-accidental trauma occurs in the head and neck area, the
      dentist might be the first person to treat the domestic violence victim. Every
      member of the dental team must be aware of the incidence and prevalence of family
      violence and the serious sequelae associated with this dysfunctional behavior.
      Each member of the team can play an important role in the early recognition of
      non-accidental trauma. Once recognized, the intervention process can begin on
      behalf of the victim.

PMID- 8668314
TI  - Casting an ever-widening net.

PMID- 8668315
TI  - Dentistry, self-esteem and criticism.
AB  - Dentistry is rich in opportunity for professional and personal gratification.
      Ongoing discussions with dentists, however, reveal increasing unhappiness in the
      profession, especially among younger practitioners. This observation is
      corroborated by Dr. H. Adelson, who found that "depression has a serious and
      adverse effect on the lives of many dentists today." Professional
      dissatisfactions do not necessarily lead to depression. But evidence shows that
      certain environmental demands, such as the economy and constraints imposed by
      insurance companies, are accelerating and subjecting dentists to significant
      emotional pressures. If these difficulties persist or worsen, a practitioner's
      self-esteem may be compromised, which in turn can affect negatively how he or she
      functions inside and outside of the office. It is my view that healthy self
      criticism can help bolster the dentist's sense of self-esteem and can work as a
      prophylaxis against depression.

PMID- 8668316
TI  - Dental economics in post-recession period.

PMID- 8668317
TI  - Making radio waves. Interview by Bob Meyers.

PMID- 8668318
TI  - Detection of bluetongue virus and African horsesickness virus in co-infected cell
      cultures with NS1 gene probes.
AB  - The serogroup specificity of the bluetongue virus (BTV) NS1 and VP3 gene probes
      was confirmed by means of northern blot hybridization. Under high-stringency
      conditions both probes hybridized to 22 BTV serotypes (18 South African
      serotypes, BTV3 from Cyprus and BTV16 from Pakistan) but not to serotypes that
      originate from Australia and India. Furthermore, NS1 gene probes of BTV and
      African horsesickness virus (AHSV) were used in a dot-spot in situ hybridization
      procedure to differentiate between BTV and AHSV in co-infected cell cultures. The
      method detects viral RNA directly i glutaraldehyde-fixed infected cell cultures
      without prior nucleic-acid extraction or purification. AHSV could be detected in
      cells infected with AHSV at a multiplicity of infection of 10(-4) PFU/cell in the
      presence of a hundred excess of co-infecting BTV. The method may have an
      application in epidemiological surveys to detect different orbiviruses in the
      same Culicoides population.

PMID- 8668319
TI  - The distribution of Pasteurella haemolytica serotypes among cattle, sheep, and
      goats in South Africa and their association with diseases.
AB  - Over an 8-year period (September 1986 to March 1994), a total of 497 organ
      specimens from sheep and goats and 96 from cattle, were received for their
      isolation of Pasteurella haemolytica. They were collected in seven geographical
      areas in South Africa (as it existed before the April 1994 elections). These
      areas include the eastern Cape, Transvaal (new name: Gauteng), Nambia, Orange
      Free State (new name: Free State), Natal (new name: KwaZulu-Natal), western Cape
      and the northern Cape. This investigation does not represent the statistical
      incidence of the organism from each region, only the distribution of serotypes
      isolated from organ specimens submitted from diseased animals in these regions.
      Pasteurella haemolytica serotype 6 was the most prevalent type isolated from
      sheep and goats, but was followed closely by types 9 and 2. From cattle, P.
      haemolytica serotype 1 comprised 39% of the isolates. In sheep and goats, the
      majority of serotypes were associated with pneumonia, followed by gangrenous
      mastitis ("blue udder") and septicaemia. The situation in cattle was similar
      regarding the incidence of pneumonia followed by septicaemia. Up to 33% of the
      isolates from cattle and sheep specimens were non-typeable.

PMID- 8668320
TI  - The use of sucrose-acetone-extracted Rift Valley fever virus antigen derived from
      cell culture in an indirect enzyme-linked immunosorbent assay and
      haemagglutination-inhibition test.
AB  - A sucrose-acetone-extracted, Madin-Darby-bovine-kidney (MDBK)-derived Rift Valley
      fever virus (RVFV) antigen was tested both in an indirect ELISA and a
      haemagglutination-inhibition test for its ability to detect serum antibodies to
      RVFV. Optimal conditions for antigen concentration, serum and conjugate dilutions
      for the ELISA were established by checkerboard titration. The specificity and
      sensitivity of ELISA were determined by the use of paired pre- and post
      vaccination sheep-serum samples. Compared with the virus neutralization test, the
      overall ELISA specificity and sensitivity were 97.4 and 97.3%, respectively.
      There was a 100% correlation between the results obtained in haemagglutination
      inhibition tests with a RVFV sucrose-acetone-extracted antigen derived from
      hamster liver, and from MDBK cells. A total of 10 582 field-serum samples (84
      cattle, 3,659 sheep, 6,839 goats) collected in 1994-1995 from animals of unknown
      vaccination status in different regions of South Africa were tested with ELISA
      for antibodies against RVFV. There were no seropositive cattle, 0.16%
      seropositive sheep and 0.12% seropositive goats. This study demonstrates the
      potential diagnostic application of cell-culture-derived, sucrose-acetone
      extracted RVFV antigen in an indirect ELISA and HI test.

PMID- 8668321
TI  - The effect(s) of carbaryl-treated seed on body maintenance and survival of the
      multi-mammate mouse, Mastomys natalensis (sensu lato).
AB  - Maintenance, expressed as change in daily body mass, and survival rates of
      Mastomys natalensis (sensu lato) were recorded from May to September 1994 in
      laboratory feeding trials, to investigate the short-term effects of a carbaryl
      insecticide on these variables. Individuals were subjected to seeds treated with
      carbaryl insecticide in three different treatments (5, 10, and 20 g of
      carbaryl/kg of seeds). Carbaryl did not have short-term adverse effects on growth
      and survival of this species when the seeds were kept in the laboratory and when
      they were exposed to environmental conditions between measurements. This suggests
      that the ingestion of carbaryl-treated seeds is not the cause of the decline in
      density of M. natalensis on rehabilitating coastal dune forests at Richards Bay.

PMID- 8668322
TI  - Detection of bovine-virus-diarrhoea-virus antibodies in cattle with an enzyme
      linked immunosorbent assay.
AB  - The serum-neutralization (SN) and the indirect-immunofluorescence (IIF) assays
      have invariably been used for detecting antibodies against bovine virus diarrhoea
      virus (BVDV) in cattle sera. An enzyme-linked immunosorbent assay (ELISA) was
      applied which has a sensitivity comparable with the SN and IIF in detecting
      antibody to BVDV. A total of 472 bovine sera were assayed and a high prevalence
      of 79.2% was recorded. Positive correlations between the ELISA and the SN were
      found when certain sera were assayed, implying that the former test could then be
      used for routine diagnosis of BVDV.

PMID- 8668323
TI  - The skull and mandible of the African elephant (Loxodonta africana).
AB  - In the present study the bones of the skull, excluding the hyoid apparatus, are
      described. All the bones are aerated by sinuses. In the occipital bone the
      squamous part is aerated from the sinus of the parietal bone, the lateral part is
      aerated from the tympanic bulla and the basal part from the sinus of the
      basisphenoid bone. Condylar foramens and hypoglossal canals are absent. A small
      interparietal bone is present at birth. At an early age it fuses with the
      surrounding cranial bones. The squamous part of the temporal bone lies sagittally
      in young animals, but moves progressively to a transverse plane as the animals
      age. A foramen lacerum is represented by jugular and oval foramens and the
      carotid canal. The body of the basisphenoid bone is excavated by the massive
      maxillary tuberosity. The latter extends to the oval foramen and contains the
      developing molar teeth. The ethmoturbinate, nasal and lacrimal bones are
      exceptionally small. In old bulls the palatine process of the incisive bones and
      their sinuses are gradually displaced by the palatine process of the maxillae.

PMID- 8668324
TI  - Effects of transformation on the hemagglutinins of Haemophilus paragallinarum.
AB  - Strain 0083 and two field isolates of H. paragallinarum were previously converted
      into NAD-independent organisms by the use of crude DNA extractions from naturally
      occurring NAD-independent H. paragallinarum isolates. Two of these transformed
      isolates [0083(T) and A745(T)] were used as DNA donors in another transformation
      experiment in which another field isolate (M85) was used as the DNA recipient.
      Transformation was confirmed by lack of NAD requirement for growth, by
      carbohydrate fermentation patterns and by a comparison of the monoclonal antibody
      patterns of the isolates before and after transformation. Previously, antigenic
      differences were observed when DNA from an NAD-independent isolate was introduced
      into strain 0083. Antigenic differences were also seen in the transformed M85
      organisms prepared in this work, and these differences were dependent on the
      antigenic patterns of the DNA donors. It was established by haemagglutination
      (HA) and haemagglutination inhibition (HI) that the hemagglutinins of 0083,
      A745/92 and M85 were not affected by transformation. The use of strains
      transformed to NAD independence for vaccine production appears to be a valid
      approach, as the transformation appears not to affect the hemagglutinins of the
      transformed organisms The major advantage would be the alleviation of the
      requirement for chicken serum or NAD in the bacterial growth medium used for
      infectious-coryza-vaccine production.

PMID- 8668325
TI  - Epidemiology of African horsesickness: antibodies in free-living elephants
      (Loxodonta africans) and their response to experimental infection.
AB  - The presence of low levels of group- and type-specific antibodies against African
      horsesickness virus in the serum of some free-living elephants was reconfirmed.
      Experimental infection resulted in conflicting results. No detectable viraemia
      nor virus could be demonstrated in the organs of the six elephant calves and none
      of them mounted significant levels of neutralizing antibodies against the virus.
      On the other hand, all calves showed a slight rise in ELISA titres. This rise,
      however, was modest when compared with the rise in experimentally infected zebra.
      The presence of low levels of group- and type-specific antibodies in the serum of
      some free-living elephants is judged to be the result of natural hyper
      immunization due to frequent exposure to infected biting insects. Elephants
      should therefore, despite the presence of low levels of antibodies, be regarded
      as poorly susceptible and unlikely to be a source of African horsesickness virus.

PMID- 8668326
TI  - Immunohistochemical identification of Cowdria ruminantium in formalin-fixed
      tissue sections from mice, sheep, cattle and goats.
AB  - An immunohistochemical staining technique in which a monospecific serum was used
      against the major antigenic protein -1 (MAP-1) of Cowdria ruminantium, was
      evaluated for the detection of C. ruminantium in formalin-fixed tissues of
      experimentally infected mice and field cases of heartwater in sheep, cattle and
      goats. Mice were infected with the mouse-pathogenic stocks: Mara, Kwanyanga,
      Welgevonden, Nonile, Vosloo, Kumm, Mali and Omatjenne. In all these cases and in
      the naturally infected cattle, sheep and goats, Cowdria colonies were identified
      as clearly-defined, brown-staining rickettsial colonies within the cytoplasm of
      endothelial cells. No positive staining was observed in the control group. This
      technique was shown to be reliable for detecting infection with C. ruminantium in
      the formalin-fixed tissues of mice and domestic ruminants.

PMID- 8668328
TI  - p16INK4a: a gene with a dual capacity to encode unrelated proteins that inhibit
      cell cycle progression.

PMID- 8668327
TI  - Serological prevalence of leptospiral antibodies in pigs in South Africa.
AB  - A serological survey for leptospiral antibodies was carried out on 5 041 abattoir
      pigs from different regions in South Africa. Antibodies to at least one serovar
      were detected in 22,2% of the animals. The serovars showing the highest
      prevalence were: icterohaemorrhagiae (12,6%), hardjo (12,1%) and bratislava
      (7,5%). The serum dilution level at which 90% of the sera reacted was 1/80 or
      1,160.

PMID- 8668329
TI  - Retardation of chemical hypoxia-induced necrotic cell death by Bcl-2 and ICE
      inhibitors: possible involvement of common mediators in apoptotic and necrotic
      signal transductions.
AB  - Inhibition of the respiratory chain reaction by cyanide, rotenone or antimycin A
      (chemical hypoxia) induces necrotic cell death characterized by apparently intact
      chromatin, remarkable mitochondrial swelling with loss of crista structure, and
      loss of plasma membrane integrity. The treatments induce no apoptotic cell death,
      as defined by fragmented nuclei with condensed chromatin, fragmented or condensed
      cytoplasm. The anti-apoptotic proteins Bcl-2 and Bcl-xL effectively retard the
      chemical hypoxia-induced necrotic cell death. The necrotic cell death is also
      retarded by inhibitors of ICE(-like) proteases, including interleukin-1beta
      converting enzyme (ICE), which are common mediators of apoptosis. These results
      indicate that Bcl-2/Bcl-xL and ICE(-like) proteases modulate apoptotic and at
      least some forms of necrotic cell death. Both cell death pathways appear to
      involve some common mediators; however necrotic or apoptotic cell death signals
      might be transduced through multiple pathways, because Bcl-2/ Bcl-xL or
      inhibitors of ICE(-like) proteases are relatively less potent in blocking
      necrotic cell death than in preventing apoptosis.

PMID- 8668331
TI  - Acute and delayed apoptosis induced by thymidine deprivation correlates with
      expression of p53 and p53-regulated genes in colon carcinoma cells.
AB  - The endogenous expression of p53 and p53-regulated genes has been examined in a
      thymidylate synthase-deficient colon carcinoma cell line (TS-) and a derived
      mutant clone (Thy4) that exhibit acute or delayed apoptotic responses,
      respectively, when released from G0 synchrony under conditions of dThd
      starvation. These cell clones demonstrate heterozygosity in p53, thereby
      expressing one wt allele and one with an A-->C point mutation at codon 240.
      Following release from G0, upregulated expression of both alleles occurred.
      During apoptosis in TS-, a wtp53 phenotype was expressed and in Thy4 during
      cytostasis, a mp53 phenotype was manifested, as determined from the ratios of
      wtp53/mp53 proteins, transactivation of p50-2 (a wtp53-responsive CAT reporter
      construct) and the endogenous expression of MDM2. Neither cytotoxicity nor
      cytostasis correlated with expression of p21Waf1/Cip1 Thy4 cells sustained
      accumulation of high levels of Bax in a wtp53-independent and dThd-independent
      manner and survival was associated with upregulated expression of Bcl-2. In
      contrast, Bax expression decreased in TS- during apoptosis, except in a highly
      resistant subpopulation that retained high levels of Bax. Data suggest that
      resistant cells (Thy4) can sustain high Bax expression and that Bcl-2 is
      upregulated in response to an apoptotic stimulus due to the absence of negative
      regulation by wtp53.

PMID- 8668330
TI  - Bcl-2 inhibits hydrogen peroxide-induced ER Ca2+ pool depletion.
AB  - The mechanism by which Bcl-2 inhibits apoptosis is unknown. The Bcl-2 protein is
      localized to intracellular membranes, including the endoplasmic reticulum (ER).
      The ER is the major intracellular reservoir of Ca2+ in non-muscle cells,
      sequestering Ca2+ for use in intracellular signaling, and is a prime target of
      oxidative damage. Because of the recent suggestion that Bcl-2 acts in an
      antioxidant pathway, we wondered whether Bcl-2 might protect the ER Ca2+ pool in
      cells exposed to reactive oxygen species. To test this hypothesis, we assessed
      the effect of hydrogen peroxide (H2O2) treatment on the ER Ca2+ pool in WEH17.2
      cells, which do not express Bcl-2, and two stable transfectants, W.Hb13 and
      W.Hb12. The Bcl-2 level by Western blotting is 4-fold higher in W.Hb12 cells
      compared to W.Hb13 cells. The ER Ca2+ pool in H2O2-treated and untreated cells
      was measured according to the amount of Ca2+ mobilized from the ER lumen into the
      cytoplasm by thapsigargin (TG), a selective inhibitor of the ER (Ca2+)-ATPase.
      H2O2 treatment produced a significant reduction in the TG-mobilizable Ca2+ pool
      in WEH17.2 and W.Hb13 cells, but not in W.Hb12 cells, indicating that
      overexpression of Bcl-2 preserves the integrity of the ER Ca2+ pool in cells
      exposed to reactive oxygen species.

PMID- 8668332
TI  - p53 transactivation domain mutant Q22, S23 is impaired for repression of
      promoters and mediation of apoptosis.
AB  - p53 is multifunctional. To assess exactly what function is critical for the
      prevention of neoplastic transformation has proven difficult. Mutants with
      substitutions at positions 22 and 23 promised to address the relevance of
      transcription transactivation since they seemed to be defective specifically for
      this function. We report here that p53 mutant Q22, S23 [p53 (22,23)] is not only
      impaired for transactivation but for the repression of the fos promoter and SV40
      early promoter. Furthermore, whereas p53 (22,23) fails to efficiently
      transactivate reporter genes in two p53-negative cell lines, it stimulates
      reporters and suppresses proliferation in two wild-type (wt) p53-positive cell
      lines strongly above the levels induced by the transfection procedure alone. This
      transactivation is refractory to inhibition by MDM-2. Finally, p53 (22,23)
      expressed from large plasmid quantity (1 microg) is crippled for the mediation of
      apoptosis in p53-negative Hep3B hepatocarcinoma cells. Nevertheless, at a
      quantity of only 10 ng, both mutant and wt p53 plasmids but not control plasmid,
      are able to induce some cell death which is not inhibitable by MDM-2. Thus, a
      correlation exists between p53's functions to regulate promoters and to
      efficiently mediate apoptosis in Hep3B cells.

PMID- 8668333
TI  - Role of a signal transduction pathway which controls disassembly of microfilament
      bundles and suppression of high-molecular-weight tropomyosin expression in
      oncogenic transformation of NRK cells.
AB  - Role of disassembly of microfilament bundles and suppression of high-molecular
      weight tropomyosin (TM) expression in growth factor- and various oncogene-induced
      transformation was studied by using NRK cells and its transformation-deficient
      mutants. In NRK cells which show a transformed phenotype by treatment with EGF
      and TGF-beta, cellular stress fibers became dissociated by EGF or EGF and TGF
      beta combination, whereas TGF-beta alone caused thicker appearance of stress
      fibers. Accompanying these changes, the expression of TM isoforms 1 and 2 was
      suppressed by treatment with EGF or EGF and TGF-beta, but elevated by TGF-beta
      with similar time courses. On the other hand, the transformation-deficient mutant
      cell lines, 39-1 and 39-3, did not show the transformed phenotypes by treatment
      with EGF and TGF-beta. Neither EGF nor EGF and TGF-beta combination affected
      cellular stress fibers and expression of TM isoforms 1 and 2 in both mutant
      lines. The relationship between the formation of stress fibers and the expression
      of TM isoforms was consistent in NRK cells, the mutant lines and their various
      oncogene-expressing sublines under various culture conditions. NRK cells
      overexpressing exogenous mouse TM isoform 2 showed markedly decreased
      susceptibility to EGF-induced dissociation of stress fibers and decreased
      anchorage-independent growth potential in the presence of EGF and TGF-beta. These
      results indicate that the transformation-deficient NRK mutant lines, 39-1 and 39
      3 have defects in an EGF signal transduction pathway which induces suppression of
      high-molecular-weight TM expression and disassembly of microfilament bundles and
      suggested that the activation of the pathway is important for morphological
      transformation and oncogenic growth in growth factors- and various oncogene
      induced transformation of NRK cells.

PMID- 8668334
TI  - Oncogenic potential of a pre-T cell receptor lacking the TCR beta variable
      domain.
AB  - In transgenic mice expressing a mutated T cell receptor (TCR) beta chain lacking
      the variable domain (DeltaV-TCRbeta) T cell differentiation is arrested at the
      CD4+ CD8+ thymocyte stage. Here, we report that these transgenic animals develop
      CD4+, CD8+, IL-2 receptor alpha-positive T cell lymphomas at a very high
      incidence. Introduction of a normal TCRbeta gene into the DeltaV-TCRbeta
      transgenic mice drastically reduces the tumor incidence, while crossing the
      DeltaV-TCRbeta transgene onto a recombinase-deficient RAG-1-/- background does
      not prevent tumor development. Therefore, the induction of T cell lymphomas is a
      property of the mutated TCRbeta chain. The DeltaV-TCRbeta chain appears at the
      cell surface as a disulfide-linked DeltaV-TCRbeta/pTalpha dimer in association
      with CD3gamma and -episilon, but not with CD3delta. This mutated preTCR/CD3
      complex is shown to induce pre-T cell proliferation and differentiation, but does
      not permit formation of a normally sized CD4+8+ thymic compartment. DeltaV
      TCRbeta transgenic mice frequently show an expansion of CD4+8+, IL-2 receptor
      alpha+ pre-T cells early in life. These cells likely represent the population
      that is subject to oncogenic transformation.

PMID- 8668335
TI  - Molecular and genetic studies on the region of translocation and duplication in
      the neuroblastoma cell line NGP at the 1p36.13-p36.32 chromosomal site.
AB  - Cytogenetic and molecular studies suggest that chromosome 1p might contain
      oncosuppressor genes involved in the pathogenesis of neuroblastoma and other
      adult tumors. The isolation of these genes by the 'positional cloning' approach
      will be facilitated by the characterization of cell lines with well defined
      chromosomal aberrations. In the present report we provide molecular data on the
      NGP neuroblastoma cell line which contains a reciprocal t(1;15) translocation.
      Two regions, possibly hosting oncosuppressor genes, have been identified: one is
      distal to the ENO1 locus, the other one is comprised between PND and A12M2 and
      corresponds to that of a constitutional t(1;17) translocation described in a
      neuroblastoma patient. Genetic data also suggest that the NGP cell line, despite
      the presence of two chromosomes 1, might be hemizygous for the subtelomeric 1p
      region.

PMID- 8668336
TI  - Expression of keratinocyte growth factor in embryonic liver of transgenic mice
      causes changes in epithelial growth and differentiation resulting in polycystic
      kidneys and other organ malformations.
AB  - Expression of human keratinocyte growth factor (KGF/FGF-7) was directed to
      hepatocytes during the later period of mouse gestation using a human
      apolipoprotein E (ApoE) gene promoter and its associated liver-specific enhancer.
      Human KGF was detectable in liver extracts and serum prepared from e17.5-e19.5
      embryos, concomitant with the appearance of morphological abnormalities in
      several organs which express KGF receptor. The most striking phenotypic
      aberration in the ApoE-hKGF transgenic embryos was marked hyperplasia and cystic
      dilation of the cortical and medullary kidney collecting duct system, a phenotype
      resembling infantile polycystic kidney disease in humans. Transgenic embryos had
      enlarged livers, with prominent biliary epithelial hyperplasia, and also
      exhibited enhanced bronchiolar epithelial and type II pneumocyte proliferation.
      There was variable hyperplasia of intestinal epithelia, and urothelium of the
      urinary bladder and ureters. When compared to age-matched littermate controls,
      marked epidermal papillomatous acanthosis and hyperkeratosis in the skin, with a
      notable decrease in the number of developing hair follicles was seen in
      transgenic embryos. The pancreas exhibited significant ductal hyperplasia, with
      an increase in the number of ductal epithelial cells staining positive for
      insulin expression. High systemic levels of KGF during the latter stages of
      embryogenesis causes abnormalities in epithelial growth and differentiation
      within multiple organ systems and results in perinatal lethality. Correct
      temporal and spatial expression of KGF during the latter stages of organ
      development is likely to play a critical role in mesenchymal-epithelial signaling
      required for normal embryonic growth and development.

PMID- 8668337
TI  - Increased neurofibromatosis 1 gene expression in astrocytic tumors: positive
      regulation by p21-ras.
AB  - The neurofibromatosis 1 (NF1) gene has been implicated in astrocyte growth
      regulation in several studies. To determine whether loss of NF1 expression is
      associated with progression towards malignancy in sporadic astrocytomas from
      individuals without NF1, twenty-eight fresh astrocytoma operative specimens (low
      and high grade tumors) and seven primary human astrocytoma cell lines were
      examined for NF1 mRNA and protein expression. In all astrocytomas examined,
      increased NF1 expression was observed in the tumors relative to normal resting
      astrocytes. This increased neurofibromin expression correlated with elevated
      levels of activated p21-ras measured in both the fresh tumor specimens and the
      primary cell lines. Furthermore, when levels of activated p21 ras were decreased
      in astrocytoma cells expressing the ras inhibitory Asn-17 dominant-negative
      mutant, levels of neurofibromin expression decreased. In addition, fibroblasts
      induced to express oncogenic activated p21-ras(val12) had increased expression of
      NF1. These results suggested that neurofibromin expression is increased in human
      astrocytic tumors as a result of positive feedback regulation by increased levels
      of activated p21-ras.

PMID- 8668338
TI  - Effect of a 10-amino acid deletion on the oncogenic activity of latent membrane
      protein 1 of Epstein-Barr virus.
AB  - A previous study has shown that the BNLF1 of Epstein-Barr virus (EBV), isolated
      from a nasopharyngeal carcinoma biopsy (BNLF1-1510), was able to transform
      Balb/3T3 cells. On the other hand, BNLF1 of a prototype virus B95-8 (BNLF1-958)
      was not transforming unless the gene was transcribed from a strong promoter. In
      this study, we have generated chimeric BNLF1 by exchanging the DNA fragments
      between BNLF1-1510 and BNLF1-958 and examined their expression and transformation
      ability in Balb/3T3 cells. Results showed that transformation of Balb/3T3 cells
      by BNLF1-1510 was not due to the excessive expression of the gene. Transfection
      of Balb/3T3 cells with chimeric BNLF1 showed that the genes with 3' 453 bp
      sequence of BNLF1-1510 were oncogenic to the cells. Study also revealed that
      changing the numbers of the 33 bp repeats in the 3' region of the two BNLF1s did
      not affect the transformation characteristics. On the other hand, deletion of a
      30 bp sequence of BNLF1-958, which is absent in BNLF1-1510, changed the gene from
      non-oncogenic to oncogenic and insertion of this 30 bp sequence into BNLF1-1510
      abolished the transformation ability. BNLF1 without this 30 bp sequence was also
      found in the tumours of other EBV-related neoplastic disease, suggesting that
      absence of this 30 bp sequence in BNLF1 may be associated with the oncogenesis of
      these diseases.

PMID- 8668339
TI  - Characterization of a human MSX-2 cDNA and its fragment isolated as a
      transformation suppressor gene against v-Ki-ras oncogene.
AB  - A cDNA (termed CT124) encoding a carboxyl-terminal fragment of the human homeobox
      protein MSX-2 was found to induce flat reversion when expressed in v-Ki-ras
      transformed NIH3T3 cells. Although the expression of endogenous MSX-2 gene is low
      in most of the normal adult tissues examined, it is frequently activated in
      carcinoma-derived cell lines. Likewise, the gene is inactive in NIH3T3 cells but
      is transcriptionally activated after transformation by v-Ki-ras oncogene,
      suggesting that the intact MSX-2 may play a positive, rather than suppressive,
      role in cell transformation. To test this possibility, we isolated a near full
      length human MSX-2 cDNA and tested its activities in two cell systems, i.e.
      fibroblast and myoblast. In NIH3T3 fibroblasts, although the gene by itself
      failed to confer a transformed phenotype, antisense MSX-2 cDNA as well as
      truncated CT124 cDNA interfered with the transforming activities of v-Ki-ras
      oncogene. In C2C12 myoblasts, MSX-2 was found to suppress MyoD gene expression,
      as do activated ras oncogenes, under certain culture conditions, and CT124 was
      found to inhibit the activities of both MSX-2 and ras in this system as well. Our
      findings not only suggest that CT124 may act as a dominant suppressor of MSX-2
      but also raise the possibility that MSX-2 gene may be an important downstream
      target for the Ras signaling pathways.

PMID- 8668340
TI  - Loss of heterozygosity of chromosome 17 in human borderline and invasive
      epithelial ovarian tumors.
AB  - Polymerase chain reaction (PCR) analysis of microsatellite polymorphisms
      corresponding to four loci which map to chromosome 17p and 11 loci which map to
      chromosome 17q was performed to screen for loss of heterozygosity (LOH) in paired
      normal and tumor tissues from 27 cases of borderline epithelial ovarian tumors
      (BEOT) and 32 cases of invasive epithelial ovarian cancers (IOC). LOH was
      observed in six of 27 (22%) of the borderline tumors and in 29 of 32 (90%) of the
      invasive ovarian cancers (P<0.001). At all 15 loci studied, a lower percentage of
      allelic loss was detected in borderline tumors (0-14%) vs invasive cancer (8
      93%). At eight loci this difference was statistically significant. For IOC, one
      common loss region was identified on chromosome 17p and four distinct common loss
      regions were on chromosome 17q, which supports the notion that multiple tumor
      suppressors may reside on chromosome 17 in IOC. These data suggest that LOH on
      chromosome 17 is an infrequent event in BEOT compared with IOC and therefore may
      not be important in the distinct pathogenesis of BEOT.

PMID- 8668341
TI  - p21 contains independent binding sites for cyclin and cdk2: both sites are
      required to inhibit cdk2 kinase activity.
AB  - Cyclin dependent kinases regulate the progression of eukaryotic cells through the
      cell cycle. p21Cip1/Waf1/Sdi1 is an inhibitor of cdk-cyclin kinase activity, and
      has been shown to form complexes with cdk-cyclins and with PCNA, an accessory
      protein of DNA polymerase delta. The kinase inhibitory domain maps to the N
      terminus (1-82) and contains the cdk2 binding site (28-82). We have generated a
      panel of deletion mutants of p21. A functional characterization of p21 mutants in
      the N-terminal domain reveals that cyclins bind to this domain independently of
      cdk2. Correlating with these results we find that p21 can associate with cyclin
      cdk kinases in two functionally distinct forms, one in which the kinase activity
      is inhibited and the other in which the kinase is still active. The cdk2 and
      cyclin binding sites on p21 are both required to inhibit kinase activity. The
      second type of interaction, in which an active cyclin-cdk complex only interacts
      with p21 either via the cyclin or the cdk2 binding site but not through both,
      does not lead to inhibition of cyclin kinase activity. These results thus provide
      a basis for understanding the mechanism by which p21, and perhaps other cdk
      cyclin kinase inhibitory proteins, suppress kinase activity.

PMID- 8668343
TI  - Isolation and characterization of Nmi, a novel partner of Myc proteins.
AB  - The Myc family of oncogenes is thought to play an important role in cell
      proliferation, differentiation, and neoplastic transformation. Although the
      structure and expression of Myc genes are well characterized, the function and
      biochemical properties of the Myc proteins are less well understood. Here, using
      a yeast genetic screen, we identified a novel gene, Nmi, that binds to N-myc and
      C-myc. It also interacts with other transcription factors in yeast. The carboxyl
      terminus of Nmi shows homology to an interferon-induced leucine zipper protein,
      IFP 35, whereas its amino terminus is homologous to a coiled-coil heptad repeat
      in the C. elegans protein, CEF59. Co-precipitation studies of Nmi with N-myc and
      C-myc confirmed the interaction in mammalian cells. Nmi mRNA is expressed at low
      levels in all fetal and adult human tissues tested, except brain. Among several
      cancer cell lines, high expression of Nmi was found in myeloid leukemias, which
      also express high levels of C-myc. Nmi gene is localized on human chromosome
      22q13.3. Translocations of this region have been reported in some human
      leukemias.

PMID- 8668342
TI  - S phase specific formation of the human Rad51 protein nuclear foci in
      lymphocytes.
AB  - The Rad51 protein, which is a homologue of the bacterial RecA protein, is
      involved in mitotic and meiotic recombination and in repair of double-strand
      breaks of DNA in yeast. The Rad51 homologue is conserved from yeast to human. In
      this study, the Rad51 protein was shown to be induced in peripheral blood
      lymphocytes (PBLs) 36 h after phytohemagglutinin (PHA) stimulation.
      Immunofluorescence study revealed that the distribution of the Rad51 protein in
      the nucleus was not uniform and focus-like staining was observed. Formation of
      the Rad51 foci was induced at 36 h after treatment of the cells with PHA. Twenty
      five percent of the cells had the foci at this time and the number of cells with
      foci declined thereafter. Cell cycle study using laser microscope by double
      staining method suggested that the appearance of the Rad51 nuclear foci was S
      phase specific. Furthermore, double staining study for the Rad51 protein and
      incorporated BrdU confirmed S phase specific appearance of the Rad51 nuclear
      foci. Formation of the Rad51 nuclear foci in PHA-stimulated lymphocytes might be
      involved in DNA recombination or DNA repair in S phase. The roles of RAD51 foci
      in S-phase will be discussed.

PMID- 8668344
TI  - Expression of FosB during mouse development: normal development of FosB knockout
      mice.
AB  - FosB, one of the members of the Fos family, is rapidly induced in many cell types
      upon stimulation and has a stimulatory effect on the proliferation of cultured
      cells. To understand the tissue distribution of FosB, we have studied its
      expression pattern by immunohistochemistry in newborn and late embryonic stage
      mice. These results show that FosB is widely expressed with the highest levels of
      expression observed in both bony and cartilagenous regions of developing bone.
      FosB is also detected within whisker follicles, liver, and epidermal tissue. To
      study the role of FosB in mammalian development we generated embryonic stem (ES)
      cells, mice and mouse embryo fibroblasts (MEFs) that are deficient for FosB. FosB
      -/- mice are born at a normal frequency, are fertile and present no obvious
      phenotypic or histologic abnormalities. FosB-deficient ES cells and MEFs
      proliferate and enter the S phase normally and we do not find upregulation of
      other fos family genes to compensate for the lack of FosB. However, we do find
      that the induction of two AP-1 containing genes is reduced after stimulation of
      FosB-deficient cells, demonstrating that FosB does indeed play a functional role
      in transcriptional regulation.

PMID- 8668345
TI  - Identification of a novel interleukin-15 (IL-15) transcript isoform generated by
      alternative splicing in human small cell lung cancer cell lines.
AB  - IL-15 is a cytokine promoting growth and differentiation of T, B and NK
      lymphocytes. By RT-PCR analysis, using primers allowing amplification of the
      entire IL-15 mRNA coding region, 9/11 small cell lung cancer (SCLC) cell lines
      displayed detectable IL-15 gene expression. In addition to the expected band
      sizing 524 bp, a larger band was also observed. Cloning and sequence analysis of
      the larger cDNA from two SCLC cell lines revealed a size of 643 hp due to the
      presence of additional 119 hp within the previously reported IL-15 cDNA sequence.
      The 119 hp sequence matched with an IL-15 genomic sequence downstream the IL-15
      second coding exon and may represent a previously unreported alternative exon
      (exon A). The SCLC-associated IL-15 mRNA isoform has a shorter open reading frame
      (ORF) due to stop codons in exon A, followed by a new AUG codon. The predicted IL
      15 precursor protein displays a shorter signal peptide but shares the same
      aminoacidic composition of mature IL-15 protein. A possible functional role of IL
      15, different from 'IL-2-like' activity, in human tumours, is suggested.

PMID- 8668346
TI  - Selective activation of the proto-oncogene c-jun promoter by the transforming
      protein v-Rel.
AB  - The transcription factor v-Rel is a transforming protein of the
      reticuloendotheliosis virus. We found that v-Rel activates the promoter of the
      proto-oncogene c-jun. Two elements in the c-jun promoter were required for the
      activation by v-Rel. One was a kB-site (v-Rel binding site), and the other was a
      c-jun promoter region between -52 and +148 (c-jun promoter (-52/+148)). Two
      promoters with the kB-site(s), those of human immunodeficiency virus (HIV) and
      SV40, were not activated by v-Rel, but their kB-sites were activated when
      introduced upstream of the c-jun promoter (-52/+148). Thus, the c-jun promoter (
      52/+148) had information for the selective activation of the c-jun promoter by v
      Rel. v-Rel bound to the c-jun kB-site with the higher affinity than c-Rel,
      thereby activating the c-jun promoter more efficiently than c-Rel. Moreover, the
      activity of v-Rel mutants upon the c-jun promoter correlates with their
      transforming activity. Thus, the c-jun promoter activation by v-Rel may play a
      role in the transformation caused by v-Rel.

PMID- 8668347
TI  - Mos proto-oncogene function during oocyte maturation in Xenopus.
AB  - The function of the Xenopus c-mos proto-oncogene product (Mos(xe)) has been
      investigated during oocyte maturation. Experiments with a new antibody able to
      immunoblot Mos(xe) demonstrated the time course of MAP kinase (MAP K) activation
      in oocytes paralleled Mos(xe) accumulation, and in activated eggs the
      deactivation of MAP K paralleled the degradation of Mos(xe). Ablation of Mos
      synthesis by microinjection of antisense oligodeoxynucleotides abolished
      activation of MAP K by progesterone, but microinjection of GST-Mos fully restored
      both MAP K activation and germinal vesicle breakdown (GVBD). The Mos(xe) level at
      metaphase of Meiosis I (MI) was 2 - 3-fold less than that at metaphase of Meiosis
      II (MII), but MAP K activation was maximal at metaphase in both MI and MII. In
      the transition between MI and MII, both cyclin B and Mos(xe) levels rapidly
      declined in the presence of cycloheximide and injection of exogenous GST-Mos(xe)
      did not prevent degradation of either protein, although MAP K was activated.
      Microinjection of GST-Mos(xe) into oocytes was able to activate MAP K before GVBD
      and H1 kinase activation, and microinjection of constitutively-activated
      thiophosphorylated MAP K induced de novo synthesis of Mos(xe) before H1 kinase
      activation, suggesting the existence of a positive feedback loop between MAP K
      and Mos(xe) accumulation.

PMID- 8668348
TI  - Identification of signalling proteins interacting with B-Raf in the yeast two
      hybrid system.
AB  - Recent studies suggested the existence of Ras/B-Raf/ MEK-1 complexes and a
      critical role for B-Raf in regulating the MAP kinase/ERKs signalling pathway. We
      report, here, that both Ras and MEK-1 proteins interact physically with B-Raf
      proteins in the yeast two-hybrid system. In addition, by screening a mouse brain
      cDNA library, we isolated additional B-Raf interacting proteins. These include
      three members of the 14-3-3 proteins family (eta, theta and zeta) and the MEK-2
      protein. We also show that c-Raf-1, previously reported to interact with beta and
      zeta 14-3-3 proteins, also interacts with eta and theta 14-3-3 proteins in the
      two-hybrid system. By using different portions of the B-Raf protein, we mapped
      the regions of the protein involved in these interactions. Specifically, we have
      characterized B-Raf specific sequences required for an efficient interaction with
      MEK proteins. We show that, consequently, B-Raf interacts with MEK-1 and MEK-2
      with a better affinity than does c-Raf-1, thus strengthening the notion that B
      Raf is a stronger MEK activator than c-Raf-l. Our results also suggest that a MEK
      specific sequence, not present in MAP kinase kinases which are not activated by
      members of the Raf family, is required for the interaction with Raf proteins.

PMID- 8668350
TI  - Deletions of the p16 gene in pediatric leukemia and corresponding cell lines.
AB  - The p16 gene (MTS1 or CDK4I) encoding an inhibitor of cyclin-dependent kinase 4
      (cdk4), has been reported to be deleted in various tumor cell lines, including
      lines derived from leukemic cells. The reported frequency of p16 gene loss is
      much higher in established cell lines than in primary tumor specimens. We
      investigated the status of the p16 gene in pediatric leukemias using 12
      established cell lines of differing phenotypes and their corresponding primary
      leukemic cells. Six of 12 cell lines, including acute lymphoblastic leukemia
      (ALL) lines of T-cell (three of four), of precursor-B cell (two of four) and of
      mixed phenotype (one of four), showed homozygous deletion of the p16 gene using
      PCR and Southern blotting. Comparison of the cell lines with their corresponding
      primary leukemic cells clearly showed that in all 12 paired samples there were
      identical findings with respect to the presence or absence of the p16 gene,
      demonstrating that loss of the gene was a feature of the primary leukemic cells.
      This is the first study to show this correlation using a panel of paired samples,
      indicating that p16 gene deletions were not an artifact of in vitro cell culture.
      Furthermore, the survival of ALL patients with p16 gene deletions was
      significantly inferior to those without deletions, suggesting that this genetic
      alteration may be a clinical prognostic factor.

PMID- 8668351
TI  - Frequent ectopic expression of a placenta-specific gene at high levels in BALB/c
      mouse mammary carcinomas.
AB  - A placenta-specific gene, MIPP, is transcriptionally regulated in BALB/c mice by
      a solo long terminal repeat (LTR) of an intracisternal A-particle (IAP), an
      endogenous retrotransposon. Expression of IAPs, which is also promoted by LTR
      sequences, is a frequent aberration in many mouse mammary tumors of BALB/c mice.
      Given that these retroelements and the placental gene have a common promoter, we
      hypothesized that the tumors also express the gene. Northern blot analysis and RT
      PCR revealed high expression of the placenta-specific gene in BALB/c mouse
      mammary preneoplasias and carcinomas of diverse etiologies, but not in normal
      mammary gland from virgin, pregnant and lactating mice. The preneoplasias and
      tumors expressed two transcripts, one of which is apparently unique to the
      mammary lesions. The other transcript is the same as one expressed in placenta
      that is not promoted by the IAP LTR. Despite the parallel expression of the
      placental gene and IAPs in the mammary tissues, RT-PCR showed that LTR sequences
      are absent from tumor-associated MIPP transcripts. Southern analysis revealed no
      gross mutations of the MIPP gene in mammary preneoplasias and tumors. The ectopic
      expression of the placenta-specific gene in BALB/c mouse mammary preneoplasias
      and carcinomas raises the possibility that it acts as an oncogene.

PMID- 8668349
TI  - Expression of dominant negative CREB reduces resistance to radiation of human
      melanoma cells.
AB  - u.v.-responsive element (URE)-binding proteins were found to include members of
      the AP1 and ATF transcription factor families. To elucidate the functional
      contribution of URE-bound proteins to the characteristics of human melanoma, we
      have used a dominant negative CREB cDNA which is mutated within the DNA-binding
      domain and cloned into a mammalian expression vector driven by the RSV promoter
      (KCREB). As such, KCREB is still capable of heterodimerizing with its associated
      proteins, yet, due to its poor binding affinity to DNA it out competes
      transcriptional activity mediated by those proteins. Human melanoma cells (MeWo)
      were transfected with KCREB and three clones, designated K1, K2, and K10 which
      express KCREB transcripts were then selected for further characterization. When
      tested for binding activities in gel shift assays, proteins prepared from the
      three clones exhibited a different set of complexes than the parent MeWo and
      control MeWo(neo) cells (transfected with empty expression vector) under normal
      growth conditions, and after u.v.-irradiation. Using CAT vector, driven by a
      tetramer URE construct, revealed a striking decrease in transcriptional activity
      in each of the three clones before as well as after u.v.-irradiation. When tested
      for radiation resistance MeWo cells were found to exhibit 42% survival to a u.v.
      dose of 16 J/m2, whereas, K1, K2 and K10 exhibited only 10.2, 3.9 and 4.2%
      survival, respectively. Exposure to 2 Gy of X-radiation led to 62.1% survival of
      MeWo as compared with 18.5% of K1 and 7.7% and 6.5% of K2 and K10, respectively.
      While no significant differences were noticed in their growth rate, all three
      clones exhibited fewer, and smaller colonies in soft agar, when compared with
      parent cells. These findings indicate that through their transcriptional
      activities, CREB and its associated proteins play an important role in the
      acquisition of characteristic phenotypes of human melanoma cells including
      resistance to u.v.-irradiation.

PMID- 8668352
TI  - Molecular biology of normal development, malignancy and its suppression.

PMID- 8668353
TI  - Effects of functional electrical stimulation on the joints of adolescents with
      spinal cord injury.
AB  - Nineteen adolescent subjects with complete spinal cord injuries resulting in
      paraplegia or tetraplegia participated in a functional electrical stimulation
      (FES) program consisting of computerized, controlled exercise and/or weight
      bearing. The effects of stimulated exercise and standing/walking on the lower
      extremity joints were prospectively studied. Plain radiographs and MRIs were
      obtained prior to and following completion of the exercise and standing and
      walking stages. In addition, the joints of five subjects were studied with
      synovial biopsies, arthroscopy, and the analysis of serum and synovial fluid for
      a 550 000 dalton cartilage matrix glycoprotein (CMGP). Pre-exercise joint
      abnormalities secondary to the spinal cord injury improved following the
      stimulation program. None of the subjects developed Charcot joint changes. Upon
      standing with FES, one subject with poor hip coverage prior to participation
      developed hip subluxation which required surgical repair. No other detrimental
      clinical effects occurred in the lower extremity joints of subjects participating
      in an FES program over a 1-year period.

PMID- 8668354
TI  - Nerve fibres in urothelium and submucosa of neuropathic urinary bladder: an
      immunohistochemical study with S-100 and neurofilament.
AB  - Intravesical administration of drugs has been used commonly in spinal cord injury
      patients to suppress detrusor hyperreflexia (eg oxybutynin, verapamil,
      terodiline) or, to initiate a micturition reflex (eg 15S 15-methyl prostaglandin
      F2 alpha, protaglandin E2); however, the response has been variable and
      sometimes, unpredictable. This prompted us to study the presence of nerve fibres
      in the vesical urothelium and submucosa in mucosal biopsies taken from the dome
      and trigone (obtained prior to performing a therapeutic procedure eg, vesical
      lithotripsy, or a diagnostic cystoscopy) in 47 consecutive, unselected
      paraplegic/tetraplegic patients with a neuropathic urinary bladder. Nerve fibres
      were demonstrated by routine immunohistochemical technique using commercially
      available monoclonal and polyvalent antibodies against S-100 (DAKO A/S, Glostrup,
      Denmark) and Neurofilament (MILAB, Malmo, Sweden). Biopsy specimens were graded
      for the presence of nerve fibres on a 0-3 scale for urothelium, and
      superficial/deep submucosa separately in a blind and randomised manner. Virtually
      no fibre presence was found in one paraplegic patient and no superficial or
      single fibres were noted in a tetraplegic patient. Absence of C-fibre hyperplasia
      (Grade 0) was found in nine cases (paraplegic: 4; tetraplegic: 5); Grade 1
      hyperplasia was observed in 17 cases (paraplegic: 4; tetraplegic: 13); Grade 2
      hyperplasia was seen in 11 cases (paraplegic: 7; tetraplegic 4); and Grade 3
      hyperplasia was noticed in eight cases (paraplegic 3: tetraplegic: 5). The
      magnitude of C-fibre hyperplasia was not significantly different between
      paraplegic and tetraplegic patients (chi(2) = 4.64; P = 0.3262). The
      relationship, if any, between the degree of C-fibre hyperplasia and duration of
      paralysis was studied by categorising patients as < 5 years, and > 5 years of
      paralysis. No evidence of single fibre or fibre bundle hyperplasia (Grade 0) was
      seen in five and six cases, grade 1 hyperplasia in six and 11 cases, grade 2
      hyperplasia in two and nine cases, and grade 3 hyperplasia in three and five
      cases respectively in these two categories of patients. (chi(2) = 1.92; P =
      0.58). The possible relationship between C-fibre hyperplasia in the vesical
      mucosa/submucosa and (i) the vesical response to intravesical drug
      administration; (ii) the vesical urothelial proliferation arrest; (iii) the
      electrical stimulation of urinary bladder by implanted electrodes (sacral
      anterior root stimulator); and (iv) long-term indwelling urethral Foley catheter
      drainage, are discussed with illustrative case reports. In conclusion, mucosal
      biopsy and study of nerve fibres in urothelium and submucosa of neuropathic
      bladder has helped to generate hypotheses on the association between C-fibre
      hyperplasia and response to intravesical pharmacotherapy and the predictive value
      of such a study in identifying those patients who are likely to respond to
      intravesical pharmacotherapy.

PMID- 8668356
TI  - Assessment of muscle electrical activity in spinal cord injury subjects during
      quiet standing.
AB  - Disturbed motor control due to a spinal cord lesion is generally considered to be
      the cause of unusual standing utilized by those people suffering from spinal cord
      injury (SCI). Electromyographic (EMG) leg muscle activity during quiet standing
      was analyzed in four functional groups of SCI subjects and compared to the data
      of healthy people. A rating system for visual assessment of the stripchart
      recording was developed and its adequacy was confirmed by comparison of the
      rating system with computerized integrated EMG values of some of the recordings.
      The division of 47 subjects into functional groups was based on their ambulatory
      capabilities ie a non-support group, crutches, cane and walker user groups. Mean
      total muscle EMG activity was the highest in the group of subjects standing
      without support and it was significantly higher when compared to the other groups
      including the control group. Comparison between more and less active legs within
      each group showed significant differences in the non-support and crutches groups,
      whereas cane, walker and control groups showed nearly symmetric EMG patterns
      during standing. Analysis of the contribution of single muscles to the asymmetry
      of standing showed significantly higher activity in hamstring and triceps surae
      muscles than in other muscles in the non-support group. No significant
      differences in the activity of single muscles compared to their contralateral
      pair between more and less active leg were obtained in the remaining groups. It
      is evident, however, that different support devices used by SCI subjects greatly
      influence EMG patterns of postural muscles. The present findings suggest that
      disturbed conduction in the spinal cord is related to altered motor strategies
      employed by SCI subjects in attempts to perform the same volitional act as before
      the injury.

PMID- 8668355
TI  - The Stockholm spinal cord injury study: 4. Psychosocial and financial issues of
      the Swedish annual level-of-living survey in SCI subjects and controls.
AB  - In a series of articles from the Stockholm Spinal Cord Injury Study (SSCIS), the
      health status of a near-total regional SCI population comprising 353 subjects has
      been investigated. The present study describes the psycho-social and financial
      consequences of SCI in this group. It is based on a level-of-living survey that
      has been used annually on 8000-14,000 Swedes since 1974. The health-focused
      version of this survey was used for data collection in the subset of 326 subjects
      in the SSCIS that were residents of the Greater Stockholm area. The normative
      material consisted of 1978 interviews of residents of the same area, provided by
      the Swedish Bureau of Statistics. The results show that SCI subjects, although
      provided with basic material commodities up to par with the general population,
      have less financial reserves and more frequently express worry about their
      finances. Less than half of the subjects are gainfully employed, when part-time
      jobs are also included. Social activities are more restricted, and more centered
      on the core social network. Several items in the survey point to a preoccupation
      with personal rather than public matters. We feel that these factors, at least to
      some degree, are consequential to separation from the workplace, with resulting
      disadvantageous financial and social effects. Intensified vocational
      rehabilitation efforts might thus be justified from both an economic and a psycho
      social point of view.

PMID- 8668357
TI  - An assessment of factors affecting neurological recovery after spinal cord injury
      with vertebral fracture.
AB  - In order to assess some of the variables associated with neurological recovery
      after traumatic spinal cord injury with vertebral fracture, a randomised sample
      of 100 patients (50 without neurological recovery, and 50 with several degrees of
      recovery) were selected out of 245 patients admitted to our hospital. Both groups
      were homogeneous with respect to time lapse to admission, hospitalization time
      and level of lesion. Of the variables considered, the intensity of the lesion
      (incomplete) and vertebral displacement (under 30%) were statistically associated
      with neurological recovery. An age under 30 years at the moment of the injury was
      also associated with neurological recovery but only in those patients with an
      incomplete lesion. No correlation was found between the other variables studied
      such as the degree of vertebral wedging, type of fracture (compression, flexion
      rotation) and management (conservative, surgical) and the neurological evolution.

PMID- 8668358
TI  - The effect of trunk support on performance during arm ergometry in patients with
      cervical cord injuries.
AB  - Earlier studies have shown that the diaphragm might have a postural function that
      could interfere with its respiratory function during arm cycling in patients with
      cervical cord injuries with impaired elbow extension. The purpose of this study
      was to evaluate the effect of trunk support on working performance in such
      patients. Ten patients with low-cervical-cord injuries performed an arm ergometer
      test without and with trunk support with at least one week between the tests. The
      work load averaged 30 (20-50) Watt. Oxygen uptake at steady state averaged 0.71
      +/- 0.09 l/min without trunk support and 0.64 +/- 0.10 l/min with trunk support,
      P < 0.05. There was no difference in blood lactate without or with trunk support.
      Maximum performance time averaged 8.3 +/- 4.3 min without trunk support and 19.5
      +/- 8.8 min with trunk support, P < 0.01. Oxygen saturation tended to decrease
      during work and returned to resting values after termination. This study showed
      that trunk support during arm ergometry in cervical-cord-injury patients with
      impaired elbow extension decreased the energy cost during sub-maximal work and
      increased the time to perform work. The results indicate that trunk stabilisation
      might improve performance of activities of daily living and that it should also
      be considered during exercise affecting the postural balance of these patients.

PMID- 8668359
TI  - Sacral insufficiency stress fracture as etiology of positional autonomic
      dysreflexia: case report.
AB  - The medical literature is replete with case reports of the syndrome known as
      autonomic dysreflexia. Although the majority of cases are known to be induced by
      either bladder or bowel distention. there does exist a small number of cases in
      which the inciting stimulus is more obscure. In such cases, a comprehensive
      medical evaluation is necessary to ensure proper identification of the source of
      irritation and the appropriate medical management of the patient. We present a
      patient with a heretofore unreported suspected etiology of autonomic dysreflexia,
      axial loading of a sacral stress fracture.

PMID- 8668360
TI  - Delayed central cord syndrome after a handstand in a child: case report.
AB  - We report a case of a central cord syndrome in a 7 year-old girl. After several
      handstands, with sudden upper thoracic back pain and weakness of the legs 2 to 3
      h later, then rapidly progressive tetraplegia with apnea. Plain X-rays and CT
      myelography of the cervical spine revealed no abnormalities. Although the initial
      neurological deficit was severe enough to require the child to be placed on a
      mechanical ventilator, she recovered to be able to walk on the 24th hospital day.
      Since the development of a central cord syndrome after handstands is exceptional
      in a child with a normal cervical spine, we report here briefly.

PMID- 8668361
TI  - Percutaneous endoscopic gastrostomy.

PMID- 8668363
TI  - [A study evaluating the correlation between the phenotype and genotype among 65
      cystic fibrosis patients].
AB  - Among 65 CF diagnosed patients with both CFTR gene mutations known genotype
      phenotype studies were performed. Correlation between pancreatic insufficiency
      and so called "severe mutations" was found. Respiratory tract symptoms do not
      seem to depend on one specific mutation as well as meconium ileus is not only
      limited to the group of patients with delta F508/delta F508 genotype. Some other
      genotype - clinical features correlation in CF patients are discussed.

PMID- 8668362
TI  - [The type and frequency of mutations in CFTR gene occurrence in patients with
      cystic fibrosis in Poland--implication of results obtained from genetic
      counseling and diagnostic screening].
AB  - Results of the study on mutations in the CFTR gene in Polish population were
      presented. Among 19 studied only 6 mutations were identified, and its frequency
      established. Molecular study as a routine diagnostic procedure in cystic fibrosis
      is proposed.

PMID- 8668365
TI  - [Comparison of study results for levels of specific antibodies using the RAST-IgE
      method and specific bronchial provocation in children with asthma].
AB  - The aim of the study was to evaluate the diagnostic power of specific-IgE
      evaluation in diagnosis of allergy to house dust mite (Dermatophagoides
      pteronyssinus, D.pt.), in relation to specific bronchial challenge. In a group of
      99 children with perennial asthma, specific-IgE evaluation and bronchial
      challenge were performed with D.pt. allergens. The bronchial challenge was
      positive in 52 cases (53%). RAST results were concordant with bronchial challenge
      from 61% (for classes > or = 1) to 75% (for specific-IgE level > 9.5 PRU/ml). The
      sensitivity for RAST class 1 was 88%, but its specificity did not exceed 30% as
      opposed to 54% and 91%, respectively for class 4. The best overall concordance
      would be obtained with RAST class 3-4 or a specific IgE level of at least 9.5
      PRU/ml but 25% would still be discordant and distributed among false-negatives
      and false-positives, for whom outside bronchial challenges, a sure diagnosis
      cannot be guaranteed.

PMID- 8668366
TI  - [Pneumocystis pneumonia in light of personal observations].
AB  - During a period of 10 months, 87 children with Pneumocystis carinii pneumonia
      accompanied transient cellular immunity disorders and with normal humoral
      immunity were observed. It is suggested that change the invasiveness of the
      parasite has changed. The necessity of taking into consideration a pneumocystis
      etiology in diagnosis of respiratory tract diseases among children is pointed
      out.

PMID- 8668364
TI  - [The usefulness of the conduction sweat test in diagnosis of cystic fibrosis].
AB  - In this paper we present a new test for evaluating the conductivity of sweat--an
      alternative to the classic Gibson-Cooke test used in diagnosis cystic fibrosis.
      Comparison of the results of 45 subjects (26 with cystic fibrosis and 19 with
      other diseases) showed a significant correlation between the two tests (r =
      0.923, p < 0.001). The conductometric Wescor test should be included in
      diagnostic procedures for cystic fibrosis.

PMID- 8668367
TI  - [Use of tarflen ventilation tubes in treatment of secretory otitis media in
      children].
AB  - The results of operative treatment of secretory otitis media in 32 children at
      the II Department of Laryngology of the Silesian Medical Academy in Zabrze are
      presented. Ventilation tubes made from a plastic called "tarflen", for temporary
      tympanic cavity drainage and middle ear ventilation were used. Satisfactory
      results confirmed by otomicroscopic, audiometric and tympanometric examinations
      were obtained. It is pointed out that surgical treatment is necessary in chronic
      cases. The possibility of serious complications in case of desistance from this
      kind of treatment are indicated. The quality of Polish ventilation tubes, making
      treatment successful, in emphasized. The problem of difficulties in diagnosing
      secretory otitis media is also presented.

PMID- 8668368
TI  - [Total carnitine level in infants with cystic fibrosis and deficit
      supplementation by means of pharmacologic preparations and diet. Introductory
      remarks].
AB  - Carnitine deficiency in the serum was found in 5 infants with cystic fibrosis,
      impaired liver function and neurological symptoms. Clinical improvement and
      progressive normalization of the carnitine level in the serum, as well of the
      biochemical parameters of liver function were obtained after enteral
      pharmacotherapy and a carnitine-rich diet.

PMID- 8668369
TI  - [Plasma proteinase inhibitors and their clinical significance].

PMID- 8668370
TI  - [Use of echocardiographic examination for infective endocarditis].
AB  - Echocardiography, both transthoracic and transesophageal techniques, is the
      procedure of choice in the diagnosis and management of patients with
      endocarditis. First of all, vegetative lesions can be detected. Echocardiography
      also plays a major role in recognition of such complications of endocarditis as:
      perivalvular abscesses, aneurysms, fistulas, rupture of valvular leaflets,
      chordae and papillary muscles or the interventricular septum. It provides useful
      information on valve destruction, severity of insufficiency, prosthetic valve
      dysfunction and, finally, it provides a chance for optimal medical and surgical
      therapy.

PMID- 8668371
TI  - [Occurrence of dentinogenesis imperfecta hereditaria (Capdepont's disease) in
      four successive generations of one family].
AB  - A case of a 6-year-old girl affected with dentinogenesis imperfecta hereditaria
      is reported. She is a member of the fourth generation of one family with the same
      condition.

PMID- 8668372
TI  - [Cat-scratch disease in two children].

PMID- 8668374
TI  - [Report from the XII European International Conference of the Society for
      Noninvasive Cardiology. 20-22 October 1994, Varese (Italy)].

PMID- 8668373
TI  - [Pneumocystis pneumonia in a newborn].

PMID- 8668375
TI  - [Specialist care in the rehabilitative period of children].

PMID- 8668376
TI  - The rockets' red glare, the bombs bursting in air: fireworks-related injuries to
      children.
AB  - OBJECTIVE: To describe the epidemiology of fireworks-related injuries to children
      treated in a pediatric emergency department. DESIGN: A descriptive study of a
      consecutive series of patients. SETTING: The emergency department of a large
      urban children's hospital. PARTICIPANTS: Children treated for injuries associated
      with fireworks during the 22-year period from 1972 through 1993. RESULTS: Three
      hundred sixteen children were treated for fireworks-related injuries. Ninety-five
      percent of patients were injured during the 3-week period of June 22 to July 14
      during the study years. Seventy-one percent of patients were male, and the
      average age was 8.5 years, with a range of 1 month to 17 years. The child was a
      bystander in 26% of cases, and adult supervision was present in 54% of cases. One
      patient died, and 11% of children required admission to the hospital, with an
      average length of stay of 7.8 days (range, 1 to 37 days). Fifteen children (5%)
      went to the operating room for treatment of injuries. Thirty-three patients (10%)
      had permanent sequelae from their injuries, including 7 children (2%) with
      complete or partial loss of vision in one eye. The eyes were injured in 29% of
      cases, followed by hands and fingers (22%), other head and face sites (18%), and
      lower extremities (16%). The primary injury was a burn in 72% of cases.
      Firecrackers were associated with 42% of injuries, followed by bottle rockets
      (12%), other types of rockets (7%), Roman candles (11%), sparklers (7%),
      fountains (5%), jumping jacks (4%), and class B (illegal) fireworks (4%). Sixty
      seven percent of sparkler-related injuries occurred among children 5 years and
      younger (Fisher's exact test, P = .000002; odds ratio [OR] = 10.00, 95%
      confidence interval 3.52 < OR < 29.24). Permanent sequelae were more common for
      eye injuries caused by rockets than eye injuries caused by other types of
      fireworks (Fisher's exact test, P = .03; OR = 6.72, 95% confidence interval 1.18
      < OR < 38.18). Charges for medical care of a fireworks-related injury averaged
      $1385 per patient (range, $44 to $15 071). CONCLUSIONS: Fireworks are associated
      with serious injuries. Findings of this large consecutive series describe the
      epidemiology of these injuries. Children and their families should be encouraged
      to enjoy fireworks at public fireworks displays conducted by professionals.
      Fireworks for individual private use should be banned.

PMID- 8668377
TI  - Capitation adjustment for pediatric populations.
AB  - OBJECTIVE: The objective of this study is to assess the predictive performance of
      current claims-based capitation adjustment methods for pediatric populations.
      Medicaid programs and other insurers may increasingly use these systems for
      capitation rate setting, physician profiling, and other purposes. METHODS: Five
      leading models, a demographic model, ambulatory care groups, ambulatory
      diagnostic groups, diagnostic cost groups, and payment amounts for capitated
      systems, were tested by using use and expenditure data for children enrolled in
      the Maryland Medicaid program and a private nonprofit health maintenance
      organization in Minnesota. The models were tested at the individual level by
      using multiple regression methods and at the group level by using split-half
      validation to create both random and nonrandom groups. One of the nonrandom
      groups was created to represent children with chronic conditions. RESULTS: The
      findings indicate that although each of the alternative methods offers an
      improvement over a demographic model, significant underpayment remained for high
      risk children, regardless of the capitation adjustment method used. CONCLUSIONS:
      It is concluded that children with chronic conditions would probably remain at
      risk for discrimination in a competitive health care market under all models
      tested. Limitations associated with current alternatives suggest the need for
      further research in the area of pediatric capitation adjustment methods.

PMID- 8668378
TI  - Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury.
AB  - OBJECTIVE: This article reviews the biochemistry and function of xanthine
      dehydrogenase (XDH) and xanthine oxidase (XO) as well as their role in hypoxia
      reoxygenation injury. Possible benefits of XO blockade are discussed.
      METHODOLOGY: The available literature was reviewed. RESULTS: It is evident that
      relatively high activities of XO are restricted to a few organs in man. Because
      positive effects of XO blockade with allopurinol have been reported even in
      organs containing relatively low activities of XO, two other possible favorable
      actions of allopurinol are mentioned. First it may act as an oxygen radical
      scavenger, and second, it may augment the adenine nucleotides and, hence,
      adenosine triphosphate concentration in the cell. CONCLUSIONS: XDH and XO may
      play an important role in a series of pathophysiologic conditions. Their role in
      hypoxia-reoxygenation injury has been critically reviewed. However, care should
      be exercised in starting randomized trials to prevent hypoxia-reoxygenation
      injury with allopurinol, especially in newborn infants. SPECULATION: XDH and XO
      are released from the liver during hypoxic conditions, for instance, and
      consequently, they may reach a number of organs via the circulation.

PMID- 8668379
TI  - Section on Urology: report of the annual meeting, San Francisco, California,
      1995.

PMID- 8668380
TI  - Changing the US polio immunization schedule would be bad public health policy.

PMID- 8668381
TI  - Poliovaccine policy--time for a change.

PMID- 8668382
TI  - Is the "therapeutic orphan" about to be adopted?

PMID- 8668383
TI  - Tuberculosis skin testing: new schools of thought.

PMID- 8668385
TI  - Does supine sleeping cause asymmetric heads?

PMID- 8668384
TI  - If too much of a good thing is bad, is too much of a bad thing BPD?

PMID- 8668386
TI  - Histiocytic necrotizing lymphadenitis with autoimmune phenomena and meningitis in
      a 14-year-old girl.

PMID- 8668387
TI  - Ceftriaxone choledocholithiasis.

PMID- 8668388
TI  - The management of opioid and benzodiazepine dependence in infants, children, and
      adolescents.

PMID- 8668389
TI  - Use and abuse of the Apgar score. Committee on Fetus and Newborn, American
      Academy of Pediatrics, and Committee on Obstetric Practice, American College of
      Obstetricians and Gynecologists.
AB  - This is a revised statement published jointly with the American College of
      Obstetricians and Gynecologists that emphasizes the appropriate use of the Apgar
      Score. The highlights of the statement include: (1) the Apgar Score is useful in
      assessing the condition of the infant at birth; (2) the Apgar score alone should
      not be used as evidence that neurologic damage was caused by hypoxia that results
      in neurologic injury or from inappropriate intrapartum treatment; and (3) an
      infant who has had "asphyxia" proximate to delivery that is severe enough to
      result in acute neurologic injury should demonstrate all of the following: (a)
      profound metabolic or mixed acidemia (pH < 7.00) on an umbilical arterial blood
      sample, if obtained, (b) an Apgar score of 0 to 3 for longer than 5 minutes, (c)
      neurologic manifestation, eg, seizure, coma, or hypotonia, and (d) evidence of
      multiorgan dysfunction.

PMID- 8668390
TI  - Unapproved uses of approved drugs: the physician, the package insert, and the
      Food and Drug Administration: subject review. American Academy of Pediatrics
      Committee on Drugs.
AB  - Physicians who prescribe a new drug that has not been approved for a specific
      indication or a specific age group frequently find themselves in a quandary.
      Physicians who prescribe "old," time-honored drugs usually do not consult the
      package insert or search for US Food and Drug Administration (FDA) approval. This
      statement was written to clarify the legal and informational status of the
      package insert and the role of the FDA in approving or not approving drugs for
      specific indications or specific age groups. The unapproved use of approved
      drugs, or so-called "off-label" use, is extremely prevalent among physicians who
      care for children. It is important that such use of compounds be brought up to
      date with current FDA policies and to emphasize the responsibility of the
      prescribing physician in the use of these compounds.

PMID- 8668391
TI  - The role of the pediatrician in implementing the Americans with Disabilities Act:
      subject review. American Academy of Pediatrics Committee on Children with
      Disabilities.
AB  - In this statement, the American Academy of Pediatrics reaffirms the importance of
      the Americans With Disabilities Act (ADA), which guarantees people with
      disabilities certain rights to enable them to participate more fully in their
      communities. Pediatricians need to know about the ADA provisions to be able to
      educate and counsel their patients and patients' families appropriately. The ADA
      mandates changes to our environment, including reasonable accommodation to the
      needs of individuals with disabilities, which has application to schools,
      hospitals, physician offices, community businesses, and recreational programs.
      Pediatricians should be a resource to their community by providing information
      about the ADA and the special needs of their patients, assisting with devising
      reasonable accommodation, and counseling adolescents about their expanded
      opportunities under the ADA.

PMID- 8668392
TI  - Ethics and the care of critically ill infants and children. American Academy of
      Pediatrics Committee on Bioethics.
AB  - The ability to provide life support to ill children who, not long ago, would have
      died despite medicine's best efforts challenges pediatricians and families to
      address profound moral questions. Our society has been divided about extending
      the life of some patients, especially newborns and older infants with severe
      disabilities. The American Academy of Pediatrics (AAP) supports individualized
      decision making about life-sustaining medical treatment for all children,
      regardless of age. These decisions should be jointly made by physicians and
      parents, unless good reasons require invoking established child protective
      services to contravene parental authority. At this time, resource allocation
      (rationing) decisions about which children should receive intensive care
      resources should be made clear and explicit in public policy, rather than be made
      at the bedside.

PMID- 8668393
TI  - Eye examination and vision screening in infants, children, and young adults.
      American Academy of Pediatrics Committee on Practice and Ambulatory Medicine,
      Section on Ophthalmology.

PMID- 8668394
TI  - Recommended childhood immunization schedule. American Academy of Pediatrics
      Committee on Infectious Diseases.

PMID- 8668395
TI  - Mantoux test in Kawasaki disease.

PMID- 8668396
TI  - Treatment of lead-exposed children.

PMID- 8668397
TI  - Treatment of lead-exposed children.

PMID- 8668398
TI  - "Back to sleep" program.

PMID- 8668399
TI  - Bilirubin problem--the debate continues.

PMID- 8668400
TI  - Lumbar puncture in meningitis?

PMID- 8668401
TI  - Lumbar puncture in meningitis?

PMID- 8668402
TI  - Teaching deficit disorder.

PMID- 8668403
TI  - Steroids and asthma.

PMID- 8668404
TI  - Steroids and asthma.

PMID- 8668405
TI  - Steroids and asthma.

PMID- 8668406
TI  - Does quality of care affect rates of hospitalization for childhood asthma?
AB  - BACKGROUND: Hospitalization rates for childhood asthma are three times as high in
      Boston, Massachusetts, as in Rochester, New York; New Haven, Connecticut, rates
      are intermediate. We undertook this study to determine how care for children
      admitted for asthma varies across these communities. METHODS: We performed a
      community-wide retrospective chart review. We reviewed a random sample of all
      asthma hospitalizations, from 1988 to 1990, of children 2 to 12 years old living
      in these communities (n = 614). Abstracted data included demographics, illness
      severity, and treatment before admission. RESULTS: Compared with Rochester
      children, Boston children were less likely to have received maintenance
      preventive therapy (inhaled corticosteroids or cromolyn [odds ratio (OR), 0.4
      (0.2, 0.9)]), acute "rescue" therapy (oral corticosteroids [OR, 0.2 (0.1, 0.4)]),
      or inhaled beta-agonist therapy [OR, 0.5 (0.3, 1.0)]. A larger proportion of
      admitted asthmatic patients in Boston (34%) were in the least severely ill group
      oxygen saturation 95% or above-compared with patients in Rochester (20%).
      CONCLUSIONS: The quality of ambulatory care, including choice of preventive
      therapies and thresholds for admission, likely plays a key role in determining
      community hospitalization rates for chronic conditions such as childhood asthma.

PMID- 8668407
TI  - Changes in intubation rates and outcome of very low birth weight infants: a
      population-based study.
AB  - OBJECTIVE: There have been indications of a recent decrease in intubation rates
      of very low birth weight (VLBW) infants in Germany. We wanted to quantify this
      decrease and analyze its effect on clinical outcome. METHODS: Population-based
      data on the treatment and outcome at hospital discharge from a statewide quality
      assurance program were analyzed for 2001 VLBW infants (500 to 1499 g) born from
      1992 to 1994 in Lower Saxony, North Germany. RESULTS: The proportion of patients
      not intubated and mechanically ventilated increased from 7% to 14% in infants
      less than 1000 g and from 28% to 44% in those greater than or equal to 1000 g (P
      < .02 and < .01, respectively). This increase was not associated with any
      significant increase in adverse outcome such as death, intraventricular
      hemorrhage, periventricular leucomalacia, or bronchopulmonary dysplasia (BPD).
      Instead, there was an increase in the proportion of infants less than 1000 g who
      survived without BPD (from 38% in 1992 to 48% in 1994; P < .05) and a decrease in
      the proportion of infants greater than or equal to 1000 g in whom BPD developed
      (from 14% to 9%; P < .05). CONCLUSIONS: The data from a statewide quality
      assurance program show a significant reduction in the aggressiveness of the
      treatment of VLBW infants, which was not associated with an increased mortality
      or morbidity. This observational study, however, cannot define whether a more
      selective approach to the intubation of VLBW infants will ultimately result in a
      better outcome. A randomized, controlled trial would be required to answer this
      clinically important question.

PMID- 8668408
TI  - Routine emergency department use for sick care by children in the United States.
AB  - BACKGROUND: The use of the emergency departments as a regular source of sick care
      has been increasing, despite the fact that it is costly and is often an
      inappropriate source of care. This study examines factors associated with routine
      use of emergency departments by using a national sample of US children. METHODS:
      Data from the 1988 National Health Interview Survey on Child Health, a nationally
      representative sample of 17710 children younger than 18 years, was linked to
      country-level health resource data from the Area Resource File. Bivariate and
      multivariate analyses were used to assess the association between children's use
      of emergency departments as their usual sources of sick care and predisposing
      need and enabling characteristics of the families, as well as availability of
      health resources in their communities. RESULTS: In 1988 3.4% or approximately 2
      million US children younger than 18 years were reported to use emergency
      departments as their usual sources of sick care. Significant demographic risk
      factors for reporting an emergency department as a usual source of sick care
      included black versus white race (odds ratio [OR], 2.08), single-parent versus
      two-parent families (OR, 1.53), mothers with less than a high school education
      versus those with high school or more (OR, 1.76), poor versus nonpoor families
      (OR, 1.76), and living in an urban versus suburban setting (OR, 1.38). Specific
      indicators of need, such as recurrent health conditions (asthma, tonsillitis,
      headaches, and febrile seizures), were not associated with routine use of
      emergency departments for sick care. Furthermore, health insurance status and
      specifically Medicaid coverage had no association with use of the emergency
      department as a usual source of sick care. Compared with children who receive
      well child care in private physicians' offices or health maintenance
      organizations, children whose sources of well child care were neighborhood health
      centers were more likely to report emergency departments for sick care (OR,
      2.01). Children residing in counties where the supply of primary care physicians
      was in the top quintile had half the odds (OR, 0.50) of reporting emergency
      departments as usual sources of sick care. CONCLUSIONS: Reliance on hospital
      emergency departments for routine sick care is strongly associated with
      demographic and social characteristics of the child and family, the type and
      source of available well child care, and the supply of primary care physicians.
      Because health insurance status was not a significant predictor of use, public
      policies aimed at reducing the use of emergency departments by children will need
      to address other factors. These include the organizational characteristics and
      responsiveness of the health care system and the motivation of families for
      routine use of hospital emergency departments.

PMID- 8668410
TI  - Thyroid screening for early discharged infants.
AB  - OBJECTIVE: As neonatal discharge before 24 hours of life becomes commonplace, the
      rejection of congenital hypothyroidism (CH) screening specimens obtained too
      early has created the need for numerous additional tests. We sought to determine
      whether the specimens obtained before 24 hours could be used safely. METHODS:
      During a 31-day period we measured thyrotropin in all thyroid-screening specimens
      that had been obtained before 24 hours. We also examined the early specimens from
      every infant diagnosed in New Jersey with CH during 1993 or 1994. RESULTS: Among
      the 663 specimens, those obtained at or before 12 hours and those from infants
      with birth weights less than 2500 g had too many low thyroxine results to be
      useful. Among the 515 specimens obtained at more than 12 to 24 hours from
      newborns weighing 2500 g or more, 37 (7%) had low thyroxine levels and 12 (2.3%)
      had thyrotropin levels of 20 microIU/mL (mU/L) or higher. Four hundred seventy
      one of the 515 infants had subsequent specimens obtained at more than 24 hours,
      and none of the results were abnormal. There was no child weighing more than or
      equal to 2500 g who was diagnosed with CH in 1993 and 1994 whose specimen
      obtained at 24 hours or less was normal. CONCLUSIONS: Accepting specimens
      obtained at more than 12 to 24 hours from infants weighing 2500 g or more would
      have resulted in more than the usual number of false-positive results but no
      false-negative results. This would have decreased the requests for additional
      specimens by more than 90%.

PMID- 8668409
TI  - A randomized trial of the effect of dust control on children's blood lead levels.
AB  - OBJECTIVE: Dust control is recommended as one of the cornerstones of controlling
      childhood lead exposure; however, the effectiveness of dust control has not been
      demonstrated for children who have low to mild elevations in blood lead (ie, less
      than 25 micrograms/dL). The objective of this study was to determine whether dust
      control, as performed by families, had an effect on children's blood lead levels
      and dust lead levels in children's homes. DESIGN: Randomized, controlled trial.
      SETTING: Community-based trial in Rochester, NY. PARTICIPANTS: One hundred four
      children, 12 to 31 months of age at baseline. INTERVENTION: Families and children
      were randomized to one of two groups. Families of children in the intervention
      group received cleaning supplies, information about cleaning areas that are often
      contaminated with lead, and a cleaning demonstration. Families in the control
      group received only a brochure about lead poisoning prevention. OUTCOME MEASURES:
      Baseline measurements of lead in blood, house dust, soil, water, and paint were
      taken from both groups. Seven months after enrollment, a second blood lead assay
      was obtained, and lead levels in household dust were measured. The main outcome
      measures were change in blood lead levels and dust lead levels by treatment
      group. RESULTS: The median blood lead level of children enrolled in the study was
      6.7 micrograms/dL (range, 1.7 to 30.6 micrograms/dL). There was no significant
      difference in the change of children's blood lead levels or dust lead levels by
      treatment group. The median change in blood lead levels among children in the
      intervention group was -0.05 micrograms/dL compared with -0.60 micrograms/dL
      among those in the control group. There also was no significant difference in the
      change of dust lead by group assignment, although there was a trend toward a
      significant difference in the percentage of change in dust lead levels on
      noncarpeted floors, which was greater among houses in the intervention group.
      CONCLUSIONS: These data suggest that an intervention that consists only of
      providing cleaning supplies and a brief description of dust control is not
      effective at reducing blood lead levels among urban children with low to mild
      elevations in blood lead levels at a 7-month follow-up.

PMID- 8668411
TI  - Efficacy of glucose-based oral rehydration therapy.
AB  - OBJECTIVE: This article reviews and synthesizes evidence in the published
      literature on the safety and efficacy of oral rehydration therapy (ORT) among
      young children with pediatric gastroenteritis in developed nations. METHODOLOGY:
      We searched the literature for randomized, controlled trials comparing the safety
      and efficacy of ORT with intravenous (IV) rehydration treatment and/or oral
      rehydration solutions (ORSs) of different sodium content. We combined the failure
      rates of each set of studies in statistical meta-analyses and conducted tests of
      homogeneity of treatment effect over all the studies and for subgroups of
      children defined by the trial type, the sodium content of the ORS, and the
      setting of care. We also conducted a multivariate logistic regression on the
      probability of failure to determine the relative importance of these factors,
      controlling for other characteristics of the trials. Other outcomes were also
      tabulated and discussed. These include the relative incidence of hypernatremia
      and hyponatremia induced by treatment; weight gain; the volume, frequency, and
      duration of diarrhea; for inpatient trials, the length of stay; and for
      outpatient trials, rates of hospitalization. RESULTS: The evidence suggests that
      among pediatric patients with gastroenteritis in developed countries, failure of
      ORT, defined as the need to rehydrate children intravenously, is infrequent. We
      found a combined overall ORT failure rate of 3.6%. We found no statistically
      significant difference in failure rates by trial type or the sodium content of
      the ORS. However, we did find some supporting evidence for a lower failure rate
      among children treated in outpatient settings. In addition, compared with
      patients rehydrated intravenously, pediatric patients treated with ORT were not
      found to be at higher risk of iatrogenic hypernatremia or hyponatremia. The
      evidence from the literature fails to show a consistent trend in favor of either
      high- or low-sodium solutions for rehydration of pediatric patients. CONCLUSIONS:
      There seems to be a great potential for improving the medical treatment of
      children with acute gastroenteritis by the greater use of ORT.

PMID- 8668412
TI  - Promoting sun awareness: evaluation of an educational children's book.
AB  - OBJECTIVE: To assess the value of early childhood education as a means of
      increasing awareness and knowledge about the sun and related skin disease(s).
      METHODS: A children's book promoting sun awareness and protection was developed.
      The next was incorporated into the health education curriculum of two third-grade
      classrooms (n = 82). The students completed a questionnaire before, immediately
      after, and 6 weeks after reading the text. Student sun awareness knowledge was
      compared using descriptive statistics and paired T-tests. RESULTS: Behaviors and
      attitudes that resulted in over-exposure to the sun's ultraviolet light were
      common among third-graders. Primary test areas included the sun's effect on skin,
      effective sunscreens, skin type, and skin cancer. Test scores showed a marked
      improvement (40% compared with baseline) in knowledge of sun protection at both
      posttests. Parents represented the greatest source of information for children
      (28 of 82) before this study, while doctors and teachers each accounted for only
      1 of 82. CONCLUSIONS: Preventive measures in childhood have the potential to
      significantly reduce the incidence of sunrelated skin diseases; however,
      education to date has been directed primarily at presents. This study
      demonstrated that an educational book for elementary school students can be an
      effective tool to increase sun awareness and knowledge. The multifaceted approach
      to prevention recommended here is similar to that of the highly successful dental
      care campaign, consisting of direct education of children by physicians,
      teachers, parents, and the media.

PMID- 8668413
TI  - Delayed diagnosis of injury in pediatric trauma.
AB  - OBJECTIVE: To define the frequency and nature of delayed diagnosis of injury
      (DDI) in pediatric trauma. DESIGN: Retrospective review. SETTING: Tertiary
      pediatric trauma center. METHODS: Medical records of 1175 pediatric trauma
      admissions from July 1, 1989, through June 30, 1992, were reviewed. RESULTS:
      Fifty (4.3%) patients had 53 DDI. Fractures accounted for 38 DDI, most commonly
      of the extremities (total, 16). The delay until injury diagnosis ranged from 1 to
      55 (median, 3) days. Patients with DDI had lower scores on the Glasgow Coma
      Scale, higher injury severity scores, and longer pediatric intensive care unit
      and hospital stays than patients without DDI. Patients with DDI more frequently
      required medical transport, emergent intubation, admission to the pediatric
      intensive care unit, and surgery. The DDI altered treatment for 68% of patients;
      10 required surgery, including second operations for 6 children. CONCLUSIONS: DDI
      represents a failure of pediatric trauma care at all levels. The severely injured
      child is at the greatest risk of DDI. All pediatric patients with trauma warrant
      ongoing evaluation to identify initially unrecognized injuries.

PMID- 8668414
TI  - Weight modification efforts reported by black and white preadolescent girls:
      National Heart, Lung, and Blood Institute Growth and Health Study.
AB  - OBJECTIVE: This study tested four hypotheses: (1) a high percentage of 9- and 10
      year-old girls are already trying to lose weight; (2) more white tha black girls
      are trying to lose weight; (3) more black than white girls are trying to gain
      weight; and (4) weight modification efforts of preadolescent girls are influenced
      by factors other than race, such as maternal criticism, body dissatisfaction, and
      socioeconomic status. DESIGN: Cross-sectional analysis of baseline data on 2379
      girls 9 and 10 years of age, which consisted of 1213 black and 1166 white
      enrollees. RESULTS: Black girls were taller and heavier and showed earlier signs
      of puberty than white girls but were less dissatisfied with their weight, body
      shape, and body parts. Approximately 40% of 9- and 10-year-old girls reported
      that they were trying to lose weight. Of those girls classified in the fourth
      quartile of body mass index (BMI), approximately 75% were trying to lose weight.
      After adjusting for BMI, no significant black and white differences in the
      prevalence of those trying to lose weight were seen, but significantly more black
      than white girls were trying to gain weight. Multiple logistic regression
      identified a high BMI, the mother telling her she was too fat, and body
      dissatisfaction as the major factors associated with trying to lose weight.
      However, chronic dieting was only associated with a high BMI and the mother
      telling her she was too fat. An important predictor of girls who were trying to
      gain weight was being black, along with having a low BMI and the mother telling
      her she was too thin. CONCLUSIONS: Attempts at gaining weight are much more
      frequent among black preadolescent girls than their white counterparts. No racial
      difference was found between black and white girls in their efforts to lose
      weight or to practice chronic dieting. Because approximately 40% of 9- and 10
      year-old girls are already trying to lose weight, pediatricians should capitalize
      on this concern by providing information on proper weight control techniques.
      Educational efforts should be directed to both the mother and the child, because
      weight control efforts of preadolescent girls are stimulated by their mothers'
      admonitions of being too fat or too thin. The high prevalence of dieting among
      the thinnest adolescent girls also needs to be addressed by pediatricians.

PMID- 8668415
TI  - Effects of in utero substance exposure on infant neurobehavior.
AB  - OBJECTIVE: This study had two objectives: (1) to assess infant behavior by using
      the NICU Network Neurobehavioral Scale (NNNS), an assessment designed
      specifically for prenatally drug-exposed infants; and (2) to control for the
      effects of polydrug use involving alcohol, marijuana, and cigarettes on the
      neurobehavioral status of the newborn infant. METHODS: The subjects and controls
      in this study were full-term infants of appropriate gestational age with no
      medical problems. At 1 to 2 days of age, 20 infants exposed to cocaine, alcohol,
      marijuana, and cigarettes; 17 infants exposed to alcohol and/or marijuana and
      cigarettes; and 20 drug-free infants were evaluated by using the Neonatal
      Intensive Care Unit Network Neurobehavioral Scale. The data were reduced to
      reflect clinically defined categories of neurobehavioral function and were
      analyzed by using analysis of variance and chi 2 statistics. RESULTS: Cocaine
      exposed infants showed increased tone and motor activity, more jerky movements,
      startles, tremors, back arching, and signs of central nervous system and visual
      stress than unexposed infants. They also showed poorer visual and auditory
      following. There were no differences in how the examination was administered to
      cocaine-exposed and nonexposed infants. Reduced birth weight and length were also
      observed in cocaine-exposed infants. CONCLUSION: Differences attributable to
      cocaine-exposed infants were related to muscle tone and motor performance,
      following during orientation, and signs of stress. However, cocaine-exposed
      infants were not more difficult to test, nor did they require an alteration in
      the examination. Both neurobehavioral patterns of excitability and lethargy were
      observed. Findings may have been due to the synergistic effects of cocaine with
      alcohol and marijuana.

PMID- 8668418
TI  - Alcohol misuse and adolescent sexual behaviors and risk taking.
AB  - OBJECTIVE: The aims of this study were to examine the associations between
      alcohol misuse and measures of early onset sexual activity and sexual risk-taking
      behaviors during adolescence and the extent to which any association between
      these two sets of behaviors could be explained by common risk factors that
      predisposed individuals to both outcomes. METHODS: Data were gathered during the
      course of a 16-year longitudinal study of a birth cohort of 953 New Zealand
      children and included: (1) self-report measures of early onset sexual activity
      (before the age of 16 years), multiple partners (three or more), and unprotected
      intercourse during the interval from 15 to 16 years; and (2) prospectively
      measured risk factors, including social background, childhood adversity, novelty
      seeking, and affiliations with delinquent peers. RESULTS: Adolescents who
      reported misusing alcohol had odds of early onset sexual activity, multiple
      partners, and unprotected intercourse that were 6.1 to 23.0 times those of young
      people who did not misuse alcohol. After adjustment for common or correlated risk
      factors, the adjusted odds ratios between alcohol misuse and early onset sexual
      activity and unprotected intercourse were reduced but remained statistically
      significant. However, no significant association between alcohol misuse and
      multiple partners was found after adjustment for common or correlated risk
      factors. CONCLUSIONS: Much of the apparent association between alcohol misuse and
      teenage sexual activity and risk taking seems to arise through the influence of
      common family, individual, and peer factors. However, alcohol misuse may also
      place teenagers at greater risk of initiating early onset sexual intercourse and
      engaging in unprotected intercourse.

PMID- 8668417
TI  - Prevalence of juvenile chronic arthritis in a population of 12-year-old children
      in urban Australia.
AB  - OBJECTIVE: To conduct a cross-sectional, community-based, point prevalence study
      of inflammatory joint disease and other rheumatic disorders in 12-year-old
      children in a metropolitan community. METHODS: After completion of a pilot study
      of 816 10-year-old children, a cross-sectional prevalence study was performed 2
      years later on a randomized sample of 2241 12-year-old children (including the
      cohort from the pilot study) from a community of approximately 221 700 children
      aged 12 years or younger, with 17 300 children aged approximately 12 years. A
      rheumatologic examination was performed on each child by a single observer after
      perusal of completed questionnaires from parents and children. RESULTS: Three of
      816 children in the pilot study were shown to have juvenile chronic arthritis
      (JCA), fulfilling the criteria of the European League Against Rheumatism for the
      diagnosis of JCA. Only 1 of 3 had a previous diagnosis of JCA. The prevalence was
      3.7 per 1000. Of 2241 children examined 2 years later, 89% returned two
      questionnaires (one completed by the parent and one by the child). At
      examination, 38 swollen joints were identified in 32 children. Nine children were
      identified with JCA, of whom 7 had not had previous diagnoses. No questions from
      the questionnaires identified the 7 children with previously undiagnosed JCA. The
      point prevalence of JCA in this community was 4.0 per 1000. Although the children
      with newly diagnosed cases tended to have mild disease, it was associated with
      significant morbidity and the potential for serious morbidity. CONCLUSIONS: This
      is the first reported prevalence study of JCA in which case ascertainment was
      based on clinical examination by a rheumatologist of children within a community.
      The prevalence of 4.0 per 1000 was significantly higher than the accepted
      prevalence of 0.6 to 1.1 per 1000. A study based on known cases would have
      significantly underestimated the true prevalence of JCA in this community, with 7
      of 9 cases being previously undiagnosed. Questionnaires were not effective in
      identifying children with undiagnosed JCA, clinical examination supported by a
      history from the parent and child providing the only reliable means of diagnosis.
      It is possible throughout the world that the numbers of undiagnosed cases of JCA
      significantly exceed the numbers of known cases with the true prevalence being
      significantly higher than the levels currently accepted.

PMID- 8668416
TI  - Late dose-response effects of prenatal cocaine exposure on newborn
      neurobehavioral performance.
AB  - OBJECTIVE: To determine in a representative sample of full-term urban newborns of
      English-speaking mothers whether an immediate or late dose-response effect could
      be demonstrated between prenatal cocaine exposure and newborn neurobehavioral
      performance, controlling for confounding factors. METHODS: The Neonatal
      Behavioral Assessment Scale (NBAS) was administered by masked examiners to a
      total sample of 251 clinically healthy, full-term infants at 2 days and/or 17
      days. Three in utero cocaine exposure groups were defined: heavily exposed (n =
      44, > 75th percentile self-reported days of use during pregnancy and/or > 75th
      percentile of meconium benzoylecognine concentration); lightly exposed (n = 79,
      less than both 75th percentiles); and unexposed (n = 101, no positive biological
      or self-report marker). At the 3-week examination there were 38 heavily exposed,
      73 lightly exposed, and 94 unexposed infants. Controlling for infant birth
      weight, gestational age, infant age at the time of examination, mothers' age,
      perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use,
      a regression analysis evaluated the effects of levels of cocaine exposure on NBAS
      performance. RESULTS: No neurobehavioral effects of exposure on the newborn NBAS
      cluster scores or on the qualifier scores were found when confounders were
      controlled for at 2 to 3 days of age. At 3 weeks, after controlling for
      covariates, a significant dose effect was observed, with heavily exposed infants
      showing poorer state regulation and greater excitability. CONCLUSIONS: These
      findings demonstrate specific dose-related effects of cocaine on 3-week
      neurobehavioral performance, particularly for the regulation of arousal, which
      was not observed in the first few days of life.

PMID- 8668419
TI  - Tuberculin skin test screening in schoolchildren in the United States.
AB  - OBJECTIVE: To determine the current practices and results of tuberculin skin test
      (TST) screening of schoolchildren in the United States. METHODS: Tuberculosis
      program staff in all states and the District of Columbia were asked about current
      requirements, practices, and results of school-based TST screening. RESULTS:
      Thirty-four states and the District of Columbia (69%) reported no current
      statewide statutes or policies for tuberculin screening of schoolchildren, and 10
      (19%) reported having statewide requirements. In 6 states (12%), requirements
      were instituted at the local level, and 24 localities in these states were known
      to require screening. Of the 34 areas requiring screening, 18 (53%) screened all
      new entrants, 7 (21%) screened children in specific grades, and 9 (26%) used
      other criteria for screening. TST results were collected for 26 (76%) of 34
      areas, and 6 areas collected results of follow-up evaluation of tuberculin
      positive children. Additionally, 8 localities in 7 states with no screening
      requirements conducted tuberculin surveys. Sixteen areas provided results. In 7
      of the 8 areas that collected information about birthplace, less than 2% of US
      born children were tuberculin positive; foreign-born children had rates 6 to 24
      times higher than US-born children. TST screening identified new cases of
      tuberculosis, less than 0.02% of the children screened. CONCLUSIONS: School-based
      tuberculin screening identified low rates of positive TST results in US-born
      children. Resources should be directed toward screening children at high risk for
      tuberculous infection, as recommended by the American Academy of Pediatrics and
      the Advisory Committee for Elimination of Tuberculosis.

PMID- 8668421
TI  - Explanation of illusory contours in terms of strength of pattern and its spread
      effect.
AB  - The generation of illusory contours is closely related to distinct parts of a
      pattern such as dots, line ends, and corner points. On the other hand, the
      remarkable property is that gaze at one point of the contours diminishes the
      illusion and a return of gaze to the whole pattern restores it. Therefore,
      illusory contours depend on local parts and the whole pattern formed by the
      parts, and fitting data on the two aspects is necessary to clarify underlying
      mechanisms. We have obtained such data from the experiments performed to
      elucidate other visual phenomena. On the basis of the data, the concepts of
      strength of pattern, strength of its spread effect, ridgelines of the spread
      effect, and a hollow of the spread effect are introduced and then various
      phenomena on illusory contours, including the Kanizsa triangle, are explained in
      terms of these concepts.

PMID- 8668420
TI  - Evidence for development of distinction of voice onset time in a child with left
      hemisphere lesion.
AB  - Following surgery for partial removal of the posterior left hemisphere at 5 mo.,
      voice onset time was assessed to 9; 11 yr. Left-hemisphere language function
      associated with voicing appeared subsumed by the right hemisphere.

PMID- 8668422
TI  - Cohesion correlates with affect in structured exercise classes.
AB  - Correlations of scores on the Group Environment Questionnaire measuring cohesion
      and the Feeling Scale ranged from .17 to .23 and support Carron's model.

PMID- 8668423
TI  - Learning style consistency across cognitive and motor settings.
AB  - 23 athletes were asked to complete the Learning Styles Inventory first focusing
      on classroom learning, then on learning in their sport. Analysis indicated that
      learning styles shift across cognitive and motor settings. As a result, to ensure
      the validity of the results, giving respondents a particular focus when taking
      the inventory may be necessary. The development of an instrument designed
      strictly for motor skills might be helpful to assess successfully learners'
      profiles for motor skill acquisition.

PMID- 8668424
TI  - In similarity judgments hunter-gatherers prefer shapes over spatial relations in
      contrast to literate groups.
AB  - Reverse strategies are used in judgments of similarity by hunter-gatherers who
      prefer using shapes (attributes) in patterns, and literates who prefer judging
      relations among shapes. The Kohs Block Design Test was given to healthy hunter
      gatherers, 19 stone-age, preliterate, Amazonian Auca Indians and 130 semi
      literate Dani and Asmat of inland Indonesian Western New Guinea. Further, 196
      literate Indonesian city dwellers served as controls. The Auca and the Dani and
      Asmat groups preferentially constructed 20 specific, "nonrandom" modifications
      similar to the Kohs Block Design Test and preserved the salient component shapes
      but neglected relations among them. Hunter-gatherers' survival depends on prompt
      assessment of the salient shapes of prey and attackers. By contrast, literacy
      skills require painstaking assessment of subtle intrapattern spatial relations
      among shapes.

PMID- 8668425
TI  - Measures of status integration in theory of suicide.
AB  - Measures of status integration in 30 American states in 1950 were associated most
      strongly with longitude, divorce rates, and the size of the urban population.

PMID- 8668426
TI  - Figure-ground organization in different phases of the perceptual alternation
      phenomenon.
AB  - Two experiments on figure-ground organization were designed to examine whether
      the regions of an ambiguous stimulus perceived as "figure" vary as a function of
      regional area and experience with the stimulus. In Exp. 1 the perceived duration
      of each interpretation was recorded during continuous viewing for 10 subjects who
      had been trained until both percepts appeared with statistical regularity
      (stationary phase). In Exp. 2 the first interpretation reported by 172 naive
      observers after a few seconds of pattern exposure was recorded. The well-known
      tendency to interpret smaller regions as figure was noted in Exp. 2 whereas the
      results of Exp. 1 suggested equal probability of the percepts. Over-all results
      suggest that alternation is learned during the transient or "early" phase of
      perception, with some stimulus features and cultural factors influencing the
      figure-ground organization. During the stationary or late phase of perception the
      subject is well practiced and the alternating of interpretations becomes largely
      automatic.

PMID- 8668427
TI  - Effect of complexity of a physical task on estimation of time to complete.
AB  - Two studies were performed to examine the effect of the complexity of a physical
      task on the estimation of the time required for its performance. Different
      paradigms for the estimation of time (prospective vs retrospective) were used
      with different methods of estimation (reproduction vs verbal estimation). In
      Study 1, 32 pairs of adults were asked to throw a ball to each other in different
      ways. The two groups were distinguished by the motor and cognitive changes
      required in moving from one task to the next. One group had to perform 10
      successive repetitions on each of five kinds of ball throws, while the other had
      to perform the same number of ball throws but with each type being split into two
      different successive sets of throws so here the task consisted of changes. In
      Study 2, 60 children (aged 7 or 8 yr.) were asked to perform a set of basketball
      tasks. The two groups were distinguished by the pace at which they had to perform
      the task, slowly or rapidly. The results of the two studies indicated a negative
      relation between the complexity of the task and the group's estimation of time.
      The reproductive method yielded shorter estimations than the verbal method. The
      results indicate that for physical activity the attentional model may well be
      valid.

PMID- 8668428
TI  - Relationship of self-concept and social desirability tendency of Hong Kong
      Chinese adults with physical disabilities.
AB  - A study was performed to investigate the relationship of scores on self-concept
      and social desirability of 214 Hong Kong Chinese adults with physical
      disabilities. No significant correlations were found between self-concept and
      social desirability; however, their social desirability scores were significantly
      related to their age, education, and occupational status.

PMID- 8668429
TI  - Simple reaction times and timing of serial reactions of adolescents with mental
      retardation, autism, and Down syndrome.
AB  - The purpose of this study was to examine the serial information processing in
      adolescents with mental retardation, autism, and Down syndrome by using a
      serially patterned tracking task. Analyses indicated that 7 adolescents with
      mental retardation, 8 with autism, and 3 with Down syndrome had significantly
      slower and more variable simple reaction times than did 10 college students.
      Also, the autistic adolescents had significantly faster mean simple reaction time
      than those with Down syndrome. On a task of tracking serial light stimulation,
      mentally retarded adolescents had significantly faster reaction time than college
      students. The autistic subjects excessively had faster anticipatory reaction time
      than did the subjects in the other three groups. On the other hand, adolescents
      with Down syndrome had markedly slower and more variable reaction time than did
      adolescents with non-Down-syndrome mental retardation. As for motor organization
      of keystrokes on the tracking task, mentally retarded adolescents responded with
      six movements, in which these individuals pressed a series of keys 1, 2, 3, 4, 5,
      and 6, as a chunk, as exhibited by college students. Adolescents with autism and
      Down syndrome, however, did not produce this movement-output chunking.

PMID- 8668430
TI  - Preschool children's comprehension of the world "handicapped".
AB  - A group of 4- and 5-yr.-old children were asked the meaning of the word
      "handicapped," while another group were asked the meaning of a nonsense word.
      Five of 15 children claimed to know the meaning of "handicapped" but none could
      supply a factual definition. Two of 15 children in the comparison group claimed
      to know the meaning of the nonsense word. Despite their lack of knowledge,
      children in both groups continued to answer questions regarding their attitudes
      toward the word. The results cast doubt on the effective use of verbal measures
      of attitudes toward persons with disabilities when the subjects are preschool
      children.

PMID- 8668431
TI  - Sources of variance affecting receipt of aggression.
AB  - 36 boys and 33 girls from a suburban high school and 24 boys and 22 girls from an
      inner-city high school rated the frequency with which four other people hit or
      kicked them during the year. The four people were a brother, sister, non-family
      male (with whom they fought most during the year), and nonfamily female (with
      whom they fought most during the year). When responses were dichotomized into
      "hit" versus "not hit" by a particular person during the year, there was no
      effect of environment (suburban vs inner-city). The percentage of boys reporting
      being hit by girls was higher than the percentage of girls reporting being hit by
      girls. People with siblings were more likely to report being hit by them than by
      a nonfamily member (although frequency of contact might account for this
      finding).

PMID- 8668432
TI  - Task-specific conjugate lateral eye movements.
AB  - Conjugate lateral eye movements induced by task-specific reflective thought were
      examined in 10 dextral men. Verbal and spatial stimuli designed to activate
      reflective thought in the left (verbal) and right (spatial) cerebral hemispheres
      of the brain were presented tachistoscopically in a darkened environment. Eye
      movements during reflective thought were monitored and scored using an infrared
      eye-tracking device. Reflective thought induced by the spatial task produced
      significantly more leftward conjugate lateral eye movement. The verbal task
      tended to produce more rightward and upward movements. The results are viewed as
      consistent with a task-specific brain-hemispheric activation model of
      contralateral conjugate eye movements during reflective thought.

PMID- 8668433
TI  - Reexamining the Snodgrass and Corwin 1988 picture identification norms.
AB  - Snodgrass and Corwin (1988) provided a database of 150 fragmented pictures
      identified by subjects only 35% of the time. However, recent research by Koch,
      Abbey, and Schmidt in 1995 with these pictures has yielded higher identification
      rates. The present study examined the difference in identification rates between
      Koch, et al., 1995 and Snodgrass and Corwin in 1988. 85 subjects were given 25
      min. to identify all 150 pictures from Snodgrass and Corwin. Of the 150 pictures,
      95 were identified more than 35% of the time. Since Snodgrass and Corwin used an
      implicit-learning task while the present study used an object-identification
      task, the present findings suggest that identification rates may be specific to
      the type of object-recognition task employed.

PMID- 8668434
TI  - Computerized information retrieval: individual differences in the use of spatial
      vs nonspatial navigational information.
AB  - Although a number of experiments have demonstrated the importance of spatial
      ability as a predictor of computer-based performance, there is little evidence
      relating to the mechanics of this association or the implications for interface
      design. Two experiments on the relative importance of spatial and nonspatial
      semantic information within the context of computerized information retrieval are
      described. The first experiment indicated that spatial ability did not interact
      with the spatial information content of the computer interface. The second
      experiment indicated that the effects of spatial ability are attenuated when
      additional nonspatial semantic information is provided.

PMID- 8668435
TI  - Primacy and recency in recognition of odours and recall of odour names.
AB  - This study examined the serial position curve for recognition of odours and
      recall of odour names, both with and without instructions for verbal elaboration.
      Participants were allocated to one of two experimental conditions, either with
      instructions to rehearse verbally the stimuli or with no elaboration
      instructions. After presentation of 17 odours, either recognition or free recall
      of the odours was tested immediately after presentation of the last target odour.
      Recognition showed evidence of primacy for the verbal elaboration condition and
      recency for both instruction conditions. Recall of odour names showed evidence of
      primacy for the verbal elaboration conditions and recency for both conditions.
      Instructions to verbalize did not significantly affect over-all performance for
      either test condition.

PMID- 8668436
TI  - Distinguishing suicide notes from completed and attempted suicides.
AB  - Four experienced raters of suicide notes were unable to distinguish suicide notes
      from 20 completers and 20 attempters at a level better than chance.

PMID- 8668438
TI  - Rates of problem behaviour among preschoolers attending nursery classes in St.
      Helena, South Atlantic.
AB  - The Preschool Behaviour Checklist was used to assess rates of problem behaviour
      among 59 preschoolers on St. Helena. The prevalence rate (6.8%) and mean scores
      obtained are among the lowest found world-wide for similarly aged children.

PMID- 8668437
TI  - Acceptable levels of tonal and broad-band repetitive and continuous sounds during
      the performance of nonauditory tasks.
AB  - Three groups of 24 subjects were exposed to a 1000-Hz tone or broad band noise in
      a sound chamber. During the exposures subjects were engaged in an easy reaction
      time test or a difficult grammatical reasoning test. For each exposure and work
      subjects adjusted the noise to a tolerance level defined by its interference with
      task performance. During the simple reaction-time task significantly higher sound
      pressure levels were accepted than during the reasoning test. At the tonal
      exposure, much lower levels were accepted than during the exposure to broad-band
      noise. For continuous sound exposures much higher levels were accepted than for
      noncontinuous exposures. For tonal exposures the difference was approximately 5
      dB, for the broad-band exposures approximately 9 dB. In a separate study the
      effects of the noncontinuity of the noise and pauses were analysed. The raised
      annoying effect of the noncontinuous noise was not more affected by the
      noncontinuity of the noise periods than by the noncontinuity of the pauses. The
      results imply that the annoying reactions to the sound will be increased for
      repetitive noise and that the reaction is highly influenced by the over-all
      noncontinuity of the exposure.

PMID- 8668439
TI  - Annoyance and discomfort during exposure to high-frequency noise from an
      ultrasonic washer.
AB  - Annoyance and discomfort during exposure to high-frequency noise from an
      ultrasonic washer have been examined in the experiments carried out with 10
      subjects. After a short exposure during which the subjects rated their annoyance
      and discomfort, a broad-band noise was matched to the ultrasound. The subjects
      were exposed to three different levels of ultrasound on three different
      occasions. Analyses showed that ultrasound causes considerable annoyance and
      discomfort even for the lowest exposure levels. No significant difference between
      annoyance and discomfort was observed. The matchings indicated, however, that the
      A-weighting, i.e., the traditional rating technique used for noise evaluations,
      overestimated the high-frequency sound when evaluating annoyance and discomfort.

PMID- 8668440
TI  - Temperament of primary caregivers and development of literacy.
AB  - Parents can strongly influence the development of reading literacy in their
      children. Constructs such as parental attitude, parental style, reading
      technique, mother-child attachment, etc. influence the development of children's
      literacy. This study examined the relationship between the temperament of 55
      primary maternal caregivers and readiness to involve their 3- to 5-yr.-old
      children in extracurricular reading activities. Mothers' temperament may foster
      activities that support reading.

PMID- 8668441
TI  - Current and ideal physique choices in exercising and nonexercising college women
      from a pilot athletic image scale.
AB  - An Athletic Image Scale including female physiques with and without muscular
      definition is currently in the developmental phase. With shading, contouring, and
      three-dimensionality not offered previously on figure-rating scales, this
      instrument was designed to examine an apparent growing interest on the part of
      women in atheletic body-image ideals. The athletic level of each figure on the
      scale was based on responses of a group of college women. The 30-figure pilot
      scale was then tested by rating current and ideal body-shape preferences of two
      groups of first-year college women, 65 who exercised regularly and 45 who engaged
      in no regular exercise. Analysis showed no relationship between current and ideal
      physique choice and exercise status. Most exercising and nonexercising women
      chose a mesomorphic ideal physique with upper-body muscularity unlikely to occur
      without substantial amounts of physical activity. The associations among exercise
      status, figure choice, subscale scores on the Eating Disorder Inventory, and Self
      esteem Scale scores were also examined. Women choosing moderately mesomorphic
      figures as their current shape had the lowest Body Dissatisfaction scale scores
      on the Eating Disorder Inventory irrespective of exercise status. Current- and
      ideal-shape preferences were not related to self-esteem scores. The pilot
      Athletic Image Scale offered several figures which seemed to be relevant to women
      although it must be noted that the scale purposely emphasized particular
      physiques. Even so, it is important to recognize that greater than sixty percent
      of the women preferred images with athletic physiques which are not offered on
      figurerating scales presently in use.

PMID- 8668442
TI  - Visual scotoma and visual afterimages: some evidence that the perceived visual
      afterimage may not be a purely retinal phenomenon: a single case study.
AB  - Observations of the differential appearance and behaviour of a deliberately
      induced visual scotoma and a patterned visual afterimage are reported. Although a
      retinal scotoma behaves like a visual afterimage in some ways, there are
      sufficient differences to suggest that the perceived visual afterimage may not be
      just the simple consequence of prolonged retinal stimulation.

PMID- 8668443
TI  - A portable visual-feedback device for reducing excessive vocal loudness in
      persons with mental retardation.
AB  - A simple portable device was employed to reduce excessive vocal loudness in two
      adults who functioned within the moderate mental retardation range (one in the
      lower and one in the upper half). The device provided these adults visual
      feedback when the voice exceeded a preset level of loudness. Data showed that the
      device was useful in helping both adults reduce excessive vocal loudness across
      different daily situations. Characteristics and applicability of the device are
      discussed.

PMID- 8668444
TI  - Temporal factors in visual perception: a differential approach.
AB  - The tradition in sensory and perceptual psychology is not to pay much attention
      to individual differences but to focus almost exclusively on normative or generic
      processes. Nevertheless, consistent individual differences may exist in sensory
      and perceptual processes, just as they do in all other areas of human behavior
      where their existence has been investigated. A preliminary study was made of
      flicker fusion frequency, apparent movement, and three other perceptual tasks as
      differential measures. With one exception, Letter Search, all of the tests were
      psychophysical rather than cognitive. All had to do with time; that is,
      perceptual speed mattered in all of them. The analysis focused on reliability, in
      the sense of consistency from trial to trial. Four of the five tests showed good
      reliabilities in this sense, while the fifth was borderline. In one test,
      Bistable Stroboscopic Motion, the dependent measure, interstimulus interval,
      showed a consistent though shallow tendency to lengthen with practice. In the
      remaining four tests practice effects were largely confined to the first two
      administrations.

PMID- 8668446
TI  - Suggestions for studies of substance abusers' responses to nonverbal facial cues.
AB  - A study of drug abusers relating scores on measures of alexithymia and
      personality with affect recognition is reviewed. While the design is novel and
      provides useful data, multiple types of substance abusers were aggregated into
      one group. An averaging effect may have thus occurred rendering the results
      difficult to interpret. Duration of abstinence may have also provided a variable
      due to catecholamine rebound, which affects nonverbal encoding abilities.

PMID- 8668445
TI  - Occlusion rate of ball texture as a source of velocity information.
AB  - When a ball is rolling on the ground toward an observer, its elements of texture
      are successively occluded. The number of the elements of texture occluded per
      unit of time determines the occlusion rate. The aim of this study was to examine
      the role of the occlusion rate of ball texture and the velocity of the ball in
      the perception of the time remaining before the arrival. If the occlusion rate is
      used to perceive the time to arrival, then timing the initiation of movement
      should depend on occlusion rate. On the other hand, if the optical variable tau
      is exclusively used, then no variation is expected. 20 subjects were required to
      avoid balls rolling directly toward them. Three different ball textures and five
      ball velocities were used, leading to 10 different occlusion rates. The results
      showed that the timing of the initiation of the movement was not modified by
      variations of occlusion rate. However, the velocity of the avoidance movement
      increased with occlusion rate. The role of timing initiation and movement
      velocity in the control of the action are discussed, and it is suggested that
      occlusion rate is perceived and taken into account in the control of avoidance
      movements.

PMID- 8668447
TI  - A grade-six reading level key for the multiple affect adjective check list
      revised.
AB  - A scoring key containing adjectives from the Multiple Affect Adjective Check List
      Revised (MAACL-R) at or below the Grade 6 reading level (MAACL-R6) was used to
      rescore data from two nonreferred samples (college students, ns = 52 and 78) and
      one referred sample of 202 from a community mental health center outpatient
      clinic. Reliability (measures of internal consistency and test-retest) and
      validity (correlations with five 5-point self-rating mood scales) were almost as
      high as those for the MAACL-R, and convergence among the MAACL-R6 scales was not
      increased. Means for the referred group were significantly higher.

PMID- 8668448
TI  - Exercise, depression, and self-esteem.
AB  - In a sample of 90 college students, engaging in exercise was not associated with
      sadness/happiness or self-esteem.

PMID- 8668449
TI  - Effects of a walking program on attributional style, depression, and self-esteem
      in women.
AB  - Few controlled studies describe the psychological effects of a walking program on
      nonclinical, premenopausal women. This experiment measured the effects of an 8
      wk. walking program on female volunteers (N = 27) age 29 to 50 years (M = 37.4)
      randomly assigned to a supervised walking group vs a nonwalking group. A repeated
      measures, multivariate design was used to analyze blood pressure, resting heart
      rate, timed mile walk, and scores on self-esteem, depression, and attributional
      style. The walking group showed significant improvement in the timed mile walk,
      diastolic blood pressure, and rated self-esteem.

PMID- 8668450
TI  - Hemispheric picture-naming hierarchies in stuttering subjects.
AB  - The present study was done to investigate the linguistic organization of the
      right hemisphere of stuttering subjects and the interhemispheric interactions
      that underlie verbal output in this population. Naming reaction times of 14
      stuttering adults were measured to unilaterally presented pictures corresponding
      to vocabulary levels of < 5.5, 9.5-10.5, and > 18.0 years of age. An analysis of
      variance of latencies showed a significant main effect for picture vocabulary
      age. Post hoc tests were interpreted as suggesting that the right hemisphere of
      stuttering subjects was capable of differential picture-encoding operations in a
      manner similar to the left hemisphere of normal speakers. Also, naming latencies
      favored left visual-field stimulations by 34 msec. Taken with significant and
      high correlations between visual fields for each level of picture vocabulary
      score, the right hemispheres of the stuttering subjects appeared responsible for
      picture-encoding operations. Left-hemispheric stimulus processing was not
      predicted, suggesting differences may exist in interhemispheric interactions
      underlying picture-naming functions in stuttering populations.

PMID- 8668451
TI  - Body stereotyping and stigmatization of obese persons by first graders.
AB  - 14 female and 15 male racially diverse first graders were individually
      interviewed after being shown a set of same-gender body silhouettes. More
      children were significantly less likely to want to befriend an endomorphic type.
      Although more children labeled the ectomorph the "good child," the difference did
      not reach significance.

PMID- 8668452
TI  - Perceived discomfort associated with working with persons with varying
      disabilities.
AB  - Perceptions of discomfort by nondisabled coworkers are a major barrier to the
      acceptance of disabled persons into work groups. This research examined whether
      reported discomfort varied by the type or nature of the disability. 151 subjects
      rated 20 types of disabilities in terms of how uncomfortable or comfortable they
      would be working closely at a nonspecified task with a person with the particular
      disability. A stable hierarchy of the 20 disabilities was found. Patterns and
      implications are discussed. Gender of the rater influenced the ratings,
      specifically females exhibited less discomfort with disabilities over-all than
      did males. Prior contact with a disabled person, either personally or at
      unspecified work, did not affect the ratings of discomfort.

PMID- 8668453
TI  - Incidence of the half-left profile pose in single-subject portraits.
AB  - The present work recorded frequencies of five poses (left profile, half-left
      profile, full-face view, half-right profile, and right profile) by examining
      4,180 single-subject portraits of various media. Statistically significant
      differences were found between the incidence of half-left and half-right
      profiles. These differences found across media, authorship, and five centuries of
      portrait work are consistent with right-hemisphere activation models in
      attentional bias and perception of emotion.

PMID- 8668454
TI  - When proper names are not forgotten: recall of eponymous medical disorders.
AB  - Names are more difficult to recall than other facts about people such as
      occupations even when the words are nominally the same, e.g., Baker and baker.
      Subjects studied face photographs labeled with a surname and a medical diagnosis.
      Eponymous disorders were selected so that a given name could be used either as
      surname or diagnosis, e.g., Ms. Hodgkins or Hodgkin's disease. Nursing students
      (n = 24) tested in a within-subjects design recalled more eponymous diseases than
      surnames. There were few instances of confusing names and diseases, but names
      were often recalled to the wrong face. Education students (n = 18) recalled fewer
      diseases than did the nurses, and there was no difference in their recall of
      names and diseases. Nursing students tested in a between-groups design (n = 22
      each) showed no impairment in name recall. The results suggest limitations in the
      role of meaningfulness in recall.

PMID- 8668455
TI  - Differential gazing and vocal response to mother and stranger of full-term and
      preterm infants across age.
AB  - Full-term infants at both 2 and 3 months and preterm ones at 3 months from due
      date vocalized more to mother than to a stranger and gazed more at a stranger
      than the mother. Preterm infants at 3 months from birth, but 6 weeks from due
      date, did not show differential responding by any mode, indicating the importance
      of maturational rather than environmental factors in these behaviors.

PMID- 8668456
TI  - Testing color discrimination without the use of special stimuli or technical
      equipment.
AB  - Recently a number of self-report inventories have been developed to provide
      quick, valid, and reliable measures of sensory function without the use of
      technical equipment. One such measure, the 10-item Color Screening Inventory, was
      developed to detect individuals with deficient color perception. In the present
      study we used a sample of 268 subjects who were tested on both the Farnsworth
      Munsell 100-hue test and the Color Screening Inventory. Analysis showed that
      inventory scores also predict continuous variations in and individuals' ability
      to discriminate colors, with an eta of .69, which explains 48% of the predictive
      variance. It was possible to describe the data using a quadratic regression
      equation which has a corrected correlation of .52. Using this, a conversion table
      was generated to allow rapid estimation of 100-hue test scores from the
      inventory. On the basis of the results, the Color Screening Inventory appears to
      be a quick and effective means of testing color discrimination without requiring
      special stimuli, technical equipment, or controlled testing environments.

PMID- 8668457
TI  - Possible lateralization of peripheral nerve conduction associated with gender.
AB  - Lateralization of peripheral nerve conduction velocity was studied in right
      handed men (n = 40) and women (n = 48). Sensory and motor velocities were
      measured in ulnar and median nerves of the right and left hands. In women, the
      mean sensory velocity was significantly faster in the left than the right hand.
      There were no significant right-left differences in men. The mean sensory
      velocity from the right hand was significantly slower in women than men, creating
      an asymmetric organization of sensory conduction in women. Estradiol in women and
      testosterone in men were suggested as playing a role in asymmetric and symmetric
      nerve conductions, respectively.

PMID- 8668458
TI  - Mental activity, health, and life-satisfaction.
AB  - Systematic study of the cultural belief in a relationship between mental health
      and longevity has not been undertaken. No scale to measure 'mental activity'
      appears available. A questionnaire measuring 'mental activity' was administered
      to 166 community respondents. From a factor analysis 4 clear factors emerged.
      Factor scores were significantly correlated with scores on life-satisfaction, but
      few relationships with subscales of a health measure emerged. Some relationships
      with choice of free-time activities were noted. Further work on the scale and its
      correlates is recommended.

PMID- 8668459
TI  - Relations between attentional and intentional neural systems.
AB  - This study explored whether preparing an arm movement influences detection of a
      visual stimulus. We cued subjects to respond with either a rightward or a
      leftward movement to the appearance of a stimulus located either in the centre,
      in the left, or in the right visual field. Programming a movement toward a
      lateral direction enhanced visual attention at that side. Rightward movements
      were associated with an attentional cost only for responses to a central
      location, while leftward movements slowed response latencies to both central and
      right-sided stimuli. We hypothesized that programming a rightward movement
      depends on the activation of intentional centers in either cerebral hemisphere.
      On the contrary, leftward movements might be only driven by the contralateral
      hemisphere.

PMID- 8668460
TI  - Personalities of women reporting incestuous abuse during childhood.
AB  - Previous studies of adult females reporting incestuous sexual abuse in childhood,
      using the Apperceptive Personality Test and Draw-a-Person Questionnaire,
      indicated abusees attributed more negative traits to their characters than did
      controls. No differences were found by type of abuse or relation to the abuser.
      In these studies abusees and controls were obtained from different sources,
      although matched on several characteristics. The present study compared 79
      incestuous abusees to 79 matched controls all drawn from the same subject pool.
      Multivariate analysis of variance identified significant differences between the
      groups. In contrast with earlier studies questionnaire scores distinguished rape
      victims from those abused without rape and distinguished those abused by older
      relatives from those abused by peers in two additional multivariate analyses of
      variance.

PMID- 8668461
TI  - Influence of British national curriculum physical education on teachers'
      behaviours associated with pupils' psychosocial development: a case study in one
      English town.
AB  - The purpose of this study was to assess the influence of British National
      Curriculum Physical Education on the quality of physical education instruction in
      the five state secondary schools in one southwestern English town in terms of
      teachers' use of behaviours related with pupils' psychosocial development during
      the 1994 summer term. Subjects were the 20 physical education teachers employed
      at the five schools. Two lessons of each teacher's choice in which they taught
      any activity to pupils in Years 7, 8, and 9 were videotaped. Lessons were coded
      with the Coaching Behavior Assessment System, an observational instrument
      designed to record the rate at which teachers use behaviours positively and
      negatively related with pupils' psychosocial development. Data generated by this
      system were entered into an SPSS programme to produce descriptive statistics.
      Regardless of the activity being taught, teachers used behaviours related to
      pupils' positive psychosocial development much more frequently than they used
      behaviours linked with pupils' negative psychosocial development. A comparison of
      the data collected at these five schools during the present study with those
      collected in the summer term of 1992 indicated that the introduction of the
      National Curriculum Physical Education did not affect teachers' use of behaviours
      associated with pupils' psychosocial development when teaching summer activities.

PMID- 8668462
TI  - Effect of velocity on judgments of relative mass.
AB  - Research indicates that people can accurately judge the relative mass of
      colliding objects, i.e., which is heavier, if the collisions viewed involve
      actual physical objects. This study explored whether such judgements are affected
      by the image velocity of the colliding objects. Videotaped collisions involving
      different screen velocities were shown to observers. The accuracy of judgments of
      collision decreased significantly at slower velocities. A velocity-threshold
      hypothesis is offered as a possible account for this finding.

PMID- 8668463
TI  - Age-related changes in postural control and locomotion.
AB  - Age-related changes in both postural control and locomotion were investigated.
      Postural control was evaluated by magnitude of body sway for 131 healthy persons
      aged 21 to 84 years. Locomotion was evaluated by walking velocity for 217 healthy
      persons aged 21 to 88 years. Analysis showed that both abilities deteriorated for
      older persons and particularly age-related changes were more remarkable in
      locomotion.

PMID- 8668464
TI  - Collaborative referencing in elderly women.
AB  - This preliminary work compared the process of collaborative referencing in
      younger and elderly women, a process which requires joint effort from both the
      speaker and the listener. Four women in their thirties and four women in their
      seventies were paired with an unacquainted partner within the same age group.
      Each pair completed six trials of a barrier task in which they had to converse
      about abstract figures to arrange them in the same order. With repetition of the
      task, both pairs of younger women reduced the number of words and turns used to
      complete the task while only one of the pairs of elderly women did so and, even
      then, used many more words than younger women to complete the task. Also, in
      comparison with elderly women, younger women were more likely to use strategies
      which facilitated least effort in completion of the task. In a task designed to
      ensure accuracy, elderly women made errors while younger women did not. These
      findings suggest that elderly women may not benefit from the collaborative nature
      of a conversational interaction as do younger women.

PMID- 8668465
TI  - Transposition of words as indicators of semantic state in aphasia.
AB  - Semantic judgment tasks, based on antecedent pronouns and on word order, were
      presented to 16 aphasic adult subjects. Responses on the elicited imitation task
      were better than on comprehension tasks, a finding which parallels the language
      acquisition behavior of children. Addition of features to a basic judgment of
      animate vs inanimate did not affect subjects' performance.

PMID- 8668466
TI  - In defence of the right shift theory.
AB  - The right shift (RS) theory of a gene for left-cerebral dominance which increases
      the probability of right-handedness is outlined, together with two proposed
      alternatives, the 1985a genetic theory of McManus and the 1993 developmental
      instability theory of Yeo and Gangestad. Similarities and differences among the
      three theories are reviewed. Both of the genetic theories can predict the
      distribution of handedness in families and in twins more efficiently than the
      developmental instability theory, and the RS theory better than the McManus
      theory.

PMID- 8668467
TI  - A new method for prescribing exercise: three-point ratings of perceived exertion.
AB  - An accurate exercise prescription for ratings of perceived exertion has
      previously depended on data from a maximal graded exercise test during which RPE
      was measured. In many clinical settings RPE is not measured; in many fitness
      settings maximal testing is not feasible. A new method using treadmill speed or
      power output of a cycle ergometer at an RPE of 13 from a submaximal test which
      can be used in these situations is described. We evaluated the accuracy of this
      method at 50%, 60%, 70%, and 85% VO2max. A total of 160 target RPEs were
      developed using traditional procedures and the new method. No significant
      differences between RPEs obtained with the two techniques were found. The mean
      difference was less than one unit of RPE. It appears that the new method is valid
      for intensities of 50% to 85% VO2max and that data from either the cycle
      ergometer or the treadmill can be used to prepare exercise prescriptions.

PMID- 8668468
TI  - Alexithymia and locus of control.

PMID- 8668469
TI  - Figural and semantic factors in change in the Ebbinghaus illusion across four age
      groups of children.
AB  - Changes in the Ebbinghaus illusion across age groups have been studied with 80
      children (ns = 20) from 4 to 8 yr. old. The distortion, whose magnitude increases
      across age groups, depends on active cognitive comparative processes. In fact, if
      some cues make the geometrically identical inducing elements semantically
      different from the central one, the illusion decreases as older children develop
      conceptual categories. Across ages 4 to 8 years not only the magnitude of the
      illusion changes but also the interfering role of the taxonomic organization.

PMID- 8668471
TI  - Differences in visuospatial judgement in reading-disabled and normal children.
AB  - Both visual and verbal impairments have been reported in two independent streams
      of research into the etiology of dyslexia or reading-disability. To address the
      question of the presence of either abnormality in reading-disabled children,
      visuospatial and phonological ability were assessed and contrasted in 39 Normal
      and 26 Reading-disabled children. To assess whether these deficits are unique to
      dyslexia, scores were also compared to those of a group of 12 Poor Readers
      ("garden-variety" backward readers with low IQs). The Benton Judgement of Line
      Orientation Test was used for its simplicity and clinical reliability: Reading
      disabled subjects performed significantly worse than Normal readers (but similar
      to Poor Readers). Reading-disabled subjects performed worse for lines in the left
      hemifield compared to Normal subjects and also had a greater tendency to scan the
      task in reverse order (left-to-right) from the usual right-to-left scanning
      pattern observed in the Normal group when performing this test. When both verbal
      and visuospatial variables were combined in a multiple regression analysis, 71%
      of reading variance could be accounted for. These results suggest that Reading
      disabled children not only have poor phonological awareness, but they also show
      visuospatial deficits. However, poor performance on both these tasks was also
      observed in the group of Poor Readers, suggesting that these deficits are not
      unique to children with specific reading disability. The results lend further
      evidence to the hypothesis that reading disability cannot solely be attributed to
      left-hemisphere dysfunction resulting in phonological impairment. There are other
      behavioral deficits, possibly caused by a common mechanism, some of which, like
      visuospatial ability, can be measured by simple behavioral tests such as the
      Judgment of Line Orientation Test.

PMID- 8668470
TI  - Motor performance of schizophrenics after mellow and frenetic antecedent music.
AB  - Previous research has yielded an inconclusive picture of the effects of music on
      motor performance. Using a 3-factor within-subjects design [mellow/4:4 time),
      frenetic/(2:8 time), and white noise music conditions], each of 19 schizophrenic
      inpatient volunteers performed a Purdue Pegboard and Finger Oscillation (Tapping)
      Test following 1-min. presentations of 3 types of music. Pegboard performance was
      higher after frenetic music but unaffected by mellow music; there was no effect
      on tapping.

PMID- 8668472
TI  - Baroreceptor activity and the induction of sleep.
AB  - Sleep onset latency was substantially reduced in an experiment for 9 adults when
      short acoustic stimuli were given in synchrony with the heartbeat compared to a
      control condition in which the same stimuli were given asynchronously. By the
      same stimulation technique sleep quality was ameliorated in a group of 10
      patients with primary insomnia.

PMID- 8668473
TI  - Comparison of visual-motor performance and nonverbal reasoning among child and
      adolescent patients in an urban psychiatric hospital.
AB  - Two groups of young psychiatric inpatients were used to compare performance on
      the Test of Nonverbal Reasoning and the Developmental Test of Visual-motor
      Integration. The older group of 230 had a mean age of 15.7 yr. and produced a
      product-moment correlation of .64 for the two tests. The younger group of 81 had
      a mean age of 11.3 yr; scores correlated .53. On the TONI, the performance of the
      adolescent girls was superior to that of the boys. On the Test of Visual-motor
      Integration, the younger girls appeared to outscore the boys, but an analysis of
      variance of sex differences with age as covariate fell short of significance.
      Results were explained in terms of subjects' differing school experience in their
      development of visuomotor and visual-reasoning skills. Caution was advised in the
      application of age-based test norms to special populations.

PMID- 8668474
TI  - Predicting perceptual defense.
AB  - Perceptual defense as a phenomenon was proposed by McGinnies in 1949. His
      findings were, in main, replicated by York, et al. in 1984 and extended by
      Perroncel, et al. in 1990. The present purpose was to assess whether four
      independent variables, one related to emotional arousal (GSR) and three, related
      to connotative word meaning (Evaluative, Potency, and Activity scores from
      Semantic Differential words used in the Perroncel, et al. study), could predict
      the perceptual defense phenomenon. The multiple correlation coefficient (R) was
      .19; however, the percent variance accounted for by the four independent
      variables was 3%. Clearly, further research is necessary to specify what factors
      predict the perceptual defense effect.

PMID- 8668475
TI  - College students' perceptions of the purposes of sports.
AB  - To examine perceptions of the desirable purpose of athletics by men and women 162
      college men, 84 of whom participated in intercollegiate athletics, and 190
      college women, 81 of whom participated in intercollegiate athletics, were
      administered the Purpose of Sport Questionnaire. Applying a two-way multivariate
      analysis of variance to their mean responses gender was significant. Post hoc
      analysis indicated that men believed enhanced competitiveness, social status, and
      high-status career opportunities to be more important purposes of sport
      participation than did women. Participants in intercollegiate athletics had
      significantly higher perceptions of enhanced competitiveness, social status, and
      high-status career opportunities as more important purposes of sport
      participation than nonparticipants. However, nonparticipants in intercollegiate
      athletics believed that acquisition of attributes that make one a good citizen
      and enhancement of self-esteem were more important purposes of sport
      participation.

PMID- 8668476
TI  - Effects of ear canal occlusion and masking on the perception of voice.
AB  - This study examined the effect of ear canal occlusion and masking noise on four
      parameters of voice: (1) average fundamental frequency, (2) intensity in decibel
      (dB), (3) maximum fundamental frequency observed in a given sample (max), and (4)
      minimum fundamental frequency observed in a given sample (min). 12 normal hearing
      undergraduates produced the vowel /i/ ten times under conditions of unoccluded
      ear canal, ear canal occluded with a sound attenuating earplug, or masking noise.
      Other than a small (.73 dB) decrease in intensity, analysis showed no significant
      changes under the occluded condition; however, the masking condition showed
      statistically significant increases in the fundamental frequency, the intensity,
      and the maximum and minimum frequency as well as an increased range of
      frequencies.

PMID- 8668479
TI  - Development of content: influences on girls' junior high school volleyball
      success in practice and achievement.
AB  - The purpose of this study was to examine the success of practice by lower- and
      higher-skilled girls in Grades 7 and 8 in response to different tasks (extension,
      refinement, and application) throughout an 11-day instructional and practice
      period for volleyball. More highly skilled girls were more successful than those
      lower in skill for all skills (forearm pass, set, serve) and tasks. Girls had
      nearly equal success in practice for different tasks.

PMID- 8668478
TI  - Fluent speech, fast articulatory rate, and delayed auditory feedback: creating a
      crisis for a scientific revolution?
AB  - In 1970 Kuhn argued that science does not progress through a process of
      accretion. It is typified, rather, by the successive emergence of different
      paradigms which during their reign dictate the direction of normal science's
      puzzle-solving activity. Normal science inevitably exposes an anomaly which
      violates expectations predicted by the reigning paradigm. The "crisis" evoking
      anomaly may induce a destructive/constructive paradigm change. Transformations
      from one paradigm to another constitute a scientific revolution and dictate the
      growth and maturation of a field. This paper suggests the recent finding, that
      stutterers experience enhancement of fluency while speaking under delayed
      auditory feedback at a fast articulatory rate, be viewed as an anomaly. By
      challenging the notion that a slowed speech rate is necessary for amelioration of
      stuttering, the anomalous finding may be perceived as a crisis in the study of
      stuttering.

PMID- 8668477
TI  - Custodial status and self concepts of Nigerian inmates remanded to prison
      custody.
AB  - 60 male Nigerian prison inmates (30 with convicted status and 30 awaiting trial)
      and 210 male noninmates were administered the Tennessee Self-concept Scale to
      test the hypotheses that (1) inmates with convicted status would obtain higher
      self-concept scores than those with ?awaiting trial? status, and (2) the self
      concept scores of prison inmates generally would be lower than those of
      noninmates. The two hypotheses were strongly supported for this sample. It was
      concluded that self-concept scores were not only related to delinquency by also
      to custodial status.

PMID- 8668480
TI  - Anticipation of coincidence, gender, and sports classification.
AB  - This study investigated the effects of sport classification and gender on
      anticipation of coincidence. 102 undergraduate male and female students from open
      skills, closed skills, and nonathletic groups were tested on the Bassin
      Anticipation Timer. The dependent measures of absolute error, constant error, and
      variable error were analyzed in a 2 (gender) x 3 (sport classification) x 4
      (speeds) design. Men had lower absolute and constant error scores than women.
      Open skills athletes were less variable in their responses while male open skills
      athletes were more accurate and less variable at the faster speeds. Performance
      on the Bassin Anticipation Timer may not be representative of athletic skills.

PMID- 8668481
TI  - A cross-modal aftereffect: auditory displacement following adaptation to visual
      motion.
AB  - It has been shown earlier that the perceived location of static sound-sources can
      be displaced (a) during visual motion and (b) following auditory motion. Here we
      combine these phenomena. The subject adapted to the horizontal visual motion of a
      surrounding drum, then (with the lights off) localized static sound-sources by
      setting the direction of a pointer. Adapting motion was clockwise or
      counterclockwise: the difference between each subject's settings following the
      opposite directions of adaptation showed small but consistent auditory
      displacements opposite to the adapting directions. This visual-auditory
      aftereffect, which is consistent with sensorineural data, challenges a general,
      if implicit, belief that aftereffects do not cross modalities.

PMID- 8668482
TI  - Relationships of personality factors with clinical dimensions and school
      achievement.
AB  - This study analyzes the association traits, psychopathological factors, and
      school achievement. High School Personality Questionnaire Clinical Analysis
      Questionnaire, and academic marks of 224 high school students (90 boys and 134
      girls) are used. It can be stated that the predictive ability of measures of
      personality traits and clinical dimensions is very weak for both boys and girls.
      The Clinical Analysis Questionnaire does not seem to be useful in the prediction
      of school achievement.

PMID- 8668483
TI  - Use of the Rorschach in forensic practice.
AB  - A review of recent survey data indicates that the Rorschach test is used
      moderately often by forensic practitioners. Several guidelines may improve
      testimony on the test.

PMID- 8668484
TI  - Discrimination of grip force for preschool children aged 5 to 6 years.
AB  - The ability to discriminate grip force was investigated in 30 preschool children
      aged 5 to 6 years in an experiment controlling for motivation and muscle fatigue.
      The subjects were required to maintain a relatively high force during the
      discrimination with forces of the standard stimulus being 1.0, 2.0, and 3.0 kgf.
      Comparison stimuli changed at an interval of 0.1 kgf. Discrimination was measured
      in terms of the lower threshold, upper threshold, and interval of uncertainty.
      Since the statistical analyses indicated that there were no significant gender
      differences, data for boys and girls were combined. Although the upper and lower
      thresholds and the interval of uncertainty increased with the force required by
      the standard stimuli, Weber fractions did not remain constant when the stimulus
      intensity changed, unlike the findings in previous studies for adults.

PMID- 8668485
TI  - Hemispheric asymmetry as a function of handedness: perception of facial affect
      stimuli.
AB  - Hemispheric asymmetry in 14 left- and 14 right-handed persons shown
      tachistoscopically presented emotional stimuli to left and right visual fields
      was examined using a forced-choice, reaction-time paradigm in which subjects were
      asked to identify positive and negative faces. Neutral faces were included within
      the two-alternative forced-choice paradigm. Reaction time and response-bias
      measures were recorded. Analysis indicated differential lateralization for left
      handed and right-handed subjects with respect to neutral affective stimuli. While
      right-handed subjects' perceptions of neutral stimuli remained consistent across
      visual fields, left-handed ones identified neutral stimuli as more positive
      (happy) when presented to the left visual field and negative (angry) when
      presented to the right visual field. Implications for differential lateralization
      patterns among left- and right-handed adults are discussed.

PMID- 8668487
TI  - Exner's Depression Index and the Harris-Lingoes MMPI-2 subscales for depression.
AB  - This study examined the relationship between scores on the Harris-Lingoes MMPI-2
      subscales for Depression and the categories of Exner's Rorschach Depression Index
      (DEPI) for 53 clients of a counselling agency. Scores on the subscale Mental
      Dullness related to the Depression Index as a whole and to the category Blends <
      4. The subscale Subjective Depression also related to the category Blends < 4.

PMID- 8668486
TI  - An investigation of a method of simplified scoring for the Kaufman Hand Movements
      test as a measure of limb apraxia.
AB  - A simplified, 3-category method for scoring the Kaufman Hand Movements test was
      devised to replace a previously used, more complex 21-category scoring method.
      The concurrent validity and diagnostic sensitivity of the rescored test as a
      measure of limb apraxia were investigated in a reanalysis of the test protocols
      of 23 aphasic adults. Using the Limb Apraxia Test as the criterion measure, a
      Pearson r of .71 and predictive validity of 100% were obtained. These results
      encourage further investigation of the Kaufman Hand Movements test as an
      efficient measure of limb apraxia.

PMID- 8668488
TI  - Disruptions in auditory and temporal processing in adults who stutter.
AB  - 10 stutterers and 10 nonstutterers' abilities to perceive accurately prosodic
      information (stress, contrast, and emotion), linguistic stimuli staggered in time
      and nonspeech stimuli (tone bursts) were examined. Analysis indicated significant
      differences between the two groups on the Staggered Spondaic Word Test and the
      stress subtest of the Sentence Disambiguation Task. In addition, 7 of the 10
      stuttering subjects performed more poorly on the three measures than
      nonstuttering subjects.

PMID- 8668489
TI  - Weight loss and psychopathology: a three-cluster MMPI typology.
AB  - The present study investigated the effects of a treatment, including diet,
      exercise, and psychoeducational groups, on the severity of the psychopathology of
      obese subjects. The 120 subjects (60 male and 60 female), aged 20 to 50 years,
      were hospitalised for about two months. The mean Body Mass Index (BMI) at the
      start was 40.9 (SD = 5.3) and at the end 34.3 (SD = 5.5). The MMPI and clinical
      interview were administered to the subjects. The aims of the study were to see if
      there was change between the beginning and the end of treatment and to
      individuate groups of subjects homogeneous for the severity of the
      psychopathology at the start of treatment and to relate the severity to changes,
      whether worsening or improving, at the end of treatment. A multivariate analysis
      of variance showed significant change in scores on the psychological variables
      after treatment. Cluster analysis divided the patients into three groups with
      different severity of psychopathology. There were significant decreases on
      Hypochondriasis, Depression, and Social Introversion. Scores of the subjects with
      the most severe psychopathological traits changed most.

PMID- 8668490
TI  - Use of modern cursive handwriting and handwriting speed for children ages 7 to 14
      years.

PMID- 8668491
TI  - Gender, gender role, and drawing skill.
AB  - Separate bodies of research suggest that performance in spatial reasoning
      covaries with gender and with gender role. Typically studies employ a spatial
      task whose variance is then used to account for differences in scores between
      gender groups or variance in a measure of gender role. A methodological issue in
      such research is that the tasks used to represent spatial reasoning may be
      differentially available or differentially appealing as a function of gender.
      Also, authors tend to analyze data in terms of either gender or gender role but
      rarely both. A collection of personality assessments administered to 204 college
      students each contained a completed Minnesota Multiphasic Personality Inventory
      (MMPI-2) and a drawing of a human figure. Within MMPI-2 are three measures of
      gender role. Drawing talent is unquestionably spatial and has the advantage of
      being equally available and encouraged among the two genders. Male gender
      predicted drawing skill. Within both genders, self-perceived masculinity in
      gender role also predicted higher scores on the drawing skill. Outcomes are seen
      as compatible with Geschwind and Galaburda's 1987 formulation regarding the
      behavioral manifestations of fetal androgenization.

PMID- 8668492
TI  - Comparison of two multidimensional coordinate systems for facial expressions.
AB  - For 20 subjects the "distance" between midpoint pair options and predicted
      midpoints for rectilinear and circumplex models is reported using 24 Lightfoot
      photographs. Data were more compatible with the rectilinear model so respondents
      were probably not using polar coordinates in representing facial expressions
      internally.

PMID- 8668493
TI  - An analysis of a performance by the violinist D. Oistrakh: the hypothetical role
      of postural tonic-static and entourage movements.
AB  - In an interdisciplinary research project carried out by a violinist and a
      psychophysiologist which is based on a videotape of a performance by the
      violinist, David Oistrakh, we draw attention to certain postural attitudes and
      movements which appear in sequences of his rendition of the Brandenburg Concerto
      N. 4 by Bach and the Concerto for Violin in D Major by Mozart. These postural
      attitudes and movements occur with a certain regularity and are particular to
      each piece of music. For example, in the Brandenburg Concerto, one can observe
      rhythmic oscillations of the musician's whole body, with a shifting of the weight
      (alternanza di appoggio) from the left to the right foot. The performer's
      movements were compared with corresponding points of the musical score. Within
      this analytical framework, we hypothesize that these movements have not only a
      mechanical postural role but an expressive aesthetic one.

PMID- 8668494
TI  - Sex differences for speech and manual skill.
AB  - Young men and women were compared on the speeded repetition of speech (ns = 20
      and 18, respectively) and manual movements (ns = 37 and 38). The repetition of a
      single speech or manual movement was used as a measure of baseline speed, against
      which to compare a sequence of movements. Males tended to be faster at repeating
      a single movement, but using baseline speed as a covariate resulted in a female
      advantage for the repetition of a sequence of movements. It was concluded that
      men have a basic motor-speed advantage, but that women may be faster at
      programming a sequence of speech or manual movements. The results are discussed
      with respect to sexual variation in the neural organization of motor programming
      systems.

PMID- 8668495
TI  - Gender affects the detection of resistive loads.
AB  - Gender differences were observed on a respiratory-resistance detection task. Men
      (n = 35) exhibited significantly lower thresholds for air flow resistance than
      women (n = 45).

PMID- 8668496
TI  - Bodily perception in the organization of postural attitude and movement.
AB  - In the present research we hypothesized that some particular areas or points of
      the body play a role in the modulation of muscular (tonic and phasic) activity.
      In particular, we hypothesized that subjects utilize some bodily points as
      constant perceptual afferences in organizing the motoric responses of the whole
      body. The bodily points (called perceptual focal points) could have the same role
      as the bow of a boat for the sailor in orienting the spatial position of the boat
      and its movement. We have observed the presence of these perceptual focal points
      in 85% of a group of undergraduate students of psychology, 21 women and 19 men,
      during a real and an imagined movement of the whole body. Results indicated also
      that, if subjects were told to modify their habitual focal points, important
      modifications in subjective feelings of instability, pleasure, and tension
      appeared.

PMID- 8668497
TI  - Male nurturing: older men don't want to share their views; young women do.
AB  - When compared to men (n = 46) and women under 30 years of age (n = 30) or women
      over 60 (n = 68), men over 60 years of age (n = 41) showed an extreme reluctance
      to answer questions about their perceptions of other men who nurture children.
      Women under 30 were comparatively willing to share their views.

PMID- 8668498
TI  - Relationships between leisure time physical activity and perceived stress.
AB  - This study investigated the relationship between physical activity during leisure
      time and perceived stress among working adults (N = 32,229). Data were gathered
      on physical activity, perceived stress, current health status, age, gender, life
      changes, ongoing problems, number of techniques used for stress reduction, and
      number of personality traits related to Type A behavior. To control for
      confounding variables Mantel-Haenszel summary risk estimates were used. Employees
      who expended more than 3.0 Kcal/kg(-1) . day(-1) in physical activity during
      leisure time were 0.78 and 0.62 times less likely to have moderate and high
      perceived stress, respectively. Working adults participating in moderate amounts
      of these activities have about half the rate of perceived stress as
      nonparticipants.

PMID- 8668499
TI  - Ability of middle-school soccer players to localize overuse leg pain correctly
      using a graphic self-report form.
AB  - This study was conducted to assess the probability of success with which middle
      school-age soccer players could correctly localize lower leg pain to sites of
      common overuse injuries, using a graphic self-report instrument. Subjects
      included 98 middle-school soccer players, ages 12 to 15 years. Players' self
      reports of leg pain were compared with the results of a blind physical
      examination. Players reporting pain of more than two weeks' duration successfully
      localized a statistically significant number of their sites of pain using the
      graphic form, providing evidence of concurrent validity. Further development is
      needed before the measure can be used in surveillance of overuse injuries in
      youth sports.

PMID- 8668500
TI  - Morphologic and anthropometric characteristics of high level Dutch korfball
      players.
AB  - In this study a morphologic and anthropometric characterisation of Dutch korfball
      players (N = 36) is performed. Data, compared with those of other sports
      populations, showed that (1) korfball athletes are smaller and lighter than
      basketball and volleyball players but heavier and taller than other team-sport
      players; (2) korfball players have less relative body fat, more lean body mass,
      more limb fat, and less or similar trunk fat than the other athletes. (3) Male
      korfball players presented a somatotype (1.9-4.4-3.4) similar to endurance
      athletes and an endomorphic value lower than or similar to the other athletes.
      (4) The only apparent similarity between female korfball somatotype (3.2-4.0-2.8)
      and other athletes' somatotypes is the dominance of mesomorphy.

PMID- 8668502
TI  - Handedness distributions in nine professional groups.
AB  - The relationships between profession and handedness were studied in approximately
      equal numbers of accountants, architects, dentists, lawyers, librarians,
      mathematicians, orthodontists, orthopedic surgeons, and psychiatrists (ns = 133
      +/- 36; N = 1196). Handedness was estimated using laterality scores derived from
      the Edinburgh Handedness Inventory and self-reported global handedness preference
      scores. Architects and lawyers had the most lefthanded average laterality scores.
      Orthopedic surgeons, mathematicians, and librarians had the most righthanded
      average laterality scores. Psychiatrists and lawyers had the most ambilateral
      laterality scores, mathematicians and librarians the least. These findings are
      discussed in relation to theories of handedness and cerebral localization of
      visuospatial and language function.

PMID- 8668501
TI  - College students' perception of men as victims of women's assaultive behavior.
AB  - Recent reviews have indicated that women assault male partners as frequently as
      men assault women. This study explored college students' awareness and acceptance
      of this finding. 371 subjects responding to a survey (91 men, 280 women)
      indicated that, while 138 were aware of the finding, 242 regardless of gender
      accepted the finding that men are frequent victims of women's assaults in
      intimate relationships.

PMID- 8668503
TI  - A virtual pattern generator for designing motor behavior tasks.
AB  - A description of the hardware and software used to create movement patterns that
      differ spatially and temporally is explained. These tasks are presented to
      participants using a virtual pattern generator.

PMID- 8668504
TI  - Visuomotor performance in children with infantile nephropathic cystinosis.
AB  - Infantile nephropathic cystinosis is a genetic metabolic disorder in which the
      amino acid cystine accumulates in various organs, including the kidney, cornea,
      thyroid, and brain. Despite normal intellect, individuals with cystinosis may
      have specific impairments in the processing of visual information. To examine
      further the specific types of deficits in visual processing found in individuals
      with cystinosis, we administered the Development Test of Visual-motor Integration
      to 26 children with cystinosis (4 to 16 yr. old) and 26 matched controls. The
      cystinosis group achieved a significantly lower standard score, raw score, and
      mean ceiling than did the control group. Qualitative analyses showed that in the
      cystinosis group, size within errors and rotation errors were more prevalent than
      in the control group. Correlational analyses showed that with advancing age, the
      cystinosis subjects tended to fall further behind their chronological age. Our
      data, together with the findings of previous studies, suggest that the
      visuospatial difficulties in children with cystinosis may be due to inadequate
      perception or processing of visually presented information. Furthermore, the
      increasing discrepancy with age may reflect a progressive cognitive impairment,
      possibly as a result of cystine accumulation in the brain over time.

PMID- 8668505
TI  - Production of facial expressions of emotion in preschool children.
AB  - 138 preschool children created faces with manipulable facial components to
      represent expressed emotions. Proportions selecting appropriate components varied
      with emotions so the task was perhaps more cognitively demanding than Ekman and
      Friesen's facial recognition task.

PMID- 8668506
TI  - The horizontal vertical illusion: evidence for strategic factors in feedback
      induced illusion decrement.
AB  - This study assessed whether feedback would improve performance on a horizontal
      vertical illusion task and whether such improvement would transfer to different
      forms of the illusion. Subjects shortened the extended vertical line of small,
      medium, and large inverted-T figures to be equal in length to the horizontal line
      before and after being shown a correctly adjusted medium-sized figure (visual
      feedback). Next, they were tested on three alternate forms of the illusion; a
      production task (drawing 1-in. lines in the horizontal and vertical planes), an
      adjustment task using L figures, and a task requiring them to choose which of
      several sailboat drawings had mast height equal to hull length. Prior to
      feedback, vertical lines were adjusted shorter than the horizontal lines on each
      size inverted-T figure. After feedback on the medium-size figure, experimental
      subjects were more accurate than the controls on each size inverted-T figure. The
      results suggest that transfer of illusion decrement was also obtained for the
      boat-selection and, to a lesser extent, the L-figure adjustment tasks but not to
      the line-production task. These findings are consistent with the notion that
      improvement after feedback is not due to structural changes in visual processing
      or to simple feedback-induced compensation in performance but involves some
      strategic or cognitive change in judging line length.

PMID- 8668507
TI  - Speculations in "Temporal delays in incorporation of events into dreams": a reply
      to Roll.
AB  - Previously we pointed out similarities between patterns of delayed incorporations
      of daytime stimuli into dreams and delayed memory processes in rats. In
      commenting upon this article, Roll argued that this reductionistic leap is
      unwarranted. We contend that it would be remiss not to make note of this
      potential connection, especially in view of recent major contributions of animal
      research to the understanding of REM sleep and dreams. We also suggest that the
      disruption-avoidance-adaptation model constitutes a preferable psychological
      explanation for the dream-lag effect than Roll's psychoanalytic model of
      repression and repetition compulsion.

PMID- 8668508
TI  - Effects of report order, identification method, and stimulus characteristics on
      multidimensional stimulus identification.
AB  - An experiment was conducted to investigate the effect of order of report,
      identification method, redundant color coding, and stimulus location under dual
      task conditions on multidimensional stimulus-identification performance. Analysis
      showed that order of report and identification method did affect speed and
      accuracy of identification. Subjects reacted faster and more accurately if this
      order of reporting stimulus-dimension values was appropriate. Physical
      identification was also faster and more accurate than identification of meaning,
      but there was no effect for redundant color coding, stimulus location, and
      difficulty of the dual task on identification. The implications of the results
      for design of visual displays were discussed.

PMID- 8668509
TI  - The optimum decision rules in the same-different paradigm.
AB  - In this paper we derive the optimum (likelihood-ratio) decision statistic for a
      same-different paradigm. The likelihood ratio is dependent on the degree of
      correlation between the two observations on each trial. For the two extreme cases
      in which the observations are either independent or highly correlated, the
      optimum decision rule is identical to each of two previously suggested decision
      rules. For these two cases, the receiver-operating characteristic (ROC) curves
      are calculated. Finally, an experimental procedure is suggested for assessing the
      decision rule actually used by the observer in a same-different task.

PMID- 8668510
TI  - The optimum decision rules for the oddity task.
AB  - This paper presents the optimum decision rule for an m-interval oddity task in
      which m-1 intervals contain the same signal and one is different or odd. The
      optimum decision rule depends on the degree of correlation among observations.
      The present approach unifies the different strategies that occur with "roved" or
      "fixed" experiments (Macmillan & Creelman, 1991, p. 147). It is shown that the
      commonly used decision rule for an m-interval oddity task corresponds to the
      special case of highly correlated observations. However, as is also true for the
      same-different paradigm, there exists a different optimum decision rule when the
      observations are independent. The relation between the probability of a correct
      response and d' is derived for the three-interval oddity task. Tables are
      presented of this relation for the three-, four-, and five-interval oddity task.
      Finally, an experimental method is proposed that allows one to determine the
      decision rule used by the observer in an oddity experiment.

PMID- 8668511
TI  - No prevalence of right-left over top-bottom spatial codes.
AB  - Reaction time is known to depend on spatial stimulus-response compatibility in
      both the horizontal and the vertical dimensions. However, if both dimensions are
      varied in the same task, horizontal but not vertical compatibility affects
      performance, even if subjects are instructed to attend to the vertical dimension
      only (Nicoletti & Umilta, 1984). Experiment 1 compared the effect of horizontal
      and vertical instructions in a task with left-versus right-handed key responses
      placed at a top versus bottom location. A horizontal-prevalence effect was
      observed only with a horizontal, and not with a vertical, instruction. This
      suggests that subjects might not have heeded the vertical instruction in the
      Nicoletti and Umilta study but instead attended to the horizontal dimension.
      Experiment 2 did not yield any horizontal prevalence with one-handed responses
      (joystick movements). This indicates that top-bottom codes become ineffective
      only if the responses suggest an exclusively horizontal response coding. In sum,
      results demonstrated multiple spatial coding of stimuli and responses under
      appropriate conditions and suggest that the right-left codes do not dominate the
      top-bottom spatial codes.

PMID- 8668512
TI  - Illusory form with inducers of opposite contrast polarity: evidence for
      multistage integration.
AB  - The perception of brightness differences in Ehrenstein figures and of illusory
      contours in phase-shifted line gratings was investigated as a function of the
      contrast polarity of the inducing elements. We presented either continuous lines
      or line-like arrangements composed of aligned dashes or dots whose spacing was
      varied. A yes/no procedure was used in which naive observers had to decide
      whether or not they perceived a brightness difference in a given Ehrenstein
      figure or an illusory contour in a phase-shifted line grating. The results show
      that brightness differences are perceived to some extent in Ehrenstein figures
      with inducers of opposite polarity of contrast; however, the percentage of yes
      response was systematically lower and response times were longer than for figures
      with inducers of the same polarity. Phase-shifted line gratings with lines of
      opposite polarity of contrast yielded stronger illusory contours and shorter
      response times than those with lines of the same polarity. When the sign of
      contrast was not the same within a given line of induction, neither differences
      in brightness nor illusory contours were perceived. The results suggest that the
      mechanisms that lead to apparent differences in brightness are more sensitive to
      input of the same contrast polarity, the mechanisms generating illusory contours
      more sensitive to input of opposite polarity. The data are discussed in the light
      of a multistage approach to illusory form perception and some implications for
      cortical models of illusory contour integration are discussed.

PMID- 8668513
TI  - Perception of musical tension in short chord sequences: the influence of harmonic
      function, sensory dissonance, horizontal motion, and musical training.
AB  - This study investigates the effect of four variables (tonal hierarchies, sensory
      chordal consonance, horizontal motion, and musical training) on perceived musical
      tension. Participants were asked to evaluate the tension created by a chord X in
      sequences of three chords [C major-->X-->C major] in a C major context key. The X
      chords could be major or minor triads major-minor seventh, or minor seventh
      chords built on the 12 notes of the chromatic scale. The data were compared with
      Krumhansl's (1990) harmonic hierarchy and with predictions of Lerdahl's (1988)
      cognitive theory, Hutchinson and Knopoff's (1978) and Parncutt's (1989) sensory
      psychoacoustical theories, and the model of horizontal motion defined in the
      paper. As a main outcome, it appears that judgments of tension arose from a
      convergence of several cognitive and psychoacoustics influences, whose relative
      importance varies, depending on musical training.

PMID- 8668514
TI  - The horizon-ratio relation as information for relative size in pictures.
AB  - The horizon-ratio relation was found to be an effective source of information for
      relative size in pictures under some conditions: when the difference in image
      size of depicted "same real size" objects was not too great (Experiment 1), and
      when the horizon line was not too high or too low in the picture (Experiment 2).
      The latter finding seemed to be linked to the observers' identification of the
      horizontal line as the horizon (and not as the edge of a finite surface). In
      addition, individual patterns of response were remarkably systematic even in the
      absence of a horizon, or any other pictorial information, (Experiment 3). It is
      suggested that in this case observers imposed a horizon on the picture on which
      to base their relative size judgments, possibly based on the observer's own eye
      level or on the content of the picture. It is concluded that although the horizon
      ratio relation provides the same kind of information as that available in the
      optic arrays from real scenes, pictorial information requires the satisfaction of
      additional constraints in order to be fully effective.

PMID- 8668515
TI  - Mental rotation of static and dynamic figures.
AB  - Previous studies comparing performance on standard (i.e., static) and dynamic
      spatial test items have concluded that the two item types measure different
      abilities. Such conclusions about the uniqueness of static and dynamic spatial
      abilities seem premature, however, since only a limited number of dynamic spatial
      tasks have been utilized in research and these have differed markedly from their
      static counterparts. In the present studies, tasks were designed to require a
      common mental operation (mental rotation) under static and dynamic conditions.
      Correlations between static and dynamic performance ranged from .80 to .90. This
      appears to suggest that the emergence of a unique dynamic ability factor depends
      on the utilization of certain specialized tasks (e.g., arrival time tasks) with
      mental operations much different than those required by conventional spatial
      tests. In other words, it is apparently the requirement for different cognitive
      processes and not the processing of stimulus motion per se that distinguishes
      performance on some dynamic tasks from performance on some standard static tasks.

PMID- 8668516
TI  - Reduction of the elevator illusion from continued hypergravity exposure and
      visual error-corrective feedback.
AB  - Ten subjects served as their own controls in two conditions of continuous,
      centrifugally produced hypergravity (+2 Gz) and a 1-G control condition. Before
      and after exposure, open-loop measures were obtained of (1) motor control, (2)
      visual localization, and (3) hand-eye coordination. During exposure in the visual
      feedback/hypergravity condition, subjects received terminal visual error
      corrective feedback from their target pointing, and in the no-visual
      feedback/hypergravity condition they pointed open loop. As expected, the motor
      control measures for both experimental conditions revealed very short lived
      underreaching (the muscle-loading effect) at the outset of hypergravity and an
      equally transient negative aftereffect on returning to 1 G. The substantial
      (approximately 17 degrees) initial elevator illusion experienced in both
      hypergravity conditions declined over the course of the exposure period, whether
      or not visual feedback was provided. This effect was tentatively attributed to
      habituation of the otoliths. Visual feedback produced a smaller additional
      decrement and a postexposure negative after-effect, possible evidence for visual
      recalibration. Surprisingly, the target-pointing error made during hypergravity
      in the no-visual-feedback condition was substantially less than that predicted by
      subjects' elevator illusion. This finding calls into question the neural outflow
      model as a complete explanation of this illusion.

PMID- 8668517
TI  - Shifts in the perceived location of a blurred edge increase with contrast.
AB  - Perceived brightness is nonlinearly related to luminance. Consequently, any
      mechanism operating on the (transformed) luminance profile of a blurred edge to
      detect its location should make errors, and the magnitude of these errors should
      increase with contrast. The perceived location of a blurred edge was measured at
      a range of contrasts and a range of blur space constants in a vernier alignment
      task. It was found that the perceived location of a blurred edge was affected by
      the contrast and the blur space constant of the edge. At low contrasts, the
      apparent location of the blurred edge was near the calculated location of the
      edge, assuming the linear transduction of luminance. At higher contrasts, the
      perceived location of a blurred edge was shifted toward the dark side of the
      edge, and the shift increased with contrast.

PMID- 8668518
TI  - Effects of attentional set and rhythmic complexity on attending.
AB  - In a target detection task involving sustained attentional monitoring, rhythmic
      properties of tone sequences were found to affect detection performance (area
      under receiver-operating characteristic curves) and reaction times. Alternating
      tone frequencies (high, low) formed three different recurrent rhythms (binary,
      trinary, mixed) which varied in complexity. Attentional set was also manipulated
      so that participants attended either to tones of both frequencies (divided) or to
      only the higher of the two tones (selective). The most interesting finding
      involved an interaction between attention set and rhythm, indicating that
      selective attending is enhanced by the most complex (mixed) rhythm, whereas
      divided attending tends to be best with the simplest rhythm (binary). Results are
      discussed in terms of a theory of dynamic attending, in which it is assumed that
      listeners actively use attending oscillators to direct attending.

PMID- 8668520
TI  - A test of the deadline model for speed-accuracy tradeoffs.
AB  - Two experiments were conducted to evaluate the deadline model for speed-accuracy
      tradeoffs. According to the deadline model, participants in speeded-response
      tasks terminate stimulus discrimination as soon as it has run to completion or as
      soon as a predetermined time deadline has arrived, whichever comes first. Speed
      is traded for accuracy by varying the time deadlines; short deadlines yield fast
      but sometimes inaccurate responses, whereas long deadlines allow for slow,
      accurate responses. A new prediction of this model, based on a comparison of
      reaction time distributions, was derived and tested in experiments involving the
      joint manipulation of speed stress and stimulus discriminability. Clear
      violations of this prediction were observed when participants made relative
      brightness judgments (Experiment 1) and when they made lexical decisions
      (Experiment 2), rejecting both the deadline model and the fast-guess model.
      Several alternative models for speed-accuracy tradeoffs, including random-walk
      and accumulator models, are compatible with the results.

PMID- 8668519
TI  - Evaluation of mental representation for same and mixed compatibility assignments.
AB  - In most studies of stimulus-response (S-R) compatibility, assignments within a
      set are either compatible or incompatible for all S-R combinations. The present
      study provided an extension of previous research by examining the situations with
      same or mixed S-R assignments for pairs of subsets from a four-choice spatial
      precuing task. Assignments of stimuli to responses for the subsets could be same
      (both subsets assigned compatibility or both assigned incompatibility) or mixed
      (one subset assigned compatibility and one subset assigned incompatibility). A
      precue stimulus provided advanced information about which subset, and thus which
      assignment, would be required for responding on each trial. Experiment 1 had four
      visual stimuli assigned to four response locations, whereas Experiment 2 had the
      four visual stimuli assigned to only two response locations. For both
      experiments, the analyses revealed similar patterns of reaction times, with
      reaction times slower in the mixed condition than in the same condition.
      Moreover, the reaction times for the compatible assignments in the mixed sets
      were slowed more than the incompatible ones in those sets. The nonprecued subset
      influenced the S-R translation processes, indicating that the nonprecued subset
      was part of the mental representation upon which subjects were making decisions.

PMID- 8668521
TI  - The sampling distribution of d'.
AB  - The distribution of sample estimated d's, although mathematically intractable,
      can be tabulated readily by computer. Such tabulations reveal a number of
      interesting properties of this distribution, including: (1) sample estimated d's
      are biased, with an expected value that can be higher or lower than the true
      value, depending on the sample size, the true value itself, and the convention
      adopted for handling cases in which the sample estimated d' is undefined; (2) the
      variance of estimated d' also depends on the convention adopted for handling
      cases in which the sample estimated d' is undefined and is in some cases poorly
      approximated by the standard approximation formula, (3) the standard formula for
      a confidence interval for estimated d' is quite accurate with at least 50-100
      trials per condition, but more accurate intervals can be obtained by direct
      computation with smaller samples.

PMID- 8668522
TI  - Prepulse effects on magnitude estimation of startle-eliciting stimuli and startle
      responses.
AB  - The present studies investigated the relationship between prepulse effects on the
      modification of the brainstem startle reflex and magnitude estimates of startle
      eliciting stimuli. In Experiment 1, startle eyeblink responses were elicited in
      24 students, half of whom were instructed to estimate the loudness of the startle
      stimulus (actual intensities of 80, 90, and 100 dB) and half of whom were
      instructed to estimate the magnitude of their eyeblink. When weak acoustic
      prepulses preceded the startle-eliciting stimulus, eyeblink amplitude was
      inhibited, and estimates of response magnitude decreased, but estimates of
      startle stimulus magnitude decreased only when 100-dB startle stimuli were
      presented. In Experiment 2, the same startle stimuli were preceded on some trials
      by a vibrotactile prepulse to the hand. In conditions in which startle amplitude
      was inhibited, startle stimulus magnitude estimates were not affected. This
      suggests that the effect of acoustic prepulses on 100-dB startle stimuli in
      Experiment 1 may have been due to loudness assimilation, an effect independent of
      the prepulse inhibition of startle responding.

PMID- 8668523
TI  - The perception of an opening from expanding motion.
AB  - The ability of humans to detect an opening's 3-D structure from expanding motion
      was tested. Computer simulations of dotted tunnels were used to generate optical
      flows typically encountered when one moves through an opening. Experiment 1
      qualitatively tested the ability to detect the shape of a tunnel's vertical
      section. The observers could choose the correct shape for each of seven simulated
      shapes. The percentages of correct responses were much higher than those under
      static conditions. Experiment 2 tested whether or not one could quantitatively
      detect the vertical-horizontal proportion of the elliptic tunnels. The results
      shows quite high correlations (r = .93-.97) between perceived proportions and
      simulated ones. The slopes of the regression lines were around 1.0. Experiment 3
      investigated the necessary stimulus duration for detecting an opening's shape.
      Relative size (width and height) was significantly detected under four-frame
      (72.7-msec) conditions by 3 out of 4 subjects. The other subject performed well
      under eight-frame conditions. These results indicate that the human visual system
      can instantly detect the 3-D structure of an opening surrounded by objects from
      expanding optical flows while one is in forward motion.

PMID- 8668524
TI  - Searching for unknown feature targets on more than one dimension: investigating a
      "dimension-weighting" account.
AB  - Search for odd-one-out feature targets takes longer when the target can be
      present in one of several dimensions as opposed to only one dimension (Muller,
      Heller, & Ziegler, 1995; Treisman, 1988). Muller et al. attributed this cost to
      the need to discern the target dimension. They proposed a dimension-weighting
      account, in which master map units compute, in parallel, the weighted sum of
      dimension-specific saliency signals. If the target dimension is known in advance,
      signals from that dimension are amplified. But if the target dimension is
      unknown, it is determined in a process that shifts weight from the nontarget to
      the target dimension. The weight pattern thus generated persists across trials,
      producing intertrial facilitation for a target (trial n + 1) dimensionally
      identical to the preceding target (trial n). In the present study, we employed a
      set of new tasks in order to reexamine and extend this account. Targets were
      defined along two possible dimensions (color or orientation) and could take on
      one of two feature values (e.g., red or blue). Experiments 1 and 2 required
      absent/present and color/orientation discrimination of a single target,
      respectively. They showed that (1) both tasks involve weight shifting, though
      (explicitly) discerning the dimension of a target requires some process
      additional to simply detecting its presence; and (2) the intertrial facilitation
      is indeed (largely) dimension specific rather than feature specific in nature. In
      Experiment 3, the task was to count the number of targets in a display (either
      three or four), which could be either dimensionally the same (all color or all
      orientation) or mixed (some color and some orientation). As predicted by the
      dimension-weighting account, enumerating four targets all defined within the same
      dimension was faster than counting three such targets or mixed targets defined in
      two dimensions.

PMID- 8668525
TI  - The transcription factors Sp1 and Oct-1 interact physically to regulate human U2
      snRNA gene expression.
AB  - The expression of human small nuclear U2 RNA genes is controlled by the proximal
      sequence element (PSE), which determines the start site of transcription, and a
      distal sequence element (DSE). The DSE contains an octamer element and three Sp1
      binding sites. The octamer, like the PSE, is essential for U2 transcription. The
      Sp1 sites contribute to full promoter activity by distance-dependent cooperative
      interactions with the transcription factors Sp1 and Oct-1. Here we show that
      purified recombinant Sp1 and Oct-1 bind cooperatively to the DSE and that they
      physically interact in vitro. Furthermore, we show that Sp1 and Oct-1 interact in
      vivo using a yeast two-hybrid system. The domain of Sp1 which interacts with Oct
      1 is confined to the region necessary for transcriptional stimulation of U2 RNA
      transcription. This region contains the glutamine-rich activation domain B and a
      serine/threonine-rich part. The results demonstrate that Sp1, in addition to
      binding to a number of other factors, also interacts directly with transcription
      factor Oct-1.

PMID- 8668526
TI  - Sequence composition effects on the stabilities of triple helix formation by
      oligonucleotides containing N7-deoxyguanosine.
AB  - A nonnatural nucleoside, 7-(2-deoxy-beta-D-erythro-pento-furanosyl)-guanine
      (d7G), mimics protonated cytosine and specifically binds GC base pairs within a
      pyrimidine - purine - pyrimidine triple helix. The differences in association
      constants (KT) determined by quantitative footprint titration experiments at
      neutral pH reveal dramatic sequence composition effects on the energetics of
      triple helix formation by oligonucleotides containing d7G. Purine tracts of
      sequence composition 5'-d(AAAAAGAGAGAGAGA)-3' are bound by oligonucleotide 5'
      d(TTTTT7GT7GT7GT7GT7GT)-3' three orders of magnitude less strongly than by 5'
      d(TTTTTmCTmCTmCTmCTmCT)-3' (KT = 1.5 x 10(6) M(-1) and KT > or = 3 x 10(9) M(-1)
      respectively). Conversely, purine tracts of sequence composition 5'
      d(AAAAGAAAAGGGGGGA)-3' are bound by oligonucleotide 5'-d(TTTTmCTTTT7G7G7G7G7G7GT)
      3' five orders of magnitude more strongly than by 5'-d(TTTTmCTTTTmCmCmCmCmCT)-3'
      (KT > or = 3 x 10(9) M(-1) and KT < 5 x 10(4) M(-1) respectively). The
      complementary nature of d7G and mC expands the repertoire of G-rich sequences
      which may be targeted by triple helix formation.

PMID- 8668527
TI  - Stability of intrastrand hairpin structures formed by the CAG/CTG class of DNA
      triplet repeats associated with neurological diseases.
AB  - Expansions of trinucleotide repeats in DNA, a novel source of mutations
      associated with human disease, may arise by DNA replication slippage initiated by
      hairpin folding of primer or template strands containing such repeats. To
      evaluate the stability of single-strand folding by repeating triplets of DNA
      bases, thermal melting profiles of (CAG)10, (CTG)10, (GAC)10 and (GTC)10 strands
      are determined at low and physiological salt concentrations, and measurements of
      melting temperature and enthalpy change are made in each case. Comparisons are
      made to strands with three times as many repeats, (CAG)30 and (CTG)30. Evidence
      is presented for stable intrastrand folding by the CAG/CTG class of triplet
      repeats. Relative to the GAC/GTC class not associated with disease, the order of
      folding stability is found to be CTG > GAC approximately = CAG > GTC for 10
      repeats. Surprisingly, the folds formed by 30 repeats of CTG or CAG have no
      higher melting temperature and are only 40% more stable in free energy than those
      formed by 10 repeats. This finding suggests that triplet expansions with higher
      repeat number may result from the formation of more folded structures with
      similar stability rather than fewer but longer folds of greater stability.

PMID- 8668528
TI  - Gene targeting in rat embryo fibroblasts promoted by the polyomavirus large T
      antigen.
AB  - We used the recombination-promoting activity of the polyomavirus large T antigen
      (T-ag) to increase the frequency of gene targeting in rat fibroblasts. We
      constructed a cell line carrying a functional polyomavirus replication origin and
      a transformation-defective middle T-ag oncogene. The structure of the locus was
      such that homologous recombination with the targeting DNA reconstituted a
      functional transforming gene and converted the cells from the normal to the
      transformed state. Introduction of the large T-ag with the targeting DNA promoted
      recombinational events that corrected the mutation in either the target locus or
      the targeting DNA. The frequency of recombination was not substantially
      influenced by the extent of homology between the recombining sequences. However,
      it was reduced when the replication origin was inactivated in the targeting DNA,
      and was reduced further when the origin was inactivated in the target locus.

PMID- 8668529
TI  - Identification of the structural and functional human homolog of the yeast
      ubiquitin conjugating enzyme UBC9.
AB  - Ubiquitin conjugating enzymes (UBCs) are a family of proteins directly involved
      in ubiquitination of proteins. Ubiquitination is known to be involved in control
      of a variety of cellular processes, including cell proliferation, through the
      targeting of key regulatory proteins for degradation. The ubc9 gene of the yeast
      Saccharomyces cerevisiae (Scubc9) is an essential gene which is required for cell
      cycle progression and is involved in the degradation of S phase and M phase
      cyclins. We have identified a human homolog of Scubc9 (termed hubc9) using the
      two hybrid screen for proteins that interact with the human papillomavirus type
      16 E1 replication protein. The hubc9 encoded protein shares a very high degree of
      amino acid sequence similarity with ScUBC9 and with the homologous hus5+ gene
      product of Schizosaccharomyces pombe. Genetic complementation experiments in a
      S.cerevisiae ubc9ts mutant reveal that hUBC9 can substitute for the function of
      ScUBC9 required for cell cycle progression.

PMID- 8668531
TI  - The exon sequence TAGG can inhibit splicing.
AB  - The fibroblast growth factor receptor-2 gene contains a pair of alternative
      exons, K-SAM and BEK, which are spliced in a cell type specific manner. We have
      shown previously that a 10 nucleotide sequence within the K-SAM exon exerts a
      negative effect on K-SAM exon splicing independent of cell type. We demonstrate
      here that this sequence works autonomously, as it can repress splicing of a
      heterologous exon, the EIIIb alternative exon of the rat fibronectin gene. By
      introducing point mutations into the 10 nucleotide sequence, we have shown that
      the functional portion is limited to 4 nucleotides, TAGG, the dinucleotide AG of
      which is particularly important. This short sequence may participate in the
      control of splicing of exons carrying it, provided that they carry weak splice
      sites.

PMID- 8668530
TI  - Target specificity of neuronal RNA-binding protein, Mel-N1: direct binding to the
      3' untranslated region of its own mRNA.
AB  - We have identified cDNAs encoding Mel-N1, the mouse homologue of a human nervous
      system-specific RNA-binding protein, Hel-N1. Two major mRNA transcripts of Mel-N1
      were detected predominantly in the adult mouse brain by Northern blot analysis.
      To gain insight into the RNA binding specificity of Mel-N1, we performed
      iterative in vitro RNA selection. The resulting in vitro selected RNAs were found
      to contain AU-rich sequences as well as a GAAA motif in the majority of clones.
      By means of in vitro binding assays we demonstrate that this GAAA sequence
      appears to significantly affect the Mel-N1 RNA-binding efficiency. Our studies
      further reveal that Mel-N1 can bind to its own 3' untranslated region (3'UTR) as
      well as to the c-fos 3'UTR, and is localized predominantly in the cytoplasmic
      region in cells, suggesting that posttranscriptional autoregulation of Mel-N1
      gene expression occurs in vivo.

PMID- 8668532
TI  - The NMR structure of 31mer RNA domain of Escherichia coli RNase P RNA using its
      non-uniformly deuterium labelled counterpart [the 'NMR-window' concept].
AB  - The NMR structure of a 31mer RNA constituting a functionally important domain of
      the catalytic RNase P RNA from Escherichia coli is reported. Severe spectral
      overlaps of the proton resonances in the natural 31mer RNA (1) were successfully
      tackled by unique spectral simplifications found in the partially-deuterated 31
      mer RNA analogue (2) incorporating deuterated cytidines [C5 (>95 atom % 2H), C2'
      (>97 atom % 2H), C3' (>97 atom % 2H), C4' (>65 atom % 2H) and C5' (>97 atom %
      2H)] [for the 'NMR-window' concept see: Foldesi,A. et al. (1992) Tetrahedron, 48,
      9033; Foldesi,A. et al. (1993) J. Biochem. Biophys. Methods, 26, 1; Yamakage,S.
      I. et al. (1993) Nucleic Acids Res., 21, 5005; Agback,P. et al. (1994) Nucleic
      Acids Res., 22, 1404; Foldesi,A. et al. (1995) Tetrahedron, 51, 10065; Foldesi,A.
      et al. (1996) Nucleic Acids Res., 24, 1187-1194]. 175 resonances have been
      assigned out of total of 235 non-exchangeable proton resonances in (1) in an
      unprecedented manner in the absence of 13C and 15N labelling. 41 out of 175
      assigned resonances could be accomplished with the help of the deuterated
      analogue (2). The two stems in 31mer RNA adopt an A-type RNA conformation and the
      base-stacking continues from stem I into the beginning of the loop I. Long
      distance cross-strand NOEs showed a structured conformation at the junction
      between stem I and loop I. The loop I-stem II junction is less ordered and shows
      structural perturbation at and around the G11 -C22 base pair.

PMID- 8668533
TI  - Processing of branched DNA intermediates by a complex of human FEN-1 and PCNA.
AB  - In eukaryotic cells, a 5' flap DNA endonuclease activity and a ds DNA 5'
      exonuclease activity exist within a single enzyme called FEN-1 [flap endo
      nuclease and 5(five)'-exo-nuclease]. This 42 kDa endo-/exonuclease, FEN-1, is
      highly homologous to human XP-G, Saccharomyces cerevisiae RAD2 and S.cerevisiae
      RTH1. These structure-specific nucleases recognize and cleave a branched DNA
      structure called a DNA flap, and its derivative called a pseudo Y-structure. FEN
      1 is essential for lagging strand DNA synthesis in Okazaki fragment joining. FEN
      1 also appears to be important in mismatch repair. Here we find that human PCNA,
      the processivity factor for eukaryotic polymerases, physically associates with
      human FEN-1 and stimulates its endonucleolytic activity at branched DNA
      structures and its exonucleolytic activity at nick and gap structures. Structural
      requirements for FEN-1 and PCNA loading provide an interesting picture of this
      stimulation. PCNA loads on to substrates at double-stranded DNA ends. In
      contrast, FEN-1 requires a free single-stranded 5' terminus and appears to load
      by tracking along the single-stranded DNA branch. These physical constraints
      define the range of DNA replication, recombination and repair processes in which
      this family of structure-specific nucleases participate. A model explaining the
      exonucleolytic activity of FEN-1 in terms of its endonucleolytic activity is
      proposed based on these observations.

PMID- 8668534
TI  - Non-hydrogen bonding 'terminator' nucleosides increase the 3'-end homogeneity of
      enzymatic RNA and DNA synthesis.
AB  - We report the use of novel non-polar nucleoside analogues as terminators of
      enzymatic RNA and DNA synthesis. Standard 'runoff' RNA synthesis by T7 RNA
      polymerase gives RNA products which have ragged ends as a result of transcription
      which often extends beyond the end of the template DNA strand. Similarly, the
      Klenow fragment of Escherichia coli DNA polymerase I tends to run past the end of
      the template strand during DNA synthesis. We report here that certain non
      hydrogen-bonding nucleoside analogues, when placed at the downstream 5'-end of a
      template DNA strand, cause the polymerases to stop more abruptly at the last
      coding nucleotide. This results in a considerably more homogeneous
      oligonucleotide being produced. Three novel nucleosides are tested as potential
      terminators: 4-methylindole beta-deoxynucleoside (M), 1-naphthyl alpha
      deoxynucleoside (N) and 1-pyrenyl alpha-deoxynucleoside (P). Comparison is made
      to an abasic nucleoside (phi) and to unterminated synthesis. Of these, M is found
      to be the most efficient at terminating transcription, and both P and M are
      highly effective at terminating DNA synthesis. It is also found that the ability
      of a nucleoside to stall synthesis when it is internally placed in the template
      strand is not necessarily a good predictor of terminating ability at the end of a
      template. Such terminator nucleosides may be useful in the preparative enzymatic
      synthesis of RNA and DNA, rendering purification simpler and lowering the cost of
      synthesis by preventing the uptake of potentially costly nucleotides into
      unwanted products.

PMID- 8668535
TI  - Extrachromosomal recombination occurs efficiently in cells defective in various
      DNA repair systems.
AB  - A series of different frameshift mutations of a firefly luciferase reporter
      plasmid was created so that no activity was obtained when they were transfected
      into mammalian cells. Co-transfection of these constructs with short fragments of
      the original sequence resulted in luciferase activity in different cell lines (A
      549, NIH 3T3 and Jurkat). The level of this activity was dependent on the length
      of the fragment, regardless of cell line examined. Two different transfection
      techniques (lipofection and adenovirus-enhanced gene transfer) gave similar
      results. It was shown by polymerase chain reaction that expression of detectable
      luciferase required recombination of the transfected molecules. Cells with
      defined defects in DNA repair pathways were examined for their ability to perform
      this extrachromosomal recombination. Cells lacking normal Ku p80, (ADP
      ribosyl)transferase, MLH1 or XP-C were all capable of restoring expression to the
      frameshifted constructs. Given the pivotal roles of the above molecules in the
      pathways of DNA repair, it seems that this recombination derives from a different
      activity.

PMID- 8668536
TI  - An essential domain in Saccharomyces cerevisiae U14 snoRNA is absent in
      vertebrates, but conserved in other yeasts.
AB  - U14 is a small nucleolar RNA (snoRNA) required for early cleavages of eukaryotic
      precursor rRNA. The U14 RNA from Saccharomyces cerevisiae is distinguished from
      its vertebrate homologues by the presence of a stem-loop domain that is essential
      for function. This element, known as the Y-domain, is located in the U14 sequence
      between two universal sequences that base pair with 18S rRNA. Sequence data
      obtained for the U14 homologues from four additional phylogenetically distinct
      yeasts showed the Y-domain is not unique to S.cerevisiae. Comparison of the five
      Y-domain sequences revealed a common stem-loop structure with a conserved loop
      sequence that includes eight invariant nucleotides. Conservation of these
      features suggests that the Y-domain is a recognition signal for an essential
      interaction. Several plant U14 RNAs were found to contain similar structures,
      though with an unrelated consensus sequence in the loop portion. The U14 gene
      from the most distantly related yeast, Schizosaccharomyces pombe, was found to be
      active in S.cerevisiae, showing that Y-domain function is conserved and that U14
      function can be provided by variants in which the essential elements are embedded
      in dissimilar flanking sequences. This last result suggests that U14 function may
      be determined solely by the essential elements.

PMID- 8668537
TI  - Hdf1, a yeast Ku-protein homologue, is involved in illegitimate recombination,
      but not in homologous recombination.
AB  - Hdf1 is the yeast homologue of the mammalian 70 kDa subunit of Ku-protein, which
      has DNA end-binding activity and is involved in DNA double-strand break repair
      and V(D)J recombination. To examine whether Hdf1 is involved in illegitimate
      recombination, we have measured the rate of deletion mutation caused by
      illegitimate recombination on a plasmid in an hdf1 disruptant. The hdf1 mutation
      reduced the rate of deletion formation by 20-fold, while it did not affect
      mitotic and meiotic homologous recombinations between two heteroalleles or
      homologous recombination between direct repeats. Hence Hdf1 participates in
      illegitimate recombination, but not in homologous recombination, in contrast to
      Rad52, Rad50, Mre11 and Xrs2, which are involved in both homologous and
      illegitimate recombination. The illegitimate recombination in the hdf1 disruptant
      took place between recombination sites that shared short regions of homology (1-4
      bp), as was observed in the wild-type. Based on the DNA end-binding activity of
      Hdf1, we discuss models in which Hdf1 plays an important role in the late step of
      illegitimate recombination.

PMID- 8668538
TI  - Initiation of herpes simplex virus thymidine kinase polypeptides.
AB  - When employed as a transgene reporter, the herpes simplex type 1 virus (HSV1)
      thymidine kinase gene (tk) is ectopically expressed in mouse testis. The
      principal testicular mRNA lacks the 5'-end of the tk reading frame. As a result
      the principal translation products, P2 and P3, are N-terminally truncated. These
      co-migrate in SDS-PAGE with polypeptides synthesised during HSV1 infection that
      were previously thought to be initiated at methionine codons ATG46 and ATG60.
      Prompted by these observations we generated modified tk genes each carrying only
      one of the first three ATG codons. Transfected cells expressed both full-length
      enzyme (P1) and P2 when only ATG1 was unmodified, P2 and P3 when only ATG46 was
      unmodified or P2 and a fourth polypeptide (P4) when only ATG60 was unmodified.
      Our observations indicate that P3 is initiated at ATG46 rather than ATG60, while
      P2 is initiated at a non-ATG codon rather than ATG46 and P4 is initiated at
      ATG60. When either of two putative non-ATG initiation codons was modified P2 was
      no longer produced. Cells mainly expressing either P1 or P3 exhibited the same
      sensitivity to Ganciclovir as cells transfected with the unaltered tk gene. P1
      and P3 both have TK activity while P4 probably has none.

PMID- 8668539
TI  - DNA rehybridization during PCR: the 'Cot effect' and its consequences.
AB  - The rate of amplification of abundant PCR products generally declines faster than
      that of less abundant products in the same tube in the later cycles of PCR. As a
      consequence, differences in product abundance diminish as the number of PCR
      cycles increases. Rehybridization of PCR products which may interfere with primer
      binding or extension can explain this significant feature in late cycles.
      Rehybridization occurs with a half-time dependent on the reciprocal of the DNA
      concentration. Thus, if multiple PCR products are amplified in the same tube,
      reannealing occurs faster for the more abundant PCR products. In RT-PCR using an
      internal control, this results in a systematic bias against the more abundant of
      the two PCR products. In RNA fingerprinting by arbitrarily primed PCR (or
      differentially display of cDNAs), very large or absolute differences in the
      expression of a transcript between samples are preserved but smaller real
      differences may be gradually erased as the PCR reaction proceeds. Thus, this 'Cot
      effect' may systematically cause an underestimate of the true difference in
      starting template concentrations. However, differences in starting template
      concentrations will be better preserved in the less abundant PCR products.
      Furthermore, the slow down in amplification of abundant products will allow these
      rarer products to become more visible in the fingerprint which may, in turn,
      allow rarer cDNAs to be sampled more efficiently. In some applications, where the
      object is to stochiometrically amplify a mixture of nucleic acids, the bias
      against abundant PCR products can be partly overcome by limiting the number of
      PCR cycles and, thus, the concentration of the products. In other cases,
      abundance normalization at later cycles may be useful, such as in the production
      of normalized libraries.

PMID- 8668540
TI  - Binding and repair of O6-ethylguanine in double-stranded oligodeoxynucleotides by
      recombinant human O6-alkylguanine-DNA alkyltransferase do not exhibit significant
      dependence on sequence context.
AB  - Double-stranded (ds) oligodeoxynucleotides (29mers) containing an O6-ethylguanine
      (O6-EtGua) flanked 5' and 3' by different bases (5'..TGT..3'; 5'..CGG..3',
      5'..GGT..3'; 5'..GGG..3'; 5'..GGA..3') were synthesized to investigate the
      binding and repair characteristics of recombinant human O6-alkylguanine-DNA
      alkyltransferase (AT) in vitro. The apparent association constant (KA(app)) of AT
      to the oligomers and the repair rate constant for O6-EtGua (k) respectively, were
      determined by gel retardation and a monoclonal antibody-based filter binding
      assay. When ds- or single-stranded (ss) oligomers with or without O6-EtGua were
      used, no major differences in KA(app) values were observed with either substrate:
      KA(app) values for native AT were 7.1 and 8.4 x 10(5) M(-1) respectively, for
      unmodified and [O6-EtGua]-containing ds-oligomers. The corresponding values for
      ss-oligomers were 1.0 and 4.9 x 10(5) M(-1). The N-terminal first 56 amino acids
      of AT only exert a limited influence on DNA binding; the KA(app) values for an N
      terminally truncated AT protein (1.1 x 10(5) M(-1)) and native AT were of the
      same order. Moreover, KA(app) was hardly affected by Cys(145)-methylated AT (2.0
      x 10(5) M(-1)). The k-values (6.5-11.5 x 10(6) M(-1)s(-1)) were not significantly
      dependent on nucleotide sequence. k-values of 5.3 and 4.0 x 10(6) M(-1)s(-1)
      respectively, were obtained with the N-terminally truncated AT protein and for
      repair of the postreplicative mispair [O6-EtGua]: T by native AT. The low
      KA(app), the negligible influence on O6 of ethylation, and the minor modulation
      KA(app) and k by varying the bases flanking O6-EtGua, all indicate that the
      binding of AT to DNA is non-specific and mediated mainly by ionic interactions
      [reduced KA(app) and k-values at increased ionic strength]. Surplus DNA reduces
      the rate of O6-EtGua repair in ds-oligomers by competitive binding of AT
      molecules. The reaction mechanism of AT with DNA in vivo requires further
      investigation.

PMID- 8668542
TI  - Asymmetric mutation around the recombination break point of immunoglobulin class
      switch sequences on extrachromosomal substrates.
AB  - Junctions at class switch recombination sites in the genome are characterized by
      a unique sequence feature. Nucleotide substitutions and small deletions are
      common on either of the two sides of the switch junction, but not on both
      together. We have previously reported an extrachromosomal substrate assay system
      for analyzing the recombination of class switch sequences. Here we have sequenced
      nine junctions on each side of the break point and compared these to 17
      recombination junctions of control substrates from the same cells. Five of the
      nine switch recombination junctions have nucleotide substitutions and deletions,
      with multiple nucleotide changes being more common. Furthermore, mutations were
      found only on a single side of the junction, just as for the recombination of
      switch sequences in the genome. In contrast, only one of 17 control substrate
      junctions had a mutation, and this was a single nucleotide insertion. This
      difference is highly significant (P < 0.00007) and indicates that the fundamental
      recombination mechanism is likely to be similar for switch sequences in the
      chromosome and on minichromosome substrates.

PMID- 8668541
TI  - Thermodynamic effects of formamide on DNA stability.
AB  - Formamide lowers melting temperatures (Tm) of DNAs linearly by 2.4-2.9 degrees
      C/mole of formamide (C(F)) depending on the (G+C) composition, helix conformation
      and state of hydration. The inherent cooperativity of melting is unaffected by
      the denaturant. dTm/dC(F)for 11 plasmid domains of 0.23 < (G+C)<0.71 generally
      fit to a linear dependence on (G+C)-content, which, however, is consistent with a
      (G+C)-independent alteration in the apparent equilibrium constant for thermally
      induced helix <--> coil transitions. Results indicate that formamide has a
      destabilizing effect on the helical state, and that sequence-dependent variations
      in hydration patterns are primarily responsible for small variations in
      sensitivity to the denaturant. The average unit transition enthalpy delta
      H(m)[see text for complete expression], exhibits a biphasic dependence on
      formamide concentration. The initial drop of -0.8 kcal/mol bp at low formamide
      concentrations is attributable to a delta delta H(m)[see text for complete
      expression], for exchange of solvent in the vicinity of the helix: displacement
      by formamide of weakly bound hydrate or counterion. The phenomenological effects
      are equivalent to lowering the bulk counterion concentration. Poly(dA.dT)
      exhibits a much lower sensitivity to formamide, due to the specific pattern of
      tightly bound, immobilized water bridges that buttress the helix from within the
      narrow minor groove. Tracts of three (A.T)-pairs behave normally, but tracts of
      six exhibit the same level of reduced sensitivity as the polymer, suggesting a
      conformational shift as tracts are elongated beyond some critical length
      [McCarthy J.G. and Rich,A. (1991) Nucleic Acids Res. 19, 3421-3429].

PMID- 8668544
TI  - A multi-well version of in situ hybridization on whole mount embryos of
      Caenorhabditis elegans.
AB  - We report an efficient procedure for in situ hybridization with a multi-well
      format on Caenorhabditis elegans embryos for large scale screening of gene
      expression patterns in this organism. Each hybridization well contains embryos at
      various stages throughout embryogenesis. The validity of the method was confirmed
      through results with control genes whose expression patterns have been reported;
      glp-1 in very early embryos, myo-2 in pharyngeal muscle and unc-54 in body wall
      muscle. Several collagen genes and a pepsinogen gene were also examined to
      establish a set of lineage-specific markers. As a pilot project, we examined
      approximately 100 unique cDNA species classified by our cDNA project, finding
      that approximately 10% of the cDNA groups were expressed in specific cells and at
      specific stages.

PMID- 8668543
TI  - Transcriptional activation by Oct-3: evidence for a specific role of the POU
      specific domain in mediating functional interaction with Oct-1.
AB  - Oct-3, a member of the POU family of transcription factors, is expressed in
      pluripotent cells of early mammalian embryos and in undifferentiated embryonal
      carcinoma cell lines. Using a variety of Oct-3 mutants, we have identified two
      different domains of Oct-3 which activate transcription in transfected mammalian
      cells. One of these domains, located in the C-terminal part of the protein, plays
      a major role in transcriptional activation when Oct-3 is bound to its cognate
      site, the octamer motif. An Oct-3 mutant containing a single amino acid
      substitution in the POU homeodomain is unable to bind the octamer target in
      vitro, yet is still able to activate transcription in an octamer-dependent
      manner. We provide evidence that transactivation by this mutant involves protein
      protein interactions with the ubiquitous octamer binding factor Oct-1. This
      interaction requires the POU-specific domain of Oct-3 and allows recruitment of
      Oct-3 to the target promoter even in the absence of Oct-3 DNA binding.

PMID- 8668546
TI  - Structure-infectivity analysis of the human rhinovirus genomic RNA 3' non-coding
      region.
AB  - The specific recognition of genomic positive strand RNAS as templates for the
      synthesis of intermediate negative strands by the picornavirus replication
      machinery is presumably mediated by cis-acting sequences within the genomic RNA
      3' non-coding region (NCR). A structure-infectivity analysis was conducted on the
      44 nt human rhinovirus 14 (HRV14) 3' NCR to identify the primary sequence and/or
      secondary structure determinants required for viral replication. Using
      biochemical RNA secondary structure probing techniques, we have demonstrated the
      existence of a single stem-loop structure contained entirely within the 3' NCR,
      which appears to be phylogenetically conserved within the rhinovirus genus. We
      also report the in vivo analysis of a number of 3' NCR deletion mutations
      engineered into infectious cDNA clones which were designed to disrupt the stem
      loop secondary structure to varying degrees. Large deletions (up to 37 nt)
      resulted in defective growth phenotypes, although they were not lethal. We
      propose that the absolute requirements for initiation of negative strand
      synthesis are less stringent than previously postulated, even though defined RNA
      secondary structure determinants may have evolved to facilitate and/or regulate
      the process of viral RNA replication.

PMID- 8668545
TI  - recA-like genes from three archaean species with putative protein products
      similar to Rad51 and Dmc1 proteins of the yeast Saccharomyces cerevisiae.
AB  - The process of homologous recombination has been documented in bacterial and
      eucaryotic organisms. The Escherichia coli RecA and Saccharomyces cerevisiae
      Rad51 proteins are the archetypal members of two related families of proteins
      that play a central role in this process. Using the PCR process primed by
      degenerate oligonucleotides designed to encode regions of the proteins showing
      the greatest degree of identity, we examined DNA from three organisms of a third
      phylogenetically divergent group, Archaea, for sequences encoding proteins
      similar to RecA and Rad51. The archaeans examined were a hyperthermophilic
      acidophile, Sulfolobus sofataricus (Sso); a halophile, Haloferax volcanii (Hvo);
      and a hyperthermophilic piezophilic methanogen, Methanococcus jannaschii (Mja).
      The PCR generated DNA was used to clone a larger genomic DNA fragment containing
      an open reading frame (orf), that we refer to as the radA gene, for each of the
      three archaeans. As shown by amino acid sequence alignments, percent amino acid
      identities and phylogenetic analysis, the putative proteins encoded by all three
      are related to each other and to both the RecA and Rad51 families of proteins.
      The putative RadA proteins are more similar to the Rad51 family (approximately
      40% identity at the amino acid level) than to the RecA family (approximately
      20%). Conserved sequence motifs, putative tertiary structures and phylogenetic
      analysis implied by the alignment are discussed. The 5' ends of mRNA transcripts
      to the Sso radA were mapped. The levels of radA mRNA do not increase after
      treatment with UV irradiation as do recA and RAD51 transcripts in E.coli and
      S.cerevisiae. Hence it is likely that radA in this organism is a constitutively
      expressed gene and we discuss possible implications of the lack of UV
      inducibility.

PMID- 8668547
TI  - Positively charged oligonucleotides overcome potassium-mediated inhibition of
      triplex DNA formation.
AB  - The formation of triplex DNA using unmodified, purine-rich oligonucleotides
      (ODNs) is inhibited by physiologic levels of potassium. Changing negative
      phosphodiester bonds in a triplex forming oligonucleotide (TFO) to neutral
      linkages causes a small increase in triplex formation. When phosphodiester bonds
      in a TFO are converted to positively-charged linkages the formation of triplex
      DNA increases dramatically. In the absence of KCl, a 17mer TFO containing 11
      positively-charged linkages at a concentration of 0.2 microM converts essentially
      all of a 30 bp target duplex to a triplex. Less than 15% of the target duplex is
      shifted by 2 microMolar of the unmodified TFO. In 130 mM KCl, triplex formation
      is undetectable using the unmodified TFO, while triplex formation is nearly
      complete with 2 microM positively-charged TFO. With increasing potassium, TFOs
      containing a higher proportion of modified linkages show enhanced triplex
      formation compared with those less modified. In contrast with unmodified TFOs,
      triplex formation with more heavily modified TFOs can occur in the absence of
      divalent cations. We conclude that replacement of phosphodiester bonds with
      positively-charged phosphoramidate linkages results in more efficient triplex
      formation, suggesting that these compounds may prove useful for in vivo
      applications.

PMID- 8668548
TI  - Base-boronated dinucleotides: synthesis and effect of N7-cyanoborane substitution
      on the base protons.
AB  - Boron-modified nucleic acids comprise a new set of DNA mimics that have potential
      biological and therapeutic applications. A series of nine dinucleotides
      containing N7-cyanoborane-2'-deoxyguanosine ((7b)dG) at the 3', 5' or both
      positions of the phosphodiester linkage have been synthesized using solution
      phase phosphoramidite chemistry. Fmoc was used as the 5'-protecting group because
      of incompatibility of the cyanoborane moiety with 5'-DMT cations generated during
      the deprotection step. The presence of the cyanoborane group was confirmed on the
      basis of Fab-MS and 1H NMR spectroscopy. The H-8 proton of (7b)dG in the
      dinucleotides shifted 0.35-0.80 p.p.m. downfield relative to that of unmodified
      dG. A comparison of the D20 exchange kinetics of the H-8 proton at 60 degrees C
      showed that H-8 of (7b)dG is very labile relative to unmodified dG, indicating
      that the N7-cyanoborane modification increases the acidity of the H-8 proton of
      (7b)dG. These studies illustrate the feasibility of synthesizing boron-containing
      oligonucleotides which are modified at the N7-guanine to block Hoogsteen pairing
      in the DNA major groove.

PMID- 8668549
TI  - Isolation and characterization of the QM promoter.
AB  - This report describes the isolation, sequencing and preliminary characterization
      of the first 1 kb of the 5'-regulatory region of the human QM gene. This region
      and the 5' -half of the transcribed region of the QM gene are enriched for C and
      G nucleotides with no bias against CpG dinucleotides--indicative of a CpG island.
      Several consensus GC boxes are present within the sequence. Most are clustered at
      the distal end, with one site present in the proximal 200 bp of the promoter.
      Electrophoretic mobility shift experiments and luciferase assays done in insect
      cells transfected with an Sp1 expression construct suggest that most of these
      sites can bind Sp1 or a closely related factor. In addition, the promoter is
      shown to be responsive to cAMP via a response element (CRE) in the proximal
      promoter. Studies with 5'-end and internal deletion mutants suggest that elements
      in the distal promoter exert their positive effect through interactions with a
      proximal element(s). Candidate proximal elements include the proximal GC box and
      a 43 bp region between a KpnI site (at -182) and a Smal site (at -139).

PMID- 8668550
TI  - Two-dimensional gel analysis of rolling circle replication in the presence and
      absence of bacteriophage T4 primase.
AB  - The rolling circle DNA replication structures generated by the in vitro phage T4
      replication system were analyzed using two-dimensional agarose gels. Replication
      structures were generated in the presence or absence of T4 primase (gp61),
      permitting the analysis of replication forks with either duplex or single
      stranded tails. A characteristic arc shape was visualized when forks with single
      stranded tails were cleaved by a restriction enzyme with the help of an
      oligonucleotide that anneals to restriction sites in the single-stranded tail.
      After calibrating the gel system with this well-studied rolling circle
      replication reaction, we then analyzed the in vivo replication directed by a T4
      replication origin cloned within a plasmid. DNA samples were generated from
      infections with either wild-type or primase-deletion mutant phage. The only
      replicative arc that could be detected in the wild-type sample corresponded to
      duplex Y forms, consistent with very efficient lagging strand synthesis.
      Surprisingly, we obtained evidence for both duplex and single-stranded DNA tails
      in the samples from the primase-deficient infection. We conclude that a
      relatively inefficient mechanism primes lagging strand DNA synthesis in vivo when
      gp61 is absent.

PMID- 8668551
TI  - Regulation of in vitro gene expression using antisense oligonucleotides or
      antisense expression plasmids transfected using starburst PAMAM dendrimers.
AB  - Starburst polyamidoamine (PAMAM) dendrimers are a new type of synthetic polymer
      characterized by a branched spherical shape and a high density surface charge. We
      have investigated the ability of these dendrimers to function as an effective
      delivery system for antisense oligonucleotides and 'antisense expression
      plasmids' for the targeted modulation of gene expression. Dendrimers bind to
      various forms of nucleic acids on the basis of electrostatic interactions, and
      the ability of DNA-dendrimer complexes to transfer oligonucleotides and plasmid
      DNA to mediate antisense inhibition was assessed in an in vitro cell culture
      system. Cell lines that permanently express luciferase gene were developed using
      dendrimer mediated transfection. Transfections of antisense oligonucleotides or
      antisense cDNA plasmids into these cell lines using dendrimers resulted in a
      specific and dose dependent inhibition of luciferase expression. This inhibition
      caused approximately 25-50% reduction of baseline luciferase activity. Binding of
      the phosphodiester oligonucleotides to dendrimers also extended their
      intracellular survival. While dendrimers were not cytotoxic at the concentrations
      effective for DNA transfer, some non-specific suppression of luciferase
      expression was observed. Our results indicate that Starburst dendrimers can be
      effective carriers for the introduction of regulatory nucleic acids and
      facilitate the suppression of the specific gene expression.

PMID- 8668553
TI  - Vectorette PCR isolation of microsatellite repeat sequences using anchored
      dinucleotide repeat primers.
AB  - We have developed a vectorette PCR approach to provide an improved method for
      isolation of microsatellite repeats. The modified procedure relies on PCR
      amplification using a vectorette-specific primer in combination with one of a
      panel of anchored dinucleotide repeat primers. The target DNA to be screened for
      microsatellite sequences can be from YAC, P1, cosmid, bacteriophage or plasmid
      clones. We have used this technique to isolate novel, polymorphic microsatellite
      repeats from clones containing the amelogenin gene (AMGX) located on human
      chromosome Xp22.3.

PMID- 8668552
TI  - Molecular weight determination of plasmid DNA using electrospray ionization mass
      spectrometry.
AB  - Ionization and molecular weight (MW) determination of megadalton size plasmid DNA
      has been achieved using electrospray ionization (ESI) with Fourier transform ion
      cyclotron resonance (FTICR) mass spectrometry. DNA molecules were shown to remain
      intact through electrospray ionization by collection on a specially prepared
      surface, followed by agarose gel electrophoresis. Individual highly charged ions
      of plasmid DNA produced by ESI were trapped in an FTICR cell for up to several
      hours and reacted with acetic acid to induce charge state shifts. Measurements of
      mass-to-charge ratios for these multiple peaks arising from charge state shifting
      give MW measurements of individual ions with an average accuracy of 0.2%. The MW
      distribution was obtained by measurements for a number of individual ions from
      the same sample [plasmid DNA: pGEM-5S MW(cal) = 1.946 MDa], yielding a MW(obs) of
      1.95 +/- 0.07 MDa for ions clustered in the vicinity of the expected MW.

PMID- 8668554
TI  - Print-capture PCR: a simple and highly sensitive method for the detection of plum
      pox virus (PPV) in plant tissues.

PMID- 8668555
TI  - Molecule by molecule PCR amplification of complex DNA mixtures for direct
      sequencing: an approach to in vitro cloning.

PMID- 8668556
TI  - A simplified genomic subtractive procedure for isolating deleted sequences.

PMID- 8668557
TI  - Scholarship: how important is it?

PMID- 8668558
TI  - Issues in conducting intervention research in long-term care settings.
AB  - Originally we proposed a straightforward experimental design using quantitative
      data to test a series of hypotheses about how changes in the mealtime context and
      mealtime interactions would influence self-feeding behaviors and imposed
      disability. The design was clean and the interventions carefully delineated. We
      used a number of strategies for reducing threats to internal validity, some of
      which worked and some of which did not. Many of the problems we encountered in
      operationalizing this clinical experiment arose, not from the particular
      environment in which we worked, but from the nature of long-term care settings
      and the staffing patterns within those settings. To some degree, the problems we
      encountered are inherent to field experimentation in nursing in general. Often
      field experiments are reported as if no problems arose in implementation, yet no
      study is problem free. We believe acknowledging and understanding some of the
      sources of field noise in field experiments are almost as important as
      understanding the results of the study itself. The field noise is an
      indispensable part of the results.

PMID- 8668559
TI  - Coping, diabetes, and the older African-American.

PMID- 8668560
TI  - Implications of U.S. health care reform for the rural elderly.
AB  - Health care services for elders living in rural areas have been limited by
      inadequate financing, lack of awareness of existing services, insufficient
      numbers of providers, and geographic dispersion of rural residents. Not all
      proposals for health care reform would help reduce these barriers, however.
      Nurses working in rural areas can facilitate the evolution of the health care
      system in several ways. A primary mechanism is the development and implementation
      of nurse-managed centers, networking with existing agencies and services to
      provide outreach programs to the underserved rural elders. Another mechanism is
      participation in professional organizations that lobby for rural health concerns.
      A third strategy is participation in program evaluation and intervention studies
      with policy-relevant implications. It is an exciting era for nurses involved in
      rural health and an opportune time to promote effective health care for older
      adults who live in rural areas.

PMID- 8668561
TI  - Understanding contemporary health and welfare services: The Social Security Act
      of 1935 and the Public Health Service Act of 1944.

PMID- 8668562
TI  - Reframing women's health in nursing education: a feminist approach.
AB  - To operate from a feminist paradigm is a new way of thinking for nurse educators.
      Feminist perspectives in nursing provide a new stage of consciousness--one that
      values women's voices, their way of knowing, and their life experiences, and,
      most important, one that challenges traditional patriarchal practices.
      Furthermore, nursing curricula with feminist perspectives provides a
      biopsychosocial approach that encourages the full recognition of variables that
      can influence women's health, such as socioeconomic status, racial and ethnic
      background, and biobehavioral factors. The debate in medicine over a specialty in
      women's health is not unique. The history of academia abounds with descriptions
      of struggles to establish new fields and disciplines. Recent specialties, such as
      pediatrics and gerontology, which are distinguished by age rather than specific
      organ or system, struggled for establishment and recognition. Historically,
      nursing curricula has emulated the biomedical model that is reductionistic and
      contradictory to nursing's holistic mission. Rather than classifying women's
      health into a separate entity, women's health may be introduced into present
      curricula by employing feminist ideals and pedagogy throughout the curriculum.
      This approach would provide a mechanism to explore women's health issues that
      were previously minimally addressed at best, or not addressed at all. More
      important, students would be provided with an opportunity to examine the societal
      effects of racism, sexism, and classism, and this education would potentially
      lead to a growing awareness of concerns specific to women and minorities.

PMID- 8668563
TI  - Langerhans' cell histiocytosis: case reports and literature review.

PMID- 8668564
TI  - A clinical and research protocol for characterizing patients with
      hypophosphatasia.

PMID- 8668565
TI  - Effect of 1- and 4-minute treatments of topical fluorides on a composite resin.
AB  - The purpose of this in vitro study was to compare the effects of a 1-min
      immersion and of 4-min immersions in an acidulated phosphate fluoride (1.23% APF)
      foam, a 1.23% APF gel, a 2.0% sodium fluoride (NaF) gel, and water on surface
      topography and on weight of a composite resin (APH). Forty composite resin
      specimens were placed into eight groups (N = 5 each). For each treatment, a group
      of specimens was immersed for either 1 or 4 min (four 1-min immersions).
      Specimens were weighed before and after each immersion. The surface topography of
      two scanning electron micrographs of each specimen was scored visually by two
      investigators. Inter-rater reliability was r = 0.75 (intraclass correlation
      coefficient). There were no significant differences in the mean visual scores or
      weight among the 1-min immersion groups. Significantly greater surface changes
      and weight loss of this composite resin occurred following 4-min immersions in
      either 1.23% APF foam or gel as compared with those immersed in either 2.0% NaF
      gel or water (P 0.0001; one-way ANOVA, Tukey's Studentized Range Test).

PMID- 8668566
TI  - A comparison of six enamel treatment procedures for sealant bonding.
AB  - This in-vitro study evaluated the effectiveness of six different enamel treatment
      procedures for bonding a dental sealant. Sixty extracted human molar teeth were
      separated into the following enamel treatment groups (10 teeth each): group 1
      (control)-etched with 37% phosphoric acid; group 2-air polished (air abraded)
      with 45 microns particles of sodium bicarbonate; group 3-air abraded with 50
      microns aluminum oxide particles; group 4-etched with 2.5% nitric acid; group 5
      air abraded with sodium bicarbonate particles and etched with 37% phosphoric
      acid; and group 6-air abraded with 50-microns aluminum oxide particles and etched
      with 37% phosphoric acid. The enamel treatment procedures were accomplished on
      intact mesial or distal surfaces. Following the enamel treatment, a sealant was
      bonded to the surfaces using a plastic matrix technique. After 24 hr of water
      storage at 37 degrees C, the specimens were debonded using an Instron machine.
      The mean shear bond strengths (MPa) were as follows: group 1-9.19 +/- 1.34 MPa;
      group 2-2.03 +/- 1.67 MPa; group 3-1.50 +/- 0.93 MPa; group 4-4.99 +/- 1.26 MPa;
      group 5-11.61 +/- 4.51; and group 6-11.14 +/- 1.70 MPa. Statistical analysis
      using a one-way ANOVA and Scheffe F-test revealed no significant difference (P >
      0.05) among groups 1,5, and 6. However, there was a significant difference (P <
      0.05) between groups 1,5, and 6 and the other three groups (2,3, and 4). In
      conclusion, 37% phosphoric acid treatment of intact enamel, or a combination of
      air abrasion with sodium bicarbonate or aluminum oxide followed by phosphoric
      acid, provides significantly higher bond strengths of a sealant material than
      enamel conditioning with 2.5% nitric acid or air abrasion with sodium bicarbonate
      or aluminum oxide.

PMID- 8668567
TI  - Intranasal midazolam better at effecting amnesia after sedation than oral
      hydroxyzine: a pilot study.
AB  - Providing amnesia about a surgery is a desired side effect of a medication. This
      study compares anterograde amnesic effects of midazolam with hydroxyzine in
      children undergoing dental treatment with those drugs plus nitrous oxide, using a
      recall test. Thirty ASAI children 24-28 months, were shown a Standard-Binet
      intelligence scale-memory for objects subtest before entering treatment room.
      Twenty-lone randomly determined children received 3.7 mg/kg hydroxyzine 45 min
      before treatment or 0.2 mg/kg intranasal midazolam in two succeeding
      appointments, alternatively. Recall in the 30-subject treatment group was 90%.
      Recall in the 21-subject treatment group was 71% for hydroxyzine and 29% for
      midazolam. Midazolam was more effective in creating amnesia than hydroxyzine in
      this study.

PMID- 8668568
TI  - The effects of nitrous oxide on behavior and physiological parameters during
      conscious sedation with a moderate dose of chloral hydrate and hydroxyzine.
AB  - The purpose of this study was to determine differences in heart rate (HR), blood
      pressure (BP), peripheral oxygen saturation (pO2), expired CO2 (CO2), and
      behavior (using two scales) comparing nitrous oxide/oxygen (N2O) with oxygen (O2)
      alone in 20 children (mean age 45 +/- 5.1 months) sedated with chloral hydrate
      (CH) and hydroxyzine in a double-blind crossover design. Administration of CH (40
      mg/kg) and hydroxyzine (2 mg/kg) was held constant for each patient visit;
      however, N2O (50%) was administered during one visit and O2 (100%) at the other
      in a randomly determined manner. Physiologic and behavioral parameters were
      collected during eight specific procedural events (e.g., administration of local
      anesthesia). Data were analyzed with a repeated-measures ANOVA, one-way ANOVA, t
      test, Kruskal Wallis ANOVA, and descriptive statistics. There was no
      statistically significant difference in any physiologic or behavioral parameter
      as a function of inhalation agent. However, significant differences were found
      for certain physiological parameters (i.e., HR [F = 5.41, P < 0.001], pO2 [F =
      6.04, P < 0.001], and CO2 [F = 2.33, P < 0.027]) and all behavioral measures (%
      crying [F = 2.82, P < 0.008], % quiet [F = 5.38, P < 0.001], % movement [F =
      3.88, P < 0.001], and % struggle [F = 2.83, P < 0.007]) of one scale (Ohio State
      University Behavioral Rating Scale [OSUBRS]) as a function of procedural events.
      Although no statistically significant differences were attributable to inhalation
      agent, evidence suggests that N2O resulted in less crying and struggling and more
      quiet behaviors than O2. Significant correlations existed between sub-categories
      of the two behavioral rating scales, suggesting some association between the
      scales. One may conclude from the results of this study that moderate doses of CH
      and hydroxyzine in combination with nitrous oxide are not associated with any
      significant potentiation effects on physiologic parameters compared with the same
      oral agents with oxygen alone. Certain procedural events (e.g., administration of
      local anesthesia) do result in patient responses that affect specific behaviors
      and physiology. Although the effects of N2O may not be statistically significant,
      generally it produces an attenuation in physiological and behavioral responses as
      measured under the conditions of this study.

PMID- 8668569
TI  - The composition of subgingival microflora in two groups of children with and
      without primary dentition alveolar bone loss.
AB  - The is study examined the relationships between the microbial composition of the
      subgingival plaque, contact loss caused by caries and alveolar bone loss (ABL) in
      primary molars. The study included 10 children with contact loss in at least two
      sites, one with ABL and one without ABL, and 10 children without ABL with sites
      with or without contact loss. The microbial composition of subgingival plaque was
      examined by dark-field microscopy and by cultures of total anaerobic bacteria,
      Actinobacillus actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg). Dark
      field microscopy confirmed that spirochetes and motile rods may be part of the
      indigenous flora of the oral cavity. More spirochetes and motile rods were
      observed in sites with ABL than in control sites in the same subject and control
      subjects without ABL. Lower numbers of cocci were seen in sites with ABL than in
      sites in children without ABL, but a significant difference was not observed
      between sites with ABL and healthy sites within the same subjects. No significant
      differences in the dark-field values were evident in sites without ABL, with or
      without contact loss. Aa and Pg were found in children and sites with or without
      ABL. In sites with Aa, larger proportions of spirochetes, lower values of cocci,
      and more colonies of Pg were evident. No significant differences in anaerobic
      bacteria were evident between sites with or without contact loss or with or
      without ABL. ABL in the primary dentition was found to be related to the
      microbial composition of the subgingival plaque, but not related to contact loss
      per se.

PMID- 8668570
TI  - Dental agenesis in hemifacial microsomia.
AB  - Hemifacial microsomia (HM) is an asymmetrical congenital deformity of the head
      and face caused by anomalous development of the structures derived from the first
      and second branchial arches. This study evaluates the incidence of agenesis and
      dental inclusions in HM patients. Sixty-three HM patients, 27 male and 36 female,
      ranging from 7 to 43 years had monolateral (61) and bilateral (2) presentation.
      From clinical examination, photographs, and various radiographs, the following
      manifestations were noted: 11 patients had tooth agenesis with at least one on
      affected side and 5 patients had dental inclusions. The greater the severity of
      HM, the greater likelihood of agenesis. Third molars were most commonly missing.
      Dental inclusions did not show a relationship to severity.

PMID- 8668571
TI  - A comparison of the pulpal response to freeze-dried bone, calcium hydroxide, and
      zinc oxide-eugenol in primary teeth in two cynomolgus monkeys.
AB  - This study assessed the pulp healing response to human freeze-dried bone (FDB) in
      two cynomolgus monkeys using 36 noncarious primary teeth pulpotomized and
      randomly assigned to three medicaments. FDB was applied on the pulp stumps and
      covered with sterile tin foil as experimental group. The two other groups
      received either calcium hydroxide [Ca(OH)2], or IRM (reinforced ZOE). All teeth
      were restored with amalgam. One animal was sacrificed at 6 weeks and the other 6
      months after treatment. Teeth were extracted and placed in 10% formalin.
      Histological evaluation indicated that 100% of teeth treated with FDB had vital
      pulps compared with 75% of the Ca(OH)2 group after 6 weeks. Dentin bridges were
      present in 87.5% of FDB versus 75% of Ca(OH)2 group. Inflammatory cells were
      absent or mild in 100% of FDB-treated versus 75% of the Ca(OH)2 group. After 6
      months, 83.3% of FDB-treated teeth had vital pulps compared with the Ca(OH)2
      group, which showed 100% pulpal necrosis. In FDB-treated pulps, 100% of teeth
      showed dentin bridges versus 50% of teeth treated with Ca(OH)2. Inflammatory
      cells were absent or mildly present in 83.3% of FDB-treated teeth while 100% of
      Ca(OH)2 showed moderate to severe inflammation. IRM-treated teeth all showed
      pulpal necrosis after 6 months. We concluded that FDB was superior to calcium
      hydroxide in treating primary pulp dentition in cynomolgus monkeys.

PMID- 8668572
TI  - Predicting pulpectomy success and its relationship to exfoliation and
      succedaneous dentition.
AB  - This study evaluated factors that affected pulpectomy (PE) success and its effect
      on the succedaneous tooth's eruption and enamel formation. Sixty-five of 250
      patients with PEs met the selection criteria and yielded 81 zinc oxide-eugenol
      PEs (30 incisors, 51 molars) followed a mean time of 90.8 months. Overall PE
      success was 77.7% with no difference between molars and incisors (P = 0.53).
      Enamel defects were observed in 18.7% of succedaneous teeth and were related (P =
      0.005) to the pre-existing infection causing excess root resorption (>1 mm
      preoperative root resorption = 44.4% defects) but were not related to
      overretention of ZOE filler (P = 1) or length of fill (P = 0.36). The PE
      procedure was not related to causing succedaneous tooth defects since teeth
      replacing PEs showed no significant increase in the incidence of defects compared
      with untreated contralateral controls (P = 0.99). There was a 20% incidence of
      succedaneous tooth anterior cross-bite or palatal eruption following incisor PEs
      and 21.6% ectopic eruption of premolars following primary molar PEs. Most PEs
      (95.9%) were lost at their normal exfoliation time or earlier, but 35.8% needed
      extraction due to overretention by soft tissue at the time of shedding.
      Pulpectomy success rates showed that the most important preoperative predictor
      was the amount of primary tooth root resorption. Greater than 1 mm of root
      resorption resulted in only a 23.1% success rate, which was significant (P =
      0.001). Pulpectomies filled short or to the apex had a significantly greater
      success (P = 0.011) than long fills. Pulpectomies correctly done do not appear to
      contribute to adverse effects on succedaneous tooth formation but have a 20%
      chance of altering the path of permanent tooth eruption.

PMID- 8668573
TI  - Congenitally missing permanent lateral incisors in conjunction with a
      supernumerary tooth: case report.

PMID- 8668574
TI  - Pre-eruptive resorption of dentin in the primary and permanent dentitions: case
      reports and literature review.

PMID- 8668575
TI  - Evaluation methods of pediatric dentistry residents, faculty and programs: our
      current status.

PMID- 8668576
TI  - Computer-based evaluation of pediatric dental residents' clinical performance.

PMID- 8668577
TI  - Identifying and quantifying graduate students' experiences during advanced
      education programs.

PMID- 8668578
TI  - The medical model for evaluating residents.

PMID- 8668579
TI  - A national in-service training examination in pediatric dentistry (PEDSITE): a
      challenge to academicians.

PMID- 8668580
TI  - A model for resident evaluation.

PMID- 8668581
TI  - Think outside the box!

PMID- 8668582
TI  - [Infected bowel syndrome].
AB  - Colonization of the gut by intestinal bacteria begins at birth and progresses
      rapidly in the immediate postnatal period. Host defense mechanisms that mediate
      enteric colonization include gastric acidity and intestinal motility. The small
      bowell overgrowth syndrome is a condition characterized by large numbers of
      bacteria, often anaerobes, in the upper intestine. Steatorrea, carbohydrate
      malabsorption and abdominal pain are frequently present. Predisposing conditions
      are localized anatomic disorders (surgical blind loops, small bowel strictures
      caused by surgery or Crohn's disease, short-gut syndrome without ileocaecal
      valve), motility derangements or reduction of gastric acidity. Diagnosis of the
      overgrowth syndrome is often difficult and quantitative cultures of jejunal
      aspirated fluid is the best diagnostic test. Antimicrobial therapy directed
      against anaerobes is often successful, but the best therapeutic approach is the
      correction of predisposing conditions, if present.

PMID- 8668583
TI  - [Alpha-interferon in the treatment of chronic hepatitis C in children].
AB  - The hepatitis C virus is the main causative agent for sporadic as well as
      parenteral cases of non-A non-B hepatitis. Alpha interferon is a biologically
      active protein produced by B lymphocytes and monocytes which can be manufactured
      by recombinant DNA technology. Treatment of chronic hepatitis C with interferon
      in adults is associated with a sustained response in 20-25% of treated cases.
      First studies provide encouraging results for the use of interferon in the
      treatment of chronic hepatitis C in children, but controlled trials using this
      drug in a larger population of children are needed.

PMID- 8668584
TI  - [Testicular and paratesticular tumors in children].
AB  - Testis tumors in children occur infrequently and exibit differences in their
      histopathology, clinical behaviour and therapy from their adult counterparts.
      From 1979 to 1994, 17 children and adolescent with testicular tumors were treated
      at the Pediatric Surgical Department of Vicenza Regional Hospital. Paratesticular
      rabdomiosarcoma were present in 3 cases, 4 patients had embrional carcinoma, 1
      Sertoli cell tumor, 2 Leydig cell gonadal stromal tumor, and leukemic infiltrates
      of the testis were clinically evident in 7 patients. We report our clinical
      series and discuss in relation to clinical characteristic, histopathology and
      therapy and conclude that the improved survival during the past decade is
      attributable to better diagnostic imaging thecniques, the availability of serum
      tumor markers to monitor disease activity and more effective chemotherapy.

PMID- 8668585
TI  - [pH-metric parameters potentially predictive of asthmatic symptomatology:
      clinical and statistical research].
AB  - The gastro-esophageal reflux (GER) usually causes digestive symptoms, failure to
      trive and/or respiratory symptoms. Furthemore the association between GER and
      asthma is well known. Nevertheless, the relationship between two pathologies and
      role of GER in aggravation of asthma are not well known. The aims of our study is
      to identify the peculiar pH-metric caracteristics of GER may be responsable of
      asthmatic symptoms in children. The study was conducted in 32 children. The
      patients were divided into two groups: Group A composed of 16 children suffering
      from non-allergic asthma characterized by prevalent nocturnal manifestation;
      Group B composed of 16 children suffering from GER, without respiratory symptoms.
      All patients underwent to 21 pH-monitoring. The pH-metric data collected in two
      groups are submitted to statistic analysis using the Student's "t" Test.

PMID- 8668586
TI  - [Beta-2 agonists, exposure to allergens and bronchial hyperreactivity in children
      with allergic asthma].
AB  - The contribution of beta 2-agonist treatment per se and the effect of beta 2
      agonists plus allergen exposure was evaluated in two groups of thirteen asthmatic
      children being treated respectively at sea level during the period of maximal
      allergen exposure and at high altitude in an environment free of the offending
      allergens. Bronchial hyperreactivity was evaluated by standardised exercise tests
      before and after treatment with salbutamol controlled release tablets (4 mg).
      Challenges were performed at the beginning and after 2 and 4 weeks of treatment.
      A fourth test was performed 2 days after stopping the treatment. Children treated
      with salbutamol at sea level (exposure to allergen) showed baseline delta PEF of
      16.9 +/- 3.4 and 13.7 +/- 4.2, 20.7 +/- 4.3, 26.0 +/- 5.1 respectively for the
      second, third and fourth test. Children treated at high altitude showed
      respectively delta PEF of 34.9 +/- 5.1, 31.1 +/- 4.9, 26.5 +/- 5.4, 27.9 +/- 5.0.
      These data suggest that oral salbutamol per se is not responsible for an increase
      in bronchial responsiveness, but eventually suggest that treatment with beta 2
      agonists at the same time as continued allergen exposure may be responsible for
      an increase in bronchial hyperresponsiveness.

PMID- 8668587
TI  - [Syncopal fainting episodes and gastroesophageal reflux].
AB  - Fainting syncopal events are caused by a transient functional neuronal paralysis.
      Reflex syncope happens for brainstem involving mediated by peripherical
      afferents. Sometimes gastroesophageal reflux (GER) has been implicated in the
      development of obstructive apnea. Gastroesophageal reflux, despite the absence of
      a clinical history of vomiting and regurgitation, is observed in a significant
      proportion of infants presenting with ALTE (Apparent Life Threatening Event): an
      episode characterized by some combination of apnea, color change, marked change
      in muscle tone, choking or gagging. Though a cause-and-effect relationship
      between GER and the development of ALTE remains to be established a possible
      direct relationship between oesophageal acidification and the onset of
      alterations in cardiopulmonary function and impairment of consciousness can be
      hypothesized. We refer the case of two female infants that developed recurrent
      ALTE(s) characterized by paleness, change in muscle tone and loss of
      consciousness. The infants resulted affected respectively by a mild and severe
      gastroesophageal reflux (score: 40, > 50); in one case an episode of GER was
      recorded by the intraoesophageal pH-monitoring during a syncopal episode. The
      treatment with antiacid drugs was effectual and the infants did not present
      ALTE(s). The cases presented are in favour of a routine search of
      gastroesophageal reflux in infants presenting with one or recurrent ALTE(s). The
      identification of these infants will permitt to develop a correct strategy of
      treatment.

PMID- 8668588
TI  - [Diagnosis of food allergy caused by fruit and vegetables in children with atopic
      dermatitis].
AB  - Atopic dermatitis (A.D.) is a frequent, complex and multifactorial disease: Food
      Allergy (F.A.), probably underestimated, especially for fruits and vegetables,
      seems to play an important pathogenetic role in children. The purpose of this
      study is to estimate, on a sample of children with A.D., the prevalence of F.A.
      (for fruits and vegetables), and the reliability of diagnosis of Prick+Prick test
      compared with the usual Prick test, RAST and challenge. Twentysix patients (17 M
      and 9 F), ranging in age from 5 months to 8 years, were enrolled in the study.
      All fulfilled the criteria of Hanifin and Rajka for the diagnosis of A.D. Food
      RAST, prick tests with inhalant and food extracts and Prick+Prick tests with
      fresh fruits and vegetables were carried out. In the case of positive result to
      fruits and vegetables with skin tests and/or RAST, open challenge for every type
      of food considered responsible was carried out, after healing or improvement of
      dermatitis. Three children (11.53%) suffered from F.A. for fruits and vegetables:
      allergy to celery of one patient was discovered only by usual Prick test; allergy
      to tomato and kiwi in another patient was spotted by Prick+Prick only; while in
      another case by both tests. In this last patient Prick+Prick test revealed a real
      allergy for 5 aliments (carrot, tomato, celery, cucumber, fennel) of which only 2
      (carrot and celery) also caused a reaction with the Prick test. The combined use
      of both tests made it possible to increase the diagnosis of F.A. both for the
      number of patients and for a complete identification of implicated foods.

PMID- 8668589
TI  - [Cardiovascular complications of Kawasaki disease: clinical cases].
AB  - The Authors report the cases of Kawasaki disease (K.D.) observed between July
      1988 and october 1991 in OO.RR.'s Pediatric Division of Foggia. The diagnosis was
      made according to the C.D.C.'s Atlanta diagnostic guidelines. All children were
      treated (whithin the first 10 days of onset of illness) with intravenous immune
      globuline (500 mg/kg/die for 5 days) and with Asa and Dypiridamol for two months
      after they were without temperature. The patients with coronaric sequelae
      repeated after 4 weeks a second cycle of intravenous immuno-globuline therapy and
      continued Asa and Dypiridamol therapy until two months after disappearance of
      coronary arterial abnormalities. All patients performed ECG at 3-15-30 days and
      at 180-360 days from the onset of illness. A mono-bidimensional ecocardiogram was
      performed twice a week in the first month, bi-monthly in the next months and
      after 180-360 days from the onset of illness. One of the 8 children developed
      coronary aneurysms, which regressed echocardiographycally during the first 6
      months after the acute illness. While the etiology and pathogenesis of K.D.
      remain incompletely understood, the clinical spectrum of the disorder and its
      long-term prognosis and treatment are becoming increasingly well defined.
      Coronary artery aneurysms developed in 15-25% of cases, with a mortality for
      coronary artery thrombosis of 1-2% of cases. Intravenous immuno-globuline
      infusion given in the early phases of the disorder reduce the incidence of
      coronary artery aneurysms therefore an early diagnosis is important to prevent
      coronary artery abnormalities.

PMID- 8668590
TI  - [Vascular hyperfragility in systemic lupus erythematosus treated with low doses
      of cortisone].
AB  - We report an unusual cutaneous manifestation of systemic lupus erythematosus
      (SLE) in a 15-year old female. The diagnosis was made on the basis of clinical
      symptoms, cutaneous hystology (positive "lupus band test") and on laboratory
      findings (hypocomplementemia, positive antinuclear antibodies and rheumatoid
      factor). Treatment with methylprednisolone (0.5 mg/kg/die) improved the clinical
      symptoms but, after 2 months, large ecchymotic lesions appeared on the lower legs
      below the knee extending as far as the ankles, likely triggered by minor local
      traumas. Coagulative function was normal, the lupic anti-coagulant factor (LAF)
      was negative, anticardiolipin antibodies were absent and there was no
      thrombocytopenia. There was only a slight increase in clotting times in vitro, in
      presence of ADP. The amount of cortisone was reduced and the type of treatment
      modified; satisfactory control of the disease was attained with deflazacort (0.3
      mg/kg/die). The ecchymosis on the lower limbs never disappeared even though they
      became slightly smaller. Ecchymotic lesions are not usually included in the wide
      range of cutaneous manifestations associated with SLE. Moreover vascular
      fragility resulting from pressure and minor traumas is known to be a cutaneous
      complication of hypercorticism; nevertheless the doses of cortisone administered
      to this patient were rather low and other clinical signs of steroid hyper-dosing
      were absent although cortisolemia assay at base and after stimulus with ACTH was
      not performed. We would suggest that the negligible platelet binding defect
      (whether primary or SLE-associated) together with the low amounts of cortisone
      administered caused ecchymotic lesions to appear in this patient suffering from a
      disease (SLE), in which the small cutaneous vessels are favourite targets.

PMID- 8668592
TI  - [Anorexic and pseudoanorexic child].
AB  - After having conducted and examined an extensive six-year survey of 1372 children
      (758 females and 614 males, from newly born babies to 12 year olds), the Authors
      evaluate the importance of anorexy; in fact, it is one of the most frequent
      reasons for parents taking their children to a pediatrician, as they often see it
      as a "problem" even when it may not be the case. It is wise not to underestimate
      the importance of anorexy and the Authors set down some guidelines including the
      research into the symptoms which may lead us to organic forms, the evaluation of
      the child's auxologic and nutritional state and an analysis of the existing
      relationship between mother and child. Defining the most frequent forms of
      anorexy as primary, they advise carrying out a diagnosis of this type only after
      the presence of other secondary forms has been excluded, especially in the first
      year of life. Besides the etiologic therapy used for the secondary forms and some
      "treatments" (therapy) which act as placebos, the Authors highlight that the real
      care to primary anorexy lies in the child's dialogue with his/her parents.

PMID- 8668591
TI  - [Determination of serum levels of tumor necrosis factor in pediatric practice:
      usefulness and limitations].
AB  - Tumor necrosis factor (TNF) is a prototypical inflammatory cytokine with a wide
      spectrum of biological activities. Therefore it could play a role in many
      immunologic and non immunologic disorders. We made a review of the literature
      concerning the significance of high TNF serum levels in pediatrics and also
      reported our preliminary results on TNF-alpha values in several pediatric
      immunologic diseases. Our data seem to confirm the importance of TNF in many
      immunologic disorders and suggest the opportunity of a more extensive analysis of
      TNF-alpha serum levels in pediatrics.

PMID- 8668593
TI  - [Obesity in pediatrics: statistical analysis of school performance of obese
      children].
AB  - We examined the school performance of 936 normal children (431 males, 434
      females) and 71 obese children (39 males, 32 females) aged between 8 and 13 years
      (mean 11 years and 6 months +/- 1 year) attending 2 primary school in a district
      of our town characterized by a good socio-cultural level. In total the subjects
      studied were 1007. Results showed that: 1) females had a school performance
      significantly higher than males (p < 0.005); 2) obese patients (both males and
      females) had a school performance significantly higher than normal children (p <
      0.001). This observation may be explained by the consideration that good school
      attendance implies: a) stress inducing a compensatory mechanism of
      hyperalimentation; b) lower physical activity. Another interpretation may also be
      suggested: children already obese attend the school more diligently in order to
      be better accepted and to counterbalance their negative self-image.

PMID- 8668594
TI  - [Decreased plasma fibronectin (pFN) level in preterm infants with infections].
AB  - Plasma fibronectic (pFN) is a high molecular weight multifunction glycoprotein,
      which augments neutrophil and macrofage phagocytosis and acts as a nonspecific
      opsonin for the reticuloendothelial system. In this study we have determined pFN
      concentrations in fifty eight preterm infants to discriminate infected from non
      infected ones. Concentrations of pFN decreased from baselin in babies with early
      or late onset infections. The changes in pFN concentrations were not found before
      sepsis, but on day 1. By day 5 pFN concentrations have increased and have been no
      longer different from controls. We have calculated sensitivity (73.68%),
      specificity (74.36%), positive (58.35%) and negative (85.29%) predictive values
      of pFN and of other markers of infections (C-reactive protein--CRP-,
      Immature/Mature neutrophil ratio--I/M n. ratio-). Adding these tests to pFN,
      provided equal specificity and positive predictive value, but increased
      sensitivity (94.73%) and negative predictive value (96.43%). Thus, low
      concentrations of pFN may be a valuable but not early marker for neonatal
      infections. The combination of pFN, CRP and I/M n. ratio increase the precision
      of diagnostic testing.

PMID- 8668596
TI  - [Dyggve-Melchior-Clausen syndrome: description of 2 further cases].
AB  - In this paper we describe the clinical and radiographic features of a spondylo
      epi-methaphyseal dysplasia. Dyggve-Melchior-Clausen syndrome. In these two new
      cases, without severe mental retardation, we have highlighted the clinical and
      radiological findings, progression of the skeletal changes that have allowed us
      to make a diagnosis.

PMID- 8668595
TI  - [Animal bites in children].
AB  - Our experiences at the "Centro di Profilassi Antirabbica" of the "Dipartimento di
      Pediatria" suggest to us some thoughts: though the seriousness of the lesions is
      important also for the patient's aestethics, mostly for girls, the physician must
      always take into consideration the infectious consequences of the bite itself.
      Among these bacterial infections mostly frequent enough are those overlapping the
      deepest wounds as the bites of cates are. Therefore adequate early preventive
      attendances (within the 24 hours) are necessary. The importance of prevention
      against rabies, luckily very rare in our country, but to be always afraid of and
      to be always taken into consideration because of its emotional impact, is to be
      highlighted.

PMID- 8668597
TI  - [Neurocysticercosis: a rare cause of convulsive crises].
AB  - The cysticercosis is an infestation caused from the larva of Taenia solium, which
      is demoniated Cysticercus cellulosae. Infestation by the encysted forms occur
      within brain, muscle, cutis, eye and more rarely within kidney, liver, thyroid.
      The cysties cause inflammation, oedema and residual calcification. In the SNC
      they are responsible for seizures, usually of focal type, hydrocephalus,
      meningitis, endocranic hypertension, stroke. One case of neurocysticercosis in a
      15 years old boy is described: the clinical pictures, the neuroradiologic images
      and the treatment are discussed.

PMID- 8668598
TI  - [Goldenhar's syndrome: a case report].
AB  - The Authors describe one case of Goldenhar's syndrome. They concentrate on the
      etiopathogenetic hypothesis and they believe it helps the gradual healing in
      time.

PMID- 8668599
TI  - [Alkaline phosphatase isoenzymes in a case of transient hyperphosphatasemia].
AB  - Authors reports the case of a seven months toddler with transient
      hyperphosphatasemia without clinical manifestations and no other hepatic or bone
      disfunctions. Resolution of both enzymes and bone isoenzymes occurs within 5
      months.

PMID- 8668600
TI  - [Case report of asymptomatic toxocariasis. A 24-month follow up].
AB  - An asympthomatic case of toxocariasis is described in a 9 years boy, who had been
      under follow-up observation for 24 months. He showed only a marked eosinophilia
      (42%) without any clinical alterations. The IgG antitoxocara dosage, performed by
      immunoenzymatic method, allowed to formulate the diagnosis. The oculistic checks,
      together with EEG carried out the time of diagnosis as well as at the end of
      follow-up did not show any alterations. No therapy was practised and the number
      of eosinophilis in to circulation went progressively down. At the end of follow
      up the percentage of eosinophilis is 7%.

PMID- 8668602
TI  - Evolving concepts in the treatment of heart failure. Introduction.

PMID- 8668601
TI  - [Intracranial hemorrhage in congenital factor II deficiency].
AB  - A case of congenital defect of factor II is reported. It concerns a newborn with
      a not traumatic haematoma due to congenital hypoprothrombinaemia, which is rarely
      described in scientific literature.

PMID- 8668603
TI  - Pathophysiology of heart failure: changing perceptions.
AB  - Heart failure occurs when myocardial muscle dysfunction prevents the heart from
      pumping enough blood at normal cardiac pressures to meet the metabolic needs of
      the body, especially during exercise, and compensatory hemodynamic and
      neurohormonal mechanisms are overwhelmed or maladaptive. Pathologic
      classifications are broadly based on the presence of systolic dysfunction
      (dilated cardiomyopathy) and diastolic dysfunction (hypertrophic or restrictive
      cardiomyopathies). Coronary artery disease, idiopathic dilated cardiomyopathy,
      and hypertension are the most frequent causes, and myocardial function may be
      impaired by some drugs. When contractility is reduced, stroke volume and cardiac
      output are decreased, and alterations in the kidneys may induce fluid retention
      to compensate for the perceived low output and reduced circulating blood volume.
      Fluid retention, in turn, causes increased preload or filling pressure and
      symptoms of pulmonary congestion. Depressed contractility also results in a
      reduction in blood pressure, leading to compensatory neurohormonal activation and
      vasoconstriction, which significantly elevate afterload, further reduce stroke
      volume, and lead to deleterious cardiac remodeling. The overall clinical approach
      includes defining the etiology, identifying precipitant factors, and assessing
      the severity of myocardial dysfunction and clinical symptoms.

PMID- 8668604
TI  - Is there a role for digoxin in patients with systolic dysfunction?
AB  - In early placebo-controlled trials in patients with heart failure who were in
      sinus rhythm, digoxin improved hemodynamics, signs and symptoms of heart failure,
      and exercise capacity, and decreased functional deterioration and the need for
      pharmacologic cointervention. A more recent trial showed that withdrawing digoxin
      from patients who were clinically stable while receiving diuretics and
      angiotensin-converting enzyme (ACE) inhibitors often resulted in clinical
      deterioration, whereas continuing the agent maintained stability. Which patients
      should initially be treated with digoxin remains to be determined. The effects of
      digoxin on mortality in patients who are receiving ACE inhibitors must also be
      established.

PMID- 8668605
TI  - Evolving role of calcium channel blockers in heart failure.
AB  - Calcium channel blockers are theoretically effective in the treatment of chronic
      systolic heart failure because of their actions as arteriolar dilators,
      antiischemic agents, and relaxants of diastolic left ventricular function, and
      because they may prevent progression of myocardial dysfunction. The first
      generation calcium channel blockers nifedipine, verapamil, and diltiazem cause
      hemodynamic and clinical deterioration and may increase the frequency of cardiac
      events in postmyocardial infarction patients with heart failure. These drugs
      depress left ventricular contractility in the short term, and can activate
      neurohormonal systems due to their hypotensive effects. The second-generation
      calcium channel blocker felodipine does not activate the sympathetic nervous and
      renin-angiotensin systems, but has no effect on exercise capacity or mortality.
      Amlodipine increases exercise time and reduces symptoms and plasma norepinephrine
      concentration in heart failure. It also reduces morbidity and mortality in New
      York Heart Association class i.v. patients with nonischemic dilated
      cardiomyopathy, and appears to be effective as primary therapy for patients with
      dilated cardiomyopathy.

PMID- 8668606
TI  - Angiotensin-converting enzyme inhibitors in left ventricular dysfunction.
AB  - Angiotensin-converting enzyme (ACE) inhibitors have been used for more than a
      decade in the treatment of chronic congestive heart failure. In recent years
      these agents have been used in patients who survived a myocardial infarction.
      However, primary care providers are often confused as to which patients would
      benefit the most, and as a result, these life-prolonging drugs are underutilized.
      The results of randomized controlled trials evaluating ACE inhibitors' effect on
      morbidity and mortality in patients with chronic congestive heart failure or
      acute myocardial infarction were evaluated. Angiotensin-converting enzyme
      inhibitors clearly improve survival in patients with symptomatic congestive heart
      failure. This survival benefit is approximately 6 months. In patients with
      asymptomatic systolic dysfunction, these agents also decrease the number of
      hospital admissions due to heart failure. Angiotensin-converting enzyme
      inhibitors also improve survival in all patients who experienced an acute
      myocardial infarction. With the plethora of evidence regarding the positive
      effects that this class of drugs has on the quality of life and survival of
      patients with systolic dysfunction, it is still unclear why clinicians are
      reluctant to use them more often. Primary care providers need to be educated on
      how to risk stratify patients to make this therapy more cost effective, and when
      these agents should be started.

PMID- 8668608
TI  - Current perspectives on beta-receptor antagonists in the treatment of symptomatic
      ventricular dysfunction.
AB  - Even though therapeutic advances have occurred, heart failure is still associated
      with significant morbidity and mortality. Digitalis, diuretics, and angiotensin
      converting enzyme inhibitors have proven effective, but in many patients still do
      not prevent progressive and debilitating heart failure. Many hormonal factors are
      involved, but two, the renin-angiotensin-aldosterone (RAA) axis and the autonomic
      nervous system, apparently are critical in the pathophysiology of progressive
      ventricular dysfunction. Pharmacologic suppression of the RAA system is
      associated with significant clinical benefit, suggesting that antagonism of
      sympathetic nervous activity with beta-receptor-blocking agents might also be
      efficacious. Major alterations of the autonomic nervous system are characteristic
      of heart failure, with excessive sympathetic activity one of the earliest
      adaptations to the condition, and important in promoting the heart failure state
      and the progression of ventricular dysfunction. Certain beta-antagonists
      administered by careful and slow up-titration from small starting dosages proved
      effective in small trials. Large-scale, randomized, placebo-controlled studies
      continue to document that beta-blockers improve ventricular function and
      symptoms, and preliminary results suggests mortality and morbidity reductions as
      well. Although intolerance to beta-antagonism does occur, the majority of
      patients can be successfully treated with these agents.

PMID- 8668610
TI  - Domestic violence. Do you know when and how to intervene?
AB  - Physicians must be alert to the possibility of abuse within the family and home.
      They should be well prepared to help victims begin the transition to a safer
      environment. An awareness of the prevalence of abuse and a high index of
      suspicion are the most effective clinical tools for assisting victims of domestic
      violence. In addition, physicians need to be familiar with reporting laws in
      their states. Comprehensive management includes not only treatment but also
      investigation of injuries, reporting of suspected abuse, referral to appropriate
      community agencies for violence management or counseling, and addressing
      underlying chemical dependency or mental disorders. Close follow-up is critical
      to both detection and prevention. Physicians are obliged not only to treat
      individuals but also to support social policies that reduce family violence.

PMID- 8668607
TI  - Angiotensin II receptor blockers: novel therapy for heart failure?
AB  - Heart failure is a severe, disabling disease that portends a short life
      expectancy. This grave prognosis may be explained by growth-promoting effects of
      angiotensin II implicated in heart failure that mediate a genetic response called
      programmed cell death. The effects of angiotensin II are inhibited by angiotensin
      converting enzyme (ACE) inhibitors, which improve exercise performance and
      quality of life, attenuate disease progression, and modestly lengthen survival.
      Unfortunately, mortality remains exceedingly high and may be partly attributable
      to augmented production of angiotensin II from a non-ACE chymase pathway.
      Angiotensin II production may therefore increase despite treatment with ACE
      inhibitors. The angiotensin II receptor antagonists are a new class of nonpeptide
      reversible inhibitors that may offer clinical promise in heart failure through
      blockade of angiotensin II actions, whether produced from ACE or non-ACE chymase
      pathways.

PMID- 8668609
TI  - Evolving concepts in the treatment of heart failure: should new inotropic agents
      carry promise or paranoia?
AB  - Heart failure is a common disorder caused by many different diseases. At the root
      of the problem is diminished myocyte contractility, which ultimately results in
      failure of the pump to generate adequate peripheral flow. An interplay of
      hemodynamic, neurohumoral, and inflammatory perturbations initially improves
      cardiac flow and cellular respiration, but ultimately worsens the syndrome.
      Inotropic drug therapy was an attractive option in patients with heart failure
      even before the pump failure aspect of the disease was recognized. Increased
      contractility should lead to increased cardiac output, which would likely
      ameliorate hemodynamic and metabolic derangements. Although inotropes increase
      cardiac contractility at least transiently, this effect does not generally
      translate into improved survival in clinical trials. Indeed, in patients with
      advanced heart failure, these drugs frequently increase death rates. It is
      important to put the issue of inotropic therapeutics into perspective when
      considering treatment options for these patients. It may well be that certain
      inotropes in yet to be defined dosages will substantially improve morbidity and
      mortality when combined with drugs designed to interdict metabolic and
      neurohumoral components of the syndrome.

PMID- 8668611
TI  - Delirium. Quick recognition, careful evaluation, and appropriate treatment.
AB  - Delirium is a common medical condition, especially in elderly hospitalized
      patients. The syndrome is characterized by a short course of confusion and
      changes in perception and behavior. Early detection can be enhanced by routine
      assessment of cognitive functioning in hospitalized patients, especially those at
      risk for delirium. Prompt recognition and aggressive treatment of the underlying
      cause are essential for a positive outcome. Supportive measures are designed to
      calm and protect the patient and provide symptomatic relief until the
      precipitating condition is corrected.

PMID- 8668612
TI  - Hyperlipidemia. When does treatment make a difference?
AB  - A high serum cholesterol level is regarded as a major contributor to the
      development of coronary atherosclerosis. Screening for hyperlipidemia should
      begin no later than age 35 for men and age 45 for women. Individuals with
      additional risk factors for coronary artery disease should be screened earlier.
      When values are not within a desirable range, further assessment should be done
      by determining high-density lipoprotein and triglyceride levels. The initial
      approach to treatment of hyperlipidemia includes diet, exercise, and weight loss.
      Smoking should be proscribed. When nonpharmacologic intervention fails, "statins"
      are increasingly being selected as agents of first choice. Recommendations for
      the busy practitioner include consistently identifying the hyperlipidemic
      patient, setting target goals for lipid values, addressing modifiable risk
      factors, and providing appropriate pharmacologic intervention (eg, aspirin,
      antioxidants, and beta blockers in patients with established disease; angiotensin
      converting enzyme inhibitors in patients with systolic dysfunction; estrogen
      replacement in selected patients) and treatment to attain target goals in
      lowering cholesterol.

PMID- 8668613
TI  - What do you know about the NPDB?

PMID- 8668614
TI  - Fibromyalgia. Recognizing and addressing the multiple interrelated factors.
AB  - Recognition of fibromyalgia is crucial to avoid extraneous, costly diagnostic
      testing and ineffective, potentially dangerous therapy. Furthermore, failure to
      recognize that symptomatic physiologic change does result in a patient's response
      to stress demeans the legitimate importance of psychiatric disease. The keys to
      successful therapy are (1) specific pharmacologic manipulation of important
      processes and prognostic factors, (2) participation in aerobic exercise, which
      increases time spent in stages 3 and 4 (non-rapid eye movement) sleep and reduces
      stress, and (3) education, which reduces worry and perceived stress.

PMID- 8668615
TI  - Urinalysis. When--and when not--to order.
AB  - Although routine urinalysis is common, the results are important in management of
      only certain diseases. Screening urinalysis to detect asymptomatic bacteriuria is
      recommended in adults 60 years of age or older, diabetic patients of any age,
      pregnant women, and adolescents. A positive result for protein on dipstick
      urinalysis should be evaluated in conjunction with other clinical and laboratory
      data (eg, the patient's age, physical findings, renal function, results of
      microscopic urinalysis). Evaluation of hematuria should always include dipstick
      analysis and microscopic examination of urine. Diabetes screening is best done
      with measurement of plasma glucose levels. Other available urinalysis tests
      include measurement of pH, specific gravity, ketones, bilirubin, and
      urobilinogen. In patients with renal or urinary tract disease, microscopic
      examination of urinary sediment is important.

PMID- 8668616
TI  - Postsplenectomy care. Strategies to decrease the risk of infection.
AB  - Primary care physicians need to be aware of the risk of infection following
      splenectomy, especially given the rapid onset and potentially fatal consequences
      of overwhelming postsplenectomy infection. Risk is highest in children, in
      patients who had the operation within the previous 2 years, and in patients who
      underwent the procedure for treatment of lymphoma or thalassemia. Three types of
      preventive measures are recommended: immunoprophylaxis (vaccines);
      chemoprophylaxis (antibiotics); and education, ranging from providing a medical
      alert bracelet to teaching about symptoms of febrile illness to advising
      immediate treatment of even a minor dog bite.

PMID- 8668617
TI  - Malnutrition in the elderly. Is it simply a matter of not eating enough?
AB  - Malnutrition is a common finding in elderly patients, especially at
      hospitalization. In those whose nutritional status is borderline, the stress of
      illness may bring about deficiency. Failure to correct malnutrition delays
      recovery and prolongs hospital stay. Inadequate intake is only one of many causes
      of nutritional deficiency in the elderly. Traditional height-weight tables are
      inexact in the elderly. To increase diagnostic accuracy in suspected
      malnutrition, several methods should be used (eg, calculation of weight loss over
      time; muscle mass-height comparisons; biochemical and hematologic measurements).
      After daily energy needs are determined--according to metabolic, activity, and
      stress expenditures--the best method of nutritional replacement must be
      determined. Enteral supplementation is the first choice because it sustains the
      integrity of the gastrointestinal tract. However, delaying implementation of
      parenteral nutrition when it is required is a common error that should be
      avoided. Continued supplementation is often needed after discharge. Depending on
      the health status of the patient, nutritional support can range from temporary
      admission to a skilled-nursing or extended-care facility to home supplementation
      through such programs as Meals on Wheels.

PMID- 8668618
TI  - Hemoptysis. Three questions that can direct management.
AB  - Hemoptysis can be a life threatening condition on its own. It can also be a
      marker of serious disease or a recurrent problem accompanying lung cancer,
      bronchiectasis, or tuberculosis. A three-step approach is of fundamental
      importance: First, ensure that the lower respiratory tract is the source of
      bleeding. Second, identify cases representing serious risk. Third, consider both
      pulmonary and systemic circulation as possible sources of bleeding. In most
      cases, a non-specific, conservative approach is successful in managing
      hemoptysis, but occasionally, surgical resection or embolization of the bleeding
      vessel is required.

PMID- 8668619
TI  - Parvovirus B19 infection. Associated diseases, common and uncommon.
AB  - Parvovirus B19 infection is common worldwide but is often asymptomatic. However,
      the virus has been implicated in numerous disorders, including aplastic crisis in
      patients with chronic hemolytic anemia, erythema infectiosum, arthropathy,
      arthritis, and fetal infections. Diagnostic tests are not routine, but several
      are available through commercial reference laboratories. Treatment ranges from
      analgesics and antipyretics for mild and self-limited illness to administration
      of commercial immunoglobulin preparations and blood transfusion for more serious
      conditions.

PMID- 8668620
TI  - Unusual presentations of gout. Tips for accurate diagnosis.
AB  - In cases of unusual presentations, such as the three cases described here, gout
      or gouty arthritis may be misdiagnosed as rheumatoid arthritis, septic arthritis,
      or other rheumatic conditions and thus inappropriately treated. Microscopic
      analysis using compensated polarized light and culture of synovial fluid helps
      distinguish gouty arthritis from other arthropathies, and the presence of
      monosodium urate crystals establishes the diagnosis of gout. When gout is
      suspected, yet the initial examination does not reveal the telltale crystals,
      reexamination of synovial fluid is warranted. It is important for physicians to
      remember, though, that diagnosis of gout does not rule out the possibility of
      concurrent arthritic conditions.

PMID- 8668621
TI  - A new malpractice defense: common sense.

PMID- 8668622
TI  - Barium enema for cancer screening.

PMID- 8668623
TI  - Alcoholism. Taking a preventive, public health approach.
AB  - Alcoholism is a common, chronic, often progressive disorder that has negative
      effects on a patient's health and severe consequences for society as well. A
      positive, public health approach that integrates medical, psychological, and
      social therapies can lead to improved outcomes for patients who abuse alcohol.
      Physicians can play an important role by educating patients to prevent alcohol
      abuse from starting, being alert to the risk factors, recognizing the signs of
      alcoholism (especially during its early stages), and initiating interventions
      designed to halt progression of this disease. Doctors should maintain a
      therapeutic stance with patients who have continued to abuse alcohol, even after
      frequent relapses. Consultation with alcoholism experts may be helpful when
      treatment is difficult or there is the possibility of a dual diagnosis.

PMID- 8668624
TI  - Clues to depression in primary care practice.
AB  - Depression is a common but highly treatable mood disorder. Unfortunately, two
      thirds of depressed patients may never receive appropriate intervention. Because
      of individual and societal barriers to the diagnosis, depressive symptoms often
      go unrecognized. However, primary care physicians are in a unique position to
      surmount these obstacles by being alert to manifestations of the disorder.
      Treatment with antidepressant drugs, psychotherapy, electroconvulsive therapy, or
      a combination of these is very efficacious. The choice of method is based on such
      factors as history of previous response, severity of disease, concomitant medical
      illness, and patient preference.

PMID- 8668625
TI  - The antiphospholipid syndrome: when does the presence of antiphospholipid
      antibodies require therapy?
AB  - To avoid wasting healthcare resources through overinvestigation in otherwise
      healthy people, it is important to remember that antiphospholipid antibodies (ie,
      lupus anticoagulant and anticardiolipin antibody) often do not signify clinical
      disease. However, when features of the antiphospholipid syndrome (APS) are also
      present, serious thrombosis may be expected. Exactly how these antibodies alter
      hemostasis to induce a hypercoagulable state remains unclear. Activated partial
      thromboplastin time may not be a reliable screening test in a minority of
      patients with lupus anticoagulant and is not useful in screening for
      anticardiolipin antibodies. When APS is strongly suspected on clinical grounds,
      definitive tests (ie, enzyme-linked immunosorbent assay for IgG, IgA, and IgM
      anticardiolipin antibodies and the dilute Russell's viper venom time test)
      followed by confirmatory tests (eg, for lupus anticoagulant) should be ordered.
      Patients with APS are at high risk for recurrent thrombosis, but questions about
      optimal clinical management remain unresolved. High-intensity or lifelong
      anticoagulation therapy should be considered in some cases. Low-molecular-weight
      heparin may ultimately prove to be the treatment of choice in pregnant APS
      patients.

PMID- 8668626
TI  - New developments in acute anticoagulation therapy: what improvements over
      traditional heparin are on the horizon?
AB  - The quest for an orally active anticoagulant to replace warfarin sodium
      (Coumadin, Panwarfin, Sofarin) in long-term use has been disappointing. Most
      advances in oral anticoagulant therapy have involved more judicious and
      efficacious use of warfarin or one of its analogues. The area of heparin
      substitutes has experienced some exciting discoveries, with most current interest
      centered on low-molecular-weight heparins. Their efficacy, safety, and perhaps
      most important, clinical utility as a once- or twice-daily unmonitored medication
      have given them a meaningful role in current anticoagulation therapy. Third
      generation anticoagulants, such as the direct thrombin inhibitors, are being
      investigated but are not ready for general clinical use. The role of ancrod
      (Arvin) from snake venom in patients with heparin-induced thrombocytopenic
      thrombosis has been clearly established. A practical issue that remains under
      discussion is the most suitable interaction between fiscal and clinical
      applications of these medications.

PMID- 8668627
TI  - Diabetic ketoacidosis and hyperosmolar nonketotic state: gaining control over
      extreme hyperglycemic complications.
AB  - Decompensated hyperglycemia is a frequent, severe complication of diabetes
      mellitus. Ketoacidosis usually occurs in patients with insulin-dependent (type I)
      diabetes, and insulin therapy is required to correct their hyperglycemic
      derangement. Hyperosmolar nonketotic state is more common in patients with non
      insulin-dependent (type II) diabetes, who usually present with severe dehydration
      and hyperosmolar plasma. They respond readily to aggressive volume expansion, and
      insulin has a lesser role in management. Some patients exhibit a mixture of
      ketoacidosis and hyperosmolarity, which suggests that the two conditions may
      represent variants of decompensated hyperglycemia that differ only by the
      magnitude of dehydration and the severity of acidosis. All diabetic patients with
      hyperglycemic decompensation should return to their usual hypoglycemic programs
      as soon as possible and receive close follow-up after hospitalization.

PMID- 8668628
TI  - The shifting healthcare marketplace: purchasers, not MCOs, are the powers that
      be.

PMID- 8668630
TI  - Common disorders of pigmentation: when are more than cosmetic cover-ups required?
AB  - The many types of pigmentation disorders may present in diverse forms and
      distributions and have various causes. They can be inherited (eg, vitiligo,
      familial periorbital hyperpigmentation), acquired (eg, postinflammatory
      pityriasis alba, idiopathic guttate hypomelanosis, Becker's nevus, melasma),
      infectious (eg, tinea versicolor), benign and self-limiting (eg, isolated cafe au
      lait spots, photocontact dermatitis), or a sign of more serious underlying
      disease (eg, multiple cafe au lait spots, malignant acanthosis nigricans).
      Primary care physicians see many patients with skin complaints and can often
      accomplish the early recognition and appropriate treatment that is paramount to
      cost-effective medicine. In many cases, an important aspect of patient care is
      education toward realistic expectations, because even with referral and use of
      extensive treatment, cosmetic results may be disappointing. Assuring patients
      that the disorder is not dangerous and providing tips on sunscreen and cosmetic
      use may be the best approach in some cases.

PMID- 8668629
TI  - Peripheral neuropathy: an often-overlooked cause of falls in the elderly.
AB  - Peripheral neuropathy is common in the elderly and results in impairments in
      distal proprioception and strength that hinder balance and predispose them to
      falls. The loss of heel reflexes, decreased vibratory sense that improves
      proximally, impaired position sense at the great toe, and inability to maintain
      unipedal stance for 10 seconds in three attempts all suggest functionally
      significant peripheral neuropathy. Physicians can help their patients with
      peripheral neuropathy to prevent falls by teaching them and their families about
      peripheral nerve dysfunction and its effects on balance and by advising patients
      to substitute vision for the lost somatosensory function, correctly use a cane,
      wear proper shoes and orthotics, and perform balance and upper extremity
      strengthening exercises.

PMID- 8668631
TI  - Relief of suffering: where the art and science of medicine meet.
AB  - The physical, emotional, and spiritual components of suffering are myriad.
      Fortunately, physicians have available an ever-increasing array of scientific
      advances to provide relief and comfort from physical pain and distress. Relief of
      the emotional and spiritual suffering that is part of the human condition
      requires more--it requires physicians to look beyond the bounds of clinical
      treatment and draw upon the time-honored wisdom of the art of medicine.

PMID- 8668632
TI  - Opportunistic fungal infections in patients with HIV disease: combating
      cryptococcosis and histoplasmosis.
AB  - Both cryptococcosis and histoplasmosis are life-threatening diseases in patients
      with advanced HIV infection. Cryptococcal disease in patients with AIDS is
      usually a systemic illness with an insidious onset of meningoencephalitis.
      Development of potent oral antifungal agents has simplified therapy, although
      patients with cryptococcal meningitis are at high risk for relapse.
      Histoplasmosis is usually disseminated in AIDS patients. Definitive diagnosis
      requires culture of the pathogen from blood or other specimens. Although
      availability of azole compounds has broadened treatment options, relapse is
      common after treatment of acute disease, and lifelong suppressive oral therapy is
      needed. Antifungal prophylaxis is not considered cost-effective at this time.

PMID- 8668633
TI  - Noninvasive positive pressure ventilation: what is its role in treating acute
      respiratory failure?
AB  - Noninvasive positive pressure ventilation (NIPPV) is a viable option in treating
      appropriately selected patients with acute respiratory failure. It is often well
      tolerated, and it avoids endotracheal intubation with its potential
      complications. Moreover, gas exchange is reportedly improved. Several issues
      relating to the use of NIPPV are unresolved, however. The optimal interface, best
      ventilator mode, and patient selection criteria have not been firmly established.
      Also, studies are needed to compare the efficacy, safety, and cost-effectiveness
      of NIPPV and standard endotracheal ventilation. Despite these unresolved issues,
      NIPPV clearly represents an important addition to the techniques available in
      managing acute respiratory failure. Except in situations in which immediate
      endotracheal intubation is required, it may become first-line therapy in elderly
      patients in whom resuscitation status is unsettled.

PMID- 8668634
TI  - Dysthymic disorder: the depression that never quits.
AB  - Dysthymic disorder, an insidious and chronic depressive mood disorder that waxes
      and wanes in intensity over several years, is fairly prevalent in healthcare
      settings. Although the explicit etiology is unknown, serotonergic dysfunction may
      be involved. Dysthymia appears to have a high rate of comorbidity, including both
      psychiatric and medical disorders. The primary care physician should maintain an
      awareness of this mood disorder, be able to screen efficiently for signs and
      symptoms, and be able to differentiate major depression from dysthymia. The
      foundation of treatment is pharmacotherapy, in particular with serotonergic
      antidepressants, although response is moderate at best. Antidepressants are
      initiated at low doses and drug trials are conducted for 3-month periods if not
      precluded by side effects. When reasonably effective, antidepressants should be
      continued for 2 to 3 years or more. Adjunctive interventions in the treatment of
      dysthymia are based on comorbid psychiatric or medical conditions. Although
      dysthymia is an insidious, difficult-to-treat disorder, intervention is
      worthwhile. Further research may elucidate more effective interventions for this
      challenging disorder.

PMID- 8668635
TI  - Should your son or daughter go to medical school?

PMID- 8668636
TI  - Saving lives through organ transplantation.

PMID- 8668637
TI  - Cancer screening with barium enema.

PMID- 8668638
TI  - A Hungarian physician's views on alcoholism.

PMID- 8668639
TI  - Heparin therapy: current regimens and principles of monitoring.
AB  - Standard heparin is currently in wide use, and along with low-molecular-weight
      heparin, its administration may well increase in the future. Present clinical
      indications are well documented. Laboratory monitoring is important and requires
      a practical understanding of therapeutic levels and of causes of spurious
      results. Like many drugs, heparin has serious potential side effects that must be
      considered both before and after starting therapy.

PMID- 8668640
TI  - Oral anticoagulant therapy: practical aspects of management.
AB  - Careful attention to the practical aspects of oral anticoagulant therapy can
      improve patient compliance and lessen the risk of bleeding complications. A
      variety of risk factors for bleeding associated with oral anticoagulant therapy
      have been defined and should be assessed before initiating therapy. Recent
      investigations have provided a means for estimating what constitutes a
      significant change in an individual patient's serial International Normalized
      Ratio (INR) by allowing for combined analytic and biologic variation in
      prothrombin time determinations. Dosing adjustments with warfarin sodium
      (Coumadin, Panwarfin, Sofarin) should be appropriate to the level of the INR and
      spread over the total weekly dosage for optimum stable control. Elderly patients
      are more sensitive to any given dose of warfarin and need a significantly lower
      total weekly dose. Attention must be paid to the vitamin K content of the diet
      and a variety of additional factors, including other drug therapy, alcohol
      consumption, and metabolic status. Hematuria or gastrointestinal bleeding should
      always be assessed, because the chance of finding a clinically significant lesion
      is good, especially when the INR has been in the therapeutic range. Although a
      minor prolongation of the INR without bleeding may be treated by watchful
      waiting, vitamin K administration and other therapeutic measures may be necessary
      for active bleeding. Comprehensive patient education is paramount and may be
      facilitated by a checklist approach. A well-informed patient provides one of the
      best defenses against bleeding complications.

PMID- 8668641
TI  - NMDA antagonists: antiepileptic-neuroprotective drugs with diversified
      neuropharmacological profiles.
AB  - In conclusion, NMDA antagonists as anticonvulsants are especially active in
      preventing the generalization of the behavioural and electrical seizures and
      display a typical spectrum of in vitro antiepileptiform activities. In addition,
      based on in vitro and in vivo limbic kindled studies, the drugs should be
      regarded more as an antiepileptiform than as an anticonvulsant drugs. As
      neuroprotective drugs, NMDA antagonists are effective against many types of
      neuronal injury and show a window of activity which does not exceed 1-2 h, thus
      suggesting an influence of NMDA receptors in the 'early' or 'acute' mechanisms of
      brain damage. Among NMDA antagonists, glycine antagonists or the morphinans
      dextromethorphan and dextrorphan showed a spectrum of antiepileptiform and
      neuroprotective activities broader than other NMDA antagonists. The primary
      pharmacological activities of NMDA antagonists are accompanied by some effects
      including perturbation of many sensory, psychological or motor processes. Typical
      behavioural and EEG changes were also induced by the drugs. In spite of the side
      effects elicited by the drugs, differential effects detected among the various
      classes of NMDA antagonists (i.e. lack of induction of typical EEG-behavioural
      effects and of typical cortical neurotoxicity) might render some of these
      suitable for full clinical application as anticonvulsant-neuroprotective drugs.

PMID- 8668642
TI  - Endogenous morphine.
AB  - This review surveys the discovery of endogenous alkaloids in mammals. The
      formation of morphine in mammalian brain was assumed in 1970. The existence of
      morphine was demonstrated by radioimmunoassay. Identification of morphine was
      performed by spectroscopic methods. The isolation of mammalian morphine raises
      the question of biosynthesis. Recently, it has been shown that the biosynthetic
      pathway is similar to that that exists in poppy.

PMID- 8668643
TI  - The effect of long-term oral captopril treatment on mesenteric blood flow in
      spontaneously hypertensive rats.
AB  - We examined the possibility that changes of the mesenteric resistance play a role
      in the development of hypertension in spontaneously hypertensive rats (SHRs).
      Genetically hypertensive (Okamoto) and normotensive Wistar rats (WKYs) were
      studied after oral treatment for 6 weeks with 100 mg of captopril dissolved in
      500 ml water daily. The paired control groups received water. During this
      treatment, the systolic blood pressure was measured non-invasively with a W+W/BP
      recorder after preheating of the conscious animals. After these procedures, the
      rats were anaesthetized, the baseline mesenteric blood flow (MBF, volts) was
      recorded with a pulsed Doppler flow-meter and the mean arterial blood pressure
      (MAP) heart rate and mesenteric vascular resistance were also measured. The
      captopril treatment failed to alter the body weight of SHRs and WKY. In the
      normotensive group, the MAP was not altered, but the MBF was moderately
      increased. In contrast, the MAP of the SHRs was markedly decreased, and the MBF
      was significantly increased. The basal MBF of the SHRs was significantly lower
      than that of the WKYs. These data suggest that the renin-angiotensin system may
      exert a tonic vasoconstrictor action on the mesenteric vasculature in SHRs. The
      increased mesenteric vascular resistance therefore plays an important role in the
      increased total peripheral resistance in the development of hypertension in SHRs.

PMID- 8668644
TI  - Haemodynamic and electrophysiological acute toxic effects of mercury in
      anaesthetized rats and in langendorff perfused rat hearts.
AB  - The acute toxic effects of HgCl2 on the cardiovascular system were studied in
      Langendorff-perfused rat hearts and in anaesthetized rats. Isovolumic systolic
      pressure (ISP), atrial and ventricular rates, and atrioventricular conduction (PR
      interval) were studied in the hearts perfused with bicarbonate buffer Krebs
      solution, at 31 degrees C, under a constant pressure of 75 mmHg. Eight hearts
      were studied at a fixed rate (200 bpm) under control conditions and at different
      HgCl2 concentrations (0.1, 1 and 10 microM). In these preparations the left
      ventricular function curves showed that Hg2+ reduces ISP development in a
      concentration-dependent manner whilst the myocardial response to increasing
      diastolic pressure is preserved. Ten additional spontaneously beating hearts were
      studied also under control conditions and at several HgCl2 concentrations (0.5,
      1, 2 and 10 microM). ISP and ECG were recorded. Again, ISP decreased after Hg2+
      treatment, but all HgCl2 concentrations produced effects of the same magnitude.
      The reduction of heart rate that also occurs during Hg2+ treatment is the
      possible explanation for the different effects of Hg2+ on the ISP obtained from
      the driven and spontaneously beating preparations. Hg2+ also decreased the atrial
      and ventricular rate driven by atria and increased the PR-interval. Several
      arrhythmias were induced, such as extrasystoles, A-V blocks, brady- and
      tachyarrhythmias and ventricular fibrillation without a clear relationship with
      Hg2+ concentrations. The possibility of an increased activity of autonomic
      neurotransmitters was also investigated. Cholinergic activity was evaluated in 14
      preparations and adrenergic activity in eight by blocking their effects with
      atropine (0.2 micrograms ml-1) and propranolol (0.1 microgram ml-1),
      respectively. Atropine reduced Hg2+ effects on ISP, heart rate and PR-interval
      while propranolol enhanced the cholinergic effects. In the anaesthetized rats the
      changes in mean arterial blood pressure (MBP), heart rate (HR), and
      atrioventricular conduction (PR-interval) were recorded and followed for 120 min.
      In five rats acute poisoning was achieved using a high dose of HgCl2 (50 mg kg
      1). MBP and HR decreased and PR-interval increased. Arrhythmias developed
      followed by ventricular fibrillation and all the animals died after 1 min. In
      nine other rats a lower dosage (5 mg kg-1) was used. MBP and HR decreased
      progressively and the PR-interval increased after 40 min. Using the same
      protocol, six other rats were pretreated with propranolol (2 mg kg-1), and seven
      with atropine (1 mg kg-1). Propranolol delayed the reduction in MBP caused by
      HgCl2. HR decreased after propranolol injection but did not change thereafter.
      The PR-interval, however, increased significantly within the first minute after
      HgCl2 injection. Atropine blocked the changes in MBP, HR and PR interval produced
      by HgCl2 during 120 min of observation. Another group treated with 0.5 mg kg-1
      was also studied but no changes of the parameters analysed were observed. The
      results suggest that, in addition to the reduction of mechanical activity, Hg2+
      affects heart rate and atrioventricular conduction, has arrhythmogenic effects,
      decreases arterial blood pressure and increases autonomic neurotransmitter
      activity.

PMID- 8668645
TI  - Effects of captopril on ischaemia-reperfusion-induced arrhythmias in an in vivo
      rat model.
AB  - The antiarrhythmic effects of captopril, an angiotensin converting enzyme (ACE)
      inhibitor, were investigated in an in vivo rat model of coronary artery ligation.
      Captopril (0.3-3 mg kg-1) or saline were administered by intravenously 10 min
      before coronary ischaemia. The left main coronary artery was then occluded for 7
      min, followed by 7 min of reperfusion. Captopril caused a marked decrease in mean
      arterial blood pressure which was transient at 0.3 and 1 mg kg-1, and at doses of
      1 and 3 mg kg-1, it produced marked bradycardia. The incidence of ventricular
      tachycardia (VT) on ischaemia was significantly reduced the captopril at a dose
      of 3 mg kg-1 only and on reperfusion at doses of 1 and 3 mg kg-1. At the same
      doses, captopril significantly reduced the mean duration of ventricular
      fibrillation (VF) on reperfusion. The incidence of mortality resulting from
      reperfusion-induced irreversible VF in the control group decreased from 42.9% to
      14.3% (NS), 21.4% (NS) and 7.7% (P < 0.05) in captopril at 0.3, 1 and 3 mg kg-1,
      respectively. Our results indicate that captopril appears to limit the
      arrhythmias following reperfusion and this may be due in part to the antiischemic
      effect associated with bradycardia and vasodepression.

PMID- 8668646
TI  - Regulation of glucose utilization by inhibition of mitochondrial fatty acid
      uptake in cardiac cells.
AB  - In order to investigate the mechanism by which fatty acid oxidation inhibitors
      regulate cardiac metabolism, the effects of 2-tetradecylglycidic acid (2-TDGA),
      and 2-bromopalmitic acid (2-BPA) on the oxidation of [1-14C]palmitate, [1
      14C]octanoate and [U-14C]glucose were studied in isolated rat myocytes. Fifty per
      cent inhibition of palmitate oxidation was achieved at 20 microM 2-TDGA and 60
      microM 2-BPA. Octanoate oxidation was also inhibited by 2-BPA. In contrast to
      their effect on palmitate oxidation, fatty acid inhibitors significantly
      stimulated the oxidation of glucose in a concentration-dependent manner.
      Moreover, the oxidation of [2-14C]pyruvate was increased two-fold by these
      compounds. The rate of uptake of [U-14C]-2-deoxyglucose was also stimulated two
      fold by these inhibitors. These studies suggest that the stimulation of glucose
      utilization via the inhibition of fatty acid oxidation may be mediated through
      the stimulation of both glucose transport and the oxidation of pyruvate by the
      pyruvate dehydrogenase complex.

PMID- 8668647
TI  - Effects of gallopamil on epinephrine and norepinephrine plasmatic levels and on
      TxB2 and beta-tg release in patients with coronary artery disease during
      adrenergic stimulus with cold pressor test.
AB  - We investigated the effect of gallopamil administration during a cold pressor
      test (CPT) in 18 patients suffering from chronic angina (CA) and in 21 healthy
      subjects. CA patients showed increased basal levels of beta-thromboglobulin and
      thromboxane B2 compared to control patients and normal plasma levels of
      catecholamines. CPT caused plasma catecholamines, beta-thromboglobulin and TxB2
      levels to rise. This rise was greater in CA patients than in control patients.
      Administration of gallopamil (50 mg kg-1 three times a day for 30 days) reduced
      plasma levels of catecholamines, beta-thromboglobulin and TxB2 blood
      concentrations either under basal conditions or after CPT. Our data suggest that
      gallopamil is able to modulate the response induced by adrenergic stress.

PMID- 8668648
TI  - Increased brain concentrations of polyamines in rats with encephalopathy due to a
      galactosamine-induced fulminant hepatic failure.
AB  - Polyamine concentrations including putrescine, spermidine and spermine were
      documented in two brain areas of rats with mild and severe stages of hepatic
      encephalopathy (HE) due to fulminant hepatic failure induced by galactosamine HC1
      injection (3 g kg-1 i.p.). In the mild stage of HE putrescine increased by 3-4
      times whereas spermidine and spermine showed a slight increase. The scenario,
      however, was found to be changed going from the mild to the severe stage of HE,
      since in this last stage spermidine and spermine showed a further rise while
      putrescine was found to be significantly lower than in the mild stage of HE in
      both the brain areas studied. The changes in the ratio among the three polyamines
      with an enhanced prevalence in the severe stage of HE of spermidine and spermine
      are likely to be related to the exhaustion of the synthetic pathway of putrescine
      or to a reduction of the interconversion to this polyamine from spermidine and
      spermine. Considering that these last two polyamines potentiate the N-methyl-D
      aspartate glutamate receptor mediated toxicity and that they might exert
      neurotoxic effects per se, there are clear reasons for suspecting an implication
      of the described changes of polyamines in the neurochemical mechanism which
      sustain HE and to surmise a potential therapeutic effect in this pathology of non
      competitive antagonists of polyamine-site on N-methyl-D-aspartate glutamate
      receptors.

PMID- 8668649
TI  - Behavioural effects of the dopamine D3 receptor agonist 7-OH-DPAT in rats.
AB  - The putative selective dopamine (DA) D3 receptor agonist, 7-OH-DPAT (25-4000
      micrograms kg-1), enhanced stretching-yawning and penile erection in male rats,
      besides respectively increasing and decreasing sedation at low (25-200 micrograms
      kg-1) and high (1600 and 4000 micrograms kg-1) doses and inducing stereotypy from
      800 micrograms kg-1 upwards. The DA D2 antagonist, (-) eticlopride (10 and 20
      micrograms kg-1), antagonized stretching-yawning and penile erection induced by a
      low dose of 7-OH-DPAT (50 micrograms kg-1) but not those produced by high doses
      (1600 and 4000 micrograms kg-1), when stereotyped behaviour, on the other hand,
      was potently inhibited. Comparative experiments performed with the DA agonist SND
      919 gave similar results.

PMID- 8668650
TI  - Evaluation of 137Cs activity in plant drugs and in some phytoderivatives from
      Chernobyl accident up to present (1986-1994).
AB  - The accident to the nuclear power plant of Chernobyl (in April 1986) caused a
      radioactive contamination in large areas of the majority of European countries.
      During the first transient time the fall-out phenomenon was the most important
      method of contamination, particularly from 131I whose relative isotopic abundance
      with respect to other released radionuclides was very high. Thereafter, 137Cs,
      owing to its long half-time and its large presence in environmental matrixes and
      so in the food chain, became the element on which the attention was to be
      focused. Plant drugs and their derivatives are, at present, of very large
      alimentary consumption among people. This can cause some problems to human
      health, so the authors have studied (from 1986 to 1994) the activity of 137Cs in
      a large number of drugs (about 5000) and in some industrial and home-made
      officinal products. Some suggestions on the Cs+,K+ ions competition in soil can
      also be derived.

PMID- 8668652
TI  - Antibacterial activity of liposomal amikacin against Pseudomonas aeruginosa in
      vitro.
AB  - The influence of liposomal amikacin on Pseudomonas aeruginosa was studied. P.
      aeruginosa clinical isolates caused release of encapsulated amikacin from
      liposomes. The liposomal amikacin proved to be active as bactericidal agent after
      3 h of incubation with P. aeruginosa. Incubation of P. aeruginosa with liposomal
      amikacin resulted in inhibition of the growth when equivalent of 2 MIC was added
      but not when equivalent of 1 MIC was added. Susceptibility of bacterial isolates
      to the liposomal amikacin varied with bacterial strain used, but generally
      encapsulation of amikacin did not enhance their antibacterial activity.

PMID- 8668651
TI  - The influence of carbon tetrachloride-induced liver damage on the inflammatory
      reaction elicited by carrageenan and its treatment with diclofenac.
AB  - The effect of impaired hepatic function on the development of the inflammatory
      process as well as on treatment with diclofenac was investigated. Carbon
      tetrachloride was used to induce liver injury and the elevation of serum
      transaminases was taken as evidence for impaired hepatic function. The
      carrageenan-induced rat hind paw oedema and the granuloma pouch were chosen as
      models of inflammation. The results of the study revealed that: (1) The intensity
      of inflammation in both models was markedly attenuated in CCl4-treated animals.
      (2) Serum total proteins were decreased in liver-injured animals particularly in
      acute experiments. (3) In liver-injured groups diclofenac showed more pronounced
      anti-inflammatory activity in chronic experiments, but not in acute ones. (4)
      Neither CCl4 nor diclofenac affected the levels of histamine and serotonin in the
      granuloma pouch exudate. The level of prostaglandins was decreased in CCl4 and in
      diclofenac-treated animals. At the same time, the leukotriene content was
      elevated. The mechanism by which CCl4 induced liver injury attenuates
      inflammatory response to carrageenan is not entirely understood. Its effect on
      protein metabolism and extravasation as well as on PG synthesis could play a
      possible role. Decreased drug metabolism may be, at least in part, responsible
      for the enhanced response of diclofenac in the cases of liver-injured animals.
      Dose adjustment of the drug in case of hepatic impairment might be necessary.

PMID- 8668653
TI  - Interaction between oxytocin and 'sidaverin' on the gravid and non-gravid rat
      uterus.
AB  - Sidaverin, a crystalline compound extracted from a polar fraction of Sida
      veronicaefolia (Lam), elicited oxytocin-like contractions in the non-gravid rat
      isolated uterus preparation with a concentration-response relationship.
      Equipotent concentrations of oxytocin and sidaverin, using matched responses,
      were approximately 0.16 U and 0.4 micrograms ml-1, respectively. Sidaverin
      induced contractile response was atropine reversible. The concentration-response
      curves for sidaverin and oxytocin were parallel, and both responses were
      inhibited by the specific oxytocin antagonist, Atosiban, indicating possible
      involvement of oxytocin receptors in the action of sidaverin. There were
      potentiation of action of one drug to that of the other, irrespective of the
      order of administration and even after washing off the first before introducing
      the second drug. In the gravid uterus, sidaverin produced contractions in
      preparations from day 1 to day 6 or 7, caused relaxation in days 7-11, and
      elicited contractions in day 11 through term, the sensitivity of the preparations
      increasing exponentially toward term with strong sustained contractions. With the
      exception of days 7-11, when sidaverin antagonized oxytocin action, it
      potentiated action of oxytocin on the gravid uterus.

PMID- 8668654
TI  - EEG power spectra and behavioral correlates in rats given chronic morphine. Lack
      of residual long-term EEG and neuronal changes.
AB  - The short-term (during tolerance to behavioural effects and withdrawal) and long
      term (3, 6, 9 and 12 months after treatment) effects of morphine on mean total
      electroencephalographic spectral power (analysed by means of fast Fourier
      transform) and band distribution (delta, theta, alpha, beta) were studied in
      freely moving young rats implanted with chronic cortical bilateral recording
      electrodes. Morphine was administered i.p. daily for 1 month at weekly increasing
      doses of 20, 50, 100 and 200 mg kg-1, and the electroencephalogram was evaluated
      for 2 h at every change of dose. Treatment with 20, 50 and 100 mg kg-1 led to a
      significant increase in mean total spectral power 30-60 min from treatment.
      However, the dose of 100 mg kg-1 led to a smaller increase than that obtained
      with 50 mg kg-1 and no change was shown with the highest dose, suggesting the
      progressive development of tolerance. The modification observed for 100 mg kg-1
      was accompanied by a relative increase in the delta and decrease in the theta and
      alpha power spectra. Between the last day of morphine and the first 3 days of
      abstinence, a progressive decrease in mean total spectral power accompanied by a
      significant increase in delta and beta and a decrease in theta and alpha
      frequency was observed. Long-term EEG activity and the counting of the pyramidal
      cells of the hippocampus failed to reveal any pathological findings after 3, 6, 9
      and 12 months.

PMID- 8668655
TI  - How much compliance is enough?

PMID- 8668656
TI  - Enteral bioavailability of human granulocyte colony stimulating factor conjugated
      with poly(ethylene glycol).
AB  - PURPOSE: The focus of this paper is to demonstrate that pegylation of a
      therapeutic protein, recombinant human granulocyte colony stimulating factor (PEG
      G-CSF), results in an increase in stability and in retention of in vivo
      bioactivity when administered by the intraduodenal route and may, therefore, be a
      suitable form of the protein for inclusion in an oral delivery formulation.
      METHODS: The ability of PEG-G-CSF to elicit a therapeutic response from the
      enteral route was investigated by two methods of intraduodenal dosing in an in
      vivo model to determine the optimal dosing method: by slow, constant infusion, or
      by a single bolus administration. RESULTS: Circulating levels of the proteins
      confirmed that PEG-G-CSF was delivered into the systemic circulation from the
      enteral route and that biological activity was retained. Bioavailability from the
      enteral route by the constant infusion method was calculated from the intravenous
      administration of the proteins to be between 1.8 and 3.5% while un-modified G-CSF
      failed to elicit a quantifiable response by this method. Bolus administration of
      PEG-G-CSF also resulted in biological activity although responses were short
      lived and significantly lower than with the pegylated formulation. CONCLUSIONS:
      The possible mechanisms of enteral delivery of PEG-G-CSF are discussed. Our
      results indicate that oral delivery of pegylated G-CSF may be possible and in
      fact, preferable to using the un-modified form of the therapeutic.

PMID- 8668657
TI  - Determination intestinal metabolism and permeability for several compounds in
      rats. Implications on regional bioavailability in humans.
AB  - PURPOSE: To investigate the regional differences in small intestinal (SI)
      metabolism and permeability for several compounds and to ascertain the potential
      significance of these differences on the reported reductions in regional
      bioavailability in humans. METHODS: The regional SI metabolism and permeability
      of captopril, didanosine (ddI), mannitol, ofloxacin and zidovudine (ZDV) were
      investigated in rats using a Single Pass Perfusion (SPIP) procedure or intestinal
      homogenates. RESULTS: ddI was metabolized to a greater extent in the upper SI
      whereas captopril was metabolized to a greater extent in the lower SI. Relatively
      low homogenate concentrations resulted in significant degradation of captopril in
      the upper and lower SI. All other compounds were stable and changes in the buffer
      system or the initial concentration did not affect the results. The SI
      permeabilities of all compounds, with the exception of mannitol, decreased
      linearly with respect to SI location and the slopes of the corresponding
      normalized regression lines were not significantly different. CONCLUSIONS: It has
      been reported that captopril and ddI demonstrate regional intestinal
      bioavailability in several species including humans. The current results suggest
      that the reported reduction in the lower SI bioavailability of captopril may be a
      result of a reduction in permeability and an increase in intestinal metabolism
      whereas for ddI, the reduction in the lower SI bioavailability appears to be
      attributable to a reduction in intestinal permeability. Other factors such as
      luminal metabolism may also significantly effect regional differences in the
      intestinal bioavailability of ddI or captopril. Based on these results, a strong
      possibility exists that ofloxacin and ZDV may also demonstrate regional
      differences in intestinal bioavailability.

PMID- 8668658
TI  - Intestinal absorption barriers and transport mechanisms, including secretory
      transport, for a cyclic peptide, fibrinogen antagonist.
AB  - PURPOSE: The intestinal absorption of DMP 728, a cyclic peptide fibrinogen
      antagonist, was examined with the goals of identifying the cause(s) of its low
      oral bioavailability and understanding the mechanisms of its intestinal
      transport. METHODS: In vitro partitioning, metabolism, and permeation through rat
      intestinal segments were evaluated. RESULTS: DMP 728 had low lipophilicity and
      low intestinal permeation rates relative to model compounds. In addition, DMP 728
      in vitro intestinal permeation in the secretory direction greatly exceeded
      transport in the absorptive direction. The secretory transport was saturable,
      glucose-dependent, and was inhibited by verapamil and by a monoclonal antibody to
      P-glycoprotein. DMP 728 likewise inhibited the secondary transport of verapamil.
      Mucosal-to-serosal permeation rates increased in going from the proximal to
      distal intestinal sites, but were lower than serosal-to-mucosal permeation rates
      for each site. CONCLUSIONS: Net secretory transport and low lipophilicity are the
      major barriers to absorption of DMP 728.

PMID- 8668660
TI  - In vitro permeability through caco-2 cells is not quantitatively predictive of in
      vivo absorption for peptide-like drugs absorbed via the dipeptide transporter
      system.

PMID- 8668659
TI  - Intravenous microdialysis in the mouse and the rat: development and
      pharmacokinetic application of a new probe.
AB  - PURPOSE: A flexible microdialysis probe was designed for intravenous sampling in
      small laboratory animals. METHODS: Surgical techniques were developed to implant
      this probe via the femoral vein in the vena cava of the mouse and the rat. The in
      and outlet of the probe were exteriorized above the tail of the animal and were
      directly connected to the microsyringe pump for perfusate delivery and to the
      injection valve for on-line HPLC analysis of the microdialysate samples. RESULTS:
      The in vitro recoveries of flurbiprofen and naproxen for these probes were 68.2
      +/- 6.9% (mean +/- S.D., n = 12) and 66.5 +/- 7.3%, respectively. The relatively
      loss by in vivo retrodialysis, measured the day after the implantation of the
      probes, was 66.1 +/- 8.8% for flurbiprofen and 60.9 +/- 9.9% for naproxen. The
      pharmacokinetics of unbound flurbiprofen were studied following i.v. bolus
      administration of flurbiprofen to the mouse (n = 4) and the rat (n = 6) with on
      line HPLC analysis of microdialysates to unbound concentrations using the in vivo
      loss of flurbiprofen by retrodialysis carried out just before the start of the
      pharmacokinetic experiment. The integrity of the probe throughout the experiment
      was monitored by continuous retrodialysis of naproxen. CONCLUSIONS: The developed
      techniques can be used to carry out routine pharmacokinetic studies in the mouse
      and the rat illustrated by our experiments with flurbiprofen, a compound with
      very high plasma protein binding.

PMID- 8668661
TI  - First-pass metabolism of diltiazem in anesthetized rabbits: role of extrahepatic
      organs.
AB  - PURPOSE: The aim of this study was to assess in vivo which organs contribute to
      the first-pass metabolism of diltiazem. METHODS: Anaesthetized rabbits received
      diltiazem into the thoracic aorta (TA) ( 1mg/kg), jugular vein (JV) (2 mg/kg),
      portal vein (PV) (4 mg/kg) or small intestine (SI) (5 mg/kg). Serial blood
      samples were withdrawn from the abnormal aorta to assay diltiazem, N-demethyl
      diltiazem (MA) and deacetyldiltiazem (M1). RESULTS: The area under diltiazem
      plasma concentration curve/time (AUC0-infinity) normalized by the dose was AUCTA
      approximately equal to AUCJV > AUCPV > AUCSI: Intestinal and hepatic diltiazem
      availability was 43 and 33%, respectively. The systemic availability of oral
      diltiazem was 12%. Diltiazem given into the SI and PV generated primarily MA, and
      injected into the JV and TA produced mainly M1. CONCLUSIONS: In rabbits, the
      intestine and the liver contribute to the first-pass metabolism of diltiazem, and
      the amount and species of metabolites generated depend upon the route of
      administration of diltiazem.

PMID- 8668662
TI  - Atom level electrotopological state indexes in QSAR: designing and testing
      antithyroid agents.
AB  - PURPOSE: To design antithyroid agents with less side effects, the
      electrotopological-state (E-state) indexes of thiourylene moiety (SN&S) was
      utilized as a guideline to develop five acrylic thiourylene-type compounds with
      reduced antioxidant property. METHODS: These agents were synthesized and screened
      for antithyroid activity in rats using 125I-thiocyanate discharge technique. In
      addition, chemiluminescence studies on the activated polymorphonuclear leukocytes
      (PMNLs) were also conducted to reveal antioxidant properties of the tested
      compounds. RESULTS: A linear relationship between the in vitro literature value
      of the formation constants of thiourylene-type compounds with iodine (Kc) and the
      SN&S was observed and utilized in designing those agents. At least one of the
      compounds (abouthiouzine) was found to have a potential value as an antithyroid
      agent. The relative efficacy of abouthiouzine [1-n-butyl-3(isonicotinamido)-2
      thiourea], after equimolar dose, was 102% and 51.5% of that of propylthiouracil
      with respect to the rate of 125I-discharge and 125I-uptake, respectively. In
      addition, chemiluminescence studies on PMNLs revealed that abouthiouzine has
      slight oxidant property. Such properties may provide advantages in avoiding the
      iatrogenic hypothyroidism and antithyroid-induced immunological reactions.
      CONCLUSIONS: The E-state approach provides guidelines to economize efforts and
      cost of designing new antithyroid drugs.

PMID- 8668663
TI  - FK506 (tacrolimus) and its immunoreactive metabolites in whole blood of liver
      transplant patients and subjects with mild hepatic dysfunction.
AB  - PURPOSE: To determine the concentrations of FK506 and its metabolites in blood
      from liver transplant patients and subjects with hepatic dysfunction. METHODS:
      HPLC was combined with an enzyme-linked immunosorbent assay (ELISA) to determine
      the concentrations of FK506 and its immunoreactive metabolites in human whole
      blood. RESULTS: In four liver transplant patient, most of the immunoreactivity
      was seen in the HPLC fractions where unchanged FK506 eluted. FK506 accounted for
      about 95% or more of the total immunoreactivity in the first days of
      posttransplant. Immunoreactivity observed in the nonFK506 fractions ranged from
      1.6% to 10.7% of the total immunoreactivity; about 30% of the nonFK506
      immunoreactivity was due to M-III(15-O-demethyl FK506). Blood from subjects with
      mild hepatic dysfunction was examined at 1.5 and 6 hours after an oral and
      intravenous dose, respectively, by HPLC-ELISA. Regardless of the route of
      administration, more than 96% of the total immunoreactivity was recovered in the
      FK506 fraction. M-III was detected in the blood of 3 of 6 subjects after an oral
      dose, but in none of these after an intravenous dose. CONCLUSIONS: ELISA is an
      appropriate method for therapeutic drug monitoring of FK506.

PMID- 8668664
TI  - Liposomal methylprednisolone in rats: dose-proportionality and chronic-dose
      pharmacokinetics/pharmacodynamics.
AB  - PURPOSE: Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the
      immune system and enhances immunosuppressive activity of the steroid. We
      performed dose-dependent and chronic dose studies of L-MPL versus MPL. METHODS:
      Male Lewis rats received 10 mg/kg i.v. bolus doses of L-MPL (Solu-Medrol). Plasma
      samples were obtained over an 8 day period and MPL concentrations were assayed by
      HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte
      proliferation induced with PHA. RESULTS: Drug concentrations declined in a
      similar manner over the first few hours following MPL or L-MPL. Free MPL was
      cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistence
      over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were
      observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg
      led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L
      MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day
      8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg
      i.v. doses of L-MPL versus MPL twice a week produce plasma drug profiles similar
      to those obtained after single doses, indicating that neither free nor liposomal
      steroid accumulates in tissues. Liposomes without drug simultaneously
      administered with MPL caused partial prolongation of plasma steroid half-life
      (8.4 hr). CONCLUSIONS: These studies clarify factors causing prolonged drug
      persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular
      pharmacokinetics, and secondary effects of the liposomes are complicating factors
      in use of L-MPL.

PMID- 8668665
TI  - Maltodextrins as lyoprotectants in the lyophilization of a model protein, LDH.
AB  - PURPOSE: Maltodextrins, partially hydrolysed starches, were evaluated as
      potential lyoprotectants and the effect of combinations of maltodextrins and PEG
      8000 on the protection of lactate dehydrogenase (LDH) was examined. METHODS: LDH
      activity assays were performed immediately before freezing and after
      reconstruction. The activity recovery was used as the parameter to evaluate the
      lyoprotectants. Differential Scanning Calorimetry (DSC) was used to measure the
      glass transition temperature (Tg') of the solutions. DSC and X ray diffraction
      were used to characterise the freeze-dried products. RESULTS: Maltodextrins were
      found to protect LDH against inactivation during freeze-drying. The lyoprotection
      obtained by these maltodextrins is dependent on their D.E. value and the
      concentration used. The maltodextrin formulations performed as good or better
      than those containing sucrose and maltose, depending on the concentration used.
      Freeze dried cakes of maltodextrin formulations were amorphous. In the case of
      low D.E. maltodextrins, lyoprotection was improved by the addition of PEG 8000 as
      a cryoprotectant. CONCLUSIONS: Maltodextrins could be considered as potential
      lyoprotectants in lyophilization of proteins.

PMID- 8668666
TI  - Polymorphism of sulfanilamide: (II) Stability hierarchy of alpha-, beta-, and
      gamma-forms from energy calculations by the atom-atom potential method and from
      the construction of the p, T phase diagram.
AB  - PURPOSE: Sulfanilamide trimorphism was chosen as a model system for comparison
      between stability hierarchies obtained from lattice-energy calculations with
      those deduced from the relative locations of the sublimation curves of polymorphs
      in the sulfanilamide p, T diagram. METHODS: The atom-atom potential (AAP) method
      was used for lattice-energy calculations. The p, T diagram was constructed by
      using crystallographic and thermodynamic data for alpha-, beta-, and gamma-forms,
      and by assigning the temperatures of the experimentally observed phase
      transitions to triple points involving the vapour phase. RESULTS: The hierarchy
      obtained with the AAP method (E alpha > or = E gamma > > E beta) differs only
      slightly from that deduced from the positions of the sublimation curves (p gamma
      > p alpha > p beta) in the p, T diagram at room temperature. No stable phase
      region was found for form alpha. Thus it is really monotropic. CONCLUSIONS:
      Provided enthalpy and volume changes at the transitions are accurate enough, it
      is possible to draw a p, T diagram that accounts for the stability hierarchy of
      polymorphs.

PMID- 8668667
TI  - Effect of change in shape factor of a single crystal on its dissolution behavior.
AB  - PURPOSE: To study the effect of change in the shape factor of real crystals on
      their dissolution behavior using a potassium dichromate crystal as a model for
      particulates in general. METHODS: A model geometry (parallelepiped) has been
      suggested for a dissolving particle. Single crystals of potassium dichromate
      which are monoclinic prisms were grown individually from supersaturated solutions
      at 40 degrees C. Dissolution studies were carried out on five such crystals in
      0.1N H2SO4 at 25 degrees C and a stirrer speed of 50 +/- 1 rpm. The five crystals
      had different degrees of non-isometricity. Initial dimensions of the crystals
      were measured using image analysis techniques. The shape factor of the dissolving
      crystal as a function of time was obtained indirectly from the dissolution data.
      RESULTS: The shape factor of a single crystal changed significantly after about
      50% dissolution. The nature of this change depended on the degree of non
      isometricity of the crystal. The change in shape factor of the dissolving crystal
      was accounted for in the Hixson-Crowell cube root law, and a modified form of the
      cube root equation was developed. This equation for dissolution explained the
      observed upward curvature in the cube root law plot. CONCLUSIONS: The shape
      factor for any non-isometric particle cannot be considered to be constant over
      the dissolution event, as is commonly assumed. This change has an appreciable
      effect on the dissolution behavior of crystals. This study is particularly of
      significance for elongated shapes like needles and platelets. By the methodology
      described here, it was possible to determine the initial shape factor of the
      crystal and the intrinsic dissolution rate constant.

PMID- 8668669
TI  - Percutaneous absorption of ketoprofen from different anatomical sites in man.
AB  - PURPOSE: The purpose of this study was to investigate the percutaneous absorption
      of ketoprofen applied topically to different anatomical sites on the body.
      METHODS: The study design was a randomized, four-way crossover in 24 healthy male
      subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours
      for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen
      solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and
      urine samples were obtained for the assay of racemic ketoprofen and ketoprofen
      enantiomers (S and R), respectively. RESULTS: The relative bioavailabilities of
      ketoprofen gel were 0.90 +/- 0.50, 1.08 +/- 0.63, and 0.74 +/- 0.38 when applied
      to the back, arm, and knee, respectively. The plasma ketoprofen C(max) for gel
      applied to the back and arm are similar (p > 0.05) but C(max) was lower when
      applied to the knee (p < 0.05). The time to C(max) ranged from 2.7 to 4.0 hours
      and was similar for gel treatments on the back and arm, but no longer for the
      knee treatment. The fraction of dose excreted in urine as total S and R
      enantiomers ranged from 5.41 to 9.10%. CONCLUSIONS: The percutaneous absorption
      of ketoprofen was similar when applied to either the back or arm but was lower
      when applied to the knee.

PMID- 8668668
TI  - Estimation of the increase in solubility of drugs as a function of bile salt
      concentration.
AB  - PURPOSE: The objective of this study was to develop a model to predict the extent
      to which bile salts can enhance the solubility of a drug, based on the
      physicochemical properties of the compound. The ability to predict bile salt
      solubilization of poorly soluble drugs would be a key component in determining
      which drugs will exhibit fed vs. fasted differences in drug absorption. METHODS:
      A correlation between the logarithm of the octanol/water partition coefficient
      [log P] of six steroidal compounds and their solubilities in the presence of
      various concentrations of sodium taurocholate at 37 degrees C, log [SR] = 2.234 +
      0.606 log [P] (r2 = 0.987) where SR is the ratio of the stabilization capacity of
      the bile salt to the solubilization capacity of water for the drug, was used to
      predict the solubility of the compounds in presence of sodium taurocholate were
      then measured. RESULTS: The predicted solubilities were within 10% of the
      experimentally observed solubilities for griseofulvin, cyclosporin A and
      pentazocine. The model overpredicted the solubility of phenytoin and diazepam in
      15 mM sodium taurocholate solution by a factor of 1.33 and 1.62 respectively.
      CONCLUSIONS: The expected increase in solubility as a function of bile salt
      concentration can be estimated on the basis of the partition coefficient and
      aqueous solubility of the compound.

PMID- 8668671
TI  - Triazolines. 34. Structure and stability relationships of novel delta 2-1,2,3
      triazoline anticonvulsants.

PMID- 8668670
TI  - The effect of octanoic acid on the binding of the enantiomers of ibuprofen and
      naproxen to human serum albumin: a chromatographic implication.
AB  - PURPOSE: The heats of reaction between the enantiomers and racemates of ibuprofen
      and naproxen and human serum albumin (HSA) are to be measured with and without
      the addition of octanoic acid. The effects of octanoic acid on the free energies
      of interaction between the drugs and HSA is to be determined and compared to that
      estimated from theoretical equations. METHODS: The heats of reaction have been
      measured directly by flow microcalorimetry. RESULTS: The data showed that
      octanoic acid lowered the 1:1 binding constants for all the drug-HSA interactions
      investigated. The effect of octanoic acid was greater on the R than on the S
      forms of the drugs as shown by the differences in free energies of interaction in
      the presence and absence of octanoic acid. CONCLUSIONS: The increased free energy
      differences for the binding of the enantiomers of both drugs to HSA in the
      presence of octanoic acid is closer to the value deemed to be necessary for the
      separation of enantiomers by Davenkov, and shows the importance of the addition
      of octanoic acid to the mobile phase in the separation of these enantiomers on
      immobilized albumin columns.

PMID- 8668673
TI  - An integrated method to determine epithelial transport and bioactivity of oral
      drug candidates in vitro.

PMID- 8668672
TI  - Concentration-dependent plasma protein binding of flurbiprofen in the rat: an in
      vivo microdialysis study.
AB  - PURPOSE: The in vivo plasma protein binding and pharmacokinetics of flurbiprofen
      were studied in awake, unrestrained rats using intravenous microdialysis
      sampling. METHODS: Flurbiprofen (20 mg/kg) was administered i.v. to 2 groups of 6
      rats: in both groups sampling was carried out by microdialysis, but in the second
      group an additional 10 blood samples were withdrawn via a jugular cannula. In
      vitro and ex vivo (following i.v. administration of flurbiprofen 20 mg/kg to
      another group of 13 rats) plasma protein binding of the drug was determined by
      equilibrium dialysis. RESULTS: The area under the unbound plasma concentration
      time profile of flurbiprofen (AUCu), determined by microdialysis sampling was
      somewhat smaller (-19%, p = 0.666) in the rats undergoing simultaneous serial
      blood sampling (2.21 +/- 0.36 micrograms.h/ml) as compared to the rats undergoing
      microdialysis sampling only (2.73 +/- 0.60 micrograms.h/ml). Comparison of total
      and unbound concentrations of flurbiprofen showed an in vivo plasma binding
      varying between 99.5% at low and 98.0% at high total flurbiprofen plasma
      concentrations. Plasma binding of flurbiprofen determined in vitro over the same
      concentration range was higher (99.5-99.9%) but also concentration-dependent.
      Plasma binding of flurbiprofen determined ex vivo, on the other hand,
      corresponded well with the in vivo binding. CONCLUSIONS: Monitoring the fraction
      of drug unbound in blood of an individual rat throughout a pharmacokinetic
      experiment has now become possible by using simultaneous sampling of blood and
      intravenous microdialysates.

PMID- 8668674
TI  - Targeting of drug to the hepatocytes by fatty acids. Influence of the carrier
      (albumin or galactosylated albumin) on the fate of the fatty acids and their
      analogs.
AB  - PURPOSE: The aim of this study was to evaluate the potential of fatty acids as
      shuttles to deliver xenobiotic inside the hepatocytes as well as to study the
      mechanism of incorporation into isolated hepatocytes when bound to native albumin
      or galactosylated albumin. Theoretically, they can enter into the hepatocytes
      after recognition of the Fatty Acid Binding Protein (FABPPM), or remain bound to
      galactosylated proteins and enter into these cells by a process known as receptor
      mediated endocytosis after selective recognition of the asialoglycoprotein
      receptor (ASGPR). METHODS: We synthesized a 3H-benzoyl adduct of lauric acid
      (BLA) (benzoyl adduct chosen to mimic any low molecular weight drug or contrast
      agent), and compared the behavior of BLA with oleic acid for their binding
      properties to carrier-proteins and the uptake mechanism by isolated hepatocytes.
      RESULTS: No significant difference was found in the binding properties of BLA for
      albumin and galactosylated albumin. The incorporation into the hepatocytes was
      found essentially depending on the FABPPM transport system whenever BLA was bound
      to albumin or to galactosylated albumin in the incubation medium: indeed, the
      transport was inhibited by phloretin (inhibitor of sodium dependent transport),
      increased when the free part of BLA was higher, and BLA was recovered in the
      cytosolic fraction of the hepatocytes. CONCLUSIONS: This study showed the
      convenience in using fatty acids as drug carriers possessing tropism for the
      hepatocytes.

PMID- 8668675
TI  - Albumin nanospheres as carriers for passive drug targeting: an optimized
      manufacturing technique.
AB  - PURPOSE: The purpose of this study was to develop a new method to produce albumin
      particles in the sub-200-nanometer range with a narrow size distribution and in a
      controlled and reproducible manner. METHODS: A new emulsion crosslinking method
      was developed using ultrasound and static mixing as homogenization steps and a
      central composite design was used to evaluate the influence of different process
      parameters on particle size, polydispersity and yield. RESULTS: Response surface
      analysis allowed the location of the most important factors. Of all the factors
      investigated, only the albumin concentration and the aqueous phase volume showed
      a significant influence on response parameters. Albumin nanospheres with sizes
      below 200 nm in diameter and very narrow size distributions were obtained in high
      yields ( > 80%). CONCLUSIONS: This study describes a new preparation method for
      albumin nanoparticles which are suitable for future drug targeting studies.

PMID- 8668676
TI  - Pharmacokinetics and biodistribution of oligonucleotide adsorbed onto
      poly(isobutylcyanoacrylate) nanoparticles after intravenous administration in
      mice.
AB  - PURPOSE: The goal of this study was to evaluate the ability of nanoparticles to
      be used as a targeted delivery system for oligonucleotides. METHODS:
      Pharmacokinetic and tissue distribution were carried out in mice by measuring
      radioactivity associated to the model oligothymidylate 33P-pdT16 loaded to
      poly(isobutylcyanoacryate) (PIBCA) nanoparticles. In addition, we have used a TLC
      linear analyzer to measure quantitatively on a polyacrylamide gel
      electrophoresis, the amount of non degraded pdT16. RESULTS: Organ distribution
      study has shown that nanoparticles deliver 33P-pdT16 specifically to the liver
      reducing its distribution in the kidney and in the bone marrow. Nanoparticles
      could partially protect pdT16 against degradation in the plasma and in the liver
      5 min after administration, whereas free oligonucleotide was totally degraded at
      the same time. CONCLUSIONS: Nanoparticles protect oligonucleotides in vivo
      against degradation and deliver them to the liver.

PMID- 8668677
TI  - Physicochemical characterization of protein-free low density lipoprotein models
      and influence of drug loading.
AB  - PURPOSE: Drug free and drug loaded protein-free low density lipoprotein (LDL)
      models consisting mainly of phospholipids, cholesterol, cholesterol esters, and
      triglycerides in ratios found for physiological LDL have been prepared. Their
      physicochemical characteristics were compared with those of physiological LDL.
      METHODS: Different characterization methods were used: photon correlation
      spectroscopy, transmission electron microscopy, X-ray solution scattering, and 1H
      nuclear magnetic resonance spectroscopy (NMR). RESULTS: Particle sizes are highly
      dependent on the preparation method and in particular on the homogenization
      conditions. Electron microscopy indicates that the size distributions of model
      systems are much broader than those of physiological LDL. The X-ray solution
      scattering patterns of the model systems display a temperature dependent maximum
      near 3.8 nm similar to that found in the patterns of physiological LDL. NMR
      indicates a comparable mobility of the lipid molecules in model particles and in
      physiological LDL. The influence of drug loading is similar to that found earlier
      for physiological LDL. In particular, the incorporation of the anti-cancer drug
      WB 4291 seems to have a fluidizing effect on the lipids in the core region of the
      particles. CONCLUSIONS: The preparation method of LDL model systems is of crucial
      importance as only the solvent evaporation method yielded systems in the size
      range of physiological LDL with acceptable high lipid concentrations. The
      fluidizing influence of temperature and drug incorporation (WB 4291) may be
      disadvantage in drug targeting.

PMID- 8668678
TI  - The influence of buffer species and strength on diltiazem HCl release from beads
      coated with the aqueous cationic polymer dispersions, Eudragit RS, RL 30D.
AB  - PURPOSE: Eudragit RL and RS 30D are pseudolatexes frequently used in the coating
      of solid dosage forms. They are based on cationic copolymers stabilized with
      quaternary ammonium groups (poly(ethylacrylate-methylmethacrylate
      trimethylammonioethyl methacrylate chloride). A pH-independent drug release is
      expected because of the quaternary nature of the cationic groups. The objective
      was to explain a distinct "pH-dependent" drug release in various buffer media
      with coated diltiazem beads. METHODS: The diltiazem HCl release from and water
      uptake of Eudragit RS/RL-coated beads was determined in various buffers of
      different buffer species, pH or concentration. RESULTS: The drug release in the
      different buffer media was in the following order: pH 5.0 acetate > pH 3.5
      formate > pH 7.4 phosphate buffer > 0.1M HCl). This "pH-dependent" drug release
      could be explained with an anion exchange process; the chloride counterions of
      the quaternary groups were exchanged with the anionic buffer species during the
      dissolution study. The water uptake of the coated beads correlated well with the
      drug release from the beads. Increasing the buffer strength (acetate buffer)
      first increased and then decreased the drug release, while increasing the ionic
      strength of different buffers with NaCl decreased the drug release and eliminated
      the observed buffer effects because of the excess of chloride ions. CONCLUSIONS:
      The anionic buffer species and not the pH had a significant effect on the
      hydration and hence on the drug release from beads coated with the cationic
      polymers, Eudragit RS and RL.

PMID- 8668680
TI  - AAPS/USP Workshop on Dissolution Calibration and Testing.

PMID- 8668679
TI  - Enhanced cellular uptake of oligonucleotides by EGF receptor-mediated endocytosis
      in A549 cells.
AB  - PURPOSE: The goal of this study was to investigate the feasibility of utilizing
      epidermal growth factor (EGF) receptor-mediated endocytosis to enhance cellular
      uptake and targeting of oligonucleotides in epithelial cancer cells. To overcome
      the problem of endosomal entrappment associated with receptor-mediated delivery,
      we also examined the effects of two fusogenic peptides, polymyxin B and influenza
      HA2 peptide, for their capability to promote cytoplasmic delivery of
      oligonucleotides. METHODS: A molecular conjugate consisting of EGF and poly-L
      lysine (PL) was synthesized and complexed with 5' fluorescently-labeled
      oligonucleotide. Cellular uptake of the complex in presence or absence of the
      fusogenic peptides was monitored fluorometrically. Microscopic studies were
      performed to visualize the intracellular distribution of the oligonucleotide.
      RESULTS: Cells treated with the complex exhibited intracellular fluorescence
      intensity significantly enhanced over free oligonucleotide-treated controls. The
      uptake of the complex was shown to occur via the EGF receptor-mediated pathway.
      Fluorescence microscopic studies revealed cellular internalization of the
      complex, however, the complex appeared to be accumulated in endocytic vesicles.
      Exposure of the cells to complex in presence of HA2 peptide and polymyxin B
      resulted in a more diffused intracellular fluorescence pattern and a
      corresponding increase in fluorescence intensity. These results are consistent
      with the known fusion and destabilizing activities of the peptides. CONCLUSIONS:
      Since EGF receptors are overexpressed in many cancer cell types, the EGF-PL
      conjugate may potentially be used as an effective and selective delivery system
      to enhance uptake of oligonucleotides into cancer cells.

PMID- 8668681
TI  - Derivatives of Dexanabinol. I. Water-soluble salts of glycinate esters.
AB  - PURPOSE: Glycinate ester-type water soluble derivatives of dexanabinol (HU-211)
      (1) a non-psychotropic cannabinoid with potential use in the treatment of brain
      damage were synthesized and evaluated as prodrugs or congeners. METHODS:
      Conventional procedures were used for the synthesis of the novel derivatives.
      Stability studies in water and blood (rat, dog, human) were performed by HPLC;
      NMDA receptor binding was determined by radio ligand [3H] MK-801-displacement;
      the neuroprotection and neurotoxicity studies were performed in cortical cell
      cultures. RESULTS: Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl-
      and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compounds were
      relatively soluble and stable in water. The quaternary ammonium salt-type
      derivatives rapidly hydrolyzed to the parent drug in various types of blood
      including human. In vitro activity studies indicated that the novel derivatives
      possess NMDA receptor binding properties. The neuroprotecting properties
      manifested by some of the new derivatives were associated with very low neuronal
      cell toxicity and are credited to parent compound released by hydrolysis during
      the experiments rather than to intrinsic activity. CONCLUSIONS: Compounds 7 and 8
      are promising water-soluble pro-drug candidates for 1; the glycinate ester 3
      might be used as an active analog.

PMID- 8668683
TI  - Effects of phospholipid chain length, concentration, charge, and vesicle size on
      pulmonary insulin absorption.
AB  - PURPOSE: Non drug loaded lipid vesicles have been investigated as promoters of
      pulmonary insulin absorption. METHODS: Physical mixtures of liposomes with
      insulin were delivered intratracheally to rats by direct instillation method at
      an insulin dose level of 1 U/kg. RESULTS: The overall hypoglycemic response,
      represented by area above the curve (AAC), correlated linearly with the lipid
      concentration for both the neutral and charged liposome-insulin preparations. The
      strongest response was observed with the positively charged liposomes followed by
      negatively charged and neutral liposome-insulin mixtures. Further toxicological
      studies indicated that charge-inducing agents, i.e., stearylamine and
      dicetylphosphate, can cause apparent disruption of pulmonary epithelial cells.
      From the difference of overall hypoglycemic response (AAC) among various
      formulations, it appears that the stronger hypoglycemic effect following
      positively charged liposome-insulin mixture is due to the membrane destabilizing
      effect on stearylamine. Optimum hypoglycemic effect was observed with a medium
      acyl-chain lipid (C10). The cumulative hypoglycemic response appeared to
      correlate inversely with the acyl carbon number of the phospholipid component
      from C10 to C18. The overall hypoglycemic effect does not appear to change within
      the liposomal size range of 0.1 micron - 1.98 microns, indicating that insulin
      absorption following intratracheal instillation is independent of the vesicle
      size within the range studied. CONCLUSIONS: Phospholipid promoted insulin
      pulmonary absorption is significantly dependent on the concentration, charge and
      acyl chain length of the phospholipids.

PMID- 8668684
TI  - Pulmonary delivery of salmon calcitonin dry powders containing absorption
      enhancers in rats.
AB  - PURPOSE: To evaluate the effects of absorption enhancers in dry powders and in
      liquids, pulmonary absorption of salmon calcitonin (sCT) in various formulations
      was measured. METHODS: The dry powder of sCT was prepared by a freeze-drying
      method with a jet mill. After intratracheal administration of sCT dry powder and
      liquid (solution) preparations to rats, plasma sCT levels and calcium levels were
      measured. RESULTS: After intratracheal administration without absorption
      enhancers, sCT in the dry powder and in the liquid were absorbed nearly to the
      same degree. Absorption enhancers (oleic acid, lecithin, citric acid, taurocholic
      acid, dimethyl-beta-cyclodextrin, octyl-beta-D-glucoside) were much more
      effective in the dry powder than in the solution. The reason may be that the
      enhancers added to the dry powder dissolved at high concentrations in a trace
      volume of the fluid lining the alveolar epithelium. CONCLUSIONS: The present
      results suggest that the pulmonary absorption of peptides and proteins can be
      greatly improved by formulating them into dry powders with smaller amounts of
      enhancers than in liquid dosage forms.

PMID- 8668682
TI  - Acyloxymethyl as a drug protecting group. Part 3. Tertiary O-amidomethyl esters
      of penicillin G: chemical hydrolysis and anti-bacterial activity.
AB  - PURPOSE: O-(N-alkylamido)methyl esters of penicillin G were studied as a new
      class of prodrugs. METHODS: The hydrolysis in aqueous buffers containing 20 %
      (v/v) of acetonitrile was investigated by HPLC. RESULTS: A U-shaped pH-rate
      profile was seen with a pH-independent process extending from pH ca. 2 to pH ca.
      10. This pathway is characterised by kinetic data that are consistent with a
      unimolecular mechanism involving rate-limiting iminium ion formation and
      penicillinoate expulsion. Penicillin G and the corresponding amide are the
      ultimate products detected and isolated, indicating that beta-lactam ring opening
      is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of
      penicillin G displayed similar in vitro antibacterial activity to penicillin G
      itself. CONCLUSIONS: Compared to the penicillin G derivatives, the much higher
      stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate
      esters (which gave rise to a Bronsted Beta 1g value of ca. -1) suggests that
      tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs
      with pKa > 4.

PMID- 8668685
TI  - A pharmacokinetic approach for evaluating cytokine binding macromolecules as
      antagonists.
AB  - PURPOSE: Cytokine binding macromolecules such as antibodies and soluble receptors
      sometimes produce undesirable agonist-like activities instead of the expected
      antagonist-like effects when the cytokine binding macromolecule extends the half
      life of a short-lived cytokine. The purpose of this paper is to identify the
      pharmacokinetic and physicochemical properties that can cause these agonist-like
      activities. METHODS: A simple pharmacokinetic model was used to determine whether
      a given cytokine binding macromolecule will function effectively as an antagonist
      in therapeutic situations in which cytokine is released chronically. RESULTS: The
      model proposed satisfactorily fits experimental data for soluble interleukin-4
      receptor and for an anti-interleukin-4 monoclonal antibody under conditions in
      which agonist-like and antagonist activity are observed. CONCLUSIONS: We show
      that the unexpected agonist-like activities result only when there is
      nonlinearity in the cytokine-cytokine receptor interaction and the cytokine
      binding macromolecule prolongs the half-life of the cytokine.

PMID- 8668686
TI  - Pharmacokinetic-pharmacodynamic modeling of the antibiotic effect of piperacillin
      in vitro.
AB  - PURPOSE: It was the aim of the present study to investigate the in vitro
      antimicrobial effects of the beta-lactam antibiotic piperacillin on Escherichia
      coli using concentration-time profiles similar to those encountered in vivo.
      METHODS: An in vitro dilution model was used to expose E. coli to various
      piperacillin concentration profiles. The antimicrobial effect was evaluated by
      determination of the number of bacteria over time. RESULTS: A modified Emax-model
      was found appropriate to describe the pharmacodynamic effect. This model was
      linked with the respective piperacillin concentrations to provide a suitable
      pharmacokinetic-pharmacodynamic (PK-PD) model. The average growth half-life in
      absence of piperacillin was 28 min and the maximum kill half-life was 25 min. The
      EC50 for the various dosing regimens averaged 5.2 micrograms/mL and was
      independent of dose. These parameters were used the simulate the bacterial
      effects of commonly administered doses or dosing regimens in humans. CONCLUSIONS:
      Based on the in vitro data a more frequent administration of piperacillin will be
      more efficacious. The proposed PK-PD-model allows a more detailed evaluation of
      dosing regimens than the use of minimum inhibitory concentrations.

PMID- 8668688
TI  - [Renal biopsy in the elderly].
AB  - Fifty years after the first percutaneous needle biopsies of the kidney, enough
      results have been obtained to evaluate indications in elderly patients, a
      population group we define as over 75 years of age. In approximately 50% of the
      patients in this group, the indication for renal biposy is a nephrotic syndrome.
      The lesions usually observed involve extramembranous glomerulonephritis or
      minimal change glomerulopathy. The biopsy may also reveal amylosis. Chronic renal
      failure is the predominant reason for nephrology consultation in the elderly.
      Although all of these patients do not undergo biopsy, in our experience, results
      show chronic glomerulopathies, mainly IgA, in about half of the case as well as
      chronic interstitial nephritis and nephroangiosclerosis. The aging process also
      leads to acute renal failure in many patients. Biopsy would not be indicated in
      case of shock, drug toxicity or obstruction but in approximately 10% of the cases
      histology can reveal a specific parenchymal lesion. The technique for renal
      biopsy is the same in elderly patients as in younger adults. Renal biopsy can be
      considered as a safe diagnostic tool of considerable importance when ordered by a
      nephrologist, performed by an experienced operator and read by a well-trained
      pathologist. In many cases it is essential to in order to provide patients over
      75 with the same quality care as younger adults.

PMID- 8668687
TI  - Interspecies scaling of bosentan, a new endothelin receptor antagonist and
      integration of in vitro data into allometric scaling.
AB  - PURPOSE: The goal of this study was to find a rational and reliable method of
      using animal data to predict the clearance of metabolised drugs in humans.
      METHODS: One such approach is to use in vitro liver models (e.g. hepatocytes and
      microsomes) to determine the relative capacities of the various animal species
      and humans to metabolise the test compound. These data can then be combined with
      the in vivo clearances in animals, to calculate the in vivo clearance in humans
      using allometric scaling techniques. In this study, this approach was evaluated
      with a new endothelin receptor antagonist, bosentan, which is eliminated mainly
      through metabolism and is characterized by very large interspecies differences in
      clearance. Therefore, this compound provided a stringent test of our new
      extrapolation method for allometric scaling. RESULTS: The results obtained with
      bosentan showed that adjusting the in vivo clearance in the different animal
      species for the relative rates of metabolism in vitro gave a far better
      prediction of human clearance than an empirical correcting factor (brain weight).
      CONCLUSIONS: This approach provided a more rational basis for predicting the
      clearance of metabolised compounds in humans.

PMID- 8668689
TI  - [Chronic pelvic pain. Expression of a psychological problem].
AB  - OBJECTIVES: Chronic pelvic pain (CPP) is one of the most difficult and perplexing
      problems encountered in gynecology. Lately CPP has been attributed, among many
      other etiologies to tension myalgia of the pelvic floor. Identification of
      trigger points, myofascial problems and the Carnett test have been considered
      helpful. We hypothesized that these are not the cause of CPP but a sign of
      psychic disturbance. METHODS: Seventy patients, 40 with CPP, 20 with organic pain
      and 10 normal controls were investigated. A pain index was defined and used. A
      blinded psychologic evaluation was conducted in all cases using the Rorschach and
      a semi structured psychologic interview. A psychometric index was calculated.
      RESULTS: The algometric test was low in controls. It was in the higher range in
      CPP patients and in both cases correlated well with the psychometric index. CPP
      patients expressed a variety of psychic disturbances. The response of patients
      with organic CPP to etiologic treatment could be predicted by the algometric
      index, low index = good response; high index = difficult follow up. CONCLUSION:
      Trigger points, tension myalgia and abdominal cellulalgia are not the cause of
      CPP. They are the sign of somatization of neurotic or psychosomatic problems in
      the pelvis. They represent a useful diagnostic tool, which will allow an
      individualized, multidisciplinary approach to diagnosis and management of CPP.

PMID- 8668690
TI  - [Paraplegia after surgical treatment of primary aorto-duodenal fistula].
AB  - A 68-year-old patient with chronic cirrhosis underwent surgical repair of the
      subrenal abdominal aorta presenting an aorto-duodenal fistula. The fistula was
      considered to be a primary fistula because it occurred without prior surgery and
      because the aorta had ruptured without formation of an aneurysm. The
      postoperative period was complicated by paraplegia further compromising the
      outcome in this severe condition. In general, there are several problems involved
      in the management of aorto-duodenal fistulae. Neither computed tomography of the
      abdomen nor gastroduodenal endoscopy are able to provide the diagnosis in all
      cases before surgery. Surgical treatment is most often conducted in an emergency
      setting requiring repair of both the digestive tract and of the vascular lesions.
      It is also important to recognize the risk of neurological events occurring intra
      operatively. Prognosis is usually poor.

PMID- 8668691
TI  - [Mucinous pancreatic ductal ectasia: mucus secreting tumor of malignant
      potential].
AB  - We report two cases of mucinous pancreatic ductal ectasia including one which
      progressed to micro-invasive carcinoma. The frequency of this tumor may be under
      estimated (24 cases reported in the literature) because of confusion with
      pseudocysts or mucinous cystadenoma. The diagnosis is made at retrograde
      cholangiopancreatography. Endosonography is useful for tumors in the head of the
      pancreas, the predominant localization. At present, there is no test which can
      distinguish malignant forms from benign mucinous ductal ectasia. Resection of the
      tumor and the surrounding pancreatitis is the only curative treatment known.
      Pancreatoduodenectomy may be discussed in elderly patients with a tumor without
      signs of malignancy.

PMID- 8668693
TI  - [Cutaneous mucinoses].
AB  - Cutaneous mucinoses are a heterogeneous group of disorders in which mucin
      accumulates in the skin or in the follicles. Mucin is a gelatinous substance
      composed of glycosaminoglycanes, especially hyaluronic acid and dermatan sulfate
      bound to small quantities of chondoitin sulfate and heparin sulfate. Though the
      causes of mucinoses remain unknown, they can be divided into distinctive
      cutaneous (primary) mucinoses, in which mucin deposition is the distinctive
      histological sign resulting in clinically distinctive lesions, and cutaneous
      disorders, in which mucin deposition is an epiphenomenon (secondary mucinoses).
      Histologically, mucin is recognized after special staining techniques using
      alcian blue and colloidal iron. The microscopic localization of the mucin deposit
      is used to distinguish between dermal and follicular forms of primary mucinoses
      and between epidermal, dermal and follicular forms of secondary mucinoses. We
      present here the clinical and histological features of primary cutaneous
      mucinoses and an updated classification. The main therapeutic schemas are
      outlined.

PMID- 8668692
TI  - [Brucella pancarditis with fatal outcome].
AB  - Brucella endocarditis was diagnosed in a 21-year-old itinerant farm worker
      hospitalized for acute pulmonary edema. History taking revealed cough, fever and
      sweating one month earlier which had been treated with antibiotics. At admission,
      echography showed lesions on the aortic valve and hemocultures identified
      Brucella meltensis. On day 7 of specific treatment with doxycycline (200 mg/day)
      and rifamycine (1200 mg/day), and despite digitalics and diuretics, left
      ventricular failure rapidly worsened, leading to cardiac arrest and death before
      emergency surgery could be performed. Autopsy showed occlusive vegetations on the
      aortic valves facing the right coronary ostium, deep ulceration of the valsava
      sinus with abscess formation and fibrino-hemorragic pericarditis involving both
      the anterior and posterior walls of the epicardium. Gram negative germs were
      evidenced in the abscess alone. This case emphasizes the potentially rapid
      destructive effect of Brucella melitensis and confirms that surgery is the safest
      therapeutic alternative for aortic valve localizations. Surgery should be
      performed without delay.

PMID- 8668694
TI  - [Pulmonary emphysema: surgical indications].
AB  - Surgery for pulmonary emphysema, with the exception of lung transplantation, is
      limited at present to resection of the emphysematous areas. The resection of a
      unique bulla within an otherwise healthy parenchyma can be indicated in case of
      complications but rarely in asymptomatic patients. When the bullae are large
      (i.e. volume greater than one-third of the hemithorax) in a patient suffering
      from diffuse emphysema, bullectomy is the ideal indication. Mortality varies from
      0 to 10%, essentially due to infection or acute respiratory failure. In most
      patients, the subjective improvement in terms of dyspnea and the objective
      improvement as measured by spirometry remains significative up to 5 years after
      surgery. Inversely, surgical resection is classically considered to be
      contraindicated in patients with small poorly-limited bullae. Recent data would
      however question this idea since subjective and objective improvement after
      reduction of the lung volume is still present 1 year after surgery in most
      patients, even those with severe obstruction. The mechanism is probably related
      to increased elastic recoil. Even if only temporary improvement can be achieved
      for a few years, the persisting course of emphysema would suggest that volume
      reduction should always be entertained as an alternative before lung
      transplantation.

PMID- 8668695
TI  - [Cerebral thrombophlebitis treated in intensive care units].

PMID- 8668696
TI  - [Candida pyelonephritis].

PMID- 8668697
TI  - [Metabolic acidosis caused by injectable sodium valproate. 6 postoperative cases
      in neurosurgery].

PMID- 8668698
TI  - [Aseptic meningitis during treatment with high-dose intravenous immunoglobulins].

PMID- 8668699
TI  - [Recurrent bilateral uveitis associated with HTLV 1 infection].

PMID- 8668700
TI  - A time to heal.

PMID- 8668701
TI  - My life as a surgeon.

PMID- 8668702
TI  - Pierre Charles-Alexandre Louis: the impact of a clinical trial.

PMID- 8668703
TI  - Mental health of medical students: the culture of objectivity in medicine.

PMID- 8668704
TI  - Martha Tomek.

PMID- 8668705
TI  - Teaching Lysenko: lessons learned from the decline of Soviet genetics.

PMID- 8668706
TI  - Reflections on a medicine clerkship.

PMID- 8668707
TI  - The reflex action: a contribution of physiology to neurology.

PMID- 8668708
TI  - A survivor's tale.

PMID- 8668709
TI  - On priorities.

PMID- 8668710
TI  - Smallpox 1945--smallpox 1996.

PMID- 8668711
TI  - Albert Sabin's monkey experiments.

PMID- 8668712
TI  - Biomedical research.

PMID- 8668713
TI  - Dr. Pader replies to Dr. Fisher (winter 1996)

PMID- 8668714
TI  - Dr. Chirls replies to Dr. Herwig (winter 1996)

PMID- 8668716
TI  - Parental consent for a minor's abortion.

PMID- 8668717
TI  - Parental consent for a minor's abortion.

PMID- 8668715
TI  - Parental consent for a minor's abortion.

PMID- 8668718
TI  - Parental consent for a minor's abortion.

PMID- 8668719
TI  - Parental consent for a minor's abortion.

PMID- 8668720
TI  - Parental consent for a minor's abortion.

PMID- 8668721
TI  - Parental consent for a minor's abortion.

PMID- 8668722
TI  - Ontogeny of the head of the Pacific hagfish (Eptatretus stouti, Myxinoidea):
      development of the lateral line system.
AB  - The head of adult hagfishes (jawless craniates, Myxinoidea) of the family
      Eptatretidae displays a number of skin grooves of uncertain origin. These grooves
      have been homologized to the neuromast lines of other craniates, and they are
      innervated by two ganglionated cranial nerves that have been interpreted as
      lateral line nerves. The grooves do not, however, contain the compound receptors
      that are typical of a lateral line (i.e. neuromasts or electroreceptors), and
      both their development and function have remained enigmatic. To elucidate the
      embryonic origin of the grooves (which should develop from placodes if they are
      homologues of the lateral line system), embryos of Pacific hagfish were examined
      by means of three-dimensional reconstructions from serial sections. Because of
      the scarcity of specimens of embryonic hagfishes, only two embryos were
      reconstructed, but these reconstructions clearly show that a number of placodes
      and placodal derivatives (i.e. sensory ridges, receptor primordia, and cranial
      ganglia) occur in the head of embryonic eptatretid hagfishes. Some of these
      placodes correspond to the lens and epibranchial placodes of other craniates, but
      there are also three other placodes which represent possible homologues of
      lateral line placodes. The topology of the placodes in this latter group
      corresponds to the topology of the grooves of adult hagfishes, and we therefore
      reach three conclusions: (i) that an embryonic lateral line system is present in
      hagfishes; (ii) that the grooves of adult hagfishes in all probability derive
      from lateral line placodes; and (iii) that the presence of lateral line placodes
      is a primitive character of craniates.

PMID- 8668723
TI  - Visual pattern memory without shape recognition.
AB  - Visual pattern memory of Drosophila melanogaster at the torque meter is
      investigated by a new learning paradigm called novelty choice. In this procedure
      the fly is first exposed to four identical patterns presented at the wall of the
      cylinder surrounding it. In the test it has the choice between two pairs of
      patterns, a new one and one the same as the training pattern. Flies show a
      lasting preference for the new figure. Figures presented during training are not
      recognized as familiar in the test, if displayed (i) at a different height, (ii)
      at a different size, (iii) rotated or (iv) after contrast reversal. No special
      invariance mechanisms are found. A pixel-by-pixel matching process is sufficient
      to explain the observed data. Minor transfer effects can be explained if a graded
      similarity function is assumed. Recognition depends upon the overlap between the
      stored template and the actual image. The similarity function is best described
      by the ratio of the area of overlap to the area of the actual image. The
      similarity function is independent of the geometrical properties of the employed
      figures. Visual pattern memory at this basic level does not require the analysis
      of shape.

PMID- 8668724
TI  - Proprioceptive hair cells on the neck of the squid Lolliguncula brevis: a sense
      organ in cephalopods for the control of head-to-body position.
AB  - Decapod cephalopods, such as cuttlefishes and squids, have a distinct neck region
      that allows movements (roll, pitch and yaw) of the head relative to the body.
      This paper describes the structure, innervation and central pathways of
      proprioceptive hair cells on the neck of the squid Lolliguncula brevis that sense
      such movements and control head-to-body position. These hair cells exist on the
      dorsal side of the neck underneath the nuchal cartilage, close to the animal's
      midline on either side of the nuchal crest. On each side, the hair cells can be
      divided into an anterior and a posterior group of 25-35 and 70-80 cells,
      respectively. An individual hair cell carries up to 300 kinocilia of equal length
      (about 30 microns), arranged in up to seven rows. The hair cells of the left and
      right anterior group are morphologically polarized in the medial direction,
      whereas the hair cells of the left and right posterior group are polarized in the
      anterior direction. The hair cells are primary sensory cells. They are innervated
      by a branch of the postorbital nerve and project ipsilaterally into the ventral
      part of the ventral magnocellular lobe. Efferent synaptic contacts are present at
      the base of the hair cells. In behavioural tests the influence of the neck hair
      cells on head position control was investigated. During imposed body rolls, a
      unilateral deafferentation of the cells caused an asymmetric change of the
      compensatory head roll response and elicited a head roll offset to the operated
      side. Bilateral deafferentation of the cells elicited a downward head pitch
      offset. This offset was superimposed on the compensatory head pitch response
      during imposed body pitch. These morphological and behavioural findings show that
      the neck hair cells and the associated nuchal cartilage structures of
      Lolliguncula brevis form a neck receptor organ that, together with statocyst and
      visual inputs, controls the position of the animal's head and body.

PMID- 8668725
TI  - Excitation, oscillations and wave propagation in a G-protein-based model of
      signal transduction in Dictyostelium discoideum.
AB  - In an earlier paper (Tang & Othmer 1994 Math. Biosci 120, 25-76), we developed a
      G-protein-based model for signal transduction in the cellular slime mould
      Dictyostelium discoideum and showed that it can account for the results from
      perfusion experiments done by Devreotes and coworkers (Devreotes et al. 1979 J.
      Cell. 80, 300-309; Devreotes & Steck 1979 J. Cell Biol. 80, 300-309; Dinauer et
      al. 1980 J. Cell Biol. 86, 537-561). The primary experimental observables are the
      amounts of cAMP secreted and the time scale of adaptation in response to various
      stimuli, and we showed that the predictions of the model agree well with the
      observations. Adaptation in the model arises from dual receptor-mediated
      pathways, one of which produces a stimulatory G protein Gs and the other of which
      produces an inhibitory G protein Gi. In this paper we use the model to simulate
      the suspension experiments of Gerisch & Wick (1975 Biochem. biophys. Res. Commun.
      65, 364-370) and the experiments done in cell cultures on Petri dishes (Tomchik &
      Devreotes 1981 Science, Wash. 212, 443-446). The model predicts excitation to
      cAMP stimuli, sustained oscillations, or spiral waves and target patterns,
      depending on the developmental stage of the cells and experimental conditions.
      The interaction between different pacemakers is also studied.

PMID- 8668726
TI  - Probabilistic secretion of quanta at somatic motor-nerve terminals: the fusion
      pore model, quantal detection and autoinhibition.
AB  - The probability of detecting first, second, and later quanta secreted at release
      sites of a motor-nerve terminal during the early release period following a nerve
      impulse has been addressed. The possibility that early quantal release
      autoinhibits later quantal release during this period has also been ascertained.
      In this investigation, a model for the secretion of a quantum at a release site
      is developed in which, following the influx and diffusion of calcium ions to a
      release site protein associated with synaptic vesicles, kappa steps of
      association of the ions with the protein then occur at rate alpha. The release
      site protein then undergoes a conformational change which may not go on to
      completion if calcium ions dissociate from the protein at rate gamma. If this
      process does reach completion then a fusion-pore between the vesicle and the
      presynaptic membrane is created; this happens at rate delta. Key assumptions of
      this fusion-pore model are that the quantal secretions from each site are
      independent of each other, and that there is a large number of vesicles, each
      with a small probability of secretion, so that the number of secretions is
      Poisson in nature. These assumptions allow analytical expressions to be obtained
      for predicting the times at which first, second and later quanta are secreted
      during the early release period following an impulse. To test the model,
      experiments were performed in which the times of first, second and later quantal
      releases were determined at discrete regions along the length of visualized motor
      terminal branches in toad (Bufo marinus) muscles. Estimates of model rate
      constants and of kappa from the times for first quantal secretions failed to give
      satisfactory predictions of the observed times of later secretions. Therefore,
      either the model fails, or the procedure used for detecting later quantal events
      as a consequence of their being masked by earlier quantal events is inadequate.
      To solve this detection problem, a two-dimensional analysis of the spread of
      charge following the secretion of a quantum at a random site on the motor
      terminal branch has been done. This allows determination of the probability that
      later quanta will be detected following secretion of earlier quanta. The
      detection model was then incorporated into the fusion-pore model to predict the
      times at which second and later quanta occur during the early release period,
      based on the estimates of the model parameters derived from the analysis of first
      quantal releases. Good estimates were now obtained for the observed times of
      second and later quantal releases, indicating that appropriate procedures must be
      adopted for adequate detection of quantal secretions. Furthermore, the
      experiments provide support for the fusion-pore model. It has been suggested that
      the binomial nature of quantal release from the entire motor-nerve terminal may
      be explained if early quantal release inhibits later quantal release during the
      early quantal release phase (M. R. Bennett & J. Robinson 1990, Proc. R. Soc.
      Lond. B 239, 329-358). Although the fusion-pore detection error model gave good
      predictions of the observed times of first, second and later quantal releases,
      these may be improved if a model for autoinhibition is included. In this model
      the first quantum was taken as giving rise to an inhibition of secretion that
      propagates to surrounding release sites with a constant velocity, v. A combined
      model incorporating the fusion-pore detection error model and that for
      autoinhibition was then used to predict second and later quantal latencies, by
      using the first quantal latencies to determine the estimates for the parameters
      in the combined model. When this analysis was done on the times for quantal
      secretion at sites on thirteen different motor-nerve terminals, the value of v
      was estimated as zero in each case, so that no autoinhibitory effect was
      observed.

PMID- 8668728
TI  - Prevention in practice.
AB  - There are many barriers that must be overcome for health providers to integrate
      appropriate health screening, health promotion, and disease prevention into their
      practices. This article delineates these barriers and offers suggestions to put
      prevention into practice.

PMID- 8668727
TI  - Myth, metaphor and hypothesis: how anthropomorphism defeats science.

PMID- 8668729
TI  - Health promotion, health protection, and preventive services.
AB  - Health promotion, health protection, and preventive services reflect the 21
      priority areas of Healthy People 2000. This article focuses on the cost
      effectiveness of health promotion and the role that primary care physicians can
      play in this initiative.

PMID- 8668730
TI  - Motivating change in health behavior. Implications for health promotion and
      disease prevention.
AB  - Motivational approaches that build on the concepts of risk and harm reduction are
      new developments in the application of behavioral sciences to health promotion
      and disease prevention. This article develops a generic approach for helping
      practitioners motivate patients to change unhealthy behaviors.

PMID- 8668731
TI  - Screening for disease, cost-effectiveness, and guidelines.
AB  - This article provides a brief overview of issues involved in selecting prevention
      maneuvers for primary care practitioners. Screening diseases, the screening tests
      themselves, patient characteristics, and cost-effectiveness are discussed.

PMID- 8668732
TI  - Preventive health care for infants birth to two years of age.
AB  - The primary health care system must place emphasis on promoting early and
      comprehensive prenatal care, providing anticipatory guidance about injury
      prevention, ensuring adequate immunization, and monitoring growth and development
      to maximize the health of infants and young children. These priorities form the
      foundation of contemporary primary prevention for infants and young children.

PMID- 8668733
TI  - Preventive health care for children.
AB  - This article discusses immunization, development, vision, blood pressure,
      dentition, behavioral, and environmental screening for preschool children. The
      authors then discuss screening for children in the early school years. Injury and
      violence prevention and topics of sexuality for the preadolescent are also
      presented.

PMID- 8668734
TI  - Preventive health care for teenagers and young adults.
AB  - Risk-taking behaviors are the major source of morbidity among adolescents. The
      authors discuss risk reduction through preventive activities. An approach is
      offered to structure preventive visits for this age group given the time and
      financial constraints of providers.

PMID- 8668735
TI  - Prevention in adults.
AB  - Disease prevention in adults presents challenges to health providers. This
      article outlines the reasons certain illnesses are targeted for prevention and
      how recommendations for specific interventions evolved.

PMID- 8668736
TI  - Screening, health promotion, and prevention in women.
AB  - Many health promotion and disease prevention recommendations are specific to
      adult women. Given their strategic position within families, women often hold the
      responsibility for the health and well-being of all family members.

PMID- 8668737
TI  - Screening, health promotion, and prevention in men.
AB  - The authors emphasize screening for prostate and testicular cancer, HIV, and
      drug/alcohol abuse. Factors such as firearm safety, violence in the home,
      smoking, and exercise are also discussed.

PMID- 8668738
TI  - Health maintenance and prevention in the elderly.
AB  - This article summarizes recommendations and current controversies to help guide
      primary care providers when caring for the elderly. Health maintenance and
      preventive care regimens are discussed within the context of a comprehensive
      evaluation of the particular patient.

PMID- 8668739
TI  - Prevention in practice. Ethnic groups.
AB  - This article focuses on people from India, Pakistan, Sri Lanka, Bangladesh, Laos,
      Cambodia, Vietnam, China, and the Pacific Islands. Health care providers must be
      aware of cultural differences, language obstacles, poverty, social isolation, and
      genetic conditions when treating these ethnic groups.

PMID- 8668740
TI  - Prevention and screening in the nursing home.
AB  - The primary care physicians must use screening procedures for the elderly that
      focus on function, with special attention paid to falls, incontinence,
      malnutrition, and sexuality. Nursing home staff and patients' families can be
      particularly helpful to the physician.

PMID- 8668741
TI  - Preventive care in pregnancy.
AB  - Pregnancy provides unique opportunities for the initiation of preventive
      practices that can have long-standing implications for a pregnant woman, her
      infant, and the entire family. The physician has an obligation to evaluate the
      safety and appropriateness of interventions. This article examines routine
      prenatal care and its rationale.

PMID- 8668742
TI  - The primary care physician as a sports medicine and exercise advocate and
      activist.
AB  - This article promotes the philosophy that every office visit can and should be a
      sports physical examination for patients of all ages. The author educates
      providers about promoting exercise and preventing the preventable sports
      injuries. Providers are encouraged to become sports and exercise community
      activists.

PMID- 8668743
TI  - Media strategies for community health advocacy.
AB  - Primary care providers have an important role to play in advocating healthy
      public policies. This article compares media advocacy with traditional uses of
      the media for health promotion.

PMID- 8668744
TI  - Recovered memories in context: thoughts and elaborations on Bowers and Farvolden
      (1996)
AB  - The recovered memory debate exposes several traditional and recent contradictions
      within psychology. Building on K. Bowers and P. Farvolden (1996), the nature of
      recovered memories has profoundly different meanings for therapeutic versus legal
      settings. Whereas memory can be distorted during the process of retrieval,
      certain techniques--such as nondirective writing--may be helpful in reducing
      suggestive influences in recall. Ironically, methods that have been found to
      produce the most accurate recollections of the past appear only subtly different
      from those that yield the greatest distortions. The recovered memory debate must
      ultimately be viewed within a cultural context, both in terms of the phenomenon
      and its treatment. The authors discuss parallels to other explanatory and
      therapeutic fads related to states of nonspecific distress.

PMID- 8668745
TI  - Relation between perceived vulnerability to HIV and precautionary sexual
      behavior.
AB  - Although virtually all major theories of health-protective behavior assume that
      precautionary behavior is related to perceived vulnerability, the applicability
      of this assumption to human immunodeficiency virus (HIV) preventive behavior has
      recently been called into question. This article uses qualitative and
      quantitative methods to review and integrate the literature relevant to the
      relation between perceived vulnerability to HIV and precautionary sexual
      behavior. Specifically, the purpose of the article is to determine whether the
      extent research supports 2 hypotheses regarding this relation; (a) Perceptions of
      personal vulnerability to HIV are reflections of current and recent risk and
      precautionary behavior, and (b) these perceptions motivate precautionary sexual
      behavior. In addition, it examines the conceptual and methodological strengths
      and weaknesses of the empirical literature on these questions and provides
      recommendations for future research.

PMID- 8668746
TI  - Concerns about drawing causal inferences from meta-analyses: an example in the
      study of gender differences in aggression.
AB  - Meta-analysis has increasingly been used as an explanatory research tool. The
      present investigation was designed to illustrate the potential limitations of
      meta-analysis for making causal inferences. Several meta-analytic investigations
      have led others to conclude that gender differences are getting smaller over
      time, however, there has been little concern regarding changes in research
      methodology over time. The present findings indicate that the gender differences
      in aggression appear to be remarkably stable when changes in study
      characteristics over time are controlled. The authors discuss the implications
      for the use of meta-analytic procedures to make causal inferences and the
      implications for understanding the causes of gender differences.

PMID- 8668747
TI  - Gender differences in aggression as a function of provocation: a meta-analysis.
AB  - In this article, we meta-analytically examine experimental studies to assess the
      moderating effect of provocation on gender differences in aggression. Convergent
      evidence shows that, whereas unprovoked men are more aggressive than women,
      provocation markedly attenuates this gender difference. Gender differences in
      appraisals of provocation intensity and fear of danger from retaliation (but not
      negative affect) partially mediate the attenuating effect of provocation.
      However, they do not entirely account for its manipulated effect. Type of
      provocation and other contextual variables also affect the magnitude of gender
      differences in aggression. The results support a social role analysis of gender
      differences in aggression and counter A. H. Eagly and V. Steffen's (1986) meta
      analytic inability to confirm an attenuating effect of provocation on gender
      differences in aggression.

PMID- 8668748
TI  - The relationship between social support and physiological processes: a review
      with emphasis on underlying mechanisms and implications for health.
AB  - In this review, the authors examine the evidence linking social support to
      physiological processes and characterize the potential mechanisms responsible for
      these covariations. A review of 81 studies revealed that social support was
      reliably related to beneficial effects on aspects of the cardiovascular,
      endocrine, and immune systems. An analysis of potential mechanisms underlying
      these associations revealed that (a) potential health-related behaviors do not
      appear to be responsible for these associations; (b) stress-buffering effects
      operate in some studies; (c) familial sources of support may be important; and
      (d) emotional support appears to be at least 1 important dimension of social
      support. Recommendations and directions for future research include the
      importance of conceptualizing social support as a multidimensional construct,
      examination of potential mechanisms across levels of analyses, and attention to
      the physiological process of interest.

PMID- 8668749
TI  - International Psychopharmacology Algorithm Project Report.

PMID- 8668750
TI  - Algorithms for the treatment of schizophrenia.

PMID- 8668751
TI  - Algorithms for the treatment of bipolar manic-depressive illness.

PMID- 8668752
TI  - Algorithms for the treatment of subtypes of unipolar major depression.

PMID- 8668753
TI  - Algorithm for the treatment of panic disorder with agoraphobia.

PMID- 8668754
TI  - Algorithm for the treatment of obsessive-compulsive disorder (OCD).

PMID- 8668755
TI  - Algorithm for schizophrenia in Japan.
AB  - An algorithm for schizophrenia and related psychotic disorders based on current
      Japanese trends in pharmacotherapy is proposed. In practice, selection of anti
      psychotics takes into account additional variables: acute and long-term side
      effects, inter- and intra-individual variation in efficacy, clinical response to
      any previously administered antipsychotics, and information on blood levels where
      clinical relevance is known. Besides pharmacotherapy, various psychosocial
      therapies are also required, especially for treating the secondary functional and
      interpersonal handicaps that result from the long-term expression of the illness.
      It should be noted that clozapine is not included in the algorithm since concerns
      about its cytotoxic effects have prevented its introduction in Japan.
      Additionally, risperidone is still under clinical evaluation in Japan, and its
      relative utility remains to be established.

PMID- 8668756
TI  - Novel French antidepressants not available in the United States.
AB  - There is little awareness in the United States and other English-speaking
      countries of a number of novel antidepressant drugs that have recently been
      developed and marketed in France. This review focuses on tianeptine, amineptine,
      minaprine, medifoxamine, and modafinil--examining both their pharmacological
      actions and their clinical efficacies. Their potential for further research or
      marketing in the United States is discussed.

PMID- 8668757
TI  - Consulting the public--token gestures or democratic right?

PMID- 8668758
TI  - Birthweight, adult risk factors and incident coronary heart disease: the
      Caerphilly Study.
AB  - OBJECTIVE: To determine the relationships between birthweight, the incidence of
      coronary heart disease, and a range of coronary heart disease risk factors that
      operate during adult life. DESIGN: Cohort study with a 10-year follow-up period.
      SETTING: The town of Caerphilly, South Wales, and five adjacent villages.
      SUBJECTS: 1,258 men aged 45-59 at time of recruitment between 1979 and 1983. MAIN
      OUTCOME MEASURES: All deaths, coronary heart disease deaths, non-fatal CHD
      events. RESULTS: The validity of the birthweight data was supported by the strong
      graded associations between birthweight and anthropometric measures in adulthood,
      particularly height, body mass index, triceps, skinfold thickness and percentage
      body fat. An inverse relationship was found between birthweight and incident
      fatal and non-fatal CHD, (P = 0.01), though no relationship was found between
      birthweight and all-cause mortality. Amongst the major CHD risk factors, only
      fibrinogen shows a statistically significant relationship with birthweight (P =
      0.008), fibrinogen levels being lower among the men with lower birthweights. When
      social and biological variables are included in models relating incident CHD and
      birthweight, the relationship between birthweight and incident fatal and non
      fatal CHD remains essentially unchanged. CONCLUSION: A graded association between
      low birthweight and later CHD has been demonstrated in this cohort. This inverse
      association cannot be explained by the measured social or behavioural variables,
      or by other risk factors operating in adult life.

PMID- 8668759
TI  - Local voices: evolving a realistic strategy on public consultation.
AB  - The publication of Local Voices in 1992 challenged Health Authorities to develop
      an effective system for their public consultation activities compatible with the
      requirements of the internal market.1 The general rhetoric was persuasive, but it
      was less clear how, and to what extent, Local Voices work would influence Health
      Authority decisions. Serious questions about the nature, purpose and impact of
      Local Voices were raised within a year of publication.2 This paper re-examines
      the issues and discusses some of the benefits and limitations of public
      consultation exercises, using as illustrations two projects carried out in East
      Lancashire, one on adult mental illness3 and the other on maternity services.4
      Particular consideration is given to the precise impact on commissioning of
      public consultation exercises, and the dilemmas and tensions which emerge as the
      commissioners consider different findings from different methodologies and
      different population subgroups. The final section of the article summarises the
      lessons learnt and sketches out a more systematic and critical approach to public
      consultation.

PMID- 8668760
TI  - Inter-agency assessment of respite care needs of families of children with
      special needs in Fife.
AB  - BACKGROUND: In response to concern about the respite care provision for parents
      of children with special needs in Fife a survey was undertaken jointly by the
      Fife Regional Council social work department and education department and Fife
      Health Board. METHODS: A postal questionnaire survey was carried out of families
      of children with special needs in Fife and a retrospective case review of
      paediatric admission in two Fife hospitals undertaken to identify episodes of
      respite care in hospital. RESULTS: Results confirmed the considerable demand for
      additional respite services and the need for a variety of types of respite care
      provision to cater for the differing needs of families. The two most commonly
      requested services were a small homely respite care centre and holiday
      playschemes. The quality of services currently provided was generally considered
      to be good. The numbers of (usually multiply handicapped) children with a
      specific need for a health professional input during respite care are relatively
      few but nevertheless are an important group which often receive respite care
      inappropriately in a hospital setting. CONCLUSIONS: The results of the survey
      informed the interagency community care planning process and led to the
      developments of a Fife-wide family-based respite care scheme and a small
      residential facility in Kirkcaldy district. The latter is jointly funded by the
      Regional Council and Health Board. The Health Board will provide nursing support
      to the small residential service so that the needs of the few severely and
      multiply handicapped children can be better met. The project represents an
      example of successful interagency collaboration which was based on a joint
      commitment to assessing health and social care needs and planning services to
      meet these needs.

PMID- 8668761
TI  - Inequalities in health: the interaction between socio-economic and personal
      circumstances.
AB  - This longitudinal study utilizes a data set from the Survey of Living Conditions
      conducted by Statistics Sweden (SCB) during the years 1980-1981 and 1988-1989. It
      comprises a representative sample of the employed Swedish population (2,861
      individuals) between the ages of 20 and 65. The objective of the study is to
      analyse the interaction between socio-economic and personal circumstances in
      explaining inequalities in health. It is based on a theoretical framework which
      presupposes that inequalities in health are likely to be explained by a
      complicated process involving a multitude of factors. At the same time,
      differential exposures and differential responses to risk factors between socio
      economic classes for certain health outcomes are determined. The joint effect on
      general health status, seven years later, of being a manual worker and having
      reported psychosomatic symptoms is 113% greater than would have been expected on
      the assumption of additivity of the singular effects of these variables. It is
      suggested that it is necessary to highlight in further research the complex
      interactions and pathways between factors associated with health outcomes to
      improve our understanding of the causal processes involved and determine
      appropriate preventive measures.

PMID- 8668763
TI  - Filariasis in the Kaiyamba Chiefdom, Moyamba District Sierra Leone: an
      epidemiological and clinical study.
AB  - In a cross-sectional epidemiological and clinical study of human filariasis, 630
      individuals were examined for Onchocerca volvulus, Wuchereria bancrofti and
      Mansonella perstans infections in five communities in the Kaiyamba Chiefdom,
      Moyamba District, Sierra Leone. The overall prevalence of O. volvulus infection
      in males 144(39.1%) and females 94(35.9%) was not significantly different and the
      sex prevalence rate between communities was also not significant (G = 3, d.f. =
      4, P > 0.05). Prevalence of O. volvulus was significantly lower (G = 42.331, d.f.
      = 5, P < 0.001) in the 5-9 age group (13.3%) compared to the 40-49 age group
      (61.9%). Sixty-four (10.2%) and 38(6.0%) of individuals examined were positive
      for W. bancrofti and M. perstans infections respectively and prevalence of both
      infections in the five communities was not significant. Mixed infections with the
      all three filaria parasites were recorded in 10(3.2%) of the individuals. One
      hundred and sixty-four (71.3%) clinical cases due to W. bancrofti were
      inflammatory in nature; 36.5% were chronic, of which, 26.6% were hydroceles and
      9.4% involved elephantiasis of both the scrotum and the lower legs. All 19(3.0%)
      of M. perstans-related clinical cases were inflammatory. Ninety-three(63.3%) of
      O. volvulus positive individuals that presented symptoms were inflammatory in
      nature, 14(9.5%) had ocular symptoms and 57(38.8%) had subcutaneous nodules.
      These data indicate that infections due to O. volvulus, W. bancrofti and M.
      perstans may be of public health importance in Sierra Leone.

PMID- 8668762
TI  - Factors associated with influenza vaccination coverage among the elderly: role of
      health care personnel.
AB  - Factors associated with acceptance of influenza vaccination in an elderly
      population were investigated in order to find ways of improving vaccination
      coverage. Three administrative districts with different vaccination coverages
      were selected, and a random sample of 10 percent (N = 497) of the elderly
      population living outside institutions was taken from the official lists
      maintained by the Central Statistical Office. The data were collected by means of
      a postal questionnaire. The questionnaire inquired about influenza vaccination
      status during the autumn 1992 campaign, demographic factors, health status,
      previous experiences and beliefs about influenza vaccination and influenza as a
      disease, and source of information about the vaccination campaign. The highest
      positive associations were found between a high influenza vaccination acceptance
      rate and the perceived need for vaccination (Relative risk (RR) 4.6, 95%
      confidence interval (CI) 2.7-7.9), belief in its effectiveness (RR 3.6, 95% CI
      2.1-6.1) and information received from health visitors (RR 2.2, 95% CI 1.8-2.6).
      Vaccination acceptance was negatively associated with a belief in its adverse
      effects, (RR 0.4, 95% CI 0.2-0.6). Information received from health visitors was
      associated with more frequent occurrence of positive beliefs about influenza
      vaccination and with higher acceptance of vaccination irrespective of positive or
      negative beliefs regarding it. In order to obtain high vaccination coverage
      health care personnel should be carefully informed about the importance of
      influenza vaccination and encouraged to inform the public.

PMID- 8668764
TI  - Copper in drinking water--an investigation into possible health effects.
AB  - A study was carried out to examine the possible relationship between levels of
      copper in drinking water and the incidence of specified childhood liver
      complaints presenting at a major UK paediatric liver unit. Public drinking water
      supplies were generally found to have levels of copper which were well below the
      EC standard of 3,000 micrograms/l. In private supplies, a slightly greater number
      of samples were found to exceed the prescribed concentration; in one instance a
      value of 26,000 micrograms/l was recorded. Data describing infant patients
      reporting to Kings College Hospital, London with specified liver complaints were
      examined. Where the address of patients could be determined (220 out of 240
      cases), all patients were found to live in areas served by public drinking water
      supplies and were, thus, unlikely to have experienced elevated drinking water
      copper concentrations.

PMID- 8668765
TI  - Selective or universal neonatal BCG immunization: what policy for a district with
      a high incidence of tuberculosis?
AB  - In the United Kingdom, BCG immunization of neonates provides good protection
      against military and meningeal disease, and probably against other forms of
      tuberculosis, in all ethnic groups. Serious adverse reactions to BCG immunization
      are rare. Cost-effectiveness studies of BCG immunization in neonates have not
      been reported and "universal' BCG immunization is not recommended in the United
      Kingdom. The Department of Health does recommend immunization for children and
      infants of immigrants from countries with a high prevalence of tuberculosis.
      There are problems associated with such a "selective' policy, as determining what
      is "high' prevalence and thus defining "at risk' groups is difficult, and there
      may be political and practical difficulties in its implementation. This may
      result in low coverage in eligible groups. A "universal' policy of BCG
      immunization for all neonates may be politically more acceptable and easier to
      implement in districts with high tuberculosis notification rates. Although there
      is no cost-effectiveness data to determine at what tuberculosis notification rate
      a universal policy should be adopted, an universal policy has been suggested for
      districts with overall notification rate of greater than 40 per 100,000. Within
      districts there may be large variations in tuberculosis notification rates
      between different areas. This is becoming more common with the amalgamation and
      merger of smaller districts into new larger purchasing organizations. New River
      Health Authority is such a district formed by the amalgamation of the former
      districts of Haringey with a high tuberculosis notification rate, and Enfield
      with a lower TB notification rate. In order to maximize coverage in the "at risk'
      neonates, a different neonatal BCG policy has been adopted in the two areas. This
      has been possible because of the flexibility of the mechanisms for contracting
      with different provider units. Although the overall notification rate was not
      thought to be sufficiently high to justify a "universal' neonatal policy
      throughout the district, a "universal' policy has been instituted in the main
      provider unit in the former district Haringey. A "selective' policy, subject to
      ongoing evaluation to ensure high coverage, continues to be operated by the main
      provider unit in the former district of Enfield.

PMID- 8668766
TI  - Tuberculosis mortality associated with AIDS and drug or alcohol abuse: analysis
      of multiple cause-of-death data.
AB  - The resurgence in tuberculosis morbidity in the mid-1980s has increased interest
      in tuberculosis mortality. We examined mortality in the United States, from
      tuberculosis in 1990, using multiple cause-of-death data to describe the impact
      of AIDS and substance abuse, defined as drug or alcohol abuse, on mortality from
      tuberculosis. Tuberculosis mortality by age showed a bimodal pattern, with a peak
      between ages 25 and 55; by race/ethnicity, black and Hispanic males had the
      highest mortality rates, and black females had rates close to those of Hispanic
      males. Although in each of the race/ethnicity categories the removal of deaths
      with AIDS resulted in mortality curves closer to those of 1980, the bimodal
      pattern remained for black and Hispanic deaths. When we examined deaths with
      tuberculosis and substance abuse, we found that substance abuse without AIDS may
      account for additional deaths contributing to the bimodal pattern seen.

PMID- 8668767
TI  - Using census information to estimate GP practice morbidity.
AB  - This paper shows how small area census data can be used to estimate the socio
      demographic characteristics of GP practices. It provides information on the
      likely accuracy of the technique by applying it to estimates of the proportion of
      elderly patients within a practice (a statistic known from other sources) and
      produces evidence which suggests that the method is most successful where
      practices serve a high proportion of patients within their catchment.

PMID- 8668768
TI  - Pulmonary histoplasmosis.
AB  - Histoplasmosis is a common infection in the central United States and is acquired
      through inhalation of airborne spores. The majority of infected persons have an
      asymptomatic, self-limiting illness. Clinical pneumonia occurs in those with
      exposure to a large number of infecting spores. Resolution of the pneumonia often
      leaves calcified pulmonary nodules, calcified mediastinal lymph nodes, or splenic
      calcifications. Chronic disease, which mimics tuberculosis, may develop in those
      with underlying emphysema. In patients with deficient cell-mediated immunity,
      Histoplasma capsulatum may disseminate throughout the body; this often is fatal.
      Delayed manifestations arise months or years after the primary infection.
      Broncholithiasis occurs when peribronchial calcific nodes produce bronchial
      obstruction. Mediastinal granuloma is the continued proliferation of fibrous
      tissue in draining mediastinal lymph nodes. These granulomas may obstruct
      adjacent veins, arteries, or airways and lead to various clinical symptoms.

PMID- 8668769
TI  - Heart disease: functional evaluation with MR imaging.
AB  - Diagnosis of cardiovascular disease requires precise assessment of both
      morphology and function. Nearly all aspects of cardiovascular function can be
      quantified with fast magnetic resonance (MR) imaging techniques. Conventional and
      breath-hold cine MR imaging can provide precise and highly reproducible
      measurements of global and regional function of the left and right ventricles.
      Velocity-encoded cine (VEC) MR imaging provides measurements of blood flow in the
      heart and great vessels. Contrast-prepared fast gradient-echo sequences can be
      used to monitor the first-pass dynamics of contrast media, thus defining
      selective regional myocardial perfusion. Recently, the feasibility of using
      breath-hold VEC MR imaging to measure flow velocity in native coronary arteries
      and coronary revascularization conduits has been shown. This will most likely
      provide a noninvasive method for testing coronary vasodilator reserve and may
      emerge as a new method for detecting asymptomatic coronary artery disease.

PMID- 8668770
TI  - Femoropopliteal angioplasty with US guidance: an example of a niche market.

PMID- 8668771
TI  - Diffuse lung uptake of Ga-67 citrate in treated lymphoma: another milestone on
      the road to understanding.

PMID- 8668772
TI  - Perspective volume rendering of CT and MR images: applications for endoscopic
      imaging.
AB  - PURPOSE: To use perspective volume rendering (PVR) of computed tomographic (CT)
      and magnetic resonance (MR) imaging data sets to simulate endoscopic views of
      human organ systems. MATERIALS AND METHODS: Perspective views of helical CT and
      MR images were reconstructed from the data, and tissues were classified by
      assigning color and opacity based on their CT attenuation or MR signal intensity.
      "Flight paths" were constructed through anatomic regions by defining key views
      along a spline path. Twelve movies of the thoracic aorta (n=3), tracheobronchial
      tree (n=4), colon (n=3), paranasal sinuses (n=1), and shoulder joint (n=1) were
      generated to display images along the flight path. All abnormal results were
      confirmed at surgery. RESULTS: PVR fly-through enabled evaluation of the full
      range of tissue densities, signal intensities, and their three-dimensional
      spatial relationships. CONCLUSION: PVR is a novel way to present volumetric data
      and may enable noninvasive diagnostic endoscopy and provide an alternate method
      to analyze volumetric imaging data for primary diagnosis.

PMID- 8668773
TI  - Femoropopliteal artery: initial and 6-month results of color duplex US-guided
      percutaneous transluminal angioplasty.
AB  - PURPOSE: To evaluate color duplex ultrasonographic (US) guidance of percutaneous
      transluminal angioplasty (PTA) of femoropopliteal artery stenoses and occlusions.
      MATERIALS AND METHODS: Twenty-four patients (11 women, 13 men; mean age, 65.0
      years) with severe claudication, abnormal ankle-arm pressure indexes, and lesions
      in the superficial femoral or popliteal artery depicted at US underwent balloon
      PTA with US guidance. US findings were confirmed before and after PTA by means of
      intravenous digital subtraction angiography. RESULTS: All of 22 segmental
      stenoses and three of four superficial femoral artery occlusions were
      successfully treated (in 23 patients). In three cases, a residual stenosis was
      detected after initial PTA, and PTA was repeated with a larger balloon catheter.
      Of the 21 patients followed up for 6 months, one had reocclusion and three had
      hemodynamically significant restenosis. CONCLUSION: Results of PTA with US
      guidance in short stenoses or occlusions of the femoral or popliteal artery are
      similar to those of PTA with fluoroscopic control.

PMID- 8668774
TI  - Benign and malignant stenoses of the stomach and duodenum: treatment with self
      expanding metallic endoprostheses.
AB  - PURPOSE: To assess palliation of inoperable stenoses of the stomach and the
      duodenum with self-expanding metallic endoprostheses. MATERIALS AND METHODS:
      Under combined endoscopic and fluoroscopic guidance, 13 Wallstents were placed in
      nine consecutive patients, two with benign and seven with malignant obstruction.
      RESULTS: Technical success was achieved in eight patients (89%). One failure was
      due to stent dislocation during implantation. No major complications occurred; in
      two patients (22%), additional stents were implanted to improve patency. During
      the follow-up, which was 1-52 weeks (mean, 17 weeks) or until death there were no
      signs of stent obstruction. In seven patients (78%), quality of life improved
      substantially with restoration of oral food intake and relief of vomiting.
      CONCLUSION: The placement of Wallstents offers good palliation of inoperable
      outlet stenoses of the stomach and the duodenum. With a combined radiologic and
      endoscopic approach, it is an easy and rapid procedure that can be performed
      without general anesthesia.

PMID- 8668775
TI  - Biliary strictures in liver transplant recipients: treatment with metal stents.
AB  - PURPOSE: To determine initial and long-term results of metal stent placement in
      biliary strictures that failed to respond to balloon dilation. MATERIALS AND
      METHODS: Sixty-one metal stents were placed in 36 liver transplant recipients
      (age range, 3 months to 71 years) with biliary strictures that failed to respond
      to balloon dilation. Patients were followed up for up to 5 years. RESULTS:
      Initial stent placement was successful in all patients. Primary patency was 44%
      at 3 years and was 0% at 5 years; secondary patency was maintained at 88% at
      those intervals. Patency associated with the Gianturco Z stent was superior to
      that with the Palmaz stent. Stents located at anastomotic sites had higher
      patency rates than those at nonanastomotic sites. Major stent-related
      complications occurred in eight patients and included two pediatric deaths.
      CONCLUSION: Metal stents can be useful in the short term but have limited
      patency, often require repeat intervention, and have substantial complications.
      Long-term success depends heavily on repeat interventions or stent removal.

PMID- 8668776
TI  - Aortic dissection: a comparative study of diagnosis with spiral CT, multiplanar
      transesophageal echocardiography, and MR imaging.
AB  - PURPOSE: To compare the usefulness of spiral computed tomography (CT),
      multiplanar transesophageal echocardiography (TEE), and magnetic resonance (MR)
      imaging in the diagnosis of thoracic aortic dissection and arch vessel
      involvement. MATERIALS AND METHODS: Forty-nine symptomatic patients with
      clinically suspected aortic dissection were examined with contrast material
      enhanced spiral CT, multiplanar TEE, and 0.5-T MR imaging (T1-weighted, cardiac
      gated, spin-echo sequences). Imaging results were confirmed at autopsy (five
      patients), intraoperative exploration (23 patients), angiography (nine patients),
      and follow-up (12 patients). RESULTS: Sensitivity in the detection of thoracic
      aortic dissection was 100% for all techniques. Specificity was 100%, 94%, and 94%
      for spiral CT, multiplanar TEE, and MR imaging, respectively. In the assessment
      of aortic arch vessel involvement, sensitivity was 93%, 60%, and 67%,
      respectively, and specificity was 97%, 85%, and 88%, respectively. CONCLUSION:
      Spinal CT and multiplanar TEE are as valuable as MR imaging in the detection of
      thoracic aortic dissection. In the assessment of the supraaortic branches, spiral
      CT is superior (P<.05).

PMID- 8668777
TI  - Cost-effectiveness of myocardial perfusion imaging with SPECT in the emergency
      department evaluation of patients with unexplained chest pain.
AB  - PURPOSE: To determine the cost-effectiveness of promptly performing myocardial
      perfusion (MP) imaging with single photon emission computed tomography (SPECT) in
      patients presenting to the emergency department with unexplained chest pain.
      MATERIALS AND METHODS: Fifty patients with unexplained chest pain underwent MP
      imaging with SPECT and technetium-99m sestamibi. The cardiologists' management
      plans before and after receipt of imaging findings were compared. Costs were
      determined from analysis of comparable admissions for the 6 months before the
      start of the study. RESULTS: The cardiologists' confidence in their clinical
      diagnosis significantly increased with use of MP imaging (P<.0001). MP imaging
      results altered management decisions in 34 patients. Twenty-nine patients were
      sent home on the basis of imaging findings. None of the patients with a normal MP
      image experienced a serious adverse cardiac event. The total savings to the
      hospital was $39,296, or $786 per patient. CONCLUSION: Performing MP imaging in
      patients with unexplained chest pain while in the emergency department is cost
      effective.

PMID- 8668778
TI  - Patient allergies: role in selective use of nonionic contrast material.
AB  - PURPOSE: To determine which aspects of patient allergies allergists and
      immunologists would recommend for the selective use of nonionic contrast
      material. MATERIALS AND METHODS: A survey about allergy and the selective use of
      nonionic contrast material was sent to 1,017 allergists and immunologists.
      RESULTS: Of 287 respondents, 262 believed that a non-contrast material-related
      allergy alone was not an indication for use of nonionic contrast material. Most
      (n=219) believed that a previous serious or life-threatening reaction was the
      best indication and that a minor reaction was not an indication. Most respondents
      believed that patients with any previous reaction to contrast material should
      receive nonionic contrast material, steroids and then nonionic contrast material,
      or no contrast material at all. CONCLUSION: Use of nonionic contrast material in
      patients with previous non-contrast material-related allergic reactions should be
      limited to patients with previous serious or life-threatening reactions.

PMID- 8668779
TI  - Adverse reactions to contrast media in CT: effects of temperature and ionic
      property.
AB  - PURPOSE: To assess the severity of adverse reactions to contrast media in
      outpatient computed tomographic (CT) examinations in a conventional clinical
      setting. MATERIALS AND METHODS: In 4,936 patients, CT was performed with four
      protocols: ionic contrast medium with sodium meglumine as the cation (in one
      protocol, contrast material was warmed to 35 degrees C before injection; in
      another protocol, it was administered at ambient temperature); warmed, ionic
      contrast medium with nonsodium pure meglumine as the cation; and warmed, nonionic
      iopamidol. RESULTS: Adverse reactions to ionic contrast material statistically
      significantly decreased (P<.05) when it was warmed before administration.
      Reactions to ionic contrast media without a sodium cation were statistically
      significantly fewer (P<.001) than reactions to those with a sodium cation. In all
      protocols, pediatric patients had fewer reactions than adult patients.
      CONCLUSION: In outpatient CT examinations, nonionic, warmed contrast medium was
      the best option because no severe reactions resulted from its use. Prevalence of
      adverse reactions was comparable to that in controlled randomized studies.

PMID- 8668780
TI  - Mesial temporal sclerosis: diagnosis with fluid-attenuated inversion-recovery
      versus spin-echo MR imaging.
AB  - PURPOSE: To compare the accuracy of a fluid-attenuated inversion-recovery (FLAIR)
      sequence with that of a conventional double spin-echo (SE) sequence in the
      identification of increased signal intensity of the hippocampus in mesial
      temporal sclerosis (MTS). MATERIALS AND METHODS: Three blinded reviewers
      independently graded the FLAIR and SE images in 36 patients with intractable
      complex partial seizures. Reproducibility was tested. At histopathologic
      examination, the criterion standard, 32 patients had MTS. RESULTS: The accuracy
      of FLAIR images was 97% versus 91% for SE images (P<.02). The radiologists
      preferred the contrast properties of FLAIR to those of SE images by a significant
      margin (P<.0001). Surgical to nonsurgical hippocampal contrast-to-noise ratio
      (C/N) measurements were better for the second echo of the SE sequence than for
      FLAIR (P<.002). Hippocampus-to-background tissue C/N was superior with FLAIR
      (P<.0001). CONCLUSION: FLAIR provides images with T2-weighted contrast and
      complete suppression of high signal intensity of CSF. Incorporation of a FLAIR
      sequence into the routine MR evaluation of patients with epilepsy is recommended.

PMID- 8668781
TI  - Prospective localization of epileptogenic foci: comparison of PET and SPECT with
      site of surgery and clinical outcome.
AB  - PURPOSE: To correlate prospective imaging findings in patients with intractable
      partial epilepsy with site of surgery and clinical outcome. MATERIALS AND
      METHODS: Thirty-five patients (25 male, 10 female) underwent positron emission
      tomography (PET; n=25), interictal single photon emission computed tomography
      (SPECT; n=33), or postictal SPECT (n=23) for localization of epileptogenic foci.
      The standard of reference was site of surgery. RESULTS: Sensitivity was 60%, 61%,
      and 52%; positive predictive value was 83%, 71%, and 55%; and localization was
      incorrect in 12% (three of 25 cases), 24% (eight of 33 cases), and 43% (10 of 23
      cases) in PET, interictal SPECT, and postictal SPECT, respectively. There was no
      statistically significant difference in localization capabilities in a comparison
      of interictal SPECT and PET (correct localization, P=.999; incorrect
      localization, P=.625). There was a trend toward higher incorrect localization
      with interictal SPECT. CONCLUSION: Postictal SPECT has low sensitivity and a high
      incorrect localization rate and should not be performed in these patients.
      Interictal SPECT with 6-8-mm full-width at half-maximum is an alternative to PET.
      However, the trend toward higher false-localization rates must be taken into
      consideration.

PMID- 8668782
TI  - Asymmetric metabolic profile in mesial temporal lobes: localized H-1 MR
      spectroscopy in healthy right-handed and non-right-handed subjects.
AB  - PURPOSE: To determine a possible asymmetric metabolic profile in right- handed
      and non-right-handed healthy subjects by comparing proton spectra from temporal
      lobes. MATERIALS AND METHODS: Twenty-eight healthy adults (17 right-handers, 11
      non-right-handers) underwent magnetic resonance (MR) imaging and single-voxel MR
      spectroscopy. N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) peak
      areas were measured. RESULTS: Volume of hippocampal formations was larger on the
      right in right-handers (right volume: 4.04 cm3 +/- 0.67 vs left volume: 3.84 cm3
      +/- 0.62; P = .00004) and in non-right-handers (right volume: 4.22 cm3 +/- 0.78
      vs left volume: 4.05 cm3 +/- 0.80; P = .004). NAA/Cho was significantly higher in
      the left temporal lobe of right-handers (right lobe: 1.53 +/- 0.18 vs left lobe:
      1.89 +/- 0.18; P=.00004) as was NAA/Cr (right lobe: 1.79 +/- 0.36 vs left lobe:
      2.45 +/- 0.45; P=.0001). No statistically significant difference was noted for
      these ratios in non-right-handers: NAA/Cho (right lobe: 1.49 +/- 0.18 vs left
      lobe: 1.61 +/- 0.35) and NAA/Cr (right lobe: 1.93 +/- 0.45 vs left lobe: 2.40 +/-
      0.70). CONCLUSION: A clear metabolic asymmetry observed in right-handers is less
      clear-cut in non-right-handers. Both tendencies should be considered when
      assessing the brain metabolism of patients with uni- or bilateral disorders, such
      as temporal lobe epilepsy.

PMID- 8668783
TI  - Health care reform and radiology.

PMID- 8668784
TI  - Hyperacute stroke: evaluation with combined multisection diffusion-weighted and
      hemodynamically weighted echo-planar MR imaging.
AB  - PURPOSE: To evaluate acute stroke with conventional, multisection diffusion
      weighted (DW), and hemodynamically weighted (HW) magnetic resonance (MR) imaging.
      MATERIALS AND METHODS: The three MR imaging techniques were performed in 11
      patients within 10 hours of the onset of acute hemiparesis. The volume of DW and
      HW abnormalities were compared with infarct volumes depicted at initial and/or
      follow-up MR or computed tomography (CT). RESULTS: Findings at DW and HW imaging
      were abnormal in nine of the 11 patients, despite normal findings at initial CT
      and/or MR. In all nine patients, infarcts were depicted at follow-up CT or MR.
      The DW abnormality was generally smaller and the HW abnormality was generally
      larger than the infarct volume determined at subsequent imaging. In the two
      patients with normal findings at DW and HW imaging, symptoms resolved completely
      within 1-48 hours. CONCLUSION: Different aspects of hyperacute cerebral ischemia
      are depicted at DW and HW imaging before infarction is depicted at conventional
      MR or CT. These techniques may improve stroke diagnosis and may contribute to
      advances in treatment.

PMID- 8668786
TI  - Spontaneous spinal epidural hematoma: findings at MR imaging and clinical
      correlation.
AB  - PURPOSE: To evaluate radiologic findings and clinical data in patients with
      spontaneous spinal epidural hematoma (SSEH). MATERIALS AND METHODS: Thirteen
      patients (10 men aged 28-71 years; three women aged 40-65 years) with SSEH from
      1986 to 1995 underwent magnetic resonance (MR) imaging; six also underwent spinal
      angiography. Patients with minor trauma, anticoagulant therapy, increased
      bleeding tendency, or vascular lesions were included. RESULTS: The incidence was
      estimated to be 0.1 patients per 100,000 patients per year. On MR images, the
      hematoma was in the anterior (n=8) or posterior (n=4) epidural space or both
      (n=1). The most common location was the upper thoracic region. T1-weighted images
      were most useful owing to the pathognomonic signal shift from isointensity with
      the cord in the early period to hyperintensity in the intermediate stage. Five
      patients had minor trauma, and four were receiving anticoagulant therapy.
      CONCLUSION: A rough estimation of the incidence of SSEH is provided,and the
      results confirm the previously described association with minor trauma and
      anticoagulant therapy and low frequency of arteriovenous malformations.

PMID- 8668785
TI  - Acute and chronic stroke: navigated spin-echo diffusion-weighted MR imaging.
AB  - PURPOSE: The authors evaluated a phase-navigated spin-echo (SE) motion-correction
      sequence for use at diffusion-weighted (DW) magnetic resonance (MR) imaging after
      cerebral infarction. MATERIALS AND METHODS: Twenty-nine patients underwent 32
      conventional T2-weighted fast SE and SE DW imaging after stroke (n=25), transient
      ischemic attack (n=3), or reversible ischemic neurologic deficit (n=1). Imaging
      was performed in a standard head holder with standard padding. Apparent diffusion
      coefficient (ADC) maps were constructed. RESULTS: DW images depicted high signal
      intensity compatible with localization of the ischemic symptoms in all cases.
      Lesions were depicted more clearly on DW than on T2-weighted images. On DW
      images, acute infarct ADC values were uniformly low (mean, 0.401x10(-5) cm2/sec
      =+/- 0.143 [standard deviation]) compared with control ADC values (mean,
      0.754x10(-5) cm2/sec +/- 0.201). ADC values of chronic infarcts were supranormal
      (mean, 1.591x10(-5) cm2/sec +/- 0.840) compared with control values (mean,
      0.788x10(-5) cm2/sec +/- 0.166). DW imaging did not show a change after transient
      ischemic attack. with reversible ischemic neurologic deficit, however,
      hyperintensity on DW images and low ADC resolved after symptoms abated.
      CONCLUSION: Clinical phase-navigated SE DW imaging improved early diagnosis of
      stroke and helped differentiate acute from chronic stroke. Changes on DW images
      are reversed after symptoms resolve.

PMID- 8668787
TI  - Petrous carotid canal stenosis in malignant osteopetrosis: CT documentation with
      MR angiographic correlation.
AB  - PURPOSE: To study the association between petrous carotid canal (PCC) and
      internal carotid artery (ICA) stenoses in patients with malignant osteopetrosis.
      MATERIALS AND METHODS: Mean and minimum PCC diameters obtained from cranial
      computed tomographic (CT) scans in 20 patients were compared with similar
      measurements in 52 control subjects. ICA caliber, evaluated with magnetic
      resonance (MR) arteriography, was correlated with age and PCC dimensions.
      RESULTS: There was a statistically significant difference between patient and
      control PCC diameters. There was a strong positive correlation between age and
      PCC diameter in the control subjects, but only a weakly positive correlation in
      the patients. One or both ICAs were stenotic on all patient MR arteriograms. MR
      angiographic stenosis grade correlated positively with age but not with PCC
      diameters. CONCLUSION: PCC and ICA stenoses occur frequently in patients with
      malignant osteopetrosis. Bony overgrowth or a "persistent fetal state" may
      produce the PPC stenoses. The findings do not support progressive PCC narrowing
      in these patients.

PMID- 8668788
TI  - Proton MR spectroscopy of the basal ganglia in healthy children and children with
      AIDS.
AB  - PURPOSE: To evaluate proton magnetic resonance (MR) spectroscopy in children with
      the acquired immunodeficiency syndrome (AIDS) and to establish an age-dependent
      spectroscopic database of the normal basal ganglia in children. MATERIALS AND
      METHODS: Eighteen healthy children and 45 children with AIDS underwent both brain
      MR imaging and single-voxel MR spectroscopy with a long-echo-time point-resolved
      technique. A large part of the region of interest studied at MR spectroscopy
      included the basal ganglia. RESULTS: Seven patients with progressive
      encephalopathy and eight with static encephalopathy had significantly lower mean
      N-acetyl aspartate (NAA)/creatine (Cr) ratios than age-matched control subjects
      (P<.02). In determining the presence of progressive encephalopathy in children
      with AIDS, MR spectroscopy appears to be more sensitive and specific than MR
      imaging and immunologic testing. Thirty patients without encephalopathy had
      normal NAA/Cr ratios but significantly lower choline/Cr ratios than age-matched
      control subjects (P<.02). CONCLUSION: Proton MR spectroscopy may be a more
      sensitive diagnostic technique than MR imaging in childhood AIDS encephalopathy.

PMID- 8668789
TI  - Can clinical parameters help reliably predict the onset of acute intracranial
      hemorrhage in infants receiving extracorporeal membrane oxygenation?
AB  - PURPOSE: To determine whether clinical parameters can be used to help predict the
      onset of acute intracranial hemorrhage (ICH) in infants receiving extracorporeal
      membrane oxygenation (ECMO). MATERIALS AND METHODS: The authors retrospectively
      reviewed cranial sonograms and intensive care unit data for 53 neonates treated
      with ECMO for intractable cardiorespiratory insufficiency. Thirty-nine boys and
      14 girls were treated between February 1988 and June 1993. Gestational age ranged
      from 34 to 43.5 weeks (mean, 39.2 weeks). Birth weights ranged from 2,200 to
      4,650 g (mean, 3,310 g). Multiple clinical variables were subjected to
      statistical analysis. RESULTS: There were 38 patients without ICH, 10 with early
      ICH (within 72 hours after cannulation), and five with late ICH (more than 72
      hours after cannulation). Analysis with bivariate scatterplots revealed almost
      complete overlap in the clinical parameters for patients in these three
      categories. Thus, use of individual variables to predict acute ICH was
      impractical. CONCLUSION: No clinical parameters helped adequately distinguish
      patients who developed ICH from those who did not.

PMID- 8668790
TI  - Resolution of intracranial calcifications in infants with treated congenital
      toxoplasmosis.
AB  - PURPOSE: To determine the natural history of intracranial calcifications in
      infants with treated congenital toxoplasmosis. MATERIALS AND METHODS: Between
      January 1982 and March 1994, cranial computed tomography was performed in 56
      infants with treated congenital toxoplasmosis when they were newborns and
      approximately 1 year old. Locations and sizes of intracranial calcifications were
      noted. RESULTS: Forty newborns had intracranial calcifications. By 1 year of age,
      calcifications diminished or resolved in 30 (75%) and remained stable in 10 (25%)
      of these treated infants. Ten (33%) of the 30 infants whose calcifications
      diminished versus seven (70%) of the 10 infants with stable calcifications
      received less intensive antimicrobial treatment than the other treated infants.
      In contrast, a small number of infants who were untreated or treated 1 month or
      less had intracranial calcifications that increased or remained stable during
      their 1st year of life. CONCLUSION: Diminution or resolution of intracranial
      calcifications was an unexpected and remarkable finding in infants with treated,
      congenital toxoplasmosis, consonant with their improved neurologic functioning.

PMID- 8668791
TI  - Acute testicular torsion: comparison of unenhanced and contrast-enhanced power
      Doppler US, color Doppler US, and radionuclide imaging.
AB  - PURPOSE: To compare the usefulness of conventional color Doppler ultrasound (US),
      unenhanced and contrast material-enhanced power Doppler US, and radionuclide
      imaging in a model of acute testicular torsion. MATERIALS AND METHODS: Twenty
      rabbits underwent unilateral 360 degree testis torsion and contralateral
      orchiopexy. Gray-scale, color Doppler, and unenhanced and contrast-enhanced power
      Doppler US were performed 4-6 hours later. The side of torsion was determined,
      and intratestis flow was graded. Within 2 hours of US, technetium-99m
      pertechnetate was intravenously administered, the rabbits were killed, and the
      testes excised for radionuclide imaging. RESULTS: Intratestis perfusion was
      detected in 85% of torsed testes at US and radionuclide imaging. The side of
      torsion was correctly diagnosed in 25% of cases with radionuclide imaging and in
      60% of cases with US. Power Doppler US demonstrated significantly greater
      intratestis flow in pexed than in torsed testes. Although the numbers of correct
      diagnosis with the three US modalities were similar, flow grades within torsed
      and normal testes were significantly different. CONCLUSION: Perfusion to torsed
      and normal testes was demonstrated equally well with color Doppler US, power
      Doppler US, and radionuclide imaging. Doppler US better depicted differences in
      intratesticular flow between torsed and normal testes.

PMID- 8668792
TI  - Agenesis of the corpus callosum: prenatal detection usually is not possible
      before 22 weeks of gestation.
AB  - PURPOSE: To determine whether agenesis of the corpus callosum can be diagnosed
      prenatally with standard ultrasonographic (US) evaluation before 22 weeks of
      gestation. MATERIALS AND METHODS: Initial scans obtained on or before 22 weeks
      and follow-up scans obtained in the third trimester were selected from all cases
      of agenesis of the corpus callosum diagnosed prenatally at the authors'
      laboratory. Follow-up was attained by means of review of the medical records and
      included imaging, karyotype, and clinical outcome. RESULTS: Among 15 fetuses with
      callosal agenesis confirmed by means of third-trimester scans, 10 had completely
      normal US scans at 16-22 weeks and five had other US abnormalities. Isolated
      callosal agenesis was identified in six children with normal development (except
      one with polydactyly). Among the others, four were developmentally delayed, three
      died, and two others had abnormal karyotype. CONCLUSION: Standard second
      trimester US before 22 weeks of gestation may not show isolated callosal
      agenesis. Fetuses with this abnormality can have normal second-trimester scans
      and develop abnormal US findings in the third trimester.

PMID- 8668793
TI  - Flutamide-associated liver toxicity during treatment with total androgen
      suppression and radiation therapy for prostate cancer.
AB  - PURPOSE: To examine the frequency and severity of toxicity associated with
      flutamide inpatients treated with total androgen suppression before and during
      pelvic radiation therapy (RT) for prostate cancer. MATERIALS AND METHODS: Sixty
      five patients with T2b-T4 prostate cancer received flutamide and goserelin
      acetate for 4 months, with RT beginning at the 3rd month. Treatment records
      including liver function test (LFT) results at baseline and during treatment were
      reviewed and toxicities noted. RESULTS: In 30 (46%) of 65 patients, flutamide was
      discontinued prematurely. Primary reasons included elevation in LFT levels
      (n=14); gastro-intestinal toxicity (n=9); decreased hemoglobin level (n=2);
      patient refusal (n=2); and arthralgia, rash, and malaise (n=1 each).
      Hepatotoxicity generally was manifest as asymptomatic transaminase level
      elevation. Grade 3-4 hepatotoxicity was noted in four of 65 patients. Mean
      aspartase aminotransferase increased from 23 (baseline) to 67 U/L (during
      flutamide treatment) (P<.02); mean alanine aminotransferase level increased from
      26 (baseline) to 94 U/L (during flutamide treatment) (P<.005). CONCLUSION:
      Flutamide toxicity was common. LFTs should be monitored during flutamide therapy.
      The role of flutamide in this treatment regimen may need to be reevaluated.

PMID- 8668794
TI  - Optimal placement of radioisotopes for permanent prostate implants.
AB  - PURPOSE: To determine which of four loading techniques most efficiently yields
      the prescribed dose to the prostate volume while limiting dose to the central
      urethral volume. MATERIALS AND METHODS: The four techniques included (a) equal
      activity and equal spacing with nomogram, (b) differential loading, (c)
      peripheral loading, and (d) spiked loading of the lobes. They were evaluated with
      regard to target coverage urethra dose, tolerance to error, and complexity of
      procedure. RESULTS: All ideal plans delivered the prescribed dose of 160 Gy to
      99% of the prostate volume. With prostate-volume expansion and source-placement
      errors, all strategies indicated that at least 71% of the target volume received
      the prescribed dose and greater than 92% of the target volume received 120 Gy.
      CONCLUSION: With source-placement errors and glandular swelling, peripheral
      loading yields the best target coverage while limiting dose to the central
      urethral volume.

PMID- 8668795
TI  - Noncritical soft tissues of the female pelvis: serial MR imaging before, during,
      and after radiation therapy.
AB  - PURPOSE: To present the findings of the irradiated noncritical soft tissues of
      the female pelvis at magnetic resonance (MR) imaging within 18 months after
      radiation therapy (RT). MATERIALS AND METHODS: The soft tissues of the pelvis of
      24 women with advanced cervical carcinoma were studied in 240 MR examinations
      scheduled before, three times during, and 7 weeks and 3, 6, 9, 12 and 18 months
      after RT. Two radiologists visually evaluated the signal intensity (SI) of the
      subcutaneous fat, muscles, and presacral space (PS) on T1- and T2-weighted and
      short inversion time inversion-recovery images. RESULTS: SI compatible with edema
      appeared in the PS, pelvic muscles, and subcutaneous fat within 3 months after
      the end of RT and was observed in 23 (96%) of the 24 patients. During the
      observation period, the edema subsided. Eighteen months after treatment, edema in
      the PS was seen in 12 (50%) of the 24 patients. CONCLUSION: The soft tissues of
      the female pelvis showed a characteristic pattern of varying edema after
      irradiation.

PMID- 8668796
TI  - Distal fallopian tube occlusion: false diagnosis with hysterosalpingography in
      cases of tubal diverticula.
AB  - PURPOSE: To evaluate the accuracy of hysterosalpingography (HSG) in the diagnosis
      of distal fallopian tube occlusion in infertile patients who were candidates for
      laparoscopic surgery. MATERIALS AND METHODS: A retrospective review of charts was
      performed for 25 patients who were scheduled to undergo laparoscopic surgery. A
      preoperative diagnosis was made at HSG of bilateral (or unilateral in case of
      previous contralateral salpingectomy) distal tube occlusion. RESULTS: At
      laparoscopy, in three patients (12%) who were scheduled for salpingostomy, the
      diagnosis of distal tube occlusion made at HSG was incorrectly positive; in the
      three patients, a single tubal diverticulum was present in the distal ampulla in
      otherwise normal, patent tubes. CONCLUSION: Bilateral tubal diverticula appear to
      be often misdiagnosed at HSG as distal tube occlusion.

PMID- 8668798
TI  - The cisterna chyli: a potential mimic of retrocrural lymphadenopathy on CT scans.
AB  - PURPOSE: To determine the normal appearance of the cisterna chyli and how it may
      mimic an enlarged retrocrural lymph node on computed tomographic (CT) images.
      MATERIALS AND METHODS: CT scans were reviewed in 18 patients (17 with cancer, one
      with benign disease) who had tubular retrocrural structures of attenuation near
      that of water. The location, diameter, length, CT attenuation, duration of
      finding, change in size, and the status of intercurrent malignancy were recorded.
      RESULTS: The cisterna chyli was variably located at T12-L1 (n=11), at T11-T12
      (n=5), and at T-12 (n=2). The average length was 3 cm. The average CT attenuation
      was 12.5 HU. On serial scans in 14 patients, the average change in size was 2.2
      mm despite progression or regression of malignant disease at other sites in 11
      patients. CONCLUSION: The cisterna chyli can mimic the appearance of an enlarged
      retrocrural lymph node. Proper identification depends on its characteristic
      location, tubular configuration, attenuation closer to that of water than soft
      tissue, and lack of substantial change in size despite changes in disease at
      other sites.

PMID- 8668797
TI  - Diffuse lung uptake of Ga-67 after treatment of lymphoma: is it of clinical
      importance?
AB  - PURPOSE: To determine if diffuse lung uptake (DLU) of gallium-67 at scintigraphy
      in patients with lymphoma is indicative of lymphomatous involvement of the lungs.
      MATERIALS AND METHODS: Thirty-eight patients (24 male, 14 female; aged 15-76
      years) with DLU were examined. The relation between DLU and lymphoma was
      investigated. Radiographic and computed tomographic findings and the persistence
      of Ga-67 uptake were investigated to detect lymphomatous involvement of the
      lungs. The relations between chemotherapy and radiation therapy, previous lung or
      heart disease, and DLU were also examined. RESULTS: DLU appeared only during or
      after chemotherapy. No clinical, radiologic, or follow-up evidence indicated that
      patients with DLU had active lymphomatous involvement of the lungs. The
      difference in survival between patients with persistent and patients with
      transient DLU was not statistically significant. No statistically significant
      correlation between DLU and any possible inductive factor was indicated at
      multivariate analysis. CONCLUSION: DLU after treatment does not indicate
      lymphomatous involvement of the lungs.

PMID- 8668799
TI  - Comparison of diagnostic performance with ventilation-perfusion lung imaging in
      different patient populations.
AB  - PURPOSE: To determine if patient age, chest radiographic abnormalities, or
      history of cardiopulmonary disease or venous thromboembolism affected diagnostic
      performance with ventilation-perfusion (V-P) imaging. MATERIALS AND METHODS:
      Receiver operating characteristic (ROC) analyses were performed on the final V-P
      imaging interpretation data obtained during the Prospective Investigation of
      Pulmonary Embolism Diagnosis (PIOPED) study. Diagnostic performance with V-P
      imaging was not substantially different in patients with varying ages, an
      abnormal chest radiograph, or a history of venous thromboembolism or
      cardiopulmonary disease. CONCLUSION: Because diagnostic performance with V-P
      imaging in detection of pulmonary embolism was similar among the patient
      populations examined, an abnormal chest radiograph or history of venous
      thromboembolism or cardiopulmonary disease does not appear to adversely affect
      overall diagnostic performance in evaluation of acute pulmonary embolism.

PMID- 8668800
TI  - Bronchioloalveolar carcinoma: focal area of ground-glass attenuation at thin
      section CT as an early sign.
AB  - PURPOSE: To assess an early thin-section computed tomographic (CT) finding of the
      localized formation of bronchioloalveolar carcinoma (BAC). MATERIALS AND METHODS:
      From October 1994 to September 1995, four consecutive patients with biopsy-proved
      BAC were studied. Thin-section CT (n=4), radiographic (n=4), pathologic (n=4),
      and positron emission tomographic (n=2) findings were analyzed. RESULTS: Chest
      radiographs showed focal areas of poorly defined nodules (n=2) and poorly defined
      opacity (n=2). At thin-section CT, lesions appeared as isolated areas of ground
      glass attenuation (n=2) and mixed areas of ground-glass attenuation and
      consolidation (n=2). The areas of ground-glass attenuation were 1.8-11 cm in
      longest diameter. A focal, isolated area of ground-glass attenuation changed into
      mixed areas with consolidation at serial CT in one patient. Mucinous and
      nonmucinous BACs were observed in two patients each. Positron emission tomography
      showed false-negative results for malignancy. CONCLUSION: Focal areas of ground
      glass attenuation at CT could be an early sign of localized BAC.

PMID- 8668801
TI  - Transthoracic needle biopsy of mediastinal lymph nodes for staging lung and other
      cancers.
AB  - PURPOSE: To determine the usefulness of transthoracic needle biopsy of
      mediastinal lymphadenopathy for staging suspected lung and other cancers.
      MATERIALS AND METHODS: Transthoracic needle biopsy of the hilum or mediastinum
      was performed in 111 patients with suspected neoplasms. Most biopsy procedures
      were performed with computed tomographic guidance on an outpatient basis. Forty
      eight adult patients had enlarged lymph nodes (defined as < or = 30 mm in the
      long axis and > or = 10 mm in the short axis). Sixty-three lesions larger than 30
      mm were arbitrarily considered to be masses and were excluded. RESULTS: Carcinoma
      was diagnosed in 40 patients. Four patients had true-negative and one patient had
      false-negative results. Sensitivity for carcinoma was therefore 98% (40 of 41).
      One patient with a negative biopsy result did not have surgical confirmation and
      was excluded from analysis. Lymphoma was excluded from analysis. Lymphoma was
      diagnosed in two patients (positive in one and suspicious in one). Pneumothorax
      occurred in 19 (34%) of 56 biopsy procedures. Chest tube treatment was required
      in eight (14%). CONCLUSION: Transthoracic needle biopsy of mediastinal
      lymphadenopathy is a safe, accurate diagnostic staging procedure. It can
      frequently be used as an alternative to mediastinoscopy in patients with
      lymphadenopathy.

PMID- 8668802
TI  - Effect of exposure variation on the clinical utility of chest radiographs.
AB  - PURPOSE: To study the effects of exposure error on the clinical utility of chest
      radiographs. MATERIALS AND METHODS: Under- and overexposed screen-film images
      were simulated by adding exposure offsets to the normalized CR log(10) exposure
      data from a computed radiography (CR) system and printed by using the
      sensitometric response of a medium-latitude system. The clinical utility of the
      overall image, lung, and soft tissue in 48 images were independently graded by
      eight radiologists. RESULTS: Most variability in image scores was due to
      differences in exposure. About 95% of the lung regions and 75% of the soft-tissue
      regions were rated as having good or ideal clinical utility at the nominal
      exposure. About 80% of the overall images were rated as good or better for
      exposures within 40% [0.15 log(10) exposure] of the nominal. The overall image
      scores were heavily influenced by the lung region, and reader tolerance for
      exposure error was greater for soft tissue than for lung. The optimal exposure
      for soft tissue was about 60% [0.25 log(10) exposure] greater than for lung;
      therefore, no single exposure was optimal for the entire image. CONCLUSION:
      Conventional medium-latitude screen-film systems have intrinsic limitations for
      capturing and displaying the wide transmittance differences in the thorax. The
      clinical utility of chest radiographs may be improved by developing better image
      capture and display techniques.

PMID- 8668803
TI  - Hepatocellular carcinoma: evaluation with biphasic, contrast-enhanced, helical
      CT.
AB  - PURPOSE: To evaluate the added value of hepatic arterial-dominant phase (HAP)
      imaging to portal venous-dominant phase (PVP) imaging in patients with
      hepatocellular carcinoma (HCC) at computed tomography (CT). MATERIALS AND
      METHODS: Sixty-six patients with proved HCC underwent biphasic contrast-enhanced
      CT. HAP and PVP images were obtained at 20-50 and 60-100 seconds, respectively.
      PVP images were evaluated for the number of HCC foci. Then, HAP images were
      reviewed to determine whether any additional HCCs were seen. RESULTS: Three
      hundred twenty-six tumor foci were seen. HAP images depicted 309 foci (95%) and
      PVP images 268 (82%). In seven patients (11%), tumor was visible only on HAP
      images. During the HAP, tumors were hyperattenuating compared with liver in 26
      patients, of mixed attenuation in 26, and hypoattenuating in 14 without
      correlation with histologic appearance. Portal vein thrombosis was identified in
      17 of 21 patients on HAP images; in 12 patients, the thrombosis was diagnosed as
      malignant with neovascularity within the thrombus or diffuse thrombus
      enhancement. CONCLUSION: Use of both HAP and PVP contrast-enhanced CT optimizes
      the evaluation of patients with or at risk for HCC.

PMID- 8668804
TI  - Focal malignant hepatic lesions: MR imaging enhanced with gadolinium
      benzyloxypropionictetra-acetate (BOPTA)--preliminary results of phase II clinical
      application.
AB  - PURPOSE: To investigate enhancement with gadolinium
      benzyloxypropionictetraacetate (BOPTA) at magnetic resonance (MR) imaging to
      detect focal malignant hepatic lesions. MATERIALS AND METHODS: A phase II trial
      was performed in 34 patients. Gd-BOPTA-enhanced spin-echo (SE) and gradient
      recalled-echo (GRE) T1-weighted MR imaging were performed at 40 and 90 minutes
      after intravenous injection of 0.05 and 0.10 mmol/kg Gd-BOPTA. RESULTS: The
      percentage of enhancement in liver parenchyma was significantly (P<.05) increased
      on GRE T1-weighted compared with SE T1-weighted images at 40 and 90 minutes after
      injection of the higher dose and compared with SE and GRE T1-weighted images
      obtained with the lower dose. The contrast-to-noise ratio of metastases was
      significantly increased on GRE T1-weighted images (0.10 mmol/kg) at 90 minutes
      compared with precontrast images. Significantly more small primary metastases
      were detected on GRE T1-weighted images (0.10 mmol/kg) at 90 minutes compared
      with precontrast SE T1-weighted images. CONCLUSION: Gd-BOPTA is a safe
      hepatobiliary contrast agent that helps detection of small metastases.

PMID- 8668805
TI  - Anatomic variants of the biliary tree: diagnosis with MR
      cholangiopancreatography.
AB  - PURPOSE: To evaluate the accuracy of magnetic resonance (MR)
      cholangiopancreatography in the diagnosis of anatomic variants of the biliary
      tree. MATERIALS AND METHODS: In 171 patients, the anatomy of the biliary tree was
      evaluated with MR cholangiopancreatography. Two independent reviewers evaluated
      the presence of anatomic variants. Contrast material-enhanced cholangiography
      that was previously performed opacified the cystic duct in 77 patients and the
      bile duct bifurcation in 93 patients, and was chosen as the standard of reference
      in the diagnosis of anatomic variants. RESULTS: MR cholangiopancreatography
      demonstrated the cystic duct in 126 patients (74%). MR cholangiopancreatography
      showed a low cystic duct insertion in 11 patients (9%), a medical cystic duct
      insertion in 22 patients (17%), and a parallel course of the cystic and hepatic
      ducts in 31 patients (25%). The bile duct bifurcation was demonstrated in 139
      patients (81%), and an aberrant right hepatic duct was demonstrated in 12
      patients (9%). CONCLUSION: MR cholangiopancreatography is accurate in the
      diagnosis of anatomic variants of the biliary tree that may increase the risk of
      bile duct injury during laparoscopic cholecystectomy.

PMID- 8668806
TI  - Fecal incontinence: transvaginal US evaluation of anatomic causes.
AB  - PURPOSE: To evaluate transvaginal ultrasonography (US) as an alternative to
      transanal US for determining the anatomic cause of fetal incontinence in women.
      MATERIALS AND METHODS: Transvaginal US of the anal canal was performed in 28
      women (aged 27-74 years) with fecal incontinence. A side-fire endorectal probe
      was inserted into the vagina and directed toward the posterior vaginal wall.
      RESULTS: The internal anal sphincter (IAS) and external anal sphincter muscles
      were imaged as independent bands in all 28 patients. The calculated mean
      thickness of the IAS in patients aged younger than 55 years was not significantly
      different from that in patients aged older than 55 years (P=.31). Posttraumatic
      anterior muscle disruptions were detected in 16 women; three also had
      rectovaginal fistulas. A rectal fistula with abscess was detected in one of 12
      patients with intact muscles. All muscle disruptions, fistulas, and abscesses
      were surgically confirmed. CONCLUSION: Transvaginal US enables determination of
      the anatomic cause of fecal incontinence, allowing the surgeon to select patients
      who would benefit form surgical repair.

PMID- 8668808
TI  - Anterosuperior labral variants of the shoulder: appearance on gradient-recalled
      echo and fast spin-echo MR images.
AB  - PURPOSE: To characterize the magnetic resonance (MR) imaging appearance of two
      anterosuperior labral variants, the sublabral foramen (SLF) and the Buford
      complex. MATERIALS AND METHODS: The axial gradient-recalled-echo (GRE) MR images
      and the fat-suppressed, T2-weighted, fast spin-echo (SE) images were reviewed in
      19 patients with arthroscopically proved SLF and 11 patients with a Buford
      complex. The anterosuperior labrum was graded as normal, detached, or absent on
      the images. RESULTS: For the patients with an SLF, the anterosuperior labrum was
      graded as detached in all patients who underwent fast SE imaging but in only 43%
      of patients who underwent GRE imaging. For the patients with a Buford complex,
      the anterosuperior labrum was graded as absent in only 30% of patients who
      underwent GRE imaging and in none of the patients who underwent fast SE imaging.
      CONCLUSION: Isolated MR abnormalities of the anterosuperior labrum may represent
      either of the two asymptomatic labral variants.

PMID- 8668807
TI  - Esophageal leiomyomatosis.
AB  - PURPOSE: To reassess the clinical and radiologic findings in patients with
      esophageal leiomyomatosis. MATERIALS AND METHODS: A search of the authors'
      radiologic archives revealed six cases of esophageal leiomyomatosis in a 22-year
      period. The clinical findings and radiologic images were reviewed
      retrospectively. RESULTS: The average age of the patients was 10.8 years (range,
      6-18 years). Five patients presented with slowly progressive dysphagia. Barium
      studies revealed smooth, tapered narrowing of the distal esophagus in five
      patients and characteristic defects on the superomedial aspect of the gastric
      fundus abutting the cardia, presumably due to bulging of this thickened mass of
      muscle into the stomach, in four patients. In two patients, computed tomography
      (CT) revealed marked thickening of the distal esophageal wall. CONCLUSION:
      Esophageal leiomyomatosis can be suggested in a pediatric patient with long
      standing dysphagia in whom smooth, tapered distal esophageal narrowing is seen at
      barium study and circumferential esophageal wall thickening is seen at CT.

PMID- 8668810
TI  - Value of selective second-look sonography by radiologists.
AB  - PURPOSE: To assess the usefulness of sonography performed by radiologists after a
      review of the sonographer's findings. MATERIALS AND METHODS: A total of 398
      sonograms were obtained in 392 patients. Sonographers presented preliminary
      images and impressions to radiologists, who performed additional imaging and
      recorded their conclusions. Radiologists also attempted to predict in which cases
      their scan was likely to show new findings or to refute the sonographer's
      findings. Follow-up data were obtained whenever the sonographer's and the
      radiologist's findings disagreed. RESULTS: In 28 cases, the radiologist made
      important new findings. Positive initial findings were refuted in 24 cases.
      Discrepant findings were seen in 22% of cases in which additional scanning was
      predicted to be beneficial, compared with only 6% of cases in which second-look
      sonography was predicted not to be of value. This difference was statistically
      significant (P<.0001). CONCLUSION: Second-look sonography by radiologists
      provides a valuable check of the sonographer's findings.

PMID- 8668809
TI  - Acute vertebral collapse due to osteoporosis or malignancy: appearance on
      unenhanced and gadolinium-enhanced MR images.
AB  - PURPOSE: To distinguish malignant from osteoporotic acute vertebral collapses.
      MATERIALS AND METHODS: Sixty-three osteoporotic and 30 malignant vertebral
      collapses were studied in 51 patients (aged 33-88 years) with T1-weighted
      magnetic resonance (MR) images (n=93), gadolinium-enhanced T1-weighted images
      (n=72), and T2-weighted images (n=53). RESULTS: Four findings were suggestive of
      osteoporosis: retropulsion of a bone fragment (10 osteoporotic cases vs 0
      malignant cases), preservation of normal signal intensity on T1-weighted images
      (43 vs four), return to normal signal intensity after gadolinium injection (42 vs
      four) with horizontal bandlike patterns, and isointense vertebrae on T2-weighted
      images (28 vs two). Six findings were suggestive of malignancy: convex posterior
      cortex (21 malignant cases vs four osteoporotic cases), epidural mass (24 vs 0),
      diffuse low signal intensity within the vertebral body on T1-weighted images (23
      vs 12) and in the pedicles (24 vs four), high or inhomogeneous signal intensity
      after gadolinium injection (17 vs 0) and on T2-weighted images (17 vs 0).
      CONCLUSION: Gadolinium-enhanced and unenhanced MR images are useful in the
      differentiation of vertebral collapses.

PMID- 8668811
TI  - Case for active physician involvement in US practice.
AB  - PURPOSE: To assess the benefit of active physician involvement in ultrasound (US)
      examinations. MATERIALS AND METHODS: Concordance of findings by technologists and
      physicians was assessed prospectively for examinations of 1,510 consecutive
      patients who underwent US during regular working hours. RESULTS: Overall
      concordance was generally good (74%). However, in cases in which a major or minor
      new diagnosis was made from the US scan, concordance rates were substantially
      lower (36% and 32%, respectively). Agreement varied with the type of examination.
      The discordance rate for obstetric examinations (17%) was only half that for
      abdominal and pelvic examinations (31%). Concordance improved with increasing
      years of experience of the technologist. CONCLUSION: An active role of physicians
      in the overall conduct of US examinations is essential to optimize provision of a
      complete, accurate report.

PMID- 8668812
TI  - A combined CT and angiography suite with a pivoting table.
AB  - In a suite with fully interactive computed tomography (CT) and C-arm fluoroscopy
      units, emergency and elective interventional procedures were performed
      successfully in 41 patients (overall time range, 40-180 minutes [mean, 80
      minutes]). The table can be manually pivoted from the fixed CT position to the
      free-floating angiography position, in an overall working space of about 40 m(2),
      with room for anesthesiology and monitoring equipment and personnel.

PMID- 8668813
TI  - CT-guided transsternal core biopsy of anterior mediastinal masses.
AB  - Computed tomography-guided transsternal biopsy was successful in 10 anterior
      mediastinal masses in 10 patients, with use of a coaxial length-matched bone
      biopsy system comprising an outer cannula and an inner eccentric drill bit. No
      complications occurred in nine of 10 biopsies (eight performed with an automatic
      cutting needle, two with a fine needle), with less discomfort than was caused by
      injection of anesthetic.

PMID- 8668814
TI  - CT-guided intraarterial chemotherapy in locally advanced tumors.
AB  - In a retrospective study, 123 patients with tumors (the majority were recurrent
      pelvic or breast neoplasms) underwent 376 cycles of intraarterial chemotherapy.
      Contrast material-enhanced computed tomography was performed to check the
      position of the catheter during 221 cycles. On the basis of findings, the
      catheter was repositioned 46 (20.8%) times because of weak contrast enhancement
      in the tumor region (n=24[10.9%]), involvement of neighboring healthy tissue
      (n=15[6.8%]), or both (n=7[3.2%]).

PMID- 8668815
TI  - Attenuation effects of biliary endoprostheses on therapeutic radiation.
AB  - Seven commercially available biliary stents were tested to determine if they
      caused any clinically important attenuation of therapeutic radiation. Attenuation
      effects were evaluated in models of brachytherapy (iridium-192 source) and
      external beam radiation therapy (cobalt-60 source), with use of parameters that
      mimicked those used in patient treatment for biliary neoplasms. No stent
      demonstrated clinically important attenuation or scatter of therapeutic
      radiation, so local dosimetry was not affected.

PMID- 8668816
TI  - Registration and alignment of three-dimensional images: an interactive visual
      approach.
AB  - A three-dimensional registration and alignment algorithm was developed to align
      single photon emission computed tomography examinations and magnetic resonance
      images. Operators manipulated images interactively with real-time visual
      feedback, with use of both internal and surface features to achieve accurate
      alignment. Operators aligned five brain phantom examinations (accuracy, 1.6
      pixels; consistency, 0.7 pixels) and eight patient brain examinations
      (consistency, 0.5 pixels).

PMID- 8668817
TI  - Drainage catheters: in vitro comparison of internal retention mechanisms.
AB  - In five drainage catheters, internal retention mechanisms (locking pigtail [14
      and 8 F], inflatable balloon [14 F], or wings [14 and 24 F]) were evaluated for
      resistance to and distortion from dislodgment. Catheters were inserted into
      simulated tissue, and weight was added until dislodgment occurred. Resistance to
      dislodgment increased when the mechanisms were locked; the locking pigtail
      supported the most weight. Distortion caused by dislodgment was minimal.

PMID- 8668818
TI  - Cervical rib simulating fracture of the first rib in suspected child abuse.

PMID- 8668819
TI  - Cost of radiologic gastrostomy.

PMID- 8668820
TI  - [Clinical, electrocardiographic and angiographic evaluation of natural reservoirs
      of Chagas' disease in the Republic of Panama].
AB  - The authors studied two groups of natural animal reservoirs for Trypanosoma
      cruzi: a wild one, the common rat Rattus rattus and the house dog, Canis canis.
      Thirty one naturally infected rats were evaluated with a technique developed by
      the authors which allows the recording of the ECG and the performance of a
      ventricular angiogram without altering the functional capacity of the animal.
      Forty four dogs were followed clinically for a period of twenty years to study
      the development of the cardiac lesion seen in the chronic phase of the disease.
      The authors demonstrate the epidemiologic importance of the dog as a reservoir
      and the ease with which the infection can be acquired from rats, which live in
      the same habitat with human patients. The most common lesions in both groups were
      ventricular and atrial arrhythmias and second degree AV block; and, in the dogs,
      also death due to refractory cardiac failure, such as is seen in the human
      patient. Right bundle branch block and dilatation of the right cardiac chambers
      was the rule in both groups. The authors discuss the pathogenesis of the ECG in
      the rat and its anatomical basis. They propose the possibility of establishing
      and standardizing this techniques in the laboratories that study rats or other
      species.

PMID- 8668821
TI  - [Gene frequency and haplotypes of the HLA system in the Panamanian population].
AB  - The authors determined the frequency of genes and haplotypes of the HLA system in
      965 panamanian men and women not related to each other, between 6 and 65 years of
      age. The HLA-A locus genes with the highest frequency (f) were A2, with f 0.1763;
      A24, f 0.1584; A30, f 0.1340; A23, f 0.1069; A3, f 0.0774. The other 20 genes
      each had less than 0.07. The genes with the highest frequency for locus HLA-B
      were B35, f 0.1946; B44, f 0.0904; B7, f 0.0774; B60 and B61, f 0.0582. For locus
      HLA-C, the most frequent genes were Cw3 with f 0.1549 and Cw4, f 0.1444. For
      locus HLA-DR, the most frequent genes were DR2 with f 0.1283; DR3, f 0.0620; DR7,
      f 0.0409. The most frequent haplotypes in the panamanian population were A2-B35
      with f 0.0382; A3-B35, f 0.0191; A24-35, f 0.0287; A24-B61, f 0.0239; A29-B44, f
      0.0287; A30-B42, f 0.0239; A23-B44, f 0.0191; A1-B8, f 0.0143. The authors
      conclude that the panamanian population exhibits a high degree of polymorphism
      for loci HLA-A, B and C, while for locu HLA-DR the frequency is the median when
      compared with that in caucasian, negro and oriental groups; and that, according
      to locus, predominant genes originating from these groups and found,
      corroborating the multiracial origen of the panamanian population.

PMID- 8668822
TI  - [Dermatology in the tropics].
AB  - The Author reviews the cases diagnosed in the Republic of Panama of Mycetoma,
      Paracoccidioidosis, Lobo's disease, Chromomycosis, Histoplasmosis,
      Rhinosporidiosis, Sporotrichosis, Lepra, Rhinoscleroma, and cutaneous and
      mucocutaneous Leishmaniasis, and mentions the observed clinical manifestations in
      order to familiarize young physicians with the tropical dermatopathology which
      occurs in the rural areas of the country.

PMID- 8668824
TI  - [Excimer laser refractive surgery].
AB  - The authors report their results of refractive surgery with Excimer Laser Panama
      (Technolas unit) on 711 eyes with refractive errors. An uncorrected visual acuity
      of 20/30 or better was obtained in 98.9% of myopic patients. In hypermetropic
      patients they obtained a visual acuity of 20/40 or better in 95.9%. In 94.7% of
      astigmatics an uncorrected visual acuity of 20/30 or better was achieved. The
      patients did not complain of disturbances common after other refractive
      procedures, such as bright radiant spots, blinding glare of fluctuating vision.
      Secondary effects were minimal and patient satisfaction was very high.

PMID- 8668823
TI  - [Complex and multiple vessel angioplasty].
AB  - The authors present the clinical history of a 66 year old woman with a previous
      anterior myocardial infarction and periinfarct ischemia as well as ischemia in
      another area not related to the scar (in the posterolateral region of the left
      ventricle) in whom they successfully performed percutaneous coronary angioplasty
      of the anterior descending and circumflex arteries since the patient was not a
      candidate for surgical revascularization because of her clinical condition.

PMID- 8668826
TI  - [Nonimmune fetal edema].
AB  - The authors present the diagnosis and treatment of a fetus with hydrops secondary
      to severe maternal anemia. The mother was treated with blood transfusion,
      digoxin, spironolactone, iron and folic acid. In the two weeks of treatment the
      hydrops was controlled and the mother had a normal delivery at the 34th week of
      gestation. The newborn presented with an Apgar 7-9, Hb of 8 gm% and a normal
      evolution.

PMID- 8668825
TI  - [Angiosarcoma of the heart and its spontaneous rupture. A rare cause of effusive
      constrictive pericarditis. A case report and review of the literature].
AB  - The authors present the clinical history of a male 44 year old patient who was
      hospitalized with the diagnosis of pericardial constriction and effusion and
      operated on as an emergency because of spontaneous cardiac rupture and was found
      to have a cardiac adenosarcoma. They review the literature in order to discuss a
      very rare cause of hemopericardium and constrictive pericarditis with
      epidemiologic, diagnostic, therapeutic and prognostic commentaries and secondly,
      to try to establish if this type case does not represent a diagnostic problem for
      the ecocardiographer since an angiosarcoma that occupies the pericardial space
      can be confused with a hemopericardium. They also mention other imaging studies
      that are used to better characterize and diagnose these tumors.

PMID- 8668827
TI  - [Human biodiversity and its effects on the pharmacological variability: CYP2D6
      and NAT2 enzymes in Amerind populations of Panama, Colombia and Costa Rica].
AB  - Human biodiversity originates partially from human microevolution, which have
      produced different populations. This biodiversity is responsible for most of the
      variability in drug response. We present the methodology employed in population
      pharmacology studies and general information about the CYP2D6 and NAT2 systems.
      We report results obtained in Embera and Ngawbe Amerindians, who are
      characterized by a low phenotypic and genotypic CYP2D6 diversity. In regard to
      NAT2, Amerindians are distinguished by a high allelic frequency of S3 and low
      ones of S1 and S2, situation which is reversed in Caucasians.

PMID- 8668828
TI  - [The ward laboratory].

PMID- 8668829
TI  - [Interactions of infection, nutrition, and immunity].

PMID- 8668830
TI  - [The differentiation of Candida albicans strains by the killer system].
AB  - The authors studied the killer effect of nine standard strains of yeasts on 146
      samples of Candida albicans isolated from the following clinical specimens: oral
      mucosa, feces, bronchial wash, sputum, vaginal secretion, urine, skin lesion,
      nail lesion and blood. Using this system it was possible to differentiate 23
      biotypes of Candida albicans. The biotypes 211, 111 and 811 were most frequently
      isolated. Most of the samples of C. albicans (98.6%) were sensitive to at least
      one or more of the nine killer strains. Using the killer system it was possible
      to show that two patients harbored the same killer biotypes, 111 and 211,
      respectively, in different clinical specimens and another patient harbored the
      same biotype (211) in bloodcultures effected in different ocasions. The
      utilization of the killer system to differentiate types among species of
      pathogenic yeasts can be a useful method to establish the eventual source of
      infection, and it is a valuable tool to control and watch for nosocomial
      infections caused by yeasts.

PMID- 8668831
TI  - [An evolutionary study of mucosal leishmaniasis (a 7- to 17-year follow-up) due
      to Leishmania (Viannia) braziliensis in Tres Bracos, Bahia].
AB  - Seventy seven (68%) patients with mucosal leishmaniasis recorded during the
      period 1976-1986 in the region of Tres Bracos, Bahia were traced and re-evaluated
      clinically, diagnostically and therapeutically. Sixty-five patients were alive.
      The families of 12 dead patients were interviewed about probable cause of death.
      The 65 patients had a fresh clinical examination supplemented when necessary by a
      skilled ENT examination. All had a titre of circulating immunofluorescent
      antibodies estimated at the time. Eight patients with active mucosal lesions had
      triturated biopsies which were cultivated in NNN medium and inoculated in
      hamsters to attempt to recover Leishmania. The isolates were identified by
      monoclonal antibodies as Leishmania (Viannia) braziliensis. Fifty-six (86%)
      patients were judged clinically cured. Nine (13%) had active lesions. Of the 12
      patients who died 5 (41%) had no signs of activity at death. Mucosal
      leishmaniasis was thought to be the direct cause of death in 3 patients. The
      field treatment programme at Tres Bracos has managed to clinically cure 61
      patients (79%) during 17 years. Follow-up periods were a mean of 10 years (range
      7-17).

PMID- 8668832
TI  - Incidence of anti-Toxoplasma antibodies in women with high-risk pregnancy and
      habitual abortions.
AB  - Toxoplasmosis is a zoonosis caused by Toxoplasma gondii, an obligate
      intracellular parasite. In pregnant women on the worldwide scale, there are
      seroprevalences from 7% to 51.3% and in women with abnormal pregnancies and
      abortions the seroprevalences vary from 17.5% to 52.3%. In Mexico, seropositivity
      has been found to vary from 18.2% to 44.8% in women with abnormal deliveries or
      abortions. This study's aim was to determine the incidence of IgG and IgM anti
      Toxoplasma antibodies in women at the Gineco-Obstetrics Hospital of the Western
      Medical Center of the Mexican Social Security Institute. Three hundred and fifty
      women with high-risk pregnancies were studied, and 122 (34.9%) were found to be
      IgG seropositive and 76 (20.7%) were IgM positive. In one group of women with
      habitual abortions there were 48 (44.9%) with the presence of IgG antibodies and
      33 (33.3%) were IgM seropositive. Seropositivity was analyzed according to age,
      occupation, socio-economic level, eating raw or poorly cooked meat, and living
      with cats.

PMID- 8668833
TI  - Clinical and epidemiological findings during a measles outbreak occurring in a
      population with a high vaccination coverage.
AB  - From March 1991 to April 1992, 250 measles suspected cases were studied in the
      Municipality of Niteroi, State of Rio de Janeiro. The median age found was 11
      years and 76.0% of the cases were in school age children. Exposure histories were
      present in 149 patients and schools were the most frequent sites of transmission
      (45.0%). Vaccination status was known for 127 studied cases and 76.4% of them had
      received measles vaccine before their first birthday. One or more complications
      were reported for 68 cases and in 8.9% of the studied cases hospitalization was
      required. Frequency of complications varied according to each age group studied
      and were more commonly encountered among children < 1 year of age (55.6%). The
      history of previous vaccination did not diminish the number of complications of
      the cases studied. The results of this work show changes in age distribution of
      measles leading to sizeable outbreaks among teenagers and young adults.

PMID- 8668834
TI  - [The epidemiological aspects of taeniasis-cysticercosis in an endemic area of
      Lagamar, Minas Gerais].
AB  - An epidemiological inquiry of humancysticercosis due to Taenia solium was carried
      out in Lagamar, Minas Gerais State, Brazil, in 1992. A survey of 1109 houses with
      3344 inhabitants was made. The inquiry included 875 (86%) families and the
      questionnaire was answered by an informer, who was the father in 80% of the
      cases. One hundred pigsties, sheltering 406 swines in extremely precarious
      conditions, were found in 100 (11.4%) houses. A history on taeniasis in some
      member of the family was verified in 300 (34.2%) houses. A history of seizures
      was referred to by 125 (14.2%) of families. The outset of convulsion in adult age
      was characterized in 39 (37.8%) families. A history of mental disorder was
      reported in 53 (6.0%) of houses. Stool examinations were positive for Taenia spp
      in 24 (1.3%) of samples examined.

PMID- 8668835
TI  - [The characteristics of Trypanosoma cruzi strains isolated from patients who have
      undergone a heart transplant].
AB  - Three strains of Trypanosoma cruzi were isolated from Chagas' disease patients
      transplanted for heart failure, after cardiac transplantation, and were studied
      in an experimental model of Chagas' disease, in mice, with evaluation of
      parasitic load, mortality and extension of inflammatory infiltrates in the heart.
      These parameters were compared with the standard strain Y. The strains had
      differences in the studied parameters, but there was no clear relationship
      between those and post-transplant evolution of the patients. Probably the
      clinical response is multifactorial and derives only in part from biological
      characteristics of the infecting T. cruzi strain, as measured in our model.

PMID- 8668836
TI  - [The evolution over time of the in-vitro resistance of Plasmodium falciparum to
      antimalarial drugs in 2 areas of the Brazilian Amazonia with distinct
      socioeconomic and geographic characteristics].
AB  - We evaluated the temporal progression of in vitro P. falciparum resistance to
      chloroquine, amodiaquine, quinine and mefloquine in two areas with distinct
      socioeconomical and geographical characteristics: Lourenco, in Amapa state and
      Paragominas, in Para state. The former region is essentially an "open" gold
      mining camp, whereas the latter is one currently undergoing a colonization
      settlement process, in addition to expanding economical activities which mainly
      include cattle raising and wood exploitation. Our results show high resistance
      rates to chloroquine in the two study areas: 79.8% and 68.4% in Lourenco and
      Paragominas, respectively. Variations in the response of P. falciparum to both
      amodiaquine and quinine were recorded throughout the study period. On the other
      hand, no mefloquine P. falciparum resistant strains could be identified, despite
      the tact we had noted a decrease in sensitivity to this antimalarial drug
      throughout the study period.

PMID- 8668837
TI  - [A comparative study between natural and artificial xenodiagnosis in chronic
      Chagas' disease patients].
AB  - In order to study the sensitivity of the xenodiagnosis technique a comparison
      between natural and artificial xenodiagnosis methods was performed in 57 chronic
      phase chagasic patients (31 female), with ages ranging from 26 to 83 years. All
      patients had demonstrable antibodies against Trypanosoma cruzi. Forty first
      instar nymphs of Dipetalogaster maximus were used for each of both methods and
      for each patient. The positivity of xenodiagnosis artificial was significantly
      higher than the routine test method. These results did show that a single
      application of 40 bugs by the artificial method yielded a similar result than 3
      applications of 40 bugs each, by the natural method. The positivity of
      xenodiagnosis was significantly higher in patients between 56-65 and 66-83 years
      old than at other ages. Males were predominant in this age group. These results
      showed the viability of artificial xenodiagnosis and its use in routine
      laboratory testing.

PMID- 8668838
TI  - [The residual effect of temephos on Aedes aegypti larvae].
AB  - One of the most used strategies for controlling Aedes aegypti is the use of the
      larvicide temephos (Abate). This larvicide has a prolonged residual effect which
      allows planning the focal treatments. This study aims to verify the duration of
      the larvicide residual effect stimulating a field situation. Plastic containers
      of one and five liters were treated with temephos and the residual effect was
      evaluated every 30 day after the treatment. Different residual effect was
      observed in the containers placed outside and inside the laboratory. The
      containers of one liter showed a longer residual effect than the five liters
      containers. The water salinity as well as the pH, during the test did not affect
      the larvicide effect.

PMID- 8668839
TI  - [Incidence, morphology and diagnostic studies of Entamoeba gingivalis, Gros,
      1849].
AB  - Entamoeba gingivalis is found only in its trophozoite form and it is postulated
      that its main transmission mechanism is through the kiss. E. gingivalis is
      considered pathogenic by some authors and commensal to others. It does not have a
      defined role in the installation of disease. To address some of this questions we
      studied a 100 patients who were seen through the Odontological Hospital from the
      Universidade Federal de Uberlandia in order to determine its frequency in the
      buccal cavity. The material were collected using swabs from four different buccal
      sites and the smears were stained by a modified Papanicolaou technique. The
      results revealed positivity index of 62%. The affinity of the dye to the food
      vacuole contents and to the ingested bacterias prevents clear visualisation of
      the central and peripherical chromatin constituents of the parasite's nucleus.
      Mouth washes with 3ml of saline from 10 patients, were used to evaluate which
      parasitological method of diagnosis (fresh, iron-haematoxylin stained, Giemsa and
      Papanicolaou) gives better visualisation of the parasite. The mouth washes
      sediment from fresh material revealed 100% of positivity and clear visualisation
      of the free form and locomotion of the trophozoites. No stained technique of the
      smear showed adequate visualisation, presenting the nucleus partially covered by
      the food vacuoles. In stained preparations by toluidine blue ultrastructure
      analysis of the morphology of parasite can be observed.

PMID- 8668840
TI  - [Abdominal angiostrongyliasis: its prevention by the destruction of infecting
      larvae in food treated with salt, vinegar or sodium hypochlorite].
AB  - There is a high prevalence of accidental human infection with Angiostrongylus
      costaricensis in some areas in southern Brazil and sometimes it presents as
      severe intestinal disease. Prophylaxis is important since there is no medical
      treatment for the disease. The ingestion of fruits and vegetables contaminated
      with the mucous secretion of infected molluscs (the intermediate hosts) is one of
      the proposed modes of transmission. Third stage larvae were incubated at 5
      degrees C for 12 hours, in solutions of saturated sodium chloride, vinegar and
      sodium hypochlorite 1.5%. The larvae had their viability tested through
      inoculation into albino mice. The percentage of larvae that established infection
      were 0% in the group treated with sodium hypochloride, 1.8% with NaCl and 2.4%
      with vinegar. In conclusion, all substances tested reduced the population of
      viable larvae and may be useful in food decontamination, as a prophylactic
      measure for abdominal angiostrongylosis.

PMID- 8668841
TI  - [The optimization of the use of economic resources for vaccination against
      hepatitis B in professionals in the health area].
AB  - In order to optimize the employment of financial resources to be allocated for
      hepatitis B vaccination programs involving health care workers, two different
      aspects were studied: the need of a pre-vaccination screening and the efficacy of
      low-doses schedules of HBV vaccine by the intradermal (ID) route. The economical
      analysis (a cost-minimization study) showed that when the prevalence of immune
      individuals is higher than 11% it is more cost-effective to perform pre
      vaccination screening. This situation was observed in the employees group. For
      students and doctors vaccination without screening was the best approach.
      Regarding the schedules, 3 doses of HBV vaccine by the intramuscular (IM) route
      (group A) were compared to first dose by the ID route and second and third doses
      by the IM route (group B) and to first and second doses by the ID route and the
      last dose by the IM route (group C). After the third dose, soroconversion rates
      in groups A and B (92% and 93%, respectively) and geometric mean titers of
      antiHBs (1278 UI/L and 789.6 UI/L) were similar, and both were different from
      group A (p < 0.05), showing that alternative vaccination schedules may be cost
      effective.

PMID- 8668842
TI  - Diabetes mellitus associated with pentamidine isethionate in diffuse cutaneous
      leishmaniasis.
AB  - The authors report a case of a male patient from Bacabal, MA with diffuse
      cutaneous leishmaniasis (DCL), for at least nine years, with 168 lesions on his
      body. These were tumour-like nodules with some ulceration. He used pentavalent
      antimonial (glucantime) and an association of gamma interferon plus glucantime
      with improvement of the lesions but relapsed later. Recently, pentamidine
      isethionate (pentacarinat) was given a dosage of 4mg/kg/weight/day on alternate
      days for 20 applications. After 3 months a similar course of 10 application was
      given 2 times. Later he developed diabetic signs with weight loss of 10kg,
      polydypsia, polyuria and xerostomia. The lower limbs lesions showed signs of
      activity. Blood glucose levels normalised and remain like this at moment.
      Attention is drawn to the fact that pentamidine isethionate should be used as a
      therapy option with care, obeying rigorous laboratory controls including a
      glucose tolerance test.

PMID- 8668843
TI  - [Clarithromycin combined with pyrimethamine in cerebral toxoplasmosis--a report
      of 2 cases].
AB  - The authors report the use and the outcome of claritromycin associated with
      pyrimethamine in the treatment of toxoplasma encephalites in two patients with
      AIDS. Both patients had the diagnosis stablished on clinical grounds, positive
      sorology (IgG) for toxoplasmosis and computed-tomographic (CT) scan of the brain
      showing lesions consistent with T. gondii encephalitis. The two patients were
      initially treated with pyrimethamine and sulfadiazine, which was changed to
      clindamycin due to allergic reactions. These reactions (skin rash) occurred with
      clindamycin as well and the patients were treated with claritromycin and
      pyrimethamine. The scheduled regimens were 1.5 to 2 g of clarithromycin plus 25
      mg of pyrimethamine. The clinical response was very good in both cases with
      regression of neurologic signs and encephalitic abnormalities observed on CT
      scan. The authors suggest that clarithromycin associated with pyrimethamine may
      be an alternative treatment for toxoplasmosis in AIDS patients, who cannot
      receive or tolerate sulfa treatment.

PMID- 8668844
TI  - [Absence of cardiac lesion attributable to Trypanosoma cruzi after at least 17
      years of a course of Chagas' disease due to transfusions].

PMID- 8668845
TI  - [The word Trypanosoma is being written in Portuguese in different ways].

PMID- 8668846
TI  - Laboratory diagnosis of viral infections of the lung.
AB  - Over the past 10 years the diagnosis of viral pneumonias and other infections of
      the respiratory tract has been greatly facilitated by the application of new
      biotechnology. Molecular and immunologic techniques have been developed for the
      detection of viral nucleic acids and proteins in clinical materials obtained from
      the lung, either by bronchoalveolar lavage or biopsy. Clinicians are now able to
      obtain a virologic diagnosis with a high degree of sensitivity and specificity,
      often within a few hours of the diagnostic procedure. We review the current
      status of the newer molecular and immunologic modalities being applied to the
      rapid laboratory diagnosis of viral infections of the lung, including direct and
      indirect fluorescent antibody staining of material from the respiratory tract,
      enzyme immunoassays, centrifugation cultures, and molecular techniques, such as
      the polymerase chain reaction. These techniques permit the rational use of
      specific antiviral therapeutic agents in patients with drug-sensitive pulmonary
      viral infections, thus improving both morbidity and mortality.

PMID- 8668847
TI  - Pathogenesis of cytomegalovirus pneumonia in immunocompromised hosts.
AB  - Cytomegalovirus (CMV) is capable of establishing persistent or latent infection
      after primary infections and reactivation in immunocompromised hosts. The
      understanding of the nature of this latency is incomplete. The acquisition of CMV
      specific immune responses appears essential for limiting primary infection and
      maintenance of a clinical state of latency. Host immunity induced by CMV
      infection includes both cellular and humoral responses. Cell-mediated responses
      by both CD4+ (T helper) and CD8+ cytotoxic T lymphocytes (CTLs) are detected in
      CMV-seropositive individuals. Studies in animal models and in immunocompromised
      patients have implicated deficiencies in class I MHC-restricted, CD8+CMV-specific
      CTL responses in the progression of experimental and human CMV infection and
      pneumonia. Adoptive transfer of CD8+CMV-specific CTLs in immunodeficient marrow
      transplant recipients provides evidence that adoptive immunotherapy with T-cell
      clones of defined specificity and function can be used to safely and successfully
      restore immunity to a human pathogen.

PMID- 8668848
TI  - Cytomegalovirus pneumonia: presentation, diagnosis, and treatment.
AB  - Cytomegalovirus (CMV) pneumonia has been one of the most important opportunistic
      infections in the immunocompromised host. The disease is particularly severe in
      allogeneic bone marrow transplant recipients, with an almost 100% mortality rate
      in untreated patients. During the last few years, major advances in diagnostic
      techniques that allow more rapid detection of CMV in bronchoalveolar lavage have
      resulted in earlier diagnosis and thereby earlier commencement of therapy.
      Furthermore, the diagnosis of CMV infection in the blood using antigenemia assay
      or polymerase chain reaction has allowed the development of preemptive therapy
      strategies, substantially decreasing the risk for the development of CMV
      pneumonia. Ganciclovir or foscarnet combined with intravenous immunoglobulin has
      improved the outcome in some patients with established disease. However,
      resistance of CMV to antiviral agents is becoming an increasingly important
      problem, particularly in patients with the acquired immunodeficiency syndrome.

PMID- 8668849
TI  - Influenza virus pneumonia: pathogenesis, treatment, and prevention.
AB  - The aim of this review is to describe the detrimental impact influenza virus has
      on an individual as well as on the community and to reinforce the strategies of
      prevention and treatment of this disease. The influenza viruses are capable of
      causing annual epidemics because of the constant changes that occur at the
      antigenic sites of the surface proteins. These antigenic changes, also known as
      antigenic drift (minor change) and antigenic shift (major change), allow the
      influenza virus to infect a substantial segment of the population with incomplete
      or no immunity. Composition of the influenza virus vaccine is changed on a yearly
      basis to provide the best match to new influenza virus strain(s) predicted to
      cause the next epidemic. Only by annual administration of influenza virus vaccine
      prior to the epidemic can health care providers expect to prevent influenza virus
      pneumonia and its associated complications in high-risk groups. Recent studies
      have demonstrated the medical prudence and cost effectiveness of preventing
      influenza virus infections in high-risk groups who are most susceptible to the
      complications of the influenza virus.

PMID- 8668850
TI  - Respiratory syncytial virus and parainfluenza virus infections in the
      immunocompromised host.
AB  - Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are common causes
      of respiratory infections in immunocompetent children under the age of 6 years.
      These viruses belong to a family of enveloped single-stranded RNA viruses, the
      paramyxoviruses. The clinical manifestations in the normal host range from mild
      illness to severe croup, bronchiolitis, and pneumonia. After the age of 6 years,
      reinfections occur, but are characterized by diminishing frequency and severity.
      In contrast to the normal adult host, severe lower respiratory tract infection
      can occur in immunocompromised adults as well as children, with significant
      morbidity and mortality. Similar to the normal host, infection with RSV occurs in
      epidemics in the winter and spring, while PIV occurs throughout the year.
      Immunocompromised hosts often have upper respiratory tract symptoms similar to
      those experienced by normal hosts, as well as a higher incidence of lower
      respiratory tract symptoms and sinusitis. Lower respiratory tract infection can
      lead to respiratory failure and death, especially in bone marrow transplant
      recipients. The diagnosis of RSV and PIV depends on the analysis of specimens
      obtained from the respiratory tract. Rapid diagnostic tests are readily available
      for RSV and are less widely used for some of the PIV serotypes. Primary cultures
      are used for both viruses, but take several days to yield a positive result.
      Ribavirin, a broad-spectrum antiviral agent, is effective against RSV and PIV in
      vitro. Clinical trials have shown ribavirin to be of benefit in treating infants
      infected with RSV. However, clinical trials in immunocompromised patients
      infected with RSV or PIV have not been carried out. Since infection with RSV and
      PIV can be severe and life-threatening and treatment with ribavirin is relatively
      benign, it seems warranted to treat immunocompromised patients infected with RSV
      or PIV with ribavirin until otherwise proven unwarranted.

PMID- 8668851
TI  - "Childhood" viruses as a cause of pneumonia in adults.
AB  - Respiratory viruses are a common cause of morbidity in childhood. Except in the
      child with immunodeficiency, the common respiratory viruses rarely pose a serious
      threat to life. Because infection with most of these viruses in childhood is
      nearly universal and usually bestows partial immunity, the "childhood respiratory
      viruses" are not generally thought of as being a cause of disease in adults.
      However, adults who work around children, who are frequently exposed to other
      adults and children with respiratory tract infections (as in a hospital clinic
      setting), or who are military recruits appear to be at risk of infection or
      reinfection with one of these agents. In addition, adults with immune deficiency
      are at a significant risk for serious infection. The risk of serious disease can
      be reduced by maximizing immunity with (re)immunization and optimal treatment of
      any underlying disorders. Tobacco smoke and respiratory irritants should be
      avoided and adults at risk for severe disease should avoid contact with infected
      children and adults as much as possible. Specific chemotherapy for viral
      pneumonia, when available, may reduce morbidity in selected individuals.

PMID- 8668852
TI  - Adenovirus and Epstein-Barr virus in lung disease.
AB  - The adenovirus and the Epstein-Barr virus are double-stranded DNA viruses capable
      of infecting the human respiratory tract and producing a wide spectrum of
      pulmonary disorders. We review the viral factors and viral-host interactions that
      may be involved in the pathogenesis of pulmonary disorders associated with
      adenoviral and Epstein-Barr virus infections, focusing on the possible role of
      acute, persistent, and latent infections. Adenovirus and Epstein-Barr virus have
      evolved a remarkable array of strategies to survive within the infected host, and
      an improved understanding of these strategies is essential to developing
      innovative therapies to effectively manipulate viral-host interactions.

PMID- 8668853
TI  - Human herpesvirus 6 as a possible cause of pneumonia.
AB  - Case reports and limited retrospective studies have established that human
      herpesvirus 6 (HHV-6) can be found in lung tissues from patients with pneumonia.
      Most cases of HHV-6-associated pneumonia involve immunocompromised patients,
      especially those who have received a bone marrow transplant or who have been
      infected by the human immunodeficiency virus. Additional data suggest that HHV-6
      commonly reactivates in immunosuppressed individuals. The virus has been
      identified in a variety of organ systems, including the respiratory tract,
      without associated pathology. A better understanding of HHV-6 pathogenesis is
      needed before rational clinical intervention for HHV-6-associated pneumonias can
      be implemented.

PMID- 8668854
TI  - Hantavirus pulmonary syndrome: clinical, diagnostic, and virologic aspects.
AB  - Hantavirus pulmonary syndrome is an acute pneumonitis with a high mortality rate
      that is caused by a newly recognized hantavirus. Four Corners virus (also known
      as Muerto Canyon virus and Sin Nombre virus) is enzootic among deer mice
      (Peromyscus maniculatus). Incidental transmission to humans can result in a
      disease characterized by rapidly progressive respiratory insufficiency, diffuse
      noncardiogenic pulmonary edema, vascular volume contraction with
      hemoconcentration, lactic acidosis, depressed cardiac output, and cardiac
      dysrhythmias preterminally. The onset of pulmonary edema is preceded by a
      prodrome of fever and severe myalgias. Characteristic laboratory abnormalities
      include thrombocytopenia, leukocytosis with prevalent immature myeloid cells, and
      the presence of immunoblastic lymphocytes in the peripheral blood. Agent-specific
      diagnosis is based on the detection of Four Corners virus-specific antibodies in
      serum by Western blot assays and the detection of Four Corners virus RNA in
      peripheral blood mononuclear cells by the reverse transcriptase-polymerase chain
      reaction. Effective treatment depends on the rapid institution of intensive care
      support.

PMID- 8668855
TI  - Anti-infective therapy for viral pneumonia.
AB  - The recognition of viruses as causes of pneumonia in both immunocompetent and
      immunocompromised hosts has expanded dramatically. The number of therapeutic
      agents available for treatment of these illness also has increased in the last
      decade. Each of these agents has demonstrated a limited therapeutic indication
      for treatment of viral pneumonia. Many of these agents inhibit viral DNA
      synthesis through actions as nucleoside analogs (such as acyclovir and
      ganciclovir). However, a variety of alternative mechanisms of inhibition of viral
      replication are used. Ribavirin, while being a nucleoside analogue, also appears
      to exert broad antiviral activity by a variety of enzymatic inhibitory
      mechanisms. Foscarnet, an inorganic pyrophosphate analogue, offers additional
      treatment options for herpesviruses by acting as a direct virus DNA polymerase
      inhibitor. The tricyclic amines amantadine and rimantadine inhibit influenza A
      replication by interfering with viral uncoating after cell penetration. Thus,
      these two agents are largely effective as prophylaxis. The search for novel
      antiviral drugs, such as neuraminadases inhibitors with selective influenza
      activity, is currently in progress.

PMID- 8668856
TI  - Vaccines in the prevention of viral pneumonia.
AB  - Vaccines to control respiratory virus infections have been limited to inactivated
      whole virus or split virus product of influenza. Over the last few years,
      advances in the understanding of immunity to and importance of these infections
      has led to the development of newer, more immunogenic inactivated influenza
      vaccines and to the exploration of live attenuated influenza vaccines. In
      parallel, both inactivated and live attenuated vaccines against respiratory
      syncytial virus and parainfluenza virus have been undergoing evaluation. More
      effective or new vaccines could reduce morbidity, reduce the frequency of
      hospitalization, and decrease the death rate. Since viral respiratory disease
      would be decreased in frequency, vaccines could reduce the use of antibiotics,
      and by so doing, preserve the usefulness of our currently available antibiotics.

PMID- 8668857
TI  - Hypertension in African Americans: a paradigm of metabolic disarray.
AB  - Hypertensive disease in African Americans manifests itself at an earlier age,
      tends to be more aggressive and difficult to treat, and is more likely to be
      associated with renal failure. Abnormalities of carbohydrate metabolism,
      specifically tissue insulin resistance, may underlie the constellation of
      clinical and pathophysiological characteristics commonly observed in African
      American hypertensive subjects. The interrelationships between insulin
      resistance, salt sensitivity, and vascular hyperresponsitivity to adrenergic
      stimuli require further clinical study, because this relationship may not only
      partly explain much of the hypertensive disease observed in African Americans,
      but may also help identify appropriate therapeutic interventions.

PMID- 8668858
TI  - Hypertension in African Americans: the role of sodium chloride and extracellular
      fluid volume.
AB  - African Americans show higher blood pressure earlier in life, and have a greater
      incidence of hypertension that is manifest earlier, is more severe and is
      associated with a greater risk of cardiovascular complications as compared with
      their white colleagues. Although a variety of mechanisms have been implicated in
      this phenomenon, a single abnormal factor is unlikely. The role of sodium (salt)
      sensitivity of blood pressure, renal function, related vasoactive factors, and
      intracellular ion transport systems will be briefly reviewed for their potential
      involvement. Speculative hypotheses concerning potential causes of the enhanced
      salt-sensitivity observed in African Americans will be offered. The implications
      of these findings for the treatment of hypertension in African Americans will
      also be briefly discussed.

PMID- 8668859
TI  - The role of cardiovascular reactivity as a mediator of hypertension in African
      Americans.
AB  - Observations on the adverse effect of chronic environmental stress on blood
      pressure in individuals, and the incidence of hypertension in populations, have
      raised the possibility that aberrant physiological responses to stressful stimuli
      may play a role in the development of human hypertension. A variety of
      investigations, both clinical and experimental, have been conducted to explore a
      neurogenic dimension in the pathogenesis of hypertension. Reactivity is defined
      as the change in blood pressure, heart rate, or other hemodynamic parameters in
      response to physical or mental stimuli. Data from clinical studies have shown
      that reactivity is a stable measurement within individuals. Augmented reactivity
      is observed in patients with hypertension compared with normotensive subjects,
      and can also be detected in the young, often associated with other risk factors
      for hypertension. Racial differences in reactivity have been shown, with enhanced
      vascular reactivity observed among blacks compared with greater cardiac
      reactivity in whites. Neither stress, nor reactivity to stress has been shown to
      have a causal role in the development of hypertension. Although augmented stress
      induced reactivity is strongly associated with groups having a greater risk for
      future hypertension, the role that reactivity plays in this process remains to be
      delineated.

PMID- 8668860
TI  - Renovasculopathies of hypertension and the rise of blood pressure with age in
      blacks and whites.
AB  - Blood pressure increases with age in all US population groups that have been
      studies, but does so faster in African Americans. Evidence from extensive
      microscopic renal vascular studies at autopsy supports the view that blood
      pressure increases with age because of progressive fibroplasia of renal
      interlobular arteries and arterioles that leads to incrementally escalating renal
      ischemia. This process precedes the development of hypertension and progresses,
      on average, faster in African Americans compared with whites. The etiology for
      fibroplasia of the renal vasculature and the reasons for its faster progression
      in African Americans remains unknown.

PMID- 8668861
TI  - Possible mediators in hypertension: renal factors.
AB  - Hypertension is more prevalent and more severe in African Americans compared with
      whites. Evidence is presented that support an important role of the kidney in the
      excess incidence of hypertension in this population group. There are quantitative
      differences in renal physiology between hypertensive African Americans and
      whites, the most dominant of which is an increased renal vascular resistance in
      African Americans that might be structural or functional. This increased renal
      vascular resistance might represent an underlying primary renal disease that has
      remained concealed among the spectrum of diseases referred to as benign
      nephrosclerosis. The answer(s) to this intriguing question will provide a better
      understanding of the kidney as a mediator and/or target of hypertension.

PMID- 8668862
TI  - Epidemiology of hypertension in African Americans.
AB  - Hypertension is more prevalent, appears at an earlier age, is more likely to be
      associated with end-organ complications, and is less likely to be treated with
      traditional therapies in African Americans compared to Americans of European
      descent. Epidemiological associations have been made between the excess burden of
      hypertension in this population group and some biological, psychosocial, and
      socioeconomic factors. These associations might be used as a starting point that
      guides research to identify the cause(s) for the higher proportion of African
      Americans with hypertension. At present, such associations can help in the design
      of risk factor intervention strategies.

PMID- 8668863
TI  - Hypertension in the African American community: social, cultural, and
      psychological factors.
AB  - The potential influence of social and psychological factors on the risk of
      hypertension within the African American community must be examined in relation
      to cultural and historical influences on the community. Blood pressure elevation
      varies dramatically between and within black populations, with socioeconomically
      disadvantaged communities in North America showing the highest levels. It is this
      historical and continuing pattern of socioeconomic disadvantage that forms the
      context in which social and psychological factors must be examined. The research
      that is reviewed in this article explicitly takes into account such factors. It
      is consistent with a model in which African Americans are engaged in a chronic
      struggle to achieve and maintain valued social and personal goals in the context
      of few socioeconomic resources. This long struggle is itself associated with
      higher blood pressure, and may also lead to the greater experience of frustration
      and anger that compounds blood pressure elevation. Conversely, there are also
      supportive social institutions in the black community, including the church and
      the extended family, that appear to provide a protective effect with respect to
      problematic circumstances and lower the risk of hypertension. The twin goals of
      lowering blood pressure therapeutically and preventing the onset of hypertension
      must include the social and cultural context of African American patients, and
      the social and psychological processes associated with hypertension.

PMID- 8668864
TI  - Blood pressure variation in blacks: genetic factors.
AB  - Persons of African descent living in the Western hemisphere, including African
      Americans, have the highest prevalence of hypertension in the world. Debate
      continues as to whether it is their African ancestry or the Western environment
      that is more important in increasing the prevalence of hypertension in the
      African Diaspora above that of indigenous Africans as well as of fellow
      inhabitants in the Western hemisphere. Current data support that hypertension in
      African Americans, like that in other population groups, arises from the
      interaction of environmental factors with a susceptible physiology that is
      determined in part by genetic factors. Dietary sodium chloride (NaCl) is an
      important environmental factor, and the inability to prevent blood pressure from
      increasing to hypertensive levels in response to the comparatively high NaCl
      content of Western diets characterizes the majority of hypertensive African
      Americans. Studies discussed herein suggest a strong genetic component for the
      physiology of "salt sensitivity." Phenotypes that are indicative of this
      sensitivity are more common in African Americans than in Americans of European
      descent and in hypertensive African Americans compared with normotensive African
      Americans. Further studies are needed to more clearly define these genetic
      markers that determine salt sensitivity.

PMID- 8668865
TI  - Role of dietary factors in the hypertension of African Americans.
AB  - Epidemiological and experimental data suggest that dietary constituents are among
      the causative factors that contribute to the higher prevalence and severity of
      hypertension in African Americans as compared with European Americans. Given the
      difficulty of cleanly separating a change in one dietary nutrient from
      concomitant changes in others, it has been difficult to reliably attribute an
      observed effect on blood pressure level and hypertension prevalence to the
      specific dietary constituent under study. Nevertheless, because hypertension is
      virtually nonexistent in societies whose dietary sodium chloride intake is very
      low, it appears that a sodium chloride intake in excess of that required to
      maintain adequate extracellular fluid volume is necessary but not sufficient for
      hypertension to be manifest. Additional factors are clearly necessary in the
      development of hypertension because most individuals, including African
      Americans, can ingest a high sodium chloride diet without developing
      hypertension. Evidence for the potential importance of other dietary constituents
      is also discussed, as are dietary strategies that effectively reduce blood
      pressure in hypertensive individuals. The data presented support the need for
      continued research into dietary constituents as potential factors contributing to
      the etiology of hypertension, as well as effective adjuncts to the management of
      this very common health problem.

PMID- 8668866
TI  - Tutorial in biostatistics. Designing studies for dose response.
AB  - 'Dose response' refers to the regression of a response on a stimulus. We review a
      number of options for dose-response designs, and compare various designs which
      may be used in practice. We start with two group designs. Next, we introduce
      basic optimal approximate design theory for simple linear and quadratic
      regression illustrating different criteria of optimality and their effect on the
      allocation of the levels of the dose. Then we obtain the efficiencies of these
      optimal approximate designs and some simple designs which have intuitive appeal
      (symmetry, equal spacing of treatments, reduced numbers of observations at the
      highest and lowest doses).

PMID- 8668867
TI  - Multivariable prognostic models: issues in developing models, evaluating
      assumptions and adequacy, and measuring and reducing errors.
AB  - Multivariable regression models are powerful tools that are used frequently in
      studies of clinical outcomes. These models can use a mixture of categorical and
      continuous variables and can handle partially observed (censored) responses.
      However, uncritical application of modelling techniques can result in models that
      poorly fit the dataset at hand, or, even more likely, inaccurately predict
      outcomes on new subjects. One must know how to measure qualities of a model's fit
      in order to avoid poorly fitted or overfitted models. Measurement of predictive
      accuracy can be difficult for survival time data in the presence of censoring. We
      discuss an easily interpretable index of predictive discrimination as well as
      methods for assessing calibration of predicted survival probabilities. Both types
      of predictive accuracy should be unbiasedly validated using bootstrapping or
      cross-validation, before using predictions in a new data series. We discuss some
      of the hazards of poorly fitted and overfitted regression models and present one
      modelling strategy that avoids many of the problems discussed. The methods
      described are applicable to all regression models, but are particularly needed
      for binary, ordinal, and time-to-event outcomes. Methods are illustrated with a
      survival analysis in prostate cancer using Cox regression.

PMID- 8668868
TI  - Statistical approaches to human brain mapping by functional magnetic resonance
      imaging.
AB  - Proper use of functional neuro-imaging through effective experimental design and
      modern statistical analysis provides new insights in current brain research. This
      tutorial has two aims: to describe aspects of this technology to applied
      statisticians and to provide some statistical ideas to neuroscientists unfamiliar
      with quantitative analytic methods that accommodate randomness. Introductory
      background material and ample references to current literature on the physics of
      magnetic resonance imaging, Fourier methods for image reconstruction and measures
      of image quality are included. Two of the statistical approaches mentioned here
      are extensions of established methods for longitudinal data analysis to the
      frequency domain. A recent case study provides real-world instances of
      approaches, problems and open questions encountered in current functional neuro
      imaging research and an introduction to the analysis of spatial time series in
      this context.

PMID- 8668869
TI  - Non-parametric two-sample tests for repeated ordinal responses.
AB  - Consider data on two groups of clusters, where each cluster consists of many
      units that respond on an ordinal scale. We develop a Mann-Whitney type test to
      determine whether a typical response from the first group is larger (or smaller)
      than a typical response from the second group.

PMID- 8668870
TI  - A model for cross-over trials evaluating therapeutic preferences.
AB  - A preference trial is a special form of cross-over trial where clinical
      conditions determine when patients change treatment, in a prescribed order. This
      can be modelled using a geometric distribution. The model can be simply fitted
      using standard logistic regression methodology. The procedure is applied to a
      trial studying the effects of bronchodilators in the treatment of chronic asthma.

PMID- 8668871
TI  - The incidence of cystic fibrosis.
AB  - We develop a statistical model for estimating cystic fibrosis (CF) incidence
      among infants born in the U.S.A. that accounts for under-diagnosis due to death
      prior to diagnosis and we apply it to the Cystic Fibrosis Foundation Patient
      Registry data for the years 1989 to 1991. The resulting estimate of incidence
      relative to live births among whites is 1:3419 while that among non-whites is
      1:12,163. As a by-product of the modelling approach, estimates of the underlying
      average diagnosis age given survival to diagnosis are 4.09 years for whites and
      4.55 years for non-whites, but this difference was not statistically significant
      and appears to demonstrate that diagnosis efforts may be approximately the same
      for whites and non-whites. Also, as another by-product of the modelling approach,
      CF mortality was estimated as more severe for females than males and marginally
      more severe for non-whites than whites. A variety of statistical methods underlie
      achievement of these results, including semi-parametric maximum likelihood,
      survival analysis, multiple imputation and bootstrap techniques.

PMID- 8668872
TI  - Bayesian imputation of predictive values when covariate information is available
      and gold standard diagnosis is unavailable.
AB  - We suggest a conceptually simple Bayesian approach to inferences about the
      conditional probability of a specimen being infection-free given the outcome of a
      diagnostic test and covariate information. The approach assumes that the
      infection state of a specimen is not observable but uses the outcomes of a second
      test in conjunction with those of the first, that is, dual testing data. Dual
      testing procedures are often employed in clinical laboratories to assure that
      samples are not contaminated or to increase the likelihood of correct diagnoses.
      Using the CD4 count and a proxy for risk behavior as covariates, we apply the
      method to obtain inferences about the conditional probability of an individual
      being HIV-1 infection-free given the individual's covariates and a negative
      outcome with the standard enzyme-linked immunoad-sorbent assay/Western blotting
      test for HIV-1 detection. Inferences combine data from two studies where
      specimens were tested with the standard and with the more sensitive polymerase
      chain reaction test.

PMID- 8668873
TI  - Robustness and power of analysis of covariance applied to data distorted from
      normality by floor effects: homogeneous regression slopes.
AB  - We investigate through computer simulations the robustness and power of two group
      analysis of covariance test applied to small samples distorted normality by floor
      effects when the regression slopes are homogeneous. We consider four parametric
      analysis of covariance tests that vary according to the treatment of the
      homogeneity of regression slopes and two t-tests on unadjusted means and on
      difference scores. Under the null hypothesis of no difference in means, we
      estimated actual significance levels by comparing observed test statistics to
      appropriate values from the F and t distributions for nominal significance levels
      of 0.10, 0.05, 0.02 and 0.01. We estimated power by similar comparisons under
      various alternative hypothesis. The hierarchical approach (that adjusts for non
      homogeneous slopes if found significant), the test that assumes homogeneous
      regression slopes, and the test that estimates separate regression slopes in each
      treatment were robust. In general, each test produced power at least equal to
      that expected from normal theory. The textbook approach, which does not test for
      mean differences when there is significant non-homogeneity, was conservative but
      also had good power. The t-tests were robust but had poorer power properties than
      the above procedures.

PMID- 8668874
TI  - Assessment of HIV testing rates among HIV infected individuals using incidence
      data on HIV and AIDS diagnoses.
AB  - This paper considers estimation of the rate HIV diagnosis in a population of HIV
      positive individuals. A number of previous papers have studied the situation
      where time of first positive HIV test is available for AIDS cases, and possibly
      for individuals who have not yet developed AIDS. In this context, AIDS diagnoses
      are linked to prior HIV diagnoses. The present paper focuses on the case where
      AIDS incidence data, and data on new HIV diagnoses, are unlinked. Although there
      is less information available when there is no linking AIDS diagnosis and HIV
      tests, it is shown that a useful assessment can be made of the pattern of HIV
      testing over time. The methodology makes use of back-projection estimates of HIV
      incidence and involves fitting a model for HIV diagnosis to the observed pattern
      of new positive HIV tests. Smooth non-parametric estimates are obtained by
      minimizing a penalized residual sum of squares. In analysis of data on HIV
      diagnoses among the homosexual/bisexual population in the state of Victoria,
      Australia, we find strong evidence of a significant decrease in testing rates
      during the latter part of the 1980s. Subsequent testing rate estimates are
      subject to greater uncertainty, but are of a comparable magnitude to estimates
      based on linked data in other countries.

PMID- 8668875
TI  - Historical HIV incidence modelling in regional subgroups: use of flexible
      discrete models with penalized splines based on prior curves.
AB  - This paper presents an approach to back-projection (back-calculation) of human
      immunodeficiency virus (HIV) person-year infection rates in regional subgroups
      based on combining a log-linear model for subgroup differences with a penalized
      spline model for trends. The penalized spline approach allows flexible trend
      estimation but requires far fewer parameters than fully non-parametric smoothers,
      thus saving parameters that can be used in estimating subgroup effects. Use of
      reasonable prior curve to construct the penalty function minimizes the degree of
      smoothing needed beyond model specification. The approach is illustrated in
      application to acquired immunodeficiency syndrome (AIDS) surveillance data from
      Los Angeles County.

PMID- 8668876
TI  - Analysis of cross-over trials for duration data.
AB  - Survival models and cross-over designs both have an established place in
      biomedical research. Surprisingly, there are a few examples of proper
      exploitation of two in combination. A number of advantages and disadvantages of
      such studies are discussed. Two examples are used to illustrate the application
      of semi-Markov models with time-varying covariates, as standard log-linear
      models, to such data.

PMID- 8668877
TI  - Multiple-outcome meta-analysis of clinical trials.
AB  - When several clinical trials report multiple outcomes, meta-analyses ordinarily
      analyse each outcome separately. Instead, by applying generalized-least-squares
      (GLS) regression, Raudenbush et al. showed how to analyse the multiple outcomes
      jointly in a single model. A variant of their GLS approach, discussed here, can
      incorporate correlations among the outcomes within treatment groups and thus
      provide more accurate estimates. Also, it facilitates adjustment for covariates.
      In our approach, each study need not report all outcomes nor evaluate all
      treatments. For example, a meta-analysis may evaluate two or more treatments (one
      'treatment' may be a control) and include all randomized controlled trials that
      report on any subset (of one or more) of the treatments of interest. The analysis
      omits other treatments that these trials evaluated but that are not of interest
      to the meta-analyst. In the proposed fixed-effects GLS regression model, study
      level and treatment-arm-level covariates may be predictors of one or more of the
      outcomes. An analysis of rheumatoid arthritis data from trials of second-line
      drug treatments (used after initial standard therapies prove unsatisfactory for a
      patient) motivates and applies the method. Data from 44 randomized controlled
      trials were used to evaluate the effectiveness of injectable gold and auranofin
      on the three outcomes tender joint count, grip strength, and erythrocyte
      sedimentation rate. The covariates in the regression model were quality and
      duration of trial and baseline measures of the patients' disease severity and
      disease activity in each trial. The meta-analysis found that gold was
      significantly more effective than auranofin on all three treatment outcomes. For
      all estimated coefficients, the multiple-outcomes model produced moderate changes
      in their values and slightly smaller standard errors, to the three separate
      outcome models.

PMID- 8668878
TI  - Coping with conflicting agendas: the bathing experience of cognitively impaired
      older adults.
AB  - The behaviors of 33 clients with cognitive impairment were examined during bath
      time using grounded theory methods. Analysis revealed that 73% of the adults
      displayed agitated behaviors during personal hygiene care. Subjects and
      caregivers were faced with conflicting agendas and attempted to cope by using a
      variety of verbal and nonverbal strategies. The strategies used by cognitively
      impaired older adults included: attaining control, sharing control, resigning
      control, and regaining inner control. Results of this study suggest that older
      adults with cognitive impairment have a repertoire of coping mechanisms that are
      used when environmental demands challenge the person's deteriorating cortical
      abilities.

PMID- 8668879
TI  - The essence of enduring and expressions of suffering: the reformulation of self.
AB  - In this study, biographical narratives of illness experiences were used to
      explicate the concepts of suffering and enduring. Three types of enduring were
      identified: enduring to survive (which occurs during physiological jeopardy),
      enduring to live (which occurs with untenable psychological stressors), and
      enduring to die (which occurs with inevitable degenerative and terminal disease).
      Suffering is defined as an emotional response to that which was endured, to the
      changed present, or to anticipating the altered future. Finally characteristics
      that differentiate enduring from suffering are delineated. The relationships
      between the two concepts are explored. Individuals move from enduring to
      suffering when they are able to acknowledge that which is being endured, and when
      they are emotionally strong enough to experience the emotional onslaught of
      suffering. If the latter is overwhelming, individuals may retreat to enduring.
      Once they have suffered enough and are able to accept the changed reality,
      individuals gain new insight and appreciation for life as a reformulated self.

PMID- 8668880
TI  - Tools of the trade: analyzing technology as object in nursing.
AB  - Key components of nursing practice are the things nurses use in their work.
      Despite the importance that technological objects have played in both practicing
      and representing the practice of nursing, they have received only tangential
      attention in empirical and ethical studies of nursing practice and in theories of
      nursing. In this paper, technology is analyzed in its mode of manifestation as
      "object." An analytic emphasis on technology as object is necessary to draw
      attention to and garner respect for the independent force that objects exert in
      human/machine interactions. In addition, giving conceptual primacy to the
      material manifestation of technology can help to clarify (even as it raises other
      questions about) the long-standing and somewhat bittersweet relationship between
      nursing and technology.

PMID- 8668881
TI  - Parents' perceptions of their children's recovery 5 to 10 years following day
      care abuse.
AB  - A follow-up study of 19 parents whose children had been physically, sexually and
      psychologically abused in day care 5 to 10 years previously, suggests that as
      perceived by the parent, over one third of the children remain clinically
      symptomatic, one third are in the normal symptomatic range, and one third are
      asymptomatic. Also, parents themselves were still distressed by the event and
      expressed concern as to their child's future interpersonal relationships. It is
      recommended that nurses provide brief counseling sessions to parents for
      management of their children's posttrauma symptoms.

PMID- 8668882
TI  - [Pharma-clinics. How I treat... supraventricular tachycardia in children].

PMID- 8668883
TI  - [Clinical case of the month. Moskowitz syndrome in a patient treated with
      ticlopidine].

PMID- 8668884
TI  - [Retinoids and acute promyelocytic leukemia. A therapeutic revolution].

PMID- 8668885
TI  - [General medicine, drug abuse and palliative care].

PMID- 8668886
TI  - [Development of late potentials in ventricular activation in myocardial
      infarction (1)].

PMID- 8668887
TI  - [Pierced ears].

PMID- 8668888
TI  - [Should one consider monitoring various products containing caffeine?].

PMID- 8668889
TI  - [Which problems arise in the hydration of elderly persons?].

PMID- 8668890
TI  - [How I explore... metabolic disorders in menopausal women].

PMID- 8668891
TI  - [Pharma-clinics. Drug of the month. Polyvalent antipneumococcal vaccine
      (Pneumune)].

PMID- 8668892
TI  - [Drug therapy as secondary prevention following myocardial infarction].

PMID- 8668893
TI  - [ACE-inhibitors in acute heart infarct].
AB  - The use of ACE-inhibitors in heart failure has been established over the past
      years. Their use is of uncertain value in the early phases of myocardial
      infarction, where they are supposed to prevent left ventricular dilatation. More
      recent studies (ISIS-4, GISSI-3) have tested early treatment by ACE-inhibitors in
      the acute phase of myocardial infarction. On one hand, it was possible to
      disprove reservations about risks (hypotension)n in a large cohort; on the other
      hand, a further reduction of mortality in hospitalized patients by 7% has been
      shown, corresponding to five patient lives saved for 1000 treated patients. Thus,
      after institution of the customary therapy of myocardial infarction (inhibitor of
      platelet aggregation, thrombolysis, beta-blocker) and after exclusion of specific
      contraindications (hypotension < 100 mmHg, renal failure) ACE-inhibitors could be
      administered in the acute phase of myocardial infarction. An analysis of the
      results from these large trials will show whether ACE-inhibitors may benefit
      groups of patients at particular risks (Killip > 1, age > 70 years, preceding
      renal failure) noticeably. ACE-inhibitors remain the treatment of choice in
      patients with developing left ventricular failure.

PMID- 8668894
TI  - [Retrobulbar neuritis--diagnosis and differential diagnosis].
AB  - The American multicenter study 'A randomized, controlled trial of corticosteroids
      in the treatment of acute optic neuritis' (5) showed how a retrobulbar neuritis
      should not be treated, Oral steroids (1 mg per kilogram of body weight per day)
      are not only ineffective but also associated with a higher rate of recurrences
      compared to high dose i.v. methylprednisolone. In the light of this study, 'low
      dose' steroid therapy for retrobulbar neuritis is contraindicated. High-dose
      methylprednisolone speeds up recovery of the visual function and lowers the
      recurrence rate two years after treatment; however, this protective effect could
      not be demonstrated after three years. These recommendations are valid only for
      primary demyelinating retrobulbar neuritis. Other less common optic neuropathies,
      such as these of microvascular origin, respond to 'low-dose' steroids; therefore,
      the diagnosis of primary demyelinating retrobulbar neuritis must be made with
      caution as a diagnosis of exclusion. This paper discusses a number of important
      optic neuropathies and gives recommendations for investigations. Compressive
      optic neuropathies and chiasmal disease will not be covered here.

PMID- 8668895
TI  - [Electrolyte disturbances and unconsciousness in a 63-year-old alcoholic
      patient].

PMID- 8668896
TI  - [Clinicopharmacological case report (3). Drug-induced angioedema].
AB  - We report the case of a patient with an angioedema during therapy with enalapril
      and tramadol. The most likely cause of the adverse effect if the ACE-inhibitor
      enalapril. A rechallenge with the ACE-inhibitor is dangerous and should not be
      performed. Because of its potential risks, further treatment with ACE-inhibitors
      should be avoided in all patients with ACE-inhibitor-induced angioedema. Possible
      therapeutic alternatives include diuretics, beta-blocking agents, calcium
      antagonists and also angiotensin II receptor antagonists.

PMID- 8668897
TI  - [Swelling of the ears, chest pain, cough].
AB  - A 62-year-old male had tender swelling of both ears with loss of hearing due to
      edematous swelling of the external auditory canal. The patient complained further
      about dry cough, pain at the costo-sternal junctions, adynamia and weight loss.
      Inflammatory parameters were markedly elevated, and histologic work-up of an
      auricular biopsy revealed lymphocytic infiltration. These findings led to the
      diagnosis of chronic recurrent polychondritis actually under control after a
      pulse of glucocorticoids followed by maintenance therapy with 5 mg prednisone.

PMID- 8668899
TI  - Proceedings of the 1994 Bari Ear Care Workshop. Bari, Italy.

PMID- 8668898
TI  - [A case from practice (347). Diabetes mellitus type II--coronary heart disease
      with status after anterior wall infarct and PTCA 1994--secondary erectile
      dysfunction].

PMID- 8668900
TI  - The prevention of hearing loss worldwide.
AB  - The prevalence of disabling hearing loss ( >40dB, average 0.5 - 4 KHz) is at
      least 120 million worldwide. It is estimated that half of this loss is
      preventable by primary means. These include genetic counselling, stricter
      supervision of ototoxic drug use, vaccination against common viral diseases,
      measles, mumps and in selected populations, rubella; vaccination against
      meningitis, better management of acute respiratory infections, noise control and
      the appropriate use of hearing protection. Education of individuals, communities
      and governments is an essential prerequisite to implementation.

PMID- 8668901
TI  - The WHO programme for the prevention of deafness and hearing impairment.
AB  - The WHO Programme for the Prevention of Deafness and hearing Impairment (PDH) was
      established in 1987 to deal with causes of avoidable hearing loss, particularly
      in developing countries. The Programme is developing its strategies on the basis
      of essential ear care as part of primary health care, and the collection of
      epidemiologically sound data on ear disease and hearing impairment. A uniform Ear
      Examination Form is being finalized, for use in field surveys. The PDH Programme
      suffers from not having adequate resources available, and few countries have so
      far taken on the prevention of deafness as a health care issue. In the Eastern
      Mediterranean, South-East Asia and Western Pacific Regions, a number of national
      programmes will hopefully develop in the near future. Particular issues for the
      next two years include ototoxicity and the management of otitis media. Overall,
      the priority is to obtain programme staff and a more adequate working budget.

PMID- 8668902
TI  - Worldwide analysis and collection centre for data on syndromic genetic hearing
      loss: a new proposal.
AB  - The remarkable number of syndromic genetic hearing loss (about 150), the extreme
      variety of clinical signs that can be associated with the hearing loss, and the
      different possible combinations make the diagnosis od syndromic genetic hearing
      loss sometimes very difficult and motivated the development of an expert system
      (G-DEAFNEX). A collection centre is proposed: to act as a referral centre, for
      patients with suspected syndromic genetic hearing loss, that aids the diagnostic
      procedure; to act as a centre for the collection of data on patients with known
      syndromic genetic hearing loss; to collaborate with Hearing International in a
      worldwide epidemiological study on syndromic genetic hearing loss; to refine the
      G-DEAFNEX expert system.

PMID- 8668903
TI  - Multidimensional analysis of speech of hearing impaired children.
AB  - The character of speech of hearing impaired children was evaluated via
      multidimensional protocol in order to provide sensitive and quantitative measures
      of assessment. 20 children (9 males and 11 females) with moderate to severe
      hearing impairment, were studied. The protocol of assessment included auditory
      perceptual assessment (APA) (documented by high fidelity audiorecording),
      audiological assessment, formal testings, aerodynamic assessment and acoustic
      analysis. APA showed addected vowels (90%), affected suprasegmental phonology;
      rate (60%), stress (80%), tonality (85%); decreased resonance (15%); affected
      voice (45%) and affected intelligibility (85%). Aerodynamic results showed highly
      significant increase in the subglottic pressure, highly significant decrease in
      glottal resistance and glottal efficiency, indicating a possible breakdown in
      respiratory, phonatory and articulatory coordination. Spectrographic results
      showed significant increase in the syllable duration; vowel duration and sentence
      duration. Visi-Pitch results showed highly significant increase in the intensity,
      significant decrease in the maximum fundamental frequency (Fo) and highly
      significant decrease in the percent pause. The accoustic findings may represent a
      quantitative correlate to some of the subjective observations of APA.

PMID- 8668904
TI  - Hearing aid systems in undeveloped, developed and industrialized countries.
AB  - The problems related with the hearing loss prevalence and deafness rehabilitation
      in Developing (D) countries are so complex that only basic needs and some
      suggestions are discussed in this paper. In fact for D countries the main
      demographic and social indi reveal the enormous gravity of the health situation
      and so the availability of a hearing aid delivery system is often considered less
      urgent and secondary to the basic unmet needs of the population. Nevertheless we
      think this concept may be applied to the adult, but for the child with a
      preverbal deafness it must deserve immediate attention in order to prevent a very
      serious handicap limiting all his life. Schematically the three types of
      handicaps developed by a child with a preverbal hearing loss are presented and
      discussed. The essential assumption, however, for any hearing aid program in D
      countries is the creation in loco of competent personnel for the prescription,
      for fitting and checking the aids. If D countries are to achieve this objective,
      industrialized countries must begin to transfer technology and training to
      develop pilote centers.

PMID- 8668905
TI  - Relationship between ENT specialists and deaf community.
AB  - The relationship between the ENT specialist and the Deaf Community is discussed
      along with the relative role of the non-medical consultants who come into contact
      with this group of people. Suggestions are made to the clinician for a correct
      approach to deaf persons: acquisition of adeguate tools for communication and
      clear and understandable information. In this communication and clear and
      understandable information. In this context, the advent of Cochlear Implants and
      their impact on the Deaf Community are taken into consideration.

PMID- 8668906
TI  - A major Italian force in the ENT diagnostic field and in hearing rehabilitation.
AB  - Amplifon, a leading italian company operating for over 40 years in the field of
      ENT diagnostic, hearing aid fitting and hearing rehabilitation, provides a major
      support to the health care and scientific world by means of a capillary sales and
      customer service network, an advanced R&D Service, a qualified Center for
      Research and Studies (CRS), an outstanding quality control and highly skilled
      personnel; its product lines comprise hearing aids and biomedical equipment.

PMID- 8668907
TI  - Proposal for the development of an audiological assistant training program.

PMID- 8668908
TI  - Health care economics: impact on hearing loss prevention in the developing world.
AB  - Health care resources are unevenly distributed: 15% of the world's population
      utilise 87%. Physician numbers vary dramatically from one region to another, as
      does disease distribution and the age of the population. All this impacts both
      what can be delivered and what is appropriate to a region. Primary prevention is
      usually effective and much cheaper than treatment or rehabilitation. Alternative
      health care models are discussed.

PMID- 8668909
TI  - The Bari Center: an audiology and otology pilot center for Mediterranean
      countries.
AB  - The Audiology and Otology Center for Mediterranean Countries began activities in
      1990. Until today, the Bari Center has sponsored meetings, coordinated research
      projects and, above all, it has been host to 5 young colleagues coming from the
      Mediterranean Area, to take part in 2 or 3 month clinical stages: two from Egypt,
      one from Syria and one from Lybia. The Center is now verifying the possibilities
      of setting up an Audiology and Otology Center in Tirana (Albania).

PMID- 8668910
TI  - Strategy for D-Country Ear Care.
AB  - The last decade's voluntary Global Ear Care work-lobbying and networking, using
      different strategies-in the whole has been positive, reflected by the creation of
      an appropriate instrument to launch concrete programmes and has also given good
      WHO-HQ relations, though without budget and adequate governmental involvement.
      The long-term goal is to get D-country Ear Care up to the same level as D-country
      eye care. One important step on this way-hopefully facilitated by the Bari
      workshop as an example of 'informal' networking and linkage of people after
      personal initiatives-is to develop an Ear Care structure in Eastern Europe and
      the Mediterranean countries functioning as successfully asd the one in Asia.

PMID- 8668911
TI  - Epidemiology of hearing problems among adults in Italy.
AB  - Estimates for the prevalence of self-reported hearing disability and measured
      hearing impairment as a function of age in the adult population of Italy are
      reported. The study was conducted in Bari, Florence, Milan, Padua, Palermo with
      questionnaire and audiological assessment; neither stage showed any gross bias
      arising from the particular cities chosen. The results have demonstrated that:
      22% of subjects think their hearing abnormal, 24.4% report some difficulty
      understanding speech, 14.5% experienced prolonged spontaneous tinnitus and 17%
      have a > or = 25 dB HL bilateral hearing impairment; hearing problems increase
      progressively with age and show no significant differences between men and women;
      the occupational groups most at risk as far as hearing impairments are concerned
      are manual workers and workers exposed to occupational noise; the systemic
      disorders most significantly connected to hearing problems are dyslipidosis,
      diabetes, hypertension, cardiovascular diseases, liver diseases and cervical
      arthrosis; among every day habits, the consumption of alcohol seems the only
      element of risk, above all for tinnitus.

PMID- 8668912
TI  - The interferon-alpha/beta responses of mice to herpes simplex virus studied at
      the blood and tissue level in vitro and in vivo.
AB  - Murine mononuclear leucocytes from bone marrow, spleen, lymph node and blood
      stimulated in vitro by UV-irradiated herpes simplex type I virus (HSV) produced
      about equal proportions of IFN-alpha and -beta determined by immunoassay.
      Thymocytes produced only IFN-alpha. The frequency of IFN-alpha/beta mRNA
      containing cells detected by in situ hybridization was highest with bone marrow
      (15 per 10(4) cells), followed by spleen (4/10(4)), lymph node (2/10(4)), blood
      (1/10(4)) and thymus (0.2/10(4)). Such IFN-alpha/beta producing cells (IPCs) were
      heavily labelled in autoradiographs, each producing about 0.4 U of IFN. After one
      intravenous injection of UV-irradiated HSV in mice, high levels of IFN-alpha and 
      beta were present in blood at 3-9h and little or none at 24h or later. Frequent
      cells strongly positive for IFN-alpha mRNA at in situ hybridization and for IFN
      alpha/beta at immunohistochemical staining were found almost exclusively in the
      marginal zones of spleens. Occasional IPCs were detected in lymph nodes but not
      in bone marrow, liver and kidneys. The marginal zone IPCs may be the major source
      of IFN in blood, and high splenic levels of IFN-alpha/beta should have efficient
      antiviral and immunoregulatory functions.

PMID- 8668913
TI  - C5b-8 step lysis of swine endothelial cells by human complement and functional
      feature of transfected CD59.
AB  - The authors established several swine endothelial cell (SEC) lines expressing
      human CD59 by transfection of cDNA, and assessed the function of the transfectant
      molecules in comparison with those of membrane cofactor protein (MCP) and decay
      accelerating factor (DAF) in an in vitro hyperacute rejection model of swine to
      human discordant xenograft. At the usual expression rate, DAF and MCP protected
      SEC from human complement mediated cell lysis, but CD59 did not block human
      complement attack on SEC. However, CD59 protects SEC from cell lysis when
      sufficiently expressed as in human umbilical vein (HUVEC). The authors examined
      why CD59 needed so many molecules to protect human complement-mediated SEC lysis
      and found that SEC underwent lysis by human C5b-8. The degree of C5b-8 step lysis
      of SEC was approximately 70% of the total activation (C5b-9). Additionally, CD59
      protected human complement activities less efficiently at the C5b-8 step than at
      the C9-step. Therefore, to overcome human complement mediated SEC lysis, C8
      activity must be inhibited by dense expression of CD59.

PMID- 8668914
TI  - Triggering of target of an antiproliferative antibody-1 (TAPA-1/CD81) up
      regulates the release of tumour necrosis factor-alpha by the EBV-B lymphoblastoid
      cell line JY.
AB  - Target of an antiproliferative antibody-1 (TAPA-1/CD81) has been shown to be non
      covalently associated to HLA-DR antigens on the cell surface of B cells. In this
      study the authors report that triggering of CD81 by MoAb 5A6 or 1D6 significantly
      (P < 0.05) up-regulates the release of tumour necrosis factor-alpha (TNF-alpha)
      by the Epstein-Barr virus-positive (EBV)-B lymphoblastoid cell line JY. The
      accumulation of TNF-alpha in the culture medium of JY cells incubated with either
      anti-CD81 MoAb was found to be dose-dependent and similar to that obtained
      following crosslinking of HLA-DR antigens with MoAb L243. The effect of the
      combination of anti-CD81 and anti-HLA-DR MoAb on the release of TNF-alpha by JY
      cells was not synergistic or additive. In addition, the combination of anti-CD81
      and anti-HLA-DR MoAb did not affect proliferation and homotypic aggregation of JY
      cells induced by each MoAb used alone. Both anti-CD81 or anti-HLA-DR MoAb induced
      protein tyrosine phosphorylation. However, different cytoplasmic proteins were
      phosphorylated following triggering of either molecule. Taken together, the data
      demonstrate that CD81 and HLA-DR antigens induce similar effector phenomena in
      the regulation of TNF-alpha release, homotypic aggregation and inhibition of JY
      cell proliferation.

PMID- 8668915
TI  - Heterogenous expression of the related MPB70 and MPB83 proteins distinguish
      various substrains of Mycobacterium bovis BCG and Mycobacterium tuberculosis
      H37Rv.
AB  - MPB70 and MPB83 are homologous cross-reactive secreted mycobacterial proteins
      with very limited species distribution. The expression of these two proteins was
      compared between several substrains of Mycobacterium bovis BCG, virulent M. bovis
      and Mycobacterium tuberculosis H37Rv. A polyclonal antibody specific for MPB70 in
      Western blotting, and a monoclonal antibody, MBS43, found to be specific for
      MPB83 in ELISA and Western blotting, were used for the comparison. The previously
      established pattern of high- and low-producing substrains of BCG for MPB70 is
      only partially applicable for MPB83. MPB70 low-producing strains are also MPB83
      low-producing, but the expression of MPB83 is much more variable than the
      expression of MPB70 in the MPB70 high-producing strains. Purified MPB83 (23 kDa)
      was found to be glycosylated. A band in SDS-PAGE at 1-2 kDa lower than that of
      purified MPB83 may represent unglycosylated MPB83. Furthermore, it was confirmed
      that purified MPB70 (22 kDa) is unglycosylated. There is cross-reactive antigen
      at 26 kDa. The MPB83 related antigen at 26 kDa was found to be the most abundant.
      These findings indicate greater heterogeneity between different substrains of BCG
      than previously realized. Virulent M. bovis produce and secrete large amounts of
      MPB70 and MPB83 while both these proteins occur in a far lower concentration in
      M. tuberculosis.

PMID- 8668916
TI  - Induction of human cytotoxic T lymphocytes by oxidized low density lipoproteins.
AB  - Oxidized low density lipoproteins (oxLDL) stimulated human blood T cells to a
      specific cytotoxic response with autologous PHA activated blood mononuclear cells
      which had been pre-incubated with oxLDL. The cytotoxic reaction was exerted by
      CD8+ enriched cells but not by CD4+ enriched cells. Allogeneic target cells from
      HLA mismatched donors were not damaged and the reaction was consistently
      inhibited by monoclonal antibody against HLA class I. Antigen-specific cytotoxic
      T cells might contribute to lysis of cells in the atherosclerotic plaque that
      have taken up oxLDL and thus participate in the inflammatory process associated
      with atherosclerosis.

PMID- 8668917
TI  - Heparin in clinical doses 'primes' granulocytes to subsequent activation as
      measured by myeloperoxidase release.
AB  - The author pre-incubated isolated human granulocytes with increasing doses of
      heparin (0-100 IU/mL) before subsequent stimulation with formyl-met-leu-phe.
      There was a dose-dependent increase in granulocyte activation as measured by
      myeloperoxidase release, quantitated in enzyme-immunoassay. This 'priming' effect
      of heparin was not due to activation of contaminating platelets or to endotoxin,
      and there was no reduction in granulocyte viability. Heparin-induced 'priming' of
      granulocytes may be clinically relevant in the setting of cardiopulmonary bypass.
      The author describes a sensitive and specific double antibody enzyme-immunoassay
      for myeloperoxidase from human granulocytes, with an inter-assay coefficient of
      variation of 12.6%, an intra-assay coefficient of variation of 4.3%, and a lower
      detection limit of 1.8 microg/l.

PMID- 8668918
TI  - Differential antigenic stimulation influences cytokine production patterns in T
      cells and CD4+ subpopulations.
AB  - The regulatory mechanisms that govern the commitment of T cells to a Th1 or Th2
      lineage in terms of cytokine production patterns have not yet been fully
      elucidated. The authors have endeavored to study the role of the antigen in
      regulating the production of cytokines. To study this matter, a panel of antigens
      was chosen to include two random poly amino acids, PA1 (Poly(1-Phe, L-Glu)Poly-dL
      Ala-PolyL-Lys), PA2 (Poly(Glu-NaAla), and two purified protein derivatives PPD1
      (H37Rv virulent) and PPD2 (H37Ra non-virulent) obtained from WHO strains of
      Mycobacterium tuberculosis. After in vivo priming, murine spleen cells were
      prepared and three groups of cells (unfractionated, T cells, and CD4+
      populations) were each separately stimulated in vitro with the original antigen
      Staphylococcal enterotoxin B (SEB) and phorbol myristate acetate (PMA). ELISA
      assays were subsequently performed on supernatants for IL-4, IL-5, IL-2 and IFN
      g. The results indicate a different cytokine pattern for the various antigenic
      stimulations. The PPD1 induced IL-5 production, while the PPD2 induced high
      levels of IFN-gamma. SEB was shown to exert a strong effect on the cytokine
      profile shifting it towards a Th1-like profile. A comparison is made between the
      cytokine patterns in different cells. The role of antigens and superantigens in
      regulating cytokine production and determining the outcome of the pathological
      process in relation to other regulatory factors is discussed.

PMID- 8668919
TI  - Humoral immune responses against particulate bacterial antigens are dependent on
      marginal metallophilic macrophages in the spleen.
AB  - Lymphoid organs are populated by different macrophage subpopulations. In the
      spleen, four subpopulations can be characterized using differences in, for
      example, morphology, localization, cell markers and repopulation kinetics after
      liposome-mediated depletion. The involvement of the different macrophage
      subpopulations in the immune response to particulate antigens was studied in vivo
      by intravenous injection of clodronate containing liposomes to eliminate the
      splenic macrophages, followed by immunization with trinitrophenylated Brucella
      abortus (TNP-BA; thymus-independent (TI)) or TNP-Lactobacillus acidophilus (TNP
      LB; thymus-dependent (TD)) at different time intervals. A strong decrease in the
      number of antibody-secreting cells (ASC) against TNP-LB was measured after
      elimination of all splenic macrophages. When TNP-LB was injected after
      repopulation of the red pulp macrophages (completed after 2 weeks), the ASC
      response was still strongly reduced. Restoration of the capacity to mount an
      immune response correlated well with the reappearance of the marginal
      metallophilic macrophages. It is concluded that this particular subset of
      macrophages is involved in the immune response to these particulate bacterial TD
      antigens. In contrast, the response against the particulate bacterial TI antigen
      TNP-BA was not impaired after depletion of splenic macrophages, although apparent
      changes in IgG isotypes were observed.

PMID- 8668920
TI  - Decrease in cAMP levels promoted by CD48-CD2 interaction correlates with
      inhibition of apoptosis in B cells.
AB  - The authors recently reported that CD2 ligation rescues B cells from antigen
      induced apoptosis by upregulation of intracellular Bcl-2 levels. However, the
      characterization of the early signals involved in apoptosis rescue by CD2
      ligation has not been well established. In this context, CD2 does not promote
      either phosphatidylinositol turnover or CA2+ mobilization in B cells. In this
      paper the authors show that CD2 interaction with its ligand CD48 also reduces the
      apoptosis induced by forskolin and the phosphodiesterase inhibitor 3-isobutyl-1
      methylxanthine and, to a much lesser extent, the apoptosis induced by cholera
      toxin in murine B splenocytes. Using a cAMP detection system sensitive to the
      picomolar range, the authors demonstrate that CD2-CD48 interaction decreases the
      intracellular cAMP concentrations induced by forskolin but not by cholera toxin.
      In comparison with the CD2-CD48 interaction, CD40-CD40 ligand interaction
      completely inhibits the apoptosis induced by cAMP increases without affecting the
      intracellular cAMP levels promoted by forskolin or cholera toxin. These results
      indicate that CD2 can also control the apoptosis at the very early steps after
      receptor signalling, such as the adenylate cyclase activity. Given that
      heterotrimeric G-proteins can mediate the adenylate cyclase activity the authors
      suggest that CD2 signalling could act through these small proteins, which would
      explain the inability of CD2 signalling to rescue from the apoptosis induced by
      cholera toxin, a Gs-protein activator. Conversely, CD40 seems to control
      apoptosis further downstream of the cAMP-PKA pathway where the survival and
      apoptotic signals are confluent, which might therefore render it a more efficient
      system to block apoptosis.

PMID- 8668921
TI  - Anti-oxidants inhibit the enhancement of the immune response caused by oil
      adjuvants.
AB  - Adjuvants are agents that can induce strong immunity to different antigens. They
      are thought to act mainly by stimulating macrophages, causing the release of
      cytokines, which in turn induce an inflammatory focus necessary for the adjuvant
      action. The authors found that catalase, ascorbic acid, N-acetylcysteine and
      glutathione are able to inhibit the enhancing effect of incomplete Freund
      adjuvant (IFA) and polyoxyethylated castor oil upon the humoral immune response
      to sheep red blood cells (SRBC). None of the anti-oxidants tested inhibited the
      basal immune response to the antigen. In addition, mice inoculated with different
      concentrations of hydrogen peroxide showed an enhanced response against SRBC,
      mimicking the effect observed with adjuvants. Delayed type hypersensitivity
      induced by SRBC in the presence of IFA was also inhibited by catalase. In
      conclusion, the report indicates that oxygen radicals are crucial molecules
      involved in the adjuvant effect observed in SRBC immunized mice.

PMID- 8668922
TI  - Suppression of tumour-specific cytotoxic T-cell responses against the syngeneic
      BALB/c plasmacytoma ADJ-PC-5 by tumour-induced CD8+ regulatory T cells via IFN
      gamma.
AB  - The mechanisms of tolerance induction by tumour cells during early stages of
      tumourigenesis were analysed in a murine model system using the highly
      immunogenic BALB/c plasmacytoma ADJ-PC-5. Early stages of tumourigenesis were
      simulated in syngeneic BALB/c mice by repeated intraperitoneal injections with
      subimmunogenic doses of X-irradiated ADJ-PC-5 tumour cells. This treatment causes
      a state of tumour-specific tolerance in a high percentage of mice, involving a
      population of CD8+ peritoneal T cells which are able to suppress a protective
      tumour-specific Tc response against this tumour. Using a primary mixed lymphocyte
      tumour cell culture (MLTC) as an in vitro system to study suppressive mechanisms
      of such regulatory T cells, the role of production or consumption of a number of
      cytokines was analysed. The data presented here demonstrate that inhibition of a
      protective Tc response against ADJ-PC-5 tumour cells is due to IFN-gamma
      production by suppressive T cells from tolerized mice, but not to IL-2
      consumption. In contrast to typical CD8+ Tc cells, ADJ-PC-5-specific CD8+ Tc
      cells do not produce IFN-gamma and are furthermore suppressed by IFN-gamma. Thus,
      tumour-induced suppressive T cells and tumour-specific Tc cells seem to represent
      functionally and phenotypically different subsets of CD8+ T cells, possibly
      pointing towards a differential activation of type-1 and type-2 CD8+ T cells
      depending on the dose of tumour cells.

PMID- 8668923
TI  - Adjuvant properties of montanide CSA 720 with a recombinant HIV P17 gag protein
      and synthetic peptide antigens.
AB  - The adjuvant properties of Montanide CSA 720 were assessed in a comparison with
      alum. BALB/c mice were immunized with recombinant HIV-1 gag protein p17
      administered in either of the two adjuvants. The serum antibody response to p17
      with Montanide CSA 720 appeared faster and reached a higher titre than with alum.
      The serum antibody response to p17 in Montanide CSA 720 was further characterized
      by a higher titre antibody directed against a 30 amino acid segment from the
      entire protein. The Montanide CSA 720 adjuvant was sufficiently strong to induce
      an antibody response against a weak synthetic peptide immunogen after two
      immunizations, while immunization with the peptide in alum generated no
      detectable serum antibody. The p17-specific proliferative response of splenocytes
      from animals immunized with recombinant protein in either adjuvant was similar.

PMID- 8668924
TI  - A non-competitive P55 TNF receptor antibody enhances the specific activity of
      lymphotoxin-alpha.
AB  - In the present study the authors elucidated the involvement of the two TNF
      receptors (TNFR) in discriminating TNF and lymphotoxin-alpha (LT-alpha) effects
      in human SW480-beta Gal and KYM-1 cell lines. A non-competitive p55 TNFR
      monoclonal antibody (MoAb) 44E strongly enhanced LT-alpha-mediated gene
      regulation and cytotoxicity up to the level of the responses caused by TNF. TNF
      induced biological responses were only weakly influenced by 44E. 44E did not
      affect both binding and the rate of dissociation of the cytokines. The
      combination of the two p55 TNFR MoAb 44E and Htr5 elicited strong TNF responses,
      while none of them were agonistic alone. When the p75 TNFR was blocked with Utr1,
      LT-alpha was still less potent than TNF in mediating CMV promoter activation and
      cytotoxicity. However, the addition of 44E in the presence of Utr1 merged the LT
      alpha dose-response curves with those obtained with TNF plus Utr1. Using
      antagonistic TNFR MoAb, the authors further showed that TNF functions through
      both TNFR types while LT-alpha mediates its effects largely via the p55 TNFR.
      These data suggest that LT-alpha is less potent than TNF due to its lower ability
      to properly trigger the p55 TNFR and because of its lack of signalling through
      the p75 TNFR.

PMID- 8668925
TI  - Inhibition by rapamycin of P-glycoprotein 170-mediated export from normal
      lymphocytes.
AB  - P-glycoprotein 170 encoded by the MDR-1 gene mediates export of substrates
      including some immunosuppressive drugs. Rapamycin was compared to cyclosporine A
      for its ability to inhibit P-glycoprotein on normal human peripheral blood
      mononuclear cells (PBMC). Rhodamine 123 dye efflux measures P-glycoprotein
      activity and inhibition of P-glycoprotein results in dye retention. Normal CD4+,
      CD8+ and B cells include a substantial subset with cyclosporine A-sensitive
      rhodamine efflux. Rh123 dye efflux is also inhibited by rapamycin at comparable
      drug levels used in transplant models. CsA is approximately 100-fold more
      effective on inhibition of PBMC P-gp than is RAPA. P-glycoprotein inhibition of
      ex vivo lymphocytes with three multi-drug resistant T-cell lines showed
      susceptibility of P-glycoprotein to rapamycin dependent on the cell type.
      Compared to cyclosporine A, the reduced ability of rapamycin to inhibit P
      glycoprotein reflects a reduced avidity in its binding to P-glycoprotein and
      perhaps increased access to the cell interior. The increased efficiency of RAPA
      as an immunosuppressive may in part be a result of its relatively low avidity for
      P-glycoprotein. The authors speculate that interactions with P-glycoprotein may
      partially modulate the immunosuppressive effects of rapamycin.

PMID- 8668926
TI  - Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to
      polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory
      bowel disease.
AB  - The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT
      alpha; TNF beta) are tandemly arranged in the central region of the MHC. They
      may, therefore, be of importance for the aetiology of MHC-associated diseases.
      The authors have prospectively studied the secretion of TNF alpha and LT alpha in
      relation to polymorphisms at positions -308 and -238 in the TNF alpha gene
      (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as
      well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and
      12 healthy controls. In the Dutch population, the alleles of these four
      polymorphisms are present in only five combinations, called TNF-haplotypes: TNF
      C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF
      alpha and LT alpha secretion were found when PBMC were cultured with T-cell
      activators, irrespective of disease. Mean TNF alpha secretion of individuals
      carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as
      compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml;
      P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount
      of TNF alpha (17 408 pg/ml; P=0.022). The TNF-C and TNF-E haplotypes differ only
      at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1
      associated TNF-I haplotype produced significantly less LT alpha when compared to
      those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the
      TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype
      thus defines a 'low secretor phenotype'. In conclusion, this is the first study
      to show associations between TNF haplotypes and TNF alpha and LT alpha secretion
      when T-cell stimulators are used. These findings will contribute to define
      disease heterogeneity in IBD and may be of relevance for understanding the
      pathogenesis of autoimmune diseases.

PMID- 8668927
TI  - Recognition of B-cell epitopes of the 65 kDa HSP in Behcet's disease.
AB  - B-cell epitopes of the mycobacterial 65 kDa heat shock protein (HSP) were mapped
      in sera from patients with Behcet's Disease (BD). A series of 47 overlapping
      synthetic peptides (15ers) derived from the sequence of the Mycobacterium
      tuberculosis 65 kDa HSP was used in ELISA. Significant increases in IgA and IgG
      antibody levels were observed with peptides 111-125, 154-172 and 311-326 in sera
      from BD, compared with those from controls. Homologous peptides derived from the
      sequence of the human mitochondrial 60 kDa HSP were then examined. Peptides 136
      150 and 336-351 showed comparable results to the homologous mycobacterial
      peptides 111-125 and 311-326, respectively. The B-cell epitopes defined in this
      investigation overlap with the T-cell epitopes the authors have previously
      reported in BD. Inhibition studies are consistent with the view that antibodies
      to each of the three B-cell epitope peptides represent a small proportion of the
      total B-cell epitope repertoire elicited by the 65 or 60 kD HSP. Sequential
      antibody studies suggest that IgA and IgG antibody titres to one or all three
      peptides tested may increase during exacerbation of ocular disease. The
      functional role of these antibodies needs to be determined, but the peptides may
      be involved in the immunopathogenesis of BD as they can induce experimental
      uveitis in Lewis rats, which is a principal manifestation of BD.

PMID- 8668928
TI  - Proceedings from the 5th International Cytomegalovirus Conference. Stockholm,
      Sweden, May 21-24, 1995.

PMID- 8668929
TI  - Cytomegalovirus after heart transplantation: definitions for the guidance of
      antiviral therapy.
AB  - Besides the current classification of cytomegalovirus (CMV) infection and disease
      we defined "CMV antigenaemia" as the marker for initiation of antiviral therapy
      (CMV hyperimmune globulin 2 ml/kg/d and ganciclovir 1000 mg/d), and "episodes of
      CMV antigenaemia"(the time from detection of antigenaemia until a subsequent
      antigenaemia assay tested negative again) indicated the time period of antiviral
      treatment. Patients were at highest risk for antigenaemia at day 38.2 +/- 20.9
      after heart transplantation. We observed 50 episodes of antigenaemia in 18
      patients. The mean duration was 7.3 +/- 6.4 days. No antigenaemia associated
      symptoms and no anti-CMV IgM was observed without preceding evidence of
      antigenaemia. Antigenaemia-associated symptoms and antigenaemia disappeared after
      antiviral therapy was initiated. Our therapy did not prevent CMV infection, but
      despite the repeated evidence of active CMV infection, no patient suffered CMV
      disease.

PMID- 8668930
TI  - Four dually resistant human cytomegalovirus strains from AIDS patients: single
      mutations in UL97 and UL54 open reading frames are responsible for ganciclovir-
      and foscarnet-specific resistance, respectively.
AB  - Four human cytomegalovirus strains with double resistance to both ganciclovir and
      foscarnet were recovered from acquired immunodeficiency syndrome (AIDS) patients.
      The four isolates were genetically unrelated and each of them consisted of a
      single viral population. In addition, for each isolate, UL97 and UL54 open
      reading frames sequencing showed a single aminoacid change in a conserved domain
      of each of the two genes.

PMID- 8668931
TI  - Immunoprophylaxis against cytomegalovirus disease.
AB  - Patients with either deficient or immature immune systems need protection against
      cytomegalovirus (CMV) disease. That maternal immunization prior to pregnancy will
      protect newborns from congenital disease is suggested by the fact that newborns
      who acquire CMV either via transfusion or transplacentally are relatively
      protected if their mothers had antibodies to CMV prior to pregnancy. For patients
      becoming partially immunocompromised following solid organ transplantation,
      protection against severe CMV disease is afforded by immunity acquired either by
      wild-type infection prior to transplantation or passive or active immunization.
      In three randomized placebo-controlled studies, live attenuated CMV vaccine has
      successfully protected seronegative recipients of kidneys from seropositive
      donors from severe CMV disease by efficiently inducing humoral and cellular
      immunity. Subunit vaccines comprised of glycoprotein gB, the viral component
      containing the majority of viral neutralizing epitopes, are in the early phases
      of study, as are strategies to provide patients with CD8+ deficiency
      immunoprophylaxis via adoptive transfer of cytotoxic T-cells expanded in vitro
      against CMV structural proteins. Given all of these facts, safe and effective CMV
      immunoprophylaxis against CMV disease is possible.

PMID- 8668932
TI  - Detection of human cytomegalovirus DNA: how, when and where?
AB  - Although several methods have been utilized for the detection and quantification
      of human cytomegalovirus (HCMV) DNA, all of them can be divided into three
      groups: (i) detection of HCMV DNA directly in tissues by in situ hybridization or
      in situ polymerase chain reaction (PCR); (ii) detection of HCMV DNA in cell or
      tissue lysates by hybridization with DNA or RNA probes differently labelled
      labels were progressively modified in order to provide an increasing sensitivity
      (hybridization products were revealed by radioactive, colorimetric or
      chemiluminescent procedures); (iii) detection of HCMV DNA in cell or tissue
      lysates by qualitative (single-step and nested) and quantitative
      (semiquantitative, competitive or noncompetitive) PCR. The selection of the
      methods to be employed depends primarily on the clinical situation which must be
      evaluated. Clinical samples for HCMV genome detection must vary accordingly.

PMID- 8668933
TI  - Regulation of human cytomegalovirus by retinoic acid.
AB  - Human cytomegalovirus (HCMV) may opportunistically use retinoic acid (RA), a
      physiologically essential control molecule of cellular differentiation, to
      advance its own replication. At present, it is not clear whether RA stimulation
      of HCMV replication is exclusively a differentiation driven event. We report that
      exposure of permissively infected primary human foreskin fibroblast cells to RA
      transcriptionally activates the viral major immediate-early promoter (MIEP) and
      enhances the production of infectious particles. These experiments implicate a
      direct involvement of RA in modulating HCMV activation.

PMID- 8668934
TI  - Direct DNA immunization of mice with plasmid DNA encoding the tegument protein
      pp65 (ppUL83) of human cytomegalovirus induces high levels of circulating
      antibody to the encoded protein.
AB  - The 65 kDa tegument protein (pp65 or rather ppUL83) of human cytomegalovirus
      (HCMV) has been shown to be a major cytotoxic T-lymphocyte target during natural
      infection, and thus appears to be an appropriate candidate to be evaluated as a
      component of a HCMV polynucleotide vaccine. We have constructed expression
      vectors pH beta-pp65, in which pp65 expression is under the control of human beta
      actin promoter, and pCMVint-pp65, in which pp65 expression is driven by the HCMV
      immediate-early promoter along with the intron A. These construct DNAs were
      utilized for the intramuscular injection into the quadriceps of BALB/c mice.
      Approximately 60% of the mice showed the presence of anti-pp65 antibodies
      following the second DNA inoculation with 100 micrograms of plasmid DNA. The anti
      pp65 antibody titer was higher in the group of mice that was injected with
      pCMVint-pp65 plasmid DNA compared to the group that was injected with pH beta
      pp65 DNA, presumably due to a higher level of pp65 expression using the former
      plasmid.

PMID- 8668935
TI  - Towards standardizations of CMV DNA PCR assays.

PMID- 8668936
TI  - Searching for antibodies specific for human cytomegalovirus: is it diagnostically
      useful? When and how.
AB  - Diagnosis of human cytomegalovirus (CMV) infection can be obtained by direct
      demonstration of the virus or virus components in pathological materials or
      indirectly through serology. Serological diagnosis gives only indirect evidence
      of the presence of the virus, and is problematic because of the immunological
      disorders occurring in most patients at risk of developing a CMV infection.
      Furthermore, antigenic reagents used in commercially available kits are not
      standardized and discordant results are often obtained. However, serology is
      cheaper than the other diagnostic tests, requires a short execution time, is safe
      and can be completely automated. Therefore, it is worthwhile exploring the
      possible application fields in which the use of serology is justified nowadays.
      This is what this review will attempt to do.

PMID- 8668937
TI  - The cytomegalovirus antigenemia assay: a plea for standardization.
AB  - Its high diagnostic accuracy, rapidity, quantitative nature and technical
      simplicity have made the cytomegalovirus (CMV) antigenaemia assay one of the
      cornerstone methods for diagnosis and management of active CMV infection in
      immunocompromised patients. Many technical variations have been introduced in an
      effort to optimize the assay. Now, standardization of the assay and quality
      control are becoming of increasing importance. In this review we first discuss
      the nature and origin of the CMV antigens in distinct blood cells during active
      CMV infection. Further, some of the most important technical variations of the
      assay are considered and a proposal for standardization is made to indicate how
      quality control might be achieved. Acceptance of these proposals by the
      international community would be an important step forward, e.g. towards
      multicentre antigenaemia-directed intervention studies.

PMID- 8668938
TI  - Cytomegalovirus genes: their structure and function.
AB  - During the past several years, studies have indicated that cytomegalovirus (CMV)
      genes can be grouped into two broad categories; those essential for replication
      in cell culture and those dispensible for virus replication. The latter group of
      genes are likely to be important for pathogenesis and host-virus interactions. As
      the field progresses, the need to utilize and establish biological systems
      capable of addressing gene function during a natural infection of cells in
      culture, or in the infected animal, is becoming more apparent. Herein, we
      describe the current status of some of those systems, what has been learned and
      where these studies may lead. Specifically, we address studies that assess
      mechanisms of gene activation and function in biologically relevant systems.
      These include (i) the identification of genes dispensible for replication in cell
      culture, (ii) the use of dispensible regions of the CMV genome to manipulate
      genetic information for assessing gene function and activation, and (iii) the
      identification of a related group of essential loci important for replication of
      human CMV (HCMV) DNA and what is presently known of the function of those genes
      during HCMV infection.

PMID- 8668939
TI  - Towards a definition of the HCMV entry pathway.

PMID- 8668940
TI  - Update on the 92.5 kDa putative HCMV fusion receptor.

PMID- 8668941
TI  - Cytomegalovirus persistence in macrophages and endothelial cells.
AB  - Although human cytomegalovirus (HCMV) rarely causes overt disease in healthy
      individuals, the virus can be a serious, even life-threatening problem in
      immunosuppressed or immune-deficient patients and in the setting of maternofetal
      primary infection. In recent years knowledge about HCMV pathogenesis has
      increased significantly. Identification of the cell types infected by HCMV in
      vivo has demonstrated that monocytes/macrophages and endothelial cells are key
      elements both in latent and acute infection with HCMV. Both cell types can be
      involved in systemic spread of virus and specific organ disease. While it has
      been demonstrated that differentiation of monocytes into macrophages renders
      these cells permissive to productive HCMV infection, there is presently limited
      knowledge about the pathogenesis of HCMV in endothelial cells (ECs). These cells
      represent the physiological interface between blood and tissues, display
      heterologous phenotypes, and are functionally variable, depending on their
      respective microanatomic environment. Microvascular ECs are the site of monocyte
      transmigration into organ tissues and therefore are likely to regulate the
      activation state of infected monocytes. Recently, macrovascular endothelium is
      receiving increasing attention due to its possible involvement in atherogenesis.
      In this overview we present recent findings on the role of monocytes/macrophages
      and endothelial cells in HCMV infection.

PMID- 8668942
TI  - Pathogenicity: animal models.
AB  - Animal models offer the opportunity to study the interaction of the virus and the
      host and to unravel the mechanism in processes such as persistence of the virus
      and virus-induced pathology. Primary infection results in a generalized infection
      as shown by the presence of virus in many organs. During viraemia the virus is
      present in mononuclear cells by which it is transported through the body. In
      neonates and in immuno-suppressed animals the infection results in multiorgan
      failure, leading to death. Recent data have shown that infection of endothelial
      cells in the microvasculature and mononuclear cells seems to be important in the
      pathogenesis of cytomegalovirus (CMV)-induced disease. After primary infection
      the virus persists in the body. Although the exact localization of the latent
      virus is unknown it is clear that during latency viral DNA is present in many
      organs. By immune suppression the virus can reactivate from its latent state. In
      addition to the direct complications attributable to the virus itself, CMV has
      modulating effects on the immune response. Although in some instances the
      infection leads to immune suppression, the virus infection can also accelerate
      inflammatory and immune responses. Studies in mice have shown that CMV infection
      can exacerbate graft-versus-host reactions, and experiments in rats using
      allogeneic transplants indicate that CMV infection results in enhanced chronic
      rejection in which acceleration of the immune response is involved. Although the
      exact mechanism is not clear, recent data indicate that cytokines, such as tumor
      necrosis factor alpha are involved in these processes.

PMID- 8668943
TI  - Induction of endothelial adhesion molecules by rat cytomegalovirus in allogeneic
      lung transplantation in the rat.
AB  - Cytomegalovirus (CMV) infection is known to be a major risk factor for the
      development of chronic transplant rejection in heart and lung transplantation. A
      possible mechanism for the induction of lung transplant rejection by CMV
      infection is the inflammatory upregulation of adhesion ligand molecules by the
      viral infection leading to an increased endothelial-leucocyte interaction. To
      study this question, an experimental model was established in the rat using a rat
      cytomegalovirus (RCMV) infection and acute lung transplant rejection in left
      single lung transplantation. The distribution of RCMV, intercellular adhesion
      molecule-1 (ICAM-1) and its leucocyte receptor CD11a (LFA-1) were investigated by
      immunohistochemistry. The viral infection was observed in transplant lungs of
      infected hosts as early as day 11. The expression of ICAM-1 on endothelial cells
      was induced and enhanced by RCMV infection, and infiltration of CD11a-positive
      leucocytes found to be increased in infected recipients. An acceleration of the
      rejection of the allografts by the hosts was found.

PMID- 8668944
TI  - Direct evidence using in situ polymerase chain reaction that the endothelial cell
      and T-lymphocyte harbor latent murine cytomegalovirus.
AB  - The latent viral genome, harbored indefinitely, threatens reactivation from its
      remote location. Although polymerase chain reaction (PCR) has detected the organs
      responsible for latency, it is not known whether latent cytomegalovirus (CMV)
      infection is maintained within organ-specific cells or ubiquitous elements such
      as macrophages, endothelial cells, or perhaps others. PCR lacks correlation with
      tissue structure. However, PCR-based in situ hybridization maintains cellular
      architecture while allowing the identification of the latently infected cells.
      Murine CMV (MCMV) nucleic acid sequences in organs of latently infected Balb/C
      mice were amplified by PCR incorporating digoxigenin-11-dUTP, holding the product
      DNA in situ (appropriate controls analyzed in parallel). Product DNA was then
      hybridized in situ with a biotinylated oligonucleotide probe for detection via
      streptavidin-alkaline phosphatase and light microscopy. Immunohistochemistry
      verified the positive cell types. Using this technique, we have shown directly in
      multiple organs of latently infected Balb/C mice including kidney (5/5), liver
      (5/5), and spleen (5/5) that the endothelial cell and/or T-lymphocyte harbor
      latent MCMV, whereas in uninfected animals, MCMV DNA was not detected. PCR-based
      in situ hybridization allows detection of the specific cell(s) harboring latent
      MCMV DNA while allowing conservation of cellular architecture.

PMID- 8668945
TI  - Cytomegalovirus latency and latency-specific transcription in hematopoietic
      progenitors.
AB  - Latency-associated transcripts have been detected in human cytomegalovirus (CMV)
      infected granulocyte-macrophage progenitors and have been shown to be encoded
      from both DNA strands in the ie1/ie2 region of the viral genome. One class
      includes differentially spliced transcripts that extends exon 1 by initiating at
      two novel start sites 292 and 356 nucleotides in the ie1/ie2 promoter/enhancer
      region, upstream of the start site used during productive infection. The other
      class includes an unspliced transcript antisense to ie1 exons 2,3, and 4. These
      transcripts are specific to latently infected cells and are not detected during
      productive infection of human fibroblast cells. Several open reading frames are
      found within these cytomegalovirus latency-specific transcripts (CLTs), including
      one 94 codons long that begins in the extended exon 1 region and is predicted to
      remain open through the exon1/2 and exon 2/3 splice junctions. Expression of
      latent transcripts was detected in bone marrow-derived hematopoietic samples from
      CMV-seropositive healthy donors but not from seronegative donors.

PMID- 8668946
TI  - The role of CD8+, CD57+ cells in human cytomegalovirus and other viral
      infections.
AB  - Peripheral blood lymphocytes expressing CD8 and CD57 determinants are a small (1
      15%) subset in healthy humans. CD8+, CD57+ peripheral blood lymphocytes may be
      divided by the level of CD8 expression, into CD8+high (CD57+) T-cells and CD8+low
      (CD57+) natural killer (NK) cells. CD8+high (CD57+) T-cell numbers are increased
      in human cytomegalovirus (HCMV)-seropositive subjects, and there is substantial
      evidence that HCMV is integral in the development of this subset in health and
      disease. Furthermore, the CD8+high (CD57+) subset is clonally derived, expressing
      a limited range of T-cell receptors, and are therefore likely to have restricted
      antigen specificity. Functionally, CD8+low(CD57+) cells exhibit NK activity,
      while CD8+high(CD57+) T-cells from healthy subjects mediate contact-dependent
      suppression in several in vitro systems including: (i) pokeweed mitogen-induced
      proliferation and immunoglobulin synthesis, and (ii) generation of antiviral MHC
      restricted cytotoxic T-lymphocytes. This is distinct from the nonspecific,
      soluble factor-mediated suppression exhibited from a phenotypically similar
      subset in human immunodeficiency virus (HIV) and bone marrow transplant
      recipients. This suggests an important immunoregulatory, suppressive role for
      CD8+high(CD57+) T-cells that may be potentiated by HCMV and altered in diseases
      associated with higher numbers of this subset including HIV, allograft recipients
      and rheumatoid arthritis.

PMID- 8668947
TI  - Interaction of human cytomegalovirus with p53: possible role in coronary
      restenosis.
AB  - Restenosis occurs in 25-50% of patients. Within 1-6 months after coronary
      angioplasty, excessive injury-induced smooth muscle cell (SMC) proliferation
      contributes to the development of restenosis; its causes remain unknown. The
      results of this study implicate human cytomegalovirus (HCMV) and HCMV-induced
      abnormalities in p53 function in the restenosis process. Almost 40% of restenosis
      lesions, obtained by atherectomy, demonstrated increased SMC p53 levels by p53
      immunopositivity; sequencing revealed the p53 to be the wild type. A strong
      correlation was found between p53 immunopositivity and the presence of HCMV DNA.
      Moreover, the HCMV IE84 protein co-immunoprecipitates with p53, and p53
      transcriptional capacity is reduced by IE84. Thus, HCMV may play a causal role in
      restenosis, which may be at least partly mediated by inhibiting p53 suppressor
      effects.

PMID- 8668948
TI  - Deletion mutants in human cytomegalovirus glycoprotein US9 are impaired in cell
      cell transmission and in altering tight junctions of polarized human retinal
      pigment epithelial cells.
AB  - Retinal cytomegalovirus (CMV) disease is one of the major manifestations of viral
      pathogenesis in immunosuppressed patients with the acquired immunodeficiency
      syndrome (AIDS). CMV infection of the retina causes directional destruction which
      begins at the optic nerve head adjacent to the retinal capillaries and
      progresses, if untreated, to retinal detachment and blindness. Infection does not
      occur across the basal membrane of the retinal pigment epithelium (RPE), adjacent
      to the highly vascularized choroid. CMV replicates in polarized RPE cells, and
      progeny virions cross apical and lateral membranes of RPE cells grown on
      permeable filter supports, but not basal membranes. Cell-cell junctions of CMV
      infected RPE cells are permeabilized, and the tight junction protein zonula
      occludens (ZO-1) is disassembled; progeny virions then spread to neighboring
      cells through the lateral cell membranes, which in polarized cells differ
      significantly in lipid and protein composition from the apical cell membranes. We
      found that CMV mutants with deletions in US9 and US8/US9 failed to spread from
      cell to cell, exhibiting a small-plaque phenotype in polarized RPE cells.
      Immunofluorescence confocal microscopy staining of ZO-1 protein revealed that RPE
      cells infected with CMV deletion mutants RV35, RV80, and RV61 did not exhibit
      altered tight junctions, in contrast to RPE cells infected with wild-type strain
      AD169 virus. Our findings indicate that US9, which is an accessory glycoprotein
      in infected foreskin fibroblasts, is required for transmission of virus across
      cell-cell junctions of polarized RPE cells. The relationship between US9
      expression and virus transmission across cell-cell boundaries suggests that US9
      may directly or indirectly permeabilize tight junction complexes of polarized RPE
      cells.

PMID- 8668949
TI  - Diagnosis of cytomegalovirus infection of the nervous system in AIDS by
      polymerase chain reaction analysis of cerebrospinal fluid.
AB  - To evaluate the diagnostic relevance and the clinical impact of the cerebrospinal
      fluid (CSF) polymerase chain reaction (PCR) for cytomegalovirus (CMV) DNA in the
      diagnosis of CMV infection of the central nervous system (CNS), 220 acquired
      immune deficiency syndrome (AIDS) patients with neurological disease were
      examined. CSF was drawn 1-180 days before death, concomitantly with clinical
      neurological disease, and autopsy was performed in all the cases. CMV DNA was
      detected in the CSF from 36 of 45 patients (82%) with CMV infection of the CNS,
      and in 2 of 175 without CMV infection of the CNS at autopsy. The sensitivity of
      the method was 82%, the specificity 99%, the positive predictive value 95%, and
      the negative predictive value 96%. An extensive CMV ventriculitis or encephalitis
      was shown by histopathology in the majority of the CSF PCR-positive patients with
      overt clinical encephalitis. Minor CMV lesions only, not likely to cause relevant
      clinical symptoms, were observed in some CSF PCR-positive patients, concomitant
      with other opportunistic CNS diseases. CSF PCR is a reliable means for diagnosis
      of CMV infection of the CNS in patients with AIDS. A positive PCR result,
      however, requires careful interpretation in the individual clinical context.

PMID- 8668950
TI  - CMV PCR in leucocytes as an early marker for the development of CMV disease in
      AIDS patients.
AB  - The relationship between cytomegalovirus (CMV) DNA in leucocytes and CMV disease
      in AIDS patients was sought. In 195 HIV-1 infected, mostly AIDS patients, CMV
      nPCR was performed in 477 peripheral EDTA blood samples which were collected also
      for CD4 cell counts (403), classic (410) and rapid virus isolation (270), and
      antigenemia tests (190). Most patients who died were autopsied.
      Immunohistopathology for CMV was performed. The first 43 patients were classified
      clinically according to having (A) verified organ involvement of CMV (15), (B)
      suspected CMV disease due to symptoms (4), or no CMV-associated disease (24). CMV
      DNA was detected in the majority of samples (66%) and patients (68%). In
      contrast, CMV in the samples was detected in only 16% by classical and 11% by
      rapid isolation and in 8.4% by the antigenemia test. Acquisition of CMV DNA in
      leucocytes became more common as the CD4 cell counts fell. Detection of CMV DNA
      was significantly associated with CMV-associated symptoms and later mortality. In
      conclusion, CMV PCR of DNA in leucocytes is a sensitive and early marker of CMV
      disease in HIV-infected AIDS patients. It might be a marker to be added to CD4
      cell counts for initiation of preemptive therapy.

PMID- 8668951
TI  - Update (1995) on clinical trials of antiviral therapy and prophylaxis for AIDS
      related cytomegalovirus disease.
AB  - An overview of the current state of antiviral therapy and prophylaxis for
      opportunistic cytomegalovirus (CMV) disease in 1995 is provided, focusing
      primarily on therapeutic trials for AIDS-related CMV retinitis. Retinitis is the
      most common serious CMV end-organ disease in AIDS; and it is the one for which
      clinical end-points can be measured most objectively and precisely. Standard
      antiviral chemotherapy for CMV retinitis consists of chronic intravenous
      treatment with either ganciclovir or foscarnet, each of which significantly
      delays loss of vision compared to no treatment. New agents such as HPMPC and new
      treatment strategies such as intravitreal ganciclovir may be more effective than
      standard treatment in delaying time to retinitis progression but are associated
      with serious toxicity problems. Preliminary data from a placebo-controlled trial
      of oral ganciclovir suggest that this agent reduces the risk of developing CMV
      end-organ disease by 50%; however, the implications of oral ganciclovir
      prophylaxis for development of antiviral drug resistance are unknown.

PMID- 8668952
TI  - Cytokines in rheumatoid arthritis. Localization in arthritic joint tissue and
      regulation in vitro.

PMID- 8668953
TI  - Towards understanding the pathogenesis of rheumatic fever.
AB  - Acute rheumatic fever results from an immunological response to group A
      streptococcal infection, but the exact nature of this response, and of the
      underlying host and organism characteristics, continues to evade researchers.
      Earlier models of rheumatic fever pathogenesis emphasised the importance of
      humoral immunity, but more recent work suggests that cellular immunity may play a
      primary role. Greater understanding of these disease mechanisms is allowing
      researchers to move towards the development of a vaccine for rheumatic fever.

PMID- 8668954
TI  - Rheumatoid arthritis in an Icelandic textbook from 1782.
AB  - In 1782, Jon Petursson, a district physician in Northern Iceland, published a
      textbook on arthritis and its remedies intended for common use. Working within a
      very simple diagnostic system, essentially comprising osteoarthritis (arthritis
      fixa) and inflammatory arthritis (arthritis vaga), he describes arthritis vaga as
      a common, chronic, symmetric, destructive, inflammatory polyarthritis, sometimes
      with systemic manifestations. It affected people of all ages with a peak
      incidence around forty, and had a female preponderance. The last observation is
      of particular interest as he knew he was contradicting all the available
      literature. Contemporary descriptions of Jon Petursson suggest that he may have
      had rheumatoid arthritis himself which would explain his excellent description of
      this disease.

PMID- 8668955
TI  - Smoking and outcome in ankylosing spondylitis.
AB  - In view of the recognised influence of smoking on the disease course of psoriasis
      and ulcerative colitis, and the association of these diseases with seronegative
      spondyloarthritis, we investigated a possible effect on outcome in ankylosing
      spondylitis. Thirtyone non-smokers, 12 exsmokers, and 10 smokers, with definite
      ankylosing spondylitis of a median duration of 20 years, were studied using
      clinical values (modified Schober, finger floor distance, total spinal movement),
      radiological (lumbar spine x-ray score), functional index, and laboratory
      assessment (ESR, CRP, Igs). There were statistically significant differences in
      the outcome between smokers and non-smokers for finger floor distance (p < 0.01),
      Schober test (p < 0.01), total spinal movement (p < 0.001), occiput-wall distance
      (p < 0.01), functional index (p < 0.01), stiffness (p < 0.01), and spine x-ray
      scores (p < 0.02). There was no statistically significant difference between the
      groups with regard to disease duration or age at onset. We conclude that smoking
      is associated with poor long term outcome in patients with ankylosing
      spondylitis.

PMID- 8668956
TI  - Raynaud's phenomenon in idiopathic carpal tunnel syndrome.
AB  - Both carpal tunnel syndrome and Raynaud's phenomonon are common conditions in the
      general population. These two different conditions frequently cause similar
      symptoms such as tingling, numbness, and "deadness of the fingers". They may also
      co-exist for instance in scleroderma or rheumatoid arthritis. In order to study
      the association, if any, between these two conditions, we studied 93 patients
      with idiopathic carpal tunnel syndrome confirmed in electro-physiological tests
      with 57 control subjects, for the presence of Raynaud's phenomenon by means of a
      previously validated questionnaire. Raynaud's phenomenon was detected
      significantly more frequently (P = 0.002) in patients with idiopathic carpal
      tunnel syndrome (36%) compared to control subjects (12%). Thus there appears to
      be an association between these two conditions. The mechanism for this is not
      clear. Sympathetic dysfunction may play a part. Practitioners should be aware of
      the similarity of the symptoms and the possibility that the two conditions may co
      exist.

PMID- 8668957
TI  - Characteristics of subjects with chronic pain, in relation to local and
      widespread pain report. A prospective study of symptoms, clinical findings and
      blood tests in subgroups of a geographically defined population.
AB  - The relation between reported chronic pain and clinical findings was studied by
      comparing survey data six months before and eighteen months after a clinical
      examination. Studied individuals (n = 165) were randomly selected from subsamples
      of an initial survey (n = 1806) to a general population. Among individuals
      reporting chronic pain 85% were assessed to have chronic pain at the examination.
      Diagnoses were found in 22% of examined pain individuals. Myofascial pain
      syndrome and myalgia were the most common findings. Compared with located neck
      shoulder pain, widespread pain had a greater impact on the individual, a worse
      prognosis regarding pain duration and working capacity, and revealed a raised
      serum urate level of unclear significance. Although no specific cause of pain is
      found in individuals with widespread pain it is important to identify and treat
      this group due to the great effects on functional capacity and the worse
      prognosis.

PMID- 8668958
TI  - Technetium-99m labelled human immunoglobulin scintigraphy predicts rheumatoid
      arthritis in patients with arthralgia.
AB  - The ability of 99mTc-IgG scintigraphy to predict the development of rheumatoid
      arthritis (RA) in 47 patients with arthralgia was investigated. 99mTc-IgG
      scintigraphy and the serum test for rheumatoid factor (RF), measured at the
      beginning of a year long study, were compared for their ability to predict RA.
      During the study 8 patients developed RA. The specificity and positive predictive
      values of RF in predicting RA were 79% and 50% respectively; and for 99mTc-IgG
      scintigraphy 97% and 88%. The sensitivity and negative predictive values of RF
      were 100% and of 99mTc-IgG-scintigraphy 88% and 97% respectively. In conclusion,
      99mTc-IgG scintigraphy has additional value to RF with respect to the prediction
      of the development of RA in patients with arthralgia.

PMID- 8668959
TI  - Comparison between scintigraphy with polyclonal immunoglobulin (99Tcm-HIG) and
      physical examination in polyarthritic disease.
AB  - 99Tcm-labelled polyclonal human immunoglobulin 99Tcm-HIG scintigraphy has been
      suggested as a technique to detect joint inflammation in arthritic disorders.
      Scintigraphy was performed in fifteen patients with active polyarthritis. All
      joints except the hips were scored clinically for swelling and pain by a
      rheumatologist and scintigraphic images were obtained at 30 minutes and four
      hours after injection of 350MBq 99Tcm-HIG. The images were assessed by a nuclear
      medicine physician according to a four grade scale. The images were easy to
      assess. There was a highly significant correlation between swelling and scan
      score, but no correlation between pain and scan score. The mechanism for the
      accumulation of activity to inflamed synovial tissue remains unclear. The mean
      values of the scan score however increased significantly between 30 minutes and 4
      hours, indicating an active binding mechanism. The method has a potential as an
      objective tool in monitoring rheumatic diseases.

PMID- 8668960
TI  - Autoantibodies to IL-1 alpha in sera from umbilical cords, children, and adults,
      and from patients with juvenile chronic arthritis.
AB  - Antibodies against interleukin-1 alpha (aAb-IL-1 alpha) have previously been
      demonstrated in sera of healthy adults and in patients with inflammatory
      diseases. In the present investigation the occurrence of aAb-IL-1 alpha was
      examined by second antibody precipitation technique in sera from umbilical cords
      (n = 11), children (n = 45), and adults (n = 20), as well as in 51 patients with
      juvenile chronic arthritis (JCA) of pauciarticular (n = 34), polyarticular (n =
      8), or systemic onset type (n = 9). RESULTS. The frequency of positive sera was
      significantly lower in children than in cord blood and adults as were the levels
      of aAb-IL-1 alpha (p < 0.0001). In the non-neonatal group of individuals the
      levels of aAb-IL-1 alpha correlated positively with age (r = 0.394, p = 0.0015).
      The frequency of sera positive for aAb-IL-1 alpha was higher in the JCA patients,
      as were the levels (p < 0.005), and correlated positively with disease activity
      as evaluated by joint score and visual analogue score.

PMID- 8668961
TI  - Effects of methotrexate, sulphasalazine and aurothiomalate on polymorphonuclear
      leucocytes in rheumatoid arthritis.
AB  - The aim of the study was to evaluate the effects of treatment with methotrexate,
      sulphasalazine and aurothiomalate on polymorphonuclear leucocytes (PMN) in
      rheumatoid arthritis (RA). Circulating PMNs from 58 RA patients treated with
      either methotrexate (n = 27), sulphasalazine (n = 16) or aurothiomalate (n = 15)
      were assayed for their chemotactic capacity and generation of superoxide anions.
      The expression of CD18/CD11b was measured for 17 RA patients treated with
      methotrexate. Chemotaxis and generation of superoxide anions were not affected by
      any of the three drugs. We found no difference in the expression of CD18/CD11b in
      RA patients treated with methotrexate compared to healthy subjects. Further
      methotrexate and aurothiomalate did not in vitro alter chemotaxis, generation of
      superoxide anion or expression of CD18/CD11b on normal PMNs. In conclusion we
      found no evidence that the effect of methotrexate, aurothiomalate or
      sulphasalazine in RA can be explained by modulation of chemotactic ability or
      superoxide anion generation of peripheral circulating PMNs.

PMID- 8668962
TI  - Intra-articular administration of polyclonal immunoglobulin G in rheumatoid
      arthritis. A double-blind, placebo-controlled pilot study.
AB  - The aim of our study was to assess local anti-inflammatory effects of high dose
      immunoglobulin G (IgG) in rheumatoid arthritis (RA). Eleven patients with
      definite RA, having flare-up of knee joint synovitis, were included in the study.
      Six received an intra-articular injection of 1 g of IgG in 10 ml saline and five
      received an intra-articular injection of 10 ml physiological saline alone. The
      effect of the treatment was evaluated clinically and by magnetic resonance
      imaging using gadolinium contrast enhancement. In one of the six patients that
      received intra-articular IgG and one of the five patients that received
      physiologic saline a modest decrease of synovial hypertrophy was noted. None of
      the patients experienced clinical signs of increased joint inflammation as a
      consequence of the treatment procedures. The results of this pilot, double-blind,
      placebo-controlled study do not support local administration of IgG as an anti
      inflammatory treatment in patients with RA.

PMID- 8668963
TI  - Prolonged remission of SLE-associated polyradiculoneuropathy after a single
      course of intravenous immunoglobulin.
AB  - Polyradiculoneuropathy is a rare and potentially severe complication of systemic
      lupus erythematosus (SLE). Treatment is not codified and response to
      corticosteroid is inconstant. We report the case of a patient with severe SLE
      associated polyradiculoneuropathy and autoimmune thrombocytopenia. Dramatic
      neurologic improvement and correction of thrombocytopenia were observed after a
      single course of high-dose intravenous immunoglobulin infusions (IVIg, 2g/kg body
      weight). Our case suggests that IVIg may be effective in the treatment of this
      unusual condition.

PMID- 8668964
TI  - Sapho syndrome associated with acne fulminans and prominent acromioclavicular
      joint involvement.
AB  - The clinical and radiological findings of a 33 year-old male patient with acne
      fulminans and associated SAPHO syndrome are described. The patient presented with
      prominent acromioclavicular joint involvement, unilateral sacroiliitis and
      subclavian vein compression which are relatively uncommon features of this
      syndrome.

PMID- 8668965
TI  - Idiopathic eosinophilic synovitis. Case report and review of the literature.
AB  - Eosinophilia of synovial fluid is an uncommon condition. The majority of the
      reported cases are associated to diseases such as rheumatoid arthritis, parasitic
      disease, hypereosinophilic syndrome, Lyme disease, and allergic processes as well
      as hemarthrosis and arthrography. Presently there are only four cases of
      eosinophilic synovitis with unknown cause. We are reporting a patient with
      oligoarthritis of the knees, massive eosinophilia, and Charcot-Leyden crystals in
      synovial fluid without associated cause. We review the clinical and biological
      features of eosinophilic synovitis and discuss its pathogenesis.

PMID- 8668966
TI  - Sudden onset unilateral renomegaly as an initial manifestation of primary
      Sjogren's syndrome in a teenage girl.
AB  - An 18-year old girl suddenly developed left-sided abdominal pain with otherwise
      normal clinical and urine examination. Ultrasound and computed tomography
      demonstrated a left renomegaly with uniformly normal structure without
      hydronephrosis, abnormal renal venous flow or ruptured extrauterine pregnancy.
      Renal biopsy showed lymphocytic interstitial nephritis, compatible with exocrine
      gland focus score abnormalities, consistent with those found in patients with
      Sjogren's syndrome. The renomegaly started to diminish after 10 days and the
      kidney reached normal size after 2 months. All objective tests for
      keratoconjunctivitis sicca and xerostomia were abnormal, although daily
      persistent dry eyes and dry mouth symptoms were absent. Serological tests showed
      high levels of anti-nuclear antibodies, anti-SS-A and anti-SS-B antibodies. Thus
      the patient fulfils the classification criteria for primary Sjogren's syndrome.
      The suddenly developed unilateral renomegaly may be an early clinical
      manifestation of this disease.

PMID- 8668967
TI  - Predictive value of rheumatoid factor isotypes for radiological progression in
      patients with rheumatoid arthritis.

PMID- 8668968
TI  - [Skin and hair].
AB  - Data deriving from comprehensive hospital monitoring systems suggest that drug
      induced skin effects occur in 2-5% of patients receiving any drug medication.
      Exanthematous (maculopapular) reaction (75%) and urticaria with/without
      angioedema (30%) are the most frequent of all cutaneous reactions to drugs. The
      incidence of cutaneous reactions relates to the quantity of the drugs which is
      prescribed and consumed worldwide. Thus penicillin, sulfonamides and nonsteroidal
      antiinflammatory drugs show the highest rate of cutaneous side effects. Drug
      reactions may be classified as either predictable (e.g. chemotherapy-induced
      alopecia) or unpredictable. Unpredictable side effects of drugs may be the result
      of allergic (type I to IV) or non-allergic reactions. Hereditary and acquired
      enzyme deficiency and variations in metabolic pathway may delay drug metabolism
      and cause nonallergic, toxic side effects. Such a mechanism is known to occur in
      patients with a low acetylation rate under hydralazine, INH or sulfonamide
      treatment. Some immunologic although nonallergic factors may facilitate eruptions
      in patients with infectious mononucleosis under ampicillin medication and in AIDS
      patients on co-trimoxazole therapy. When a cutaneous drug reaction is diagnosed,
      withdrawal of the drug is recommended. In instances in which patients display
      mild drug eruptions and no alternative therapy is available, the drug may be
      continued. However, it should be kept in mind that mild morbiliform eruption is
      often the initial presentation of toxic epidermal necrolysis. In AIDS patients
      sulfonamides most frequently have been implicated as a risk factor for the
      development of toxic epidermal necrolysis. In other than type 1 hypersensitivity
      reactions, skin testing and in vitro tests have low sensitivity and specificity.

PMID- 8668969
TI  - [Risks in diagnostic and therapeutic invasive cardiological procedures].
AB  - The risk of invasive cardiologic interventions being associated with morbid and
      mortal events is substantially related to the absolute numbers in whom these
      procedures are performed and this, in turn, is due to the epidemiologic
      significance of diseases of the cardiovascular system in industrialized
      countries. Diagnostic cardiac catheterization with coronary angiography is an
      invasive procedure with a relatively low risk of complications ( approximately
      1%) or death (approximately 0.1%). Percutaneous transluminal coronary angioplasty
      (PTCA), on the other hand, carries a risk of complications of approximately 4%
      and has a mortality of approximately 1%. The major source of complications with
      intracoronary stent implantations relates to their thrombogenicity with acute or
      subacute closure of the vessel (rate of complications 6-15%, mortality
      approximately 2%). In vessels of < or = 3 mm in diameter, the restenosis rate of
      a stenotic lesion treated with a stent approximates that of conventional PTCA
      (one third). Patients with reduced left ventricular ejection fraction are at
      substantial risk if treated with drugs instead of bypass surgery (better long
      term survival in the latter group.

PMID- 8668970
TI  - ["Arrhythmica" or: history, extent and practical consequences of pro-arrhythmia
      effects].
AB  - It has been known for many years that antiarrhythmic drugs may have a potential
      proarrhythmic effect. But it was not until two very important prospective studies
      were published, of Velebit et al. (1982) and in particular the CAST study (1989),
      that the extent and potentially deleterious consequences of the proarrhythmic
      effect were realized. This review attempts to lessen some doubts that have
      emerged in the management of antiarrhythmic therapy and the prophylaxis of
      cardiac arrhythmias, in particular for general practitioners and specialists in
      internal medicine. First, it is pointed out that the diagnosis "healthy heart" is
      only permissible after careful clinical investigation and in some cases special
      studies (e.g. echocardiogram). Reasonable therapy (or non-therapy) is then
      proposed for the current arrhythmias having regard to left (or right) ventricular
      function, the patient's age, the implicated disease and the individual
      circumstances. Electrotherapy (catheter ablation and implantation of a
      cardioverter-defibrillator) is mentioned as being superior to drug therapy in
      some patients with supraventricular and ventricular arrhythmias.

PMID- 8668971
TI  - [Iatrogenic falls].
AB  - One third of community-dwelling people, aged 65 years and over, experience a fall
      each year, and for institutionalized persons the fall frequency is 1.6 times a
      year. A fracture results in 5% of falls, one in five of which is a hip fracture.
      In view of this epidemic among the elderly it is obvious that preventive measures
      are needed. From the patient's history and the clinical assessment a risk of
      falls can be defined and this should influence decisions regarding drug
      treatment. Anamnestic data from relatives or neighbours can be important clues to
      the circumstances of a fall. Supine and standing blood pressure readings
      (orthostatic drop?) and testing of mobility provide relevant clinical
      information. To reduce the fall risk in elderly people, drug therapy should not
      induce daytime fatigue, sedation or drowsiness. Confusion and orthostatic blood
      pressure drop should be avoided. Long-term drug therapy should be modified or
      interrupted during acute illness. Electrolyte imbalance should be prevented.

PMID- 8668972
TI  - [Iatrogenic driving incapacity].
AB  - The most frequent reasons for iatrogenic incapacity to drive are unreported or
      untreated cases of alcohol and drug abuse, medication which impairs driving
      competence, and sleep-apnea syndrome. Some 50% of traffic injuries and fatalities
      in Switzerland would appear to be avoidable through a more consistent policy.

PMID- 8668973
TI  - [Trials with roentgen photography. 1896].

PMID- 8668974
TI  - [Vitamins and metals: possible hazards for humans].
AB  - Administration of vitamins or metals may cause severe side effects. Retinoids
      (derivatives of vitamin A) used for the treatment of various skin disorders are
      teratogenic, hepatotoxic and may induce a substantial increase in serum lipids. A
      case report demonstrates that vitamin D supplementation in a patient under total
      parenteral nutrition can cause hypercalcemia. The isolated administration of
      vitamin B1, without concomitant vitamin B6 and nicotinamide may precipitate
      potentially life-threatening pellagra encephalopathy. Repeat blood transfusions
      may produce clinically overt organ hemosiderosis, e.g. cirrhosis of the liver,
      diabetes mellitus or myocardiopathy. The literature contains reports on a few
      cases of sarcoma associated with orthopedic metal implants. The controversial
      issue of the potential dangers of dental amalgams is briefly mentioned.

PMID- 8668975
TI  - [Are there psychological factors which lead to iatrogenic disorders?].
AB  - Behind iatrogenic disturbances caused by psychological factors lies the
      dependence of present day medicine on the reductionist scientific paradigm of the
      18th century. The latter excludes psychological and social factors from the
      "scientific equation". Only absolute objectivity and neutrality in the observer,
      and the avoidance of personality and history in the patient, are held to be
      valid. The patient's individual reality, as influencing his individual
      physiology, is not considered. The results are errors in diagnosis (e.g. with
      patients suffering from chronic pain), abuse (including sexual) of women
      patients, and insufficient care of cancer patients. Psychological iatrogenic
      disturbances can be reduced by training medical students in biopsychosocial
      interrelations and by self-experience courses for physicians.

PMID- 8668976
TI  - [Nonsteroidal antirheumatic drugs and acetylsalicylic acid: adverse effects
      distal to the duodenum].
AB  - An increasing number of case reports and controlled trials have drawn attention
      to NSAID-induced side effects in the lower gastrointestinal tract. In this review
      we also report 9 cases of colonic ulcers and 7 cases of diaphragm disease of the
      ascending colon, most of them associated with the long-term intake of slow
      release diclofenac. NSAIDs not only can exacerbate preexisting conditions such as
      inflammatory bowel disease or diverticular disease, but may also induce de novo
      enteropathy, colitis, collagenous colitis ulcers and strictures. Complications
      such as bleeding, perforation or bowel obstruction may require surgery. From the
      literature and our own experience we conclude that the use of slow release
      formulations has shifted the toxicity of NSAIDs from the upper to the lower
      gastrointestinal tract. This must be considered in differential diagnosis and
      checked by endoscopy if appropriate.

PMID- 8668977
TI  - [Iatrogenic hyperkalemia].
AB  - Iatrogenic causes are important contributors to hyperkalemia in clinical
      practice. Most iatrogenic causes are drug-related, involving interference by the
      drugs with potassium metabolism at the level of renal handling and/or
      transcellular distribution of potassium. By discussion of the mechanisms of
      iatrogenic hyperkalemia it is hoped that the incidence of this potentially
      serious complication can be reduced.

PMID- 8668978
TI  - [Iatrogenic respiratory and sleep disorders and snoring].
AB  - Four different examples from the field of pulmonary and in particular sleep
      medicine are quoted to demonstrate how iatrogenic damage can be avoided or
      reduced. Teamwork and sound professional know-how are key elements in achieving
      this goal in this field.

PMID- 8668979
TI  - [Adverse effects due to unstable blood products].
AB  - Most discussions of blood transfusion cover risks and side effects, while the
      daily benefits of donor systems and transfusion concepts for modern medicine are
      taken for granted. Even though in this report side effects are a major part of
      the content, we should be aware that today's component concept leads to a
      remarkable quality level of blood products. After a historical introduction we
      present a patient with transfusion transmitted anti-hepatitis A IgM antibodies
      and a delayed type hemolytic transfusion reaction induced by a boostered anti-Fyb
      alloantibody. This case demonstrates that the safety of transfusions depends on
      both the blood product and the patient's transfusion history. In the second part
      we summarize side effects from transfused blood products: (1) transmission of
      infectious diseases and the risk of blood products testing falsely negative, (2)
      immune mediated side effects, (3) immuno-modulations by blood transfusions, (4)
      side effects caused by human error. Minimizing transfusion risks is not only the
      task of the doctors specialized in transfusion medicine, but can only be achieved
      by close cooperation between all the persons associated with each step, from
      motivating unpaid blood donors, evaluation of donors, phlebotomy, viral testing,
      preparation of components, storage, and transportation conditions, to adequate
      indications and transfusions for the patients.

PMID- 8668980
TI  - [Trials with roentgen photography. 1896].

PMID- 8668981
TI  - [Methotrexate treatment of rheumatoid arthritis].
AB  - Weekly low dose methotrexate has a beneficial efficacy: toxicity ratio compared
      to other disease-modifying antirheumatic drugs. Methotrexate shows one of the
      most pronounced effects on disease activity, with improvement of functional
      status and slowing of radiological progression of joint destruction. In addition,
      the short- and medium-term withdrawal rate is low and due to usually minor side
      effects. However, major complications such as interstitial pneumonitis, hepatic
      fibrosis and osteopathy deserve special attention, in particular during long-term
      treatment. Careful patient selection and monitoring, in close cooperation between
      the rheumatologist and general practitioner, contribute to optimal security of
      methotrexate treatment. The present overview summarizes scientific data and makes
      practical recommendations.

PMID- 8668982
TI  - [Candidiasis of the liver following successful chemotherapy of acute myeloid
      leukemia (Fab type 6) and recovery with oral fluconazole therapy].
AB  - The spectrum of disseminated candidiasis includes both an acute and chronic
      presentation. In contrast to the acute form, chronic disseminated candidiasis
      (hepatosplenic candidiasis) often occurs late after granulocytopenic episodes in
      patients undergoing chemotherapy, usually for acute leukemia. We discuss a female
      patient who underwent extensive successful chemotherapy for acute myelogenous
      leukemia (FAB type 6) and who developed chronic hepatosplenic candidiasis 19
      months later. Therapy with amphotericin B and flucytosine was not successful and
      a cure was effected only after long-term oral fluconazole treatment. Diagnostic
      problems, possible reasons for the observed failure of amphotericin B treatment,
      and the current use of fluconazole in disseminated candidiasis are discussed.

PMID- 8668983
TI  - [Idiopathic hypoparathyroidism--a rare disease?].
AB  - Five patients with nonfamilial idiopathic hypoparathyroidism were observed in a
      peripheral hospital. There was no association with other autoimmune disorders
      such as hypothyroidism, adrenal insufficiency or pernicious anemia. Only in one
      patient with tetany was the diagnosis clinically obvious; all the others
      presented with unusual clinical symptoms. These manifestations of chronic
      hypocalcemia are presented, as well as the diagnostic workup and therapeutic
      management. We suggest that idiopathic hypoparathyroidism is not a very rare
      disease, but one which is often missed because of the unusual clinical picture.

PMID- 8668984
TI  - [Cardiac pacemaker dysfunction secondary to outside interference: a review].
AB  - Electromagnetic signals from various sources may cause interference with
      pacemakers. The safety systems developed by manufacturers are generally
      effective. Nevertheless, some electromagnetic sources, particularly those found
      in the medical environment, can induce transitory or permanent pacemaker
      dysfunction. This paper presents the various sources of electromagnetic signals
      to which a pacemaker may be exposed. Taking into account the available
      literature, it attempts to clarify those which are really deleterious for the
      pacemaker and how to avoid them.

PMID- 8668985
TI  - Scientific imagination and integrity.

PMID- 8668986
TI  - Not the "Dark Ages".

PMID- 8668987
TI  - Tobacco research.

PMID- 8668988
TI  - Tobacco research.

PMID- 8668989
TI  - Disputed results now just a footnote.

PMID- 8668990
TI  - NASA life sciences. Panel backs joint Bion mission.

PMID- 8668991
TI  - Embryo report opens old wounds.

PMID- 8668992
TI  - Tobacco studies. UC objects to research restrictions.

PMID- 8668993
TI  - Evolutionary and systematic biologists converge.

PMID- 8668994
TI  - Protein matchmaker may lead new gene therapy to the altar.

PMID- 8668995
TI  - Putting prions to the test.

PMID- 8668996
TI  - The shrewd grasp of RNA polymerase.

PMID- 8668997
TI  - Rho returns: its targets in focal adhesions.

PMID- 8668998
TI  - On catching fly balls.

PMID- 8668999
TI  - On catching fly balls.

PMID- 8669000
TI  - Bioinformatics: new frontier calls young scientists.

PMID- 8669001
TI  - Aggressive behavior in childhood and early adolescence: an ecological
      developmental perspective on youth violence.
AB  - This article reviews recent research on the development of aggressive behavior in
      childhood and early adolescence using an ecological perspective that focuses on
      social development in the family, school, peer group, and community. Special
      emphasis is placed on family processes and early childhood peer relations that
      appear to tip developmental trajectories toward social rejection at school and
      use of aggression to achieve social goals in interpersonal relationships. The
      article discusses implications for preventing youth violence.

PMID- 8669002
TI  - Client self-determination and professional intervention: striking a balance.
AB  - Social workers find themselves caught in the cross fire between two imperatives:
      (1) outcome-oriented and competency-based practice requisites and (2) the
      principle of client self-determination. In this context, the authors hypothesize
      that social workers use a wide range of gradations along a continuum of practice
      directiveness. Furthermore, there is ethical justification for this diverse role
      repertoire. Directiveness modalities are influenced by specific conditional
      factors that guide practitioner behavior. A study is described that empirically
      explores and amplifies these hypotheses.

PMID- 8669003
TI  - A group design for HIV-negative gay men.
AB  - The social work and psychotherapeutic literature is replete with information on
      the psychosocial needs of HIV-positive gay men and gay men living with AIDS.
      However, scant information focuses on an often-overlooked population: HIV
      negative gay men. This article examines the development of a group design that
      addresses the unique psychosocial needs of HIV-negative gay men. A 12-week, time
      limited group focused on the effects of the AIDS epidemic on HIV-negative gay
      men's psychosocial functioning, including its potential exacerbation of common
      developmental issues such as exclusion, loss, survivor guilt, and lack of
      validation; the use of insight interventions and psychosocial problem solving;
      and the development of a working focus and group goals to improve psychosocial
      functioning in this population. Initial evaluations by group members using this
      design show promise; however, empirical evidence is essential to verify its
      effectiveness.

PMID- 8669004
TI  - Laparoscopic antireflux surgery.
AB  - Gastroesophageal reflux disease is very common, and there continues to be a need
      for gastroesophageal reflux surgery despite improved medical therapy. With the
      relatively new option of laparoscopic antireflux surgery, many more of these
      procedures are now being performed. In order to perform these well, one must
      select patients carefully, evaluate them fully, and adhere to the technical
      principles required to achieve consistently good results.

PMID- 8669005
TI  - Laparoscopic management of achalasia.
AB  - Cardiomyotomy for achalasia is one of the ideal procedures for the video
      endoscopic approach. Magnification of the operative field during laparoscopic
      surgery allows precise division of the muscle fibers with excellent results. The
      number of reports on cardiomyotomy performed with laparoscopic (and
      thoracoscopic) access is growing. They all show the same excellent results as for
      conventional (open) myotomy, with minimal morbidity, short hospital stay, and
      early return to routine activity.

PMID- 8669006
TI  - Laparoscopic splenectomy.
AB  - Dramatic decreases in length of hospital stay and time to complete recovery with
      laparoscopic cholecystectomy have led to the development of more advanced
      laparoscopic procedures. The rationale, technique, and early results with
      laparoscopic splenectomy are described in this article. Laparoscopic splenectomy
      is a complex procedure with a real potential for significant operative bleeding,
      but it can be accomplished successfully in greater than 80% of selected patients
      with minimal blood loss. If successful, length of stay is reduced in most
      patients to 1 to 3 days, but this benefit is not always seen in patients with
      complicated medical problems or with massive splenomegaly. The effects of
      increased blood loss in patients whose operations are converted to open
      operations are also not yet clear. Laparoscopic splenectomy is a procedure with
      great potential, but it is still in evolution.

PMID- 8669007
TI  - Laparoscopic appendectomy and the management of gynecologic pathologic conditions
      found at laparoscopy for presumed appendicitis.
AB  - A laparoscopic approach to patients with possible appendicitis has increased in
      popularity. In this article it is compared to the traditional open appendectomy,
      and the management of frequently found gynecologic pathology masquerading as
      appendicitis is described.

PMID- 8669008
TI  - Laparoscopic herniorrhaphy.
AB  - There is little doubt that laparoscopic herniorrhaphy has assumed a place in the
      pantheon of hernia repair. There is also little doubt that further work needs to
      be done to determine the exact role that laparoscopic hernia repair should play
      in the surgical armamentarium. Hernias have been surgically treated since the
      early Greeks. In contrast, laparoscopic hernia repair has a history of only 6
      years. Even within that short time, laparoscopic hernia repair techniques have
      not remained unchanged. This is obviously a technique in evolution, as indicated
      by the abandonment of early repairs ("plug and mesh" and IPOM) and the gradual
      gain in pre-eminence of the TEP repair. During the same time frame, surgery
      itself has evolved into a discipline more concerned with cost-effectiveness,
      outcomes, and "consumer acceptance." Confluence of these two developments has led
      to a situation in which traditional concerns regarding surgical procedures (i.e.,
      recurrence rates or complication rates) assume less of a role than cost
      effectiveness, learnability, marketability, and medical-legal considerations. No
      surgeon, whether practicing in a academic setting or a private practice, is
      exempt from these pressures. Laparoscopic hernia repair therefore seems to fit
      into a very specialized niche. In our community, the majority of general surgeons
      are only too happy to not do laparoscopic hernia repairs. On the other hand, in
      our experience, certain indications do seem to cry out for a laparoscopic
      approach. At our own center we have found that laparoscopic repairs can indeed be
      effective, and even cost-effective, under specific circumstances. These include
      completing a minimal learning curve, utilizing the properitoneal approach,
      minimizing the use of reusable instruments, using dissecting balloons as a time
      saving device, and very specific patient selection criteria. At present these
      include patients with bilateral inguinal hernias on clinical examination,
      patients with recurrent unilateral or bilateral hernias, and patients who,
      because of economic pressures, must return to work within 10 days of surgery.
      Within these limitations we feel that the laparoscopic approach definitely has a
      place in repair of inguinal hernias. In the future new techniques, decreased
      equipment costs, and the ability to use local anesthesia may increase the
      applicability of laparoscopic herniorrhaphy.

PMID- 8669009
TI  - Changing indications for laparoscopic cholecystectomy. Stones without symptoms
      and symptoms without stones.
AB  - In less than a decade, laparoscopic methods have dramatically improved the safety
      and convenience of cholecystectomy. As a result, the number of cholecystectomies
      performed nationwide has increased significantly. Whether this increase is a
      reflection of any major change in operative indications is unclear; the actual
      answer may vary from community to community. Silent gallstones continue to
      represent a sometimes contentious therapeutic dilemma. Because their natural
      history is unlikely to have changed, the management guidelines previously
      established for open cholecystectomy continue to have relevance today. Thus, it
      can be agreed that the majority of patients with silent gallstones do not require
      a cholecystectomy. The changing risk-benefit ratio suggests that some
      liberalization of these guidelines may now be in order. Already a number of
      transplantation surgeons have begun to recommend pretransplant cholecystectomy
      for asymptomatic patients who are found to have gallstones during screening.
      Available evidence also appears to support the use of pre-emptive laparoscopic
      cholecystectomy for other indications such as in selected women of childbearing
      age, young children, and patients with very large gallstones. The problem of
      silent gallstones in diabetics continues to be more enigmatic, but some
      complicated diabetics are probably best managed with operation. Other patient
      groups who are at high risk of having adverse outcomes from expectant management
      will be more precisely identified by future research efforts. Laparoscopic
      cholecystectomy should also be helpful in patients with various forms of
      acalculous biliary disease. However, special caution is advisable in approaching
      chronic acalculous cholecystitis until more specific and reproducible diagnostic
      methods are further validated.

PMID- 8669010
TI  - Endoscopic approaches to common bile duct injuries.
AB  - Operative injury of the biliary tree is not a new complication of cholecystectomy
      but has become increasingly more visible during the emergence of the laparoscopic
      approach. Optimal treatment of such problems depends upon early recognition and
      strategic planning of a therapeutic approach. ERCP has become increasingly
      important in identifying bile leaks and their source after cholecystectomy. A
      high index of suspicion is mandatory in patients complaining of discomfort
      several days after surgery, and liberal use of CT or ultrasound imaging helps
      identify bile leaks before peritonitis is severe. Once bile leaks or ductal
      injury are suspected, ERCP should be performed to confirm the leak, identify its
      site and cause, and help define a therapeutic plan. In minor leaks, endoscopic
      diversion by sphincterotomy or stenting provides a rapid solution. In more
      significant injuries where ductal integrity is intact, endoscopic dilatation and
      stenting may play a role in closing leaks and resolving strictures while averting
      surgery. Where injury is severe, ERCP, often combined with transhepatic
      cholangiography, helps to rapidly assess the extent of injury and plan a strategy
      for operative repair.

PMID- 8669011
TI  - Laparoscopic management of peptic ulcer disease.
AB  - Laparoscopic surgery has heralded a new era for the operative management of
      peptic ulcer disease. With a mean hospital stay of 3.5 days,22 a recurrence rate
      of 4% to 11%,1,3 and a morbidity from dumping and diarrhea of 1% to 2%,21
      laparoscopic proximal gastric vagotomy can truly provide a good alternative to
      medical therapy. Despite the high cost of medical care and surgical equipment, a
      laparoscopic vagotomy should be cost effective compared with life-long
      pharmacologic management of peptic ulcer disease. Several different operative
      procedures have been discussed, with similar outcomes. The surgeon has a choice
      of several approaches, depending on his or her training and level of skill. As
      surgeons gain experience with laparoscopic surgery, we are able to offer
      consistently good results with low recurrence rates and negligible morbidity and
      mortality. Minimally invasive surgery has rekindled the operative treatment of
      peptic ulcer disease.

PMID- 8669012
TI  - Laparoscopic adrenalectomy.
AB  - Laparoscopic adrenalectomy has become a viable option for removal of adrenal
      pathology and is becoming preferred over the conventional technique. With the
      conventional technique, many approaches are available, which vary according to
      pathology, diameter of the adrenal mass, location of the lesion, and patient
      morphology. Knowledge of anatomy is essential, because careful hemostasis and
      delicate tissue handling are necessary to make adrenal surgery a success.

PMID- 8669013
TI  - Laparoscopic pancreatectomy.
AB  - Laparoscopic access to the retroperitoneum is safe and feasible. Pancreatic
      resection requires complete familiarity with two-handed technique and knowledge
      of pancreatic anatomy. At present, only benign diseases should be approached
      laparoscopically, unless institutional review board approval exists for malignant
      disease.

PMID- 8669014
TI  - Laparoscopy in trauma.
AB  - Laparoscopy is a nearly century-old technique that has experienced a resurgence
      of interest from surgeons since the development of technology that has broadened
      its applications. Although laparoscopy has been used to evaluate patients with
      possible abdominal trauma, its use for this purpose is limited by the
      availability of other diagnostic procedures that may be more suitable for
      particular circumstances and are more accurate for certain injuries. Laparoscopy
      is contraindicated in patients who are hypovolemic or hemodynamically unstable
      and should not be performed in patients with clear indications for celiotomy. It
      may not be appropriate for patients with cardiac dysfunction, nor for those with
      significant head injuries who are at risk for intracranial hypertension. Its best
      applications may be in stable patients with stab wounds or those with tangential
      gunshot wounds of the abdomen. The likelihood of missing hollow visceral injuries
      depends upon the indications for conversion to celiotomy. If peritoneal violation
      or the presence of a small amount of blood in the peritoneal cavity is used as an
      indication for celiotomy, then the missed injury rate will be low but the
      unnecessary celiotomy rate will be diminished only slightly compared with a
      policy of mandatory celiotomy. Excessive enthusiasm for laparoscopy in trauma
      might result in its use when other diagnostic measures or simple observation are
      more appropriate. The desire to perform a procedure can be compelling, especially
      in circumstances in which the general surgeon would not operate upon a patient
      but simply provide postoperative care after other surgeons have operated. The use
      of laparoscopy for these purposes can only be condemned, as it increases the
      costs and risks of care without improving the outcome. The role of laparoscopy in
      trauma is evolving, and further research into its diagnostic role and therapeutic
      applications is clearly needed.

PMID- 8669015
TI  - Laparoscopy for staging and palliation of gastrointestinal malignancy.
AB  - The use of laparoscopy in the treatment of malignant diseases is one of the great
      advances of surgery in the last few decades. Its roles as a diagnostic modality,
      a staging tool, and a therapeutic avenue for the various malignancies of the
      abdominal cavity continue to expand. The benefits to cancer patients with regard
      to reduced morbidity and shorter hospitalizations are well established. As video,
      optical, insufflation, and instrumentation technologies advance further,
      laparoscopic techniques for the treatment of cancer can only multiply in depth
      and breadth.

PMID- 8669016
TI  - Laparoscopic colon resection.
AB  - Laparoscopic colectomy, usually performed in a laparoscopy-assisted fashion, is a
      technically difficult operation not easily mastered by the average surgeon and
      requiring a skilled team for its successful completion. There is a significant
      learning curve for the procedure, and conversion to open colectomy has been
      necessary in about 25% of cases in collected series. As such, its popularity has
      increased only slowly, and currently it is appropriate for treatment of benign
      colonic disease and as a palliative approach for unresectable carcinoma. Although
      the procedure produces an adequate tissue resection, concern about trocar site
      tumor recurrences has led to the general consensus that the procedure should
      currently be done only in a prospective investigational protocol setting for the
      treatment of curable colorectal carcinoma. These studies are expected to yield
      the data critically needed to assess its role in treating this disease.
      Experience to date suggests that laparoscopic colectomy can be performed with
      morbidity and mortality lower than or comparable to those of open colectomy. It
      likely is associated with less postoperative pain and a shorter hospitalization
      and has the potential for modestly more rapid recovery of gastro-intestinal
      function than open colectomy.

PMID- 8669017
TI  - Laparoscopic pelvic lymphadenectomy.
AB  - The most common laparoscopic procedure performed in urologic surgery today is the
      pelvic lymphadenectomy. A good understanding of basic laparoscopic technique and
      the anatomy of the pelvis will allow the surgeon to avoid pitfalls and lead to a
      successful operation.

PMID- 8669018
TI  - Flexible endoscopy as an adjunct to laparoscopic surgery.
AB  - The combination of flexible endoscopy and laparoscopy has allowed a creative
      approach to management of both benign and malignant gastrointestinal diseases.
      Historically, attempts to incorporate intraluminal endoscopy with laparoscopy
      were made early in the historical development of laparoscopy, especially as an
      aid to stage gastric cancer. The most common modern application is that of
      flexible choledochoscopy by laparoscopic cholecystectomy. Other innovative uses
      include localization of tumors, control of upper gastrointestinal bleeding,
      gastric tumor excision and biliary decompression, and bowel resection. With
      imagination guided by sound surgical principles, the combined use of laparoscopy
      and intraluminal endoscopy should expand the boundaries of general surgery.

PMID- 8669019
TI  - The difficult laparoscopy.
AB  - As others have emphasized, a progressive and structured training process is
      necessary to understand and avoid the potential pitfalls of laparoscopy. A
      surgeon who is poorly trained or has minimal skills and experience finds that
      many cases are "difficult." Nevertheless, even those with appropriate skill and
      experience encounter intellectual and technical challenges in laparoscopy. It is
      also very important to realize that some procedures simply should not be done
      laparoscopically. A review of 77,604 laparoscopic cholecystectomies documented
      that more than half the deaths were from technical complications occurring during
      the procedure. Traditional methods of surgery may have their own characteristics
      of limitations and morbidity, but in most cases, the old operation might still be
      a very good one in the face of unfavorable laparoscopic conditions.

PMID- 8669020
TI  - Training and privileging for new procedures.
AB  - Hands-on training for advanced laparoscopic procedures is more difficult to
      obtain than for basic laparoscopy, but because morbidity and mortality rates for
      these technically demanding procedures are higher, adequate training is essential
      and obtained, ideally, through a formal fellowship in advanced laparoscopy.
      Shorter preceptorships can provide adequate training but are more difficult to
      find. Few advanced laparoscopic procedures are experimental, but the safety of
      each must be ensured before a hospital awards privileges for their performance.
      Vigilance regarding local and national outcomes of these new procedures is
      essential in this rapidly evolving field.

PMID- 8669021
TI  - Reporting results of laparoscopic procedures. The state-wide registry approach.
AB  - The rapid development of technology facilitating minimally invasive surgery has
      challenged the surgical community to evaluate the safety and efficacy of these
      new techniques even as they were being widely utilized. The publication of
      retrospective series in a few institutions was followed by widespread adoption of
      laparoscopic cholecystectomy and subsequent reports of increased complications
      from the procedure. Other laparoscopic procedures such as antireflux operations
      and colectomy for cancer require greater technical skill and hold potential for
      significant morbidity. Because a prospective, randomized clinical trial is
      unlikely for these procedures, other measures of results need to be examined. A
      state registry is one such outcome study to be considered. In the state of Oregon
      we designed and implemented a voluntary registry program for these advanced
      procedures. Although the antireflux procedures are apparently being done safely,
      conclusions that can be drawn from such a registry are limited because of
      incomplete data collection. For a registry to be maximally effective, an
      automatic method of data accumulation is needed that will capture all cases that
      are done as well as follow-up information.

PMID- 8669022
TI  - The laparoscopic surgical value package and how surgeons can influence costs.
AB  - "Quality first and costs second" should be our motto. As surgeons we need to get
      involved with our procedures, but with the knowledge of the strengths and
      weaknesses of both outcome and cost analysis-that is, value assessment. The key
      to evaluating a procedure is to determine its value. This can be done only by
      physicians cognizant of the disease process and value assessment. The value is
      determined by assessing a procedure's utilization, outcomes, and costs.
      Utilization allows early treatment and avoids neglected disease. Therefore, the
      appropriateness of the utilization can be determined only by an outcome study. An
      outcome study is another term for quality assessment. Outcomes deal with
      morbidity, mortality, and the long- and short-term effects of the procedure.
      Overall, an increase of quality in a global perspective decreases the costs of
      the procedure to the health care community. Costs must remain secondary to
      outcomes. A cost analysis of LC has shown that surgeons can influence the
      majority of OR costs, and these are the direct variable type. Costs are usually
      not comparable between hospitals. Within each hospital, costs can be successfully
      used to assess efficiency and demand elasticity. An attempt to decrease costs
      directly is a maneuver that, when applied solely by nonmedical individuals, will
      most likely decrease quality. When the quality can be maintained (as assessed
      only by a practitioner), then a decrease in global costs increases value. The
      concept of increasing value by increasing quality without an attempt to decrease
      costs is a very important principle that the health care system must learn in our
      ever-challenging medical environment. Business administrators have decreased
      costs without consideration of quality assessment. Consider the additional impact
      of taking these cost savings and paying dividends to investors rather than
      reinvesting the monies into medical research or new technology. Quality declines
      first in patient choice, then referring physician choice, and finally short- and
      long-term results. When will this decline be apparent if quality assessments are
      not completed concurrently with cost analysis?

PMID- 8669023
TI  - Neurosurgery in 50 years.

PMID- 8669024
TI  - Progress in the management of patients with aneurysmal subarachnoid hemorrhage: a
      single hospital review for 20 years. Part I: Younger patients.
AB  - BACKGROUND: This study was carried out to clarify if there has been any
      improvement in the outcome of patients with aneurysmal subarachnoid hemorrhage
      during the past 20 years. Because elderly patients have apparently poorer
      prognoses than younger patients, patients older than 70 years were analyzed
      separately in the following article. METHODS: Five hundred seventy-one patients
      with aneurysmal subarachnoid hemorrhage, under 70 years, who were consecutively
      admitted to Kagawa Prefectural Central Hospital from July 1972 to December 1992,
      were reviewed. These patients were divided into four groups according to the time
      of admission. The ultimate outcome was evaluated by means of Glasgow Outcome
      Scale 6 months after the ictus. RESULTS: Changes in treatment protocol in this
      period included the induction of early surgery and the invention of a variety of
      modalities for the treatment of cerebral vasospasm. This resulted in a distinct
      increase in patients who actually underwent direct aneurysm clipping. Outcome has
      been significantly improved during this period, especially in patients with Hunt
      and Kosnik grade III (p<0.05, chi2). Patients in good clinical condition at
      follow-up (Glasgow Outcome Scale: good recovery) increased from 8.7% to 60.7%.
      Mortality decreased from 28.7% to 10.7%. CONCLUSIONS: Current therapeutic
      modalities have significantly improved the outcome of patients with aneurysmal
      subarachnoid hemorrhage. Rebleeding before early surgery remains as a major cause
      of unfavorable outcome and further progress on this subject is mandatory.

PMID- 8669025
TI  - Progress in the management of patients with aneurysmal subarachnoid hemorrhage: a
      single hospital review for 20 years. Part II: Aged patients.
AB  - BACKGROUND: We have reported improvement in the outcome of the younger patients
      with aneurysmal subarachnoid hemorrhage in the preceding article. The purpose of
      this article is to study if the same management protocol has simultaneously
      benefited the elderly patients. METHODS: One hundred twenty-nine patients with
      aneurysmal subarachnoid hemorrhage, over 70 years old, who were consecutively
      admitted to Kagawa Prefectural Central Hospital from July 1972 to December 1992,
      were reviewed. Patient grouping and outcome evaluation were the same as those of
      younger patients. RESULTS: Changes in treatment protocol in this period, which
      were similar to those of the younger counterparts, resulted in an increased
      number of patients who actually underwent aneurysm clipping. Although the outcome
      evaluated at 6 months after initial hemorrhage was significantly poorer than that
      of the younger counterparts, there have been some improvements during the study
      period. Patients in good clinical condition at 6 months' follow-up (Glasgow
      Outcome Scale: Good Recovery) increased from 37.5% to 42.9% in grades I-II and
      from 0% to 23.1% in grade III, respectively. CONCLUSIONS: The improvement in the
      outcome of elderly patients was less remarkable than that observed in younger
      patients. Significantly higher incidence of preoperative rebleeding and
      postoperative symptomatic vasospasm has proven to be the major cause of mortality
      and major morbidity at present. More careful and sophisticated perioperative care
      is required in elderly patients with aneurysmal subarachnoid hemorrhage.

PMID- 8669026
TI  - The ocular ischemic syndrome in carotid artery occlusive disease: ophthalmic
      color Doppler flow velocity and electroretinographic changes following carotid
      artery reconstruction.

PMID- 8669027
TI  - Intraradicular and intradural lumbar disc herniation: experiences with nine
      cases.
AB  - BACKGROUND: Intraradicular or intradural disc herniation is a very rare
      complication of spinal degenerative processes. The aim of our study is to analyze
      the clinical spectrum, the mechanism, and the treatment of this acute spinal
      pathology. METHODS: Retrospective clinical examination was performed in nine
      personal cases of intradural disc herniation: among these, six were associated
      with lateral perforation, the remaining three with intradural herniation and
      ventral perforation. A review of the literature concerning mainly the frequency
      pathogenesis and diagnosis of intradural disc herniation has also been done.
      RESULTS: Nine cases of intradural herniations comprise 1.51% of the 593 cases of
      ruptured lumbar disc that underwent surgery from 1980 to 1992. The site most
      frequently involved is at level L4-L5, and 30% of patients have previously
      undergone surgery for lumbar disc herniation. Most patients reported in
      literature and in our present series have been complaining of a chronic history
      of sciatica, complicated later by bilateral neurologic signs. In the present
      series, diagnosis was obtained by means of myelography and computerized
      tomography; magnetic resonance imaging was performed in one case. All patients
      underwent surgery, reporting excellent results in five cases and good results in
      the other four. Surgery was performed either with an interlaminar approach or
      with a bilateral laminectomy in cases of ventral perforation. CONCLUSIONS: There
      is no typical neuroradiologic picture of intraradicular herniation, while a total
      or subtotal block is frequently observed in intradural ventral perforations.
      Dural perforation is often an unexpected intraoperative finding. Surgical
      treatment is always necessary. Favorable results are obtained if surgical
      treatment is carried out before the neurologic deficit becomes too pronounced.

PMID- 8669028
TI  - Intraoperative stimulation of pedicle screws: a new method for verification of
      screw placement.
AB  - Pedicular fixation of the lumbosacral spine has become a popular procedure for
      improving fusion rates. Even in experienced hands, it can be associated with a
      significant rate of screw malpositioning and potential nerve root injury. In this
      report, we describe a technique for improving screw localization utilizing evoked
      electromyography responses from direct stimulation of pedicle instrumentation.

PMID- 8669029
TI  - Migration of bullet in the spinal canal: a case report.
AB  - As the spinal canal expands at T10 level naturally, it has been thought that the
      migration of a bullet within the spinal canal above this level is prevented and
      the migration of a bullet may only occur between T10 and S1 level. Here, a very
      rare case of a bullet traversing the length of the spinal canal is reported.

PMID- 8669030
TI  - The role of cytotoxic chemotherapy in the treatment of malignant brain tumors.

PMID- 8669031
TI  - Adenocarcinoma of Meckel's cave: case report.
AB  - A rare localization of adenocarcinoma in Meckel's cave is reported in a 58-year
      old woman, who had a 5-month history of pain and altered sensation in the second
      division of the left trigeminal nerve. Removal of the lesion was achieved by a
      subtemporal route. Histology showed this to be an adenocarcinoma. The patient
      underwent investigations for a primary tumor; the investigations were all
      negative, and the patient was subsequently treated with a course of radiotherapy.
      At 4-month follow-up, there was no evidence of recurrence, and she remains
      symptomatically well. The various mechanisms of secondary localization are
      discussed.

PMID- 8669032
TI  - Intracranial meningeal melanocytoma: case report.
AB  - A case of meningeal melanocytoma of the left sphenoid wing is reported and the
      other nine cases in the literature are reviewed. Meningeal melanocytoma is a
      benign melanotic tumor that derives from the melanocytes of the leptomeninges and
      may occur anywhere in the cranial and spinal meninges. Electron microscopy well
      demonstrates melanin and melanosomes within the tumor cells. The
      immunohistochemical pattern of this tumor includes strong positivity for S-100
      protein, vimentin, and antimelanoma antibody and negativity for epithelial
      membrane antigen, neuron-specific enolase, cytokeratin, and glial fibrillary
      acidic protein. Complete surgical removal is the treatment of choice, whereas
      radiotherapy is usually unnecessary. In spite of benign biologic behavior of
      meningeal melanocytoma, the prognosis remains uncertain, because of the possible
      local recurrences.

PMID- 8669033
TI  - Successful removal of large pineal region meningiomas: two case reports.
AB  - BACKGROUND: Pineal region meningiomas are extremely rare tumors and comprise
      about 8% of tumors of this region. Two cases of large pineal region meningiomas
      in young males are presented. METHODS: Computed tomography (CT) scan and cerebral
      angiography were used to evaluate the patients preoperatively. Both patients were
      operated on through an occipital transtentorial approach either as a single- or
      two-stage procedure. RESULTS: Preoperative work-up revealed that both tumors
      received their main blood supply from the posterior lateral choroidal arteries
      and were therefore originating from the velum interpositum cerebri (superior tela
      choroidea). Complete tumor removal was effected in the first patient using a
      right occipital transtentorial approach. In the second patient, after partial
      removal using the same approach, complete resection was achieved at a second
      stage via the left occipital transtentorial approach 3 months later. CONCLUSION:
      Cerebral angiography, which must include vertebral angiography, is important in
      the preoperative surgical planning of these tumors. The occipital transtentorial
      approach provides good access. However, a two-stage procedure using right and
      left sides may be necessary for large meningiomas receiving a bilateral blood
      supply from both posterior lateral choroidal arteries. Diagnosis, the surgical
      approach, and methods of tumor excision are discussed.

PMID- 8669034
TI  - Resection of olfactory groove meningiomas: technical note revisited.
AB  - BACKGROUND: Although large olfactory groove meningiomas present in the midline,
      tumor volume is often unequally distributed to one side. Most surgeons favor a
      bifrontal craniotomy with retraction or partial resection of the frontal lobes to
      resect these tumors. However, frontal lobe retraction is not without
      complications. METHODS: We present a technical note regarding the resection of
      these large olfactory groove meningiomas. We describe the advantages of a
      unilateral frontal craniotomy complemented with orbital osteotomy. RESULTS: The
      orbital osteotomy has considerably reduced the need for frontal lobe retraction
      and avoids partial resection of the frontal lobe to uncap the tumor. Utilizing
      this approach we have been able to remove the tumor from one side, followed by an
      incision to the falx cerebri in order to remove the tumor from the other side.
      With this approach, we have gained excellent visualization of the tumor in its
      entirety. Moreover, this approach permits the surgeon to intercept the arteries
      emerging from the skull base during the initial stages of the procedure.
      CONCLUSIONS: Unilateral frontal craniotomy and orbital osteotomy has obviated the
      need to retract or resect the frontal lobe when resecting large olfactory groove
      meningiomas, which extend to either side of the falx. Because surgery is
      performed from one side, olfaction may also be preserved on the contralateral
      side.

PMID- 8669035
TI  - The effect of the treatment of high-dose methylprednisolone on Na(+)-K(+)/Mg(+2)
      ATPase activity and lipid peroxidation and ultrastructural findings following
      cerebral contusion in rat.
AB  - BACKGROUND: Although use of corticosteroid in the management of head trauma has
      caused a great deal of controversy, corticosteroids have long been an adjunct in
      the management of severe closed head injury. The glucocorticoid steroid
      methylprednisolone (MP) has been proven to have significant antioxidant effect
      when administered in an antioxidant-high dose after central nervous system
      injury. METHODS: The sodium-potassium activated and magnesium dependent adenosine
      5'-triphosphatase (Na(+)-K(+)/Mg(+2) ATPase EC.3.6.1.3.) activity, lipid
      peroxidation, and early ultrastructural findings were determined during the
      immediate posttraumatic period in rats. Mechanical brain injury was produced when
      a calibrated weight-drop device is allowed to fall on the skull's convexity over
      the right hemisphere, 1 to 2 mm lateral from the midline. In group I, rats were
      used to determine Na(+)-K(+)/Mg(+2) ATPase activity, the extent of lipid
      peroxidation, by measuring the level of malondialdehyde content and normal
      ultrastructural findings in two different brain areas (cerebral cortex and brain
      stem). In group II, physiologic saline was administered right after trauma in the
      same amount as methylprednisolone. In group III rats, methylprednisolone (30
      mg/kg) was administered intravenously right after trauma. RESULTS: Na(+)
      K(+)/Mg(+2) ATPase activity significantly decreased in the cerebral cortex and in
      brain stem within 2 hours after trauma (p < 0.05). There was significant
      difference in malondialdehyde content between groups II and III (p < 0.05).
      Methylprednisolone treatment reduced malondialdehyde content and induced the
      recovery of Na(+)-K(+)/Mg(+2) activity. CONCLUSIONS: These data suggest that
      inactivation of Na(+)-K(+)/Mg(+2) ATPase is closely correlated to changes of
      lipid peroxidation and the alteration of the ultrastructural findings in the
      early phases after head trauma. The glucocorticoid steroid methylprednisolone has
      been proven to have significant effect in activation of Na(+)-K(+)/Mg(+2) ATPase
      with significant reduction of malondialdehyde content.

PMID- 8669036
TI  - What is metanalysis?

PMID- 8669037
TI  - Frontal lobe ataxia.
AB  - BACKGROUND: Gait abnormalities often result from disorders intrinsic to the
      cerebellum. Gait difficulties resulting from frontal lobe disease are less common
      but well recognized. The pathophysiologic mechanism of this type of ataxia is not
      well understood. One promising explanation implicates involvement of the
      frontopontocerebellar tract (Arnold's bundle). This tract originates in the
      frontal lobe in Brodmann's area 10 and carries information on intended movement
      to the contralateral cerebellum via the pontocerebellar peduncle. Interruption of
      this tract deprives the cerebellum of this information, thus impairing
      coordination and locomotion. METHODS: A patient is described with a large
      bilateral, medialorbital, frontal lobe lesion, progressive gait impairment, and
      dysarthria. The lesion is defined by magnetic resonance imaging (MRI) and
      positron emission tomography (PET) using 18-fluorodeoxyglucose. The cystic
      component of the lesion was drained surgically. RESULTS: The PET scan using 18
      fluorodeoxyglucose showed a normal metabolic rate in the brain stem, a 10%-15%
      decrease in metabolism in the thalmus and a symmetric decrease of only 15% in the
      cerebellum bilaterally. The MRI of the cerebellum did not show any significant
      atrophy. The patient's speech improved, but there was minimal change in her gait
      ataxia after surgical drainage and partial removal of the cystic frontal lobe
      lesion. CONCLUSIONS: The patient's syndrome supports the view that frontal lobe
      ataxia is an established although rare clinical entity, and this report adds
      original information defining the syndrome with MRI and PET studies. The 15%
      metabolic decrease in the cerebellum with PET is highly supportive of the
      syndrome of frontal lobe ataxia and not pathology intrinsic to the cerebellum.
      The syndrome of frontal lobe ataxia in this patient is due to interruption of the
      frontopontocerebellar pathway originating in Brodmann's area 10.

PMID- 8669038
TI  - Advice to young neurosurgeons.

PMID- 8669039
TI  - The future: is it cost-effective?

PMID- 8669040
TI  - [Daylight processing system in radiotherapy. Technical changes and cost benefit
      analysis].
AB  - BACKGROUND: In radiotherapy portal and verification imaging take an important
      place in daily quality assurance procedures. Different types of films and
      cassettes have to be used to gain an optimal result for photon and electron
      beams. MATERIALS AND METHODS: We describe a modification of a machine for
      daylight processing, which has been technically enabled not only to process all X
      rays from simulator, brachytherapy, CT and MRI but all film materials from portal
      and verification imaging as well without changing system's configuration. Using a
      light gap, verification films are automatically differentiated from portal films
      or from film material from simulation and the cassettes are automatically loaded
      with the new verification film. Furtheron, we took some attention on cost
      effectivity. RESULTS: The daylight processing machine is sufficiently integrated
      into daily routine work load and spares a lot of staff time. Higher primary costs
      are overbalanced within a few years by lower supporting costs (Table 1). This is
      especially due to lower film material costs (Table 2), but also a result of staff
      time reduction. CONCLUSIONS: Radiotherapeutic departments may gain much comfort
      using a daylight processing machine as development unit.

PMID- 8669041
TI  - [Local recurrences of soft tissue sarcomas in adults: a retrospective analysis of
      prognostic factors in 102 cases after surgery and radiotherapy].

PMID- 8669042
TI  - [Radiotherapy and/or chemotherapy in children with primitive neuroectodermal
      tumor (PNET) of the pineal region].

PMID- 8669043
TI  - [Pathological findings from the National Surgical Adjuvant Breast Project (NSABP)
      Protocol B-17. Intraductal carcinoma (ductal carcinoma in situ)].

PMID- 8669044
TI  - [Intraductal extension of primary invasive breast carcinoma treated by breast
      conservative surgery].

PMID- 8669045
TI  - [Mathematical models and computer simulations: a useful tool or a confusing game?
      Concerning the editorial by H.P. Beck-Bornholdt and H.H. Dubben in Strahlenther.
      Onkol. 171 (1995), 473-474 (No. 8)].

PMID- 8669046
TI  - [Acute gastrointestinal side effects of radiotherapy. What is certain in the
      treatment?].
AB  - PURPOSE: Radiotherapy, especially in the abdominal region, is frequently
      associated with gastrointestinal side effects. METHODS: The article reviews the
      current knowledge about pathophysiological background, clinical symptoms and the
      treatment strategies of the major gastrointestinal side effects. RESULTS: Several
      basics are investigated and depending on this knowledge some special treatment
      strategies have been developed (5-HT3-receptor-antagonists in the treatment of
      nausea, Figure 1, Table 2). The treatment of stomatitis, esophagitis, enteritis
      and proctitis still remains symptomatic and is not yet standardized (Tables 3 to
      6). There are some promising results with smectit (enteritis) and sucralfat.
      Special dental attendance should be performed before initiating radiotherapy of
      the head and neck region. Technical improvement in radiotherapy will also help to
      reduce side effects. CONCLUSION: In order to minimize gastrointestinal side
      effects, it is necessary to further investigate the pathophysiology of acute and
      late toxicity.

PMID- 8669047
TI  - [Results of radiotherapy in recurrences of soft tissue sarcomas].
AB  - PURPOSE: Published data for radiotherapy in soft tissue sarcomas refer in most of
      the cases to the use of irradiation for primary tumors. Experiences of
      radiotherapy in local recurrences are limited. The own treatment results of a
      multimodal treatment approach in a large number of patients will be analyzed for
      local tumor control rates, survival rates, side effects and prognostic factors
      and will be compared to the literature. PATIENTS AND METHODS: At the University
      Hospital Hamburg-Eppendorf a total of 98 patients with local recurrences of soft
      tissue sarcomas were irradiated between 1980 and 1993. The median age of the
      patients was 55 years. There was a large variety of different histologies.
      Grading was evaluable in 95 cases: G1 24 patients, G2 21 patients and G3 50
      patients. Localisation was dominated by the extremities with 64.3%. Recurrences
      were reclassified: 21 patients had rT1-tumors and 77 patients had rT2-tumors.
      Twelve cases showed lymph node metastases and 9 patients distant metastases.
      Generally treatment included surgery and postoperative irradiation. R
      classification showed R0 in 25, R1 in 20 and R2 in 48 cases. Neutrontherapy was
      prefered in 57 cases and neutron- and photontherapy in 22 cases. Local tumor
      control rates and survival rates were calculated using the Kaplan-Meier method.
      Side effects were scored using the RTOG/EORTC scoring system. Univariate and
      multivariate analyses were applied to evaluate prognostic factors. RESULTS: Local
      tumor control rates at 5 years were 56.4%, for G1 75.2%, G2 52.5%, G3 47.1%, rT1
      66.0%, rT2 53.6%, R0 63.4%, R1 42.3% and R2 53.2%, N0 61.1% vs. N1 31.7%.
      Survival rates at 5 years were 45.2%, for G1 64.8%, G2 66.9%, G3 25.0%, rT1
      60.0%, rT2 41.5%, R0 64.2%, R1 49.3% and R2 32.7%. Acute side effects were scored
      as grade 1 and grade 2. The rate of grade 3 and 4 late effects was about 6%.
      Lymph node status was a significant factor for local control. Grade, residual
      tumor status, type of irradiation and the applied neutron dose were significant
      factors for survival. CONCLUSIONS: Nowadays no standard treatment exists for
      local recurrences of soft tissue sarcomas. Treatment should be interdisciplinary.
      Local recurrences should be avoided by the consequent use of surgery and
      radiotherapy. It is important that local recurrences should be detected early.
      Neutrontherapy may bring advantages for local control of recurrences with
      macroscopic tumor residuals.

PMID- 8669048
TI  - [Total skin electron beam irradiation in cutaneous T-cell lymphoma].
AB  - PURPOSE: Patients with cutaneous T-cell lymphoma are treated in Germany mostly by
      dermatological local therapy like corticosteroids or PUVA-irradiation. Total skin
      electron beam irradiation is used rarely, even though it has a potentially
      curative character. We present an analysis of patients, who received a total skin
      electron beam irradiation after having progressive disease following other
      treatment modalities. PATIENTS AND METHODS: Twenty-one patients (mean age 58.9
      years) in different stages were treated (stage IB and IIA n = 4, stage IIB n = 8,
      stage III n = 3, stage IV n = 6). All patients had progressive disease under
      other forms of local therapy. The irradiation was performed from 6 directions per
      hemibody using 2 axial fields which have each an 18 degree angle to the
      horizontal level. Six and 7 MeV fast electrons were used. Total dose was between
      8 and 36 Gy in single dosis of 1 x 4 up to 5 x 2 Gy per week. In underdosed areas
      and areas of tumors of the skin boost irradiation with small fields was given.
      RESULTS: All patients had a good tumor regression (complete remission: n = 10,
      partial remission: n = 11). With the follow-up between 4 and 93 months total- and
      recurrence-free survival was 18 and 7 months (median). Patients in early stages
      with slow but complete remission of the symptoms had the best prognosis. Because
      of the small case number there was no significant difference between the groups.
      There were no severe side effects of the radiotherapy noted. CONCLUSION: Our
      analysis shows on a small patient number, that total skin electron beam
      irradiation has a good palliative effect on patients who have progressive disease
      following other types of treatment like PUVA or corticosteroids. The recurrence
      free survival of 2 out of 4 patients with early stage disease (I-IIA) up to 93
      month shows the potentially curative character of the treatment.

PMID- 8669049
TI  - [Local efficiency of percutaneous radiotherapy in lung cancer. Analysis of 215
      repeated bronchoscopies in relation to applied radiation dosage].
AB  - PURPOSE: During a locoregional radiotherapy with curative attempts of lung cancer
      patients bronchoscopic examinations with biopsies and/or cytologic lavages were
      repeated to assess the accuracy of limiting the total dose to 60 Gy. In order of
      the applied dose macroscopic changements of the endoluminal tumor and microscopic
      elimination should be made out. The correlation between macro- and microscopical
      regression should allow a statement about reliability of single results. The
      clinical course and a conventional thoracic X-ray examination seemed to be a to
      large-meshed screen to evaluate the effect at the end of therapy. The aim was to
      improve the criterias of success and to adapt and optimize the radiation dose
      individually. PATIENTS AND METHODS: The prospective, together with the
      pneumologists, defined treatment concept included the repetition of bronchoscopic
      evaluations after the application of 60 Gy and 80 Gy. These radiation doses from
      60 Gy up to 80 Gy have been given with a shrinking-field technique to the
      mediastinum and the primary. In order to record statistically the optical tumor
      changements we were urged to create a so-called bT-score. The structure of this
      score was orientated towards the periphery of the tracheobronchial tree. RESULTS:
      Hundred and forty-four patients with endoscopically and histologically verified
      bronchogenic carcinomas were treated. On the subjects 215 re-bronchoscopies
      accomplished with biopsies were performed and allowed to analyze the macro- and
      microscopical behavior under treatment. A histological/cytological elimination of
      tumor was achieved after 60 Gy in 35.1%, after 80 Gy in 62.3%. Macroscopically no
      tumor was visible after 60 Gy in 43.6%, after 80 Gy in 82%. A correlation between
      identical micro- and macroscopical observations was only seen in 61%,
      respectively in 71%. CONCLUSIONS: The escalation of the radiation dose from 60 Gy
      up to 80 Gy with shrinked fields could increase the local tumor sterilization
      rate by 1.8 times from 35.1% to 62.3%. The refining and completion of usually
      known parameters by endoscopical and histological examinations seems to be an
      acceptable way to define individual radiation doses. The quality of the performed
      therapy can be better determined. A predestination of the total dose to a limit
      of 60 Gy does not ensure a macro- and microscopical elimination of the tumor and
      may be inferior to an individually adaptation of the dose.

PMID- 8669050
TI  - [Radiation protection through cytokine release by N-acetylcysteine].
AB  - BACKGROUND: Interleukin-1, tumornecrosisfactor-alpha and interferon-gamma
      endogenously provide protection of the hematopoietic system against radiation.
      Thiols have already been used successfully as radioprotective agents. In this
      study the effect von N-acetylcysteine (NAC) on the release of interleukin-1 alpha
      and beta (IL-1), interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and
      tumornecrosisfactor-alpha (TNF-alpha) was assessed in an in vitro assay. PATIENTS
      AND METHODS: Whole blood samples from 8 healthy volunteers were stimulated with
      7.5 micrograms/ml PHA. NAC was added at concentrations of 0.6, 6, 12 and 24
      mmol/l. Subsequently the samples were irradiated with a dose of 18 Gy according
      to preceding validation experiments. RESULTS: IL-1 alpha, IL-1 beta b and IL-2:
      In comparison to stimulation and radiation alone the addition of 0.6 and 6
      mmol/l, with IL-2 also 12 mmol/l, NAC resulted in a significant increase of the
      cytokine-concentrations. The highest concentration of 24 mmol/l NAC, however,
      resulted in a decrease beyond control levels. IFN-gamma and TNF-alpha: Until 12
      mmol/l NAC no changes were observed. 24 mmol/l NAC resulted in a significant
      decrease, too. CONCLUSION: N-acetylcysteine is capable to co-stimulate
      radioprotective cytokines like IL-1 alpha and IL-1 beta and to enhance IL-2 in
      vitro, whereas higher doses result in a suppression.

PMID- 8669051
TI  - Results of treatment of inoperable recurrences of laryngeal cancer after total
      laryngectomy.
AB  - BACKGROUND/PURPOSE: The results of conventional radiotherapy in patients with
      inoperable recurrence of laryngeal cancer after total laryngectomy are bad.
      Therefore experimental methods including neutron therapy and combination of chemo
      and radiotherapy have been used. This presentation evaluates results of
      different treatment modalities in patients with inoperable recurrences of
      laryngeal cancer after total laryngectomy. PATIENTS AND METHODS: Forty-two
      patients with inoperable recurrences of laryngeal cancer after total laryngectomy
      were treated. Thirty patients received radiotherapy alone, and 12 patients
      received multidrug chemotherapy and radiotherapy. Patients were irradiated with
      cobalt-60 beam, neutron beam and with mixed cobalt-60 and neutron beam. The tumor
      dose in cobalt-60 therapy was 60 Gy in 20 to 30 fractions. In 8 patients
      additional dose of 10 to 20 Gy in 5 to 10 fractions was given to the reduced
      field. The doses used in neutron irradiation varied from 10 to 13 Gy in 5 to 20
      fractions. RESULTS: In 20 patients (47.6%) complete regression after therapy was
      observed, but only 9 (21.4%) patients survived without evidence of disease at 2
      years after radiotherapy. In patients treated with radiotherapy alone the 2-year
      disease-free survival was observed in 16.7% and in patients who received
      induction chemotherapy with Cisplatin followed by radical irradiation the 2-year
      disease-free survival was observed in 40%. CONCLUSION: The results of therapy of
      inoperable recurrence of laryngeal cancer after total laryngectomy remain bad.
      Radiotherapy combined with multidrug chemotherapy including cisplatin may
      contribute to some improvement of the patients survival.

PMID- 8669052
TI  - [Classifications of 202 tibial fractures in dogs and cats].
AB  - 202 Tibial fractures, in 138 dogs and 64 cats, were classified according to the
      system of Unger. The animals were presented between 1989 and 1994 to four Dutch
      veterinary orthopaedic referral clinics. In addition to the type of fracture,
      demographic information was taken into account including the species, the age of
      the patient, the size of the breed, the treatment, whether it was a open or
      closed fracture and the orthopaedic clinic. Possible correlation between the type
      of fracture and the variables, as well as correlations among the latter, were
      examined statistically. In this study 73% of the tibial fractures in dogs and
      cats were in the diaphysis, oblique fracture being the most frequent (24%).
      Proximal tibial fractures in dogs were usually extra-articular and 87% of these
      involved avulsion of the tibial tubercle. Malleolar fractures accounted for 57%
      of the distal fractures. A significant correlation was found between the
      localization of the fracture (proximal, diaphyseal or distal) and the species
      (cat or dog), between an avulsion fracture of the tibial tubercle and the age in
      dogs, between an incomplete tibial fracture and the age, between a malleolar
      fracture and a complicated (i.e., open) fracture, between a butterfly fracture
      and a complicated fracture, and between the applied therapy and the orthopaedic
      clinic. The classification system of Unger is very useful for inventory and
      documentation, but because of the lack of data about physeal fractures, the
      degree of injury to the surrounding soft tissues, and the influence of
      differences between surgeons, it cannot be used to determine therapy.

PMID- 8669053
TI  - [A dog named Wanda and comparative pathobiology].

PMID- 8669054
TI  - [Prevention of swine dysentery].

PMID- 8669055
TI  - [The forensic medical significance of the method of committing crimes in cases of
      serial murders with a sexual motivation].
AB  - Type of bodily injuries, method of their infliction, localization, and number,
      coupled with special severity and committed from sexual motives permit a forensic
      medical expert, with due consideration for investigation findings in cases with
      serial murders, by analogy to come to a conclusion that the crimes were committed
      by one and the same individual.

PMID- 8669056
TI  - [Biochemical study of the tissue lipids in a human corpse in a state of
      adipocere].
AB  - Scanty and contradictory published data made the authors carry out examinations
      of human tissues in a state of adipocere using visual, stereomicroscopic,
      biochemical methods, and numerous physical tests. Adipocere developing under
      natural conditions and extracted from human corpses and experimentally obtained
      adipocere were found to be quite the same. Biochemical studies of adipocere to
      detect phospholipids and the percent of ratio of total lipids and their classes
      were carried out for the first time.

PMID- 8669057
TI  - [A method for differential cytolysis in the molecular genetic expert
      identification of material evidence: problems in optimizing the procedure].
AB  - The authors discuss the problem of selective derivation of the genetic material
      of spermatozoa for molecular genetic identification from mixed biological traces
      containing sperm on material evidence. Possible methods of improving the efficacy
      of differential lysis of cells present in mixed traces are analyzed. Effects of
      some routinely used extractants on biological substrata, most often contaminating
      the sperm in expert material, have been studied, and conditions for their most
      complete elimination from objects of investigation optimized.

PMID- 8669058
TI  - [The use of the polymerase chain reaction in the forensic medical study of
      hairs].
AB  - In order to detect polymorphic DNA sequences in the bulbs of single human hairs,
      polymerase chain reaction (PCR) was used. Specific hypervariable regions of ApoB
      gene, D1S80 locus, and sex-specific sequences of X/Y chromosomes were amplified.
      The amount of DNA isolated from single hair bulbs was measured by fluorometry.
      Methodological aspects of using PCR for forensic medical examinations of single
      hairs are discussed.

PMID- 8669059
TI  - [The use of proteases for enhancing the sensitivity of reactions to detect group
      isohemagglutinins in the forensic medical study of blood stains].
AB  - Group a and b isohemagglutinins are much better detected in blood stains by
      enzyme-treated, but not native red cells. This is specially true for antibodies
      of poorly dissolved strains, whose group antibodies can be detected virtually
      only by enzyme-treated red cells in papain extracts possessing the highest
      immunological activity. Two sensitive methods for the detection of
      isohemagglutinins have been developed: extract titration and modified Lattes'
      method, permitting a reliable detection of group antibodies in old blood stains,
      undetectable by routine methods.

PMID- 8669060
TI  - [The gas chromatographic analysis of irritating substances].
AB  - Conditions for gas-liquid and chromato-mass-spectrometric analyses of
      chloracetone, dinitril o-chlorobenzylidene malonic acid, and pelargonic acid
      morpholide have been developed. The proposed methods may be used for
      identification of these compounds in investigation of material evidence in cases
      involving the use of defence gas weapons.

PMID- 8669061
TI  - [The nature and mechanogenesis of pelvic bone fractures in children from exposure
      to the impact from blunt solid objects in a diagonal direction from the front and
      the side].
AB  - Fifty cases of pelvic injuries in children are analyzed. The injuries were
      inflicted by blunt objects in the diagonal direction from the front from the
      side. Twenty-five of these (135 fractures) were expert cases, 25 (120 fractures)
      experimental observations. Both experimental and expert observations were divided
      into 3 groups depending on the angle between the direction of traumatic force
      action and the plane of the pelvic ring: those in the pelvic ring plane, and at
      angles of 45 and 90 degrees to it. In all the three groups strikes to the upper
      branch of the pubic bone with blunt objects from the front from the side in the
      diagonal direction led to development of various strained deformed states of the
      pelvis, each of which was characterized by specific mechanogenesis, localization,
      and morphology of fractures.

PMID- 8669062
TI  - [Experimental psychological aspects of preventing aggressive behavior].
AB  - Aggressive manifestations were studied by ISTA psychodiagnostic method in 156
      subjects never checked up by a psychiatrist. Three groups were singled out, which
      were characterized by the predominance of one of three forms of aggression
      realization in their behavior: constructive (91 subjects), destructive (43
      subjects), and deficit (22 subjects). MMPI method helped identify the
      psychological and psychopathological features of the examines. The results
      demonstrate the possibility of a differentiated approach to study of aggressive
      states and to development of measures to prevent destructive behavior.

PMID- 8669063
TI  - [Tetralin poisoning].

PMID- 8669064
TI  - [A case of acute peroral poisoning by the preparation Nitrafen].

PMID- 8669065
TI  - [Unresolved problems in departments of the forensic medical expertise of corpses
      in the Russian Federation].

PMID- 8669066
TI  - [Personal-likeness identification based on the corpse and intravital photography.
      Methodological recommendations No. 94/266. Approved by the Ministry of Health and
      the Medical Industry of Russia 3 July 95].

PMID- 8669067
TI  - [One of the versions of the prolongation of the Uglich tragedy].

PMID- 8669068
TI  - [Forensic medical expertise in manual strangulations].
AB  - Presents analysis of mortality caused by strangulation by hands, based on files
      and author's own observations. The principal mechanisms of compression of the
      neck with parts of human body are singled out: with one or two hands, with one or
      two forearms, with the arm and forearm, with the knee, shin, or foot. The most
      incident injuries to soft tissues of the neck, sublingual bone, and
      laryngotracheal cartilages detected by experts at autopsy and at additional
      fractological examination of the hyoid laryngotracheal complex are described. A
      conclusion about the mechanism of formation of injuries of this complex inflicted
      by compression of the neck by hands is made.

PMID- 8669069
TI  - [The effect of the ossification processes of the hyoid bone and laryngeal
      cartilages on the formation of injuries to the organs of the neck].
AB  - Effects of ossification processes on the incidence and specific features of
      injuries to sublingual bone, thyroid and ring-like cartilages were studied by
      stereomicroscopy of the skeletal preparations of these anatomical formations for
      the first time. The results of examination of cases with hanging permit us doubt
      the opinion universally acknowledged in forensic medicine that the possibility of
      injuries of the sublingual bone and laryngeal cartilages increases with their
      ossification.

PMID- 8669070
TI  - [Dying out or neglect?].

PMID- 8669071
TI  - [Current incentives for geriatrics. Organizations for the aged confer with
      administrators of the VWS].

PMID- 8669072
TI  - [The 'pleasant events schedule' for the elderly].
AB  - The coping with depression course is a psychoeducational treatment modality for
      unipolar depression. Increasing the number of pleasant events in the lives of
      participants is one of the central themes of the course. The Pleasant Events
      Schedule is a very useful instrument in this course. The coping with depression
      course as well as the pleasant events schedule are adapted for the use in older
      persons. The scores of 163 older persons on the Dutch version of the Pleasant
      Events Schedule are used to estimate the psychometric value of the schedule.
      Furthermore, the social learning theory of depression, developed by Lewinsohn, is
      described. This theory forms the theoretical basis of the course and the
      schedule.

PMID- 8669073
TI  - [Limitations in feeding behavior in nursing home patients].
AB  - Disabilities in nutrition behaviour of 250 residents and 264 newly admitted
      patients, 65 years and older, of a nursing home were related to their main
      disorder (stated as the reason for admission). More than 60% of the newly
      admitted patients and 80% of the residents suffered from disabilities in one or
      more of the four following aspects of nutrition behaviour: mostly in making a
      choice, often in bringing food to the mouth and chewing and to a lesser extent in
      swallowing food. Most of the residents also needed help in obtaining extras and
      preparing their sandwich meal. Disabilities in choosing, feeding and chewing were
      particularly frequent in the group of psychogeriatric patients while disabilities
      in swallowing were relatively frequent in the group of newly admitted
      neurological patients. The most frequent type of help offered in the case of a
      disability existed, was personal support and adaptation of the consistency of the
      food; devices to enable the patient to function independently were rarely used.
      The care needed by nursing home patients in nutrition behaviour, which can vary
      between and within patients between deserves more attention because it can
      determine the intake of food.

PMID- 8669074
TI  - [Peripheral arthritis in family practice].
AB  - Osteoarthritis is a common disease of the cartilage in a joint for which the
      general practitioner (GP) is frequently consulted. In this contribution the
      current policy of GPs is described with respect to patients with peripheral
      osteoarthritis. For this purpose, the medical records of 196 patients from 14
      Dutch general practitioners were studied with regard to the GPs management, and
      the GPs were interviewed about their management. Also, the burden of
      osteoarthritis was assessed in terms of quality of life for 198 patients.
      Moreover, the effects of two nonsteroidal treatments (nabumetone versus
      piroxicam) were studied in 198 patients. GPs management is heterogeneous. The
      results of the interviews supported this finding. The quality of life of patients
      with osteoarthritis was significantly reduced in several areas of daily living.
      After treatment with nonsteroidals the patients' status improved, according to
      both the GPs and the patients. The GPs and the patients' perspective on change
      correlated weakly. In future research, it would be interesting to explore these
      two perspectives.

PMID- 8669075
TI  - [Apolipoprotein E polymorphism and Alzheimer disease].
AB  - At present a reliable and specific diagnostic test of Alzheimer's disease is not
      available. Thus far, diagnosis is based on clinical criteria despite their
      occasional inadequacy. Post mortem search for neuropathological hallmarks can
      establish the diagnosis with certainty. In the present case control study we
      performed an apoE genotyping for 21 patients, divided into an Alzheimer-positive
      and an Alzheimer-negative group after neuropathological search. As described in
      the literature, the apoE-epsilon 4 allele was overrepresented in the Alzheimer
      positive group, while in the Alzheimer-negative group the apoE-epsilon 3 allele
      dominated. The epsilon 4 allele of the apoE gene may be considered as a
      biological risk factor for the development of Alzheimer's disease. Especially in
      geriatric patients with cognitive impairment, apoE genotyping seems to be a
      supplementary tool for risk assessment.

PMID- 8669076
TI  - Studies of antibodies in the sera of patients who have made red cell
      autoantibodies.
AB  - BACKGROUND: In patients in whom autoantibodies of broad specificity
      (panagglutinins) are present in the serum, adsorption studies are often necessary
      to identify alloantibodies that are simultaneously present. STUDY DESIGN AND
      METHODS: Samples from 138 patients in whom the direct antiglobulin test was
      positive and antibody was present in the serum were studied. When antibody
      identification studies before or after initial adsorption suggested the presence
      of an alloantibody, additional alloadsorptions were performed. RESULTS: Among the
      samples from 138 patients, 71 contained only panagglutinating autoantibody, and
      another 19 contained either autoantibodies or alloantibodies that were not
      accompanied by panagglutinins. The remaining 48 samples contained both
      panagglutinins and a total of 62 antibodies that appeared to be alloimmune in
      nature. Alloadsorption with antigen-negative red cells showed that 29 (47%) of
      the apparent alloantibodies were in fact partially adsorbed autoantibodies that
      mimicked alloantibodies by their reactions. CONCLUSION: Initial autoadsorption
      often left unadsorbed alloantibodies and autoantibodies with mimicking
      specificities. Initial alloadsorption more often left only true alloantibodies
      unadsorbed. From the screening tests, it appeared that 43 percent of the 138
      patients were alloimmunized. Recognition of the mimicking nature of the partially
      adsorbed autoantibodies found that the real incidence of alloimmunization in the
      patients was 23 percent. Recognition of this phenomenon considerably simplifies
      the selection of blood for transfusion to these patients.

PMID- 8669077
TI  - Comparison of the polyethylene glycol antiglobulin test and the use of enzymes in
      antibody detection and identification.
AB  - BACKGROUND: The polyethylene glycol indirect antiglobulin test for detection of
      red cell antibodies was compared with a proven, highly sensitive test system
      using papain. STUDY DESIGN AND METHODS: Parallel, prospective testing of 1508
      samples with polyethylene glycol and with albumin and papain evaluated the
      sensitivity and specificity of polyethylene glycol. Retrospective analysis of
      antibody specificities was performed for the 2 years before and the 2 years after
      the institution of polyethylene glycol testing. RESULTS: Of 1508 prospective
      screens, 53 (3.5%) had discordant results: 5 were positive only in polyethylene
      glycol and 48 were positive only in albumin and papain. Upon antibody
      identification, the 5 samples that were positive only in polyethylene glycol
      showed 1 anti-D, 2 warm autoantibodies, and 2 false-positive results. The 48
      samples that were positive only in albumin and papain showed 1 each of the
      following: anti-Le(b); anti-P1; anti-S; high-titer, low-avidity antibody; and
      cold autoantibody; there were 43 false-positive results. False-positive results
      totaled 12 (0.8%) with polyethylene glycol and 53 (3.5%) with albumin and papain.
      The retrospective analysis of antibody specificity with polyethylene glycol
      showed a significant increase in the detection of Fy(a) and/or Fy(b) (p < 0.0002)
      and Jk(b) (p < 0.0002) antibodies and a decrease in the detection of Le(a) and/or
      Le(b) antibodies (p < 0.0002). CONCLUSION: Polyethylene glycol retained the high
      sensitivity of the albumin and papain, while significantly lowering the number of
      false-positive results and decreasing the detection of antibodies of doubtful
      clinical significance.

PMID- 8669078
TI  - Point mutations characterize KEL10, the KEL3, KEL4, and KEL21 alleles, and the
      KEL17 and KEL11 alleles.
AB  - BACKGROUND: The Kell blood group system is complex, consisting of five sets of
      alleles and expressing high- and low-incidence antigens and at least 11 other
      independently expressed antigens. The molecular basis of two sets of alleles:
      KEL1 (K) and KEL2 (k) and KEL6 (Jsa) and KEL7 (Jsb) have been elucidated as
      single-base mutations leading to amino acid changes. The molecular basis for the
      KEL3 (Kpa), KEL4 (Kpb), and KEL21 (Kpc) alleles, the KEL11(Cote) and KEL17(Wka)
      alleles, and for KEL10 (UIa) is now reported. STUDY DESIGN AND METHODS: Genomic
      DNA from unrelated individuals with KEL:3,-4,-21 [Kp(a+b-c-)], KEL:-3,-4,21 [Kp(a
      b-c+)], KEL:17,-11, and KEL:10 (UIa) phenotypes was amplified by polymerase chain
      reaction (PCR) with primers for the 19 exons of KEL. The PCR products were
      sequenced and compared to the DNA sequences of a common Kell system phenotype,
      KEL:-3,4,-21,-17,-10. Base mutations found were confirmed by restriction fragment
      length polymorphism analysis in which DNA of unrelated persons with similar red
      cell phenotypes was used. RESULTS: In all cases, single-base mutations were
      responsible for the expression of the various antigens. In KEL3 (Kpa), KEL4
      (Kpb), and KEL21 (Kpc), point mutations at the same codon in exon 8, encoding
      amino acid residue 281, distinguish the three genes. KEL4 has the CGG codon for
      arginine, KEL3 has the TGG codon for tryptophan, and KEL21 has the CAG codon for
      glutamine. KEL17 has a T1025C mutation in exon 8, encoding a valine-to-alanine
      amino acid change at residue 302. KEL10 has an A1601T mutation in exon 13,
      encoding a glutamic acid-to-valine change at residue 494. In all cases, the point
      mutations created restriction enzyme sites, and PCR-based restriction fragment
      length polymorphisms confirmed that these point mutations occurred in unrelated
      persons with the same red cell phenotype. CONCLUSION: Single-base substitutions
      characterize the KEL3, KEL21, KEL17, and KEL10 genes. The allelic relationship of
      KEL3, KEL4, and KEL21 was confirmed because the mutations occur in the same
      codon, expressing different amino acids. PCR-based restriction fragment length
      polymorphisms can be used to distinguish genotypes.

PMID- 8669079
TI  - Genotyping of KEL1 and KEL2 of the human Kell blood group system by the
      polymerase chain reaction with sequence-specific primers.
AB  - BACKGROUND: Kell is a major antigenic system in human red cells, with more than
      20 identified antigens. KEL1 and KEL2 are two opposing low- and high-frequency
      alleles. Immunization to KEL1 is clinically significant, because anti-KEL1 can
      cause severe reactions to transfusion of incompatible blood, as well as hemolytic
      disease of the newborn. At the nucleotide level, the difference between the KEL2
      and KEL1 alleles is a single-base change within exon 6 that results in the
      substitution of methionine (ATG) for threonine (ACG) at position 193. STUDY
      DESIGN AND METHODS: An assay using polymerase chain reaction and sequence
      specific primers to genotype for the KEL1 and KEL2 alleles has been developed. It
      uses two allele-specific forward primers for either KEL1 or KEL2 and a single
      reverse-consensus primer. RESULTS: A validation study of 42 serologically typed
      samples (5 KEL:1,-2 [K+k-]; 23 KEL:1,2 [K+k+]; and 14 KEL:-1,2 [K-k+]) was
      performed. A concordance rate of 100 percent (42/42 samples) was observed between
      polymerase chain reaction with sequence-specific primers and serologic typing.
      CONCLUSION: This rapid, nonradioactive, Kell system genotyping assay does not
      require the additional steps of probe hybridization or restriction enzyme
      digestion. This application of polymerase chain reaction with sequence-specific
      primers should prove particularly useful in Kell system genotyping of amniotic
      cells to identify pregnancies at risk for hemolytic disease of the newborn.

PMID- 8669080
TI  - Flow cytometric quantitation of serum anti-D in pregnancy.
AB  - BACKGROUND: The major cause of fetal hemolytic disease is maternal immunization
      to D in D-incompatible pregnancies. To prevent complications, D-incompatible
      pregnancies are monitored for the level of maternal anti-D. At present, the
      monitoring of anti-D levels is performed by the indirect antiglobulin test
      complemented by quantitation by the technique used in an automated antibody
      detection and quantitation instrument. STUDY DESIGN AND METHODS: Flow cytometry
      was used to quantitatively determine the level of anti-D in serum and to analyze
      the IgG subclass distribution and the presence of IgM anti-D in these samples.
      The results were compared to the indirect antiglobulin test titer and to the
      results obtained by the technique used in an automated antibody detection and
      quantitation instrument. RESULTS: Flow cytometry allowed sensitive and accurate
      determinations of anti-D levels with low interassay and intra-assay variability,
      both for serum samples and standard curves. CONCLUSION: Flow cytometry is a
      simple, rapid, and reliable method for determining the serum levels of D
      antibodies and their Ig subclass distribution. It is therefore well suited for
      the monitoring of women during D-incompatible pregnancies.

PMID- 8669081
TI  - Involvement of Ser103 of the Rh polypeptides in G epitope formation.
AB  - BACKGROUND: Almost all red cells that carry D and/or C antigens also express the
      G antigen (Rh12). A study was conducted on the molecular background of the G
      epitope. STUDY DESIGN AND METHODS: Two unrelated donors with the rare ccDEe, G-
      phenotype and one donor with the ccEe, G+ phenotype were studied. Genomic DNA and
      cDNA of these donors were studied with polymerase chain reaction, Southern blot,
      and sequence analysis, with special focus on exon 2, because it is only in this
      exon that there are supposed to be similarities between RHD and the RHC allele,
      but not between RHD and the RHc allele. RESULTS: In both ccDEe, G- donors, a
      nucleotide substitution was found in exon 2 of RHD; T307 was replaced by C307,
      which predicted a Ser->Pro substitution at amino acid position 103 of the D
      polypeptide. The ccEe, G+ donor carried the complete exon 2 of RHD. Moreover,
      despite the absence of all known D epitopes, this donor also carried RHD
      characteristics in exons 1 to 3 and exon 9 and further downstream. CONCLUSION:
      Ser103, encoded by exon 2 of the RH genes, is involved in G epitope formation.

PMID- 8669082
TI  - Characterization of antibodies produced by S-s- individuals.
AB  - BACKGROUND: Historically, classification of U- and U variant (U+var) individuals
      has been made by hemagglutination and adsorption and elution studies performed
      with polyclonal U antisera. Molecular studies and serologic tests with a potent
      monoclonal anti-He have shown that U+var red cells, some of which are He+,
      possess an altered form of glycophorin B. STUDY DESIGN AND METHODS: Seventeen
      sera, previously determined to contain anti-U, were tested with a panel of red
      cells of common and rare MNS types. RESULTS: Five sera contained anti-U only, and
      12 sera contained broadly reactive antibodies with apparent, but inseparable,
      anti-U,He or anti-U,N,He specificities. CONCLUSION: The majority of antibodies
      produced by S-s-U- individuals are anti-U plus anti-glycophorin B and are
      analogous to the broadly reactive antibodies produced by En(a-) individuals whose
      red cells lack glycophorin A or have altered glycophorin A. To avoid further
      immunization of patients with anti-U, sera used for classification of S-s-U-
      donors should be selected to detect S-s- red cells that possess altered forms of
      glycophorin B.

PMID- 8669083
TI  - Neutralization of Knops system antibodies using soluble complement receptor 1.
AB  - BACKGROUND: Antibodies of the Knops system have been referred to as
      nonneutralizable because they cannot be inhibited with serum, saliva, or urine.
      Because the Knops system antigens have been located on complement receptor 1
      (CR1), the question of whether the antibodies could be neutralized with soluble
      CR1 (sCR1) produced by recombinant DNA techniques was studied. STUDY DESIGN AND
      METHODS: First, radiolabeled immunoprecipitation techniques were used to test
      sCR1 for the expression of the high-incidence Knops system antigens. Then, a
      total of 45 antibodies were neutralized with sCR1, including the following: one
      each of anti-Cr(a), -Dr(a), -Do(b), -Hy, -Ge, -Jr(a), -Sc1, -Jk(a), -Cs(a), and 
      Kp(b); two each of anti-Lu(b), -Yt(a), and -JMH; three each of anti-McC(a), -Rg,
      and -Sl(a); and four each of anti-Ch, -Kn(a), -Yk(a), -Kn/McC. In addition, two
      examples of anti-Kn(a) + K, one example of anti-Sl(a) + K + Fy(a), and one
      example of anti-Yk(a) + E were tested. The sCR1 was added to each test serum and
      6-percent albumin was added to the control; this was followed by neutralization
      incubation for 5 minutes at 25 degrees C. The antibody samples were then tested
      by a low-ionic-strength solution, anti-human globulin technique. RESULTS: The
      sCR1 expressed Kn(a), McC(a), Sl,a and Yk(a). All Knops system antibodies (n =
      22) were neutralized by the sCR1, but none of the other 23 alloantibodies
      decreased in reactivity. The samples containing antibodies of two specificities
      showed inhibition of the Knops system antibody but not of the second antibody.
      CONCLUSION: This neutralization method, in which recombinant protein is used,
      provides an expedient and definitive method of identifying Knops system
      antibodies.

PMID- 8669084
TI  - Determinants of red cell, platelet, plasma, and cryoprecipitate transfusions
      during coronary artery bypass graft surgery: the Collaborative Hospital
      Transfusion Study.
AB  - BACKGROUND: Very little is known about the determinants of blood transfusions in
      patients undergoing coronary artery bypass graft surgery. STUDY DESIGN AND
      METHODS: To identify factors that influenced the transfusion of red cells,
      platelets, plasma, and cryoprecipitate, statistical methods were used to study
      2476 consecutive diagnosis-related group 106 and 107 patients in five teaching
      hospitals who underwent coronary artery bypass surgery between January 1, 1992,
      and June 30, 1993. RESULTS: The likelihood of red cell transfusion was
      significantly associated with 10 preoperative factors: 1) admission hematocrit,
      2) the patient's age, 3) the patient's gender, 4) previous coronary artery bypass
      surgery, 5) active tobacco use, 6) catheterization during the same admission, 7)
      coagulation defects, 8) insulin-dependent diabetes with renal or circulatory
      manifestations, 9) first treatment of new episode of transmural myocardial
      infarction, and 10) severe clinical complications. Platelet and/or plasma
      transfusions were strongly associated with the dose of red cells transfused.
      Transfusion requirements and other in-hospital outcomes were associated with
      patient characteristics, surgical procedure (reoperation vs. primary procedure),
      and the conduits used for revascularization (venous graft only, venous and
      internal mammary artery graft, or internal mammary artery graft only). Blood
      resource use and donor exposures were evaluated with respect to the risk to
      patients of contracting hepatitis C virus and human immunodeficiency virus
      infections. CONCLUSION: The classification of coronary artery bypass graft
      patients on the basis of attributes known preoperatively and by conduits used
      yields subsets of patients with distinctly different transfusion requirements and
      in-hospital outcomes.

PMID- 8669085
TI  - Monitoring for undertransfusion.
AB  - BACKGROUND: Most published reviews and audits of blood and blood component
      transfusion have focused on the issue of overtransfusion and on the inappropriate
      use of red cell components. There is growing concern that efforts to curb
      unnecessary transfusions may result in a trend toward undertransfusion of
      patients. There is little published information that addresses this issue or the
      magnitude of this practice. STUDY DESIGN AND METHODS: Undertransfusion was
      evaluated by examining the transfusion records from a 3-month period for 55
      patients who met the study criteria of having either a hemoglobin level < 7 g per
      dL or a platelet count of < 10 x 10(9) per L. If the identified patient did not
      receive a transfusion within 24 hours of the reported hemoglobin level or
      platelet count, the medical record was reviewed by a resident physician. RESULTS:
      A total of 213 individual hemoglobin levels and platelet counts, representing the
      55 patients, met our transfusion criteria. All except 8 of the identified
      patients received red cells and/or platelet transfusions. Reasons for not
      transfusing red cells included the patient's response to nutritional support and
      iron supplementation, refusal of blood, and noncompliance. Reasons for not
      transfusing platelets included falsely low platelet count because of platelet
      clumping in vitro, contraindication based on clinical diagnosis (e.g., immune
      thrombocytopenic purpura), and the patient's death before transfusion.
      CONCLUSION: Red cell and platelet transfusions were appropriately ordered for all
      patients who met the transfusion criteria. Undertransfusion is not a problem at
      this institution according to the criteria established. It is recommended that
      other institutions expand their blood utilization audits to include investigation
      for evidence of undertransfusion. Further research regarding the issue of
      undertransfusion is warranted and could be expanded to include other components.

PMID- 8669086
TI  - Infusible platelet membrane microvesicles: a potential transfusion substitute for
      platelets.
AB  - BACKGROUND: Several substitutes for intact, viable platelets have been used for
      transfusion, both to people and in animal models, with varied success. Infusible
      platelet membrane (IPM) is prepared from human platelets. IPM retains the
      glycoprotein (GP)lb receptor and has platelet factor 3 activity (procoagulant
      activity). However, factor V, serotonin, a cytoplasmic marker enzyme (purine
      nucleotide phosphorylase), GPIIb/IIIa complex, and HLA class I and II antigens
      are all absent in IPM. STUDY DESIGN AND METHODS: IPM is prepared from outdated
      platelets. The platelets were disrupted by freezing and thawing; they were washed
      and heated to inactivate possible viral contaminants, and then the sonicated
      membrane microvesicle fraction was separated and lyophilized. The hemostatic
      activity of IPM was measured by its ability to reduce the prolonged bleeding time
      in thrombocytopenic rabbits. RESULTS: Administration of IPM at a dose of 2 mg per
      kg results in a substantial reduction in the bleeding time. In a series of 23
      experiments, a median preinjection bleeding time of 15 minutes was reduced to 6
      minutes within 4 hours after IPM administration. Administration of IPM did show a
      mild enhancement in the thrombogenicity index, as measured in the Wessler rabbit
      model. This enhancement is, however, not significant, as a thrombogenicity index
      value of up to 0.6 is clinically acceptable. CONCLUSION: IPM may have clinical
      potential as a substitute for platelets in the treatment of bleeding due to
      thrombocytopenia.

PMID- 8669087
TI  - Photosensitized inactivation of Plasmodium falciparum in human red cells by
      phthalocyanines.
AB  - BACKGROUND: Photodynamic treatment of red cell concentrate with phthalocyanines
      and red light inactivates lipid-enveloped viruses such as vesicular stomatitis
      virus and human immunodeficiency virus. This procedure is evaluated for its
      ability to enhance the viral safety of red cell concentrate for transfusion. It
      is of interest to study whether photodynamic treatment could also inactivate
      parasites in blood (e.g., Plasmodium falciparum). STUDY DESIGN AND METHODS: Red
      cells parasitized by P. falciparum were treated with phthalocyanines and red
      light and then cultured in vitro for 48 hours. The percentage of parasitemia was
      then estimated by microscopic examination of the red cells. RESULTS: Of the
      phthalocyanines studied, the one that proved to be the most effective was
      HOSiPcOSi(CH3)2(CH2)3N(CH3)2 (Pc4). The extent of parasite inactivation increased
      with light dose and decreased with an increase in hematocrit. At a hematocrit of
      60 percent and 2 microM Pc 4, >or= 3 log10 kill occurred at a light dose of 60 J
      per cm2. This is a lower dose than is required for >or= 6 log10 of vesicular
      stomatitis virus inactivation (90 J/cm2). CONCLUSION: Photodynamic treatment with
      Pc 4 could make red cell concentrate not only virally safe for transfusion but
      also safe with respect to transmitting malaria.

PMID- 8669088
TI  - Third-generation recombinant immunoblot assay: comparison of reactivities
      according to hepatitis C virus genotype.
AB  - BACKGROUND: Recombinant immunoblot assay (RIBA) is widely used as a supplemental
      test in hepatitis C virus (HCV) confirmatory algorithms. As this assay is based
      on HCV type 1, its performance was examined with the common European HCV
      genotypes (1, 2, and 3). STUDY DESIGN AND METHODS: A study was performed to
      retest in third-generation RIBA (RIBA-3) all 146 second-generation RIBA (RIBA-2)
      positive polymerase chain reaction-positive samples detected by second-generation
      enzyme-linked immunosorbent assays and having known HCV genotypes (74 HCV type 1,
      21 type 2, 51 type 3). RIBA band intensities were examined according to HCV
      genotype. An additional 90 RIBA-3-confirmed PCR-positive samples (47 HCV type 1,
      5 type 2, 38 type 3) detected by third-generation enzyme-linked immunosorbent
      assays were also examined. RESULTS: In the first group of 146 samples, the RIBA-3
      NS4 (c100p) band showed a marked improvement in sensitivity for the detection of
      HCV types 2 and 3 over that of the c100 antigen of RIBA-2, but the mean band
      intensities of HCV types 2 and 3 remained significantly lower than those of type
      1. Improved sensitivity of the NS3 band of RIBA-3 to HCV type 3 was also
      apparent, but, again, the mean band intensity measured was lower for type 3 than
      for either type 1 or type 2. The c22 band of RIBA-2 and RIBA-3 exhibited equal
      sensitivity for all HCV genotypes. These differences were also apparent when RIBA
      3 was used in conjunction with third-generation enzyme-linked immunosorbent
      assays. CONCLUSION: The current RIBA-3 lacks sensitivity to the NS4 antibody for
      HCV types 2 and 3. The incorporation of type-specific components to other
      genotypes for NS4 (and NS3) antigens should be considered by the manufacturers.

PMID- 8669089
TI  - Hepatitis C virus (HCV) genotype analysis in apparently healthy anti-HCV-positive
      Parisian blood donors.
AB  - BACKGROUND: As only a few studies have examined the prevalence of various
      hepatitis C virus (HCV) subtypes in blood donors, information about the
      variability and route of infection in apparently healthy persons is limited.
      STUDY DESIGN AND METHODS: Blood donations collected at a large Parisian hospital
      (52,441) were investigated for antibodies to HCV. Serum samples were screened
      with an enzyme immunoassay. All HCV-positive donations were retested with a
      second enzyme immunoassay and confirmed by immunoblot. The HCV genotype was
      determined for all polymerase chain reaction-positive subjects. Untypable
      genotypes were sequenced in the NS5B region. RESULTS: In total, 83 (0.26%) blood
      donors were anti-HCV positive. Men (0.34%) were significantly more likely to be
      infected (p < 0.001) than women (0.19%). Prevalence rates in men between 20 and
      39 years of age were higher than those in similar women (p = 0.01), but greater
      in women aged from 50 to 65 years (p = 0.05). Fifty-five sera were viremic, of
      which 49 could be genotyped by a line probe assay. One new HCV type 1 subtype and
      three new HCV type 2 subtypes were discovered. In total, 28, 10, 11, 5, and 1
      serum samples were grouped into HCV types 1 through 5, respectively, involving a
      total of 13 subtypes. The mean age of HCV type 2-infected donors was 42 +/- 11
      years, but that for type 3-infected subjects was only 30 +/- 4 years (p =
      0.0048). Forty-nine subjects showed elevated alanine aminotransferase levels; 39
      (80%) of these subjects were viremic (p < 0.05). CONCLUSION: Among the sampled
      population, an HCV prevalence rate of 0.26 percent was found, with the five most
      common European genotypes causing the infections. Four new subtypes were
      discovered. Correlation between genotype and risk factors was not apparent, but
      links with age, sex, and ethnic origin emerged.

PMID- 8669090
TI  - Effect of blood donation on the establishment of normal ranges of lymphocyte
      subsets.
AB  - BACKGROUND: Absolute counts of CD4+ T-lymphocytes are used in the management of
      patients with human immunodeficiency virus infection. Low absolute counts of
      CD3+CD4+ cells have also been observed in healthy people--a phenomenon called
      idiopathic CD4 lymphocytopenia. It is common practice for normal ranges for
      lymphocyte subsets to be derived from samples taken from blood donors. STUDY
      DESIGN AND METHODS: A sample of EDTA blood was taken through the donation line
      tubing, after donation from 565 blood donors in Sydney, Australia, who were
      selected from a range of age groups. An additional 12 donors provided a
      predonation sample as well as a postdonation sample. Hematologic assays were
      performed on two analyzers. Samples were stained for CD3, CD4, CD8, CD19, and
      CD56 and analyzed on a flow cytometer. RESULTS: Three donors were found to have
      absolute CD3+CD4+ counts < 300 cells per microL. The percentage of CD3+CD4+ cells
      was found to increase with age. Both the percentage and the absolute count of
      CD3+CD8+ cells decreased with age, which resulted in an increased CD4:CD8 ratio
      with age. Men had consistently higher absolute counts of CD3-CD56+ cells than
      women. The 12 additional donors all had greater percentages of CD3+CD4+ cells and
      lower absolute counts for CD3+, CD3+CD4+, CD3+CD8+, CD19+ and CD3-CD56+ cells
      after donation than they had before donation (p < 0.001). CONCLUSION: It is not
      satisfactory to base normal ranges for lymphocyte subsets on donor blood, from
      which the blood sample has been obtained after donation.

PMID- 8669091
TI  - Characterization of the hybrid RHD gene leading to the partial D category IIIc
      phenotype.
AB  - BACKGROUND: A D-positive white woman was found to have produced alloanti-D
      leading to hemolytic disease of the newborn in her third D-positive child. The
      maternal D was identified as the partial D category IIIc antigen (DIIIc). The
      molecular basis of this phenotype was studied. STUDY DESIGN AND METHODS: The
      proposita and her relatives were phenotyped for Rh system antigens with standard
      reagents. D(IIIc) typing of D-positive red cells was done with serum that
      contained anti-D from the proposita. Southern blot analysis and RHD-specific
      polymerase chain reactions were performed with genomic DNA. Rh transcripts were
      cloned and sequenced. RESULTS: Six relatives of the proposita were found to
      express the DIIIc phenotype, which traveled with Ce. The DIIIc phenotype was
      inherited in a Mendelian fashion. Southern blot analysis showed an identical
      digestion pattern in D(IIIc) individuals and in DD controls. Three different Rh
      transcripts were found. Two Rh transcripts were derived from RHCE (RHce and
      RHCe). The RHD-derived Rh transcript was the same as that of the published RHD
      sequence, apart from exon 3, which appeared to be exon 3 of RHCE. At the genomic
      level, RHD exon 3 was missing in all individuals expressing D(IIIc). CONCLUSION:
      This study shows the characteristics of a new hybrid D-CE-D allele encoding
      D(IIIc). It may be concluded that exon 3 of RHD is not involved in the formation
      of any of the D epitopes known at present, but rather encodes a new D epitope or
      D epitopes, as yet undefined by monoclonal anti-D reagents.

PMID- 8669092
TI  - An unusual case of autoimmune hemolytic anemia with reticulocytopenia, erythroid
      dysplasia, and an IgG2 autoanti-U.
AB  - BACKGROUND: Autoantibodies with anti-U specificity, usually in combination with
      autoantibodies of other specificities, have occasionally been identified in
      association with autoimmune hemolytic anemia. A case of life-threatening
      autoimmune hemolytic anemia, characterized by several atypical features,
      including apparent intravascular hemolysis associated with an IgG2 anti-U,
      reticulocytopenia, and bone marrow dyserythropoiesis is described. CASE REPORT: A
      36-year-old man with a severe case of acute-onset autoimmune hemolytic anemia was
      admitted to another hospital; he had a hematocrit of 15 percent, elevated
      bilirubin and lactate dehydrogenase, and positive direct and indirect
      antiglobulin tests. He received 7 units of incompatible red cells without
      improvement in hematocrit, and he was transferred to University Hospitals of
      Cleveland (OH). He was jaundiced and became syncopal in the sitting position. His
      serum was reddish pink; he had a hematocrit of 11.8 percent and a reticulocyte
      count of 2.5 percent. No spherocytes were observed in the peripheral blood smear.
      Shortly after admission, the hematocrit fell to 6.9 percent. He was given 3 units
      of "least-incompatible" red cells and was started on prednisone, with little
      improvement. An IgG2 autoanti-U was detected in his serum. Seven units of U- red
      cells were transfused over the next 4 days. The hematocrit improved to 23 percent
      and continued to rise without further transfusion. A bone marrow examination,
      initially revealing erythroid hyperplasia accompanied by dyserythropoiesis,
      became morphologically normal. Drug studies failed to show evidence of drug
      related hemolysis. He remains well 2 years after discharge without evidence of
      recurrent hemolysis. CONCLUSION: Severe life-threatening autoimmune hemolytic
      anemia, in this instance induced by an autoanti-U, may be associated with IgG2
      autoantibody and characterized by apparent intravascular hemolysis and bone
      marrow dyserythropoiesis. Early treatment with U- blood, in addition to steroids,
      may be beneficial.

PMID- 8669093
TI  - Identification of a crossreactive epitope within hepatitis C virus core antigen:
      resolution by third-generation hepatitis C virus assays.

PMID- 8669095
TI  - Blood banking is not a "pharmaceutical industry".

PMID- 8669094
TI  - More on the cost-effectiveness of white cell reduction.

PMID- 8669096
TI  - Outcome of subcutaneous islet transplantation improved by polymer device.
AB  - Syngeneic transplantation of rat islets into subcutaneous tissue failed to cure
      streptozocin diabetes. The reason is unknown, but poor vascularization may play a
      role. We hypothesize that if a well-vascularized subcutaneous site could be
      created, islet grafts would do well. Four hundred freshly isolated mouse islets
      were transplanted syngeneically under the renal capsule or into the
      intraperitoneal cavity and compared with 800 islets in subcutaneous tissue of
      streptozocin-diabetic mice. Four weeks after transplantation, 14 of 14 under the
      renal capsule, 4 of 8 in the intraperitoneal site, and 0 of 7 in the subcutaneous
      tissue site achieved normoglycemia. To create vascularized organoids, we
      transplanted 800 mouse islets into polyvinyl alcohol (PVA) or polyglycolic acid
      (PGA) polymers in subcutaneous tissue of streptozocin-diabetic mice either
      immediately (four in PVA and six in PGA) or 7 days (four in PVA and four in PGA)
      after implantation. Four weeks after transplantation, the mean blood glucose
      level and body weight had no change with PVA. However, the mean body weight
      increased significantly with PGA and 3/10 became normoglycemic. When
      transplanting 400 islets with PGA polymers intraperitoneally, all animals (n=5)
      remained hyperglycemic 3 months later. In contrast, four of five recipients
      transplanted with 800 islets with PGA polymers subcutaneously became
      normoglycemic. The grafts from successful animals contained numerous
      revascularized islets containing a substantial amount of insulin. These
      preliminary results indicate that subcutaneous islet transplantation using PGA
      polymers can improve the metabolic status and, in some cases, even cure diabetes
      in streptozocin-diabetic mice.

PMID- 8669097
TI  - Advantages of using a cell separator and metrizamide gradients for human islet
      purification.
AB  - Human islet transplantation has a high rate of failure, often due to primary
      nonfunction, which suggests that islets are damaged during the processing of the
      pancreas. The preparation of human islets for transplantation is still a complex
      process that requires large teams of surgical and laboratory personnel. To
      overcome this problem, we have adopted the use of the IBM 2991 COBE cell
      separator and a metrizamide/Ficoll density medium that is easy to prepare. Twenty
      seven pancreatic glands have been processed using the COBE cell separator, 23 of
      which were purified in metrizamide/Ficoll gradients and 4 in bovine serum albumin
      gradients. The results show an improvement of recovery and viability in these
      preparations when compared retrospectively with manual gradients. More
      importantly, the time required for purification was shortened to one fourth the
      usual time and total processing time is about half as long. Moreover, a team of
      two laboratory staff was regularly able to prepare islets for transplantation,
      reducing the separation time from 7 hr to 3.5 hr. We conclude that the automatic
      cell separator and metrizamide-based separation medium are useful modifications
      of current islet purification methods.

PMID- 8669098
TI  - Successful biolistic transformation of mouse pancreatic islets while preserving
      cellular function.
AB  - To utilize gene therapy, we required an efficient method to transfect intact
      islets before their use in transplantation. The biolistic method transforms cells
      by bombarding them with microprojectiles coated with DNA. Once internalized, the
      DNA is solubilized and expressed. We used the firefly luciferase gene driven by
      the human cytomegalovirus immediate early promoter as a reporter construct in
      freshly isolated BALB/c mouse islets to compare the transfection efficiency using
      either the biolistic method, lipofection, or recombinant adenoviral infection
      (n=4 in each case). The biolistic method achieved, on average, a 35-fold higher
      level of luciferase activity than the lipofection method (mean +/- SEM: 42.6 +/-
      14.2 vs. 1.1 +/- 0.2 relative light units (RLU)/islet). Adenoviral infection
      achieved, on average, a further 25-fold higher level of luciferase activity than
      the biolistic method (1136.0 +/- 542.0 RLU/islet). The average proportion of
      islets recovered 48 hr after the biolistic blast was 53% (n=20). The average
      number of dissociated cells found to express the foreign gene product using beta
      galactosidase as a reporter construct was 3% (n=6). Furthermore, nontransformed
      and biolistically transformed islets responded similarly to an in vitro glucose
      challenge (stimulation index of insulin release at 20.0 mM glucose/insulin
      release at 2.8 mM glucose = 2.8 and 3.0, respectively, P=0.9). Syngeneic,
      biolistically transfected islets functioned to reverse the diabetic state when
      transplanted (500 islets) beneath the renal capsule of alloxan-induced diabetic
      BALB/c recipients (n=7). This methodology can achieve efficient transfection of
      pancreatic islets while preserving their function and thus holds promise for ex
      vivo gene therapy of isolated islets prior to transplantation.

PMID- 8669099
TI  - Cardioprotective effect of nicorandil in histidine-tryptophan-ketoglurate
      solution during the cold storage of isolated hearts.
AB  - We compared the efficacy of using histidine-tryptophan-ketoglurate (HTK) solution
      with that of University of Wisconsin (UW) solution for heart preservation in an
      isolated rat heart preparation. Nicorandil (NCR) exerts its action as an ATP
      sensitive potassium channel opener at low extracellular potassium concentrations,
      and HTK solution has a low potassium concentration. Therefore, we also
      investigated the efficacy of using HTK solution with NCR following 12-hr
      preservation. Hearts isolated from male Wistar rats were mounted on a Langendorff
      apparatus to estimate baseline aortic flow (AF), coronary flow (CF), cardiac out
      put (CO), heart rate (HR), systolic pressure (SP), aortic mean pressure, and the
      rate-pressure product (RPP). The hearts were divided into four groups: group 1, 8
      hr storage in UW solution; groups 2 and 3, 8- or 12-hr storage in HTK solution,
      respectively; and group 4, 12-hr storage in HTK solution with NCR. They were
      arrested and stored at 4 degrees C in each preservation solution. Following
      storage, they were reperfused and postpreservative function was measured to
      assess cardiac functional recovery. Concentrations of creatine phosphokinase,
      troponin-T, and lactate in the coronary perfusate were measured. Frozen tissue
      samples from groups 3 and 4 were analyzed for adenylate content and cGMP. The
      myocardial water content was also measured. The recovery of AF, CF, CO, SP, and
      RPP in group 2 was significantly improved compared with that in group 1 (P<0.05).
      The recovery of AF, CF, CO and HR in group 4 was significantly better than that
      in group 3 (P<0.05). Creatine phosphokinase leakage in group 2 and troponin-T
      leakage in group 4 were significantly reduced (P<0.05 vs. groups 1 and 3,
      respectively). Total adenine nucleotides and the adenylate energy charge in group
      4 were well sustained (P<0.05 vs. group 3). These results suggest that HTK
      solution is more effective than UW solution for cardiac preservation, and that
      NCR provides still better protection.

PMID- 8669100
TI  - One-year follow-up of an open-label trial of FK506 for primary kidney
      transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group.
AB  - Patients undergoing primary cadaveric kidney transplantation were followed for 1
      year as part of a phase II, multicenter, open-label concentration-ranging trial
      of FK506 and cyclosporine. One hundred twenty patients were randomly assigned to
      a cyclosporine-based regimen or one of three FK506-based regimens designed to
      achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough
      whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, or 0.4
      mg(kg/day, respectively. Patients with toxicity to FK506 had their target
      concentration reduced by lowering the dose of FK506. Ninety-two patients
      completed a 1-year follow-up to determine patient and graft survival and long
      term safety. At 1-year, the patient survival rate was 98% for FK506 and 92% for
      cyclosporine, and the graft survival rate was 93% and 89% in the FK506 and
      cyclosporine groups, respectively. The incidence of acute rejection was
      significantly lower (14% FK506, 32% cyclosporine, P=0.048) at day 42 after
      transplantation. However, the incidence of rejection episodes requiring treatment
      at 1 year was similar in both groups (33% for FK506 and 32% for cyclosporine).
      Nephrotoxicity occurred with a similar frequency with FK506 and cyclosporine, but
      the incidence of neurotoxic events and the incidence of new insulin use were
      higher among FK506-treated patients. The target range of whole blood levels that
      optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The
      corresponding recommended initial dose of FK506 for kidney transplant recipients
      is 0.2 mg/kg/day. These results indicate that the efficacy and safety of FK506
      were comparable to that for cyclosporine for primary immunosuppression in
      patients undergoing cadaveric kidney transplantation.

PMID- 8669101
TI  - Determinants of graft survival after renal transplantation.
AB  - We studied multiple determinants of graft survival at a single center and the
      effects of nonimmunologic graft loss on transplant survival. This retrospective
      study examined the results of 589 cadaver donor transplants performed between
      1986 and 1992. Graft survival rates were calculated using Kaplan-Meier estimates
      for both overall graft survival (all causes of graft loss) and immunologic graft
      survival (function lost due to acute or chronic rejection and noncompliance).
      Cadaver graft survival was significantly poorer with an increasing degree of DR
      mismatch (P=0.02). An analysis of pretransplant variables showed graft loss risk
      was highest with greater DR mismatches, two B-antigen mismatch, higher donor
      serum creatinine, and younger recipient age. After transplantation, acute
      rejection was the most significant factor associated with long-term graft
      survival. Our data demonstrate a significant advantage for zero DR and one DR
      mismatch cadaver donor transplants, with excellent immunologic graft survival.
      This study suggests that a combination of immediate graft function, prevention of
      acute rejection by appropriate early immunosuppressive therapy, and acceptable DR
      match enhances cadaveric graft survival.

PMID- 8669102
TI  - Pathologic features of acute renal allograft rejection associated with donor
      specific antibody, Analysis using the Banff grading schema.
AB  - Alloantibody frequently appears during the immune response to alloantigens in
      renal transplant recipients. We studied whether the presence of antibody against
      donor class I antigens correlated with the clinical and pathologic features of
      acute rejection episodes. We identified patients who had (1) clinical evidence of
      acute rejection, (2) a renal biopsy showing pathologic features of acute
      rejection, defined by the Banff criteria, and (3) pre- and posttransplant sera
      screened against donor T cells. We divided these patients into those with or
      without donor-specific alloantibody reactive with donor T cells. Of 44 patients
      with biopsy-proven rejection, 20 were antibody negative (Ab-R) and 24 were
      antibody positive (Ab+R). The biopsies from Ab+R patients had a higher incidence
      of severe vasculitis (P=0.0009) and glomerulitis (P=0.01). Fibrin thrombi in the
      glomeruli and/or vessels, fibrinoid necrosis, and dilatation of peritubular
      capillaries were also more frequent in the Ab+R group. Infarction was present in
      biopsy specimens from 9/24 Ab+R patients versus none in the Ab-R group (P=0.002).
      The Ab+R biopsy specimens more often had polymorphonuclear leukocytes in the
      peritubular capillaries (P=0.003). In contrast, specimens of Ab-R patients showed
      tubulitis more often than the specimens of Ab+R patients: moderate and severe
      tubulitis was present in 19/20 (95%) Ab-R patients versus 12/24 (50%) Ab+R
      patients (P=0.002). Graft loss was increased in Ab+R patients, particularly in
      the first 3 months (12/24 compared with 3/20, P=0.025). Thus, during biopsy
      proven acute rejection episodes, anti-class I antibody correlates with severe
      vascular lesions, glomerulitis, and infarction, whereas more severe tubulitis
      predominates in rejection episodes without antibody.

PMID- 8669103
TI  - Serum C-reactive protein. A useful and economical marker of immune activation in
      renal transplantation.
AB  - This study investigated whether serial daily measurements of serum C-reactive
      protein (sCRP) in 187 renal allograft recipients could help discriminate episodes
      of renal dysfunction due to rejection or cyclosporine (CsA) nephrotoxicity and
      help adjust immunosuppression in the early posttransplant period. Excellent
      primary graft function was associated with an initial peak of sCRP on day 2 after
      transplant (median, 29 microg/ml; range, 4 to >200 microg/ml) with a return to
      <20 microg/ml in all patients by day 5 (median, 7 microg/ml; range, 2-19
      microg/ml). Stable graft function (mean creatinine, 155 microg/ml) was
      accompanied by a median sCRP of 4 microg/ml (range, 1-19 microg/ml). In 30
      episodes of rejection responsive to methylprednisolone, sCRP was initially
      significantly raised to a median of 49 microg/ml (P<0.001) but fell rapidly in
      response to treatment to a median of 11 microg/ml and continued to fall. In 19
      episodes of rejection unresponsive to methylprednisolone, median initial sCRP
      levels were significantly higher (P<0.001) at 119 microg/ml and were still at a
      median of 77 microg/ml at the end of the treatment. Twenty-four patients in whom
      renal dysfunction was associated with CsA nephrotoxicity showed no increase in
      sCRP concentrations; median sCRP concentrations remained at <5 microg/ml
      throughout the episodes. A similar pattern was seen in patients with acute
      tubular necrosis. Serial sCRP measurements provide economical and reproducible
      evidence of immune activation, help discriminate renal dysfunction due to CsA
      nephrotoxicity or rejection, and allow appropriate modification of
      immunosuppressive therapy.

PMID- 8669104
TI  - Renal hemodynamics after lung transplantation. A prospective study.
AB  - Renal function impairment is common after solid organ transplantation, due to the
      nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory
      failure, renal function is often impaired. This renal function impairment may
      predispose patients to further renal function impairment after lung
      transplantation. Therefore, renal hemodynamics were measured in 44 patients
      before lung transplantation and 1, 6, 12, 18, 24, and 30 months after
      transplantation. After transplantation, a decline in renal function occurred,
      with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12
      months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5%
      at 12 months and remained stable thereafter. Changes in effective renal plasma
      flow (ERPF) were less pronounced than those of effective renal blood flow, due to
      a fall in hematocrit after transplantation. Blood pressure and renal vascular
      resistance increased significantly, consistent with the effects of cyclosporine.
      Prior to transplantation, renal function impairment with intense renal
      vasoconstriction had been found in a subset of the patients. Remarkably, the
      decrease in renal function after transplantation was less pronounced in patients
      with renal function impairment prior to transplantation, as indicated by
      significant negative correlations between pretransplantation GFR and the
      percentage change in GFR after transplantation, and pretransplantation ERPF and
      the percentage change in ERPF after transplantation. This suggests that the net
      course of renal hemodynamics after lung transplantation is the result of the
      opposed effects of cyclosporine nephrotoxicity and the favorable effects of the
      normalization of respiratory status. In conclusion, after lung transplantation a
      decline in renal function occurs that is less pronounced in patients with renal
      function impairment and intense renal vasoconstriction prior to transplantation.
      Such a renal function impairment, therefore, should not be considered a
      contraindication to lung transplantation.

PMID- 8669105
TI  - Rapid en bloc technique for pancreas-liver procurement. Improved early liver
      function.
AB  - It is our experience that warm dissection in the porta hepatis as well as
      extensive organ mobilization during combined pancreas-liver procurements may
      cause posttransplant dysfunction of the liver. To avoid this, we recently
      utilized a rapid en bloc procurement technique with minimal warm dissection and
      division of the liver and pancreas ex vivo. Fifteen procurements were performed
      using this rapid en bloc technique; seventeen procurements involved extensive
      dissection followed by sequential in situ procurement of the liver and pancreas
      grafts. The control group consisted of 15 age-matched patients who received
      livers when no pancreas was harvested. Dissection time was 157 +/- 13 min (mean
      +/- SEM) in the in situ group, 78 +/- 3 min in the en bloc group (P<0.02), and 51
      +/- 6 min in the liver only group (P<0.02). There was no difference in donor age,
      cold ischemia time, or recipient United Network for Organ Sharing status.
      Pancreata obtained using the en bloc technique all had immediate function and
      there were no episodes of acute pancreatitis. Early liver graft function, as
      assessed by lactate dehydrogenase, serum glutamic oxaloacetic transaminase, serum
      glutamic pyruvic transaminase, and total bilirubin levels, was significantly
      lower in the en bloc and liver only group when compared with the in situ group.
      The total hospital stay was also significantly lower in these groups. We conclude
      that the rapid en bloc technique decreases operative time during the donor
      operation. Procurement-related injury to the liver graft is minimized without
      compromising pancreas graft function.

PMID- 8669106
TI  - Antibody to CD18 reduces neutrophil and T lymphocyte infiltration and vascular
      cell adhesion molecule-1 expression in cardiac rejection.
AB  - Most antirejection therapies target immune activation but may not reduce
      leukocyte infiltration into the graft. The leukocyte integrin CD18 has been shown
      to be important for leukocyte migration in vitro. We postulated that antibody
      blockade of CD18 might reduce the migration of different leukocyte subpopulations
      into myocardium during rejection. Using a rabbit model, we evaluated the effect
      of a monoclonal antibody to CD18 on the infiltration of neutrophils
      (polymorphonuclear leukocytes [PMNs]), T lymphocytes, and macrophages into
      cardiac grafts. In addition, vascular cell adhesion molecule-1 (VCAM-1)
      expression was assessed to determine the relationship between leukocyte
      infiltration and VCAM-1 expression, an unblocked alternate adhesion pathway.
      Donor hearts from Stauffland rabbits were transplanted heterotopically into the
      cervical position of New Zealand White recipients. Recipient rabbits received
      either monoclonal antibody to CD18 daily without other immunosuppression (n=51),
      saline injections as placebo controls (n=52), or nonfunctional isotype-matched
      antibody (n=4). Recipient rabbits were killed at 1 hr, 6 hr, 24 hr, 3 days, and 7
      days after transplantation (10-12 rabbits per group at each time point). PMNs, T
      lymphocytes, and macrophages were differentiated by routine staining and
      immunocytochemistry, respectively, and quantified as the number of cells per
      standardized field. VCAM-1 expression was examined immunocytochemically in 30
      treated and 30 control transplanted hearts. Monoclonal antibody to CD18
      significantly reduced the infiltration of PMNs and T lymphocytes into myocardium
      during rejection, but did not affect the infiltration of macrophages. Blocking
      the CD18/intercellular adhesion molecule-1 adhesion pathway also resulted in a
      decrease in VCAM-1 expression, which correlated in time with the reduction in T
      lymphocyte infiltration.

PMID- 8669107
TI  - Quantitating immunosuppression. Estimating the 50% inhibitory concentration for
      in vivo cyclosporine in mice.
AB  - Cyclosporine (CsA) blocks T cell responses in vitro by inhibiting the phosphatase
      activity of calcineurin (CN) and thus preventing the activation of cytokine
      transcription. In the study presented here, we measured the extent of inhibition
      of these functions in the tissues of CsA-fed mice. Mice fed increasing doses of
      CsA were assessed for CsA blood and tissue levels, spleen cell CN activity, ex
      vivo spleen cell cytokine induction by A23187, and in vivo interferon-gamma
      induction during an allogeneic response. The CN activity of spleen homogenates
      and cell suspensions and the ex vivo cytokine responses of spleen cells from CsA
      treated mice were inhibited with a 50% inhibitory concentration (IC50) greater
      than 300 microg/L. The in vivo interferon-gamma response to an allogeneic ascites
      tumor was also inhibited by CsA treatment, with IC50s between 517 and 886
      microg/L. The true IC50 for CsA in vivo may be even higher, as CsA levels in
      spleen and kidney were 4-fold higher than concomitant blood levels. We conclude
      that inhibition of CN activity by systemically administered CsA leads to a
      parallel reduction in cytokine gene induction in response to an allogeneic
      stimulus. In light of our previous clinical findings that therapeutic levels of
      CsA in renal transplant patients were associated with only partial inhibition of
      CN activity, these current results support the concept that partial CN inhibition
      can account for both the immunosuppression and the immunocompetence of CsA
      treated patients.

PMID- 8669108
TI  - Plasma prostaglandin E1 concentrations and hemodynamics during intravenous
      infusions of prostaglandin E1 in humans and swine.
AB  - Prostaglandin (PG) E1 administered intravenously has been used for the treatment
      of primary nonfunction of hepatic allografts and fulminant hepatic failure. It
      has been proposed that this therapy may improve hepatic blood flow via the
      vasodilating properties of PGE1. However, PGE1 undergoes extensive metabolic
      inactivation by the lung and the concentration of PGE1 reaching the liver during
      intravenous administration has not been determined. Thus, we measured plasma PGE1
      concentrations in patients with hepatic dysfunction being treated with PGE1 and
      in a swine model of PGE1 infusion. We also determined the hemodynamic effects of
      PGE1 infusion in swine. Blood was sampled from the pulmonary artery, carotid
      artery, portal vein, and hepatic vein in swine infused with PGE1 (range, 0.67-4.9
      microg/kg/hr) demonstrating: (1) a pulmonary extraction ratio of PGE1 of 0.78 +/-
      0.12, (2) a splanchnic extraction ratio of PGE1 of 0.54 +/- 0.23, and (3) levels
      of PGE1 in the systemic circulation of </= 78 pg/ml, even at the highest infusion
      rates. Despite significant increases in body temperature and pulse rate, hepatic
      hemodynamics were not affected by the PGE1 infusions in healthy swine. Seven
      patients receiving intravenous PGE1 for hepatic dysfunction (0.11-1.30
      microg/kg/hr) had a pulmonary extraction ratio of 0.69 +/- 0.17. Systemic
      arterial concentrations of PGE1 were </= 62 pg/ml. These results suggest that due
      to clearance of PGE2 in the pulmonary and splanchnic circulations, current
      clinical protocols for intravenous administration of PGE1 are not likely to
      affect perihepatic hemodynamics.

PMID- 8669109
TI  - Restoration of immune abnormalities in diabetic BB rats after pancreas
      transplantation. I. Macrochimerism of donor-graft-derived RT6+ T cells
      responsible for restoration of immune responsiveness and suppression of
      autoimmune reaction.
AB  - Diabetes-prone (DP) BB rats (RT1(u), RT6.1) spontaneously develop insulin
      dependent diabetes mellitus (IDDM) and the disease manifestation resembles that
      in human IDDM. DP rats are immunodeficient with severe T lymphocytopenia due to
      the absence of T cells expressing the RT6 differential alloantigen, which have
      immunoregulatory functions. MHC- and non-MHC-compatible Wistar Furth (WF; RT1(u),
      RT6.2) pancreases were transplanted into DP rats. WF pancreas grafts were
      destroyed by IDDM recurrence (insulitis), but not by rejection, with a mean
      survival time of 65.3 +/- 21.7 days. To prevent the recurrence of IDDM in the
      grafts, monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte
      function-associated antigen-1 were administered. WF pancreas grafts were
      indefinitely accepted (>108.0 +/- 26.8 days) in monoclonal antibody-treated DP
      recipients. The number of T cells was increased and cellular immune responses
      restored only in the DP rats that had accepted grafts. The increased number of T
      cells was due to the peripheral appearance of donor-type RT6.2+ T cells, which
      represented 34.3 +/- 7.0% of total splenic T cells. The cytotoxicity of splenic T
      cells to WF islet cells was suppressed in the presence of RT6+ T cells in vitro.
      These findings demonstrated that stable macrochimerism of donor-derived RT6+ T
      cells could restore the immune responses and prevent the recurrence of IDDM in
      the DP recipients.

PMID- 8669110
TI  - RO 31-8220, a novel protein kinase C inhibitor, inhibits early and late T cell
      activation events.
AB  - The improvement of graft survival over the past decade has mainly been due to the
      development of more highly specific immunosuppressive agents, such as
      cyclosporine (CsA) and FK506. CsA and FK506 inhibit T cell activation by
      interfering with the calcium-mediated pathway, one of two pathways needed for T
      cell activation. The other pathway, mediated by protein kinase C (PKC), is not
      currently a target of any clinically used immunosuppressive agent. The purpose of
      this study was to assess the immunosuppressive properties of Ro 31-8220, a member
      of a new family of potent and selective PKC inhibitors. Peripheral blood
      mononuclear cells were isolated from the blood of normal human donors and
      utilized in a series of standard immunological assays. Three discrete activation
      events were inhibited by Ro 31-8220: mitogen-induced interleukin (IL)-2
      production (IC50 80 nM), IL-2-dependent T lymphoblast proliferation (IC50 350
      nM), and IL-2Ralpha (CD25) expression (control cells were 83% CD25+, mean
      fluorescence intensity = 163 +/- 4, 400-nM-treated cells were 56% CD25+, mean
      fluorescence intensity = 130 +/- 7). Noninhibitory doses of CsA (8 nM) or FK506
      (0.2 nM) suppressed mitogen-induced IL-2 production by 60-80% when combined with
      a noninhibitory dose (25 nM) of Ro 31-8220, indicating the potent synergy between
      these agents. The ability of Ro 31-8220 to inhibit both early and late activation
      events and to synergize with CsA/FK506 suggests that this family of compounds has
      great potential as immunosuppressive agents and as probes with which to elucidate
      the role of PKC in T cell activation.

PMID- 8669111
TI  - Kinetics of induction of transplantation tolerance with a nondepleting anti-Cd4
      monoclonal antibody and donor-specific transfusion before transplantation. A
      critical period of time is required for development of immunological
      unresponsiveness.
AB  - The combination of a depleting anti-Cd43 monoclonal antibody (mAb) and a single
      donor-specific transfusion before transplantation has been shown to induce
      operational transplantation tolerance in the majority of cardiac allograft
      recipients in a mouse model. To examine a protocol which might be more clinically
      relevant, we have modified this tolerance-inducing protocol by substituting the
      depleting with a nondepleting anti-Cd4 mAb. We show that this form of
      pretreatment can also induce immunologic unresponsiveness in most recipients
      (C3H/He, H2(k)), provided a critical period of time, in this case 28 days, is
      allowed between pretreatment and transplantation of a fully mismatched heart
      graft (H2(b)). When only 1 or 2 weeks were allowed between pretreatment and
      transplantation, only slight graft prolongation was obtained when compared with
      recipients receiving anti-Cd4 mAb alone, at these time points. Maintenance of
      tolerance in this model was due, at least in part, to active mechanisms as
      immunologic unresponsiveness to donor antigens could be transferred to naive
      syngeneic mice by splenocytes from recipients bearing long-term functioning
      grafts. These findings suggest that a population of regulatory cells develop
      after pretreatment with nondepleting anti-Cd4 mAb and donor-specific transfusion,
      and that it takes at least 1 month for these cells to expand and effectively
      drive the recipient's immune system toward immunologic unresponsiveness.

PMID- 8669112
TI  - Complete withdrawal of immunosuppression in allograft recipients. A study in
      rhesus monkeys.
AB  - The influence of pretransplant blood transfusions on kidney allograft survival
      after cessation of immunosuppressive treatment was studied in 11 rhesus monkeys.
      The animals were conditioned by three pretransplant blood transfusions. After an
      induction treatment with cyclosporine (CsA), the immunosuppression was stopped
      and the natural course of the graft was followed. In two monkeys long-term graft
      survival without immunosuppression was obtained (2.5 and 4.25 years). In a third
      monkey, permanent allograft acceptance was achieved after complete cessation of
      immunosuppression. The monkey is still alive with a well-functioning graft for
      more than 13 years after cessation of immunosuppression. This monkey had received
      CsA for 12 months, two MHC DR-matched blood transfusions, and no repeated
      mismatches between graft and blood transfusion donors. We speculate that blood
      transfusions may influence allograft function in two opposite ways. As reported
      previously in man, MHC class-II-matched transfusions appear to beneficially
      influence allograft survival. This effect seems to be negated by a mismatched MHC
      class II antigen in the blood transfusion donor which is also present in the
      organ donor -- a so-called repeated mismatch. Further studies in rhesus monkeys
      are required to confirm and extend these results. In the future, these
      observations might help in developing a protocol that opens up the possibility of
      cessation of immunosuppression in transplant patients.

PMID- 8669113
TI  - Ischemic colitis secondary to venous thrombosis. A rare presentation of
      cytomegalovirus vasculitis following renal transplantation.
AB  - Gastrointestinal complications occur after renal transplantation in up to 16% of
      patients. Cytomegalovirus (CMV) vasculitis can affect the gastrointestinal tract
      with significant manifestations, including colonic ulceration, bleeding, and
      perforation. We present a case of CMV vasculitis in a renal transplant patient
      that caused middle and left colic vein thrombosis and resultant ischemic colitis.
      There was no evidence of arterial involvement. To our knowledge, this is the
      first reported case of ischemic colitis secondary to large vein thrombosis
      associated with CMV infection.

PMID- 8669114
TI  - Renal transplantation in a case of mannosidosis.
AB  - Mannosidosis is an inherited autosomal recessive mucopolysaccharidosis. Patients
      affected accumulate mannose-rich compounds in various tissues and excrete an
      increased quantity of oligosaccharides with mannose as a component. A case of
      type II mannosidosis with end-stage renal failure is reported. The patient, after
      6 years of regular hemodialysis treatment, received a kidney transplant. At the
      time this article was written, the graft was functioning well and thesaurismotic
      renal deposits had not been observed. The clinical course of mannosidosis was
      silent and the patient's quality of life was good. Although the risk of
      recurrence could not be excluded, it seems that renal transplantation can be
      safely offered to patients affected with mannosidosis type II, in the rare
      setting of chronic renal failure.

PMID- 8669115
TI  - Multiple primary malignancies in a renal transplant patient.
AB  - Organ transplantation and the use of immunosuppressive therapy has been
      associated with an increased incidence of malignancy. We report the case of a
      long-term renal transplant recipient who developed concomitant skin cancers, non
      Hodgkin's lymphoma, and malignant fibrous histiocytoma. The development of three
      seemingly unrelated cancers in the same patient illustrates the favorable host
      environment in transplant patients for the development of malignancies.

PMID- 8669116
TI  - Persistence of cyclosporine after withdrawal of the drug in a patient with
      chronic liver transplant rejection. Role of the monoethylglycinexylidine test.
AB  - Patients with chronic rejection of liver allografts may show persistently high
      cyclosporine levels. This phenomenon may be due to a down-regulation of the P450
      cytochrome system. The monoethylglycinexylidine test was useful in confirming
      this hypothesis.

PMID- 8669117
TI  - Guidance of ganciclovir therapy with pp65 antigenemia in cytomegalovirus-free
      recipients of livers from seropositive donors.

PMID- 8669118
TI  - Myelosuppression associated with azathioprine-allopurinol interaction after heart
      and lung transplantation.
AB  - It is widely recommended that, during concurrent therapy with allopurinol, the
      azathioprine dosage should be decreased by at least two thirds. We
      retrospectively studied compliance with this guideline in 24 patients who had
      commenced allopurinol at a median of 33 months (range, 2-145 months) after heart
      and/or lung transplantation. The median reduction in azathioprine dose at
      initiation of allopurinol was 73.3% but ranged from 0% to 90% (>67% in 14
      patients). Within 3 months, 11 (46%) of the patients became leukopenic (white
      blood cell count <4 x 10(9)/L), 7/23 (30%) became moderately anemic (hemoglobin
      <10 g/dl), and 5/23 (22%) became thrombocytopenic (platelets <150 X 10(9)/L).
      Decreasing the dose of azathioprine by two thirds or greater reduced but did not
      abolish the risk of myelotoxicity. These data highlight the need for close
      hematological monitoring of patients treated with this drug combination. Agents
      other than allopurinol should be considered for treating hyperuricemia after
      thoracic organ transplantation.

PMID- 8669119
TI  - The identity of proliferating donor-derived cells in tolerant mice.

PMID- 8669120
TI  - Surgical treatment itself induces bacterial translocation.

PMID- 8669121
TI  - A criticism of the data on arterial ketone body ratio of living donors from
      Shinshu University.

PMID- 8669122
TI  - California dreamin' 'bout endothelin: emerging new therapeutics.
AB  - Progress in our understanding of endothelins has been extremely rapid since their
      discovery in 1988. A number of pharmaceutical companies have developed potent,
      orally active, nonpeptide endothelin receptor antagonists with efficacies in a
      wide variety of animal disease models and potential for treating human disease.
      However, only time will tell whether or not these compounds are developed into
      drugs that are perceived as worthy of a place in the therapeutic marketplace. If
      this is the case, endothelin will have been promoted from the status of striking
      scientific discovery to therapeutic target in a remarkably short period.

PMID- 8669123
TI  - Structure and regulation of phospholipase D.

PMID- 8669124
TI  - Redox state, NMDA receptors and NO-related species.

PMID- 8669125
TI  - Conformational induction versus conformational selection: evidence from
      allosteric enhancers.

PMID- 8669126
TI  - Benzodiazepines on trial: a research strategy for their rehabilitation.
AB  - Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, tolerance,
      dependence, and the potential for drug abuse plague the clinical use of
      anxiolytic benzodiazepines. Benzodiazepine and non-benzodiazepine ligands that
      are in current clinical use act as full allosteric modulators of GABA-gated Cl-
      channels, and on chronic administration trigger compensatory changes in the
      subunit expression of GABAA receptors. In these putative abnormal receptors, full
      allosteric modulators have low intrinsic activity and potency, and tolerance and
      dependence ensue. In this review, Erminio Costa and Alessandro Guidotti discuss
      the development of partial allosteric modulators, such as imidazenil, which have
      high potency and low intrinsic activity at GABA-gated Cl- channels. Since in
      animals tolerant to full allosteric modulators imidazenil also fails to show
      cross-tolerance, it is an example of a new type of anxiolytic and anticonvulsant
      drug acting at GABAA receptors via benzodiazepine recognition sites.

PMID- 8669127
TI  - [The formation of the karyosphere in the oogenesis of insects and amphibians].
AB  - This review deals with the authors' own and literary data on the ultrastructural
      and cytochemical organization of insect and amphibian oocyte nuclei, with special
      attention being paid to the karyosphere and its capsule. The evidence provided is
      supplemented with data on isolated karyospheres in Rana temporaria oocytes. A
      conclusion is made that the karyosphere is a complex structure which contains all
      chromosomes in the limited space of the oocyte nucleus, and that these
      chromosomes are, as a rule, in the process of inactivation. It is inferred that
      the karyosphere capsule commonly appears in gigantic oocyte nuclei (more than 100
      micron in diameter) containing extrachromosomal DNA. The analogy of capsule
      organization in different invertebrate and vertebrate species is discussed, in
      addition to the involvement of presumably homologous nuclear structures (e.g.
      derivatives of synaptonemal complexes and nuclear envelope) in capsule formation.
      It is assumed that the karyosphere capsule is a specially organized part of the
      nuclear matrix. The capsule provides nuclear compartmentalization and chromosome
      localization in the germinal vesicle. Studies of this sort open up new
      possibilities to further investigation of intranuclear morphogenesis.

PMID- 8669128
TI  - [Saltatory movements of the cytoplasmic granules in the cells of an ESK culture].
AB  - Saltatory movements of large (0.3-0.8 micron) granules in the cytoplasm of PK
      cells were described in norm and after nocodazole and sodium azide treatments. In
      untreated cells the length of single movements was up to 2 micron and even more
      (sometimes up to 5 micron). Nocodazole at a concentration of 0.2 micron and
      sodium azide at a concentration of 20 micron inhibited all rapid movements longer
      than 1.2 micron, but did not affect the frequency of movements shorter than 1
      micron. The effect of nocodazole was reversible: the long rapid movements were
      seen resumed after its removal. A comparison of histograms (length versus
      frequency) of the rapid movements of granules in norm and after nocodazole and
      sodium azide treatments made it possible to conclude that real saltations (ATP
      and microtubule-dependent motions) are rapid translocations which exceed 1
      micron.

PMID- 8669129
TI  - [The polyploidization characteristics of the hepatocytes of the mouse-like
      hamster Calomyscus mystax].
AB  - A cytophotometric measurement of DNA content in hepatocytes of maturing mouse
      like hamsters was made. Cells belonging to ordinary mammalian ploidy classes 2c,
      2c x 2, 4c, and 4c x 2 made about 90% of the hepatocyte population. The share of
      binucleated cells wa high (about 80%), the majority of these cells being 2c X 2
      hepatocytes. Binucleated cells with tetraploid and diploid nuclei occur in almost
      every animal. An average hepatocyte ploidy level in mouse-like hamster is 4.6c.
      The main peculiarity of parenchymal liver cell populations is that up 5% of
      hepatocytes contain 3--11 nuclei of different ploidy classes. Multinucleated
      cells increase in number from 1.5% to 4% within the period from one year (the age
      of maturation) to two years. Later on their percentage does not change. It is
      found that in binucleated and multinucleated hepatocytes DNA synthesis can
      proceed asynchronously. Asynchrony in DNA synthesis elevates as the number of
      nuclei increases. Among the 2c x 2 and 2c x 3 cells an uneven distribution of 3H
      thymidine label can occur, respectively, in 5 and in 50% cases, whereas all the
      cells with more than 3 nuclei display an uneven an uneven 3H-thymidin label
      distribution. The formation of multinucleated cells is supposed to be associated
      with asynchrony in DNA-synthesis in binucleated cells and with the restitution of
      mitosis.

PMID- 8669130
TI  - [Individual variability in the number of stem cells in mammalian tissues].
AB  - The distribution of animal groups (3--4 control or gamma-irradiated mice per
      group) were obtained when analysing published data on the mean number of the CFUs
      in the femoral bone marrow or stem cells of small intestinal crypt. Almost 50% of
      such groups have the mean number less than the geometric mean. The mean value for
      the group of animals deviation from the expected geometric mean for all animal
      population for more than 2.5 times, both for the larger values and for the
      smaller, was about 5% in such groups for the marrow CFUs and 20% for intestinal
      stem cells. The percentage of mice, that died from acute radiation sickness after
      acute irradiation, was related with the parameter D(0), that characterized the
      CFUs survivability on the exponential part of the survivability curve. The
      negative correlation (r = -0.83) was determined between the mean value of the
      small intestine crypt stem cells and the ability of intestinal stem cells to the
      radiation damage reparation, evaluated through the parameter D(q) of the stem
      enterocyte survival curve for this animal groups.

PMID- 8669131
TI  - [The physical mapping of human chromosomes. The use of the polymerase chain
      reaction on unique DNA sequences with a known location on chromosome 3].
AB  - 16 pairs of oligonucleotide primers, complementary to unique DNA sequences of
      human chromosome 3, were synthesized. For 10 of these, fragments of expected
      length were generated in polymerase chain reaction (PCR). These fragments may be
      used as markers for detailed physical mapping of this chromosome. The above
      primers were used in PCR in order to analyse a hybrid mice-human cell line which
      contained presumably a fragment of human chromosome 3. The presence of human DNA
      in the hybrid line has been shown, but no ultimate evidence was received to
      confirm its location in human chromosome 3. By means of primers, complementary to
      the butyrylcholinesterase gene (BCHE), pools of clones from the yeast total
      library of human DNA were analysed, and then the pool and later the individual
      [correction of undividual] clone, containing a fragment of BCHE gene, were
      identified.

PMID- 8669132
TI  - [The small Alu-like RNA from the A-431 cell line specifically regulates the
      activity of the RNA polymerase III from human placental nuclei].
AB  - The influence of small Alu-like RNA, isolated from specific RNP complexes (alpha
      RNP), on the activity of RNA polymerase III in cell-free system has been studied.
      The RNAs transcribed in vitro from Alu-DNA template (BLUR, 8) were isolated and
      subjected to polyacrylamide gel electrophoresis. A specific stimulation of RNA
      polymerase III activity by alpha-RNA was demonstrated.

PMID- 8669133
TI  - [The control mechanisms of the electrokinetic properties of human erythrocytes in
      emotional stress].
AB  - A study was made of the influence of psycho-emotional strain, experienced by
      students when taking examinations, on the erythrocyte electrophoretic mobility
      (EPM). It has been shown that students under psycho-emotional strain the mean
      value of EPM remains the same, but changes were observed in the form of EPM
      distribution, while estimated by asymmetry and excession coefficients. Similar
      results were obtained when adrenalin was added to the blood.

PMID- 8669134
TI  - [Cellular interactions in the intracellular parasitism of cryptosporidia. I. The
      effect of Cryptosporidium parvum on the phosphatase activity in the small
      intestine enterocytes of experimentally infected newborn rat pups].
AB  - Cytochemical methods for detection of non-specific phosphatases were employed at
      the light microscope level for identification of enzymatic activity in the small
      intestine of new-born rats (6--11 days old), both infected and non-infected with
      the intestinal coccidium Cryptosporidium parvum. In the new-born rats, the level
      of alkaline and especially acid phosphatase is originally very low, suggesting
      their insignificant involvement in digestion processes in suckling animals
      compared to rats of older age (3 month old). However, a heavy colonization of the
      brush border of the intestinal villi of the new-born rats with cryptosporidia
      results in obvious inactivation of phosphatases in the infected enterocytes, in
      contrast to the neighbouring parasite-free host cells. The general picture of
      metabolic interaction between cells of a unicellular parasite (C. parvum) and
      those of its metazoan host (rat) much resembles that observed in the course of
      Elmeria spp. infection, but differs from that induced by Toxoplasma gondii
      endogenous stages in the cat intestine. Details of cell interaction with
      intracellular parasitism need additional studies at the ultrastructural level.

PMID- 8669135
TI  - The herpes simplex virus type 1 transactivator ICPO mediates aberrant
      intracellular localization of the viral helicase/primase complex subunits.
AB  - The infected cell polypeptide 0 (ICP0) protein of herpes simplex virus type 1
      (HSV-1) is a promiscuous transactivator. When expressed by transfection, ICP0
      forms spherical structures in the nucleus. Using a double-label
      immunofluorescence assay, we have found that the HSV-1 helicase/primase complex
      subunits accumulate within ICP0 structures in cotransfected cells. This
      phenomenon was also observed in cells coexpressing ICP0 and UL6, a protein
      thought to be involved in the cleavage and/or packaging of viral genomes. ICP0
      structures were found to be proteinaceous by immunoelectron microscopy. These
      results suggest that ICP0 may interact nonspecifically with a variety of viral
      proteins.

PMID- 8669136
TI  - [Mathematical model of the cyclic variability of the influenza virus].
AB  - A mathematical model has been constructed on the basis of the hypothesis of
      cyclic variability of influenza A agent. This model simulates shift changes as a
      sequence of pulses of antigenic activity of five subtypes, these pulses being
      shifted in respect of each other and repeating in cycles.

PMID- 8669137
TI  - [Production of type I interferons in the body exposed to yeast RNA-tiloron
      molecular complexes].
AB  - Molecular complexes forming as a result of interaction between yeast RNA
      preparations with 2,7-bis[-(diethylaminoethoxy)-fluorene]-9-on dihydrochloride
      (tilorone) administered parenterally to mice cause the appearance of interferon
      in high titers compatible to those induced by standard inductors of
      polyribonucleotide origin, poly(I)-poly(C) and larifan. Some physiologic
      conditions of interferonogenesis have been studied. The above molecular complexes
      in the dose range used experimentally were completely nontoxic. Hence, these
      complexes are promising agents for interferon induction.

PMID- 8669138
TI  - [Effect of mesodiencephalic modulation on peripheral blood immunocompetent cells
      in viral-bacterial infections].
AB  - The effect of mesodiencephalic modulation (MDM) on peripheral blood
      immunocompetent cells during a mixed viral/bacterial infection was studied in 10
      patients aged 15 to 35 suffering from acute respiratory diseases complicated by
      lacunar tonsillitis. Control group consisted of 10 patients aged 16 to 42. A
      course of MDM consisted of 4-5 daily 10-min sessions. MDM alleviated the course
      of respiratory diseases complicated by lacunar tonsillitis at the expense of
      activating body response to inflammation and due to immunomodulating effect of
      electropulse exposure on lymphocyte subpopulations.

PMID- 8669139
TI  - [Ultrastructural analysis of pathological changes in ferrets with experimental
      canine distemper].
AB  - Morphologic study of the lungs, liver, spleen, and kidneys of ferrets infected
      with canine distemper virus has been carried out. Electron microscopy revealed
      virus reproduction in bronchial epithelial cells, types I and II alveolocytes,
      bile duct epitheliocytes, and hepatocytes. Mononuclear phagocyte system cells
      infected with the virus were found in all the examined organs. The most expressed
      pathological changes were observed in the lungs.

PMID- 8669140
TI  - [Lissaviruses].

PMID- 8669141
TI  - [Development of an optimal scheme for calculating results of the use of an
      immunoenzyme test-system for determining the antigenic activity of a cultured
      antirabies vaccine].
AB  - Ninety-eight lots of commercial antirabies vaccine manufactured by Immunopreparat
      Research and Production Amalgamation have been tested using enzyme immunoassay
      system for the detection of rabies virus antigens. Comparison of different
      variants of interpreting and expressing the results helped define the optimal
      method for assessment of vaccine titer and reference values: optical density
      value equal to 0.2 is taken as the cut-off. Antigenic activity of the vaccine may
      be expressed in international units, similarly as immunogenic activity.

PMID- 8669142
TI  - [Genetic differentiation of hantaviruses using the polymerase chain reaction and
      sequencing].
AB  - Thirty-two hantavirus strains and 8 samples of lung tissue from rodents collected
      in different regions of Russia have been examined by molecular biological
      methods. Two methodological approaches have been employed for the study of
      genetic relationships between the viruses: nested PCR assay and common RT-PCR
      with subsequent direct sequencing of 200 and 365 base pair of G2 protein encoding
      regions of M-segment, respectively, and the resultant sequences were compared
      with those of the prototype hantavirus. The study revealed a mosaic pattern of
      distribution of different hantavirus genotypes on the territory of Russia.

PMID- 8669143
TI  - [Preparation of monoclonal antibodies to super early human cytomegalovirus
      proteins and their use for detecting infected cells].
AB  - Twenty-six mouse hybridomas producing monoclonal antibodies (MAB) to human
      cytomegalovirus (CMV) proteins have been obtained. MAB produced by three
      hybridomas were studied in detail. MAB were active in indirect immunofluorescence
      and solid-phase enzyme immunoassay, being directed to the super-early viral
      protein p72. Use of the resultant MAB for analysis of CMV-infected cells
      demonstrated that by specificity and sensitivity of viral antigen detection they
      were not inferior to anti-CMV antibodies manufactured by Ortho, USA. Screening of
      258 patients with suspected CMV infection showed that these MAB may be used for
      immunofluorescent detection of CMV antigens in the material isolated from
      patients and infected subjects.

PMID- 8669144
TI  - [Survival of Marburg virus infectivity on contaminated surfaces and in aerosols].
AB  - Marburg virus was shown to survive for up to 4-5 days on contaminated surfaces.
      In aerosol it was not stable, the specific rate of its inactivation being 0.05
      min-1. This brought the authors to a conclusion that a relatively close contact
      is needed for virus transmission from man to man, although the possibility of
      aerosol transmission of the infection may be appreciably increased in case of the
      hemorrhagic syndrome with a high level of viremia.

PMID- 8669145
TI  - [Current strategies for vaccine prevention of influenza].
AB  - Six-year immunologic surveillance of schoolchildren vaccinated according to
      different schedules in the town of Novgorod demonstrated the efficacy of overall
      vaccinations of children and young people with live anti-influenza vaccines in
      autumn and winter for 2 years. Then an interval of 3 years is to be made,
      followed by another 2-year revaccination cycle, provided the same serologic
      subtypes of influenza A and B are still circulating.

PMID- 8669146
TI  - [Prophylactic effectiveness of a live recombinant influenza type A vaccine in
      immunizing children aged 3-14 years].
AB  - Children aged 3 to 14 were immunized with live recombinant influenza A vaccine;
      about 120,000 children were followed up for 6 months. Analysis of the morbidity
      (excepting ARVI and influenza) of the immunized and control groups permitted a
      conclusion about the safety of the preparation. The protective index of vaccine
      efficacy during influenza epidemic caused by A/Taiwan/1/86(H1N1) virus was 1.3 to
      1.42. Live recombinant influenza vaccine is recommended for public health to be
      used for protection of children aged 3 to 14 from influenza.

PMID- 8669147
TI  - [A method of concentrating viruses in environmental water sources].
AB  - The authors propose an effective and simple method for the collection and
      concentration of enteroviruses from environmental water bodies, which is based on
      adsorption properties of macroporous glass (MPG). MPG enveloped in water
      permeable coating permits concentration directly in the water. Poliomyelitis
      viruses were 100-1000-fold concentrated in laboratory trials. The advantages of
      the new method in comparison with the routine gauze tampon method were
      demonstrated in experiments with the indicator virus carried out at sewage works
      and under field conditions.

PMID- 8669148
TI  - [Disinfecting action of chloramine B on Marburg virus].

PMID- 8669149
TI  - [Nonisotopic variant of quantitative analysis using polymerase chain reaction for
      diagnosing HIV infection].

PMID- 8669150
TI  - [Dot-blot analysis in laboratory diagnosis of hemorrhagic fever with renal
      syndrome].
AB  - A sensitive micro EIA utilizing antigen or antibody dotted onto nitrocellulose
      filters (Dot-ELISA, Dot-blot) has been developed for laboratory diagnosis of
      hemorrhagic fever with the renal syndrome (HFRS) by detecting the virus specific
      IgM and IgG in the sera of HFRS patients and the antigen in crude lung
      suspensions of wild rodents. Measurements of specific IgM and IgG in paired HFRS
      sera collected during the first month of the disease showed clear-cut
      seroconversion and 100% correlation with the results of immunofluorescent test.
      The results of antigen detection in lung suspensions of 605 wild rodents trapped
      in various regions of Russia were identical to standard ELISA results. This rapid
      and inexpensive test may be useful in early serologic diagnosis of HFRS and in
      field serological and epizootological studies.

PMID- 8669151
TI  - [Japanese encephalitis in citizens of Russia who travel abroad].
AB  - Typical and atypical forms of Japanese encephalitis (JE) in the Russians visiting
      Asian countries endemic for JE are described. A patient who contracted the
      disease in China developed 5 months after returning to Russia acute
      meningoencephalitis with mental disorders and a lethal outcome on day 5 with
      bulbar symptoms. JE virus (strain SP-69) was isolated from his brain. By
      antigenic and genetic properties this strain occupies an intermediate position
      between Jagar-01 and Nakayama serotypes. A pregnant woman (6 months gestation)
      who lived in Birma for 3 years suffered from encephalitis running a protracted
      (more than 6 months) course; mildly manifest pyramidal signs were detected in her
      one-year-old infant with a normal mental status. Serologic studies showed that
      the disease was caused by infection with Jagar-01 serotype of JE virus. A patient
      contracting the disease 1 month after arrival in Japan developed a recurrent
      pattern of the illness: the diagnosis of JE was confirmed by repeated detection
      of virus-neutralizing anti-bodies in the blood and liquor. None of the patients
      was vaccinated against JE. Indications to prophylactic vaccination of subjects
      leaving for countries endemic for JE are discussed.

PMID- 8669152
TI  - Integration of health care delivery. Report of a WHO Study Group.
AB  - WHO defines health by use of the term "well-being". Many people have a more
      limited view, however, seeing health as no more than the absence of illness. This
      limited view is reflected in the various "vertical" programmes that aim to combat
      a specific disease or carry out a particular medical intervention. The
      achievements of vertical programmes have been tremendous in eradicating or
      reducing disease. But there remains the obvious but very important problem that a
      programme that deals with one disease has but limited effect when health is
      influenced by a range of different factors. Health care has to be provided in an
      integrated manner if it is to have maximum impact in raising health standards.
      This report by the WHO Study Group on Integration of Health Care Delivery is a
      frank assessment of ways to achieve a more holistic approach to health promotion
      and care. This means not just bringing together different elements of the health
      system but also strengthening health-related activities in other sectors. The
      report looks at ways countries have tried to do this-some successful and some not
      so successful. The report proposes a model of an integrated district health care
      system. It is a model in which different levels of health care and different
      approaches to health care both coexist and complement each other. A detailed plan
      of action contains guidelines for health care integration at district, as well as
      national and international, levels. The report will be useful for policy-makers,
      planners and all who have responsibility for organizing a health care system that
      most fully meets the needs of the whole community.

PMID- 8669153
TI  - Hypertension control. Report of a WHO Expert Committee.
AB  - Hypertension is the commonest cardiovascular disorder, affecting about 20% of the
      adult population in many countries. It is linked with coronary heart disease,
      stroke, congestive heart failure and renal dysfunction and is one of the major
      risk factors for cardiovascular mortality, which accounts for 20-50% of all
      deaths. Raised awareness of the public health and economic implications of
      hypertension is now directing attention to the need for long-term control
      programmes that focus on primary prevention, early detection and adequate
      treatment. This report of a WHO Expert Committee reviews the epidemiology and
      pathophysiology of hypertension, enumerates its risk factors and predictors, and
      makes specific proposals for its prevention and control in populations. Current
      approaches to the assessment and management of patients with hypertension are
      discussed, with emphasis on the general usefulness of systolic blood pressure
      measurements and on the special features of hypertension in children and
      adolescents, women, elderly people and those with diabetes. The potential impact
      of lifestyle changes is evaluated, together with the various pharmacological
      treatment options. While recognizing the need to take account of resource
      constraints and diversity in health care systems, the Committee recommends that
      hypertension control programmes are set up worldwide as part of a comprehensive
      strategy to reduce total cardiovascular risk. Its practical recommendations for
      policy, hypertension management and research are intended to guide decision
      makers in public health, managers of control programmes and physicians and to
      facilitate the selection of cost-effective means of controlling hypertension in
      different socioeconomic settings.

PMID- 8669154
TI  - Multiple organ failure.

PMID- 8669155
TI  - Differences in esophageal cancer treatments.

PMID- 8669156
TI  - Rate of ipsilateral breast tumor recurrence.

PMID- 8669157
TI  - [New trends in the therapy of cardiac insufficiency. Symposium, Buhl, 5-7
      February 1993].

PMID- 8669158
TI  - Atherosclerosis and cholesterol. The end of the controversy?

PMID- 8669159
TI  - [Pulmonary mycobacteriosis due to Mycobacterium xenopi" in-vitro sensitivity to
      classical antitubercular agents and clinical development].
AB  - Out of 11 patients suffering from Mycobacterium xenopi lung disease, 9 were
      treated with an empiric antituberculous triple chemotherapy until specific
      identification and antibiogram were available. Despite the important "in vitro"
      resistance to drugs, most of the patients improved; in the other patients, the
      impairment was always due to the underlying pathology. We conclude that the "in
      vivo" response of M. xenopi infections to antituberculous drugs is little
      influenced by the "in vitro" sensitivity.

PMID- 8669160
TI  - Belgian multicentre study on the in vitro activity of cefepime against gram
      negative bacilli.
AB  - The in vitro activity of cefepime has been compared with that of cefotaxime,
      ceftazidime, aztreonam, and piperacillin against 1826 Enterobacteriaceae
      including 537 inducible Enterobacteriaceae (Enterobacter spp., Serratia spp.,
      Citrobacter spp,. Morganella morganii) and 572 non-fermenters, including 401
      Pseudomonas aeruginosa and 111 Acinebacter spp. isolated from hospitalized
      patients in 28 Belgian hospitals. Overall, cefepime was found substantially more
      active than the third-generation cephalosporins, aztreonam and piperacillin
      against Enterobacteriaceae species producing inducible type I cephalosporinases.
      Notably, cefepime remained active against 96% of Enterobacteriaceae resistant to
      cefotaxime, ceftazidime or aztreonam while it displayed a similar activity
      against E. coli and the other Enterobacteriaceae. Against non-fermenters,
      cefepime was found less active than ceftazidime but more than cefotaxime or
      aztreonam.

PMID- 8669161
TI  - Erythropoietin and the anemia of cancer.
AB  - The pathogenesis of the anemia of cancer involves the combination of a shortened
      erythrocyte survival in circulation with the failure of bone marrow to increase
      red cell production in compensation. Inappropriate red cell production is itself
      related to a conjunction of factors, including impaired availability of
      reticuloendothelial storage iron, inadequate erythropoietin (Epo) response to
      anemia, and overproduction of cytokines which are capable of inhibiting
      erythropoiesis. Many of these cytokines may interfere with erythropoietin
      production by the kidney. Consequently inadequate serum erythropoietin levels are
      often encountered in cancer patients, though more frequently in those with solid
      tumors or multiple myeloma than in those with other hematologic malignancies.
      There is little evidence supporting a negative impact of chemotherapy, including
      cisplatin, on erythropoietin production. Rather, chemotherapy usually causes a
      transient elevation of serum Epo. Red cell transfusions are often administered to
      cancer patients, possibly resulting, among other deleterious effects, in
      enhancement of tumor growth. Recombinant human erythropoietin (rHuEpo) has thus
      been proposed as an alternative. RHuEpo has been shown to be safe and effective
      in correcting the anemia of cancer and reducing the need for transfusions. The
      response rate is as good in hematologic malignancies as in solid tumors, but it
      is extremely poor in those with myelodysplastic syndromes. The effect of rHuEpo
      does not differ among patients receiving or not receiving chemotherapy, including
      cisplatin. The probability of response is also similar in patients with adequate
      or inappropriate erythropoietin production before therapy, although the doses
      used are usually 2 to 3 times higher than in renal failure patients.

PMID- 8669162
TI  - [Acute tubulo-interstitial nephropathy with uveitis: apropos of case].
AB  - We report another case of acute interstitial nephritis with uveitis (TINU
      syndrome) in a 35-year-old woman. About thirty cases were described since the
      first ones 20 years ago. We discuss the assessment needed to reach the diagnosis.
      The evolution is unusually favourable with steroid therapy.

PMID- 8669163
TI  - Fatal septic shock due to Lancefield group G streptococci.
AB  - We describe two cases of fatal septic shock caused by Lancefield group G
      streptococci. Both were community-acquired and occurred in previously healthy
      adults. Both patients died in severe multiple organ failure despite prompt
      antibiotic therapy. Serological typing of bacterial cultures identified the T
      protein antigen as serotype 300, but this was thought to be of little relevance
      to the pathogenesis; T-protein antigens are useful as epidemiological markers. M
      typing and PCR (polymerase chain reaction) detection of the streptococcal
      pyrogenic exotoxin genes were found to be negative suggesting that this highly
      pathogenic organism may represent a new M-type.

PMID- 8669164
TI  - Digital necrosis associated with chronic myeloid leukaemia: a rare paraneoplastic
      phenomenon ... or toxicity of recombinant interferon?

PMID- 8669165
TI  - Catheter-related intracardiac septic thrombosis.

PMID- 8669166
TI  - Combined treatment with methotrexate and ursodeoxycholic acid in non-cirrhotic
      primary biliary cirrhosis.
AB  - In the treatment of patients with primary biliary cirrhosis (PBC), methotrexate
      (MTX) and ursodeoxycholic acid (UDCA) have both been associated with clinical,
      biochemical, and histologic improvement. Studies with methotrexate have only been
      performed in uncontrolled conditions. We conducted a prospective controlled study
      on the combined treatment with methotrexate and ursodeoxycholic acid, comparing
      the clinical, biochemical, and histologic evolution in six untreated patients
      with that in eight patients treated with MTX 15 mg/week in association with UDCA
      500 mg/day. All patients had noncirrhotic PBC and were followed up for two years.
      A significant decrease of alkaline phosphatase, glutamic pyruvic transaminase,
      and gamma-glutamyltranspeptidase was found in the methotrexate/ursodeoxycholic
      acid treated-group, as compared to the control group. The clinical and histologic
      evolution, however, was not significantly different in the two groups.
      Methotrexate toxicity consisted of interstitial pneumonitis in one, of a
      transient rise of transaminases at three months in five, and of a significant
      decrease of blood platelets and white blood cells after two years of treatment.
      In controlled conditions, a two-year treatment with methotrexate and
      ursodeoxycholic acid does not produce a significant clinical or histologic
      benefit. Based on this experience, and taking into account the possible risks
      associated with this therapy, the empiric use of methotrexate cannot be
      recommended in patients with non-cirrhotic PBC.

PMID- 8669167
TI  - Polymerase chain reaction amplification of human papillomavirus DNA from
      archival, Papanicolaou-stained cervical smears.
AB  - OBJECTIVE: To test the applicability of four protocols in recovering DNA suitable
      for amplification with the polymerase chain reaction (PCR) in archival,
      Papanicolaou-stained cervical smears. STUDY DESIGN: The most efficient method was
      used to isolate DNA from 11 archival, Papanicolaou-stained smears with cytopathic
      changes due to human papillomavirus (HPV) infection to confirm the presence of
      HPV DNA. RESULTS: beta-Globin was successfully amplified in all smears, while HPV
      DNA was detected in 6 of 11. Four of the four HPV DNA-negative smears were
      classified as high grade squamous intraepithelial lesions. Failure to detect HPV
      DNA might have been due to the low copy number of HPV DNA or deletion of the L1
      region. CONCLUSION: High cellularity and the method of recovering DNA from the
      smear are important determinants of successful amplification of HPV DNA in
      archival cervical smears.

PMID- 8669168
TI  - Freeze substitution and freeze drying for stable, long-term preservation of
      cytologic specimens for immunostaining.
AB  - OBJECTIVE: To develop a new method of fixing and preserving cytologic specimens
      for immunostaining after long-term storage at room temperature. STUDY DESIGN: The
      method consists of three steps: fixation, freeze substitution or freeze drying,
      and storage. To test the method, we used the human small cell lung carcinoma cell
      line Lu-135, which expresses a high level of mutant p53 protein and exhibits
      strong nuclear staining when reacted with an anti-p53 antibody. A smear of Lu-135
      cells was fixed in a mixture of methanol and ether (50:50=vol/vol) or sprayed
      with a fixative containing isopropyl alcohol, methanol and polyethylene glycol.
      The fixed cells were freeze substituted by immersing them in a dry
      ice/methanol/ether bath and then were freeze dried under a vacuum. The smear was
      then placed in a 50-mL conical tube containing silica gel. The tube was sealed
      and stored at room temperature. RESULTS: Freeze substituted cells that were fixed
      with methanol/ether and stored for more than six months retained strong p53
      positivity, as strong as that of the control cells, which had been fixed and
      stored in methanol. CONCLUSION: Freeze substitution and freeze drying are an
      alternative method of preserving cytologic specimens.

PMID- 8669169
TI  - Detection of perforin in human peritoneal fluid T-lymphocytes.
AB  - OBJECTIVE: Perforin is a specific marker of functionally active cytotoxic T
      lymphocytes (CTLs) and natural killer (NK) cells. The purpose of this study was
      to detect perforin-positive lymphocytes in ascites secondary to various
      gynecologic malignancies and nonneoplastic conditions. STUDY DESIGN: Fifty-three
      unselected peritoneal fluid specimens submitted for cytopathologic diagnosis were
      used. A monoclonal antibody to human perforin was used to examine its expression
      in mononuclear cells from ascites specimens using a standard immunoperoxidase
      technique. RESULTS: Strong perforin expression by 15-30% of mononuclear cells was
      detected in 10 of the 13 patients with severe alcoholic hepatitis, 3 of the 5
      patients with chronic active hepatitis without cirrhosis and 1 patient with an
      autoimmune disorder of unknown etiology. The lymphocytes showed variable
      positivity for T cell markers (CD2, CD4, CD8 and CD56). Perforin was not detected
      in ascites specimens obtained from patients with such nonneoplastic disorders as
      cirrhosis or end stage renal or cardiac failure. Similarly, ascites specimens
      from patients with various gynecologic malignancies were negative for perforin
      positive lymphocytes. CONCLUSION: The detection of cytotoxic lymphocytes in
      peritoneal fluid obtained from patients with liver injury may have implications
      for the pathogenesis of this disease.

PMID- 8669170
TI  - Lactoferrin in thyroid lesions: immunoreactivity in fine needle aspiration biopsy
      samples.
AB  - OBJECTIVE: Lactoferrin is an iron-binding protein that has been used for
      distinguishing normal from neoplastic conditions in many different tissues. In
      order to improve evaluation of thyroid lesions, we studied the lactoferrin
      immunoreaction in cytologic smears obtained by fine needle aspiration and in
      biopsy samples from primary neoplasms and from adenomatous goiter. STUDY DESIGN:
      A retrospective study on fine needle aspiration cytology samples and
      corresponding available biopsies from thyroid lesions in patients examined at Sao
      Paulo County Hospital between 1982 and 1992, performed in order to evaluate
      lactoferrin immunoreactivity in morphologically well characterized samples from
      neoplastic and nonneoplastic lesions. Immunoperoxidase procedures were performed
      using monospecific polyclonal rabbit antihuman lactoferrin as a primary antibody
      and biotinylated goat antirabbit IgG as a secondary antibody. Amplification was
      performed with the avidin-biotin-peroxidase complex, and the color sign of the
      positive reactions was developed using a diaminobenzidine solution. RESULTS:
      Lactoferrin was not detected in cytologic smears from goiters, whereas only one
      biopsy was slightly positive (1/21, or 4.76%). One smear from adenoma showed low
      positive staining (1/19, or 5.26%), which was present in 4 of 13 biopsies
      (30.77%) from adenoma. Papillary carcinomas were positive in 19 of 33 smears
      (57.58%) and in 100% of biopsies, whereas 31.25% (5/16) of follicular carcinoma
      smears were positive for lactoferrin, detected in all the biopsy samples.
      CONCLUSION: Lactoferrin immunoreactivity was strongly associated with neoplastic
      proliferation and may be used as a useful auxiliary marker to distinguish
      malignant from benign thyroid lesions in cytologic smears and biopsy samples.

PMID- 8669171
TI  - Size of thyrocyte nuclei in aspirates from follicular adenomas: correlation with
      patients' ages.
AB  - OBJECTIVE: To determine whether the size of thyrocyte nuclei in aspirates from
      follicular adenoma correlates with the age of patients. STUDY DESIGN: The
      karyometric parameters were evaluated in routine aspirates, obtained from 27
      patients with follicular adenoma as diagnosed in postoperative histopathologic
      examinations. The ages of the patients ranged from 11 to 70 years (36.8 +/- 16.3,
      x +/- SD). The cytologic examination of all the aspirates before surgery revealed
      "follicular neoplasms." The karyometric evaluation was performed with Karyometry
      Manager, version 1.2, an image analysis computer system. RESULTS: Neither the
      mean nuclear volume, mean nuclear intersection area nor mean nuclear perimeter
      correlated with the ages of the patients. CONCLUSION: These results suggest that
      in contrast to nodular goiter, in the cytologic examination of follicular
      neoplasms, the ages of patients should be disregarded when interpreting the size
      of thyrocyte nuclei.

PMID- 8669172
TI  - Studies on intranuclear inclusions and nuclear grooves in papillary thyroid
      cancer by light, scanning electron and transmission electron microscopy.
AB  - OBJECTIVE: To successively examine intranuclear inclusions and nuclear grooves in
      the same papillary thyroid cancer specimens using a light microscope (LM),
      scanning electron microscope (SEM) and transmission electron microscope (TEM).
      STUDY DESIGN: We stained cells by the Papanicolaou method after fixation in 1.25%
      glutaraldehyde for LM and then attempted to observe them successively by SEM-TEM
      after fixation in 2% paraformaldehyde and 2% osmium tetroxide. RESULTS: On SEM,
      intranuclear inclusions were observed as elevated parts, like hills, and nuclear
      grooves were observed as deep fissures or shallow cracks, sometimes with a few in
      one cell. On TEM, both intranuclear inclusions and nuclear grooves seemed formed
      by the nuclear membranes. Intranuclear inclusions also possessed cytoplasm and/or
      cytoplasmic organelles within some expanded areas in the nuclear grooves.
      CONCLUSION: It was evident from our three-step technique that intranuclear
      inclusions and nuclear grooves were essentially the same structures.

PMID- 8669173
TI  - Nondiagnostic fine needle aspiration biopsy of the thyroid gland: a diagnostic
      dilemma.
AB  - OBJECTIVE: To evaluate all nondiagnostic fine needle aspiration biopsy (FNAB)
      specimens from the thyroid gland with subsequent histopathologic diagnoses at
      Ottawa Civic Hospital. The criterion for specimen adequacy used in our
      institution was also reexamined to determine if it was too stringent. STUDY
      DESIGN: Review of 114 nondiagnostic FNAB samples from 91 patients with subsequent
      histopathologic diagnoses formed the basis of this study. Specimen adequacy was
      determined by the presence of 8-10 fragments of well-preserved follicular cells
      on at least two smears. RESULTS: Review of the 91 surgical specimens found 50
      nodular goiters, 23 follicular adenomas, 6 macrofollicular adenomas, 5 cases of
      thyroiditis, 5 true cysts, 1 papillary carcinoma and 1 minimally invasive
      follicular carcinoma. Forty-two percent of lesions showed cystic change. In
      addition, nine cases of papillary microcarcinoma were diagnosed. A considerable
      difference in the rate (22% vs. 45%) of inadequate thyroid FNAB samples was
      identified among different groups of physicians at our institution. CONCLUSION:
      Ninety-eight percent of the patients with nondiagnostic FNAB of the thyroid gland
      had benign lesions. This finding encouraged us to continue using our criteria for
      adequacy because of the importance of a negative report. The higher rate of
      nondiagnostic thyroid aspiration in our series may reflect the varied experience
      of the different aspirators at our institution and/or the cystic nature of many
      of the lesions.

PMID- 8669174
TI  - Serous surface carcinoma of the peritoneum: useful role of cytology in
      differential diagnosis and follow-up.
AB  - OBJECTIVE: To determine the role of cytology in differentiating serous surface
      carcinoma of the peritoneum (SSCP) from other morphologically similar tumors,
      including ovarian carcinoma and other peritoneal lesions, and to define the value
      of cytology in the follow-up of patients with SSCP. STUDY DESIGN: Twenty-one
      ascitic fluids and seven peritoneal washings obtained from 19 patients with
      histologically confirmed SSCP were reviewed and their cytologic features
      tabulated and analyzed. RESULTS: Eighteen of the specimens were from initial
      diagnostic paracenteses or exploratory laparotomies. These showed mostly three
      dimensional tumor cell clusters, as well as single malignant cells, with
      occasional papillae. The cytoplasm was abundant and often vacuolated. The
      cytomorphologic features of SSCP enabled differentiation from other conditions
      involving the peritoneal surface, including mesothelial hyperplasia, malignant
      mesothelioma, endometriosis and endosalpingiosis. However, there were no
      characteristic features that differentiated SSCP from metastatic serous carcinoma
      of the ovary. Four of the peritoneal washings were from second-look operations;
      in each of these cases the presence of tumor cells in the cytologic preparations
      correlated with positive biopsy results. Furthermore, six of the paracenteses
      were performed for recurrent ascites and enabled detection of recurrent disease,
      obviating the need for invasive procedures. CONCLUSION: Cytomorphologic
      examination of ascitic fluids and peritoneal washings serves a valuable role in
      the initial diagnosis of SSCP, in the detection of recurrent disease and as a
      useful adjunct to multiple biopsies in the second-look operation. It can
      differentiate SSCP from several other lesions but not from serous carcinoma of
      the ovary.

PMID- 8669175
TI  - CA-15.3 assay in effusions: comparison with carcinoembryonic antigen and CA-125
      assay and cytologic diagnosis.
AB  - OBJECTIVE: To compare the sensitivity of CA-15.3 with cytologic diagnosis and
      carcinoembryonic antigen (CEA) and CA-125 content and to determine if elevated CA
      15.3 suggests a breast primary. STUDY DESIGN: A retrospective study of 111
      consecutive effusions. CEA was measured by enzyme immunoassay (cutoff > 5 ng/mL),
      CA-125 by radioimmunoassay (cutoff > 5,000 micron/mL) and CA-15.3 by
      radioimmunoassay (cutoff > 15 micron/mL). Results were correlated with cytologic
      diagnosis, histology (when available), clinical and radiologic data, and follow
      up. RESULTS: The results were: benign, 39; malignant, 72; sensitivities and
      specificities: cytology, 76%/100%; CEA, 80%/97%; CA-125 22%/100%; and CA-15.3,
      69%/89%. The sensitivity of CEA and cytology was 97% and of CA-15.3 and cytology,
      87%. Neither mean (293.4 micron/mL) nor range of CA-15.3 predicted a breast
      primary. Falsely elevated CEA and CA-15.3 were noted in ascites with fecal
      contents from colonic perforation. High CA-125 and low CEA predicted an
      ovarian/endometrial primary. CONCLUSION: CA-15.3 assay in effusions is not
      recommended since it neither enhances the sensitivity of cytologic diagnosis nor
      predicts a breast primary.

PMID- 8669176
TI  - Fine needle aspiration diagnosis of hepatocellular carcinoma in metastatic sites.
AB  - OBJECTIVE: To describe the fine needle aspiration (FNA) findings in metastatic
      hepatocellular carcinoma (HCC). STUDY DESIGN: The cytologic findings in 15 cases
      of extrahepatic metastatic HCC diagnosed by FNA biopsy were reviewed. RESULTS:
      The anatomic sites of the FNAs were: musculoskeletal (four biopsies from 3
      patients), adrenal (4 patients), regional lymph nodes (4 patients), pancreas (2
      patients) and pelvic region (1 patient). The 15 aspirates came from 14 patients,
      11 of whom had a biopsy-proven primary HCC. In two of the remaining patients, the
      FNA diagnosis of HCC in the metastatic site was the initial diagnosis. In one of
      these patients the diagnosis was strongly suspected on clinical grounds, but in
      the other case it was unsuspected. In the remaining patient the liver mass and
      massive retroperitoneal adenopathy were biopsied concurrently. A trabecular
      pattern was observed in the smears and/or cell block preparations in nine cases.
      Eleven cases were well to moderately differentiated. Three cases were of large
      cell pleomorphic type. The remaining case was poorly differentiated. CONCLUSION:
      Familiarity with the FNA cytology of HCC should allow its diagnosis in metastatic
      sites in most instances, even without a history of primary liver cancer.

PMID- 8669177
TI  - Hepatoblastoma in fine needle aspirates.
AB  - OBJECTIVE: To analyze cytomorphologic characteristics of hepatoblastoma (HB) and
      evaluate the feasibility of recognizing its histologic subtypes in smears. STUDY
      DESIGN: Fine needle aspirates from 14 primary and 1 metastatic HB were
      reexamined. The diagnosis of HB was confirmed by tissue examination (10 cases)
      and by clinical and laboratory findings alone (5 cases). RESULTS: In 12 samples,
      neoplastic cells resembled immature hepatocytes but were smaller and had a higher
      nuclear/cytoplasmic ratio. In nine of these smears the cells were rather uniform,
      while the other three presented with moderate pleomorphism. The cells were
      arranged in three-dimensional clusters, loose sheets, cords, rosettelike
      structures and occasional pseudopapillae and were dispersed. CONCLUSION: With
      knowledge of the cellular features and architectural patterns of HB, a reliable
      diagnosis could be obtained in 12/15 cases without the use of special techniques.
      In the remaining three aspirates the tumor cell population partly or entirely
      differed from normal hepatocytes, requiring ancillary techniques for proper
      diagnosis. On reexamination of the 10 cases with tissue diagnoses, 4/6 mixed HBs
      could be correctly subtyped, whereas the distinction between embryonal and fetal
      cells in four cases of epithelial HB seemed questionable.

PMID- 8669178
TI  - Aspiration cytology of renal cell carcinoma and adenoma in childhood.
AB  - OBJECTIVE: To describe the cytologic features of renal cell carcinoma (RCC) and
      renal papillary adenoma in children. STUDY DESIGN: Analysis of three cases of RCC
      and one of renal papillary adenoma. RESULTS: Cytologic features of pediatric RCC
      were essentially the same as those seen in adults and are characterized by cells
      with abundant, vacuolated cytoplasm with pleomorphic nuclei. RCC should be
      distinguished from the more common Wilms' tumor. Cells with abundant, vacuolated
      cytoplasm and absence of blastemal cells were two important distinguishing
      features. A large number of papillae, intranuclear inclusions and magenta bodies
      were important cytologic features of renal papillary adenoma. CONCLUSION:
      Cytologic features of RCC and adenoma in childhood are characteristic, and
      preoperative diagnosis of these cases is possible by aspiration cytology.

PMID- 8669179
TI  - Fine needle aspiration cytology of mycetoma.
AB  - OBJECTIVE: To describe fine needle aspiration cytology of mycetoma and determine
      its usefulness in diagnosis. STUDY DESIGN: The study group consisted of 14
      patients with different types of mycetoma lesions, which were aspirated. Smears
      were reviewed without knowing the type of mycetoma, and the findings were
      compared with those observed in histologic sections. RESULTS: In mycetoma, the
      causative organisms have a distinct appearance on cytologic smears. They are
      surrounded and infiltrated by neutrophils in a background of polymorphous,
      inflammatory cells consisting of neutrophils, histiocytes, lymphocytes, plasma
      cells, macrophages and foreign body giant cells. This allows differentiation from
      artifacts and inflammatory lesions caused by other bacteria and fungi. The
      distinction between eumycetoma and actinomycetoma in fine needle aspiration
      cytology was found to be as accurate as is histopathology when the grains were
      present. CONCLUSION: These results demonstrate that mycetoma can be accurately
      diagnosed by fine needle aspiration cytology. The technique is simple,
      inexpensive, rapid and sensitive. It can be used in the routine diagnosis of
      mycetoma, in epidemiologic surveys and in material collection.

PMID- 8669180
TI  - Cytologic characteristics of tubulolobular carcinoma of the breast.
AB  - OBJECTIVE: To determine the cytologic characteristics of tubulolobular carcinoma,
      a rare tumor of the breast in which the histologic features of both tubular and
      lobular carcinoma are combined. STUDY DESIGN: Review of fine needle aspirates and
      corresponding intraoperatively prepared touch imprints of eight cases of
      tubulolobular carcinoma. RESULTS: Low nuclear grade of tumor cells, low mitotic
      activity, intracytoplasmic vacuoles, single filing of cells and presence of
      tubular structures were observed in both preparations in most cases. Apocrine
      cells and a relatively clean background, both of which are generally considered
      to be cytologic indicators of benign breast conditions, were variably present.
      CONCLUSION: Tubulolobular carcinoma should be strongly considered in the
      differential diagnosis when the cytologic features of both tubular and lobular
      carcinoma coexist, particularly in cases in which the distinction between tubular
      and lobular carcinoma may have therapeutic implications.

PMID- 8669181
TI  - Fine needle aspiration biopsy of superficial sites in patients with hemostatic
      defects.
AB  - OBJECTIVE: To ascertain the incidence and types of complications of fine needle
      aspiration biopsies (FNABs) of superficial sites in patients with uncorrected
      congenital or acquired hemostatic defects. STUDY DESIGN: All patients with
      hemostatic defects who were seen in a community-based, private fine needle
      aspiration and medical laboratory practice were identified. Prospectively and
      retrospectively collected data concerning complications, biopsy findings and
      laboratory data on the hemostatic defects were collated and analyzed. RESULTS:
      Twenty-one patients encountered over a period of about nine years were
      identified. Warfarin sodium therapy was the most common cause of a hemostatic
      defect (12 patients), and lymph nodes were the most often aspirated structure (7
      patients). Other than a small echymosis in one patient, there were no
      complications. CONCLUSION: FNAB of superficial sites using the technique
      described is a safe procedure in patients with uncorrected hemostatic defects.

PMID- 8669182
TI  - Quality control of immunocytochemical staining of effusions using a standardized
      method of cell processing.
AB  - OBJECTIVE: To improve the quality and reproducibility of immunocytochemical
      staining of effusions by using a standardized method of cell processing. STUDY
      DESIGN: The study included the specimens of 108 effusions (44 benign, 56
      adenocarcinoma metastases and 8 mesotheliomas). Hemorrhagic effusions were lysed
      using isotonic ammonium chloride. All pellets were fixed in 1% paraformaldehyde
      dissolved in phosphate-buffered saline (PBS), pH 7.4, and washed in PBS. A Burker
      counting chamber was used to adjust the pellets to a standard cell concentration.
      The panel of monoclonal antibodies (MAbs) included MOC-31, Ber-EP4 and
      anticarcinoembryonic antigen (anti-CEA). The alkaline phosphatase/anti-alkaline
      phosphatase technique was applied. RESULTS: Standardized material processing
      resulted in reproducible specimens with good preservation of cell morphology,
      reduction of nonspecific interaction and good immunostain intensity. MAbs MOC-31
      and Ber-EP4 gave similar results: both were positive in all adenocarcinomas. Anti
      CEA was positive in 73%. Benign effusions showed no expression. In contrast to
      the literature, seven mesotheliomas showed variable membranous expression of MOC
      31 and Ber-EP4. CONCLUSION: High-quality immunostaining results were obtained by
      using a standardized method of cell processing. MAbs MOC-31 and Ber-EP4 cannot be
      used as differentiation markers between mesotheliomas and adenocarcinomas.
      Discrepancies in immunocytochemical staining results may be caused partly by
      differences in cell preparation.

PMID- 8669183
TI  - External quality assurance in cervical/vaginal cytology: Interlaboratory
      agreement in the Emilia-Romagna region of Italy.
AB  - OBJECTIVE: To evaluate the diagnostic agreement between seven cervical/vaginal
      cytology laboratories participating in the first external quality assurance (EQA)
      scheme developed in Italy. STUDY DESIGN: Between 1991 and 1993, 110 cytologic
      smears were selected and classified by a committee and circulated and reported on
      by the laboratories according to the 1988 Bethesda System. Agreement was
      evaluated with the kappa statistic. Systematic disagreement was assessed by means
      of the Wilcoxon signed rank test. RESULTS: Interlaboratory kappa values varied
      between .01 and .29 (group score, .11) for sample adequacy and between .53 and
      .78 (group score, .67) for epithelial abnormalities. The lowest specific kappa
      values were observed for the three classes of sample adequacy (unsatisfactory,
      .07; less than optimal [LTO], .10; satisfactory [SAT], .14) and for the class of
      atypical cells of undetermined significance (ACUS), (.29). As compared with the
      study committee, 5/7 laboratories showed a systematic (P<.01) tendency to
      undercall sample adequacy. Agreement on epithelial abnormalities was also
      analyzed according to the pattern of adequacy reported by paired laboratories
      (LTO/LTO, LTO/SAT, SAT/SAT). As compared with smears designated SAT/SAT, those
      classified as LTO/SAT were associated with lower specific kappa values for
      agreement on the presence of carcinoma and ACUS and with equal or greater values
      for agreement on the other classes, suggesting an arbitrary use of notations of
      LTO inversely related to the severity of epithelial lesions. CONCLUSION: EQA
      schemes, as applied to cervical/vaginal cytology, can shed light on major
      deficiencies in specific diagnostic areas.

PMID- 8669184
TI  - Prevalence, identification and significance of fiber contaminants in cervical
      smears.
AB  - OBJECTIVE: To determine the prevalence of fiber contaminants, to provide
      morphologic descriptions of various fiber types and to try to understand the
      significance of their presence in cervical smears. STUDY DESIGN: Fibers from
      cotton swab tips, hair, cardboard slide transporters, Cytobrush bristles and
      three commercial brands of tampons were smeared onto glass slides, Papanicolaou
      stained and examined. Then a prospective study of consecutively screened
      cervicovaginal smears from 1,368 women was undertaken to identify fiber
      contaminants. RESULTS: Fibers were identified in 178 cases (13%). In 120, the
      fibers were considered extrinsic, commonly having the microscopic features of
      cardboard. In 58, the fibers were considered to be intrinsic to the smear because
      of their presence in the same plane and alignment as the cells, an associated
      inflammatory cell reaction, and adherent or absorbed cellular products,
      occasionally hemosiderin. The most common intrinsic fibers were cotton and rayon.
      No statistically significant relationship was identified for the presence of
      intrinsic fibers and patients' ages, stated menstrual dates or pathologic
      lesions. CONCLUSION: Fiber contaminants are commonly present in cervicovaginal
      smears, usually do not originate in the patient (are "extrinsic") and have no
      pathologic significance. Knowledge of the microscopic features of fiber
      contaminants enables them to be identified confidently and distinguished from
      fungal hyphae and other filamentous pathogens.

PMID- 8669185
TI  - Efficacy of monolayer preparations for cervical cytology: emphasis on suboptimal
      specimens.
AB  - OBJECTIVE: To compare specimen adequacy and detection of disease in conventional
      cytologic smears and CytoRich monolayer preparations. STUDY DESIGN: Five hundred
      sixty pairs of conventional smears and monolayer preparations were compared. The
      conventional smear was made first, and the remaining cells were rinsed off into a
      vial containing transport medium. Monolayer slides were then prepared using the
      CytoRich system. RESULTS: Evaluation of cases for specimen adequacy based on the
      Bethesda System demonstrated that the CytoRich method eliminated preparations of
      poor quality, reducing significantly the number of suboptimal specimens (28.3%
      for conventional vs. 8.4% for CytoRich). The final diagnosis concurred in 82.8%
      of cases. In 8 cases the CytoRich slide showed a low grade or more severe lesion,
      while the conventional smear was "atypical" (ASCUS) in 7 cases of squamous
      intraepithelial lesion and unsatisfactory in 1 case of invasive carcinoma. In
      three cases the conventional smear showed a low or high grade lesion, while the
      CytoRich slide was atypical. CONCLUSION: The CytoRich method significantly
      reduces suboptimal preparations and the associated ambiguous or inconsistent
      diagnoses. It detects cervical abnormalities better than does the conventional
      smear. It may result in cost savings for the community and benefit patients since
      unnecessary recalls are avoided.

PMID- 8669186
TI  - Sample size calculations for rescreening cytologic smears.
AB  - OBJECTIVE: To describe a method of calculating sample size if rescreening of
      cytologic material becomes necessary for legal or other reasons. The number of
      specimens to be reexamined must be large enough to provide adequate confidence in
      the results and small enough to minimize the cost of investigation. CONCLUSION:
      Except under very unusual conditions, the sample size is larger than generally
      thought.

PMID- 8669187
TI  - Mortality from cervical carcinoma in Mexico: impact of screening, 1980-1990.
AB  - OBJECTIVE: To determine the temporal mortality trends of uterine cervical cancer
      in Mexico for the period 1980-1990. STUDY DESIGN: In Mexico, data from death
      certificates are collected in a national repository at the National Institute of
      Statistics, Geography and Informatics. These data were analyzed to obtain
      mortality trends, and regional variations were obtained for the same period using
      a Poisson regression model. RESULTS: The official mortality figure for cervical
      cancer for the study period was 37,982 cases. Subregistration due to
      misclassification was evident, particularly in the first five years of the study
      period; however, poor quality of information was proportionally distributed
      across the different age groups. A standardized analysis by quinquennia showed a
      steady mortality trend during the last 10 years, with slightly upward significant
      trends within some age groups (beta=0, P<.05). High regional variations in
      cervical cancer mortality risks were found using a Poisson regression model.
      Twenty-four states in Mexico showed an increased mortality risk when compared
      with Mexico City; seven states showed a steady or downward trend. CONCLUSION: The
      results show the ineffectiveness of the cancer screening program, underscoring
      the need to ensure access to and the quality of the cervical cancer screening
      program in order to decrease mortality rates.

PMID- 8669188
TI  - Diagnostic efficacy and validity of the ThinPrep method in cervical cytology.
AB  - OBJECTIVE: To examine the efficacy of the ThinPrep method, an automated, fluid
      based technique for the collection and preparation of exfoliated and aspirated
      cells in cervical cytology. STUDY DESIGN: A total of 251 patients participated.
      From each patient a sample was obtained by scraping with a wooden spatula, split
      and prepared with both conventional Papanicolaou and ThinPrep methods. In the
      ThinPrep processor, epithelial cells were homogenized in a vial of preservative
      solution and randomly sampled onto a microscopic slide. From a single vial of
      sample suspension a series of 10 ThinPrep slides of the same quality were made.
      All cells were concentrated within an approximately 20-mm-diameter circle in a
      uniform, thin layer on the ThinPrep slide. RESULTS: Twenty-five percent of the
      screening area, 10% of the epithelial cells observed and 50% of the screening
      time were required to arrive at a final diagnosis as compared with the
      Papanicolaou smear. Virtually complete concurrence was ascertained between the
      Papanicolaou and ThinPrep diagnoses, for direct agreement of 95.3% and agreement
      within one diagnostic grade of 99.5%. CONCLUSION: An overall improvement was
      ascertained in the preparation of microscopic slides and the recognition of
      abnormal cells with the ThinPrep method.

PMID- 8669189
TI  - Nipplelike protrusions in endocervical and other cells: further observations.
AB  - OBJECTIVE: To explore the possibility that artifact, such as externally applied
      mechanical stress, may contribute to the formation of nipplelike nuclear
      protrusions in certain predisposed cells. STUDY DESIGN: The following specimens
      were examined for the presence and morphology of nipplelike protrusions: 100
      endocervical smears, 40 bronchial specimens (brushings, washings and
      bronchoalveolar lavage) and fine needle aspirates of seven lactating adenomas and
      10 fibroadenomas of the breast. RESULTS: Nipplelike nuclear protrusions in
      endocervical cells were present in the majority of gynecologic endocervical
      smears showing abundant endocervical cells virtually regardless of menstrual
      status. They were observed frequently in bronchial specimens and fine needle
      aspirates of lactating adenoma of the breast. CONCLUSION: It appears that
      nippling in cytologic preparations is a common phenomenon, particularly in benign
      endocervical and bronchial columnar cells, and may be found in other tissues and
      some neoplasms as well. The apparent nonspecificity of nippling, together with
      the association with other phenomena, such as nuclear "holes", stripped nuclei,
      nuclear distortion and cellular degeneration, strongly suggests that nippling may
      be largely the result of mechanical stress during smearing, brushing or other
      phases of specimen procurement or preparation. Nucleoli may serve as a nidus for
      nipple formation. Other qualities of a cell, including fragility and cytoplasmic
      features, may predispose it to the formation of nippling.

PMID- 8669190
TI  - Influence of smear quality on the rate of detecting significant cervical
      cytologic abnormalities.
AB  - OBJECTIVE: To determine the correlation between cervical smear quality and the
      rate of detecting significant epithelial abnormalities. STUDY DESIGN: Smear
      quality was assessed routinely in a series of 68,328 cervical spatula and
      spatula/brush combination smears received by our laboratory during 1993. Quality
      was assessed using a semiquantitative method, evaluating the presence of
      endocervical cells, metaplastic squamous cells, endocervical mucus and overall
      squamous cellularity. RESULTS: Smear quality was graded as unsatisfactory, poor
      (18,680 smears), fair (9,739 smears) or good (39,909 smears); unsatisfactory
      smears were eliminated from the analysis. There was a highly significant
      correlation between smear quality and the rate of detecting significant
      epithelial abnormalities (chi 2=127.52, df=2, P<.001). CONCLUSION: Smear quality
      is an important issue. Many significant abnormalities are potentially missed
      because of poor smear quality.

PMID- 8669191
TI  - Cytologic features of well-differentiated villoglandular adenocarcinoma of the
      cervix.
AB  - OBJECTIVE: To evaluate the cytologic features of villoglandular adenocarcinoma of
      the cervix in cervical smears. STUDY DESIGN: Eleven cervical smears from six
      patients with histologically proven villoglandular adenocarcinoma were reviewed.
      RESULTS: All smears were positive for tumor upon retrospective evaluation and
      revealed similar cytologic features. The tumor cells were abundant and were shed
      in sheets, tight clusters and tissue fragments. Papillary projections, clusters
      with smooth borders and flattened cells at the periphery, strips with peripheral
      nuclear palisading and pseudostratification, and rosettes were present. Nuclear
      crowding and overlapping were prominent. The nuclei were small, ovoid and
      hyperchromatic. The chromatin was granular and evenly distributed. Nucleoli were
      absent or inconspicuous. Mitoses were present. CONCLUSION: VGA may cause
      diagnostic difficulty because it shares some morphologic similarities with
      adenocarcinoma in situ, squamous cell carcinoma in situ involving endocervical
      glands, endometrial cells directly sampled with the Cytobrush and reactive
      endocervical cells. However, the above constellation of features should permit a
      cytologic diagnosis.

PMID- 8669192
TI  - Cytopathology in the Socialist Republic of Vietnam.
AB  - OBJECTIVE: To determine the differences and similarities between cytopathology
      practice in Vietnam and North America. STUDY DESIGN: Through the sponsorship of
      Friendship Bridge, we traveled to Hanoi and Ho Chi Minh City, Vietnam, in January
      1994. By visiting hospitals and medical centers in each city, we observed how
      economic, demographic and social factors affected cytopathology practice.
      RESULTS: In Vietnam, the resources of the medical system, cytopathology in
      particular, are devoted to diagnosis rather than prevention. Consequently,
      screening tests, such as the Papanicolaou smear for the detection of cervical
      vaginal lesions, are not performed on a routine basis. There are regional
      differences in Vietnam in the employment of common techniques, such as fine
      needle aspiration biopsy. CONCLUSION: Although limited in funds, cytopathology is
      widely practiced and serves an important role in the medical system of Vietnam.

PMID- 8669193
TI  - Cytologic manifestations of respiratory syncytial virus pneumonia in
      bronchoalveolar lavage fluid: a case report.
AB  - BACKGROUND: Respiratory syncytial virus (RSV) pneumonia in immunocompromised
      patients, especially bone marrow transplant recipients, is associated with high
      mortality. Early diagnosis in these cases is important because antiviral therapy
      with ribavirin is effective in reducing mortality. CASE: A 45-year-old male with
      multiple myeloma who underwent autologous peripheral stem cell transplantation
      subsequently developed bilateral pulmonary infiltrates. A bronchoalveolar lavage
      specimen demonstrated the cytologic changes associated with RSV pneumonia.
      Infection with RSV was confirmed by indirect immunofluorescence, enzyme
      immunoassay and, later, on histology and electron microscopy at autopsy.
      CONCLUSION: Recognition of the cytologic changes associated with RSV pneumonia in
      immunodeficient patients can be life saving since this would initiate
      confirmatory immunologic studies and therapy.

PMID- 8669194
TI  - Nonasbestos ferruginous bodies in sputum from a patient with graphite
      pneumoconiosis: a case report.
AB  - BACKGROUND: Inhalation of graphite dust can cause lung disease, mostly in the
      form of mixed-dust pneumoconiosis in individuals working in the metallurgic
      industry or graphite mines. The morphologic landmark of graphite pneumoconiosis
      is nonasbestos ferruginous bodies with a black graphite core. CASE: In the sputum
      of an 81-year-old male, characteristic nonasbestos ferruginous bodies were
      identified. The occupational history confirmed long exposure to natural graphite
      in metallurgy. CONCLUSION: By the identification of typical ferruginous bodies,
      the screening of sputum smears may confirm the clinical and radiologic suspicion
      of pneumoconiosis and may contribute to determining its causes.

PMID- 8669195
TI  - Solid glomus tumor presenting as an axillary mass: report of a case with
      morphologic study, including cytologic characteristics.
AB  - BACKGROUND: Glomus tumors are usually small, painful, subungual nodules causing
      no diagnostic difficulties. Less obvious is the characterization of the solid,
      deep-seated variant. CASE: A 32-year-old female presented with a solid, painless
      tumor in the right axillary region. A fine needle aspirate was initially
      interpreted as ectopic breast tissue. Subsequent morphologic studies on the
      lumpectomy specimen revealed a solid glomus tumor. CONCLUSION: The cytologic
      appearance of glomus tumors is at most suggestive. Whenever the diagnosis is
      considered, appropriate immunohistochemical studies should be added to
      consolidate it.

PMID- 8669196
TI  - Cytology of Langerhans cell histiocytosis in effusions: a case report.
AB  - BACKGROUND: Langerhans cell histiocytosis is a relatively rare disorder of
      children, characterized by abnormal proliferation of Langerhans cells. There has
      been no report on the cytologic appearance of Langerhans cells in effusions.
      CASE: A 20-year-old had a 12-year history of the disease, since he was 8 years
      old. He had multiple mass lesions in the bones, lung and liver, and Langerhans
      cells appeared in the pleural fluid and ascites. They had indented, twisted or
      grooved nuclei, with a finely or coarsely granular chromatin pattern. Some of the
      nuclei were eccentrically located, and prominent nucleoli were occasionally seen.
      Immunohistochemically the cells showed positivity for S-100 protein. Electron
      microscopic examination revealed abortive Birbeck granules. CONCLUSION: The
      cytologic appearance was somewhat accentuated and different from that reported
      for other sites. Immunohistochemical staining for S-100 protein and/or electron
      microscopic examination should be employed.

PMID- 8669197
TI  - Fine needle aspiration cytology of undifferentiated (embryonal) sarcoma of the
      liver: a case report.
AB  - BACKGROUND: Undifferentiated sarcoma of the liver is a rare tumor of childhood.
      The histology has been well documented, but the histogenesis is controversial.
      The cytologic characteristics of this neoplasm in aspiration material have not
      been previously documented. CASE: The cytologic features in a 9-year-old male
      were pleomorphic malignant cells, multinucleate giant cells, numerous hyaline
      globules and myxoid matrix. CONCLUSION: The cytologic features of
      undifferentiated sarcoma of the liver are distinctive and different from those of
      other childhood liver tumors. Awareness of the tumor's cytomorphology can result
      in a confident preoperative diagnosis.

PMID- 8669198
TI  - Meningeal involvement in multiple myeloma: report of a case with cytologic and
      immunocytochemical diagnosis.
AB  - BACKGROUND: Multiple myeloma (MM) with meningeal involvement is a very rare
      phenomenon. Only 37 cases of plasma cell neoplasia (MM and plasma cell leukemia)
      with meningeal involvement have been reported. CASE: A 60-year-old male with
      stage IIIA light lambda chain MM returned nine months after the diagnosis with
      back pain, lower right extremity paresthesias and gait disturbance. A lumbar
      puncture revealed atypical plasma cells in the cerebrospinal fluid (CSF), and
      immunocytochemical studies showed a cytoplasmic monoclonal light lambda chain. A
      diagnosis of myelomatous meningitis was made, and the patient received
      intrathecal chemotherapy and craniospinal irradiation. He died six months after
      the diagnosis of meningeal disease. CONCLUSION: The present case and a review of
      the literature show that clinical manifestations of meningeal myeloma are non
      specific. MM with meningeal involvement is accompanied frequently by circulating
      atypical plasma cells or plasma cell leukemia. Atypical plasma cells in the CSF
      are an important finding for the diagnosis of meningeal myeloma, and their
      neoplastic nature can be best identified by immunocytochemical analyses. Patients
      with meningeal myelomatosis can have a good response to treatment initially, but
      their prognosis is poor.

PMID- 8669199
TI  - Fine needle aspiration diagnosis of ciliated hepatic foregut cysts: a report of
      three cases.
AB  - BACKGROUND: Ciliated hepatic foregut cysts, albeit rare, are important to
      consider in liver aspirates obtained for evaluation of possible neoplastic
      disease. CASES: In three cases, liver fine needle aspirates showed features
      consistent with ciliated hepatic foregut cysts. Two of these aspirates were
      obtained to evaluate possible metastatic disease prior to resection of primary
      tumors, one of the lung and one of the bladder. A third case had radiologic
      findings suggestive of a cystic neoplasm. The fine needle aspirate material from
      these cases revealed clusters of tall, columnar cells with basally oriented
      nuclei and prominent apical terminal plates with cilia. These features are
      consistent with ciliated hepatic foregut cysts. CONCLUSION: This entity, although
      originally described in the late 19th century, to our knowledge has not been
      reported to occur in fine needle aspirate material and should be included in the
      differential diagnosis of cystic lesions of the liver.

PMID- 8669200
TI  - Fine needle aspiration biopsy diagnosis of a gastrointestinal stromal tumor
      utilizing transmission electron microscopy.
AB  - BACKGROUND: Gastrointestinal stromal tumors are spindle cell tumors with no
      specific cell lineage occurring in the gastrointestinal tract and cytologically
      resemble other benign and malignant spindle cell tumors. Distinctive
      ultrastructural features in some of these tumors have not been previously
      emphasized. CASE: A 76-year-old, white female presented with multiple tumor
      masses distributed in the large bowel. Fine needle aspiration biopsy demonstrated
      a cellular aspirate composed of spindle cells, some of which were loosely arrayed
      and some of which were in cohesive clusters. Many of the cells contained long
      cytoplasmic processes. Ultrastructurally the cells demonstrated long cytoplasmic
      processes upon which multiple shorter, fingerlike projections arose. Subsequent
      surgical resection confirmed the cytologic and ultrastructural findings.
      CONCLUSION: Electron microscopy has a role to play in the diagnosis of
      gastrointestinal stromal tumors.

PMID- 8669201
TI  - Fine needle aspiration cytology of acinar cell carcinoma of the pancreas: a
      report of two cases.
AB  - BACKGROUND: Fine needle aspiration in lieu of needle biopsy is widely used for
      the diagnosis of pancreatic neoplasms. The cytologic features of ductal
      carcinomas are well characterized, but the appearances of less common pancreatic
      neoplasms, such as acinar cell carcinoma (ACC), are not well described. CASES: We
      present the cytologic, histologic, immunocytochemical and ultrastructural
      features of two cases of ACC. The tumors occurred in a 36-year-old woman and 43
      year-old man. The aspirate from one case contained neoplastic cells with smooth
      contoured nuclei containing one or two prominent nucleoli. The aspirated material
      from the second case was necrotic, with numerous neutrophils and scattered nests
      of tumor cells similar to those present in the first case. Histologically, both
      tumors manifested solid and acinar patterns, and each contained some cells with
      periodic acid-Schiff-positive granules that were resistant to diastase. The
      neoplasms were immunochemically positive for trypsin and negative for
      neuroendocrine markers. Ultrastructurally, the aspirate from one case
      demonstrated apical microvilli, zymogenlike granules and abundant rough
      endoplasmic reticulum. CONCLUSION: Uncommon pancreatic neoplasms may be difficult
      to diagnose due to their cytologic and histologic subtleties. Supplemental
      studies including immunocytochemistry, cytochemistry and electron microscopy are
      important in facilitating their identification.

PMID- 8669202
TI  - Fine needle aspiration diagnosis of a mesenteric myelolipoma: a case report.
AB  - BACKGROUND: Extraadrenal myelolipomas are very rare tumors, with a
      characteristic, though nonspecific, radiologic appearance. Tissue sampling is
      necessary for diagnosis, and although most of these tumors are asymptomatic,
      surgical excision is often indicated. CASE: A 59-year-old male was found to have
      a large mass within the mesentery of the abdomen, incidentally discovered during
      an ultrasound examination for renal lithiasis. Computed tomography-guided fine
      needle aspiration biopsy yielded mature adipose tissue admixed with hematopoietic
      elements. CONCLUSION: FNA proved to be a rapid and effective modality for the
      diagnosis of this distinctly uncommon tumor.

PMID- 8669203
TI  - Cytologic appearance of sinus histiocytosis with massive lymphadenopathy: a case
      report.
AB  - BACKGROUND: Sinus histiocytosis with massive lymphadenopathy is a benign, massive
      lymphadenopathy, usually cervical, of unknown etiology. CASE: Cytologic smears
      revealed a polymorphic population of cells consisting of mature lymphocytes,
      plasma cells, occasional neutrophils and many histiocytes, characteristically
      showing emperipolesis. A reactive lymphadenopathy was diagnosed. The
      histopathologic diagnosis on open biopsy specimen was sinus histiocytosis with
      massive lymphadenopathy. CONCLUSION: Cytologic diagnosis of sinus histiocytosis
      with massive lymphadenopathy is possible with high accuracy provided that the
      cytologic findings are interpreted in the appropriate clinical context. The
      cytologic examination also can help with follow-up.

PMID- 8669204
TI  - Diagnosis of soft tissue sarcomas on aspiration smears.

PMID- 8669205
TI  - Can a malignant fibrous histiocytoma of the kidney be diagnosed by needle
      aspiration?

PMID- 8669206
TI  - Uniform standards for performing and interpreting the results of aspiration
      biopsy of the breast.

PMID- 8669207
TI  - Intraabdominal lesions: fine needle sampling without suction vs. fine needle
      aspiration.

PMID- 8669208
TI  - Granular cell tumor of the mammary skin.

PMID- 8669209
TI  - Papillary cystic tumor of the pancreas diagnosed by preoperative brushing
      cytology of the pancreatic duct.

PMID- 8669210
TI  - Observation of "intermediate filament buttons" in fine needle aspirates of Merkel
      cell carcinoma.

PMID- 8669211
TI  - Embryonal rhabdomyosarcoma mimicking an adenoid cystic carcinoma in needle
      aspiration biopsy.

PMID- 8669212
TI  - Histiocytosis X of the thyroid.

PMID- 8669213
TI  - Signet ring cell differentiation of transitional cell carcinomas of the bladder.

PMID- 8669214
TI  - Cytology of trichosporonosis.

PMID- 8669215
TI  - Primary pulmonary plasmacytoma diagnosed by transthoracic needle aspiration
      cytology and immunocytochemistry.

PMID- 8669216
TI  - Evaluation of morphine for patient controlled analgesia with the Infusor system
      after opiate-free locoregional anesthesia for osteotomy of the foot.
AB  - Efficacy and safety of a PCA protocol, without loading dose or background
      infusion, was investigated in 40 consenting patients after osteotomy of the foot.
      All patients had intrathecal lidocaine 5% 1.8 ml preoperatively. Postoperative
      pain relief was provided with morphine from a Baxter Travenol infusor with PC
      module. The morphine concentration was 2 mg/ml or 3 mg/ml. In order to reach the
      analgesic blood concentration as quickly as possible, the patients were
      instructed to start PCA from the very first moment pain occurred. The patients
      breathed room air. The nursing staff evaluated respiratory and cardiovascular
      parameters, pain and side effects. Although mean VAS scores were higher than 3 in
      the early postoperative phase, no supplementary analgesics were required. One
      patient had urine retention. One patient had a drop in blood pressure at the
      start of morphine, which was quickly restored with the administration of
      colloids. Oxygen saturations were lower (SpO2 < 95%) the first hours
      postoperatively, especially at the first assessment where no morphine was
      administered. Pain or relative hypovolaemia could be an explanation. Dry mouth
      and sleepiness were the most frequently reported side-effects, followed by
      dizziness, vomiting and nausea. Sweating and itching were less frequently
      reported. The occurrence of the side effects was the highest during the first
      postoperative day. We conclude that even when morphine is used in PCA without
      loading dose or background infusion after opiate-free locoregional analgesia,
      close monitoring is necessary for at least 5 hours.

PMID- 8669217
TI  - The effects of imipramine, amitriptyline and clonidine administered by
      iontophoresis on the pain threshold.
AB  - We performed iontophoresis of aqueous solution of imipramine and amitriptyline,
      tricyclic antidepressant, and clonidine, an alpha 2 agonist, in a total of 30
      healthy adult volunteers. Analgesic effects were compared among the 3 drugs by
      measurement of the pain threshold using a thermopainmeter. No significant changes
      in the pain threshold were observed with imipramine or amitriptyline. On the
      other hand, clonidine significantly increased the pain threshold, compared with
      the control value before iontophoresis. Although the effects of iontophoresis of
      clonidine were smaller than the previously reported effects of iontophoresis with
      other drugs, these effects seemed to be due to the action of clonidine itself not
      associated with electric stimulation. More marked effects may be obtained with
      changes in the conditions of iontophoresis.

PMID- 8669218
TI  - Evaluation of methylnaltrexone for the reduction of postoperative vomiting and
      nausea incidences.
AB  - We examined the effect of methylnaltrexone on the incidence of postoperative
      nausea and vomiting in a prospective double-blind placebo controlled study. One
      hundred and twenty female patients undergoing laparoscopic major gynecological
      surgery were allocated randomly to receive either 20 mg methylnaltrexone or
      placebo IV at the end of surgery. Postoperative nausea and vomiting was evaluated
      for 6 h after admission to the PACU and assessed by number of episodes and degree
      of severity. The incidences of nausea and vomiting for the placebo group were 27
      and 18 percent, respectively. The corresponding values for the methylnaltrexone
      group were 20 and 10 percent. We conclude that methylnaltrexone did not prevent
      nor significantly reduced the incidence and severity of postoperative nausea and
      vomiting following a balanced anesthetic technique in gynecological procedures.

PMID- 8669219
TI  - One week treatment with cimetidine does not attenuate the cortisol response to a
      short corticotropin test in stable intensive care patients: a prospective,
      randomized, and controlled study.
AB  - Cimetidine is commonly used for stress ulcer prophylaxis in intensive care
      patients. Cimetidine contains an imidazole structure. Similar drugs have been
      shown to inhibit steroid synthesis by blocking cytochrome P450-dependent
      reactions in the adrenal cortex. It is suggested that bolus injections of
      cimetidine suppress the normal corticosteroid production. This might be
      deleterious since a decreased cortisol response seems to be associated with
      increased mortality during chronic severe stress. We therefore performed a
      prospective, randomized, and controlled study to assess the effect of a short
      term continuous infusion of either cimetidine or ranitidine, a non-imidazole H2
      pantagonist, upon cortisol secretion in a cohort of hemodynamically stable
      intensive care patients. Twenty patients were consecutively enrolled following
      determined inclusion criteria and divided in three treatment groups: 6 controls,
      7 cimetidine- and 7 ranitidinetreated subjects. Both cimetidine (1200 mg) and
      ranitidine (200 mg) were administered by infusion pump over 24 hrs. A short
      corticotropin test was done within 24 hrs after admission (d0) and repeated 7
      days thereafter (d7). On both occasions, plasma cortisol was measured immediately
      before the test and 30 min afterwards. The three treatment groups presented a
      normal cortisol response at d0 and d7. Peak cortisol levels after stimulation did
      not show any significant difference for both the cimetidine and the ranitidine
      group, either at d0 or at d7. Moreover, this response at d0 and d7 was also not
      significantly different from the one observed in the controls. From this study we
      can conclude that one week treatment with conventional intravenous doses of
      cimetidine does not induce significant alterations of the cortisol response in
      hemodynamically stable ICU patients.

PMID- 8669220
TI  - Can alpha 2-adrenoceptor agonists reverse or prevent tolerance to the
      antinociceptive activity of opioids in rats?
AB  - The present study was designed to investigate the possible role of some alpha 2
      agonists in the phenomenon of tolerance to opioid-induced antinociception. To do
      so, the alpha 2-agonists were tested alone and in combination with opioids in
      naive and repeatedly fentanyl-treated rats in the tail withdrawal reaction (TWR)
      test. Under the treatment schedule used, rats became tolerant to fentanyl and
      cross-tolerance was observed with other opioids. The alpha 2-agonists alone were
      inactive in opioid naive and repeatedly fentanyl-treated rats. The potentiating
      interaction between the alpha 2-agonists and fentanyl in naive animals diminished
      considerably after the repeated fentanyl treatment. Adding an alpha 2-agonist to
      high doses of fentanyl during repeated treatment resulted in a complete tolerance
      to both compounds. Using lower, but equipotent antinociceptive drug combinations
      of alpha 2-agonists and opioids, resulted in less tolerance. Alpha 2-agonists are
      thus unable to directly overcome tolerance to the antinociceptive activity of
      fentanyl in tolerant animals. Nevertheless, by lowering the dose of the opioid
      for an equipotent antinociceptive activity, alpha 2-agonists are able to delay
      the onset of tolerance, probably based on the concept of opioid receptor sparing.

PMID- 8669221
TI  - Influence of sufentanil on propofol anesthesia using a target controlled infusion
      system.
AB  - We assessed the effect of three different dosings of sufentanil on induction,
      maintenance and recovery characteristics of a propofol target controlled infusion
      anesthesia in twenty-four patients scheduled for laparoscopic cholecystectomy.
      The patients were allocated randomly to receive a sufentanil bolus of 15, 30 or
      45 micrograms followed by a continuous infusion of sufentanil of 15, 30 or 45
      micrograms/h respectively. The maintenance propofol anesthesia was titrated to
      achieve hemodynamic stability. Recovery was assessed by noting the times at which
      patients opened their eyes and correctly gave their birth date. The predicted
      propofol blood concentration was noted at loss of consciousness, at different
      times of surgery and at the recovery events. A threefold increase of sufentanil
      dosing did not significantly affect the induction times nor recovery times
      following propofol anesthesia. The recovery parameters were determined by the
      total amount of propofol administered. The mean predicted propofol blood
      concentrations measured at induction, during maintenance and recovery (opening of
      eyes) were 3.4-3.9 micrograms/ml, 4.0-4.8 micrograms/ml and 1.1-1.4 micrograms/ml
      respectively and were not significantly influenced by the sufentanil dosing.

PMID- 8669222
TI  - Mivacurium chloride for short laparoscopic procedures.
AB  - We have studied the effects of mivacurium after induction of anesthesia with
      fentanyl-propofol in healthy adult women. Anesthesia was maintained with nitrous
      oxide in oxygen and continuous infusion of propofol (6-10 mg/kg/hr.). A
      myorelaxograph (Datex NMT 100) measuring the responses of the adductor pollicis
      to Train of Four (TOF) stimulations of the ulnar nerve was installed after
      induction. Three bolus dosages of mivacurium were administered just after
      induction: 0.15 mg/kg (group A), 0.17 mg/kg (group B) and 0.19 mg/kg (group C).
      Intubation was attempted at 75% TI-suppression. The conditions of intubation were
      good to excellent in the three groups except for one patient in group A (0.15
      mg/kg). Successful intubation was performed faster in group C(p = 0.017). The
      curarization time was significantly longer in group C(0.19 mg/kg) vs the other
      groups (p = 0.002). As soon as the first signs of recovery (TI increment)
      appeared, a continuous infusion of mivacurium (10 micrograms/kg/min) was started
      to maintain a complete neuromuscular block. After stopping the continuous
      infusion, there were no differences in spontaneous recovery between groups A and
      B but patients from group C showed a lenghtening of the recovery time. There is
      no effect of the different bolus dosages on vital signs. We conclude that a bolus
      dosage of 0.19 mg/kg after induction of anesthesia with fentanyl-propofol offers
      the best choice when a rapid sequence of induction is required. Mivacurium could
      be an interesting muscle relaxant in one-day surgery even if a risk of prolonged
      curarization exists due to its degradation by plasma cholinesterases.

PMID- 8669223
TI  - A day-care pain clinic--its possibilities and limitations in the treatment of
      cancer patients.
AB  - A day-care unit was established to extend facilities of the pain clinic. During
      its first 2 years of operation 79 patients with cancer-related pain have been
      treated. Most patients were admitted because of intractable pain but also
      suffered other symptoms mainly concerning the gastrointestinal and respiratory
      tract. For more than half of the patients and their families, psychosocial
      problems were also an important issue. The central aim of the pain management
      programme is to improve the quality of life of patients with cancer-related pain
      through appropriate drug based or anesthetic interventions. Control of other
      symptoms and counseling for both patient and family are an integral part of the
      holistic approach. The first initial clinical experiences show that the day-care
      unit provides a noticeable improvement in patient care and constitutes an
      excellent link between the out- and inpatient therapeutic possibilities.

PMID- 8669224
TI  - Sleep and the temporal lobe.
AB  - The main interest in the association between sleep and temporal lobe dysfunction
      is based on the activation of ictal and interictal epileptic phenomena. The
      clinical semiology of NREM and REM parasomnias may resemble complex partial
      seizures. The differentiation between epilepsy and dissociated states of
      wakefulness and sleep is of high diagnostic and therapeutic importance. Systems
      within temporal lobe structures are also responsible for disturbed sleep or
      dyssomnia. The limbic brain is connected with different nodal points in the
      network underlying sleep organisation and participates in both sleepinducing and
      arousal mechanisms. Experimental amygdala kindling, an animal epilepsy model
      involving temporal structures, induces disturbed sleep patterns favouring waking
      and light sleep. In epilepsy unstable disrupted and superficial sleep patterns
      prevail without overt seizures. Sleep-fragmentation and deprivation may impair
      daytime functioning and cognitive performance by lowering the seizure-threshold.
      The recognition of dyssomnia and of excessive sleepfragmentation and sleepiness
      has obvious implications for behavioural and drug treatment.

PMID- 8669225
TI  - The fronto-temporal component in mild and moderately severe head injury.
AB  - The history of the identification of the so-called (fronto-)temporal lobe
      contusion is reviewed. Treatment of minor head injuries actually starts with the
      right diagnosis. Injuries of the temporal lobe, characterized by a comparatively
      long period of post-traumatic amnesia should be distinguished from minor head
      injuries (cerebral concussion). Treatment of minor head injuries should include
      good information and explanation of the medical aspects of minor head injuries to
      prevent the so called post-concussional syndrome, with long lasting sequelae.
      Changes of neurotransmitter metabolism in various kinds of head injuries have
      been known for many years. Treatment with precursors of neurotransmitters
      (particularly physostigmine and L-DOPA) can be useful in unconsciousness and
      amnestic syndromes.

PMID- 8669226
TI  - Personality, emotions and the temporolimbic system: a neuropsychological
      approach.
AB  - Over the past decade a view has emerged that there is both a lateralization of
      control of certain emotional processes, the right hemisphere being dominant, and
      a localization of control to the limbic system, the frontal and temporal lobes.
      Many changes in personality, social behaviour and emotions can be seen in
      patients with temporal lobe lesions. Examples of these changes are a deficit in
      the interpretation of emotional components of language, a reduction in the
      frequency and intensity of facial expressions, an impairment of the judgement of
      mood, facial expressions and emotional situations. Buried within the depths of
      the brain is the limbic system which represents the most primitive features of
      our emotional system and contains several nuclei. Of special interest are the
      hypothalamus, amygdala, hippocampus and septal nuclei, the social-emotional
      functions they mediate and the neural circuit that supports their activity.

PMID- 8669227
TI  - Focal retrograde amnesia: a multi-faceted disorder?
AB  - In this paper I review the recently introduced syndrome of focal retrograde
      amnesia-a disproportionate impairment of remote memory in the presence of normal
      or near normal anterograde memory. It is concluded that the modal form of the
      syndrome has been reliably demonstrated and that the underlying pathology
      involves damage to the temporal lobes and relative sparing of the hippocampal
      formation. A variant of the syndrome associated with parietal and occipital lobe
      damage is also presented. Finally, a third type of focal retrograde amnesia
      associated with minor brain trauma is considered to be or primarily psychogenic
      origin.

PMID- 8669228
TI  - Rehabilitation and management of memory problems.

PMID- 8669229
TI  - Cranial nerve palsies due to internal carotid artery dissection: seven cases.
AB  - Cranial nerve palsies are rare complications of internal carotid artery (ICA)
      dissections. The aim of this study is to evaluate the incidence of cranial nerve
      palsies in consecutive patients with ICA dissection and to describe clinical and
      radiological characteristics and their evolution over time. This study was
      conducted in 52 consecutive patients with dissection of the ICA. We have analyzed
      clinical data of patients with cranial nerve palsy as complication of ICA
      dissection. We defined ICA dissection as angiographic evidence of a string sign,
      double lumen, or internal flaps or visualization on magnetic resonance imaging
      (MRI) or computed tomographic scans of an enlarged arterial wall due to the
      hematoma. Of 52 consecutive patients with ICA dissection 7 had cranial nerve
      palsies: 2 had an involvement of the Vth cranial nerve and 5 had lower cranial
      nerve palsies. Five patients totally recovered while 2 did not after a 2 to 10
      month period. The frequency of cranial nerve palsies associated with ICA
      dissection is higher in our study than in those of the literature. Many patients
      presenting with cranial nerve palsies due to ICA dissection without any ischemic
      event are probably not referred to stroke units. Angiography is less sensitive
      than cervical MRI to detect such patients. Cranial nerve palsies could either be
      due to compression by the enlarged ICA wall or an ischemia of the nerve.

PMID- 8669230
TI  - Epilepsy surgery in Belgium, the Flemish experience.
AB  - Between January 1992 and June 1995, 160 patients were presurgically evaluated for
      medically refractory epilepsy by the Epilepsy Monitoring and Surgery Team at the
      University Hospital of Gent. All these patients underwent a comprehensive
      presurgical evaluation, including extensive neurological history and examination,
      video-EEG monitoring of interictal EEG and habitual seizures, CT and optimum MR.
      In a large subgroup of these patients a comprehensive neuro-psychological
      examination and interictal 18FDG-PET were performed. After the non-invasive phase
      of the presurgical evaluation, a bilateral carotid angiography and intracarotid
      amytal procedure was planned in 27 patients to establish hemispheric language
      dominance and bilateral memory function. After proper selection, 14 patients
      underwent invasive video-EEG monitoring with intracranial implantation of
      parenchymal and/or subdural electrodes to further document the area of seizure
      onset. From the initial group of 160 potential surgical candidates, 40 patients
      (20 M, 20 F) with mean age of 31 years (range: 2 months-55 years) and mean
      duration of uncontrolled seizures of 16 years (range: 2 months-47 years)
      eventually underwent a surgical procedure. 30/40 patients were on high dose
      antiepileptic polytherapy. Optimum MR detected structural abnormalities, confined
      to a limited brain area, in 39 patients. These abnormalities were of space
      occupying nature in 21 cases; an atrophic lesion was suspected in 17 patients.
      Structural abnormalities were most frequently located in the temporal lobe (n =
      26) and the frontal lobe (n = 7). Video-EEG monitoring documented complex partial
      seizures in 32 patients with occasional secondary generalisation in 14. In most
      of these patients, seizures could be subclassified as being of temporal lobe
      origin based on clinical and EEG criteria. Two patients had only simple partial
      seizures. One patient with Sturge-Weber syndrome and a strictly unilateral
      angioma had hemiconvulsions. A mentally retarded patient with Lennox-Gastaut
      syndrome had different types of seizures. After non-invasive and invasive
      exploration, the area of seizure onset could be determined in all patients.
      Standard or modified temporal lobectomy +/- hippocampectomy were the most
      commonly performed procedures (n = 26). In 5 patients complete lesionectomies
      were performed for epileptogenic structural lesions in and outside the temporal
      lobe. In 2 patients only partial lesionectomies were possible; in 5 patients only
      biopsies could be performed. Anterior 2/3 callosotomy and hemispherectomy were
      each performed in one patient. Postsurgical seizure control, after average follow
      up of 20 months (range: 6-40 months), was excellent in 27 patients who became
      seizure-free. In these patients antiepileptic therapy was tapered 2 years after
      surgery. An additional 4 patients continue to experience non-disabling simple
      partial seizures only. Patients in whom only biopsies or partial lesionectomies
      were performed have poor seizure control. Three patients died as a result of the
      intrinsic malignancy of their space-occupying lesion. Two patients who are
      seizure free experienced a moderate postoperative hemiparesis with subtotal
      recovery. Overall quality of life was substantially improved both in patients who
      became entirely seizure free or who experienced a very significant reduction in
      seizure frequency. Presurgical evaluation and epilepsy surgery are a labour
      intensive but rewarding therapeutic alternative for patients with medically
      refractory epilepsy. Besides providing therapeutic efficacy, comprehensive
      presurgical evaluation and epilepsy surgery allow for fruitful clinical
      neurological research.

PMID- 8669231
TI  - Clinically unexpected multiple sclerosis in patients with mental disorders. A
      series of 7301 psychiatric autopsies.
AB  - Some studies have indicated that silent and perhaps pure mental forms of multiple
      sclerosis (MS) exist. With the aim of examining that, the records of 9478
      autopsies from patients with mental disorders were reviewed. A total of 7252 had
      both clinical and histological diagnosis, and 7301 had only pathoanatomical
      diagnosis. Twenty-three patients were suspected of having MS, which were
      confirmed histologically in 14. None had unsuspected, silent or a pure mental
      form of MS. It is concluded that the risk of mistaking MS for a psychiatric
      disorder is small in MS high-risk area.

PMID- 8669232
TI  - MR examination of an atypical tethered cord.

PMID- 8669233
TI  - Symposium on Alzheimer's disease. Antwerp, May 11-13, 1995. Abstracts.

PMID- 8669234
TI  - The effect on joint fluid concentration of neuropeptide Y by intra-articular
      injection of glucocorticoid in temporomandibular joint arthritis.
AB  - Twenty-two patients (29 joints) with temporomandibular joint (TMJ) arthritis of
      specific or unspecific nature were given one intra-articular glucocorticoid (GC)
      injection. The effect on subjective symptoms and clinical signs in the
      craniomandibular system and on joint aspirate concentration of neuropeptide Y
      like immunoreactivity (NPY-LI) was evaluated at follow-up visits 2-3 or 4-6 weeks
      after treatment. In the patients with specific inflammatory joint disease the
      treatment resulted in an improvement of symptoms and clinical signs and in a
      reduction in the TMJ level of NPY-LI 2-3 weeks after treatment. In the patients
      with unspecific inflammatory joint disease there was also an improvement in the
      clinical variables and a reduction in the NPY-LI level after 2-3 weeks, but not
      on a statistically significant level. The results of this study show that intra
      articular GC treatment causes a short-term decrease of the TMJ fluid level of NPY
      LI in patients with specific inflammatory joint disease, while symptoms and signs
      improve.

PMID- 8669235
TI  - A 3-year follow-up of temporomandibular disorders in rheumatoid arthritis and
      ankylosing spondylitis.
AB  - Sixteen individuals with rheumatoid arthritis (RA) and 19 individuals with
      ankylosing spondylitis (AS) participated in this 3-year follow-up study. The
      individuals in each disease group were allocated to an experimental group (E
      group) and a comparison group (C group). They were investigated by questionnaire,
      clinical examination of the stomatognathic system, and laboratory tests. The
      individuals of the two E groups had performed a physical training program of the
      stomatognathic system during 3 weeks. After 3 years most of the patients in the E
      groups reported an unaltered or decreased severity of symptoms and signs from the
      stomatognathic system compared with the initial status. The clinical dysfunction
      score according to Helkimo (CDS) was lower in the RA group, and the mouth opening
      capacity was larger than before training. In the AS group there was no long-term
      change in the CDS but an increase of mouth opening capacity. The general
      inflammatory disease process in the RA group showed an increased activity during
      this follow-up period as assessed by erythrocyte sedimentation rate. This study
      suggests that local physical training of the stomatognathic system has a positive
      effect in individuals with RA.

PMID- 8669236
TI  - Bonding strength of glass ionomers to dense synthetic hydroxyapatite and
      fluoroapatite ceramics.
AB  - The bonding strength of two glass ionomers, a resin-modified and a conventional
      one, to dense synthetic hydroxyapatite (HA) and fluoroapatite (FA) ceramics was
      compared by measuring the shear strength between the ionomers and the apatites.
      Before the glass ionomers were applied on the apatites, the surfaces of HA and FA
      plates were either fine-polished or acid-etched after fine polishing.
      Commercially pure titanium (CP Ti) plates were used as a control. The effects of
      polyacrylic acid (PAA) surface preconditioning on bonding strength were also
      studied. The results show that the ionomers bind to HA significantly more
      strongly than to FA in all cases. The resin-modified material showed a
      significantly higher shear strength to apatites than the conventional one. Acid
      etching increased the shear strength significantly for the conventional glass
      ionomer to both HA and FA, and 25% PAA preconditioning increased the shear
      strength significantly for the resin-modified glass ionomer to both HA and FA. It
      was concluded that glass ionomers seemed to bind to apatite chemically, and the
      bonding strength was influenced by the cohesive strength of the ionomers and the
      surface roughness of the apatites. The dense synthetic apatites seemed to be good
      test materials for bonding evaluations of glass ionomers to mineral tissue.

PMID- 8669237
TI  - Complications requiring hospitalization after third-molar surgery.
AB  - A retrospective study of patients hospitalized for complications after third
      molar surgery during a 10-year period showed that of the total 19 cases, 15
      presented as infections. Five admissions were attributable to surgery performed
      by oral surgeons, including two cases of postoperative bleeding, two infections,
      and one displaced root fragment. Fourteen patients admitted after surgery by
      general dental practitioners included 12 acute and 2 chronic infections. Apart
      from daily smoking, no medical problems or other risk factors were associated
      with the complications. According to assessments of regional volume of third
      molar surgery by general dental practitioners and oral surgeons, the rates of
      serious postoperative infections were 2.8.10(-4) and 6.5.10(-5) cases per
      operation, respectively. This difference in infection rates may be explained by
      less surgical training and experience in general dental practice.

PMID- 8669238
TI  - Changes in utilization and cost sharing within the Danish National Health
      Insurance dental program, 1975-90.
AB  - The aims of the analysis were 1) to examine the development in utilization of
      dental care provided for adults in Denmark under the National Health Insurance
      during the period 1975-90; 2) to assess the appropriateness of available dental
      care statistics for studies of oral health trends; and 3) to analyze the price
      development of dental services during 1975-90 and its impact on patient and
      Insurance expenses, respectively. Utilization and economic data were retrieved
      from available registers and analyzed. Three trends were found. First, the
      utilization has increased more than what could be explained by the population
      increase; secondly, the panorama of dental services changed from predominantly
      restorative/extraction services to predominantly diagnostic/preventive services.
      Thirdly, the price paid by Danish adults for dental care increased
      disproportionately to other price developments in society. On the basis of
      traditional health economic theory this development could be expected to affect
      demand for dental services negatively.

PMID- 8669239
TI  - Changes in demand for dental care among Danish adults, 1975-90.
AB  - The aims of this study were 1) to analyze changes in and determining factors for
      demand for dental care among Danish adults during 1975-90, and 2) to apply
      standard cohort analysis on sequential cross-sectional survey data, thereby
      enabling the separation and examination of age, period, and cohort effects.
      Samples of non-institutionalized Danes aged 15 years and more were interviewed in
      1975 (n = 1204), 1980 (n = 1108), 1985 (n = 1123), and 1990 (n = 1003), in
      accordance with a standardized questionnaire. Overall demand for dental care
      increased from 59% in 1975 to 76% in 1990; the younger the respondents, the
      higher the demand. Standard cohort table analysis indicated that the main effect
      derived from cohort succession; that is, the higher demand of the new cohorts
      entering the population remained higher than that of previous cohorts. Logistic
      regression analysis indicated that from 1980 to 1990 the significant predictors
      for regular dental care shifted from being predominantly predisposing and need
      variables to predominantly enabling and need variables.

PMID- 8669240
TI  - Some aspects of dental health in young adult Indian vegetarians. A pilot study.
AB  - The effect of a vegetarian diet on oral health status could be manifold, but
      reports have so far mainly appeared from within Western populations. This study
      reports the oral health status of southeast Indian vegetarians, obtained by means
      of a questionnaire, clinical examination, and study cast evaluations. The
      material comprised 30 vegetarians and 25 sex- and age-matched non-vegetarian
      controls. Comparison between the samples included dietary and oral hygiene
      habits, health-related variables, caries prevalence, and dentoalveolar
      characteristics. The questionnaire showed significantly less consumption of
      between-meal sweets and more widespread use of a soft toothbrush by the
      vegetarians. The vegetarians had a significantly higher degree of tooth wear than
      the non-vegetarians, but no difference in the degree of wear between women and
      men in either group was found. The vegetarians had a significantly higher
      tendency towards crowding in the maxillary arch, numerically higher DMFT, and
      greater number of cervical buccal defects than the controls. The results of this
      study suggest that the Indian vegetarian diet may produce certain effects on the
      oral health, associations that need to be studied further.

PMID- 8669241
TI  - Dental caries determinants in an adult Portuguese population and a comparison
      with Norwegian adults.
AB  - The present epidemiologic dental caries study indicates a high number of decayed
      surfaces (mean, 13.5 +/- 11.8 (SD)) in a Portuguese population of 30- to 39-year
      olds from Porto. The most influential determinants for variation in carious
      surfaces were oral hygiene, gender, salivary buffer capacity, and missing teeth.
      By entering the most influential independent variables in a final multiple
      classification analysis, the total explained variance in carious surfaces was
      27%. A comparison with results from a similar Norwegian dental health study
      showed that the biologic factors of importance for number of carious surfaces
      were the same, whereas the sociocultural determinants differed.

PMID- 8669242
TI  - Flexure strength of resin-modified glass ionomer cements and their bond strength
      to dental composites.
AB  - The flexure strength of three resin-modified glass ionomer cements and one
      conventional glass ionomer cement and their bond strength to dental composites
      were studied by measuring the three-point bending and the shear strengths. The
      bond strengths between the dental composite and the resin-modified glass ionomer
      cements were dependent on the curing modes. Resin-modified glass ionomer cements
      bonded significantly more strongly to cured dental composites than dental
      composites bonded to cured resin-modified glass ionomer cements. However, the
      dental composites showed a significantly stronger bonding to the resin-modified
      glass ionomer cements than to the cured conventional glass ionomer cement, to
      which the dental composite did not adhere without acid etching. The flexure
      strengths of the resin-modified glass ionomer cements were significantly improved
      compared with the conventional one but were still significantly lower than that
      of the dental composites.

PMID- 8669243
TI  - Root surface defects in rat molar induced by 1-hydroxyethylidene-1,1
      bisphosphonate.
AB  - Cementum surface alterations induced by 1-hydroxyethylidene-1,1-bisphosphonate
      (HEBP) in the maxillary first molars in rats were studied by means of scanning
      electron microscopy. Single or triple injections of HEBP inhibit the formation of
      acellular extrinsic fiber cementum and delay the formation of cellular mixed
      fiber cementum. The results indicate the importance of acellular extrinsic fiber
      cementum as a protection barrier against root resorption and the different
      mechanisms underlying the formation of the two cementum varieties.

PMID- 8669244
TI  - Impact of medical and life-style factors on number of teeth in 68-year-old men in
      southern Sweden.
AB  - The aim of the present study was to investigate the impact of general health and
      life-style factors on the number of remaining teeth in 68-year-old men living in
      the city of Malmo, Sweden. The study included 483 men (participation rate, 78%).
      Poor self-assessed health, frequent medical attendance, diabetes, and oral
      dryness were related to fewer remaining teeth. Number of teeth was negatively
      correlated to concentrations of triglycerides and alkaline phosphatases in serum
      and to glucose in blood but positively correlated to serum urea. Various dietary
      variables including consumption of sucrose-containing products and nutritional
      quality were not related either to number of teeth or to prevalence of
      edentulousness. Smoking and high consumption of coffee or alcohol were associated
      with fewer remaining teeth. Multiple logistic regression analyses showed that
      social class, frequency of dental attendance, smoking, and serum concentrations
      of triglycerides and urea had an independent effect on number of teeth.

PMID- 8669245
TI  - Caries prevalence and oral hygiene in Lithuanian children and adolescents.
AB  - Contrary to what is observed in many Western societies, the caries prevalence
      among children and adolescents in the Baltic States remains high. The aims of the
      present study were to describe the caries prevalence and oral hygiene among 7-,
      12-, and 15-year-old Lithuanians and to correlate the caries prevalence with
      fluoride content in the drinking water, oral hygiene, gender, ethnicity, and
      pattern of sugar consumption. The investigation was based on cluster samples, and
      the clinical investigation was performed in accordance with criteria defined by
      WHO. High DMFT values were registered (mean DMFT = 1.3 among 7-year-olds; DMFT =
      4.9 among 12-year-olds and 7.0 among 15-year-olds) and were associated with low
      fluoride content in the drinking water and poor oral hygiene. Girls showed higher
      DMFT values than boys. No correlation between pattern of sugar consumption and
      caries prevalence could be disclosed.

PMID- 8669246
TI  - Mineral loss in incipient caries lesions quantified with laser fluorescence and
      longitudinal microradiography. A methodologic study.
AB  - The laser fluorescence method (LAF) was validated with longitudinal
      microradiography (LMR) for assessment of mineral loss in incipient caries lesions
      in human enamel. Fluorescence radiance scans and LMR recordings were made of 36
      enamel slabs with incipient lesions. Original sound values for fluorescence
      radiance and enamel amount (kg.m-2) at the lesion site were reconstructed by a
      computer algorithm. Changes in fluorescence radiance and amount of enamel in each
      measuring point were calculated. The reconstruction method was tested on 20 sound
      enamel surfaces. The differences between measured and reconstructed values were 
      0.13 +/- 0.17% with LAF and 0.002 +/- 0.005 kg.m-2 with LMR. The repeatability of
      the caries quantification was tested by measuring one lesion 20 times. The
      fluorescence loss in this lesion was 18.2 +/- 1.0%. The enamel loss was 0.09 +/-
      0.02 kg.m-2. The correlation between measurements with the two methods was r =
      0.73. The non-destructive laser fluorescence method was concluded to be a
      sensitive and valid method for quantification of mineral loss in enamel caries
      lesions.

PMID- 8669247
TI  - Case reports: a world of controversy.

PMID- 8669248
TI  - [Long-term results of active-passive ligament repair of the external lateral
      ligament of the ankle].
AB  - We reviewed 95 ankles at an average of 9 years after an "activo-passive"
      operation performed for chronic lateral instability. All the patients had
      suffered recurrent ankle sprain or instability, with pain in 67 patients. Ten
      ankles showed a subtalar injury at operation. Degenerative changes were noted in
      11 ankle joints. On review, 81 ankles (85%) were stable. The 14 cases with
      persistent instability had developed the problem one to five years after
      operation. Two cases presented with limitation in mobility. Osteoarthritis, found
      in 15 ankles, was severe in only two, and had been present on preoperative films.
      We found no correlation between functional results (talar tilt, anterior-drawer
      test) and radiological evaluation. The "activo-passive" operation provides long
      term stabilization with preservation of the ankle and of subtalar mobility
      without severe osteoarthritis.

PMID- 8669249
TI  - Effect of graft position on laxity after anterior cruciate ligament
      reconstruction. Stress radiography in 90 knees 2 to 5 years after autograft.
AB  - The effect of tibial and femoral graft placement on radiographic laxity after
      anterior cruciate ligament reconstruction was studied in 90 knees. All the knees
      were operated according to the Marshall-MacIntosh procedure with a through-the
      condyle technique. Graft position and laxity were determined on lateral x-rays
      (static and mechanically assisted 200 Newtons anterior drawer strain). No
      relation was observed between tibial tunnel position and radiographic laxity. In
      fact few variations in placement were recorded. Femoral tunnel placement was more
      dispersed, and it strongly influenced the radiographic laxity (p = 0.0001).
      Laxity was minimal when the center of the femoral tunnel was 6 mm below the
      intercondylar notch roof and 2.5 mm behind the posterior margin of the notch. No
      correlations were observed between tunnel positions and function evaluated with
      the ARPEGE score. These results stressed the importance of the femoral graft
      placement to control laxity after anterior cruciate ligament reconstruction, and
      allowed determination in vivo of a position for which minimal laxity could be
      expected. Since the method determining the femoral graft placement in the present
      study was not precise, we now use fluoroscopic control to determine drill-guide
      position.

PMID- 8669250
TI  - Results of excision of the interdigital nerve in the treatment of Morton's
      metatarsalgia.
AB  - Thirty-one patients (thirty-two feet) had excision of the interdigital nerve as
      treatment of their Morton's metatarsalgia. A longitudinal dorsal incision was
      used in all cases. Twenty-five out of 32 cases had a macroscopically visible
      neuroma, and only two had no evidence of a neuroma on histological examination.
      All thirty-two patients were available for follow-up at an average of 44.7 months
      (range 14 to 71 months) postoperatively. Eighty-one per cent of the patients had
      a good or excellent result, 12.5% had a fair result, with residual pain and some
      restriction of activities, and 6.5% had no improvement after their operation. It
      is noteworthy that 19 patients (60%) benefitted from wearing adapted shoes or
      inner soles for a considerable time after the operation. Even at final follow-up,
      only 10 patients (30%) had no restrictions in the choice of their shoes.

PMID- 8669251
TI  - Grip strength in patients with tennis elbow. Influence of elbow position.
AB  - We measured the grip force in 20 chronic tennis elbows: The grip strength,
      measured with the elbow in 90 degrees flexion as well as in full extension, was
      significantly less (p < 0.001) on the pathological side when compared to the
      other, uninvolved side. on the pathological side, the grip strength measured with
      the elbow in full extension, was significantly reduced when compared to the grip
      strength measured with the elbow at 90 degrees flexion (p < 0.0001). on the
      normal side, the grip strength measured with the elbow in extension was not
      significantly different when compared to the grip strength measured with the
      elbow in 90 degrees flexion.

PMID- 8669252
TI  - Is there a correlation between mobility of the thumb and mechanical hand
      function?
AB  - Is there a correlation between thumb mobility and mechanical hand function? The
      metacarpophalangeal mobility, the web, grip force and dexterity were measured on
      volunteers. Statistical analysis showed a good correlation between the dominant
      and nondominant hand. Thumb mobility shows no correlation with grip force and
      dexterity while the width of the webspace has a clear influence on them. We could
      not find a compensatory mechanism between thumb mobility and the first web.

PMID- 8669253
TI  - Intramedullary fixation of forearm fractures in adults.
AB  - The authors present a retrospective study of acute fractures of the diaphysis of
      the radius or ulna, or both, in adults treated by intramedullary nailing. Seventy
      diaphyseal fractures in 38 patients (30 men and 8 women) were treated by
      intramedullary fixation. The mean age of the patients was 31.5 years. Union
      occurred in 66 fractures (94%). The average union-time was 73 days. Compared with
      the results published by other authors, using the same evaluation criteria, union
      time with the intramedullary technique was shorter than with other techniques.
      Union-rates and functional results were similar to those in comparable studies.
      Closed nailing does have many advantages, including early union, low incidence of
      infection, small scars, less blood loss, and short operating time with minimal
      surgical trauma.

PMID- 8669254
TI  - Proprioception of knee joints with a lesion of the medial meniscus.
AB  - We assessed knee-joint proprioception in 23 patients with an isolated lesion of
      the medial meniscus. Thirteen patients were tested prior to their arthroscopic
      operation, and 10 patients were examined after partial arthroscopic resection of
      the injured meniscus. As a control group we evaluated 30 healthy volunteers with
      clinically normal knee joints. For documentation of the proprioceptive
      capabilities we performed a special angle reproduction test which was described
      in the literature. Additionally the subjects were tested with and without a knee
      bandage, to test its influence on knee-joint proprioception. Our results showed
      that preoperatively a significant deterioration in proprioception was present
      compared with the control group. We could not find any influence of the knee
      bandage on the proprioception of the injured knee. The postoperative group of
      patients showed a significantly better proprioceptive capability compared to the
      preoperative patients. The postoperative results also did not show any
      significant difference as compared to those of the control group.

PMID- 8669255
TI  - Idiopathic necrosis of the capitate.
AB  - Avascular necrosis of the capitate bone in a 38-year-old man is presented. The
      patient was treated by intercarpal fusion of the capitate, lunate and scaphoid
      bone to relieve pain.

PMID- 8669256
TI  - Ectopic bone formation due to a distal venting hole in intramedullary nailing.
AB  - A case report is presented on ectopic bone formation around a distal venting hole
      drilled in the femur to prevent pulmonary embolism. We no longer recommend this
      technique, because it is ineffective and has its own complications.

PMID- 8669257
TI  - Dislocation of the distal radioulnar joint associated with a transstyloid
      radiocarpal fracture dislocation. A case report and review of the literature.
AB  - Dislocations of the distal radio-ulnar joint (DRUJ) can be isolated or combined
      with fractures. Cases of DRUJ dislocations have been described with Galleazi
      fractures, open radius and ulna fractures and intraarticular fractures of the
      distal radius. We report a case of a volar DRUJ dislocation combined with a
      transstyloid radio-carpal dislocation. Because of severe instability of the
      wrist, open reduction of the radial styloid combined with an open reduction of
      the dislocated DRUJ is advised.

PMID- 8669258
TI  - [Transient osteoporosis of the hip. Presentation of a case and literature
      review].
AB  - We present a case of idiopathic transient osteoporosis of the hip in a 43 year
      old male. The patient presented with pain in the hip and limb. Hip x ray showed
      osteoporosis and scintigraphy revealed a diffuse uptake in the femoral head.
      Magnetic resonance imaging showed decreased signal intensity on the T1 weighted
      images and increased signal intensity on T2 weighted images in the femoral head
      and neck. Blood tests were normal. Healing was achieved by restricting weight
      bearing and administering calcitonin and calcium. Radiographic remineralization
      occurred simultaneously with clinical resolution.

PMID- 8669259
TI  - Isolated fracture of the coracoid process of the scapula.
AB  - We present a case of an isolated fracture of the coracoid process in a 49-year
      old woman. Healing after conservative treatment was entirely satisfactory, with
      radiographic union and painless normal range of movement.

PMID- 8669260
TI  - Osteoarthritis of the elbow following an extensive Darrach procedure.
AB  - Extensive radiohumeral joint degeneration was found at the elbow in a 41-year-old
      woman after an (extensive) Darrach procedure. Arguments supporting the hypothesis
      of a proximal migration of the radius are presented.

PMID- 8669261
TI  - Septic arthritis of the shoulder due to Streptococcus agalactiae.
AB  - The authors report a case of septic arthritis of the shoulder-joint due to group
      B beta-hemolytic Streptococci (Streptococcus agalactiae) in a 63-year-old female
      patient. These germs are a major cause of meningitis and septicemia in newborns
      and pregnant women. In adults, men and nonpregnant women, they have been a rare
      cause of septic arthritis.

PMID- 8669262
TI  - Preventing neuroma formation in finger amputation.

PMID- 8669263
TI  - [Patellar subluxation: where are we today in 1995? Acta Orthopaedica Belgica
      61:155-168, 1995. J.Y. Dupont].

PMID- 8669264
TI  - Arthroscopic treatment of triangular fibrocartilage complex lesions of the wrist.
AB  - The arthroscopic treatments (suture, debridement and "wafer" resection of the
      distal ulna) performed for TFCC lesions in 42 patients were retrospectively
      reviewed. Overall results were disappointing, with a better outcome for isolated
      lesions, for sutured TFCC's and degenerative lesions.

PMID- 8669265
TI  - Functional endoscopic sinus surgery under local anaesthesia: possibilities and
      limitations.
AB  - Functional endoscopic sinus surgery under local anaesthesia with one single
      intramuscular injection of systemic premedication (pethidine and promethazine)
      and careful local preparation (decongestive nose drops, cocaine application and
      lidocaine infiltration). It is well tolerated and accepted in 95% of the
      patients. Blood loss is minimal and pain during the operation is rare. Major and
      minor orbital and intracranial complications were not seen. Local anaesthesia
      with this kind of surgery offers many advantages and is preferable to general
      anaesthesia when possible.

PMID- 8669266
TI  - Our technique of partial inferior turbinoplasty: long-term results evaluated by
      rhinomanometry.
AB  - Conservative surgical technique (Partial inferior turbinoplasty) for enlarged
      inferior turbinates, not responding to adequate local and systemic therapy is
      described. Short and long term results are evaluated. Relief of nasal obstruction
      is reported in 94.7% of the patients. There is a good correlation between this
      success-rate and the objective measurements of the nasal resistance by active
      anterior rhinomanometry. Rhinorrhea or postnasal drip was still present in 34.2%.
      Atrophic changes in the nasal mucosa were not observed. Early post-operative
      epistaxis was found in 5.3% of the patients. Late post-operative epistaxis did
      not occur.

PMID- 8669267
TI  - Occupational exposure to dust and sinonasal cancer. An analysis of 386 cases
      reported to the N.C.C.S.F. Cancer Registry.
AB  - An analysis of 386 sinonasal cancer cases reported during the 1978-1994 period to
      the registry of the Christian Sickness Fund is presented. The relationship
      between this tumor and previous occupational exposure to carcinogens is
      investigated by a descriptive case study. Of 386 cases comprising 294 males and
      92 females, 139 were adenocarcinomas which in 88 revealed an occupation as
      woodworker. In 169 sinonasal cancers the professional history indicates an
      exposure to dust of different origin, but mainly wood, textile, cereals, cement
      and leather. The primary tumor of 87 sinonasal adenocarcinomas in woodworkers was
      in 77% ethmoidal, 12.2% maxillary, 6.8% nasal and 4-sphenoidal. These findings
      confirm the results of previous reports on sinonasal cancer from other European
      countries.

PMID- 8669269
TI  - A study comparing rates of deflation of nasal balloons used in epistaxis.
AB  - A study was set up to compare the rates of deflation between three commonly used
      nasal balloons for securing haemostasis in epistaxis, namely Brighton balloons,
      Simpson Balloons, and Foley catheters. Brighton balloons were found to have the
      slowest rate of deflation, followed by Simpson balloons. Foley catheter balloons
      have the fastest rate of deflation, having deflated to less than half their
      original diameter by day five. However, these differences are relatively small.

PMID- 8669268
TI  - The activity of recent anti-allergic drugs in the treatment of seasonal allergic
      rhinitis.
AB  - Two experiments were performed during the pollen season to study the activity of
      different antiallergic drugs in the treatment of seasonal allergic rhinitis.
      Nasal allergen challenge (NAC) was performed to mimic an acute attack of allergic
      rhinitis and to objectively evaluate the effect of the drugs on the early-phase
      reaction during the season. The first study assessed the effect of H1 (Cetirizine
      10 mg a day) and of a combination of H1 (Cetirizine 10 mg) plus H2 (Cimetidine
      800 mg a day) antagonists on nasal symptoms, mediator release and eosinophil
      count in a group of 16 patients with seasonal allergic rhinitis. During the same
      season a second study compared in a randomized way (2 parallel groups) the effect
      of Budesonide (Rhinocort Aqua) and Azelastine (Allergodil nasal spray) in a group
      of 14 patients. Results showed that both antihistamines, applied topically of
      dosed orally, reduced sneezing even when significant increases of histamine
      concentration in nasal secretions were evidenced immediately after NAC. When a
      combination of Cetirizine and Cimetidine was administered, a significant (p <
      0.01) reduction of nasal airway resistance and increase of nasal airflow after
      NAC were demonstrated as well. In addition, topical application of Budesonide
      showed a strong (p < 0.01) effect on the infiltration and activation of
      eosinophils during the season, and on tryptase release after NAC. These effects
      lasted at least for one week after therapy.

PMID- 8669270
TI  - Cytomegalovirus as precipitating factor of acute bacterial sinusitis in an
      immunocompetent patient. A case report.
AB  - The authors report the first case of cytomegalovirus (CMV) isolated from the
      maxillary sinus of an immunocompetent patient with acute bacterial sinusitis. CMV
      has not been previously reported in the maxillary sinus of immunocompetent
      patients. The authors' hypothesis is that CMV can act as a precipitating factor
      for acute bacterial sinusitis.

PMID- 8669271
TI  - Acoustic rhinometry: practical aspects of measurement.
AB  - Rhinological diagnosis using acoustic rhinometry (AR) is described. The
      reliability of the test is improved by using a variable geometry craniostat
      allowing identical repositioning of the subject's head in various tests.

PMID- 8669272
TI  - Primary malignant melanoma of the larynx. A case report.
AB  - Malignant melanoma of the larynx is a rare tumor. Until now only 50 cases have
      been reported. This article presents a new case of a primary malignant melanoma
      of the larynx and review of the literature.

PMID- 8669273
TI  - A case of multiple post-anginal complications.
AB  - The paper presents an unusual case of multiple post-anginal complications in a 21
      year old male patient that included a peritonsillar abscess, parapharyngeal space
      phlegmon, a deep intrafascial phlegmon of the neck, internal jugular vein
      thrombophlebitis, septicopyemia, lung abscess and pneumonia, and a pyothorax. The
      patient was cured surgically and with broad-spectrum antibiotics and antifungal
      medication. The unusual course of the disease with presumed mycotic etiology as a
      complication of antibiotic therapy is discussed.

PMID- 8669274
TI  - Stylohyoid chain ossification: choice of the surgical approach.
AB  - The embryological, clinical and radiological features of an abnormal stylohyoid
      chain ossification is reviewed. The common embryological origin of the styloid
      apophysis, the styloid ligament and the lesser cornu of the hyoid bone allows the
      concept of a stylohyoid entity. The pathogenesis of the ossification of the
      stylohyoid chain enables us to distinguish Eagle's syndrome, the stylohyoid
      syndrome and the pseudo-stylohyoid syndrome. The choice between medical and
      surgical treatment particularly surgery by external approach, is discussed.

PMID- 8669275
TI  - Labyrinthine fistulae.

PMID- 8669276
TI  - The etiology of idiopathic sudden sensorineural hearing loss. A review of the
      literature.
AB  - Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is defined and the
      literature on the etiology of ISSHL is reviewed. Existing hypotheses on the
      etiology of ISSHL are judged on experimental, clinical, laboratory, radiological
      and post mortem histological evidence. It is concluded that a viral pathogenesis
      of ISSHL needs further attention in therapy and research.

PMID- 8669277
TI  - Therapy of idiopathic sudden sensorineural hearing loss. A review of the
      literature.
AB  - The literature on therapy of Idiopathic Sudden Sensorineural Hearing Loss (ISSHL)
      is reviewed. Clinical trails are judged on comparativeness, internal and external
      validity. It is concluded that steroids are only treatment available with a
      significant beneficial effect on ISSHL. Recommendations are made with regard to a
      well designed clinical trail on the treatment of ISSHL.

PMID- 8669278
TI  - The potential of electroanalytical techniques in pharmaceutical analysis.
AB  - With the considerable progresses observed in analytical instrumentation, it was
      of interest to survey recent trends in the field of electroanalysis of drugs.
      Potentiometric, voltammetric and amperometric techniques were scrutinized both in
      terms of historical evolution and in terms of potentialities with respect to the
      analysis of drugs in various matrices. With regard to the former, it appeared
      that numerous original selective electrodes (for drugs and ions) have been
      studied and several ion-selective electrodes have been successfully
      commercialized. Improvements are still expected in this field in order to find
      more robust membrane matrices and to minimize the surface fouling.
      Electrochemistry is well suited for trace metal analysis. A renewed interest in
      potentiometric stripping analysis is observed and is stimulated by the power of
      computers and microprocessors which allow rapid signal recording and data
      handling. Polarography and its refinements (Pulsed Waveform, Automation,...) is
      ideally applied for trace metal analysis and speciation. The technique is still
      useful in the analysis of drug formulations and in biological samples provided
      that the method is adequately validated (selectivity!). The same holds for solid
      electrodes which are currently routinely applied as sensitive detectors after
      chromatographic separation. New instrumentation is soon expected as regard
      electrochemical detection in capillary electrophoresis. Actually, in order to
      increase the responses and improve the selectivity, solid electrodes are facing
      exponential research dedicated to surface modifications. Perm-selectivity,
      chelations catalysis, etc. may be considered as appropriate strategies.
      Microelectrodes and screen printed (disposable) sensors are of considerable
      interest in cell culture e.g. for single cell excretion analysis and in field
      (decentralized) assays, respectively. Finally several biosensors and
      electrochemical immunoassays have been successfully development for the selective
      and sensitive analysis of drugs.

PMID- 8669279
TI  - [Comparative studies on freeze dryers of one and two chamber systems].
AB  - Authors carried out a comparative study on freeze--dryers of one--and two chamber
      systems. Samples containing dextran and mannitol were used for the control of
      process-uniformity. Moisture content of the products were monitored during the
      sublimation process and after closing the ampules by colouring of the CoCl2
      labelled samples. They put forward proposals for the combined measurement of
      barometric vapor pressure and product temperature in order to improve safety.

PMID- 8669280
TI  - Rheological studies of creams. II. Effect of water content on rheological
      characteristics.
AB  - 25 creams with different water content was prepared by means of five self
      emulsifying waxes. The variables were the ratio of the structure forming
      components of the lipophilic phase, the hydrophilic emulsifier and the water
      content. It was concluded from the flow curves, that the investigated creams were
      thixotropic systems independently of the water content. The yield value, the
      initial, the equilibrium and the plastic viscosity decreased exponentially with
      the concentration of the emulsified water. The slope of the linearized
      exponential curve is an important structural parameter. The measure of the this
      parameter provides information about the position of water in the gel structure.

PMID- 8669281
TI  - Rheological studies of creams. III. Effect of lipophilic phase on consistency.
AB  - The 3rd part of the serial analyses the correlation between the rheological
      characteristics of creams and the composition of the lipophilic phase. It is
      proved qualitatively by comparison of flow curves of systems with identical water
      content, and quantitatively by changes of initial, equilibrium and plastic
      viscosity, that the main factor in structure formation is the interboundary
      interaction of the hydrophilic and the lipophilic phase. This interaction can be
      characterised by determining wetting. A correlation between the contact angle of
      wetting between the hydrophilic and lipophilic phases (the quantitative model of
      the interboundary interaction) and the rheological parameters was identified. A
      logarithmic relationship was established between the contact angle of wetting and
      the yield value and structural viscosity.

PMID- 8669282
TI  - Stability-indicating assay of mequitazine in bulk and pharmaceutical tablets.
AB  - Simple and selective spectrophotometric procedures for the determination of
      mequitazine in its pharmaceutical tablets are described. The method was based on
      the formation of complex between mequitazine and palladium in presence of methyl
      cellulose in buffered or unbuffered media. The two procedures provide a mean of
      following the oxidative decomposition of the investigated drug. The apparent
      molar absorptivities at 460 and 500 nm were 2810 and 2840 and with Sandell's
      sensitivity of 0.116 and 0.103 for the buffered and unbuffered solutions,
      respectively. At the same time, Beer's law was obeyed in a concentration range of
      2.4-7.2 mg% and the regression line equations were derived with correlation
      coefficients of 0.9997 and 0.9999 for buffered and unbuffered reactions,
      respectively. The validity of the method was further confirmed using the standard
      addition method. The proposed procedures demonstrate high percentage of recovery
      with good accuracy and precision.

PMID- 8669283
TI  - Analytical investigation of beta-lactam antibiotics in pharmaceutical
      preparations. IX. Colorimetric determination of six cephalosporins of second and
      third generation in the range of micromolar concentrations.
AB  - A sensitive, accurate, precise and the same time simple and rapid method for the
      colorimetric determination of some cephalosporins of the second and third
      generations, such as: cefoxitin sodium (CFXT), cefaclor (CFCL), cefamandole
      nafate (CFMD), ceforanide l-lysine (CFRN), cefotaxime sodium (CFTX), and
      cefurozime sodium (CFRX) was described. The new method proposed is based: a) On
      the reduction of Fe(III) to Fe(II) by the drug analysed and b) On complexation of
      Fe(II) formed with o-Phenanthroline (O-Phen) consistently the formation of the
      well known highly stable orange-red coloured chelate complex [Fe(II)-(o-Phen)3]2+
      which exhibits an absorption maximum at lambda = 510 nm (pH 4.50 +/- 0.2). Beer's
      law is obeyed for: 1.0 - 37.5 microgram mL-1 for CFX, 1.0 - 25.0 microgram mL-1
      for CFMD, CFRN, and CFTX and 2.0 - 37.5 microgram mL-1 for CFTX and CFCL, while
      the apparent molar absorptivity ( epsilon in L mol-1cm-1) and the Sandell's
      sensitivity in (ngcm-2) both referred to the drug analyzed, are 1.29 x 10(4);
      34.7 (CFXT), 7.61 x 10(3); 50.7 (CFCL), 3.33 x 10(4); 15.4 (CFMD), 2.60 x 10(4);
      17.6 (CFRN) respectively. The regression line equation for each one of the above
      studied cephalosporins were calculated with a correlation coefficient 0.9997 < r
      < 1.0000; the accuracy and the precision of the method was considered as very
      satisfactory, while the results of a statistical analysis by means of the
      Student's t-test and the variance ratio F-test prove that no significant
      difference was observed between the results of the proposed method and those of
      official one.

PMID- 8669284
TI  - Angiotensin and the brain.
AB  - A brief account for the renal renin-angiotensin system (RAS), its inhibitors and
      receptors, as for the presence of an intrinsic cerebral RAS is initially
      provided. The review is then focused upon the circumventricular organs as
      cerebral targets for blood-borne angiotensin II (Ang II) and on centrally
      mediated Ang II effects. These concern influences upon the cardiovascular system,
      water balance, sodium balance, and ACTH-cortisol secretion.

PMID- 8669285
TI  - No effects of large doses of catecholamines on vascular permeability in isolated
      blood-perfused dog lungs.
AB  - Neurogenic pulmonary oedema (NPO) is believed to be induced by intense activation
      of the sympathetic nervous system, characterized by massive secretion of
      catecholamines into the blood stream. There is a possibility that NPO is partly
      the result of increased vascular permeability. However, the mechanism for an
      increase in pulmonary vascular permeability is not known. The present study was
      designed to test the hypothesis that large doses of catecholamines increase
      pulmonary microvascular permeability directly. Adrenaline or noradrenaline (100
      and 300 micrograms) was injected as a bolus into isolated dog lungs perfused with
      heparinized autologous blood at constant pressure. Adrenaline or noradrenaline
      produced sustained lung weight loss although both catecholamines increased
      pulmonary capillary pressure, assessed by double occlusion pressure, by 2-5 mmHG
      above baseline. Vascular permeability, as measured by the capillary filtration
      coefficient and the isogravimetric capillary pressure, did not change
      significantly from baseline at 30 and 60 min after catecholamine. Finally, the
      final-to-initial wet lung weight ratio of the catecholamine-treated lungs did not
      differ from that of saline-injected control lungs. Thus, we conclude that
      circulating catecholamines, even at supraphysiological doses, do not increase
      permeability in isolated blood-perfused dog lungs.

PMID- 8669286
TI  - The intestinal tract and the pathophysiology of arterial hypertension: an
      experimental study on Dahl rats.
AB  - Salt depleted rabbits and humans excrete an oral sodium load more quickly via the
      kidneys than an intravenous one. This has been ascribed to the presence of a
      sodium sensor in the gastrointestinal tract which in some way can influence renal
      function. The purpose of this study was to investigate this response in the Dahl
      rats. Renal and faecal sodium excretion was followed in the two strains of rats
      (normotensive, saltresistant (SR/Jr) and hypertensive, saltsensitive (SS/Jr)
      rats). After 4 days on a low salt diet they were given NaCl (1.5 mmol k(-1) body
      wt) either by gavage or intravenously. SR/Jr rats showed an increased renal
      sodium excretion both after oral and intravenous sodium repletion. The excretion
      was 2-3 times greater after th oral than after the intravenous administration.
      The SS/Jr rats augmented their renal sodium excretion only after the oral load,
      although the sodium excretion was significantly less than in SR/Jr rats. In fact,
      during the first 8 h after giving sodium orally the renal excretion of sodium was
      on an average eight times larger in the SR/Jr than in the SS/Jr rats. Renal
      excretion of sodium was similar in the two strains after intravenous
      administration. We conclude that the hypertensive SS/Jr rats have great
      difficulties in excreting an oral sodium load, a phenomenon that may be of
      importance in the pathophysiology of arterial hypertension in this strain of
      rats.

PMID- 8669287
TI  - Comparison of the effects of 2-deoxyglucose and immobilization on secretion and
      synthesis rate of catecholamines in the adrenal gland: a microdialysis study in
      conscious rats.
AB  - Using microdialysis, extracellular 3,4-dihydroxyphenylalanine (DOPA),
      noradrenaline (NA) and adrenaline (AD) concentrations in the adrenal gland were
      monitored in conscious rats during and after 60 min of immobilization (IMM) as
      well as after injection of 500 mg kg(-1) 2-deoxyglucose (2-DG). IMM produced a
      rapid and transient increase in secretion of AD (20-fold), NA (13-fold) and DOPA
      (3.6-fold). This was accompanied by an increase in blood pressure (+18 mmHG) and
      heart rate (+146 b.p.m.). Repeated exposure to IMM (daily 60 min, for 5 days) had
      no influence on either catecholamine secretion of haemodynamic profiles,
      indicating the lack of habituation to stressful conditions. Unlike IMM, the
      stress of 2-DG-induced central neuroglucopenia stimulated the release of AD
      without affecting NA secretion. AD levels peaked (5.1-fold increase) 40-60 min
      after 2-DG injection and then slowly declined. 2-DG induced no changes in blood
      pressure but reduced the heart rate (-48 b.p.m.). In separate experiments, steady
      state dialysate DOPA levels, reached during continuous infusion of decarboxylase
      inhibitor NSD 1015 into adrenal gland tissue through the dialysis probe, served
      as an index of adrenomedullary tyrosine hydroxylase (TH) activity. IMM evoked a
      marked response in TH activity (DOPA formation increased 2.7-fold), which
      remained elevated 60 min after the cessation of stress when AD and NA secretion
      had already fallen to baseline. After 2-DG, despite significant hormonal
      response, adrenal TH activity was unchanged. These results give clear evidence
      that IMM and 2-DG-induced neuroglucopenia may be considered as two different
      types of stressful stimuli.

PMID- 8669288
TI  - Redistribution of body fluids during postural manipulations.
AB  - Inter-compartmental body-fluid distribution is contingent upon posture, exercise
      state and environmental temperature. This investigation aimed at quantifying the
      distribution of intra- and extravascular fluid volumes during postural
      manipulations. Fluid shifts were measured in eight males utilizing a
      simultaneous, radionuclide dilution technique, in which radioiodinated serum
      fibrinogen, radiochromated erythrocytes, radiobromine and tritiated water were
      used to measure plasma, red cell, extracellular and total body water volumes.
      Subjects were exposed to three postural changes [seated (control), supine and
      standing] for 30 min at an air temperature of 22.0 degrees C, with each posture
      separated by 30 min seated rest. Total body water content remained stable
      throughout postural changes (P = 0.842). Relative to seated volumes, BV increased
      by 89 mL when supine, and decreased by 406 mL while standing (P = 0.003), with
      such shifts being primarily a result of plasma movement (P = 0.011). Red cell
      volume changes were not significant. Vascular fluid lost during standing was
      filtered into the interstitial compartment (P = 0.014), with the extracellular
      and intracellular volumes remaining unaffected. (P = 0.271 and P = 0.800,
      respectively). These observations confirmed the influence of posture on inter
      compartmental body-fluid distribution. The intravascular fluid loss when standing
      was caused by the filtration of plasma into the interstitium, while, during
      supine rest, intravascular volume increased, reflecting fluid flux from the
      interstitium to the circulation.

PMID- 8669289
TI  - Sodium and dopamine excretion in prehypertensive Dahl rats during severe
      hypervolaemia.
AB  - As opposed to the salt-resistant Dahl-R rat the salt-sensitive Dahl-S has a
      defective renal dopamine DA1 receptor that may be involved in its susceptibility
      to develop hypertension during a high salt diet. To compare the ability of
      prehypertensive Dahl-R and Dahl-S to respond to a severe isotonic sodium load,
      renal function was monitored during a severe form of acute isotonic volume
      expansion (10% VE). Mean arterial blood pressure before VE was similar in Dahl-R
      and Dahl-S and decreased in both strains by 6% during VE. The accumulated sodium
      excretion during VE in Dahl-R was 411 +/- 64 micromol 100 min(-1) g(-1) kidney wt
      (kw) which was not different from that in Dahl-S (420 +/- 95 micromol 100 min(-1)
      g(-1) kw). The accumulated dopamine excretion (a mirror of renal dopamine
      synthesis) during VE was also similar in Dahl-R (134 +/- 13 ng 100 min(-1) g(-1)
      kw) and Dahl-S (126 +/- 16 ng 100 min(-1) g(-1) kw). The excretion of DOPAC, the
      main metabolite of Dahl-S, glomerular filtration rate and systemic haematocrit
      did not differ between the strains before, during or after VE. To conclude, in
      spite of a defective renal DA1 receptor prehypertensive Dahl-S do not respond
      with an attenuated natriuretic or dopamine excretory response when subjected to a
      severe isotonic sodium load. The results do not support a sodium retaining role
      over a defective DA1 receptor in the salt-sensitive hypertension in Dahl-S.

PMID- 8669290
TI  - Effects of endothelins on renin secretion from rat kidneys.
AB  - Using a preparation of isolated rat kidneys perfused at constant renal artery
      pressure (80 mmHG) we investigated the role of endothelins in the regulation of
      renin release. Addition of three related endothelins (ET-1, ET-2, ET-3) at a
      concentration of 10 pmol L(-1) tended to enhance renin secretion rates. Higher
      doses (100 pmol L(-1), 1 nmol L(-1)) of different ETs such as the selective ETB
      receptor agonist sarafotoxin S6c (100 pmol L(-1), 1 nmol L(-1)) inhibited renin
      release and increased renal vascular resistance with similar potency. These
      effects of ETs were blunted when calcium ions were removed from the perfusate.
      Renin release activated by isoproterenol (10 nmol L(-1)) was also significantly
      reduced with ET-1, -2 and -3 (1 nmol L(-1)). BQ-123 (500 nmol L(-1)), a selective
      ETA receptor antagonist, only attenuated, whilst the non-selective ET receptor
      blocker bosentan (Ro 47-0203, 10 micro mol L(-1)) almost abolished the renal
      vasopressor and renin inhibitory action of ET-1 and sarafotoxin S6c. BQ-123 and
      bosentan alone did not affect either perfusate flow or basal renin secretion
      rates in isolated perfused kidneys. These findings indicate that all three ET
      peptides equipotently inhibit renin secretion from the kidneys. Most of the
      vasopressor and renin inhibitory effect of ETs is mediated by ETB rather than ETA
      receptors involving a calcium-dependent signal transduction mechanism. Moreover,
      our results suggest that intrarenally released ETs do not contribute to the
      regulation of renin secretion from isolated perfused rat kidneys.

PMID- 8669291
TI  - Efferent renal nerve stimulation inhibits the antihypertensive function of the
      rat renal medulla when studied in a cross-circulation model.
AB  - The aim of this study was to investigate the effects of renal nerve stimulation
      on the humoral renal antihypertensive system. An isolated kidney (IK) was
      perfused at normal or high arterial pressures from a normotensive assay rat by
      means of a perfusion pump. Perfusion pressure (PP) to the IK was 90 mmHg for a
      control period of 30 min. In three of five experimental groups PP was then
      increased to 175 mmHg. In two of the groups the renal nerves were stimulated at 2
      (P-175(2Hz)) or 5 Hz (P-175(5Hz)) for 60 min. The remaining group served as a
      control (P-175C). In two groups IK pressure was maintained at 90 mmHg with 5 Hz
      nerve stimulation (P-90(5Hz) or without nerve stimulation (P-90C). MAP of the
      assay rat decreased by 22 and 27% (P < 0.001) in the P-175C and P-175(2Hz)
      groups, respectively during the 60 min period of nerve stimulation, but remained
      stable in P-175(5Hz). Renal blood flow increased in the IK when PP was increased
      in P-175C, but did not change significantly in P-175(2Hz) or P-175(5Hz). Blood
      pressure remained constant in the assay rat when the IK was perfused at 90 mmHg.
      The renal excretory functions of the IK decreased in a frequency dependent manner
      by 2 and 5 Hz renal nerve stimulation compared with P-175C. We conclude that 5 Hz
      renal nerve stimulation inhibits the pressure dependent release of humoral
      depressor substances from an IK perfused at 175 mmHg, whereas this is not seen
      when stimulating at 2 Hz. It is suggested that hte release of antihypertensive
      substances from the renal medulla requires an increased renomedullary blood flow.

PMID- 8669292
TI  - Sympathetic vascular control of the laryngeo-tracheal, bronchial and pulmonary
      circulation in the pig: evidence for non-adrenergic mechanisms involving
      neuropeptide Y.
AB  - Neuropeptide Y (NPY) and noradrenaline (NA) are co-stored in sympathetic
      perivascular nerves of the airway mucosa and lung. THe superior laryngeal,
      bronchial and pulmonary vascular responses were therefore studied in
      anaesthetized pigs after systemic injections of NPY and NA and after stimulation
      (2 or 10 Hz, 15 V, 5 ms) of the cranial and caudal portions of hte cervical
      sympathetic trunk or the stellate ganglia. NPY and NA increased vascular
      resistance, suggesting vasoconstriction in all three vascular beds. Stimulation
      of the cervical sympathetic trunk in the cranial direction caused clear-cut
      vasoconstriction and a decrease in the superficial blood flow in the laryngeal
      and tracheal circulation supplied by the superior laryngeal artery. This vascular
      response may be related to release of NA at 2 Hz and possibly also NPY at 10 Hz,
      since a remaining vasoconstrictor response at 10 Hz was present in reserpinized
      preganglionically transected pigs when tissue content of NA but not NPY was
      depleted. The decrease in superficial blood flow in the tracheal mucosa on
      sympathetic stimulation was absent after reserpine, however. Stimulation of the
      cervical sympathetic trunk in caudal direction provoked vasoconstriction in the
      bronchial and pulmonary vascular beds in control pigs. The basal tone of these
      two vascular beds was not influenced on electrical stimulation after reserpine
      pretreatment, however, suggesting involvement of NA and possibly aslo NPY, which
      were both depleted by reserpine. Electrical stimulation of the stellate ganglia
      also evoked reserpine-sensitive vasoconstriction in both the bronchial and
      pulmonary vascular beds. The left stellate ganglion dominated the vasomotor
      response in the bronchial circulation, whereas the right side mainly influenced
      the pulmonary circulation and the heart.

PMID- 8669293
TI  - Effect of sympathetic modulation and sympatho-vagal interaction on heart rate
      variability in anaesthetized dogs.
AB  - Changes in the function of the autonomic nervous system underlying changes in
      heart rate variability are not fully understood. Furthermore, decreased heart
      rate variability has been found to be related to poor prognosis, for example, in
      patients with coronary artery disease. Our aim was to study how modulation in
      sympathetic stimulation at various frequencies is transferred into heart rate
      variation, and how the interaction between sympathetic and parasympathetic inputs
      can affect the high-frequency component of heart rate variability. We stimulated
      electrically cardiac sympathetic and vagal nerves in anaesthetized, vagotomized,
      spinal anaesthetized dogs. We controlled the frequency and magnitude of the
      modulation in programmed stimulation patterns and analysed the resulting changes
      in heart rate variability by power spectral analysis. We found that modulations
      in sympathetic stimulation were reflected in the high-frequency component of
      heart rate variability, as well as in the low- and medium-frequency components.
      In addition, a novel finding was that sympathetic stimulation reduced the
      magnitude of the high-frequency variations caused by vagal stimulation. This
      suggests that, although the high-frequency component of heart rate variability is
      mainly under parasympathetic regulation, it may also be influenced by the
      sympathetic nervous system.

PMID- 8669294
TI  - Glucagon secretory response to hypoglycaemia, adrenaline and carbachol in
      streptozotocin-diabetic rats.
AB  - Glucagon response to insulin-induced hypoglycaemia is impared in diabetes, but
      the mechanism is not established. Pancreatic A cell hyporesponsiveness to
      adrenergic or cholinergic stimulation could contribute to the impairment. We
      therefore compared the plasma glucagon responses to intravenous infusion of
      adrenaline (1200 ng kg(-1) min(-1) for 20 min) or to intravenous injection of the
      cholinergic agonist carbachol (50 micrograms kg(-1)) in chloral hydrate
      anaesthetized rats made diabetic with the use of streptozotocin (80 mg kg(-1)
      subcutaneously) 6 weeks before and in anaesthetized control rats. Insulin was
      infused intravenously to reduce plasma glucose levels to below 1.8 mmol L(-1). As
      expected, the plasma glucagon response was reduced by approximately 45% in
      streptozotocin-diabetic rats compared with controls (P = 0.045). During
      adrenaline infusion, plasma glucagon levels increased by 277 +/- 92 pg mL(-1) in
      controls (P = 0.009) and by 570 +/- 137 pg mL(-1) in the diabetic rats (P =
      0.002). Thus, the plasma glucagon response to adrenaline was approximately
      doubled in the diabetic rats (P = 0.045). Following carbachol injection, plasma
      glucagon levels were raised by 1211 +/- 208 pg mL(-1) (P < 0.001) in controls but
      only by 555 +/- 242 pg mL(-1) in the diabetic rats (P = 0.049). Thus, the plasma
      glucagon response to carbachol was impared by approximately 58% in the diabetic
      rats (P = 0.028). We conclude that carbachol-stimulated glucagon secretion is
      impared concomitantly with the impared glucagon response to hypoglycaemia in
      streptozotocin-diabetic rats, whereas adrenaline-induced glucagon secretion is
      exaggerated. We suggest that a reduced pancreatic A cell responsiveness to
      cholinergic stimulation could contribute to the impairment of the glucagon
      response to insulin-induced hypoglycaemia in diabetes.

PMID- 8669295
TI  - Taurine efflux is a cell volume regulatory process in proximal renal tubules from
      the teleost Carassius auratus.
AB  - The potential role of taurine transport associated with volume regulation in
      renal tissue and isolated proximal renal tubules was studied in the teleost
      Carassius auratus (goldfish). The cellular taurine content in renal tissue
      fragments incubated in isosmotic solution (290 mOsm) (7.8 +/- 0.9 (SD) micromol g
      wet wt(-1)) decreased by 60% following exposure to hyposmotic medium (100 mOsm).
      The rate coefficient for [14C]taurine efflux in renal tissue and in isolated
      proximal renal tubules was strongly stimulated following hyposmotically or urea
      activated cellular swelling. The stimulated basolateral taurine efflux pathway
      exhibited channel-like functional characteristics since (a) [14C]taurine influx
      was stimulated in parallel with the osmolality-dependent taurine efflux and (b)
      this efflux could not be stimulated by high medium taurine concentrations (40 mM)
      applied 10 min following the osmolality reduction (trans-stimulation test).
      Administration of the 5-lipoxygenase inhibitor ETH 615-139 (20 microM) during
      hyposmotic stimulation inhibited regulatory volume decreases but had no effect on
      taurine efflux. In addition, hyposmotically induced taurine efflux was slightly
      but significantly inhibited by the cyclooxygenase inhibitor indomethacin (10
      microM). The taurine efflux was also dependent on both extra- and intracellular
      Ca2+. It is concluded that taurine is likely to coparticipate with KCl as an
      osmoeffector during RVD in Carassius proximal renal tubule cells. Cellular
      swelling seems to activate a basolateral taurine transport pathway with
      functional properties of a channel. This efflux mechanism appears to be partly
      regulated by Ca2+. Such a transport pathway could play a role in the cell volume
      regulatory mechanisms participating during transepithelial solute and water
      transport.

PMID- 8669296
TI  - Myosin heavy chains in skeletal muscles of the common shrew (Sorex araneus):
      absence of a slow isoform and transitions of fast isoforms with ageing.
AB  - Myosin heavy chain (MHC) composition in seven skeletal muscles of the common
      shrew (Sorex araneus) was analysed by gradient SDS-PAGE and immunoblotting with
      monoclonal antibodies. Characteristic for the studied muscles (diaphragm, lateral
      gastrocnemius, medial gastrocnemius, masseter, plantaris, soleus and tibialis
      anterior) was a total absence of the slow isoform, MHCI; all muscles were
      exclusively composed of two fast isoforms MHCIId and MHCIIb. In young adults the
      amount of MHCIId varied between 34% (tibialis anterior) and 97% (masseter). In
      over-wintered senescent individuals MHCIId was clearly the dominant isoform in
      all muscles studied; the lowest MHCIId content was measured for tibialis anterior
      (69%), while in diaphragm, masseter and soleus it was practically the sole
      isoform (over 96%). Ageing associated isoform transition from MHCIIb to MHCIId
      occurred in all seven muscles studied (P < 0.05).

PMID- 8669297
TI  - 5-Hydroxytryptamine: initiator of phase 3 of migrating motor complex.

PMID- 8669298
TI  - [The Societe Royale de Medecine Mentale de Belgique in search of its history].

PMID- 8669299
TI  - [125 years of Acta Psychiatrica Belgica. Bulletin of the Societe Royale de
      Medecine Mentale de Belgique].

PMID- 8669300
TI  - [Ethics and psychiatry].

PMID- 8669301
TI  - [Role of freedom in psychiatric theories].
AB  - All the theories of mind used in the treatment of mental illnesses are based on
      one or another kind of determinism. Therefore, psychiatrists are obliged to
      conceive the subjective free will of their patients as a psychological function
      that their theories do not explain. As a result of it, they encounter many
      difficulties in the ethical aspects of their therapeutical choices. Following the
      ideas of A. Pichot, F. Varela and Ph. Meire, the author proposes an
      autoreferential conception of the cerebral functions and its link with mind. He
      shows how it is possible to give a theoretical place to human free will. He
      indicates the clinical advantages of such a model, giving the free will of the
      patient a therapeutical role, and making the ethical choices of the psychiatrist
      easier.

PMID- 8669302
TI  - [Ethical implications in the psychotherapeutic relationship].
AB  - The psychotherapeutical relationship is part of the communication sciences.
      Therefore some authors as e.g. J. Habermas consider the ethics of the
      psychotherapeutical relationship to be paradigmatical for the ethics of
      communication. The ethical problems of psychotherapy are particularly important,
      since the patient-psychotherapist relationship is the main instrument of therapy.
      The ethical problems vary according to the type of psychotherapeutical
      relationship, which in turn depends on the form of psychotherapy. Therefore the
      ethical problems will successively be considered in the psychoanalytically
      oriented psychotherapies, the behavior therapies and the systemic therapies.
      Finally the more general ethical problem of the relations of psychotherapists
      with power will be discussed.

PMID- 8669303
TI  - [Psychological roots of ethics].
AB  - The drive to murder, so-called Cain drive by L. Szondi is properly human. As non
      ethic, it opens up the dialectics of ethics. Because it is a drive, it includes
      in itself the possibility of its own surpassing.

PMID- 8669304
TI  - [Ethics and research: ethical considerations in clinical research].
AB  - Two subjects are discussed: the use of placebo controls in clinical trials and
      informed consent. Particularly in trials of drugs for disorders for which there
      exist effective treatments, the use of placebo is still controversial, although
      anyhow in violation of the Declaration of Helsinki. Informed consent aims at
      giving a subject all the necessary information to allow him to decide, with full
      knowledge, whether to accept a particular treatment or experimental protocol. Its
      importance would seem, albeit essential, to be rather illusory.

PMID- 8669305
TI  - [Between deontology and ethics, does the institution become respectable?].
AB  - Deontology draws one's inspiration from Ethics. From this occurrence it seems
      important to avoid confusion between the first and the second. Psychiatry belongs
      truly to medical training. Nevertheless considering freedom pathology is its main
      particularity. This is the reason why human freedom must, at all cost, be
      preserved. This one is essential whenever individual subjectivity is concerned.
      The fundamental reference remains Human Rights Convention; even if opposed to
      principle of reality, one is necessarily obliged to a conflictual accommodation.

PMID- 8669306
TI  - [Assisted procreation: ethics and passions].
AB  - In vitro fertilization has become a subject of major ethical debate filled with
      passion and for two main reasons: On the one hand, it has posed in a very clear
      way the problem of the status of the human embryo, a problem intrinsically
      related to the debate on the voluntary termination of pregnancy. On the other
      hand, it looks again at the debate on access to these techniques, to the
      legitimacy of the desire for a child and to debate on the new families and from
      there, questions sexuality, life and death, subjects of fundamental existence.
      The authors analyses the phenomenon, develops a lay approach to embryo status and
      from there defends a vision of freedom of access to assisted procreation.

PMID- 8669307
TI  - [Child sex abuse: pretext to a return of sexual repression].
AB  - This article is based on observations and thoughts during intensive
      psychotherapeutic work with 997 sexually abused children and their parents after
      they had been reported to the Confidential Doctor Center Kind in Nood of the VUB
      (between 1986 and 1994). Without denying the existence of sexual abuse of
      children, it is important not to exaggerate this phenomena, which can be
      described as the Child Sexual Abuse Panic Syndrome. Doing this only gives way to
      denial and indignation or scandalization and revenge, and certainly does not lead
      to a clear analysis of the problem. Accurate observation enables some existing
      myths to become unravelled: abusive fathers are seldom power robots, mothers are
      not always warm-hearted, innocent creatures and children are not black boxes
      without feeling and sexual desires. The underlying message is about the bitter
      fight against modernization of sexuality, which seems again experienced as
      dangerous. However it is fear for a free, adult sexuality that is at the core of
      sexual exploitation of children, which should encourage caution in professional
      answers to this delicate issue.

PMID- 8669308
TI  - [Ethical questions about methadone].
AB  - The author approaches ethical questions raised by use of methadone in opiates
      addiction: reduction of drug phenomenon to a strict medical problem, illusion of
      technical mastery, responsibility of pharmaceutical engineering, medicine under
      repressive constraint, reduction of damages linked to prohibition. The
      communication ends on a question about management of drug problems which today
      encourages a healthy vision of consumption behaviour rather than a "good way of
      use".

PMID- 8669309
TI  - Anatomical variations of the human vestibular aqueduct. Part I. A radioanatomical
      study.
AB  - Variations in the size and shape of the human vestibular aqueduct were evaluated
      in 118 plastic casts of unselected specimens of human temporal bones. They were
      examined by conventional radiography and by high resolution CT. The degree of the
      mastoid and perilabyrinthine pneumatization was defined and classified into 3
      types. The dimensions of the peripheral portion of the aqueduct were found to be
      related to the extent of the perilabyrinthine pneumatization.

PMID- 8669310
TI  - Anatomical variations of the human vestibular aqueduct. Part II. A
      radioanatomical study.
AB  - The human vestibular aqueducts are classified into 3 types and into the types
      hyper-, normo- and hypoplastic. The types correspond with each other up to over
      85%. For a better understanding of the radioanatomy and for the proper
      interpretation of radiograms, we describe the presence of a flat recess-like
      widening of the peripheral portion of the aqueduct, as well as other findings.

PMID- 8669311
TI  - The proximal portion of the vestibular aqueduct. A radioanatomical investigation.
AB  - PURPOSE: To obtain information on the morphology of the proximal portion of the
      vestibular aqueduct. MATERIAL AND METHODS: One hundred plastic casts of temporal
      bone were examined with a dissection microscope at high magnifications in order
      to evaluate the proximal portion of the vestibular aqueduct. The difficulties in
      reproducing these minute structures were solved by light scanning photography.
      RESULTS: There is usually more than one paravestibular canaliculus (PVC) around
      the proximal portion of the vestibular aqueduct closely related to an intra-and a
      periaqueductal vascular network. An estimate was made of the number of PVCs and
      their widths measured. The origins of the PVCs at the wall of the vestibule were
      identified and their widths were measured. Numerous vascular sulci and
      impressions of a vascular network on the inside of the bony wall of the vestibule
      were revealed close to the internal aqueductal aperture. The pattern of the
      channels and the number of the paravestibular canaliculi were not influenced by
      the pneumatization of the temporal bone. CONCLUSION: The significance of these
      vascular structures and their influence on the radiographic reproducibility of
      the proximal portion of the vestibular aqueduct is discussed.

PMID- 8669312
TI  - Anatomical variations of the tympanic and mastoid portions of the facial nerve
      canal. A radioanatomical investigation.
AB  - PURPOSE: To obtain information on the morphology of the tympanic and mastoid
      portions of the facial nerve canal, and on the appearance of unusual vascular
      channels and anomalies such as dehiscences. MATERIAL AND METHODS: One hundred and
      two temporal bone preparations were examined by conventional radiography to
      evaluate mastoid pneumatization. Of these, 73 were examined by high resolution CT
      in order to test the ability of the method to detect dehiscences in the bony wall
      of the tympanic portion of the canal and the accompanying channels along its
      mastoid portion. Subsequently produced plastic preparations were used to measure
      the length and width of these 2 portions of the facial canal. RESULTS: Our study
      reports observations on the three-dimensional morphology of the canal in the
      plastic casts. The study shows variations in the course and dehiscences of the
      tympanic portion. Additional bony channels along the mastoid portion are
      described. These results supplement those in previous investigations. CONCLUSION:
      The measurement results agree with those of previous investigations. The course
      of the tympanic portion is S-shaped and has an impression on its upper surface.
      High resolution CT reproduces dehiscences of the bony canal in a percentage
      similar to that of microscopical methods and in relevant sites. Pneumatization
      does not influence the dimensions of the 2 portions.

PMID- 8669313
TI  - Radioanatomical detail of the human temporal bone in relation to pneumatization.
      A correlative radioanatomical investigation.

PMID- 8669314
TI  - [Arterial hypertension, left ventricular hypertrophy and cardiovascular risk].

PMID- 8669315
TI  - [Circadian rhythm at the onset of symptoms in clinical cases of myocardial
      infarction. Our first five hundred cases].
AB  - Following previous studies, we conducted an inquiry into acute myocardial
      infarction in our ward (Medicine 2, St. John Hospital, Oporto) regarding the
      exact time of the onset of symptoms. The results now published are of the first
      five hundred cases. These results show three peaks of greater frequency in the
      onset of symptoms--morning, afternoon and evening, as well as a certain degree of
      nocturnal protection. Our intention is to continue this study.

PMID- 8669316
TI  - [Neuro-brucellosis. Report of 8 cases].
AB  - Brucellosis is an endemic disease in Portugal. There was an increase in incidence
      in 1994. Neurobrucellosis (NB), although only occurring in 5 to 10% of cases of
      cases of chronic infection, has heterogeneous forms of presentation which makes
      differential diagnosis difficult. By reviewing four years of in-patient clinical
      files in the neurology Ward of St. Antonio dos Capuchos Hospital, the authors
      study the clinical features, complementary tests, therapy and evolution of
      differential diagnosis of eight patients with neurobrucellosis.

PMID- 8669317
TI  - [Cerebrovascular accidents. Case material based on hospital records].
AB  - Perceiving that inaccuracy of clinical records is the rule rather than the
      exception, the author examines the data base of the Amarante Regional Hospital
      with particular relevance to the patients who were hospitalized with cerebral
      vascular accident (CVA) in the Department of Internal Medicine during 1990, 1991
      and 1992. The objective is to view the existing computerised hospital database as
      a source of information for future studies within the clinical field and, at the
      same time, to be aware of the department's casuistry and to contribute to the
      epidemiological understanding of the population who lives in the area of
      influence of this hospital. In this department, 24% of all the hospitalised
      patients had either a recent CVA or had already had one previously. On the whole,
      the disease affected both sexes in an equal manner, but females later than males.
      The mortality rate was greater in patients with CVA (17%) than in those without
      CVA (9%) and was also greater in CVA-females (19%) than in CVA-males (15%). The
      intercurrences in the community were the cause of admission in 26% of the
      hospitalised patients with a CVA, and were mainly respiratory, metabolic and
      urinary diseases, and appeared to be more serious in males. The mortality rate in
      patients with intercurrences (19%) was only exceeded by that caused by hemorragic
      accidents (22%). The author examines and discusses the instances of error during
      the construction and data gathering of the database and draws his own
      conclusions.

PMID- 8669318
TI  - [Hypertensive crises].
AB  - The goal of the accurate treatment of an hypertensive crisis is to reduce the
      critically elevated blood pressure to a safer level, in an hemodynamic point of
      view, although not necessarily normal. The authors stress that a prompt and
      correct diagnosis in distinguishing hypertensive emergencies from urgencies, in
      understanding its pathophysiology and the knowledge of available drugs is
      essential for a successful management.

PMID- 8669319
TI  - [Transverse myelitis].
AB  - The authors report three clinical cases of acute transverse myelitis in young
      patients with emphasis given to the seriousness of this kind of pathology, the
      need to exclude a potentially treatable cause and the controversial
      corticosteroid treatment.

PMID- 8669320
TI  - [Cerebellar hematomas in a patient with atrial myxoma].
AB  - We describe a case report of a 69 year old woman with atrial myxoma, presented as
      a cerebellar syndrome caused by ischemic infarctions of the posterior
      circulation. The transthoracic 2D echocardiogram provided the diagnosis of a left
      atrial myxoma. Seven months after surgical removal of the cardiac tumor, the
      cerebellar syndrome worse with the acute development of intracranial
      hypertension. A CT scan detected multiple hematomas of both lobes and vermix of
      the cerebellum and hydrocephalus. These late neurologic complications permitted
      us to suspect and discuss some diagnostic hypotheses. Cardiac myxomas are rare
      and their presentation as early neurologic manifestations occur in 20-25% of the
      cases. The late neurologic complications of myxoma are even more rare, only a few
      cases being reported in world literature.

PMID- 8669321
TI  - [Autoimmune hemolytic anemia and ulcerative colitis].
AB  - Although several associations of autoimmune disorders with ulcerative colitis
      have been reported, autoimmune hemolytic anemia is extremely rare. We report a
      case of a 35 year-old white woman with a twelve-year history of mild ulcerative
      colitis treated in the last 5 years with 5-amino-salycilic acid who developed a
      severe autoimmune hemolytic anemia. We discuss some particular aspects of the
      association of these two immunologically mediated disorders as well as the
      controversial aspects of autoimmune hemolytic anemia therapy in this context.

PMID- 8669322
TI  - [Hysterical psychoses revisited].
AB  - The author, after reviewing the literature about hysterical psychosis, briefly
      presents some of the surveys made in this area. The point of departure are the
      Hollender and Hirsh criteria for hysterical psichosis defined in 1964. These
      authors assumed that the clinical picture responds to a psychopathological entity
      which results from a single process. The other surveys presented try to prove
      this concept through case report and epidemiological research. The author
      concludes leaving this concept as an open question, suggesting that this could be
      a pathway for further research.

PMID- 8669323
TI  - [Pathologic states related to alcoholism].
AB  - The Author reviews the pathological consequences of chronic alcoholism with
      particular emphasis to the consequences of malnutrition, especially vitamin B-1
      deficiency, immune deficiencies, adaptation of cytochrome 2E1, testicular
      atrophy, alterations of the skin, bones, liver, muscles, cardiac and
      neuropsychiatric.

PMID- 8669324
TI  - [Ethics in medicine. On the example of Egas Moniz].

PMID- 8669325
TI  - [Ethical committees of clinical research: Good present. Better future?].

PMID- 8669326
TI  - [Low incidence of mutations in codon 12 of the c-K-ras gene in bladder cancer].
AB  - During vesical carcinogenesis a variety of genetic alterations such as oncogene
      mutation or loss of suppressor genes have been detected. Codon 12 mutation of the
      c-K-ras gene has been seen with a high frequency in several human neoplasias but
      its participation in the development of vesical cancers has not been fully
      dilucidated. Using the DNA restriction fragments polymorphism (RFLP) technique
      enhanced by a polymerase chain reaction (PCR) a study has been made of codon 12
      mutation at the c-K-ras gene in 55 patient with vesical cancer undergoing surgery
      between 1991 and 1992. The tumoral stage was superficial (Ta-Tl) in 24 cases,
      infiltrant (T2-T4) in 28 cases and unknown in 3 cases. Two patients (3.6%) showed
      codon 12 mutation at the c-K-ras gene. One case was a fast evolving infiltrant
      tumour (T2-T3) which caused death of the patient after 4 months while the other
      case was a surface tumour (G2Ta) which relapsed early, the pathological anatomy
      revealing a stage T2-T3 squamous carcinoma. Our results suggest that codon 12
      mutation at the c-K-ras gene is not a meaningful genetic change in the genesis of
      vesical cancer. Its emergence, however, appears to be related to a more
      aggressive tumoural behaviour.

PMID- 8669327
TI  - [Final results of complete hormone blockade versus monotherapy in prostatic
      metastatic cancer. PSA implications].
AB  - Of 102 patients with metastatic prostate cancer, 52 were treated with
      orchidectomy and 50 with CHB; 22 of these received a LHRH analog + Flutamide and
      28 orchidectomy + Flutamide. No differences were seen in either arm in terms of
      age (69.9 vs 70.2 years) or initial PSA (493.3 vs 486.5 ng/ml) variables. After
      three months treatment, CHB achieved a decrease of PSA higher than monotherapy
      (52.9 vs 34.5 ng/ml) p<0.01 as well as minimum PSA level during follow-up (41.2
      vs 17.5 ng/ml) (p<0.001). Initial clinical response rates were higher in the
      group treated with complete blockade (42.3% vs 52%) (p=n.s.). Overall, no
      significant differences were seen between the actuarial curves of biological
      progression, clinical progression and survival, with expected mean values of 13
      vs 12, 14 vs 15 and 34 vs 28 months, respectively. However, when survival was
      considered as a function of bone disease dissemination, a greater survival rate
      was seen in patients with minimal M1 disease (p<0.05), and there were no
      differences between the M2 and M3 arms.

PMID- 8669328
TI  - [Urothelial inverted papilloma].
AB  - Review of 60 cases of inverted urothelial papilloma published in our country in
      different urological journals. Analysis of clinical, diagnostic and therapeutical
      issues. Also an analysis is made of the possible association with other
      neoplasias or their malignant development.

PMID- 8669329
TI  - [Oxalate: its role in lithogenesis and composition of calcium oxalate lithiasis].
AB  - A prospective study was conducted on 374 patients with urinary lithiasis, aiming
      to analyze the participation of oxalate in the lithogenesis and composition of
      the calcium oxalate calculi, alone or associated to other factors. METHODOLOGY:
      Metabolic urinary study of the patient and analysis of calculi with infrared
      spectrography and optical microscopy. RESULTS: 26.3% patients had hyperoxaluria
      and 77.5% of the calculi contain calcium oxalate; these are 167 cases of calcium
      oxalate, 110 of oxalate and calcium phosphate and 13 cases of mixed calcium
      oxalate and uric acid lithiasis. 43.4% patients with pure monohydrate calcium
      oxalate calculi have hypercalciuria, 22.6% hyperoxaluria and 19% hyperuricosuria.
      Dihydrated calcium oxalate calculi are related to high hypercalciuria in 65%
      cases and to significant hyperoxaluria in 35% cases. 45% patients present a
      single lithogenic factor, either hypercalciuria (49.6%), hyperoxaluria (20.6%),
      hyperuricosuria (13.74%), hypocitraturia (9%), urinary infection (1.5%), A.T.R.
      (2.25%) or acid oliguria (3%).

PMID- 8669330
TI  - [Epidemics of urinary calculi in la Ribera de Navarra (II). Analytic studies].
AB  - Presentation of the analytical results from the patients seen for lithiasic
      disease (LD) over a two-year period at the Hospital Reina Sofia, Tudela. This
      Hospital covers a homogeneous Health Area including 22 villages and a population
      of 76,000 people. The clinical cases of 785 patient diagnosed with LD between May
      1988 and 1990 May are analyzed. Microhaematuria in fresh urine is detected in
      64.20% patients and crystalluria in 33.37%. Significant bacteriuria is present in
      5.73% of total patients with prevalence of E. coli in 42.4%. Only 2 cases of
      hyperparatiroidism were diagnosed during the study period but later another two
      cases of HPT were detected in bone injuries studied due to rheumatic disease. No
      normocalcemic HPT cases were diagnosed among suspected cases. The metabolic
      studies were of little use in our experience, maybe because of non-availability
      of basic analytical determinations such as citraturia. Nevertheless, higher
      values of urinary volume, calciuria and uricemia and lower values of magnesemia
      and magnesiuria were found in lithiasic patients that in control ones. Neither
      oxaluria or the remaining analytical parameters provide differential data.
      Hypercalciuria higher than 300 mg in seen in 28.6% of studied patients and in
      12.5% of the control group.

PMID- 8669331
TI  - [Cefminox versus cefotaxime in the treatment of complicated urinary tract
      infection].
AB  - A comparative study of Cefminox, a new cefamicin, and Cefotaxime was conducted to
      evaluate the efficacy and safety of the former in the treatment of complicated
      urinary infection, and to correlate in both cases the bacteriological response
      with isolates MICs. To this end a phase III, randomized, blind and controlled
      clinical trial was conducted in 22 patients who met the study's preestablished
      criteria, 19 of which were evaluable. Both treatments achieved 100% clinical
      efficacy, while microbiological eradication was accomplished in 90.9% patients
      treated with Cefminox and 75% patients who received the comparator. Cefminox
      shows greater in vivo activity than that expected for the MICs, excellent
      efficacy and safety.

PMID- 8669332
TI  - [Transitional cell tumor of the bladder in children: report of a case].
AB  - Transitional cell tumours of the bladder in children are exceptionally rare. This
      paper presents a new case in an 11-year old patient. The benignity of these
      tumours during the paediatric age can be verified due to the low infiltration
      incidence; some authors, however, describe cases of relapses which are commented
      upon. The careful follow-up that has to be done in this type of patients is
      underlined.

PMID- 8669333
TI  - [Abscessed brucellar prostatitis. An infrequent location].
AB  - Explanation of one case of abscessified brucellar prostatitis in a 44-year old
      patient. The emphasis is placed on the high incidence of brucellosis in the
      province of Soria and the rarity of the prostatic location of this condition.
      Also, a revision is made of the diagnostic methodology and current therapeutical
      approaches. The crucial role of the endocavitary ultrasound techniques both for
      diagnosis as well as treatment and case follow-up is highlighted.

PMID- 8669334
TI  - [Congenital urethral diverticulum].
AB  - Presentation of two cases of congenital diverticula of the bulbar urethra. The
      objective of this paper is to discuss the etiopathogenic theories, sings and
      symptoms, current diagnostic methods and therapeutic indications, and to conclude
      that this type of diverticula do not present a florid symptomatology, endoscopy
      being the best diagnostic and therapeutic method. Finally, a review of the
      literature is made based on two clinical cases.

PMID- 8669335
TI  - [Tuberculous prostatic abscess in a patient with AIDS].
AB  - Despite of prostate abscesses having become an uncommon disease, a number of
      cases has been described lately specially in immunodepressed patients caused by
      infrequent agents, such as Mycobacterium tuberculosis. This paper describes the
      case of one HIV-positive patient, diagnosed with a prostate abscess within a
      tuberculous dissemination. The best diagnostic method is considered to be the
      transrectal ultrasound (TRU), the choice therapy being drainage by ultrasound
      guided transperineal percutaneous puncture.

PMID- 8669336
TI  - [Brachytherapy in the treatment of prostatic carcinoma].
AB  - Radiotheraphy of prostatic cancer began using brachitherapy. In 1910 Paschkis and
      in 1911 Pasteau reported treatment of prostatic carcinoma with radium needles. In
      1952, Flocks began implanting a colloidaly radioactive gold-198 solution into the
      prostate after surgical exploration. This approach was optimized by Carlton in
      1965 using solid gold-198 implants combined with external beam therapy. In 1972
      Withmore et al reported the use of iodine-125 seeds for interstitial irradiation.
      In 1977 Court and Chassagne introduced after loading techniques using iridium
      192. This technique has been developed further by Syed et al. In these settings
      interstitial radiotherapy is used as localized boost in combination with external
      beam therapy. Prostate brachytherapy can be divided into temporary implantation
      using high activity sources, or permanent brachytherapy using the interstitial
      implantation of iodine-125 or palladium-103 sources. We reported an overview.

PMID- 8669337
TI  - Ageing is riskier than it looks.

PMID- 8669338
TI  - Primitive reflexes and dementia: results from the Canadian Study of Health and
      Aging.
AB  - We report on the prevalence of primitive reflexes (PR) and their association with
      cognitive, behavioural, functional and clinical characteristics in 2914 Canadians
      65 years and older. Data were collected as part of the Canadian Study of Health
      and Aging (1990-92) and included individuals living in the community and in
      institutions. PR were more commonly found in demented subjects. Demented subjects
      with prehensile PR (i.e. grasp, traction, suck) had significantly more functional
      and behavioural problems and were more severely demented. The presence of any PR
      increased the likelihood of other neurological findings (e.g. bradykinesia).
      Vascular dementia (VD) cases were more likely to have unilateral primitive PR
      than probable Alzheimer's disease (Pro AD) and Parkinson's dementia (PD) cases.
      PD cases were more likely to have glabellar and traction responses. While more
      common among the demented, PR lacked sufficient sensitivity to be an early
      diagnostic tool for dementia. Prehensile PR may help to define particular types
      or severity of dementia.

PMID- 8669339
TI  - Predictors of hospital contact by very elderly people: a pilot study from a
      cohort of people aged 75 years and over.
AB  - We wished to test the hypothesis that elderly people with impaired cognitive
      function were heavier users of both outpatient and inpatient hospital services.
      In a retrospective cohort study, 144 elderly people aged 75-97 years (50 men and
      94 women) identified from a prevalence survey of dementia were traced over an
      average period of 4 years. They were categorized into three groups: cognitively
      impaired, physically frail and physically healthy. Elderly people with impaired
      cognitive function had fewer contacts with outpatient services (p = 0.0003) but
      did not differ in inpatient service use from subjects with normal cognitive
      function. Cognitively impaired people who lived alone had longer hospital stays
      (p = 0.002) and a higher admission rate to geriatric wards (p = 0,009). Negative
      self-rated health was an important factor predicting more contacts for men with
      inpatient services and geriatric outpatient services (both p = 0.002). Use of
      surgical outpatient services was associated with use of surgical inpatient
      services by the physically healthy group only (p = 0.0003). After adjusting for
      age, sex and physical health, cognitively impaired subjects were nearly twice as
      likely to die within four years as the other two groups (RR = 1.89).

PMID- 8669340
TI  - Factors associated with the wish to die in elderly people.
AB  - This study aimed to determine the prevalence of the wish to die in elderly people
      and investigate the factors associated with it, in particular, whether factors
      other than depression contribute to the wish to die. Data were obtained from an
      Australian epidemiological survey of people aged 70 or more. Survey participants
      were asked whether, in the last two weeks, they had felt that they wanted to die
      and, if so, if they had had such thoughts repeatedly. Three classes of possible
      risk factors were investigated: sociodemographic factors (age, sex, marital
      status), mental health (depression, cognitive impairment), and physical health
      (poor self-rated health, disability, pain, sensory impairment, and living in a
      nursing home or hostel). Only 21 of 923 elderly persons reported repeatedly
      having had a wish to die during the previous two weeks. Although the wish to die
      was associated with depression, there were several other factors also associated
      with it independently of depression: not being married, poor self-rated health,
      disability, pain, hearing impairment, visual impairment, living in a nursing home
      or hostel. A small minority expressed the wish to die but had a normal mood
      state. It was concluded that the wish to die is associated with several factors
      in addition to depression and may be present in individuals with few depressive
      symptoms. There is a need to investigate whether factors associated with the wish
      to die are treatable and whether this can restore the desire to live.

PMID- 8669341
TI  - The Barthel ADL index: factor structure depends upon the category of patient.
AB  - The validity and reliability of the Barthel index were studied in 60 geriatric
      patients, 87 stroke patients, and 102 patients with hip fracture, using a factor
      analysis methodology which explicitly accounts for the ordinal nature of the
      scoring on each item. The findings substantiate that the Barthel index is
      unidimensional among stroke patients, but not among geriatric patients or
      patients with hip fracture. In the latter two groups, one factor related to
      mobility, the other to bodily functions. A sum-score to characterize geriatric
      and hip fracture patients does not take into account the complex structure of the
      Barthel index.

PMID- 8669342
TI  - The Barthel ADL index one year after stroke: comparison between relatives' and
      occupational therapist's scores.
AB  - The activities of daily living of 54 patients 1 year after stroke were rated with
      the Barthel Index by an occupational therapist (OT). A physician independently
      rated the same patients from interviews with their nearest relative. The mean sum
      score obtained by the doctor was 16.7, while the mean sum-score obtained by the
      OT was 17.1. In more than 80% of the patients, the difference in sum-score was
      two points or less, which was considered to reflect acceptable agreement.
      Weighted kappa values of each item varied between 0.42 and 0.92, indicating
      moderate agreement for the items 'grooming' and 'bladder' and good or very good
      agreement for the other items. There was a statistically significant bias in the
      bladder item; the doctor's score being lower than that of the OT. The other items
      showed no significant bias. The probability of disagreement between the two
      raters increased with the patient's age; no other factors were found to be
      related to disagreement.

PMID- 8669343
TI  - Reliability of the revised functional autonomy measurement system (SMAF) for
      epidemiological research.
AB  - The Functional Autonomy Measurement System (SMAF) is an instrument designed to
      assess disabilities related to 29 functions with a four-point scale (from 0:
      independent to -3: dependent). For epidemiological studies, a total score and
      five sub-scores can be obtained. A revised version was developed adding a -0.5
      level to many items to indicate an activity accomplished independently but with
      difficulty. The objective of the study was to verify the test-retest and inter
      rater reliability of the total score and sub-scores of the SMAF. Ninety subjects
      were randomly recruited in nine different residential settings ranging from home
      to long-term-care hospitals. Half of the subjects were assessed by the same nurse
      within a 2-week interval (test-retest) and the other half were assessed twice by
      two different nurses within the same interval (inter-rater). Results show intra
      class correlation coefficients (ICC) of 0.95 and 0.96 for the total scores on
      test-retest and inter-rater reliability, respectively. The ICC were over 0.74 for
      all sub-scores for both types of reliability. A small systematic bias was present
      for two SMAF subscores on the inter-rater reliability. The addition of a new
      level did not modify the reliability of the scale.

PMID- 8669344
TI  - Factors associated with healing leg ulceration with high compression.
AB  - To investigate factors relevant to the healing of leg ulceration by high
      compression, patients were interviewed using a standard questionnaire prior to
      treatment with a four-layer bandage high-compression system in six community
      ulcer clinics. We explored the relation of size, ulcer duration and medical
      history to healing. Cumulative healing rates were high using this method, being
      69% after 12 weeks and 83% after 24 weeks. Twelve-week healing rates varied
      slightly between clinics, ranging from 62% to 83%. Univariate analysis of the
      total group showed that male sex (RR = 0.77, p = 0.023), poor limb joint mobility
      (RR = 0.39, p < 0.001), poor general mobility (RR = 0.49, p = 0.015), treatment
      at home (RR = 0.52, p < 0.001), ulcer size > 10 cm2 (RR = 0.37, p < 0.001),
      history of deep vein thrombosis (RR = 0.67, p = 0.016) and ulcer duration >6
      months (RR = 0.35, p < 0.001) were significantly inversely associated with
      healing, Ulcer size, duration, limb joint mobility and general mobility were
      significant independent factors in multivariate analysis.

PMID- 8669345
TI  - The relationship between white matter low attenuation on brain CT and vascular
      risk factors: a memory clinic study.
AB  - In order to discover the prevalence of white matter low attenuation (WMLA) in the
      brain and its relationship to vascular risk factors in our Memory Disorders
      Clinic patients we assessed brain CT scans of 202 patients referred to our clinic
      between January 1991 and December 1992. One hundred patients (49.5%) had WMLA,
      and the prevalence increased with increasing severity of cognitive impairment. It
      was 12% in patients with no evidence of dementia, 32% in those with isolated
      memory loss, and 59%) in patients with possible or probable dementia. There was a
      correlation between WMLA and systolic blood pressure, heart disease, peripheral
      vascular disease, focal neurological signs on examination and central atrophy on
      CT. No correlation was found between WMLA and low blood pressure, blood glucose
      or cholesterol level. Our findings indicate that WMLA probably plays an important
      role in cognitive impairment, and that thromboembolic rather than haemodynamic
      factors are probably more important in its pathogenesis.

PMID- 8669346
TI  - Does the use of the Geriatric Depression Scale make redundant the need for
      separate measures of well-being on geriatrics wards?
AB  - Patients (n = 321) on geriatrics wards were asked to complete two or three of
      four well-being measures: the Geriatric Depression Scale, Philadelphia Geriatric
      Center Morale Scale, Southampton Self-esteem Scale and the Bradburn Affect
      Balance Scale. Analyses, including factor analysis, correlations and box-and
      whisker plots, were carried out to investigate similarities In patient profiles
      provided by the different scales. The GDS showed similar profiles to the other
      measures, particularly the self-esteem scale, discriminating at the 'high' as
      well as 'low well-being' ends of the scales. These results indicate that, as far
      as clinical practice is concerned, additional use of such well-being measures may
      be unnecessary. Examination of different approaches to assessing well- being in
      clinical practice is required, for example measures of 'life strengths'.

PMID- 8669347
TI  - Diabetes and cognitive impairment: a community-based study of elderly subjects.
AB  - To ascertain whether diabetes in elderly people is associated with cognitive
      impairment, we offered all residents of Melton Mowbray aged 75, 80 and 85 years
      both a modified glucose tolerance test (1985 WHO criteria) and Folstein mental
      state examination (MMSE, 23/24 cut-off). Analysis of the results, stratified by
      age, revealed that subjects with known diabetes were more likely than normal
      subjects to have low MMSE [odds ratio 3.30 (95% CI 1.3 to 8.5)], whilst newly
      found diabetic subjects were less likely to have low MMSE [odds ratio 5(-14) (95%
      CI 9(-25) to 0.003)]. The difference between known and newly found diabetic
      subjects might relate to duration of diabetes. The increased frequency of
      cognitive impairment in known diabetic subjects may be pertinent to the safe use
      of hypoglycaemic agents.

PMID- 8669348
TI  - A randomized controlled trial of a home exercise programme for elderly people
      with poor mobility.
AB  - Eighty-six elderly people with limited mobility and dependence in at least one
      activity of daily living were recruited to a home exercise study. The subjects
      (mean age 82 years) were allocated at random to either a strength exercise group,
      a mobility exercise group or a health education group. Subjects were visited for
      30 minutes every 3-4 weeks by a physiotherapist who gave both verbal and written
      instruction. Sixty-nine of the original 86 completed the 6-month study, with five
      drop-outs from the strength group, ten drop-outs from the mobility group, and two
      drop-outs from the health education group. By the end of the study, there were no
      significant differences between the groups with regard to changes in outcome
      variables. The results showed a trend towards improvement in both the exercise
      groups in both Sit to Stand and Timed Get Up and Go tests, but this failed to
      attain statistical significance. Further work is required to identify the optimal
      exercise intervention for this subgroup of the elderly population.

PMID- 8669349
TI  - Active euthanasia and physician-assisted suicide in Dutch nursing homes:
      patients' characteristics.
AB  - We wished to obtain information about the principal and subsidiary diagnoses,
      sex, age, marital status, religion and background characteristics of Dutch
      nursing home patients to whom euthanasia/assisted suicide (EAS) was administered.
      We performed an exploratory, descriptive, retrospective study involving all Dutch
      nursing home physicians (NHPs) who in September 1990 were members of the Dutch
      Association of Nursing Home Physicians (NVVA; n = 713). An anonymous printed
      questionnaire in two parts was used. Part 1 was intended for all respondents and
      was expected to give insight into the nature and extent of EAS in Dutch nursing
      homes. Part 2 was intended only for respondents who had indicated in part 1 that
      they had administered EAS. They were asked to describe their last case of EAS.
      The study covered the period from 1986 to mid-1990. There was an 86% response.
      The respondents described 86 cases of EAS. Sixty-nine of these took place in a
      nursing home. The majority of patients to whom EAS was administered were
      suffering from a malignant neoplasm (53%). EAS was administered more often to men
      than to women. The average age of the patients was 70.9 years. When EAS was
      administered, the patients on average had been in the nursing home for 13.1
      months. Dutch nursing home patients who were given EAS differed in various
      respects from 'the average nursing home patient'. The principal diagnosis for
      patients who were given EAS was a malignancy, whereas relatively few physically
      ill nursing home patients die as a result of a malignancy. The patients to whom
      EAS was administered were younger and more often male. EAS patients had been in
      the nursing home for a shorter time than the other somatic (physically disabled)
      patients who died during the study period.

PMID- 8669350
TI  - Gloucester hospital-at-home: a randomized controlled trial.
AB  - Hospital-at-Home schemes have been claimed to hasten the discharge of elderly
      orthopaedic patients, and are becoming increasingly popular with health service
      managers. In an attempt to measure the benefits of such a scheme when applied to
      elderly medical patients, we prospectively randomized 60 consecutive referrals of
      patients approaching discharge either to the Hospital-at-Home (HAH)
      rehabilitation team, or to conventional discharge (CD) preparation and
      domiciliary support. Patients allocated to HAH were discharged on average 5 days
      earlier than CD, while 64% of each group remained at home during 6 months follow
      up. Improvements in independence were modest, and similar in the two groups,
      though a trend favoured HAH.

PMID- 8669351
TI  - The relationship between the mini-mental state examination and cognitive
      functioning in normal elderly adults: a componential analysis.
AB  - The relationship between the Mini-Mental State Examination (MMSE) and selected
      cognitive performance indices was examined in a sample of 251 non-demented adults
      over 75 years of age. MMSE items were divided into I 1 binomial content domains
      and an examination of these revealed that only seven had sufficient variability
      to predict cognitive performance. A factor analysis with these items yielded
      three factors, reflecting memory, spatial skill, and the ability to follow
      commands. After controlling for age and education, these factor scores were
      included as predictors of specific cognitive tasks including two measures of free
      recall, and two measures of visuospatial skill. The memory factor score was a
      strong predictor of the two free recall tasks and block design. The spatial
      factor score contributed to the prediction of the two visuospatial measures, as
      well as free recall of organizable words. The results suggest that, in normal
      ageing, the predictive value of the MMSE is due to subset of cognitively
      demanding items that are heavily influenced by both memory and visuospatial
      skills.

PMID- 8669352
TI  - Evaluation of bone density with peripheral quantitative computed tomography in
      healthy premenopausal, perimenopausal, and postmenopausal women.
AB  - We compared bone mass in premenopausal, perimenopausal, and postmenopausal women
      using peripheral quantitative computed tomography to measure separately cortical,
      trabecular, and total bone density. Trabecular bone density was lower (p < 0.05)
      in the perimenopausal women than in the healthy premenopausal women. In
      perimenopausal women, trabecular bone density showed a significant linear
      regression with age (r = 0.554, p < 0.001), but cortical bone density did not (r
      = 0.130, p = 0.447). The group of postmenopausal women had significantly lower
      bone mass in all three bone compartments than the premenopausal and
      perimenopausal women. These findings confirm the existence of a significant loss
      of trabecular bone mass in the perimenopausal period.

PMID- 8669353
TI  - Review: diogenes syndrome.

PMID- 8669354
TI  - Rehabilitation after hip fracture.

PMID- 8669355
TI  - Review: Binswanger's disease, leukoaraiosis and dementia.

PMID- 8669356
TI  - [Central odontogenic fibroma: apropos of a case].

PMID- 8669357
TI  - [Free antebrachial flap with radial pedicle. I. Theoretic considerations and
      indications in maxillofacial reconstruction].
AB  - The authors detail the anatomical, physiological, and clinical considerations of
      the free forearm flap. These characteristics determine the many indications of
      this flap in the maxillofacial surgical reconstruction. Contraindications are
      quasi inexistent. The second part of this work analyses the surgical and
      microsurgical operative technique use for the authors. All different parts of
      this work are discussed upon a deep review of the recent literature.

PMID- 8669358
TI  - Multiple impacted and erupted supernumerary premolars.
AB  - The authors present a case of a 22-years-old patient with five supernumerary
      impacted and erupted premolars in the mandible. This dental anomaly is relatively
      rare occurring from 0.14% to 0.64% of the general population. About 75% of
      supernumerary premolars seen to be erupted.

PMID- 8669359
TI  - Clinical examination of the T.M.J. interobserver reliability.
AB  - A clinical study was performed on 18 healthy persons, chosen at random and
      without major T.M.J. complaints, by 4 different examiners (2 physiotherapists and
      2 oral and maxillo-facial surgeons). The main goal was to examine the
      interobserver reliability of the different clinical examination methods commonly
      used in the department of Oral and Maxillo-Facial surgery and physiotherapy. The
      clinical examination consisted of bilateral palpation of the active movements of
      the T.M.J., evaluation of the passive movements and evaluation by specific manual
      distraction and compression tests. Statistical processing was performed with a
      Pearson correlation coefficient. The critical positive value for a good
      correlation was never reached. Although evaluation of 5 subjects with minor
      complaints, shows a low tendency of positive correlation. Therefore,
      interobserver reliability for the examination of the T.M.J. seems to be fictive
      in an at random sample. Examination of pathologic cases may be more concordant.

PMID- 8669360
TI  - [Sialolithiasis. Observations on 155 cases].

PMID- 8669361
TI  - Conscious midazolam sedation in third molar surgery--aspects of post-operative
      patient evaluation.
AB  - This study was conducted on 426 patients undergoing third molar surgery to
      evaluate their opinion on surgery and the follow-up period concerning
      postoperative behaviour, pain, and complaints. Two groups were formed as patients
      had to choose between local anaesthesia only or additional conscious sedation by
      means of intravenous midazolam (0.1 mg/kg). Women and younger patients preferred
      conscious sedation. Surgery was described as significantly less distressing by
      the sedated group. No difference in the evaluation of the follow-up period
      between both groups existed. Patients of the midazolam group took more
      analgesics, tended to stay longer in bed and reported on protracted cooling. Non
      sedated persons older than 30 years complained about a slower decrease in
      postoperative pain. According to these findings, sensitive, cautious patients
      tend to prefer conscious sedation which is reflected in their behaviour. No
      relationship between the evaluation of surgery itself and the follow-up period
      could be found.

PMID- 8669362
TI  - [Antebrachial free flap with radial pedicle. II. Surgical technique].
AB  - The authors detail the anatomical, physiological, and clinical considerations of
      the free forearm flap. These characteristics determine the many indications of
      this flap in the maxillofacial surgical reconstruction. Contraindications are
      quasi inexistent. The second part of this work analyse the surgical and
      microsurgical operative technique use for the authors. All different parts of
      this work are discussed upon a deep review of the recent literature.

PMID- 8669363
TI  - High-resolution SPECT of the temporomandibular joint in chronic craniofacial pain
      disorders: a pilot study.
AB  - Chronic craniofacial pain disorders commonly cause physicians diagnostic
      difficulties. The purpose of this study was, on one hand, to detect pathological
      focuses of the craniofacial skeleton using a new system of high-resolution single
      photon emission computertomography (SPECT), and on the other hand, to compare the
      results with those obtained via high-field magnetic resonance imaging (MRI) as
      far as temporomandibular joint affections are concerned. SPECT can be regarded as
      a supplementary diagnostic mean for patients displaying the symptoms of chronic
      craniofacial pain disorders, especially in cases where clinical and paraclinical
      investigations do not coincide or which are refractory to treatment, not least to
      differentiate between somatic and psychogenic causes, respectively.

PMID- 8669364
TI  - Compound odontoma associated with a primary molar.
AB  - The authors describe a case of a compound odontoma located between the roots of a
      primary molar. It is a very unusual location. The primary tooth and the odontoma
      were extracted and a slide was obtained with the cutting grinding system.

PMID- 8669365
TI  - Periostitis ossificans.
AB  - Mandibular periostitis ossificans was assessed in a 18-year-old black boy. This
      form of chronic osteomyelitis (Garre osteomyelitis) resulted from a periostitis
      on the 4.8 in association with an infected and ankylosed 4.7. Clinically a firm
      swelling of the right mandibular angle was noticeable. The diagnosis was
      confirmed by computed tomography and biopsy. After extraction of the causative
      teeth, in combination with an antibiotic treatment, a good evolution was
      obtained. The possible pathogenesis and the differential diagnosis are discussed.

PMID- 8669366
TI  - Lymphoepithelial cyst of the parotid gland.
AB  - Cystic lesions of the parotid gland are not common and are often erroneously
      diagnosed as benign tumors. Lymphoepithelial cysts are only rarely diagnosed in
      the parotid gland. The term "lymphoepithelial cyst" is used because it is a
      descriptive term and takes no account of the origin and development of these
      cysts. An origin from sequestered lymph nodes epithelium in the parotid gland may
      be a feasible explanation for the origin of these cysts.

PMID- 8669367
TI  - Acceleration and timing of fertile ovulation in cyclic mares with a deslorelin
      implant.
AB  - In a blinded trial, the effectiveness and safety of 2.2 mg of the GnRH analog
      deslorelin acetate, administered in a short-term implant (STI) to normally
      cycling mares in estrus with a dominant ovarian follicle of 30 mm in diameter or
      larger, were evaluated, using a placebo implant as a negative control. A total of
      39 mares received treatments at admittance with pre-randomized implants
      containing either 2.2 mg or 0 mg deslorelin. Mares were teased daily and examined
      rectally with ultrasound at 24 h intervals to determine time to ovulation and
      duration of estrus. The number of breedings and the pregnancy rate at 18 (+/- 3)
      and 38 (+/- 3) days were recorded, as were systemic side effects and local
      reactions at the implantation sites. Pregnancies resulting from breedings during
      the treatment estrus and/or from breedings during the next estrus were followed
      and the early and late pregnancy loss rate, the number of pregnancies going to
      term and of live-born foals was recorded. Mean follicle diameter at treatment was
      not significantly different between the deslorelin and placebo treatment group
      with 41.6 mm and 40.8 mm, respectively. Treatment with deslorelin STI reduced the
      time interval to ovulation significantly from 69.5 +/- 25.48 h to 42.7 +/- 12.35
      h (p < 0.001). The percentage of mares having ovulated within 48 h rose from
      26.3% to 95.0%, respectively, for placebo and deslorelin STI (p < 0.001). As a
      consequence, the duration of estrus in days and the percent of animals requiring
      more than 1 breeding were significantly reduced in deslorelin treated animals
      from 5.4 days to 4.6 days, and from 55.6% to 5.0%, respectively (p = 0.009 and =
      0.001). The percent of mares pregnant from breedings at the treatment estrus
      (65.0% versus 44.4%) or the next estrus (83.3% versus 92.3%) was satisfactory and
      similar for deslorelin and placebo treated mares (p > 0.005), and in 70.0% and
      66.7% of these once or twice bred mares did pregnancies go to term and live foals
      were born.

PMID- 8669368
TI  - Anaesthetics for general anaesthesia in growing pigs.
AB  - A comparison was made between different anaesthetics for general anaesthesia in
      growing pigs, with focus on minor surgery under field conditions and for
      experiments in clinical research. Healthy cross-breed pigs (Hampshire x Yorkshire
      x Swedish Landrace) weighing 20-45 kg were used. The anaesthetics combinations
      compared were 1) azaperone plus metomidate (AM), 2) Zoletil (zolazepam +
      tiletamine) plus xylazine (ZX), and 3) Zoletil plus xylazine plus ketamine (ZXK).
      Parameters measured were: heart rate, respiratory rate, blood pressure, body
      temperature, and depth of analgesia (pin-prick). Minor surgery was performed to
      test the reliability of the "pin-prick" tests. It was clearly shown that AM
      produces anaesthesia with good cardiovascular stability and is a drug combination
      that is suitable for minor surgery. ZX also produces a good anaesthesia
      characterized by reliable and rapid induction. Good cardiovascular function is
      maintained, and the laryngeal relaxation makes intubation possible. These
      characteristics are very useful in a laboratory environment, as easy handling to
      avoid stress is necessary for research. Although it is difficult to evaluate the
      quality of analgesia from this study, it is concluded that ZX did not provide a
      superior anaesthesia and analgesia compared to AM in crossbreed pigs. However,
      these drugs are too expensive for regular use in ambulatory practice. The effects
      of ZXK resemble those of ZX, but the ZXK-drug combination has no anaesthetic
      advantages and is more laborious to work with.

PMID- 8669369
TI  - Significance of the epithelial crypts at the bovine utero-tubal junction in the
      pre-ovulatory phase of sperm regulation.
AB  - Because polyspermic fertilisation is a pathological condition in mammals, arising
      from an excess of spermatozoa at the site of initial sperm-egg contact and
      leading to early death of the embryo, consideration has been given to the manner
      whereby the utero-tubal junction may contribute to a reduction in the numbers of
      spermatozoa entering the Fallopian tubes. This seems especially important in
      cattle since the utero-tubal junction does not exhibit swollen polypoid processes
      that might act physically to reduce the number of spermatozoa entering the
      isthmus from the uterus. In tissues prepared from animals close to the time of
      ovulation, large numbers of simple glands were visible in the uterine surface and
      throughout the region of the utero-tubal junction and its ridges extending into
      the isthmus. The glands appeared as crypts, slits or craters. On the basis of a
      figure of 500 glands situated close to the utero-tubal junction and some 2-10
      spermatozoa located within each gland, these conservative estimates suggest a
      temporary arrest of 1-5x10(3) spermatozoa, thereby contributing to the steeply
      diminishing sperm gradient before the site of fertilisation. There would thus
      appear to be a vital physical role for the simple glands and clefts that
      predominate in this region, functioning importantly in the pre-ovulatory interval
      to pave the way for normal monospermic fertilisation. More subtle forms of sperm
      regulation by glycoprotein molecules are also considered.

PMID- 8669370
TI  - Relations between udder infection and somatic cells in camel (camelus
      dromedarius) milk.
AB  - Quarter milk samples (n = 391) from 101 camels were examined to study the
      occurrence and causes of mastitis in traditionally managed camels in eastern
      Sudan and to evaluate the value of the California Mastitis Test (CMT), somatic
      cell count (SCC) and adenosine triphosphate (ATP) in the detection of subclinical
      mastitis in the camel. One hundred and seventy (43.5%) of the quarter milk
      samples yielded pathogenic bacteria. Streptococcus agalactiae, other
      Streptococcus spp., Staphylococcus aureus, coagulase-negative staphylococci, and
      Escherichia coli were isolated from milk. Thirty-two (8.2%) quarter milk samples
      yielded mixed cultures, and 189 (48.3%) yielded no growth. Mean values for CMT,
      SCC and ATP were higher for quarters infected with major pathogens. However, a
      significant number of quarter milk samples had elevated values in these tests but
      were from quarters from which no bacteria were isolated. The ability of the tests
      to predict a positive bacteriology increased slightly when 2 or 3 tests were
      combined.

PMID- 8669371
TI  - Housing of pregnant sows in loose and confined systems--a field study. 2. Claw
      lesions: morphology, prevalence, location and relation to age.
AB  - A field study of 36 Norwegian sow herds was conducted over a 12 month period, 18
      herds had loose housing of pregnant sows and 18 herds had confined (stalled or
      tethered) dry sows. Fifteen of the loose housing herds had partly slatted
      concrete floors while 3 herds had other kinds of flooring. The types of claw
      lesions that were observed in these herds are described. The most prevalent
      lesions on both loose sows and confined sows were side wall cracks, heel lesions,
      cracks in the white line and overgrown heels. The lateral hind claws were the
      most frequent location for lesions and they were more severe than at other sites.
      These lesions tended to show a bilateral occurrence. More than 96% of slaughtered
      loose sows and 80% of slaughtered confined sows had at least 1 lesion on the
      lateral hind claws. The prevalence of claw lesions showed no obvious age pattern.
      However the prevalence seemed to be lower for the first litter sows and increased
      slightly thereafter, especially in the confined herds.

PMID- 8669372
TI  - Housing of pregnant sows in loose and confined systems--a field study. 3. The
      impact of housing factors on claw lesions.
AB  - The relationship of claw lesions to housing was studied in 36 sow herds. Eighteen
      herds with loose housing of pregnant sows and 18 herds with confined (stalled or
      tethered) pregnant sows, were followed over a 12 month period. Fifteen of the
      loose housing herds had partly slatted concrete floors, while 3 herds had other
      types of flooring. The mean herd prevalence proportion of sows with major claw
      lesions in loose housing herds with partly slatted floors was about twice as high
      as in the herds with confined sows. In the only loose housing herd with deep
      litter based on straw, the prevalence proportion of sows with major claw lesions
      was lower than any of the other loose or confined herds. Within herds with loose
      sows on partly slatted floors, the prevalence proportion of sows with major claw
      lesions seemed to be higher in the loose housing compartment than in the
      farrowing compartment. The prevalence proportion of sows with major claw lesions
      did not differ between loose herds with plastic slats and loose herds with
      concrete slats.

PMID- 8669373
TI  - The effect of claw lesions and claw infections on lameness in loose housing of
      pregnant sows.
AB  - During a 12-month period lameness, claw lesions and claw infections were studied
      in 15 herds with loose housing of pregnant sows on partly slatted concrete
      floors. Of these herds, 12 herds had concrete slats and 3 herds had plastic
      slats. The mean prevalence proportion of lame sows in the herds was 13.1%. The
      risk of lameness increased with increasing claw lesion score and with the
      presence of claw infections. In the herds with concrete slats, the relative risk
      of lame sows was 2.4 times higher than in the herds with plastic slats. In the
      herds with poor floor hygiene, the relative risk of lameness was 2.8 times higher
      than in the herds with dry and clean floors. The mean prevalence proportion of
      sows with claw infections at the 3 separate examinations in the 15 herds was
      3.8%. Claw infections were more prevalent in herds with dirty floors and in herds
      with little space per animal (< 2 m2). In the herds with concrete slats, the
      relative risk of claw infections was 2 times higher than in the herds with
      plastic slats.

PMID- 8669374
TI  - A transtracheal catheter for recording the static tracheal pressure in the
      exercising horse.
AB  - After giving an account of the principles of pressure measurement in flowing air
      and a review of the literature on tracheal catheters, the authors describe the
      construction, the introduction and the function of their own transtracheal
      catheter. This is a teflon catheter with several side-ports which is introduced
      into the cervical trachea by a guide technique. After introduction, the catheter
      is stiffened by the insertion of 2 steel wires. The catheter was studied in model
      experiments concerning: a) the ability to measure the static pressure in flowing
      air, and b) the dynamic accuracy of a recording system built up around the
      catheter. The results indicated that the intratracheal pressure sensed in
      exercising horses well reflected the static pressure, and that the dynamic
      accuracy of the recording system was good to about 60 Hz. The present technique
      of recording the intratracheal pressure was used on 122 occasions in 69
      exercising horses with only one complication referable to the catheter occurring.
      The transtracheal route of catheterisation may be superior, as catheters
      introduced by this route do not appear to influence the function of the pharynx
      and larynx. In contrast, nasotracheal catheters that traverse the larynx, might
      interfere with the respiratory function.

PMID- 8669375
TI  - Staphylococcal and other bacterial species associated with intramammary
      infections in Danish dairy herds.
AB  - Four thousand six hundred forty-five quarter milk samples from 1179 cows from 20
      commercial dairy herds were examined in order to determine the prevalence of
      bacterial species. A total of 859 isolates from 839 (18.1%) culture positive
      samples could be assigned to 34 different species and subspecies. Diagnostics of
      staphylococcal species was based on conventional procedures able to differentiate
      between all 36 species and subspecies presently acknowledged. Staphylococcus
      aureus was found in 10.2% of the samples and was the most common species
      isolated. Streptococcus dysgalactiae (1.6%) and Streptococcus uberis (1.4%) were
      the second and third most common species isolated. Seventeen different coagulase
      negative staphylococcal species (CNS) were found in 4.1% of the samples. The most
      frequently isolated CNS were S. epidermidis (1.3%), S. chromogenes (1.0%) and S.
      simulans (0.7%). Isolates of S. aureus were phage typed, and isolates of S.
      epidermidis were investigated by phage typing, antibiogram typing, and biotyping.
      A total of 378 (79.9%) isolates of S. aureus could be typed by phages, assigning
      them to 18 different phage types. However, 6 phage types accounted for 92.1% of
      the typable isolates. One to 2 phage types predominated within each herd. Eleven
      (18%) isolates of S. epidermidis could be typed by phages, assigning the isolates
      to 3 different types. Biotyping of S. epidermidis produced a total of 8 different
      types, the most common accounting for 29.5% of the isolates. A total of 6
      different antibiogram types were observed among all isolates of S. epidermidis.
      Resistance towards penicillin (36.1%), tetracycline (9.8%) and streptomycin
      (9.8%), were recorded in the isolates of S. epidermidis. However, 35 (57.4%) of
      the isolates were susceptible to all 12 antibiotics tested.

PMID- 8669376
TI  - Endocrine changes after mating in pregnant and non-pregnant llamas and alpacas.
AB  - Plasma concentrations of oestradiol-17 beta, progesterone, 15-keto-dihydro-PGF2
      alpha and luteinizing hormone (LH) were monitored in llamas and alpacas after
      mating with an intact male. Concentrations of LH and PGF2 alpha metabolite were
      high immediately after copulation. Ovulation occurred in 92% of the animals. The
      first significant increases in progesterone were recorded on day 4 after mating.
      In non-pregnant animals the lifespan of the corpus luteum was estimated to be 8-9
      days. Luteolysis occurred in association with the release of PGF2 alpha. In
      pregnant animals, a transient decrease in progesterone concentrations was
      observed between days 8 and 18 in both species. No significant changes in PGF2
      alpha secretion were registered during this period. Oestradiol-17 beta
      concentrations were high on the day of mating, declined to low values on day 4,
      and started to increase again on day 8. Peak values after luteolysis in non
      pregnant animals were significantly higher than those registered in pregnant
      ones. Furthermore, concentrations of oestradiol-17 beta were elevated for a
      longer period in non-pregnant than in pregnant animals. The results suggest that
      progesterone from the corpus luteum exerts a negative influence on follicular
      activity in pregnant animals by reducing oestradiol-17 beta secretion.

PMID- 8669377
TI  - Hematological and blood biochemical effects of fasting and subsequent oral
      administration of endotoxin in prepubertal gifts.
AB  - The main objective of the present study was to investigate the effects of short
      term fasting in gilts on endocrinological and blood biochemical parameters and,
      further, the effects of subsequent oral endotoxin (ET) administration. Group 1
      was fasted for 30 h and then received feed with ET added. Group 2 was fasted for
      30 h but received standard feed at refeeding. In group 3, gilts were fed every 6
      h for 30 h. The major effects of fasting were: gradually increased concentration
      of plasma prostaglandin F2 alpha metabolite, serum total bilirubin, serum free
      fatty acids, and decreased serum glucose. The values were normalized within 1-4 h
      of refeeding. Twelve hours after refeeding, the ET-refed gilts showed higher
      levels of serum total bile acids and polymorphonuclear leukocytes than those in
      group 2. It is possible that the observed changes during fasting reflect either
      an increased intestinal uptake of naturally present endotoxin or a reduced
      endotoxin detoxifying capacity of the liver. The increased bile acid
      concentration and polymorphonuclear leukocyte count following refeeding with ET
      feed may indicate that orally administered ET is to some extent absorbed from the
      gut.

PMID- 8669378
TI  - Clinical picture and antibody response to experimental Sarcoptes scabiei var.
      vulpes infection in red foxes (Vulpes vulpes).
AB  - Three red foxes (Vulpes vulpes) were experimentally infected with Sarcoptes
      scabiei isolated from a naturally infected wild red fox. A fourth red fox served
      as a control. The first signs of sarcoptic mange became evident on the 31st day
      post infection (dpi). The signs gradually increased thereafter and between dpi 49
      and 77 characteristic lesions of hyperkeratosis developed. Two of the infected
      foxes developed severe sarcoptic mange, and one of these animals died on dpi 121.
      The third fox developed a chronic hyperkeratotic lesion on its back, at the site
      where the mites had been applied. On dpi 127 the surviving foxes were treated
      systemically with ivermectin, and within 4 weeks the skin lesions had healed
      except on the pinnae of one animal. Antibodies to S. scabiei var. vulpes were
      demonstrated in the infected foxes by an ELISA with which seroconversion was seen
      around 4 weeks post infection (wpi). Western blot analysis of sequential sera of
      the infected animals demonstrated antibody activity consistently after the 2nd
      wpi. The fourth, non-infected, fox did not show any skin lesions throughout the
      experimental period nor any specific antibodies to S. scabiei var. vulpes.

PMID- 8669379
TI  - Comparison of the prevalence and incidence of infection with bovine virus
      diarrhoea virus (BVDV) in Denmark and Michigan and association with possible risk
      factors.
AB  - Based on 2 previous surveys on the occurrence of infection with bovine virus
      diarrhoea virus (BVDV) in Danish and Michigan dairy herds, the prevalence and
      incidence of the infection were compared. The presence of certain possible risk
      factors for the occurrence of infection in the 2 areas were summarized and it was
      investigated if any of these risk factors had significant effect on the presence
      of animals persistently infected (PI) with BVDV in the dairy herds. Information
      on the cattle population density in the 2 areas was obtained from statistical
      yearbooks. Further information for the individual farms on age distribution,
      housing of animals, herd size, pasturing and purchasing policy was gathered. The
      prevalence of PI animals was more than 10 times higher in Denmark as compared to
      Michigan. In herds without PI animals, the annual incidence of seroconversion as
      calculated from the age specific prevalence of antibody carriers varied in most
      age groups between 20-25% in Denmark and between 5-10% in Michigan. All
      investigated risk factors except for herd size were in favour of a lower
      prevalence of infection in Michigan. The use of having animals on pasture and at
      the same time having purchased more than 40 animals within recent 3 1/2-4 years
      were significantly associated with presence of PI animals in the dairy herds (p =
      0.01) when tested by the Mantel-Haenszel chi 2. Using multivariable logistic
      regression, the occurrence of PI animals was found to be significantly related to
      the study area (Michigan and Denmark) as well as to herd size and purchase
      intensity.

PMID- 8669380
TI  - The effect of energy balance on ovarian activity in a herd of Norwegian cattle.
AB  - The study involved 34 primiparous cows fed ad libitum grass silage and fixed
      amounts of concentrate per cow and stage of lactation. It revealed that number of
      days from calving to maximum progesterone concentration in first luteal phase was
      negatively related to (p < 0.05) energy balance summarized over weeks 3-12 post
      partum. One standard deviation improvement of the summarized energy balance
      relative to the mean reduced the length of the anovulatory period by 12 days.
      Similarly, an improved energy balance enhanced progesterone secretion during the
      oestrus cycle and early pregnancy, as measured by 3 variables; 1) maximum
      progesterone concentration in first luteal phase, 2) cumulative progesterone
      secretion bounded by the maximum concentrations in first and in third luteal
      phase and 3) cumulative progesterone secretion in the first month of pregnancy.
      All results were supported by the estimated regression coefficients of the 4
      ovarian activity variables on summarized non-estrified fatty acids and
      acetoacetate variables.

PMID- 8669381
TI  - Pubertal development of intersertoli cell junctions in the testis of corriedale
      ram lambs.
AB  - The ultrastructure of the tight junctional complex of pubertal ram lamb Sertoli
      cells was studied in immersion-fixed samples and related to clinical data and a
      light microscopical classification of the degree of spermatogenesis attained in
      the corresponding seminiferous tubule. Although the process followed the general
      mammalian developmental trend for tight junction complex formation, 2 unusual
      ultrastructural features were detected: the presence of an active Golgi complex
      during the early stage of tight junction formation and the transitory presence of
      ribosomes on both faces of the ectoplasmic cisternae bordering the developing
      junctions. The significance of these findings is discussed.

PMID- 8669382
TI  - Flow-cytometric studies of the phagocytic capacities of equine neutrophils.
AB  - Methodological aspects of flow-cytometric evaluation of the phagocytic properties
      of equine neutrophils were elucidated. The kinetics of attachment and ingestion
      were studied, and the phagocytic process was more rapidly completed when serum
      opsonized yeast cells were used than with use of IgG-opsonized yeast cells.
      Trypan blue was successfully used to quench fluorescence of non-ingested yeast
      cells. There were only minor differences in the kinetics of phagocytosis between
      quenched and unquenched samples, indicating that attachment is rapidly followed
      by ingestion. Trypan blue quenching caused loss of cells with light scattering
      properties of granulocytes, although this did not affect the determined
      frequencies of truly phagocytic neutrophils. Aggregation of yeast cells proved to
      be a disturbance but not an obstacle to the determination of frequencies of
      actively phagocytic cells. Flow cytometry is well suited for studies of
      phagocytosis of yeast cells by equine neutrophils, and the trypan blue quenching
      provides a means of eliminating false-positive events due to aggregation of yeast
      cells. The main advantage of the flow-cytometric method is the possibility of
      rapid processing of a large number of samples, making the method useful for
      studies of herds.

PMID- 8669383
TI  - Motivation and characterization of finnish meat inspection veterinarians.
AB  - A questionnaire survey on the factors affecting the motivation and work attitudes
      of Finnish veterinary meat inspectors was conducted. Traditional meat inspection
      on the slaughtering line and in the emergency department took up most of the
      weekly work time (15.8% and 15.8%, respectively). Emergency slaughtering (29%)
      and general hygiene control (29%) were considered the most important tasks of
      veterinary meat inspectors. Assurance of meat safety (68%) was cited as the most
      important single reason for meat inspection. Veterinary meat inspectors were of
      the opinion that they do not play an important role in the training of
      slaughterhouse personnel, although they considered training to be a very
      important means for promoting hygienic work methods among workers. Three
      orientations of the respondents toward meat inspection and slaughterhouse
      operations were revealed from the survey: hygiene, education, and emergency
      slaughter work orientation. Meat inspection veterinarians may feel isolated from
      the other personnel responsible for maintaining quality and hygiene. The
      orientation and possible isolated position of veterinary meat inspectors should
      be given more attention in both the basic undergraduate and postgraduate training
      of veterinary meat inspectors.

PMID- 8669384
TI  - Assessment of sperm viability by measurement of ATP, membrane integrity and
      motility in frozen/thawed bull semen.

PMID- 8669385
TI  - Mycoplasma hyponeumoniae and Mycoplasma hyosynoviae infection in cases of
      fibrinous pericarditis in slaughter pigs.

PMID- 8669386
TI  - Long-term carotid access in the goat: observations on application of a totally
      implantable catheter system.

PMID- 8669387
TI  - The effect of blood sampling on plasma cortisol in female reindeer (rangifer
      tarandus tarandus L).

PMID- 8669388
TI  - African endocrine infertility: a review.

PMID- 8669389
TI  - The menace of beta-lactamase production on antibiotic prescription in community
      acquired-infections in Nigeria.
AB  - Antibiotic resistance is a major clinical problem in the management of infectious
      diseases. The production of beta-lactamases by pathogens of all grades which has
      spread extensively during the last decade has further narrowed down the choice of
      antibiotics. Those antibiotics that are efficacious are costly and not readily
      available. The purposes of this study therefore were: To evaluate the incidence
      of beta-lactamase producing organisms responsible for common community-acquired
      infections. To evaluate the incidence of bacterial resistance to commonly
      prescribed antibiotics in the general practice. Nitrocefin strip was used to test
      each isolate for beta-lactamase production. All isolates were tested against five
      commonly prescribed antibiotics and a new oral cephalosporin. A nationwide survey
      revealed that 78% of community-acquired pathogens produced beta-lactamases while
      more than 50% of most community isolated showed in-vitro resistance to most
      commonly prescribed antibiotics. We conclude that treatment of bacterial
      infections are becoming more difficult and more costly. There is need therefore
      to continually review the susceptibility profiles of community-acquired
      pathogens.

PMID- 8669390
TI  - Leucocyte count, platelet count and erythrocyte sedimentation rate in pulmonary
      tuberculosis.
AB  - We have evaluated the haematological values of 50 adult patients with untreated
      pulmonary tuberculosis (PTB) and compared them with those of 50 normal age and
      sex-matched controls. Anaemia (usually mild) and an invariably (but moderately)
      elevated ESR were observed as expected. Thrombocytopaenia and thrombocytosis were
      observed in equal number of patients (18% respectively). We observed significant
      lymphopaenia (rather than lymphocytosis) in these untreated PTB patients,
      occurring in 46% (p < 0.0001). Lymphocytosis was observed in only 6% of the PTB
      patients. Another interesting observation was neutrophilic leucocytosis, which
      occurred in 40% of the patients. We would suggest that in evaluating results of
      haematological values in suspected cases of PTB, lymphopaenia rather than
      lymphocytosis, should be considered.

PMID- 8669391
TI  - Plasmid profiles and antibiotic susceptibility patterns of Staphylococcus aureus
      isolates from Nigeria.
AB  - In an investigation into the problems of infections due to Staphylococcus aureus
      in Nigeria, 100 strains were isolated from various hospitals in Lagos. The
      strains were screened for the presence of plasmids and for susceptibility to
      antimicrobial agents. Plasmids were extracted by modification of the method of
      Takahashi and Nagono[1]. The plasmids were diverse in nature. The strains were
      found to be highly resistant to commonly prescribed antibiotics.

PMID- 8669392
TI  - Radiotherapy of childhood malignancies in Nigeria.
AB  - Malignant tumours in children rank fourth after carcinoma of the cervix, breast,
      and head and neck tumours among the malignancies managed by radiotherapy in
      Nigeria. The management of these tumours constitute a myriad of problems which
      are probably responsible for the overall poor survival results observed. This
      paper analyzed and discussed the epidemiology, presentation and radiotherapeutic
      management of 122 paediatric malignancies seen and managed between 1981-84 at the
      radiotherapy unit of the Lagos University Teaching Hospital, Nigeria. This unit
      was up till 1986 the only radiotherapy service available in Nigeria and the rest
      of the Anglophone West African states. The potential beneficial role of a
      multidisciplinary approach in the management of these tumours is stressed.
      Several other factors which may improve the quality of care and survival among
      this group of patients are discussed. The recent upgrading of radiotherapy
      services in Nigeria through the Technical cooperation assistance programme of the
      International Atomic Energy Agency in Vienna has further improved the scope of
      radiotherapy facilities in the country. This is expected to result in improved
      standards of patient care, and survival.

PMID- 8669393
TI  - Leukocyte counts in falciparum malaria in African children from an endemic area.
AB  - Total leukocyte counts were done in 180 apparently healthy rural school children
      aged 6-12 years in a malaria endemic area in southwestern Nigeria. Total
      leukocyte counts and their distribution in aparasitaemic and asymptomatic
      parasitaemic children were similar. Total leukocyte counts, and the relationship
      between the density of parasitaemic and total leukocyte counts were studied in 55
      consecutive children presenting with acute symptomatic falciparum malaria.
      Children without parasitaemia were older and had lower total leukocyte counts
      when compared with children with parasitaemia (7.61 +/- 4.11 x 10(9)/L Vs 9.04 +/
      5.0 x 10(9)/L), but the difference was not statistically significant (P > 0.05).
      In non-hyperparasitaemic children and in hyperparasitaemic children with
      percentage infected red cells < 10%, there was poor correlation between density
      of parasitaemia and total leukocyte counts. However, at > or = 10% parasitaemia,
      there was a positive correlation (r = 0.55; P = 0.032) between increasing
      parasitaemia and leukocytosis. Combination of hyperparasitaemia ( > 5%
      parasitaemia) and leukocytosis ( > 12 x 10(9)/L) occurred in 15% of the children
      and was not a poor prognostic index in the absence of other evidence of severe or
      complicated disease, as response to oral mefloquine was prompt. This would
      suggest that in African children from an endemic area, this combination is not a
      reliable indicator of severity or poor prognosis in falciparum malaria.

PMID- 8669394
TI  - Carbohydrate tolerance in patients with tropical ataxic neuropathy--A human model
      of chronic cyanide intoxication.
AB  - Patients with tropical ataxic neuropathy (TAN) have been shown to have chronic
      cyanide intoxication. Glucose tolerance test data in a group of 88 patients with
      TAN and 88 matched controls who were studied several years ago were analysed. A
      standard glucose tolerance test (SGTT) with 50 gm dextrose preceded by 50 mgs
      cortisone acetate orally 8 1/2 and 2 hours before the tests were performed. The
      SGTT was considered abnormal if the capillary blood glucose at 0.60 and 120 were
      greater than 120, 200 and 140 mg/100 ml (6.6, 11.1, 7.8 mmol/l) respectively.
      Capillary blood glucose considered abnormal for CGTT were 205 and 155 mg/100 ml
      at 60 and 120 (113 and 8.6 mmol/I) respectively. The SGTT was abnormal in 1 of
      the TAN patients and 2 controls while CGTT was abnormal in 9 TAN patients and 7
      controls. However, all controls with abnormal CGTT were older than 50 years while
      only 1 TAN patient was older than 50 and 6 were 30 years or younger (p = 0.0105),
      Fischer's probability test. The results suggest a greater statistical risk for
      subjects with TAN 30 years or younger to have an abnormal CGTT. While this does
      not predict the future development of diabetes, our observation indicates the
      need for better designed prospective studies among such patients in developing
      countries.

PMID- 8669395
TI  - Mortality in childhood head injury in Ibadan.
AB  - The clinical records of patients who were 15 years and younger and who attended
      our casualty department between July 1989 and June 1990 because of head injury
      were retrospectively analysed in order to determine the mortality rate and
      evaluate the management of the patients prior to death. One hundred and sixty
      such patients were identified. They comprised 5.7% of the 2,812 children and 2%
      of all patients seen during this period. There were 20 deaths in this group,
      giving a mortality of 12.5%. This rate was greater than that for all patients in
      this age group (1.3%) and all age groups (1.2%) of patients attending the
      casualty department during this period. Whereas, children with head injury
      comprised 2% (160/8,192) of all patients, the deaths in this group comprised 19%
      (10/107) of all deaths in casualty during this period. Of the 12 patients for
      whom case records were available, 8 were seen elsewhere before referral. Four
      patients talked prior to death, suggesting the existence of a treatable mass
      lesion, while 8 patients were in coma from the onset of head injury to the time
      of death. Airway management was inadequate in all the patients. The interval to
      death was less than 2 hours in 7 patients. Only 4 of the patients were evaluated
      by the neurosurgical service prior to death. These observations suggest that: (1)
      head injury is a cause of high mortality among children attending our casualty
      department; (2) there are preventable factors contributing to death.

PMID- 8669396
TI  - Non-retrobulbar anaesthesia for trabeculectomy.
AB  - A prospective clinical trial using sub-conjunctival (Sub-Tenon's) anaesthesia for
      trabeculectomy is reported. Forty-one eyes of 22 consecutive patients with
      glaucoma had trabeculectomy performed using the sub-conjunctival method of local
      anaesthesia. The effectiveness of the anaesthetic, intra-operative and post
      operative complications were recorded. Sub-conjunctival injection of local
      anaesthesia was found to be painless and free from the complications associated
      with retrobulbar injections. Surgery was also found to be easier as a
      conjunctival bleb was already raised allowing easy access to the sub-conjunctival
      space. Voluntary eye movements remained but did not interfere with surgery.

PMID- 8669397
TI  - Maternal and cord blood lactate and 3-hydroxybutyrate levels during labour in
      Nigerian women.
AB  - In this preliminary study, maternal and fetal blood lactate and 3-hydroxybutyrate
      (3-OHB) levels were assayed by specific enzymatic spectrophotometric methods in
      two groups of parturient Nigerian women during the three labour stages and their
      newborn: (i) thirty two women with babies' Apgar score > or = 6, and, (ii)
      eighteen women with babies' Apgar scores a 5. Cord blood was collected within 1
      min. of cord clamping. In all the patients there was a lactate gradient between
      the foetus and mother. Neonates with Apgar score < 5 had greater cord blood 3-OHB
      levels. This could indicate reduced utilisation and/or increased production of
      this metabolite. Since in states of glucose deprivation as could be found in
      placenta insufficiency, 3-OHB is utilised by the foetus for the synthesis of
      essential cerebral lipids. It is speculated that the immediate poor clinical
      condition of babies with low Apgar scores may be a consequence of reduced
      synthesis of these cerebral lipids as they were unable to utilise circulating 3
      OHB. The rapid response to routine resuscitative measures in these newborn babies
      could also indicate improved 3-OHB utilisation secondary to an improved tissue
      oxygenation status. These hypotheses from the basis for further studies.

PMID- 8669398
TI  - Clinical features of HIV seropositive Zambian subjects.
AB  - Data was collected from 1595 anti-HIV positive patients out of which 90% of the
      patients were from the Copperbelt province, and the rest from five out of the
      eight other provinces of Zambia. One-hundred and one positive HIV patients were
      less than 2 years of age, 69 were aged 2 to 14 years and 1418 were aged above 15
      years. The male to female ratio was about 1:1 at all ages, except that there was
      an excess of males below 5 years. Of the four most frequent symptoms or signs,
      loss of weight or malnutrition was regarded in about 50% of seropositive patients
      at all ages; generalized lymphadenopathy was seen in at least 35% of all age
      groups and most frequently at 2-14 (60%); chronic watery diarrhoea was most
      common at less than 2 years (44%) and least common in older children (17%);
      chronic chest infections had highest frequency in children 2-14 years (59%) and
      lowest in adults (32%). Intensive education of children before they are sexually
      active is the best hope for controlling the epidemic.

PMID- 8669399
TI  - Impact of rapid urbanization on mosquitoes and their disease transmission
      potential in Accra and Tema, Ghana.
AB  - The total of 75 mosquito species recorded in Accra have declined to 28 species.
      Contributing factors to this decline and the reduction in prevalence of malaria
      and bancroftian filariasis in Accra presently include extensive water pollution
      and a fairly high daily mosquito mortality due to several factors including loss
      of natural adult resting places, use of mosquito repellents and the probable
      increase of Anopheles arabiensis population. Presently low yellow fever incidence
      is due inter alia to loss of its feral vectors and reduced intradomiciliary
      breeding of Aedes aegypti (L) although more common species like A. gambiae s.l.,
      A. aegypti and C. p. quinquefasciatus could between them transmit many other
      arboviruses. However because of ready availability of human blood, spill-over of
      viruses from reservoir hosts to man will be rare. Ipso factor, malaria is the
      most common mosquito-borne disease with centripetal distribution of prevalence.

PMID- 8669400
TI  - Treatment of slipped capital femoral epiphysis with severe displacement (report
      of 14 hips in 12 non Caucasian patients).
AB  - This paper presents a report of a study of 14 hips in 12 non Caucasian patients
      treated for severe slipped capital femoral epiphysis. There were four Sudanese,
      two Syrians, and six Libyan patients. Three hips in two patients had severe acute
      slip and eleven hips in ten patients had severe chronic slip. Patients with
      severe acute slip were treated by closed reduction and internal fixation.
      Patients with severe chronic slip were treated by open replacement of the femoral
      epiphysis using the procedure advocated by Dunn and Angel[1]. One patient treated
      for acute severe slip developed over reduction of the epiphysis after closed
      manipulation. The results were good in all the three hips with acute slip. Two
      hips with severe chronic slip developed avascular necrosis and chondrolysis.
      Considering the results in this small series, closed reduction and internal
      fixation is a satisfactory method of treatment for severe acute slip while
      results of open replacement of the epiphysis for severe chronic slip has high
      incidence of complication in non caucasian patients as compared to those reported
      for caucasians.

PMID- 8669401
TI  - Intestinal parasitic infections among rural farming communities in eastern Sierra
      Leone.
AB  - A study carried out in four rural, mainly farming villages in the Gorama
      Chiefdom, Kono District, Eastern Sierra Leone revealed that intestinal helminth
      infections are prevalent in this area of Sierra Leone. Out of the 1164 persons of
      all ages who were examined, 853 (73.5%) proved positive for at least one
      intestinal helminth infection. Ascaris lumbricoides was the most common helminth
      encountered (37.5%), followed by hookworms, 12.9%; Trichuris trichiura, 12.6%;
      Schistosoma mansoni, 5.6%; Strongyloides stercoralis, 3.8%; tapeworms 1.0%, and
      multiple infections were common. Adults used poorly built pit latrines, while
      children defecated indiscriminately and unsupervised around houses and in the
      nearby bush. In addition, in most of the villages, domestic water was obtained
      from polluted streams and rivers. Only one village had protected pipe borne water
      supply. The high prevalence of intestinal helminth infections in this area
      results from constant infection and reinfection caused by poor sewage disposal,
      poor environmental health, and the low socioeconomic status prevailing in these
      communities.

PMID- 8669402
TI  - Fresh scaphoid fractures (analysis of 45 cases).
AB  - A study of fresh scaphoid fractures, treated at King Khalid University Hospital
      between 1983 to 1990, is presented. In a study of 45 patients, there were 43
      males (95.5%) and two females (4.5%). Twenty-five patients (55.5%) had fractures
      on the right side and twenty (44.5%) on the left side. Six patients (13.3%) had
      fractures in the proximal third, thirty-five (77.7%) in the middle third and four
      (9%) in the distal third. Among the fractures located in the middle third, twenty
      two (62.8%) were displaced and thirteen (37.2%) were undisplaced. Patients
      included in this study had initial treatment by immobilization in a below elbow
      thumb spica cast. Ten patients after failure of conservative treatment were
      treated by compression screw osteosynthesis. In this study, it has been observed
      that plaster cast immobilisation is a satisfactory method of treatment for stable
      undisplaced fractures, while results in patients with unstable-displaced
      fractures are poor and they are best treated by early open reduction and internal
      fixation. By assessing the results of this study it is recommended that all
      scaphoid fractures should be assessed for stability. The treatment by plaster
      cast should be reserved for fractures involving distal third of scaphoid and for
      stable fractures of middle and proximal third. The unstable and displaced
      fractures should be treated by early screw fixation.

PMID- 8669403
TI  - Body composition in 5-18-y-old obese children and adolescents before and after
      weight reduction as assessed by deuterium dilution and bioelectrical impedance
      analysis.
AB  - The aim of the present study was to develop an equation for the prediction of
      total body water (TBW) from bioelectrical impedance analysis (BIA) in obese
      children and adolescents before and after weight reduction. In 146 obese subjects
      with a mean age of 12.7 +/- 3.0 y (5.5-17.8 y), TBW was measured by using
      deuterium dilution as well as the resistance index (RI; ht2/resistance) using BIA
      before and after weight loss. Initially, the RI correlated well with measured TBW
      (r2 = 0.92, P < 0.001). A multiple-regression analysis using forward stepwise
      selection of the variables RI, sex, age, weight, height, and waist-hip ratio
      revealed that the equation TBW = 0.35 x RI + 0.27 x age + 0.14 x weight - 0.12
      predicts most accurately individual values of TBW before weight loss (adjusted r2
      = 0.96, SEE = 1.9 L) with a mean error of predicted TBW of 1.40 +/- 1.38 L. This
      equation was validated in 1000 random samples (bootstrap-sampling method), giving
      a mean r2 of 0.95. During the weight-reduction program, which included an energy
      restricted diet and an extensive exercise program, the patients lost 7.7 +/- 3.2
      kg, leading to a small decrease in TBW of 0.4 +/- 1.5 L. When the developed
      prediction equation was applied to the data after weight loss, an r2 value of
      0.94 between measured and calculated TBW and a mean error of 2.18 +/- 1.89 L was
      obtained. Validation of the equation in 1000 random samples after weight loss
      again gave a mean r2 value of 0.95. Individual changes in predicted TBW
      correlated only weakly with those of measured TBW (r = 0.21, P < 0.05). Thus,
      individual TBW values before and after weight loss can be predicted by BIA with
      acceptable accuracy by using the developed equation. However, prediction of small
      individual changes in TBW during weight loss is not possible by BIA.

PMID- 8669404
TI  - The enzymatic antioxidant system in blood and glutathione status in human
      immunodeficiency virus (HIV)-infected patients: effects of supplementation with
      selenium or beta-carotene.
AB  - To investigate the effects of selenium or beta-carotene supplementation in human
      immunodeficiency virus (HIV)-infected patients, who are known to have
      deficiencies of selenium and vitamin A, we evaluated the blood enzymatic
      antioxidant system, including superoxide dismutase (SOD), selenodependent
      glutathione peroxidase (GPX), and catalase (Cat); glutathione (GSH) status; and
      plasma selenium concentration. The placebo group consisted of 18 HIV-infected
      patients with no supplementation, the selenium group was composed of 14 patients
      receiving oral selenium treatment, and the beta-carotene group comprised 13
      patients receiving oral beta-carotene supplementation. All groups were studied
      for 1 y. At the beginning of the study, a significantly higher SOD activity (P <
      0.001) was observed in all HIV-infected patients compared with uninfected control
      subjects, and GPX activity at baseline was higher in the placebo (P < 0.004) and
      selenium (P < 0.014) groups than in the control subjects. These higher enzyme
      activities could be related to an increased synthesis of these enzymes in
      erythrocyte precursors under oxidative stress. Moreover, we observed
      significantly lower GSH values in all HIV-infected patients than in control
      subjects at the beginning of the study (P < 0.001). After selenium or beta
      carotene supplementation, no significant difference was observed for SOD activity
      compared with baseline. On the contrary, GPX activity increased significantly
      after selenium treatment (P < 0.04 between 3 and 6 mo), whereas a slight increase
      was found after beta-carotene treatment. Similarly, a significant increase in GSH
      values was observed at 12 mo compared with baseline both after selenium
      supplementation (P < 0.001) and beta-carotene supplementation (P < 0.01). Because
      GPX and GSH play an important role in the natural enzymatic defense system in
      detoxifying hydrogen peroxide in water, selenium supplementation could be of
      great interest in protecting cells against oxidative stress. The lower efficiency
      of beta-carotene could be attributed to the seriousness of the pathology at the
      time of recruitment into the beta-carotene group.

PMID- 8669405
TI  - Energy value of moderate alcohol consumption by humans.
AB  - We investigated the effects of an equal-energetic substitution of ethanol for
      dietary carbohydrate in high-and low-fat diets on energy expenditure and body
      composition. During the controlled feeding study, subjects maintained their
      weights and consumed only food and drink provided by the US Department of
      Agriculture Beltsville Human Nutrition Research Center's Diet Study Facility.
      Subjects (16 men and 32 women) were divided equally into two groups and consumed
      either a high-or low-fat diet for 16 wk. The feeding period was divided into two
      8-wk periods during which either ethanol or carbohydrate was added to the diet
      (5% of total daily energy intake) in a crossover design. The metabolizable energy
      content of the diets (with supplements) was determined for all subjects through
      measurement of total food intake and fecal and urinary losses for 7 d during both
      8-wk periods. Energy expenditure, measured for 24 h in a room calorimeter at the
      end of each 8-wk period, was the same for both periods. Metabolizable energy
      intake and changes in total-body energy content were used to calculate the total
      amount of energy expended by each subject for 7 wk during each 8-wk period. Total
      energy expenditure for 7 wk was the same when subjects consumed either ethanol or
      carbohydrate. These data clearly show that on an energy basis ethanol and
      carbohydrate are utilized in the diet with the same efficiency. These data are
      consistent with the efficiency of use of alcohol for maintenance of metabolizable
      energy being the same as that for carbohydrate.

PMID- 8669406
TI  - Muscle glycogen storage after prolonged exercise: effect of the frequency of
      carbohydrate feedings.
AB  - We reported previously that intake of carbohydrate foods with a high glycemic
      index (GI) produced greater glycogen storage and greater postprandial glucose and
      insulin responses during 24 h of postexercise recovery than did intake of low-GI
      carbohydrate foods. In the present study we examined the importance of the
      greater incremental glucose and insulin concentrations on glycogen repletion by
      comparing intake of large carbohydrate meals ("gorging") with a pattern of
      frequent, small, carbohydrate snacks ("nibbling"), which simulates the flattened
      glucose and insulin responses after low-GI carbohydrate meals. Eight well-trained
      triathletes [x +/- SEM: 25.6 +/- 1.5 y of age, weighing 70.2 +/- 1.9 kg, and with
      a maximal oxygen uptake (VO2max) of 4.2 +/- 0.2 L/min] undertook an exercise
      trial (2 h at 75% VO2max followed by four 30-s sprints) to deplete muscle
      glycogen on two occasions, 1 wk apart For 24 h after each trial, subjects rested
      and consumed the same diet composed exclusively of high-GI carbohydrate foods,
      providing 10 g carbohydrate/kg body mass. The "gorging" trial provided the food
      as four large meals of equal carbohydrate content eaten at 0, 4, 8, and 20 h of
      recovery, whereas in the "nibbling" trial each of the meals was divided into four
      snacks and fed at hourly intervals (0-11, 20-23 h). However, there was no
      significant difference in muscle glycogen storage between the two groups over the
      24 h (gorging: 74.1 +/- 8.0 mmol/kg wet wt; nibbling: 94.5 +/- 14.6 mmol/kg wet
      wt). The results of this study suggest that there is no difference in
      postexercise glycogen storage over 24 h when a high-carbohydrate diet is fed as
      small frequent snacks or as large meals, and that a mechanism other than lowered
      blood glucose and insulin concentrations needs to be sought to explain the
      reduced rate of glycogen storage after consumption of low-GI carbohydrate foods.

PMID- 8669407
TI  - Fat distribution and cardiovascular risk factors in obese adolescent girls:
      importance of the intraabdominal fat depot.
AB  - The regional distribution of body fat has repeatedly been found to be a
      significant and independent risk factor for cardiovascular disease in both obese
      men and women. To determine whether abnormalities in the lipid-lipoprotein
      profile and systolic and diastolic blood pressure are related to specific fat
      depots early in the course of obesity, we used magnetic resonance imaging to
      measure accurately intraabdominal and subcutaneous fat masses in 14 obese [body
      mass index (BMI; in kg/m2) 30 +/- 1.3] and 10 nonobese (BMI: 21 +/- 0.5)
      adolescent girls matched for age and Tanner stage of development. Intraabdominal
      and subcutaneous fat depots were two- to threefold greater in obese than in
      nonobese girls (P < 0.01). Total cholesterol, triacylglycerol, low-density
      lipoprotein (LDL) cholesterol, basal insulin, and systolic and diastolic blood
      pressure were significantly higher in obese adolescent girls than in control
      subjects. In obese girls, intraabdominal fat but not BMI or waist-to-hip ratio
      was highly correlated with basal insulin (r = 0.55, P < 0.04), triacylglycerols
      (r = 0.53, P < 0.03), and high-density-lipoprotein (HDL) cholesterol (r = -0.54,
      P < 0.04). Femoral adipose tissue was inversely related to triacylglycerol (r = 
      0.51) and LDL cholesterol (r = -0.56, P < 0.05) concentrations in obese girls.
      The study indicates that early in the natural history of obese adolescent girls,
      cardiovascular risk factors are related to the amount of intraabdominal fat.

PMID- 8669408
TI  - Iron deficiency, development, and cognitive function.

PMID- 8669409
TI  - Rapid maturation in adolescence results in greater obesity in adulthood: the
      Amsterdam Growth and Health Study.
AB  - In this study, the effect of rapid and slow biological maturation on the
      development of obesity was investigated in boys (n = 79) and girls (n = 98),
      initially aged a mean of 13 y, and measured six times between 1977 and 1991.
      Obesity was determined by measuring body mass index (BMI; in kg/m2) and by
      summing four skinfold thicknesses. Biological maturation was operationalized by
      skeletal age, the age of peak height velocity (PHVage) for boys, and the age of
      menarche for girls. Multiple analyses of variance for repeated measurements
      showed that based on either skeletal age or PHVage, BMI for rapidly maturing boys
      was significantly higher than for slowly maturing boys between 13 and 27 y of
      age. Based on skeletal age, rapid maturers also showed higher mean sums of
      skinfold thicknesses over this period. For girls, BMI and sums of skinfold
      thicknesses for the rapidly maturing girls, based on either skeletal age or age
      at menarche, were also higher than for the slowly maturing girls over the entire
      period of study. In conclusion, individuals who matured rapidly in adolescence
      were, in general, more obese than slowly maturing adolescents between 13 and 27 y
      of age. Rapid maturation seems to have long-term consequences for obesity and
      should therefore be considered a risk indicator for the development of obesity.

PMID- 8669410
TI  - Relation of energy, fat, and fiber intakes to plasma concentrations of estrogens
      and androgens in premenopausal women.
AB  - To evaluate whether diet may influence the incidence of hormone-dependent cancers
      through an effect on blood estrogen and androgen concentrations, we analyzed diet
      blood hormone relations in a cross-sectional study. Dietary energy, fat, and
      fiber intakes were estimated from 7-d food records completed by 90 premenopausal
      women on days 14-20 of their menstrual cycles. Fasting blood specimens were
      collected on days 5-7, 12-15, and 21-23 of each participant's cycle and pooled to
      create follicular-, midcycle-, and luteal-phase samples, respectively, for
      analysis. Energy intake was associated inversely with plasma androstenedione and
      dehydroepiandrosterone sulfate (DHEAS), averaged across the three menstrual cycle
      phases, and directly with the probability of a luteal-phase rise in progesterone.
      For each additional 1 MJ (239 kcal) consumed, androstenedione decreased by 6.0%
      (95% CI: -8.4%, -3.6%), DHEAS decreased by 5.1% (95% CI: -9.6%, -0.4%), and the
      probability of a progesterone rise increased by 60% (95% CI: 5%, 145%). After
      energy intake was adjusted for, the ratio of polyunsaturated to saturated fat
      (P:S) in the diet was significantly inversely associated with plasma estradiol
      and estrone during the luteal phase of the menstrual cycle. For each 0.1
      increment in the P:S, there was a 7.6% (95% CI: -14.3%, -0.5%) decrease in
      estradiol and a 6.8% (95% CI: -12.7%, -0.6%) decrease in estrone. Results of this
      cross-sectional study support a relation between both energy and fat ingestion
      and plasma sex hormone concentrations in premenopausal women.

PMID- 8669411
TI  - Whole-body protein turnover in the fed state is reduced in response to dietary
      protein restriction in lactating women.
AB  - We examined the adaptive responses of body protein metabolism in the fed state to
      dietary protein restriction in lactating women to determine whether rates of body
      protein degradation and synthesis were lower than those of nonlactating women.
      Thirteen healthy women (five lactating, four nonlactating postpartum, four
      nulliparous) aged 28-32 y were given protein intakes of 1.5, 0.4, and 1.0 g.kg
      1.d-1 over three consecutive 3-d periods, respectively. At the end of each
      period, while in the fed state, subjects received orally a single bolus dose of
      [1-13C]leucine. A 24-h urine collection was obtained simultaneously. Whole-body
      protein metabolism was characterized by using the end product model based on
      nitrogen excretion and leucine catabolism. Nitrogen flux and rates of protein
      degradation and synthesis in the fed state were significantly lower at a dietary
      protein intake of 1.0 g.kg-1.d-1 in lactating women than in their nonlactating
      postpartum counterparts. Net protein retention in the fed state was significantly
      higher at a dietary protein intake of 1.0 g.kg-1.d-1 in lactating than in
      nonlactatating postpartum and nulliparous women because of the relatively greater
      reduction in protein degradation than in protein synthesis. These studies suggest
      that lactating women rapidly adapt to dietary protein restriction by down
      regulating protein metabolism, and that 13C-labeled amino acid tracers in
      combination with urinary nitrogen excretion serve as useful metabolic markers for
      the adequacy of the dietary protein content of lactating women.

PMID- 8669412
TI  - Feeding formula without arachidonic acid and docosahexaenoic acid has no effect
      on preferential looking acuity or recognition memory in healthy full-term infants
      at 9 mo of age.
AB  - Preferential looking acuity and novelty preference (a test of recognition memory)
      were determined by using Teller Acuity Cards and the Fagan Test of Infant
      Intelligence, respectively, for 399-433 healthy full-term infants at 39 +/- 1 wk
      of age. Duration of breast-feeding and age of infant at introduction and amount
      and type of formula were determined by questionnaire. Seventy-four infants (17%)
      were never breast-fed; another 92 infants (21%) were still receiving breast milk
      as the milk source at 39 wk of age. There were no differences in visual acuity or
      novelty preference among the infants when they were stratified by incidence or
      duration of breast-feeding. The formulas met current Canadian guidelines with >
      or = 0.7% of energy as linolenic acid, but had no docosahexaenoic or arachidonic
      acid. The studies indicate that formulas containing adequate linoleic and
      linolenic acids, without arachidonic or docosahexaenoic acid, impose no
      measurable deficits in performance in these visual and cognitive developmental
      tests at 9 mo of age in healthy full-term infants.

PMID- 8669413
TI  - Postprandial appearance of dietary deuterated cholesterol in the chylomicron
      fraction and whole plasma in healthy subjects.
AB  - This study examined the appearance of dietary cholesterol in the chylomicron
      fraction (chylomicrons plus chylomicron remnants) and whole plasma in healthy
      normolipidemic subjects during a 0-7-h postprandial period. Six adult males were
      given two diet sequences in random order: a low-fiber diet (standard Western diet
      for 14 d) followed by a labeled low-fiber test meal or a fiber-supplemented diet
      (40 g oat bran/d for 14 d) followed by a labeled oat bran (40 g) test meal. The
      test meals provided 192.5 mg cholesterol, including 80.1 mg octadeuterated
      cholesterol. Fasting and hourly postmeal blood samples were obtained for 7 h.
      Isotopic cholesterol ratios [tracer:(tracer+native cholesterol)] were determined
      by gas chromatography-mass spectrometry. Chylomicron triacylglycerol and
      cholesterol concentrations peaked after 2-3 h and returned to baseline after 7 h.
      After the low-fiber test meal, the isotopic cholesterol ratio continuously
      increased until 7 h in the chylomicron fraction (4.2 +/- 1.2 x 10(-3)) and whole
      plasma (1.04 +/- 0.39 x 10(-3)). At 7 h postprandial, the maximum dietary
      cholesterol concentration in the chylomicron fraction and plasma cholesterol was
      1 in 99 and 1 in 397 cholesterol molecules, respectively. No marked differences
      were obtained after the high-fiber sequence compared with the low-fiber one;
      there was a comparable isotopic cholesterol ratio and concentration in the
      chylomicron fraction and a slightly lower (-44%, P < 0.10) 0-7 h area under the
      curve whole-plasma deuterated cholesterol concentration. Thus, dietary
      cholesterol supplied as a single meal does not simultaneously appear in the
      chylomicron fraction postprandially with endogenous cholesterol and
      triacylglycerols and fiber feeding does not markedly alter this process in
      healthy normolipidemic humans.

PMID- 8669414
TI  - Effects of inherent responsiveness to diet and day-to-day diet variation on
      plasma lipoprotein concentrations.
AB  - We studied the biological variability and responsiveness to dietary fat of plasma
      lipoprotein cholesterol and triacylglycerol concentrations. Ten normal persons
      were studied on 3 consecutive days while they were eating their unrestricted
      usual diets and after 8, 9, and 10 d of eating a constant high-fat and low-fat
      diet administered in a crossover design. The changes in plasma low-density
      lipoprotein (LDL)-cholesterol concentrations from baseline with the high-fat diet
      were inversely correlated with the changes from baseline with the low-fat diet (r
      = -0.74, P = 0.01), as well as with the changes from the low-fat to high-fat diet
      (r = -0.93, P < 0.001). The extent of increases in plasma LDL-cholesterol
      concentrations from the baseline to the high-fat diet were positively correlated
      with the increases from the low-fat to the high-fat diet (r = 0.93, P < 0.001).
      The responses of high-density-lipoprotein (HDL) cholesterol were not consistently
      correlated. The within-person between-day CV of LDL decreased from 10% with the
      unrestricted diet to 6% (P < 0.05) with the high-fat diet and to 7% with the low
      fat diet (NS). The CV of total triacylglycerol (22%) and very-low-density
      lipoprotein (VLDL) triacylglycerol (48%) on the unrestricted diet significantly
      decreased by 51-59% during both controlled diets (P = 0.03-0.06). The CV of HDL
      cholesterol was 5.3% during baseline, 4.2% during the high-fat diet, and 3.2%
      during the low-fat diet (P = 0.4, 0.19, respectively). In summary, individuals
      have a reproducible plasma LDL-cholesterol response when changing their dietary
      fat intake. The day-to-day variation in total triacylglycerol, VLDL
      triacylglycerol, and LDL-cholesterol concentrations decreases when day-to-day
      dietary variation is eliminated.

PMID- 8669415
TI  - Kinetics of plasma arginine and leucine in pediatric burn patients.
AB  - The dynamic status of whole-body arginine and leucine was investigated in eight
      severely burned (mean 55% of body surface area) pediatric patients (mean age 5.3
      y) at a mean of 16 d after their initial injury. Plasma amino acid kinetics were
      estimated by using primed constant intravenous infusions of L-[13C
      guanidino]arginine and L-[I-13C]leucine given for 4 h. Each patient was studied
      twice within 2 d. The patients were studied either in a "basal" state, which
      involved removal of amino acids from the total parenteral nutrition (TPN)
      solution for 8 h before the tracer study, or while receiving complete TPN.
      Nitrogen intake was 0.58 +/- 0.08 g.kg-1.d-1 with nonprotein energy intake
      equivalent to 197 +/- 29 kJ.kg-1.d-1. Plasma leucine and arginine fluxes
      (mumol.kg-1.h-1) were 208 +/- 35 and 108 +/- 18 for basal and 290 +/- 38 and 195
      +/- 22 for TPN periods, respectively. Leucine oxidation was 42 +/- 7 and 59 +/- 9
      mumol.kg-1.h-1 for basal and TPN periods, respectively, indicating a higher rate
      of leucine loss in the absence of a leucine intake than that expected for healthy
      individuals. The arginine kinetic data implied little net de novo arginine
      synthesis and further suggested increased rates of arginine degradation from burn
      injury. The expected rate of urea excretion, based on the basal rate of leucine
      oxidation, agreed closely with the measured output of urinary urea. These
      findings suggest that arginine is a conditionally indispensable amino acid for
      maintaining body protein homeostasis and nutrition in severely burned pediatric
      patients. The metabolic response of these children appears to be quantitatively
      similar to that for severely burned adult patients.

PMID- 8669416
TI  - Calcium retention estimated from indicators of skeletal status in adolescent
      girls and young women.
AB  - To determine clinically useful predictors of calcium retention during
      postpubertal growth, calcium balance, bio-chemical markers of bone turnover, and
      anthropometric variables were determined in 14 girls aged 11-14 y and in 11 young
      women aged 19-30 y. Subjects participated in a 3-wk calcium-balance study with a
      calcium intake of 1332 mg/d. Biochemical markers of bone turnover (serum
      osteocalcin, total alkaline phosphatase, bone alkaline phosphatase, tartrate
      resistant acid phosphatase, and urinary cross-linked N-teleopeptides of type I
      collagen and hydroxyproline as the creatinine ratios) were measured in fasting
      samples. Total-body bone mineral density and total-body calcium content were
      significantly higher in adults than in adolescents (1.17 compared with 1.05 g/cm2
      and 1019 compared with 791 g, respectively). At the observed retention of 326
      mg/d, adolescents would require 2 y to reach the total bone calcium of the young
      adults. All biomarkers of bone turnover were strikingly higher in adolescents
      than in adults and were strongly correlated with calcium retention. A multiple
      regression model using a biochemical marker of bone turnover (serum osteocalcin)
      and postmenarcheal age (a measure of sexual maturation) described 75% of the
      variability in calcium retention.

PMID- 8669417
TI  - Amelioration of the inhibition of fibrinolysis in elderly, obese subjects by
      moderate energy intake restriction.
AB  - A possible cause of accelerated atherothrombosis in the syndrome of insulin
      resistance appears to be an elevated blood concentration of plasminogen activator
      inhibitor type-1 (PAI-1). Insulin resistance occurs with aging, attributable
      partly to increased adiposity. Scarce information exists regarding the effects of
      weight loss in elderly, obese individuals on PAI-1 concentrations. Consequently,
      weight loss (9 +/- 1 kg) was induced by energy intake restriction in 19 elderly,
      obese individuals, and its effect on fibrinolytic system peptides was measured.
      Initially elevated PAI-1 concentrations decreased by 50%, with a simultaneous
      decrease in the concentration of tissue-type plasminogen activator (t-PA)/PAI-1
      complexes but no significant change in t-PA suggested a decrease in inhibition of
      the fibrinolytic system. The concentration of plasmin/antiplasmin complexes (PAP
      complex) increased by approximately 20%, indicating augmented fibrinolytic system
      activity. The decline in PAI-1 correlated with that of the decrease in body
      weight (r = 0.5, P < 0.05) and fat mass losses (r = 0.46, P < 0.05). The increase
      in PAP complexes correlated with weight and fat mass losses (r = 0.4 and r =
      0.46, respectively; P < 0.05 for both). No correlation was seen between
      fibrinolytic system variables and baseline concentrations of substrates or
      insulin, but the change in PAI-1 correlated with the change in plasma
      triacylglycerols (r = 0.58, P < 0.05). Results indicate that energy restriction
      sufficient to induce moderate weight loss leads to diminution of elevated plasma
      PAI-1 and relief of inhibition of the fibrinolytic system in elderly, obese
      subjects. To the extent that these changes are associated with a decrease in the
      progression of vasculopathy, weight loss in elderly, obese individuals may be a
      useful means to reduce cardiovascular morbidity and mortality.

PMID- 8669418
TI  - A follow-up study on the effects of calcium-supplement withdrawal and puberty on
      bone acquisition of children.
AB  - Recent calcium supplementation trials in children have confirmed a positive but
      moderate effect of calcium intake on bone mineral accretion. However, the lasting
      effect of a higher bone mineral mass after calcium-supplement withdrawal is not
      known. This is an 18-mo follow-up study conducted after an 18-mo controlled
      calcium supplementation trial to study the persistent effect of higher bone
      mineral mass in children. Radial bone mineral mass was determined by single
      photon absorptiometry; lumbar spine and femoral neck bone mineral mass were
      evaluated by dual-energy X-ray absorptiometry in 84 healthy Hong Kong children at
      age 8.5 y and these evaluations were repeated at age 10 y. Pubertal status was
      determined by Tanner staging. At the end of the follow-up, the differences in
      percentage gains in lumbar spine bone mineral content (12.1 +/- 8.2% compared
      with 14.9 +/- 10.05%, P = 0.24) and lumbar spine area (8.6 +/- 5.1% compared with
      9.4 +/- 5.5%, P = 0.47) between the study and control groups disappeared. Dietary
      calcium intakes during follow-up were similar for the two groups (555 and 640
      mg/d, P = 0.23). In multiple-regression analyses, pubertal status was the
      strongest correlate of bone acquisition and linear growth in the study period. In
      conclusion, higher percentage gains in bone mineral mass in childhood by calcium
      supplementation for 18 mo were reversible. Our study showed that the benefits of
      calcium supplementation disappear after treatment is withdrawn. Longer-term
      calcium trials are necessary to determine whether peak bone mass can be modified
      through sustained supplementation so that appropriate calcium intakes can be
      determined.

PMID- 8669419
TI  - Thermic and metabolic responses to oral glucose in obese subjects with non
      insulin-dependent diabetes mellitus treated with insulin or a very-low-energy
      diet.
AB  - Increased resting energy expenditure (REE) and a blunted thermic effect of
      glucose (TEF) have been reported in obese subjects with non-insulin-dependent
      diabetes mellitus (NIDDM). I questioned whether the abnormal REE and TEF would be
      corrected by normalizing glycemia with insulin or a very-low-energy diet (VLED).
      Three male and four female obese subjects with NIDDM [weighing 108 +/- 6 kg and
      with body mass index (in kg/m2) of 39 +/- 2] received a weight-maintaing formula
      diet containing 95 g protein/d for 15 d then a 1.7-MJ, 93-g-protein VLED for 27
      d. Insulin was given from days 1 to 8 in doses sufficient to normalize glycemia.
      REE was measured weekly and TEF was measured on days 8 and 15 of isoenergetic
      feeding and 28 d after the VLED by using a ventilated-hood indirect calorimeter.
      Weight decreased 9.8 +/- 1 kg during the VLED. REE was 3% lower with insulin
      treatment than during hyperglycemia (7878 +/- 364 compared with 8125 +/- 381
      kJ/d, P = 0.002). REE decreased by 20% to 6494 +/- 280 kJ/d by week 4 of the
      VLED. After 112 g oral glucose, increments in energy expenditure were
      significantly greater during isoenergetic feeding with insulin than without (7.5
      +/- 1.3% compared with 4.3 +/- 0.9% above REE) and after the VLED (10.5 +/- 1.0%
      above REE, P < 0.05). Plasma glucose excursions were greatest without exogenous
      insulin (peak 21.5 +/- 1.8 mmol/L at 120 min, 16.3 +/- 1.9 mmol/L at 225 min).
      Plasma fatty acid excursions were the lowest with insulin treatment. The
      integrated plasma glucose and fatty acid responses above baseline did not differ
      among studies; the integrated insulin and C-peptide responses were greater after
      the VLED. Cumulative nonoxidative glucose disposal (stored glucose) was higher
      with insulin therapy than without (52 +/- 6 compared with 35 +/- 7 g/210 min, P <
      0.05) and increased significantly to 66 +/- 6 g after the VLED (compared with the
      isoenergetic diet without insulin). TEF correlated significantly with integrated
      C-peptide and insulin responses. The percentage increase in TEF with euglycemia
      (with insulin and VLED) correlated with the percentage increase in stored glucose
      (P < 0.05). The greater TEF was associated with a greater insulin response, which
      was probably responsible for the greater stored glucose.

PMID- 8669420
TI  - Supplementation with carotenoids corrects increased lipid peroxidation in
      children with cystic fibrosis.
AB  - Evidence of lipid peroxidation previously documented in cystic fibrosis (CF)
      implies an imbalance between free radical generation and antioxidant defense
      mechanisms. The aim of the present study was to examine the relation between
      plasma concentrations of malondialdehyde, a marker of lipid peroxidation, and the
      exogenous antioxidant line of defense. Malondialdehyde concentrations (90.2 +/-
      4.7 nmol/L) in 25 children with CF aged 9.6 +/- 0.8 y were higher (P < 0.001)
      than concentrations (69.1 +/- 2.6 nmol/L) in 17 children used as control subjects
      and were not correlated with any marker of disease severity. In contrast with
      their all-rac-alpha-tocopherol status, which was normal as a result of routine
      supplementation with a 200-mg dose of all-rac-alpha-tocopheryl acetate/d, beta
      carotene was very low. A 2-mo open trial in which 12 children with CF aged 11.5
      +/- 0.8 y were given 4.42 mg (8.23 mumol) beta-carotene three times per day led
      to normalization of the malondialdehyde concentration in all but 1 patient, in
      conjunction with an increase of plasma beta-carotene from 0.08 +/- 0.03 to 3.99
      +/- 0.92 mumol/L. Their plasma concentrations were inversely correlated (r = 
      0.54, P = 0.006) [corrected] with malondialdehyde when the values measured pre-
      and posttreatment were pooled. We conclude that beta-carotene deficiency
      contributes to lipid peroxidation in CF and that supplementation may eventually
      prove to be a useful adjunct for the management of the disease.

PMID- 8669421
TI  - Plasma alpha-tocopherol, retinol, and carotenoids in children with falciparum
      malaria.
AB  - Cross-sectional interactions by malaria status were investigated between plasma
      alpha-tocopherol, retinol, and several carotenoids (lutein, beta-cryptoxanthin,
      lycopene, and alpha- and beta-carotene) and indicators of disease severity (blood
      parasite count, hemoglobin concentration), acute-phase response (plasma albumin
      and ceruloplasmin concentrations), hepatic involvement (plasma alanine
      aminotransferase), oxidant status and antioxidant status (plasma thiobarbituric
      acid-reactive material and ascorbate), nutritional (weight-for-age) and carrier
      protein [retinol binding protein (RBP)] status, and cholesterol concentration (as
      a proxy for lipoprotein) in 100 consecutively admitted children with malaria.
      There were 50 children with severe and 50 with mild malaria and 50 age- and sex
      matched control subjects. alpha-Tocopherol, retinol, and all the carotenoid
      concentrations were lower in the patients than in the control subjects (P <
      0.001). The differences were greater in severe than in mild malaria, except for
      lutein. In severe malaria only, both retinol and alpha-tocopherol correlated with
      albumin, ceruloplasmin, and RBP concentrations whereas in all three groups
      retinol correlated with RBP and alpha-tocopherol correlated with cholesterol (all
      P < 0.01)). Using multivariate analysis on data from all patients combined,
      cholesterol was the most significant factor explaining the variance in alpha
      tocopherol (29%) whereas RBP was responsible for 95% of the variance in retinol.
      Plasma cholesterol and RBP values in turn (in the absence of alpha-tocopherol and
      retinol, respectively) were influenced primarily by acute-phase markers (mainly
      albumin and ceruloplasmin). Alanine aminotransferase (r = -0.17) and
      thiobarbituric acid-reactive material (r = -0.17) also showed a small
      contribution to the variance of RBP but 60-70% remained unexplained. In
      conclusion, low plasma lipid-soluble micronutrient concentrations in malaria are
      strongly influenced by the reductions in their carrier molecules, which, in turn,
      are low as a consequence of the acute-phase response.

PMID- 8669422
TI  - Analgesic nephropathy. Proceedings of a symposium. June 1995.

PMID- 8669423
TI  - Acetaminophen and adverse chronic renal outcomes: an appraisal of the
      epidemiologic evidence.
AB  - This article critically reviews existing epidemiologic studies of the association
      between habitual acetaminophen use and chronic renal disease exclusive of
      neoplasia. Relevant primary studies were identified by searching the Medline
      database from 1966 to March 1995. There are several case reports of analgesic
      nephropathy following exposure to acetaminophen alone, but the accuracy with
      which other causes of this lesion were excluded is unclear. Three case control
      studies have found an increased risk (odds ratio range, 2 to 4) with habitual
      acetaminophen exposure for papillary necrosis, chronic renal failure, or end
      stage renal disease. These studies have been open to confounding by indication.
      It is also difficult to determine the risk with acetaminophen alone given the
      prevalent use of analgesic mixtures in the populations studied. Two prospective
      cohort studies have suggested an increased risk of renal impairment or papillary
      calcification following regular analgesic exposure. One of these studies was of
      subjects taking phenacetin-containing analgesic mixtures and the study population
      of the other was too small to reach statistically significant conclusions. Recent
      study results have raised the possibility that habitual acetaminophen use could
      increase the likelihood or rate of progression of chronic renal disease in
      general. This review suggests that there is currently insufficient evidence to
      conclude that habitual use of acetaminophen as a sole analgesic is associated
      with an increased risk of chronic renal disease. Further research is required to
      examine this question. Prudence suggests that habitual use of acetaminophen
      should be discouraged in the absence of strong medical indications.

PMID- 8669424
TI  - Therapeutic uses of aspirin in renal diseases.
AB  - Inhibition, by aspirin, of platelet aggregation, prostaglandin synthesis, smooth
      muscle cell proliferation, and thromboxane genesis has potential therapeutic uses
      in renal diseases. Clinically, some benefit from aspirin has been shown in some
      forms of glomerulonephritis but not in others, such as renovascular hypertension,
      pregnancy-induced hypertension, and diabetic nephropathy. Experimentally, aspirin
      aided in amelioration of cyclosporine toxicity and in preservation of explanted
      kidneys being prepared for transplantation.

PMID- 8669425
TI  - Does aspirin cause acute or chronic renal failure in experimental animals and in
      humans?
AB  - There are conflicting reports on the ability of aspirin as a single agent to
      cause acute or chronic renal failure in experimental animals. Chronic
      administration of aspirin alone over 18 to 68 weeks in doses of 120 to 500
      mg/kg/d has been reported to cause renal papillary necrosis in rats. However,
      some investigators have been unable to produce renal papillary necrosis in other
      species or in rats given lower divided doses comparable to therapeutic doses used
      in humans. In a variety of rat strains, aspirin administered as a single high
      dose intravenously or by oral gavage produces acute tubular necrosis of proximal
      tubules, rarely accompanied by renal papillary necrosis in susceptible strains.
      Several human studies have addressed the chronic nephrotoxicity of aspirin alone
      or relative risk of end-stage renal disease in association with aspirin use after
      correction for other analgesics. With the exception of one case control study
      demonstrating a low, but statistically significant risk of end-stage renal
      disease in association with aspirin use, all other case control studies and
      several prospective studies have been unable to identify a significant risk of
      chronic renal failure in patients using aspirin alone in therapeutic doses. In
      healthy adults, short-term aspirin administration in therapeutic doses has no
      effect on creatinine clearance, urine volume, osmolar clearance, or sodium and
      potassium excretion. However, in predisposed individuals with glomerulonephritis,
      cirrhosis, and chronic renal insufficiency, and in children with congestive heart
      failure, short-term aspirin use in therapeutic doses may precipitate reversible
      acute renal failure. Acute aspirin intoxication (>300 mg/kg) frequently causes
      acute renal failure and doses of 500 mg/kg may be lethal. Chronic salicylate
      intoxication has been reported to cause reversible or irreversible acute renal
      failure in association with a pseudosepsis syndrome.

PMID- 8669426
TI  - Acetaminophen: acute and chronic effects on renal function.
AB  - Acetaminophen (APAP) is normally metabolized in the liver and kidney by P450
      enzymes. No toxicity is observed with therapeutic doses of APAP. However, after
      ingestion of large quantities of APAP (>2,000 mg/kg), highly reactive quinones,
      metabolites of APAP, are generated; these react with glutathione and sulfhydryl
      groups on critical proteins, resulting in cellular dysfunction and hepatic and
      renal toxicity. The P450 metabolizing enzymes differ somewhat in character
      between the liver and kidney. Factors that enhance renal toxicity include chronic
      liver disease, possibly gender, concurrent renal insults, and conditions that
      alter the activity of P450-metabolizing enzyme systems. Acute renal toxicity is
      characterized by cellular injury primarily confined to the proximal tubule and
      significant reductions in glomerular filtration rate. However, there is little
      evidence that chronic administration of APAP contributes to chronic renal disease
      and analgesic nephropathy. The only report on this subject suggests that
      combination therapy with aspirin is required for medullary damage in rats. No
      evidence exists for the development of chronic analgesic nephropathy with APAP
      alone. Epidemiologic studies in healthy individuals have failed to demonstrate a
      significant correlation between APAP use and chronic renal disease and classic
      analgesic nephropathy. Therefore, large doses of APAP can produce both renal and
      hepatic failure, but little evidence exists for production of classic analgesic
      nephropathy with the use of APAP alone.

PMID- 8669427
TI  - Acetaminophen/aspirin mixtures: experimental data.
AB  - The pertinent literature concerning the experimental induction of analgesic
      nephropathy is reviewed. Based on the accumulated data from animal experiments
      that induced a pathologic lesion resembling chronic analgesic nephropathy, of the
      limited number of analgesics tested, aspirin seems to be the most nephrotoxic of
      the commonly available analgesics. When aspirin is combined with other
      analgesics, the limited data available suggest at least an additive nephrotoxic
      effect, if not a synergism. The histologic presentation of acute intoxication is
      substantially different from that following chronic ingestion. With improvements
      in pathologic analysis of experimental results, future studies may well provide
      more insight as to the significance, relative contribution, and risk of
      combination analgesic products in inducing experimental analgesic nephrotoxicity.

PMID- 8669428
TI  - Pathophysiologic mechanisms in analgesic-induced papillary necrosis.
AB  - The nonnarcotic analgesics have been implicated as a significant cause of chronic
      renal failure worldwide. Epidemiologic studies of habitual abuse and necropsy
      studies show a strong relationship between the two. Animal studies designed to
      elucidate underlying mechanisms have been hampered because the lesion occurs
      infrequently and only after very high doses are given for prolonged periods;
      however, the Fischer 344 and Wistar rats appear to be more sensitive, and
      substantial new information should be forthcoming. In this review, some of the
      evidence for the possible mechanisms of papillary necrosis are presented:
      prostaglandin inhibition, reduction or redistribution of renal blood flow, direct
      cellular injury, free radical formation, and immunologic injury. At present, most
      data support prostaglandin inhibition and reduction or redistribution of renal
      blood flow, but direct cellular injury also appears to be very important.

PMID- 8669429
TI  - Combination analgesic-induced kidney disease: the Australian experience.
AB  - Analgesic nephropathy is a unique drug-induced kidney disease characterized
      pathologically by renal papillary necrosis and chronic interstitial nephritis,
      and is the result of excessive consumption of combination antipyretic analgesics.
      The clinical features of the disorder relate mainly to the papillary necrosis,
      renal colic, and obstructive uropathy and the development of chronic renal
      failure in a small percentage of patients. There are significant geographic
      variations in the clinical features that may be related to the differing
      combinations of analgesics. The pathogenesis of the disease is in part related to
      the kidneys' ability to concentrate drugs in the papillae. The following sequence
      of events presents a plausible explanation for the evolution of the disease. If a
      combination of phenacetin and aspirin is ingested, the following steps occur.
      Phenacetin is converted in the gut and liver to acetaminophen by first-pass
      metabolism. Acetaminophen is then taken up by the kidney and excreted. During its
      excretion, acetaminophen becomes concentrated in the papillae of the kidney
      during physiologic degrees of antidiuresis, the concentration being up to five
      times the intracellular concentration of other tissues. Acetaminophen undergoes
      oxidative metabolism by prostaglandin H synthase to a reactive quinoneimine that
      is conjugated to glutathione. If acetaminophen is present alone, there is
      sufficient glutathione generated in the papillae to detoxify the reactive
      intermediate. If the acetaminophen is ingested with aspirin, the aspirin is
      converted to salicylate and salicylate becomes highly concentrated in both the
      cortex and papillae of the kidney. Salicylate is a potent depletor of
      glutathione. The mechanism is not completely understood; however, the inhibition
      of the production of NADPH via the pentose shunt is a possible explanation. With
      the cellular glutathione depleted, the reactive metabolite of acetaminophen then
      produces lipid peroxides and arylation of tissue proteins, ultimately resulting
      in necrosis of the papillae.

PMID- 8669430
TI  - Combination analgesic involvement in the pathogenesis of analgesic nephropathy:
      the European perspective.
AB  - Analgesic nephropathy (AN) is a chronic renal disease characterized by renal
      papillary necrosis and interstitial nephritis caused by excessive consumption of
      analgesic mixtures. In a recent study, diagnostic criteria for AN, based on a
      computed tomography scan investigation without contrast, were presented. The
      observation of a decreased renal mass of both kidneys combined with either bumpy
      contours or papillary calcifications was found to have a high diagnostic
      performance. Although several case control studies and two prospective studies
      demonstrated the association between analgesic abuse and nephropathy, the
      nephrotoxicity of the different analgesic products had not been clearly
      established. Analgesic abuse can be defined as a daily consumption of analgesic
      mixtures over a several-year period. Abuse of single analgesics is rare; it has
      been clearly demonstrated that abusers prefer analgesic mixtures. In Belgium, the
      prevalence of AN was positively related to the sales of analgesic mixtures
      containing two analgesic components plus caffeine and/or codeine. This
      relationship could not be observed for analgesics containing only one analgesic
      component plus caffeine and/or codeine. Moreover, during a European multicenter
      study, nephrotoxicity of different combinations of analgesic mixtures (all
      containing caffeine and/or codeine) could be documented in the absence of any
      previous phenacetin consumption. Epidemiologic observations in Sweden, France,
      and Belgium regarding incidence of AN, sales figures of analgesics, and
      legislative measurements concerning analgesic consumption supported the previous
      observations.

PMID- 8669431
TI  - The renal effects of nonsteroidal anti-inflammatory drugs: summary and
      recommendations.
AB  - The renal effects of nonsteroidal anti-inflammatory drugs are reviewed with
      special emphasis on the clinical, pathophysiologic, and risk factors for acute
      renal failure. Renal papillary necrosis and chronic renal insufficiency can occur
      with the prolonged use of these drugs, although the prevalence of this
      manifestation of nonsteroidal anti-inflammatory drug nephrotoxicity is unknown.
      Current recommendations based on a critical literature survey are provided, along
      with a list of suggested areas in which more research is needed.

PMID- 8669432
TI  - Nonrenal toxicities of acetaminophen, aspirin, and nonsteroidal anti-inflammatory
      agents.
AB  - Approximately 2% of the United States population consumes an analgesic,
      antipyretic, or nonsteroidal antiinflammatory drug (NSAID) each day. Aspirin and
      acetaminophen have been available to the public without a prescription (over-the
      counter) for decades, while most NSAIDs are still only available with a
      prescription from a physician. The recent trend of switching NSAIDs from
      prescription to over-the-counter status may be perceived by some as an indication
      of their inherent safety. However, all these agents have been associated with a
      unique but overlapping safety profile. In fact, significant adverse events (AEs)
      on multiple organ systems, including the kidney and gastrointestinal tract, have
      been reported with most of these agents. In this review, the incidence of the
      nonrenal AEs of aspirin, acetaminophen, and selected NSAIDs are tabulated. The
      strengths of the causative associations are highlighted, the relative risks for
      the gastrointestinal and cardiovascular AEs are discussed, and the relationship
      to patient risk factors and drug characteristics, such as dose and half-life, are
      reviewed. The selection of the optimal agent for an individual patient depends on
      the balance between the desired pharmacodynamic response, the patient's
      pharmacotherapy history, and the degree of AE risk one is willing to accept.
      Therapy should be initiated in all settings with the lowest possible dosage since
      the incidence of the major AEs is dose related.

PMID- 8669433
TI  - Habitual use of acetaminophen as a risk factor for chronic renal failure: a
      comparison with phenacetin.
AB  - Six epidemiologic studies in the United States and Europe indicate that habitual
      use of phenacetin is associated with the development of chronic renal failure and
      end-stage renal disease (ESRD), with a relative risk in the range of 4 to 19. As
      a result of these and other studies, phenacetin has now been withdrawn from the
      market in most countries. However, three case control studies, one each in North
      Carolina, northern Maryland, and West Berlin, Germany, showed that habitual use
      of acetaminophen is also associated with chronic renal failure and ESRD, with a
      relative risk in the range of 2 to 4. These studies suggest that both phenacetin
      and acetaminophen may contribute to the burden of ESRD, with the risk of the
      latter being somewhat less than that of the former. This apparent difference in
      risk may not be due to differences in nephrotoxic potential of the drugs
      themselves. A lower relative risk would be expected for acetaminophen if the risk
      of both drugs in combination with other analgesics was higher than the risk of
      either agent alone. Thus, acetaminophen has been used both as a single agent and
      in combination with other analgesics, whereas phenacetin was available only in
      combinations. The possibility that habitual use of acetaminophen alone increases
      the risk of ESRD has not been clearly demonstrated, but cannot be dismissed.

PMID- 8669434
TI  - Substitution of arginine for glycine at position 154 of the alpha 1 chain of type
      I collagen in a variant of osteogenesis imperfecta: comparison to previous cases
      with the same mutation.
AB  - A substitution of arginine for glycine at amino acid position 154 of the alpha
      1(I) collagen chain was found in a father and his three children. The phenotype
      of the patients includes manifestations of types I and III/IV osteogenesis
      imperfecta, but appears to be milder than that of the previously described two
      unrelated patients that had the identical mutation in the alpha 1(I) collagen
      chain. The variability in the phenotype raises the possibility of epistatic loci
      or environmental effects on expression of the disorder.

PMID- 8669435
TI  - X/autosome translocation in three generations ascertained through an infant with
      trisomy 16p due to failure of spreading of X-inactivation.
AB  - We report on a reciprocal translocation t(X;16)(q28;p12) detected in a newborn
      girl with clinical manifestations of partial trisomy 16p. A balanced
      translocation was found in the mother and in the maternal grandmother.
      Replication studies on lymphocytes and fibroblasts showed nonrandom X
      inactivation in both the patient and her mother. In the mother, the derivative X
      (der(X)) was active, whereas the normal X was late replicating. In contrast, in
      the patient the der(X) was late replicating, and there was no spreading of X
      inactivation onto the autosomal segment, thus giving an explanation for the full
      clinical picture of partial trisomy 16p.

PMID- 8669436
TI  - Renal insufficiency is a component of COACH syndrome.
AB  - Two sisters, ages 23 years and 6 years, respectively, were found to have
      congenital ataxia, bilateral coloboma, mental retardation and abnormal liver
      function. Magnetic resonance imaging showed cerebellar vermis hypoplasia in the
      younger girl and liver biopsy showed hepatic fibrosis in the older sister. This
      combination of findings suggested a diagnosis of COACH syndrome which is
      characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital
      ataxia, coloboma, and hepatic fibrosis. COACH syndrome is a newly recognized
      condition. So far, five cases have been reported from three sibships. We report
      two additional cases from one sibship and suggest that several other cases may
      already exist in literature that were not recognized as having COACH syndrome.
      The occurrence of multiple cases in single sibships suggests autosomal recessive
      inheritance. In addition to previously described findings typical of COACH
      syndrome, the older of our patients showed progressive renal insufficiency with
      fibrocystic changes on renal biopsy. Renal function has not been described
      consistently in previous reports of COACH syndrome but has been abnormal in all
      cases in which it has been investigated. We suggest that renal insufficiency
      should be considered a common manifestation of COACH syndrome.

PMID- 8669437
TI  - Ichthyosis-characteristic appearance-mental retardation syndrome with distinct
      histological skin abnormalities.
AB  - In this report, we describe a 2.5-year-old severely mentally retarded boy with
      peculiar appearance and generalized ichthyosis, born to consanguineous Turkish
      parents. The histological finding in the skin biopsy of unusually large oval
      keratohyalin granules in the granular cells is unique, and hitherto has not been
      reported in other ichthyosis-mental retardation syndromes.

PMID- 8669438
TI  - Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): a Brazilian case.
AB  - This is a report on a Brazilian patient with spondyloepimetaphyseal dysplasia
      with joint laxity (SEMDJL; MIM 271640), a rare autosomal recessive skeletal
      dysplasia characterized by dwarfism, articular hypermobility, progressive
      intractable spinal malalignment, a typical facies and a propensity to joint
      dislocation and subluxation. The condition has been described only in 20 children
      of Afrikaans-speaking parents in South Africa. This is the first report of a non
      Afrikaans patient with this genetic entity.

PMID- 8669439
TI  - Three-generation family with resemblance to Townes-Brocks syndrome and
      Goldenhar/oculoauriculovertebral spectrum.
AB  - The Townes-Brocks syndrome (TBS) is comprised of a triad including characteristic
      anal, thumb, and ear anomalies. There are many other organ system abnormalities
      which may be present. However, the literature does not emphasize craniofacial
      findings except with reference to the typical ear configuration. A three
      generation family is described in which craniofacial manifestations were
      prominent and a Goldenhar-like condition was considered as the most likely
      diagnosis. However, with the recent birth of an affected male who had an
      imperforate anus, the diagnosis of TBS was also considered. The family manifests
      a variety of Goldenhar-like findings, including epibulbar dermoids, hemifacial
      microsomia, preauricular tags, macrostomia, and micrognathia in addition to
      classical ear, radial, and anal findings of TBS. We report on this family to
      point out a possible biological relationship of these two conditions.

PMID- 8669440
TI  - DNA methylation patterns in human tissues of uniparental origin using a zinc
      finger gene (ZNF127) from the Angelman/Prader-Willi region.
AB  - In order to further our understanding of the epigenetic modifications of DNA and
      its role in imprinting, we examined DNA methylation patterns of human tissues of
      uniparental origin. We used complete hydatidiform moles (CHM), which are totally
      androgenetic conceptions, to examine the paternal methylation pattern in the
      absence of a maternal contribution and we used ovarian teratomas to represent the
      maternal counterpart. We carried out an analysis of DNA methylation of a gene
      which has been shown to contain sites which are differentially methylated in a
      parent-specific fashion. The gene, ZNF127, is located on chromosome 15q11-q13 in
      the region associated with Prader-Willi and Angelman syndromes. The parent-of
      origin DNA methylation has been postulated to reflect the presence of an imprint
      and recent studies have confirmed that ZNF127 is differentially expressed only
      from the paternal chromosome. We identified a unique pattern of hyper- and
      hypomethylated sites in androgenetic conceptions which was nearly identical to
      the paternal pattern found in sperm. This may represent the paternal germ-line
      methylation imprint. We also studied partial hydatidiform moles, non-molar
      triploid conceptions, normal chorionic villi, and somatic tissue. These all
      demonstrated a modified DNA methylation pattern characteristic of normal
      chorionic villi with only limited findings of the imprint. Our results suggest
      that human androgenetic conceptions may provide an excellent model to analyze
      epigenetic DNA modifications, such as methylation, in imprinted genes. The
      paternal allele-specific methylation imprint will also be useful clinically to
      confirm the androgenetic nature of suspected molar conceptions in which parental
      blood samples may not be available.

PMID- 8669441
TI  - Craniofrontonasal syndrome: study of 41 patients.
AB  - Of 41 patients with craniofrontonasal syndrome, 35 were female and 6 were male.
      Although most cases were sporadic, 7 familial instances were found.
      Craniofrontonasal syndrome represents a unique, incompletely understood X-linked
      disorder. Unusual manifestations in females included thick, wiry, and curly hair
      (49%), anterior cranium bifidum (6%), axillary pterygia (9%), unilateral breast
      hypoplasia (postpubertal; 11%), and asymmetric lower limb shortness (14%).

PMID- 8669442
TI  - Cerebrofaciothoracic syndrome.
AB  - We report on a patient with a large septum pellucidum, hypodensity of gray
      matter, hypertelorism, and costovertebral anomalies. Only 5 previous cases have
      been described with this distinctive phenotype. Autosomal recessive inheritance
      seems likely.

PMID- 8669443
TI  - Maternal serum markers levels in consecutive pregnancies: a possible genetic
      predisposition to abnormal levels.
AB  - The study comprised 2,361 women, each with two consecutive normal uncomplicated
      pregnancies screened at 15-20 weeks gestation for maternal serum alpha
      fetoprotein levels (AFP). In 1,816 of these women, maternal serum human chorionic
      gonadotropin (hCG) levels were tested as well. The proportion of women who had a
      second high AFP level (> or = 2.0 MOM) in their subsequent pregnancy was 6.5-fold
      higher as compared with the proportion of women who had normal levels of AFP in
      their first tested pregnancy. The relative chance of having a second positive
      result of a low level of AFP (AFP < or = 0.5 MOM) in subsequent pregnancies was
      3.8-fold higher. The relative chances of having a second positive result of high
      or low levels of hCG were 3.9- and 2.2-fold higher, respectively. It is concluded
      that there is a predisposition for abnormal levels of serum markers that is
      influenced by genetic and/or environmental factors. Therefore it is suggested
      that the individual's risk of having a Down syndrome baby, or other adverse
      pregnancy outcome that is derived from the serum markers' levels, should be
      adjusted taking into account unexplained high or low levels in previous
      pregnancies. A screening policy is suggested which is designed to yield a lower
      false-positive rate without affecting the detection rate of abnormal pregnancies.
      More data are needed before an accurate adjustment based on previous results can
      be made.

PMID- 8669444
TI  - Molecular studies of translocations and trisomy involving chromosome 13.
AB  - Twenty-four cases of trisomy 13 and one case with disomy 13, but a de novo
      dic(13,13) (p12p12) chromosome, were examined with molecular markers to determine
      the origin of the extra (or rearranged) chromosome. Twenty-one of 23 informative
      patients were consistent with a maternal origin of the extra chromosome. Lack of
      a third allele at any locus in both paternal origin cases indicate a somatic
      duplication of the paternal chromosome occurred. Five cases had translocation
      trisomy: one de novo rob(13q14q), one paternally derived rob(13q14q), two de novo
      t(13q13q), and one mosaic de novo t(13q13q)/r(13). The patient with a paternal
      rob(13q14q) had a maternal meiotic origin of the trisomy; thus, the paternal
      inheritance of the translocation chromosome was purely coincidental. Since there
      is not a significantly increased risk for unbalanced offspring of a t(13q14q)
      carrier and most trisomies are maternal in origin, this result should not be
      surprising; however, it illustrates that one cannot infer the origin of
      translocation trisomy based on parental origin of the translocation. Lack of a
      third allele at any locus in one of the three t(13q13q) cases indicates that it
      was most likely an isochromosome of postmeiotic origin, whereas the other two
      cases showed evidence of recombination. One balanced (nontrisomic) case with a
      nonmosaic 45, -13, -13, +t(13;13) karyotype was also investigated and was
      determined to be a somatic Robertsonian translocation between the maternal and
      paternal homologues, as has been found for all balanced homologous Robertsonian
      translocations so far investigated. Thus, it is also incorrect to assume in de
      novo translocation cases that the two involved chromosomes are even from the same
      parent. Despite a maternal origin of the trisomy, we cannot therefore infer
      anything about the parental origin of the chromosomes 13 and 14 involved in the
      translocation in the de novo t(13q14q) case nor for the two t(13;13) chromosomes
      showing a meiotic origin of the trisomy.

PMID- 8669445
TI  - Micromelic dwarfism with cone epiphyses, metaphyseal dysplasia, and vertebral
      segmentation defects.
AB  - We present the clinical and radiological findings in a newborn male with severe
      micromelic dwarfism, short neck, short and narrow upper thorax, and
      brachydactyly. At the age of 1 year mental development is slightly retarded. The
      X-ray findings of severe vertebral segmentation defects and a generalized
      metaphyseal skeletal dysplasia did not lead to a final, conclusive diagnosis. The
      present patient may be the first example of a new type of micromelic spondylo-epi
      metaphyseal dysplasias.

PMID- 8669446
TI  - Additional case of craniofacial and digital anomalies as reported by Harrod et
      al.
AB  - In 1977 Harrod et al. [BD:OAS XIII (3B): 111-115] reported 2 brothers with an
      unusual syndrome of mental retardation, unusual facial appearance, large
      protruding ears, arachnodactyly, hypogenitalism, failure to thrive, and minor
      anomalies. We report on a 46-year-old man with striking resemblance to the
      children described by Harrod who also has secondary megacolon and varicose veins,
      suggesting a connective tissue disorder.

PMID- 8669447
TI  - Aneuploidy among prenatally detected neural tube defects.
AB  - We have reported previously a 10% aneuploidy detection rate among 39 cases of
      fetal neural tube defects (NTD). Subsequently we amassed an additional experience
      of over 17,000 prenatal diagnosis cases over a 5-year period. During this period
      106 cases of NTDs were identified; 44 with anencephaly, 62 with open spina
      bifida. The average maternal age of this population with NTDs was 29 years (15
      40); 6 patients declined amniocentesis. Six of 100 cytogenetic studies were
      aneuploid; one anencephalic fetus had inherited a maternal marker chromosome, and
      5 NTD cases had trisomy 18. The average maternal age of the aneuploid cases was
      31 (19-40); 3 were 35 years or older. Four of 5 trisomy 18 cases had multiple
      congenital anomalies (MCA). The overall aneuploidy detection rate in our cohort
      was 5-6%, while aneuploidy occurred in 2% of the isolated NTD cases, and 24% of
      the MCA cases. Combining the earlier experience, 4/39 aneuploidy (2 trisomy 18,
      4p+, del 13q) yields an aneuploidy detection frequency of 10/145 (7%), of which
      most (7/10) had trisomy 18. These data support fetal karyotyping for accurate
      diagnosis, prognosis, and recurrence-risk counseling.

PMID- 8669448
TI  - Craniosynostosis, microcephaly, hydrancephaly, humero-radial synostosis, and
      thumb aplasia: a new syndrome?
AB  - We describe a growth-retarded newborn infant with craniosynostosis, microcephaly,
      hydrancephaly, oligodactyly, humero-radial synostosis, and normal chromosomes.
      The combination of anomalies has hitherto been unreported and we consider this to
      be a "new" syndrome.

PMID- 8669449
TI  - SHORT syndrome: a new case with probable autosomal dominant inheritance.
AB  - A further case of SHORT syndrome is reported. This 9-year-old Italian boy was
      short of stature and had partial lipodystrophy, minor facial anomalies, mild
      hyperextensibility of joints, ocular depression, Rieger anomaly, delay in speech
      development and in dental eruption. The father and sister showed a striking
      similarity to the propositus. Moreover, the sister had bilateral and symmetrical
      lens opacities, which have not been reported previously in affected subjects or
      their relatives. A variable expression of an autosomal dominant gene can be
      considered in the present family.

PMID- 8669450
TI  - Cytogenetic and molecular analysis of inv dup(15) chromosomes observed in two
      patients with autistic disorder and mental retardation.
AB  - A variety of distinct phenotypes has been associated with supernumerary inv
      dup(15) chromosomes. Although different cytogenetic rearrangements have been
      associated with distinguishable clinical syndromes, precise genotype-phenotype
      correlations have not been determined. However, the availability of chromosome 15
      DNA markers provides a means to characterize inv dup(15) chromosomes in detail to
      facilitate the determination of specific genotype-phenotype associations. We
      describe 2 patients with an autistic disorder, mental retardation, developmental
      delay, seizures, and supernumerary inv dup(15) chromosomes. Conventional and
      molecular cytogenetic studies confirmed the chromosomal origin of the
      supernumerary chromosomes and showed that the duplicated region extended to at
      least band 15q13. An analysis of chromosome 15 microsatellite CA polymorphisms
      suggested a maternal origin of the inv dup(15) chromosomes and biparental
      inheritance of the two intact chromosome 15 homologs. The results of this study
      add to the existing literature which suggests that the clinical phenotype of
      patients with a supernumerary inv dup(15) chromosome is determined not only by
      the extent of the duplicated region, but by the dosage of genes located within
      band 15q13 and the origin of the normal chromosomes 15.

PMID- 8669451
TI  - Molecular diagnosis of Prader-Willi syndrome: comparison of cytogenetic and
      molecular genetic data including parent of origin dependent methylation DNA
      patterns.

PMID- 8669452
TI  - Townes-Brocks syndrome associated with mental retardation.

PMID- 8669453
TI  - Oral-facial-digital syndrome with retinal abnormalities: report of a new case.

PMID- 8669454
TI  - Including family history leads to over-estimation of prior risk in MSAFP
      assessment.

PMID- 8669455
TI  - PW71 methylation test for Prader-Willi and Angelman syndromes.

PMID- 8669456
TI  - Neurodevelopmental changes with age in Ullrich-Turner syndrome.

PMID- 8669457
TI  - Tumor-associated hyaluronan. Providing an extracellular matrix that facilitates
      invasion.

PMID- 8669458
TI  - Lessons from skin blistering: molecular mechanisms and unusual patterns of
      inheritance?

PMID- 8669459
TI  - Increased hyaluronan at sites of attachment to mesentery by CD44-positive mouse
      ovarian and breast tumor cells.
AB  - The mouse ovarian ascites tumor, MOT, and mammary ascites tumor, TA3/St, served
      as models to follow changes in hyaluronan levels during tumor growth, attachment,
      and invasion. Subsequent to introduction of tumor cells into the peritoneal
      cavity, hyaluronan accumulated intraperitoneally and at the initial sites of
      attachment of tumor cells and cell clumps to the mesenteric surface; the latter
      co-localized with sites of fibrin deposition as reported earlier. Subsequently,
      high levels of hyaluronan accumulated throughout the interior of the mesentery.
      Because neither tumor cell line synthesized substantial amounts of hyaluronan in
      culture, the large accumulations observed in the mesenteries and ascites fluid of
      tumor-bearing animals most likely resulted from increased synthesis and secretion
      by peritoneal-lining mesothelial cells and/or fibroblasts in response to
      stimulation by the tumor cells or their products. TA3/St tumor cells were
      universally positive for the hyaluronan receptor, CD44, whereas approximately 90%
      of MOT tumor cells were CD44-negative. However, the great majority of MOT or
      TA3/St cells that initially attached to the mesentery were strongly CD44
      positive. We propose that hyaluronan-rich matrix is involved in tumor cell
      attachment to the mesentery possibly via interaction with tumor cell surface
      CD44.

PMID- 8669460
TI  - Localization of human herpes-like virus type 8 in vascular endothelial cells and
      perivascular spindle-shaped cells of Kaposi's sarcoma lesions by in situ
      hybridization.
AB  - Kaposi's sarcoma (KS) is a neoplasm that develops as multifocal lesions
      characterized by a histological picture that includes irregularly shaped vascular
      spaces surrounded by perivascular and interstitial spindle-shaped cells,
      extravasated erythrocytes, and an inflammatory mononuclear cell infiltrate.
      Recently, the DNA sequences of a novel human gamma-herpesvirus-like (HHV-8) agent
      have been detected by polymerase chain reaction in KS associated with acquired
      immune deficiency syndrome (AIDS-KS), classical KS, and African endemic KS. The
      present study was done to identify the specific cells within KS tumors that
      contain the viral DNA. Fourteen skin biopsy specimens, including three classical
      KSs, six AIDS-KSs, three normal skin specimens, and two common warts from healthy
      individuals, were examined by polymerase chain reaction for the presence of the
      HHV-8 DNA sequences. HHV-8 DNA were present in all nine KS specimens but not
      detectable in the five non-KS tissue samples. Using in situ hybridization, we
      found the HHV-8 DNA sequences to be predominantly localized to the nuclei of
      endothelial cells lining the vascular slits and some perivascular spindle-shaped
      cells, in two of three KS and four of six AIDS-KS tissue sections examined. The
      HHV-8-positive cells of KS specimens were concurrently shown to also be positive
      for factor-VIII-related antigen by immunohistochemical staining. The presence of
      the DNA of HHV-8 in the nuclei of KS cells further supports the possibility that
      this agent may play a role in the pathogenesis of this tumor.

PMID- 8669461
TI  - Selective binding of soluble Abeta1-40 and Abeta1-42 to a subset of senile
      plaques.
AB  - Alzheimer's disease is characterized by the progressive accumulation of amyloid
      beta protein (Abeta) in senile plaques and cerebral amyloid angiopathy. It is not
      known whether the plaque growth is a continuous and homogeneous process or
      whether some plaques have a more rapid evolution. As plaques grow by the
      deposition of Abeta, we used an in situ binding technique to analyze the
      deposition of fluorescein-conjugated and biotinylated Abeta1 40 and Abeta1-42 in
      cryosections of brains from Alzheimer's disease patients. Only a subset of senile
      plaques but all cerebrovascular Abeta deposits were labeled by both Abeta1-40 and
      Abeta1-42. Striking differences in binding were observed among adjacent plaques.
      Quantitative analysis showed that on average 60% of all plaques were labeled with
      Abeta1-42 and 31% of all plaques were labeled with Abeta1-40 (n=7; P<0.001).
      Confocal laser scanning microscopy of double-labeled sections revealed that the
      newly deposited Abeta was only partially co-localized to pre-existing Abeta and
      apolipoprotein E and was not co-localized to heparan sulfate proteoglycan. Abeta
      binding was preserved after glycolytic pretreatment with periodic acid. Our
      results suggest that at a given time point only a subset of active senile plaques
      accumulate A(beta) and that plaque growth may be conditioned by the presence of
      other distinct plaque components different from Abeta, apolipoprotein E or
      heparan sulfate proteoglycan.

PMID- 8669462
TI  - Effects of mutation and growth rates on patterns of microsatellite instability.
AB  - The detection of somatic microsatellite (MS) alterations in tumors is often
      interpreted as a sign of underlying genomic instability. However, it is unclear
      why the proportions of altered MS loci vary between different mutator phenotype
      tumors. We present a simple mathematical analysis that can account for some of
      these differences, recognizing that the mutations accumulated in a tumor reflect
      both its mutation rate and number of cell divisions. Only a small proportion of
      mutated MS loci are expected in tumors with normal or low mutation rates. In
      contrast, tumors with high mutation rates may or may not acquire mutations
      depending on the numbers of divisions that proceed the onset of the mutator
      phenotype. The majority of MS loci should accumulate mutations if high mutation
      rates are acquired early in tumor progression. Somatic MS mutations provide clues
      to both the mode and tempo of tumori-genesis.

PMID- 8669463
TI  - Long-term culture and immortalization of epithelial cells from normal adult human
      pancreatic ducts transfected by the E6E7 gene of human papilloma virus 16.
AB  - Pancreatic cancer is one of the most lethal cancers in humans. The majority of
      these cancers arise from the pancreatic duct epithelium. Research into the
      pathogenesis of pancreatic carcinoma has largely relied on animal models. In
      vitro models of pancreatic carcinogenesis using propagable cultured epithelial
      cells derived from the pancreatic ducts of rats and hamsters have been described.
      A human model, however, has been nonexistent due to the unavailability of
      propagable cultured duct epithelial cells derived from normal human pancreas. We
      report here a reproducible method for the long-term culture of pancreatic duct
      epithelial cells derived from normal and benign adult human pancreata by
      infection with a retrovirus containing the E6 and E7 genes of the human papilloma
      virus 16. One of these cell lines has become immortal and has propagated
      continuously for more than 20 passages. They remain anchorage dependent in their
      growth and nontumorigenic in nude mice. These cell lines and the methodology
      described here to establish them may provide new avenues for in vitro studies of
      the roles played by duct epithelium in human pancreatic diseases and cancers.

PMID- 8669464
TI  - Biotin- or digoxigenin-conjugated nucleotides bind to matrix vesicles in
      atherosclerotic plaques.
AB  - The present study analyzes the staining pattern of DNA in situ end-labeling
      techniques of human and rabbit atherosclerotic plaques. Both the terminal
      deoxynucleotidyl transferase end-labeling and the in situ nick translation
      technique detected, besides apoptotic nuclei, numerous round vesicles with
      diameters from 0.5 to 5 microns within the atherosclerotic plaques. These
      vesicles did not contain DNA but contained calcium. A pretreatment with EDTA or
      citric acid abolished the labeling of the vesicles but did not influence the
      detection of apoptotic nuclei. Ultrastructurally, the vesicles were of variable
      diameter and density, and their aspect was compatible with matrix vesicles, which
      are well known in epiphyses during bone formation. The larger vesicles contained
      cell organelles, and the small vesicles were very dense. X-ray microanalysis
      demonstrated high calcium and phosphorus levels within the most dense vesicles.
      Different stages of the process were present in the plaques. In this way we could
      demonstrate that cytoplasmic fragmentation of smooth muscle cells and subsequent
      formation of matrix vesicles are a frequent finding in atherosclerotic plaques.
      The association of apoptotic cell death and formation of matrix vesicles could be
      an interesting pathway in explaining calcification of atherosclerotic plaques.
      Both the terminal deoxynucleotidyl transferase end-labeling and the in situ nick
      translation technique detected simultaneously apoptotic nuclei and matrix
      vesicles if calcium is not removed from the sections.

PMID- 8669465
TI  - Comparison of regional variability in lung-specific gene expression using a novel
      method for RNA isolation from lung subcompartments of rats and mice.
AB  - The lung is composed of a complex assemblage of more than 40 different cell
      types. Therefore, investigative techniques that rely on samples derived from
      whole lung homogenates, whether for biochemical measurements of metabolism or the
      analysis of gene expression, are inherently insensitive to cell type or region
      specific differences. Microdissection has previously been successful for defining
      region-specific metabolic activity in the lung. Tissues obtained by this
      technique exhibit good viability and permit reproducible enzyme activity
      measurements. In this paper, a technique for isolating RNA from lung
      subcompartments obtained by microdissection is described. The method is straight
      forward and results in high quality RNA that can be used to quantify specific
      mRNAs in microscopically selected lung subcompartments by complementary DNA or
      RNA hybridization techniques. This technique provides a significant increase in
      sensitivity over techniques based on whole lung homogenates because RNA
      contributed by relevant lung subcompartments is enriched. The high sensitivity of
      the method makes it feasible to compare differences in mRNA expression 1) within
      different regions of the lung in the same animal, 2) in the same region in
      different animals and between different species, and 3) between susceptible and
      nonsusceptible sites in conditions of focal lung injury.

PMID- 8669466
TI  - Compound heterozygosity for a dominant glycine substitution and a recessive
      internal duplication mutation in the type XVII collagen gene results in
      junctional epidermolysis bullosa and abnormal dentition.
AB  - Junctional epidermolysis bullosa is a heterogeneous autosomal recessively
      inherited blistering skin disorder associated with fragility at the dermal
      epidermal junction. Previously, mutations in this condition have been described
      in the three genes for the anchoring filament protein laminin 5 (LAMA3, LAMB3,
      and LAMC2), in the gene encoding the hemidesmosome-associated beta4 integrin
      (ITGB4), and in the gene for the hemidesmosomal protein type XVII collagen
      (COL17A1/BPAG2). In this study, we report a patient with a form of junctional
      epidermolysis bullosa with skin fragility and dental anomalies who is a compound
      heterozygote for a novel combination of mutations, ie, a glycine substitution
      mutation in one allele and an internal duplication in the other allele of
      COL17A1. The patient also has two offspring, both of whom have inherited the
      glycine substitution mutation, whereas the other COL17A1 allele is normal. The
      latter individuals show no evidence of skin fragility but have marked dental
      abnormalities with enamel hypoplasia and pitting. The clinical phenotype of
      junctional epidermolysis bullosa in the proband in this family probably arises
      due to a combination of the glycine substitution and the internal duplication in
      COL17A1, whereas the dental abnormalities of her offspring may be the result of
      the glycine substitution in COL17A1 alone, resulting in this dominantly inherited
      clinical phenotype.

PMID- 8669467
TI  - Widespread neuronal expression of the presenilin-1 early-onset Alzheimer's
      disease gene in the murine brain.
AB  - Mutations in the presenilin-1 (S182) gene have been genetically linked to early
      onset Alzheimer's disease. To clarify the underlying molecular mechanism through
      which presenilin-1 is involved in the pathogenesis of this neurodegenerative
      disorder, the regional and cellular transcription profile of this gene was
      characterized in primary cells isolated from the murine brain by Northern blot
      hybridization using digoxigenin-labeled riboprobes. Our results indicate that
      presenilin-1 mRNA transcripts are widely distributed throughout the adult mouse
      brain. Furthermore, immunohistochemical labeling of hybridized sections indicates
      that expression was predominantly localized to neuronal cells. Neurons in the
      hippocampus and cerebral cortex, which are severely compromised in Alzheimer's
      disease, showed prominent expression of presenilin-1. In contrast, white matter
      areas and endothelial cells do not appear to express presenilin-1 to detectable
      levels. presenilin-1 transcripts, however, are also present less frequently in
      certain nonneuronal cell populations such as ependymal cells in the choroid
      plexus. Analysis of primary cells isolated from murine brain supported the
      results obtained by in situ hybridization and showed that cultured primary
      neurons and astrocytes express presenilin-1. Overall, it appears that the pattern
      of presenilin-1 gene expression parallels that previously described for the
      amyloid precursor protein.

PMID- 8669468
TI  - Cellular localization of the Trk neurotrophin receptor family in human non
      neuronal tissues.
AB  - We investigated the distribution of the high-affinity neurotrophin receptors
      TrkA, TrkB, and TrkC in a wide range of normal non-neuronal tissues of adult
      human by immunohistochemical methods. Trk immunoreactivity (IR) was detected at
      various levels in all tissues examined, except for the heart and liver. The
      gastric parietal cells showed strong TrkA and TrkC IR and all of the Trks had IR
      for the putative intestinal neuroendocrine cells. In the pancreas, TrkA and TrkC
      IR was detected in the sub-intralobular ducts, whereas TrkB IR was found
      specifically in the alpha-islet cells. The lymph node and spleen exhibited TrkB
      IR in monocytes/macrophages. The adrenal cortex showed selective TrkA IR with
      TrkC IR in the medulla. In the reproductive system, TrkA IR was detected in the
      prostatic epithelial cells, TrkC in the ovarian theca and granulosa cells, TrkA
      and TrkC in the secretory-phase endometrium, and TrkA in the mammary ducts. The
      kidney showed strong TrkA and TrkC IR in it tubules, but no Trk receptors were
      present in the glomeruli. In the skin, TrkA and TrkB/TrkC were present in the
      basal and granular layers of the epidermis, respectively.

PMID- 8669469
TI  - ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not
      endothelium and mediate binding of lymphocytes in vitro.
AB  - The expression of cell adhesion molecules (CAMs) in the choroid plexus was
      studied in normal brain and during experimental autoimmune encephalomyelitis
      (EAE) in the SJL/J mouse during inflammation induced by intracerebral injection
      of killed Corynebacterium parvum in the C3H/He mouse. Both ICAM-1 and VCAM-1, but
      not MAdCAM-1, were constitutively expressed on choroid plexus epithelium but not
      on the fenestrated capillary endothelial cells within the choroid plexus. During
      EAE, we observed an up-regulation of ICAM-1 and VCAM-1 and de novo expression of
      MAdCAM-1 on choroid plexus epithelial cells. In contrast, endothelial cells in
      the choroid plexus were not induced to express any of the investigated CAMs. In
      in situ hybridization analysis we demonstrated that ICAM-1, VCAM-1, and MAdCAM-1
      were locally synthesized and that the amount of their mRNAs increased in the
      inflamed choroid plexus. In vitro, primary choroid plexus epithelial cells could
      be induced to express ICAM-1, VCAM-1, and MAdCAM-1 on their surface after
      treatment with proinflammatory cytokines such as tumor necrosis factor-alpha,
      interleukin-1, interferon-gamma, and lipopolysaccharide. To investigate the
      functional status of the expressed CAMs we performed Stamper-Woodruff binding
      assays on frozen sections of inflamed and naive brains. ICAM-1, VCAM-1, and
      MAdCAM-1 expressed in choroid plexus epithelial cells mediated binding of
      lymphocytes via their known ligands LFA-1 and alpha4-integrin, respectively. The
      expression of ICAM-1, VCAM-1, and MAdCAM-1 on choroid plexus epithelial cells
      together with the lack of their expression on the fenestrated choroid plexus
      endothelium raises the possibility that the epithelial blood-cerebrospinal-fluid
      barrier plays an important role in the immunosurveillance of the central nervous
      system.

PMID- 8669470
TI  - Expression of neurofilaments and of a titin epitope in thymic epithelial tumors.
      Implications for the pathogenesis of myasthenia gravis.
AB  - Autoantibodies against both striated muscle proteins, particularly titin, and the
      acetylcholine receptor are a hallmark of thymoma-associated myasthenia gravis.
      However, the stimulus for these responses remains enigmatic as whole titin is not
      detectable in these tumors. This study reports that in thymomas with cortical
      differentiation many of the neoplastic epithelial cells expressed low and medium
      molecular weight neurofilaments detected with several antibodies (on selections
      and blots) and at the RNA level (by reverse transcriptase polymerase chain
      reaction). Moreover, higher molecular weight forms sharing at least one epitope
      with titin were detectable slightly less frequently, as were the more strongly
      phosphorylated epitopes. In stark contrast, in medullary and mixed thymomas, and
      especially in the normal thymus, immunoreactivity with anti-neurofilament
      antibodies was rare. This aberrant overexpression of a titin epitope by
      epithelial cells with antigen-presenting phenotype in an inappropriate cortical
      microenvironment suggests that they might autosensitize maturing T cells there
      and so initiate anti-titin autoimmunity in these patients.

PMID- 8669471
TI  - Thrombospondin 1 synthesis and function in wound repair.
AB  - Thrombospondin 1 (TSP1) is a multifunctional extracellular matrix molecule that
      belongs to a family of homologous glycoproteins. TSP1 can be produced by many
      cell types that are involved in wound repair, including keratinocytes,
      fibroblasts, endothelial cells, and macrophages. To investigate the kinetics of
      TSP1 synthesis in wounds, mRNA from murine full thickness excisional dermal
      wounds was analyzed. TSP1 mRNA was undetectable in normal skin but was present in
      early wounds. After day 1, TSP1 mRNA levels within wounds slowly decreased,
      returning to undectable day 10. In situ hybridization revealed that the primary
      source of the TSP1 mRNA within wounds was macrophage-like cells in the
      inflammatory infiltrate. To explore the function of TSP1 production in sites of
      injury, wounds were treated with antisense TSP1 oligomers. Antisense-treated
      wounds contained 55 to 66% less TSP1-positive macrophages than control and
      exhibited a marked delay in repair. This delay included a decreased rate of re
      epithelialization as well as a delay in dermal reorganization. The results
      suggest that TSP1 production by macrophages facilitates the repair process and
      provide evidence that TSP1 production is an important component of optimal wound
      healing.

PMID- 8669472
TI  - Hyaluronan distribution in the normal epithelium of esophagus, stomach, and colon
      and their cancers.
AB  - The distribution of hyaluronan (HA) in normal gastrointestinal wall and in tumors
      originating from their epithelium was studied using a specific probe prepared
      from cartilage proteoglycan (bHABC, biotinylated hyaluronan binding complex). The
      normal stratified squamous epithelium of esophagus showed an intense HA staining
      in the basal and lower intermediate layers, whereas the simple epithelia in the
      stomach and large intestine were HA negative. Esophageal in situ carcinomas
      expressed HA also in the cell layers close to the luminal surface, in regions
      normally negative. Most of the invasive squamous cell carcinomas maintained their
      HA expression, but in very poorly differentiated types the tumor parenchyma was
      devoid of HA. In both gastric and colonic adenocarcinomas the tumor parenchyma
      showed no HA. The stromal tissue was intensely HA positive in all tumors. Cancer
      cells invading the intestinal smooth muscle were surrounded by copious amounts of
      HA, whereas the muscular layer was otherwise very poor in HA staining. These
      results show that relatively well differentiated carcinoma cells themselves
      retain the high or low HA expression pattern of their original epithelium,
      whereas tumors stimulate HA deposition in the surrounding stroma.

PMID- 8669473
TI  - Fibroblast-dependent induction of a murine skin lesion with similarity to human
      common blue nevus.
AB  - In an attempt to define epithelial-mesenchymal interactions in skin appendage
      formation, we have been studying a nude mouse grafting model that permits the
      combination of heterotypic and heterochronic epithelial and mesenchymal cells. In
      this study using neonatal hair bud cells combined with various mesenchymal cell
      preparations, we show that one can regenerate near-complete skin with intact
      epidermal and dermal layers plus mature hair follicles. It was determined that
      the character of the resulting regenerated skin could be manipulated as a
      function of the specific mesenchymal component. Lack of dermal cells resulted in
      a scar, whereas inclusion of a suspension of dissociated total dermal cells
      resulted in near-complete skin regeneration, and in the presence of follicular
      papilla fibroblasts (both hair-inductive and non-hair-inductive) or NIH3T3
      fibroblasts, the reconstitution had similarity to the common blue nevus. The
      results indicate that 1) a stimulant of human common blue nevus can be produced
      in an animal model, 2) the underlying disorder of the lesion in mice appears to
      be entirely dermal in origin, arising independent of the epidermal component, and
      3) complex dermal cell interactions involving lesion-initiative and lesion
      suppressive activities underlie the pathogenesis. This experimental system will
      serve as a valuable tool in elucidating cutaneous dermal-epidermal signals in
      normal skin as well as the alteration of these signals in malformations such as
      the hamartoma described here.

PMID- 8669474
TI  - Melanoma-associated expression of transforming growth factor-beta isoforms.
AB  - Melanocytic neoplasia is characterized by the aberrant overproduction of multiple
      cytokines in vitro. However, it is largely unknown how cytokine expression
      relates to melanoma progression in vivo. Transforming growth factor beta (TGF
      beta) is a multifunctional cytokine commonly produced by cultured melanoma cells.
      The in situ expression of all three TGF-beta isoforms (TGF-beta1, -2, and -3) was
      determined immunohistochemically in melanocytes and in 51 melanocytic lesions
      using isoform-specific antibodies. Significant linear trends of expression were
      observed from melanocytes through nevi and primary and metastatic melanomas for
      all three isoforms. TGF-beta1 was expressed by some melanocytes and almost
      uniformly by nevi and melanomas. TGF-beta2 and -3 were not expressed in normal
      melanocytes but were expressed in nevi and early and advanced primary (radial and
      vertical growth phase) and metastatic melanomas in a tumor-progression-related
      manner. TGF-beta2 was heterogeneously expressed in advanced primary and
      metastatic melanomas, whereas TGF-beta3 was uniformly and highly expressed in
      these lesions. Thus, expression of TGF-beta isoforms in melanocytes and
      melanocytic lesions is heterogeneous and related to tumor progression, and
      expression of TGF-beta2 and TGF-beta3 commences at critical junctures during
      progression of nevi to primary melanomas.

PMID- 8669475
TI  - Immunolocalization and gene expression of oxytocin receptors in carcinomas and
      non-neoplastic tissues of the breast.
AB  - Recent evidence indicates that oxytocin (OT), in addition to the induction of
      myometrial and myoepithelial cell contraction, can influence proliferation and
      differentiation in developing mammary glands and in breast cancer cells, hence
      the interest in detecting and locating OT receptors (OTRs). We produced rabbit
      antisera and a monoclonal antibody against a synthetic peptide corresponding to
      the carboxy terminus of the predicted OTR sequence. We tested their specificity
      in immunoblasts and immunocytochemical tests. All of the antibodies specifically
      stained myometrium (at term of pregnancy). In the human breast, OTRs were
      detected in myoepithelial cells along ducts of normal lobules and in sclerosing
      adenosis. Intraductal cells in benign hyperplastic lesions were also positive.
      OTRs were demonstrated in cases of primary and metastatic carcinomas of the
      breast. In the same tissues, OTR gene expression was shown by reverse
      transcriptase polymerase chain reaction procedures detecting the specific mRNA.
      These results suggest that the interaction between OT and its receptors might
      play a role in the origin and evolution of non-neoplastic lesions and carcinomas
      of the breast.

PMID- 8669476
TI  - Immunohistochemical analysis of retinoic acid receptor-alpha in human breast
      tumors: retinoic acid receptor-alpha expression correlates with proliferative
      activity.
AB  - Retinoids are known to prevent mammary carcinogenesis in rodents and inhibit the
      growth of human breast cancer cells in vitro. Previously we demonstrated that
      retinoid inhibition of proliferation of human breast cancer cell lines is largely
      mediated by retinoic acid receptor (RAR)-alpha. In this study we describe for the
      first time the histological distribution of RAR-alpha in 33 breast lesion
      specimens as determined by immunostaining with RAR-alpha antibody. Nuclear
      staining was observed in tumor tissue and normal portions of the breast samples.
      Connective tissue exhibited relative uniform staining, whereas a wide range of
      RAR-alpha expression was found in the epithelial tumor cells. RAR-alpha protein
      was expressed at significantly higher levels in tumors with greater proliferative
      activity as determined by immunostaining with Ki-67 antibody. This suggests that
      RAR-alpha expression may be altered with tumor progression. Although a positive
      correlation between RAR-alpha mRNA levels and estrogen receptor status of breast
      tumors has previously been documented, we did not find such a relationship at the
      protein level. As RAR-alpha plays a major role in retinoid-mediated growth
      inhibition of human breast cancer cell in vitro, our findings suggest that
      patients with highly proliferating tumors could be responsive to retinoid
      independently of their responsiveness to (anti)-estrogens.

PMID- 8669477
TI  - Cyclic stretching force selectively up-regulates transforming growth factor-beta
      isoforms in cultured rat mesangial cells.
AB  - Glomerular distention from increased intraglomerular pressure stretches mesangial
      cells (MCs). Stretching MCs in culture stimulates extracellular matrix
      accumulation, suggesting that this may be a mechanism for glomerular hypertension
      associated glomerulosclerosis. We examined whether mechanical stretching serves
      as a stimulus for the synthesis and activation of the prosclerotic molecule
      transforming growth factor (TGF)-beta, thus providing a potential system for auto
      induction of extracellular matrix. Rat MCs cultured on flexible-bottom plates
      were subjected to cyclic stretching for up to 3 days and then assayed for TGF
      beta mRNA, secretion of TGF-beta, and localization of active TGF-beta by
      immunostaining. MCs contained mRNA for all three mammalian isoforms of TGF-beta.
      Cyclic stretching for 36 hours increased TGF-beta1 and TGF-beta3 mRNA levels
      approximately twofold, without altering the levels of TGF-beta2 mRNA. This was
      followed at 48 to 72 hours by the increased secretion of both latent and active
      TGF-beta1. Latent, but not active, TGF-beta3 secretion also increased whereas the
      levels of TGF-beta2 were unaffected by mechanical force. The stretching force in
      this system is unequally distributed over the culture membrane. Localization of
      active TGF-beta by immunostaining demonstrated that the quantity of cell
      associated cytokine across the culture was directly proportional to the zonal
      amplitude of the stretching force. These results demonstrate that stretching
      force stimulates MCs to selectively release and activate TGF-beta1. This
      mechanical induction of TGF-beta1 may help explain the increased extracellular
      matrix associated with intraglomerular hypertension.

PMID- 8669478
TI  - Interferon-gamma-producing T cells in giant cell vasculitis represent a minority
      of tissue-infiltrating cells and are located distant from the site of pathology.
AB  - Giant cell vasculitis is an arteritis that predominantly affects medium- and
      large-sized arteries. Genetic risk factors and clonal expansion of selected CD4+
      T cell specificities in the vascular lesions support the model that giant cell
      arteritis is a T-cell-driven disease. Interferon (IFN)-gamma production in the
      tissue is intimately associated with the formation of the inflammatory
      infiltrates. Antigens inducing stimulation of T cells are unknown. To provide
      indirect evidence for the type and the tissue localization of the antigen, we
      examined CD4+ T cells in the lesions that secrete IFN-gamma. Temporal artery
      specimens from patients with giant cell arteritis were analyzed bu two-color
      immunohistochemistry applying antibodies to T cell markers. IFN-gamma, the
      interleukin-2 receptor alpha-chain (CD25) and talin, a cytoskeletal protein that
      is reorganized in T cells interacting with antigen-presenting cells.
      Proliferating cells in the lesions were identified through the expression of the
      Ki-67 nuclear antigen. More than 90% of tissue-infiltrating IFN-gamma-producing
      cells were CD4+ CD45RO+. They represented a minute subset (2 to 4%) of tissue
      infiltrating T cells. IFN-gamma+ T cells aggregated in the adventitial layer of
      the inflamed artery where they were either diffusely distributed or arranged in
      clusters. The majority of IFN-gamma-secreting T cells expressed CD25. IFN-gamma+
      T cells included a fraction of cells that had reorganized the cytoskeletal
      protein talin, indicating an interaction of the T cell receptor and an antigen
      presenting cell. A subset of IFN-gamma-expressing T cells was undergoing
      proliferation in the tissue. IFN-gamma-producing T cells in vasculitic lesions of
      giant cell arteritis express several markers that identify them as T cells that
      have recently been stimulated through their antigen-specific receptor. These
      putatively disease-relevant T cells represent only a very minor fraction of
      tissue-infiltrating cells. Their preferential accumulation in the adventitia is
      most compatible with the model that they contact the relevant antigen primarily
      in this particular region of the artery. Their regulatory function appears to
      extend into the inner media and intima where pathological changes in giant cell
      arteritis are most pronounced.

PMID- 8669479
TI  - Cytokine secretion and adhesion molecule expression by granuloma T lymphocytes in
      Mycobacterium avium infection.
AB  - Mice experimentally infected with Mycobacterium avium develop a chronic disease
      characterized by widespread noncaseating granulomas. In this report, we describe
      the phenotype and cytokine secretion profile of these granuloma-infiltrating
      effector T lymphocytes. In response to specific antigen, granuloma T cells and,
      to a lesser extent, spleen cells secrete interferon-gamma, but no interleukin-4
      or -5. The importance of this Th1-like response to the host was demonstrated by
      the massively increased bacterial load and lethal disease in interferon-gamma
      knockout mice. One function of localized cytokine secretion is to recruit
      inflammatory T cells bearing surface adhesion molecules complementary to counter
      receptors on vascular endothelial cells. Granuloma T cells express high levels of
      these pro-inflammatory adhesion molecules but have down-regulated their
      expression of L-selectin (CD62L). The expression of these adhesion molecules on
      granuloma-infiltrating T lymphocytes would alter the migration pathway of these
      cells and is likely to be important in facilitating the traffic of effector T
      cells to the granulomatous inflammatory site. In addition, T cells from
      Schistosoma mansoni granulomas express the same set of adhesion molecules,
      showing that this phenotype is not specifically dependent upon the Th1 pattern of
      cytokine secretion.

PMID- 8669480
TI  - Endothelial constitutive nitric oxide synthase protein and mRNA increased in
      rabbit atherosclerotic aorta despite impaired endothelium-dependent vascular
      relaxation.
AB  - Atherosclerotic arteries are well known to exhibit impaired endothelium-dependent
      relaxation (EDR), but the exact mechanism of this impairment remains unclear.
      Recently, endothelial constitutive nitric oxide synthase (ECNOS), which generates
      nitric oxide and mediates EDR, was cloned, and ECNOS mRNA expression was reported
      to be modified by various cytokines, lipoproteins, and shear stress. To
      investigate the expression of ECNOS mRNA and protein in atherosclerotic arteries
      with impaired EDR, thoracic aortas isolated from Watanabe heritable
      hyperlipidemic (WHHL) rabbits were examined by using in situ hybridization and
      immunohistochemistry. Compared with thoracic aortas from Japanese White rabbits,
      WHHL aortas exhibited significantly impaired EDRs, although both in situ
      hybridization and immunohistochemistry exhibited enhanced expression of ECNOS
      mRNA and protein in WHHL aortas. There was no significant relationship between
      expression of ECNOS mRNA and protein of endothelial cells and age of the examined
      WHHL aortas. These data suggest that the mechanism of impaired EDR in
      atherosclerotic arteries is not due to the decrease in ECNOS mRNA and protein.

PMID- 8669481
TI  - Acute inflammatory reaction after myocardial ischemic injury and reperfusion.
      Development and use of a neutrophil-specific antibody.
AB  - Reperfusion of the infarcted canine myocardium after 1 hour of ischemia is
      associated with an acute inflammatory infiltrate at the border of the infarct. In
      this paper, we demonstrate that early margination and emigration of neutrophils
      originate in thin-walled (approximately 5 micrometers) venous cisterns that
      average 200 micrometers in length and vary from 10 to 70 micrometers in width and
      show strong constitutive expression of both ICAM-1 and P-selectin; this class of
      vessels (venous cisterns) appears to be a unique feature in heart. A monoclonal
      antibody (SG8H6) with specificity for canine neutrophils was developed that
      allowed much more sensitive immunohistochemical detection of neutrophils in
      tissue and allowed us to follow tissue infiltration with time. Samples from 1
      hour of reperfusion revealed dense margination and substantial emigration of
      neutrophils associated with the venous cisterns and collecting venules. By 2
      hours, there was intense local emigration to the extravascular space between
      cardiac myocytes. By 3 hours, the infiltrate extended deeper into the infarct,
      and there was a continuous border zone of neutrophil infiltration that overlapped
      a region where intact cardiac myocytes strongly expressed ICAM-1 mRNA and
      extended into the necrotic tissue. At later times, neutrophil migration into
      infarcted tissue continued to progress. Neutrophil transmigration into reperfused
      myocardium is more extensive than previously described, and its extravascular
      distribution during early reperfusion is primarily in the viable border zone of
      the myocardium where myocyte ICAM-1 mRNA is found. These data are compatible with
      the hypothesis that extravascular neutrophils may participate in reperfusion
      injury.

PMID- 8669482
TI  - Apolipoprotein J/clusterin induction in myocarditis: A localized response gene to
      myocardial injury.
AB  - The function of apolipoprotein J (apoJ) is unknown, but it has been hypothesized
      to be cytoprotective. In the normal heart, abundant apoJ mRNA and protein are
      expressed in atrial myocytes; no expression is detected in ventricular myocytes.
      To provide clues about the role of apoJ in the heart, the response of apoJ to
      heart disease, including three models of myocarditis and two models of in vivo
      pressure overload hypertrophy, were examined. In the disease model studied
      extensively, myosin-induced myocarditis, in situ hybridization detected induction
      of apoJ mRNA in ventricular myocytes immediately before histological evidence of
      injury. ApoJ message in ventricular myocytes reached high levels as myocarditis
      became more severe. Evidence of early apoJ induction, before inflammation and
      injury, also occurred in viral myocarditis. ApoJ mRNA was not present in the
      inflammatory or interstitial cells during myocarditis. In areas of severe
      inflammation and myocardial fiber degeneration, apoJ showed a gradient of
      expression, with highest levels in myocytes immediately surrounding the lesion
      and diminishing with increasing distance. ApoJ protein also accumulated in
      myocytes at the interface between degenerated myocardial tissue and the
      surrounding cardiac tissue. During cardiac hypertrophy that occurred without
      associated inflammation or cell damage, ventricular apoJ mRNA was not detected.
      When ischemic damage accompanied hypertrophy, apoJ was induced in the ventricular
      myocytes near the lesion borders. The correlation of apoJ induction with
      ventricular tissue damage, but not hypertrophy, suggests that apoJ is a repair
      response protein. We propose that apoJ functions to limit tissue injury and/or
      promote tissue remodeling.

PMID- 8669483
TI  - Expression of very low density lipoprotein receptor in the vascular wall.
      Analysis of human tissues by in situ hybridization and immunohistochemistry.
AB  - The recently cloned very low density lipoprotein (VLDL) receptor binds
      triglyceride-rich, apolipoprotein-E-containing lipoproteins with high affinity.
      The observation that VLDL receptor mRNA is abundantly expressed in extracts of
      tissues such as skeletal muscle and heart, but not liver, has led to the
      hypothesis that this receptor may facilitate the peripheral uptake of
      triglyceride-rich lipoproteins. However, little information is available
      concerning the types of cells that express this receptor in vivo. As expression
      of the VLDL receptor in the vascular wall might have important implications for
      the uptake and transport of triglyceride-rich lipoproteins, and perhaps
      facilitate the development of atherosclerosis in hypertriglyceridemic
      individuals, we used in situ hybridization and immunohistochemistry to determine
      whether VLDL receptor mRNA and protein was expressed in human vascular tissue. We
      observed expression of the receptor by both endothelial and smooth muscle cells
      within normal arteries and veins, as well as within atherosclerotic plaques. In
      the latter, the VLDL receptor was also expressed by macrophage-derived foam
      cells. The widespread distribution of the VLDL receptor in vascular tissue
      suggests a potentially important role for this receptor in normal and
      pathophysiological vascular processes.

PMID- 8669484
TI  - Expression and cytokine regulation of glucocorticoid receptors in Kaposi's
      sarcoma.
AB  - Development of Kaposi's sarcoma (KS) after glucocorticoid therapy has been
      observed in a variety of clinical states including human immunodeficiency virus-1
      infection and recent in vitro studies provided evidence for a direct stimulation
      effect of glucocorticoid hormones on KS cell proliferation. The importance of
      glucocorticoids in KS pathogenesis is further highlighted by the finding that
      glucocorticoids synergize with cytokines to promote acquired immune deficiency
      syndrome (AIDS)-associated KS (AIDS-KS) growth. Furthermore, cytokine effects
      were abrogated by the glucocorticoid antagonist RU-486. As glucocorticoid action
      is mediated through activation of their intracellular cognate receptors, we
      hypothesized that enhanced responsiveness of AIDS-KS cells to glucocorticoids may
      be due to elevated glucocorticoid receptor (GR) content. Indeed, high expression
      of GRs in AIDS-KS tumor biopsies was detected both at the level of mRNA and
      protein. Quantitative measurements of GRs in these specimens by a sensitive
      immunoassay showed that GR content was significantly elevated in the tumor tissue
      (4663 fmol/mg protein) compared with the uninvolved skin of the same patients
      (2777 fmol/mg protein), both of which were markedly above the normal skin of
      healthy donors (893 fmol/mg protein). Immunocytochemical analysis confirmed the
      presence of GRs in the cytoplasm and the nucleus of KS cells. Interestingly, four
      major KS cytokines, namely interleukin-1beta, interleukin-6, tumor necrosis
      factor-alpha, and oncostatin M, all of which are known autocrine growth factors
      for AIDS-KS cells, significantly increased the expression of functional GRs in
      cultured AIDS-KS cells. The latter result may explain, at least in part, the
      synergistic effect of glucocorticoid and oncostatin M on AIDS-KS cell
      proliferation. Thus, the high levels of GR expression in AIDS-KS and the up
      regulation of GRs by KS-growth-promoting factors may confer enhanced and
      sustained sensitivity to the stimulatory effects of glucocorticoids. The data
      presented also provide molecular bases for therapeutic interventions targeting
      GRs in this disease.

PMID- 8669485
TI  - Human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) DNA in Kaposi's
      sarcoma lesions, AIDS Kaposi's sarcoma cell lines, endothelial Kaposi's sarcoma
      simulators, and the skin of immunosuppressed patients.
AB  - We used the polymerase chain reaction on 63 tissue specimens of histologically
      staged classic Kaposi's sarcoma (KS) from 40 patients, 14 specimens from 14
      acquired immune deficiency syndrome (AIDS)-KS cases (all from the same geographic
      area over a 10-year period), and peripheral blood mononuclear cells from 1 of the
      non-AIDS KS patients to amplify a specific 210-bp genomic sequence of the newly
      discovered KS-associated herpesvirus (KSHV). Also tested were 86 benign and
      malignant endothelial lesions, which potentially simulated each KS histological
      stage and were further matched by age approximation and by sex with a classical
      KS specimen. The lesions included hemangioma, lymphangioma, pyogenic granuloma,
      and angiosarcoma. KSHV was also sought in multiple well characterized vascular
      endothelial cell lines from AIDS-KS lesions and in 20 mainly cutaneous benign and
      malignant lesions from 15 immunosuppressed transplant patients. Overall, 92% of
      KS tissue specimens, representing 88% of classical KS and 100% of AIDS-KS
      patients, and in addition the sample of peripheral blood mononuclear cell DNA,
      were positive as visualized on ethidium bromide gels and confirmed by Southern
      blot hybridization (only 1 case was negative on gell visualization but positive
      on Southern blot), thus confirming the close association of KSHV with KS of
      different clinical forms. None of the various other endothelial lesion, skin
      lesions in immunosuppressed patients, or AIDS-KS endothelial cell lines contained
      amplifiable KSHV DNA, which indicates that reactivation of KSHV is not present in
      the skin lesions of immunosuppressed patients and probably is not a ubiquitous
      agent that secondarily infects proliferative endothelium. The absence of
      amplifiable virus DNA in the cultured endothelium of KS suggests that the
      stimulus for angioproliferation originates in another host cell or under
      conditions not reproduced in culture. The polymerase chain reaction is a specific
      and sensitive means of verifying KS in the differential diagnosis of
      angioproliferative lessons.

PMID- 8669486
TI  - Molecular characterization of primary mediastinal B cell lymphoma.
AB  - Primary mediastinal B cell lymphoma (PMBL) is a diffuse large B cell lymphoma
      (DLCL) postulated to arise from noncirculating thymic B lymphocytes. Because of
      its distinctive clinical and morphological features and putative unique cellular
      origin, PMBL is generally considered a distinct clinicopathological entity.
      Little is known, however, about the molecular characteristics of PMBL. Therefore,
      we analyzed 16 PMBLs for molecular alterations involving the bcl-1, bcl-2, bcl-6,
      c-myc, H-ras, K-ras, N-ras, and p53 genes and for Epstein-Barr virus infection,
      which are commonly involved in lymphoid neoplasia. Employing a combination of
      Southern blotting and/or polymerase chain reaction and single-strand conformation
      polymorphism assays, we detected genetic alterations in 7 of the 16 (44%) PMBLs.
      Whereas the bcl-6 gene is rearranged in up to 45% of DLCLs, rearrangement of the
      bcl-6 gene was detected in only 1 of these 16 (6%) PMBLS. Point mutations of the
      5' noncoding region of the c-myc gene were demonstrated in 3 other cases (19%),
      although c-myc gene rearrangements were not seen by Southern blotting. Missense
      point mutations of the p53 gene were identified in 3 additional PMBLs (19%).
      Alterations of the bcl-1, bcl-2, or ras genes and evidence of Epstein-Barr virus
      infection were not observed. In conclusion, a variety of molecular lesions occur
      in PMBLs and may be involved in their pathogenesis. This molecular genetic
      pattern bears little resemblance to that known for other B cell malignancies,
      including DLCL. In particular, the infrequent occurrence of bcl-6 gene
      rearrangement in PMBLs distinguishes them from other DLCLs of B cell origin,
      suggesting that PMBLs do not represent a distinct subtype of DLCL.

PMID- 8669487
TI  - Studies on fenestral contraction in rat liver endothelial cells in culture.
AB  - Liver endothelial cells possess fenestrae, which are pores supported by a
      cytoskeleton ring composed of actin and myosin. Fenestrae are dynamic structures
      that can contract or dilate, although the mechanism for this phenomenon remains
      to be elucidated. Staining of actin and/or of myosin permitted measurement of
      fenestral diameter and area in cultured rat liver endothelial cells using
      digitized video-intensified fluorescence microscopy with image analysis. Within 1
      minute of incubation with 0.1 micromol/L serotonin, fenestral diameter and area
      decreased by 24 +/- 5% and 56 +/- 7%, respectively. Contraction of fenestrae by
      serotonin was inhibited by chelation of extracellular Ca2+ with EGTA and by
      addition of Ca2+ channel blockers, such as dilthiazem and verapamil. The response
      of fenestrae to serotonin was mimicked by addition of a Ca2+ ionophore, A23187.
      Serotonin inhibited cAMP production, had no effect on inositol phosphate
      production, and activated phospholipase A2, causing release of arachidonic acid.
      These results suggest that contraction of fenestrae is associated with Ca2+
      influx. In response to 0.1 micromol/serotonin, intracellular Ca2+ levels
      increased within 3 to 5 seconds from 150 nmol/L to >400 nmol/l followed by rapid
      phosphorylation of the 20-kd subunit of myosin light chain; both events dependent
      on extracellular Ca2+.

PMID- 8669488
TI  - Ontogeny and immunohistochemical localization of thymus-dependent and thymus
      independent RT6+ cells in the rat.
AB  - RT6 is a cell surface alloantigen that identifies a regulatory subset of
      peripheral T cells in the rat. Diabetes-prone BB rats are deficient in peripheral
      RT6+ T cells and develop spontaneous autoimmune insulin-dependent diabetes
      mellitus. Diabetes-resistant BB rats have normal numbers of RT6+ T cells, and
      insulin-dependent diabetes mellitus can be induced in these animals by in vivo
      depletion of peripheral RT6+ cells. Athymic rats are also severely deficient in
      peripheral RT6+ T cells. Although very different with respect to the peripheral
      RT6+ cell compartment, normal, athymic, and diabetes-prone BB rats all generate
      RT6+ intestinal epithelial lymphocytes (IELs). The goal of these studies was to
      analyze the ontogeny of RT6+ IELs and peripheral lymphoid cells by in situ
      immunohistochemistry. We observed the following. 1) RT6+ IELs appear before
      alpha(beta) T-cell-receptor- expressing IELs in diabetes-prone BB, diabetes
      resistant BB, and athymic WAG rats. 2) In vivo depletion of peripheral RT6+ T
      cells in diabetes-resistant BB rats using a cytotoxic monoclonal antibody is not
      accompanied by depletion of RT6+ IELs. 3) A population of RT6+ T-cell-receptor
      negative IELs is present in normal, euthymic diabetes-resistant BB rats,
      constitutes a larger percentage of the euthymic but lymphopenic diabetes-prone BB
      rat IEL population, and is the predominant IEL phenotype in athymic WAG rats.
      These results suggest that RT6+ cells are composed of both thymus-dependent and
      thymus-independent cell subsets that have different developmental characteristics
      and may differ in function.

PMID- 8669489
TI  - Pancreastatin secretion by pituitary adenomas and regulation of chromogranin B
      mRNA expression.
AB  - Pancreastatin, a carboxyl-terminal amidated peptide derived from chromogranin
      (Cg)A, inhibits secretion of insulin and parathyroid hormone. Our recent studies
      found significant amounts of immunoreactive pancreastatin in all pituitary
      adenomas except prolactin adenomas. To analyze the effects of pancreastatin on
      pituitary cell function, 17 cultured pituitary adenomas were examined for
      immunoreactive pancreastatin and pancreastatin secretion by the tumors. The
      effects of pancreastatin on pituitary hormone secretion and on pituitary hormone
      (follicle-stimulating hormone and prolactin), CgA, and CgB mRNA levels were also
      examined. Immunoreactive pancreastatin and CgA were present diffusely in
      gonadotroph and null cell adenomas, but only a few prolactin adenoma cells
      expressed pancreastatin or CgA. When cells were treated with hypothalamic
      peptides, gonadotroph adenomas were the only group that released increased
      amounts of pancreastatin in response to gonadotropin-releasing hormone (10(-7)
      mol/L). Pancreastatin (10(-7) mol/L) treatment did not stimulate pituitary
      hormone secretion significantly. In situ hybridization analyses showed that
      gonadotropin-releasing hormone and pancreastatin treatment led to significant
      increases in CgB and follicle-stimulating hormone mRNAs in gonadotroph adenomas,
      whereas CgA mRNA levels did not change significantly. These results show that
      there is a differential distribution of pancreastatin secretion in pituitary
      adenomas and that the hypothalamic hormone gonadotropin-releasing hormone and the
      CgA-derived peptide pancreastatin can regulate CgB mRNA in gonadotroph adenomas,
      suggesting an autocrine effect of pancreastatin on pituitary tumor function.

PMID- 8669490
TI  - Microsatellite instability in preinvasive and invasive head and neck squamous
      carcinoma.
AB  - To investigate the extent and significance of microsatellite instability in head
      and neck carcinogenesis we analyzed DNA extracted from normal squamous
      epithelium, severe dysplasia, and corresponding carcinoma specimens from 20
      patients by multiplex polymerase chain reaction. Loci on chromosomes 3p, 5p, 5q,
      8p, 9p, 9q, 11q, 17p, 17q, 18p, 18q were selected for analysis. Our results show
      that three of the dysplasias (15.0%) and six of the invasive carcinoma (30.0%)
      manifested instability at multiple loci. Two of the dysplastic lesions had
      identical alterations in the corresponding carcinomas and one showed instability
      differences in only two of eight loci. Normal squamous epithelium lacked
      microsatellite instability. No apparent association between smoking, alcohol use,
      or family history of cancer and instability was found in this small cohort.
      Invasive carcinomas with instability were relatively more poorly differentiated
      and had a higher stage and a high proliferative fraction. Our study indicates
      that microsatellite instability is 1) noted in a small subset of dysplastic
      lesions of head and neck squamous epithelium and 2) present in approximately one
      third of invasive lesions, usually with aggressive characteristics, and may
      clinically be a late event associated with tumor progression.

PMID- 8669491
TI  - Expression of topoisomerase IIalpha is associated with rapid cell proliferation,
      aneuploidy, and c-erbB2 overexpression in breast cancer.
AB  - The role of molecular markers predicting the response to cytotoxic chemotherapy
      is not established. A potential predictive factor, topoisomerase IIalpha, is a
      target for certain cytotoxic drugs, and its concentration has been shown to
      correlate with chemosensitivity in vitro. We evaluated expression of topo IIalpha
      immunohistochemically in 230 breast cancer samples and studied its association
      with known clinicopathological factors and factors previously shown to predict
      response to cytotoxic drugs. Topo IIalpha protein expression was found in 0.6 to
      39.4% (10.6 +/- 7.9%, mean +/- SD) of breast carcinoma cells, whereas expression
      was undetectable in nonmalignant breast epithelium. Topo IIalpha protein
      expression correlated well with semi-quantitative mRNA in situ hybridization (P =
      0.007). A significant association was found between the proportion of topo
      IIalpha-positive cells and low estrogen and progesterone receptor content
      (P<0.0001), high grade (P<0.0001), DNA aneuploidy (P=0.003), and c-erbB-2
      oncoprotein overexpression (P<0.0001). Topo IIalpha expression was not associated
      with clinical variables, such as age of the patient, primary tumor size, or
      axillary nodal status. A highly significant linear correlation was found between
      topo IIalpha and tumor proliferation rate (S-phase fraction, r=0.46; P<0.0001).
      Because hormone receptors, grade, and ploidy are associated with tumor
      proliferation rate, topo IIalpha expression was adjusted for S-phase fraction to
      reveal the proliferation-independent clinopathological associations. According to
      the analysis of co-variance, only aneuploidy (P=0.0003) and c-erb-2
      overexpression (P=0.01) were associated with proliferation-adjusted expression of
      topo IIalpha. In conclusion, the close association of Topo IIalpha with other
      potential predictive factors (tumor proliferation rate, c-erbB-2 oncoprotein)
      suggests that topo IIalpha, having a defined role as a target for cytotoxic
      drugs, may be a valuable predictor of response to chemotherapy.

PMID- 8669493
TI  - Addictive sexual behavior.
AB  - A rationale for the conceptualization of repetitive sexual behaviors as an
      addiction is presented. Five cases treated by individual psychotherapy are
      described and certain problems inherent in such treatments are delineated. Other
      treatment approaches, such as those involving the use of medication, twelve-step
      groups and cognitive-behavioral techniques are also detailed.

PMID- 8669492
TI  - Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and
      cerebrovascular pathology associated with Alzheimer's disease.
AB  - The presence of apolipoprotein E-epsilon4 (APOE-epsilon4) allele has been
      implicated as a risk factor for Alzheimer's disease (AD). We examined the
      frequencies of APOE-epsilon4 alleles in age-matched controls and subgroups of 190
      AD subjects exhibited cerebral amyloid angiopathy (CAA) and other frequently
      associated lesions. CAA was evident in 96% of the AD subjects, which were divided
      into two groups, one bearing mild or no apparent CAA and the other with moderate
      to severe CAA. APOE-epsilon4 allele frequency (48%) in the latter advanced CAA
      group was six times higher than in those who exhibited mild CAA. In the advanced
      CAA subjects, the occurrence of an epsilon4 allele was increased by a factor of
      17 (95% confidence interval, 7.56 to 38.9). This was despite the fact that
      neocortical amyloid-beta plaque densities in the two groups were similar and that
      all of the AD subjects had met the accepted neuropathological criteria. We also
      observed that the degree of CAA severity was greatest in the group of subjects
      with the epsilon4/epsilon4 genotype. The association between CAA and APOE
      epsilon4 was further implicated in two non-AD subjects among neurological
      controls with severe CAA. These two subjects, both homozygous for the APOE
      epsilon4 allele, were primarily diagnosed as having Creutzfeldt-Jakob disease and
      Pick's disease in the absence of significant neocortical amyloid deposition.
      Allele frequency comparisons between neurological control subjects with CAA and
      those without likewise accorded a strong relationship between the APOE-epsilon4
      allele and the presence of CAA. More remarkably, the epsilon4 allele frequency
      was highly associated with AD subjects exhibiting lobar or intracerebral
      hemorrhage, all of whom had advanced CAA. We observed that 36% of the AD subjects
      had concomitant cerebrovascular pathology resulting from single infarcts,
      multiple microinfarcts, ischemic white matter lesions, or petechial hemorrhages.
      Although the difference in APOE genotype distribution between subjects with and
      without cerebrovascular lesions did not reach statistical significance, we did
      note that the frequency of the epsilon4 allele was significantly higher in
      subjects with such pathology as compared with those without. However, we found no
      evidence to suggest that the acquisition of an APOE-epsilon4 allele or one of the
      alleles, epsilon2 or epsilon3, was a factor in the occurrence of atherosclerosis
      localized in the basal surface arteries. Analyses of our sample also confirm that
      there was a lower frequency of the APOE-epsilon2 allele in AD subjects and that
      the frequency of the epsilon4 allele in AD subjects with concomitant diffuse Lewy
      body disease was intermediate between controls and AD subjects. Our results
      suggest that the APOE-epsilon4 allele is a significant factor in the development
      of CAA in AD and reveal the possibility that APOE is an independent factor in CAA
      and other vascular abnormalities associated with AD.

PMID- 8669494
TI  - Transtheoretical practice of psychotherapy.
AB  - A developmental model forms the framework for the transtheoretical practice of
      psychotherapy. Major preoedipal and oedipal events, interfaced with significant
      two-person (mother-child) and three-person (father-mother-child) influences-
      dyadic deficit, dyadic conflict, triadic deficit, triadic conflict--are
      instrumental in the formation of different relationship patterns in treatment
      that transcend classical versus selfobject transferences. Therapeutic as well as
      countertherapeutic stances and strategies are elucidated.

PMID- 8669495
TI  - The "erotic transference": some technical and countertransferential difficulties.
AB  - This paper highlights dynamics that may interfere with the therapist's
      identifying and addressing the erotic transference: (1) deficient training; (2)
      theoretical orientations that devalue the transference while espousing a "real"
      relationship including self-disclosure; (3) countertransference responses to the
      erotic transference; and (4) clinical errors of focusing on the manifest erotic
      transference while overlooking significant but latent pre-oedipal, oedipal,
      aggressive, or selfobject issues. Inattention to these dynamics may render the
      therapist vulnerable to sexual acting out with his patient.

PMID- 8669496
TI  - Understanding and differentiating clients' positive feelings in psychotherapy.
AB  - The positive feelings patients experience towards their therapists have important
      diagnostic and treatment considerations. This article reviews and integrates the
      literature on the therapeutic alliance, the positive transference, and the
      idealizing transference. Examples are provided to help clinicians understand and
      differentiate their patients' positive feelings.

PMID- 8669497
TI  - Reinventing the mother-daughter relationship.
AB  - Theories on mother-daughter relationships have long been one-sided and
      biologically biased. The resulting images put the mental and physical health of
      mothers and daughters at risk. This article examines the mothers' perspective,
      and highlights the mutuality and dynamics in the mother-daughter relationship.
      New perspectives for therapeutic activities are opened up.

PMID- 8669498
TI  - Ideological singularity as a defense against clinical complexity.
AB  - Despite the existence of several theories in psychiatry, strict adherence to one
      is common. Sources of singularity include education, training, and the highly
      separate development of the theories. However, a deeper source may be the
      inherent uncertainty of psychiatric symptoms and research. Singularity may
      contribute to patient confusion and public stigma.

PMID- 8669499
TI  - Acting out and the narrative function: reconsidering Peter Blos's concept of the
      second individuation process.
AB  - The role and meaning of narratives in psychoanalytically oriented psychotherapy
      has begun to be explored over the past few years. Little, if any, of this
      material has been related to adolescent psychotherapy and it is the purpose of
      this paper to make some preliminary inquiries into how narratives might operate
      in this sphere. To explore this hypothesis, Peter Blos's ideas on adolescent
      acting out are related to a theory of narrative developed by the French
      philosopher Paul Ricoeur. Blos conceives of adolescent acting out as a part of
      attempts by adolescents to develop a coherent identity in what he refers to as a
      second individuation process. A link is proposed between adolescent acting out
      and Ricoeur's notion of narrative as the structure that undergirds the process of
      identity formation.

PMID- 8669500
TI  - Meeting managed care: An identity and value crisis for therapists.
AB  - The micromanagement of the psychotherapy enterprise by private insurance
      interests has placed clinicians in new and unfamiliar roles in relation to their
      patients and to the professional marketplace. The value systems compatible with
      most managed care organizations are divergent from those held by an earlier
      generation of mental health professionals.

PMID- 8669501
TI  - Psychotherapy supervision in the 1990s: some observations and reflections.
AB  - This paper identifies and discusses 10 broad-based themes or conclusions that
      could be drawn about the field of psychotherapy supervision now. These
      conclusions focus on various facets of clinical supervision theory, research, and
      practice; in so doing, they bring to light current supervision issues, problems,
      advances, and needs that seemingly merit our attention and consideration.

PMID- 8669502
TI  - Socioeconomic status and weight control practices among 20- to 45-year-old women.
AB  - OBJECTIVES: This study examined the relationship between socioeconomic status
      (SES) and weight control practices in women. METHODS: SES, defined by family
      income, was examined in an economically diverse sample of 998 women in relation
      to dieting practices by means of multivariate regression analyses controlling for
      age, ethnicity, smoking, and body mass index. RESULTS: SES was positively
      associated with healthy, but not unhealthy, weight control practices; inversely
      related to energy and fat intake; and positively associated with weight concern
      and perceived social support for healthy eating and exercise. SES gradients were
      particularly striking at the low end of the income distribution (i.e., family
      income < or = $10,000 per year). The SES gradient in body mass index persisted in
      analyses controlling for attitudes and behaviors. CONCLUSIONS: Economic
      deprivation may contribute to high rates of obesity among lower SES women. The
      reasons for this require further research.

PMID- 8669503
TI  - The regionalization of perinatal care in Wales and Washington State.
AB  - OBJECTIVES: The purpose of this study was to compare perinatal regionalization
      and neonatal mortality in Wales and Washington State. METHODS: The 28 hospitals
      in Wales and the 80 hospitals in Washington State that offered maternity services
      and the 218,326 births that occurred in these hospitals in 1989 and 1990 were
      studied. Surveys were used to identify the neonatal technology and the referral
      policies of each hospital, and linked data from birth and death certificates were
      used to examine birthweight-specific neonatal mortality rates for all babies born
      in these hospitals. RESULTS: Welsh district general hospitals (broadly equivalent
      to Level II perinatal centers in the United States) have more sophisticated
      neonatal technology than their Washington State counterparts and appear less
      likely to refer small or preterm babies to regional or subregional centers.
      Neonatal mortality rates were quite similar in the two settings. CONCLUSIONS:
      Perinatal care in Wales appears to be less regionalized than in a similar region
      in the United States. The relative lack of perinatal regionalization in Wales may
      contribute to duplication and underutilization of expensive neonatal
      technologies. National health care systems do not, in and of themselves, lead to
      optimal regionalization of services.

PMID- 8669504
TI  - Mammography use among sociodemographically diverse women: the accuracy of self
      report.
AB  - OBJECTIVE: This study sought to determine the accuracy of self-report of
      mammography experience among 392 ethnically diverse women aged 50 to 74. METHODS:
      Subjects were randomized to the telephone or mail condition and surveyed.
      RESULTS: Thirty-one percent of women reported accurately the exact month and year
      of their most recent mammogram; 54% reported accurately within +/- 3 months, and
      83% reported accurately within the year. Greater accuracy was associated with
      exam recency, White race, and non-Hispanic ethnicity, but not with age,
      education, or income. Most women could correctly report the reason for, the
      findings of, and the payor of their mammograms but knew little about how much
      they or their insurance paid. CONCLUSIONS: For population surveillance of
      mammography in the past year, self-report data are generally valid. However,
      clinical studies requiring more precise dates must use such data with caution.
      The telephone method, as compared with mail, appears to be a better option for
      some variables.

PMID- 8669505
TI  - High-density-lipoprotein cholesterol and types of alcoholic beverages consumed
      among men and women.
AB  - OBJECTIVES: Differences by sex in the relationship between high-density
      lipoprotein (HDL) cholesterol and consumption of alcoholic beverages were
      examined in 1516 individuals. METHODS: Questionnaires and blood-sample data from
      cross-sectional surveys were analyzed. RESULTS: Both beer and liquor were
      independently associated with increased HDL cholesterol in the total group, in
      men, and in women after covariates were controlled for. Wine was associated with
      a significant increase in HDL cholesterol in women only. CONCLUSIONS: Among women
      and men, amount may be more important than type of alcoholic beverage consumed.
      The independent effect of wine on HDL cholesterol among men remains unclear since
      few men in this population consumed wine exclusively or in large quantities.

PMID- 8669507
TI  - The future of epidemiology: a humanist response.

PMID- 8669506
TI  - Can conflict resolution training increase aggressive behavior in young
      adolescents?

PMID- 8669508
TI  - Nonconsensual participation in genetic studies.

PMID- 8669509
TI  - The population "wolf" and demographic entrapment in Rwanda.

PMID- 8669510
TI  - Ambient carbon monoxide and hospitalizations for heart failure: earlier findings.

PMID- 8669511
TI  - From alcohol and breast cancer to beef and BSE--improving our communication of
      risk.

PMID- 8669512
TI  - Community solutions to community problems--preventing adolescent alcohol use.

PMID- 8669513
TI  - Understanding and treating obesity.

PMID- 8669514
TI  - Topics for our times: can we learn from the care of persons with mental illness
      in developing countries?

PMID- 8669515
TI  - Hospitalizations for injury in New Zealand: prior injury as a risk factor for
      assaultive injury.
AB  - OBJECTIVES: This study sought to determine the degree to which injury
      hospitalization, especially for assaultive injury, is a risk for subsequent
      hospitalization due to assault. METHODS: A New Zealand hospitalization database
      was used to perform a retrospective cohort study. Exposure was defined as an
      injury hospitalization, stratified into assaultive and nonassaultive mechanisms.
      Hospitalizations for an assault during a 12-month follow-up period were measured.
      RESULTS: Individuals with a prior nonassaultive injury were 3.2 times more likely
      to be admitted for an assault than those with no injury admission (95% confidence
      interval [CI] = 2.7, 3.9). The relative risk associated with a prior assault was
      39.5 (95% CI = 35.8, 43.5), and the subsequent admission rate did not vary
      significantly by sex, race, or marital or employment status. Among those
      readmitted for an assault, 70% were readmitted within 30 days of the initial
      hospitalization. CONCLUSIONS: Prior injury is a risk for serious assault, and the
      risk is even greater if the injury is due to assault. Risk of readmission for
      assault is largely independent of demographic factors and greatest within 30 days
      of the initial assault.

PMID- 8669516
TI  - Preventing diabetic foot disease: lessons from the Medicare therapeutic shoe
      demonstration.
AB  - OBJECTIVES: Every year about 38,000 elderly people with diabetes have a lower
      extremity amputation. Therapeutic shoes are prescribed by clinicians specializing
      in foot care to prevent foot ulcerations and amputations among at-risk patients
      with diabetes. Medicare ran a 3-year demonstration of a therapeutic-shoe benefit
      for beneficiaries with diabetes. Medicare added the benefit nationwide in May
      1993. METHODS: This paper describes the benefit and its implementation in the
      demonstration based on demonstration records, a patient survey, and discussions
      with clinicians and shoe suppliers before and during the demonstration. RESULTS:
      During the demonstration, far fewer beneficiaries applied for the therapeutic
      shoes than were eligible for them. The paper discusses reasons for the low
      beneficiary application rate and the associated low participation rate among
      physicians treating patients with diabetes. CONCLUSIONS: The benefit is unlikely
      to be used any more in the national program than in the demonstration unless
      physicians are educated in the role therapeutic shoes can play in diabetic foot
      disease, they prescribe the shoes for their patients, and they increase their
      patients' awareness of the shoes' value.

PMID- 8669517
TI  - Work site-based cancer prevention: primary results from the Working Well Trial.
AB  - OBJECTIVES: This paper presents the behavioral results of the Working Well Trial,
      the largest US work site cancer prevention and control trial to date. METHODS:
      The Working Well Trial used a randomized, matched-pair evaluation design, with
      the work site as the unit of assignment and analysis. The study was conducted in
      111 work sites (n = 28,000 workers). The effects of the intervention were
      evaluated by comparing changes in intervention and control work sites, as
      measured in cross-sectional surveys at baseline and follow-up. The 2-year
      intervention targeted both individuals and the work-site environment. RESULTS:
      There occurred a net reduction in the percentage of energy obtained from fat
      consumption of 0.37 percentage points (P = .033), a net increase in fiber
      densities of 0.13 g/1000 kcal (P = .056), and an average increase in fruit and
      vegetable intake of 0.18 servings per day (P = .0001). Changes in tobacco use
      were in the desired direction but were not significant. CONCLUSIONS: Significant
      but small differences were observed for nutrition. Positive trends, but no
      significant results, were observed in trial-wide smoking outcomes. The observed
      net differences were small owing to the substantial secular changes in target
      behaviors.

PMID- 8669518
TI  - A cross-national trial of brief interventions with heavy drinkers. WHO Brief
      Intervention Study Group.
AB  - OBJECTIVES: The relative effects of simple advice and brief counseling were
      evaluated with heavy drinkers identified in primary care and other health
      settings in eight countries. METHODS: Subjects (1260 men, 299 women) with no
      prior history of alcohol dependence were selected if they consumed alcohol with
      sufficient frequency or intensity to be considered at risk of alcohol-related
      problems. Subjects were randomly assigned to a control group, a simple advice
      group, or a group receiving brief counseling. Seventy-five percent of subjects
      were evaluated 9 months later. RESULTS: Male patients exposed to the
      interventions reported approximately 17% lower average daily alcohol consumption
      than those in the control group. Reductions in the intensity of drinking were
      approximately 10%. For women, significant reductions were observed in both the
      control and the intervention groups. Five minutes of simple advice were as
      effective as 20 minutes of brief counseling. CONCLUSIONS: Brief interventions are
      consistently robust across health care settings and sociocultural groups and can
      make a significant contribution to the secondary prevention of alcohol-related
      problems if they are widely used in primary care.

PMID- 8669519
TI  - Project Northland: outcomes of a communitywide alcohol use prevention program
      during early adolescence.
AB  - OBJECTIVES: Project Northland is an efficacy trial with the goal of preventing or
      reducing alcohol use among young adolescents by using a multilevel, communitywide
      approach. METHODS: Conducted in 24 school districts and adjacent communities in
      northeastern Minnesota since 1991, the intervention targets the class of 1998
      (sixth-grade students in 1991) and has been implemented for 3 school years (1991
      to 1994). The intervention consists of social-behavioral curricula in schools,
      peer leadership, parental involvement/education, and communitywide task force
      activities. Annual surveys of the class of 1998 measure alcohol use, tobacco use,
      and psychosocial factors. RESULTS: At the end of 3 years, students in the
      intervention school districts report less onset and prevalence of alcohol use
      than students in the reference districts. The differences were particularly
      notable among those who were nonusers at baseline. CONCLUSIONS: The results of
      Project Northland suggest that multilevel, targeted prevention programs for young
      adolescents are effective in reducing alcohol use.

PMID- 8669520
TI  - Recovery from alcohol problems with and without treatment: prevalence in two
      population surveys.
AB  - OBJECTIVES: The purpose of this study was to determine the prevalence of recovery
      from alcohol problems with and without treatment, including whether such
      recoveries involved abstinence or moderate drinking. METHODS: Data from two
      surveys of randomly selected adults in the general population were analyzed.
      Random-digit dialing was used to conduct telephone interviews with 11,634 and
      1034 respondents. Respondents 20 years of age or older were categorized on the
      basis of drinking status and history. RESULTS: Both surveys found that most
      individuals (77.5% and 77.7%) who had recovered from an alcohol problem for 1
      year or more did so without help or treatment. A sizable percentage (38% and 63%)
      also reported drinking moderately after resolving their problem. CONCLUSIONS:
      These two surveys are among the first to report prevalence rates for recovery
      from alcohol problems for treated and untreated individuals and for moderation
      and abstinence outcomes.

PMID- 8669521
TI  - Persons with dual diagnoses of substance abuse and major mental illness: their
      excess costs of psychiatric care.
AB  - OBJECTIVES: This study examined the costs of psychiatric treatment for seriously
      mentally ill people with comorbid substance abuse as compared with mentally ill
      people not abusing substances. METHODS: Three different sources of data were used
      to construct client-level files to compare the patterns of care and expenditures
      of 16,395 psychiatrically disabled Medicaid beneficiaries with and without
      substance abuse: Massachusetts Medicaid paid claims; Department of Mental Health
      state hospital inpatient record files; and community support service client
      tracking files. RESULTS: Psychiatrically disabled substance abusers had
      psychiatric treatment costs that were almost 60% higher than those of nonabusers.
      Most of the cost difference was the result of more acute psychiatric inpatient
      treatment. CONCLUSIONS: Although the public health and financial costs of high
      rates of comorbidity are obvious, the solutions to these problems are not.
      Numerous bureaucratic and social obstacles must be overcome before programs for
      those with dual diagnoses can be tested for clinical effectiveness.

PMID- 8669522
TI  - Alcohol consumption among the elderly in a general population, Erie County, New
      York.
AB  - OBJECTIVES: Relatively few studies of drinking among the elderly have been
      completed despite the growing proportional representation of the elderly in the
      US population. This study sought to estimate the prevalence of and to observe
      whether active or health-oriented lifestyles are associated with heavy drinking
      among the elderly. METHODS: Random-digit dialing telephone interviews were
      conducted with 2325 Erie County, New York, general population residents aged 60
      years or older. RESULTS: The prevalence of heavy drinking was 6%. Adjusted
      analyses showed positive associations between heavy drinking and being male,
      having suburban residency, and currently using cigarettes. Negative relationships
      were observed between heavy drinking and socioeconomic status, rural residency,
      and degree of health orientation. Age and level of active lifestyle were not
      significant contributors to the model. CONCLUSIONS: Of the studied variables,
      health orientation offers the greatest opportunity to address heavy drinking
      among the elderly.

PMID- 8669523
TI  - Are smokers with alcohol disorders less likely to quit?
AB  - OBJECTIVES: This study examined the likelihood of smoking cessation in smokers
      with a prior history of alcoholism. METHODS: Data came from an epidemiologic
      study of 1007 young adults, randomly selected from those insured in a large
      health maintenance organization (HMO) in southeast Michigan. Cox proportional
      hazards models with time-dependent covariates were used to estimate the hazards
      ratios of quitting in smokers with current and past alcoholism, with smokers with
      no history of alcoholism as a reference. Sex, race, and education were
      controlled. RESULTS: Smokers with active alcoholism in the preceding year were
      60% less likely to quit than were smokers with no history of alcoholism. In
      contrast, smokers whose alcoholism had remitted were at least as likely to quit
      as smokers with no history of alcoholism. Compared with persistent alcoholism,
      remission of alcoholism was associated with more than a threefold increase in the
      likelihood of subsequent smoking cessation. CONCLUSIONS: The findings suggest
      that discontinuation of alcoholism might increase the potential for successful
      smoking cessation.

PMID- 8669524
TI  - Violence and substance use among North Carolina pregnant women.
AB  - OBJECTIVES: Prenatal patients were studied to examine the proportion of women who
      had been violence victims, women's patterns of substance use (cigarettes,
      alcohol, and illegal drugs) before and during pregnancy, and relationships
      between violence and substance use. METHODS: More than 2000 prenatal patients in
      North Carolina were screened for violence and substance use. Relationships
      between violence and patterns of substance use before and during pregnancy were
      examined, as well as women's continuation of substance use during pregnancy as a
      function of violence and sociodemographic factors. RESULTS: Twenty-six percent of
      the women had been violence victims during their lives. Before pregnancy, 62% of
      the women had used one or more substances; during pregnancy, 31% had used one or
      more substances. Both before and during pregnancy, violence victims were
      significantly more likely to use multiple substances than nonvictims.
      Continuation of substance use during pregnancy was significantly more likely
      among violence victims than nonvictims. CONCLUSIONS: Care providers should screen
      women for violence as well as for substance use and should ensure that women are
      provided with appropriate interventions.

PMID- 8669525
TI  - Can physical activity minimize weight gain in women after smoking cessation?
AB  - OBJECTIVES: The purpose of this study was to examine prospectively whether
      exercise can modify weight gain after smoking cessation in women. METHODS: Data
      were analyzed from a 2-year follow-up period (1986-1988) in the Nurses' Health
      Study, an ongoing cohort of 121,700 US women aged 40 to 75 in 1986. RESULTS: The
      average weight gain over 2 years was 3.0 kg in the 1474 women who stopped
      smoking, and 0.6 kg among the 7832 women who continued smoking. Among women
      smoking 1 to 24 cigarettes per day, those who quit without changing their levels
      of exercise gained an average of 2.3 kg more (95% confidence interval [CI] = 1.9,
      2.6) than women who continued smoking. Women who quit and increased exercise by
      between 8 to 16 MET-hours (the work metabolic rate divided by the resting
      metabolic rate) per week gained 1.8 kg (95% CI = 1.0, 2.5), and the excess weight
      gain was only 1.3 kg (95% CI = 0.7, 1.9) in women who increased exercise by more
      than 16 MET-hours per week. CONCLUSIONS: Smoking cessation is associated with a
      net excess weight gain of about 2.4 kg in middle-aged women. However, this weight
      gain is minimized if smoking cessation is accompanied by a moderate increase in
      the level of physical activity.

PMID- 8669526
TI  - Smooth-muscle tumors of the vulva. A clinicopathological study of 25 cases and
      review of the literature.
AB  - The clinical and pathological features of 25 smooth-muscle tumors of the vulva
      were analyzed. The patients ranged in age from 17 to 67 (mean, 37.6) years; two
      were pregnant. Twenty-three tumors were 1.5 to 16 (mean, 5.2) cm in greatest
      dimension; the size of two tumors was unknown. Microscopic examination showed
      that 16 tumors were circumscribed, six had focally infiltrative margins, and the
      margins could not be evaluated in three tumors. Fourteen tumors were composed
      mainly of spindle cells; two of these tumors had prominent myxoid stroma. Seven
      tumors were predominantly epithelioid and had a prominent hyalinized or myxoid
      stroma; often the cells had a plexiform pattern. Four tumors contained an
      approximately equal number of epithelioid and spindle cells. Ten tumors had mild,
      nine moderate, and six severe cytologic atypia. Mitotic figures ranged from 0 to
      10 (average, 1.8) per 10 high-power fields (hpf). Immunohistochemically, all the
      tumors stained for one or more muscle markers. Thirteen of 17 tumors were
      positive for estrogen receptors, and 16 of 18 were positive for progesterone
      receptors. Follow-up information ranging from 1 month to 19 years (average, 5
      years) was available in 19 cases. Four tumors recurred locally, and one patient
      with recurrent tumor died of metastases 7 months after the initial operation. We
      propose an expanded criteria to distinguish between leiomyomas and
      leiomyosarcomas of the vulva. Tumors that manifest three or all of the four
      following features should be considered sarcomas: > or = 5 cm in greatest
      dimension, infiltrative margins, > or = 5 mitotic figures per 10 hpf, and
      moderate to severe cytologic atypia. Those that have only one of these
      characteristics should be diagnosed as leiomyoma, and those that exhibit only two
      of these features should be considered benign but atypical leiomyomas. The
      sarcomas should be excised with widely negative margins; the leiomyomas and the
      atypical leiomyomas should be excised conservatively, with long-term, careful
      follow-up.

PMID- 8669527
TI  - Bronchiolitis obliterans-organizing pneumonia (BOOP)-like variant of Wegener's
      granulomatosis. A clinicopathologic study of 16 cases.
AB  - The classic histologic features of Wegener's granulomatosis (WG) in lung include
      necrotizing granulomatous inflammation and necrotizing vasculitis. Recently,
      several histologic variants have been recognized, including cases characterized
      by bronchocentric inflammation, a marked eosinophil infiltrate, alveolar
      hemorrhage, and capillaritis or interstitial fibrosis. We report 16 cases of
      another variant in which bronchiolitis obliterans-organizing pneumonia (BOOP)
      like fibrosis represents the main histologic finding. The extensive geographic
      necrosis characteristic of Wegener's granulomatosis was absent in all cases,
      although small suppurative granulomas, minute foci of bland necrosis, and
      microabscesses were common. All cases showed the typical necrotizing vasculitis
      of Wegener's granulomatosis. Other frequent findings included darkly staining
      multinucleated giant cells, prominent acute inflammation, aggregates of
      epithelioid histiocytes, hemosiderin-filled macrophages, and areas of nonspecific
      parenchymal fibrosis. The clinical and radiographic features of this variant of
      Wegener's granulomatosis appear to be indistinguishable from the classic type.
      Pathologists need to be aware that Wegener's granulomatosis can occasionally
      manifest histologic changes suggestive of BOOP. The diagnosis will not be
      overlooked if additional features, especially vasculitis, suppurative granulomas,
      tiny necrotic zones, microabscesses, and multinucleated giant cells, are
      appreciated.

PMID- 8669528
TI  - Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and
      clinical correlations.
AB  - Malignant epithelial masses within prostatic duct lumens have been equated with
      several conflicting entities, including Gleason cribriform grade 3 carcinoma and
      cribriforming dysplasia. We identified 51 radical prostatectomy cancers
      containing intraductal lesions among 130 cases, with total cancer volumes between
      4 and 10 cc. Such lesions with duct lumen-spanning septa or masses were rare in
      areas away from invasive cancer (22 foci), while dysplasia (prostatic
      intraepithelial neoplasia) was common (1,490 foci). Consequently, these lesions
      were interpreted as being part of the evolution of invasive carcinoma rather than
      precursors; they were designated "intraductal carcinoma" as distinct from
      dysplasia. Intraductal cancer areas within invasive carcinoma usually represented
      cancer extension within the branches of a single segment of the duct-acinar
      system from near the urethra to the gland capsule. In 51% of cases with
      intraductal spread, the invasive component produced large ( > 0.5 mm) tumor
      masses in perineural spaces, which in turn correlated strongly with extensive
      capsule penetration and frequent positive surgical margins selectively at the
      superior nerve pedicle. The amount of grade 4/5 cancer, the amount of intraductal
      carcinoma, and the large perineural tumor mass appeared to be related to
      postprostatectomy progression of cancer, as measured by elevation of
      ultrasensitive serum prostate-specific antigen. It was concluded that intraductal
      prostatic adenocarcinoma is a common morphologic entity with precisely defined
      histologic criteria and a unique biologic significance, as reflected by an
      enhanced capacity for extensive spread within ducts and perineural spaces. It was
      proposed that the diversity of diagnoses attached to most cribriform malignant
      lesions can be unified by the concept of this single entity.

PMID- 8669529
TI  - DNA cytophotometry and prognosis in typical and atypical bronchopulmonary
      carcinoids. A clinicomorphologic study of 100 neuroendocrine lung tumors.
AB  - Surgical material obtained from 100 patients with typical carcinoids (TC) and
      atypical carcinoids (AC) of the lung (including 100 primary, four residual
      tumors, and four lymph node or distant metastases) was investigated by
      conventional histology and scanning DNA cytophotometry. Of the 60 TC (96%), 58
      exhibited euploid DNA histograms compared with only 20 (50%) of the 40 AC. The
      morphologic findings were related to the patients' survival (median observation
      period, 9 years). Statistical analyses disclosed the histologic type of disease
      (TC versus AC) and the DNA content of tumors (euploid versus aneuploid) to affect
      prognosis significantly (p < 0.001). Deaths resulting from tumor were exclusively
      observed among patients with atypical (eight of 40) or DNA aneuploid carcinoids
      (eight of 22). Six patients were alive with persistent tumor manifestations 3 to
      20 years after initial diagnosis, four with DNA diploid primary carcinoids. The
      presence of lymph node metastases alone was not associated with poor prognosis as
      long as the primary tumor or the related metastases showed a diploid DNA content.
      DNA cytophotometry thus might be regarded as an adjunctive prognostic criterion
      in individual carcinoid cases.

PMID- 8669530
TI  - Primary squamous cell carcinoma of the ovary. Report of 37 cases.
AB  - A total of 37 cases of ovarian primary squamous cell carcinoma (SCC)-19
      associated with a dermoid cyst (SCCD), seven associated with endometriosis
      (SCCE), and 11 pure (SCCP)-are described. The last 18 cases belong within the new
      World Health Organization category of SCC in the surface epithelial-stromal
      category. The 19 patients with SCCD were 21-75 (mean, 52) years old; three of the
      carcinomas were in situ and seven, six, and three tumors were stages I, II, and
      III, respectively. The tumors and associated dermoid cysts were 6-35 cm in
      greatest dimension, usually forming mural nodules with intracavitary protrusion
      and focal necrosis and hemorrhage; two, seven, and seven tumors were grades 1, 2,
      and 3, respectively. SCCD was focally associated with a columnar epithelial cyst
      lining in 13 cases, suggesting an origin therein. One patient with stage I, grade
      1 SCCD also had squamous cell carcinoma in situ (CIS) of the cervix. The seven
      patients with SCCE were 29-70 (mean, 49) years old, and one, three, one, and two
      tumors were stages I, II, III, and IV, respectively; all of the tumors were grade
      3. One was associated with squamous cell carcinoma in situ of the cervix. The 11
      patients with SCCP were 27-73 (mean, 56) years old, and one, four, five, and one
      tumors were stages I, II, III, and IV, respectively. The tumors were 6-26 cm in
      greatest diameter, usually solid with focal necrosis; one and 10 tumors were
      grades 2 and 3, respectively. Three patients with SCCP also had cervical squamous
      cell carcinoma in situ. The patients with SCCE had a poorer overall survival than
      those with SCCD. Five of the six patients with SCCE for whom adequate follow-up
      information was available died of their disease (mean survival, 5 months); also,
      in all five cases of SCCE reported in the literature, the patients died of their
      disease (mean survival, 4 months). The stage of the tumor and its grade
      correlated best with overall survival for all three types of SCC.

PMID- 8669531
TI  - Nodal nevi and cutaneous melanomas.
AB  - Nevocytes in melanoma-draining lymph nodes can be mistaken for melanoma
      metastases and may possibly transform to melanoma. During the development of a
      new technique for managing high-risk primary melanomas, selective lymph node
      dissection, we examined 4,821 nodes from 208 melanoma patients by light
      microscopy and immunohistochemistry. Nodal nevi were identified in 49 of 226
      lymphadenectomy specimens (22%), a frequency considerably higher than previously
      recorded (5-6%). Nevi occurred in 57 of 4,821 nodes (1.2%), in 84% of patients in
      one node, in 13% of patients in two nodes, and in 3% of patients in three nodes.
      Nevocytes were detected in hematoxylin and eosin-stained sections in 38 of 49
      cases (78%) and exclusively by immunocytochemistry with an antibody to S-100
      protein in 11 of 49 (22%). Nevi were in the peripheral capsule in 93% of cases
      and in internal trabecula in the remaining 7%. Nevocytes surrounded a small
      vessel in 33% of cases. Nevi were more frequent in axillary (37 of 140, 26%) and
      cervical nodes (seven of 40, 18%) than in inguinal nodes (five of 46, 11%). Nevi
      were more frequent in sentinel nodes, the first nodes on the lymphatics draining
      a primary melanoma (11 of 284, 3.9%), than in nonsentinel nodes (46 of 4,537,
      1.01%; p < 0.0008). One of 1,071 nodes from 50 patients with breast cancer (0.1%)
      and none of 521 nodes from 50 patients with pelvic cancer contained nevocytes.
      That nodal nevi are selectively present in melanoma patients raises the
      possibility of their origin from nodal melanocytes influenced by tumor products.
      Alternatively, the association may indicate that the nevocytes of cutaneous nevi
      can be disrupted and displaced by the growth of an adjacent melanoma.

PMID- 8669532
TI  - Osteoblastoma: varied histological presentations with a benign clinical course.
      An analysis of 55 cases.
AB  - The presence of epithelioid osteoblasts, lace- or sheet-like osteoid production,
      and a permeative pattern of tumor growth in osteoblastomas is thought to be
      associated with an aggressive clinical behaviour. This study assessed the
      prognostic significance of these and other histologic parameters by analyzing a
      large group of cases. Histologic material obtained from 55 patients who had
      osteoblastoma diagnosed and treated at Memorial Sloan-Kettering Cancer Center was
      analyzed. Additionally, the radiographic images were studied and the lesions were
      radiologically staged as stage 1 (quiescent), stage 2 (active), or stage 3
      (aggressive). Epithelioid osteoblasts were detected in 14% of the cases without
      any mitotic activity. Lace- or sheet-like osteoid was present in 36% of the cases
      studied. A permeative pattern of tumor growth was present in 15% of lesions in
      all but one arising in the short tubular or large flat bones. Thirty-four percent
      of the lesion were in stage 1, 48% in stage 2, and 17% in stage 3. All stage 1
      tumors involved long tubular bones, whereas all stage 3 tumors arose in the short
      tubular or flat bones. Local recurrence was noted in 16% of patients, all of whom
      had stage 2 lesions. One patient with a vertebral tumor eventually died with
      persistent disease. No association between the histologic features and disease
      outcome was demonstrated. The clinically aggressive behavior of osteoblastoma is
      not related to particular histologic features, but rather to the skeletal
      location. Mitotic activity is not present in osteoblasts in the osteoblastoma.

PMID- 8669533
TI  - Clinical and cost impact of second-opinion pathology. Review of prostate biopsies
      prior to radical prostatectomy.
AB  - Despite numerous studies evaluating second-opinion surgical programs, we are
      unaware of work evaluating the cost effectiveness of a second opinion for
      pathology prior to surgery. One of six pathologists reviewed the pathology of the
      outside needle biopsies of 535 consecutive men referred to Johns Hopkins Hospital
      for radical prostatectomy over a 12-month period (from October 1993 until October
      1994) before the men underwent surgery. Of the 535 needle biopsies initially
      diagnosed on the outside as adenocarcinoma of the prostate, seven (1.3%) were
      reclassified as benign upon pathology review at Johns Hopkins Hospital. The most
      common lesion misinterpreted as adenocarcinoma was adenosis or less pronounced
      examples of adenosis consisting of foci of crowded glands (five cases). Foci of
      atrophy in the remaining two cases were misdiagnosed as adenocarcinoma of the
      prostate. Upon subsequent clinical work up, six of seven men were considered not
      to have adenocarcinoma, and their surgery was cancelled. The cost for reviewing
      all 535 preoperative needle biopsies was $44,883, which included the cost of
      immunohistochemical studies for high-molecular-weight cytokeratin and repeat
      biopsies and ultrasounds in men whose diagnoses were reversed. The total cost of
      the radical prostatectomies had the six men undergone surgery was estimated at
      $85,686, including hospitalization, anesthesia, radical prostatectomy pathology,
      and surgery. This cost savings did not include other costs resulting from lost
      wages, morbidity, or potential litigation. Second-opinion pathological evaluation
      of prostate biopsy before radical prostatectomy is cost effective and has a major
      impact on clinical treatment for a subset of patients.

PMID- 8669534
TI  - The so-called bile duct adenoma is a peribiliary gland hamartoma.
AB  - The cell phenotype of so-called bile duct adenoma (BDA) was investigated
      immunohistochemically using monoclonal antibodies to two recently identified
      antigens (designated D10 and 1F6) extracted from human liver and cultured biliary
      epithelium. The acini and tubules of BDA consisted of serous and mucous cells
      that expressed D10 and 1F6. The intrahepatic peribiliary glands of normal liver,
      comprising intramural mucous glands and extramural tubuloalveolar seromucinous
      glands, similarly expressed D10 and 1F6 antigens. Antigen 1F6 was present in the
      cells forming the canals of Hering and normal bile ductules but not in
      interlobular and larger bile ducts. Proliferating bile ductules associated with
      large bile duct obstruction and alcoholic cirrhosis or the epithelia of the von
      Meyenberg complex and polycystic liver did not exhibit this combined profile of
      D10 and 1F6 expression and mucous cells. These findings suggest an origin of BDA
      from peribiliary glands rather than from bile ductules or ducts. Consistent with
      this view was our finding that 18 of the 30 BDA were spatially related to a large
      calibre bile duct. Therefore, BDA, well known for its benign behavior is a small
      mass of disorganized but mature peribiliary gland acini and tubules within a
      variable amount of stroma and should properly be called a peribiliary gland
      hamartoma.

PMID- 8669535
TI  - Gastric and esophageal intraepithelial lymphocytes in pediatric celiac disease.
AB  - Celiac disease (CD) is associated with marked mononuclear cell inflammation in
      the small intestinal mucosa. This study was performed to evaluate analogous
      changes in the gastric and esophageal mucosa of pediatric patients with CD, with
      emphasis on epithelial lymphocytosis. We evaluated intraepithelial lymphocytes
      (IELs) in 23 gastric (no.IELs/100 epithelial cells) and 14 esophageal mucosal
      biopsy specimens (IELs/hpf) from 23 pediatric cases of CD and 10 nonceliac
      matched controls. Four patients had postgluten withdrawal biopsy specimens
      reviewed, and one of these had further postgluten challenge biopsy specimens
      evaluated as well. Gastric specimens from the CD cases showed a significantly
      increased IEL count (20.5 +/- 14.4; range, 4-50) compared to controls (3.4 +/-
      1.9; range, 1-8; p < 0.001), which also correlated directly with the histologic
      severity of the small intestinal disease as assessed by the degree of villous
      shortening. Sixteen (69.5%) of 23 gastric specimens showed > 8 IELs, which was
      the highest value obtained in control specimens. The four posttreatment specimens
      showed a significant reduction in the gastric IEL counts from a mean of 19.8 to
      3.5 IELs/100 epithelial cells (p < 0.001). The single case that had a further
      postgluten challenge biopsy showed a return to the pregluten withdrawal IEL
      count. However, the degree of gastric intraepithelial lymphocytosis did not
      correlate with any of the clinical data, such as age, gender, presenting
      symptoms, or serum antibody levels (antigliadin, antireticulin, or
      antiendomysium). Furthermore, no differences were observed in the IEL count in CD
      esophageal specimens (5.3 +/- 2.6; range, 2-10) compared to controls (5.2 +/-
      1.5; range, 3-8; p = 0.935). These findings suggest that an immune-mediated
      lymphocytic response linked to gluten occurs in the gastric epithelium, similar
      to that seen in the small intestine of pediatric patients with CD. Therefore,
      gastric intraepithelial lymphocytosis may represent a concurrent manifestation of
      CD rather than a separate entity in the pediatric population.

PMID- 8669536
TI  - Infantile hemangioendothelioma of the liver in a neonate. Immunohistochemical
      observations.
AB  - The study documents the immunohistochemical features of a case of infantile
      hemangioendothelioma (IHE) of the liver, which was found incidentally at autopsy
      in a 44-day-old girl. A precardial apical systolic murmur and hepatomegaly were
      found on day 4 of life. The tumor was multifocal and histologically composed of
      vascular channels lined by endothelial cells that were positive for von
      Willebrand factor, CD31, vimentin, and Ulex europaeus agglutinin 1, and that were
      invested in a continuous basement membrane (BM) on the antiluminal border. The
      endothelial cells, especially in the region of intravascular buds, showed
      intracytoplasmic synthesis of BM components (laminin and collagen IV). Underlying
      the endothelial cells were cells with cytoplasm that was positive for alpha
      smooth muscle actin and antimuscle actin and negative for desmin, and that were
      enveloped with BM. The immunophenotype, appearance, and location of these cells
      are characteristic of pericytes. We found neither signs of endocrine secretion
      nor hepatitis B virus in the tumor tissue. The appearance of this tumor in the
      neonatal period supports a fetal origin of IHE.

PMID- 8669537
TI  - Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases
      compared with 916 nonmediastinal large B-cell lymphomas, a GELA ("Groupe d'Etude
      des Lymphomes de l'Adulte") study.
AB  - Among non-Hodgkin's lymphomas, primary mediastinal large B-cell lymphoma (PMLCL)
      has been considered a separate entity that has specific clinical and histological
      aspects and a poor prognosis. In this study, we reexamined the clinicopathologic
      features and the response to current treatment of 141 PMLCL and compare them with
      916 nonmediastinal large B-cell lymphomas (NMLCL) recorded in the same period and
      treated with similar combined chemotherapy. The clinical features of PMLCL at
      diagnosis were largely homogeneous and distinct from NMLCL, with a predilection
      for young women (59% with a mean age of 37 years versus 42% with a mean age of 54
      years), bulky tumor (77% versus 7%, p < 10(4)), high serum lactic dehydrogenase
      (LDH) level 76% versus 51%, p < 10(4)), and frequent intrathoracic extension to
      adjacent organs such as pleura, pericardium, and lung. By contrast, extrathoracic
      or hematologic dissemination was uncommon (2% of bone marrow involvement versus
      17%). All patients had diffuse large B-cell nonimmunoblastic, nonanaplastic
      lymphomas. Histological analysis of the 141 PMLCL evaluated two common patterns:
      the presence of large cells with clear cytoplasm (found in 38% of cases) and the
      presence of fibrosis (marked in 25% of cases). The presence of clear cells or
      intense fibrosis did not constitute prognostic indicators. Immunologic and
      molecular analysis assessed the profile of bcl-2 expression and the presence of
      Epstein-Barr virus (EBV) in PMLCL: 30% expressed a high level of bcl-2 protein;
      EBER RNAs were detected by in situ hybridization in only two of the 41 cases
      tested. Monotypic light chain restriction could be demonstrated in seven of the
      41 PMLCL tested on fixed-section. Treated with polychemotherapy regimens without
      radiotherapy, 79% of PMLCL patients achieved a complete remission compared with
      68% in the NMLCL patient group (p = 0.01). Overall, 3-year survival rates were
      estimated at 66 and 61%, respectively (p = 0.05), and disease-free survival rates
      were not significantly different (61 versus 64%). Stratified analysis on the
      International Prognostic Index (based on age, tumor stage, serum LDH level, and
      performance status) showed no difference in the overall and disease-free
      survivals between the two lymphoma groups. In conclusion, PMLCL can be combined
      with other diffuse large B-cell lymphomas on morphologic grounds; it is not
      associated with EBV. It responds favorably to treatment and should be managed
      like other high-grade lymphomas of equivalent histology. However, the uncommon
      clinical presentation makes it a distinct entity.

PMID- 8669538
TI  - A case of von Recklinghausen's disease with bilateral pheochromocytoma-malignant
      peripheral nerve sheath tumors of the adrenal and gastrointestinal autonomic
      nerve tumors.
AB  - A 48-year-old man with neurofibromatosis type 1 presented with chest pain,
      paroxysmal hypertension, tachycardia, and progressive respiratory insufficiency.
      Clinical investigation displayed calcified tumors in the anterior mediastinum and
      pararenal region. Histological examination at autopsy revealed composite tumors
      consisting of pheochromocytoma and malignant peripheral nerve sheath tumor
      (MPNST) at two sites: the left adrenal gland and the region surrounding the
      inferior vena cava, probably corresponding to the right adrenal gland. The MPNST
      component showed a varied histological appearance, including hyalinized bands
      with polygonal cells, a cartilaginous and myxoid stroma, a hemangiopericytomatous
      architecture, and a fibrosarcomatous structure, which suggested osteosarcoma,
      chondrosarcoma, angiosarcoma, and fibrosarcoma, respectively. In addition, based
      on the ultrastructural findings, the gastrointestinal tract was involved with
      mesenchymal tumors showing neurogenic differentiation. These lesions suggest the
      divergent cellular differentiation of neural crest-derived cells to mesenchymal
      elements as well as neuroectodermal neoplasms.

PMID- 8669539
TI  - Pleomorphic lipoma.

PMID- 8669540
TI  - Inflammatory tumor.

PMID- 8669541
TI  - Inflammatory tumor.

PMID- 8669542
TI  - Extranuchal nuchal fibroma.

PMID- 8669543
TI  - [Bell's palsy in ENT emergency ward. Retrospective study of 169 cases].
AB  - Retrospective study covering 169 Bell's palsies out of 196 peripheral palsies,
      attended at ENT emergency ward (Son Dureta Hospital, Majorca), between January
      1992 and December 1993. In our series Bell's palsy, the so called "a frigore",
      accounted for the most prevalent peripheral palsies seen. No significative
      differences could be appreciate regarding the sex or the affected side. Nor
      significant variations in seasonal frequency. The incidence by ages revealed two
      outstanding picks in the 3rd and the 8th decade.

PMID- 8669544
TI  - [Vascular anomalies presenting as middle ear mass].
AB  - We study several cases of patients who presented clinical symptoms indicating the
      presence of a middle ear mass (tinnitus, hearing loss, otorrhea, otorrhagia...).
      We had to rule out the presence of an expanding tumour (either in the form of a
      cholesteatoma or a glomus tumor) and the existence of vascular anomalies of the
      middle ear (enlarged jugular bulb or jugular megabulb deformity). Due to the
      possibility of a different treatment in each particular case (radiotherapy,
      radical surgery, jugular vein ligation or even no treatment at all), the relative
      value of various imaging techniques and/or a possible surgical approach before
      arriving to a conclusive diagnosis, is discussed.

PMID- 8669545
TI  - [Report of 3 cases of adenoid cystic carcinoma of the palate. Clinical,
      histological and therapeutical considerations].
AB  - Three cases of adenoid cyst carcinoma of the palate are reported. In this study
      clinical features, pathological findings, treatment and prognosis are analyzed.
      In the 1st and 2nd cases we unfortunately verified that the course of the tumors
      based in a slow-continuous infiltrating spread. Moreover, in our first patient a
      late diagnosis of it made the prognosis become worse. In the 1st one, radical
      surgery is proposed for the adenoid cyst carcinoma diagnosed at an early stage
      without tumoral dissemination.

PMID- 8669546
TI  - Facial neuroma and magnetic resonance imaging.
AB  - The aim of this paper is to present a new case of facial neuroma. Its clinical
      appearance was uncommon, displaying symptoms characterized by sudden facial
      paralysis. Diagnostic armamentarium is discussed emphasizing the importance of
      magnetic resonance imaging (MRI). Therapeutical strategy with the techniques of
      facial rehabilitation are contemplated.

PMID- 8669547
TI  - [Validity of videolaryngoscopy in detecting laryngeal structural changes].
AB  - STUDY OBJECTIVE: To determinate the validity of videolaryngoscopy on diagnose of
      laryngeal diseases versus other laryngoscopic methods. DESIGN: Retrospective
      study covering 2 years (1992 and 1993). SETTING: 267 were the consulting patients
      because of dysphony. This collective was ranged in 2 groups. Group A included
      those hoarse individuals in whom was detected a growth, confirmed afterwards by
      means of direct laryngoscopy, biopsy and pathologists examination of a smear.
      Group B was formed for dysphonics with no organic changes seen through indirect
      laryngoscopy. INTERVENTIONS: All patients underwent indirect laryngoscopy
      (laryngeal mirror) and videolaryngoscopy. Patients showing an organic lesion
      underwent, also, suspension direct laryngoscopy, biopsy and histopathological
      control (reference's measurement). In all laryngoscopic procedures were
      determinated presence or absence of laryngeal changes (organic or functional) and
      the glottic area involved. RESULTS: In 156 patients direct laryngoscopies were
      performed. Organic lesion could be confirmed in 154 cases. The relative
      sensibility of videolaryngoscopy versus laryngeal mirror account for 0.4 and its
      negative predictive value for 0.26. The correlation videolaryngoscopy direct
      laryngoscopy results in 1. CONCLUSIONS: Videolaryngoscopy is a method with major
      sensibility and negative predictive value as indirect laryngoscopy with mirror.
      But the latter is indispensable in diagnosis of laryngeal organic lesions and
      must be done prior to microlaryngoscopie direct examination.

PMID- 8669548
TI  - [Asymptomatic thoracic and abdominal tumors with lymph nodes metastasis as a
      reason for consultation].
AB  - OBJECTIVE: To determine the incidence of metastatic cancer to the neck from
      asymptomatic primary tumors in thorax, abdomen or pelvis. DESIGN: Two years term
      (January 1992 to December 1993) retrospective study. PATIENTS AND METHOD:
      Presentation of 57 patients with a neck mass which through puntion-aspiration
      (FNB), cervicotomy and biopsy confirmed any type of carcinoma. RESULTS: In 39
      cases (68.42%) a primary tumor either in the pharynx or mouth were affirmative of
      growth; in other 10 (17.54%) the site of the primary remainded unknown; and 8
      cases (14.04%) the primary tumor even asymptomatic could be localized inside the
      thorax or abdomen (3 pulmonary, 2 kidney, 1 stomach, 1 prostate and 1 esophagus).
      In other 2 occurrences, a cervicofacial association existed (1 case a synchronic
      growth of the hypopharynx-prostate, the other one cavum pharyngis and lung).
      COMMENTS: Cases diagnosed as asymptomatic thoracic or abdominal tumors are
      commented and its bibliography reviewed. The same as diagnostic strategy in
      hidden primaries aiming to the probability of ascertain the sitting in each
      diagnostic stage.

PMID- 8669549
TI  - [Retropharyngeal abscess].
AB  - We present 2 cases of retropharyngeal abscess in adults as complication of acute
      tonsillitis and cervical pyogenic osteomyelitis, respectively. These cases
      confirm that retropharyngeal abscess has a significant morbi-mortality despite of
      new antibiotic drugs introduced. A review of the present characteristics of the
      complaint is treated in this paper.

PMID- 8669550
TI  - [Yag-laser for the treatment of laryngeal and oral hemangiomas].
AB  - Laryngeal and bucal hemangiomas are uncommon, although they carry with them,
      because of its sitting, a vital risk. The AA. report 2 hemangioma cases, one
      localized on the edge of the tongue, the other one on the aryepiglottic fold.
      Both were treated with photocoagulation by neodymiun-yttrium-aluminium (Nd-YaG)
      laser, with favorable follow-up and few complications.

PMID- 8669551
TI  - [Removal and processing inner ear specimens for morphological research on guinea
      pig ear].
AB  - Seventy (70) dissections of temporal bones of grown-up guinea pigs were done by
      the AA. in order to get a suitable approach to obtain inner ear studies, aiming
      at a morphological investigation.

PMID- 8669552
TI  - [Trans-septo-sphenoidal transnasal approach for microsurgery of hypophyseal
      tumors].
AB  - The surgical treatment of hypophyseal tumors has improved from external approach
      (transcranial-subtemporal) to the trans-septo-transphenoidal approach. Since the
      last thirty years this way to access has been increasingly used, because it
      provides an excellent exposure, little bleeding, is rapidly and easily performed
      with less morbi-morality and has smoother postoperative period. A retrospective
      study of 16 patients whose hypophyseal tumors were treated surgically using the
      trans-septo-sphenoidal transnasal (maxillary-premaxillary) approach is presented.
      All these patients were seen in the E.N.T. Department of Alicante's General
      University Hospital, between January 1990 and June 1993. The trans-septo
      sphenoidal transnasal via avoids some of the problems of the sublabial trans
      sphenoidal procedure; namely longer operating time, oral contamination of the
      surgical field, subsequence difficulties due to the lack of sensibility and
      discomfort of the upper jax area and postoperative alterations in the projection
      of the septal-columelar tip.

PMID- 8669553
TI  - Ampoule labelling.

PMID- 8669554
TI  - Unrecognised environmental pollution by desflurane.

PMID- 8669555
TI  - Anaesthetic problems in the Nance Insley syndrome.

PMID- 8669556
TI  - "Prongs" on double-lumen tubes.

PMID- 8669557
TI  - Propofol--an interesting new side effect?

PMID- 8669558
TI  - What changes drug metabolism in critically ill patients?--II Serum inhibits the
      metabolism of midazolam in human microsomes.
AB  - Serum samples from five critically ill patients were incubated with microsomes
      prepared from three human livers. The activity of cytochrome P450 3A4 was
      assessed by measuring the disappearance of midazolam and the appearance of 1
      hydroxy midazolam in the incubates. Significant inhibition of the ability of this
      enzyme to metabolise midazolam was seen. This occurred in incubates containing
      serum samples from critically ill patients and not in those containing serum from
      two normal volunteers. The mechanism of this inhibition is unknown, but several
      possibilities are discussed.

PMID- 8669559
TI  - Malignant hyperthermia--a large kindred linked to the RYR1 gene.
AB  - Malignant hyperthermia susceptibility is genetically heterogeneous. The ryanodine
      receptor gene on the long arm of chromosome 19 represents an important candidate
      gene but not all families with malignant hyperthermia demonstrate ryanodine
      receptor mutations or linkage to this region of 19q. Linkage to chromosome 17 in
      the region of the adult muscle sodium channel alpha subunit gene has been
      suggested in some families; others are not linked to either of these loci. For
      most families the in vitro muscle contracture test remains the only reliable
      method of predicting susceptibility to malignant hyperthermia. We have performed
      linkage analysis in a large family group with malignant hyperthermia in which the
      in vitro muscle contracture test had been carried out using the procedure
      standardised by the European Malignant Hyperthermia Group. None of the published
      ryanodine receptor gene mutations associated with malignant hyperthermia
      susceptibility were detected in affected individuals but linkage to intragenic
      ryanodine receptor markers strongly suggest that this gene is involved in
      malignant hyperthermia susceptibility in this family. This enabled accurate
      predictive testing by DNA analysis in 11 untested subjects at 50% risk.

PMID- 8669560
TI  - The relationship between anaesthetic uptake and cardiac output.
AB  - The hypothesis that anaesthetic uptake during maintenance of anaesthesia is
      related to cardiac output was tested on 21 patients undergoing cardiac surgery.
      Using a computer-controlled closed breathing system, enflurane was administered
      to maintain an end-expired concentration of 1%. Cardiac output was measured by
      thermodilution using a pulmonary artery catheter. A clear qualitative but not
      quantitative relationship was demonstrated. Changes in anaesthetic requirements
      at a constant end-expired concentration are a better guide to changes in cardiac
      output than changes in end-expired carbon dioxide with constant ventilation in
      patients undergoing cardiac surgery.

PMID- 8669561
TI  - The use of bromothymol blue and sodium thiopentone to confirm tracheal
      intubation.
AB  - The possibility of using chemical changes to confirm correct tracheal tube
      placement was investigated with a view to their use in developing countries where
      more sophisticated methods are unavailable. The effect of bubbling expired gases
      through a 10% solution of bromothymol blue and a 0.25% solution of thiopentone
      led to chemical changes producing, in the case of bromothymol blue, a colour
      change and in that of thiopentone, precipitation, probably due to a change in pH
      caused by carbon dioxide. We also discovered that the time to precipitation of
      the thiopentone could be greatly reduced if it was mixed with a precise quantity
      of lignocaine. These simple end points can reliably confirm the correct placement
      of a tracheal tube at least as rapidly as the correct use of capnography.

PMID- 8669562
TI  - A 5-year survival study of general surgical patients aged 65 years and over.
AB  - A prospective 5-year survival study of 900 patients, aged 65 years and over,
      undergoing a general surgical procedure, demonstrated that following an initial
      high mortality rate the survival of the group as a whole approached that of an
      age-matched population. Non-elective admissions, age 75 years and over, ASA grade
      4-5 and major surgery were associated with a high early mortality. Mortality
      associated with malignancy extended over 1 year. The study reinforces the
      conclusion that age alone should be no bar to surgery and anaesthesia, endorses
      the findings of the National Confidential Enquiry into Peri-operative deaths and
      emphasises the need to re-examine the provision of anaesthetic and surgical
      services in District General Hospitals. The benefits of elective admission in the
      very old are highlighted, along with the potential for extension of day case
      surgery.

PMID- 8669563
TI  - Uptake of desflurane during anaesthesia.
AB  - The amount of desflurane required to maintain an end-expired concentration of 8%
      was measured in 30 ASA 1 and 2 patients undergoing elective spinal surgery. The
      anaesthetic was administered using a computer-controlled closed circle system.
      After an initial period during which the expired concentration of desflurane was
      stabilised (4 min) the rate of uptake showed a bi-exponential decline. Mean
      cumulative usage of desflurane was 10.1 ml of liquid at 30 min, 14.8 ml at 60
      min, 25.4 ml at 120 min, 35.8 at 180 min.

PMID- 8669564
TI  - The effect of epidural blockade on gastric intramucosal pH in the peri-operative
      period.
AB  - Patients undergoing major surgery are at risk of developing gut ischaemia and
      multiple organ failure. The gastric tonometer provides a relatively non-invasive
      method of assessing the adequacy of gut blood flow. Patients who develop repeated
      episodes of splanchnic ischaemia in the postoperative period, as evidenced by a
      low gastric intramucosal pH, have a higher mortality than those who do not. This
      randomised, controlled study was conducted to assess the effect of epidural
      blockade with bupivacaine on gastric intramucosal pH measurements in patients
      undergoing major surgery. A significantly lower proportion of patients with
      epidural blockade developed gastric intramucosal pH values < 7.32 postoperatively
      compared to controls (3/15 versus 13/16, p < 0.001). The significance of these
      results is discussed.

PMID- 8669565
TI  - Re-establishment of paralysis using mivacurium following apparent full recovery
      from mivacurium-induced neuromuscular block.
AB  - Recent published data suggest that despite apparently satisfactory recovery from
      nondepolarising block (train-of-four ratios in excess of 0.90), even very small
      doses of additional relaxant may re-establish significant paralysis. We sought to
      verify this observation and quantify its magnitude. Twelve adult patients were
      studied under nitrous oxide-propofol-opioid anaesthesia and neuromuscular block
      was monitored electromyographically. Train-of-four stimuli were delivered to the
      ulnar nerve every 20 s throughout the period of observation. After baseline
      stabilisation, an initial bolus of mivacurium 25 micrograms.kg-1 was administered
      and the twitch depression noted. When the twitch was stable for two consecutive
      stimuli, a second bolus, calculated to produce approximately 90% twitch
      depression, was administered. Recovery was then allowed to proceed spontaneously
      until the train-of-four ratio reached 0.95. At that time a second 25
      micrograms.kg-1 dose was administered and the effect on twitch height recorded.
      Using the slope for the log-dose/logit dose-response relationship of mivacurium
      (5.5), it was possible to estimate any change in the ED50 of mivacurium. The
      control ED50 of mivacurium (calculated from the initial dose of mivacurium)
      averaged 43 micrograms.kg-1. When the same dose of drug was given at 95% recovery
      of the train-of-four ratio, the ED50 was reduced to 19 micrograms.kg-1 (p <
      0.0001). Hence, there remains a considerable reduction in the neuromuscular
      margin of safety even at a train-of-four ratio of 0.95.

PMID- 8669566
TI  - Peri-operative management of diabetic patients. Any changes for the better since
      1985?
AB  - Two hundred and seven anaesthetists in the Oxford region were sent a
      questionnaire asking about their peri-operative management of patients with
      diabetes mellitus. One hundred and seventy two valid returns were received. The
      results of this survey were compared with those of a similar survey conducted in
      1985. A greater proportion of anaesthetists in 1993 would maintain their diabetic
      patients with a peri-operative blood glucose concentration of less than 10 mmol.l
      1. Anaesthetists are more likely to be interventional in their management of
      diabetic patients than in 1985 and the methods used have changed in relative
      popularity. In 1993 diabetic patients undergoing major surgery were most commonly
      managed with separate infusions of insulin and glucose, while in 1985 the
      combined infusion of glucose, insulin and potassium was the most popular
      technique. The use of protocols in hospitals may increase the degree of
      uniformity of practice between anaesthetists.

PMID- 8669567
TI  - Antiemetic efficacy of prophylactic ondansetron in laparoscopic cholecystectomy.
      A randomised, double-blind, placebo-controlled trial.
AB  - The antiemetic efficacy of ondansetron given prophylactically was investigated in
      a randomised, double-blind, placebo-controlled trial of 63 patients undergoing
      laparoscopic cholecystectomy. The patients received intravenously prior to
      anaesthesia either ondansetron 4 mg or placebo. The same standardised general
      anaesthetic technique was used. Nausea, emetic episodes and the need for rescue
      medication were recorded for 24 h postoperatively. Nausea was experienced by 64%
      of the patients in the ondansetron group and 56% in the placebo group, and emetic
      episodes occurred in 45% and 50% of the patients in the two groups, respectively.
      The proportions of patients given rescue antiemetic medication were 45% and 44%,
      respectively. No clinically important adverse events were observed. In
      conclusion, ondansetron given prior to anaesthesia in a dosage of 4 mg did not
      prevent postoperative nausea and vomiting after laparoscopic cholecystectomy.

PMID- 8669568
TI  - Anaesthesia for day-care arthroscopy. A comparison between desflurane and
      isoflurane.
AB  - A study was undertaken to compare desflurane- and isoflurane-based anaesthesia in
      patients undergoing day-care arthroscopic surgery. Anaesthesia was induced with
      propofol 2-3 mg.kg-1 and a laryngeal mask airway was inserted after loss of the
      eyelash reflex. Patients were then randomly divided into two groups to receive
      maintenance anaesthesia with either isoflurane or desflurane delivered in oxygen
      and nitrous oxide. Alfentanil was used as the analgesic during the operation.
      Early recovery was assessed by measurement of the times to eye opening,
      extubation and ability to give a date of birth. Psychomotor recovery was assessed
      by performance on the finger tapping and perceptive accuracy tests. Mood was
      evaluated using visual analogue mood scores and the mood adjective checklist.
      Discharge times were also measured. Early recovery was significantly quicker
      following desflurane anaesthesia but no differences between the groups were found
      in psychomotor tests. The mood adjective checklist showed that patients in the
      isoflurane group had a greater total mood score and were more calm than those in
      the desflurane group; this was particularly evident 2 h after anaesthesia. The
      discharge times were similar for the two groups. Desflurane is a satisfactory
      alternative to isoflurane for day care anaesthesia.

PMID- 8669569
TI  - A practical evaluation of four human-powered portable airway aspirators.
AB  - The establishment of a clear airway is a vital part of basic life support and
      mechanical devices are available to assist the clearance of the upper airway
      during resuscitation. The performances of four human-powered devices, currently
      available in the United Kingdom, were compared with the relevant British
      Standard. The ease of use of the devices by 20 experienced and 20 novice
      resuscitators was assessed. Three of the four devices met all British Standard
      criteria tested whereas the fourth failed on one test only. These devices are
      generally simple to use. However, two devices ('Res-Q-Vac' and 'Ambu Maxi Suction
      Pump') were more user friendly. The incidence of airway contamination during
      resuscitation and the current recommended resuscitation protocols suggest that
      there is a need for increased emphasis on these airway adjuncts in life-support
      training. Wider access to basic life support equipment inside and outside
      hospital premises may improve resuscitation outcome.

PMID- 8669570
TI  - Regional anaesthesia for repeat Caesarean section in a patient with phantom limb
      pain.
AB  - The triggering of phantom limb pain by subarachnoid or epidural anaesthesia has
      been well described leading to the suggestion that neuraxial regional anaesthesia
      is relatively contraindicated in lower limb amputees. We report our experience of
      the provision of anaesthesia for repeat Caesarean section on two occasions in
      such a patient. Intrathecal fentanyl and morphine supplementation of bupivacaine
      successfully abolished peri-operative phantom limb pain, whereas epidural
      anaesthesia was associated with recurrence of phantom limb pain upon regression
      of the block.

PMID- 8669571
TI  - Forum. An evaluation of the levering laryngoscope.
AB  - This study was undertaken to evaluate the effect of the levering laryngoscope on
      the view obtained at laryngoscopy. Two hundred and ten consecutive patients who
      required tracheal intubation were studied. The view at laryngoscopy with the
      levering laryngoscope blade in the neutral and elevated positions was recorded.
      In patients in whom there was a Cormack and Lehane grade 3 view of the larynx
      with the blade in the neutral position, elevation of the levered tip of the blade
      significantly improved the visualisation of the larynx. In patients where the
      view of the larynx was grade 1 or 2 with the blade in the neutral position,
      elevation of the levered tip often (23%) resulted in the view being impaired.
      This was not a clinical problem as the blade could simply be returned to the
      neutral position. The levering laryngoscope is a useful additional aid to
      laryngeal visualisation.

PMID- 8669572
TI  - The use of the McCoy laryngoscope in patients with simulated cervical spine
      injuries.
AB  - We studied the laryngoscopic view in 167 patients with their head and necks held
      in the neutral position with manual in-line stabilisation and cricoid pressure to
      simulate the patient with a suspected cervical spine injury. Each patient
      underwent laryngoscopy using both a McCoy and a Macintosh laryngoscope. The best
      view obtained by each larngoscope was graded according to standard guidelines.
      The results showed that the McCoy was never worse than the Macintosh. It improved
      the Macintosh grade by 1 grade in 41% and by 2 grades in 8% (p < 0.001).
      Difficult laryngoscopy, defined as the inability to see the glottis (grade 3 or
      4), was found in 56 (33%) with the Macintosh laryngoscope and only eight (5%) (P
      < 0.001) with the McCoy laryngoscope. We suggest that patients with a suspected
      cervical spine injury and a full stomach should be intubated using a McCoy in
      preference to a Macintosh laryngoscope.

PMID- 8669573
TI  - Analysis of 1500 laryngeal mask uses by one anaesthetist in adults undergoing
      routine anaesthesia.
AB  - An analysis of 1500 laryngeal mask airway uses by one anaesthetist using the
      standard insertion technique was conducted to determine successful insertion
      rates, position by fibreoptic larynoscopy, complication rates and whether there
      is a long-term learning curve. The correlation between laryngeal mask airway
      placement and modified Mallampati grade was also determined. The first time
      insertion rate was 95.5% with an overall failure rate after three attempts of
      0.4%. One hundred and fifteen patients were Mallampati III or IV. All failed
      placements were Mallampati I or II. Problems occurred in 94 patients (6.27%), but
      oxygen saturation decreased below 90% on only ten occasions and below 80% on one
      occasion. There were no episodes of regurgitation. The vocal cords were visible
      from the mask aperture bars in 97.1%. Comparison of insertion rates, fibreoptic
      position and complications for the first and second 750 insertions provides
      evidence for a 'long' term learning curve. These data could be used as a guide
      for 'optimal' or expected successful laryngeal mask airway insertion rates in
      adults undergoing routine anaesthesia.

PMID- 8669574
TI  - Learning fibreoptic skills in ear, nose and throat clinics.
AB  - We have compared the progress of anaesthetists taught fibreoptic techniques on
      awake patients in ear, nose and throat clinics with that of anaesthetists taught
      by traditional methods. Twelve anaesthetists participated in the study and were
      randomly allocated to the ear, nose and throat group or to the traditional
      training group. Each individual in the ear, nose and throat group attended the
      outpatient clinic and performed ten nasendoscopies on awake patient, whose upper
      airway had been anaesthetised with cocaine, under the supervision of an ear, nose
      and throat surgeon. Each individual in the traditional roup performed ten
      nasendoscopies on anaesthetised oral surgery inpatients under the supervision of
      an anaesthetist. To assess the effectiveness of the two training methods, each
      anaesthetist in each group then attempted ten fibreoptic nasotracheal intubations
      on anaesthetised oral surgery patients. There was no significant difference
      between either the success rates or mean successful tracheoscopy times between
      the two groups. Nasendoscopy training in the ear, nose and throat clinic appears
      to be good way of learning fibreoptic skills, which can then be readily applied
      to fibreoptic tracheal intubation in anaesthetic practice.

PMID- 8669575
TI  - The effect of extradural ketamine on onset time and sensory block in extradural
      anaesthesia with bupivacaine.
AB  - In a randomised, double blind study of 30 patients, we have compared two regimens
      for extradural anaesthesia: 20 ml bupivacaine 0.5%, 25 mg (0.5 ml) ketamine, 1 in
      200,000 adrenaline; and 20 ml bupivacaine 0.5%, 0.5 ml 0.9% saline, 1 in 200,000
      adrenaline. The main outcome measures were onset time to acceptable bilateral
      anaesthesia and postoperative analgesic duration. The time to onset of
      anaesthesia was reduced by 8 min in the bupivacaine-ketamine group compared with
      the bupivacaine alone group. In addition, the anaesthetic levels were two
      segments higher in the bupivacaine-ketamine group (T7 versus T9). Side effects
      were similar in both groups and there was no significant difference in
      postoperative analgesic requirements between the two groups. The addition of
      ketamine to bupivacaine given epidurally appears to be useful in the reduction of
      onset time to blockade.

PMID- 8669576
TI  - Rotameter sequence--a variant of 'read the label'.

PMID- 8669577
TI  - Pressure testing the anaesthetic machine and breathing system.

PMID- 8669578
TI  - Another problem with a circle system.

PMID- 8669579
TI  - Carbon monoxide, soda lime and volatile agents.

PMID- 8669580
TI  - Patient transfer; what to do about the 'spaghetti'.

PMID- 8669581
TI  - The McCoy levering laryngoscope blade.

PMID- 8669582
TI  - Capnometers for 'out-of-hospital' use.

PMID- 8669583
TI  - How much droperidol in combination with PCA morphine?

PMID- 8669584
TI  - Calcium chloride; a reminder.

PMID- 8669585
TI  - Pain on administration of rocuronium.

PMID- 8669586
TI  - Electronic anaesthetic logbooks; standards for data entry.

PMID- 8669587
TI  - Fentanyl-induced laryngospasm.

PMID- 8669588
TI  - Movement, monitoring and electroconvulsive therapy.

PMID- 8669589
TI  - Use of the fibreoptic laryngoscope for tracheal intubation in infants.

PMID- 8669590
TI  - Anaesthesia for Jehovah's Witnesses.

PMID- 8669591
TI  - Level 1 fluid warmer and Gelofusine.

PMID- 8669592
TI  - Cardiac standstill, pulmonary artery catheterisation and left bundle branch
      block.

PMID- 8669594
TI  - Type of needle point and nerve damage.

PMID- 8669593
TI  - The laryngeal mask airway and the multiple injured patient.

PMID- 8669595
TI  - Anaesthetic considerations for a possible malignant hyperthermia susceptible
      fetus.

PMID- 8669596
TI  - Metabolic gas exchange during anaesthesia.

PMID- 8669597
TI  - Bellamy Gardner's open ether mask.

PMID- 8669598
TI  - A study of the combined haemodynamic effects of dobutamine and enoximone in
      patients taking beta adrenoceptor antagonists.
AB  - We conducted a randomized, double-blind investigation to determine whether
      enoximone affects the actions of dobutamine in patients taking beta adrenoceptor
      antagonists. We studied sixteen patients with good ventricular function after
      coronary artery bypass operations. All patients were taking a beta adrenoceptor
      antagonist. The patients received a standardized intravenous anaesthetic, which
      was maintained throughout the investigation. They received a masked infusion,
      containing either normal saline or enoximone. Haemodynamic data were recorded
      before, during, and after an infusion of dobutamine, which was given at three
      different rates. Patients receiving enoximone had a greater cardiac output, a
      higher heart rate and a lower systemic vascular resistance than patients
      receiving saline. They also required an average of 1500 ml more intravenous
      colloid in the immediate postoperative period to achieve haemodynamic stability.
      Dobutamine produced a consistent, significant peripheral vasoconstriction, but no
      inotropic or chronotropic effect. There was no significant difference in this
      effect between the two groups, and it was not influenced by concurrent therapy
      with enoximone. The alpha adrenergic action of dobutamine prevented us from using
      high enough rates of infusion to explore any interaction between the inotropic
      actions of dobutamine and enoximone.

PMID- 8669599
TI  - Changes in vancomycin pharmacokinetics in critically ill infants.
AB  - We aimed to assess the pharmacokinetics of vancomycin in critically ill infants,
      and to evaluate the standard recommended dose of 10 mg/kg 6 hourly. All infants
      admitted to the Baragwanath Hospital ICU who had arterial lines in situ, and for
      whom vancomycin 10 mg/kg 6 hourly was prescribed for an infective insult and who
      had parental consent, were included in the study. Vancomycin was infused over 60
      minutes. Serum samples were taken immediately before the dose and at 30, 60, 120
      and 300 minutes after the end of the vancomycin infusion, on days 2 and 8 of
      therapy. Extrapolated peak concentration (Cmax), trough concentration (Cmin),
      apparent volume of distribution (Vd), elimination half-life (t1/2el) and
      clearance (CL) were determined for each patient. Day 2 values were compared with
      those of day 8. Day 2 serum concentrations were assayed on 20 patients and day 8
      concentrations in 15. The mean vancomycin Vd on day 2 (0.81 l/kg) was
      significantly (P = 0.007) larger than that on day 8 (0.44 l/kg). The change in Vd
      resulted in a significant change in mean Cmax (29.1 vs 35.5 micrograms/ml) (P =
      0.02) and mean t1/2el (5.3 vs 3.4h) (P = 0.01) over the treatment period.
      Critically ill infants displayed a large initial volume of distribution which
      probably resulted from aggressive fluid resuscitation. This also results in a
      large variation in other pharmacokinetic parameters, namely Cmax and t1/2el.
      Although the routine monitoring of vancomycin serum concentrations remain
      controversial, we feel that in view of these large pharmacokinetic variations,
      the critically ill infant is a specific group where monitoring of vancomycin
      serum levels is indicated.

PMID- 8669600
TI  - Release of inflammatory mediators in association with collection of wound
      drainage blood during orthopaedic surgery.
AB  - Ten patients undergoing hip replacement surgery were studied regarding activation
      of complement and leukocytes in association with collection of wound drainage
      blood. The blood was collected postoperatively but not reinfused due to the
      possible risks with reinfusion of blood containing inflammatory mediators. Blood
      samples for analysis of complement activation (TCC), leukocyte activation (PMN
      elastase) and cytokines (Interleukin-6) were drawn preoperatively from the
      patients. Blood samples were also drawn intraoperatively from the wound. Samples
      were also drawn from the collected wound drainage blood, before and after blood
      was passed through a microporous filter. There were elevated concentrations of
      TCC, PMN elastase and IL-6 in the collected wound drainage blood before and after
      the filter. The filtration did not significantly reduce the concentrations of
      these factors. In the wound blood the concentrations were higher compared to
      those found in the systemic blood preoperatively, but lower compared to
      concentrations found in the collected drainage blood. The study demonstrates that
      the collection of wound drainage whole blood is associated with activation of
      complement, release of PMN elastase and cytokines.

PMID- 8669601
TI  - The effect of oral cisapride premedication on fasting gastric volumes.
AB  - The aim of this study was to determine whether fasting gastric volumes could be
      reduced by preoperative administration of cisapride. One hundred and twenty-one
      patients undergoing elective general anaesthesia were randomly allocated to
      receive either cisapride 20 mg plus diazepam 10 mg or placebo tablets plus
      diazepam 10 mg, two hours prior to induction. Immediately following induction
      blind gastric aspiration was performed using a 16Fr multiorificed orogastric
      tube. Gastric volume, pH, and cisapride blood concentration were measured at this
      time. Gastric volumes were significantly smaller in the cisapride group, 20.5 (SD
      22.2) ml compared to placebo 28.2 (SD 26.0) ml but there was no significant
      difference with respect to pH. Some patients in both groups had large gastric
      volumes despite fasting. No significant adverse effects were noted with
      cisapride.

PMID- 8669602
TI  - What is the role of absorption atelectasis in the genesis of perioperative
      pulmonary collapse?
AB  - During anaesthesia the combination of breathing at low lung volume, the
      administration of nitrous oxide and high inspired oxygen concentrations produces
      conditions that favour absorption atelectasis. Measures such as adding nitrogen
      to the inspired mixture and avoiding high inspired oxygen concentrations would
      reduce the amount of perioperative atelectasis if gas absorption was important in
      the genesis of perioperative pulmonary collapse. Experimental results demonstrate
      that these measures do not protect against atelectasis. This indicates that
      absorption atelectasis does not play a significant role in the genesis of
      perioperative pulmonary collapse. Compression atelectasis may be the underlying
      mechanism.

PMID- 8669603
TI  - The impact of heat and moisture exchanging humidifiers on work of breathing.
AB  - In this study the resistive work or breathing (WOB) associated with eleven
      commercially available heat and moisture exchangers (HMEs) was evaluated for gas
      flow rates of 20 to 60 l.min-1. The Gibeck Humid-Vent 2S Flex was also assessed
      after 24 hours patient usage (n = 50). The WOB associated with these devices was
      compared with that of standard endotracheal tubes and standard humidifying
      circuits with flex-tube connectors. The range of work imposed by the eleven HMEs
      approximated the range shown by water bath circuitry when used with two different
      commonly used flex-tube connectors. The excess WOB attributed to the HMEs was
      significantly less than that imposed by standard endotracheal tubes. After 24
      hours of patient use, 96% of the Gibeck HMEs tested demonstrated a resistive WOB
      within the range of the two flex-tube connectors. To assess the clinical
      significance of this circuit-related WOB, we compared respiratory variables in 40
      patients breathing on either CPAP or pressure support ventilation, using a
      variation in flex-tube resistance which imposed a range of WOB comparable to that
      shown by the HMEs. A small but statistically significant reduction was found for
      both the peak flow (48 +/- 1.4 vs 45 +/- 1.1 l.min-1, P < 0.0005) and the minute
      volume (8.6 +/- 0.35 vs 7.9 +/- 0.31, l, P < 0.0005). These data suggest that the
      range of resistive work imposed by commercially available HMEs has a small but
      potentially significant effect on clinical respiratory parameters.

PMID- 8669604
TI  - Quantitative measurement of nasal production of nitric oxide in awake humans.
AB  - The aim of this study was to determine, quantitatively, the production of nitric
      oxide (NO) in the nose and nasopharynx. Subjects were instructed to perform a
      Valsalva manoeuvre with their mouth open as gas was aspirated from a closely
      fitting nasal CPAP mask by a chemiluminescence analyser (Sievers 270B, Sievers
      Instrument Corp. Boulder, Colorado, U.S.A.). Room air was free to flow in through
      the mouth and out through the nose and hence to the analyser. The manoeuvre was
      continued until a smooth plateau of at least 20 seconds in duration was achieved
      on a chart recorder. The mean plateau concentrations were 176 (+/- 39.6) parts
      per billion (ppb) for males and 135.8 (+/- 24.4) ppb for females. The mean male
      production of NO was 15.8 nanomol/min which was significantly different from that
      of females of 12.5 nanomol/min (Mann-Whitney U Test; P < 0.01). By measuring the
      concentration of NO in gas aspirated from the nose during Valsalva manoeuvre, we
      excluded the respiratory tract below the glottis from our sampling and as such
      results represent the portion of NO produced in the nose and nasopharynx. These
      findings suggest that nasally produced NO is produced in sufficient quantities to
      act as a continuous pulmonary vasodilator, being inspired preferentially into
      areas of greatest ventilation, thus perhaps acting to continually match
      ventilation to perfusion.

PMID- 8669605
TI  - Limited usefulness of urinary dipsticks to screen out catheter-associated
      bacteriuria in ICU patients.
AB  - The use of urinary dipsticks to screen out sterile urine specimens was
      investigated in catheterized ICU patients. During a three-month period, each
      urine sample quantitatively cultured was concurrently tested at the bedside with
      a dipstick. A total of 102 urine samples taken from 43 patients were analysed.
      Thirty-eight of them showed bacterial or yeast growths (incidence rate, 37%). The
      negative predictive value of the leukocyte esterase pad and/or the nitrate test
      pad to screen out sterile urine samples was 81%, indicating that dipsticks cannot
      routinely be proposed to select catheterized ICU patients for quantitative
      culture of urine.

PMID- 8669607
TI  - Acute pain management in Australia and New Zealand.

PMID- 8669606
TI  - A comparison of two transcutaneous monitors for the measurement of arterial PO2
      and PCO2 in neonates.
AB  - We examined the ability of two transcutaneous devices (Fastrac, Sensormedics
      Corporation, Yorba Linda, California, U.S.A. and Hewlett Packard M1018A, Hewlett
      Packard Component Monitoring System, Hewlett Packard, North Hollywood, U.S.A.) to
      measure arterial PCO2 and PO2 in neonates. Thirty-seven neonates had
      transcutaneous oxygen measured with the Hewlett Packard (HPO2 group), 38 neonates
      had transcutaneous carbon dioxide measured with the Hewlett Packard (HPCO2 group)
      and the Fastrac was used on 27 neonates (FTCO2 group). Both devices were operated
      with electrode temperatures of 43.5 degrees C although an additional ten subjects
      were studied using the Fastrac with an electrode temperature of 43.0 degrees C.
      The mean differences (transcutaneous--arterial) and upper and lower limits of
      agreement were calculated for each group. For the HPO2 group they were 3.78 mmHg
      (-12.23 to 19.80 mmHg), for the HPCO2 group they were 0.40 mmHg (-4.50 to 5.30
      mmHg) and for the FTCO2 they were -0.96 mmHg (-7.85 to 5.92 mmHg). For the
      Fastrac group at an electrode temperature of 43.0 degrees C the mean difference
      and limits of agreement were -1.00 mmHg and -4.58 mmHg to 2.58 mmHg. The average
      sensitivity and specificity for both machines for the detection of hypocarbia
      were 82% and 92% respectively while for hypercarbia they were 90% and 94%
      respectively. For hypoxaemia, the sensitivity and specificity were 40% and 94%
      while for hyperoxaemia the sensitivity and specificity were 83% and 97%. We
      conclude that both machines provide a useful supplement to arterial PCO2
      measurements and the Fastrac performs better at 43.0 degrees C. The measurement
      of PO2 is less accurate but is still of clinical use.

PMID- 8669608
TI  - Australian intensive care educational links with Asian countries.
AB  - A survey examining the level of Australian Intensive Care Unit involvement in the
      education of Asian critical care doctors and nurses was performed. Of the 49
      hospitals surveyed, 34% have ongoing links. An analysis of countries involved,
      proportion of medical and nursing numbers, and whether the teaching was performed
      in Australia or the Asian country was undertaken. The survey revealed that a high
      proportion of Australian Intensive Care Units are actively involved, or would
      consider future participation, in educational links with Asian units.

PMID- 8669609
TI  - Massive rhabdomyolysis following cardiopulmonary bypass.

PMID- 8669610
TI  - Atrial thrombosis induced by percutaneous central venous catheter: a potential
      hazard during cardiac surgery diagnosed by intra-operative transoesophageal echo.

PMID- 8669611
TI  - Real-time ultrasound-guided central venous access via the subclavian approach.

PMID- 8669612
TI  - Balloon occlusion of the abdominal aorta during caesarean hysterectomy for
      placenta percreta.

PMID- 8669613
TI  - Amniotic fluid embolism syndrome: case report and review.

PMID- 8669614
TI  - Amniotic fluid embolism.

PMID- 8669615
TI  - Headache during epidural top-ups in labour--a sign of reduced intracranial
      compliance.

PMID- 8669616
TI  - Pneumocephalus: an unusual complication of resuscitation.

PMID- 8669617
TI  - Anterior traction of the tongue--a forgotten aid to awake fibreoptic intubation.

PMID- 8669618
TI  - Testing the laryngeal mask.

PMID- 8669619
TI  - Klippel-Feil syndrome.

PMID- 8669620
TI  - Postoperative atrial fibrillation due to full bladder.

PMID- 8669621
TI  - Fibreoptic intubation via a laryngeal mask in an infant with Goldenhar syndrome.

PMID- 8669622
TI  - The taste of propofol.

PMID- 8669623
TI  - Breath-guided intubation--blind but not deaf.

PMID- 8669624
TI  - The circuit mount.

PMID- 8669625
TI  - Hepatic necrosis after cardiac surgery.

PMID- 8669626
TI  - "Difficult" airway terminology.

PMID- 8669627
TI  - Hyponatraemia in the transurethral resection of prostate syndrome.

PMID- 8669629
TI  - Transient femoral nerve palsy after ilioinguinal block.

PMID- 8669628
TI  - A comparison of postoperative thrombotic potential following abdominal aortic
      surgery, carotid endarterectomy, and femoro-popliteal bypass.
AB  - Postoperative changes in procoagulant, anticoagulant, and antifibrinolytic
      factors were compared in patients undergoing abdominal aortic surgery, carotid
      endarterectomy, and femoro-popliteal bypass. There were increases in plasma
      fibrinogen (P < 0.01) and factor VIII coagulant (P < 0.01) levels following all
      three procedures. There were decreases in antithrombin III (P < 0.01) and protein
      C (P < 0.01), and increases in thrombin-antithrombin complex levels (P < 0.01) in
      the abdominal aortic group only. There were no significant changes in type 1
      plasminogen activator inhibitor levels following any of the procedures. The
      results indicate that all three procedures are associated with an increased
      potential for thrombosis due to increases in procoagulant factors. However,
      patients undergoing abdominal aortic surgery are particularly at risk due to
      concurrent decreases in natural anticoagulant factors. Specific antithrombotic
      therapy should be considered for all patients undergoing vascular surgery, but
      particularly for those undergoing major procedures such as abdominal aortic
      surgery.

PMID- 8669630
TI  - Airway monitoring in the post anaesthetic recovery room.

PMID- 8669631
TI  - Post suxamethonium myalgia--will we never learn?

PMID- 8669632
TI  - Respiratory arrest with patient-controlled analgesia.

PMID- 8669633
TI  - LMA failure.

PMID- 8669634
TI  - Arterial catheter failure.

PMID- 8669635
TI  - Intraoperative nasotracheal to orotracheal tube change in a patient with Klippel
      Feil syndrome.

PMID- 8669636
TI  - Gastric intramucosal pH.

PMID- 8669637
TI  - Upper airway obstruction in Parkinson's disease.

PMID- 8669638
TI  - Further reflections on "a blind guided technique for endobronchial intubation".

PMID- 8669639
TI  - Two methods of measuring oxygen saturation: why the Bland and Altman statistical
      technique is necessary.

PMID- 8669640
TI  - H. influenzae and asplenia.

PMID- 8669641
TI  - Fatal cardiovascular collapse following propofol induction in high-risk patients.

PMID- 8669642
TI  - Transient bilateral cortical blindness due to hypoxemia.

PMID- 8669643
TI  - A testing torticollis.

PMID- 8669644
TI  - Cervical spine instability in rheumatoid arthritis.

PMID- 8669645
TI  - A simple method of nitric oxide delivery and analysis.

PMID- 8669646
TI  - Severe hypokalaemia due to lignocaine toxicity.

PMID- 8669647
TI  - An assessment of tonometry and regional splanchnic blood flow during aortic cross
      clamping in the pig.
AB  - We aimed to evaluate the tonometer in the assessment of gastrointestinal
      ischaemia induced by an infrarenal aortic cross-clamp. Nine anaesthetized pigs
      were cannulated for haemodynamic monitoring and radionuclide labelled microsphere
      (RLM) injection. Gastric and sigmoid tonometers were positioned. After
      haemodynamic stabilization an infrarenal aortic cross-clamp was applied. Animals
      were sacrificed at the completion of the study and tissue sampled from the
      stomach and sigmoid colon for regional blood flow measurements. Measurements were
      made pre-clamp, post-clamp, pre-release and post-release. Haemodynamic
      parameters, gastric intramucosal pH (pHi) and blood flow did not change
      throughout the experiment. Arterial pH increased during cross-clamp and returned
      to baseline post-release. Arterial bicarbonate fell post release. Sigmoid blood
      flow fell during cross-clamp. The sigmoid pHi fall, delayed until pre-release,
      remained low post-release. Although there was a consistent fall in sigmoid pHi,
      63% of post-clamp values remained within the baseline range. We conclude that
      maintaining haemodynamic parameters around baseline values resulted in
      maintenance of gastric mucosal perfusion as indicated by a steady gastric pHi.
      However, below the aortic cross-clamp, delay between change in sigmoid colon
      blood flow and change in pHi and wide variation in sigmoid pHi limits the value
      of an individual pHi measurement in detecting ischaemia.

PMID- 8669648
TI  - The development of hypercoagulability state, as measured by thrombelastography,
      associated with intraoperative surgical blood loss.
AB  - Thrombelastographic evidence of hypercoagulability, including shortening of r
      time (P < 0.01); shortening of k-time (P < 0.01); and widening of trace angle (P
      < 0.01) were observed in a group of 21 Chinese surgical patients when (a) the
      amount of blood loss was at an estimated 10% of total blood volume and (b) the
      amount of blood loss was at an estimated 15% of blood volume. The amount of blood
      loss was documented by haemoglobin measurements. No evidence of
      hypercoagulability was observed at around one hour into the operation in the
      absence of bleeding. We conclude that a mild to moderate degree of surgical blood
      loss with haemodilution is associated with the development of hypercoagulability
      as measured by thrombelastography. Further studies looking at the thrombebolic
      outcome in such groups of patients is warranted. It is also suggested that
      caution should be exercised in the use of intraoperative isovolaemic
      haemodilution until the phenomenon is further investigated.

PMID- 8669649
TI  - Cerebral effects of propofol following bolus administration in sheep.
AB  - The effects of bolus administration of propofol (50 mg, 100 mg and 200 mg) on
      cerebral blood flow and cerebral metabolic rate for oxygen were examined in a
      chronically catheterized sheep preparation. Depth of anaesthesia was
      simultaneously measured using a withdrawal response to a noxious electrical
      stimulus and it was demonstrated that the 100 mg dose induced moderate sedation
      while the 200 mg dose induced relatively deep anaesthesia. Propofol caused
      transient dose-dependent decreases in cerebral blood flow, despite minimal
      changes in blood pressure. These were accompanied by parallel decreases in
      cerebral metabolic rate but no change in cerebral oxygen extraction. As
      cerebrovascular responses in the sheep appear similar to those in man, the
      parallel changes in cerebral blood flow and metabolic rate demonstrated in this
      study supports the suitability of propofol as a neuroanaesthetic agent.

PMID- 8669650
TI  - Ether before anaesthesia.

PMID- 8669651
TI  - Analgesia for acute musculoskeletal trauma: low-dose subcutaneous infusion of
      ketamine.
AB  - Low-dose ketamine by subcutaneous infusion (0.1 mg/kg/h) was compared in double
      blind fashion with intermittent morphine (0.1 mg/kg intravenously, four-hourly)
      as analgesic regimen in 40 ASA-I adults after acute musculoskeletal trauma. Pain
      was assessed using visual analogue scales and sedation was graded on a four point
      rank drowsiness score. Objective cardiovascular and respiratory parameters and
      patient acceptability in terms of supplementary analgesia and early mobilization
      were also recorded. Pain relief was better with the ketamine infusion than with
      intermittent morphine (P < 0.001). Patients were more awake and alert with
      ketamine infusion as evidenced by the drowsiness score (P < 0.001). Peak
      expiratory flow rate improved significantly with the ketamine infusion (P <
      0.05). None of the patients in ketamine group required supplementary analgesia (P
      < 0.001) and the patients could be easily mobilized for traction/splintage as
      compared with patients in the control group (P < 0.001). The incidence of nausea
      and vomiting in the morphine group was high (P < 0.01). The study shows that
      subcutaneous infusion of ketamine provides safe and effective analgesia in acute
      musculoskeletal trauma.

PMID- 8669652
TI  - Rocuronium bromide in dental day case anaesthesia--a comparison with atracurium
      and vecuronium.
AB  - We have compared intubating conditions at 60 seconds, onset times and reversal
      characteristics of the new steroidal nondepolarizing muscle relaxant rocuronium
      with atracurium and vecuronium. A dose of approximately 1.75 X ED90 of each agent
      was used to assess their relative suitability for brief day case dental
      procedures requiring intubation. The anaesthetic technique included propofol,
      fentanyl, nitrous oxide/oxygen and isoflurane. Electromyography was used to
      assess neuromuscular blockade. The percentage of good or excellent intubating
      conditions at 60 seconds was 80% for rocuronium but only 12.5% each for
      atracurium and vecuronium. The mean percentage block at 60 seconds was 55.1% for
      rocuronium, compared to 9.2% for atracurium and 8.3% for vecuronium. Rocuronium
      had the fastest onset time to maximum block (mean 313 sec) compared to atracurium
      (mean 391.9 sec) and vecuronium (mean 331.9 sec). The duration of action of
      rocuronium was shorter than either atracurium or vecuronium, times for
      spontaneous recovery to 75% block being 22.2 min, 29.6 min and 26.3 min
      respectively. The neostigmine evoked recovery indices were rocuronium 4.2 min,
      atracurium 6.6 min and vecuronium 3.7 min. Maximum blockade of greater than 97%
      was achieved with all three relaxants.

PMID- 8669653
TI  - Intraoperative ventilation with air and oxygen during laparoscopic
      cholecystectomy decreases the degree of postoperative hypoxaemia.
AB  - We studied the effects of intraoperative use of air in oxygen (O2) (FiO2 = 0.33)
      versus nitrous oxide (N2O) in O2 (FiO2 = 0.33) on the degree of postoperative
      hypoxaemia in 30 patients undergoing laparoscopic cholecystectomy. Patients were
      randomly allocated to receive either general anaesthesia with air (Group A, n =
      15) or with N2O (Group N, n = 15). Arterial gas tensions were measured before, 24
      h and 48 h after surgery while breathing room air. The mean PaO2 24 h and 48 h
      postoperatively decreased significantly in both groups compared with the
      preoperative values. The mean PaO2 24 h postoperatively in Group N (74.6 +/- 6.4
      mmHg) tended to be lower than that in Group A (78.1 +/- 8.3 mmHg). The mean PaO2
      48 h postoperatively in Group N (75.0 +/- 7.8 mmHg) was significantly lower than
      that in Group A (83.5 +/- 7.9 mmHg) (P < 0.05). On the contrary, the mean PaCO2
      did not show any significant change during 48 h postoperatively in either group.
      Our results suggest that ventilation with N2O and O2 during laparoscopic
      cholecystectomy is associated with a lower degree of postoperative hypoxaemia.

PMID- 8669654
TI  - Patient-controlled epidural analgesia following caesarean delivery: a comparison
      of pethidine and fentanyl.
AB  - Pethidine and fentanyl have both been used to provide patient-controlled epidural
      analgesia (PCEA) following caesarean delivery. Both have been compared with
      epidural morphine but these drugs have not been compared with each other. Patient
      controlled epidural analgesia was used in a prospective, randomized, double
      blind, cross-over trial to compare fentanyl and pethidine for postoperative
      epidural analgesia in women having elective caesarean deliveries. Two groups
      received either PCEA fentanyl or pethidine with a cross-over to the other drug
      after 24 hours. Results from 45 patients showed no difference in pain level
      outcomes, but pethidine scored better in all side-effects except for drowsiness
      at 48 hours. Patients were more satisfied with pethidine (P = 0.015) and overall
      65% of patients preferred pethidine. We conclude that pethidine is a suitable
      drug for patient-controlled epidural analgesia and leads to greater patient
      satisfaction than does fentanyl.

PMID- 8669655
TI  - Evaluation of a disposable device for patient-controlled epidural analgesia after
      caesarean section.
AB  - We evaluated a disposable device (Baxter PCA Infusor) for patient-controlled
      epidural analgesia (PCEA) using pethidine in twenty women after lower segment
      caesarean section. Efficacy, as measured by visual analogue pain scores, was
      comparable with historical controls from PCEA studies using electronic devices.
      Three patients reported inadequate analgesia, attributable in two cases to
      problems with epidural catheter. PCEA was stopped in one patient because of side
      effects. Pethidine consumption ranged from 125 to 1500 mg (median 575 mg) in 48
      hours. Plasma concentrations of pethidine varied widely. Disposable devices for
      PCEA after caesarean section provide an alternative to bolus administration or
      PCEA using more expensive and cumbersome electronic devices, although we suggest
      currently available apparatus requires modifications to improve clinical
      performance.

PMID- 8669657
TI  - Echocardiography assessment of left ventricular function in the critically ill.
AB  - Echocardiography is fast becoming the technique of choice for noninvasive
      evaluation of left ventricular function in the critically ill patient. Current
      technology allows for assessment of overall left ventricular performance and for
      diastolic and systolic function. Doppler technology has greatly enhanced the
      diagnostic capability of two-dimensional echocardiography. The critical care
      physician should be aware not only of currently available techniques, but also
      those which will be used in the routine care of the critically ill subject in the
      foreseeable future.

PMID- 8669656
TI  - Percutaneous dilational tracheostomy--a clinical study evaluating two systems.
AB  - Percutaneous dilational tracheostomy (PDT), first described in the 1950s, has
      become a common bedside technique in the Intensive Care Unit (ICU). This study
      compares the early complications associated with the use of the Ciaglia PDT (Cook
      Critical Care, Bloomington, USA) technique, with the newly available Portex PDT
      technique (Portex Ltd., UK). The Ciaglia technique was adopted in this ICU in
      July 1994 and twenty-nine patients had a tracheostomy using this set until
      January 1995. Complications during the procedure were collected prospectively.
      When the Portex PDT set became available in January 1995, it was decided to
      assess the complication rate of this technique and compare them to the previously
      collected data using the Ciaglia PDT set. Twenty-five patients have had a
      tracheostomy using the Portex PDT set. There has been no mortality associated
      with either PDT set. Bleeding requiring intervention occurred in two patients in
      the Ciaglia group and three patients in the Portex Group. All these patients had
      a bleeding diathesis. Loss of airway control occurred on one occasion in the
      Ciaglia group due to premature removal of the endotracheal tube. The first
      routine tracheostomy tube change at day 7 was complicated in four cases in the
      Ciaglia group. One infected stoma was noted in the Ciaglia group at day 7. Both
      techniques result in rapid, safe placement of a tracheostomy tube in critically
      ill patients in the ICU, obviating the need for surgical referral and transport
      to the operating room.

PMID- 8669658
TI  - Deaths attributed to anaesthesia in New South Wales, 1984-1990.
AB  - The New South Wales Special Committee Investigating Deaths Under Anaesthesia
      classified 1503 deaths before full recovery from anaesthesia occurring between
      1984 and 1990. 172 deaths were attributed to anaesthesia, including 11 in which
      the anaesthetic choice or management could not be criticized. In the remaining
      161 an average of 1.8 errors per case were identified, the most frequent being
      inadequate preparation of the patient (in 72 cases), inadequate postoperative
      care (52 cases), the technique of anaesthesia chosen (44 cases) and overdose (43
      cases). Death was most commonly attributed to anaesthesia in elderly patients
      (modal age group 70-79), in males (1.9:1) and was most commonly associated with
      abdominal and orthopaedic operations. Urgent non-emergency cases, 10% of the 1503
      cases classified, constituted 26% of those deaths attributed to anaesthesia. One
      death attributable to anaesthesia occurred per 20,000 operations and the rate of
      such deaths was 0.44 per 100,000 population per annum.

PMID- 8669659
TI  - Review of efficiencies and patient satisfaction in Australian and New Zealand day
      surgery units: a pilot study.
AB  - A pilot study was performed in eight Australasian day surgery facilities with a
      purpose of identifying common trends and differences. A prospective study was
      designed in which information was collected on 826 patients over a two-week
      period. Patients were well matched for age, anaesthetic type and mean surgical
      time. Three facility types were identified and results were statistically
      corrected for any differences that ASA status, age and surgical time may have
      made. Patient preoperative waiting time, recovery room times, delayed discharge
      time and unanticipated admission rates showed favourable outcome trends for free
      standing facilities compared with hospital-integrated facilities where day
      patients had a shared recovery with inpatients. Similar trends were seen with
      patient opinions of waiting times and recovery periods. In summary, this pilot
      study has demonstrated the impact of different facility types on efficiencies and
      patient satisfaction both of which have important cost implications and relevance
      to those involved in continuous quality improvement processes in day surgery.

PMID- 8669660
TI  - Attitudes and practices of New Zealand anaesthetists with regard to epidural and
      subarachnoid anaesthesia.
AB  - A survey was conducted among 259 New Zealand specialist anaesthetists to assess
      attitudes and practices with regard to epidural or subarachnoid anaesthesia
      (ESA). Ninety-four per cent replied and virtually all of the respondents
      indicated that they performed ESA at some time. ESA was used by most
      anaesthetists for most patients undergoing major hip or knee surgery, abdomino
      perineal resection, cystectomy, caesarean section or transurethral resection of
      the prostate, ESA was used is about half of patients undergoing abdominal aortic
      aneurysm repair, femoro-popliteal bypass or thoracotomy and there was marked
      variation between anaesthetists in the frequency of using ESA for these
      procedures. There was broad consensus about the importance of a number of factors
      that might influence the decision to employ ESA; in particular that systemic
      sepsis and prolonged bleeding time were important contraindications and that
      patient preference and chronic lung disease were important indications. However
      respondents were equally divided as to whether they felt that recent myocardial
      infarction or congestive heart failure constituted indications or
      contraindications to ESA.

PMID- 8669662
TI  - Loss of cerebral pressure autoregulation and vasoreactivity to carbon dioxide
      after cerebral hypoxia.

PMID- 8669661
TI  - Inhaled aerosolized prostacyclin as a selective pulmonary vasodilator for the
      treatment of severe hypoxaemia.
AB  - Two case reports are presented where inhaled aerosolized prostacyclin (IAP) was
      used to good effect as a selective pulmonary vasodilator. It was used in the
      treatment of a patient with severe hypoxaemia secondary to amniotic fluid
      embolism and for hypoxaemia secondary to the acute respiratory distress syndrome
      (ARDS) in a patient with acute on chronic liver failure and intra-abdominal
      sepsis. An apparent dose-response curve is demonstrated in the second case. A
      dose of IAP of 30-40 ng/kg/min produced an effect on oxygenation in the patient
      with liver failure equal to that seen at the maximal dose of (50 ng/kg/min).
      Reduction in dose below 30 ng/kg/min resulted in a deterioration in oxygenation
      towards baseline/pre-treatment levels. Inhaled aerosolized prostacyclin is a
      potent pulmonary vasodilator with little or no systemic hypotensive effect. It is
      simple to administer and would appear to be a viable alternative to inhaled
      nitric oxide.

PMID- 8669663
TI  - Pneumothorax during laparoscopic Nissen fundoplication.

PMID- 8669664
TI  - Respiratory arrest in two children following postoperative flushing of
      suxamethonium from the deadspace of intravenous cannulae.

PMID- 8669665
TI  - Accidental nicardipine overdosage without serious maternal or neonatal
      consequence.

PMID- 8669666
TI  - Complex pharmacology of malignant hyperthermia.

PMID- 8669667
TI  - Effects of the serotonin2 receptor agonist DOI on skeletal muscle specimens from
      malignant hyperthermia-susceptible patients.
AB  - BACKGROUND: Administration of serotonin2 (5-HT2) receptor agonists in pigs
      triggers malignant hyperthermia (MH) and psychotic-like behavior. Both can be
      reduced by 5-HT2 receptor antagonists. Furthermore, an increase in the plasma
      concentration of 5-HT has been found during onset of halothane-induced MH in
      pigs. Therefore, in this study, the in vitro effects of the 5-HT2 receptor
      agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were investigated in
      muscle specimens from MH-susceptible (MHS) and -negative (MHN) patients. METHODS:
      After MH classification using the caffeine-halothane contracture test (CHCT),
      surplus muscle specimens from 23 MHS and 17 MHN patients were used to examine the
      effects of DOI. In the first study, DOI was added to the bath in a concentration
      of 0.02 mM. In a second experiment, muscles were preincubated for 60 min with
      0.02 mM DOI, and subsequently, halothane was added incrementally to the organ
      bath (0.11-0.22-0.44 mM) for 15 min according to the CHCT protocol. The in vitro
      effects of DOI on contracture development and muscle twitch were measured for 120
      min in both investigations. RESULTS: Muscle specimens form all patients developed
      contractures after administration of DOI, characterized by a significantly
      earlier development of contracture in MHS (16.8 +/- 1.7 min) than in MHN (66.3 +/
      5.8 min) muscles (P < 0.05). There was no overlap between the groups in the
      range of times. The onset of contracture development after DOI was prolonged by
      halothane in specimens from MHN patients (89.7 +/- 5.6 min) but not MHS patients.
      Preincubation with DOI increased the halothane-induced contractures in specimens
      from MHS patients compared to the results of the CHCT. The contracture
      development in specimens from MHS patients was larger than from MHN patients. At
      the end of the experiment, contractures had reached a maximum of 12.9 +/- 1.1 mN
      in specimens from MHS and 5.3 +/- 0.6 mN in MHN patients (P < 0.05). The
      additional administration of halothane led to significantly increased
      contractures in specimens from MHS individuals (15.9 +/- 0.9 mN) at 120 min.
      However, the contracture development decreased significantly to 3.1 +/- 0.4 mN in
      MHN muscles. Muscle twitch after DOI administration was reduced significantly in
      specimens from MHS and MHN patients. CONCLUSIONS: A functional or structural
      altered serotonin system might be involved in the development of MH in humans.

PMID- 8669668
TI  - Pharmacokinetics of propofol in adult patients undergoing coronary
      revascularization. The Multicenter Study of Perioperative Ischemia Research
      Group.
AB  - BACKGROUND: Propofol is increasingly used for cardiac anesthesia and for
      perioperative sedation. Because pharmacokinetic parameters vary among distinct
      patient populations, rational drug dosing in the cardiac surgery patient is
      dependent on characterization of the drug's pharmacokinetic parameters in
      patients actually undergoing cardiac procedures and cardiopulmonary bypass (CPB).
      In this study, the pharmacokinetics of propofol was characterized in adult
      patients undergoing coronary revascularization. METHODS: Anesthesia was induced
      and maintained by computer-controlled infusions of propofol and alfentanil, or
      sufentanil, in 41 adult patients undergoing coronary artery bypass graft surgery.
      Blood samples for determination of plasma propofol concentrations were collected
      during the predefined study periods and assayed by high-pressure liquid
      chromatography. Three-compartment model pharmacokinetic parameters were
      determined by nonlinear extended least-squares regression of pooled data from
      patients receiving propofol throughout the perioperative period. The effect of
      CPB on propofol pharmacokinetics was modeled by allowing the parameters to change
      with the institution and completion of extracorporeal circulation and selecting
      the optimal model on the basis of the logarithm of the likelihood. Predicted
      propofol concentrations were calculated by convolving the infusion rates with
      unit disposition functions using the estimated parameters. The predictive
      accuracy of the parameters was evaluated by cross-validation and by a prospective
      comparison of predicted and measured levels in a subset of patients. RESULTS:
      Optimal pharmacokinetic parameters were: central compartment volume = 6.0 l;
      second compartment volume = 49.5 l; third compartment volume = 429.3 l; Cl1
      (elimination clearance) = 0.68 l/min; Cl2 (distribution clearance) = 1.97 l/min1;
      and Cl3 (distribution clearance) = 0.70 l/min. The effects of CPB were optimally
      modeled by step changes in V1 and Cl1 to values of 15.9 and 1.95, respectively,
      with the institution of CPB. Median absolute prediction error was 18% in the
      cross-validation assessment and 19% in the prospective evaluation. There was no
      evidence for nonlinear kinetics. Previously published propofol pharmacokinetic
      parameter sets poorly predicted the observed concentrations in cardiac surgical
      patients. CONCLUSIONS: The pharmacokinetics of propofol in adult patients
      undergoing cardiac surgery with CPB are dissimilar from those reported for other
      adult patient populations. The effect of CPB was best modeled by an increase in
      V1 and Cl1. Predictive accuracy of the derived pharmacokinetic parameters was
      excellent as measured by cross-validation and a prospective test.

PMID- 8669669
TI  - Normothermic continuous blood cardioplegia improves electrophysiologic recovery
      after open heart surgery.
AB  - BACKGROUND: Myocardial protection during open heart surgery is based on
      administration of oxygenated blood cardioplegia, the preferred temperature of
      which is still under debate. The current randomized study was designed to
      prospectively evaluate the quality of myocardial protection and the functional
      recovery of the heart with either normothermic (group N) or hypothermic (group H)
      oxygenated blood cardioplegia. METHODS: Under continuous electrocardiographic
      Holter monitoring, 42 patients were randomly scheduled to receive either
      normothermic (33.5 degrees C) or hypothermic (10 degrees C) cardioplegia
      solutions during coronary bypass grafting surgery. Blood samples for creatinine
      phosphokinase, creatinine phosphokinase-MB, lactate, epinephrine, and
      norepinephrine were withdrawn during cardiopulmonary bypass via a coronary sinus
      cannula. RESULTS: Active cooling in group H on initiation of cardiopulmonary
      bypass was characterized by transition through ventricular fibrillation in 75% of
      patients, whereas in group N atrial fibrillation occurred in 65% of patients. On
      myocardial reperfusion, sinus rhythm spontaneously resumed in 95% of group N
      patients compared to 25% in group H (P = 0.0003). In the latter, 75% of patients
      developed ventricular fibrillation often followed by complete atrioventricular
      block, which necessitated temporary pacing for a mean duration of 168 +/- 32 min.
      Both groups showed a similar incidence of intraventricular block and ST segment
      changes. However, the incidence of ventricular premature beats in the first 16 h
      after cardiopulmonary bypass was significantly greater in group H (P < 0.05), 20
      +/- 26/h, compared to 3 +/- 5/h in group N. Blood concentrations of lactate,
      creatinine phosphokinase, epinephrine, and norepinephrine increased gradually
      during the operation, but the differences between the groups were not
      significant. CONCLUSIONS: The current prospective human study suggests that the
      increased susceptibility for ventricular fibrillation and dysrhythmia, and the
      delayed recovery of the conduction system after hypothermic myocardial
      protection, are related to temperature-induced changes in vital cellular
      functions of the conduction tissue in the postischemic period. Both cardioplegic
      methods provide adequate myocardial protection but normothermic oxygenated blood
      cardioplegia may accelerate recovery of the heart after cardiopulmonary bypass.

PMID- 8669670
TI  - Comparison of the effects of etomidate, propofol, and thiopental on respiratory
      resistance after tracheal intubation.
AB  - BACKGROUND: Tracheal intubation frequently results in reversible
      bronchoconstriction. Propofol has been reported to minimize this response in
      healthy patients and in asthma patients, but may be unsuitable for
      hemodynamically unstable patients for whom etomidate may be preferable. The
      current study examined respiratory resistance after tracheal intubation after
      induction with either thiopental, etomidate, or propofol. A supratherapeutic dose
      of etomidate was used to test the hypothesis that the bronchoconstrictive
      response could be minimized by deep intravenous anesthesia. METHODS: Seventy
      seven studies were conducted in 75 patients. Anesthesia was induced with either
      2.5 mg/kg propofol, 0.4 mg/kg etomidate, or 5 mg/kg thiopental. Respiratory
      resistance was measured at 2 min after induction. RESULTS: Respiratory resistance
      at 2 min was 8.1 +/- 3.4 cmH2O.1(-1).s (mean +/- SD) for patients receiving
      propofol versus 11.3 +/- 5.3 for patients receiving etomidate and 12.3 +/- 7.9
      for patients receiving thiopental (P < or = 0.05 for propofol vs. either
      etomidate or thiopental). CONCLUSIONS: Respiratory resistance after tracheal
      intubation is lower after induction with propofol than after induction with
      thiopental or after induction with high-dose etomidate.

PMID- 8669671
TI  - Thoracic epidural anesthesia via the lumbar approach in infants and children.
AB  - BACKGROUND: In upper abdominal or chest surgery, the segmental approach to
      thoracic epidural space has the advantage of reducing the total dose of local
      anesthetic needed. This approach, however, is associated with greater risk of
      neurologic damage or dural puncture. The aim of this study was to assess the
      success and the degree of difficulty in advancing a 19-G catheter from the lumbar
      epidural space to the thoracic level in patients aged 0-96 months. METHODS: In 39
      patients undergoing abdominal surgery, the cutaneous distance between the L4-L5
      and T10-T11 interspaces was measured, and an appropriate length of 19-G catheter
      was inserted into the epidural space through an 18-G Tuohy needle with bevel
      directed cephalad. The intent was to advance the full length of catheter measured
      to reach the objective. The tips were observed radiologically, and all those
      positioned cephalad to the T12 level were considered well placed. The degree of
      difficulty in advancing the catheter was classified as easy, difficult, or
      impossible. Complications reported were vascular and/or spinal puncture and
      difficulty removing the catheter. RESULTS: The catheter tip reached T10-T12 in 7
      patients, L2 in 1, L3 in 8, and L4-L5 in 23. Forty-eight percent of the catheters
      described as easily advanced remained at the L4-L5 level, and only 22% reached
      the desired level. Difficult insertions occurred in eight patients, in whom the
      objective was never reached. One case of intravascular insertion was reported.
      All catheters were removed without difficulty. CONCLUSIONS: The 19-G catheter is
      inappropriate for use in reaching the thoracic epidural space by the lumbar
      approach. Easy entrance of a catheter is not a reliable sign of having reached
      the desired level.

PMID- 8669672
TI  - Concentration-effect relationships of eltanolone given as a bolus dose or
      constant rate intravenous infusion to healthy male volunteers.
AB  - BACKGROUND: The primary purpose of this study was to evaluate concentration
      effect relationships of the new steroid anesthetic eltanolone during recovery
      from a bolus dose and constant rate intravenous infusion in healthy male
      volunteers. METHODS: Ten subjects received a bolus dose of 0.75 mg/kg eltanolone
      over 20 s. A 2-h constant rate intravenous infusion of eltanolone was given to
      five subjects at a rate of 2 mg.kg-1.h-1 and to another five subjects at a rate
      of 3.5 mg.kg-1.h-1. Recovery performance was assessed as the time required to
      reach different end-points and by means of three different psychomotor tests.
      RESULTS: A low interindividual variability was found in the serum concentration
      of eltanolone at the pharmacodynamic end-points during recovery. The Cp50 value
      for "eye opening" was 382 micrograms/L (95% confidence interval, 285-489) after a
      bolus dose corresponding to a median time of 16 min (range 8-25). After
      eltanolone infusion, the Cp50 value for "eye opening" was 507 micrograms/L (95%
      confidence interval, 425-605) and the corresponding median time was 21 min (range
      8-25) in the low-dose group and 49 min (range 31-66) in the high-dose group. The
      Cp50 values at the same effect end-points in the bolus group were less than those
      in the infusion groups, probably because of insufficient equilibration time
      between serum and the effect compartment. CONCLUSIONS: Recovery characteristics
      of eltanolone were predictable because of a relatively low interindividual
      variability in serum concentrations but with a slow blood:effect compartment
      equilibration.

PMID- 8669673
TI  - Reduction in the shivering threshold is proportional to spinal block height.
AB  - BACKGROUND: Hypothermia is nearly as common, and may be as severe, during spinal
      and epidural anesthesia as during general anesthesia. The authors have proposed
      that thermoregulatory failure results when regional anesthesia increases apparent
      leg skin temperature to a level far exceeding actual leg skin temperature.
      Extensive dermatomal blocks will alter thermal input to the hypothalamus from a
      greater skin-surface area more than less extensive ones and thus might be
      expected to impair central thermoregulatory control more. Accordingly, they
      tested the hypothesis that reduction in the shivering threshold is directly
      related to the number of dermatomes blocked during spinal anesthesia. METHODS:
      Eleven men, aged 62 +/- 6 yr (mean +/- SD), undergoing urologic surgery were
      studied. Ice-cold lactated Ringer's solution was administered intravenously
      before spinal blockade and the shivering threshold (triggering core temperature)
      was established. Spinal anesthesia then was induced using a randomly assigned
      dose of 0.5% bupivacaine (2-4 ml). Again, sufficient cold lactated Ringer's
      solution was given to induce shivering. Tympanic membrane, ambient and skin
      temperatures were measured, and extent of block was defined by loss of
      temperature discrimination. Presence of shivering was evaluated by a blinded
      observer. Mean upper-body skin and ambient temperatures, cooling rates and
      intravenous fluid volumes at the two thresholds were compared using paired, two
      tailed t tests (P < 0.05). Linear regression defined the relationship between
      reduction in shivering threshold and the number of dermatomes blocked. RESULTS:
      There were no significant differences between mean upper-body skin and ambient
      temperatures, cooling rates or intravenous fluid volumes at the control and
      spinal shivering thresholds. Spinal anesthesia reduced the shivering threshold in
      direct relation to the number of dermatomes blocked: delta threshold = 0.74 -
      0.06 (dermatomes blocked); r2 = 0.58, P < 0.006. CONCLUSIONS: Extensive spinal
      blockade impairs central thermoregulatory control more than less extensive
      blockade. Clinicians can thus anticipate more core hypothermia during extensive
      than during restricted spinal blockade.

PMID- 8669674
TI  - Induction, recovery, and safety characteristics of sevoflurane in children
      undergoing ambulatory surgery. A comparison with halothane.
AB  - BACKGROUND: Sevoflurane is an inhalational anesthetic with characteristics suited
      for use in children. To determine whether the induction, recovery, and safety
      characteristics of sevoflurane differ from those of halothane, the following open
      labeled, multicenter, randomized, controlled, phase III study in children
      undergoing ambulatory surgery was designed. METHODS: Three hundred seventy-five
      children, ASA physical status 1 or 2, were randomly assigned in a 2:1 ratio to
      receive either sevoflurance or halothane, both in 60% N2O and 40% O2. Anesthesia
      was induced using a mask with an Ayre's t piece or Bain circuit in four of the
      centers and a mask with a circle circuit in the fifth center. Maximum inspired
      concentrations during induction of anesthesia were 7% sevoflurane and 4.3%
      halothane. Anesthesia was maintained by spontaneous ventilation, without tracheal
      intubation. End-tidal concentrations of both inhalational anesthetics were
      adjusted to 1.0 MAC for at least 10 min before the end of surgery. Induction and
      recovery characteristics and all side effects were recorded. The plasma
      concentration of inorganic fluoride was measured at induction of and 1 h after
      anesthesia. RESULTS: During induction of anesthesia, the time to loss of the
      eyelash reflex with sevoflurane was 0.3 min faster than with halothane (P <
      0.001). The incidence of airway reflex responses was similar, albeit infrequent
      with both anesthetics. The total MAC.h exposure to sevoflurane was 11% less than
      the exposure to halothane (P < 0.013), although the end-tidal MAC multiple during
      the final 10 min of anesthesia was similar for both groups. Early recovery as
      evidenced by the time to response to commands after sevoflurane was 33% more
      rapid than it was after halothane (P < 0.001), although the time to discharge
      from hospital was similar for both anesthetics. The mean ( +/- SD) plasma
      concentration of inorganic fluoride 1 h after discontinuation of sevoflurane was
      10.3 +/- 3.5 microM. The overall incidence of adverse events attributable to
      sevoflurane was similar to that of halothane, although the incidence of agitation
      attributable to sevoflurane was almost threefold greater than that attributable
      to halothane (P < 0.004). CONCLUSIONS: Sevoflurane compared favorably with
      halothane. Early recovery after sevoflurane was predictably more rapid than after
      halothane, although this was not reflected in a more rapid discharge from the
      hospital. The incidence of adverse events was similar for both anesthetics.
      Clinically, the induction, recovery, and safety characteristics of sevoflurane
      and halothane are similar. Sevoflurane is a suitable alternative to halothane for
      use in children undergoing minor ambulatory surgery.

PMID- 8669675
TI  - Magnetic resonance imaging of cerebrospinal fluid volume and the influence of
      body habitus and abdominal pressure.
AB  - BACKGROUND: Although the cerebrospinal fluid (CSF) is the pathway of anesthetic
      delivery and the diluent for neuraxially administered drugs, little is known
      about its volume, including variability among individuals, longitudinal
      distribution, or influence of body habitus. Models made to investigate
      subarachnoid anesthetic distribution lack valid dimensions. CSF volume was
      measured in volunteers, and the effect of obesity and abdominal compression on
      CSF volume was evaluated using magnetic resonance imaging. METHODS: Low thoracic
      and lumbosacral axial magnetic resonance images of 25 healthy volunteers were
      obtained at 8-mm intervals by fast spin-echo sequence, which highlights CSF. A
      repeat image series was performed in 15 subjects during external abdominal
      compression. In two subjects, images were obtained without compression for the
      entire vertebral column. Dural sac and spinal cord areas were determined in a
      blinded fashion for each image using video/digital analysis. Area of the sac
      minus area of the cord constituted area of CSF and roots ("CSF/root"); this area
      multiplied by 8 mm resulted in CSF/root volume per section. RESULTS: There is
      great interindividual variability in CSF/root volume. From the T11-T12 disc to
      the sacral terminus of the dural sac, the mean volume for all subjects is 49.9 +/
      12.1 ml (mean +/- SD; range 28.0-81.1 ml). This volume was significantly less in
      relatively obese subjects (42.9 +/- 9.5 ml) than in nonobese subjects (53.5 +/-
      12.9 ml). Abdominal compression decreased CSF/root volume by 3.6 +/- 3.2 ml.
      Sections through intervertebral foramina showed the biggest decrease with
      abdominal compression, with a lesser change in sections with veins and no change
      in the absence of these anatomic features. Total vertebral CSF/root volume in two
      subjects was 94.84 and 120.01 ml, respectively. CONCLUSIONS: CSF volume is widely
      variable between individuals. The decreased CSF volume that results from
      increased abdominal pressure, such as with obesity or pregnancy, may produce more
      extensive neuraxial blockade through diminished dilution of anesthetic. The
      mechanism by which increased abdominal pressure decreases CSF volume is probably
      inward movement of soft tissue in the intervertebral foramen, which displaces
      CSF.

PMID- 8669676
TI  - Cardiovascular responses during sedation after coronary revascularization.
      Incidence of myocardial ischemia and hemodynamic episodes with propofol versus
      midazolam. Institutions of the McSPI Research Group.
AB  - BACKGROUND: Propofol sedation offers advantages for titration and rapid emergence
      in the critically ill patient, but concern for adverse hemodynamic effects
      potentially limits its use in these patients. The current study compares the
      cardiovascular effects of sedation with propofol versus midazolam during the
      first 12 h after coronary revascularization. METHODS: Three hundred fifty-one
      patients undergoing coronary revascularization were anesthetized using a
      standardized sufentanil/midazolam regimen, and assigned randomly to 12 h of
      sedation with either propofol or midazolam while tracheally intubated. The
      incidence and characteristics of hemodynamic episodes, defined as heart rate less
      than 60 or greater than 100 beats/min or systolic blood pressure greater than 140
      or less than 90 mmHg, were determined using data electronically recorded at 1-min
      intervals. The presence of myocardial ischemia was determined using continuous
      three-channel Holter electrocardiography (ECG) and of myocardial infarctions (MI)
      using 12-lead ECG (Q wave MI, Minnesota Code) or creatine kinase isoenzymes (CK
      MB) analysis (non-Q wave MI, peak CK-MB > 70 ng/ml, or CK-MB > 70 IU/I). RESULTS:
      Ninety-three percent of patients in both treatment groups had at least one
      hemodynamic episode during the period of postoperative sedation. Propofol
      sedation resulted in a 17% lower incidence of tachycardia (58% vs. 70%, propofol
      vs. midazolam; P = 0.04), a 28% lower incidence of hypertension (39% vs. 54%; P =
      0.02), and a greater incidence of hypotension (68% vs. 51%; P = 0.01). Despite
      these hemodynamic effects, the incidence of myocardial ischemia did not differ
      between treatment groups (12% propofol vs. 13% midazolam; P = 0.66), nor did its
      severity, as measured by ischemic minutes per hour monitored (8.7 +/- 5.8 vs. 6.2
      +/- 4.6 min/h, propofol vs. midazolam; P = 0.19) or ischemic area under the curve
      (6.8 +/- 4.0 vs. 5.3 +/- 4.2; P = 0.37). The incidence of cardiac death (one per
      group), Q wave MI (propofol, n = 7; midazolam, n = 3; P = 0.27), or non Q wave MI
      (propofol, n = 16; midazolam, n = 18; P = 0.81) did not differ between treatment
      groups. CONCLUSIONS: Hemodynamic episodes occur frequently in the first 12 h
      after coronary revascularization. Compared with a standard sedation regimen
      (midazolam), propofol sedation appears to modulate postoperative hemodynamic
      responses by reducing the incidence and severity of tachycardia and hypertension
      and increasing the incidence of hypotension. Both sedation regimens appear
      similarly safe with respect to myocardial ischemia. These findings indicate that
      propofol infusion provides effective sedation without deleterious hemodynamic
      effects in patients recovering from cardiac surgery.

PMID- 8669677
TI  - Prospective study of the incidence of transient radicular irritation in patients
      undergoing spinal anesthesia.
AB  - BACKGROUND: There is considerable controversy regarding the role of subarachnoid
      5% hyperbaric lidocaine in the syndrome transient radicular irritation (TRI).
      This randomized, double-blinded, prospective study was designed to determine the
      incidence of TRI and identify factors possibly contributing to its development.
      METHODS: One hundred fifty-nine ASA physical status 1 or 2 patients undergoing
      outpatient knee arthroscopy or unilateral inguinal hernia repair were
      prospectively randomized to receive spinal anesthesia with 5% hyperbaric
      lidocaine with epinephrine (60 mg with 0.2 mg epinephrine for arthroscopy or 75
      mg with 0.2 mg epinephrine for hernia repair), 2% isobaric lidocaine without
      epinephrine (60 mg for arthroscopy or 75 mg for hernia repair), or 0.75%
      hyperbaric bupivacaine without epinephrine (7.5 mg for arthroscopy or 9.0 mg for
      hernia repair) in a double-blinded fashion. On the 3rd postoperative day,
      patients were contacted by a blinded investigator and questioned regarding the
      incidence of postoperative complications including TRI, defined as back pain with
      radiation down one or both buttocks or legs occurring within 24 h after surgery.
      Postoperatively, time from injection to block resolution, ambulation, voiding,
      and ready for discharge were recorded by a postanesthesia care unit nurse blinded
      to the group assignment. RESULTS: The incidence of TRI was greater in patients
      receiving lidocaine than in those receiving bupivacaine (16% vs. 0%; P = 0.003).
      There was no difference in the incidence of TRI between the patients receiving 5%
      hyperbaric lidocaine with epinephrine and those receiving 2% isobaric lidocaine
      without epinephrine (16% vs. 16%; P = 0.98). The incidence of TRI was greater in
      patients undergoing arthroscopy than in those undergoing hernia repair (13% vs.
      5%; P = 0.04). There was no difference in discharge times in patients receiving
      bupivacaine versus those receiving hyperbaric lidocaine with epinephrine (292 vs.
      322 min; P = 0.61). CONCLUSIONS: The incidence of TRI is greater with lidocaine
      than bupivacaine, decreasing the lidocaine concentration to 2% does not prevent
      TRI, and surgical position may be an important contributing factor. Discharge
      times at our institution are not different when equipotent doses of 0.75%
      hyperbaric bupivacaine or 5% hyperbaric lidocaine with 0.2 mg epinephrine are
      used in ambulatory patients undergoing spinal anesthesia.

PMID- 8669678
TI  - Dantrolene sodium can increase or attenuate activity of skeletal muscle ryanodine
      receptor calcium release channel. Clinical implications.
AB  - BACKGROUND: Dantrolene sodium (DS) is a direct-acting skeletal muscle relaxant
      whose only known action is to block calcium release from intracellular storage
      sites. The exact site of action for DS is unknown, but its efficacy in treating
      and preventing anesthetic-induced malignant hyperthermia (MH) is well
      established. METHODS: Single ryanodine (Ry1) receptor calcium release channels
      were incorporated into a planar lipid bilayer for electrophysiologic recording
      and for subsequent analysis of the channel's gating and conductance properties.
      The cellular effects of low DS concentrations were investigated by isometric
      contracture tension responses in biopsied MH human and dog muscle fascicles and
      in normal, single fibers from human vastus lateralis muscle. RESULTS: Two
      concentration-dependent DS effects on the isolated Ry1 receptor were discovered,
      suggesting at least two different binding sites. At nanomolar concentrations, DS
      activated the channel by causing three-to fivefold increases in open-state
      probability and dwell times. At micromolar concentrations, DS first increased
      then reduced activity in the channels; with the dominant effect being reduced
      activity. A 20 nm concentration of DS produced significant contracture tension in
      human muscle from one MH subject and caused potentiation of twitch in muscle from
      another MH patient. Halothane contracture in MH dog muscle was followed by an
      additional increase in tension when treated with 20 nm DS. Other investigations
      on chemically skinned, human fibers showed that calcium loaded in the
      sarcoplasmic reticulum was partially released by nM DS. CONCLUSIONS: The study
      results suggest that at least two binding sites for DS exist on the Ry1 receptor
      calcium channel. A low-affinity (microM) site is associated with reduced channel
      gating and open-state dwell time and may relate to the established pharmacologic
      muscle relaxant effect of DS. The proposed high-affinity (nM) DS binding site
      activates the channel, producing Ca2+ release to the myoplasm, which, under
      environmentally adverse conditions, could damage genetically predisposed MH
      muscle. Such a phenomenon, if it occurs in DS treated MH patients, could generate
      a recrudescence of the syndrome.

PMID- 8669679
TI  - Chlorocresol, an additive to commercial succinylcholine, induces contracture of
      human malignant hyperthermia-susceptible muscles via activation of the ryanodine
      receptor Ca2+ channel.
AB  - BACKGROUND: A defect in the ryanodine (Ry1) receptor Ca2+ channel has been
      implicated as one of the possible underlying causes of malignant hyperthermia
      (MH), a pharmacogenetic disorder characterized by sustained muscle contracture.
      The disease is triggered by common halogenated anesthetics and skeletal muscle
      relaxants, such as succinylcholine. This study tested whether the functional
      properties of the Ry1 receptor Ca2+ channel are affected by chlorocresol, a
      preservative added to a commercial preparation of succinylcholine (Midarine) and
      other parenteral compounds. METHODS: In vitro contracture testing was carried out
      on muscle biopsies from malignant hyperthermia-susceptible (MHS) and -negative
      (MHN) individual according to the protocol of the European MH group. Ca2+ flux
      studies on isolated rabbit sarcoplasmic reticulum fractions were measured
      spectrophotometrically by following the A710-790 of the Ca2+ indicator
      antipyrylazo III. RESULTS: Chlorocresol causes muscle contracture in MHS muscles
      at a concentration of 25-50 microM and potentiates the caffeine contracture
      response in human MHS muscles. Sub-threshold (20 microM) concentrations of
      chlorocresol increase both the Kd and the Vmax of caffeine-induced Ca2+ release
      from isolated rabbit terminal cisternae. CONCLUSIONS: These data suggest that, in
      muscle from MHS individuals, the enhanced Ca2+ released from the sarcoplasmic
      reticulum may not be due to the effect of succinylcholine alone but rather to the
      action of the preservative chlorocresol added to the drug.

PMID- 8669680
TI  - Acute lung injury after instillation of human breast milk or infant formula into
      rabbits' lungs.
AB  - BACKGROUND: Recent interest in shortening the fasting interval after ingestion of
      milk products demonstrated large volumes of breast milk in the stomach 2 h after
      breastfeeding. Although aspiration is a rare event, if it were to occur with
      human breast milk, it is important to understand the extent of the lung injury
      that might occur. Therefore, the response to instillation of acidified breast
      milk and infant formula in the lungs of adult rabbits was studied. METHODS: In 18
      anesthetized adult rabbits, 1 of 3 fluids (in a volume of 0.8 ml.kg-1 and pH
      level of 1.8, acidified with hydrochloric acid); saline, breast milk, or infant
      formula (SMA, Wyeth, Windsor, Ontario), was instilled into the lungs via a
      tracheotomy. The lungs were ventilated for 4 h after instillation. Alveolar-to
      arterial oxygen gradient and dynamic compliance were measured before and at
      hourly intervals after instillation. After 4 h, the rabbits were killed and the
      lungs were excised. Neutrophil infiltration was quantitated by a pathologist
      blinded to the instilled fluid. A histologic control group of four rabbits was
      ventilated under study conditions without any intratracheal fluid instillation.
      RESULTS: Alveolar-to-arterial oxygen gradient increased and dynamic compliance
      decreased significantly during the 4 h after instillation of both breast milk and
      infant formula compared with baseline measurements and with saline controls (P <
      0.05). The neutrophil counts in the lungs from the saline, breast milk, and
      formula rabbits were significantly greater than those in the control group.
      CONCLUSIONS: Instillation of acidified breast milk or infant formula (in a volume
      of 0.8 ml.kg-1 and pH level of 1.8) into rabbits' lungs induces acute lung injury
      of similar intensity that lasts at least 4 h.

PMID- 8669681
TI  - Rapid rewarming causes an increase in the cerebral metabolic rate for oxygen that
      is temporarily unmatched by cerebral blood flow. A study during cardiopulmonary
      bypass in rabbits.
AB  - BACKGROUND: Jugular venous hemoglobin desaturation during the rewarming phase of
      cardiopulmonary bypass is associated with adverse neuropsychologic outcome and
      may indicate a pathologic mismatch between cerebral blood flow (CBF) and cerebral
      metabolic rate for oxygen (CMRO2). In some studies, rapid rewarming from
      hypothermic cardiopulmonary bypass results in greater jugular venous hemoglobin
      desaturation. The authors wished to determine if rewarming rate influences the
      temperature dependence of CBF and CMRO2. METHODS: Anesthetized New Zealand white
      rabbits, cooled to 25 degrees C on cardiopulmonary bypass, were randomized to one
      of two rewarming groups. In the fast group (n = 9), aortic blood temperature was
      made normothermic within 4 min. In the slow group (n = 9), aortic blood
      temperature was made normothermic over 25 min. Cerebral blood flow (microspheres)
      and CMRO2 (Fick) were determined at baseline (25 degrees C), and at brain
      temperatures of 28 degrees, 31 degrees, 34 degrees, and 37 degrees C during
      rewarming. RESULTS: Systemic physiologic variables appeared similar between
      groups. At a brain temperature of 28 degrees C, CMRO2 was 47% greater in the fast
      rewarming group than in the slow group (2.2 +/- 0.5 vs. 1.5 +/- 0.2 ml O2.100 g
      1. min-1, respectively; P = 0.01), whereas CBF did not differ (48 +/- 18 vs. 49
      +/- 8 ml.100 g-1.min-1, respectively; P = 0.47). Throughout rewarming, CBF
      increased as a function of brain temperature but was indistinguishable between
      groups. Cerebral metabolic rate for oxygen differences between groups decreased
      as brain temperatures increased. CONCLUSIONS: Cerebral venous hemoglobin
      desaturation with rapid rewarming is caused by an increase in CMRO2 that is
      temporarily greater than the increase in CBF. This mismatch may indicate a
      transient abnormality in flow-metabolism coupling, or the effect of temperature
      gradients on oxygen transfer from hemoglobin to brain.

PMID- 8669682
TI  - Prolonged regional nerve blockade. Injectable biodegradable bupivacaine/polyester
      microspheres.
AB  - BACKGROUND: Biodegradable microspheres are a useful method of drug delivery
      because they are both injectable and biodegradable, eliminating the need for
      surgical implantation or removal. Previous work has characterized implantable
      preparations of local anesthetics in polymer pellets for prolonged regional
      anesthesia. In this article, the authors characterize injectable suspensions of
      bupivacaine-polymer microspheres and examine whether they can produce prolonged
      blockade of the sciatic nerve in rats. METHODS: Microspheres were prepared using
      polylactic-co-glycolic acid polymers loaded with 75% w/w bupivacaine by a solvent
      evaporation method. Bupivacaine release from microspheres was determined in vitro
      by ultraviolet spectroscopy and scintillation counting. Sensory and motor
      blockade of the rat sciatic nerve were assessed in vivo after injection of
      microsphere suspensions. RESULTS: Depending on the type of microspheres, the
      dose, and the additive used, mean duration of sciatic nerve block ranged from 10
      h to 5.5 days. Incorporation of 0.05% w/w dexamethasone into the microspheres
      resulted in significant prolongation of block (up to 13-fold), and only
      preparations that contained dexamethasone produced blocks lasting beyond 1 day.
      Bupivacaine was released in a controlled manner in vitro. Dexamethasone does not
      substantially slow bupivacaine release from microspheres in vitro. CONCLUSIONS:
      Prolonged percutaneous blockade of peripheral nerves is feasible. The recovery
      from blockade is complete, and plasma bupivacaine levels are far below the range
      associated with systemic toxicity. The mechanisms underlying the dexamethasone
      block-prolonging effect are under investigation.

PMID- 8669683
TI  - Thiopental uncouples hippocampal and cortical synchronized
      electroencephalographic activity.
AB  - BACKGROUND: Thiopental produces a concentration-dependent continuum of effects on
      the cortical electroencephalogram (EEG) that has been linked to behavioral
      measures of anesthetic depth. The complexity of the response, however, limits a
      clear insight into the neurophysiologic actions of thiopental. The current study
      investigated thiopental actions on cortical EEG and hippocampal electrical
      activity, to determine whether similar effects occur on both structures and to
      compare synchronized activity between these structures. METHODS: Thiopental was
      administered intravenously via an implanted catheter in freely moving rats.
      Arterial blood oxygen/carbon dioxide concentration, thiopental concentrations,
      and temperature were monitored and controlled. Neocortical EEG was recorded from
      implanted dural surface electrodes and hippocampal neuron electrical activity was
      recorded from stereotaxically placed microelectrodes. Pharmacokinetic models were
      used to determine effect site concentrations. RESULTS: Thiopental produced an
      increase in EEG frequency and amplitude at low concentrations (15-20
      micrograms/ml total plasma, approximately 10 microM unbound), which produced a
      loss of righting reflex. This was followed by a frequency decrease and burst
      suppression activity at higher concentrations (50-80 micrograms/ml, approximately
      60 microM), which produced a loss of tail pinch and corneal reflexes. Higher
      concentrations of thiopental ( > 60 micrograms/ml) uncoupled synchronized burst
      discharges recorded in hippocampus and cortex. Isoelectric EEG activity was
      associated with concentrations of 70-90 micrograms/ml (approximately 80 microM)
      and a deep level of anesthesia; motor reflexes were abolished, although
      cardiovascular reflexes remained. In all frequency bands, similar concentration
      EEG effect relationships were observed for cortical and hippocampal signals, only
      differing in the magnitude of response. A reversed progression of effects was
      observed on recovery. CONCLUSIONS: The results confirm earlier findings in humans
      and animals and demonstrate that both the hippocampus and neocortex exhibit burst
      suppression and isoelectric activity during thiopental anesthesia. Thiopental
      induced synchronized burst activity was depressed by progressively higher
      concentrations. The lost synchronization suggests a depression of synaptic
      coupling between cortical structures contributes to anesthesia.

PMID- 8669684
TI  - Synaptic mechanisms of thiopental-induced alterations in synchronized cortical
      activity.
AB  - BACKGROUND: Anesthetic depth after barbiturate administration has been correlated
      with distinct electroencephalogram (EEG) patterns. The current study used a rat
      neocortical brain slice micro-EEG preparation to investigate synaptic mechanisms
      underlying thiopental-induced transitions in synchronized neuronal activity.
      METHODS: Concentration-dependent cellular actions of thiopental were investigated
      in brain slices using specific pharmacologic probes, whole cell patch clamps, and
      extracellular field recordings. Theta-Like micro-EEG oscillations were elicited
      in neocortical slices by mimicking subcortical cholinergic and gamma-aminobutyric
      acid (GABA) afferent input with carbachol (100 microM), a cholinergic agonist,
      and bicuculline (10 microM) a GABAA antagonist. RESULTS: In the presence of 20
      microM thiopental, micro-EEG slowing from theta (7.3 +/- 0.9 Hz, mean +/- SD, n =
      19) to delta frequencies (2.5 +/- 0.5 Hz, n = 11) was associated with a threefold
      prolongation of inhibitory currents. Burst suppression activity occurred at 50
      microM thiopental, and appeared to result from direct activation of GABAA-gated
      chloride currents, observed with voltage clamp recordings, and mimicked with a
      direct acting GABAA agonist, muscimol (1 microM). Isoelectric activity occurred
      at 100 microM thiopental, and likely resulted from reduced glutamatergic
      transmission, evidenced by depressed excitatory postsynaptic potentials.
      Glutamatergic excitation was required for burst suppression activity, because
      glutamate receptor antagonists blocked thiopental-induced bursts; forcing a
      transition to isoelectric activity. CONCLUSIONS: Thiopental produced a continuum
      of EEG-like states in brain slices similar to those observed in vivo. The
      progression of thiopental-induced effects appear to have resulted from specific
      cellular actions that were recruited in a concentration-dependent manner.
      Progressive enhancement of synaptic inhibition followed by depression of
      excitatory transmission led to micro-EEG frequency slowing, burst suppression,
      and isoelectric activity.

PMID- 8669686
TI  - Circulatory effects of hypoxia, acute normovolemic hemodilution, and their
      combination in anesthetized pigs.
AB  - BACKGROUND: Because hemodilution decreases the oxygen-carrying capacity of blood,
      it was hypothesized that severe hemodilution would decrease the tolerance to
      alveolar hypoxia. METHODS: Hemodynamics, oxygen transport, and blood lactate
      concentrations were compared in ten pigs with normal hematocrit (33 +/- 4%), and
      ten hemodiluted pigs (hematocrit 11 +/- 1%; mean +/- SD) anesthetized with
      ketamine-fentanyl-pancuronium during stepwise decreases in inspired oxygen
      fraction (FIO2; 1.0, 0.35, 0.21, 0.15, 0.10, 0.05). RESULTS: Median systemic
      oxygen delivery (DO2SY) became critical (the DO2SY value when arterial lactate
      exceeded 2.0 mmol.l-1) at 10.4 ml.kg-1.min-1 (range 6.9-16.1) in hemodiluted
      animals and at 11.8 ml.kg-1.min-1 (5.9-32.2) in animals with normal hematocrits
      (NS). The relationship between mixed venous oxygen saturation and arterial
      lactate values was less consistent and median critical mixed venous oxygen
      saturation was higher (P < 0.05) in the hemodiluted group (35%, range 21-64),
      than in animals with normal hematocrits (21%, 7-68%). In animals with normal
      hematocrit, decreasing FIO2 from 1.0 to 0.10 resulted in a decrease in DO2SY from
      26.3 +/- 9.1 to 9.3 +/- 3.9 ml.kg-1.min-1 (P < 0.01). Cardiac output did not
      change, systemic oxygen extraction ratio increased from 0.23 +/- 0.08 to 0.68 +/-
      0.13 (P < 0.01), and arterial lactate from 0.9 +/- 0.2 to 3.4 +/- 3.0 mmol.l-1 (P
      < 0.05). Cardiac venous blood flow, as measured by retrograde thermodilution,
      increased from 5.7 +/- 2.9 to 12.6 +/- 5.7 ml.kg-1.min-1 (P < 0.01). When FIO2
      was reduced to 0.05, three animals became hypotensive and died. In the second
      group, hemodilution increased cardiac output and systemic oxygen extraction ratio
      (P < 0.01). Cardiac venous blood flow increased from 4.1 +/- 1.7 to 9.8 +/- 5.1
      ml.kg-1.min-1 (P < 0.01), and cardiac venous oxygen saturation from 22 +/- 5 to
      41 +/- 10% (P < 0.01). During the subsequent hypoxia, cardiac output and DO2SY
      were maintained until FIO2 = 0.15 (DO2SY = 10.1 +/- 3.3 ml.kg-1.min-1). Cardiac
      venous blood flow was then 18.5 +/- 10.7 ml.kg-1.min-1 (P < 0.01), but in spite
      of this, myocardial lactate production occurred. At FIO2 = 0.10 (DO2SY = 7.7 +/-
      3.0 ml.kg-1.min-1), arterial lactate concentration increased to 8.5 +/- 2.3
      mmol.l-1 (P < 0.01), and most animals became hypotensive. All hemodiluted animals
      died when FIO2 was decreased to 0.05 (P < 0.01 when compared to animals with
      normal hematocrit). CONCLUSIONS: Systemic and myocardial lactate production
      occurred at similar systemic oxygen delivery rates in hemodiluted and
      nonhemodiluted animals. Mixed venous oxygen saturation may be a less reliable
      indicator of inadequate oxygen delivery during hemodilution.

PMID- 8669685
TI  - Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin.
AB  - BACKGROUND: Animals subjected to immunostimulatory conditions (sepsis) exhibit
      decreased total cytochrome P450 content and decreased P450-dependent drug
      metabolism. Cytochrome P450 function is of clinical significance because it
      mediates the metabolism of some opioid and hypnotic drugs. The authors tested the
      hypothesis that reduced P450 function and decreased drug metabolism in sepsis are
      mediated by endotoxin-enhanced synthesis of nitric oxide. METHODS: Hepatic
      microsomes were prepared from male Sprague-Dawley rats in nontreated rats, rats
      pretreated with phenobarbital and rats receiving aminoguanidine or NG-L
      monomethyl-arginine alone. Nitric oxide synthesis was augmented for 12 h with a
      single injection of bacterial lipopolysaccharides. Nitric oxide synthase was
      inhibited with aminoguanidine or N(G)-L-monomethyl-arginine during the 12 h of
      endotoxemia in some animals. Plasma nitrite and nitrate concentrations were
      measured in vivo, and total microsomal P450 content, and metabolism of
      ethylmorphine and midazolam in vitro. RESULTS: Administration of endotoxin
      increased plasma nitrite and nitrate concentrations, decreased total cytochrome
      P450 content, and decreased metabolism of ethylmorphine and midazolam. Inhibition
      of nitric oxide formation by aminoguanidine or N(G)-L-monomethyl-arginine
      partially prevented the endotoxin-induced effects in the nontreated and
      phenobarbital-treated groups. Aminoguanidine or N(G)-L-monomethyl-arginine alone
      did not have an effect on either total cytochrome P450 content or P450-dependent
      drug metabolism. Plasma nitrite and nitrate concentrations correlated
      significantly negatively with P450 content (nontreated r = -0.88, phenobarbital r
      = -0.91), concentrations of formed formaldehyde (nontreated r = -0.87,
      phenobarbital r = -0.95), and concentrations of midazolam metabolites (4-OH
      midazolam nontreated r = -0.88, phenobarbital r = -0.93, and 1'-OH midazolam
      nontreated r = -0.88, phenobarbital r = -0.97). CONCLUSIONS: Altered hepatic
      microsomal ethylmorphine and midazolam metabolism during sepsis is mediated in
      large part by nitric oxide.

PMID- 8669687
TI  - Differential nerve block. Direct measurements on individual myelinated and
      unmyelinated dorsal root axons.
AB  - BACKGROUND: Clinically, differential block is manifested by the loss of small
      fiber mediated sensation (e.g., temperature) two or more dermatomes beyond the
      sensory limit for large fiber mediated sensations. These observations support the
      belief that sensitivity to local anesthetics is inversely proportional to axon
      diameter. This study reports the first measurements of differential sensitivity
      to lidocaine in individual myelinated and unmyelinated mammalian dorsal root
      axons. METHODS: Lumbar dorsal roots and vagus nerves were isolated from
      anesthetized adult rats and maintained in vitro in a perfusion/recording chamber
      at 37 +/- 0.3 degrees C. Using single fiber techniques, evoked action potentials
      in individual myelinated and unmyelinated axons were digitized and recorded for
      subsequent analysis. Axons were exposed to lidocaine at 150, 260, or 520 microM.
      Sensitivity to local anesthetic was assessed by measuring the incidence of
      conduction block and the magnitude of conduction velocity slowing under steady
      state conditions. RESULTS: Data were obtained from 77 dorsal root axons and 41
      vagal axons. The estimated steady-state EC50 lidocaine concentration for
      myelinated dorsal root axons (232 microM) was comparable to that for unmyelinated
      axons (228 microM). Similarly, the incidence of conduction block was not
      significantly different among dorsal root axon groups. However, unmyelinated
      dorsal root axons were significantly less sensitive to the conduction velocity
      slowing effect of lidocaine than their myelinated counterparts (P < 0.01). The
      incidence of conduction block in short (mean length 13.5 mm) dorsal root axons
      was not significantly different from that in long (mean length 22.4 mm) axons.
      Compared with dorsal root axons, the estimated EC50s for vagal myelinated and
      unmyelinated axons (345 and 285 microM, respectively), while lower were not
      significantly different. However, the incidence of conduction block at 260 microM
      lidocaine was significantly lower (16.7% vs. 56.7%; P < 0.05) in vagal myelinated
      axons. CONCLUSIONS: Although no difference in sensitivity to the conduction
      blocking effects of lidocaine could be demonstrated among dorsal root axons,
      myelinated axons were more sensitive to the conduction velocity slowing effects
      of lidocaine. This differential effect cannot explain clinical observations of
      differential nerve block. Differential sensory block with lidocaine may depend on
      factors (e.g., physiologic function) related only indirectly to individual axon
      conduction velocity (diameter).

PMID- 8669688
TI  - Effect of volatile anesthetics with and without verapamil on intracellular
      activity in vascular smooth muscle.
AB  - BACKGROUND: Although halothane and isoflurane inhibit receptor agonist-induced
      smooth muscle contraction by inhibiting Ca2+ influx via the L-type voltage
      dependent Ca2+ channels, their effects on pharmacomechanical coupling remained to
      be clarified. The intracellular action of both anesthetics was studied during
      agonist-induced contractions using the Ca2+ channel blocker verapamil. METHODS:
      Isolated spiral strips of rat thoracic aorta with endothelium removed were
      suspended for isometric tension recordings in physiologic salt solution.
      Cytosolic concentration of Ca2+ ([Ca2+]i) was measured concomitantly using fura-2
      Ca2+ fluorescence. Muscle contraction was evoked by the receptor agonists with 30
      nm norepinephrine or 10 microM prostaglandin F2 alpha (PGF2 alpha), followed by
      exposure to halothane, at 0%, 1%, 2%, and 3% or isoflurane, at 2% and 4%. The
      effects of the anesthetics were compared with those of 0.1-1 microM verapamil (n
      = 8 for each condition). To clarify the intracellular action of the volatile
      anesthetics on agonist-induced contractions, this procedure was repeated for the
      anesthetics only in the presence of 1 microM verapamil (n = 8 for each
      condition). The effects of both anesthetics were also examined in nonreceptor
      mediated contractions evoked with a 1-microM dose of the protein kinase C
      activator, 12-deoxyphorbol 13-isobutylate, which increases the Ca2+ sensitivity
      of the contractile elements (n = 8 for each). RESULTS: Halothane, isoflurane, and
      verapamil suppressed norepinephrine-and PGF2 alpha-induced increases in muscle
      tension and [Ca2+]i in a concentration-dependent manner. The Ca2+-tension
      regression lines suggested that the volatile anesthetics reduced Ca2+ sensitivity
      of the contractile elements during PGF2 alpha-induced contraction. Pretreatment
      of the muscle strip with verapamil revealed that halothane and isoflurane
      released Ca2+ during norepinephrine-induced contraction and that [Ca2+]i-tension
      relationship was modulated during PGF2 alpha-induced contractions. Halothane at
      2% and 3% and isoflurane at 4% suppressed 12-deoxyphorbol 13-isobutylate-induced
      increases in muscle tension, whereas they enhanced increases in [Ca2+]i,
      indicating that both anesthetics suppressed Ca2+ sensitivity during 12
      deoxyphorbol 13-isobutylate-induced contraction. CONCLUSIONS: Verapamil
      pretreatment unmasked the intracellular action of the anesthetics. Halothane and
      isoflurane influenced pharmacomechanical coupling during agonist-induced
      contraction.

PMID- 8669689
TI  - Electroencephalographic burst suppression is not required to elicit maximal
      neuroprotection from pentobarbital in a rat model of focal cerebral ischemia.
AB  - BACKGROUND: Barbiturates have previously been demonstrated to reduce focal
      cerebral ischemic brain damage. However, the dose of drug required to elicit
      maximal neuroprotection has not been defined. The authors' hypothesized that
      doses of pentobarbital substantially lower than those required to cause
      electroencephalographic burst suppression would result in maximal magnitudes of
      reduction of cerebral infarct volume. METHODS: Wistar rats underwent 90 min of
      filament occlusion of the middle cerebral artery while either awake (control), or
      anesthetized with intravenous sodium pentobarbital administered to preserve an
      active electroencephalogram (15-23 mg.kg-1.h-1) or a pattern of burst suppression
      (45-60 mg.kg-1.h-1; n = 17). During ischemia and for the first 6 h of
      recirculation, brain temperature was rigorously controlled at 38.0 +/- 0.2
      degrees C. Rats were allowed a recovery interval of 7 days after which neurologic
      function and cerebral infarct volume were assessed. In nonischemic rats
      undergoing a similar anesthetic protocol, the cerebral metabolic rate of glucose
      utilization was measured at each anesthetic depth. RESULTS: Relevant physiologic
      values were similar between groups. Total infarct volume (mean +/- SD) was
      smaller in the active electroencephalogram group than in the control group (124
      +/- 68 mm3 versus 163 +/- 66 mm3; P < 0.05). Increasing the dose of pentobarbital
      (burst suppression) did not further decrease infarct volume (128 +/- 54 mm3).
      Neurologic score and infarct volume were positively correlated (P < 0.001).
      Cerebral metabolic rate of glucose utilization was reduced by 56% in the burst
      suppression group versus 43% in the active electroencephalogram pentobarbital
      group (P < 0.001). CONCLUSIONS: Sodium pentobarbital administered at either dose
      (active electroencephalogram or burst suppression) resulted in an approximately
      equal to 25% reduction of cerebral infarct size, indicating that burst
      suppression is not required to elicit maximal neuroprotective efficacy.

PMID- 8669690
TI  - Etomidate and thiopental inhibit the release of endothelium-derived
      hyperpolarizing factor in the human renal artery.
AB  - BACKGROUND: Endothelium-derived hyperpolarizing factor is thought to be a
      cytochrome P450-derived arachidonic acid metabolite that hyperpolarizes vascular
      smooth muscle cells by opening Ca(2+)-activated K+ channels (K+Ca channels). In
      the rabbit carotid artery both volatile and intravenous anesthetics inhibit the
      acetylcholine-stimulated release of endothelium-derived hyperpolarizing factor.
      Because the release of this factor may help to maintain vascular tone in humans
      under conditions of a failing nitric oxide synthesis, e.g., in atherosclerosis,
      the effects of two intravenous anesthetics, thiopental and etomidate, on the
      endothelium-derived hyperpolarizing factor-mediated relaxant response to
      acetylcholine were investigated in human isolated renal artery segments. METHODS:
      The segments were suspended in Krebs-Henseleit solution (37 degrees C) containing
      the cyclooxygenase inhibitor diclofenac (1 microM) and preconstricted with
      norepinephrine (6 microM). Relaxations caused by acetylcholine (1 microM) were
      compared in the presence and absence of the nitric oxide synthase inhibitor N(G)
      nitro-L-arginine (0.1 mM) in control segments and in segments exposed to
      etomidate or thiopental (0.03-0.3 mM). In addition, the effects of the two
      anesthetics on the relaxant response to the nitric oxide donors glyceryl
      trinitrate (3 microM) and sodium nitroprusside (0.1 microM) were examined.
      RESULTS: The relaxant response to acetylcholine, which was resistant to both
      nitric oxide synthase and cyclooxygenase blockade, was markedly reduced by the
      K+Ca channel antagonist tetrabutyl ammonium (3 mM) and the cytochrome P450
      inhibitor clotrimazole (30 microM). Both etomidate and thiopental, at a
      concentration of 0.3 mM, selectively attenuated the relaxant response to
      acetylcholine in N(G)-nitro-L-arginine-treated segments, but did not affect
      relaxations elicited by glyceryl trinitrate or sodium nitroprusside. CONCLUSIONS:
      Etomidate and thiopental inhibit the endothelium-derived hyperpolarizing factor
      mediated relaxant response to acetylcholine in the human renal artery, an effect
      that appears to be attributable to the cytochrome P450-inhibiting properties of
      these anesthetics.

PMID- 8669691
TI  - Mass spectrometry provides warning of carbon monoxide exposure via
      trifluoromethane.
AB  - BACKGROUND: The chemical breakdown of isoflurane, enflurane, or desflurane in
      dried carbon dioxide absorbents may produce carbon monoxide. Some mass
      spectrometers can give false indications of enflurane during anesthetic
      breakdown. METHODS: During clinical anesthesia with isoflurane or desflurane, the
      presence of carbon monoxide in respiratory gas was confirmed when enflurane was
      inappropriately indicated by a clinical mass spectrometer that identified
      enflurane at mass to charge ratio = 69. In vitro, isoflurane, enflurane, or
      desflurane in oxygen was passed through dried carbon dioxide absorbents at 35,
      45, and 55 degrees C. Gases were analyzed by gas chromatography and by mass
      spectrometry. RESULTS: Mass spectrometry identified several clinical incidents in
      which 30-410 ppm carbon monoxide was measured in respiratory gas.
      Trifluoromethane was produced during in vitro breakdown of isoflurane or
      desflurane. Although these inappropriately indicated quantities of "enflurane"
      correlated (r2 > 0.95) to carbon monoxide concentrations under a variety of
      conditions, this ratio varied with temperature, anesthetic agent, absorbent type,
      and water content. CONCLUSIONS: Trifluoromethane causes the inappropriate
      indication of enflurane by mass spectrometry, and indicates isoflurane and
      desflurane breakdown. Because the ratio of carbon monoxide to trifluoromethane
      varies with conditions, this technique cannot be used to quantitatively determine
      the amount of carbon monoxide to which a patient is exposed. If any warning of
      anesthetic breakdown results from this technique then remedial steps should be
      taken immediately to stop patient exposure to carbon monoxide. No warning can be
      provided for the breakdown of enflurane by this technique.

PMID- 8669692
TI  - Video analysis of prolonged uncorrected esophageal intubation. Level One Trauma
      Anesthesia Simulation Group.

PMID- 8669693
TI  - Single-lung ventilation in pediatric patients.

PMID- 8669694
TI  - Sensitivity to mivacurium in a patient with mitochondrial myopathy.

PMID- 8669695
TI  - Blind intubation through the laryngeal mask airway for management of the
      difficult airway in infants.

PMID- 8669696
TI  - Cardiogenic shock after electroconvulsive therapy.

PMID- 8669697
TI  - Transient muscular spasm after a large dose of intrathecal sufentanil.

PMID- 8669698
TI  - Early application of the cross-suture splint to teeth avulsed at tracheal
      intubation.

PMID- 8669699
TI  - Vasomotor effects of isoflurane in the coronary circulation.

PMID- 8669700
TI  - Epinephrine should not be part of an epidural test dose.

PMID- 8669702
TI  - Hotline fluid warming fails to maintain normothermia.

PMID- 8669701
TI  - Epinephrine should not be part of an epidural test dose.

PMID- 8669703
TI  - Neurolytic celiac plexus block: can paraplegia and death after neurolytic celiac
      plexus block be eliminated?

PMID- 8669704
TI  - Epidural catheter insertion and satisfactory analgesia.

PMID- 8669705
TI  - Antagonism of residual mivacurium blockade: setting the record straight.

PMID- 8669706
TI  - Peripheral nerve stimulator for unassisted nerve blockade.

PMID- 8669707
TI  - Is general anesthesia required?

PMID- 8669708
TI  - Simulation of intraluminal gas transport processes in the microcirculation.
AB  - Intraluminal resistance to gas transport between the microcirculation and tissue
      was neglected for a half-century following the early work of Krogh. In recent
      years it has come to be understood that this neglect is seriously in error. This
      paper reviews the background for the long period of misdirection, and progress in
      placing the simulation of gas transport processes on a more accurate,
      quantitative basis.

PMID- 8669709
TI  - Microvascular thermal equilibration in rat cremaster muscle.
AB  - A new experimental approach was developed to obtain the first direct measurements
      of the axial countercurrent thermal equilibration in a microvascular tissue
      preparation using high resolution infrared thermography. Detailed surface
      temperature measurements were obtained for an exteriorized rat cremaster muscle
      in which pharmacological vasoactive agents were used to change the local blood
      flow Peclet number from 1 to 14 in the feeding artery. Under normal conditions,
      only the 1A arteries (> 70 microns diameter) showed thermal nonequilibration with
      the surrounding tissue. The theoretical model developed by Zhu and Weinbaum (28)
      for a two-dimensional tissue preparation with arbitrarily embedded countercurrent
      vessels was modified to include axial conduction and the presence of the
      supporting glass slide. This modified model was used to interpret the
      experimental results and to relate the surface temperature profiles to the bulk
      temperature profiles in the countercurrent artery and vein and the local average
      tissue temperature in the cross-sectional plane. Surface temperature profiles
      transverse to the vessel axis are shown to depend significantly on the tissue
      inlet temperature. The eigenfunction for the axial thermal equilibration depends
      primarily on the blood flow Peclet number and the environmental convective
      coefficient. The theoretical results predict that when rho(ar)*Pe is less than 1
      mm (the range in our experiments), axial conduction is the dominant mode of axial
      thermal equilibration. For 1 < rho(ar)*PE < 3 mm, countercurrent blood flow
      becomes comparable to axial conduction, whereas, when rho(ar)*Pe > 3 mm,
      countercurrent blood flow is the dominant mode of axial thermal equilibration.
      Therefore, for rho(ar)*Pe > 3 mm the axial equilibration length is proportional
      to the blood flow Peclet number, as predicted previously by Zhu and Weinbaum in a
      study in which axial conduction was neglected. It also is shown that the axial
      decay of the tissue temperature at low perfusion rates can be described by a
      simple one-dimensional Weinbaum-Jiji equation with a newly derived conduction
      shape factor.

PMID- 8669710
TI  - A visualization-based analysis method for multiparameter models of capillary
      tissue-exchange.
AB  - In order to successfully use a model for parameter identification, it must be
      carefully analyzed. Current analysis methods, however, are ad hoc and provide
      only partial information. We extended these methods through the application of
      stacked dimensions, a scientific visualization method. The end result of our
      extensions are multi-dimensional parametric model-images. These images depict a
      model as a function of all its parameters in a single graphic. We applied
      parametric model-images to model verification (behavioral analysis), sensitivity
      analysis, and identifiability analysis. We applied our methodology to the
      evaluation of pulmonary vascular capillary-transport models. Results have shown
      that the visualization-based method provides a more complete view of a model's
      behavior and its other characteristics. Furthermore, our method has also proven
      to be more computationally efficient than the traditional approaches.

PMID- 8669711
TI  - Three-dimensional reconstruction of the flow in a human left heart by using
      magnetic resonance phase velocity encoding.
AB  - Intraventricular flows have been correlated with disease and are of interest to
      cardiologists as a possible means of diagnosis. This study extends a method that
      use magnetic resonance (MR) to measure the three-dimensional nature of these
      flows. Four coplanar, sagittal MR slices were located that spanned the left
      ventricle of a healthy human. All three velocity components were measured in each
      slice and 18 phases were obtained per beat. With use of the MR magnitude images,
      masks were created to isolate the velocity data within the heart. These data were
      read into the software package, Data Visualizer, and the data from the four
      slices were aligned so as to reconstruct the three-dimensional volume of the left
      ventricle and atrium. By representing the velocity in vectorial form, the three
      dimensional intraventricular flow field was visualized. This revealed the
      presence of one large line vortex in the ventricle during late diastole but a
      more ordered flow during early diastole and systole. In conclusion, the use of MR
      velocity acquisition is a suitable method to obtain the complex intraventricular
      flow fields in humans and may lead to a better understanding of the importance of
      these flows.

PMID- 8669712
TI  - Mechanics of porcine coronary arteries ex vivo employing impedance planimetry: a
      new intravascular technique.
AB  - Our objective was to evaluate methodological aspects of impedance planimetry, a
      new balloon catheter-based technique, for the investigation of coronary artery
      mechanical wall properties. We used a four ring-electrode electrical impedance
      measuring system that was located inside a balloon. Two of the electrodes were
      used for excitation and connected to a generator producing a constant alternating
      current of 250 mA at 5 kHz. The other two electrodes for detection were placed
      midway between the excitation electrodes. The balloon was distended with
      electrically conducting fluid through an infusion channel. The vessel cross
      sectional area (CSA) was measured according to the field gradient principle by
      measuring the impedance of the fluid inside the balloon. Impedance planimetry was
      applied in the three major branches of the coronary arteries of seven extracted
      porcine hearts to assess luminal CSAs in response to internal pressurization. The
      biomechanical wall properties were evaluated by computing the strain [(r - r0) x
      r0(-1), where r is the vessels inner radius computed as (CSA x pi-1)1/2 and r0 is
      the radius of the vessel at a minimal distension pressure], the tension [(r x
      dP), where dP is the transmural pressure difference], and the pressure elastic
      modulus (delta P x r x delta r-1). We found that in vitro testing demonstrated
      that impedance planimetry was accurate and reproducible. The technique has
      controllable sources of error. Measurements were performed with consecutively
      increasing pressures in the range 1-25 kPa (8-188 mmHg, 0.01-0.25 atm). The CSAs
      increased nonlinearly and were significantly larger in the left anterior
      descendent coronary artery (LAD) (1 kPa, mean 5.0 mm2; 25 kPa, mean 21.8 mm2)
      than in both the left circumflex (Cx) (4.5-16.0 mm2) and the right coronary
      artery (RCA) (2.8-15.6 mm2) (analysis of variance, P < 0.001 for both). The
      circumferential wall tension-strain relation showed exponential behavior. For a
      given strain, tension values for LAD were significantly lower than those of Cx (P
      < 0.01). The pressure elastic modulus-strain relation also was exponential, and
      values for Cx were significantly lower than values for LAD (P < 0.001) and RCA (P
      < 0.05). Impedance planimetry was applied to the study of coronary artery
      biomechanics ex vivo. The LAD had the largest CSA, and the Cx was the least
      compliant. Methodological aspects of an in vivo introduction of the method
      require additional evaluation.

PMID- 8669714
TI  - Efficient and accurate computation of the electric fields of excitable cells.
AB  - The numerical computation of the electric fields produced by excitable cells is
      important in many applications. Traditionally, a potential formulation was used.
      An integral formulation based on the differentiation of Green's theorem, which
      solves directly for the electric field, is presented herein. This is desirable
      because the electric field is proportional to current density, which can be
      calculated on the cell membrane. Fredholm equations of the second kind are
      produced, which are more appropriate than are those of the first kind (produced
      by formulations based on potential). Analytic formulae are presented to calculate
      the required matrix entries for zeroth order triangular elements that are
      generally used for field computations in boundary element methods. Results
      indicated that significantly more accurate answers may be obtained with
      significantly less computation by formulating the problem directly in terms of
      electric field as opposed to potential. This approach has the additional
      advantage that, for equal intracellular and extracellular conductivities, only
      one matrix must be generated, and no system of simultaneous equations must be
      solved; this drastically reduces storage and computation requirements. Examples
      are given to illustrate this technique and to compare the electric field
      formulation with the potential formulation.

PMID- 8669713
TI  - Spatial potential and current distributions along transvenous defibrillation
      electrodes: variation of electrode characteristics.
AB  - The therapeutic efficacy of an endocardial defibrillation lead system can be
      improved by controlling the profile of current delivery through a suitable choice
      of electrode characteristics, which include the length, radius, number of
      conductor elements, electrode resistance, and point of connection to the voltage
      source. Such control will minimize tissue and lead damage during long-term use.
      In this study, a semianalytical model was developed to study cylindrical
      electrodes of different constructions in an idealized electrolytic medium.
      Simulations were performed to investigate the effects of varying the electrode
      characteristics on the spatial voltage and current distributions and
      interelectrode resistance for cylindrical electrodes of different constructions.
      The results show that, for transvenous electrodes of realistic dimensions, the
      current distributions are determined largely by the edge effects. The edge
      effects increase as the aspect ratio of the electrode (length/radius) decrease.
      The multiple edges resulting from wrapping conductor elements over a
      nonconducting base are found to increase the nonuniformity and the current
      density over the conductor-covered surface. The model is used to demonstrate two
      techniques of controlling the current distribution. The first method involve
      modifying the electrode resistivity profile and point of connection. In the
      second approach, the electrode surface is covered with a thin film having a model
      computed resistance profile. By using either methods to produce isocurrent
      electrodes, the interelectrode resistance is found to increase.

PMID- 8669715
TI  - Assessing microvascular volume change and filtration from venous hematocrit
      variation of canine liver and lung.
AB  - The volume increase of canine liver after 1 min of a 10 mmHg elevation in hepatic
      venous pressure has been reported as 251 ml/kg tissue. An analysis of the
      transient hematocrit variation in hepatic venous blood indicated that 16% of the
      volume change results from transcapillary filtration, 72% from microvascular
      expansion, and 12% from macrovascular expansion. In the analysis, we first used
      the temporal change of the liver volume to determine the time course of the
      filtration and microvascular and macrovascular volume change. We next deduced,
      for a permeable microcirculation with a microvascular hematocrit lower than the
      feed hematocrit (the Fahraeus effect), how the filtration and microvascular
      volume change (MVC) produce a hematocrit variation in the blood leaving
      microcirculation. By accounting for the dispersion of the blood flow, the
      analysis predicted a hematocrit variation in the hepatic venous blood that
      matched well with the measured variation over the 1-min course of experiment. A
      reasonable fit with the hematocrit variation of pulmonary blood also was obtained
      for experiment with an 8 mm/Hg increase in the arterial and venous pressure
      perfusing the canine left lower lung lobe. The tissue and vascular volume
      increase at 1 min was 149 ml/kg tissue with 4% as a result of filtration, 41% as
      a result of microvascular expansion, and 55% as a result of macrovascular
      expansion. The large MVCs from the hepatic and pulmonary circulation indicate
      their microcirculations function as a reservoir in controlling blood volume
      redistribution.

PMID- 8669716
TI  - Chaotic oscillations in microvessel arterial networks.
AB  - A mathematical model of a multibranched microvascular network was used to study
      the mechanisms underlying irregular oscillations (vasomotion) observed in
      arteriolar microvessels. The network's layout included three distinct terminal
      arteriolar branches originating from a common parent arteriole. The biomechanical
      model of the single microvessel was constructed to reproduce the time pattern of
      the passive and active (myogenic) response of arterioles in the hamster cheek
      pouch to a step-wise arterial pressure change. Simulation results indicate that,
      as a consequence of the myogenic reflex, each arteriole may behave as an
      autonomous oscillator, provided its intraluminal pressure lies within a specific
      range. In the simulated network, the interaction among the various oscillators
      gave rise to a complex behavior with many different oscillatory patterns.
      Analysis of model bifurcations, performed with respect to the arterial pressure
      level, indicated that modest changes in this parameter caused the network to
      shift between periodic, quasiperiodic, and chaotic behavior. When arterial
      pressure was changed from approximately 60-150 mm Hg, the model exhibited a
      classic route toward chaos, as in the Ruelle-Takens scenario. This work reveals
      that the nonlinear myogenic mechanism is able to produce the multitude of
      different oscillatory patterns observed in vivo in microvascular beds, and that
      irregular microvascular fluctuations may be regarded as a form of deterministic
      chaos.

PMID- 8669717
TI  - A simulation of three-dimensional systolic flow dynamics in a spherical
      ventricle: effects of abnormal wall motion.
AB  - Alterations in left ventricle (LV) wall motion induced by ischemia will affect
      flow dynamics, and these altered flow fields can be used to evaluate LV pumping
      efficiency. LV chamber flow fields were obtained in this study by solving the
      discretized three-dimensional Navier-Stokes equations for viscous, incompressible
      unsteady flow by using the finite analytic method. Several cases of abnormal wall
      motion (AWM) were simulated by a manipulation of the boundary conditions to
      produce regions of hypokinesis, akinesis, and dyskinesis. These solutions were
      used to determine the central ejection region (CER), defined as the region of
      flow domain in which the obtained velocity field vectors are aligned +/- 3
      degrees from the LV long axis. A CER coefficient was computed from information on
      the location and orientation of the CER within the LV cavity. Contraction of the
      spherical ventricle produced a vector field that was symmetric with respect to
      the long axis. For the simulations of AWM, an asymmetrical flow pattern
      developed, became more pronounced with increasing severity of AWM, and resulted
      in a shorter CER that shifted toward the ischemic region. The CER coefficients
      decreased monotonically with increased severity in AWM from 0.948 in the normal
      case to a low of 0.164 for the most severe case of AWM. The CER coefficient
      quantitatively displayed the sensitivity of the flow patterns to even moderate
      degrees of hypokinesis. In addition, visualization of the three-dimensional flow
      field reinforced the necessity of three-dimensional simulations to capture
      aspects of the flow that existing methods of two-dimensional flow imaging that
      use ultrasound may miss.

PMID- 8669718
TI  - Specific impedance of canine blood.
AB  - The specific impedance of canine erythrocytes suspended in plasma was measured in
      the frequency range from 5 kHz to 1 MHz in samples from three animals in the
      hematocrit range from zero to packed cells at a temperature of 39 degrees C;
      measurements were made with a conductivity cell using four electrodes and a
      current density of 21 microA/cm2. With the use of impedance spectroscopy, data
      were fitted to an equivalent circuit model; model parameters in turn were fitted
      as functions of hematocrit. The resultant model can be used to predict specific
      impedance (real and reactive components) as a function of hematocrit and
      frequency over a frequency range from 5 kHz to 1 MHz and a hematocrit range from
      0 to 80. Over a normal range of hematocrits and at frequencies less than 100 kHz,
      the current is almost exclusively confined to the plasma, and the specific
      impedance is nearly equal to the real component; however, at higher frequencies,
      the complex nature of specific impedance becomes important.

PMID- 8669719
TI  - The mechanical properties of the human cervical spinal cord in vitro.
AB  - The response of spinal cord tissue to mechanical loadings is not well understood.
      In this study, isolated fresh cervical spinal cord samples were obtained from
      cadavers at autopsy and tested in uniaxial tension at moderate strain rates.
      Stress relaxation experiments were performed with an applied strain rate and peak
      strain in the physiological range, similar to those seen in the spinal cord
      during voluntary motion. The spinal cord samples exhibited a nonlinear stress
      strain response with increasing strain increasing the tangent modulus. In
      addition, significant relaxation was observed over 1 min. A quasilinear
      viscoelastic model was developed to describe the behavior of the spinal cord
      tissue and was found to describe the material behavior adequately. The data also
      were fitted to both hyperelastic and viscoelastic fluid models for comparison
      with other data in the literature.

PMID- 8669720
TI  - Left-right asymmetry of visual evoked potentials in brain-damaged patients: a
      mathematical model and experimental results.
AB  - The left-right asymmetry in the potential amplitude on the scalp was studied in
      poststroke patients by using flash visual evoked potential (VEP) and a numerical
      two-dimensional model of the head. The left-right asymmetry of the VEP was
      measured in three patients after thrombosis, in one after hemorrhage, and in one
      healthy subject. The numerical model used computed tomography images to define
      the different compartments of the head. The volume conductor equation for the
      potential distribution created by a dipole source in the occipital region was
      solved numerically with use of a finite volume method. Left-right asymmetry was
      calculated with several values of conductivity of the damaged region. The
      experimental results revealed a negative asymmetry in the three patients after
      thrombosis (i.e., the potential amplitude over the ischemic hemisphere was
      smaller than that over the intact hemisphere), whereas, in the patient after
      hemorrhage, a positive asymmetry was found. Nonsignificant left-right asymmetry
      was found in the healthy subject. The numerical model revealed that the
      electrical conductivity of the damaged tissue has a major effect on the left
      right asymmetry. Negative asymmetry, such as that found for patients after
      thrombosis, was obtained when the conductivity of the damaged region was greater
      than that of the brain, whereas positive asymmetry (hemorrhage patient) was
      obtained when that conductivity was smaller than that of the brain. This finding
      indicates that the left-right asymmetry in the scalp VEP of patients after brain
      damage may be a result of changes in the conductivity of the volume conductor
      (the ischemic region) between the source and the electrodes.

PMID- 8669722
TI  - Membrane potential fluctuations of human T-lymphocytes have fractal
      characteristics of fractional Brownian motion.
AB  - The voltage across the cell membrane of human T-lymphocyte cell lines was
      recorded by the whole cell patch clamp technique. We studied how this voltage
      fluctuated in time and found that these fluctuations have fractal
      characteristics. We used the Hurst rescaled range analysis and the power spectrum
      of the increments of the voltage (sampled at 0.01-sec intervals) to characterize
      the time correlations in these voltage fluctuations. Although there was great
      variability in the shape of these fluctuations from different cells, they all
      could be represented by the same fractal form. This form displayed two different
      regimes. At short lags, the Hurst exponent H = 0.76 +/- 0.05 (SD) and, at long
      lags, H = 0.26 +/- 0.04 (SD). This finding indicated that, over short time
      intervals, the correlations were persistent (H > 0.5), that is, increases in the
      membrane voltage were more likely to be followed by additional increases.
      However, over long time intervals, the correlations were antipersistent (H <
      0.5), that is, increases in the membrane voltage were more likely to be followed
      by voltage decreases. Within each time regime, the increments in the fluctuations
      had characteristics that were consistent with those of fractional Gaussian noise
      (fGn), and the membrane voltage as a function of time had characteristics that
      were consistent with those of fractional Brownian motion (fBm).

PMID- 8669721
TI  - An E-selectin-IgG chimera supports sialylated moiety dependent adhesion of colon
      carcinoma cells under fluid flow.
AB  - To further characterize the molecular mechanisms that govern carcinoma cell
      adhesion to stimulated endothelium, we studied the adhesion of a human colon
      carcinoma cell line, KM12-L4, to an E-selectin-IgG1 chimera and interleukin (IL)
      1 beta-stimulated human umbilical vein endothelial cells (HUVEC) under in vitro
      fluid flow conditions. Between 0.6 and 1.8 dynes/cm2, KM12-L4 cells attach to and
      roll on IL-1 beta-stimulated HUVEC. The adhesion is E-selectin dependent and
      diminished upon pretreatment of the KM12-L4 cells with neuraminidase
      (neuraminidase sensitive). Between 0.7 and 1.8 dynes/cm2, surfaces coated with an
      E-selectin-IgG1 chimera support attachment and rolling of KM12-L4 cells. The
      adhesion to the E-selectin-IgG1 chimera is blocked by an antibody to the lectin
      domain of E-selectin and is neuraminidase sensitive. Rolling KM12-L4 cells
      exhibit variable velocity motion over both IL-1 beta-stimulated HUVEC and E
      selectin-IgG1 chimera-coated surfaces. Our results provide the first direct
      evidence that sialylated moieties are involved in the adhesion of carcinoma cells
      to IL-1 beta-stimulated endothelium under flow conditions; E-selectin-IgG1
      chimeras can support cell attachment and rolling under defined flow conditions;
      the topology of the endothelium is not the sole cause of variable velocity motion
      observed in cell rolling systems.

PMID- 8669723
TI  - Hemodynamic effects of calcium chloride in a canine model of acute propranolol
      intoxication.
AB  - STUDY OBJECTIVE: To evaluate the hemodynamic effects of calcium chloride in a
      canine model of acute propranolol toxicity. METHODS: Two minutes after the
      completion of a propranolol infusion (10 mg/kg), a bolus of .125 mL/kg 10% CaCl
      solution followed by an infusion of .375 mL/kg over the next 30 minutes or a
      bolus and subsequent infusion of an equivalent volume of normal saline solution
      was administered to each dog. RESULTS: CaCl yielded significant improvements in
      propranolol-induced decreases in cardiac index and stroke volume compared with
      saline solution-treated control animals (overall alpha = .05). Furthermore, CaCl
      administration resulted in earlier improvement in propranolol-induced alterations
      in mean arterial pressure, maximal left ventricular pressure change over time,
      and peripheral vascular resistance compared with saline solution (overall alpha =
      .05). We observed no difference between treatment groups in response to
      propranolol-induced bradycardia or QRS-interval prolongation. CONCLUSION: In this
      model of acute propranolol toxicity, CaCl therapy improved depressed hemodynamic
      status, mainly by a positive inotropic action.

PMID- 8669724
TI  - Ectopic pregnancy: prospective study with improved diagnostic accuracy.
AB  - STUDY OBJECTIVE: To assess the utility of ultrasonography, quantitative serum
      beta-human chorionic gonadotropin (beta-hCG) level, history, and physical
      examination in the diagnosis of ectopic pregnancy (EP) in the emergency
      department. METHODS: We prospectively studied 481 consecutive pregnant patients
      who presented to an urban ED with first-trimester abdominal pain or vaginal
      bleeding. History, physical examination findings, quantitative beta-hCG values,
      sonography findings, surgical findings, and final diagnosis were collected after
      patient enrollment in the study. We assessed the proportions of pregnant patients
      experiencing pain or bleeding with EPs versus those with abnormal and normal
      intrauterine pregnancies (IUPs). RESULTS: Pregnant women with abdominal pain or
      vaginal bleeding received beta-hCG values; positive radioimmunoassays prompted
      ultrasonography; indeterminate ultrasonography findings resulted in admission.
      Thirteen percent of patients had confirmed EPs; 99.5% of patients discharged from
      the ED had documented IUPs. Transvaginal sonography in the ED established EP or
      IUP in 75%. For EP detection, sonography is 69% sensitive and 99% specific.
      Single beta-hCG levels are useful in predicting EP; a beta-hCG value of 1,000
      mIU/mL or lower shows a fourfold higher risk of EP. History and physical
      examination do not reliably diagnose or rule out EP; of EP patients, 9% reported
      no pain and 36% lacked adnexal tenderness. CONCLUSION: To prevent delayed
      diagnosis of EP in urban centers, pregnant women with abdominal pain or vaginal
      bleeding require evaluation by transvaginal ultrasonography. Indeterminate
      ultrasonography findings necessitate further evaluation. A beta-hCG level of
      1,000 mIU/mL or lower should heighten suspicion of EP.

PMID- 8669725
TI  - Low-threat-to-life motor vehicle injuries. National Highway Traffic Safety
      Administration.

PMID- 8669726
TI  - Serum methanol in the absence of methanol ingestion.

PMID- 8669727
TI  - Low-voltage electrical injury.

PMID- 8669728
TI  - Heated lidocaine.

PMID- 8669729
TI  - GI cocktail.

PMID- 8669730
TI  - Delayed use of intravenous mannitol in ciguatera (fish poisoning)

PMID- 8669731
TI  - Practice parameter: neuroimaging in the emergency patient presenting with seizure
      (summary statement). American College of Emergency Physicians, American Academy
      of Neurology, American Association of Neurological Surgeons, American Society of
      Neuroradiology.

PMID- 8669732
TI  - Seroprevalence of tetanus antibodies among adults older than 65 years.
AB  - STUDY OBJECTIVE: To define the extent of immunity against tetanus among patients
      older than 65 years of age by measuring antitetanus antibody levels. METHODS: A
      convenience sample of 129 patients from an urban comprehensive care geriatric
      center was studied. Serum was obtained and enzyme-linked immunosorbent assay
      (ELISA) testing performed. Twenty health care providers, aged 25 to 40 years,
      were tested for comparison. RESULTS: In 64 (50%) of 129 study patients,
      antitetanus antibody levels did not reach protective levels. Fifty-four (59%) of
      92 women and 10 (27%) of 37 men did not have adequate titers. All 20 health care
      workers had protective titers. CONCLUSION: Elderly patients are substantially
      less likely than young individuals to have adequate immunity against tetanus.
      Emergency physicians must take this into consideration when evaluating tetanus
      immunization status in injured elderly patients.

PMID- 8669733
TI  - Drug use patterns at major rock concert events.
AB  - STUDY OBJECTIVE: To describe alcohol and drug use patterns in patients presenting
      to first aid stations at major rock concerts. METHODS: We retrospectively
      reviewed all charts generated at the first aid stations of five major rock
      concerts featuring the rock groups Pink Floyd, the Grateful Dead, and the Rolling
      Stones. The first aid stations, located at a sports stadium, were staffed by
      paramedics, emergency medicine nurses, and physicians. We recorded the following
      data: patient demographics, history of drug or ethanol use, time spent by patient
      in first aid station, treatment rendered, diagnosis, and patient disposition.
      RESULTS: A total of 253, 286 spectators attended the five concert events. The
      rate of use of the first aid station was 1.2 per 1,000 patrons. The average age
      of the patrons was 26.3 +/- 7.9 years (range, 3 to 56 years). The most common
      diagnoses were minor trauma 130 (42%) and ethanol or illicit drug intoxication 98
      (32%). Of the patients treated, 147 (48%) admitted to using illicit drugs or
      ethanol while attending the concerts. The median time spent in the first aid
      station was 15 +/- 22.5 minutes (range, 5 to 150 minutes). One hundred patients
      (32.5%) were treated and released, 98 (32%) were transported to emergency
      departments, and 110 (35.5%) signed out against medical advice. CONCLUSION: Minor
      trauma and the use of illicit drugs and ethanol were common in spectators
      presenting to first aid stations at these concert events. Physicians and
      paramedical personnel working at rock concerts should be aware of the current
      drug use patterns and should be trained in treating such drug use.

PMID- 8669734
TI  - Emergency medicine credentials in St Louis and Kansas City: does the presence of
      an emergency medicine residency program have a geographic difference?
AB  - STUDY OBJECTIVE: To compare emergency physician (EP) credentialing
      characteristics in two metropolitan areas of Missouri: Kansas City, which has had
      an emergency medicine (EM) residency program since 1973, and St Louis, which is
      without a program approved by the Accreditation Council for Graduate Medical
      Education. METHODS: A cross-sectional, descriptive survey concerning EP training,
      certification, and practice characteristics was administered by standardized
      telephone interviews. Participants were all emergency department directors in
      Kansas City and St Louis general hospital EDs serving more than 10,000 patients
      annually. RESULTS: Twenty Kansas City EDs, with an annual census of 20,250 +/-
      7,200; and 30 St Louis EDs, with an annual census of 27,100 +/- 13,800, were
      surveyed. In Kansas City, 68% of practicing EPs were EM trained, versus 10% in
      St. Louis (P < .0005). The percentage of board-certified EPs was also greater in
      Kansas City than in St Louis (82% versus 42%, P < .0005). Eighty-six percent of
      ED directors in St Louis, compared with 30% in Kansas City, reported that they
      did not attempt to recruit EM-trained staff or that recruitment was difficult (P
      < .0005). CONCLUSION: The presence of an EM residency training program is
      associated with favorable EP credentialing characteristics in the Kansas City
      metropolitan area. This information may prove useful to institutions attempting
      to establish EM training programs in areas where none currently exist.

PMID- 8669735
TI  - Emergency medicine residents' perspectives on injury prevention.
AB  - STUDY OBJECTIVE: To determine emergency medicine residents' perspectives and
      opinions concerning the relevance of injury prevention to emergency medicine and
      their exposure to formal instruction and readings in this subspecialty area.
      METHODS: A survey was mailed between November 1992 and February 1993 to all 461
      residents and 1992 graduates of the 13 emergency medicine residency programs in
      California. RESULTS: Three hundred ninety questionnaires (85%) were returned.
      Ninety-seven percent of respondents said they believed injury prevention is
      pertinent to emergency medicine. Sixty-two percent said they believed inadequate
      time in residency is devoted to this subject, and 70% said there should be a
      greater focus on injury prevention in their training. Only 44% of the respondents
      said they had received lectures and 28% of the respondents said they consistently
      read journal articles on injury prevention. There were no statistically
      significant differences between the level of the respondents' training and their
      answers to the questions. CONCLUSION: Although most emergency medicine residents
      consider injury prevention pertinent to emergency medicine and important to their
      training, most perceived a lack of formal instruction on injury prevention during
      their training and did not consistently read articles on this subspecialty area.

PMID- 8669736
TI  - Prehospital endotracheal intubation of children by paramedics.
AB  - STUDY OBJECTIVE: To describe the experience of an emergency medical services
      system with the use of liberal indications for prehospital pediatric endotracheal
      intubation. METHODS: We performed a retrospective review of prehospital and
      hospital patient records in an urban and suburban prehospital care system. The
      study included all children aged 15 years or younger who were intubated in the
      prehospital setting by King County paramedics from January 1, 1984, to December
      31, 1990. RESULTS: During the 7-year study period, 654 children were intubated,
      of which 355 (54%) were study patients. The median age of the patients was 3
      years; 60% had an injury diagnosis. On arrival of the paramedics, 60% of the
      patients were in sinus rhythm, 62% had a systolic blood pressure of 70 mm Hg or
      greater, and 56% had a respiratory rate of 10 breaths per minute or greater. The
      Glasgow Coma Scale score was 8 or lower in 83% of the patients. Succinylcholine
      was used to facilitate intubation in 47% of patients. On arrival at the emergency
      department, 79% of the patients were in sinus rhythm; 75% had an adequate blood
      pressure (70 mm Hg or greater); 86% had a PaO2 value of 100 mm Hg or greater; and
      74% had a PaCO2 value of 45 mm Hg or lower. Complications of intubation, more
      than half of which were classified as minor, were noted in 22.6% of patients. We
      were unable to determine the number of failed intubation attempts. Most of the
      patients (58%) survived to hospital discharge. Among cardiac arrest victims, only
      12% survived. CONCLUSION: In a setting where paramedics practice with close
      medical direction, applying liberal indications for pediatric intubation and
      permitting the use of succinylcholine allowed paramedics to intubate children of
      different ages and diagnoses.

PMID- 8669737
TI  - Pediatric injuries from cardiopulmonary resuscitation.
AB  - STUDY OBJECTIVE: To assess the type, rate, and severity of unanticipated
      complications of CPR (external cardiac compressions and ventilation) in a
      pediatric population. METHODS: A retrospective review was undertaken of the
      records from all deceased children ( < 12 years old) who had been given CPR
      during an 8-year period (1988 through 1995). Patients with historical or physical
      evidence of preceding trauma were excluded. Clinical and autopsy records were
      abstracted for patient demographics, clinical findings, duration of CPR, persons
      administering CPR, and medical examiner summaries. RESULTS: Two hundred eleven
      children (mean age, 19.0 months) met the inclusion criteria and were entered into
      the study. The most common cause of cardiac arrest was sudden infant death
      syndrome (56%), followed by drowning (8%), congenital heart disease (7%), and
      pneumonia (4%). Mean duration of CPR was 45 minutes (range, 3 to 180 minutes).
      Fifteen children (7%) had at least one injury as a result of CPR; 7 (3%) had
      injuries that were considered medically significant. These included
      retroperitoneal hemorrhage (n = 2), pneumothorax (n = 1), pulmonary hemorrhage (n
      = 1), epicardial hematoma (n = 1), and gastric perforation (n = 1); in spite of
      prolonged resuscitation performed with variable degrees of skill, only one
      patient was noted to have rib fractures. CONCLUSION: Significant iatrogenic
      injuries are rare in children who receive CPR; they occur in approximately 3% of
      cases. Recognizing the possibility of a complication may help in the management
      of children who survive cardiac arrest. Regardless of resuscitation history,
      abuse should be considered whenever traumatic injuries are encountered.

PMID- 8669738
TI  - Analysis of federally imposed penalties for violations of the Consolidated
      Omnibus Reconciliation Act.
AB  - STUDY OBJECTIVE: To identify the incidence of federally imposed penalties for
      violations of the Consolidated Omnibus Reconciliation Act (COBRA). METHODS: Under
      the Freedom of Information Act, we retrieved a copy of any document related to
      fines imposed on, settlements made by, or litigation against physicians or
      hospitals as a result of COBRA violations from the Office of the Inspector
      General. Under a separate inquiry, also under the Freedom of Information Act, we
      requested and received from the central office of the Health Care Financing
      Administration the National Composite Log showing the status of all complaint
      investigations pursuant to COBRA since the inception of the law. RESULTS: One
      thousand seven hundred fifty-seven complaint investigations were authorized. Of
      the 1,729 investigations completed, 412 (24%) were found to be out of compliance
      with federal regulations. Of these, 27 cases resulted in fines imposed on
      hospitals. These fines ranged from $1,500 to $150,000 with a mean of $33,917, a
      median of $25,000, and standard deviation of $35,899. The six fines that were
      imposed against physicians ranged in value from $2,500 to $20,000 with a mean of
      $8,500, a median of $7,500, and an SD of $8,612. Seven hospitals but no
      physicians were terminated from the Medicare program for COBRA violations.
      CONCLUSION: The incidence of federally imposed penalties for COBRA violations is
      low given the multitude of patient transfers that have occurred since the
      enactment of COBRA. The growing concern regarding this issue may be related to
      current litigation efforts to broaden the scope and applications of these laws.

PMID- 8669739
TI  - Withholding and withdrawing medical treatment: an emergency medicine perspective.
AB  - In emergency medicine, a significant difference rightfully persists between the
      withholding and withdrawal of life-sustaining medical treatment. The
      justification for this difference stems part from the nature of emergency medical
      practice and the unique manner in which clinicians apply many ethical principles.
      In the usual setting, the decision to withhold further medical treatment is done
      quietly, often without input from the patients surrogate decisionmaker, whereas
      withdrawal of ongoing medical treatment can be more obvious and difficult. This
      situation is reversed in the emergency medicine setting. The withholding of
      emergency medical treatment is much more problematic than later withdrawal of
      unwanted or useless interventions. Emergency physicians and prehospital providers
      often lack vital information about their patients' identities, medical
      conditions, and wishes. Society also has specific expectations of emergency
      physicians. Because of the nature of emergency medicine, both in the prehospital
      and the emergency department settings, the distinction between withdrawal and
      withholding of medical treatment has never disappeared and is not likely to do so
      in the future.

PMID- 8669740
TI  - Rapid-sequence intubation of the pediatric patient. Pediatric Emergency Medicine
      Committee of the American College of Emergency Physicians.
AB  - Airway compromise is the most common cause of death and severe morbidity in
      acutely ill and injured children. Rapid-sequence intubation (RSI) is a technique
      for emergency airway control designed to maximize successful endotracheal
      intubation while minimizing the adverse physiologic effects of this procedure.
      RSI requires familiarity with patient evaluation, airway-management techniques,
      sedation agents, neuromuscular blocking agents, additional adjunctive agents, and
      postintubation management techniques. Emergency physicians should use RSI
      techniques in the endotracheal intubation of critically ill children.

PMID- 8669741
TI  - Ultrasound versus radiography in the detection of soft-tissue foreign bodies.
AB  - STUDY OBJECTIVE: To determine the usefulness of ultrasound and radiography in
      detecting foreign bodies in soft-tissue models closely duplicating puncture-wound
      trauma and hand anatomy. METHODS: In this randomized, blinded descriptive study,
      two radiologists independently evaluated 120 chicken thighs for foreign bodies
      with the use of standard two-view radiography and 7.5-MHz transducer
      ultrasonography. All chicken thighs were manipulated with hemostats to ensure
      uniform tissue damage. In 60 thighs, one foreign body had been inserted (10 each:
      gravel, metal, glass, cactus spine, wood, and plastic). RESULTS: The sensitivity
      of ultrasound in detecting gravel was 40%, that for metal was 45%, that for glass
      was 50%, that for cactus spine was 30%, that for wood was 50%, and that for
      plastic was 40%. The overall sensitivity, specificity, and false-negative and
      false-positive rates for ultrasound were 43%, 70%, 50%, and 30%, respectively. No
      individual foreign body had an ultrasound detection rate of 50%. Radiography
      detected foreign bodies generally considered radiopaque (gravel, glass, metal)
      98% of the time, but it never detected bodies considered radiolucent (wood,
      plastic, cactus spine). The false-negative and false-positive rates for
      radiography were 50% and 1.6%, respectively. CONCLUSION: Ultrasound detection of
      foreign bodies by skilled operators in this animal model revealed poor
      sensitivity and specificity. Radiographic detection was highly sensitive for
      foreign bodies considered radiopaque. Our data suggest that ultrasound should not
      be relied on to rule out the possibility of a retained foreign body in the distal
      extremities.

PMID- 8669742
TI  - Medical journals and the science of peer review: raising the standard.

PMID- 8669743
TI  - Federal anti-patient-dumping provisions: the first decade.

PMID- 8669744
TI  - Rapid-sequence intubation comes of age.

PMID- 8669745
TI  - Development of emergency medicine in Lebanon.

PMID- 8669746
TI  - Neostigmine for the treatment of neurotoxicity following envenomation by the
      Asiatic cobra.
AB  - Envenomation by the monocellate cobra (Naja kaouthia) is usually manifested
      clinically as neurotoxicity and local tissue necrosis. Treatment often requires
      administration of large quantities of antivenin, resulting in a high incidence of
      serum reactions. In cases where antivenin administration may be delayed for
      several hours or administration is contraindicated, the use of the
      anticholinesterase drug neostigmine may temporarily reverse the potentially
      lethal neurological effects of the venom. Detailed in this report is the case of
      immediate and dramatic reversal of envenomation symptoms following the
      administration of the anticholinesterase neostigmine methyl sulfate.

PMID- 8669747
TI  - Acute carpal tunnel syndrome in a diver: evidence of peripheral nervous system
      involvement in decompression illness.
AB  - Conclusive evidence for involvement of the peripheral nervous system in
      decompression illness is lacking. We report a case of decompression illness
      associated with shoulder pain and the clinical features of median nerve injury at
      the wrist. Initial recompression and hyperbaric oxygen treatment produced prompt
      relief of all symptoms and signs, but carpal tunnel syndrome subsequently
      recurred. Nerve conduction studies confirmed median nerve conduction delay at the
      wrist. Repeat measurements after treatment with hyperbaric oxygen showed
      electrophysiologic improvement that was consistent with improvement in symptoms.
      We believe this is the first objectively substantiated case of injury to the
      peripheral nervous system caused by decompression illness.

PMID- 8669748
TI  - Unexpected sudden death in a young pregnant woman: unusual presentation of
      neurosarcoidosis.
AB  - We report the case of a young, previously healthy woman who was brought to the
      emergency department in cardiac arrest and who died despite resuscitative
      efforts. An autopsy revealed the cause of death to be sarcoidosis of the brain
      stem and cerebellum with secondary obstructive hydrocephalus. Neurosarcoidosis
      presenting as sudden death has not previously been reported. A review of the
      medical conditions that may precipitate sudden death in young adults is
      presented.

PMID- 8669749
TI  - Effect of a mask and pneumotachograph on tracheal and nasopharyngeal pressures,
      respiratory frequency, and ventilation in horses.
AB  - OBJECTIVE: To investigate the effect of a mask and pneumotachograph on
      ventilation, respiratory frequency, and tracheal and nasopharyngeal pressures in
      horses running on a treadmill. DESIGN: Six horses ran at 50, 75, and 100% of the
      speed that resulted in maximum oxygen consumption, with and without a mask and
      pneumotachograph. Tracheal and pharyngeal inspiratory and expiratory pressures,
      respiratory frequency, and arterial blood gases were measured. ANIMALS: Six
      Standardbred horses. PROCEDURE: Oxygen consumption was measured during an
      incremental exercise test to determine the speed that resulted in maximal oxygen
      consumption for each horse. Tracheal and pharyngeal pressures were measured,
      using transnasal tracheal and pharyngeal side-hole catheters connected to
      differential pressure transducers. Carotid arterial blood samples were collected
      and PAO2, PaCO2, and pH were measured with a blood gas analyzer. RESULTS: Peak
      tracheal and pharyngeal inspiratory pressures were significantly more negative,
      peak tracheal and pharyngeal expiratory pressures were significantly more
      positive, and respiratory frequency was significantly lower (all P < 0.05) at all
      speeds when horses wore a mask. The PaCO2 was higher and arterial pH and PaO2
      were lower (P < 0.05) when horses wore a mask. CONCLUSIONS: The mask and
      pneumotachograph altered upper airway pressures, respiratory frequency, and
      ventilation in horses running on a treadmill.

PMID- 8669750
TI  - Canine glyceraldehyde-3-phosphate dehydrogenase complementary DNA: polymerase
      chain reaction amplification, cloning, partial sequence analysis, and use as
      loading control in ribonuclease protection assays.
AB  - OBJECTIVE: To use canine glyceraldehyde-3-phosphate dehydrogenase complementary
      DNA (GAPDH cDNA) as a template in ribonuclease (RNase) protection assays to
      measure canine GAPDH mRNA expression. DESIGN AND PROCEDURE: Primers designed from
      the human GAPDH gene were used to amplify a 191-base pair canine GAPDH cDNA by
      reverse-transcription polymerase chain reaction. The cDNA was sequenced, and used
      as a template for RNase protection assay. SAMPLE POPULATION: Total RNA was
      isolated from a canine squamous carcinoma cell line. RESULTS: Canine GAPDH cDNA
      had a high degree of homology to human, rat, and mouse GAPDH. In vitro
      transcription of canine GAPDH cDNA was used to produce complementary RNA that
      detected canine GAPDH mRNA by RNase protection assay. CONCLUSION: Canine GAPDH
      cDNA is a useful loading control to be used in RNase protection assays measuring
      mRNA expression in canine cells or tissues.

PMID- 8669751
TI  - Isolation and characterization of alpha 1-protease inhibitor from canine plasma.
AB  - OBJECTIVE: To improve a previously described purification process by producing a
      higher yield and purity of alpha 1-protease inhibitor (alpha 1-PI) from canine
      plasma. ANIMALS: Plasma pool from 10 clinically normal male dogs. PROCEDURE:
      Canine alpha 1-PI was purified by use of ammonium sulfate precipitation, ion
      exchange chromatography, and 3 affinity chromatographic procedures: concanavalin
      A-Sepharose, thiol, and hemoglobin-Sepharose. Characterization was performed by
      gel electrophoresis, isoelectric focusing, and immunoblot analysis. The N
      terminal amino acid sequence was obtained by use of the Edman degradation method
      and a gas amino acid sequencer. RESULTS: Canine alpha 1-PI was purified with a
      yield of approximately 7% and a 54-fold increase in specific inhibitory activity.
      The inhibitor had a molecular weight of 59,000 and had 2 major patterns after
      isoelectric focusing: fast and intermediate in homozygous and/or heterozygous
      forms. Edman degradation revealed glutamic acid as the starting amino acid from
      the N-terminal sequence. Homologies of the N-terminal sequence of canine alpha 1
      PI with those of sheep, horse, and human alpha 1-protease inhibitors were 54, 46,
      and 41%, respectively. CONCLUSIONS: Canine protease inhibitor is analogous to the
      alpha 1-protease inhibitors of sheep, human beings, and mice in terms of
      molecular weight, amino acid composition, and inhibitory activity against
      trypsin. Although the method described had a yield of 7%, the final product
      retained inhibitory activity and was pure. CLINICAL RELEVANCE: The availability
      of pure canine alpha 1-PI, as well as the specific antibodies, will facilitate
      studies on the fecal excretion and structural heterogeneity of this protein in
      dogs with naturally acquired protein-losing enteropathy.

PMID- 8669752
TI  - Detection of Toxoplasma gondii in feline and canine biological samples by use of
      the polymerase chain reaction.
AB  - OBJECTIVE: To develop a polymerase chain reaction (PCR) technique to identify
      Toxoplasma gondii DNA in biological samples from cats and dogs. DESIGN: To
      artificially create samples that would mimic those acquired in a clinical setting
      from animals with naturally acquired toxoplasmosis. Using these samples, a PCR
      test to identify T gondii DNA was developed. SAMPLE POPULATION: Feline and canine
      aqueous humor, CSF, serum, and blood samples. PROCEDURE: Tachyzoites of several
      strains of T gondii grown in cell culture were added to feline and canine aqueous
      humor, CSF, serum, and blood samples. Protocols for identifying T gondii DNA by
      use of the PCR were developed. RESULTS: The DNA from as few as 10 tachyzoites of
      T gondii could be identified in feline and canine aqueous humor, CSF, and serum
      samples. One hundred tachyzoites could be identified in blood samples.
      CONCLUSIONS: Toxoplasma gondii can be identified in feline and canine biological
      samples by use of the PCR. CLINICAL RELEVANCE: Correlation of clinical disease to
      T gondii serum antibodies provides only a presumptive diagnosis of toxoplasmosis.
      Use of PCR to detect T gondii DNA in biological samples from cats and dogs may
      provide a sensitive tool for the antemortem diagnosis of toxoplasmosis and may be
      most beneficial when used in conjunction with serum antibody titers.

PMID- 8669753
TI  - Fractionation of canine serum calcium, using a micropartition system.
AB  - OBJECTIVE: To determine usefulness of a micropartition system for calcium
      fractionation of canine serum, and to establish reference values for protein
      bound, complexed, and ionized calcium fractions in clinically normal dogs.
      DESIGN: Performance characteristics of a micropartition system were evaluated,
      using serum from clinically normal dogs. This micropartition system was then used
      to determine a reference range for calcium fractions. ANIMALS: 13 clinically
      normal dogs. PROCEDURE: Dog serum was placed in the micropartition system, and
      spun for 20 minutes at 1,300 x g. Total calcium concentration, ionized calcium
      concentration, and pH were measured in whole serum, and total calcium
      concentration was measured in the ultrafiltrate. The protein-bound fraction was
      calculated by subtracting total calcium of the ultrafiltrate from total calcium
      of whole serum. The ionized calcium measurement of whole serum was subtracted
      from the total calcium measurement of the ultrafiltrate, determining the
      complexed calcium fraction. RESULTS: During validation of the ability of the
      micropartition system to separate calcium fractions, no significant amount of
      serum calcium was adsorbed by the plastic micropartition system or membrane. The
      micropartition membrane separated the protein-bound calcium fraction (retentate)
      from the ultrafiltrate, which contained ionized and complexed fractions of
      calcium. Concentrations of protein-bound, ionized, and complexed calcium from
      clinically normal dogs were determined to be 3.40 +/- 0.63, 5.49 +/- 0.17, and
      1.01 +/- 0.30 mg/dl, representing 34, 56, and 10% of the total calcium
      concentration, respectively. CONCLUSIONS: This method is a rapid, repeatable
      means to completely fractionate serum calcium, and most importantly provides
      accurate assessment of the protein-bound and complexed calcium fractions.
      CLINICAL RELEVANCE: Complete assessment of calcium fractions may increase
      sensitivity for detection of disease processes that affect calcium metabolism.

PMID- 8669754
TI  - Evaluation of travel and use as a risk factor for seropositivity to Ehrlichia
      risticii in horses of New York state.
AB  - OBJECTIVES: To determine whether mean annual frequency and destination of equine
      travel was associated with exposure to Ehrlichia risticii and whether these
      associations were modified by horses' place of residence. DESIGN: Cross-sectional
      study. SAMPLE POPULATION: 511 equine operations containing 2,587 horses were
      visited in New York state from a target population of 39,000 operations.
      PROCEDURE: Each horse was tested for serum antibodies against E risticii, using
      indirect fluorescent antibody. Information on the horse's travel history, farm's
      management practices, and surrounding ecology was obtained by personal interview
      and resource maps. Statistical analyses were performed on 2 cohorts of animals:
      all horses enrolled in the study and horses born on the property or that resided
      at least 4 years on the farm. Three county-based risk regions (RR) were
      identified by use of cluster analysis. RESULTS: Mean seroprevalence for each of
      the 3 RR was 2.4 (low risk), 8.5 (moderate risk), and 18.5% (high risk) for
      cohort 1 and 2.5, 8.0, and 18.4% for cohort 2. Among cohorts 1 and 2, pleasure
      riding and breeding trips were associated with exposure to E risticii, but horse
      residence (low, moderate, or high RR) was an effect modifier for these
      associations. Among cohort 1 and stratifying the analysis according to the RR for
      the travel destination, trail riding at low RR and trail riding at high RR were
      associated with exposure. Among cohort 2 and stratifying the analysis according
      to the RR for the travel destination, breeding trips were associated with
      exposure, and strong effect modification was present for horse residence (low,
      moderate, or high RR). CONCLUSIONS: Only certain types of travel to specific RR
      were associated with higher risk of exposure to E risticii. In many instances,
      travel was not associated, or was associated, with a reduced risk of exposure.

PMID- 8669755
TI  - Cross-sectional evaluation of environmental, host, and management factors
      associated with risk of seropositivity to Ehrlichia risticii in horses of New
      York state.
AB  - OBJECTIVES: To locate counties within New York state with a high seroprevalence
      among the equine population, to determine host, management, and environmental
      factors that were associated with seropositivity to Ehrlichia risticii, and to
      determine evidence for arthropod- or helminth-mediated transmission of E risticii
      to horses. DESIGN: Cross-sectional study. SAMPLE POPULATION: A random sample of
      3,000 of the 39,000 equine operations in New York state was selected, and 2,587
      horses from 511 operations were tested. PROCEDURE: Blood samples were collected
      from horses and tested for seropositivity, using the indirect fluorescent
      antibody technique. Data on each horse and each farm's management were obtained
      by personal interview. The significance of each factor on the risk of
      seropositivity was evaluated, using mixed-effect logistic regression. RESULTS:
      The seroprevalence among E risticii-nonvaccinated horses was 7.3%. The county
      specific seroprevalence ranged from 0 to 27%, with higher-risk counties located
      at low elevation. Farms at higher risk for having seropositive horses were
      located predominately at low elevation with no bodies of water nearby. Risk of
      seropositivity was associated with time spent in a stall or run-in shed, with
      frequency of application of fly spray, and, depending on duration of residency at
      the farm, with frequency of deworming with benzimidazole and pyrantel.
      Standardbreds were 2 to 3 times more likely to have been exposed, compared with
      Thoroughbreds. Depending on duration of residency at the farm, male and middle
      age horses were at higher risk. Up to 32% of the variance for a horse to test
      seropositive for E risticii on the logit scale was attributable to farm-level
      random effects, but the nested social group random effect was not significant.
      CONCLUSIONS: Arthropods and helminths may have a role in the transmission of this
      disease. Several management factors may directly or indirectly modify the risk of
      exposure to E risticii, allowing for the possibility of additional control
      measures besides traditional vaccination strategies.

PMID- 8669756
TI  - Familial basis of exertional rhabdomyolysis in quarter horse-related breeds.
AB  - OBJECTIVES: To trace pedigrees from affected horses, identify likely contributing
      founder horses, and determine the conditional probability of founder genotypes.
      DESIGN: Muscle biopsy records from the Neuromuscular Disease Laboratory at the
      University of California-Davis and the University of Minnesota were searched to
      identify horses with a polysaccharide storage myopathy and exercise
      intolerance/rhabdomyolysis. Pedigrees containing 5 to 6 generations were obtained
      where possible. ANIMALS: 13 Quarter Horses, 4 American Paint Horses, 3
      Appaloosas, and 3 Quarter Horse crossbreds (16 mares, 4 geldings, and 3
      stallions) were identified with polysaccharide storage myopathy. Pedigrees were
      available for 18 horses. PROCEDURE: Inbreeding coefficients, founder
      contributions, and conditional probability of founder genotypes were calculated.
      RESULTS: Three stallions (A, B, and C) were featured prominently in the
      pedigrees. Stallions A and B descended from a common sire. On average, A
      contributed 8.8% (range, 0 to 23%) of the genes in affected horses, B contributed
      4.2% (range, 0 to 14%), and C contributed 3.0% (range, 0 to 14%). The sire and
      dam of 4 horses were descendants of stallion A, the sire and dam of 1 horse were
      descendants of stallion B, and the sire and dam of 11 horses were descendants of
      a combination of stallions A and B. The pattern of inheritance resembled an
      autosomal recessive disorder. Assuming this pattern of inheritance, the
      conditional probability that these founders were carriers or recessive for the
      trait was > 99.29% for stallions A and B and 92% for stallion C. CONCLUSIONS:
      Results support a familial basis for polysaccharide storage myopathy and
      associated exertional rhabdomyolysis in Quarter Horse-related breeds. The strong
      contribution of particular founder stallions to the gene pool in some lines of
      Quarter Horses may explain the high incidence of exertional rhabdomyolysis in
      these horses.

PMID- 8669757
TI  - Performance traits, hoof mineral composition, and hoof characteristics of bulls
      in a 112-day postweaning feedlot performance test.
AB  - OBJECTIVE: To evaluate relations between hoof and performance data from bulls fed
      in a 112-day standardized postweaning feedlot performance test. ANIMALS AND
      DESIGN: Breeds included were Angus (n = 20), Brangus (n = 19), Hereford (n = 31),
      and Simmental (n = 53). Hoof measurements, scores, and a 0.5-g hoof tissue sample
      were obtained from the right forefoot of bulls on days 1 and 112 of 4 tests
      conducted in 3 locations in Arkansas. Data were analyzed, using least squares
      ANOVA. The model used included an overall mean, breed, farm of origin within
      breed, initial age, and initial weight within breed and residual. Residual and
      canonical correlations of the traits studied were calculated. RESULTS: Residual
      correlations were found between some hoof minerals. Canonical correlations
      between performance traits and hoof minerals, between hoof characteristics and
      hoof minerals, and between hoof characteristics and performance traits were 0.62
      and 0.45 (P < 0.005), 0.54 and 0.40 (P < 0.05), and 0.56 (P < 0.01) and 0.26 (P >
      0.05), respectively. CONCLUSIONS: These data suggest that a relation exists
      between performance traits and hoof mineral composition and hoof characteristics
      and mineral composition. The visual scoring system for these data did not
      genetically separate bulls on the basis of claw quality. CLINICAL IMPLICATIONS:
      By selecting bulls with high claw quality, cattle producers are decreasing the
      chances of premature culling because of hoof laminitis. Therefore, by obtaining
      hoof measurements and mineral composition in a feedlot performance test,
      producers should have the tools to select bulls for increased lifetime
      performance.

PMID- 8669758
TI  - Study of hereditary cerebellar degeneration in cats.
AB  - OBJECTIVE: To elucidate the nature of ataxia observed in 3 cats spanning 2
      generations. DESIGN: Experimental breeding was attempted to confirm heritability
      of the disease and establish the mode of inheritance; the original 3 cats and
      their offspring were studied. ANIMALS: Seven diseased cats spanning 3 generations
      and 11 neurologically normal cats. PROCEDURE: Cats were examined by use of the
      following methods: clinical observation, hematologic and serum biochemical
      examinations, neurologic examination, electrodiagnostics, magnetic resonance
      imaging, lysosomal enzyme activity assay, horizontal transmission test, and
      virologic and pathologic examinations. RESULTS: All kittens (1 male and 3
      females) obtained by backcrosses developed pure cerebellar dysfunction from the
      age of 7 to 8 weeks onward. It became progressively worse, but not fatal, between
      1 and 2.5 months. Prenatal or perinatal infection with feline panleukopenia
      virus, inherited lysosomal storage diseases, including gangliosidosis and
      mannosidosis, and feline hereditary neuroaxonal dystrophy were excluded. Magnetic
      resonance imaging indicated that size of the cerebellum of diseased cats was
      markedly reduced. Cerebellar cortical degeneration, especially with extensive
      destruction of Purkinje cells, was observed microscopically. CONCLUSION: The
      disease was concluded to be cerebellar degeneration of a new clinical form in
      cats having an autosomal recessive mode of inheritance. CLINICAL RELEVANCE: When
      cerebellar dysfunction is diagnosed in a cat, hereditary cerebellar degeneration
      of this type should be considered in the differential diagnosis.

PMID- 8669759
TI  - Kinetics of the humoral immune response to multiple treatments with exogenous
      gonadotropins and relation to ovarian responsiveness in domestic cats.
AB  - OBJECTIVE: To investigate ovarian responses and kinetics of gonadotropin-binding
      immunoglobulin production in domestic cats repeatedly treated with equine
      chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) at short or
      long treatment intervals. DESIGN: Queens were treated 3 or 4 times with a
      standard eCG/hCG regimen at short (49 to 57 days) or long (130 to 135 days)
      intervals and subjected to laparoscopy after each treatment to evaluate ovarian
      follicular development. Serial serum samples were assessed by ELISA for the
      presence of eCG-binding immunoglobulins. ANIMALS: 11 clinically normal sexually
      mature female cats. RESULTS: Queens repeatedly stimulated with eCG/hCG at long
      intervals typically had no decrease (P > 0.05) in ovarian follicle production or
      in maturity of recovered oocytes, whereas queens treated at short intervals had
      reduced (P < 0.05) follicular development and compromised oocyte maturity by the
      third stimulation. For both interval groups, ELISA data indicated individual
      variability in seroconversion after eCG/hCG challenge exposure. In general,
      queens treated at short intervals had higher peak anti-eCG immunoglobulin titer
      than did queens treated at long intervals; high titer at the time of eCG/hCG
      injection, or rapid increases in titer immediately after injection were
      predictive (P < 0.05) of poor ovarian responses. CONCLUSIONS: Results suggest
      that individual variability in immune responses and intervals between repeated
      gonadotropin treatments determine whether queens develop immunologically mediated
      ovarian refractoriness to exogenous gonadotropins. Intervals of at least 4 months
      between successive eCG/hCG treatments are recommended for assisted reproductive
      procedures in domestic and nondomestic cats.

PMID- 8669761
TI  - Effect of dose on the immune response and persistence of Salmonella choleraesuis
      infection in swine.
AB  - OBJECTIVE: To establish the effect of dose on persistence of and immune response
      to Salmonella choleraesuis in swine. DESIGN: 19 Salmonella-free pigs were
      allotted to 4 groups. Groups 1 (n = 5), 2 (n = 5), and 3 (n = 5) were inoculated
      intranasally with 10(9), 10(6), and 10(3) colony-forming units of S choleraesuis,
      respectively. Group 4 (n = 4) served as uninoculated controls. PROCEDURE: Pigs
      were monitored for clinical signs of disease and bacterial shedding. Serum and
      lymphocytes were obtained to measure immune responses. Pigs from groups 1, 2, and
      4 were necropsied at postinoculation (PI) weeks 6 and 15. Pigs from groups 3 and
      4 were necropsied at PI weeks 6 and 10. RESULTS: Pigs in group 1 shed S
      choleraesuis through PI week 15 and were tissue positive at PI weeks 6 and 15.
      Pigs in group 2 were tissue positive for S choleraesuis until PI week 6 and
      continued shedding through PI week 9. Salmonella choleraesuis was not recovered
      at any time from pigs in groups 3 or 4. Pigs in groups 1, 2, and 3 had serum IgG
      and IgM titers to S choleraesuis lipopolysaccharide and soluble antigens. Pigs in
      all groups had a lymphocyte response to concanavalin A, and pigs in groups 1 and
      2 had a lymphocyte response to S choleraesuis endotoxin. Pigs in group 1 had a
      lower stimulation index in response to both antigens, indicating some form of
      lymphocyte immunosuppression. CONCLUSIONS: Persistence of S choleraesuis in host
      tissues is dose dependent. Short-term persistence can occur after a dose as low
      as 10(6) colony-forming units of S choleraesuis. Higher doses result in
      development of long-term carrier status, which may be related to the observed
      lymphocyte immunosuppression.

PMID- 8669760
TI  - Role of milk fractions, serum, and divalent cations in protection of mammary
      epithelial cells of cows against damage by Staphylococcus aureus toxins.
AB  - OBJECTIVE: To determine the effect of milk and blood serum constituents on
      cytotoxicity of Staphylococcus aureus on mammary epithelial cells. DESIGN: In
      vitro incubation of cells with cytotoxic agents and milk and serum constituents.
      SAMPLE POPULATION: Mammary cells, milk, and blood obtained from 3 cows.
      PROCEDURE: Staphylococcal alpha-toxin and culture supernatants from S aureus M60
      and an alpha-toxin-negative mutant of M60 were incubated with bovine mammary
      epithelial cells in the presence of milk fractions, serum, and divalent cations.
      Propidium iodide fluorescence was used as a measure of cell damage. RESULTS: Skim
      milk and milk whey inhibited S aureus cytotoxic agents. Skim milk protected
      against alpha-toxin damage to a greater extent than milk whey. Serum from an
      adult animal was more protective than was fetal serum. Milk fat and serum albumin
      had no protective effect. Divalent calcium and Mg2+ were more effective
      inhibitors of mammary epithelial cell damage caused by alpha-toxin than of damage
      attributable to M60 culture supernatant. Divalent calcium and Mg2+ at
      concentrations similar to those of free Ca2+ and Mg2+ in normal bovine milk
      decreased cytotoxic damage attributable to alpha-toxin. However, concentrations
      similar to those of total Ca2+ and Mg2+ in normal milk were required to decrease
      cell damage caused by M60 culture supernatant. The alpha-toxin-negative mutant
      was less cytotoxic than the M60 parent strain. CONCLUSIONS: Casein, as well as
      Ca2+ and Mg2+ in bovine milk, inhibit the cytotoxic effect of S aureus on mammary
      epithelial cells.

PMID- 8669762
TI  - Pathogenesis of plaque variants of porcine reproductive and respiratory syndrome
      virus in pregnant sows.
AB  - OBJECTIVE: To determine whether porcine reproductive and respiratory syndrome
      virus plaque variants vary in their pathogenicity in causing late-term
      reproductive failure. DESIGN: Four groups of 2 sows each at 86 days of gestation
      were inoculated intranasally with PRRSV small (MN-Hs) and large (MN-HI) plaque
      variants, field isolate, and cell culture medium, respectively. In addition, 2
      sows each at 86 days of gestation were inoculated intranasally or IM with MN-Hs
      virus. ANIMALS: 14 pregnant sows. PROCEDURE: Inoculated sows were allowed to
      deliver at term, and each litter was examined for clinical abnormality and
      presence of virus. RESULTS: Two sows infected with MN-Hs virus delivered 14 live
      and 5 dead pigs, whereas 2 sows infected with MN-HI virus delivered 0 live and 25
      dead pigs. Two sows inoculated with a field isolate (MN-W) delivered 10 live and
      20 dead pigs. Two control sows had 26 normal fetuses at slaughter at 107 days of
      gestation. Virus was isolated from 16 (66.7%) of 24 liveborn pigs, 9 (64.3%) of
      14 stillborn pigs, and 3 (12.0%) of 25 mummified fetuses of the 6 infected sows.
      Subsequently, 4 MN-Hs-infected sows delivered 40 live and 11 dead pigs.
      CONCLUSIONS: Marked difference in the pathogenicity in pregnant sows between
      porcine reproductive and respiratory syndrome virus strains was documented. The
      MN-Hs virus is considered to be of low pathogenicity, but the other viruses are
      highly pathogenic for late-term pregnant sows.

PMID- 8669763
TI  - Influence of four diets on uric acid metabolism and endogenous acid production in
      healthy beagles.
AB  - OBJECTIVE: To evaluate the influence of 3 diets used to dissolve or prevent
      ammonium urate uroliths in dogs, and a diet formulated for growth, on 24-hour
      excretions of uric acid, ammonia, net acid, titratable acid, bicarbonate, and
      creatinine; 24-hour urine volumes; pH values of 24-hour urine samples; plasma
      uric acid concentration; serum creatinine concentration; and endogenous
      creatinine clearance values. DESIGN: Randomized block. ANIMALS: Six
      reproductively intact female Beagles, 3.9 to 4.2 years old, weighing 8.5 to 11.1
      kg. PROCEDURES: Four diets were evaluated for their ability to dissolve magnesium
      ammonium phosphate hexahydrate (struvite) uroliths (diet S); to minimize uric
      acid excretion (diet U); to minimize clinical signs associated with renal failure
      (diet K); and to promote growth in pups (diet P). Each diet was fed for 14 days;
      then 24-hour urine samples were collected. An adult maintenance diet was fed
      during a 7-day washout period. RESULTS: Consumption of diet U was associated with
      lowest plasma uric acid concentration, lowest 24-hour urinary uric acid, ammonia,
      titratable acid, and net acid excretions, lowest endogenous creatinine clearance
      values, highest 24-hour urinary bicarbonate excretion and urine pH values, and
      highest 24-hour urine volumes. Consumption of diet P was associated with opposite
      results; results of consumption of diets S and K were intermediate between those
      for diets U and P. CONCLUSION: Consumption of diet U by healthy Beagles is
      associated with reduced magnitude of urinary excretion of uric acid and ammonia,
      with alkaluria, and with polyuria, which may be beneficial in the management of
      ammonium urate uroliths in dogs. CLINICAL RELEVANCE: Results support use of diet
      U for management of ammonium urate urolithiasis in dogs.

PMID- 8669764
TI  - Serologic responses of cattle and other animals infected with Neospora caninum.
AB  - OBJECTIVE: To examine cross-reactivity among Neospora caninum and closely-related
      apicomplexans. DESIGN: Sera from animals were examined for antibody production to
      N caninum and cross-reactivity to Toxoplasma gondii. ANIMALS: Cattle were
      experimentally infected with 3 tissue cyst-forming protozoan parasites N caninum,
      T gondii, and Sarcocystis sp, and calves were monospecifically inoculated with
      the intestinal coccidia, Eimeria bovis and Cryptosporidium parvum. Similar
      studies were done in laboratory rabbits inoculated with N caninum, T gondii,
      Hammondia hammondi, and Sarcocystis sp. Additionally, sera were obtained from
      ewes, lambs, goats, sows, cats, rats, and mice inoculated with N caninum
      tachyzoites. PROCEDURE: The indirect fluorescent antibody (IFA) and ELISA
      antibody tests (cattle only) were used to examine reactivity to N caninum; the
      modified direct agglutination, Sabin-Feldman dye, and IFA tests were used to
      evaluate reactivity to T gondii. RESULTS: Serologic cross-reactivity among N
      caninum, T gondii, and Sarcocystis sp was none or minimal by the IFA test. There
      was some reactivity to N caninum by the use of ELISA in cattle inoculated with
      Sarcocystis sp. CONCLUSIONS: The IFA test for N caninum was specific for the
      diagnosis of neosporosis in animals.

PMID- 8669765
TI  - Characterization of chronotropic and dysrhythmogenic effects of atropine in dogs
      with bradycardia.
AB  - OBJECTIVE: To characterize the magnitude, character, and time course of
      chronotropic and dysrhythmogenic responses of dogs with vagally mediated
      bradycardia to atropine sulfate. DESIGN: Latin square design. ANIMALS: Seven
      clinically normal adult mixed-breed dogs. PROCEDURE: Vagally mediated bradycardia
      was induced with morphine and fentanyl citrate. Atropine (0.02 mg/kg of body
      weight) was administered i.v., s.c., or i.m.. Electrocardiograms were recorded
      continuously for 5 minutes before and for 35 minutes after atropine
      administration or until a sustained parasympatholytic response was observed. Data
      were digitized, analyzed independently for changes in atrial and ventricular
      rate, and compared between different routes of administration. RESULTS: All dogs
      developed second-degree atrioventricular (AV) block after i.v. administration of
      atropine, and 71% of dogs developed AV block after s.c. or i.m. administration.
      The AV block arose and resolved more rapidly with i.v. administration than with
      s.c. or i.m. administration. The AV block was principally attributable to an
      increase in the atrial rate prior to increases in the ventricular rate. Atropine,
      regardless of route of administration, potentiated baseline ventricular
      bradycardia in 62% of the experiments (mean heart rate decrease of 16 beats/min;
      decreased to < 20 beats/min in 2 dogs for < or = 10 seconds). Duration of the
      bradycardic potentiation was longer with s.c. administration (9.1 minutes, s.c.,
      vs 1.4 minutes, i.v., and 4.6 minutes, i.m.). Parasympatholytic rate was higher
      for i.v. than s.c. or i.m. administration (128 beats/min vs 92 beats/min and 101
      beats/min). Two dogs given atropine s.c. failed to resolve the AV block and
      attain sinus rhythm. CONCLUSIONS: Administration of 0.02 mg of atropine/kg by
      i.v., i.m., and s.c. routes for vagally mediated bradycardia in dogs consistently
      induces AV block and occasional brief potentiation of ventricular bradycardia.
      CLINICAL RELEVANCE: Parasympathomimetic effects occur and resolve most rapidly
      and consistently, and the stable parasympatholytic effect is of greatest
      magnitude after i.v. administration. Thus, vagally mediated bradycardia in
      clinically normal dogs appears to be best abolished by i.v. administration of
      atropine.

PMID- 8669766
TI  - Involvement of (n-6) essential fatty acids and prostaglandins in liver lipid
      accumulation in Japanese quail.
AB  - OBJECTIVE: To investigate the involvement of (n-6) essential fatty acids, such as
      linoleic acid [18:2(n-6)] or gamma-linolenic acid [18:3(n-6)], and of
      prostaglandins on liver lipid accumulation in Japanese quail. DESIGN: Effects of
      graded amounts of aspirin, which inhibits prostaglandin synthesis, on liver
      weight were determined in experiment 1. Experiment 2 was designed to clarify the
      effect of dietary essential fatty acid sources and inhibition of prostaglandin
      synthesis on the liver fat and fatty acid profile. ANIMALS: Female Japanese
      quail. PROCEDURE: In experiment 1, from 1 to 3 weeks of age, birds were fed ad
      libitum the essential fatty acids-free or linoleic acid-adequate (2%) diets with
      graded amounts of aspirin (0, 0.1, 0.2, and 0.4%). In experiment 2, from 1 to 4
      weeks of age, birds were fed the same amount of essential fatty acids-free,
      linoleic acid-adequate, or gamma-linolenic acid (0.4%) diets with (0.2%) or
      without aspirin. RESULTS: In experiment 1, in groups given the essential fatty
      acids-free diet, liver weight increased with an increase in dietary aspirin
      concentration. In experiment 2, gamma-linolenic acid completely prevented liver
      triacylglycerol and cholesterol accumulation induced by the essential fatty acids
      free diet. Aspirin treatment significantly lowered plasma prostaglandin F2 alpha
      concentration, but did not affect liver lipid concentrations. In groups fed the
      essential fatty acids-free diets, however, aspirin treatment increased liver
      weight and liver triacylglycerol concentration by 20 and 40%, respectively.
      CONCLUSIONS: gamma-Linolenic acid or its metabolites, but not linoleic acid
      itself, are important factors in reducing fatty liver in Japanese quail with the
      essential fatty acids-deficient condition.

PMID- 8669767
TI  - Effects of hematocrit and erythrocyte deformability on pulmonary vascular
      pressures in perfused pony lungs.
AB  - OBJECTIVE: To evaluate the contribution of hematocrit and RBC deformability to
      pulmonary vascular pressures of racehorses. DESIGN: Pony lungs were isolated and
      right and left lungs were perfused separately with blood. The effects of changing
      hematocrit and of pentoxifylline treatment were evaluated. ANIMALS: 11 healthy
      mixed-breed ponies. PROCEDURE: Ponies were anesthesized, blood was collected, and
      lungs were removed and perfused with blood at constant flow rate. RESULTS:
      Increasing the hematocrit from 35% to 65% resulted in increases in pulmonary
      arterial pressure (53%, 45%), capillary shear stress (45%, 32%), and total
      vascular resistance (92%, 143%) at low (352 +/- 33 ml/min) and high (1,442 +/- 48
      ml/min) flow rates, respectively. Pulmonary artery pressures were lower (10%,
      11%) when lungs were perfused with blood from pentoxifylline-treated ponies,
      compared with blood from control ponies with low hematocrit (PCV, 30%) and low
      flow rate and with high hematocrit (PCV, 45%) and high flow rate, respectively.
      Decreases in capillary shear stress and total vascular resistance were also
      observed for pentoxifylline-treated blood. CONCLUSIONS: Increases in hematocrit
      equivalent to those occurring during competitive racing activity contribute
      substantially to pulmonary vascular pressures in horse lungs. Administration of
      pentoxifylline to ponies reduced RBC deformability and attenuated increases in
      pulmonary vascular pressures. CLINICAL RELEVANCE: Treatment of racehorses with
      pentoxifylline may reduce exercise-associated increases in pulmonary vacular
      pressure, thereby attenuating exercise-induced pulmonary hemorrhage.

PMID- 8669769
TI  - Scotopic threshold response of the electroretinogram of dogs.
AB  - OBJECTIVE: To study characteristics of the scotopic threshold response (STR) in
      dogs. DESIGN: We recorded the electroretinogram (ERG) in anesthetized Beagles
      under several recording conditions to examine characteristics of the STR.
      ANIMALS: Seven clinically normal Beagles. PROCEDURE: Beagles were paralyzed by
      continuous i.v. administration of muscle relaxant and were artificially
      ventilated with a gas mixture of nitrous oxide and oxygen during experiments.
      Corneal ERG were recorded, using full-field white stimuli, under several
      recording conditions. RESULTS: The canine STR was a simple corneal negative
      response elicited by dim stimuli below the b-wave threshold. Maximal amplitude of
      the canine STR was approximately 50 to 120 microV, much larger than those of
      other animal species, such as human beings, monkeys, and cats. Peak latency of
      the maximal STR was approximately 75 to 96 milliseconds. The spectral sensitivity
      of the canine STR corresponded to that of the canine rod visual pigment. The
      canine STR was completely eliminated by dim background light, which had no
      suppressive effect on the a- and b-waves. By using such dim background light, we
      could record the photoreceptor-derived a-wave in the ERG intensity series.
      CONCLUSIONS: In Beagles, the STR strongly influences the ERG waveforms recorded
      under the dark-adapted condition. Special attention may be necessary in using the
      dark-adapted ERG to assess the retinal photoreceptor function. Canine STR is
      expected to be a good indicator of assessment of the proximal retinal function in
      dogs, and Beagles might be a good experimental animal for the study of the STR.

PMID- 8669768
TI  - Effects of inhalation anesthetic agents on response of horses to three hours of
      hypoxemia.
AB  - OBJECTIVE: To study the effects of inhalation anesthetic agents on the response
      of horses to 3 hours of hypoxemia. DESIGN: Controlled crossover study. ANIMALS:
      Five healthy adult horses. PROCEDURE: Horses were anesthetized twice: once with
      halothane, and once with isoflurane in O2. Anesthetized horses were positioned in
      left lateral recumbency. Constant conditions for the study began at 2 hours of
      anesthesia. A constant agent dose of 1.2 minimum alveolar concentration, PaO2 of
      50 +/- 5 mm of Hg, and PaCO2 of 45 +/- 5 mm of Hg were maintained for 3 hours.
      Circulatory measurements were made at 0.5, 1, 2, and 3 hours of hypoxemia
      (anesthesia hours 2.5, 3, 4, and 5). Blood was collected from horses for
      biochemical analyses before anesthesia, within a few minutes after standing, and
      at 1, 2, 4, and 7 days after anesthesia. RESULTS: Cardiac index was greater (P =
      0.018) during isoflurane than halothane anesthesia. Cardiac index remained
      constant during the 3 hours of hypoxemia during halothane anesthesia, whereas it
      decreased from the baseline during isoflurane anesthesia. Marginally
      nonsignificant P values for an agent difference were detected for arterial O2
      content (P = 0.051), and oxygen delivery (P = 0.057). Serum activities of
      aspartate transaminase (P = 0.050) and sorbitol dehydrogenase (P = 0.017) were
      higher in halothane-anesthetized horses than in isoflurane-anesthetized horses.
      Circulatory function was better in hypoxemic horses anesthetized with isoflurane
      than with halothane. Isoflurane resulted in less muscular injury in hypoxemia
      horses than did halothane anesthesia. Halothane anesthesia and hypoxemia were
      associated with hepatic insult. CONCLUSION: Isoflurane is better than halothane
      for hypoxemic horses.

PMID- 8669770
TI  - Cardiopulmonary effects of desflurane in cats.
AB  - OBJECTIVE: To evaluate the cardiopulmonary effects of 2 anesthetic planes of
      desflurane (DES) during spontaneous ventilation (SV) and controlled ventilation
      (CV) in cats. DESIGN: Repeated Latin square. ANIMALS: Eight healthy adult cats.
      PROCEDURE: Each cat received 1.3 times the minimum alveolar concentration (MAC)
      of DES and 1.7 MAC of DES in oxygen during CV and SV. The data were analyzed as a
      repeated measures design. Heart rate, cardiac output, arterial blood pressure,
      pulmonary artery pressure, respiratory rate, PaO2, PaCO2, pHa, PCV, and serum
      total protein concentration were measured during each treatment. Stroke volume,
      cardiac index, total peripheral resistance, and oxygen consumption were
      calculated. RESULTS: Cardiac index and stroke volume were not different between
      1.3 and 1.7 MAC of DES, but CV decreased cardiac index and stroke volume (P <
      0.05). Systolic arterial pressure was decreased during 1.7 MAC of DES and during
      CV. Mean arterial blood pressure was decreased at 1.7 MAC during CV, but not SV.
      The PaCO2 was higher at 1.7 MAC than at 1.3 MAC during SV. Spontaneously
      ventilating cats at 1.7 MAC had higher pulmonary artery pressures than other
      treatments. The PCV was decreased during CV. CONCLUSION: 1.7 MAC of DES causes
      decreased systolic and mean arterial pressures and marked hypercapnia, but
      cardiac index is not affected. The hypercapnia is probably responsible for the
      increased pulmonary artery pressures in the spontaneously ventilating cats during
      1.7 MAC. Hypercapnia can be corrected by CV but this reduces cardiac output.

PMID- 8669771
TI  - Effect of prepuberal and postpuberal gonadectomy on heat production measured by
      indirect calorimetry in male and female domestic cats.
AB  - OBJECTIVE: To use indirect calorimetry to compare heat production between
      gonadectomized and sexually intact male and female cats. DESIGN: Male (n = 6) and
      female (n = 6) kittens were gonadectomized at 7 weeks or 7 months of age, or left
      sexually intact. Body heat production was measured by indirect calorimetry in all
      cats at 12, 18, and 24 months of age. ANIMALS: 18 male and 18 female clinically
      normal domestic shorthair cats. PROCEDURE: Heat production was measured, using an
      open-circuit, respiratory, indirect calorimeter. All cats underwent calorimetry
      at 12, 18, and 24 months of age. The heat coefficient, a measure of resting
      metabolic rate, was calculated for each cat at each test; heat coefficient is
      defined as logarithm of heat (kcal/h) divided by logarithm of body weight (kg).
      RESULTS: Heat production did not vary with age in male or female cats. Heat
      coefficient was higher in sexually intact male and female cats than in
      gonadectomized male and female cats at 12, 18, and 24 months of age (12 months,
      females, P < 0.01, males, P = 0.04; 18 months, females, P < 0.01, males, P =
      0.02; and 24 months, females and males, P < 0.01). CONCLUSIONS: These data
      suggest that resting metabolic rate in cats decreases after gonadectomy. CLINICAL
      RELEVANCE: A decrease in metabolic rate is synonymous with a decrease in caloric
      requirements. Gonadectomized animals fed in a manner similar to sexually intact
      animals may be predisposed to obesity and its sequelae.

PMID- 8669772
TI  - Effects of intramuscular or interpleural administration of morphine and
      interpleural administration of bupivacaine on pulmonary function in dogs that
      have undergone median sternotomy.
AB  - OBJECTIVE: To evaluate effects of interpleural or IM administration of morphine
      and interpleural administration of bupivacaine on pulmonary function in dogs that
      have undergone median sternotomy. DESIGN: Experimental trial. ANIMALS: 18 healthy
      dogs. PROCEDURE: Dogs underwent median sternotomy and were randomly assigned to
      groups of 6 dogs each. Group-A dogs were given morphine (1.0 mg/kg of body
      weight) i.m.; group-B dogs were given 0.5% bupivacaine (1.5 mg/kg)
      interpleurally; and group-C dogs were given morphine (1.0 mg/kg) interpleurally.
      Heart rate; systolic, diastolic, and mean arterial pressures; rectal temperature;
      pain score; and arterial blood gas partial pressures were measured and pulmonary
      function testing was performed immediately after extubation (time 0) and up to 48
      hours later. Serum cortisol and morphine concentrations were measured at time 0
      and up to 12 hours after surgery. RESULTS: There was a significant decrease in
      pH, PaO2, mean oxygen saturation of hemoglobin, and dynamic compliance; and a
      significant increase in PaCO2, alveolar-arterial difference in partial pressure
      of oxygen, pulmonary resistance, and work of breathing for dogs in all groups
      after surgery. Serum cortisol concentrations were significantly increased,
      compared with preoperative values, in all dogs. Serum cortisol concentrations
      were significantly higher in group-B dogs between 3 and 5 hours after surgery,
      compared with group-A dogs. CONCLUSIONS: Median sternotomy was associated with
      significant alterations in pulmonary function. Effects of interpleural
      administration of bupivacaine and morphine were similar to effects of i.m.
      administration of morphine.

PMID- 8669773
TI  - Noninvasive kinematic analysis of the walk in healthy large-breed dogs.
AB  - OBJECTIVES: To use computer-assisted kinematic analysis to describe the walk in
      healthy dogs and to adapt Fourier transformation for analysis of the data.
      DESIGN: Evaluation of normal walk in dogs, using kinematic and force plate
      analysis. SAMPLE POPULATION: 15 healthy large-breed dogs. PROCEDURE: Morphometric
      data were collected to describe the sample population. Temporal and distance
      variables were measured to describe the walk. Flexion and extension movements
      were described for the scapulohumeral, cubital, carpal, coxofemoral,
      femorotibial, and tarsal joints. Fourier transformation was adapted to facilitate
      analysis of the joint angle waveforms. RESULTS: Unique and complex patterns of
      flexion and extension movements were observed for each joint studied. The walk
      had consistency of movement in the sample population in temporal and distance
      variables and joint movements. Variances attributable to intra- and interdog
      differences were similar and 1 to 2 orders of magnitude smaller than the mean
      Fourier coefficients from which they were calculated for all 6 joints. The number
      of essential Fourier coefficients required to represent the joint angle waveforms
      was 3 for the coxofemoral joint, 5 each for the femorotibial, scapulohumeral,
      cubital, and carpal joints, and 6 for the tarsal joint. CONCLUSIONS: Computer
      assisted kinematic gait analysis proved to be a reliable and consistent technique
      for assessment of movement at the walk in dogs, and Fourier transformation was
      shown to be an effective tool for analysis of the kinematic data. CLINICAL
      RELEVANCE: The database derived from the normal sample population in this study
      can be used as a model of musculoskeletal function at the walk for future
      comparisons with disease and treatment.

PMID- 8669774
TI  - Use of force-plate analysis of gait to compare two surgical techniques for
      treatment of cranial cruciate ligament rupture in dogs.
AB  - OBJECTIVE: To use ground reaction forces and related impulses as an objective
      measurement of limb function in the comparison of 1 extracapsular and 1
      intracapsular surgical technique for repair of cranial cruciate ligament rupture
      in dogs. ANIMALS: 18 healthy dogs. DESIGN: All dogs underwent force-plate
      analysis of gait prior to transection of the left cranial cruciate ligament. The
      dogs were randomly allotted to 3 groups. The ligamentous instability was
      corrected, using a modified retinacular imbrication technique (MRIT) in 1 group
      and an under-and-over technique in another group. No attempt was made to correct
      the ligamentous instability in a control group. Clinical grading of lameness and
      force-plate analysis of gait were performed at 4, 8, 12, 16, and 20 weeks after
      surgery. PROCEDURE: Peak vertical force and vertical, braking, and propulsion
      impulses were recorded for each limb at each time. The degree of clinical
      lameness was graded at each time. RESULTS: Left hind limb peak vertical forces
      and vertical impulses were significantly decreased at all times after surgery in
      the control and under-and-over technique group, compared with values before
      surgery. Dogs of the MRIT group had improved by 20 weeks, with no significant
      differences between left hind limb peak vertical forces or vertical impulses
      recorded before surgery and at 20 weeks. CONCLUSION: Peak vertical forces and
      vertical impulses in dogs undergoing MRIT repair after experimentally created
      cranial cruciate ligament rupture are not significantly different when values
      recorded for the operated limb at 20 weeks after surgery are compared with those
      recorded prior to surgery.

PMID- 8669775
TI  - Effect of locally injected medications on healing of pad wounds in dogs.
AB  - OBJECTIVE: To ascertain the effects of locally injected immunostimulant and
      tripeptide-copper complex (TCC) on improving healing of pad wounds. DESIGN:
      Wounds in pads of large dogs were injected with either medication or physiologic
      saline solution (controls). Healing was evaluated. ANIMALS: 12 mature English
      Pointers. PROCEDURE: Full-thickness 6 x 8-mm wounds in metatarsal and third and
      fourth digital pads were injected with immunostimulant or TCC at 0, 3, and 6 days
      after wounding. Wounds on control dogs were injected with physiologic saline
      solution. Using planimetric measurements at 0, 3, 6, 14, and 21 days, rates of
      healing were evaluated. Biopsy of the digital pad wounds at 3, 6, and 14 days was
      used to evaluate collagen content by hydroxyproline analysis. Biopsy specimens
      were also evaluated for type-I and type-III collagen, using Sirius red
      differential staining. RESULTS: Effect on healing rate and hydroxyproline content
      was best during the first week for immunostimulant. Immunostimulant- and TCC
      injected wounds had more type-I collagen than did controls at 6 days; TCC
      injected wounds had the most type-I collagen. At 14 days, the amount of type-I
      collagen in TCC-injected wounds was significantly greater than that in other
      wounds. CONCLUSIONS: Tested medications had positive effects on healing of pad
      wounds. CLINICAL RELEVANCE: Intralesional injection of medications helps ensure
      their presence for enhancement of wound healing. The benefit could be lost with
      topical use in a bandage if the bandage is lost or becomes wet.

PMID- 8669776
TI  - Women and mental health: an introduction.

PMID- 8669777
TI  - Women's mental health: the new national focus.

PMID- 8669778
TI  - Women, work, and family: mental health issues.

PMID- 8669779
TI  - Spousal abuse and violence against women: the significance of understanding
      attachment.

PMID- 8669780
TI  - Aging women: issues of mental health and maltreatment.

PMID- 8669781
TI  - Hispanic women and mental health.

PMID- 8669782
TI  - Mental health issues in African-American women.

PMID- 8669784
TI  - Asian-American women: cultural and mental health issues.

PMID- 8669783
TI  - Teenage parents and their offspring.

PMID- 8669785
TI  - African-American women: considering diverse identities and societal barriers in
      psychotherapy.
AB  - Effective psychotherapy with African-American women explicitly requires cultural
      literacy and competence of its practitioners. Cultural literacy includes
      understanding the collective social plight of African-American women and the
      individual client in the context of the prevailing reality of race, gender, and
      sexual orientation bias and the interpersonal and institutional barriers that
      result from that bias. Cultural literacy presumes a willingness on the part of
      the therapist to educate himself or herself about the clients cultural background
      and milieu and validate the client's accurate perceptions of discrimination and
      bias and their impact on the client's life. Cultural competence may be seen as
      the appropriate level of technical skill in applying those concepts to the
      understanding of the client and the conduct of the psychotherapeutic inquiry. The
      culturally literate practitioner will acknowledge and appreciate the wide range
      of diversity within African-American women as a group. The individual client's
      intrapsychic and familial endowments and personal relationship history as they
      are embedded in the aforementioned context should be carefully explored and
      understood as well as are all relevant social factors. Finally, therapists must
      be willing to scrutinize their own feelings and motivations for working with
      African-American women. What should follow is a careful analysis of the
      developmental interactions of these variables, how they promote an individual's
      view of the world, her perceptions of her options, her strategies for negotiating
      institutional barriers, her relationships with other persons, as well as any
      contributions she makes, consciously or unconsciously, to her own dilemma. A
      culturally literate and antiracist therapist must begin with an understanding of
      the role of multiple identities and oppressions in client's lives and must have
      or be willing to acquire a familiarity with the clients' cultural and ethnic
      heritage and the role of institutional barriers in a client's life. This includes
      clients' varying experiences of their ethnic and cultural history. The therapist
      must also be willing to acknowledge each client's personal barriers and resources
      by exploring significant figures, relationships, and their patterns, and events
      in their personal lives. Having done all of this, the therapist must avoid the
      temptation to reduce a client's dilemma to a series of dichotomized "either-ors."
      Rarely is institutional oppression the sole source of all of a client's
      difficulties. The struggle of negotiating discriminatory barriers may at times be
      less painful to explore than troubled or conflicted personal histories with loved
      and trusted figures. It is essential to strike an appropriate balance between
      prematurely dismissing a client's realistic complaints about discrimination and
      focusing on such complaints exclusively. Similarly, exploring or exposing
      personal difficulties in a client's life should not be used to minimize problems
      that are a function of the client's oppressed status. While there are realistic
      racist and sexist barriers in the world that African-American women share as a
      group, each individual has her own unique experience and understanding of that
      reality, and that is what the therapist seeks ultimately to understand. The
      therapist must avoid romanticizing the strengths forged from African-American
      women's struggles with institutional barriers by neglecting to appreciate the
      often debilitating effects of those struggles. Furthermore, the temptation to use
      these struggles as an explanation for all of a client's problems must be avoided
      as well. Exposing or exploring the parameters of characterological difficulty or
      psychopathology in a client does not mean that she is to "blame" for everything
      that happens to her or that racism and sexism are just excuses for internal
      deficiencies.

PMID- 8669786
TI  - Depression in the young.

PMID- 8669787
TI  - Sexual abuse of children: prevalence, effects, and treatment.

PMID- 8669788
TI  - Eating disorder research in the past decade.

PMID- 8669789
TI  - Images of madness: a portfolio of nineteenth-century women.

PMID- 8669790
TI  - Differential treatment: considerations for the female alcoholic.

PMID- 8669791
TI  - [Mediastinal malignant schwannoma disclosed by pericardial tamponade in von
      Recklinghausen disease].
AB  - The authors report a case of a 47-years-old patient with Von Recklinghausen's
      disease. He was admitted with pericardial tamponade. 2D echocardiography showed,
      in addition to the compressive pericardial effusion, an enormous intrapericardial
      tumor compressing the left cardiac cavities. The patient died soon after
      pericardial drainage. The post-mortem examination revealed the diagnosis of
      malignant schwannoma of the left costo-vertebral gutter with an anterior
      intrapericardial development. A review of the literature showed that malignant
      schwannomas are seldom localized in the mediastinum, are associated with Von
      Recklinghausen's disease in 2 to 13% of cases, and have a poor prognosis.
      Pericardial tamponade is an exceptional presenting sign of mediastinal malignant
      schwannoma.

PMID- 8669792
TI  - [Systemic cholesterol embolism].
AB  - The authors report two cases of cholesterol embolism and review the literature on
      this subject. Cholesterol crystal emboli are very serious complication of
      atheroma, generally situated in the aorta and usually in patients in their
      sixties. The frequency of cholesterol embolism is 20% in autopsy studies in this
      population. The embolic process accounts for the polymorphic clinical feature.
      Clinical signs are always delayed in relation to triggering factors. The symptoms
      can sometimes simulate a systemic disease. Cutaneous signs are present in 40 to
      75% of cases. Acute renal failure is present in 30% of cases. Other signs may
      also be observed: alteration of the general state, fever, neurological disorders,
      pain of the lower limbs, myalgia, gastrointestinal haemorrhage or perforation,
      ischaemic colitis, pancreatitis, mesenteric or coronary angina. A triggering
      factor is revealed in 80% of cases: aortic surgery, retrograde aortic
      catheterization, fibrinolysis or oral anticoagulant treatment. The prognosis is
      poor due to the clinical context, the patient's age and the absence of any
      specific treatment. The short-term mortality is 60 to 80% according to various
      series. The best treatment is prevention: carefully assess the indication for an
      endovascular procedure in an atheromatous patient; if necessary, perform
      transoesophageal ultrasonography to evaluate the risk; whenever possible change
      the incision in vascular investigations or operative procedures in high-risk
      patients.

PMID- 8669793
TI  - [What are the indications for myocardial scintigraphy?].
AB  - Myocardial scintigraphy is a noninvasive technique of functional blood flow
      imaging whose indications are often poorly defined. The various practical
      modalities of the examination, as well as the tracers currently available in
      France are reviewed. The diagnostic value in the detection of coronary disease is
      then described, with emphasis on the complementarity of scintigraphy and the
      other techniques, particularly the stress test, and by trying to position
      scintigraphy in the context of the optimal diagnostic strategy. Finally, the
      prognostic value of scintigraphy, its value in post-infarction assessment and in
      the functional evaluation of known coronary stenoses are discussed.

PMID- 8669794
TI  - [15 years of coronary angioplasty: focus on the different techniques].
AB  - The growth of transcutaneous coronary angioplasty in the 1980s and early 1990s
      was particularly rapid, as about 42,000 procedures were performed in France in
      1994. This treatment for coronary atherosclerosis now constitutes a valid
      alternative to surgical or medical treatment. New treatment modalities for
      coronary atherosclerosis have been added to the original balloon technique. Two
      types of coronary angioplasty can now be performed depending either by flattening
      and crushing the atheroma against the arterial wall (balloon, stent) or by
      destroying and fragmenting it (Rotablator, Laser, directional atherectomy). Among
      these new instruments, vascular stents have reduced the incidence of restenosis
      and have improved the safety of interventional cardiology, while others, such as
      Rotablator and Laser, allow the treatment of lesions inaccessible to the balloon.
      Directional atherectomy, by allowing specific excision, will occupy an important
      place in future developments of interventional cardiology, which is still a
      relatively young specialty.

PMID- 8669795
TI  - [A new cause of hereditary venous thrombosis: activated protein C resistance].

PMID- 8669796
TI  - [Chemotherapy and cardiotoxicity].
AB  - Among the various anticancer drugs, used alone or in combination during courses
      of chemotherapy, anthracyclines (leader: doxorubicin) are responsible for direct
      myocardial toxicity, which can exceptionally be acute, but more often chronic
      with a delayed onset. This cardiotoxicity is directly proportional to the
      cumulative dose administered and the recommended total dose for doxorubicin is
      550 mg/m2. The risk factors able to potentiate cardiotoxicity must be analysed
      before starting chemotherapy and follow-up by ultrasonography and/or isotope
      ejection fraction must be repeated before each course. The treatment of
      anthracycline-induced heart failure consists of digitalis alkaloids combined with
      angiotensin converting enzyme inhibitors. The cardiac toxicity of 5FU is
      currently explained by the theory of coronary spasm, based on clinical findings
      such as chest pain associated with ischaemic electrical modifications. The
      incidence of this toxicity is low, but it can be fatal. Exceptional examples
      include the cardiotoxicity induced by high-dose cyclophosphamide responsible for
      acute haemorrhagic myocarditis, potentiation of the cardiotoxic effect of
      anthracyclines by dacarbazine and plicamycin, and serious ventricular and
      supraventricular arrhythmias induced by amsacrine. Among the various cytokines
      used in oncology, interferon is responsible for heart failure, reversible after
      stopping treatment, but also for ventricular arrhythmias, or even sudden death,
      the pathophysiology of which still remains unclear.

PMID- 8669797
TI  - [Outpatient treatment of deep venous thromboses].
AB  - Deep vein thromboses (DVT), which are serious because of their associated risk of
      pulmonary embolism and troublesome due to the possible development of a post
      phlebitic syndrome, require rigorous management. However, the diagnosis is
      facilitated by Doppler ultrasound and treatment by low molecular weight heparins
      (LMWH) is simple to administer and follow. It is therefore logical to propose out
      patient treatment, provided certain rigorous rules are respected: establishment
      of an objective diagnosis of DVT, as the clinical signs are relatively
      nonspecific, admission to hospital of patients with a haemorrhagic risk or
      presenting a contraindication to anticoagulants, extensive DVT (extending beyond
      the mid-femoral zone), floating thrombus, patients with moderate signs may
      suggest pulmonary embolism. The recommended dosage for LMWH is 100 IU/kg twice a
      day (s.c.) (or 175 IU/kg once a day for the LMWH most recently available in
      France) which must be followed by oral anticoagulants for 5 months (aspirin is
      not sufficiently effective). Contention and rigorous clinical follow-up are
      obviously essential. The management of DVT is fascinating and requires
      coordination of several competent specialists.

PMID- 8669798
TI  - [Transient ischemic attack: threatened cerebral infarction syndrome].
AB  - A transient ischaemic attack is "an episode of focal neurological dysfunction of
      ischaemic origin, with a sudden onset, which resolves entirely in less than 24
      hours". This 24-hour limit is actually only theoretical: a "real" transient
      ischaemic attack recovers in less than half an hour. More prolonged transient
      ischaemic attacks share the same mechanisms and the same prognosis as rapidly
      regressive constituted ischaemic accidents. The transient ischaemic attack
      constitutes a precious warning sign, indicating the need for systematic
      assessment looking for the cause of this accident and appropriate preventive
      measures depending on the results of this assessment: treatment of vascular risk
      factors, platelet antiaggregants, oral anticoagulants, carotid endarterectomy.
      These measures can reduce the risk of development of cerebral infarction,
      estimated to be 25% during the 5 years following the transient ischaemic attack
      in non-treated patients.

PMID- 8669799
TI  - [Physical exercise and the heart: benefits, indications, intensity, modalities].

PMID- 8669800
TI  - [Ambulatory treatment of chronic cardiac insufficiency].
AB  - Considerable progress has been made in the medical treatment of chronic heart
      failure. A large number of patients with NYHA class II and III heart disease can
      be improved to class I and II. Treatment is maintained on an outpatient basis in
      order to prevent episodes of acute failure, while avoiding the adverse effects of
      drugs at high doses or in combination. Diuretics are still the drug class most
      frequently prescribed, especially loop diuretics (furosemide) which have the
      advantage of being able to be used in patients with renal failure. Aldosterone
      antagonists have the pathophysiological value of reducing the development of
      myocardial fibrosis. Digitalis alkaloids have a positive inotropic effect, which
      is even observed in the presence of sinus rhythm and which is associated with
      slowing of the heart rate in tachyarrhythmias. Angiotensin converting enzyme
      inhibitors are among the most recently used drugs. They decrease the left
      ventricular post-load and prevent activation of the renin-angiotensin-aldosterone
      system. Phosphodiesterase inhibitors cannot be administered orally in the long
      term and are therefore not suitable for outpatient treatment. However, they are
      very effective by intravenous injection during the acute phase of heart failure
      and cardiogenic shock in hospital.

PMID- 8669801
TI  - [What dose of aspirin should be prescribed in patients with coronary disease?].
AB  - Aspirin is prescribed in almost all coronary patients. However, the prescription
      modalities tend to vary, partly because of the absence of phase II development of
      this molecule as an antithrombotic agent in coronary patients. The dose of 162.5
      mg has been shown to be effective during the acute phase of myocardial
      infarction, but we do not know whether this is the most effective dose. A higher
      dose, in particular 500 mg to 1 g, would have the advantage of more rapidly and
      more completely blocking platelets during an acute thrombotic phase. After this
      first high dose, lower doses, less than 100 mg, could be administered in the long
      term. These low doses of aspirin, generally 75 mg, have been demonstrated, in
      stable angina, to decrease infarction and sudden death by more than 30%. This
      dose has also been demonstrated to be effective in the long-term in unstable
      angina, but once again this low dose should be introduced after an initial higher
      dose for this acute coronary syndrome. A primary prevention study is currently
      underway using the dose of 75 mg per day following the trial in American
      physicians using a dose of 320 mg every second day. Long-term low doses have a
      clearly demonstrated efficacy in chronic prevention and have the advantage of
      inducing much fewer adverse effects, particularly gastrointestinal haemorrhage.
      In conclusion, a high initial dose should be recommended in acute coronary
      syndromes and a low dose, less than 100 mg, should be recommended for chronic
      prevention. Buffered forms, protecting the stomach, and sustained-release forms
      are impatiently awaited to further improve the benefit/risk ratio of aspirin,
      which is nevertheless already excellent.

PMID- 8669802
TI  - [New therapeutic data in inflammatory colitis].

PMID- 8669804
TI  - [Intraductal pancreatic adenomatosis. Apropos of a new case].
AB  - A 49-year-old diabetic patient with abdominal pain was found upon ultrasonography
      and computed tomography to have a cystic mass in the head of the pancreas with
      dilation of the main pancreatic duct. The head of the pancreas and duodenum were
      removed surgically. Examination of the operative specimen showed chronic
      pancreatitis, dilation of the main pancreatic duct, and impacted mucus in the
      secondary ducts with villous proliferation of the ductal epithelium, establishing
      the diagnosis of intraductal adenomatosis. There was no evidence of malignancy.
      The resection margin was involved, and consequently the remainder of the pancreas
      was removed six months after the initial surgical procedure. A review of the
      literature showed that intraductal adenomatosis tends to spread and carries a
      high risk of malignant transformation. Surgery is required because of the risk of
      pancreatic duct obstruction and pancreatic cancer. Intraductal adenomatosis of
      the pancreas shares many characteristics with other adenomatous proliferations of
      the gastrointestinal tract (colorectal villous adenoma, bile duct adenomatosis),
      including presence of villous structures with increased mucus production, a
      tendency to spread massively, and a high risk of malignant transformation.

PMID- 8669803
TI  - [The value of rectosigmoidoscopy and the bacteriologic culture of colon biopsies
      in the etiologic diagnosis of acute diarrhea of adults. A prospective study of 65
      patients].
AB  - The goal of this study was to evaluate the contribution of sigmoidoscopy with
      bioptic microbiology to the etiologic diagnosis of acute diarrhea in adults.
      Patients and methods. Sixty-five patients with acute diarrhea were included
      prospectively from February 1993 to November 1994. Ages ranged from 17 to 83
      years. In each patient, two stool samples were cultured and three examined for
      parasites. Clostridium difficile toxin was looked for in the 18 patients who had
      taken antimicrobials before onset of the diarrhea. Sigmoidoscopy with collection
      of biopsy specimens for bacteriologic cultures was performed routinely. Results.
      A pathogenic organism was identified in 35 patients (54%). Eighteen patients
      (28%) had positive stool cultures. Clostridium difficile toxin was detected in
      six patients. Colonic biopsy cultures were positive in 26 patients (40%).
      Endoscopic findings established the diagnosis of pseudomembranous colitis with
      negative tests for C. difficile toxin in two patients, diverticulitis in one,
      ischemic colitis in two, and cryptogenic colitis in seven. Conclusions.
      Sigmoidoscopy ensured the diagnosis in over 72% of cases of acute diarrhea. This
      investigation complements stool cultures and should be done routinely in adults
      with severe acute diarrhea.

PMID- 8669805
TI  - [Peptic ulcer and gastritis in the time of Helicobacter pylori].

PMID- 8669806
TI  - [Surgical treatment of hepatocarcinoma in cirrhosis].
AB  - In 1986, our institution published the first results of surgical resection of
      hepatocarcinoma in cirrhotic patients. The aim of this paper is to present long
      term results of this surgical management. From April 1978 to February 1992, 74
      patients were operated on at the surgical clinic of University Medical Center of
      Rennes (35000) France. There were 60 hepatectomies and 14 transplantations. The
      mean age was 60.2 years-9 years and the sex ratio: 70 males and 4 females. The
      etiology was alcoholic in 43 patients (58%), post hepatitis (B and C) in 22
      patients (30%) and due to hemochromatosis in 9 patients (12%). According to the
      Child Pugh classification, 48 patients were Child A, 11 Child B and one Child C
      in the hepatectomy group and 9 patients Child A and 5 Child B in transplantation
      group. The operative mortality was 10% in hepatectomy group and 35.7% in liver
      transplantation group. Overall survival was 61.8% at 1 year, 47.1% at 2 years,
      38.2% at 3 years and 20% at 5 years. 5 year survival is 21.4% after
      transplantation and 18.5% after resection. This difference is not significant. In
      conclusion, according to 5 years survival and to operative mortality the
      treatment of choice is hepatectomy in HCC in cirrhotic patients. However the best
      treatment is the prevention of cirrhosis.

PMID- 8669807
TI  - [Extrahepatic cancer in cirrhosis patients. A retrospective clinical study of 164
      diagnosed cancers in 2060 cirrhosis patients].
AB  - A retrospective study of 2060 inpatients with cirrhosis of the liver identified
      164 patients with extrahepatic cancer, a 20-fold increase over the expected
      number. Gastrointestinal, ENT, pulmonary, and hematologic malignancies
      predominated. Extrahepatic cancers occur more often and at an earlier age in
      patients with cirrhosis of the liver than in the population at large.

PMID- 8669808
TI  - Immunohistochemical expression of insulin-like growth factor 1 and its receptor
      in normal and neoplastic human adrenal cortex.
AB  - BACKGROUND: Insulin-like growth factor 1 (IGF-1) may influence cellular growth,
      differentiation and secretion. MATERIAL AND METHODS: Cryosectioned normal human
      adrenal glands (n = 6), cortical adenoma (n = 21), and carcinoma (n = 17) were
      stained immunohistochemically for IGF-1 and its receptor, and human
      adrenocortical cancer cells expressing the receptor were analysed for influences
      on proliferation. RESULTS: Normal cortical parenchyma generally displayed faint
      IGF-1 reactivity and intracellular receptor staining. Similar labelling
      encompassed the adenomas, but only 6 of them were receptor reactive. IGF-1
      expression was conspicuous in 11 carcinomas, and 6 of them displayed cell surface
      receptor reactivity. All aldosterone producing lesions were receptor antibody
      unreactive. Recombinant IGF-1 dose-dependently stimulated the cell proliferation,
      and this effect was reversed by the receptor antibody. CONCLUSION: IGF-1 may
      interact with function and proliferation of the human adrenal cortex with
      particular reference to cortical carcinomas lacking discernible aldosterone
      excess.

PMID- 8669809
TI  - Immunocytochemical observation of multidrug resistance (MDR) p170 glycoprotein
      expression in human osteosarcoma cells. The clinical significance of MDR protein
      overexpression.
AB  - Resistance to several cytotoxic agents (MultiDrug Resistance MDR), including
      anthracyclines, vinca alkaloids and epipodophylline derivatives can occur in
      human osteosarcoma (OS) cells, detected by the overexpression of a 170 kD
      glycoprotein (p170), as a result of increased expression of the MDR gene (mdr1).
      The p170 glycoprotein in normal cells is a membrane transport system protein and
      its quantitative increase results in increased drug efflux and decreased
      intracellular drug concentration. Normal renal epithelial cells express p170 as a
      function of their secretory duties therefore this human tissue was used as a
      positive tissue control in our immunocytochemical study. This partially
      retrospective immunocytochemical study was carried out on routine, 10% neutral
      formalin fixed, decalcified, paraffin embedded, tissue sections of 43 OSs,
      treated between 1981 and 1993 at the Orthopaedic Hospital of Los Angeles. The
      immunoperoxidase antigen detection protocol, submitted by Hsu et al (1981) was
      employed. The search for p170 was carried out with three newly developed
      monoclonal antibodies (MoABs) (JSB-I, C-219 and C-494, from Signet Laboratories,
      Dedham, MA 02026). The initial expression of MDR was not detectable in seven OSs.
      36/43 OSs expressed p170 on/in their cells. Heterogenous cellular
      microenvironment and various grades of differentiation features were also
      determined in the examined OSs. In 17/43 OS cases presence of intensive staining
      (probably overexpression) of p170 protein was registered. The 43 OSs exhibited
      different staining patterns with each MoAB. MoAB JSB-I reacted with a
      transmembranic antigen epitope. The long incubation time with C-219 resulted in
      heterogeneous cytoplasmic staining. MoAB C-494 also produced an intensive
      staining mainly localized on the cell membrane of the OS cells. These
      statistically significant immunocytochemical results suggest a direct correlation
      between the quantitative presence of p170 glycoprotein in human OS cells and the
      efficacy of the employed chemotherapy. Future observations employing the in situ
      hybridization technique will allow the quantitative measurement of the primary or
      secondary presence of MDR glycoprotein in human OS cells.

PMID- 8669810
TI  - Adriamycin resistance modulation induced by lonidamine in human breast cancer
      cells.
AB  - The effect of Lonidamine (LND), an energolytic chemosensitizing agent, on the MDR
      (multidrug resistant) phenotype of a human breast cancer cell line (MCF-7) has
      been studied. The intracellular adriamycin (ADR) accumulation and distribution,
      the plasma membrane potential and the P170 glycoprotein phosphorylation, have
      been analysed after LND treatment. The analysis of the subcellular localisation
      of ADR in both wild type and resistant MCF-7 cells treated with ADR or ADR + LND
      revealed that LND induced an ADR intracellular redistribution in both cell lines.
      MCF-7 ADR resistant cells exposed to LND (50 micrograms/ml) showed a change in
      the electrical charges distribution across the plasma membrane and a time
      dependent reduction of P170 phosphorylation (70% at 24 hr). These effects were
      associated with a marked increase in intracellular ADR accumulation in resistant
      cells.

PMID- 8669811
TI  - IP6-induced growth inhibition and differentiation of HT-29 human colon cancer
      cells: involvement of intracellular inositol phosphates.
AB  - Inositol hexaphosphate (InsP6 or IP6) ubiquitous in plants and animals is not
      only a natural antioxidant, but may also be the precursor/storage of
      intracellular inositol phosphates, important for various cellular functions. A
      novel anti-tumor action of InsP6 was demonstrated in models of experimental colon
      and mammary carcinogenesis in vivo. We now show its effects on growth and
      differentiation of HT-29 human colon carcinoma cells in vitro. A dose- and time
      dependent (0.33-20 mM InsP6 and 1-6 days treatment) growth inhibition was
      observed as tested by MTT- incorporation assay. The inhibition was statistically
      significant (p < 0.05) at 1 mM concentration as early as first day after
      treatment and continued up to 6 days. DNA-synthesis was also suppressed by InsP6
      and significantly inhibited as early as 6 h after treatment at 1 mM concentration
      (p < 0.05) and continued to 48 h (p < 0.01). The expression of proliferation
      marker PCNA was down-regulated (p < 0.05) by InsP6 (1 and 5 mM) after 48 h of
      treatment. To investigate the mechanism of action of InsP6 the intracellular
      phosphatases (including phytase) were inhibited by F to slow down the
      dephosphorylation of InsP6. Ion-exchange chromatographic separation of
      intracellular inositol phosphates demonstrated a 84-98% decrease of Ins, InsP1
      and InsP2 InsP3 was reduced by 39% and InsP4 and InsP5 by 21% and 13%
      respectively, whereas intracellular InsP6 was increased by 24.6% at 5 min
      following 3H-InsP6. Since neither the rate of uptake of 3H-InsP6 was unaffected,
      nor was the efficacy of growth inhibition altered by F inhibition of phytase,
      data suggest that contrary to the popular misconception, phytase plays no role in
      influencing the anti-neoplastic action of InsP6. Alkaline phosphatase activity
      (brush border enzyme, associated with absorptive cell differentiation), increased
      following 1 and 5 mM InsP6 treatment for 1-6 days. The expression of a mucin
      antigen associated with goblet cell differentiation and defined by the monoclonal
      antibody CMU10 was augmented (p < 0.0001) by InsP6. The tumor mucin marker Gal
      GalNAc, expressed by precancer and cancer of colon, but not by the normal cells
      showed a time-dependent biphasic change by InsP6; an increased expression after 1
      day of treatment followed by suppression after 2 days suggest progression of
      mucin synthesis and differentiation of cancer cells with reversion to normal
      phenotype. Because the tumor marker Gal-GalNAc is a) easily detected in rectal
      mucin of patients with colonic cancer and precancer with high sensitivity and
      specificity, and b) suppressed by InsP6 treatment, it can be used to monitor the
      efficacy of chemoprevention by InsP6 or other such agents. Since InsP6 a natural
      dietary ingredient of cereals and legumes, inhibits growth and induces terminal
      differentiation of HT-29 cancer cells, it is an excellent candidate for adjuvant
      chemotherapy and prevention of cancer.

PMID- 8669812
TI  - Human monoclonal antibody developed against a metastasizing paraganglioma:
      preparation and preclinical studies.
AB  - A tumor cell line, named HS, was established from a bone metastasis of a patient
      with metastasizing paraganglioma. In vitro immunization of normal human
      peripheral blood mononuclear cells by coculturing with viable HS cells, followed
      by fusion with mouse myeloma cells, yielded a stable human/murine heterohybridoma
      producing the highly specific monoclonal anti-body KM-155. This MAB KM-155 is a
      member of the IgG3 subclass and shows no alpha GAL glycosylation that is specific
      for mouse but not for human antibodies. In pilot preclinical studies it could be
      demonstrated that MAB KM-155 is highly efficient in targeting a KM-155 antigen
      expressing human tumor developing in nu/nu mice after xenografting. Moreover, the
      growth of KM-155 antigen-expressing human tumors in nu/nu mice was largely
      inhibited when the concentration of circulating MAB KM-155 was maintained at a
      high enough level by serial injections.

PMID- 8669813
TI  - Somatic mutations in the neurofibromatosis 1 gene in gliomas and primitive
      neuroectodermal tumours.
AB  - The increased frequency of glioma among neurofibromatosis 1 (NF1) patients
      suggests a general involvement of the NF1 gene in glioma tumourigenesis. Using
      the methodology of conventional Southern blotting with a complete panel of
      overlapping partial cDNAs covering the whole NF1 gene, we screened 31 gliomas of
      several different subtypes and 3 primitive neuroectodermal tumours (PNETs) from
      non-NF1 patients for aberrant restriction patterns in their tumour DNA samples.
      Clear evidence for somatic mutation events at the NF1 gene locus was found in 1
      astrocytoma, 2 glioblastomas, 1 ependymoma and 1 PNET with an astrocytic
      component. These results suggest that the NF1 gene is important in suppressing
      tumours of neuroectodermal origin.

PMID- 8669814
TI  - Dinaline inhibits amino acid transport and proliferation of colon carcinoma cells
      in vitro.
AB  - The human colon carcinoma cell line SW707 was incubated with different
      concentrations (7 microM - 540 microM) of the novel antineoplastic drug 4-amino
      N(2'-aminophenyl)benzamide (GOE1734, dinaline) to study the effects on 3H-alpha
      aminoisobutyric acid (AIB) - and 14C-methionine uptake as well as on 3H-thymidine
      incorporation into DNA. Additionally, adenine nucleotide pools were determined by
      high performance liquid chromatography (h.p.l.c.), and cell cycle distribution by
      flow cytometry. 24 h exposure to low concentrations of dinaline caused mild cell
      proliferation which turned into a cytostatic effect within a further 24 h without
      drug exposure. High concentrations of dinaline, however, were found to be
      cytostatic and then cytotoxic after corresponding time intervals. Dinaline caused
      a concentration-dependent decrease in sodium-dependent AIB uptake. Immediately
      after exposure the effect ranged from 67%-36% of control uptake. One day later an
      incomplete recovery not exceeding 70% of control was found for the three highest
      concentrations. This differed significantly from sodium-dependent methionine
      uptake which was initially decreased by 24%-36% but recovered within one hour and
      was enhanced one day after exposure. Significant differences were also measured
      for sodium-independent AIB uptake and sodium-independent methionine uptake
      immediately, 1 and 4 h after exposure. Adenine nucleotide pools were mildly
      increased immediately and 4 h after exposure. Thymidine incorporation into DNA
      was decreased by 70% to 84% immediately after exposure, and no full recovery was
      seen in the subsequent observation period. Cell cycle analyses revealed a block
      at the S phase entrance. Changes in thymidine incorporation and S phase fraction
      were highly correlated. The inhibition of the sodium-dependent uptake of AIB
      might indicate interaction of dinaline with cell membrane functions at low
      concentrations, the increase in methionine uptake points to enhanced protein
      synthesis following drug withdrawal and the impaired thymidine incorporation into
      DNA results from the cytostatic effect of dinaline. Taken together, the results
      show that SW707 colon carcinoma cells exposed to dinaline demonstrate distinct
      but reversible changes in amino acid transport, protein metabolism, DNA synthesis
      and cell proliferation, thus giving a correlation with observations in vivo.

PMID- 8669815
TI  - IL-12-mediated activation of MHC-unrestricted cytotoxicity of human PBMC
      subpopulations: synergic action of a plant rhamnogalacturonan.
AB  - IL-12 mediated activation of human MHC-unrestricted cytotoxicity was studied with
      freshly isolated, highly enriched CD56 +CD3- NK cells (95.98%),
      monocytes/macrophages (90-95%) and CD3 + T cells (95-98%). Activation of NK cell
      cytotoxicity and monocyte cytotoxicity by IL-12 were independent of exogenous IL
      2 and IFN gamma. Activation of CD3+T cells to MHC-unrestricted cytotoxicity
      required coactivation by anti-CD3 antibody. The enhanced cytotoxicities were
      directed against NK-sensitive as well as NK-resistant target cells and coincided
      with enhancement of effector cell/target cell conjugate formation. The specific
      cytotoxicity of all three activated effector cell populations was further
      increased in the presence of rhamnogalacturonan. These increases were based on an
      additional increase of effector cell/target cell conjugate formation that is
      based on rhamnogalacturonan-mediated bridging between effector cells and target
      cells. Simultaneous enhancement of cytotoxicity indicates involvement of
      receptors on effector cells cross-reacting with acetylrhamnose (6-deoxymannose)
      that might play an important role in human MHC-unrestricted cytotoxicity against
      tumor cells.

PMID- 8669816
TI  - Determination of erythrocyte polyamines as a predictive method in tumour
      diagnosis. An animal study with chemically induced tumours.
AB  - There have been numerous attempts in the past to use polyamine determinations in
      body fluids for tumour diagnosis. Since spermidine (Spd) and spermine (Spm) are
      mainly transported in blood by erythrocytes, this study was concerned with the
      diagnostic possibilities of red blood cell (RBC) polyamine determinations. In
      tumour-grafted animals we observed that RBC polyamine levels correlated with the
      tumour mass progression and increased before the tumour was palpable.
      Discrepancies between the evolution of RBC polyamine levels in tumour-grafted
      animals and in cancer patients were probably due to the non-continuous growth of
      the tumours in patients. Therefore, an animal model was sought which mimicked the
      clinical situation. In the present experiments, ethylnitrosourea induced tumours
      were used which, in analogy to the clinical situation, had an undetermined time
      of the appearance in a non-predetermined proportion of the animals. RBC
      polyamines were determined over a period of 7 months in 154 rats. A total of
      2,290 RBC polyamine determinations were performed during this study. The data
      clearly demonstrate the appearance of elevated Spd concentrations in advance of
      tumour diagnosis by conventional clinical methods. In 71% of the rats which later
      developed a tumour, abnormal Spd levels (> 40 nmol/8.109 RBC) preceded, by 35 +/-
      31 days, the first clinical symptoms for the presence of a tumour. In 29% of the
      animals, abnormal RBC Spd concentrations were observed at the time of tumour
      diagnosis. Elevation of Spm concentrations (> 6 nmol/8.10(9) RBC) was less
      frequent. RBC polyamine levels did not allow discrimination between malignant and
      non malignant tumours. This confirms earlier findings that RBC polyamines are
      markers of the cell proliferation rate, but not for the presence of a malignant
      tumour. Elevated RBC polyamine concentrations are an index of the intensity of
      hyperplastic processes, which can be clinically used for the early detection of
      proliferative phases of tumours, thus allowing timely therapeutic measures.

PMID- 8669817
TI  - Corticosteroids and medroxyprogesterone acetate inhibit the induction of E
      selectin on the vascular endothelium by MDA-MB-231 breast cancer cells.
AB  - The vascular endothelium plays a critical role in cancer metastasis by directing
      circulating cancer cells into extravascular tissues and by expressing cell
      adhesion molecules. The authors investigated the interaction between breast
      cancer cells and vascular endothelial cells in the expression of E-selectin, and
      the effect of corticosteroids or medroxyprogesterone acetate (MPA) on such
      interaction. An MDA-MB-231 cell line, derived from human breast cancer induced E
      selectin on the cell surface of human umbilical vascular endothelial cells. This
      induction was enhanced with a supplement of mononuclear cells of peripheral blood
      added to the culture medium. Corticosteroids and MPA blocked the induction of E
      selectin proportional to concentration. Anti-IL-1 beta, but not anti-IL1 alpha or
      TNF a, antibodies blocked induction. These findings suggest that MDA-MB-231
      cells induce expression of E-selectin on vascular endothelium by releasing IL-1
      beta directly or indirectly, but this induction is blocked by corticosteroids and
      MPA. Corticosteroids and MPA may inhibit cancer metastasis by blocking E-selectin
      expression on the vascular endothelium.

PMID- 8669818
TI  - Influence of cyclopropyl antiestrogens on the cell cycle kinetics of MCF-7 human
      breast cancer cells.
AB  - Five cyclopropyl compounds, previously shown to exhibit pure antiestrogenic
      activity in the mouse uterotropic assay and antiproliferative activity of MCF-7
      human breast cancer cells in culture, were examined for their influence on the
      cell cycle kinetics of MCF-7 cells. The DNA-histogram of a single cell suspension
      was obtained on Coulter Epics V after fixing the cells in 70 % ethyl alcohol and
      staining in propidium iodide. Tamoxifen increased the percentage of cells in G1
      phase with a concomitant decrease in percentage of cells in S-phase, in an
      estradiol reversible manner. Cyclopropyl compound 7a increased the percentage of
      cells in G1-phase, in an estradiol-irreversible manner. Further, compounds 5a,
      5c, 7a and 7b decreased the percentage of cells in S-phase and increased
      percentage of cells in the G2M-phase, in an estradiol-irreversible manner. Of the
      five cyclopropyl compounds tested, only 4d had no influence on the cytokinetic
      parameters, even though this compound was found to exhibit antiproliferative
      activity on MCF-7 cells equal to that of tamoxifen. In conclusion, all of the
      cyclopropyl compounds, except 4d, altered cell cycle parameters of MCF-7 cells in
      a manner different than that of tamoxifen. Thus, the results of this study
      indicate that, although these cyclopropyl compounds are antiestrogenic, they
      produce antiproliferative activity by a distinct mechanism of action in estrogen
      receptor positive breast cancer cells.

PMID- 8669819
TI  - Induction of DNA fragmentation in human myelogenous leukaemic cell lines by
      phenothiazine-related compounds.
AB  - A series of phenothiazine, benzo[a]phenothiazine and benz[c]acridine derivatives
      were compared for their ability to induce nucleosome-sized DNA fragmentation (a
      biochemical hallmark of apoptosis), using agarose gel electrophoresis and a
      fluorescence activated cell sorter. Significant DNA fragmentation-inducing
      activity was detected in 12H-benzo[a]phenothiazine, 5-oxo-5H
      benzo[a]phenothiazine and 9-methyl-12H-benzo[a]phenothiazine, which induced the
      monocytic differentiation of human myelogenous leukaemic cell lines. On the other
      hand, an other three benzo[a]phenothiazines, six 10-[n-(phthalimido)alkyl]-2
      substituted-10H-phenothiazines, six 1-(2-chloroethyl)-3-(2-substituted-10H
      phenothiazin-10-yl)alkyl-1- ureas, and twelve benz[c]acridines showed little or
      no DNA fragmentation-inducing activity. Active benzo[a]phenothiazines induced DNA
      fragmentation in four human myelogenous leukaemic cell lines (HL-60, ML-1, U-937,
      THP-1), but not in human T-cell leukaemic MOLT-4 and erythroleukaemic K-562 cell
      lines, which were also resistant to other apoptosis-inducing agents. Ca2+
      depletion from the culture medium did not significantly affect their DNA
      fragmentation-inducing activity. The differentiation and apoptosis-inducing
      activity of benzo[a]phenothiazines have an important role for their medicinal
      efficacy.

PMID- 8669820
TI  - Effect of para-aminobenzoic acid on the pharmacokinetics and urinary excretion of
      cis-diamminedichloroplatinum(II) in rats.
AB  - Para-aminobenzoic acid (PABA) has been previously reported as being an inhibitor
      of DDP toxicity, and its use did not result in any observable loss in antitumor
      activity of DDP. The following studies investigated the effect of PABA on the
      pharmacokinetics and urinary excretion of cis-diamminedichloroplatinum(II) (DDP)
      in male Sprague-Dawley rats. DDP was injected i.p. at the dose of 7.5 mg/kg in
      normal saline alone and with a concurrent i.p. injection of PABA (100 mg/kg). The
      combined treatment with PABA produced a significant increase in the plasma
      concentrations of total platinum, without affecting the levels of platinum
      species in the plasma ultrafiltrate. Similar results were also obtained in
      additional studies in rats receiving the same dose of DDP plus PABA through
      different routes of administration (i.e. DDP i.v. and PABA i.p.). Both the area
      under the total platinum plasma concentration-time curve (AUC) up to 60 min and
      AUC0-120 min were increased by PABA by an average of 113% and 66% respectively.
      The administration of PABA in rats was followed by a substantial reduction in
      total urinary excretion of platinum (P < 0.05) and by a significant (P < 0.01)
      lower concentration of DDP derived platinum in the urine collected during the
      first 4 h after treatment. The renal clearance of filterable platinum was reduced
      by PABA by an average of 67.5% from 1.11 to 0.36 ml/min/100 g body wt. Total 24-h
      urinary excretion of platinum was also decreased, although not significantly, by
      PABA. Urine volumes from rats treated with DDP+PABA were similar to those from
      animals receiving DDP alone. HPLC studies indicate that PABA reacts readily with
      the species generated from DDP in vitro, while the agent is essentially
      unreactive toward the parent DDP and does not influence its decomposition rate.
      The overall data of this study suggest that the protective effect exerted by PABA
      on DDP toxicity may be at least partially due to its ability to interact with
      aquated DDP as well as to alter the renal excretion of platinum.

PMID- 8669821
TI  - Centromere or telomere: who is the boss?

PMID- 8669822
TI  - Effect of progestin treatment on estradiol-and growth factor-stimulated breast
      cancer cell lines.
AB  - BACKGROUND: Reports about the effects of progestins on cell proliferation are
      contradictory. We investigated the effect of progesterone, medroxyprogesterone
      acetate, megestrol acetate, ORG 2058 and the antiprogestin RU 486 on two hormone
      dependent cell lines, T47D and MCF-7 (characterized by a different content of
      PgR). The aim of the study was to understand the eventual ability of progestins
      to interfere with cell proliferation stimulated by estradiol and various growth
      factors (TGF-a, IGF-I, IGF-II). MATERIAL AND METHODS: MCF-7 and T47D cells were
      maintained in DMEM/F12 medium supplemented with 2% FCS while experiments were
      carried out in the same culture medium using DCC-stripped FCS. RESULTS: In the
      absence of estradiol, all tested progestins generally tended to stimulate cell
      growth in the T47D cell line, but in the MCF-7 cell line only the highest
      concentrations (10(-6) M and 10(-7) M) were found to be stimulatory. In contrast,
      in the presence of 10(-8) M estradiol, progestins tended to inhibit cell growth
      stimulation in MCF-7 and T47D cell lines. The antiprogestin RU 486 exerted a
      stimulatory effect similar to that promoted by estradiol itself in MCF-7 cells.
      Instead, in T47D cells, RU 486 did not modify cell growth in the absence of
      estradiol, but tended to counteract the estradiol-promoted cell proliferation. In
      MCF-7 cells, medroxyprogesterone acetate and megestrol acetate were also able to
      effectively counteract the cell growth induced by TGF-alpha. However, none of
      these progestins was able to abolish cell proliferation promoted by IGF-I or IGF
      II. CONCLUSION: We therefore concluded that failure to respond to progestin
      treatment may be due to the very heterogeneous nature of human breast tumors and
      to the inability of these molecules to interfere with the IGF-R pathway.

PMID- 8669823
TI  - The effect of ICI 164384 and beta-interferon on the growth and steroid receptor
      profile of breast cancer cell lines.
AB  - We investigated the effect of a concomitant treatment of ICI 164384 and B
      interferon (beta-IFN) on the growth of estrogen-receptor-positive (ER+) and
      estrogen-receptor-negative (ER-) breast cancer cell lines and on their steroid
      receptor profiles. ICI 164384 reduced cell proliferation not only in ER+ but also
      in ER- cell lines and completely suppressed the stimulation induced by estradiol
      (E2) in hormone-sensitive cell lines, MCF7 and T47D. When associated with beta
      IFN, ICI 164384 increased the inhibitory effect exerted by the low concentration
      of beta-IFN. Moreover, ICI 164384, singly or in association with beta-IFN, did
      not affect ER and PgR concentration in ER- cell lines, whereas in ER+ cell lines
      we observed an almost total disappearance of ER and PgR. In conclusion, our study
      seems to indicate that, although beta-IFN is able to control the proliferation of
      hormone-sensitive and hormone-independent subclones, it does not further improve
      the antiproliferative activity of ICI 164384. In contrast, the presence of ICI
      164384, which does not induce the selection of resistant subclones under the same
      experimental conditions in which TAM does, may improve the efficacy of low
      concentration of beta-IFN and prevent the development of a secondary TAM-induced
      resistance.

PMID- 8669824
TI  - Overexpression of C-myc, Ras and C-erbB-2 oncoproteins in carcinoma of unknown
      primary origin.
AB  - The role of oncogenes in carcinoma of unknown primary site (CUP) has not yet been
      elucidated. In the present study the expression of the c-myc p62, ras p21 and c
      erB-2 p185 oncoproteins were studied by a 3-step immunoperoxidase technique in 26
      cases of CUP. Positive immunoreactivity was observed in 96% of the cases for c
      myc, 92% for ras and in 65% for c-erb-2, with at least half of tumor cells
      labelled in 85%, 92% and 58% respectively. The degree of staining intensity was
      considered moderate or strong in more than half of the cases for all oncogene
      products. In conclusion, our results showed that patients with CUP have an
      extremely high overexpression of all three oncogenes studied. Nevertheless, the
      biological role of these overexpressed oncoproteins, their relationship with
      different histological or clinical parameters and their diagnostic or prognostic
      value need further evaluation.

PMID- 8669825
TI  - Expression of catenins in human cancer cells and its regulation by n-6
      polyunsaturated fatty acids.
AB  - Catenins (alpha, beta, and gamma) are a group of proteins linking E-cadherin with
      the cytoskeleton. Reduced expression of alpha catenin has been shown in some
      cancer lines and tissues and is related to the invasive nature of tumour cells.
      This study examined the effects of n-6 PUFAs on the expression of catenins in a
      range of human cancer cells by Western blotting. Although most of the cell lines
      expressed similar levels of beta and gamma catenins, a number of cell lines
      expressed low levels of alpha catenin. Treatment of cells with gamma linolenic
      acid (GLA) increased alpha catenin expression in most cell lines, while beta
      catenin levels were reduced, and gamma catenin expression was unchanged. Linoleic
      acid and arachidonic acid had not significant effects. We conclude that in human
      cancer cell lines, the expression of alpha and beta catenins can be regulated by
      gamma linolenic acid.

PMID- 8669826
TI  - Nitrobenzylthioinosine-binding protein overexpression in human breast, liver,
      stomach and colorectal tumour tissues.
AB  - Using high-affinity [3H]nitrobenzylthioinosine (NBMPR) equilibrium binding
      assays, fresh human tumour tissues were consistently found to be over expressing
      NBMPR binding proteins at levels 1.5 to 5-fold higher than in corresponding
      normal tissues. The mean Bmax values for breast (n = 6), liver (n = 2) and
      stomach (n = 4) tumour tissues were 2.89 +/- 0.76, 0.5I +/- 0.03 and 1.38 +/-
      0.43 fmol/micrograms of plasma membrane protein, respectively. These values were
      all significantly higher (p < 0.05, student paired t-test) than those for the
      normal tissues (Bmax's = 0.97 +/- 0.05, 0.20 +/- 0.02 and 0.51 +/- 0.05
      fmol/microgram of protein for breast, liver and stomach, respectively). For
      colorectal tissues (n = 10), the mean Bmax value for the tumour specimens (1.36
      +/- 0.24 fmol/microgram of protein) was also significantly higher (p < 0.005,
      student paired t-test) than those for the normal specimens taken 5 cm (0.42 +/-
      0.03 fmol/microgram of protein) and 10 cm (0.47 +/- 0.04 fmol/(g of protein) away
      from tumour site. There were no consistent and significant differences in the
      binding affinities between tumour and normal tissues in these four tissue types
      (Kd values ranged from 0.07 to 1.0 nM, p > 0.05, student paired t-test).

PMID- 8669827
TI  - Dihydrotestosterone affects the growth of hormone-unresponsive breast cancer
      cells: an indirect action.
AB  - Cell to cell interaction, which plays a crucial role in breast cancer growth, may
      be regulated by steroid hormones. This study examined dihydrotestosterone (DHT)
      effects on the interaction between the steroid receptor positive MCF-7 and the
      steroid receptor negative MDA-MB-231 breast cancer cell lines. The growth of MDA
      MB-231 cells was inhibited by medium conditioned by MCF-7 cells grown in presence
      of DHT but not by medium conditioned by MCF-7 cells grown in presence of both DHT
      and the antiandrogen hydroxyflutamide. Trypsin pretreatment of conditioned medium
      abolished its growth-inhibitory effect on hormone-unresponsive cells. DHT itself
      did not affect the growth of MDA-MB-231 cells when directly added to their
      culture medium. Data suggest that DHT stimulates, via the androgen receptor, the
      androgen-responsive breast cancer cells to produce a peptide factor(s) capable of
      inhibiting the growth of hormone-unresponsive cells.

PMID- 8669828
TI  - The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to
      induce hyperglycemia in SCID mice.
AB  - A reduced glucose tolerance or frank diabetes mellitus is a frequent finding in
      patients with pancreatic cancer. The aim of this study was to verify whether the
      pancreatic cancer cell line MIA PaCa2 was able to produce any factor which could
      induce hyperglycemia in SCID (severe complete immunodeficient) mice. MIA PaCa2
      cells were cultured in Dulbecco's modified Eagle's medium (DMEM) for 7 days.
      Twenty-five female SCID mice were used. They were daily i.p. injected with 300 ul
      of cell culture supernatants (Group T, n = 13) or with 300 ul of DMEM (Group C, n
      = 12) and followed up for 82 days. Blood glucose levels were significantly higher
      in Group T than in Group C on days 10 and 25. Intravenous glucose tolerance test,
      success-fully performed in 9 animals (4 controls and 5 treated), demonstrated a
      significantly reduced glucose tolerance in Group T compared to Group C mice. At
      sacrifice, plasma and pancreatic insulin and glucagon levels did not vary between
      groups. The ratio between pancreatic and plasma insulin was significantly lower
      in Group T than in Group C. We conclude that: 1. The pancreatic cancer cell line
      MIA PaCa2 produces one or more soluble factors able to cause hyperglycemia in
      vivo; 2. this effect is not immunologically mediated, and 3. this/these factor/s
      could both interfere with the pancreatic beta cells and/or with insulin
      peripheral action.

PMID- 8669830
TI  - Modification of the blood-brain barrier permeability following intracarotid
      infusion of vinorelbine.
AB  - The effects of the antineoplastic compound, vinorelbine, on the permeability of
      the blood-brain barrier (BBB) to the complex Evans blue/albumin were studied.
      Vinorelbine, at a dose range from 5 to 10 mg/kg, was infused (4 ml/kg over 2 min)
      into the left carotid artery of anesthetised male Sprague-Dawley rats. BBB
      disruption was evaluated, qualitatively, by the appearance in the infused
      hemisphere of intravenously administered Evans blue dye (2%). Six groups of 3
      rats were studied for preliminary assays to define the dose and delay between
      infusion and sacrifice. Twenty four rats (12 controls and 12 test rats) were used
      to define the effect of vinorelbine. These effects of vinorelbine were dose
      dependent and after 3 hours, 10 mg/kg of vinorelbine caused Evans blue/albumin
      exudation in gray and white matter. This study shows that the intracarotid
      infusion of vinorelbine in this rat model system increases BBB permeability only
      with a high dose. Sufficient concentrations of drug may be obtained in cerebral
      tissue without significant BBB disruption.

PMID- 8669829
TI  - Elevated mutagen susceptibility in cultured lymphocytes of oral cancer patients.
AB  - Mitomycin C (MMC)-induced lymphocytic sister chromatid exchange (SCE) frequency
      was studied in 40 oral cancer (OC) patients, 40 normal tobacco chewers (NC) and
      in 40 normal healthy individuals not consuming tobacco/areca nut in any form.
      Significantly higher MMC-induced SCE/cell values were observed among OC patients
      as compared to healthy non-chewer controls as well as NC. Although the mean SCE
      frequency for NC was comparable to that of healthy controls, three individuals
      showed an SCE rate higher than the highest observed among controls. The
      comparable frequency of the tobacco habit in these three individuals with that of
      the rest of the thirty-seven individuals indicated the possible involvement of
      factors other than tobacco consumption for the higher susceptibility to mutagens.

PMID- 8669831
TI  - Cytotoxicity of antitumor agents toward cultured murine leukemia L1210 cells
      under a serum-deprived apoptotic condition.
AB  - Apoptosis is known to be induced in L1210 cells that are cultured in serum
      deprived medium. In this study, inhibitory effects of some antitumor agents on
      the growth of L1210 cells cultured in a normal and a serum-deprived medium were
      compared. All the antitumor agents examined were equally cytotoxic to cells in
      both media, indicating that the cytotoxic effects of these agents were not
      coupled with programmed apoptosis so as to induce synergistic cell death. The
      single cell-gel electrophoresis assay (comet assay) revealed that antitumor
      agents induced DNA strand breakage in a dose-dependent manner under either normal
      or serum-deprived culture conditions without any synergistic increases in DNA
      strand breakage.

PMID- 8669832
TI  - Modifications of tumor-associated antigen expression on human lung cancer cells
      by hyperthermia and cytokine.
AB  - The effect of hyperthermia and cytokine (IFN-gamma) in the expression of
      carcinoembryonic antigen (CEA) on the surface of cells was studied in vitro. The
      human lung cancer cell line, GLL-1, was used. The results demonstrate increase in
      CEA expression after hyperthermia. The magnitude of elevated CEA expression
      increased with increasing temperature (41-43 degrees C). Time-course study
      demonstrated that the peak CEA expression was 3 days after heating at 43 degrees
      C. The relative CEA expression was 1.3 at 1 day, 1.6 at 2 days, 1.9 at 3 days,
      1.8 at 4 days, and 1.5 at 5 days, respectively. Hyperthermia plus IFN-gamma
      showed a synergistic effect in the expression of CEA. The four fold marked
      increase of CEA expression was detected. Furthermore, the pattern of time-course
      of CEA expression in hyperthermia combined with IFN-gamma was different from that
      in hyperthermia alone.

PMID- 8669833
TI  - Up-regulation of heat shock protein 70 in adenocarcinomas of the lung in smokers.
AB  - Tumour samples of smokers (n = 32) and non-smokers (n = 21) with previously
      untreated adenocarcinomas of the lung were analysed, immunohistochemically, for
      expression of the heat shock protein 70 (hsp70). A correlation between smoking
      habits and expression of hsp70 was found. Of the tumours from the 21 non-smokers
      12 (57%) and of the 32 smokers 24 tumours (75%) showed high hsp70 expression. The
      expression of hsp70 depended on the number of cigarettes smoked daily. Of the
      patients who smoked more than 20 cigarettes, 16 out of 18 had tumours with a high
      hsp70 expression (89%; p = 0.028).

PMID- 8669835
TI  - The value of fine needle aspiration cytology in the diagnosis of breast
      proliferative lesions.
AB  - In order to further characterize fine needle aspiration cytology of breast
      proliferative lesions, we analyzed 723 FNA of patients with palpable breast
      abnormalities who underwent physical, mammographic and/or echographic
      examination. In 28 biopsies (3.9%), the final cytologic diagnosis was a
      proliferative lesion, a group of uncommon breast proliferative diseases not yet
      explored, in which cytology is sufficiently cellular with plenty of atypical
      elements but not suspicious of carcinoma. Histologic material was available in 22
      cases and represented the basis of this retrospective evaluation. Among the
      positive proliferative lesions (PPL), 10 cases were infiltrating ductal
      carcinomas and 1 was a microinvasive carcinoma; whereas for the negative
      proliferative lesions (NPL), in 8 cases the histologic findings demonstrated
      fibrocystic changes, in 1 a fibroadenoma and in 1 a cystosarcoma phyllodes. The
      cytologic criteria utilized to define breast proliferative lesions were the
      following: increased cellularity, occasional single atypical cells, decreased
      cellular cohesion, crowded, enlarged and overlapping nuclei with three
      dimensional groupings with prominent nucleoli and chromatic changes. The
      cytologic characteristics examined demonstrated that the PPL are characterized by
      single atypical cells with nuclear alterations such as coarsely granular
      chromatin with a thick nuclear membrane and numerous prominent nucleoli. These
      features are common to many malignancies, therefore surgical biopsy confirmation
      is suggested.

PMID- 8669834
TI  - Comparison of the prognostic significance of current and modified histological
      grades in breast carcinomas.
AB  - Paraffin sections of 185 breast carcinomas were reexamined in order to compare
      the current SBR histoprognostic grade (SBR) with to modified methods of grading
      recently proposed by two groups, Le Doussal et al (MSBR) and Elston et al (SBR
      Elston). In each tumor, the SBR, MSBR, SBR-Elston, and each of their components
      were correlated with recurrence, metastases and survival rates (follow up 7 to 96
      months, m = 52, SD = 19) (Kaplan-Meier test). The Nottingham prognostic index
      (NPI) was computed for each patient, the histological type reevaluated and both
      were also correlated with the patient follow up. Our results show that the three
      methods of grading were significantly (p < 0.0001) correlated. The three grades,
      were significantly correlated with metastases and survival, but not with the
      recurrence rates. The differentiation, the nuclear pleomorphism and the mitoses
      count also correlated with the metastases rate and overall survival but the
      mitoses number appeared to be a stronger prognostic indicator. The MSBR grading
      made it possible to refine the prognostic of the tumors usually scored as SBR
      grade 2. The NPI significantly correlated with metastases and survival (p <
      0.0001), whereas the histological types were found to have no prognostic
      significance.

PMID- 8669836
TI  - Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary
      glands: an immunohistochemical study.
AB  - The tyrosine kinase receptor family, including the epidermal growth factor
      receptor (EGF-R), c-erbB2 and, more recently, the c-erbB3, has been recognized as
      being of particular importance in many human malignancies. This study was
      undertaken to define the role of c-erb B2 and c-erbB3 in adenoid cystic
      carcinomas (A.C.C.) of the salivary glands. Sixteen cases of A.C.C. were studied
      immunohistochemically, using antibodies against each erbB gene family product.
      EGF-R was not detected in any of these samples but c-erbB2 and c-erbB3 gene
      products (ERBB2and ERBB3) were demonstrated in all A.C.C. sections with some
      degree of straining. Tubular and cribriform patterns overexpressed particularly
      large amounts of ERBB2 and ERBB3. Strong staining was mainly demonstrated in
      tumor cells of the invasive area. These results suggested that overexpression of
      ERBB2 and ERBB3 is related to tumor differentiation and invasion in adenoid
      cystic carcinomas.

PMID- 8669837
TI  - Prognostic significance of TGF-beta 1 and TGF-beta 2 expressions in female breast
      cancer.
AB  - A series of 273 breast cancer biopsies were analysed immunohistochemically for
      the expression of transforming growth factor beta-1 (TGF-beta 1) and beta-2 (TGF
      beta 2) as related to standard prognostic factors and patient survival. TGF-beta
      1 expression was found in 160/273 (59%) and TGF-2 in 110/273 (40%) of tumour
      specimens. Both isoforms were expressed in 89/273 (33%) of cases. TGF-beta 1
      alone was expressed in 71/273 (26%) of cases and TGF-beta 2 alone was expressed
      in 19/273 (7%) of cases. The expression of TGF-beta 1 and TGF-beta 2 were both
      uniformly related to some other favourable prognostic factors. The expression of
      TGF-beta 2 without the expression of TGF-1 was significantly related to
      favourable disease outcome. The result of this study is in agreement with the
      previous studies of TGF-beta mRNA and also in vitro studies, but the result
      differs from some previous immunohistological studies. This study also suggests
      that the expression of TGF beta may have independent prognostic value over the
      expression of TGF-beta 1.

PMID- 8669838
TI  - Serum melatonin in multiple myeloma: natural brake or epiphenomenon?
AB  - Melatonin (MEL), the main hormone produced by the pineal gland, seems to exert
      antineoplastic activity both in vitro and in vivo. Moreover, several studies
      reported increased melatonin blood levels in cancer patients. Plasma melatonin
      concentrations were determined in 46 patients with multiple myeloma and in 31 age
      matched healthy subjects (57.8 +/- 6.9 versus 55.2 +/- 8.9 years). Venous blood
      was drawn between 7.30 and 9.30 a.m. and melatonin was assayed using a
      commercially available radioimmunoassay. The data were analysed by Student's t
      test and results reported as mean values +/- standard deviation. The patients
      with multiple myeloma showed significantly higher mean melatonin serum levels
      than healthy subjects (21.6 +/- 13.5 versus 12.1 +/- 4.8 pg/ml; p < 0.001). This
      behaviour could actually represent a phenomenon secondary to an altered endocrine
      metabolic balance caused by an increased demand of the developing tumor. On the
      other hand, the increased melatonin secretion might be considered as a
      compensatory mechanism due to its antimitotic action and therefore as an effort
      to secrete substances capable of regulating neoplastic growth.

PMID- 8669839
TI  - A randomized comparison of triptorelin and tamoxifen as treatment of progressive
      ovarian cancer.

PMID- 8669840
TI  - The use of a whey protein concentrate in the treatment of patients with
      metastatic carcinoma: a phase I-II clinical study.
AB  - Glutathione (GSH) concentration is high in most tumour cells and this may be an
      important factor in resistance to chemotherapy. Previous in-vitro and animal
      experiments have shown a differential response of tumour versus normal cells to
      various cysteine delivery systems. More specifically, an in-vitro assay showed
      that at concentrations that induce GSH synthesis in normal human cells, a
      specially prepared whey protein concentrate, Immunocal, caused GSH depletion and
      inhibition of proliferation in human breast cancer cells. On the basis of this
      information five patients with metastatic carcinoma of the breast, one of the
      pancreas and one of the liver were fed 30 grams of this whey protein concentrate
      daily for six months. In six patients the blood lymphocyte GSH levels were
      substantially above normal at the outset, reflecting high tumour GSH levels. Two
      patients (#1, #3) exhibited signs of tumour regression, normalization of
      haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte
      GSH levels towards normal. Two patients (#2, #7) showed stabilisation of the
      tumour, increased haemoglobin levels. In three patients (#4, #5, #6,) the disease
      progressed with a trend toward higher lymphocyte GSH levels. These results
      indicate that whey protein concentrate might deplete tumour cells of GSH and
      render them more vulnerable to chemotherapy.

PMID- 8669841
TI  - Concomitant administration of two standard regimens of chemotherapy and
      radiotherapy in advanced squamous carcinoma of the head and neck: a feasibility
      study.
AB  - BACKGROUND: In advanced squamous cell carcinoma of the head and neck, the
      superiority of a chemo-radiotherapy combination over radiotherapy alone has been
      strongly suggested. However, the best modality to combine the two treatments has
      still to be determinated. A pilot study was designed, testing a combination of
      two standard chemo- and radiotherapy regimens concomitantly administered.
      MATERIALS AND METHODS: 26 patients, with unresectable squamous cell carcinoma of
      the head and neck, were treated with three cycles of chemotherapy (cisplatin 20
      mg/m2/day and fluorouracil 200 mg/m2/day as an intravenous bolus, for 5
      consecutive days, every 21) simultaneously delivered with radiation (66-70 Gy/33
      35 fractions/7 weeks). In order to reduce the mucoseal toxicity. observed in the
      first 15 patients, 1 week of pause was inserted after the third week of treatment
      in the subsequent 11 patients. RESULTS: Grade III-IV mucositis was detected in
      40% of patients treated without pause after the third week of treatment and in 9%
      of those treated with. Complete responses were obtained in 13/26 patients (50%)
      and partial responses in 8/26 (31%). 1 stable disease, 3 early deaths (1 because
      of toxicity) and 1 lost before being evaluated were considered as treatment
      failures (19%). CONCLUSIONS: This concomitant chemo-radiotherapy approach showed
      a good antitumour activity but mucoseal toxicity is too high if no pause is
      planned during the treatment.

PMID- 8669842
TI  - Combined chemo-radiation and hyperthermia for locally advanced soft tissue
      sarcoma: response and toxicity.
AB  - BACKGROUND: Evaluation of the primary effects and acute adverse reactions of
      combined chemo-radiation and hyperthermia for patients with locally advanced soft
      tissue sarcoma. MATERIALS AND METHODS: Eight patients with locally advanced soft
      tissue sarcoma underwent a combination of radiation therapy, continuous infusion
      of doxorubicin, and once weekly hyperthermia. RESULTS: Complete response was
      obtained in 2 patients and partial response in 3. Level 4 skin reaction was
      developed in 4 patients who had superficially located tumour. Treatment
      interruption more than three days was required in only one patient who developed
      level 4 pharyngitis. Five patients developed grade 3 leukopenia, 2 had grade 4
      leukopenia requiring administration of haematopoietic growth factor. Two patients
      developed radiation pneumonitis which required steroid medication. No symptomatic
      cardiotoxicity was observed. There was no acute morbidity during the treatment.
      CONCLUSIONS: The intensive combination therapy provided good local responses or
      at least palliation for most of the patients entered without increasing treatment
      morbidity.

PMID- 8669843
TI  - Prognostic value of Ki-67 expression, ploidy and S-phase fraction in patients
      with pancreatic cancer.
AB  - The prognostic value of Ki-67 expression, ploidy and s-phase fraction was
      evaluated in 133 patients with pancreatic cancer. Formalin-fixed paraffin
      embedded surgical specimens of pancreatic ductal adenocarcinomas were stained
      with a polyclonal Ki-67 antibody. Ploidy and s-phase fraction was assessed by
      flow cytometry. The median percentage of Ki-67 positive nuclei was 26% (range 0
      90%). The level of Ki-67 immunoreactivity was associated with TNM-stage, surgical
      resectability, tumour grade, ploidy and S-phase fraction. Ninetythree patients,
      with a nuclear expression of Ki-67 in < 50% of malignant cells, had a median
      survival of 12.8 months compared with 5.5 months for 25 patients with Ki-67 > or
      = 50% (p = 0.0008). Ploidy (p < 0.0001) and SPF (p = 0.002) were also significant
      prognostic factors in a univariate survival analysis. In a multivariate analysis,
      stage (or alternatively resectability), grade, ploidy and postoperative
      chemotherapy emerged as independent prognostic factors. When ploidy was excluded
      from the Cox multivariate model, S-phase fraction also predicted prognosis
      independently. Ploidy and S-phase fraction are independent prognostic factors in
      patients with pancreatic cancer. A high level of Ki-67 immunoreactivity is also
      an indicator of poor prognosis but seems to add little prognostic information to
      that provided by traditional parameters such as stage, resectability and grade.

PMID- 8669844
TI  - Expression of insulin-like growth factor II in female breast cancer as related to
      established prognostic factors and long-term prognosis.
AB  - The expression of insulin-like growth factor II (IGF-II) was analysed
      immunohistochemically in a series of 211 breast cancers with special reference to
      standard prognostic factors and patient survival. IGF-II was expressed both in
      the cancer cells and in stromal cells, in 84% and 50% of cases, respectively. IGF
      II expression in cancer cells was related to a non-metastatic disease at
      diagnosis (p = 0.03), low tumour grade (p = 0.02), DNA diploidy (p = 0.02) and S
      phase fraction under 7% (p = 0.001). IGF-II negativity was positively correlated
      to morphometric SD of nuclear area (p = 0.0003), nuclear perimetry (p = 0.002),
      SD of nuclear perimetry (p = 0.02), minimum nuclear diameter (p = 0.005) and
      maximum nuclear diameter (p = 0.003). The expression of IGF-II in stromal cells
      was related to low histological grade (p = 0.02), mitotic index under 10/mm2 (p =
      0.01), mild nuclear pleomorphism (p = 0.03), DNA diploidy (p = 0.08), SD of
      nuclear area (p = 0.006), mean nuclear perimeter (p = 0.05), minimum nuclear
      diameter (p = 0.005) and maximum nuclear diameter (p = 0.007) in that the nuclear
      factor values were higher in tumours without stromal IGF-II expression. In
      univariate and multivariate survival analysis, immunohisto-chemically detected
      expression of IGF-II had no independent prognostic value over standard prognostic
      factors. Despite the fact that expression of IGF-II was inversely related to
      several histopathological features of malignancy, the clinical behaviour of
      breast cancer seemed to be independent of IGF-II expression.

PMID- 8669845
TI  - Serum evaluation of basic FGF in breast cancer patients.
AB  - Basic fibroblast growth factor (bFGF) is a potent endothelial cell mitogen found
      in a variety of normal and tumour tissues and is of prognostic relevance in human
      malignancies such as renal cell carcinoma and leukaemia. This study presents the
      data of 104 serum samples of 20 patients suffering from breast cancer. Mean serum
      levels of bFGF in these patients were 13.9 +/- 17. 1 (min 0, max 56.4) pg/ml and
      2.4 +/- 5.9 (min 0, max 24.7) pg/ml, respectively (p = 0.01). Basic FGF reached a
      sensitivity of 61% at a specificity of 87% when applying a cut-off level of 5
      pg/ml. A continuous increase of bFGF serum levels before the clinical detection
      of relapse (lead time) was seen in 3 out of 8 cases with a mean lead time of 4
      months. Preoperative serum levels were not of prognostic value and showed no
      correlation with axillary lymph node metastasis. These preliminary results
      indicate that, in breast cancer patients, soluble bFGF may be useful in early
      detection of primary tumours, recurrences and monitoring of therapy.

PMID- 8669846
TI  - Biochemical modulation of 5-fluorouracil with methotrexate in advanced colorectal
      cancer patients pretreated with adjuvant 5-fluorouracil and leucovorin.
AB  - PURPOSE: 5-fluoracil (5-FU) remains the standard treatment in advanced colorectal
      cancer patients. An increasing number of recurring patients, however, have
      already received this drug as adjuvant after surgery. An attempt to increase 5-FU
      cytotoxicity through biochemical modulation is justified in this setting. In our
      study, a combination regimen of methotrexate followed by 5-FU, with leucovorin
      rescue, was employed. METHODS: Patients were required to have symptomatic,
      measurable, inoperable lesions from colorectal cancer, recurring after adequate
      radical surgery of the primary tumor and adjuvant 5-FU + leucovorin concluded at
      least 3 months before recurrence. Patients received methotrexate. 250 mg/m2 as a
      2-hour i.v. infusion, followed by two doses of 5-FU, 500 mg/m2 as i.v. bolus 1
      hour and 21 hours after the end of methotrexate infusion. Leucovorin rescue, 15
      mg orally every six hours for 7 times, was started 1 hour after the second 5-FU
      dose. The cycle was repeated every 2 weeks. RESULTS: Twenty-two patients entered
      the trial, and 21 were evaluable. An objective response was observed in one
      patient (4.8%), 7 patients (33.3%) obtained tumor regression < 50% or disease
      stabilization. Thirteen patients (61.9%) progressed. Median survival in the whole
      group was 11 months. Subjective responses were observed in 7 patients (33.3%).
      Toxicity was mild. CONCLUSIONS: Biochemical modulation with methotrexate does not
      seem a satisfactory means of increasing 5-FU activity, when the patient has been
      previously exposed to 5-FU plus leucovorin. On the other hand, any possible
      advantages in terms of quality and prolongation of life with this schedule were
      obtained at the cost of very acceptable toxicity.

PMID- 8669847
TI  - The measurement of plasma D-dimer (DD) levels in the follow-up of patients with
      ovarian cancer.
AB  - Peripheral blood samples for the measurement of DD and CA 125 were drawn from 39
      patients with ovarian cancer at different times from first surgery. Both median
      DD and CA 125 levels were significantly higher in the 20 samples drawn from
      patients with clinically evident disease than in the 37 samples from patients
      without clinical evidence of disease (477 vs 300 ng/ml p = 0.006, and 66 vs 11
      U/ml, p < 0.0001, respectively). DD levels did not correlate with CA 125 levels.
      The sensitivity, specificity and diagnostic accuracy of the tests in the
      assessment of clinical disease status were as follows: 65%, 62% and 63% for DD
      (cut-off = 416 ng/ml); 70%, 92% and 84% for CA 125 (cut-off = 35 U/ml); 90%, 59%
      and 70% for DD "or" CA 125; and 45%, 95% and 77% for DD "and" CA 125. DD levels
      correlated with the clinical course of disease in ovarian cancer patients.
      However, the concomitant determination of DD and CA 125 did not improve the
      reliability of CA 125 assay alone in the follow-up of these patients.

PMID- 8669848
TI  - Somatuline (BIM 23014) and tamoxifen treatment of postmenopausal breast cancer
      patients: clinical activity and effect on insulin-like growth factor-I (IGF-I)
      levels.
AB  - Somatostatin analogues have been shown to suppress some hormones and growth
      factors involved in breast tumour growth and a direct in vivo and clinical
      antimumour effect has recently been reported. In our study the effects of
      tamoxifen, combined with a depot somatostatin analogue in 33 postmenopausal
      untreated breast cancer patients, have been evaluated. Blood samples were
      obtained before treatment, after 14 days and then monthly, in order to evaluate
      the behaviour of serum IGF-I, GH and somatuline levels. The drug combination
      resulted in a significant and synergistic reduction of plasma IGF-I
      concentration. No significant changes of serum GH were observed. 12.5% of
      patients exhibited a complete response and 37.5% a partial response for an
      overall objective response rate of 50% (95% CL 35-69%). The high remission rate
      reported, the absence of overlapping side effects between tamoxifen and
      somatuline and the synergistic activity on IGF-I suppression justify a further
      evaluation of the drug-combination.

PMID- 8669849
TI  - Pilot trial of a combination comprising of consecutive oral administration of
      UFT, and two-divided administration of CDDP in non-small cell lung cancer.
AB  - A pilot study of a combination therapy comprising of consecutive oral
      administration of UFT, and two-part divided administration of CDDP was undertaken
      in patients with inoperative non-small cell lung cancer, based on the synergistic
      effects of CDDP and 5FU. UFT was administered orally at a dosage of 400 mg/m2 for
      two consecutive weeks (Day 1-Day 14) and CDDP was administered twice by
      intravenous infusion, once on Day 4 and again on Day 8. The unit dose of CDDP was
      increased sequentially, from 40 mg/m2 in step 1, to 50 mg/m2 in step 2, and then
      to 60 mg/m2 in step 3, with safety being confirmed during the process. The
      numbers of patients registered for each dose level were 3, 3, and 20,
      respectively. Evaluation of toxicities could be conducted for all the patients
      except one. No toxicities of grade 3 or higher were observed in step 1 or 2.
      There was no problem with continuous administration of UFT. The following
      toxicities of grade 3 or higher were observed in step 3: leukocytopenia in 2
      patients; reduction of the hemoglobin count in 1; decrease in creatinine
      clearance in 2; anorexia in 3; and nausea and vomiting in 3. Bone marrow
      suppression was mild and transient. Renal failure and digestive symptoms, which
      were proved to be transient and treatable by symptomatic treatment, were also
      observed. The step 3 administration was effective in 8 (47.1%) of the 17 patients
      with measurable lesions (95% CI: 23-71%). In conclusion, since it was determined
      that the dose employed in step 3 should be recommended and that it could be
      expected to exhibit antitumour effects with mild bone-marrow suppression, a large
      scale phase II study should be conducted in no prior treatment non-small cell
      lung cancer.

PMID- 8669850
TI  - The effect of diagnostic delay in patients with Hodgkin's lymphoma.
AB  - BACKGROUND: The aim of the study was to document the delay in diagnosis of
      Hodgkin's disease (HD) and clarify the impact on clinical stage and survival in
      our region. MATERIAL AND METHODS: A retrospective study of the records of 50
      patients treated for primary HD in northern-Norway in the time period 1985 - 1993
      was performed in November 1994. The diagnostic delay related to clinical stage,
      age, sex, relapse or death were registered. RESULTS: The median delay was 4
      months (range 0 - 48 months). The histological subgroup lymphocyte predominance
      (LP) HD had a significant prolonged delay (p = 0.038). There was no correlation
      between delay in diagnosis and age, sex, B-symptoms, stage of disease, recurrent
      disease or death of disease. CONCLUSION: The diagnostic delay in patients with HD
      does not seem to have any significant influence on stage distribution, relapse
      rate or short-term survival. The aggressiveness of the tumour may be the
      important parameter.

PMID- 8669851
TI  - Clinical value of TPS, CEA and CA 15-3 in breast cancer patients.
AB  - Serum TPS, CA 15-3 and CEA levels were measured in 121 women with breast cancer.
      The combination of TPS (which measures tumour activity) and CA 15-3 (which
      measures tumour mass) had a sensitivity of 72% to detecting metastatic disease (n
      = 71). All 3 markers could significantly discriminate local versus distant
      metastatic relapsed breast cancer and TPS was more often elevated in the case of
      bone metastases. In a total of 46 relapsed patients and 49 situations which
      required therapeutic changes because of progressive disease, the response to
      treatment (hormonal or chemotherapy) was recorded together with tumour marker
      changes (25% +/-). After 3 months of therapy TPS (68%) responded earlier and
      faster than CEA (38%) or CA 15-3 (49%) with no progression (SD+PR+CR). The
      correlation with clinical deterioration after 6 months of therapy was 44% for TPS
      33% for CEA and 28% for CA 15-3. In patients with bone metastases, TPS in
      addition to CA 15-3 could be used to monitor therapy.

PMID- 8669852
TI  - Comparative prognostic value of Ki-67 and MIB-1 proliferation indices in breast
      cancer.
AB  - BACKGROUND: Tumor proliferation index was evaluated in 246 samples of breast
      carcinoma using Ki-67 and MIB-1 monoclonal antibodies on frozen and paraffin
      sections, respectively, with the purpose to compare the two proliferation indices
      from both a quantitative and prognostic point of view. MATERIALS AND METHODS: All
      determinations were performed with the same immunohistochemical procedure (Avidin
      Biotin Complexes). The prognostic relevance of tumor proliferation index, defined
      by both the antibodies, was investigated in 127 patients. Ki-67 and MIB-1 median
      values were used to obtain two groups of patients at different risk and life
      table analysis (Mantel-Cox) was performed to assess the probabilities of overall
      survival (OS) and relapse-free survival (RFS). The median time of observation was
      61 months. RESULTS: Ki-67 and MIB-1 values were exponentially distributed with
      overlapping ranges varying from 2% to 90%. Ki-67 mean and median values were
      16.7% and 14.0%, respectively, compared to 22.5% and 20% for MIB-1. Ki-67 and MIB
      1 mean values were statistically different (t = -4.396; p < 0.001), while no
      difference was observed for MIB-1 mean values on frozen and paraffin sections (t
      = 1.35; p = n.s.). Ki-67 and MIB-1 values were statistically correlated
      (Spearman's coefficient = 0.75; p < 0.0001) and directly associated (agreement
      rate = 79.3%; p < 0.0001). Patients with tumors having a high proportion of MIB-1
      positive cells showed a higher 5-year probability of relapse of disease (43.7%
      versus 27.6%; p = 0.02) and death (35.4% versus 15.8%; p = 0.007) than those with
      a low one. In parallels Ki-67 was found to be prognostically relevant for OS
      (32.2% versus 16.2%; p = 0.02) but not for RFS (40.7% versus 27.9%; p = 0.10).
      CONCLUSIONS: Such results indicate that the detection of proliferative activity
      on paraffin sections with MIB-1 monoclonal antibody provides in formation
      analogous to or even better than that obtained with Ki-67 antibody on frozen
      ones. Moreover, it represents a valuable tool to obtain kinetic data on "routine"
      histological samples and, above all, to give prognostic evaluations on the
      clinical outcome of breast cancer patients.

PMID- 8669853
TI  - Hepatocellular carcinoma in young patients: histology, cellular differentiation,
      HBV infection and oncoprotein p53.
AB  - The study of 226 cases of hepatocellular carcinoma (HCC) in a homogenous rural
      Southern African population is based on the assessment of histology, HBV
      infection, p53 oncoprotein and transforming growth factor alpha (TGFa)
      expression. Epidemiological and morphological observations were compared to HCC
      observed in 89 cases from pathological files in Poland and published information
      from Japan and Italy. Comparatively high number of young patients with HCC in
      Africa presented high rates of HBV infection, p53 oncoprotein overexpression and
      high HBsAg/p53 correlation rates. In all patients histological grading of HCC was
      inversely related to p53 and TGFa expression. No significant differences in
      histological grading of HCC and patients' mean age were noted between various
      population groups. The association of hepatic cirrhosis was at least twice as
      common in non-African patients, whereas iron overload was noted almost
      exclusively in African patients livers. Signs of HBV infection were lowest in
      Japanese female patients. The mechanism by which early HBV infection contributes
      to hepatocarcinogenesis at an early stage of life is confirmed by epidemiological
      observations in Poland and by the clear association of p53 gene with HBsAg and
      the age of patients.

PMID- 8669854
TI  - Tumor-associated trypsin inhibitor (TATI) and cancer antigen 125 (CA125) in
      patients with epithelial ovarian cancer.
AB  - In 180 patients with epithelial ovarian cancer and 214 women with benign pelvic
      pathologies, serum levels of TATI (cut-off point 21 ng ml-1) and CA 125 (cut-off
      point 35 U ml-1) were determined. Data were correlated with tumour stage,
      histological type and tumour grade. Overall, when used as a single marker, TATI
      showed a sensitivity of 63% and a specificity of 72%, whereas the sensitivity and
      specificity of CA 125 > 35 U ml-1 were 80% and 82% respectively. A combination of
      the two markers increased the sensitivity to 91% (TATI > 21 ng ml-1 or CA 125 >
      35 U ml-1), whereas the specificity decreased to 65%. TATI was clearly superior
      in diagnosing mucinous carinomata of the ovaries; the rate of true positive
      findings was 64% versus 50% for CA 125. Unlike CA 125, TATI levels correlated
      well with tumour grade. In conclusion, CA 125 remains the single tumour marker of
      choice in the diagnosis of malignant epithelial ovarian cancer, while TATI
      appears to be a valuable complementory marker with a higher sensitivity in cases
      of poorly differentiated and mucinous carcinomata.

PMID- 8669855
TI  - Multivariate analysis of six serum tumor markers (CEA, CA 50, CA 242, TPA, TPS,
      TATI) and conventional laboratory tests in the diagnosis of
      hepatopancreatobiliary malignancy.
AB  - A prospective study of 277 patients with benign (n = 212) and malignant (n = 65)
      hepatopancreatobiliary disease was carried out to evaluate the value of six serum
      tumour markers (CEA, CA 50, CA 242, TPA, TPS, TATI) and 16 conventional
      laboratory tests in the distinction between benign and malignant diseases. In
      univariate analysis, all tumour marker tests except TATI showed significantly (p
      < 0.001) higher serum values in the patients with malignant disease than in the
      patients with benign disease. Among the conventional laboratory tests serum
      bilirubin, alkaline phosphatase and leucine aminopeptidase showed significantly.
      (p < 0.001) higher values in the patients with malignant disease, whereas serum
      protein and amylase levels were significantly (p < 0.01) higher in the patients
      with benign disease. In a multivariate analysis, serum bilirubin (p < 0.001),
      antithrombin III (p < 0.01) and blood hemoglobin (p < 0.05) were the most
      significant independent predictors of hepatopancreatobiliary malignancy. To sum
      up the contributions of the best tests a diagnostic score (DS) was developed. The
      sensitivity of DS in detecting malignancy was 73% with a specificity of 82% and
      an efficiency of 79%. In conclusion, our results speak against the use of
      multiple tumour marker tests, and rather suggest the use of a relatively limited
      amount of conventional laboratory tests in the distinction between benign and
      malignant hepatopancreatobiliary disease.

PMID- 8669856
TI  - A novel tree-structured analysis for non-invasive diagnosis of gastric
      adenocarcinoma.
AB  - Non-invasive diagnosis of gastric adenocarcinoma (GAC) is usually difficult due
      to the low sensitivity and specificity of serologic markers,including pepsinogens
      and gastrin. For the improvement of the diagnostic values of these markers, a
      "recursive partitioning and amalgamation" algorithm was employed to construct a
      decision protocol. A total of 636 subjects including 161 healthy subjects, 163
      patients with GAC, 196 with gastric ulcer and 116 with duodenal ulcer were
      enrolled. Serum levels of gastrin, pepsinogen I, pepsinogen II, and the ratio of
      pepsinogen I / pepsinogen II were determined for each of the subjects. The
      proposed "decision tree" classifies subjects into five subgroups with different
      risks of GAC and peptic ulcer, based on the information of age, serum pepsinogen
      and gastrin levels. Using this novel analysis system, an expected probability of
      GAC or ulcers could be obtained. Patients with an age > 62 years and a serum
      level of pepsinogen I < or = 33 ng/ml were strongly indicated for further
      confirmatory tests of GAC. This treestructured analysis is also helpful in
      clarifying the interactions between various serologic markers and demographic
      factors.

PMID- 8669857
TI  - Geographic variation of breast cancer in Taiwan: international and migrant
      comparison.
AB  - BACKGROUND: Breast cancer is increasing rapidly in Taiwan. A geographic
      variation, international comparison and migrant study has become essential for
      the development of hypotheses to account for this. MATERIALS AND METHODS: Age
      adjusted mortality rates of breast cancer patients from all precincts and
      townships of Taiwan were calculated for a geographic variation study, and
      summarized for an international comparison. Age-specific and adjusted incidence
      rates of breast cancer in Taipei City were used for a migrant study. RESULTS: Age
      adjusted mortality from breast cancer was highest in the Taipei and lowest in
      aboriginal areas. Oriental countries have significantly lower mortality rates
      from breast cancer but the incidence of breast cancer among Chinese women, and
      the difference between younger and older age groups has increased together with
      the degree of westernization in residential areas. Chinese women were found to
      have lower incidence rates than white women of the same area. We concluded that
      diet, reproductive behavior, and hereditary factors are involved in the
      development of breast cancer.

PMID- 8669858
TI  - Extragonadal germ cell tumor: a clinical study.
AB  - Among 18 patients with primary extragonadal germ cell tumors (8 seminoma and 10
      non- seminoma), the disease involved the mediastinum (7), the retroperitoneum
      (8), multiple lymph nodal sites (2) and the pinealis gland (1). Seventeen
      patients received cisplatin-based chemotherapy as part of the initial treatment.
      Fifteen patients (83%) achieved complete remission (6 seminoma and 9 non
      seminoma): 12 of them are relapse-free after a median follow-up of 82 months
      (range 13-138). Five-year overall survival was 65%. No statistically significant
      survival difference was found between mediastinal and retroperitoneal tumors or
      patients with seminoma and nonseminoma.

PMID- 8669859
TI  - Heterogeneity in proliferation markers in colorectal cancer.
AB  - BACKGROUND: The intratumoral heterogeneity in different markers of proliferation,
      and the immunohistochemical overexpression of the p53 protein-a possible
      regulator of proliferation-have been investigated to only a minor extent in
      colorectal cancer. The evaluation of tumour biopsy samples, especially
      preoperatively, when multiple sampling is not always feasible, must be based upon
      markers being more or less homogeneously expressed. MATERIALS AND METHODS: Three
      different DNA-labelling techniques were investigated in multiple biopsy samples
      (2-10, median 4) from 19 tumours obtained from 18 patients. Anti
      bromodeoxyuridine and Ki-67 monoclonal antibodies were used to detect nuclei of
      proliferating cells in adjacent tumour sections. Adjacent tumour material was
      analysed by flow cytometry of propidium iodide labelled nuclei. In addition,
      overexpression of the p53 protein was detected using the monoclonal anti-p53
      antibody DO-7 RESULTS: There was considerable intratumoral heterogeneity in the
      labelling indices. No correlation was found between overexpression of the p53
      protein and markers for proliferation, as indicated by observations made using
      three different methods. In contrast, the staining for p53 protein was either
      homogeneously positive or negative. CONCLUSIONS: The results indicate that
      analyses of proliferation in preoperatively obtained tumour biopsies are of
      limited value for prognostic prediction, or other purposes, in view of the
      extensive intratumoral heterogeneity shown with three different markers.

PMID- 8669860
TI  - Serum proteinase activities in head and neck squamous cell carcinoma patients.
AB  - Proteinases are known to be involved in carcinogenesis, and various substrates
      are now available to measure the activity of these enzymes. No suitable serum
      tumour marker for head and neck squamous cell carcinoma (HNSCC) exists at this
      moment. Therefore, we compared proteinase-activity in serum of 20 untreated HNSCC
      patients with that of 20 non-cancer individuals. When N-benzoyl-DL-arginine-beta
      naphtylamide (BANA) was used as the substrate, proteinase-activity seemed higher
      among patients, but this difference disappeared after adjustment for alcohol and
      tobacco consumption. Applying N-a-benzoyloxycarbonyl-L-arginyl-L-arginine-7-amido
      4-methylcou marine (ZAAM) as the substrate no difference was found. Addition of E
      64, an inhibitor of cysteine proteinase showed that cathepsin B contributed
      minimally to the ZAAM-specific activity.

PMID- 8669861
TI  - CD-44 is not involved in the metastatic spread of ovarian cancer in vivo.
AB  - It has been shown that isoforms of the adhesion molecule CD44 are involved in the
      metastatic spread of several human malignancies. To determine whether CD44 plays
      a role in metastasis of human ovarian cancer, the tumours and corresponding
      metastases of 28 patients were investigated. CD44 was detected by
      immunohistochemistry in 2 primary tumours (7.1%) and 3 metastases (10.7%). In no
      case did both the primary tumour and metastasis show CD44 expression
      simultaneously. The results presented here suggest that CD44 does not play a
      crucial role in the metastatic spread of human ovarian cancer.

PMID- 8669862
TI  - Effect of keyhole limpet hemocyanin (KLH) and bacillus Calmette-Guerin (BCG)
      instillation on carcinoma in situ of the urinary bladder.
AB  - Patients with histologically verified carcinoma in situ (CIS) of the urinary
      bladder (13 primary and 8 secondary CIS) were treated with intravesical
      instillations of Keyhole Limpet Hemocyanin (KLH) (20 mg KLH weekly for 6 weeks,
      then monthly for 1 year or bimonthly for 2 subsequent years. Patients, non
      responding to 2 courses of KLH were then treated with regular Bacillus Calmette
      Guerin instillations (120 mg BCG-Connaught strain). The follow-up period ranged
      from 10 to 54 months (mean 23.5 months). 7 patients (33%) were free of tumor
      after the first therapeutical KLH course and 4 patients (19%) presented a
      complete-remission after the second KLH course (total primary response: 52%). 5
      patients (24%) remained free of tumor during the established follow-up period
      (mean 31.7 months) and no evidence of further tumor progression occurred in
      patients after two courses of KLH treatment. However, 2 patients (9.5%) had to be
      cystectomized after KLH instillations because of progressive disease or tumor
      recurrence. 8 patients (38%) had to be radically cystectomized because of CIS
      persistence or progression after KLH and subsequent BCG treatment. Altogether 9
      patients (42.8%) presented long-term remissions, with a mean duration of 31.3
      months. Instillations of KLH did not induce major side effects; however,
      instillations of BCG caused severe dysuria in 60% and fever in 40% of patients.

PMID- 8669863
TI  - Elevation of serum type IV collagen in liver cancer as well as liver cirrhosis.
AB  - Studies on the level of serum type IV collagen (IV C) have usually been focused
      on the disease with diffuse hepatic fibrosis. To investigate whether serum level
      of IV C was predictive for the development of liver cancer as well as liver
      cirrhosis, serum IV C level was measured by a one-step sandwich enzyme
      immunoassay. The mean level of serum IV C was 73.3 +/- 31.3 ng/ml in 48 controls.
      The levels (ng/ml) of IV C were 396.4 +/- 254.9, 429.6 +/- 320.7, 420.6 +/-
      322.8, and 362.9 +/- 247.4 respectively in 11 patients with chronic hepatitis, 11
      with liver cirrhosis, 16 with hepatocellular carcinoma (HCC) with cirrhosis, 10
      with HCC without cirrhosis, and 10 with metasatic liver cancer, which were
      significantly higher than that in controls (p < 0.05). Serum IV C levels were
      also evaluated using a cut-off value which was determined as the mean plus two
      standard deviations in the controls, 136 ng/ml. The elevations above the cut-off
      value were observed in 91, 100, 80, and 90% respectively of 11 patients with
      cirrhosis, 16 with HCC with cirrhosis, 10 with HCC without cirrhosis, and 10 with
      metastatic liver cancer, while only one (9%) of 11 chronic hepatitis patients and
      none (0%) of 48 controls had elevated levels. The levels of serum IV C were
      analysed with regard to age, sex, serum levels of albumin, globulin,
      transaminases, alpha-fetoprotein, and diameter of liver mass, a significant
      difference being observed only between the diameter of HCC and serum level of IV
      C (p < 0.01). These results indicate that the measurement of serum IV C is a
      useful for the determination of primary and metastatic liver cancer as well as
      liver cirrhosis.

PMID- 8669864
TI  - The clinical impact of FEM regimen (5-fluorouracil, 4-epidoxorubicin and
      mitomycin-C) in advanced gastric cancer patients.
AB  - The activity of FEM regimen in metastatic gastric cancer patients was assessed in
      seventy-seven patients receiving, as palliative treatment, 5FU 600 mg/m2 i.v. on
      days 1, 8, 29, 36; epiADR 70 mg/m2 i.v. on days 1, 29; MIT-C 10 mg/m2 i.v. on
      days 1, 29. Cycles were repeated every 58 days. One patient achieved a complete
      response and 12 a partial response, resulting in an overall response rate of 16%
      (95% CI: 8% to 24%). Median remission duration was 6 months. Median survival time
      for all patients was 8 months. Side-effects were mild and principally in the form
      of leukopenia (three episodes grade III). Our results support the recent findings
      about the lack of effectiveness of this regimen. Although it is a safe and well
      tolerable chemotherapeutic combination, FEM regimen should not be recommended as
      routinary treatment for gastric cancer patients who are not eligible for clinical
      trials.

PMID- 8669865
TI  - Extraskeletal osteosarcoma of the mediastinum associated with long-term patient
      survival. A case report.
AB  - The authors report a case of mediastinal extraskeletal osteosarcoma showing
      immunohistochemical and ultrastructural features of epithelial differentiation
      and associated with a long-term patient survival. The possible role of flow
      cytometric DNA analysis in defining the prognosis of this tumor is discussed.

PMID- 8669867
TI  - Lack of expression of c-erbB-2 oncoprotein in human esophageal squamous cell
      carcinomas.
AB  - Fifty-one cases of esophageal squamous cell carcinoma were immunohistochemically
      investigated with monoclonal c-erbB 2 oncoprotein antibody. No tumor showed
      plasma membrane immunostaining for c-erbB-2 protein. Occasionally, unspecific
      cytoplasmic staining was found in minor tumor cell populations. The present
      results show that c-erbB-2 oncoprotein is not overexpressed in esophageal
      squamous cell carcinomas and does not play a central role in the tumorigenesis.

PMID- 8669866
TI  - Expression of the CD44 glycoprotein (lymphocyte-homing receptor) in untreated
      human breast cancer and its relationship to prognostic markers.
AB  - CD44 is a cell surface glycoprotein which has been suggested to be associated
      with aggressive histological features in breast cancer (BC). It has also been
      implicated in conferring metastatic potential to rat carcinoma cells. The aim of
      this study was to determine the potential value of CD44 as a
      prognostic/metastatic marker in BC by means of immunohistochemistry. The
      expression of the CD44 glycoprotein was investigated in tumours from 52 untreated
      female patients with BC, using the monoclonal antibody A3D8. 10 samples of normal
      breast tissue were randomly obtained and also investigated with respect to CD44
      expression. DNA ploidy, the S-phase fraction (SPF) and oestrogen-(OR) and
      progesterone-receptor (PgR) contents in the tumours were determined and together
      with the prognostic markers of age, tumour size, tumour grade and lymph node
      status, correlated with CD44 expression in BC. Also, the distribution of CD44
      tumour cell expression was compared with expression of the permeability drug
      resistance glycoprotein (P-gp) in this material. Expression of CD44 on carcinoma
      cells was observed in 21/52 cases (40%). Capillary endothelial reactivity of the
      tumours occurred in 42 cases (80%). Non-neoplastic epithelial breast tissue was
      positive in 2/10 (20%) samples and capillary vessels in 7/10 (70%). Carcinoma
      CD44 cell expression was not associated with age, tumour size, tumour grade, DNA
      ploidy, SPF, hormone-receptor contents or lymph node metastases. There was a
      statistical correlation between CD44 and P-gp expression in breast carcinoma
      cells which may suggest a connection between adhesion molecules and drug
      resistance. These findings do not support an association between CD44 expression
      and adverse prognostic features or lymph node metastases in BC. Capillary CD44
      staining was a common feature in BC. There appeared to be an upward regulation in
      CD44 expression in BC compared with the normal breast tissue.

PMID- 8669868
TI  - Tissue and serum metalloproteinase (MMP-2) expression in advanced ovarian serous
      cystoadenocarcinomas: clinical and prognostic implications.
AB  - OBJECTIVE: The object of this study was to analyse the tissue and serum
      metalloproteinase (MMP-2), an enzyme which degrades the basement membrane
      collagen type IV, as a potential marker useful in prognostic evaluation and
      clinical monitoring of the follow-up, in patients with advanced ovarian serous
      cystadenocarcinoma. MATERIALS AND METHODS: Tissue MMP-2 expression was determined
      in 21 FIGO stage III ovarian serous cystadenocarcinomas treated with primary
      surgery and adjuvant chemotherapy, and compared to 10 cystadenomas used as
      controls. Retrospective analysis of clinical data allowed the comparison of
      accepted prognostic factors to tissue MMP-2 expression for impact on disease-free
      survival. In fourteen out of 21 patients, serum MMP-2 levels were also analysed.
      RESULTS: Compared to cystadenomas, the tissue MMP-2 expression was significantly
      (P < 0.001) higher in serous cystadenocarcinomas. A significant relationship was
      observed between tissue MMP-2 and disease-free survival (P = 0.0003),
      independently of tumor architectural grade, lymph nodal status and residual
      disease after debulking surgery. Recurrence risk in patients whose carcinomas had
      a tissue MMP-2 > or = 29% was significantly higher than that in patients whose
      carcinomas demonstrated lower tissue MMP-2 expression (P = 0.004). Serum MMP-2
      levels correlated with tissue staining, and also expressed a significant
      relationship with disease-free survival (P = 0.002). CONCLUSIONS: Tissue MMP-2
      seems to be a prognostic indicator in patients with FIGO stage III ovarian serous
      cystadenocarcinoma, significantly correlated with recurrence risk and apparently
      independent of tumor architectural grade, lymph nodal status, and residual
      disease after debulking surgery. An interesting relationship was observed between
      tissue staining and MMP-2 serum levels.

PMID- 8669869
TI  - Neutrophil and monocyte phagocytic functions in patients with colorectal
      adenocarcinoma during fluorouracil therapy.
AB  - Neutrophil and monocyte phagocytic functions, i.e % of phagocytic cells,
      ingestion and intracellular microbe killing were determined in 51 patients with
      colorectal adenocarcinoma, 43 with localized disease and 8 with distant
      metastases. Phagocytic functions were determined at the time of diagnosis,
      following surgery are before each of 6 cycles of fluorouracil chemotherapy. Four
      of six phagocytic parameters determined were decreased at diagnosis while all 6
      decreased following surgery. During chemotherapy, neutrophil phagocytic activity
      recovered to normal value while all other neutrophil and monocyte functions
      remained decreased. Even so, neutrophil ingestion and monocyte phagocytic and
      bactericidal activities increased reaching from time to time values significantly
      higher than that found before the start of chemotherapy. The results showed
      significant alterations of neutrophil and monocyte phagocytosis in colorectal
      adenocarcinoma patients at the time of diagnosis, with further decrease following
      surgery. Fluorouracil chemotherapy did not exert suppressive effects on these
      functions; on the contrary, it seemed to support, or at least not to prevent,
      their partial recovery.

PMID- 8669870
TI  - Concordance between serum and cytosolic levels of CEA, CA125 and SCC antigens in
      patients with non-small cell lung cancer.
AB  - The relationship between serum and cytosolic levels of carcinoembryonic (CEA),
      squamous-cell carcinoma (SCC) and CA125 antigens was determined in 122 patients
      with non-small cell lung cancer. A pronounced serum-cytosol gradient and a high
      degree of dispersion in the distribution of serum and cytosol marker
      concentrations was detected. In addition, the degree of concordance between TM
      levels in the two compartments, determined by the intraclass correlation
      coefficient (ICC) index, was low (ICC = 0.42 for CEA; 0.35 for CA 125; and 0.27
      for SCC). Tumour stage and histological type both played a limited role in the
      serum-cytosol relationship. As tumour stage advanced, the concordance between
      serum and cytosolic TM level became more pronounced. In addition, each
      histological type showed a distinctive pattern of expression of serum and
      cytosolic tumour markers, and a specific degree of concordance between levels in
      serum and cytosol. However, the ICC indices were always under 0.51, indicating
      that the importance of these factors is minor. The data obtained indicate that
      the relationship between serum and cytosolic concentration is moderate. The
      differences found according to stage grouping and histological subtype are so
      small that no clear-cut message for clinical practice can be drawn.

PMID- 8669871
TI  - Significance of urinary tissue polypeptide specific antigen (TPS) determination
      in patients with urothelial carcinoma.
AB  - Tissue polypeptide specific antigen (TPS) is the M3 epitope of the tissue
      polypeptide antigen, and a specific epithelial proliferation marker. To examine
      the benefit of urine TPS (UTPS) measurement in the diagnosis and classification
      of biological properties of transitional cell carcinoma (TCC), a radioimmunoassay
      of U-TPS was measured in patients with active TCC (n = 56), at tumor-free status
      (n = 36), with inflammatory urological disease (n = 44), and age-sex adjusted
      normal subjects (n = 75). Both neoplastic and inflammatory urological diseases
      had an increase in U-TPS levels (U/gm creatinine) compared to normal individuals
      (p = 0.0005), while it normalized in tumor-free condition (p = 0.007). For
      patients with active TCC, a strong positive association was observed between U
      TPS values and both histological grading (p = 0.05) and positive cytology (p =
      0.05). U-TPS levels were significantly higher in the presence of nodal or
      systemic metastasis (p = 0.008 by ANOVA test). Measurement of U-TPS appeared to
      be an indicator of poor outcome for patients with bladder cancer (p = 0.05 by t
      test) for a mean follow-up of 26 months. The results indicate that determination
      of U-TPS can be a supplement in assessing the biological properties of TCC, and
      may be helpful in identifying patients who need meticulous peri-operative staging
      survey.

PMID- 8669872
TI  - Assessment of response to carboplatin in patients with hormone-refractory
      prostate cancer: a critical analysis of drug activity.
AB  - The clinical presentation of prostate-hormone refractory tumours in 90% of
      patients is characterised by sclerotic bone metastasis which is not assessable by
      classic phase II response criteria. Restriction of investigational study of new
      agents to the minority of patients, with bidimensionally measurable lesions,
      assessable by conventional WHO response criteria, has been criticised because
      such cases may represent a highly selected tumour cell population. To circumvent
      this problem, a variety of response criteria have been proposed. However,
      prostate specific antigen (PSA) levels have become an integral component, used
      singly or in combination with other markers of response evaluation. As a result,
      different response proportions could also be reported using the same single agent
      in this category of patients. This study repors a different evaluation of
      carboplatin activity by using WHO, NPCP modified criteria and PSA post-therapy
      decline as measures of carboplatin activity. It is suggested that treatment
      efficacy in this category of patients wold be more correctly measured by the
      proportion of patients who "fail treatment" after a reasonable number of therapy
      courses, rather than those achieving a conflicting definition of "objective
      response". Finally, in hormone refractory prostate cancer PSA post therapy
      declines may represent a measure of treatment efficacy and can be used as a
      surrogate end point for clinical phase II trials.

PMID- 8669873
TI  - Superficial spreading type of early gastric lymphomas.
AB  - Recent advances in diagnostic techniques have increased the apparent incidence of
      gastric lymphomas at an early stage. However, the clinical features of the
      superficial spreading type of early gastric lymphoma are not well-documented. We
      retrospectively examined the clinicopathologic features of 5 patients with the
      superficial spreading type of early gastric lymphoma. These tumours were MALTomas
      which had a characteristically difficult diagnosis and indistinct tumour margins,
      and a high incidence of lymph node involvement was found. We conclude that
      satisfactory treatment of this neoplasm requires a wide resection of the stomach
      with extensive lymph node dissection.

PMID- 8669874
TI  - Expression of epidermal growth factor receptor (EGFR) in breast cancer as related
      to clinical, prognostic and cytometric factors.
AB  - A series of 213 female breast carcinomas were analysed immunohistochemically for
      the expression of epidermal growth factor receptor (EGFR), with special emphasis
      on its possible prognostic significance. A total of 114/213 tumors (53.5%) were
      EGFR positive. EGFR was almost exclusively expressed in the cytoplasm of the
      cancer cells, but in a few cases, the cell membranes showed EGFR positive
      staining as well. EGFR expression was related to the histological grade of the
      tumours in that a linear decrease of the staining was found in parallel with the
      decreasing tumour differentation (P = 0.024). On the other hand, axillary lymph
      node status (P = 0.95), histological type (P = 0.60), tumor size (P = 0.87), DNA
      index (P = 0.56), S-phase (P = 0.80), mitotic index (P = 0.72), or estrogen (ER)
      and progesterone receptor (PR) content (P = 0.45) did not show any statistical
      correlation with the EGFR expression. EGFR positivity as an independent factor,
      had little (if any) effect on the patients prognosis. Tumor size (P = 0.004),
      axillary lymph node involvement (P = 0.024) and PR positivity (P = 0.008) were
      the single most significant prognostic factors in multivariate survival analysis.
      The results indicate that, in clinical breast cancer, immunohistochemical
      assessment of EGFR provides no prognostic information additional to the well
      established prognostic factors.

PMID- 8669875
TI  - Chronomodulated infusion of 5-fluorouracil, folinic acid and carboplatin in
      colorectal cancer: a pilot study.
AB  - We investigated if chronomodulated infusion of fluorouracil, folinic acid in
      combination with carboplatin shows antitumor efficacy in patients advanced
      metastatic colorectal cancer. Thirteen patients entered into the study. Each
      treatment cycle consisted of a 5 day course of continuous venous infusion of 5
      fluorouracil (5-FU; 500 mg/m2/die), folinic acid (FA; L-form, 150 mg/m2/die) and
      carboplatin (CBDCA; the dose being calculated according to the Calvert's
      formula). Patients received the drugs according to the circadian-modified
      infusion schedule with a sinusoidally modulated delivery with peak flow rate at
      4.00 AM for 5-FU and FA and 4.00 PM for CBDCA. Overall a total number of 54
      cycles were administered. Two partial responses and one minor response were
      observed among the 5 untreated patients. Five patients had progression of
      disease. Stabilization of previously progressive disease was obtained in the 5
      remaining patients. These preliminary results show that the combination of 5-FU,
      FA and CBCDA infused at circadian-modulated rate has moderate activity in
      colorectal cancer, specially in previously untreated patients, with a mild and
      acceptable toxicity.

PMID- 8669876
TI  - The application of fibrin glue after axillary lymphadenectomy in the surgical
      treatment of human breast cancer.
AB  - Experimental studies point out that a reduction of lymph flow can be obtained by
      the local application of fibrin glue following axillary lymphadenectomy in the
      surgical treatment of breast cancer. In a prospective study the influence of
      human fibrin glue on postoperative axillary lymph secretion and the period of
      drainage of the wound cavity were evaluated. In 40 patients, 5 ml of fibrin glue
      (Tissucol) was applied to the wound cavity by the use of a spray applicator
      (Tissumat) immediately after axillary dissection of the lymph nodes. For drainage
      of the wound area Redon suction-drains were used. The daily amount of
      postoperative lymph secretion was measured and drains were removed at a lymph
      secretion of less than 20 ml. 40 patients who underwent surgery and axillary
      lymphadenectomy without subsequent application of fibrin glue sourced as control
      group. No significant difference concerning the total amount of lymph secretion,
      the mean period of drainage or the incidence of lymphatic cysts was observed. In
      our study, the expected occlusion of the wound cavity by the application of
      fibrin glue after axillary lymphadenectomy did not lead to any advantage when
      compared with the control group.

PMID- 8669877
TI  - Immunohistochemical detection of ras p21 oncoprotein in undifferentiated and well
      differentiated epithelial carcinomas of the human ovary.
AB  - Expression of ras p21 oncoproteins in human ovarian carcinomas was examined
      immunohistochemically by using a monoclonal antibody(clone RAS 10) with respect
      to the degree of their histological differentiation. To achieve this, the
      intensity of staining for the protein was compared between undifferentiated and
      well differentiated carcinomas, i.e. extreme subtypes of common epithelial
      carcinomas. The former was composed of 8 "solid" carcinomas and the latter, 11
      serous, 8 mucinous, 4 endometrioid and 4 clear cell carcinomas. All the cases
      examined, including both undifferentiated and well-differentiated carcinomas,
      showed a positive reaction to this antibody. Staining intensity and the number of
      positive cells somewhat varied among the cases. Additionally, 2 cases of ovarian
      epithelial tumors of low malignant potential (I,MP) were stained with this
      antibody. Both the cases were positive, but the number of positive cells seemed
      to be rather less than that found in the carcinoma groups. Thus, no differences
      in ras p21 expression were observed between the cases examined in spite of the
      differences in the degree of differentiation of the epithelial ovarian
      carcinomas. However, the possibility remained that the number of positive cells
      could be an indicator of malignant potential, enabling us to distinguish LMPs
      from carcinomas.

PMID- 8669879
TI  - Serum and tissue distribution of a fragment of cytokeratin 19 (cyfra 21-1) in
      lung cancer patients.
AB  - A sensitive and relatively specific tumoral marker for lung epidermoid carcinomas
      could be used to identify patients likely to benefit from new therapeutic
      protocols. The cyfra 21-1 fragment of cytokeratin 19 has raised much hope in this
      regard amongst both technologists and clinicians. In a study of 195 subjects, we
      have shown by means of a serum assay that the usual cut-off value for this marker
      (3.3 ng/ml) can be lowered to 1.5 ng/ml without loss of specificity, and with an
      increase in sensitivity. There was a good correlation between serum marker level
      and tumor extension, but though cyfra 21-1 was not predictive of the suitability
      of a patient for surgery. A decrease of cyfra-21-1 was observed after complete
      resection of the tumor. There was no relation between serum assay results and
      immunohistochemical findings.

PMID- 8669878
TI  - The additive effect of peripheral blood stem cells, harvested with low-dose
      cyclophosphamide, to autologous bone marrow reinfusion on hematopoietic
      reconstitution after ablative chemotherapy in breast cancer patients with
      localized disease.
AB  - The additive effect of peripheral blood stem cells (PBSCs) to autologous bone
      marrow transplantation (ABMT) on haematopoietic reconstitution, after ablative
      chemotherapy in patients with locally advanced breast cancer, was evaluated.
      Patients were treated with induction chemotherapy, followed by ablative
      chemotherapy consisting of mitoxantrone and thiotepa. Group I (n = 14) received
      ABMT and granulocyte macrophage-colony stimulating factor (GM-CSF), group II (n =
      11) received ABMT, PBSCs and granulocyte-colony stimulating factor (G- CSF).
      PBSCs were harvested after a low-dose cyclophosphamide (750 mg/m2), followed by G
      CSF. Stem cell harvest was routinely started 12 days after cyclophosphamide.
      Compared to group I, group II showed a significant reduction in the median number
      of days for leukocytes < 0.5 x 10(9)/L 4.5 days, leukocytes < 1.0 x 10(9) / l 5.5
      days, platelets < 20 x 10(9)/ l 9 days and platelets < 40 x 10(9) / l 12.5 days.
      The median number of transfusions of platelets fell from 11.5 to 7 and of red
      blood cells from 8.5 to 6. The median hospitalisation duration declined from 40.5
      to 30 days, fever above 38 degrees C with 7.5 days, fever above 38.5 degrees C
      with 4 days and antibiotic treatment with 8.5 days in group I versus group II.
      Improvement of haematological recovery, duration of fever and hospitalisation was
      observed by the addition of PBSCs, obtained after a relatively low-dose
      cyclophosphamide and G-CSF and stem cell pheresis on fixed days, to autologous
      bone marrow and growth factor in the period after ablative chemotherapy.

PMID- 8669880
TI  - Interferon response depends on viral transcription in human papillomavirus
      containing lesions.
AB  - Human papillomaviruses (HPVs) express various proteins which have been proven to
      interact with some cellular functions playing a role in cell cycle progression
      and differentiation. Therefore, these viral gene products might be candidates for
      interfering with IFN-mediated antiproliferative actions. Condyloma biopsies from
      patients subsequently demonstrated to be responsive or non-responsive to IFN
      treatment were investigated. mRNA levels of HPV genes and IFN-responsive genes
      were determined by RT-PCR and correlated with IFN responsiveness. Patients
      clinically nonresponsive to IFN demonstrated a characteristic HPV transcriptional
      activity differing from responder patients. Nonresponders expressed mostly early
      E7 mRNAs; responders demonstrated higher expression of the late L1 gene. This
      differential transcription of infecting HPV also correlated with the extent of
      IFN mediated antiproliferative effect. A hypothesis for further study is that HPV
      E7 may inhibit IFN responsiveness, while HPV L1 may promote IFN responsiveness.

PMID- 8669882
TI  - Benign fibrous mesothelioma: report of a case.
AB  - A case of fibrous benign mesothelioma is reported, together with some
      considerations on the diagnosis and the treatment of this rare tumour.
      Preoperative diagnosis is often impossible and so surgery is of great value both
      for treatment and diagnosis.

PMID- 8669881
TI  - Biochemical picture of bone metabolism in breast cancer patients with bone
      metastases.
AB  - A panel of bone turn-over markers was assessed in 75 normocalcemic patients
      bearing bone metastases from breast cancer (BC), and in 25 advanced/metastatic BC
      patients without clinical appearance of bone involvement. 115 healthy women,
      stratified in three subgroups according to age served as controls. Bone formation
      was investigated by measuring serum carboxyterminal propeptide of type I
      procollagen (PICP), Bone Gla Protein (BGP, osteocalcin), bone isoenzyme of
      alkaline phosphatase (BALP); bone resorption by measuring serum carboxyterminal
      telopeptide of type I collagen (ICTP), fasting urinary hydroxyproline/creatinine
      (OHPro/Cr) and calcium/creatinine (Ca/Cr). In patients with bone metastases the
      percent of supranormal values (higher than mean plus 2 SD of the age-matched
      controls) ranged between 25% and 40% for indices of bone formation, about 73% for
      both ICTP and OHPro/Cr and about 30% for Ca/Cr. The median levels of all bone
      turn-over markers were higher in bone metastatic patients than in those without
      apparent skeletal involvement, but significance was attained only for OHPro/Cr,
      Ca/Cr and BALP. Supranormal levels of ICTP and OHPro/Cr were also found in about
      65-70% of patients without apparent skeletal involvement. ICTP and Ca/Cr
      significantly correlated with bone pain score, BALP, ICTP, Ca/Cr significantly
      correlated with the number of tumour appearances in bone. In conclusion, the bone
      resorption indices, ICTP and OHPro/Cr, are much more frequently elevated than
      bone formation indices in BC patients with or without skeletal involvement. Their
      potential use in the early detection of bone metastases is hampered by the
      insufficient knowledge on specificity. Among the biochemical markers evaluated,
      Ca/Cr, ICTP and BALP, due to correlation with clinical aspects, appear the most
      interesting for follow-up studies.

PMID- 8669883
TI  - Restorative effect of romurtide for thrombocytopenia associated with intensive
      anticancer drug treatment and/or irradiation in patients with gastrointestinal
      cancer.
AB  - In 55 gastrointestinal cancer patients the mean change ratios for platelets were,
      respectively, 1.22 +/- 0.75 and 0.67 +/- 0.45, in the romurtide administration
      (30 cases) and non-administration (25 cases) groups, [statistically significant
      difference (p < 0.005)]. The number of cases in each group with a decrease in
      platelet count was 13 (43%) and 20 (80%) with and without romurtide,
      respectively. The difference was statistically significant, (p < 0.01). In
      addition, the number of cases with a marked decrease ( < 6 x 10(4)/mm3) in
      platelet count was 2 (7%) and 7 (28%) with and without romurtide, respectively,
      reaching statistical significance (p < 0.05). For patients treated with a bolus
      administration of 450 mg/m2 carboplatin (27 cases), the mean change ratios for
      leukocytes and platelets in the romurtide administration group (13 cases) were
      1.10 +/- 0.52 and 1.23 +/- 0.59, respectively. Meanwhile, in the romurtide non
      administration group the mean change ratios for leukocytes and platelets were,
      respectively, 0.74 +/- 0.27 and 0.74 +/- 0.42, a statistically significant
      reduction (p < 0.05) compared with the romurtide administration group. The number
      of cases with an increase in the number of lymphocytes after i.v. administration
      was significantly more than that observed after s.c. administration (p < 0.01).
      These results indicate that romurtide has a restorative effect on
      thrombocytopenia similar to that displayed for leukocytopenia when given as
      concomitant therapy with anticancer drugs and/or irradiation in patients
      undergoing intensive treatment for gastrointestinal cancer.

PMID- 8669884
TI  - Expression of growth factors and their receptors in human early colorectal
      carcinomas: immunohistochemical study.
AB  - Human colorectal carcinomas have been demonstrated to express a variety of growth
      factors and their cognate receptors, forming multi-autocrine, juxtacrine and/or
      paracrine loops. Little information, however, is available on their expression in
      early colorectal carcinomas in which two genetic pathways exist, i.e. adenoma
      carcinoma sequence and de novo carcinoma. This study was conducted in a total of
      68 early colorectal carcinomas invading the submucosa, which were subdivided into
      two categories by the presence of adenomatous components, namely (a) 38
      carcinomas with an adenomatous component and (b) 30 carcinoma without an
      adenomatous component. The tumous were also classified as polypoid, flat elevated
      and flat depressed type. Formalin-fixed, paraffinembedded specimens were
      immunostained for epidermal growth factor (EGF), transforming growth factor
      alpha(TGFalpha), cripto, EGF-receptor(EGFR) and c-ERBB2 gene product. Of the 68
      early colorectal carcinomas, EGF, TGF-alpha, cripto, EGFR and c-ERBB2 products
      were detected at various degrees 24(35%), 50(74%), 31(46%), 11(16%), and 34(50%),
      respectively. The expression was compared between 35 polypoid carcinomas with an
      adenoma component (suitable for adenoma-carcinoma sequence), 14 flat carcinomas
      without an adenoma component (possible de novo carcinomas). A significantly
      higher incidence (P < 0.05) of expression of the following was noted; TGF-alpha
      in the polypoid carcinomas with an adenoma component, and EGF and c-ERBB2 gene
      product in the carcinomas without an adenoma component. There was no significant
      difference in the incidence of cripto and EGFR, implying common events between
      two categories. These results indicate that two pathways exist in tumourigenesis,
      in which the growth factors and their receptors are expressed in different
      manners. TGF-alpha might play a crucial role in carcinomas arising from adenoma,
      while EGF and c-ERBB2 gene products are strongly indicative of de novo
      carcinomas.

PMID- 8669885
TI  - GLUT1 expression in human breast carcinoma: correlation with known prognostic
      markers.
AB  - BACKGROUND: Breast cancers have been shown to have increased glucose uptake and
      utilization, and to express the facilitative glucose transporter Glut1. The aim
      of this study was to determine the biological significance of Glut1 expression in
      breast cancer. METHODS: Paraffin sections of 118 breast cancers were
      immunostained with antibody to Glut1. The percent of Glut1-positive cancer cells
      in each tumor was correlated with known prognostic markers, and with patient
      outcome. RESULTS: Glut1 was expressed in 42% of the tumors. Glut1
      immunoreactivity correlated positively with the proliferative activity as
      determined by Ki-67 immunostaining, and with the total histologic score, and
      showed negative correlation with bcl-2 immunostaining. There was no correlation
      between the percent of Glut1-immunoreactive cancer cells and estrogen receptor
      status, tumor size, or lymph node status. CONCLUSIONS: 1) Glut1 expression is
      increased in breast cancers with higher grade and proliferative activity, and 2)
      glucose transport in the majority of breast cancers may be mediated by a glucose
      transporters other than Glut1.

PMID- 8669886
TI  - N-myc protein expression in human breast carcinoma: prognostic implications.
AB  - The overexpression of N-myc gene and its protein products has been thought to be
      limited to cases of neuroblastoma, retinoblastoma and small cell lung carcinoma,
      but there is increasing evidence of its wider distribution in human tumors. This
      study showed that the protein of N-myc gene is associated in normal, benign and
      malignant human breast tissues. We found that N-myc oncoprotein is overexpressed
      in most breast carcinomas and that N-myc overexpression is significantly
      correlated with clinical stage, and histological grading of the tumors, and, more
      importantly with the clinical outcome of the patients. Analysis of DNA, mRNA and
      protein levels suggested that the high N-myc expression in breast cancer occurs
      without concomitant gene amplification. The finding of a direct inverse
      correlation between N-myc overexpression and the prognosis of patients with
      breast carcinoma suggests that N-myc expression may be useful as a prognostic
      factor in human breast cancer.

PMID- 8669888
TI  - Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and
      clinical efficacy.
AB  - Oral administration of the prodrug valacyclovir results in enhanced
      bioavailability and significantly greater plasma concentrations of acyclovir than
      can be achieved with oral doses of acyclovir itself. The results of clinical
      trials with valacyclovir have demonstrated significant benefits in the resolution
      of pain associated with herpes zoster infection. Efficacy parameters were similar
      for valacyclovir and acyclovir in the treatment of herpes simplex; however the
      results were achieved with lower and less-frequent doses of valacyclovir. The
      cost of a course of therapy with valacyclovir is expected to be similar to that
      of other antivirals. The potential clinical benefits of valacyclovir will likely
      be apparent in the case of acyclovir-resistant herpesvirus infections, where high
      dose intravenous treatment with acyclovir has been necessary. Most of these
      resistant viruses have been encountered in immunocompromised patients, and the
      resistance has been attributed to inadequate exposure to the drug. Because
      optimal levels of acyclovir are achieved with a simpler dosing regimen of
      valacyclovir, compliance may be improved in many patients, thus reducing the
      incidence of resistant virus.

PMID- 8669889
TI  - Hydrocephalus induction in mice infected with herpes simplex virus type 2 after
      antiviral treatment.
AB  - By using antiviral chemotherapy to moderate the lethal effect of wild-type herpes
      simplex virus type 2 (HSV-2), a new mouse model for herpes simplex virus (HSV)
      induced hydrocephalus was developed. Groups of BALB/c mice were infected either
      intracerebrally (i.c.) or intraperitoneally (i.p.) with a lethal dose of HSV-2.
      The antiviral agent 2'-fluoro-5-methylarabinosyluracil (FMAU) was administered
      i.p. 2 days after virus inoculation. By day 21, 80 and 71.4% of the mice infected
      i.c. or i.p., respectively, survived. The surviving animals were randomly
      subdivided into different groups and some were challenged i.c. or i.p. with a
      lethal or superlethal dose of homologous virus. The mice were sacrificed at 2 or
      3 months after the initial virus infection. Neuropathological changes of the
      brains were assessed. Dilation of lateral and third ventricles was noted in the
      animals initially inoculated i.c., especially in all the animals inoculated i.c.
      and challenged i.c. with a superlethal virus inoculum, but not in those
      inoculated i.p. Microscopic examination of hydrocephalic brains revealed evidence
      of viral meningoencephalitis. Two different mechanisms of ventricular enlargement
      in this animal model are proposed. This model is relevant since HSV-induced cases
      of hydrocephalus have been reported to occur in humans and in particular
      neonates. Issues of virus persistence and expression, long-term evaluation for
      disease progression, and intervention strategies could be examined with this
      model.

PMID- 8669887
TI  - Immunochemotherapies versus chemotherapy as adjuvant treatment after curative
      resection of operable breast cancer.
AB  - In our previous study, oral adjuvant combination chemotherapy of 5-fluorouracil,
      cyclophosphamide, mitomycin C, and predonisolone (FEMP) after curative resection
      of operable breast cancer with vascular invasion in the tumor and/or in the
      metastatic lymph node was found to be more effective than one course of mitomycin
      C or cyclic course of mitomycin C. In the present study, we have assessed the
      efficacy of protein-bound polysaccharide (PSK) or levamisole (LMS) in addition to
      FEMP. Between January 1980 and December 1990, 227 operable breast cancer patients
      with vascular invasion in the tumor and/or in the metastatic lymph node were
      randomized into FEMP, FEMP + LMS, or FEMP + PSK. The risk ratio was lower in the
      FEMP + PSK group compared to the FEMP group. In disease-free survival or overall
      survival, there was no significant difference between the three groups, however,
      the survival curve of the FEMP + PSK group tended to be better than that of the
      FEMP group(logrank, P = 0.0706; generalized Wilcoxon, P = 0.0739). Side effects
      were observed at a low incidence, but they were mild and tolerable.
      Immunochemotherapy using PSK improved the prognosis of patients with operable
      breast cancer with vascular invasion.

PMID- 8669890
TI  - Evidence that the amino acid region 124-203 of glycoprotein G from the
      respiratory syncytial virus (RSV) constitutes a major part of the polypeptide
      domain that is involved in the protection against RSV infection.
AB  - The first 230 residues of the 298-amino acid glycoprotein G of respiratory
      syncytial virus (RSV) are sufficient to confer complete resistance to challenge
      with live RSV, whereas the first 180 residues completely failed (Olmsted et al.
      (1989) J. Virol. 63, 411-420). The characterization of a protective epitope
      corresponding to the amino acid region 174-187 of the G protein (Trudel et al.
      (1991) Virology 185, 749-757) suggests that interruption of this region in the
      180 residue truncated polypeptide may be responsible for its inability to confer
      protection and consequently that the 174-187 region may play a major role in the
      protection effected by the protein G. To support these hypotheses, we examined
      the ability of the amino acid region 124-203 of glycoprotein G to confer
      protection. The corresponding peptide was expressed as a non-fusion protein in a
      recombinant vaccinia virus designated VG27. Immunization of BALB/c mice with this
      recombinant efficiently induced the production of antibodies capable of
      recognizing both the parental glycoprotein G and peptide 174-187. Furthermore,
      upon challenge with RSV, a significant decrease of infectious particles was found
      in the lungs of mice immunized with VG27 as compared with non-immunized mice. Our
      results suggest that the 124-203 amino acid region of the RSV G protein
      constitutes a major part of the domain involved in protection.

PMID- 8669891
TI  - Anti-human cytomegalovirus activity and toxicity of sulfonated anthraquinones and
      anthraquinone derivatives.
AB  - Sulfonated anthraquinones and other anthraquinone derivatives were evaluated for
      anti-human cytomegalovirus (HCMV) activity, cytotoxicity and genotoxicity. Acid
      blues 40 and 129, acid black 48, alizarin violet R and reactive blue 2 were the
      most active compounds having selective indices of greater than 30 and EC50 values
      of 4-30 microM. When tested against a clinical isolate, the 4 compounds were 2-
      to 5-fold less active. The antiviral activity was distinctly separate from the
      virucidal activity (> 1000 microM). The compounds were weakly toxic to either log
      phase or stationary cells in most of the following cytotoxicity assays: neutral
      red uptake assay, lactic acid dehydrogenase assay, trypan blue exclusion assay
      and radiolabeled macromolecular precursor uptake assays. Using a genotoxicity
      assay, the comet assay, only reactive blue 2 and acid black 48 were found to
      cause DNA strand breakage. This occurred at concentrations of 30 and 170 microM,
      respectively. These results suggest that these compounds could be a prototype for
      synthesizing even more effective HCMV-inhibitory anthraquinone derivatives.

PMID- 8669892
TI  - Inhibition of human immunodeficiency virus type 1 wild-type and mutant reverse
      transcriptases by the phenyl ethyl thiazolyl thiourea derivatives trovirdine and
      MSC-127.
AB  - A new class of very potent and selective non-nucleoside inhibitors of HIV reverse
      transcriptase (RT) has recently been identified. The prototype compound
      trovirdine (LY 300046 HCl) and one analogue, MSC-127, have been studied with
      respect to inhibition of wild-type HIV-1 RT and RT with various mutations known
      to give rise to resistance to other non-nucleoside RT inhibitors, namely Leu100-
      >Ile (Ile100), Glu138-->Arg (Arg138), Tyr181-->Cys (Cys181) and Tyr188-->His
      (His188). The inhibition of HIV-1 RT by trovirdine and MSC-127 was reversible and
      template dependent. Trovirdine inhibited HIV-1 RT with an IC50 of 0.007 microM
      when employing heteropolymeric primer/template (oligo-DNA/ribosomal RNA) and dGTP
      as substrate. Enzyme kinetic studies showed that inhibition of RT by trovirdine
      was non-competitive with regard to deoxynucleoside triphosphates and
      uncompetitive with respect to varied primer/template under steady-state
      conditions. The amino acid changes Leu100, Tyr181 and Tyr188 gave rise to 25-,
      147- and 12-fold decrease in inhibition by trovirdine. Enzyme-kinetic studies on
      trovirdine have been carried out using various RT mutants and compared to the
      properties of the earlier reported non-nucleoside RT inhibitors 9-Cl-TIBO,
      nevirapine and L-697,661.

PMID- 8669893
TI  - Antiviral activity of selected acyclic nucleoside analogues against human
      herpesvirus 6.
AB  - Human herpesvirus 6 (HHV-6) was examined in vitro for its sensitivity to a broad
      range of nucleoside analogues, including acyclovir (ACV), ganciclovir (GCV),
      penciclovir (PCV), buciclovir (BCV), brivudin (BVDU), the N7-isomer of 6
      deoxyganciclovir (S2242), foscarnet (phosphonoformic acid, PFA), and several
      acyclic nucleoside phosphonate (ANP) analogues such as (S)-HPMPA, (S)-HPMPC, PMEA
      and PMEDAP. Antiviral efficacy was monitored microscopically by the inhibitory
      effect of the compounds on HHV-6-induced cytopathic effect in human T
      lymphoblastoid HSB-2 cells. In addition, a newly developed
      immunofluorescence/flow cytometric assay (FACS) was used to determine HHV-6
      specific antigen expression. A close correlation was observed between the
      antiviral data obtained by the microscopic assay and the flow cytometric assay.
      Marked antiviral efficacy was noted for S2242, PFA and the ANP analogues (S)
      HPMPA, (S)-HPMPC, (S)-cHPMPC, (S)-3-deaza-HPMPA, (S)-3-deaza-cHPMPA, (S)-HPMPG
      and (R)-HPMPG. Also, PMEA and PMEDAP proved highly active against HHV-6
      infection, whereas (S)-FPMPA and (R)-PMPDAP were inactive. ACV was only slightly
      protective against HHV-6, and no activity was found for GCV, PCV, BCV and BVDU.
      Overall, the efficacy of the nucleoside analogues against HHV-6 appeared to
      correlate with their efficacy against human cytomegalovirus (HCMV).

PMID- 8669894
TI  - Inhibition of neurotropic mouse retrovirus replication in glial cells by
      synthetic oligo(2'-O-methyl)ribonucleoside phosphorothioates.
AB  - Synthetic oligo(2'-O-methyl)ribonucleoside phosphorothioate, FS-25, which is
      complementary to the splicing acceptor site of neurotropic mouse retrovirus (FrC6
      virus), and non-complementary analogs including 2'-O-methylinosine homo oligomer
      (MIS-25), both inhibited viral infection in glial cells. In addition, FS-25 and
      MIS-25 partially suppressed viral production of glial cells persistently infected
      with FrC6 virus. Both FS-25 and MIS-25 potently inhibited reverse transcriptase
      activity of the FrC6 virus in a cell-free system. Addition of these compounds
      before or after second-round infection of the FrC6 virus inhibited the
      accumulation of unintegrated viral DNA. These results indicate that these
      compounds fundamentally inhibit retrovirus production in glial cells in the same
      manner in which they inhibit HIV production, by blocking several viral
      replication pathways including fresh infection, second-round infection, and
      reverse transcription of the viral genome. Our novel neurotropic retrovirus is a
      useful experimental model for the development of drugs against HIV infection.

PMID- 8669895
TI  - Proceedings of the 17th Symposium on Biotechnology for Fuels and Chemicals. Vail,
      Colorado, May 7-11, 1995.

PMID- 8669896
TI  - Pretreatment of sugar cane bagasse for enhanced ruminal digestion.
AB  - Crop residues, such as sugar cane bagasse (SCB), have been largely used for
      cattle feeding. However, the close association that exists among the three major
      plant cell-wall components, cellulose, hemicellulose, and lignin, limits the
      efficiency by which ruminants can degrade these materials. Previously, we have
      shown that pretreatment with 3% (w/w) phosphoric acid, under relatively mild
      conditions, increased considerably the nutritional value for SCB. However, in
      this preliminary study, pretreated residues were not washed prior to in situ
      degradability assays because we wanted to explore the high initial solvability of
      lowmol-wt substances that were produced during pretreatment. We have now studied
      the suitability of water-and/or alkali-washed residues to in situ ruminal
      digestion. Alkali washing increased substrate cellulose content by removing most
      of the lignin and other residual soluble substances. As a result the ruminal
      degradability of these cleaner materials had first-order rate constants five
      times higher than those substrates with higher lignin content (e.g., stem
      exploded bagasse). However, alkali washing also increased the time of ruminal lag
      phase of the cellulosic residue, probably because of hemicellulose and/or lignin
      removal and to the development of substrates with higher degree of crystallinity.
      Therefore, longer lag phases appear to be related to low microbial adherence
      after extensive water and alkali extraction, as Novell as to the slower process
      of cellulase induction during ruminal growth. The kinetic data on ruminal
      digestion were shown to be very well adjusted by a nonlinear model. Although
      pretreatment enhances substrate accessibility, the occurrence of an exceedingly
      high amount of lignin byproducts within the pretreated material reduces
      considerably its potential degradability.

PMID- 8669897
TI  - Peculiarities of the regulation of fermentation and respiration in the crabtree
      negative, xylose-fermenting yeast Pichia stipitis.
AB  - The respiration of Pichia stipitis was not repressed by either high
      concentrations of fermentable sugars or oxygen limitation. Fermentation was not
      induced by high sugar concentrations, but was inactivated by aerobic conditions.
      The activity of pyruvate dehydrogenase was constitutive. In contrast, pyruvate
      decarboxylase, alcohol dehydrogenase, and aldehyde dehydrogenase were induced by
      a reduction in the oxygen tension. It was demonstrated that in P. stipitis, the
      pyruvate decarboxylase is not induced by a signal from glycolysis. Contrary to
      Saccharomyces cerevisiae, the pyruvate decarboxylase was not inhibited by
      phosphate.

PMID- 8669898
TI  - Inactivation of an aldehyde/alcohol dehydrogenase gene from Clostridium
      acetobutylicum ATCC 824.
AB  - A nonreplicative plasmid containing an internal aad gene fragment has been
      integrated into the chromosome of Clostridium acetobutylicum ATCC 824.
      Transformation was accomplished by electroporation with relatively high
      concentrations of methylated plasmid DNA. Southern hybridization experiments
      revealed that integration occurred by single crossover homologous recombination
      inactivating the aad gene. Integrants were relatively stable after 25
      generations. Inactivation of the aad gene drastically reduced solvent production.
      This result suggests that aldehyde/alcohol dehydrogenase(AAD) plays a important
      role in butanol production.

PMID- 8669899
TI  - Screening for L-arabinose fermenting yeasts.
AB  - Utilization of pentose sugars (D-xylose and L-arabinose) derived from
      hemicellulose is essential for the economic conversion of biomass to ethanol.
      Xylose-fermenting yeasts were discovered in the 1980s, but to date, no yeasts
      have been found that ferment L-arabinose to ethanol in significant quantities. We
      have screened 116 different yeasts for the ability to ferment L-arabinose and
      have found the following species able to ferment the sugar: Candida auringiensis,
      Candida succiphila, Ambrosiozyma monospora, and Candida sp. (YB-2248). Though
      these yeasts produced ethanol concentrations of 4.1 g/L or less, they are
      potential candidates for mutational enhancement of L-arabinose fermentation.
      These yeasts were also found to ferment D-xylose.

PMID- 8669900
TI  - Increased xylose reductase activity in the xylose-fermenting yeast Pichia
      stipitis by overexpression of XYL1.
AB  - The Pichia stipitis xylose reductase gene (XYL1) was inserted into an autonomous
      plasmid that P. stipitis maintains in multicopy. The plasmid pXOR with the XYL1
      insert or a control plasmid pJM6 without XYL1 was introduced into P. stipitis.
      When grown on xylose under aerobic conditions, the strain with pXOR had up to 1.8
      fold higher xylose reductase (XOR) activity than the control strain. Oxygen
      limitation led to higher XOR activity in both experimental and control strains
      grown on xylose. However, the XOR activities of the two strains grown on xylose
      were similar under oxygen limitation. When grown on glucose under aerobic or
      oxygen-limited conditions, the experimental strain had XOR activity up to 10
      times higher than that of the control strain. Ethanol production was not
      improved, but rather it decreased with the introduction of pXOR compared to the
      control, and this was attributed to nonspecific effects of the plasmid.

PMID- 8669901
TI  - The relationship between growth enhancement and pet expression in Escherichia
      coli.
AB  - The pet operon consists of genes coding for enzymes responsible for ethanol
      production and consists of pyruvate dehydrogenase and alcohol dehydrogenase II
      from the high-performance ethanologen Zymomonas mobilis. This article describes
      the physiological influence of pet expression in Escherichia coli B (ATCC 11303)
      in terms of growth rate and overall concentrations of cell mass and catabolic end
      products achieved under well-defined cultivation conditions that included
      constant pH and carbon (energy) limitation. Glucose, mannose, and xylose were
      used as substrates, because they represent the principal fermentable components
      of lignocellulosic biomass and because fermentation of these sugars involves
      different metabolic pathways. Two different types of ethanologenic recombinants
      were used-a strain in which pet expression was via a multicopy plasmid (pLO1297)
      and a chromosomal integrant, strain KO11. Under the condition of sugar substrate
      limitation, there was no growth enhancement by pet expression with either glucose
      or mannose. Whereas the host strain produced exclusively lactic acid from glucose
      and mannose, both recombinants produced mostly ethanol. Both the plasmid-carrying
      strain and the pet integrant exhibited slower growth compared to the host culture
      with glucose or mannose as fermentation substrate. With mannose, the plasmid
      recombinant grew appreciably slower than either the host culture or the
      recombinant KO11. Use of a magnesium-deficient medium produced different results
      with glucose since substrate and turbidometric measurements proved to be
      unreliable in terms of estimating overall biomass levels. At pH 6.3, pet
      expression improved overall biomass yield; but at pH 7.0, the cell yields
      exhibited by the plasmid recombinant and the host strain were the same. E. coli B
      did not grow well on xylose as sole carbon source. With xylose, pet expression
      increased the growth rate, but had no effect on the overall biomass yield. In
      comparing our observations with the reports of others, it was concluded that the
      effect of pet expression on growth of E.coli is dependent on several different
      biochemical, physiological, genetic, and environmental factors, which largely
      precludes a statement of generality regarding this phenomenon.

PMID- 8669902
TI  - Factors contributing to the loss of ethanologenicity of Escherichia coli B
      recombinants pL0I297 and KO11.
AB  - To be economic and to be compatible with modern continuous bioconversion systems,
      it is imperative that the process organism exhibits an extremely high degree of
      stability. In the case of ethanol production from lignocellulosic biomass,
      functional stability of the potential process biocatalyst can be assessed in
      terms of the capacity to sustain high-performance fermentation during the
      continuous fermentation of biomass-derived sugars. This investigation employed
      glucose- or xylose-limited chemostat culture to examine the functional stability
      of two patented, genetically engineered E. coli-namely E. coli B (ATCC 11303)
      carrying the Zymomonas genes for pyruvate decarboxylase and alcohol dehydrogenase
      II on a multicopy plasmid pLOI297 and a chromosomal pet integrant of strain
      11303, designated as strain KO11. Both recombinants carry markers for antibiotic
      resistance and have been reported to exhibit genetic stability in the absence of
      antibiotic selection. Chemostats were fed with Luria broth (LB) (with 25 g/L
      sugar) at a dilution rate of 0.14 and 0.07/h when the feed medium was glucose-LB
      and xylose-LB, respectively. They pH was controlled at 6.3. With glucose, both
      recombinants exhibited a rapid loss of ethanologenicity even when selection
      pressure was imposed by the inclusion of antibiotics in the feed medium. With
      strain KO11, increasing the concentration of chloramphenicol from 40 to 300 mg/L,
      resulted in a retardation in the rate of loss of ethanologenicity, but it did not
      prevent it. Under xylose limitation, the plasmid-bearing recombinant appeared to
      be stabilized by antibiotics, but this did not reflect genetic stability, since
      the slower-growing revertant was washed out at a dilution rate of 0.07/h. With
      both recombinants, interpretation of functional stability with xylose was
      complicated by the inherent ethanologenicity associated with the host culture.
      Based on an average cost for large bulk quantities of antibiotics at $55/kg and
      an amendment level of 40 g/m3, the estimated economic impact regarding the
      potential requirement for operational stabilization by antibiotics in a plant
      operating in batch mode varied from a maximum of 29 cents/gal of E95 ethanol for
      antibiotic amendment of all fermentation media to a minimum of 0.45 cents/gal
      where antibiotics were used exclusively for the preparation of the inocula for
      every fourth batch fermentation cycle. The high degree of instability observed in
      these continuous fermentations does not auger well for the proposed potential
      industrial utility of these patented, genetically engineered constructs for the
      production of fuel ethanol from biomass and wastes.

PMID- 8669903
TI  - Studies on nutrient requirements and cost-effective supplements for ethanol
      production by recombinant E. coli.
AB  - This article describes a systematic study of the nutritional requirements of a
      patented recombinant ethanologenic Escherichia coli (11303:pLO1297) and provides
      cost-effective formulations that are compatible with the production of fuel
      ethanol in fermentations of lignocellulosic prehydrolysate characterized by high
      xylose conversion efficiency. A complex and nutrient-rich laboratory medium,
      Luria broth (LB), provided the benchmark with respect to fermentation performance
      standard. Xylose fermentation performance was assessed in terms of the target
      values for operational process parameters established by the US National
      Renewable Energy Laboratory (NREL)-final ethanol concentration (25 g/L), xylose
      to-ethanol conversion efficiency (90%), and volumetric productivity (0.52 g/L.h).
      Biomass prehydrolysates that are rich in xylose also contain acetic acid, and in
      anticipation of a need to reduce acetic acid toxicity, the fermentors were
      operated with a pH control set-point of 7.0 Growth and fermentation in the
      minimal defined salts (DS) medium was only about 15% compared to the reference
      medium. Amendment of the minimal medium containing 6 wt% xylose with both
      vitamins and amino acids resulted in improved growth, but the volume productivity
      (0.59 g/L.h) was still only about 54% of that with LB (1.1g/L.h). Formulations
      directed at cost reduction through the use of less expensive commercial complex
      nutritional supplements were within 90% of the NREL process target with respect
      to yield and provided a productivity at about 80% of the LB medium, but were not
      economical. Corn steep liquor (CSL) at about 7-8 g/L was shown to be a complete
      source of nutritional requirements and supported a fermentation performance
      approaching that of LB. At a cost of CSL of $50/t(dry wt), the economic impact of
      using this amount CSL as the sole nutritional supplement in a cellulosic ethanol
      plant was estimated to be about 4 cents/gal of ethanol.

PMID- 8669904
TI  - Production, characterization and application of the cellulase-free xylanase from
      Aspergillus niger.
AB  - The effects of carbon source on xylanase and cellulase production were studied.
      The extract of steam-exploded corn stover was found to be the best raw material
      for producing cellulase-free xylanase. The xylanolytic enzymes of Aspergillus
      niger An-76 were purified by chromatography, and the properties of the four
      purified components were analyzed. When the enzyme was used to treat the birch
      Kraft pulp, and followed by a subsequent CEH bleaching, a brightness of 6.8% SBD
      more than that of the untreated one using the same chlorine dosage, or a saving
      of nearly 50% of chlorine consumption with the same brightness, was realized.

PMID- 8669905
TI  - Fermentation of orange peel hydrolysates by ethanologenic Escherichia coli.
      Effects of nutritional supplements.
AB  - Orange peel, an abundant byproduct of the citrus processing industry, is
      converted to a mixture of glucose, galacturonic acid, fructose, arabinose,
      galactose, and xylose by hydrolysis with mixed pectinase and cellulase enzymes.
      All these sugars can be fermented to ethanol or ethanol and acetic acid by the
      recombinant bacterium Escherichia coli KO11. The fermentation efficiency is
      improved by the addition of yeast extract, tryptone, mixed amino acids, corn
      steep liquor, or by proteolytic digestion of endogenous proteins. Batch
      fermentations of supplemented peel hydrolysate containing 111 g/L of initial
      total sugars produced 35-38 g/L of ethanol in 48-72 h and a 75-85% yield.

PMID- 8669906
TI  - Cloning and expression of full-length Trichoderma reesei cellobiohydrolase I
      cDNAs in Escherichia coli.
AB  - The process of converting lignocellulosic biomass to ethanol via fermentation
      depends on developing economic sources of cellulases. Trichoderma reesei
      cellobiohydrolase (CBH) I is a key enzyme in the fungal cellulase system;
      however, specific process application requirements make modification of the
      enzyme by site-directed mutagenesis (SDM) an attractive goal. To undertake SDM
      investigations, an efficient, cellulase-free host is required. To test the
      potential of Escherichia coli as a host, T. reesei CBH I cDNA was expressed in E.
      coli strain GI 724 as a C-terminal fusion to thermostable thioredoxin protein.
      Full-length expression of CBH I was subsequently verified by molecular weight,
      Western blot analysis, and activity on soluble substrates.

PMID- 8669907
TI  - Hexokinase production from S. cerevisiae. Culture conditions.
AB  - The effects of pH (4.0, 4.5, or 5.0), temperature (T) (30, 35, or 40 degrees C)
      and dissolved oxygen (DO) (0.2, 2.0, 4.0,or 6.0 mg O2/L) on hexokinase and
      invertase formation by yeast were studied. The highest enzyme activities were
      attained at pH 4.0, DO = 4.0 mg O2/L, and T = 35 or 40 degrees C.

PMID- 8669908
TI  - Culture of the astaxanthinogenic yeast Phaffia rhodozyma in low-cost media.
AB  - Growth of the yeast Phaffia rhodozyma was carried out in a simplified medium
      based on less expensive nutrient sources, such as diluted sugar cane juice, urea,
      and sodium phosphate. The usual content of the astaxanthin, an oxygenated pink
      carotenoid useful for fish flesh staining, was improved along with with good cell
      yields (respective values of > 1300 micrograms/g cells and > 5 g cells/L were
      observed). Yeast invertase and urease must therefore play an important role in
      the implementation of low-cost culture media.

PMID- 8669910
TI  - Bioprocessing research.

PMID- 8669909
TI  - Effect of culture conditions on xylitol production by Candida guilliermondii FTI
      20037.

PMID- 8669911
TI  - Pretreatment of sugar cane bagasse hemicellulose hydrolysate for xylitol
      production by yeast.
AB  - A total of six known xylitol-producing yeast strains were screened for production
      of xylitol from xylose. Candida sp. 11-2 proved to be the best producer. It was
      chosen to study its ability to produce xylitol from hemicellulose hydrolysate
      derived from sugar cane bagasse. The hydrolysate was prepared by dilute sulfuric
      acid (2-3% [w/v]) hydrolysis, with a high-solid, low-liquid ratio followed by
      leaching. Owing to the inhibitors present in the hydrolysate, different
      treatments were studied to overcome its effect. In order to reach higher xylitol
      productivity, treated hydrolysates were concentrated by vacuum evaporation in
      rotavapor to provide a higher initial xylose concentration. After treatment,
      Candida sp. 11-2 was able to ferment xylose in hemicellulose hydrolysate to
      produce xylitol.

PMID- 8669912
TI  - Continuous alcoholic fermentation process in a tower reactor with recycling of
      flocculating yeast.
AB  - The influence of different substrate concentrations on the performance of a
      continuous system of alcohol production by fermentation using a tower reactor
      with recycling of flocculating yeasts was investigated. All experiments were
      carried out using a flocculating yeast strain IR-2, isolated from fermented food,
      and identified as Saccharomyces cerevisiae. Cane sugar juice was used as a
      substrate with sugar concentrations of 160, 170, 180, 190, and 200 g/L. Constant
      values of dilution rate, 0.20 h-1, temperature, 30 degrees C, and pH 3.3, were
      used. The performance of the reactor was observed to be efficient with high
      substrate concentrations. Maximum productivities of 18 g/L/h 99% substrate
      conversion and ethanol concentrations of 90 g/L were obtained using 200 g/L of
      sugar in the feedstock. For substrate concentrations of 160 g/L, a maximum yield
      of 0.45 g of ethanol/g of sugar was observed or 90% of the theoretical value.

PMID- 8669913
TI  - Bioprocessing of sweet sorghum with in situ-produced enzymes.
AB  - Enzyme-assisted ensiling (ENLAC), using in situ-produced enzymes from Gliocladium
      sp. TUB-F-498, preserved 80% of the sugar content of sweet sorghum, and
      facilitated its extraction by countercurrent diffusion. The in situ enzyme was
      produced on the extracted sweet sorghum pulp by an 8-d solid substrate
      fermentation (SSF) with a yield of 4.6 cellulase and 400 IU/g dry wt xylanase.
      Two percent of the fermented substrate had cellulase and xylanase levels
      equivalent or superior to levels found in the commercial enzymes Celluclast and
      Viscozyme Novo at the 0.025% application level in ENLAC. The in situ-production
      of enzymes on recyclable substrates may reduce bioprocessing costs significantly.
      In this ENLAC process, the cost of the in situ enzymes is estimated to be about
      $0.12/MT substrate, compared to $9.5/metric ton (MT) for the commercial enzymes,
      a cost reduction of nearly 80-fold.

PMID- 8669914
TI  - Improvement of productivity of yeast cell with a novel airlift loop reactor.
AB  - Two different strains of baker's yeast are cultivated using a fed-batch process
      with a novel airlift loop reactor. The reactor can be operated not only under
      steady-state conditions as the traditional airlift loop reactor, but also under
      forced periodically operational conditions in which the direction of liquid
      circulating flow is alternatively changed. Compared with the traditional steady
      state operation, both the growth rate and yield of cells are much higher in the
      forced periodic operation.

PMID- 8669915
TI  - Cellulose degradation and ethanol production by thermophilic bacteria using
      mineral growth medium.
AB  - Growth of thermophilic cellulase-utilizing bacteria in a vitamin-free growth
      medium is reported for both a previously described strain, Clostridium
      thermoclelum 31549, and now isolates HJA1 and HJA2. Formation of fermentation
      products with and without vitamins was similar for strains HJA1 and HJA2 as well
      as for the enrichment cultures from which these stains were derived. Strain HJA2
      was maintained in continuous culture on a vitamin-free mineral medium with Avicel
      as the carbon source for over a week. At a 38 h residence time, Avicel conversion
      was higher (81%) at pH 6.42 than at pH 6.97 (73%) or at 6.01 (58%). Ethanol and
      acetate were produced in significant amounts by strain JHA2 at all pH values
      tested (6.97, 6.42, 6.01). Lactic acid was the primary fermentation product at pH
      6.97, but was not a significant product at both the lower values. Efforts to grow
      thermophilic, cellulose-utilizing bacteria at pH < 6.0 were unsuccessful for
      described strains, new isolates, and enrichment cultures.

PMID- 8669916
TI  - Development of an epi-fluorescence assay for monitoring yeast viability and
      pretreatment hydrolysate toxicity in the presence of lignocellulosic solids.

PMID- 8669917
TI  - Reactor comparisons for the biodegradation of thiodiglycol, a product of mustard
      gas hydrolysis.
AB  - An environmentally benign method for the mineralization of sulfur mustard has
      been proposed involving chemical hydrolysis of sulfur mustard to thiodiglycol,
      and then the biological degradation of thiodiglycol to generate biomass and
      gaseous carbon dioxide. Alcaligenes xylosoxidans (SH91) was isolated based on its
      ability to utilize thiodiglycol as a sole carbon source. This article compares
      different biological reactor designs and experimentally assesses their relative
      effectiveness in degrading thiodiglycol using pure cultures of SH91. The reactor
      configurations studied are batch, continuous stirred-tank reactor (CSTR), and
      CSTR with cell recycle. From the results, it is clear that the CSTR with cell
      recycle offers superior performance for a given residence time or volume. These
      pure culture data are necessary for accurate design of a pilot-scale system where
      mixed cultures will be employed because of a possible incomplete chemical
      hydrolysis step.

PMID- 8669918
TI  - A case study of the natural attenuation of gas condensate hydrocarbons in soil
      and groundwater.
AB  - Condensate liquids have been found to contaminate soil and groundwater at two gas
      production sites in the Denver Basin operated by Amoco Production Co. These sites
      have been closely monitored since July 1993 to determine whether intrinsic
      aerobic or anaerobic bioremediation of hydrocarbons occurs at a sufficient rate
      and to an adequate end point to support a no-intervention decision. Groundwater
      monitoring and analysis of soil cores suggest that intrinsic bioremediation is
      occurring at these sites by multiple pathways, including aerobic oxidation,
      Fe(III) reduction, and sulfate reduction.

PMID- 8669919
TI  - Biodegradation of mixed wastes in continuously operated cyclic reactors.
AB  - The problem of simultaneous biodegradation of two dissimilar substrates in a
      continuously operated cyclic reactor was studied both at the theoretical and
      experimental levels using a simple model system. The system involved media
      containing mixtures of glucose and phenol as carbon sources. A pure culture of
      Pseudomonas putida (ATCC 17514) was employed. Independent kinetic experiments
      have revealed that glucose and phenol are involved in a crossinhibitory
      uncompetitive kinetic interaction. The dynamics of a cyclically operated reactor
      were analyzed using the principles of bifurcation theory for forced systems.
      Experimental results have confirmed the theoretical predictions. Implications of
      the results for the design of waste-treating facilities are discussed.

PMID- 8669920
TI  - Effect of temperature and yeast extract on microbial respiration of sediments
      from a shallow coastal subsurface and vadose zone.
AB  - As a part of our study on microbial heterogeneity in subsurface environments, we
      have examined the microbial respiration of sediment samples obtained from a
      coastal site near Oyster, VA. The sediments at the site are unconsolidated, fine
      to coarse beach sand and gravel. A Columbus Instruments Micro-Oxymax Respirometer
      was used to measure the rate of carbon dioxide (CO2) production during the
      respiration of the sediment samples. The rate of respiration of the sediment
      samples ranged from 0.035-0.6 microL CO2/h/g of the sediment. The sediment
      samples showing maximum (0.6 microL CO2/h/g) and minimum (0.035 microL CO2/h/g)
      production of CO2 were selected to study the effect of micronutrient-yeast
      extract (0.5 and 1.0 micrograms/g of the sediment) and water (0.5 and 1.0 mL) on
      the rate of CO2 production. The rate of CO2 production increased with the
      addition of water, but increased approx 2 orders of magnitude (from 0.26 to an
      average of 23.5 microL CO2/h/g) when 1.0 g/g yeast extract was added to the
      sediment samples. In these coastal sediments, temperature, depth, and addition of
      water influenced microbial activity, but the addition of 1.0 microgram/g yeast
      extract as a micronutrient rapidly increased the rate of CO2 production 2 orders
      of magnitude.

PMID- 8669921
TI  - Filamentous growth in activated sludge.
AB  - Bulking and foaming in activated sludge have been associated with filamentous
      overgrowth. Filamentous Nocardia amarae and nonfilamentous Pseudomonas auruginosa
      were cultured using fatty acids (C2-C24) as the sole carbon. N. amarae could
      utilize all acids tested for growth, whereas P. auruginosa hardly grew on acids
      with 12 or more carbons. Maximum specific growth rate and saturation constant of
      N. amarae on C24, at 0.048 h-1 and 1.520 g COD/L, respectively, were much lower
      than that of P. auruginosa, showing that N. amarae had a relatively stronger
      affinity for long-chain fatty acids. N. amarae was competitive in activated
      sludge processes that receive sewage containing a high proportion of long-chain
      fatty acids, oils, and fats.

PMID- 8669922
TI  - The effect of antibiotics on nitrification processes. Batch assays.
AB  - The effect of different antibiotics at several concentrations of ampicillin (0
      250 mg/L), benzylpenicillin (0-250 mg/L), novobiocine (0-150 mg/L),
      oxytetracycline (0-250 mg/L), and chloramphenicol (0-50 mg/L) on a stabilized
      nitrifying sludge was evaluated under aerated and lithoautotrophic conditions. No
      effect resulting from the presence of antibiotics on the biomass and nitrate
      production was noticed. The specific growth rate and volumetric nitrification
      rate average values for the controls were 8.28 x 10-3/h-1 and 2.74 x 10-3 g/L.h,
      respectively. Similar rate values were found when different kinds of antibiotic
      and concentrations were tested. These results may be explained by the nature of
      the floc or the instability of the antibiotics.

PMID- 8669923
TI  - Sequential anaerobic-aerobic biodegradation of PCBs in soil slurry microcosms.
AB  - Many industrial locations have identified the need for treatment of
      polychlorinated biphenyl (PCB) wastes and remediation of PCB-contaminated sites.
      Biodegradation of PCBs is a potentially effective technology for treatment of PCB
      contaminated soils and sludges; however, a practicable remediation technology has
      not yet been demonstrated. In laboratory experiments, soil slurry microcosms
      inoculated with microorganisms extracted from PCB-contaminated Hudson River
      sediments have been used for anaerobic dechlorination of weathered Aroclor 1248
      in contaminated soil with a low organic carbon content. Anaerobic incubation was
      then followed by exposure to air, addition of biphenyl, and inoculation with
      Pseudomonas sp. LB400, an aerobic PCB degrader. The sequential anaerobic-aerobic
      treatment constituted an improvement compared to anaerobic or aerobic treatment
      alone by reducing the total amount of PCBs remaining and decreasing the tendency
      for end products to accumulate in humans. A 70% reduction of PCBs was observed
      during sequential treatment with products containing fewer chlorines and having a
      shorter half-life in humans than the original PCBs. The aerobic treatment alone
      was also quite effective as a stand-alone treatment reducing the PCBs by 67%. The
      results represent a case in which anaerobic river sediment organisms have been
      successfully transferred to a matrix free of river or lake sediments.

PMID- 8669924
TI  - Estimating biodegradative gene numbers at a JP-5 contaminated site using PCR.
AB  - We have utilized a most-probable-number polymerase chain reaction (MPN-PCR)
      procedure to estimate gene numbers and biodegradative potential at a jet fuel (JP
      5) contaminated site undergoing the first phase of bioremediation. Nucleic acid
      analysis was used to determine whether a lack of genetic potential for
      bioremediation was responsible for low levels of oxygen utilization at the site.
      Total community DNA was extracted and analyzed by PCR for genes (nahAc,alkB, and
      xylE) known to be involved in the degradation of certain JP-5 constituents.
      Results indicate that significant aromatic biodegradative potential exists at the
      site and outlying areas not subjected to engineered remediation, suggesting that
      physical and/or chemical factors are inhibiting oxygen delivery. xylE and nahAc
      were often present in significant portions of the microbial community, whereas
      alkB was rarely detected. This study illustrates the utility of molecular
      techniques in evaluating biodegradative potential in the field during active
      bioremediation.

PMID- 8669925
TI  - Natural history and treatment effects in Guillain-Barre syndrome: a multicentre
      study.
AB  - A retrospective multicentre study was performed to investigate the natural
      history and treatment effects in childhood Guillain-Barre syndrome in a large
      number of patients. Structured questionnaires were sent to 155 paediatric
      hospitals for details of patients who conformed to internationally accepted
      diagnostic criteria and who were treated from spring 1989 to summer 1994. Sixty
      nine hospitals reported data of 175 patients aged 11 months to 17.7 years. At the
      height of the disease 26% of the patients remained able to walk, but 16% had to
      be artificially ventilated. The median time from onset of symptoms to first
      recovery was 17 days, to walk unaided 37 days, and to be free of symptoms 66
      days. There was a large group with a benign and a smaller one with a more
      protracted course. At long term follow up, 98/106 patients were free of symptoms
      and the remainder were able to walk unaided. Maximum disability grade was the
      most powerful prognostic factor. In children unable to walk but not yet
      tetraplegic, immunoglobulins were able to accelerate recovery. Corticosteroids
      were less potent. Plasmapheresis could not be evaluated because it was
      administered only in the most severe cases. The natural history of Guillain-Barre
      syndrome in children is extremely variable and more benign than in adults.
      Treatment with immunoglobulins should be considered in patients unable to walk.
      Corticosteroids are not as effective and should be withheld except when, in
      protracted courses, suspicion of chronic inflammatory demyelinating
      polyneuropathy arises.

PMID- 8669926
TI  - Cerebrospinal fluid soluble L-selectin (sCD62L) in meningoencephalitis.
AB  - The leucocyte adhesion molecule L-selectin (CD62L) is rapidly cleaved off
      proteolytically after cell activation, generating soluble L-selectin (sCD62L)
      molecules. sCD62L concentrations were determined in 185 cerebrospinal fluid (CSF)
      samples obtained from children aged 1 month to 17 years. In 36 CSF samples of
      children with meningoencephalitis, sCD62L was significantly higher (median 209
      fmol/ml) than in samples of children with other febrile diseases (n = 67, median
      50 fmol/ml) or non-febrile disorders (n = 82, median 44 fmol/ml). There was a
      positive correlation between CSF protein and CSF sCD62L (rS = 0.68), suggesting
      that a disturbed blood-brain barrier contributes to raised sCD62L concentrations
      in the CSF. However, the CSF sCD62L/protein ratio of children with
      meningoencephalitis was significantly higher than in children with other febrile
      diseases or non-febrile disorders, indicating that sCD62L concentrations in
      children with meningoencephalitis were higher than expected from plasma leakage
      alone. It is concluded that both an impaired blood-brain barrier and the
      generation of sCD62L by infiltrating leucocytes contribute to raised CSF sCD62L
      concentrations in children with meningoencephalitis.

PMID- 8669927
TI  - Renal function in acute falciparum malaria.
AB  - Renal function was assessed in 40 children during the acute illness and after
      recovery from falciparum malaria. Creatinine clearance was significantly lower
      during the acute illness than after recovery. Six of 18 children with impaired
      creatinine clearance (< 50 ml/min/1.73 m2) had evidence of acute tubular
      dysfunction. Hyponatraemia occurred in 12.5% during the acute phase. Fractional
      sodium excretion was raised in 27% during the acute illness and continuing sodium
      wastage occurred in 17% after recovery. Plasma potassium was significantly higher
      and fractional potassium excretion (FeK) significantly lower during the acute
      illness than after recovery. There was a positive correlation between FeNa and
      FeK both during and after recovery from the illness but they did not exactly
      mirror each other in every individual. Urine sodium:potassium ratios were similar
      during and after recovery from the illness and was related to FeNa. Fractional
      glucose excretion was zero. Mild proteinuria occurred in 40% during the acute
      illness but were not related to creatinine clearance, body temperature at
      presentation, or peripheral parasite density. Proteinuria was absent after
      recovery. Acute intrinsic renal impairment occurs during apparently
      'uncomplicated' falciparum malaria in children.

PMID- 8669928
TI  - Vision impairment in Liverpool: prevalence and morbidity.
AB  - A database related to the activities of the Liverpool vision assessment team was
      used to identify all children with vision impairment aged 0-16 years, resident in
      Liverpool, UK, on 1 April 1995. Prevalence rates were calculated for all children
      with vision impairment, and separately for two groups: those with uncomplicated
      vision impairment, and those with additional pathology. Visual tract pathologies
      were tabulated and compared. Associated handicapping conditions were defined and
      the extent of multiple disability was investigated for all vision impaired
      children, for very low birthweight children, and for those with cortical visual
      impairment. Of 199 children with vision impairment, 69 (35%) had uncomplicated
      impairment and 130 (65%) had additional and usually multiple pathology. There
      were 111 boys (56%); the excess of males was not statistically significant.
      Prevalence rates per 10,000 population were 18.1 for all vision impairment, 6.3
      for uncomplicated vision impairment, and 11.8 for vision impairment complicated
      by additional pathology. Genetically determined disease accounted for over half
      the cases of uncomplicated vision impairment. Among the 130 children with
      additional pathology, cortical visual impairment was the commonest visual tract
      finding, affecting 64 (49%); 86% had learning difficulties; 53% had cerebral
      palsy. Multidisability (two or more disabling conditions in addition to vision
      impairment) affected half the entire childhood vision impairment population.
      These data should assist health and education authorities to determine the size
      of the vision impairment problem and how it relates to other disabilities in
      childhood, and can facilitate resource allocation and service planning.

PMID- 8669929
TI  - Prediction of early outcome in resolving chronic lung disease of prematurity
      after discharge from hospital.
AB  - In an attempt to identify those infants with resolving chronic lung disease of
      prematurity (CLD) at greatest risk of sudden infant death syndrome or acute life
      threatening event (SIDS/ALTE), or readmission to hospital following discharge,
      recordings of arterial oxygen saturation were made on 35 infants. Recordings were
      collected while the infants were breathing room air. Movement artefact was
      excluded and the data analysed to provide the mean individual arterial oxygen
      saturation (MSaO2), and the variability of the mean individual oxygen saturation
      (delta MSaO2). These data were related to clinical outcome recorded over the
      three months following investigation. A MSaO2 less than 90% on discharge
      predicted hospital admission within three months with a sensitivity of 1 and a
      specificity of 0.76, and SIDS/ALTE with a sensitivity of 1 and a specificity of
      0.75. A delta MSaO2 greater than 6% predicted SIDS/ALTE with a sensitivity 0.88
      and specificity of 1. Infants with resolving chronic lung disease of prematurity
      who are at risk of increased morbidity and mortality can be assessed by accurate
      measurement of mean arterial saturation.

PMID- 8669930
TI  - Short stay facilities: the future of efficient paediatric emergency services.
AB  - Many children admitted to hospital can stay for 24 hours or less. Short stay
      facilities offer such children rapid stabilisation and early discharge with
      considerable financial saving. A 12 month study was completed in which data were
      collected from the children's emergency annex (CEA) at Westmead Hospital in
      Sydney's western suburbs. This university based teaching hospital provides care
      for a large paediatric population as well as three other district hospitals with
      limited children's bed capacity. From April 1994 to April 1995, 1300 children
      were admitted and entered into a database of general and hospital-specific
      information. Critical incident monitoring was undertaken and follow up with
      review within 24-72 hours for all children. The CEA increased hospital efficiency
      significantly by reducing bed days, with a saving of over $500,000 to the
      department. The average length of stay was 17.5 hours, and 58% of users were
      children of 2 years and under. Only 3% remained beyond 24 hours, and another 4%
      were admitted to inpatient beds for continued management of the primarily
      diagnosed condition. No critical incident was reported during this 12 month
      period. Short stay facilities are efficient and cost-effective for children with
      acute illness who can be rapidly stabilised with early discharge without critical
      incident. Children 12 months and under are particularly suited to this type of
      facility. Short stay facilities should be used to augment efficiency within
      children's emergency services which have high turnover and limited bed capacity.

PMID- 8669932
TI  - Severe aplastic anaemia in the Nordic countries: a population based study of
      incidence, presentation, course, and outcome.
AB  - PURPOSE: Incidence data for severe aplastic anaemia (SAA) in children are scanty
      and vary. Few population based studies have been reported. A retrospective and
      prospective study was conducted to determine the incidence and course of SAA.
      PATIENTS AND METHODS: All children with a diagnosis of SAA in the Nordic
      countries from 1982 through 1993 were registered and have been followed up since
      1987. RESULTS: A total of 101 children were diagnosed with SAA. The mean annual
      child population was 4.31 million. A constant incidence of 1.95/million
      children/year was found: 2.4 for boys and 1.5 for girls. A non-significant
      increase of cases occurred from November to March. Possible aetiological agents
      were noted in 29%. The actuarial survival was 79% after one year and 68% after
      five years without significant difference between boys and girls. CONCLUSION: The
      incidence of SAA in the Nordic countries remains stable with a preponderance
      among boys. SAA has still a high initial mortality and a risk of late deaths.

PMID- 8669931
TI  - Bone mineral content in cystic fibrosis patients: correlation with fat-free mass.
AB  - OBJECTIVE: To assess the bone mineral content in well nourished patients with
      cystic fibrosis and to seek a correlation with fat-free mass. METHODS: Fourteen
      cystic fibrosis patients aged 6 to 20 years were studied and compared to 14
      healthy controls matched for gender, age, and nutritional status. Bone mineral
      content was determined by dual energy x ray absorptiometry (DEXA). RESULTS:
      Nutritional inquiry showed higher ingestion of macronutrients and micronutrients
      by cystic fibrosis patients than by controls. Mean whole skeleton bone mineral
      content was 1.184 (SD 0.536) kg in cystic fibrosis patients and 1.229 (0.576) kg
      in controls (p = 0.84). Mean lumbar spine bone mineral content was 0.031 (0.013)
      kg and 0.031 (0.016) kg, respectively (p = 0.99). Anthropometry, bioelectrical
      impedance analysis, and DEXA showed that fat-free mass was similar in the two
      groups. Bone mineral content was strongly correlated to fat-free mass. Mean blood
      calcium, phosphorus, serum 25-hydroxyvitamin D (25-OHD), parathyroid hormone
      (PTH), and osteocalcin were similar in both groups. CONCLUSIONS: Bone mineral
      content and body composition are normal in a well nourished young cystic fibrosis
      population. Osteopenia previously reported in cystic fibrosis patients probably
      has nutritional origins and is therefore not related to a primary defect in bone
      mineral metabolism.

PMID- 8669933
TI  - Logarithmic quantitation model using serum ferritin to estimate iron overload in
      secondary haemochromatosis.
AB  - Nineteen children and adolescents receiving repeated transfusions and
      subcutaneous desferrioxamine treatment were investigated in an attempt to
      quantitate iron overload non-invasively. Before patients were started on
      desferrioxamine individual relationships were correlated for 12 to 36 months
      between transfused iron, absorbed iron estimated gastrointestinally, and
      increasing serum ferritin concentrations. Patients with inflammation, increased
      liver enzymes, or haemolysis were excluded from analysis. The relationship
      between the variables could be described by a logarithmic regression curve (y =
      transfused iron [plus eventually gastrointestinally absorbed iron] = iron
      overload = a+b log [x = serum ferritin]) for each individual patient. All
      patients showed close correlation (R2) between x and y (median R2 of 0.909, 0.98,
      and 0.92 in thalassaemia, aplastic anaemia, and sickle cell anaemia patients,
      respectively). When started on desferrioxamine, current serum ferritin
      concentrations were used to derive the iron overload from each individual
      regression curve. The derived estimated iron overload ranged from 0.6 g to 31 g.
      Left ventricular dilatation was observed in three patients with beta thalassaemia
      and in one patient with aplastic anaemia with median iron overload of 20.7 (14.1
      31.3) g and 24.0 g respectively. Hypothyroidism was found in four patients with
      beta thalassaemia and one patient with aplastic anaemia with iron overload
      between 14.7 (6.8 and 26.1) g and 15.1 g respectively. Human growth hormone
      deficiency was detected in three patients with beta thalassaemia with an iron
      overload of 4.2 (3.5-6.8) g; all three patients had excellent desferrioxamine
      compliance.

PMID- 8669934
TI  - Diagnosis and clinical associations of zinc depletion following bone marrow
      transplantation.
AB  - Following the emergence of biochemical zinc deficiency after bone marrow
      transplantation, the clinical value of plasma alkaline phosphatase activity as an
      early indicator of biochemical zinc depletion was investigated in this group of
      patients. Serial measurements of plasma zinc and alkaline phosphatase activities
      in 28 consecutive children (median age 8.7 years; 16 males) undergoing bone
      marrow transplantation were carried out and clinical associations recorded. A
      significant fall in plasma zinc occurred after the bone marrow transplant, and 19
      children developed biochemical zinc deficiency (Zn < 11 mumol/l) at a median of 7
      days following the transplant. Zinc depletion was more common in younger patients
      and in children with diarrhoea. A positive correlation was found between plasma
      zinc and alkaline phosphatase activities. Zinc depleted patients had more febrile
      episodes of longer duration and were more likely to have a positive blood
      culture. Haemopoetic recovery was not affected by zinc deficiency. Following zinc
      supplementation, alkaline phosphatase showed a significant increase. The
      sensitivity of a low alkaline phosphatase as a screening test for biochemical
      zinc deficiency was 83%, with a specificity of 86%. Low alkaline phosphatase
      activity following bone marrow transplant is an indication for zinc supplements.

PMID- 8669935
TI  - Audit of height measurement at age 3 years: results of a survey of Scottish
      health boards.
AB  - Height measurement at about the age of 3 years is accepted as a routine practice
      by all 15 Scottish health boards and is a recommendation of the Hall report
      Health for all Children. As part of a Scotland-wide project to assess the
      feasibility of audit of preschool surveillance programmes using routinely
      collected data, all boards were asked for information about this procedure. The
      results show that, while all boards confirmed its usefulness as a screening
      measure, only one board was realistically able to audit height measurement at
      this age at all stages using routinely available data. The whole screening
      process, including programme management, equipment validation, staff training and
      referral criteria, was examined using the quality standards defined in the Hall
      report. Results showed a wide variation between boards. For example, fewer than
      half of the boards provided guidelines for height measurement at age 3 to all
      professionals involved. The availability of even basic outcome data, such as
      numbers of children measured at this age was patchy, although this will improve
      with the introduction of the national computerised preschool surveillance system.
      Two boards have no plans to record such data routinely. In conclusion, before
      outcome data can be used and relied on, health boards and trusts need to develop
      local guidelines including quality standards such as age limits for measurement,
      programme management, provision of equipment, and review and referral criteria
      for inclusion into contracts.

PMID- 8669936
TI  - Recurrent limb pain in schoolchildren.
AB  - OBJECTIVES: To determine the prevalence, causes and clinical features of short
      lasting recurrent limb pain (recurrent limb pain) in children. DESIGN: Population
      based study in two stages, with an initial screening questionnaire followed by
      clinical interviews and physical examination of symptomatic children. SETTING: 67
      primary and secondary schools in the city of Aberdeen. SUBJECTS: 2165 children
      representing a random 10% sample of all schoolchildren aged between 5-15 years.
      MAIN OUTCOME MEASURES: (a) The causes of limb pain in children, (b) the
      prevalence of recurrent limb pain in schoolchildren, (c) the relationship of
      recurrent limb pain to childhood migraine. RESULTS: Sports and playground
      injuries were the most common cause of limb pain, affecting 9% of all children.
      The prevalence rate of recurrent limb pain was 2.6% (95% confidence interval 1.9
      to 3.4). Episodes of recurrent limb pain had similar trigger factors, associated
      symptoms, and relieving factors to episodes of headache in children with
      migraine. CONCLUSIONS: Recurrent limb pain is a common cause of limb pain, with a
      prevalence rate of 2.6%. The close clinical and epidemiological similarities
      between recurrent limb pain and childhood migraine suggest a common pathogenesis.

PMID- 8669937
TI  - Severe combined immunodeficiency (SCID) associated neutropenia: a lesson from
      monozygotic twins.
AB  - A case of severe combined immunodeficiency (SCID) in monozygotic twin sisters was
      detected at 3 months of age with neutropenia in one twin and a normal
      differential count in the other. The neutropenic twin, suffering from severe skin
      ulcers, was successfully treated with granulocyte colony stimulating factor (G
      CSF). Discordant occurrence of neutropenia in identical twins shows that there
      may be a non-genetic cause for the neutropenia in SCID. Suppression of
      myelopoiesis was probably induced by activated maternal T cells. The neutropenia
      in this case may thus be classified as SCID associated neutropenia, as opposed to
      reticular dysgenesis, in which the neutropenia is G-CSF refractory and is most
      probably caused by a genetic stem cell defect. A response to G-CSF in a
      neutropenic child with SCID can be clinically beneficial and might help to
      distinguish between G-CSF unresponsive reticular dysgenesis and G-CSF responsive
      SCID associated neutropenia.

PMID- 8669938
TI  - Histidinaemia: a benign metabolic disorder.
AB  - Histidinaemia is a relatively common inherited metabolic disorder with an
      incidence similar to phenylketonuria. This paper reports the long term outcome of
      patients diagnosed by newborn screening in the north west of England. Between
      1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional
      neonatal screening programme (incidence 1:11,083). A further five children were
      detected following diagnosis in a sibling. Of the 113, nine were lost to follow
      up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet
      (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were
      reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and
      4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data
      were converted to standard deviation scores (IQ SDS) to account for increasing IQ
      norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis
      or with the mean plasma histidine throughout life. Growth was normal in all
      patients. There was no apparent benefit from a low histidine diet in early
      childhood. In contrast to other studies, there was no excess of clinical
      symptoms. On the basis of these findings, histidinaemia is a benign metabolic
      disorder that does not require treatment.

PMID- 8669939
TI  - Amino acid profile in Down's syndrome.
AB  - Fasting plasma and urinary amino acid concentrations were studied under carefully
      controlled conditions in 22 children with Down's syndrome and in age matched
      controls. The only significant difference between the groups was a higher mean
      plasma lysine concentration in Down's syndrome patients compared to controls.

PMID- 8669940
TI  - Hypocitraturia in patients with urolithiasis.
AB  - The urinary citrate/creatinine ratio was evaluated in 25 children with idiopathic
      calcium urolithiasis and 24 controls. The mean (SD) urinary citrate/creatinine
      ratio in controls and patients was 0.510 (0.205) and 0.181 (0.076), respectively,
      a statistically significant difference. In neither group was there a relation
      between age and urinary citrate excretion.

PMID- 8669942
TI  - Self directed learning.
AB  - The ability to acquire skills in self directed learning may be the key link
      between undergraduate education, postgraduate training, and continuing
      professional development. If future and current practitioners are to adopt an
      ongoing reflective and critical approach to practice, we should aim to provide
      learning opportunities that promote self confidence, question asking and
      reflection, openness and risk taking, uncertainty and surprise. Teaching
      techniques that encourage these skills are being introduced widely and have been
      shown to be at least as effective as traditional methods of education while
      promoting more enjoyment and enthusiasm among both staff and students.

PMID- 8669941
TI  - Intensive interventions in conduct disorders.

PMID- 8669944
TI  - Asthma knowledge attitudes and quality of life in adolescents.

PMID- 8669943
TI  - Management of cleft lip and palate.
AB  - The complex nature of treatment for CL/P, a condition that requires a large
      multidisciplinary team treating patients from birth to maturity, has been
      outlined. Subjecting centres' outcomes to audit should precede heeding the
      current siren calls for paediatricians to refer children exclusively to a
      particular surgical speciality. A growing body of evidence has shown a close
      correlation between quality of outcome and the availability of high volume
      centralised care by dedicated teams, as has been proved and accepted for years in
      other fields such as surgery in infancy, childhood malignancies, and cystic
      fibrosis.

PMID- 8669945
TI  - Blood pressure and smoking: observations on a national cohort.

PMID- 8669946
TI  - Cutaneous polyarteritis nodosa.

PMID- 8669947
TI  - Foot pathology in insulin dependent diabetes.

PMID- 8669948
TI  - Lymphadenopathy.

PMID- 8669949
TI  - Lymphadenopathy.

PMID- 8669950
TI  - Nesidioblastosis unravelled.

PMID- 8669951
TI  - Ionic control of beta cell function in nesidioblastosis. A possible therapeutic
      role for calcium channel blockade.
AB  - A preterm female infant presented with intractable hypoglycaemia within 10
      minutes of delivery. Normoglycaemia could be maintained only by the intravenous
      infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic
      hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma
      insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5
      mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only
      a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy
      was performed and histological 'nesidioblastosis' confirmed. In vitro
      electrophysiological studies using patch clamp techniques on isolated pancreatic
      beta cells characterised the ionic basis for insulin secretion in
      nesidioblastosis. The beta cells were depolarised in low ambient glucose
      concentrations with persistently firing action potentials; these were blocked
      reversibly by the calcium channel blocking agent verapamil. Persistent
      postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine.
      This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and
      increased in duration the child's tolerance to fasting from 3 to 10.5 hours.
      These data allude to an abnormality in the ionic control of insulin release in
      nesidioblastosis and offer a new logical approach to treatment which requires
      further evaluation.

PMID- 8669952
TI  - Growth and endocrine function after near total pancreatectomy for
      hyperinsulinaemic hypoglycaemia.
AB  - Seven children, with a mean (SD) age of 4.6 (2.1) years, who as infants (21 (7.5)
      days) underwent near total (95-98%) pancreatectomy for persistent
      hyperinsulinaemic hypoglycaemia of infancy (PHHI) were studied. At birth all the
      infants were macrosomic. Four infants had been born after a difficult labour, of
      whom three had moderate birth asphyxia and respiratory distress. All had normal
      thyroid function. After surgery transient hyperglycaemia was manifest in six of
      the children and required insulin treatment for 5.8 (3.8) weeks, and transient
      hypoglycaemia was encountered in one child and responded well to increased
      carbohydrate intake and diazoxide for three weeks. Six of the children rapidly
      crossed down their length and weight centiles during the first year after
      surgery. At the end of the first year these children were at or below the 5th
      centile of height and weight for their age and gender. After a period of 4.6
      (2.1) years, their mean (SD) height score was -2.57 (0.5), growth velocity 3.9
      (0.75) cm/year, and growth velocity SD score -2.1 (0.55)l these were
      significantly low and denoted significant growth retardation. The growth hormone
      peak responses to provocation with clonidine were normal (13.5 (2.8)
      micrograms/l). However, the circulating insulin-like growth factor-I (IGF-I)
      concentrations were significantly decreased (79 (34) ng/ml). Three of the
      children developed diabetes at two and a half, five, and seven years after
      surgery, two others had impaired oral glucose tolerance and six out of the seven
      children had an impaired C peptide response to glucagon. Defective insulin
      secretion in these children might directly inhibit IGF-I synthesis in the liver.
      The body mass index of the pancreatectomised children was 14.9 (0.5) and was
      normal for age and gender; they had a normal 72 hour faecal fat content and
      normal serum albumin concentration. These data indicated grossly adequate
      exocrine pancreatic function. It appears that children requiring near total
      pancreatectomy for PHHI have normal developmental milestones but defective linear
      growth with impaired insulin secretion and low IGF-I production despite normal
      growth hormone response to provocation.

PMID- 8669953
TI  - Standards for total body fat and fat-free mass in infants.
AB  - Data on body composition in conjunction with reference centiles are helpful in
      identifying the severity of growth and nutritional disorders in infancy and for
      evaluating the adequacy of treatment given during this important period of rapid
      growth. Total body fat (TBF) and fat-free mass (FFM) were estimated from total
      body electrical conductivity (TBEC) measurements in 423 healthy term Caucasian
      infants, aged 14-379 days. Cross sectional age, weight, and length related
      centile standards are presented for TBF and FFM. Centiles were calculated using
      Altman's method, based on polynomial regression and modelling of the residual
      variation. The TBF percentage steeply increased during the first half year of
      life, and slowly declined beyond this age. Various simple TBEC derived
      anthropometric prediction equations for TBF and FFM are available to be used in
      conjunction with these standards. Regression equations for the P50 and the
      residual SD, depending on age, weight, or length, are provided for constructing
      centile charts and calculating standard deviation scores.

PMID- 8669954
TI  - The changing clinical pattern of Reye's syndrome 1982-1990.
AB  - OBJECTIVE: To describe trends in the clinical pattern of Reye's syndrome in the
      British Isles between 1982 and 1990; and to determine the relation between any
      changes and the June 1986 warnings against the use of aspirin in children.
      DESIGN: Development, and application to reported cases, of a scoring system
      designed such that patients showing the typical clinical and pathological
      features of 'classical' Reye's syndrome scored highly. The relations between
      'Reye scores' and a number of explanatory variables were explored using
      multivariable analysis. SETTING: British Isles. SUBJECTS: 445 cases fulfilling
      the Reye's syndrome case definition reported to the surveillance scheme between
      January 1982 and December 1990. MAIN OUTCOME MEASURE: Individual 'Reye score'.
      RESULTS: Cases with high scores were more likely to have occurred in the 4 1/2
      year period before June 1986 compared with the subsequent period (p < 0.006).
      Numbers of cases in the low and intermediate score categories declined by about
      50% after June 1986, whereas those in the high category fell by 79%. High scorers
      were more likely to have received aspirin (p < 0.0001) and were older than
      intermediate and low scorers (p < 0.008). No relation was identified between
      score and season of onset. CONCLUSIONS: The decline in Reye's syndrome after the
      aspirin warnings cannot be explained entirely, as has been proposed, by improved
      diagnosis of 'Reye-like' inherited metabolic and other disorders: this would not
      account for the greater decline of the high scoring subgroup which also contained
      those cases most likely to resemble 'classical' Reye's syndrome and to have
      received aspirin. This study provides further evidence for the role of aspirin in
      a subset of cases meeting the standard diagnostic criteria for Reye's syndrome
      and supports the need to consider this disorder as a heterogeneous group of
      conditions including Reye-like inherited metabolic disorders.

PMID- 8669955
TI  - Endocrinology and auxology of sibships with non-classical congenital adrenal
      hyperplasia.
AB  - The symptoms, auxological characteristics, and stimulated 17-hydroxyprogesterone
      (17-OHP) concentrations in a group of patients with non-classical 21-hydroxylase
      deficiency (NCCAH) were compared with those of their siblings. Ten index cases
      consisting of nine females and one male patient aged 3-33 years and 16 siblings
      were studied. In the sibling group five subjects were slightly virilised and of
      these, two females were found to have NCCAH according to their stimulated 17-OHP
      concentrations. The remaining nine siblings, who were not virilised, all had
      normal stimulated 17-OHP concentrations. Among the total NCCAH group (index cases
      and affected siblings) eight patients had the diagnosis made within two years of
      the onset of symptoms. In four patients diagnosis was delayed until adulthood. In
      seven patients investigated, bone age was significantly increased before
      treatment. The mean height and body mass index Z scores of the affected patients
      as a total group or when divided according to skeletal maturity were not
      significantly different from either the normal mean or from their unaffected
      siblings. Virilised siblings of patients with NCCAH should have stimulated 17-OHP
      levels measured to exclude the disease. Patients with NCCAH do not appear to be
      at risk of short adult stature despite increased bone age in childhood.

PMID- 8669956
TI  - Factors affecting the variation in plasma phenylalanine in patients with
      phenylketonuria on diet.
AB  - The optimal dietary management of children with phenylketonuria (PKU) has rarely
      been rigorously explored. The aim of this study was to assess longitudinally the
      effects of three factors thought to influence plasma phenylalanine concentrations
      in PKU: total energy intake; protein intake from natural foods allowed freely in
      addition to allocated phenylalanine exchanges; and the distribution of protein
      substitute throughout the day. Nineteen subjects, 15 girls and four boys aged 1
      16 years, were enrolled. Food intake was weighed, and twice daily plasma
      phenylalanine concentrations measured during either 3-day or 4-day periods, for a
      total of 21 days throughout six months. There was a negative correlation between
      the percentage of protein substitute eaten by the time of the evening meal and
      the fall in plasma phenylalanine concentration during the day (r = -0.941; p <
      0.0001). On average, 49% of pre-evening meal plasma phenylalanine concentrations
      were less than 100 mumol/l in children who had taken at least 65% of their
      protein substitute by the time of their evening meal. There was no correlation
      between excess natural protein intake from freely allowed foods and (a) pre
      breakfast or pre-evening meal plasma phenylalanine concentrations or (b) the
      daily change between pre-breakfast and pre-evening meal concentrations. Nor was
      there any correlation between excess natural protein intake on the previous day
      and plasma phenylalanine concentration on the following morning. Energy intake
      was not correlated with plasma phenylalanine concentrations. It is therefore
      preferable to distribute the protein substitute evenly through the day in order
      to achieve stable phenylalanine concentrations, rather than to carry out further
      fine manipulation of the phenylalanine intake, which would make management of the
      diet even more difficult.

PMID- 8669957
TI  - Family stress and metabolic control in diabetes.
AB  - The common clinical assumption that stress has a deleterious effect on metabolic
      control in insulin dependent diabetes mellitus (IDDM) has not been confirmed in
      children and adolescents. This cross sectional study of 43 children and
      adolescents with IDDM and their families examined the relations between family
      life stress, family social support, and metabolic control. High family life
      stress was found to be strongly correlated with HbA1c in the whole group (n = 43)
      and in children under 12 years (n = 27) when considered separately. Family social
      support was not found to be directly related to HbA1c, but was found to buffer
      the effects of family life stress. These findings support the hypotheses that
      family stress affects metabolic control in IDDM and that good social support
      buffers these deleterious effects.

PMID- 8669958
TI  - Family structure, neonatal infection, and hay fever in adolescence.
AB  - OBJECTIVE: To determine whether increased numbers of siblings and infection in
      early life protect against allergic sensitisation. DESIGN: Historical cohort
      study. SETTING: Sheffield, UK. SUBJECTS: 11,765 children aged 11-16 years for
      whom a history of neonatal infectious illness had been recorded systematically at
      1 month of age. METHODS: A history of hay fever and family structure was obtained
      by postal questionnaire; neonatal illness history was ascertained from health
      visitor records; 723 children underwent skin prick testing with mixed grass
      pollen extract. RESULTS: The prevalence of hay fever was reduced (p < 0.0001)
      among children of younger mothers, and those from larger families. The number of
      older siblings exerted a stronger independent effect than the number of younger
      siblings (p < 0.001). Infants breast fed exclusively during the first month were
      at higher risk (p < 0.05) of subsequent hay fever, independent of demographic
      factors. Adolescents at high risk of hay fever by virtue of their family
      structure were more likely to be sensitised to grass pollen (p < 0.002). No
      significant relations emerged between hay fever and infection in the first month
      of life, even among children born in June. CONCLUSIONS: The association of hay
      fever with family structure is not due to reporting bias and reflects an
      environmental influence on allergic sensitisation. The effects of sibship size,
      birth order, and infant feeding are consistent with a protective influence of
      postnatal infection. The first month of life and the first postnatal exposure to
      allergen are not the critical periods during which this protective effect is
      determined.

PMID- 8669959
TI  - Breathing, sleep state, and rectal temperature oscillations.
AB  - Overheating may cause terminal apnoea and cot death. Rectal temperature and
      breathing patterns were examined in normal infants at home during the first 6
      months of life. Twenty one infants had continuous overnight rectal temperature
      and breathing recordings for 429 nights (mean 20.4 nights, range 7-30) spaced
      over the first six months of life. Periods when breathing was 'regular' were
      directly marked on single night records. Sleep state was determined from
      respiratory variables. 'Regular' breathing was a reliable marker of 'quiet' sleep
      (specificity 93%). The duration of 'quiet' sleep increased from 6 to 22 minutes
      from two weeks to three months of age and then remained static, as did the
      proportion of sleep spent in the quiet phase (9% to 34%). Rectal temperature fell
      during 66% of quiet sleep and usually rose during rapid eye movement (REM) sleep.
      The drop in rectal temperature was maximal at the start of quiet sleep, whereas
      the maximum rise during REM sleep was reached after 10 to 15 minutes.
      Oscillations in rectal temperature are associated with changes in sleep and
      breathing state. The maturation of rectal temperature patterns during the first
      six months of life are closely related to a maturation of sleep state and
      breathing patterns.

PMID- 8669960
TI  - Lung function after allogeneic bone marrow transplantation for leukaemia or
      lymphoma.
AB  - Longitudinal data were analysed on the lung function of 25 of 29 survivors of
      childhood leukaemia or lymphoma, who had been conditioned with cyclophosphamide
      and total body irradiation before allogeneic bone marrow transplantation, to test
      whether children are particularly vulnerable to pulmonary damage after
      transplantation. None developed chronic graft-versus-host disease. Transfer
      factor and lung volumes were reduced immediately after bone marrow
      transplantation, but increased during the following years. However, at the last
      follow up, 4-13 years (median 8) after transplantation, patients had
      significantly reduced transfer factor, total lung capacity, and forced vital
      capacity (-1.0, -1.2, and -0.8 SD score, respectively), and increased ratio of
      forced expiratory volume in one second to forced vital capacity (+0.9 SD score).
      None of the patients had pulmonary symptoms, and changes were unrelated to their
      age at bone marrow transplantation. In conclusion, patients had subclinical
      restrictive pulmonary disease at a median of eight years after total body
      irradiation and allogeneic bone marrow transplantation.

PMID- 8669961
TI  - Final height of patients who underwent bone marrow transplantation during
      childhood.
AB  - OBJECTIVE: To determine the impact on final adult height of bone marrow
      transplantation. METHODS: The final height of 28 long term survivors (18 males;
      10 females), allografted before or at the onset of puberty, at a median age of
      10.8 years (range 6.3 to 14.6) and who did not receive growth hormone (GH)
      treatment or other growth promoting agents, was evaluated. Median follow up
      period after bone marrow transplantation was 7.9 years (range 3.2 to 11.4), and
      age at the most recent evaluation 18.1 years (range 15.6 to 24.5). Height values
      were expressed in standard deviation score (SDS) from the mean of the normal
      population. Height at bone marrow transplantation was compared with final height
      as well as with parental genetic height. Patients were divided into three groups:
      severe aplastic anaemia (SAA): three patients given no radiotherapy; leukaemia
      total body irradiation (TBI): 14 patients with acute or chronic leukaemia
      conditioned with chemotherapy and TBI; leukaemia-TBI with previous cranial
      radiation therapy (CRT): 11 patients. None of the patients had solid tumour.
      RESULTS: There was a decrease in final height SDS compared to pre-transplantation
      height SDS (paired t test, p < 0.0001). All patients except one reached an adult
      height above -2.0 SDS. A significant decrease in height SDS was found in the TBI
      and the CRT groups (paired t test, p = 0.02 and p = 0.0002, respectively).
      Whereas height SDS value at the time of transplant was higher than the genetic
      height SDS, final height SDS values were lower. CONCLUSIONS: Despite the decrease
      in height SDS found after bone marrow transplantation, 27 of the 28 patients
      spontaneously achieved what is considered to be a normal height SDS (above -2.0
      SDS). This should be taken into account when considering GH treatment in children
      who underwent bone marrow transplantation for malignant haematological diseases.

PMID- 8669962
TI  - Abnormal anatomy of the lumbosacral region imaged by magnetic resonance in
      children with anorectal malformations.
AB  - OBJECTIVE: To investigate the frequency of lumbosacral anomalies, the association
      with urogenital abnormalities, and the correlation with defaecation pattern by
      magnetic resonance imaging (MRI). METHODS: A prospective analysis was performed
      of routine MRI in patients with anorectal malformations. Between 1990 and 1994,
      MRI was performed in 43 such patients: 31 boys and 12 girls. Twenty four had a
      high anorectal malformation, 16 had a low anorectal malformation, and three had
      Currarino's triad. MRI was performed before reconstruction in 26, and
      postoperatively in 17. Urogenital anomalies were found in 21. RESULTS:
      Abnormalities of the spinal cord and spine were found with MRI in 20 patients
      (46.5%); caudal regression syndrome in 10, tethered cord in two, a combination of
      both in three, and other spinal anomalies in five. These anomalies were found in
      30% of the patients with low anorectal malformations, and in 50% with high
      anorectal malformations. In patients with urogenital malformations, MRI more
      often showed spinal anomalies (13/21, 62%) than in patients without (7/22, 32%).
      In high anorectal malformations, defaecation was more often a problem in patients
      with spinal anomalies (12/15, 80%) than in patients without (2/8, 25%).
      CONCLUSIONS: Spinal anomalies in the lumbosacral region were found with MRI in
      46.5% of patients with anorectal malformations. Since presence of these anomalies
      seems to be related to clinical outcome, MRI should be performed routinely in all
      such patients.

PMID- 8669964
TI  - Lung resection in cystic fibrosis patients with localised pulmonary disease.
AB  - The results of lobar resection to treat severe localised bronchiectasis in six
      children with cystic fibrosis are described. Sustained clinical improvements
      occurred in children undergoing this surgical approach to treatment. Detailed
      assessment and intensive preoperative and postoperative medical treatment are
      essential to a favourable outcome in carefully selected patients.

PMID- 8669963
TI  - A national survey of screening for congenital dislocation of the hip.
AB  - OBJECTIVE: To identify current screening and management practices for congenital
      dislocation of the hip (CDH), and determine the extent to which ultrasound
      imaging of the hips is practised throughout the United Kingdom and the Irish
      Republic. METHODS: Postal questionnaire to paediatricians responsible for the
      routine neonatal care of infants in all maternity units in the UK and the Irish
      Republic. RESULTS: Questionnaires were returned for 254 maternity units (92%
      response rate). By 1994, 69% of maternity units had access to ultrasound imaging
      of the hips, compared to 14% in 1984. Ultrasound imaging of the hip was not used
      for universal primary screening, but in 93% of units was undertaken for further
      assessment of infants with clinically detected hip instability or those
      identified as being at high risk of CDH, or both. Clinical screening of newborn
      infants was performed by junior paediatricians, but training with a 'Baby Hippy'
      hip simulator model was provided in only 37% of units. Treatment of clinically
      detected hip instability, initiated by an orthopaedic surgeon in 93% of units,
      varied widely in type and duration. CONCLUSIONS: Ultrasound imaging of the hip is
      increasingly used in the UK for secondary, rather than primary, screening.
      Current recommendations are implemented to a variable extent nationally, and the
      existing wide variation in screening and management for CDH reflects a lack of
      research evidence to support current screening practices. The effectiveness of
      screening for CDH needs to be established.

PMID- 8669965
TI  - The potential effect of the UK 1990 height centile charts on community growth
      surveillance.
AB  - The UK 1990 height charts are derived from an up to date dataset and introduce a
      change in the centile lines, particularly the addition of the 0.4th centile. This
      study examined the likely impact of these changes. Height data from London school
      children (1990-1993) were examined using Tanner and Whitehouse (TW) and UK 1990
      charts. Numbers of children with height below TW 3rd centile were compared with
      numbers below the UK 1990 3rd and 0.4th centiles. The TW charts identified only
      1% of children below the TW 3rd centile, while the UK 1990 charts identified 3%
      below the 3rd and 0.4% below the 0.4th centiles. If the 3rd centile remains as
      the referral 'cut off' for short stature, the introduction of the UK 1990 charts
      would increase current workload two- to three-fold, while a change to the 0.4th
      centile would reduce it by 50%. A significant number of children with
      abnormalities may be excluded from further assessment as a result of this latter
      change. In this small scale community study it is not possible to assess the
      consequences of this change. The heights at diagnosis of children with growth
      hormone (GH) deficiency (peak GH < 20 mU/l during a standard provocation test)
      were therefore compared to the 0.4th centile (UK 1990 charts). Sixty eight
      children with heights < 2nd centile (UK 1990 charts) currently receiving GH
      replacement (17 female, 51 male, aged 9.7, SD 3.5, years) were assessed, and of
      these, 28 (41%) had heights at diagnosis between 0.4th and 2nd centile, with a
      mean height standard deviation score of -2.32 (SD 0.21). This suggests that if
      the 0.4th centile were to be used as the sole criterion for referral for slow
      growth, a significant proportion of children with abnormality would not be
      referred for further assessment. The UK 1990 2nd centile should replace the TW
      3rd centile. Children below this should undergo an intermediary medical
      assessment to confirm height measurement, to exclude from referral children with
      mild familial short stature and to identify concerns regarding the child.

PMID- 8669966
TI  - Vertical transmission of Kaposi's sarcoma.
AB  - AIDS related Kaposi's sarcoma is commonly seen in homosexual men, only
      occasionally in men and women with heterosexually acquired HIV, and extremely
      rarely in children. The case of an HIV infected mother and her vertically
      infected child who both developed visceral Kaposi's sarcoma is reported. It is
      proposed that the putative Kaposi's sarcoma agent may also be transmitted
      vertically.

PMID- 8669967
TI  - CD40 ligand deficiency presenting as unresponsive neutropenia.
AB  - A male child presented with recurrent respiratory infections, otitis media, and
      oral ulceration and was found to be neutropenic. Investigations showed
      hypogammaglobulinaemia with normal serum IgM and a novel deletion in the gene for
      CD40 ligand on his X chromosome. Intravenous gammaglobulin did not lead to
      resolution of his neutropenia; G-CSF was also necessary.

PMID- 8669968
TI  - The epidemiology of paediatric inflammatory bowel disease.
AB  - A retrospective study of the incidence and prevalence of paediatric inflammatory
      bowel disease over an 11 year period was undertaken in South Glamorgan. Over this
      time the incidence of Crohn's disease more than doubled from 1.30 cases per
      100,000 childhood population per year in the period 1983-1988, to 3.11 cases per
      100,000 population per year in the period 1989-1993. In contrast, the incidence
      of ulcerative colitis remained the same throughout the study period at 0.71 per
      100,000 per year. In 1993 the prevalence of Crohn's disease in the childhood
      population was 16.6 per 100,000 and of ulcerative colitis, 3.42 per 100,000.

PMID- 8669969
TI  - Enteroviral pharyngitis diagnosed by reverse transcriptase-polymerase chain
      reaction.
AB  - The role of enteroviruses in childhood pharyngitis was investigated using
      enteroviral specific reverse transcriptase-polymerase chain reaction (RT-PCR).
      Viral/bacterial throat swabs were taken from 50 children with acute pharyngitis
      and 26 controls. A positive culture was identified in only 26% of children with
      pharyngitis (adenovirus 10%, group A streptococci 2%), and none of the controls.
      Enteroviral RT-PCR was positive in 8% of the pharyngitis group and none of the
      controls. Enteroviruses are an important cause of pharyngitis in childhood.

PMID- 8669970
TI  - Fibrosing colonopathy in cystic fibrosis.
AB  - The introduction of enteric coated pancreatic enzyme supplements in the early
      1980s was undoubtedly one of the major advances in the care of children with
      cystic fibrosis. Further refinements in the presentation of these preparations
      inevitably followed, to improve patient acceptability and compliance. The
      emergence of fibrosing colonopathy took clinicians dealing with cystic fibrosis
      completely by surprise, and in the last two years there has been a gradual
      appreciation that as far as pancreatic enzyme products are concerned 'More is not
      necessarily better'. However, it is encouraging that, in the UK, there have been
      no histologically confirmed cases in children receiving high strength pancreatic
      enzyme preparations since July 1994. Hopefully this trend will continue and the
      causal factors will be defined, ensuring that this serious complication can be
      effectively prevented in the future.

PMID- 8669971
TI  - Writing and marking examinations for paediatrics.
AB  - Examinations are an essential element of medical education, which generates
      vehement debate but unfortunately a relative lack of rigorous critical analysis.
      There appears to be a background anxiety that research findings that might
      suggest an examination has been less than fair will lead to endless arguments
      with candidates who have failed that examination. It is a major responsibility of
      all those involved in examining to seek evidence of the fairness, reliability,
      and validity of the methods and the organisation of the tests. Computers have
      made analysis of results much easier. Access to shared banks of all types of
      questions and answer sheets should allow examiners to select the subject first
      and the assessment tool second but from a range of tested and continually
      modified questions which allow comparison of candidates' performance both in time
      and between institutions. The creation of examination materials and their
      evaluation must be considered as valuable an activity as research in academic
      life. There is little point in child health research if the advances in knowledge
      and skills that this generates cannot be shown to have been acquired eventually
      by present and future paediatricians.

PMID- 8669972
TI  - [Belgian tropical medicine is fully alive].

PMID- 8669973
TI  - [Contribution of a mathematical model in the control of a parasitosis: the case
      of human African trypanosomiasis due to Trypanosoma brucei gambiense].
AB  - Trypanosoma brucei gambiense sleeping sickness transmitted by tsetse flies
      (Glossina spp.) is lethal if not treated adequately. The endemicity was generally
      well under control in the sixties. However, since the seventies the disease is
      returning in most of its old foci, with alarming endemic levels in several areas.
      Mathematical modelling provides a rational basis for finding the optimal
      strategies to control these recrudescences. We present a deterministic model of
      the basic transmission of trypanosomiasis between human and vector hosts in
      natural situations. The parameters were quantified on the basis of available
      evidence from the literature. The model predicts a stable equilibrium state with
      very high prevalences: approximately 95% of humans and 27% of flies being
      infected. The model further shows that the build-up of an epidemic is initially
      very slow, and it takes several months before the equilibrium state is reached.
      Consequently communities have enough time to avoid catastrophic situations by
      migrating to safer areas. If is therefore unlikely that such high equilibrium
      situations will occur in practice. The expression of the basic reproductive rate
      R0, the number of new infections during the lifetime of an infected subject with
      high values of R0 implies that efforts to diminish transmission to levels where
      the disease cannot maintain itself in the population, have to be substantial. The
      necessary reduction of fly numbers in order to enable eradication, has been
      calculated. In almost all situations a reduction of at least 90% is necessary,
      which is in accordance with the field experiences of vector control programmes.
      The present model can be considered as a starting point in the further
      development of a complete simulation model, which could be applied in supporting
      decision making in trypanosomiasis control.

PMID- 8669974
TI  - [Foci of onchocercosis in Burundi: their extent and population at risk].
AB  - Active case detection in health centres and epidemiological surveys made it
      possible to determine the extent of onchocerciasis endemic regions in Burundi.
      The largest endemic region, in the north-west of the country, covers almost
      totally the province of Cibitoke and partially the adjoining province of Bubanza.
      The population at risk is 330,000. The endemic region in the south-west of
      Burundi covers more than one third of the province of Bururi and has 230,000
      people at risk. The smallest endemic region is in the province of Rutana (south
      east), where 52,000 people live.

PMID- 8669975
TI  - [Seroprevalence of hepatitis C virus among persons visiting the Burundi health
      services].
AB  - The epidemiology of hepatitis C (HCV), especially on the African continent, is
      not well known. In this study, we investigated the presence of antibodies to HCV
      in 685 out-patients, seen in several health care centers or hospitals in
      different regions in Burundi from January to February 1991. Serological tests of
      the second generation were used. The global prevalence varied from 3.2% to 14.1%
      according to the center. Urban seroprevalence tended to be higher than rural
      prevalence. Also, with increasing age, a higher prevalence was observed. Anti-HCV
      antibodies were absent in patients younger than 21, while specific antibodies
      were detected in 23.1% of patients older than 50. Although the prevalence in men
      (10.4%) was higher than in women (7.4%), this difference was not statistically
      significant. Taking into account the selection of subjects participating in this
      evaluation, the results can not be extrapolated to the general population. No
      association between HCV and human immunodeficiency virus (HIV) was seen in this
      study. In contrast to previously described results from studies using reagents of
      the first generation, no cross-reactions were observed with anti-malarial
      antibodies.

PMID- 8669976
TI  - Clinical manifestations of dengue haemorrhagic fever in children in Bandung,
      Indonesia.
AB  - To describe the clinical manifestations of dengue haemorrhagic fever (DHF) all
      children with a clinical diagnosis of DHF admitted to the paediatric ward of the
      Dr. Hassan Sadikin General Hospital (Bandung, Indonesia) between April 1st 1991
      and September 30th 1993 were enrolled in a prospective study. Of the 306 children
      with a clinical diagnosis of DHF on admission in only 128 (41.8%) the diagnosis
      of DHF was confirmed by HI test. Of the confirmed cases, 24 (19%) developed shock
      and 1 (0.7%) died. Of the 174 cases with a negative HI test, 33 (19%) developed
      shock and 4 (2%) died. Four of the children died of shock before an
      hemagglutination inhibitor (HI) test was performed. The overall case mortality
      rate was 2.9%. The symptoms and signs of the 128 children with serologically
      confirmed DHF included fever or a history of fever (100%), petechiae (29.7%),
      epistaxis (39.1%), other forms of bleeding (5.5%), a positive Tourniquet test
      (78.1%), hepatomegaly (46.9%), epigastric pain (61.7%), vomiting (55.5%),
      thrombocytopenia < 100,000/mm3 (3.2% on admission and 15.3% during
      hospitalisation). Four (3%) children developed encephalopathy and 1 child an
      acute liver failure. In order to decrease the mortality associated with DHF early
      diagnosis and adequate case management are essential.

PMID- 8669977
TI  - Diagnosis of amoebic infection of the liver: report of 36 cases.
AB  - The classical clinical picture of amoebic infection of the liver consists of
      fever, right upper quadrant pain and hepatomegaly. In recent years, the
      widespread availability of ultrasound and serology made an early diagnosis
      possible, which could result in less prominent clinical pictures. Thirty six
      cases of liver amoebiasis diagnosed in Antwerp between 1985 and 1992, were
      reviewed. Three patients acquired their infection in Belgium. For the other
      patients, the average delay between arrival in Belgium and the first symptoms was
      5.64 months. The classical triad of clinical signs (fever, right upper quadrant
      pain and hepatomegaly), was observed in only 13.9% of the patients, whereas it
      was much more frequent in earlier studies (68-75%). The right lobe was the most
      frequently affected (94%). The colour of the liquid, obtained by puncture, was
      brown in 61% of patients in whom it was reported. Amoebic cysts were found in the
      stools of only one patient. Amoebic serology was initially negative in only one
      patient, but became positive on second testing. Chest X-rays were abnormal in 34%
      of the patients. All patients who develop unexplained fever during the year after
      a stay in tropical countries should undergo an abdominal ultrasound examination
      and serological testing for Entamoeba histolytica.

PMID- 8669978
TI  - Diagnosis of pyogenic abscesses by ultrasound.
AB  - Pyogenic infections are common in tropical countries and draining pus is one of
      the most frequent surgical operations all over the developing world. While
      superficial abscesses are easily detectable by clinical means the diagnosis of
      deeper abscesses in muscles, joints, parenchymatous organs and body cavities is
      frequently difficult or even impossible. In those situations B-mode ultrasound
      represents a valuable diagnostic tool. Furthermore, diagnosis may be confirmed or
      defined by ultrasound guided needle aspiration and ultrasound-guided drainage.
      Those measures may save surgical interventions and cost. Based on our experience
      with more than 3820 ultrasound examinations in 2746 patients of Northern Zaire
      sonographic characteristics of pyogenic abscesses are defined. Clinical examples
      of pyogenic affections with the corresponding ultrasound morphology are
      presented.

PMID- 8669979
TI  - [Impact of the introduction of a partogram on maternal and perinatal mortality.
      Study performed in a maternity clinic in Niameny, Niger].
AB  - Maternal mortality remains one of the major problems in public health today
      especially in developing countries where maternal mortality is estimated to be
      between 500 and 1000 deaths for 100,000 live births. In 1987, the safe motherhood
      initiative was launched with the objective of reducing maternal mortality by 50%
      within ten years. One of the methods introduced to reduce the high incidence of
      maternal and neonatal mortality in developing countries, is the partogram, a
      visual means used in evaluating a normal delivery. It acts as an early warning
      system, allowing for the early detection of abnormal evolution in labour as well
      for the mother as for the foetus. This instrument was introduced in all the
      maternity wards in Niger in 1990 by the Ministry of Public Health. A study was
      conducted in one of the maternities of the capital to ascertain the effectiveness
      of this new instrument to both the mother during labor and the newborn child.
      1299 women in labor, primi-and multiparous, participated in the study. Two groups
      were formed: one consisted of women that delivered prior to the introduction of
      the partogram, the second group was comprised of women who delivered after its
      introduction. The results of this study have shown that the introduction of the
      partogram: reduces the amount of time that a women is in labor, improves the
      follow-up care the pregnant woman receives, results in a more timely decision
      made by the health official, and consequently, a prompt referral to a specialised
      center. The authors estimate that, if used correctly, the introduction of this
      instrument can have along with other appropriate measures, a considerable impact
      in the reduction of maternal and neonatal mortality.

PMID- 8669980
TI  - [The method of cumulated amounts: a simple and efficient technique for
      epidemiological monitoring. Application to the epidemiological monitoring of
      malaria in the French Army in Gabon].

PMID- 8669981
TI  - Tolperisone: evaluation of the lidocaine-like activity by molecular modeling.
AB  - Tolperisone (1), a muscle relaxant with lidocaine-like activity, was compared to
      lidocaine (2) by molecular modeling methods. Conformational search analysis has
      been employed to find the global minima of these compounds along with numerous
      low energy conformations from which specific conformers were extracted that show
      good superimposition of the structural features important for protein binding.
      Two additional compounds, mepi- (3) and bupivacaine (4), were included in the
      analysis to validate the method as these ligands show very close structural and
      pharmacological relationship to lidocaine (2) and are assumed to bind to an
      identical site. As a result we find conformers of all four ligands that have
      exactly the same position and orientation of the potential sites for hydrogen
      bonding with the rest of the molecule showing close comparison of the three
      dimensional geometry. Semiempirical calculations furthermore reveal good
      agreement of the electrostatic potentials of these conformations indicating
      similar interactions with a receptor. We conclude that tolperisone (1) and
      lidocaine (2) despite their chemical divergence can still attach to identical
      protein binding sites.

PMID- 8669982
TI  - Syntheses and biological activities of new N1-aryl substituted quinolone
      antibacterials.
AB  - A series of quinolones with a systematically varied substitution at the phenyl
      ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P,
      Rm) and the pKa values have been determined as well as the microbiological
      activity: The MIC values for eight different strains of three Gram-positive and
      three Gram-negative species and the inhibitory concentrations of DNA supercoiling
      (IC90 and IC100) were determined. From a principal component and a QSAR analysis
      relationships between antibacterial activity concerning the whole-cell system and
      electronic properties as well as the length of the substituents at the phenyl
      rings could be derived. The activity in a cell-free system was governed by the
      lipophilicity and the width of the substituents. It is speculated that the
      quinolones take a defined place in the DNA gyrase-DNA complex which is
      characterized by polar amino acids. This is in agreement with findings from
      studies of mutant gyrases.

PMID- 8669983
TI  - Platelet aggregation inhibiting and anticoagulant effects of oligoamines, Part
      33. From tetradecane- to octacosanediamines.
AB  - Twenty alkanediamines were designed according to structure-activity relationships
      drawn from previous parts of this series and synthesized. Their general structure
      is CH3-(CH2)n-CHNH2-(CH2)m-CHNH2-(CH2)n-CH3, (n = 2-10; m = 3-6). Twelve of them
      inhibited the aggregation of human blood platelets in concentrations between 3-10
      micromol/L halfmaximally (Born test, inducer collagen). With increasing m a
      decreasing n is necessary to achieve the optimum activity. In the most active
      compounds (7b, 7e, 7p) it is found that m + n = 9. When the nitrogen functions
      are hydroxyalkylated secondary amines with similar antiplatelet effects are
      obtained. The conversion of the amino groups into syndronimines is accompanied by
      the loss of activity. The bisethoxycarbonylderivatives of 7f and 7m (8f, 8m)
      exhibited antithrombotic effects in rats after oral administration.

PMID- 8669984
TI  - Comparative conformational analysis of CCK-B agonist Boc-Trp-Phg-Asp-(1-Nal)-NH2
      and CCK1-B antagonist Boc-Trp-Phg-Asp-(1-Nal)-N(Me)2 using 1HNMR spectroscopy and
      restrained molecular dynamics.
AB  - The tetrapeptide Boc-Trp-Phg-Asp-(1-Nal)-NH2 is a potent CCK-B agonist.
      Interestingly, bis-methylation of the C-terminal carboxamide group of this
      compound leads to Boc-Trp-Phg-Asp-(1-Nal)-N(Me)2 which behaves as a CCK-B
      antagonist in electrophysiological studies on hippocampal neurones (Corringer et
      al., 1993). In order to ascertain whether bismethylation of the terminal
      carboxamide group has an influence on the conformational preferences of the
      peptide, we have undertaken a comparative conformational analysis of the two
      tetrapeptides by the combined use of 2D NMR spectroscopy and restrained molecular
      dynamics. The solution conformation of the two peptides were examined by 1H NMR
      in a d6-DMSO/H2O (80:20) mixture. 1H-1H distance constraints, derived from 2D
      NOESY and ROESY experiments, were used as inputs for subsequent restrained
      molecular dynamics simulations. Comparison of the NMR and molecular modeling data
      indicates different conformational preferences for these two peptides.
      Interestingly, the aromatic side chains of the CCK-B antagonist Boc-Trp-Phg-Asp
      (1-Nal)-N(Me)2 in its preferential conformation, overlap their corresponding
      moieties in the two non peptide CCK-B antagonists L-362,260 and LY-288,513. The
      differences in conformational behaviour of the studied tetrapeptides could, at
      least in part, account for their opposite agonist/antagonist profile, a findings
      which could serve for the design of new conformationally restricted CCK-B
      analogs.

PMID- 8669985
TI  - New potent azomethine prodrugs of the histamine H3-receptor agonist (R)-alpha
      methylhistamine containing a heteroarylphenyl partial structure.
AB  - The therapeutic value of histamine H3-receptor ligands is under current
      investigation. On the basis of recently described diary limine prodrugs of the
      histamine H3-receptor agonist (R)-alpha-methylhistamine (1) as a series of new
      azomethine prodrugs containing five- and six-membered heterocycles were
      synthesized and tested for their in vitro hydrolysis rates and in vivo activity
      after oral application. It was found that electron-deficient six-membered
      heterocycles drastically destabilized the imine double bond so that these
      prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five
      membered heterocycles appeared to be highly effective for the CNS delivery of 1,
      and a remarkable correlation between chemical structure and pharmacokinetic
      profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2
      propyl]imino] (1H-pyrrol-2-yl)methyl]phenol (8c), the 2-furanyl analogue 8d, and
      its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently
      described halogenated diaryl imine prodrugs of 1. However, in contrast to any
      other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1
      in the CNS and can thus be regarded as a 'retard' prodrug. Assuming that a
      therapeutic indication of histamine H3-receptor agonists will soon be
      established, these highly potent heteroarylphenyl azomethine prodrugs, which
      already serve as valuable pharmacological tools, may also become potential drugs
      in clinical use.

PMID- 8669986
TI  - Synthesis and antiplatelet activity of 1-tert-butylamino-3-(3-thienyloxy)-2
      propanols.
AB  - The synthesis of new 1-tert-butylamino-3-(3-thienyloxy)-2-propanols by two
      alternative methods is described. Their initial antiplatelet activity evaluation
      against ADP, adrenaline, and collagen is reported, and the preliminary structure
      activity relationships are established. The appropriateness of further
      pharmacological investigations, especially for the best compound of the series
      1f, is indicated.

PMID- 8669987
TI  - Gait analysis of spinal cord injured subjects: effects of injury level and
      spasticity.
AB  - OBJECTIVE: To identify abnormalities in the gait of spinal cord injured (SCI)
      subjects, particularly in relation to injury level and spasticity. DESIGN: Case
      control study comparing the gait of SCI individuals with matched controls. Video
      motion analysis was used to collect data on temporal and kinematic variables.
      Spasticity was assessed using the Ashworth score and pendulum test. Data
      regarding age, height, weight, mechanism, and level of injury were also
      collected. SETTING: Spinal cord injury clinic of a tertiary care hospital.
      PARTICIPANTS: Twenty-seven SCI individuals volunteered to participate in the
      study. All had retained walking ability (Frankel D) and could ambulate
      independently for a minimum of 10m with or without walking aids. Individuals with
      cauda equina injuries were excluded from the study. Age, gender, etiology of
      injury, and interval since injury were not used as exclusion criteria. Ten age-,
      sex-, and anthropomorphically matched controls were also recruited. RESULTS:
      Subjects with thoracic injures demonstrated reduced cadence, forward velocity,
      and knee angular velocity, whereas lumbar injuries resulted in reduced stride
      length and ankle velocities. These differences were statistically significant (p
      < .05). Gait in individuals with cervical injuries was not significantly
      different. CONCLUSIONS: Kinematic gait analysis is a sensitive means of
      quantifying gait abnormalities. Spasticity and injury level determine the pattern
      of abnormality in gait after spinal cord injury.

PMID- 8669988
TI  - Identification of static and dynamic postural instability following traumatic
      brain injury.
AB  - OBJECTIVE: Quantitative evaluation of static and dynamic aspects of postural
      instability as a long-term consequence of traumatic brain injury (TBI). DESIGN:
      Experimental two-group design. SETTING: Outpatient rehabilitation department.
      PATIENTS AND OTHER PARTICIPANTS: From a consecutive sample of TBI patients at
      least 6 months after trauma, 20 subjects were selected who complained of reduced
      gross motor skills but showed no sensorimotor impairments in a standard
      neurological examination (11 men, 9 women; mean age 36.2 +/- 10.7 years).
      Thirteen patients had sustained mild, 2 moderate, and 5 severe TBI. Twenty
      healthy controls were matched for age and gender. INTERVENTION: None. MAIN
      OUTCOME MEASURES: A dual-plate force platform recorded the amplitude and velocity
      of the center-of-pressure fluctuations in the anteroposterior (AP) and lateral
      (LAT) sway directions during quiet standing. Also, the speed and fluency of
      weight shifting using visual feedback was registered. Both balance tasks were
      combined with an arithmetic task, whereas quiet standing was also tested with
      visual deprivation. RESULTS: Compared to controls, TBI patients showed an
      increase of over 50% in AP and LAT sway, and a weight-shifting speed 20% lower.
      Dual-task interference was never significant. Visual deprivation was most
      detrimental for the TBI patients, particularly for LAT sway control. CONCLUSION:
      A long-term overall reduction in both static and dynamic control of posture can
      be present after TBI, even in patients without clear neurological deficits. Force
      plate recordings can identify such (latent) balance problems. Visual deprivation
      during quiet standing appears a simple, sensitive test for postural instability
      related to sensory integration deficits.

PMID- 8669989
TI  - Knee recurvatum in gait: a study of associated knee biomechanics.
AB  - OBJECTIVES: To quantitatively evaluate peak knee extensor torque values imparted
      to the posterior knee structures during gait in patients with knee recurvatum
      compared with torque values observed in control subjects, and to assess the
      predictive value of the degree of knee hyperextension and other clinical factors
      in estimating peak knee extensor torque. DESIGN: A retrospective analysis of
      clinical and quantitative gait data obtained from patients and control subjects.
      SETTINGS: A gait laboratory. SUBJECTS: Forty-one consecutive patients with
      neurologically based impairments presenting with knee hyperextension during gait
      (52 limbs) and 46 able-bodied control subjects. MAIN OUTCOME MEASURE: Peak knee
      extensor torque during the stance period of the gait cycle. RESULTS: Although
      overall, the patient average peak extensor torque was significantly greater (p <
      .001) than the control subjects' average value, knee extensor torques were within
      or below a +/- 1 standard deviation range for control subjects in 25% (13) of
      limbs tested. Peak knee hyperextension angle was a poor predictor of peak
      extensor torque; there was statistical significance (coefficient .061,p < .001)
      only for hyperextension angles of < or = 4 degrees. Multiple regression
      incorporating hyperextension angle and other clinical variables to predict peak
      knee extensor torque resulted in an adjusted r2 of .53. CONCLUSION: Patients with
      knee recurvatum have variable peak extensor torque values associated with their
      knee hyperextension. Knowledge of knee hyperextension angle and other clinical
      factors are only partially useful in predicting a patient's peak knee extensor
      torque imparted to the posterior knee structures during walking.

PMID- 8669990
TI  - Video assessment of rearfoot movements during walking: a reliability study.
AB  - OBJECTIVE: Rearfoot motion, particularly rearfoot pronation, has been associated
      with many foot and leg pathologies. The assessment of abnormal rearfoot pronation
      frequently involves the use of video assessment in both clinical and research
      settings, but the reliability of this assessment has not been addressed. DESIGN:
      In this study, 14 participants were videotaped during walking. Five clinicians
      individually viewed the recordings on two separate occasions and assessed whether
      the participant's rearfoot motion was abnormal. SETTING: University Gait Analysis
      Laboratory. PATIENTS OR OTHER PARTICIPANTS: Patients from the university's
      podiatry clinic were assessed for rearfoot motion by five experienced clinicians.
      INTERVENTION: Because this was a reliability study, no intervention was
      undertaken. MAIN OUTCOME MEASURES: Clinicians were asked to assess the videotape
      of the patients walking and indicate on a 3-point scale if they considered the
      person to be abnormally pronating. Retest and intertester results were compared.
      RESULTS: The results indicated that there was poor intertester agreement (kappa =
      .19). Retest agreement, while slightly higher, varied from poor to fair (kappa = 
      .12 to kappa = 59). CONCLUSIONS: Although video recordings have been thought to
      enhance reliability of assessment of rearfoot motion, the results indicated that
      the exclusive use of video recordings in the assessment of motion of the rearfoot
      was not reliable.

PMID- 8669991
TI  - Standing balance during internally produced perturbations in subjects with
      hemiplegia: validation of the balance scale.
AB  - OBJECTIVE: To examine the concurrent validity of the Berg Balance Scale (BBS) in
      subjects with hemiparesis after stroke by correlating functional balance
      performance on the BBS with laboratory measures of balance (center of pressure
      [CP] and electromyographic [EMG] activity of leg musculature during rapid arm
      flexion and during quiet stance). DESIGN: Concurrent validation study.
      Consistency of performance was determined through repeat measures obtained from
      13 subjects. SETTING: Laboratory. PATIENTS: Twenty-four volunteers with
      longstanding hemiparesis from cerebrovascular accident (CVA) were tested. MAIN
      OUTCOME MEASURES: BBS scores were compared with CP excursion speed during (1)
      self-initiated rapid unilateral arm flexion with the nonhemiplegic arm and (2)
      quiet stance. The peak tangential arm acceleration and the sequence of EMG events
      in the posterior leg muscles were monitored during the arm flexion movement.
      RESULTS: In the arm flexion condition, BBS performance was significantly
      correlated with arm acceleration and CP excursion speed (multiple regression R =
      .81). BBS performance was also related to the presence of anticipatory activation
      of ipsilateral hamstrings during the rapid arm flexion movement. BBS performance
      and CP excursion speed during quiet stance were also significantly related (r =
      .76). The initial and repeat measures were not significantly different in
      magnitude (paired tests of difference, p < .01). CONCLUSION: The BBS appears to
      reflect differing abilities to tolerate the internally produced perturbation to
      standing balance associated with forward arm flexion in individuals with
      hemiparesis from CVA.

PMID- 8669992
TI  - Measuring functional limitations in rising and sitting down: development of a
      questionnaire.
AB  - OBJECTIVE: Develop and test a self-administered questionnaire that measures
      perceived and actual functional limitations in rising and sitting down. SETTING:
      Private practices for physical therapy and outpatient clinics of hospitals and
      rehabilitation centers. PATIENTS: 345 outpatients (43% male, aged 14 to 92 years)
      with different grades of functional limitations and different types of lower
      extremity orthopedic or rheumatologic disorders. METHODS: The Questionnaire
      Rising and Sitting Down (QR&S) was developed on the basis of a literature review
      and careful operationalization of functional limitations. Five dimensions
      concerning different objects (high chair, low chair, toilet, bed, and car) and
      one global dimension were postulated to be contained in the instrument. Mokken
      scale analysis was used to test the postulated dimensions (scalability
      coefficient H). Furthermore, robustness with respect to patient characteristics
      was determined, as well as intratest reliability (reliability coefficient Rho),
      test-retest reliability (intraclass correlation coefficient [ICC]), content
      validity (coverage of operationalized aspects), and construct validity (testing
      of seven hypotheses). RESULTS: Mokken scale analysis confirmed the existence of 5
      object dimensions (H = .53-.59). However, two global dimensions were found (H =
      .50-.54). The resulting hierarchical scales, consisting of subsets of the 32
      final QR&S items, are robust and measure functional limitations in a reliable
      (Rho .77-.91; ICC .72-.90) and valid (3 out of 4 aspects covered, 2 hypotheses
      rejected for 3 out of 7 scales) manner. CONCLUSION: The QR&S is a reliable and
      valid self-administered questionnaire. It consists of hierarchical scales and
      measures perceived and actual functional limitations in rising and sitting down.

PMID- 8669993
TI  - Contralateral shoe-lift: effect on oxygen cost of walking with an immobilized
      knee.
AB  - OBJECTIVE: Evaluate the effect of a contralateral shoe-lift on the oxygen cost of
      walking with an artificially immobilized knee. DESIGN: A prospective quantitative
      evaluation of oxygen cost of walking under varying conditions. Subjects walked
      (1) normally (N), (2) with one knee immobilized (1), (3) with one knee
      immobilized and with a one-half-inch shoe-lift applied to the contralateral shoe
      (I1/2"L), and (4) with one knee immobilized and with a one-inch shoe-lift (I1"L).
      SETTING: Exercise physiology laboratory. SUBJECTS: Ten able-bodied subjects
      without known cardiopolmonary or musculoskeletal problems. MAIN OUTCOME MEASURE:
      Breath-by-breath oxygen consumption measurements in mL/kg/m. RESULTS: Oxygen cost
      on average was 20% more with the knee immobilized (I) compared to normal (N)
      (mean difference = .0298 +/- .0245mL/kg/m, p = .002). Oxygen cost was
      significantly less (11% versus 20% above that of normal walking) with the half
      inch shoe-lift (mean difference between I1/2" and I = .0167 +/- .0138mL/kg/m, p =
      .002). Similarly, oxygen cost was significantly less (12% versus 20% above that
      of normal walking) with the one-inch shoe-lift (mean difference between I1"L and
      I = .0142 +/- .0116, p = .002). CONCLUSION: This study demonstrates that a
      subject with an immobilized knee requires less energy to walk with a
      contralateral shoe-lift and provides scientific evidence for prescribing a shoe
      lift in patients with an immobilized knee as a result of knee joint fusion, knee
      immobilization as a result of casting or orthotics, or spastic paretic stiff
      legged gait associated with upper motor neuron disease.

PMID- 8669994
TI  - Back school in a first episode of compensated acute low back pain: a clinical
      trial to assess efficacy and prevent relapse.
AB  - OBJECTIVE: To assess the efficacy of a back school program for patients with a
      first episode of acute work-related low back pain requiring compensation. DESIGN:
      A randomized single-blind controlled trial. SETTING: A private physiatrics
      outpatient clinic. PATIENTS: The mean duration of low back pain was 15 days.
      INTERVENTION: Eligible patients were randomized to a standard treatment program
      that included daily physiotherapy (n = 86) or the same program with the addition
      of back school (n = 82). The back school program consisted of three 90-minute
      sessions given by a single trained instructor at 0, 1, and 8 weeks. MAIN OUTCOME
      MEASURES: The primary outcomes were the time off work for the presenting episode
      of back pain and the number and duration of recurrences in the year following the
      study onset. Secondary outcomes included the level of pain, spinal mobility,
      active straight-leg raising, and functional disability assessed by the Oswestry
      and Roland-Morris scales. RESULTS: Those randomized to the back school group
      gained significantly more knowledge, based on the multiple choice examination (p
      = .0001) and performed the exercise program significantly better (p = .0001) than
      the standard care group. There were no differences between the two treatment
      groups for either of the primary outcomes. The median time to return to work from
      randomization was 33 days for both the back school and the standard care groups
      (p = .48). The number of compensated recurrences of low back pain over 1 year was
      similar (back school = 14, standard care = 10, p = .16), as was the median
      duration of these episodes (back school = 25 days, standard care = 70 days, p =
      .21). There were no significant differences favoring the back school group for
      any of the secondary outcomes at the posttreatment, 6-month, or 12-month
      assessments. CONCLUSION: A back school intervention in addition to standard care
      resulted in no reduction in the time to return to work or the number or duration
      of recurrences of low back pain requiring compensation over a period of one year.

PMID- 8669995
TI  - Neck flexor muscle strength, efficiency, and relaxation times in normal subjects
      and subjects with unilateral neck pain and headache.
AB  - OBJECTIVE: To determine the test-retest reliability of a new method for measuring
      muscular strength, efficiency, and relaxation times of the neck flexor
      musculature of healthy adults, and to compare these neck flexor muscle properties
      in subjects who have unilateral neck pain and headache with those in controls.
      DESIGN: Subjects lay supine and isometrically flexed their necks against a force
      transducer attached to the back of a webbing and velcro helmet. Electromyograms
      (EMGs) were recorded from surface electrodes on the sternocleidomastoid (SCM)
      muscles. Two consecutive sessions of five contractions of varying levels of
      effort from minimal through moderate and maximal effort were analyzed. SETTING:
      Ambulatory referral center. PARTICIPANTS: Volunteer control subjects (n = 10, 3
      men and 7 women) were recruited from hospital and university personnel. Volunteer
      neck pain subjects (n = 10, 3 men and 7 women) were recruited from a physiatric
      chronic pain practice and a hospital outpatient physical therapy practice.
      RESULTS: In the controls, the intraclass correlation coefficients (ICCs) for the
      first two maximum neck flexion contractions were; peak force ICC = .81; peak
      force/body weight ICC = .75; average force ICC = .75; force relaxation time ICC =
      .73; SCM EMG relaxation times: right ICC = .60 and left ICC = .67. Comparing
      sessions 1 and 2 the intraclass correlations for SCM efficiencies were right ICC
      = .58 and left ICC = .97. The peak force in controls (mean = 45.3 +/- 17.6N) was
      reduced by 50% in the neck pain subjects (mean = 22.4 +/- 13.1N) (p = .004).
      Similarly, peak force/body weight in the neck pain subjects (X = 0.3 +/- 0.2N/kg)
      was 46% of control (mean = 0.7 +/- 0.2N/kg) (p = .001), and average force in the
      neck pain subjects (X = 12.1 +/- 7.5N) was 43% of controls (mean = 28.5 +/-
      11.0N) (p = .001). In two neck pain subjects. SCM, EMG and force relaxation times
      were abnormally long in both the affected and the unaffected SCM muscles,
      exceeding the control values by greater than 3 standard deviations. The
      difference between the right SCM efficiency of the control subjects (mean = 0.3
      +/- 0.2N/ microV) and the affected SCM efficiency of the neck pain subjects (mean
      = 0.1 +/- 0.1 N/microV) approached the p < .05 criterion for significance (p =
      .055). CONCLUSION: The technique was found to be highly reliable for the
      measurement of neck flexor peak force, peak force/body weight, average force, and
      force relaxation time, and moderately reliable for the quantitation of SCM EMG
      relaxation times and SCM efficiency. All force values were significantly lower in
      the neck pain population compared with the controls. In the neck pain population,
      force and SCM EMG relaxation times, as well as efficiencies, suggested
      abnormalities. Neck pain subjects showed no significant differences in SCM EMG
      relaxation time or SCM efficiency between affected and unaffected SCM muscles.

PMID- 8669996
TI  - Sport stretching: effect on passive muscle stiffness of short hamstrings.
AB  - OBJECTIVE: To evaluate the effects of one 10-minute stretch on muscle stiffness
      in subjects with short hamstrings. DESIGN: Randomized control trial. SETTING:
      Laboratory for human movement sciences in the department of rehabilitation of a
      university hospital. SUBJECTS: Sixteen students from the Department of Human
      Movement Sciences participated with informed consent in the experiment. Subjects
      were limited to men and women without a history of neurological and orthopedic
      disorders. To select subjects with short hamstrings, the finger-ground distance
      had to be greater than 0cm (unable to touch the floor when bending forward) and
      the manual leg lifting was not to exceed 80 degrees. One group of 10 subjects
      performed static stretching exercises during 10 minutes interspersed with
      relaxing, whereas the untreated group of 6 subjects was used as a control. MAIN
      OUTCOME MEASURES: The instrumental straight-leg-raising set-up enables the
      measurement of the force needed to lift the leg, range of motion (ROM), pelvic
      femoral angle, and the electromyogram of the hamstrings. These variables provide
      information about the stiffness, elongation, and state of activity of the
      hamstring muscles. RESULTS. One 10-minute sport stretch resulted in a significant
      increase in passive muscle moment, ROM, and elongation of the hamstrings. There
      was no significant change in the course of the passive muscle stiffness curve
      with respect to the prestretch stiffness curve. CONCLUSIONS: One session of
      static stretching does not influence the course of the passive muscle stiffness
      curve. The increased ROM, i.e., the extensibility of the hamstrings, results from
      an increase in the stretch tolerance.

PMID- 8669997
TI  - Function-based payment model for inpatient medical rehabilitation: an evaluation.
AB  - OBJECTIVE: To describe the components of a function-based prospective payment
      model for inpatient medical rehabilitation that parallels diagnosis-related
      groups (DRGs), to evaluate this model in relation to stakeholder objectives, and
      to detail the components of a quality of care incentive program that, when
      combined with this payment model, creates an incentive for provides to maximize
      functional outcomes. DATA SOURCES: This article describes a conceptual model,
      involving no data collection or data synthesis. DATA SYNTHESIS: The basic payment
      model described parallels DRGs. Information on the potential impact of this model
      on medical rehabilitation is gleaned from the literature evaluating the impact of
      DRGs. The conceptual model described is evaluated against the results of a Delphi
      Survey of rehabilitation providers, consumers, policymakers, and researchers
      previously conducted by members of the research team. CONCLUSIONS: The major
      shortcoming of a function-based prospective payment model for inpatient medical
      rehabilitation is that it contains no inherent incentive to maximize functional
      outcomes. Linkage of reimbursement to outcomes, however, by withholding a fixed
      proportion of the standard FRG payment amount, placing that amount in a "quality
      of care" pool, and distributing that pool annually among providers whose
      predesignated, facility-level, case-mix-adjusted outcomes are attained, may be
      one strategy for maximizing outcome goals.

PMID- 8669998
TI  - Electrical stimulation and biofeedback effect on recovery of tenodesis grasp: a
      controlled study.
AB  - OBJECTIVE: Evaluate the effectiveness of electrical stimulation and biofeedback
      on the recovery of tenodesis grasp in tetraplegic individuals during the initial
      phase of acute rehabilitation. DESIGN: A 2 x 2 block design was used with
      subjects randomized to treatment groups. Forty-five subjects completed the study.
      SETTING: Inpatient occupational therapy department. SUBJECTS: Inpatients with
      tetraplegia, first admission for rehabilitation after an acute spinal cord
      injury. INTERVENTIONS: The four treatment groups were: conventional treatment,
      electrical stimulation, biofeedback, and combined electrical stimulation and
      biofeedback. The treatment period was between 5 and 6 weeks. MAIN OUTCOME
      MEASURES: Manual muscle testing and scoring of activities of daily living
      performance by a blinded evaluator. RESULTS: All four treatment groups showed
      improvements. No treatment group was superior to the others. CONCLUSIONS:
      Biofeedback and electrical stimulation alone or in combination offer no
      advantages over conventional rehabilitation treatment of wrist extensors in
      tetraplegic patients after spinal cord injury.

PMID- 8669999
TI  - Pneumonia associated with aspiration following stroke.
AB  - OBJECTIVE: To determine the association between demonstrated aspiration and
      pneumonia in stroke patients. METHODS: Chart review of 441 consecutive stroke
      patients admitted to a stroke rehabilitation unit within 4 months of their stroke
      over an 8-year period. Videofluoroscopic modified barium swallow (VMBS) was
      performed on all patients suspected of aspirating. In all patients, the presence
      or absence of pneumonia was noted. RESULTS: Eighty-four of the 441 (19.0%) stroke
      patients transferred for rehabilitation demonstrated aspiration of thin liquids
      on VMBS. Twelve of the 441 (2.7%) developed pneumonia while in hospital, either
      in the acute or rehabilitation phases. The incidence of pneumonia among proven
      aspirators on VMBS was 10 of 84 (11.9%) patients. Two of the 357 (0.6%) patients
      who were presumed nonaspirators developed pneumonia. Brain stem and right
      hemispheric stroke patients had a higher incidence of pneumonia. CONCLUSIONS:
      Pneumonia is an uncommon complication of stroke. However, approximately 12% of
      stroke rehabilitation patients diagnosed as aspirators on VMBS developed
      pneumonia, a 20-fold increase over presumed nonaspirators. VMBS is a potentially
      valuable tool in determining those patients at risk of aspiration pneumonia.

PMID- 8670000
TI  - "Subclinical" orthostatic hypotension is associated with dizziness in elderly
      patients with Parkinson disease.
AB  - OBJECTIVE: To investigate risk factors associated with subjective complaints of
      dizziness in 12 elderly patients with Parkinson disease (PD), in whom no obvious
      cause for this symptom could be found. DESIGN: A case-controlled study, with
      patients prospectively recruited in a nonblinded fashion. SETTING: Patients were
      seen by one physician at a neurology outpatient clinic between August 1993 and
      August 1994. SUBJECTS: Thirty-six patients, all over age 65 years and all with
      PD; 12 complained of dizziness; 24 did not. INTERVENTIONS: Patients and controls
      were screened for blood pressure changes, postural instability, motor severity,
      multiple sensory deficits, drug use, cardiovascular disease, and diabetes
      mellitus. MAIN OUTCOME MEASURES: An orthostatic decrease of systolic BP > 15 mmHg
      (odds ratio = 6.5; 95% confidence interval = 1.22 - 34.52; chi 2mh = 6.7; p <
      .01) and an orthostatic decrease of diastolic BP > 5mmHg (odds ratio = 11; 95%
      confidence interval = 3.15 - 38.39; chi 2mh = 7.14; p < .01) were significant
      risk factors for complaints of dizziness. RESULTS: The only significant risk
      factors linked with dizziness were orthostatic decreases in systolic (15 mmHg)
      and diastolic (5 mmHg) blood pressure. CONCLUSIONS: An orthostatic decrease in
      blood pressure is associated with unexplained feelings of dizziness in elderly PD
      patients.

PMID- 8670002
TI  - Botulinum toxin A in the treatment of spasticity: functional implications and
      patient selection.
AB  - OBJECTIVE: To explore the range of functional indications and benefit of
      botulinum toxin A (BTA) in spastic patients. DESIGN: Case report of a series of
      patients selected for BTA treatment. Clinical information was collected in a
      prospective fashion on each patient. SETTING: Freestanding acute rehabilitation
      hospital. PATIENTS: 39 consecutive patients with 40 limbs with acquired
      spasticity. INTERVENTION: All 39 patients received BTA injections into muscles
      targeted for treatment based on functional indications. MAIN OUTCOME MEASURES:
      Objective evaluation of outcome was measured by Ashworth Scale, goniometry,
      ambulation score, and brace wear scale. Subjective measures included patient self
      report of improvement and pain relief. RESULTS: Mean BTA dose per limb was 180
      units, mean number of muscles injected per limb was 2. Twenty-nine patients had
      subjective and/or objective improvement with treatment. Mean Ashworth Scale
      improvement was one point. Mean gain in active range of motion (AROM) was 17.0
      degrees, and in passive range of motion (PROM) 18.4 degrees. Brace tolerance
      improved in 14 of 22 patients and pain relief occurred in 10 of 13 patients.
      There were no adverse effects, and there was no difference in duration of effect
      compared to dystonia patients. CONCLUSION: BTA is a useful intervention in the
      treatment of spasticity, with the majority of patients demonstrating improvement
      on objective measures of tone and function, and reporting improvement on
      subjective measures. Careful patient selection will maximize functional benefit.

PMID- 8670001
TI  - Clinical assessment of spasticity in spinal cord injury: a multidimensional
      problem.
AB  - OBJECTIVE: To determine the relation between various components of spasticity
      evaluated clinically in persons with spinal cord injury (SCI). DESIGN: Case
      series evaluating spasticity using clinical scales commonly referenced in
      contemporary literature, including the Penn Spasm Frequency Scale, the Ashworth
      Scale, and standard scales of tendon taps, clonus, and plantar stimulation.
      SETTING. A Veterans Affairs Medical Center Spinal Cord Injury Center. PATIENTS.
      Eighty-five spinal cord injured individuals with varying degrees of spasticity.
      RESULTS: Correlations demonstrated weak relationships between Spasm Frequency
      Scale and self-report scales of interference with function (.407) and painful
      spasms (.312). No clinical examination score correlated with self-report scores
      greater than 0.4. Three clinical examination scores correlated modestly (> 0.5)
      Ashworth score with patellar tendon taps (.553), ankle clonus with Achilles
      tendon tap (.663), and patellar tendon tap with adductor tendon tap (.512). Two
      other clinical scales correlated weakly (> 0.4)-Achilles tendon tap with patellar
      tendon tap (.417) and plantar reflex with adductor tendon taps (.423).
      CONCLUSIONS: Clinical scales currently used to evaluate spasticity in SCI
      correlate poorly with each other, suggesting that they each assess different
      aspects of spasticity. The use of any single scale is likely to underrepresent
      the magnitude and severity of spasticity in the SCI population. In the absence of
      agreement among these various scales and with the absence of an appropriate
      criterion standard for evaluation of spasticity, assessments of spasticity,
      whether clinical or neurophysiological in nature, should be comprehensive in
      scope.

PMID- 8670003
TI  - Emergency care in patients wearing body casts.
AB  - OBJECTIVE: To describe a body cast modification that allows rapid chest exposure
      for cardiopulmonary resuscitation and alert the medical community to the 3% to 5%
      incidence of cardiopulmonary arrest in the hospital while wearing such a cast.
      DESIGN. Single trial timed cast cutting, multiple trial cast shell loading, and
      clinical observations of perforated casts for cracking or breakage. SETTING:
      University hospital castroom, mechanical engineering laboratory. INTERVENTION:
      Body casts mounted on a life-sized torso mold were perforated at 2-inch (50 mm),
      1-inch (25 mm), or 1/2 inch (12 mm) intervals around the chest with a 12-mm
      diameter vibrating drill. Using a cast saw, the chest piece of each body cast was
      removed and the time recorded. Engineering studies were performed on two cast
      shells with and without 12-mm-wide holes up to 1/2" (12 mm) apart, loading the
      fiberglass to the point of failure and recording the data. Body casts with 1" (25
      mm)-interval holes worn by 40 patients were examined after 12 weeks for evidence
      of failure. MAIN OUTCOME MEASURES: Chest piece removal times of body cast shells
      with and without holes were compared. Loading data of cast shells were compared
      to determine if holes as close as 1/2" (12 mm) significantly weakened the cast.
      Forty casts, perforated at 1-inch (25 mm) intervals, were observed for failure
      after 12 weeks of wear. RESULTS: Chest exposure time of a mold encased in a
      fiberglass cast was reduced from 1 minute to 15 seconds; plaster cast removal was
      reduced from 3 minutes to 1 minute. Engineering studies of perforated casts
      showed no significant decrease in strength. Casts with and without holes could
      support chest forces of up to 330 pounds. No failure was observed in casts with
      perforations 1 inch (25 mm) apart worn for 12 weeks. CONCLUSION: Perforated body
      casts reduced removal time to 15 seconds without weakening of the cast and
      provide lifesaving time to perform effective CPR.

PMID- 8670004
TI  - Upper limb reflex sympathetic dystrophy associated with occult malignancy.
AB  - Reflex sympathetic dystrophy, characterized by pain, swelling, vasomotor
      instability, and trophic changes in an extremity, has been infrequently described
      in patients with occult malignancy. Two cases of reflex sympathetic dystrophy
      associated with local tumor involvement are reported. Both patients had a history
      of cancer in clinical remission. Despite aggressive physical therapy measures,
      the patients' symptoms persisted. Workup of the first patient found an apical
      paravertebral mass in the lung; biopsy revealed recurrent breast carcinoma. In
      the second case, workup found an axillary mass contiguous with the lower brachial
      plexus. Biopsy revealed lymphoma, a second primary malignancy. In both cases,
      medical treatment of the tumor was instituted, with consequent improvement of
      hand and shoulder function. Both patients required prolonged hospitalization and
      multiple procedures that might have been avoided if malignancy had been
      suspected. Spontaneous development of reflex sympathetic dystrophy in patients
      with a history of cancer should alert the physician to the possibility of occult
      malignancy.

PMID- 8670005
TI  - Guillain-Barre syndrome: an unusual complication after snake bite.
AB  - The mortality rate of the Formosan krait bite has been reported to be 23%; death
      is from respiratory paralysis caused by neuromuscular junctions being blocked by
      bungarotoxin. This article presents the first case report of Guillain-Barre
      syndrome after snake envenomization. The patient presented with symmetric paresis
      and sensory signs in the upper and lower limbs, autonomic dysfunction, facial
      nerve involvement, and mild elevated cerebrospinal fluid protein at about 4 weeks
      after the bite. Electrodiagnostic studies revealed profound sensory and motor
      polyneuropathy. Repeated electrophysiologic findings confirmed nerve
      regeneration. The patient reached satisfactory functional outcome after a short
      term intensive rehabilitation program despite severe axonal degeneration. This
      article also discusses the possible mechanism of immunopathogenesis of Guillain
      Barre syndrome after krait bite.

PMID- 8670006
TI  - Computed tomography--guided aspiration of a ganglion cyst of the anterior
      cruciate ligament: a case report.
AB  - This report describes the case of a ganglion cyst of the anterior cruciate
      ligament in a 26-year-old man who had long-standing intermittent knee pain with
      locking. The cyst was successfully aspirated under computed tomography guidance,
      with complete resolution of symptoms. A literature review is presented along with
      diagnostic and treatment approaches for this uncommon finding.

PMID- 8670007
TI  - Evolution and vision.

PMID- 8670008
TI  - Trimethyl lead neurotoxicity in the rat: changes in glial fibrillary acidic
      protein (GFAP).
AB  - The literature on the toxicology of lead provides little evidence of the
      neurotoxicity of organic lead compounds. Toxicant-induced changes in the
      concentration of glial fibrillary acidic protein (GFAP) in the brain may help
      clarify at which stage of neurotoxicity astrocytes are affected and whether GFAP
      may provide an index of toxicity. Male F344 rats (> 42 days old) were exposed to
      0 (control), 8 or 16 ppm lead as trimethyl lead (TMPb) in drinking water for up
      to 14 days. Weight Gain was significantly reduced in both exposed groups. Control
      rats had the expected brain regional pattern of GFAP concentration with the
      highest in the hippocampus and cerebellum and lowest in the cerebral cortex. The
      hippocampus was the region very sensitive to TMPb, with increased GFAP in rats
      exposed to 8 and 16 ppm TMPb with decreases in GFAP in rats exposed to 8 and 16
      ppm TMPb for 14 days. There was a significant time-response in rats exposed to 8
      ppm TMPb with decreases in GFAP on day 7 and increases on day 14. A hypothesis
      concerning this biphasic change in GFAP concentrations is discussed. The results
      indicate that GFAP may be used to indicate the role of the astrocyte in the
      neurotoxicity of TMPb. GFAP concentration, as biomarker of TMPb effect, was as
      sensitive to TMPb as body weight and thus may provide a marker of neurotoxicity.

PMID- 8670009
TI  - Medical surveillance studies of workers exposed to low level benzene.
AB  - The paper presents th results of an investigation of haematotoxicity in workers
      exposed to low benzene concentrations. Forty-seven female workers in the
      shoemaking industry, exposed to solvent mixture and twenty-seven non-exposed
      controls were examined. Benzene concentrations in the working atmosphere ranged
      from 1.9 to 14.8 ppm. Significant differences in the levels of benzene in blood
      and phenols in pre- and post-shift urine between the exposed and control groups
      confirmed benzene exposure. Haemoglobin level and mean corpuscular haemoglobin
      concentration were significantly lower, and mean corpuscular volume was higher in
      the shoemaking workers than in controls. In the subgroup of shoemaking workers
      exposed to benzene concentrations of 5 ppm or lower, no differences in
      haematological parameters were found. In conclusion, exposure to a benzene
      concentration lower than 5 ppm does not appear to produce an increased level of
      abnormal haematological outcomes detectable in routine medical surveillance. The
      results of the study corroborate the present maximum permissible concentrations
      (5 ppm) as a protective limit preventing the onset of haematotoxic non
      leukemogenic effects of chronic benzene exposure.

PMID- 8670010
TI  - Prevalence of sensitization to Dermatophagoides pteronyssinus in several
      industrial populations.
AB  - Skin tests with Dermatophagoides pteronyssinus were carried out by the standard
      prick method in six groups of industrial workers: meat processing workers (n =
      107), brewery workers (n = 96), animal food workers (n = 40), swine farmers (n =
      32), paper-mill workers (n = 132) and wool-textile workers (n = 111). The control
      group consisted of 158 subjects who were tested during the preemployment
      examinations and had not worked in industrial plants before. Skin reactions were
      read after 20 minutes by measuring the largest urtica diameter in millimeters. A
      diameter >3 mm was considered to be a sign of a positive skin reaction. In
      relation to the control group a significant (P < 0.01) higher prevalence of
      positive skin reaction to D. pteronyssinus was found among the meat processing
      workers (41-13%, animals food workers (30 vs. 13%), swine farmers (34 vs. 13%)
      and wool-textile workers (32% vs. 13%). Results of the standard prick rest were
      not significant for the brewery workers (21 vs. 13%) and the paper-mill workers
      (21 vs. 13% in controls). Our results demonstrate the need for applying specific
      individual health measures if working conditions favour the growth and
      reproduction of house dust mites.

PMID- 8670011
TI  - [Occupational medicine in Croatia today. Organization and manpower].
AB  - According to the Health Manpower Register, run by the Croatian National Institute
      of Public Health, in October 1995 the country's health institutional work force
      included 381 occupational health specialists, 34 of whom were in private
      practice. Of the total, only 188 (49%) worked in occupational health, 163 (43%)
      in general medicine and 30 (8%) in other services. In all, the Occupational
      Health Service (without private practice) employed 649 persons. Of these, 230
      were physicians (200 specialists, 8 medical specialty trainees and 22 general
      practitioners), 136 university-trained health workers and 200 health workers with
      secondary school education. The Occupational Health Service operated through 127
      units in 65 Croatian communities and towns. Seventy-eight units provided
      specialized medical care only, 20 comprehensive medical care, and 29 curative
      services only. Such organizational mix is a consequence of the transitional
      period since the passage and coming into force in August 1993 of the Health Care
      Act which has defined occupational health as a purely preventive activity at the
      primary health care level. Most occupational health specialists who work for the
      General Medical Service have jobs in major towns like Zagreb, Rijeka and Sisak.

PMID- 8670012
TI  - [Insurance for work-related accidents and occupational diseases].
AB  - According to Article 51 of the Health Insurance Law, a new class of compulsory
      insurance - employer's compulsory health insurance - should be used in practice.
      In applying this article of the Law, the employer is bound to provide sources for
      all medical and other care needed by the insured in the case of an accident at
      work or an occupational disease. The employer is obliged to reinsure that class
      of risk with the insurance companies that idemnity the costs of medical treatment
      if these costs incur as a consequence of the insured risk (accident at work or
      occupational disease). The Croatian Institute for the Health Insurance is
      intermediary between various medical care units, employers and insurance
      companies. On the examples of four different cases the paper aims at
      demonstrating the need for quick and efficacious collection of both insurance and
      medical documentation, the need for professional assessment of that
      documentation, and the need for closer cooperation between medical experts
      working with insurance companies and medical supervisors working with the
      Croatian Institute for Health Insurance.

PMID- 8670013
TI  - [Respiratory findings in workers with no occupational exposure to air pollutants
      in the workplace].
AB  - The prevalence of acute and chronic respiratory symptoms and diseases as well as
      ventilatory capacity were studied in 806 workers without occupational exposure to
      air pollutants. The established prevalence of chronic respiratory symptoms was
      similar to that found in the general pollution. It was also higher in smokers
      than in non-smokers. Relatively a very small number of workers (only smokers)
      complained of acute symptoms during work shift. The measured ventilatory capacity
      values were not significantly different from the predicted values. There was a
      significant increase in all ventilatory capacity values during work shift (FVC,
      FEV1, FEF50, FEF25) which varied from +1.9 to 9.8% of the preshift values. In
      older workers (>40 years of age) as well as in those with longer exposure (<40
      years) and those with shorter employment (<10 years). Smoking habit appears to be
      the major factor responsible for the development of lung impairment in workers
      not exposed to atmospheric pollution.

PMID- 8670014
TI  - [Criteria for diagnosis of occupational asbestosis of the pulmonary parenchyma
      and pleura].
AB  - The criteria for acknowledgement of occupational parenchymal asbestosis were set
      out in the List of Occupational Diseases of 1983, under paragraph 26. In spite of
      this, some occupational health specialists and invalidity committees acknowledge
      the disease only when it meets the criteria recommended in the Conclusions of a
      Workshop on Asbestosis, held in former Yugoslavia, although such criteria were
      never legally implemented. According to these criteria asbetosis of the lung is
      recognized only when parenchymal profusion is subcategory profusion is
      subcategory 2/1 and higher, or at least subcategory 1/1 with visible pleural
      plaques and/or bilateral calcifications. In the Department of Occupational Health
      of the Institute for Medical Research and Occupational Health in Zagreb chest X
      rays were taken and examined in 350 workers occupationally exposed to asbestos.
      In 51 (15%) of the workers lung fibrosis was excluded (profession of the
      parenchyma was subcategory 0/-) and in 53 (15%) fibrosis of the parenchyma could
      not be excluded or confirmed on the basis of the X-rays. In the remaining 246
      (70%) the X-rays demonstrated clearly visible fibrosis and, depending on the
      parenchymal profusion, the finding was classified as subcategory 0/1 - 2/1 and
      higher, i.e. in 9% of the workers subcategory 1/1 was accompanied by visible
      bilateral pleural plaques. According to the Criteria from the Conclusions of a
      Workshop, on the basis of parenchymal profusion, asbestosis of the lungs would
      have to be acknowledged in 4% of those examined, while in 9% of the workers with
      parenchymal profusion of subcategory 1/1 or 1/2 asbestosis could be acknowledged
      only if visible bilateral plaques or pleural calcifications were present. On the
      other hand, according to the List of Occupational Diseases, only 15% of the
      examined workers offered no ground for acknowledging occupational parenchymal
      asbestosis. In another 15% of the examination, by which parenchymal asbestosis
      could be confirmed or excluded. Asbestosis of the lungs is a disease sui generis
      which should, with a positive work history, always be recognized as an
      occupational disease, after other etiology of the parenchymal fibrosis has been
      excluded. The extent of parenchymal profusion, other asbestosis-related diseases
      and/or impaired ventilatory or diffusive function of the lungs are not decisive.

PMID- 8670015
TI  - [Standardization of diagnostic criteria for occupational asbestosis of the lungs
      and lung parenchyma].
AB  - A reliable method for evaluation of asbestosis-related non-malignant respiratory
      impairment as occupational disease is described. The method is based on an
      algorithm which consists of the following elements: a positive full work history,
      chest radiography (International Labour Organisation), ventilatory lung function
      measurement, determination of diffusing capacity for carbon monoxide,
      histopathological examination, computerized tomography, and high resolution
      computerized tomography for persons with a negative differential diagnosis. The
      algorithm is meant to contribute to the standardization of diagnostic criteria
      for assessment of occupational lung diseases. Its use is also proposed for
      assessment of other occupational diseases.

PMID- 8670016
TI  - [Liability in occupational asbestosis and its harmful sequelae].
AB  - A total of 139 cases of occupational asbestosis were registered in companies
      working with asbestosis in Croatia between the years 1985 and 1994. In the period
      from 1992 to 1994 thirty-five diseased workers sued in court for compensation of
      damage. In all suits and at all levels, the employer was judged to be responsible
      for the damage. Questioning the exclusiveness of responsibility, or at least co
      responsibility for the other parties involved in the structure of occupational
      use of asbestos, the authors ascertained, in all the 35 cases of occupational
      asbestosis from the sample, that the full responsibility lay with the third party
      - the State - as representing the unity of the legal, executive and judicious
      powers.

PMID- 8670017
TI  - Interactions of essential and/or toxic metals and metalloid regarding
      interindividual differences in susceptibility to various toxicants and chronic
      diseases in man.
AB  - The review is a synthesis of the most recent evidence for the important role of
      the interactions of essential and/or toxic metals and metalloids regarding human
      health and diseases. Information is presented on the mechanisms of interaction
      between various metals and/or metalloids (including the influence of pH, exposure
      duration, and other exposure variables such as life-style factors in main),
      possible differences in the susceptibility to adverse health effects between man
      and other mammals, and the role of metals and metalloids in oxidative stress
      mediated diseases, antioxidant defence system, adaptive response and genetic
      repair processes. With regard to generally large interindividual differences in
      the susceptibility to various toxicants in humans, further epidemiological
      research in the quantitative contribution of between lead, cadmium, copper, zinc
      and selenium, based on biological monitoring, is recommended. Interaction of
      these elements may explain individual susceptibility to various chronic diseases,
      even those showing transgenerational characteristics (such as significantly
      lowered sperm count and fertilizing capacity of men over the last five decades,
      known to have occurred in the general population world-wide).

PMID- 8670018
TI  - Phenotypic plasticity in the lower pharyngeal jaw dentition of Astatoreochromis
      alluaudi (Teleostei: Cichlidae).
AB  - The potentially molluscivorous cichlid fish Astatoreochromis alluaudi is known to
      exhibit a pronounced phenotypic plasticity in its pharyngeal jaw apparatus. Two
      phenotypes (wild-caught snail-eating specimens and specimens raised on soft food)
      were examined for differences in the number, size, shape, spacing and wear of
      functional teeth on the lower pharyngeal jaw. During growth, snail-eating
      specimens maintain tooth numbers but invest in teeth of a larger size (width and
      depth). In contrast, specimens fed a soft diet invest in more teeth, their size
      remaining unchanged except for the central, most posterior teeth. All changes in
      the dentition must be achieved through successive tooth generations. Serial
      microradiographs in the caudal area of the lower pharyngeal jaw, a region that is
      most significant in food processing, indicated that functional teeth in hard-food
      specimens more often show a successor below. This may be due to more time needed
      for larger replacement teeth to form and possibly to a shorter replacement cycle
      linked to the greater wear of the functional teeth. It is hypothesized that
      maintenance of tooth numbers and increase of tooth size in hard-food specimens is
      achieved by a one-for-one replacement and expansion of the tooth-bearing region
      and possibly by closer spacing of the teeth. Increase of tooth numbers in the
      soft-food specimens is probably achieved through the establishment of new tooth
      loci at the margins of the dentigerous area in addition to a one-for-one
      replacement.

PMID- 8670019
TI  - Mononuclear cells in salivary glands of normal and isoproterenol-treated rats.
AB  - The purpose of this study was to analyse the phenotypical distribution of
      resident cells of the mononuclear phagocyte system in rat salivary glands, and to
      determine whether isoproterenol induces alterations in macrophage and lymphocyte
      surface-marker expression. Frozen sections of gland tissues were prepared from
      five normal rats, and from six rats treated with 20 mg/kg isoproterenol/day for
      10 days. A panel of six monoclonal antibodies was used to identify membrane
      markers associated primarily with monocytes (ED1), mature tissue macrophages
      (ED2), lymphoid macrophages (ED3), MHC class II (Ia) antigens (OX6), CD5-positive
      T lymphocytes (OX19), and rat B lymphocytes (OX33). Double-labelling techniques
      were used to detect the coexpression of ED1/ED2 and OX6/ED2 mononuclear cell
      markers in the major salivary glands. ED2-positive macrophages were predominant
      in all three major glands, ranging from 96 cells/0.87 mm2 field in the parotid
      gland to 165 cells/0.87 mm2 in the submandibular. OX19-positive T lymphocytes
      were rarely observed in submandibular and parotid glands but represented a
      distinguishing feature of the sublingual. Moderate numbers of ED3-positive
      macrophages also were detected in sublingual tissues. In the submandibular and
      parotid glands, isoproterenol resulted in a decrease in ED2-positive cells, but
      ED2-positive macrophages increased in sublingual glands with isoproterenol.
      Isoproterenol resulted in a decrease in MHC class II antigen expression on
      submandibular and sublingual mononuclear cells but an induction of Ia antigen in
      the parotid gland. Double labelling revealed that isoproterenol induced
      coexpression of ED1/ED2 markers on mononuclear cells in the submandibular glands,
      but ED1/ED2-positive cells were absent from other glands. However, coexpression
      of MHC class II markers on ED2-positive cells in the sublingual and parotid
      glands of normal rats was frequently observed, with isoproterenol decreasing
      coexpression in the sublingual gland and increasing it in the parotid. B
      lymphocytes were not detected in any of the glands examined. These findings
      indicate that important differences exist in normal resident mononuclear cell
      subsets among the major salivary glands of the rat. The differential effects of
      isoproterenol on inflammatory cells may reflect important differences in local
      salivary gland immunoregulation. Although salivary gland inflammation induced by
      isoproterenol does not appear to result from immune mechanisms, the rich
      population of T lymphocytes and ED3-positive macrophages, and presence of MHC
      class II antigens, suggest that the sublingual gland may function as an immune
      organ and have a role in mucosal immunity.

PMID- 8670020
TI  - Immunocytochemical localization of fibronectin and a 165-kDa membrane protein in
      the odontoblast layer under initial carious lesions in man.
AB  - The possible role of fibronectin in dental tissue repair was investigated by
      comparing its distribution and that of the 165-kDa fibronectin-binding membrane
      protein (165 kDa-FnBP) in odontoblasts underlying carious and sound dentine. By
      immunoperoxidase and light microscopy, fibronectin was localized in the dentine
      underlying the carious lesion, mainly on the surface of the tubule walls, whereas
      it could not be detected in neighbouring sound zones. The antibody to the 165 kDa
      FnBP strongly reacted with the membrane of odontoblasts underlying the lesion,
      although those facing sound dentine did not express this antigen.
      Ultrastructurally the 165 kDa-FnBP was localized in the cell membrane at the
      apical portion of odontoblasts, including the process membrane, beneath the
      initial lesion; fibronectin was detected in the dentinal area close to the
      process, and also in contact with its external surface. By a high-resolution
      immunogold procedure, the proteins were colocalized at the external surface of
      odontoblast processes. These data suggest that fibronectin present in human
      carious dentine could modulate the behaviour of underlying odontoblasts by means
      of newly expressed 165 kDa-FnBP.

PMID- 8670021
TI  - Spatial distribution of enamel proteins and fibronectin at early stages of rat
      incisor tooth formation.
AB  - Enamel proteins are secreted very early during amelogenesis, that is prior to
      mantle dentine formation, raising the possibility that they may participate in
      epithelial-mesenchymal interactions taking place during tooth development. These
      first enamel proteins associate with elements of the basement membrane interposed
      between the differentiating ameloblasts and odontoblasts. Fibronectin, a
      component of the basement membrane, is redistributed and accumulates along the
      apical portion of odontoblasts during their terminal differentiation. In order to
      determine whether any correlation exists between the redistribution of
      fibronectin and the secretion of the first enamel proteins, the spatial
      distribution of these two extracellular matrix proteins was examined during the
      presecretory stage of amelogenesis. Male Wistar rats were perfused with a
      formaldehyde-based fixative, and undemineralized and EDTA demineralized incisors
      were dehydrated in methanol and embedded in Lowicryl K4M resin. Ultrathin tissue
      sections were then processed for post-embedding, colloidal-gold
      immunocytochemistry with antibodies to enamel proteins, fibronectin or type III
      collagen. In the region of ameloblasts facing pulp, labelling for fibronectin was
      weak and mostly associated with the lamina fibroreticularis of the basement
      membrane separating differentiating ameloblasts and odontoblasts. As the mantle
      predentine formed the immunoreaction for fibronectin increased, particularly in
      the region of the basement membrane. Enamel proteins were also immunodetected in
      association with the lamina fibroreticularis and gradually accumulated as patches
      within mantle dentine and at its interface with ameloblasts. Von Korff collagen
      bundles, present between odontoblasts and in dentine, were immunolabelled for
      fibronectin and for type III collagen. Patches of granular material,
      immunoreactive for fibronectin and/or enamel proteins, were found along the
      odontoblastic processes and cell bodies. Although no evidence was obtained
      indicating a precise colocalization of fibronectin and enamel proteins, the
      results confirm that these two proteins can be found within similar extracellular
      compartments during mantle predentine-dentine formation. These data suggest that
      enamel proteins, by themselves or synergistically with other proteins, may play a
      part in the differentiation and/or formative events taking place at the
      ameloblast-odontoblast interface during the early stages of tooth development.

PMID- 8670022
TI  - Tenascin expression in mucocutaneous diseases and related lesions of human oral
      mucosa.
AB  - The expression of tenascin was assessed immunohistochemically. In normal oral
      mucosa, immunoreactivity for tenascin was seen either as a delicate line
      underlining the epithelium or in the stromal papillae. In oral lichen planus, a
      marked enhancement of tenascin immunoreactivity in the lamina propria was
      associated with focal infiltrates of inflammatory cells and seemed to reflect the
      intensity of inflammation. In lichenoid reactions in which only a sparse
      inflammatory infiltrate was present a band-like tenascin reactivity was seen.
      Oral psoriform reactions and chronic hyperplastic candidosis showed a prominent
      tenascin reaction in the connective tissue papillae among infiltrates of
      inflammatory cells. The results show that tenascin content is increased in oral
      mucocutaneous diseases and related lesions and that the abundance of tenascin
      reflects the intensity of the inflammatory reaction.

PMID- 8670023
TI  - Nuclear matrix-intermediate filament proteins of the dental follicle/enamel
      epithelium and their changes during tooth eruption in dogs.
AB  - Tooth eruption activates a localized resorption and formation of alveolar bone
      and these activities depend upon the adjacent parts, coronal and basal,
      respectively, of the dental follicle-enamel epithelium. In this study the nuclear
      matrix-intermediate filament (NM-IF) proteins of these tissues were isolated in
      order to continue investigations into the molecular mechanisms underlying
      eruption. Dental follicles were removed from the third and fourth premolar of
      dogs at 13, 16 and 20 weeks (pre-, early, and mid-to-late eruption of these
      teeth) and NM-IF proteins were extracted from the coronal and basal halves. Most
      of the NM-IF protein profiles of these coronal and basal parts on one
      dimensional, sodium dodecyl sulphate-polyacrylamide gel electrophoresis were
      remarkably constant, indicating an essentially uniform cellular composition.
      However, differences between these tissues were observed and some of these
      changed during eruption. Based on recent observations that nuclear matrix changes
      reflect and may even mediate cell-specific changes in gene expression, these
      findings suggest that changes in nuclear matrix proteins may be related to the
      molecular basis for some aspects of differential gene expression in the coronal
      and basal regions of the dental follicle and account for the ability of these
      tissues to activate bone resorption and formation during tooth eruption.

PMID- 8670024
TI  - Effect of inferior alveolar nerve axotomy on immune cells and nerve fibres in
      young rat molars.
AB  - Denervation has been a useful approach to the investigation of interactions
      between nerve fibres and the pulp-dentine complex. Information on the
      immunological implications of axotomy is still lacking. The effect of axotomy on
      CD43+, CD4+, CD11b+ and I-A antigen-expressing cells in both the distal segment
      of the cut inferior alveolar nerve and in the first molar pulp of young rats was
      evaluated. Nerve fibres immunoreactive to protein gene product (PGP) 9.5, the
      neuropeptides substance P and calcitonin gene-related peptide (CGRP), and
      neuropeptide Y were visualized also by use of the avidin-biotin peroxidase
      complex method. Recruitment of macrophages was found in the distal segment of the
      sectioned inferior alveolar nerve 2 days after axotomy, with a further increase
      in number during the 6-day observation period. However, in the dental pulp, the
      number of CD43+, CD4+, CD11b+ and I-A antigen-expressing cells was almost
      unaffected. An almost complete sensory denervation of the first mandibular molar
      pulp was obtained 2 days after axotomy. After 6 days, the mesial part of the
      coronal pulp still remained denervated, while regenerated nerve fibres had
      reached both the root pulp and the distal part of the coronal pulp. Nerve fibres
      immunoreactive to neuropeptide Y were slightly reduced in density 2 days after
      axotomy, and after 6 days the localization of neuropeptide Y-immunoreactive
      fibres was changed compared to the control, with fibres also distributed in the
      odontoblast layer close to dentine. Hence, following axotomy in young rats, an
      almost complete sensory denervation is achieved in the first molar, whereas nerve
      fibres immunoreactive to neuropeptide Y change their distribution pattern, with
      fibres located close to the dentine after 6 days. Due to the almost unchanged
      number and distribution of immunocompetent cells in the pulp after axotomy, the
      young rat molar pulp may represent a suitable and useful experimental model to
      study neuro-immune interactions.

PMID- 8670026
TI  - A histological, lectin and S-100 histochemical study of the developing prenatal
      human sublingual salivary gland.
AB  - Lectin and S-100 protein histochemistry during fetal growth and development (10
      38th gestational weeks) of these glands was studied. The histological development
      of glandular structures followed the known pattern for other salivary glands.
      Using biotinylated lectins Ulex europeus-I, Dolichos biflorus, Glycine maximus
      (soyabean), Helix pomatia, Arachis hypogaea (peanut) and Triticum vulgare
      (wheatgerm), the binding level and, by implication, the concentration of
      associated specific oligosaccharide available for binding was low at 10 to 19
      weeks and generally higher as maturity increased through the middle and late
      stages of development. S-100 protein reactivity was demonstrated in the cytoplasm
      of basophil acinar cells of the gland primordia from their origin. Stereological
      analysis of these developing salivary glands showed a highly significant
      progressive increase in proportional gland volume occupied by acini from 25% at
      20 weeks to 60% at 38 weeks (p < 0.0001), and a comparable halving of the
      relative gland volume occupied by connective tissue in the same period (p <
      0.0001). The extent of these changes depended upon the stage of differentiation
      and maturation of the glands but by the late stage of fetal development,
      histochemical reactions were similar to known adult patterns.

PMID- 8670025
TI  - Lubrication of human and bovine enamel compared in an artificial mouth.
AB  - Bovine enamel has been a good model for human enamel across a broad range of
      studies. The present work sought to consider if bovine enamel would be a suitable
      substitute for human enamel in experiments on simulated oral lubrication. Enamel
      samples of the same size were prepared from bovine and human teeth for use as
      maxillary and mandibular elements in a miniature artificial mouth. Sliding speeds
      from 1.99 to 7.84 mm/s and occlusal forces of 3.8-19.5 N were used. Water and
      four solutions consisting of a mucin-rich fraction, a statherin-rich fraction,
      3[(3-cholamidopropyl)-dimethylammonio]-1-propanesulphonate and sodium dodecyl
      sulphate were evaluated. The high correlations between widely different
      lubricants on the two enamel substrates gives confidence in the use of bovine
      enamel as a model for human enamel in salivary lubrication studies. Knoop
      hardness indentations on enamel samples were combined with friction data and
      calculations of the true contact area to give a method for the indirect
      determination of surface shear. The calculated surface shear value was compared
      with published values obtained by punch shear testing.

PMID- 8670027
TI  - Chorda-evoked opening of tight junctions in rat submandibular salivary acini
      demonstrated by microperoxidase.
AB  - The permeability of these junctions from the interstitium to the lumen was
      examined by using an ultrastructural tracer, microperoxidase, in conjunction with
      electron microscopy. In the resting gland, the reaction product of
      microperoxidase was seen in the interstitial and intercellular spaces, but not
      within acinar lumina; thus the tight junction was impermeable to microperoxidase
      (junction closed). Intraductal injection of hypertonic sucrose solution (1000
      mOsm; 30 microliters) caused a sustained elevation of the luminal pressure,
      indicating osmotic water flow into the lumen due to the presence of a hypertonic
      solution. In this gland no opening of the tight junctions was observed. In the
      chorda-stimulated gland, microperoxidase entered the lumen through the tight
      junctions, that is, they became permeable to microperoxidase (junction open).
      These findings suggest that chorda stimulation opens the acinar tight junctions
      and that the paracellular secretory pathway may be involved in the secretion of
      small molecules and water from the submandibular acini.

PMID- 8670028
TI  - The effects of antidepressant drugs on salivary flow and content of sodium and
      potassium ions in human parotid saliva.
AB  - Stimulated parotid saliva was collected, using the Carlson-Crittenden cup, from
      normal controls and patients on antidepressant drugs. The saliva from patients
      using amitriptyline, dothiepin (tricyclics), fluoxetine and paroxetine (selective
      serotonin re-uptake inhibitors; SSRI) was analysed for flow rate, [Na+] and [K+],
      and was compared with that from unmedicated, non-depressed volunteers for all
      variables. The tricyclic antidepressants produced a significant reduction in flow
      (amitriptyline, p < 0.01; dothiepin, p < 0.05), and consequent decrease in [Na+]
      and increase in [K+]. These effects were presumably due to muscarinic receptor
      blockade. The SSRIs produced no significant change in these variables. A
      prospective study of dothiepin in non-depressed patients confirmed that it
      decreases stimulated parotid flow. This finding also suggested that depression
      itself contributed little to the oral dryness observed in and reported by the
      depressed patients. The patients' subjective rating of oral dryness related well
      to a reduction in stimulated flow. This applied to those taking either tricyclics
      or SSRI, both showing a reduced flow rate relative to control (p < 0.001 and p <
      0.05, respectively). This amounted to a 58% reduction in flow rate in the
      tricyclic group. The data suggest that measurement of stimulated parotid salivary
      flow is a reliable indicator of drug-induced oral dryness.

PMID- 8670029
TI  - Human dentine as a hydrogel.
AB  - The pores (tubules) of human dentine in 0.02-cm planoparallel sections of newly
      extracted permanent teeth were investigated. By the conventional scanning
      electron microscopy these pores appear empty, but by the newly developed scanning
      probe microscopy the presence of a complex matrix could be established. By
      measuring the transport of neutral myoglobin by diffusion alone and
      diffusion+bulk flow, the area of dentine occupied by the matrix was calculated to
      be 1.9 +/- 0.9% and 2.3 +/- 0.5%, respectively. The hydraulic conductivity was
      surprisingly small, 1.35 +/- 0.55 x 10(-7) ml/(s.cm2 dentine) at a pressure
      difference of 0.1 kPa across a 1-cm thick section. This suggests a hydrogel with
      a relatively dense network, the width of meshes estimated at 2 x 30 nm. In line
      with this concept, enzymatic degradation of the organic matter increased the
      hydraulic conductivity 3000 times. By studying the transport of negatively
      charged myoglobin, the matrix was calculated to carry 18 mEq/l of positive
      charges. Due to the consequent attraction of small, negative ions and thence of
      water, the pressure within the matrix would be about 1.33 kPa, a force which will
      act to immobilize the water in the channels. The concept of a hydrogel in the
      dentine tubules was also supported by the finding that shielding the charges with
      bathing media of high ionic strength reduced the hydraulic conductivity.

PMID- 8670030
TI  - Identification and classification of species within the Streptococcus sanguis
      group.
AB  - A biochemical identification scheme has been produced that allows for the
      differentiation of nine distinct species within the Streptococcus sanguis group.
      The species are S. sanguis, S. gordonii, S. crista, S. oralis, S. parasanguis, S.
      defectivus, S. adjacens and S. mitis, which have been previously described, and a
      new species, S. australis; in addition two distinct subspecies, S. oralis subsp.
      corona and S. oralis subsp. mitior, have been identified. DNA-DNA hybridization
      confirmed the separation of strains into the species. A new type of peptidoglycan
      peptide linkage, lys-ala-gly was also found within the species S. parasanguis and
      S. australis that has not been observed within the streptococci previously. DNA
      fingerprinting was shown to be a useful method for discriminating between strains
      within species, but did not allow discrimination between species.

PMID- 8670031
TI  - Establishment of peripheral blood and gingival T lymphocyte clones responsive to
      Porphyromonas gingivalis.
AB  - T cells are central to the immune response to infection and studies have
      indicated a local immunoregulatory imbalance may exist in human periodontal
      disease. Since Porphyromonas gingivalis is generally recognized as a major
      periodontopathogen, the aim of this study was to establish T cell lines and
      clones specific to P. gingivalis from the gingival tissues and peripheral blood
      of P. gingivalis--infected subjects. Two subjects were selected from two groups
      of individuals (one from each group) established on the basis of P. gingivalis in
      their plaque and the presence of serum antibodies which react with P. gingivalis
      antigens. The two groups differed however in their clinical susceptibility (adult
      periodontitis) or resistance (gingivitis) to periodontal breakdown. The mean ages
      +/- standard error of the mean of the two groups were 47.9 +/- 2.2 and 49.6 +/-
      3.7, respectively, so that resistance in the gingivitis group was related to the
      age of the subjects. T cell lines and clones were established from the peripheral
      blood of one patient from each of the two groups and also from the gingival
      tissues of the same periodontitis subject. This study has demonstrated the
      capability of establishing P. gingivalis-specific T cell lines and clones from P.
      gingivalis-infected subjects and FACS analysis of the T cell receptor variable
      regions demonstrated that the clones were indeed monoclonal. The CD4:CD8 ratios
      of the peripheral blood-derived T cell lines were 1.2 and 0.4 for the gingivitis
      derived line and the periodontitis-derived line, respectively, thus supporting
      the clinical differences displayed by the two subjects.

PMID- 8670032
TI  - The strength of auto-cured and light-cured materials. The shear punch test.
AB  - This paper examines the versatility of the shear punch test as described by
      Roydhouse and suggests that it should be considered as an alternative to the
      present standard compressive strength test for glass ionomer cements and flexural
      strength for composite resins. The shear punch test can be used for examining
      small thin specimens, about 1.0 mm thick and 8.0 mm in diameter, of both auto
      cured and light-cured restorative materials such as composite resins and glass
      ionomer cements. The preparation of the specimen is simple and does not require a
      precision mould or subsequent machining to size except that, after curing, it may
      need to be abraded gently to obtain flat parallel test surfaces. The test
      apparatus consists of a punch approximately 3.0 mm in diameter opposing a true
      fitting matching die. The specimen is supported over the die section and the
      punch is advanced through it in a compression cage. The formula used to calculate
      the shear strength allows for variation in specimen thickness and thus provides
      comparative data between materials. It also allows examination of the effects of
      variations in manipulation, maturation and storage of each material. It is
      suggested this test should be considered as an alternative to the present
      compression and flexural strength tests because it would provide a single
      strength test for a range of restorative materials being manipulated under a
      variety of circumstances. It is of particular significance for testing the light
      cured materials because it examines a specimen size below that of the diameter of
      the exit window of a normal clinical light curing unit and also at a thickness
      where depth of cure of the material is not a problem.

PMID- 8670033
TI  - Split-mouth study of sealant retention with carbon dioxide laser versus acid etch
      conditioning.
AB  - A split mouth clinical trial was undertaken to compare the retention of fissure
      sealants placed using laser or acid conditioning. After a mean follow-up period
      of 14.5 months, the retention rate for laser conditioning was greater than that
      for acid etching (97.9 per cent versus 94.6 per cent, respectively), although
      this difference was not statistically significant. No adverse effects occurred
      during or subsequent to laser conditioning procedures. It is concluded that
      carbon dioxide laser conditioning is a viable alternative to acid etching for
      fissure sealing.

PMID- 8670034
TI  - The effect of steam sterilization on the properties of set dental gypsum models.
AB  - The aim of this study was to investigate the viability of autoclave sterilization
      of set dental gypsum models. The effects of autoclaving on the strength, surface
      hardness and dimensions of specimens of plaster, stone and diestone were
      investigated. In addition, sodium succinate was used to minimize any changes
      produced by autoclaving. It has been shown that dental gypsum casts can be
      successfully steam sterilized. The results showed that for fully-dried gypsum
      products, autoclaving at 132 degrees C for 5 minutes rendered the casts
      unacceptable for use. Autoclaving at 121 degrees C for 16 minutes had less effect
      although casts were still not satisfactory, with the main problems being
      excessive expansion for plaster and significant strength and surface hardness
      loss for stone and diestone. The effect of three additional treatment procedures
      was examined and the least degradation was observed when the casts were soaked in
      1 per cent sodium succinate solution and dried prior to autoclaving, then soaked
      in water immediately after. Using this procedure the average change in properties
      for plaster, stone and diestone respectively were: loss of strength 36, 21 and 28
      per cent, loss of surface hardness 34, 21 and 33 per cent, and linear expansion
      0.05, 0.09 and 0.13 per cent. Further refinement may improve the procedure.

PMID- 8670035
TI  - The effect of endodontic access cavity preparation and subsequent restorative
      procedures on molar crown retention.
AB  - Preparation of an endodontic access cavity through a full crown may affect its
      retention. This study was undertaken to investigate the effects on molar crown
      retention of endodontic access cavities and their subsequent restoration. Thirty
      human molars were mounted in resin, crown preparations were cut and their surface
      areas were determined. Vented metal copings were cemented with zinc phosphate and
      the forces required to displace each coping were measured using a tensile-testing
      machine. The copings were recemented, access cavities were cut and their surface
      areas determined prior to the displacement forces being re-measured. The copings
      were recemented, assigned to two groups, and the access cavities were restored-
      Group 1 with amalgam; Group 2 with glass ionomer (GIC). Displacement forces were
      re-measured and the copings were recemented. The occlusal margins of the access
      cavities were bevelled and restored again prior to displacement forces being
      remeasured. Mean displacement forces were - Group 1: Original (kg force), 37.86
      +/- 3.97; After access cavity, 29.28 +/- 3.22; Amalgam, 50.21 +/- 4.71; Amalgam +
      bevel, 46.45 +/- 6.21. Group 2: Original, 42.77 +/- 4.49; After access cavity,
      39.25 +/- 5.91; GIC, 48.11 +/- 3.55; GIC + bevel, 39.63 +/- 5.31. Statistical
      analyses with paired t tests showed that retentive values with access cavities
      were significantly lower than with intact crowns. Amalgam or GIC restorations
      increased retention beyond original values, significantly with amalgam. Bevelled
      occlusal margins decreased retention of crowns with restored access cavities but
      this was not significantly different from the original values. A significant
      relationship existed between total surface areas of the crown preparations, areas
      of the occlusal tables, and retentive values for crowns without access cavities.
      The access cavity area, as a proportion of the total area of the preparation, was
      related to the decrease in retention.

PMID- 8670036
TI  - Exfoliative cytology in clinical oral pathology.
AB  - Exfoliative cytology is a rapid, non-invasive procedure for assessing dysplastic
      change within the oral epithelium. The indications for oral exfoliative cytology
      are reviewed and a technique for cell collection and smear examination is
      presented. The value of exfoliative cytology in oral cancer screening programmes
      as a public health measure is discussed.

PMID- 8670037
TI  - High magnification in situ viewing of wound healing in oral mucosa.
AB  - Microscope endoscopy is a technique which allows high resolution, non-invasive
      examination of soft tissues. This study employed microscope endoscopy to examine
      the process of healing following exposure of the oral mucosa to carbon dioxide
      laser radiation. On the wound boundaries, cellular debris and the laser-induced
      char layer were shed as epithelial migration occurred. Wounds healed by secondary
      intention, with complete epithelial closure by 72 hours. A marked vascular
      response was evident from 6 to 48 hours following wounding, a time period
      coincident with the known pattern of blood vessel activation and infiltration of
      the wound site by leukocytes. The use of microscope endoscopy as an adjunct to
      biopsy and other invasive diagnostic methods in the assessment and follow-up of
      soft tissue pathology may have value in clinical practice.

PMID- 8670038
TI  - The role of adhesion molecules in oral cancer.
AB  - Cell-cell and cell-matrix interactions are mediated by adhesion molecules. By
      altering interactions between epithelial cells, extracellular matrix and
      leukocytes, changes in adhesion molecule expression can influence tumour
      development and metastasis. This study compared the adhesion molecule profile of
      oral squamous cell carcinoma (SCC) with normal buccal mucosa. The pattern of
      expression of adhesion molecules differed between normal epithelial cells and
      tumour cells, while leukocytes and endothelial cells adjacent to the tumour
      showed a pattern common to inflammatory sites. Aberrations in cell adhesion
      receptors on tumour cells may contribute to the unique biologic behaviour of
      individual tumours.

PMID- 8670039
TI  - The prognosis of oral mucosal squamous cell carcinomas: a comparison of clinical
      and histopathological grading and of laminin and type IV collagen staining.
AB  - Changes in the distribution of basement membrane components have been described
      in dysplastic lesions and in oral mucosal squamous cell carcinomas (OMSCC). The
      purpose of this study was to determine if these changes were related to
      pathological grade and if so, whether this had prognostic implications. Fifty
      formalin-fixed, paraffin-embedded specimens of OMSCC, with five or more years
      clinical follow-up, were studied using an immunoperoxidase technique for the
      detection of the basement membrane components, laminin and type IV collagen. The
      immunoreactivity of each component was evaluated and semiquantitatively scored as
      minimal, moderate or extensive and the results compared with the tumour size,
      node involvement and metastasis (TNM) clinical staging system and
      histopathological features. OMSCC were characterized by minimal or moderate
      staining with small islands of neoplastic cells frequently lacking staining for
      laminin and type IV collagen. Deposition of these components decreased with
      increased histopathological grade and absence of staining was more commonly
      associated with a poor prognosis. In particular the pattern of type IV collagen
      staining frequently differed from laminin staining. Neither of these parameters
      offered an advantage over TNM clinical staging with regard to prognosis. It was
      concluded that variations in laminin and type IV collagen immunoreactivity
      occurred in OMSCC and that high histopathological grade tumours with considerably
      diminished staining with anti-laminin and anti-type IV collagen carried a poor
      prognosis.

PMID- 8670040
TI  - Studies of the inflammatory process and malignant potential of oral mucosal
      lichen planus.
AB  - Oral mucosal lichen planus (OMLP) is a well recognized mucosal disease with
      unknown aetiology. Considerable controversy exists as to whether OMLP is
      intrinsically premalignant, or if the disorder facilitates the development of
      oral mucosal squamous cell carcinoma (OMSCC) by external factors. The aim of the
      present studies was to investigate the expression of c-erbB-2 protein in the
      keratinocytes of the initial biopsies of oral mucosal disorders diagnosed as OMLP
      with no evidence of epithelial dysplasia and to compare the results with the
      expression of c-erbB-2 protein in subsequent biopsies obtained from the same
      patients. These results were compared with the findings from another 26 biopsies
      from patients with OMLP and control groups (patients with dysplasia with no
      evidence of OMLP, patients with OMSCC with no evidence of OMLP and normal oral
      mucosa). The expression of the c-erbB-2 protein was evaluated by
      immunohistochemical staining of the gene product with the avidin-biotin-complex
      method using both fresh frozen and paraffin-embedded tissue sections. Five of the
      initial biopsies from patients with OMLP expressed the c-erbB-2 protein and one
      did not. None of the OMLP cases that subsequently showed evidence of dysplasia
      expressed the c-erbB-2 protein and of the OMSCC specimens from the patients with
      OMLP, 2 were negative and 1 expressed c-erbB-2 protein. Within the other group of
      OMLP specimens 3 (3/26) were negative for c-erbB-2 staining. The specimens from
      the control groups all expressed the c-erbB-2 protein. The results indicated the
      probability of the absence of c-erbB-2 staining being an indication of a
      potential for neoplastic transformation in OMLP with dysplastic changes.

PMID- 8670041
TI  - Epithelial growth fraction and expression of p53 tumour suppressor gene in oral
      submucous fibrosis.
AB  - The incidence of squamous cell carcinoma in patients with oral submucous fibrosis
      (OSF) exceeds 7 per cent. The proliferative cell nuclear antigen (PCNA) is a
      convenient marker of epithelial cell proliferation and p53 tumour suppressor gene
      mutations or deletions are frequent in oral cancer. The present study estimated
      the basal epithelial cell growth fraction using a standard immunohistological
      method for the detection of nuclear PCNA from 20 Nepalese patients with OSF as
      31.8 per cent compared with 7.6 per cent for oral mucosa from 43 normal subjects
      (p < 0.001) and 39.4 per cent for 44 patients with oral cancer. The PCNA growth
      fraction correlated significantly with that derived by Ki-67 labelling. There was
      no correlation between the growth fraction and the severity of epithelial
      dysplasia found is OSF. Abnormal expression of p53 protein identified by
      immunohistochemistry with a panel of antibodies was found in 70 per cent of the
      OSF specimens, and 21 per cent of mucosal specimens from subjects with clinically
      normal mouths. PCNA-positive cells and p53 expression were restricted to the
      basal epithelial layer in OSF. The unexpected finding of p53 protein in
      clinically healthy mucosa was confined to subjects aged over 40 years who smoked
      tobacco, a known risk factor for oral cancer. There was no association between
      p53 expression and epithelial atypia scores in OSF. It is concluded that the
      proportion of actively cycling epithelial cells is increased in OSF and that p53
      tumour suppressor gene mutations or deletions may be prevalent. Confirmation by
      molecular biology techniques of this genetic damage is now needed.

PMID- 8670042
TI  - Growth and bone remodelling in a scorbutic rat model.
AB  - This study used the scorbutic Osteogenic Disorder Shionogi rat model and a
      specific diet to reliably induce a state of sub-scurvy scorbutus. Under these
      conditions overall somatic growth was assessed, as well as that of the caudal
      vertebrae, as an example of scorbutic bone growth. Tail loops were then used to
      mechanically stress mature caudal vertebrae under scorbutic conditions, and the
      vertebrae's adaptation to these applied forces was assessed, using measurements
      of bend deformation and histologic analysis of osteogenesis. Scorbutic animals
      exhibited significant somatic growth retardation (p < 0.05), and abnormal
      reductions in osteogenesis and periosteal responsiveness to growth. Scorbutic
      vertebrae also showed greater bend angles of deformation (p < 0.05), and a marked
      reduction in cortical osseous remodelling and periosteal differentiation. It
      appeared that the sub-scurvy scorbutic bones were smaller, weaker and less able
      to adapt to physical stresses: this pattern was reflected at the histologic
      level.

PMID- 8670043
TI  - Structure-function relationships in the FK506-binding protein (FKBP) family of
      peptidylprolyl cis-trans isomerases.

PMID- 8670044
TI  - Insulin and insulin-like growth factor-1 stimulate dephosphorylation of paxillin
      in parallel with focal adhesion kinase.
AB  - Paxillin and focal adhesion kinase (pp125FAK) co-localize in focal adhesions;
      recently insulin has been shown to stimulate the dephosphorylation of pp125FAK;
      however, its effect on paxillin is unknown. We show that insulin and IGF-1 can
      stimulate the dephosphorylation of paxillin in CHOT (overexpress human insulin
      receptors) and CHO delta CT69 (overexpress insulin receptors lacking C-terminal
      69 amino acids) cells. Furthermore, the insulin-receptor C-terminus is not needed
      for either insulin or IGF-1 to stimulate paxillin or pp125FAK dephosphorylation
      in the CHO (Chinese-hamster ovary) cell lines used.

PMID- 8670045
TI  - Protein biotinylation in higher plants: characterization of biotin
      holocarboxylase synthetase activity from pea (Pisum sativum) leaves.
AB  - Biotin holocarboxylase synthetase was partially purified from pea leaves by a
      sequence of ammonium sulphate fractionation and DEAE 52-cellulose chromatography.
      Enzyme activity was assayed using apo-(biotin carboxyl carrier protein) from an
      Escherichia coli bir A mutant affected in biotin holocarboxylase synthetase
      activity. Conditions for optimal catalytic activity and biochemical parameters of
      the plant enzyme were determined. This is the first direct evidence of the
      existence of biotin holocarboxylase synthetase activity in plants.

PMID- 8670046
TI  - A mutation in the RET proto-oncogene in Hirschsprung's disease affects the
      tyrosine kinase activity associated with multiple endocrine neoplasia type 2A and
      2B.
AB  - We demonstrate that a Hirschsprung (HSCR) mutation in the tyrosine kinase domain
      of the RET proto-oncogene abolishes in cis the tyrosine-phosphorylation
      associated with the activating mutation in multiple endocrine neoplasia type 2A
      (MEN2A) in transiently transfected Cos cells. Yet the double mutant RET2AHS
      retains the ability to form stable dimers, thus dissociating the dimerization
      from the phosphorylation potential. Co-transfection experiments with single and
      double mutants carrying plasmids RET2A and RET2AHS in different ratios
      drastically reduced the phosphorylation levels of the RET2A protein, suggesting a
      dominant-negative effect of the HSCR mutation. Also, the phosphorylation
      associated with the multiple endocrine neoplasia type 2B (MEN2B) allele was
      affected in experiments with single and double mutants carrying plasmids co
      transfected under the same conditions. Finally, analysis of the enzymic activity
      of MEN2A and MEN2B tumours confirmed the relative levels of tyrosine
      phosphorylation observed in Cos cells, indicating that this condition, in vivo,
      may account for the RET transforming potential.

PMID- 8670047
TI  - Activation of a protein tyrosine phosphatase and inactivation of Raf-1 by
      somatostatin.
AB  - Human somatostatin receptor 3 ('hsstr3') was transiently expressed in NIH 3T3
      cells stably transformed with Ha-Ras (G12V). Somatostatin activated a protein
      tyrosine phosphatase and inactivated the constitutively active, membrane
      associated form of the Raf-1 serine kinase present in these cells in vivo and in
      vitro.

PMID- 8670048
TI  - Transgenic mice expressing the human ornithine decarboxylase gene under the
      control of mouse metallothionein I promoter.
AB  - We have generated a transgenic mouse line harbouring the human ornithine
      decarboxylase gene under the control of mouse metallothionein I promoter. Even in
      the absence of an exposure to heavy metals, ornithine decarboxylase was over
      expressed in heart, testis, brain, and especially in liver, of the transgenic
      animals. An exposure of the transgenic mice to zinc further enhanced the enzyme
      activity to a level which in liver represented up to 8000-fold increase in
      comparison with non-transgenic animals. The striking stimulation of liver
      ornithine decarboxylase activity upon treatment of the transgenic mice with zinc
      was accompanied by a nearly 150-fold increase in the hepatic putrescine content
      as compared with similarly treated non-transgenic animals. Even though the liver
      putrescine concentration reached that of spermidine and spermine in the
      transgenic animals, the contents of the higher polyamines only transiently
      increased upon zinc administration and then returned to the basal level. These
      findings once again indicate that mammalian cells possess extremely powerful
      regulatory machinery to prevent an over-accumulation of spermidine and spermine
      in non-dividing cells, and that very high tissue putrescine concentrations can be
      tolerated, at least for periods of a few days, with seemingly no phenotypic
      changes.

PMID- 8670049
TI  - Mechanisms of NADPH oxidase activation: translocation of p40phox, Rac1 and Rac2
      from the cytosol to the membranes in human neutrophils lacking p47phox or
      p67phox.
AB  - On neutrophil stimulation, the cytosolic components of NADPH oxidase, p67phox,
      p47phox, p40phox, as well as the Ras-related G-proteins Rac1 and Rac2, are
      translocated from the cytosol to cell membranes where they associate with a
      flavocytochrome b, forming a functional complex responsible for the production of
      oxygen radicals in phagocytes. In this paper we show that (a) in neutrophils from
      a patient with a form of chronic granulomatous disease (CGD) in which p67phox is
      absent, p47phox and Rac2, but not p40phox and Rac1 were translocated from the
      cytosol to the membrane on stimulation with formylmethionyl-leucylphenylalanine
      (fMLP) or phorbol 12-myristate 13-acetate (PMA); (b) in neutrophils from a
      patient with a form of CGD in which p47phox is absent, p67phox, p40phox and Rac1
      failed to associate with the membrane on stimulation with fMLP or PMA, whereas
      Rac2 was translocated as in normal neutrophils. We also show that in neutrophils
      from a patient lacking p67phox, the amount of cytosolic p40phox was decreased by
      about 40%. These findings indicate that, on neutrophil stimulation, p67phox
      mediates the translocation of p40phox and Rac1 from the cytosol to cell membranes
      and that Rac2 associates with the membranes independently of p47phox and p67phox.

PMID- 8670051
TI  - Mode of action and active site of an extracellular peroxidase from Pleurotus
      ostreatus.
AB  - The properties of the haem environment of an extracellular peroxidase from
      Pleurotus ostreatus were studied by electronic absorption spectroscopy. A high
      spin ferric form was predominant in the native enzyme and a high-spin ferrous
      form in the reduced enzyme. Cyanide was readily bound to the haem iron in the
      native form, thereby changing the enzyme to a low-spin cyano adduct. The
      electronic absorption spectra of the enzyme were similar to those of lignin
      peroxidase from Phanerochaete chrysosporium. Compound III of the enzyme was
      formed after the addition of an excess of H2O2 to the native enzyme, and
      thereafter spontaneously reverted to the native form. The enzyme oxidized 1-(3,5
      dimethoxy-4-hydroxyphenyl)-2-(2-methoxyphenoxy)-1,3-dihydroxyp ropane in the
      presence of H2O2 to produce 1-(3,5-dimethoxy-4-hydroxyphenyl)-2-(2
      methoxyphenoxy)-1-oxo-3-hydroxypr opane , 2,6-dimethoxyhydroquinone, 2-(2
      methoxyphenoxy)-3-hydroxypropanal, 2-(2-methoxyphenoxy)-3-hydroxypropanoic acid,
      2,6-dimethoxy-1,4-benzoquinone and guaiacol. A similar oxidation pattern was
      demonstrated with a one-electron oxidant, ammonium cerium(IV)nitrate. Free
      radicals were detected as intermediates of the enzyme-mediated oxidation of 1
      (3,5-dimethoxy-5-hydroxyphenyl)-2-(2-methoxyphenoxy)-1,3-dihydroxyp ropane and
      acetosyringone. These results can be explained by the mechanisms involving an
      initial one-electron oxidation of the lignin substructure. This radical may
      undergo C alpha-C beta cleavage, C alpha-oxidation and alkyl-phenyl cleavage.

PMID- 8670050
TI  - Characterization of sheep lacrimal-gland peroxidase and its major physiological
      electron donor.
AB  - A soluble sheep lacrimal-gland peroxidase was purified to apparent homogeneity.
      It had a native molecular mass of 75 kDa with a subunit molecular mass of 82 kDa
      and an isoelectric point of 6.5. Western blotting showed that it shares some of
      the enzyme antigenic determinants in common with other soluble peroxidases. The
      enzyme exhibits a Soret peak at 410 nm which is shifted to 431 nm by 5 equiv. of
      H2O2 due to the formation of compound II. The latter is, however, unstable and
      gradually returns to the native state. The enzyme forms complexes with CN- and N3
      and is reduced by dithionite showing a characteristic reduced peroxidase
      spectrum. Although the enzyme oxidizes I-, SCN- and Br- optimally at pH 5.5.,
      5.25 and 5.0 respectively, at physiological pH, it oxidizes I- and SCN- only.
      Since extracellular SCN- concentration is much higher than I-, SCN- may act as
      the major electron donor to the enzyme. The second-order rate constants for the
      reaction of the enzyme with H2O2 (k+1) and of compound I with SCN- (k+2) were 4 X
      10(7) M-1 X s-1 and 8.1 X 10(5) M-1 X s-1 respectively. A plot of log Vmax
      against pH yields a sigmoidal curve consistent with a single ionizable group on
      the enzyme with a pK(a) value of 5.75, controlling thiocyanate oxidation. In a
      coupled system with the peroxidase, H2O2, SCN-, GSH, NADPH and glutathione
      reductase, peroxidase-catalysed SCN- oxidation by H2O2 could be coupled to NADPH
      consumption. The system is proposed to operate in vivo for the efficient
      elimination of endogenous H2O2.

PMID- 8670052
TI  - Effect of a triplex-binding ligand on triple helix formation at a site within a
      natural DNA fragment.
AB  - We have used DNase I footprinting to examine the effect of a triplex-binding
      ligand on the formation of parallel intermolecular DNA triple helices at a mixed
      sequence target site contained within a natural DNA fragment (tyrT). In the
      presence of 10 microM ligand (N-[2-(dimethylamino)ethyl]-2-(naphthyl)quinolin-4
      ylamine), the binding of CTCTTTTTGCTT (12G) to the sequence GAGAAAAATGAA
      (generating a complex containing 8 x T x AT, 1 x G x TA and 3 x C+ x GC triplets)
      was enhanced 3-fold at pH 5.5. When the oligonucleotide CTCTTTTTTCTT (12T) was
      substituted for 12G (replacing G x TA with T x TA) there was a large reduction in
      affinity for the target sequence. However, this was stabilized by about 300-fold
      in the presence of the ligand, requiring a similar concentration to produce a
      footprint as 12G in the absence of the ligand. When the sequence of the target
      site was altered to GAGAAAAAAGAA, generating an uninterrupted run of purines
      [tyrT(46A)], the binding of 12T (generating a complex containing 9 x T x AT, and
      3 x C+ x GC triplets) was enhanced 3-fold by 10 microM of the triplex-binding
      ligand. However, although the binding of 12G to this sequence generating a
      complex containing a G x AT triplet, was much weaker, this too was stabilized by
      about 30-fold by the ligand, requiring a similar concentration as the perfect
      matched oligonucleotide (12T) in the absence of the ligand. A secondary, less
      stable footprint was also observed in these fragments when using either 12T or
      12G, which was evident only in the presence of the triplex-binding ligand. This
      site, which contained a number of triplet mismatches, appears to be realated to
      the formation of four or five central T x AT triplets. This reduction in the
      stringency of oligonucleotide binding by the triplex-binding ligand promotes the
      formation of complexes at non-targeted regions but may also have the potential
      for enabling recognition at sites that contain regions where there are no
      specific triplet matches.

PMID- 8670053
TI  - ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded
      conjugate export pump.
AB  - We have previously shown that the multidrug resistance protein (MRP) mediates the
      ATP-dependent membrane transport of the endogenous glutathione conjugate
      leukotriene C4 (LTC4) and of structurally related anionic conjugates of
      lipophilic compounds [Jedlitschky, Leier, Buchholz, Center and Keppler (1994)
      Cancer Res. 54, 4833-4836; Leier, Jedlitschky, Buchholz, Cole, Deeley and Keppler
      (1994) J. Biol. Chem. 269, 27807-27810]. We demonstrate in the present study that
      MRP also mediates the ATP-dependent transport of GSSG, as shown in membrane
      vesicles from human leukaemia cells overexpressing MRP (HL60/ADR cells) or HeLa
      cells transfected with an MRP expression vector (HeLa T5 cells) in comparison
      with the respective parental or control cells. The Km value for ATP-dependent
      transport of GSSG was 93 +/- 26 microM (mean value +/- S.D., n=5) in membrane
      vesicles from HeLa T5 cells. GSH, at a concentration of 100 microM, was not a
      substrate for any significant ATP-dependent MRP-mediated transport. The transport
      of GSSG was competitively inhibited by LTC4, by the leukotriene D4 receptor
      antagonist 3-([{3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl}-{(3-dimethylamino-3-
      oxopropyl)-thio}-methyl]thio)propanoic acid (MK 571) and by S-decylglutathione,
      with K1 values of 0.3, 0.6 and 0.7 microM respectively. These studies identify
      MRP as the membrane glycoprotein which mediates the ATP-dependent export of GSSG
      from these cells.

PMID- 8670054
TI  - The ability of POU family transcription factors to activate or repress gene
      expression is dependent on the spacing and context of their specific response
      elements.
AB  - The different forms of the Oct-2 and Brn-3 POU family transcription factors can
      have distinct effects on their target promoters involving both the activation and
      repression of gene expression. To investigate the requirements for these effects
      we have altered both the context and spacing of the two TAATGARAT binding sites
      for these factors within the herpes simplex virus immediate-early 3 gene
      promoter. We show that the activation of this promoter by Brn-3a and its
      repression by Brn-3b is dependent on the correct spacing of these binding sites.
      In contrast, repression of the promoter by Oct-2.4 and Oct-2.5 is dependent on
      both the spacing and context of these sites with the requirements for repression
      by Oct-2.4 or Oct-2.5 being different. These effects are discussed in the context
      of the mechanisms by which POU factors activate or repress their target genes.

PMID- 8670055
TI  - Isolation of a mouse theta glutathione S-transferase active with methylene
      chloride.
AB  - A glutathione S-transferase metabolizing methylene chloride has been isolated
      from mouse liver using a variety of chromatographic methods. N-terminal and
      internal amino acid sequences show that the enzyme, designated GST T1-1*, is
      closely related to the rat Theta-class GST 5-5. The mouse enzyme, molecular mass
      25000 Da, has been isolated to homogeneity in active form with an approximate
      yield of 2% of the cytosolic activity towards methylene chloride. GST T1-1* has a
      specific activity of about 5.5 micromol/min per mg of protein whereas the rat GST
      5-5 is reported to have a specific activity of about 11 micromol/min per mg of
      protein [Meyer, Coles, Pemble, Gilmore, Fraser and Ketterer (1991) Biochem. J.
      274, 409-414], demonstrating that both the rat and mouse enzymes have similar
      activity with this substrate. Limited evidence was obtained for a second enzyme,
      with a similar molecular mass (25400 Da), which had an N-terminal sequence
      identical to that of rat GST 12-12. This protein, which was sequenced from a band
      on a gel, was extremely labile and could not be isolated to homogeneity. The
      partially purified enzyme was not active with methylene chloride.

PMID- 8670056
TI  - The disulphide bond structure of thyroid-stimulating hormone beta-subunit.
AB  - Previously only one of the six disulphide bonds within the beta-subunit of bovine
      thyrotropin (bTSH beta) has been unequivocally assigned. In the present
      investigation, the fluorescent alkylating reagent 5-N
      [(iodoacetamidoethyl)amino]naphthalene-1-sulphonic acid has been employed as part
      of a double-alkylation strategy to allow the relative reactivities and the
      location of the six disulphide bonds of bTSH beta, after selective reduction, to
      be assigned by using reversed-phase HPLC peptide mapping techniques and
      associated methods of structural analysis. The most reactive disulphide bond was
      Cys88-Cys95; the second most reactive group of disulphide bonds involved the half
      cystine residues Cys16, Cys19, Cys67 and Cys105 with the experimental results
      consistent with the assignment of disulphide bonds to Cys16-Cys67 and Cys19
      Cys105. The least reactive group of half-cystine residues consisted of Cys2,
      Cys27, Cys31, Cys52, Cys83 and Cys85. The isolation, by high-performance ion
      exchange chromatography, of a partly reduced bTSH beta derivative in which only
      the half-cystine residues Cys31, Cys85, Cys88 and Cys95 were labelled enabled the
      assignment of a previously uncharacterized disulphide bond to Cys31-Cys85. The
      remaining two assignments, Cys2-Cys52 and Cys27-Cys83, were made by comparison
      with the recently published human chorionic gonadotropin crystal structure. The
      flexibility of the double-labelling approach used in these studies demonstrates
      that only very small quantities are required for proteins containing an extensive
      number of half-cystine residues such as TSH beta, owing to the combination of the
      high resolution of the reversed-phase HPLC peptide mapping procedures and the
      sensitivity of the fluorimetric detection method.

PMID- 8670057
TI  - Phosphonamidate analogues of dipeptides with carboxypeptidase A and beta
      lactamase-inhibitory activity: elucidation of the mechanism of beta-lactamase
      inhibition by electrospray mass spectrometry.
AB  - A series of phosphonamidate compounds with different P1' amino acid residues have
      been shown to be irreversible inactivators of the serine beta-lactamase from
      Enterobacter cloacae P99. The efficiency of inhibition (based on k2/K values) of
      P99 by these derivatives, ordered in decreasing potency, is: beta-phenyl-beta-Ala
      > L-Phe > beta-Ala > Gly > D-Phe > D-Pro > D-thiazolidine. The D- and L-Phe
      compounds also inhibit carboxypeptidase A. The proline and thiazolidine
      derivatives were phosphonamidate methyl esters, whereas the others were salts of
      diacids. Electrospray mass spectrometry showed that equimolar mixtures of the P99
      enzyme with each of the following derivatives, Gly, D-Phe, L-Phe, beta-Ala and
      beta-phenyl-beta-Ala, effected efficient adduct formation (70-95% of enzyme
      modified), illustrating the particularly active nature of some of these
      compounds. All the primary amino acid derivatives gave a similar mass increment,
      which suggests the displacement of the variable P1' part of the molecule. This
      observation provides evidence that the compounds phosphonylate the active-site
      serine, with the phosphonamidate bond as the scissile bond and the amino acid as
      the leaving group. The thiazolidine derivative (phosphonamidate methyl ester)
      also appeared to work by the same mechanism. The comparable proline derivatives
      caused lower than expected mass shifts of 227-229, and therefore it is proposed
      that with these compounds both the amino acid and the phosphonamidate ester
      methoxy group were displaced at the phosphorus atom during the inhibition
      process. Therefore, electrospray mass spectrometry has provided both a measure of
      potency and a rationale for the mechanism of inhibition of P99 by these
      compounds.

PMID- 8670058
TI  - Optimized heterologous expression of the human zinc enzyme glyoxalase I.
AB  - DNA coding for human glyoxalase I was isolated from a HeLa cell cDNA library by
      means of PCR. The deduced amino acid sequence differs form previously isolated
      sequences in that a glutamic acid replaces an alanine in position 111. This
      variant cDNA may represent the more acidic isoform of glyoxalase I originally
      identified at the protein level. An expression clone was constructed for high
      level production of glyoxalase I in Escherichia coli. For optimal yield of the
      recombinant protein, silent random mutations were introduced in the cDNA coding
      region. Antisera against human glyoxalase I were used to select a high-level
      expression clone. This clone afforded 60 mg of purified enzyme per litre of
      culture medium. Addition of a zinc salt to the culture medium was essential to
      obtain an active enzyme and a stoicheiometric metal content. The functional
      characterization of the recombinant enzyme included determination of kinetic
      constants for methylglyoxal, phenylglyoxal and p-phenylphenylglyoxal, as well as
      inhibition studies. The kinetic properties of recombinant glyoxalase I were
      indistinguishable from those of the enzyme purified from human tissues.

PMID- 8670059
TI  - Development of an aqueous-space mixing assay for fusion of granules and plasma
      membranes from human neutrophils.
AB  - Several models have been developed to study neutrophil degranulation. At the most
      basic level, phospholipid vesicles have been used to investigate the lipid
      interactions occurring during membrane fusion. The two major forms of assays used
      to measure phospholipid vesicle fusion are based either on the dilution of tagged
      phospholipids within the membrane of the two fusing partners or the mixing of the
      aqueous contents of the vesicles. Although problems exist with both methods, the
      latter is considered to be more accurate and representative of true fusion. Using
      8-aminonaphthalene-1,3,6-trisulphonic acid (ANTS) as a fluorescent marker, we
      have taken advantage of the quenching properties of p-xylenebispyridinium bromide
      ('DPX') to develop a simple aqueous-space mixing assay that can be used with any
      sealed vesicle. We compared our new assay with more conventional assays using
      liposomes composed of phosphatidic acid (PA) and phosphatidylethanolamine (PE),
      obtaining comparable results with respect to Ca2+-dependent fusion. We extended
      our studies to measure the fusion of neutrophil plasma-membrane vesicles as well
      as azurophil and specific granules with PA/PE (1:3) liposomes. Both specific
      granules and plasma-membrane vesicles fused with PA/PE liposomes at [Ca2+] as low
      as 500 microM, while azurophil granules showed no fusion at [Ca2+] as high as 12
      mM. These differences in the ability of Ca2+ to induce fusion may be related to
      differences observed in whole cells with respect to secretion.

PMID- 8670060
TI  - Bilirubin glucuronidation by intact Gunn rat fibroblasts expressing bilirubin UDP
      glucuronosyltransferase.
AB  - Crigler-Najjar (CN) disease is an inherited disorder of bilirubin metabolism. The
      disease is caused by a deficiency of the hepatic enzyme bilirubin UDP
      glucuronosyltransferase (B-UGT). Patients with CN disease have high serum levels
      of the toxic compound, unconjugated bilirubin. The only defect in bilirubin
      metabolism of CN patients is the absence of B-UGT activity. The transplantation
      of cells able to glucuronidate bilirubin should therefore lower serum bilirubin
      levels. The Gunn rat is the animal model of CN disease. Primary Gunn rat
      fibroblasts (GURF) were transduced with a recombinant retrovirus, capable of
      transferring B-UGT cDNA. A cell line was obtained expressing B-UGT at a level
      comparable to hepatocytes. Bilirubin added to the culture medium of these cells
      was glucuronidated and excreted. The B-UGT activities of transduced GURF and
      freshly isolated Wistar hepatocytes were compared at different bilirubin
      concentrations. The specific B-UGT activities of these two cell types were
      comparable when physiological bilirubin concentrations (5-10 microM) were present
      in the culture media. At higher bilirubin concentrations (20-80 microM) the
      hepatocytes were more active than the transduced GURF. We conclude that with the
      addition of only one enzyme (B-UGT) fibroblasts can perform the complete set of
      reactions necessary for bilirubin glucuronidation. The difference in B-UGT
      activity between transduced GURF and hepatocytes at 20-80 microM bilirubin can be
      explained by lower UDP-glucuronic acid and glutathione S-transferase levels in
      GURF. Our findings also indicate that these cells could be used to develop
      extrahepatic gene therapy for CN disease.

PMID- 8670061
TI  - Noradrenaline increases glucose transport into brown adipocytes in culture by a
      mechanism different from that of insulin.
AB  - Glucose uptake into brown adipose tissue has been shown to be enhanced directly
      by noradrenaline (norepinephrine) released from sympathetic nerves. In this study
      we characterized the glucose transport system in cultured brown adipocytes, which
      responds to noradrenaline as well as insulin, and analysed the mechanism
      underlying the noradrenaline-induced increase in glucose transport. Insulin
      increased 2-deoxyglucose (dGlc) uptake progressively at concentrations from 10(
      11) to 10(-6) M, with maximal stimulation at 10(-7) M. Noradrenaline
      concentrations ranging from 10(-8) to 10(-6) M also enhanced dGlc uptake, even in
      the absence of insulin. The effects of noradrenaline and insulin on dGlc uptake
      were additive. The stimulatory effect of noradrenaline was mimicked by the beta3
      adrenergic agonist, BRL37344, at concentrations two orders lower than
      noradrenaline. Dibutyryl cyclic AMP also mimicked the stimulatory effect of
      noradrenaline, and the antagonist of cyclic AMP, cyclic AMP-S Rp-isomer, blocked
      the enhancement of glucose uptake due to noradrenaline. Furthermore Western blot
      analysis with an anti-phosphotyrosine antibody revealed that, in contrast with
      insulin, noradrenaline apparently does not stimulate intracellular
      phosphorylation of tyrosine, suggesting that the noradrenaline-induced increase
      in dGlc uptake depends on elevation of the intracellular cyclic AMP level and not
      on the signal chain common to insulin. When cells were incubated with insulin,
      the content of the muscle/adipocyte type of glucose transporter (GLUT4) in the
      plasma membrane increased, with a corresponding decrease in the amount in the
      microsomal membrane. In contrast, noradrenaline did not affect the subcellular
      distribution of GLUT4 or that of the HepG2/erythrocyte type of glucose
      transporter. Although insulin increased Vmax. and decreased the Km value for
      glucose uptake, the effect of noradrenaline was restricted to a pronounced
      decrease in Km. These results suggest that the mechanism by which noradrenaline
      stimulates glucose transport into brown adipocytes is not due to translocation of
      GLUT but is probably due to an increase in the intrinsic activity of GLUT, which
      is mediated by a cyclic AMP-dependent pathway.

PMID- 8670062
TI  - Dictyostelium discoideum contains three inositol monophosphatase activities with
      different substrate specificities and sensitivities to lithium.
AB  - The small ion lithium, a very effective agent in the treatment of manic
      depressive patients, inhibits the mammalian enzyme inositol monophosphatase,
      which is proposed as the biological target for the effects of lithium. In this
      study we investigated Dictyostelium discoideum inositol monophosphatase activity.
      Partial purification of the proteins in the soluble cell fraction using anion
      exchange chromatography revealed the presence of at least three enzyme activities
      capable of degrading inositol monophosphate isomers. The first activity was
      similar to the monophosphatase found in mammalian cells, as it degraded Ins(4)P,
      Ins(1)P and to a lesser extent Ins(3)P, was dependent on MgCl2 and inhibited by
      LiCl in a uncompetitive [corrected] manner. The second enzyme activity was
      specific for Ins(4)P; the enzyme activity was not dependent on MgCl2 and not
      inhibited by LiCl. The third monophosphatase activity degraded especially
      Ins(3)P, but also Ins(4)P and Ins(1)P; increasing concentrations of MgCl2
      inhibited this enzyme activity, whereas LiCl had no effect. In vivo, LiCl induces
      a reduction of inositol levels by about 20%. In [3H]inositol-labelled cells LiCl
      causes a 6-fold increase in the radioactivity of [3H]Ins(1)P, a doubling of
      [3H]Ins(4)P and a slight decrease in the radioactivity in [3H]Ins(3)P. These data
      indicate that the biological effects of lithium in Dictyostelium are not due to
      depletion of the inositol pool by inhibition of inositol monophosphatase
      activity.

PMID- 8670063
TI  - Identification and characterization of two distinct calmodulin-binding sites in
      the Trpl ion-channel protein of Drosophila melanogaster.
AB  - Two putative light-sensitive ion channels have been isolated from Drosophila,
      encoded by the transient-receptor-potential (trp) and transient-receptor
      potential-like (trpl) genes. The cDNA encoding the Trpl protein was initially
      isolated on the basis that the expressed protein binds calmodulin. Using both
      fusion proteins and a synthetic peptide, we now show that two calmodulin-binding
      sites are present in the C-terminal domain of the Trpl protein, CBS-1 and CBS-2.
      CBS-1 binds calmodulin in a Ca2+-dependent fashion, requiring Ca2+ concentrations
      above 0.3-0.5 microM for calmodulin binding. In contrast, CBS-2 binds the Ca2+
      free form of calmodulin, with dissociation occurring at Ca2+ concentrations
      between 5 and 25 microM. Phosphorylation of a serine residue within a peptide
      encompassing CBS-1 by cyclic AMP-dependent protein kinase (PKA) abolishes
      calmodulin binding, and phosphorylation of the adjacent serine by protein kinase
      C appears to modulate this phosphorylation by PKA. Interpretation of these
      findings provides a novel model for ion-channel gating and modulation in response
      to changing levels of intracellular Ca2+.

PMID- 8670064
TI  - Mitochondrial differentiation during the early development of the brine shrimp
      Artemia franciscana.
AB  - During the early development of Artemia there is an increase in mitochondrial
      enzyme activities of about one order of magnitude, whereas the activities of two
      cytoplasmic enzymes tested as controls remain unaltered. The mitochondrial enzyme
      activation correlates with (i) large changes in mitochondrial morphology, (ii) a
      5-fold increase in the amount of the H+-ATP synthase beta-subunit and (iii) a
      dramatic increase in the steady-state level of mitochondrial mRNAs, whereas
      mitochondrial rRNA concentrations remain mostly unchanged. In contrast, the level
      of mitochondrial DNA does not change significantly during the first 20 h after
      resumption of development. After hatching, the mitochondrial DNA content
      increases twice in parallel with one round of cellular division, thus indicating
      that mitochondrial and nuclear replication are coupled in Artemia postgastrular
      development. The data presented strongly suggest that mitochondrial maturation in
      the absence of significant mitochondrial proliferation is responsible for the
      dramatic increase in mitochondrial function that takes place after resumption of
      development in Artemia.

PMID- 8670065
TI  - Biologically active monomeric and heterodimeric recombinant human calpain I
      produced using the baculovirus expression system.
AB  - Calpain I is a heterodimeric protein that is part of a family of calcium
      activated intracellular cysteine proteases presumed to play a role in mediating
      signals transduced by calcium. Expression of bioactive recombinant human calpain
      I has been achieved using the baculovirus expression system, by either co
      infection with two viruses, each expressing one of the subunits, or infection
      with a single virus containing both subunits. The approximately 80 kDa catalytic
      subunit exhibited calcium-dependent proteolytic activity when expressed alone or
      with the approximately 30 kDa regulatory subunit. Baculoviral recombinant calpain
      I appeared fully active in that the catalytic subunit in unpurified cell extracts
      exhibited calcium-dependent autocatalytic cleavage at the correct locus. The
      amount of approximately 80 kDa subunit accumulated at steady state was greatly
      increased by co-expression of the approximately 30 kDa subunit, suggesting a
      possible role for enzyme stabilization by the latter subunit. The recombinant
      human calpain I was purified to near homogeneity and compared with purified
      native human erythrocyte calpain I. The recombinant and native enzymes had
      equivalent inhibition constants for structurally diverse calpain inhibitors,
      identical calcium activation profiles, and similar specific activities,
      demonstrating the suitability of using the recombinant protein for studies of the
      native enzyme.

PMID- 8670066
TI  - Comparative cellular processing of the human immunodeficiency virus (HIV-1)
      envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases.
AB  - We present here the pulse and pulse-chase analysis of the biosynthesis of the
      envelope glycoprotein gp160 and its intracellular processing by the
      subtilisin/kexin-like convertases furin, PACE4, PC1, PC5 and its isoform PC5/6-B.
      We demonstrate that furin and to a much lesser extent PACE4, PC5/6-B and PC1 are
      candidate enzymes capable of processing gp160 intracellularly. Furthermore we
      show that furin can also process gp160/gp120 into gp77/gp53 products by cleavage
      at the sequence RIQR/GPGR just preceding the conserved GPGR structure found at
      the tip of the hypervariable V3 loop. The results show that processing into gp120
      could occur at or before the trans-Golgi network (TGN) where sulphation of the
      oligosaccharide moieties of gp160 was detected. In contrast, the formation of
      gp77/gp53 by furin is a late event occurring after exit from the TGN. Our data
      also revealed that the alpha glucosidase I inhibitor N-butyldeoxynojirimycin,
      although affecting the oligosaccharide composition of gp160, does not impair the
      processing of either gp160 or gp120 by either furin or PACE4. Finally, the co
      expression of the [Arg355, Arg358]-alpha-1-antitrypsin Portland variant was shown
      to potently inhibit the processing of both gp160 and gp120 by these convertases.

PMID- 8670068
TI  - Fatty acids regulate the expression of lipoprotein lipase gene and activity in
      preadipose and adipose cells.
AB  - During fasting, a reduction in lipoprotein lipase (LPL) activity has been
      observed in rat fat pad with no change in enzyme mass, whereas LPL mRNA and
      synthesis are increased, suggesting that insulin and/or fatty acids (FA) regulate
      LPL activity post-translationaly [Doolittle, Ben-Zeev, Elovson, Martin and
      Kirchgessner (1990) J. Biol. Chem. 265, 4570-4577]. To examine the role of FA,
      either preadipose Ob1771 cells or Ob1771 and 3T3-F442A adipose cells were exposed
      to long-chain FA and to 2-bromopalmitate, a non-metabolized FA. A rapid (2-8 h)
      and dose-dependent increase (up to 6-fold) in LPL mRNA occurred, primarily due to
      increased transcription, which is accompanied by a decrease (down to 4-fold) in
      LPL cellular activity. Under these conditions, secretion of active LPL was nearly
      abolished. Removal of FA led to full recovery of LPL activity. LPL gene
      expression in 3T3-C2 fibroblasts was not affected by FA treatment. However fatty
      acid-activated receptor transfected-3T3-C2 cells, which show FA responsiveness,
      had increased LPL gene expression upon FA addition. LPL synthesis and cellular
      content appeared unaffected by FA treatment, whereas secretion of LPL was
      inhibited. These results indicate that FA regulate the post-translational
      processing of LPL. It is proposed that the regulation of LPL activity by FA is
      important with regard to the fine-tuning of FA entry into adipocytes during
      fasting/feeding periods.

PMID- 8670067
TI  - Kinetic and spectroscopic properties of the cyanide complexes of ferrous
      haemoglobins I and IV from trout blood.
AB  - The cyanide ion is a ligand of ferrous as well as ferric haemoproteins and this
      study presents a kinetic characterization of the dissociation of its complexes
      with the two main haemoglobin components from trout blood. Both these
      haemoglobins bind oxygen co-operatively at neutral or alkaline pH values but one
      of them is insensitive to pH and allosteric effectors (haemoglobin I, HbI) while
      the other (haemoglobin IV, HbIV) is strongly sensitive and shows the so-called
      Root effect (i.e. the incomplete oxygen saturation in air-equilibrated solutions
      at pH values of < 6.5). Comparison of the kinetics of dissociation of cyanide
      from ferrous forms of HbI and HbIV reveals that: (i) cyanide dissociates in both
      cases by a complex reaction, and, at least in the case of HbIV, this may be
      attributed to functional differences between the alpha and beta subunits; (ii)
      the reaction is only scarcely co-operative in HbI and not at all so in HbIV; and
      (iii) the Bohr and Root effects are not manifested in this reaction. The
      functional heterogeneity of ferrous alpha and beta chains of trout HbI has not
      been observed for any other ligand; moreover, the observation that co-operativity
      for cyanide dissociation is expressed by human haemoglobin but not by trout HbIV
      is surprising.

PMID- 8670069
TI  - Induction of the mammalian stress response gene GADD153 by oxidative stress: role
      of AP-1 element.
AB  - GADD153 is a CCAAT/enhancer-binding-protein-related gene that may function to
      control cellular growth in response to stress signals. In this study, a variety
      of oxidant treatments were shown to stimulate endogenous GADD153 mRNA expression
      and to transcriptionally activate a GADD153 promoter-reporter gene construct in
      transfected HeLa cells. Both commonalities and distinctions in the induction of
      GADD153 by H2O2 and the thiol-reactive compound arsenite were demonstrated.
      GADD153 mRNA induction by both H2O2 and arsenite was potentiated by GSH
      depletion, and completely inhibited by N-acetyl-cysteine. o-Phenanthroline and
      mannitol blocked GADD153 induction by H2O2, indicating that iron-generated
      hydroxyl radical mediates this induction. Concordantly, GSH peroxidase
      overexpression in WI38 cells attenuated GADD153 mRNA induction by H2O2. However,
      GADD153 induction by arsenite was only modestly reduced in the same cells,
      suggesting a lesser contribution of peroxides to gene activation by arsenite. We
      also demonstrated that oxidative stress participates in the induction of GADD153
      by UVC (254 nm) irradiation. Finally, both promoter-deletion analysis and point
      mutation of the AP-1 site in an otherwise intact promoter support a significant
      role for AP-1 in transcriptional activation of GADD153 by UVC or oxidant
      treatment. Indeed, exposure of cells to oxidants or UVC stimulated binding of Fos
      and Jun to the GADD153 AP-1 element. Together, these results demonstrate that
      both free-radical generation and thiol modification can transcriptionally
      activate GADD153, and that AP-1 is critical to oxidative regulation of this gene.
      This study further supports a role for the GADD153 gene product in the cellular
      response to oxidant injury.

PMID- 8670070
TI  - P2-purigenic receptors regulate phospholipase C and adenylate cyclase activities
      in immortalized Schwann cells.
AB  - Schwann cells play an important role in both the development and regeneration of
      peripheral nerves. Proliferation and differentiation of Schwann cells are
      critically dependent on changes in the levels of cAMP. ATP is a fast excitatory
      transmitter in the peripheral nervous system, inducing depolarization of the
      vagus nerve through occupancy of P2-purinergic receptors. In the present study we
      demonstrate that extracellular ATP stimulates phospholipase C and inhibits
      adenylate cyclase activities in cultured Schwann cells. Addition of ATP
      inhibited, in a concentration-dependent manner, forskolin- or isoprenaline
      stimulated adenylate cyclase activity. The rank order of potency corresponding to
      different purinergic receptor agonists was 2-methylthio-ATP > ATP = ADP > or =
      adenosine 5'-[gamma-thio]triphosphate (ATP[S]) > UTP, consistent with the
      involvement of a P2y subtype. Adenosine and adenosine 5'-[alpha,beta-methylene]
      triphosphate (pp[CH2pA) were ineffective. Preincubation with pertussis toxin
      completely blocked this inhibitory effect. When Schwann cells were pre-labelled
      with myo-[3H]inositol and incubated in Hanks' balanced salt solution containing
      Ca2+ and Mg2+, addition of ATP[S] resulted in a concentration-dependent increase
      in the release of InsP with a concomitant increase in intracellular free [Ca2+]
      ([Ca2+]i). Under these conditions, the effects of both ATP and UTP were of lower
      magnitude. Removal of Ca2+ and Mg2+ from the assay medium resulted in a
      significant increase in the effects of ATP[S], ATP and UTP. The decreased
      response observed in the presence of both bivalent cations (1.2 mM Ca2+ and 1 mM
      Mg2+) could not be explained either by increased degradation of ATP by Ca2+/Mg2+
      dependent nucleotidases or by cation influx. The rank order of potency for the
      effects of agonists on phospholipase C activity was ATP[S] = adenosine 5'[gamma
      imido]triphosphate > ATP -UTP > ADP, indicating the involvement of a P(2U)
      receptor subtype in this response. Adenosine, AMP and pp[CH2]pA were ineffective.
      These results demonstrate that immortalized Schwann cells express P(2U) and P(2Y)
      purinoceptors, which are coupled to stimulation of phospholipase C and inhibition
      of adenylate cyclase, respectively. Our observations unveil signal-transduction
      pathways that may be used by ATP to regulate proliferation and differentiation of
      Schwann cells, and ultimately to influence nerve homeostasis.

PMID- 8670071
TI  - Lipoprotein lipase stimulates the binding and uptake of moderately oxidized low
      density lipoprotein by J774 macrophages.
AB  - Lipoprotein lipase (LPL) stimulates the uptake of low-density lipoprotein (LDL)
      and very-low-density lipoprotein (VLDL) in different cell types, including
      macrophages, through bridging of LPL between lipoproteins and extracellular
      heparan sulphate proteoglycans (HSPG). Because macrophages produce LPL and
      because modified lipoproteins are present in the arterial wall in vivo, we
      wondered whether LPL also enhances the uptake of oxidized LDL by J774
      macrophages. LDL samples with different degrees of oxidation, as evaluated by
      relative electrophoretic mobility (REM) as compared with native LDL are used as
      well as native and acetylated LDL. Addition of 5 microg/ml LPL to the J774 cell
      culture medium stimulated the binding of both native LDL and moderately oxidized
      LDL (REM < 3.5) 50-100-fold, and their uptake was stimulated approx. 20-fold. The
      LPL-mediated binding of native LDL and moderately oxidized LDL was dose
      dependent. Preincubation of the cells with heparinase (2.4 units/ml) inhibited
      the stimulatory effect of LPL, indicating that this LPL-mediated stimulation was
      due to bridging between the lipoproteins and HSPG. The binding to J774
      macrophages of severely oxidized LDL (REM=4.3) was stimulated less than 3-fold by
      LPL, whereas its uptake was not stimulated significantly. The binding and uptake
      of acetylated LDL (AcLDL) were not stimulated by LPL, although the LPL-molecule
      itself does bind to AcLDL. Measurements of the cellular lipid content showed that
      addition of LPL also stimulated the accumulation in the cells of cholesteryl
      ester derived from both native LDL and moderately oxidized LDL in a dose
      dependent manner. We conclude that our results present experimental evidence for
      the hypothesis that LPL serves as an atherogenic component in the vessel wall.

PMID- 8670072
TI  - Phosphatidylcholine increases the secretion of triacylglycerol-rich lipoproteins
      by CaCo-2 cells.
AB  - The regulation of lipid synthesis and secretion by phosphatidylcholine was
      investigated in CaCo-2 cells grown on semi-permeable filters. In cells incubated
      with 1 mM taurocholate and 100-500 microM phosphatidylcholine, cholesteryl ester
      synthesis was decreased, triacylglycerol synthesis was increased modestly,
      whereas phospholipid synthesis was unaffected. Acyl-CoA-cholesterol
      acyltransferase activity was decreased secondary to a decrease in the substrate
      (cholesterol) supply. The basolateral secretion of newly synthesized
      triacyglycerol and triacyglycerol mass was significantly increased by
      phosphatidylcholine, whereas cellular triacylglycerol mass decreased. This effect
      was no specific for phosphatidylcholine as phosphatidylethanolamine and
      phosphatidylserine also increased the secretion of newly synthesized
      triacylglycerols. Dioleoylphosphatidylcholine was as effective as egg
      phosphatidylcholine in increasing triacylglycerol transport.
      Dipalmitoylphosphatidylcholine, in contrast, was without effect.
      Phosphatidylcholine also increased the basolateral secretion of apolipoprotein B
      (apoB) mass without altering apoB mRNA levels. Disruption of the Golgi apparatus
      by monensin or brefeldin A prevented the increase in apoB secretion by
      phosphatidylcholine. Compared with microsomes prepared from control cells, those
      from cells incubated with phosphatidylcholine contained more newly synthesized
      apoB. The percentage of new synthesized apoB isolated from teh lumen of
      microsomes (as an estimate of apoB destined for secretion), however, was similar
      in the two preparations. Thus in CaCo-2 cells incubated with phosphatidylcholine,
      the transport of apoB and triacylglycerols is increased whereas cholesteryl ester
      synthesis and secretion are decreased. A normally functioning secretory pathway
      is required for phosphatidylcholine to increase triacylglycerol-rich lipoprotein
      secretion.

PMID- 8670073
TI  - Lipoxygenase treatment render low-density lipoprotein susceptible to Cu2+
      catalysed oxidation.
AB  - Oxidative modification of low-density lipoprotein (LDL) has been implicated in
      foam-cell formation at all stages of atherosclerosis. Since transition metals and
      mammalian 15-lipoxygenases are capable of oxidizing LDL to its atherogenic form,
      a concerted action of these two catalysts in atherogenesis has been suggested.
      Cu2+-catalysed LDL oxidation is characterized by a kinetic lag period in which
      the lipophilic antioxidants are decomposed and by a complex mixture of unspecific
      oxidation products. We investigated the kinetics of the 15-lipoxygenase-catalysed
      oxygenation of LDL and found that the enzyme is capable of oxidizing LDL in the
      presence of the endogenous lipophilic antioxidants. In contrast with the Cu2+
      catalysed reaction, no kinetic lag phase was detected. The pattern of products
      formed during short-term incubations was highly specific, with cholesterol
      esterified (13S)-hydroperoxy-(9Z,11E)-octadecadinoic acid being the major
      product. However, after long-term incubations the product pattern was less
      specific. Preincubation with 15-lipoxygenase rendered human LDL more susceptible
      to Cu2+-catalysed oxidation as indicated by a dramatic shortening of the lag
      period. Addition of Cu2+ to lipoxygenase-treated LDL led to a steep decline in
      its antioxidant content and to a greatly reduced lag period. Interestingly, if
      normalized to a comparable hydroperoxide content, autoxidation and addition of
      exogenous hydroperoxy fatty acids both failed to overcome the lag period. The
      local peroxide concentrations in various LDL subcompartments will be discussed as
      a possible reason for this unexpected behaviour.

PMID- 8670074
TI  - Purification and characterization of a plasma membrane ferricyanide-utilizing
      NADH dehydrogenase from Ehrlich tumour cells.
AB  - A ferricyanide-utilizing NADH dehydrogenase (NADH-ferricyanide oxidoreductase)
      from the plasma membrane of Ehrlich ascites tumour cells has been purified about
      1500-fold to apparent homogeneity. The method comprises the isolation of an
      enriched plasma membrane fraction, solubilization with Triton X-100, ion-exchange
      chromatography, ammonium sulphate precipitation, Cibacron Blue chromatography and
      fast-protein liquid chromatography with a Superose-6 gel filtration column. The
      specific activity of the final pool was more than 61 units/mg protein. The pure
      enzyme examined by SDS/PAGE displayed only one type of subunit with an apparent
      molecular mass of 32.0 kDa. The molecular mass of the native protein (117.0 kDa)
      was estimated by gel filtration; these results suggest a protein composed of four
      subunits of identical molecular mass. The enzyme was stable in the pH interval
      between 6 and 9, with maximum activity at pH values from 7.5 to 8.5. The purified
      enzyme showed Michaelis-Menten kinetics for the substrates, with apparent K(m)
      values of 4.3 X 10(-5) M and 6.7 X 10(-5) M for NADH and ferricyanide
      respectively. The isolated protein was strongly inhibited by Zn2+ and the thio
      specific reagents mersalyl and p-chloromercuribenzenesulphonic acid.

PMID- 8670075
TI  - Kinetic study of the plasma-membrane potential in procyclic and bloodstream forms
      of Trypanosoma brucei brucei using the fluorescent probe bisoxonol.
AB  - The characteristics of the plasma-membrane potential of procyclic and bloodstream
      forms of Trypanosoma brucei brucei (cultured cells) were investigated using the
      fluorescent anionic probe bisoxonol. Observation of a stable and representative
      plasma-membrane potential in the resting state required careful washing,
      centrifugation and maintenance of the cells at room temperature before
      measurement. Bloodstream forms were more prone to depolarization during washing
      at 4 degrees C than procyclic cells. The higher fluorescence observed in the
      presence of long slender cells than in the presence of procyclic cells shows that
      the plasma-membrane potential is more negative in the insect form. Healthy dilute
      cells can sustain their plasma-membrane potential for hours in the presence of
      external glucose. The presence of a high K+ concentration in the medium did not
      promote by itself the depolarization of either type of cell. Study of bisoxonol
      fluorescence as a function of time allowed us to follow the kinetics of the
      action of metabolic inhibitors in the presence of various ions. o-Vanadate (1 mM)
      was found to depolarize bloodstream-form cells rapidly but only in a phosphate
      free NaCl buffer. Omeprazole and strophanthidin also specifically depolarized
      bloodstream-form trypanosomes. However, NN'-dicyclohexylcarbodi-imide depolarized
      both types of cell, but more rapidly for bloodstream-form cells. Bloodstream-form
      trypanosomes appear to use mainly a vanadate-sensitive Na+ pump to maintain their
      Na+-diffusion gradient. However, most of the ATPase inhibitors tested had little
      or no effect on the plasma-membrane potential of procyclics suggesting that this
      form of trypanosome may rely on several regulation mechanisms.

PMID- 8670076
TI  - Functional expression of a human thrombin receptor in Sf9 insect cells: evidence
      for an active tethered ligand.
AB  - Desensitization of recombinant human thrombin receptors expressed in Sf9 insect
      cells was compared with native thrombin receptors in megakaryoblast
      erythroleukaemia (HEL) cells. Addition of thrombin (2 units/ml) or agonist
      peptide SFLLRN (10 microM) to HEL cells, or to Sf9 cells infected with
      recombinant baculovirus containing the thrombin receptor cDNA, produced an
      increase in the free cytosolic Ca2+ concentration ([Ca2+]i) as measured by fura
      2. The response in HEL cells was transient, reflecting a rapid homologous
      desensitization. In contrast, [Ca2+]i in Sf9 cells expressing the thrombin
      receptor increased rapidly to a peak value that slowly declined, but remained
      elevated for at least 12 min following stimulation by thrombin. The sustained
      [Ca2+]i response to thrombin was not reversed by washout of thrombin or by any
      subsequent addition of hirudin. Pretreatment of Sf9 cells with either thrombin (2
      units/ml) or SFLLRN (10 or 50 microM) for 5 min produced a shift in the ED50 for
      SFLLRN (added 10 min after washout) from 0.4 microM to 20 and 7 microM,
      respectively. Thus, desensitization of thrombin receptors expressed in Sf9 cells
      occurs slowly and reflects a decrease in receptor affinity. The sustained [Ca2+]i
      response in Sf9 cells stimulated by thrombin may reflect continuous activation by
      the tethered ligand. To test this hypothesis, the effect of protease treatment
      during the sustained phase of the response was examined. Addition of either
      aminopeptidase M or thermolysin reversed the sustained response to SFLLRN, but
      only thermolysin reversed the sustained response to thrombin. Thermolysin had no
      effect on the change in [Ca2+]i observed following carbachol stimulation of Sf9
      cells expressing the M5 muscarinic receptor. Furthermore, following thermolysin
      treatment, the cells remained responsive to a subsequent application of SFLLRN.
      These results demonstrate that the tethered ligand remains active for extended
      periods of time after thrombin stimulation and suggests that further hydrolysis
      by extracellular proteases may represent an important mechanism of rapid receptor
      deactivation.

PMID- 8670077
TI  - Cloning and characterization of the 5' end and promoter region of the chicken
      acetyl-CoA carboxylase gene.
AB  - Acetyl-CoA carboxylase is a rate-limiting enzyme in the biogenesis of long-chain
      fatty acids. In the present study, the 5' end and flanking region of the acetyl
      CoA carboxylase (ACC) gene was analysed in the chicken. A genomic clone was
      isolated containing the first three exons, the third one containing the ATG
      codon. Using nuclease-mapping experiments and primer-extension analyses, the
      transcription-initiation site was located 153 nucleotides upstream of the ATG
      codon. In contrast with rat ACC gene expression, reverse transcriptase PCR
      analysis performed on chicken liver mRNA did not reveal alternative splicing in
      the 5'-untranslated region of these messengers. The promoter region is very G+C
      rich, and contains no TATA or CAAT boxes. Analysis by transient transfection in a
      human hepatoma cell line (HepG2) demonstrates that the promoter activity requires
      the presence of symmetrical sequences located upstream of the GC boxes.
      Transcription of this gene is found to be controlled by tri-iodothyronine in
      HepG2 cells, but the sequence responsible for the tri-iodothyronine response is
      not the consensus tri-iodothyronine-responsive element localized in the promoter.
      These results bring new insights to the regulation of the chicken ACC gene which
      differs from that of the rat.

PMID- 8670078
TI  - Site-specific glycosylation of human immunoglobulin G is altered in four
      rheumatoid arthritis patients.
AB  - Alterations in the glycosylation of human IgG have been shown to occur in
      rheumatoid arthritis (RA). However, the precise nature and location of these
      changes have not been fully established. Therefore we carried out a detailed
      analysis of the oligosaccharides chemically released from intact human serum IgG
      and fragments of the molecule. Serum samples were from three healthy ('normal')
      individuals, and from four patients with RA. Site-specific glycolsylation of the
      glycoprotein was shown to occur, which extended to sites even within the Fab
      fragment. These were differences in galactosylation, sialylation and the presence
      of a bisecting N-acetylglucosomide. Disease related alterations were also shown
      to be site-specific. In particular, an increase in the proportion of
      agalactosylated oligosaccharides occurred on the Fc fragment in RA (P=0.057),
      but, in contrast to previous reports there was an increase on the light chain in
      the proportion of fully galactosylated, bisected and core fucosylated
      oligosaccharides (from 13% of total in normal to between 18 and 35% in RA,
      P=0.057)). There was also an Fab-specific increase in oligosaccharides bearing a
      bisecting N-acetylglucosamine and a core fucose (P=0.075) The site-specific
      glycosylation changes described in this paper reveal the complexity of the
      regulatory mechanism, perhaps reflecting the many levels at which regulation can
      occur.

PMID- 8670079
TI  - Properties of chicken erythrocyte histone deacetylase associated with the nuclear
      matrix.
AB  - Histone H2B is deacetylated more rapidly than H3 and H4 in chicken immature
      erythrocytes. Histone deacetylase from chicken immature erythrocytes was
      partially purified, and the histone specificities of the multiple histone
      deacetylase forms were determined. Ion-exchange (Q-Sepharose) and gel-exclusion
      (Superdex 200) chromatography of extracts from erythrocyte nuclei showed two
      forms (HD1 and HD2) of histone deacetylase. HD1, with a molecular mass of about
      55 kDa, preferred free H3-H4 relative to H2A-H2B, while HD2, with a molecular
      mass of approx. 220 kDa, had a slight preference for H3-H4. HD1 and HD2 differed
      in pH- and ion-strength-dependence. HD2 dissociated into HD1 when treated with
      1.6 M NaCl or when applied to a Q-Sepharose column. The enzymic properties of
      nuclear-matrix-bound histone deacetylase showed a striking difference from that
      of HD1 and HD2, particularly in its strong preference for H2A-H2B. Treatment of
      the nuclear matrix with 1.6 M NaCl and 1% 2-mercaptoethanol solubilized histone
      deacetylase which chromatographed as 400 and 220 kDa forms on a Superdex 200
      column. The solubilized enzyme retained its histone preference for H2A-H2B.
      Chromatography of the nuclear-matrix-derived enzyme on Q-Sepharose yielded one
      peak of enzyme activity with chromatographic properties and histone specificities
      similar to those of HD1. These results provide support for the active form of the
      enzyme in situ being a high-molecular mass complex associated with proteins that
      are components of the nuclear matrix. Substrate preference of the enzyme is
      governed by the proteins associated with the histone deacetylase.

PMID- 8670080
TI  - The endopeptidase activity and the activation by Cl- of angiotensin-converting
      enzyme is evolutionarily conserved: purification and properties of an an
      angiotensin-converting enzyme from the housefly, Musca domestica.
AB  - A soluble 67 kDa angiotensin-converting enzyme (ACE) has been purified by
      lisinopril-Sepharose affinity column chromatography from adult houseflies, Musca
      domestica. The dipeptidyl carboxypeptidase activity towards benzoyl-Gly-His-Leu
      was inhibited by captopril (IC50 50 nM) and fosinoprilat (IC50 251 nM), two
      inhibitors of mammalian ACE, and was activated by Cl- (optimal Cl- concentration
      600 mM). Musca ACE removed C-terminal dipeptides from angiotensin I, bradykinin
      [Leu5]enkephalin and [Met5]enkephalin and also functioned as an endopeptidase by
      hydrolysing dipeptideamides from [Leu5]enkephalinamide and [Met5]enkephalinamide,
      and a dipeptideamide and a tripeptideamide from substance P. Musca ACE was also
      able to cleave a tripeptide from both the N-terminus and C-terminus of
      luteinizing hormone-releasing hormone, with C-terminal hydrolysis predominating.
      Maximal N-terminal tripeptidase activity occurred at 150 mM NaCl, whereas the C
      terminal tripeptidase activity continued to rise with increasing concentration of
      Cl- (0-0.5 M). Musca ACE displays properties of both the N- and C-domains of
      human ACE, indicating a high degree of conservation during evolution of the
      substrate specificity of ACE and its response to Cl-.

PMID- 8670081
TI  - Probing serpin reactive-loop conformations by proteolytic cleavage.
AB  - Several crystal structures of intact members of the serine proteinase inhibitor
      (or serpin) superfamily have recently been solved but the relationship of their
      reactive-loop conformations to those of circulating forms remains unclear. Here
      we examine reactive-loop conformational changes of anti-trypsin and anti-thrombin
      by using limited proteolysis and binary complex formation with synthetic
      homologous reactive-loop peptides. Proteolysis at the P10-P9, P8-P7 and P7-P6 of
      anti-trypsin was distorted by binary complex formation. The P1'-P2' bond in anti
      thrombin was more accessible to proteolysis after binary complex formation,
      whereas cleavage at the P4-P3 bond was variably altered by synthetic peptide
      insertion. The proteolytic accessibility of the reactive-site P1-P1' bond of anti
      trypsin and anti-thrombin binary complexes was identical with that of the native
      form and no cleavage was observed in the hinge region (P15-P10) of either
      protein, whether native or as binary complexes. these results fit with the
      proposal that the hydrophobic reactive loop of serpins adopts a modified helical
      conformation in the circulation, with the hinge region being partly incorporated
      into the A beta-pleated sheet. This loop can be displaced by peptides and induced
      to adopt a new conformation similar to the three-turn helix of ovalbumin. Both
      the native and binary complexed forms of anti-thrombin showed a greatly increased
      proteolytic sensitivity in the presence of heparin, indicating that heparin
      either induces a conformational change in the local structure of the helical
      reactive loop or facilitates the approximation of enzyme and inhibitor.

PMID- 8670082
TI  - Selection of hammerhead ribozymes for optimum cleavage of interleukin 6 mRNA.
AB  - Four GUC triplets in the coding region of the MRNA of interleukin 6 (IL-6) were
      examined for their suitabilty to serve as a target for hammerhead ribozome
      mediated cleavage. This selection procedure was performed with the intention to
      downregulate IL-6 production as a potential treatment of those diseases in which
      IL-6 overexpression is involved. Hammerhead ribozymes and their respective short
      synthetic substrates (19-mers) were synthesized for these four GUC triplets.
      Notwithstanding the identical catalytic core sequences, the difference in base
      composition of the helices involved in substrate binding caused substantial
      variation in cleavage activity. The cleavage reactions on the 1035 nucleotide IL
      6 mRNA transcript revealed that two ribozymes were able to cleave this substrate,
      showing a decrease in catalytic efficiency to 1/30 and 1/300 of the short
      substrate. This study indicates that the GUC triplet located at nucleotide 510 of
      the mRNA of IL-6 is the best site for hammerhead ribozyme-mediated cleavage. We
      suggest that in future targeting of chemically modified hammerhead ribosomes for
      cleavage of IL-6 RNA should be directed at this location.

PMID- 8670083
TI  - A unique combination of plasma membrane Ca2+-ATPase isoforms is expressed in
      islets of Langerhans and pancreatic beta-cell lines.
AB  - Changes in free intracellular Ca2+ concentration regulate insulin secretion from
      pancreatic beta-cells. The existence of steep Ca2+ gradients within the beta-cell
      requires the presence of specialized Ca2+ exclusion systems. In this study we
      have characterized the plasma membrane Ca2+-ATPases (PMCAs) which extrude Ca2+
      from the cytoplasm. PMCA isoform- and subtype-specific mRNA expression was
      investigated in rodent pancreatic alpha- and beta-cell lines, and in human and
      rat islets of Langerhans using reverse-transcription PCR with primers flanking
      the calmodulin-binding region of rat PMCA. The expression pattern of PMCA 1 and 2
      was conserved in different species and islet-cell types since both rat and human
      islets of Langerhans and all cell lines tested contained the 1b and 2b forms.
      PMCA 4 isoform subtypes, however, were expressed in a cell-type-specific manner
      since beta-cells expressed PMCA 4b only, whereas in islets of Langerhans, which
      contain alpha, beta, delta and polypeptide-secreting cells, PMCA 4a and 4b were
      simultaneously present. No evidence was obtained for the expression of PMCA 3.
      Characterization of the beta-cell Ca2+-pump protein showed that it shared several
      similarities with the erythrocyte PMCA. It is a P-type ATPase; its phosphorylated
      intermediate was stabilized by La3+; it reacted with a PMCA-specific antibody;
      and it was not N-glycosylate. However, the beta-cell PMCA had a higher molecular
      mass than that of the erythrocyte; this difference could be explained by either
      predominant translation of the PMCA2 form, which has a molecular mass 3-8 kDa
      higher than the erythrocyte PMCA 1 and 4 proteins, or by a possible sequence
      insertion. Thus a unique combination of functionally distinct PMCA isoforms (1b,
      2b, 4b) participates in Ca2+ homoeostasis in the beta-cell.

PMID- 8670084
TI  - A murine platelet-activating factor receptor gene: cloning, chromosomal
      localization and up-regulation of expression by lipopolysaccharide in peritoneal
      resident macrophages.
AB  - A murine gene encoding a platelet-activating factor receptor (PAFR) was cloned.
      The gene was mapped to a region of the D2.2 band of chromosome 4 both by
      fluorescence in situ hybridization and by molecular linkage analysis. Northern
      blot analysis showed a high expression of the PAFR message in peritoneal
      macrophages. When C3H/HeN macrophages were treated with bacterial
      lipopolysaccharide (LPS) or synthetic lipid A, the PAFR gene expression was
      induced. Bacterial LPS, but not lipid A, induced the level of PAFR mRNA in LPS
      unresponsive C3H/HeJ macrophages. These induction patterns were parallel to those
      of tumor necrosis factor-alpha mRNA. Thus the PAFR in macrophages is important in
      LPS-induced pathologies.

PMID- 8670085
TI  - Thapsigargin activates univalent- and bivalent-cation entry in human neutrophils
      by a SK&F I3 96365- and Gd3+-sensitive pathway and is a partial secretagogue:
      involvement of pertussis-toxin-sensitive G-proteins and protein phosphatases 1/2A
      and 2B in the signal-transduction pathway.
AB  - The Ca2+-ATPase inhibitor thapsigargin (TG) activates bivalent-cation early in
      human neutrophils via depletion of intracellular Ca2+ stores bu little is known
      about the underlying mechanism and the functional role of TG-induced cation
      entry. We studied the effects of TG on univalent- and bivalent cation entry,
      lysozyme release and superoxide-anion (O2-) formation in human neutrophils. TG,
      like the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine
      (fMLP), stimulated entry of Ca2+, Mn2+, Ba2+, Sr2+ and Na+ in a 1-{beta-[3-(4
      methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride (SK&F
      96365)- and Gd3+-sensitive manner. The inhibitors of protein phosphates 1/2A,
      calyculin A and okadaic acid, diminished TG-induced cation influxes, whereas the
      inhibitors of protein phosphatase 2B, cyclosporin A and FK-506, were
      potentiators. Pertussis toxin (PTX) partially inhibited the effects of TG on Ca2+
      and Mn2+ entry. TG and fMLP activated inward currents with a linear current
      voltage relationship and a reversal potential at about 0 mV. TG activated
      lysozyme release and potentiated fMLP-induced O2- formation. TG-induced lysozyme
      release was inhibited by SK&F 96365, PTX and the removal of extracellular Ca2+ or
      Na+. Our data show that TG activates a non-selective and SK&F 96365- and Gd3+
      sensitive cation entry pathway and is a partial secretagogue. TG-stimulated
      cation entry involves PTX-sensitive G-proteins and protein phosphatases, with
      protein phosphatases 1/2A and 2B playing opposite roles.

PMID- 8670086
TI  - Characterization of the binding of diadenosine 5',5'''-P1,P4-tetraphosphate
      (Ap4A) to rat liver cell membranes.
AB  - Diadenosine polyphosphates present in the extracellular environment can, through
      interaction with appropriate purinoceptors, influence a range of cellular
      activities. Here we have investigated the nature of the ligand:receptor
      interactions involved in diadenosine 5',5'''-P1, P4-tetraphosphate (Ap4A)
      mediated stimulation of glycogen breakdown in isolated rat liver cells. [2
      3H]Ap4A showed specific binding to both intact isolated liver cells and plasma
      membrane fractions prepared from isolated liver cells. HPLC analysis confirmed
      that binding was mediated by intact Ap4A and not by potential breakdown products
      (e.g. ATP, adenosine, etc.). Binding of [2-3H]Ap4A, to isolated liver cell plasma
      membrane preparations, was successfully displaced by a range of both naturally
      occurring and synthetic diadenosine polyphospates with the rank order potency
      Ap4A > or = Ap5A > Ap6A > Ap3A > Ap2A. [2-3H]Ap4A binding was not displaced by P1
      effectors but was successfully displaced by a range of P2 effectors with the rank
      order potency 2-methylthio-ATP > ATP > ATP > or = adenosine 5'-[alpha beta
      methylene]triphosphate > adenosine 5'-[beta gamma-methylene]triphospate. These
      findings are consistent with the interaction of Ap4A with a P2y-like subclass of
      purinoceptor and are discussed in relation to (1) the known purinoceptor
      populations in liver cell plasma membranes and (2) observations concerning the
      binding of diadenosine polyphosphates to purinoceptors in other tissues.

PMID- 8670087
TI  - The delta- and epsilon-subunits of bovine F1-ATPase interact to form a
      heterodimeric subcomplex.
AB  - The delta-subunit of bovine F1-ATPase was expressed from a bacterial vector at
      fairly high level in Escherichia coli, but the yield of bovine epsilon-subunit
      was rather low under similar conditions. However, co-expression of the proteins
      from a dicistronic operon delta-epsilon in the same expression vector, produced
      both of them in good yield in a soluble form in the bacterial cytoplasm, and by
      chromatography it was found that the delta- and epsilon-subunits were associated
      in a stable complex. The amino groups in the complex were labelled exhaustively
      by chemical reaction under denaturing conditions with ethyl-[1-14C]acetimidate.
      The alpha-amino groups of the proteins were unmodified, but complete reaction of
      all epsilon-amino groups in both proteins was demonstrated by determination of
      the molecular masses of the modified proteins by electrospray MS. The modified
      subunits were separated by denaturing gel electrophoresis, and from measurements
      of the ratio of incorporated radioactivities and the lysine contents of the
      proteins, it was calculated that the subcomplex contains equimolar amounts of the
      two proteins. As the apparent molecular mass of the complex determined by gel
      filtration was 29 kDa, it appears that the complex contains one copy of each
      protein. It is likely that the delta- and epsilon subunits are associated in a
      similar manner in the bovine F1-ATPase complex, and that, like a bacterial
      homologue of the delta-subunit, they interact with the gamma- and beta-subunits.

PMID- 8670089
TI  - In vitro toxicity of beta-amyloid.

PMID- 8670090
TI  - Sequence identity between the rat and human vasopressin V1a receptors.

PMID- 8670088
TI  - The conformation of Alzheimer's beta peptide determines the rate of amyloid
      formation and its resistance to proteolysis.
AB  - Amyloid beta-peptide (A beta) is found in an aggregated poorly soluble form in
      senile or neuritic plaques deposited in the brain of individuals affected by
      Alzheimer's disease (AD). In addition soluble A beta (sA beta) is identified
      normally circulating in human body fluids. In this study we report that synthetic
      peptides containing the sequences 1-40 and 1-42 of A beta, and A beta analogues
      bearing amino acid substitutions can adopt two major conformational states in
      solution: (1) an amyloidogenic conformer (A beta ac) with a high content of beta
      sheet and partly resistant to proteases and (2) a non-amyloidogenic conformer (A
      beta nac) with a random coil conformation and protease-sensitive. The differences
      in the fibrillogenesis rate and in the protease resistance among the several A
      beta peptides studied depend mainly on the relative propensity for adopting the
      amyloidogenic conformation, which in the absence of external factors is largely
      conditioned by the primary structure of the peptide. A beta nac containing the
      sequence 1-40, 1-42 or bearing amino acid substitutions (Dutch variant of A beta)
      was protease-sensitive and unable to form a significant amount of amyloid even at
      high concentrations or after long incubations. The finding of the simultaneous
      existence of different A beta conformers with distinct abilities to form amyloid
      may help to explain why A beta is found in both soluble and fibrillar forms in
      vivo.

PMID- 8670091
TI  - The inter-alpha-inhibitor family: from structure to regulation.
AB  - Inter-alpha-inhibitor (IalphaI) and related molecules, collectively referred to
      as the IalphaI family, are a group of plasma protease inhibitors. They display
      attractive features such as precursor polypeptides that give rise to mature
      chains with quite distinct fates and functions, and inter-chain glycosaminoglycan
      bonds within the various molecules. The discovery of an ever growing number of
      such molecules has raised pertinent questions about their pathophysiological
      functions. The knowledge of this family has long been structure-oriented, whereas
      the structure/function and structure/regulation relationships of the family
      members and their genes have been largely ignored. These relationships are now
      being elucidated in events such as gene transcription, precursor processing,
      changes in plasma protein levels in health and disease and binding capacities
      that involve hyaluronan as well as other plasma proteins as ligands. This review
      presents some recent progress made in these fields that paves the way for an
      understanding of the functions of IalphaI family members in vivo. Finally, given
      the wealth of heterogeneous, complicated and sometimes contradictory
      nomenclatures and acronyms currently in use for this family, a new, uniform,
      nomenclature is proposed for IalphaI family genes, precursor polypeptides and
      assembled proteins.

PMID- 8670093
TI  - Cloning and expression of a cDNA encoding a mouse brain orphanin FQ/nociceptin
      precursor.
AB  - By using a reverse transcription-PCR approach we have cloned a peptide precursor
      from mouse brain which contains the sequence of orphanin FQ/nociceptin. The mouse
      sequence of orphanin FQ/nociceptin is identical at the amino acid level with that
      isolated from rat and porcine brain. Northern analysis of the mRNA encoding the
      precursor reveals a single band of approx. 1 kb, with the highest levels in the
      brain and much lower levels in kidney and spleen. Southern analysis is consistent
      with a single gene. The precursor peptide from mouse contains two putative
      peptides. Upstream from the orphanin FQ/nociceptin is a 41-amino-acid peptide
      which is almost identical, except for a six-amino-acid insertion, with the
      corresponding 35-amino-acid peptide predicted from the rat sequence.
      Interestingly, the mouse contains a triple AEPGAD repeat within this peptide that
      is not seen in the rat sequence. Downstream from the orphanin FQ/nociceptin
      sequence is another 17-amino-acid peptide which is identical with that found in
      the rat.

PMID- 8670092
TI  - Biotin carboxyl carrier protein and carboxyltransferase subunits of the multi
      subunit form of acetyl-CoA carboxylase from Brassica napus: cloning and analysis
      of expression during oilseed rape embryogenesis.
AB  - In the oilseed rape Brassica napus there are two forms of acetyl-CoA carboxylase
      (ACCase). As in other dicotyledonous plants there is a type I ACCase, the single
      polypeptide 220 kDa form, and a type II multi-subunit complex analogous to that
      of Escherichia coli and Anabaena. This paper describes the cloning and
      characterization of a plant biotin carboxyl carrier protein (BCCP) from the type
      II ACCase complex that shows 61% identity/79% similarity with Anabaena BCCP at
      the amino acid level. Six classes of nuclear encoded oilseed rape BCCP cDNA were
      clones, two of which contained the entire coding region. The BCCP sequences
      allowed the assignment of function to two previously unassigned Arabidopsis
      expressed sequence tag (EST) sequences. We also report the cloning of a second
      type II ACCase component from oilseed rape, the beta-carboxyltransferase subunit
      (betaCT), which is chloroplast-encoded. Northern analysis showed that although
      the relative levels of BCCP and betaCT mRNA differed between different oilseed
      rape tissues, their temporal patterns of expression were identical during embryo
      development. At the protein level, expression of BCCP during embryo development
      was studied by Western blotting, using affinity-purified anti-biotin polyclonal
      sera. With this technique a 35 kDa protein thought to be BCCP was shown to reside
      within the chloroplast. This analysis also permitted us to view the differential
      expression of several unidentified biotinylated proteins during embryogenesis.

PMID- 8670094
TI  - Synergistic binding of inhibitors to the protease from HIV type 1.
AB  - Inhibition of the protease in HIV is a potentially useful approach for the
      treatment of AIDS. In the course of evaluating inhibitors of the HIV-1 protease,
      we observed a strong synergism between certain inhibitors that might be expected
      to bind to different sites in this enzyme. The binding affinity of
      carbobenzyloxyisoleucinylphenylalaninol, for example, is increased 125-fold in
      the presence of carbobenzyloxyglutaminylisoamylamide. These synergistic effects
      between inhibitors have specific structural requirements that correlate well with
      the known substrate preference of the enzyme. The modular basis for this
      phenomenon remains to be elucidated but it could involve substrate-induced
      conformational change as part of the reaction mechanism. Similar effects have
      been reported previously for several zinc proteases. Thus this work extends the
      observation to a different class of enzymes and suggests that the phenomenon
      might be widespread.

PMID- 8670095
TI  - A 33 kDa serine proteinase from Scedosporium apiospermum.
AB  - An extracellular proteinase produced by the filamentous fungus Scedosporium
      apiospermum has been purified and characterized. Initially, in vitro conditions
      for enzyme synthesis were investigated. The highest yield of enzyme production
      was obtained when the fungus was cultivated in modified Czapek-Dox liquid medium
      supplemented with 0.1% bacteriological peptone and 1% (w/v) glucose as the
      nitrogen and carbon sources respectively. Purification to homogeneity of the
      proteinase was accomplished by (NH4)2SO4 precipitation, followed by gel
      filtration through Sephadex G-75 and finally affinity chromatography through
      immobilized phenylalanine. Analysis of the purified enzyme by SDS/PAGE revealed a
      single polypeptide chain with an apparent molecular mass of 33 kDa. Further
      investigation of its physical and biochemical properties disclosed numerous
      similarities with those of the previously described serine proteinase of
      Aspergillus fumigatus. The enzyme was not glycosylated and its pI was 9.3.
      Proteinase activity was optimum between 37 and 50 degrees C and at pH 9.0, but
      remained high within a large range of pH values between 7 and 11. The inhibition
      profile and N-terminal amino acid sequencing confirmed that this enzyme belongs
      to the subtilisin family of serine proteinases. In agreement with this, the
      specific synthetic substrate N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide proved to
      be an excellent substrate for the proteinase with an estimated Km of 0.35 mM.
      Like the alkaline proteinase of A. fumigatus, this enzyme was able to degrade
      human fibrinogen, and thus may act as a mediator of the severe chronic
      bronchopulmonary inflammation from which cystic fibrosis patients suffer.

PMID- 8670097
TI  - Effect of amino acid residues at the cleavable site of substrates on the
      remarkable activation of thermolysin by salts.
AB  - The activity of thermolysin in the hydrolysis of N-[3-(2-furyl)acryloyl]-glycyl-L
      leucine amide and N-carbobenzoxy-L-aspartyl-L-phenylalanine methyl ester is
      remarkably enhanced in the presence of high concentrations (1-5 M) of neutral
      salts [Inouye (1992) J. Biochem. (Tokyo) 112, 335-340]. In this study, the effect
      of salts on such activity has been examined using a series of substrates,
      furylacryloyl dipeptide amides, which have various hydrophobic amino acids at the
      cleavable bond. Although the enzyme activity varies widely depending on the
      substrate employed, the degree of activation at a given concentration of NaCl is
      considerably similar. This indicates that the degree of activation is not
      dependent on the hydrophobicity of the amino acid side chains at the scissile
      bond of the substrates. The molecular activity, kcat, and Michaelis constant, Km,
      were evaluated separately for substrates N[3-(2-furyl)acryloyl]-L-leucyl-L
      alanine amide and N-[3-(2-furyl)acryloyl]L-phenyl-alanyl-L-alanine amide, and the
      activation was found to be brought about only by an increase in k(cat'). The
      effectiveness of monovalent cations on the increase of k(cat) was determined to
      follow the order of Na(+)>K(+)>Li(+).

PMID- 8670098
TI  - Rapana thomasiana grosse (gastropoda) haemocyanin: spectroscopic studies of the
      structure in solution and the conformational stability of the native protein and
      its structural subunits.
AB  - 1. The stability towards pH changes, thermal and chemical (guanidine
      hydrochloride) denaturation of the oxy- and apo-forms of the native Rapana
      thomasiana haemocyanin and its structural subunits, RHSS1 and RHSS2, has been
      investigated using fluorescence and CD spectroscopy. The association of the
      subunits into haemocyanin aggregates increases considerably the melting
      temperature and the free energy of stabilization in water. The guanidine
      hydrochloride denaturation of the aggregated oxygen-transporting protein depends
      slightly on the protein concentration. The denaturation of the individual
      subunits is concentration-independent. Rapana haemocyanin is 5.9-7.5 kJ/mol more
      stable than the constituent polypeptide chains. 2. Upon excitation of the native
      haemocyanin and the subunits at 295 or 280 nm the fluorescence emission is
      determined by tryptophyl residues 'buried' deeply in the hydrophobic interior of
      the protein globules. This is confirmed by quenching experiments with acrylamide,
      caesium and iodide ions. The efficiency of the radiationless energy transfer
      between the phenol (donor) and indole (acceptor) fluorophores in the three
      species, native haemocyanin, RHSS1 and RHSS2, has been determined. An efficient
      'interchain' energy transfer between tyrosyl and tryptophyl residues from
      different polypeptide chains occurs in the non-dissociated form of the
      haemocyanin. 3. The tryptophan emission of the oxyhaemocyanin, oxy-RHSS1 and oxy
      RHSS 2 is strongly quenched by the copper-dioxygen complex at the active site and
      the respective quantum yields of fluorescence of the oxygenated species are 4-7
      times lower than those of the apo-forms. Protonated imidazole groups quench the
      fluorescence of neighbouring exited indole rings, probably by charge-transfer
      complex formation.

PMID- 8670096
TI  - Evidence for a Zn(2+)-binding site in human serum butyrylcholinesterase.
AB  - Purified human serum butyrylcholinesterase after treatment with either of the
      metal chelators EDTA or NaCN was able to bind to a Zn(2+)-chelate-Sepharose
      affinity column and was eluted from the column by EDTA or imidazole. Prior EDTA
      treatment of the enzyme was essential for binding to this affinity column. The
      enzyme could be labelled with (65)Zn(2+) after EDTA treatment of the enzyme.
      Diethylpyrocarbonate modification of histidine residues in the EDTA-treated
      enzyme resulted in the abolition of both binding to the Zn(2+)-chelate-Sepharose
      column and labelling by (65)Zn(2+). Stoicheiometry of (65)Zn(2+) binding
      indicated approximately 0.85 mol of Zn(2+)/mol of subunit of the EDTA-treated
      enzyme. EDTA or NaCN treatment resulted in the loss of thermal stability of the
      enzyme at 37 degrees C which could not be reversed by Zn(2+). Whereas the
      cholinesterase activity of butyrlcholinesterase was not affected by EDTA, there
      was significant loss of its carboxypeptidase activity in the presence of EDTA,
      and the loss could be reversed by added ZnCl2. These results suggest the presence
      of a Zn(2+)-binding site on human serum butyrylcholinesterase and the involvement
      of histidine residues in the metal binding. The presence in human serum
      butyrylcholinesterase of a sequence HXXE...H found in many known Zn(2+)
      containing enzymes supports these findings.

PMID- 8670099
TI  - Tissue Factor residue Asp44 regulates catalytic function of the bound proteinase
      Factor VIIa.
AB  - The coagulation pathways are initiated by the cell-surface receptor Tissue Factor
      (TF), which binds the serine proteinase coagulation Factor VIIa (VIIa), resulting
      in enhanced catalytic function, both amidolytic, towards small pseudo-substrates,
      and proteolytic, towards macromolecular substrates. Here we implicate Asp44 in TF
      as a ligand-interactive residue that, in contrast with previously characterized
      binding residues, is involved in the enhancement of VIIa catalytic function.
      Whereas charge neutralization by replacement of Asp44 with Asn did not reduce
      function of human TF, the exchange by Ala resulted in mutants with 8-fold reduced
      affinity for binding of VIIa. Enhancement of VIIa amidolytic function by TF Ala44
      was reduced by 20-25% relative to wild-type and support of proteolytic function
      was diminished 6-fold indicating that this cofactor residue is significantly
      enhancing proteolysis of the macromolecular substrate by VIIa. Replacement of
      Asp44 by Glu, Thr, and Arg exhibited a less severe phenotype with an approx. 4
      fold reduced affinity for VIIa and a 2-3 fold diminished activation of Factor X.
      The improved activity of these mutants as compared with the Ala replacement is
      consistent with functional importance of an extended side chain at this position.
      The specific influence of the Asp44 exchange on catalytic function of the TF x
      VIIa complex indicates fine specificity of the TF ligand interface in mediating
      receptor and cofactor function.

PMID- 8670100
TI  - Expression of lignin peroxidase H8 in Escherichia coli: folding and activation of
      the recombinant enzyme with Ca2+ and haem.
AB  - An engineered cDNA from Phanerochaete chrysosporium encoding both the mature and
      pro-sequence regions of Lip isoenzyme H8 (Lip) has been successfully
      overexpressed in Escherichia coli. The recombinant protein (LipP*) was
      sequestered in inclusion bodies. The reduced-denatured polypeptide has been
      purified by differential solubilization, and the active enzyme recovered after
      controlled in vitro refolding (albeit in low yield), by glutathione-mediated
      oxidation of disulphides, in a folding medium containing an intermediate
      concentration of urea, Ca2+, and haem. The procedure is analogous to that
      previously described for the production of active recombinant horseradish
      peroxidase (HRP-C*) from inclusion-body material. It is quite possible,
      therefore, that this type of procedure may be suitable for the recovery of most,
      if not all, active recombinant peroxidases. The resultant LipP* has spectral
      characteristics identical with that of the native enzyme as isolated from
      Phanerochaete chrysosporium. Its specific activity measured in the standard
      veratryl alcohol (VA) assay was 39 micromol of VA oxidized/min per mg of protein,
      a value which compares extremely favourably with that of the native enzyme (36
      micromol of VA/min per mg). Although levels of active enzyme obtained are not yet
      as high as in the case of HRP-C* (1% conversion of crude inactive LipP*
      polypeptide into pure fully active Lip), it is envisaged that further refinement
      of the expression/folding/activation procedures will provide sufficient protein
      for biophysical characterization of both the wild-type and site-directed mutants.

PMID- 8670101
TI  - Subcellular trafficking kinetics of GLU4 mutated at the N- and C-terminal.
AB  - The glucose transporter isoform, GLUT4, has been expressed in Chinese hamster
      clones and its subcellular trafficking has been determined following labelling at
      the cell surface with the impermeant bis-mannose photolabel, 2-N-(1-azi-2,2,2
      trifluoroethyl)benzoyl-1,3-bis(D-mannos -4-yloxy)-2-propylamine (ATM-BMPA). ATM
      BMPA-tagged GLUT4 leaves the cell surface rapidly and equilibrates to give an
      internal/surface distribution ratio of approx. 3.5 after 60 min. GLUT4 in which
      the N-terminal phenylalanine-5 and glutamine-6 are mutated to alanine-N-(FQ-AA)
      and in which the C-terminal leucine-489 and -490 are mutated to alanine C-(LL-AA)
      have low internal/surface ratios of 0.64 and 1.24 respectively. If all cell
      surface transporters are able to recycle, as would be the case for a two-pool
      recycling model with a single intracellular pool, then analysis suggests that the
      wild-type GLUT4 distribution ratio is dependent on endocytosis and exocytosis
      rate constants of 0.074 and 0.023 min(-1). These values are similar, but not
      identical, to those found for GLUT4 trafficking in adipocytes. The distribution
      of the N-(FQ-AA) transporter appears to be due to a decrease in endocytosis with
      reduced intracellular retention, while the distribution of the C-(LL_AA)
      transporter appears to be mainly due to poor intracellular retention. These
      results are also considered in terms of a consecutive intracellular pool model in
      which GLUT4 targeting domains alter the distribution between recycling endosomes
      and a slowly recycling compartment. In this case the more rapid apparent
      exocytosis of the mutated GLUT4 is due to their failure to reach a slowly
      recycling compartment with a consequent return to the plasma membrane by default.
      It is suggested that overexpression of transporters increases the proportion that
      are recycled in this way. Wortmannin is shown to decrease glucose transport
      activity and cell-surface photolabelled transporters in a manner consistent with
      an inhibition of transporter recycling. Studies on the rate of loss of transport
      activity and ATB-BMPA-tagged transporter in wortmannin-treated cells confirm that
      the N-(FQ-AA) mutant is endocytosed more slowly than the wild-type GLUT4. Taken
      together, these results suggest that the mutation at either the N- or the C
      terminal domain can reduce movement to a slowly recycling intracellular
      compartment but that neither domain alone is entirely sufficient to produce wild
      type GLUT4 trafficking behaviour.

PMID- 8670102
TI  - Interactions of integrin GPIIb/IIIa-derived peptides with fibrinogen investigated
      by NMR spectroscopy.
AB  - Three peptides derived from platelet receptor glycoprotein alphaIIbBeta3
      (GPIIb/IIIa) have been identified recently as fibrinogen-binding sequences: GPIIb
      300-314 and 656-667 and GPIIIa 211-223. NMR spectroscopy has been used here to
      investigate the interactions of these peptides with parent fibrinogen. Based on
      resonance broadening and chemical-shift changes of peptides in the presence and
      absence of fibrinogen, interactions in the fast ligand-exchange regime are
      apparent and interfacial residues can be proposed. Positively charged arginines
      and histidines, along with several hydrophobic residues, are implicated as being
      crucial to the binding process. Transferred nuclear Overhauser effects and
      distance geometry calculations allow discussion of probable conformations in
      peptide-'bound' states. These identifications are consistent with other
      biological/chemical data and provide the basis for further studies aimed at
      understanding fibrinogen-mediated platelet aggregation on the molecular level.

PMID- 8670103
TI  - Evidence for an UDP-glucuronic acid/phenol glucuronide antiport in rat liver
      microsomal vesicles.
AB  - The transport of glucuronides synthesized in the luminal compartment of the
      endoplasmic reticulum by UDP-glucuronosyltransferase isoenzymes was studied in
      rat liver microsomal vesicles. Microsomal vesicles were loaded with p-nitrophenol
      glucuronide (5 mM), phenolphthalein glucuronide or UDP-glucuronic acid, by a
      freeze-thawing method. In was shown that: (i) the loading procedure resulted in
      millimolar intravesicular concentrations of the different loading compounds; (ii)
      addition of UDP-glucuronic acid (5 mM) to the vesicles released both
      intravesicular glucuronides within 1 min; (iii) glucuronides stimulated the
      release of UDP-glucuronic acid from UDP acid-loaded microsomal vesicles; (iv)
      trans-stimulation of UDP-glucuronic acid entry by loading of microsomal vesicles
      with p-nitrophenol glucuronide, phenolphthalein glucuronide, UDP-glucuronic acid
      and UDP-N-acetyl-glucosamine almost completely abolished the latency of UDP
      glucuronosyltransferase, although mannose 6-phosphatase latency remained
      unaltered; (v) the loading compounds by themselves did not stimulate UDP
      glucuronosyltransferase activity. This study indicates that glucuronides
      synthesized in the lumen of endoplasmic reticulum can leave by an antiport, which
      concurrently transports USP-glucuronic acid into the lumen of the endoplasmic
      reticulum.

PMID- 8670104
TI  - Expression of the rat GLUT1 glucose transporter in the yeast Saccharomyces
      cerevisiae.
AB  - We expressed the rat GLUT1 facilitative glucose transporter in the yeast
      Saccharomyces cerevisiae with the use of a galactose-inducible expression system.
      Confocal immunofluorescence microscopy indicated that a majority of this protein
      is retained in an intracellular structure that probably corresponds to
      endoplasmic reticulum. Yeast cells expressing GLUT1 exhibited little increase in
      glucose-transport activity. We prepared a crude membrane fraction from these
      cells and made liposomes with this fraction using the freeze-thaw/sonication
      method. In this reconstituted system, D-glucose-transport activity was observed
      with a Km for D-glucose of 3.4 +/- 0.2 mM (mean +/- S.E.M.) and was inhibited by
      cytochalasin B (IC50= 0.44 +/- 0.03 microM), HgCl2 (IC50)= 3.5 +/- 0.5 microM),
      phloretin (IC50= 49 +/- 12 microM) and phloridzin (IC50= 355 +/- 67 microM). To
      compare these properties with native GLUT1 we made reconstituted liposomes with a
      membrane fraction prepared from human erythrocytes, in which the Km of D-glucose
      transport and ICs of these inhibitors were approximately equal to those obtained
      with GLUT1 made by yeast. When the relative amounts of GLUT1 in the crude
      membrane fractions were measured by quantitative immunoblotting, the specific
      activity of the yeast-made GLUT1 was 110% of erythrocyte GLUT1, indicating that
      GLUT1 expressed in yeast is fully active in glucose transport.

PMID- 8670105
TI  - Purification of the synaptosomal plasma membrane (Ca(2+) + Mg(2+))-ATPase from
      pig brain.
AB  - The Ca(2+)-ATPase from the synaptosomal plasma membrane has been purified nearly
      to homogeneity from pig brain by a new procedure involving the calmodulin
      affinity-chromatography technique. This is a convenient alternative to the
      standard methods for the purification of the plasma membrane Ca(2+)-ATPase from
      different sources that were unsuitable to purify the enzyme from pig brain. The
      main feature of this procedure is the use of 15% (v/v) glycerol as stabilizing
      agent, instead of acidic phospholipid. By using this protocol the enzyme was
      purified 36-fold with respect to the plasma membrane vesicle fraction, showing a
      specific activity of 2.3 i.u. in the presence of acidic phospholipid. In
      SDS/PAGE, it appears as a single protein band around Mr140 000 that can be
      phosphorylated by [gamma-(32)P]ATP in the presence of La(3+) and recognized by
      specific antibodies against the plasma membrane Ca(2+)-ATPase from pig antral
      smooth muscle. Calmodulin activates the enzyme 1.5-1.8-fold in the presence of
      phosphatidylcholine but not in the presence of phosphatidylserine.

PMID- 8670106
TI  - Uridine diphosphoxylose enhances hepatic microsomal UDP-glucuronosyltransferase
      activity by stimulating transport of UDP-glucuronic acid across the endoplasmic
      reticulum membrane.
AB  - The UDP-glucuronosyltransferase (UGT) system fulfils a pivotal role in the
      biotransformation of potentially toxic endogenous and exogenous compounds. Here
      we report that the activity of UGT in rat liver is stimulated by UDP-xylose. This
      stimulation was found in native microsomal vesicles as well as in the intact
      endoplasmic reticulum (ER) membrane, as studied in permeabilized hepatocytes,
      indicating the potential physiological importance of UDP-xylose in the regulation
      of UGT. We present evidence that UDP-xylose enhances UGT activity by stimulation
      of (i) the uptake of UDP-glucuronic acid across the ER membrane and (ii) the
      elimination of the UDP and/or UMP reaction product out of the ER lumen. UDP-xyloe
      produced a marked trans-stimulation of microsomal UDP-glucuronic acid uptake when
      it was present within the lumen of the ER. When UDP-xylose was presented at the
      cytosolic side of the ER, it acted as a weak inhibitor of UDP-glucuronic acid
      uptake. Likewise, cytosolic UDP-glucuronic acid strongly trans-stimulated efflux
      of intravesicular UDP-xylose, whereas cytosolic UDP-xylose was inefficient in
      trans-stimulating efflux of UDP-glucuronic acid. Microsomal UDP-xylose influx was
      markedly stimulated by UMP and UDP. Such stimulation was only apparent when
      microsomes had been preincubated and thereby preloaded with UMP or UDP,
      indicating that UMP and UDP exeted their effect on UDP-xylose uptake by trans
      stimulation from the luminal side of the ER membrane.

PMID- 8670107
TI  - Control of metabolic flux through the quinate pathway in Aspergillus nidulans.
AB  - The quinic acid ulitization (qut) pathway in Aspergillus nidulans is a
      dispensable carbon utilization pathway that catabolizes quinate to
      protocatechuate via dehydroquinate and dehydroshikimate(DHS). At the usual in
      vitro growth pH of 6.5, quinate enters the mycelium by means of a specific
      permease and is converted into PCA by the sequential action of the enzymes
      quinate dehydrogenase, 3-dehydroquinase and DHS dehydratase. The extent of
      control on metabolic flux exerted by the permease and the three pathway enzymes
      was investigated by applying the techniques of Metabolic Control Analysis. The
      flux control coefficients for each of the three quinate pathway enzymes were
      determined empirically, and the flux control coefficient of the quinate permease
      was inferred by use of the summation theorem. There measurements implied that,
      under the standard growth conditions used, the values for the flux control
      coefficients of the components of the quinate pathway were: quinate permease,
      0.43; quinate dehydrogenase, 0.36; dehydroquinase, 0.18; DHS dehydratase, <0,03.
      Attempts to partially decouple quinate permease from the control over flux by
      measuring flux at pH 3.5 (when a significant percentage of the soluble quinate is
      protonated and able to enter the mycelium without the aid of a permease) led to
      an increase of approx. 50% in the flux control coefficient for dehydroquinase.
      Taken together with the fact that A. nidulans has a very efficient pH homeostasis
      mechanism, these experiments are consistent with the view that quinate permease
      exerts a high degree of control over pathway flux under the standard laboratory
      growth conditions at pH 6.5. The enzymes quinate dehydrogenase and 3
      dehydroquinase have previously been overproduced in Escherichia coli, and
      protocols for their purification published. The remaining qut pathway enzyme DHS
      dehydratase was overproduced in E. coli and a purification protocol established.
      The purified DHS dehydratase was shown to have a K(m) of 530 microM for its
      substrate DHS and a requirement for bivalent metal cations that could be
      fulfilled by Mg(2+), Mn(2+) or Zn(2+). All three qut pathway enzymes were
      purified in bulk and their elasticity coefficients with respect to the three
      quinate pathway intermediates were derived over a range of concentrations in a
      core tricine/NaOH buffer, augmented with necessary cofactors and bivalent cations
      as appropriate. Using these empirically determined relative values, in
      conjunction with the connectivity theorem, the relative ratios of the flux
      control coefficients for the various quinate pathway enzymes, and how this
      control shifts between them, was determined over a range of possible metabolic
      concentrations. These calculations, although clearly subject to caveates about
      the relationswhip between kinetic measurements in vitro and the situation in
      vivo, were able to successfully predict the hiearchy of control observed under
      the standard laboratory growth conditions. The calculations imply that the
      hierarchy of control exerted by the quinate pathway enzymes is stable and
      relatively insensitive to changing metabolite concentrations in the ranges most
      likely to correspond to those found in vivo. The effects of substituting the type
      I 3-dehydroquinases from Salmonella typhi and the A. nidulans AROM protein (a
      pentadomain protein catalysing the conversion of 3-deoxy-D-arabinoheptulosonic
      acid 7-phosphate into 5-enolpyruvylshikimate 3 phosphate), and the Mycobacterium
      tuberculosis type II 3-dehydroquinase, in the quinate pathway were investigated
      and found to have an effect. In the case of S. typhi and A. nidulans,
      overproduction of heterologous dehydroquinase led to a diminuation of pathway
      flux caused by a lowering of in vivo quinate dehydrogenase levels increased above
      those of the wild type. We speculate that these changes in qu

PMID- 8670108
TI  - Alpha and beta isoforms of ryanodine receptor from chicken skeletal muscle are
      the homologues of mammalian RyR1 and RyR3.
AB  - To define the relationship between the two ryanodine receptor (RyR) isoforms
      present in chicken skeletal muscle, we cloned two groups of cDNAs encoding the
      chicken homologues of mammalian RyR1 and RyR3. Equivalent amounts of the two
      chicken isoform mRNAs were detected in thigh and pectoral skeletal muscles. RyR1
      and RyR3 mRNAs were co-expressed in testis and cerebellum whereas RyR3 mRNA was
      expressed also in the cerebrum and heart. The full-length sequence of the chicken
      RyR3 cDNA was established. The RyR3 receptor from chicken had the same general
      structure as mammalian and amphibian RyRs. The 15089 nt cDNA encoded a 4869-amino
      acid-long protein with a molecular mass of 552445. The predicted amino acid
      sequence of the chicken RyR3 showed 86.9% identity to mammalian RyR3 and 85.6% to
      frog RyR3. Antibodies specific for chicken RyR1 and RyR3 recognized two different
      proteins with an apparent molecular mass of about 500 kDa. The two proteins
      differ slightly in their apparent molecular mass on SDS/PAGE: the protein
      recognized by antibodies against RyR3 had a higher mobility than the protein
      recognized by the antiserum against RyR1. Antibodies against RyR1 detected a
      protein already present in chicken skeletal muscle from 12-day-old embryos and
      older, while antibodies against RyR3 isoform detected a protein in muscle from
      only 18-day-old embryos and older. The expression patterns of RyR1 and RyR3
      superimpose with those previously reported for the alpha and beta isoforms
      respectively. We conclude that alpha and beta isoforms present in chicken
      skeletal muscle are the homologues of mammalian RyR1 and RyR3.

PMID- 8670109
TI  - Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits
      apoptosis by blocking the processing of CPP32.
AB  - Interleukin-1 beta converting enzyme (ICE)-like proteases, which are synthesized
      as inactive precursors, play a key role in the induction of apoptosis. We now
      demonstrate that benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z
      VAD.FMK), an ICE-like protease inhibitor, inhibits apoptosis by preventing the
      processing of CPP32 to its active form. These results suggest that novel
      inhibitors of apoptosis can be developed which prevent processing of proforms of
      ICE-like proteases.

PMID- 8670110
TI  - Characterization, cell-surface expression and ligand-binding properties of
      different truncated N-terminal extracellular domains of the ionotropic glutamate
      receptor subunit GluR1.
AB  - To identify the location of the first transmembrane segment of the GluR1
      glutamate receptor subunit artificial stop codons have been introduced into the N
      terminal domain at amino acid positions 442, 510, and 563, namely just before and
      spanning the proposed first two transmembrane regions. The resultant truncated N
      terminal fragments of GluR1, termed NT1, NT2, and NT3 respectively were expressed
      in Cos-7 cells and their cellular distribution and cell-surface expression
      analysed using an N-terminal antibody to GluR1. All of the fragments were fully
      glycosylated and were found to be associated with cell membranes but none was
      secreted. Differential extraction of the cell membranes indicated that both NT1
      and NT2 behave as peripheral membrane proteins. In contrast NT3, like the full
      subunit, has integral membrane protein properties. Furthermore only NT3 is
      expressed at the cell surface as determined by immunofluorescence and cell
      surface biotinylation. Protease protection assays indicated that only NT3 had a
      cytoplasmic tail. Binding studies using the selective ligand [(3)H]alpha-amino-3
      hydroxy-5-methyl-4-isoxazolepropionate ([(3)H]AMPA) demonstrated that NT3 does
      not bind ligand. Together these results indicate that the first transmembrane
      domain of the GluR1 subunit lies between residues 509 and 562, that the N
      terminal domain alone cannot form a functional ligand-binding site and that this
      domain can be targeted to the cell surface provided that it has a transmembrane
      spanning region.

PMID- 8670112
TI  - Cloning and expression in vitro of human xanthine dehydrogenase/oxidase.
AB  - To study the expression of human xanthine dehydrogenase/oxidase (hXDH/XO), we
      cloned the cDNA covering its complete coding sequence and characterized it by
      translation in vitro in rabbit reticulocyte lysates and by transient expression
      in COS-1 cells. Two specific protein products with approximate molecular masses
      of 150 and 130 kDa were detected in both expression systems. These products are
      compatible with the molecular sizes of XDH/XO, and these peptides also showed
      immunoreactivity with polyclonal anti-hXDH antibodies. Significant XDH/XO enzyme
      activity (277 +/- 54 pmol/min per mg of protein) was measured in lysates of
      transfected COS cells, whereas in control transfections the activities were below
      the detection limit of our assay (0.2 pmol/min per mg of protein). The COS cells
      expressed the enzyme predominantly (89.8 +/- 0.3%) in the dehydrogenase form.

PMID- 8670111
TI  - Analysis of inverse agonism at the delta opioid receptor after expression in Rat
      1 fibroblasts.
AB  - A cDNA encoding the mouse delta opioid receptor was expressed stably in a Rat 1
      fibroblast cell line. Expression of this receptor was demonstrated both in ligand
      binding studies and by reverse transcriptase-PCR. In membranes of clone D2 cells
      the opioid peptide [D-Ala(2)]-leucine enkephalin (DADLE) produced a robust,
      concentration-dependent, stimulation of basal high-affinity GTPase activity; the
      prototypic opioid antagonist naloxone and the highly selective and potent delta
      opioid ligands H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic[Ch2-NH]Phe-Phe-OH
      (TIPP[psi]) had little effect but N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI174864)
      caused a marked dose-dependent inhibition of this activity (Tic, 1,2,3,4
      tetrahydroisoquinolin-2-yl-carbonyl]; Aib, alpha-aminobutyric acid). This effect
      of ICI174864 was reversed by TIPP[psi] and attenuated after treatment of the
      cells with pertussis toxin. No stimulation by DADLE or inhibition by ICI174864
      was observed in Rat 1 fibroblasts that did not express the delta opioid receptor.
      Basal binding of [(35)S]guanosine 5'-O-(3-thio-triphosphate) to membranes of
      clone D2 cells was also stimulated by DADLE and inhibited by ICI174864; both of
      these effects were reversed by co-incubation with TIPP[psi]. When cholera toxin
      catalysed [(32)P]ADP-ribosylation was performed on membranes of clone D2 cells in
      the absence of guanine nucleotides, a 40 kDa G1-family polypeptide was labelled
      in addition to both the long and short isoforms of Gsalpha. Labelling of the 40
      kDa polypeptide was enhanced by addition of DADLE and fully attenuated by
      addition of ICI174864. In contrast, labelling of the isoforms of Gsalpha was
      unaffected by either opioid ligand. Again, both the positive effect of DADLE and
      the inhibitory effect of ICI174864 were prevented by co-incubation with TIPP[psi]
      which, in isolation, had little effect on cholera toxin-catalysed [(32)P]ADP
      ribosylation of either Gs or Gi. These data demonstrate that the delta opioid
      receptor displays a spontaneous activity when expressed in this genetic
      background. Attenuation of this activity is produced by ICI174864, which by
      acting as an 'inverse agonist' in this system, functionally uncouples the
      expressed receptor from the cellular G-protein population. The complete
      attenuation of agonist-independent cholera toxin-catalysed [(32)P]ADP
      ribosylation of Gi demonstrated that ICI174864 acts as an inverse agonist with
      high intrinsic activity at this receptor.

PMID- 8670113
TI  - Na+/Pi co-transport alters rapidly cytoskeletal protein polymerization dynamics
      in opossum kidney cells.
AB  - We studied with biochemical and immunofluorescent techniques the interactions
      between the actin microfilament and tubulin microtubule cytoskeleton and Na+/P1
      co-transport in opossum kidney cells, a line with proximal tubular
      characteristics. On brief (5 min) incubation of the cells with a low (0.1 mM)
      concentration of Pi, a rapid F-actin depolymerization takes place, which fails to
      occur in cells incubated under similar conditions with 1 mM Pi. The disassembly
      of actin microfilaments could be quantitatively expressed as a 33% increase in
      the ration of monomeric G-actin to polymerized F-actin (G/F-actin ration from
      0.80 +/- 0.03 to 1.06 +/- 0.06, n = 28, P<0.01), owing to a significant decrease
      in the latter. Under these conditions microfilaments were also markedly
      destabilized, as shown by their diminished resistance to graded cytochalasin B
      concentrations. In addition, incubation of opossum kidney cells with low Pi
      concentrations (0.1 mM) resulted within 5 min in a substantial depolymerization
      of microtubules, shown by immunofluorescence microscopy and measured as a 70.9 +/
      6.9% (n = 11, P<0.01) decrement by immunoblot analysis. These changes, which
      occur only when extracellular Pi concentrations are kept low, seem to be related
      to a significant increase within 5 min in the rate of cellular Pi uptake by 25.5%
      under these conditions. The shifts in the dynamic equilibria between monomeric
      and polymerized actin and tubulin in response to cellular Pi uptake were
      transient, being fully reversible within 30 min. Moreover, the effect of Pi
      seemed to be specific because inhibition of its uptake by phosphonoformic acid
      blunted microtubular disassembly markedly. In contrast, measurement of Pi uptake
      in the presence of agents known to stabilize cytoskeletal structures showed a
      substantial decrease with phallacidin, which stabilized microfilaments, whereas
      the microtubule stabilizer taxol had no apparent effect. These results indicate
      that acute alterations in the polymerization dynamics and stability of both
      microfilaments and microtubules are involved in the modulation of Na+/Pi co
      transport and suggest important cytoskeletal participation in proximal tubular
      transport functions.

PMID- 8670114
TI  - Cloning and expression of pig kidney dopa decarboxylase: comparison of the
      naturally occurring and recombinant enzymes.
AB  - L-Aromatic amino acid decarboxylase (dopa decarboxylase; DDC) is a pyridoxal 5'
      phosphate (PLP)-dependent homodimeric enzyme that catalyses the decarboxylation
      of L-dopa and other L-aromatic amino acids. To advance structure-function studies
      with the enzyme, a cDNA that codes for the protein from pig kidney has been
      cloned by joining a partial cDNA obtained by library screening with a synthetic
      portion constructed by the annealing and extension of long oligonucleotides. The
      hybrid cDNA was then expressed in Escherichia coli to produce recombinant
      protein. During characterization of the recombinant enzyme it was unexpectedly
      observed that it possesses certain differences from the enzyme purified from pig
      kidney. Whereas the later protein binds 1 molecule of PLP per dimer, the
      recombinant enzyme was found to bind two molecules of coenzyme per dimer.
      Moreover, the Vmax was twice that of the protein purified from tissue. On
      addition of substrate, the absorbance changes accompanying transaldimination were
      likewise 2-fold greater in the recombinant enzyme. Examination of the respective
      apoenzymes by absorbance, CD and fluorescence spectroscopy revealed distinct
      differences. The recombinant apoprotein has no significant absorbance at 335 nm,
      unlike the pig kidney apoenzyme; in the latter case this residual absorbance is
      associated with a positive dichroic signal. When excited at 335 nm the pig kidney
      apoenzyme has a pronounced emission maximum at 385 nm, in contrast with its
      recombinant counterpart, which shows a weak broad emission at about 400 nm.
      However, the holoenzyme-apoenzyme transition did not markedly alter the
      respective fluorescence properties of either recombinant or pig kidney DDC when
      excited at 335 nm. Taken together, these findings indicate that recombinant pig
      kidney DDC has two active-site PLP molecules and therefore displays structural
      characteristics typical of PLP-dependent homodimeric enzymes. The natural enzyme
      contains one active-site PLP molecule whereas the remaining PLP binding site is
      most probably occupied by an inactive covalently bound coenzyme derivative; some
      speculations are made about its origin. The coenzyme absorbing bands of
      recombinant DDC show a modest pH dependence at 335 and 425 nm. A putative working
      model is presented to explain this behaviour.

PMID- 8670115
TI  - Hormonal regulation of glucose transport in a brown adipose cell preparation
      isolated from rats that shows a large response to insulin.
AB  - Isolated brown adipose cells from rats are prepared whose viability is indicated
      by the expected stimulation of oxygen consumption by noradrenaline and counter
      regulation of this oxygen consumption response by insulin. Insulin stimulates 3-O
      methyl-D-glucose transport by approx. 15-fold in the absence of adenosine, and
      adenosine augments this response at least 2-fold. The insulin-stimulated
      translocation of the glucose transporter GLUT4 from an intracellular compartment
      to the plasma membrane is readily detected by subcellular fractionation and
      Western blotting, and the appearance of GLUT4 on the cell surface in response to
      insulin is demonstrated by bis-mannose photolabelling. Isoprenaline also
      stimulates glucose transport activity but only by approx. 3-fold; this effect is
      not altered by adenosine. Isoprenaline increases insulin-stimulated glucose
      transport activity in the absence of adenosine but decreases it in the presence
      of adenosine. These results demonstrate that although the regulation of glucose
      transport by insulin in brown adipose cells is qualitatively similar to that in
      white adipose cells, counter-regulation by adenosine and isoprenaline is at least
      quantitatively and may be qualitatively different. Isolated brown adipose cells
      from rats thus represent an excellent model for further examination of the
      mechanism by which multiple hormone signalling pathways interact to control
      glucose transport and GLUT4 subcellular trafficking.

PMID- 8670116
TI  - Cloning, sequencing and expression of the transferrin-binding protein 1 gene from
      Actinobacillus pleuropneumoniae.
AB  - Two outer-membrane proteins are involved in the uptake of iron from transferrin
      by certain Gram-negative bacteria, transferrin-binding proteins 1 and 2. The gene
      encoding transferrin-binding protein 1 from a serotype 1 isolate of the Gram
      negative pathogen Actinobacillus pleuropneumoniae was cloned, and a fragment
      encoding 700 amino acids of Tbp1 was expressed in Escherichia coli. We also
      report here sequencing of the tbpl gene and a comparison of the deduced amino
      acid sequence with Tbpls from related species. The predicted polypeptide product
      of tbpl is a 106 kDa protein with a 22-residue signal peptide.

PMID- 8670117
TI  - Sodium-proton exchange stimulates Ca2+ release from acidocalcisomes of
      Trypanosoma brucei.
AB  - Acidocalcisomes are acidic vacuoles present in trypanosomatids that contain a
      considerable fraction of intracellular Ca2+ [Vercesi, Moreno and Docampo (1994)
      Biochem. J. 304, 227-233; Scott, Moreno and Docampo (1995) Biochem. J. 310, 789
      794; Docampo, Scott, Vercesi and Moreno (1995) Biochem. J. 310, 1005-1012]. The
      data presented here indicate that Na+ stimulates Ca2+ release from the
      acidocalcisomes of digitonin-permeabilized Trypanosoma brucei procyclic
      trypomastigotes in a dose-dependent fashion, this effect being enhanced by
      increasing pH of the medium from 7.0 to 7.8. The hypothesis that this Na+ effect
      was mediated by alkalinization of the acidocalcisomes via a Na+/H+ antiporter was
      supported by experiments showing that Na+ promotes release of Acridine Orange
      previously accumulated in these vacuoles. This putative antiporter did not
      transport Li+ and was not sensitive to the amiloride analogue 5-(N-ethyl-N
      isopropyl)amiloride. Addition of the Na+/H+ ionophore monensin to intact cells
      loaded with fura 2, in the nominal absence of extracellular Ca2+ to preclude Ca2+
      entry, was followed by an increase in cytosolic Ca2+ concentration ([Ca2+]i),
      which was more accentuated in the presence of extracellular Na+. An increase in
      intracellular pH (pHi) of BCECF-loaded cells was detected after addition of
      monensin in the presence of extracellular Na+, whereas a dramatic decrease in pHi
      was detected in its absence, thus indicating the presence of a significant amount
      of releasable protons in the acidic compartments. These results are consistent
      with the presence of a Na+/H+ antiporter in the acidocalcisomes that could be
      involved in the regulation of pH1 and [Ca2+]1 in these parasites.

PMID- 8670118
TI  - Sustained signalling from the insulin receptor after stimulation with insulin
      analogues exhibiting increased mitogenic potency.
AB  - The metabolic and mitogenic potencies of six different insulin analogues were
      determined by measuring glucose transport in primary adipocytes and DNA synthesis
      in CHO cells respectively. Three analogues showed a disproportionately high
      mitogenic potency compared with their metabolic potency, and were up to 7 times
      more mitogenically than metabolically potent when compared with human insulin.
      The mitogenic/metabolic potency ratio of the analogues was found to be inversely
      correlated with the insulin receptor dissociation rate constant (Kd) in an
      exponential fashion (r=0.99), with a disproportionately greater increase in
      mitogenic potential compared with metabolic potential for analogues with Kd
      values of less than 40% of that of human insulin. To investigate the molecular
      mechanisms behind the correlation between the increased half-life of the receptor
      ligand complex (low Kd) and mitogenicity, 3 h time-course experiments were
      performed. Slow ligand dissociation from the insulin receptor induced a parallel
      sustained activation of the insulin receptor tyrosine kinase. A similar pattern
      was observed for insulin receptor autophosphorylation and Shc phosphorylation,
      whereas the duration of insulin receptor substrate-1 phosphorylation with low-Kd
      analogues and with insulin was similar Thus the increased half-life of the ligand
      receptor complex induces sustained activation of the insulin receptor tyrosine
      kinase and sustained phosphorylation of Shc, which may be the cause of the
      disproportionately high mitogenic potency seen for some insulin analogues.

PMID- 8670119
TI  - High-glucose incubation of human umbilical-vein endothelial cells does not alter
      expression and function either of G-protein alpha-subunits or of endothelial NO
      synthase.
AB  - Alterations in G-protein-controlled signalling pathways (primarily pathways
      controlled by Gs and Gi) have been reported to occur in animal models of diabetes
      mellitus. We have therefore studied the effect of a long-term exposure of human
      umbilical vein endothelial cells to elevated concentrations of glucose on
      expression and function of G-protein subunits and endothelial NO synthase. Long
      term incubation in high glucose (30 mM for 15 days) did not affect the levels of
      Gialpha-2, Gqalpha, the splice variants (long and short form) of Gsalpha, and the
      G-protein beta-subunits or adenylate cyclase activity; basal, as well as
      isoprenaline-, forskolin- and guanosine 5'-[gamma-thio]triphosphate-stimulated
      enzyme activities were comparable in high- and low-glucose-treated cells, thus
      ruling out any functional changes in the stimulatory pathway. Pretreatment of
      endothelial cells with pertussis toxin blocked a substantial fraction (50%) of
      the mitogenic response to serum factor(s) which depend(s) of functional Gi2. The
      sensitivity of cells cultured in high glucose was comparable with that of the
      paired controls maintained in normal glucose (EC50 = 3.1 +/- 0.5 and 3.3 +/- 0.4
      ng/ml respectively). Similarly, we failed to detect any differences in
      endothelial NO synthase expression, or intracellular distribution and basal
      activity of the enzyme in endothelial cells cultured in high glucose. Stimulation
      of NO synthase in intact cells revealed a comparable response to the calcium
      ionophore (A23187). In contrast, stimulation with histamine (which acts via H1
      receptors predominantly coupled to Gq) resulted in a significantly increased
      response in the cells maintained in high glucose. These data are suggestive of an
      altered H1-histamine receptor-Gq-phospholipase C pathway in endothelial cells
      cultured in high glucose concentrations, but rule out any glucose-induced
      functional changes in Gs- and Gi-controlled signalling pathways.

PMID- 8670120
TI  - Epidermal growth factor administration decreases liver glycogen and causes mild
      hyperglycaemia in mice.
AB  - Several laboratories report different effects of epidermal growth factor (EGF) on
      glycogen metabolism in hepatocytes. The discrepancies may be attributed to
      differences in the experimental conditions. It is therefore important to
      establish the actual effect of EGF in vivo. Because large physiological
      variations of EGF concentration in plasma occur in mice, we used this species to
      address this question. In freshly isolated mouse hepatocytes, EGF increased
      glycogen degradation in a dose-dependent manner. The maximal effect (36% increase
      over basal glycogenolysis) was smaller than maximal effects of classical
      glycogenolytic hormones like adrenaline or glucagon (more than 150% increase over
      basal). This is in keeping with the smaller effect of EGF on phosphorylase a
      activity. In contrast with these hormones, EGF did not inhibit glycolysis. Thus
      these effects of EGF in mouse hepatocytes are similar to those recently described
      by us in rat hepatocytes [Quintana, Grau, Moreno, Soler, Ramirez and Soley (1995)
      Biochem J 308, 889-894]. When administered to whole animals, EGF increased
      phosphorylase a activity, decreased the glycogen content in the liver and caused
      mild hyperglycaemia. Taking together the results obtained for isolated cells and
      for whole animals, we suggest that the glucosyl residues released from glycogen
      are used mostly by the liver rather than released to the circulation. This would
      be different from the action of the classical glycogenolytic hormones, adrenaline
      and glucagon.

PMID- 8670121
TI  - Rapid reduction of nitric oxide by mitochondria, and reversible inhibition of
      mitochondrial respiration by nitric oxide.
AB  - Nitric oxide (NO) inhibited the respiration rate of mitochondria isolated from
      rat heart at sub-micromolar concentrations of NO. The inhibition was rapidly and
      completely reversible, indicating that NO does not damage mitochondria. The
      sensitivity of respiration to NO depended on the oxygen concentration, substrate
      type and respiratory state of the mitochondria, consistent with NO competing with
      oxygen at cytochrome oxidase. Mitochondria catalysed a rapid rate of NO
      breakdown, which was greater in the absence of oxygen and was partly inhibited by
      cyanide and azide, suggesting that at least part of the NO breakdown was due to
      reduction of NO by cytochrome oxidase. The rapid rate of this breakdown suggests
      that mitochondrial breakdown of NO may be significant physiologically.

PMID- 8670123
TI  - Protein sorting in Plasmodium falciparum-infected red blood cells permeabilized
      with the pore-forming protein streptolysin O.
AB  - Plasmodium falciparum is an intracellular parasite of human red blood cells
      (RBCs). Like many other intracellular parasites, P. falciparum resides and
      develops within a parasitophorous vacuole which is bound by a membrane that
      separates the host cell cytoplasm from the parasite surface. Some parasite
      proteins are secreted into the vacuolar space and others are secreted, by an as
      yet poorly defined pathway, into the RBC cytosol. The transport of proteins from
      the parasite has been followed mainly using morphological methods. In search of
      an experimental system that would allow (i) dissection of the individual steps
      involved in transport from the parasite surface into the RBC cytosol, and (ii) an
      assessment of the molecular requirements for the process at the erythrocytic side
      of the vacuolar membrane, we permeabilized infected RBCs with the pore-forming
      protein streptolysin O using conditions which left the vacuole intact. The
      distribution of two parasite proteins which served as markers for the vacuolar
      space and the RBC cytosol respectively was analysed morphologically and
      biochemically. In permeabilized RBCs the two marker proteins were sorted to the
      same compartments as in intact RBCs. The protein which was destined for the RBC
      cytosol traversed the vacuolar space before it was translocated across the
      vacuolar membrane. Protein transport could be arrested in the vacuole by removing
      the RBC cytosol. Translocation across the vacuolar membrane required ATP and a
      protein source at the erythrocytic face of the membrane, but it was independent
      of the intracellular ionic milieu of the RBC.

PMID- 8670122
TI  - A limited upstream region of the human sucrase-isomaltase gene confers glucose
      regulated expression on a heterologous gene.
AB  - We have previously shown that glucose can exert a repressive effect on the
      transcription of the sucrase-isomaltase (SI) gene in the differentiated
      enterocyte-like human colon carcinoma cell lines HT-29 and Caco-2. To
      characterize the region through which glucose exerts this effect, three different
      length fragments of the 5'-flanking region of the human SI gene were linked to
      the reporter gene luciferase in an episomal vector carrying a hygromycin
      resistance gene. These fragments were used for transfection into a clone of the
      Caco-2 cell line, PF11, which has high glucose consumption and only expresses SI
      at high levels when cultured in the presence of a low supply of glucose. By using
      the stably transformed PF11 cells grown either in standard high glucose (25 mM)
      or in low glucose (1 mM) it was possible to show that the smallest fragment of
      the SI promoter, extending from bases -370 to +30, contains all the information
      required for the glucose repression of the reporter gene luciferase.

PMID- 8670124
TI  - The cDNA for the ubiquitin-52-amino-acid fusion protein from rat encodes a
      previously unidentified 60 S ribosomal subunit protein.
AB  - Rat cDNAs for a 52-amino-acid ribosomal protein (CEP52) that is typically formed
      as a ubiquitin fusion protein, were cloned following reverse transcription and
      PCR amplification. CEP52 sequence conservation is demonstrated by the similarity
      of the human and rat cDNA sequences and the identity of the predicted proteins.
      Amplification of rat cDNA with a primer specific for the 3' non-coding region of
      the CEP52 gene, in combination with a consensus primer for the 5' end of the
      ubiquitin coding sequence, provided evidence that the rat CEP52 gene is fused to
      a ubiquitin reading frame. Direct sequence analysis of this PCR product confirmed
      the in-frame fusion of a ubiquitin coding sequence to the rat CEP52 gene.
      Antibodies against a synthetic CEP52 peptide were used to show that expressed
      CEP52 is associated with the 60 S ribosomal subunit, and that is is not linked to
      ubiquitin. The quantity of CEP52 found in different tissues is quite variable,
      but appears to correspond to the amount of ribosomes present. Although the human,
      Arabidopsis thaliana and Nicotiana tabacum CEP52 genes contain introns within the
      CEP52 coding region, the rat CEP52 coding sequence appears to lack insertions.

PMID- 8670125
TI  - Di-isodityrosine, a novel tetrametric derivative of tyrosine in plant cell wall
      proteins: a new potential cross-link.
AB  - A novel amino acid, di-isodityrosine, has been isolated from hydrolysates of cell
      walls of tomato cell culture. Analysis by UV spectrometry, partial derivatization
      with 2,4-dinitrofluorobenzene and mass and NMR spectrometry show that the
      compound is composed to two molecules of isodityrosine, joined by a biphenyl
      linkage. The possible reactions involved in the formation of this molecule in
      vivo are discussed, as is the possibility that it could form an interpolypeptide
      linkage between cell wall proteins such as extensin, and hence aid in the
      insolubilization of the protein in the wall.

PMID- 8670126
TI  - Omega-3 polyunsaturated fatty acids increase purine but not pyrimidine transport
      in L1210 leukaemia cells.
AB  - Here we show that in vitro supplementation of L1210 murine lymphoblastic
      leukaemia cells with n-3 polyunsaturated fatty acids results in considerable
      changes in the fatty acid composition of membrane phospholipids. Incubations for
      48 h with 30 microM eicosapentaenoic acid (20:5, n-3; EPA) or docosahexaenoic
      acid (22:6, n-3; DHA) results primarily in substitution of long chain n-6 fatty
      acids with long-chain n-3 fatty acids. This results in a decrease in the n-6/n-3
      ratio from 6.9 in unsupplemented cultures to 1.2 or 1.6 for EPA and DHA
      supplemented cultures, respectively. Coincident with these changes in membrane
      fatty acid composition, we observed a 5-fold increase in the rate of adenosine (5
      microM) uptake via a nitrobenzylthioinosine (NBMPR)-sensitive nucleoside
      transporter in EPA- and DHA-supplemented L1210 cells, relative to unsupplemented
      cells. This seemed to result from a decrease in the Km for adenosine from 12.5
      microM in unsupplemented cultures to 5.1 microM in DHA-treated cultures.
      Guanosine (50 microM) transport was similarly affected by DHA with a 3.5-fold
      increase in the initial rate of uptake. In contrast, pyrimidine transport, as
      measured by uptake of thymidine and cytidine, was not similarly affected,
      suggesting that substrate recognition had been altered by fatty acid
      supplementation. Studies using [(3)H]NBMPR showed that there was no effect of EPA
      or DHA on either the number of NBMPR-binding sites or the affinity of these sites
      for NBMPR. This observation suggests that the increases in adenosine and
      guanosine transport were not due to increases in the number of transported sites
      but rather that EPA and DHA directly or indirectly modulate transporter function.

PMID- 8670127
TI  - Evidence for an inhibitory feedback loop regulating simian virus 40 large T
      antigen fusion protein nuclear transport.
AB  - Nuclear protein import is central to eukaryotic cell function. It is dependent on
      ATP, temperature and cytosolic factors, and requires specific targeting sequences
      called nuclear localization signals (NLSs). Nuclear import kinetics was studied
      in vitro using digitonin-permeabilized cells of the HTC rat hepatoma cell line
      and a fluorescently labelled beta-galactosidase fusion protein carrying amino
      acids 111-135 of the simian virus 40 large T-antigen (T-ag), including the NLS.
      Nuclear accumulation was rapid, reaching steady-state after about 80 min at 37
      degrees C (t1/2 at about 17 min). Surprisingly, maximal nuclear concentration was
      found to be directly proportional to the concentration of the cytosolic extract
      and of cytoplasmic T-ag protein. Neither preincubation of cells for 1 h at 37
      degrees C before the addition of T-ag protein nor the addition of fresh transport
      medium after 1 h and continuation of the incubation for another hour affected the
      maximal nuclear concentration. If cells were allowed to accumulate T-ag protein
      for 1 h before the addition of fresh transport medium containing different
      concentrations of T-ag protein and incubated for a further hour, the maximal
      nuclear concentration did not change unless the concentration of T-ag protein in
      the second transport mixture exceeded that in the first, in which case the
      nuclear concentration increased. Nuclear import of T-ag thus appeared (i) to be
      strictly unidirectional over 2 h at 37 degrees C and (ii) to be regulated by an
      inhibitory feedback loop, whereby the cytosolic concentration of protein appears
      to determine directly the precise end point of nuclear accumulation. This study
      represents the first characterization of this previously undescribed mechanism of
      regulation of nuclear protein import.

PMID- 8670129
TI  - A non-toxic two-chain ribosome-inactivating protein co-exists with a structure
      related monomeric lectin (SNA III) in elder (Sambucus nigra) fruits.

PMID- 8670128
TI  - Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa
      gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit
      aortic smooth muscle cells.
AB  - The migration and proliferation of vascular smooth muscle cells (SMCs) during
      neointima formation in atherosclerosis and angioplasty restenosis is mediated by
      certain growth factors and cytokines, one action of which may be to promote
      basement-membrane degradation. To test this hypothesis further, the effects of
      such growth factors and cytokines on the synthesis of two basement-membrane
      degrading metalloproteinases, namely the 72 kDa gelatinase (MMP-2, gelatinase A)
      and the 95 kDa gelatinase (MMP-9, gelatinase B) and three tissue inhibitors of
      metalloproteinases (TIMPs) was studied in primary cultured rabbit aortic SMCs.
      Expression of the 95 kDa gelatinase was increased by phorbol myristate acetate,
      foetal calf serum, thrombin and interleukin-1alpha (IL-1alpha); platelet-derived
      growth factor (PDGF) BB alone had no effect but acted synergistically with IL
      1alpha. A selective protein kinase C inhibitor, Ro 31-8220, abolished induction
      of the 95 kDa gelatinase. In contrast, none of the agents tested modulated the
      synthesis of the 72 kDa gelatinase. We conclude that maximal up-regulation of 95
      kDa gelatinase expression requires the concerted action of growth factors and
      inflammatory cytokines mediated, in part, by a protein kinase C-dependent
      pathway. TIMP-1 and TIMP-2 were highly expressed, and their synthesis was not
      affected by growth factors or cytokines. Expression of TIMP-3 mRNAs was, however,
      increased by PDGF and transforming growth factor beta, especially in combination.
      Divergent regulation of gelatinase and TIMP expression implies that either net
      synthesis or net degradation of basement membrane can be mediated by appropriate
      combinations of growth factors and cytokines.

PMID- 8670130
TI  - Identification of 14-3-3 proteins in human platelets: effects of synthetic
      peptides on protein kinase C activation.
AB  - The 14-3-3 proteins inhibit protein kinase C (PKC) activity in vitro and contain
      conserved sequences that resemble the pseudosubstrate domain of PKC and the C
      terminus of the annexins. In the present study we have identified the isoforms of
      14-3-3 in human platelets and used synthetic peptides derived from the regions
      with similarity to PKC and annexins to examine the potential role of 14-3-3 in
      regulating platelet activity. Immunoblotting studies with isoform-specific
      antisera raised against the acetylated peptides corresponding to the N-termini of
      14-3-3 showed that these cells express high levels of the beta, gamma and zeta 14
      3-3 isoforms. In addition, low levels of the epsilon and eta 14-3-3 isoforms were
      detected. In washed, saponin-permeabilized platelets incubated with [gamma
      32P]ATP, thrombin- and phorbol 12-myristate 13-acetate (PMA)-induced
      phosphorylation of several proteins (66, 45, and 20kDa) was inhibited by
      preincubation with AS peptide (KNVVGARRSSWRVISSIEQK) based on the pseudosubstrate
      like region of the 14-3-3 family. A control peptide of similar size had no effect
      on PKC-mediated phosphorylation. PMA caused a rapid translocation of PKC activity
      from the cytosol to the particulate fraction of saponin-permeabilized platelets
      that was unaffected by either the AS peptide or a peptide derived from the
      annexin-like 14-3-3 domain (MKGDYYRYLAEVATGDD). These results suggest that
      isoforms of the 14-3-3 family may play an important physiological role as
      inhibitors of PKC activity in human platelets but are unlikely to be involved in
      controlling association of PKC with the membrane.

PMID- 8670132
TI  - Overexpression of neuronal nitric oxide synthase in insect cells reveals
      requirement of haem for tetrahydrobiopterin binding.
AB  - Nitric oxide synthase (NOS) catalyses the conversion of L-arginine into L
      citrulline and nitric oxide. Recently we have developed a method for expression
      of recombinant rat brain NOS in baculovirus-infected Sf9 cells and purification
      of the enzymically active enzyme [Harteneck, Klatt, Schmidt and Mayer (1994)
      Biochem J. 304, 683-686]. To study how biosynthetic manipulation of the NOS
      cofactors haem, FAD/FMN, and tetrahydrobiopterin (H4biopterin) affects the
      properties of the isolated enzyme, Sf9 cells were infected in the absence and
      presence of haemin chloride (4 microg/ml), riboflavin (0.1.mM), and the inhibitor
      of H4biopterin biosynthesis 2,4-diamino-6-hydroxypyrimidine (10 mM). In the
      absence of haemin, NOS was expressed to a very high level but remained
      predominantly insoluble. Purification of the soluble fraction of the expressed
      protein showed that it had poor activity (0.35 micromol of citrulline x mg(-1) x
      min(-1)) and was haem-deficient (0.37 equiv. per monomer). Supplementing the
      culture medium with haemin resulted in pronounced solubilization of the expressed
      enzyme, which had a specific activity of approximately 1 micromol of citrulline x
      mg(-1) x min(-1) and contained 0.95 equiv. of haem per monomer under these
      conditions. Unexpectedly, the amount of H(4) biopterin endogenously present in
      the different NOS preparations positively correlated with the amount of enzyme
      bound haem (y = 0.066+0.430x; r = 0.998). Radioligand binding experiments
      demonstrated that haem-deficient enzyme preparations containing 30-40% of the
      holoenzyme bound only approximately 40% of H4biopterin as compared with haem
      saturated controls. These results suggest that the prosthetic haem group is
      essentially involved in the correct folding of NOS that is a requisite for
      solubilization of the protein and tight binding of H4biopterin.

PMID- 8670131
TI  - Possible involvement of a tyrosine kinase-dependent pathway in the regulation of
      phosphoinositide metabolism by vanadate in normal mouse islets.
AB  - The potential roles of protein tyrosine kinases (TKs) and of phosphotyrosine
      phosphatases (PTPs) in pancreatic islet function are not known. In this study, we
      investigated whether vanadate, a potent PTP inhibitor, affects phosphoinositide
      (PI) metabolism by a TK-dependent pathway in isolated mouse islets. To avoid the
      confounding effects of changes in Ca2+ influx, all experiments were performed in
      the absence of Ca2+. In the presence of 15mM glucose, vanadate, acetylcholine
      (ACh) or [Arg]vasopressin (AVP) strongly stimulated InsP production. Vanadate
      also increased PtdInsP levels in membranes. The TK inhibitor genistein (not its
      inactive analogues genistin and daidzein) significantly reduced vanadate effects,
      but was without effect in the absence of stimulation or in the presence of ACh or
      AVP. Islet proteins resolved by SDS/PAGE were analysed by immunobloting with anti
      phosphotyrosine antibody. Under control conditions, several phosphotyrosyl
      proteins (PYPs) were present. Vanadate increased phosphotyrosine residues on
      several PYPs, notably two proteins of 145 and 85 kDa. This effect was prevented
      by genistein, p145 and p85 could correspond to phospholipate Cgamma(PLCgamma) and
      the regulatory subunit of PtdIns-3-kinase (PtdIns-3K) respectively. Both proteins
      are expressed in islets, as revealed by immunoblots with specific antibodies.
      Tungstate, another PTP inhibitor, reproduced vanadate effects, but inhibition of
      PtdIns-3K by wortmannin failed to affect vanadate-increased PtdInsP levels.
      Incubation of the islets in the presence of 10% (v/v) fetal calf serum instead of
      BSA increased InsP production and this effect was prevented by genistein. These
      results suggest that inhibition of PTP increases InsP production in mouse islets
      by a TK-dependent pathway. They also provide evidence for a potential role of TK
      and PTP in pancreatic B-cell function.

PMID- 8670134
TI  - Characterization of the hydroxymethylglutaryl-CoA lyase precursor, a protein
      targeted to peroxisomes and mitochondria.
AB  - We previously showed that human liver hydroxymethylglutaryl-CoA (HMG-CoA) lyase
      (HL; EC 4.1.3.4) is found in both mitochondria and peroxisomes. HL contains a 27
      residue N-terminal mitochondrial targeting sequence which in cleaved on
      mitochondrial entry, as well as a C-terminal Cys-Lys-Leu peroxisomal targeting
      motif. Because peroxisomal HL has a greater molecular mass and more basic pI
      value than mitochondrial HL, we predicted that peroxisomal HL retains the
      mitochondrial leader. To test this hypothesis, we expressed both the precursor
      (pHL) and mature (mHL) peptides in Escherichia coli and studied their properties.
      pHL purified by ion-exchange and hydrophobic chromatography had a pI of 7.6 on
      FPLC chromatofocusing and a molecular mass of 34.5 kDa on SDS/PAGE, similar to
      our findings for peroxisomal HL. For purified mHL, pI (6.2) and molecular mass
      (32 kDa) values resemble those of mitochondrial HL. Purified pHL is similar to
      mHL in K(m) for HMG-CoA (44.8 microM), k(cat) (6.3 min(-1)) and pH optimum (9.0
      9.5). However, the quaternary structures of pHL and mHL differ. On Superose 12
      FPLC gel filtration and also on ultrafiltration, both in the presence and in the
      absence of HMG-CoA), pHL behaves as a monomer whereas mHL migrates as a dimer. We
      conclude that the HL percursor is probably identical to peroxisomal HL, that its
      catalytic properties resemble those of mature mitochondrial HL, and that the
      mitochondrial leader peptide prevents dimerization on pHL.

PMID- 8670133
TI  - Ligand binding kinetics and dissociation of the human embryonic haemoglobins.
AB  - The three human embryonic haemoglobins have been studied using a range of stopped
      flow and flash photolysis experiments. The association and dissociation kinetics
      and equilibrium constants for the tetramer-dimer reactions of the deoxy and
      oxygenated forms have been investigated and found to be characterized by
      constants similar to those of the human adult protein. The rates of oxygen
      dissociation from the embryonic haemoglobins have been measured and appear to be
      responsible for the high oxygen-binding affinity associated with the embryonic
      proteins compared with the adult protein. The pH dependence of the oxygen
      dissociation rate constants also accounts for the rather unusual, previously
      described, Bohr effects characteristic of the embryonic haemoglobins. A general
      scheme has been developed coupling both the dimer-tetramer equilibria and ligand
      binding steps observed following photolysis of the liganded forms of the human
      embryonic haemoglobins.

PMID- 8670135
TI  - Heparin enhances the catalytic activity of des-ETW-thrombin.
AB  - The thrombin mutant, des-ETW-thrombin, lacking Glu(146), Thr(147), and Trp(148)
      within a unique insertion loop located at the extreme end of the primary
      specificity pocket, has been shown previously to exhibit reduced catalytic
      activity with respect to macromolecular and synthetic thrombin substrates and
      reduced or enhanced susceptibility to inhibition. Investigation of the hydrolysis
      of peptidyl p-nitroanilide substrates by des-ETW-thrombin showed increased
      activity in the presence of heparin and other sulphated glycosaminoglycans. No
      effect was observed upon the activity of wild-type thrombin. Heparin was found to
      decrease the K(m) for cleavage of four thrombin-specific substrates by des-ETW
      thrombin by 3-4-fold. Similarly, pentosan polysulphate (PPS) decreased the K(m)
      with these substrates by 8-10-fold. Heparin also increased the rate of inhibition
      of des-ETW-thrombin by antithrombin III and D-phenylalanyl-prolyl
      arginylchloromethane (PPACK). The inhibition of des-ETW-thrombin by a number of
      thrombin-specific peptide boronic acids also showed significant reduction in the
      final K(i) in the presence of heparin, due to reduction in the off-rate. A
      peptide analogue of a sequence of hirudin which binds thrombin tightly to exosite
      I (fibrinogen recognition site) potentiated the activity of des-ETW-thrombin
      against peptide p-nitroanilide substrates in a manner similar to heparin. The
      K(i) for the inhibition of des-ETW-thrombin by p-aminobenzamidine was decreased
      by these ligands from 9.7 mM to 7.5 mM, 5.1 mM, and 2.5 mM in the presence of
      heparin, hirudin peptide and PPS respectively, suggesting the increased catalytic
      activity is due to enhanced access to the primary specificity pocket. The
      positive influence of these ligands on des-ETW-thrombin was reversed in the
      presence of ATP or ADP; the latter has previously been shown to inhibit thrombin
      activity by blocking initial interaction with fibrinogen at exosite 1. Because
      the effect of heparin and PPS is similar to that of hirudin peptide, it is
      proposed that the most likely mechanism is that binding at the heparin-binding
      site (thrombin exosite 2) facilitates interaction at exosite 1 causing a
      conformational change which partially corrects the defective ground-state binding
      of the mutant thrombin. Although no effect was observed upon the activity of wild
      type thrombin, our findings do provide further evidence of an allosteric property
      of thrombin which may control the geometry of, and access to, the primary
      specificity pocket.

PMID- 8670136
TI  - Peptidyl vinyl sulphones: a new class of potent and selective cysteine protease
      inhibitors: S2P2 specificity of human cathepsin O2 in comparison with cathepsins
      S and L.
AB  - Peptidyl vinyl sulphones are a novel class of extremely potent and specific
      cysteine protease inhibitors. They are highly active against the therapeutically
      important cathepsins O2, S and L. The highest kinact/K1 values exceed 10(7)M(-1)
      x s(-1) for cathepsin S and 10(5)M(-1) x s(-1) for cathepsins O2 and L. To study
      the primary specificity site of the novel human cathepsin O2 and the
      effectiveness of this novel class of inhibitors, a series of peptidyl vinyl
      sulphones with variations in the P2 residue was synthesized. Leucine in the P2
      position was proven to be the most effective residue for cathepsin O2 and also
      for cathepsins S and L. Cathepsins O2 and S share a decreased accessibility
      towards P2 hydrophobic non-branched residues such as aminohexanoic acid
      (norleucine), methionine and oxidized methionine, but are distinguished by their
      different affinity towards phenylalanine in the P2 position. In contrast,
      cathepsin S accepts a broader range of hydrophobic residues in its S2 subsite
      than cathepsins O2 and L. The primary specificity-determining subsite pocket S2
      in cathepsin O2 appears to be spatially more restricted than those of cathepsins
      S and L.

PMID- 8670137
TI  - Time-dependent pseudo-activation of hepatic glycogen synthase b by glucose 6
      phosphate without involvement of protein phosphatases.
AB  - During a 30 min incubation at 25 degrees C in the presence of 5-10 mM glucose 6
      phosphate, pure glycogen-bound glycogen synthase b from dog liver was
      progressively converted into a form that was fully catalytically active in the
      presence of 10 mM Na2SO4 plus 0.5 mM glucose 6-phosphate. The latter enzyme was
      unlike synthase a (which does not require glucose 6-phosphate for activity), and
      unlike synthase b (which is strongly inhibited by sulphate). The conversion was
      insensitive to various inhibitors of Ser/Thr-protein phosphatases and alkaline
      phosphatases, and was therefore termed 'pseudo-activation'. Kinetically, pseudo
      activation increased the V(max) 4-fold without affecting the K(m) for the
      substrate UDP-glucose. Pseudo-activation appeared to be an irreversible process,
      but several lines of evidence argue against a limited proteolysis. Pseudo
      activation of glycogen synthase occurred also readily in a rat liver cytosol, but
      it was not observed with purified synthase from skeletal muscle. These
      observations have important implications for the assay of liver gycogen-synthase
      phosphatase; the possible physiological implications remain to be explored.

PMID- 8670139
TI  - The primary structure of monomeric yeast glyoxalase I indicates a gene
      duplication resulting in two similar segments homologous with the subunit of
      dimeric human glyoxalase I.

PMID- 8670138
TI  - Activation of chicken liver dihydrofolate reductase by urea and guanidine
      hydrochloride is accompanied by conformational change at the active site.
AB  - It has been reported that the activation of dihydrofolate reductase (DHFR) from
      L1210 mouse leukaemia cells by KCl or thiol modifiers is accompanied by increased
      digestibility by proteinases [Duffy, Beckman, Peterson, Vitols and Huennekens
      (1987) J. Biol. Chem. 262, 7028-7033], suggesting a loosening up of the general
      compact structure of the enzyme. In the present study, the peptide fragments
      liberated from the chicken liver enzyme by digestion with trypsin in dilute
      solutions of urea or guanidine hydrochloride (GuHCl) have been separated by FPLC
      and sequenced. The sequences obtained are unique when compared with the known
      sequence of DHFR and thus allow the points of proteolytic cleavage identified for
      the urea- and GuHCl-activated enzyme to be at or near the active site. It was
      also indicated by the enhanced fluorescence of 2-p-toluidinylnaphthalene 6
      sulfonate that conformational changes at the active site in dilute GuHCl parallel
      GuHCl activation. The above results indicate that the activation of DHFR in
      dilute denaturants is accompanied by a loosening up of its compact structure
      especially at or near the active site, suggesting that the flexibility at its
      active site is essential for the full expression of its catalytic activity.

PMID- 8670140
TI  - Structure and critical residues at the active site of spermidine/spermine-N1
      acetyltransferase.
AB  - Spermidine/spermine-N1-acetyltransferase (SSAT) is a key enzyme in the
      degradation of polyamines. Alanine-scanning mutagenesis of all eight arginine
      residues was used to investigate the arginine residues involved in acetyl-CoA
      binding. The results indicate that Arg101, Arg142 and Arg143 are important for
      such binding. The apparent Km values for acetyl-CoA were significantly increased
      when any one of these residues was replaced by an alanine residue. These
      mutations also abolished the ability of acetyl-CoA to protect the protein from
      digestion by trypsin. Co-expression of the inactive R101A (Arg101 --> Ala) mutant
      and an E152K (Glu152 --> Lys) mutant, previously known to inactivate SSAT, led to
      restoration of activity, showing that the active enzyme is a dimer with residues
      contributed by both subunits. The double mutant R101A/E152K acted as a dominant
      negative when co-expressed with the wild-type SSAT. Transfection of COS-7 cells
      with a plasmid producing this mutant greatly attenuated the increase in SSAT
      activity brought about by N1, N12-bis(ethyl)spermine. These results indicate that
      the double mutant R101A/E152K-SSAT protein can be used to evaluate the importance
      of SSAT activity in response to exogenous polyamines or polyamine analogues.

PMID- 8670141
TI  - Synthesis and physiological activity of heterodimers comprising different splice
      forms of vascular endothelial growth factor and placenta growth factor.
AB  - Vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) are
      members of a dimeric-growth-factor family with angiogenic properties. VEGF is a
      highly potent and specific mitogen for endothelial cells, playing a vital role in
      angiogenesis in vivo. The role of PIGF is less clear. We expressed the monomeric
      splice forms VEGF-165, VEGF-121, PIGF-1 and PIGF-2 as unfused genes in
      Escherichia coli using the pCYTEXP expression system. In vitro dimerization
      experiments revealed that both homo- and hetero-dimers can be formed from these
      monomeric proteins. The dimers were tested for their ability to promote capillary
      growth in vivo and stimulate DNA synthesis in cultured human vascular endothelial
      cells. Heterodimers comprising different VEGF splice forms, or combinations of
      VEGF/PIGF splice forms, showed mitogenic activity. The results demonstrate that
      four different heterodimeric growth factors are likely to have as yet
      uncharacterized functions in vivo.

PMID- 8670142
TI  - Nicotinate-adenine dinucleotide phosphate-induced Ca(2+)-release does not behave
      as a Ca(2+)-induced Ca(2+)-release system.
AB  - We investigated the dependence of nicotinate-adenine dinucleotide phosphate
      (NAADP)-induced Ca2+ release from intracellular stores of sea urchin egg
      homogenates, upon extravesicular Ca2+. In contrast to the Ca2+ release induced
      inositol 1',4',5'-triphosphate (IP3) or cyclic ADP-ribose (cADPR), the Ca2+
      release induced by NAADP was completely independent of the free extravesicular
      Ca2+ over a wide range of concentrations (0-0.1 mM). The Ca2+ release triggered
      by either cADPR or IP3 was biphasically modulated by extravesicular Ca2+, and the
      Ca2+ release by these agents was abolished when the extravesicular Ca2+ was
      removed by chelation with 2 mM EGTA. On the other hand, NAADP-triggered Ca2+
      release was not influenced by EGTA. These data indicate that while both cADPR and
      IP3 systems behave as functional Ca(2+)-induced Ca2+ release mechanisms, NAADP
      activates a Ca2+ release mechanism which is independent of the presence of
      extravesicular Ca2+. Therefore, the NAADP-sensitive Ca2+ release mechanisms may
      have a unique regulatory impact upon intracellular Ca2+ homoeostasis.

PMID- 8670144
TI  - Isolation and characterization of a 30 kDa protein with antifungal activity from
      leaves of Engelmannia pinnatifida.
AB  - During the course of screening plants for novel antifungal activity, we found
      that a high-molecular-mass fraction of an extract from leaves of Engelmannia
      pinnatifida exhibited potent and broad-spectrum antifungal activity. In this
      study a 30 kDa protein from E. pinnatifida leaves was purified to homogeneity by
      ammonium sulphate precipitation, gel filtration, Mono-Q and C18 reverse-phase
      column chromatographies. The purified protein showed potent antifungal activity
      against various plant pathogens with as little as 50 ng. The N-terminal amino
      acid sequence of the purified protein was determined as XXTKFDFFTLALQXPAXF, where
      X indicates an unidentified residue. This sequence showed 35-50% sequence
      identity with purified style glycoproteins associated with self-incompatibility
      from wild tomato, tobacco and petunia, a phosphate-starvation-induced
      ribonuclease from cultured tomato cells and the SIR 63.4 kDa protein from yeast.

PMID- 8670143
TI  - Effects of the type of divalent cation, Ca2+ or Mg2+, bound at the high-affinity
      site and of the ionic composition of the solution on the structure of F-actin.
AB  - F-actins containing either Ca2+ or Mg2+ at the single high-affinity site for a
      divalent cation differ in their dynamic properties [Carlier (1991) J. Biol. Chem.
      266, 1-4]. In an attempt to obtain information on the structural basis of this
      difference, we probed the conformation of specific sites in the subunits of Mg-
      and Ca-F-actin with limited proteolysis by subtilisin and trypsin. The influence
      of the kind of polymerizing salt was also investigated. At high proteinase
      concentrations required for digestion of actin in the polymer form, subtilisin
      gives a complex fragmentation pattern. In addition to the earlier known cleavage
      between Met47 and Gly48 in the DNAse-I-binding loop, cleavage of F-actin between
      Ser234 and Ser235 in subdomain 4 has recently been reported [Vahdat, Miller,
      Phillips, Muhlrad and Reisler (1995) FEBS Lett. 365, 149-151]. Here we show that
      actually a larger segment, comprising residues 227-235, is removed and the bond
      between Leu67 and Lys68 in subdomain 2 is split in both G- and F-actin, and that
      the differences in the fragmentation patterns of the G- and F-forms are accounted
      for by the protection of the bond 47-48 in F-actin. The subtilisin and trypsin
      cleavage sites in segment 61-69, subtilisin sites in segment 227-235 and trypsin
      sites between Lys373 and Cys374 were less accessible in Mg-F-actin than in Ca-F
      actin. These are intramolecular effects, as similar changes were observed on
      Ca2+/Mg2+ replacement in G-actin. The cation-dependent effects, in particular
      those on segment 61-69, were however less pronounced in F-actin than in G-actin.
      The results suggest that substitution of Mg2+ for Ca2+, and KCl-induced
      polymerization of CaATP-G-actin, bring about a similar change in the conformation
      of subdomain 2 of the monomer. The presence of Mg2+ at the high-affinity site
      also resulted in an increased protection of the bond 47-48. This latter appears
      to be an intermolecular effect because it is specific for F-actin. The
      susceptibility to subtilisin and trypsin was also strongly influenced by the kind
      and concentration of polymerizing salt. The digestion patterns suggest that the
      exposure and/or flexibility of the regions containing the cleavage sites diminish
      with enhancement of the ionic strength of the solution. The results are discussed
      in terms of the current models of F-actin.

PMID- 8670145
TI  - Novel isoforms of synexin in Xenopus laevis: multiple tandem PGQM repeats
      distinguish mRNAs in specific adult tissues and embryonic stages.
AB  - Synexin (annexin VII) is a calcium-dependent, phospholipid-binding and membrane
      fusion protein in the annexin gene family, which forms calcium channels and may
      play a role in exocytotic secretion. We report here the cloning and
      characterization of five novel isoforms of cDNAs encoding Xenopus synexin from
      brain, oocyte and stage 24 cDNA libraries. The most prevalent Xenopus synexin has
      1976 bp of cDNA sequence, which contains a 1539 bp open reading frame of 512
      amino acids encoding a 54 kDa protein. This Xenopus protein is 6 kDa larger than
      the previously reported human and mouse synexins with which it shares approx. 73%
      identity in the C-terminal region and approx. 44% identity in the N-terminal
      region. Further studies with PCR revealed the molecular basis of the substantial
      divergence in the Xenopus synexin's N-terminal domain. The domain equivalent to
      the mammalian tissue-specific cassette exon occurs at a different position and is
      variable in size and sequence. The most interesting observation relates to the
      occurrence of different forms of synexin due to the varying numbers of tandem
      PGQM repeats that are expressed differently in different adult tissues and
      embryonic stages. For these reasons we have labelled this set of unique isoforms
      annexin VIIb, referring to mammalian forms, which lack the PGQM tandem repeats,
      as annexin VIIa. In spite of these differences from annexin VIIa, the form of
      recombinant annexin VIIb with three PGQM repeats was found to be catalytically
      active. We interpret these results to indicate that the actual calcium and
      phospholipid binding sites are conserved in Xenopus, and that the variations
      observed between members of the synexin gene family in the regulatory domain
      clearly point towards the tissue- and stage-specific roles of individual members,
      possibly involving the exocytotic process.

PMID- 8670146
TI  - Decreased sensitivity of very-low-density lipoprotein secretion to the inhibitory
      effect of insulin in cultured hepatocytes from lactating rats.
AB  - Hepatocytes were prepared from 10-11-day lactating rat dams and from lactating
      dams which had been weaned for periods of either 1-2 days or 7 days. Hepatocytes
      from each group were cultured for periods of up to 48 h in a chemically defined
      medium. Compared with those from the 7-day weaned animals, hepatocytes from the
      lactating rats were resistant to the inhibitory effects of insulin on the
      secretion of very-low-density lipoprotein (VLDL) triacylglycerol (TAG). These
      differences persisted for up to 48 h in culture. Hepatocytes from the 1-2 day
      weaned animals remained relatively insulin-resistant in this respect. Similar
      differences in the response to insulin were not observed for the secretion of
      VLDL apolipoprotein B. TAG production increased and ketogenesis decreased in the
      hepatocytes from the lactating compared with those from the 7-day weaned rats.
      Insensitivity of the liver to the normal effects of insulin on the secretion of
      VLDL TAG may arise from a need to maintain an adequate flux of hepatic lipids to
      the lactating mammary gland in order to meet the large demand for milk-fat
      production.

PMID- 8670147
TI  - A role of asialoglycoproteins for plasma-membrane-induced inhibition of the
      switching from alpha 1 to beta subtypes in adrenergic response during primary
      culture of rat hepatocytes.
AB  - Adrenergic responses of rat hepatocytes were studied by measuring
      Ins(1,4,5)P3(for the response via alpha 1-subtype receptors) and cAMP (for beta
      subtype response) generation during brief incubation of cells with respective
      agonists. Hepatocytes from young rats with an age of 1 week displayed a very high
      beta response without a significant alpha 1 response. The beta response decreased
      and the alpha 1 response increased progressively as the age increased; the
      response was almost exclusively via alpha 1 receptors in hepatocytes of adult
      rats 9 weeks or more old. The beta response developed, again at the expense of
      the alpha 1 response, in hepatocytes from adult rats during the primary culture
      at low cell densities [(1-2.5) x 10(4) cells/cm2]. Such "alpha 1 to beta subtype
      switching' of adrenergic responses in vitro was totally inhibited by adding
      plasma membranes prepared from adult rat liver into the low-cell-density culture,
      but not inhibited at all by membranes from young rat liver. The inhibitory effect
      of adult rat liver membranes was lost when the membranes had been exposed to
      endoglycosidase F or beta-galactosidase but was not affected by prior treatment
      with sialidase. On the contrary, young rat liver membranes became inhibitory to
      "alpha 1 to beta subtype switching' after prior treatment with sialidase. Thus
      glycoproteins with unsialylated galactosyl termini on the surface of adult rat
      hepatocytes are likely to function as a determinant of the relative development
      of alpha 1/beta subtypes of adrenergic responses; the beta response is
      predominant in hepatocytes in the juvenile, presumably as a result of sialylation
      of the galactosyl termini of the functional glycoproteins.

PMID- 8670148
TI  - Phosphorylation of a cAMP-specific phosphodiesterase (HSPDE4B2B) by mitogen
      activated protein kinase.
AB  - A cAMP-specific phosphodiesterase, HSPDE4B2B, was found to be phosphorylated when
      expressed in Sf9 cells or yeast. Deletion of amino acids 81-151 and 529-564 had
      no effect on the phosphorylation of HSPDE4B2B. Mass spectrometric analysis of
      purified HSPDE4B2B(1-564). HSPDE4B2B(81-564) and HSPDE4B2B(152-528) showed that
      phosphorylation occurred predominantly on Ser487 and Ser489. The stoicheiometry
      of phosphorylation was 1.2:1 (Ser487:Ser487, 489). There was no evidence by MS
      for a non-phosphorylated form of HSPDE4B2B(81-564) or HSPDE4B2B(152-528) when
      expressed in Sf9 cells. There was no detectable phosphorylation of purified
      HSPDE4B2B(152-528) expressed in Escherichia coli. Radiolabelling experiments with
      32P revealed that phosphorylation of HSPDE4B2B(152-528) expressed in Sf9 cells
      was abolished when Ser487 and Ser489 were mutated to alanines. Analysis of the
      amino acid sequence revealed that Ser487 and Ser489 of HSPDE4B2B conform to the
      consensus motifs for phosphorylation by mitogen-activated protein kinase (MAP
      kinase) and casein kinase II respectively. Kinetic experiments in vitro showed
      that MAP kinase-phosphorylated E.coli expressed and purified HSPDE4B2B(151-528)
      with a K(m) of 63 microM and a Vmax of 3.0 mumol/min per mg. In comparison, MAP
      kinase phosphorylated myelin basic protein with a Km of 26.0 microM and a Vmax of
      5.5 mumol/min per mg under the same conditions. Using MS and mutational analysis
      we found that MAP kinase-phosphorylated E. coli expressed HSPDE4B2B(152-528)
      exclusively at Ser487. These results suggest that phosphodiesterases could
      contribute to the cross-talk between the cAMP and MAP kinase signalling pathways.

PMID- 8670149
TI  - Differentiation of BC3H1 smooth muscle cells changes the bivalent cation
      selectivity of the capacitative Ca2+ entry pathway.
AB  - Differentiation of BC3H1 cells leads to expression of a variety of proteins
      characteristic of smooth muscle and to changes in the behaviour of intracellular
      Ca2+ stores. Treatment of both differentiated and undifferentiated cells with
      thapsigargin (2 microM) emptied their intracellular Ca2+ stores, and in the
      presence of extracellular Ca2+ caused an increase in cytosolic [Ca2+] that
      rapidly reversed after its removal. The amplitudes of these capacitative Ca2+
      entry signals were 101 +/- 8 nM (n = 42) in differentiated cells and 188 +/- 16
      nM (n = 35) in undifferentiated cells. Mn2+ entry in thapsigargin-treated cells,
      measured by recording the quenching of cytosolic fura 2 fluorescence, was 374 +/-
      26% (n = 34) and 154 +/- 7% (n = 41) of control rates in differentiated and
      undifferentiated cells, respectively. Empty stores caused Ba2+ entry to increase
      to 282 +/- 20% (n = 8) of its basal rate in differentiated cells and to 187 +/-
      20% (n = 8) in undifferentiated cells. Rates of Ca2+ extrusion, measured after
      rapid removal of extracellular Ca2+ from cells in which capacitative Ca2+ entry
      had been activated, were similar in differentiated (t1/2 = 23 +/- 2 s, n = 7) and
      undifferentiated (23 +/- 1 s, n = 6) cells. The different relationships between
      capacitative Ca2+ and Mn2+ signals are not, therefore, a consequence of more
      active Ca2+ extrusion mechanisms in differentiated cells, nor are they a
      consequence of different fura 2 loadings in the two cell types. We conclude that
      during differentiation of BC3Hl cells, the cation selectivity of the capacitative
      pathway changes, becoming relatively more permeable to Mn2+ and Ba2+. The change
      may result either from expression of a different capacitative pathway or from
      modification of the permeation properties of a single pathway.

PMID- 8670151
TI  - Structural environment of an essential cysteine residue of xylanase from Chainia
      sp. (NCL 82.5.1).
AB  - N-(2,4-Dinitroanilino)maleimide (DAM) reacts covalently with the thiol group of
      the xylanase from Chainia leading to complete inactivation in a manner similar to
      N-ethylmaleimide, but provides a reporter group at the active site of the enzyme.
      Increasing amounts of xylan offered enhanced protection against inactivation of
      the xylanase by DAM. Xylan (5 mg) showed complete protection, providing evidence
      for the presence of cysteine at the substrate-binding site of the enzyme.
      Kinetics of chemical modification of the xylanase by DAM indicated the
      involvement of 1 mol of cysteine residue per mol of enzyme, as reported earlier
      [Deshpande, Hinge and Rao (1990) Biochim. Biophys. Acta 1041, 172-177]. The
      second-order rate constant for the reaction of DAM with the enzyme was 3.61 x
      10(3) M-1.min-1. The purified xylanase was alkylated with DAM and digested with
      pepsin. The peptides were separated by gel filtration. The specific modified
      cysteinyl peptide was further purified by reverse-phase HPLC. The active-site
      peptide was located visually by its predominant yellow colour and characterized
      by a higher A340 to A210 ratio. The modified active-site peptide has the
      sequence: Glu-Thr-Phe-Xaa-Asp. The sequence of the peptide was distinctly
      different from that of cysteinyl peptide derived from a xylanase from a
      thermotolerant Streptomyces species, but showed the presence of a conserved
      aspartic acid residue consistent with the catalytic regions of other glucanases.

PMID- 8670150
TI  - Bile acid stimulation of early growth response gene and mitogen-activated protein
      kinase is protein kinase C-dependent.
AB  - Hepatic stellate cells are exposed to elevated bile acid levels during hepatic
      injury and fibrogenesis. Upon activation, the stellate cell becomes a major
      effector cell during the development of hepatic fibrosis and cirrhosis. Bile
      acids may function as costimulatory signalling molecules. This hypothesis was
      tested in vitro using rat-derived hepatic stellate cells. Bile acids were studied
      at concentrations that occur during cirrhosis in vivo. Conjugated and
      unconjugated bile acids rapidly induced egr and fos gene expression as well as
      cytoplasmic mitogen-activated protein kinase (MAPK) activation. Protein kinase C
      was required for both egr induction and MAPK activation. These studies imply that
      bile acids could contribute to the perpetuation of hepatic fibrosis by helping to
      keep the stellate cell in an activated state.

PMID- 8670152
TI  - Demonstration that 1-trans-epoxysuccinyl-L-leucylamido-(4-guanidino) butane (E
      64) is one of the most effective low Mr inhibitors of trypsin-catalysed
      hydrolysis. Characterization by kinetic analysis and by energy minimization and
      molecular dynamics simulation of the E-64-beta-trypsin complex.
AB  - 1-trans-Epoxysuccinyl-L-leucylamido(4-guanidino)butane (E-64) was shown to
      inhibit beta-trypsin by a reversible competitive mechanism; this contrasts with
      the widely held view that E-64 is a class-specific inhibitor of the cysteine
      proteinases and reports in the literature that it does not inhibit a number of
      other enzymes including, notably, trypsin. The K1, value (3 x 10(-5) M)
      determined by kinetic analysis of the hydrolysis of N alpha-benzoyl-L-arginine 4
      nitroanilide in Tris/HCl buffer, pH 7.4, at 25 degrees C, I = 0.1, catalysed by
      beta-trypsin is comparable with those for the inhibition of trypsin by
      benzamidine and 4-aminobenzamidine, which are widely regarded as the most
      effective low Mr inhibitors of this enzyme. Computer modelling of the beta
      trypsin-E64 adsorptive complex, by energy minimization, molecular dynamics
      simulation and Poisson-Boltzmann electrostatic-potential calculations, was used
      to define the probable binding mode of E-64; the ligand lies parallel to the
      active-centre cleft, anchored principally by the dominant electrostatic
      interaction of the guanidinium cation at one end of the E-64 molecule with the
      carboxylate anion of Asp-171 (beta-trypsin numbering from Ile-1) in the S1
      subsite, and by the interaction of the carboxylate substituent on C-2 of the
      epoxide ring at the other end of the molecule with Lys-43; the epoxide ring of E
      64 is remote from the catalytic site serine hydroxy group. The possibility that E
      64 might bind to the cysteine proteinases clostripain (from Clostridium
      histolyticum) and alpha-gingivain (one of the extracellular enzymes from
      phyromonas gingivalis) in a manner analogous to that deduced for the beta-trypsin
      E-64 complex is discussed.

PMID- 8670153
TI  - Oligomannosides or oligosaccharide-lipids as potential substrates for rat liver
      cytosolic alpha-D-mannosidase.
AB  - We have previously reported the substrate specificity of the cytosolic alpha-D
      mannosidase purified from rat liver using Man9GlcNAc, i.e. Man alpha 1-2Man alpha
      1-3(Man alpha 1-2Man alpha 1-6)Man alpha 1-6(Man alpha 1-2Man alpha 1-2Man alpha
      1-3) Man beta 1-4G1cNAc, as substrate [Grard, Saint-Pol, Haeuw, Alonso,
      Wieruszeski, Strecker and Michalski (1994) Eur. J. Biochem. 223, 99-106]. Man9
      G1cNAc is hydrolysed giving Man5GlcNAc, i.e. Man alpha 1-2 Man alpha 1-2Man alpha
      1-3(Man alpha 1-6)Man beta 1-4GlcNAc, possessing the same structure as the
      oligosaccharide of the dolichol pathway formed in the cytosolic compartment
      during the biosynthesis of N-glycosylprotein glycans. We study here the activity
      of the purified cytosolic alpha-D-mannosidase towards the oligosaccharide
      diphosphodolichol intermediates formed during the biosynthesis of N-glycans, and
      also towards soluble oligosaccharides released from the endoplasmic reticulum
      which are glucosylated or not and possessing at their reducing end either a
      single N-acetylglucosamine residue or a di-N-acetylchitobiose sequence. We
      demonstrate that (1) dolichol pyrophosphate oligosaccharide substrates are poorly
      hydrolysed by the cytosolic alpha-D-mannosidase; (2) oligosaccharides with a
      terminal reducing di-N-acetylchitobiose sequence are not hydrolysed at all; (3)
      soluble oligosaccharides bearing a single reducing N-acetylglucosamine are the
      real substrates for the enzyme. These results suggest a role for alpha-D
      mannosidase in the catabolism of glycans released from the endoplasmic reticulum
      rather than in the regulation of the biosynthesis of asparagine-linked
      oligosaccharides.

PMID- 8670154
TI  - Expression of Drosophila trpl cRNA in Xenopus laevis oocytes leads to the
      appearance of a Ca2+ channel activated by Ca2+ and calmodulin, and by guanosine
      5'[gamma-thio]triphosphate.
AB  - The effects of expression of the Drosophila melanogaster Trpl protein, which is
      thought to encode a putative Ca2+ channel [Phillips, Bull and Kelly (1992) Neuron
      8, 631-642], on divalent cation inflow in Xenopus laevis oocytes were
      investigated. The addition of extracellular Ca2+ ([Ca2+]0) to oocytes injected
      with trpl cRNA and to mock-injected controls, both loaded with the fluorescent
      Ca2+ indicator fluo-3, induced a rapid initial and a slower sustained rate of
      increase in fluorescence, which were designated the initial and sustained rates
      of Ca2+ inflow respectively. Compared with mock-injected oocytes, trpl-cRNA
      injected oocytes exhibited a higher resting cytoplasmic free Ca2+ concentration
      ([Ca2+]i), and higher initial and sustained rates of Ca2+ inflow in the basal (no
      agonist) states. The basal rate of Ca2+ inflow in trpl-cRNA-injected oocytes
      increased with (1) an increase in the time elapsed between injection of trpl cRNA
      and the measurement of Ca2+ inflow, (2) an increase in the amount of trpl cRNA
      injected and (3) an increase in [Ca2+]0. Gd3+ inhibited the trpl cRNA-induced
      basal rate of Ca2+ inflow, with a concentration of approx. 5 microM Gd3+ giving
      half-maximal inhibition. Expression of trpl cRNA also caused an increase in the
      basal rate of Mn2+ inflow. The increases in resting [Ca2+]1 and in the basal rate
      of Ca2+ inflow induced by expression of trpl cRNA were inhibited by the
      calmodulin inhibitors W13, calmodazolium and peptide (281-309) of (Ca2+ and
      calmodulin)-dependent protein kinase II. A low concentration of exogenous
      calmodulin (introduced by microinjection) activated, and a higher concentration
      inhibited, the trpl cRNA-induced increase in basal rate of Ca2+ inflow. The
      action of the high concentration of exogenous calmodulin was reversed by W13 and
      calmodazolium. When rates of Ca2+ inflow in trpl-cRNA-injected oocytes were
      compared with those in mock-injected oocytes, the guanosine 5'-[beta
      thio]diphosphate-stimulated rate was greater, the onset of thapsigargin
      stimulated initial rate somewhat delayed and the inositol 1,4,5-trisphosphate
      stimulated initial rate markedly inhibited. It is concluded that (1) the divalent
      cation channel activity of the Drosophila Trpl protein can be detected in Xenopus
      oocytes: (2) in the environment of the Xenopus oocyte the Trpl channel admits
      some Mn2+ as well as Ca2+, is activated by cytoplasmic free Ca2+ (through
      endogenous calmodulin) and by a trimeric GTP-binding regulatory protein, but does
      not appear to be activated by depletion of Ca2+ in the endoplasmic reticulum; and
      (3) expression of the Trpl protein inhibits the process by which the release of
      Ca2+ from intracellular stores activates endogenous store-activated Ca2+
      channels.

PMID- 8670156
TI  - Recombinant human tumour necrosis factor-alpha suppresses synthesis, activity and
      secretion of lipoprotein lipase in cultures of a human osteosarcoma cell line.
AB  - The effect of recombinant human tumour necrosis factor-alpha (TNF-alpha) on
      synthesis, activity and secretion of lipoprotein lipase (LPL) was examined using
      a human osteosarcoma cell line, osteosarcoma Takase (OST). Treatment of OST cells
      with TNF-alpha decreased LPL synthesis, resulting in a decrease in expression of
      activity and secretion of LPL. When OST cells were incubated with glycerol tri[1
      14C]palmitate, TNF-alpha decreased dose- and time-dependently the production of
      14CO2 and the amounts of radioactivity incorporated into cellular triacylglycerol
      and phospholipid. The similar reduction of synthesis and activity of LPL as
      suppression of CO2 production and cellular lipid synthesis indicated that the
      suppression of 14CO2 production and 14C-labelled lipid synthesis was secondary.
      TNF-alpha also suppressed expression of proliferating cell nuclear antigen,
      indicating that it had an anti-proliferative activity on OST cells. The findings
      suggest that one cause of the anti-proliferative activity of TNF-alpha is the
      suppression of the LPL-mediated supply of non-esterified fatty acids as an energy
      source for growth.

PMID- 8670155
TI  - Entry of polyunsaturated fatty acids into the brain: evidence that high-density
      lipoprotein-induced methylation of phosphatidylethanolamine and phospholipase A2
      are involved.
AB  - The conversion of phosphatidylethanolamine (PE) into phosphatidylcholine (PC) by
      a sequence of three transmethylation reactions is shown to be stimulated by the
      apolipoprotein E-free subclass of high-density lipoprotein (HDL3) in isolated
      bovine brain capillary (BBC) membranes, HDL3-induced stimulation of BBC membranes
      pulsed with [methyl-14C]methionine causes a transient increase in each methylated
      phospholipid, i.e. phosphatidyl-N-monomethylethanolamine (PMME), phosphatidyl-NN
      dimethylethanolamine (PDME) and PC. PC substrate arising from the activation of
      PE N-methyltransferase (PEMT) is hydrolysed by a phospholipase A2 (PLA2), as
      demonstrated by the accumulation of lysophosphatidylcholine (lyso-PC). When PE
      containing [14C]arachidonic acid in the sn-2 position ([14C]PAPE) is incorporated
      into BBC membranes, HDL3 stimulation induces the formation of PMME, PDME, PC and
      lyso-PC and the release of [14C]arachidonic acid, which correlates with the
      previous production of lyso-PC, suggesting that HDL3 stimulates a PLA2 that can
      release polyunsaturated fatty acids (PUFA). Both PEMT and PLA2 activities depend
      on a HDL3 concentration in the range 0-50 micrograms/ml and are strictly
      dependent on HDL3 binding, because HDL3 modified by tetranitromethane is no
      longer able to bind to specific receptors and to trigger PEMT and PLA2
      activation. Moreover, HDL3 prelabelled with [14C]PAPE can stimulate PDME and lyso
      PC synthesis in BBC membranes in the presence of S-adenosylmethionine, suggesting
      that HDL3 can supply BBC membranes in polyunsaturated PE and can activate enzymes
      involved in PE N-methylation and PUFA release. The results support the hypothesis
      of a close relationship between HDL3 binding, PE methylation and PUFA release,
      and suggest that the PC pool arising from PE could be used as a pathway for the
      supply of PUFA to the brain.

PMID- 8670158
TI  - SDS-resistant aggregation of membrane proteins: application to the purification
      of the vesicular monoamine transporter.
AB  - The vesicular monoamine transporter, which catalyses a H+/ monoamine antiport in
      monoaminergic vesicle membrane, is a very hydrophobic intrinsic membrane protein.
      After solubilization, this protein was found to have a high tendency to
      aggregate, as shown by SDS/PAGE, especially when samples were boiled in the
      classical Laemmli buffer before electrophoresis. This behavior was analysed in
      some detail. The aggregation was promoted by high temperatures, organic solvents
      and acidic pH, suggesting that it resulted from the unfolding of structure
      remaining in SDS. The aggregates were very stable and could be dissociated only
      by suspension in anhydrous trifluoroacetic acid. This SDS-resistant aggregation
      behaviour was shared by very few intrinsic proteins of the chromaffin granule
      membrane. Consequently, a purification procedure was based on this property. A
      detergent extract of chromaffin granule membranes enriched in monoamine
      transporter was heated and the aggregates were isolated by size-exclusion HPLC in
      SDS. The aggregates, containing the transporter, were dissociated in the presence
      of trifluoroacetic acid and analysed on the same HPLC column. This strategy might
      be of general interest for the purification of membrane proteins that exhibit SDS
      resistant aggregation.

PMID- 8670157
TI  - Evidence for a non-capacitative Ca2+ entry during [Ca2+] oscillations.
AB  - Current models for the agonist-induced activation of Ca2+ entry from the
      extracellular medium in non-excitable cells generally emphasize a capacitative
      mechanism whereby Ca2+ entry is activated simply as a result of the emptying of
      intracellular Ca2+ stores, without any direct involvement of inositol phosphates.
      To date, the activation and control of Ca2+ entry have generally been studied
      under conditions where the agonist-sensitive stores undergo a profound and
      sustained depletion. However, responses under more normal physiological
      conditions typically involve the cyclical release and refilling of the stores
      associated with oscillations in [Ca2+], and the nature and control of entry under
      these conditions has received relatively little attention. In this study, using
      isolated cells from the exocrine avian nasal gland as a model system, we show
      that: (a) the agonist-enhanced rate of Mn2+ quench is independent of the cyclical
      emptying and refilling of the agonist-sensitive Ca2+ pool during oscillations;
      (b) the Ca2+ entry pathway is maintained in an activated state for extended
      periods following inhibition of oscillations under conditions in which agonist
      sensitive stores can be shown to be full; (c) no Ca2+ entry could be detected in
      oscillating cells in experiments that followed a definitive protocol for the
      demonstration of capacitative entry; and (d) on initial exposure to low agonist
      concentrations, activation of Ca2+ entry preceded any detectable release of Ca2+
      from the stores. We conclude that the essential characteristics of the control of
      Ca2+ entry during oscillations are incompatible with current capacitative models.

PMID- 8670160
TI  - Purification and characterization of an extracellular (1 --> 6)-beta-glucanase
      from the filamentous fungus Acremonium persicinum.
AB  - An endo-(1 --> 6)-beta-glucanase has been isolated from the culture filtrates of
      the filamentous fungus Acremonium persicinum and purified by (NH4)2SO4
      precipitation followed by anion-exchange and gel-filtration chromatography.
      SDS/PAGE of the purified enzyme gave a single band with an apparent molecular
      mass of 42.7 kDa. The enzyme is a non-glycosylated, monomeric protein with a pI
      of 4.9 and pH optimum of 5.0. It hydrolysed (1 --> 6)-beta-glucans (pustulan and
      lutean), initially yielding a series of (1 --> 6)-beta-linked oligoglucosides,
      consistent with endo-hydrolytic action. Final hydrolysis products from these
      substrates were gentiobiose and gentiotriose, with all products released as beta
      anomers, indicating that the enzyme acts with retention of configuration. The
      purified enzyme also hydrolysed Eisenia bicyclis laminarin, liberating glucose,
      gentiobiose, and a range of larger oligoglucosides, through the apparent
      bydrolysis of (1 --> 6)-beta- and some (1 --> 3)-beta-linkages in this substrate.
      K(m) values for pustulan, lutean and laminarin were 1.28, 1.38, and 1.67 mg/ml
      respectively. The enzyme was inhibited by N-acetylimidazole, N-bromosuccinimide,
      dicyclohexylcarbodi-imide, Woodward's Reagent K, 2-hydroxy-5-nitrobenzyl bromide,
      KMnO4 and some metal ions, whereas D-glucono-1,5-lactone and EDTA had no effect.

PMID- 8670159
TI  - Leishmania mexicana p12cks1, a homologue of fission yeast p13suc1, associates
      with a stage-regulated histone H1 kinase.
AB  - We have isolated a Leishmania mexicana homologue of the fission yeast suc1 gene
      using PCR with oligonucleotides designed to conserved regions of cdc2 kinase
      subunits (cks). The product of cks1 is a 12 kDa polypeptide, which has 70%
      identity with human p9cks1 and 44% identity with fission yeast p13suc1.p12cks1
      was detected in the three life-cycle stages of L. mexicana by immunoblotting.
      Recombinant p12cks1 (p12cks1his) bound to agarose beads was used as a matrix to
      affinity-select histone H1 kinase complexes from Leishmania, yeast and bovine
      extracts. Immunoblotting showed that yeast and bovine cdc2 kinase bound to
      p12cks1his, thus demonstrating functional homology between L. mexicana p12cks1
      and yeast p13suc1. Histone H1 kinase activity was found at a high level in the
      proliferative promastigote and amastigote forms of L. mexicana, but at a low
      level in the non-dividing metacyclic form. These activities are likely to be the
      same as the leishmanial p13suc1 binding kinase (SBCRK) described previously
      [Mottram, Kinnaird, Shiels, Tait and Barry (1993) J. Biol. Chem. 268, 21044
      21051]. A distinct cdc2-related kinase, L. mexicana CRK1, was also found to
      associate with p12cks1his but affinity-depletion experiments showed that CRK1 was
      not responsible for the histone H1 kinase activity associating with p12cks1his in
      promastigote cell extracts. The finding that p12cks1 associates with at least two
      cdc2-related kinases, SBCRK and CRK1, is consistent with the presence of a large
      gene family of cdc2-related kinases in trypanosomatids, a situation thought to be
      more similar to higher eukaryotes than yeast.

PMID- 8670161
TI  - Metabolic fate of oleic acid, palmitic acid and stearic acid in cultured hamster
      hepatocytes.
AB  - Unlike other saturated fatty acids, dietary stearic acid does not appear to raise
      plasma cholesterol. The reason for this remains to be established, although it
      appears that it must be related to inherent differences in the metabolism of the
      fatty acid. In the present study, we have looked at the metabolism of palmitic
      acid and stearic acid, in comparison with oleic acid, by cultured hamster
      hepatocytes. Stearic acid was taken up more slowly and was poorly incorporated
      into both cellular and secreted triacylglycerol. Despite this, stearic acid
      stimulated the synthesis and secretion of triacylglycerol to the same extent as
      the other fatty acids. Incorporation into cellular phospholipid was lower for
      oleic acid than for palmitic acid and stearic acid. Desaturation of stearic acid,
      to monounsaturated fatty acid, was found to be greater than that of palmitic
      acid. Oleic acid produced from stearic acid was incorporated into both
      triacylglycerol and phospholipid, representing 13% and 6% respectively of the
      total after a 4 h incubation. Significant proportions of all of the fatty acids
      were oxidized, primarily to form ketone bodies, but by 8 h more oleic acid had
      been oxidized compared with palmitic acid and stearic acid.

PMID- 8670162
TI  - Cloning and functional expression of glycosyltransferases from parasitic
      protozoans by heterologous complementation in yeast: the dolichol phosphate
      mannose synthase from Trypanosoma brucei brucei.
AB  - The gene for the enzyme dolichol phosphate mannose (Dol-P-Man) synthase from the
      parasitic protozoan Trypanosoma brucei brucei (T. brucei) was cloned by screening
      a T. brucei cDNA library and then sequenced. The library was constructed in a
      yeast expression vector and the positive clone was identified by complementation
      of a temperature-sensitive defect in the yeast strain DPM 1-6 [Orlean, Albright
      and Robbins (1988) J. Biol. Chem. 263, 17499-17507]. The insert of this clone
      displayed an open reading frame of 801 nucleotides coding for a putative protein
      of 267 amino acids. The deduced protein sequence showed an identity of 49% and a
      similarity of 69% with the published yeast sequence. Additional features of the
      T. brucei sequence are the presence of a putative signal sequence, a C-terminal
      transmembrane domain, a consensus sequence for phosphorylation by cAMP-dependent
      protein kinase and a stretch of five nucleotides immediately upstream from the
      putative initiation codon that could function as a prokaryotic ribosome binding
      site. A consensus sequence for dolichol binding (FI/VXF/YXXIPFXF/Y) found in the
      yeast protein could not be detected in the putative transmembrane domain of the
      T. brucei sequence. Biochemical characterization of the recombinant protein
      showed that it is functionally expressed in the yeast strain DPM 1-6 and
      Escherichia coli. In both constructs Dol-P-Man synthesis was shown in a cell-free
      system. Synthesis was stimulated by exogenous dolichol phosphate and inhibited by
      amphomycin. These results confirm that we have cloned the T. brucei Dol-P-Man
      synthase by heterologous complementation in yeast, an approach that might be
      applicable for other glycosyltransferases from various sources.

PMID- 8670163
TI  - Active synthesis of C24:5, n-3 fatty acid in retina.
AB  - The formation of 14C-labelled long-chain and very-long-chain (n-3) pentaenoic and
      hexaenoic fatty acids was studied in bovine retina by following the metabolism
      of. [14C]-docosapentaenoate [C22:5, n-3 fatty acid (22:5 n-3)], [14C]
      docosahexaenoate (22:6 n-3), and [14C]acetate. With similar amounts of 22:5 n-3
      and 22:6 n-3 as substrates, the former was actively transformed into 24:5 n-3,
      whereas the latter was virtually unmodified. Labelled 24:5, 26:5, 24:6 and 22:6
      were formed from [1-14C]22:5 n-3, showing that pentaenoic fatty acids including
      24:5 n-3 can be elongated and desaturated within the retina. When retinal
      microsomes were incubated with [1-14C]22:5 n-3, 24:5 n-3 was the only fatty acid
      formed. In retinas incubated with [14C]acetate, 24:5 n-3 was the most highly
      labelled fatty acid among the polyenes synthesized, 24:6 n-3 being a minor
      product. Such selectivity in the elongation of two fatty acids identical in
      length, 22:5 n-3 and 22:6 n-3, despite the fact that 22:5 is a minor and 22:6 a
      major fatty acid constituent of retina, suggests that the active formation of
      24:5 n-3 plays a key role in n-3 polyunsaturated fatty acid (PUFA) metabolism.
      This compound might give rise to even longer pentaenes via elongation, and to the
      major PUFAs of retina, 22:6 n-3, by 6-desaturation and chain shortening. Of all
      retinal lipids, a minor component, triacylglycerol (TG), incorporated the largest
      amounts of [14C]22:5 and 22:6. TG also concentrated most of the [14C]24:5 formed
      in retina, whether from [14C]22:5 n-3 or from [14C]acetate, suggesting an
      important role for this lipid in supporting PUFA metabolism and the synthesis of
      22:6 n-3.

PMID- 8670164
TI  - Protein kinase C isoforms epsilon, eta, delta and zeta in murine adipocytes:
      expression, subcellular localization and tissue-specific regulation in insulin
      resistant states.
AB  - The Ca(2+)-insensitive protein kinase C (PKC) isoforms epsilon, eta, delta and
      zeta are possible direct downstream targets of phosphatidylinositol 3-kinase (P13
      K), and might therefore be involved in insulin signalling. Although isoform
      specific changes in PKC expression have been reported for skeletal muscle and
      liver in insulin-resistant states, little is known about these isoforms in
      adipocytes. Therefore we studied (1) expression and subcellular localization of
      these isoforms in murine adipocytes, (2) translocation of specific isoforms to
      membranes in response to treatment with insulin and phorbol 12-myristate 13
      acetate (PMA) and (3) regulation of expression in insulin-resistant states. The
      PKC isoforms epsilon, eta, delta and zeta are expressed in adipocytes.
      Immunoreactivity for all isoforms is higher in the membranes than in the cytosol,
      but subcellular fractionation by differential centrifugation shows an isoform
      specific distribution within the membrane fractions. PMA treatment of adipocytes
      induces translocation of PKC-epsilon and -delta from the cytosol to the membrane
      fractions. Insulin treatment does not alter the subcellular distribution of any
      of the isoforms. 3T3-L1 adipocytes express PKC-epsilon and -zeta, and PKC-epsilon
      expression increases with differentiation from preadipocytes to adipocytes. PKC
      epsilon expression decreases in an adipose-specific and age/obesity-dependent
      manner in two insulin-resistant models, the brown-adipose-tissue-deficient mouse
      and db/db mouse compared with control mice. We conclude that, although none of
      the isoforms investigated seems to be activated by insulin, the decrease in PKC
      epsilon expression might contribute to metabolic alterations in adipocytes
      associated with insulin resistance and obesity.

PMID- 8670165
TI  - Mechanism of bile salt-induced mucin secretion by cultured dog gallbladder
      epithelial cells.
AB  - 1. Hypersecretion of gallbladder mucin has been proposed to be a pathogenic
      factor in cholesterol gallstone formation. Using cultured gallbladder epithelial
      cells, we demonstrated that bile salts regulate mucin secretion by the
      gallbladder epithelium. In the present study we have investigated whether
      established second messenger pathways are involved in bile salt-induced mucin
      secretion. 2. The effect of activators and inhibitors on mucin secretion was
      studied by measuring the secretion of [3H]N-acetyl-D-glucosamine-labelled
      glycoproteins. Intracellular cAMP content of the cells was measured using a
      radioimmunoassay. 3. Incubation of the cells with 10 mM taurocholate did not
      increase the intracellular cAMP content (25.7 versus control 22.8 pmol of cAMP/mg
      of protein). No stimulation of mucin secretion was observed after incubation with
      1-100 microM concentrations of the calcium ionophores ionomycin and A23187. The
      stimulatory effect of 10 mM tauroursodeoxycholate (TUDC) on mucin secretion could
      not be inhibited by the addition of EDTA. Activation of protein kinase C (PKC) by
      1 microgram/ml phorbol 12-myristate 13-acetate (PMA) caused an increase in mucin
      secretion (342% versus control 100%), comparable with the effect of 40 mM TUDC.
      The effect of 10 ng/ml PMA could partially be inhibited by a concentration of 2
      microM of the PKC inhibitor staurosporin. Staurosporin had no inhibitory effect
      on mucin secretion induced by TUDC. 4. In gallbladder epithelial cells bile salts
      do not stimulate mucin secretion via one of the classical signal transduction
      pathways. We hypothesize that bile salts act on mucin secretion via a direct
      interaction with the apical membrane.

PMID- 8670166
TI  - C-myc is required for the G0/G1-S transition of primary hepatocytes stimulated
      with a deleted form of hepatocyte growth factor.
AB  - Primary rat hepatocytes stimulated in vitro with the addition of a deleted form
      of hepatocyte growth factor (dHGF) enter the S-phase 48 h after addition of the
      growth factor. The c-myc gene is believed to play a role in a variety of cellular
      stages, such as proliferation, differentiation and cell death. In primary
      hepatocytes c-myc was expressed constitutively at both mRNA and protein levels,
      independently of the growth conditions. dHGF induced significant c-myc expression
      at times correlated with the long-lasting pre-S phase, and no induction was
      observed at the G0/G1 traverse compared with the unstimulated hepatocytes. An
      antisense construct coding for all three exons of c-myc was imported into
      hepatocytes by using the transferrin receptor-mediated endocytosis methodology
      (transferrinfection). Expression of the antisense construct inhibited the
      biosynthesis of the c-Myc protein, however it did not interfere with the
      expression of c-met, encoding the receptor for HGF/dHGF. Continuous expression of
      the antisense construct inhibited entry of the hepatocytes into the S-phase.
      Regulated induction of the antisense c-myc by dexamethasone for up to 6 h in
      culture, did not interfere with the entry of hepatocytes into the S-phase. c-myc
      expression was shown to be required between 6 and 12 h in dHGF-stimulated
      hepatocytes, and inhibition of its expression during this time by the antisense
      myc construct did not allow these cells to enter the S-phase. Inhibition of c-myc
      biosynthesis between 24 and 48 h hours slightly affected the DNA synthetic
      response. It is proposed that the expression of c-Myc protein interferes with the
      "priming' of hepatocytes to become responsive to growth-factor stimuli, or in the
      absence of such stimuli it interferes with the maintenance of a non-proliferating
      phenotype and subsequent in vitro de-differentiation.

PMID- 8670167
TI  - Reconstitution of the [4Fe-4S] cluster in FNR and demonstration of the aerobic
      anaerobic transcription switch in vitro.
AB  - The FNR protein of Escherichia coli is a redox-responsive transcription regulator
      that activates and represses a family of genes required for anaerobic and aerobic
      metabolism. Reconstitution of wild-type FNR by anaerobic treatment with ferrous
      ions, cysteine and the NifS protein of Azotobacter vinelandii leads to the
      incorporation of two [4Fe-4S]2+ clusters per FNR dimer. The UV-visible spectrum
      of reconstituted FNR has a broad absorbance at 420 nm. The clusters are EPR
      silent under anaerobic conditions but are degraded to [3Fe-4S]+ by limited
      oxidation with air, and completely lost on prolonged air exposure. The
      association of FNR with the iron-sulphur clusters is confirmed by CD
      spectroscopy. Incorporation of the [4Fe-4S]2+ clusters increases site-specific
      DNA binding about 7-fold compared with apo-FNR. Anaerobic transcription
      activation and repression in vitro likewise depends on the presence of the iron
      sulphur cluster, and its inactivation under aerobic conditions provides a
      demonstration in vitro of the FNR-mediated aerobic-anaerobic transcriptional
      switch.

PMID- 8670168
TI  - Purification and characterization of a tetrameric alpha-macroglobulin proteinase
      inhibitor from the gastropod mollusc Biomphalaria glabrata.
AB  - The alpha-macroglobulin proteinase inhibitors (alpha Ms) are a family of proteins
      with the unique ability to inhibit a broad spectrum of proteinases. Whereas
      monomeric, dimeric and tetrameric alpha Ms have been identified in vertebrates,
      all invertebrate alpha Ms characterized so far have been dimeric. This paper
      reports the isolation and characterization of a tetrameric alpha M from the
      tropical planorbid snail Biomphalaria glabrata. The sequence of 18 amino acids at
      the N-terminus indicates homology with other alpha Ms. The subunit mass of
      approx. 200 kDa was determined by matrix-assisted laser desorption/ionization
      time-of-flight mass spectrometry and SDS/PAGE. The quaternary structure was
      determined by sedimentation equilibrium centrifugation and native pore-limit
      electrophoresis. Evidence for a thioester is provided by the fact that
      methylamine treatment prevents the autolytic cleavage of the snail alpha M
      subunit and results in the release of 4 mol of thiols per mol of snail alpha M.
      The snail alpha M inhibited the serine proteinase trypsin, the cysteine
      proteinase bromelain and the metalloproteinase thermolysin. The spectrum of
      proteinases inhibited, together with the demonstration of steric protection of
      the proteinase active site and a "slow to fast' conformational change after
      reacting with trypsin, all suggest that the inhibitory mechanism of the snail
      alpha M is similar to the "trap mechanism' of human alpha 2-macroglobulin.

PMID- 8670169
TI  - Effect of antisense oligonucleotides on the expression of hepatocellular bile
      acid and organic anion uptake systems in Xenopus laevis oocytes.
AB  - A Na(+)-dependent bile acid (Na+/taurocholate co-transporting polypeptide; Ntcp)
      and a Na(+)-independent bromosulphophthalein (BSP)/bile acid uptake system
      (organic-anion-transporting polypeptide; oatp) have been cloned from rat liver by
      using functional expression cloning in Xenopus laevis oocytes. To evaluate the
      extent to which these cloned transporters could account for overall hepatic bile
      acid and BSP uptake, we used antisense oligonucleotides to inhibit the expression
      of Ntcp and oatp in Xenopus laevis oocytes injected with total rat liver mRNA. An
      Ntcp-specific antisense oligonucleotide co-injected with total rat liver mRNA
      blocked the expression of Na(+)-dependent taurocholate uptake by approx. 95%. In
      contrast, an oatp-specific antisense oligonucleotide when co-injected with total
      rat liver mRNA had no effect on the expression of Na(+)-dependent taurocholate
      uptake, but it blocked Na(+)-independent uptake of taurocholate by approx. 80%
      and of BSP by 50%. Assuming similar expression of hepatocellular bile acid and
      organic anion transporters in Xenopus laevis oocytes, these results indicate that
      Ntcp and oatp respectively represent the major, if not the only, Na(+)-dependent
      and Na(+)-independent taurocholate uptake systems in rat liver. By contrast, the
      cloned oatp accounts for only half of BSP transport, suggesting that there must
      be additional, non-bile acid transporting organic anion uptake systems in rat
      liver.

PMID- 8670170
TI  - Contrasting effects of phorbol ester and agonist-mediated activation of protein
      kinase C on phosphoinositide and Ca2+ signalling in a human neuroblastoma.
AB  - The effects of protein kinase C (PKC) activation on muscarinic receptor-mediated
      phosphoinositide and Ca2+ signalling were examined in the human neuroblastoma, SH
      SY5Y. Carbachol evoked rapid transient elevations of Ins(1,4,5)P3 and
      intracellular [Ca2+] followed by lower sustained elevations. Phorbol 12,13
      dibutyrate (PDBu) preferentially attenuated transient phases. Removal of the
      transplasmalemmal Ca2+ gradient coupled with depletion of intracellular Ca2+
      stores with thapsigargin also reduced carbachol-mediated Ins(1,4,5)P3
      accumulation. Under these conditions, PDBu virtually abolished Ins(1,4,5)P3
      responses to carbachol thereby implicating both Ca(2+)- and PKC-sensitive
      components. PDBu also reduced agonist-mediated accumulation of inositol
      phosphates and depletion of lipids, thereby eliminating an effect of PKC on
      Ins(1,4,5)P3 metabolism or phosphoinositide synthesis. In electroporated cells,
      PDBu inhibited Ins(1,4,5)P3 accumulation mediated by carbachol or guanosine 5'
      [gamma-thio]-triphosphate, the latter indicating that some PDBu-sensitive
      elements were downstream of the receptor. The PKC inhibitor, Ro-318220, protected
      against PDBu but did not enhance responses to maximal concentrations of
      carbachol, indicating no feedback inhibition by agonist-activated PKC. Muscarinic
      antagonist activity of Ro-318220 complicated such assessment at low agonist
      concentrations. Carbachol or PDBu induced cytosol to membrane translocation of
      PKC alpha. This was faster and possibly greater with PDBu, which may explain the
      lack of feedback by agonist-activated PKC. These results indicate that, in SH
      SY5Y cells, PDBu activation of PKC preferentially inhibits rapid muscarinic
      receptor-mediated phosphoinositide and Ca2+ responses via suppression of
      PtdIns(4,5)P2 hydrolysis. This is at least partially through inhibition of Gq
      protein/phosphoinositidase C coupling. However, at least at high agonist
      concentrations, a major agonist-mediated PKC feedback is not present in these
      cells.

PMID- 8670171
TI  - Identification of a second human acetyl-CoA carboxylase gene.
AB  - Acetyl-CoA carboxylase (ACC), an important enzyme in fatty acid biosynthesis and
      a regulator of fatty acid oxidation, is present in at least two isoenzymic forms
      in rat and human tissues. Previous work has established the existence of a
      265,000 Da enzyme in both the rat and human (RACC265; HACC265) and a higher
      molecular-mass species (275,000-280,000 Da) in the same species (RACC280;
      HACC275). An HACC265 gene has previously been localized to chromosome 17. In the
      present study, we report cloning of a partial-length human cDNA sequence which
      appears to correspond to HACC275 and its rat homologue, RACC280, as judged by
      mRNA tissue distribution and cell-specific regulation of mRNA/protein expression.
      The gene encoding this isoenzymic form of ACC has been localized to the long arm
      of human chromosome 12. Thus, ACC is represented in a multigene family in both
      rodents and humans. The newly discovered human gene and its rat homologue appear
      to be under different regulatory control to the HACC265 gene, as judged by tissue
      specific expression in vivo and by independent modulation in cultured cells in
      vitro.

PMID- 8670172
TI  - Structural composition and functional characterization of soluble CD59:
      heterogeneity of the oligosaccharide and glycophosphoinositol (GPI) anchor
      revealed by laser-desorption mass spectrometric analysis.
AB  - CD59 (protectin) is a glycophosphoinositol (GPI)-anchored inhibitor of the
      membrane attack complex of complement found on blood cells, endothelia and
      epithelial cells. In addition to the lipid-tailed CD59, soluble lipid-free forms
      of CD59 are present in human body fluids. We have investigated the detailed
      structural composition of the naturally occurring soluble urinary CD59 (CD59u)
      using peptide mapping, anion-exchange chromatography, sequential exoglycosidase
      digestion and matrix-assisted laser-desorption mass spectrometry (MALDI-MS).
      CD59u exhibited an average M(r) of 12444 in MALDI-MS. Mass analysis of the
      isolated C-terminal peptide (T9) indicated that a GPI-anchor (at Asn-77) without
      an inositol-associated phospholipid was present in soluble CD59u. By using
      residue-specific exoglycosidases, chemical modification and MALDI-MS structures
      of seven different GPI-anchor variants were determined. Variant forms of the
      anchor had deletions and/or extensions of one or more monosaccharide units.
      Sialic acid linked to an N-acetylhexosamine-galactose arm was found in two GPI
      anchor variants. The N-linked carbohydrate side chain of CD59u (at Asn-18) also
      displayed considerable heterogeneity. The predominant oligosaccharide chains were
      fucosylated biantennary and triantennary complexes with variable sialylation.
      Mono Q anion-exchange chromatography resolved urinary CD59 into nine different
      fractions that bound equally well to the terminal complement SC5b-8 complexes.
      Despite binding to C5b-8, soluble CD59u inhibited complement lysis at an approx.
      200-fold lower efficiency than erythrocyte CD59. These results document the
      structural heterogeneity of both the GPI anchor and N-linked oligosaccharide of
      CD59 and demonstrate that the phospholipid tail is needed for the full functional
      activity of CD59. The site of cleavage between the diradylglycerol phosphate and
      inositol suggests that a mammalian phospholipase D could be involved in the
      solubilization of GPI-anchored proteins.

PMID- 8670173
TI  - Characterization of pig colonic mucins.
AB  - Pig colonic mucins isolated from the adherent mucus gel in the presence of
      proteinase inhibitors were solubilized by homogenization and the component mucins
      fractionated by CsC1 density-gradient centrifugation. Polymeric and reduced pig
      colonic mucin were both largely excluded on Sepharose CL-2B, papain-digested
      colonic mucin was included. The M(r) values of polymeric, reduced and digested
      mucins were 5.5 x 10(6), 2.1 x 10(6) and 0.6 x 10(6) respectively. This suggests
      that pig colonic mucin is comprised of 2-3 subunits, each subunit containing 3-4
      glycosylated regions. The intrinsic viscosities of polymeric, reduced and
      digested mucin were 240 ml.g-1, 100 ml.g-1 and 20 ml.g-1 respectively. Polymeric
      pig colonic mucin comprised 16% protein per mg of glycoprotein and was rich in
      serine, threonine and proline (43% of total amino acids). There were approx. 150
      disulphide bridges and 53 free thiol groups per mucin polymer. A seventh of the
      protein content was lost on reduction. This protein was particularly rich in
      proline and the hydrophobic amino acids. Papain-digested pig colonic mucin
      contained 11% protein per mg of glycoprotein and was rich in serine, threonine,
      glutamate and aspartate. All types of amino acids with the exception of aspartate
      were lost on digestion. The amino acid analysis of the proteolytically digested
      regions of pig colonic mucin are markedly different to the tandem repeat regions
      of the human mucin genes shown to be expressed in the colon.

PMID- 8670174
TI  - P2u purinoceptor regulation of mucin secretion in SPOC1 cells, a goblet cell line
      from the airways.
AB  - The SPOC1 cell, a novel goblet cell line derived from rat trachea, was tested for
      its ability to exhibit regulated mucin secretion in response to purinergic (P2)
      agonists. High-molecular mass glycoconjugates (HMMGs) purified by CsCl-density
      gradient centrifugation had a buoyant density of 1.45 g/ml. The purified HMMG
      material exhibited a single major band with an apparent molecular mass of greater
      than 1000 kDa in SDS/ polyacrylamide gels stained with silver or blotted and
      stained with soya-bean agglutinin. [3H]HMMG was resistant to proteoglycan
      degrading enzymes, but was susceptible to neuraminidase. The HMMG was approx. 91%
      carbohydrate by weight, and the glycosides were O-linked. The HMMG amino acid
      composition was enriched in Ser and Thr (sum 27%). Thus SPOC1-cell HMMG possess
      the characteristics of mucin. Mucin secretion by SPOC1 cells, grown on permeable
      supports and perfused luminally, was stimulated by ATP, UTP and adenosine 5'
      [gamma-thio]triphosphate (100 microM) 4-5-fold over a baseline of 4 ng/min. The
      three dose-effect relations were nearly identical (K0.5 approximately 4 microM).
      SPOC1 cells grown on plastic and rat tracheal epithelial primary cells responded
      similarly to ATP and/or UTP. SPOC1 cells failed to respond to other purinergic
      agonists, either luminally or serosally, and consequently seem to possess an
      apical membrane P2u purinoceptor. SPOC1-cell total RNA was probed for P2u
      purinoceptor mRNA. Using conserved primers for both reverse transcriptase and
      PCR, a single band of the predicted size was observed, which had a nucleotide
      base sequence identical with the rat P2u purinoceptor mRNA. Thus SPOC1 cells
      secrete mucin under the control of a P2u purinoceptor; they should prove useful
      in dissecting the associated cellular regulatory pathways.

PMID- 8670175
TI  - Processing of chromogranins in chromaffin cell culture: effects of reserpine and
      alpha-methyl-p-tyrosine.
AB  - Bovine chromaffin cell cultures were treated with either reserpine or alpha
      methyl-p-tyrosine for up to 10 days. Afterwards the cells were harvested and the
      degree of proteolytic processing of secretogranin II, chromogranin A and
      chromogranin B was determined by immunoblotting and HPLC followed by RIA. There
      was a significant increase in the proteolysis of all three chromogranins after 4
      6 days in the presence of reserpine. The small peptides formed in the presence of
      reserpine in vitro are also produced in vivo. A similar effect was observed with
      alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, but the response
      took up to 10 days to develop. Both drugs decreased catecholamine levels but
      reserpine was more effective, reaching a high degree of depletion after 4 days.
      In addition, experiments in vitro indicate that low millimolar amounts of either
      adrenaline (IC50 5.2 mM) or noradrenaline (IC50 2.4 mM) can significantly impair
      the proteolytic activity of recombinant murine prohormone convertase 1 when
      assayed with synthetic fluorogenic and/or peptidyl substrates. We conclude that a
      lowering of catecholamine levels in chromaffin granules leads to a concomitant
      increase in proteolytic processing of all secretory peptides. Apparently within
      chromaffin granules the endoproteases are inhibited by catecholamines and thus
      their removal leads to increased proteolysis.

PMID- 8670176
TI  - Diving behaviour and haemoglobin function: the primary structure of the alpha-
      and beta-chains of the sea turtle (Caretta caretta) and its functional
      implications.
AB  - The amino acid sequence of the alpha- and beta-chains of haemoglobin (Hb) from
      the loggerhead sea turtle (Caretta caretta) has been determined. Comparison with
      that of human Hb shows differences in several residues involved in both alpha 1
      beta 1 and alpha 1 beta 2 packing contacts. On the whole, in spite of the
      mutations, the essential characteristics of both interfaces seem to be
      maintained. The functional properties of the sea turtle Hb have been investigated
      at different temperatures and as a function of proton, chloride and organic
      phosphate concentrations. In addition to overall similarities shared with most of
      the vertebrate Hbs previously described, this molecule shows significant
      differences which could be related to the life behaviour of the turtle. In fact,
      while the shape of the Bohr-effect curve is well adapted for gas exchange during
      prolonged dives, the very small enthalpy change for O2 binding ensures that O2
      delivery becomes essentially insensitive to the temperature changes of the
      environment. Moreover, and similarly to the case of emperor penguin Hb, the small
      alkaline Bohr effect appears to be only choride-linked, since the pH dependence
      of the O2 affinity is abolished in the absence of this ion. These functional
      characteristics are discussed on the basis of the primary structure of alpha- and
      beta-chains.

PMID- 8670177
TI  - Respiratory mucins: identification of core proteins and glycoforms.
AB  - At least eight mucin apoproteins are expressed by the tracheobronchial
      epithelium, but it is not known which, if any, of these are major constituents of
      the respiratory secretions responsible for the formation of the mucus gel. To
      address this we have isolated mucins from normal, asthmatic and chronic
      bronchitic secretions. The asthmatic mucin reduced subunits were fractionated
      into four populations (I-IV) by anion-exchange HPLC. Amino acid and
      monosaccharide compositional analysis, as well as M(r) and size measurements,
      indicate that two of these populations (I and II) are glycoforms of the same or
      related apoprotein(s) and that the other populations contain two different
      apoproteins. A panel of antibodies and antisera recognizing the variable number
      tandem repeat (VNTR) of specific mucin apoproteins did not, as predicted, react
      with the glycosylated molecules, but after deglycosylation the majority of these
      probes (with the exception of those to MUC2, which were negative) reacted at a
      low level with each of the subunit populations. In contrast, an antiserum against
      a non-VNTR sequence of MUC5AC identified one of the populations (III) as the
      MUC5AC mucin. The MUC5AC reduced subunit had an M(r) of 2.2 x 10(6) and an RG
      (radius of gyration) of 57 nm. The genetic identities of the major mucin
      (populations I and II) and a minor component (population IV) were not
      established. The MUC5AC mucin was also identified as a major component in the
      pooled normal secretions from 20 individuals, whereas in a chronic bronchitic
      sample it was only a minor constituent. Furthermore, in all these different
      respiratory secretions the MUC5AC mucin appears as a similar biochemical entity,
      as assessed by Mono Q chromatography and agarose electrophoresis, suggesting that
      it may have a well-defined pattern of glycosylation in the respiratory tract.

PMID- 8670178
TI  - Biosynthesis of anandamide and related acylethanolamides in mouse J774
      macrophages and N18 neuroblastoma cells.
AB  - Anandamide (arachidonoylethanolamide, AnNH) has been recently proposed as the
      endogenous ligand at the brain cannabinoid receptor CB1. Two alternative pathways
      have been suggested for the biosynthesis of this putative mediator in the central
      nervous system. Here we present data (1) substantiating further the mechanism by
      which AnNH is produced by phospholipase D (PLD)-catalysed hydrolysis of N
      arachidonoylphosphatidylethanolamine in mouse neuroblastoma N18TG2 cells, and (2)
      suggesting for the first time that AnNH is biosynthesized via the same mechanism
      in a non-neuronal cell line, mouse J774 macrophages, together with other
      acylethanolamides and is possibly involved in the control of the
      immune/inflammatory response. Lipids from both neuroblastoma cells and J774
      macrophages were shown to contain a family of N-acylphosphatidylethanolamines (N
      aPEs), including the possible precursor of AnNH, N-arachidonoyl-PE. Treatment
      with exogenous PLD, but not with exogenous phospholipase A2 and ethanolamine,
      resulted in the production of a series of acylethanolamides (AEs), including
      AnNH, from both cell types. The formation of AEs was accompanied by a decrease in
      the levels of the corresponding N-aPEs. Enzymically active homogenates from
      either neuroblastoma cells or J774 macrophages were shown to convert synthetic N
      [3H]arachidonoyl-PE into [3H]AnNH, thus suggesting that in both cells an enzyme
      is present which is capable of catalysing the hydrolysis of N-aPE(s) to the
      corresponding AE(s). Finally, as previously shown in central neurons, on
      stimulation with ionomycin, J774 macrophages also produced a mixture of AEs
      including AnNH and palmitoylethanolamide, which has been proposed as the
      preferential endogenous ligand at the peripheral cannabinoid receptor CB2 and,
      consequently, as a possible down-modulator of mast cells. On the basis of this as
      well as previous findings it is now possible to hypothesize for AnNH and
      palmitoylethanolamide, co-synthesized by macrophages, a role as peripheral
      mediators with multiple actions on blood cell function.

PMID- 8670179
TI  - Expression of extracellular matrix molecules in human mesangial cells in response
      to prolonged hyperglycaemia.
AB  - Post-mitotic cultures of human mesangial cells were maintained in media
      containing 4-30 mM D-glucose for up to 28 days. Changes in mRNA and protein
      levels for specific macromolecules occurred between 7 and 14 days after
      initiating hyperglycaemic conditions. Slot blot analysis showed 2-3-fold
      increases in mRNAs for collagen type I, fibronectin, versican and perlecan,
      whereas mRNA for decorin was increased by up to 20-fold. Levels of mRNAs for
      biglycan and syndecan were unaffected by hyperglycaemic culture. Reverse
      transcriptase PCR (RT-PCR) confirmed that decorin mRNA levels are greatly
      elevated and also showed increased transcription of the TGF-beta 1 gene in
      hyperglycaemic cultures. Western analysis and ELISA indicated accumulations of
      collagen types I and III, laminin and fibronectin in the cell layers and media of
      hyperglycaemic cultures with increasing time. Type IV collagen did not accumulate
      in either compartment of hyperglycaemic mesangial cell cultures. Collagen types
      I, III, and fibronectin did not accumulate in the cell layers of hyperglycaemic
      human dermal fibroblasts, indicating a cell-specific response in mesangial
      cultures. Decorin and versican, but not biglycan, were increased in the
      hyperglycaemic mesangial cell culture media. There were no apparent changes in
      core proteins for decorin and biglycan in fibroblast media. Transforming growth
      factor beta 1 (TGF-beta 1) in hyperglycaemic mesangial cell cultures increased 5
      fold after 7 days, but decreased thereafter to only approx. 2-fold after 28 days.
      The changes in TGF-beta 1 mRNA, as detected by RT-PCR, and protein followed one
      another closely.

PMID- 8670180
TI  - Characterization of cell-specific modulatory element in the murine ornithine
      decarboxylase promoter.
AB  - The promoter of the murine ornithine decarboxylase (ODC) gene contains, adjacent
      to the TATA box, a cAMP response element (CRE)-like motif that interacts with
      specific nuclear proteins. Here we examine the role of this CRE-like element
      (CREL) in ODC promoter activation in proliferating cells. Mutations that
      abolished binding of nuclear proteins to CREL influenced only marginally the cAMP
      induction of the reporter constructs driven by 1.6 kb of the ODC promoter.
      Instead, these mutations altered the basal promoter function in a cell-specific
      manner, in that they reduced the promoter activity in CV-1 cells, but increased
      it in NIH/3T3, CHO and HeLa cells. Thus, depending on the cell type, the CREL
      motif is able to confer either repression or activation on ODC gene
      transcription. In contrast with 1.6 kb promoter constructs, the same mutations in
      the context of a shorter sequence (proximal 133 nt) reduced the promoter strength
      in all cell types studied. The ability of the CREL element to attenuate
      transcription seems to be connected with the function of some upstream regulatory
      elements. Differences in nuclear proteins binding to CREL, as studied by
      electrophoretic mobility shift assays (EMSAs), did not explain the findings on
      cell-type specificity in transcriptional activation, as mutations in CREL
      abrogated formation of specific CREL-protein complexes in all cell lines
      examined. The protein complexes interacting with CREL were not recognized by
      antibodies specific for CRE-binding proteins CREB-1 and CREB-2, or activating
      transcription factors ATF-1, ATF-2 and ATF-3. EMSA experiments also demonstrated
      co-operative interactions between the CREL motif-binding proteins and other
      nuclear proteins, such as Sp1, interacting with CG-rich sequences of the
      promoter. In conclusion, the proximal ODC promoter contains a well-conserved
      regulatory element, which is clearly different from the CRE/ATF element. This
      motif acts in concert with other distal and proximal elements in a complex cell
      specific manner.

PMID- 8670181
TI  - Albumin binding of unconjugated [3H]bilirubin and its uptake by rat liver
      basolateral plasma membrane vesicles.
AB  - Using highly purified unconjugated [3H]bilirubin (UCB), we measured UCB binding
      to delipidated human serum albumin (HSA) and its uptake by basolateral rat liver
      plasma membrane vesicles, in both the absence and presence of an inside-positive
      membrane potential. Free UCB concentrations ([Bf]) were calculated from UCB-HSA
      affinity constants (K'f), determined by five cycles of ultrafiltration through a
      Centricon-10 device (Amicon) of the same solutions used in the uptake studies. At
      HSA concentrations from 12 to 380 microM, K'f (litre/mol) was inversely related
      to [HSA], irrespective of the [Bf]/[HSA] ratio. K'f was 2.066 x 10(6) + (3.258 x
      10(8)/[HSA]). When 50 mM KC1 was isoosmotically substituted for sucrose, the K'f
      value was significantly lower {2.077 x 10(6) + (1.099 x 10(8)/[HSA])}. The
      transport occurred into an osmotic-sensitive space. Below saturation ([Bf] < or =
      65 nM), both electroneutral and electrogenic components followed saturation
      kinetics with respect to [Bf], with K(m) values of 28 +/- 7 and 57 +/- 8 nM
      respectively (mean +/- S.D., n = 3, P < 0.001). The Vmax was greater for the
      electrogenic than for the electroneutral component (112 +/- 12 versus 45 +/- 4
      pmol of UCB. mg-1 of protein. 15 s-1, P < 0.001). Sulphobromophthalein trans
      stimulated both electrogenic (61%) and electroneutral (72%) UCB uptake. These
      data indicate that: (a) as [HSA] increases, K'f decreases, thus increasing the
      concentration of free UCB. This may account for much of the enhanced hepatocytic
      uptake of organic anions observed with increasing [HSA]. (b) UCB is taken up at
      the basolateral membrane of the hepatocyte by two systems with K(m) values within
      the range of physiological free UCB levels in plasma. The electrogenic component
      shows a lower affinity and a higher capacity than the electroneutral component.
      (c) It is important to calculate the actual [Bf] using a K'f value determined
      under the same experimental conditions (medium and [HSA]) used for the uptake
      studies.

PMID- 8670182
TI  - Expression of calponin mRNA in porcine aortic endothelial cells.
AB  - Using reverse transcription polymerase chain reaction (RT-PCR), we determined the
      expression of the mRNAs for basic calponin isoforms, namely h1 and h2 forms, in
      the porcine aortic endothelial cells (PAECs) and aortic smooth muscle cells
      (PASMCs). The mRNAs for both h1 and h2 calponin isoforms were expressed in PAECs
      as well as in PASMCs. However, the expression of h2 isoform mRNA was more
      abundant than h1 isoform in PAECs, while h1 isoform was more abundant than h2 in
      PASMCs. These findings indicated the existence of calponin mRNA and the
      predominance of h2 over h1 calponin isoform in PAECs. It is suggested that h2 as
      well as h1, calponin isoform might have a physiological role in vascular
      endothelial cell. This is the first report which describes the existence of
      calponin h2-dominant cells.

PMID- 8670183
TI  - Accumulation of somatic nucleotide substitutions in mitochondrial DNA associated
      with the 3243 A-to-G tRNA(leu)(UUR) mutation in encephalomyopathy and
      cardiomyopathy.
AB  - To understand the pathogenesis of mitochondrial encephalomyopathy and
      cardiomyopathy, we analyzed the sequence heterogeneity of the skeletal muscle
      mitochondrial DNA from a patient with Mitochondrial Encephalomyopathy, Lactic
      Acidosis, and Stroke-like episodes (MELAS). A mtDNA segment of 347 bp amplified
      from the total DNA was cloned into a vector. Analysis of 60 independent clones
      (20,800 bp in total) revealed the 3243 A-->G transition in all the sequenced
      clones and additional nucleotide substitutions at 5 sites in 10 clones. The
      frequency of mutant clones (10/60) in the MELAS patient was significantly higher
      [chi2 = 10.909, P < 0.05] than that in an age-matched skeletal muscle control
      (0/60) as well as in a normal placenta (2/60). These results support our
      hypothesis that secondary somatic mtDNA mutations can be initiated by the 3243 A-
      >G mutation and that the accumulation of somatic mutation in individuals with
      deleterious inherited mitochondrial genotype can contribute to the progressive
      mitochondrial dysfunction in MELAS.

PMID- 8670184
TI  - Angiotensin II attenuates vascular contractility in the rabbit mesenteric artery.
AB  - We observed the effects of angiotensin II (AII) on the contractile response and
      the Ca2+ transient induced by high K+ solution in the rabbit mesenteric artery.
      In the control condition, the repeated application of high K+ solution with 90
      min interval induced a gradually increasing contraction, which was accompanied
      with a significant elevation of the intracellular calcium concentration
      ([Ca2+]i). Treatment of the tissue with AII for one to two hours abolished the
      incremental response of the contraction. The change in [Ca2+]i induced by high K+
      solution, however, was not significantly different with and without treatment
      with AII. Pretreatment of the tissue with actinomycin D abolished the inhibitory
      action of AII on the incremental contraction, indicating the involvement of a
      transcriptional process. These results indicate that AII impairs vascular
      contractility through the modulation of Ca(2+)-sensitivity of the contractile
      machinery.

PMID- 8670185
TI  - Detection of DNA fragments encompassing the deletion junction of mitochondrial
      genome.
AB  - Deletions and occasional duplications in mitochondrial DNA have been known to be
      present in mitochondrial diseases and in aged tissues. The junctional sequences
      of the rearrangements must be determined for detecting duplication, but its
      procedures seem laborious for routine examination. The joint method of long
      polymerase chain reaction plus digestion by three restriction enzymes provides a
      simple method to detect and map the deletion sites of mitochondrial DNA.

PMID- 8670187
TI  - Bone cells required for osteoclastic resorption but not for osteoclastic
      differentiation.
AB  - It is generally considered that osteoblastic cells are essential for osteoclast
      formation. We tested the ability of hemopoietic tissue to differentiate
      osteoclastic characteristics in the absence of osteoblastic cells. We found that
      large numbers of calcitonin-receptor positive (CTRP) cells can be induced by
      prostaglandin E2 and 1,25(OH)2 vitamin D3, in cultures of hemopoietic mouse
      spleen. Moreover, spleen stromal cells were equivalent to bone marrow stromal
      cells in CTRP-cell induction. The spleen CTRP cells did not resorb bone, but were
      rapidly induced to full resorptive activity upon osteoblast addition. Thus, bone
      cells may not be essential for osteoclast formation, but rather are required to
      activate and regulate the resorptive function of mature osteoclasts.

PMID- 8670186
TI  - Inhibition of proliferation of chondrocytes by specific receptors in response to
      retinoids.
AB  - All-trans retinoic acid inhibited the proliferation of chondrocytes derived from
      rat xiphoid cartilage when added to the culture medium at 10(-10)-10(-8) M.
      Proliferation of mouse clonal osteoblastic cells was also inhibited to a
      significant extent by all-trans retinoic acid. However, no such inhibitory
      effects on rat smooth muscle cells and human fibroblasts were observed. Flow
      cytometric analyses of chondrocytes labeled with propidium iodide revealed that
      all-trans retinoic acid arrested chondrocytes at the G1 phase of the cell cycle.
      Since 9-cis retinoic acid, which is synthesized enzymatically from all-trans
      retinoic acid, also inhibited the proliferation of chondrocytes, we investigated
      the subtypes of retinoic acid receptors in chondrocytes. Northern blot analysis
      revealed high levels of mRNA for retinoid X receptor alpha (RXR alpha), moderate
      levels of mRNA for retinoic acid receptor gamma (RAR gamma), and low levels of
      mRNA for RAR alpha and RXR beta. The mRNA for RAR beta and RXR gamma were not
      detected. These results suggest that retinoids are associated with the inhibition
      of proliferation of chondrocytes via both families of nuclear receptors, namely,
      RARs and RXRs.

PMID- 8670188
TI  - Measurement of activin B in human saliva and localization of activin subunits in
      rat salivary glands.
AB  - The present paper is the first report to demonstrate that measurable amounts of
      activin B are secreted into the saliva. The results show wide fluctuations in
      activin B concentrations during the menstrual cycle with peak values detected at
      the follicular phase. Estrogen replacement therapy was found to increase salivary
      activin B levels in post-menopausal subjects. The concentration in males was
      negligible. These data suggest that activin B concentrations in the human saliva
      may be under hormonal regulation and propose that salivary activin B measurements
      may prove useful in investigating the as yet less well defined local and/or
      physiological roles of activin B. The present paper reports, in addition, the
      immunohistochemical localization of activin/inhibin subunits in the duct systems
      of the rat submandibular, sublingual and parotid salivary glands.

PMID- 8670189
TI  - The phosphorylation state of the 110 kDa component of the yeast spindle pole body
      shows cell cycle dependent regulation.
AB  - The 110 kDa component of the yeast spindle pole body (SPB) encoded by the
      SPC110/NUF1 gene is an essential protein which is important for the generation of
      a functional mitotic spindle in the yeast Saccharomyces cerevisiae. Spc110p
      exists in a number of forms which differ in mobility upon separation by SDS
      polyacrylamide gel electrophoresis. We show that this heterogeneity is due to
      differential phosphorylation on serine or threonine residues and that Spc110p
      phosphorylation varies throughout the cell cycle. Specifically, the
      phosphorylated form Spc110p appears as cells progress from S-phase and is
      coincident with the presence of preanaphase mitotic spindles. Thus
      phosphorylation of Spc110p occurs at the stage in the cell cycle where SPBs
      acquire the competence to organize a mitotic spindle and could therefore
      represent an important regulatory event.

PMID- 8670190
TI  - Different pathways of inhibitory effects of wortmannin on exocytosis are revealed
      by video-enhanced light microscope.
AB  - Exocytosis of secretory granules, including histamine, in rat basophilic leukemia
      (RBL-2H3) cells, which exhibit Ca(2+)-dependent secretion of granules when
      stimulated with antigen or Ca(2+)-ionophore (A23187), was observed under a video
      enhanced light microscope. Exocytotic events of individual granules including
      fusion, extrusion, and membrane retrieval were visualized in individual cells
      stimulated with antigen or A23187. Exocytosis of granules stimulated with A23187
      showed two peaks in its time courses. The earlier one of the peaks was inhibited
      by wortmannin ( > 100 nM), as an inhibitor of myosin light chain kinase (MLCK),
      and the other was not. Exocytosis by antigen-stimulation, however, showed only
      one peak, which was inhibited by low concentration of wortmannin ( < 50 nM) as an
      inhibitor of phosphatidylinositol 3-kinase (PI3-kinase). These results indicate
      that quantitative analysis of exocytosis visualized by video-enhanced light
      microscope reveals two different pathways, through P13-kinase and MLCK, of
      inhibitory effects on exocytosis by wortmannin in RBL-2H3 cells.

PMID- 8670191
TI  - Expression of biologically active isoforms of the tumor angiogenesis factor VEGF
      in Escherichia coli.
AB  - Vascular endothelial growth factor (VEGF) was identified as an endothelial cell
      specific mitogen that induces angiogenesis and vascular permeability in vivo.
      VEGF is a homodimeric protein which contains three intramolecular and two
      intermolecular disulfide bridges. Here, we report on an efficient procedure for
      recombinant production of VEGF isoforms VEGF121 and VEGF165 in Escherichia coli.
      The proteins were solubilized from inclusion bodies, refolded, and purified by
      chromatographic methods. The final protein products were almost completely in the
      dimeric conformation, bound to VEGF receptor FLT1 with a Kd of 30 pM, stimulated
      proliferation of human umbilical vein endothelial cells half-maximally at a
      concentration of 30 pM, and induced in vivo neovascularization and vascular
      permeability on the chicken chorioallantoic membrane.

PMID- 8670192
TI  - Melatonin protects LDL from oxidation but does not prevent the apolipoprotein
      derivatization.
AB  - Protective effect of melatonin against Cu++ induced peroxidative modification of
      low density lipoprotein (LDL) was studied in vitro. Melatonin was used for this
      purpose because of its known scavenging capacity against hydroxyl and peroxyl
      radicals. It was demonstrated by the diene formation kinetic analysis that
      melatonin protected polyunsaturated fatty acids of LDL lipids against
      peroxidation. Lag time duration was prolonged, peak time was delayed, whereas
      rate of diene formation was decreased in melatonin treated LDL; however,
      parameters related to apolipoprotein (apo-B) showed that the protein was
      derivatized. Fluorescence, relative electrophoretic mobility, lysine residues
      analysis data, as well as the uptake by macrophages all showed properties similar
      to those of oxidised LDL. Present data suggest that by-products of melatonin
      oxidation might react with lysine residues of apo-B, transforming LDL in its
      atherogenic form.

PMID- 8670193
TI  - Induction of procollagen type I gene expression and synthesis in human hepatic
      stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenals is
      related to their molecular structure.
AB  - 4-Hydroxy-2,3-nonenal (HNE) has been shown to induce procollagen type I gene
      expression and synthesis in hepatic stellate cells (HSC), i.e. the cells
      responsible for deposition of collagen and other extracellular matrix proteins in
      fibrotic liver. Here we report that the stimulatory effect of HNE mostly depends
      on the contemporary presence of the hydroxyl group in position C4 and of the
      double bond between position C2 and C3 since equimolar concentrations of 2,3
      nonenal as well as of nonenal did not procollagen type I synthesis either at mRNA
      or at protein levels. Accordingly to this concept, all the other 4-hydroxy-2,3
      alkenals of different chain length tested on cultured human HSC (4-hydroxy-2,3
      hexenal, 4-hydroxy-2,3-octenal and 4-hydroxy-2,3-undecenal) strongly induced
      procollagen type I gene expression and synthesis. The stimulatory effect of 4
      hydroxy-2,3-alkenals may depend on the well known ability of these aldehydes to
      react with either SH-groups or NH2-groups of functional proteins.

PMID- 8670194
TI  - Intracellular control of IP3-independent Ca2+ oscillations in pancreatic acini.
AB  - In pancreatic acini, the high affinity cholecystokinin (CCK) receptor agonist,
      CCK-OPE which utilizes the phospholipase A2 (PLA2)/arachidonic acid (AA) pathway,
      dose-dependently increased intracellular Ca2+ spike frequency and amplitude. An
      uncoupler of proton gradients, FCCP, abolished Ca2+ oscillations and amylase
      secretion induced by CCK-OPE. Furthermore, FCCP or decreasing extravesicular pH
      inhibited ATP-dependent 45Ca2+ uptake into the endoplasmic reticulum (ER)
      fraction. On the other hand, cytosolic acidification induced by Na(+)-free medium
      led to Ca2+ oscillations. Depletion of intracellular ATP by antimycin resulted in
      an abolition of the response to CCK-OPE. Administration of the K+ ionophore,
      valinomycin, abolished the action of CCK-OPE. Decreasing K+ concentrations
      outside the ER vesicles inhibited ATP-dependent 45Ca2+ uptake and AA-induced
      45Ca2+ release. Caffeine inhibited the actions of CCK-OPE, whereas ryanodine did
      not have any effects. These data suggest that IP3-independent Ca2+ oscillations
      mediated by the PLA2 cascades involve the release of intracellular Ca2+ by AA and
      reuptake of Ca2+ by an ATP-dependent Ca2+/H+ antiport. Furthermore, the presence
      of K+ membrane potential gradient across the ER membrane is required for normal
      Ca2+ oscillations.

PMID- 8670195
TI  - Identification and characterization of an ecto-ATPase activity in rat Sertoli
      cells.
AB  - A membrane associated extracellular ATPase (ecto) has been identified on rat
      Sertoli cells. Sertoli cell ecto-ATPase demonstrated a Km for ATP of 114 muM and
      a V(max) of 1.79 mumol/min/2 x 10(5) cells and was activated by either Mg2+ or
      Ca2+. This ecto-ATPase hydrolyzes other nucleoside triphosphates, but is inactive
      with ADP. The effects of some possible inhibitors of ectonucleotidases on the
      breakdown of extracellular ATP by Sertoli cells were also investigated.

PMID- 8670197
TI  - Tissue-specific regulation of malic enzyme by thyroid hormone in the neonatal
      rat.
AB  - Two recent studies have claimed that thyroid hormone administration accelerates
      malic enzyme gene expression in the neonatal brain in contrast to the well
      documented lack of effect of triiodothyronine on malic enzyme gene expression in
      the adult brain. Since these observations conflict with earlier observations in
      our laboratory, we reinvestigated the effect of thyroid hormone status on the
      ontogeny of malic enzyme gene expression in the neonatal rat. Neither
      hypothyroidism nor hyperthyroidism influenced the ontogenesis of malic enzyme
      activity in neonatal brain whereas the patterns of gene expression and enzyme
      activity in liver were markedly affected. Our results suggest that tissue
      specific factors in brain block thyroid hormone-induced gene expression by
      thyroid hormone.

PMID- 8670196
TI  - Requirement of multiple DNA-protein interactions for inducible expression of RNR3
      gene in Saccharomyces cerevisiae in response to DNA damage.
AB  - The RNR3 gene encodes the large subunit of ribonucleotide reductase.
      Transcription of this gene is induced 12-fold in response to DNA damage or by a
      DNA replication blocker. To investigate cis-acting regulation, deletion analysis
      of the promoter region of the RNR3 gene was performed and we identified two
      upstream-repressing sequences in the RNR3 regulatory region. An 18-base-pairs
      fragment, termed DNA-damage responsive element 1 (DRE1) located between -212 and 
      194 in this region was found to be essential for the induction of RNR3. This
      fragment contained a negatively acting sequence where a protein factor bound to
      the region during normal growth but disappeared by exposure to 4-nitroquinoline-1
      oxide. The other repressive element homologue to DRE1 was located at -263 to 
      254. One possible upstream-activating sequence which regulates the basal
      expression of RNR3 was also found. These results show that at least three
      potential cis-elements are necessary for the inducible expression of yeast
      expression of yeast RNR3 in response to DNA damage.

PMID- 8670198
TI  - Detection of HOXA1 expression in human breast cancer.
AB  - Homeodomain-containing proteins are transcription factors that regulate the
      coordinated expression of multiple genes involved in development, differentiation
      and malignant transformation. To better understand the role played by these
      proteins in breast cancer cells, we demonstrate, using semi-quantitative RT-PCR
      experiments, that progestin induces HOXA1 mRNAs in MCF7 cells. This is the first
      evidence of regulation of a HOX gene by steroids. Moreover, we detected HOXA1
      expression in a variety of human breast cancer lesions, suggesting that HOXA1 may
      be required for the establishment of breast cancer cells phenotype. We propose
      that HOXA1 gene could be one of the orchestrators that regulate breast epithelial
      cell differentiation and that alteration of HOXA1 expression could play a role in
      breast cancer progression.

PMID- 8670199
TI  - Identification of the proteolytic enzyme which cleaves human p75 TNF receptor in
      vitro.
AB  - The extracellular domains of the human 55 and 75 kD TNF receptors (p55 and p75
      TNF-R) are proteolytically cleaved to produce 30 and 40 kD soluble fragments,
      respectively. In this study, the enzymatic activity involved in the cleavage of
      human p75 TNF-R, named TNF-R releasing enzyme (TRRE), was identified in the
      culture supernatant of PMA-stimulated THP-1 cells using an activity assay system
      established by our group. When THP-1 cells were stimulated with PMA, TRRE was
      released rapidly into the supernatant, reaching maximal activity within 3 hours.
      The release of TRRE into the culture supernatant depended on the concentration of
      PMA and FCS. TRRE activity was partially inhibited by chelating agents,
      suggesting that TRRE may be a metallo-protease-like enzyme. This is the first
      successful attempt to establish a stable TRRE source with a reliable assay
      system.

PMID- 8670200
TI  - Cloning, functional expression and tissue distribution of the human P2Y6
      receptor.
AB  - In order to isolate new subtypes of P2Y purinoceptors, a human placenta cDNA
      library was screened at middle stringency with a P2Y4 probe. The purification and
      the sequencing of several clones led us to identify a 984 base pair open reading
      frame encoding a new human P2Y receptor. It appeared later that this sequence
      corresponds to the human ortholog (88% amino acid identity) of the rat receptor
      recently cloned by Chang et al (J. Biol. Chem. 270, 26152-26158, 1995) and called
      P2Y6. Northern blot analysis detected human P2Y6 receptor messenger RNA in human
      spleen, placenta, thymus, intestine, and blood leukocytes. In 1321N1 cells stably
      expressing the human P2Y6 receptor, the formation of IP3 was stimulated by
      nucleotides with the following order of potency: UDP > 5-bromo-UPT > UTP > ADP >
      2-methylthio-ATP >> ATP. The P2Y6 receptor, together with the previously cloned
      P2Y4 subtype (Communi et al., J. Biol. Chem., 270, 30849-30852, 1995), belongs
      thus to a subfamily of pyrimidinoceptors inside the P2Y family.

PMID- 8670201
TI  - Suppression of the hypersensitive response in potato by acetyl salicylic acid.
AB  - Increased salicylic acid has been correlated with systemic acquired resistance in
      several plants. Inoculation of potato plants with the pathogen Phytophthora
      Infestans or inducers from the fungus, arachidonic acid and eicosapentaenoic acid
      also induce systemic acquired resistance in the plant. We now report that
      treatment of potato tuber slices with acetyl salicylic acid markedly reduces the
      resistant response of these tissues.

PMID- 8670202
TI  - cAMP and protein kinase A stimulate acidification of rat liver endosomes in the
      absence of chloride.
AB  - Endosomes and lysosomes are acidified by an electrogenic proton pump in parallel
      with a chloride conductance and in kidney both of these may be regulated by cAMP.
      In vitro exposure of isolated rat liver endosomes to cAMP, PKA and GTP-gamma S
      stimulated acidification of "early" endosomes with or without C1-, but not in the
      absence of K+. cAMP and PKA also increased acidification rates of purified "late"
      endosomes, multivesicular bodies, CURL vesicles and lysosomes. "Early" endosomes
      prepared from livers perfused with cAMP also exhibited increased rates of
      acidification. cAMP and PKA had no consistent effects on steady-state
      intravesicular pH or proton efflux rates. Thus, acidification of several types of
      liver endocytic vesicles was stimulated by cAMP and PKA in the presence and
      absence of chloride, possibly due to changes in the proton pump itself and/or a
      cation conductance.

PMID- 8670203
TI  - Bone morphogenetic protein-12 and -13 inhibit terminal differentiation of
      myoblasts, but do not induce their differentiation into osteoblasts.
AB  - Effects of bone morphogenetic protein (BMP)-12 and BMP-13, new members of the BMP
      family which belong to the transforming growth factor (TGF)-beta superfamily, on
      terminal differentiation of myoblasts were examined in C2C12 and L-6 myoblasts.
      When the myoblasts were cultured with BMP-12 or BMP-13, the expression of the
      myosin heavy chain and the formation of multinucleated myotubes mRNA in L-6
      cells. The inhibitory effects of BMP-12 and BMP-13 on myogenic differentiation
      were similar to the effects of BMP-2, though their potencies were lower than BMP
      2. Unlike BMP-2, neither BMP-12 nor BMP-13 induced alkaline phosphatase activity
      in C2C12 myoblasts. The differences in the biological activities of these new
      BMPs suggest that the intracellular signalling pathway used by BMP-12 and BMP-13
      differs from that of BMP-2.

PMID- 8670204
TI  - B-type natriuretic peptide isolated from frog cardiac ventricles.
AB  - A new natriuretic peptide with 27 amino acid residues has been isolated from
      cardiac ventricles of the bullfrog, Rana catesbeiana. Since this ventricular
      peptide had high sequence identity to B-type (brain) natriuretic peptide (BNP),
      especially to chicken BNP (74%), we named it bullfrog BNP. Thus, semi-aquatic
      amphibians have tetrapod-type BNP, but do not seem to have fish-type ventricular
      natriuretic peptide (VNP) in their ventricles. Compared with other known BNPs,
      the C-terminus of bullfrog BNP was elongated by two amino acid residues and was
      not amidated. Bullfrog BNP dose-dependently decreased arterial blood pressure in
      the bullfrog with a potency twofold greater than that of human ANP. Bullfrog BNP
      also exhibited vasodepressor, natriuretic and diuretic activities in the rat, but
      it was 1/3, 1/7, and 1/17 as potent as human ANP in this mammalian species.

PMID- 8670205
TI  - Tyrosine phosphorylation of a 94-kDa protein associated with GRB2/ASH is
      implicated in the signal transduction of hematopoietic survival factors.
AB  - Grb2/Ash is an adapter molecule that contains Src-homology (SH) 2 and 3 domains.
      We have examined Grb2/Ash-associated proteins in hematopoietic cells, and have
      noted a 94-kDa phosphotyrosine-containing protein (pp94) among them. It was shown
      that the SH2 domain of Grb2/Ash is necessary for the binding of pp94 to Grb2/Ash
      from the binding experiments using the GST Fusion proteins and the
      phosphotyrosine analogue phenylphosphate. Tyrosine phosphorylation of pp94 was
      rapid and transient, and was only observed when the cells were stimulated with
      factors that were absolutely required for survival of the cells (survival
      factors). The kinase inhibitors, staurosporine and genistein, inhibit the
      proliferation UT-7 cells. However, genistein does not inhibit the survival of the
      cells while staurosporine inhibits both the proliferation and the survival of the
      cells. Tyrosine phosphorylation of pp94 was sensitive to staurosporine but
      resistant to genistein. It is possible that tyrosine phosphorylation of pp94
      might be related to the survival rather than to the proliferation of the cells.

PMID- 8670207
TI  - A novel monoclonal antibody to N-myristoyl glycine moiety found a new N
      myristoylated HIV-1 p28gag protein in HIV-1-infected cells.
AB  - A novel monoclonal antibody was raised against a synthetic N-myristoyl glycine
      that is characteristic of all N-myristoylated proteins. The immunoreaction
      suppressed in the presence of hemocyanin as well as albumin conjugated with N
      myristoyl glycine and other N-myristoyl glycyl peptides, while underivatized and
      myristoyl amino acid proteins or various fatty acids other myristic acid exerted
      no effect. The antibody specifically reacted with N-myristoylated pp60c-src in
      human colon adenocarcinoma cells, N-myristoylated pp60v-src in Rous sarcoma virus
      infected cells, and N-myristoylated Gag precursor protein Pr55gag in HIV-1
      producing cells. Furthermore, the antibody immunoreacted with a new N
      myristoylated p28gag derived from HIV-1 gag protein. The antibody is shown to be
      a very useful tool for identification of N-myristoylated proteins.

PMID- 8670206
TI  - Src kinase plays an essential role in integrin-mediated tyrosine phosphorylation
      of Crk-associated substrate p130Cas.
AB  - A novel signaling molecule p130Cas has been shown to undergo tyrosine
      phosphorylation in response to integrin-mediated cell adhesion. In this study, we
      have attempted to identify kinases that mediate Cas phosphorylation in integrin
      signaling by examining various mutant cell lines that do not express either
      p125FAK, c-Scr, c-Fyn or c-Abl. We found that deficiency of c-Src but not of
      other kinases completely abrogated integrin-mediated Cas phosphorylation.
      Importantly, paxillin phosphorylation was not compromised in each mutant cell
      line examined. These results suggest that c-Src primarily mediates adhesion
      dependent Cas phosphorylation. As for paxillin phosphorylation, there may exist
      substantial redundancy amongst multiple kinases. Finally, adhesion-induced Cas
      phosphorylation resulted in its association with c-Crk adapter protein via the
      Crk-SH2 domain. Thus, Cas plays a role in the transmission of integrin-initiated
      signals through tyrosine phosphorylation and subsequent binding to c-Crk.

PMID- 8670208
TI  - The utility of fluorescent in vivo reporter genes in molecular cardiology.
AB  - In vivo reporter genes can be used in different ways in molecular cardiology. In
      this paper studies are presented using the green fluorescent protein and one of
      its mutants, S65T-GFP, as in vivo reporter genes. With this new molecular tool we
      studied cell type specificity of the murine ventricular myosin light chain 2
      promoter, positive cell identification prior to patch clamp procedures, and the
      use of fluorescence activated cell sorting of transiently transfected mammalian
      cells.

PMID- 8670209
TI  - Effect of insulin on the phospholipase-D activity of untreated and insulin
      pretreated (hormonally imprinted) Tetrahymena.
AB  - Insulin treatment of the unicellular Tetrahymena enormously increases the
      activity of phospholipase D (PLD) within 30 min. Insulin pretreatment (hormonal
      imprinting) does not influence basal PLD activity after 24 h. The second insulin
      treatment failed to stimulate PLD activity in insulin imprinted Tetrahymena. The
      results suggest the presence of the functional PLD activity in Tetrahymena and
      that hormonal imprinting modifies signal transduction to PLD, as previously
      reported in calmodulin activation and phophatidylinositol 4,5-bis-phosphate
      (PIP2) synthesis.

PMID- 8670210
TI  - Age-related changes in the activities of antioxidant enzymes and lipid
      peroxidation status in ventral and dorsolateral prostate lobes of noble rats.
AB  - In this investigation, the activities of five enzymes (catalase, superoxide
      dismutase, glutathione peroxidase, glutathione reductase, glucose-6
      dehydrogenase) involved in oxygen radical (OR)-detoxification and antioxidative
      defense were measured in conjunction with an index of lipid peroxidation in major
      prostatic lobes of young (2 month-old) and old (9 month-old) rats. Selective
      decreases in catalase and glutathione peroxidase activities were observed in the
      ventral prostate lobe (VP), while a general decline in the activities of all five
      enzymes studied was noted in the dorsolateral prostate lobes (DLPs) of senescent
      rats. The extent of lipid peroxidation, measured as concentrations of
      thiobarbituric acid-reactive products, was greatly elevated in both VP and DLP of
      old rats. These results demonstrate for the first time that reduction in
      antioxidant capacity and elevation in peroxidative damage occur in rat prostate
      during aging. aging. We postulate that these prooxidative alterations promote
      diseases in the aging prostate.

PMID- 8670211
TI  - Chromosomal proteins HMG-14 and HMG-17 are synthesized throughout the S-phase in
      Burkitt's lymphoma.
AB  - Here we test whether the targeting of chromosomal proteins HMG-14 and HMG-17 to
      transcriptionally active regions is due to coincidence of the synthesis of these
      proteins with the replication and assembly of active chromatin. Cells from the
      Burkitt's lymphoma line CA46 were synchronized with mimosine. The mRNA levels and
      the protein synthesis rates of HMG-14/-17 were determined at various stages
      during the S phase. The expression pattern of HMG-14/-17 was essentially constant
      throughout this phase of the cell cycle. The half-life for HMG-14/-17 protein
      corresponded to the doubling time of the cells. These results indicate that HMG
      14/-17 are synthesized throughout S-phase and persist through the cell cycle.
      Targeting of HMGs to active genes is not simply due to the timing of their
      synthesis during S phase.

PMID- 8670212
TI  - A mechanism for action of extremely low frequency electromagnetic fields on
      biological systems.
AB  - This report outlines a simple mechanism, based on the Hall Effect, by which
      static and low frequency (50-60 Hz) pulsed electromagnetic fields (PEMFs) can
      modify cation flow across biological membranes and alter cell metabolism. We show
      that magnetic fields commonly found in the environment can be expected to cause
      biologically significant interactions between transported cations and basic
      domains of cation channel proteins. We calculate that these interactions generate
      forces of a magnitude similar to those created by normal transmembrane voltage
      changes known to gate cation channels. Thus PEMFs are shown to have the potential
      of regulating flow through cation channels, changing the steady state
      concentrations of cellular cations and thus the metabolic processes dependent on
      cation concentrations.

PMID- 8670213
TI  - Cloning and quantification of galanin-1 receptor expression by mucosal cells
      lining the human gastrointestinal tract.
AB  - Recent studies suggest that galanin receptors may be expressed by mucosal
      epithelial cells lining the GI tract and play a role in regulating ion transport.
      However, no information exists as to which receptor subtype is expressed by these
      mucosal cells, or the relative distribution of such receptors within the GI
      tract. In this study we cloned the human galanin-1 receptor (huGal 1-R) from
      small intestinal RNA, and demonstrate its expression in endoscopically obtained
      mucosal pinch biopsies by RT-PCR from the esophagus to the rectum. Semi
      quantitative PCR (SQ-PCR) was performed and revealed the largest amount of huGal
      1-R message in the duodenum and the least amount in the gastric fundus. This
      study for the first time directly demonstrates the presence and quantity of huGal
      1-R message in human G1 tract mucosal epithelial cells, and suggests that this
      subtype is of primary importance in regulating galanin-induced changes in
      intestinal absorption.

PMID- 8670214
TI  - Trypanosoma cruzi: participation of intracellular Ca2+ during metacyclic
      trypomastigote-macrophage interaction.
AB  - The interaction between Trypanosoma cruzi, the protozoan causative of Chagas's
      disease, and its host cell is a complex process in which multiple signals
      including those of Ca2+ are involved. Macrophage cytosolic Ca2+ levels were
      studied during the interaction of these cells with metacyclic trypomastigotes of
      T. cruzi, since this event is an initial step in the natural infection. In this
      model we detected an increase in the macrophage cytosolic Ca2+ concentration
      after infection, or incubation with a metacyclic lysate or with isolated
      membranes, suggesting that these increments could be necessary for parasite
      invasion. This fact was confirmed by treating macrophages with a Ca2+ chelator or
      a Ca2+ channel antagonist which decreased the infection percentages while
      parasitization levels increased after treatment with Ca2+ channel agonist.

PMID- 8670215
TI  - Heterogeneity of the human Secretor alpha(1,2)fucosyltransferase gene among
      Lewis(a+b-) non-secretors.
AB  - The human Secretor alpha (1,2)fucosyltransferase gene determines the ABH secretor
      status and influences the Lewis phenotype of an individual. Two different se
      alleles with point mutations, C571 to T and G849 to A respectively, in the coding
      region were identified in Le(a+b-) non-secretors from one of the Taiwanese
      indigenous groups. The base substitutions predict the alteration of Arg191 and
      Trp283 to stop codons respectively, resulting in deletion of the Secretor
      enzyme's C-terminal segment. Both alleles of the Secretor locus in all Le(a+b-)
      non-secretors, but not in Le(a+b-) secretors, were further demonstrated to be
      either one of these two se alleles with nonsense mutations. These results suggest
      two new molecular bases for the null se allele responsible for the formation of
      the non-secretor phenotype.

PMID- 8670216
TI  - Retinoic acid differentially up-regulates the gene expression of retinoic acid
      receptor alpha and gamma isoforms in embryo and adult rats.
AB  - The diverse biological effects of retinoic acid (RA) are exerted by its nuclear
      receptor-mediated gene expression. One of the two nuclear retinoic acid receptor
      subfamilies is composed of three subtypes of the all-transretinoic acid receptor
      (RAR-alpha, RAR-beta, and RAR-gamma). Furthermore, several isoforms are generated
      from each of three RARs by differential promoter usage and/or alternative
      splicing. It is thus thought that the developmental stage-specific actions of RA
      are modulated through the spatio-temporal expression of the subtype and isoforms
      of RARs. In this study, the auto-regulation of the RAR subtypes (RAR-alpha total,
      RAR-beta total and RAR-gamma total) and their major isoforms (RAR-alpha 1, alpha
      2, RAR-beta 1, beta 2 and RAR-gamma 1, gamma 2) by RA was examined by means of
      Northern blotting in the 11.5 day embryo and maternal tissues by administering
      pregnant rats with an excess of all-trans RA. The expression of RAR-beta isoforms
      as well as the RAR-beta total was auto-regulated by RA in all maternal tissues
      and embryos examined. The gene expression of RAR-alpha 2, which was not affected
      by RA in the maternal tissues, was up-regulated in embryos, though there were no
      significant effects of RA on the levels of RAR-alpha 1 and the alpha total in the
      maternal tissues and the embryos. Likewise, RA did not affect the levels of RAR
      gamma 1 and gamma total. However, unlike RAR-alpha 2, RAR-gamma 2 expression was
      up-regulated by RA only in the maternal tissues. Thus, these results indicates
      that two retinoic acid receptor isoforms (RAR-alpha 2 and RAR-gamma 2) are
      differentially auto-regulated in embryo and adult rats.

PMID- 8670217
TI  - Dermal papilla cells derived from beard hair follicles secrete more stem cell
      factor (SCF) in culture than scalp cells or dermal fibroblasts.
AB  - As stem cell factor (SCF) and its receptor, c-kit, are involved in hair
      pigmentation, SCF is probably produced in the skin, possibly by the regulatory
      follicular dermal papilla. Since androgens often alter the type and color of
      hair, probably via the dermal papilla, they may regulate its SCF production. SCF
      produced by beard and non-balding scalp dermal papilla cells in the presence, or
      absence, of 10nM testosterone was assayed by ELISA. After 24 h, beard cells
      produced significantly (p = 0.001) more SCF than scalp cells, while beard and
      scalp fibroblasts secreted significantly (p = 0.04) less SCF. Testosterone in
      vitro had no effect on SCF secretion. These results support the hypotheses that
      the dermal papilla is a local source of SCF in hair follicles and that androgens
      would alter SCF production only at specific points of the hair cycle.

PMID- 8670218
TI  - Preparation, purification, and spectrophotometric characterization of cytochrome
      P450 1A2 conjugated with polyethylene glycol monomethyl ether.
AB  - Rabbit cytochrome P450 1A2 was modified with succinimidyl carbonate poly(ethylene
      glycol) monomethyl ether, purified by size exclusion high performance liquid
      chromatography, and lyophilized. Modification of cytochrome P450 1A2 caused no
      structural deformation of the heme as evidenced by the similarity of the spectral
      signatures for both the ferric form and the ferrous-CO complex to the respective
      forms for the unmodified enzyme. Ethoxyresorufin O-deethylation activity in the
      presence of iodosobenzene for the modified enzyme was comparable to that of the
      native enzyme.

PMID- 8670219
TI  - Rabbit liver phosphofructokinase: rapid purification and phosphorylation site
      identification.
AB  - Liver phosphofructokinase can be selectively precipitated by the addition of
      protamine sulfate to a heat-treated crude extract and redissolved, giving nearly
      full recovery of catalytic activity in combination with a 67-fold increase in
      specific activity. We have incorporated protamine sulfate precipitation into a
      five step purification procedure that can be completed in one day--giving 47%
      recovery of electrophoretically homogeneous liver phosphofructokinase having a
      specific activity of 50 units/mg. The radio-labeled fragment isolated from a CNBr
      digest of liver phosphofructokinase that has undergone in vitro phosphorylation
      catalyzed by the cAMP-dependent protein kinase has the sequence
      AEYVSGELEHVTRRSLS.

PMID- 8670220
TI  - DNA triple helix stabilization by bisguanidinyl analogues of biogenic polyamines.
AB  - The polycationic nature of biogenic polyamines such as spermine (SPM, 1) and
      spermidine (SPD, 2) plays an important role in selective binding to polyanionic
      nucleic acids. These interactions are mediated by electrostatic and hydrogen
      bonding forces which led to stabilization of DNA duplexes and triplexes.
      Transformation of primary amino groups in these molecules into corresponding
      guanidinium functions is expected to amplify the electrostatic component
      resulting in improved binding. An easy chemical transformation route as described
      here gives rise to bisguanidinated derivatives of spermine (SPMG, 3) and
      spermidine (SPDG, 4). Both enhances DNA duplex stability over the parent
      polyamines whereas SPMG is more selective for stabilization of DNA triplexes even
      at pH 7.0. The results have implication for designing of new DNA binding ligands.

PMID- 8670221
TI  - Human growth hormone deletion mutant (hGH44-191) binds with high affinity to
      lactogenic receptors but not to somatogenic receptors.
AB  - The carboxyl-terminal hGH fragment, hGH44-191, displays diabetogenic activity. To
      understand whether this biological activity is mediated through somatogenic or
      lactogenic receptors, we investigated the ability of hGH44-191 to bind both
      receptor classes. We found that hGH44-191 could not compete with [125I]hGH or
      [125I]bGH for bovine liver somatogenic binding sites. Additionally, hGH44-191
      could not displace [125I]hGH from the somatogenic receptor sites when human liver
      microsomes were used as the receptor source. In contrast, hGH44-191 effectively
      competed with [125I]hGH for lactogenic receptor sites of lactating mammary gland
      microsomes and of bovine liver microsomes. In summary, hGH44-191 does not bind to
      somatogenic receptors but does not bind to lactogenic receptors. These data
      suggest that the biological actions of hGH44-191 could be mediated through
      lactogenic receptors.

PMID- 8670222
TI  - The primary structure of rat ribosomal protein L14.
AB  - The amino acid sequence of the rat 60S ribosomal subunit protein L14 was deduced
      from the sequence of nucleotides in two recombinant cDNAs. Ribosomal protein L14
      has 213 amino acids (the NH2-terminal methionine is removed after translation of
      the mRNA); the molecular weight is 23,193. Hybridization of the cDNA to digests
      of nuclear DNA suggests that there are 6 to 8 copies of the L14 gene. The mRNA
      for the protein is about 800 nucleotides in length. Rat L14 is related to a
      number of previously unidentified ribosomal proteins from other eukaryotes but
      not to any from archaebacteria or eubacteria. The carboxyl-terminal amino acid
      sequences of rat L14 and of chicken histone H1 are related. Mutation of the
      Drosophila melanogaster homolog of rat L14 causes a severe Minute phenotype.

PMID- 8670223
TI  - Overexpression of phospholipid hydroperoxide glutathione peroxidase suppressed
      cell death due to oxidative damage in rat basophile leukemia cells (RBL-2H3).
AB  - The role of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in the
      cellular defense against oxidative stress was investigated in a novel cell model.
      We isolated stable transfectants of RBL-2H3 cells that overexpressed PHGPx. The
      activity of PHGPx in RBL2H3 cells that had been transfected with the 761bp cDNA
      for rat PHGPx (RPHGPx2) that we had cloned previously was 3.8 times higher than
      that in parent cells and in cells that had been mock-transfected with the vector
      without a cDNA insert. Cells that overexpressed PHGPx were three times more
      resistant than parent cells and mock-transfected cells to the cytotoxic effects
      of an radical initiator (AAPH) that induced the oxidative stress. This resistance
      to damage by AAPH of cells that overexpressed PHGPx was not observed after
      pretreatment with buthionine sulfoximine (BSO), an inhibitor of the synthesis of
      glutathione. Overexpression of PHGPx could suppress the peroxidation of membrane
      lipids and, in particular, the production of phosphatidylcholine hydroperoxide by
      AAPH in RBL2H3 cells. PHGPx was also able to prevent cell death in response to
      extracellular attack by a lipid peroxide. This is the first report to indicate
      directly that PHGPx can scavenge phosphatidylcholine hydroperoxide, which induces
      oxidative damage at the cellular level.

PMID- 8670224
TI  - High-level expression of mouse inducible nitric oxide synthase in Escherichia
      coli requires coexpression with calmodulin.
AB  - We report a method to generate and purify large quantities of fully active mouse
      iNOS from E. coli, and show that calmodulin coexpression is essential to generate
      the active iNOS. E. coli were transformed with a plasmid containing mouse iNOS
      with a six-histidine tag on its N-terminus or were cotransformed with piNOS and a
      distinct plasmid that contained human calmodulin. Protein expression was induced
      by IPTG followed by culture at room temperature. Coexpression with calmodulin
      enabled production of active iNOS (20 mg/L culture), of which half could be
      recovered in pure form by sequential metal chelate and 2', 5' ADP Sepharose
      chromatography. The calmodulin-replete iNOS was dimeric, contained normal
      quantities of heme, flavins, and tightly bound calmodulin, and had high NO
      synthesis activity (0.7 - 1.2 mumol NO/min per mg). In contrast, calmodulin
      deficient iNOS was monomeric, devoid of flavins and heme, and had no NO synthesis
      activity. We conclude that calmodulin is essential to fold and stabilize mouse
      iNOS.

PMID- 8670225
TI  - Alpha-subunit of farnesyltransferase is phosphorylated in vivo: effect of protein
      phosphatase-1 on enzymatic activity.
AB  - Farnesyltransferase is a heterodimer consisting of a 49 kDa alpha-subunit and a
      46 kDa beta-subunit. In this report, we demonstrate that the endogenous
      heterodimeric farnesyltransferase protein is phosphorylated at the alpha-subunit
      in vivo and phosphorylation plays a role in the regulation of farnesyltransferase
      activity. In vivo 32P-labeling of PC-12 cells followed by immunoprecipitation
      with specific anti rat alpha-subunit IgG showed a labeled alpha-subunit protein
      band at an expected molecular mass of 49 kDa. Treatment of PC-12 cells with
      protein phosphatase inhibitor, Calyculin A, resulted in a decrease in FTase
      activity, and phophoserine/phosphothreonine-specific protein phosphatase-1
      treatment of PC-12 and GM37 cell extracts resulted in 100% and 375% increase in
      farnesyltransferase activity, respectively, compared to untreated extracts.

PMID- 8670226
TI  - Native lipoproteins inhibit platelet activation induced by oxidized lipoproteins.
AB  - Copper-catalyzed oxidation of low-density lipoproteins (LDL) (0.8 g protein/l
      LDL, 20 mumol/l CuSo4, 37 degrees C) resulted in the formation of thiobarbituric
      reactive substances that was substantially completed at 24 hrs whereas their
      formation from high-density lipoproteins (HDL) plateaued at only 25% of that
      amount after 8 hrs. The oxidized lipoproteins induced aggregation and increases
      in [Ca2+]i in washed platelets, but not in platelet-rich plasma, and these
      activating effects were not inhibited by aspirin or EGTA but were inhibited by
      both of the native lipoproteins. These results show that oxidized HDL, like
      oxidized LDL, have platelet activating ability and suggest that the native
      lipoproteins may play a crucial role in preventing the oxidized lipoprotein
      mediated platelet activation.

PMID- 8670227
TI  - A sensitive RNase protection assay to detect transcripts from potentially
      functional human endogenous L1 retrotransposons.
AB  - A high background of read-through transcripts from degenerate human L1
      retrotransposons is present in almost all human cell types. This prevents the
      detection of RNA transcripts from potentially functional elements. To overcome
      this, we have developed an RNase protection assay based on the reconstructed
      consensus sequence for the 5' end of the major L1 family. In the human Ntera2D1
      teratocarcinoma cell line, this assay readily detected L1 transcripts that were
      located primarily in the cytoplasm and where 20% were in filterable particles. By
      this assay, potentially functional L1 elements are also transcriptionally active
      in lymphocytes from some but not all normal individuals. Together with the full
      length protection product, there were three other discrete L1 RNAs, two of which
      (305 and 275 bases) were transcribed from the 5' end of the L1 element. These
      smaller L1 RNAs do not appear to be derived from transcripts from divergent L1
      families but are either discrete shorter transcripts or specifically processed
      products from longer initial transcripts.

PMID- 8670228
TI  - Induction of CD38/NADase and its monoclonal antibody-induced tyrosine
      phosphorylation in human leukemia cell lines.
AB  - We previously reported that CD38 characterized as an ecto-enzyme of NAD+
      glycohydrolase (NADase) was specifically induced by retinoic acid (RA) in human
      promyelocytic leukemia HL-60 cells and that anti-CD38 monoclonal antibody (mAb)
      induced tyrosine phosphorylation of cellular proteins in the RA-differentiated
      cells. In the present study, we found that CD38/NADase was induced in human
      monocytic leukemia THP-1 cells not only by RA but also by dibutyryl cAMP, which
      had no effect on the induction of CD38 in HL-60 cells. Similarly in the RA
      differentiated HL-60 cells, tyrosine phosphorylation by anti-CD38 mAb was also
      observed in the CD38-expressing THP-1 cells, regardless of whether CD38 was
      induced by RA or dibutyryl cAMP. Such tyrosine phosphorylation was, however, not
      observed in human lymphoblastic leukemia Jurkat cells which had been treated by
      RA to produce CD38. Thus, the induction of CD38/NADase appeared to be not limited
      for RA-dependent differentiation and not always linked to protein-tyrosine
      phosphorylation in human leukemic cell lines.

PMID- 8670229
TI  - Subdomain structure of the matrix attachment region located within the mouse
      immunoglobulin kappa gene intron.
AB  - Using the matrix attachment region (MAR) derived from Ig kappa gene intron, we
      assessed the importance of internal subregions required for the specific binding
      to the nuclear matrix. Relative affinities of MAR subfragments were compared in
      an in vitro binding reaction with isolated matrix. Cleavage at the near-centric
      MboII site generated two subfragments retaining a significant binding affinity.
      Dimerization of these subfragments greatly increased the affinity. Only a partial
      segment (130 bp) of the 3' fragment was necessary to restore the binding. The
      dimerization effect was lost when the monomer units were separated by nonMAR
      spacers of 500 bp <. This bipartite organization of Ig kappa MAR could be a
      general feature of AT-rich MARs, regardless of their genomic locations.

PMID- 8670230
TI  - Insulin-like growth factor 1 binding protein 3 synthesis by aortic endothelial
      cells is a function of cell density.
AB  - Proliferating bovine aortic endothelial cells in culture do not express the
      insulin-like growth factor 1 binding protein 3 gene, in contrast to the genes
      encoding binding proteins 2, 4, 5, and 6. The binding protein 3 gene is activated
      only at cell confluency with continual transcription thereafter, for at least an
      eight-day post-confluent period, both in the presence or absence of serum.
      Secretion of protein product into the medium parallels transcription. DNA
      synthesis is inversely related to the amount of total insulin-like growth factor
      1 binding protein 3 in the culture medium. The addition of anti-binding protein 3
      antibody to media significantly increases the rate of DNA synthesis by
      extensively post-confluent cells. These data suggest (1) aortic endothelial cells
      are an important source of circulating binding protein 3, (2) binding protein 3
      has an inhibitory effect upon the growth of endothelial cells, (3) the triggering
      of binding protein 3 synthesis after confluency suggests a role in maintaining
      the growth-arrested monolayer state of the cells in vivo.

PMID- 8670232
TI  - Discrimination of two functions of photoreceptor cGMP phosphodiesterase gamma
      subunit.
AB  - cGMP phosphodiesterase, a key enzyme in phototransduction, is composed of P alpha
      beta and two P gamma S. P gamma has two functions in P alpha beta regulation: (I)
      an inhibitor of cGMP hydrolysis and (II) a stimulator of cGMP binding to their
      noncatalytic sites. Here we show for the first time that these functions can be
      discriminated. P gamma release by GTP-bound transducing from P alpha beta was
      stimulated by NaCl in a concentration-dependent manner. However,
      phosphodiesterase activity in membranes washed with NaCl-free buffer already
      reached the maximum level. [3H]-cGMP binding of P alpha beta in membranes washed
      with NaCl required more P gamma than that in membranes washed without NaCl. Other
      salts had a similar effect. Identical P gamma was released under different
      [NaCl]. These results indicate that P gamma for the function (I) is released in
      low [salt], but P gamma for the function (II) is released in high [salt]. These P
      gamma functions may be expressed separately in phototransduction.

PMID- 8670231
TI  - Mechanism of oxidative damage of dog kidney Na/K-ATPase.
AB  - Oxidative modification of kidney Na/K-ATPase was found to be accompanied by a
      decrease in the amount of sulfhydryl groups accessible for Elmann reagent with
      subsequent transformation of kinetic behavior of the enzyme. Oxidation of Na/K
      ATPase with 20 mM hydrogen peroxide during 20 min results in about 50% inhibition
      of its activity and subsequent transformation of complex substrate-velocity
      dependence into the simple hyperbolic curve. In terms of kinetic analysis the
      suggestion was made that partial oxidation of Na/K-ATPase by hydrogen peroxide
      results in disordering of interprotomer interaction in the oligomeric complex of
      Na/K-ATPase.

PMID- 8670233
TI  - Effects of glucosylceramide synthase inhibitor and ganglioside GQ1b on
      synchronous oscillations of intracellular Ca2+ in cultured cortical neurons.
AB  - To evaluate the role of endogenous gangliosides in synapse formation, the
      glucosylceramide synthase inhibitor, D-threo-1-phenyl-2-decanoylamino-3
      morpholino-1-propanol (D-PDMP), was used to deplete glycosphingolipids (GSLs) of
      cultured rat cerebral cortical neurons. Synapse formation between the neurons was
      estimated by the synchronous oscillation of synaptic activity monitored by fura-2
      calcium imaging. Treatment with D-PDMP resulted in dose- and time-dependent
      decreases in the frequency of synchronous oscillations. When a series of
      gangliosides (GM3, GM1, GD3, GD1b, GT1b, and GQ1b) was supplemented to the GSL
      depleted cells, only GQ1b was able to normalize the decreased frequency by D
      PDMP. These results suggest that de novo synthesis of a particular molecular
      species of the gangliosides, GQ1b, is essential for synapse formation and
      synaptic activity.

PMID- 8670234
TI  - Localization, expression, and the role in fertilization of spermosin, an ascidian
      sperm trypsin-like protease.
AB  - In order to elucidate the role of spermosin (a novel sperm trypsin-like protease)
      in ascidian fertilization, we developed an antibody against the ascidian
      spermosin: the antibody appears specific to the spermosin but not to the acrosin.
      By Western blot analysis, spermosin was found to be expressed just before and
      during the spawning season. Immunocytochemical studies have shown that spermosin
      is localized on the sperm head. It was found that the spermosin was released from
      the sperm during the sperm reaction, and the anti-spermosin antibody, but not
      control antibody, inhibited the fertilization in a concentration-dependent
      manner. These results indicate that spermosin plays an essential role in ascidian
      fertilization.

PMID- 8670235
TI  - The S-oxalin, N-acetyl-S-oxalylcysteamine, inhibits lymphocyte proliferation, IL
      2 production and utilization.
AB  - S-Oxalins are a recently described class of cell metabolites that appear to
      function as negative regulators of proliferation. Previously we have shown that
      exogenous S-oxalylglutathione (GS-Ox) inhibits the proliferation of lymphocytes
      by inhibiting the production and utilization of IL-2. In the present study the
      synthetic S-oxalin, N-acetyl-S-oxalylcysteamine (ACS-Ox), was utilized in similar
      experiments to determine whether GS-Ox itself, or possibly some metabolite formed
      following initial conversion of GS-Ox by gamma-glutamyltransferase (GGT), is
      responsible for the effects (ACS-Ox is not metabolized by GGT). ACS-Ox inhibited
      DNA synthesis in lymphocytes stimulated by concanavalin A similarly to GS-Ox. IL
      2 production and utilization and IL-2R expression were inhibited as well. ACS-Ox
      also inhibited the proliferation of IL-2 dependent cells at the same
      concentration as GS-Ox. Because the effects of GS-Ox and ACS-Ox are so similar,
      presumably the S-oxalin itself, rather than some metabolite, is responsible for
      the observed effects. Transfer of oxalyl groups from S-oxalins to various
      proteins thiols is the most likely mechanism involved.

PMID- 8670236
TI  - Linker histones inhibit T4 and Escherichia coli DNA ligases.
AB  - Based on some preliminary observations that linker histones strongly inhibit the
      activity of prokaryotic DNA ligases, we studied the effect of these histones on
      the ligation of short restriction DNA fragments by either T4 or E. coli DNA
      ligases. The inhibitory effect was strong, but it appeared only after two
      molecules of H1 bound to a approximately 200 bp-long DNA fragment. A similar
      pattern of inhibition (but at much higher concentration) was observed with the
      isolated globular domain of histone H5. That the inhibition was specific to the
      linker histones became clear when other basic proteins, such as the core histone
      octamer or cytochrome C, were tested. They did not inhibit the ligases but rather
      significantly stimulated them. The other major linker DNA-binding protein in
      chromatin, the non-histone protein HMG1, showed no significant effect on the
      ligase activity.

PMID- 8670237
TI  - Abnormalities in the mitochondrial permeability transition in diabetic rats.
AB  - Evidence of mitochondrial dysfunction in diabetes led us to examine whether
      diabetes altered the nature of the mitochondrial permeability transition. Our
      data reveal three diabetes-associated abnormalities in PT function: consistently
      delayed induction with calcium-phosphate, a variable delay with calcium-t-butyl
      hydroperoxide (t-BuOOH), and an enhanced magnitude of response. The consistently
      delayed induction in calcium and phosphate is correlated with serum glucose
      levels, and is consistent with known changes in calcium uniporter function in
      diabetics. These data expand our knowledge of diabetes-associated abnormalities
      in mitochondrial function, represent the first evidence that the PT is altered by
      chronic disease, and provide potential partial mechanistic explanations for the
      previously observed resistance of diabetic tissues to ischemia-reperfusion injury
      and the altered Ca2+ homeostasis in diabetics.

PMID- 8670239
TI  - Conserved expression of a B-type nuclear lamin in different tissues of the sea
      urchin.
AB  - To study patterns of lamin expression in sea urchins, monoclonal and polyclonal
      antibodies were used to probe 2-D immunoblots of Strongylocentrotus purpuratus
      and Lytechinus pictus embryos and adult tissues. Three major charge isoforms of a
      single M(r) 70,000 lamin are common to different tissues of S. purpuratus, and
      are accompanied by two-to-four more variable minor charge variants. L. pictus
      expresses and M(r) 70,000 lamin that is distinct from that of S. purpuratus in
      pI, yet displays essentially the same pattern of major and minor charge isoforms.
      The results demonstrate that the single lamin gene product so far identified in
      sea urchin embryos appears to be constitutively expressed in most cells, and that
      three major charge isoforms are common to these different cell types.

PMID- 8670238
TI  - Second zinc finger mutants of thyroid hormone receptor selectively preserve DNA
      binding and heterodimerization but eliminate transcriptional activation.
AB  - Transcriptional regulation by thyroid hormone is mediated through its nuclear
      receptors (TRs), which bind to target responsive elements as homodimers or as
      heterodimers with 9-cis retinoic acid receptors (RXRs). We examined the
      dimerization and functional properties of TRs containing mutations in the first
      and second zinc finger regions of the DNA binding domain. Interestingly, a
      mutation (R158G) in the loop of second zinc finger, or a chimeric mutant in which
      the second zinc finger of the glucocorticoid receptor (GR) was substituted for
      that of the TR, did not form homodimer, but still bound as a heterodimer with RXR
      alpha. Despite the presence of heterodimer formation, these mutants were
      functionally inactive in transfection assays. We conclude that sequences within
      the loop of the second zinc finger may play an important role in stability in
      vivo or transcriptional activation of the TR.

PMID- 8670240
TI  - Simultaneous measurement of intracellular pH, calcium, and tension in rat
      mesenteric vessels: effects of extracellular pH.
AB  - In rat mesenteric vessels changes in external pH (pHo) alter tension. Changes in
      intracellular pH (pHi) and calcium ([Ca2+]i) have both been suggested to underlie
      the tension changes. As no simultaneous measurements of pHi and [Ca2+]i had been
      made, however, the relative importance and temporal relationship between pHi
      [Ca2+]i and tension were unknown. In order therefore to gain a clearer
      understanding of the mechanisms involved, we have made simultaneous measurements
      of these parameters using carboxy-SNARF and INDO-1. Raising pHo caused rises in
      pHi, Ca2+ and tension. The increases in pHi preceded increases in [Ca2+]i, which
      preceded the increases in tension. Similar but opposite effects were observed
      when pHo was decreased. We conclude that the change in [Ca2+]i upon alteration of
      pHo is subsequent to that of pHi.

PMID- 8670241
TI  - Cloning of Xenopus TFIIS and its expression in oocytes and early embryos.
AB  - The transcriptional factor TFIIS has been cloned from Xenopus laevis. The length
      of the cDNA is 1668bp and contains the complete open reading frame of 303 amino
      acids. Xenopus TFIIS has high homologies to its human and mouse counterparts. In
      Northern blot analyses, TFIIS mRNAs that consisted of four different sizes were
      expressed relatively highly from the early stages of Xenopus oogenesis. During
      oocyte maturation, the pattern of Xenopus TFIIS messages showed a transient peak
      of expression. TFIIS mRNA occurred maternally and its level increased in later
      stage embryos. These data suggest that TFIIS mRNA is expressed in a
      developmentally regulated way in Xenopus laevis.

PMID- 8670242
TI  - Amino acids in highly conserved regions near the C-terminus of rat prolactin
      (PRL) play critical roles similar to those in binding of human GH to the PRL
      receptor.
AB  - The fourth helix (helix 4) in the human growth hormone (hGH) molecule plays a
      role in binding to the GH receptor as well as the PRL receptor through
      topologically different amino acids. This study investigated the function of
      amino acids in the predicted helix 4 of rat prolactin (rPRL) using site-directed
      mutagenesis. Twenty mutants for 7 amino acid residues were expressed in COS-1
      cells and their receptor binding and Nb2 proliferation activities were assayed.
      It was found that R174 (R at residue number 174), K179, and D181 are
      indispensable for PRL function, while D176, S177 and C189 are important to some
      extent. When these results were compared with those reported for binding of hGH
      to its receptors, the binding of PRL to the PRL receptor was shown to involve
      amino acids topologically similar to those in the binding of hGH to the PRL
      receptor, rather than those in the binding of hGH to the GH receptor.

PMID- 8670244
TI  - Identification and isolation of the bactericidal domains in the proteinase
      inhibitor aprotinin.
AB  - Aprotinin is a protein proteinase inhibitor of 58 amino acids, located in bovine
      mast cells which also possesses antibacterial activity. Digestion of aprotinin by
      clostripain yielded three antimicrobial oligopeptide fragments with the sequences
      RPDFCLEPPYTGPCK (residues 1-15), IIRYFYNAKAGLCQTFVYGGCR (residues 18-39) and
      AKRNNFKSAEDCMRTCGGA (residues 40-58). With the exception of residues 16 (alanyl)
      and 17 (arginyl) they cover the whole aprotinin structure. The three
      oligopeptides were synthesized and found to exert a broad spectrum of
      antimicrobial activities. Most potent was oligopeptide IIRYFYNAKAGLCQTFVYGGCR
      which at a concentration of 7 x 10(-9) M exhibited a high bactericidal activity
      against the eleven gram-positive and gram-negative bacterial strains tested. None
      of the purified oligopeptides showed any antiproteolytic activity. Our results
      suggest that aprotinin has multiple antimicrobial domains which are independent
      of the antiproteolytic function of the original molecule.

PMID- 8670243
TI  - ATP depletion affects NPM translocation and exportation of rRNA from nuclei.
AB  - Nucleophosmin/B23 (NPM) is a nucleolar phosphoprotein which shifts from nucleoli
      to the nucleoplasm in cells treated with certain cytotoxic agents (NPM
      translocation). NPM requires GTP for localization into nucleoli (J. Biol. Chem.
      268, 5823-5827, 1993). To understand more about NPM's dynamic localization, the
      effects of lowering ATP on NPM-translocation and rRNA synthesis were studied.
      When the ATP level in HeLa cells was reduced by sodium azide, NPM-translocation
      was blocked. Similar results were obtained when ATP was depleted by other agents,
      suggesting that ATP depletion was responsible for the blocking of NPM
      translocation. It was found that newly synthesized rRNA accumulated in the nuclei
      during ATP-depletion. Significantly larger than normal nucleoli were also
      observed. These results indicate that NPM may be involved in the transportation
      of newly synthesized ribosomes.

PMID- 8670245
TI  - Transcription of the rat angiotensin II type 2 receptor gene.
AB  - The promoter region of the rat angiotensin II type 2 receptor gene was cloned and
      the nucleotide sequences were determined. A computer homology search for a 1.2 Kb
      promoter region showed that there are several consensus cis DNA elements such as
      C/EBP, NF-IL6, GRE and AP1 in this region. Primer extension experiments showed
      that there is one transcription initiation site 15 bp-downstream of the TATA box.
      Deletion mutants of the 1.2 Kb segment were prepared and fused to a luciferase
      reporter gene. These type 2 receptor promoter-luciferase constructs were
      introduced into PC12W cells, a pheochromocytoma cell line expressing the type 2
      receptor, and luciferase activity was measured. It showed that (1) a DNA segment
      between -1208 bp and -749 bp suppresses the promoter activity of type 2 receptor
      gene, (2) a positive regulatory element is present in a DNA segment between -749
      bp and -216 bp; and (3) a DNA segment between -44 bp +58 bp is important for the
      basal promoter activity of the type 2 receptor gene.

PMID- 8670246
TI  - Association between plasma membrane (Ca+Mg) ATPase and calpain/calpastatin system
      in rat erythrocytes.
AB  - We studied the activity of plasma membrane (Ca+Mg)ATPase from erythrocytes of
      Milan hypertensive rat strain (MHS) and Milan low calpastatin rat strain (MLCS),
      that show an activity level of the specific calpain inhibitor, calpastatin, about
      five fold reduced in comparison with the Milan normotensive rat strain (MNS),
      while the protease activity level is similar. This imbalance of
      calpain:calpastatin ratio leads to a decrease of the erythrocyte plasma membrane
      (Ca+Mg)ATPase activity and to the appearance of 124 kDa fragments, which are the
      typical products of proteolytic calpain action on the 136 kDa (Ca+Mg)ATPase
      native form.

PMID- 8670247
TI  - Characterization of a recombinant chimeric plasminogen activator composed of Gly
      Pro-Arg-Pro tetrapeptide and truncated urokinase-type plasminogen activator
      expressed in Escherichia coli.
AB  - A chimeric plasminogen activator, GPRP-u-PA (144-411), consisting of the Gly-Pro
      Arg-Pro tetrapeptide fused to the N-terminal of a truncated urokinase-type
      plasminogen activator (comprising Leu 144 through Leu 411), was produced by
      expression of the corresponding chimeric cDNA in Escherichia coli cells. After
      renaturation, the chimera was purified to homogeneity with specific amidolytic
      activity of 100,000 IU/mg protein. The chimera showed 6-fold greater affinity for
      fibrin clots than native low molecular weight urokinase (LUK) and 1.5-fold
      greater affinity than a chemical conjugate, GPRP-LUK, generating via coupling Gly
      Pro-Arg-Pro tetrapeptide to native low molecular weight urokinase. The chimera
      had 2 to 3 fold greater fibrinolytic potency than native LUK in vitro. Fibrinogen
      had no influence on fibrinolysis of the chimera. The chimera consumed much less
      fibrinogen than native LUK.

PMID- 8670248
TI  - Identification and immunolocalization of type X collagen at the ligament-bone
      interface.
AB  - In some ligaments, ligamentous collagen fibrils attach to bone by first passing
      through non-mineralized and mineralized fibrocartilage present at the ligament
      bone interface. To understand better the function of these fibrocartilages,
      collagens present at the femoral insertion of the bovine medial collateral
      ligament were isolated and characterized. Types II and IX collagens were
      identified in pepsin digests of the tissue in addition to type X collagen
      originally thought to be associated with the cartilages undergoing endochondral
      bone formation. Presence of type X collagen was confirmed by immunoblotting and
      by immunofluorescence localization using laser confocal microscopy. Type X
      collagen was localized predominantly in the mineralized zone of the ligament
      insertion. These data indicated that type X collagen may play a role in ligament
      attachment to bone.

PMID- 8670249
TI  - Evidence that glutathione peroxidase RNA and manganese superoxide dismutase RNA
      bind the same protein.
AB  - Rat lung extract contains protein that binds to a cis element in the 3'
      untranslated region of glutathione peroxidase (GPx) mRNA; this region is located
      200 bases downstream of the stop codon and 77 bases downstream of the
      selenocysteine insertion sequence. GPx mRNA-binding protein (GPx-BP) has the
      following characteristics in common with Mn superoxide dismutase mRNA-binding
      protein (MnSOD-BP): 1. RNA-binding activity is redox-sensitive; free sulfhydryl
      groups on the protein are required for binding. 2. RNA-binding activity is
      enriched in a 130,000 x g supernatant fraction and is inhibited by RNA in the
      polysomal fraction. 3. The MnSOD and GPx cis elements compete with each other for
      protein binding. 4. UV crosslinking studies with each probe reveal a [32P]
      labeled protein of the same apparent molecular mass, 56 kDa. These observations
      provide evidence that MnSOD and GPx RNAs bind the same protein.

PMID- 8670251
TI  - Human leukocyte integrin CD18 promoter directs low levels of expression of a
      mutated human CD4 reporter gene in leukocytes of transgenic mice.
AB  - The human leukocyte integrin CD18 molecule exists on the leukocyte surface in
      heterodimeric complexes with individual CD11 subunits, which mediate important
      leukocyte adhesion reactions. The CD18 subunit is developmentally regulated with
      the highest levels present on mature leukocytes of all lineages. To identify the
      regulatory sequences responsible for the tissue- and stage-specific expression of
      the CD18 subunit, we used 3.5 kb of regulatory sequence upstream from the human
      CD18 gene transcription start site to drive expression of a modified human CD4
      reporter gene in transgenic mice. Despite the inclusion of Sp1 and PU.1 sites in
      the construct, and the generation of founder lines possessing multiple copies of
      the transgene, the reporter gene was expressed in low levels in the leukocytes of
      the transgenic mice. These studies indicate that although PU.1 and Sp1 sites are
      required for CD18 promoter activity in vitro, additional regulatory regions
      appear to be required for high levels of copy number dependent expression in
      vivo.

PMID- 8670250
TI  - Stimulation of c-jun and c-myb in rat Sertoli cells following exposure to
      retinoids.
AB  - Circulating hormones are engaged in initiating and controlling the process of
      spermatogenesis, however, the Sertoli cell tight junctions prevent these
      substances from directly influencing the spermatogenic cells. Thus, the Sertoli
      cells play a vital role in regulating the spermatogenic process. Our studies
      correlate retinoid action with the transactivation of genes which encode the
      transcription factors, Jun and Myb, in the Sertoli cells of the rat testis, a
      retinol-dependent organ. We examined the mRNA levels for the protooncogene, c
      jun, a member of the AP-I transcription complex, as well as mRNA levels for the
      protooncogene, c-myb, following retinoid stimulation. The major changes observed
      were a significant up-regulation in c-jun mRNA beginning at 30 min which reached
      a four-fold peak over controls at 1 h while the c-myb mRNA level exhibited a
      delay in up-regulation which rose abruptly to a significant three-fold peak over
      controls at 1 h. Interestingly, a variation in transcript size for c-jun (5.4 kb)
      was also detected in rat Sertoli cells. The significant 50% rise in the c-jun
      mRNA levels at 30 min prior to the rapid rise in the c-myb message at 1 h
      suggests that Jun may be involved in the transactivation of c-myb gene
      expression. These data support the model that retinoid modulation of these
      immediate early genes is the first step in a process which initiates a cascade of
      vitamin A-inducible gene expression in rat Sertoli cells necessary for
      maintaining spermatogenesis.

PMID- 8670252
TI  - Interaction of 1,2,3,4-tetrahydroisoquinoline with some components of cigarette
      smoke: potential implications for Parkinson's Disease.
AB  - Tetrahydroisoquinoline (TIQ), a presumed proneutrotoxin linked with Parkinson's
      disease (PD), was found to interact with some components of cigarette smoke to
      give N-(cyanomethyl)-TIQ (CMTIQ), N-(1'-cyanoethyl)-TIQ (CETIQ), N-(1'
      cyanopropyl)-TIQ (CPTIQ), N-(1'-cyanobutyl)-TIQ (CBTIQ), and 1-cyano-TIQ (1CTIQ).
      The in vitro formation of these compounds under physiological conditions occurs
      rapidly and with a high yield. Significant differences in the recovery of the
      different compounds were obtained when the data obtained from Burley tobacco were
      compared to those obtained from Bright tobacco. Following chronic administration
      of TIQ and a solution of cigarette smoke to rats, the presence of some of these
      compounds was also detected in the brain.

PMID- 8670253
TI  - Synthesis of the bacteriophage lambda P protein in amino acid-starved Escherichia
      coli cells.
AB  - It was demonstrated previously that in isoleucine-starved Escherichia coli relA
      mutants harboring a plasmid derived from bacteriophage lambda the lambda O
      protein is not synthesized. However, a protein which coprecipited with the lambda
      O during immunoprecipitation with anti-lambda O serum was synthesized during the
      relaxed response. Here we found that this protein is the lambda P gene product.
      Despite significant inhibition of transcription from the pR promoter (which
      produces mRNA for the lambda P protein synthesis) during the stringent response,
      the lambda P protein was efficiently synthesized in relA- as well as relA+
      strains starved for isoleucine, threonine and histidine, whereas the synthesis
      was negligible during starvation for arginine and leucine. The synthesis of the
      lambda P protein in amino acid-starved cells is sensitive to rifampicin. Thus we
      presume that this phenomenon is not caused by eventual increased stability of the
      lambda P mRNA but rather is an effect of preferential translation of this mRNA
      and incorporation of limited amount of amino acids arising in the starved cells
      as a result of intracellular proteolysis. One of possible explanations of the
      mechanism of this phenomenon may suggest that the same signals can be recognized
      in both prokaryotic and eukaryotic cells during initiation of translation at non
      AUG codons.

PMID- 8670254
TI  - Glutathione-linked thiol peroxidase activity of human serum albumin: a possible
      antioxidant role of serum albumin in blood plasma.
AB  - A 65-kDa molecular mass of thiol-specific antioxidant protein was purified from
      human plasma and identified as human serum albumin (HSA) by the analysis of amino
      terminal amino acid sequence. This protein exhibited the preventive effects
      against the inactivation of glutamine synthetase activity and the peroxidation of
      lipid by a metal-catalyzed oxidation system. These antioxidant activities were
      supported by a thiol-reducing equivalent such as DTT and reduced glutathione. The
      thiol-specific antioxidant activity of HSA was greatly activated by halide ion,
      especially by chloride ion. HSA showed a significant capability to destroy H2O2
      in the presence of reduced glutathione, resulting in the production of oxidized
      glutathione. Both the preventive activity against the glutamine synthetase
      inactivation and the peroxidase activity were completely abolished by the
      reactions of HSA with N-ethylmaleimide and iodoacetate, chemical modification
      agents for sulfhydryl of protein, only in the presence of thiol-reducing
      equivalent such as DTT. These results suggest that serum albumin acts as a major
      and predominate antioxidant exerting a glutathione-linked thiol peroxidase
      activity which removes reactive oxygen species such as H2O2 within blood plasma.

PMID- 8670255
TI  - Inhibition of 6-phosphogluconate dehydrogenase by carbamylation and protection by
      alpha-crystallin, a chaperone-like protein.
AB  - Carbamylation of lens proteins may contribute to cataract formation in
      populations with high levels of blood urea. Urea comes to equilibrium with
      cyanate. Changes induced by cyanate binding to lens crystallin have been
      described but little is known about the carbamylation of the enzymes. The present
      study investigated the in vitro carbamylation of 6-phospho-D-gluconate
      dehydrogenase (E.C.1.1.1.44) and its effect on the enzymic activity, as well as a
      possible way to prevent the cyanate binding to the enzyme. The covalent cyanate
      binding to protein inactivated the enzyme in a concentration-dependent fashion.
      Aspirin and paracetamol did not protect the enzyme against inactivation by
      carbamylation, while alpha-crystallin was specifically protective as compared
      with other control proteins, consistent with its suggested role as a molecular
      chaperone.

PMID- 8670256
TI  - Analysis of DNase I hypersensitive site of the ELP gene.
AB  - The chromatin structure of the ELP gene was analyzed by DNase I hypersensitivity.
      A strong DNase I hypersensitive site (Y1DH) was identified at the exon 1 region
      of the ELP gene in steroidogenic Y1 cells. A strong DNase 1 hypersensitive site
      (ECDH2) downstream of the exon 8 of the ELP gene and a weak DNase 1
      hypersensitive site (ECDH1) upstream of the exon 2 of the ELP gene was identified
      in undifferentiated EC cells. These differences of the DNase I hypersensitive
      sites may be related to the differential expression of ELP isoforms in Y1 cells
      and EC cells. In addition, the gel shift assay and DMS protection assay revealed
      that ELP binds to the ECDH2 region.

PMID- 8670257
TI  - Structural characterization of a new galactofuranose-containing glycolipid
      antigen of Paracoccidioides brasiliensis.
AB  - An acidic glycolipid (Band 1), purified from P. brasiliensis by a combination of
      ion exchange chromatography, HPLC, and HPTLC, was found to be reactive with sera
      of all patients with paracoccidioidomycosis (PCM). Monosaccharide analysis of
      Band 1 yielded mannose and galactose in a 2:1 ratio, while mild acid hydrolysis
      and mild periodate oxidation/NaB3H4 reduction indicated the presence of a
      terminal galactofuranose. Preliminary analysis of 1H-NMR and MS data suggests
      that the structure of the glycan is Galf beta 1-->6(Manp alpha 1-->3)Manp beta 1-
      >2Ins (Ins = myo-inositol). Removal of the galacto-furanose decreased by 60-80%
      the reactivity of sera from PCM patients with Band 1, suggesting that this
      residue is immunodominant. With the presumed absence of galactofuranose in
      mammalian hosts, compounds containing this residue may be useful targets for
      therapy of several parasitic and fungal diseases.

PMID- 8670258
TI  - cAMP-dependent phosphorylation of neurofilament proteins NF-L and NF-M inhibits
      their coassembly into filaments in vitro.
AB  - The effects of cAMP-dependent phosphorylation of neurofilament proteins NF-L and
      NF-M on the coassembly of the two proteins into filaments in vitro was examined.
      Sedimentation velocity experiments revealed that phosphorylated NF-M sedimented
      more slowly and resisted salt-induced aggregation. Filaments reconstituted from
      various mixtures of proteins were pelleted were pelleted and examined by gel
      electrophoresis and electron microscopy. Phosphorylation of either protein
      inhibited the formation of heteropolymer filaments containing NF-L and NF-M.
      However, phosphorylated proteins were fully competent in forming heterooligomeric
      assembly intermediates; therefore, phosphorylation blocks a later stage of
      filament assembly.

PMID- 8670260
TI  - On mechanical preprocessing in the cochlea: the three great hearing theories
      combined.
AB  - Since otoacoustic emissions were discovered, the old idea of a second (active)
      filter in the cochlea has been pursued with considerable dedication. In this
      contribution a concept explaining the action of the second filter is presented,
      which is derived from high-frequency resonance: The outer hair cells are excited
      when the traveling wave breaks rather than when it reaches its peak amplitude.
      They vibrate at a much higher frequency, i.e. their mechano-electrical resonant
      frequency. The amplitude of the exciting stimulus is very small, but in keeping
      with the chaos theory it is amplified by self-organization to a level sufficient
      for physiologic excitation. This concept helps to explain the hitherto
      unexplained frequency changes of spontaneous otoacoustic emissions.

PMID- 8670259
TI  - P2U purinergic activation leads to the cell cycle progression from the G1 to the
      S and M phases but not from the G0 to G1 phase in vascular smooth muscle cells in
      primary culture.
AB  - The regulation of the cell cycle by extracellular UTP was investigated in rat
      aortic smooth muscle cells in primary culture (VSMCs) by means of an
      immunocytochemical analysis of cell cycle-specific nuclear antigens. UTP induced
      a rise in the cytosolic Ca2+ concentration ([Ca2+]i) of VSMCs, which was
      desensitized by pretreatment with ATP, but not with 2-methylthioATP nor alpha,
      beta-methyleneATP. The incubation of serum-deprived G0 cells with platelet
      derived growth factor (PDGF) induced cell cycle progression into the G1 phase
      without any further progression into the S and M phases, while none of the
      nucleotides had any effect on the cell cycle of the G0 cells. The incubation of
      the PDGF-pretreated cells at the G1 phase with 2-methylthioATP or alpha, beta
      methyleneATP had no effect on the cell cycle of G1 cells, while the incubation of
      the G1 cells with UTP, ATP, and ATP gamma S stimulated cell cycle progression
      into the S and M phases. These results thus indicate that P2U purinergic
      activation mediates a [Ca2+]i transient and a progression growth factor effect of
      nucleotides in VSMCs.

PMID- 8670261
TI  - Oxidation of cysteine residues from alpha-A crystallin during cataractogenesis of
      the human lens.
AB  - Although it has been known for many years that opacification of the human lens is
      accompanied by oxidation of cysteine sulfhydryl groups to half-cystine residues,
      nothing is known concerning the exact amino acid sequences involved in this
      oxidative process. Since alpha-A crystallin is one of the major proteins of the
      lens, and since a decrease in its molecular chaperone activity has been
      implicated in possible mechanisms of cataract formation, alpha-A crystallin was
      purified from total lens proteins by reverse phase chromatography, followed by
      digestion with lys-C endoprotease. Mass spectral analysis of the digest indicated
      that in normal transparent lenses, cys-131 and cys-142 from alph-A crystallin are
      present as a mixture of cysteine sulfhydryl and half-cysteine disulfide groups,
      while identical analysis from cataractous lenses demonstrated undetectable levels
      of the cysteine sulfhydryl group. Together, these results demonstrate for the
      first time, the involvement of specific cysteine residues in the oxidative
      mechanism of human lens opacification.

PMID- 8670262
TI  - The atrial natriuretic peptide gene in patients with familial primary open-angle
      glaucoma.
AB  - Family history is a major risk factor in the development of primary open-angle
      glaucoma. The atrial natriuretic peptide system has been implicated in the
      underlying pathophysiology of the disease. This study looked for any alterations
      in the ANP gene and 5' proximal promoter regions of the ANP gene, in 53 patients
      from familial primary open-angle glaucoma families. The ANP gene was amplified by
      a long-PCR technique from peripheral blood DNA. Gross insertions or deletions in
      the gene were sought and allelic frequencies at two restriction fragment length
      polymorphism (RFLP) sites within the gene (Sca I, Hpa II) were compared with
      allelic frequencies obtained from 60 normal controls with no known family history
      of glaucoma or ocular hypertension. PCR-based single strand conformation
      polymorphism analysis was then used to search for possible point mutations in the
      5' proximal promoter region of the ANP gene, which is known to contain regulatory
      elements which modify gene transcription. No gross alterations in the ANP gene or
      differences in allelic frequencies at the RFLP sites within the gene were
      observed. PCR-SSCP analysis of the 5' proximal promoter region of the gene
      revealed mutations in 10 patients in the -595 to -384bp region (19% of patients).
      Mutations in the 5' proximal promoter region of the ANP gene may contribute to
      altered ANP transcription in at least a proportion of patients with familial
      glaucoma.

PMID- 8670263
TI  - Extracellular ubiquitin regulates the growth of human hematopoietic cells.
AB  - We investigated the effects of extracellular ubiquitin on the colony formation of
      human hematopoietic progenitor cells (CFU-GM, CFU-E and BFU-E) and a granulocyte
      colony stimulating factor (G-CSF)-dependent human myeloblastic leukemic cell
      line, OCI/AML/1a. Ubiquitin exhibited inhibitory effects on CFU-GM, CFU-E, BFU-E
      and OCI/AML/1a colony formation. Extracellular ubiquitin also inhibited the
      growth of KT3 (T lymphoblast), K562 (erythroleukemia) and Daudi (Burkitt's
      lymphoma) cells, stimulated the growth of HL60 (promyelocytic leukemia) and
      Jurkat (T-ALL) cells and showed no effect on the growth of U937 cells (monocytic
      leukemia). These results indicate that another, previously unrecognized function
      of extracellular ubiquitin is to regulate hematopoiesis.

PMID- 8670264
TI  - Dynamin II binds to the trans-Golgi network.
AB  - Two dynamin II-specific antibodies were used to detect dynamin II attached to
      highly purified Golgi membranes of HepG2 cells. Within the Golgi apparatus
      dynamin II is predominantly localized to the trans-Golgi network, as shown by
      immunoelectron microscopy. Increased binding of dynamin II to the trans-Golgi
      network in the presence of GTP-gamma-S and a reduced binding upon stimulation of
      secretion by phorbolester indicates that dynamin II may have a function in post
      Golgi vesicle transport.

PMID- 8670265
TI  - Regulation of chloride channel trafficking by cyclic AMP via protein kinase A
      independent pathway in A6 renal epithelial cells.
AB  - The apical membrane of renal epithelial A6 cells has 3 and 8 pS Cl- channels.
      Both types of the channels were blocked by NPPB (5-Nitro-2-(3-phenylpropylamino)
      benzoic acid; 100 microM). 8-bromo-cAMP (Br-cAMP) increased the open probability
      of 3 pS Cl- channel and this action was inhibited by pretreatment with H89, an
      inhibitor of cAMP-dependent protein kinase (PKA). On the other hand, the number
      of 8 pS Cl- channel was increased by Br-cAMP. The increase in number of 8 pS Cl-
      channel by Br-cAMP was inhibited by brefeldin A (a blocker of movement of
      membrane protein from an intracellular pool to the cell surface) but not by H89.
      These observations indicate that cAMP could activate the 3 pS Cl- channel through
      PKA-dependent phosphorylation, and that cAMP could stimulate translocation of the
      8 pS Cl- channel through PKA-independent pathways. We conclude that PKA
      independent pathways are involved in cAMP signaling mechanisms in addition to PKA
      dependent pathways.

PMID- 8670266
TI  - Comparison of the effects of calponin and a 38-kDa caldesmon fragment on
      formation of the "strong-binding" state in ghost muscle fibers.
AB  - We studied the conformational changes in actin filaments induced by the binding
      of calponin or a 38-kDa fragment of caldesmon, two actin-binding proteins known
      to inhibit actin-activated ATP hydrolysis by phosphorylated smooth muscle myosin.
      The F-actinin myosin-free muscle fibers (ghost fibers) was labeled with
      fluorescein-5-maleimide and the conformational change in actin was determined by
      polarized fluorimetry. Data show that both calponin and the 38-kDa caldesmon
      fragment inhibit the conformational changes in F-actin that are compatible with
      the "strong-binding" state between myosin heads and actin. Tropomyosin slightly
      reduced the effect produced by calponin, but enhances the effect produced by the
      38-kDa caldesmon fragment.

PMID- 8670267
TI  - Confocal fluorescence microscopy for antibodies against a highly conserved
      sequence in SH2 domains.
AB  - We have prepared monoclonal antibodies for a highly conserved sequence
      (GTFLVRESETTK) in SH2 domains. Mouse IgG1s (12E and 32D) prepared against a
      peptide-conjugated keyhole lympet hemocyanin specifically bound the antigenic
      peptide but not the carrier protein. Western blot analysis showed that one IgG1
      (12E) recognized mainly 62 kDa proteins (possibly src-family tyrosine kinases)
      from triton X-100 extracts of RBL-2H3 cells and that another (32D) recognized
      mainly 32 and 110 kDa proteins. Confocal fluorescence microscopy showed that the
      SH2 domains had a diffuse cytoplasmic distribution and were not present in the
      nucleus. Following antigen stimulation, a markedly different cellular
      distribution was observed in the cells stained with 12E and 32D IgGs. 12E IgGs
      strongly stained the plasma membranes while 32D IgGs stained small granules in
      the cytoplasm. As 12E IgGs bound 62 kDa proteins on Western blotting, the results
      suggest that tyrosine kinases cluster along the plasma membranes and/or than
      conformational changes occur in the domains after antigen stimulation.

PMID- 8670268
TI  - Voltage-dependent potassium channels in white adipocytes.
AB  - Macroscopic membrane currents of white adipocytes were studied using the whole
      cell variant of the patch-clamp technique. These cells were obtained by
      differentiating preadipocytes fro rat epididymal tissue. In all differentiated
      cells outward currents exhibiting sigmoidal activation kinetics were observed
      with amplitudes ranging from 0.5 to 6 nA. The outward current showed activation
      thresholds at approximately -25 to -35 mV. The ion channels underlying the
      macroscopic current were highly selective for K+. Their selectivity was typical
      for K+ channels, with relative permeabilities of K+ > NH4+ > Cs+, Na+. The
      potassium current was blocked by tetraethylammonium, 4-aminopyridine, barium and
      cobalt. These results demonstrate the existence of voltage dependent potassium
      channels in mature white adipose cells.

PMID- 8670269
TI  - An alternatively spliced isoform of the Spi-B transcription factor.
AB  - Spi-B is an Ets transcription factor related to the oncoprotein Spi-1/PU.1 and
      highly expressed in B lymphoid cells. The Ets proteins share a conserved Ets
      domain that mediates specific DNA binding. Spi-B binds DNA sequences containing a
      core 5'-GGAA-3' and activates transcription through this motif. Up to date, the
      biological function of Spi-B remains unknown. Here, we describe the
      characterization of an alternatively spliced variant of Spi-B, named deltaSpi-B,
      which has lost the Ets domain. In B lymphoid cells, deltaspi-B and spi-B mRNAs
      were present simultaneously in a ratio of around 10%. DeltaSpi-B product was not
      able to bind DNA and was recovered in cytoplasmic cellular extracts. We raise the
      hypothesis that delta Spi-B might affect Spi-B function by recruiting factors
      involved in Spi-B activity.

PMID- 8670270
TI  - The catalytic properties of human hepatitis B virus polymerase.
AB  - The DNA-dependent DNA polymerase (DDDP) and RNA-dependent DNA polymerase (RDDP)
      activities of hepadnavirus polymerases are both essential for viral replication.
      Human hepatitis B virus (HBV) polymerase has been successfully expressed in
      Escherichia coli as a fusion protein in frame with maltose-binding protein. The
      present study was undertaken to characterize these two activities and introduce
      an in vitro assay system. In situ activity gel assays show that the polymerase
      has both types of activities. One hundred thirty-four kilodaltons of active full
      length product was proteolytically cleaved into approximately 73 kDa of active
      fragment by proteinase K preincubation. Mutation of conserved YMDD motif also
      confirms that the activities were due to the recombinant polymerase and that this
      motif is essential to polymerase activity. Two activities of the polymerase show
      their optima under conditions of 1 mM (DDDP) or 0.25 mM (RDDP) of MnCl2, 400 mM
      KCl, 37 degrees C (DDDP) or 24 degrees C (RDDP), and pH 7.0-7.7. Substitution of
      Mg2+ for Mn2+ results in reduction of processivity, which may explain why Mn2+
      supports nucleotide incorporation to a higher level than Mg2+. The polymerase is
      resistant to aphidicolin. Actinomycin D acts selectively on DDDP activity,
      whereas phosphonoformic acid inhibits both activities. The in vitro HBV
      polymerase assay system demonstrated herein will be useful for screening
      potential HBV polymerase inhibitor for the development of anti-HBV drugs.

PMID- 8670271
TI  - Localization of the dystrophin binding site at the carboxyl terminus of beta
      dystroglycan.
AB  - Alpha- and beta-dystroglycan form a heteromeric transmembrane complex linking the
      extracellular matrix to the cytoskeleton. In muscle beta-dystroglycan interacts
      with dystrophin on the inside of the cell and with alpha-dystroglycan, which
      binds the extracellular matrix protein laminin, on the outside. Dystroglycan is
      expressed not only in muscle but also in other tissues. We cloned beta
      dystroglycan from rabbit brain by RT-PCR and expressed deletion mutants of the
      beta-dystroglycan cytoplasmic domain as GST-fusion proteins. We identified the
      dystrophin binding region on beta-dystroglycan by protein overlay and co
      precipitation assays with skeletal muscle dystrophin and recombinant apo
      dystrophin I. We demonstrate that the beta-dystroglycan carboxyl terminus
      interacts with dystrophin and that the binding site is restricted to the last 20
      amino acids. Our data also suggest that the region adjacent to the beta
      dystroglycan transmembrane domain might modulate beta-dystroglycan-dystrophin
      interaction.

PMID- 8670272
TI  - Carnosine sustains the retention of cell morphology in continuous fibroblast
      culture subjected to nutritional insult.
AB  - L- Carnosine (beta-alanyl L-histidine), occurring abundantly in skeletal muscles,
      has been suggested to possess antioxidant and anti-aging properties. Using three
      different experimental approaches (microscopic, flow cytometric and ELISA for one
      of the markers of DNA oxidative damage) this study on rat embryonic fibroblasts
      demonstrates that L-carnosine at 30 mM concentration sustains the retention of
      cell morphology even during a nutritional insult for five weeks. Also, L
      carnosine significantly reduces the formation of 8-hydroxy deoxyguanosine (8-OH
      dG) in the cells after four weeks of continuous culture. Thus it could be
      inferred that the anti-senescent effect of L-carnosine is probably linked to its
      inhibition of formation of intracellular 8-OH dG during oxidative stress.

PMID- 8670273
TI  - Carnitine transport defect in fibroblasts of juvenile visceral steatosis (JVS)
      mouse.
AB  - Juvenile visceral steatosis (JVS) mice are associated with systemic carnitine
      deficiency (Kuwajima, et al., 1991). In order to investigate the cause of this
      deficiency, we compared fibroblast carnitine transport activities in normal mice
      and JVS mice. The kinetic analysis showed that in formal fibroblasts, the Km and
      Vmax values for saturable uptake was 15.6 microM and 2.56 pmol/min/mg protein,
      respectively. In JVS fibroblasts, however, saturable uptake was not observed.
      There was no great difference in the linear component of uptake between normal
      and JVS fibroblasts. At the physiological concentration (50 microM) of carnitine,
      the fibroblast carnitine transport activity in JVS mice was decreased to 18% of
      that in normal mice. Thus there is hardly any carnitine transport activity in the
      fibroblasts of JVS mice, indicating that the JVS mouse can be regarded as an
      animal model of primary carnitine deficiency.

PMID- 8670274
TI  - Purification and properties of transglutaminase from soybean (Glycine max)
      leaves.
AB  - Transglutaminase was purified to homogeneity from leaves of soybean (Glycine
      max). The molecular weight of the enzyme estimated by gel filtration and sodium
      dodecyl sulfate polyacrylamide gel electrophoresis was 80,000 daltons. This
      purified enzyme catalyzed the incorporation of [14C]-putrescine into N,N'
      dimethylcasein as a protein substrate. With N,N'-dimethylcasein, the Km values
      for putrescine, spermidine and spermine were 109, 42 and 69 microM, respectively.
      The optimum pH and temperature for the enzyme reaction were 7.6 and 37 degrees C.
      Ca2+ was not an absolute requirement for enzyme activity unlike animal
      transglutaminases. The enzyme was activated by dithiothreitol, but inhibited by
      GTP. With molecular weight of this enzyme, this inhibition of enzyme activity by
      GTP indicates that this enzyme is very similar to known tissue transglutaminases
      in animals.

PMID- 8670275
TI  - Retinyl methyl ether: binding to transport proteins and effect on transcriptional
      regulation.
AB  - Retinyl methyl ether (RME) which prevents cancers of the rat mammary gland, binds
      to cellular retinol-binding protein and serum retinol-binding protein but not to
      cellular retinoic acid-binding protein or to the nuclear retinoid receptors,
      RARs/RXRs. Since the biochemical effects of retinoids likely involve activation
      or suppression of RAR/RXR-mediated gene transcription, we evaluated such activity
      of RME by performing cotransfection assays involving CV-1 cells, expression
      vectors containing RAR and/or RXR cDNA, and an appropriate reporter vector. In
      the concentration range of 10(-9)-10(-6), RME did not activate transcription by
      either of the heterodimers (RARalpha, beta or gamma/RXR alpha) or the homodimer
      (RARalpha/RARalpha). The retinoid, however, exhibited concentration-dependent
      inhibitory effects on the basal level of transcriptional activity (no other
      retinoid added) of both the RAR beta- and RARgamma/RXRalpha heterodimers and of
      the retinoic acid-induced transcriptional activation of the RARgamma/RXRalpha
      receptors. Thus, RME acted as a retinoic acid antagonist, a role possibly
      involved in its cancer preventive activity.

PMID- 8670277
TI  - cDNA cloning and genomic structure of human bone morphogenetic protein-3B (BMP
      3b).
AB  - BMP-3b (also termed GDF-10) is a novel BMP-3 related protein recently discovered
      in rat femur tissue by molecular cloning. In this paper, we have isolated cDNA
      and the gene for human BMP-3b and determined their structure. Cloned human BMP-3b
      cDNA with a size of 2632 base pairs encodes a 478 amino acid precursor protein
      sharing 83% identity with rat BMP-3b. The human BMP-3b gene is composed of 3
      exons and spans approximately 13 kilobases of DNA. The 5' flanking region carries
      no typical TATA box but G+C rich sequences. Southern blot analysis revealed that
      the BMP-3b gene is situated in a single locus of chromosome 10. By Northern
      analysis, human BMP-3b transcripts were detected primarily in femur, brain, lung,
      skeletal muscle, pancreas and testis.

PMID- 8670276
TI  - All-trans retinoic acid increases peptidylarginine deiminases in a newborn rat
      keratinocyte cell line.
AB  - We studied the expression of peptidylarginine deiminases (EC 3.5.3.15) in an
      immortalized newborn rat keratinocyte cell line. No measurable enzyme activities
      were noted in either growing or confluent cultures. The enzyme activity was
      increased by all-trans retinoic acid in dose- and time-dependent manners. The
      enzyme activity was resolved into two peaks by anion exchange chromatography. The
      minor peak resembled enzyme preparations obtained from the epidermis in earlier
      studies. The major peak was indistinguishable from rat muscle peptidylarginine
      deiminase in the chromatographic and Western blotting profiles. Northern blot
      hybridization showed a major band in retinoic acid-treated cells migrating
      slightly behind muscle peptidylarginine deiminase mRNA.

PMID- 8670278
TI  - Two-peak kinetic curve of the chemiluminescence in phorbol-induced macrophage.
AB  - Phorbol-1,2-myristate-1,3-acetate can induce rat macrophage to emit
      chemiluminescence. The kinetic curve of the chemiluminescence clearly showed two
      peaks when a proper ratio of phorbol-1,2-myristate-1,3-acetate and macrophage
      were mixed. It was proved that the first one mainly came from the oxygen free
      radicals and the second one from NO generated in the phorbol-1,2-myristate-1,3
      acetate stimulated cells by using the substitute and inhibitor of NO synthase.

PMID- 8670279
TI  - Stoichiometry of BkdR to substrate DNA in Pseudomonas putida.
AB  - BkdR is the transcriptional activator of the bkd operon of Pseudomonas putida,
      which encodes branched chain keto acid dehydrogenase. BkdR binds to a large
      region of DNA between its own structural gene and the first gene of the bkd
      operon. The object of the present studies was to determine the stoichiometry of
      binding as part of an effort to understand the action of BkdR in regulation of
      the bkd operon. [35S]BkdR was prepared and found to be essentially 100% active in
      the gel shift assay. Only one complex was formed under all the conditions used.
      The stoichiometry of BkdR binding to its specific substrate DNA was three
      tetramers per mold substrate DNA. L-valine did not affect the stoichiometry
      although this ligand was previously shown to affect the DNase I protection
      pattern. The addition of nonspecific DNA to the incubation mixture also did not
      affect this stoichiometry.

PMID- 8670280
TI  - A protein AA-variant derived from a novel serum AA protein, SAA1 delta, in an
      individual from Papua New Guinea.
AB  - A major protein AA amyloid protein was purified and characterised from a Papua
      New Guinnean individual. This AA protein differed from all previously
      characterised SAA variants by the combination of Ala52, Val57, Asn60, Phe68,
      Phe69 and Gly72. Since the prevalence of AA-amyloidosis is unusually high in
      Papua New Guinea this AAdelta must originate from a novel SAAdelta which may
      represent a particularly amyloidogenic variant.

PMID- 8670281
TI  - Identification of a cDNA encoding a thiazide-sensitive sodium-chloride
      cotransporter from the human and its mRNA expression in various tissues.
AB  - We report here the identification of a cDNA encoding a human thiazide-sensitive
      sodium-chloride cotransporter (hTSC) using a PCR-based method. The homology of
      the hTSC with rat TSC (rTSC) and rat bumetanide-sensitive sodium-potassium
      chloride cotransporter (rBSC) was 86% and 64%, respectively, at the nucleotide
      level, and 92% and 61%, respectively, at the amino acid level. Using fluorescence
      in situ hybridization (FISH), the hTSC gene has been mapped to chromosome 16q13.
      Northern blot analysis using polyA+RNA from various human tissues, revealed a
      major 4.5 kb transcript and a minor 6.5 kb specifically in the kidney, but low
      level of expression was also observed in small intestine, placenta, prostate,
      colon, and spleen.

PMID- 8670282
TI  - The tumor suppressor protein APC colocalizes with beta-catenin in the colon
      epithelial cells.
AB  - The APC gene is mutated in familial adenomatous polyposis and sporadic colorectal
      tumors. The product of this gene is a 300 kDa cytoplasmic protein associated with
      catenin. In the present study, we examined the subcellular localization of the
      APC protein and beta-catenin in the mouse colon by double-labeling
      immunocytochemistry. While the APC protein was localized in the lateral and
      apical cytoplasm and in microvilli of the epithelial cells, beta-catenin was
      present exclusively in the lateral cytoplasm. Double-labeling-immunoelectron
      microscopy demonstrated precise colocalization of the APC protein and beta
      catenin along the lateral plasma membrane. These results suggest that the APC
      protein functions in cooperation with beta-catenin in the lateral cytoplasm but
      has other functions independent of beta-catenin in the apical cytoplasm and in
      microvilli.

PMID- 8670284
TI  - Inhibition of influenza virus RNA polymerase and nucleoprotein genes expression
      by unmodified, phosphorothioated, and liposomally encapsulated oligonucleotides.
AB  - We have demonstrated that antisense phosphodiester (ODNs) and phosphorothioate
      oligonucleotides (S-ODNs) inhibit CAT (chloramphenicol acetyltransferase) protein
      expression in the clone 76 cell line, which is a derivative of the murine C127
      cell line. This cell line expresses the influenza virus RNA polymerase and
      nucleoprotein (NP) genes in response to treatment with dexamethasone.
      Phosphodiester, phosphorothioate, and liposomally encapsulated oligonucleotides
      with four target sites (PB1, PB2, PA, and NP) were synthesized and tested for
      inhibitory effects by a CAT-ELISA assay using the clone 76 cell line. The ODNs
      and S-ODNs complementary to the sites of the PB2-AUG and PA-AUG initiation codons
      showed highly inhibitory effects. On the other hand, the inhibitory effect of the
      S-ODNs targeted to PB1 was considerably decreased in comparison with the other
      three target sites. Liposome encapsulation afforded oligomer protection in serum
      containing medium and substantially improved cellular accumulation. The liposomal
      encapsulated oligonucleotides exhibited higher inhibitory activity than the free
      oligonucleotides. The activities of the unmodified oligonucleotides are
      effectively enhanced by using the liposomal carrier.

PMID- 8670285
TI  - Human inducible nitric oxide synthase gene is transcriptionally regulated by
      nuclear factor-kappaB dependent mechanism.
AB  - We previously showed a sequence of the 5'-flanking region of the human inducible
      nitric oxide synthase (hiNOS) gene that included putative cis-acting elements. A
      reported plasmid containing the 5'-flanking region of the hiNOS gene upstream
      from its reporter gene was constructed, and then transiently or stably
      transfected into human cells known to express the hiNOS gene following cytokine
      stimulation. The transfected cells showed the inducibility of the reporter
      activity following interleukin-1beta stimulation. Reporter inducibility
      disappeared in cells transfected with a plasmid mutated in the putative nuclear
      factor (NF)-kappaB binding region. In addition the induction was inhibited by a
      treatment of anti-oxidant, pyrrolidinedithiocarbamate, known as an NF-kappaB
      inhibitor. Our results demonstrate that the promotor including the NF-kappaB
      region is functional and that the hiNOS gene is transcriptionally regulated via
      NF-kappaB activation in human cells.

PMID- 8670283
TI  - Sequence and expression of the mouse homologue to human phospholipase C beta3
      neighboring gene.
AB  - We describe the isolation and expression of a murine homologue of the
      Phospholipase C beta3 Neighboring Gene (PNG), located in the MEN1 region on
      chromosome 11q13. The PNG cDNA was isolated using a human PNG cDNA clone
      (SOM172). Human and mouse PNG do not have any marked similarity to other known
      genes on the DNA level, but the predicted protein display similarity to the C
      terminal part of Phospholipase C beta2. Northern blots with mouse PNG probes
      revealed expression of a 1 kb message in multiple tissues, and an additional 2.3
      kb band in testis. The predicted murine protein contains 203 amino acids. In situ
      hybridization histochemistry displayed png mRNA expression in several tissues of
      the midstage mouse embryo, including the central nervous system. In late stage
      embryos, png was highly expressed in skeletal muscle, retina and neocortex. In
      the adult animal, expression was restricted to testis and thymus.

PMID- 8670287
TI  - Total synthesis of a miniferredoxin.
AB  - A miniferredoxin has been designed based on the Desulfovibrio gigas ferredoxin II
      structure and has been successfully synthesized. The 31 amino acid apoprotein was
      synthesized via standard Fmoc solid phase peptide synthesis and in vitro cluster
      insertion carried out. The UV-visible spectrum of the miniferredoxin (peak at 300
      nm and a shoulder at 405 nm) shows the same features as that of the D. gigas
      ferredoxin. Cyclic voltammetry indicated a quasireversible electrode process with
      a midpoint potential of -370mV vs NHE, which demonstrates that the miniferredoxin
      is redox active. From these and EPR studies, we propose the incorporation of a
      Fe4S4 cluster.

PMID- 8670286
TI  - Soluble form of Lamp II in purified rat liver lysosomes.
AB  - Lamp II (for lysosomal associated membrane protein II) is an integral type I
      glycoprotein. It consists of a very large and heavily glycosylated luminal
      domain, a single transmembrane segment, and a short cytoplasmic tail. We show
      that in highly purified lysosomes from rat liver, Lamp II, immunodetected with a
      monoclonal antibody on Western blots, it surprisingly distributed between a
      membrane bound form and a "soluble" form. The partition of the protein between
      the membrane and the content of lysosomes is strongly pH dependent. The soluble
      Lamp II population is sensitive to pH dependent aggregation as it is for many
      lysosomal content enzymes.

PMID- 8670288
TI  - Induction of proinflammatory cytokine expression in experimental acute Chagasic
      cardiomyopathy.
AB  - One of the hallmarks of Chagas' disease (caused by Trypanosoma cruzi) is
      progressive cardiomyopathy. The disease is associated with increased serum TNF
      alpha levels, and TNF-alpha is known to depress cardiac function. It is, however,
      not known whether the cytokines are produced within the infected myocardium. One
      month-old male Lewis rats were injected with cell culture-derived T. cruzi
      trypomastigotes and killed 15 days post-infection. As compared to normal animals,
      histologic analysis of infected animals revealed dense infection with amastigotes
      within myocytes and a minimal inflammatory infiltrate in the myocardium. Northern
      blot analysis of total RNA revealed no signal for IL-1beta or TNF-alpha, and a
      weak signal for IL-6 in the control rat hearts, and high levels of expression for
      the three genes in the infected rats. Western blots revealed results similar to
      that of mRNA levels, suggesting that, in addition to mechanical damage, infection
      by T. cruzi induces proinflammatory cytokine production in the myocardium itself,
      which may further exacerbate the pathology, and affect adversely myocardial
      function.

PMID- 8670289
TI  - Endothelin-converting enzyme: substrate specificity and inhibition by novel
      analogs of phosphoramidon.
AB  - Endothelin converting enzyme was partially purified by detergent extraction and
      ion exchange chromatography from porcine aortic endothelial cells. This
      kinetically homogeneous preparation catalyzes the hydrolysis of porcine big
      endothelin-1 to endothelin-1 with a pH optimum of 7. Human big endothelins-1, -2,
      and -3 are also hydrolyzed, but at progressively lower rates. Fragments of big
      porcine endothelin-1 comprising residues 16-39 and 16-29 are good substrates, but
      additional C-terminal truncations are devoid of substrate activity. Endothelin
      converting enzyme is characteristically inhibited by phosphoramidon and other
      metalloproteinase inhibitors including EDTA, o-phenanthroline, and
      diethylpyrocarbonate, but not by inhibitors of other classes of proteases or
      thiorphan. The inhibition by phosphoramidon is competitive with big porcine
      endothelin-1 suggestive of a common binding site for substrate and inhibitor. A
      number of novel analogs of phosphoramidon were synthesized by modifying various
      regions of the molecule and tested for inhibitory activity. The most potent of
      these, a methylphosphonic acid, has an IC50 of 0.05 microM.

PMID- 8670291
TI  - 6-Bromoflavone, a high affinity ligand for the central benzodiazepine receptors
      is a member of a family of active flavonoids.
AB  - 6-Bromoflavone, obtained by bromination of flavanone, binds to central
      benzodiazepine receptors with a Ki=70 nM and has a clear anxiolytic activity in
      mice, at 0.5 mg/kg i.p. A survey of the structure/affinity relationship for those
      receptors in a series of natural and synthetic flavonoids is presented.

PMID- 8670290
TI  - Analysis of allogeneic and syngeneic rat heart transplants using 23Na magnetic
      resonance spectroscopy.
AB  - This study defines the total sodium-23 magnetic resonance spectroscopy (23Na MRS)
      signal from in vivo heterotopic rat heart transplants in the early post
      transplant period and examines the utility of this noninvasive method for
      monitoring allograft rejection. Measurements were performed at 4.7 T. Syngeneic
      (n = 6) and allogeneic (n = 6) donor hearts were transplanted into the neck of
      recipient rats. There were 27 MRS observations between days 0 and 29 post
      transplant. Heart grafts were excised at various intervals post-transplant for
      histologic examination. Allogeneic heart grafts rejected between days 4 and 5
      post-transplant while syngeneic grafts continued to beat. All hearts showed
      ischemic damage. Allogeneic hearts showed cellular rejection by Day 1. 23Na MRS
      showed a steady elevation in signal in the 3 days prior to rejection and a sharp
      rise after rejection. 23Na MRS accurately identified full rejection and was also
      sensitive to the rejection process.

PMID- 8670292
TI  - Surface active peptide-mediated porphyrin aggregation.
AB  - Surface active pentapeptide [2(HCOO-). Lys-Ala-Ala-Lys(Z)-Tyr-OCH3] has been
      synthesized and its micelle formation investigated using conductometric, pH
      metric, and UV spectroscopic techniques. The double head double tail peptide
      molecules are shown to interact with water soluble meso-tetrakis (4
      sulfonatophenyl)-porphyrin [TPPS]H2 to form characteristic H-type aggregate at
      low concentrations, as evidenced by UV-Vis and fluorescence spectroscopic
      techniques. Spectroscopic analysis reveals that the aggregate contains 1:2
      porphyrin-peptide combination. The equilibrium constant for the formation of
      peptide-porphyrin complex has been obtained by using absorption spectral data.
      The present studies provide new insight into the peptide-porphyrin interaction.

PMID- 8670293
TI  - The ribosomal protein gene RPS3 is an essential single copy gene of the yeast
      Saccharomyces cerevisiae.
AB  - The communication reports the cloning, sequencing, and analysis of the RPS3 gene
      from yeast, which codes for the ribosomal protein YS3. Sequence analyses of a
      2.45 kb DNA fragment revealed an open reading frame with the potential to code
      for a 240 amino-acid long protein. The first 20 amino acids display a 90%
      identity to a 20 amino-acid long protein sequence of yeast ribosomal protein S3,
      that was obtained by protein sequencing of purified yeast ribosomal proteins. The
      promoter region of the RPS3 gene contains several upstream conserved sequence
      elements (UASrpg, T-rich region) that usually regulate transcription of ribosomal
      protein genes. Northern blot experiments demonstrate that this ORF is transcribed
      into an approximately 900 nt long mRNA. The major start site of transcription is
      located near position -20. The RPS3 gene is a single copy gene in yeast. Its
      disruption yields non viable haploid spores of Saccharomyces cerevisiae.

PMID- 8670294
TI  - cDNA cloning of rasp-1, a novel gene encoding a plasma protein associated with
      liver regeneration.
AB  - We constructed a cDNA library using mRNA isolated from liver 48 hr after
      hepatectomy (HX) and screened it by differential hybridization using cDNA from
      normal and regenerating rat liver. We isolated one clone termed regeneration
      associated serpin-1 (rasp-1) that was expressed in normal liver but was
      upregulated approximately 3-4 fold by 48 hr after HX. DNA sequence analysis of
      rasp-1 indicated that it encoded a novel 436 amino acid secreted protein.
      Moderate homology was found with several members of the serpin family of serine
      protease inhibitors. The 1.7 kb raps-1 mRNA was highly expressed in liver but not
      in brain, heart, kidney, lung, testis or spleen. We also found the RASP-1 protein
      in normal and HX rat plasma using a polyclonal antibody generated against a
      deduced peptide of rasp-1. Rasp-1 may encode a novel serine-protease inhibitor
      associated with liver regeneration.

PMID- 8670295
TI  - Oxidized LDL induces apoptosis in cultured smooth muscle cells: a possible role
      for 7-ketocholesterol.
AB  - In the multifunctional pathogens of atherosclerosis, oxidatively modified low
      density lipoprotein (LDL) plays a central role in atherogenesis. We searched to
      find out whether oxidized LDL (ox-LDL) could induce apoptosis in smooth muscle
      cells (SMCs). The induction of apoptosis was demonstrated by terminal
      deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling and DNA
      fragmentation. Ox-LDL induced apoptosis in a concentration dependent manner in
      the cells. The structural and biological changes in ox-LDL may be attributed to
      lysophosphatidylcholine (lyso-PC) accumulation and lipid peroxidation. To
      determine whether lyso-PC or lipid peroxide is responsible for the biological
      effect of ox-LDL, we incubated SMCs with lyso-PC or 7-ketocholesterol. Lyso-PC
      did not induce apoptosis, but 7-ketocholesterol did induce apoptosis. We conclude
      that ox-LDL induces apoptosis in SMCs and that this apoptosis contributes to
      lipid peroxidation. This mechanism may be important in determining the course of
      atherogenesis.

PMID- 8670296
TI  - The vascular endothelial cell specific membrane antigen HECMA 112 is
      immunochemically indistinguishable from vascular VE-cadherin.
AB  - The human endothelial membrane antigens HECMA 112 and VE-cadherin were
      immunochemically compared. The antibodies 1.3.1 against HECMA 112 and 7B4 against
      VE-cadherin recognized the same protein in extracts of tissue as well as of
      cells. The antigen HECMA 112 was immunoprecipitated by anti-VE-Cadherin antibody
      7B4.

PMID- 8670297
TI  - Cloning and characterization of mouse tec promoter.
AB  - Tec is a cytoplasmic protein-tyrosine kinase highly expressed in hematopoietic
      precursor cells. To investigate the mechanism regulating its expression, we
      cloned and characterized the mouse tec promoter. The promoter region does not
      contain the authentic TATA or CAAT box but has several consensus binding motifs
      for GATA and SP1. The nucleotide sequence surrounding the major transcription
      initiation site determined 5' RACE-PCR appeared to be homologous to the
      "initiator" consensus sequence which is frequently found in genes lacking TATA
      and CAAT. The promoter activity of the 5' flanking region was confirmed by using
      the luciferase assay. The present analysis will provide insights into the
      mechanism for the expression and regulation of the Tec molecule.

PMID- 8670298
TI  - A family of novel DNA-binding nuclear proteins having polypyrimidine tract
      binding motif and arginine/serine-rich motif.
AB  - NP220 is a DNA-binding nuclear protein originally cloned from human cell lines.
      Human NP220 (hNP220) has an arginine/serine-rich motif found in non-small nuclear
      RNP splicing factors (SR proteins) and shares three domains (MH1, MH2 and MH3)
      with an acidic nuclear matrix protein, matrin 3. The MH2 domain repeats three
      times and has homology to the polypyrimidine tract-binding motif of heterogeneous
      nuclear RNP I/L. NP220 also has a DNA-binding domain and nine repeats of the
      sequence LVTVDEVIEEEDL (acidic repeat). We have now isolated mouse equivalents of
      NP220 (mNP220s) and found that NP220s form a family of proteins with four members
      produced by alternative splicing of a common pre-mRNA. Two longer forms
      (NP220alpha and NP220beta) have all functional domains mentioned above while two
      shorter forms (NP220gamma and NP220delta) lack the DNA-binding domain and the
      acidic repeat. The structural aspects of NP220s are distinct from that of the SR
      proteins but rather resemble U2AF and Tra2 which activate a specific 3'-splicing
      site of specific genes in response to differentiation-dependent signals.

PMID- 8670299
TI  - Antisense inhibition of the RAD51 enhances radiosensitivity.
AB  - The mammalian RAD51 gene is a homologue of the yeast RAD51 and E. coli RecA
      genes, which are involved in recombination and DNA repair. We examined the role
      of RAD51 protein in mouse cells using RAD51 antisense phosphorothioate
      oligonucleotides (ODNs). The extraluminal delivery of 50 nM or 100 nM of
      antisense ODNs with lipofection to mouse cells resulted 90% suppression of RAD51
      protein expression. The antisense ODNs significantly inhibited the cell growth
      and the treated cells became more sensitive to gamma-irradiation than the control
      groups. These results indicate mouse RAD51 plays an essential role in cell
      proliferation and radioresistant activity.

PMID- 8670300
TI  - Pioglitazone improves insulin signaling defects in skeletal muscle from Wistar
      fatty (fa/fa) rats.
AB  - The effects of pioglitazone, a novel antidiabetic insulin-sensitizing agent, on
      insulin signaling in skeletal muscles from genetically obese Wistar fatty rats
      and their lean littermates were studied. Increased tyrosine phosphorylation
      levels of insulin receptors (IRs) and insulin receptor substrate 1 (IRS-1) in
      response to insulin were not observed in fatty rats. Insulin-stimulated
      phosphatidylinositol (PI) 3-kinase activity was reduced in fatty rats.
      Administration of pioglitazone (3 mg/kg/day) to fatty rats for 10 or 18 days
      reversed the decline in the insulin-stimulated tyrosine phosphorylated IR and IRS
      1 levels and the reduced insulin-stimulated PI 3-kinase activities. In contrast,
      insulin-stimulated tyrosine phosphorylation of IR and IRS-1 and PI 3-kinase
      activity in lean rats was not changed by pioglitazone. IR expression in fatty
      rats was down-regulated, which was not affected by pioglitazone. There was no
      difference between the PI 3-kinase expression levels in fatty and lean rats and
      pioglitazone did not change these expression levels. These results indicate that
      pioglitazone can correct the insulin signaling defects of Wistar fatty rats,
      thereby ameliorating insulin resistance.

PMID- 8670301
TI  - Whey protein stimulated the proliferation and differentiation of osteoblastic
      MC3T3-E1 cells.
AB  - We examined the effects of whey protein on osteoblastic MC3T3-E1 cells. This
      protein caused dose-dependent increases in [3H]thymidine incorporation and DNA
      content in the cells. It also increased the total protein and hydroxyproline
      contents in the cells. These activities were heat resistant when the protein was
      heated at 75 degrees C to 90 degrees C for 10 min. Heat-treated whey protein was
      first fractionated on a Mono S column, and the active fraction (basic protein
      fraction) was then applied to Superose 12. The molecular weights of the active
      components were approximately 10,000 and 14,000 Da, as determined with gel
      filtration. The inner solution of an everted gut-sac incubated in a solution of
      intact BP (basic protein), pepsin-digested BP or pepsin/pancreatin-digested BP
      also stimulated the [3H]thymidine incorporation. Thus these active components can
      possibly permeate or be absorbed by the intestines. We propose the possibility
      that the active component in the whey protein plays an important role in bone
      formation by activating osteoblasts.

PMID- 8670302
TI  - Comparison of different quantitative PCR procedures in the analysis of the 4977
      bp deletion in human mitochondrial DNA.
AB  - Four quantitative PCR procedures were compared to analysing the level of the 4977
      bp deletion in human mitochondrial DNA. A single preparation of total cellular
      DNA from the heart of a 69-year-old female subject was used for all four methods.
      We estimated the deletion to represent 0.005% of total mtDNA molecules using the
      serial dilution procedure and two internal standard methods with two separate
      sets of reference recombinant plasmids. However, the value obtained with the
      kinetic PCR analysis was 0.5%, two orders of magnitude higher. The internal
      standard procedures are likely to be the most accurate among the four methods
      used, but the more technically convenient serial dilution method would also be an
      appropriate choice.

PMID- 8670303
TI  - Cloning and tissue distribution of a novel P2X receptor from rat brain.
AB  - We have isolated the cDNA for a novel member (P2X6) of the ATP-gated ion channel
      family. The rat P2X6 nucleotide sequence encodes a 379 amino acid protein that
      conserves all the structural features of previously cloned P2X receptors,
      including the two putative transmembrane domains predicted by hydrophobicity
      plots. In situ hybridization analysis of rat brain sections showed a wide pattern
      of mRNA expression that is virtually identical to that already described for
      P2X4. Injection of P2X6 cRNA in Xenopus oocytes did not give rise to ATP
      activated channels. Coexpression of P2X6 with P2X4 subunits produced currents
      which were not discernibly different from those of P2X4 expressed alone.

PMID- 8670304
TI  - Characterization and chromosomal localization of the human A2a adenosine receptor
      gene: ADORA2A.
AB  - The gene for the stimulatory G protein-coupled human A2a adenosine receptor was
      isolated and sequence analysis revealed two exons that are interrupted by an
      intron of approximately 6.4 kb. An intron is located in the same region in the
      human A1 and A2b adenosine receptor genes. Comparison of the A2a genomic and cDNA
      sequences reveals two nucleotide differences in the coding region and the
      presence of an aberrant sequence in the 5'208 base pairs of the A2a cDNA
      including a polymorphism in the third base of codon Tyr-361 and Gly codon which
      was always detected at residue 392, indicated that the Arg codon present in the
      cDNA may be an artifact. Fluorescent in situ hybridization and PCR analysis of
      human-hamster hybrid cell panels shows that the A2a receptor gene is localized to
      chromosome 22q11.2. This is in contrast with previous reports (subsequently
      retracted) which mapped the A2a gene to chromosome 11q11-13.

PMID- 8670305
TI  - Cuprous ions activate glibenclamide-sensitive potassium channel in liver
      mitochondria.
AB  - Cuprous ions at micromolar concentrations induced swelling of rat liver
      mitochondria in isotonic solutions of potassium thiocyanate and potassium
      acetate. The swelling in K-acetate in the presence of the protonophore
      [corrected] carbonyl cyanide m-chloropenylhydrazone was partly inhibited by
      glibenclamide. In K(+)-containing media, Cu+ collapsed the mitochondrial membrane
      potential formed by operation of the respiratory chain with succinate or
      tetramethyl p-phenylenediamine + ascorbate as substrates or by the proton-pumping
      ATPase. In contrast, in K(+)-free media, isotonic sucrose or choline chloride,
      but not in NaC1, Cu+ induced a transient potassium gradient potential. These
      results indicate that cuprous ions at low concentrations, apart from promoting
      the electroneutral K+/H+ exchange, facilitate the uniport of K+, presumably by
      activating the mitochondrial potassium channel sensitive to glibenclamide.

PMID- 8670307
TI  - [Crystalline and molecular structure of the K+-complex of meso-valinomycin,
      cyclo(-(D-Val-L-Hyi-L-Val-D-Hyi)3-).KAuCl4].
AB  - Crystal structure of the complex of meso-valinomycin with KAuCl4
      (C60H102N6O18KAuCl4) was determined using direct X-ray diffraction analysis. The
      conformational state of the complex is similar to that determined earlier for
      free meso-valinomycin. Characteristic of it is the centrosymmetric bracelet shape
      stabilized by six intramolecular NH...OC hydrogen bonds of 4 --> 1 type. The K+
      ion is located in an inner negatively charged octahedral cavity formed by six
      carbonyl oxygen atoms of ester groups. The observed differences in conformational
      angles of the complex and free are caused by readjustment of the geometry of the
      ion-binding cavity to the size of the ion bound during complexation.

PMID- 8670306
TI  - Functional expression and cellular mRNA localization of a G protein-activated K+
      inward rectifier isolated from rat brain.
AB  - We have cloned by homology screening from a rat brain cDNA library a GIRK3-type
      (Kir 3.3) inwardly rectifying K+ channel subunit with high structural similarity
      to other subfamily members whose activity is thought to be controlled by receptor
      stimulated G proteins. When heterologously expressed both in Xenopus oocytes and
      in mammalian COS-7 cells, rbGIRK3 subunits individually fail to form functional
      channels. In contrast, when coexpressed with other GIRK subunits, rbGIRK3 gives
      rise to prominent currents which are enhanced by the stimulation of coexpressed 5
      HT1A receptors. In situ hybridizations show that of all GIRK subunits rbGIRK3 is
      most widely distributed and strongly expressed throughout the rat brain and thus
      may play an important role in central signal processing.

PMID- 8670308
TI  - [Study of the role of histidine residues in the function of uridine phosphorylase
      from Escherichia coli K-12 by protein engineering].
AB  - Using site-directed mutagenesis, mutant genes of the E.coli UDPase that coded
      proteins with point substitutions of histidine residues (i.e., H8N, H47N, H101N,
      H122N, H152N, H179N, and H240N) were constructed. Study of the enzymatic activity
      of mutant UDPases showed that histidine-asparagine substitutions at the positions
      47, 101, 152, 179, and 240 do not affect protein functioning. Whereas H122N and
      H8N substitutions inhibit the activity of UDPase by 60 and 100%, respectively.
      This evidences the important functional role of the His122 and His8 residues for
      the formation of the active site fo the enzyme.

PMID- 8670309
TI  - [Mapping of the genes for ribosomal proteins S26, L19, and L32 on human
      chromosomes].
AB  - A fragment of cDNA and an intron-containing fragment of the human L19 ribosomal
      protein (RPL19) gene, and introns of the human ribosomal proteins S26 (RPS26) and
      L32 (RPL32) genes were cloned and sequenced. The intron-containing genes of these
      ribosomal proteins were mapped to human chromosomes by means of polymerase chain
      reaction (PCR) using a human/rodent hybrid DNA panel.

PMID- 8670310
TI  - [Design of recombinant Escherichia coli strains, determining the secretory
      expression of artificial human granulocyte-macrophage colony-stimulating factor
      genes].
AB  - A number of recombinant plasmids for expression of artificial genes encoding
      human granulocyte-macrophage colony stimulating factor (GM-CSF) were constructed.
      A hybrid gene was obtained that contains a sequence encoding the leader peptide
      and a tandem of two IgG-binding domains of protein A from Staphylococcus aureus
      coupled, through an enteropepdidase linker, to a synthetic gmcsf gene. The
      construction enables Escherichia coli to carry out biosynthesis of the hybrid
      protein and its subsequent transport into the periplasmic space of bacteria.
      Another hybrid gene, combining sequences for the signal peptide of the E.coli
      outer membrane protein OmpA and GM-CSF, was obtained using polymerase chain
      reaction. The localization of the mature protein produced by the hybrid gene was
      found to depend on the strength of the promoter used.

PMID- 8670311
TI  - [The 5'-region of mink ribosomal protein S26 cDNA: sequencing and comparative
      analysis].
AB  - The 5'-terminal region of the mink S26 ribosomal protein cDNA was cloned using
      polymerase chain reaction. The nucleotide sequences of the 5'-UTR (24 bp) and a
      120-bp fragment of the coding region of RPS26 mRNA were determined. The homology
      between the coding regions of the human and mink RPS26 mRNAs proved to be 90.8%.
      The nucleotide sequences of the 5'-UTRs of mink, human, and rat RPS26 mRNAs, as
      well as mRNAs of the Drosophila S31 protein and Neurospora crp-5 protein, which
      are homologous to mammalian RPS26, were compared. A highly conserved 9-bp
      sequence located immediately upstream of the AUG codon was revealed in the 5'-UTR
      of the RPS26 mRNAs from different species.

PMID- 8670312
TI  - [Photoaffinity modification of amino acid derivatives of oligonucleotides in a
      complementary complex].
AB  - Intracomplex photochemical interaction of photoactive derivatives R-CONH(CH2)3NH
      pGATACCAA, where R= p-azidotetrafluorophenyl (I) or 2-nitro-5-azidophenyl (II),
      and 5'-phospho-p-azidoanilide pGATACCAA (III) with a target - oligonucleotide
      *pGGTATCp (IV) and its derivatives *pGGTATCp-NH(CH2)3NHX, where X = H (V), Phe
      (VI), or Lys (VII), was studied. According to electrophoretic data, photoreagent
      (I) gives rise to a covalent photoadduct with compound (IV) as well as with
      derivatives (VI) and (VII). In the case of reagent (II), only targets (V) - (VII)
      including aliphatic amino groups participate in the photocoupling. Upon
      irradiation of the duplexes comprising photoreagent (III) and targets (V)-(VII),
      the process is accompanied by the cleavage of the reagent's oligonucleotide
      moiety off the photomodification product. A plausible mechanism of the cleavage
      is discussed.

PMID- 8670313
TI  - [Study of the mechanism of chemical ligation of DNA by cyanogen bromide].
AB  - The mechanism of chemical ligation with cyanogen bromide in the presence of an N
      substituted morpholine was studied. Addition of the cyano group to the tertiary
      nitrogen atom of the N-substituted morpholine with the formation of a quaternary
      ammonium cation is shown to be the first step of the reaction; it is this cation
      that activates the oligonucleotide phosphate group. This method of activation can
      be used to obtain phosphodiester derivatives of nucleotides without DNA duplex.
      Optimal conditions of the chemical ligation were selected.

PMID- 8670314
TI  - Decrease in cellularity and expression of adhesion molecules by anti-tumor
      necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid
      arthritis.
AB  - OBJECTIVE: The effect of chimeric anti-tumor necrosis factor alpha (TNF alpha)
      monoclonal antibody (MAb) therapy on synovial inflammation was studied in order
      to address the hypothesis that anti-TNF alpha therapy leads to down-regulation of
      adhesion molecules and a decrease in inflammatory cell influx in synovial tissue
      (ST). METHODS: The immunohistologic features of synovial biopsy specimens, both
      before and 4 weeks after anti-TNF alpha MAb (cA2) therapy, were studied in 14
      patients with rheumatoid arthritis (RA). The patients either received a placebo
      (n = 2), or were given intravenous doses of cA2 at 10 mg/kg (n = 5) or 20 mg/kg
      (n = 7). RESULTS: A significant (P < 0.03) reduction in the mean scores for T
      cells and for the adhesion molecules, vascular cell adhesion molecule 1 and E
      selectin, was observed after therapy with 10 mg/kg or 20 mg/kg of cA2 in RA
      patients. CONCLUSION: The reduced expression of adhesion molecules, and the
      decrease in cellularity of rheumatoid ST after cA2 administration support the
      hypothesis that the antiinflammatory effect of anti-TNF alpha therapy might be
      partly explained by down-regulation of cytokine-inducible vascular adhesion
      molecules in ST, with a consequent reduction of cell traffic into joints.

PMID- 8670315
TI  - Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor
      alpha antibody in rheumatoid arthritis.
AB  - OBJECTIVE: To assess whether monoclonal antibody to tumor necrosis factor alpha
      (TNF alpha) reduces endothelial activation in rheumatoid arthritis (RA). METHODS:
      Levels of serum E-selectin, intercellular adhesion molecule 1 (ICAM-1), and
      vascular cell adhesion molecule 1 (VCAM-1), and circulating leukocytes
      (differential counts) were measured in RA patients before and up to 4 weeks after
      infusion of either placebo or chimeric anti-TNF alpha antibody cA2 (1 or 10
      mg/kg). RESULTS: Treatment with anti-TNF alpha decreased serum E-selectin and
      ICAM-1 levels, with the earliest detectable changes observed on days 1-3 after
      anti-TNF alpha infusion. No effect on VCAM-1 levels was detected. In parallel,
      there was a rapid and sustained increase in circulating lymphocytes. The extent
      of the decrease in serum E-selectin and ICAM-1 levels and the increase in
      lymphocyte counts was significantly higher (P < or = 0.05) in patients in whom a
      clinical benefit of anti-TNF alpha was observed ( > or = 20% response, by Paulus
      criteria, at week 4) compared with that in patients who failed to respond to anti
      TNF alpha at this time point. CONCLUSION: We propose that decreased serum levels
      of adhesion molecules may reflect diminished activation of endothelial cells in
      the synovial microvasculature, leading to reduced migration of leukocytes into
      synovial joints, and thus prolonging the therapeutic effect of anti-TNF alpha in
      RA.

PMID- 8670316
TI  - Dose-range and dose-frequency study of recombinant human interleukin-1 receptor
      antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study
      Group.
AB  - OBJECTIVE: To preliminarily evaluate the safety and efficacy of different dose
      levels and dosing frequencies of recombinant human interleukin-1 receptor
      antagonist (rHuIL-1Ra) in the treatment of patients with rheumatoid arthritis
      (RA). METHODS: One hundred seventy-five patients with active RA were enrolled in
      a randomized, double-blind trial of rHuIL-1Ra administered by subcutaneous
      injection. There were 9 treatment groups in the trial. During the initial 3-week
      treatment phase, patients were treated with 20, 70, or 200 mg rHuIL-1Ra,
      administered either once, 3 times, or 7 times per week, followed by a 4-week
      maintenance phase, during which all patients received the treatment-phase dose
      once per week. To maintain the blindness of the study, patients received daily
      injections of either rHulL-1Ra or placebo on the days rHuIL-1Ra was not
      administered. RESULTS: Recombinant HuIL-1Ra was well tolerated. The most frequent
      adverse event was injection-site reactions, which were reported in 62% of
      patients and caused 8 patients (5%) to withdraw prematurely from the study. Five
      patients (3%) developed serious adverse reactions unrelated to dose or dosing
      frequency. Due to the lack of a placebo arm and to the multiple small treatment
      groups, a definitive statement regarding efficacy could not be made. However, by
      the end of the 3-week treatment phase, daily dosing appeared more effective than
      weekly dosing when assessed by the number of swollen joints, the investigator and
      patient assessments of disease activity, pain score, and C-reactive protein
      levels. CONCLUSION: These preliminary data suggest that rHuIL-1Ra may be safely
      administered by subcutaneous injection to RA patients. The frequency of dosing
      appears to be important in determining clinical response, with daily
      administration providing the most benefit. A placebo-controlled trial is in
      progress to further assess the clinical usefulness and to better define
      appropriate doses of rHuIL-1Ra in patients with RA.

PMID- 8670317
TI  - A double-blind, placebo-controlled study of anti-CD5 immunoconjugate in patients
      with rheumatoid arthritis. The Xoma RA Investigator Group.
AB  - OBJECTIVE: To evaluate the efficacy of an anti-CD5 ricin-linked immunoconjugate
      (CD5-IC) in patients with rheumatoid arthritis (RA). METHODS: A total of 104
      evaluable patients were enrolled in a multicenter, double-blind, multiple-dose,
      placebo-controlled study of CD5-IC. RESULTS: Treatment with CD5-IC in doses up to
      8 mg/m2/day for 4 days in 1 month failed to produce marked or prolonged T cell
      depletion and was no more effective than placebo in ameliorating disease
      manifestations. An unexpectedly high placebo response was observed in 48% of the
      patients. Adverse events were correlated with the dose of CD5-IC, but the
      treatment was generally well-tolerated. CONCLUSION: At the doses used in this
      study, CD5-IC was ineffective for treating RA.

PMID- 8670318
TI  - Association of tumor necrosis factor microsatellite polymorphisms with HLA
      DRB1*04-bearing haplotypes in rheumatoid arthritis patients.
AB  - OBJECTIVE: To investigate 1) tumor necrosis factor (TNF) microsatellite allele
      frequencies in rheumatoid arthritis (RA), and 2) associations between TNF
      microsatellites and RA-associated HLA specificities in order to build up extended
      HLA haplotypes. METHODS: Eighty-five caucasoid patients with RA and 109 healthy
      caucasoid controls were typed for TNF microsatellites a-d using fluorescent
      labeled primers and semiautomated genotyping. A further 56 RA patients who were
      selected for having certain HLA-DRB1 types were also typed for these TNF
      microsatellites. Linkage disequilibria between TNF and HLA alleles were
      calculated, and extended haplotypes were established. RESULTS: The TNFa6 allele
      frequency was significantly increased in the RA patients compared with the
      controls (P = 0.0019, odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.3
      4.6), an increase that was further evident in patients who were HLA-DRB1*0401
      homozygous (P = 0.0003, OR 7.3, 95% CI 2.2-24.4). This increase was found to be
      due to association with HLA-DRB1*0401. No TNF microsatellite allele was found to
      be associated with HLA-DRB1*0404. Three HLA extended haplotypes were identified
      in the RA group: 1) HLA-DRB1*0401;TNFd4;TNFa6;TNFb5;HLA-B44; HLA-Cw5;HLA-A2, 2)
      HLA-DRB1*0301;TNFd2; TNFa2;TNFb3;HLA-B8;HLA-Cw7;HLA-A1, and 3)
      TNFd5;TNFc2;TNFa2;TNFb1;HLA-B62;HLA-Cw3. CONCLUSION: TNF microsatellites found to
      be associated with RA do not appear to be independent of class II HLA
      associations.

PMID- 8670320
TI  - Lack of association between augmentation mammoplasty and systemic sclerosis
      (scleroderma).
AB  - OBJECTIVE: To examine the possible association between augmentation mammoplasty
      and systemic sclerosis (SSc; scleroderma). METHODS: Eight hundred thirty-seven
      women with a clinical diagnosis of SSc, recruited as a volunteer sample from 3
      university-based, tertiary care scleroderma clinical research centers, and 2,507
      race-matched local control women, recruited by the technique of random-digit
      dialing and frequency-matched on age, completed a questionnaire providing data on
      history of augmentation mammoplasty, including possible complications of the
      procedure. The odds ratio (OR) and 95 percent confidence interval (95% CI) for
      the association of augmentation mammoplasty with SSc were estimated by
      multivariate logistic regression analysis with adjustment for age, race and
      center, and by conditional logistic regression analysis with adjustment for age.
      RESULTS: Eleven (1.31%) of the 837 cases reported a history of augmentation
      mammoplasty prior to diagnosis of SSc, compared with 31 (1.24%) of the 2,507
      controls. The adjusted OR from the unmatched analysis was 1.07 (95% CI 0.53
      2.13), while that from the matched analysis was 1.11 (95% CI 0.55-2.24).
      CONCLUSION: These results fail to demonstrate a significant association between
      augmentation mammoplasty and SSc, and are consistent with those reported from
      other epidemiologic studies.

PMID- 8670319
TI  - Protein metabolism in rheumatoid arthritis and aging. Effects of muscle strength
      training and tumor necrosis factor alpha.
AB  - OBJECTIVE: To determine the effects of rheumatoid arthritis (RA) on whole-body
      protein metabolism. METHODS: We examined protein metabolism and its hormonal and
      cytokine mediators before and 12 weeks after progressive resistance muscle
      strength training in 8 healthy young (mean +/- SD age 25 +/- 2 years) and 8
      healthy elderly (70 +/- 5 years) men and women, and in 8 adults with RA (42 +/-
      13 years). An additional 6 healthy elderly subjects (69 +/- 3 years) served as a
      swimming-only control group. RESULTS: Subjects with RA had higher rates of
      protein breakdown than did young or elderly healthy subjects (79.9 +/- 17.2
      versus 60.3 +/- 5.8 and 63.7 +/- 12.4 mumoles/gm total body potassium/hour,
      respectively, P < 0.05), while there was no effect of age per se. Patients
      treated with methotrexate had normal rates of protein breakdown (P < 0.01 versus
      RA without methotrexate; P not significant versus healthy young subjects).
      Increased protein catabolism in RA was no longer evident after strength training.
      In multiple regression analysis, levels of tumor necrosis factor alpha (TNF
      alpha) (r = 0.47, P = 0.01) and growth hormone (r = -0.51, P = 0.006) were
      associated with protein breakdown, and plasma glucagon levels were inversely
      correlated with protein synthesis (r = -0.45, P = 0.02). Growth hormone (r = 
      0.56, P = 0.002) and glucagon (r = 0.45, P = 0.04, levels were associated with
      protein oxidation. CONCLUSION: Adults with RA have increased whole-body protein
      breakdown, which correlates with growth hormone, glucagon, and TNF alpha
      production.

PMID- 8670321
TI  - Pilot study of antithymocyte globulin in systemic sclerosis.
AB  - OBJECTIVE: Between June 1, 1992 and August 31, 1994 we conducted an open pilot
      study of antithymocyte globulin (ATGAM; Upjohn, Kalamazoo, MI) in 10 patients
      with early systemic sclerosis (SSc) to assess whether this agent might prevent
      the progression of cutaneous and pulmonary involvement in this disease. METHODS:
      Adult patients with early SSc (< 3 years) and evidence of progressive skin and
      pulmonary disease were enrolled. All patients were hospitalized and received a
      single course of intravenous ATGAM, at a dosage of 10 mg/kg over 4 hours, on 5
      consecutive days. Patients were followed up at weeks 1, 2, 3, and 4, and months
      2, 4, 6, and 12. Patients were considered to be improved if the Rodnan skin score
      decreased > or = 25%, to be worse if the skin score increased > or = 25%, and to
      be not improved if the skin score was within 25% of baseline. For pulmonary
      involvement, patients were considered to be improved if either the diffusing
      capacity for carbon monoxide or the forced vital capacity was increased > or =
      10%, worse if decreased by > or = 10%, and stable if within 10% of baseline.
      RESULTS: Most patients tolerated the treatment well, although 1 patient developed
      an allergic reaction necessitating discontinuation of treatment, 1 developed a
      serum sickness reaction after completion of therapy, and 1 developed a central
      venous access-related axillary vein thrombosis. Two patients died of SSc-related
      complications during the followup period. At 12 months, only 2 patients showed
      improvement in both skin and pulmonary function measures, whereas 5 patients were
      worse and 3 were stable. CONCLUSION: At the dosage administered in this study,
      ATGAM appears ineffective in improving the skin and pulmonary features of SSc.

PMID- 8670322
TI  - Comprehensive noninvasive assessment of cardiac involvement in limited systemic
      sclerosis.
AB  - OBJECTIVE: To assess cardiovascular abnormalities in patients with limited
      systemic sclerosis (SSc), using noninvasive cardiac techniques. METHODS: Sixty
      three patients with limited SSc were prospectively evaluated with Doppler
      echocardiography and thallium-201 perfusion scintigraphy after a cold-stress test
      and radionuclide ventriculography. RESULTS: In the patients with limited SSc,
      there was a significantly high prevalence of abnormal left- and right-diastolic
      function parameters (P = 0.001 and P = 0.0002, respectively), thickening of
      papillary muscles (46%; P = 0.003), and mild mitral regurgitation (49%; P <
      0.0001), compared with controls. Systolic pulmonary arterial hypertension was
      detected in 9 patients (14%), and pericardial effusion in 11 patients (18%). In
      64% of patients with limited SSc, an ischemic response was detected on the
      thallium cold-stress scan; similarly, an ischemic response was detected in 57% of
      patients with primary Raynaud's phenomenon (P < 0.0001 versus controls).
      CONCLUSION: Although the frequency of cardiovascular symptoms was low in patients
      with limited SSc, a significant rate of cardiovascular abnormalities was found by
      noninvasive cardiac techniques.

PMID- 8670323
TI  - Evidence of free radical-mediated injury (isoprostane overproduction) in
      scleroderma.
AB  - OBJECTIVE: Free radical-induced oxidative stress with consequent lipid
      peroxidation and resultant tissue damage has been suggested as a potential
      mechanism of the pathogenesis of scleroderma. However, because reliable
      measurement of lipid peroxidation in vivo is difficult, it has not been possible
      to adequately examine this hypothesis. We have previously described a series of
      bioactive prostaglandin F2-like compounds, termed F2-isoprostanes, produced in
      vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of
      arachidonic acid and have shown them to be a reliable measure of lipid
      peroxidation in vivo. In the present study, we determined whether scleroderma is
      associated with enhanced oxidative stress. METHODS: As a measure of oxidative
      stress, we determined urinary concentrations of a tetranor-dicarboxylic acid
      metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in 8 patients with
      scleroderma (representing a wide spectrum of disease, including limited disease
      with refractory digital ulceration or pulmonary hypertension, and diffuse
      disease) and in 10 healthy control subjects. RESULTS: F2IP-M concentrations were
      significantly higher in patients with scleroderma (mean +/- SEM 3.41 +/- 0.64
      ng/mg of creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine)
      (P = 0.002). These elevations occurred in patients with limited disease and in
      those with diffuse disease. CONCLUSION: The increased level of urinary F2IP-M
      supports the hypothesis that free radical-induced oxidative injury occurs in
      scleroderma and provides a biologic marker whose relationship to disease activity
      and disease therapy may be important. These findings may also provide a rationale
      for exploring whether antioxidant therapy may influence the natural course of the
      disease.

PMID- 8670324
TI  - Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An
      immunogenetic, serologic, and clinical analysis.
AB  - OBJECTIVE: To determine the frequency, clinical associations, and any major
      histocompatibility complex correlations of antifibrillarin antibodies in patients
      with systemic sclerosis (SSc). METHODS: Antifibrillarin antibodies were
      determined by indirect immunofluorescence, immunoblotting, and
      immunoprecipitation, and HLA class II alleles by DNA oligotyping, in a large
      cohort of SSc patients. RESULTS: Antifibrillarin was found in 8% of 335 SSc sera
      and was significantly more common in blacks (16%) than whites (5%), in males
      (33%) than females (14%), and in patients with cardiac, renal, or gut
      involvement. The HLA class II haplotype DRB1*1302, DQB1*0604 was found
      significantly more frequently in SSc patients with antifibrillarin compared with
      race-matched normal controls and 260 SSc patients without antifibrillarin. In
      addition, 1 or more of the HLA-DQB1 alleles *0604, *0301, *0602, and/or *0302 was
      found in all antifibrillarin-positive patients, and 62% of the antifibrillarin
      positive patients had 2 of these HLA-DQB1 alleles, a highly significant
      difference from both race-matched normal controls and antifibrillarin-negative
      SSc patients. CONCLUSION: Antifibrillarin, although an infrequent nucleolar
      autoantibody, is a marker for severe SSc, especially in blacks and males, and is
      strongly associated with a unique HLA haplotype, as well as with combinations of
      certain HLA-DQB1 alleles.

PMID- 8670325
TI  - Early expression of E-selectin, tumor necrosis factor alpha, and mast cell
      infiltration in the salivary glands of patients with systemic sclerosis.
AB  - OBJECTIVE: To assess the predictive value of early endothelial E-selectin and
      tumor necrosis factor alpha (TNF alpha) expression, as well as mast cell
      infiltration, in the subsequent progression to systemic sclerosis (SSc) in
      patients with Raynaud's phenomenon (RP) and abnormal nailfold capillaroscopic
      findings. METHODS: Clinical criteria were evaluated, and immunostaining was
      performed on lip biopsy samples from 22 patients with RP and abnormal
      capillaroscopic results. None of these patients initially fulfilled the American
      College of Rheumatology criteria for SSc. RESULTS: E-selectin, TNF alpha, and
      mast cell infiltration were found in 9, 10, and 8 of 11 patients, respectively,
      whose disease progressed to SSc, and in 0, 2, and 1 of 11 patients, respectively,
      whose disease did not progress to SSc (P < 0.001, P < 0.01, and P < 0.01,
      respectively). CONCLUSION: E-selectin, TNF alpha, and mast cell infiltration are
      detectable in the very early stages of SSc, prior to the onset of skin changes.

PMID- 8670326
TI  - Sicca syndrome associated with hepatitis C virus infection.
AB  - OBJECTIVE: To determine the prevalence of hepatitis C virus (HCV) infection in
      patients with sicca syndrome, and to determine the clinical, immunologic, and
      genetic characteristics of sicca syndrome associated with HCV. METHODS: We
      conducted a prospective study in a university hospital immunology-rheumatology
      department. Sixty-two consecutive patients with sicca syndrome according to the
      European criteria for Sjogren's syndrome were included. HCV infection was
      diagnosed in patients with positive recombinant immunoblot assay findings and the
      presence of viral RNA in serum and saliva. Rheumatoid factor (RF), cryoglobulins,
      antinuclear antibodies, and anti-SS-A/SS-B antibodies were sought. HLA typing was
      performed on all patients. RESULTS: The prevalence of HCV infection in patients
      with sicca syndrome was 19%. The incidence of neurologic involvement was
      significantly increased in patients with sicca syndrome associated with HCV
      infection (24% versus 4%; P < 0.03), as was elevations in transaminase levels
      (87.5% versus 16%; P < 0.0001). RF and cryoglobulins were more frequent in HCV
      positive sicca syndrome patients (62% versus 30%; P < 0.03, and 56% versus 10%; P
      < 0.001, respectively). In contrast, anti-SS-A/SS-B antibodies were present in
      38% of HCV-negative sicca syndrome patients, but in only 1 HCV-positive sicca
      syndrome patient (P < 0.01). No significant difference in HLA type was observed.
      Viral RNA was present in the saliva of 83% of HCV-positive sicca syndrome
      patients, but in none of the HCV-negative sicca syndrome patients. CONCLUSION: We
      observed a high prevalence of HCV infection in our patients with sicca syndrome.
      HCV-positive sicca syndrome patients had specific clinical characteristics and
      were seronegative for SS-A/SS-B antibodies. Moreover, HCV RNA was present in the
      saliva of patients with HCV-associated sicca syndrome.

PMID- 8670327
TI  - Reactive arthritis in patients attending an urban sexually transmitted diseases
      clinic.
AB  - OBJECTIVE: To assess the prevalence, clinical manifestations, associated genital
      infections, and HLA associations of reactive arthritis (ReA) among patients
      attending an urban sexually transmitted diseases (STD) clinic. METHODS: Using a
      standardized questionnaire, 271 consecutive adults, primarily black, with
      possible or proven Chlamydia trachomatis genital infection were screened for
      symptoms of ReA. A followup questionnaire was administered 6 weeks later by mail.
      Patients who reported at least 1 symptom were evaluated by a rheumatologist. HLA
      B typing was performed on patients with objective ReA features. RESULTS: Nine of
      217 patients (4.1%) with genital infection/inflammation had objective ReA
      features. Chlamydial or nongonococcal STD syndromes were diagnosed in 8 of these
      9 patients (88%). Genital infection/inflammation was asymptomatic in 78% of
      patients with ReA features. HLA-B27 or other B7-cross-reactive group antigens
      were not associated with the occurrence of ReA. CONCLUSION: Nongonococcal genital
      infections, often asymptomatic, can trigger a relatively mild ReA in a larger
      number of exposed patients than previously thought, irrespective of the
      individual's HLA status.

PMID- 8670329
TI  - Familial aggregation of primary Raynaud's disease.
AB  - OBJECTIVE: To determine the occurrence of familial aggregation of primary
      Raynaud's disease. METHODS: Twenty-three patients with primary Raynaud's disease
      and their first-degree relatives were assessed by questionnaire and, when
      possible, by physical examination. The same procedures were performed on the
      patients' spouses and the spouses' first-degree relatives, who served as the
      control group. RESULTS: The prevalence of Raynaud's disease was significantly
      higher in the families of the probands than in the control families when assessed
      by questionnaire (26.1% versus 5.5%; P < 10(-5)), and by physical examination
      (11.2% versus 2.8%; P = 0.015). CONCLUSION: These findings demonstrate that there
      is significant familial aggregation of primary Raynaud's disease.

PMID- 8670328
TI  - Sensitivity and specificity of plasma and urine complement split products as
      indicators of lupus disease activity.
AB  - OBJECTIVE: To determine if measurement of serum complement split products (C4d,
      Bb, C5b-9) is better than conventional C3 and C4 measurements in distinguishing
      patients with varying degrees of lupus disease activity, and to determine if the
      presence of C3d in urine is helpful in distinguishing lupus patients with from
      those without early lupus nephritis. METHODS: Lupus disease activity was
      prospectively determined at 3 consecutive visits an average of 4 months apart,
      using the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus
      Erythematosus Disease Activity Index (SLEDAI), and physician global assessment
      (PGA). Blood samples were evaluated for the presence of C4d, Bb, and C5b-9 by
      quantitative microassay plate enzyme immunoassay at each patient visit. We
      characterized urinary excretion of C3 fragments (with attention to C3d) by sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis with Western blotting.
      RESULTS: Thirty-one SLE patients were enrolled in the study. The mean SLAM score
      and the mean SLEDAI score each correlated well with the PGA at all 3 visits. A
      SLAM score of 6 and a SLEDAI score of 4 had the best overall sensitivity and
      specificity for predicting moderate-to-severe disease activity by PGA (100% and
      73%, respectively, for the SLAM and 86% and 94%, respectively, for the SLEDAI).
      Serum C4d and Bb were more sensitive indicators of current moderate-to-severe
      lupus disease activity at all 3 visits than were serum C5b-9, C3, and C4. C3 and
      C4 were more specific indicators of moderate-to-severe disease activity. Serum
      C4d and Bb were more sensitive at predicting moderate-to-severe disease activity
      at subsequent visits than were C5b-9, C3, and C4. Urine C3d was better than C3,
      plasma C4d, Bb, C5b-9 and anti-double-stranded DNA antibody in distinguishing
      patients with from those without acute lupus nephritis (P = 0.02). CONCLUSION:
      C4d and Bb are sensitive indicators of moderate-to-severe lupus disease activity
      and may be most helpful in situations where conventional measurements are not,
      such as in lupus patients whose C3 and C4 levels remain normal despite evidence
      of clinical disease activity. It appears from this study that detection of urine
      C3d may be a simple way of measuring complement activation in the setting of
      lupus renal disease. The availability of instruments for clinical disease
      activity measurement such as the SLAM and the SLEDAI may enable more consistent
      definition of lupus disease activity and may thus provide a means for better
      examining the role of complement activation products in predicting lupus disease
      activity in larger patient populations.

PMID- 8670330
TI  - Inhibition and prevention of monosodium urate monohydrate crystal-induced acute
      inflammation in vivo by transforming growth factor beta1.
AB  - OBJECTIVE: We investigated the effects of transforming growth factor beta 1 (TGF
      beta 1) on monosodium urate monohydrate (MSU) crystal-induced acute inflammation
      in vivo. METHODS: One hour after MSU crystal-induced acute inflammation was
      produced in the rat subcutaneous air pouch model, the effects of recombinant
      human TGF beta 1 (rHuTGF beta 1; 10-100 pg/animal) and ultrapure TGF beta 1
      (UPTGF beta 1; 100 and 500 pg/animal) were assessed, based on absolute and
      differential white blood cell counts in the exudate. The effects of 10 pg of
      rHuTGF beta 1 preincubated with a specific anti-TGF beta antibody, and the
      effects of coinjection of crystals and rHuTGF beta 1, were also studied. RESULTS:
      UPTGF beta 1 and rHuTGF beta 1 markedly reduced MSU crystal-induced inflammation.
      Recombinant human TGF beta 1 also reduced inflammation when administered
      concomitantly with MSU crystals. Moreover, rHuTGF beta 1 and UPTGF beta 1,
      injected 1 hour after MSU crystal injection, reduced the inflammatory response in
      a dose-dependent manner. Injection of rHuTGF beta 1 (100 pg/animal) resulted in a
      > 90% reduction in the maximal white blood cell count, achieved 6 hours after
      crystal injection. Preincubation of rHuTGF beta 1 with a specific anti-TGF beta 1
      antibody significantly (P < 0.01) reversed the inhibitory effect of rHuTGF beta 1
      on the inflammatory response. Consistent with the regulation of inflammatory cell
      recruitment into the joint, the percentage of monocytes markedly decreased (P <
      0.01) following local injection with rHuTGF beta 1 6 hours after MSU crystal
      injection. CONCLUSION: Exogenous TGF beta 1 prevents and inhibits MSU crystal
      induced acute inflammation in vivo. Its role in the self-limitation of gouty
      attacks deserves consideration, among the various other factors involved.

PMID- 8670331
TI  - Leukocyte infiltration in synovial tissue from the shoulder of patients with
      polymyalgia rheumatica. Quantitative analysis and influence of corticosteroid
      treatment.
AB  - OBJECTIVE: To investigate the immunologic features of synovitis in patients with
      polymyalgia rheumatica (PMR) and to assess the modifications induced by
      corticosteroids. METHODS: Arthroscopic biopsies of shoulder synovium were
      obtained from 12 patients with untreated PMR and from 7 patients with PMR that
      had been treated. Immunohistochemistry was performed on frozen sections utilizing
      a panel of monoclonal antibodies and computerized image analysis. RESULTS:
      Synovitis was present in 10 of 12 (83%) untreated patients and in only 2 of 7
      (29%) treated patients. The synovitis was characterized by vascular proliferation
      and leukocyte infiltration. Infiltrating cells consisted predominantly of
      macrophages and T Lymphocytes. Almost all T lymphocytes were CD45RO positive. A
      few neutrophils, but no B cells, natural killer cells, or gamma/delta T cells
      were found. Intense expression of HLA class II antigens (DR moreso than DP moreso
      than DQ) was found in the lining layer cells as well as in macrophages and
      lymphocytes. DR, but not DP or DQ, was expressed by the endothelium of a few
      vessels. Class II antigen expression correlated with the number of macrophages
      and lymphocytes. Macrophage infiltration of arteriole walls was observed in 1
      untreated patient without giant cell arteritis (GCA). In untreated patients,
      there was a positive correlation between the percentage of infiltrating T cells
      and the duration of disease. Steroid therapy was associated with a significant
      reduction in the number of blood vessels and of HLA class II expression. One
      treated patient who no longer had symptoms of PMR still had active synovitis: a
      relapse occurred 4 months after the biopsy. CONCLUSION: Our findings support the
      hypothesis that synovitis is a major cause of the musculoskeletal symptoms of
      PMR. There are immunologic similarities with the vascular inflammation observed
      in GCA. Corticosteroids act on both the vascular and cellular components of
      synovitis.

PMID- 8670332
TI  - Effect of classification on the incidence of polyarteritis nodosa and microscopic
      polyangiitis.
AB  - OBJECTIVE: Polyarteritis nodosa (PAN) has been used as a generic term for
      systemic vasculitis. The distinction between classic PAN and microscopic
      polyangiitis (MPA) has not always been made. The aims of this study were to
      compare the American College of Rheumatology (ACR) criteria for PAN with the
      Chapel Hill Consensus Conference (CHCC) definitions of classic PAN and MPA, and
      to estimate the annual incidence of PAN and MPA. METHODS: The 1990 ACR criteria
      and CHCC definitions for systemic vasculitis were applied to an unselected cohort
      of 130 patients with systemic vasculitis attending a single district hospital in
      the UK between February 1, 1988 and January 31, 1994. RESULTS: Eight patients who
      met the ACR criteria for PAN and who also met the CHCC definition of MPA but not
      classic PAN were identified. A further 5 patients met the CHCC definition of MPA
      but not the ACR criteria for any other type of systemic vasculitis. No patient
      who met the CHCC definition of classic PAN was identified. The annual incidence
      of MPA was calculated to be 3.6/million (95% confidence interval 1.7-6.9), and
      the annual incidence of PAN (ACR criteria) was 2.4/million (95% confidence
      interval 0.9-5.3). CONCLUSION: Classic PAN as defined by the CHCC is rare,
      because small vessel involvement is excluded from this definition.

PMID- 8670333
TI  - Colchicine in breast milk of patients with familial Mediterranean fever.
AB  - OBJECTIVE: To clarify whether colchicine is excreted in breast milk, and to
      compare its concentrations in the serum and breast milk of lactating women who
      have familial Mediterranean fever (FMF). METHODS: Using a specific
      radioimmunoassay, we determined colchicine concentrations in the serum and breast
      milk of 4 patients at various time points, following oral administration of the
      drug. The study evaluated 4 patients with FMF who had been taking colchicine on a
      long-term basis. RESULTS: Colchicine was found to be excreted in breast milk. Its
      levels ranged between 1.9 and 8.6 ng/ml, which were similar to those found in the
      serum (parallel concentration time curves). However, there appeared to be a
      considerable variation in colchicine milk concentration among the different
      patients, which might be related to individual breast milk composition and,
      possibly, to other nutritional or metabolic factors. CONCLUSION: The extensive
      peripheral tissue binding and relatively low concentration of colchicine in
      breast milk suggests that the amount ingested by the infant is small.
      Furthermore, based on our clinical experience, nursing appears to be safe for
      lactating women with FMF who continue to take colchicine.

PMID- 8670334
TI  - Pediatric rheumatology in adult rheumatology practices in Washington state.
AB  - OBJECTIVE: To determine both the extent to which adult rheumatologists treat
      children and their level of comfort in doing so. METHODS: A questionnaire was
      sent to all 77 physicians in the state of Washington who were listed as adult
      rheumatologists in the American College of Rheumatology (ACR) directory. RESULTS:
      Sixty-six questionnaires (86%) were returned; 50 were identified as being from
      private-practicing adult rheumatologists and were the focus of this study. Sixty
      two percent of the respondents reported that they care for children; predictors
      included increased exposure to pediatric rheumatology during fellowship (P =
      0.003), increased distance from Seattle (P = 0.001), and listing oneself in the
      ACR directory as treating children (P = 0.03). Most respondents reported feeling
      discomfort in treating children younger than 6 years of age, treating Kawasaki
      disease, and treating polyarteritis nodosa, but most reported feeling comfortable
      treating children with chronic arthritides. Impediments to referring to a
      pediatric rheumatologist included distance (median distance 35 miles),
      convenience for the family, personal preference, and experience in caring for
      children. Twenty-nine percent reported difficulties referring to a pediatric
      rheumatologist outside of one's managed care plan. Adult rheumatologists
      expressed interest in continuing medical education dealing with pediatric
      rheumatology, preferably with a lecture format in their home communities.
      CONCLUSION: A significant number of adult rheumatologists care for children.
      Pediatric rheumatologists should provide both educational and consultative
      support for these adult rheumatologist colleagues.

PMID- 8670335
TI  - Human synovial mast cells. I. Ultrastructural in situ and in vitro immunologic
      characterization.
AB  - OBJECTIVE: To examine the ultrastructure of human synovial mast cells in situ, to
      identify immunologic and nonimmunologic stimuli that activate these cells in
      vitro, and to quantify a number of preformed and de novo-synthesized mediators.
      METHODS: We conducted an ultrastructural study of synovial mast cells in situ and
      performed immunoelectron microscopy localization of tryptase and chymase.
      Isolated synovial mast cells were analyzed biochemically, immunologically, and
      functionally in vitro and compared with cells from human lung, heart, and skin.
      RESULTS: Ultrastructural study of synovial tissue revealed mast cells with
      homogeneously dense, scrolled, crystal, and mixed granules, and lipid bodies in
      the cytoplasm. A small percentage of mast cells showed evidence of degranulation.
      Immunoelectron microscopy demonstrated the subcellular localization of tryptase
      and chymase over granules of > 90% of the mast cells, which were of the MCTC
      subtype. Isolated synovial mast cells released histamine in response to
      immunologic (anti-IgE and anti-Fc epsilon receptor I [anti-Fc epsilon RI]) and
      nonimmunologic (substance P, recombinant human stem cell factor, and 48/80)
      stimuli, but did not respond to recombinant human C5a in vitro. Synovial mast
      cells differed from those isolated from other human tissues, in a variety of
      immunologic and biochemical features. There was a linear correlation between the
      percentage of histamine secretion and tryptase release (r = 0.79, P < 0.001)
      induced by cross-linking of Fc epsilon RI. Cross-linking of IgE with anti-IgE on
      synovial mast cells induced de novo synthesis of prostaglandin D2 (mean +/- SEM
      87.5 +/- 4.9 ng/10(6) cells) and of leukotriene C4 (57.6 +/- 17.8 ng/10(6)
      cells). CONCLUSION: Mast cells ultrastructurally characterized in situ in
      synovial tissue were seen to differ from mast cells previously isolated from
      other human tissues. This raises the possibility that the local microenviroment
      influences their phenotype. Isolation of mast cells from human synovia can be
      useful for studying their role and their mediators in patients with arthritis.

PMID- 8670336
TI  - A matrix metalloproteinase-generated aggrecan neoepitope as a marker of skeletal
      maturation and aging in cartilage.
AB  - OBJECTIVE: To quantify the matrix metalloproteinase-induced neoepitope
      F(M/V)DIPEN (Phe-[Met/Val]-Asp-Ile-Pro-Glu-Asn341) in guinea pig and rabbit
      cartilage during aging. METHODS: Cartilage was taken from the stifle joint, nasal
      septum, and xiphoid process in guinea pigs and rabbits at selected ages. The
      cartilage was then extracted and evaluated for F(M/V)DIPEN levels by
      radioimmunoassay. RESULTS: In the 3 tissues studied, there were major increases
      in F(M/V)DIPEN levels during skeletal maturation and aging in both the guinea pig
      and rabbit cartilage. Except for spontaneous osteoarthritis that develops in
      guinea pigs with aging, increases in the neoepitope were not correlated with
      arthritis pathology. CONCLUSION: Increases in the level of F(M/V)DIPEN in
      cartilage occur as a result of skeletal maturation and aging. This physiologic
      accumulation of F(M/V)DIPEN in cartilage should be considered when using the
      neoepitope as a disease marker in arthritis.

PMID- 8670337
TI  - Antibiotic prophylaxis and treatment of reactive arthritis. Lessons from an
      animal model.
AB  - OBJECTIVE: To study the effect of antibiotic prophylaxis and treatment of
      reactive arthritis (ReA), using an experimental model. METHODS: Yersinia
      enterocolitica O:8, when injected intravenously into Lewis rats, causes a sterile
      arthritis closely resembling human ReA in 70% of the animals. Arthritis develops
      in 1-2 weeks; in some of the animals it remains chronic, and exacerbations occur.
      This model was applied to study the effect of a 7-day treatment with
      ciprofloxacin, using 2 different dosages (20 or 100 mg/kg/day) and 4 different
      schedules for initiation of treatment. The effects were evaluated by determining
      the daily arthritis score, the number of rats developing arthritis, and fecal
      excretion of Yersinia. In addition, weight gain was monitored. At autopsy (35 or
      60 days after inoculation with bacteria), samples were obtained for determination
      of Yersinia-specific antibodies in the serum. At the same time, samples were
      collected from mesenteric lymph nodes, lung, spleen, and liver for bacterial
      cultures, and from the ankle joints for histologic evaluation. In a separate
      experiment, ciprofloxacin concentrations in samples from serum and mesenteric
      lymph nodes were analyzed by high performance liquid chromatography. RESULTS: A 7
      day course with 100 mg/kg/day of ciprofloxacin, started on day 3 after bacterial
      inoculation, completely prevented the development of ReA and eliminated Yersinia
      during the 60-day experiment. If a dosage of 20 mg/kg/day was used, development
      of acute arthritis was prevented, but some of the animals had positive fecal
      cultures at the end of experiment. If antibiotic treatment was started on day 5,
      the preventive effect was still observed, but was less pronounced. If the
      treatment was started at the peak of the development of arthritis, no effect on
      arthritis was observed. CONCLUSION: These results indicate that if any effect of
      antibiotic treatment in Yersinia-triggered ReA is to be expected, the treatment
      must be started early and given in sufficient dosage. However, antibiotic
      treatment has no effect on fully developed arthritis.

PMID- 8670338
TI  - Dorsal defect of the patella: an uncommon cause of knee pain.

PMID- 8670339
TI  - Progression of rheumatoid arthritis following bone marrow transplantation. A case
      report with a 13-year followup.
AB  - The progression of rheumatoid arthritis (RA) is documented in a patient receiving
      a sex-mismatched, allogeneic bone marrow transplant (BMT) for gold-induced marrow
      aplasia. DNA typing confirmed a high probability of a full donor engraftment
      (complete chimerism). Although the RA was in complete remission 2 years post-BMT,
      clinical, laboratory, histologic, and radiologic evidence of the recurrence of
      synovitis from 3-13 years post-BMT is presented. Implications of these
      observations for theories of the pathogenesis of RA and the future of
      immunotherapies are discussed.

PMID- 8670340
TI  - Focal myositis presenting as pseudothrombophlebitis of the neck in a patient with
      mixed connective tissue disease.
AB  - This report describes a case of focal myositis in a patient with mixed connective
      tissue disease. The patient presented with diffuse neck swelling and
      pseudothrombophlebitis of the left internal jugular vein. Other clinical features
      included a high fever, elevated erythrocyte sedimentation rate, and prompt
      improvement after administration of high-dose intravenous corticosteroid therapy.
      Criteria for polymyositis were absent, serum levels of creatine kinase remained
      normal, and there was no sign of recurrence during 3 years of followup. Results
      of immunoprecipitation for anti-Jo-1 and other myositis-specific autoantibodies
      remained negative in serial serum samples obtained before, during, and after the
      episode.

PMID- 8670341
TI  - Pravastatin-induced rhabdomyolysis in a patient with mixed connective tissue
      disease.

PMID- 8670342
TI  - Musculoskeletal manifestations of invasive group A streptococcal infection.

PMID- 8670343
TI  - Finding a valid model for human Wegener's granulomatosis: comment on the article
      by Tomer et al.

PMID- 8670344
TI  - Tenidap in rheumatoid arthritis: comment on the article by Blackburn et al.

PMID- 8670345
TI  - Cytokines in polymyalgia rheumatica.

PMID- 8670346
TI  - Analysis of anti-U1 RNA antibodies in patients with connective tissue diseases:
      comment on the article by Hoffman et al.

PMID- 8670385
TI  - Brachial plexitis: a rare and often misdiagnosed postoperative complication.
AB  - Surgeons should be aware of the brachial plexitis syndrome in order to properly
      make an early diagnosis and educate the patient and his family on the etiology of
      this syndrome. It is characterized by the acute onset of shoulder pain, weakness,
      and paralysis in patients following a variety of surgical procedures.

PMID- 8670387
TI  - Rigid anchoring of the forehead to the frontal bone in endoscopic facelifting: a
      new technique.
AB  - A new method for internal fixation of the skull in endoscopic facelifting has
      been developed using a so-called V-tunnel drill system which eliminates the need
      for pins and screws to anchor the suspended forehead. This system consists of a
      conventional drill and a V-tunnel guide. The technique involves anchoring the
      scalp by means of galea/periosteal stitches and sewing it to the bone with PDS
      sutures after a V-shaped tunnel has been drilled in the external table to a depth
      of 5 mm. The sutures can be easily positioned and stitched through the V-tunnel
      without endangering the cerebrum. This versatile V-tunnel drill procedure is very
      easy and simple and has many foreseeable applications.

PMID- 8670386
TI  - Postliposuction histologic alterations of adipose tissue.
AB  - The author studied seven patients who received suction assisted lipectomy prior
      to classic abdominal dermolipectomies. The liposuction sessions were performed
      180, 150, 60, 30, 15, 12, 8, and 5 days before the abdominoplasties. Histologic
      studies disclosed extensive amounts of dead adipocytes and free fat within the
      aspirated area. The pockets left behind were filled with serum hemorrhagic
      material and evolved to the healing process. Collagen synthesis was increased
      initially then followed by gradual decrease and a remodeling process. Our
      findings suggest that liposuction techniques preserve some vessels and nerves,
      but the final resolution may take several months or years, depending on the
      amount of tissue damage.

PMID- 8670388
TI  - Endoscopic forehead-scalp flap fixation with K-wire.
AB  - A new technique of direct fixation of the endoscopically elevated scalp
      periosteal flap to the underlying skeleton using transcutaneous K-wires is
      described. The technique is very simple to perform. It is expedient. The
      instrument requirement is minimal. The level of elevation of the brow can be
      determined and fixed reliably. Postoperative care is simple and is accepted well
      by the patients. A couple of instrumentation options are described.

PMID- 8670389
TI  - A new concept in blepharoplasty.
AB  - Apart from what may be considered complications, the intervention of any
      aesthetic surgery can have undesired effects (scar sequelae, normal regional
      dynamic disorders, edema, iatrogenic acceleration of the aging process in the
      area). The orbital region is particularly sensitive to these undesirable effects
      due to its situation and the importance of the eyelids in facial sign language.
      The sum of these undesirable effects and not infrequent complications often place
      the plastic surgeon in a compromising situation. It is for this reason that in
      recent years we have made a special effort to analyze causes, to design new
      techniques, and to evaluate the combination of different techniques in an attempt
      to minimize these undesirable effects, so as to be able to offer patients more
      natural and safer results. It is with this intention that this paper records some
      anatomical and functional details of the eyelids, analyzes the physiology of the
      aging process, and examines some classic and modern techniques.

PMID- 8670390
TI  - Lip rejuvenation using chemical abrasion and padding with expanded
      polytetrafluoroethylene implants.
AB  - Aesthetic improvement of the lips is a problem that must be treated in a totally
      independent way from the rest of the face because degeneration of the lips is
      tied to genetic or acquired factors for which no long-term procedure is
      effective. The effectiveness of resurfacing of large and small wrinkles using
      chemical abrasion has long been recognized. Labial padding, using supple Gore
      Tex(R) implants that are cut to size and placed where necessary provides the
      desired result while preserving the function of the lip. Usually requested by the
      younger patient, it can be used in combination with chemical abrasion in the more
      mature patient. This technique is not only quick, tested, very effective, and
      definitive, but totally reversible if needed, which allows us to widen the
      indications with great safety.

PMID- 8670391
TI  - Galea and subgalea graft for lip augmentation revision.
AB  - In this paper we will review the results obtained during the last 2 years with
      the aponeurotic galea and subgalea for vermillion lip augmentation. The survey
      was carried out on 42 patients who displayed either an absence of or reduction in
      the vermillion of one or both lips or a senile lip. In all cases the surgical
      procedure introduced aponeurotic galea and subgalea in the space found between
      the orbicular lip muscle and the vestibular mucus, just behind the vermillion.
      All the operations were performed under local anaesthetic. The size of the
      aponeurotic galea fragment removed varied in length between 10 and 12 cms. and in
      width between 1 and 2 cms., using the following parameters for its dimensions:
      the previous volume of the lips, and the distance between the two buccal
      commissures when in the "smile position."

PMID- 8670392
TI  - Abdominoplasty with two fusiform plications.
AB  - Two-fusiform plications are recommended for contouring the abdomen to produce a
      slimmer waistline in abdominoplasty, rather than the classical median xiphoid
      pubic fusiform plication. This procedure was accomplished in 11 patients. After
      the dermoadipose flap was undermined, two fusiform shapes were marked at the
      transition of the sheaths of the rectus abdominis muscles with the external
      obliques. The slimmer waistline produced intraoperatively was maintained during
      the late postoperative period (mean 20 months), without loss of the natural
      contour between the rectus muscles. Maintenance of the natural contours of the
      abdominal muscles is of fundamental importance to reduce the embarrassment of a
      postabdominoplasty flat abdomen.

PMID- 8670393
TI  - Aesthetic reductive rhinoplasty to facilitate reconstruction of the nose.
AB  - The authors present an original approach to the problem of the reconstruction of
      the nasal pyramid after a demolition for neoplasia. Reductive rhinoplasty is done
      at the same time as demolition, so that the remaining gap in the soft tissues is
      reduced to the point where it can be repaired with a local flap. The positive
      aspects of this method are its excellent aesthetic results, comparative ease, and
      quick execution. The negative aspects are it is limited to defects of less than
      half of the nasal pyramid and it cannot be used for defects of nostrils; there
      have also been isolated cases of psychological problems from the sudden physical
      change.

PMID- 8670394
TI  - Intramuscular gluteal implants.
AB  - The authors present a new space for the placement of gluteal implants in
      augmentation gluteoplasty. Placement of implants in this intramuscular anatomical
      space offers a good cosmetic result and seems to satisfy the demands of
      augmentation gluteoplasty in terms of safety, reproducibility, and esthetics.

PMID- 8670395
TI  - Ten year evolution of liposuction.
AB  - The author very briefly reviews the evolution of liposuction beginning with the
      pioneering work of Yves-Gerard Illouz, through the contributions of Doctors
      Toledo, Gasparotti, Klein, and Zocchi. This brief historical review is
      accompanied by cases demonstrating his experiences with these techniques.

PMID- 8670406
TI  - The Argentine Precordillera: A Traveler from the Ouachita Embayment of North
      American Laurentia
AB  - The Argentine Precordillera is a continental fragment rifted from the Ouachita
      embayment of the southern margin of Laurentia (North America) during Cambrian
      time [about 515 million years ago (Ma)] and accreted to the western margin of
      Gondwana (South America) during Ordovician time (about 455 Ma). Similarities of
      Cambrian stratigraphic successions and faunas, Grenville basement rocks, and
      dimensions link the Argentine Precordillera to the Ouachita embayment. Evidence
      of rifting during Cambrian time and of a wide ocean basin during Ordovician time
      indicates that the Precordillera traveled as an independent microcontinent to
      collide with Gondwana.

PMID- 8670407
TI  - Evidence for Widespread 26Al in the Solar Nebula and Constraints for Nebula Time
      Scales
AB  - A search was made for 26Mg (26Mg*) from the decay of 26Al (half-life = 0.73
      million years) in Al-rich objects from unequilibrated ordinary chondrites. Two Ca
      Al-rich inclusions (CAIs) and two Al-rich chondrules (not CAIs) were found that
      contained 26Al when they formed. Internal isochrons for the CAIs yielded an
      initial 26Al/27Al ratio [(26Al/27Al)0] of 5 x 10(-5), indistinguishable from most
      CAIs in carbonaceous chondrites. This result shows that CAIs with this level of
      26Al are present throughout the classes of chondrites and strengthens the notion
      that 26Al was widespread in the early solar system. The two Al-rich chondrules
      have lower 26Mg*, corresponding to a (26Al/27Al)0 ratio of approximately 9 x 10(
      6). Five other Al-rich chondrules contain no resolvable 26Mg*. If chondrules and
      CAIs formed from an isotopically homogeneous reservoir, then the chondrules with
      26Al must have formed or been last altered approximately2 million years after
      CAIs formed; the 26Mg*-free chondrules formed >1 to 3 million years later still.
      Because 26Mg*-containing and 26Mg*-free chondrules are both found in Chainpur,
      which was not heated to more than approximately400&deg;C, it follows that parent
      body metamorphism cannot explain the absence of 26Mg* in some of these
      chondrules. Rather, its absence indicates that the lifetime of the solar nebula
      over which CAIs and chondrules formed extended over approximately5 million years.

PMID- 8670396
TI  - Injectable silicone: cause of facial nodules, cellulitis, ulceration, and
      migration.
AB  - Fifty-four patients with problems following "medical grade" silicone injections
      into the face and legs were seen from 1974 until 1995. Complications consisted of
      chronic cellulitis, nodules, foreign body reactions, and movement of material to
      near and distant parts of the body. These difficulties usually demonstrated
      themselves many years after injection. It is suggested that problems occur
      despite good technique, good material, and small amounts injected. Because the
      side effects are unpredictable and often uncorrectable, further studies must be
      performed to insure silicone's safety.

PMID- 8670408
TI  - "Single-Electron Parametron": Reversible Computation in a Discrete-State System
AB  - The energy dissipation in a proposed digital device in which discrete degrees of
      freedom are used to represent digital information (a "single-electron
      parametron") was analyzed. If the switching speed is not too high, the device may
      operate reversibly (adiabatically), and the energy dissipation &Escr; per bit may
      be much less than the thermal energy scale kBT (where kB is Boltzmann's constant
      and T is temperature). The energy-time product &Escr;tau is, however, much
      greater than Planck's constant Planck's over 2pi, at least in the standard
      "orthodox" model of single-electron tunneling that was used in these
      calculations.

PMID- 8670409
TI  - "Tubules-Within-a-Tubule" Hierarchical Order of Mesoporous Molecular Sieves in
      MCM-41
AB  - The recently discovered mesoporous aluminosilicate MCM-41 consists of hexagonal
      arrays of nanometer-sized cylindrical pores. It is shown that this material can
      be synthesized by cooperative condensation of silicate and cylindrical cationic
      micelles. Careful control of the surfactant-water content and the rate of
      condensation of silica at high alkalinity resulted in hollow tubules 0.3 to 3
      micrometers in diameter. The wall of the tubules consisted of coaxial cylindrical
      pores, nanometers in size, that are characteristic of those of MCM-41. The
      formation of this higher order structure may take place through a liquid crystal
      phase transformation mechanism involving an anisotropic membrane-to-tubule phase
      change. The hierarchical organization of this "tubules-within-a-tubule" particle
      texture is similar to that of the frustules of marine diatoms.

PMID- 8670410
TI  - Oil-Water Interface Templating of Mesoporous Macroscale Structures
AB  - Ordered mesostructured porous silicas that are also macroscopically structured
      were created by control of the interface on two different length scales
      simultaneously. Micellar arrays controlled the nanometer-scale assembly, and at
      the static boundary between an aqueous phase and an organic phase, control was
      achieved on the micrometer to centimeter scale. Acid-prepared mesostructures of
      silica were made with the p6, Pm3n, and the P63/mmc structures in the form of
      porous fibers 50 to 1000 micrometers in length, hollow spheres with diameters of
      1 to 100 micrometers, and thin sheets up to 10 centimeters in diameter and about
      10 to 500 micrometers in thickness. These results might have implications for
      technical applications, such as slow drug-release systems or membranes, and in
      biomineralization, where many processes are also interface-controlled.

PMID- 8670411
TI  - Mongolian Tree Rings and 20th-Century Warming
AB  - A 450-year tree-ring width chronology of Siberian pine (Pinus sibirica Du Tour)
      growing at timberline (2450 meters) in the Tarvagatay Mountains in west central
      Mongolia shows wide annual growth rings for the recent century. Ecological site
      observations and comparisons with instrumental temperature records indicate that
      the ring widths of these trees are sensitive to annual temperature variations.
      Low-frequency variations in the Tarvagatay tree-ring record are similar to those
      in a reconstruction of Arctic annual temperatures, which is based on 20 tree-ring
      width series from northern North America, Scandinavia, and western Russia. The
      results indicate that recent warming is unusual relative to temperatures of the
      past 450 years.

PMID- 8670412
TI  - Photopolymerization and Mass-Independent Sulfur Isotope Fractionations in Carbon
      Disulfide
AB  - Irradiation of gaseous carbon disulfide [CS2(g)] at 313 nanometers produces a
      dark brown aerosol of (CS2)x. Its thermal decomposition products include disulfur
      (S2), carbon monosulfide (CS), and (CS)x. The photopolymerization process is
      accompanied by a large mass-independent isotopic fractionation of sulfur (a 5 to
      10 per mil sulfur-33 excess and a 61 to 84 per mil sulfur-36 deficit). Excess
      sulfur-33 has been observed in several classes of meteorites. Photochemical
      production of (CS2)x may be important in the origin and evolution of
      cosmochemical environments such as the presolar nebula, meteorites, asteroids,
      and planetary atmospheres.

PMID- 8670413
TI  - A Statistical Model of the Fluctuations in the Geomagnetic Field from
      Paleosecular Variation to Reversal
AB  - The statistical characteristics of the local magnetic field of Earth during
      paleosecular variation, excursions, and reversals are described on the basis of a
      database that gathers the cleaned mean direction and average remanent intensity
      of 2741 lava flows that have erupted over the last 20 million years. A model
      consisting of a normally distributed axial dipole component plus an independent
      isotropic set of vectors with a Maxwellian distribution that simulates secular
      variation fits the range of geomagnetic fluctuations, in terms of both direction
      and intensity. This result suggests that the magnitude of secular variation
      vectors is independent of the magnitude of Earth's axial dipole moment and that
      the amplitude of secular variation is unchanged during reversals.

PMID- 8670414
TI  - Absorption of Solar Energy in the Atmosphere: Discrepancy Between Model and
      Observations
AB  - An atmospheric general circulation model, which assimilates data from daily
      observations of temperature, humidity, wind, and sea-level air pressure, was
      compared with a set of observations that combines satellite and ground-based
      measurements of solar flux. The comparison reveals that the model underestimates
      by 25 to 30 watts per square meter the amount of solar energy absorbed by Earth's
      atmosphere. Contrary to some recent reports, clouds have little or no overall
      effect on atmospheric absorption, a consistent feature of both the observations
      and the model. Of several variables considered, water vapor appears to be the
      dominant influence on atmospheric absorption.

PMID- 8670415
TI  - Subnanometer-Diameter Wires Isolated in a Polymer Matrix by Fast Polymerization
AB  - The preparation and analysis of inorganic-organic polymer nanocomposites
      consisting of inorganic nanowires and multiwire "cables" in a random-coil organic
      polymer host is reported. Dissolution of inorganic (LiMo3Se3)n wires in a
      strongly coordinating monomer, vinylene carbonate, and the use of a rapid
      polymerization in the presence of a cross-linking agent produce nanocomposites
      without phase separation. Polymerization of dilute solutions yields a material
      containing mostly (Mo3Se3(-))n mono- and biwires, 6 to 20 angstroms in diameter
      and 50 to 100 nanometers long. Polymerization of more concentrated liquid
      crystalline solutions yields a nanocomposite containing oriented multiwire
      cables, 20 to 40 angstroms in diameter and up to 1500 nanometers long, that
      display optical anisotropy and electrical conductivity.

PMID- 8670416
TI  - Visualization of slow axonal transport in vivo.
AB  - In axons, cytoskeletal constituents move by slow transport. However, it remains
      controversial whether axonal neurofilaments are dynamic structures in which only
      subunits are transported or whether filaments assemble in the proximal axon and
      are transported intact as polymers to the axon terminus. To investigate the form
      neurofilament proteins take during transport, neurons of transgenic mice lacking
      axonal neurofilaments were infected with a recombinant adenoviral vector encoding
      epitope-tagged neurofilament M. Confocal and electron microscopy revealed that
      the virally encoded neurofilament M was transported in unpolymerized form along
      axonal microtubules. Thus, neurofilament proteins are probably transported as
      subunits or small oligomers along microtubules, which are major routes for slow
      axonal transport.

PMID- 8670417
TI  - Immunodeficiency in protein kinase cbeta-deficient mice.
AB  - Cross-linking of the antigen receptor on lymphocytes by antigens or antibodies to
      the receptor results in activation of enzymes of the protein kinase C (PKC)
      family. Mice homozygous for a targeted disruption of the gene encoding the PKC
      betaI and PKC-betaII isoforms develop an immunodeficiency characterized by
      impaired humoral immune responses and reduced cellular responses of B cells,
      which is similar to X-linked immunodeficiency in mice. Thus PKC-betaI and PKC
      betaII play an important role in B cell activation and may be functionally linked
      to Bruton's tyrosine kinase in antigen receptor-mediated signal transduction.

PMID- 8670418
TI  - Activation of Pyk2 by stress signals and coupling with JNK signaling pathway.
AB  - The c-Jun amino-terminal kinase (JNK) is activated by various heterotrimeric
      guanine nucleotide-binding protein (G protein)-coupled receptors, inflammatory
      cytokines, and stress signals. Yet, upstream mediators that link extracellular
      signals with the JNK signaling pathway are currently unknown. The tyrosine kinase
      Pyk2 was activated by tumor necrosis factor alpha, by ultraviolet irradiation,
      and by changes in osmolarity. Overexpression of Pyk2 led to activation of JNK,
      and a dominant-negative mutant of Pyk2 interfered with ultraviolet light- or
      osmotic shock-induced activation of JNK. Pyk2 represents a cell type-specific,
      stress-sensitive mediator of the JNK signaling pathway.

PMID- 8670419
TI  - Cooperative DNA binding and sequence-selective recognition conferred by the STAT
      amino-terminal domain.
AB  - STAT proteins (signal transducers and activators of transcription) activate
      distinct target genes despite having similar DNA binding preferences. The
      transcriptional specificity of STAT proteins was investigated on natural STAT
      binding sites near the interferon-gamma gene. These sites are arranged in
      multiple copies and required cooperative interactions for STAT binding. The
      conserved amino-terminal domain of STAT proteins was required for cooperative DNA
      binding, although this domain was not essential for dimerization or binding to a
      single site. Cooperative binding interactions enabled the STAT proteins to
      recognize variations of the consensus site. These sites can be specific for the
      different STAT proteins and may function to direct selective transcriptional
      activation.

PMID- 8670420
TI  - Diffusional mobility of Golgi proteins in membranes of living cells.
AB  - The mechanism by which Golgi membrane proteins are retained within the Golgi
      complex in the midst of a continuous flow of protein and lipid is not yet
      understood. The diffusional mobilities of mammalian Golgi membrane proteins fused
      with green fluorescent protein from Aequorea victoria were measured in living
      HeLa cells with the fluorescence photobleaching recovery technique. The diffusion
      coefficients ranged from 3 x 10(-9) square centimeters per second to 5 x 10(-9)
      square centimeters per second, with greater than 90 percent of the chimeric
      proteins mobile. Extensive lateral diffusion of the chimeric proteins occurred
      between Golgi stacks. Thus, the chimeras diffuse rapidly and freely in Golgi
      membranes, which suggests that Golgi targeting and retention of these molecules
      does not depend on protein immobilization.

PMID- 8670421
TI  - Central hypotensive effects of the alpha2a-adrenergic receptor subtype.
AB  - alpha2-Adrenergic receptors (alpha2ARs) present in the brainstem decrease blood
      pressure and are targets for clinically effective antihypertensive drugs. The
      existence of three alpha2AR subtypes, the lack of subtype-specific ligands, and
      the cross-reactivity of alpha2AR agonists with imidazoline receptors has
      precluded an understanding of the role of individual alpha2AR subtypes in the
      hypotensive response. Gene targeting was used to introduce a point mutation into
      the alpha2aAR subtype in the mouse genome. The hypotensive response to alpha2AR
      agonists was lost in the mutant mice, demonstrating that the alpha2aAR subtype
      plays a principal role in this response.

PMID- 8670422
TI  - Cardiovascular regulation in mice lacking alpha2-adrenergic receptor subtypes b
      and c.
AB  - alpha2-Adrenergic receptors (alpha2ARs) are essential components of the neural
      circuitry regulating cardiovascular function. The role of specific alpha2AR
      subtypes (alpha2a, alpha2b, and alpha2c) was characterized with hemodynamic
      measurements obtained from strains of genetically engineered mice deficient in
      either alpha2b or alpha2c receptors. Stimulation of alpha2b receptors in vascular
      smooth muscle produced hypertension and counteracted the clinically beneficial
      hypotensive effect of stimulating alpha2a receptors in the central nervous
      system. There were no hemodynamic effects produced by disruption of the alpha2c
      subtype. These results provide evidence for the clinical efficacy of more subtype
      selective alpha2AR drugs.

PMID- 8670423
TI  - Functional uncoupling of linked neurotransmitter effects by combinatorial
      convergence.
AB  - Physiological signaling pathways both diverge and converge-a single
      neurotransmitter can have multiple effects and multiple transmitters can have the
      same effects-in the same target cell. Divergence couples the effects of a
      transmitter together in a relatively fixed ratio. Different physiological
      circumstances may require a different ratio, however; the coupling must be made
      modifiable. This can be achieved through convergence. If two transmitters couple
      the effects in different ratios, then combinations of the transmitters can yield
      all intermediate ratios of the effects, thus functionally uncoupling them. This
      mechanism is analyzed in a well-understood, simple invertebrate neuromuscular
      circuit.

PMID- 8670424
TI  - Organization of diphtheria toxin T domain in bilayers: a site-directed spin
      labeling study.
AB  - The diphtheria toxin transmembrane (T) domain was spin-labeled at consecutive
      residues in a helical segment, TH9. After binding of the T domain to membranes at
      low pH, the nitroxide side chains generated by spin labeling were measured with
      respect to their frequency of collision with polar and nonpolar reagents. The
      data showed that the helical structure of TH9 in solution is conserved, with one
      face exposed to water and the other to the hydrophobic interior of the bilayer.
      Measurement of the depth of the nitroxide side chains from the membrane surfaces
      revealed an incremental change of about 5 angstroms per turn, which is consistent
      with a transmembrane orientation of an alpha helix. These results indicate that
      the helix forms the lining of a transmembrane water-filled channel.

PMID- 8670425
TI  - Genome sequence of a human tumorigenic poxvirus: prediction of specific host
      response-evasion genes.
AB  - Molluscum contagiosum virus (MCV) commonly causes asymptomatic cutaneous
      neoplasms in children and sexually active adults as well as persistent
      opportunistic acquired immunodeficiency syndrome (AIDS)-associated disease.
      Sequencing the 190-kilobase pair genome of MCV has now revealed that the virus
      potentially encodes 163 proteins, of which 103 have homologs in the smallpox
      virus. MCV lacks counterparts to 83 genes of the smallpox virus, including those
      important in suppression of host responses to infection, nucleotide biosynthesis,
      and cell proliferation. MCV possesses 59 genes that are predicted to encode
      previously uncharacterized proteins, including major histocompatibility complex
      class I, chemokine, and glutathione peroxidase homologs, which suggests that
      there are MCV-specific strategies for coexistence with the human host.

PMID- 8670521
TI  - Bone density, bone markers and bone radiological features in mastocytosis.
AB  - We examined the association between severity of disease in mastocytosis and
      skeletal manifestation and bone markers in 16 patients varying in extent of
      mastocytosis as determined by the urine excretion of methylimidazoleacetic acid.
      Both osteoporosis and osteosclerosis were found. Bone density in the hip was
      significantly higher (p < 0.05) in both men and women with an enhanced histamine
      metabolite excretion. Patients with only moderately increased mast cell mass had
      low bone mineral density in the hip, osteoporosis and vertebral fractures. The
      different skeletal disease patterns in mastocytosis might be the effect on
      osteoblasts and osteoclasts of biologically active substances. Mast cells release
      a number of vasoactive substances, including histamine which promotes osteoblasts
      and heparin and prostaglandin D2 which induce bone resorption by activation of
      osteoclasts. Systemic mastocytosis is a rare disease characterized by multi-organ
      infiltration by mast cells and with varying skeletal manifestations including
      osteoporosis. Treatment with bisphosphonates may be beneficial in arresting
      osteoporosis in this disorder.

PMID- 8670522
TI  - Quality of life after open-heart surgery in patients over 75 years old.
AB  - In a postal study we used the Nottingham Health Profile questionnaire to assess
      the quality of life of elderly survivors of open-heart surgery. From January 1984
      to October 1993, 146 patients over 75 years of age underwent open-heart surgery
      in the Department of Cardiovascular Surgery at Beasancon (France). Eleven
      patients (7. 5%) died in the immediate post-operative course. Patients' mean
      follow-up was 3.4 +/- 2.4 years. Fourteen patients died during follow-up. One
      hundred and four completed Nottingham Health Profile questionnaires were
      returned. Five per cent of the patients lived in an old people's home. Six per
      cent of the patients were unable to walk at all. One patient out of five felt
      isolated. Fifteen per cent of the patients were in constant pain. Half of the
      patients took sleeping pills. Conversely, 87% of the patients felt an improvement
      after surgery. Sixty-two per cent continued to drive. Ninety-seven patients (92%)
      did at least one of the following three activities: watched television, listened
      to the radio, read books or magazines. Fifty-eight patients (56%) walked on a
      regular basis. The different types of pathology, of surgical procedures and
      whether or not a pacemaker was implanted during the post-operative course were
      not reflected in the quality of life (QOL) scores. After cardiac surgery, most of
      the patients were physically autonomous and related to their exterior world.

PMID- 8670523
TI  - Respiratory rehabilitation, exercise capacity and quality of life in chronic
      airways disease in old age.
AB  - Respiratory rehabilitation improves exercise capacity and quality of life in
      younger patients but is untried in the aged. We aimed to: (a) assess
      repeatability of the 6-minute walk test, factors affecting it and its relation to
      quality of life in elderly patients with chronic obstructive airways disease
      (COAD); (b) assess compliance of such patients with an intensive respiratory
      rehabilitation protocol; (c) pilot the assessment of the effect of respiratory
      rehabilitation on the 6-minute walk test in these patients. Seventeen subjects
      with stable, symptomatic COAD were recruited, 15 (six men), 70-89 (mean 76)
      years, completed the study. Mean (standard deviation) 1-second forced expiratory
      volume (FEV1) = 49 (5)% predicted. Six-minute walk tests were repeated single
      blind, 2-10 days apart. Quality of life was measured using Guyatt respiratory
      questionnaire. Patients underwent 12 weeks incremental respiratory rehabilitation
      (x4/day step-ups, unweighed arm raises, inflating balloons). Baseline 6-minute
      walk was repeatable and was correlated with the log Guyatt dyspnoea score (r =
      0.65, p = 0.006). In multiple regression neither age nor FEV1 predicted walk
      distance: body mass index, maximal expiratory mouth pressure; calorie intake.
      Mean (SEM) 6-minute walk distance after-rehabilitation was greater than baseline
      (p = 0.003). Elderly patients with COAD tolerate intensive respiratory
      rehabilitation and a controlled, blinded study is needed.

PMID- 8670524
TI  - Prevalence of Helicobacter pylori infection in elderly inpatients and in
      institutionalized old people: correlation with nutritional status.
AB  - Helicobater pylori plays an important role in the aetiology and development of
      peptic ulcer disease. The prevalence of H. pylori infection increases with age,
      and is influenced by low socioeconomic status and poor hygiene owing to person-to
      person transmission of the organism by the oral-faecal route. The aim of this
      study was to investigate the prevalence of H. pylori infection, detected
      serologically, in elderly patients admitted to a geriatric rehabilitation ward
      and in a sample of institutionalized old subjects. Nutritional status was also
      evaluated in order to examine its relation to H. pylori infection. The overall
      prevalence of H. pylori infection was 70.8%, the prevalence in hospitalized
      patients being 72.9% and in institutionalized subjects 68.7%. No significant
      correlation was observed between anti-H. pylori IgG levels and either age or
      length of stay in the institution. We found no difference between H. pylori
      positive and negative patients as regards their self-sufficiency and cognitive
      functions. The prevalence of anti-H. pylori antibodies in the serum was not
      related to blood variables (including nutritional indices), history of drug
      consumption (in particular nonsteroidal anti-inflammatory drugs), dyspeptic
      symptoms, or alcohol and smoking habits.

PMID- 8670525
TI  - Predictors of fall-related injuries among community-dwelling elderly people with
      dementia.
AB  - To determine the annual incidence of fall-related injuries among community
      dwelling elderly people with dementia and to identify the factors predicting
      those likely to sustain such injuries, we conducted a cohort study with a one
      year follow-up. As predicting factors, we paid particular attention to
      behavioural problems and difficulties in helping with activities of daily living
      based on the Assessment of Basic Care for the Demented (ABCD) scale. Thirty-five
      of 86 final study subjects and nine of 98 final control subjects sustained fall
      related injuries. Significant factors associated with fall-related injuries to
      demented elderly subjects were ABCD score (adjusted odds ratio 0.73, 95%
      confidence interval 0.60-0.89), history of falls in the past year (3.65, 1.34
      9.95), and Barthel index score (1.04, 1.00-1.08). This highlights the predictive
      value of better physical function but more difficult care status in relation to
      ADL for fall-related injuries.

PMID- 8670526
TI  - Physiological factors and medications as predictors of injurious falls by elderly
      people: a prospective population-based study.
AB  - To determine the physiological factors and medications predicting injurious falls
      among the elderly population, the authors conducted a prospective study in a
      rural home-dwelling population aged 70 years or over, initially 979 persons (377
      men and 602 women), from 1 January 1991 to 31 December 1992, in Northern Finland.
      The independent risk factors for all falling injuries, falls leading to minor
      injuries and ones leading to major injuries were determined. In men, the
      independent risk factors for all injuries were gait disturbances [odds ratio (OR)
      = 3.5] and the use of digitalis (OR = 2.2), those for minor injuries were gait
      disturbances (OR = 2.7) and the use of calcium blockers (OR = 3.0), and those for
      major injuries were the absence of a quadriceps reflex (OR = 4.8), gait
      disturbances (OR = 2.8) and the use of digitalis (OR = 2.9). In women, the
      corresponding independent risk factors were short step length (OR = 32.1), the
      use of calcium blockers (OR = 2.5) and the use of medications for improving
      peripheral circulation (OR = 3.7) for all injurious falls, path deviation (OR =
      2.3) the use of calcium blockers (OR = 2.8) and the use of anti-inflammatory
      drugs (OR = 2.1) for minor injuries, and foot deformity (OR = 2.0), short step
      length (OR = 15.8), the use of long-acting benzodiazepines (OR = 4.0) and the use
      of calcium blockers (OR = 2.4) for major injuries. In order to prevent injurious
      falls, attention should be given to the prescription of tranquillizers,
      cardiovascular medications and anti-inflammatory drugs. The walking abilities of
      elderly people should be maintained and chronic diseases leading to peripheral
      neuropathy should be treated adequately.

PMID- 8670527
TI  - Changes in sensory organization test scores with age.
AB  - The goals of this study were to collect normative data on asymptomatic,
      ambulatory, community-dwelling adults on a standard diagnostic test of vestibular
      function in balance and to determine if their responses differ significantly from
      younger adults. Subjects were divided into four age groups, 18-44 years (young),
      45-69 years (middle-aged), 70-79 (old), and 80-89 (elderly). Subjects were seen
      in the neurotologic diagnostic laboratory at a tertiary care facility. Their
      dynamic balance was tested under a variety of sensory conditions using the
      EquiTest (NeuroCom), a standard diagnostic test. The data from one subtest, the
      Sensory Organization Test (SOT) were evaluated. These data showed significant age
      associated declines in overall score and changes in movement strategy. These
      results suggest that those parts of the vestibular system involved with balance
      have age-related declines through the end of the life span, even in asymptomatic
      people, and that these changes do not level off but continue into the ninth
      decade. Therefore, when elderly people are evaluated for balance disorders age
      appropriate norms should be used. These results also suggest that declines in
      motor performance on laboratory tests are not directly related to reduced
      independence in essential activities of daily living in elderly people.

PMID- 8670529
TI  - The diagnosis of vascular dementia in the light of the new criteria.
AB  - Recently new criteria for diagnosing vascular dementia (VaD) have been suggested
      by (a) the State of California Alzheimer's Disease Diagnostic and Treatment
      Centres (ADDTC) and (b) the NINDS-AIREN group after an international workshop
      convened by the National Institute for Neurological Disorders and Stroke (NINDS),
      with support from the Association Internationale pour la Recherche et
      l'Enseignement en Neurosciences (AIREN). We have retrospectively applied the new
      criteria to two groups of patients who are thought by us to be suffering from
      VaD. The first group (20 patients) had a raised Hachinski Ischaemic Score, i.e. 7
      or more (mean HIS = 9.5), and a second group (20 patients) with an HIS between 4
      and 6 points (mean HIS = 4.9). In group 1, 19 patients fulfilled the ADDTC
      criteria for probable or possible VaD, compared with 16 patients who fulfilled
      the NINDS-AIREN criteria. In group 2, 11 patients fulfilled the ADDTC criteria
      for probable or possible VaD, compared with only five patients who fulfilled the
      NINDS-AIREN criteria. This suggests that the ADDTC criteria may be more sensitive
      than the NINDS-AIREN criteria and the HIS. However, post-mortem validation
      studies of the new criteria are needed to determine if the improved sensitivity
      of the ADDTC criteria is at the expense of their specificity.

PMID- 8670528
TI  - Prevalence of abnormal levels of serum tumour markers in elderly people.
AB  - The study was conducted to evaluate the prevalence of abnormal levels of several
      serum tumour markers in an institutionalized elderly population. Serum tumour
      markers assay of carcinoembryonic antigen (CEA), the carbohydrate antigens CA 19
      9, CA 72-4 and CA 15-3 (Enzymun-test, Boehringer Mannheim GmbH Diagnostic), alpha
      fetoprotein (AFP) and prostate specific antigen (PSA) (Abbot Diagnostic Division)
      were performed in 228 unselected, institutionalized elderly subjects, whose mean
      age (SD) was 82.4 (5. 79) range (66-99 years). Patients with acute or neoplastic
      diseases were excluded from the study. The serum markers were also measured in 52
      healthy young adults (controls). Using the established threshold values, 92
      subjects (40%) were found to have at least one elevated marker. PSA was elevated
      in 33%, CA 19-9 in 16%, CEA in 11. 5%, CA 15-3 in 11%, CA 72-4 in 8% and AFP in
      3%. We found a significant difference in the serum levels between the two groups
      for CEA, CA 19-9. CA 15-3, and PSA (p < 0.0001). Healthy aged people appear to
      have an elevated prevalence of elevated levels of serum tumour markers. The
      results suggest that apart from PSA, elevated antigen levels in elderly subjects
      are related to the ageing process itself rather than to occult pathology.

PMID- 8670531
TI  - Self-perceived health and symptoms of elderly persons with diabetes and impaired
      glucose tolerance.
AB  - The aim of this study was to describe self-perceived health and symptoms of
      elderly persons with diabetes mellitus (DM) or impaired glucose tolerance (IGT)
      and to explore whether there are special symptoms associated with undiagnosed DM
      or IGT. The study population consisted of community-living northern Finnish
      persons aged 70 years of over (n=379). Poor self-perceived health and high number
      of symptoms were most common among previously diagnosed diabetic persons.
      Undiagnosed diabetes and especially IGT did not predict poorer self-perceived
      health or higher number of symptoms compared with non-diabetic status. We
      conclude that in older subjects neither undiagnosed diabetes nor IGT can be
      traced by worsened health perceptions or on the basis of symptoms.

PMID- 8670530
TI  - Myasthenia gravis and elderly people.
AB  - Myasthenia gravis is probably commoner than previously suspected, the annual
      incidence being nearer 9-10/million than earlier figures of 2-4/million. The
      current study found an annual incidence in Croyden of 9.1 per million (95%
      confidence limits 5.7-13.8 per million). Of the 22 patients (59%) seen in Croyden
      with newly diagnosed myasthenia gravis during the past 7 years, 13 were aged over
      60. In a separate study of the age distribution of positive acetylcholine
      receptor antibody assays, 51% were 60 years or above in 1991, and 64% in 1994.
      The peak age in both sexes was 70-80, and numbers were greatest in men aged 60
      80.

PMID- 8670532
TI  - The efficacy and safety of inhaled salmeterol 50 microg bd in older patients with
      reversible airflow obstruction.
AB  - Twenty-eight patients aged 64-88 years with reversible airflow obstruction,
      showing a diurnal variation in peak expiratory flow rate (PEFR) of over 15% or
      symptoms of airflow obstruction on 4 days of the last week of the run-in period,
      were entered into a randomized, double-blind, placebo-controlled, cross-over
      study to evaluate the efficacy of salmeterol 50 microg twice daily by metered
      dose inhaler. Salmeterol or matching placebo were each given for 28 days. Mean
      morning PEFR was 258.71/min on slameterol and 242. 41/min on placebo (adjusted
      mean difference = 16.31/min; 95% CI = 7. 4, 25.21/min;p = 0.0011). Diurnal
      variation in PEFR was 7.31/min on salmeterol and 17.51/min on placebo (adjusted
      mean difference = 10. 31/min; 95% CI -2.0, 0.5 actuations/day; p = 0.0015). After
      28 days of treatment the patients' assessment of efficacy was statistically
      significantly in favour of salmeterol (p = 0.05). Salmeterol was well tolerated
      as assessed by pulse, blood pressure, haematological and biochemical variables
      and number of adverse events. Salmeterol 50 microg bd is an effective and well
      tolerated therapy for elderly patients with reversible airflow obstruction.

PMID- 8670533
TI  - Activity levels and cognitive functioning in an elderly community sample.
AB  - The influence of self-reported and informant-reported activity levels on
      Crystallized Intelligence, Fluid Intelligence, Memory and the Mini-Mental State
      Examination was investigated in a sample of 858 community-dwelling elderly
      subjects. Both self-reported and informant-reported activity levels explained
      variance beyond that accounted for by sex, sensory functioning, activities of
      daily living, medical conditions, current health problems and education. Age
      accounted for additional variance once activity and the other contextual
      variables were entered. Interaction effects indicated that inactivity was
      associated with poorer performance on fluid intelligence in older rather than
      younger elderly subjects and that inactivity was predictive of poor crystallized
      intelligence at younger ages. Higher informant-rated activity levels moderated
      the effects of education, so that higher activity offset effects associated with
      low education on memory tasks. The mount of variance explained by activity levels
      was modest.

PMID- 8670534
TI  - Effects of sensory aids on the quality of life and mortality of elderly people: a
      multivariate analysis.
AB  - The present study aimed at clarifying the relationships between the use of
      sensory aids and the quality of life (QOL) and mortality of elderly people
      suffering from sensory deprivation. We carried out a cross-sectional survey on
      the QOL and the sensory status of an elderly cohort and a 6-year longitudinal
      follow-up of mortality rates among 1192 non-institutionalized people aged 70-75
      years in a North Italian town. We classified respondents into three groups: those
      with functionally adequate visual and hearing acuity (n = 275); those with
      sensory impairment, corrected by the use of sensory aids (n = 680), and those
      with uncorrected sensory impairment (n = 245). In the whole sample, multiple
      logistic regression analyses showed that an uncorrected sensory deprivation was
      associated with a significant and independent impairment of mood, self
      sufficiency in instrumental activities of daily living and social relationships.
      Such impairments were not apparent in the subjects with sensory impairments who
      were using sensory aids. In men with uncorrected sensory impairment the
      unadjusted 6-year mortality rate was almost twice that of the other two groups,
      which did not differ from each other. No corresponding differences were detected
      in women. Multivariate analysis showed that the effect of the sensory aid status
      on mortality was indirect and mediated through the global physical health status
      and the social relationships. We conclude that our cross-sectional data
      demonstrate an association between uncorrected sensory deprivation and a low QOL;
      such an association was not present in subjects with corrected sensory
      deprivation.

PMID- 8670535
TI  - Case-control study of hazards in the home and risk of falls and hip fractures.
AB  - The importance of environmental hazards in the home as risk factors for falls and
      fractures is uncertain. A case-control study was conducted, involving people aged
      65 years and over referred to an occupational therapy department for home
      assessment. There were 52 subjects with a recent hip fracture, 43 fallers
      (subjects with two or more falls in the past year but no hip fracture), and 157
      non-fallers (subjects without hip fracture and with fewer than two falls in the
      past year). Subjects' homes were assessed for environmental hazards by
      occupational therapists using a structured home assessment form comprising 35
      potential hazards. Overall, the homes of fallers were no more hazardous than the
      homes of non-fallers. However, fallers with cognitive impairment had
      significantly more hazards in their homes than non-fallers with cognitive
      impairment. A wide range of environmental hazards was associated with hip
      fractures. Many of the findings of this study could be due to bias inherent in
      the case-control design. To overcome the inadequacies of observational studies
      for the investigation of home hazards and falls, randomized trials are
      recommended to determine if removing hazards reduces the risk of falls and
      fractures.

PMID- 8670536
TI  - First steps in building ACME--an admission case-mix system for the elderly.
AB  - In the United Kingdom, specialists in Geriatric Medicine usually have a major
      role in treating acute medical problems of elderly people, in addition to running
      rehabilitation services and continuing care. The proportion of the different
      types of patients varies widely from service to service, however, making it
      difficult for clinicians to compare their performance with that of colleagues.
      Existing casemix measurement systems are usually designed to deal with a more
      homogeneous patient group (e.g. rehabilitation, long-stay care) and/or are too
      detailed for day-to-day use. We describe our attempts to devise a simple casemix
      system which would be of practical day-to-day use for individual specialists in
      Geriatric Medicine. We have classified patients according to (1) the acuteness
      and potential for recovery of their presenting illness and (2) their functional
      status (based on simple measures of mobility and cognitive impairment). These
      factors have been incorporated into a three-point score, CMIX, which was capable
      of explaining 19.5% of the variability in duration of stay in a prospective study
      of 400 new admissions in two centres. In contrast, age and sex explained only 1%
      of variability in these patients. The pattern of patient outcome also differed
      significantly between the three CMIX categories. We also propose a simple
      graphical method of classifying outcome which should prove useful for audit
      purposes even when our casemix system is not employed.

PMID- 8670537
TI  - Age distribution of patients treated in hospital for chronic obstructive
      pulmonary disease.
AB  - A discharge register maintained by the National Research and Development Center
      for Welfare and Health was employed to study the use of hospital services,
      attributable to chronic obstructive pulmonary disease (COPD), in Finland. From a
      total population of 5 million COPD caused 113,016 hospital treatment periods
      during 1983-92 of persons aged 35 years or over. In men the need of hospital
      treatment for COPD started to rise sharply after the age of 50. Men aged 73 had
      the highest amount of admissions (3962 admissions per 10-year period). Women aged
      68 had the highest amount of admissions (802 admissions per 10-year period). The
      highest admission rate per 1000 inhabitants was found for men at the age of 82
      (37.0 admissions per 1000 population/ year) and for women at the age of 77 (3.8
      admissions per 1000 population/year). During the 10-year period a total of 27,008
      new COPD patients aged 35 or over received hospital care. The highest number of
      new admissions occurred among both sexes at the age of 71 (750 admissions per 10
      year period in men and 233 admissions per 10-year period in women). This means
      that most of admissions are due to elderly COPD patients seeking treatment
      repeatedly. As the populations in the developed countries are ageing, the
      significance of COPD for the health care system is growing.

PMID- 8670538
TI  - Assessment of activities of daily living in dementia: development of the Bristol
      Activities of Daily Living Scale.
AB  - A new assessment of Activities of Daily Living has been developed specifically
      for use with people with dementia. The assessment is a carer rated instrument
      consisting of 20 daily-living abilities. The scale has 'face validity', assessing
      items rated as important by and using levels of ability generated by carers. It
      has 'construct' validity as demonstrated by principal components analysis. It has
      'concurrent' validity in that it correlates well with observed task performance.
      It has good 'test-retest' reliability as measured by Cohen's Kappa and it
      correlates well with the Mini-Mental State Examination. Carers report that it is
      easy to use and it is relatively short. The authors believe the scale will be
      useful when assessing demented patients in the community or as part of clinical
      research trials.

PMID- 8670540
TI  - Informant ratings of cognitive decline of elderly people: relationship to
      longitudinal change on cognitive tests
AB  - Formal assessment of cognitive decline with cognitive tests can be difficult,
      requiring either two measurement points or a comparison of 'hold' with 'don't
      hold' tests. Informant-based assessment provides an alternative approach because
      informants can adopt a longitudinal perspective and directly rate cognitive
      change. A study was carried out to assess the validity of informant ratings
      collected by means of the Informant Questionnaire on Cognitive Decline in the
      Elderly (IQCODE). A community sample of 500 subjects aged 74 or over underwent
      four cognitive tests on two occasions 3&half; years apart. On the second
      occasion, informants filled out the IQCODE. Subjects rated as having moderate or
      severe decline were found to have greater change on the cognitive tests. These
      findings support the validity of informant ratings of cognitive decline.

PMID- 8670541
TI  - Delay in the diagnosis of bacteraemic urinary tract infection in elderly
      patients.
AB  - Collaboration between clinicians and microbiologists revealed that many patients
      with subsequently proven urinary tract infection (UTI) present with symptoms
      suggestive of chest infection. A retrospective analysis was performed on patients
      over 50 years old with community acquired bacteraemic UTI proven by blood
      cultures. The main presenting features were confusion (30%), cough (27%),
      dyspnoea (28%) and new urinary symptoms (20%). The initial clinical diagnosis was
      UTI in 43% and chest infection in 24%. Chest infection was diagnosed more often
      in those over 70 years old than those aged 50-70 years old (chi 2 = 7.2, p =
      0.007). The majority had pyuria but less than half of the urine samples arrived
      in the laboratory on the day of admission, fewer from the older patients than the
      younger (chi 2 = 2.57, p = 0.10). These results demonstrate that UTI frequently
      presents with respiratory features and that the diagnosis of UTI is often
      delayed. Sampling the urine with a catheter may be justified to enable diagnosis
      on the day of admission.

PMID- 8670542
TI  - The nutritional status of Finnish home-living elderly people and the relationship
      between energy intake and chronic diseases.
AB  - The nutritional status and the impact of non-progressive chronic diseases on
      energy intake were determined in 90 home-living people aged from 73 to 94 years.
      The nutritional status was assessed by dietary, anthropometric, biochemical and
      haematological methods. Energy intake (6.0, SD 1.7 MJ) in women was low compared
      with the Nordic Nutrient Recommendation but in men it (8.0, SD 2.1 MJ) was in
      keeping with this recommendation. Despite the low energy intake the mean BMI
      value of women was moderately high (27, SD 5.3 kg/m2). In men the mean was 26, SD
      4.0 kg/m2. The intakes of vitamins and minerals met the recommendation, except
      for those of folic acid and zinc. The blood levels of both these two nutrients
      were within reference limits. Men suffering from chronic diseases received less
      (p < 0.015) energy (7.5, SD 1.76 MJ) than other men (8.9, SD 2.0 MJ). This
      relationship was not found in women. In conclusion, the nutritional status of
      people aged over 70 years old living at home was good. The presence of chronic
      diseases affected the energy intake in men but not in women.

PMID- 8670543
TI  - The management of urinary incontinence in residential and nursing homes for older
      people.
AB  - We assessed the management of urinary incontinence amongst older people in
      residential and nursing homes and examined strategies for continence care in the
      homes. A random sample of local authority and private residential and nursing
      homes was drawn from an earlier census of long-term care. Strategies for
      continence care, the standard of care provided and the need for more help were
      determined by means of a structured questionnaire and the observations of a
      continence adviser. A random selection of residents in each of the homes was
      assessed for the presence, severity and symptoms of urinary incontinence, for
      symptom control and physical dependency. Eighty-seven per cent of the homes used
      pads and 83% daytime toileting to promote continence care but only 52% practised
      night-time toileting and 49% the use of clear toilet signs. A greater emphasis
      was placed on incontinence management rather than continence promotion, the
      latter being "good' in only 32% of homes. Although the majority of homes reported
      having adequate access to aids and appliances, 39% of residents had severe
      symptoms of urinary incontinence resulting in bed-wetting and wetting of
      clothing. Substantial social and psychological effects were found; 87% of
      residents needed changes in their management of the condition and incontinence
      management was "good' in only 47% of homes. Although 73% of homes were optimistic
      about offering good continence care, they were infrequently supported by
      continence nurses (30% of homes) or specialist continence doctors (9% of homes).
      Consequently 57% requested more help from the specialist services. The high
      prevalence of severe and uncontrolled symptoms of urinary incontinence combined
      with the lack of support received by the homes for the management of these
      residents indicated the urgent need for a greater input from the specialist
      continence service.

PMID- 8670544
TI  - Fat malabsorption in elderly patients with cardiac cachexia.
AB  - Malnutrition resulting from chronic congestive heart failure (cardiac cachexia,
      CC) is not uncommon and contributes to mortality and morbidity especially of
      elderly people. The aetiology of cardiac cachexia is probably multifactorial. We
      have assessed whether malabsorption of fat is associated with CC and if so
      whether it is due to small-bowel bacterial overgrowth. Three groups of subjects
      were studied: 29 (20 women) patients (mean age 76.1 years) with controlled
      congestive heart failure and weight loss (CC); 14 (seven women) patients (mean
      age 74.0 years) with controlled congestive heart failure and no weight loss (non
      cachexia, NON-CC); and 29 (20 women) healthy controls (mean age 74.9 years). Fast
      absorption was quantified using the cumulative 6 h 14CO2 exhalation in the 14C
      triolein breath test and small-bowel bacterial overgrowth was quantified using
      the cumulative 8 h 14CO2 exhalation in the 14C-glycocholic acid breath test. The
      cumulative 6 h 14CO2 exhalation in the triolein breath test was reduced in the CC
      group (p = 0.001) implying impaired fat absorption. There was no evidence of
      small-bowel bacterial overgrowth in any group. Impaired absorption of fat was
      related to the clinical severity of heart failure and its duration. Impaired fat
      absorption is associated with cardiac cachexia. It is not due to small-bowel
      bacterial overgrowth. The aetiology of fat malabsorption in heart failure
      requires further studies.

PMID- 8670545
TI  - A prospective study of urinary retention and risk of death after proximal femoral
      fracture.
AB  - Older age, dementia syndrome and impaired mobility are well recognized risk
      factors for fatality after fracture of the proximal femur. Urinary retention is
      recognized as a common complication of elective total hip replacement. In this
      investigation, we estimated the incidence of urinary retention associated with
      hip fracture in older women and assessed its relationship to 2-year post
      operative fatality. Over a 7-month period, 309 women aged 65 and over were
      admitted to one trauma unit with hip fracture. Readings of post-voiding residual
      volume were taken on admission (pre-operative), within 24 hours of operation
      (post-operative) and 5-7 days post-operatively (recovery). Of the 309 patients,
      244 (79%) had readings of post-voiding residual volume taken on admission; 90/244
      (37%) had retention pre-operatively, 122/216 (56%) post-operatively and 40/183
      (22%) in the recovery phase. One year after operation 305 patients were traced
      and median follow-up was 2 years. Older age, cognitive impairment, polypharmacy,
      impaired mobility and urinary retention on admission and during recovery were
      associated with a higher fatality in the first post-operative year. Pre-operative
      urinary retention is common among older women with proximal femoral fracture and
      affects over half post-operatively. Retention is one of several factors
      associated with higher fatality.

PMID- 8670546
TI  - Ambulatory blood pressure and cardiac rhythm disturbances in elderly
      hypertensives: relation to left ventricular mass and filling pattern.
AB  - In order to define cardiac hypertensive involvement a group of 25 consecutive
      elderly male hypertensive outpatients and 25 age-matched male normotensive
      controls underwent full non-invasive assessment of cardiac status by resting 12
      lead electrocardiography, Doppler-echocardiographic examination and simultaneous
      ambulatory blood pressure and electrocardiographic monitorings. Elderly
      hypertensives showed a higher prevalence of electrocardiographic left ventricular
      hypertrophy, an increased echocardiographic left ventricular mass, an impaired
      left ventricular filling pattern and more frequent ventricular arrhythmias when
      compared with normotensive controls. In elderly patients, left ventricular mass
      was found to be correlated with 24-hour ambulatory blood pressure (r = 0.47, p <
      0.01) and 24-hour ambulatory blood pressure variability (r = 0.52, p < 0.01),
      while ventricular arrhythmias were correlated with left ventricular mass (r =
      0.52, p < 0.01), the Doppler synthetic index of diastolic function E/A ratio (r =
      -0.56, p < 0.01) and both 24-hour systolic (r = 0.54, p < 0.01) and diastolic (r
      = 0.59, p < 0.01) ambulatory blood-pressure variabilities. These data suggest
      that hypertension induces in elderly patients an impairment of cardiac structure
      and function comparable with that already shown in younger hypertensives.
      Therefore, the assessment of hypertensive target-organ damage currently employed
      in younger subjects should be also considered in elderly hypertensives, at least
      when no other relevant medical disease is present.

PMID- 8670547
TI  - Predictive validity of a postal questionnaire for screening community-dwelling
      elderly individuals at risk of functional decline.
AB  - Screening elderly individuals who are at risk of functional decline in the
      community is essential in order to implement effective programmes of assessment
      and surveillance in a context of secondary prevention. The postal questionnaire
      technique consists of sending a simple questionnaire to all elderly individuals
      living in a defined area in order to identify those who are at risk. The
      objective of this study was to develop a postal questionnaire and to test its
      capacity to predict functional decline in community-dwelling elderly people. A 21
      item postal questionnaire was sent with a birthday card to a representative
      sample of community-dwelling individuals over the age of 75 years (n = 842). One
      month after sending the questionnaire, all subjects were contacted by a nurse for
      an in-home interview (n = 655) that included assessment of functional autonomy.
      One year later, the subjects (n = 607) were reassessed by the same nurse. Of the
      eligible subjects, 87.4% returned the postal questionnaire. During the year
      following the completion of the postal questionnaire, 43 subjects died, 13 were
      institutionalized and 109 had experienced a significant decrease on the autonomy
      scale, for a total annual occurrence of functional decline of 27.2%. Age and 14
      of the 21 items of the questionnaire were associated with a significant relative
      risk of functional decline. The relative risk associated with not responding to
      the questionnaire was 2.1. A stepwise logistic regression analysis showed that
      six items were independent predictors of functional decline. This 6-item
      Sherbrooke Postal Questionnaire identifies as positive 56% of the population with
      75% sensitivity and 52% specificity. We conclude that a postal questionnaire is a
      feasible and valid technique for screening elderly individuals at risk for
      functional decline.

PMID- 8670548
TI  - The need for a new biological model in geratology.
AB  - Disease classes have hitherto been based on anatomical pathology and structural
      lesions belonging to an earlier ecological medical model involving
      classification. The diseases of ageing now coming to dominate clinical practice
      evolve across the clinical threshold in middle age parallel to changes occurring
      in the internal environment. The concept 'multiple pathology' used to describe
      the plural features of biological changes now requires new intellectual tools by
      which to understand overlap phenomena. Boolean algebra and Set Theory are
      proposed as the relevant enabling concepts, and their application to modern
      clinical practice is discussed.

PMID- 8670549
TI  - Health and nutritional status of elderly Greek migrants to Melbourne, Australia.
AB  - The health (self-reported health conditions) and nutritional status (food and
      nutrient intake, nutritional biochemistry, anthropometry) of 189 elderly Greeks
      living in Melbourne, Australia were described and compared with 104 elderly
      Greeks living in a rural town in Greece (Spata) using a validated health and food
      frequency questionnaire. Spata was chosen because the traditional diet is
      maintained by the community and may act as a 'surrogate' measure of diets
      prevalent in Greece prior to the Melbourne sample's migration to Australia in the
      1960s. This enabled identification of dietary trends that may be contributing to
      the deteriorating health of elderly migrant Greeks. Compared with Spata Greeks,
      Melbourne Greeks had significantly greater intakes of animal foods (meat),
      legumes, protein, margarine, polyunsaturated fats, beer and lower intakes of
      cereals, carbohydrates, wine and olive oil. The contribution of these dietary
      differences, as well as the influence of high storage-iron levels, impaired
      immunity and greater prevalence of obesity and abdominal fatness, to the
      increasing prevalence of heart disease and cancer (especially amongst women)
      requires further study.

PMID- 8670551
TI  - Increase of antimicrobial resistance of faecal aerobic gram-negative bacteria in
      a geriatric hospital.
AB  - Antimicrobial resistance of faecal aerobic Gram-negative bacteria to eight
      different antimicrobials was determined by a velvet replica-plating method in
      1988 and 1933. Faecal samples were taken from 131 geriatric inpatients in the
      Turku City Hospital with a hospitalization of more than 7 days. From 1987 to 1992
      the use of first and second generation cephalosporins and ciprofloxacin increased
      from 3.32 defined daily doses (DDD) per bed to 24.25 DDD/bed and from 0.63
      DDD/Bed to 28.11 DDD/bed, respectively. A statistically significant increase was
      observed in the frequency of samples resistant (with >= 1% of resistant colonies)
      to cefuroxime (p = 0.0004) and ceftazidime (p = 0.037) in patients who received
      antimicrobial therapy and to ampicillin (p = 0.046) in patients who had not
      received antimicrobial therapy. In addition, despite the decreased use of
      sulphonamides and trimethoprim (from 17.11 DDD/bed to 5.54 DDD/bed) no
      significant changes in the frequency of resistant faecal samples were observed.
      Use of ciprofloxacin has been found to cure resistance plasmids from bacteria in
      vitro. However, despite the increased use of ciprofloxacin, no decrease in faecal
      bacteria resistant to any of the other antimicrobials (i.e. trimethoprim) studied
      was observed.

PMID- 8670550
TI  - Is medication use by community-dwelling elderly people influenced by cognitive
      function?
AB  - To determine whether medication use differs by cognitive status among community
      dwelling elderly, a survey was made of a stratified random sample of 4110 black
      and white participants, aged 65 or older from the Duke Established Populations
      for Epidemiologic Studies of the Elderly in five adjacent urban and rural
      counties in the Piedmont area of North Carolina. Main outcome measures were usage
      of prescription medications, non-prescription medications, and medicines within
      therapeutic classes in the previous 2 weeks as determined during an in-home
      interview; and total number of prescription and non-prescription medicines used
      in the previous 2 weeks. Multivariate analyses, using weighted data adjusted for
      sampling design, were conducted to assess the association between drug use
      patterns and cognitive status, as assessed by the Short Portable Mental Status
      Questionnaire, while adjusting for demographic, health status, and access to
      health care factors. Participants with cognitive impairment (13.7% of sample)
      were less likely to use any prescription medications (Adjusted OR = 0.66, 95% CI
      = 0.48-0.90) or any non-prescription medications (Adjusted OR = 0. 71, 95% CI =
      0.56-0.89) than cognitively intact subjects. Both groups took a similar number of
      prescription and non-prescription medications. Those who were cognitively
      impaired were less likely to take analgesics (Adjusted OR = 0.66, 95% CI = 0.52
      0.83), but were more likely to take central nervous drugs (Adjusted OR = 1.55,
      95% CI 1.18-2.04) than those who were cognitively intact. We conclude that drug
      use patterns by community-dwelling elderly people differ with cognitive status.
      Future research needs to examine medication use by specific causes of cognitive
      impairment.

PMID- 8670552
TI  - Prevalence of ageing-associated cognitive decline in an elderly population.
AB  - Different diagnostic definitions have been proposed for use in the
      characterization of mild cognitive disorders associated with ageing. Previously,
      we reported a high (38.4%) prevalence of age-associated memory impairment (AAMI)
      using the National Institute of Mental Health criteria in an elderly population.
      Recently, a work group of the International Psychogeriatric Association proposed
      criteria for 'ageing-associated cognitive decline' (AACD). The objective of this
      study was to evaluate the prevalence of AACD in an elderly population. We
      examined 403 randomly selected subjects (68-78 years of age) with tests of
      memory, cognitive processing, attention, verbal and visuoconstructive functions
      and with a structured questionnaire for health status and subjective complaints
      of cognitive decline. In all, 26.6% of the subjects (24.4% of women, 30. 1% or
      men) fulfilled the AACD criteria. The prevalence was slightly related to age and
      education. The rate was lowest in the oldest age of 75 - 78 years (20.5%) and
      highest in the age of 71 -74 years (30%). Subjects with less than 4 years of
      education had the lowest (14.3%) and subjects with more than 6 years of education
      had the highest rate (29.4%) for AACD. However, the differences between these
      subgroups were not statistically significant. These results suggest that the
      prevalence of AACD is lower than that of AAMI. As AAMI tends to identify a very
      heterogeneous subject group, the AACD diagnosis, which takes into account age and
      education specific norms in its inclusion criteria, might prove superior to AAMI
      in differentiating a meaningful subgroup from an elderly population both for
      research purposes and in clinical settings.

PMID- 8670553
TI  - Subcutaneous morphine infusion by syringe driver for terminally ill patients.
AB  - The study aimed to find whether subcutaneous morphine administration by syringe
      driver for terminally ill patients in a Dutch nursing home led to higher morphine
      doses and earlier death than routine morphine administration. The data comprised
      the files of all patients dying over a 2 year period in a 355-bed nursing home in
      Delft in the Netherlands. Thirty-eight per cent of the patients had been given
      morphine, 29% by continuous subcutaneous syringe driver. In comparing the
      patients given morphine with and without a syringe driver no differences emerged
      in mean age, sex, length of admission, type of ward, diagnosis, duration of
      morphine administration and mean dose. The data indicate that subcutaneous
      morphine administration by syringe driver decreases dose frequency problems and
      improves the control of pain and other symptoms in the last week before death.
      There was no evidence that administration of morphine in this way shortens
      survival.

PMID- 8670554
TI  - Cognitive decline in patients with Alzheimer's disease, vascular dementia and
      senile dementia of Lewy body type.
AB  - One hundred and twenty-four patients with DSM-III-R dementia were assessed with a
      standardized battery which included the Geriatric Mental State Schedule, the
      History and Aetiology Schedule, the Secondary Dementia Schedule and the CAMCOG.
      Patients with Alzheimer's disease, vascular dementia and senile dementia of Lewy
      body type (SDLT) all had a similar degree of cognitive impairment at the time of
      the baseline interview. Patients with Alzheimer's disease and vascular dementia
      each experienced a mean decline of 27 points in patients with SDLT. Patients with
      SDLT had a significantly greater decline of verbal fluency than both the other
      groups. Women were significantly more impaired than men at the time of the
      baseline assessment but experienced a similar decline during the year of follow
      up.

PMID- 8670555
TI  - Fire fatalities in elderly people.
AB  - Fatal dwelling-house fires account for 10% of all accidental deaths in the United
      Kingdom with one-quarter of the deaths being of elderly people. No study had
      described the characteristics of elderly individuals who die in fires. We report
      results from a retrospective review of all fatal dwelling-house fires in Scotland
      from 1980 to 1990. Of 1096 people dying in fires, 243 (23%) were aged over 75.
      When compared with patients under the age of 75, older patients were
      significantly less likely to be smokers. Significantly more fires killing elderly
      people were caused by faulty or misused electrical items in the house,
      particularly electric blankets. These differences between elderly and younger
      individuals dying in dwelling-house fires may suggest that preventive strategies
      for the elderly population require a different emphasis from those for younger
      people.

PMID- 8670556
TI  - Aspartame pharmacokinetics - the effect of ageing.
AB  - Aspartame is an intense sweetener which is increasingly used in the UK. It is
      registered at an acceptable daily intake (ADI) of 40 mg/kg, although there are no
      previous data relating to the metabolism of aspartame in older people. Twelve
      young and 12 elderly volunteers each received a single dose of approximately 40
      mg/kg of aspartame. Baseline concentrations of phenylalanine (the main metabolite
      of aspartame) rose after ingestion with a significantly higher maximum
      concentration (Cmax) (81.3 vs. 63.3 micromol/1, p<0.01) and area under the plasma
      concentration-time curve extrapolated to infinity AUC 9(0-infinity)(518.7 vs.
      353.5 micromol . h/l, p<0.01) in the elderly group. The higher concentrations
      reflected a significant fall in volume of distribution (V) from 2.03 to 1.59 1/kg
      (p <0.05) and clearance (CL) from 7.3 to 4.9 ml/min/kg (p <0.005) in the elderly
      group. The greater effect on CL than on V resulted in a small but non-significant
      rise in elimination half life (3.5 to 3.9 hours). The sizes of the differences
      were modest implying that there is no need on pharmacokinetic grounds for a
      change in the ADI for older people.

PMID- 8670557
TI  - Gastro-intestinal protein loss in elderly patients with cardiac cachexia.
AB  - Undernutrition resulting from chronic congestive heart failure (cardiac cachexia,
      CC) increases morbidity and mortality particularly in elderly people. The
      aetiology of CC is thought to be multifactorial. We have assessed the presence of
      gastro-intestinal protein loss in a group of patients with CC and a group of
      healthy age-and sex-matched controls. Gastro-intestinal protein loss was measured
      using the chromic chloride test in 29 patients with CC [mean age 76.1 (SD4.4)
      years] and 29 healthy controls [mean age 74.9 (SD 4.8) years]. The patients were
      undernourished in terms of anthropometric measurements compared to controls. The
      patients had a significantly lower mean ejection fraction [41.5(18.3)% vs.
      65.5(2. 2)%] and higher mean pulmonary artery pressure [89.4(19.9)mmHg vs.
      19.3(8.1) mmHg]. The recovery of radioactivity in a 5-day stool collection was
      similar in the two groups [patients vs. controls: 1. 0(0.7)% vs. 0.98(0.6)%,
      p=0.9]. These values are within the expected normal range. We conclude that
      gastro-intestinal protein loss is not a significant factor in the production of
      cardiac cachexia.

PMID- 8670558
TI  - Quantitative and qualitative alterations of acute-phase proteins in healthy
      elderly persons.
AB  - To assess acute-phase proteins in relation to ageing, we measured serum
      concentrations of C-reactive protein of AGP in 131 healthy elderly individuals
      (aged >/= 65 years) living independently in the community, and 47 healthy younger
      individuals. Concentrations of CRP in the older persons (median = 3.0 microg/ml)
      were significantly greater than in the younger group (median = 0.9 microg/ml, p =
      0. 0003). Concentrations of SAA and AGP were similar in the two groups, but AGP
      glycosylation forms with reduced binding affinity for concanavalin-A (changes
      that have been observed in chronic inflammatory states) were increased in the
      elderly sample (p<0.0001). These findings suggest that both quantitative and
      qualitative alterations of acute-phase proteins occur with physiological ageing
      in humans.

PMID- 8670559
TI  - Is depression in elderly people followed by dementia? A retrospective cohort
      study based in general practice.
AB  - We used a retrospective cohort study design to test the hypothesis of a relation
      between old-age depression and subsequent dementia. The study sample comprised
      19103 patients aged 50 or more and born after 1910, included in a family-practice
      based registration network. We estimated odds ratio (OR) and 95% confidence
      interval (95% CI) for a diagnosis of dementia in patients with or without
      previous late-onset depression and survival analysis, including hazard ratios
      resulting from Cox regression analysis. The OR for a diagnosis of dementia
      subsequent or not to late-onset depression was found at survival analysis: p =
      0.26 (log rank test). Hazard ratio for patients with and without previous old age
      depression and subsequent dementia in patients aged 50 or more and born after
      1910. This supports the hypothesis of old-age depression being a predictor, and
      possibly a causal factor, of subsequent dementia.

PMID- 8670560
TI  - Dementia in resuscitation policy: a prospective study of a psychogeriatric ward
      in a Dutch general teaching hospital.
AB  - Resuscitation decisions during the first 6 weeks were analysed for 97 admissions
      to a psychogeriatric ward of a general teaching hospital. Seventy-seven patients
      (79%) had a written 'do not resuscitate' (DNR) order on admission and 74 patients
      (875) had a written DNR order after 6 weeks. Morbidity was assessed with a pre
      arrest morbidity (PAM) index and a modified PAM index (MPI). Dementia influenced
      the presence of a DNR order, both because lack of effectiveness of CPR and lack
      of quality of life. Age was related to a DNR order. The MPI was associated with
      the presence of a written DNR order, while the PAM score failed to reach
      significance. Six weeks after admission DNR orders were predictable by the four
      variables of dementia, the use of antidepressants, age and PAM, in that order.
      The association of the use of antidepressants with the presence of a written DNR
      order was surprising. The use of antidepressants is not the same as the diagnosis
      of depression. Because of the design, our results cannot permit any conclusion
      whether depression acts as an additional factor considered in decision-making in
      psychogeriatric patients. We suggest that depression and its correlates should be
      considered in discussions and studies about DNR.

PMID- 8670561
TI  - The good side after stroke: ipsilateral sensory-motor function needs careful
      assessment.
AB  - Twenty subjects were examined 4-6 weeks after stroke to establish whether a
      sensory-motor ipsilateral deficit occurs early after stroke. Each underwent a
      timed test of repetitive side-to-side movement of both the upper and lower limbs
      ipsilateral to the cerebral infarct, and an assessment of motor disability using
      the Motor Assessment Scale. Results were compared with a group studied almost a
      year after their stroke, and with 41 age-matched healthy volunteers. There was a
      significantly worse performance (p < 0.005) on the right ipsilateral side, but
      not the left ipsilateral side, compared with normal volunteers, a finding similar
      to that of a group previously studied about a year after the stroke. There was no
      relationship between the severity of the motor deficit and performance of the
      side, possibly owing to reduction in cerebral activation as a result of a right
      hemispheric lesion. These observations have importance in rehabilitation and
      education as well as practical skills, including driving a car and maintaining
      balance.

PMID- 8670562
TI  - Helicobacter pylori infection in asymptomatic elderly subjects living at home or
      in a nursing home: effects on gastric function and nutritional status.
AB  - Age and close living conditions are known to be risk factors for the acquisition
      of Helicobacter pylori (HP) infection. It is unknown whether institutionalization
      of asymptomatic, elderly subjects is an additional risk factor and whether
      gastric function and nutritional status are affected by the HP infection. The
      study sample comprised 102 subjects over 65 years of age: 52 living in a nursing
      home and 50 at home. No subject had symptoms or previous pathology related to the
      upper digestive tract. In all subjects, serum levels of specific anti-HP
      antibodies were determined. Gastric function was evaluated by levels of
      pepsinogen A (PGA), pepsinogen C (PGC) and gastrin. The nutritional status of the
      subject was evaluated by measuring: albumin, haemoglobin, iron, ferritin,
      transferrin, vitamin B12, and folic acid in blood, and body mass index and mid
      arm muscle area. The prevalence of anti-HP antibodies was 86.5% in
      institutionalized subjects (men: 100%; women:76.6%, p <0.05) and 82.0% in
      subjects living at home (men:86.3%; women:76.3%). No differences between the two
      groups were observed in levels of serum anti-HP antibodies and PGC was
      identified. In neither group were differences observed between serum positive (HP
      + ve) and negative (HP - ve) subjects with respect to the biohumoral and
      anthropometric indices of nutritional status. We conclude: (1) the seroprevalence
      of the HP infection was high (82-86%) in asymptomatic elderly patients living
      either at home or in an institution; (2) the presence of specific IgG anti-HP
      antibodies in asymptomatic elderly individuals, at home or in a nursing home, was
      not associated with changes in PGA levels in institutionalized subjects; (3)
      nutritional indices were not influenced by the presence of anti-HP antibodies.

PMID- 8670563
TI  - Retardation by restricted feeding of age-related changes in steroidogenic
      activity of rat pre- and post-ovulatory follicles.
AB  - Reproductive ageing in female rodents is accompanied by changes in circulating
      peptide and steroid hormones leading to irregular, lengthened oestrous cycles
      prior to loss of fertility. In this study, the effect of ageing is reported on
      steroid hormone synthesis within individual ovarian follicles and its retardation
      by restricted feeding for two groups of ad libitum fed animals (114 and 350 days)
      and two groups of diet-restricted animals (350 and 600 days). Follicles from ad
      libitum fed animals of 350 days showed a transition in follicular steroid hormone
      synthesis to release elevated amounts of oestradiol-17beta on all days of the
      cycle. This age-related change in follicle steroid release was significantly
      delayed by maintaining animals on a restricted feeding regime, and was not
      complete even by 600 days of age. This effect of diet as a means to manipulate
      ageing of the follicular steroidogenic pathways provides a useful system for
      investigating the control of reproductive ageing in rodents.

PMID- 8670564
TI  - Seasonal changes in haemostatic factors in young and elderly subjects.
AB  - Morbidity and mortality from cardiovascular disease are more common in colder
      seasons, especially in elderly people. Previous studies have shown higher
      fibrinogen levels in old people in the winter months. The present studies of
      haemostatic factors in relation to age and season have shown that fibrinogen,
      tissue plasminogen activator (tPA), protein S and protein C levels are higher in
      old (aged 75 years and over) than young (aged 25-30 years) subjects while
      antiplasmin levels are lower in old people. Antiplasmin and protein C levels are
      lower in winter in both young and old while plasminogen activator inhibitor (PAI)
      is higher, and tPA higher in old people only. This study illustrates the complex
      interrelationships of the haemostatic system and may suggest that in 'successful'
      elderly people the fibrinolytic system may alter to maintain the delicate balance
      between thrombogenic and fibrinolytic activity. Nevertheless, the results
      presented here suggest that both old age and cold weather may increase the risk
      of atherothrombotic disease.

PMID- 8670565
TI  - Collaboration with orthopaedic surgeons.

PMID- 8670566
TI  - The effectiveness of the 'over-75' health checks.

PMID- 8670567
TI  - MHC-encoded TAP genes in rheumatic diseases.

PMID- 8670568
TI  - The provision of rheumatological information.

PMID- 8670569
TI  - Proteoglycan-degrading activity associated with the 40 kDa collagen-binding
      fragment of fibronectin.
AB  - The osteoarthritis (OA) process is characterized by the progressive destruction
      of articular cartilage. There is a loss of cartilage proteoglycan content and
      disorganization of the collagen network, as well as an increase in other non
      collagenous protein such as fibronectin (Fn). Increased proteolytic activity may
      lead to the degradation of native Fn and generation of Fn proteolytic fragments.
      Among them, the 45 kDa collagen-binding Fn fragment can be autoactivated in vitro
      into a 40 kDa fragment. This 40 kDa fragment induces an average of 30% of
      proteoglycan release per day from human OA cartilage explants and can degrade
      proteoglycan using dead cartilage sections. Proteoglycan-degrading activity
      related to the 40 kDa Fn fragment was decreased up to 66% by fetal calf serum
      (10%), but was not prevented by protein synthesis inhibitors (cycloheximide or
      actinomycin D). The action of this 40 kDa Fn fragment was greater on OA than on
      normal cartilage. This study suggests that enzymatic activity induced by the 40
      kDa collagen-binding fragment of Fn might be involved in cartilage matrix
      turnover.

PMID- 8670570
TI  - Production of binding proteins and role of the insulin-like growth factor I
      binding protein 3 in human articular cartilage explants.
AB  - The aim of this study was to determine the production of insulin-like growth
      factor binding proteins (IGFBP) and the role of the IGFBP-3 in human normal (n =
      2) and osteoarthritic (OA) articular cartilage (n = 14) explants. Binding
      proteins were studied in the medium by Western ligand blotting and Western
      blotting. Proteoglycan synthesis under insulin-like growth factor I (IGF-I)
      stimulation was studied after a pulse of 35SO4(2-) in the presence or absence of
      added IGFBP-3. Osteoarthritic explants released a doublet of IGFBPs with a 39/43
      kDa Mr corresponding to the binding protein 3. Constitutive production from
      unstimulated OA cartilage was higher than from normal cartilage. IGF-I induced a
      20-fold increase and IL-1 a 2-fold increase in IGFBP-3 release. A minor band
      around 30 kDa was also detectable. Studies of proteoglycan (PG) synthesis showed
      that the majority of OA cartilage explant samples responded weakly to IGF-I (100
      ng/ml) stimulation (+33%), while the others were high responders (+180%). Co
      incubation of IGF-I with recombinant (r) IGFBP-3 did not affect the rate of PG
      synthesis. However, while pre-incubation with rIGFBP3 for 72 h did not change the
      rate of PG synthesis in the high-responder group, it strongly increased PG
      synthesis in the low-responder group. This study demonstrates that the ability of
      IGF-I to enhance proteoglycan synthesis varied among the OA samples and may in
      part be dependent on the local level of IGFBP-3. This implies pathophysiological
      considerations in the limits of IGF-I action during the OA process.

PMID- 8670571
TI  - Antibodies to endothelial cells and to beta 2-glycoprotein I in the
      antiphospholipid syndrome: prevalence and isotype distribution.
AB  - The aim of this study was to analyse the prevalence and isotype distribution of
      antibodies to endothelial cells (aEC) and to beta 2-glycoprotein I (a beta 2GPI)
      in the antiphospholipid syndrome (APS). Fifteen patients with an APS [nine
      associated with systemic lupus erythematosus (SLE) and six "primary'] and 15 with
      SLE without an APS were prospectively studied. The aEC were determined by an
      enzyme-linked immunosorbent assay (ELISA) using endothelial cells derived from
      human umbilical vein and the a beta 2GPI by ELISA using highly purified beta
      2GPI. A positive titre of aEC was detected in 20 out of 30 patients (67%), but in
      none of the control group. Ten patients had both IgG and IgM isotypes, five had
      IgG only and five had only IgM. Thirteen patients with the APS (87%) were found
      to have a positive titre of aEC, while only seven with SLE but without a history
      of APS (47%) had aEC (P < 0.05). Nine patients with the APS (60%) had a positive
      titre of a beta 2GPI (four had both IgG and IgM isotypes, one had IgG only and
      four had only IgM), while none of the patients without an APS (0%) had these
      antibodies (P < 0.001). A significant association was also found between the
      presence of aPL and aEC (P < 0.05), as well as between aPL and a beta 2GPI (P <
      0.001). Both aEC and a beta 2GPI can be found in the APS. This reinforces the
      theory that APS represents a complex autoimmune disorder in which several
      autoantibodies co-exist with aPL.

PMID- 8670573
TI  - Predominance of IgM anti-U1RNP antibodies in patients with systemic lupus
      erythematosus.
AB  - Anti-U1RNP antibodies occur in patients with mixed connective tissue disease
      (MCTD), systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other
      ill-defined connective tissue diseases. To associate the isotypes of anti-U1RNP
      antibodies with the diagnosis of the disease, namely SLE or MCTD, sequential sera
      of patients positive for anti-U1RNP antibodies by counterimmunoelectrophoresis
      (CIE) (32 with SLE, 35 with MCTD) were tested for IgG and IgM anti-U1RNP
      antibodies by enzyme-linked immunosorbent assay (ELISA) using affinity-purified
      U1snRNP complexes. Results from ELISA were confirmed by RNA precipitation. IgG
      RNA precipitation of HeLa cellular extracts was performed using the bulk of the
      IgG fraction removed from each serum after binding to protein A-Sepharose beads.
      IgM RNA precipitation was carried out on the IgM fraction of the serum bound to
      protein A-Sepharose-rabbit anti-human IgM immune complexes. RNAs were
      electrophoresed in 10.5% acrylamide-7 M urea gels and detected with the silver
      stain. ELISA showed that all sera were positive to IgG anti-U1RNP, while 12 of
      the 35 MCTD and 21 of the 32 SLE patients possessed IgM anti-U1RNP (P < 0.025).
      IgM anti-U1RNP reactivity was found during the follow-up in 20% of 44 sera from
      17 MCTD patients and 68% of 112 sera from 23 SLE patients (P < 0.0001). IgG from
      all the sera precipitated U1RNPs. Eight of the MCTD sera also precipitated U2RNPs
      and 14 of the SLE sera U2 and/or U4/U6, U5 RNPs. IgM from MCTD sera did not
      precipitate URNPs, while IgM from SLE sera precipitated predominantly U1RNPs.
      These data suggest that IgM anti-U1RNP antibodies occur predominantly in patients
      with SLE. The occurrence of IgG anti-U1RNP without IgM is more frequent in MCTD.

PMID- 8670572
TI  - Genetic analysis of TAP2 in systemic lupus erythematosus patients from two ethnic
      groups.
AB  - The aim of this study was to determine whether the TAP2 (Transporter associated
      with Antigen Processing 2) locus is involved in susceptibility to systemic lupus
      erythematosus (SLE). We adopted the interethnic approach to overcome problems in
      the analysis resulting from linkage disequilibrium. The TAP2 gene polymorphisms
      of the codons corresponding to amino acid positions 379, 565 and 665 were
      investigated by amplification refractory mutation system polymerase chain
      reaction (ARMS-PCR) in 186 patients (151 white Europeans, 35 Afrocaribbeans) and
      183 controls (79 white Europeans, 104 Afrocaribbeans). In the European SLE
      patients, the frequency of the TAP2 type V-A-TA was marginally lower compared
      with the control group (31% vs 42%), with negative linkage disequilibrium between
      this TAP2 type and DR3 probably accounting for the difference. For the European
      SLE patients, we confirmed a significant association of DR3 with disease status
      [odds ratio = 4.16, 95% confidence interval (CI), 2.08-8.39] and in the patients
      with DR3 there was a significantly high frequency of the TAP2 type V-A-T-. In the
      Afrocaribbean SLE patients, any associations of disease status with TAP2
      phenotype were the inverse of those in the European patients. Thus, in these
      patients the frequency of V-A-TA was higher than in controls (46% vs 26%, OR =
      2.4, 95% CI 1.01-5.74), while the frequency of V-A-T- was lower (26% vs 40%, not
      significant). Despite possible sampling error, the lack of a difference in TAP2
      status between cases and controls within ethnic groups and, if anything, an
      inverse association across ethnic groups, makes it unlikely that the TAP2
      polymorphism studied here is of primary relevance to SLE susceptibility.

PMID- 8670574
TI  - The value of isotype determination of serum antibodies against Chlamydia for the
      diagnosis of Chlamydia reactive arthritis.
AB  - In clinical rheumatology, the diagnosis of Chlamydia reactive arthritis is
      difficult because an incomplete form of the disease can closely resemble an
      undifferentiated seronegative mono/oligoarthritis. We investigated whether
      measuring specific isotypes of anti-Chlamydia antibodies in serum can improve the
      diagnosis, by comparing such antibody concentrations in the serum of patients
      with well-defined disease, i.e. Chlamydia trachomatis sexually acquired reactive
      arthritis (CT-SARA), with other arthritides. Antibody levels were determined by
      enzyme-linked immunosorbent assay (ELISA). When considering two different
      isotypes and their combination, the best sensitivity (63%) was obtained for IgM
      and/or IgA results with a specificity of 81%. The patients with CT-SARA and SARA
      had the highest levels of antibodies of all isotypes tested. It is concluded
      that, in our experimental conditions, only very high values of specific isotypes
      could indicate a diagnosis of Chlamydia reactive arthritis.

PMID- 8670575
TI  - Synovial fluid and serum antibodies against Chlamydia in different forms of
      arthritis: intra-articular IgA production in Chlamydia sexually acquired reactive
      arthritis.
AB  - Since the presence of Chlamydia has been shown in synovial fluid (SF) from some
      patients with Chlamydia reactive arthritis, we investigated whether anti
      Chlamydia antibodies present in the joint are derived from the circulation or are
      locally produced. We compared titres of IgG, IgM and IgA antibodies against
      Chlamydia, and against a control antigen (tetanus toxoid), by an enzyme-linked
      immunosorbent assay (ELISA), in paired samples of serum and SF from Chlamydia
      trachomatis sexually acquired reactive arthritis (CT-SARA) patients and from
      patients with other forms of arthritis. The ratio of serum/SF IgA anti-Chlamydia
      antibodies was significantly decreased in CT-SARA patients. It is concluded that,
      in our experimental conditions, we found evidence for intra-articular production
      of IgA anti-Chlamydia antibodies.

PMID- 8670576
TI  - Serum YKL-40 levels in healthy children and adults. Comparison with serum and
      synovial fluid levels of YKL-40 in patients with osteoarthritis or trauma of the
      knee joint.
AB  - YKL-40 is a recently discovered human glycoprotein which is related in amino acid
      sequence to the chitinase protein family. YKL-40 is a major secretory protein of
      human chondrocytes and synoviocytes, and could play a role in tissue remodelling.
      The aim of the study was to establish the serum YKL-40 level in normal subjects
      and to evaluate serum YKL-40 as a marker for osteoarthritis. Serum YKL-40 was 80
      micrograms/l in healthy children (n = 476) and 102 micrograms/l in healthy adults
      (n = 260). No age or sex differences were found in serum YKL-40 in subjects
      younger than 70 yr, but thereafter serum YKL-40 increased significantly. Patients
      with late-stage osteoarthritis of the knee (n = 37) had significantly higher
      serum YKL-40 (1.5-fold; P < 0.01) compared to healthy age-matched subjects,
      whereas patients with early-stage osteoarthritis of the knee or recent torn
      cruciate ligaments or menisci did not have elevated serum YKL-40. The level of
      YKL-40 in serum and synovial fluid correlated significantly, and 10-fold higher
      values were found in synovial fluid. YKL-40 levels in serum and synovial fluid of
      patients with acute severe synovial inflammation were significantly higher (P <
      0.05-P < 0.001) than those in patients with no, light or moderate synovitis of
      the knee joint. Furthermore, YKL-40 correlated significantly (P < 0.01) with the
      amino-terminal propeptide of type III procollagen, but not with serum C-reactive
      protein. Our data indicate that YKL-40 in synovial fluid and serum may reflect
      human articular cartilage degradation and the degree of synovial inflammation in
      the knee joint.

PMID- 8670577
TI  - Knee laxity in patients with osteoarthritis and rheumatoid arthritis.
AB  - Thirty-four patients with osteoarthritis (OA) and 32 patients with rheumatoid
      arthritis (RA) were studied to determine the effects of OA and RA on the laxity
      of the knee joints. Laxity was measured with the Genucom Knee Analysis System.
      The antero-posterior laxity of the OA and RA knees was greater than the control,
      normal knees in the early stage, and decreased with the severity of disease in
      OA, but not in RA. Severe OA and RA were associated with a restricted internal
      external rotation at the knee joint compared with the control. Internal-external
      rotation decreased with worsening of both diseases. Varus-valgus laxity tended to
      increase slightly with the severity of disease. While the morphological changes
      of the cruciate ligaments in advanced OA and RA were not statistically different,
      the laxity of OA-afflicted knees was affected slightly by the severity of the
      damage to the cruciate ligaments.

PMID- 8670578
TI  - Termination of disease-modifying drugs in psoriatic arthritis: study of 109
      courses of treatment.
AB  - Our aim is to study the termination of disease-modifying anti-rheumatic drugs
      (DMARDs) in psoriatic arthritis (PsA) and the causes of withdrawal. We have
      reviewed the prospective protocols of patients with PsA and collected the data on
      treatments and causes of withdrawal. Fifty-four out of 96 patients (48 male and
      48 female) have undergone one or more courses of DMARD (n = 109). The life-table
      analysis shows a survival rate of 6 months for gold sodium thiomalate (GOLD) and
      sulphasalazine (SSZ), and 16 months for methotrexate (MTX). The Mantel-Haenszel
      test finds statistical differences between GOLD and MTX. There are no differences
      between MTX and SSZ or between GOLD and SSZ. The absence of differences for MTX
      and SSZ could be explained by the heterogeneity of both groups. The most common
      cause of withdrawal for GOLD and SSZ are adverse effects.

PMID- 8670579
TI  - A randomized trial of testosterone therapy in males with rheumatoid arthritis.
AB  - Thirty-five male patients, aged 34-79 yr, with definite rheumatoid arthritis (RA)
      were recruited from out-patient clinics and randomized to receive monthly
      injections of testosterone enanthate 250 mg or placebo as an adjunct therapy for
      9 months. Endpoints included disease activity parameters and bone mineral density
      (BMD). At baseline, there were negative correlations between the ESR and serum
      testosterone (r = -0.42, P < 0.01) and BMD (hip, r = -0.65, P < 0.01). A total of
      29.6% of all patients had at least one vertebral fracture, most having multiple
      fractures. Back pain, however, was not more prevalent in fracture patients (55%
      vs 50%). Disease activity was significantly higher in the fracture group (joint
      score P < 0.05, rheumatoid factor P < 0.01). Thirty patients completed the trial,
      15 receiving testosterone and 15 receiving placebo. There were significant rises
      in serum testosterone, dihydrotestosterone and oestradiol in the treatment group.
      There was no significant effect of treatment on disease activity overall, five
      patients receiving testosterone underwent a "flare'. Differences in mean BMD
      following testosterone or placebo were non-significant (spine: +1.2% vs -1.1%;
      femur: -0.3% vs +0.3%). There was no suggestion of a positive effect of
      testosterone on disease activity in men with RA.

PMID- 8670580
TI  - Are we making the most of the Stanford Health Assessment Questionnaire?
AB  - For many years, the Stanford Health Assessment Questionnaire (HAQ) has provided
      an effective measure of disability. Recently, some debate has emerged about
      whether or not the HAQ is an "ordinal' or "interval' scale. The opportunity to
      test its level of measurement arose when the scale was applied in a community
      survey which undertook a two-stage random sample using postal questionnaires to
      ascertain the health care needs of those with arthritis. The HAQ data are fitted
      to the Rasch model which tests for the presence of certain desirable
      characteristics of measurement, e.g. unidimensionality. The fit of the data to
      the model for those self-reporting rheumatoid arthritis (RA) was adequate. The
      transformed HAQ score, derived from the Rasch analysis, is compared with the
      ordinary HAQ (raw) score. This shows that, for those with RA, incremental units
      of the raw score at the margins of the scale reflect an increasing level of
      (dis)ability compared to similar units in the centre of the scale. Thus, the
      traditional HAQ score (range 0-3) is an ordinal score. The findings also indicate
      that scoring all 20 items may lead to greater sensitivity. Questions are also
      raised about the construct validity for those with other types of arthritis. For
      osteoarthrosis, the grip item does not appear to belong to the same underlying
      construct as the other items.

PMID- 8670581
TI  - A letter from Japan.

PMID- 8670582
TI  - The role of the rheumatology nurse practitioner in primary care: an experiment in
      the further education of the practice nurse.
AB  - The aim of the project was to explore the possibility of conferring, on the
      practice nurse (PN), the skills and knowledge of the rheumatology nurse
      practitioner (RNP), hitherto, exclusively, a member of the hospital team. A
      trained and experienced RNP paid a series of regular visits to participating
      general practices in SE London. The subjects were 11 PNs and 30 patients with
      chronic rheumatic diseases. Interactive sessions involving the RNP, PN and
      patients were set up with a view to (1) instructing the PNs in the role of the
      RNP in the education and care of patients, and (2) educating patients about their
      disease and its treatment. Practice nurse and patient questionnaires were used to
      assess PN and patient knowledge before and after the instructional sessions. Only
      eight out of the 392 (2%) practices approached participated in the project and,
      even with these, difficulties were encountered, arising from the PNs' workload
      and pattern of work, and the reluctance of the general practitioners to enter a
      new project in the present climate of change in the NHS, unless clear and
      immediate financial advantages were in prospect. Statistically significant
      results were obtained in before/after comparisons of patient and nurse knowledge
      scores (P < 0.00001 and P = 0.001, respectively) following the RPN visits. The
      basic instructional format is sound and workable. A PN, if allocated protected
      time and appropriate patients, can acquire the knowledge and skills needed to
      manage patients with chronic rheumatic diseases in primary care. Both the
      instruments of measurement used can register changes over time, leading in a
      small number of patients (30) and PNs (11) to a statistically highly significant
      result.

PMID- 8670583
TI  - Phosphatidyl serine-dependent antiprothrombin antibody is exclusive to patients
      with lupus anticoagulant.
AB  - We conducted this study to determine whether antiprothrombin antibody (aPT) [to
      prothrombin (PT) alone or PT/phosphatidyl serine (PS) complex] actually existed
      in patients with lupus anticoagulant (LA) and/or anticardiolipin antibody (aCL).
      aPT to PT alone was positive in 2/7 LA-positive (29%) and 3/7 LA/aCL-positive
      (43%) patients. aPT to PT/PS complex was positive in 4/7 LA-positive (57%) and
      4/7 LA/aCL-positive (57%) patients in the presence of Ca2+. However, none of the
      aCL-positive patients without LA or the LA/aCL-negative patients were positive
      for aPT and aPT/PS. Thus, we confirmed the existence of aPT and aPT/PS
      specifically among LA-positive patients. However, the clinicopathological
      significance of aPT and aPT/PS in this clinical setting is yet to be clarified.

PMID- 8670584
TI  - Antibodies to four gram-negative bacteria in rheumatoid arthritis which share
      sequences with the rheumatoid arthritis susceptibility motif.
AB  - The bacteria Proteus, Serratia, Escherichia and Pseudomonas possess sequences
      resembling the rheumatoid arthritis susceptibility sequence EQRRAA, but
      antibodies were elevated only to Proteus in 66 RA patients (P<0.001) when
      compared to 61 active ankylosing spondylitis patients and 60 controls.

PMID- 8670585
TI  - Enterococcal arthritis with avascular necrosis in a lupus patient.

PMID- 8670586
TI  - Tertiary hyperparathyroidism after long-term phosphate supplementation in adult
      onset hypophosphataemic osteomalacia.
AB  - We report the development of tertiary hyperparathyrodism in a patient with a
      sporadic form of adult-onset hypophosphataemic osteomalacia who had been treated
      with vitamin D or calcitriol and large doses of phosphate. This observation
      suggests that even with concomitant vitamin D or calcitriol therapy, long-term
      oral phosphate supplementation may lead to the development of hypercalcaemic
      hyperparathyrodism. Caution is recommended when relatively large doses of
      phosphate are used to treat hypophosphataemic osteomalacia of diverse causes.

PMID- 8670588
TI  - Letter to the Editor. Tenidap versus Diclofenac in rheumatoid arthritis

PMID- 8670587
TI  - Letter to the Editor. Atypical Cogan's syndrome associated with antineutrophil
      cytoplasmic autoantibodies

PMID- 8670589
TI  - Letter to the Editor. #Pregnancy, schizophrenia and rheumatoid arthritis

PMID- 8670590
TI  - Specialist training into the new millennium: the price of conformity with Europe.

PMID- 8670591
TI  - The consequences of the Calman Report on academic rheumatology.

PMID- 8670592
TI  - Expression of bcl-2 in rheumatoid arthritis.
AB  - Since defective apoptosis has been suggested to play a role in the development of
      autoimmune diseases, we have investigated the expression of the proto-oncogene
      bcl-2 in patients with rheumatoid arthritis (RA). The expression of bcl-2 was
      studied in peripheral blood (PB) and synovial fluid (SF) lymphocytes and synovial
      tissues (ST) from patients with RA using immunohistochemistry, flow cytometry and
      nucleic acid hybridization. Patients with reactive arthritis (ReA) or
      osteoarthritis (OA) and healthy individuals were used as controls. The expression
      of bcl-2 protein in PB lymphocytes and the expression of bcl-2 mRNA in PB
      mononuclear cells (PBMC) was similar in healthy controls and patients with RA.
      However, bcl-2 protein expression was significantly reduced in SF lymphocytes
      when compared to PB lymphocytes. Similar results were observed with lymphocytes
      from patients with ReA, and irrespective of whether total lymphocytes, T cells or
      different T-cell subsets were studied. In the synovial sections, the expression
      of bcl-2 was restricted to lymphocytes, and bcl-2+ cells were observed in the
      majority of samples from patients with RA, OA and ReA. These data indicate that
      the expression of bcl-2 is not increased in the lymphocytes or ST derived from
      patients with RA. Instead, decreased expression of bcl-2 protein in SF
      lymphocytes compared to PB lymphocytes was demonstrated. We suggest that bcl-2
      does not play a significant role in the pathogenesis of RA.

PMID- 8670593
TI  - Diagnostic value of anti-RA33 antibody, antikeratin antibody, antiperinuclear
      factor and antinuclear antibody in early rheumatoid arthritis: comparison with
      rheumatoid factor.
AB  - The goal of this prospective longitudinal study was to determine the serological
      profile of early rheumatoid arthritis (RA), and to test whether antikeratin
      antibody (AKA), antiperinuclear factor (APF), anti-RA33 antibody and antinuclear
      antibodies (ANA) had an additional diagnostic value when prescribed after
      rheumatoid factor (RF)-detecting methods. Sixty-nine patients with early
      polyarthritis suggestive of RA, seen between 1991 and 1993, were included. Five
      autoantibodies (i.e. RF, AKA, APF, RA33, ANA) were looked for at regular
      intervals. After 24 months follow-up, patients were classified as having RA (n =
      49), unclassified polyarthritis (UP; n = 15) or other rheumatic diseases. Among
      patients with early RA, the sensitivity of these markers was 40.8% for RF, 36.7%
      for AKA, 28.6% for APF and 28.6% for anti-RA33. Among RF-negative RA patients,
      51.7% were positive for AKA, APF, anti-RA33 antibodies and/or ANA. Positivity of
      the three recent markers usually persisted throughout follow-up, whereas RF was
      lost by 58% of patients with early, RF-positive, treated RA. Using multivariate
      analysis, only latex, RF test and AKA or APF had an independent and statistically
      significant diagnostic value for early RA. Our data suggest that RF and AKA (or
      APF) should be concomitantly determined for diagnosis in patients with suspected
      early RA.

PMID- 8670594
TI  - Antineutrophil cytoplasmic antibodies in systemic lupus erythematosus.
AB  - Antineutrophil cytoplasmic antibodies (ANCA) with specificity for proteinase-3
      (PR3) are associated with Wegener's granulomatosis, and ANCA directed to
      myeloperoxidase (MPO) with other idiopathic vasculitides. Inflammation of small
      sized blood vessels is a hallmark of systemic lupus erythematosus (SLE). We
      evaluated the prevalence of ANCA in SLE, their antigenic specificities, and their
      possible relation to clinical disease patterns and activity. Plasma samples from
      84 patients with SLE were tested for ANCA during remission. Plasma samples from
      the 25 patients who relapsed during a follow-up of 32 months were serially
      analysed for ANCA in a 6 month period preceding and including the relapse. The
      presence of ANCA was assessed by indirect immunofluorescence (IIF) and ELISA for
      antibodies to PR3, MPO, lactoferrin (LF), elastase (HLE) and cathepsin-G (CG). We
      related the presence of ANCA to disease patterns, activity and duration. ANCA by
      IIF were difficult to interpret dut to the presence of antinuclear antibodies
      (ANA). By ELISA, we found no anti-PR3 or anti-HLE. Anti-MPO (n = 7), anti-LF (n =
      13) and anti-CG (n = 10) were detected, generally in low titres. The presence of
      ANCA of defined specificity was not associated with specific clinical subsets.
      The prevalence of ANCA was higher in patients who developed relapses than in
      those who did not (P < 0.01). However, levels of ANCA did not fluctuate in the
      period preceding the relapse. ANCA of various specificities occur in SLE. Their
      presence is not associated with specific clinical disease entities. The higher
      frequency of ANCA in relapsing patients compared to those who do not relapse may
      suggest that ANCA are involved in disease expression. Their diagnostic
      significance is limited.

PMID- 8670595
TI  - Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404.
AB  - The frequency of HLA-DRB1 alleles was determined in 68 Caucasoid patients with
      polymyalgia rheumatica (PMR) and 140 controls using polymerase chain reaction
      (PCR) sequence-specific oligonucleotide typing. In keeping with previous studies,
      an increased frequency of DRB1*04 was observed in patients [55.9% vs 35.0%, odds
      ratio (OR) 2.4, 95% confidence interval (CI) 1.3-4.4]. HLA-DRB1*0101 frequency
      was also increased in patients, although less confidence could be placed on this
      association (19.1% vs 14.3%, OR 1.4, 95% CI 0.6-3.3). HLA-DRB1*04 subtyping
      indicated that the frequencies of both DRB1*0401 (38.2% vs 22.1%, OR 2.2, 95% CI
      1.0-4.3) and DRB1*0404 (16.2% vs 5.0%, OR 3.7, 95% CI 1.2-11.1) were specifically
      raised. An increased frequency of the RA shared epitope (QKRAA/QRRAA) was also
      observed in this group (75.0% vs 44.2%, OR 3.8, 95% CI 1.9-7.6). When the
      analysis was restricted to only DRB1*04-negative patients and controls, the
      frequencies of DRB1*0301, *11 and *08 were marginally raised. However, no obvious
      relationship appeared to exist between PMR susceptibility and DRB1 alleles
      carrying the DYF conserved epitope in the second hypervariable region.
      Autoantibodies to thyroid antigens were present in 23% of patients. An increased
      frequency of DRB1*0301 was observed in patients with thyroid microsomal
      antibodies compared to those without (54.5% vs 24.6%, OR 3.7, 95% CI 0.8-17.0).
      This increase was not observed in patients with thyroglobulin autoantibodies.
      These data indicate that both DRB1*0401 and *0404 are associated with PMR, and
      that this may extend to include DRB1*0101. The immunogenetic profile of
      susceptibility markers in this condition appears to be similar to that in
      rheumatoid arthritis.

PMID- 8670596
TI  - Aminohexane bisphosphonate suppresses bone turnover in postmenopausal women more
      rapidly than oestrogen-gestagen therapy.
AB  - Although animal studies suggest that there may be major differences between the
      effects of bisphosphonates and ovarian hormones on skeletal metabolism, whether
      this also holds for their actions in patients is unknown. To address this
      question, we compared the effects of 12 weeks treatment with HRT on bone turnover
      markers in osteopenic postmenopausal women with those of an amino-bisphosphonate.
      Women within 15 yr of the menopause, with a lumbar and/or femoral neck bone
      mineral density 1 S.D. below the predicted value, received either oestradiol
      valerate 2 mg and dydrogesterone 5 mg (E/D; n = 16) or aminohexane bisphosphonate
      400 mg (AHBP; n = 9). Urine and serum samples were collected on two separate
      occasions before starting treatment, and 1, 2, 4, 8 and 12 weeks afterwards. To
      assess bone resorption, we measured the urinary deoxypyridinoline/creatinine
      ratio (DPD/crea), while serum alkaline phosphatase (ALP), osteocalcin and C
      terminal propeptide of type I collagen (CICP) were analysed to assess bone
      formation. Repeated measures analysis of variance revealed a highly significant
      decrease in DPD/crea over the treatment period. Furthermore, this pattern of
      response differed significantly between the two treatment groups, since DPD/crea
      was maximally suppressed within 2 weeks of starting AHBP, while E/D showed little
      decrease until 8 weeks. AHBP was also found to suppress ALP, osteocalcin and CICP
      more rapidly than E/D, the former reducing these markers by 8 weeks, while E/D
      caused little inhibition even by 12 weeks. We conclude that, in the doses used in
      this study, AHBP appears to suppress bone turnover significantly more rapidly
      than E/D, suggesting that clinically important differences may exist in the
      effects of bisphosphonates and ovarian hormones on bone metabolism.

PMID- 8670597
TI  - CD8 lymphocyte subsets in active polymyalgia rheumatica: comparison with elderly
      onset and adult rheumatoid arthritis and influence of prednisone therapy.
AB  - The aim of this study was to evaluate CD8 lymphocyte subsets in active
      polymyalgia rheumatica (PMR), to determine whether low percentages of CD8+ cells
      could be used to differentiate PMR from elderly-onset (EORA) and adult rheumatoid
      arthritis (RA), and to investigate the effects of prednisone on CD8 lymphocyte
      subsets. A significant reduction of percentages and absolute numbers of
      CD8bright+ cells was observed in patients with active PMR. Both CD8bright+, CD57-
      and CD8bright+, CD57+ subsets were significantly reduced. Reduced percentages of
      CD8+ cells were observed in 55% of patients with active PMR/giant cell arteritis
      (GCA), in 23% with EORA and in 44% with adult RA. Prednisone therapy in PMR
      patients, after only 1 week, increased the lymphocyte count and the absolute
      numbers of lymphocyte subsets significantly. However, the percentages of
      CD8bright+ cells remained persistently low for the 2 yr study period in 80% of
      the patients with low pre-treatment levels. Our results demonstrate that CD8 cell
      percentage is a poor epidemiological discriminator for PMR diagnosis.
      Notwithstanding the rise in absolute numbers of CD8 cell subsets induced by
      prednisone, the persistently low percentages of CD8+ cells in a group of PMR
      patients indicate an abnormality connected with the disease.

PMID- 8670598
TI  - Reduced CD8+ T-cell concentration in peripheral blood of patients with carotid
      artery stenosis: relation to arteritis temporalis.
AB  - The percentage and numbers of CD8+ T cells are markedly decreased in peripheral
      blood from patients with arteritis temporalis. Transient cerebral ischaemic
      attacks (TIA) or brain infarctions have been frequently reported as the first and
      only clinical manifestation, and signs of carotid artery stenosis have been
      reported in 15-20% of patients with arteritis temporalis. We used a determination
      of the CD8+ T-cell subset to evaluate patients with TIA. Concentrations of CD8+ T
      cells were measured in the peripheral blood of 24 patients with TIA. The cohort
      investigated was consecutive, but adjusted to have a 50% a priori probability of
      carotid artery stenosis. An ultrasound Doppler investigation of the carotid
      arteries was performed in all patients. Controls were 24 healthy subjects of
      comparable age and sex. Median percentage and concentrations of CD8+ T cells were
      significantly lower in patients with TIA and carotid artery stenosis compared
      with (1) patients with TIA and no carotid stenosis (CD8+ %: 13.5 vs 26; CD8+ x
      10(9)/1: 0.24 vs 0.44, P < 0.001) and (2) healthy controls (CD8+ %: 13.5 vs 22.5;
      CD8+ x 10(9)/1: 0.24 vs 0.52, P < 0.001). The prevalence of a carotid artery
      stenosis in the combined first and second quartile of CD8+ % (CD8+ % <or= 15) was
      80% (95% CI: 44-97%) and in the combined third and fourth quartile 28.5% (95% CI:
      8-58%) (P = 0.03). The positive predictive value for carotid artery stenosis was
      80%, an incremental ruling in gain of 60%. The negative predictive value was 71%.
      In patients with TIA and carotid artery stenosis, a reduced percentage and
      numbers of the CD8+ T-cell subset were significantly more frequent than in
      patients with no stenosis. No other signs of arteritis temporalis were found.

PMID- 8670599
TI  - Prediction of permanent work disability in a follow-up study of early rheumatoid
      arthritis: results of a tree structured analysis using RECPAM.
AB  - The objectives of this study are: (a) to determine the occurrence of permanent
      work disability (PWD) in early rheumatoid arthritis (RA); (b) to identify
      prognostic groups of patients; (c) to assess the employment rates for these
      groups over time. Seventy-three gainfully employed consecutive out-patients with
      early RA (> or = 5 ARA 1958 criteria, disease duration < or = 12 months) at time
      one (T1) were re-examined at time two (T2) after a mean follow-up of 6 yr (S.D.
      +/- 2 yr). Potential risk factors, identified at T1, for PWD at T2 were entered
      in a tree structured survival analysis using RECPAM (RECursive Partition and
      AMalgamation). Cumulative 3 yr employment rates (3-yrER +/- S.E.M.) were computed
      from the resulting Kaplan-Meier curves. At T2, PWD occurred in 27 of the 73
      patients (37%). The fastest decline in the employment rate was found within the
      first 3 yr of the disease onset, with a 3-yrER reduced to 73 +/- 5%. The group
      with the poorest prognosis (n = 14; 3-yrER 14 +/- 9%) was defined by age > or =
      50 yr with either ESR > or = 60 mm/h or the combination of modified functional
      class (1-7) > or = 4 with a disease duration > or = 7 months. An intermediate
      group (n = 38; 3-yrER 79 +/- 6%) was defined by (a) age > or = 50 yr and low or
      moderate disease activity, (b) age < 50 yr and more strenuous job-related
      physical requirements, (c) age < 50 yr and less strenuous work, but joint count >
      or = 15. No case of PWD occurred in 21 individuals aged < 50 yr with a joint
      count < 15 and less physically demanding jobs. PWD occurs early in a substantial
      number of patients with RA. RECPAM defines risk profiles that can readily be
      applied in actual clinical situations and allow an estimation of the risk of PWD
      at different time points using the resulting Kaplan-Meier curves.

PMID- 8670600
TI  - The epidemiology of spondylodiscitis in ankylosing spondylitis--a controlled
      study.
AB  - Spondylodiscitis is well recognized in ankylosing spondylitis (AS), but little is
      known about its epidemiology. We therefore reviewed 147 consecutive patients with
      AS using lumbar and thoracic spine radiographs. For each patient with
      spondylodiscitis, two age- and sex-matched controls were selected. Twelve
      individuals (8%) had spondylodiscitis, affecting a total of 32 disc spaces: 10
      thoracic, 22 lumbar. The mean age at onset was 21 +/- 4.1 yr, significantly
      younger than that of the controls (28.5 +/- 10.1 yr, P = 0.004). Half of the 12
      patients had multiple lesions (between two and six levels). The most common site
      was the lower thoracic spine with additional lumbar spine involvement. Only two
      of the 12 patients (17%) had symptoms localized to the lesions. Neither trauma
      nor infection were considered to be causes of the spondylodiscitis. IN
      CONCLUSION: (1) spondylodiscitis occurs in approximately 8% of patients with AS;
      (2) these patients have early onset of disease; (3) multiple-level lesions in the
      spine are not uncommon among those with spondylodiscitis; (4) lesions are usually
      asymptomatic.

PMID- 8670601
TI  - Sulphasalazine in psoriatic arthritis: a randomized, multicentre, placebo
      controlled study.
AB  - A prospective double-blind, placebo-controlled, randomized study of 24 weeks
      duration was carried out comparing the efficacy and tolerability of
      sulphasalazine (SSZ) versus placebo in patients with psoriatic arthritis. A total
      of 120 patients were included in nine centres. All patients had active disease
      and fulfilled the criteria of definite psoriatic arthritis of at least 3 months
      duration. They received either SSZ (2.0 g/day) or placebo. Efficacy variables
      included pain, patient's overall assessment of joint and skin improvement,
      morning stiffness, Ritchie articular index, ESR and CRP. An intention-to-treat
      (ITT) analysis was performed for the 117 patients who qualified (three patients
      did not qualify due to missing data after baseline). A per-protocol analysis was
      performed for the 81 patients who completed the 6 months study period (SSZ = 38,
      placebo = 43). Major reasons for withdrawal were inadequate response (SSZ = 4,
      placebo = 7) and adverse events (SSZ = 8, placebo = 12). Pain was the only
      statistically significantly different primary outcome variable at end point in
      favour of SSZ in the ITT analysis. No significant differences were present in
      other clinical or biological variables, although there was a trend in favour of
      SSZ for some variables. SSZ, at a dose of 2.0 g/day, appeared to be a safe
      treatment in patients with psoriatic arthritis. At this dosage, its efficacy was
      only demonstrated for the pain variable.

PMID- 8670602
TI  - Cyclosporin A in the treatment of systemic lupus erythematosus: results of an
      open clinical study.
AB  - In order to define the effects and safety of cyclosporin A (CsA) in systemic
      lupus erythematosus (SLE), we conducted an open clinical trial with 16 SLE
      patients. During an observation period of up to 64 months and an average
      treatment period of 30.3 months, 16 SLE patients, who did not have adequate
      disease control or experienced side-effects with their previous immunosuppressive
      therapy, were treated with CsA (3-5 mg/kg). In 3/16 patients, CsA treatment was
      discontinued because of side-effects, in two because of inefficacy and in 2/16
      because of a pregnancy. Four out of 16 patients had a flare of disease during CsA
      therapy 7, 24, 36 and 40 months after initial response to therapy; one patient
      stopped CsA treatment after 54 months of successful disease control. Four out of
      16 patients are still on CsA. The best beneficial effect was observed in 10
      patients with proteinuria, which decreased from 4.7 +/- 2.6 to 1.5 +/- 1.1 g/24
      h. In 3/3 patients with thrombocytopenia and 3/3 patients with leucocytopenia,
      platelets and leucocytes returned to normal values. The most frequent side
      effects were hypertension and deterioration of renal function (3/16) and
      hypertrichosis (5/16). According to the preliminary results of this study, CsA
      was well tolerated and able to control disease activity over an extended time
      period. These data should encourage investigators to perform a multicentre
      controlled trial on CsA therapy in SLE.

PMID- 8670603
TI  - Ultrasonographic features of diabetic cheiroarthropathy.
AB  - Ultrasonography was used to measure flexor tendon sheath thickness in 14 insulin
      dependent (IDDM) diabetics with diabetic cheiroarthropathy (DCA) and compared to
      17 IDDM patients without DCA along with 10 healthy volunteers. Assessment was
      also made of the presence of systemic diabetic microvascular disease
      complications. A blinded visual 'eyeball' report on the ultrasound scans by a
      radiologist found hypoechoic thickening of the flexor tendon sheaths in 12 of the
      14 patients with DCA, three of the 17 unaffected diabetics and two of the healthy
      volunteers (Fisher's exact, P < 0.001). However, further quantitation of tendon
      sheath thickness separated patients with DCA from others. In all patients with
      DCA, tendon sheath thickness was > or = 1 mm (median 1.8 mm, range 1.0-2.3 mm)
      and < or = 1 mm in the other two groups (medians 0.6 and 0.5 mm, range 0.3-1.0
      mm) (Kruskal-Wallis, P < 0.001). All patients with DCA had evidence of systemic
      microvascular disease complications, particularly proliferative retinopathy
      (82%). It appears that flexor tendon sheath thickening in the hand is an integral
      part of the pathology in DCA and is easily demonstrated by ultrasound. It is
      closely associated with overt diabetic microvascular disease complications.

PMID- 8670604
TI  - Rheumatic diseases and the development of rheumatology in Vietnam.

PMID- 8670605
TI  - Unusual complications of cervical spine surgery for cervical myelopathy in
      rheumatoid arthritis.
AB  - Cervical myelopathy is a recognized complication of rheumatoid arthritis and
      other inflammatory arthropathies. In a significant proportion of patients,
      surgical stabilization of the cervical spine offers the best opportunity for
      improvement of symptoms and long-term survival. We report two cases that
      illustrate some potential complications of cervical spine surgery and which also
      emphasize the need for vigilance when caring for patients in this group.

PMID- 8670606
TI  - Increased bacterial urease activity in faeces in juvenile chronic arthritis:
      evidence of altered intestinal microflora?
AB  - The intestinal microflora was indirectly evaluated in juvenile chronic arthritis
      (JCA) by analysing enzyme activities--urease, beta-glucosidase and beta
      glucuronidase--in faeces. In 18 out of 26 JCA patients, the illness had been
      diagnosed during the past year. The control group was composed of eight age
      matched control patients and 18 family members of JCA patients (3-36 yr). The
      mean [95% confidence interval (CI)] urease activity, but not the activities of
      beta-glucosidase and beta-glucuronidase, in faeces from the JCA group differed
      from that in the control group: 32.3 (26.6-38.1) nmol/min/mg protein vs 24.0
      (16.8-31.6), P = 0.07. The difference was more marked in a comparison of JCA
      patients with family members (P = 0.03). In a subgroup of subjects, the effect of
      10 days oral bacteriotherapy with Lactobacillus GG on faecal enzyme activities
      was then investigated (n = 8 JCA patients, n = 8 control patients). This short
      term oral bacteriotherapy reduced the increased urease activity in faeces of JCA
      patients. Keeping in mind the small number of subjects, it may be inferred from
      the present results that the increased urease activity in JCA is specific for the
      disease, suggesting altered intestinal microflora in JCA.

PMID- 8670607
TI  - Paediatric rheumatology: clinical practice review. Physiotherapy and occupational
      therapy for juvenile chronic arthritis: custom and practice in five centres in
      the UK, USA and Canada
AB  - Physiotherapy and occupational therapy are widely accepted as being of central
      importance for the treatment of juvenile chronic arthritis (JCA). However, these
      approaches have rarely been subject to critical scrutiny. The aims of this report
      are to highlight some of the inter-centre similarities and differences observed
      in the implementation of physical and occupational therapy for JCA, and to
      emphasize the need for scientifically controlled research in this area. During a
      series of visits to several paediatric rheumatology units in the UK, USA and
      Canada, three aspects of the service were noted: treatment philosophy, physical
      interventions used for the treatment of JCA and quality-of life and independence
      training activities. There was general consensus with the philosophy that early
      physical intervention was a vital part of the treatment plan for JCA, although
      all therapists were concerned that compliance with treatment modalities was poor.
      Differences between units in the approach to acute arthritis, the use of foot
      othoses and wrist splints, the treatment of joint contractures and the use of
      general quality-of-life training activities were noted. Although it was widely
      recognized that controlled research into the efficacy of physical intervention
      was needed, no centre had a co-ordinated plan for such investigations. Keywords:
      Juvenile chronic arthritis, Physiotherapy, Occupational therapy

PMID- 8670608
TI  - Letter to the editor. Heterotopic ossification complicating long-term sedation

PMID- 8670609
TI  - Letter to the editor. Scurvy, osteoporosis and megaloblastic anaemia due to
      alleged food intolerance

PMID- 8670610
TI  - Letter to the editor. Low-dose corticosteroids and blindness in giant cell
      arteritis

PMID- 8670611
TI  - Letter to the editor. Cardiac abnormalities in a patient with localized
      scleroderma

PMID- 8670612
TI  - Letter to the editor. Accidental overdose of Prednisolone and methotrexate

PMID- 8670613
TI  - CLEANUP: a fast computer program for removing redundancies from nucleotide
      sequence databases.
AB  - A key concept in comparing sequence collections is the issue of redundancy. The
      production of sequence collections free from redundancy is undoubtedly very
      useful, both in performing statistical analyses and accelerating extensive
      database searching on nucleotide sequences. Indeed, publicly available databases
      contain multiple entries of identical or almost identical sequences. Performing
      statistical analysis on such biased data makes the risk of assigning high
      significance to non-significant patterns very high. In order to carry out
      unbiased statistical analysis as well as more efficient database searching it is
      thus necessary to analyse sequence data that have been purged of redundancy.
      Given that a unambiguous definition of redundancy is impracticable for biological
      sequence data, in the present program a quantitative description of redundancy
      will be used, based on the measure of sequence similarity. A sequence is
      considered redundant if it shows a degree of similarity and overlapping with a
      longer sequence in the database greater than a threshold fixed by the user. In
      this paper we present a new algorithm based on an "approximate string matching'
      procedure, which is able to determine the overall degree of similarity between
      each pair of sequences contained in a nucleotide sequence database and to
      generate automatically nucleotide sequence collections free from redundancies.

PMID- 8670614
TI  - A comparison of some neural and non-neural methods for identification of
      phytoplankton from flow cytometry data.
AB  - Four artificial neural network paradigms (multilayer perceptron networks,
      learning vector quantization networks, and radial and asymmetric basis function
      networks) and two statistical methods (parametric statistical classification by
      modelling each class with Gaussian distributions, and non-parametric density
      estimation via the K-nearest neighbour method) were compared for their ability to
      identify seven freshwater and five marine phytoplankton species from flow
      cytometric data. Kohonen self-organizing maps were also used to examine
      similarities between species. Optimized networks and statistical methods
      performed similarly, correctly identifying between 86.8% and 90.1% of data from
      freshwater species, and between 81.3% and 84.1% of data from marine species.
      Choice of identification technique must therefore be made on the basis of other
      criteria. We highlight the way each method partitions the data space and thereby
      separates the data clusters, and discuss the relative merits of each with
      reference to complexity of data boundaries, training time, analysis time and
      behaviour when presented with 'novel' data.

PMID- 8670615
TI  - Positional sequencing by hybridization.
AB  - Sequencing by hybridization (SBH) is a promising alternative to the classical DNA
      sequencing approaches. However, the resolving power of SBH is rather low: with
      64kb sequencing chips, unknown DNA fragments only as long as 200 bp can be
      reconstructed in a single SBH experiment. To improve the resolving power of SBH,
      positional SBH (PSBH) has recently been suggested; this allows (with additional
      experimental work) approximate positions of every l-tuple in a target DNA
      fragment to be measured. We study the positional Eulerian path problem motivated
      by PSBH. The input to the positional eulerian path problem is an Eulerian graph
      G(V, E) in which every edge has an associated range of integers and the problem
      is to find an Eulerian path e1,...,e/E/ in G such that the range of ei contains
      i. We show that the positional Eulerian path problem is NP-complete even when the
      maximum out-degree (in-degree) of any vertex in the graph is 2. On a positive
      note we present polynomial algorithms to solve a special case of PSBH (bounded
      PSBH), where the range of the allowed positions for any edge is bounded by a
      constant (it corresponds to accurate experimental measurements of positions in
      PSBH). Moreover, if the positions of every l-tuple in an unknown DNA fragment of
      length n are measured with O(log n) error, then our algorithm runs in polynomial
      time. We also present an estimate of the resolving power of PSBH for a more
      realistic case when positions are measured with theta (n) error.

PMID- 8670616
TI  - NAMOT2--a redesigned nucleic acid modeling tool: construction of non-canonical
      DNA structures.
AB  - Using a new set of reduced coordinates developed for describing regular and
      unusual nucleic acid structures, we have revised our nucleic acid modeling tool
      NAMOT2. NAMOT2 is general in terms of modeling different nucleic acid structures.
      A set of modifiable libraries allows users to customize their modeling
      environment. With this set of libraries, NAMOT2 can be used to model non
      canonical structures such as parallel-stranded, triple-stranded and quadruple
      stranded nucleic acid molecules. For modeling irregular structures (junctions,
      hairpin loops, etc.), we introduce a structural recipe approach. The complete
      procedure using NAMOT2 to construct the structure of a specific molecule is
      treated as the recipe for that structural motif. The existing recipes can be
      modified to generate new recipes for different structural motifs. Several
      examples of nucleic acids with non-canonical structures were modeled using
      NAMOT2. These examples include a DNA-drug complex, a DNA cube, a six-arm junction
      and a curved DNA molecule.

PMID- 8670618
TI  - HTP: a neural network-based method for predicting the topology of helical
      transmembrane domains in proteins.
AB  - In this paper we describe a microcomputer program (HTP) for predicting the
      location and orientation of alpha-helical transmembrane segments in integral
      membrane proteins. HTP is a neural network-based tool which gives as output the
      protein membrane topology based on the statistical propensity of residues to be
      located in external and internal loops. This method, which uses single protein
      sequences as input to the network system, correctly predicts the topology of 71
      out of 92 membrane proteins of putative membrane orientation, independently of
      the protein source.

PMID- 8670617
TI  - Alignments of DNA and protein sequences containing frameshift errors.
AB  - Molecular sequences, like all experimental data, are subject to error. Many
      current DNA sequencing protocols have very significant error rates and often
      generate artefactual insertions and deletions of bases (indels) which corrupt the
      translation of sequences and compromise the detection of protein homologies. The
      impact of these errors on the utility of molecular sequence data is dependent on
      the analytic technique used to interpret the data. In the presence of frameshift
      errors, standard algorithms using six-frame translation can miss important
      homologies because only subfragments of the correct translation are available in
      any given frame. We present a new algorithm which can detect and correct
      frameshift errors in DNA sequences during comparison of translated sequences with
      protein sequences in the databases. This algorithm can recognize homologous
      proteins sharing 30% identity even in the presence of a 7% frameshift error rate.
      Our algorithm uses dynamic programming, producing a guaranteed optimal alignment
      in the presence of frameshifts, and has a sensitivity equivalent to Smith
      Waterman. The computational efficiency of the algorithm is O(nm) where n and m
      are the sizes of two sequences being compared. The algorithm does not rely on
      prior knowledge or heuristic rules and performs significantly better than any
      previously reported method.

PMID- 8670619
TI  - Search of periodicities in primary structure of biopolymers: a general Fourier
      approach.
AB  - We discuss a new convenient way to study periodical patterns in primary
      structures of biopolymers which appeared recently. For the sequence of a
      biopolymer the symbolic correlation function is constructed, which is used as a
      digital sequence thus allowing us to perform a Fourier transform. Another
      fruitful technical improvement is the closing of the sequence in the ring with
      further scanning of the ring length, which allows the study of periods of the
      order of the sequence length. This approach makes it possible to take into
      account any scores describing similarity between symbols and to compare results
      obtained using different Fourier-like and correlation matrix techniques. An
      algorithm to compute Fourier spectrum power allows detection of vague periods in
      sequences containing strong repeats. A PASCAL program, SYMFOUR, has been written
      and tested on both sequences with periodical patterns, already reported, and
      sequences and other sites interesting from a biological point of view.

PMID- 8670620
TI  - Two-dimensional graphical representation of DNA sequences and intron-exon
      discrimination in intron-rich sequences.
AB  - We have shown earlier that analysis of DNA sequences using a two-dimensional
      graphical representation provides considerable information on new global sequence
      patterns and homologies, repeated structures, relative base abundances, probable
      evolutionary paths and evolutionary divergence. We have also reported that at a
      more micro level the graphical representation reveals distinct differences in the
      features of intron and exon segments of eukaryotic sequences. In this paper, the
      distinguishing features of the intron and exon segments are exploited to show,
      through several examples of different gene structures, that an averaging
      procedure over the slopes of the representative maps provides an easy technique
      to differentiate between probable intron and exon regions. We thus expect that
      this method will enable a rapid search and preliminary indication of possible
      locations of protein coding regions in long eukaryotic sequences.

PMID- 8670621
TI  - On-line tools for sequence retrieval and multivariate statistics in molecular
      biology.
AB  - We have developed a World-Wide Web server for browsing sequence collections
      structured under the ACNUC format and for performing multivariate analyses on
      sequences. General collections (like GenBank or EMBL), as well as specialized
      data banks (like Hovergen and NRSub) can be accessed. This system allows complex
      queries to be constructed, and the result of each query, represented by a list of
      sequences, is stored on the server. It is then possible to reuse this list to
      compute multivariate analyses on the sequences. Two examples of applications are
      shown. The first one consists in a study of codon usage with correspondence
      analysis on all the protein genes of Haemophilus influenzae Rd. This study allows
      the highly expressed genes and the integral membrane proteins of this organism to
      be identified. The second one consists in an ordering of 70 aligned protein
      sequences of growth hormone with principal coordinate analysis. With this method,
      we are able to re-establish the patterns of relationships between the sequences
      previously determined with tree building programs.

PMID- 8670622
TI  - Identification of functional elements in unaligned nucleic acid sequences by a
      novel tuple search algorithm.
AB  - We present an algorithm to identify potential functional elements like protein
      binding sites in DNA sequences, solely from nucleotide sequence data.
      Prerequisites are a set of at least seven not closely related sequences with a
      common biological function which is correlated to one or more unknown sequence
      elements present in most but not necessarily all of the sequences. The algorithm
      is based on a search for n-tuples which occur at least in a minimum percentage of
      the sequences with no or one mismatch, which may be at any position of the tuple.
      In contrast to functional tuples, random tuples show no preferred pattern of
      mismatch locations within the tuple nor is the conservation extended beyond the
      tuple. Both features of functional tuples are used to eliminate random tuples.
      Selection is carried out by maximization of the information content first for the
      n-tuple, then for a region containing the tuple and finally for the complete
      binding site. Further matches are found in an additional selection step, using
      the ConsInd method previously described. The algorithm is capable of identifying
      and delimiting elements (e.g. protein binding sites) represented by single short
      cores (e.g. TATA box) in sets of unaligned sequences of about 500 nucleotides
      using no information other than the nucleotide sequences. Furthermore, we show
      its ability to identify multiple elements in a set of complete LTR sequences
      (more than 600 nucleotides per sequence).

PMID- 8670633
TI  - PET activation of posterior temporal regions during auditory word presentation
      and verb generation.
AB  - Previous studies using positron emission tomography (PET) report blood flow
      changes in superior and middle temple gyri associated with auditory and language
      tasks (Petersen et al., 1988, 1989; Wise et al., 1991; Demonet et al., 1992;
      Howard et al., 1992; Sergent et al., 1992; Zatorre et al., 1992; Petrides et al.,
      1993; Raichle et al., 1994; Fiez et al., 1995). An important issue is whether
      these changes reflect the activation of a single functional region or multiple
      regions with distinct functional contributions. In the present study, we examined
      this issue by focusing upon two tasks for which we have previously reported
      posterior temporal blood flow changes: listening to auditorily presented words
      (Petersen et al., 1988, 1989), and generation of a verb in response to a visually
      presented noun (Raichle et al., 1994); see also Wise et al. (1991). We began by
      further characterizing a left temporoparietal region of change previously
      associated with auditory word presentation. This previously reported response was
      replicated, and the results were extended by demonstrating presentation of
      pseudowords also produced activation. We next asked whether the activation
      associated with auditory word presentation could be distinguished from that
      associated with the generation of verbs in response to visually presented nouns.
      It was found that the activations associated with these two tasks could be both
      functionally and spatially dissociated. Thus, two posterior temporal areas
      associated with auditory word presentation and verb generation appear to
      represent distinct areas concerned with word processing. More generally, the
      results demonstrate an approach for assessing the independence of two activated
      areas.

PMID- 8670634
TI  - Dissociating verbal and spatial working memory using PET.
AB  - Three experiments used position emission tomography (PET) to study the neural
      basis of human working memory. These studies ask whether different neural
      circuits underly verbal and spatial memory. In Experiment 1, subjects had to
      retain for 3 sec. either the names of four letters (verbal memory) or the
      positions of three dots (spatial memory). The PET results manifested a clear cut
      double dissociation, as the verbal task activated primarily left-hemisphere
      regions whereas the spatial task activated only right-hemisphere regions. In
      Experiment 2, the identical sequence of letters was presented in all conditions,
      and what varied was whether subjects had to remember the names of the letters
      (verbal memory) or their positions in the display (spatial memory). In the verbal
      task, activation was concentrated more in the left than the right hemisphere; in
      the spatial task, there was substantial activation in both hemispheres, though in
      key regions, there was more activation in the right than the left hemisphere.
      Experiment 3 studied only verbal memory, and showed that a continuous memory task
      activated the same regions as the discrete verbal task used in Experiment 1.
      Taken together, these results indicate that verbal and spatial working memory are
      implemented by different neural structures.

PMID- 8670635
TI  - PET studies of phonetic processing of speech: review, replication, and
      reanalysis.
AB  - Positron emission tomography was used to investigate cerebral blood flow (CBF)
      changes associated with the processing of speech. In a first experiment, normal
      right-handed volunteers were scanned under two conditions that required phonetic
      processing (discrimination of final consonants and phoneme monitoring), and one
      baseline condition of passive listening. Analysis was carried out by paired-image
      subtraction, with MRI overlay for anatomical localization. Comparison of each
      phonetic condition with the baseline condition revealed increased CBF in the left
      frontal lobe, close to the border between Broca's area and the motor cortex, and
      in a left parietal region. A second experiment showed that this area was not
      activated by a semantic judgement task. Reanalysis of data from an earlier study,
      in which various baseline conditions were used, confirmed that this region of
      left frontal cortex is consistently involved in phonetic tasks. The findings
      support a model whereby articulatory processes involving a portion of Broca's
      area are important when phonetic segments must be extracted and manipulated,
      whereas left posterior temporal cortex is involved in perceptual analysis of
      speech.

PMID- 8670636
TI  - Evidence for a two-stage model of spatial working memory processing within the
      lateral frontal cortex: a positron emission tomography study.
AB  - Previous work in nonhuman primates and in patients with frontal lobe damage has
      suggested that the frontal cortex plays a critical role in the performance of
      both spatial and nonspatial working memory tasks. The present study used positron
      emission tomography with magnetic resonance imaging to demonstrate the existence,
      within the human brain, of two functionally distinct subdivisions of the lateral
      frontal cortex, which may subserve different aspects of spatial working memory.
      Five spatial memory tasks were used, which varied in terms of the extent to which
      they required different executive processes. When the task required the
      organization and execution of a sequence of spatial moves retained in working
      memory, significant changes in blood flow were observed in ventrolateral frontal
      cortex (area 47) bi-laterally. By contrast, when the task required active
      monitoring and manipulation of spatial information within working memory,
      additional activation foci were observed in mid-dorsolateral frontal cortex
      (areas 46 and 9). These findings support a two-stage model of spatial working
      memory processing within the lateral frontal cortex.

PMID- 8670637
TI  - Object and spatial visual working memory activate separate neural systems in
      human cortex.
AB  - Human and nonhuman primate visual systems are divided into object and spatial
      information processing pathways. In the macaque, it has been shown that these
      pathways project to separate areas in the frontal lobe and that the ventral and
      dorsal frontal areas are, respectively, involved in working memory for objects
      and spatial locations. A positron emission tomography (PET) study was done to
      determine if a similar anatomical segregation exists in humans for object and
      spatial visual working memory. Face working memory demonstrated significant
      increases in regional cerebral blood flow (rCBF), relative to location working
      memory, in fusiform, parahippocampal, inferior frontal, and anterior cingulate
      cortices, and in right thalamus and midline cerebellum. Location working memory
      demonstrated significant increases in cRBF, relative to face working memory, in
      superior and inferior parietal cortex, and in the superior frontal sulcus. Our
      results show that the neural systems involved in working memory for faces and for
      spatial location are functionally segregated, with different areas recruited in
      both extrastriate and frontal cortices for processing the two types of visual
      information.

PMID- 8670638
TI  - Cellular bases of brain energy metabolism and their relevance to functional brain
      imaging: evidence for a prominent role of astrocytes.

PMID- 8670639
TI  - Demonstrating the implicit processing of visually presented words and
      pseudowords.
AB  - This study demonstrates that even when subjects are instructed to perform a
      nonlinguistic visual feature detection task, the mere presence of words or
      pseudowords in the visual field activates a widespread neuronal network that is
      congruent with classical language areas. The implication of this result is that
      subjects will process words beyond the functional demands of the task. Therefore,
      contrasting brain activity in a word task that explicitly requires a cognitive
      function with a word task in which the function is activated implicitly will not
      necessarily isolate the brain area of interest. Furthermore, in most brain
      regions, we found that pseudowords, which have unfamiliar phonological
      associations and no associated semantic association, produce greater activation
      than words. Greater brain activity associated with pseudowords illustrates that
      unfamiliar stimuli that are unable to access word associations may activate the
      neuronal network more strongly than familiar words for which access occurs with
      ease.

PMID- 8670640
TI  - Novelty and familiarity activations in PET studies of memory encoding and
      retrieval.
AB  - Nine young right-handed men viewed colored pictures of people, scenes, and
      landscapes. Then, 24 hr later while undergoing PET scanning, they viewed
      previously studied (OLD) pictures in one type of scan, and previously not seen
      (NEW) pictures in another. The OLD-NEW subtraction of PET images indicates
      familiarity, and the NEW-OLD indicates novelty. Familiarity activations,
      signalling aspects of retrieval, were observed in the left and right frontal
      areas, and posterior regions bilaterally. Novelty activations were in the right
      limbic regions, and bilaterally in temporal and parietal regions, including area
      37. These latter activations were located similarly to novelty activations in
      previous PET studies using visual words and auditory sentences, suggesting the
      existence of brain regions specializing in transmodal novelty assessment. The
      effects of novelty are seen both behaviorally and in replicable patterns of
      cortical and subcortical activation. We propose a 'novelty/encoding hypothesis':
      (1) novelty assessment represents an early stage of long-term memory encoding;
      (2) elaborate, meaning-based encoding processes operate on the incoming
      information to the extent of its novelty, and therefore (3) the probability of
      long-term storage of information varies directly with the novelty of the
      information.

PMID- 8670641
TI  - The hippocampo-neocortical dialogue.
AB  - In gross anatomical terms, the hippocampal archicortex can be conceived as an
      "appendage' of the large neocortex. In contrast to neocortical areas, the main
      output targets of the hippocampus are the same as its main inputs (i.e., the
      entorhinal cortex). Highly processed information about the external world (the
      content) reaches the hippocampus via the entorhinal cortex, whereas information
      about the "internal world' (the context) is conveyed by the subcortical inputs.
      Removal of the context makes the content illegible, as demonstrated by the
      observation that the behavioral impairment following surgical removal of
      hippocampopetal subcortical inputs is as devastating as removing the hippocampus
      itself. From its strategic anatomical position and input-output connections, it
      may be suggested that the main function of the hippocampal formation is to modify
      its inputs by feeding back a processed "reafferent copy' to the neocortex. I
      hypothesize that neocortico-hippocampal transfer of information and the
      modification process in neocortical circuitries by the hippocampal output take
      place in a temporally discontinuous manner and might be delayed by minutes,
      hours, or days. Acquisition of information may happen very fast during the
      activated state of the hippocampus associated with theta/gamma oscillations.
      Intrahippocampal consolidation and the hippocampal-neocortical transfer of the
      stored representations, on the other hand, is protracted and carried by discrete
      quanta of cooperative neuronal bursts during slow wave sleep.

PMID- 8670642
TI  - A brief history of time (constants).
AB  - That the cerebral cortex processes information at prodigious speeds cannot be
      doubted. Yet the passive time constant, tau(m), of neurons, often thought of as a
      measure of the neuron's "response time' to synaptic input, is relatively long. In
      the 1950s, tau(m) was estimated to be only a few milliseconds for mammalian
      central neurons; with improvement in recording techniques, its estimated value
      grew over the years and it now stands near 20-100 msec. However, as we will argue
      here, the functional meaning of tau(m) is ambiguous. On the basis of a newly
      introduced definition of local delay, we show that the time window for synaptic
      integration in passive dendritic trees can be much smaller than the time
      constant. We argue that the voltage response to very brief synaptic inputs is
      essentially independent of tau(m). We discuss how tau(m) can change dynamically
      with the global activity of the network, as well as the difficulties of defining
      a time constant in structures with voltage-dependent elements. We conclude that
      the classically defined tau(m) only provides a very rough estimate, typically an
      overestimate, of the response time of neurons and that alternative measures are
      required to capture the dependency of the time course of the membrane potential
      on ligand-gated and/or voltage-dependent membrane conductances.

PMID- 8670643
TI  - Cortical networks for visual reaching: physiological and anatomical organization
      of frontal and parietal lobe arm regions.
AB  - The functional and structural properties of the dorsolateral frontal lobe and
      posterior parietal proximal arm representations were studied in macaque monkeys.
      Physiological mapping of primary motor (MI), dorsal premotor (PMd), and posterior
      parietal (area 5) cortices was performed in behaving monkeys trained in an
      instructed-delay reaching task. The parietofrontal corticocortical connectivities
      of these same areas were subsequently examined anatomically by means of
      retrograde tracing techniques. Signal-, set-, movement-, and position-related
      directional neuronal activities were distributed nonuniformly within the task
      related areas in both frontal and parietal cortices. Within the frontal lobe,
      moving caudally from PMd to the MI, the activity that signals for the visuo
      spatial events leading to target localization decreased, while the activity more
      directly linked to movement generation increased. Physiological recordings in the
      superior parietal lobule revealed a gradient-like distribution of functional
      properties similar to that observed in the frontal lobe. Signal- and set-related
      activities were encountered more frequently in the intermediate and ventral part
      of the medial bank of the intraparietal sulcus (IPS), in area MIP. Movement-and
      position-related activities were distributed more uniformly within the superior
      parietal lobule (SPL), in both dorsal area 5 and in MIP. Frontal and parietal
      regions sharing similar functional properties were preferentially connected
      through their association pathways. As a result of this study, area MIP, and
      possibly areas MDP and 7m as well, emerge as the parietal nodes by which visual
      information may be relayed to the frontal lobe arm region. These parietal and
      frontal areas, along with their association connections, represent a potential
      cortical network for visual reaching. The architecture of this network is ideal
      for coding reaching as the result of a combination between visual and somatic
      information.

PMID- 8670645
TI  - Effects of spinal dorsal column transection on the response of monkey anterior
      parietal cortex to repetitive skin stimulation.
AB  - The pattern of 14C-2-deoxyglucose (2DG) labeling in anterior parietal cortex was
      evaluated in three groups of experimental subjects: (1) subjects in which all
      spinal pathways projecting at short latency to the contralateral hemisphere were
      intact, (2) subjects with either unilateral or bilateral transection of the
      dorsal column pathway, and (3) subjects in whom a two-stage tractotomy (dorsal
      column isolation) restricted short-latency mechanoreceptor drive to that conveyed
      via the dorsal column pathway. Macaca fascicularis and Macaca arctoides monkeys
      were studied. When the spinal cord pathways projecting at short latency to
      contralateral anterior parietal cortex were intact, controlled vibrotactile or
      skin brushing stimuli evoked one or, more rarely, several loci of maximal 2DG
      uptake (typically 1.5-2.5 mm in diameter) in the topographically appropriate
      location(s) within area 3b and/or area 1. The labeling at each locus of maximal
      2DG uptake extended continuously across layers II-VI. Each locus of maximal 2DG
      uptake was bordered on one or more sides by irregularly shaped zones of below
      background 2DG uptake that could extend without interruption from area 3b into
      area 3a, and/or from area 1 into area 2. In the absence of skin stimulation,
      little or no above-background 2DG uptake occurred at any locus within areas 3b
      and 1 of subjects in which the dorsal column pathway on the opposite side of the
      spinal cord was intact. In subjects with a complete transection of the spinal
      dorsal column the global 2DG pattern evoked by a repetitive skin stimulus in
      contralateral anterior parietal cortex was a near mirror image of the pattern
      evoked by the same stimulus in intact subjects. In the absence of the dorsal
      column path, neither 10-25 Hz vibrotactile nor brushing stimulation evoked above
      background uptake at the topographically appropriate location(s) within
      contralateral area 3b and/or area 1. Instead, a prominent region of below
      background 2DG uptake occupied the topographically appropriate location in area
      3b and/or area 1, and the region of suppressed 2DG uptake was bounded by one or
      more regions of above-background 2DG uptake that extended from areas 3b or 1 into
      area 3a and/or into area 2. When a two-stage spinal tractotomy prevented stimulus
      evoked short-latency input from reaching contralateral anterior parietal cortex
      via pathways other than the dorsal column, the 2DG activity patterns evoked in
      contralateral cortex by either brushing or vibrotactile stimuli were similar to
      the patterns obtained when the somatosensory pathways on the opposite side of the
      spinal cord were intact. A neural network model was developed to evaluate the
      hypothesis that the observed cortical effects of dorsal column transection might
      be attributable, at least in part, to inhibitory interactions among anterior
      parietal cortical regions that receive their principal input from different
      spinal cord pathways. The model incorporated known features of (1) the cortical
      projection of spinal somatosensory pathways, (2) anterior parietal intrinsic and
      long-distance horizontal connectivity, and (3) certain neurotransmitter/receptor
      systems characteristic of sensory neocortex. Simulations of the model network
      provided results consistent with the idea that repetitive skin stimuli evoke
      maladaptive, time-dependent corticocortical interactions within anterior parietal
      cortex contralateral to a dorsal column lesion. The observations indicate that
      corticocortical interactions account for the (1) near mirror-image pattern
      (relative to the normal Mexican hat-like pattern) of anterior parietal stimulus
      evoked 2DG uptake observed in subjects with a dorsal column lesion, (2) unusual
      time-dependent response properties of individual area 3b and 1 neurons or neuron
      populations deprived of dorsal column input (Dreyer et al., 1974; Vierck et al.,
      1990a; Makous and Vierck, 1994), and (3) abnormal time-dependent characteristics
      of tactile perception in monkeys with dorsal colum

PMID- 8670644
TI  - Suprathreshold auditory cortex activation visualized by intrinsic signal optical
      imaging.
AB  - The suprathreshold tonotopic organization of rat and guinea pig auditory cortex
      was investigated using intrinsic signal optical imaging through a thinned skull.
      Optical imaging revealed that suprathreshold pure sine wave tone stimulation (25
      80 dB) evoked activity over large cortical areas that were tonotopically
      organized. Three-dimensional surface plots of the activated areas revealed
      "patchy' auditory-evoked activity consisting of numerous local peaks and valleys
      building to a maximum. Subsequent detailed electrophysiological mapping in the
      same subjects confirmed the localization of auditory-evoked activity based on
      optical imaging, including responses to a test frequency at cortical loci more
      than 2 octaves away from the threshold-defined isofrequency contour. The success
      of this technique in visualizing auditory cortex functional organization at
      suprathreshold stimulus levels will allow for future investigations of auditory
      cortex frequency representation, including representational plasticity induced by
      a variety of experimental manipulations.

PMID- 8670646
TI  - Functional topography: multidimensional scaling and functional connectivity in
      the brain.
AB  - In neuroimaging, functional mapping usually implies mapping function into an
      anatomical space, for example, using statistical parametric mapping to identify
      activation foci, or the characterization of distributed changes with spatial
      modes (eigenimages or principal components) (Friston et al., 1993a). This article
      is about a complementary approach, namely, mapping anatomy into a functional
      space. We describe a simple variant of multidimensional scaling (principal
      coordinates analysis; Gower, 1966) that uses functional connectivity as its
      metric. The scaling transformation maps anatomy into a functional space. The
      topography, or proximity relationships, in this space embody the functional
      connectivity among brain regions. The higher the functional connectivity, the
      closer the regions. Functional connectivity is defined here as the correlation
      between remote neurophysiological events. The technique represents a descriptive
      characterization of anatomically distributed changes in the brain that reveals
      the structure of corticocortical interactions in terms of functional
      correlations. To illustrate the approach we have analyzed data from normal
      subjects and schizophrenic patients obtained with PET during the performance of
      word generation tasks. In particular, we focus on prefrontotemporal integration
      in normal subjects and show that, in schizophrenia, the left temporal regions and
      prefrontal cortex evidence abnormal functional connectivity.

PMID- 8670647
TI  - Systematic regional variations in the loss of cortical cholinergic fibers in
      Alzheimer's disease.
AB  - The loss of cortical cholinergic fibers in Alzheimer's disease was investigated
      using choline acetyltransferase immunohistochemistry and acetylcholinesterase
      histochemistry. Within both the normal and Alzheimer's cerebral cortex, the two
      methods revealed an identical pattern of fiber staining. In the normal brain,
      cholinergic fiber density was highest in limbic and paralimbic cortical zones,
      intermediate in most sensory-motor and association zones, and lowest within the
      primary visual and visual association areas of the occipital lobe. In general,
      supragranular cortical layers contained a higher density of cholinergic fibers,
      and most of these were oriented vertically. In Alzheimer's disease, an overall
      55% loss of cortical cholinergic fibers was detected. There was, however, marked
      regional variations in the extent of this loss in different cortical areas.
      Cortical areas within the temporal lobe, particularly the temporal association
      areas, displayed a dramatic loss of cholinergic fibers. By contrast, the anterior
      cingulate cortex, primary visual, primary somatosensory, and primary motor cortex
      displayed a relative preservation of cholinergic fibers. As a whole, greater loss
      of cholinergic fibers was detected in supragranular layers and in fibers oriented
      vertical to the cortical surface. These results indicate that cholinomimetic
      therapies are likely to have different effects on cholinergic transmission in
      various cortical areas. The precise mechanisms that lead to the regional
      variations in cortical cholinergic denervation in Alzheimer's disease remain to
      be elucidated.

PMID- 8670648
TI  - Development of horizontal projections in layer 2/3 of ferret visual cortex.
AB  - Pyramidal cells in layer 2/3 of cat striate cortex extend long axons that form
      clustered projections linking iso-orientation columns. Using extracellular
      biocytin injections in brain slices, the formation of these projections was
      examined in the ferret to determine whether horizontal projections exhibit
      similar patterns of development in the ferret and the cat, and to relate the time
      course of horizontal projection formation to the onset of patterned visual
      experience and orientation selectivity. Soon after the first appearance of axon
      collaterals in layer 2/3, around postnatal day 22 (P22), pyramidal cell axons
      were uniformly distributed and unbranched for up to 1 mm from the cell body. By
      P26, axons began to form secondary branches 1-2 mm from the cell body, with
      little evidence for distinct clusters. The first indication of selective
      elaboration of secondary branches and retraction of unbranched collaterals
      occurred around P28. By P34, patchy regions of axon branches emerged, though
      unbranched collaterals were still present, followed by distinct, adult-like
      clusters by P45. Although the general pattern of horizontal projection formation
      closely resembles that seen in the cat (Callaway and Katz, 1990), the ferret
      circuitry matures earlier than that of the cat relative to the time of eye
      opening. Since eye opening in ferrets occurs between P30 and P32, this system of
      orientation-specific patches begins to develop in the absence of patterned visual
      input and when most cortical cells are not yet orientation selective, suggesting
      a prominent role for spontaneous activity in initiating cluster formation. The
      refinement of clustered connections, however, does occur synchronously with the
      maturation of orientation-selective responses (Chapman and Stryker, 1993).

PMID- 8670649
TI  - Functional development of the corticocortical pathway for motion analysis in the
      macaque monkey: a 14C-2-deoxyglucose study.
AB  - The corticocortical pathway for motion analysis transmits visual information from
      striate cortex (V1) via V2, V3d, superior temporal sulcal areas MT, MST, and FST
      to motion-sensitive areas in the floor and upper bank of the anterior part of the
      superior temporal sulcus (AST). We studied the functional development of this
      pathway by applying the 14C-2-deoxyglucose method to rhesus monkeys (Macaca
      mulatta) ranging in age from 2 d to 3-4 years. A comparison of local cerebral
      glucose utilization (LCGU) in an intact and a visually deafferented hemisphere in
      each animal across the age range revealed that this pathway, immature at birth,
      reaches adult-like levels at 3 months of age. This developmental time course is
      reflected both in absolute LCGU and in the interhemispheric LCGU differences in
      all the areas of the pathway. At all ages, the interhemispheric difference in
      LCGU is largest in V1 and gradually declines along the pathway until a minimum is
      reached in AST. This decline likely reflects an increasing proportion of
      nonvisual inputs to the higher-order areas of the pathway. Measurements like
      those above taken in areas of inferior parietal cortex indicate that they mature
      at the same rate as those in the motion analysis pathway. However, comparison
      with findings on the functional development of the temporal areas of the
      occipitotemporal pathway for object vision (Bachevalier et al., 1991) suggests
      that areas along the motion analysis pathway and those in parietal cortex mature
      about 1 month earlier.

PMID- 8670650
TI  - Interhemispheric modulation of somatosensory receptive fields: evidence for
      plasticity in primary somatosensory cortex.
AB  - Extracellular recordings were made from single and multiple neurons in primary
      somatosensory cortex (area 3b) of macaque monkeys and flying foxes. When a small
      region of area 3b (or adjacent area 1) in the opposite hemisphere was cooled,
      thereby blocking activity that is normally transferred via the corpus callosum,
      larger receptive fields (RFs) were immediately unmasked for most neurons. RF
      expansion presumably reflects the expression of afferent inputs that are normally
      inhibited, suggesting that callosal inputs provide a source of tonic inhibition
      that contributes to the shaping of neuronal RFs. Quantitative analyses of single
      neuron responses revealed other effects that were consistent with a release from
      inhibition, such as increases in response magnitude to stimulation of points
      within the original RF and decreases in response latency. An unexpected finding
      was the reversal of these unmasking effects with extended periods of cooling: RFs
      returned to their original dimensions and within-field response magnitude
      decreased. In contrast to the initial effects, this reversal of disinhibition
      cannot be readily explained by an unmasking of previously unexpressed inputs. Any
      explanation for the reversal requires an increase in the efficacy of interneuron
      mediated inhibition, and presumably occurs in response to ongoing, altered
      patterns of activity.

PMID- 8670651
TI  - Human cingulate and paracingulate sulci: pattern, variability, asymmetry, and
      probabilistic map.
AB  - Recent advances in functional neuroimaging of the human cerebral cortex revived
      interest in the study of the cortical morphology at both macro- and microscopic
      levels. By means of high-resolution magnetic resonance imaging (MRI), in vivo
      images of the human brain can be acquired and used to aid localization of the
      functional maps. The goal of the present study was to determine variability in
      the occurrence and location of the cingulate sulcus (CS) and the paracingulate
      sulcus (PCS). Brain MRIs of 247 healthy young volunteers were obtained and
      transformed into a standardized stereotaxic space (Talairach and Tournoux, 1988).
      The CS and PCS were marked in 494 hemispheres using software capable of real-time
      movement through a 3-D volume. The markers were used to generate a probabilistic
      map of the CS and PCS. The individual MRI images were also evaluated for the
      presence and location of the following morphological features: the continuity of
      the CS, the presence of vertically oriented branches of the CS, the presence of
      the PCS, and the presence of the intralimbic sulcus. The results revealed
      considerable variability in the location of some of the above morphological
      features and a striking hemispheric asymmetry in the prominence of the PCS. The
      results of four previous blood-flow activation studies of speech control were
      used to illustrate the relevance of our morphological findings for functional
      neuroimaging of the human anterior cingulate cortex.

PMID- 8670652
TI  - Failure to respond autonomically to anticipated future outcomes following damage
      to prefrontal cortex.
AB  - Following damage to specific sectors of the prefrontal cortex, humans develop a
      defect in real-life decision making, in spite of otherwise normal intellectual
      performance. The patients so affected may even realize the consequences of their
      actions but fail to act accordingly, thus appearing oblivious to the future. The
      neural basis of this defect has resisted explanation. Here we identify a
      physiological correlate for the defect and discuss its possible significance. We
      measured the skin conductance responses (SCRs) of 7 patients with prefrontal
      damage, and 12 normal controls, during the performance of a novel task, a card
      game that simulates real-life decision making in the way it factors uncertainty,
      rewards, and penalties. Both patients and controls generated SCRs after selecting
      cards that were followed by penalties or by reward. However, after a number of
      trials, controls also began to generate SCRs prior to their selection of a card,
      while they pondered from which deck to choose, but no patients showed such
      anticipatory SCRs. The absence of anticipatory SCRs in patients with prefrontal
      damage is a correlate of their insensitivity to future outcomes. It is compatible
      with the idea that these patients fail to activate biasing signals that would
      serve as value markers in the distinction between choices with good or bad future
      outcomes; that these signals also participate in the enhancement of attention and
      working memory relative to representations pertinent to the decision process; and
      that the signals hail from the bioregulatory machinery that sustains somatic
      homeostasis and can be expressed in emotion and feeling.

PMID- 8670653
TI  - Functional anatomy of pointing and grasping in humans.
AB  - The functional anatomy of reaching and grasping simple objects was determined in
      nine healthy subjects with positron emission tomography imaging of regional
      cerebral blood flow (rCBF). In a prehension (grasping) task, subjects reached and
      grasped illuminated cylindrical objects with their right hand. In a pointing
      task, subjects reached and pointed over the same targets. In a control condition
      subjects looked at the targets. Both movement tasks increased activity in a
      distributed set of cortical and subcortical sites: contralateral motor, premotor,
      ventral supplementary motor area (SMA), cingulate, superior parietal, and dorsal
      occipital cortex. Cortical areas including cuneate and dorsal occipital cortex
      were more extensively activated than ventral occipital or temporal pathways. The
      left parietal operculum (putative SII) was recruited during grasping but not
      pointing. Blood flow changes were individually localized with respect to local
      cortical anatomy using sulcal landmarks. Consistent anatomic landmarks from MRI
      scans could be identified to locate sensorimotor, ventral SMA, and SII blood flow
      increases. The time required to complete individual movements and the amount of
      movement made during imaging correlated positively with the magnitude of rCBF
      increases during grasping in the contralateral inferior sensorimotor, cingulate,
      and ipsilateral inferior temporal cortex, and bilateral anterior cerebellum. This
      functional-anatomic study defines a cortical system for "pragmatic' manipulation
      of simple neutral objects.

PMID- 8670654
TI  - Multiple spatial/behavioral correlates for cells in the rat postsubiculum:
      multiple regression analysis and comparison to other hippocampal areas.
AB  - Head direction cells in the rat postsubiculum fire in relation to the momentary
      directional heading of the animal, with each cell firing only when the animal
      faces in one particular direction. To understand how this signal might be
      generated, one useful step is to discover what other cell types, in addition to
      the head direction cells, may exist in the postsubiculum, since these cells might
      be involved in helping to generate the direction-specific activity. Here
      postsubicular cells were recorded as animals navigated in a cylindrical recording
      chamber. It was found that, in addition to head direction cells, the
      postsubiculum contains cells that show several other types of spatial/behavioral
      correlates, including angular velocity of the head, running speed, and location.
      Ten percent of the cells were classified as angular velocity cells, and they
      resembled vestibular afferent fibers, with antagonistic responses to clockwise
      versus counterclockwise turns. In addition, numerous other cell types were
      observed. These latter cells were harder to classify, but all showed a
      significant correlation with one or more of the above variables. These findings
      suggest that the head direction cell signal may be at least partly based on the
      angular velocity, running speed, and locational signals observed here.

PMID- 8670655
TI  - Acetylcholinesterase staining in human auditory and language cortices: regional
      variation of structural features.
AB  - Cholinergic innervation of the cerebral neocortex arises from the basal forebrain
      and projects to all cortical regions. Acetylcholinesterase (AChE), the enzyme
      responsible for deactivating acetylcholine, is found within both cholinergic
      axons arising from the basal forebrain and a subgroup of pyramidal cells in
      layers III and V of the cerebral cortex. This pattern of staining varies with
      cortical location and may contribute uniquely to cortical microcircuitry within
      functionally distinct regions. To explore this issue further, we examined the
      pattern of AChE staining within auditory, auditory association, and putative
      language regions of whole, postmortem human brains. The density and distribution
      of acetylcholine-containing axons and pyramidal cells vary systematically as a
      function of auditory processing level. Within primary auditory regions AChE
      containing axons are dense and pyramidal cells are largely absent. Adjacent
      cortical regions show a decrease in the density of AChE-containing axons and an
      increase in AChE-containing pyramidal cells. The posterior auditory and language
      regions contain a relatively high density of AChE-containing pyramidal cells and
      AChE-containing axons. Although right and left posterior temporal regions are
      functionally asymmetrical, there is no apparent asymmetry in the general pattern
      of AChE staining between homologous regions of the two hemispheres. Thus, the
      pattern of AChE staining covaries with processing level in the hierarchy of
      auditory cortical regions, but does not vary between the functionally distinct
      right and left posterior regions. An asymmetry in the size of layer III AChE-rich
      pyramidal cells was present within a number of cortical regions. Large AChE-rich
      pyramidal cells of layer III were consistently greater in size in the left
      hemisphere as compared to the right. Asymmetry in layer III pyramidal cell size
      was not restricted to language-associated regions, and could potentially have a
      variety of etiologies including structural, connectional, and activational
      differences between the left and right hemisphere.

PMID- 8670656
TI  - Regulation of calcium-binding protein immunoreactivity in GABA neurons of macaque
      primary visual cortex.
AB  - Monocular deprivation produces an imbalance in visual drive from the two eyes,
      which in adult macaque V1 leads to marked changes in the neurochemistry of GABA
      interneurons. Such changes were further examined by studying immunoreactivity for
      calbindin, calretinin, and parvalbumin, three calcium-binding proteins that mark
      distinct subpopulations of GABA neurons, in macaques that had been monocularly
      deprived by intravitreal injection of tetrodotoxin. Deprivation for 5 d or longer
      produced a reversal in the normal pattern of calbindin immunostaining in layer
      III, from one in which intense neuronal immunostaining surrounded the cytochrome
      oxidase-rich puffs to one in which it occupied the puffs. Over the same period,
      calbindin immunostaining in other layers was reduced across the entire width of
      deprived-eye columns or extended into flanking regions of normal-eye columns. In
      contrast, reduction in parvalbumin immunostaining occurred only in deprived-eye
      columns and included only terminals with short periods of deprivation (up to 17
      d) but both terminals and somata with longer periods. No change in calretinin
      immunoreactivity was observed. These findings demonstrate that GABA neurons of
      macaque V1 vary in their response to monocular deprivation according to their
      neurochemistry and position, suggesting that the weight of inputs from the two
      eyes and the intrinsic characteristics of each GABA population determine how a
      neuron responds to a change in visual input.

PMID- 8670657
TI  - Deviant auditory stimuli activate human left and right auditory cortex
      differently.
AB  - Infrequent "deviant' auditory stimuli embedded in a homogeneous sequence of
      "standard' sounds evoke a neuromagnetic mismatch field (MMF), which is assumed to
      reflect automatic change detection in the brain. We investigated whether MMFs
      would reveal hemispheric differences in cortical auditory processing. Seven
      healthy adults were studied with a whole-scalp neuromagnetometer. The sound
      sequence, delivered to one ear at time, contained three infrequent deviants
      (differing from standards in duration, frequency, or interstimulus interval)
      intermixed with standard tones. MMFs peaked 9-34 msec earlier in the right than
      in the left hemisphere, irrespective of the stimulated ear. Whereas deviants
      activated only one MMF source in the left hemisphere, two temporally overlapping
      but spatially separate sources, one in the temporal lobe and another in the
      inferior parietal cortex, were necessary to explain the right-hemisphere MMFs. We
      suggest that the bilateral MMF components originating in the supratemporal cortex
      are feature specific whereas the right-hemisphere parietal component reflects
      more global auditory change detection. The results imply hemispheric differences
      in sound processing and suggest stronger involvement of the right than the left
      hemisphere in change detection.

PMID- 8670658
TI  - Relation between patterns of intrinsic lateral connectivity, ocular dominance,
      and cytochrome oxidase-reactive regions in macaque monkey striate cortex.
AB  - To help understand the role of long-range, clustered lateral connections in the
      superficial layers of macaque striate cortex (area V1), we have examined the
      relationship of the patterns of intrinsic connections to cytochrome oxidase (CO)
      blobs, interblobs, and ocular dominance (OD) bands, using biocytin based
      neuroanatomical tracing, CO histochemistry, and optical imaging. Microinjections
      of biocytin in layer 3 resulted in an asymmetric field (average anisotropy of
      1.8; maximum spread--3.7 mm) of labeled axon terminal clusters in layers 1-3,
      with the longer axis of the label spread oriented orthogonal to the rows of blobs
      and imaged OD stripes, parallel to the V1/V2 border. These labeled terminal
      patches (n = 186) from either blob or interblob injections (n = 20) revealed a
      71% (132 out of 186) commitment of patches to the same compartment as the
      injection site; 11% (20 out of 186) to the opposite compartment, and 18% (34 out
      of 186) to borders of blob-interblob compartments, indicating that the
      connectivity pattern is not strictly blob to blob, or interblob to interblob (p <
      0.005; chi(2)). In injections placed within single OD domains (n = 11), 54% of
      the resulting labeled terminal patches (43 out of 79) fell into the same OD
      territories as the injection sites, 28% (22 out of 79) into the opposite OD
      regions, and 18% (14 out of 79) on borders, showing some connectional bias toward
      same-eye compartments (p < 0.02; ANOVA). Individual injection cases, however,
      varied in the degree (50-100% for CO patterns, 22-100% for OD patterns) to which
      they showed same-compartment connectivity. These results reveal that while
      connectivity between similar compartments predominates (e.g., blob to blob, right
      eye column to right eye column), interactions do occur between functionally
      different regions.

PMID- 8670659
TI  - Prefrontal cortex and working memory for spatial response, spatial location, and
      visual object information in the rat.
AB  - In the first experiment, rats were trained on a working memory task for a spatial
      response (right-left turn) information using a delayed matching-to-sample
      procedure. Following lesions of the medial prefrontal cortex (MPF), which
      includes anterior cingulate and medial precentral cortex, there was a profound
      working memory deficit even at the shortest delay. In the second experiment, rats
      were trained on a working memory task for spatial location information using a
      delayed matching-to-sample procedure. Following lesions of the MPF, there was
      only a mild working memory deficit, whereas following dorsal hippocampal lesions
      there was a profound working memory deficit even at the shortest delay. In the
      third experiment, rats were trained on a working memory task for visual object
      information using a delayed nonmatching-to-sample procedure. Following lesions of
      the MPF, there were no working memory deficits, whereas following lesions of the
      prelimbic and infralimbic cortex there was a profound working memory deficit even
      at the shortest delay. The results suggest that different neural subregions of
      the prefrontal cortex mediate working memory for specific attribute information.

PMID- 8670660
TI  - The sources of visual information to the primate frontal lobe: a novel role for
      the superior parietal lobule.
AB  - Reaching movements are performed in order to bring the hand to targets of
      interest. It is widely believed that the distributed cortical network underlying
      visual reaching transforms the information concerning the spatial location of the
      target into an appropriate motor command. Modern views decompose this process
      into sequences of coordinate transformations between informational domains. The
      set of cortical areas and pathways by which the information on target location is
      relayed from the visual areas of the occipital lobe to the motor areas of the
      frontal lobe have, so far, been poorly understood. Recent data from different
      fields of neuroscience offer the basis for a new definition of the cortical
      system subserving reaching and, at the same time, for a reconsideration of the
      nature of the underlying visuo-to-motor transformation.

PMID- 8670661
TI  - The functional organization of local circuits in visual cortex: insights from the
      study of tree shrew striate cortex.
AB  - We have used a combination of anatomical and physiological techniques to explore
      the functional organization of vertical and horizontal connections in tree shrew
      striate cortex. Our studies of vertical connections reveal a remarkable
      specificity in the laminar arrangement of the projections from layer IV to layer
      III that establishes three parallel intracortical pathways. The pathways that
      emerge from layer IV are not simple continuations of parallel thalamocortical
      pathways. Layer IV and its connections with layer II/III restructure the inputs
      from the LGN, combining the activity from ON and OFF channels and from the left
      and right eye and transmit the products of this synthesis to separate strata
      within the overlying layers. In addition, studies of two other prominent vertical
      connection pathways, the projections from layer VI to layer IV and from layer
      II/III to layer V suggest that the parallel nature of these systems is
      perpetuated throughout the cortical depth. Our studies of horizontal connections
      have revealed a systematic relationship between a neuron's orientation preference
      and the distribution of its axon arbor across the cortical map of visual space.
      Horizontal connections in layer II/III extend for greater distances and give rise
      to a greater number of terminals along an axis of the visual field map that
      corresponds to the neuron's preferred orientation. These findings suggest that
      the contribution of horizontal inputs to the response properties of layer II/III
      neurons is likely to be greater in regions of visual space that lie along the
      axis of preferred orientation (endzones) than along the orthogonal axis (side
      zones). Topographically aligned horizontal connections may contribute to the
      orientation preference of layer II/III neurons and could account for the axial
      specificity of some receptive field surround effects. Together, these results
      emphasize that specificity in the spatial arrangement of local circuit axon
      arbors plays an important role in shaping the response properties of neurons in
      visual cortex.

PMID- 8670662
TI  - Motor areas of the medial wall: a review of their location and functional
      activation.
AB  - Our goal in this review is to provide an anatomical framework for the analysis of
      the motor functions of the medial wall of the hemisphere in humans and laboratory
      primates. Converging evidence indicates that this region of the frontal lobe
      contains multiple areas involved in motor control. In the monkey, the medial wall
      contains four premotor areas that project directly to both the primary motor
      cortex and the spinal cord. These are the supplementary motor area (SMA) on the
      superior frontal gyrus and three motor areas buried within the cingulate sulcus.
      In addition, there is evidence that a fifth motor field, the pre-SMA, lies
      rostral to the SMA proper. Recent physiological observations provide evidence for
      functional differences among these motor fields. In the human, no consensus
      exists on the number of distinct motor fields on the medial wall. In this review,
      we summarize the results of positron emission tomography (PET) studies that
      examined functional activation on the medial wall of humans. Our analysis
      suggests that it is possible to identify at least four separate cortical areas on
      the medial wall. Each area appears to be relatively more involved in some aspects
      of motor behavior than others. These cortical areas in the human appear to be
      analogous to the pre-SMA, the SMA proper, and two of the cingulate motor areas of
      the monkey. We believe that these correspondences and the anatomical framework we
      describe will be important for unraveling the motor functions of the medial wall
      of the hemisphere.

PMID- 8670663
TI  - Retinotopic organization of human visual cortex: departures from the classical
      model.
AB  - Retinotopic mapping strategies similar to those used for invasive
      electrophysiological studies to identify multiple visual areas in monkeys have
      been adapted for noninvasive studies in humans, using magnetic recordings of
      brain activity in conjunction with anatomical magnetic resonance imaging. The
      retinotopic organization of the primary visual area (V1) in the left hemisphere
      of human subjects was examined by presenting a small patterned stimuli near the
      vertical and horizontal meridians in the lower right visual field. In contrast
      with the classical model of V1 retinotopy, our results suggest that the
      representation of the horizontal meridian does not necessarily correspond in a
      one-to-one manner with the base of the calcarine fissure and that some lower
      field stimuli can activate regions in the lower bank of the fissure. The results
      also indicate significant individual variability in the details of how V1 maps
      around the calcarine fissure.

PMID- 8670664
TI  - Rewiring of transcortical projections to middle suprasylvian cortex following
      early removal of cat areas 17 and 18.
AB  - Retrograde tracers were injected into middle suprasylvian (MS) cortex of two
      groups of experimental adult cats that had incurred removal of visual areas 17
      and 18 on either the day of birth (P1), or at 1 month of age (P28). Tracers were
      also injected into the same region of intact and adult ablated control cats. The
      locations and numbers of labeled neurons in the experimental and control groups
      were compared. Following lesions on P1, but at no other age, increased numbers of
      neurons projected to MS cortex. Virtually all of the additional neurons were
      located in the superficial layers of the ventral posterior suprasylvian (vPS)
      cortex. These results demonstrated that (1) neurons with ipsilateral
      transcortical axons have the potential to reconfigure their projections after
      early, localized cortical damage elsewhere in the cortex of the same hemisphere;
      (2) this reconfiguration involves expansion of specific projections and is not a
      generalized capacity of all cortical neurons; (3) the expansion is modality
      specific; and finally, (4) the ability of cortical neurons to reorganize
      projections is limited in time. The expanded projection from vPS to MS cortex may
      contribute to neuronal compensations and the sparing of visually guided behaviors
      previously demonstrated in cats with neonatal visual cortex damage, and is a
      testament to the latent capacities immature cerebral cortex neurons possess to
      establish new projections following restricted damage to the cerebral cortex
      early in life.

PMID- 8670665
TI  - Differential expression of acetylcholinesterase in the developing barrel cortex
      of three rodent species.
AB  - Acetylcholinesterase (AChE) is transiently expressed in several immature axon
      systems. Its presence in developing thalamocortical afferents has led to the use
      of enzyme histochemistry to visualize this axon system in rats. Because of the
      spatiotemporal distribution of the enzyme in the rat neocortex, it has been
      suggested that AChE plays a role in the establishment of thalamocortical
      connectivity. We show here that AChE is distributed in a pattern that is markedly
      different in SI cortex of rats as compared to that of mice and hamsters. In rat
      pups, AChE-rich patches are distributed in a vibrissa-related array in the SI
      cortex soon after birth, whereas regions of cortex that lie between individual
      patches, and between rows of patches, are impoverished in the enzyme. In
      contrast, sections through flattened cortices from PND3 and older mice and
      hamsters reveal lightly stained AChE-positive spots in the center of barrel
      cores, while barrel walls remain devoid of AChE; septae that divide individual
      barrels are densely enzyme positive. Differences in laminar localization of the
      enzyme for all three species are also visible. In the thalamus of postnatal rats,
      both the ventral posterior medial (VPM) and ventral posterior lateral (VPL)
      nuclei express AChE, correlating with the presence of enzyme-containing patches
      throughout the barrelfield cortex. In the other two rodents, however, the enzyme
      is present in VPL but not in VPM, despite the fact that in these species the
      cortical barrels associated with both thalamic nuclei have very little of the
      enzyme. Thus, the relationship between the distribution of AChE in nuclei of the
      thalamic ventrobasal complex and the presence of AChE in the terminals of their
      cortical axons in the barrelfield is not consistent across different rodent
      species. Our results call for caution in the use of AChE histochemistry as a
      universal marker for immature thalamocortical axons, and challenge the generality
      of currently hypothesized roles for this transiently expressed enzyme during the
      development of the rodent thalamocortical projection.

PMID- 8670666
TI  - Visuotopic reorganization in the primary visual cortex of adult cats following
      monocular and binocular retinal lesions.
AB  - The effect of discrete monocular retinal lesions on the representation of the
      visual field in the primary visual area (V1) was investigated in adult cats.
      Lesions were created using argon lasers, 8 d to 4(1/2) months prior to
      electrophysiological recording. This produced lesion projection zones (LPZs) in
      V1, 1.6-9.5 mm wide, that were deprived of their normal input from one eye, but
      that received a normal input from the other eye. Nevertheless, at the majority of
      recording sites within these zones neuronal responses were elicited by
      stimulation of the lesioned eye, with receptive fields being displaced onto
      regions of retina surrounding the lesion, while receptive fields determined
      through stimulation of the normal eye followed the normal visuotopic organization
      of V1. However, neuronal responses to stimulation of the lesioned eye within the
      LPZs were characterized by rapid habituation and unusually low firing rates in
      comparison with responses to stimulation of the normal eye. Stimulation of the
      normal eye temporarily marked the responsiveness of neurons within the LPZ to
      stimulation of the lesioned eye. The proportion of neurons responsive to
      stimulation of the lesioned eye was higher just inside the borders of the LPZs
      than at the centers of these zones. However, neurons responsive to stimulation of
      the test eye were found up to 3.6 mm from the perimeter of the LPZs, and
      therefore the shifts in the visuotopic map caused by retinal lesions cannot be
      explained solely on the basis of the normal scatter of receptive fields and point
      image size in V1. The proportion of cells responsive to stimulation of the
      lesioned eye was highest in the infragranular layers, and lowest in the
      supragranular layers. By combining a restricted lesion of one eye with laser
      photocoagulation of the optic disc of the other eye, the effects of the normal
      eye on the lesion-induced visuotopic reorganization were also investigated.
      Neither chronic nor acute deactivation produced any discernible further changes
      in visuotopy or in the characteristics of neuronal responses to stimulation of
      the eye with the discrete lesions. Our findings show that the representations of
      the two eyes in adult visual cortex are capable of independent reorganization.
      These findings parallel those of work in auditory cortex, suggesting that
      topographic reorganization in primary sensory areas of adult cortex may be
      governed by similar mechanisms.

PMID- 8670667
TI  - Functional significance of long-term potentiation for sequence learning and
      prediction.
AB  - Population coding, where neurons with broad and overlapping firing rate tuning
      curves collectively encode information about a stimulus, is a common feature of
      sensory systems. We use decoding methods and measured properties of NMDA-mediated
      LTP induction to study the impact of long-term potentiation of synapses between
      the neurons of such a coding array. We find that, due to a temporal asymmetry in
      the induction of NMDA-mediated LTP, firing patterns in a neuronal array that
      initially represent the current value of a sensory input will, after training,
      provide an experienced-based prediction of that input instead. We compute how
      this prediction arises from and depends on the training experience. We also show
      how the encoded prediction can be used to generate learned motor sequences, such
      as the movement of a limb. This involves a novel form of memory recall that is
      driven by the motor response so that it automatically generates new information
      at a rate approximate for the task being performed.

PMID- 8670668
TI  - The origin and topography of long-range intrinsic projections in cat visual
      cortex: a developmental study.
AB  - We investigated the morphological features of long range intrinsically projecting
      neurons and their pattern of axonal arborization in cat area 17 at different
      stages of postnatal development. In one set of experiments intracortically
      projecting cells were retrogradely labeled in vivo with rhodamine latex beads and
      then visualized by in vitro filling with Lucifer yellow. In another approach,
      intracortical fibers including the cells of origin were labeled postmortem in
      fixed brains with the lipophilic carbocyanine dye Dil. The results of this study
      indicate that the long-range intrinsic circuitry of the primary visual cortex
      develops in three major steps. The first step consists of the development of
      unclustered long-range axons in the two outer compartments of the cerebral
      cortex, layer I and the subplate. These early connections could serve as a
      scaffold for the organization of the tangential architecture of the neocortex as
      they originate from cells that are the first to receive synaptic input from
      extrinsic afferents. The second step consists of the outgrowth of horizontal axon
      collaterals originating from cells located in layers II-VI. During the first 2-3
      weeks these connections still differ from those in the adult because they span
      shorter distances, originate more often from neurons with morphological features
      of nonpyramidal cells, and lack the precise clustering of the mature connections.
      The third step consists of a selection process that leads to the elimination of
      axon terminals from locations between the clusters of tangentially projecting
      neurons. This selection starts at the end of the second postnatal week and,
      hence, overlaps in time with the still proceeding elongation of axons and
      continues beyond the end of the fourth postnatal week when axon length has
      reached its maximal extent. This refinement process enhances the specificity of
      long-range connections and is probably influenced by visual experience.

PMID- 8670669
TI  - Nonuniform alteration of dendritic development in the cerebral cortex following
      prenatal cocaine exposure.
AB  - Prenatal exposure to cocaine has the potential to modify normal brain development
      and result in behavioral dysfunction. We used a new animal model in which cocaine
      was administered intravenously during prenatal development in pregnant rabbits
      twice daily at low dosages. Analysis of brain development focused on two areas of
      the cerebral cortex, anterior cingulate and primary visual, in which dopamine
      afferents, a target of cocaine, are differentially distributed. All postnatal
      rabbits exposed to cocaine prenatally exhibited normal features of cortical
      organization, including thickness, lamination patterns, and cytoarchitectonic
      differentiation. General axonal and astroglial organization, assessed by
      neurofilament-H and glial fibrillary acidic protein immunostaining, also was
      unchanged in the cocaine-exposed animals. Analysis of dendritic organization was
      done using antibodies against microtubule-associated protein 2 (MAP2), which
      reveals mostly the larger apical shafts of cortical pyramidal cells. In the
      anterior cingulate cortex of adolescent rabbits exposed to cocaine in utero,
      there is a marked decrease in both dendritic bundling and typical long, straight
      MAP2-stained profiles. In normal animals, the long, bundled dendrites area
      readily traced in a single focal plane from layer III or V pyramidal cell somata
      to the pial surface in saline-treated animals. Instead, the drug-exposed animals
      contained many more short segments of MAP2-stained dendrites that could be viewed
      coursing in and out of the plane of focus in the sections. Apical dendrites in
      mature visual cortex appeared normal in the cocaine-exposed rabbits. Examination
      of MAP2 staining at various postnatal ages revealed that the dendritic changes
      expressed in the adolescent anterior cingulate cortex appeared less robust, but
      still evident at birth. By P10-14, dendritic modifications were similar to the
      adult. Counts of the number of MAP2-positive dendritic profiles crossing the
      layer II-III interface reached a nadir of 50% in the cocaine-exposed animals,
      indicative of a change in the organization of the apical dendrites compared to
      the control animals. Dendritic profiles of anterior cingulate neurons, filled by
      1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil),
      confirmed that in the cocaine offspring, the dendrites coursed in an irregular,
      wavy manner from deep to superficial layers, suggestive of dendrites that were
      longer than normal, although cortical thickness was unchanged. The altered
      dendritic profiles also were seen in Golgi-impregnated neurons. The data indicate
      that prenatal exposure to cocaine can lead to specific alterations of neuronal
      growth that are long lasting. The lack of dendritic changes in visual cortex
      suggests that the drug does not modify development of cortical regions uniformly.
      This study also provides a new focus on the anterior cingulate cortex as a site
      in which aberrant structure-function relationships following prenatal cocaine
      exposure should be examined in both animal models and clinically.

PMID- 8670670
TI  - Cortical target depletion and the developing lateral geniculate nucleus:
      implications for trophic dependence.
AB  - The dependence of the developing dorsal lateral geniculate nucleus (LGd) on
      visual cortex for survival has been well documented. Complete removal of visual
      cortex during early postnatal development results in degeneration of the LGd. To
      further explore the nature of this trophic relationship, we depleted variable
      proportions of the principal targets of geniculocortical axons, layer IV neurons,
      and also variable proportions of the supragranular neurons by intraperitoneal
      injections of different dosages of a mitotic inhibitor MAM (methylazoxymethanol
      acetate) into pregnant hamsters at the time when these neurons were being
      generated in the ventricular zone. We demonstrate that after more than 75% loss
      of layer IV there is no reduction in cell number in the LGd. HRP (horseradish
      peroxidase) injections into the LGd in adult animals reveal an essentially normal
      pattern of termination without evidence of rerouting of geniculocortical axons to
      other cortical areas, nor compensatory increase in arborization in layer VI and
      VIb (subplate). Geniculocortical axons terminate principally in the middle
      stratum of the depleted cortex above layer V, with obvious reduction in both the
      extent and density of arborization. After higher dosages of MAM treatment
      resulting in more severe cell loss in layers II-IV with the apparent loss of
      layer IV, the extent and density of geniculocortical arborization are further
      reduced. Reduction in size as well as total number of geniculate neurons become
      detectable. Above depletions of 75% of layer IV neurons, the number of surviving
      LGd neurons is linearly related to the total number of remaining layer II-IV
      neurons in the cortex. These findings are discussed in light of the possible
      trophic mechanisms that match cell populations in number during development.

PMID- 8670671
TI  - Cortical target depletion and ingrowth of geniculocortical axons: implications
      for cortical specification.
AB  - During the early development of the neocortex, thalamocortical axons arrive
      potentially in time to instruct migrating cortical neurons in several aspects of
      local differentiation, such as number of layer IV neurons and efferent
      connectivity. Migration of layer IV neurons into the cortical plate just precedes
      thalamocortical invasion, suggesting that these neurons could cue or tropically
      direct thalamic ingrowth. To explore the interactions of layer IV neurons and
      their thalamocortical input, we administered a mitotic inhibitor
      methylazoxymethanol acetate (MAM) intraperitoneally to time d pregnant hamsters
      on E14 when layer IV neurons are normally being generated in striate cortex.
      Reduced numbers of cortical neurons overall, the absence of small diameter
      granule neurons, and the absence of the zone of reduced density of callosally
      projecting neurons suggest that neither the depletion of layer IV cells in the
      ventricular zone nor thalamic afferents in the subplate or cortical plate
      respecify the later generated cohort of neurons (presumptive layer II/III
      neurons) to acquire morphological and connectional properties of layer IV. Dil
      injections into the dorsal lateral geniculate nucleus (LGd) of animals from
      embryonic (E15) and postnatal (P7) ages show that the final position of thalamic
      axons with respect to layer V is not affected by the absence of E14 neurons. In
      the normal visual cortex, geniculocortical axons have begun their arborization in
      their presumptive target layer in the upper cortex immediately below the
      undifferentiated cortical plate on P4, while in MAM animals, this process occurs
      1 d later. The extent and density of arborization is much reduced in the thinner
      cortex of the MAM animals. We thus find no evidence for instruction of migrating
      neurons by thalamocortical axons to assume the layer IV phenotype; if instruction
      does occur, it must take place in a very restricted time window. Thalamic axons
      can also find their laminar position in the absence of cells of this phenotype.

PMID- 8670673
TI  - Adjacent visual cortical complex cells share about 20% of their stimulus-related
      information.
AB  - The responses of adjacent neurons in inferior temporal (IT) cortex carry signals
      that are to a large degree independent (Gawne and Richmond, 1993). Adjacent
      primary visual cortical neurons have similar orientation tuning (Hubel and
      Wiesel, 1962, 1968), suggesting that their responses might be more redundant than
      those in IT. We recorded the responses of 26 pairs of adjacent complex cells in
      the primary visual cortex of two awake monkeys while using both a set of 16 bar
      like stimuli, and a more complex set of 128 two-dimensional patterns. Linear
      regression showed that 40% of the signal variance of one neuron was related to
      that of the other when the responses to the bar-like stimuli were considered.
      However, when the responses to the two-dimensional stimuli were included in the
      analysis, only 19% of the signal variance of one neuron was related to that of
      the adjacent one, almost exactly the same results as found in IT. An information
      theoretic analysis gave similar results. We hypothesize that this trend toward
      independence of information processing by adjacent cortical neurons is a general
      organizational strategy used to maximize the amount of information carried in
      local groups.

PMID- 8670672
TI  - The cerebral cortex of the rat and visual attentional function: dissociable
      effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex
      lesions on a five-choice serial reaction time task.
AB  - Dissociable effects of bilateral excitotoxic lesions of different regions of the
      rat neocortex, including medial prefrontal and anterior cingulate cortices, were
      investigated in a five-choice serial reaction time task that provides several
      indices of the accuracy and speed of attentional function. Whereas medial
      prefrontal cortical lesions impaired performance of the task as revealed by a
      reduction in choice accuracy, an increase in the latency to respond correctly to
      the visual target and enhanced perseverative responding, lesions of the anterior
      cingulate cortex specifically increased premature responding. By contrast,
      lateral frontal cortical lesions did not significantly disrupt baseline
      performance of the task, but rather increased the latency to respond correctly to
      the visual target during various behavioral manipulations, for example, when the
      length of the intertrial interval was varied unpredictably and during
      interpolation of distracting bursts of white noise. Lesions of the parietal
      cortex failed to disrupt any aspect of task performance investigated. These
      behavioral effects in the five-choice task were compared with the effect of these
      same lesions on acquisition and retention of a one-trial passive avoidance task.
      The main finding from this paradigm was that lesions of the lateral frontal
      cortex produced a significant disruption to the retention of passive avoidance,
      which stands in marked contrast to the successful retention observed by animals
      of the other lesion groups. In addition, this pattern of results reveals that the
      'disinhibitory' effect of cingulate cortex lesions are relatively specific to the
      five-choice attentional task. Finally, the results of the present study are
      compared with the findings of previous experiments using the five-choice task,
      which have examined the effect of selective manipulations of the ascending
      noradrenergic, cholinergic, dopaminergic, and serotonergic projections. In
      particular, the deficits in attentional function observed following cholinergic
      lesions of the nucleus basalis magnocellularis appear to be attributable to
      cholinergic denervation of the medial frontal cortex. These results are discussed
      in terms of the role of parallel distributed neural systems within the neocortex
      that mediate continuous attentional performance in the rat.

PMID- 8670674
TI  - Neuronal clones in the cerebral cortex show morphological and neurotransmitter
      heterogeneity during development.
AB  - The mammalian cerebral cortex, although a structure of great complexity, is
      characterized by a high degree of organization where the proportions, spatial
      relationships, and properties of the various cell types are rigidly controlled.
      The mechanisms responsible for the creation of such a rigid distribution of cell
      types are not known. Lineage studies in adult rats have suggested that each of
      the cortical progenitor cells lining the telencephalic ventricles during
      embryonic development gives rise to progeny of the same phenotype (homogeneous
      clones). However, the possibility that homogeneous clones are the result of
      complex processes affecting both the final number and the phenotype of clonally
      related cells during development has not been investigated. In the present study,
      we followed the development of cortical cell lineages labeled with retroviral
      injections at embryonic day (E) 16 in rats of 7, 14, or 21 d of age using
      electron microscopy and immunocytochemistry for the neurotransmitters glutamate
      and GABA. We found that a significant number of cortical clones at postnatal day
      (P) 7 and P14, and fewer at P21, showed mixed pyramidal/nonpyramidal cell
      composition. We sometimes observed that "mixed" neuronal clones contained cells
      immunoreactive for both glutamate and GABA. In the general population of cortical
      cells, "bireactive" neurons represented 3.7% of all neurons at P7, 18% at P14,
      and 0.6% in adult rats. Although the change in the composition of neuronal clones
      between the third week of postnatal life and adulthood may be due to changes in
      the phenotype of some developing neurons, we would like to suggest that it is
      probably due to selective neuronal cell death.

PMID- 8670675
TI  - Representational capacity of face coding in monkeys.
AB  - We examine the distributed nature of the neural code for faces represented by the
      firing of visual neurons in the superior temporal sulcus of monkeys. Both
      information theory and neural decoding techniques are applied to determine how
      the capacity to represent faces depends on the number of coding neurons. Using a
      combination of experimental data and Monte Carlo simulations, we show that the
      information grows linearly and the capacity to encode stimuli grows exponentially
      with the number of neurons. By decoding firing rates, we determine that the
      responses of the 14 recorded neurons can distinguish between 20 face stimuli with
      approximately 80% accuracy. In general, we find that N neurons of this type can
      encode approximately 3(2(04N)) different faces with 50% discrimination accuracy.
      These results indicate that the neural code for faces is highly distributed and
      capable of accurately representing large numbers of stimuli.

PMID- 8670676
TI  - Short-lasting classical conditioning induces reversible changes of
      representational maps of vibrissae in mouse SI cortex--a 2DG study.
AB  - It has been known for several years that receptive field properties of sensory
      cortical neurons can be altered by learning experiences. We attempted to
      visualize a global change of the cortical body map induced by learning. In order
      to do this a short-duration classical conditioning involving stimulation of a row
      of mystacial vibrissae in mice was followed with 2-deoxyglucose (2DG) mapping of
      functional activity. Three conditioning sessions that paired stimulation of a row
      of whiskers with a tail shock produced an increase of the functional
      representation in somatosensory cortex (SI) of a row of the whiskers stimulated
      during the training. This plastic change of vibrissal representation in SI was
      visualized with 2DG autoradiography a day after completion of training. The
      expansion of representation was the most pronounced in cortical layer IV, and to
      a lesser extent, in layer IIIb. The expansion was observed in conditioned but not
      in pseudoconditioned mice or in animals that received only the conditioned
      stimulus. If training was discontinued, the enlargement of vibrissal
      representation progressively faded. The reversal could be accelerated by a
      behavioral extinction procedure. This study gives the pictorial demonstration of
      rapid, transient, and extinguishable learning-dependent changes in SI cortical
      maps.

PMID- 8670677
TI  - Hyperexcitability in a model of cortical maldevelopment.
AB  - The presence of developmental cortical malformations has been associated with the
      occurrence of epilepsy, and correlative anatomic-clinical electrophysiological
      studies suggest that microdysgenic lesions may actually initiate epileptiform
      activity. We have investigated the electrophysiological properties of an animal
      model of polymicrogyria created by making cortical freeze lesions in rat pups at
      P0 or P1. Such lesions create microgyri with histological features similar to
      those of human polymicrogyria. We have determined that there is a focal region of
      hyperexcitability around the lesion in this rat microgyrus. Field potentials
      evoked by stimulation within a few millimeters of the microgyrus have
      characteristics typical of epileptiform activity. This aberrant activity is seen
      as early as 12 d after the lesion, as well as in animals as old as 118 d.
      Immunochemical staining for the calcium binding protein, parvalbumin, shows a
      decrease in neuronal and neuropil staining within the microgyrus. These findings
      suggest that inhibition might be decreased within the lesion, which may
      contribute to generation of the adjacent hyperexcitable region. These results
      demonstrate that this animal model is appropriate for examining the mechanisms
      contributing to epileptogenesis associated with a cortical malformation.

PMID- 8670678
TI  - NADPH-diaphorase-positive neurons in primate cerebral cortex colocalize with GABA
      and calcium-binding proteins.
AB  - Neurons in the monkey cerebral cortex containing nicotinamide adenine
      dinucleotide phosphate-diaphorase (NADPH-d) can be divided into two distinct
      types, both nonpyramidal. Type I neurons have a large soma (diameter 20-50
      microm), a dense NADPH-d histochemical reaction, and are distributed throughout
      the cortex, but mainly in the subcortical white matter, and are mostly aspiny.
      Type II cells have a small soma ( Together with previous observations that almost
      all cortical NADPH-d cells in various subprimates are like type I cells, we
      suggest that type II cells may form a group of NADPH-d-rich neurons
      differentiated in higher mammalian cortex from a subpopulation of calbindin
      containing GABAergic interneurons, and these nitric oxide-synthesizing cells may
      play a role in control of intracortical neuronal activity characteristic of
      higher cerebral functions in advanced mammals.

PMID- 8670679
TI  - Distinctive forms of partial retrograde amnesia after asymmetric temporal lobe
      lesions: possible role of the occipitotemporal gyri in memory.
AB  - We tested the hypothesis that partial forms of retrograde amnesia were associated
      with highly asymmetric lesions to the inferior and anterior-medial temporal lobe.
      Postencephalitic subjects EK and DR were both impaired on standardized retrograde
      memory tests, but showed strikingly different profiles in cognitive tasks of name
      stem completion, name:face matching, temporal ordering, forced choice
      recognition, and occupational judgments of famous names and faces from the past 3
      decades. EK sustained left inferior and anterior-medial temporal lobe lesion with
      a small right temporal polar lesion, and showed near-complete loss of retrieval,
      knowledge, and familiarity associated with famous names but minimal deficiencies
      with famous faces. DR sustained right inferior and anterior-medial temporal lobe
      lesion and showed a milder retrograde loss limited to utilizing famous face
      prompts in name stem completion, name:face matching, occupational judgments, and
      forced choice recognition. These impairments were also different from the memory
      retrieval deficit, but intact recognition shown by a case of ruptured anterior
      communicating artery aneurysm with presumed basal forebrain damage. We
      hypothesize that EK's extensive loss of famous name knowledge was related to left
      inferior temporal lobe damage, particularly in the lateral and medial
      occipitotemporal gyri. This region in the left temporal lobe may serve as a
      critical processing area for retrograde memory that permits activation of
      established semantic, temporal, and visual (i.e., facial) associations
      biographically dependent on the category of proper names. On the basis of
      connectional anatomy patterns in the nonhuman primate, this region receives
      extensive hippocampal output and is interconnected with the temporal polar region
      and cortical association areas, which have been implicated in retrieval and
      storage aspects of retrograde memory. In the right hemisphere, the
      occipitotemporal gyri may serve an important role in famous face processing as
      part of a bilateral neural network.

PMID- 8670680
TI  - Complementary distribution of collagen type IV and the epidermal growth factor
      receptor in the rat embryonic telencephalon.
AB  - We previously identified an interaction between collagen type IV and the EGF
      receptor that regulates the differentiation of a limbic cortical phenotype in
      vitro (Ferri and Levitt, 1995). In the present study, we map the expression of
      the EGF receptor and collagen type IV in the embryonic telencephalon of the rat.
      At embryonic day (E) II, the earliest age examined, both proteins are coexpressed
      throughout the ventricular zone in the cerebral wall; this zone remains
      immunoreactive throughout corticogenesis (E14-E19). The cells comprising the
      subventricular zone are the most intensely immunoreactive for the EGF receptor,
      although little collage type IV is detected in this region. In contrast,
      postmitotic neurons that leave the proliferative zones are negative for the
      receptor. Moreover, during the peak of neuronal migration, the intermediate zone
      lacks collagen type IV immunoreactivity. Neurons that settle in the cortical
      plate once again exhibit EGF receptor immunoreactivity; this same zone is devoid
      of collagen type IV. By E19, coexpression of both proteins is evident only in the
      rostral extension of the subventricular zone, the pathway of migrating cells
      leading to the olfactory bulb. The temporal and spatial overlap of the EGF
      receptor and collage type IV in the cortical progenitor pool in vivo indicates
      that these molecules may participate in the initial decisions of neuronal
      differentiation. Their modified distribution during cortical maturation suggests
      a changing role for both proteins.

PMID- 8670681
TI  - Quantitative magnetic resonance imaging of human brain development: ages 4-18.
AB  - Brain magnetic resonance images (MRI) of 104 healthy children and adolescents,
      age 4-18, showed significant effects of age and gender on brain morphometry.
      Males had larger cerebral (9%) and cerebellar (8%) volumes (P < 0.0001 and P =
      0.008, respectively), which remained significant even after correction for height
      and weight. After adjusting for cerebral size, the putamen and globus pallidus
      remained larger in males, while relative caudate size was larger in females.
      Neither cerebral nor cerebellar volume changed significantly across this age
      range. Lateral ventricular volume increased significantly in males (trend for
      females), with males showing an increase in slope after age 11. In males only,
      caudate and putamen decrease with age (P = 0.007 and 0.05, respectively). The
      left lateral ventricles and putamen were significantly greater than the right (P
      = 0.01 and 0.001, respectively). In contrast, the cerebral hemispheres and
      caudate showed a highly consistent right-greater-than-left asymmetry (P < 0.0001
      for both). All volumes demonstrated a high degree of variability. These findings
      highlight gender-specific maturational changes of the developing brain and the
      need for large gender-matched samples in pediatric neuropsychiatric studies.

PMID- 8670682
TI  - Induction of c-fos mRNA in rat medial prefrontal cortex by antipsychotic drugs:
      role of dopamine D2 and D3 receptors.
AB  - The present studies compared the effects of acute and chronic administration of
      haloperidol or clozapine on c-fos mRNA expression in the rat medial prefrontal
      cortex. Acute administration of clozapine, but not haloperidol robustly increased
      c-fos mRNA expression in the infralimbic and prelimbic cortex of the rat. Even
      though most c-fos mRNA-expressing neurons in the clozapine- treated animals were
      localized in deep cortical layers, labeled neurons were found organized into
      several cell bridges connecting the superficial and deep layers of the cortex.
      After chronic treatment with clozapine, c-fos mRNA was reduced by approximately
      60% of that seen acutely; however, the columns of c-fos mRNA expressing neurons
      did not show the same magnitude of tolerance. Haloperidol had no significant
      effect even after chronic treatment. We examined further the role of dopamine D2
      versus D3 receptors in c-fos gene induction in the infralimbic cortex by studying
      the acute effects of remoxipride and U-99194A. Remoxipride, a selective D2
      antagonist in vitro, induced c-fos mRNA at very low doses and lost its ability to
      alter c-fos mRNA at higher doses. Interestingly, U-99194A, an antagonist with 20
      fold selectivity for D3 over D2 receptors, also produced greater induction of c
      fos mRNA at lower doses. We hypothesize that blockade of D3 receptors may enhance
      c-fos gene expression in the medial prefrontal cortex but that of D2 receptors
      may prevent the same.

PMID- 8670683
TI  - Changes in limbic and prefrontal functional interactions in a working memory task
      for faces.
AB  - Regional cerebral blood flow, measured with positron emission tomography, was
      used to identify brain regions that play a special role(s) in a working memory
      task for faces. Perceptual matching (no retention interval), short-delay (average
      = 3.5 s retention interval), intermediate-delay (average = 12.5 s), and long
      delay (21 s) tasks were considered. From the idea that brain function is the
      result of neural interactions, the data were analysed using anatomically based,
      covariance structural equation modeling. In perceptual matching, the dominant
      functional interactions were observed among the ventral cortical areas, from
      extrastriate regions, to the anterior temporal, and into the inferior prefrontal
      cortex. These interactions decreased with longer delay intervals. In the short
      delay functional model, interactions along this ventral stream in the right
      hemisphere appeared to be rerouted through limbic areas with strong interactions
      among the hippocampal region, the anterior and posterior cingulate, and the
      inferior prefrontal cortices. For the intermediate-delay model, the
      hippocampocingulate interactions continued, but showed a shift to more left
      hemisphere involvement. In the long-delay network, interactions within the right
      limbic circuit were reduced in favor of strong bilateral inferior prefrontal and
      frontocingulate interactions. Effects from the prefrontal cortex, especially from
      the left hemisphere, to temporal and occipito-temporal cortices were particularly
      strong in the long-delay model, suggesting recruitment of some of the same
      circuits primarily involved in face perception. The strong corticolimbic
      interactions at short and intermediate delays may represent maintenance of an
      iconic representation of the face during the retention interval. However, at
      longer delays, where image was more difficult to maintain, a frontocingulate
      occipital network was used that could represent an expanded encoding strategy
      resulting in a more resilient memory.

PMID- 8670684
TI  - Areas PMLS and 21a of cat visual cortex: two functionally distinct areas.
AB  - We have compared the receptive field properties of neurons recorded from
      visuotopically corresponding regions of area 21a and the posteromedial lateral
      suprasylvian area (PMLS) of cat visual cortex. In both areas, the great majority
      of neurons were orientation-selective and binocular, and their responses to
      moving contours were modulated by simultaneous in-phase or anti-phase motion of
      large textured background stimuli ('visual noise'). However, despite the great
      hodological similarity between the two areas, PMLS neurons had on average
      significantly higher peak discharge rates, exhibited substantially greater
      direction selectivity indices, and preferred substantially higher stimulus
      velocities than area 21a neurons. Furthermore, the majority of binocular neurons
      in the PMLS area and in area 21a were dominated respectively by contralateral and
      ipsilateral eyes. Finally, while 46% of PMLS neurons were excited by movement of
      visual noise per se, only 25% of area 21a neurons could be excited by such
      stimuli. We argue that the PMLS area, like its presumed primate homologue the
      middle-temporal (MT) area, is mainly involved in motion analysis. By contrast,
      area 21a appears to be involved in pattern analysis rather than motion analysis.
      It is likely that phylogenetically area 21a derives from the PMLS area.

PMID- 8670685
TI  - Activation of human prefrontal cortex during spatial and nonspatial working
      memory tasks measured by functional MRI.
AB  - Separate working memory domains for spatial location, and for objects, faces, and
      patterns, have been identified in the prefrontal cortex (PFC) of nonhuman
      primates. We have used functional magnetic resonance imaging to examine whether
      spatial and nonspatial visual working memory processes are similarly dissociable
      in human PFC. Subjects performed tasks which required them to remember either the
      location or shape of successive visual stimuli. We found that the mnemonic
      component of the working memory tasks affected the hemispheric pattern of PFC
      activation. The spatial (LOCATION) working memory task preferentially activated
      the middle frontal gyrus (MFG) in the right hemisphere, while the nonspatial
      (SHAPE) working memory task activated the MFG in both hemispheres. Furthermore,
      the area of activation in the left hemisphere extended into the inferior frontal
      gyrus for nonspatial SHAPE task. A perceptual target (DOT) detection task also
      activated the MFG bilaterally, but at a level approximately half that of the
      working memory tasks. The activation in the MFG occurred within 3-6 s of task
      onset and declined following task offset. Time-course analysis revealed a
      different pattern for cingulate gyrus, in which activation occurred upon task
      completion. Cingulate gyrus activation was greatest following the SHAPE task and
      was greater in the left hemisphere. The present results support the prominent
      role of the PFC and, specifically, the MFG in working memory, and indicate that
      the mnemonic content of the task affects the relative weighting of hemispheric
      activation.

PMID- 8670686
TI  - Active representation of shape and spatial location in man.
AB  - Neural activity during the delay period of spatial delayed response (DR) and
      delayed matching (DM) tasks was investigated by positron emission tomography. A
      distributed cortical system was activated in each condition. The bilateral
      dorsolateral prefrontal cortex (DLPFC) was activated in the delay period of both
      tasks; activation was of higher significance on the right in the DR task and the
      left in the DM task, and extended to the anterolateral prefrontal cortex in the
      DM condition. Active representation of spatial location in the DR task was
      associated with co-activation of the medial and lateral parietal cortex and the
      extrastriate visual cortex. Active representation of shape in the DM task was
      associated with co-activation of medial and lateral parietal cortex and the
      inferior temporal cortex. Response-related activity was observed in both tasks.
      Activation of anterior cingulate, inferior frontal, lateral promotor and rostral
      inferior parietal cortex was observed in the DR condition, a task characterized
      by preparation of a movement to a predetermined location. In contrast,
      preparation to move to an undetermined location in the DM task was associated
      with activation predominantly in rostral SMA.

PMID- 8670687
TI  - Prenatal development of parvalbumin immunoreactivity in the human striate cortex.
AB  - In human primary visual cortex, parvalbumin (PV) is expressed by Cajal-Retzius
      cells in layer I by 20 weeks of gestation (20W), but its immunoreactivity is
      mostly lost by term. PV immunoreactivity in layers II-VI mainly develops later,
      from 26 to 34W, following an approximately 'inside-outside' sequence in a series
      of bands. PR-positive perikarya appear in layer V by 20W, but only in small
      numbers. They increase in number and staining intensity by 26W. By 30W a band of
      densely labelled somata and neuropil occupies layers IVC-VI. By 34W a second,
      less dense, band of cell bodies and neuropil appears in IVB and IVCalpha,
      separated from the deep band by IVCbeta which is cell-sparse and almost fibre
      free. Between 38 and 40W, a third minor band consisting mainly of fibres is seen
      in layer IVA. Reactive cell bodies form clusters, and the neuropil staining is
      mosaic-like. PV-positive neurons are of two main types: large with wide dendritic
      arbor, and smaller with simpler dendrites. However, a few have characteristics of
      pyramidal cells, and a few others resemble glial cells. The laminar pattern of PV
      immunoreactive somata in human striate cortex is established by term, rather than
      postnatally as in most mammals, implying that PV may be involved in neuronal
      development in prenatal human striate cortex.

PMID- 8670688
TI  - The distribution of callosal connections correlates with the pattern of
      cytochrome oxidase stripes in visual area V2 of macaque monkeys.
AB  - In visual area V2 of monkeys, cytochrome oxidase (CO) histochemistry reveals a
      system of stripe-like subregions where densely labeled thick and thin stripes and
      pale interstripes can be recognized. Several lines of evidence suggest that CO
      stripe-like subregions are associated with functional streams in the visual
      cortex. In the present study, the distribution of retrogradely labeled callosal
      cells in V2 and the pattern of CO staining were correlated using tangential
      sections through the flattened cortex. Spectral and coherency analyses of the
      callosal and CO patterns were performed to assess quantitatively the degree of
      spatial correlation between these two patterns. The results showed that labeled
      callosal cells accumulated along the V1/V2 border and in finger-like bands that
      protruded up to 7-8 mm into V2. These callosal bands were in register with thick
      and thin CO stripes, with relatively few labeled callosal cells found in
      interstripe regions. This finding supports the notion that the distribution of
      callosal connections in the visual cortex is dictated not only by the topography
      of visual areas, but also by the arrangement of cortical functional streams.
      Further, these results extend to interhemispheric pathways the notion of
      functional specificity currently associated mainly with some visual
      intrahemispheric pathways.

PMID- 8670689
TI  - Short-term synaptic plasticity in the visual cortex during development.
AB  - The maturation of short-term synaptic plasticity was studied in slices of the
      visual cortex obtained from rats during the first 47 days of postnatal life.
      Responses of cortical neurons to repetitive stimulation of the white matter at
      frequencies >5 Hz were examined by recording intracellularly at the resting
      membrane potential level. Paired-pulse facilitation, an increase in the
      excitatory intracellular response following an initial response, was present in
      approximately 40% of the neurons studied from postnatal day 5 (P5) to P10. Most
      of the remaining neurons studied at these ages did not reveal paired-pulse
      interactions. There was a progressive, age-related increase in the proportion of
      cells displaying paired-pulse depression, a decrease in the second excitatory
      response relative to the first, and a concomitant decrease in the proportion of
      cells displaying paired-pulse facilitation. Thus, at P31-P47 approximately half
      of the neurons revealed depression of synaptic transmission following an initial
      stimulus, while most of the other neurons displayed a lack of temporal
      interactions. At these later ages, inhibitory potentials also displayed paired
      pulse interactions. Maturation of paired-pulse depression of the excitatory
      response is temporally correlated with the development of intracortical
      inhibitory mechanisms and may reflect subtractive or shunting inhibition in the
      postsynaptic neuron as well as presynaptic inhibitory mechanisms. Consistent with
      a role of GAGAergic inhibition, application of GABA receptor antagonists produced
      reversible blockade of paired-pulse depression. In conclusion, cortical neurons
      display substantial maturation in short-term synaptic plasticity during the first
      postnatal month. Temporal facilitation may be important in enhancing excitatory
      neurotransmission at a time when synapses are very immature. In the mature
      cortex, suppressive temporal interactions could provide an important substrate
      for neuronal processing of visual information.

PMID- 8670690
TI  - Anterior tongue stimulation with amiloride suppresses NaCl saltiness, but not
      citric acid sourness in humans.
AB  - Suppression of the saltiness of NaCl solutions by amiloride, a sodium channel
      blocker, has previously been reported a number of times in humans. This
      suppression was seen with techniques that involved stimulation of small areas of
      the tongue. It was not certain, however, whether amiloride would suppress
      saltiness with stimulation of a much larger area of the tongue; one published
      study, in fact, found negative results with whole mouth stimulation. For this
      study, eight subjects dipped a large part of the anterior portion of the tongue
      into a 10-ml sample of NaCl solution, or a NaCl and amiloride solution, and
      reported its magnitude of saltiness intensity. The results show that amiloride
      suppressed the saltiness of NaCl when a large area of the anterior tongue was
      stimulated. Consistent with previous studies, there was individual variability
      across subjects in this suppressive effect of amiloride. This study also used
      this method to test the effects of amiloride on the sourness of citric acid,
      which was not expected to be affected. No suppression of sourness was seen with
      amiloride.

PMID- 8670691
TI  - Numerical simulation of environment modulation of chemical signal structure and
      odor dispersal in the open ocean.
AB  - Hydrodynamic models were used to simulate the dispersal of a model fish pheromone
      at three characteristic depth regimes (mixed layer, and 300 and 1000 m) of broad
      extent in the open ocean at the scale of individual organisms. The models were
      calibrated to experimental studies of dye dispersal at these depths and the
      goldfish pheromone system was used as the model odorant. There are profound
      differences in the time course and geometry of dispersing odor fields with
      depths. Below the thermocline odor fields spread primarily as horizontal patches
      with dispersal rates about five times slower at 1000 m as compared to 300 m. In
      the mixed layer, odors disperse rapidly in all directions and the maximum radial
      distance of spread of a physiologically active odor patch is less than half of
      the deep water value. Increases in the threshold sensitivity of olfactory
      receptors can greatly increase effective odor field size. Chemical signals impact
      the encounter dynamics among oceanic organisms by affecting the distance at which
      the target (emitting) individual is perceived. Perception distances due to
      olfactory cues can be significantly greater than for other senses in pelagic
      oceanic environments. Environment specific modulation of odor fields then affects
      the signal properties and therefore utility of chemoreception that, in turn, bear
      on encounter probabilities and transfer functions in oceanic ecosystems.

PMID- 8670692
TI  - Responses of primate taste cortex neurons to the astringent tastant tannic acid.
AB  - In order to advance knowledge of the neural control of feeding, we investigated
      the cortical representation of the taste of tannic acid, which produces the taste
      of astringency. It is a dietary component of biological importance particularly
      to arboreal primates. Recordings were made from 74 taste responsive neurons in
      the orbitofrontal cortex. Single neurons were found that were tuned to respond to
      0.001 M tannic acid, and represented a subpopulation of neurons that was distinct
      from neurons responsive to the tastes of glucose (sweet), NaCl (salty), HCl
      (sour), quinine (bitter) and monosodium glutamate (umami). In addition, across
      the population of 74 neurons, tannic acid was as well represented as the tastes
      of NaCl, HCl quinine or monosodium glutamate. Multidimensional scaling analysis
      of the neuronal responses to the tastants indicates that tannic acid lies outside
      the boundaries of the four conventional taste qualities (sweet, sour, bitter and
      salty). Taken together these data indicate that the astringent taste of tannic
      acid should be considered as a taste quality, which receives a separate
      representation from sweet, salt, bitter and sour in the primate cortical taste
      areas.

PMID- 8670694
TI  - Induction of a calcium-dependent long-term enhancement of excitability in the
      rate olfactory bulb.
AB  - We have investigated whether a transient increase in extracellular calcium
      concentration is able to induce long-term modification of neuronal excitability
      in the olfactory bulb. High-calcium artificial cerebrospinal fluid containing
      picrotoxin (Ca-PTX solution) was applied locally near the mitral cell layer
      through a push-pull device for 10 min in anaesthetized rats. Changes in the
      neuronal excitability were monitored through electrically-evoked field
      potentials. Application of the Ca-PTX solution induced a rapid increase in the
      granule cell response amplitude, whereas mitral/tufted cells response amplitude
      increased more progressively and reached its maximum within a few hours. The
      increase in mitral/tufted cells response and granule cells response reached
      between 30 and 100% in experiments which lasted for 4-8 h. Pre-application of
      amino-phosphonovalerate (NMDA receptor blocker) potently reduced both short- and
      long-term enhancement produced by the Ca-PTX solution. Neither application of the
      high calcium solution alone nor the picrotoxin solution alone induced long-term
      changes. The results point out the possible importance of Ca2+ and NMDA receptors
      in persistent forms of olfactory bulb plasticity. Relevance of this phenomenon in
      normal olfactory bulb physiology remains to be examined.

PMID- 8670693
TI  - Taste responses in the nucleus of the solitary tract in saccharin-preferring and
      saccharin-averse rats.
AB  - A minority of rats consistently reject the taste of sodium saccharin at
      concentrations that the majority find palatable. We chose rats that selected
      either water (WP), or 0.03 M NaSaccharin (SP) in two-bottle preference tests and
      monitored single unit responses to a range of taste qualities in the nucleus of
      the solitary tract. WP rats gave significantly greater responses to Na/Li salts
      and QHCl. Their responses to sugars were equal to those from SP rats. Total
      activity to NaSaccharin did not differ between the two groups, but its
      distribution across the three identified neuron types did. The response was
      skewed from one in which sugar (S) and sodium salt (N) participated nearly
      equally (SP) to one dominated by the activity of N cells and nearly devoid of an
      S cell contribution (WP rats). Accordingly, the response profile for NaSaccharin
      was correlated nearly as well with those of the sugars (+ 0.60) as with the Na/Li
      salts (+ 0.73) in SP rats, but was reshaped in WP rats to be nearly identical
      with those of the salts (+ 0.85) and unlike sugars (+ 0.30). In their heightened
      sensitivity to stimuli that humans call salty and bitter, and in their rejection
      of the complex taste of NaSaccharin, WP rats showed many of the characteristics
      of human tasters of PTC/PROP.

PMID- 8670695
TI  - Food deprivation increases the rat's preference for a fatty flavor over a sweet
      taste.
AB  - Previous research indicates that food deprivation increases the rat's preference
      for high-fat over low-fat foods. Since these foods differ in their flavors and
      post-ingestive effects, both factors may be implicated. The present study
      investigated preferences in food deprived and non-deprived rats using non
      nutritive mineral oil emulsion (MO) and saccharin solution (SAC), which have a
      fatty flavor and sweet taste, respectively. The deprived rats consumed more MO
      than SAC in one- and two-bottle tests, while the non-deprived rats ingested as
      much SAC as MO in one-bottle tests and preferred SAC in two-bottle tests. Several
      aspects of the data suggest that the deprivation-related shift in preference
      between MO and SAC was determined by changes in long-term energy balance. A
      follow-up conditioning experiment discarded the possibility that the observed
      preference shift was related to differential reinforcing effects of the two
      substances. In conclusion, long-term food restriction increases the preference
      for an oily flavor over a sweet taste via a mechanism that does not involve
      nutritive feedback. It remains to be determined to what extent this alternation
      in flavor preference influences food selection when post-ingestive nutritive
      feedback can influence food choice.

PMID- 8670696
TI  - 45-kDa GTP-binding protein from rat olfactory epithelium: purification,
      characterization and localization.
AB  - The rat olfactory epithelium contains a specific water-soluble 45-kDa protein.
      This protein is recognized by anti-peptide antibodies which react with alpha
      subunits of the known G-proteins. The 45-kDa protein has been isolated using DEAE
      chromatography and gel-exclusion chromatography. The content of 45-kDa protein is
      about 2% of the total soluble proteins of the olfactory mucosa and it is located
      at the mucociliary surface. According to photo-affinity labeling, the 45-kDa
      protein possesses a high affinity to GTP and exhibits low GTP hydrolytic
      activity. The functions of the 45-kDa protein are discussed.

PMID- 8670697
TI  - Changes in taste threshold over the life span of the Sprague-Dawley rat.
AB  - Taste thresholds for sucrose, NaCl, QHCl and citric acid were examined over the
      lifetime of seven rats. Significant yet subtle decreases in taste sensitivity
      were observed in the oldest subjects only.

PMID- 8670698
TI  - Changes in taste perception following mental or physical stress.
AB  - Taste perception depends not only on the chemical and physical properties of
      tastants, but may also depend on the physiological and psychological conditions
      of those who do the tasting. In this study, the effects of mood state on taste
      sensitivity was evaluated in humans who were exposed to conditions of mental or
      physical fatigue and tension. Taste responses to quinine sulfate (bitter), citric
      acid (sour) and sucrose (sweet) were tested. The intensity of the taste
      sensations were recorded by a computerized time-intensity (Tl) on-line system.
      Subjects performed mental tasks by personal computer or physical tasks by
      ergometer for 10-40 min. Before and after these sessions, the duration of the
      after-taste and the intensity of the sensation of taste were recorded by the Tl
      system, and in addition, psychological mood states were evaluated with POMS
      (Profile of Mood State). Tl evaluation showed that after the mental tasks, the
      perceived duration of bitter, sour and sweet taste sensations was shortened
      relative to the control. Total amount of bitterness, sourness and sweetness was
      also significantly reduced. Furthermore, the maximum intensity of bitterness was
      significantly reduced. There were no significant differences in bitterness and
      sweetness sensations following physical tasks. However, relative to before the
      physical task, the duration of the after-taste of sourness was significantly
      shortened by the physical task. After the physical task, the buffering capacity
      of saliva was significantly increased. Thus mental and physical tasks alter taste
      perception in different ways; the mechanisms underlying these changes remain to
      be determined.

PMID- 8670699
TI  - Construction of a quantitative three-dimensional model for odor quality using
      comparative molecular field analysis (CoMFA).
AB  - A quantitative structure-activity relationship (QSAR) study of odorants was
      performed taking an odor as an activity. As an example, we took the 'green odor
      of pyrazine derivations' as an activity. Conformational analysis of the pyrazine
      derivatives was performed, and conformers were selected using the longest side
      length of a circumscribed box (LLCB) as a criterion. Comparative molecular field
      analysis (CoMFA) was used to elucidate the three-dimensional (3D) structural
      features of the derivatives. As a result, it was found that the steric and
      electrostatic features of the derivations were correlated with human olfactory
      detection threshold values. We constructed a quantitative 3D model using the
      graphic views of CoMFA and partial structures of the derivatives. The prediction
      of human olfactory detection threshold values of other pyrazine derivatives with
      green odor was possible by using the 3D model. As another example, we took the
      'sweet odor of compounds with various structures' as an activity. A quantitative
      3D model for sweet odor was constructed in the same manner. Analysing the
      structural features of odorants by CoMFA and constructing 3D models for several
      important odor qualities would help to (i) explain or predict human olfactory
      detection threshold values of interesting odorants, (ii) design new odorants by
      suggesting the steric and electrostatic requirements, and (iii) elucidate the
      mechanism of odorant-receptor interaction.

PMID- 8670700
TI  - Detection of tastes in mixture with other tastes: issues of masking and aging.
AB  - When one taste (masker) is strong enough, it can completely mask another task
      (target) of different quality. How strong the masker must be to do this depends
      on how strong the target is. As the target concentration is increased, the
      masking concentration must be increased, too, but in ever-increasing proportion.
      To quantify the conditions for such complete masking, the target's detection
      threshold was measured as a function of the masker's concentration, from zero to
      strong. This was done for 12 binary combinations of sucrose, sodium chloride,
      citric acid and quinine hydrochloride. The 12 functions generated show that some
      tastants mask each other much more efficiently than others. Masking gives new
      insight into the role of aging in taste: older (66-90 years) subjects'
      thresholds, regardless of masking concentration, always measured a constant
      factor higher than younger (18-29 years) subjects' thresholds (about two to seven
      times higher, depending on target tastant). Thus, with increasing level of the
      masker, the thresholds of young and elderly go up in parallel. Thresholds of
      tastants in water alone are false predictors of elderly persons' ability to
      perceive ingredients like salt and sugar condiments in foods, where, because of
      masking, their thresholds can be several times higher than in water. Age
      manifested itself relatively mildly in sucrose and citric acid, moderately in
      sodium chloride, and strongly in quinine hydrochloride.

PMID- 8670701
TI  - The role of perceptual and structural similarity in cross-adaptation.
AB  - Cross-adaptation, the decrease in sensitivity to one odorant following exposure
      to a different odorant, is affected by odorant similarity, both perceptual and
      structural, but the precise relationship is obscure. The present series of
      studies was designed to explore various aspects of perceptual and structural
      similarity as they relate to cross-adaptation. In Experiment 1, cross-adaptation
      was assessed between androstenone and five odorants that share a common urinous
      note with androstenone, but retain unique perceptual characteristics; only the
      compound judged most perceptually similar to androstenone cross-adapted it. In
      Experiment 2, odorants both perceptually and structurally similar (androstenone
      and androstanone) displayed significant, mutual cross-adaptation. Furthermore,
      magnitude estimates for androstanone were significantly reduced following
      exposure to 3-methylidene-5 alpha-androstane (3M5A), a structurally similar,
      perceptually odorless compound. This finding appears to be the first
      demonstration that an odorless compound can affect, via cross-adaptation, the
      perception of an odorous compound. Finally, in Experiment 3, significant,
      asymmetric cross-adaptation was observed between compounds that are perceptually
      and structurally dissimilar (4-cyclohexylcyclohexanone [4-CHCH] and
      androstenone). These findings indicate that the role of similarity in cross
      adaptation is difficult to quantify and emphasize the numerous odorant
      characteristics that can affect cross-adaptation.

PMID- 8670702
TI  - Pheromones as tools for olfactory research.Introduction.
AB  - We have long been fascinated by the unique ability of odors to stir our emotions
      and to evoke long-forgotten memories, but certain odors play a much more
      fundamental role in that they vastly improve an organism's chances for
      reproductive success and survival. These odorants are called pheromones, a term
      commonly applied to semiochemicals that are released by one member of a species
      and evoke a specific reaction or reactions from members of the same species.
      Pheromones are known for both the specificity and the potency of their actions,
      which can be behavioral and/or neuroendocrinological. Pheromones can stimulate
      individuals to aggregate, to disperse, or to react defensively in the presence of
      a predator, but they are probably best known for bringing the sexes together.
      Some pheromones have also been found to trigger a dramatic release of pituitary
      hormones in several vertebrate species. Although first identified in insects,
      more recent studies show that sex pheromones influence the lives of a wide range
      of organisms, from microbes to man. The hormonally-derived sex pheromones in
      teleost fish, and the airborne pheromones of moths are two systems that
      illustrate how scientists have used these specialized chemical signals as
      important tools to investigate the morphology, physiology and biochemistry of
      olfactory-receptor systems, the mechanisms of odor-information processing in the
      brain, and the diverse range of behaviors and endocrinological changes associated
      with pheromonal communication. While our focus is on these two animal models,
      other examples, including mammalian pheromone systems, are also discussed.

PMID- 8670703
TI  - Biological responsiveness to pheromones provides fundamental and unique insight
      into olfactory function.
AB  - When exposed to the odor of conspecifics, most organisms exhibit an adaptive
      behavioral response, particularly if the individuals are sexually mature.
      Evidence increasingly suggests that behavioral responsiveness to these odors,
      which are termed 'pheromones', reflects neuroethological mechanisms associated
      with olfactory function. Reproductive pheromones, which are the best understood,
      are commonly used by both invertebrates and vertebrates. In both instances they
      are generally comprised of mixtures of compounds and behavioral responsiveness to
      them is largely instinctual, sexually-dimorphic, and attributable to a
      specialized component(s) of the olfactory system. While pheromonal responsiveness
      in some systems (e.g. moths) appears highly stereotypic and symptomatic of a
      relatively simple 'labeled line', behavioral responsiveness of other animals
      (e.g. rodents) can be modified by experience, suggesting a more complex
      underlying central mechanism. In any case, our understanding of these fascinating
      systems is progressing only because of an active dialogue between behavioral and
      neurological investigations. This review briefly examines how behavioral studies
      have provided fundamental insight into the neuroethology of olfactory function by
      drawing comparisons between some of the better understood sex pheromone systems
      which have been described in heliothine moths, the goldfish, and the pig. Many
      similarities between invertebrate and vertebrate pheromone systems are noted.

PMID- 8670704
TI  - Peripheral mechanisms of pheromone reception in moths.
AB  - Moths pheromones mostly consist of two or a few chemical components in a species
      specific ratio. Each component is perceived by a particular type of receptor
      cell. Some pheromone components can inhibit the behavioral responses to other
      pheromone components. A single pheromone molecule is sufficient to elicit a nerve
      impulse. The dose-response curve of single pheromone receptor neurons increases
      over many decades of stimulus intensity. Pheromone receptor cells can resolve
      single stimulus pulses up to a frequency of 10 pulses/s. Electrophysiological and
      biochemical studies on perireceptor events suggest that the pheromone molecules
      interact with the receptor cell while bound to a reduced form of the pheromone
      binding protein. The enzymatic degradation of pheromone found on the antennae is
      much too slow to account for the decline of the receptor potential after end of
      stimulation. The postulated rapid deactivation of the odor molecules absorbed
      might be performed by an oxidation of the pheromone binding protein. Several
      second messenger systems seem to be involved in the cellular transduction
      mechanism (IP3, diacylglycerol, cGMP, Ca2+). It is, however, not excluded that
      pheromone molecules can gate single ion channels directly and thus elicit the
      elementary receptor potentials, observed at weak stimulus intensities.

PMID- 8670705
TI  - Central mechanisms of pheromone information processing.
AB  - An advantage of using pheromones in olfactory studies is that they are chemical
      signals for which receptor neurons are evolved and thus elicit biologically
      relevant odour-information to be processed in the brain. In many vertebrate and
      insect species, the olfactory system is separated into a 'main' and an
      'accessory' division, the latter mediating pheromone information. In moths, the
      pheromone information is first processed in the brain in a large and sexually
      dimorphic structure, the macroglomerular complex (MGC) of the antennal lobe (AL).
      Also in vertebrates the pheromone information is processed in specific or
      modified glomerular complexes. One principle question is whether individual
      olfactory glomeruli are functional units, processing specific information
      concerning both the chemical quality and spatiotemporal features of the stimulus,
      like the pheromone plume. Indeed it has been shown that the axons of different
      pheromone-selective receptor neurons project into different MGC-glomeruli.
      Intracellular recordings from the AL projection (output) neurons also show that
      information about single components of the pheromone blend is preserved in some
      output pathways, whereas other output neurons respond in a unique fashion to the
      blend. The information about interspecific signals, which interrupts pheromone
      attraction, is processed in a specific MGC-glomerulus and is to a large extent
      kept separate from the pheromone information throughout the AL. Many of the
      output neurons accurately encode changes in the temporal characteristics of the
      stimulus.

PMID- 8670706
TI  - Abstracts of the International Symposium of Gustatory Signal Transduction
      Mechanisms, Nagasaki, 1995

PMID- 8670707
TI  - An empirical test of Olsson's interaction model using mixtures of tastants.
AB  - In 1994, Olsson published a model predicting the intensity and quality of an odor
      mixture percept on the basis of the intensities of the unmixed components.
      Whether this model can also be used for mixtures of dissimilar tasting substances
      was investigated for sucrose/citric acid mixtures. The identification data
      revealed asymmetrical mixture suppression, which does not support the model. The
      intensity responses were in accordance with the definitions employed for level
      independence and hypo-additivity. However, the intensity judgements suggest
      deviations from symmetry and exhibited compromise, which violates two other
      principles. A comparison with previously published data shows that these
      violations probably occur for other mixture types, too. It is concluded that the
      Olsson interaction model cannot describe interactions in mixtures of dissimilar
      tasting components accurately.

PMID- 8670708
TI  - Psychophysical and psychohedonic functions of four common food flavours in
      elderly subjects.
AB  - This study was designed to determine the cause of potential differences in
      optimal preferred flavour concentrations in four common food items between young
      and elderly subjects. The main objective was to investigate whether the
      differences in concentration-pleasantness functions could be attributed to
      differences in concentration-intensity (psychophysical) functions, or to
      differences in intensity-pleasantness (psychohedonic) functions. Groups of
      elderly subjects (n = 31) and young subjects (n = 25) judged four series of food
      items (bouillon, tomato soup, chocolate custard and orange lemonade), each with
      five geometrically spaced flavour concentration levels. In addition, all
      participants judged a series of grey surfaces as a reference series. Stimuli were
      judged on a 10-point scale with respect to perceived intensity and pleasantness.
      The results showed that the responses to the various stimuli in the series of
      grey surfaces were almost equivalent for young and elderly subjects. The older
      subjects had higher optimal flavour concentrations than young subjects for each
      of the four food items. The differences could be attributed to differences in
      both psychophysical and psychohedonic functions for all four flavours. However,
      changes in psychohedonic functions were less pronounced for the savoury flavours
      than for the sweet flavours. The higher optimal preferred flavour concentration
      level for the elderly could be partly explained by the phenomenon that the
      elderly need higher concentration levels than young subjects in order to obtain a
      similar perceived intensity level.

PMID- 8670709
TI  - Atypical olfactory glomeruli subset of the rat: quantitative study and
      organization of the peripheral afferents.
AB  - The atypical glomeruli constitute a particular subset of olfactory glomeruli in
      the rat olfactory bulb which is mainly characterized by a strong centrifugal
      cholinergic innervation. In the present study, the topographical organization of
      the mucoso-bulbar projection of these glomeruli was analysed using small
      injections of WGA-HRP into the anterior nasal cavity of adult rats. The atypical
      olfactory glomeruli were visualized on adjacent bulbar sections using
      acetylcholinesterase histochemistry. A mean of 29 atypical glomeruli per bulb was
      observed in several areas of the posterior half of the olfactory bulb. Following
      the rostro-caudal axis of the olfactory bulb, the first atypical glomeruli were
      located in lateral positions, then in dorsal and ventral ones. The most posterior
      atypical glomeruli were located in the bulbar medial side. Concerning the
      projections from the periphery to the atypical glomeruli, various WGA-HRP
      patterns of labelling were observed. When the surface area of injection sites in
      the anterior part of the olfactory sheet was between 30 and 40 mm2, half of the
      atypical population was labelled with the atypical glomeruli being heavily
      labelled. All sites of distribution previously described were represented. When
      the surface area of injection sites was inferior to 20 mm2, only some positions
      distributed along the bulbar antero-posterior axis were represented. These
      atypical glomeruli were generally partially labelled. Taken together, these
      results suggest that, although atypical glomeruli are restricted in the posterior
      olfactory bulb, they receive peripheral projections diffusely organized along the
      antero-posterior axis of the olfactory mucosa. This profile was compared with
      that of other classical olfactory glomeruli.

PMID- 8670710
TI  - Chemoreceptive control of feeding processes in hydra.
AB  - Cnidarians are the simplest metazoans to exhibit satiety after feeding. When
      hydra are fed to repletion, they close their mouths and cease to capture prey. As
      feeding stops, contractions of the tentacles and body column increase. Our
      earlier experiments showed that a gel chromatographic fraction of prey substances
      inhibits prey capture. We now present evidence that the same fraction reduces the
      duration of mouth opening induced by reduced glutathione (GSH) and inhibits the
      binding of GSH to its putative receptor. The fraction also induces column
      contractions which are similar to those normally seen in sated animals. Prey
      substances, of unfractionated homogenate, also induce post-feeding tentacle
      contractions similar to those seen in sated animals. Gut distention does not
      appear to induce behavior associated with satiety. Therefore, these experiments
      suggest that chemoreception of prey substances induce satiety in hydra.

PMID- 8670711
TI  - Evaluating the 'Labeled Magnitude Scale' for measuring sensations of taste and
      smell.
AB  - The Labeled Magnitude Scale (LMS) is a semantic scale of perceptual intensity
      characterized by a quasi-logarithmic spacing of its verbal labels. The LMS had
      previously been shown to yield psychophysical functions equivalent to magnitude
      estimation (ME) when gustatory, thermal and nociceptive stimuli were presented
      and rated together, and the upper bound of the LMS was defined as the 'strongest
      imaginable oral sensation'. The present study compared the LMS to ME within the
      more limited contexts of taste and smell. In Experiment 1, subjects used both
      methods to rate either taste intensity produced by sucrose and NaC1 or odor
      intensity produced by acetic acid and phenyl ethyl alcohol, with the upper bound
      of the LMS defined as either the 'strongest imaginable taste' or the 'strongest
      imaginable odor'. The LMS produced psychophysical functions equivalent to those
      produced by ME. In, Experiment 2 a new group of subjects used both methods to
      rate the intensity of three different taste qualities, with the upper bound of
      the LMS defined as the 'strongest imaginable [sweetness, saltiness, or
      bitterness]'. In all three cases the LMS produced steeper functions than did ME.
      Experiment 3 tested the hypothesis that the LMS yields data comparable to ME only
      when the perceptual domain under study includes painful sensations. This
      hypothesis was supported when the LMS again produced steeper functions that ME
      after subjects had been explicitly instructed to omit painful sensations (e.g.
      the 'burn' of hot peppers) from the concept of 'strongest imaginable taste'. We
      conclude that the LMS can be used to scale sensations of taste and smell when
      they are broadly defined, but that it should be modified for use in scaling
      specific taste (and probably odor) qualities. The implications of these results
      for theoretical issues related to ME, category-ratio scales and the size of the
      perceptual range in different sensory modalities are discussed.

PMID- 8670712
TI  - GUST27 and closely related G-protein-coupled receptors are localized in taste
      buds together with Gi-protein alpha-subunit.
AB  - Gustatory, like olfactory signalling is probably mediated by seven-transmembrane
      receptors and coupling GTP-binding proteins (G proteins). We investigated the
      expression of a subset of these receptors and the Gi protein alpha-subunit by
      using their specific antibodies. Based on our previous finding that the mRNA for
      GUST27, one of these receptors, is expressed in rat lingual epithelia, we first
      prepared an antibody to the synthetic nonapeptide, H-Ser-Tyr-Ser-Gln-Ile-Ala-Ser
      Ser-Leu-OH, which corresponds to the third intracellular domain of GUST27 and
      also to those of a subset of related receptors whose occurrence can be predicted
      by PCR. Immunohistochemical studies with rat circumvallate papillae indicated
      that the anti-GUST27 antibody reacted with many of the taste buds examined, with
      strong signals appearing in particular taste cells. We then carried out a similar
      immunohistochemical experiment with an antibody to the Gi protein alpha-subunit
      and found that this subunit is also expressed in taste buds as demonstrated in
      the case of gustducin and transducin. Taken together, these results strongly
      suggest that GUST27 and closely related receptors, as well as Gi alpha proteins,
      are involved in intracellular taste signal transduction.

PMID- 8670714
TI  - Introduction: Neurotransmitters and neuromodulators in gustation

PMID- 8670713
TI  - Are the tastes of polycose and monosodium glutamate unique?
AB  - To study whether Polycose and monosodium L-glutamate (L-MSG) have unique tastes
      differing from the traditional four basic tastes, chemosensory profiles were
      established for Polycose, L-MSG and a group of related compounds (sucrose,
      maltose, monosodium D-glutamate (D-MSG), sodium chloride, calcium chloride).
      Flavors were assessed using whole-mouth tests in human subjects with nose open or
      clamped to reduce olfactory input. Polycose (a mixture of glucose-based
      oligosaccharides) had a flavor consisting of an olfactory component and a maltose
      like taste. L-MSG and D-MSG profiles differed from each other, and from NaCl and
      CaCl2. L-MSG had a lower threshold and a higher frequency of 'other' tastes than
      the D form. The data do not support a 'polysaccharide' taste, but suggest a
      chiral receptor site for 'umami' taste.

PMID- 8670715
TI  - Neuromodulation of transduction and signal processing in the end organs of taste.
AB  - Chemical synapses transmit gustatory signals from taste receptor cells to sensory
      afferent axons. Chemical (and electrical) synapses also provide a lateral pathway
      for cells within the taste bud to communicate. Lateral synaptic pathways may
      represent some form of signal processing in the peripheral end organs of taste.
      Efferent synaptic input may also regulate sensory transduction in taste buds. To
      date, the synaptic neurotransmitter(s) or neuromodulator(s) released at chemical
      synapses in taste buds have not been identified unambiguously. This paper
      summarizes the attempts that have been made over the past 40 years to identify
      the neuroactive substances acting at taste bud synapses. We review the four
      traditional criteria for identifying chemical transmitters elsewhere in the
      nervous system-localization, uptake/degradation, release and physiological
      actions- and apply these criteria to neuroactive substances in taste buds. The
      most complete evidence to date implicates serotonin as a neuromodulator of taste
      transduction in the end organs. However, studies also suggest that adrenergic,
      cholinergic and peptidergic neurotransmission may be involved in taste buds.

PMID- 8670716
TI  - Immunohistochemical localization of neuropeptides and neurotransmitters in the
      nucleus solitarius.
AB  - The nucleus tractus solitarii (NTS), which receives visceral afferent information
      from the cardiovascular, respiratory, gastrointestinal and taste systems,
      contains multiple neurotransmitters and neuropeptides throughout its rostral to
      caudal extent. The neurotransmitters and neuropeptides immunoreactivity is
      located predominately in varicose fibers and small puncta throughout the
      neuropil. In addition, immunoreactive NTS neurons for a variety of
      neurotransmitters and neuropeptides are present in subnuclear regions. The
      neuroactive substances localized immunohistochemically in the NTS include
      acetylcholine, the neuropeptides, substance P, methionine- and leucine
      enkephalin, beta-endorphin, cholecystokinin, neurotensin, galanin, calcitonin
      gene-related peptide, somatostatin, FMRMamide, neuropeptide Y, angiotensin II,
      vasoactive intestinal polypeptide, vasopressin, oxytocin, thyrotropin-releasing
      hormone, luteinizing hormone-releasing hormone, atrial natriuretic peptide, the
      catecholamines, dopamine, norepinephrine, epinephrine, serotonin, histamine and
      the amino acids, GABA and glutamate. The pattern of innervation for each
      neurotransmitter and neuropeptide is not homogeneously distributed throughout the
      NTS. Each substance has a unique pattern within the NTS as each subnuclear region
      contains different immunohistochemical staining patterns and densities of fibers.
      At the ultrastructural level both neurotransmitters and neuropeptides are present
      in synaptic terminals that are in contact with different parts of the neuronal
      membranes. Typically, the labeled terminals contain both small, clear vesicles
      and large, dense core vesicles with the exception of synaptic terminals
      containing acetylcholine, GABA and glutamate which do not typically have the
      large, dense core vesicles. The most frequent post-synaptic target are dendrites
      and spinous processes. Less frequently, synaptic contacts are present on the cell
      soma.

PMID- 8670717
TI  - Neurotransmitter and neuromodulator activity in the gustatory zone of the nucleus
      tractus solitarius.
AB  - The rostral nucleus of the solitary tract (rNST) is the first central relay in
      the gustatory pathway. While previous investigations have provided a wealth of
      information on the pattern of central terminations of gustatory afferent fibers,
      the morphology of synaptic connections of rNST neurons and responses of second
      order neurons to taste stimuli applied to the tongue, little is known regarding
      the neurophysiological characteristics of synaptic transmission in rNST. We have
      used an in vitro brain slice preparation of the rNST to study the intrinsic
      biophysical properties, neuropharmacology and synaptic responses of rNST neurons.
      These experiments have revealed that rNST neurons respond to the excitatory amino
      acid neurotransmitter glutamate, as well as the inhibitory amino acid
      neurotransmitter gamma amino butyric acid (GABA). By use of glutamate receptor
      agonists and antagonists we have shown that rNST neurons have AMPA/kainate and
      NMDA ionotropic glutamate receptors, as well as matabotropic glutamate receptors.
      In addition, rNST neurons respond to both GABAA and GABAB receptor agonists. The
      nature of the transmission at the synapse between primary afferent fibers and
      second order neurons in rNST has been examined by electrical stimulation of the
      solitary tract to elicit post-synaptic potentials (PSP). Three types of
      monosynaptic PSP result from stimulation of the solitary tract: excitatory post
      synaptic potentials, inhibitory post-synaptic potentials, and a complex mixture
      of excitatory and inhibitory potentials. These new discoveries provide details
      about synaptic transmission in rNST and thereby clarify the underlying mechanism
      by which gustatory information is processed.

PMID- 8670718
TI  - Sensory afferent neurotransmission in caudal nucleus tractus solitarius--common
      denominators.
AB  - The nucleus of the solitary tract (NTS) receives a wide range of sensory inputs
      including gustatory, gastrointestinal and cardiorespiratory which are loosely
      segregated viscerotopically to subnuclei. Our laboratory has focused on a
      dorsomedial area of caudal NTS (mNTS) which is critical for cardiovascular
      reflexes. Using a brainslice, we study primarily mNTS neurons mono-synaptically
      activated by solitary tract stimulation. mNTS neurons show varying degrees of
      delayed excitation, spike frequency adaptation and after hyperpolarizations.
      Sensory afferent transmission is mediated by glutamate acting at post-synaptic
      non-NMDA receptors. Glutamate release depends on at least four different
      presynaptic calcium channels with N-type predominating. This profile of
      presynaptic calcium channels in NTS is also present at the peripheral soma, but
      absent from the baroreceptor sensory endings. Many peptides are associated with
      these sensory neurons and several modulate glutamatergic transmission in mNTS.
      Angiotensin II facilitates excitatory responses to sensory afferent activation by
      a presynaptic mechanism. Caudal NTS appears to have a framework of synaptic and
      cellular mechanisms in common with other NTS areas and peptides may play a
      critical role modulating this framework.

PMID- 8670719
TI  - Lens epithelial cell mRNA. III. Elevated expression of macrophage migration
      inhibitory factor mRNA in galactose cataracts.
AB  - A lens epithelial (LE) cell cDNA clone, designated Clone 156, was isolated from a
      mature rat LE cDNA library by methods of subtractive hybridization. The cDNA
      sequence of Clone 156 was 521 nucleotides in length, excluding the poly(T)-tail,
      and it encoded an open reading frame of 115 amino acids. The translated protein
      shared extensive sequence similarities with macrophage migration inhibitory
      factor (MIF) from mouse lens and human T-cell lymphocytes. Northern blot
      hybridization showed that rat lens MIF mRNA is about 500 nucleotides in length
      and that its expression in mature rat lens is relatively low in comparison with
      that in other rat tissues. The expression of MIF mRNA in LE of normal rats and of
      rats treated by feeding a diet of 50% (w/w) galactose was studied by quantitative
      RT-PCR. The results showed that the expression of MIF mRNA in a 20-day
      galactosemic rat LE increased twelvefold as compared to that found in control LE.
      From the results of this study and from what we know about the locale of
      epithelial cell differentiation in mature rat lenses, it is being proposed that
      the increase in abundance of MIF mRNA in the cataractous rat lens is correlated
      with the enhanced proliferation of the undifferentiated epithelial cells.

PMID- 8670720
TI  - Hyaluronan and chondroitin sulfate in rabbit tears.
AB  - The concentrations of hyaluronan (HA) and chondroitin sulfate (CS) in rabbit
      tears were determined using high performance liquid chromatography. The tears
      were taken from both normal eyes and eyes with a corneal epithelial defect. The
      concentration of CS was 7.61 times higher than that of HA in the tears of normal
      eyes. When the concentration of CS isomers was compared, the highest
      concentration was observed in chondroitin 6-sulfate (C6S), followed by
      chondroitin 4-sulfate (C4S) and chondroitin (C0S), in that order. When the
      corneal epithelium was removed from the left eye using a trephine and
      microscissors, a significant increase was detected in the concentrations of HA
      and C6S in tears of the left eye one day after removal, whereas no change was
      observed in those of the right eye. In addition, a significant positive
      correlation was observed between the increased amount of HA concentration and the
      healing rate of the corneal epithelium. These results suggest that the increase
      of HA concentration in tears is associated with spontaneous corneal epithelial
      healing.

PMID- 8670721
TI  - Natriuretic peptide receptors on human trabecular meshwork cells.
AB  - The effects of natriuretic peptides on cGMP formation and [125I]ANP binding in
      human trabecular meshwork cells were investigated. CNP at 1 microM stimulated
      cGMP formation approximately 18-25 fold, with a half maximal effective
      concentration approximately 20-30nM. BNP at 1 microM stimulated approximately 7
      fold, while ANP stimulated cGMP formation 2-fold at 1 microM but had little or no
      effect at concentrations below 1 microM. Displacement binding of [125I]ANP to
      intact TM cells in the presence of unlabeled ANP indicated a single binding site
      with a dissociation constant approximately 0.15nM.c-ANP, which binds specifically
      to natriuretic peptide C receptors, displaced > 95% [125I]ANP binding to surface
      receptor sites with a half-maximal effective concentration comparable to that of
      ANP or BNP. c-ANP had no inhibitory effect on CNP stimulation of cGMP formation.
      The data suggest that human TM cells possess natriuretic peptide B receptors as
      the primary guanylyl cyclase-containing subtype and C receptors as the
      numerically predominant subtype of natriuretic peptide receptors.

PMID- 8670722
TI  - Correlation between the progression of optic disc and visual field changes in
      glaucoma.
AB  - Visual field test and optic disc evaluation are the standard examination
      techniques used to detect the onset and progression of glaucoma. This explorative
      study was performed to assess the temporal correlation between visual field and
      optic disc changes in eyes with ocular hypertension and well-established
      glaucoma. Eighty-six hypertensive and 16 glaucomatous eyes were followed up for a
      period of up to 9 years (average 4.4 yrs) using kinetic and computerized static
      perimetry and optic disc manual morphometry. Perimetric changes were based on a
      series of strict criteria and optic disc changes were based as a reduction in the
      baseline rim area/disc area ratio (R/D) measurement exceeding the 99% confidence
      interval for intraobserver reproducibility (7.7%). Optic disc changes were found
      prior to visual field changes in four hypertensive eyes, whereas visual field
      changes were found prior to disc changes in six glaucomatous eyes (p = 0.042).
      The results of our explorative study suggest that quantitative optic disc
      analysis may be more sensitive than visual field examination in detecting early
      glaucomatous changes, whereas visual field examination may be more sensitive than
      quantitative optic disc analysis in detecting glaucomatous progressions in eyes
      with well established glaucoma.

PMID- 8670723
TI  - Binding of Acanthamoeba to hydrogel contact lenses.
AB  - The numbers of Acanthamoeba binding to new hydrogel contact lenses of different
      polymer and water content were determined with two quantitative methods, a
      radiolabeled-cell method and a detaching-fluid method. Numbers of amoebae
      retained on nonionic lenses increased with increasing water content of the
      lenses. With both nonionic and ionic lenses numbers of associated amoebae
      decreased with successive rinsing steps. The retentions of amoebae on unworn
      hydrogel lenses, in contrast to the irreversible adhesion of bacteria, were
      tenuous and appeared to be effected mainly by surface tension, surface charge and
      water content.

PMID- 8670724
TI  - Protein phosphorylation in Golgi, endosomal, and endoplasmic reticulum membrane
      fractions of lacrimal gland.
AB  - Ca2+/calmodulin- and cAMP-dependent protein kinase activities were characterized
      in two subcellular membrane samples. Membranes from rat lacrimal gland were
      isolated by differential and density gradient centrifugation into six density
      windows. The present study focused on membranes from density windows III and V
      which contain mixtures of apical, Golgi, endosomal, and endoplasmic reticulum
      membranes in different proportions. Phosphorylation of membrane proteins was
      measured by incubating the samples in [g-32P]ATP and separating the proteins by
      discontinuous SDS-PAGE followed by autoradiography. The amount of phosphate
      incorporated into specific peptide bands was quantified by densitometry.
      Ca2+/calmodulin-dependent protein kinase phosphorylated a 52,000 MW peptide in
      membranes from both density windows with a maximal increase from 0.3 to 66 microM
      free Ca2+. Trifluoperazine and promethazine, two inhibitors of Ca2+/calmodulin
      dependent protein kinases, inhibited this phosphorylation. cAMP-dependent protein
      kinase phosphorylated a 22,000 MW peptide and a 91,000 MW peptide which were
      present in membranes from density window III only. We conclude that a
      Ca2+/calmodulin-dependent protein kinase activity is present in membranes from
      both density window III and V whereas a cAMP-dependent protein kinase activity is
      present only in membranes from density window III.

PMID- 8670725
TI  - Confocal imaging of the keratocyte network in porcine cornea using the fixable
      vital dye 5-chloromethylfluorescein diacetate.
AB  - This study reports on the combined use of an aldehyde fixable, cell viability
      fluoroprobe, 5-chloromethylfluorescein diacetate (CMFDA), confocal laser scanning
      microscopy and digital image reconstruction, to produce high resolution images of
      corneal keratocyte preparations in situ. The central region of freshly enucleated
      porcine corneae were removed and stained overnight at 4 degrees C with CMFDA. The
      tissue was washed, fixed, and frozen for cryosectioning in either a horizontal or
      antero-posterior orientation. Sections from anterior, central and posterior
      stroma were examined with a confocal microscope, and the digital images rendered
      as three-dimensional stereo reconstructions. Fluorescent CMFDA which completely
      permeated the cell bodies and extremes of the finest ramifying cell processes of
      all keratocytes provided exceptional high resolution images of the three
      morphologically distinct cell subpopulations at different levels of the stroma,
      and enabled improved characterisation of each cell type. Anteriorly was a thin,
      dense, non-lamellar network of keratocytes subjacent Bowman's membrane. In the
      central stroma, keratocytes were arranged in layers, the cell bodies had a
      flattened pyramidal or stellate shape, and the fine cell processes formed
      extensive distal ramifications. Immediately anterior to Descemet's membrane a
      small subpopulation of keratocytes with large cell bodies and short branched
      processes was identified. Extensive and diverse cell-to-cell contacts were
      orientated in all stromal planes, including ramping cell bridges between
      keratocyte lamellae in the central stroma. The use of the cell viability dye
      CMFDA is feasible and valuable for enhancing the visibility of entire keratocyte
      population in the intact cornea. Diverse multi-directional cell processes and
      intercellular contacts throughout the keratocyte network suggest a strong
      capacity for direct communication and cohesion in the maintenance and repair of
      the stromal matrix. Keratocytes closely related to the epithelium and endothelium
      have unique morphologies which may relate to specialised functions of these
      interface cells.

PMID- 8670726
TI  - Retinal vascular endothelial growth factor (VEGF) mRNA expression is altered in
      relation to neovascularization in oxygen induced retinopathy.
AB  - The temporal and spatial expression of vascular endothelial cell growth factor
      (VEGF) mRNA was studied in normal developing cat retina, and in oxygen induced
      retinopathy. Unexposed control and oxygen-exposed animals (80 h of 80% oxygen
      from day 3, n = 16) were studied at 1, 2, 4, and 6 weeks after birth. India ink
      injected retinal flat mounts were used to study vessel progression, and in situ
      hybridizations using retinal cross sections were used to assess VEGF mRNA
      accumulation. In controls, as the retina matured, VEGF mRNA hybridization was
      evident in the ganglion cell layer in a scattered line of distinct cells prior to
      the ingrowth of vessels, involved the most cells in regions just peripheral to
      invading vessels and persisted in a fewer positive cells, widely spaced in the
      vascularized retinas of control, six week animals. In the inner nuclear layer,
      hybridization initially appeared diffusely and later became localized to a narrow
      portion of that layer and persisted there. In animals with oxygen induced
      retinopathy, a substantial increase in hybridization was observed in both the
      ganglion cell and inner nuclear layers of the avascular retina anterior to the
      advancing neovascularization. VEGF hybridization decreased abruptly to background
      levels in both layers at the point were neovascularization met avascular retina.
      By six weeks, when the neovascularization reached the ora, there was a return of
      VEGF mRNA in the inner nuclear layer which was similar to normal control
      expression. A low level of unchanging expression was also observed in the retinal
      pigment epithelium in both groups at all ages. These results indicate that VEGF
      mRNA abundance is regulated during retinal vascularization and is increased in
      relation to oxygen induced neovascularization, suggesting that VEGF may play an
      important role in both normal retinal vessel development and in the
      pathophysiology of retinopathy of prematurity.

PMID- 8670727
TI  - Circadian rhythm of intraocular pressure in the rat.
AB  - To define the characteristics of the diurnal variation of intraocular pressure
      (IOP) in eyes of awake rats, ten male brown Norway rats were entrained to a 12
      hour light:12-hour dark (12L:12D) lighting schedule and were conditioned to IOP
      measurement with the TonoPen XL tonometer while awake, using only 0.5%
      proparacaine HCl anesthesia. The IOP measurements were performed in 4
      experiments: Preliminary-IOP was measured at 6-hour intervals in both eyes of
      each animal, to determine correlation between right and left eyes; Light:Dark
      lighting remained the same as in the preliminary experiment, but the measurement
      schedule was altered so that measurements were obtained at 4-hour intervals in
      alternating eyes, over two 24-hour light cycles; Dark:Dark-animals were placed in
      constant dark (0L:24D) and, after 72 h, measurements were obtained at 4-hour
      intervals in alternating eyes. Animals were then re-entrained to the previous
      12L:12D schedule for 7 days, after which they were returned to constant dark and
      the experiment was repeated; and Dark:Light-animals were entrained to a reversed
      light:dark cycle (12D:12L) for 28 days, after which measurements were obtained in
      the same fashion as in the Light:Dark experiment. Close agreement was found
      between right- and left-eye IOPs. Animals on a 12L:12D schedule exhibited lowest
      IOP while the lights were on (19.3 +/- 1.9 mm Hg), and highest (31.3 +/- 1.3 mm
      Hg) while the lights were off. Pressure changes anticipated the change from light
      to dark and dark to light. This pattern persisted in constant dark, and was
      reversed when the cycle was changed to 12D:12L. Brown Norway rats possess a
      regular rhythm of IOP that is entrained by the cycle of light and dark, and
      persistence of this rhythm in constant dark establishes it as a circadian rhythm.
      Furthermore, our results indicate that reliable and physiologically meaningful
      IOP measurements can be obtained in awake rats using the TonoPen XL tonometer.

PMID- 8670728
TI  - Cell-attached patch clamping of the intact rabbit ciliary epithelium.
AB  - Following thorough removal of adhering aqueous humor, we have succeeded in patch
      clamping the intact rabbit ciliary epithelium in the cell-attached and inside-out
      excised-patch modes. Rapidly fluctuating currents ("chatter activity') were
      observed during recordings conducted for as long as 1 h. Chatter activity did not
      reflect seal instability since interconversion was noted between chatter activity
      and transitions between stable open and closed states, excision of patches into
      the bath was associated with substantial shifts in the reversal potential, and
      chatter activity could be triggered by sustained hyperpolarization, but was
      insensitive to stretch. The chatter channel was identified as cation-nonselective
      from the reversal potentials both in the cell-attached and excised-patch modes.
      The channel's kinetics were similar to those of the cGMP-activated
      phototransduction channel. The results of PCR amplifications of fragments in cDNA
      libraries from both human ciliary body and human nonpigmented ciliary epithelial
      (NPE) cells indicated that human ciliary epithelial cells transcribe message for
      the retinal phototransduction channel. The possible role of the phototransduction
      channel in expressing chatter activity was further explored by perfusing
      preparations with a known activator of that channel (cGMP) and with a known
      inhibitor (L-cis-diltiazem). Neither agent significantly affected chatter
      behavior. We conclude that: (1) this is the first demonstration of the
      feasibility of patch-clamping the intact ciliary epithelium; (2) the NPE cells
      display chatter activity arising from rapidly fluctuating transitions of a cation
      nonselective channel; (3) NPE cells can transcribe message for the cation
      nonselective phototransduction channel; and (4) if the observed chatter activity
      is from a homologue of the photo-transduction channel, the homologue is
      pharmacologically distinct.

PMID- 8670729
TI  - Ocular surface upregulation of intercellular adhesive molecule-1 (ICAM-1) by
      local interferon-gamma (IFN-gamma) in the rat.
AB  - Inflammatory mediators such as interferon-gamma (IFN-gamma) are known to induce
      the expression of class II HLA (HLA-DR) and intercellular adhesion molecule 1
      (ICAM-1) in a variety of cell types including epithelial cells. The coexpression
      of ICAM-1 and HLA-DR has been implicated in the pathogenesis of immune mediated
      ocular disease. We investigated the expression of ICAM-1 on the ocular surface of
      the rat eye following subconjunctival administration of IFN-gamma. A dose
      response study was performed using 100, 1,000 and 10,000 IU IFN-gamma/dose. The
      presence of ICAM-1 was determined using a standard immuno-peroxidase staining
      technique. The cornea, limbus, and conjunctiva were evaluated. The degree of
      reaction product in each area was graded by a masked observer. We found
      constitutive expression of ICAM-1 on the conjunctiva but not on the cornea. There
      was a significant relationship between the dose of IFN-gamma and the intensity of
      ICAM-1 staining on the conjunctiva (p < or = 0.05) and on the limbus (p < or =
      0.04). Subconjunctival IFN-gamma had no effect on the expression of ICAM-1 in the
      cornea.

PMID- 8670730
TI  - Measurement of interleukin-4 and histamine in superficial cells of conjunctiva in
      patients with allergic conjunctivitis.
AB  - Interleukin 4 (IL-4) may play a role in the development of allergic disease. We
      questioned whether IL-4 related phenomenon occurred on the surface of the
      conjunctiva during allergic conjunctivitis. Ten patients with cedar pollen
      allergic conjunctivitis and 10 patients with postsurgical conjunctivitis were
      enrolled in this study. Cells were collected by brush cytology from the upper
      palpebral conjunctiva. After the cells were cultured for 24 hours, the levels of
      IL-4, IgE, and histamine were measured in the supernatants. An ELISA was used for
      histamine and a highly sensitive sandwich ELISA for IL-4 and IgE. Conjunctival
      cells were also stained and fixed by May-Grunwalds stain solution. The number of
      superficial cells, especially lymphocytes, were compared in the two groups. The
      total number of cells collected by brush cytology did not differ in allergic vs.,
      postsurgical conjunctivitis. Lymphocytes were similarly present in such
      specimens. The levels of IL-4 (p = 0.01) and histamine (p = 0.02) significantly
      increased in the specimens from patients with allergic conjunctivitis, although
      IgE was not detected in both groups. There was a correlation between the level of
      IL-4 and histamine (p = 0.0001). Conjunctival cells in allergic conjunctivitis
      produced a larger amount of IL-4 and histamine for cedar pollen compared to the
      postsurgical conjunctivitis. As with other allergic diseases, IL-4 may play a
      role similar to that of histamine in the development of allergic conjunctivitis.

PMID- 8670731
TI  - A sheet-like form of alpha-crystallin.
AB  - Complexes containing alpha-crystallin were isolated from crosslinked lens extract
      using an affinity column constructed with monoclonal antibodies specific for
      alpha-crystallin. The affinity-purified protein was compared with alpha
      crystallins before and after crosslinking. Electron microscopy revealed sheet
      like structures in the cross-linked protein from the lens extract compared with
      spherical structures for the others. Studies on the amino acid composition,
      tryptophan microenvironments and the interaction with a monoclonal antibody
      revealed that the complexes consist almost entirely of alpha-crystallin. These
      results indicate that under certain conditions, alpha-crystallin subunits can
      adopt a sheet-like form.

PMID- 8670732
TI  - Evaluation of retinal susceptibility to light damage in pigmented rats
      supplemented with beta-carotene.
AB  - The present study evaluated the influence of beta-carotene supplementation on the
      susceptibility of the retina to light damage. Long-Evans pigmented rats were
      supplemented with beta-carotene by either dietary or intraperitoneal
      administration, and beta-carotene levels in plasma, liver and retina were
      determined by high performance liquid chromatography. Other animals from each
      group were exposed to ultraviolet-A light at a dose of 8.1 J/cm2 in their right
      eye only, and photoreceptor cell losses determined by light microscopic
      morphometry. In supplemented animals, beta-carotene levels increased markedly in
      the liver, and were elevated from non-detectable to detectable in the plasma and
      retina, relative to nonsupplemented controls. In each tissue, beta-carotene
      levels were found to be higher in animals receiving intraperitoneal
      supplementation as compared to dietary. Beta-carotene supplementation by either
      route did not protect the retina against photoreceptor cell loss measured at two
      weeks following UVA exposure. Preliminary observations indicated that beta
      carotene supplementation decreased the incidence of light-induced retinal pigment
      epithelium destruction.

PMID- 8670733
TI  - Effects of polyhexamethylene biguanide and chlorhexidine on four species of
      Acanthamoeba in vitro.
AB  - We determined the relative minimal inhibitory and minimal amoebicidal
      concentrations of chlorhexidine digluconate and polyhexamethylene biguanide for
      four species of Acanthamoeba. The amoebae were grown in peptone-glucose-yeast
      extract broth for 72 h in tissue culture flasks. Either washed trophozoites
      (approximately 10(5)) or cysts (approximately 10(5)) were incubated in the
      enrichment broth in 96 well microtiter trays. Antimicrobial concentrations of the
      biguanides were determined from microscopic examinations of methylene blue uptake
      and from subcultures. In general, killing was time dependent. Minimal amoebicidal
      concentrations at 24 h ranged from 50 to 100 mg/ml and to as low as 25 mg/ml by
      72 h. Trophozoites were killed more rapidly than cysts. Both biguanides had
      similar levels of activity. A synergistic combination of chlorhexidine and
      polyhexamethylene biguanide (total concentration 25 mg/ml) was most evident for
      A. castellanii and A. polyphaga. Cysts of A. culbertsoni and A. hatchetti stained
      more rapidly after exposure to the combination of biguanides than to the single
      biguanides, but there were no statistically significant differences in the final
      numbers of dead or stained cysts after exposure to the combination or to the
      single biguanides.

PMID- 8670734
TI  - Arf 193nm excimer laser corneal surgery and photo-oxidation stress in aqueous
      humor and lens of rabbit: one-month follow-up.
AB  - Twenty male albino rabbits were studied. Four animals served as controls; the
      remaining 16 animals represented the treated group. All the treated animals were
      exposed to the same amount of energy delivered by the excimer laser (pulse rate:
      20 Hz, fluence 250mJ/cm2; number of pulses: 6032; cumulative UV dose 1508 J/cm2)
      and were divided into eight groups of 2 animals each (four eyes). Samples of
      aqueous humor and lens were obtained at the following intervals: 5, 10, 20 and 40
      min and 1, 2, 3 and 4 weeks after photorefractive keratectomy (PRK). The levels
      of reduced and oxidized glutathione, hydrogen peroxide, ascorbic acid and
      malondialdehyde were determined. Aqueous humor analyses, twenty min after PRK,
      showed no significant differences with pre-treatment values, while the observed
      variations in lens were constantly present over the entire follow-up period (one
      month). These findings suggest that the biochemical lens alterations induced by
      PRK may represent the earliest events relevant to cataractogenesis in the rabbit.

PMID- 8670736
TI  - Meibomian gland phospholipids.
AB  - The content of the meibomian gland lipid exprimate is known, but little is known
      about the phospholipids that comprise the glandular cells. The purpose of the
      present study is to identify and quantitate the phospholipid complement of the
      meibomian gland cells that produce the lipid secretion of meibomian oil and which
      is vital to tear film stability. Eyelids (n = 50) were excised from rabbits, and
      after surgical removal of surrounding tissues, the tarsal plates with and without
      expressing meibomian oil were extracted and phospholipids of the plates
      quantified by 31P nuclear magnetic resonance (NMR). Seventeen phospholipids were
      quantified from tarsal plates expressed of oil and tarsal plates containing
      meibomian oil: alkylacylphosphatidylcholine (AAPC), dihydrosphingomyelin (DHSM),
      dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin),
      ethanolamine plasmalogen (EPLAS), lysoethanolamine plasmalogen,
      lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine,
      phosphatidic acid, phosphatidylcholine (PC), phosphatidylethanolamine (PE),
      phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sphingomyelin
      (SM), sphingosylphosphorylcholine. The six zwitterionic and neutral
      phospholipids, DHSM, EPLAS, PE, SM, AAPC, and PC together comprise 79.5% of the
      total meibomian gland phospholipid profile (in meibomian oil this value is
      84.2%). The zwitterionic and neutral phospholipids dominate meibomian gland
      phospholipid profiles. Since the meibomian gland cells undergo holocrine
      secretion and form the meibomian glad secretion, such a composition is consistent
      with the hypothesis that a chemically stable lamellar surfactant layer
      phospholipids bind non-polar meibomian oil to the aqueous layer of the tear film.

PMID- 8670735
TI  - Peptide hydrolysis in lens: role of leucine aminopeptidase, aminopeptidase III,
      prolyloligopeptidase and acylpeptidehydrolase.
AB  - The distribution of leucine aminopeptidase, aminopeptidase III,
      prolyloligopeptidase and acylpeptidehydrolase activities in different regions of
      a bovine lens was determined and correlated with the distribution of crystallin
      fragments (measured as < 18 kDa protein) and water-insoluble proteins in the same
      lens. A gradient of activity was observed for all the peptidases tested, with the
      highest specific activity present in the cortical fibers which decreased to one
      half or below in the inner cortical fibers and nucleus. An inverse correlation
      between peptidase activities and the amount of crystallin fragments was observed
      in different regions of the lens. However, a direct correlation between the water
      insoluble protein content and the crystallin fragments was observed in all fibers
      of the same lens. The amount of crystallin fragments and the amount of water
      insoluble proteins increased from 2.7% and 8% in the outer cortical fibers to 13%
      and 68% in the nucleus of the same lens. The water-insoluble fraction from both
      cortical and nuclear fibers however displayed 4-5 fold more crystallin fragments
      compared to that present in the water-soluble fraction of the same preparation.
      When the bovine lens cortical and nuclear extracts were tested for their ability
      to hydrolyze the peptide substrate, Ile-Ser-bradykinin, the cortical extract was
      found to be at least ten times superior to the nuclear extract. Prior
      inactivation of prolyloligopeptidase and other serine proteases by
      diisopropylfluorophosphate however diminished the ability of the cortical extract
      to hydrolyze peptide substrates. Bovine lens cortical extract was able to
      completely hydrolyze alpha-melanocyte stimulating hormone as well as N-Acetyl-Met
      Asp-Arg-Val-Leu-Ser-Arg-Tyr showing the presence of active acylpeptidehydrolase
      facilitating the complete hydrolysis of N-terminally blocked peptides. The human
      lens extract was found to contain both diisopropylfluorophosphate sensitive and
      resistant enzymes capable of hydrolyzing peptide substrates.

PMID- 8670737
TI  - cDNA cloning of an abundant human lacrimal gland mRNA encoding a novel tear
      protein.
AB  - An abundant 1.05 kb human lacrimal gland mRNA has been characterized by cDNA
      cloning. It encodes a predicted 180 residue, 20546 Da secreted protein, with a
      charge of +11 at ph 7 and 24.5% proline, designated as Basic Proline-rich
      Lacrimal Protein (BPLP), Southern blot analysis is consistent with a single BPLP
      gene. BPLP lacks any distinct repetitive structure, and is unrelated to the
      salivary proline-rich protein super-family. The pre-proprotein shows modest
      overall similarity to a superfamily comprising human PRPb, the mouse MSG
      proteins, and rat VCS-alpha 1, VCS-beta 1 and submandibular apomucin. BPLP also
      contains a domain with similarity to the Zp2 protein domain found in several
      otherwise unrelated proteins. Northern blot analysis indicated that the BPLP gene
      is also expressed at modest levels in the human submandibular gland, and in situ
      hybridization demonstrated expression of BPLP in the secretory endpieces of the
      human lacrimal gland. The BPLP cDNA clone defines a new human tear protein, and
      should provide a useful phenotypic marker of differentiation in in vitro studies
      of lacrimal gland function.

PMID- 8670738
TI  - Effect of dipyridamole on vascular responses of porcine ciliary arteries.
AB  - This study investigated the effects of dipyridamole in isolated porcine ciliary
      arteries (diameter 200-250 microns). Isolated porcine ciliary arteries were
      suspended in myograph chambers filled with modified Krebs-Ringer solution (37
      degrees C; 95% O2/5% CO2) for isometric tension recording. Dipyridamole induced
      concentration-dependent relaxations of porcine ciliary arteries with endothelium
      precontracted with thromboxane analogue U-46619 (10(-6)M), KCl (50 mM), or
      endothelin-1 (10(-8)M). Removal of the endothelium of the ciliary vessels and
      preincubation of the arteries with L-NAME (10(-5)M), or indomethacin (10(-5)M),
      or the combination of the two drugs significantly reduced the relaxation to
      dipyridamole (p = 0.002-0.03). Similar vascular responses could be observed in a
      time-dependent analysis of the effect of a single concentration dipyridamole (10(
      4)M). The stimulator of cAMP forskolin also caused relaxations. Endothelin-1 (10(
      12)-10(-7)M) and U-46619 (10(-10)-10(-6)M) induced potent contractions of porcine
      ciliary arteries. Preincubation with dipyridamole (10(-5)M) reduced contractions
      to endothelin-1 as compared to control (p < 0.004), while contractions to U-46619
      were only slightly affected under these conditions (n.s.). These findings
      demonstrate that dipyridamole is a vasodilator in porcine ciliary arteries.
      Endothelial nitric oxide and prostacyclin contribute importantly to the effects
      of dipyridamole. Further studies are required to show whether these properties of
      dipyridamole may also occur in vivo and offer clinical use in patients with
      ocular vasospasms and other ophthalmic vascular dysfunctions.

PMID- 8670739
TI  - An experimental model for the evaluation of lipid peroxidation in lens membranes.
AB  - Lipid peroxidation has been associated with a number of specific manifestations
      related both to lens aging and cataract development. The assessment of the effect
      of various naturally occurring prooxidants as well as the development of
      antioxidant strategies has often been limited by the lack of appropriate and
      simple experimental models. In this study we discuss the adaptation of a method
      based on the incorporation of a fluorescent probe (parinaric acid) into
      biological membranes to monitor early stages of lipid peroxidation. After
      establishing the appropriate conditions, the method can be successfully applied
      to study peroxidation in bovine lens membranes, allowing for the evaluation of
      the effect of several free radical generating systems, including the following
      metal-dependent initiators: ascorbate/ iron, hydrogen peroxide/copper and cumene
      hydroperoxide/ copper. The inhibitory effect of the chelating agent diethylene
      triaminepenta-acetic acid and the competitive hydroxyl radical scavenger
      sorbitol, was consistently observed on parinaric acid degradation, on hydroxyl
      radical yield and on the amount of thiobarbituric acid reactive material
      produced. It could be shown that oxidative degradation of the probe gives direct
      information on lens membrane susceptibility to a specific peroxidation system.
      Parinaric acid can therefore be used as an efficient oxidation probe to evaluate
      oxidative damage inflicted to lens membranes by different systems, allowing also
      the evaluation of the antioxidant effect of various drugs including those with
      potential anticataractogenic effect.

PMID- 8670740
TI  - The effect of postnatal growth retardation on abnormal neovascularization in the
      oxygen exposed neonatal rat.
AB  - Severe retinopathy of prematurity (ROP) occurs in the smallest and sickest of
      premature infants. We hypothesized that, in a rat model of oxygen induced
      retinopathy, abnormal neovascularization would occur more frequently in larger
      litters where the pups are subject to postnatal growth retardation. Four litters
      of newborn Sprague-Dawley rats were studied; rats were randomly mixed to form two
      large litters (n = 25 each) and two small litters (n = 10 each). All litters were
      exposed to 7 days cyclic hyperoxia and hypoxia followed by 5 days in room air.
      ADPase stained retinae were evaluated in a masked manner for the presence and
      severity of abnormal neovascularization. Fluorescein perfused retinae were
      digitized and the ratios of vascularized:total retinal area were calculated using
      computer assisted image analysis. As expected, final weight in the large litters
      was less than in the small litters (15.3 +/- 3.8g vs. 23.4 +/- 2.1g, p < 0.001).
      Neovascularization occurred in 53% of rats in the large litters vs. 15% in the
      small litters (p = 0.009). Rats with retinae demonstrating neovascularization
      were smaller than those without (16.2 +/- 4.7g vs. 19.6 +/- 5.0g, p = 0.016). The
      severity of neovascularization in clock h was inversely correlated with final
      weight (rs = -0.35, p = 0.01) and ratio of vascularized:total retina area (rs = 
      0.46, p < 0.001). Smaller rat pups raised in larger litters, with resultant
      growth retardation, develop more frequent and more severe abnormal retinal
      neovascularization. Our results correlate with clinical experience in the
      premature infant.

PMID- 8670741
TI  - Measurement of transmission of ultraviolet and visible light in the living rabbit
      cornea.
AB  - Corneal transmittance in pigmented rabbits was measured at ultraviolet and
      visible wavelengths from the ratio of fluorescence of dyes in the anterior
      chamber to fluorescence of the same dyes in a quartz cuvette. Aqueous humor was
      drained through a limbal incision and the anterior chamber was reformed with a
      mixture of a viscoelastic material and a fluorophore (fluorescein, O-methyl
      pyranine, or sulforhodamine B). Excitation spectra, emission spectra, or both
      were measured in the anterior chamber with a new scanning ocular
      fluorophotometer, at wavelengths between 250 nm and 700 nm. Fluorescence spectra
      were also measured from the same fluorophore in a quartz cuvette. External
      transmittance of the cornea was calculated at each wavelength from the ratio of
      fluorescence in the anterior chamber to fluorescence in the cuvette.
      Transmittance was 93% +/- 1.4% (mean +/- SD, n = 8 rabbits) at 500 nm and was 89%
      to 93% between 370 nm and 500 nm. Transmittance decreased to 82% +/- 5.7% at 350
      nm, to 50% +/- 5.9% at 310 nm, and to less than 2% at 290 nm. Between 370 nm and
      500 nm, the wavelength range most frequently used in fluorophotometry, average
      transmittance varied by less than 5%. These results suggest that fluorescence
      measured at two or more wavelengths within this spectrum needs little if any
      correction for differential attenuation by the cornea. At wavelengths shorter
      than 370nm, measurements should be corrected. This technique provides a simple
      and minimally invasive means of studying visible and ultraviolet transparency of
      the cornea in the living eye.

PMID- 8670742
TI  - Inhibition of naphthalene cataract in rats by aldose reductase inhibitors.
AB  - Naphthalene-induced cataract in rat lenses can be completely prevented by
      AL01576, an aldose reductase inhibitor (ARI). In an attempt to understand the
      mechanism of this inhibition, several ARIs were examined to compare their
      efficacies in preventing naphthalene cataract, using both in vitro and in vivo
      models. Two classes of ARIs were tested: One group including AL01576, AL04114 (a
      AL01576 analog) and Sorbinil contained the spirohydantoin group, while Tolrestat
      contained a carboxylic acid group. Furthermore, to clarify if aldose reductase
      played a role in naphthalene-induced cataractogenesis in addition to its role in
      sugar cataract formation, a new dual cataract model was established for ARI
      evaluations. This was achieved by feeding rats simultaneously with high galactose
      and naphthalene or incubating rat lenses in culture media containing high
      galactose and naphthalene dihydrodiol. Under these conditions, both cortical
      cataract and perinuclear cataract developed in the same lens. It was found that
      at the same dosage of 10 mg/kg/day, both AL01576 and AL04114 completely prevented
      all morphological and biochemical changes in the lenses of naphthalene-fed rats.
      Sorbinil was less efficacious, while Tolrestat was inactive. AL01576 showed a
      dose-response effect in preventing naphthalene cataract and at 10 mg/kg/day, it
      was also effective as an intervention agent after cataractogenesis had begun.
      With the dual cataract model, Tolrestat prevented the high galactose-induced
      cortical cataract but showed no protection against the naphthalene-induced
      perinuclear cataract. AL01576, on the other hand, prevented both cataract
      formations. Results for dulcitol and glutathione levels were in good agreement
      with the morphological findings. AL04114, and ARI as potent as AL01576 but
      without its property for cytochrome P-450 inhibition, displayed similar efficacy
      in preventing naphthalene cataract. Based on these results, it was concluded that
      the prevention of the naphthalene cataract probably results from inhibition of
      the conversion of naphthalene dihydrodiol to 1,2-dihydroxynaphthalene and that
      the effect of the ARIs cannot be explained by their inhibition of the dihydrodiol
      dehydrogenase activity of aldose reductase.

PMID- 8670743
TI  - Age-related changes of glycosidases in human retinal pigment epithelium.
AB  - This study was undertaken to determine whether there are age-related changes in
      the specific activities of several glycosidases in fresh retinal pigment
      epithelial cells (RPE) isolated from the posterior pole of human donor eyes. One
      hundred and twenty-one pairs of eyes from human donors, between the ages of 43
      and 95 years, were obtained from the National Disease Research Interchange (NDRI,
      Philadelphia, PA) and the Cleveland Ohio Eye Bank within 18 to 24 h of death.
      None had histories of diabetes, hepatitis, HIV infection, intraocular surgery, or
      documented age-related macular degeneration, although several older donors with
      evidence of drusen were included in the study. RPE cells were isolated from the
      posterior third of the retina using the conventional rush method and homogenized
      with a glass, Broeck tissue grinder. All post-nuclear supernatants were analyzed
      for glycosidase activity; a smaller number of nuclear pellets were assayed to
      verify that the majority of the enzyme activity was associated with the post
      nuclear sypernatants. Glycosidase activity was quantitated fluorometrically by
      measuring the enzymatic release of umbelliferone from synthetic substrate
      preparations, specific for each enzyme. Total protein was determined by a micro
      BCA protein assay. Regression analysis revealed statistically significant age
      related decreases for the specific activities of alpha-mannosidase (p = 0.0001),
      beta-galactosidase (p = 0.0001), N-acetyl-beta-glucosaminidase (p = 0.0001), and
      N-acetyl beta galactosaminidase (p = 0.0001) in fresh human donor RPE cells taken
      from the region of the posterior third of the retina that included the macula.
      Mannose and N-acetyl-glucosamine are major carbohydrate monomers of the
      oligosaccaride chains of human rhodopsin, and a relatively high percentage of the
      oligosaccharide chains are galactosylated. Defects in their degradation may lead
      to the accumulation of undigested residual material in the RPE.

PMID- 8670744
TI  - Cleavage of structural components of mammalian vitreous by endogenous matrix
      metalloproteinase-2
AB  - Our goal was to determine if the major endogenous vitreous matrix
      metalloproteinase (MMP-2) could digest known collagenous components of the
      vitreous body. Matrix metalloproteinase-2 and its associated inhibitors were
      isolated from porcine vitreous by affinity column chromatography. The inhibitors
      were inactivated by chemical modification with dithiothreitol and iodoacetamide.
      The latent MMP-2 was then activated with the organo-mercurial, p-aminophenyl
      mercuric acetate (APMA). Bovine vitreous fibrillar collagens (types II, V/XI and
      IX) were isolated by pepsin extraction and differential salt precipitation.
      Intact type IX collagen was purified by selective salt precipitation followed by
      ion exchange and size exclusion chromatography. These isolated collagens were
      incubated for 6 to 24 h with different concentrations of activated MMP-2, and the
      extent of collagen degradation was analyzed. Activated MMP-2 was also introduced
      into freshly isolated vitreous gels and the degree of liquefaction was
      determined. Our results showed that the activated MMP-2 has no apparent effect
      upon type II collagen but can degrade type V/XI collagen and type IX collagen
      fragments (COL2 and COL2 + COL3). In addition, when the type IX collagen was in
      the intact helical form, MMP-2 appeared to selectively digest alpha3 (IX) chains.
      This suggested that vitreous MMP-2 preferentially cleaved certain vitreous
      collagen chains into large fragments than small peptides. MMP-2 also disrupted
      the vitreous gel in vitro, releasing proteins but not hexuronic acid or sulfated
      glycosaminoglycans into the liquefied supernatant. We conclude that MMP-2
      activity should be considered as a potential mechanism of vitreous liquefaction
      that is seen in aging and various pathological states. Keywords: matrix
      metalloproteinase; type II collagen; type IX collagen; type V/XI collagen;
      vitreous; pig

PMID- 8670745
TI  - Contribution of Na(+)-glucose cotransport to the short-circuit current in the
      pigmented rabbit conjunctiva.
AB  - The objective of this study was to determine whether Na(+)-glucose cotransport
      contributed to the residual short-circuit current (Isc) in the pigmented rabbit
      conjunctiva not accounted for by Cl- secretion. The Isc of the pigmented rabbit
      conjunctiva was measured following exposure of its mucosal or serosal side to
      varying concentrations of D-glucose or phloridzin in a glutathione-bicarbonated
      Ringer's solution (GBR). Addition of D-glucose to the mucosal side of the
      conjunctiva bathed in glucose-free GBR elevated Isc up to 26 +/- 6% in a dose
      dependent manner (K0.5 = 1.2 mM), while mucosal (but not serosal) addition of
      phloridzin reduced the Isc (IC50 = 0.05 mM) of the conjunctiva bathed in regular
      GBR. In a mucosal Na(+)-free medium, neither 20 mM D-glucose nor 0.5 mM
      phloridzin was effective. In a mucosal glucose-containing medium, deletion of Na+
      reduced Isc up to 27 +/- 4%. It was, however, restored to its initial value upon
      the addition of 17.5-141 mM Na+ to a medium containing 5 mM D-glucose. Hill plot
      analysis of Isc elevation at 141 mM Na+ in the presence of varying D-glucose
      concentrations in the mucosal bathing fluid yielded a Hill coefficient of 0.86.
      There is, therefore, evidence for the apical localization of phloridzin-sensitive
      Na(+)-coupled D-glucose transport that exhibits apparent 1:1 stoichiometry, being
      responsible for the maximal 26% increase in the Isc.

PMID- 8670746
TI  - The ciliary ganglion and vitreous cavity shape.
AB  - PURPOSE: To learn the influence of the ciliary ganglion on the postnatal growth
      of eyes with unimpaired visual input and of eyes beneath an image diffusing
      goggle. METHODS: Newborn chicks received unilateral ciliary ganglionectomy or
      unilateral sham operation and were reared either with or without a goggle
      ipsilateral to the surgical procedure. Ocular refractions and ultrasound
      measurements were made on anesthetized chicks; eyes enucleated postmortem were
      measured in axial and equatorial dimensions with calipers and studied
      histologically. RESULTS: Excessive growth of open eyes in the equatorial
      dimensions followed ciliary ganglionectomy and became more pronounced as the
      chicks grew older. There was only a modest increase in axial growth.
      Ganglionectomy also induced relative hyperopia; lens thinning contributed to this
      effect and likely was a direct result of disrupted parasympathetic input to the
      ciliary muscle. Ganglionectomy also slightly increased the thickness of the
      choroid in the posterior pole but not in more peripheral locations. CONCLUSION:
      We conclude that the ciliary ganglion exerts an inhibitory influence on the
      postnatal growth of open eyes; the main effect is in the equatorial dimension of
      the vitreous cavity, with a smaller effect on axial length. Ciliary
      ganglionectomy exerted minimal influence on the development of experimental
      myopia, known to be induced by the goggle regimen. The amount of equatorial
      expansion in goggle-induced myopia was greater than after ganglionectomy alone,
      indicating that other factors besides the ciliary ganglion can influence the
      equatorial dimension of the vitreous cavity.

PMID- 8670747
TI  - Dimerization of tear lysozyme on hydrophilic contact lens polymers.
AB  - PURPOSE: Following the solubilization of protein from patient worn soft contact
      lenses and subsequent analysis via SDS-PAGE, an unidentified 30 kDa protein
      deposit was commonly observed. The mysterious deposit was found to accumulate on
      a variety of soft contact lens material. METHODS: Acuvue, Cibasoft, Excelens and
      Newvue soft contact lenses were worn by three asymptomatic patients using both
      daily-wear and extended wear regimens. To characterize the unknown deposit, human
      tear samples and lens eluted protein were subjected to SDS-PAGE, immunoblotting,
      enzymatic assays and protein sequencing. RESULTS: Results show that the 30 kDa
      protein deposit is the homologous dimer of tear lysozyme. Polymerized lysozyme
      was found on each of the three lens materials within one h of wear. However, the
      dimer was not present in the normal tear film. CONCLUSIONS: Therefore, this
      dimerization phenomenon is the result of an aggregation and interaction of
      lysozyme with various soft contact lens polymers.

PMID- 8670748
TI  - Comparative effects of linoleic acid and linoleic acid hydroperoxide on growth
      and morphology of bovine retinal pigment epithelial cells in vitro.
AB  - PURPOSE: Outer segments of the photoreceptor rods that are phagocytized by the
      retinal pigment epithelial (RPE) cells contain a high proportion of
      polyunsaturated fatty acids (PUFA). PUFA are susceptible to lipid peroxidation.
      We hypothesized that the resulting peroxides could injure RPE cells leading to
      retinal degeneration. Accordingly, we compared the effects of linoleic acid (LA)
      and its hydroperoxide (LHP) on the growth and morphology of RPE cells using laser
      scanning microscopy and transmission microscopy. METHODS: We counted the number
      of RPE cells after incubation for 24 and 48 hrs with concentrations of LA or LHP
      of 0.035, 0.175, and 0.35 mM. To observe the actin filaments, cultured RPE cells
      were stained with rhodamine phalloidin. The cells were prefixed with 2%
      glutaraldehyde and postfixed in 1% osmium tetroxide. Specimens were embedded in
      Epon 812 after dehydration, and the ultrathin sections were doubly stained with
      2% uranyl acetate and 2% lead acetate for examination by transmission electron
      microscopy. RESULTS: Exposure to LA or LHP produced dose-dependent damage to RPE
      cells with a significantly greater effects of LHP than LA. After incubation for
      24 hrs with 0.35 mM LA, the number of vacuoles in RPE cells exceeded that
      observed in control RPE cells by 365 nm laser microscopy. Exposure to 0.35 mM LHP
      for 24 hrs produced a pycnotic nucleus, with diffuse and granular
      autofluorescences observed in and around it. Exposure of RPE cells to 0.35 mM LA
      for 24 hrs showed that the LA incorporated into the lysosomes was digested and
      released extracellularly from lysosomes via exocytotic vesicles. However, such
      exposure to LHP damaged the RPE cells, including the membranes in the pinocytotic
      vesicles. The packed membranes resembled myelin. CONCLUSIONS: While the LA
      incorporated into the lysosomes was released extracellularly, LHP persisted in
      the RPE cells, being observed as autofluorescent lipofuscin-like materials. LHP
      was cytotoxic, and caused damage to the membranes of pinocytotic vesicles and
      lysosomes.

PMID- 8670749
TI  - Proto-oncogene expression in cAMP and TPA-mediated neuronal differentiation in a
      human retinal cell line KGLDMSM.
AB  - PURPOSE: A human retinal cell line, KGLDMSM, developed by SV-40T antigen gene
      transfection, is stable in culture for a long period, unlike the primary cells.
      The cell line shows some degree of morphological differentiation with limited
      extension of stublike neurites upon transfer to defined medium. In our effort to
      explore genes implicated in neuritic extension and neuronal differentiation seen
      in response to cAMP and TPA, we have analyzed time dependent induction of a
      variety of proto-oncogenes: c-myc, H-ras, c-ras, and c-fos. METHODS: Cells were
      adapted to grow in defined media and exposed to differentiation inducing agents
      cAMP, TPA, Retinoic Acid, and sodium butyrata. Cells were assessed for phenotypic
      changes and altered expression of proto-oncogenes as evaluated by Northern Blot
      analysis and immunocytochemistry. RESULTS: Exposure of the cells to cAMP and TPA
      induced dramatic changes, with 100% of the cells extending neuritic processes.
      However, other differentiation inducing agents such as retinoic acid and sodium
      butyrata failed to elicit any response. We report that agents that promote
      neuritic extension also induce expression of c-fos. Transcriptional activation of
      c-fos in response to cAMP (30 min) and TPA (1hr) is also accompanied by
      expression of fos gene product as evaluated by using fos antibody. No fos
      expression was seen in uninduced cells. CONCLUSION: In retinal cell line KGLDMSM,
      agents that enhance neuronal differentiation (cAMP, TPA) also induce c-fos
      expression. Expression of c-fos may be a necessary prerequisite in neuronal
      differentiation and the established retinal cell line offers an excellent cell
      model for dissecting the molecular events underlying neuronal differentiation.

PMID- 8670751
TI  - An HPLC radiotracer method for assessing the ability of L-Cysteine prodrugs to
      maintain glutathione levels in the cultured rat lens
AB  - Purpose. To apply a high performance liquid chromatographic radiotracer method to
      test a variety of L-cysteine prodrugs and one dipeptide prodrug for their ability
      to synthesize glutathione in cultured rat lenses. Method. Rat lenses were
      incubated for 48 h in a medium containing [14C(U)]-glycine and prodrugs.
      Following homogenization and derivatization, lens extracts were analyzed to
      determine the extent of biosynthetic incorporation of this labeled amino acid
      into [14C]-glutathione using high performance liquid chromatography with
      radioisotope and ultraviolet absorption detection. All of the thiazolidine
      prodrugs contained masked sulfhydryl groups to stabilize them against air
      oxidation. L-buthionine-(S,R)-sulfoximine - an inhibitor of the first step in
      glutathione biosyntesis - was present in media containing the dipeptide prodrug.
      Results. In all cases, a large [14C]-labeled peak eluted just prior to [14C]
      glutathione. This peak had some characteristics of the mixed disulfide of
      glutathione and L-cysteine, viz., L-cysteine/glutathione disulfide, but requires
      further investigation in order to be positively identified. Of the eleven L
      cysteine prodrugs investigated, the most effective was 2(R,S)-methylthiazolidine
      4(R)-carboxylic acid, which increased the rate of [14C]-glutathione biosynthesis
      35% over that of the controls. A number of other L-cysteine prodrugs were
      somewhat effective, increasing glutathione synthesis 5-30% over the controls,
      while several L-cysteine prodrugs were totally ineffective. The only dipeptide
      prodrug investigated, viz., gamma-L-glutamyl-L-cysteine ethyl ester, increased
      the biosynthesis of [14C]-glutathione 18% over control. Biosynthetic rates based
      on ultraviolet absorption of the derivatized glutathione demonstrated a similar
      pattern, the compounds most effective in synthesizing [14C]-glutathione generally
      yielding the highest ultraviolet glutathione concentrations and the ineffective
      compounds showing the lowest concentrations. Conclusions. 2(R,S)
      methylthiazolidine-4(R)-carboxylic acid, 2(R,S)-n-propylthiazolidine-4(R)
      carboxylic acid and N-acetyl-L-cysteine were the only compounds that were
      statistically significant in yielding higher levels of both ultraviolet and
      radioactive glutathione as compared to their respective controls. Thus, these
      prodrugs have very promising anti-cataract potential. Keywords: glutathione;
      HPLC; lens; rat; thiazolidine

PMID- 8670750
TI  - Cytokine effects on phagocytosis of rod outer segments by retinal pigment
      epithelial cells of normal and dystrophic rats.
AB  - PURPOSE: Phagocytosis of rod outer segments (ROS) is an important function of
      retinal pigment epithelial (RPE) cells. Since the details of the process are not
      fully known, we studied effects of cytokines produced by RPE and photoreceptor
      cells on phagocytosis of ROS by rat RPE cells. METHODS: RPE cells were isolated
      and cultivated from two strains of rats: Sprague-Dawley (SD) rats with normal
      phagocytosis and Royal College of Surgeons (RCS) rats, which have genetic
      deficiencies in ROS phagocytosis. A double immunofluorescence staining technique
      was used to study the effects in vitro of several cytokines on phagocytosis of
      ROS. RESULTS: We found that transforming growth factor beta-1 (TGF-beta 1) had
      dose-dependent effects on RPE cells of both strains of rat: at a concentration of
      10 ng/ml, TGF-beta 1 significantly (p < 0.01) reduced total ROS (to 74% of
      control in SD rats and to 51% of control in RCS rats), reduced bound ROS (to 56%
      of control in SD rats and to 48% in RCS rats), and increased the ratio of
      ingested ROS to total ROS (to 140% in SD rats but not significantly in RCS rats).
      Treatment of medium with anti-TGF-beta 1 antibody before incubation of RPE cells
      of SD rats with TGF-beta 1 decreased the magnitude of these effects. The cytokine
      acidic fibroblast growth factor (aFGF, 10 ng/ml) affected RPE cells of SD rats
      only, decreasing ROS ingested to 56% of control and the ratio of ingested ROS to
      total ROS to 64% of control. We also examined effects of basic fibroblast growth
      factor and insulin-like growth factor. None of the cytokines tested increased
      ingestion of ROS by RPE cells of RCS rats. CONCLUSIONS: Our results suggest that
      TGF-beta 1 and aFGF have roles in regulating ROS phagocytosis by normal and
      dystrophic RPE cells in the rat.

PMID- 8670752
TI  - Levels of crystallin fragments and identification of their origin in water
      soluble high molecular weight (HMW) proteins of human lenses.
AB  - PURPOSE: The aims of this study were to determine in the human lens water soluble
      high molecular weight (WS-HMW)-proteins: (a) the levels of degraded polypeptides
      (crystallin fragments), and (b) the in vivo cleavage sites in the parent
      crystallins to produce the major fragments. METHODS: The WS-HMW proteins (Mr > 15
      x 10(6) daltons) were isolated as a void volume peak from homogenates of lenses
      of donors of different ages using Agarose A 15m gel-filtration chromatography.
      The degraded polypeptides (Mr < 18 kDa), present in the WS-HMW proteins, were
      separated by a preparative SDS-PAGE method and quantified as a percent of total
      WS-HMW proteins. In addition, the parent crystallins of the major polypeptides
      were identified by the Western blot method using antibodies raised either to the
      whole crystallin molecule or to desired regions at N- and C-terminals or middle
      of individual crystallins. The partial N-terminal sequences of purified
      individual polypeptides were determined to identity the cleavage sites in parent
      crystallins. RESULTS: The levels of degraded polypeptides as percent of the total
      WS-HMW proteins increased with aging, i.e. about 5% in lenses of 16 to 19 year
      old-donors compared to 27% in the 60-80 year-old-donors. As many as thirteen
      polypeptide species with Mr's between 3 to 17 kDa were separated from WS-HMW
      proteins by a preparative SDS-PAGE method. The Western blot analyses showed that
      the polypeptides originated from alpha-, beta- and gamma-crystallins and the
      cleavage sites varied in different regions of crystallins as identified by
      partial N-terminal sequence analyses. CONCLUSIONS: The data showed an age-related
      increase in levels of degraded polypeptides in the WS-HMW proteins and the
      polypeptides were derived from alpha-, beta- and gamma-crystallins.

PMID- 8670754
TI  - Fiber cell morphology and cytoplasmic texture in cataractous and normal human
      lens nuclei.
AB  - PURPOSE: The goal of this study was to compare the ultrastructure of the oldest
      cells in opaque and transparent human lenses. METHODS: Age-related nuclear
      cataracts, late-onset diabetic nuclear cataracts and normal aged lenses were
      examined by transmission electron microscopy. Cross-sectional profiles of fiber
      cells in the embryonic, fetal and juvenile nuclear regions were obtained to
      facilitate direct comparisons between lens regions and between sample groups.
      Image analysis was performed to determine cross-sectional areas of fiber cells in
      each region. RESULTS: The average cross-sectional area increased approximately
      sixfold from the outer to the inner nuclear regions in all lenses measured. In
      each nuclear region, fiber cells displayed a characteristic size, shape,
      arrangement and type of interdigitations which were consistently seen in all the
      lenses examined. Some lenses had more complex interdigitations than others. Gap
      junctions were identified as pentalamellar structures having 16 nm width and
      appeared identical throughout the nuclei of both normal and cataractous lenses.
      The cytoplasm of all lenses was smooth and free of large density variations.
      However, the cytoplasm of some cataractous lenses appeared more granular in
      texture than noncataractous lenses. Cellular degeneration, debris or large
      cellular defects were not seen in the cores of cataractous lens nuclei.
      CONCLUSIONS: These results indicate that only minor ultrastructural differences
      exist between the oldest fiber cells in normal and cataractous lenses, and that
      the presence of extensive cellular damage and disruptions is not necessary for
      the generation of nuclear opacities in aged lenses. Our observations suggest that
      light scattering sufficient for vision impairment may involve structural
      alterations much smaller than previously proposed.

PMID- 8670753
TI  - Differences in the anti-basement membrane zone antibodies in ocular and pseudo
      ocular cicatricial pemphigoid.
AB  - PURPOSE: Ocular cicatricial pemphigoid (OCP) is a chronic autoimmune cicatrizing
      disease which affects the conjunctiva and other squamous epithelium, resulting in
      a scarring process. A similar process, limited only to the conjunctiva, observed
      in some patients using eye drops for the treatment of glaucoma, is called pseudo
      ocular cicatricial pemphigoid (P-OCP). Immunofluorescence studies demonstrate
      deposition of immunoglobulins and complement components in the basement membrane
      zone (BMZ) of the conjunctiva and an anti-basement membrane zone antibody in the
      serum of patients. A striking association between OCP and MHC class II gene
      DQB1*0301 has been observed. The purpose of this study was to determine some of
      the differences in the binding of OCP and P-OCP sera to different lysate in an
      immunoblot assay, in an attempt to partially characterize the OCP and P-OCP
      antigens. Furthermore, we wanted to determine if the MHC class II gene
      association of P-OCP is similar to that of OCP. METHODS: We studied sera from 11
      patients with active ocular cicatricial pemphigoid and seven patients with pseudo
      ocular cicatricial pemphigoid and controls. Indirect immunofluorescence (IIF)
      studies were done using monkey esophagus and salt split normal human skin as
      substrate. A sensitive immunoblot assay (IBA) was developed using normal human
      epidermis, dermis and conjunctiva as substrate. Typing for MHC class II genes was
      performed on eight pseudo-ocular cicatricial pemphigoid patients by dot-blot
      analysis and compared to 38 matched controls. RESULTS: Weak staining of the
      basement membrane zone was observed in nine of ten ocular cicatricial pemphigoid
      sera and five of seven pseudo-ocular cicatricial pemphigoid sera in the IIF assay
      using monkey esophagus. Using salt split human skin as substrate, ten of eleven
      ocular cicatricial pemphigoid sera demonstrated low titer weak binding to the
      epidermal side of the split. No consistent pattern of staining was seen with
      pseudo-ocular cicatricial pemphigoid sera. Ten of the 11 ocular cicatricial
      pemphigoid sera demonstrated binding to 230, 205, 160 and 85 kDa proteins in the
      IBA using normal human epidermis and conjunctiva lysates. When the lysates were
      first reacted with BP sera and then immunoblotted with ocular cicatricial
      pemphigoid sera, the 230, 160, and 86 kDa bands disappeared, and only the 205 kDa
      band persisted. The sera of five of seven pseudo-ocular cicatricial pemphigoid
      patients bound to 290, 230, 205, 180, 97, and 85 kDa proteins in the epidermis
      and conjunctiva. However, the 230, 205, 180, and 85 kDa proteins are depleted
      when the lysates are first reacted with BP and ocular cicatricial pemphigoid
      sera. In the dermal lysate, the pseudo-ocular cicatricial pemphigoid sera
      recognize 400, 290, 150 and 45 kDa proteins. None of these are absorbed by BP,
      ocular cicatricial pemphigoid or pemphigus vulgaris or epidermolysis bullosa
      acquisita sera. The 290 kDa proteins identified in the dermis and epidermis are
      distinct from each other. No binding was seen with control sera with the 3
      lysates. Statistically, dot-blot analysis did not demonstrate a significant
      increase in the frequency of the MHC DQB1*0301 gene. CONCLUSIONS: Patients with
      ocular cicatricial pemphigoid and pseudo-ocular cicatricial pemphigoid produce
      several autoantibodies. However, there are similarities and differences between
      them. The MHC class II genes associated with pseudo-ocular cicatricial pemphigoid
      are different from those with ocular cicatricial pemphigoid. This provides a new
      model system to study the immune abnormalities in idiopathic and drug-related
      organ specific autoimmunity.

PMID- 8670755
TI  - Time change of nicardipine effect on choroidal circulation in rabbit eyes.
AB  - PURPOSE: To investigate the time course of effects of intravenous administration
      of a calcium antagonist, nicardipine, on the choroidal circulation of rabbit eyes
      using a laser speckle tissue circulation analyzer. METHOD: The rabbit fundus was
      illuminated by a diode laser spot and its image speckle was detected by an image
      sensor. The difference between the average of the speckle intensity (Imean) and
      the speckle intensity for successive scannings was calculated, and the ratio of
      Imean to this difference was defined as normalized blur (NB); a quantitative
      index of tissue blood velocity. The average NB over the field measured (0.620.62
      mm in the choroid) was calculated to give Nb(av). Under general anesthesia, 0.4
      ml/kg of 0.01% nicardipine hydrochloride dissolved in physiological saline was
      injected intravenously in a group of albino rabbits (control group) for
      measurement in the choroid (nicardipine groups). To serve as control, 0.4 ml/kg
      of physiological saline was injected in other groups of albino rabbits (control
      groups). Nb(av) was recorded at 1-min intervals for the first 5 min and at 5-min
      intervals for the next 85 min. During the experiment mean femoral arterial blood
      pressure (FABPm), pulse rate (PR), arterial blood pH, Pco2 and Po2 body
      temperature (BT) and intraocular pressure (IOP) were also monitored. Before and
      45 min after nicardipine administration, the choroidal blood flow measurement
      using the microsphere technique and the Nb(av) measurement were carried out in
      the same eye in another group of rabbits. RESULTS: Only the rabbits which did not
      show any significant change in the PR, pH, Pco2, Po2 and BT during the experiment
      were accepted. FABPm in the nicardipine group dropped to the minimum at 1 min
      postadministration and this level remained significantly lower than that in the
      control group up to 15 min post-injection, while te 10P did not show any
      significant change. The Nb(av) in the nicardipine group showed a significant
      increase after the FABPm return to the baseline, which was maintained throughout
      the experiment. The averaged increase between 30 and 90 minutes after
      administration was 27 +/- 1% (mean +/- S.E.M., n = 10). Relative increase in
      choroidal blood flow determined by the microsphere technique showed a good
      correlation (r = 0.90, P < 0.001, n = 12) with those determined by Nb(av) after
      nicardipine administration. CONCLUSIONS: The present result indicates that the
      time course of drug effects on the choroidal circulation can be noninvasively and
      sensitively followed by Nb(av) measurements. Further, it was shown that
      nicardipine may have considerable potential for the treatment of ocular diseases
      associated with insufficient choroidal blood flow and that nicardipine's effects
      here observed deserve to be further studied in humans.

PMID- 8670756
TI  - An intravitreal device providing sustained release of cyclosporine and
      dexamethasone.
AB  - PURPOSE: A device that releases cyclosporine and dexamethasone into the eye for
      extended periods of time might be beneficial in diseases such as proliferative
      vitreoretinopathy and uveitis. In this study we examine the pharmacokinetics and
      toxicity of cyclosporine and dexamethasone combined in an intravitreal sustained
      release device and the toxicity of a similar device containing only dexamethasone
      in rabbits. METHODS: Rabbits were divided into three groups for (1) evaluation of
      the drug tissue levels and device release kinetics following implantation of a
      device containing 100 micrograms of cyclosporine labeled with 2 microCi of 3H
      cyclosporine and 2 mg of dexamethasone; (2) evaluation of the toxicity of this
      intravitreal device; and (3) evaluation of the toxicity of a similar device
      containing 2 mg of dexamethasone only. Cyclosporine was measured using a
      scintillation counter and dexamethasone was measured by high pressure liquid
      chromatography (HPLC). Toxicity was evaluated by electroretinography, clinical
      examination, and light microscopy. RESULTS: Vitreous concentrations of
      cyclosporine (+/- standard deviation) averaged 0.06 (+/- 0.02) microgram/ml over
      10 weeks. The average dexamethasone concentration over the 10 week period was 2.9
      (+/- 0.9) micrograms/ml. Devices containing cyclosporine and dexamethasone
      released each drug at rates similar to devices containing cyclosporine or
      dexamethasone alone. Devices containing both cyclosporine and dexamethasone
      caused reversible depressions in the b-wave amplitude of photopic and scotopic
      electroretinograms (ERG's). There was no evidence of toxicity associated with the
      devices containing dexamethasone only. There was no drug-related toxicity evident
      on clinical or histopathologic examination of eyes with devices containing the
      combination of cyclosporine and dexamethasone or dexamethasone alone.
      CONCLUSIONS: We conclude that the device maintains potentially therapeutic levels
      of both cyclosporine and dexamethasone in the vitreous. Reversible
      electroretinographic abnormalities are attributable to cyclosporine. A sustained
      release device containing cyclosporine and dexamethasone may be useful for
      reducing inflammation in diseases such as proliferative vitreoretinopathy and
      uveitis.

PMID- 8670757
TI  - Macrophages during fibrosis following scleral fistulising surgery in a rat model.
AB  - PURPOSE: Glaucoma filtration surgery can fail in a minority of patients as a
      result of fibrosis in the subconjunctival bleb space and closure of the scleral
      fistula. In this study, the rat eye has been used as an experimental model for
      fistulising surgery in order to evaluate the clinical manifestation of bleb
      failure with the morphological events of the wound healing process. METHODS: A
      conjunctival bleb was successfully formed in 25 rats and was examined daily using
      slit lamp microscopy to evaluate postoperative inflammation and the presence of a
      bleb. At defined post-operative time points, serial frozen sections of eyes were
      stained immunohistochemically using a panel of monoclonal antibodies directed
      against known surface markers on rat immune/inflammatory cells. Positively
      stained cells were counted (a) in the bleb site, (b) at the sclerostomy and (c)
      at the suture site. RESULTS: Following an initial post-operative inflammation, a
      surgically formed sclerostomy and conjunctival bleb underwent a granulation and
      scarring response so that by 7-19 days the bleb had disappeared. Using the
      monoclonal antibodies applied in this study, it was possible to show that
      macrophages most likely play a major and pivotal role throughout the sequence of
      events that lead to repair of the fistula and closure of the bleb. It was also
      noted that the presence of an otherwise inert nylon suture used to close the
      incised conjunctiva can serve as a focus for macrophages. CONCLUSION: The rat has
      been successfully used as an experimental model of fistulising surgery and its
      subsequent failure. The use of a panel of monoclonal antibodies directed against
      specific surface markers on immune-inflammatory cells, highlighted macrophages to
      be prominent in all stages of this wound healing process.

PMID- 8670758
TI  - Distribution and metabolism of intravitreal cidofovir and cyclic HPMPC in
      rabbits.
AB  - PURPOSE: This study was designed to evaluate the intraocular distribution and
      metabolism of the antiviral nucleotide analogs cidofovir and cyclic 1-[(S)-3
      hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) in New Zealand white rabbits
      following intravitreal administration. METHODS: Male rabbits received either 14C
      cidofovir or 14C-cyclic HPMPC by intravitreal injection into both eyes (50
      micrograms/eye, 11 microCi/eye). Two animals per group were sacrificed at 24, 48,
      72 or 240 h post-dose. Ocular tissues, kidney and liver were oxidized to
      determine total radioactivity and metabolites were determined by HPLC. RESULTS:
      At 24 h post-dose, total radioactivity was 9.96 and 5.18 micrograms-equiv/g for
      cidofovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54
      micrograms-equiv/g, respectively, in retina. Although the initial vitreal
      clearance was 2-fold faster for the cyclic analog, the estimated terminal
      elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) were similar
      for both drugs. By 240 h post-dose, radioactivity in all ocular tissues was
      approximately ten-fold higher for cidofovir. Radioactivity in vitreous at 240 h
      after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and
      cidofovir-phosphocholine. CONCLUSIONS: The long retinal half-life observed
      presumably reflects formation of phosphorylated cidofovir within retinal cells.
      Cidofovir achieved a ten-fold higher level of phosphorylated drug in retina than
      cyclic HPMPC: Therefore, intravitreal cidofovir may be expected to suppress
      progression of retinitis for a longer period than an equivalent intravitreal dose
      of cyclic HPMPC: The intravitreal half-life of cidofovir was 20-fold longer than
      that of ganciclovir in the same animal model.

PMID- 8670759
TI  - EM immunolocalization of alpha-crystallins: association with the plasma membrane
      from normal and cataractous human lenses.
AB  - PURPOSE: To integrate past biochemical findings with past morphological
      observations of area insoluble material isolated from cataract and aged normal
      lenses, by determining the spatial distribution of alpha-crystallins associated
      with the plasma membrane (PM) of nuclear cataractous and age matched normal human
      lenses. METHODS: Lenses were homogenized, pelleted and washed several times in
      0.05M Tris-Cl (pH 7.2) containing 100mM KCl, 1 mM MgCl2 and 2mM beta
      mercaptoethanol, followed by several washes in 8M urea. Urea insoluble pellets
      (UIP) were labeled before fixation and embedding with rabbit serum raised against
      alpha-crystallins, followed by goat anti-rabbit IgG conjugated to 5nm gold.
      Approximately 300 gold particles associated with the PM were counted, for each
      lens, on several electron microscopy (EM) micrographs. The number of gold
      particles/um of PM, number of individual vs clusters of gold particles were
      determined. RESULTS: Micrographs from both normal and cataractous human lenses
      clearly demonstrated the association of alpha-crystallins with the PM. Also
      apparent was the abundant labeling of the PM for cataractous lenses as compared
      to normal lenses. Quantification of the gold labeling revealed that not only was
      there an increase in the amount of labeling/um of PM in cataract lenses, but
      there was also an increased percentage of gold in clusters. These clusters were
      not only more numerous in cataractous lenses, but also contained a greater number
      of gold/cluster. CONCLUSIONS: These findings provide morphological evidence that
      the PM in nuclear cataract lenses is associated with large aggregates of alpha
      crystallin.

PMID- 8670760
TI  - An improved diagnostic test for rod cone dysplasia 1 (rcd1) using allele-specific
      polymerase chain reaction.
AB  - PURPOSE: To develop an improved diagnostic test for rod-cone dysplasia type 1
      (rcd1). The rcd1 phenotype is an early onset, autosomal recessive disease caused
      by a mutation in the canine rod cyclic GMP phosphodiesterase beta-subunit (PDE6B)
      gene. A G to A transition in codon 807 at nucleotide position 2420 results in a
      stop codon. This is the only disease causing mutation detected so far in the
      canine PDE6B gene. METHODS: Allele specific primers were designed in which the 3
      end had the nucleotide corresponding to either the wild type or the mutant rcd1
      allele. PCR was done using the allele specific primers in combination with a
      common primer complementary to the opposite strand to distinguish between the
      wild type and the rcd1 alleles. RESULTS: The wild type and rcd1 alleles were
      identified successfully in two independent ASPCRs done with two different sets of
      allele specific primers. Further, both alleles could be amplified in a single
      tube and distinguished based on the size difference of the PCR products using one
      allele specific primer of altered length by the addition of a 9 nucleotide long
      linker. CONCLUSIONS: We have developed an improved diagnostic test for the
      disease based on ASPCR such that the presence or absence of different size
      amplified fragments provides direct determination of the genotype. In contrast to
      previously reported diagnostic tests, this method is more efficient because it
      eliminates the need for any further manipulation of the PCR product.

PMID- 8670761
TI  - Disturbances in the distribution of neurotransmitters in the rat retina after
      ischemia.
AB  - PURPOSE: Disturbances in neurotransmitter distribution have been observed in
      cerebral ischemia in the pathophysiologic process of excitotoxicity. The goal of
      this study was to examine the effect of pressure-induced retinal ischemia on the
      distribution of the retinal neurotransmitters glutamate and gamma-aminobutyric
      acid (GABA) within the rat retina. METHODS: Animals were subjected to increased
      intraocular pressure of 110 mm Hg for 45 min using an intracameral hydrostatic
      pressure device. The distribution of glutamate and GABA immunoreactivity (IR) was
      determined at 0, 2, 4, 8 and 24 hrs after reperfusion by immunogold with silver
      intensification. RESULTS: Three phases of neurotransmitter immunoreactivity
      patterns were discernible following retinal ischemia. Immediately following
      reperfusion (Phase I), a shift of GABA-IR from inner retinal neurons to the
      Mueller cells and their processes was noted. In contrast, despite marked
      decreases in neuronal glutamate-IR, a less pronounced shift of glutamate-IR to
      the Muller cells was simultaneously noted. This shift of neurotransmitter IR to
      the Mueller cells was transient with the gradual reappearance of IR within the
      inner retinal neurons noted 2-8 hrs after reperfusion (Phase II). Phase III began
      at 8 hrs after reperfusion with progressive loss of GABA-IR noted in the inner
      retina; by 24 hrs, secondary loss of inner retinal glutamate-IR was evident with
      corresponding dropout and pyknosis of inner retinal neurons apparent.
      CONCLUSIONS: The distribution of glutamate-IR and GABA-IR was significantly
      altered following retinal ischemia. The alteration noted in Phase I suggested
      that the regulation of glutamate by Mueller cells was disrupted by this ischemic
      insult leading to glutamate excitotoxicity, and delayed neuronal cell
      degeneration as evidenced by the subsequent loss of inner retinal
      immunoreactivity in Phase III.

PMID- 8670762
TI  - Morphological and ultrastructural changes induced in corneal epithelial cells by
      HIV-1 and HHV-6 in vitro.
AB  - PURPOSE: The purpose of this study was to determine whether HIV-1 and HHV-6 are
      capable of infecting and inducing morphological and ultrastructural changes in
      corneal epithelial cells in vitro. METHODS: Primary and transformed corneal
      epithelial cell cultures were infected with HIV-1 or HHV-6 in vitro and analyzed
      for the presence or absence of viral antigens, DNA sequences, viral particles and
      inclusions. RESULTS: HIV-1 antigens were detected in 8% of the HIV-1 infected
      cells and early HHV-6 antigens were present in 12% of the HHV-6 infected cells.
      The presence of viral DNA sequences in the cultures confirmed these findings.
      Cells infected with HIV-1 morphologically were not different from uninfected
      cells, whereas the morphology of HHV-6 infected cells was very similar to cells
      infected with other human herpesviruses. Cytoplasmic tubuloreticular inclusions
      were detectable in corneal epithelia cells infected with HIV-1 and intact viral
      particles were visible only in PBMC used to recover HIV-1 from these cultures.
      Viral inclusions were also observed in corneal epithelial cells infected with HHV
      6. CONCLUSION: These data indicate that HIV-1 and HHV-6 are capable of infecting
      corneal epithelial cells in vitro, but the viruses are not entering these cells
      via CD4 or galC receptors. This basic information is important in determining the
      pathogenic mechanism(s) involved in the development of AIDS-associated corneal
      disorders.

PMID- 8670763
TI  - Transforming growth factor beta-1 and beta-2 in human tear fluid.
AB  - PURPOSE: To evaluate human tear fluid for transforming growth factor beta
      isoforms 1 and 2 (TGF-beta1 and TGF-beta2). METHODS: To accomplish this, human
      tears were evaluated for TGF-betas by quantitative antibody sandwich ELISA
      (sELISA), mink lung epithelial cell (MLEC) growth inhibition bioassay and western
      blotting. Various physical and chemical treatments were used to activate TGF-beta
      in these assays. RESULTS: TGF-betas could not be detected in untreated or heated
      tears by sELISA; however, mean TGF-beta1 concentrations of 2.32 ng/ml were
      detected in acid-activated tears by sELISA. Furthermore, 10.54 ng/ml of TGF-beta1
      and 2.98 ng/ml of TGF-beta2 were detected in tears treated with the mucolytic
      agent, acetylcysteine. Total TGF-beta bioactivity in human tears measured by the
      MLEC assay was found to be 13.04 ng/ml in untreated tears and 24.85 ng/ml in acid
      activated tears. Approximately one-half TGF-beta in tear specimens was
      biologically active (mean = 52%, range 39-71%). Total tear TGF-beta bioactivity
      could be completely neutralized by recombinant human TGF-beta1 latency associated
      peptide (rh TGF-beta1 LAP). Mean neutralization of tear TF-beta bioactivity was
      83% by TGF-beta1-specific antisera, and was 13% by TBF-beta2-specific antisera.
      Immunoreactive TBF-beta bands at approximately 12.5 and 95 kD were observed in
      immunoblots of reduced acidified tears. A high molecular weight (MW) TGF-beta
      band (>203 dD) was noted in untreated tears; however, this band disappeared
      following treatment with acetylcysteine. CONCLUSIONS: The results of these
      studies indicate that TGF-beta1 and TGF-beta2 are present in human tear fluid,
      and TGF-beta1 is the predominant isoform. There appear to be factors in human
      tears capable of binding TGF-beta.

PMID- 8670764
TI  - Production and secretion of transforming growth factor beta (TGF-beta) by the
      human lacrimal gland.
AB  - PURPOSE: Transforming growth factor beta (TGF-beta) isoforms 1 and 2 have
      recently been detected in stimulated human tear fluid. The purpose of this study
      was to determine if these TGF-sbeta are produced and secreted by the lacrimal
      gland. METHODS: To accomplish this, reverse transcriptase polymerase chain
      reaction (RT-PCR) was used to detect expression of TGF-beta1 and TGF-beta2 mRNAs
      in normal human and rabbit lacrimal gland biopsies. Northern blot analyses were
      used for comparing the relative levels of expression of these TGF-beta mRNAs in
      rabbit lacrimal glands. Human lacrimal gland biopsies were evaluated by
      immunohistochemistry for production of TGF-beta1, TGF-beta1 latency associated
      peptide (LAP), and TGF-beta2 proteins. Supernatants of unstimulated and carbachol
      stimulated human lacrimal gland explant cultures were evaluated for secretion of
      TGF-beta1 and TGF-beta2 by ELISA: RESULTS: TGF-beta1 and TGF-beta2 mRNA
      expression was found in all human and rabbit lacrimal gland specimens by RT-PCR.
      A greater level of expression of TGF-beta1 than TGF-beta2 mRNA in the rabbit
      lacrimal gland was noted by Northern blot. In human lacrimal gland biopsies, TGF
      beta1 and TGF-beta1 LAP were detected in acinar and ductal epithelia by
      immunohistochemistry. TGF-beta2 specific antibodies stained a small percentage of
      acinar and ductal epithelia, as well as material within the lumens of tubulo
      acinar complexes in one-third of these glands. TGF-beta1 was detected in
      supernatants of human lacrimal gland explants, and the concentration of TGF-beta1
      increased by an average of 280% after carbachol-stimulation (p = 0.004). TGF
      beta2 could not be detected in unstimulated or stimulated human lacrimal gland
      supernatants. CONCLUSIONS: The results of these experiments indicate that TGF
      beta1 and TGF-beta2 are produced by and TGF-beta1 is secreted by the human
      lacrimal gland. They also suggest that the lacrimal gland may be one source of
      TGF-beta in human tear fluid.

PMID- 8670765
TI  - The accurate assessment of changes in retinal vessel diameter using multiple
      frame electrocardiograph synchronised fundus photography.
AB  - PURPOSE: Detection and precise quantification of changes in retinal vessel
      diameter by image analysis techniques is important in a number of fields of
      research. The retinal vessels have been shown to exhibit pulse related changes in
      diameter. These may need to be taken into account when studying diameter changes
      due to other causes. This study examined the effect of using multiple fundus
      photographs with and without electrocardiographic synchronisation on the size and
      statistical significance of changes in mean retinal vessel diameter. METHODS:
      Twelve fundus photographs spaced throughout the cardiac cycle by
      electrocardiographic synchronisation were taken in 10 normal volunteers: (a) at
      rest, (b) during isometric exercise, and (c) during oxygen inhalation. Vessel
      diameters were measured using a computer assisted image analysis system.
      Subsequently smaller sample sizes, with and without electrocardiograph
      synchronisation were modeled from the available data. RESULTS: With a group of
      ten subjects six or more electrocardiograph synchronised photographs enable
      reliable detection of small diameter changes (1.4%) induced by isometric
      exercises while other methods either failed to detect change or were unreliable
      at doing so. With six subjects twelve synchronised photographs were required to
      reliably detect a change of the same magnitude. Larger diameter changes (5.4%)
      were detected by any method including a single unsynchronised photograph.
      CONCLUSIONS: Multiple frame electrocardiograph synchronized fundus photography
      permits more accurate detection of small changes in retinal vessel diameter.

PMID- 8670766
TI  - The effects of intravitreally injected endothelin-1 on the iris-ciliary body
      microvasculature in rabbits.
AB  - PURPOSE: We previously reported that intravitreal injection of 0.5 microg of
      endothelin-1 (ET-1) caused both a sustained reduction of intraocular pressure
      (IOP) and decreased aqueous production in the rabbit eye. On the theory that
      these effects might have resulted from a sustained reduction of blood flow to the
      ciliary body due to ET-1-mediated vasoconstriction, in the present study we
      attempted to determine if ET-1 causes any changes in the vascular caliber of the
      iris-ciliary body. METHODS: ET-1 solution (0.5 microg) was injected into the
      vitreous of one eye of each of 10 albino rabbits; the same amount of vehicle was
      injected into the contralateral eyes. One h following these injections in five of
      the rabbits and 24 h following them in the other five rabbits, ocular
      microvascular castings were obtained under controlled physiologic conditions, and
      the amount of vasoconstriction of the arterioles branching from the major
      arterial circle of the iris (MAC) and supplying the iris-ciliary body was
      measured by a scanning electron microscope and expressed as a percentage.
      RESULTS: The ET-1 caused a statistically significant focal vasoconstriction in
      the treated eyes as compared with the contralateral, control eyes (9.9% at 1 h
      and 6.2% at 24 h; both P = . 0001). CONCLUSIONS: Intravitreally injected ET-1
      caused statistically significant, but only mild vasoconstriction of the
      arterioles supplying the ciliary processes.

PMID- 8670767
TI  - Macular flicker electroretinograms in Best vitelliform dystrophy.
AB  - PURPOSE: The aim of this study was to evaluate the function of the neurosensory
      retina in Best vitelliform macular dystrophy (BMD) by recording the focal
      electroretinogram (ERG) fundamental and 2nd harmonic components, which are known
      to be dominated by receptoral and postreceptoral activity, respectively. METHODS:
      FERGs were recorded in response to a uniform field (9 x 9 deg) flickered
      sinusoidally at either 8 Hz or 32 Hz (peak frequencies for the 2nd and
      fundamental harmonic, respectively). The fundamental component of the response to
      the 32-Hz stimulus and the 2nd harmonic of the response to the 8-Hz stimulus were
      measured in their amplitudes and phases. The fundamental-2nd harmonic amplitude
      ratio was taken as an index of the relative changes in the FERG components.
      Eleven patients with BMD and vitelliform stage macular lesions were evaluated.
      Results were compared with those obtained from 13 patients with Type 2 Stargardt
      macular dystrophy (STD) according to the Noble and Carr Classification, and 29
      normal control subjects. Four BMD and four STD patients were also followed
      electrophysiologically over a 48 month period. RESULTS: Compared to controls, BMD
      patients showed losses of both FERG fundamental and 2nd harmonic amplitudes, and
      an increase in the fundamental and increase in the fundamental-2nd harmonic
      ratio. STD patients also showed losses of both fundamental and 2nd harmonic, but
      the fundamental-2nd harmonic ratio was normal. In BMD patients, but not in those
      with STD, the fundamental amplitude tended to decrease over the follow-up period.
      CONCLUSIONS: The results indicate that BMD involves neurosensory abnormalities
      early in the disease process. The increased fundamental-2nd harmonic ratio
      suggests that a postreceptoral dysfunction may be present in addition to that of
      photoreceptors. This differs from STD, where losses appear to affect primarily
      the receptoral retina. Receptoral losses in BMD may progress throughout the
      medium-term follow up.

PMID- 8670768
TI  - Influence of dynamic contact of hard contact lens materials on corneal epithelial
      cells examined by rose bengal staining.
AB  - PURPOSE: To establish a method for evaluation of less irritating contact lens
      materials by dynamic contact with cornea, we examined epithelial and endothelial
      cell injury to the porcine cornea caused by rotatory rubbing with four kinds of
      hard contact lenses (HCL). METHODS: The HCLs used were (1) polymethylmethacrylate
      (PMMA) HCL, (2) gas-permeable HCL composed of a graft co-polymer of dextran
      derivative and methylmethacrylate (MMA) (Suncon Mild II(TM), 12 Dk), (3) gas
      permeable HCL composed of a graft co-polymer of dextran derivative, a monomer
      containing silicone, a monomer containing fluorine and MMA (New Dx HCL-136, 32
      Dk), and (4) gas-permeable HCL composed of a monomer containing silicone, a
      monomer containing fluorine and MMA(RGPL-A, 216 Dk). Using a specially designed
      apparatus, we produced a standardized injury to the epithelium or endothelium of
      porcine corneas by holding the HCL against the corneal surface while rotating the
      lens rapidly. RESULTS: After rotatory rubbing of the HCL on the epithelium, the
      degree of rose bengal staining of the epithelial cells, indicating degeneration
      of the cells and mucin detachment, were significantly different among these HCLs
      (New Dx HCL-136 < Suncon Mild II(TM), PPMA < RGPL-A), and the cell injury rates
      of the endothelium were also significantly different among them (Suncon Mild
      II(TM) < New Dx HCL-136, PMMA < RGPL-A). The water-wettability of HCLs was not
      directly correlated with cell injury rates on epithelial and endothelial cells.
      CONCLUSIONS: Both the New Dx HCL-136 and Suncon Mild II(TM), which have a common
      composition of graft co-polymer of dextran derivative, are less irritating to the
      epithelium and to the endothelium. Also a very few patients complaints regarding
      Suncon Mild II(TM) wearing in individuals with dry eyes have been reported.
      Therefore, we would expect that the New Dx HCL-136 should be satisfactory for
      wear by individuals with dry eyes.

PMID- 8670769
TI  - Tear meniscus measurement in the diagnosis of dry eye.
AB  - PURPOSE: Assessment of the tear film meniscus is a quantitative, minimally
      invasive, direct measurement of tear film quantity. The aim of this study was to
      assess the efficacy of tear meniscus parameter measurement in the diagnosis of
      dry eye. METHODS: Tear meniscus radius of curvature, height, width and cross
      sectional area (TMC, TMH, TMW, XSA) were determined by photographing an optic
      section of the inferior tear meniscus (colored with a min volume of fluorescein)
      at 12 x magnification, and then scanning developed images into a computer
      analysis program. Fifteen dry eye subjects and 15 age-matched controls were
      assessed. Dry eye subjects satisfied the criteria of a rose bengal staining score
      >/= 1, and a mean phenol red thread 15s wetted length </= 10 mm. RESULTS: TMC,
      TMH and XSA were all reduced in magnitude in the dry eye group compared to the
      control group (mean +/- SD; TMC: 0.314 +/- 0.160 mm vs. 0.545 +/- 0.259 mm, TMH:
      0.244 +/- 0.089 mm vs. 0.461 +/- 00.173 mm, XSA: 0.0082 +/- 0.0048 mm2 vs. 0.0176
      +/- 0.0103 mm2, ANOVA, p < 0.05). Both TMC and TMH showed good diagnostic
      accuracy (166.7% and 160% respectively), with a dry eye referent value of </=0.35
      mm for each parameter. TMC and TMH also showed strong correlations with the
      cotton thread test, non-invasive breakup time, and ocular surface staining scores
      (p < 0.01). TMH was the most powerful predictor of tear film insufficiency.
      CONCLUSIONS: This study has shown tear meniscus assessment to be a useful
      alternative to existing tests for dry eye.

PMID- 8670770
TI  - Postnatal developmental expression of glutamine and related amino acids in the
      rat retinas.
AB  - PURPOSE: To evaluate postnatal developmental changes in the amounts of retinal
      glutamate, glutamine and GABA, and in the distribution of retinal glutamine in
      the rat. METHODS: Free amino acids were extracted from rat retinas of different
      postnatal stages, and the concentrations of glutamate, glutamine and GABA were
      determined by HPLC. Also, anti-glutamine antibody was raised and an
      immunocytochemistry was performed with paraffin-embedded retinal sections in
      parallel with free amino acid analyses. RESULTS: Glutamate occurred in high
      concentrations at the birth and showed a stable pool, while glutamine and GABA
      remained low until postnatal day 3 or 5, and gradually increased in the
      developing rat retinas. Glutamine immunolabeling was observed in the retinal
      pigment epithelium and in a subpopulation of presumed amacrine cells in the early
      postnatal days. It was also found in Muller cells and in some ganglion cells or
      displaced amacrine cells in the ganglion cells layer. Glutamine immunolabeling
      was transiently observed also in horizontal cells. Finally, the immunolabeling
      was dominant in the inner and outer plexiform layers in the adult retinas.
      CONCLUSIONS: Postnatal developmental increase in the levels of glutamine and GABA
      might be dependent on the maturation of neurons or glial cells that possess the
      activity of the key enzymes of each amino acid. It was suggested that an
      expression of glutamine immunolabeling can be a marker of neurons that utilize
      glutamine as a precursor for glutamate or GABA, and of Muller cell maturations in
      postnatal early stage of the retina, while it changes to demonstrate the
      locations of glutamine cycle in the retina with adult characteristics.

PMID- 8670771
TI  - Modulation of HLA-DR and CD1a expression on human cornea with low-dose UVB
      irradiation.
AB  - PURPOSE: To evaluate the effects of low-dose UVB irradiation of HLA and CD1a
      expression and the toxic effects of UVB on human corneas. METHODS: 24 pairs of
      human corneas from 24 donors were studied. One cornea from each pair was randomly
      irradiated with UVB (100 mJ/cm2) after enucleation. All corneas were then organ
      cultured for 2, 7, 14 or 21 days. Endothelium was studied after enucleation and
      organ culture. Following preservation, corneas were evaluated by means of light
      microscopy, morphometry and TEM. HLA and CD1a staining was performed using an
      immuno-alkaline-phosphatase technique. RESULTS: Endothelial cell loss during
      organ culture averaged 9.1% in the UVB group and 9.2% in the control group (NS).
      The number of rosette and reformation figures (p = 0.004) and the coefficient of
      variation (p = 0.014) were higher in the control group. Epithelial sloughing was
      more accentuated in the UVB group. We observed the same moderate ultrastructural
      injuries in both groups. In the epithelium, the average number of HLA-DR+ cells
      per field was 0.12 in the UVB group and 0.42 in the control group (p = 0.035). In
      the stroma, these figures were respectively 1.04 and 1.34 (p = 0.026). In the
      epithelium, the average number of CD1a + cells was respectively 0. 025 and 0.078
      (p = 0.019). In the preservation mediums, the average percentage of CD1a + cells
      was 0.07% in the UVB group and 0.27% in the control group (p = 0.014).
      CONCLUSIONS: Low-dose UVB (100 mJ/cm2) decreases HLA-DR and CD1a expression of
      organ-cultured human corneas and induces moderate corneal injuries. Low-dose UVB
      might be useful for preventing allograft rejection.

PMID- 8670772
TI  - Propranolol suppression of ocular HSV-1 recurrence and associated corneal lesions
      following spontaneous reactivation in the rabbit.
AB  - PURPOSE: Hyperthermia has been shown to induce HSV-1 ocular shedding in mice.
      Systemic administration of propranolol significantly reduced the recovery of
      infectious virus in the tears, cornea, and trigeminal ganglia of mice subjected
      to hyperthermia. The present study was performed to determine the effects of
      systemic propranolol on ocular shedding and recurrent corneal epithelial lesions
      in the rabbit model. METHODS: New Zealand white rabbits were infected with HSV-1
      strain McKrae or 17Syn+. After latency was established, the animals were treated
      with systemic propranolol or saline (control) and examined by slit lamp
      biomicroscopy for corneal lesion. Tear film swabs were cultured to determine the
      frequency and duration of viral shedding. RESULTS: Propranolol caused a
      significant reduction in the frequency and duration of ocular HSV-1 shedding and
      a reduction in the frequency of recurrent corneal epithelia disease, compared
      with saline treatment. CONCLUSIONS: These results suggest that beta-adrenergic
      receptor blockers such as propranolol could be useful in suppressing HSV-1 ocular
      recurrences and corneal disease.

PMID- 8670773
TI  - Effect of UVB radiation on corneal aldehyde dehydrogenase.
AB  - PURPOSE: A Class 3 aldehyde dehydrogenase happens to be a major soluble protein
      constituent of the cornea. Its role is conjectured to be manifold: to protect the
      tissue from oxidative damage by eliminating the toxic aldehydes produced upon
      lipid peroxidation under oxidative stress, to act as an UV-absorber, and to
      maintain the level of the coenzyme NADH in the cornea. We have studied the effect
      of UVB on the structure and enzyme activity of corneal aldehyde dehydrogenase.
      METHODS: Aldehyde dehydrogenase was irradiated at 295 nm for varying periods of
      time and change in its enzyme activity assayed. The structural changes in the
      molecule accompanying irradiation were monitored using fluorescence and circular
      dichroism spectroscopy, and its hydrodynamic behavior and surface hydrophobicity
      studied using gel filtration chromatography and binding of the hydrophobic
      fluorophore ANS. The protective ability of aldehyde dehydrogenase in preventing
      aggregation of photolabile proteins, such as Gamma-crystallin of the eye lens,
      was studied by monitoring the scattering value of the test protein with
      irradiation by UVB. RESULTS: Aldehyde dehydrogenase is seen to undergo
      photodamage with alterations in its quaternary structure, though no significant
      change is noticed in the peptide chain conformation. Under such conditions the
      molecule continues to act as a protectant by preventing aggregation of
      photolabile proteins such as the eye lens Gamma-crystallin. CONCLUSIONS: Our
      earlier studies have shown that the free sulfhydryl groups are important for the
      antioxidant abilities of aldehyde dehydrogenase. Its protective ability towards
      photoaggregation of Gamma-crystallin seen here might arise both due to: (i)
      oxyradical quenching and (ii) the increased surface hydrophobicity of the
      molecule upon irradiation, which allows it to bind to, and thus inhibit the
      aggregation of interacting proteins.

PMID- 8670774
TI  - Validation of laser Doppler interferometric measurements in vivo of axial eye
      length and thickness of fundus layers in chicks.
AB  - Purpose. Laser Doppler interferometry (LDI) permits the measurement of
      intraocular distances to a precision of better than 20 microm. The signal complex
      from the posterior segment of the eye consists of four peaks in the chick, an
      animal frequently used in ocular development studies. The present study sought to
      identify anatomical landmarks corresponding to these LDI peaks. Methods.
      Distances obtained with LDI at the posterior pole were compared to axial length
      components measured with three independent methods: vernier calipers, tissue
      sections and high frequency A-scan ultrasound. Results. LDI reflections appear to
      originate from the retinal inner limiting membrane, Bruch's membrane and the
      inner and outer scleral surfaces. Conclusions. The non-invasive and highly
      precise nature of LDI measurements enables repetitive and accurate assessment of
      intraocular distances. Such measurements should prove particularly useful for the
      assessment of short-term cyclic variations in intraocular distances as well as
      post-natal eye growth.

PMID- 8670775
TI  - Bacterial contamination of anaerobic vitreous cultures: using techniques employed
      for endophthalmitis.
AB  - PURPOSE: To investigate the occurrence of contaminated cultures of vitreous
      specimens from non-infected eyes obtained using anaerobic techniques employed for
      endophthalmitis. METHODS: Vitreous specimens were obtained using meticulous
      sterile techniques employed for endophthalmitis from seventeen patients
      undergoing pars plana vitrectomy for non-infective indications: vitreous
      hemorrhage (12 eyes), retinal detachment (3), Coat's disease (1), and congenital
      dislocated lens(1). Vitreous specimens were inoculated in the operating room onto
      an anaerobic blood agar plate and into thioglycolate broth. Bacterial growth
      occurring before 10 days was considered positive. RESULTS: Three organisms were
      isolated from three separate eyes. One colony of Staphylococcus species was
      isolated on an anaerobic blood agar plate on day 3. A single colony of
      Propionibacterium acnes grew on an anaerobic blood agar plate on day 6. Alpha
      hemolytic streptococci grew from thioglycolate broth on day 10. CONCLUSIONS:
      Growth as detected in this study might represent contaminating rather than an
      infecting organism in an eye suspected of having endophthalmitis.

PMID- 8670776
TI  - The evolution of ocular toxoplasmosis in anti-interferon gamma treated mice.
AB  - PURPOSE: A clinico-histopathological cross correlation was made to study the
      mechanism of tissue damage in toxoplasmic retino-choroiditis during an
      experimental reactivation of chronic toxoplasmosis and to compare the influence
      of treatment by sulfadiazine on the retinal lesions. METHODS: Chronically
      infected Swiss-Webster mice were treated, six weeks after infection, with an
      avirulent strain of Toxoplasma gondii (Beverley strain) with polyclonal rabbit
      antibody directed against murine interferon gamma. RESULTS: Mice treated by anti
      interferon gamma developed clinical lesions between day 5 and day 30 (lesions
      including single foci of retinochoroiditis, multifocal lesions or diffuse areas
      of retinal necrosis). These lesions did not arise from borders of pre-existing
      scars. The retina was photographed with an operating microscope fitted with a 90
      diopter lens. Biological study showed a significant rise of parasitic loads in
      the eye and brain. Histological examination is in favour of free organism
      dissemination via retinal vessels; the lesions are restricted to the inner retina
      and ciliary body, the parasites migrated from extra-ocular cysts via the
      vasculature. No cysts were seen at the beginning of the study; they were found at
      the scar phase and appeared in mice treated with sulfadiazine. The clinical
      lesions were not caused by cysts but by coagulated necrosis in the retinal
      tissue. Parasite migration may have played a trigger role. CONCLUSIONS: The
      retinal damage was constituted either as a result of a toxic effect of the
      organisms or as a hypertensive reaction to the toxoplasma organism. The results
      of this study showed that the treatment with anti interferon gamma was sufficient
      to reactivate chronic infection.

PMID- 8670777
TI  - Stimulation of retinal pigment epithelial cell growth by neuropeptides in vitro.
AB  - PURPOSE: The proliferation of many cell types are regulated by cytokines and
      neuropeptides by autocrine and paracrine mechanisms. Retinal pigment epithelial
      (RPE) cells are also regulated by cytokines. But RPE cells are very close to the
      neural retina which has some neuropeptides. The present study was to investigate
      the effects of neuropeptides on the growth of RPE cells. METHODS: RPE cells were
      obtained from the eyes of 11 day old chick embryos and cultured in Dulbecco's
      modified Eagle's culture medium containing 10% fetal calf serum. The growth of
      RPE cells was evaluated by [3H]-thymidine uptake. RESULTS: Substance P, beta
      endorphin and calcitonin gene-related peptide markedly stimulated the growth of
      RPE cells. The effects of methionine-enkephalin, somatostatin and vasoactive
      intestinal peptide were intermediate. The strongest effects of substance P, beta
      endorphin and calcitonin gene-related peptide were observed at 10(-6) to 10(-7)
      M. The stimulation of RPE cells with beta-endorphin was inhibited by naloxone,
      suggesting that the stimulation with beta-endorphin is mediated by an opioid
      receptor. beta-endorphin and substance P induced RPE cell growth stimulating
      activity. Leucine-enkephalin and neuropeptide Y did not affect the growth of RPE
      cells. CONCLUSIONS: These results suggest that neuropeptides play an important
      role in the regulation of RPE cell growth.

PMID- 8670779
TI  - Investigations into the loss of glutathione from lenses in organ culture.
AB  - PURPOSE: To investigate possible causes and implications of the decrease in
      glutathione concentration in rat lenses during organ culture. METHODS: Freshly
      excised lenses were incubated in modified TC-199 medium. Ellman's Reagent or the
      GSH-400 assay were used to assay glutathione levels in lenses cultured for
      different times and under a variety of altered culture conditions. RESULTS: In
      lenses from young rats the glutathione decrease was not ameliorated by reduction
      of oxygen tension in the incubator, nor by supplementation of the culture medium
      with various antioxidants or sulfhydryl compounds, nor with the amino acid
      precursors of glutathione. Addition of 2-mercaptoethanol stimulated cysteine
      transport into the lens but had only a modest effect in maintaining the level of
      glutathione. The decrease in glutathione concentration was less in cultured
      lenses from older rats. Lenses from rhesus monkeys exhibited no decrease in
      glutathione levels when maintained in organ culture for up to 48 h. CONCLUSIONS:
      The basis for the decreased glutathione in cultured young rat lenses is still
      uncertain. The data from the present study indicate a definite relationship
      between glutathione loss and age for cultured rat lenses, with young lenses being
      much more susceptible. The resistance of cultured monkey lenses to loss of
      glutathione demonstrates species differences in this property which may be
      relevant to previously reported differences in susceptibility to oxidative
      damage.

PMID- 8670778
TI  - A new wound healing model of retinal pigment epithelial cells in sheet culture.
AB  - PURPOSE: To evaluate some RPE cell functions, such as wound healing, in a
      preparation more similar to in situ conditions, we developed a method to obtain
      and culture retinal pigment epithelial (RPE) cells as a sheet. And we assessed
      the effects of fetal bovine serum (FBS) on the rate of RPE wound healing.
      METHODS: We prepared RPE sheet cultures by incubating rat eyes in 0.1% proteinase
      K for 13 min, peeling away the neural retina-RPE complex, and then incubating the
      tissue for 1 h to promote spontaneous separation of the RPE sheet from the
      retina. After several days of incubation, the cultured sheets of RPE cells were
      examined by phase-contrast microscopy, scanning and transmission electron
      microscopy and immunocytochemistry. We made round defects 1 mm in diameter in
      cultured RPE sheets and estimated the rate of wound closure in media with
      different concentrations of FBS (0 to 10%). RESULTS: The RPE cells cultured in
      sheets retained their in situ features, including microvilli, tight junctions and
      gap junctions, and the distribution of actin and cytokeratin filaments. A wound
      was noted to close with restoration of a polygonal configuration. The rate of
      wound closure depended on serum concentration in the culture medium; when
      supplemented with 10% fetal bovine serum, wound closure was complete in
      approximately 40 h. CONCLUSIONS: The RPE sheet-culture technique we developed
      thus provides a suitable model for studying such RPE cell functions as wound
      healing or phagocytosis.

PMID- 8670780
TI  - A rapid HPLC method for the quantification of GSH and GSSG in ocular lens.
AB  - Purpose. To develop a rapid and accurate method for the quantification of reduced
      glutathione (GSH) and oxidized glutathione (GSSG) using micro-quantities of
      ocular lens. Methods. The epithelium, cortex and nucleus of the lens were
      separated and also the whole lens was homogenized in 3% metaphosphoric acid. The
      homogenate was ultrafiltered by centrifugation at 10,000 g in an Amicon
      microconcentrator, molecular weight cut off 3,000 g. The method does not require
      prior derivatization of the glutathiones. The filtrate was analyzed on a
      Microsorb-MV by a high performance liquid chromatography (HPLC) column using an
      isocratic solvent system (3% methanol and 10 mM potassium phosphate, pH 3.0) and
      detection at 200 nm. RESULTS: The GSH and GSSG were eluted from the HPLC column
      at retention times 5 and 10 min, respectively. The detection limit was 100 pmoles
      applied to the column. The recovery of GSH and GSSG added to the tissue samples
      was 97-100%. CONCLUSIONS: A fast and sensitive HPLC-method for the quantification
      of picomole quantities of GSH and GSSG in ocular lens, which does not require
      prior derivatization, has been developed.

PMID- 8670781
TI  - Entactin modulates the attachment of rabbit corneal epithelial cells.
AB  - PURPOSE: To understand the biological activity of entactin, a component of the
      basement membrane of the corneal epithelium, we investigated the ability of
      rabbit corneal epithelial cells to attach to an entactin matrix and the effect of
      entactin on the cells' attachment to other corneal basement proteins. METHODS:
      Multiwell plastic plates were coated with bovine serum albumin (BSA), alone or
      with BSA and entactin, laminin, fibronectin or collagen type IV. Cultured rabbit
      corneal epithelial cells were seeded on the plates. After incubation (usually 90
      min), the cells were fixed and stained with 1% crystal violet. The number of
      attached cells was counted under a light microscope. RESULTS: The numbers of
      attached cells increased in proportion to both the incubation period and the
      concentration of entactin coated. Furthermore, the number of cells attached to
      the entactin-coated plate was greater than the number attached to the BSA-coated
      plate for each incubation period (30 to 120 min). Likewise, when laminin-coated
      plates were treated with entactin, the number of the attached cells increased in
      proportion to the concentration of entactin. However, entactin did not affect the
      cellular attachment of fibronectin or type IV collagen. Cellular attachment to
      entactin was partially inhibited by the cells' preincubation with the synthetic
      peptide (GRGDSP). CONCLUSIONS: The present results showed that cultured corneal
      epithelial cells adhere to entactin and that entactin stimulated the attachment
      of these cells to the laminin matrix. These findings suggest that entactin plays
      a specific role in maintaining the normal integrity of the corneal epithelium.

PMID- 8670782
TI  - Additive effects of extra cellular matrix proteins and platelet derived mitogens
      on human retinal pigment epithelial cell proliferation and contraction.
AB  - PURPOSE: In proliferative vitreoretinopathy (PVR) retinal pigment epithelial
      cells (RPE) cells are thought to synthesize and interact with extracellular
      matrix (ECM) proteins to form fibrocellular membranes attached to the retina,
      which the cells then progressively contract detaching the retina. Haemorrhage
      into the eye is an exacerbating factor in the pathology. To investigate some of
      the possible interactions between ECM proteins, platelet mitogens and RPE cells
      in this study, we examined the combined effect of platelet derived mitogens and
      ECM proteins on RPE cell proliferation and contraction. METHODS: Cells were
      cultured on a range of individual ECM proteins as well as on the ECM deposited by
      normal vitreous fluid and exposed to platelet mitogens. Effects on cell
      proliferation and cell detachment from these substrates and tissue culture
      plastic were examined. RESULTS: We report additive/synergistic effects of
      platelet mitogens (PDGF and TGFb1) as well as bFGF, with ECM proteins (laminin,
      fibronectin, collagen 1 and vitreous-deposited ECM) on RPE proliferation. Further
      we report stimulation of RPE cell contraction on vitreous proteins when exposed
      to serum prepared from platelet-rich plasma. In this context it was noticeable
      that it was cells grown on vitreous matrix plus pigment rather than cells grown
      on clear vitreous that exhibited this behaviour. CONCLUSIONS: This study supports
      a combined action of platelet mitogens and matrix proteins in inducing RPE cell
      proliferation and contractility and provides a simple in vitro model of some of
      the late stages of PVR.

PMID- 8670784
TI  - Effect of transforming growth factor-beta on plasminogen activator production of
      cultured human uveal melanoma cells.
AB  - PURPOSE: Human uveal melanoma cells have been shown to produce plasminogen
      activator (PA), an enzyme which can enhance tumor metastasis by promoting
      degradation of extracellular matrix. This study used cultured human uveal
      melanoma cells to determine whether the PA production of uveal melanoma cells
      could be modulated by transforming growth factor-beta2 (TGF-beta2), a mitogen
      present in the uvea. METHODS: Five different cell lines of human uveal melanoma
      of differing cellular morphology (2 spindle, 2 epithelioid, 1 mixed) derived from
      tumors from different locations in the eye (3 choroidal, 1 ciliochoroidal, 1
      orbital) were grown in serum-free media, in the presence or absence of TGF-beta2
      (1ng/ml to 100ng/ml). After 24 hrs, the conditioned media were collected and
      quantitated for PA activity by measuring the radial diffusion in fibrin-agarose
      clot and for total PA concentration using an enzyme-linked immunoassay. RESULTS:
      Among the cell lines studied, all produced PA. Cell lines derived from
      intraocular tumors secreted tissue-type PA (tPA), and TGF-beta2 stimulated tPA
      activity and secretion of cell lines containing epithelioid cells but had no
      effect on spindle cells. In contrast, tumor cells isolated from an orbital tumor
      secreted urokinase (uPA), activity and secretion of which was inhibited by TGF
      beta2. CONCLUSIONS: We conclude that cultured human uveal melanoma cells produce
      either tPA or uPA, and TGF-beta2 can have a variable effect on PA production of
      these cells.

PMID- 8670783
TI  - Attenuation of 4-hydroxynonenal-induced cataractogenesis in rat lens by butylated
      hydroxytoluene.
AB  - PURPOSE: We have previously shown that 4-hydroxynonenal (4-HNE) causes
      opacification of cultured rat lenses and that a novel group of glutathione S
      transferases (GSTs) exhibit high specific activity towards 4-HNE. Previous
      studies have shown that t-butylated hydroxy toluene (BHT) induced GSTs in
      cultured rat lens. Therefore, the purpose of the present studies was to
      investigate if the opacification of rat lenses exposed to 4-HNE is ameliorated by
      pre-culturing the lenses in media containing BHT. METHODS: Rat lenses were
      divided into four groups. Group I and II were controls and groups III and IV were
      cultured in the presence of 100 microM 4-HNE. Groups II and IV were pre-cultured
      in the media containing 10 microM BHT for 24 hrs which was designated as 0 time
      point. Lenses were withdrawn at 24 and 72 h and evaluated for opacification by
      digital image analysis. Induction of the specific GST isozyme (gammaGST8-8) was
      studied in the lens epithelium by immunohistochemical studies. Results. Digital
      image analysis revealed amelioration in opacification induced by 4-HNE, when the
      lenses were precultured with BHT. Immunohistochemical studies show that BHT
      induced GST8-8 several folds in the epithelium. CONCLUSIONS: These studies
      indicate that pretreatment with BHT would increase the lens capacity to detoxify
      4-HNE by conjugating it with GSH, thus assigning an important detoxication role
      to this specific GST isozyme in oxidative cataract.

PMID- 8670785
TI  - The source of fluid and protein in serous retinal detachments.
AB  - PURPOSE: To investigate the source and protein content of sub-retinal fluid in
      self-forming experimental serous retinal detachments. METHODS: Detachments were
      induced in Dutch rabbit eyes using rose bengal photosensitization to cause
      choriocapillaris injury and thrombosis. Serous detachments formed spontaneously
      within the next 24 h. Subretinal fluid was withdrawn 2, 8 and 24 hrs after
      photosensitization, and was analyzed for osmolality and albumin content by gel
      electrophoresis. RESULTS: The albumin concentration in the subretinal fluid of
      light-induced detachments was 68% of serum level at 3 h after light damage, and
      rose close to serum level by 24 h. The osmolality of subretinal fluid 24 h after
      light damage was essentially the same as serum and vitreous fluid. CONCLUSIONS:
      The subretinal protein and fluid in light-induced detachments in the central
      retina of the rabbit must come from the choroid, since there are no intrinsic
      retinal blood vessels in that region of the fundus. These data demonstrate that
      serous retinal detachments can form from choroidal fluid.

PMID- 8670786
TI  - Endothelin protein expression in tear glands of the rabbit.
AB  - PURPOSE: Endothelin-1 (ET-1) has been found to accelerate rabbit corneal
      epithelial wound healing in vivo and proliferation of rabbit and bovine
      epithelial cells in vitro. We have now determined that endothelin-like
      immunoreactivity (ET-LI) is present in the tear fluid of New Zealand white
      rabbits, and we have addressed the question of whether it is produced by the tear
      glands (lacrimal gland and Harderian gland). METHODS: Tears were obtained with
      capillary pipettes and lacrimal gland fluid was collected by cannulation. ET-LI
      was determined with a sandwich-enzyme immunoassay. The reverse transcriptase
      polymerase chain reaction (RT-PCR) was employed to determine if there are gene
      transcripts for prepro ET-1 in tear glands. ET-LI in the tear glands was
      evaluated using immunohistochemistry. RESULTS: The tears contained 13.85 +/- 3.94
      pg/ml (mean +/- SEM, n = 6) ET-LI and the lacrimal gland fluid had 24.90 +/- 6.00
      pg/ml (n = 6). The plasma contained 0.89 +/- 0.20 pg/ml (n = 6). Gene transcripts
      were identified for prepro ET-1 in the lacrimal and Harderian glands. Specific
      staining for ET-LI was found in the epithelial cells of the ducts of the lacrimal
      gland and the acinar cells of the Harderian gland. CONCLUSIONS: The higher
      concentrations of ET-LI in the tears and the lacrimal gland fluid than in plasma
      along with prepro ET-1 gene transcripts in the tear glands suggest that they
      secrete ET-1.

PMID- 8670787
TI  - Comparison of leucine aminopeptidase and aminopeptidase III activities in lens.
AB  - PURPOSE: To evaluate the relative contribution of leucine aminopeptidase and
      aminopeptidase III activities to the total aminopeptidase activity in bovine and
      human lenses under in vivo pH conditions. METHODS: Bovine and human lens extracts
      were fractionated on a Sephadex G-200 column at pH 6.9 and 8.5 and all the
      fractions were assayed with Leu-pNA and Arg-pNA as substrates at in vivo lens pH
      (6.9) and optimum pH for leucine aminopeptidase, (8. 5). The major peptidases
      were purified and their activities compared with that of LAP and AP III isolated
      from bovine lens. The ability of bovine and human lens extracts and purified
      bovine lens LAP and AP III to hydrolyze various peptide bonds in synthetic
      peptides, VHLPTVEK, bradykinin and Ile-Ser-bradykinin was determined by amino
      acid analysis of the reaction products. RESULTS: Sephadex G-200 gel
      chromatography and assay of all the fractions at pH 6.9 showed that the elution
      volume for the predominant aminopeptidase present in bovine lens extract is the
      same as that of purified AP III from the same lenses. However, when the assays
      were done at pH 8.5, the major activity eluting from the Sephadex G-200 column
      was found in fractions having LAP. A similar study of human lens extracts at pH
      6. 9 and 8.5 showed one major peak with elution volume corresponding to that of
      purified bovine lens AP III: The human lens extracts displayed a very low level
      of LAP activity. The hydrolysis pattern of peptide substrates by AP III
      paralleled that of bovine and human lens extract at pH 6.9. The X-Pro bond
      resistant to LAP in peptide substrate, VHLTPVEK was hydrolyzed by AP III as well
      as lens extracts. CONCLUSION: Both bovine and human lenses have very low LAP
      activity compared to AP III activity at in vivo pH 6.9. AP III, by its higher
      activity, broad specificity and its ability to cleave peptide bonds that are
      resistant to LAP, is likely to play a major role in lens during epithelial cell
      differentiation into fiber cells and complete hydrolysis of peptides generated in
      vivo.

PMID- 8670788
TI  - Some P. aeruginosa pilus-binding proteins of human corneal epithelium are
      cytokeratins.
AB  - PURPOSE: The purpose of this study was to determine whether any of the previously
      identified human corneal epithelial pilus-binding proteins were cytokeratins.
      METHODS: Soluble human corneal epithelial proteins (hcep) were separated by one
      dimensional (1-D) and two-dimensional (2-D) gel electrophoresis under reducing
      conditions and transferred to nitrocellulose membrane for Western blot analysis.
      To characterize pilus-binding hcep (major proteins of < 21, 38, 45, 66 and 97 kDa
      and minor proteins, including a 55 kDa protein), blots were immunostained using
      three anti-keratin antibodies, including Pruss monoclonal antibody (MAb),
      specific for all classes of IFs, AE5 MAb, specific for a 64 kDa cytokeratin, and
      J7 polyclonal antibody (PAb), specific for a 55 kDa cytokeratin. In addition,
      major pilus-binding proteins were cut from 1-D SDS gel, electroeluted, dot
      blotted onto nitrocellulose membrane, and similarly analyzed. In addition, to
      further test whether any pilus-binding proteins were cytokeratins, soluble hcep
      were immunoprecipitated by MAb XLR-3, a specific anti-pilus antibody, after
      incubation with bacterial pili. The immunoprecipitated proteins were separated by
      SDS-PAGE and transferred onto nitrocellulose membrane. The blotted
      immunoprecipitated proteins were immunostained using Pruss MAb and MAb XLR-3.
      RESULTS: Immunoblots using Pruss MAb showed immunostaining of hcep of approximate
      molecular weights 45, 48, 55, 62 and 66 kDa. Other immunoblot analysis using AE5
      MAb allowed identification of a 66 and a 45 kDa protein in both 1-D and dot blot
      analysis of eluted hcep. J7 PAb specifically immunostained a 55 kDa protein. In 2
      D gel immunoblots, three 55 kDa proteins were immunostained by J7. Three proteins
      of molecular weights 45, 55 and 66 kDa, isolated after incubation of hcep and
      pili by immunoprecipitation with MAb XLR-3, also were positively immunostained by
      the Pruss MAb. CONCLUSIONS: Two of the previously identified major pilus-binding
      proteins of 45 and 66 kDa are cytokeratins.. Additionally, the 55 kDa minor pilus
      binding protein is also a cytokeratin and appears to carry different electric
      charges. Novel approaches such as these provide new insight into the pathogenesis
      of P. aeruginosa infection in human cornea, and may lead to improved prevention
      and treatment of bacterial induced corneal disease.

PMID- 8670789
TI  - Heterogeneity and uniqueness of ornithine aminotransferase mutations found in
      Japanese gyrate atrophy patients.
AB  - PURPOSE: To identify mutations in ornithine aminotransferase (OAT) in seven
      Japanese families with gyrate atrophy (GA), an autosomal recessive chorioretinal
      degeneration of the eye caused by a generalized biochemical deficiency in OAT;
      mutations in the OAT gene have shown a high degree of molecular heterogeneity.
      METHODS: DNA was prepared from patients' fibroblasts and analyzed by polymerase
      chain-reaction amplification of the OAT gene sequence, denaturing gradient gel
      electrophoresis, and direct sequencing for identification of the mutations.
      RESULTS: Eight different mutations were identified in seven unrelated Japanese GA
      patients with hyperornithinemia, confirming the high genetic heterogeneity of
      this disease. Five of these mutations were new, including one causing a
      pyridoxine-responsive disease, and all eight mutations have been found only in
      Japanese GA patients. Consistent with some similarity between the Japanese and
      Finnish populations in genetic isolation and homogeneity, there was a
      preponderance of homozygous mutations (five out of seven patients) as was
      previously reported for 16 Finnish GA pedigrees. CONCLUSION: The eight Japanese
      OAT mutations represent a group of heterogenous mutations unique to a specific
      population pool.

PMID- 8670790
TI  - Neurotransmitters in the retina.
AB  - Processing of visual information within the retina depends in large measure upon
      a complement of chemical neurotransmitters which are released at synaptic
      contacts between individual neurons. Numerous investigators have participated in
      the identification of many of these transmitters and their assignment to specific
      neuronal subpopulations. However, it is now clear that the action of each
      transmitter depends upon the receptor molecules to which it binds.
      Multidisciplinary studies are underway to characterize these receptors as well as
      to investigate transporter molecules which may serve not only to inactivate
      certain neurotransmitters but may also function in their release.

PMID- 8670791
TI  - The import receptor for the peroxisomal targeting signal 2 (PTS2) in
      Saccharomyces cerevisiae is encoded by the PAS7 gene.
AB  - The import of peroxisomal matrix proteins is dependent on one of two targeting
      signals, PTS1 and PTS2. We demonstrate in vivo that not only the import of
      thiolase but also that of a chimeric protein consisting of the thiolase PTS2
      (amino acids 1-18) fused to the bacterial protein beta-lactamase is Pas7p
      dependent. In addition, using a combination of several independent approaches
      (two-hybrid system, co-immunoprecipitation, affinity chromatography and high copy
      suppression), we show that Pas7p specifically interacts with thiolase in vivo and
      in vitro. For this interaction, the N-terminal PTS2 of thiolase is both necessary
      and sufficient. The specific binding of Pas7p to thiolase does not require
      peroxisomes. Pas7p recognizes the PTS2 of thiolase even when this otherwise N
      terminal targeting signal is fused to the C-terminus of other proteins, i.e. the
      activation domain of Gal4p or GST. These results demonstrate that Pas7p is the
      targeting signal-specific receptor of thiolase in Saccharomyces cerevisiae and,
      moreover, are consistent with the view that Pas7p is the general receptor of the
      PTS2. Our observation that Pas7p also interacts with the human peroxisomal
      thiolase suggests that in the human peroxisomal disorders characterized by an
      import defect for PTS2 proteins (classical rhizomelic chondrodysplasia punctata),
      a functional homologue of Pas7p may be impaired.

PMID- 8670792
TI  - The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic
      ATPase required for stability of the PTS1 receptor.
AB  - In humans, defects in peroxisome assembly result in the peroxisome biogenesis
      disorders (PBDs), a group of genetically heterogeneous, lethal recessive
      diseases. We have identified the human gene PXAAA1 based upon its similarity to
      PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris.
      Expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16
      unrelated members of complementation group 4 (CG4) of the PBD. Consistent with
      this observation, CG4 patients carry mutations in PXAAA1. The product of this
      gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a
      predominantly cytoplasmic protein. Substitution of an arginine for the conserved
      lysine residue in the ATPase domain of Pxaaa1p abolished its biological activity,
      suggesting that Pxaaa1p is an ATPase. Furthermore, Pxaaa1p is required for
      stability of the predominantly cytoplasmic PTS1 receptor, Pxr1p. We conclude that
      Pxaaa1p plays a direct role in peroxisomal protein import and is required for
      PTS1 receptor activity.

PMID- 8670793
TI  - Pip2p: a transcriptional regulator of peroxisome proliferation in the yeast
      Saccharomyces cerevisiae.
AB  - In Saccharomyces cerevisiae, peroxisomes are the exclusive site for the
      degradation of fatty acids. Upon growth with the fatty acid oleic acid as sole
      carbon source, not only are the enzymes of beta-oxidation and catalase A induced,
      but also the peroxisomal compartment as a whole increases in volume and the
      number of organelles per cell rises. We previously identified a cis-acting DNA
      sequence [oleate response element (ORE)] involved in induction of genes encoding
      peroxisomal proteins. The aim of our investigation was to test whether a single
      mechanism acting via the ORE coordinates the events necessary for the
      proliferation of an entire organelle. Here we report the cloning and
      characterization of the oleate-specific transcriptional activator protein Pip2p
      (pip: peroxisome induction pathway). Pip2p contains a typical Zn(2)-Cys(6)
      cluster domain and binds to OREs. A pip2 deletion strain is impaired in growth on
      oleate as sole carbon source and the induction of beta-oxidation enzymes is
      abolished. Moreover, only a few, small peroxisomes per cell can be detected.
      These results indicate that fatty acids activate Pip2p, which in turn activates
      the transcription of genes encoding beta-oxidation components and acts as the
      crucial activator of peroxisomes.

PMID- 8670794
TI  - Myristoylated and non-myristoylated forms of the pH sensor protein hisactophilin
      II: intracellular shuttling to plasma membrane and nucleus monitored in real time
      by a fusion with green fluorescent protein.
AB  - Hisactophilins are myristoylated proteins that are rich in histidine residues and
      known to exist in Dictyostelium cells in a plasma membrane-bound and a soluble
      cytoplasmic state. Intracellular translocation of these proteins in response to
      pH changes was monitored using hisactophilin fusions with green fluorescent
      protein (GFP) and confocal laser scanning microscopy. Both the normal and a
      mutated non-myristoylated fusion protein shuffled within the cells in a pH
      dependent manner. After lowering the pH, these proteins translocated within
      minutes between the cytoplasm, the plasma membrane and the nucleus. The role of
      histidine clusters on the surface of hisactophilin molecules in binding of the
      proteins to the plasma membrane and in their transfer to the nucleus is discussed
      on the basis of a pH switch mechanism.

PMID- 8670795
TI  - Neuroserpin, an axonally secreted serine protease inhibitor.
AB  - We have identified and chromatographically purified an axonally secreted
      glycoprotein of CNS and PNS neurons. Several peptides derived from it were
      microsequenced. Based on these sequences, a fragment of the corresponding cDNA
      was amplified and used as a probe to isolate a full length cDNA from a chicken
      brain cDNA library. Because the deduced amino acid sequence qualified the protein
      as a novel member of the serpin family of serine protease inhibitors, we called
      it neuroserpin. Analysis of the primary structural features further characterized
      neuroserpin as a heparin-independent, functional inhibitor of a trypsin-like
      serine protease. In situ hybridization revealed a predominantly neuronal
      expression during the late stages of neurogenesis and in the adult brain in
      regions which exhibit synaptic plasticity. Thus, neuroserpin might function as an
      axonally secreted regulator of the local extracellular proteolysis involved in
      the reorganization of the synaptic connectivity during development and synapse
      plasticity in the adult.

PMID- 8670796
TI  - Functional analyses of active site residues of human lysosomal
      aspartylglucosaminidase: implications for catalytic mechanism and autocatalytic
      activation.
AB  - Aspartylglucosaminidase (AGA) is a lysosomal asparaginase that participates in
      the breakdown of glycoproteins by cleaving the amide bond between the asparagine
      and the oligosaccharide chain. Active AGA is an (alphabeta)2 heterotetramer of
      two non-identical subunits that are cleaved proteolytically from an enzymatically
      inactive precursor polypeptide. On the basis of the three-dimensional structure
      recently determined by us, we have here mutagenized the putative active site
      amino acids of AGA and studied by transient expression the effect of targeted
      substitutions on the enzyme activity and catalytic properties of AGA. These
      analyses support the novel type of catalytic mechanism, suggested previously by
      us, in which AGA utilizes as the nucleophile the N-terminal residue of the beta
      subunit and most importantly its alpha-amino group as a base that increases the
      nucleophilicity of the OH group. We also provide evidence for autocatalytic
      activation of the inactive AGA precursor and putative involvement of active site
      amino acids in the proteolytic processing. The data obtained on the structure and
      function of AGA would indicate that AGA is a member of a recently described novel
      class of hydrolytic enzymes (amidohydrolases) sharing a common structural
      determinant in their three-dimensional structure and whose catalytic mechanisms
      with an N-terminal nucleophile seem basically to be similar.

PMID- 8670797
TI  - Calnexin and calreticulin promote folding, delay oligomerization and suppress
      degradation of influenza hemagglutinin in microsomes.
AB  - Calnexin (CNX) and calreticulin (CRT) are molecular chaperones that bind
      preferentially to monoglucosylated trimming intermediates of glycoproteins in the
      endoplasmic reticulum. To determine their role in the maturation of newly
      synthesized glycoproteins, we analyzed the folding and trimerization of in vitro
      translated influenza hemagglutinin (HA) in canine pancreas microsomes under
      conditions in which HA's interactions with CNX and CRT could be manipulated.
      While CNX bound to all folding intermediates (IT1, IT2 and NT), CRT was found to
      associate preferentially with the earliest oxidative form (IT1). If HA's binding
      to CNX and CRT was inhibited using a glucosidase inhibitor, castanospermine
      (CST), the rate of disulfide formation and oligomerization was doubled but the
      overall efficiency of maturation of HA decreased due to aggregation and
      degradation. If, on the other hand, HA was arrested in CNX-CRT complexes, folding
      and trimerization were inhibited. This suggested that the action of CNX and CRT,
      like that of other chaperones, depended on an 'on-and-off' cycle. Taken together,
      these results indicated that CNX and CRT promote correct folding by inhibiting
      aggregation, preventing premature oxidation and oligomerization, and by
      suppressing degradation of incompletely folded glycopolypeptides.

PMID- 8670799
TI  - Subunit positional effects revealed by novel heteromeric inwardly rectifying K+
      channels.
AB  - Kir 4.1 is an inward rectifier potassium channel subunit isolated from rat brain
      which forms homomeric channels when expressed in Xenopus oocytes; Kir 5.1 is a
      structurally related subunit which does not. Co-injection of mRNAs encoding Kir
      4.1 and Kir 5.1 resulted in potassium currents that (i) were much larger than
      those seen from expression of Kir 4.1 alone, (ii) increased rather than decreased
      during several seconds at strongly negative potentials and (iii) had an
      underlying unitary conductance of 43 pS rather than the 12 pS seen with Kir 4.1
      alone. In contrast, the properties of Kir 1.1, 2.1, 2.3, 3.1, 3.2 or 3.4 were not
      altered by coexpression with Kir 5.1. Expression of a concatenated cDNA encoding
      two or four linked subunits produced currents with the properties of co-expressed
      Kir 4.1 and Kir 5.1 when the subunits were connected 4-5 or 4-5-4-5, but not when
      they were connected 4-4-5-5. The results indicate that Kir 5.1 associates
      specifically with Kir 4.1 to form heteromeric channels, and suggest that they do
      so normally in the subunit order 4-5-4-5. Further, the relative order of subunits
      within the channel contributes to their functional properties.

PMID- 8670798
TI  - The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have
      distinct roles in recognition of a non-native protein and protein refolding.
AB  - The properties of molecular chaperones in protein-assisted refolding were
      examined in vitro using recombinant human cytosolic chaperones hsp90, hsc70,
      hsp70 and hdj-1, and unfolded beta-galactosidase as the substrate. In the
      presence of hsp70 (hsc70), hdj-1 and either ATP or ADP, denatured beta
      galactosidase refolds and forms enzymatically active tetramers. Interactions
      between hsp90 and non-native beta-galactosidase neither lead to refolding nor
      stimulate hsp70- and hdj-1-dependent refolding. However, hsp90 in the absence of
      nucleotide can maintain the non-native substrate in a 'folding-competent' state
      which, upon addition of hsp70, hdj-1 and nucleotide, leads to refolding. The
      refolding activity of hsp70 and hdj-1 is effective across a broad range of
      temperatures from 22 degrees C to 41 degrees C, yet at extremely low (4 degrees
      C) or high (>41 degrees C) temperatures refolding activity is reversibly
      inhibited. These results reveal two distinct features of chaperone activity in
      which a non-native substrate can be either maintained in a stable folding
      competent state or refolded directly to the native state; first, that the
      refolding activity itself is temperature sensitive and second, that hsp90, hsp70
      (hsc70) and hdj-1 each have distinct roles in these processes.

PMID- 8670800
TI  - Calmodulin binding to glutamate decarboxylase is required for regulation of
      glutamate and GABA metabolism and normal development in plants.
AB  - Glutamate decarboxylase (GAD) catalyzes the decarboxylation of glutamate to CO2
      and gamma-aminobutyrate (GABA). GAD is ubiquitous in prokaryotes and eukaryotes,
      but only plant GAD has been shown to bind calmodulin (CaM). Here, we assess the
      role of the GAD CaM-binding domain in vivo. Transgenic tobacco plants expressing
      a mutant petunia GAD lacking the CaM-binding domain (GADdeltaC plants) exhibit
      severe morphological abnormalities, such as short stems, in which cortex
      parenchyma cells fail to elongate, associated with extremely high GABA and low
      glutamate levels. The morphology of transgenic plants expressing the full-length
      GAD (GAD plants) is indistinguishable from that of wild-type (WT) plants. In WT
      and GAD plant extracts, GAD activity is inhibited by EGTA and by the CaM
      antagonist trifluoperazine, and is associated with a CaM-containing protein
      complex of approximately 500 kDa. In contrast, GADdeltaC plants lack normal GAD
      complexes, and GAD activity in their extracts is not affected by EGTA and
      trifluoperazine. We conclude that CaM binding to GAD is essential for the
      regulation of GABA and glutamate metabolism, and that regulation of GAD activity
      is necessary for normal plant development. This study is the first to demonstrate
      an in vivo function for CaM binding to a target protein in plants.

PMID- 8670801
TI  - IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential
      effector for cdc42Hs.
AB  - Proteins that associate with the GTP-bound forms of the Ras superfamily of
      proteins are potential effector targets for these molecular switches. A 195 kDa
      protein was purified from cell lysates by affinity chromatography on immobilized
      cdc42Hs-GTP and a corresponding cDNA was isolated. Sequence analysis revealed
      localized identities to calponin, the WW domain, unconventional myosins and to
      the rasGAP-related domain (GRD) contained in IRA, NF-1, SAR1 and rasGAP. p195 was
      found to be identical to IQGAP1, a protein previously reported to bind ras.
      Purified recombinant p195/IQGAP1 bound to and inhibited the GTPase activity of
      cdc42Hs and rac whereas no interaction with ras was detected. The C-terminal half
      of IQGAP1 containing the GRD bound to cdc42 and rac in a GRD-dependent fashion,
      but a smaller fragment containing only the GRD did not. Cdc42 was also co
      immunoprecipitated from cell lysates with antibody specific to p195/IQGAP1.
      Calmodulin also co-immunoprecipitated with p195/IQGAP1 and was found to associate
      with fragments containing the IQ domain. Expression of a cDNA fragment encoding
      the GRD inhibited the CDC24/CDC42 pathway in yeast, but no effect on ras was
      observed. In mammalian cells, both endogenous and ectopically expressed
      p195/IQGAP1 were localized to lamellipodia and ruffling cell membranes, where co
      localization with actin was apparent. These results suggest that IQGAP1 is an
      effector target for cdc42Hs and may mediate the effects of this GTPase on cell
      morphology.

PMID- 8670802
TI  - Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor
      beta: evidence for tissue-specific modulation of receptor function.
AB  - The diverse functions of thyroid hormone (T3) are presumed to be mediated by two
      genes encoding the related receptors, TRalpha and TRbeta. However, the in vivo
      functions of TRalpha and TRbeta are undefined. Here, we report that targeted
      inactivation of the mouse TRbeta gene results in goitre and elevated levels of
      thyroid hormone. Also, thyroid-stimulating hormone (TSH), which is released by
      pituitary thyrotropes and which is normally suppressed by increased levels of
      thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-)
      mice. These findings suggest a unique role for TRbeta that cannot be substituted
      by TRalpha in the T3-dependent feedback regulation of TSH transcription. Thrb-/-
      mice provide a recessive model for the human syndrome of resistance to thyroid
      hormone (RTH) that exhibits a similar endocrine disorder but which is typically
      caused by dominant TRbeta mutants that are transcriptional inhibitors. It is
      unknown whether TRalpha, TRbeta or other receptors are targets for inhibition in
      dominant RTH; however, the analysis of Thrb-/- mice suggests that antagonism of
      TRbeta-mediated pathways underlies the disorder of the pituitary-thyroid axis.
      Interestingly, in the brain, the absence of TRbeta may not mimic the defects
      often associated with dominant RTH, since no overt behavioural or neuroanatomical
      abnormalities were detected in Thrb-/- mice. These data define in vivo functions
      for TRbeta and indicate that specificity in T3 signalling is conferred by
      distinct receptor genes.

PMID- 8670803
TI  - Tight association of GRB2 with receptor protein-tyrosine phosphatase alpha is
      mediated by the SH2 and C-terminal SH3 domains.
AB  - Receptor protein-tyrosine phosphatase alpha (RPTPalpha), a transmembrane member
      of the extensive family of protein-tyrosine phosphatases (PTPs), is
      constitutively phosphorylated on Tyr789, a consensus binding site for the SH2
      domain of the SH3-SH2-SH3 adaptor protein GRB2. We have previously shown that
      GRB2 binds to P.Tyr789 in vivo and in vitro via its SH2 domain. Here, we report
      that not only the GRB2 SH2 domain, but also the C-terminal SH3 domain is involved
      in binding to RPTPalpha in vitro and in vivo. Although the N-terminal SH3 domain
      of GRB2 is essential for binding to the Ras guanine nucleotide exchange factor
      Son of Sevenless (Sos), an RPTPalpha-GRB2-Sos complex could not be detected. The
      inclusion of peptides encompassing an hSos1 proline-rich motif in cell lysates
      resulted in enhanced binding of RPTPalpha to GRB2 in vitro, suggesting that
      steric hindrance prohibits formation of the RPTPalpha-GRB2-Sos complex. In vitro
      binding experiments indicated that the binding of GRB2 to Sos/dynamin and
      RPTPalpha was mutually exclusive. Analysis of in vitro binding kinetics coupled
      with results from transient co-transfections demonstrated that RPTPalpha is
      tightly bound to GRB2. The site of interaction of the C-terminal SH3 domain of
      GRB2 with RPTPalpha was mapped using deletion mutants to an 18-residue region in
      the N-terminal PTP domain. Arg469, within this region, was identified as one of
      the residues that is involved in the interaction with the C-terminal SH3 domain
      of GRB2. RPTPalpha residues 469-486 are localized close to the catalytic site
      cleft in the structure of the N-terminal PTP-domain, suggesting that interaction
      with the C-terminal SH3 domain may block access to the catalytic site, thus
      inhibiting RPTPalpha activity.

PMID- 8670804
TI  - Oligomerization and phosphorylation of the Ire1p kinase during intracellular
      signaling from the endoplasmic reticulum to the nucleus.
AB  - The transmembrane kinase Ire1p is required for activation of the unfolded protein
      response (UPR), the increase in transcription of genes encoding endoplasmic
      reticulum (ER) resident proteins that occurs in response to the accumulation of
      unfolded proteins in the ER. Ire1p spans the ER membrane (or the nuclear membrane
      with which the ER is continuous), with its kinase domain localized in the
      cytoplasm or in the nucleus. Consistent with this arrangement, it has been
      proposed that Ire1p senses the accumulation of unfolded proteins in the ER and
      transmits the signal across the membrane toward the transcription machinery,
      possibly by phosphorylating downstream components of the UPR pathway. Molecular
      genetic and biochemical studies described here suggest that, as in the case of
      growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in
      response to the accumulation of unfolded proteins in the ER and is phosphorylated
      in trans by other Ire1p molecules as a result of oligomerization. In addition to
      its kinase domain, a C-terminal tail domain of Ire1p is required for induction of
      the UPR. The role of the tail is probably to bind other proteins that transmit
      the unfolded protein signal to the nucleus.

PMID- 8670805
TI  - A pathway in the yeast cell division cycle linking protein kinase C (Pkc1) to
      activation of Cdc28 at START.
AB  - In an effort to study further the mechanism of Cdc28 function and cell cycle
      commitment, we describe here a genetic approach to identify components of
      pathways downstream of the Cdc28 kinase at START by screening for mutations that
      decrease the effectiveness of signaling by Cdc28. The first locus to be
      characterized in detail using this approach was PKC1 which encodes a homolog of
      the Ca(2+)-dependent isozymes of the mammalian protein kinase C (PKC) superfamily
      (Levin et al., 1990). By several genetic criteria, we show a functional
      interaction between CDC28 and PKC1 with PKC1 apparently functioning with respect
      to bud emergence downstream of START. Consistent with this, activity of the MAP
      kinase homolog Mpk1 (a putative Pkc1 effector) is stimulated by activation of
      Cdc28. Furthermore, we demonstrate a cell cycle-dependent hydrolysis of
      phosphatidylcholine to diacylglycerol (a PKC activator) and choline phosphate at
      START. Diacylglycerol production is stimulated by Cdc28 in cycling cells and is
      closely associated with Cdc28 activation at START. These results imply that the
      activation of Pkc1, which is known to be necessary during bud morphogenesis, is
      mediated via the CDC28-dependent stimulation of PC-PLC activity in a novel cell
      cycle-regulated signaling pathway.

PMID- 8670806
TI  - The 'destruction box' of cyclin A allows B-type cyclins to be ubiquitinated, but
      not efficiently destroyed.
AB  - The destruction of mitotic cyclins by programmed proteolysis at the end of
      mitosis is an important element in cell cycle control. This proteolysis depends
      on a conserved motif of nine residues known as the 'destruction box', which is
      located 40-50 residues from the N-terminus. The sequences of the A- and B-type
      destruction boxes are slightly different, which might account for the differences
      in timing of their destruction. When the cyclin A-type destruction box was
      substituted for the normal one in cyclin B1 or B2, however, the resulting
      constructs were unexpectedly stable, although the converse substitution of B-type
      destruction boxes in cyclin A permitted normal degradation. We compared the
      ubiquitination of various cyclin constructs, and found that whereas mutation of
      the highly conserved residues in the destruction box strongly reduced the level
      of ubiquitinated intermediates, the stable destruction box 'swap' constructs did
      form such adducts. Thus, while ubiquitination is probably necessary for cyclin
      destruction, it is not sufficient. We also found that poly-ubiquitinated cyclin
      derivatives are still bound to p34cdc2, which is not detectably ubiquitinated
      itself, raising the questions of how cyclin and cdc2 dissociate from one another,
      and at what stage, in the process of degradation.

PMID- 8670808
TI  - Drosophila goosecoid participates in neural development but not in body axis
      formation.
AB  - In vertebrate embryos, the homeobox gene goosecoid (gsc) is expressed in the
      gastrula organizer region and in later arising embryonic tissues including the
      foregut anlage. Ectopic expression and loss-of-function studies have demonstrated
      that Xenopus gsc elicits a dorsalizing activity that contributes to body axis
      formation. Here we report that the gsc gene is conserved in invertebrates. In
      Drosophila, D-gsc is expressed most strongly in the foregut anlage, which gives
      rise to the foregut proper and the stomatogastric nervous system (SNS). D-gsc
      expression overlaps with one of the three SNS precursor groups invaginating from
      the foregut anlage. Embryos mutant for D-gsc gastrulate normally but show
      disrupted invagination in the SNS primordium and lack one specific SNS ganglion.
      In addition, D-gsc mutant embryos show a less well defined defect in foregut
      arrangement. Our results indicate that this invertebrate homolog of gsc is not
      required for gastrulation but plays a role in neurogenesis in post-gastrula
      Drosophila embryos.

PMID- 8670807
TI  - Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but
      not apoptosis.
AB  - The activation of conditional alleles of Myc induces both cell proliferation and
      apoptosis in serum-deprived RAT1 fibroblasts. Entry into S phase and apoptosis
      are both preceded by increased levels of cyclin E- and cyclin D1-dependent kinase
      activities. To assess which, if any, cellular responses to Myc depend on active
      cyclin-dependent kinases (cdks), we have microinjected expression plasmids
      encoding the cdk inhibitors p16, p21 or p27, and have used a specific inhibitor
      of cdk2, roscovitine. Expression of cyclin A, which starts late in G1 phase,
      served as a marker for cell cycle progression. Our data show that active G1
      cyclin/cdk complexes are both necessary and sufficient for induction of cyclin A
      by Myc. In contrast, neither microinjection of cdk inhibitors nor chemical
      inhibition of cdk2 affected the ability of Myc to induce apoptosis in serum
      starved cells. Further, in isoleucine-deprived cells, Myc induces apoptosis
      without altering cdk activity. We conclude that Myc acts upstream of cdks in
      stimulating cell proliferation and also that activation of cdks and induction of
      apoptosis are largely independent events that occur in response to induction of
      Myc.

PMID- 8670809
TI  - Evidence that a combined activator-repressor protein regulates Dictyostelium
      stalk cell differentiation.
AB  - The ecmA gene is expressed in Dictyostelium prestalk cells and is inducible by
      differentiation-inducing factor (DIF), a low-molecular-weight lipophilic
      substance. The ecmB gene is expressed in stalk cells and is under negative
      control by two repressor elements. Each repressor element contains two copies of
      the sequence TTGA in an inverted relative orientation. There are activator
      elements in the ecmA promoter that also contain two TTGA sequences, but in the
      same relative orientation. Gel retardation assays suggest that the same protein
      binds to the ecmB repressor and the ecmA activator. We propose that DIF induces
      prestalk cell differentiation by activating this protein and that the protein
      also binds to the promoters of stalk-specific genes, acting as a repressor that
      holds cells in the prestalk state until culmination is triggered.

PMID- 8670810
TI  - Human TAF(II28) promotes transcriptional stimulation by activation function 2 of
      the retinoid X receptors.
AB  - Transcriptional activation in vitro involves direct interactions of
      transactivators with the TATA binding protein (TBP) and the TBP-associated
      factors (TAF(II)s) which constitute the TFIID complex. However, the role of
      TAF(II)s in transcriptional regulation in mammalian cells has not been addressed.
      We show that activation function 2 of the retinoid X receptors (RXR AF-2) does
      not activate transcription from a minimal promoter in Cos cells. However,
      coexpression of human (h) TAF(II)28 promotes a strong ligand-dependent activity
      of the RXR AF-2 on a minimal promoter and potentiates the ability of the RXRalpha
      AF-2 to activate transcription from a complex promoter. The expression of
      hTAF(II)28 also potentiated transactivation by several nuclear receptors, notably
      the oestrogen and vitamin D3 receptors (ER and VDR), whereas other classes of
      activator were not affected. The effect of hTAFII(28) on RXR AF-2 activities did
      not appear to require direct RXR-TAFII(28) interactions, but correlated with the
      ability of hTAFII(28) to interact with TBP. In contrast to Cos cells, the RXR AF
      2s had differential abilities to activate transcription from a minimal promoter
      in HeLa cells, and a lesser increase in their activity was observed upon hTAFII28
      coexpression. Moreover, coexpression of hTAFII(28) did not increase but rather
      repressed activation by the ER and VDR AF-2s in HeLa cells. In agreement with
      these data, showing that TAF(II)28 is limiting in the AF-2 activation pathway in
      Cos cells, TAF(II)28 is selectively depleted in Cos cell TFIID.

PMID- 8670811
TI  - A mechanism for repression of class II gene transcription through specific
      binding of NC2 to TBP-promoter complexes via heterodimeric histone fold domains.
AB  - Negative co-factor 2 (NC2) regulates transcription of the class II genes through
      binding to TFIID and inhibition of pre-initiation complex formation. We have
      isolated and cloned NC2, and investigated the molecular mechanism underlying
      repression of transcription. NC2 consists of two subunits, termed NC2alpha and
      NC2beta, the latter of which is identical to Dr1. The NC2 subunits dimerize and
      bind to TATA binding protein (TBP)-promoter complexes via histone fold domains of
      the H2A-H2B type. Repression of basal transcription requires the histone fold and
      carboxy-terminal domains of the NC2 subunits. Several mechanisms probably
      contribute to transcriptional repression. Binding of NC2 inhibits association of
      TFIIB with TBP-promoter complexes. NC2 binds directly to DNA, and binding of NC2
      to TBP-promoter complexes affects the conformation of DNA, which could be one
      cause for the inhibition of TFIIB. In addition, multimerization of repressor-TBP
      complexes on DNA might inhibit the assembly of the pre-initiation complex. We
      suggest that binding of the repressor to TRP-promoter complexes establishes a
      mechanism that controls the rate of transcription by RNA polymerase II.

PMID- 8670812
TI  - Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in
      transgenic mice.
AB  - The Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) is a pleiotropic protein
      which has been characterized extensively both biochemically and functionally. It
      is the only one of the identified latent protein-encoding genes to be
      consistently expressed in viral-associated endemic Burkitt's lymphoma cells. As
      such, it is the only candidate viral protein to possibly perform a maintenance
      function in the tumour pathology. Despite this, no oncogenic activity has been
      attributed to the protein in tissue culture assays. The experiments described
      here were initiated to explore the activity of the protein in B cells in vivo.
      EBNA-1 transgenic mice were generated with transgene expression directed to the B
      cell compartment using the mouse Ig heavy chain intron enhancer. Transgene
      expression was demonstrated in the lymphoid tissues of mice of two independent
      lines. Transgenic positive mice of both lines succumb to B cell lymphoma. The B
      cell tumours are monoclonal, frequently of follicular centre cell origin and
      remarkably similar to those induced by transgenic c-myc expression. These results
      demonstrate that EBNA-1 is oncogenic in vivo and suggest that the gene product
      may play a direct role in the pathogenesis of Burkitt's lymphoma and possibly
      other EBV-associated malignancies.

PMID- 8670813
TI  - Propagation of the yeast prion-like [psi+] determinant is mediated by
      oligomerization of the SUP35-encoded polypeptide chain release factor.
AB  - The Sup35p protein of yeast Saccharomyces cerevisiae is a homologue of the
      polypeptide chain release factor 3 (eRF3) of higher eukaryotes. It has been
      suggested that this protein may adopt a specific self-propagating conformation,
      similar to mammalian prions, giving rise to the [psi+] nonsense suppressor
      determinant, inherited in a non-Mendelian fashion. Here we present data
      confirming the prion-like nature of [psi+]. We show that Sup35p molecules
      interact with each other through their N-terminal domains in [psi+], but not [psi
      ] cells. This interaction is critical for [psi+] propagation, since its
      disruption leads to a loss of [psi+]. Similarly to mammalian prions, in [psi+]
      cells Sup35p forms high molecular weight aggregates, accumulating most of this
      protein. The aggregation inhibits Sup35p activity leading to a [psi+] nonsense
      suppressor phenotype. N-terminally altered Sup35p molecules are unable to
      interact with the [psi+] Sup35p isoform, remain soluble and improve the
      translation termination in [psi+] strains, thus causing an antisuppressor
      phenotype. The overexpression of Hsp104p chaperone protein partially solubilizes
      Sup35P aggregates in the [psi+] strain, also causing an antisuppressor phenotype.
      We propose that Hsp104p plays a role in establishing stable [psi+] inheritance by
      splitting up Sup35p aggregates and thus ensuring equidistribution of the prion
      like Sup35p isoform to daughter cells at cell divisions.

PMID- 8670814
TI  - RNA-DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at
      replication start sites: an implication for RNA-DNA hybrids serving as primers.
AB  - Critical elements of a mammalian mitochondrial DNA heavy-strand replication
      origin include a promoter and three downstream conserved sequence blocks (CSBIII,
      CSBII and CSBI). We found recently that a stable and persistent RNA-DNA hybrid
      forms during in vitro transcription at Saccharomyces cerevisiae mitochondrial
      origins; hybrid formation was dependent on the conserved CSBII element. We report
      here that during in vitro transcription with human mitochondrial RNA polymerase,
      stable and persistent RNA-DNA hybrid formation is also evident at the human
      mitochondrial heavy-strand origin. As predicted, hybrid formation was dependent
      on the GC-rich CSBII element. The human RNA-DNA hybrids terminate within or
      downstream of CSBI at locations implicated in initiation of mitochondrial DNA
      replication. Interestingly, efficient hybrid formation in the human system is
      influenced by sequence 5' to the RNA-DNA hybrid, including the CSBIII element.
      These results suggest that the RNA-DNA hybrids formed during transcription across
      the mitochondrial DNA heavy-strand origin provide RNA primers for initiation of
      mitochondrial DNA replication.

PMID- 8670815
TI  - The rpsO mRNA of Escherichia coli is polyadenylated at multiple sites resulting
      from endonucleolytic processing and exonucleolytic degradation.
AB  - The rpsO monocistronic messenger, encoding ribosomal protein S15, is destabilized
      upon polyadenylation occurring at the hairpin structure of the transcription
      terminator t1. We report that mRNA fragments differing from the monocistronic
      transcript by their 3' termini are also polyadenylated in the absence of
      polynucleotide phosphorylase and RNase II. Some of these 3' extremities result
      from endonucleolytic cleavages by RNase E and RNase III and from exonucleolytic
      degradation. Most of these mRNA fragments are destabilized upon polyadenylation
      with the exception of the RNA species generated by RNase III. RNase E appears to
      reduce the amount of poly(A) added at the transcription terminator t1.

PMID- 8670816
TI  - Transgene silencing of the al-1 gene in vegetative cells of Neurospora is
      mediated by a cytoplasmic effector and does not depend on DNA-DNA interactions or
      DNA methylation.
AB  - The molecular mechanisms involved in transgene-induced gene silencing
      ('quelling') in Neurospora crassa were investigated using the carotenoid
      biosynthetic gene albino-1 (al-1) as a visual marker. Deletion derivatives of the
      al-1 gene showed that a transgene must contain at least approximately 132 bp of
      sequences homologous to the transcribed region of the native gene in order to
      induce quelling. Transgenes containing only al-1 promoter sequences do not cause
      quelling. Specific sequences are not required for gene silencing, as different
      regions of the al-1 gene produced quelling. A mutant defective in cytosine
      methylation (dim-2) exhibited normal frequencies and degrees of silencing,
      indicating that cytosine methylation is not responsible for quelling, despite the
      fact that methylation of transgene sequences frequently is correlated with
      silencing. Silencing was shown to be a dominant trait, operative in
      heterokaryotic strains containing a mixture of transgenic and non-transgenic
      nuclei. This result indicates that a diffusable, trans-acting molecule is
      involved in quelling. A transgene-derived, sense RNA was detected in quelled
      strains and was found to be absent in their revertants. These data are consistent
      with a model in which an RNA-DNA or RNA-RNA interaction is involved in transgene
      induced gene silencing in Neurospora.

PMID- 8670817
TI  - The structure and function of the replication terminator protein of Bacillus
      subtilis: identification of the 'winged helix' DNA-binding domain.
AB  - The replication terminator protein (RTP) of Bacillus subtilis impedes replication
      fork movement in a polar mode upon binding as two interacting dimers to each of
      the replication termini. The mode of interaction of RTP with the terminus DNA is
      of considerable mechanistic significance because the DNA-protein complex not only
      localizes the helicase-blocking activity to the terminus, but also generates
      functional asymmetry from structurally symmetric protein dimers. The functional
      asymmetry is manifested in the polar impedance of replication fork movement.
      Although the crystal structure of the apoprotein has been solved, hitherto there
      was no direct evidence as to which parts of RTP were in contact with the
      replication terminus. Here we have used a variety of approaches, including
      saturation mutagenesis, genetic selection for DNA-binding mutants, photo cross
      linking, biochemical and functional characterizations of the mutant proteins, and
      X-ray crystallography, to identify the regions of RTP that are either in direct
      contact with or are located within 11 angstroms of the replication terminus. The
      data show that the unstructured N-terminal arm, the alpha3 helix and the beta2
      strand are involved in DNA binding. The mapping of amino acids of RTP in contact
      with DNA, confirms a 'winged helix' DNA-binding motif.

PMID- 8670818
TI  - Control of expression of the I factor, a LINE-like transposable element in
      Drosophila melanogaster.
AB  - I factors are LINE-like transposable elements in the genome of Drosophila
      melanogaster. They normally transpose infrequently but are activated in the
      germline of female progeny of crosses between males of a strain that contains
      complete elements, an I or inducer strain and females of a strain that does not,
      an R or reactive strain. This causes a phenomenon known as I-R hybrid dysgenesis.
      We have previously shown that the I factor promoter lies between nucleotides 1
      and 30. Here we demonstrate that expression of this promoter is regulated by
      nucleotides 41-186 of the I factor. This sequence can act as an enhancer as it
      stimulates expression of the hsp7O promoter in ovaries in the absence of heat
      shock. Within this region there is a site that is required for promoter activity
      and that is recognized by a sequence-specific binding protein. We propose that
      this protein contributes to the enhancer activity of nucleotides 41-186 and that
      reduced I factor expression in inducer strains is due to titration of this
      protein or others that interact with it.

PMID- 8670820
TI  - Distinct DNA sequence and structure requirements for the two steps of V(D)J
      recombination signal cleavage.
AB  - Cleavage of V(D)J recombination signals by purified RAG1 and RAG2 proteins
      permits the dissection of DNA structure and sequence requirements. The two
      recognition elements of a signal (nonamer and heptamer) are used differently, and
      their cooperation depends on correct helical phasing. The nonamer is most
      important for initial binding, while efficient nicking and hairpin formation
      require the heptamer sequence. Both nicking and hairpin formation are remarkably
      tolerant of variations in DNA structure. Certain flanking sequences inhibit
      hairpin formation, but this can be bypassed by base unpairing, and even a
      completely single-stranded signal sequence is well utilized. We suggest that DNA
      unpairing around the signal-coding border is essential for the initiation of
      V(D)J combination.

PMID- 8670819
TI  - bowel, an odd-skipped homolog, functions in the terminal pathway during
      Drosophila embryogenesis.
AB  - The terminal genes of Drosophila specify non-segmented regions of the larval body
      that are derived from the anterior and posterior regions of the early embryo.
      Terminal class genes include both maternal-effect loci (typified by the receptor
      tyrosine kinase torso) that encode components of a signal transduction cascade
      and zygotic genes (e.g. tailless and huckebein) that are transcribed at the poles
      of the embryo in response to the local activation of the pathway. We have
      characterized a zygotic gene, bowel, that was identified as a zinc finger homolog
      of the pair-rule segmentation gene odd-skipped. bowel transcripts are initially
      expressed at both poles of the blastoderm embryo and in a single cephalic stripe.
      This pattern depends upon torso and tailless activity, but is not affected in
      huckebein mutants. We isolated and sequenced five mutations that affect the bowel
      protein, including a nonsense mutation upstream of the zinc fingers and a
      missense mutation in a putative zinc-chelating residue. bowel mutants die as late
      embryos with defects in terminal derivatives including the hindgut and
      proventriculus. Our results indicate that the developmental roles of odd-skipped
      and bowel have diverged substantially, and that bowel represents a new member of
      the terminal hierarchy that acts downstream of tailless and mediates a subset of
      tailless functions in the posterior of the embryo.

PMID- 8670822
TI  - Bacterial defense against aging: role of the Escherichia coli ArcA regulator in
      gene expression, readjusted energy flux and survival during stasis.
AB  - Using two-dimensional gel electrophoresis and N-terminal amino acid sequencing
      analysis, we demonstrate that a mutant of the global regulatory protein ArcA
      fails to decrease the synthesis of the TCA cycle enzymes malate dehydrogenase,
      isocitrate dehydrogenase, lipoamide dehydrogenase E3 and succinate dehydrogenase
      in response to stasis, while the increased production of the glycolysis enzymes
      phosphoglycerate mutase and pyruvate kinase is unaffected. Microcalorimetric and
      respiratory measurements show that the continued production of TCA cycle enzymes
      in the (delta)arcA mutant is manifested as an elevated rate of respiration and
      total metabolic activity during starvation. The (delta)arcA mutant is severely
      impaired in surviving prolonged periods of exogenous carbon starvation, a
      phenotype that can be alleviated by overproducing the superoxide dismutase SodA.
      In addition, flow cytometry demonstrates that starving (delta)arcA mutant cells,
      in contrast to wild-type cells, fail to perform reductive division, remain large
      and contain multiple chromosomal copies. We suggest that the ArcA-dependent
      reduced production of electron donors and the decreased level and activity of the
      aerobic respiratory apparatus during growth arrest is an integral part of a
      defense system aimed at avoiding the damaging effects of oxygen radicals and
      controlling the rate of utilization of endogenous reserves.

PMID- 8670821
TI  - The xanthopsins: a new family of eubacterial blue-light photoreceptors.
AB  - Photoactive yellow protein (PYP) is a photoreceptor that has been isolated from
      three halophilic phototrophic purple bacteria. The PYP from Ectothiorhodospira
      halophila BN9626 is the only member for which the sequence has been reported at
      the DNA level. Here we describe the cloning and sequencing of the genes encoding
      the PYPs from E.halophila SL-1 (type strain) and Rhodospirillum salexigens. The
      latter protein contains, like the E.halophila PYP, the chromophore trans p
      coumaric acid, as we show here with high performance capillary zone
      electrophoresis. Additionally, we present evidence for the presence of a gene
      encoding a PYP homolog in Rhodobacter sphaeroides, the first genetically well
      characterized bacterium in which this photoreceptor has been identified. An ORF
      downstream of the pyp gene from E.halophila encodes an enzyme, which is proposed
      to be involved in the biosynthesis of the chromophore of PYP. The pyp gene from
      E.halophila was used for heterologous overexpression in both Escherichia coli and
      R.sphaeroides, aimed at the development of a holoPYP overexpression system (an
      intact PYP, containing the p-coumaric acid chromophore and displaying the 446 nm
      absorbance band). In both organisms the protein could be detected
      immunologically, but its yellow color was not observed. Molecular genetic
      construction of a histidine-tagged version of PYP led to its 2500-fold
      overproduction in E.coli and simplified purification of the heterologously
      produced apoprotein. HoloPYP could be reconstituted by the addition of p-coumaric
      anhydride to the histidine-tagged apoPYP (PYP lacking its chromophore). We
      propose to call the family of photoactive yellow proteins the xanthopsins, in
      analogy with the rhodopsins.

PMID- 8670823
TI  - An essential ubiquitin-conjugating enzyme with tissue and developmental
      specificity in th nematode Caenorhabditis elegans.
AB  - The ubc-2 gene in Caenorhabditis elegans encodes a ubiquitin-conjugating enzyme
      (E2) homologous to yeast UBC4 and UBC5. UBC4 and UBC5 are individually
      dispensable class I E2 enzymes involved in the degradation of short-lived and
      abnormal proteins. Transgenic analysis using ubc-2-lacZ fusions and in situ
      immunofluorescence indicate that ubc-2 is abundantly expressed in most tissues of
      embryos and early larvae, but becomes specific to the nervous system in L4 larvae
      and adults. This suggests that the functions of this type of E2 are
      developmentally regulated in C.elegans. This hypothesis is supported by antisense
      analysis, which shows that blocking the expression of ubc-2 has a more severe
      effect in early developmental stages than in later stages. Through
      complementation of previously identified essential genes in the vicinity of ubc
      2, we demonstrate that ubc-2 corresponds to let-70, a gene essential for
      C.elegans larval development. One let-70(ubc-2) allele contains a His75-->Tyr
      substitution, while another has an altered splice donor site.

PMID- 8670824
TI  - DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease
      in apoptosis.
AB  - Radiosensitive cell lines derived from X-ray cross complementing group 5 (XRCC5),
      SCID mice and a human glioma cell line lack components of the DNA-dependent
      protein kinase, DNA-PK, suggesting that DNA-PK plays an important role in DNA
      double-strand break repair. Another enzyme implicated in DNA repair, poly(ADP
      ribose) polymerase, is cleaved and inactivated during apoptosis, suggesting that
      some DNA repair proteins may be selectively targeted for destruction during
      apoptosis. Here we demonstrate that DNA-PKcs, the catalytic subunit of DNA-PK, is
      preferentially degraded after the exposure of different cell types to a variety
      of agents known to cause apoptosis. However, Ku, the DNA-binding component of the
      enzyme, remains intact. Degradation of DNA-PKcs was accompanied by loss of DNA-PK
      activity. One cell line resistant to etoposide-induced apoptosis failed to show
      degradation of DNA-PKcs. Protease inhibitor data implicated an ICE-like protease
      in the cleavage of DNA-PKcs, and it was subsequently shown that the cysteine
      protease CPP32, but not Mch2alpha, ICE or TX, cleaved purified DNA-PKcs into
      three fragments of comparable size with those observed in cells undergoing
      apoptosis. Cleavage sites in DNA-PKcs, determined by antibody mapping and
      microsequencing, were shown to be the same for CPP32 cleavage and for cleavage
      catalyzed by extracts from cells undergoing apoptosis. These observations suggest
      that DNA-PKcs is a critical target for proteolysis by an ICE-like protease during
      apoptosis.

PMID- 8670825
TI  - Molecular mechanism and species specificity of TAP inhibition by herpes simplex
      virus ICP47.
AB  - The immediate early protein ICP47 of herpes simplex virus (HSV) inhibits the
      transporter for antigen processing (TAP)-mediated translocation of antigen
      derived peptides across the endoplasmic reticulum (ER) membrane. This
      interference prevents assembly of peptides with class I MHC molecules in the ER
      and ultimately recognition of HSV-infected cells by cytotoxic T-lymphocytes,
      potentially leading to immune evasion of the virus. Here, we demonstrate that
      recombinant, purified ICP47 containing a hexahistidine tag inhibits peptide
      import into microsomes of insect cells expressing human TAP, whereas inhibition
      of peptide transport by murine TAP was much less effective. This finding
      indicates an intrinsic species-specificity of ICP47 and suggests that no
      additional proteins interacting specifically with either ICP47 or TAP are
      required for inhibition of peptide transport. Since neither purified nor induced
      ICP47 inhibited photocrosslinking of 8-azido-ATP to TAP1 and TAP2 it seems that
      ICP47 does not prevent ATP from binding to TAP. By contrast, peptide binding was
      completely blocked by ICP47 as shown both by photoaffinity crosslinking of
      peptides to TAP and peptide binding to microsomes from TAP-transfected insect
      cells. Competition experiments indicated that ICP47 binds to human TAP with a
      higher affinity (50 nM) than peptides whereas the affinity to murine TAP was 100
      fold lower. Our data suggest that ICP47 prevents peptides from being translocated
      by blocking their binding to the substrate-binding site of TAP.

PMID- 8670826
TI  - Stable binding of the herpes simplex virus ICP47 protein to the peptide binding
      site of TAP.
AB  - The herpes simplex virus (HSV) ICP47 protein inhibits the MHC class I antigen
      presentation pathway by inhibiting the transporter associated with antigen
      presentation (TAP) which translocates peptides across the endoplasmic reticulum
      membrane. At present, ICP47 is the only inhibitor of TAP. Here, we show that
      ICP47 produced in bacteria can block human, but not mouse, TAP, and that heat
      denaturation of ICP47 has no effect on its ability to block TAP. ICP47 inhibited
      peptide binding to TAP without affecting ATP binding, consistent with previous
      observations that the peptide binding and ATP binding sites of TAP are distinct.
      ICP47 bound to TAP with a higher affinity (KD approximately 5 x 10(-8) M) than
      did peptides, and ICP47 did not dissociate from TAP. ICP47 was not transported by
      TAP and remained sensitive to proteases added from the cytosolic surface of the
      membrane. Peptides acted as competitive inhibitors of ICP47 binding to TAP, and
      this inhibition required a 100- to 1000-fold molar excess of peptide. These
      results demonstrate that ICP47 binds to a site which includes the peptide binding
      domain of TAP and remains bound to this site in a stable fashion.

PMID- 8670827
TI  - The solution structure of the bovine leukaemia virus matrix protein and
      similarity with lentiviral matrix proteins.
AB  - In the mature virion, retroviral matrix proteins are found in association with
      the inner face of the viral membrane. They play a critical role in determining
      the morphogenesis of virus assembly. We have determined the three-dimensional
      solution structure of the bovine leukaemia virus (BLV) matrix protein by
      heteronuclear nuclear magnetic resonance. The protein contains four principal
      helices that are joined by short, partially structured loops. Despite no sequence
      similarity with the lentiviruses, the structure shows an intriguing homology with
      the equivalent protein from the human and simian immunodeficiency viruses. A root
      mean-square deviation of 3.78 angstrom is observed over the backbone atoms of 36
      equivalent helical positions. The similarity implies a possible common assembly
      unit for the matrix proteins of type C retroviruses.

PMID- 8670828
TI  - Characterization of a novel component of the peroxisomal protein import apparatus
      using fluorescent peroxisomal proteins.
AB  - Fluorescent peroxisomal probes were developed by fusing green fluorescent protein
      (GFP) to the matrix peroxisomal targeting signals PTS1 and PTS2, as well as to an
      integral peroxisomal membrane protein (IPMP). These proteins were used to
      identify and characterize novel peroxisome assembly (pas) mutants in the yeast
      Pichia pastoris. Mutant cells lacking the PAS10 gene mislocalized both PTS1-GFP
      and PTS2-GFP to the cytoplasm but did incorporate IPMP-GFP into peroxisome
      membranes. Similar distributions were observed for endogenous peroxisomal matrix
      and membrane proteins. While peroxisomes from translocation-competent pas mutants
      sediment in sucrose gradients at the density of normal peroxisomes, >98% of
      peroxisomes from pas10 cells migrated to a much lower density and had an
      extremely low ratio of matrix:membrane protein. These data indicate that Pas10p
      plays an important role in protein translocation across the peroxisome membrane.
      Consistent with this hypothesis, we find that Pas10p is an integral protein of
      the peroxisome membrane. In addition, Pas10p contains a cytoplasmically-oriented
      C3HC4 zinc binding domain that is essential for its biological activity.

PMID- 8670829
TI  - Mitochondrial import of only one of three nuclear-encoded glutamine tRNAs in
      Tetrahymena thermophila.
AB  - The mitochondrial genome of Tetrahymena does not appear to encode enough tRNAs to
      perform mitochondrial protein synthesis. It has therefore been proposed that
      nuclear-encoded tRNAs are imported into the mitochondria. T.thermophila has three
      major glutamine tRNAs: tRNA(Gln)(UUG), tRNA(Gln)(UUA) and tRNA(Gln)(CUA). Each of
      these tRNAs functions in cytosolic translation. However, due to differences
      between the Tetrahymena nuclear and mitochondrial genetic codes, only
      tRNA(Gln)(UUG) has the capacity to function in mitochondrial translation as well.
      Here we show that approximately 10-20% of the cellular complement of
      tRNA(Gln)(UUG) is present in mitochondrial RNA fractions, compared with 1% or
      less for the other two glutamine tRNAs. Furthermore, this glutamine tRNA is
      encoded only by a family of nuclear genes, the sequences of several of which are
      presented. Finally, when marked versions of tRNA(Gln)(UUG) and tRNA(Gln)(UUA)
      flanked by identical sequences are expressed in the macronucleus, only the former
      undergoes mitochondrial import; thus sequences within tRNA(Gln)(UUG) direct
      import. Because tRNA(Gln)(UUG) is a constituent of mitochondrial RNA fractions
      and is encoded only by nuclear genes, and because ectopically expressed
      tRNA(Gln)(UUG) fractionates with mitochondria like its endogenous counterpart, we
      conclude that it is an imported tRNA in T.thermophila.

PMID- 8670830
TI  - Homotypic vacuole fusion requires Sec17p (yeast alpha-SNAP) and Sec18p (yeast
      NSF).
AB  - In Saccharomyces cerevisiae, vacuoles are inherited by the formation of tubular
      and vesicular structures from the mother vacuole, the directed projection of
      these structures into the bud and the homotypic fusion of these vesicles. We have
      previously exploited a cell-free inheritance assay to show that the fusion step
      of vacuole inheritance requires cytosol, ATP and the GTPase Ypt7p. Here we
      demonstrate, using affinity-purified antibodies and purified recombinant
      proteins, a requirement for Sec17p (yeast alpha-SNAP) and Sec18p (yeast NSF) in
      homotypic vacuole fusion in vitro. Thus, Sec17p and Sec18p, which are typically
      involved in heterotypic transport steps, can also be involved in homotypic
      organelle fusion. We further show that vacuole-to-vacuole fusion is stimulated by
      certain fatty acyl-coenzyme A compounds in a Sec18p-dependent fashion. Finally,
      our data suggest the presence of a cytosolic factor which activates vacuole
      membrane-bound Sec18p.

PMID- 8670831
TI  - A point mutation in the microtubule binding region of the Ncd motor protein
      reduces motor velocity.
AB  - Non-claret disjunctional (Ncd) is a kinesin-related microtubule motor protein in
      Drosophila that functions in meiotic spindle assembly in oocytes and spindle pole
      maintenance in early embryos. The partial loss-of-function mutant ncdD retains
      mitotic, but not meiotic, function. The predicted NcdD mutant protein contains a
      V556-->F mutation in the putative microtubule binding region of the Ncd motor
      domain. Here we report an analysis of the properties of recombinant Ncd and NcdD
      proteins. A GST-NcdD fusion protein translocated microtubules approximately 10
      fold more slowly than the corresponding wild-type protein in gliding assays. The
      maximum microtubule-stimulated ATPase activity of an NcdD motor domain protein
      was reduced approximately 3-fold and an approximately 3-fold greater
      concentration of microtubules was required for half-maximal stimulation of ATPase
      activity, compared with the corresponding wild-type protein. The Km for ATP and
      basal rate of ATP turnover were, in contrast, similar for the NcdD mutant and
      wild-type Ncd motor domain proteins. Pelleting assays demonstrated that the
      binding of the mutant NcdD motor protein to microtubules was reduced in the
      absence of nucleotide, relative to wild-type. The reduced velocity of NcdD
      translocation on microtubules is therefore correlated with reductions in
      microtubule-stimulated ATPase activity and affinity of the mutant motor for
      microtubules. The characteristics of the NcdD motor explain its meiotic loss of
      function, and are consistent with partial motor activity of Ncd being sufficient
      for its mitotic, but not its meiotic, role.

PMID- 8670832
TI  - Rho-dependent membrane folding causes Shigella entry into epithelial cells.
AB  - The small GTPase rho is functionally involved in the formation of cytoskeletal
      structures like stress fibers or focal adhesion plaques. Shigella entry into HeLa
      cells induces a blossom-like membrane structure at the bacterial entry site. We
      show here that this membrane-folding process is rho-dependent. The three rho
      isoforms were recruited into bacterial entry sites with differential localization
      relative to the membrane structure. A rho-specific inhibitor abolished Shigella
      induced membrane folding and impaired bacterial entry accordingly. S1-myosin
      labeling indicated that rho was involved in Shigella-induced actin polymerization
      but not actin nucleation in the bacterial invasion site. This provides a major
      link in the signalization cascade allowing entry of a bacterial pathogen into a
      eukaryotic cell.

PMID- 8670833
TI  - Kv8.1, a new neuronal potassium channel subunit with specific inhibitory
      properties towards Shab and Shaw channels.
AB  - Outward rectifier K+ channels have a characteristic structure with six
      transmembrane segments and one pore region. A new member of this family of
      transmembrane proteins has been cloned and called Kv8.1. Kv8.1 is essentially
      present in the brain where it is located mainly in layers II, IV and VI of the
      cerebral cortex, in hippocampus, in CA1-CA4 pyramidal cell layer as well in
      granule cells of the dentate gyrus, in the granule cell layer and in the Purkinje
      cell layer of the cerebellum. The Kv8.1 gene is in the 8q22.3-8q24.1 region of
      the human genome. Although Kv8.1 has the hallmarks of functional subunits of
      outward rectifier K+ channels, injection of its cRNA in Xenopus oocytes does not
      produce K+ currents. However Kv8.1 abolishes the functional expression of members
      of the Kv2 and Kv3 subfamilies, suggesting that the functional role of Kv8.1
      might be to inhibit the function of a particular class of outward rectifier K+
      channel types. Immunoprecipitation studies have demonstrated that inhibition
      occurs by formation of heteropolymeric channels, and results obtained with Kv8.1
      chimeras have indicated that association of Kv8.1 with other types of subunits is
      via its N-terminal domain.

PMID- 8670834
TI  - A splice variant of the neurotrophin receptor trkB with increased specificity for
      brain-derived neurotrophic factor.
AB  - The trkB gene codes for a receptor tyrosine kinase, which is essential for the
      development of the peripheral nervous system. This receptor can be activated by
      three different neurotrophins: BDNF, NT-4/5 and NT-3. The extracellular domain of
      trkB was found to be encoded in 10 exons corresponding to receptor subdomains
      previously identified on the basis of protein sequence comparisons. Exon 9 was
      skipped in a novel tyrosine kinase transcript of the trkB gene, designated ctrkB
      Short (ctrkB-S). While the previously described trkB receptor ctrkB-Long (ctrkB
      L) and trkB-S receptors were activated similarly by BDNF, trkB-S interacted
      poorly with NT-4/5 and NT-3 as measured by ligand binding, ligand-induced
      autophosphorylation and ligand-dependent activation of p21ras. Efficient
      activation of ctrkB-S by NT-3 was restored by a single amino acid replacement in
      NT-3 (D15A). Both trkB-L and trkB-S transcripts were detected in embryonic
      neurons.

PMID- 8670835
TI  - Characterization of a new melanocyte-specific gene (QNR-71) expressed in v-myc
      transformed quail neuroretina.
AB  - Quail neuroretina cells (QNR) infected with the v-myc-expressing retrovirus MC29
      become pigmented after several passages in vitro. After differential screening of
      a cDNA library constructed from these cells, we have isolated a cDNA clone (QNR
      71) which identifies an RNA expressed only in the pigmented layer of the retina
      and in the epidermis. This gene can also be induced in other cell types
      transformed by MC29, suggesting that QNR-71 may be regulated by the v-myc
      protein. Sequence analysis showed that the QNR-71 cDNA exhibits stretches of
      homologies with melanosomal proteins encoding genes. From bacterially expressed
      QNR-71 peptides we obtained rabbit antisera able to specifically recognize two
      proteins of 95 and 100 kDa in pigmented retinal cells, but not in the
      neuroretina. To study the regulation of QNR-71, we used promoter fragments linked
      to the CAT reporter gene, in transient co-expression assay. We observed an
      increase in CAT expression with a c-MYC and microphtalmia (mi) expression
      vectors. Both MYC and mi activate the QNR-71 promoter through direct binding to a
      CATGTG site present in the promoter fragment.

PMID- 8670836
TI  - Truncated, desensitization-defective neurokinin receptors mediate sustained MAP
      kinase activation, cell growth and transformation by a Ras-independent mechanism.
AB  - We have used the neurokinin NK-2 receptor as a model to examine how receptor
      desensitization affects cellular responses. The liganded receptor transiently
      activates phospholipase C (PLC) and is rapidly phosphorylated on Ser/Thr residues
      in its C-terminal domain. Mutant receptors lacking this domain mediate persistent
      activation of PLC. We now show that, in transfected Rat-1 cells, mutant receptor
      mediates ligand-induced DNA synthesis, morphological transformation and growth in
      soft agar, whereas wild-type (wt) receptor does not. Wt receptor causes only
      transient MAP kinase activation. In contrast, MAP kinase activation by mutant
      receptor is sustained for >4 h. Neither wt nor mutant receptor couples to Ras
      activation. Downregulation of protein kinase C (PKC) has little effect on MAP
      kinase activation, DNA synthesis and transformation. Mutant receptors also
      promote stronger protein tyrosine phosphorylation and stress fibre formation than
      does wt receptor. Thus, C-terminal truncation allows the NK-2 receptor to signal
      sustained MAP kinase activation, cell growth and transformation by a Ras- and PKC
      independent mechanism. Our results reveal the importance of the C-terminal
      'desensitization domain' in suppressing the oncogenic potential of a prototypic
      PLC-coupled receptor.

PMID- 8670837
TI  - Dual role of cAMP and involvement of both G-proteins and ras in regulation of
      ERK2 in Dictyostelium discoideum.
AB  - Dictyostelium discoideum expresses two Extracellular signal Regulated Kinases,
      ERK1 and ERK2, which are involved in growth, multicellular development and
      regulation of adenylyl cyclase. Binding of extracellular cAMP to cAMP receptor 1,
      a G-protein coupled cell surface receptor, transiently stimulates
      phosphorylation, activation and nuclear translocation of ERK2. Activation of ERK2
      by cAMP is dependent on heterotrimeric G-proteins, since activation of ERK2 is
      absent in cells lacking the Galpha4 subunit. The small G-protein rasD also
      activates ERK2. In cells overexpressing a mutated, constitutively active rasD,
      ERK2 activity is elevated prior to cAMP stimulation. Intracellular cAMP and cAMP
      dependent protein kinase (PKA) are essential for adaptation of the ERK2 response.
      This report shows that multiple signalling pathways are involved in regulation of
      ERK2 activity in D.discoideum.

PMID- 8670839
TI  - Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in
      yeast.
AB  - Iron deprivation of Saccharomyces cerevisiae induces transcription of genes
      required for high-affinity iron uptake. AFT1 mediates this transcriptional
      control. In this report, the 5'-flanking region of FET3, which encodes a copper
      dependent oxidase required for iron transport, was analyzed and found to contain
      a DNA sequence responsible for AFT1-regulated gene expression. AFT1 was capable
      of interacting specifically with this DNA sequence. A core element within this
      DNA sequence necessary for the binding of AFT1 was also determined. In vivo
      footprinting demonstrated occupancy of the AFT1 binding site in cells deprived of
      iron and not in cells grown in the presence of iron. Thus, the environmental
      signal resulting from iron deprivation was transduced through the regulated
      binding of AFT1 to the FET3 promoter, followed by the activation of
      transcription. A regulon of genes under the control of AFT1 could be defined.
      AFT1 was able to bind to a consensus binding site (PyPuCACCCPu) in the 5' region
      of FRE1, FRE2, FTR1, FTH1 and CCC2.

PMID- 8670841
TI  - The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are
      phosphorylated and excluded from the condensed chromosomes during mitosis.
AB  - In yeast, the SNF/SWI complex is believed to regulate transcription by locally
      altering the chromatin structure. At the present time, three human homologues of
      yeast SNF/SWI proteins have been characterized: hbrm and BRG-1, homologues of
      SNF2/SWI2, and hSNF5, a homologue of SNF5. We show here that, during mitosis,
      hbrm and BRG-1 are phosphorylated and excluded from the condensed chromosomes. In
      this phase of the cell cycle, the level of hbrm protein is also strongly reduced,
      whereas the level of BRG-1 remains constant. The mitotic phosphorylation of hbrm
      and BRG-1 is found not to disrupt the association of these proteins with hSNF5
      but correlates with a decreased affinity for the nuclear structure in early M
      phase. We suggest that chromosomal exclusion of the human SNF/SWI complex at the
      G2-M transition could be part of the mechanism leading to transcriptional arrest
      during mitosis.

PMID- 8670842
TI  - Activation of the serum response factor by p65/NF-kappaB.
AB  - This study demonstrates that the NF-kappaB subunit p65 can act like an accessory
      protein for the serum response factor (SRF) in transfection assays. p65
      functionally synergizes with SRF to activate the transcription of a reporter
      construct dependent only on the serum response element (SRE). The synergy of the
      two factors requires neither a kappaB motif nor direct contact of p65 with DNA.
      Consistent with these results, a physical complex containing p65 and SRF is
      observed in vitro. Synergy of the factors is independent of the previously
      described activation domains present on p65, ruling out indirect effects of p65,
      but synergy is dependent on the activation domain of SRF. The complexing of p65
      and SRF is mediated by a segment of the SRF DNA binding domain, a region of the
      protein which has also been reported to inhibit its own activation domain. We
      speculate that p65, upon direct or facilitated interaction with SRF, may relieve
      the inhibitory activity of this segment, thus enabling the activation domain of
      SRF to become fully functional. In contrast to p65, the p50 subunit of NF-kappaB
      does not interact significantly with SRF, either functionally or physically. The
      data suggest the intriguing possibility that NF-kappaB may participate in the
      regulation of SRE-dependent promoters, expanding the range of activities of this
      rapidly activatable transcription factor.

PMID- 8670843
TI  - pX, the HBV-encoded coactivator, interacts with components of the transcription
      machinery and stimulates transcription in a TAF-independent manner.
AB  - The X protein of hepatitis B virus (HBV) coactivates activators bearing potent
      (mostly acidic) activation domains. Here, we investigated the molecular
      mechanisms of this coactivation. We show that pX interacts with general
      transcription factors TFIIB and TFIIH, as well as with the potent activation
      domain of VP16. TFIIB interacts with both pX and VP16 simultaneously. In
      addition, the RNA polymerase II enzyme itself binds to pX. By reducing the
      activity of cellular coactivators, through squelching, we intensify the
      dependence of the activator on pX-mediated coactivation. Squelching is
      essentially diminished in the presence of pX, both in vivo and in vitro. The
      target of pX in this activity is the template-bound activator, and not the
      squelcher. Furthermore, by following transcription in a TAF-deprived reaction, we
      demonstrate absolute dependence of the activator on the activity of pX. We
      propose that pX coactivates transcription by substituting cellular coactivators
      in activator-preinitiation complex interactions.

PMID- 8670844
TI  - Identification of two DNA-binding sites on the globular domain of histone H5.
AB  - The nature of the complexes of histones H1 and H5 and their globular domains (GH1
      and GH5) with DNA suggested two DNA-binding sites which are likely to be the
      basis of the preference of H1 and H5 for the nucleosome, compared with free DNA.
      More recently the X-ray and NMR structures of GH5 and GH1, respectively, have
      identified two basic clusters on opposite sides of the domains as candidates for
      these sites. Removal of the positive charge at either location by mutagenesis
      impairs or abolishes the ability of GH5 to assemble cooperatively in 'tramline'
      complexes containing two DNA duplexes, suggesting impairment or loss of its
      ability to bind two DNA duplexes. The mutant forms of GH5 also fail to protect
      the additional 20 bp of nucleosomal DNA that are characteristically protected by
      H1, H5 and wild-type recombinant GH5. They still bind to H1/H5-depleted
      chromatin, but evidently inappropriately. These results confirm the existence of,
      and identify the major components of, two DNA-binding sites on the globular
      domain of histone H5, and they strongly suggest that both binding sites are
      required to position the globular domain correctly on the nucleosome.

PMID- 8670845
TI  - A DNA binding motif coordinating synthesis and degradation in proofreading DNA
      polymerases.
AB  - The functional significance of the conserved motif 'YxGG/A', located between the
      3'-5' exonuclease and polymerization domains of eukaryotic-type DNA polymerases,
      has been studied by site-directed mutagenesis in phi29 DNA polymerase. Single
      substitutions at this region were obtained, and 11 phi29 DNA polymerase mutant
      derivatives were overproduced in Escherichia coli and purified to homogeneity.
      Nine mutants showed an altered polymerase/3'-5' exonuclease balance on a
      template/primer DNA structure, giving rise to three different mutant phenotypes:
      (i) favored polymerization (high pol/exo ratio); (ii) favored exonucleolysis (low
      pol/exo ratio); and (iii) favored exonucleolysis and null polymerization.
      Interestingly, these three different phenotypes could be obtained by mutating a
      single amino acid at the 'YxGG/A' motif. All different phenotypes could be
      directly related to defects in DNA binding at a particular active site. Thus, a
      high pol/exo ratio was related to a poor stability at the 3'-5' exonuclease
      active site. On the contrary, a low pol/exo ratio or null polymerization capacity
      was related to a poor stability at the polymerization active site and either a
      normal or an increased accessibility to the exonuclease active site. These
      results allow us to propose that this motif, located in the connecting region
      between the N-terminal and C-terminal domains, has a primary role in DNA binding,
      playing a critical role in the coordination or cross-talk between synthesis and
      degradation.

PMID- 8670846
TI  - Excision of cytosine and thymine from DNA by mutants of human uracil-DNA
      glycosylase.
AB  - Uracil-DNA glycosylase (UDG) protects the genome by removing mutagenic uracil
      residues resulting from deamination of cytosine. Uracil binds in a rigid pocket
      at the base of the DNA-binding groove of human UDG and the specificity for uracil
      over the structurally related DNA bases thymine and cytosine is conferred by
      shape complementarity, as well as by main chain and Asn204 side chain hydrogen
      bonds. Here we show that replacement of Asn204 by Asp or Tyr147 by Ala, Cys or
      Ser results in enzymes that have cytosine-DNA glycosylase (CDG) activity or
      thymine-DNA glycosylase (TDG) activity, respectively. CDG and the TDG all retain
      some UDG activity. CDG and TDG have kcat values in the same range as typical
      multisubstrate-DNA glycosylases, that is at least three orders of magnitude lower
      than that of the highly selective and efficient wild-type UDG. Expression of CDG
      or TDG in Escherichia coli causes 4- to 100-fold increases in the yield of
      rifampicin-resistant mutants. Thus, single amino acid substitutions in UDG result
      in less selective DNA glycosylases that release normal pyrimidines and confer a
      mutator phenotype upon the cell. Three of the four new pyrimidine-DNA
      glycosylases resulted from single nucleotide substitutions, events that may also
      happen in vivo.

PMID- 8670847
TI  - Identification of contacts between topoisomerase I and its target DNA by site
      specific photocrosslinking.
AB  - Vaccinia DNA topoisomerase, a eukaryotic type I enzyme, binds and cleaves duplex
      DNA at sites containing the sequence 5'-(T/C)CCTT. We report the identification
      of Tyr70 as the site of contact between the enzyme and the +4C base of its target
      site. This was accomplished by UV-crosslinking topoisomerase to bromocytosine
      substituted DNA, followed by isolation and sequencing of peptide-DNA
      photoadducts. A model for the topoisomerase-DNA interface is proposed, based on
      the crystal structure of a 9 kDa N-terminal tryptic fragment. The protein domain
      fits into the DNA major groove such that Tyr70 is positioned close to the +4C
      base and Tyr72 is situated near the +3C base. Mutational analysis indicates that
      Tyr70 and Tyr72 contribute to site recognition during covalent catalysis. We
      propose, based on this and other studies of the vaccinia protein, that DNA
      backbone recognition and reaction chemistry are performed by a relatively well
      conserved 20 kDa C-terminal portion of the vaccinia enzyme, whereas
      discrimination of the DNA sequence at the cleavage site is accomplished by a
      separate N-terminal domain, which is less conserved between viral and cellular
      proteins. Division of function among distinct structural modules may explain the
      different site specificities of the eukaryotic type I topoisomerases.

PMID- 8670848
TI  - Template-free generation of RNA species that replicate with bacteriophage T7 RNA
      polymerase.
AB  - A large variety of different RNA species that are replicated by DNA-dependent RNA
      polymerase from bacteriophage T7 have been generated by incubating high
      concentrations of this enzyme with substrate for extended time periods. The
      products differed from sample to sample in molecular weight and sequence, their
      chain lengths ranging from 60 to 120. The mechanism of autocatalytic
      amplification of RNA by T7 RNA polymerase proved to be analogous to that observed
      with viral RNA-dependent RNA polymerases (replicases): only single-stranded
      templates are accepted and complementary replica strands are synthesized. With
      enzyme in excess, exponential growth was observed; linear growth resulted when
      the enzyme was saturated by RNA template. The plus strands, present at 90% of the
      replicating RNA species, were found to have GG residues at both termini.
      Consensus sequences were not found among the sequences of the replicating RNA
      species. The secondary structures of all species sequenced turned out to be
      hairpins. The RNA species were specifically replicated by T7 RNA polymerase; they
      were not accepted as templates by the RNA polymerases from Escherichia coli or
      bacteriophage SP6 or by Qbeta replicase; T3 RNA polymerase was partially active.
      Template-free production of RNA was completely suppressed by addition of DNA to
      the incubation mixture. When both DNA and RNA templates were present,
      transcription and replication competed, but T7 RNA polymerase preferred DNA as a
      template. No replicating RNA species were detected in vivo in cells expressing T7
      RNA polymerase.

PMID- 8670849
TI  - An RNA conformational change between the two chemical steps of group II self
      splicing.
AB  - As for nuclear pre-mRNA introns, the splicing pathway of group II self-splicing
      introns proceeds by two successive transesterifications involving substrates with
      different chemical configurations. These two reactions have been proposed to be
      catalysed by two active sites, or alternatively by a single active site
      rearranging its components to accommodate the successive substrates. Here we show
      that the structural elements specific for the second splicing step are clustered
      in peripheral structures of domains II and VI. We show that these structures are
      not required for catalysis of the second chemical step but, instead, take part in
      a conformational change that occurs between the two catalytic steps. This
      rearrangement involves the formation of a tertiary contact between part of domain
      II and a GNRA tetraloop at the tip of domain VI. The fact that domain VI, which
      carries the branched structure, is involved in this structural rearrangement and
      the fact that modifications affecting the structures involved have almost no
      effect when splicing proceeds without branch formation, suggest that the
      conformational change results in the displacement of the first-step product out
      of the active site. These observations give further support to the existence of a
      single active site in group II introns.

PMID- 8670850
TI  - Membrane regulation of the chromosomal replication activity of E. coli DnaA
      requires a discrete site on the protein.
AB  - The capacity of DnaA protein to initiate DNA synthesis at the chromosomal origin
      is influenced profoundly by the tightly bound nucleotides ATP and ADP. Acidic
      phospholipids can catalyze the conversion of inactive ADP-DnaA protein into the
      active ATP form. Proteolytic fragments of the nucleotide form of DnaA protein
      were examined to determine regions of the protein critical for functional
      interaction with membranes. A 35 kDa chymotryptic and 29 kDa tryptic fragment
      retained the tightly bound nucleotide. The fragments, whose amino-termini are
      within three residues of each other, but differ at their carboxyl ends, showed
      strikingly different behavior when treated with acidic phospholipids. The larger
      chymotryptic fragment released the bound nucleotide in the presence of acidic,
      but not neutral phospholipids. In contrast, the smaller tryptic fragment was
      inert to both forms of phospholipids. Acidic membranes, but not those composed of
      neutral phospholipids, protect from tryptic digestion a small portion of the
      segment that constitutes the difference between the 29 and 35 kDa fragments. The
      resulting 30 kDa tryptic fragment, which possesses this protected region,
      interacts functionally with acidic membranes to release the bound effector
      nucleotide. Inasmuch as the anionic ganglioside GM1, a compound structurally
      dissimilar to acidic glycerophospholipids, efficiently releases the nucleotide
      from DnaA protein, an acidic surface associated with a hydrophobic environment is
      the characteristic of the membrane that appears crucial for regulatory
      interaction with DnaA protein.

PMID- 8670851
TI  - Crystal structure of bacteriophage T4 deoxynucleotide kinase with its substrates
      dGMP and ATP.
AB  - NMP kinases catalyse the phosphorylation of the canonical nucleotides to the
      corresponding diphosphates using ATP as a phosphate donor. Bacteriophage T4
      deoxynucleotide kinase (DNK) is the only member of this family of enzymes that
      recognizes three structurally dissimilar nucleotides: dGMP, dTMP and 5
      hydroxymethyl-dCMP while excluding dCMP and dAMP. The crystal structure of DNK
      with its substrate dGMP has been determined at 2.0 A resolution by single
      isomorphous replacement. The structure of the ternary complex with dGMP and ATP
      has been determined at 2.2 A resolution. The polypeptide chain of DNK is folded
      into two domains of equal size, one of which resembles the mononucleotide binding
      motif with the glycine-rich P-loop. The second domain, consisting of five alpha
      helices, forms the NMP binding pocket. A hinge connection between the domains
      allows for large movements upon substrate binding which are not restricted by
      dimerization of the enzyme. The mechanism of active centre formation via domain
      closure is described. Comparison with other P-loop-containing proteins indicates
      an induced-fit mode of NTP binding. Protein-substrate interactions observed at
      the NMP and NTP sites provide the basis for understanding the principles of
      nucleotide discrimination.

PMID- 8670852
TI  - The chloroplast ycf7 (petL) open reading frame of Chlamydomonas reinhardtii
      encodes a small functionally important subunit of the cytochrome b6f complex.
AB  - The small chloroplast open reading frame ORF43 (ycf7) of the green unicellular
      alga Chlamydomonas reinhardtii is cotranscribed with the psaC gene and ORF58.
      While ORF58 has been found only in the chloroplast genome of C.reinhardtii, ycf7
      has been conserved in land plants and its sequence suggests that its product is a
      hydrophobic protein with a single transmembrane alpha helix. We have disrupted
      ORF58 and ycf7 with the aadA expression cassette by particle-gun mediated
      chloroplast transformation. While the ORF58::aadA transformants are
      indistinguishable from wild type, photoautotrophic growth of the ycf7::aadA
      transformants is considerably impaired. In these mutant cells, the amount of
      cytochrome b6f complex is reduced to 25-50% of wild-type level in mid-exponential
      phase, and the rate of transmembrane electron transfer per b6f complex measured
      in vivo under saturating light is three to four times slower than in wild type.
      Under subsaturating light conditions, the rate of the electron transfer reactions
      within the b6f complex is reduced more strongly in the mutant than in the wild
      type by the proton electrochemical gradient. The ycf7 product (Ycf7) is absent in
      mutants deficient in cytochrome b6f complex and present in highly purified b6f
      complex from the wild-type strain. Ycf7-less complexes appear more fragile than
      wild-type complexes and selectively lose the Rieske iron-sulfur protein during
      purification. These observations indicate that Ycf7 is an authentic subunit of
      the cytochrome b6f complex, which is required for its stability, accumulation and
      optimal efficiency. We therefore propose to rename the ycf7 gene petL.

PMID- 8670853
TI  - Homophilic adhesion of E-cadherin occurs by a co-operative two-step interaction
      of N-terminal domains.
AB  - Cluster formation of E-cadherin on the cell surface is believed to be of major
      importance for cell-cell adhesion. To mimic this process the extracellular part
      of mouse E-cadherin (ECAD) was recombinantly fused to the assembly domain of rat
      cartilage oligomeric matrix protein (COMP), resulting in the chimeric protein
      ECAD-COMP. The COMP domain formed a five-stranded alpha-helical coiled-coil. This
      enabled the formation of a pentameric ECAD with bundled C-termini and free N
      termini. The pentameric protein construct ECAD-COMP and the monomeric ECAD were
      expressed in human embryonal kidney 293 cells. Electron microscopy, analytical
      ultracentrifugation, solid phase binding and cell attachment assays revealed that
      pentamers showed strong self-association and cell attachment, whereas monomers
      exhibited no activity. At the high internal concentration in the pentamer the N
      terminal EC1 domains of two E-cadherin arms interact to form a ring-like
      structure. Then the paired domains interact with a corresponding pair from
      another pentamer. None of the four other extracellular domains of E-cadherin is
      involved in this interaction. Based on these results, an in vivo mechanism is
      proposed whereby two N-terminal domains of neighbouring E-cadherins at the cell
      surface first form a pair, which binds with high affinity to a similar complex on
      another cell. The strong dependence of homophilic interactions on C-terminal
      clustering points towards a regulation of E-cadherin mediated cell-cell adhesion
      via lateral association.

PMID- 8670854
TI  - Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane
      copper transporter Ctr1p in the apparent absence of endocytosis.
AB  - The cell surface protein repertoire needs to be regulated in response to changes
      in the extracellular environment. In this study, we investigate protein turnover
      of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p, in
      response to a change in extra-cellular copper levels. As Ctr1p mediates high
      affinity uptake of copper into the cell, modulation of its expression is expected
      to be involved in copper homeostasis. We demonstrate that Ctr1p is a stable
      protein when cells are grown in low concentrations of copper, but that exposure
      of cells to high concentrations of copper (10 microM) triggers degradation of
      cell surface Ctr1p. This degradation appears to be specific for Ctr1p and does
      not occur with another yeast plasma membrane protein tested. Internalization of
      some Ctr1p can be seen when cells are exposed to copper. However, yeast mutant
      strains defective in endocytosis (end3, end4 and chc1-ts) and vacuolar
      degradation (pep4) exhibit copper-dependent Ctr1p degradation, indicating that
      internalization and delivery to the vacuole is not the principal mechanism
      responsible for degradation. In addition, a variant Ctr1p with a deletion in the
      cytosolic tail is not internalized upon exposure of cells to copper, but is
      nevertheless degraded. These observations indicate that proteolysis at the plasma
      membrane most likely explains copper-dependent turnover of Ctr1p and point to the
      existence of a novel pathway in yeast for plasma membrane protein turnover.

PMID- 8670855
TI  - Porins of Escherichia coli: unidirectional gating by pressure.
AB  - OmpC and PhoE porins of Escherichia coli were examined by the patch-clamp
      technique following reconstitution in liposomes, and were observed primarily in
      the open (conducting) state. With application of negative voltage and positive
      hydrostatic pressure, OmpC exhibited marked gating towards a more closed state
      whereas PhoE remained largely unaffected by pressure application. Hybrid chimeric
      OmpC-PhoE proteins showed an increased tendency for pressure-dependent gating as
      the OmpC proportion in the chimeric molecule increased. In addition, several PhoE
      mutants with amino acid substitutions and insertions in either the L3 or L4 loop
      of the monomer exhibited pressure sensitivity comparable with the wild-type OmpC
      porin. Our data support the structural plasticity model of porins and are
      consistent with the 'charge-screening-unscreening' hypothesis that describes how
      these proteins may exist in distinct conformations.

PMID- 8670856
TI  - In vivo membrane assembly of split variants of the E.coli outer membrane protein
      OmpA.
AB  - The two-domain, 325 residue outer membrane protein OmpA of Escherichia coli is a
      well-established model for the study of membrane assembly. The N-terminal domain,
      consisting of approximately 170 amino acid residues, is embedded in the membrane,
      presumably in the form of a beta-barrel consisting of eight antiparallel
      transmembrane beta-strands. A set of 16 gene variants carrying deletions in the
      membrane-embedded domain of OmpA was constructed. When pairs of these mutant
      genes were co-expressed in E.coli, it was found that a functional OmpA protein
      could be assembled efficiently from two complementary protein fragments. Assembly
      was found when the polypeptide chain was split at the second or third periplasmic
      turn. All four protein termini were located in the periplasmic space.
      Interestingly, duplication of transmembrane strands five and six led to a variant
      with an unusual topology: the N-terminus of one fragment and the C-terminus of
      the other fragment were exposed at the cell surface. This is the first
      demonstration of correct membrane assembly of split beta-structured membrane
      proteins. These findings are important for a better understanding of their
      folding/assembly pathway and may have implications for the development of
      artificial outer membrane proteins and for the cell surface display of
      heterologous peptides or proteins.

PMID- 8670857
TI  - Competition between folding and glycosylation in the endoplasmic reticulum.
AB  - Using carboxypeptidase Y in Saccharomyces cerevisiae as a model system, the in
      vivo relationship between protein folding and N-glycosylation was studied. Seven
      new sites for N-glycosylation were introduced at positions buried in the folded
      protein structure. The level of glycosylation of such new acceptor sites was
      analysed by pulse-labelling under two sets of conditions that are known to reduce
      the rate of folding: (i) addition of dithiothreitol to the growth medium and (ii)
      introduction of deletions in the propeptide. A variety of effects was observed,
      depending on the position of the new acceptor sites. In some cases, all the newly
      synthesized mutant protein was modified at the novel site while in others no
      modification took place. In the most interesting category of mutants, the level
      of glycosylation was dependent on the conditions for folding. This shows that
      folding and glycosylation reactions can compete in vivo and that glycosylation
      does not necessarily precede folding. The approach described may be generally
      applicable for the analysis of protein folding in vivo.

PMID- 8670858
TI  - Bacterial glycoproteins: a link between glycosylation and proteolytic cleavage of
      a 19 kDa antigen from Mycobacterium tuberculosis.
AB  - Protein glycosylation has an important influence on a broad range of molecular
      interactions in eukaryotes, but is comparatively rare in bacteria. Several
      antigens from Mycobacterium tuberculosis, the causative agent of human
      tuberculosis, have been identified as glycoproteins on the basis of lectin
      binding, or by detailed structural analysis. By production of a set of alkaline
      phosphatase (PhoA) hybrid proteins in a mycobacterial expression system, the
      peptide region required for glycosylation of the 19 kDa lipoprotein antigen from
      M.tuberculosis was defined. Mutagenesis of two threonine clusters within this
      region abolished lectin binding by PhoA hybrids and by the 19 kDa protein itself.
      Substitution of the threonine residues also resulted in generation of a series of
      smaller forms of the protein as a result of proteolysis. In a working model to
      account for these observations, we propose that the role of glycosylation is to
      regulate cleavage of a proteolytically sensitive linker region close to the
      acylated N-terminus of the protein.

PMID- 8670859
TI  - A novel nuclear structure containing the survival of motor neurons protein.
AB  - Spinal muscular atrophy (SMA) is a common, often fatal, autosomal recessive
      disease leading to progressive muscle wasting and paralysis as a result of
      degeneration of anterior horn cells of the spinal cord. A gene termed survival of
      motor neurons (SMN), at 5q13, has been identified as the determining gene of SMA
      (Lefebvre et al., 1995). The SMN gene is deleted in > 98% of SMA patients, but
      the function of the SMN protein is unknown. In searching for hnRNP-interacting
      proteins we found that SMN interacts with the RGG box region of hnRNP U, with
      itself, with fibrillarin and with several novel proteins. We have produced
      monoclonal antibodies to the SMN protein, and we report here on its striking
      cellular localization pattern. Immunolocalization studies using SMN monoclonal
      antibodies show several intense dots in HeLa cell nuclei. These structures are
      similar in number (2-6) and size (0.1-1.0 micron) to coiled bodies, and
      frequently are found near or associated with coiled bodies. We term these
      prominent nuclear structures gems, for Gemini of coiled bodies.

PMID- 8670860
TI  - Constitutively active mutants of the alpha 1B-adrenergic receptor: role of highly
      conserved polar amino acids in receptor activation.
AB  - Site-directed mutagenesis and molecular dynamics simulations of the alpha 1B
      adrenergic receptor (AR) were combined to explore the potential molecular changes
      correlated with the transition from R (inactive state) to R (active state). Using
      molecular dynamics analysis we compared the structural/dynamic features of
      constitutively active mutants with those of the wild type and of an inactive
      alpha 1B-AR to build a theoretical model which defines the essential features of
      R and R. The results of site-directed mutagenesis were in striking agreement with
      the predictions of the model supporting the following hypothesis. (i) The
      equilibrium between R and R depends on the equilibrium between the deprotonated
      and protonated forms, respectively, of D142 of the DRY motif. In fact,
      replacement of D142 with alanine confers high constitutive activity to the alpha
      1B-AR. (ii) The shift of R143 of the DRY sequence out of a conserved 'polar
      pocket' formed by N63, D91, N344 and Y348 is a feature common to all the active
      structures, suggesting that the role of R143 is fundamental for mediating
      receptor activation. Disruption of these intramolecular interactions by replacing
      N63 with alanine constitutively activates the alpha 1B-AR. Our findings might
      provide interesting generalities about the activation process of G protein
      coupled receptors.

PMID- 8670861
TI  - Structure of a specific peptide complex of the carboxy-terminal SH2 domain from
      the p85 alpha subunit of phosphatidylinositol 3-kinase.
AB  - We have determined the solution structure of the C-terminal SH2 domain of the p85
      alpha subunit of human phosphatidylinositol (PI) 3-kinase (EC 2.7.1.137) in
      complex with a phosphorylated tyrosine pentapeptide sequence from the platelet
      derived growth factor receptor using heteronuclear nuclear magnetic resonance
      spectroscopy. Overall, the structure is similar to other SH2 domain complexes,
      but displays different detail interactions within the phosphotyrosine binding
      site and in the recognition site for the +3 methionine residue of the peptide,
      the side chain of which inserts into a particularly deep and narrow pocket which
      is displaced relative to that of other SH2 domains. The contacts made within this
      +3 pocket provide the structural basis for the strong selection for methionine at
      this position which characterizes the SH2 domains of PI3-kinase. Comparison with
      spectral and structural features of the uncomplexed domain shows that the long BG
      loop becomes less mobile in the presence of the bound peptide. In contrast,
      extreme resonance broadening encountered for most residues in the beta D', beta E
      and beta F strands and associated connecting loops of the domain in the absence
      of peptide persists in the complex, implying conformational averaging in this
      part of the molecule on a microsecond-to-millisecond time scale.

PMID- 8670862
TI  - Newly assembled cyclin B-cdc2 kinase is required to suppress DNA replication
      between meiosis I and meiosis II in starfish oocytes.
AB  - Micro-injection of catalytically inactive GST-cdc2-K33R or GST-cdk2-K33R fusion
      proteins, each of which efficiently titrates cyclin B in oocytes and prevents
      assembly of cyclin B-cdc2 complexes, readily induces premature DNA replication in
      starfish oocytes after emission of the first polar body. Moreover, partial
      ablation of cyclin B mRNA by micro-injection of antisense oligonucleotides
      facilitates premature DNA replication induced by the dominant-negative cdc2 and
      cdk2 mutant proteins. We thus propose that enhanced translation of cyclin B after
      GVBD, a universal feature of oocyte maturation in the animal kingdom, and
      subsequent assembly of cyclin B-cdc2 complexes, are part of the checkpoint that
      prevents DNA replication in the oocyte after emission of the first polar body.
      MAPK inactivation is neither required for premature DNA replication after the
      first meiotic cell cycle nor for DNA replication after completion of meiotic
      maturation. However, micro-injection of a N-terminally truncated form of the
      budding yeast STE11 protein, that constitutively maintains MAPK active after the
      second meiotic cleavage, prevents fertilized eggs from proceeding into
      embryogenesis, and arrests them at G2, as is the case in unfertilized eggs that
      cannot inactivate MAPK after the second meiotic cleavage. We thus propose that
      MAPK functions in meiotic maturation by preventing unfertilized eggs from
      proceeding into parthenogenetic development.

PMID- 8670863
TI  - Two S-phase checkpoint systems, one involving the function of both BIME and Tyr15
      phosphorylation of p34cdc2, inhibit NIMA and prevent premature mitosis.
AB  - We demonstrate that there are at least two S-phase checkpoint mechanisms
      controlling mitosis in Aspergillus. The first responds to the rate of DNA
      replication and inhibits mitosis via tyrosine phosphorylation of p34cdc2. Cells
      unable to tyrosine phosphorylate p34cdc2 are therefore viable but are unable to
      tolerate low levels of hydroxyurea and prematurely enter lethal mitosis when S
      phase is slowed. However, if the NIMA mitosis-promoting kinase is inactivated
      then non-tyrosine-phosphorylated p34cdc2 cannot promote cells prematurely into
      mitosis. Lack of tyrosine-phosphorylated p34cdc2 also cannot promote mitosis, or
      lethality, if DNA replication is arrested, demonstrating the presence of a second
      S-phase checkpoint mechanism over mitotic initiation which we show involves the
      function of BIME. In order to overcome the S-phase arrest checkpoint over mitosis
      it is necessary both to prevent tyrosine phosphorylation of p34cdc2 and also to
      inactivate BIME. Lack of tyrosine phosphorylation of p34cdc2 allows precocious
      expression of NIMA during S-phase arrest, and lack of BIME then allows activation
      of this prematurely expressed NIMA by phosphorylation. The mitosis-promoting NIMA
      kinase is thus a target for S-phase checkpoint controls.

PMID- 8670864
TI  - The Saccharomyces cerevisiae kinetochore contains a cyclin-CDK complexing
      homologue, as identified by in vitro reconstitution.
AB  - We have developed methods to reconstitute the centromere DNA (CEN)-bound
      Saccharomyces cerevisiae kinetochore complex, CBF3, from isolated CBF3 components
      in vitro. This revealed that cooperation of at least three CBF3 components is
      imperatively required to form an activity that specifically binds to the
      centromere DNA in vitro. Two of the CBF3 proteins, Cbf3a and Cbf3b, that were
      used in the reconstitution were obtained from heterologous systems. In contrast,
      Cbf3c, the third CBF3 component known, had to be purified from S. cerevisiae to
      obtain a Cbf3c preparation that was competent to reconstitute the CBF3-CEN
      complex in combination with Cbf3a and Cbf3b. This led to the identification of a
      29 kDa protein that co-purified with Cbf3c. The 29 kDa protein was shown to be a
      fourth component of CBF3 and therefore was named Cbf3d. Analysing the Cbf3d gene
      revealed that Cbf3d exhibits strong homology to p19SKP1, a human protein that is
      part of active cyclin A-CDK2 complexes. Therefore, Cbf3d is the only CBF3 protein
      that has a known homologue in higher eukaryotes and may provide the anchor that
      directs cell cycle-regulated proteins to the kinetochore.

PMID- 8670866
TI  - Temporal reiteration of a precise gene expression pattern during nematode
      development.
AB  - The nematode Caenorhabditis elegans is contained within a multifunctional
      exoskeleton, the cuticle, that contains a large number of distinct collagens. As
      the nematode proceeds from the egg through four larval stages to the adult,
      transition between larval stages is marked by synthesis of a new cuticle and
      subsequent moulting of the old one. This is a cyclically repeated developmental
      event, frequently described as the moulting cycle. We have examined the temporal
      expression of a group of six genes encoding distinct cuticular collagens. As
      expected, mRNA abundance for each of the six genes tested is found to oscillate,
      peaking once during each larval stage. Unexpectedly, the periods of abundance for
      each gene do not coincide, different genes being expressed at different times
      relative to one another within the moulting cycle. We detect a programme of
      temporally distinct waves of collagen gene expression, the precise pattern of
      which is repeated during each of the four larval stages. This multiphasic pattern
      of oscillating cuticular collagen gene expression indicates an unexpected
      complexity of temporal control during the nematode moulting cycle and has
      implications for collagen trimerization and cuticle synthesis.

PMID- 8670865
TI  - Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel
      cytosolic dual-specificity phosphatase.
AB  - The Pyst1 and Pyst2 mRNAs encode closely related proteins, which are novel
      members of a family of dual-specificity MAP kinase phosphatases typified by
      CL100/MKP-1. Pyst1 is expressed constitutively in human skin fibroblasts and, in
      contrast to other members of this family of enzymes, its mRNA is not inducible by
      either stress or mitogens. Furthermore, unlike the nuclear CL100 protein, Pyst1
      is localized in the cytoplasm of transfected Cos-1 cells. Like CL100/ MKP-1,
      Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo. In
      addition, Pyst1 is able to form a physical complex with endogenous MAP kinase in
      Cos-1 cells. However, unlike CL100, Pyst1 displays very low activity towards the
      stress-activated protein kinases (SAPKs) or RK/p38 in vitro, indicating that
      these kinases are not physiological substrates for Pyst1. This specificity is
      underlined by the inability of Pyst1 to block either the stress-mediated
      activation of the JNK-1 SAP kinase or RK/p38 in vivo, or to inhibit nuclear
      signalling events mediated by the SAP kinases in response to UV radiation. Our
      results provide the first evidence that the members of the MAP kinase family of
      enzymes are differentially regulated by dual-specificity phosphatases and also
      indicate that the MAP kinases may be regulated by different members of this
      family of enzymes depending on their subcellular location.

PMID- 8670867
TI  - The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic
      mice.
AB  - The oncogene product from the avian reticuloendotheliosis virus strain T, v-Rel,
      is a member of the Rel/ NF-kappa B family of transcription factors. The mechanism
      by which v-Rel induces oncogenic transformation remains unclear. Several attempts
      to transform mammalian cells with v-Rel have failed, suggesting that v-Rel
      transformation may be a species-specific event. However, here we demonstrate that
      v-Rel, but not a truncated c-Rel, expressed under the control of the lck
      promoter, efficiently induced malignancies in transgenic mice. Most of the
      animals died before 10 months of age and developed immature, multicentric
      aggressive T-cell leukemia/lymphomas. Most tumors contain CD4+CD8+ cells or CD4
      CD8+ cells, which have an immature rather than a mature peripheral phenotype. No
      tumor development was observed in control littermates and transgenic mice
      expressing a truncated form of c-Rel. Tumor formation was correlated with the
      presence of constitutive p50/v-Rel DNA binding activity and overexpression of
      several kappa B-regulated genes in v-rel transgenic thymocytes. However, v-Rel is
      also transforming in transgenic thymocytes lacking p50, indicating that p50/v-Rel
      heterodimer formation is not essential for the transforming activity of v-Rel.
      The transforming activity of v-Rel in p50 null mice has been identified as v
      Rel/v-Rel homodimers. Since tumors represent immature T-lymphocytes, constitutive
      v-Rel expression appears to be leukemogenic at earlier stages of T-cell
      development. These v-Rel mice should aid in the study of lymphoma development, T
      cell development and NF-kappa B regulation.

PMID- 8670868
TI  - A central role for Stat3 in IL-6-induced regulation of growth and differentiation
      in M1 leukemia cells.
AB  - Interleukin-6 (IL-6) induces either differentiation or growth of a variety of
      cells. Little is known about the molecular basis of this cellular decision. The
      family of signal transducer and activator of transcription (Stat) proteins are
      involved in signaling through a variety of cytokine and growth factor receptors,
      although their biological roles have not been established. To address whether
      Stat proteins play roles in IL-6-induced growth or differentiation, we introduced
      two types of mutant Stat3 acting in a dominant-negative manner into M1 leukemic
      cells which respond to IL-6 with growth arrest and terminal differentiation. We
      show that dominant-negative forms of Stat3 inhibited both IL-6-induced growth
      arrest at G(0)/G1 and macrophage differentiation in the M1 transformants.
      Blocking of Stat activation resulted in inhibition of IL-6-induced repression of
      c-myb and c-myc. Furthermore, IL-6 enhanced the growth of M1 cells primarily
      through shortening the length of the G1 period when Stat3 was suppressed. Thus IL
      6 generates both growth-enhancing signals and growth arrest- and differentiation
      inducing signals at the same time. Stat3 may be a key molecule which determines
      the cellular decision from cell growth to differentiation in M1 cells.

PMID- 8670869
TI  - The gap protein knirps mediates both quenching and direct repression in the
      Drosophila embryo.
AB  - Transcriptional repression is essential for establishing localized patterns of
      gene expression during Drosophila embryogenesis. Several mechanisms of repression
      have been proposed, including competition, quenching and direct repression of the
      transcription complex. Previous studies suggest that the knirps orphan receptor
      (kni) may repress transcription via competition, and exclude the binding of the
      bicoid (bcd) activator to an overlapping site in a target promoter. Here we
      present evidence that kni can quench, or locally inhibit, upstream activators
      within a heterologous enhancer in transgenic embryos. The range of kni repression
      is approximately 50-100 bp, so that neighboring enhancers in a modular promoter
      are free to interact with the transcription complex (enhancer autonomy). However,
      kni can also repress the transcription complex when bound in promoter-proximal
      regions. In this position, kni functions as a dominant repressor and blocks
      multiple enhancers in a modular promoter. Our studies suggest that short-range
      repression represents a flexible form of gene regulation, exhibiting enhancer- or
      promoter-specific effects depending on the location of repressor binding sites.

PMID- 8670870
TI  - TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation
      function AF-2 of nuclear receptors.
AB  - Nuclear receptors (NRs) act as ligand-inducible transcription factors which
      regulate the expression of target genes upon binding to cognate response
      elements. The ligand-dependent activity of the NR activation function AF-2 is
      believed to be mediated to the transcription machinery through transcriptional
      mediators/intermediary factors (TIFs). We report here the cloning of the 160 kDa
      human nuclear protein TIF2, which exhibits all properties expected for a mediator
      of AF-2: (i) it interacts in vivo with NRs in an agonist-dependent manner; (ii)
      it binds directly to the ligand-binding domains (LBDs) of NRs in an agonist- and
      AF-2-integrity-dependent manner in vitro; (iii) it harbours an autonomous
      transcriptional activation function; (iv) it relieves nuclear receptor
      autosquelching; and (v) it enhances the activity of some nuclear receptor AF-2s
      when overexpressed in mammalian cells. TIF2 exhibits partial sequence homology
      with the recently isolated steroid receptor coactivator SRC-1, indicating the
      existence of a novel gene family of nuclear receptor transcriptional mediators.

PMID- 8670871
TI  - Requirements for dE2F function in proliferating cells and in post-mitotic
      differentiating cells.
AB  - The transcription factor E2F is a target of the retinoblastoma tumor suppressor
      protein (pRB) and may mediate pRB regulation of S phase entry in mammalian cells.
      The recent identification of mutant alleles of the Drosophila E2F gene (dE2F) has
      shown that dE2F is required for embryogenesis. dE2F-mutant embryos lack a co
      ordinated program of gene expression which accompanies S phase entry and DNA
      synthesis declines to levels that are barely detectable. We have investigated the
      role of the dE2F gene at later stages of development. dE2F is expressed in
      several larval tissues and is required for cell proliferation in the eye imaginal
      disc. Surprisingly, dE2F expression persists in post-mitotic cells of the eye
      disc of third-instar larvae. The loss of dE2F function in these cells causes a
      novel phenotype, characterized by loss of photoreceptors and abnormal rhabdomere
      cell morphology. These results show that dE2F is required at multiple stages of
      development and suggest that E2F may have an important function in post-mitotic
      cells in addition to its role during cell proliferation.

PMID- 8670872
TI  - Ectopic expression of dE2F and dDP induces cell proliferation and death in the
      Drosophila eye.
AB  - The deregulation of E2F activity is thought to contribute to the uncontrolled
      proliferation of many tumor cells. While the effects of overexpressing E2F genes
      have been studied extensively in tissue culture, the consequences of elevating
      E2F activity in vivo are unknown. To address this issue, transgenic lines of
      Drosophila were studied in which ectopic expression of dE2F and dDP was targeted
      to the developing eye. The co-expression of dDP or dE2F disrupted normal eye
      development, resulting in abnormal patterns of bristles, cone cells and
      photoreceptors. dE2F/dDP expression caused ectopic S phases in post-mitotic cells
      of the eye imaginal disc but did not disrupt the onset of neuronal
      differentiation. Most S phases were seen in uncommitted cells, although some
      cells that had initiated photo-receptor differentiation were also driven into the
      cell cycle. Elevated expression of dE2F and dDP caused apoptosis in the eye disc.
      The co-expression of baculovirus p35 protein, an inhibitor of cell death,
      strongly enhanced the dE2F/dDP-dependent phenotype. These results show that, in
      this in vivo system, the elevation of E2F activity caused post-mitotic cells to
      enter the cell cycle. However, these cells failed to proliferate unless rescued
      from apoptosis.

PMID- 8670875
TI  - The beta-globin locus control region enhances transcription of but does not
      confer position-independent expression onto the lacZ gene in transgenic mice.
AB  - The beta-globin locus control region (LCR) confers high levels of position
      independent, copy number-dependent expression onto globin transgenes. Here > 40
      independent transgenic mouse lines and founders that carried the LCR in cis with
      the beta-globin gene promoter driving a lacZ reporter gene were studied.
      Expression of the lacZ transgene was assayed by measuring beta-galactosidase
      enzyme activity in fetal liver extracts, the levels of which correlated with the
      quantity of lacZ mRNA determined using RNase protection assays. Unexpectedly,
      expression of the lacZ transgene was found to show strong position effects,
      varying as much as 700-fold per transgene copy. These position effects occurred
      even if the whole beta-globin gene was incorporated as part of the lacZ reporter
      gene. Moreover, DNase I-hypersensitive sites appeared in the transgene LCR in
      high expressing but not in low expressing lines, suggesting that the LCR itself
      was position dependent. In contrast, MEL cell clones, in which transcriptionally
      active integration sites were selected for, gave < 13-fold variation in
      expression per copy of an LCR-lacZ construct. These results show that the lacZ
      reporter affects the ability of the LCR to activate chromatin in mice and that
      culture cells are not an adequate model for position-independent gene expression
      studies.

PMID- 8670876
TI  - The functional conservation of proteins in evolutionary alleles and the dominant
      role of enhancers in evolution.
AB  - Drosophila paired- embryos can be rescued to viable adults by the evolutionary
      alleles prd-Gsb and prd-Pax3, which express the Drosophila Gooseberry and mouse
      Pax3 proteins under the control of the paired cis-regulatory region. As prd-Gsb
      uncovers a prd function involved in the proper abdominal segmentation of adults,
      evolutionary alleles, defined and constructed in this manner, may often be weak
      and thus serve to discover hitherto unknown functions of a gene. Our findings
      show that the Gooseberry and Pax3 proteins have conserved most or all functions
      of the related Drosophila Paired protein although their C-terminal halves appear
      unrelated in sequence but not in 3-D structure essential for function. It follows
      that the acquisition of new cis-regulatory regions rather than the divergence of
      the C-terminal coding regions has been the primary device for the functional
      diversification of the Drosophila genes paired and gooseberry and the mouse Pax3
      gene. The operation of this mechanism in insects as well as vertebrates suggests
      a major role in evolution.

PMID- 8670877
TI  - Combinatorial interplay of promoter elements constitutes the minimal determinants
      for light and developmental control of gene expression in Arabidopsis.
AB  - Higher plants are able to integrate environmental and endogenous signals to
      regulate gene expression for optimal development. To define the minimal sequence
      requirement sufficient to integrate light and developmental signals in
      controlling promoter activity, we carried out a systematic analysis of the roles
      of four well-conserved 'light-responsive elements (LREs)' common to many nuclear
      encoded photosynthetic genes. A gain-of-function assay using basal promoter
      reporter fusions in stable transgenic Arabidopsis was employed to demonstrate
      that pairwise combinations of the LREs, but not the individual elements alone,
      can confer light-inducible expression to the reporter gene independently of the
      basal promoter context and the light-triggered morphological changes. The
      activity of the synthetic promoters with the paired LREs can be modulated at
      least by the phytochrome system. Further, those synthetic light-regulated
      promoters confer a photosynthetic cell-specific expression pattern and respond to
      the chloroplast development state. Our data suggest that distinct combinatorial
      interactions of LREs can serve as minimal autonomous promoter determinants which
      integrate light and developmental signals and modulate promoter activity.

PMID- 8670879
TI  - Specificity of hammerhead ribozyme cleavage.
AB  - To be effective in gene inactivation, the hammerhead ribozyme must cleave a
      complementary RNA target without deleterious effects from cleaving non-target
      RNAs that contain mismatches and shorter stretches of complementarity. The
      specificity of hammerhead cleavage was evaluated using HH16, a well-characterized
      ribozyme designed to cleave a target of 17 residues. Under standard reaction
      conditions, HH16 is unable to discriminate between its full-length substrate and
      3'-truncated substrates, even when six fewer base pairs are formed between HH16
      and the substrate. This striking lack of specificity arises because all the
      substrates bind to the ribozyme with sufficient affinity so that cleavage occurs
      before their affinity differences are manifested. In contrast, HH16 does exhibit
      high specificity towards certain 3'-truncated versions of altered substrates that
      either also contain a single base mismatch or are shortened at the 5' end. In
      addition, the specificity of HH16 is improved in the presence of p7 nucleocapsid
      protein from human immunodeficiency virus (HIV)-1, which accelerates the
      association and dissociation of RNA helices. These results support the view that
      the hammerhead has an intrinsic ability to discriminate against incorrect bases,
      but emphasizes that the high specificity is only observed in a certain range of
      helix lengths.

PMID- 8670878
TI  - Activation of the IL-2 gene promoter by HTLV-I tax involves induction of NF-AT
      complexes bound to the CD28-responsive element.
AB  - The tax gene product of the type I human T-cell leukemia virus (HTLV-I) is a
      potent transcriptional activator of various growth-related cellular genes,
      including that encoding interleukin-2 (IL-2). Tax activation of many of these
      target genes appears to be mediated by the NF-kappa B/Rel and CREB/ATF family of
      cellular transcription factors. However, the mechanism by which Tax
      transactivates the IL-2 gene remains unclear. In the present study, we
      demonstrate that neither NF-kappa B/Rel nor CREB/ATF is sufficient for Tax
      mediated activation of the IL-2 promoter. Two novel nuclear protein complexes are
      induced by Tax and specifically bind to an IL-2 gene enhancer, the CD28
      responsive element (CD28RE). Immunobiochemical analyses suggest that these DNA
      binding complexes contain at least two members of the nuclear factor of activated
      T cells, NF-ATp and NF-ATc. However, the CD28 binding NF-AT complexes do not
      contain Jun and Fos family proteins that have been proposed to serve as NF-AT
      partners in the activation of the IL-2 NF-AT motif. Transient transfection
      studies demonstrate that the in vivo expressed NF-ATp binds to the CD28RE probe
      and enhances Tax-mediated activation of this critical IL-2 enhancer. We
      demonstrate further that binding of NF-AT to CD28RE is critical for Tax
      activation of the IL-2 promoter. Together, these results suggest a novel
      mechanism of Tax-mediated activation of the IL-2 gene, which involves the
      induction of NF-AT-containing CD28RE binding complexes.

PMID- 8670880
TI  - Replacement of two non-adjacent amino acids in the S.cerevisiae bi2 intron
      encoded RNA maturase is sufficient to gain a homing-endonuclease activity.
AB  - Two homologous group I introns, the second intron of the cyt b gene, from related
      Saccharomyces species differ in their mobility. The S.capensis intron is mobile
      and encodes the I-ScaI endonuclease promoting intron homing, whilst the
      homologous S.cerevisiae intron is not mobile, but functions as an RNA maturase
      promoting splicing. These two intron-encoded proteins differ by only four amino
      acid substitutions. Taking advantage of the remarkable similarity of the two
      intron open reading frames and using biolistic transformation of mitochondria, we
      show that the replacement of only two non-adjacent residues in the S.cerevisiae
      maturase carboxy-terminal sequence is sufficient to induce a homing-endonuclease
      activity without losing the splicing function. Also, we demonstrate that these
      two activities reside in the S.capensis bi2-encoded protein which functions in
      both splicing and intron mobility in the wild-type cells. These results provide
      new insight into our understanding of the activity and the evolution of group I
      intron-encoded proteins.

PMID- 8670881
TI  - Intrinsic signaling function of APP as a novel target of three V642 mutations
      linked to familial Alzheimer's disease.
AB  - APP695 is a transmembrane precursor of Abeta amyloid. In familial Alzheimer's
      disease (FAD), three mutations V642I/F/G were discovered in APP695, which has
      been suggested by multiple studies to be a cell surface signaling receptor. We
      previously reported that normal APP695 encodes a potential GO-linked receptor
      with ligand-regulated function and that expression of the three FAD mutants (FAD
      APPs), not normal APP, induces cellular outputs by GO-dependent mechanisms. This
      suggests that FAD-APPs are constitutively active GO-linked receptors. Here, we
      provide direct evidence for this notion. Reconstitution of either recombinant FAD
      APP with GO vesicles induced activation of GO, which was inhibitable by pertussis
      toxin, sensitive to Mg2+ and proportional in quantity to the reconstituted
      amounts of FAD-APP. Consistent with the dominant inheritance of this type of FAD,
      this function was dominant over normal APP, because little activation was
      observed in APP695-GO vesicles. Experiments with antibody competition and
      sequence deletion indicated that His657-Lys676 of FAD-APP, which has been
      specified as the ligand-dependent GO-coupling domain of normal APP, was
      responsible for this constitutive activation, confirming that the three FAD-APPs
      are mutationally activated APP695. This study identifies the intrinsic signaling
      function of APP to be a novel target of hereditary Alzheimer's disease mutations,
      providing an in vitro system for the screening of potential FAD inhibitors.

PMID- 8670882
TI  - Identification of a novel Rac1-interacting protein involved in membrane ruffling.
AB  - The Rac GTP binding proteins are implicated in actin cytoskeleton-membrane
      interaction in mammalian cells. In fibroblast cells, Rac has been shown to
      mediate growth factor-induced polymerization of actin to form membrane ruffles
      and lamellipodia. We report here the isolation of a noval Rac1-interacting
      protein, POR1. POR1 binds directly to Rac1, and the interaction of POR1 with Rac1
      is GTP dependent. A mutation in the Rac1 effector binding loop shown to abolish
      membrane ruffling also abolishes interaction with POR1. Truncated versions of
      POR1 inhibit the induction of membrane ruffling by an activated mutant of Rac1,
      V12Rac1, in quiescent rat embryonic fibroblast REF52 cells. Furthermore, POR1
      synergizes with an activated mutant of Ras, V12Ras, in the induction of membrane
      ruffling. These results suggest a potential role for POR1 in Rac1-mediated
      signaling pathways.

PMID- 8670883
TI  - Ca2+ triggers massive exocytosis in Chinese hamster ovary cells.
AB  - We have tracked the cell surface area of CHO cells by measuring the membrane
      capacitance, Cm. An increase in cytosolic [Ca2+], [Ca2+]i, increased the cell
      surface area by 20-30%. At micromolar [Ca2+]i the increase occurred in minutes,
      while at 20 microM or higher [Ca2+]i it occurred in seconds and was transient.
      GTPgammaS caused a 3% increase even at 0.1 microM [Ca2+]i. We conclude that CHO
      cells, previously thought capable only of constitutive exocytosis, can perform
      Ca2+-triggered exocytosis that is both massive and rapid. Ca2+-triggered
      exocytosis was also observed in 3T3 fibroblasts. Our findings add evidence to the
      view that Ca induces exocytosis in cells other than known secretory cells.

PMID- 8670884
TI  - Molecular basis of two subfamilies of immunoglobulin-like chaperones.
AB  - The initial encounter of a microbial pathogen with the host often involves the
      recognition of host receptors by different kinds of bacterial adhesive organelles
      called pili, fimbriae, fibrillae or afimbrial adhesins. The development of over
      26 of these architecturally diverse adhesive organelles in various Gram-negative
      pathogens depends on periplasmic chaperones that are comprised of two
      immunoglobulin-like domains. All of the chaperones possess a highly conserved
      sheet in domain 1 and a conserved interdomain hydrogen-bonding network. Chaperone
      subunit complex formation depends on the anchoring of the carboxylate group of
      the subunit into the conserved crevice of the chaperone cleft and the subsequent
      positioning of the COOH terminus of subunits along the exposed edge of the
      conserved sheet of the chaperone. We discovered that the chaperones can be
      divided into two distinct subfamilies based upon conserved structural differences
      that occur in the conserved sheet. Interestingly, a subdivision of the chaperones
      based upon whether they assemble rod-like pili or non-pilus organelles that have
      an atypical morphology defines the same two subgroups. The molecular dissection
      of the two chaperone subfamilies and the adhesive fibers that they assemble has
      advanced our understanding of the development of virulence-associated organelles
      in pathogenic bacteria.

PMID- 8670885
TI  - The ubiquitin conjugation system is required for ligand-induced endocytosis and
      degradation of the growth hormone receptor.
AB  - The ubiquitin-dependent protein degradation system has recently been implicated
      in downregulation of signal transducing receptors. Growth hormone receptor (GHR)
      cDNA was transfected into Chinese hamster ovary cells, which exhibit a
      temperature-sensitive defect in ubiquitin conjugation (CHO-ts20), as well as into
      wild-type cells (CHO-E36). Upon binding of growth hormone (GH), two GHR
      polypeptides dimerize and initiate signal transduction. In CHO-E36 and in CHO
      ts20 at the permissive temperature the GHR was ubiquitinated and degraded in a GH
      dependent fashion. However, at the non-permissive temperature in CHO-ts20 cells,
      neither GH-dependent uptake nor degradation of the GHR was observed, while in CHO
      E36 cells both GHR uptake and degradation were accelerated. Incubation of CHO-E36
      cells with inhibitors of endosomal/lysosomal function (NH4Cl, bafilomycin A1)
      markedly reduced ligand-induced GHR degradation. Our results indicate that a
      functional ubiquitin conjugating system is required for GH-induced endocytosis
      and that degradation of both the exoplasmic and cytoplasmic portions of the GHR
      occurs within the endosomal/lysosomal compartment.

PMID- 8670886
TI  - The ABC transporter proteins Pat1 and Pat2 are required for import of long-chain
      fatty acids into peroxisomes of Saccharomyces cerevisiae.
AB  - Peroxisomes of Saccharomyces cerevisiae are the exclusive site of fatty acid beta
      oxidation. We have found that fatty acids reach the peroxisomal matrix via two
      independent pathways. The subcellular site of fatty acid activation varies with
      chain length of the substrate and dictates the pathway of substrate entry into
      peroxisomes. Medium-chain fatty acids are activated inside peroxisomes hby the
      acyl-CoA synthetase Faa2p. On the other hand, long-chain fatty acids are imported
      from the cytosolic pool of activated long-chain fatty acids via Pat1p and Pat2p,
      peroxisomal membrane proteins belonging to the ATP binding cassette transporter
      superfamily. Pat1p and Pat2p are the first examples of membrane proteins involved
      in metabolite transport across the peroxisomal membrane.

PMID- 8670887
TI  - Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid
      differentiation potential and reveal developmental differences in cell survival.
AB  - Mice expressing both a bcl-2 and a myc transgene within the B lymphoid cell
      compartment invariably develop novel immature haemopoietic tumours. The likely
      cell of origin of these tumours was identified by a common pattern of cell
      surface marker expression on a subset of cells comprising approximately 1% of
      normal mouse bone marrow. The bcl-2-myc tumour cells could be induced to
      differentiate into either B lymphocytes or macrophages in culture with certain
      cytokines and feeder cells. Analysis of their progression into the B lymphoid
      lineage revealed that Igk locus transcription can precede Igh as well as Igk
      rearrangement. Surprisingly, the undifferentiated tumour cells died rapidly in
      culture, even in the presence of multiple cytokines, but they proliferated on
      monolayers of stromal cells derived from haemopoietic tissues. Thus, even with
      Bcl-2 levels that protect more differentiated cells, these immature bi-potential
      progenitor cells require a stromal-induced signal for survival. These results
      provide insight into the process of lineage commitment and suggest new levels of
      control of cell survival during early steps in haemopoietic development.

PMID- 8670888
TI  - Proteasomes play an essential role in thymocyte apoptosis.
AB  - Cell death in many different organisms requires the activation of proteolytic
      cascades involving cytosolic proteases. Here we describe a novel requirement in
      thymocyte cell death for the 20S proteasome, a highly conserved multicatalytic
      protease found in all eukaryotes. Specific inhibitors of proteasome function
      blocked cell death induced by ionizing radiation, glucocorticoids or phorbol
      ester. In addition to inhibiting apoptosis, these signals prevented the cleavage
      of poly(ADP-ribose) polymerase that accompanies many cell deaths. Since overall
      rates of protein degradation were not altered significantly during cell death in
      thymocytes, these results suggest that the proteasome may either degrade
      regulatory protein(s) that normally inhibit the apoptotic pathway or may
      proteolytically activate protein(s) than promote cell death.

PMID- 8670889
TI  - Involvement of the proteasome in the programmed cell death of NGF-deprived
      sympathetic neurons.
AB  - Sympathetic neurons undergo programmed cell death (PCD) upon deprivation of nerve
      growth factor (NGF). PCD of neurons is blocked by inhibitors of the interleukin
      1beta converting enzyme (ICE)/Ced-3-like cysteine protease, indicating
      involvement of this class of proteases in the cell death programme. Here we
      demonstrate that the proteolytic activities of the proteasome are also essential
      in PCD of neurons. Nanomolar concentrations of several proteasome inhibitors,
      including the highly selective inhibitor lactacystin, not only prolonged survival
      of NGF-deprived neurons but also prevented processing of poly(ADP-ribose)
      polymerase which is known to be cleaved by an ICE/Ced-3 family member during PCD.
      These results demonstrate that the proteasome is a key regulator of neuronal PCD
      and that, within this process, it is involved upstream of proteases of the
      ICE/Ced-3 family. This order of events was confirmed in macrophages where
      lactacystin inhibited the proteolytic activation of precursor ICE and the
      subsequent generation of active interleukin-1beta.

PMID- 8670890
TI  - A bacterial invasin induces macrophage apoptosis by binding directly to ICE.
AB  - Shigella, the etiological agent of dysentery, kills macrophages by inducing
      apoptosis. Deletion mutants in the invasion invasion plasmid antigen B (ipaB) of
      Shigella flexneri are not cytotoxic. Here, we localized IpaB to the cytoplasm of
      macrophages infected with S. flexneri. Purified IpaB induced apoptosis when
      microinjected into macrophages, indicating that IpaB is sufficient to induce
      apoptosis. Using a GST-IpaB fusion protein as a ligand in affinity purification,
      we isolated four IpaB binding proteins from macrophages which were identified as
      the precursor and the mature polypeptides of interleukin-1beta converting enzyme
      (ICE) or a highly homologous protease. We found that IpaB binds directly to ICE
      and this enzyme is activated during S. flexneri infection. Furthermore, specific
      inhibitors of ICE prevented Shigella-induced apoptosis.

PMID- 8670891
TI  - Cathepsin D protease mediates programmed cell death induced by interferon-gamma,
      Fas/APO-1 and TNF-alpha.
AB  - A functional approach of gene cloning was applied to HeLa cells in an attempt to
      isolate positive mediators of programmed cell death. The approach was based on
      random inactivation of genes by transfections with antisense cDNA expression
      libraries, followed by the selection of cells that survived in the presence of
      the external apoptotic stimulus. An antisense cDNA fragment identical to human
      cathepsin D aspartic protease was rescued by this positive selection. The high
      cathepsin D antisense RNA levels protected the HeLa cells from interferon-gamma-
      and Fas/APO-1-induced death. Pepstatin A, an inhibitor of cathepsin D, suppressed
      cell death in these systems and interfered with the TNF-alpha-induced programmed
      cell death of U937 cells as well. During cell death, expression of cathepsin D
      was elevated and processing of the protein was affected, which resulted in high
      steady-state levels of an intermediate, proteolytically active, single chain form
      of this protease. Overexpression of cathepsin D by ectopic expression induced
      cell death in the absence of any external stimulus. Altogether, these results
      suggest that this well-known endoprotease plays an active role in cytokine
      induced programmed cell death, thus adding cathepsin D to the growing list of
      proteases that function as positive mediators of apoptosis.

PMID- 8670893
TI  - The hybrid histidine kinase DokA is part of the osmotic response system of
      Dictyostelium.
AB  - We have used PCR to identify a Dictyostelium homolog of the bacterial two
      component system. The gene dokA codes for a member of the hybrid histidine kinase
      family which is defined by the presence of conserved amino acid sequence motifs
      corresponding to an N-terminal receptor domain, a central kinase and a C-terminal
      response regulator moiety. Potential function of the regulator domain was
      demonstrated by phosphorylation in vitro. dokA mutants are deficient in the
      osmoregulatory pathway, resulting in premature cell death under high osmotic
      stress. Under less stringent osmotic conditions, cells grow at a normal rate, but
      development at the multicellular stage is altered. dokA is a member of a family
      of histidine kinase-like genes that play regulatory roles in eukaryotic cell
      function.

PMID- 8670892
TI  - Dominant dwarfism in transgenic rats by targeting human growth hormone (GH)
      expression to hypothalamic GH-releasing factor neurons.
AB  - Expression of human growth hormone (hGH) was targeted to growth hormone-releasing
      (GRF) neurons in the hypothalamus of transgenic rats. This induced dominant
      dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of
      a GRF-hGH transgene, has been characterized in detail, and has been termed Tgr
      (for Transgenic growth-retarded). hGH was detected by immunocytochemistry in the
      brain, restricted to the median eminence of the hypothalamus. Low levels were
      also detected in the anterior pituitary gland by radioimmunoassay. Transgene
      expression in these sites was confirmed by RT-PCR. Tgr rats had reduced
      hypothalamic GRF and mRNA, in contrast to the increased GRF expression which
      accompanies GH deficiency in other dwarf rats. Endogenous GH mRNA, GH content,
      pituitary size and somatotroph cell number were also reduced significantly in Tgr
      rats. Pituitary adrenocorticotrophic hormone (ACTH) and thyroid-stimulating
      hormone (TSH) levels were normal, but prolactin content, mRNA levels and
      lactotroph cell numbers were also slightly reduced, probably due to feedback
      inhibition of prolactin by the lactogenic properties of the hGH transgene. This
      is the first dominant dwarf rat strain to be reported and will provide a valuable
      model for evaluating the effects of transgene expression on endogenous GH
      secretion, as well as the use of GH secretagogues for the treatment of dwarfism.

PMID- 8670894
TI  - A two-component histidine kinase gene that functions in Dictyostelium
      development.
AB  - A mutant which failed to complete development was isolated from a population of
      cells that had been subjected to insertional mutagenesis using restriction enzyme
      mediated integration. The disrupted gene, dhkA, encodes the conserved motifs of a
      histidine kinase as well as the response regulator domain. It is likely that the
      histidine in DhkA is autophosphorylated and the phosphate passed to one or more
      response regulators. Such two-component systems function in a variety of
      bacterial signal transduction pathways and have been characterized recently in
      yeast and Arabidopsis. In Dictyostelium, we found that DhkA functions both in the
      regulation of prestalk gene expression and in the control of the terminal
      differentiation of prespore cells.

PMID- 8670895
TI  - The spindle pole body component Spc98p interacts with the gamma-tubulin-like
      Tub4p of Saccharomyces cerevisiae at the sites of microtubule attachment.
AB  - Tub4p is a novel tubulin found in Saccharomyces cerevisiae. It most resembles
      gamma-tubulin and, like it, is localized to the yeast microtubule organizing
      centre, the spindle pole body (SPB). In this paper we report the identification
      of SPC98 as a dosage-dependent suppressor of the conditional lethal tub4-1
      allele. SPC98 encodes an SPB component of 98 kDa which is identical to the
      previously described 90 kDa SPB protein. Strong overexpression of SPC98 is toxic,
      causing cells to arrest with a large bud, defective microtubule structures,
      undivided nucleus and replicated DNA. The toxicity of SPC98 overexpression was
      relieved by co-overexpression of TUB4. Further evidence for an interaction
      between Tub4p and Spc98p came from the synthetic toxicity of tub4-1 and spc98-1
      alleles, the dosage-dependent suppression of spc98-4 by TUB4, the binding of
      Tub4p to Spc98p in the two-hybrid system and the co-immunoprecipitation of Tub4p
      and Spc98p. In addition, Spc98-1p is defective in its interaction with Tub4p in
      the two-hybrid system. We suggest a model in which Tub4p and Spc98p form a
      complex involved in microtubule organization by the SPB.

PMID- 8670896
TI  - A novel role for the budding yeast RAD9 checkpoint gene in DNA damage-dependent
      transcription.
AB  - Cells respond to DNA damage by arresting cell cycle progression and activating
      several DNA repair mechanisms. These responses allow damaged DNA to be repaired
      efficiently, thus ensuring the maintenance of genetic integrity. In the budding
      yeast, Saccharomyces cerevisiae, DNA damage leads both to activation of
      checkpoints at the G1, S and G2 phases of the cell cycle and to a transcriptional
      response. The G1 and G2 checkpoints have been shown previously to be under the
      control of the RAD9 gene. We show here that RAD9 is also required for the
      transcriptional response to DNA damage. Northern blot analysis demonstrated that
      RAD9 controls the DNA damage-specific induction of a large 'regulon' of repair,
      replication and recombination genes. This induction is cell-cycle independent as
      it was observed in asynchronous cultures and cells blocked in G1 or G2/M. RAD9
      dependent induction was also observed from isolated damage responsive promoter
      elements in a lacZ reporter-based plasmid assay. RAD9 cells deficient in the
      transcriptional response were more sensitive to DNA damage than wild-type cells,
      even after functional substitution of checkpoints, suggesting that this
      activation may have an important role in DNA repair. Our findings parallel
      observations with the Escherichia coli SOS system and suggest the existence of an
      analogous eukaryotic network coordinating the cellular responses to DNA damage.

PMID- 8670897
TI  - Multiple p21ras effector pathways regulate nuclear factor of activated T cells.
AB  - The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major
      target for p21ras and calcium signalling pathways in the IL-2 gene and is induced
      by p21ras signals acting in synergy with calcium/calcineurin signals. One p21ras
      effector pathway involves the MAP kinase ERK-2, and we have examined its role in
      NFAT regulation. Expression of dominant negative MAPKK-1 prevents NFAT induction.
      Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor
      Elk-1, but does not substitute for activated p21ras and synergize with
      calcium/calcineurin signals to induce NFAT. Expression of dominant negative
      N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering
      with the ERK-2 pathway. The transcriptional activity of the NFAT binding site is
      mediated by a complex comprising a member of the NFAT group and AP-1 family
      proteins. The induction of AP-1 by p21ras also requires Rac-1 function. Activated
      Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT.
      Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for
      activated p21ras and synergize with calcium signals to induce NFAT. Thus, p21ras
      regulation of NFAT in T cells requires the activity of multiple effector pathways
      including those regulated by MAPKK-1/ERK-2 and Rac-1.

PMID- 8670898
TI  - Functional similarity in appendage specification by the Ultrabithorax and
      abdominal-A Drosophila HOX genes.
AB  - In Drosophila, the Ultrabithorax, abdominal-A and Abdominal-B HOX genes of the
      bithorax complex determine the identity of part of the thorax and the whole
      abdomen. Either the absence of these genes or their ectopic expression transform
      segments into the identity of different ones along the antero-posterior axis.
      Here we show that misexpression of Ultrabithorax, abdominal-A and, to some
      extent, Abdominal-B genes cause similar transformations in some of the fruitfly
      appendages: antennal tissue into leg tissue and wing tissue into haltere tissue.
      abdominal-A can fully, and Abdominal-B partially, substitute for Ultrabithorax in
      haltere development. By contrast, when ectopically expressed, the three genes
      specify different segments in regions of the main body axis like notum or
      abdomen. Insects may have originally used the HOX genes primarily to specify this
      main body axis. By contrast, the homeotic requirement to form appendages is, in
      some cases, non-specific.

PMID- 8670899
TI  - Phosphorylation of Drosophila Jun by the MAP kinase rolled regulates
      photoreceptor differentiation.
AB  - Drosophila Jun (D-Jun) is a nuclear component of the receptor tyrosine kinase/Ras
      signal transduction pathway which triggers photoreceptor differentiation during
      eye development. Here we show that D-Jun is a substrate for the ERK-related
      Drosophila MAP kinase Rolled, which has previously been shown to be a part of
      this pathway. A D-Jun mutant that carries alanines in place of the Rolled
      phosphorylation sites acts as a dominant suppressor of photoreceptor cell fate if
      expressed in the eye imaginal disc. In contrast, a mutant in which the
      phosphorylation sites are replaced by phosphate-mimetic Asp residues, as well as
      a VP16-D-Jun fusion protein, can promote photoreceptor differentiation. These
      data implicate Jun phosphorylation in the choice between neuronal and non
      neuronal fate during Drosophila eye development.

PMID- 8670900
TI  - Quantitation of putative activator-target affinities predicts transcriptional
      activating potentials.
AB  - We quantitate the 'activating potentials' of deletion and point mutation variants
      of a 42 amino acid yeast transcriptional activating region excised from the yeast
      activator GAL4 and, using surface plasmon resonance, we measure the relative
      affinities of these molecules for a variety of proteins, including plausible
      target proteins as well as GAL80, a specific inhibitor of GAL4. We find a
      remarkable correlation between the relative activating potentials of the
      derivatives and their relative affinities for yeast TBP and for yeast TFIIB;
      other tested proteins interacted significantly more weakly, if at all. These
      results provide an especially strong argument that TBP and TFIIB are activating
      region targets. We also show, using one set of yeast activating region mutants,
      that activator-target interactions are strongly correlated with the length of the
      activating region, that the effect of point mutants is highly dependent on the
      length of the activating region mutated and that, unlike interactions with TBP
      and TFIIB, interaction with the specific inhibitor GAL80 is destroyed by deletion
      of certain critical residues in the C-terminal half of the 42 amino acid
      activating region.

PMID- 8670901
TI  - RRN3 gene of Saccharomyces cerevisiae encodes an essential RNA polymerase I
      transcription factor which interacts with the polymerase independently of DNA
      template.
AB  - RRN3 is one of the RRN genes specifically required for the transcription of rDNA
      by RNA polymerase I (Pol I) in Saccharomyces cerevisiae. We have cloned the gene,
      determined the nucleotide sequence, and found that it is an essential gene which
      encodes a protein of calculated molecular weight of 72 369. Extracts prepared
      from rrn3 mutants were defective in in vitro transcription of rDNA templates. We
      used extracts from a strain containing an epitope-tagged Rrn3 protein to purify a
      factor that could complement the mutant extracts. Using immunoaffinity
      purification combined with Mono Q chromatography, we obtained an essentially pure
      preparation of Rrn3p which complements the mutant extracts. By carrying out
      template commitment experiments, we found that Rrn3p is not part of the pre
      initiation complex that is stable through multiple rounds of transcription. We
      also found that pre-incubation of Rrn3p with purified Pol I leads to stimulation
      of transcription upon subsequent mixing with DNA template and other transcription
      reaction components. Single-round transcription experiments using the detergent
      Sarkosyl showed that this stimulation is due to increased efficiency of formation
      of a Sarkosyl-resistant pre-initiation complex. Thus, Rrn3p appears to interact
      directly with Pol I, apparently stimulating Pol I recruitment to the promoter,
      and is distinct from two other Pol I-specific transcription factors, the Rrn6/7
      complex and the Rrn5/9/10 complex (UAF), characterized previously.

PMID- 8670902
TI  - All four core histone N-termini contain sequences required for the repression of
      basal transcription in yeast.
AB  - Nucleosomes prevent the recognition of TATA promoter elements by the basal
      transcriptional machinery in the absence of induction. However, while
      Saccharomyces cerevisiae histones H3 and H4 contain N-terminal regions involved
      in the activation and repression of GAL1 and in the expression of heterochromatin
      like regions, the sequences involved in repressing basal transcription have not
      yet been identified. Here, we describe the mapping of new N-terminal domains, in
      all four core histones (H2A, H2B, H3 and H4), required for the repression of
      basal, uninduced transcription. Basal transcription was monitored by the use of a
      GAL1 promoter-URA3 reporter construct whose uninduced activity can be detected
      through cellular sensitivity to the drug, 5-fluoroorotic acid. We have found for
      each histone that the N-terminal sequences repressing basal activity are in a
      short region adjacent to the structured alpha-helical core. Analysis of
      minichromosome DNA topology demonstrates that the basal domains are required for
      the proper folding of DNA around the chromosomal particle. Deletion of the basal
      domain at each histone significantly decreases plasmid superhelical density,
      which probably reflects a release of DNA from the constraints of the nucleosome
      into the linker region. This provides a means by which basal factors may
      recognize otherwise repressed regulatory elements.

PMID- 8670903
TI  - Btcd, a mouse protein that binds to curved DNA, can substitute in Escherichia
      coli for H-NS, a bacterial nucleoid protein.
AB  - In an Escherichia coli mutant devoid of H-NS, a bacterial nucleoid protein, mouse
      protein Btcd was able to substitute for H-NS in two tested functions. It restored
      cell motility and repression of the expression of the bgl operon. Btcd1, a mutant
      Btcd protein deleted of its zinc finger and thus having reduced DNA binding,
      failed to substitute for H-NS. Mouse protein Btcd was shown to repress the bgl
      operon at the level of transcription initiation and to bind preferentially to a
      curved DNA fragment encompassing the bgl promoter. These effects of Btcd on
      bacterial gene transcription can be accounted for by the binding of Btcd or H-NS
      to a curved DNA sequence near a promoter. A few mammalian proteins have been
      shown to substitute for their Escherichia prototypes involved in DNA and RNA
      transactions. The efficiency of Btcd protein in substituting for H-NS in
      Escherichia suggests its possible involvement in regulating gene expression in
      mouse cells.

PMID- 8670904
TI  - The small RNA, DsrA, is essential for the low temperature expression of RpoS
      during exponential growth in Escherichia coli.
AB  - dsrA encodes a small, untranslated RNA. When over-expressed, DsrA antagonizes the
      H-NS-mediated silencing of numerous promoters. Cells devoid of DsrA grow normally
      and show little change in the expression of a number of H-NS-silenced genes.
      Expression of a transcriptional fusion of lacZ to dsrB, the gene next to dsrA, is
      significantly lower in cells carrying mutations in dsrA. All expression of beta
      galactosidase from the dsrB::lacZ fusion is also dependent on the stationary
      phase sigma factor, RpoS. DsrA RNA was found to regulate dsrB::lacZ indirectly,
      by modulating RpoS synthesis. Levels of RpoS protein are substantially lower in a
      dsrA mutant, both in stationary and exponential phase cells. Mutations in dsrA
      decrease the expression of an RpoS::LacZ translational fusion, but not a
      transcriptional fusion, suggesting that DsrA is acting after transcription
      initiation. While RpoS expression is very low in exponential phase at
      temperatures of 30 degrees C and above, at 20 degrees C there is substantial
      synthesis of RpoS during exponential growth, all dependent on DsrA RNA. dsrA
      expression is also increased at low temperatures. These results suggest a new
      role for RpoS during exponential growth at low temperatures, mediated by DsrA.

PMID- 8670905
TI  - The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces
      cerevisiae are members of the DEXH-box protein family of putative RNA helicases.
AB  - The primary structure of the 200 kDa protein of purified HeLa U5 snRNPs (U5
      200kD) was characterized by cloning and sequencing of its cDNA. In order to
      confirm that U5-200kD is distinct from U5-220kD we demonstrate by protein
      sequencing that the human U5-specific 220 kDa protein is homologous to the yeast
      U5-specific protein Prp8p. A 246 kDa protein (Snu246p) homologous to U5-200kD was
      identified in Saccharomyces cerevisiae. Both proteins contain two conserved
      domains characteristic of the DEXH-box protein family of putative RNA helicases
      and RNA-stimulated ATPases. Antibodies raised against fusion proteins produced
      from fragments of the cloned mammalian cDNA interact specifically with the HeLa
      U5-200kD protein on Western blots and co-immunoprecipitate U5 snRNA and to a
      lesser extent U4 and U6 snRNAs from HeLa snRNPs. Similarly, U4, U5 and U6 snRNAs
      can be co-immunoprecipitated from yeast splicing extracts containing an HA-tagged
      derivative of Snu246p with HA-tag specific antibodies. U5-200kD and Snu246p are
      thus the first putative RNA helicases shown to be intrinsic components of snRNPs.
      Disruption of the SNU246 gene in yeast is lethal and leads to a splicing defect
      in vivo, indicating that the protein is essential for splicing. Anti-U5-200kD
      antibodies specifically block the second step of mammalian splicing in vitro,
      demonstrating for the first time that a DEXH-box protein is involved in mammalian
      splicing. We propose that U5-200kD and Snu246p promote one or more conformational
      changes in the dynamic network of RNA-RNA interactions in the spliceosome.

PMID- 8670906
TI  - Evidence for the presence of a small U5-like RNA in active trans-spliceosomes of
      Trypanosoma brucei.
AB  - The existence of the Trypanosoma brucei 5' splice site on a small RNA of uniform
      sequence (the spliced leader or SL RNA) has allowed us to characterize the RNAs
      with which it interacts in vivo by psoralen crosslinking treatment. Analysis of
      the most abundant crosslinks formed by the SL RNA allowed us previously to
      identify the spliced leader-associated (SLA) RNA. The role of this RNA in trans
      splicing, as well as the possible existence of an analogous RNA interaction in
      cis-splicing, is unknown. We show here that the 5' splice site region of the SL
      RNA is also crosslinked in vivo to a second small RNA. Although it is very small
      and lacks a 5' trimethylguanosine (TMG) cap, the SLA2RNA possesses counterparts
      of the conserved U5 snRNA stem-loop 1 and internal loop 1 sequence elements, as
      well as a potential trypanosome snRNA core protein binding site; these combined
      features meet the phylogenetic definition of U5 snRNA. Like U5, the SLA2 RNA
      forms an RNP complex with the U4 and U6 RNAs, and interacts with the 5' splice
      site region via its putative loop 1 sequence. In a final analogy with U5, the
      SLA2 RNA is found crosslinked to a molecule identical to the free 5' exon
      splicing intermediate. These data present a compelling case for the SLA2 RNA not
      only as an active trans-spliceosomal component, but also for its identification
      as the trypanosome U5 structural homolog. The presence of a U5-like RNA in this
      ancient eukaryote establishes the universality of the spliceosomal RNA core
      components.

PMID- 8670907
TI  - Trans-acting factors regulate the expression of CD44 splice variants.
AB  - Variant isoforms of the cell surface glycoprotein CD44 (CD44v) are expressed
      during development, in selected adult tissues and in certain metastatic tumor
      cells. CD44v differ from the standard isoform (CD44s) by up to ten additional
      exon sequences included by alternative splicing. By cell fusion experiments, we
      have obtained evidence for the existence of cell-type specific trans-acting
      factors recruiting CD44 variant exon sequences. Stable cell hybrids of CD44s and
      CD44v expressing cells indicated a dominant mechanism for variant-exon inclusion.
      In transient interspecies heterokaryons of human keratinocytes and rat
      fibroblasts, the ability of the keratinocytes to include all variant exon
      sequences in CD44 was conferred completely on the rat fibroblast nucleus. Fusions
      of cells with complex CD44 splice patterns do not permit interpretation of splice
      control by the relative abundance of a single trans-acting factor, but rather by
      (a) positively acting factor(s) recruiting variant exon sequences in the 3' to 5'
      direction and additional factors selecting individual exons. Since the pancreatic
      carcinoma cell line BSp73ASML (in contrast to the cervix carcinoma cell lines
      SiHa and ME180) could not transfer its specific splice pattern in cell fusions,
      we conclude that in some tumors, splicing is also controlled by mutation of cis
      acting recognition sites.

PMID- 8670909
TI  - The nuclear targeting and nuclear retention properties of a human DNA repair
      protein O6-methylguanine-DNA methyltransferase are both required for its nuclear
      localization: the possible implications.
AB  - Human O6-methylguanine-DNA methyltransferase (MGMT) protects human cells from the
      mutagenic effects of alkylating agents by repairing the O6-alkylguanine residues
      formed by these agents in the nuclear DNA. We report here a study showing a
      possible two-step model for the nuclear localization of the 21 kDa human protein.
      The first step is the translocation of the protein from the cytosol to the
      nucleus. This appears to require the nuclear targeting property associated with
      the holoprotein in combination with a cellular factor(s) to effect the nuclear
      translocation of MGMT. The second step involves the nuclear retention of MGMT (to
      prevent its export from the nucleus). This requires a basic region (PKAAR, codons
      124-128) that can bind to the non-diffusible DNA elements in the nucleus.
      Supporting data for such mechanisms are: (i) the holoprotein can target the
      cytosolic 110 kDa beta-galactosidase into the nucleus; (ii) purified recombinant
      MGMT requires a cellular factor for transport across the nuclear membrane; (iii)
      nuclear MGMT can be removed selectively by DNase I; (iv) the repair-positive
      K125L mutant, which alters the PKAAR motif, remains in the cytosol and fails to
      bind DNA in vitro; and (v) polypeptide containing the PKAAR motif has no nuclear
      targeting property. Interestingly, mutants in another basic region, KLLKVVK
      (codons 101-107) are DNA binding and repair deficient but entirely nuclear. As
      these substitutions affect the functional properties of human MGMT, they are
      potential targets for genetic screening of individuals for risk assessment to
      alkylating agents.

PMID- 8670908
TI  - Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a
      processivity defect of the reverse transcriptase enzyme.
AB  - Human immunodeficiency virus type 1 (HIV-1) variants with resistance mutations in
      the reverse transcriptase (RT) gene appear during drug therapy with the
      nucleoside analogue 2',3'-dideoxy-3'-thiacytidine (3TC). These resistance
      mutations alter the methionine (Met) residue of the conserved YMDD motif, which
      is part of the catalytic core of the RT enzyme. Isoleucine (Ile) variants are
      initially observed, followed by the appearance and eventual outgrowth of viruses
      encoding valine (Val). Similar replication kinetics were measured for wild-type
      and 3TC-resistant HIV-1 viruses in tissue culture infections of a T cell line,
      but we measured reduced polymerase activity for the two mutant RT enzymes
      compared with the wild-type enzyme (Ile = 43% and Val = 67%). Gel analysis of the
      reverse transcription products revealed that both 3TC-resistant RT mutants
      produce significantly shorter cDNA molecules than the wild-type enzyme [Met
      (wt)>Val>Ile], indicating that 3TC-resistant RT polymerases are less processive
      enzymes. Interestingly, these enzyme defects were more pronounced under limiting
      dNTP concentrations and we therefore assayed virus replication in primary cells
      that contain relatively low dNTP levels. Under these conditions, we measured
      significantly reduced replication kinetics for the 3TC-resistant HIV-1 variants
      [Met (wt)>Val>Ile]. If the level of virus replication can be similarly reduced in
      3TC-treated patients that develop drug-resistant HIV-1 variants, this may be of
      considerable clinical benefit.

PMID- 8670910
TI  - SMC proteins constitute two subunits of the mammalian recombination complex RC-1.
AB  - Recombination protein complex RC-1, purified from calf thymus nuclear extracts,
      catalyzes cell-free DNA strand transfer and repair of gaps and deletions through
      DNA recombination. DNA polymerase E, DNA ligase III and a DNA structure-specific
      endonuclease co-purify with the five polypeptide complex. Here we describe the
      identification of two hitherto unknown subunits of RC-1. N-terminal amino acid
      sequences of the 160 and 130 kDa polypeptides display up to 100% identity to
      proteins of the structural maintenance of chromosomes (SMC) subfamilies 1 and 2.
      SMC proteins are involved in mitotic chromosome segregation and condensation, as
      well as in certain DNA repair pathways in fission (rad18 gene) and budding (RHC18
      gene) yeast. The assignment was substantiated by immuno-cross-reactivity of the
      RC-1 subunits with polyclonal antibodies specific for Xenopus laevis SMC
      proteins. These antibodies, and polyclonal antibodies directed against the bovine
      160 and 130 kDa polypeptides, named BSMC1 and BSMC2 (bovine SMC), inhibited RC-1
      mediated DNA transfer, indicating that the SMC proteins are necessary components
      of the reaction. Two independent assays revealed DNA reannealing activity of RC
      1, which resides in its BSMC subunits, thereby demonstrating a novel function of
      these proteins. To our knowledge, this is the first evidence for the association
      of mammalian SMC proteins with a multiprotein complex harboring, among others,
      DNA recombination, DNA ligase and DNA polymerase activities.

PMID- 8670922
TI  - Occlusal morphology in Turner syndrome.
AB  - The prevalence of malocclusion in 32 Turner syndrome patients, age 7-16.7 years,
      was investigated. The sample was subdivided according to karyotype, and 72 normal
      girls, aged 7.1-16.1 years, served as controls. Compared with normal girls
      overjet did not differ significantly while overbite was significantly reduced in
      45X patients. The prevalence of distal molar occlusion, anterior and lateral open
      bite and lateral crossbite was significantly increased. Most significant
      differences were found between 45X patients and controls. Mosaic and
      isochromosome for the long arm of X karyotypes showed the same pattern of
      malocclusion, but with greater variation. No significant differences were found
      comparing 45X patients with mosaic and isochromosome for the long arm of X
      karyotypes. The results indicate that patients with structural and/or numerical
      aberration of the X chromosome, develop a specific pattern of malocclusion with
      deviations in sagittal, vertical and transversal directions.

PMID- 8670911
TI  - The var genes of Plasmodium falciparum are located in the subtelomeric region of
      most chromosomes.
AB  - PfEMP1, a Plasmodium falciparum-encoded protein on the surface of infected
      erythrocytes is a ligand that mediates binding to receptors on endothelial cells.
      The PfEMP1 protein, which is encoded by the large var gene family, shows
      antigenic variation and changes in binding phenotype associated with alterations
      in antigenicity. We have constructed a yeast artificial chromosome contig of
      chromosome 12 from P. falciparum and show that var genes are arranged in four
      clusters; two lie amongst repetitive subtelomeric sequences and two occur in the
      more conserved central region. Analysis of parasite chromosomes by pulsed field
      gel electrophoresis (PFGE) demonstrates that most contain var genes and two
      dimensional PFGE has shown that var genes are located at chromosome ends
      interspersed amongst repetitive sequences present in the subtelomeric complex.
      Analysis of a var gene located in the subtelomeric region of chromosome 12 has
      shown that it has close homologues at the opposite end of the chromosome and in
      the subtelomeric region of two other chromosomes. This suggests that
      recombination between heterologous chromosomes has occurred in the subtelomeric
      regions of these chromosomes. The subtelomeric location of var genes dispersed
      amongst repetitive sequences has important implications for generation of
      antigenic variants and novel cytoadherent specificities of this protein.

PMID- 8670923
TI  - Morphological associations between the Angle classes.
AB  - The association between the Angle classification and craniofacial form has been
      analysed with the aid of multiple linear regression analysis in a sample of 170
      children, before orthodontic treatment had started. It was found that part of the
      differences between Class II, Class I, and Class III was accounted for by
      systematical variation in a coherent set of midface and cranial base dimensions.
      These variations were in harmony with each other: the cranial base angle Ba-S-N
      closed and the legs S-N and S-Ba shortened systematically from Class II, over
      Class I, to Class III. The juvenile mandible notably was not systematically
      different. Because the cranial base provides the framework for the maxilla to be
      built upon, it is concluded that in juveniles the midface above anything else
      creates the characteristic difference between the three Angle classes, not the
      mandible. The Angle classification of malocclusion, therefore, represents three
      arbitrary markers on a morphological continuum.

PMID- 8670924
TI  - A multidisciplinary approach to oral rehabilitation with osseointegrated implants
      in children and adolescents with multiple aplasia.
AB  - Oral rehabilitation of children with extensive aplasia includes a number of
      dental considerations as well as attention to psychological and physical
      development. The well-documented results of the use of implants in adults have
      raised the question of the use of implants and the timing of this procedure in
      children and adolescents with multiple aplasia. Eight-years' experience of a
      multidisciplinary approach to oral rehabilitation of children with extensive
      aplasia is described. Special emphasis is placed on early diagnosis, careful
      therapy planning, and co-ordination and timing of different parts of the therapy.
      The specific considerations from the point of view of paediatric dentists,
      orthodontists, oral surgeons, and prosthodontists are presented. A system for
      integrating all these aspects and knowledge will be a guarantee for high
      professional standards and a successful outcome. To exemplify the
      multidisciplinary approach, three treated cases are presented.

PMID- 8670925
TI  - Moments and forces delivered by transpalatal arches for symmetrical first molar
      rotation.
AB  - The moments and forces delivered by round transpalatal arches of steel and of
      beta-titanium (TMA) for symmetrical derotation of molars were studied in
      laboratory experiments. Three sizes of arches were tested in two series. In the
      first series, the degree of activation was checked for symmetry in a computer
      based strain-gauge measuring system. In the second series, the activation was
      carried out in a way simulating clinical use. The mesio-distal and transverse
      forces and the derotating moments at full activation and during derotation in
      steps of 5 degrees were measured. At full activation, the steel arches delivered
      relatively large moments which, however, decreased rapidly during deactivation.
      The TMA arches had a larger working range. It was not possible to achieve full
      symmetry of the moments at the two ends of the arch. The difference of the two
      moments resulted in forces acting on the two anchorage teeth in a mesio-distal
      direction. These forces were generally small but could reach clinically relevant
      magnitude. The derotation resulted in a contractive force of up to 2.7 N which
      has to be compensated for by expansion. The mode of activation simulating
      clinical use resulted in reasonably constant forces and moments. The use of a
      vice to hold the arch during activation was found to be of great help and is
      recommended in the clinical setting. Because of the larger working range, TMA
      arches are recommended if substantial derotation is needed.

PMID- 8670926
TI  - Effects of a doubled orthodontic force magnitude on tooth movement and root
      resorptions. An inter-individual study in adolescents.
AB  - The aim of this clinical and histological study was to compare the effects of two
      controlled, continuous forces of 50 cN (approximately 50 g) and 100 cN
      (approximately 100 g) on tooth movement and root resorptions. The patients,
      consisting of 32 individuals, 14 boys and 18 girls (mean age 13.1 years), were
      divided into four groups of eight individuals. The experimental periods were 4
      and 7 weeks. In this investigation, designed as an inter-individual study, only
      the maxillary first premolar on the right side was utilized. The test tooth was
      buccally moved by means of a fixed orthodontic appliance. A continuous, weekly
      controlled force of 50 cN was applied to 16 premolars and a force of 100 cN to
      the remaining 16 test teeth. The force declined on average 22 per cent during the
      first week when 50 cN was applied and 27 per cent when 100 cN was applied. Tooth
      movements were studied on dental casts using a coordinate measuring machine.
      After 4 and 7 weeks, the tooth movements ranged between 0.5 and 3.4 mm (4 weeks)
      and 2.7 and 7.1 mm (7 weeks) for 50 cN and between 1.0 and 2.9 mm (4 weeks) and
      2.2 and 8.3 mm (7 weeks) for 100 cN, with no significant difference when the
      force magnitude was doubled. Root resorptions were registered in histological
      sections in all experimental teeth, more frequently after application of 50 cN
      compared with 100 cN after 7 weeks. However, the severity of root resorption
      (extension and depth of resorbed root contour and size of root area on
      histological sections) did not differ significantly when the applied force was
      doubled to 100 cN. Great individual variations were noted regarding both the
      magnitude of tooth movement and amount of root resorption.

PMID- 8670927
TI  - Treatment response to maxillary expansion and protraction.
AB  - A prospective clinical trial was conducted to determine the skeletal and dental
      contributions to the correction of overjet and overbite in Class III patients.
      Thirty patients (12 males and 18 females with a mean age of 8.4 +/- 1.7 years)
      were treated consecutively with protraction headgear and fixed maxillary
      expansion appliances. For each patient, a lateral cephalogram was taken 6 months
      before treatment (T0); immediately before treatment (T1); and 6 months after
      treatment (T2). The time period (T1-T0) represented changes due to 6 months of
      growth without treatment; (T2-T1) represented 6 months of growth and treatment.
      Each patient served as his/her own control. Cephalometric analysis described by
      Bjork (1947) and Pancherz (1982a,b) was used. Sagittal and vertical measurements
      were made along the occlusal plane (OLs) and the occlusal plane perpendicular
      (OLp), and superimposed on the mid-sagittal cranial structure. The results
      revealed the following: with 6 months of treatment, all subjects were treated to
      Class I or overcorrected to Class I or Class II dental arch relationships.
      Overjet and sagittal molar relationships improved by an average of 6.2 and 4.5
      mm, respectively. This was a result of 1.8 mm of forward maxillary growth, a 2.5
      mm of backward movement of the mandible, a 1.7-mm of labial movement of maxillary
      incisors, a 0.2-mm of lingual movement of mandibular incisors, and a 0.2-mm of
      greater mesial movement of maxillary than mandibular molars. The mean overbite
      reduction was 2.6 mm. Maxillary and mandibular molars were erupted occlusally by
      0.9 and 1.4 mm, respectively. The mandibular plane angle was increased by 1.5
      degrees and the lower facial height by 2.9 mm. Individual variations in response
      to maxillary protraction was large for most of the parameters tested. Significant
      differences in treatment changes between male and female subjects were found only
      in the vertical eruption of mandibular incisors and maxillary and mandibular
      molars. These results demonstrate that significant overjet and overbite
      corrections can be obtained with 6 months of maxillary protraction in combination
      with a fixed expansion appliance.

PMID- 8670929
TI  - Quantitative evaluation of correlation of skull morphology in families in an
      attempt to predict growth change.
AB  - The purpose of the present study was to obtain quantitative values for human
      skull structures in a cross-sectional analysis of offspring and their parents.
      The offspring were classified into three groups according to age. For each of 11
      maxillo-facial and nine dento-alveolar structural angular measurements, the mean
      and SD were calculated for each set of paternal, maternal, midparent and
      offspring. The standard deviation unit (SDU) values were calculated from the
      disparity between the measured value in a given individual, i.e. father, mother,
      midparent, offspring, and their corresponding group mean value. Three disparity
      values (D.v.), expressed by the difference between the SDU values in each pair
      (father-offspring, mother-offspring and midparent-offspring), were developed to
      evaluate the degree of familial resemblance for each of 20 morphometric
      measurements, and the differences among these values in three age groups were
      then investigated. The similarity ratio (S.r.), expressing the degree of
      correlation to the father and mother, was derived by processing the D.v. The
      relationship between the maxillo-facial S.r. and the dento-alveolar S.r. was
      analysed in each age group. There were significant differences between the D.v.
      in families and those in unrelated control groups. Consistency between the S.r.
      for maxillo-facial and that for dento-alveolar measurements was found in the
      older age groups. It is concluded that individual growth of skull morphology
      might be more predictable using the present method.

PMID- 8670930
TI  - A skull-holding device for experimental cephalometric research.
AB  - This paper describes and illustrates an innovative versatile skull-holding device
      for experimental research in cephalometrics. Repositioning of the skulls was
      evaluated and found to be highly reproducible.

PMID- 8670931
TI  - An in vitro study of the bond strength of light-cured glass ionomer cement in the
      bonding of orthodontic brackets.
AB  - The search to improve the properties of dental adhesives has lead to the
      development of light-cured glass ionomer cements. Using human teeth in vitro, the
      present study tested the shear/peel bond strengths of two light-cure materials
      ('Variglass VLC' and 'Fuji Lining LC') against a 'no-mix' composite orthodontic
      adhesive ('Right-On') and a chemically cured glass ionomer cement ('Ketac-Cem').
      The light-cured materials were found to have an inferior bond strength compared
      with the two control adhesives. Based on the findings of this study, there is no
      evidence to support the use of the materials tested for the bonding of
      orthodontic brackets.

PMID- 8670934
TI  - Letters to the Editor

PMID- 8670932
TI  - Dummy-sucking behaviour in 3-year old Norwegian and Swedish children.
AB  - Forty 3-year-old dummy-sucking children (22 Swedes and 18 Norwegians) together
      with one of their parents, were shown a specially prepared videotape for 15
      minutes The child had free access to its dummy while watching the video. The
      dummy-sucking time and sucking reactions to the different film sequences were
      registered. The presence or absence of a posterior crossbite was recorded as well
      as the upper and lower intercanine arch widths. Dummy-suckers in these
      populations have earlier been reported to have different prevalences of posterior
      crossbite. The prevalence of posterior crossbite was especially high for Swedish
      girls. The results showed that Norwegian boys used their dummies significantly
      less, and the Swedish girls had significantly narrower upper dental arches than
      the other children. Dummy-sucking reactions to frightening, cheerful or boring
      parts of the video were not significantly different among the children. All the
      children showed compassion for the film characters, and all the children used the
      dummy when going to sleep. The study lends support to the hypothesis that dummy
      sucking influences arch widths and increases the likelihood for development of a
      posterior crossbite.

PMID- 8671097
TI  - A troubled youth: relations with somatization, depression and anxiety in
      adulthood.
AB  - BACKGROUND: Childhood experiences profoundly affect later functioning as an
      adult. Family practitioners are well-placed to discover the links between
      childhood troubles and later somatization, depression or anxiety. OBJECTIVES: We
      aimed to study the interrelation of somatization, depressive and anxiety
      disorders in frequently attending patients in general practice; to investigate
      whether these problems are related to a childhood history of illness experiences,
      deprivation, life events and abuse; and to determine the independent
      contributions of these childhood factors to the prediction of adult somatization,
      depressive and anxiety disorders. METHODS: One hundred and six adult general
      practice patients with high consultation frequency were studied. Somatization was
      operationalized as a more comprehensive version of DSM-III-R somatization
      disorder (5 complaints; SSI 5/5). For depression (ever depressive and/or
      dysthymic) and anxiety (panic, phobias and/or generalized anxiety) DSM-III-R
      criteria were used. Using a structured questionnaire we assessed illness
      experiences, deprivation of parental care, abuse (sexual/physical) and other life
      events before age 19. RESULTS: The overlap between somatization, depression and
      anxiety was largely accounted for by 16 patients with a triple problem:
      somatization and depression and anxiety. Somatization was specifically related to
      deprivation, depression to other life events. Abuse (prevalence 16%)
      independently predicted psychiatric problems in general. Youth experiences before
      age 12 were most important. CONCLUSIONS: The high prevalence of triple problems
      suggests a need to reconsider concepts like somatic anxiety and anxious
      depression. The specificity of the relation between deprivation and somatization
      and of the relation between other life events and depression indicates that
      distinct causal mechanisms (in youth) contribute to these problems.

PMID- 8671098
TI  - The relationship between complaint-related cognitions in referred patients with
      irritable bowel syndrome and subsequent health care seeking behaviour in primary
      care.
AB  - BACKGROUND: It is generally accepted that it is important to explore patients'
      beliefs and fears about the meaning of their symptoms during medical
      consultations. OBJECTIVE: To discover how referral behaviour of GPs and attention
      to dysfunctional cognitions of medical specialists affect the subsequent health
      care seeking behaviour of patients with irritable bowel syndrome. METHOD:
      Questionnaires were distributed to GPs and to doctors and patients at an
      outpatient clinic in the University Hospital of Nijmegen. RESULTS: The results of
      the present study indicate that doctors' attention to the complaint-related
      cognitions of IBS-patients is also related to a reduced use of medical health
      services in primary care. On the other hand, when referred IBS-patients continue
      to attribute their complaints to a somatic abnormality even after such an
      abnormality has been ruled out through extensive physical examinations, the
      subsequent use of medical health services in primary care is likely to increase.
      Moreover, GPs' referral behaviour appears to strengthen these dysfunctional
      somatic attributions in IBS-patients. CONCLUSION: These unfavorable consequences
      might be avoided by handling cognitions and anxiety more specifically during
      medical consultations in primary as well as secondary care.

PMID- 8671099
TI  - Measuring the prevalence of diabetes mellitus in a Greek primary health care
      district.
AB  - BACKGROUND: Diabetes mellitus is a common disease in developed countries, but in
      Greece national figures on its prevalence are lacking. OBJECTIVES: The aim of
      this study was to identify the burden of known diabetes mellitus through its
      estimation in the area of responsibility of the Spili Health Centre, based on the
      health information system that had been established in Primary Health Care in
      rural Crete. METHOD: The diagnosis of diabetes was retrospectively documented by
      reviewing all medical records (n = 47151) at the Spili Health Centre and its five
      regional outposts during the period 1/6/1988-1/7/1993. The diagnostic criteria of
      WHO were used to establish the diagnosis. RESULTS: After excluding the patients
      who had died, we found 210 patients with diabetes mellitus. Thirty cases were
      evaluated with OGTT because of mild but not diagnostic elevations of fasting
      plasma glucose, on more than one occasion. The prevalence of diabetes after age
      and sex standardization of that for the European population was estimated at
      1.52% (1.31% in males and 1.68 in females). CONCLUSIONS: Our study shows that: 1)
      the role of the GPs and one appropriate information system in measuring the
      prevalence of known diabetes mellitus are now considered important within the
      Greek context; 2) diabetes mellitus seems not to be a rare disease in rural
      Crete. The estimated prevalence appears to be similar to the prevalence rates
      reported in other areas of rural Greece.

PMID- 8671100
TI  - Annual visits to patients over the age of 75--who is missed?
AB  - BACKGROUND: In the UK, the GP contract requires annual consultations and offers
      of home visits to the elderly. However, as many as 50% of elderly people refuse
      the offer of a health screen. OBJECTIVE: To describe the characteristics of
      elderly people who declined the offer of an annual home visit. METHOD: All
      elderly people aged 75 years and over, registered with a general practice of 13
      full time and 3 part time doctors with a list size of 33,000 people, were offered
      a home visit. Data from this prospective cohort were linked with data from a
      community survey two years previously, which had achieved a 95% response rate.
      The main outcome measures were perceived health status, perceived loneliness,
      morale score, physical and mental disability, use of primary care and social
      services. RESULTS: Thirty-six percent of all elderly people registered with the
      practice declined to take up the offer of a home visit. Those refusing a visit
      had not recently joined the practice and had very similar distributions of all
      demographic and most health and wellbeing characteristics to those who took up
      the offer. However, those declining appeared to have higher levels of morale (P =
      0.010) and less contact with the general practitioner (P = 0.021) including an
      average of three weeks longer since last consultation with their general
      practitioner than those accepting the visit. CONCLUSIONS: There appears little
      evidence in this population that elderly people who decline a home visit are
      necessarily part of an 'iceberg' of unmet need.

PMID- 8671101
TI  - Local clinical guidelines: description and evaluation of a participative method
      for their development and implementation.
AB  - BACKGROUND: National guidelines are rarely followed by immediate change in
      clinical behaviour. We present our experience of an active educational method for
      local development and implementation of a guideline. OBJECTIVE: To evaluate the
      effectiveness of a participative method for developing local clinical guidelines.
      METHODS: A trial in a district of the effect of guideline development
      incorporating active participation of intended recipients on subsequent relevant
      prescribing. It was carried out in Wirral Family Health Services Authority
      district (the Wirral peninsula) comprising 69 general practices covering a
      population of 345,763. An exemplar guideline on 'hypertension in the elderly' was
      developed by the method described. The principal recommended drug was
      bendrofluazide 2.5 mg once daily. The differences in prescribed daily doses (PDD)
      of bendrofluazide 2.5 mg tablets per quarter per 1000 prescribing units (age
      weighted population) between the intervention district and England as a whole was
      measured. RESULTS: Comparison of the intervention district with England data
      demonstrates a median difference of 122.49 PDD before and 206.34 PDD after
      guideline production, this change is statistically highly significant (Mann
      Whitney two-tailed P < 0.0001; 95% CI = 36.51-104.77). Grouped regression
      analysis shows no significant difference (0.89) in slope gradients before
      guideline production (P = 0.35, 95% CI = -3.97-5.76), but the difference in slope
      gradients after (12.95) is statistically highly significant (P < 0.0001; 95% CI =
      8.17-17.73). The data suggests that the change in clinical behaviour persisted
      for at least two years. CONCLUSION: Participation of intended recipient general
      practitioners and local specialists in the development of a guideline by an
      active educational method as described was followed by a favourable change in
      clinical behaviour which persisted for at least two years.

PMID- 8671102
TI  - Effects of instruction by practice assistants on inhaler technique and
      respiratory symptoms of patients. A controlled randomized videotaped intervention
      study.
AB  - BACKGROUND: Many patients with asthma or chronic obstructive pulmonary disease
      use their medication inhalers incorrectly. General practitioners, pharmacists and
      other health care providers do not always have the opportunity to instruct
      patients in correct inhaler technique. OBJECTIVE: To find out whether the inhaler
      technique and respiratory symptoms of patients can be improved after instruction
      by practice assistants. METHODS: Single blind, randomized intervention study in
      which 48 patients who had been using a dry powder inhaler for at least one month
      took part. Their inhaler technique was videotaped on two visits with a two-week
      interval between visits. The inhaler technique on the videos was subsequently
      scored by two experts on nine criteria. At both visits the patients completed a
      questionnaire about their respiratory symptoms. After the first video, 25
      patients were randomly chosen to receive instruction from one of six practice
      assistants who had followed a one evening course about inhaler instruction, and
      who had been issued an instruction-set. RESULTS: The patients who received
      instruction had a significantly greater reduction in number of mistakes at the
      second visit than the patients who did not (P = 0.01). The instructed patients
      also reported less dyspnoea at the second visit (P = 0.03). No effect of
      instruction was found on wheezing, cough and sputum production. CONCLUSION: The
      inhaler technique of patients can be improved significantly by the instruction of
      patients by trained practice assistants, possibly resulting in less dyspnoea.

PMID- 8671103
TI  - A comparison of methods for measuring patient satisfaction with consultations in
      primary care.
AB  - BACKGROUND: Attention needs to be paid to comparing and standardizing methods for
      measuring patient satisfaction with consultations in primary care. OBJECTIVES: To
      compare the Medical Interview Satisfaction Scale (MISS) and the Consultation
      Satisfaction Questionnaire (CSQ) in terms of acceptability, distribution of
      responses, reliability and gather evidence of validity. In addition, to compare
      the scores of patients completing the questionnaires immediately after the
      consultation in the general practitioners' surgeries with those completing the
      questionnaires later at home. METHODS: The two questionnaires were bound as a
      single instrument with order determined at random. This was given to patients
      immediately after their consultations in eight practices in South Glamorgan.
      RESULTS: One hundred and ninety-eight of 316 (63%) patients completed and
      returned questionnaires. The distributions of patient satisfaction scores for the
      two questionnaires were very similar. For the MISS: mean 76.6% (SD 11.4); for the
      CSQ mean 7.2% (SD 12.6). Correlations between sub-scales ranged from 0.58-0.84
      for the MISS and from 0.40-0.79 for the CSQ. The correlation between the overall
      scales was 0.82. Levels of reliability for the scales and sub-scales were fair to
      good ranging from 0.78-0.96 for the MISS and from 0.73-0.94 for the CSQ.
      CONCLUSIONS: The study does not identify one scale as being superior in
      psychometric terms, however by demonstrating consistency of responses it provides
      support for the scales as measures of patient satisfaction for use in primary
      care. The level of inter-correlation suggests that the sub-scales may not be
      clearly independent of each other and suggests that total scores may be
      preferred. Lower levels of satisfaction are expressed if patients complete
      questionnaires at home rather than in general practitioners' surgeries.

PMID- 8671104
TI  - The costs and benefits of asking patients for their opinions about general
      practice.
AB  - BACKGROUND: Patient views are important in the evaluation of the quality of
      health care. The use of surveys needs to be evaluated to determine their cost
      effectiveness and benefits. OBJECTIVES: To determine the costs of conducting
      patient opinion surveys in general practice and to find out how effective patient
      surveys are in stimulating changes which are beneficial for patient care. METHOD:
      Postal questionnaire to all 102 medical audit advisory groups (MAAGs) and 98
      family health services authorities (FHSAs) in England and Wales, followed by
      postal questionnaire to 302 general practices reported to have conducted surveys,
      sampled by the type or questionnaire used. Numbers of MAAGs and FHSAs reporting
      surveys in general practice; types of questionnaire used; estimated costs;
      changes made; and benefits identified were measured. RESULTS: Eighty-five (83%)
      MAAGs and 75 (77%) FHSAs responded. One hundred and fifty-four (96%) of MAAGs or
      FHSAs reported survey activity. Types of questionnaire used were 1) designed by
      the practice, 2) designed by the MAAG or FHSA, possibly in collaboration with a
      practice, or 3) standard 'off-the-shelf'. One hundred and thirty-three (44%)
      practices responded. Total costs to a practice of conducting a survey ranged from
      nothing to over 2200 Pounds. Questionnaires designed by the practice are likely
      to be more costly than other designs. Some practices had surveys provided free of
      charge by MAAG or FHSA. Sixty-one per cent of practices said changes had been
      implemented and a further 22% of practices said changes were planned. The most
      common change was to appointment systems. Benefits were identified for patients,
      staff, the practice, the MAAG or FHSA and the NHS. Surveys also brought benefits
      in relationships and understanding. Only 8.2% of practices felt the costs of
      surveys outweighed the benefits. CONCLUSIONS: Many practices are surveying
      patients' opinions. Surveys can be costly but MAAGs and FHSAs can provide
      expertise and resources. Surveys using any of the types of questionnaire are
      likely to lead to changes and identifiable benefits. Benefits of surveys are
      perceived by the majority of practices to outweigh the costs.

PMID- 8671105
TI  - Patients' evaluations of their consultations with primary health clinic doctors
      in the United Arab Emirates.
AB  - BACKGROUND: Patient satisfaction must be taken into account when evaluating the
      quality of medical care, along with health status outcome measures. OBJECTIVES:
      The aims of the study were to characterize the composition of consultations with
      government primary health clinic doctors in the United Arab Emirates and explore
      which factors mediate Emirati patients' satisfaction. METHODS: One hundred and
      fifty-two patients at a Primary Health Clinic were interviewed by structured
      questionnaire. RESULTS: Most of the 152 patients interviewed rated their
      consultations positively; but less than a tenth were completely satisfied.
      Components associated with patient satisfaction in developed countries (such as
      taking a history and advising how to deal with the condition) also had the same
      impact in the United Arab Emirates. The doctor's decision about whether or not to
      include a component was usually perceived as appropriate by the patient.
      Nonetheless, patients tended to give higher ratings to doctors who discussed
      issues with them and whom they perceived as empathic. Mothers consulting the
      doctor about their children's health were especially sensitive to such factors.
      CONCLUSIONS: Among the issues discussed is whether doctors should more routinely
      be addressing social, family and affective issues; so shaping patients'
      expectations that such components are appropriate an sometimes vital. Although
      difficult, given the lack of continuity of care in primary health clinics, the
      present study suggests that Emirati patients would be comfortable with, and many
      would value, inclusion of such components.

PMID- 8671106
TI  - A new measure of patient satisfaction with mammography. Validation by factor
      analytic technique.
AB  - BACKGROUND AND OBJECTIVES: The success of national breast screening programmes
      hinges on women's adherence. By monitoring patients' perceptions, potential
      barriers to attendance may be detected, measured and possibly alleviated.
      Consequently a new questionnaire MGQ, measuring patients' experience of and
      satisfaction with mammography, has been developed. As discomfort is a predictor
      of non-attendance, a dimension measuring physical and psychological discomfort
      was included. METHODS: The internal structure of observed variables was tested
      using factor analysis as part of the validation process. The study was conducted
      in six radiological departments in Norway including 550 patients presenting for
      mammography. The analysis suggested eight factors explaining 56.7% of the
      variance. RESULTS: Construct validity was supported since the factor scales
      covered all hypothesized dimensions and all but one subdimension. The factors
      were internally consistent and externally independent, indicating that distinct
      aspects of patients' experience with mammography may be assessed and thus
      possibly improved. CONCLUSIONS: A relationship between pain and re-attendance was
      suggested as pain and worries about the next mammography belonged to the same
      factor. This underlines the importance of including a discomfort dimension when
      monitoring patient satisfaction with mammography.

PMID- 8671107
TI  - Why do people consult the doctor?
AB  - BACKGROUND: Symptoms are an everyday part of most peoples' lives and many people
      with illness do not consult their doctor. The decision to consult is not based
      simply on the presence or absence of medical problems. Rather it is based on a
      complex mix of social and psychological factors. OBJECTIVES: This literature
      review seeks to explore some of the pathways to care and those factors associated
      with low and high rates of consultation. METHODS: The paper examines the impact
      of socioeconomic and demographic factors on consultation rates and, using a
      revised version of the Health Belief Model, it highlights the psychological
      factors which influence decisions to seek medical care. Barriers which can
      inhibit consultation are discussed, as the decision to seek care will only result
      in a consultation if there is adequate access to care. RESULTS AND CONCLUSIONS:
      Whilst poor health status and social disadvantage increase both "objective"
      medical need and in turn, consultation rates, a range of other social and
      psychological factors have been shown to influence consulting behaviour.

PMID- 8671108
TI  - Treatments for postherpetic neuralgia--a systematic review of randomized
      controlled trials.
AB  - BACKGROUND: A number of different therapies have been used for postherpetic
      neuralgia. We decided to conduct a systematic review of existing randomized
      controlled trials. OBJECTIVE: To determine the efficacy of available therapies
      for relieving the pain of established postherpetic neuralgia. METHODS: We
      performed a systematic review, including meta-analysis, of existing randomized
      controlled trials. Eleven published trials and one unpublished trial were
      identified which met the inclusion criteria and were included in the current
      review. RESULTS: Pooled analysis of the effect of tricyclic antidepressants
      demonstrate statistically significant pain relief (OR 0.15, CI 0.08-0.27).
      Pooling of the results of the three trials comparing the effects of capsaicin and
      placebo could not be done due to heterogeneity. This heterogeneity was mainly
      attributable to an unpublished trial which differed in terms of the dose and
      duration of treatment. When this study was omitted, no heterogeneity was found
      and the pooled analysis revealed a statistically significant benefit (OR 0.29,
      95% CI 0.16-0.54). However, problems with blinding in patients using capsaicin
      may have accounted for the positive effect. One small study of vincristine
      iontophoresis compared to placebo also yielded a favourable result (OR 0.05, 95%
      CI 0.01-0.26). Other treatment evaluated include lorazepam, acyclovir, topical
      benzydamine, and acupuncture. We found no evidence that these are effective in
      relieving pain associated with postherpetic neuralgia. CONCLUSION: Based on
      evidence from randomized trials, tricyclic anti-depressants appear to be the only
      agents of proven benefit for established postherpetic neuralgia.

PMID- 8671109
TI  - The key informant technique.
AB  - BACKGROUND AND OBJECTIVE: This article considers the role of the key informant
      technique as a qualitative research method and examines the potential
      contribution of the approach to health care research. METHOD: The principles
      underlying the technique and the advantages and disadvantages are considered,
      illustrated with examples from a range of social science studies. RESULTS AND
      CONCLUSION: An example of the author's own use of key informants in a study of
      the professional relationship between general practitioners and specialists is
      described.

PMID- 8671111
TI  - Missing the meaning and provoking resistance; a case of myalgic
      encephalomyelitis.
AB  - BACKGROUND: The interaction between a clinician and a patient who put his
      problems down to myalgic encephalomyelitis is described. Despite attempting a
      patient-centred approach, the doctor acted on his own understanding of the
      meaning of this diagnosis without gaining proper insight into what it meant for
      the patient. This failure not only led to damaged rapport, it may have
      contributed to delayed recovery. OBJECTIVES: The unsatisfactory nature of this
      encounter led the clinician to consider more effective consulting techniques.
      METHODS AND RESULTS: A hypothetical interaction is constructed in which the
      clinician uses reflective listening statements to understand the patient's true
      meaning of this self-diagnosis. CONCLUSIONS: Despite well intentioned attempts to
      be patient-centered through widening the consultation beyond the biomedical to
      include personal and contextual factors, clinicians may still end up imposing
      their own medical meaning on patient's words. Damaged rapport is a signal that
      another track could be more fruitful and reflective listening is one strategy
      which enables clinicians to check that they fully understand the patient's
      meaning. Provoking resistance by following strategies which are not appropriate
      for the patient might then be avoided.

PMID- 8671112
TI  - Critical reading using the READER acronym at an international workshop.

PMID- 8671110
TI  - Doing randomized controlled trials in a developing country: some practical
      realities.
AB  - BACKGROUND: Formal randomized controlled trial results are often reported. The
      difficulties of doing such trial are not. Developing countries represent a new
      field in which trials can be undertaken. In this context even less is known about
      the practicalities involved. METHOD AND RESULTS: A randomized, double-blind,
      parallel study took significantly longer than expected to complete and subject
      recruitment and participation fell short of expectations. Different recruitment
      strategies were used and these performed differently in terms of enrolling
      trialists. Subjects most frequently left the trial in its early stages.
      CONCLUSIONS: Possible explanations for these findings include the demography of
      the country, cultural factors, and the existence of an established doctor-patient
      relationship.

PMID- 8671117
TI  - Antihypertensive therapy in older patients with isolated systolic hypertension:
      the Syst-Eur experience in general practice
AB  - Background and objective. This interim report from the Syst-Eur trial
      investigated the level of blood pressure control achieved during the double-blind
      period in patients followed in general practices. Methods. In the Syst-Eur trial
      elderly patients (60 years or older) with isolated systolic hypertension were
      randomized to either active or placebo treatment. Active treatment consisted of
      nitrendipine combined with enalapril and/or hydrochlorothiazide to reduce
      systolic pressure to Results. This analysis was restricted to patients of general
      practitioners who had been followed for at least 12 months. The placebo (N = 204)
      and active treatment (N = 217) groups had similar characteristics at
      randomization. At one year, the difference in sitting pressure between the two
      treatment groups was 10 mmHg systolic and 4 mmHg diastolic. Fewer patients
      remained on monotherapy in the placebo than in the active treatment group and on
      placebo the second and third line medications were started earlier. Nitrendipine
      tablets were discontinued in 10 patients on placebo and in 21 patients assigned
      to active treatment (P Conclusions. A significant blood pressure reduction can be
      achieved and maintained in older patients with isolated systolic hypertension
      followed by general practitioners. Whether this blood pressure reduction results
      in a clinically meaningful decrease of cardiovascular complications is under
      investigation. Keywords. Antihypertensive treatment, general practice, isolated
      systolic hypertension, randomized clinical trial.

PMID- 8671122
TI  - Anxiety and depression in general practitioners: associations with type of
      parctice, fundholding, gender and other personal characteristics
AB  - Background. There is evidence both that a doctor's own well-being is closely
      associated with efficiency and positive attitude to patients, and that levels of
      stress, anxiety and depression in doctors are rising. Objective. This postal
      survey aimed to measure anxiety and depression levels in general practitioners in
      1994 and identify any associations with personal and practice characteristics.
      Method. All general practitioners with patients in Staffordshire were invited to
      complete the Hospital Anxiety and Depression (HAD) scale. Results. Six hundred
      and twenty of 896 general practitioners replied (response rate 69%). No gender
      differences were found in rates of anxiety and depression; overall, 19% of
      respondents were 'cases' of depression and 16% others had borderline depression
      scores. Anxiety 'caseness' was associated with living alone, amount of on-call
      duties undertaken, and being fourth/fifth wave fundholders. Depression 'caseness'
      was associated with having little free time from practice work, amount of on
      call, being single handed, and working in a non-training practice. Conclusions.
      The authors concluded that the level of mental ill-health in general
      practitioners is a matter of concern and is associated with workload. Keywords.
      Anxiety, depression, general practitioners, personal characteristics, practice
      characteristics.

PMID- 8671127
TI  - Correspondence: Research and history

PMID- 8671129
TI  - Effect of Helicobacter pylori eradication therapy on dyspeptic symptoms in
      primary care.
AB  - OBJECTIVE: The aim was to explore the effect of eradication therapy on dyspeptic
      symptoms in patients with known peptic ulcer disease (PUD). METHOD: A total of
      164 known dyspeptics and 147 non-dyspeptic attenders at six UK general practices
      were recruited. The Helisal Rapid Blood test was performed in the practices and
      eradication therapy left to the preference of the general practitioner. Patients
      were followed prospectively by a Likert scaled symptom questionnaire and record
      review. The symptom questionnaire distinguished between patients known to have
      dyspepsia and those not. RESULTS: There was a statistically significant decrease
      in dyspeptic symptoms in patients with known PUD who received eradication therapy
      (n = 43, Z = -2.63, P = 0.009). CONCLUSIONS: Eradication of Helicobacter pylori
      in primary care can lead to a reduction in consumption of H2 receptor antagonists
      and hence cost savings. This study demonstrates that dyspeptic symptoms also
      decrease. The questionnaire could be used in further studies to evaluate the
      effect of management on dyspeptic symptoms in the primary care setting.

PMID- 8671130
TI  - What do patients expect from consultations for upper respiratory tract
      infections?
AB  - BACKGROUND AND OBJECTIVE: A cross-sectional survey was conducted amongst patients
      who consulted for upper respiratory tract infections (URTI) at 22 private
      practitioners' offices. METHOD: A total of 505 adult patients and 504 guardians
      (parents or grandparents of child patients) completed a self-administered
      questionnaire. RESULTS: The majority thought that URTI would not resolve on its
      own, while half thought that injections would speed recovery. But 78% disagreed
      with the statement that "taking multiple medications means faster recovery".
      Although 91% consulted for medicines, only 36% went specifically for antibiotics
      and 20% for injections. More than half would accept it if the doctor advised no
      medicine. More guardians (85%) than adult patients (69%) went for reassurance and
      to exclude complications. Using logistic regression analysis, the more educated
      respondents and the working guardians had higher knowledge scores, while the
      working guardians and respondents who knew the viral cause were less likely to
      worry and to demand antibiotics and injections. CONCLUSION: Much patient
      education and a change in doctors' prescribing habits in the management of URTI
      are needed in Hong Kong.

PMID- 8671132
TI  - Headache and neck or shoulder pain--family learnt illnesses behaviour? The Bardu
      Muscoloskeletal Study, 1989-1990.
AB  - OBJECTIVE: To explore the gender difference in reporting headache and neck or
      shoulder pain, we analysed the association between reported own headache and
      reporting the same complaints among first grade relatives. Based on these
      associations we discuss 'learning' of illnesses within the family structures.
      METHOD: A cross-sectional study based on a self-administered postal questionnaire
      of musculoskeletal complaints in the total population aged 20-70 years was
      carried out. A population based study was conducted in the municipality of Bardu,
      northern Norway. A total population of men and women aged 20-70, altogether 2409
      people, were sent a questionnaire. After one postal reminder 1939 questionnaires
      were returned, a response rate of 80.5%. The return rate was slightly higher
      among the eldest. The sex distribution was the same in both the responders and
      the non-responders. RESULTS: The females in the family and the brothers and
      sisters were the main family members imprinting the way in which the children
      were deciphering symptoms like headache and neck or shoulder pain later in life.
      These illnesses were changed to a very little extent by the impact from the
      spouse.

PMID- 8671131
TI  - A randomized controlled trial of electromagnetic therapy in the primary care
      management of venous leg ulceration.
AB  - OBJECTIVE: The aim was to establish the potential efficacy, tolerability and side
      effect profile of electromagnetic therapy as an adjunct to conventional dressings
      in the treatment of venous leg ulcers. METHOD: A prospective, randomized, double
      blind controlled clinical trial was carried out in a dedicated leg ulcer clinic
      based in one urban general practice. Nineteen patients with leg ulcers of
      confirmed venous aetiology were assessed. The main outcome measures were rate and
      scale of venous leg ulcer healing, changes in patient-reported pain levels,
      quality of life, degree of mobility, side effect profile and acceptability to
      patients and staff. RESULTS: Sixty-eight per cent of patients attending this
      dedicated clinic achieved improvements in the size of their ulcer (4, 21%, healed
      fully) and in reduced pain levels (P < 0.05) during the trial, despite the
      chronicity of ulcer histories. Patients treated with electromagnetic therapy at
      800 Hz were found at day 50 to have significantly greater healing (P < 0.05) and
      pain control (P < 0.05) than placebo therapy or treatment with 600 Hz. All
      patients reported improved mobility at the end of the study. The electromagnetic
      therapy was well tolerated by patients, with no differences between groups in
      reporting adverse events, and proved acceptable to staff. CONCLUSIONS: Despite
      the small numbers in this pilot study, electromagnetic therapy provided
      significant gains in the healing of venous leg ulcers and reduction in pain.

PMID- 8671133
TI  - Drug prescribing in hospital as experienced by general practitioners: East versus
      West Germany.
AB  - BACKGROUND AND OBJECTIVES: Drugs prescribed by the general practitioner (GP) are
      often changed during hospitalization. This study set out to test the hypothesis
      that the extent of drug change and the information provided by the hospital
      determines the GPs' assessment of hospital co-operation. The perception of drug
      change and hospital co-operation may also be influenced by the degree of
      institutional separation of primary and secondary care. Therefore we compared
      GPs' respective attitudes in 'East' and 'West' Germany. METHOD: In 1993, a
      representative sample of 'eastern' and 'western' German doctors received a
      structured questionnaire; 554 doctors (63%) participated. RESULTS: Fifty-seven
      per cent of the western and 39% of the eastern GPs believed that their medication
      was changed in hospital in more than 60% of their patients. Only a minority of
      eastern (10%) and western (15%) doctors described the information provided by the
      hospitals as more or less satisfactory. More western than eastern doctors (56%
      versus 32%) expressed dissatisfaction with hospital co-operation. Respondents in
      eastern Germany who felt sufficiently informed about hospital drug change were
      more likely to express satisfaction with the hospital doctors' co-operation. In
      the former area of West Germany the judgement of co-operation was significantly
      better if the extent of drug change and the frequency of generic drug replacement
      by original brand-name drugs were lower. CONCLUSIONS: The study showed that
      hospital-initiated drug change is a matter of concern, especially for GPs who are
      working in an area with a tradition of strictly separated primary and secondary
      care.

PMID- 8671134
TI  - Factors predicting differences among general practitioners in test ordering
      behaviour and in the response to feedback on test requests.
AB  - BACKGROUND: In a population of 85 general practitioners diagnostic test ordering
      behaviour has been changed by means of repeated individual feedback provided
      since 1985. OBJECTIVES: We studied practitioner and practice characteristics
      which may explain differences in test ordering behaviour and in the extent to
      which general practitioners tend to change their behaviour according to the
      feedback. METHOD: In order to trace such variables, 75 general practitioners were
      interviewed. In our study request data from individual general practitioners were
      related to data from several questionnaires. RESULTS: We found no practice
      characteristics which were of influence on the number of test requests by the
      general practitioner. Explanatory practitioner characteristics for this were
      found to be years of experience and working hours per week in practice.
      CONCLUSIONS: More years of experience as a general practitioner and a shorter
      duration of consultations correlated with a better response to advice given in
      the feedback.

PMID- 8671135
TI  - General practitioners' attitudes to variations in referral rates and how these
      could be managed.
AB  - BACKGROUND: Hospital referral rates have received widespread attention for both
      clinical and economic reasons. OBJECTIVE: This study was undertaken to find out
      the views of general practitioners in North Yorkshire on current arrangements for
      the feedback of routine referral data, perceived factors that influenced their
      referral behaviour and changes that might help their referral decisions. METHOD:
      Survey questions were chosen from the issues raised during semi-structured
      interviews with 11 selected practices. A postal questionnaire was sent to all 114
      general practices in North Yorkshire. RESULTS: A 60% (68/114) response rate was
      obtained from the postal questionnaire. The majority of practices agreed that the
      referral information supplied by them was accurate (77%) and that the feedback of
      this data was useful (66%). Uncertainty of diagnosis/management and patient
      pressure were the two most commonly agreed factors that were suggested as
      influencing referral behaviour. Training in procedures and use of clinical
      guidelines were the most popular changes chosen as being helpful in referral
      decision making. CONCLUSIONS: The feedback of routine referral data is considered
      accurate and useful, and should continue. Expanding opportunities for the
      training of general practitioners in specific skills and the development of
      clinical guidelines for the management and referral of commonly suggested areas
      would be helpful to general practitioners in making referral decisions.

PMID- 8671136
TI  - Shared care: a review of the literature.
AB  - This review examines broad issues of concern regarding the primary/secondary care
      interface. The main purpose was to identify areas of good practice which could be
      adapted for more general use. One of the most fundamental aspects identified was
      communication, which is discussed in some detail. Also covered are shared
      prescribing and disease management. The data suggest that the most effective
      system(s) of shared care has yet to be established. Further qualitative and
      economic evaluations are required, taking into account patient preferences.
      Although the literature does describe certain practice exemplars, it is clear
      that inter- and intra-professional communication continues to be a problem.
      Whilst information technology may provide some of the solutions, it is concluded
      that a culture change, which compels health professionals to make sharing of
      patient information a much higher priority, is required.

PMID- 8671138
TI  - Selection of key community descriptors for community-orientated primary care.
AB  - BACKGROUND: Community-oriented primary care (COPC) requires the development of
      practical tools if it is to be carried out. A previous study demonstrated a
      practical approach to carrying out one portion of a community assessment for COPC
      using a few representative health indicators. OBJECTIVE: To determine the
      validity of this process elsewhere, we tested whether these findings were
      generalizable to other settings and to the same setting a decade later. METHOD:
      In a cross-sectional study design, data on 18 health indicators were collected
      for census tracts in two target areas and for the entire state of Ohio, USA, for
      1990. A factor analysis was performed to identify factors underlying the health
      indicators in the three areas examined. RESULTS: Two underlying factors, termed
      age and poverty, were present in all locations and over time. Each factor was
      defined by core indicators and a cluster of associated indicators. CONCLUSIONS:
      These results suggest that one part of a COPC community assessment can be done by
      selecting very few indicators. The distribution of indicators of age and income
      explains the variability of most of the health related indicators studied. These
      factors are stable over time and location. A community assessment should include
      indicators which, at a minimum, provide information on these two factors.

PMID- 8671137
TI  - The effect of a computer-generated patient-held medical record summary and/or a
      written personal health record on patients' attitudes, knowledge and behaviour
      concerning health promotion.
AB  - OBJECTIVE: The aim of the study was to examine the effect of a computer-generated
      patient-held medical record summary (CHR) and/or a written personal health record
      (PHR) on patients' attitudes, knowledge and behaviour concerning health
      promotion. METHOD: It was conducted in five general practices in Oxfordshire.
      Patients aged 25-65 years in each practice were randomly assigned to receive
      either a CHR plus PHR, CHR only, PHR only, or no personal record. Patients were
      recruited by mail (one practice) or opportunistically by nurses (four practices).
      Health checks were carried out using the randomly assigned record, which the
      patient retained. Attitudes to patient-held records, and pre- and post
      intervention knowledge and behaviour concerning health promotion, were assessed
      using questionnaires. Only those who responded to 'before' and 'after'
      questionnaires were included in the analysis. RESULTS: A sample of 261 patients
      was obtained from mail recruitment and 103 from opportunistic nurse recruitment.
      Patients receiving a CHR as part of mail recruitment were significantly more
      likely to attend for a health check (P = 0.016). Those receiving both PHR and CHR
      were more likely to keep (P = 0.014) and use (P = 0.029) the record. Those
      receiving PHR as part of the package improved their knowledge of health promotion
      and became more aware of and more likely to change their life-style (P = 0.022).
      CONCLUSIONS: The effectiveness of a computer-generated patient-held health
      summary and an explanatory booklet together is greater than either separately in
      changing patients' knowledge attitudes and behaviour concerning health promotion.

PMID- 8671139
TI  - The International Classification of Primary Care (ICPC): new applications in
      research and computer-based patient records in family practice.
AB  - The international Classification of Primary Care (ICPC) has now been available to
      the family medicine community for a decade as the main ordering principle of its
      domain. Research data and practical experiences with ICPC, as well as the
      development of new concepts in family medicine, have resulted in new
      applications. The structure of episodes of care to be included in a computer
      based patient record has been further developed and refined. ICPC as the ordering
      principle of patient data is now available in 19 languages. Its conversion
      structure with the International Classification of Diseases (ICD-10) allows the
      highest possible level of specificity in a patient's problem list necessary in
      patient care, while the compatibility of the ICPC drug codes with the Anatomic
      Therapeutic Chemical Classification Index allows the systematic inclusion of data
      on prescription.

PMID- 8671140
TI  - Classification of severity of health problems in family/general practice: an
      international field trial.
AB  - BACKGROUND: A methodology is needed for classification of health problems by
      severity. OBJECTIVES: We aimed to test the Duke Severity of Illness Checklist
      (DUSOI) for feasibility and usefulness. METHOD: The DUSOI was field tested
      internationally by 22 family/general practitioners in 9 countries. RESULTS: The
      DUSOI was found to be feasible for rating severity of illness of health problems
      in family/general practice. The measure was shown to be clinically useful in
      older patients and those with chronic and more severe health problems.
      Variability of severity ratings was less within the same rater than between
      different raters (i.e. higher intrarater than interrater reliability). Clinical
      face validity was supported by the finding that DUSOI ratings classified patients
      with the same diagnosis and those with different diagnoses according to the
      severity differences that would be expected clinically. CONCLUSIONS: Although
      research is needed to improve reliability and to test validity further, the DUSOI
      was shown in the present study to be a methodology that is reasonable for
      consideration as an international classification of health problems by their
      severity in primary care patients.

PMID- 8671143
TI  - Selections from current literature: the role of free radicals and antioxidants in
      disease

PMID- 8671141
TI  - Qualitative methods in general practice research: experience from the Oceanpoint
      Study.
AB  - BACKGROUND: The Oceanpoint Study is a collaborative study between general
      practice and medical anthropology. METHODS: The study involved a qualitative
      ethnographic approach including long-term participant observation, in-depth
      interviews, health diaries and focus group discussions. Qualitative methods are
      suited to describing the phenomenological perspectives of people through the
      generation of rich detailed accounts which leave participants' perspectives
      intact. RESULTS: The use of these methods in this study has enabled the
      researchers to explore a range of community beliefs and practices concerning
      health and illness. The underlying concerns and approach of general practice
      medicine are similar to those of the qualitative research tradition. CONCLUSIONS:
      The experience of being a general practitioner parallels the experience of an
      ethnographer conducting qualitative research and the paper explores the
      similarities and differences between them and discusses the usefulness of such
      collaborative research.

PMID- 8671144
TI  - Association of University Departments of General Practice; Abstracts of the 25th
      annual scientific meeting

PMID- 8671142
TI  - Sore throat management in general practice.
AB  - This paper discusses primary care management of sore throat in the context of
      recent national 'consensus' guidelines from the Drugs and Therapeutics Bulletin.
      The guidelines advise taking a throat swab, using typical clinical features where
      swabs are not available, and suggest that antibiotics shorten the duration of
      symptoms and prevent complications. Systematic reviews and individual studies
      indicate that the evidence for prescribing antibiotics for most presentations of
      sore throat in general practice is marginal, and the benefits are probably
      outweighed by the likely costs of antibiotics. Using clinical scorecards or
      symptom clusters to identify individuals who would benefit from treatment is
      insensitive with low predictive value, although inexpensive. Using throat swabs
      as a gold standard for diagnosis is inappropriate since they are neither very
      specific nor sensitive, and will greatly increase costs of management. The
      relative lack of evidence for the efficacy of antibiotics and for the use of
      throat swabs from primary care research, and also an unbalanced perspective of
      dangers and complications related predominantly to a secondary care setting,
      underlines the problem of achieving valid consensus guidelines. Guidelines not
      firmly based on evidence appropriate to the intended setting are more likely to
      be received sceptically and hinder getting research into practice.

PMID- 8671146
TI  - Further concepts on regulators of the sex ratio in human offspring. Non-optimal
      maturation of oocytes and the sex ratio.

PMID- 8671147
TI  - Interpregnancy intervals, high maternal age and seasonal effects on the human sex
      ratio.

PMID- 8671148
TI  - Differential implantation rates and variations in the sex ratio.

PMID- 8671149
TI  - The statistical implication of the 'number of replacements' in embryo transfer.

PMID- 8671150
TI  - Role of gonadotrophin releasing hormone baseline concentrations in the control of
      pituitary gonadotrophin and ovarian steroid secretion in the pseudopregnant rat.
AB  - To study the effect of moderately elevated gonadotrophin releasing hormone (GnRH)
      baseline concentrations during the luteal and the follicular phase,
      pseudopregnant rats were infused s.c. with GnRH at several doses for 5 days.
      These rats were also treated with oestradiol or sham-treated during the last 3
      days of GnRH treatment. GnRH infusions started on day 7 or day 3 of the luteal
      phase of the ovulatory cycle; in the rat, the luteal phase or pseudopregnancy
      lasts about 10 days. Luteinizing hormone (LH) and follicle stimulating hormone
      (FSH) responses were induced by i.v. injection of GnRH on days 12 (after expected
      luteolysis) or on day 8 (before expected luteolysis). In normal rats the LH and
      FSH responses induced by GnRH on day 12 were higher than on day 8 (approximately
      160 and approximately 50% respectively). In GnRH-infused rats the LH and FSH
      responses were not increased. In these rats the luteal phase was extended (the
      plasma progesterone concentrations remained high) and the onset of the follicular
      phase was postponed (plasma oestrogen concentrations did not increase).
      Oestradiol increased the day 12 LH and FSH responses; this effect of oestradiol
      was suppressed by GnRH infusion. On day 8, exogenous oestradiol also increased
      the LH and FSH responses, but again the effect of oestradiol was suppressed when
      the animals were concomitantly infused with GnRH. These data may suggest that in
      the rat, GnRH baseline concentrations participate in the neuroendocrine system
      controlling gonadotrophin secretion and hence the ovulatory cycle.

PMID- 8671151
TI  - Ovulation induction using s.c. pulsatile gonadotrophin-releasing hormone:
      effectiveness of different pulse frequencies.
AB  - To determine the ovarian response to a fixed dose of gonadotrophin-releasing
      hormone (GnRH) administered s.c. at four different pulse frequencies, 20 patients
      with hypothalamic amenorrhoea were treated over 41 cycles using a dose of 20
      ng/kg/pulse. These patients were randomly assigned to receive GnRH at pulse
      frequencies of 60, 90, 120 or 180 min. GnRH was administered s.c. using portable
      infusion pumps. Subjects were paid volunteers with a diagnosis of hypothalamic
      amenorrhoea. All patients had low to less than detectable serum concentrations of
      luteinizing hormone and follicle stimulating hormone on 8 h serial sampling, and
      normal serum concentrations of prolactin and androgen, including androstenedione,
      testosterone and dihydroepiandrosterone sulphate. Six of the 20 patients were
      enrolled in the protocol to achieve a pregnancy, while 14 were volunteers using a
      barrier method of contraception. Highest ovulation rates were achieved using
      pulse frequencies of 90 and 120 min (60 and 88% of cycles respectively).
      Ovulation occurred significantly less often with frequencies of 60 and 180 min
      (12 and 38% respectively; P </= 0.05). Pregnancy was achieved in four of the six
      patients who desired a pregnancy at pulse frequencies of 90 (three out of three)
      and 120 (one out of one) min. No pregnancies occurred at pulse frequencies of 60
      (none out of one) and 180 (none out of one) min. When ovulatory cycles were
      considered, oestradiol concentrations were not different among pulse frequencies
      but varied significantly between ovulatory and anovulatory cycles. Integrated
      luteal progesterone concentrations for 90 and 120 min frequencies (118.26 +/-
      25.89 and 125.15 +/- 32. 10 ng/ml/luteal phase respectively) were significantly
      higher than for 60 and 180 min (80.1 +/- 48.2 and 42.75 +/- 26.48 ng/ml/luteal
      phase respectively). Ovulation may be induced by a broad range of pulse
      frequencies. Pulse frequencies of 90 or 120 min for s.c. GnRH appear to induce
      more reliably the sequence of follicular development, ovulation and normal luteal
      function than frequencies of either 60 or 180 min. Significantly higher ovulation
      rates occurred at 90 and 120 min by s.c. administered GnRH.

PMID- 8671152
TI  - Elevated ambulatory day-time blood pressure in women with polycystic ovary
      syndrome: a sign of a pre-hypertensive state?
AB  - The aim of this study was to evaluate office and 24 h blood pressures in women
      with polycystic ovary syndrome (PCOS) and normal controls in relation to insulin
      sensitivity. Office blood pressure, insulin sensitivity (euglycaemic
      hyperinsulinaemic clamp) and body fat distribution (skin-folds, waits:hip ratio)
      were investigated in 36 women with PCOS and 55 controls [body mass index (BMI)
      for PCOS patients, mean (confidence interval) 26.3 (24.6-28.2); controls, 25.1
      (24.0-26.9)], and ambulatory 24 h blood pressure was recorded in representative
      subgroups of 17 and 16 women respectively. Compared with the controls, the women
      with PCOS had higher day-time systolic (mean +/- SD, 126 +/- 11 versus 119 +/- 12
      mm Hg, P < 0.05) and mean arterial blood pressures (92 +/- 7 versus 86 +/- 7 mm
      Hg, P < 0.05) in ambulatory recordings, and greater increases in pulse rate (70%;
      P < 0.05) from night to day-time recordings, whereas the groups did not differ
      significantly in day-time diastolic blood pressure (74 +/- 6 versus 70 +/- 6 mm
      Hg, P = 0.05) or in night-time recordings. The women with PCOS had a more
      pronounced truncal-abdominal fat distribution (P < 0.05) and a lower insulin
      mediated glucose disposal (P < 0.01) during the clamp. The increased day-time
      blood pressures in women with PCOS persisted after adjusting for BMI, body fat
      distribution and insulin resistance. It is concluded that women with PCOS have an
      increased prevalence of labile blood pressure, which may indicate a pre
      hypertensive state, adding a further risk factor for cardiovascular disease in
      these women.

PMID- 8671153
TI  - Polycystic ovary syndrome - from gynaecological curiosity to multisystem
      endocrinopathy.
AB  - Recent progress in the diagnosis, pathophysiology, long-term ramifications and
      treatment of polycystic ovary syndrome has been rapid but the pathogenesis
      remains a challenging enigma and the treatment symptomatic. Objective ultrasound
      criteria for diagnosis are being formulated and have enabled an appreciation of
      the true prevalence and the associated clinical and biochemical manifestations.
      Although a heterogeneous syndrome, the final common pathway seems to involve a
      dysregulation of enzymes responsible for ovarian androgen biosynthesis, possibly
      influenced by insulin, growth factors and luteinizing hormone. A single gene
      defect, inherited in an autosomal dominant pattern, has been proposed. The
      treatment is necessarily symptomatic, depending on the needs of the patient. Long
      term deleterious sequelae now emerging may demand suppression of the syndrome
      earlier in life. As the most prevalent cause of anovulatory infertility, a
      further elucidation of the basic pathogenesis is needed to allow the application
      of more specific and successful modalities of treatment.

PMID- 8671154
TI  - The effects of post-ovulatory administration of onapristone on the developmnent
      of a secretory endometrium.
AB  - The purpose of this study was to assess the ability of the anti-progestin
      onapristone administered in the immediate post-ovulatory period to disrupt
      endometrial differentiation as a potential method of fertility control. In all,
      10 healthy female volunteers were given 400 mg onapristone 2 days after the mid
      cycle luteinizing hormone (LH) surge in urine (LH+2). An endometrial biopsy was
      taken 4 or 6 days after the LH surge (i.e. LH+4 or LH+6) in a control cycle and
      on the corresponding day of the treatment cycle. Biopsies were assessed for
      histological dating and immunolocalization of oestrogen receptors, progesterone
      receptors and 15-hydroxyprostaglandin dehydrogenase (PGDH). On day LH+12, blood
      was taken for the measurement of insulin-like growth factor binding protein-1
      (IGFBP-1) and placental protein 14 (PP14). Hormonal measurements in blood and
      urine were used to monitor the effects on the menstrual cycle. In addition, the
      concentration of cortisol in plasma was measured to determine if this dose of
      onapristone exerted significant anti-glucocorticoid activity. Treatment with
      onapristone retarded the development of secretory changes within the endometrium
      without affecting the length of the luteal phase. Intense nuclear immunostaining
      of oestrogen and progesterone receptors was evident in glands and stroma after
      treatment, suggesting that the progesterone-dependent down-regulation of steroid
      receptors was inhibited by the anti-progestin. Onapristone also affected the
      production of luteal phase endometrial proteins, as judged by the pronounced
      reduction in immunostaining of PGDH within the glands and the significant
      reduction in plasma concentrations of PP14. However, plasma concentrations of
      IGFBP-1 did not differ between cycles. Onapristone did not appear to exert
      significant anti-glucocorticoid activity because concentrations of cortisol were
      unaffected. These findings suggest that onapristone could potentially be used as
      a method of postovulatory fertility control.

PMID- 8671155
TI  - Effects of growth hormone releasing hormone on rat ovarian steroidogenesis.
AB  - During the last decade, it has been shown that each part of the somatotrophic
      axis can influence granulosa cell function. Growth hormone releasing hormone
      (GHRH) may be effective through the release of hypophyseal growth hormone (GH)
      and the subsequent increase of insulin-like growth factors (IGF). There is also
      some evidence that GHRH could act directly on ovarian function. The aim of this
      study was to determine the mechanism through which GHRH affects granulosa cell
      steroidogenesis in the ovary. Granulosa cells were obtained from immature,
      oestrogen- treated rats supplemented with or without follicle stimulating hormone
      (FSH) in vivo and were cultured for 48 h to evaluate steroid production. GHRH was
      administered either in vivo at the same time as FSH, or in vitro in the presence
      or absence of testosterone and FSH. Our results show that co-treatment with GHRH
      and FSH in vivo induced significant increases in plasma IGF-I concentrations and
      steroid production by cultured granulosa cells. The addition of GHRH to culture
      medium did not significantly alter steroid production by either non
      differentiated (no FSH in vivo) or differentiated (FSH in vivo granulosa cells.
      In contrast, treatment in vitro with IGF-I significantly increased
      steroidogenesis in both cases. Our results suggest that any physiologically
      significant effect of GHRH on ovarian function is probably to be exerted via
      activation of the somatotrophic axis and the subsequent amplification of ovarian
      FSH responsiveness by IGF-I.

PMID- 8671156
TI  - Short term pituitary desensitization: effects of different doses of the
      gonadotrophin-releasing hormone agonist triptorelin.
AB  - Gonadotrophin-releasing hormone agonists (GnRHa) are used to prevent inadequate
      luteinizing hormone (LH) surges during ovarian stimulation in in-vitro
      fertilization (IVF). Dose studies for optimal dose assessment are lacking and
      unfavourable effects of the agonist on granulosa function and oocyte quality have
      been suggested. This double-blind randomized study was undertaken to assess the
      effect of four different doses to triptorelin on the degree of desensitization of
      the pituitary, and the recovery time of pituitary function after withdrawal of
      the agonist. Sixty-six regularly cycling women were allocated to a treatment
      group (n = 32) and a control group (n = 34). To assess the degree of pituitary
      desensitization and restoration in the treatment group, gonadotrophin releasing
      hormone (GnRH) challenges (100 microg, i.v.) were performed during treatment (day
      17), and 2, 4 and 6 days after discontinuation of treatment. At the same time
      blood samples for oestradiol and triptorelin concentrations were drawn. In the
      control group a GnRH test was performed on day 2 of the menstrual cycle. Both
      pituitary desensitization during and pituitary recovery after agonist treatment,
      expressed as the LH response to exogenous GnRH, appeared to be dose dependent. As
      the use of reduced dosages still offers a considerable degree of pituitary
      suppression, studies on dose adjustments in the use of triptorelin, in ovarian
      stimulation in IVF are warranted.

PMID- 8671157
TI  - A bioequivalence study of two urinary follicle stimulating hormone preparations:
      Follegon and Metrodin.
AB  - The purpose of this study was to demonstrate bioequivalence between two follicle
      stimulating hormone (FSH)-only gonadotrophin preparations (Follegon(R) and
      Metrodin(R)) after a single i.m. injection of IU FSH in-vivo bioactivity. A total
      of 16 healthy normally cycling females were treated for 7 weeks with a high-dose
      oral contraceptive containing 50 microg ethinyl oestradiol plus 2.5 mg
      lynestrenol (Lyndiol(R)) to suppress endogenous gonadotrophin production. After 3
      and 5 weeks or oral contraceptive treatment, each subject received 300 IU
      Follegon or Metrodin in a random order. Frequent blood sampling was performed to
      measure immunoreactive FSH for pharmacokinetic analysis. After normalization for
      the immunodose administered, Follegon and Metrodin were bioequivalent with
      respect to the extent and the rate of absorption, the elimination half-life and
      plasma clearance per kg. The time taken to reach peak plasma FSH concentrations
      was shorter with Follegon than with Metrodin. Because bioequivalence was proved
      for the major pharmacokinetic variables, it can be assumed that Follegon and
      Metrodin are also equally effective inovulation induction, in-vitro fertilization
      and embryo transfer programmes and the treatment of male infertility.

PMID- 8671159
TI  - Severe ovarian hyperstimulation syndrome and combined intrauterine and tubal
      pregnancy after in-vitro fertilization and embryo transfer.
AB  - Ovarian hyperstimulation syndrome (OHSS) and heterotopic pregnancy are two well
      recognized entities occurring after in-vitro fertilization (IVF). This is the
      first reported case of a severe OHSS and coexistent heterotopic pregnancy after
      IVF and embryo transfer. Diagnosis of tubal pregnancy was obscured both by
      stimulated ovaries which prevented accurate ultrasound definition and the
      coexistence of an intrauterine pregnancy which accounted for human chorionic
      gonadotrophin (HCG) concentrations and also for aggravation of the OHSS. The
      roles of transvaginal ultrasound, diagnostic laparoscopy and early paracentesis
      in the management of this rare complication of assisted reproductive technologies
      are discussed.

PMID- 8671158
TI  - A case of hypergonadotrophinaemia associated with very high isolated
      concentrations of immunologically and biologically active luteinizing hormone.
AB  - A very rare case of a menstruating infertile woman with isolated luteinizing
      hormone (LH) hypergonadotrophinaemia is presented. There were no signs indicating
      the presence of a pituitary microadenoma, and LH had normal bioactivity and
      normal molecular weight. Likewise, no mutation was detected in the coding region
      of the LH beta-chain gene. In a non-stimulated cycle and a clomiphene citrate
      cycle, the patient developed an unruptured cyst. The patient ovulated and
      conceived twice following the addition of human chorionic gonadotrophin. A
      partial resistance at the ovarian LH receptor site, perhaps caused by a mutation,
      is a possible explanation for these findings. Another possibility is a
      malfunction in the signal transduction system of LH beyond the receptor level.

PMID- 8671160
TI  - Successful induction ovulation and completed pregnancy using recombinant human
      luteinizing hormone and follicle stimulating hormone in a woman with Kallmann's
      syndrome.
AB  - The induction of ovulation in women with hypogonadotrophic hypogonadism requires
      follicle stimulating hormone (FSH) for follicular growth and both FSH and
      luteinizing hormone (LH) to induce optimal follicular steroidogenesis. The
      development of human recombinant FSH and LH means that individually tailored
      doses of both hormones can be used with the aim of inducing unifollicular
      ovulation. This report describes the use of recombinant human FSH and LH for the
      induction of ovulation and conception in the second cycle of treatment, and
      subsequently a successfully completed pregnancy in a woman with Kallmann's
      syndrome.

PMID- 8671161
TI  - Analysis of health insurance cover for reproductive immunology.
AB  - The objective of this study was to document the current state of health insurance
      cover for reproductive immunology in the USA. A survey of couples who had given
      birth to a child within the last 2 years while they were being treated with
      lymphocyte immunotherapy at the Reproductive Medicine Clinic of the Finch
      University of Health Sciences/The Chicago Medical School (FUHS/CMS), North
      Chicago, IL, USA, produced 61 completed questionnaires from couples in 16 states,
      representing a response rate of 55%. The Reproductive Medicine Clinic at the
      FUHS/CMS is a major centre that treats couples with reproductive immunological
      problems. These couples had experienced repeated pregnancy losses that were
      diagnosed as immunological in nature. This prospective study documents the
      insurance reimbursement of couples receiving lymphocyte immunotherapy who
      subsequently became parents. The findings indicate that 80% of couples had
      insurance claims initially denied for reproductive immunotherapy-related
      services. The most common reason given for a denied claim was that the treatment
      was experimental. Couples took further action and almost all received cover.
      Cover for immunotherapy-related services averaged 65% of the cost. The percentage
      of expenses covered by the insurance was quite variable. The survey indicates
      that insurance cover is provided if patients are willing to take action.

PMID- 8671162
TI  - Outcome study using an administrative database: terminal salpingostomy, physician
      case load and live birth rates.
AB  - Information on the outcome following salpingostomy performed for infertility in
      everyday practice is needed to counsel patients, determine the best approach to
      this condition and clarify whether the outcome is superior when surgery is
      performed by a physician who maintains a high volume of ongoing experience. A
      total of 547 consecutive subjects were identified over a 5 year period using the
      Alberta Health Care Claims Database. Their claims history was analysed over a
      follow-up of 2-7 years, to identify pregnancy-related events, loss to follow-up
      and events which would result in sterility. Pregnancies were cross-checked with
      the only in-vitro fertilization programme serving the region. The overall
      cumulative live birth and tubal pregnancy rates were 11.7 and 7.2% respectively.
      Live birth rates were significantly higher when practitioners had performed >10
      procedures within the study period. Live birth rates would appear to be
      substantially lower in everyday practice than following surgery performed by
      acknowledged experts. A high volume of ongoing experience appears to be
      associated with superior live birth rates. It is unclear whether this association
      relates to case selection, surgical expertise or both variables.

PMID- 8671163
TI  - The impact of ovarian cystectomy on ovarian response to stimulation during in
      vitro fertilization cycles.
AB  - This study was carried out to investigate whether ovarian cystectomy interferes
      with follicular recruitment and the number of oocytes retrieved in an in-vitro
      fertilization (IVF) cycle. Patients who had previously undergone unilateral
      ovarian cystectomy (n = 90) and control patients (n = 90) with no history of
      ovarian surgery were included in our study. The parameters compared were the
      number of follicles recruited and the number of oocytes obtained from each ovary.
      In patients who had undergone surgery, the normal ovaries recruited a
      significantly higher number of follicles (P < 0.001) and yielded a significantly
      higher number of oocytes (P < 0.001) compared with the contralateral ovaries
      which had undergone cystectomy. In the control patients, no significant
      differences were identified between the left and right ovaries. These results
      demonstrate that ovarian cystectomy reduces follicle and oocyte numbers in
      ovulation induction cycles.

PMID- 8671164
TI  - Randomized controlled trial of cervical cap with intracervical reservoir versus
      standard intracervical injection to inseminate cryopreserved donor semen.
AB  - A prospective controlled study of donor insemination without sperm preparation or
      ovarian stimulation was performed to compare the use of a cervical cap
      incorporating an intracervical reservoir with a standard intracervical injection
      technique to inseminate 0.5 ml cryopreserved semen. Treatments were alternated in
      successive cycles in each patient after initial randomized selection. A total of
      198 patients had 635 treatment cycles (median 3, range 1-7), 309 with reservoir
      and 326 by standard injection. A total of 56 women became pregnant, 24 (7.8% per
      cycle) with the reservoir and 32 (9.8% per cycle) by injection. There were no
      significant differences between the pregnancy rates per cycle overall or cycle
      specific cumulative rates calculated using the life-table method. There were no
      significant differences in age, parity, baseline gonadotrophin measurements, mid
      luteal serum progesterone concentrations, frequency of adverse fertility factors
      in the woman or her partner's cause of infertility between women who conceived
      and those who failed to conceive. We conclude that use of a cervical reservoir
      and cap for donor insemination does not offer any advantage over standard
      intracervical insemination.

PMID- 8671165
TI  - Serum relaxin and the major endometrial secretory proteins in in-vitro
      fertilization and down-regulated hormone-supported and natural cycle frozen
      embryo transfer.
AB  - Relaxin has been postulated to be a modulator of the expression of the
      endometrial secretory proteins, insulin-like growth factor binding protein (IGFBP
      1) and placental protein 14 (PP14). This study evaluated the expression of
      relaxin in relation to concentrations of these secretory proteins along with
      oestradiol, progesterone and human chorionic gonadotrophin in groups of pregnant
      and non-pregnant patients who underwent differing assisted conception treatments.
      Serum samples were taken from 88 patients at 8 and 12 days after embryo transfer.
      At 12 days after embryo transfer, relaxin concentrations in the pregnant patients
      who had undergone in-vitro fertilization (IVF) or natural cycle frozen embryo
      transfer were significantly higher than those who did not conceive in these
      groups (mean concentrations 8334 versus 28 and 2608 versus 62 pg/ml respectively,
      P<0.001). However concentrations in the pregnant patients who had hormone support
      and transfer of frozen embryos were not significantly different from the patients
      who did not conceive after the same treatment. Although relaxin expression was
      associated with corpus luteum activity, it was not related to the number of
      corpora lutea in IVF patients. A wide range of relaxin concentrations was seen to
      be compatible with a healthy pregnancy. These serum relaxin concentrations were
      not found to be directly related to the serum concentrations of IGFBP-1, PP14 or
      the other factors assessed in this study.

PMID- 8671166
TI  - Future fertility following conservative management of complete abortion.
AB  - Dilatation and curettage is the usual procedure implemented in cases of
      incomplete or missed abortion in the first trimester of pregnancy. The management
      of complete abortion depends on pregnancy age. We examined the possibility that
      conservative management of complete abortion can be effective and does not affect
      future fertility. A total of 172 women who presented with complete abortion to
      our Ambulatory Gynecological Clinics of the Dan Region, Israel, were managed
      conservatively. Of 161 who desired to become pregnant, 118 (73%) conceived within
      18 months. We conclude that it is possible to avoid curettage in the management
      of complete abortion of<8 weeks' gestational age with little or no effect on
      future fertility.

PMID- 8671167
TI  - In-vitro fertilization: the experience of treatment, pregnancy and delivery.
AB  - The present study compares the evidence of pregnancy and delivery among in-vitro
      fertilization (IVF) parents (45 couples), other formerly infertile parents (35
      couples) and fertile parents (35 couples). All deliveries concerned primaparous
      women and singleton births. In addition, the burden of fertility treatments was
      investigated. Results show that the psychological burden of the treatments
      exceeds the physical burden. Fertility treatments were judged very worthwhile.
      Complications during pregnancy were more frequently reported by IVF mothers and
      other initially infertile mothers than by fertile mothers. However, controlling
      for the older age in both formerly infertile groups (IVF and non-IVF), no
      significant difference was found. No differences appeared regarding the
      evaluation of the development of the delivery. IVF parents and other infertile
      parents evaluated the pregnancy as more stressful than fertile parents. However,
      mothers experienced their delivery as more exceptional, and fathers experienced
      the pregnancy as more exceptional. In addition, IVF fathers enjoyed the pregnancy
      more than fathers from the other groups.

PMID- 8671168
TI  - Fertility after ectopic pregnancy: first results of a population-based cohort
      study in france.
AB  - The purpose of this paper was to evaluate the reproductive outcome after ectopic
      pregnancy (EP) from a population-based register in the centre of France. Since
      1992, all the women aged 15-44 years, who permanently reside in the target area
      and who were treated either by surgical or medical procedures for an ectopic
      pregnancy in one of the area centres, have been registered and prospectively
      followed until 45 years of age. The analysis presented was based on the 155 women
      registered between January 1992 and March 1994 who were followed up for at least
      6 months, and who were seeking a new pregnancy. The mean follow-up period was 16
      months. A total of 102 women (66%) obtained a pregnancy. The first conception was
      intrauterine for 92 women, and 10 had a recurrence of ectopic pregnancy. Risk
      factors of recurrence were prior spontaneous abortion and prior tubal damage. For
      those women who conceived, the mean time to obtain pregnancy ('time to
      pregnancy') was 4.8 months. The 1 year cumulative intrauterine pregnancy rate
      (i.e. the probability of obtaining an intrauterine pregnancy within 1 year of
      seeking pregnancy) was 70%. After multivariate analysis by a Cox regression, the
      factors associated with higher fertility were age < 30 years, high educational
      level and no prior tubal damage.

PMID- 8671169
TI  - Nurses performing embryo transfer: successful outcome of in-vitro fertilization.
AB  - This prospective study demonstrates the feasibility and outcome of embryo
      transfer performed by nursing staff with medical cover available. Of 771 patients
      who had embryo transfer, 679 (88%) had their embryo transfer performed by a
      nurse. In 92 cases (12%) a doctor performed the embryo transfer, either as the
      first operator, or having been brought in to assist the nurse who experienced
      difficulty. The pregnancies per transfer for nurse transfer was 246/679 (36%) and
      where a doctor performed the transfer 20/68 (29%). These data show a high
      comparable success rate when a nurse performed the embryo transfer, and a low
      incidence of direct medical involvement.

PMID- 8671170
TI  - Associations between ultrasound indices of follicular blood flow, oocyte recovery
      and preimplantation embryo quality.
AB  - The aim of this study was to elucidate possible relationships between ultrasound
      indices of follicular blood flow, oocyte recovery and the subsequent production
      and morphological quality of preimplantation embryos. A total of 27 women with
      bilateral tubal occlusion, undergoing treatment for infertility by in-vitro
      fertilization and embryo transfer, contributed data from 29 cycles. Transvaginal
      ultrasonography with colour Doppler imaging and pulsed Doppler spectral analysis
      was used to obtain indices of blood flow for each follicle immediately before it
      was aspirated. The main outcome measures for each follicle were the pulsatility
      index, peak systolic velocity, recovery or non-recovery of an oocyte and the
      subsequent production or non-production of an embryo. A total of 126 follicles
      were studied, 102 oocytes were recovered and 58 embryos (49 at grades I or II)
      were produced. There were six clinical pregnancies (pregnancy rate 27.3% per
      embryo transfer, 22.2% per patient). There was a significant correlation (P <
      0.0001, chi2 test) between whether or not follicular blood flow was detected and
      whether or not an oocyte was recovered. The sensitivity of a test based on the
      presence of detectable blood flow and the subsequent recovery of an oocyte was
      74% and the positive predictive value was 93%. The peak systolic velocity (PSV,
      measured in cm/s, mean +/- SD) in follicles with detectable blood flow was
      significantly higher in follicles that were associated with the production of a
      preimplantation embryo (19.7 +/- 10.8) compared with those that were not (9.9 +/-
      5.3, P < 0.0001, Student's t-test). There was a 70% chance of producing a grade I
      or II embryo if the follicular blood velocity was >/=10 cm/s, compared with 14%
      if the PSV was <10 cm/s, or 18% if no blood flow was detected. We conclude that
      there is a physiological relationship between follicular blood velocity, oocyte
      recovery and the production of a high-grade preimplantation embryo, which may
      form the basis of a useful clinical test.

PMID- 8671171
TI  - Functional life-span of the dominant follicle in pharmacologically induced
      anovulatory cycles.
AB  - With the purpose of measuring the duration of the functional life-span (FLS) of
      the anovulatory follicle in women under continuous low-dose progestogen
      treatment, the oestradiol curve of Norplant implant users was retrospectively
      analysed. From all the data collected during the previous 5 years at the
      Department of Biomedical Research at the Family Planning Clinic of Profamilia,
      Santo Domingo, Dominican Republic, data from all 29 Norplant implant users
      showing follicular activity without luteal activity were selected for this
      retrospective analysis. Serial blood sampling twice or three times a week for 5
      or 6 consecutive weeks had been taken in all subjects. The duration of the FLS of
      the dominant follicle in anovulatory cycles was defined at the period from the
      first day of ascending oestradiol curve until the day preceding onset of menses.
      The mean FLS of the dominant follicle in anovulatory cycles under continuous low
      dose progestogen administration was 21.1 +/- 4.2 days, independently of the
      length of the menstrual cycle. The duration of the FLS of the anovulatory
      dominant follicle appears not to be different from the duration of a normal
      follicle/corpus luteum unit.

PMID- 8671172
TI  - Semen parameters and sperm morphology in men in unexplained recurrent spontaneous
      abortion, before and during a 3 year follow-up period.
AB  - To investigate the role of the 'male factor' in the pathogenesis of recurrent
      spontaneous abortion (RSA), especially sperm morphology abnormalities, 120
      previously selected couples with unexplained RSA were studied for sperm
      parameters retrospectively and prospectively. The patients were subdivided into
      three subgroups, depending on their reproductive outcome during the 3 years of
      follow-up study: (i) 48 RSA couples who achieved a successful pregnancy; (ii) 39
      RSA couples who experienced further abortions, and (iii) 33 RSA couples who
      experienced infertility during the follow-up period. A semen analysis was
      performed twice at the time of inclusion in this study, and twice again during
      the 3 year follow-up period. No significant differences in semen parameters were
      observed between RSA males and fertile controls. Instead, significant differences
      were observed between the group of RSA couples who experienced infertility during
      the follow-up and the other two groups (RSA couples who achieved successful
      pregnancy and RSA couples who experienced miscarriages and no live birth during
      the follow-up) for sperm concentration (P < 0.01 and P < 0.01 respectively),
      sperm motility (P < 0.01 and P < 0.01 respectively) and sperm morphology
      abnormalities (P < 0.01 and P < 0.01 respectively). Sperm morphology
      abnormalities do not seem to be involved in determining RSA; instead, they are an
      aetiological factor in determining infertility in patients, along with the other
      semen parameters, in the RSA couple's subsequent reproductive life. Semen
      analysis is an important test in the clinical management of RSA couples.

PMID- 8671174
TI  - Correlation between testicular histology and outcome after intracytoplasmic sperm
      injection using testicular spermatozoa.
AB  - A comprehensive study is presented of a series of 124 infertile men undergoing
      testicular sperm retrieval for intracytoplasmic sperm injection (ICSI). In this
      study we correlated the histological changes observed in the testicular tissue
      with the results of the wet preparation and the outcome after ICSI using
      testicular spermatozoa. In all patients with normal spermatogenesis and
      hypospermatogenesis spermatozoa were recovered from the wet preparation. The
      sperm recovery rate as 84% in patients with incomplete germ-cell-aplasia and
      maturation arrest, while in patients with complete germ-cell aplasia or
      maturation arrest this figure was 76%. In these patients more specimens were
      sampled and fewer spermatozoa were recovered. Since no spermatozoa were recovered
      in only 10 patients, ICSI with testicular sperm was performed in the remaining
      114 couples (91.9%). The normal fertilization rate was 57. 8%. The fertilization
      rate was significantly lower in couples among whom the husband showed germ-cell
      aplasia and maturation arrest. Overall, 55.2% of normally fertilized oocytes
      developed into embryos showing <=50% of anucleate fragments. There were no major
      differences between the different histological categories in terms of embryonic
      development in vitro. The overall pregnancy rates per testicular sperm extraction
      (TESE) procedure, per ICSI procedure and per transfer were respectively 36.3,
      39.5 and 43.7%. The overall implantation rate per embryo (sacs/embryos replaced)
      was 20.3%. A lower implantation rate was observed in couples among whom the
      husband had maturation arrest (not statistically significant). The above data
      show that testicular biopsies may have an important therapeutic role in the
      management of infertility in azoospermic patients.

PMID- 8671173
TI  - Progesterone does not potentiate the acrosome reaction in human spermatozoa: flow
      cytometric analysis using CD46 antibody.
AB  - The study was designed in order to investigate the action of progesterone on the
      spontaneous and ionophore-induced human spermatozoa acrosome reaction in vitro.
      The principle of the assay system is flow cytometric analysis of CD46 antibody
      binding to the inner acrosomal membrane. The technique is a simple and objective
      method of analysis, allowing fluorescent analysis of a large segment (5000
      spermatozoa) of the spermatozoa population under investigation, with concomitant
      isolation of the live fraction of the spermatozoa population. Four concentrations
      of progesterone (1, 25, 50, and 100 microg/ml) were examined for their effects on
      spermatozoa capacitated for 4 and 24 h. In addition, motility parameters were
      examined by the CellSoft 2000 automated semen analyser system. Analysis of
      variance revealed that progesterone had no effect on either the spontaneous
      acrosome reaction or the ionophore-induced acrosome reaction at both 4 h and 24 h
      of spermatozoa capacitation times. Further, no effects on sperm motility
      parameters or on spermatozoa viability could be attributed to progesterone. We
      therefore conclude that progesterone has no objectively measurable effects on
      either the sperm acrosome reaction or sperm motility parameters, as measured in
      normal sperm populations.

PMID- 8671175
TI  - Efficacy of intracytoplasmic sperm injection using intentionally cryopreserved
      epididymal spermatozoa.
AB  - Microsurgical epididymal sperm aspiration was a great advance in the therapy of
      patients with non-reconstructable, obstructive azoospermia, most notably
      congenital bilateral absence of the vas deferens. Using conventional in-vitro
      fertilization, pregnancies were rarely achieved because the rate of oocyte
      fertilization was extremely poor. However, the use of retrieved spermatozoa in
      conjunction with intracytoplasmic sperm injection (ICSI) has dramatically
      increased the likelihood of embryo formation. Typically, sperm and oocyte
      harvesting are performed simultaneously. We have investigated whether frozen
      thawed spermatozoa work as well as fresh spermatozoa. When we had concluded from
      our own population of patients (groups I and II) that they did, we adopted a
      policy of aspirating spermatozoa, primarily cryopreserving them and using them
      for ICSI at a later date. We found the fertilization rates of this latter cohort
      of patients (group III) to be excellent (37% per oocyte), and the ongoing
      pregnancy rate is quite satisfactory (40% per couple, 29% per cycle). We offer
      this approach as an alternative to the traditional scheme because it markedly
      eases the burden of partner scheduling on both the couple and the clinicians
      involved. In addition, assurance of the availability of male partner spermatozoa
      can be attained prior to beginning ovulation induction.

PMID- 8671176
TI  - Sperm morphology assessment using strict criteria and male fertility under in
      vivo conditions of conception.
AB  - The clinical significance of sperm morphology assessment according to very strict
      criteria was determined using semen samples of randomly chosen males from couples
      not submitted to assist procreation techniques, with a median duration of
      infertility of 4 years (range 1-17; n = 89). The relationships of sperm
      morphological properties to the results of standard sperm analysis, including the
      differentiation of round cells in semen by monoclonal antibodies and semen
      cultures, the testing of sperm functional capacity in vitro with the standardized
      sperm-cervical mucus penetration test (SCMPT) and the subsequent pregnancy rate
      under in-vivo conditions of conception, were evaluated in a prospective study.
      The quick staining method (DiffQuick(R) stain) for sperm morphology proved to be
      practical and suitable for routine use. The percentage of normal forms according
      to strict criteria ranged from 1 to 36%, with a median of 12%. Morphological
      findings were not markedly related to the medical history, but significant
      relationships between standard parameters of sperm analysis, in particular the
      sperm count, the progressive motility and standard sperm morphology, were found.
      The percentage of normal forms was not significantly associated with the
      microbial colonization of semen samples but was negatively related to high
      leukocyte rates. Semen samples with a higher percentage of normal spermatozoa
      (shown, for example, for >4,> 7 or >=14% normal) were significantly more frequent
      in cases of an adequate SCMPT. The subsequent pregnancy rate within an
      observation period of 12 months was 20.2%. The pregnancy rate under in-vivo
      conditions was significantly higher when semen samples had a better sperm
      morphology, with significant differences for thresholds at 4, 7 and 14% of
      strictly normal forms. Although sperm morphology is only one among a multiplicity
      of factors determining fertility, the results suggest that the evaluation of
      sperm morphology using strict criteria provides valuable information during basic
      infertility investigations.

PMID- 8671177
TI  - Sexual arousal and the quality of semen produced by masturbation.
AB  - The influence of sexual arousal on the quality of semen produced by masturbation
      was investigated. One group of 29 patients referred to our andrology outpatient
      clinic (group A) and one group of 14 healthy potential sperm donors filled out a
      questionnaire after having produced two semen samples, at least 1 month apart, by
      masturbation. Changes in questionnaire scores between first and second visit were
      compared with changes in semen characteristics between those two occasions to
      identify statistically significant correlations. A second group of 23
      subfertility patients (group B) were asked to produce a semen sample by
      masturbation in a designated room at the hospital without additional sexual
      stimulation, and a second sample while viewing a sexually explicit video.
      Differences in questionnaire scores and semen characteristics obtained with
      visual erotic stimulation (VES) and without VES were analysed. In group A, the
      change in sexual arousal and change in intensity of orgasm correlated with change
      in semen volume (r = 0.38, P < 0.05; r = 0.48, P < 0.01 respectively). In healthy
      donors and group B, however, no such correlation was found. With VES in group B,
      significantly higher scores were given for 'feeling at ease/relaxed' (P < 0.01),
      'sexual arousal' (P < 0.001), 'quality of erection' (P = 0.01), 'intensity of
      orgasm' (P < 0.05), 'satisfaction after orgasm' (P < 0.05), and 'ease with which
      orgasm was achieved' (P < 0.001) with VES compared to without VES. There was no
      statistically significant improvement in semen quality with VES compared to
      without VES. It is concluded that sexual arousal has no significant influence on
      the quality of an ejaculate produced by masturbation. On the other hand,
      providing a patient with a sexually stimulating video is obviously a facilitative
      factor when the patient 'has to' produce a semen sample for analysis. The use of
      visual erotic stimulation is recommended when patients and donors have to produce
      a semen sample in the university surroundings of a fertility clinic.

PMID- 8671178
TI  - Oxytocin affects the release of steroids, insulin-like growth factor-I,
      prostaglandin F2alpha and cyclic nucleotides by human granulosa cells in vitro.
AB  - The aim of the present experiments was to examine the effects of oxytocin (1-10
      000 ng/ml) on hormone and cyclic nucleotide secretion by human granulosa cells
      cultured in a serum-supplemented medium. The release of progesterone, oestradiol,
      insulin-like growth factor-I, prostaglandin F2alpha, cAMP and cGMP into the
      incubation medium was analysed by radioimmunoassay. An inhibition of
      progesterone, but not of oestradiol release was observed. Oxytocin also
      stimulated insulin-like growth factor-I, prostaglandin F2alpha, cAMP and cGMP
      output. The results suggest an involvement of oxytocin in the autocrine/paracrine
      regulation of steroid, insulin-like growth factor, prostaglandin and cyclic
      nucleotide release by human ovarian cells.

PMID- 8671179
TI  - Cryobiology of non-human primate oocytes.
AB  - The responses to various stresses involved with cryopreservation protocols were
      investigated using non-human primate oocytes. Fluorescence microscopy was used to
      assess the status of the F-actin microfilament system of rhesus monkey oocytes
      after exposure to different concentrations of glycerol. The F-actin organization
      around the cortex and in the transzonal processes was modified by exposure to 1.0
      ot 2.0 M glycerol at ambient temperature. These effects were reduced
      significantly when exposure to glycerol was combined with cooling to O degrees C.
      Cynomolgus monkey oocytes were also subjected to hyperosmotic stress and observed
      for morphological changes. An irregular shrinkage phenomenon was observed with
      germinal vesicle or metaphase I but not metaphase II (MII) oocytes. The irregular
      shrinkage became uniform and spherical when the oocytes were pretreated with
      ethyleneglycol-bis-(beta-aminoethyl ether)N,N,N'N' tetraacetic acid (EGTA) before
      exposure to hypertonic solution. Also, in-vitro-matured MII oocytes from
      cynomolgus monkeys were used to determine crucial biophysical parameters for
      freezing primate oocytes. The permeability of oocyte plasma membrane to water,
      Lpg, and its activation energy, ELp, were determined between 0 and -12 degrees C
      in the absence of cryoprotective additives. The Lpg was found to be 3.8x10(-14)
      m3N/s and the ELp was 141.5 kJ/mol. the pre-exponential kinetic and exponential
      thermodynamic parameters of intracellular ice formation were determined to be
      8x108 m2/S and 2. 2x10(9) K5 respectively. By combining models of water transport
      and intracellular ice formation, the cumulative fraction of oocytes with
      intracellular ice as a function of the cooling rate was also predicted, and it
      was shown to correlate reasonably with experimental observations.

PMID- 8671180
TI  - Reducing the time of sperm-oocyte interaction in human in-vitro fertilization
      improves the implantation rate.
AB  - Human oocyte development was evaluated after a reduced time exposure to
      spermatozoa in vitro. A total of 119 patients were assigned to two study groups
      in a randomized prospective study in which each patient's oocytes were exposed to
      spermatozoa for either 1 h (group 1 - 58 patients) or the standard 16 h
      incubation period (group 2 - 61 patients). The fertilization rate obtained in
      group 1 was higher than in group 2 (285/393, 73%, and 272/410, 66% respectively),
      suggesting that the spermatozoa-oocyte interaction occurs within 1 h. This was
      confirmed in a study in vitro using fluorescently labelled spermatozoa and normal
      oocyte-cumulus complexes. Spermatozoa enter the cumulus complex within 15 min,
      traverse the cumulus layer within 3 h, and first appear in the oocyte cortex at 4
      h post-insemination. The incidence of polyspermy was higher in oocytes exposed to
      spermatozoa for 16 h (3%) than for 1 h (1%). There was no difference in the
      cleavage rate or morphological characteristics of embryos from both study groups.
      However, when evaluating the timing of embryo development, group 1 generated a
      significantly higher percentage of four to five cell embryos when compared to
      group 2 (55 versus 39%; P < 0.001), documented at 40 h post-insemination. The
      implantation and pregnancy rates for group 1 were 11 and 28%, while the
      corresponding rates for group 2 were 8 and 15%. This suggests that a reduced
      exposure of oocyte to spermatozoa favours embryo viability, possibly due to a
      decrease in potential damage from sperm metabolic waste products.

PMID- 8671181
TI  - Oolemma characteristics in relation to survival and fertilization patterns of
      oocytes treated by intracytoplasmic sperm injection.
AB  - The aim of this study was to analyse the various reactions displayed by the
      oolemma to the penetrating pipette during intracytoplasmic sperm injection (ICSI)
      and correlate them with clinical factors, oocyte survival and fertilization
      patterns. Three types of oolemma responses were observed: normal breakage, when
      the injection needle created an invagination that ruptured at the approximate
      centre of the egg; sudden breakage, when the membrane broke without creating a
      funnel; and difficult breakage, when the membrane did not break or broke after
      several penetration attempts. A total of 2928 oocytes were analysed with the
      following observations: 73.9% (n = 2164) experienced normal breakage, 11.8% (n =
      345) sudden breakage, and 14. 3% (n = 419) difficult breakage. The survival rate
      and number of normally fertilized oocytes were significantly lower and the
      incidence of digynic oocytes was significantly higher in the sudden breakage
      group; furthermore, in this group a significantly shorter length of stimulation
      was observed along with lower serum oestradiol concentrations when compared to
      oocytes experiencing normal and difficult breakage patterns. These recorded
      patterns were predictive of the survival and fertilization ability of the
      injected oocytes, as well as the incidence of digyny. The link between membrane
      behaviour and various clinical parameters appears to indicate a correlation
      between the modality of stimulation and oolemma characteristics.

PMID- 8671182
TI  - Inhibitory effect of glucose and phosphate on the second cleavage division of
      hamster embryos: is it linked to metabolism?
AB  - Hamster embryos cannot complete the second cleavage division in vitro in the
      presence of glucose and inorganic phosphate (Glu/Pi). Embryos can recover from an
      8 h (12:30-20:30 h) exposure to Glu/Pi, although cleavage is retarded by 10 h and
      continued development to the blastocyst stage is rare (2%). The vulnerability of
      2-cell embryos to Glu/Pi changes during the cell cycle, being greatest just prior
      to cleavage which occurs at approximately 21:00 h: exposure to Glu/Pi from 12:30
      14:30 h allowed 94% development to morulae/blastocysts while exposure from 18:30
      20:30 h decreased morula/blastocyst development to 48%. This inhibitory effect is
      also modulated by the length of exposure and energy substrate composition of the
      culture medium. It is unclear how Glu/Pi interferes with cleavage, but a
      metabolic explanation is likely because (i) metabolic inhibitors L
      glyceraldehyde, iodoacetate and cystamine exacerbated the effect and (ii) the
      organization of active mitochondria observed with Rhodamine 123 and confocal
      microscopy is disturbed by Glu/Pi.

PMID- 8671183
TI  - Immunocytochemical localization of growth factors and their receptors in human
      pre-embryos and Fallopian tubes.
AB  - We utilized indirect immunocytochemistry to demonstrate the presence of growth
      factors and their receptors in human pre-embryos and Fallopian tubes. In pre
      embryos, only transforming growth factor-alpha (TGF-alpha) and the intracellular
      domain of epidermal growth factor receptor (EGFR) were found at the 4-cell stage.
      In 8- to 14-cell pre-embryos, TGF-alpha, the intracellular and extracellular
      domains of EGFR, and insulin-like growth factor-I and its receptor were found.
      Antibodies against TGF-alpha stained all Fallopian tube specimens, while the
      extracellular domains of EGFR was only found in specimens from patients with
      either blood type A or AB. These results suggest a cross-reactivity between the
      extracellular domain of the EGFR and blood group antigens. Our novel
      demonstration of growth factor receptor staining in human pre-embryos shows that
      growth factor receptor localization is dependent on the developmental stage of
      human pre-embryos. We have also established a potentially important link between
      the Fallopian tube which secretes growth factors and the localization of growth
      factor receptors in pre-embryos. These findings are compatible with the
      hypothesis that tubal secretions are embryotrophic for the early development of
      the pre-embryo.

PMID- 8671184
TI  - Leukaemia inhibitory factor significantly enhances the blastocyst formation rates
      of human embryos cultured in serum-free medium.
AB  - The aim of this study was to investigate the effect of leukaemia inhibitory
      factor (LIF) on human blastocyst formation rates in vitro. To do this, it was
      first necessary to devise a complex serum-free medium (CSFM) in which to test its
      activity. Blastocyst formation rates in CSFM microdrops (18.4%) showed no
      difference to those obtained previously for embryos cultured in 1 ml T6 medium
      containing 10% serum (25%). The majority of blastocysts were of optimal
      blastocyst grade (BG1/BG2) as compared to the poor grade (BG3). The percentage of
      BG1/BG2 blastocysts was decreased in CSFM microdrops (10.2%) compared to that
      observed in T6 medium (24.8%). Addition of 1000 IU/ml LIF to CSFM microdrops
      increased the blastocyst formation rate from 18.4 to 43.6% (P = 0.025) and
      increased the percentage of BG1/BG2 blastocysts (33%; P = 0.025) to levels
      comparable with those observed in T6 medium. Thus LIF significantly increased the
      quality and number of human blastocysts formed in CSFM medium, increasing the
      potential for blastocyst transfer in human in-vitro fertilization (IVF).

PMID- 8671185
TI  - Natural cycle in-vitro fertilization with embryo cryopreservation prior to
      chemotherapy for carcinoma of the breast.
AB  - Chemotherapeutic treatment for malignant disease may cause infertility secondary
      to gonadal failure. In-vitro fertilization (IVF) with embryo cryopreservation
      prior to chemotherapy has been described as a means of preserving future
      fertility potential. However, the supraphysiological levels of sex steroids that
      result from ovarian stimulation for IVF may, at least theoretically, stimulate
      growth of malignant cells in a patient with a hormonally sensitive tumour such as
      carcinoma of the breast. This report describes a patient with carcinoma of the
      breast who underwent IVF in the natural cycle prior to embarking on a course of
      combination chemotherapy. Of three oocytes retrieved, two fertilized and were
      cryopreserved. This case represents a novel application of IVF with embryo
      cryopreservation in the natural cycle. Although embryo thawing and transfer have
      not yet been attempted, the patient has already benefitted psychologically from
      having the opportunity to assume an element of control over her reproductive
      future. Should pregnancy occur, this would be the first report of human pregnancy
      from cryopreserved embryos obtained in a natural cycle.

PMID- 8671186
TI  - Results of modified laparoscopically assisted neovaginoplasty in 18 patients with
      congenital absence of vagina.
AB  - Construction of a neovagina using pelvic peritoneum via a laparoscopically
      assisted approach was used in 18 patients with congenital absence of the vagina.
      A better operative procedure is reported, which was modified from our preliminary
      technique, and the results of treatment are evaluated. Pelvic peritoneum was used
      for construction of a vagina, replacing a laparotomy by a minimally invasive
      laparoscopic approach. During follow-up, the advantages of our procedures are:
      (i) minimal likelihood of 'poor take' or later contraction because an autograft
      peritoneal epithelial line is used; (ii) minimal short and long term care is
      required; (iii) the technique is simple in experienced hands and has all the well
      recognized benefits of minimal invasive surgery; (iv) the average length of
      neovagina is adequate and patency and depth can be maintained with minimal
      dilatation; (v) the neovagina, with epithelial lining resembling that of a normal
      vagina, facilitates comfortable sexual intercourse; (vi) the procedure is
      unaccompanied by dyspareunia or scarring, which are frequently associated with
      other techniques; (vii) less emotional stress and better cosmetic and economic
      benefits are noted.

PMID- 8671187
TI  - Vascular smooth muscle alpha-actin distribution around endometrial arterioles
      during the menstrual cycle: increased expression during the perimenopause and
      lack of correlation with menorrhagia.
AB  - Menorrhagia affects approximately 9% of all women, increasing to 20% during the
      perimenopause. The majority of menstrual loss occurs through the spiral
      arterioles - specialized endometrial vessels that are intimately involved in
      controlling menstruation. Our aim was to compare the distribution of vascular
      smooth muscle alpha-actin using immunohistochemical techniques in the endometrium
      of women before and during the perimenopause and with or without menorrhagia. We
      hypothesized that differences in vessel numbers and types exhibiting alpha-actin
      staining would exist between these groups, reflecting structural/functional
      differences. The results showed that perimenopausal menorrhagic women had
      significantly more smooth muscle alpha-actin expression than non-perimenopausal
      controls in four out of five menstrual cycle stages (P < 0.05), while
      perimenopausal non-menorrhagic women demonstrated a significant increase at the
      mid-proliferative stage only (P < 0.007). No significant differences occurred
      between women with or without menorrhagia before or during the perimenopause.
      Perimenopausal women had significantly more straight arterioles (P < 0.02) than
      women prior to perimenopause at the late secretory stage, while non
      perimenopausal women demonstrated significantly higher numbers of spiral
      arterioles (P < 0.002) in the early secretory stage, although this difference had
      disappeared by the late secretory stage. In conclusion, we found no major
      differences in endometrial vascular smooth muscle alpha-actin staining between
      women with and without menorrhagia, but significant increases in alpha-actin
      staining in women showing perimenopausal symptoms.

PMID- 8671189
TI  - Bicervical uterus and septate vagina: report of a previously undescribed
      Mullerian anomaly.
AB  - A case of non-septate uterus with double cervix and complete longitudinally
      septate vagina is described. This previously undescribed Mullerian anomaly has
      been detected by complete clinical and instrumental investigations (transvaginal
      ultrasonography, urography, hysterosalpingography, hysteroscopy and laparoscopy).
      Aetiological hypotheses are discussed and we suggest adding the uterovaginal
      malformation described in this report to the embryological classification
      recently proposed by Acien et al. (1991, 1992) which postulates isolated
      Mullerian anomalies as a consequence of a minor mesonephric defect.

PMID- 8671188
TI  - Human Fallopian tubal epithelial cells in vitro: establishment of polarity and
      potential role of intracellular calcium and extracellular ATP in fluid secretion.
AB  - A pure population of human Fallopian tubal epithelial cells has been isolated by
      enzyme digestion, grown in primary culture and used to explore the biochemical
      basis of oviduct fluid secretion. Confluence was achieved in 3-7 days.
      Immunocytochemical labelling for cytokeratins indicated that the cells were
      epithelial in nature and formed extensive desmosomal contacts, producing a
      polarized layer in culture. By growing the cells on collagen-impregnated filters,
      a small transepithelial electrical potential difference could be recorded, with
      the apical side of the cells negative with respect to the basal side. In
      addition, the consumption of glucose and the appearance of lactate were greater
      on the basal than on the apical side of the cells. Because intracellular Ca2+
      ([Ca2+]i) is well established as a signal transduction agent in epithelial fluid
      secretion, the effect of a wide range of agonists on [Ca2+]i in isolated tubal
      epithelial cells was studied using Fura-2. The only agent which induced a change
      in [Ca2+]i was extracellular ATP. The transients induced were dependent on both
      intracellular and extracellular calcium. ATP added to the basal side of the cells
      of the polarized layer induced a transient increase in the potential difference.
      The data are consistent with a potential role for extracellular ATP in the
      regulation of human tubal fluid formation.

PMID- 8671190
TI  - Vascular endothelial growth factor (VEGF) concentrations are elevated in
      peritoneal fluid of women with endometriosis.
AB  - Active endometriosis is characterized by hypervascularization both within and
      surrounding the implant; therefore the presence of angiogenic factors in the
      peritoneal environment would be of great importance. Vascular endothelial growth
      factor (VEGF) is a potent angiogenic factor involved in both physiological and
      pathological angiogenesis. We sought to determine if VEGF was present in the
      peritoneal fluid of women with and without endometriosis, and to establish if
      differences exist between these groups. VEGF was present in all patients sampled.
      The fluid from patients with endometriosis contained significantly greater
      amounts of VEGF than controls. Cyclic variations in VEGF concentration were seen
      in fluid from patients with endometriosis, the VEGF concentration in
      proliferative phase being significantly higher than in the secretory phase. The
      concentration of VEGF in this fluid was also significantly higher than that found
      in the proliferative and secretory phases of women without endometriosis. No
      cyclic variations in VEGF were seen in the control group. We suggest that
      elevated levels of VEGF in the peritoneal fluid of patients with endometriosis
      may be critical in the pathogenesis of endometriosis.

PMID- 8671191
TI  - Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of
      the rectovaginal septum.
AB  - A computerized morphometrical investigation was performed on endometriotic tissue
      from the peritoneum (n = 225) and rectovaginal nodules (n = 65) to compare
      histologically and stereologically the rectovaginal septum endometriotic nodule
      to peritoneal endometriosis. Mitotic activity, stromal vascularization and the
      epithelium/stroma ratio were found to be significantly different in peritoneal
      and rectovaginal endometriosis. The evaluation revealed a major role of glandular
      epithelium in rectovaginal nodules where the stroma sometimes appeared absent
      around glandular epithelium. The study demonstrated opposite effects of
      gonadotrophin-releasing hormone agonists (GnRHa) and lynestrenol on the two
      lesions. Indeed, in peritoneal endometriosis, after GnRHa therapy, our study
      demonstrated a lower rate of mitosis and poor stromal vascularization. The same
      drug was unable to induce the same effects in the nodule although, in contrast,
      lynestrenol has a strong effect on nodule vascularization. In conclusion, it is
      suggested that the rectovaginal adenomyotic nodule is a specific disease,
      different from peritoneal endometriosis. It is not the consequence of 'deep
      infiltrating' endometriosis but can probably develop from Mullerian rests present
      in the rectovaginal septum.

PMID- 8671194
TI  - Does high voltage electricity have an effect on the sex distribution of
      offspring?

PMID- 8671195
TI  - In-vitro maturation of human testicular spermatozoa.

PMID- 8671196
TI  - Women's hormone concentrations and the increasing rates of ectopic pregnancy.

PMID- 8671197
TI  - Control for tubal disease before ascribing ectopic pregnancy to hormone
      imbalance.

PMID- 8671198
TI  - Oestrogens and progesterone concentrations and risk of ectopic pregnancy: an
      epidemiological point of view.

PMID- 8671199
TI  - Is the rising incidence of ectopic pregnancy unexplained?

PMID- 8671200
TI  - Chromosomal abnormalities and ectopic pregnancy? New directions for aetiological
      research.

PMID- 8671201
TI  - The hidden side of ectopic pregnancy: the hormonal factor.

PMID- 8671202
TI  - Post-coital sperm retrieval could lead to the wider approval of assisted
      conception by some religions.

PMID- 8671204
TI  - Dexamethasone during ovulation induction for in-vitro fertilization: a pilot
      study
AB  - The purpose of the present study was to determine whether adrenal androgen
      suppression with dexamethasone (DEX) during ovulation induction improves the
      outcome of in-vitro fertilization (IVF) cycles. A total of 25 patients with serum
      dehydroepiandrosterone sulphate (DHEAS) concentrations >2.5 &mgr;/ml were
      randomized to receive either 0.5 mg DEX daily or placebo during ovulation
      induction with leuprolide acetate down-regulation plus human menopausal
      gonadotrophins (HMG). Nine patients undergoing a subsequent IVF cycle were
      crossed over to the other treatment group. Ovarian responsiveness and IVF outcome
      variables analysed included number of follicles >12 mm in diameter, serum
      oestradiol concentrations on the day of human chorionic gonadotrophin (HCG)
      administration, number of ampoules of HMG administered, number of oocytes
      retrieved, percentage of oocytes fertilized, number of embryos transferred,
      implantation rate and numbers of clinical pregnancies and live birth pregnancies.
      The 31 randomized IVF cycles revealed a trend towards a higher implantation rate
      for the placebo-treated group compared to the DEX-treated group (24 versus 10%; P
      = 0.07). The remainder of the IVF cycle variables revealed no statistically
      significant differences. In conclusion, the suppression of adrenal androgens with
      DEX in women with DHEAS concentrations >2.5 &mgr;/ml appears to have no
      beneficial effects on ovarian responsiveness or clinical or live birth pregnancy
      rates. Key words: dexamethasone/IVF/ovulation induction

PMID- 8671203
TI  - Annual patterns of luteinizing hormone, follicle stimulating hormone,
      testosterone and inhibin in normal men.
AB  - Reproductive functions in most animals demonstrate seasonal fluctuations that
      allow young to be born at a time of the year favourable for their survival.
      Whether there is a seasonal change in the human reproductive system is unclear.
      In the present study, we measured serum concentrations of luteinizing hormone,
      follicle stimulating hormone, testosterone and inhibin in the same 16 normal men
      sampled monthly for 1 year. A statistically significant increase in all four
      measured hormones was found in June, with a nadir in August. Our findings suggest
      that a circannual rhythm of gonadotrophins and testicular hormones exists in
      normal men. The mechanism leading to this rhythm and the importance of the rhythm
      in human biology are unknown.

PMID- 8671205
TI  - Effect of low weekly doses of mifepristone on ovarian function and endometrial
      development.
AB  - The effect of a low dose of mifepristone (RU486) on ovarian and endometrial
      function was studied in 14 healthy women. The study included one control and two
      treatment cycles. During the treatment cycles, either 2.5 mg (n = 9) or 5 mg (n =
      5) of mifepristone was administered once weekly. The concentration of ovarian
      steroids and luteinizing hormone (LH) in urine was measured daily, cortisol in
      blood once weekly and glycodelin (placental protein 14; PP14) at the time of
      menstruation. Ovarian function was monitored by vaginal ultrasound. An
      endometrial biopsy was taken in each cycle in the mid-luteal phase, based on self
      measurement of the LH peak, or on cycle day 22 if no LH peak could be detected.
      In the evaluation of the results, the outcome of the enzyme immunoassay of LH was
      used to date the biopsy. Endometrial progesterone and oestrogen receptors and
      Dolichus biflorus agglutinin (DBA) lectin binding were measured. Ovulation was
      not inhibited by treatment with mifepristone, and an LH peak could be determined
      in all control and treatment cycles. However, in four subjects (one with the
      higher and three with the lower dose) the follicular phase was prolonged by 6-13
      days. The duration of the luteal phase and the concentrations of pregnanediol and
      oestrone glucuronide were not affected by treatment. A dose of 5 mg, and to a
      lesser extent 2.5 mg, mifepristone once weekly caused desynchronization of
      endometrial development. Endometrial progesterone receptor, but not oestrogen
      receptor, concentration was significantly increased by the higher dose. A
      significant reduction in DBA-lectin binding and in serum glycodelin
      concentrations was also found. Thus, low doses of mifepristone do not inhibit
      ovulation but delay endometrial development and impair secretory activity.
      Whether these effects are sufficient to prevent implantation remains to be
      established.

PMID- 8671206
TI  - Relationship between tumour necrosis factor alpha and sex steroid concentrations
      in the follicular fluid of women with immunological infertility.
AB  - Experimental evidence suggests a tight relationship between cytokines and the
      reproductive system. Tumour necrosis factor alpha (TNF alpha), a cytokine
      produced by activated macrophages and mesenchymal cells, seems to participate in
      the control of fertility. Therefore, the present study was undertaken to evaluate
      the concentrations of TNF alpha in the follicular fluid of female patients with
      immunological infertility, as well as the possible role of this cytokine in
      follicular development. Concentrations of TNF alpha, 17 beta-oestradiol,
      progesterone, androstenedione and testosterone were measured in the follicular
      fluid of patients with immunological infertility and patients with a tubal factor
      of infertility, who served as a control group. Patients with immunological
      infertility had significantly higher concentrations of TNF alpha in their
      follicular fluid compared to the control group. In contrast, oestradiol
      concentrations were significantly lower in the former group. The intrafollicular
      concentrations of the other steroids measured did not differ significantly
      between the two groups. The fertilization rate of ova from follicles included in
      the study was significantly lower in patients with immunological infertility
      compared to control subjects (19.1 and 57.1% respectively). In conclusion, this
      study shows that patients with infertility of immunological origin have increased
      follicular fluid concentrations of TNF alpha and lower oestradiol concentrations.
      We speculate that elevated TNF alpha concentrations in the human follicle may
      negatively influence both ovulation-and fertilization-related events.

PMID- 8671207
TI  - Immunoreactive endothelin-1, endothelin-2 and big endothelin-1 in follicular
      fluids of women undergoing ovulation induction for in-vitro fertilization.
AB  - Endothelin-like immunoreactivity specific for endothelin-1 (ET-1), endothelin-2
      (ET-2) or big endothelin-1 (big ET-1) was measured, using commercially available
      radioimmunoassay kits, in follicular fluid collected at the time of oocyte
      aspiration from 36 women undergoing ovulation induction by human menopausal
      gonadotrophin (HMG). The relationship of ET concentrations to HMG dose, peak
      serum oestradiol concentration, the number and size of follicles (by ultrasound),
      the number of retrieved oocytes and the fertilization rate per retrieved oocyte
      were studied. Overall, 94% of follicular fluid samples were positive for ET-1,
      92% were positive for ET-2, and 100% were positive for big ET-1. Mean ET-1, ET-2
      and big ET-1 concentrations were 17.23 +/- 12.20, 32.42 +/- 14.32 and 34.55 +/-
      16.34 pg/ml respectively. Endothelin-like immunoreactivity in follicular fluid
      samples was found in an order of ET-1 < ET-2 < big ET-1. There was a highly
      significant positive correlation (r = 0.8711,P = 0.001, n = 32) between
      follicular ET-1 and ET-2 concentrations. No significant correlation of follicular
      big ET-1 was established either with ET-1 or ET-2. However, big ET-1 was found to
      be negatively correlated with number of oocytes (P = 0.03) and number of
      follicles (P = 0.04). Control plasma ET-1 and follicular ET-1 were not
      significantly different. There was no significant correlation between ET
      concentrations and any of the other studied parameters. The results demonstrated
      that immunoreactive ET-1, ET-2 and big ET-1 exist in human follicular fluid
      collected at the time of oocytes retrieval for in-vitro fertilization and may be
      involved in the regulation of reproductive function. The clinical significance
      and physiological role of follicular fluid ET deserve further studies.

PMID- 8671208
TI  - Stress and stress-related hormones during in-vitro fertilization treatment.
AB  - Whether stress and infertility are linked as cause or consequence is unclear, and
      there is no consensus on the most appropriate methods for measuring stress in
      infertile women. To address this question, we measured changes in biochemical and
      questionnaire-based assessments of stress in infertile women. Median baseline,
      follicular phase and pre-operative serum prolactin (229, 311 and 457 mIU/l)
      cortisol (278, 369 and 496 nmol/l) and state anxiety score (38, 40 and 49)
      respectively all increased during stimulated in-vitro fertilization (IVF)
      treatment. There was no such increase in a control group having similar
      laparoscopic surgery unrelated to infertility, or in women having unstimulated
      IVF without laparoscopy, suggesting that anxiety levels are greatest in
      stimulated IVF, increase as a result of the treatment, and are adequately
      reflected by state anxiety scores. Baseline serum prolactin in unstimulated IVF
      (384 mIU/l) was significantly higher than control (177 mIU/l), although this was
      not reflected in serum cortisol or state anxiety score. Trait anxiety was
      constant within and between groups, suggesting that stress is not contributing
      greatly to the infertility. Women who achieved a pregnancy had similar state
      anxiety scores to those who failed, suggesting that the degree of anxiety
      observed during IVF treatment is unlikely to influence the chance of pregnancy.
      There was a trend towards lower trait anxiety in women who became pregnant, but
      the numbers were small.

PMID- 8671209
TI  - Internal jugular vein thrombosis caused by resistance to activated protein C as a
      complication of ovarian hyperstimulation after in-vitro fertilization.
AB  - We present a case of a 24 year old woman who became pregnant (twins) after human
      menopausal gonadotrophin (HMG)-induced ovarian stimulation, in-vitro
      fertilization (IVF) and subsequent embryo transfer. She developed a right
      internal jugular vein thrombosis as a complication of severe ovarian
      hyperstimulation syndrome (OHSS) 28 days after embryo transfer. The thrombosis
      developed in spite of anticoagulation with low-dose heparin. Later a resistance
      to activated protein C (APC) or Dahlback disease was diagnosed. Due to a new test
      procedure (accelerin inactivation test), the diagnosis was possible even under
      anticoagulation treatment. The coincidence of hyperstimulation and internal
      jugular vein thrombosis with the concurrent diagnosis of resistance to APC has
      not been published previously. The benefit of general screening for resistance to
      APC before admission to the IVF programme should be weighed. Targeted selection
      of a group of high-risk women would therefore be made possible.

PMID- 8671210
TI  - Immunology of human implantation: an evolutionary perspective.
AB  - The concept of the fetus as an allograft, which has been much cherished by
      reproductive immunologists, is in need of re-appraisal. We speculate that the
      relationship between the allogeneic conceptus and mother is not governed by the
      laws of classical transplantation immunity. Instead, this relationship is more
      akin to the allorecognition system seen in invertebrates.

PMID- 8671211
TI  - Financial impact in the Italian Health Service of laparoscopic versus laparotomic
      surgery for the treatment of ovarian cysts.
AB  - To assess the cost of two procedures for the removal of ovarian cysts, 200 pre
      menopausal women were recruited for the surgical removal of ovarian cysts by
      laparoscopy (n = 100) and laparotomy (n = 100) according to case-control
      criteria. Patients operated by laparoscopy (mean age +/- SD 32.22 +/- 9.98 years)
      and laparotomy (mean age +/- SD 29.57 +/- 6.62 years) for ovarian cysts (mean
      diameters +/- SD 4.98 +/- 3.62 and 4.83 +/- 2.78 cm) had a post-surgical hospital
      stay of 3.12 +/- 0.41 and 7.25 +/- 1.08 days (P < 0.001) respectively. The total
      rate of complications occurring in patients operated by laparoscopy was 9 versus
      53% (P < 0.001) of those operated by laparotomy; body temperature > 38 degrees C
      was recorded in 52/100 of patients operated by laparotomy versus 6/100 of those
      operated by laparoscopy. The mean cost for each pure surgical treatment performed
      by laparoscopy was US $498.17 versus US $642.47 when it was performed by
      laparotomy (P < 0.001). The laparoscopic surgical approach is more expensive in
      the first 36 operations, thereafter becoming cheaper. The mean of the entire
      overall expenditure was US $1142.08 and US $2138.72 for laparoscopy and
      laparotomy (P < 0.001) respectively. The entire expenditure for laparoscopy is
      higher than laparotomy only until eight operations. In conclusion, laparoscopy
      versus laparotomy has resulted in a saving of US $14,429.3 for 100 operations
      while the saving on entire costs was US $99,664.8.

PMID- 8671213
TI  - Analysis of the attitudes and emotional processes in couples undergoing
      artificial insemination by donor.
AB  - Osgood's Semantic Differential Questionnaire was used to study 40 couples
      undergoing an artificial insemination by donor (AID) programme. The following
      reference concepts were used: Father, Mother, Work, Marriage, Myself, Children,
      Pregnancy, Guilt, Sex and Family. The results show that women consider ?being a
      Mother' as something emotionally ?warm', take a positive position, feel ?nervous'
      and wish the event happened quickly; this is significantly different to men, who
      give less importance to this fact. Men are more concerned about the pregnancy and
      consider it a ?hard', ?strong' and ?heavy' experience. The score in the concept
      Guilt significantly stands out from the rest of the concepts in both men and
      women; it is also striking how AID women relate the concept Mother with the
      concept Father, whereas men establish the association between Mother and Work.

PMID- 8671212
TI  - Uterine rupture following hysteroscopic lysis of synechiae due to tuberculosis
      and uterine perforation.
AB  - A patient with genital tuberculosis who conceived with in-vitro fertilization and
      embryo transfer following hysteroscopic synechiolysis complicated by a fundal
      uterine perforation subsequently presented with uterine rupture at 36 weeks
      gestation. Immediate Caesarean section and repair of the ruptured uterus were
      performed. Women with a history of uterine perforation should be counselled
      regarding the risk of uterine rupture during their subsequent pregnancies.

PMID- 8671214
TI  - Fertility treatment and risk of breast cancer.
AB  - The relationship between fertility treatment and breast cancer was investigated
      in a multicentric case-control study conducted in Italy on 2569 women with
      incident, histologically confirmed breast cancer and 2588 control women admitted
      to hospitals for acute, non-neoplastic, non-hormonal or gynaecological
      conditions, unrelated to fertility problems. The odds ratio of breast cancer was
      1.08 (95% confidence interval 0.8-1.5) in those reporting fertility treatment
      compared with those who did not receive fertility treatment. Similarly, the odds
      ratio was 0.60 for women with tubal occlusion, 0.99 for those reporting hormonal
      imbalances and 1.32 for other/unspecified reasons. There was no consistent
      pattern of risk according to age at treatment and time since treatment. Women
      reporting fertility treatment with drug use had an odds ratio of 1.43, while
      those who did not report drug therapy had an odds ratio of 0.85. None of these
      odds ratio estimates was significant. Likewise, there was no heterogeneity among
      strata of parity, menopausal status, education and family history of breast
      cancer. Thus, our study, while providing reassuring evidence on the relationship
      between fertility treatment and breast cancer risk, cannot exclude the
      possibility that the use of specific drugs may be related to breast
      carcinogenesis.

PMID- 8671216
TI  - Quantitative post-coital test: sperm counts in cervical mucus after enzymatic
      liquefaction.
AB  - The post-coital test involves direct microscopic examination of sperm number and
      motility in cervical mucus. The results depend on the quality of the mucus and
      the distribution of spermatozoa within the sample. To progress from such
      qualitative data to quantitative measurements of the spermatozoa present in post
      coital mucus, we have developed methods to measure sperm concentrations in
      enzymatically liquefied post-coital cervical mucus. The mucus score and sperm
      motility were measured prior to mucus liquefaction, and, together with sperm
      concentration, they allowed the calculation of the total number of motile
      spermatozoa present. A combination of bromelin and glycosidases proved to be more
      efficient in achieving reliable mucus liquefaction than treatment with bromelin
      alone, and was used to liquefy a series of 36 post-coital test samples. Total
      sperm numbers ranged between 19 x 10(3) and 16.8 x 10(6). Of the samples, 75%
      contained < 3 x 10(6) spermatozoa, and 39% contained < 1 x 10(6) spermatozoa.
      Sperm motility was very high in these samples, except for a distinct subset of
      samples (19%) in which the total sperm motility was markedly decreased ( < 20%).
      The measurement of sperm concentration in liquefied cervical mucus will help to
      determine normal values for the post-coital test, and to estimate the number of
      motile spermatozoa reaching the upper female genital tract.

PMID- 8671215
TI  - A detailed study of the effect of videoframe rates of 25, 30 and 60 Hertz on
      human sperm movement characteristics.
AB  - A comparison was made of the movement characteristics of human spermatozoa
      analysed at three videoframe rates (25, 30 and 60 Hz) using two computerized
      motility analysers from Hamilton-Thorn Research (the HTM-2030 and the IVOS)
      operating at 25 and 30 Hz respectively. Analysis at 30 and 60 Hz was performed on
      the IVOS. The use of uncapacitated, capacitated and pentoxifylline-stimulated
      spermatozoa ensured a full range of movement characteristics was analysed. The
      velocity parameters curvilinear velocity and average path velocity were highly
      frame-rate dependent, and mean values increased with videoframe rate. An
      interaction of framing rate and time of data collection resulted in an increase
      in straight-line velocity with framing rate. Mean lateral head displacement and
      linearity were similar at 25 or 30 Hz but significantly depressed at 60 Hz. Beat
      cross frequency increased by 74% when analysed at 60 rather than 30 Hz. The
      following criteria: curvilinear velocity > 100 microns/s, linearity < 65% and
      lateral head displacement > 7.5 microns, were used to define hyperactivated
      spermatozoa. Significantly more hyperactivated cells were identified at 30 Hz
      than 25 Hz (1-10%) but not at 60 Hz. A different population of cells is likely to
      have been identified as hyperactivated at 60 Hz due to alterations in component
      movement parameters from which the definition of hyperactivation was derived. In
      conclusion, direct comparisons should not be drawn between data analysed at 25
      and 30 Hz. Analysis at 60 Hz introduced complex alterations which made simple
      comparisons with 30 Hz data invalid.

PMID- 8671217
TI  - Sperm counts in enzymatically liquefied cervical mucus: quantitative validation
      using donor cervical mucus.
AB  - The post-coital test evaluates the penetration of spermatozoa into cervical
      mucus; it relies on subjective measurements and therefore lacks precision.
      Enzymatic liquefaction of cervical mucus allows sperm concentration to be
      measured in post-coital test samples, but the reliability of such measurements is
      not known. Donor cervical mucus was used as a model to test the accuracy and
      sensitivity of sperm quantification in liquefied cervical mucus. Donor cervical
      mucus was dissolved by enzymatic treatments in the presence of known numbers of
      spermatozoa and the recovery of sperm cells was assessed after liquefaction of
      the samples. Enzymatic treatment of cervical mucus with a combination of bromelin
      and glycosidases resulted in reliable and fast liquefaction of the samples. The
      accuracy of sperm concentration measurements was 89 +/- 10% (mean +/- SD, n =
      50), and the sensitivity limits were 1 x 10(6) and 0.2 x 10(6) spermatozoa/ml for
      quantitative concentration measurement and qualitative sperm detection
      respectively. This study demonstrates that liquefaction of cervical mucus by
      combined protease and glycosidases allows accurate and sensitive determination of
      sperm concentration in the sample. Therefore we believe that valuable data can be
      obtained for sperm concentration and total sperm counts in post-coital tests,
      that should help to improve the reliability of the post-coital test.

PMID- 8671219
TI  - Results of cytogenetic analysis in men with severe subfertility prior to
      intracytoplasmic sperm injection.
AB  - Intracytoplasmic sperm injection (ICSI) is increasingly becoming the treatment of
      choice for severe male subfertility. Cytogenetic evaluation of men with
      andrological subfertility reveals an increased incidence of chromosomal
      abnormalities when compared with the normal population. We performed chromosomal
      analysis on the male partners of 32 couples referred for andrological
      subfertility. In two of these men, constitutional chromosomal translocations were
      diagnosed prior to ICSI [(45,XY,t(21;22)(p11;q11) and 46,XY,t(22;Y)(p11;q12)].
      Since ICSI bypasses many potential barriers of fertilization, successful
      pregnancy can be achieved despite the presence of severely impaired spermatozoa
      in a population at high risk for chromosomal aberrations. It is well known that
      the presence of a chromosomal aberration plays a significant role in partial or
      complete spermatogenic arrest. ICSI does not seem to increase the risk of fetal
      chromosomal abnormalities when a spermatozoon from a chromosomally normal male is
      used. To exclude a higher risk for spontaneous abortion and fetal chromosomal
      abnormalities, we advocate cytogenetic screening of males with severe male
      subfertility who opt for ICSI.

PMID- 8671218
TI  - Deterioration of sperm quality in young healthy Belgian men.
AB  - We have retrospectively analysed the sperm characteristics of 416 consecutive
      healthy young men who presented themselves in the past 19 years as candidate
      sperm donors. Ejaculate volume increased slightly (P = 0.067), and average sperm
      concentration decreased (P = 0.035) by 12.4 x 10(6)/ml over the observation
      period, so that sperm count per ejaculate remained unchanged (P = 0.91). In
      contrast, sperm morphology (r = - 0.23, P < 0.0001), rapid progressive motility
      (r = - 0.42, P < 0.0001) and total motility (r = - 0.33, P < 0.0001) presented an
      important and time-related decrease. When a quadratic model was used rather than
      a linear one to analyse the data on rapid progressive motility, there appeared to
      have been no further decline since 1990. The average proportion of spermatozoa
      with normal morphology decreased from 39.2% in the period 1977-1980 to 26.6% in
      1990-1995 (P < 0.0001), and the mean percentage of spermatozoa with rapid
      progressive motility decreased from 52.7 to 31.7% (P < 0.0001). The percentage of
      candidate donors with sperm characteristics below the 5th percentile cut-off
      value of a normal fertile population increased from 13 to 54% during the
      observation period (P < 0.0001). Since the technique of semen analysis has
      remained essentially unchanged in-so-far as has been practically possible, as has
      the method of recruitment of candidate sperm donors, the observed deterioration
      of sperm characteristics is considered to reflect degeneration of sperm
      production among men aged between 20 and 40 years.

PMID- 8671220
TI  - Vas deferens aspiration and intracytoplasmic injection of frozen-thawed
      spermatozoa in a case of anejaculation in a diabetic man.
AB  - By using aspiration from the vas deferens, apparently good quality spermatozoa
      can be obtained for in-vitro fertilization (IVF) in cases of non-treatable
      anejaculation. Being squeezed from the epididymis during aspiration, the
      spermatozoa may be immature and their fertilizing capacity lower than that of
      ejaculated spermatozoa. Our case report describes a couple who achieved pregnancy
      when intracytoplasmic sperm injection (ICSI) was carried out with frozen-thawed
      spermatozoa aspirated from the vas deferens of a man whose anejaculation was
      associated with diabetes mellitus. In the aspiration, 50 x 10(6) spermatozoa were
      obtained. One half of them was frozen, and the other half was used fresh for
      conventional IVF, resulting in total fertilization failure of all the oocytes.
      The second treatment was ICSI, in which eight out of 11 oocytes injected with
      frozen-thawed spermatozoa showed normal fertilization. The second frozen embryo
      transfer resulted in a normal pregnancy.

PMID- 8671221
TI  - Effect of human chorionic gonadotrophin on the detachment of human granulosa
      cells from extracellular matrix layered onto glass or plastic.
AB  - We have previously shown that human granulosa cells cultured on a thin layer of
      extracellular matrix (ECM) are lost from culture in the absence of gonadotrophin.
      We now examine the effect of plating ECM onto glass or plastic. Such a comparison
      revealed that loss of cells from control cultures was more rapid when ECM was on
      glass, whereas cultures maintained with human chorionic gonadotrophin (HCG)
      showed greater stability when ECM was on plastic. The dose range of HCG required
      for the effect on cell retention was similar to that required for stimulation of
      progesterone production. Electron microscopy of cells freshly released as
      clusters revealed that many cells appeared undamaged, and confocal microscopy of
      cells stained with propidium iodide showed an absence of fragmented nuclei. Taken
      together, this evidence suggests that apoptosis is not the cause of cell release.
      We conclude that cells are released from culture, not as a result of cell death,
      but via an active process suppressed by HCG.

PMID- 8671222
TI  - Birth of normal mice after removal of the supernumerary male pronucleus from
      polyspermic zygotes.
AB  - Each year, world wide, tens of thousands of zygotes derived from the in-vitro
      insemination of human oocytes undergo polyspermic fertilization. These embryos
      must presently be discarded because it has never been demonstrated in any mammal
      that polyspermic zygotes can develop normally to term after removal of the
      supernumerary male pronucleus. Our study was undertaken to test the developmental
      potential of polyspermic zygotes corrected by micromanipulation. Mouse oocytes
      were inseminated zona-free, and polyspermic zygotes were manipulated so as to
      remove one of the two male pronuclei. Surviving embryos were then observed for
      further development in vitro and after transfer into pseudopregnant females. Of
      58 zygotes manipulated, 18 developed to the blastocyst stage and were
      transferred. Five animals (two male and three females) were born. The agouti coat
      colour marker confirmed the genotypes of the gametes. All five animals developed
      to normal-appearing adults, and all five produced at least 10 normal offspring.
      One adult founder animal was karyotyped and found to have a normal chromosome
      complement. These results demonstrate for the first time that a mammalian egg
      that has undergone polyspermic fertilization can develop normally after
      restoration of the diploid state by micromanipulation. Accordingly, the results
      provide impetus for attempting to rescue polyspermic human embryos.

PMID- 8671223
TI  - The sperm centriole: its inheritance, replication and perpetuation in early human
      embryos.
AB  - The inheritance, replication and perpetuation of the sperm centriole in the early
      human embryo are reported. Both normal monospermic and abnormal dispermic embryos
      (n = 127) were examined by transmission electron microscopy. Centrioles were
      traced from fertilization to the hatching blastocyst stage. The sperm proximal
      centriole is introduced into the oocyte at fertilization and remains attached to
      the expanding spermhead during sperm nuclear decondensation, as it forms the male
      pronucleus. A sperm aster is initially formed after the centriole duplicates at
      the pronuclear stage. At syngamy, centrioles occupy a pivotal position on
      opposite spindle poles, when the first mitotic figure is formed. Bipolar spindles
      were found in the majority of embryos, while tripolar spindles were seen in four
      dispermic embryos at syngamy. Two single centrioles were detected at two poles of
      two tripolar spindles, while two additional centrioles were located on the sides
      of a bipolar spindle of a dispermic embryo. Sperm tails were detected near
      spindle poles at syngamy and in later embryos. Typical centrioles showing the
      characteristic pin-wheel organization of nine triplets of microtubules were
      evident. During centriolar replication, the daughter centriole grows laterally
      from the parent and gradually acquires pericentriolar material (PCM). The two
      centrioles are surrounded by a halo of electron-dense PCM, which nucleates
      microtubules, thus making it a typical centrosome. The usual alignment of
      diplosomes at right angles to each other was maintained. Centrioles were detected
      at all stages of embryonic cleavage from the 1-cell through 8-cell stages, right
      up to the hatching blastocyst stage. They were closely associated with nuclei at
      interphase, when they were often replicating, and were prominently located at
      spindle poles during the first four cell cycles. In blastocysts, they were
      detected in trophoblast, embryoblast and endoderm cells respectively. It is
      evident that the sperm centrosome is the functional active centrosome in human,
      while the female is inactive but may contribute some centrosomal material to the
      zygote centrosome. It is very likely that the paternal centriole is the ancestor
      of the centrioles in fetal and adult somatic cells.

PMID- 8671225
TI  - Comparison of uterine blood flow characteristics between spontaneous and
      stimulated cycles before embryo transfer.
AB  - The Doppler blood flow characteristics of uterine arteries were evaluated
      prospectively in 57 patients undergoing embryo transfer. A total of 32 women
      underwent frozen-thawed (FT) embryo transfer during a spontaneous menstrual cycle
      (FT-embryo transfer), and 25 patients underwent in-vitro fertilization treatment
      (IVF-embryo transfer). The endometrial thickness, pulsatility index (PI), maximum
      peak systolic velocity (MPSV), minimum diastolic velocity (MDV) and flow velocity
      waveform type of the uterine artery blood flow were assessed with transvaginal
      colour Doppler ultrasonography before embryo transfer. The mean (SD) endometrial
      thickness was 9.2 (2.0) mm in FT-embryo transfer patients and 12 (3.4) mm in IVF
      embryo transfer patients (P < 0.0003). There were no conception cycles in which
      the uterine arteries bilaterally had a flow velocity waveform with an absent end
      diastolic flow. Compared to spontaneous cycles, the median PI was statistically
      lower and the MDV was higher in IVF cycles. In contrast, no difference was found
      in the median MPSV values between the two groups. There was no difference in
      Doppler velocimetry measurements between the conception and non-conception cycles
      in either the FT-embryo transfer or the IVF-embryo transfer groups. In
      conclusion, an inadequate uterine blood flow impaired implantation, while optimum
      uterine blood perfusion did not necessarily lead to conception.

PMID- 8671224
TI  - Morphometric, immunohistological and three-dimensional evaluation of the
      endometrium of menopausal women treated by oestrogen and Crinone, a new slow
      release vaginal progesterone.
AB  - Recently advanced computerized technology was applied to the investigation of
      morphometric, immunohistological and three-dimensional changes of the endometrial
      mucosa in order to evaluate quantitatively the effects of three doses of a new
      slow-release vaginal progesterone on the endometrium in post-menopausal women. A
      total of 20 menopausal women, deprived of ovarian function, were given oestrogen
      for 12 days and a combined therapy of oestrogen (administered orally) and
      progesterone for another 12 day period. Progesterone was administered vaginally
      through a new gel (Crinone) utilizing a bioadhesive, biocompatible polymer as a
      base to achieve a sustained release effect. An endometrial biopsy was taken
      before treatment, after oestrogen-only treatment and after the oestro-progestogen
      therapy. Before treatment, all the patients exhibited an atrophic endometrium.
      After oestrogen-only treatment, typical proliferative changes occurred: an
      increase in the endometrium thickness, an increase in the mitotic index, numerous
      cylinder-like glands and no coiled glands, and high concentrations of oestrogen
      receptors (ER) and progesterone receptors (PR). After the oestro-progestogen
      therapy, whatever the dose of progesterone given, a secretory transformation of
      the endometrial mucosa occurred, mitotic activity decreased significantly, more
      ramified and coiled glands were observed, and a decrease in PR content was noted
      in epithelial and stromal nuclei, and a decrease in PR content was also observed
      in epithelial nuclei but not in stromal nuclei. Accurate new techniques of image
      analysis have shown that crinone therapy could eliminate the proliferative
      effects of oestrogen treatment in post-menopausal women, despite doses as low as
      45 mg of progesterone administered vaginally every other day. The results suggest
      that the sustained release effects of Crinone are clinically relevant.

PMID- 8671226
TI  - Ultrasound studies of vascular and morphological changes in the human uterus
      after a positive self-test for the urinary luteinizing hormone surge.
AB  - The aim of the study reported here was to establish complementary data for
      changes in uterine size, echogenicity and vascularity during the menstrual cycle
      relative to a positive self-test for urinary luteinizing hormone (LH) and day 1
      of next menses. Thirteen volunteers (aged 23-32 years) with apparently regular
      menstrual cycles were recruited from the nursing staff. The plan was to examine
      all women by transvaginal ultrasonography with colour Doppler imaging on day 11
      of the menstrual cycle. A urinary LH self-test was to be used daily until a
      positive result was obtained and the women were to be re-scanned daily until the
      dominant follicle had ruptured. All women were then to be scanned at least every
      48 h (within +/- 2 h of the same time of day) until day 6 of the next menstrual
      cycle. Matched samples of peripheral blood were taken at the time of each scan
      for hormone analysis. The main outcome measures were the times of follicular
      rupture, a positive test result for urinary LH and the start of menses, uterine
      volume, cavity length, endometrial thickness and grade, pulsatility index (PI),
      and time-averaged and peak systolic maximum velocities in uterine and radial
      arteries and in subendometrial vessels. Nine women fulfilled the criteria for an
      ovulatory cycle, and seven provided data over the complete study. The principal
      changes relative to a positive urinary LH test were (i) a continued rise in
      endometrial thickness to days 3 and 4 (this index then remained relatively
      constant, but the layered appearance was lost) and (ii) a gradual decrease in the
      uterine arterial PI. There was a significant rise in uterine volume, cavity
      length and uterine arterial PI around the time of the next menses, and a fall in
      endometrial thickness and blood velocity in the uterine and radial arteries and
      subendometrial vessels. The data may have implications for the assessment of
      reproductive status and the design of future studies on disorders of implantation
      or menstruation.

PMID- 8671227
TI  - Uterine glandular area during the menstrual cycle and the effects of different in
      vitro fertilization related hormonal treatments.
AB  - The human uterine glandular epithelium undergoes a sequence of well characterized
      changes during the menstrual cycle that presumably play an important role in
      preparation for blastocyst implantation. The aim of this study was to measure
      objectively glandular volume over the entire menstrual cycle and compare the
      results with eight different clinical superovulation or hormone replacement
      therapy (HRT) subject groups. Endometrial biopsies were taken from control normal
      menstrual cycle subjects (n = 96), and eight other smaller groups of women who
      had received different in-vitro fertilization (IVF) related treatments. The total
      area of glandular epithelium was objectively measured from routine histological
      slides using computerized image analysis. Control menstrual cycle results showed
      a significantly greater gland area in the early secretory stage of the cycle than
      at any time between the early proliferative through to the mid-late proliferative
      stages (P < 0.05). IVF patients receiving clomiphene citrate and human menopausal
      gonadotrophin had a significantly smaller glandular area than those in the
      control groups at equivalent stages of the menstrual cycle. The use of
      progesterone supplementation removed this significant difference. Patients on the
      ?Flare' regime had the highest gland area, although this was not significantly
      different from controls. Buserelin down-regulation gave a gland area that was
      closest to the normal cycle controls. The three HRT groups showed high
      variability in gland volume between patients. The results from this study
      demonstrate that superovulation can cause significant alterations in endometrial
      gland volume, but that these do not necessarily preclude implantation.

PMID- 8671228
TI  - Peritoneal fluid cytokines and the relationship with endometriosis and pain.
AB  - It is generally accepted that the current scoring system for endometriosis has
      little correlation with clinical symptoms such as pain, and therefore we may
      deduce that either endometriosis does not cause pain, or that the current scoring
      system does not indicate the biological activity of the disease. Pain may occur
      because the presence of endometriosis produces an intraperitoneal inflammatory
      response, and several studies have shown that the cytokine content of peritoneal
      fluid differs between women with and without endometriosis. We studied the
      relationship between tumour necrosis factor alpha (TNF alpha), platelet-derived
      growth factor (PDGF), interleukin (IL)-6, IL-4 and TNF (alpha and beta) activity
      in peritoneal fluid and the clinical history of pain and infertility. TNF alpha
      concentrations were increased in peritoneal fluid of women with endometriosis and
      of infertile women; PDGF concentrations were increased in peritoneal fluid of
      parous women; IL-6 was increased in peritoneal fluid of women with adhesions; IL
      4 was absent from peritoneal fluid. PDGF and IL-6 concentrations were cycle
      related, with the highest amounts in the menstrual and proliferative phases
      respectively. We failed to demonstrate any association between concentrations of
      cytokines in vitro and pain symptoms or severity of endometriosis.

PMID- 8671229
TI  - Visible and non-visible endometriosis at laparoscopy in fertile and infertile
      women and in patients with chronic pelvic pain: a prospective study.
AB  - In 100 consecutive patients who were undergoing laparoscopy for infertility
      (group 1, n = 52), chronic pelvic pain (group 2, n = 18) or tubal sterilization
      (group 3, n = 30, asymptomatic fertile women), peritoneal biopsies were taken
      from areas of visually normal peritoneum of uterosacral ligaments. Twenty-six
      patients in group 1 (50%), eight patients in group 2 (44.4%) and 13 patients in
      group 3 (43.3%), were found to have laparoscopic evidence of endometriosis
      elsewhere in the pelvis. The majority of women (80.7% in group 1, 87.5% in group
      2, and 100% in group 3) had stage I disease. The incidence of the distinctive
      appearances of the lesions was similar in the three groups of patients and 7% of
      all women or 15% (7/47) of those patients having endometriosis at laparoscopy had
      only subtle (non-?typical') endometriotic peritoneal lesions. Uterosacral
      biopsies showed the presence of endometriotic tissue in three cases (5.7%), two
      cases (11%) and three cases (10%) in groups 1, 2, and 3 respectively. One of the
      two patients in group 2 and two of the three patients in group 3 had no evidence
      of endometriosis at laparoscopy; thus histological study revealed the presence of
      endometriosis in normal peritoneum in 11% (5/47) of patients having macroscopic
      endometriosis and in 6% (3/53) of patients without endometriosis at laparoscopy.
      Previous oral contraceptive users were significantly higher among women having
      macroscopic and/or microscopic endometriosis than among women without the
      condition. In conclusion, our prospective study shows a high prevalence (45-50%)
      of endometriosis (including microscopic forms) in both patients with chronic
      pelvic pain and asymptomatic women (fertile and infertile), thus supporting the
      modern concept that in many women endometriosis may be a paraphysiological
      condition while probably only in some patients small amounts of endometriosis are
      an ?annoyance' with implications to their reproductive health and may produce
      symptoms (e.g. pelvic pain) and therefore should be defined as a ?dis-ease'.
      Previous use of oral contraceptives may increase the risk of developing
      endometriosis.

PMID- 8671230
TI  - Endometrial cathepsin D immunostaining throughout ovulatory and anovulatory
      menstrual cycles.
AB  - The results of histological examination of the endometrium are normal in most
      patients with unexplained sterility. Cathepsin D is a ubiquitous lysosomal
      protease regulated by progesterone in the endometrium. Assays of concentrations
      of cathepsin D might be useful in determining the functional responses of the
      endometrium to progesterone. To examine this possibility, we quantified
      immunostaining of endometrial cathepsin D using an image analysis system in women
      with regular menstrual cycles. An endometrial sample was obtained during the
      proliferative and luteal phases from 17 women with ovulatory menstrual cycles and
      at the beginning and during the last 14 days of a cycle from 15 women having
      anovulatory menstrual cycles. In endometrial glands of ovulatory women, cathepsin
      D protein immunostaining increased during the cycle and was significantly higher
      during the luteal than during the proliferative phase [51 +/- 38.1 arbitrary
      units (AU) versus 118.2 +/- 58.9 AU; P < 0.01]. This increase was also observed
      in stromal cells, although to a lesser extent (28.6 +/- 26.9 versus 41.5 +/- 43.1
      AU; P = NS). In the endometrium of women with anovulatory menstrual cycles,
      cathepsin D staining was high both for the proliferative and the luteal biopsies
      in glands (respectively 95 +/- 43 and 104 +/- 51.3 AU) and stromal cells
      (respectively 61.8 +/- 33.8 and 75 +/- 32.6 AU). In women with ovulatory cycles,
      cathepsin D staining was localized in the apical part of glandular cells during
      the proliferative phase and diffused throughout the cytoplasm during the luteal
      phase. In contrast, in women with anovulatory cycles, cellular localization of
      cathepsin D remained apical in glands, regardless of the day of biopsy. In
      conclusion, this study shows that the cytoplasmic localization of cathepsin D
      might be a qualitative biological indicator of endometrial gland responses to
      progesterone. This could be a useful tool for evaluating cell function, which is
      poorly tested by histology alone.

PMID- 8671231
TI  - Simplified ultralong protocol of gonadotrophin-releasing hormone agonist for
      ovulation induction with intrauterine insemination in patients with
      endometriosis.
AB  - The present study was designed to assess the usefulness of the simplified
      ultralong protocol of gonadotrophin-releasing hormone agonist (GnRHa) for
      ovulation induction with intrauterine insemination (IUI) in patients with various
      stages of endometriosis. A prospective randomized trial was set up to compare the
      simplified ultralong protocol (ULP) and the long protocol (LP) of GnRHa for
      ovulation induction with IUI in patients with endometriosis. There was no
      evidence of other factors in infertility in any patient. In the ULP group (39
      patients), 4 weeks after a single injection of 3.75 mg Decapeptyl had been given,
      daily s.c. administration of 0.1 mg Decapeptyl was initiated and continued for at
      least 2 weeks prior to ovarian stimulation. In the LP group (41 patients), daily
      s.c. administration of 0.1 mg Decapeptyl was initiated from the mid-luteal phase
      of the cycle preceding the stimulation cycle. After 14 days of administration,
      ovarian stimulation was started if pituitary desensitization had been achieved.
      The amount of gonadotrophins required, number of days of gonadotrophin
      administration, serum oestradiol response, and the number of mature follicles
      were comparable in both groups. The clinical pregnancy rate per cycle was
      significantly higher in the ULP group at 48.7% (19/39) compared with 26.8%
      (11/41) in the LP group. The miscarriage rates were 21.1% (4/19) in the ULP group
      and 18.2% (2/11) in the LP group. In patients with stage I or II endometriosis,
      there was no significant difference between the two groups with respect to
      clinical pregnancy rate per cycle (47.4 versus 35.0%). In patients with stage III
      or IV endometriosis, the clinical pregnancy rate per cycle was significantly
      higher in the ULP group at 50.0% (10/20) compared with 19.0% (4/21) in the LP
      group. This study suggests that a simplified ULP of GnRHa could give better
      chances of achieving pregnancy in endometriosis patients undergoing assisted
      reproductive technologies and that this protocol may be more useful in patients
      with an advanced stage of endometriosis.

PMID- 8671232
TI  - Age of onset of pain symptoms in non-twin sisters concordant for endometriosis.

PMID- 8671233
TI  - A prospective study of early pregnancy loss.
AB  - The New York State Early Pregnancy Detection Study was a prospective study of
      early pregnancy loss, between implantation and menses, in 217 women attempting to
      become pregnant during 1989-1992. Women collected urine samples on three
      consecutive mornings during the late luteal phase of their menstrual cycle, for
      up to 12 cycles, contributing samples for 1253 menstrual cycles. Urinary human
      chorionic gonadotrophin (HCG), measured using an immunoradiometric assay, was the
      biomarker for pregnancy. We observed a range of early pregnancy loss (EPL) rates,
      from a low estimate of 11.0% to a high estimate of 26.9%, depending on the
      definition used and the subgroup analysed. Based on a definition of 3 days of HCG
      concentration > or = 4.00 pmol/l, 2 days > or = 5.33 pmol/l or the last day of
      HCG > or = 6.67 pmol/l, we identified 115 positive cycles; 95 cycles were
      clinically confirmed pregnancies and 20 cycles were EPL, giving an EPL rate of
      17.4% [95% confidence interval (CI) 11.0-25.6]. In addition, we observed an EPL
      rate of 19.5% (95% CI 11.3-30.1) for samples collected within a 15 day window
      around menses, and a rate of 20.3% (95% CI 11.3-32.2) for samples limited to the
      first three menstrual cycles. Because studies use urine collection schemes other
      than daily sampling, the definition of pregnancy will be crucial in defining EPL.

PMID- 8671234
TI  - Progesterone receptor immunoreactivity at the maternofetal interface of first
      trimester pregnancy: a study of the trophoblast population.
AB  - The aim of our study was to localize oestrogen receptor (ER) and progesterone
      receptor (PR) in the trophoblast population at the maternofetal interface in
      early pregnancy. Rat monoclonal antibodies to human ER and PR were used to study
      44 cases of chorionic villi and 82 cases of decidua using an immunocytochemical
      method. The PR-immunoreactive products were localized in the nuclei of
      syncytiotrophoblast and cytotrophoblast cells of the villi. Specific staining was
      also present in the cytoplasm. Villous stroma and vessels were stained
      occasionally. Using cytokeratin staining in an adjacent section or double
      staining with PR and cytokeratin, the distribution of invading trophoblast cells
      and their PR expression were examined. In decidual stroma, a type of interstitial
      cell was identified which simultaneously expressed cytokeratin and PR in the
      cytoplasm, indicating that the invading trophoblast cells may express PR. All
      extravillous populations at the interface were positive for PR, including the
      syncytial lining of the decidual surface, the cytotrophoblast column, the
      cytotrophoblast shell and the interstitial trophoblast. The immunoreactivity of
      PR was also localized in the nuclei of vascular endothelial cells, whereas Factor
      VIII was localized in the cytoplasm of the same cells, thus confirming their
      endothelial nature. In contrast to PR, little ER could be detected in the
      trophoblast cell population using anti-ER antibody D75 in our study.

PMID- 8671235
TI  - Transvaginal intratubal methotrexate treatment of ectopic pregnancy. Report of
      100 cases.
AB  - Between November 1988 and December 1993, 100 patients with a common, unruptured
      ectopic pregnancy were treated with 1 mg/kg injection of intratubal methotrexate
      under transvaginal sonographic control. Patients were not excluded from this
      series on the basis of the size of the adnexal mass, the term of ectopic
      pregnancy or initial beta-human chorionic gonadotrophin (HCG) concentrations.
      Patients were excluded following uncertain diagnosis, signs of a ruptured ectopic
      pregnancy, or a significant haemoperitoneum on ultrasound scans. The mean age of
      the patients was 29.5 years (range 20-41). The mean gestational age and initial
      HCG concentration were 7.5 weeks (5-11) and 11,614 mIU/ml (192-105,000
      respectively). Of the 100 patients, 22 (22%) had an ectopic pregnancy with active
      cardiac activity. Complete resolution was obtained in 78 out of these 100 ectopic
      pregnancies. Of these, 66 patients (85%) needed only one intratubal methotrexate
      injection, and 12 patients (15%) required a second i.m. methotrexate injection of
      1 mg/kg. In this study, local treatment with one single intratubal methotrexate
      injection was successful in only 66% of patients. The mean resolution time for
      reduction of beta-HCG concentrations was 23.5 days (range 7-40). There was no
      statistically significant correlation between initial beta-HCG concentrations and
      outcomes after methotrexate treatment of ectopic pregnancy in our study. Where
      embryonal heart beats were observed, the success rate of the procedure was 40.9%
      (nine out of 22 cases). In the absence of cardiac activity, or when ultrasound
      examination showed no embryo, the success rate achieved was 84.6% (66 out of 78
      cases) (P < 0.01). In all, 34 patients were considered to be incompletely cured
      after only one intratubal methotrexate injection: 12 patients required a second
      i.m. injection, a stagnation of beta-HCG concentrations was observed in 15
      patients, abdominal pain occurred in six patients, and one patient suffered tubal
      rupture with haemoperitoneum. A total of 22 patients required secondary surgical
      management (salpingectomy). No biochemical or clinical side-effects of
      methotrexate treatment occurred. Tubal alteration ascribable to methotrexate
      injection occurred in one patient in our study. Out of 75 patients in this series
      who wished to conceive, 21 (28%) became pregnant within 1 year with the following
      outcomes: 11 pregnancies at term, three miscarriages, one induced abortion and
      six recurrent ectopic pregnancies (four occurred on the same side). Our findings
      suggest that treatment of common unruptured ectopic pregnancy without prior
      selection of patients, by a single intratubal methotrexate administration was
      associated with a 66% success rate. This was dependent only on the presence of
      embryonal heart beats and there was no correlation between the success rate and
      initial beta-HCG concentrations. Successful outcome after methotrexate
      administration for ectopic pregnancy could be perfected by way of an improved
      selection of patients based on inactive embryonal hearts and absence of a
      visualized embryo.

PMID- 8671236
TI  - Cumulative pregnancy rate following in-vitro fertilization: the significance of
      age and infertility aetiology.
AB  - During the years 1984-1992, 951 couples completed 2252 in-vitro fertilization
      (IVF) treatment cycles at the In-Vitro Fertilization Unit of The Chaim Sheba
      Medical Centre. This study was conducted to evaluate the success of IVF using the
      cumulative pregnancy rate (CPR), with special emphasis on the optimal number of
      treatment cycles, the age of the patients and female infertility factors. It was
      found that the CPR showed a constant rise during the six initial IVF treatments
      (56% CPR), and plateaued in the subsequent three cycles (63% CPR). Various female
      infertility factors did not influence this rate. Women > or = 40 years of age
      have a significantly lower CPR. Thus, it was concluded that the CPR in IVF
      declined after the sixth initial treatment cycle, and in women > or = 40 years of
      age. The infertility factor did not significantly influence CPR.

PMID- 8671237
TI  - Treatment of anovulatory infertility: the problem of multiple pregnancy.
AB  - The aim of the study was to assess patient, treatment and cycle characteristics
      in relation to the risk of multiple conception following ovulation induction in
      order to reduce the prevalence of this complication of treatment. We performed a
      retrospective analysis of 208 pregnancy cycles achieved in the Middlesex Hospital
      outpatient fertility unit. These pregnancies were achieved in 175 anovulatory
      women who conceived after gonadotrophin or pulsatile GnRH therapy. The multiple
      conception rate was 13.4%. After spontaneous reductions and abortions the
      multiple delivery rate was 9.6%. Clinical features associated with an increased
      risk of multiple pregnancies were the presence of polycystic ovary syndrome and
      secondary infertility. Comparison between different protocols of ovulation
      induction revealed no relationship with the risk of multiple conceptions.
      Although total number of follicles was increased in the multiple conception
      cycles, the distribution of follicles according to their diameter on the day of
      human chorionic gonadotrophin (HCG) administration was similar in multiple and
      singleton conception cycles. Thus, the risk of multiple conception could not be
      attributed to an increased number of follicles of any particular size but
      directly related to the total number of the cohort follicles ( > or = 14 mm) and
      leading follicles > or = 17 mm), rising from 7% with one follicle to 33% with six
      or more follicles. As we could not find a specific pattern of follicular
      development that could be associated with multiple conception, we conclude that
      the difference in the ovarian response leading to multiple conception is
      quantitative rather than qualitative. The data presented enable the assessment of
      the risk of multiple conception in any given cycle.

PMID- 8671238
TI  - Fetal heart rate and umbilico-placental Doppler flow velocity waveforms in early
      pregnancies with a chromosomal abnormality and/or an increased nuchal
      translucency thickness.
AB  - Fetal heart rate, umbilical artery pulsatility index, end-diastolic flow, nuchal
      translucency thickness and placental thickness were recorded in 250 women with a
      viable singleton pregnancy undergoing chorionic villous sampling for fetal
      karyotyping at 11-14 weeks of gestation. The fetal karyotype was normal in 210
      cases and abnormal in 40, including 21 with trisomy 21, 13 with trisomy 18, three
      with triploidy, two with monosomy X and one with trisomy 13. A total of 52
      fetuses with a normal karyotype had a nuchal translucency > or = 3 mm and were
      considered separately. There was a stable and significant increase in the mean
      fetal heart rate in trisomy 21 pregnancies compared to controls. No significant
      difference was found for the other variables between the groups. In chromosomally
      normal fetuses with an increased nuchal thickness, the development of fetal heart
      rate and compliance of the umbilico-placental circulation were within the normal
      ranges. Some fetuses with trisomy 18 or triploidy had an increased resistance to
      blood flow in the umbilical artery, which was probably due to abnormal placental
      development.

PMID- 8671239
TI  - Is intracytoplasmic sperm injection (ICSI) a safe procedure? What do we learn
      from early pregnancy data about ICSI?
AB  - The aim of this study was to evaluate the safety of the intracytoplasmic sperm
      injection (ICSI) procedure by analysing early pregnancy data from ICSI and in
      vitro fertilization (IVF) patients. In all, 50 ICSI pregnancies were compared
      with 226 IVF pregnancies. Comparisons were made during the first 9 weeks after
      the theoretical last menstrual period (7 weeks after oocyte retrieval) with
      regard to epidemiological data, plasma hormonal concentrations and transvaginal
      ultrasonographical findings. Although patients were significantly (P < 0.001)
      younger in ICSI (31 years) than in IVF pregnancies (33 years), their duration of
      infertility was similar. Miscarriage and multiple gestation rates were not
      significantly different in ICSI pregnancies (respectively 24 and 24%) from those
      found after IVF (32 and 29%). The probability of developmental arrest of the
      intrauterine sac (miscarriages and vanishing twins) was similar in both ICSI
      (16%) and IVF (25%) cases. The mean plasma hormonal concentrations starting from
      day 11 after oocyte retrieval were similar in both groups. Every ICSI and IVF
      pregnancy showed an embryo with cardiac activity at 7 weeks. Early pregnancy data
      did not show any abnormal findings for pregnancies achieved using ICSI compared
      to those achieved by IVF.

PMID- 8671240
TI  - Morphological interactions of human first trimester placental villi co-cultured
      with decidual explants.
AB  - Abnormalities of pregnancy such as pre-eclampsia and intrauterine growth
      retardation are characterized by shallow trophoblastic invasion of the placental
      bed, the precise molecular pathophysiology of which remains to be fully
      elucidated. An in-vitro model involving a co-culture of first trimester placental
      villi and decidua parietalis explants (of 8-12 weeks gestation) was developed and
      used to characterize the migration and local invasion of trophoblast cells.
      Trophoblast proliferation (confirmed by Ki-67 immunostaining), differentiation
      and loose attachment of placental villi to the underlying decidual epithelium or
      stroma occurred within the first 24 h of co-culture. This was followed by erosion
      of the syncytial layer of the placental villi and commencement of a progressive
      cytotrophoblast invasion after 48 h of co-culture, which continued until 120 h,
      when the experiments were terminated. E-cadherin was expressed at the interfaces
      between trophoblast cells within the villi, but expression of this adhesion
      molecule seemed to be down-regulated in the invasive trophoblast cells. Our
      results suggest that the model could be useful in investigating the factors that
      control early human placentation and the feto-maternal interface.

PMID- 8671241
TI  - Preparation of a population of macrophages from human third trimester decidua.
AB  - Human decidua in the third trimester of pregnancy contains at least four
      different cell types (stromal cells, macrophages, T-lymphocytes and
      granulocytes). The contributions of these cells to the overall function of the
      tissue are not known, although it is anticipated that both stromal cells and
      macrophages will produce the prostaglandins involved in labour. In addition, the
      decidua produces cytokines, but the cellular source has not been identified. As a
      first stage to addressing these questions, we have developed magnetic separation
      methods to obtain enriched populations of decidual macrophages which contain at
      least 5 x 10(6) cells. We found that a preparation of up to 10(7) cells which are
      up to 80% pure (as assessed by a fluorescence-activated cell sorting procedure)
      and approximately 90% pure (as assessed by immunocytochemistry) can be obtained
      reliably with this method. These cells are viable for at least 48 h in culture
      after the enrichment procedure, and produce prostaglandins after stimulation with
      interleukin-1 beta.

PMID- 8671242
TI  - Addition of kallikrein and/or human serum to a discontinuous Percoll gradient.

PMID- 8671243
TI  - Techniques of embryo transfer.

PMID- 8671244
TI  - Empty follicle syndrome.

PMID- 8671245
TI  - Laparoscopic unwinding of hyperstimulated ovaries during the second trimester of
      pregnancy.

PMID- 8671246
TI  - Prophylactic intravenous albumin for the prevention of severe ovarian
      hyperstimulation syndrome.

PMID- 8671248
TI  - Opinion. Polycystic ovary syndrome

PMID- 8671247
TI  - Preimplantation diagnosis in disease control, not eugenics.

PMID- 8671249
TI  - A role for glycoconjugates in human development: the human feto-embryonic defence
      system hypothesis.
AB  - The mechanisms underlying the protection of the human embryo/fetus from the
      maternal immune response are poorly understood. Substantial evidence indicates
      that carbohydrate recognition plays a primary role in the sequestration of
      leukocytes during inflammatory processes, lymphocyte homing, and initial gamete
      binding. Our previous studies suggest a possible convergence in the types of
      carbohydrate sequences recognized during initial human gamete binding and
      immune/inflammatory cell interactions. Our more recent findings indicate that
      oligosaccharides participating in such processes are also associated with soluble
      glycoconjugates found in the human placenta, amniotic fluid, and decidua. We
      theorize that such glycoconjugates may abrogate the maternal immune/inflammatory
      response by blocking the primary adhesive interactions required for the
      expression of such activities. Foreign embryonic cells may also be protected by
      surface expression of oligosaccharide sequences that suppress immune effector
      cell action in a manner not dependent upon classical major histocompatibility
      (MHC) recognition. Glycoconjugates expressing selectin ligands may also manifest
      a potent contraceptive effect that may also be beneficial for both the mother and
      the developing embryo/fetus. This hypothesis provides a preliminary framework for
      understanding how temporally and spatially restricted immunosuppressive effects
      could be expressed in utero that protect the human embryo/fetus during this
      period of human development.

PMID- 8671251
TI  - Evaluating ovarian reserve: follicle stimulating hormone and oestradiol
      variability during cycle days 2-5.
AB  - A prospective measurement of follicle stimulating hormone (FSH) and oestradiol
      between cycle days 2 and 5 was conducted to investigate the intra- and inter
      cycle variability in a healthy population of women with regular menstrual
      intervals. Daily serum samples were obtained from 44 women for a total of 66
      cycles on cycle days 2, 3, 4 and 5. FSH concentrations were consistent on all
      cycle days measured. Oestradiol concentrations on cycle day 2 were not different
      from cycle day 3, but concentrations on cycle day 4 and cycle day 5 were
      statistically different from both cycle day 2 and cycle day 3 by analysis of
      variance (P < or = 0.05). Evaluation of functional ovarian reserved by cycle day
      3 FSH measurement has become the standard in most assisted reproductive
      technology programmes. The recent change in FSH standardization coupled with the
      inflexibility of cycle day 3 testing has led to a re-evaluation of testing
      protocols. Cycle day 3 appears to have emerged as a dictum because most ovulation
      induction protocols are initiated on cycle day 3, 4 or 5. Flexibility of sampling
      day can be introduced as suggested by these results. The additional information
      ascertained from oestradiol testing as applied to evaluation of ovarian reserve
      warrants further investigation.

PMID- 8671250
TI  - Circulating immunoreactive and bioactive follicle stimulating hormone
      concentrations in anovulatory infertile women and during gonadotrophin induction
      of ovulation using a decremental dose regimen.
AB  - Our purpose was to determine whether decreased follicle stimulating hormone (FSH)
      activity, either systemic or at the follicular level, is involved in impaired
      follicle growth associated with normogonadotrophic anovulation. To differentiate
      between the possible levels of disturbance, bioactive (BIO-FSH; using the in
      vitro rat granulosa cell aromatase bioassay) and immunoreactive (IRMA-FSH) FSH
      serum concentrations of three groups of subjects were compared: (i) 172
      normogonadotrophic anovulatory infertile women during baseline conditions, (ii)
      22 clomiphene-resistant polycystic ovary syndrome patients undergoing ovulation
      induction by exogenous gonadotrophins using a decremental dose regimen, and (iii)
      nine regularly cycling controls. BIO-FSH [13.2 (range 0.8-29.5) IU/l] and IRMA
      FSH [4.4 (range 1.2-9.3) IU/l] concentrations in anovulatory women during
      baseline conditions were significantly lower than maximum concentrations reached
      during the follicular phase in controls [18.7 (13.2-23.4) and 6.4 (5.7-10.0) IU/l
      respectively], but were not significantly different from initial concentrations
      in controls [10.4 (7.2-19.6) and 4.8 (2.8-8.2) IU/l respectively]. Moreover,
      concentrations of IRMA-FSH and BIO-FSH were negatively correlated (r = -0.25, P =
      0.01, and r = -0.24, P = 0.02 respectively) with the interval between last
      vaginal bleeding and blood sampling. Maximum concentrations of IRMA-FSH [7.6 (3.9
      10.9) IU/l] during ovulation induction by gonadotrophins were not significantly
      different from maximum [6.4 (5.7-10.0) IU/l] concentrations in controls, whereas
      maximum BIO-FSH concentrations [13.5 (8.7-17.4) versus 18.7 (13.2-23.4) IU/l]
      were significantly lower. Our findings suggest that (i) circulating FSH does not
      reach concentrations that are sufficient to induce normal follicle development in
      anovulatory women during baseline conditions, and (ii) the FSH threshold for
      ovarian stimulation of this patient group is not different from normal.

PMID- 8671252
TI  - Identification of gonadotrophin surge-inhibiting factor (GnSIF)/attenuin in human
      follicular fluid.
AB  - Evidence from several laboratories suggests that the ovaries of many species
      produce a non-steroidal factor called gonadotrophin surge-inhibiting or
      attenuating factor (GnSIF) which may regulate the response of the pituitary to
      gonadotrophin-releasing hormone (GnRH) and as such, may modulate the timing
      and/or amplitude of the luteinizing hormone (LH) surge. We have recently isolated
      a candidate GnSIF from porcine follicular fluid (PFF). Porcine GnSiF is a 69 kDa
      protein which has undetectable inhibin and follistatin immunological and
      biological activity. The present study was designed to purify and identify GnSIF
      from human follicular fluid. GnSIF activity was measured as suppression of GnRH
      stimulated LH secretion from rat pituitary cells in primary culture. Human
      follicular fluid (approximately 500 ml) was recovered from patients undergoing in
      vitro fertilization (IVF). GnSIF was purified by heparin-sepharose, Q-sepharose,
      S-sepharose, and hydrophobic interaction chromatography followed by isoelectric
      focusing. Gel electrophoresis and Western blot were used to identify human GnSIF
      and compare it with porcine GnSIF. Using these steps, we obtained a highly
      purified preparation of GnSIF that manifests in-vitro bioactivity and
      chromatography characteristics similar to those observed for porcine GnSIF and
      that hybridizes with a porcine GnSIF antibody. Following treatment with human
      chorionic gonadotrophin/human menopausal gonadotrophin (HMG/HCG), human
      follicular fluid contained roughly 25% of the GnSIF (per mg protein) present in
      porcine follicular fluid. We conclude that GnSIF is present in human follicular
      fluid and may participate in the regulation of gonadotrophin secretion in this
      species.

PMID- 8671253
TI  - An aminopeptidase inhibitor, bestatin, enhances progesterone and oestradiol
      secretion by porcine granulosa cells stimulated with follicle stimulating hormone
      in vitro.
AB  - We examined the presence of cell surface aminopeptidase on cultured porcine
      granulosa cells by employing the aminopeptidase assay using alanine-p
      nitroanilide and histochemical staining using L-leucyl-beta-naphthylamide.
      Porcine granulosa cells obtained from follicles 4-5 mm in diameter were cultured
      for 7 days. The aminopeptidase assay showed that the porcine granulosa cell
      culture had aminopeptidase activity and that this activity was inhibited in a
      dose-dependent manner by bestatin which binds to cell surfaces and inhibits cell
      surface aminopeptidases. Histochemical staining also indicated that cultured
      granulosa cells had aminopeptidase activity. Porcine granulosa cells were
      cultured in the presence or absence of porcine follicle stimulating hormone (FSH,
      3.125 nmol/l) and/or bestatin (0.4, 4.0 and 40.0 micrograms/ml) for 7 days, and
      the production of progesterone and oestradiol was measured. In the presence of
      porcine FSH, the production of progesterone and oestradiol by granulosa cells was
      increased significantly by approximately 5- and 2-fold respectively. These
      increases were enhanced further by bestatin (40.0 micrograms/ml). In the absence
      of porcine FSH, progesterone production was enhanced by bestatin (40.0
      micrograms/ml), whereas no significant effect of bestatin on oestradiol secretion
      was observed. These findings indicate that the inhibition of membrane-bound
      aminopeptidase(s) on the cell surfaces affects the steroidogenesis of granulosa
      cells, and that these aminopeptidase(s) are important regulators of granulosa
      cell differentiation.

PMID- 8671254
TI  - Endometrial responses to hormone replacement therapy: the bleeding pattern.
AB  - Little information is available concerning the response of the endometrium to
      exogenous sex steroid therapy, particularly in the post-menopausal state. In this
      study we examined the variability of the bleeding pattern in 103 post-menopausal
      women receiving cyclical sequential combined hormone replacement therapy (HRT)
      over 6 months. All patients kept menstrual diary cards to record the onset,
      duration and subjective assessment of the severity of bleeding. We defined a
      cycle as starting from the commencement of treatment till the day of onset of
      bleeding. Two groups were identified amongst 99 women who experienced bleeding:
      those with a mean cycle length of 29 or more days (late bleeders, n = 50) and
      those with shorter mean cycle length (early bleeders, n = 49). The former were
      characterized by less variability in cycle length and bleeding that was of
      shorter duration. Four women experienced no bleeding. There were no significant
      differences between the two groups in age, year since the menopause, weight,
      height, body mass index (BMI), parity, or in the previous use of HRT. The only
      significant difference was in their smoking habits. This suggests a possible link
      of a hypo-oestrogenic state to poor cycle control.

PMID- 8671256
TI  - Cystic fibrosis mutation screening in healthy men with reduced sperm quality.
AB  - The majority of men with cystic fibrosis (CF) are infertile due to a bilateral
      congenital absence of the vas deferens (CBAVD). However, clinically affected CF
      patients present a spectrum of genital phenotypes ranging from normal fertility
      to severely impaired spermatogenesis and CBAVD. Recently, it has become apparent
      that CF can manifest itself as isolated CBAVD in the absence of other clinical
      symptoms. The present study was undertaken to test the possible involvement of
      the CF gene in the aetiology of male infertility other than CBAVD. Semen
      specimens from 127 unrelated healthy males with various diagnoses of reduced
      sperm quality were screened for a panel of 13 mutations in the cystic fibrosis
      transmembrane conductance regulator (CFTR) gene. Fourteen of 80 (17.5%) healthy
      men with infertility due to reduced sperm quality and 3 of 21 (14.3%) men with
      azoospermia had at least one CF mutation (one azoospermic male was a compound
      heterozygote). The frequency of mutations in our sample of infertile males was
      significantly higher than the expected CF carrier frequency in the local
      population (P = 0.00139). No mutations were found in a control group of 26
      individuals with normal semen parameters. This increased frequency of CF
      mutations in healthy men with reduced sperm quality and in men with azoospermia
      without CBAVD suggests that the CFTR protein may be involved in the process of
      spermatogenesis or sperm maturation apart from playing a critical role in the
      development of the epididymal glands and the vas deferens.

PMID- 8671255
TI  - beta 2-Glycoprotein I-dependent anticardiolipin antibodies as a predictor of
      adverse pregnancy outcomes in healthy pregnant women.
AB  - Our aim was to elucidate prospectively whether beta 2-glycoprotein I-dependent
      anticardiolipin antibodies (beta 2GPI-dependent aCL; autoimmune type) can predict
      an adverse pregnancy outcome in healthy pregnant women and whether beta 2GPI
      dependent aCL should be applied for routine screening of the pregnant population.
      A prospective cohort study was performed on 1600 healthy pregnant women from whom
      blood samples were obtained at about week 10 of gestation. We used a modified
      enzyme-linked immunosorbent assay with which to divide the subjects into three
      study groups: beta 2GPI-independent aCL positive, beta 2GPI-dependent aCL
      positive and aCL negative. Their subsequent pregnancy outcomes were ascertained
      and the three study groups were compared statistically for the following poor
      pregnancy outcomes: intrauterine fetal death (IUFD) after 12 gestational weeks,
      intrauterine growth retardation (IUGR) and pre-eclampsia. The total number of
      patients eligible for this study was 1125. The prevalence of beta 2GPI-dependent
      aCL positive was eight (0.7%), beta 2GPI-independent aCL positive was 17 (1.5%)
      and aCL negative was 1100 (97.8%). Beta 2-GPI-dependent aCL positivity was
      significantly associated with poor pregnancy outcome: 25.0% of beta 2GPI
      dependent aCL-positive and 0.5% of aCL-negative patients experienced IUFD
      [relative risk 52.4; 95% confidence interval (CI), 12.7-216.3; P = 0.0009]; 37.5%
      of beta 2GPI-dependent aCL-positive and 2.9% of aCL-negative patients experienced
      IUGR (relative risk 18.4; 95% CI, 4.6-74.0; P = 0.001); and 50.0% of beta 2GPI
      dependent aCL-positive and 4.0% aCL-negative patients experienced pre-eclampsia
      (relative risk 22.1; 95% CI, 5.7-85.7; P = 0.0002). In contrast, beta 2GPI
      independent aCL did not show any significant association with such adverse
      pregnancy outcomes. beta 2GPI-dependent aCL are significantly highly associated
      with adverse pregnancy outcomes in healthy pregnant women and can be used for
      prediction purposes, whereas beta 2GPI-independent aCL cannot. Our results
      suggest that routine screening for beta 2GPI-dependent aCL should be introduced
      for the general pregnant population.

PMID- 8671257
TI  - Fertility after laparoscopic myomectomy of large intramural myomas: preliminary
      results.
AB  - Fertility outcome following laparoscopic myomectomy was evaluated. A prospective
      clinical study was carried out between October 1990 and October 1993 in 21
      infertile patients who underwent laparoscopic myomectomy for a myoma measuring >
      or = 5 cm in diameter. The overall rate of intrauterine pregnancy was 33.3%
      (seven patients). Out of 12 patients with infertility factors associated with
      uterine myomas, three (25.0%) became pregnant, whereas four (44.4%) out of nine
      patients with no other associated infertility factor became pregnant. No uterine
      rupture was observed. Out of the seven pregnancies, four were spontaneous and
      began within 1 year of the operation. The other three were achieved after in
      vitro fertilization in patients with associated infertility factors. In the four
      patients who gave birth by Caesarean section, no adhesions were found on the
      myomectomy scar. From these preliminary results, laparoscopic surgery for myomas
      seems to offer comparable results with those obtained by laparotomy.

PMID- 8671259
TI  - In-vitro fertilization outcome in women with hydrosalpinx.
AB  - Recent studies have suggested that the presence of hydrosalpinx has a negative
      effect on in-vitro fertilization (IVF) outcome, with markedly diminished
      implantation and pregnancy rates, and increased early pregnancy loss. We
      evaluated the impact of hydrosalpinx on IVF outcome in a large population with
      tubal factor infertility: 63 patients with hydrosalpinx and 60 without
      hydrosalpinx (no hydrosalpinx) underwent 103 and 89 IVF cycles respectively.
      Hydrosalpinx was diagnosed by hysterosalpingography and/or laparoscopy prior to
      IVF. Patients were further subdivided into those with or without elevated
      quantitative serum Chlamydia trachomatis IgG antibody (Ab) titres. All couples
      with elevated serum Ab titres (l: 16 or more) were treated with doxycycline (100
      mg bid.) 10 days prior to the first IVF cycle. In all, 88 women (71.5%) had
      elevated C. trachomatis Ab: 47 women (74.6%) with hydrosalpinx had elevated
      titres, compared to 41 (68.3%) in the no hydrosalpinx group. There were no
      significant differences in mean age, number of mature oocytes obtained, and
      number of embryos transferred between the two groups. There was a trend for a
      higher implantation rate and ongoing pregnancy rate in the no hydrosalpinx group
      compared to the hydrosalpinx group (12.6 versus 9.8%, and 33.7 versus 24.8%
      respectively); however, this did not reach statistical significance. The
      incidence of early pregnancy loss was similar in the two groups. Two ectopic
      pregnancies were noted in the hydrosalpinx group compared to none in the no
      hydrosalpinx group. As expected, the prevalence of elevated titres of C.
      trachomatis IgG Ab in patients with tubal factor infertility presenting for
      assisted reproductive treatment was high. In contrast to recently published
      reports, our study did not confirm a negative effect of hydrosalpinx on IVF
      outcome when antibiotic treatment was given prior to assisted reproductive
      treatment. Prospective multicentre studies evaluating the effect of hydrosalpinx
      and its treatment on IVF outcome are needed.

PMID- 8671258
TI  - Salpingectomy improves the pregnancy rate in in-vitro fertilization patients with
      hydrosalpinx.
AB  - The objective of this study was to assess the impact on pregnancy outcome of
      excising hydrosalpinx(ges) in patients with repeated in-vitro fertilization (IVF)
      failures. A group of 15 patients who had previously undergone failed IVF attempts
      and had unilateral or bilateral hydrosalpinx was subjected to an operative
      laparoscopy with excision of the affected tube(s). Of these, 10 patients
      underwent a unilateral salpingectomy and five had a bilateral salpingectomy.
      Stimulated cycles of IVF and/or cryo-thaw cycles were then carried out post
      salpingectomy and the results were compared to those of pre-salpingectomy cycles.
      There was no statistically significant difference between the number of mature
      eggs retrieved, peak oestradiol concentrations, number of days to human chorionic
      gonadotrophin administration, or number of pre-zygotes frozen in the stimulated
      cycles pre- versus post-salpingectomy. Pre-salpingectomy, 15 patients underwent
      38 stimulated cycles and eight patients underwent 14 cycles with cryopreserved
      thawed embryos, achieving one pregnancy from a fresh transfer that resulted in a
      miscarriage. Post-salpingectomy, eight patients underwent 12 stimulated cycles,
      achieving five clinical pregnancies (two miscarriages and three ongoing
      pregnancies, i.e. either delivered or a pregnancy > or = 20 weeks), and nine
      patients underwent 10 cycles with cryopreserved-thawed embryos, achieving four
      clinical pregnancies (one miscarriage and three ongoing). We conclude that
      excision of hydrosalpinx(ges) improves the pregnancy potential after IVF, and
      that new and repeat IVF patients should be counselled accordingly.

PMID- 8671260
TI  - An unexpected guest in follicular fluid.
AB  - Parasitic infection as the only or concomitant cause of infertility in Caucasian
      women is rare. A parasitic infection may also present itself quite unexpectedly
      as a coincidental finding as shown with this case report. Moving microfilariae of
      Mansonella perstans were found in the aspirated follicular fluid of a patient who
      underwent in-vitro fertilization (IVF) with embryo transfer because of tubal
      pathology due to Chlamydia trachomatis. The patient also appeared to have a
      Schistosoma infection. To our knowledge, the presence of parasites in follicular
      fluid has never been reported before. We expect that infertility physicians may
      be confronted with parasitic infections more often, not only in patients
      originating from tropical countries but also in Western women as a result of a
      tendency to travel more frequently to exotic and (sub)tropical countries.

PMID- 8671261
TI  - Contraceptive use and attitudes in Italy 1993.
AB  - Surveys conducted between 1979 and 1991 indicated that contraceptive practice in
      Italy underwent rapid changes over that period. In order to assess current
      contraceptive use and attitudes, a survey was conducted among a random sample of
      2000 Italian women aged 15-45 years. Replies were received from 1542 women
      (77.1%). Of the self-defined non-sterile, sexually active women who wished to
      avoid pregnancy, 30.3% were using oral contraceptives, 8.1% an intrauterine
      device, and 1.1% sterilization, while 29.6% were using traditional methods,
      principally coitus interruptus. In reply to questions about the relative
      advantages and disadvantages of various contraceptive methods, women expressed
      worries with respect to the safety of oral contraceptives, intrauterine devices
      and sterilization. Relatively high percentages of women answered 'do not know'
      with respect to the various aspects of intrauterine devices, periodic abstinence
      and sterilization that were investigated. In view of the findings of previous
      studies, the current data obtained suggested that traditional methods are being
      gradually displaced by modern methods in Italy. Nevertheless, the use of
      traditional contraceptive is widespread, the same probably being true of
      inconsistent use of condoms. Furthermore, lack of information on the
      contraceptive options available seems to be a central issue in Italy.

PMID- 8671262
TI  - Two essential steps for a successful intracytoplasmic sperm injection: injection
      of immobilized spermatozoa after rupture of the oolema.
AB  - A total of 740 cycles of intracytoplasmic sperm injection (ICSI) were performed:
      625 cycles when < 6 x 10(5) total motile spermatozoa were harvestable from the
      ejaculate and 115 cycles in cases with a history of previous fertilization
      failure after classic in-vitro fertilization or subzonal sperm injection. An
      average of two pronuclei were observed in 63% of the injected oocytes, allowing
      725 transfers of a maximum of three embryos (98%). Of 214 pregnancies initiated,
      179 were established (25% of ICSI attempts). Because the fertilization rates from
      our initial 80 ICSI cycles were 2-fold less than those achieved previously, we
      changed the injection procedure and analysed, in 740 ICSI attempts, the
      importance of interfering technical factors and how to establish a successful
      ICSI programme. A remarkable change in the fertilization rate up to 68% (595
      cycles) occurred when two steps in the injection procedure were performed well,
      i.e. immobilization of the spermatozoon and placement of the spermatozoon into
      the ooplasm after cytoplasmic aspiration into the pipette until oolema rupture.
      This immobilization, by touching the tail with the pipette, is mandatory for
      increasing the percentage of fertilization, even with totally non-motile
      spermatozoa (41%). Because aspiration of the cytoplasm is an invasive part of the
      ICSI procedure and influences the quality of the embryos, it is essential to
      reduce the amount of cytoplasm drawn into the pipette. This could be attained by
      using a spikeless injection pipette with the smallest possible internal diameter.

PMID- 8671263
TI  - Oocyte donation programme: results obtained with intracytoplasmic sperm injection
      in cases of severe male factor infertility or previous failed fertilization.
AB  - Intracytoplasmic sperm injection was carried out in 15 oocyte donation cycles of
      15 infertile couples where oocytes had failed to fertilize after in-vitro
      fertilization (IVF) procedures or where the male partner had severe male factor
      infertility. A total of 62 oocytes were donated, but only 46 of these, in
      metaphase II, were injected. Of the injected oocytes, 31 (67.3%) had two
      pronuclei the morning after the injection procedure. On the following day, 29
      embryos were obtained (93% of the fertilized oocytes) and 25 were transferred.
      Two patients were not successful and consequently did not undergo embryo
      transfer. A total of five clinical pregnancies were obtained, giving pregnancy
      rates of 33.3 and 38.4% per started cycle and embryo transfer respectively.

PMID- 8671264
TI  - A simple method for assessment of the human acrosome reaction of spermatozoa
      bound to the zona pellucida: lack of relationship with ionophore A23187-induced
      acrosome reaction.
AB  - Acrosome reactions induced by the calcium ionophore A23187 and zona pellucida
      (ZP) were studied. Sperm samples were obtained from fertile men or men with
      normal semen analysis and normal sperm-ZP binding. Oocytes were obtained, with
      the consent of the patients, after the failure of fertilization in vitro. Motile
      spermatozoa selected by a swim-up technique were incubated with 10 microM A23187
      for 1 h, four oocytes for 2 h or solubilized ZP (4 ZP/microliters) for 2 h.
      Spermatozoa bound to the ZP were dislodged and collected in a small volume of
      phosphate-buffered saline by aspirating the oocytes with a glass pipette with an
      inner diameter (120 microns) slightly smaller than the diameter of the oocyte.
      The acrosome status of the spermatozoa was determined using fluorescein-labelled
      Pisum sativum agglutinin. The proportion of spermatozoa undergoing the acrosome
      reaction on the ZP at 2 h varied over a wide range (5-99%), but the agreement
      between results for the same semen sample exposed to different groups of oocytes
      was good: the standard deviations of the differences being 9%. Pre-incubation of
      spermatozoa for 2 h did not increase the ZP-induced acrosome reaction. Re
      incubation of ZP with the same sperm suspension for 2 h after removing ZP-bound
      spermatozoa from the first 2 h incubation produced a significantly lower ZP
      induced acrosome reaction in the second incubation (22 +/- 16%) than in the first
      incubation (30 +/- 14%; P < 0.001, n = 20). There was no significant difference
      in the ZP-induced acrosome reaction with oocytes with ZP which had or had not
      been penetrated by spermatozoa during the in-vitro fertilization insemination.
      Pre-incubation of spermatozoa with solubilized ZP blocked sperm-ZP binding.
      However, the acrosome reaction induced by solubilized ZP (4 ZP/microliters) was
      significantly lower than the acrosome reaction induced by intact ZP (10 +/- 5 and
      30 +/- 13% respectively, n = 11, P < 0.001), but there was a high correlation
      (Spearman r = 0.822, P < 0.01) between the results. On the other hand, although
      the average of the acrosome reaction was similar for A23187 (42%) and for ZP
      (43%), there was no significant correlation between the results for the two
      stimuli (n = 60). In conclusion, a useful method for assessing the ZP-induced
      acrosome reaction has been developed using oocytes which failed to fertilize in
      vitro. The lack of a relationship between the result of the chemical (A23187) and
      physiological (ZP) stimuli for the acrosome reaction in the same subjects
      questions the biological basis of using A23187 for tests of sperm function.
      Solubilized human ZP in a concentration that blocks sperm-ZP binding is a less
      efficient inducer of the acrosome reaction than is intact ZP. It is possible that
      the three-dimensional structure of the ZP is important for induction of the
      acrosome reaction or that spermatozoa which bind to the ZP are more likely to
      acrosome react. Assessment of the physiological acrosome reaction for diagnosis
      of sperm defects which interfere with the fertilization process should be
      concentrated on the spermatozoa which are capable of binding to the ZP.

PMID- 8671265
TI  - Ageing and sperm function.
AB  - To evaluate the fertilizing capacity of spermatozoa from elderly men, ejaculates
      from 29 older fathers (mean age 50.3 years) were compared with those from 35
      younger fathers (mean age 32.2 years). In addition to conventional semen
      parameters, sperm functions were studied that have been reported to be positively
      correlated with the fertilization rate: progressive motility, acrosin activity,
      inducible acrosome reaction, and chromosome condensation. Sperm concentration and
      follicle stimulating hormone concentration differed significantly in both groups.
      With regard to sperm functions there were no differences between older men and
      younger men, except for decreased sperm motility in the older group which,
      however, reached nearly normal values according to World Health Organization
      criteria. Decreased fertility of older couples is obviously more dependent on the
      age of the female partner. The significance of genetic risks remains to be
      clarified, especially when methods of assisted reproduction are applied.

PMID- 8671266
TI  - Human seminal plasma inhibits brain nitric oxide synthase activity.
AB  - Nitric oxide is a chemical messenger which functions as a neurotransmitter or as
      a cytotoxic agent. Nitric oxide synthase (NOS) has been isolated from various
      mammalian reproductive tissues. The presence or absence of NOS in spermatozoa has
      not yet been reported. We therefore tested human and murine spermatozoa for NOS
      activity by measuring the conversion of arginine to citrulline. No activity was
      found either in human or in murine spermatozoa. Human native semen and human
      seminal plasma exerted an inhibition on brain NOS activity, as assayed on rat
      brain cytosolic fractions. This inhibitory effect was dependent on the amount of
      protein present in the human seminal plasma. No inhibitory effect was observed
      when homogenates of washed spermatozoa were tested. The human seminal plasma did
      not affect the Michaelis constant (Km) of NOS for L-arginine (endogenous NOS
      substrate) whereas the maximal velocity (Vmax) was reduced, suggesting that it
      contains a non-competitive inhibitor of brain NOS. This inhibitory component was
      virtually insensitive to heat; a 10 min treatment to 95 degrees C only slightly
      reduced its ability to inhibit brain NOS. The physiological relevance of our
      observations remains to be elucidated. Human seminal plasma may exert an
      inhibition of nitric oxide synthesis on cells other than spermatozoa or on cells
      from the male or female genital tract, modulating directly or indirectly (via
      modulation of reactive oxygen species formation) the functional state of the
      spermatozoa.

PMID- 8671267
TI  - The role of transrectal ultrasonography in the elucidation and treatment of an
      unusual case of azoospermia.
AB  - We report a case of male infertility with low ejaculate volume and azoospermia.
      An infected seminal vesicle cyst that induced partial obstruction of the seminal
      duct system was diagnosed by transrectal ultrasound. After transrectal cystic
      aspiration and decompression, a normal spermogram was obtained.

PMID- 8671268
TI  - The effect of stress on semen reduction in the marmoset monkey (Callithrix
      jacchus).
AB  - This study compared a number of semen parameters of two separate groups of the
      common marmoset monkey (Callithrix jacchus) in order to determine the effect of a
      continuous potentially stressful situation on these parameters, and thus on the
      monkey's reproductive ability. The semen from 16 adult male marmoset monkeys was
      collected and analysed to compare semen parameters between a 'normal' (control)
      group (n = 9) and a 'blood withdrawn' ('stress') group (n = 7). The semen
      parameter values observed in the control were: pH 7.51 +/- 0.22, volume 40.2 +/-
      27.2 microliters, concentration 27.3 +/- 14.8 x 10(4)/microliters, motility 47.4
      +/- 15.9%, grade of velocity 3.5 +/- 1.2, and normal morphological forms 51.8 +/-
      13.7%. The 'blood withdrawn' group of marmoset monkeys showed significantly lower
      semen volume and sperm concentration than the 'normal' group. In addition, total
      count of spermatozoa, normal spermatozoa, motile spermatozoa and normal motile
      spermatozoa per ejaculate per monkey was significantly reduced in the 'blood
      withdrawn' group. The semen of these monkeys also revealed a significantly higher
      percentage of abnormally-shaped sperm heads than the normal group, and cases of
      impotence and sham ejaculation were recorded. Our study revealed that the
      continuous withdrawal of a small volume of blood from a group of marmoset monkeys
      appeared to be stressful to these monkeys and as a result, influenced their semen
      parameters, possibly making them less fertile. In addition, electroejaculation
      was found to be possibly harmful to the monkey's reproductive ability.

PMID- 8671269
TI  - CA 125 in seminal plasma: correlation with semen parameters.
AB  - Ovarian cancer marker CA 125 was measured in human seminal plasma, and the
      concentrations ranged between 22 and 1149 U/ml, and between 39 and 4711
      U/ejaculate. This very high patient-to-patient variability was in contrast to a
      much lower within-patient variability, which was comparable to that of other
      semen parameters. No significant differences in CA 125 concentration were found
      in seminal plasma from normospermic patients, patients with male factors,
      vasectomized men, and in aliquots of samples which led to a pregnancy, via
      artificial insemination or in-vitro fertilization. The seminal plasma CA 125
      concentration was not correlated with sperm count, motility and morphology. In
      contrast, seminal plasma CA 125 concentrations correlated with the age of the
      patient (P < 0.001) and inversely with the volume of the ejaculate (P < 0.001).
      These correlations were independent of each other. CA 125 did not correlate with
      the prostatic marker zinc, but did do so with the seminal vesicle marker fructose
      and the epididymal marker carnitine.

PMID- 8671270
TI  - Reduction of postoperative adhesion formation after laparoscopic ovarian
      cystectomy.
AB  - The purpose of this randomized, open-label study was to assess the efficacy of
      the product Interceed absorbable adhesion barrier in the prevention of adhesion
      formation on the ovary after laparoscopic ovarian cystectomy. A total of 25
      patients requiring laparoscopic bilateral ovarian cystectomy were enrolled into
      this study. After removal of ovarian cysts, peri-adnexal adhesions, and
      peritoneal irrigants, and the attainment of meticulous haemostasis, the random
      assignment of one ovary for wrapping with Interceed was revealed to the surgeon.
      The other ovary served as the untreated control. A follow-up laparoscopy was
      performed 8-30 weeks after the initial procedure in 17 patients. Significantly
      fewer adhesions formed at the Interceed treated ovaries compared with the control
      (untreated) ovaries (P < 0.05). In terms of adhesion-free outcome, 76% (13/17) of
      Interceed treated ovaries and 35% (6/17) of control ovaries were free of
      adhesions. A significant reduction was observed in the area of the sutured
      ovaries involved with adhesions when Interceed (6%) was used, compared with
      controls (20%). The reduction of adhesion formation was not related to the size
      of the cysts at the initial procedure. No adverse events were reported by any
      patient during the study. In conclusion, Interceed was found to be safe and
      effective in reducing the incidence of postoperative adhesion formation in
      patients undergoing laparoscopic ovarian cystectomy.

PMID- 8671271
TI  - Complete and partial luteinized unruptured follicle syndrome after ovarian
      stimulation with clomiphene citrate/human menopausal gonadotrophin/human
      chorionic gonadotrophin.
AB  - A total of 31 clomiphene citrate/human menopausal gonadotrophin (HMG)/human
      chorionic gonadotrophin (HCG)-stimulated cycles in 28 patients were investigated
      to determine the fate of each of the matured follicles. A standard stimulation
      regimen was adhered to, and ultrasound as well as hormonal monitoring was
      performed. All follicles were measured by vaginal ultrasound at -12, +35 and +45
      h relative to HCG administration and at 7 days after HCG administration. Of the
      220 follicles, 107 (48.6%) ruptured. The number of ruptured follicles per cycle
      was correlated with the mid-luteal progesterone concentration (r = 0.63, P =
      0.0005). The probability of follicular rupture was related to follicular diameter
      at 12 h before HCG administration; 6% of follicles < 12 mm in diameter ruptured
      compared with 87% of follicles 18-19 mm. A complete luteinized unruptured
      follicle (LUF) syndrome was observed in six cycles (20%). In these cycles,
      follicular growth and oestradiol, progesterone, luteinizing hormone (LH) and
      follicle stimulating hormone (FSH) concentrations at 12 h before HCG
      administration were similar to those in cycles with follicular rupture. However,
      mid-luteal progesterone concentrations were lower in complete LUF cycles (46.97
      +/- 8.95 nmol/l versus 108.74 +/- 12.27 nmol/l; P = 0.02). These data demonstrate
      that in stimulated cycles many follicles, usually the smaller ones, fail to
      rupture, even after HCG administration. Complete LUF syndrome, despite a strong
      exogenous ovulatory signal, and the absence of any difference in peri-ovulatory
      hormonal parameters, indicates that the defect causing LUF resides in the
      follicle itself and/or hormonal changes during the follicular phase.

PMID- 8671272
TI  - Elevated liver function tests in a case of moderate ovarian hyperstimulation
      syndrome.
AB  - Ovarian hyperstimulation syndrome is a recognized complication of ovulation
      induction. Abnormalities in liver function have been considered to be a rare
      manifestation of the severe form of ovarian hyperstimulation syndrome (OHSS). A
      28 year old woman with primary infertility underwent ovulation induction and
      intrauterine insemination. She was diagnosed with moderate OHSS and was followed
      as an outpatient. Early in her course of treatment she complained of upper right
      quadrant pain. Her work-up included an upper right quadrant ultrasound which
      showed only moderate ascites. Liver function tests at that time were elevated in
      a hepatocellular damage pattern. Liver function test elevations, as well as the
      ovarian hyperstimulation, resolved spontaneously in 10 days. Transient
      abnormalities in liver function do not appear to be limited to the most sever
      forms of OHSS.

PMID- 8671273
TI  - Zona thinning with the use of laser: a new approach to assisted hatching in
      humans.
AB  - From 1993 to 1994, in our centre, laser-assisted hatching was performed on 2- to
      4-cell stage embryos obtained from in-vitro fertilization (IVF) patients. We
      treated 376 embryos from 96 patients with repeated IVF failures (two to four
      attempts) (group A) and 397 embryos from 111 patients undergoing IVF for the
      first time (group B). Embryos were transferred immediately after the laser
      treatment. Both groups were compared to control groups (A' and B') whose embryos
      were transferred with intact zona pellucida (ZP). The resulting clinical
      pregnancies were 41 in A and 44 in B versus 24 in A' and 23 in B' respectively.
      The pregnancy rates per patient were 42.7 and 39.6% versus 23.1 and 19% in the
      control groups (P < or = 0.05), while the implantation rates per embryo were
      12.2% in A and 11.8% in B versus 7.3% and 7.1%. These results show that laser
      zona thinning of human embryos at 48 h after egg retrieval significantly
      increases the implantation and pregnancy rate (P < or = 0.05).

PMID- 8671274
TI  - Oocyte morphology does not correlate with fertilization rate and embryo quality
      after intracytoplasmic sperm injection.
AB  - The fertilization rates and further development of 528 human metaphase II oocytes
      directly injected by a single spermatozoon were analysed with respect to their
      morphological features at the light microscopy level at the time of retrieval.
      The deviations of oocyte morphology which were most frequently observed, after
      removal of cumulus cells, were dark incorporations, dark zona pellucida, large
      perivitelline space, spots, vacuoles, refractile bodies and irregular shape.
      These deviations correlated neither with the fertilization rate nor with the
      embryo quality score, as compared to 'ideal' oocytes. Since the majority of
      oocytes displayed deviations from the 'ideal' morphotype but were still
      fertilized and developed in culture at a normal rate, they were probably as
      normal as 'ideal' oocytes. Since some of these morphotypes, such as refractile
      bodies, have been shown to be associated with failure of fertilization, it seems
      that intracytoplasmic sperm injection may be an appropriate method of treatment
      for couples in whom repeated failure of in-vitro fertilization is associated with
      the retrieval of dysmorphic oocytes in the presence of normal semen
      characteristics.

PMID- 8671275
TI  - Co-culture of 1-cell outbred mouse embryos on bovine kidney epithelial cells:
      effect on development, glycolytic activity, inner cell mass:trophectoderm ratios
      and viability.
AB  - In an attempt to enhance embryo development, we have co-cultured 1-cell OF1 mouse
      embryos on bovine kidney epithelia (Madine-Darby bovine kidney; MDBK) cells in a
      complex medium called complex mouse tubal fluid (cMTF; based on the energy
      substrate levels found in the mouse oviduct, containing non-essential amino
      acids, glutamine and EDTA). To determine the quality of the blastocysts obtained,
      we examined several parameters: morphology, total cell numbers, inner cell mass
      (ICM):trophectoderm (TE) ratio, glycolytic activity and viability after transfer.
      A significantly lower number of blastocysts developed on MDBK cells compared with
      cMTF medium. cMTF blastocysts had a significantly higher glycolytic activity and
      a lower blastocyst cell number than those grown in co-culture, while both in
      vitro groups had higher ICM:TE ratios compared with in vivo. Blastocysts grown on
      MDBK cells displayed an elevated ICM number compared with those grown in cMTF
      medium alone. However, the percentage of fetuses after transfer remained
      drastically low in both culture groups compared with in-vivo blastocysts. In
      conclusion, co-culture did not increase the number of zygotes reaching the
      blastocyst stage. Although co-culture blastocysts show some similarities to in
      vivo embryos in cell number and glycolytic activity, no enhancement in viability
      was observed.

PMID- 8671276
TI  - Comparison of cryopreservation of supernumerary pronuclear human oocytes obtained
      after intracytoplasmic sperm injection (ICSI) and after conventional in-vitro
      fertilization.
AB  - A comparison was made of pronuclear stage human oocytes obtained either after
      classical in-vitro fertilization (IVF) or after intracytoplasmic sperm injection
      (ICSI). After ICSI or IVF, three fertilized oocytes from each patient were kept
      in culture for a further 24 h before embryo transfer. The surplus oocytes were
      cryopreserved using the 'open freezing system' and 1,2-propanediol and sucrose as
      cryoprotectants. A cohort of 817 and 1626 oocytes in pronuclear stage were frozen
      after IVF and ICSI respectively. Of these, 333 and 744 zygotes have been thawed,
      of which 78 and 76.5% were morphologically intact zygotes after IVF and ICSI
      respectively. From the 204 (ICSI) and 89 (IVF) zygote transfers performed, 34
      (17%) and 18 (20%) pregnancies were established. Both groups showed a similar
      abortion rate of approximately 20%. It is concluded that pronuclear stage oocytes
      resulting from ICSI can be successfully frozen/thawed and the survival and
      pregnancy rates achieved are comparable to those for zygotes obtained after IVF.

PMID- 8671278
TI  - Polyploidy and failed fertilization in in-vitro fertilization are related to
      patient's age and gamete quality.
AB  - A review of 392 cycles of in-vitro fertilization (IVF) was carried out in order
      to identify whether any factors such as sperm concentration at insemination,
      sperm motility or morphology, oocyte grading, number of oocytes retrieved,
      patient age, follicular stimulation protocols or duration of follicular growth,
      could be associated with the incidence of polyploidy or completely failed
      fertilization. The majority of polypronuclear fertilizations occurred in mature
      oocytes and in patients < 37 years of age and the incidence of polyploidy was
      strongly associated with fertilization and pregnancy rates. Fertilization rates
      were highest with mature oocytes. A significant linear trend was observed with
      failed fertilization and sperm concentration, morphology and motility. High rates
      of failed fertilization were found in patients > 37 years of age and with one to
      five oocytes retrieved. No significant difference was seen in stimulation
      protocols and oocyte grading between oocytes that fertilized and those that did
      not. Cycles with good sperm morphology and motility, the presence of mature
      oocytes, the retrieval of a large number of oocytes and younger maternal age seem
      to provide the best chance for IVF success.

PMID- 8671277
TI  - Developmental potential of embryos produced by in-vitro fertilization from
      gonadotrophin-releasing hormone antagonist-treated macaques stimulated with
      recombinant human follicle stimulating hormone alone or in combination with
      luteinizing hormone.
AB  - We previously demonstrated, in luteinizing hormone (LH)-deficient macaques, that
      follicular growth and maturation occurred with administration of exogenous
      (recombinant human) follicle stimulating hormone (r-hFSH) alone, and that the
      oocytes recovered fertilized at a notably higher rate than their counterparts
      from animals receiving both r-hFSH and r-hLH (Zelinski-Wooten et al., 1995).
      Here, the developmental potential of embryos produced from animals treated with r
      hFSH alone or in combination with r-hLH was evaluated. Embryos (n = 127) were
      cryopreserved, thawed and either co-cultured on buffalo rat liver cells until the
      hatched blastocyst stage or transferred to synchronized recipients. Although
      embryos from each treatment group demonstrated a similar ability to develop to
      hatched blastocysts with a definitive inner cell mass, a significant difference
      was seen in cryosurvival (56 versus 78%) and in developmental rate to the hatched
      blastocyst (12 versus 10 days) between embryos from the r-hFSH alone and the
      combination group respectively. Pregnancies resulted following oviductal embryo
      transfers in both groups, with corpus luteum rescue occurring on days 12-16 of
      the luteal phase. In summary, r-hFSH alone during the pre-ovulatory interval is
      adequate for the gametogenic events required to produce embryos that develop
      either in vitro or in vivo; however, exposure to r-hLH may improve embryo
      viability and the rate of development.

PMID- 8671279
TI  - Examination of the safety of intracytoplasmic injection procedures by using
      bovine zygotes.
AB  - We have evaluated the safety of intracytoplasmic sperm injection(ICSI) procedures
      by using bovine zygotes. Bovine zygotes were injected with a small amount (2-3
      pl) of either medium alone or medium containing polyvinylpyrrolidone (PVP) (sham
      ICSI, without spermatozoon) using the same procedure as ICSI, and the subsequent
      in-vitro embryonic development and embryo quality (number of cells/blastocyst)
      were examined. Control zygotes which had not been injected were similarly
      evaluated after in-vitro development. The sham-ICSI of either medium alone or
      medium containing PVP into bovine zygotes had no harmful effects on the rate of
      normal fertilization and on the rate of development to hatched blastocyst stage
      compared with those of controls (P > 0.05). In addition, no harmful effects were
      observed in the number of cells per blastocyst (embryo quality). The results
      suggest, for the first time, that the ICSI procedures currently used for animal
      and human ICSI are neither detrimental to embryonic development nor detrimental
      to embryo quality.

PMID- 8671280
TI  - Sex-related differences in the developmental rate of in-vitro matured/in-vitro
      fertilized ovine embryos.
AB  - Sex determination of in-vitro matured/in-vitro fertilized ovine embryos cultured
      in synthetic oviduct fluid (SOF) medium was performed by the polymerase chain
      reaction amplification of specific Y DNA sequences so as to test the influence of
      sex on developmental growth during the preimplantation period. At 144 h post
      insemination, embryos with a blastocoel were classified as the fast-developing
      group, whereas those showing a blastocoel only after this length of time were
      classified as the slow-developing group. At 144 h post-insemination, fast
      developing embryos were cultured separately and some were classified according to
      the size of their blastocoel. At the end of culture (207 h post-insemination),
      all embryos were classified according to both their developmental stage and their
      morphological quality. The male:female sex ratio of fast-developing embryos was
      significantly higher than the expected ratio of 50%. More males were observed at
      the most advanced developmental stage at both 144 and 207 h post-insemination.
      The proportion of males did not differ between the good- and poor-quality groups,
      although a skewed sex ratio was observed with embryos of better quality at the
      most developed stage. In conclusion, embryos at the most developed stage were
      predominantly male and were derived mainly from the fast-developing group,
      raising the possibility of a deviation in the sex ratio after the transfer of in
      vitro matured/in-vitro fertilized ovine embryos.

PMID- 8671281
TI  - The dynamics of rapid sperm transport through the female genital tract: evidence
      from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy.
AB  - Vaginal ultrasonography of uterine peristalsis during the follicular phase of the
      menstrual cycle demonstrates an increasing frequency and intensity of
      subendometrial and myometrial peristaltic waves as the follicular phase
      progresses. During this time the numbers of contraction waves with a fundo
      cervical direction decrease considerably in favour of waves of contraction with a
      cervico-fundal direction. There is evidence that rapid sperm transport through
      the female genital tract is passive and is provided by these uterine
      contractions. Using hysterosalpingoscintigraphy, rapid sperm transport was
      studied by placing technetium-labelled albumin macrospheres of sperm size at the
      external os of the uterine cervix and following their path through the female
      genital tract. Ascension of the macrospheres occurred immediately following
      deposition at the external os of the cervix. As early as 1 min thereafter, the
      macrospheres had reached the intramural and isthmical part of the tube.
      Quantitatively, the extent of ascension increased with progression of the
      follicular phase. While only a few macrospheres entered the uterine cavity and
      even fewer the tubes during the early follicular phase, the proportion of
      macrospheres that entered the uterine cavity increased dramatically during the
      mid-follicular phase despite continuing limited entry into the tube. During the
      late follicular phase there was considerable ascension of the macrospheres which
      was directed preferentially into the tube ipsilateral to the dominant follicle.
      These data indicate that rapid transport of the spermatozoa through the female
      genital tract is under the endocrine control of the dominant follicle, ensuring
      the preferential accumulation of spermatozoa at the site of fertilization.

PMID- 8671283
TI  - Large ovarian endometriomas.
AB  - The management of large endometriomas was described in a series of 814 patients.
      Combined therapy using gonadotrophin-releasing hormone agonist (GnRHa) and carbon
      dioxide laser laparoscopy was proposed. Drainage and GnRHa for 12 weeks provoked
      a reduction of the endometrioma size up to 50% of the initial value. After
      vaporization of the internal wall, a cumulative pregnancy of 51% after 1 year was
      achieved. A recurrence rate of 8% was observed for a follow-up of 2-11 years.
      Histological data demonstrated that the epithelium covering the ovary which is
      the mesothelium can invaginate in the ovarian cortex. Some of the invaginations
      were seen to be continuous with endometrial tissue, strongly suggesting the
      metaplasia theory in the pathogenesis of ovarian endometrioma.

PMID- 8671282
TI  - Heat shock proteins in human endometrium throughout the menstrual cycle.
AB  - Human endometrium is a steroid-sensitive tissue and there is evidence that
      supports the viewpoint that heat shock proteins (HSP) are implicated in the
      regulation of steroid function. Therefore, in this study we examined the
      expression of various members of the heat shock family of proteins in the steroid
      responsive human endometrium. Western blot analysis revealed that the expression
      of HSP90 showed minimal changes throughout the menstrual cycle. When normalized
      to the amount of HSP90, the expression of HSP27, HSP60 and the constitutive form
      of heat shock protein 70 (HSC70) increased progressively during the late
      proliferative and early secretory phases, and diminished in the mid- to late
      secretory and menstrual phases. In contrast, the inducible form of heat shock
      protein 70 (HSP70) did not undergo these changes. The cellular and subcellular
      localizations of these proteins were examined in human endometria by
      immunohistochemical staining. With the exception of HSP70, which was found
      primarily in the epithelial cells, the immunoreactivity for other heat shock
      proteins was found in both the stroma and the epithelium. Immunoreactivity for
      HSP27 was found in the lymphoid aggregates within endometrial stroma, and both
      HSP27 and HSP90 were found in endothelial cells. The immunoreactive heat shock
      proteins were found in the nuclei and/or cytoplasm of cells. However, no
      consistent nuclear versus cytoplasmic staining emerged, and such localization was
      irrespective of the site, the cell type or the phase of the menstrual cycle. Our
      findings show that endometrium has a full complement of heat shock proteins. The
      menstrual cycle-dependent changes in the amounts of heat shock protein suggest
      regulation by steroid hormones.

PMID- 8671284
TI  - Effect of progestogen therapy on follicular development, related hormone
      concentrations and fertilization in vitro in unstimulated cycles and unexplained
      and endometriosis-associated infertility.
AB  - Evidence of pituitary-ovarian dysfunction in unexplained and endometriosis
      associated infertility has been reported previously. Hormone-suppressive therapy
      is often used in an attempt to improve fertility, although benefits have not been
      proven. Our study examines the effect of progestogen (medroxyprogesterone
      acetate) treatment on women with endometriosis-associated and unexplained
      infertility, compared with women with tubal damage as functional controls. Pre
      ovulatory follicular size and serum and follicular fluid hormone concentrations
      were measured, and oocyte collection and in-vitro fertilization were attempted,
      in natural cycles totally unperturbed by exogenous gonadotrophins, for two cycles
      before and two cycles following treatment with medroxyprogesterone acetate for 2
      months. In the endometriosis and unexplained infertility groups, compared with
      the tubal group, the treatment led to significant reductions in the integrated
      luteinizing hormone (LH) values (483 versus 664, 559 versus 762 and 864 versus
      820 notional IU/l respectively). There were no changes in serum oestradiol or
      follicular fluid oestradiol, progesterone, follicle stimulating hormone or LH
      concentrations after treatment. The results suggest that progestogen therapy has
      no beneficial effect on the pituitary-ovarian dysfunction which contributes to
      endometriosis-associated and unexplained infertility.

PMID- 8671285
TI  - A sporadic case of delayed implantation after in-vitro fertilization in the
      human?
AB  - A possible case of delayed implantation after in-vitro fertilization (IVF) is
      described. The patient was sterilized in 1981, and made fertile again by tubal
      anastomosis in 1988. In 1990 and 1992 the patient had two right-sided tubal
      pregnancies, the first was treated with prostaglandin instillation, the second
      with salpingectomy. In connection with the salpingectomy in 1992, the left tube
      was observed to be constricted in the middle part and with phimosis of the
      ostium. In 1994 three IVF embryos were transferred, but 15 days after the
      transfer, serum human chorionic gonadotrophin (HCG) was negative (< 10 IU/ml).
      Seven weeks after the embryo transfer, menstruation was still missing, and the
      serum HCG was now positive (329 IU/ml). Subsequent ultrasound scans were
      compatible with an intrauterine pregnancy, progressing normally, but 5 weeks
      delayed compared with the oocyte aspiration. The pregnancy was successfully
      carried to term. Such a long delay in detection of HCG, in association with a
      normal pregnancy, has not been described in the literature before.

PMID- 8671286
TI  - What factors predetermine the risk of having a high-order multiple pregnancy with
      gamete intra-fallopian transfer?
AB  - Limiting the number of oocytes transferred at gamete intra-Fallopian transfer
      (GIFT) has limited the incidence of high-order pregnancy but at the same time
      compromised the fertility potential of some patients. A review of 300 patients
      who have undergone GIFT using a flexible approach as to the number of oocytes
      transferred identifies the patients at risk of high-order pregnancy as those aged
      under 30 years in whom more than six oocytes are returned and whose partner's
      spermatozoa have high progressive motility.

PMID- 8671287
TI  - A more realistic approach to the cumulative pregnancy rate after in-vitro
      fertilization.
AB  - As most studies overestimate the cumulative pregnancy rate, a method is proposed
      to estimate a more realistic cumulative pregnancy rate by taking into account the
      reasons for an early cessation of treatment with in-vitro fertilization (IVF).
      Three methods for calculating cumulative pregnancy rates were compared. The first
      method assumed that those who stopped treatment had no chance at all of
      pregnancy. The second method, the one used most often, assumed the same
      probability of pregnancy for those who stopped as for those who continued. The
      third method assumed that only those who stopped treatment, because of a medical
      indication, had no chance at all of pregnancy and that the others who stopped had
      the same probability of pregnancy as those who continued treatment. Data were
      used from 616 women treated at the University Hospital Nijmegen, Nijmegen, The
      Netherlands. The cumulative pregnancy rates after five initiated IVF cycles for
      the three calculation methods were in the ranges 37-51% for the positive
      pregnancy test result, 33-55% for a clinical pregnancy and 30-56% for an ongoing
      pregnancy. As expected, the first method underestimated the cumulative pregnancy
      rate and the second overestimated it. The third method produced the most
      realistic cumulative pregnancy rates.

PMID- 8671288
TI  - In-vivo and in-vitro assessment of the influence of ritodrine and oxytocin on the
      placental secretion of human chorionic gonadotrophin and placental lactogen.
AB  - The purpose of this study was to evaluate, in vivo and in vitro, the influence of
      ritodrine and oxytocin on the placental release of human chorionic gonadotrophin
      (HCG) and placental lactogen (HPL). The in-vivo study was performed on maternal
      sera collected before and 1 h after the onset of either ritodrine treatment (50
      micrograms i.v./min; administered to 15 women at risk of premature labour) or
      oxytocin infusion (2 mU i.v./min; administered to 21 women for acceleration of
      slow labour). The in-vitro study was performed on human term placental explants
      incubated in the presence of 4-400 ng ritodrine/ml or 15-1500 microU oxytocin/ml.
      HCG and HPL were measured by radioimmunoassay on maternal sera and incubation
      media. Maternal circulating concentrations of HCG and HPL remained unaffected
      after 1 h of ritodrine or oxytocin treatment. The in-vitro release of HCG and HPL
      by placental explants was not modified when ritodrine or oxytocin was added to
      the incubation media. The lack of influence of ritodrine and oxytocin on the
      placental secretion of HCG and HPL suggests that beta 2-adrenergic and oxytocin
      receptors are not involved in the releasing process.

PMID- 8671289
TI  - Infectious processes: an infrequent cause of first trimester spontaneous
      abortions.
AB  - A systematic assessment of infections beginning early in pregnancy is necessary
      to determine the true role of infections in pregnancy loss, given that infections
      could readily arise only after fetal demise. To this end, we have prospectively
      determined the frequency of infections in pregnant women who were subjects in a
      multi-centre US study. Insulin-dependent diabetic subjects and controlled
      subjects were recruited either before conception (86%) or at the latest within 21
      days of conception (14%). We collected data prospectively on all important risk
      factors and potential confounding variables, seeing 386 diabetic subjects weekly
      and 432 control subjects every other week during the first trimester. At each
      visit we inquired about untoward events and explicitly about fever or infections.
      We found no clinical evidence that infection occurred more often in the 116
      subjects experiencing pregnancy loss as compared to the 702 having successful
      pregnancies. This held both for the 2 week interval in which a given loss was
      recognized clinically as well as in the prior 2 week interval. Similar findings
      were not only observed for both the control as well as diabetic subjects but also
      when data were stratified by genital infection only or by systemic infection
      only. Our prospective data suggest that the attributable risk of infection in
      first trimester spontaneous abortion is small.

PMID- 8671290
TI  - High implantation and pregnancy rates with testicular sperm extraction and
      intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia.
AB  - Thirty-two infertile couples with obstructive and non-obstructive azoospermia
      were included in this study. Testicular sperm extraction (TESE) was performed in
      16 obstructive azoospermic cases where microsurgical sperm aspiration (MESA) or
      percutaneous sperm aspiration (PESA) were impossible because of totally destroyed
      epididymis and 16 non-obstructive azoospermia cases with severe spermatogenetic
      defect where the testicles were the only source of sperm cells. A total of 288
      oocytes was obtained from 32 females and 84% were injected. The fertilization
      rates (FR) with 2 pronuclei (PN) and cleavage rate were 50.8 and 68.2%
      respectively. A total of 15 pregnancies was achieved (53% per embryo transfer),
      nine from the obstructive and six from the non-obstructive group. Four
      pregnancies resulted in clinical abortion (26.6%). The ongoing pregnancy rate was
      39.2% per embryo transfer (ET) and 34.3% per started cycle. A high implantation
      rate was also achieved (26.6% in non-obstructive and 30% in obstructive
      azoospermia group). Using testicular spermatozoa in combination with ICSI in both
      obstructive and non-obstructive azoospermic groups, high implantation and
      pregnancy rates can be achieved.

PMID- 8671291
TI  - A new type of CO2 laser avoids power density loss due to absorption and the
      blooming effect by the CO2 gas environment.
AB  - The aim of this study was to compare the acute tissue effects of a standard CO2
      laser (Ultrapulse 5000) with a new design (Ultrapulse 5000L) that utilizes a
      different carbon isotope (C13) in the rat uterine horn model. Following
      laparotomy, measured laser injuries were effected with the Ultrapulse 5000 or
      Ultrapulse 5000L lasers via a laparoscope using CO2 or air for insufflation.
      Serial sections of the lesions were, thereafter, obtained to evaluate depth and
      width of total injury, width of defect and thermal damage zone. When CO2 was used
      as the insufflating gas, Ultrapulse 5000L laser was associated with significantly
      deeper lesions compared to the Ultrapulse 5000 system for the two tested pulsed
      energy levels (P < 0.0001). The width of total injury and thermal damage zone
      were significantly less with the former laser compared to the latter. The width
      of the defect was, however, significantly larger with the Ultrapulse 5000L laser
      for the 200 millijoule pulsed energy level, whereas it was comparable for the 75
      millijoule level. When air was used as the insufflation gas, all four parameters
      of tissue injury were comparable between the two types of laser (P > 0.05). The
      adverse effects on the CO2 laser beam and the resultant altered tissue effects
      that occur in a regular CO2 environment are avoided by the use of the Ultrapulse
      5000L or an air environment.

PMID- 8671292
TI  - Micro-epididymal sperm aspiration or percutaneous epididymal sperm aspiration?
      The dilemma.

PMID- 8671293
TI  - Letter. Micro-epididymal sperm aspiration or percutaneous epididymal sperm
      aspiration? The dilemma

PMID- 8671294
TI  - Fetoscopy, fetal-tissue sampling and the ESHRE guidelines on prenatal diagnosis.

PMID- 8671295
TI  - A fertile woman with Kartagener's syndrome and three consecutive pregnancies.

PMID- 8671296
TI  - Ectopic pregnancy and seasonality.

PMID- 8671297
TI  - Legislation on reproductive technologies in India.

PMID- 8671299
TI  - The future of oral contraceptives: research priorities.

PMID- 8671301
TI  - Differences in venous thromboembolism-risk are related to causes other than
      product characteristics.

PMID- 8671303
TI  - The public warnings on cardiovascular disease and third-generation oral
      contraceptives were not justified.

PMID- 8671302
TI  - Health policy and third-generation oral contraceptives.

PMID- 8671304
TI  - Debate. Plea for realism and honesty in results of infertility treatment

PMID- 8671305
TI  - What's your success rate? Dr. X comes to America.

PMID- 8671306
TI  - The A.R.T. of embroidery.

PMID- 8671307
TI  - Debate concluded. Possible immunological complications

PMID- 8671308
TI  - Debate concluded. Frozen pre-embryos in Denmark

PMID- 8671309
TI  - Cryostorage of human embryos: time to decide.

PMID- 8671310
TI  - Commonsense as applied to eugenics: response to Testart and Sele.

PMID- 8671311
TI  - Medically-assisted procreation: a maturing technology or a premature fear?
      Response to Testart and Sele.

PMID- 8671312
TI  - Intravenous immunoglobulin treatment of pregnant patients with unexplained
      recurrent abortions.
AB  - Intravenous immunoglobulins, first given to recurrent aborters with anti
      phospholipid syndrome, have been administered to unexplained aborters since 1986.
      They probably have immunomodulatory properties beyond supplying blocking
      antibodies. When pregnancy was confirmed, women were started with a loading dose
      which was repeated every 3-4 weeks until the second trimester. Dosages were
      empirical. Pregnancy rates ranged between 50 and 82%. The main maternal
      complications, i.e. allergic reactions and infections, were rare.

PMID- 8671313
TI  - Serum levels of insulin-like growth factor-1, IGF binding protein-1 and insulin
      and the response to human menopausal gonadotrophins in women with polycystic
      ovary syndrome.
AB  - In order to determine which factors influence the large variations in sensitivity
      to gonadotrophins witnessed in women with polycystic ovary syndrome (PCOS), a
      prospective study was conducted of the correlation between basal clinical and
      endocrinological features and gonadotrophin requirements of 20 women with
      clomiphene-resistant PCOS undergoing ovulation induction. Baseline evaluation of
      serum concentrations of luteinizing hormone (LH), follicle stimulating hormone
      (FSH), testosterone, fasting insulin, insulin-like growth factor-1 (IGF-1), IGF
      binding protein-1 (IGFBP-1) and sex hormone-binding globulin (SHBG) were
      performed before administering gonadotrophin-releasing hormone agonist (GnRHa).
      Two weeks later, human menopausal gonadotrophin (HMG) was given in a standard
      individualized protocol according to ovarian response, until human chorionic
      gonadotrophin (HCG) was given. Serum concentrations of insulin, IGF-1, and IGFBP
      1 were unaffected by GnRHa. The BMI correlated positively with insulin and
      inversely with IGFBP-1 serum concentrations and insulin and IGFBP-1 were
      inversely correlated. The amount of HMG required correlated positively with BMI
      and insulin concentrations and inversely with IGFBP-1 in the whole group and
      these correlations were maintained in the sub-group of lean women. No correlation
      was observed between HMG requirements and IGF-1 or other hormones. Women with
      hyperinsulinaemia and low IGFBP-1 concentrations required significantly more HMG.
      Multiple regression analysis revealed that insulin concentration is the most
      significant determinant of HMG requirement even when dissociated from BMI. We
      concluded that requirements of HMG in PCOS is not merely determined by obesity
      but by a cardinal role of insulin concentrations which, when high, induce,
      hypothetically, a hyperandrogenic intrafollicular milieu.

PMID- 8671314
TI  - Spontaneous ovarian hyperstimulation mimicking an ovarian tumour.
AB  - Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy is
      exceedingly rare. We report a case of ovarian hyperstimulation presenting as
      bilateral ovarian masses in association with spontaneous pregnancy, occurring in
      a woman with disturbed liver function. A possible mechanism is discussed.

PMID- 8671315
TI  - Incidence of chromosome 21 disomy in human spermatozoa as determined by
      fluorescent in-situ hybridization.
AB  - We have evaluated the incidence of chromosome 21 disomy in decondensed sperm
      heads from nine normal men using a locus-specific DNA probe for chromosome 21,
      and a centromeric probe for chromosome 6 as a control. The results show that the
      incidence of chromosome 21 disomy (0.38%) is significantly higher than disomy for
      chromosome 6(0.14%). No differences were found among the individuals analysed.

PMID- 8671316
TI  - Residual uterine septum of less than 1 cm after hysteroscopic metroplasty does
      not impair reproductive outcome.
AB  - The objective of this study was to ascertain if incomplete correction leaving a
      residual uterine septum of < or = 1 cm affects fertility outcome. Reproductive
      outcome in 17 women with a residual septum of between 0.5 cm and 1 cm after
      hysteroscopic metroplasty was compared to that in 51 women with no residual
      septum or one of < 0.5 cm. Septal lysis was performed with microscissors or
      resectoscope. One month after operative hysteroscopy, abdominal ultrasonography
      was performed on all the women and those with a residual septum of > 1 cm then
      underwent a second operative hysteroscopy to complete the lysis. The cumulative
      pregnancy and birth rates were calculated and the curves compared using the log
      rank test. The cumulative 18 month probability of becoming pregnant was 44.5% in
      the patients with residual septum and 52.7% in those with no residual septum (not
      significantly different), and the cumulative 18 month probability of giving birth
      to a child was 27.5 and 36% respectively (also not significant). The presence of
      a residual uterine septum of between 0.5 and 1 cm as shown by ultrasonography
      appears not to worsen the reproductive prognosis compared with that in women in
      whom the septum has been completely or almost completely corrected.

PMID- 8671317
TI  - The value of hysteroscopic evaluation in patients with preclinical in-vitro
      fertilization abortions.
AB  - The study was conducted on 144 women who experienced preclinical abortions, i.e.
      a transitory rise in beta-human chorionic gonadotrophin (HCG) without any
      clinical or sonographic evidence of pregnancy, to identify the relationship
      between preclinical abortions and intrauterine pathology. Hysteroscopy was
      performed 1-2 weeks after the decline of beta-HCG concentrations to negative
      values. Intrauterine adhesions were detected in three patients (2.1%), most of
      these being of the mild type. Concomitant intrauterine abnormalities, mainly
      uterine septa, were found in 14 (9.7%) cases. We believe that preclinical
      abortions do not predispose intrauterine adhesions and curettage is superfluous.
      An incomplete uterine septum seems to be the major factor predisposing this early
      pregnancy wastage. Hysteroscopy following this condition is an easy and efficient
      means for both identifying intrauterine pathology and excluding adhesions.

PMID- 8671318
TI  - Intrauterine insemination: evaluation of the results according to the woman's
      age, sperm quality, total sperm count per insemination and life table analysis.
AB  - We report on 332 infertile couples who underwent 1115 cycles of intrauterine
      insemination (IUI) with washed husband's semen. The indication for IUI was an
      abnormal post-coital test due to either a male or cervical infertility factor.
      The mean number of IUI cycles per patients was 3.4, the overall pregnancy rate
      18.7%, and the pregnancy rate per cycle 5.6%. The cumulative pregnancy rate
      calculated by life table analysis showed that 16.0% of pregnancies occurred in
      the first three treatment cycles, while the cumulative pregnancy rate was 26.9%
      by the sixth cycle. The outcome of the therapy was adversely affected if the
      woman's age was > 39 years and/or total motile sperm count per insemination was <
      1 x 10(6). No pregnancy occurred in women older than 44 years or in cases with a
      total motile sperm count before semen preparation of < 1 x 10(6).

PMID- 8671320
TI  - A comparison of three methods for detecting the acrosome reaction in human
      spermatozoa.
AB  - This study was designed to compare three different fluorescent probes to assay
      the acrosome reaction in human spermatozoa: chlortetracycline (CTC), mannosylated
      bovine serum albumin (BSA) labelled with fluorescein (MAF), and quinacrine (QN).
      Normal human sperm ejaculates were washed and allowed to swim up for 30-60 min.
      Samples were examined under epifluorescence for the percentage of the acrosome
      reacted spermatozoa, as detected by the three probes. There was no significant
      differences between samples of fresh, uncapacitated spermatozoa evaluated with
      CTC, MAF or QN; all gave < 10% reacted. Following capacitation for 3 h, the
      percentage of spontaneously reacted spermatozoa was higher than in fresh
      spermatozoa; CTC and MAF gave the same percentage (12%), while QN indicated a
      higher percentage (18%) of reacted spermatozoa (P < 0.001). Following exposure to
      ionophore A23187 at 1 h, the percentage of acrosome reactions increased to a mean
      of 31% as detected with CTC or MAF; the mean percentage (45%) was significantly
      higher with QN (P < 0.0001). Further incubation up to 2 h with A23187 did not
      change these percentages. These results suggest that the QN probe detects the
      onset stage of the acrosome reaction, whereas the CTC and MAF probes detect the
      later stages in which the acrosomal cap is lost. Use of the two types of probe
      provides a means for finer resolution of the time course of the acrosome reaction
      in the human spermatozoa.

PMID- 8671319
TI  - Ovarian activity and vaginal bleeding patterns with a desogestrel-only
      preparation at three different doses.
AB  - A randomized, double-blind, group-comparative study was performed over a 6 month
      period to compare ovarian suppression and vaginal bleeding during the use of
      three oral contraceptives containing doses of 30, 50 or 75 micrograms
      desogestrel. A total of 44 female volunteers with regular cycles and established
      ovulation by ultrasonography were recruited from an out-patient clinic in a
      university hospital and asked to participate in the study. Ultrasonography and
      serum oestradiol and progesterone measurements were performed during two
      assessment periods. The 75 microgram dose showed complete suppression of
      ovulation and a more acceptable bleeding pattern than the lower doses. The 75
      microgram dose of desogestrel is the most promising dose for the development of a
      new progestogen-only oral contraceptive agent.

PMID- 8671321
TI  - Semen donor recruitment: a study of donors in two clinics.
AB  - We report on a comparative study of semen donors at two London (UK) clinics which
      have different recruitment and payment policies. Results presented here include
      data on the demographic characteristics, motivations, means of recruitment and
      attitudes towards payments of the donors, as well as their disclosure to others
      about the donation. Donors from the two clinics were found to differ on the above
      points. Comparisons with other studies are made and implications for donors
      recruitment are discussed.

PMID- 8671322
TI  - A new concept for the extraction of testicular spermatozoa as a tool for assisted
      fertilization (ICSI).
AB  - A new method is described for the enzymatic preparation of testicular tissue to
      obtain vital spermatozoa for ICSI. The tissue obtained from both testes by biopsy
      is studied by means of the semi-thin section method as well as being cryo
      preserved. If spermatid formation is assured by semi-thin section histology,
      vital spermatozoa from the cryo-preserved portion of testicular tissue are
      enzymatically prepared. In this way it is possible to optimize the reproductive
      medical treatment for those couples in whom an extracorporal fertilization of
      oocytes by means of testicular spermatozoa is being considered.

PMID- 8671323
TI  - Fertility with testicular sperm extraction and intracytoplasmic sperm injection
      in non-obstructive azoospermic men.
AB  - In non-obstructive azoospermia spermatozoa can usually only be isolated from the
      testicles, and thus the most promising treatment model is testicular sperm
      extraction (TESE). Hormone concentrations, testicular volume determinations and
      testicular biopsy results are not uniform enough to select potential candidates
      for successful TESE and intracytoplasmic sperm injection (ICSI) approaches in
      advance. The aim of this study was to assess the efficacy of using ICSI with
      testicular spermatozoa in cases of non-obstructive azoospermia and to compare the
      inclusion criteria and sperm existence in the testicles in sperm obtainable and
      non-obtainable groups. All men showed either complete or incomplete (n = 14)
      maturation arrest in spermatogenesis, severe hypospermatogenesis (n = 10) or
      Sertoli cell-only syndrome (n = 5) in their testicular biopsies. Only 14 out of a
      total of 29 men provided enough spermatozoa for the ICSI procedure, while no
      spermatozoa were found in the testicular samples of the remaining 15 men. Out of
      123 oocytes obtained from 14 females, 101 were injected with the husbands'
      testicular sperm cells. Total fertilization failure was observed in three cases.
      Of 39 oocytes fertilized, 38 cleaved. The fertilization and cleavage rates were
      38.6 and 97.4% respectively. The pregnancy rate was 20.7% per initiated cycle. In
      the group from whom spermatozoa were obtainable, the pregnancy rate was 42.9% per
      initiated cycle and 54.5% per embryo transfer. A total of six pregnancies were
      achieved, of which two were twins and four were singletons. One singleton
      pregnancy resulted in abortion in the first trimester. There was no statistical
      difference concerning the serum follicle stimulating hormone concentration,
      testicular volume and biopsy results in groups in which spermatozoa were
      obtainable or not. In conclusion, although the association of TESE with ICSI
      obtained pregnancies for some patients with non-obstructive azoospermia, further
      studies are needed to determine the inclusion criteria for successful TESE.

PMID- 8671324
TI  - The possible meaning of transferrin and its soluble receptors in seminal plasma
      as markers of the seminiferous epithelium.
AB  - Transferrin (Tf) and soluble transferrin receptors (S-Tf-R) were measured by
      enzyme immunoassay in seminal plasma of 130 semen samples. The mean concentration
      of S-Tf-R in cases with normozoospermia was 10.4 IU/ml (95% confidence interval:
      9.5-11.3) and it was significantly lower in patients with oligozoospermia (6.6,
      95% CI: 5.8-7.5, P < 0.001), asthenozoospermia (8.5, 95% CI: 5.5-10.7, P < 0.05),
      azoospermia of primary testicular origin (7.9, 95% CI: 6.1-9.6, P<0.05) and post
      vasectomy samples (5.9, 95% CI: 5.4-6.9, P < 0.001). The concentration of S-Tf-R
      in post-vasectomy samples was lower than that in patients with azoospermia of
      primary testicular origin (P < 0.05; positive likelihood ration = 7 at value of
      8.3 IU/ ml). S-Tf-R was positively correlated with motile sperm concentration (r
      = 0.50, P < 0.0001), percentage motility (r = 0.38, P < 0.001), percentage of
      normal forms (r = 0.43, P < 0.001), sperm linear velocity (r = 0.42, P < 0.001),
      and ATP concentration (r = 0.67, P < 0.0001). Follicle stimulating hormone (FSH)
      was found to be negatively correlated with the concentrations of both Tf (r = 
      0.31, P < 0.05) and of S-Tf-R (r = -0.45, P < 0.01). The mean concentration of Tf
      in seminal plasma was 50.4 micrograms/ml (35.9-67.2) in samples with
      normozoospermia (n = 22), and the concentration was significantly lower in
      patients with oligozoospermia (P < 0.05), azoospermia of testicular origin (P <
      0.001), and post-vasectomy samples (P < 0.001). Seminal Tf was correlated with
      motile sperm concentration (r = 0.36, P < 0.001), percentage of motile
      spermatozoa (r = 0.25, P < 0.05), linear velocity (r = 0.24, P < 0.05) and ATP
      concentration (r = p.44, P < 0.001). The concentration of Tf was positively
      correlated with that of S-Tf-R both in cases with spermatozoa present (r = 0.66,
      P < 0.001), and in cases with azoospermia of testicular origin (r = 0.51, P <
      0.05) but not in vasectomy cases. It is concluded that S-Tf-R in seminal plasma
      is a marker of spermatogenesis and may give information on the presence or
      absence of spermatogenetic cells in cases with azoospermia. Further
      investigations are needed to assess its usefulness for clinical practice.

PMID- 8671325
TI  - Semen analysis in HIV seropositive men and in subjects at high risk for HIV
      infection.
AB  - The main purpose of this research was (i) to perform a comparative study of sperm
      parameters in human immunodeficiency virus (HIV) seropositive and high risk
      subjects in order to identify any possible alterations in the semen which
      specifically result from HIV infection and (ii) to study the p24 antigen as an
      early diagnostic marker of infection in high risk subjects. HIV seropositive
      subjects showed no significant variations regarding sperm densities, motility and
      viscosity compared to high risk subjects and controls. On the other hand, these
      HIV seropositive subjects showed (a) a significantly higher percentage of
      cytoplasmic droplet forms and immature germ cells, perhaps caused by an early
      failure of epididymal function and/or by a condition of stress affecting
      spermatogenesis after HIV infection and (b) a significantly higher level of
      spermiophage cells, suggesting that HIV activates mechanisms that increase
      spermiophagy. In addition, HIV seropositive men showed a significant positive
      correlation between blood CD4+ and sperm motility as well as a significant
      inverse correlation between CD4+ and sperm abnormalities. This is perhaps due to
      a decrease in testosteronaemia leading to defective epididymal sperm maturation.
      To date, p24 has not been found in the serum or seminal plasma of high risk
      subjects. The longitudinal study in progress should provide further information
      on this point.

PMID- 8671326
TI  - Delivery following intracytoplasmic injection of mature sperm cells recovered by
      testicular fine needle aspiration in a case of hypergonadotropic azoospermia due
      to maturation arrest.
AB  - This is the first reported delivery following intracytoplasmic sperm injection
      (ICSI) of mature live testicular sperm cells collected in a case of
      hypergonadotrophic azoospermia with maturation arrest. The 30 year old couple
      presented with primary infertility of 11 years duration, the man being submitted
      in childhood to five orchidopexy operations for the treatment of cryptorchism. He
      had elevated serum follicle stimulating hormone (FSH; 18.8 IU/I), an atrophic
      left testis and a normal sized right testis, the biopsy of which diagnosed
      maturation arrest and focal scarring. The couple refused donor insemination for
      religious reasons and the only option was an attempt at testicular sperm
      collection. Multiple testicular and epididymal fine needle aspirations were
      performed, using an aspiration handle loaded with 20 ml syringe and 21-23 gauge
      butterfly needles. The mature spermatozoa recovered were used to inseminate the
      oocytes by ICSI. Prior to this procedure, the patient's wife underwent ovulation
      induction using a long protocol of mid-luteal gonadotrophin-releasing hormone
      analogue/human menopausal gonadotrophin (GnRHa/HMG). At oocyte retrieval, ten
      oocytes were recovered. Eight live sperm cells were recovered from the aspirates
      of the right testis. Following ICSI into four metaphase II and two metaphase I
      oocytes, one mature oocyte was fertilized, cleaved and was transferred to the
      uterus 48 h after oocyte retrieval. The patient conceived and delivered a 3300 g
      boy at term. In conclusion, our results demonstrate that this novel approach
      should be considered in cases with hypergonadotrophic azoospermia due to
      testicular failure. Further experience is needed to establish the exact criteria
      for its use.

PMID- 8671327
TI  - Spermatid injection into human oocytes. I. Laboratory techniques and special
      features of zygote development.
AB  - Spermatid injection into the oocyte cytoplasm has been shown recently to yield
      viable human embryos developing to term after transfer to the mother. This study
      provides details of the laboratory techniques related to round spermatid
      injection (ROSI) and elongated spermatid injection (ELSI) and focuses on some
      special features of zygote development associated with the use of these types of
      sperm precursor cells for fertilization. A spermatid-enriched fraction was
      obtained by centrifugation of cells from azoospermic ejaculates through a
      discontinuous Percoll gradient column. Individual round or elongated spermatids
      were identified in this fraction and injected deep into oocytes. Oocyte
      activation was boosted by a vigorous aspiration of the ooplasm at the time of
      injection. The fertilization rates after ROSI and ELSI were 45 and 44%
      respectively. A single large syngamy nucleus was detected in 36% of the zygotes
      that previously showed two normal-sized pronuclei. This condition did not appear
      to delay the first cleavage division. These observations underscore the
      importance of distinguishing the syngamy nucleus of diploid zygotes from the
      female pronucleus of haploid, parthenogenetically activated eggs.

PMID- 8671328
TI  - Spermatid injection into human oocytes. II. Clinical application in the treatment
      of infertility due to non-obstructive azoospermia.
AB  - We have reported recently the first birth after intrauterine transfer of embryos
      obtained by injection of round spermatids into oocytes in cases of unexpected
      azoospermia. Here we provide a complete documentation of the series of 11 cases
      in which this novel method of infertility treatment was employed. In four of
      these cases, elongated spermatids were identified in the ejaculate, and it was
      decided to perform elongated spermatid injection (ELSI). In the other six cases,
      only round spermatids were present, and round spermatid injection (ROSI) was
      done. In one case, ROSI was given preference to ELSI because of a very poor
      viability status of elongated spermatids present in the ejaculate. Fertilization
      of at least one oocyte was achieved in 10 of the 11 treatment cycles; the
      fertilization rate in these 10 cycles ranged between 7 and 100% with a mean value
      of 45%. All of the two-pronucleated zygotes cleaved and were transferred to the
      patient's uterus. A singleton pregnancy was achieved in two ROSI cycles. Both
      pregnancies developed uneventfully and resulted in the birth of normal infants.
      These data show the intra-ooplasmic injection of spermatids obtained from the
      ejaculate may become the treatment of first choice in patients with non
      obstructive azoospermia.

PMID- 8671329
TI  - The Acridine Orange test: a clinically relevant screening method for sperm
      quality during infertility investigation?
AB  - To determine the clinical usefulness of Acridine Orange (AO) staining of
      spermatozoa as a screening test for the evaluation of semen quality during basic
      infertility investigation, semen smears from 103 randomly chosen males of
      subfertile couples were examined. The median duration of infertility was 4.5
      years (range 1-15) and the median age was 33 years (range 21-43). The outcome of
      AO staining ranged from 5 to 81%, with a median of 24%, green fluorescent
      spermatozoa. Results were not significantly related to the parameters of semen
      analysis (sperm count, motility, standard morphology, viability, pH and volume,
      as well as fructose concentration and number of found cells) or to local sperm
      antibody testing and semen cultures. Fluorescence after AO staining was also not
      related to sperm functional capacity (evaluated using sperm-mucus interaction
      tests in vitro and in vivo), or the medical history of the patient. No
      significant differences in the AO test outcome were seen in patients with
      explained and unexplained infertility, or with regard to subsequent fertility
      [with a median value of 21% (range 5-46) green fluorescence in the fertile group,
      compared with a median value of 28% (range 9-81) green fluorescence in the other
      men]. The results of this prospective study indicate that under the usual
      conditions of conception, the AO test is not clinically useful as a screening
      procedure to determine semen quality during basic infertility investigation.

PMID- 8671330
TI  - Localization and characterization of white blood cell populations within the
      human ovary throughout the menstrual cycle and menopause.
AB  - The purpose of this investigation was to localize and characterize white blood
      cell populations in the human ovary through its physiological life cycle. Ovaries
      from 30 women of reproductive age and from three post-menopausal women were
      embedded in paraffin or frozen. Clinical information and pathology review were
      used to obtain accurate menstrual cycle information and to ensure the absence of
      ovarian disease. Tissue sections were stained for leukocyte phenotypes and the
      numbers of white blood cells in the ovary were semiquantitatively assessed by two
      separate examiners using a 0-3 plus (+) scoring system. Our results demonstrated
      that macrophages and T lymphocytes were the primary immune cells of the ovary,
      the concentrations of which were dependent on the location and stage of
      development of the structures containing leukocytes. Developing follicles
      contained few (+) macrophages located in the theca, while atretic follicles
      possessed moderate (+2) numbers in the granulosa and few (+) to moderate (+2)
      numbers in the theca. Newly formed corpora lutea contained few (+) macrophages,
      while regressing corpora lutea contained abundant (+3) numbers. Human leukocyte
      antigen (HLA)-DR positive cells were located predominantly at sites where
      macrophages were present. T lymphocytes were generally not present in the
      developing follicle but focal, small (+) numbers were observed in blood vessels
      of the theca. Atretic follicles contained few (+) T lymphocytes in the granulosa
      and few (+) to moderate (+2) numbers in the theca. Few (+) T lymphocytes were
      present in new corpora lutea, while moderate (+2) to abundant (+3) numbers were
      present in regressing corpora lutea. T lymphocytes at all sites were UCHL1
      positive. The CD4 (T helper) to CD8 (T suppressor) ration in the corpus luteum
      was 1:1. B-lymphocytes and natural killer cells were generally absent in the pre
      menopausal ovary. The post-menopausal ovary, in contrast, only contained few (+)
      macrophages, T lymphocytes and natural killer cells in the stroma. In conclusion,
      our results indicate that the human ovary is an immunologically dynamic tissue
      containing activated macrophages and T lymphocytes which provide an anatomical
      basis for immunoendocrine interactions within the ovary.

PMID- 8671331
TI  - Different protein patterns derived from follicular fluid of mature and immature
      human follicles.
AB  - The purpose of our study was to compare the protein patterns originating from
      fluids of mature and immature human follicles in order to gain further insight
      into their biochemical composition. A total of 10 patients were stimulated for in
      vitro fertilization (IVF) using different stimulation protocols. Follicular
      fluids were aspirated transvaginally and analysed microscopically for the
      presence of oocytes. Follicular fluids were stored at -18 degrees C. Samples of
      500 microliters were processed for two-dimensional gel electrophoresis. Up to 60
      proteins in various groups could be detected. Seven protein spots were selected
      for chemical analysis by cutting them out of the gels and subjecting them to
      internal amino acid sequencing procedures. Our results can be summarized as
      follows: (i) major differences were not detected between the protein patterns
      from the various mature follicles of a particular patient, nor were significant
      differences observed in the proteins derived from follicular fluids collected
      from the seven patients with mature follicles; (ii) considerable differences were
      observed in the protein patterns derived from fluids of immature compared with
      mature follicles. Fluid from the three patients with immature follicles contained
      many fewer proteins, some of which were expressed at low levels. We conclude that
      the observed variations in protein composition of follicles of different
      developmental age reflect their physiological condition and serve as biomedical
      markers for follicular maturity.

PMID- 8671332
TI  - Transvaginal interstitial laser treatment of the ovary: a feasibility study in
      cows.
AB  - In 12 cows, transvaginal interstitial laser treatment (TILT) of the ovaries was
      performed using a neodynium:yttrium aluminium-garnet laser to investigate the
      feasibility of a new treatment approach for clomiphene-resistant patients with
      chronic hyperandrogenic anovulation. Powers of 1 and 2 W during 5 min of exposure
      were used. Sonographic changes of thermal damage during TILT, the extent and
      healing of the lesions by light microscopy and ultrasound during 3 month follow
      up and adhesion formation were studied. During laser irradiation, a
      hyperechogenic zone developed around the fibre tip, with a mean +/- SD diameter
      of 4.4 +/- 2.0 mm at 1 W and 6.9 +/- 1.5 mm at 2. W. The mean diameters of the
      histological lesions 2 days after treatment were 7.3 +/- 2.5 mm at 1 W and 13.0
      +/- 2.1 mm at 2 W. During follow-up, the mean diameter of both the histologically
      and the sonographically assessed lesions decreased, although transvaginal
      sonography (TVS) systematically and significantly underestimated the thermal
      damage. Lesions healed by fibrosis and no adhesions were present. TILT of the
      ovaries in cows is easy to perform and produces central or subcapsular necrosis
      without adhesions. TVS gives an indication of thermal damage but underestimates
      the extent of tissue damage in cow ovaries. Obviously, this study does not allow
      conclusions to be drawn concerning its safety and efficacy in man.

PMID- 8671333
TI  - The paradoxical effects of pentoxifylline on the binding of spermatozoa to the
      human zona pellucida.
AB  - In the presence of pentoxifylline, human spermatozoa are induced to increase
      certain motion characteristics; however, the role of this drug in fertilization
      remains equivocal. In this study, the influence of pentoxifylline on one aspect
      of fertilization, that is sperm-zona binding, has been examined. Results from a
      fluorescence label competitive zona binding (CZB) test showed that spermatozoa
      exposed to a pentoxifylline challenge of between 0.1 and 5 mM, which was
      curtailed after 1 h by washing, had a decreased (P < 0.01) ability to bind to
      intact zona compared with control spermatozoa. The washing procedures also
      removed (decrease P < 0.01 compared with peak values) some of the enhanced motion
      characteristics induced by pentoxifylline. These results were in contrast with
      those obtained using experimental conditions that maintained an increased
      curvilinear velocity (VCL) and lateral head displacement (ALH) (increase P <
      0.001 above baseline controls) in the continued presence of pentoxifylline. Using
      a hemizona binding (HZB) assay, 3 mM pentoxifylline increased (P < 0.001) sperm
      zona binding almost 20% above zona binding with unexposed control spermatozoa. It
      was concluded that, in the presence of pentoxifylline, there is increased sperm
      binding to the zona pellucida; however, if the drug is removed by washing, the
      sperm binding to the zona is decreased in concert with the removal of the
      enhanced motion characteristics. The application of zona solubilization by acidic
      conditions in a microchamber enabled the precise determination of sperm numbers
      in both of the sperm-zona binding assays, and the results demonstrated that a
      wide variation in sperm numbers was observed in each test, with 63-580
      spermatozoa bound in the CZB assay and 56-1340 spermatozoa bound on a hemizona.

PMID- 8671334
TI  - Efficacy of oocytes donated by older women in an oocyte donation programme.
AB  - Population and insemination studies indicate that women experience declining
      fertility with ageing. The question therefore arises whether older women are
      suitable oocyte donors. This study addresses this issue by examining the
      relationship between oocyte donor age and clinical outcome in a large oocyte
      donation programme. We retrospectively reviewed data from 458 consecutive oocyte
      donation cycles completed by 164 different designated oocyte donors. Data were
      divided into two groups: group A, cycles with donors aged 21-30 years at the time
      of follicular aspiration (193 cycles, 88 donors); and group B, cycles with donors
      aged 31-40 years at the time of follicular aspiration (265 cycles, 86 donors).
      Five donors, because of ageing during repetitive donations, contributed data to
      groups A and B. In a given cycle, all oocytes for a recipient came from only one
      designated donor. Comparing the two donor groups, there was no difference in the
      amount of gonadotrophin used to achieve optimal stimulation; however, more
      oocytes were obtained from group A than group B donors (16.8 +/- 6.9 and 15.1 +/-
      8.1 respectively, P < 0.05). Similar percentages of oocytes were fertilized in
      each group, resulting in the transfer of comparable numbers of embryos (4.5 +/-
      1.1 and 4.4 +/- 1.3 respectively). Comparable clinical pregnancy rates were
      achieved (group A, 36%; group B, 37%). The spontaneous abortion rates were also
      similar (group A, 20%; group B, 12%), resulting in comparable ongoing and
      delivered pregnancy rates per cycle (group A, 29%; group B, 32%) and per embryo
      transferred (group A, 6.4%; group B, 7.3%). In conclusion, women of proven
      fertility should not be excluded from donating oocytes simply because of their
      age. There exists a cohort of fertile women who resist the decreasing fecundity
      and increasing spontaneous abortion rates associated with ageing. With careful
      screening, many women of proven fertility can donate oocytes until the age of 40
      years with an efficacy equal to that of younger women. Given the relative
      shortage of suitable oocyte donors, and increasing requests from recipients with
      previous donor oocyte babies to obtain oocytes from the same, now older, donor,
      the findings of this study are of practical clinical importance.

PMID- 8671335
TI  - Blastocyst formation following intracytoplasmic injection of in-vitro derived
      spermatids into bovine oocytes.
AB  - Various types of male gametes, such as spermatozoa, spermatids and spermatids
      obtained after the in-vitro division of secondary spermatocytes, were injected
      into the in-vitro matured bovine oocytes in order to examine the possibility of
      utilizing in-vitro derived spermatids for intracytoplasmic injection. There were
      no significant differences in the development of bovine oocytes injected with
      various types of male gametes (cleavage rate, 31.0-37.8%; morula rate, 11.1
      18.2%; blastocyst rate, 4.4-1.4%). Similarly, 22.0% of sham-injected oocytes
      (injection of medium plus polyvinylpyrrolidone) cleaved parthenogenetically but
      none of them developed to morula stage. There were no significant differences in
      embryo quality (assessed by cell number) of blastocysts obtained by the
      injections of various types of male gametes (124.0 +/- 9.6-152.5 +/- 15.5). This
      study demonstrates that various types of spermatogenic cells can be used for
      intracytoplasmic injection of oocytes to produce viable embryos.

PMID- 8671336
TI  - Fertilization promoting peptide, a tripeptide similar to thyrotrophin-releasing
      hormone, stimulates the capacitation and fertilizing ability of human spermatozoa
      in vitro.
AB  - Recent studies have demonstrated that a prostatic tripeptide similar in structure
      to thyrotrophin-releasing hormone (TRH) can stimulate the in-vitro capacitation
      and fertilizing ability of epididymal mouse spermatozoa. Therefore we have
      proposed that this tripeptide be referred to as fertilization promoting peptide
      (FPP). Using chlortetracycline fluorescence analysis and the hamster oocyte
      penetration test (HOPT), we have obtained evidence that FPP can also promote the
      capacitation and fertilizing ability of ejaculated human spermatozoa in vitro.
      FPP (25-200 nM) caused a significant increase in the proportion of B-pattern
      uncapacitated cells, with no significant stimulation of acrosomal exocytosis.
      Comparison of FPP with two structurally similar tripeptides, TRH and pyroglutamyl
      phenylalanylprolineamide, at 50 nM revealed that only FPP could significantly
      promote capacitation. Finally, after a brief exposure to progesterone to induce
      acrosomal exocytosis in capacitated cells, FPP-treated suspensions penetrated a
      significantly higher proportion of oocytes than the untreated controls when
      assessed in the HOPT. The presence of FPP in human seminal plasma at
      concentrations similar to those used here suggests that, in vivo, FPP may play a
      positive role in promoting human sperm function.

PMID- 8671337
TI  - Sperm chromatin anomalies can influence decondensation after intracytoplasmic
      sperm injection.
AB  - In this study we investigated whether morphology and chromatin anomalies in human
      spermatozoa can influence fertilization after intracytoplasmic sperm injection
      (ICSI). We examined unfertilized oocytes, using the fluorochrome Hoechst 33342,
      to determine whether a relationship exists between failure of fertilization and
      sperm chromatin quality. Sperm chromatin packaging quality was assessed using the
      chromomycin A3 (CMA3) fluorochrome, and the presence of DNA damage in
      spermatozoa, using in-situ nick translation, Normal males present sperm
      parameters with a normal morphology of > 20%, CMA3 fluorescence of < 30% and
      exhibit endogenous nicks in < 10% of their spermatozoa. When patients were
      separated according to these values no difference was observed in their
      fertilization rates after ICSI. When the unfertilized ICSI oocytes were examined,
      we found that patients with CMA3 fluorescence of <30% and nicks in < 10% of their
      spermatozoa had only 17.5 and 21.6% respectively of their unfertilized oocytes
      containing spermatozoa that remained condensed. In contrast, patients with higher
      CMA3 and nick values had a significantly higher number, 41.2 and 48.9%, of their
      unfertilized oocytes containing condensed spermatozoa. sperm morphology did not
      show any such pattern. The percentage of spermatozoa which had initiated
      decondensation in unfertilized oocytes was not influenced by morphology, CMA3
      fluorescence or nicks. In light of these results we postulate that poor chromatin
      packaging and/or damaged DNA may contribute to failure of sperm decondensation
      after ICSI and result in failure of fertilization.

PMID- 8671338
TI  - Effects of clomiphene citrate stimulation on endometrial structure in infertile
      women.
AB  - Investigations into the effect of clomiphene citrate stimulation on endometrial
      differentiation were retrospectively performed in the mid-luteal phase on 21
      patients undergoing ovulation induction prior to artificial insemination. A high
      incidence of irregular endometrial development was seen using morphological and
      morphometric criteria; in addition, increasing stromal oedema after clomiphene
      citrate treatment was observed. Measurable differences in glandular development
      (i.e. numbers of glands and glandular epithelial height) were found in early
      luteal phase biopsies (LH+2/+6) from patients treated with clomiphene citrate and
      normal fertile controls. Impaired endometrial development in the early luteal
      phase, which is a sensitive interval in preparation for implantation, might lead
      to an effective asynchrony between embryonic and uterine development and
      unfavourably influence the outcome of implantation.

PMID- 8671339
TI  - Stromal cell interaction and relevance to predecidual events and menstruation.
AB  - Endometrial stromal cells play a vital role during decidualization and
      implantation. The aim of this study was to analyse the cyclic ultrastructural
      variations of stromal fibroblasts, granulocytes and blood-derived cells which
      invade the stroma during various stages of the menstrual cycle. Diverse opinions
      exist in the literature regarding the origin, fate and function of the
      endometrial granulocytes. Our study is in agreement with available immunological
      data and shows that (i) fibroblasts and granulocytes are distinct cell types in
      the stroma, (ii) they exhibit distinct changes across the menstrual cycle and
      (iii) fibroblasts are not the common progenitor for granulocytes and predecidual
      cells in the secretory phase endometrium, as suggested by previous investigators.
      The infiltration of eosinophils, platelets, macrophages, neutrophils, etc.,
      during the menstrual phase makes the stroma a potential source of growth factors
      and cytokines which may regulate the process of regression and regeneration of
      the endometrium. Furthermore, we propose that endometrial granulocytes could be
      the source of decidual prolactin because the ultrastructural morphology of their
      secretory granules closely resembles that of the prolactin-secreting cells in the
      pituitary.

PMID- 8671340
TI  - Magnetic resonance relaxation time in evaluating the cyst fluid characteristics
      of endometrioma.
AB  - To determine whether the cyst fluid characteristics of endometrioma can be
      evaluated by magnetic resonance imaging (MRI), 36 endometriomas obtained from 24
      patients (age range 21-43 years; mean 34 years) were studied. MRI was performed <
      2 weeks before laparoscopy or laparotomy. Comparative studies of the density and
      concentration of iron in the endometrioma and the signal intensity (SI) of MRI
      [calculated relaxation time T1 value, calculated relaxation time T2 value, signal
      intensity on a T1-weighted image (T1SI) and on a T2-weighted image (T2SI) of the
      cyst; T1SI/signal intensity of the gluteus maximus muscle (MSI), and T2SI/MSI of
      the cyst] were performed. The density of the cyst fluid and its iron
      concentration were found to be directly proportional. There was a significant
      relationship between the concentration of iron and the T2SI, T2SI/MI and
      calculated T2 values. In particular, the concentration of iron and the ration of
      T2SI/ MSI were inversely proportional. Therefore, T2SI/MSI reflected the
      concentration of iron in endometriomas without recourse to measurement of the
      calculated T2 value, which suggests that the MRI and T2 signal intensity may be
      useful for evaluating the cyst fluid characteristics of endometriomas.

PMID- 8671341
TI  - Decreased amounts of antibodies to 22 and 18 kDa antigens in the peritoneal fluid
      of patients with endometriosis
AB  - Accumulated evidence implicates immunological alterations in endometriosis. The
      purpose of this study was to look for variations in antibodies to distinct
      antigens in peritoneal fluid of women with and without endometriosis. Peritoneal
      fluid was aspirated from 17 women undergoing laparoscopy for tubal ligation and
      37 patients complaining of symptoms of pain and/or infertility. Peritoneal fluid
      antibodies to a standard preparation of peritoneal fluid antigens were detected
      by Western blot analysis using peroxidase-labelled anti-human immunoglobulin G
      antibodies specific to the Fc region. Antibodies to distinct antigens were
      quantified by estimating the ratio of the relative optical density between
      samples and a standard amount of antibodies. Marked changes were found in the
      antibody detection to two antigens having apparent molecular weights of 22 and 18
      kDa. The intensity of the antibody signal was significantly weaker in the
      peritoneal fluid from endometriosis patients (0.36 &plusmn; 0.06 and 0.46
      &plusmn; 0.06) compared with that in women without endometriosis (0.62 &plusmn;
      0.08 and 0.75 &plusmn; 0.06). It was also weaker in patients without
      endometriosis presenting with infertility (0.36 &plusmn; 0.07 and 0.47 &plusmn;
      0.08), but only the 18 kDa antigen result was significant. After adjusting for
      infertility, the P values for the 18 and 22 kDa bands were 0.03 and 0.28 (not
      significant) respectively in the group of endometriosis patients. These changes
      were not related to the phase of the menstrual cycle. These data suggest an
      alteration in the immune response to two distinct antigens in the peritoneal
      fluid from women with endometriosis and infertility. Further evaluation of these
      two antigens and their antibodies would be of interest to help understand
      endometriosis and its associated infertility. Keywords:
      antibodies/antigens/endometriosis/peritoneal fluid/Western blot analysis

PMID- 8671342
TI  - Laparoscopic treatment of deep endometriosis located on the uterosacral
      ligaments.
AB  - The goal of this study was to assess the efficiency of laparoscopic surgical
      treatment of pain for patients presenting deep endometriosis located on the
      uterosacral ligaments. To this end we analysed a continuous series of 21 patients
      treated by laparoscopic surgery between January 1993 and June 1994. In all these
      cases treatment consisted of resection of all the uterosacral ligament(s)
      presenting deep endometriotic lesions together with exercise of all other
      endometriotic lesions. No complications were observed per- or postoperatively.
      The results were assessed for all the patients with a minimum follow-up of one
      year. The efficiency of the treatment varied according to the symptoms. Patients
      who presented dysmenorrhoea (19 cases) improved in 84.2% of cases (16 patients).
      Out of the 17 patients who presented deep dyspareunia, improvement was evident
      for 94.1% of cases (16 patients). The chronic pelvic pain suffered improved in
      seven out of nine cases (77.7%). Patients who benefited from an improvement rated
      it excellent or satisfactory in over 80% of cases. These results demonstrate
      that, provided the surgeon is highly skilled in laparoscopy, laparoscopic surgery
      is efficient for the treatment of patients presenting painful symptoms related to
      deep endometriotic implants located on the uterosacral ligaments.

PMID- 8671343
TI  - Is hormonal treatment efficacious in the management of ovarian cysts in women
      with histories of endometriosis?
AB  - In a controlled, randomized study, we evaluated the effectiveness of various
      hormonal regimens in treating 70 women (mean age 34.7 +/- 5.7 years) who had
      unilateral of bilateral ovarian cysts presumed to be physiological (functional)
      and a history of endometriosis. The patients were assigned randomly to one of the
      following groups: group I (control), no treatment; group II, oral contraceptives
      (35 micrograms ethinyl oestradiol and 1 mg norethindrone); group III, oral
      contraceptives (50 micrograms ethinyl oestradiol and 1 mg norethindrone); group
      IV, danazol 800 mg/day. Serum CA-125 concentrations were measured in 32 women.
      All medications were taken continuously for 6 weeks. Subjects were re-evaluated
      by pelvic examination and transvaginal ultrasound. Those with persistent cysts
      were offered diagnostic and possible operative laparoscopy. As 11 patients did
      not complete the study and five did not follow-up, the final study population
      comprised 54 women. At 6 weeks follow-up, complete resolution of cysts was found
      in: group I, 12 out of 18 (66.7%); group II, five out of none (55.6%); group III,
      eight out of 14 (57.1%); and group IV, seven out of 13 (53.9%). Two of the 22
      women with persistent cysts opted for 6 weeks further medical therapy and
      achieved complete resolution; 19 underwent laparoscopy, and one was lost to
      follow-up. All laparoscopic findings revealed benign masses. We found no
      statistically significant effect when hormonal treatment was compared with
      expectant management. There was no correlation between serum CA-125
      concentrations and the persistence of resolution of cysts.

PMID- 8671344
TI  - Delay in the diagnosis of endometriosis: a survey of women from the USA and the
      UK.
AB  - We investigated the length of time between the onset of pain symptoms and the
      surgical diagnosis of endometriosis in women from the UK and the USA. A total of
      218 women with surgically confirmed disease, recruited through endometriosis self
      help groups, completed a postal questionnaire. The mean +/- SD delay in diagnosis
      for women from the USA was 11.73 +/- 9.05 years, significantly higher than the
      equivalent delay of 7.96 +/- 7.92 years for women from the UK (P < 0.01). The
      stage of disease did not effect the length of time between the onset of symptoms
      and diagnosis. Therefore there is considerable delay in the diagnosis of
      endometriosis for women from both the UK and the USA. Efforts to reduce this
      delay are required to minimize the suffering of women with this disease.

PMID- 8671345
TI  - The role of a single free beta-human chorionic gonadotrophin measurement in the
      diagnosis of early pregnancy failure and the prognosis of fetal viability.
AB  - The prospective controlled study investigated the concentrations of free beta
      human chorionic gonadotrophin (HCG) subunit in 554 women with a singleton
      intrauterine or tubal pregnancy. They presented with vaginal bleeding and/or
      abdominal pain in the first 18 weeks of pregnancy. The control group comprised
      156 women with musculoskeletal pain and no vaginal bleeding. Their pregnancies
      continued to term. The study group comprised 398 women (141 threatened-continuing
      pregnancies, 37 threatened-miscarriages, 185 non-continuing pregnancies and 35
      tubal pregnancies). Free beta-HCG concentrations were significantly lower in the
      non-continuing, threatened-miscarriage and tubal pregnancy groups [mean 4.62,
      6.50 and 4.27 ng/ml respectively; 95% confidence interval (CI) 3.75-5.69, 4.46
      9.48 and 2.92-6.2 respectively] than in the control and threatened-continuing
      groups (mean 41.61 and 48.22 ng/ml respectively; 95% CI 34.53-50.13 and 42.03
      55.32 respectively) (P < 0.001 in all cases). A cut-off value at 20 ng/ml was
      found to differentiate between the 'viable' (control and threatened-continuing)
      and the 'abnormal' (non-continuing, threatened-miscarriage and tubal)
      pregnancies, with 88.3% sensitivity and 82.6% positive predictive value. An
      excellent diagnostic and prognostic usability of free beta HCG was confirmed by a
      receiver operating characteristic curve plot. In conclusion, a single serum free
      beta-HCG measurement taken in early pregnancy is valuable in the immediate
      diagnosis of early pregnancy failure and the long-term prognosis of viability.

PMID- 8671347
TI  - Twin pregnancy following embryo transfer on day 7 of the luteal phase in an
      oocyte donation programme.
AB  - We report a case of a 42 year old female patient with hypergonadotrophic
      hypogonadism requiring oocyte donation. Spontaneous ovulation occurred during a
      hormonal replacement treatment cycle and three embryos were transferred 7 days
      after documented ovulation. This resulted in a viable twin pregnancy. The twins
      were genetically distinct from the mother. To the best of our knowledge this is
      the first reported case of a successful transfer of embryos on day 7 of the
      luteal phase leading to a viable pregnancy in an oocyte donation programme.

PMID- 8671346
TI  - In-vivo study of diazepam transfer across the first trimester human placenta.
AB  - Diazepam transfer by the first trimester human placenta was investigated at
      pregnancy termination between 6 and 12 weeks of gestation. Fetal fluid samples
      were obtained from the exocoelomic and amniotic cavities of 65 pregnancies
      between 8 and 25 min following the i.v. administration of 0.1 mg/kg diazepam to
      the mother. Diazepam was detected in one-third of coelomic fluid samples and two
      thirds of amniotic fluid samples. Maternal serum and urine diazepam
      concentrations correlated negatively and positively respectively, with time from
      drug injection to sampling. Individual diazepam concentrations were low on the
      fetal side, and the corresponding concentrations were independent of maternal
      serum concentrations and the time from drug injection to sampling. Amniotic fluid
      diazepam content increased significantly with advancing gestational age. A
      multiple regression analysis showed that the diazepam content of the coelomic
      fluid was not influenced by maternal serum diazepam concentration, the time from
      drug injection to sampling or gestational age, whereas only gestational age
      contributed to the diazepam content of amniotic fluid. These data demonstrate
      that the placental transfer of diazepam occurs from week 6 of gestation, indicate
      a preferential transfer of this drug to the amniotic cavity and suggest that
      diazepam may accumulate in fetal circulation and tissues during organogenesis.

PMID- 8671348
TI  - Calcitonin gene-related peptide reverses the hypertension and significantly
      decreases the fetal mortality in pre-eclampsia rats induced by NG-nitro-Lmethyl
      ester
AB  - We recently established that the chronic inhibition of nitric oxide production
      with NG-nitro-L-arginine methyl ester (L-NAME) increases blood pressure and fetal
      mortality in pregnant rats. Using this animal model, we have investigated whether
      calcitonin gene-related peptide (CGRP) can reverse the pre-eclampsia-like
      conditions produced by L-NAME. CGRP and L-NAME were chronically infused s.c. into
      pregnant rats separately or together starting on day 17 of gestation; a control
      group was given saline infusions. Systolic blood pressure was measured on
      gestational days 17, 18, 19 and 22 and post-partum days 1 and 2. The weight and
      mortality of the pups were recorded immediately after spontaneous delivery.
      Animals treated with L-NAME exhibited significant elevations of blood pressure on
      days 18, 19 and 22 of gestation and during post-partum, increased pup mortality
      (18.4 versus 0.0%) and decreased pup weights (5.14 &plusmn; 0.07 versus 6.20
      &plusmn; 0.06 g). The co-administration of L-NAME and CGRP prevented the
      gestational (not the post-partum) L-NAME hypertension and decreased pup mortality
      to 6.4% but did not reverse the decreased fetal weight (5.31 &plusmn; 0.06 g).
      Our data indicate that CGRP (i) participates in regulation of the vascular
      adaptations that occur during normal pregnancy, (ii) has beneficial effects on
      the hypertension and increased mortality of experimental preeclampsia, and (iii)
      may exert differential effects on the systemic (i.e. maternal) and fetal
      components of uteroplacental circulation. These findings may have important
      clinical implications. Keywords: CGRP/nitric oxide/pre
      eclampsia/pregnancy/progesterone

PMID- 8671349
TI  - Maternal serum concentrations of pregnancy associated placental protein A and
      pregnancy specific beta-1-glycoprotein in multifetal pregnancies before and after
      fetal reduction.
AB  - Placental function in multifetal pregnancies before and after embryo reduction
      was investigated by measuring maternal serum concentrations of pregnancy
      associated placental protein-A (PAPP-A) and pregnancy specific beta-1
      glycoprotein (SP-1). Three groups of pregnant women were studied following
      assisted reproduction; groups 1 and 2, were 12 singleton and 12 twin pregnancies
      respectively, and group 3 comprised 12 women with multifetal pregnancies
      undergoing embryo reduction. PAPP-A and SP-1 were measured serially at 8-21 weeks
      gestation. In all pregnancies, maternal serum PAPP-A and SP-1 increased with
      gestation. In twin pregnancies the mean concentrations of SP-1 were significantly
      higher than in singletons at all gestations, whereas for PAPP-A, concentrations
      were similar between these groups. In multifetal pregnancies before embryo
      reduction, the serum concentrations of both proteins were significantly higher
      than in twin pregnancies. Following reduction, the concentrations of PAPP-A
      remained significantly higher than for twins throughout, whereas the
      concentrations of SP-1 gradually converged towards those of twins; by 19 weeks
      there was no difference between the means of the two groups. These findings
      suggest that circulating concentrations of SP-1 reflect total placental mass,
      which is proportional to the number of live fetuses, whereas the pattern of PAPP
      A changes suggests that this protein is produced by the placenta, decidua and
      other tissues.

PMID- 8671350
TI  - Impact of the in-vitro fertilization process on emotional, physical and
      relational variables.
AB  - The purpose of the study was to examine the stress associated with in-vitro
      fertilization (IVF) concurrently with other physical and relational variables,
      and to compare these reactions with those reported during a menstrual cycle
      without treatment. Women (n = 20) completed a daily symptom checklist for one
      complete menstrual cycle without treatment and one complete IVF cycle. The
      checklist included items related to stress, optimism, physical discomfort and
      marital and social relationships. Daily ratings during IVF were compared with
      those obtained during the no-treatment menstrual cycle. IVF was associated with
      more stress, optimism and physical discomfort than a menstrual cycle without
      treatment, and with greater changes to marital and social relationships. The
      pattern of results shows that the stress associated with IVF is less salient when
      examined in the context of reactions in other areas of functioning. The findings
      suggest that the emotional impact of IVF might be less pronounced during the
      actual treatment process than is generally assumed from studies focusing on the
      impact of treatment failure. Variables such as optimism and physical discomfort
      which have previously received less attention in the literature were
      significantly affected by IVF treatment.

PMID- 8671352
TI  - The ETEP protocol for recurrent miscarriage.

PMID- 8671353
TI  - Letter. The ETEP protocol for recurrent miscarriage

PMID- 8671351
TI  - Ethical and legal aspects of assisted reproduction practice in Asia.
AB  - This report describes the ethical and legal aspects of assisted reproduction
      technology (ART) that have been instituted in Asian countries. The data were
      collected by a questionnaire circulated to ART units in Asia. These are Taiwan,
      Singapore, Korea, Indonesia, Thailand, Japan, Iran, India, Jordan, Malaysia,
      China, Israel, Hong Kong, Pakistan, Lebanon, Saudi Arabia, and Persian Gulf
      countries. According to the survey, there are approximately 260 ART centers in
      Asia (half of which are in Japan). On a global basis each ART centre in Asia
      serves an average population of 13 million people. On the other hand, in those
      Asian countries where the standards of living are relatively high, the
      availability of ART services, including the more sophisticated and costly ART
      procedures like micromanipulation, is similar to that in the Western world. In
      most of the Asian countries practising ART, however, no state registry exists.
      Taiwan is the only country that has specific legislation, and in six other
      countries some kind of ministerial regulations are practised. We conclude that
      ART is now practised in 20 countries in Asia. The prevailing rules and cultural
      heritage in many of these Asian countries has a major influence on the
      implementation of ART in Asia. However, in view of the complicated and sensitive
      issues involved, and as no supervision on ART clinics exists in most of the Asian
      countries, we advocate that some kind of quality control should be urgently
      instituted in all centres practising ART. In this way, it is hoped that the
      highest standards be attained for all parties concerned.

PMID- 8671354
TI  - Trend of spontaneous abortions in Italy 1980-91.

PMID- 8671355
TI  - Twins of different races: choice or technical blunder.

PMID- 8671356
TI  - Colour Doppler imaging and polycystic ovary syndrome.

PMID- 8671357
TI  - Letter. Colour Doppler imaging and polycystic ovary syndrome

PMID- 8671358
TI  - Time to revolutionize ovarian stimulation.

PMID- 8671359
TI  - Is ICSI associated with risks of genetic disease? Implications for counselling,
      practice and research.

PMID- 8671360
TI  - The risk of chromosomal abnormalities following ICSI.

PMID- 8671361
TI  - Micromanipulative assisted fertilization - still clinical research.

PMID- 8671362
TI  - Debate. Assisted reproductive techniques - are we avoiding the genetic issues?

PMID- 8671363
TI  - Micro-assisted fertilization and sperm chromosome abnormalities.

PMID- 8671364
TI  - Genetic anomaly and ICSI.

PMID- 8671365
TI  - Laparoscopic myomectomy today. Why, when and for whom?

PMID- 8671366
TI  - Genetic and non-genetic determinants of the human sex ratio at birth.

PMID- 8671367
TI  - Gamete donation mirrors society.

PMID- 8671368
TI  - Recovery of corpus luteum function after prolonged deprivation from gonadotrophin
      stimulation.
AB  - Three women with hypogonadotrophic hypogonadism, all desiring pregnancy,
      participated in a prospective open study attempting to assess the ability of the
      human corpus luteum to recover after 7 days of deprivation from gonadotrophin
      stimulation. Follicular growth was induced by gonadotrophins. An endogenous
      luteinizing hormone (LH) surge was induced by the s.c. injection of a
      gonadotrophin-releasing hormone agonist. For luteal support, 10 mg/day oral
      medroxyprogesterone acetate were given for 7 days, after which a single i.m.
      injection of human chorionic gonadotrophin (HCG) was administered. Monitoring
      during the follicular phase consisted of daily measurements of serum oestradiol,
      LH and follicle stimulating hormone (FSH) concentrations, and of follicular
      growth by transvaginal ultrasonography. During the luteal phase, monitoring
      consisted of measurements of serum concentrations of LH, FSH, oestradiol,
      progesterone, 17-hydroxyprogesterone and beta-HCG. Ovulation and luteinization
      occurred in two patients, demonstrated by transient marked increases in serum
      progesterone and 17-hydroxyprogesterone concentrations which decreased to basal
      preovulatory values and increased again following the administration of HCG 7
      days later. In the third patient, ovulation and luteinization did not occur, and
      the subsequent administration of HCG did not result in an increase in
      progesterone concentration. Of the two patients who ovulated, one conceived and
      the second had a luteal phase of 15 days duration. Our preliminary results
      suggest that the human corpus luteum can be 'rescued' and can function normally
      after 7 days of deprivation from gonadotrophin stimulation in patients with
      hypogonadotrophic hypogonadism.

PMID- 8671369
TI  - Twenty-four hour patterns of prolactin secretion during lactation and the
      relationship to suckling and the resumption of fertility in breast-feeding women.
AB  - In breast-feeding women prolactin released in response to suckling is essential
      for the maintenance of lactation. This physiological hyperprolactinaemia is also
      associated with lactational infertility. However, it is not clear whether there
      is any direct relationship between changes in prolactin per se and the duration
      of infertility. To address this question, our study determined the pattern of
      prolactin secretion in relation to suckling and the return of ovarian activity in
      the same cohort of breast-feeding women. Blood samples were withdrawn at 10 min
      intervals for 24 h from 09:00 to 09:00 h at either 4 (n = 9) or 8 weeks (n = 11)
      post-partum when the women had completely suppressed ovarian activity, at the
      time of the introduction of supplements to the baby (n = 17), a time associated
      with reduction of suckling activity, at first menses while still breast-feeding
      (n = 13) and in the follicular phase (n = 9) of the first menstrual cycle after
      weaning. During sampling, mothers and babies continued their normal pattern of
      suckling activity. The pattern of prolactin release was very variable at each
      stage of lactation, depending on the pattern of suckling. Frequent suckling was
      associated with elevated prolactin concentrations during the 24 h period
      throughout lactation. When suckling was less frequent, prolactin concentrations
      fell to baseline values between breast-feeds, but prolactin was released in
      response to all suckling episodes. An increase in prolactin concentrations at
      night, independent of suckling, was only evident once breast-feeding had ceased.
      The prolactin response to suckling declined significantly only after the return
      of menses at 33.6 +/- 3.5 weeks post-partum. There was no relationship between
      the duration of amenorrhoea and the plasma concentrations of prolactin over 24 h,
      or day or night separately, throughout lactation. However, there was a strong
      correlation (r = 0.843; P < 0.01) between the timing of the introduction of
      dietary supplements to the baby and the duration of amenorrhoea. These results
      suggest that there may be no precise link between the release of prolactin during
      lactation and the duration of lactational infertility in breast-feeding women.

PMID- 8671370
TI  - The influence of dietary sodium restriction on renal and ovarian renin and
      prorenin production during ovarian stimulation.
AB  - In a prospective study, the effect of dietary sodium restriction on plasma and
      follicular fluid renin and prorenin concentrations and on fertilization measures
      was investigated during ovarian stimulation. In all, 18 women undergoing ovarian
      stimulation for in-vitro fertilization and embryo transfer were randomly divided
      into groups with and without sodium restriction. Plasma renin and prorenin
      concentrations were higher in the low sodium than in the normal sodium group.
      Plasma renin concentrations showed a mid-luteal rise. Plasma prorenin
      concentrations increased 4-fold on the day of oocyte retrieval, followed by a
      gradual decline to basal values. The low sodium group had more follicles than the
      normal sodium group. Neither follicular fluid renin and prorenin concentrations,
      nor the total amount of follicular fluid renin and prorenin per ovary differed
      significantly between the two groups. Oocyte yield and fertilization rates were
      similar in both groups. These rates were correlated with neither renin nor
      prorenin concentrations in follicular fluid. We conclude that sodium restriction
      did not influence cyclic plasma variation of renin or prorenin or follicular
      fluid renin and prorenin concentrations. In addition, fertilization rates were
      not affected by sodium restriction.

PMID- 8671371
TI  - Oestradiol and immunoreactive inhibin-like secretory patterns following
      controlled ovarian hyperstimulation with urinary (Metrodin) or recombinant
      follicle stimulating hormone (Puregon).
AB  - Inhibin (and its alpha-subunit) may be of particular value as a marker for
      follicular development in in-vitro fertilization (IVF) in comparison with the
      classic follicle stimulating hormone (FSH)-dependent marker oestradiol in
      patients following pituitary desensitization and treatment with recombinant FSH
      (rFSH). This preparation lacks luteinizing hormone (LH), which is essential for
      thecal cell androgen secretion and thus oestradiol production. Our study has
      assessed oestradiol and immunoreactive inhibin-like secretion following ovarian
      stimulation with rFSH or a purified urinary FSH preparation (Metrodin) (uFSH). A
      randomized, assessor-blind study was initiated using patients receiving a single
      treatment cycle of IVF (using fresh embryos) following pituitary desensitization
      with intranasal buserelin (500 microg daily) and the i.m. injection of either
      rFSH (n = 38) or uFSH (n = 17). Ovarian ultrasound examinations were performed
      and bloods (10 ml) collected prior to FSH treatment and every 1-2 days until
      ovulation induction with human chorionic gonadotrophin. LH and FSH concentrations
      were measured by an immunoradiometric assay, and inhibin-like immunoreactivity by
      a radioimmunoassay and an enzyme-linked immunosorbent assay, both with alpha
      subunit specificity. Oestradiol concentration was measured with a coated tube
      radioimmunoassay. Following desensitization, basal LH, FSH and oestradiol
      concentrations were measured, as was that of immunoreactive inhibin. Following
      treatment with either rFSH or uFSH, LH concentrations remained low while FSH
      concentrations rose to a plateau of 5.6-6.7 IU/l in both groups. In contrast, the
      concentration of oestradiol was higher (P < 0.05) with rFSH than with uFSH in the
      last four days of treatment, a pattern that was repeated for inhibin-like
      immunoreactivity. The change in oestradiol and inhibin concentrations during
      treatment was approximately 2-fold higher with rFSH. The total number of
      follicles obtained with rFSH was similar to that with uFSH. However, the number
      of follicles with a diameter of >/= 15 mm was higher the rFSH group, and there
      was a concomitant increase in the number of oocytes recovered. Oestradiol
      concentration and inhibin-like immunoreactivity (determined by either method)
      were associated with total follicle number and number of follicles >/= 15 mm in
      diameter, as well as with each other (P < 0.001). When ovarian hormone output was
      normalized per follicle produced, oestradiol output was higher for rFSH than for
      uFSH P = 0.04). Inhibin output was clearly higher using rFSH than uFSH. There
      were seven pregnancies (one miscarriage) with rFSH and two with uFSH. Despite
      similar concentrations od FSH in patients, rFSH (Puregon) appears to be more
      potent in vitro in terms of follicular number, ovarian hormone secretion (both
      concentration and output/follicle) and oocyte recovery. In both groups, LH
      concentrations of approximately 1.3 IU/l were sufficient to support oestradiol
      secretion similar to that normally found in IVF programmes using human menopausal
      gonadotrophin preparations containing large amounts of LH. Despite known problems
      of specificity with the assays od inhibin, its measurement was of similar value
      to oestradiol as a marker of follicular development.

PMID- 8671372
TI  - Adipocyte insulin action during the normal menstrual cycle.
AB  - The relationship between the menstrual cycle and insulin sensitivity is unclear.
      The aim of this study was to investigate insulin sensitivity during the normal
      menstrual cycle using the physiological insulin target organ adipose tissue. A
      total of 23 normal healthy volunteers were studied, nine of whom were in the
      follicular phase, and 14 of whom were age and body mass index-matched and in the
      luteal phase of the menstrual cycle. Adipocyte insulin receptor binding was
      measured and adipocyte insulin action was assessed by measuring initial rates of
      3-O-methylglucose uptake and by inhibition of lipolysis. The maximum specific
      insulin receptor binding was significantly higher in subjects studied during the
      follicular phase of the menstrual cycle compared to subjects studied during the
      luteal phase (1.81 +/- 0.13 versus 1.36 +/- 0.15% per 10 cm2 cell surface, P <
      0.05). Maximum rates of 3-O-methylglucose transport were 1.70 +/- 0.22 versus
      1.75 +/- 0.22 pmol/10 cm2/5 s in the follicular and luteal phase respectively and
      were not significantly different between the two groups. The maximum percentage
      lipolysis inhibition observed was 42. 5 +/- 7.5% in the follicular phase and 39.9
      +/- 7.4% in the luteal phase (not significant). This study demonstrated that
      there is a reduction in insulin receptor binding in the luteal phase of the
      normal ovulatory menstrual cycle. The post-receptor action of insulin is not
      affected between the two phases of the menstrual cycle.

PMID- 8671373
TI  - European consensus development conference on menopause. European Menopause
      Society.
AB  - A Consensus Development Conference was organized by the European Menopause
      Society (EMS) and held from September 8-10, 1995 in Montreux, Switzerland. The
      consensus was based on public lectures presented by international experts. More
      than 1300 people interested in the menopause assisted at the presentations,
      including representatives of the European National Menopause Societies, the
      International Menopause Society, the pharmaceutical industry and several national
      health services. After a closed meeting, the panel presented its proposition to
      the delegates and discussed the Consensus Proposition with the audience before
      the final proposition was adopted. The aim of the EMS was to present common basic
      principles accepted by all European countries. Such a consensus has been missing
      until now, when the multitude of different and sometimes contradictory approaches
      in use today in Europe are considered.

PMID- 8671374
TI  - Progesterone-induced immunosuppression is not mediated through the progesterone
      receptor.
AB  - Progesterone is a known immunosupressant in humans and may be important in
      treatment regimens for women with immunological and endocrinological reproductive
      failure. The molecular mechanism of progesterone-mediated immunosuppression
      remains controversial. We used the reverse transcriptase polymerase chain
      reaction (RT-PCR) technique to detect progesterone receptor RNA in human
      peripheral blood mononuclear cells (PBMCs). No expression could be documented in
      PBMCs from men or women representing various reproductive states. We also used
      the glucocorticoid receptor antagonist RU 43044 to address the hypothesis that
      progesterone exerts immunomodulatory effects via interactions with the
      glucocorticoid receptor. Both hydrocortisone (10(-6) and 10(-7) M) and
      progesterone (10(-5), 10(-6) and 10(-7) M) inhibited phytohaemagglutinin-induced
      lymphocyte proliferation in a dose-dependent fashion. RU 43044 (10(-5) M)
      significantly reversed the immunosuppressive effect od hydrocortisone but not
      that of progesterone. These studies indicate that human PBMCs do not express the
      classical progesterone receptor. Our results further suggest that progesterone
      does not mediate its immunomodulatory effects via interaction with the
      glucocorticoid receptor. Interaction with other members of the steroid and
      thyroid hormone receptor superfamily, local conversion to other steroid
      substances or non-classical receptor-mediated mechanisms may be involved.

PMID- 8671375
TI  - Beyond recanalizing proximal tube occlusion: the argument for further diagnosis
      and classification.
AB  - Proximal tube occlusion (PTO) accounts for 20% of tubal factor cases. The
      classification into nodular (salpingitis isthmica nodosa or endometriosis), non
      nodular (true fibrotic occlusion) and so-called pseudo occlusion (detritus,
      polyps, hypoplastic tubes) is essential. Using falloposcopy, PTO that is already
      diagnosed by laparoscopy and hysterosalpingography (HSG) can be confirmed or
      bypassed (false PTO); patients with false PTO were placed on a temporary waiting
      period. Nodular and pseudo occlusion patients were pre-treated with gonadotrophin
      releasing hormone analogue (GnRH-a) for at least 6 weeks to shrink the underlying
      pathology, after which tubal re-catheterization was performed. In a prospective
      study starting in July 1993, 53 patients prediagnosed as having PTO were examined
      by falloposcopy. Three of these patients had non-nodular occlusion and were
      directed to microsurgical repair (conservative treatment not possible). A total
      of 19 cases revealed patent tubes with healthy mucosa and no underlying pathology
      (false PTO). Of the remaining 31 patients, 18 were classified as nodular and 13
      as pseudo occlusion. In all of these patients at least one tube was patent after
      GnRH-a treatment. After a 6 month period, 37% of the false PTO patients achieved
      a spontaneous pregnancy (6% per cycle). The spontaneous pregnancy rate in the
      true PTO group was significantly lower (10% per patient, 1.6% per month; P <
      0.05). Using assisted reproduction techniques, in particular gamete intra
      Fallopian transfer (GIFT), as a subsequent treatment for the true PTO group, a
      pregnancy rate of 50% per cycle was achieved. A retrospective analysis of our
      entire PTO population (n = 109) showed a spontaneous pregnancy rate after
      achieving tubal patency (using falloposcopy and GnRH-a) that was dramatically low
      (1.8%), with no difference between the nodular and pseudo groups. The chance for
      pregnancy can be enhanced significantly (P < 0.001) using assisted reproduction
      techniques (GIFT) following tubal re-catheterization and GnRH-a treatment.

PMID- 8671377
TI  - Treatment of adnexal torsion using operative laparoscopy.
AB  - The aim of this work was to clarify the value and application of operative
      laparoscopic treatment for adnexal torsion. We included in our study all patients
      (n = 27) who presented with an intra-operative diagnosis of torsion of the adnexa
      between January 1989 and May 1995. A total of 28 adnexal torsions were treated.
      Treatment was carried out by laparoscopic surgery in 75% of cases (21 torsions):
      in one-half of the cases (14 torsions) it was possible to achieve conservative
      laparoscopic treatment. The nature of the lesions and the experience of the
      surgeons are two factors which closely govern the outcome of surgical treatment.
      For those patients presenting a benign pathology, laparoscopic surgery was used
      to treat 84% of cases in the series. All the patients presenting a benign
      pathology and operated upon since 1993 have received laparoscopic surgical
      treatment. No major complications (peritonitis, thrombotic emboli, coagulation
      problems) were observed after conservative laparoscopic surgery. These results
      demonstrate that, provided the surgeons are sufficiently experienced, treatment
      by conservative laparoscopic surgery for adnexal torsion is both safe and
      reliable. In the years to come more work must be done to assess the vitality of
      the adnexa so that as many patients as possible can benefit from conservative
      treatment.

PMID- 8671376
TI  - Post-operative adhesions after laparoscopic electrosurgical treatment for
      polycystic ovarian syndrome with the application of Interceed to one ovary: a
      prospective randomized controlled study.
AB  - In this prospective, randomized, controlled clinical study, 21 women underwent a
      second-look laparoscopy 2-11 weeks after standardized laparoscopic
      electrosurgical treatment for polycystic ovarian syndrome (PCOS). Following
      bilateral ovarian treatment, one ovary was randomly chosen to have Interceed
      applied to its surface using a specially designed applicator, with the other
      ovary serving as a control. Peri-adnexal adhesions of significant extent and
      severity developed in 57% of the women and 38% of the adnexa. The incidence of
      adhesions on the Interceed-treated side was 43%, while on the control side it was
      33%. In addition, the extent and severity of the adhesions appeared to be similar
      on the Interceed-treated and control side. However, larger numbers would be
      required to determine statistically the effects of Interceed on de-novo adhesion
      formation after laparoscopic electrosurgical treatment of PCOS, as described
      here.

PMID- 8671378
TI  - Transvaginal hysterosonographic evaluation of septate uteri: a preliminary
      report.
AB  - The objective of this study was to evaluate the diagnostic value of
      hysterosonography in septate uterine congenital abnormalities and more
      particularly in septate uteri. A total of 14 patients with a history of repeated
      spontaneous abortion or infertility who had previously undergone
      hysterosalpingography were included in this study. Patients were first examined
      by standard transvaginal ultrasound. Hysterosonography was then carried out by
      the intrauterine injection of an isotonic saline solution. The septate uteri were
      diagnosed by hysterosonography in all 14 patients (100%). Hysterosonography
      permitted the measurement of the thickness and height of the septum.
      Hysterosonography and transvaginal ultrasound enabled the correct diagnosis of
      malformation type in eight cases (57%). The accuracy of hysterosonography in
      postoperative control was greater than that of hysteroscopy. Transvaginal
      hysterosonography with saline solution is a low-cost, easy and helpful
      examination method for septate uteri. We propose that hysterosonography should be
      performed for the primary investigation of infertility and repeated miscarriages.

PMID- 8671379
TI  - Does the absence or presence of seminal fluid matter in patients undergoing
      ovulation induction with intrauterine insemination?
AB  - Sperm preparations for intrauterine insemination (IUI) generally do not include
      seminal fluid, and it is not known whether the absence of this component affects
      pregnancy rates. Therefore we evaluated the effect of high intravaginal seminal
      fluid deposition on clinical pregnancy rates in patients undergoing ovulation
      induction and IUI therapy. A prospective, randomized, double-blind study was
      designed for an infertile population in a university-based infertility practice.
      Patients were randomized to receive high vaginal deposition of either seminal
      fluid separated from the husband's ejaculate (study group) or normal saline
      solution (control group). Intercourse was restricted. A comparison of clinical
      pregnancy rates per cycle between study and control groups showed no significant
      difference between them [22/164 (13.4%) and 19/155 (12.3%) respectively].
      Furthermore, in non-participants with unregulated intercourse, the pregnancy rate
      per cycle was not significantly different (40/307; 13.0%). Miscarriage rates
      between the study and control groups were similar. As high intravaginal
      deposition of seminal fluid at the time of IUI does not improve the clinical
      pregnancy rate in patients undergoing ovulation induction and IUI therapy, our
      study suggests that, after ejaculation, clinically significant biological
      contributions of seminal fluid to the achievement of pregnancy are bypassed by
      well-timed IUI.

PMID- 8671380
TI  - Background pregnancy rates in an infertile population.
AB  - The objective of this cohort study was to determine the true spontaneous
      background pregnancy rate in an infertile population. A total of 9079 treatment
      months in infertile couples with infertility of a least 1 year's duration were
      recorded in a medical school affiliated infertility setting. Results indicated
      that the spontaneous clinical pregnancy rate in an infertile population was 2.
      02% per inactive treatment month, resulting in a cumulative rate after 12 months
      of 19.9%. It was concluded that couples with a history of infertility have a low
      but significant background pregnancy rate, which needs to be considered alongside
      the effectiveness of various treatment modalities.

PMID- 8671381
TI  - Hydrosalpinx affects the implantation of previously cryopreserved embryos.
AB  - The presence of hydrosalpinx has been reported to negatively affect the pregnancy
      and implantation rate after in-vitro fertilization (IVF) with embryo transfer.
      Hydrosalpinges are able to enlarge during ovarian stimulation with a possible
      increased passage of tubal fluid into the endometrial cavity. We report the
      effect of hydrosalpinges during the transfer of previously cryopreserved/thawed
      embryos during a natural cycle. In all, 14 transfers in 0 patients with a
      sonographically-documented hydrosalpinx during the studied cycle (group I) were
      compared to 98 cycles in 74 patients with tubal disease but no such sonographic
      finding (group II). Both pregnancy and implantation rates were significantly
      lower in group I (7.14 versus 24.49% and 5.0 versus 10. 8% respectively). The
      presence of hydrosalpinx negatively affects pregnancy and implantation rates
      during natural cycles.

PMID- 8671382
TI  - Outcome of intracytoplasmic sperm injection with testicular spermatozoa in
      obstructive and non-obstructive azoospermia.
AB  - From 1 August 1993 until 30 September 1994, 69 couples suffering from azoospermia
      underwent testicular sperm extraction and intracytoplasmic sperm injection. In 50
      couples with obstructive azoospermia a total of 631 metaphase-II oocytes were
      injected after testicular sperm extraction yielding a 2-PN fertilization rate of
      57%. In female patients <40 years of age an ongoing pregnancy rate per transfer
      of 42% (14/33) was obtained. So far, eight healthy babies have been born,
      including two singletons and three twin gestations. In 19 couples with non
      obstructive azoospermia a total of 264 metaphase-II oocytes were injected after
      testicular sperm extraction, yielding a 2-PN fertilization rate of 58%. An
      ongoing pregnancy rate per transfer of 31% (5/16) was established. So far, six
      healthy babies have been born including one singleton, one twin and one triplet
      gestation.

PMID- 8671383
TI  - The outcome of intracytoplasmic sperm injection is unrelated to 'strict criteria'
      sperm morphology.
AB  - Sperm morphology was assessed according to the 'strict criteria' established for
      in-vitro fertilization treatment in the semen samples used for 354 consecutive
      treatment cycles for intracytoplasmic sperm injection (ICSI). The semen samples
      were classified according to the three predictive categories of the Tygerberg
      strict criteria: excellent prognosis (>14% morphologically normal spermatozoa),
      good prognosis (4-14%) and poor prognosis (<4%). It was found that 37 (10.5%) of
      the ICSI cycles belonged to the excellent prognosis category, 197 (55.6%) to the
      good prognosis category, and 120 (33.9%) to the poor prognosis category. The
      outcomes of the ICSI treatments were evaluated and compared with the sperm
      morphology classification in order to determine whether the strict criteria could
      aid in predicting the outcome of ICSI. The fertilization rates in the three
      categories were 61.6, 66.8, and 61.9%, the pregnancy rates per oocyte retrieval
      18.9, 24.9, and 28.3%, and the implantation rates 9.9, 13.0, and 14.9%
      respectively. No significant differences were found in fertilization, pregnancy,
      or implantation rates between the three prognosis categories, i.e. the poor
      prognosis category had an equal chance of obtaining pregnancy compared with the
      good prognosis category. The results indicate that strict sperm morphology is not
      related to the outcome of ICSI.

PMID- 8671384
TI  - Aggressive sperm immobilization prior to intracytoplasmic sperm injection with
      immature spermatozoa improves fertilization and pregnancy rates.
AB  - This study was conducted to determine whether the mode of sperm immobilization
      prior to intracytoplasmic sperm injection (ICSI) influences fertilization by
      immature spermatozoa. Of the 837 ICSI cycles evaluated, 81 were performed with
      epididymal or testicular spermatozoa; 35 cycles with epididymal spermatozoa
      immobilized in the standard fashion resulted in fertilization and pregnancy rates
      of 48.3 and 51.4% respectively. When a more aggressive sperm immobilization
      technique (i.e. permanently crimping the sperm flagellum between the midpiece and
      the rest of the tail) was applied in 17 cycles, the resultant fertilization and
      pregnancy rates were significantly (P < 0.05) higher: 82.0 and 82.4%
      respectively. Similar increases in fertilization and ensuing pregnancy rates were
      also observed in ICSI cycles with the aggressive immobilization of frozen-thawed
      epididymal spermatozoa (eight cycles) versus standard immobilization (16 cycles).
      However, the fertilization rates for ICSI using testicular spermatozoa (five
      cycles) were basically the same, regardless of the immobilization technique.
      Furthermore, for ejaculated spermatozoa (756 cycles), the fertilization rates
      following aggressive sperm immobilization were also positively affected (73.4%),
      although no statistical differences in the clinical pregnancy rates were found.
      Because aggressive immobilization appears to affect sperm membrane
      permeabilization, the enhanced fertilization patterns observed in immature
      spermatozoa following aggressive immobilization may suggest a different membrane
      constitution in these spermatozoa. These findings indicate that immature gametes
      may require additional manipulation to enhance the post-ICSI events essential for
      adequate nuclear decondensation.

PMID- 8671385
TI  - Prediction of the in-vitro fertilization (IVF) potential of human spermatozoa
      using sperm function tests: the effect of the delay between testing and IVF.
AB  - To examine the diagnostic significance of several criteria of semen quality and
      to determine whether their prognostic value is eroded by the time interval
      between assessment and the attempt at in-vitro fertilization (IVF) with embryo
      transfer, 73 couples undergoing IVF and embryo transfer therapy were studied. The
      ability of human spermatozoa to achieve fertilization in vitro was examined in
      relation to the conventional semen profile, sperm morphology, the computer-aided
      assessment of sperm movement, ionophore-induced acrosome reaction, acridine
      orange staining, and chemiluminescent signals induced by phorbol ester and N
      formyl-methionyl-leucyl-phenylalanine (FMLP). Spermatozoa were examined both in
      semen and after preparation on Percoll, some weeks prior to IVF. Fertilization
      rates were noted to be significantly correlated with elements of sperm movement
      characteristics, sperm morphology, and reactive oxygen species generation.
      Prediction of fertilization rates in a stepwise multiple regression analysis was
      obtained using four variables: sperm morphology, FMLP-induced chemi-luminescence
      and sperm movement characteristics (beat cross frequency and straightness) (r
      approximately 0.5). When multiple logistic regression analysis was used to
      predict which samples would achieve fertilization rates above and below a 50%
      threshold, three variables of predictive value including linearity, average path
      velocity and FMLP-induced chemiluminescence were selected. Combination of these
      variables classified the samples achieving good or poor fertilization with an
      overall accuracy of 83.6%. The time interval between semen assessment and IVF had
      little effect on the predictive value of these tests. In conclusion, the
      fertilizing ability of human spermatozoa is related to sperm morphology,
      attributes of sperm movement and reactive oxygen species production. The time
      delay between testing and IVF did not appear to affect predictive accuracy.

PMID- 8671386
TI  - A combination of norethindrone acetate and leuprolide acetate blocks the
      gonadotrophin-releasing hormone agonistic response and minimizes cyst formation
      during ovarian stimulation.
AB  - A protocol utilizing both leuprolide acetate (LA) and norethindrone acetate
      (NETA) in subjects undergoing ovarian suppression prior to follicle aspiration
      proved more effective than LA alone in reducing the incidence of ovarian cyst
      formation without affecting clinical outcome. Patients (n = 105) undergoing
      ovarian stimulation followed by follicle aspiration and in-vitro fertilization
      (IVF) were prospectively randomized and studied. Study measures included ovarian
      suppression days, days of human menopausal gonadotrophin (HMG) stimulation, serum
      oestradiol concentrations, number of cycles developing de novo cysts (>15 mm),
      number of induced flare responses (day 8 oestradiol >=50 pg/ml), number of office
      visits, total dose exogenous gonadotrophins, number oocytes retrieved, and
      clinical pregnancy and delivery rates per retrieval. Patients undergoing IVF
      received either LA alone (n = 58; controls) or LA and NETA (n = 47; study group)
      for the first 8 days of their cycle. Results comparing NETA/LA versus LA
      demonstrated: serum oestradiol 20.7 +/- 3.9 versus 57.3 +/- 9.4 pg/ml
      respectively on day 8 of ovarian suppression (P P < 0.01); and only three
      individuals (6.4%) using NETA/LA developed ovarian cysts >15 mm compared to 15
      (25.9%) controls (P < 0.01). No differences were observed for days of
      stimulation, peak oestradiol attained, total dosage of exogenous gonadotrophins,
      or number of aspirated oocytes. Neither were there differences in the clinical
      pregnancy (26.8 versus 22.6%) nor in delivery rates (19.5 versus 20. 8%). We
      conclude that the addition of NETA to LA enhances ovarian suppression and lessens
      ovarian cyst formation, thereby significantly decreasing the overall cost per
      cycle.

PMID- 8671387
TI  - The role of pregnancy-specific beta-1 glycoprotein (SP1) in assessing the human
      blastocyst quality in vitro.
AB  - The advent of new culture techniques resulting in more than 60% of embryos
      developing in vitro to the blastocyst stage suggests that blastocyst transfer in
      humans with its potential to increase in-vitro fertilization success rates could
      be a feasible option. Blastocyst quality markers, however, are required to ensure
      that an increase in numbers is not achieved at the expense of lowering quality.
      We have previously reported a morphology based method for grading blastocysts.
      The current study sought to determine whether the secretion of pregnancy-specific
      beta-1-glycoprotein (SP1) (a trophoblast product known to be associated with
      fetal well-being) by blastocysts of differing quality was reflected in the
      morphological grading. SP1 concentrations were measured in the culture medium of
      grade 1 (n = 19), grade 2 (n = 4) and grade 3 (n = 4) blastocysts as well as
      vacuolated morulae (n = 6) daily from day 1 to day 14. Cumulative SP1
      concentrations secreted by blastocysts were significantly higher than those
      secreted by vacuolated morulae. However, SP1 levels could not distinguish between
      blastocysts of differing morphological grades. The inconsistent pattern of
      secretion suggests that at this early stage of development, SP1 secretion is
      probably not sufficiently defined to allow any differences in levels to be
      reflected by the morphological grading.

PMID- 8671388
TI  - Improved fertilization and implantation rates after non-touch zona pellucida
      microdrilling of mouse oocytes with a 1.48 microm diode laser beam.
AB  - The safety of microdrilling the zona pellucida of mouse oocytes with a 1.48
      microm diode laser has been investigated by determining the ability of mouse
      oocytes to fertilize in vitro and develop in vivo. Mice born after transfer of
      control and zona pellucida-microdrilled embryos into foster mothers were
      submitted to anatomical and immunohistochemical investigations, and their
      aptitude to breed was assessed in two subsequent generations. Decoronization of
      the oocytes with hyaluronidase induced a reduction of the fertilization and
      implantation rates, which was attributed to a zona hardening phenomenon. After
      laser zona pellucida microdrilling, these rates were restored to those obtained
      with embryos derived from untreated oocyte-cumulus complexes. Pups derived from
      zona pellucida microdrilled embryos were comparable with those obtained from
      control embryos, confirming the lack of deleterious effects of the laser
      treatment. In conclusion, the 1.48 microm diode laser allows safe microdrilling
      of the zona pellucida of mouse oocytes after decoronization with hyaluronidase.
      Based on the health of the F2 generation and the lack of neuroanatomical and
      neurochemical differences, we concluded that this technology may be investigated
      in the human, particularly when the zona pellucida represents the main impediment
      for fertilization or embryo hatching.

PMID- 8671389
TI  - Fractal analysis of capacitating human spermatozoa.
AB  - While head centroid-derived kinematic values have been determined for the
      trajectories of hyperactivated human spermatozoa, the definitions are not robust
      with respect to image sampling frequency and track analysis methods. The
      determination of the fractal dimension of a trajectory has been suggested as an
      alternative descriptive parameter for hyperactivated motility. Here, we have
      investigated two methods for the determination of the fractal dimension of a
      trajectory. A simple but useful equation was found to be: D = log(n)/[log (n +
      log (d/L)], where the n is the number of intervals in the trajectory, d is the
      planar extent of the curve and L is the length of the trajectory. This equation
      was not influenced by scaling of the trajectory. A fractal dimension (D) >=1.30
      was found to define hyperactivated trajectories, and D <= 1.20 defined non
      hyperactivated trajetories, reconstructed at both 30 and 60 Hz. However, when
      circling tracks were studied, all had D > 1.30, even though they were classified
      as non-hyperactivated by curvilinear velocity and/or amplitude of lateral head
      displacement values. An analysis of a series of non-ideal track segments
      suggested a relationship between a track's linearity and its fractal dimension.
      It was determined by a linear regression analysis that the fractal dimension of a
      trajectory was inversely proportional to its linearity (r = -0.77, P < 0.001).
      Although the fractal dimension of a trajectory is a good indicator of its
      regularity (describing its space-filling properties), it should not be used as
      the sole criterion for the classification of a trajectory as hyperactivated.

PMID- 8671390
TI  - Comparative study of the effect of human cervical mucus and a cervical mucus
      substitute, Healonid, on capacitation and the acrosome reaction of human
      spermatozoa in vitro.
AB  - The present study was designed to investigate the effect of human cervical mucus
      on capacitation and the acrosome reaction of human spermatozoa and compare its
      effect to that of a cervical mucus substitute, sodium hyaluronate (Healonid).
      Spermatozoa from donors of proven fertility were isolated from semen using
      cervical mucus, Healonid or a direct swim-up (acting as the control). Sperm
      capacitation and the acrosome reaction were monitored by the chlortetracycline
      assay. In the mucus-treated group, there was a significantly higher percentage of
      capacitated spermatozoa, but a low incidence of spontaneous and A23187-induced
      acrosome reactions compared to the control. The use of Healonid during sperm
      isolation mimicked the effect of mucus relatively successfully. Since mucus and
      Healonid show very little chemical similarity, this finding would imply that
      cervical mucus exerts a physical effect during its interaction with spermatozoa,
      although a chemical effect cannot be completely dismissed. In conclusion, this
      study confirms early reports describing the ability of cervical mucus to
      capacitate spermatozoa but at the same time conserve sperm function. The finding
      that Healonid exerts an almost identical effect on spermatozoa would lend support
      to its use as a cervical mucus substitute during in-vitro fertility assessments
      and research studies.

PMID- 8671391
TI  - A flexible protocol for the induction of recipient endometrial cycles in an
      oocyte donation programme.
AB  - Synchronization of the availability of good quality oocytes from donors and
      adequate endometrial maturation of recipients are very important for the success
      of an oocyte donation programme. A flexible protocol for the endometrial
      preparation of recipients is important in timing embryo transfer between days 17
      and 19 of the cycle ('window of receptivity'). The purpose of this study was to
      evaluate the effect of the length of oestradiol administration to recipients on
      pregnancy outcome. Oestrogen administration was 8 mg/day, but its length varied
      prospectively from 6 to 27 days, followed by the addition of progesterone (100 mg
      daily i.m.) for 2-4 days according to the availability of good quality oocytes.
      Pregnancy outcome was evaluated regardless of age, indication for oocyte donation
      or number of embryos transferred per patient. The pregnancy rate per cycle was
      comparable when oestradiol was administered from 6 to 11 days before progesterone
      addition, while it dropped significantly thereafter. The variation in
      progesterone administration did not affect pregnancy outcome. These findings
      provide us with a greater flexibility by allowing us to vary oestradiol
      administration to recipients from 6 to 11 days prior to progesterone, reducing
      considerably, therefore, the need to cancel embryo transfer because of oocyte
      unavailability. Thus we can arrange to transfer embryos between days 17 and 19 of
      the recipient's cycle so as to obtain the best possible clinical outcome.

PMID- 8671392
TI  - Endothelial cell proliferation in the endometrium of women with menorrhagia and
      in women following endometrial ablation.
AB  - Local endometrial aberrations are thought to be the major contributing factor to
      essential menorrhagia. Here we have examined the role of endometrial
      angiogenesis, the growth of new blood vessels, in essential menorrhagia. Our
      study tested two hypotheses: firstly that angiogenesis is disturbed in the
      endometrium of women with menorrhagia; and secondly that when menstrual blood
      loss is decreased following endometrial ablation, an endometrial environment
      favouring normal angiogenesis has returned. Angiogenesis was measured by
      endothelial cell proliferation. Proliferating endothelial cells were identified
      by an immunohistochemical double staining technique. A total of 57 women
      participated in this study, of whom 19 were controls, 20 had menorrhagia and 18
      were 3-6 months post-ablation. There was a significant increase in endothelial
      cell proliferation in the endometrium of patients with menorrhagia compared with
      the control endometrium. Conversely, post-ablation endometrium showed a non
      significant decrease in endothelial cell proliferation. The increased endothelial
      cell proliferation in the endometrium of patients with menorrhagia was not the
      result of a general increase in endometrial cellular proliferation and did not
      result in a change in endothelial cell concentration compared with control
      endometrium. These results support the hypothesis that angiogenesis is disturbed
      in the endometrium of patients with menorrhagia and normalized in post-ablation
      endometrium.

PMID- 8671393
TI  - Changes in activity of superoxide dismutase in the human endometrium throughout
      the menstrual cycle and in early pregnancy.
AB  - To investigate the possible role of the superoxide radical and its scavenging
      system in the human endometrium, the immunohistochemical distribution of
      superoxide dismutase (SOD), activities of SOD and lipid peroxide concentrations
      were studied in the human endometrium throughout the menstrual cycle and in early
      pregnancy. The endometrial epithelium showed a positive immunostaining for Cu, Zn
      SOD and Mn-SOD throughout the entire menstrual cycle and in early pregnancy. In
      the stroma, weak immunostaining for Cu,Zn-SOD and moderate immunostaining for Mn
      SOD were observed in the predecidual cells in the late secretory phase. Decidual
      cells in early pregnancy showed strong immunostaining for Cu,Zn-SOD and Mn-SOD.
      Total SOD activity in the endometrium increased from early proliferative phase to
      mid-late proliferative phase and further increased in the mid-secretory phase,
      and decreased in the late secretory phase. The total SOD activity in the
      endometrium of of early pregnancy was the same level as that in the mid-secretory
      phase. Cu,Zn-SOD and Mn-SOD activities changed in a similar manner to total SOD
      activity throughout the menstrual cycle and in early pregnancy. Lipid peroxide
      concentration in the endometrium increased from early proliferative phase to mid
      late proliferative phase and further increased in the late secretory phase.
      However, lipid peroxide concentration in the endometrium of early pregnancy was
      the same as that in the mid-secretory phase. These results suggested that the
      superoxide radical and its scavenging system may play an important role in the
      regulation of human endometrial function.

PMID- 8671394
TI  - Evaluation of oestrogen and progesterone receptor expression in uterine mucosal
      lymphocytes.
AB  - Expression of the oestrogen and progesterone receptors on uterine mucosal
      leukocytes has been examined by dual immunohistology. Neither the oestrogen
      receptor nor the progesterone receptor was expressed by lymphocytes, macrophages
      or the distinctive population of uterine natural killer (NK) cells. Although the
      accumulation and survival of these NK cells appears to be hormonally dependent,
      the effects must therefore be indirect.

PMID- 8671395
TI  - Prognostic application of magnetic resonance imaging in patients with
      endometriomas treated with gonadotrophin-releasing hormone analogue.
AB  - We evaluated the usefulness of magnetic resonance imaging (MRI) for assessing the
      response of patients with endometriomas to medical therapy. MRI was performed
      before and after treatment in 20 consecutive patients with at least one
      endometrioma with a maximal diameter >10 mm diagnosed by laparoscopy who received
      900 microg of buserelin acetate daily for 6 months. Patients were categorized as
      good responders (group I, n = 13) and poor responders (group II, n = 7) depending
      on the results of a third-look laparoscopy performed 6 months after treatment. We
      determined the ratio of the signal intensity (SI) of the endometrioma to the SI
      of the gluteus maximus muscle on T2-weighted images [T2SI/M (muscle) SI] and the
      volume of the endometrium. The volume decreased by >50% in 61.5% of the good
      response group and 57.1% of the poor-response group. There was no significant
      difference between the two groups. The T2SI/MSI decreased in 12 of 13 patients in
      group I but in only one of seven patients in group II, a significant difference
      (P < 0.05) between the two groups. In the good-response group, there was a
      positive linear correlation between the decrease in the volume of the
      endometrioma and the decrease in the T2SI/MSI after treatment (r = 0. 561, P <
      0.05). Therefore, the T2SI/MSI determined from MR images may be useful in
      assessing the therapeutic response of patients with endometriomas.

PMID- 8671396
TI  - A comparative analysis of embryo implantation potential in patients with severe
      teratozoospermia undergoing in-vitro fertilization with a high insemination
      concentration or intracytoplasmic sperm injection.
AB  - The objective of this study was to assess fertilization, implantation and
      pregnancy rates in infertile patients with severe teratozoospermia [P (poor
      prognosis) pattern sperm morphology assessed by strict criteria] treated by in
      vitro fertilization (IVF) using a high insemination concentration (HIC), or by
      intracytoplasmic sperm injection (ICSI). This was a retrospective cohort study
      performed in an academic tertiary institution. The outcome of 115 consecutive
      ICSI cycles was compared to that of a similar number of cycles of IVF with HIC
      performed during a similar time frame and matched by woman's age and basal serum
      (cycle day 3) follicle stimulating hormone concentrations. The inclusion criteria
      were sperm morphology </=4% normal forms (P pattern) and >/=1x10(6) total motile
      spermatozoa per ejaculate. The diploid fertilization rate in the HIC-IVF group
      was 86% and in the ICSI group 68% (P < 0.05). Importantly, an equal number of
      embryos was transferred to both groups of patients. The morphological quality of
      the embryos (proportion of transfers having superior morphology embryo scores)
      was significantly better in the ICSI group than in the patients receiving HIC
      IVF. Although there was a clear trend for better implantation and pregnancy rates
      in the ICSI group, these differences were not statistically significant. We
      conclude that, although HIC-IVF resulted in a higher fertilization rate than ICSI
      in patients with severe teratozoospermia, ICSI produced a significantly higher
      proportion of morphologically superior embryos with a tendency towards a higher
      implantation potential. Therefore, teratozoospermic patients having adequate
      numbers of motile spermatozoa should be offered ICSI as an alternative to
      modified (HIC) IVF treatment.

PMID- 8671397
TI  - Localization of VEGF and expression of its receptors flt and KDR in human
      placenta throughout pregnancy.
AB  - Vascular endothelial growth factor (VEGF) is a potent secreted angiogenic growth
      factor. Its action is mediated through the tyrosine kinase receptors flt and KDR.
      We here examine, in detail, the distribution of this ligand and its receptors in
      human placentae throughout gestation. In the first trimester, in-situ
      hybridization revealed uneven distribution of flt mRNA around the villous
      trophoblast indicating spatial regulation. Temporal regulation of flt was
      observed with no flt mRNA expression detected in villi from mid-gestational
      placenta, while low levels were found in term villi. Extravillous trophoblast was
      found to contain both mRNA encoding flt and flt-like immunoreactivity throughout
      pregnancy. In contrast, KDR mRNA was found only in association with endothelial
      cells. Within the decidua the anti-flt antibody stained multiple cell types
      during the first trimester of pregnancy but only the extravillous trophoblast
      later in gestation. VEGF immunoreactivity tended to co-localize with the staining
      for flt. These results indicate that VEGF may exert an important role within both
      the placental villi and the maternal decidua in relation to the growth,
      differentiation and migration of trophoblast and that this is mediated primarily
      through the spatial and temporal regulation of the flt receptor rather than the
      KDR receptor.

PMID- 8671398
TI  - Biochemical changes in the cervical tissue of rabbit induced by interleukin-8,
      interleukin-1beta, dehydroepiandrosterone sulphate and prostaglandin E2: a
      comparative study.
AB  - The aim of this research was to study and compare the mechanism of action of
      interleukin (IL)-8, IL-1beta dehydroepiandrosterone sulphate (DHEA-S) and
      prostaglandin (PG)E2 on the cervix. Five equal groups of pregnant rabbits (n =
      45) were tested by either placebo or tested drugs in the form of vaginal
      suppositories once daily for 3 days. The suppositories contained human
      recombinant IL-8 (100 ng), IL-1beta (200 ng), DHEA-S (10 mg) or PGE2 (1 mg). All
      rabbits were tested by one dose, two doses or three doses. Consistency,
      dilatation and water contents were estimated 24 h after the last dose of
      treatment. Leukocyte infiltration of the cervices was studied after staining the
      cervical tissue sections with antirabbit RT2 monoclonal antibodies. Relative
      collagen concentration was assessed after staining with Picrosirius Red.
      Collagenase, gelatinase and elastase activities were measured in 100 mg of
      homogenized cervical connective tissue. Water contents were significantly
      increased in all tested cervices. Neutrophil numbers were increased in IL-8 and
      IL-1beta groups after the second dose of treatment (P < 0.0005 and 0.001
      respectively). In the PGE2 group, neutrophils were increased after the third dose
      of treatment, whereas in DHEA-S group no significant changes were observed.
      Collagen content was significantly decreased in IL-8, IL-1beta and PGE2 groups
      after the first dose of treatment (P < 0.004, and 0.005 and 0.03 respectively).
      In the DHEA-S group, the decrease in collagen content occurred after the third
      dose (P < 0.05). Collagenase activity was markedly increased in IL-8, IL-1, and
      DHEA-S groups after the second dose of treatment (P < 0.001, 0.003 and 0.007
      respectively). No significant increase in collagenase activity was found in PGE2
      group. Gelatinase activity was significantly increased in IL-8, IL-1beta, PGE2
      and DHEA-S groups after the second dose of treatment (P < 0.008, 0.01, 0.003 and
      0.05 respectively). Also, elastase activity was increased after the second dose
      of treatment in all groups (P < 0.001, 0.001, 0.001 and 0.006 respectively). Our
      data suggest that ripening of the cervix in rabbit can be initiated by different
      mechanisms. Cytokines play a vital role in cervical ripening, especially IL-8 and
      IL-1. IL-8 is one of the factors which could ripen the cervix in a manner similar
      to the physiological process at term.

PMID- 8671399
TI  - The role of relaxin in the pregnancy associated reduction in plasma osmolality.
AB  - Recent data suggest that the ovarian peptide relaxin is responsible for the
      pregnancy-associated fall in plasma osmolality in the rat. In order to test
      whether relaxin has the same role during human pregnancy, plasma osmolality,
      electrolytes, urea and creatinine were measured in samples obtained at 10, 20 and
      30 weeks gestation from singleton pregnancies conceived following ovum donation
      (OD, n = 12), spontaneously (N, n = 12) and following in-vitro fertilization and
      embryo transfer (IVF, n = 14). These groups were chosen, as relaxin
      concentrations throughout pregnancy are undetectable (OD), elevated (IVF) or
      normal (N). Thus, if relaxin alone is responsible for the fall in plasma
      osmolality associated with pregnancy in the human, then plasma osmolality would
      be expected not to fall during pregnancy in the OD group and to show a consistent
      decline from OD to N to IVF throughout pregnancy. Plasma osmolality fell
      significantly during pregnancy in both the OD and N groups, but not the IVF
      group. In addition, plasma osmolality was only significantly greater in OD when
      compared with IVF group at 10 weeks gestation; thereafter there were no
      significant differences between the groups with regard to plasma osmolality.
      Similarly, at 10 weeks the plasma concentrations of sodium and potassium were
      significantly higher in the OD than in either the N or IVF groups. Thus, although
      relaxin may be important in the initial control of plasma osmolality, other
      factors, probably derived from or regulated by the feto-placental unit, supersede
      it as pregnancy advances.

PMID- 8671400
TI  - Ovulation induction combined with intrauterine insemination in women 40 years of
      age and older: is it worthwhile?
AB  - The use of ovulation induction combined with intrauterine insemination (IUI) as a
      treatment for subfertility in women with patent Fallopian tubes has increased in
      recent years. Little is known regarding the efficacy of this treatment in women
      aged >/=40 years. We reviewed our data in our ovulation induction with IUI
      programme for 168 consecutive patients aged >/=40 years undergoing a total of 469
      cycles of treatment. Either sequential clomiphene citrate and human menopausal
      gonadotrophins or daily gonadotrophins were utilized along with timed IUI
      insemination. In 402 completed cycles, 28 clinical pregnancies occurred. The
      pregnancy loss rate was 34.4%. The overall ongoing/viable pregnancy rates per
      initiated and completed cycles were 4.47 and 5.22% respectively. No viable
      pregnancies occurred in 136 cycles in women aged >/=43 years. The
      ongoing/variable cycle fecundity rates for women aged 40, 41, and 42 years were
      9.6, 5.2, and 2.4% per cycle respectively. When utilized in women aged >=40
      years, ovulation induction with IUI is most likely to result in successful
      pregnancy in women 40-42 years of age. Women >/=43 years should consider other
      alternatives such as adoption or egg donation.

PMID- 8671401
TI  - Obstetric and perinatal outcome of pregnancies following intracytoplasmic sperm
      injection.
AB  - The aim of this study was to describe the obstetric and perinatal outcome for
      births following intracytoplasmic sperm injection (ICSI). Of 210 infants born,
      140 were singletons and 70 were twins. There were no triplets or higher births.
      The multiple birth frequency was 20%. Overall, 17% of deliveries were preterm,
      although for singleton pregnancies the incidence was reduced to 9%. The median
      birth weight of all live born infants was 3168 g and singletons 3470 g. Of all
      infants, 17% had a low birth weight (<2500 g) and 2% had a very low birth weight
      (<1500 g). Two major malformations occurred in two singleton children and four
      minor malformations occurred in four children. This was within the range of
      expected values in Sweden. Karyotyping was performed in 58 pregnancies. All of
      them were normal. The perinatal mortality was 0.5%. In conclusion, in this
      observational study from Sweden of the first infants born after ICSI in our
      programme, the incidence of multiple births, preterm births, low birth weight
      babies and congenital malformations was low compared with other series of in
      vitro fertilization pregnancies not associated with ICSI.

PMID- 8671402
TI  - Uterine rupture in first or second trimester of pregnancy after in-vitro
      fertilization and embryo transfer.
AB  - We report five cases of early rupture of cornual pregnancy with history of
      previous salpingectomy and cornual resection following in-vitro fertilization
      (IVF) and embryo transfer. We discuss the predisposing factors, diagnostic and
      therapeutic modalities in these patients. A high index of suspicion is required
      for an early diagnosis. It is imperative that the physicians who care for the
      patients be fully aware of the possibility of such a complication in a high risk
      population; therefore, appropriate counselling and close follow-up might help to
      avoid such obstetrical catastrophes, by termination of pregnancy, either
      surgically or medically.

PMID- 8671403
TI  - Successful pregnancy following oocyte donation in a patient with Diamond-Blackfan
      syndrome and premature ovarian failure.
AB  - Diamond-Blackfan anaemia (DBA) is a rare congenital condition characterized by
      profound anaemia associated with an absence of red cell precursors on bone marrow
      examination. This report represents the first case of pregnancy following egg
      donation in a patient with DBA and premature ovarian failure. The patient was a
      24 year old woman who had been diagnosed with DBA when aged 6 months. Shortly
      after menarche, the patient became amenorrhoeic and was diagnosed as suffering
      from premature ovarian failure. She was entered onto an assisted conception
      programme and conceived after one cycle of egg donation. The pregnancy was
      characterized by a gradual decline in haemoglobin concentration, reaching a low
      of 8.1 g/dl, necessitating a single blood transfusion at 29 weeks of gestation.
      The patient suffered preterm rupture of the membranes at 29 weeks gestation and
      was delivered by emergency Caesarean section at 30 weeks of gestation because of
      chorioamnionitis and breech presentation. Comparing this case with other reports
      of pregnancy in patients with DBA, our patient suffered a less dramatic fall in
      haemoglobin concentration and required only a single blood transfusion. It is
      suggested that because the pregnancy arose from donated genetic material, this
      may have conferred some protective effect.

PMID- 8671404
TI  - Egg-sharing in assisted conception: ethical and practical considerations.
AB  - The present acute shortage of eggs for donation cannot be overcome unless
      adequate guidelines are set to alleviate the anxieties regarding payments, in
      cash or kind, to donors. The current Human Fertilisation and Embryology Authority
      (HFEA) guidelines do not allow direct payment to donors but accept the provision
      of lower cost or free in vitro fertilization (IVF) treatment to women in
      recognition of oocyte donation to anonymous recipients. Egg-sharing achieved in
      this way enables two infertile couples to benefit from a single surgical
      procedure. However, the practical guidelines related to this approach are ill
      defined at the present time leading to some justifiable uncertainty. A pilot
      study was therefore undertaken in order to establish the place of egg-sharing in
      an assisted conception programme. The current HFEA guidelines on medical
      screening of patients, counselling, age and rigid anonymity between the donor and
      recipient were followed. The study involved 55 women (25 donors and 30
      recipients) in 73 treatment cycles involving fresh and frozen-thawed embryos.
      Donors were previous IVF patients who, regardless of their ability to pay, shared
      their eggs equally with matched anonymous recipients. They paid only for their
      consultations and tests right up to the point of being matched with a recipient.
      The sole recipient paid the cost applicable in egg donation of a single egg
      collection, although both received embryo transfers. The results indicate that
      although the recipients were older than the donors (41.4 +/- 0.9 versus 31.6 +/-
      0.5 years), and there was no difference in the mean number of eggs allocated, the
      percentage fertilization rates, or the mean number of embryos transferred, there
      were more births per patient amongst recipients than amongst donors (30 versus
      20%). We conclude that providing the donors are selected carefully, this scheme
      whereby a sub-fertile donor helps a sub-fertile recipient is a very constructive
      way of solving the problem of the shortage of eggs for donation. There are also
      the advantages of including a group of women who would otherwise be denied
      treatment. Problems related to 'patient coercion' can, in our view, be fully
      overcome by the application of strict common-sense safeguards. The ideal of pure
      altruism is not without its medical and moral risk. The success of egg-sharing
      depends on shared interests and a degree of altruism between the donor, the
      recipient and the centre. The current HFEA guidelines should be applauded for
      enabling a highly effective concept of mutual help to develop.

PMID- 8671405
TI  - Partner consent for sperm donation.
AB  - The current practice of demanding the consent of the spouse for sperm donation is
      analysed. Three aspects of marriage may be involved: (i) sexual exclusivity and
      adultery, (ii) family composition and (iii) procreational exclusivity. The
      different justifications for giving the partner the right to participate in the
      decision-making process are critically scrutinized. The perspective taken in this
      article is that the transfer of gametes must be understood and situated within
      the moral framework of the relationship between donor and partner. Depending on
      the kind of relationship the donor has with his partner, he may be morally
      obliged to consult his procreational partner. In a close relationship, all
      decisions concerning the use of one's reproductive faculties should be joint
      decisions. However, it is not the task of the clinic or the physician to see that
      donors honour their agreements and commitments. The clinic should not seek the
      partner's consent, although in the counselling sessions it should be pointed out
      to the donor that he may have a responsibility to inform his partner and to
      confer with her on his donation.

PMID- 8671406
TI  - Autoimmune disorders and reproductive failure.

PMID- 8671407
TI  - Ovarian hyperstimulation: effects of GnRH analogues. Ovarian hyperstimulation
      syndrome after using gonadotrophin-releasing hormone analogue as a trigger of
      ovulation: causes and implications.

PMID- 8671408
TI  - Ovarian hyperstimulation: effects of GnRH analogues. Does triggering ovulation
      with gonadotrophin-releasing hormone analogue prevent severe ovarian
      hyperstimulation syndrome?

PMID- 8671409
TI  - Ovarian hyperstimulation: effects of GnRH analogues. Triggering the final stage
      of ovulation using gonadotrophin-releasing hormone analogues: effective dose,
      prevention of ovarian hyperstimulation syndrome and the luteal phase.

PMID- 8671410
TI  - Oocyte donation: reflections on past work and future directions.

PMID- 8671411
TI  - Problems with oocyte donation.

PMID- 8671412
TI  - Anonymous egg donation and dignity.

PMID- 8671413
TI  - Oocyte donation. Fools rush in where angels fear to tread.

PMID- 8671414
TI  - The temporary anatomical structures prominent in the first trimester may be
      fulfilling exchange functions assigned to the placenta in the second and third
      trimester.
AB  - The extra-embryonic coelom (EEC) and secondary yolk sac are prominent structures
      in the gestational sac during the first trimester of human pregnancy, at a time
      before the definitive placental circulation becomes established. We propose that
      the EEC and yolk sac play a critical role in the nutrition of early pregnancy,
      fulfilling exchange functions which are assumed by the placenta at a later stage.

PMID- 8671415
TI  - Rachel's ladders or how societal situation determines reproductive therapy.

PMID- 8671416
TI  - A protocol using a low dose of gonadotrophin-releasing hormone agonist might be
      the best protocol for patients with high follicle-stimulating hormone
      concentrations on day 3.
AB  - We studied 98 in-vitro fertilization (IVF) patients with a high basal follicle
      stimulating hormone (FSH; >6.5 IU/l) concentration on day 3 who were treated with
      a low dose gonadotrophin-releasing hormone agonist (GnRHa) protocol and who had
      received in the previous 6 months a long protocol with GnRHa in a depot formula.
      The evaluation was made using the previous IVF cycle of the same patient as a
      control. The mean +/- SD age of the patients was 34.1+/-4.2 years. The use of a
      low dose agonist protocol ended with significantly less ampoules (37.5 versus
      46.1), a shorter duration of stimulation (10.7 versus 12.3 days), a higher
      oestradiol concentration on day 8 (1068 versus 495 pg/ml), a higher number of
      mature oocytes (5.9 versus 4.4) and a higher number of good quality embryos (3.3
      versus 2.3). The cancellation rate was lower (11 versus 24%). A GnRHa low dose
      protocol may be the protocol of choice for patients with high FSH concentrations
      on day 3. Larger randomized studies are needed to confirm these data.

PMID- 8671417
TI  - Aorto-subclavian thromboembolism: a rare complication associated with moderate
      ovarian hyperstimulation syndrome.
AB  - The case of an arterial aorto-subclavian thromboembolism associated with a
      moderate ovarian hyperstimulation syndrome (OHSS) and following ovulation
      induction for in-vitro fertilization in a young woman is reported. Because of the
      lack of response to systemic thrombolysis, a left postero-lateral thoracotomy was
      performed on day 8 after embryo transfer. A fibrinocruoric embolus situated at
      the junction of the left subclavian artery from the aorta was removed through a
      left subclavian arteriotomy. The distal axillary embolus was removed by a
      retrograde balloon catheter embolectomy. A moderate OHSS was observed. The
      ovarian stimulation and OHSS-related risks of thromboembolism are discussed. We
      conclude that, in the absence of risk factors, counselling about possible
      complications resulting from stimulation must be emphasized.

PMID- 8671418
TI  - Severe ovarian hyperstimulation syndrome despite low plasma oestrogen
      concentrations in a hypogonadotrophic, hypogonadal patient.
AB  - Ovarian hyperstimulation syndrome (OHSS) is the most serious, life-threatening,
      iatrogenic complication of ovulation induction. The importance of excessive
      oestradiol concentrations on the day of human chorionic gonadotrophin (HCG)
      administration as a predictor and factor in the pathophysiology of OHSS has been
      extensively studied and discussed. We present the case report of a woman with
      hypogonadotrophic hypogonadism who developed severe OHSS during ovulation
      induction with urinary human follicle stimulating hormone (FSH) and HCG in the
      presence of low circulating oestradiol concentrations. The implication of FSH
      treatment and complications in hypogonadotrophic hypogonadal patients, and the
      role of preovulatory oestradiol concentrations in the prediction of OHSS, are
      discussed.

PMID- 8671419
TI  - Anti-endometrial antibodies in women measured by an enzyme-linked immunosorbent
      assay.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed to measure anti
      endometrial antibody concentrations in the serum of women with endometriosis.
      Pooled cytosolic protein extracts from the endometrial gland cells of 10 women
      were used as an antigen source. Serum samples were obtained from women with
      endometriosis before (n = 51) and after 6 months treatment with danazol or
      nafarelin (n = 30). Control sera came from women with a normal pelvis at
      laparoscopy, performed for sterilization (n = 23) or the investigation of pain
      and/or infertility (n = 22), 13 women with Rokitansky syndrome, and 10 umbilical
      cord bloods and adult males. There were no significant differences in serum anti
      endometrial antibody concentrations before and after treatment, or between women
      with endometriosis and without endometriosis. Concentrations were lower in male
      and cord blood serum than in female's serum (P < 0.0001). We conclude that the
      ELISA is not a useful diagnostic tool for endometriosis unless more specific
      antigens can be isolated.

PMID- 8671420
TI  - Antiphospholipid antibodies in women having in-vitro fertilization.
AB  - Antiphospholipid antibodies have an established association with pregnancy
      complications such as recurrent miscarriage, growth retardation, placental
      abruption and stillbirth but their mechanism of action is unclear. We have
      investigated whether antiphospholipid antibodies occur more frequently in women
      having in-vitro fertilization (IVF) and whether their presence is associated with
      the likelihood of failed implantation. We studied 240 women undergoing IVF
      treatment who were </=38 years and had attempted fewer than three previous IVF
      cycles. Antiphospholipid antibodies (anticardiolipin and antiphosphatidyl serine
      immunoglobulin G and immunoglobulin M) were present in 36 out of 240 (15%) of the
      study population and were not associated with a failed IVF cycle or miscarriage.
      There was no association between the cause of infertility and the presence of
      antiphospholipid antibodies. Antiphospholipid antibodies were not detected more
      frequently in women with previous attempts at IVF compared with women having
      their first cycle, indicating that the high incidence of these antibodies is not
      due to the IVF treatment. There was a strong association between the presence of
      antiphospholipid antibodies and intrauterine growth retardation in singleton
      pregnancies (P < 0.005). We recommend routine screening for the presence of
      antiphospholipid antibodies in women having IVF in order to identify those
      pregnancies at increased risk of intrauterine growth retardation.

PMID- 8671422
TI  - Doppler colour flow analysis of uterine and ovarian arteries prior to and after
      surgery for tubal sterilization: a prospective study.
AB  - Female sterilization by tubal ligation is a very common method of birth control.
      A relationship between tubal sterilization and subsequent development of
      menstrual disorders has been described in the literature but a biological
      mechanism explaining such an association has not yet been demonstrated. The aim
      of this study was to evaluate the influence of tubal ligation by the Pomeroy
      technique on ovarian and uterine artery blood flow using pre- and post-surgical
      Doppler assessments. We studied prospectively 20 patients undergoing laparotomy
      for tubal ligation. All patients had a Doppler blood flow assessment before and
      after surgery, conducted in the mid-follicular phase of their cycle. The
      pulsatility index (PI) of the right uterine artery ranged from 1.44 to 3.86 (mean
      2. 23) when measured prior to surgery and from 1.36 to 2.85 (mean 2.13) when
      measured after surgery. In the left uterine artery, the PI ranged from 1.67 to
      3.17 (mean 2.17) and from 1.69 to 2.88 (mean 2. 22) before and after surgery
      respectively. The difference was not statistically significant. The PI of the
      right ovarian artery ranged from 1.38 to 3.48 (mean 2.41) prior to surgery and
      from 1.48 to 3.23 (mean 2.29) after surgery. In the left ovarian artery, the PI
      ranged from 1.36 to 3.62 (mean 2.54) and from 1.85 to 4.00 (mean 2.61) before and
      after surgery respectively. Again, the difference was not statistically
      significant. Our results suggest that tubal sterilization performed by Pomeroy's
      technique does not induce immediate alterations in the vascular flow of either
      ovarian or uterine arteries.

PMID- 8671421
TI  - Human endometrial stromal cells as a source of soluble intercellular adhesion
      molecule (ICAM)-1 molecules.
AB  - Intercellular adhesion molecule (ICAM)-1-mediated cell-cell adhesion is essential
      for various immunological functions, including natural killer (NK) cell-mediated
      cytotoxicity against endometrium. The present study was designed to establish
      whether shedding of ICAM-1 from cultured endometrial stromal cells occurred and
      to characterize its potential functional significance in endometrial physiology
      and pathology. The shed sICAM-1 molecule was detected and quantified in
      supernatants from endometrial stromal cultures and in peritoneal fluid by a
      specific enzyme-linked immunosorbent assay. The results of this study indicate
      that cultured endometrial stromal cells constitutively shed ICAM-1 from their
      surface. This ability is regulated during the menstrual cycle, as it appears to
      be higher in the proliferative than in the secretory phase of the cycle (16.93 +/
      2.2 and 7.7 +/- 1.76 ng/ml respectively). In order to evaluate whether the
      release of sICAM-1 could interfere with cell-mediated lysis of endometrium we
      compared the determinations of sICAM-1 in endometrial supernatants with the
      ability of such supernatants to suppress NK cell-mediated cytotoxicity toward
      endometrial targets. A significant correlation (r = 0.6, P < 0.05) was found
      between the sICAM-1 concentration in endometrial supernatants and the percentage
      of inhibition of NK cell-mediated lysis exerted by the same supernatant samples.
      Finally, endometrial stromal shedding of sICAM-1 appears to be related to
      endometriosis since endometrial stromal cultures obtained from patients with
      advanced stages of the disease released significantly higher amounts of the
      soluble protein compared to the control group (P < 0.05). sICAM-1 is a soluble
      molecule which can interfere with immunological functions, and its shedding may
      be one of the mechanisms by which refluxed endometrial cells escape
      immunosurveillance.

PMID- 8671423
TI  - Salpingectomy - the laparoscopic surgical choice for ectopic pregnancy.
AB  - The aim of this study was to assess the fertility outcome after ectopic pregnancy
      (EP) treated by laparoscopic salpingectomy. Among the 375 patients who underwent
      this operation between January 1983 and December 1993, there were 145 patients
      who desired pregnancy and whose contralateral tube was not obstructed. The
      overall rate of intrauterine pregnancy (IUP) was 50.3%, with an EP rate of 15.2%.
      These results were analysed according to the patients' past history together with
      the condition of the contralateral tube at the time of the laparoscopy. We
      defined two groups. Group 1 included patients who had no previous history of
      tubal surgery and whose contralateral tube was normal. Group 2 comprised those
      patients who had a previous history of tubal surgery and/or those whose tube was
      pathological, but not obstructed. Postoperative fertility of the patients in
      group 1 was significantly higher than that of the patients in group 2, with IUP
      rates of 75 and 36.6% respectively (P < 0.001), and a risk of EP recurrence of
      9.6 and 18.3% respectively. In group 1, the actuarial IUP rate at 24 months was
      significantly higher than that for the patients in group 2 (66.7 versus 36.9%; P
      < 0.001). The patient's past history and the condition of the contralateral tube
      were the two major factors related to fertility outcome after laparoscopic
      salpingectomy for EP. In patients with no past history of tubal surgery or
      infertility and whose contralateral tube was normal, the fertility results after
      laparoscopic salpingectomy appeared comparable to those observed after
      conservative laparoscopic treatment.

PMID- 8671424
TI  - Reproducibility of the interpretation of hysterosalpingography in the diagnosis
      of tubal pathology.
AB  - The aim of the study was to estimate the inter- and intra-observer
      reproducibility of the interpretation of hysterosalpingography (HSG) in the
      diagnosis of tubal pathology, and associate reproducibility with diagnostic
      accuracy. Four observers evaluated 143 HSGs twice, on proximal tubal obstruction,
      distal tubal obstruction, hydrosalpinx and peritubal adhesions. Diagnostic
      laparoscopy with chromopertubation was considered to be the reference strategy.
      Reproducibility (inter- and intra-observer agreement) was expressed in terms of
      kappa-values. Accuracy was expressed in terms of sensitivity, specificity and
      likelihood ratios. kappa-values for reproducibility between observers were almost
      perfect for proximal obstruction, substantial for distal obstruction and
      hydrosalpinx, and moderate for adhesions. kappa-values for reproducibility within
      observers were almost perfect for proximal obstruction and substantial for distal
      obstruction, hydrosalpinx and adhesions. HSG had a high specificity for proximal
      obstruction, but a low sensitivity. Distal obstruction, absence of hydrosalpinx
      and adhesions had a poor accuracy. The likelihood ratio for the presence of
      hydrosalpinx was high. In conclusion, proximal tubal obstruction detected on HSG
      changes the pre-test probability of proximal tubal obstruction from 16 to 50%.
      Proximal tubal patency detected on HSG changes the pre-test probability of
      proximal tubal patency from 16 to 9%. It is unlikely that a lack of
      reproducibility of the interpretation of proximal tubal patency is responsible
      for the low sensitivity; alternative explanations are artefacts occurring while
      performing HSG or an imperfect reference strategy diagnostic laparoscopy. HSG is
      of limited use in diagnosing distal tubal obstruction and hydrosalpinx, and has
      no value in the detection of peritubal adhesions.

PMID- 8671426
TI  - Discrimination between chronological and ovarian age in infertile women aged 35
      years and older: predicting pregnancy using basal follicle stimulating hormone,
      age and number of ovulation induction/intra-uterine insemination cycles.
AB  - A marked decline in fertility rates has been demonstrated in women > 35 years of
      age. We have previously demonstrated the importance of basal follicle stimulating
      hormone (FSH) concentrations plus chronological age to predict pregnancies in
      women aged >/=40 years undergoing ovulation induction therapy. The purpose of the
      current study was to extend our previous study and determine the impact of age,
      basal FSH concentrations and ovulation induction/inter-uterine insemination (IUI)
      treatment cycles on pregnancy rates in infertile women age >/=35 years. This
      prospective observational study was performed at a tertiary university fertility
      centre. Assessments of basal hormonal status and ovulation induction protocols
      were performed. The main outcome measured was clinical pregnancies. A total of
      770 treatment cycles in 179 women aged >/=35 years were analysed. The impact of
      basal FSH concentrations on treatment outcomes could be bifurcated into a
      favourable group (FSH </=23 mIU/ml) and a poor prognosis group (FSH >/= mIU/ml).
      A multivariate logistic regression model was generated which accurately predicted
      pregnancies. There was a high degree of correlation between predicted pregnancies
      and observed pregnancies (r = 0.86). We conclude that age, number of treatment
      cycles and the interaction term basal FSH x age are useful and significant
      predictors of pregnancies in patients aged >/=35 years undergoing ovulation
      induction/IUI therapy.

PMID- 8671425
TI  - The effect of human menopausal gonadotrophin and highly purified, urine-derived
      follicle stimulating hormone on the outcome of in-vitro fertilization in down
      regulated normogonadotrophic women.
AB  - It has been suggested that the luteinizing hormone (LH) activity of human
      menopausal gonadotrophin (HMG) preparations used for ovarian stimulation in in
      vitro fertilization (IVF) may have adverse effects on reproductive outcome. In
      the present prospective, randomized trial of 218 infertile couples this notion
      was investigated. A total of 114 women were treated with Pergonal (HMG group) and
      104 with Fertinorm HP (HP-FSH group). The two groups were comparable with regard
      to duration of infertility, cause of infertility, age and number of previous IVF
      attempts and all had normal basal gonadotrophin concentrations before treatment
      was started. A standard hormonal treatment consisting of pituitary down
      regulation with gonadotrophin-releasing hormone analogue (GnRHa) for 14 days
      starting on cycle day 21, followed by either HMG or highly purified follicle
      stimulating hormone (HP-FSH), three ampoules (225 IU) per day for 7 days, was
      used in all cases. The daily hormone dose was thereafter individualized according
      to the ovarian response. A maximum of two pre-embryos were transferred after 3
      days of culture. Luteal support with progesterone (300 mg per day intravaginally)
      was used in all cases. Serum concentrations of oestradiol, FSH and LH were
      measured on days 1 and 8 of stimulation and on the day of oocyte retrieval. The
      mean number of days of stimulation, mean number of ampoules of HMG or HP-FSH
      used, mean total motile sperm count on the day of oocyte retrieval and mean
      numbers of oocytes retrieved (13.4 versus 13.7) or pre-embryos transferred (1.8
      versus 1.8) were similar for both groups. Significantly (P < 0.05) more cycles in
      the HP-FSH group (17 = 16%) were cancelled due to complete failure of
      fertilization than in the HMG group (7 = 6%). The mean fertilization rate was
      significantly (P < 0.05) higher in the HMG group (56%) than in the HP-FSH group
      (50%), and significantly more transferable pre-embryos were obtained in the HMG
      than in the HP-FSH group (mean: 4.0 versus 3.2; P < 0.01). Serum hormone
      concentrations were similar to the two groups on stimulation day 1, but differed
      significantly with regard to FSH, LH and oestradiol on stimulation day 8. The
      clinical outcome was similar in the two groups, with an ongoing pregnancy rate (>
      12 weeks of gestation) per started cycle of 33% in the HMG group and 29% in the
      HP-FSH group. The clinical abortion rates were similar (10 and 14%), and the
      implantation rate was 30% in each group. In conclusion, no detrimental effect of
      the LH activity of HMG on the clinical outcome of IVF in GnRHa down-regulated
      normogonadotrophic women was found. To the contrary, some beneficial effects of
      HMG on fertilization rates and pre-embryo development as compared with HP-FSH
      were demonstrated. These effects, as well as the differences in serum hormone
      concentrations during ovarian stimulation, may be caused by differences in LH
      content and/or in the composition of FSH isoforms of the HMG and HP-FSH
      preparations.

PMID- 8671427
TI  - Mechanism of action of the intrauterine contraceptive device: evidence for a
      specific biochemical deficiency in the endometrium.
AB  - The precise mechanism of action of the intrauterine contraceptive device (IUCD)
      is uncertain. In this study we compared the circulating concentrations of a
      specific endometrial protein, placental protein 14 (PP14), in 62 women with an
      IUCD and 16 controls. The concentrations of PP14 were substantially lower in IUCD
      users. There was no difference in the concentrations of another and less specific
      endometrial protein, insulin-like growth factor binding protein-1 (IGFBP-1).
      There was no difference in PP14 concentrations between those women with and
      without intermenstrual bleeding. We conclude that the reduced concentrations of
      PP14 in IUCD users reflect defective endometrial function in these women,
      probably related to the contraceptive effect. We propose that the measurement of
      PP14 might be a means of comparing the efficiency of different devices.

PMID- 8671428
TI  - Seminal plasma can be a predictive factor for male infertility.
AB  - Seminal plasma from ejaculates of 10 healthy, fertile volunteers and 63 infertile
      males was analysed for superoxide dismutase (SOD) and xanthine oxidase (XO)
      activities using a chemiluminometer. There was not statistically significant
      difference in the activity of either enzyme between control and infertile
      populations (113 +/- 74 IU/ml for SOD and 1.17 +/- 0.52 IU/ml for XO) in samples
      from normozoospermic ejaculates. Sperm progressive motility was positively
      correlated with SOD activity in seminal plasma of corresponding ejaculates (P <
      0.05) and negatively with XO activity (P < 0.001). An 'oxido-sensitive' index was
      defined as the SOD/XO ratio and was found to be inversely related to sperm
      progressive motility samples (P < 0.01). Analysing this index among all tested
      samples of semen including those with pathological spermiograms, as well as
      normospermic (N) samples we found statistically significant (elevated)
      differences in oligoasthenoteratospermia (OAT) in comparison with N (P <0.05);
      OAT samples were also significantly different from oligospermic (O) and
      oligoteratospermic (OT) samples (P < 0.05). This suggests that the 'oxido
      sensitive' index of seminal plasma may be a simple diagnostic factor, useful in
      the determination of male infertility.

PMID- 8671429
TI  - Antibiotic treatment based on seminal cultures from asymptomatic male partners in
      in-vitro fertilization is unnecessary and may be detrimental.
AB  - We questioned the policy of routine microbiological culture of semen prior to in
      vitro fertilization (IVF) with a view to prescribing antibiotics to reduce the
      risk of introducing seminal infection into the embryo culture system. An initial
      retrospective study examined serum microbiology reports of 449 couples undergoing
      IVF or gamete intra-Fallopian transfer (GIFT). In semen samples taking >/=1 days
      to reach the microbiology laboratory compared with same-day delivery there was
      increased frequency of significant culture of enterococci (27 versus 15%, P <
      0.01). In samples taking >/=2 days there was increased frequency of significant
      culture of Gram-negative bacilli (31 versus 12%, P < 0.01) and of overall culture
      of other potentially pathogenic organisms (26 versus 14%, P < 0.01). We
      questioned diagnostic accuracy and relevance. Therefore, in a prospective study,
      semen and high vaginal swabs obtained on the day of oocyte collection were
      cultured from 100 couples having IVF or GIFT, of whom 52 male partners had been
      treated with antibiotics following positive pre-IVF semen culture. The presence
      of bacteria in semen samples used only for IVF (n = 90) did not reduce
      fertilization rates nor lead to infection of the embryo culture system. However,
      there was an increased incidence of significant culture of vaginal Gram-negative
      bacilli in patients with treated partners compared with untreated partners [15/52
      (29%) versus 5/48 (10%), P < 0.05]. Thus antibiotic therapy in the male partner
      may increase the likelihood of inoculation of antibiotic-resistant pathogenic
      bacteria from the vagina into the embryo culture system during vaginal oocyte
      collection. In asymptomatic patients, microbiological screening of semen samples
      prior to IVF treatment and subsequent treatment with antibiotic therapy in those
      with positive cultures appears to be unnecessary and may be detrimental to IVF
      outcome.

PMID- 8671430
TI  - The value of palpation, varicoscreen contact thermography and colour Doppler
      ultrasound in the diagnosis of varicocele.
AB  - Three non-invasive methods for the detection of a varicocele were evaluated in 63
      men presenting with infertility. Physical examination, varicoscreen contact
      thermography and colour Doppler ultrasound were compared with spermatic
      venography as reference strategy. Physical examination had a sensitivity of 71%.
      Whether the non-palpable varicoceles are all subclinical is questionable since
      the specificity of physical examination was 69%. Varicoscreen proved be quick,
      easy and cheap but of no clinical value (sensitivity 97%, specificity 9%). Colour
      Doppler ultrasound using strict criteria was a good diagnostic tool (sensitivity
      97%, specificity 94%). No imaging difference was seen with colour Doppler
      ultrasound among clinical and subclinical varicoceles. Since the debate on
      treating all degrees of varicocoeles is ongoing, we suggest that Doppler
      sonography should be a routine examination in infertile men.

PMID- 8671431
TI  - Effectiveness of pentoxifylline in semen preparation for intrauterine
      insemination.
AB  - Pentoxifylline, an inhibitor of cAMP phosphodiesterase activity, favours
      intracellular cAMP concentration increase. In-vitro treatment of semen with
      pentoxifylline leads to marked augmentation of sperm motility, enhancement of
      acrosome reaction, increase of sperm penetration into zona-free hamster oocytes,
      and protection of the sperm plasma membrane. Such properties indicate that the
      drug may be a useful tool for semen preparation in assisted reproduction, but its
      real effectiveness in improving fertilization rates is still uncertain, mainly in
      association with intrauterine insemination (IUI). Theoretically sperm motility
      should play an extremely important role for positive results in IUI. Therefore, a
      retrospective clinical trial was planned in order to evaluate whether addition of
      pentoxifylline to the previously standardized in-vitro treatment of semen had
      improved the percentage of pregnancies after homologous IUI. The study involved
      55 sterile couples (33 classified infertile for male factor and 22 for other
      factors) who underwent a total of 150 cycles of homologous IUI: 101 for male
      factor infertility and 49 for other factors (anovulation n = 26, endometriosis n
      = 2, idiopathic n = 21). Out of the 101 cycles performed for male factor
      infertility, 61 underwent the standard preparation of semen and were followed by
      seven pregnancies (pregnancy rate = 11.5%) while 40 had a semen preparation with
      pentoxifylline addition and were followed by 11 pregnancies (pregnancy rate =
      27.5%) with a significant difference between the two procedures (P < 0.05). Out
      of the 49 cycles carried out for factors different from male infertility, 10
      underwent the standard preparation of semen and were followed by two pregnancies
      (pregnancy rate = 20.0%), while 39 had pentoxifylline addition and were followed
      by nine pregnancies (pregnancy rate = 23.1%). The difference between the two
      groups was not significant. Abortions and malformations were equally distributed
      in the standard treatment and in the pentoxifylline group.

PMID- 8671432
TI  - Relationships between motility parameters, morphology and acrosomal status of
      human spermatozoa.
AB  - A total of 130 semen samples were examined for motility (by computer-assisted
      sperm analysis), morphology and acrosomal status. A high positive correlation was
      found between percentages of normal forms and progressive motility in the whole
      semen (r = 0.539, P < 0. 0001) as well as in the Percoll fraction (r = 0.702, P <
      0.0001). Among the specific abnormalities, acrosome defects were most highly
      correlated with progressive motility (r = -0.492, P < 0.0001, in the Percoll
      fraction). The percentage of total spontaneously acrosome-reacted spermatozoa in
      the Percoll fraction was negatively correlated with the progressive motility (r =
      -0.499, P < 0.0001) and with the percentage of normal forms (r = 0.430, P <
      0.0001). Surprisingly, the percentage of total spontaneously acrosome-reacted
      spermatozoa was poorly linked with head abnormalities but displayed significant
      positive correlations with the percentages of bent tails (r = 0.359, P < 0.0001)
      and of coiled tails (r = 0.371, P < 0.0001). These data suggest that sperm
      defects are often linked together, reflecting spermiogenesis and/or epididymal
      dysfunctions.

PMID- 8671433
TI  - Kobe earthquake and reduced sperm motility.
AB  - We investigated a possible relationship between the Kobe earthquake (January 17,
      1995) and the quality of semen. We assessed sperm concentration and motility of
      27 male patients who had a concentration of more than 30 million/ml and >40%
      sperm motility within 5 months before the earthquake. Twelve male patients from
      districts with a magnitude of <4 on the Richter scale showed no difference in
      sperm concentration and motility before and after the earthquake. Of 15 male
      patients from districts with a magnitude of >6, five patients whose houses
      received no damage showed no distinct changes in sperm concentration and
      motility. In contrast, 10 patients whose houses were partially or completely
      destroyed showed significantly (P < 0.001) lower sperm motility after the
      earthquake than before, although no significant difference of sperm concentration
      could be observed. Of these latter 10 patients, seven could be followed. In six
      patients, sperm motility was restored between 2 and 9 months after the
      earthquake; the sperm motility in one patient, whose father died a victim of the
      house crash, has not yet recovered. Thus, the acute stress resulting from such a
      catastrophic earthquake could be a possible cause of reduced sperm motility.

PMID- 8671435
TI  - Effects of enclomiphene and zuclomiphene on basal and gonadotrophin-stimulated
      progesterone secretion by isolated subpopulations of small and large ovine luteal
      cells.
AB  - We examined the effects of enclomiphene and zuclomiphene, alone and in
      combination with oestradiol, on basal and gonadotrophin-stimulated progesterone
      secretion by isolated subpopulations of both large (granulosa-lutein) and small
      (theca-lutein) ovine luteal cells. Isolated large and small luteal cells derived
      from intact, enucleated ovine corpora lutea were incubated for 48-120 h with or
      without 22R-hydroxycholesterol or pregnenolone (2.5 microM) and a range of
      enclomiphene, zuclomiphene, and/or oestradiol concentrations (3-100 microM), both
      with and without ovine luteinizing hormone (100 ng/ml). Spent media were assayed
      in duplicate for progesterone content by radioimmunoassay. Enclomiphene,
      zuclomiphene, and oestradiol exhibited equivalent dose-dependent inhibitory
      effects on basal and gonadotrophin-stimulated small and large ovine luteal cell
      progesterone secretion under all substrate conditions. Both cell types became
      more sensitive to clomiphene inhibition with increasing time in culture. In
      combined treatments, the effects of oestradiol and either enclomiphene or
      zuclomiphene became additive in longer-term cultures and were never antagonistic.
      In this model system, (i) clomiphene, like oestradiol, appears to inhibit 3beta
      hydroxysteroid dehydrogenase activity, (ii) both stereoisomers act as oestrogen
      agonists, (iii) neither demonstrates any anti-oestrogenic properties, and (iv)
      both large and small luteal cells become more sensitive to clomiphene inhibition
      with increasing duration of exposure.

PMID- 8671434
TI  - Successful combination of transrectal electroejaculation and intracytoplasmic
      sperm injection in the treatment of anejaculation.
AB  - We describe the case of a couple whose infertility was caused by the absence of
      seminal emission following retroperitoneal surgery for testicular cancer.
      Ejaculate could be retrieved from the husband by rectal probe electroejaculation
      (RPE) but sperm quality was so poor that conventional in-vitro fertilization was
      impossible. With intracytoplasmic sperm injection of spermatozoa retrieved by RPE
      - a combination not reported previously - we were able to induce a pregnancy with
      successful outcome.

PMID- 8671436
TI  - Tumour necrosis factor-alpha inhibits follicle-stimulating hormone-induced
      granulosa cell oestradiol secretion in the human: dependence on size of follicle.
AB  - This study investigated the effects of tumour necrosis factor-alpha (TNF) on
      human granulosa cells taken from ovaries of 11 premenopausal women undergoing
      oophorectomy during the luteal phase of the cycle for reasons unrelated to
      ovarian pathology. Granulosa cells from follicles ranging from 5-10 mm diameter
      (small) and from >10-25 mm (large) were subjected to culture for 48 and 96 h.
      Granulosa cells were cultured with human FSH (1 ng/ml), testosterone (1 microM)
      and human TNF (10 ng/ml), each alone, and in various combinations. In granulosa
      cells of small follicles, FSH alone increased progesterone and cAMP accumulation
      and the conversion of testosterone to oestradiol. In granulosa cells of large
      follicles, FSH increased progesterone and cAMP accumulation but not the
      conversion of testosterone to oestradiol. Only in granulosa cells of small
      follicles did TNF significantly inhibit FSH-induced conversion of testosterone to
      oestradiol but it was not apparent until the second 48 h of culture and
      concomitantly TNF did not alter the ability of FSH to stimulate progesterone and
      cAMP accumulation. In granulosa cells of large follicles, TNF did not alter FSH
      stimulated oestradiol, progesterone or cAMP accumulation. Interestingly,
      progesterone accumulation in the presence of TNF and FSH was significantly
      greater in granulosa cells of large follicles than in granulosa cells of small
      follicles. The results indicate that TNF suppresses FSH-induced oestradiol
      secretion in granulosa cells from small follicles and this modulatory effect of
      TNF appears to be independent of decreases in progesterone and cAMP. The
      potential physiological significances of these findings is that TNF may be a
      relevant cytokine in suppressing FSH-induced oestradiol secretion and follicular
      growth during the luteal phase of the cycle.

PMID- 8671437
TI  - Localization and expression of zonula occludens-1 tight junction-associated
      protein in baboon (Papio anubis) corpora lutea.
AB  - The identification of the cell junction-forming proteins connexin-43, a gap
      junction protein and E-cadherin, which is a component of adherent junctions, in
      the corpus luteum of both humans and baboons suggests that cell-cell interactions
      and metabolic cooperation must occur in this tissue. Occluding junctions are a
      third type of junction which form a physical barrier between cells. Thus, our
      aims in this study were firstly to examine the presence of the tight junction
      associated protein zonula occludens-1 (ZO-1) by immunohistochemistry, and
      secondly to determine the concentrations of this protein in the early-, mid- and
      late luteal phase baboon corpora lutea of the menstrual cycle by a Western
      analysis. ZO-1 was localized mainly at the periphery of the luteal cells, and the
      intensity of immunoreactivity varied through the luteal phase, with comparatively
      stronger immunoreactivity in the mid-luteal phase than the early and late luteal
      phases. Atretic corpora lutea were devoid of activity. By Western analysis, bands
      of immunoreactivity were observed at 225 kDa, further confirming the presence of
      the protein. Maximum activity, as determined by densitometry, was observed in the
      mid-luteal phase. These data infer the presence of tight junctions in the corpus
      luteum and suggest that expression of the ZO-1 protein forming these junctions
      may be hormonally regulated within this tissue.

PMID- 8671438
TI  - Cryopreservation of human ovarian tissue using dimethylsulphoxide and propanediol
      sucrose as cryoprotectants.
AB  - Pieces of ovarian cortical tissue (0.3-2 mm in diameter) were obtained during
      gynaecological operations by biopsy or as a result of oophorectomy from 19 women
      aged 19-44 years. The tissue was frozen in a programmable freezer using one of
      two different cryoprotectants, either 1.5 M dimethylsulphoxide (DMSO), or a
      combination of 1,2-propanediol (1.5 M) and sucrose (0.1 M). After
      cryopreservation lasting from 24 h to 5 weeks, the ovarian pieces were thawed and
      studied histologically. Specimens taken before and after cryopreservation with
      either protectant showed no signs of tissue necrosis. Follicles at similar
      developmental stages were found before and after freezing. The proportions of
      follicles showing signs of atresia, 27% in the non-frozen tissue and 19% in the
      frozen-thawed tissue, were not significantly different. Oocytes, too, had the
      same appearance after freezing and thawing with both cryoprotectants as was seen
      in the specimens taken before freezing. These results suggest that
      cryopreservation of human ovarian tissue is feasible. However, the normality of
      the oocytes taken from tissue which has been frozen still needs to be
      established. Cryopreservation of ovarian tissue would be potentially an excellent
      method for storage of human oocytes once methods for their maturation in vitro
      have been developed.

PMID- 8671439
TI  - Fertilization, embryonic development and implantation of mouse oocytes with one
      or two laser-drilled holes in the zona, and inseminated at different sperm
      concentrations.
AB  - The zonae pellucidae of mouse oocytes were photo-ablated by an ultraviolet laser
      (337.1 nm) to create one or two 10 microm holes. The pulse energy used was
      approximately 3 microJ/s, with a frequency of 10 pulse/s. These laser zona
      drilled (LZD) oocytes with one hole (LZD1) or two holes (LZD2) and the zona
      intact controls were inseminated with spermatozoa at standard concentrations of
      5x10(4), 5x10(5), 1x10(6) and 2x10(6)/ml. Fertilization was significantly
      improved at all sperm concentrations in LZD1 and LZD2 oocytes as compared to the
      controls. However, there was no significant difference in fertilization rates
      between LZD1 and LZD2. LZD2 produced significantly higher numbers of blastocysts
      at day 5. Hatching was significantly enhanced in the presence of either one or
      two holes in the zona. Polyploidy was generally absent, except in LZD2 oocytes
      (1%) inseminated at higher sperm concentrations. Differential cell counts of
      expanded LZD blastocysts were similar to those of the controls. Significantly
      fewer LZD2 blastocysts implanted and produced viable fetuses than LZD1 and
      control blastocysts. Morphological abnormalities of the fetuses were absent in
      all three groups. Laser zona-drilling using the ultraviolet laser was shown to be
      fast, efficient and safe.

PMID- 8671440
TI  - Insulin-like growth factor-binding proteins produced by Vero cells, human
      oviductal cells and human endometrial cells, and the role of insulin-like growth
      factor-binding protein-3 in mouse embryo co-culture systems.
AB  - Co-culturing embryos on helper cells can mimic the in-vivo environment, thereby
      enhancing embryo development in vitro. Insulin-like growth factors (IGF) and
      their binding proteins (IGFBP) also enhance embryo development. To investigate
      the kinds of IGFBP produced by various cell monolayers and the effects of IGFBP-3
      on mouse embryo co-culture systems, 2-cell ICR mouse embryos were cultured in
      either human tubal fluid medium alone or in the presence of Vero cells, human
      oviductal cells or endometrial cells. The helper cells were analysed
      immunohistochemically to investigate the types of IGFBP produced by various cell
      monolayers. The concentrations of IGF-I and IGFBP-3 in media obtained from the
      culture of embryos alone, cells alone or cells plus embryos were determined by
      radioimmunoassays. On day 7, more blastocysts hatched in the co-culture groups
      (73% in the Vero cell group, 76% in the endometrial cell group and 74% in the
      oviductal cell group) than in the control group (43%) (P < 0.0001). The results
      of immunohistochemistry revealed that (i) all three cell groups produced a lot of
      IGFBP-1, -2 and -3, but only a little of IGFBP-4 and -5; and (ii) IGFBP-1, -2,
      and -3 were present in blastocysts in either the presence or absence of helper
      cells. The IGF-I secreted by cell monolayers or embryos was undetectable
      (detection limit 0.83 microg/l). The IGFBP-3 concentrations in media obtained
      from co-cultured embryos and cells were significantly higher than in media
      without embryos (median values in oviductal cell culture medium, 165 versus 127
      microg/l, P = 0.04; median values in endometrial cell culture medium, 277.5
      versus 183.5 microg/1, P = 0. 0002; median values in Vero cell culture medium,
      219 versus 120 microg/l, P = 0.011). Although IGFBP-3 concentration in the medium
      that contained embryos alone was undetectable by radioimmunoassay (detection
      limit 1.1 microg/l), immunohistochemistry demonstrated the presence of IGFBP-3 in
      the embryos. Co-culture in systems in which there was an increased production of
      IGFBP-3 led to an improved development of mouse embryos. IGFBP can improve the
      binding of IGF to cell surface receptors of target tissue, and thus enhance the
      effect of limited IGF concentrations in promoting embryo development in a co
      culture system. We conclude that Vero cells, human endometrial cells and
      oviductal cells produce IGFBP-1, -2, -3, -4 and -5. IGFBP-3 may play a role in
      embryotrophic potential by either regulating the action of IGF or directly
      enhancing embryo development.

PMID- 8671441
TI  - The development of mouse zygotes after fusion with synchronous and asynchronous
      cytoplasm.
AB  - Cytoplasts with diameters of 40-45, 50-55 and 70-75 microm, derived from mouse
      oocytes at the germinal vesicle, metaphase II and zygote stages were incorporated
      into zygotes by electrofusion. Manipulated (n = 867) and culture-control (n =
      1114) embryos were cultured in vitro and transferred to pseudo-pregnant
      recipients at the blastocyst stage. When synchronous cytoplasts measuring 40-45
      and 50-55 microm in diameter were incorporated into 138 and 86 zygotes
      respectively, only one embryo in each group (not significant) became arrested at
      the 1-cell stage. A total of 124 (89.9 compared with 91. 6% for controls) and 69
      embryos (80%, P < 0.001 compared with 91.6% for controls) reached the blastocyst
      stage respectively. In the first group, 66 out of 106 blastocysts implanted (62.2
      compared with 54.9% for controls; not significant), however, only 24 (22.6
      compared with 40.2% for controls, P < 0.001) were viable in comparison with
      controls. There were four groups of zygotes that received metaphase II
      cytoplasts. In the first group, 200 zygotes were fused with 40-45 microm
      cytoplasts. The second group of 145 zygotes were fused with cytoplasts of the
      same size derived from aged oocytes. In the third and fourth groups, 38 and 36
      zygotes were fused with 50-55 and 70-75 microm cytoplasts respectively. In the
      first two groups, none of the embryos arrested at the 1-cell stage, but in the
      other groups the rates were 15 out of 38 (39.5%) and 36 out of 36 (100%)
      respectively. These zygotes remained arrested at the pronuclear stage and
      contained large inflated pronuclei. The blastocyst formation rates were 183 out
      of 200 (91.5 compared with 91.6% for controls, not significant), 109 out of 145
      (75.2% lower than controls, P < 0.05) and 14 out of 38 (39.5% lower than
      controls, P < 0.0001) respectively. In the first two groups 109 and 25
      blastocysts were transferred, of which 76 (69.7%) and 15 (60.0%) implanted. This
      was higher than control embryos (54.9%, P < 0.01) for the first group and similar
      to controls for the second group. In the first group, 60 embryos (55%) were
      viable on day 10 of transfer in comparison with controls (40.2%, P < 0.05) while
      in the second group, 11 embryos (44.0%, not significant) were viable on day 10 of
      transfer. Zygotes that received germinal vesicle stage cytoplasts developed
      poorly and the implantation rate was significantly reduced. The present study
      confirms the importance of the ooplasmic domain in meiotic maturation and
      preimplantation development. Our results suggest that implantation may be
      enhanced by transfer of a small amount of metaphase II cytoplasm to the mouse
      embryo during the 1-cell stage; however, fusion of intact zygotes with cytoplasts
      > 45 microm appeared largely detrimental. The mechanisms responsible for these
      changes are yet unknown.

PMID- 8671442
TI  - Unexpected low oxygen tension of intravaginal culture.
AB  - The goal of this study was to assess whether the metabolic activity of gametes or
      the local environment had a greater influence on the pH, pO2 and pCO2 of the
      culture medium in the intravaginal culture (IVC) technique. The pH, pO2 and pCO2
      of the culture medium in four groups of intravaginal cryotubes with or without
      spermatozoa and oocytes, together with the pO2 and pCO2 of vaginal epithelium,
      were measured before and 48 h after IVC. Hermetically closed cryotubes sealed in
      a cryoflex envelope were used throughout. Similar results were obtained from all
      four groups. The pH and pCO2 were unchanged but pO2 significantly decreased
      during IVC, presumably because of equilibration with the low pO2 (5 mmHg) and
      pCO2 (49 mmHg) present in the vaginal epithelium. A second series of experiments
      was then performed with standard culture conditions using culture medium with or
      without motile spermatozoa in cryotubes covered with cryoflex maintained in air
      supplemented with 5% CO2. The pH, pO2 and pCO2 were all unchanged in all samples.
      When the samples were maintained in air only, the pH increased, pO2 remained
      unchanged and pCO2 decreased, presumably because of equilibration with the low
      pCO2 (0. 3 mmHg) present in the air. However, when the samples were cultured
      under venous blood, the pH and pO2 decreased and pCO2 increased, presumably
      because of the high pCO2 and low pH of venous blood. Thus the pO2 and pCO2 of the
      culture medium were able to equilibrate with the local environmental gas milieu
      owing to the permeability of O2 and CO2 through the plastic material. IVC results
      in a constant pH due to an identical pCO2 in the vaginal epithelium but in a
      reduced pO2 concentration due to the lower pO2 in the vaginal epithelium.

PMID- 8671443
TI  - Fertilization and development of mouse oocytes cryopreserved using a
      theoretically optimized protocol.
AB  - Rational design of a cryopreservation protocol was demonstrated by using
      theoretical models of the cryopreservation process to develop an optimal freezing
      protocol for mouse oocytes. A coupled mechanistic model of the processes of
      freeze-induced cell dehydration and intracellular ice formation was developed,
      and cryomicroscopical measurements of intracellular ice formation kinetics were
      used to determine biophysical parameters required by the model, and to test model
      predictions of the freezing behaviour of mouse oocytes. A simple phenomenological
      model for oocyte damage resulting from exposure to concentrated electrolyte and
      cryoprotectant solutions during cryopreservation was obtained by defining a cost
      function equal to the duration of the freezing protocol. A two-step freezing
      protocol was theoretically optimized by using a sequential simplex algorithm to
      minimize the cost function, subject to the constraint that the predicted
      probability of intracellular ice formation remain below 5%, yielding a putative
      optimum at the cooling rate B = 0.59 degrees C/min, and plunge temperature Tp = 
      67 degrees C. By systematically varying B and Tp about these values in
      experiments with mouse oocytes cryopreserved in 1.5 M dimethyl sulphoxide, the
      maximal recovery of intact oocytes with a normal morphology (82%) was obtained
      for B = 0.5 degrees C/min and Tp = -80 degrees C. Further evaluation of the
      fertilizability and developmental capacity of oocytes cryopreserved using the
      optimized protocol yielded cleavage to the 2-cell stage in 65% of oocytes
      inseminated, and blastocyst formation in 50% of these 2-cell embryos.

PMID- 8671444
TI  - Pregnancy resulting from intracytoplasmic injection of cryopreserved spermatozoa
      recovered from testicular biopsy.
AB  - We report a clinical pregnancy occurring in a 31 year old patient following
      intracytoplasmic sperm injection (ICSI) of cryopreserved spermatozoa obtained
      from a testicular biopsy. This was the couple's second attempt at an ovarian
      stimulated cycle resulting in the collection of 17 metaphase II ova which were
      all injected with progressively motile spermatozoa. A fertilization rate of 58%
      and a cleavage rate of 90% were achieved. This report is our first case of ICSI
      using cryopreserved testicular spermatozoa which resulted in normal
      fertilization, embryo development and an on-going singleton pregnancy.

PMID- 8671445
TI  - Pregnancies after intracytoplasmic sperm injection with cryopreserved testicular
      spermatozoa.
AB  - In 25 patients (14 suffering from obstructive azoospermia, six from non
      obstructive azoospermia, three from asthenoazoospermia and two from absence of
      ejaculation) spermatozoa were extracted from testicular biopsies.
      Intracytoplasmic sperm injection (ICSI) with fresh testicular spermatozoa was
      performed in 18 cases; spermatozoa in excess were cryopreserved in pills. No
      pregnancies were achieved. In the remaining seven patients, testicular
      spermatozoa were retrieved and cryopreserved during a diagnostic testicular
      biopsy. After thawing, sperm motility was assessed in 17 cases (68%), and 18 ICSI
      with cryopreserved testicular spermatozoa were performed. The mean two-pronuclear
      (2PN) fertilization rate was 59%, the mean cleavage rate was 92%, and six
      clinical pregnancies were achieved, all of them still ongoing (pregnancy rate
      33%). A comparison of the results of ICSI carried out with fresh or cryopreserved
      testicular spermatozoa showed that the mean 2PN fertilization rates per cycle (53
      compared with 55%), mean cleavage rates per cycle (99 compared with 96%) and
      embryo quality were not significantly different. In conclusion, cryopreservation
      of testicular spermatozoa is feasible, even in patients with non-obstructive
      azoospermia, and the results of ICSI with frozen-thawed testicular spermatozoa
      are similar to those obtained using fresh testicular spermatozoa.
      Cryopreservation of testicular spermatozoa may avoid repetition of testicular
      biopsies to retrieve spermatozoa for successive ICSI cycles in patients in whom
      the only source of motile spermatozoa is the testicle.

PMID- 8671446
TI  - Reduction of blood flow impedance in the uterine arteries of infertile women with
      electro-acupuncture.
AB  - In order to assess whether electro-acupuncture (EA) can reduce a high uterine
      artery blood flow impedance, 10 infertile but otherwise healthy women with a
      pulsatility index (PI) >=3.0 in the uterine arteries were treated with EA in a
      prospective, non-randomized study. Before inclusion in the study and throughout
      the entire study period, the women were down-regulated with a gonadotrophin
      releasing hormone analogue (GnRHa) in order to exclude any fluctuating endogenous
      hormone effects on the PI. The baseline PI was measured when the serum oestradiol
      was <=0.1 nmol/l, and thereafter the women were given EA eight times, twice a
      week for 4 weeks. The PI was measured again closely after the eighth EA
      treatment, and once more 10-14 days after the EA period. Skin temperature on the
      forehead (STFH) and in the lumbrosacral area (STLS) was measured during the
      first, fifth and eighth EA treatments. Compared to the mean baseline PI, the mean
      PI was significantly reduced both shortly after the eighth EA treatment (P <
      0.0001) and 10-14 days after the EA period (P < 0.0001). STFH increased
      significantly during the EA treatments. It is suggested that both of these
      effects are due to a central inhibition of the sympathetic activity.

PMID- 8671447
TI  - The production of tumour necrosis factor alpha (TNF-alpha) by human endometrial
      cells in culture.
AB  - The production of tumour necrosis factor alpha (TNF-alpha) by cultured human
      endometrial epithelial and stromal cells prepared from endometrium obtained at
      different stages in the menstrual cycle has been investigated. TNF-alpha was not
      detectable in the supernatants of stromal cell cultures prepared from endometrial
      tissue obtained at any time in the menstrual cycle. TNF-alpha production by
      endometrial epithelial cells in culture varied depending on the time in the cycle
      at which the endometrial tissue was taken. Cells prepared from tissue obtained
      during the late proliferative phase of the cycle produced more TNF-alpha than
      those prepared from tissue obtained at other times in the cycle. In addition, a
      small increase in TNF-alpha production was seen by cells prepared from tissue
      obtained during the mid-secretory phase of the cycle. Interleukin 1 (IL-1) (1.4
      140 pmol/l) caused a dose-dependent increase in TNF-alpha production by cells
      prepared from both proliferative and secretory endometrium. Maximum IL-1
      stimulated increases in TNF-alpha production were similar in cells from both
      proliferative and secretory endometrium and typically reached from four to 10
      times basal values. High doses of progesterone, either alone or in the presence
      of oestradiol, also affected TNF-alpha production by epithelial cells. TNF-alpha
      production by cells prepared from proliferative endometrium was increased by
      progesterone. In contrast, TNF-alpha production by cells prepared from secretory
      endometrium was decreased in the presence of progesterone. The effects of
      steroids on TNF-alpha production were less marked than that of IL-1, with values
      increasing or decreasing to a maximum of three times the basal value. Placental
      protein 14 (PP14) (0.18 and 1.8 nmol/l) also increased TNF-alpha production by
      cells prepared from proliferative tissue, but had no effect on its production by
      cells prepared from secretory endometrium. PP14-stimulated TNF-alpha levels
      typically only reached a maximum of two times basal values.

PMID- 8671448
TI  - Female age predicts embryonic implantation after ICSI: a case-controlled study.
AB  - From 1 October 1991 until 31 December 1993, 1270 cycles for intracytoplasmic
      sperm injection were performed. Of these, 71 (5.6%) were carried out in women
      >/=40 years of age. The semen characteristics in couples >/=40 years of age or
      <40 years were similar. The mean male age for the older group of women was 47.1
      years (range 34-67) versus 35 years (25-71) for the younger group of women (P <
      0.001). The mean female age was 41.9 years (range 40-47) and 31.8 years (range 23
      39). The numbers of cumulus-oocyte complexes and metaphase-II oocytes were
      significantly lower in women >/=40 years of age (P < 0.001). The mean numbers of
      replaced embryos were respectively 2.3 (133/59) in women >/=40 years of age and
      2.5 (160/63) in women <40 years of age. The delivery rate per retrieval and per
      transfer was significantly lower in women >/=40 years of age (P < 0.05). The
      delivery rates per retrieval and per transfer were respectively 7% (5/71) and
      8.5% (5/59) in the older group of women versus 22.5% (16/71) and 25.4% (16/63) in
      the younger group. Female age is the predictive factor for embryonic
      implantation.

PMID- 8671449
TI  - Establishment and characterization of a cytotrophoblast cell line from normal
      placenta of human origin.
AB  - A cell line has been established from human placentae at the first trimester of
      normal pregnancy. The cell line was obtained by culture of purified
      cytotrophoblast cells in serum-free medium supplemented with epidermal growth
      factor, insulin, dexamethasone and 0.1% bovine serum albumin. The cells can be
      subcultured for >30 passages in one to three splits. All the cells were
      mononuclear epithelial-like cells positive to cytokeratin 18, gonadotrophin
      releasing hormone (GnRH), neuropeptide Y, neurotensin, leucine-enkephalin,
      dopamine and 5-hydroxytryptamine immunocytochemical staining. The cells secreted
      GnRH, progesterone and oestradiol (in the presence of testosterone) but little
      human chorionic gonadotrophin and no beta-endorphin. The cell line showed human
      karyotypes and had a population doubling time of 48 h in serum-free medium.
      However, the cells would stop growing in the medium containing fetal bovine
      serum. A normal cytotrophoblast cell line established in serum-free medium will
      be particularly useful in the study of cytotrophoblast cell proliferation and
      differentiation.

PMID- 8671450
TI  - Pregnancy outcome after multifetal pregnancy reduction to twins compared with
      spontaneously conceived twins.
AB  - Multifetal pregnancy reduction (MFPR) appears to be an efficacious method for
      improving the perinatal outcome of 'high order' multifetal gestations. The
      present study was undertaken to evaluate pregnancy outcomes after MFPR to twins
      in comparison with spontaneously conceived twins. In all, 10 patients with
      quadruplet gestation (group 1) and 30 patients with triplet gestation (group 2),
      who underwent MFPR to twins, were prospectively enrolled. Pregnancy
      complications, gestational age at delivery, mode of delivery and birthweights
      were compared with 30 consecutive spontaneous twin gestations (group 3) matched
      by maternal age and parity. Mean gestational age at delivery and mean
      birthweights were significantly lower in group 1, compared with groups 2 and 3
      (33.2, 35.9, 36.9 weeks, and 1843, 2209, 2361 g respectively). The incidence of
      pregnancy complications was significantly higher in group 1 compared with group
      3. There was also a clear trend of increased incidence of specific pregnancy
      complications in group 1 compared with groups 2 and 3, especially premature
      contractions (PMC; 50, 27 and 13% respectively), and pregnancy-induced
      hypertension (PIH; 40, 23 and 7% respectively). In conclusion, the initial number
      of fetuses before reduction was inversely correlated with gestational age at
      delivery and birthweight, and positively correlated with pregnancy complications.
      Contrary to previous studies, we found a higher incidence of pregnancy
      complications after MFPR compared with spontaneous twins, especially PMC and PIH.

PMID- 8671451
TI  - Decreased interleukin-2 production by rat uterine artery, aorta and uterine
      tissues during pregnancy.
AB  - Changes in size and function during pregnancy are unique to the uterine artery.
      The aim of this study was to determine the interleukin (IL)-6 activity of the
      uterine artery wall tissue in pregnant rats. A total of 18 Charles River white
      rats (nine virgin and nine in midpregnancy) were used for the study. Bilateral
      uterine arteries were obtained, together with reference tissues from aorta and
      uterus. IL-6 production was measured as optical density (OD)/mg protein, in
      control culture media, and in the presence of stimulants including IL-1, tumour
      necrosis factor alpha and lipopolysaccharide. Polyclonal rabbit anti-human IL-6
      antibodies were used to assess IL-6 activity. In control culture medium, uterine
      artery tissue samples from virgin rats produced significantly higher
      concentrations of IL-6 than samples obtained from pregnancy animals (1.8 +/- 0.3
      versus 0.9 +/- 0.25 OD/mg protein respectively (mean +/- SE, P = 0.001).
      Stimulation by lipopolysaccharide increased IL-6 activity of the uterine artery
      wall. In comparison with the uterine artery, the aorta produced higher activities
      of IL-6, and its production in virgin animal samples was higher than during
      pregnancy. Stimulants increased IL-6 production by both aorta and uterus tissues.
      Neutralization of IL-6 activity was obtained in a range of 77-93% in all samples.
      The lower level of IL-6 activity during pregnancy in the uterine artery and in
      reference tissues including aorta and uterus, may be related to acceptance of
      pregnancy by maternal tissues.

PMID- 8671452
TI  - Pregnancies achieved with testicular and ejaculated spermatozoa in combination
      with intracytoplasmic sperm injection in men with totally or initially immotile
      spermatozoa in the ejaculate.
AB  - The efficacy of intracytoplasmic sperm injection (ICSI) employing testicular and
      ejaculated spermatozoa was assessed in 24 couples with totally or initially
      immotile spermatozoa. No criteria were employed in selecting which patients would
      be treated with testicular or ejaculated spermatozoa. The men were chosen at
      random. Testicular spermatozoa obtained by testicular sperm extraction were used
      in 14 and ejaculated spermatozoa were used in 10 of these couples. In all cases.
      asthenozoospermia was total in their basal semen sample. In 12 male partners,
      spermatozoa were totally immotile before and after Percoll gradient fractionation
      (totally immotile). In the remaining 12 men, spermatozoa initially showed a total
      absence of motility; however, some of the spermatozoa had showed very poor
      motility (0. 1%) after Percoll gradient fractionation and a 1.5-2.0 h incubation
      period (initially immotile). Of these 24 total asthenozoospermic males, 14 also
      had total teratozoospermia. The fertilization and cleavage rates in the
      testicular and ejaculated sperm groups were 53. 5 and 96.3 and 54.5 and 94.4%
      respectively. One cycle resulted in complete fertilization failure, and in 23
      embryo transfer cycles a total of 10 pregnancies were obtained (41.6%). Eight
      pregnancies were achieved in the testicular sperm group, while only two
      pregnancies were obtained in the ejaculated sperm group. Four pregnancies, two
      from the ejaculated sperm group and two from the testicular sperm group, resulted
      in clinical abortions in the first trimester. Of the remaining six pregnancies,
      two have already resulted in healthy births and four pregnancies are now in the
      second or third trimester in the testicular sperm group. Using testicular
      spermatozoa in combination with ICSI can be an alternative mode of treatment in
      cases with totally or initially immotile spermatozoa in the ejaculate. Very low
      pregnancy rates have been obtained and no ongoing pregnancy has been achieved
      using ejaculated spermatozoa in these cases.

PMID- 8671453
TI  - Spontaneous conception and intrauterine pregnancy in a symptomatic missed
      abortion of ectopic pregnancy conceived in the previous cycle.
AB  - We encountered a rare case of combined intrauterine and extrauterine pregnancy
      that occurred following separate spontaneous ovulations. A 33 year old woman
      visited our hospital with the chief complaint of abdominal pain on April 16,
      1993. Her last menstruation was from March 23 for 6 days. However, the urinary
      human chorionic gonadotrophin (HCG) on April 19 was 1024 IU/l. Pelvic examination
      and ultrasonography indicated an extrauterine pregnancy, which was confirmed by
      laparotomy and histological identification of trophoblast cells. The urinary HCG
      concentration markedly decreased after the operation. However, the HCG level
      increased again on the fifth post-operative day, and a gestational sac (11 mm)
      was identified in the uterine cavity on the 11th post-operative day, indicating
      that this intrauterine pregnancy was established following spontaneous ovulation
      which occurred before the removal of the extrauterine pregnancy. This case
      indicates that a combined pregnancy can occur not only after simultaneous
      multiple ovulations but also after the separate spontaneous ovulations.

PMID- 8671454
TI  - Double cervix and vagina with a normal uterus: an unusual Mullerian anomaly.
AB  - A 34 year old woman presented with primary infertility and duplication of the
      cervix and vagina. Laparoscopy demonstrated a normal uterus and
      hysterosalpingography revealed a normal uterine cavity communicating with both
      cervices. This rare Mullerian anomaly is inconsistent with our current
      understanding of Mullerian development. An alternative embryological mechanism is
      reviewed to account for this and other anomalies which do not fit into existing
      classification systems.

PMID- 8671455
TI  - Delayed cleavage of human oocytes after intracytoplasmic sperm injection.

PMID- 8671456
TI  - Improving the recovery and handling of spermatozoa from testicular homogenates.

PMID- 8671457
TI  - Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation
      syndrome.

PMID- 8671459
TI  - Spontaneous pregnancy after previous pregnancy by oocyte donation due to
      premature ovarian failure.

PMID- 8671460
TI  - Information access and donated gametes.

PMID- 8671462
TI  - A patient's guide to donor insemination and in-vitro fertilization clinics.

PMID- 8671463
TI  - HFEA's patient guidelines penalize the value of embryo preservation.

PMID- 8671464
TI  - ART regulation: the Australia viewpoint.

PMID- 8671465
TI  - Comparing the British and American approaches to regulating ART programmes.

PMID- 8671466
TI  - About the HFEA patients' guide to donor insemination and in-vitro fertilization
      (IVF) clinics - are we crossing the rubicon?

PMID- 8671467
TI  - Procreatics and honesty.

PMID- 8671468
TI  - ART reporting: the American view.

PMID- 8671469
TI  - Spermatid conception: a stage too early, or a time too soon?

PMID- 8671470
TI  - Ovarian hyperstimulation syndrome: pre-ovulatory serum concentrations of
      interleukin-6, interleukin-1 receptor antagonist and tumour necrosis factor-alpha
      cannot predict its occurrence.
AB  - The pathogenesis of the ovarian hyperstimulation syndrome (OHSS) is poorly
      understood. Since significant elevations in cytokines are found in OHSS, our
      objective was to conduct a prospective case-controlled study to assess if pre
      ovulatory cytokine serum concentrations can predict its occurrence. The study
      group was selected from in-vitro fertilization patients who subsequently
      developed severe OHSS, along with a matched group who did not develop this
      complication (n = 20), and a healthy normal control group (n = 10). Interleukin-6
      (IL-6), interleukin-1 receptor antagonist (IL-1RA) and tumour necrosis factor
      alpha (TNFalpha) measurements were performed with sensitive immunoassays and
      confirmed with bioassays. Serum IL-6 (mean concentrations +/- SEM: 4. 38 +/- 0.36
      pg/ml), IL-1RA (829 +/- 292 pg/ml) and TNFalpha (15.5 +/- 1.32 pg/ml)
      concentrations did not show differences throughout the normal menstrual cycle
      group. Cytokine variability and pre-ovulatory values were similar in OHSS
      compared to controlled ovarian hyperstimulation (COH) patients. However, average
      follicular phase serum IL-6 concentrations were higher in OHSS (8.71 +/- 0.41
      pg/ml) and COH (7.66 +/- 0.38 pg/ml) patients than in normally menstruating women
      (4.34 +/- 0.99 pg/ml) (P < 0.0001). Pre-ovulatory serum IL-6 concentrations were
      also higher in OHSS (9 +/- 0.94 pg/ml) and COH (7.3 +/- 0.97 pg/ml) patients than
      in controls (4.57 +/- 1.1 pg/ml) (P < 0.01 and P < 0.04 respectively). All IL-1RA
      and TNFalpha concentrations were comparable in all the groups. This study
      suggests that cytokine measurements cannot be used to predict the occurrence of
      OHSS prior to the administration of human chorionic gonadotrophin.

PMID- 8671471
TI  - Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome.
AB  - The objective of this study was to follow the kinetics of four inflammatory
      cytokines in the plasma and ascitic fluid of seven patients who developed severe
      ovarian hyperstimulation syndrome (OHSS) after induction of ovulation for in
      vitro fertilization. Blood samples were obtained from these patients at three
      different times: upon hospitalization; when significant clinical improvement was
      evident; and after complete resolution. Samples were analysed for interleukin-1
      (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor
      alpha (TNF-alpha). Ascitic fluid was obtained by therapeutic paracentesis from
      all study patients during the active phase and analysed for these cytokines. Two
      control groups were available: the first included 15 women undergoing controlled
      ovarian stimulation for in-vitro fertilization without developing OHSS, while the
      second consisted of 25 healthy women not undergoing ovulation induction or any
      other medical treatment. High concentrations of IL-1, IL-6 and TNF-alpha were
      detected in all individuals upon admission for severe OHSS. Concentrations
      dropped significantly along with clinical improvement, reaching normal values
      after complete resolution. A statistically significant correlation was found
      between plasma cytokine concentrations and certain biological characteristics of
      the syndrome such as leukocytosis, increased haematocrit, and elevated plasma 17
      beta-oestradiol concentrations. Ascitic fluid obtained from the study patients
      contained high IL-6 and IL-8 concentrations, while other cytokines were
      unaltered. These results suggest close association between inflammatory cytokines
      and the pathophysiology of the ovarian hyperstimulation syndrome.

PMID- 8671472
TI  - Immunohistochemical study of steroidogenesis and cell proliferation in polycystic
      ovarian syndrome.
AB  - We evaluated the immunolocalization of the steroidogenic enzymes involved in the
      production of ovarian steroids, including the cholesterol side-chain cleavage
      enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (HSD), 17alpha-hydroxylase
      (P450c17) and aromatase (P450arom), oestrogen receptor (ER) and androgen receptor
      (AR), a steroidogenic transcription factor. Ad4-binding protein (Ad4BP) and a
      cell cycle-related nuclear antigen, Ki67, in five patients with polycystic
      ovarian syndrome (PCOS). Results were compared with those from normal cycling
      human ovaries to study in situ ovarian steroidogenesis and cell proliferation in
      polycystic ovaries (PCO). We classifed the follicles morphologically according to
      the development of granulosa types: type A, more than four layers (n = 7); type
      B, one to three layers (n = 11); and type C, theca interna cells only (n = 21).
      ER and P450arom were not observed in any of the follicles examined. In type A
      follicles, P450scc, 3beta-HSD, P450c17, AR and Ad4BP were observed in theca cells
      in all seven follicles examined, but the granulosa cells were positive only for
      Ad4BP (4/7) and AR (7/7). These immunohistolocalization patterns resembled those
      in non-selected antral follicles of normally cycling human ovaries. In theca
      cells from types B and C follicles, follicles positive for the steroidogenic
      enzymes, AR and Ad4BP were decreased in number. There were no significant
      differences between types A and B PCO follicles in the Ki67 labelling index of
      granulosa or theca cells, and between PCO and antral follicles from normally
      cycling human ovaries. Data demonstrate that the follicles of PCO are by no means
      atretic and are actively involved in both steroidogenesis and cell proliferation.
      The absence of ER and aromatase expression in the granulosa cells of PCO may be
      important in abnormal follicular development in patients with PCOS.

PMID- 8671473
TI  - Ovarian reserve test with the gonadotrophin-releasing hormone agonist buserelin:
      correlation with in-vitro fertilization outcome.
AB  - A gonadotrophin-releasing hormone agonist stimulation test determination of
      follicle stimulating hormone (FSH) concentrations before and 2 h after buserelin
      injection was carried out in 78 in-vitro fertilization cycles, and compared with
      basal FSH concentrations to predict ovarian response. Ovarian response was
      quantified by the ratio of peak oestradiol concentration divided by the total
      dose of human menopausal gonadotrophin (HMG) administered, the most reproducible
      parameter in 11 patients who underwent two treatment cycles. Stimulation outcome
      was highly related to the buserelin test, the best prognostic indicator being the
      sum of FSH concentrations. However, basal FSH concentration achieved similar
      correlations, even in those patients aged > 35 years. Sensitivity, specificity,
      positive and negative predictive values of basal FSH concentration and sum of FSH
      concentrations were similar. Low basal concentration and sum of FSH
      concentrations were both associated with a better ovarian response. Construction
      of receiver operator characteristic curves demonstrated that basal FSH
      concentration was more informative than the sum of FSH concentrations. Finally,
      the sum of FSH concentrations did not increase the prediction of ovarian response
      variability. We conclude that the buserelin test is strongly predictive of
      stimulation outcome, but is no more informative than the usual screening. We
      suggest that the performance of other stimulation tests should be clearly
      compared with that of basal FSH concentration.

PMID- 8671474
TI  - Comparison of gonadotrophin-releasing hormone analogues and human chorionic
      gonadotrophin for the induction of ovulation and prevention of ovarian
      hyperstimulation syndrome: a case-control study.
AB  - Gonadotrophin-releasing hormone analogue (GnRHa) has been suggested as an
      alternative to human chorionic gonadotrophin (HCG) for triggering ovulation,
      while preventing ovarian hyperstimulation syndrome (OHSS). Since a prospective,
      controlled study would be unethical at this point, we used a retrospective, case
      self control approach to compare GnRHa with HCG in that context. A group of 16 in
      vitro fertilization (IVF) patients who had severe OHSS in previous cycles, in
      which HCG was given to trigger ovulation, were studied in subsequent cycles in
      which GnRHa was used. Each GnRHa cycle (case) was compared to a previous HCG
      cycle that resulted in OHSS (self control). None of these subsequent cycles
      resulted in severe OHSS. The use of GnRHa did not affect the number of oocytes
      retrieved or their quality. Serum oestradiol concentrations on the day of
      ovulation triggering were significantly (P < 0.01) higher in the GnRHa cycles
      compared to HCG cycles. Exogenous progesterone and oestradiol were effective in
      maintaining relatively constant serum oestradiol and progesterone serum
      concentrations during the luteal phase. Pregnancy rate per cycle was similar in
      the two groups. In conclusion, the use of GnRHa to induce ovulation in IVF
      patients, who are at high risk for developing OHSS, effectively eliminates this
      risk without affecting other parameters of the stimulation cycle.

PMID- 8671475
TI  - A 'sweet' indication for ovulation induction.
AB  - In diabetic patients, euglycaemia at the time of conception is crucial for the
      success of the pregnancy. In consideration of the difficulty in achieving and
      maintaining tight glycaemic control for long periods, we administered clomiphene
      citrate, which is usually indicated in cases of absent or infrequent ovulation,
      to enhance fecundability in 10 pregestational diabetic patients. All conceived
      within one to three cycles of the drug, and nine delivered healthy term babies
      after uneventful pregnancies; one aborted spontaneously in the eighth gestational
      week. No effect of the drug on the diabetes was noted as based on measurements of
      glycosylated haemoglobin and fructosamine concentrations and the absence of
      changes in the patients' insulin requirements. In the light of these successful
      results, and in view of the importance of euglycaemia at the beginning of
      diabetic pregnancies, we suggest a new 'sweet' indication for the use of
      clomiphene citrate.

PMID- 8671476
TI  - Subtle progesterone rise after the administration of the gonadotrophin-releasing
      hormone antagonist cetrorelix in intracytoplasmic sperm injection cycles.
AB  - In the present study, subtle serum progesterone rise (>= 1.1 ng/ml) during the
      late follicular phase is reported, for the first time to our knowledge, in
      patients using a potent gonadotrophin-releasing hormone (GnRH) antagonist,
      Cetrorelix, in combination with human menopausal gonadotrophin (HMG) for ovarian
      stimulation prior to intracytoplasmic sperm injection (ICSI). In five out of 24
      patients (20%) serum progesterone levels were >/= 1.1 ng/ml. The cycle
      characteristics of the patients were similar in both groups. No premature
      endogenous luteinizing hormone (LH) surge occurred and the serum LH
      concentrations were constantly low during the follicular phase. The 17-beta
      oestradiol and follicle stimulating hormone (FSH) exposure were higher in cycles
      with premature luteinization. The greater oestradiol and FSH exposure confirm
      that one of the possible factors inducing subtle serum progesterone rise is the
      increased oestradiol and FSH-induced LH receptivity in granulosa cells.

PMID- 8671478
TI  - The indirect immunobead test for seminal antisperm antibodies and fertilization
      rates at in-vitro fertilization.
AB  - A series of 183 patients with positive indirect immunobead tests on semen was
      studied to determine the correlation in semen between specific antibody types,
      binding sites, antibody concentration, and fertilizing ability. IgM was present
      in only 44 ejaculates and was present in sufficient quantity to cause significant
      binding to immunobeads (i.e. >20% of motile donor spermatozoa) in only three of
      them. There was no correlation between the percentages of motile donor
      spermatozoa that bound IgA and IgG immunobeads but the two classes of beads
      generally bound to the same region of the spermatozoa. A total of 63 couples went
      on to attempt in-vitro fertilization (IVF) treatment, all with mature eggs
      recovered. Of these mature eggs, 44% were fertilized and cleaved normally in
      comparison to 68% in a group of patients with tubal disease. Fertilization rates
      in individuals followed a bimodal distribution with a substantial number of
      couples experiencing zero or very poor rates (0-20%), the mode for the remainder
      lying between 60 and 80%. The fertilization rate tended to decrease as the amount
      of antibody increased. The percentage of donor spermatozoa that bound to
      immunobeads, taken as the greater of IgA and IgG, was selected by logistic
      regression as a significant predictor of poor fertilization (rate <=25%). The
      predictive power of the equation was improved by including the motile normal
      sperm concentration but the equation could only account for a small proportion of
      the total variation in fertilization rate. The presence of antibodies to the
      sperm head was highly correlated with the antibody concentration but was not
      selected as a predictor of fertilization. We conclude that the nature of the
      antigen against which the seminal antisperm antibody is directed may be as
      important as the antibody concentration in affecting sperm function. There seems
      to be little practical value in measuring IgM in seminal plasma.

PMID- 8671477
TI  - Antibodies to chlamydia trachomatis in semen and relationship with parameters of
      male fertility.
AB  - To screen for infection with Chlamydia trachomatis in semen samples from
      asymptomatic men in couples consulting for infertility and to determine the
      relationship of seminal chlamydial antibodies with clinically relevant parameters
      of male fertility, 197 randomly chosen patients were enrolled in a prospective
      study. The median duration of infertility was 4 years (range 1-18). Screening for
      C. trachomatis and chlamydial antibodies of the immunoglobulin (Ig) A and IgG
      classes were performed in ejaculates and, in parallel, endocervical material from
      the partners of the patients and serum samples from both partners were evaluated.
      A comprehensive examination of semen quality included sperm analyses, semen
      cultures, local antisperm antibody (ASA) testing, the determination of potential
      infection markers, and sperm-cervical mucus interaction testing in vitro (SCMPT)
      and in vivo (post-coital testing). Chlamydial IgA antibodies were found in the
      semen samples of 18.8% (37/197) of the patients, while chlamydial IgG antibodies
      were found in 8.1% (16/197) of the patients. Screening for C. trachomatis was
      negative in all semen and cervical specimens. Only 5.5% of men remembered a past
      genital infection. Chlamydia antibodies (IgA/Ig/G) in semen were significantly
      correlated with chlamydia IgG antibodies in serum samples (P < 0.001). No marked
      relationship was found between the presence of seminal chlamydial antibodies and
      the major parameters of sperm analysis, semen cultures, local ASA and sperm
      penetration testing as an indicator of functional capacity. Seminal chlamydial
      antibodies were not significantly associated with potential infection or
      inflammation markers in aliquots of the same ejaculates. However, a significant
      relationship of chlamydial antibodies in patients' semen with past genital
      infections of their female partners was found with clinical relevance for a tubal
      infertility factor. The results indicate that in asymptomatic patients the
      presence of chlamydial antibody IgA or IgG in semen is not associated with
      reduced semen quality, potential seminal infection markers or impaired functional
      capacity as important determinants of male fertility; however, seminal chlamydial
      antibodies suggesting a previous sexually transmitted disease are significantly
      related to a tubal infertility factor of female partners.

PMID- 8671479
TI  - Comparison between hysterosalpingo-contrast sonography and sonographically
      controlled selective tubal catheterization.
AB  - Hysterosalpingo-contrast sonography was compared with sonographically controlled
      selective tubal catheterization (STC) in 26 infertile women who complained of
      infertility. Both procedures were carried out on a single examination date. A
      group of 10 patients first underwent hysterosalpingo-contrast sonography followed
      by STC, while 16 first had STC followed by hysterosalpingo-contrast sonography.
      The main outcome measure was tubal patency. A total of 52 Fallopian tubes was
      assessed. Hysterosalpingo-contrast sonography showed 39 tubes (75%) and STC 46
      (89%) to be patent, 13 tubes (25%) and six tubes (12%) were diagnosed to be
      proximally occluded, by means of hysterosalpingo-contrast sonography and STC
      respectively. Concordant diagnosis with both methods was made in 43 of 52 tubes
      (83%). When hysterosalpingo-contrast sonography was followed by STC, the
      concordance rate was 85%. When STC was followed by hysterosalpingo-contrast
      sonography, the concordance rate was 81%. In one patient the diagnosis of
      proximal occlusion of one tube as determined by hysterosalpingo-contrast
      sonography and STC had to be correlated in laparoscopy. In a patient, who after
      hysterosalpingo-contrast sonography and STC, was suspected to have bilateral
      proximal occlusion of the tubes, considerable bilateral proximal stenosis and
      distal occlusion was documented at laparoscopy. In conclusion, sonographically
      controlled STC may correct a misdiagnosis in cases where hysterosalpingo-contrast
      sonography leads to the finding of proximal tubal obstruction. The combination of
      hysterosalpingo-contrast sonography and STC as an out-patient investigation
      method for tubal patency assessment in infertile women avoids anaesthesia and
      radiation. For this reason we recommend the combination of sonographically
      controlled STC with hysterosalpingo-contrast sonography, at least in cases where
      proximal tubal occlusion is suspected after hysterosalpingo-contrast sonography.
      The influence of the order in which the two methods are used on the results of
      both should be investigated in a randomized study.

PMID- 8671480
TI  - Laparoscopic myomectomy of large symptomatic leiomyoma using airlift gasless
      laparoscopy: a preliminary report.
AB  - Despite the expanding role of laparoscopic surgery in many gynaecological fields,
      some discrepancies still exist regarding the efficacy of laparoscopic myomectomy
      in treating patients with large symptomatic leiomyoma. In this report, a better
      operative procedure and the results of treatment are evaluated. Patients (n = 14)
      presenting with infertility, menorrhagia, pressure symptoms or pelvic mass
      associated with a large leiomyoma were managed with laparoscopic myomectomy using
      airlift gasless laparoscopy. Uterine size ranged from 14 to 24 weeks gestational
      age and the weight of the myoma ranged from 246 to 669 g (mean 454); operative
      time ranged from 78 to 165 min (mean 104) and blood loss from 90 to 580 ml (mean
      201). No major complication occurred during the operation or follow-up. All
      except one patient were discharged within 72 h of the operation and resumed
      normal activity within 1 week. When myomectomy is indicated, the airlift gasless
      laparoscopic approach appears to offer a better alternative to abdominal or
      pneumoperitoneum laparoscopic surgery in selected cases. Airlift gasless
      laparoscopy has several advantages: (i) small abdominal incisions and minimal
      endoscopic equipment are required; (ii) the excised leiomyomata mass can be
      easily cut into strips and removed through the small abdominal incision; (iii)
      the uterine defect can be more efficiently repaired using easily performed suture
      techniques; (iv) high-pressure irrigation and large-volume suction devices can be
      used without fear of decompressing the pneumoperitoneum; and (v) the potential
      risk of metabolic and haemodynamic derangements during pneumoperitoneum
      laparoscopy are obviated. Gasless laparoscopy also has some disadvantages. The
      exposure obtained with gasless laparoscopy is not as good, under some
      circumstances, as that achieved by pneumoperitoneum. For patients who are thin,
      and even those with moderate obesity, the exposure obtained with airlift
      mechanical suspension is adequate; however, morbidly obese patients with previous
      abdominal surgery with suspected pelvic adhesions can incur some problems during
      the operation because of a poor operative field.

PMID- 8671481
TI  - Mucocele formation 20 years after an appendiceal uterine transplantation for
      infertility mistaken for hydrops tubae profluens.
AB  - A 56 year old woman was admitted to our hospital with a 9-year history of
      recurrent, lower abdominal pain and mucoid vaginal discharge 20 years after an
      appendiceal uterine transplantation. The removal of the uterus and the attached
      appendix resulted in the disappearance of the symptoms. A mechanism linking the
      appendiceal mucoid discharge with abdominal pain in this menopausal patient is
      suggested.

PMID- 8671482
TI  - Late luteal phase dydrogesterone in combination with clomiphene or tamoxifen in
      the treatment of infertility associated with irregular and infrequent
      menstruation: enhancing patient compliance.
AB  - This pilot study was undertaken to determine whether dydrogesterone administered
      in the late luteal phase might have a potential benefit for infertility
      associated with irregular and infrequent menstruation. Between April 1994 and
      February 1995, 54 normo-prolactinaemic women received either tamoxifen, if there
      was evidence of polycystic ovaries and/or increased luteinizing hormone (LH)
      secretion, or clomiphene together with dydrogesterone 10 mg twice daily on days
      21-26 of the menstrual cycle. A total of 23 women (42.6%) conceived (10.7% per
      cycle). In 192 non-conception cycles the average cycle length was 29.6 days; 182
      cycles (94.8%) were 34 days or less. Patients found the rapid onset of regular
      menstruation to be encouraging and compliance was excellent. Controlled studies
      are indicated to determine whether the addition of dydrogesterone to oral ovarian
      stimulation is beneficial.

PMID- 8671484
TI  - Semen parameters as predictors of in-vitro fertilization: the importance of
      strict criteria sperm morphology.
AB  - This study evaluated 120 couples undergoing in-vitro fertilization treatment to
      determine which semen parameter(s) predicted fertilization and whether there was
      any consistent relationship between strict criteria and standard assessment of
      sperm morphology. Strict criteria morphology was the only significant predictor
      of fertilization (P = 0.0006, r2 = 0.09), with a sensitivity of 94% and a
      specificity of 40%. A 12% cut-off point presented a negative predictive value of
      98% and a positive predictive value of 22%. The probability of satisfactory
      fertilization is 40% with morphology <4%, which increases to 97% with normal
      morphology (>=12%). The receiver operating characteristic curve deviated
      significantly from the diagonal with a 76% area under the curve, making this a
      superior predictive test. This was augmented by likelihood ratios (LR) of 8. 25
      (LR+) for results with <4% normal morphology and 0.15 (LR-) for results with >/=
      12% normal morphology by strict criteria. While there was some correlation
      between strict criteria and standard assessment of morphology (r = 0.35), the
      former explained only 12% (r2 = 0.12) of the variability in the latter. This
      study concludes that strict criteria morphology predicts fertilization, while
      other semen parameters do not. A 12% cut-off point makes strict criteria
      morphology an excellent predictor of satisfactory fertilization, while a value
      <4% is a good predictor of poor fertilization.

PMID- 8671483
TI  - Endometrial lymphomyeloid cells in abnormal uterine bleeding due to
      levonorgestrel (Norplant).
AB  - Endometrial lymphomyeloid cell subsets were evaluated in samples from normal
      women and from women with abnormal uterine bleeding due to subcutaneous
      levonorgestrel implants (Norplant) or an intrauterine device (IUD). The frequency
      of CD3(+), CD68(+), CD43(+) and endometrial granulated lymphoid cells was
      evaluated by immunohistochemical or phloxine-tartrazine staining of formalin
      fixed paraffin-embedded samples. In normal women, cyclic variation in
      lymphomyeloid subsets was seen. In women using Norplant for contraception, the
      frequency of CD3(+), CD68(+) and CD43(+) cells was dramatically decreased,
      compatible with endometrial atrophy. When Norplant users with abnormal bleeding
      were compared to women without bleeding, however, the number of CD68(+) cells was
      significantly increased and the number of CD3(+) and CD43(+) cells was preserved,
      contrary to the hypothesis that this group would show a greater degree of atrophy
      and hence, tissue fragility. A similar pattern was seen in a preliminary study of
      women with bleeding associated with use of copper-only IUD contraception, and in
      samples taken from late secretory and menstrual biopsies from normal cycling
      women. Whether these changes in endometrial lymphomyeloid cells represent a
      result of bleeding arising from a common mechanism or rather cause the uterine
      bleeding is discussed.

PMID- 8671485
TI  - Evaluation of motility, freezing ability and embryonic development of murine
      epididymal sperm after coculture with epididymal epithelium.
AB  - Murine sperm from the caput, corpus and cauda epididymis were cocultured with
      epididymal epithelial cells of their own region or more distal regions, in the
      presence and absence of androgens (testosterone and dihydrotestosterone).
      Epithelial cell cultures were used 3 or 10 days after preparation in a complex
      tissue culture medium (Chang's) as plated tubules. The coculture studies
      involving spermatozoa and oocytes with epithelial cells were carried out in T6
      medium. Motility of caput spermatozoa was maintained for 24 h in the presence of
      day 3 corpus and cauda epithelial cells and hormones but not under other
      conditions. Likewise, the motility of corpus spermatozoa was maintained for 24 h
      in the presence of day 3 cauda epithelial cells and hormones but not other
      conditions. Fertilization of zona-intact oocytes by epididymal spermatozoa was
      not affected by their coculture for 24 h with epithelial cells but fertilization
      rates for zone-free oocytes were increased for caput spermatozoa cocultured with
      more distal epithelial cells. Fertilization rates for both zona-intact and zone
      free oocytes were increased for corpus spermatozoa cocultured with more distal
      cauda epithelial cells. The developmental capacity of embryos derived from caput
      spermatozoa was not significantly increased by coculture with epithelial cells
      but those derived from corpus spermatozoa cocultured with cauda epithelial cells
      were significantly increased. We conclude that the presence of more distal
      epithelial cells of the mouse epididymis maintains motility in culture, increases
      the ability of caput and corpus spermatozoa to fertilize zona-free oocytes and
      increases the developmental capacity of embryos formed from corpus spermatozoa.
      These observations demonstrate the function of epididymal regions in the
      maturation of murine spermatozoa for fertilization and embryo development.

PMID- 8671486
TI  - Changes in chromatin condensation of human spermatozoa during epididymal transit
      as determined by flow cytometry.
AB  - Inasmuch as caput epididymal and even testicular spermatozoa are now being used
      to generate pregnancies by direct injection into the oocyte, differences in the
      chromatin of spermatozoa from proximal and distal locations in the epididymis
      were studied. Acridine Orange staining was used to investigate chromatin
      structure in human spermatozoa which had left the testis and were undergoing
      maturation in the epididymis. Measurement of green and red fluorescence
      intensities of human spermatozoa by flow cytometry demonstrated a decrease in
      binding of Acridine Orange to DNA as the spermatozoa traversed the epididymis.
      Using spermatozoa from the cauda epididymis as the standard, the percentages of
      spermatozoa from the efferent duct, proximal corpus epididymis, midcorpus
      epididymis, distal corpus epididymis, proximal cauda epididymis and distal cauda
      epididymis that had matured with regard to chromatin condensation were 28 +/- 5,
      39 +/- 3, 49 +/- 5, 64 +/- 5, 69 +/- 6 and 74 +/- 4% respectively. It may be
      concluded that eggs fertilized by ejaculated spermatozoa receive a more highly
      condensed form of chromatin than that received by eggs inseminated with proximal
      epididymal or testicular spermatozoa.

PMID- 8671487
TI  - Consensus workshop on advanced diagnostic andrology techniques. ESHRE (European
      Society of Human Reproduction and Embryology) Andrology Special Interest Group.
AB  - The Workshop reviewed four areas of advanced diagnostic andrology identified in
      the World Health Organization's 1992 Laboratory Manual for the Examination of
      Human Semen and Sperm-Cervical Mucus Interaction as 'research tests'. These were
      computer-assisted sperm analysis (CASA), acrosome reaction tests, the zona-free
      hamster egg penetration test and sperm-zona pellucida binding tests. For each
      topic, the Workshop Report comprises an overview of the particular field, a
      chronicle of the discussion that followed and a statement of the specific
      consensus points that were established. Free discussion allowed the elaboration
      of several general concepts that are presented here as the Workshop participants'
      perceived framework for future work in this area. While it was recognized that
      large-scale screening of male partners using advanced sperm function tests is
      almost certainly totally impractical on grounds of cost and lack of adequate
      services, urgent consideration was recommended for the development of a sperm
      function testing strategy capable of providing the likelihood of pregnancy for
      given diagnostic situations within certain timeframes. Establishing a clear
      definition of the role of diagnostic andrology in male infertility should be a
      primary focus of the Special Interest Group's activities. Further initiatives,
      including training courses, workshops, symposia and multicentre research studies,
      will be accorded high priority. Similar consideration will also be given to
      protocols for facilitating rational management decisions to ensure cost-effective
      therapeutic strategies, including consideration of the hierarchy of complexity
      and cost versus predicted fecundity. In addition, it was recognized that we need
      a greater understanding of the genetic basis of male infertility and how this
      impacts on the achievement of a viable pregnancy, while also minimizing the
      burden of genetic defects on the next generation.

PMID- 8671488
TI  - DNA fragmentation of oocytes in aged mice.
AB  - To investigate whether female fertility decreases with age due to poor oocyte
      quality, we examined the presence of DNA fragmentation in ovulated oocytes from
      young, mature and aged mice. Oocytes from three age groups of female mice (7-8,
      20-24 and 40-48 weeks) were retrieved from the oviducts 15 h after human
      chorionic gonadotrophin (HCG) injection. Oocytes from each mouse were incubated
      in a CO2 incubator for 0-60 h in human tubal fluid (HTF). After incubation, each
      oocyte was stained with the terminal deoxynucleotidyl transferase-mediated dUDP
      nick-end labelling (TUNEL) method. The rate of DNA fragmentation (interpreted as
      apoptotic changes) was significantly higher for oocytes from aged mice, and the
      fertilization rate was significantly lower, compared with oocytes from young and
      mature mice. Our results suggest that DNA fragmentation of oocytes might be one
      of the reasons for poor oocyte quality and lower fertility in the aged group.

PMID- 8671489
TI  - A model conforming the decline in follicle numbers to the age of menopause in
      women.
AB  - The store of primordial follicles in the ovary is fixed before birth and dwindles
      with age until it is unable to provide enough Graafian stages to sustain
      menstrual cyclicity. According to a simple bi-exponential model of ageing, the
      rate of follicle disappearance increases at age 37.5 years (or when 25 000
      follicles remain) so that the numbers fall to approximately 1000 at 51 years, the
      median age of menopause in the population. This study attempts to produce a
      biologically more realistic model of follicle disappearance and harmonizes
      follicle dynamics with the distribution of menopausal ages from an American
      survey. The step-change in the rate of follicle attrition was replaced by a model
      which assumed that this rate changes more gradually with the size of the follicle
      store. This produced a distribution of predicted menopausal ages (based on an
      assumed threshold of 1000 follicles) which was closer to observed data. The fit
      further improved when the model was modified by having a threshold that varied
      across the population. Using such a stochastic threshold model for menopause, the
      number of fertile years remaining could be forecast with an acceptable margin of
      uncertainty if it ever becomes possible to estimate the size of the follicle
      store in vivo.

PMID- 8671490
TI  - Low temperature storage and grafting of human ovarian tissue.
AB  - Ovarian tissue storage at low temperatures is a promising new method for
      protecting young cancer patients from the sterilizing effects of chemotherapy
      and/or radiotherapy. Tissue can be stored and returned to the body in due course
      as a thin cortical graft since the primordial follicles are distributed
      peripherally and are relatively resistant to ischaemia. Slices of tissue donated
      by healthy patients were trimmed to a uniform size and preserved by slow freezing
      to liquid nitrogen temperatures for up to 2 months in one of the following
      cryoprotectants: dimethylsulphoxide, ethylene glycol, glycerol, propylene glycol.
      Their viability was assessed by counting follicles in histological sections 18
      days after grafting under the kidney capsules of severe combined immunodeficiency
      (SCID) mice, and the results were expressed as percentages of the numbers in
      comparable pieces of ungrafted tissue. While only 10% of the total number of
      follicles was found in the glycerol group compared to controls, significantly
      higher percentages (44-84%) survived cryopreservation in the other media. The
      tissues were sterile when frozen and thawed without a cryoprotectant. These
      results suggest that if comparable results could be achieved by autografting, a
      patient's fertility should be safeguarded from cytotoxic treatment.

PMID- 8671491
TI  - The presence of multinucleated blastomeres in human embryos is correlated with
      chromosomal abnormalities.
AB  - The purpose of the present study was to determine whether the presence of one or
      more multinucleated blastomeres during early embryonic development is associated
      with chromosomal abnormalities in sibling blastomeres of that embryo. Embryos
      with multinucleated cells (n = 47) detected on day 2 or 3 or development were
      compared to dividing embryos without multinucleation. Arrested embryos were
      excluded from this study. Chromosome abnormalities were detected using
      fluorescent in-situ hybridization (FISH) with X, Y, 18 and 13/21 chromosome
      specific probes. Of 47 embryos included in this study, 76.6% were chromosomally
      abnormal, compared to 50.9% in the control group (P < 0.001). Excluding
      aneuploidy, which is originated in the gametes and not the embryo, the
      differences were even higher, with 74.5% of multinucleated embryos being
      chromosomally abnormal compared to 32.3% of non-multinucleated embryos (P <
      0.001). Day of multinucleation appearance, number of nuclei per cell, number of
      multinucleated cells per embryo and developmental quality of the embryos as well
      as the type of fertilization (intracytoplasmic sperm injection versus standard
      insemination) were not found to affect the rate of chromosomal abnormalities in
      embryos with multinucleated cells. These results suggest that embryos with
      multinucleated cells may not be suitable for replacement and should be excluded
      unless no other embryos are available.

PMID- 8671492
TI  - Centrifugation of bovine oocytes for nuclear micromanipulation and sperm
      microinjection.
AB  - The reproductive biotechnologies of intracytoplasmic sperm microinjection,
      nuclear transfer and DNA microinjection require the visualization of cytoplasmic
      components and nuclei of oocytes and early embryonic cells. Bovine oocytes were
      matured and fertilized in vitro, and then centrifuged at the germinal vesicle,
      metaphase II and pronuclear stages and at syngamy. These (n = 536) were examined
      using light and transmission electron microscopy. The organelles stratified in
      five distinct zones in a consistent pattern in both oocytes and zygotes, though
      relative fractions changed in organelle composition after fertilization. These
      comprised a centripetal lipid zone, below which was a vesicular zone, then a
      supra-equatorial band of smooth endoplasmic reticulum (SER), a clear zone and a
      centrifugal mitochondrial zone. Cortical granules were located peripherally,
      single or clumped together, in the clear and mitochondrial zones. The nuclei were
      usually found associated with the SER or Golgi membranes, and chromatin was
      clumped at one pole within the nucleus. The maturation spindles were often
      located beneath the oolemma in all zones, while the first mitotic spindle was
      usually located in the clear zone. Some of the oocytes were activated by
      centrifugation and completed maturation.

PMID- 8671493
TI  - Sperm interaction with human oviductal cells in vitro.
AB  - In this article we describe the in-vitro interaction between human spermatozoa
      and oviductal epithelial cell monolayers. Freshly obtained spermatozoa were added
      to culture dishes containing human oviductal cells (co-culture), culture medium
      (control) or culture medium which had previously been used for culture of
      oviductal cells (conditioned medium). At 0, 5, 24, and 48 h of incubation the
      percentage of motile spermatozoa was determined and their motion characteristics
      analysed. Aliquots were taken to determine the percentage of acrosome-reacted
      spermatozoa. The spermatozoa were motile for a longer period in the presence of
      oviductal cells (54 +/- 9% co-culture versus 18 +/- 3% control, at 48 h) and the
      kinetics of the acrosome reaction exhibited a different pattern. In the control
      the percentage of reacted spermatozoa increased progressively throughout
      incubation. In co-culture, there was an increase only at 5 h; thereafter, the
      percentage of acrosome reactions did not change. Spermatozoa incubated in
      conditioned medium exhibited a behaviour halfway between the control and the co
      culture. The pattern of sperm movement was not different in any of the
      experimental conditions. Although there was no binding between spermatozoa and
      oviductal epithelial cells, the frequency of the ciliary beat increased after
      spermatozoa were added to the oviductal cell monolayers. These results suggest
      that incubation with oviductal cells increases sperm survival, stabilizes the
      acrosome, and modifies the frequency of ciliary beat.

PMID- 8671494
TI  - Temperature change in cryo-containers during short exposure to ambient
      temperatures.
AB  - Times have been defined for the handling of 0.25 ml embryo cryostraws and semen,
      in either 0.5 ml cryostraws or 1.0 ml cryovials containing 0.5 ml material,
      before potentially detrimental changes in temperature take place. When handling
      cryovials the time lag is relatively long, with 78.8 +/- 2.6 s being available to
      manipulate the vials before -80 degrees C is reached and 335.4 +/- 3. 8 s until
      the eutectic point (approximately -7 degrees C) is reached. However the situation
      with cryostraws is less tolerant. Both 0.25 and 0.5 ml versions reach
      temperatures >-80 degrees C within 40 s, and the eutectic point is reached in
      79.0 +/- 2.0 s in 0.25 ml cryostraws. These time/temperature data have proved
      useful in educating new technicians, as well as clinicians and nurses who may
      also handle frozen human material, in the need to minimize the ambient
      temperature exposure time of stored specimens so as to maintain optimal post-thaw
      viability.

PMID- 8671495
TI  - Preliminary experience with human oocyte cryopreservation using 1,2-propanediol
      and sucrose.
AB  - Feasibility of cryopreservation of mature human oocytes using 1, 2-propanediol
      and sucrose was studied initially utilizing 1 and 2 day old unfertilized oocytes.
      Of these 285 aged oocytes 55% survived thawing, and 41% of 128 oocytes
      inseminated by single sperm intracytoplasmic injection (ICSI) fertilized
      normally. Limited embryonic development occurred in 51% of these embryos (n = 27)
      observed for the next 4 days. Cryosurvival of fresh donated oocytes (n = 81) was
      poorer (n = 20; 24.7%), while fertilization (n = 13; 65%) and embryo development
      (100%) was good prior to uterine transfer on day 3. Eight oocyte recipient cycles
      were undertaken, in which cryopreserved donated oocytes were thawed and
      inseminated by ICSI. Five of these cycles reached embryo transfer, and three
      pregnancies were initiated though none went successfully to term. Oocyte
      cryopreservation will ultimately facilitate oocyte donation procedures; however,
      cryosurvival of fresh frozen oocytes must be improved to at least the degree
      observed with aged unfertilized oocytes.

PMID- 8671496
TI  - The factors affecting sperm binding to the zona pellucida in the hemizona binding
      assay.
AB  - Sperm binding to the zona pellucida is a prerequisite for fertilization. the
      hemizona binding assay (HZA) is commonly used to evaluate the zone-binding
      capacity of spermatozoa. The present study reports three factors that affect HZA.
      They were the base medium used, the protein source and the size of pipette used
      for removing loosely bound spermatozoa during HZA. The number of spermatozoa
      bound on the hemizona was compared between (1) Earle's balanced salt solution
      (EBSS) and Ham's F-10, and (2) between human serum and bovine serum albumin
      (BSA). Results indicated that EBSS and human serum both significantly increase
      the number of bound spermatozoa when compared to Ham's F-10 (P < 0.0001, paired t
      test) and BSA (P < 0.05, paired t-test) respectively. Pipettes of different
      diameters were used to study the effect of size in removing loosely bound
      spermatozoa on hemizona. Data showed that the diameter of the pipette should be
      >/=200 mm, in order not to remove bound spermatozoa excessively. These results
      emphasize the importance of standardization of the protocol of the hemizona assay
      worldwide to be able to compare results between different laboratories.

PMID- 8671497
TI  - Improved cleavage rate of human embryos cultured in antibiotic-free medium.
AB  - Retarded development and blastomere fragmentation of human preimplantation
      embryos represent a common phenomenon in in-vitro culture systems. Even though
      media composition is generally formulated to meet embryo nutritional
      requirements, the influence of antibiotic supplementation has not been
      investigated thoroughly. The present study was performed to evaluate the effects
      of antibiotics on embryo morphology and growth in modified culture media. A total
      of 196 zygotes from 18 couples was cultured in three different media: (i)
      conventional medium (n = 99, control group); (ii) medium modified with half the
      standard antibiotic concentration (n = 54; and (iii) antibiotic-free medium (n =
      43); 49 embryos from the control group were selected at the zygote stage and
      transferred to the patients on day 2. The remaining 147 zygotes were cultured to
      the blastocyst stage for cryopreservation; their morphology and cell number were
      assessed daily at 40, 64, 88 and 112 h post-insemination. Overall cleavage rate
      was 95% and embryo scoring revealed 91% grade 1 embryos throughout the culture
      period in the three media. Significantly higher cleavage rates were obtained in
      the antibiotic-free medium at each observation, including the blastocyst stage,
      when compared to the other two groups. In addition, no notable improvement was
      observed in the embryos cultured in a reduced concentration of antibiotics. In
      conclusion, antibiotic supplementation of media has an adverse effect on the
      growth rate of preimplantation embryos, even in reduced concentrations,
      suggesting that antimicrobial drugs may interfere with the timing of cleavage
      events either by delaying or blocking embryo development.

PMID- 8671498
TI  - Effect of different co-culture systems in early human embryo development.
AB  - The objective of this study was to examine the effects of different culture
      systems on the development of early human embryos in vitro. A total of 460
      fertilized oocytes from 82 cycles of patients was transferred into one of four
      systems: (1) into droplets of Ham's F10 medium + 12% normal human serum (NHS);
      (2) co-cultured on a human granulosa monolayer; (3) co-cultured with bovine
      oviductal epithelial cells (BOEC); or (4) co-cultured with bovine uterine
      epithelial cells (BUEC). The percentage of cleavage and the morphological
      appearance of embryos were recorded daily for 72 h in each system using an
      inverted phase-contrast microscope. The results showed that the proportions of
      the fertilized oocytes which developed to the four-cell stage 48 h after
      retrieval were, by culture system: (1) 70% (84/120); (2) 74% (85/115); (3) 78%
      (91/117); and (4) 76% (82/108). At 72 h after retrieval, the proportions of the
      eight-cell stage were, by culture system: (1) 45% (38/84); (2) 62% (53/85); (3)
      75% (68/91); and (4) 70% (57/82). We concluded that a higher proportion of
      fertilized oocytes developed to embryos at the eight-cell stage in systems 2, 3
      and 4 than in system 1. This indicates the beneficial effect of co-culture of
      human embryos with granulosa cell, BOEC and BUEC monolayers, which may be due to
      various factors.

PMID- 8671499
TI  - High incidence of triploidy in in-vitro fertilized oocytes from a patient with a
      previous history of recurrent gestational trophoblastic disease.
AB  - The patient described has a history of recurrent gestational trophoblastic
      disease following spontaneous conception. She subsequently underwent two cycles
      of in-vitro fertilization (IVF) for management of infertility related to tubal
      obstruction. IVF of the oocytes retrieved showed a significantly high incidence
      of abnormal fertilization resulting in the development of triploid embryos. This
      report explores the possible association of an oocyte defect predisposing to
      abnormal fertilization, resulting in a high incidence of triploid embryos. Since
      the development of partial hydatidiform moles is related to the origin of
      triploidy, this phenomenon is suggested to explain the occurrence of recurrent
      trophoblastic disease in this patient. We propose the use of intracytoplasmic
      sperm injection (ICSI) as a therapeutic option to minimize the incidence of
      triploidy in future IVF cycles; donor oocyte IVF would be another alternative.

PMID- 8671500
TI  - Non-competitive anti-oestrogenic actions of progesterone antagonists in primate
      endometrium: enhancement of oestrogen and progesterone receptors with blockade of
      post-receptor proliferative mechanisms.
AB  - Previous studies have shown that the progesterone antagonists (antiprogestins)
      inhibit oestrogen-dependent endometrial proliferation in ovariectomized monkeys,
      without having affinity to the oestrogen receptor (ER). This study was designed
      to investigate the effect of the antiprogestins mifepristone (RU 486) and
      onapristone (ZK 98,299), on the concentration of ER and progesterone receptor
      (PR) in the endometrium of long-term ovariectomized cynomolgus monkeys (Macaca
      fascicularis). In untreated monkeys, tissue preparations bound in total 228 +/-
      68 pmol [3H]-oestradiol/g protein (ER), and 119 +/- 42 pmol [3H]-R5020/g protein
      (PR). These values were not significantly different from the total binding
      capacities of tissues from monkeys treated with RU 486 alone or primates treated
      with oestradiol plus progesterone. Treatment with oestradiol alone almost doubled
      the ER and PR concentrations. Combined treatment with oestradiol and RU 486
      enhanced the ER and PR concentrations in a dose-dependent manner: 1 mg/kg body
      weight (bw) RU 486/kg increased both ER and PR contents about 3-fold. The dose of
      5mg/kg bw RU 486 or onapristone increased the ER and PR concentrations almost 6-
      and 5-fold respectively, compared with the oestradiol-treated controls. Our
      results demonstrate that RU 486 and onapristone increased the endometrial ER and
      PR concentrations far beyond the physiological level in ovariectomized,
      oestradiol-treated monkeys. Whether the over-expression of ER and PR in the
      presence of antiprogestins is causally related to the antiproliferative impact of
      antiprogestins in the endometrium (non-competitive anti-oestrogenic effects) or
      is an independent action in unknown.

PMID- 8671501
TI  - Endometrial thickness as a predictor of pregnancy after in-vitro fertilization
      but not after intracytoplasmic sperm injection.
AB  - An ultrasonographic evaluation of the endometrium was performed in 158 patients
      undergoing ovarian stimulation for an in-vitro assisted reproduction programme.
      Endometrial thickness was evaluated in 109 patients undergoing in-vitro
      fertilization (IVF) for female indications and in 49 patients undergoing
      intracytoplasmic sperm injection (ICSI) for male indications. The maximal
      endometrial thickness was measured on the day of human chorionic gonadotrophin
      (HCG) administration by longitudinal scanning of the uterus on the frozen image
      using electronic callipers placed at the junction of the endometrium-myometrium
      interface at the level of the fundus. Cases in which the endometrial thickness
      was >/=10 mm were included in group A; cases in which the endometrial thickness
      was <10 mm were assigned to group B. The age of the patients, serum 17-beta
      oestradiol concentrations on the day of HCG administration, the length of
      follicular stimulation, the number of follicles, 17-beta oestradiol
      concentrations per follicle on the day of HCG and the number of embryos
      transferred were analysed in each case. When comparing endometrial thickness and
      results in IVF and ICSI patients, an endometrium <10 mm predominated in IVF
      patients (27.5%) compared with those undergoing ICSI (16.7%) (P = 0.05);
      conversely an endometrium >=10 mm was more frequent in ICSI than in IVF patients.
      The incidence of pregnancy was higher in IVF group A patients (32/79; 41%) than
      in IVF group B patients (5/30; 17%) (P = 0.03), whereas no significant difference
      was found between ICSI group A (13/42; 31%) and ICSI group B (3/7; 43%) patients.
      Thus, a higher percentage of IVF patients had thin endometrium when compared with
      ICSI patients; thin endometrium was a prognostic indicator of pregnancy only in
      the case of a female indication for infertility (IVF). A thin endometrium in
      cases of female infertility may reflect a previous or present uterine pathology,
      whereas in indications of male infertility (i.e. cases using ICSI), in the
      absence of any associated uterine pathology, the presence of a thin endometrium
      is not predictive.

PMID- 8671502
TI  - Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of
      rapid sperm transport in patients with endometriosis and infertility.
AB  - Women suffering from infertility in association with mostly mild endometriosis
      were subjected to vaginal sonography of uterine peristalsis during the menstrual
      period, the early, mid- and late follicular phases, and the mid-luteal phase of
      the menstrual cycle. The data obtained were compared with those of healthy
      controls. Women with endometriosis displayed a marked uterine hyperperistalsis
      that differed significantly from the peristalsis of the controls during the early
      and mid-follicular and mid-luteal phases. During the late follicular phase of the
      cycle, uterine peristalsis in women with endometriosis became dysperistaltic,
      arrhythmic and convulsive in character, while in controls peristalsis continued
      to show long and regular cervico-fundal contractions. Hysterosalpingoscintigraphy
      during the early, mid- and late follicular phases revealed that hyperperistalsis
      in the early and mid-follicular phases of patients with endometriosis resulted in
      a dramatic increase in the transport of inert particles from the vaginal depot,
      through the uterus into the tubes and also into the peritoneal cavity. During the
      late follicular phase of the cycle, the dysperistalsis observed in women with
      endometriosis resulted in a dramatic reduction of uterine transport capacity in
      comparison with the healthy controls. We consider uterine hyperperistalsis to be
      the mechanical cause of endometriosis rather than retrograde menstruation.
      Dysperistalsis in the late follicular phase of patients with endometriosis may
      compromise rapid sperm transport. Uterine hyperperistalsis and dysperistalsis are
      considered to be responsible for both reduced fertility and the development of
      endometriosis.

PMID- 8671503
TI  - The benefits of mid-luteal addition of human chorionic gonadotrophin in in-vitro
      fertilization using a down-regulation protocol and luteal support with
      progesterone.
AB  - Luteal support is essential in in-vitro fertilization (IVF) when long-acting
      gonadotrophin-releasing hormone agonist (GnRHa) is used. Because progesterone
      lacks luteotrophic stimulation, it seems to be the drug of choice in cases with
      an increased risk of ovarian hyperstimulation syndrome (OHSS). The aim of this
      study was to assess the beneficial effect of the mid-luteal addition of human
      chorionic gonadotrophin (HCG) in IVF, using a down-regulation protocol and luteal
      support with progesterone, in a prospective randomized study. The study included
      170 IVF cycles down-regulated with long-acting GnRHa which were supported with 50
      mg/day progesterone i.m. during the luteal phase. Patients were evaluated in the
      mid-luteal period. Those without clinical signs of OHSS, oestradiol
      concentrations <1000 pg.ml and progesterone concentrations <50 ng/ml were
      randomly allocated to either the addition of 2500 IU HCG (HCG+ group) or no HCG
      (HCG- group). End luteal phase progesterone concentrations among non-pregnant
      patients were used to assess the contribution of exogenous progesterone and to
      categorize pregnancies according to their corpus luteum function. Similar low
      OHSS (2.7 and 1.8%) and pregnancy (30 and 29%) rates were observed in the HCG+
      and HCG-groups respectively. Of the 26 pregnancies in the HCG+ cases, there was
      only one case with reduced corpus luteum function, compared with 12 or the 25
      pregnancies among HCG-patients. Cases with reduced corpus luteum function
      required continuous progesterone support and presented lower betaHCG
      concentrations and a higher rate of adverse pregnancy outcome. We conclude that
      mid-luteal HCG addition does not affect pregnancy rate, but in fact helps to
      preserve corpus luteum function and avoids the need for further supplementation
      during early pregnancy.

PMID- 8671504
TI  - Prospective follow-up study of 423 children born after intracytoplasmic sperm
      injection.
AB  - In order to evaluate the safety of the intracytoplasmic sperm injection (ICSI)
      procedure, a prospective follow-up study of 423 children born after ICSI was
      carried out. The aim of this study was to compile data on karyotypes, congenital
      malformations, growth parameters and developmental milestones. Before starting
      the infertility treatment, couples were asked to participate in a follow-up study
      including genetic counselling and prenatal diagnosis. The follow-up study of the
      child was based on a visit to the paediatrician-geneticist at birth or at 2
      months of age, at 1 year and at 2 years of age when a physical examination for
      major and minor malformations and a psychomotoric evaluation were done. Between
      April 1991 and September 1994, 320 pregnancies obtained after ICSI led to the
      birth of 423 children (222 singletons, 186 twins and 15 triplets). Prenatal
      diagnosis determined a total of 293 karyotypes, one of which was abnormal (0.3%),
      and four were benign familial structural aberrations, all inherited from the
      paternal side. A total of 14 (3.3%) major malformations were observed, defined as
      those causing functional impairment or requiring surgical correlation.
      Neurological or developmental problems at the age of 2 months were found in 14
      children, four of whom were multiples. Compared to most registers of children
      born after assisted reproduction and to registers of malformations in the general
      population, the figure of 3.3% major malformations is within the expected range.
      Before drawing any firm conclusion, further careful evaluations of the available
      data are necessary.

PMID- 8671505
TI  - Perinatal outcome and follow-up of 82 children aged 1-9 years old conceived from
      cryopreserved embryos.
AB  - Embryo cryopreservation is routinely used in in-vitro fertilization (IVF)-embryo
      transfer programmes. Yet very few studies have reported the follow-up of children
      conceived with frozen/thawed embryos. This study was designed to follow up the
      total cohort of children conceived with cryopreserved embryos in A. Beclere
      Hospital in Clamart, France between 1986 and 1994. We were able to study 89
      children, aged 1-9 years old, out of the 93 conceived during this period (lost to
      follow-up: 4.3%). The prematurity rate was 14.7% for the singleton and 85.7% for
      the twins. Half of these premature deliveries occurred during the 36th week of
      amenorrhea. In all, 8% of the singleton and 28.6% of the twins were small for
      gestational age. At the time of the study, only three children aged 1 and 2 years
      old were below the 10th percentile. The total malformation rate was 3.4% when two
      abortions performed during the study period were added to the one (short ureter)
      found in our study group. The medical and surgical illness as well as principal
      acquisitions for children <5 years old and scholastic performance for older
      children did not show pathological features.

PMID- 8671506
TI  - Immunohistochemical evidence for increased numbers of 'classic' CD57+ natural
      killer cells in the endometrium of women suffering spontaneous early pregnancy
      loss.
AB  - Despite increasing knowledge about the cell populations that exist in the
      decidualized endometrium in normal early human pregnancy, little is known about
      the decidual leukocyte populations in women suffering spontaneous early pregnancy
      loss. Decidual leukocytes were investigated in 40 cases of spontaneous abortion
      using a panel of monoclonal antibodies specific for leukocytes, macrophages, T
      cells, B cells and 'classic' CD57(+) natural killer (NK) cells and an avidin
      biotin peroxidase immunohistochemical technique. Endometrial granulated
      lymphocytes (eGL), the predominant decidual leukocyte population in the first
      trimester of normal human pregnancy, were demonstrated with the phloxine
      tartrazine stain. There were significantly fewer leukocytes in decidua in
      spontaneous abortion, but the numbers of eGL, macrophages and T cells did not
      differ significantly between normal and pathological pregnancies. eGL and
      macrophages accounted for a greater proportion of the decidual leukocyte
      population in spontaneous abortion. Of the 40 spontaneous abortion cases, 20 had
      significantly increased numbers of 'classic' CD57(+) NK cells when compared with
      normal human pregnancy. A proportion of spontaneous abortions may occur because
      of increased 'classic' CD57(+) NK cell numbers in the decidua, which could become
      activated by local cytokines to attack the trophoblast.

PMID- 8671507
TI  - Association of bacterial vaginosis with a history of second trimester
      miscarriage.
AB  - The aim of this study was to determine whether bacterial vaginosis (BV) is
      associated with a history of recurrent pregnancy loss. A total of 500 consecutive
      patients attending the Recurrent Miscarriage Clinic were screened for the
      presence of BV. In women who had had at least one late miscarriage BV was found
      twice as commonly (27/130; 21%) as in women who had had only early losses
      (31/370; 8%) (P < 0.001). The difference was even larger (26 versus 8%) if women
      who had had term pregnancies were excluded. Moreover, BV was found three times
      more commonly in Afro-Caribbean women [17 (29%) of 58] than in Caucasian women
      [36 (9%) of 379] and, in both groups of women, BV was diagnosed at least twice as
      frequently in those with a history of at least one late miscarriage than in those
      who had experienced first trimester pregnancy losses only (P < 0. 001). The
      condition occurred twice as often among smokers than non-smokers and, in both
      groups, it was at least twice as common in women with a history of at least one
      late miscarriage as in those who had had early pregnancy losses only (P < 0.001).
      However, the relationship between BV and smoking was independent of ethnic
      origin. Women who douched with chloroxylenol were mostly Afro-Caribbean and had
      BV more than twice as often as women who did not douche.

PMID- 8671508
TI  - In-vitro fertilization treatment for unexplained recurrent abortion: a pilot
      study.
AB  - To determine the effectiveness of in-vitro fertilization (IVF) and embryo
      transfer for patients with unexplained habitual abortion, we carried out a
      prospective observational study using a historical comparison group. A total of
      12 couples with three or more (mean 4. 91, range 3-10 miscarriages) first
      trimester spontaneous abortions of unknown aetiology were treated with IVF and
      embryo transfer (group 1). Patients underwent IVF after combined gonadotrophin
      releasing hormone agonist/gonadotrophin treatment for ovarian stimulation, and
      three to four embryos were replaced into the uterus in all women. Eight of the 12
      women (66.6%) in group 1 became pregnant (one patient after a frozen-thawed
      embryo transfer), and all of them had viable pregnancies. A patient with 10
      previous abortions became pregnant and carried to term after IVF and embryo
      transfer, and subsequently miscarried two new spontaneous gestations. A
      historical comparison group (group 2) included the last eight women with
      unexplained recurrent abortion (mean 4, range 3-8 miscarriages) who underwent the
      same investigations for the condition and received identical early supportive
      care in their next spontaneous pregnancy as patients in group 1. Three of the
      eight pregnancies in group 2 ended in an abortion. Our results suggest that IVF
      and embryo transfer may be a new therapeutic approach for unexplained recurrent
      miscarriage.

PMID- 8671509
TI  - Combined intra-uterine and extra-uterine pregnancy associated with mild
      hyperstimulation syndrome after clomiphene ovulation induction.
AB  - We report a combined intra-uterine and tubal pregnancy associated with mild
      ovarian hyperstimulation syndrome (OHSS) following ovulation induction by
      clomiphene. The diagnosis of ectopic pregnancy was originally missed until
      rupture occurred. OHSS confused the clinical picture, the important diagnostic
      feature being the fall in the haemoglobin concentration. The patient had a left
      partial salpingectomy and the uterine pregnancy progresses normally.

PMID- 8671511
TI  - The risk of aortic dissection in women with Turner syndrome.

PMID- 8671510
TI  - Steroids and male immunological infertility.

PMID- 8671512
TI  - The difference in outcome of in-vitro culture of human testicular spermatozoa
      between obstructive and non-obstructive azoospermia.

PMID- 8671545
TI  - Perspectives on epidemiology in europe.

PMID- 8671546
TI  - Case counting in epidemiology: limitations of methods based on multiple data
      sources.
AB  - BACKGROUND: The application of capture-recapture methods in epidemiology has been
      proposed as an alternative to field surveys. This methodology is important for
      the future of epidemiology and deserves a critical analysis. METHODS: This paper
      reviews conditions for applying the capture-recapture models to epidemiological
      data, taking into account practical considerations, in particular the problem of
      case definition. RESULTS: The underlying assumptions are particularly restrictive
      resulting in a theoretical limitation of their applicability. In spite of the
      statistical developments designed to overcome these difficulties, the practical
      conditions for using the existing lists are often not fulfilled (availability,
      confidentiality). The major restriction is on the quality of the data which are
      often far below the standards required in specific prevalence surveys and which
      may differ between lists. This may result in a dramatic lack of specificity. The
      definition of the virtual subgroup of patients missing in all lists as generated
      by the statistical procedure, is questionable particularly when counting living
      patients. Field studies would be necessary for validation. CONCLUSIONS: In some
      particular situations (e.g. deceased patients, rare diseases), this methodology
      may provide a useful approximation to the number of ill subjects events, but
      users should be aware of their poor specificity. It can also be useful to
      complement data from surveillance systems by careful cross-checking with
      independent sources of information. Currently, this method cannot, in any way,
      replace direct population prevalence or incidence surveys.

PMID- 8671547
TI  - Socioeconomic status, migration and the risk of breast cancer in Italy.
AB  - BACKGROUND: High socioeconomic status and migration to a higher risk area have
      been linked to increased breast cancer risk. To evaluate the occurrence of breast
      cancer in women of different social class and residential history, we conducted a
      multicentre case-control study in Italy. METHODS: A total of 2569 cases of
      incident breast cancer were ascertained in northern, central and southern Italy.
      The controls were 2588 women admitted for a wide spectrum of acute conditions to
      the same hospitals where cases had been hospitalized. The effect of socioeconomic
      variables was evaluated with multiple logistic regression after stratification
      and adjustment for age, origin, centre, and selected reproductive and dietary
      factors. RESULTS: Compared to housewives, managers and professionals had a 1.7
      fold increased risk, whereas the relative risk was 0.7 and 0.6 respectively in
      helpers and manual workers. The risk of breast cancer also increased with
      increasing social level of the husbands's occupation and subjects's number of
      years of schooling. Women who originated in central and southern Italy, and
      migrated to northern Italy after age 24, but not those who migrated at a younger
      age, had a relative risk of 0.6 and 0.7 respectively, compared to lifelong
      residents in northern Italy. CONCLUSIONS: Our findings show that correlates of
      sociocultural level and place of origin exert an influence on breast cancer risk
      which is not accounted for completely by known risk factors (i.e. reproductive
      and menstrual characteristics and recent dietary habits). Such influence may thus
      occur early in life.

PMID- 8671548
TI  - Trends in cervical cancer mortality in South Africa.
AB  - BACKGROUND: Cervical cancer is an important cause of death throughout the world,
      especially in less developed countries. Reports of trends in cervical cancer
      mortality from less developed countries have been limited by poor data quality
      and inaccurate population estimates. This paper examines trends in cervical
      cancer mortality in South Africa from 1949 to 1990 and discusses the impact of
      cytology screening on these trends. METHODS: Analysis of national mortality
      statistics and reconstructed population data. RESULTS: The age-standardized
      mortality rates for Whites declined after the mid 1960s, while that for Coloureds
      rose, particularly before the 1970s. These trends were affected predominantly by
      trends among women in the 35-64 age range. CONCLUSIONS: The pattern of mortality
      in successive birth cohorts for Whites is consistent with a reduction in age
      specific mortality following the advent of cytological screening. The same
      pattern is not evident in trends for Coloureds, among whom screening has
      apparently had a minor impact if any at all. The apparent lack of impact of
      screening in those groups of women most at risk of cervical cancer lends weight
      to demands for the implementation of equitable and rational screening programmes
      for cervical cancer in South Africa and internationally.

PMID- 8671549
TI  - Dietary salt, nitrate and stomach cancer mortality in 24 countries. European
      Cancer Prevention (ECP) and the INTERSALT Cooperative Research Group.
AB  - BACKGROUND: High salt and nitrate intake are considered as risk factors for
      stomach cancer, but little is known about possible interactions. This ecological
      study examines the respective importance of both factors for stomach cancer
      mortality at the population level using data obtained under standardized
      conditions and with biochemical analyses performed in the same laboratories.
      METHODS: Randomly selected 24-hour urine samples from 39 populations, sampled
      from 24 countries (N = 5756 people for sodium, 3303 for nitrate) were obtained
      from the INTERSALT study. Median sodium and nitrate levels were age- and sex
      standardized between ages 20-49 years and averaged per country. Ecological
      correlation-regression analyses were done in relation to national stomach cancer
      mortality rates. RESULTS: The Pearson correlation of stomach cancer mortality
      with sodium for the 24 countries was: 0.70 in men and 0.74 in women (both P <
      0.001) and with nitrate: 0.63 (P = 0.001) in men and (P < 0.005) in women. In
      multiple regression of stomach cancer mortality, using sodium and nitrate as
      independent variables the adjusted R2 was 0.61 in men and 0.54 in women (both P <
      0.001). Addition of the interaction term (sodium x nitrate) to the previous model
      increased the adjusted R2 to 0.77 in men, and to 0.63 in women. The analysis of
      this model showed that the importance of nitrate as risk factor for stomach
      cancer mortality increased markedly with higher sodium levels. However, the
      relationship of stomach cancer mortality with sodium was always stronger than
      with nitrate. CONCLUSIONS: Salt intake, measured as 24-hour urine sodium
      excretion, is likely the rate-limiting factor of stomach cancer mortality at the
      population level.

PMID- 8671550
TI  - Twenty-four hour urinary nitrate excretion in 48 populations from 30 countries:
      an ECP-INTERSALT collaborative study.
AB  - BACKGROUND: There is considerable interest in the possible role of nitrate in
      gastric carcinogenesis, but little information on nitrate intake around the
      world. This is the first study to give comprehensive standardised data on nitrate
      excretion as a marker of intake, using 48 worldwide population samples. METHODS:
      Urinary nitrate excretion has been shown to be a valid measure of nitrate intake
      in people under 50. This report presents data on 24-hour urinary nitrate
      excretion from urine collections obtained in the INTERSALT study, based on random
      samples of men and women aged 20-49 from each of 48 population samples in 30
      countries. RESULTS: There was large variation in urinary nitrate excretion both
      within and between samples; within-sample (individual) distributions tended to be
      skewed towards higher values. Median values of the samples ranged from 0.42
      mmol/day (Labrador, Canada) to 3.52 (Beijing, People's Republic of China) in men
      and 0.44 mmol/day (Colombia) to 3.44 (Beijing) in women. Overall, median values
      were higher in men than women by 11% on average (higher in men in 37 of 48
      population samples). Comparison by geographical region of median values for men
      and women combined showed relatively low values in the samples in North America
      and Northern Europe (range 0.46-0.88 mmol/day), slightly higher values in Western
      Europe and Africa (0.68-1.11), and intermediate to high values in Southern
      Europe, Eastern and Central Europe and India (0.86-2.47). The highest median
      values were found in the Far Eastern samples (up to 3.48). Median values in the
      Central and South American samples ranged from 0.48 mmol/day (Colombia) to 1.37
      (Xingu Indians of Brazil, and Argentina). CONCLUSIONS: For the first time, these
      data give standardized information on urinary nitrate excretion from different
      geographical regions of the world, and provide a basis for the further
      exploration of the role of nitrate in the aetiology of disease in human
      populations.

PMID- 8671551
TI  - Italian style brewed coffee: effect on serum cholesterol in young men.
AB  - BACKGROUND: Increases in blood lipids have been observed in humans when coffee is
      brewed by the boiling method. The purpose of this study was to evaluate if giving
      up Italian coffee might reduce blood cholesterol levels. METHODS: Eighty-four
      normolipidaemic young adult males, after a 3-week baseline (BL), were randomly
      assigned to three different regimens of coffee consumption: espresso (E), mocha
      (M), and no coffee, but tea (T). The average coffee consumption during
      intervention (I) was 3.1 +/- 1.2 and 2.8 +/- 1.1 cups per day for espresso and
      mocha group respectively (espresso: 25-35 ml/cup; mocha: 40-50 ml/cup). Total
      cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were measured
      eight times during the study. Dietary pattern, alcohol consumption, smoking
      habits, drug use, and anthropometric data were also recorded. RESULTS: The
      changes observed in serum cholesterol concentration between baseline and
      intervention were not statistically different in all groups. The changes were 0.0
      mmol/l (T), +0.01 mmol/l (E) and +0.05 mmol/l (M) for total serum cholesterol; 0
      mmol/l (T), -0.02 mmol/l (E) and -0. 03 mmol/l (M) for HDL-C; -0.13 mmol/l (T),
      +0.02 mmol/l (E) and -0. 05 mmol/l (M) for LDL-C. Serum triglycerides showed a
      significant increase during intervention (P < 0.01 by ANOVA) in all groups with a
      change of 0.18 mmol/l, 0.18 mmol/l and 0.22 mmol/l, for tea, espresso and mocha
      group respectively. CONCLUSIONS: The results indicate that coffee brewed in the
      Italian way does not alter blood levels of total cholesterol, HDL-cholesterol and
      LDL-cholesterol, since no significant differences were observed in these blood
      parameters after a 6-week break from coffee consumption.

PMID- 8671552
TI  - Plasma fibrinogen and its correlates in urban Japanese men.
AB  - BACKGROUND: The intention of the study was to examine determinants of plasma
      fibrinogen concentrations in Japanese men. METHODS: A cross-sectional study was
      conducted in 1991 among 995 male employees aged 40-59 years in two urban
      companies. RESULTS: The overall mean value (standard deviation) of plasma
      fibrinogen concentration was 257 (57) mg/dl. There was a strong dose-response
      relationship between cigarette smoking and plasma fibrinogen concentration.
      Plasma fibrinogen was positively associated with age and serum total cholesterol,
      and inversely associated with ethanol intake, dietary intake of sea foods such as
      squid, octopus or shrimp. Intake of other major protein and lipid resources such
      as meat, eggs and milk, or intake of vegetables was not related to plasma
      fibrinogen. An effect of dietary intake of sea foods on plasma fibrinogen was
      small but significant after controlling for the other covariates; an 80 g/week
      larger intake of sea foods was associated with a 3.9 mg/dl (95% confidence
      interval: 0.5, 7.3) lower fibrinogen concentration. CONCLUSIONS: This study
      confirms the relation of known coronary risk factors to plasma fibrinogen in
      Japanese men, and suggests that dietary intake of sea foods affects plasma
      fibrinogen concentrations.

PMID- 8671553
TI  - The relationship of blood lead and dietary calcium to blood pressure in the
      normative aging study.
AB  - BACKGROUND: Previous studies have demonstrated a positive relationship between
      elevated blood lead (BPb) and blood pressure (BP), but few have additionally
      examined the role of dietary calcium. METHODS: The cross-sectional relationship
      between BPb and BP and the possible protective influence of increased dietary
      calcium on that relationship was examined among 798 male participants in the
      Normative Aging Study (NAS), a cohort of older men with relatively low BPb
      levels. RESULTS: The age range of these subjects was 43-93 years (mean = 66.1, SD
      = 7.4 years) and blood lead concentrations ranged form 0.5 to 35 mcg/dl (median =
      5.6 mcg/dl). For the cohort overall, neither ln blood lead nor dietary calcium
      were significantly correlated with BP. In multivariate linear regression analyses
      that adjusted for age, body mass index, dietary calcium intake (adjusted for
      total calorie intake), alcohol intake, sitting heart rate, kilocalories/week
      expended in exercise, haematocrit, and smoking status, a unit increase in ln BPb
      predicted an increase on 1.2 mmHg diastolic blood pressure (DBP) (95% CI : 0.11,
      2.2; P = 0.03). Adjusted calcium intake of 800 mg/day predicted a decrease of 3.2
      mmHg systolic blood pressure (SBP) (95% CI : -5.6, -0.24, P = 0.03). There was no
      evidence of an interaction between dietary calcium intake and blood lead on BP.
      When the analyses were restricted to those men <=74 years old, a unit increase in
      ln BPb predicted an increase of 1.6 mmHg DBP (n = 681; 95% CI : 0.42, 2.7; P =
      0.007). However, when men on antihypertensive medication (AHM) were excluded from
      the analyses, ln BPb was not significantly associated with increased DBP nor was
      adjusted calcium significantly associated with SBP. CONCLUSIONS: The study did
      support the hypothesis that increased BPb was associated with increased DBP in a
      cohort of older men with low blood lead, but there was no evidence of interaction
      between BPb and dietary calcium on BP. However, the relationship between
      increased BPb and DBP did not hold when those on anti-hypertensive medications
      were excluded.

PMID- 8671554
TI  - Deaths related to Hurricane Andrew in Florida and Louisiana, 1992.
AB  - BACKGROUND: Information about circumstances leading to disaster-related deaths
      helps emergency response coordinators and other public health officials respond
      to the needs of disaster victims and develop policies for reducing the mortality
      and morbidity of future disasters. In this paper, we describe the decedent
      population, circumstances of death, and population-based mortality rates related
      to Hurricane Andrew, and propose recommendations for evaluating and reducing the
      public health impact of natural disasters. METHODS: To ascertain the number and
      circumstances of deaths attributed to Hurricane Andrew in Florida and Louisiana,
      we contacted medical examiners in 11 Florida counties and coroners in 36
      Louisiana parishes. RESULTS: In Florida medical examiners attributed 44 deaths to
      the hurricane. The mortality rate for directly-related deaths was 4.4 per 1 000
      000 population and that for indirectly-related deaths was 8.5 per 1 000 000
      population. In Louisiana, coroners attributed 11 resident deaths to the
      hurricane. Mortality rates were 0.6 per 1000 000 population for deaths directly
      related to the storm and 2.8 for deaths indirectly related to the storm. Six
      additional deaths occurred among non-residents who drowned in international
      waters in the Gulf of Mexico. In both Florida and Louisiana, mortality rates
      generally increased with age and were higher among whites and males. CONCLUSIONS:
      In addition to encouraging people to follow existing recommendations, we
      recommend emphasizing safe driving practices during evacuation and clean-up,
      equipping shelters with basic medical needs for the population served, and
      modifying zoning and housing legislation. We also recommend developing and using
      a standard definition for disaster-related deaths, and using population-based
      statistics to describe the public health effectiveness of policies intended to
      reduce disaster-related mortality.

PMID- 8671555
TI  - Mortality trends in a cohort of opiate addicts, Catalonia, Spain.
AB  - BACKGROUND: Opiate addiction affects young adults whose life expectancy is
      reduced as a consequence of their habit. In the midst of the AIDS epidemic, the
      present study objective was to analyse recent overall and cause-specific
      mortality trends among opiate addicts in Catalonia (Spain). METHODS: Mortality
      was assessed retrospectively in an opiate addict cohort assembled from admissions
      to hospital emergency wards and drug treatment centres during the period 1985
      1991. The cohort included 12 711 opiate addicts (12 045 men and 3666 women) aged
      15-44 years. Overall and cause-specific mortality trends were analysed using age
      as the time scale and Cox regression with staggered entry determined by the age
      at entry in the study. Annual trends were adjusted by sex and source of entry,
      and were stratified by length of opiate use. RESULTS: Mortality rates increased
      throughout the entire period from 13.8 to 34.8 deaths per 1000 person-years, with
      a statistically significant increase in 1987-1988 and 1988-1989. In a model
      including age, gender, source of entry and length of drug use, risk increased
      significantly in men and for longer length of use, but not with age and for
      source of entry into the study cohort. The causes of death associated with high
      mortality rates were AIDS and the causes directly related to addiction.
      CONCLUSIONS: A threefold increase in mortality rates was observed during the
      period, mainly accounted for by AIDS and direct addiction-related causes. Length
      of opiate use was an important determinant of mortality.

PMID- 8671556
TI  - Twenty-four year mortality in World War II US male veteran twins discordant for
      cigarette smoking.
AB  - BACKGROUND: This study was undertaken to test the constitutional hypothesis which
      attributes the association of tobacco smoking with morbidity and mortality to
      genetic predispositions to smoking and/or disease. METHODS: Subjects were World
      War II veterans, born in the US between 1917 and 1927, and surveyed at mean age
      47 for present and past smoking habits. Twenty-four year mortality follow-up data
      were available for 1515 male twin pairs discordant for lifelong cigarette
      smoking. Using the first or only death of a smoking-discordant pair, 24-year
      relative risks of mortality were calculated by zygosity, cause of death, amount
      smoked, and age at death. RESULTS: We found that active smokers at baseline,
      regardless of zygosity, had a higher risk of death than their co-twins who had
      never smoked or quit smoking (monozygotic pairs: relative risk [RR] = 2.5; 95%
      confidence interval [CI] : 1.3-6.1 and RR = 1.7; 95% CI : 1.2-2.5; dizygotic
      pairs: RR = 2.4; 95% CI : 1.4-3.8 and RR = 2.0; 95% CI : 1.7-3.3). The elevated
      risk of death among smokers was due to deaths from lung cancer (monozygotic
      pairs: RR = 5.0; 95% CI: 2. 6-15.0; dizygotic pairs: RR = 11.0; 95% CI : 4.3
      45.0) or deaths from cardiovascular diseases (monozygotic pairs: RR = 3.9; 95% CI
      : 1.9-115; dizygotic pairs: RR = 2.8; 95% CI : 1.7-4.9). Apart from these
      findings the relationship of smoking with all-cause mortality was stronger for
      earlier/younger deaths and for heavy to moderate smoking. CONCLUSIONS: The
      present results, from the largest and longest-studied series of smoking
      discordant twins negate the constitutional hypothesis that genetic or early
      shared familial influences underlie the significant association between tobacco
      smoking and premature mortality.

PMID- 8671557
TI  - Socioeconomic differences in 'avoidable' mortality in Sweden 1986-1990.
AB  - BACKGROUND: 'Avoidable' mortality is commonly studied as an indicator of the
      outcome of health care. In this study socioeconomic differences in avoidable
      mortality in Sweden from 1986 to 1990 are analysed and related methodological
      issues discussed. METHODS: The 1985 Swedish Population and Housing Census was
      linked to the National Cause of Death Register 1986-1990. Mortality from
      potentially 'avoidable' causes of death was analysed for the age group 21-64
      years. Analyses were performed for different socioeconomic groups, blue-collar
      workers, white-collar workers and the self-employed as well as for individuals
      outside the labour market. Standardized Mortality Ratios were calculated using
      standardization by age and sex. RESULTS: For all indicators studied, the death
      rates for those not in work were higher than for people at work. The largest
      differences were found for chronic bronchitis, diabetes, bacterial meningitis,
      ulcer of the stomach and duodenum, chronic rheumatic heart disease, asthma and
      hypertensive and cerebrovascular disease. For these causes of death the risk of
      dying was between 3.1 and 7.5 times greater in the non-working population than in
      the work-force. The differences in avoidable mortality between blue-collar
      workers and white-collar workers and the self-employed were, however, much
      smaller. For most of the indicators no significant differences were found. For
      ulcers of the stomach and duodenum, however the death rate for blue-collar
      workers was 2.8 times higher than those for other categories in work.
      CONCLUSIONS: The small difference in mortality outcome for different
      socioeconomic groups within the work-force indicates an equal quality of care for
      these groups. The greatly increased risk among the non-working population,
      however, is a warning sign. These results may be due to a 'healthy worker'
      effect. The measurement of socioeconomic differences in mortality may be
      dependent on the time-period chosen between occupational exposure and mortality
      outcome.

PMID- 8671559
TI  - The association between maternal education and postneonatal mortality. Trends in
      Norway, 1968-1991.
AB  - BACKGROUND: This study examines whether the association between maternal
      educational level and postneonatal death has changed over time. METHODS: All
      single survivors of the neonatal period in Norway in three periods, 1968-1971,
      1978-1981 and 1989-1991 were studied. There were 582 046 births and 1717
      postneonatal deaths. Logistic regression analyses were applied. RESULTS: There
      has been an increasing inverse relationship between maternal educational level
      and postneonatal mortality in recent years. There was no statistically
      significant association between educational level and postneonatal mortality in
      the late 1960s. In the second period (1978-1981) the association is statistically
      significant for first-born children. In the third period (1989-1991) postneonatal
      mortality for first-born and later-born children was associated with maternal
      educational level, with adjusted odds ratios of 2.5 and 2.1 respectively. The
      overall level of education has increased tremendously, and the proportion of
      women with the lowest level of education has decreased from 56.3 to 10.7% in the
      period under study. CONCLUSIONS: The underlying causes of changes in the impact
      of educational level are hard to determine and are indicative of the complexity
      of using maternal educational level as an indicator of social status over time.
      Possible mechanisms by which certain variables may covary with educational level,
      and thus have an adverse effect on postneonatal mortality, are discussed. The
      fact that the inverse association between educational level and postneonatal
      mortality has increased over time should be a matter for concern. It may indicate
      that the growth of the welfare state has not reached all segments of the
      population.

PMID- 8671558
TI  - The impact of primary health care services on under-five mortality in rural
      Niger.
AB  - BACKGROUND: Despite large investments in basic primary health care in sub-Saharan
      Africa over the past two decades, quantifying the contribution of national
      programme efforts to the reduction of infant/child mortality in the region has
      proven difficult. This study takes advantage of the phased implementation of the
      national Rural Health Improvement Program in Niger and conveniently timed survey
      data to reassess programme impact on under-five mortality during the 1980-1985
      period. METHODS: Health service use and under-five mortality rates for children
      born in the 5 years prior to the 1985 survey are compared for three groups of
      villages: villages served by a dispensary, villages served by village health
      teams (VHT), and villages without access to modern primary care services. Multi
      level regression analyses using both household- and community-level variables are
      undertaken in estimating the magnitude of effects. RESULTS: Children residing in
      villages proximate to health dispensaries were approximately 32% less likely to
      have died during the study period than children without access to modern health
      services. Village health teams were not, however, associated with significantly
      lower mortality probabilities. Formal test for endogeneity indicated that these
      effects were not the result of non-uniform/non-random allocation of resources.
      CONCLUSIONS: The findings are largely supportive of the key premise underlying
      selective primary health care interventions - that packages of basic services can
      be effectively mounted nationally in poor countries and have a significant impact
      over a short time period. In Niger, less than optimal implementation of VHT
      appears to have reduced the magnitude of the impact achieved.

PMID- 8671560
TI  - The effects of maternal education on child nutritional status depend on socio
      environmental conditions.
AB  - BACKGROUND: Previous studies have shown an inconsistency in the association
      between maternal education and child nutritional status across socioeconomic
      levels. This may be because the beneficial effects of education are only
      significant when resources are sufficient but not abundant. METHODS: Associations
      were examined for differences across socioeconomic levels using data collected
      from 41 rural communities of Benin for 435 children aged 13-36 months. Village
      level indicators of household wealth were used together with child z-scores to
      partition the sample into three levels of socio-environment relative to
      conditions more or less conducive to child growth. RESULTS: Using an interactive
      linear regression model it was shown that for the population of children of women
      who had no more than 4 years of formal schooling, the association of maternal
      education and child weight differed significantly across the socio-environment.
      The relationship was flat and non-significant in the lowest socio-environment,
      positive and significant (P < 0.05) in intermediate conditions, and weakly
      positive under the best socio-environment conditions. Among children of mothers
      attaining higher levels of education, an unexpected negative association was
      found. It could be that maternal education had enabled women to participate in
      activities outside the home without simultaneously ensuring adequate child care.

PMID- 8671561
TI  - Self-perceived health status and inequalities in use of health services in Spain.
AB  - BACKGROUND: Socioeconomic differences have been described among the Spanish
      population. The purpose of this study was to investigate whether these variations
      are associated with differences in the use of health services between
      socioeconomic groups in Spain, taking into account self-perceived health as a
      measure of need. METHODS: Data were obtained from the 1987 Spanish National
      Health Survey. Socioeconomic position was measured by educational level and
      household income. Health care use was measured in two ways: prevalence of having
      consulted a doctor and of hospitalization over a defined period of time. Logistic
      regression models were used to analyse the relationship of interest. RESULTS:
      After adjustment for age, an inverse association was seen between education and
      both consultation with a doctor and hospitalization. A very different picture
      emerged when the association between socioeconomic position and probability of
      health service use was examined according to level of self-perceived health.
      Among those with poor or very poor health, people in higher educational groups
      showed the greatest probability of consulting a doctor (odds ratio [OR] = 1.41,
      95% confidence interval [CI] : 0.89-2.23) or of being hospitalized (OR = 1.79,
      95% CI : 1.09-2.93) compared to those in the lower educational groups. The
      corresponding OR for household income were 1.02 (95% CI : 0.74-1.42) for
      consultation with a doctor and 1.67 (95% CI : 1.15-2.44) for hospitalization.
      These finding were broadly similar for men and women. CONCLUSIONS: There is a
      socioeconomic variation in the pattern of use of health services in Spain in the
      sense that among those with poor self-perceived health, the more privileged have
      higher levels of health services use than others.

PMID- 8671562
TI  - A controlled intervention in reduction of redundant hospital days.
AB  - BACKGROUND: Inappropriate use of hospital services, in the form of unjustified
      hospital stay days (HSD), constitutes a major burden on a health budget.
      Reduction of unjustified HSD was achieved in a medical ward in a previous
      intervention study. METHODS: A controlled intervention aimed at reducing
      unjustified hospital stay was performed on 155 paediatric inpatients and 248
      controls, by applying pre-set criteria for hospitalization and comparing to
      results in previous studies. RESULTS: Unjustified stay was decreased from 32.6%
      to 14.8% on the study ward, and from 25.7% to 19.3% on the control ward. The
      children on both wards did not differ significantly in rates of subsequent out of
      hospital mortality, re-admission, and the subjective evaluation of health by
      their parents one month following discharge. CONCLUSIONS: This study demonstrates
      that despite the fact that the per cent of unjustified HSD on a paediatric wars
      is much lower than on medicine or surgery, a significant reduction in unjustified
      stay can be achieved by intervention programme.

PMID- 8671563
TI  - Validation of questionnaire and bronchial hyperresponsiveness against respiratory
      physician assessment in the diagnosis of asthma.
AB  - BACKGROUND: The Tasmanian Asthma survey (TAS) and the International Study of
      Asthma and Allergies in Childhood (ISAAC) have used questionnaires to measure the
      prevalence of asthma in adults and children. We have investigated the validity of
      these questionnaires by comparing response to questionnaire with a physician
      assessment of asthma status in the past 12 months. METHODS: Ninety-three adults
      were given the TAS questionnaire to complete and 361 children were given the
      ISAAC questionnaire. Ninety-one adults and 168 children completed bronchial
      challenge with hypertonic saline. A consultation with a respiratory physician
      blinded to the results of the questionnaire and bronchial challenge was given to
      all subjects. RESULTS: In both adults and children, questionnaires showed high
      agreement with respiratory physician diagnosis with respect to asthma symptoms in
      the past 12 months. For the TAS questionnaire the positive and negative
      predictive values (95% confidence limits) for physician diagnosis for adults were
      0.89 (0.68-0.98) and 0.94 (0. 86-0.98) respectively. The instrument was also
      sensitive 0.80 (0. 58-0.93) and highly specific 0.97 (0.90-0.99). For the ISAAC
      questionnaire the positive and negative predictive vales for physician diagnosis
      of asthma in children were 0.61 (0.50-0.71) and 0.94 (0.88-0.98) respectively.
      Sensitivity and specificity were 0.85 (0.73-0.93) and 0.81 (0.76-0.86)
      respectively. Compared to the physician diagnosis, the sensitivity of bronchial
      hyperresponsiveness (BHR) for asthma was low for adults 0.39 (0.21-0. 61) and
      children 0.54 (0.48-0.67) as were the positive predictive values: 0.55 (0.31
      0.79) for adults and 0.64 (0.449-0.77) for children. A definition of asthma
      requiring both a positive questionnaire response and BHR was highly specific but
      not sensitive for adults 0.37 (0.20-0.59) or children 0.47 (0.35-0.60).
      CONCLUSIONS: Both the TAS and ISAAC questionnaires are valid instruments for the
      determination of asthma symptoms in the past 12 months.

PMID- 8671564
TI  - Do patients with severe asthma run an increased risk from ischaemic heart
      disease?
AB  - BACKGROUND: Knowledge of the mortality outcome of asthma is limited to hospital
      case series follow-up. METHODS: To provide estimates of the mortality and cause
      of death in patients with asthma comparison of observed and expected number of
      deaths in patients with asthma for the observation period 1962-1986 was made. The
      study group was 262 patients aged 19-81 years with severe asthma. The group was a
      total sample of patients with a daily treatment of oral steroids more than one
      year, 1962-1963, from the city of Goteborg. RESULTS: Mortality from all causes
      was significantly raised among the asthmatics (179 deaths versus 83.5 expected,
      relative risk (RR) - 2.1, 95% confidence interval (CI) : 1.8-2.5). There was an
      excess mortality from ischaemic heart disease 58 versus 29.9 deaths (RR = 1.9,
      95% CI : 1.4-2.4), especially among women (RR = 2.4, 95% CI : 1.7-2.2). However,
      there was also an increased mortality from asthma (39 versus 0.4 deaths) and
      chronic obstructive pulmonary disease (11 versus 0.5 deaths). CONCLUSIONS: These
      findings suggest that subjects with severe asthma, especially women, have an
      increased mortality from ischaemic heart disease. The results may reflect
      confounding, mainly smoking and physical inactivity. Other explanations may be
      side effects of the antiasthmatic drugs or an effect of longstanding airway
      obstruction.

PMID- 8671565
TI  - Sensory impairments and physical disability in aged women living at home.
AB  - BACKGROUND: Studies of the impact of visual or hearing impairments on physical
      disability in older people have provided conflicting results. Furthermore, the
      consequences of the loss of such visual functions as depth perception or contrast
      sensitivity have rarely been studied. We examined the relationship of visual
      acuity, depth perception, contrast sensitivity, and hearing difficulty to the
      ability of older women living at home to accomplish instrumental activities of
      daily living independently. METHODS: Data on self-reported physical disability
      and hearing impairment, as well as objective measures of functional vision and
      physical ability were collected from a sample of 1210 community-dwelling women
      aged 75 years and older. Multivariate logistic regression modelling was used to
      assess the strength of the association between physical disability and sensory
      impairments, controlling for age, education level, motor limitations, and
      prevalent chronic diseases. RESULTS: Women with low visual acuity or low contrast
      sensitivity were significantly more likely to be physically dependent than women
      with good vision. Contrast sensitivity was, however, a better predictor than
      functional acuity, after controlling for age, education level, motor limitations
      and chronic medical conditions (adjusted odds ratio: 5.1; 95% confidence
      interval: 2.0-12.9). Depth perception was not related to physical disability.
      Women with serious hearing difficulty had significantly increased odds of
      dependency (4.1; 1. 4-12.1). CONCLUSIONS: Severe sensory impairments are strongly
      related to physical dependency in older women. It may be useful to add a test of
      contrast sensitivity to the traditional acuity test to predict better which
      elderly individuals may have difficulty carrying out routine daily activities.

PMID- 8671566
TI  - Occupation, employment status and chronic inflammatory bowel disease in Denmark.
AB  - BACKGROUND: Certain occupational groups have formerly been identified as having
      higher risks of suffering from chronic inflammatory bowel diseases. These were
      evaluated in an independent data set. METHODS: A cohort, comprising all 2 273 872
      male and female Danes aged 20-59 years on 1 January 1986 were followed up for
      hospitalizations due to chronic inflammatory bowel disease until 31 December
      1990. RESULTS: From 1981 to 1990 6296 first time admissions occurred. The
      incidence increased from 1981-1985 to 1986-1990. Of 363 male and 213 female
      occupational groups eight and five groups respectively had statistically
      significant raised standardized hospitalization ratios. Among 15 groups
      previously found to have significant odds ratios only female office staff and
      health occupations were found to have statistically significant raised
      standardized hospitalization ratios. Ratios for occupational groups with non
      daytime work were not statistically significant. Compared to occupations without
      sedentary work occupations with predominantly sedentary work had a standardized
      hospitalization ratio of 125 (95% confidence interval [95% CI] : 116.9-133.1).
      Self-employed had low hospitalization rates, while 'other salaried staff' and
      'not economically active' had high rates. CONCLUSIONS: We found no consistent
      pattern of occupations at increased risk except that sedentary work may increase
      the risk of attracting chronic inflammatory bowel disease.

PMID- 8671567
TI  - Risk factors for peptic ulcer in Shanghai.
AB  - OBJECTIVES: To investigate the combined effects of Helicobacter pylori infection
      and traditional risk factors for peptic ulcer. METHODS: A case-control study was
      conducted in chemical factories in Shanghai, China. The cases were 500 people
      with peptic ulcer randomly selected from all staff who met the selection
      criteria. The controls were 500 employees randomly selected from the same
      factories as the cases. RESULTS: The infection rate for H. pylori was 81% among
      the cases and 70% among the controls and 85% of all ulcers were duodenal. Current
      cigarette smoking was common among male cases (80%) and male controls (64%).
      Univariate analysis suggested that male gender, age, lower socioeconomic status,
      cigarette smoking, family history of peptic ulcer and infection with H. pylori
      were all associated with increased risk of peptic ulcer. Separate analyses were
      performed by sex and occupational group to avoid confounding by cigarette smoking
      and age. Multivariate analyses showed that for all women and for male staff
      members, only family history was significantly predictive of peptic ulcer or
      duodenal ulcer. Among male workers or drivers, however, all the major risk
      factors were statistically significantly associated with increased risk.
      CONCLUSIONS: In a population where the rate of infection with H. pylori is high,
      the traditional risk factors for peptic ulcer or duodenal ulcer (i.e. family
      history, male gender, increasing age, lower socioeconomic status and cigarette
      smoking) are still significant predictors of increased risk of ulcer. If men with
      ulcers (or with a family history of peptic ulcer) gave up cigarette smoking,
      morbidity could be reduced in this population.

PMID- 8671568
TI  - A generalization of Hewitt's test for seasonality.
AB  - BACKGROUND: Hewitt's statistic for seasonality in monthly data is the maximal
      rank sum among all possible rank sums derived using consecutive 6-month periods.
      In this paper, Hewitt's test is extended to include those instances where 3, 4 or
      5-month pulses or periods of raised incidence are hypothesized. METHODS: Monte
      Carlo methods are used to drive the approximate distribution of the test
      statistic under the null hypothesis, when the length of the hypothesized period
      is k = 3, 4, or 5. A combinatorial method is used to derive exact levels for the
      test statistic. The test is applied to monthly data on adolescent suicide.
      Finally, the power of the test is compared with the chi2 statistic using Monte
      Carlo simulation. RESULTS: The distribution of the test statistic was found and
      used to test the null hypothesis of no seasonal variation in monthly adolescent
      suicides, using a period of k = 3 months. The null hypothesis was rejected,
      indicating seasonality in the data. Monte Carlo simulations show the test
      statistic to be more powerful than the chi2 statistic when sample sizes are
      small. CONCLUSIONS: This generalization of Hewitt's test should be most useful in
      those instances where the researcher wishes to carry out a quick and simple test
      of the null hypothesis of no seasonality against the alternative of a
      predetermined 3, 4, or 5 month period of raised incidence. When there is no a
      priori hypothesis about the appropriate length of period.

PMID- 8671569
TI  - Use of relatives of cases as controls to identify risk factors when an
      interaction between environmental and genetic factors exists.
AB  - BACKGROUND: The difficulty in detecting relevant risk factors for chronic
      diseases (such as breast and colon cancer) may be due to heterogeneity in the
      populations of studied cases, and one source of heterogeneity may be differential
      genetic susceptibility predisposing to differential environmental sensitivity.
      METHODS: The purpose of this investigation is to determine whether the estimates
      of odds ratios are modified by using relatives as controls when risk factors
      interact with an underlying genetic factor. RESULTS: We demonstrate that using
      relative controls in matched case-control studies produces odds ratios different
      from population-based odds ratios. This difference is dependent on the amount of
      interaction between the genetic and environmental factors and on the genetic
      correlation between relatives. CONCLUSIONS: In the case of a common disease, the
      use of relatives as controls could be helpful in detecting interaction between an
      exposure and an underlying genetic factor when the genetic factor is common.

PMID- 8671570
TI  - Chlamydia pneumoniae antibodies in chronic obstructive pulmonary disease.
AB  - BACKGROUND: The significance of persistent or recurrent respiratory infections in
      adult life for the development of chronic obstructive pulmonary disease (COPD) is
      still to a large extent unknown. A few clinical and experimental animal studies
      suggest that peripheral airways diseases may be due to the cumulative effects of
      recurrent respiratory infections over an extended period. METHODS: C. pneumoniae
      specific IgG and IgA antibody levels were determined in two elderly groups of
      male patients with COPD and in control subjects without the disease. The first
      group (N = 36) consisted of patients who were hospitalized due to an acute
      exacerbation of COPD. The second group of patients (N = 54) and the controls (N =
      321) were participants in a community survey on respiratory diseases in the
      elderly. The criteria for seropositivity were defined as an IgG titre of >=16.
      RESULTS: 89% of the hospitalized patients (group I) and 66% of the non
      hospitalized patients (Group II) were IgA seropositive as compared to 55% of the
      controls. Derived from the logistic regression analysis, the odds ratio (OR) WAS
      7.4 (95% CI : 2.1-25.7) between group I and the controls and 1.5 (0.7-2.9)
      between group II and controls. Furthermore, the difference in the age-adjusted
      geometric mean titres (GMT) of lgA antibodies between the group I and the
      controls was significant (53.0 for the patients versus 19.1 for the controls). On
      the contrary, no significant differences between the patients and the controls
      were found either in the proportion of IgG-seropositive or in the GMT of IgG
      antibodies. Two of the 29 patients with an exacerbation of COPD, for whom paired
      sera were available, showed an antibody response suggesting a current acute or
      reactivated chlamydial infection. CONCLUSIONS: The results showed that C.
      pneumoniae lgA antibodies are found more frequently and in higher concentrations
      in COPD patients than in disease-free controls. The finding may indicate a
      chronic C. pneumoniae infection in these patients. The association persisted
      after controlling for the potential confounding effect of smoking.

PMID- 8671572
TI  - False positive tests for anti-hepatitis C antibodies and the problem of notifying
      blood donors.
AB  - BACKGROUND: All donated blood in Israel is tested for anti-hepatitis C virus
      (HCV) antibodies by enzyme immunoassay (EIA) and donors are notified of the
      result. There is evidence that at low antibody titres, the percentage of false
      positives may be high, with consequent labelling of healthy people as being
      infected with HCV. AIM: In this study we examined the correlation between anti
      HCV antibody titres determined by a second generation EIA test with supplemental
      EIA tests and evidence of abnormal liver function. METHODS: Blood samples of 201
      Israeli civilians who donated blood during 1992 and were repeat reactive for anti
      HCV antibody based on second generation EIA, were tested by a supplemental test.
      Follow-up data were obtained from the donors and their family physicians.
      RESULTS: Results of anti-HCV EIA tests on two separate occasions of blood
      donation were highly correlated with each other (r = 0.86). Positive supplemental
      tests and abnormal liver function tests were found only in those subjects with
      high antibody titres. Furthermore low antibody titres were more prevalent during
      the winter months, suggesting that seasonal intercurrent infections may increase
      the percentage of false positives. CONCLUSIONS: A high proportion of blood donors
      labelled as anti-HCV antibody positive based on low antibody titres, may not be
      at increased risk of carrying HCV. Since labelling would result in creating
      unnecessary anxiety among blood donors, it is important to confirm such results
      with test such as radioimmunoblot assay (RIBA).

PMID- 8671571
TI  - Child mortality following standard, medium or high titre measles immunization in
      West Africa.
AB  - BACKGROUND: The World Health Organization (WHO) recommended the use of high titre
      measles vaccine in 1989. Subsequent long term follow-up of several trials yielded
      results suggesting higher mortality among children inoculated with medium and
      high titre vaccines compared to standard titre vaccines, although none of the
      individual trials found significant differences in mortality. METHODS: Long term
      survival after standard, medium and high titre measles vaccines has been
      investigated in a combined analysis of all West African trials with mortality
      data. In trials from Guinea-Bissau, The Gambia and Senegal, children received
      medium or high titre vaccines from 4 months of age and were compared to control
      groups recruited at the same time later receiving standard titre vaccine from 9
      months of age. All children were followed up to at least 3 years old. RESULTS:
      Combining trials of high titre vaccines showed higher mortality among the high
      titre group compared to the standard group: mortality ratio (MR) = 1.33 (95% CI :
      1.02-1. 73). Mortality among recipients of medium titre vaccines was not
      different from that in the standard vaccine group, MR = 1.11 (95% CI: 0.54-2.27).
      In a combined analysis by sex, the adjusted mortality ratios comparing high titre
      vaccine with standard vaccine were 1.86 (95% CI : 1.28-2.70) for females and 0.91
      (95% CI : 0.61-1.35) for males. The trials were not designed to study long term
      mortality. Adjustments for several possible sources of bias did not alter the
      results. CONCLUSIONS: The combined analysis showed a decreased survival related
      to high titre measles vaccine compared with standard titre vaccines, though
      solely among females. As a result of these studies from West Africa and a study
      from Haiti, WHO has recommended that high titre measles vaccine no longer be
      used.

PMID- 8671573
TI  - Verbal autopsy as a tool for diagnosing HIV-related adult deaths in rural Uganda.
AB  - BACKGROUND: In general, information on the causes of adult deaths in developing
      countries is scarce. More specifically, relatively little is known about the
      effect of HIV-1 associated disease on adult mortality in general populations. In
      this study we have used a verbal autopsy technique to ascertain whether adult
      deaths were associated with HIV-1 in a rural population with a prevalence of HIV
      1 infection of 8%, and used HIV-1 antibody status to validate the verbal autopsy
      findings. METHODS: All adult deaths in the population cohort that occurred
      between December 1990 and November 1993 were identified through a monthly death
      registration system. Approximately 2 months after death, a relative of the
      deceased was interviewed by a trained nurse, and questionnaires were assessed by
      at least two independent clinicians; all were unaware of the HIV serostatus of
      the deceased. RESULTS: A total of 155 adult deaths was assessed, i.e. 53% of all
      recorded adult deaths. Of those assessed half were HIV-1 positive. In all 47% of
      deaths were classified as HIV-related. The overall specificity and positive
      predictive value of the verbal autopsy tool were both 92%; in those aged 13-44
      years (83 adults) the corresponding values were 85% and 95% respectively. The
      verbal autopsy estimated HIV-1 attributable mortality fraction was similar to the
      calculated fraction based on prospective data. CONCLUSIONS: The results of this
      study suggest that verbal autopsy studies may assist in providing data on HIV
      associated mortality in general populations and may be useful as surveillance
      tools.

PMID- 8671574
TI  - Breast cancer and ethylene oxide exposure.

PMID- 8671576
TI  - Epidemiologic measures of impact of community health promotion projects.

PMID- 8671578
TI  - Detection of slow-fast limit cycles in a model for electrical activity in the
      pancreatic beta-cell.
AB  - In this paper we consider a model for the phenomenon of bursting electrical
      activity in the pancreatic beta-cell. Consisting of three coupled first-order
      nonlinear differential equations, the model describes the dynamics of the
      membrane potential, the activation parameter for the voltage-gated potassium
      channel, and the intracellular calcium concentration. The bursting electrical
      activity depends on fast and slow processes with distinctly different time scales
      which, when taken to the limit of highly diversified dynamics, allow the
      application of the singular perturbation method. Explicit conditions are derived
      which differentiate various dynamic behaviours and identify, in particular, the
      limit cycles composed of alternate slow and fast transitions. Computer
      simulations are then presented to support our theoretical predictions.

PMID- 8671579
TI  - Mixing matrices: Necessary constraints in populations of finite size
AB  - This paper analyses the constraints used to define the elements of mixing
      matrices employed in deterministic models of the transmission dynamics of
      sexually transmitted infections. These matrices define the degree to which the
      choice of sexual partners in a population is assortative (like with like) or
      dissassortative (like with unlike) in populatiions stratified by sexual activity
      (i.e. the number of different sexual partners per unit of time). An expanded set
      of constraints is described which defines patterns of mixing on the assortative
      to disassortative spectrum in populations of finite size. The relevance of these
      new constraints to past work in this area is assessed. Keywords: mixing matrices

PMID- 8671580
TI  - Risk-sensitive optimal harvesting and control of biological populations
AB  - Theory recently developed elsewhere is introduced, to a more applied and
      biological audience, for the optimal control of linear systems with a risk
      sensitive exponential of a quadratic (LEQG) cost function, and for the optimal
      control of fully nonlinear systems through the risk-sensitive maximum principle
      (RSMP). The LEQG theory is extended, in this study, to give solutions for locally
      optimal stochastic control of nonlinear systems. Examples and applications are
      given of the extended theory, using simple, heuristic logistic models and more
      complex multicohort models of fisheries. Implementations of the nonlinear RSMP
      are described. The results show how the theories can be applied to biological
      harvesting and control problems. They also shed some light upon the character of
      the dynamics of the risk-sensitive optimal solutions, which have been little
      explored. Keywords: population dynamics; resource management; fisheries; risk.

PMID- 8671581
TI  - A mathematical model of the first steps of tumour-related angiogenesis: capillary
      sprout formation and secondary branching.
AB  - The growth of a solid tumour is dependent on an adequate supply of nutrients. A
      tumour can establish a blood supply by inducing neighbouring blood vessels to
      sprout and grow towards it, a process known as angiogenesis. The tumour cells may
      secrete a number of diffusible chemicals which stimulate endothelial cell to
      migrate, to rearrange themselves into capillary tubes or sprouts, and to
      proliferate. In this paper we focus firstly upon the early stage of angiogenesis
      wherein the endothelial cells group together in the parent vessel to form the
      initial capillary-sprout buds. A mathematical model for the formation of the
      capillary buds is presented which focuses on the potential role that haptotaxis
      may play. In Section 2 we turn attention to the endothelial cells within the
      growing and developing capillary sprouts as they migrate towards the tumour
      cells. Once again the potential role of haptotaxis is focused upon.

PMID- 8671582
TI  - Some drug-resistant models for cancer chemotherapy. Part 1: Cycle-nonspecific
      drugs.
AB  - The pioneering mathematical analyses for describing the phenomenon of clonal
      selection, whereby cancer cells mutate and become resistant to treatment, were
      carried out by Goldie & Coldman (1979, 1983). The present analysis yields more
      generalized drug-resistant models arising in chemotherapy treatment when cycle
      nonspecific (CNS) drugs (i.e. drugs which are toxic to cells irrespective of
      their position in the cell cycle) are deployed. This is accomplished by modifying
      models developed by Wheldon (1988) and Usher (1994) for investigating the effect
      of chemotherapy drugs on homogeneous cell populations (i.e. in the absence of
      drug resistance); both types of migration, of drug-sensitive cells to drug
      resistant cells, and the possibility of a migration of drug-resistant cells to
      drug-sensitive cells, are incorporated into the models. Subsequently, drug
      concentrations are sought such that both the drug-resistant cell subpopulation
      and the drug-sensitive cell subpopulation either simultaneously decay or remain
      of constant size. The analysis reveals that the role played by the migration of
      drug-resistant cells to drug-sensitive cells is significant, if it occurs, when
      seeking appropriate drug concentrations. The qualitative results from these
      models provide further insight into the effective treatment of cancer by
      chemotherapy in the presence of drug resistance.

PMID- 8671583
TI  - A multiple-pathway model for the diffusion of drugs in skin.
AB  - A mathematical model for the diffusion of drugs in skin is presented. The
      penetration of the drug by both transcellular and intercellular pathways, as well
      as its interchange between these pathways, is considered. A pharmacologically
      motivated asymptotic limit is identified and analysed to obtain, in particular,
      an analytical expression for the flux of drug to the blood at steady state.
      Relevant model data is discussed, and some numerical results are also presented.

PMID- 8671584
TI  - Changes in antigen densities on leukocyte subsets correlate with progression of
      HIV disease.
AB  - In a cross-sectional study of 154 HIV-infected and 33 uninfected healthy adults,
      we show that characteristic changes in the levels of expression of leukocyte
      surface antigens occur in the HIV-infected individuals. These changes, which
      collectively occur on virtually every leukocyte subset, are specific: a
      particular antigen may increase or decrease on one subset of PBMC but remain
      constant on another. Furthermore, within any particular subset, the levels of one
      or more antigens may change, while the levels of other surface antigens on the
      same cells remain constant. Some of these antigens density changes have been
      noted before, e.g. increased CD20 on B cells, and increased CD38 and HLA-DR on
      CD8 T cells. However, the multiparameter flow cytometry methodology used here
      reveals changes in a substantially larger number of surface markers, some of
      which are restricted to fine subsets of PBMC, such as naive or memory T cell
      subsets. For many of these antigens, the change in expression correlates with
      absolute CD4 counts >500/microl; others differ only in those with counts
      >100microl. The changes in antigen densities we observed on B and T cells are
      consistent with the observation of a persistent quasi-activated state of these
      cells in HIV-infected individuals. Similarly, the altered expression of the
      signal-transducing molecules CD7 and CD16 that we demonstrated for NK cells may
      correlate with the functional defects previously demonstrated in NK cells. Thus,
      measurements of antigen densities such as those demonstrated here may provide
      surrogate markers for the altered functional capacities of PBMC subsets in HIV
      infected individuals, and may thereby provide a much simpler assay for
      immunocompetence than in vitro functional assays.

PMID- 8671585
TI  - Trypanosoma cruzi infection in MHC-deficient mice: further evidence for the role
      of both class I- and class II-restricted T cells in immune resistance and
      disease.
AB  - The role of T cell population in immune control of Trypanosoma cruzi infection
      and subsequent development of disease has been examined using gene knockout mice
      deficient in the expression of either or both class I and Class II MHC. Mice
      deficient in either class I- or class II-restricted T cell populations show a
      striking similarity in their mortality rate, parasite load and tissue
      inflammatory response following infection with the Brazil strain of T. cruzi. In
      both cases all animals died during the acute phase of the infection with high
      parasitemias and high parasite loads in the heart and skeletal muscle, but with
      reduced tissue inflammatory response. Mice deficient in both class I and class II
      MHC expression demonstrated even higher numbers of circulating and tissue
      parasites, essentially non-existent tissue inflammatory responses, and succumbed
      to infection earlier than single-deficient mice. MHC class I-deficient mice which
      survive into the chronic phase following infection with the M/78 or M/80 clones
      of T. cruzi have both relatively higher tissue parasite loads and more extensive
      and severe inflammatory responses than control immunocompetent mice.
      Immunologically, the acute infection in the double-deficient mice was accompanied
      by a marked increase in CD4(-)CD8(-)alphabetaTCR+ cells in the spleen.
      Surprisingly, both class I- and class II-deficient mice produce detectable but
      sub-normal levels of anti-parasite antibodies while double-deficient mice
      produced little to no detectable anti-parasite antibody. These results establish
      the importance of both class I- and class II-restricted T cells in immune control
      of circulating blood stages and intracellular states of T. cruzi. In addition,
      this work reinforces the relationship between tissue parasite load and the
      severity of the inflammatory lesions in chronically infected animals.

PMID- 8671586
TI  - Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha
      double-deficient mice.
AB  - To investigate the roles of tumor necrosis factor (TNF) and lymphotoxin (LT)
      alpha in the development and function of the immune system, the Tnf and Ltalpha
      genes were simultaneously inactivated in mice by homologous recombination. These
      mutant mice are highly susceptible to Listeria monocytogenes infection and
      resistant to endotoxic shock induced by the combined administration of D
      galactosamine (D-GaIN) and lipopolysaccharide (LPS). Their splenic
      microarchitecture is disorganized, characterized by the loss of the clearly
      defined marginal zone, ill defined T and B cell areas, and absence of MAdCAM-1
      and reduced ICAM-1, VCAM-1 and Mac-1 expression. They are devoid of peripheral
      lymph nodes and Peyer's patches, and show a strong reduction of IgA+ plasma cells
      in the intestinal lamina propria. The alymphoplasia is accompanied by a marked B
      lymphocytosis and reduced basal lg levels. Ig depositions in the renal glomerulus
      and a strong up-regulation of MHC class I antigen expression on endothelial cells
      of different tissues are observed. The primary humoral immune response towards
      sheep red blood cells reveals a defective IgG isotype switch, while that against
      vesicular stomatitis virus is normal. The cytotoxic T cell responses are
      attenuated, although still effective, against vaccinia, lymphocytic
      choriomeningitis virus (LCMV-ARM) and LCMV-WE. In conclusion, the combined
      inactivation of Tnf and Ltalpha confirms their essential role in the normal
      development and function of the immune system.

PMID- 8671587
TI  - Differential requirements for co-stimulatory signals from B7 family members by
      resting versus recently activated memory T cells towards soluble recall antigens.
AB  - The interaction between CD28 on T cells with CD80 (B7-1) and CD86 (B7-2) on APCs
      is considered to be of critical importance for primary T cell activation both in
      vivo and in vitro. The relative importance of this co-stimulatory signal in
      memory T cell activation is, however, less clear, and was therefore studied by in
      vitro experiments on T cell responses to soluble recall antigens using peripheral
      blood mononuclear cells or T cell clones. Our data demonstrate that B7-2
      represents the major co-stimulatory signal for the activation of resting
      peripheral blood memory T cells with recall antigens, as evidenced by the effects
      of anti-B7-1 and anti-B7-2 on T cell proliferation as well as on IL-2 and INF
      gamma production. Since CTLA-4-lg and anti-CD28 Fab fragments had similar
      inhibitory effects to the combination of anti-B7-1 plus anti B7-2, the
      involvement of a third co-stimulatory CD28/CTLA-4 ligand is unlikely. Despite the
      strong effects of B7-blocking agents, a variable fraction of the memory T cells
      was resistant to inhibition. Moreover, T cell clones or in vitro preactivated T
      cells could efficiently be restimulated by soluble atigens on autologous APCs in
      the absence of B7-1 or B7-2 co-stimulation. These data show that most memory T
      cells that are freshly isolated from the blood are still dependent on CD28
      triggering for their activation. However, recently activated T cells can
      apparently bypass the requirement for B7 and use other co-stimulatory signals for
      reactivation, a finding with important implications for the development of
      immunosuppressive strategies.

PMID- 8671588
TI  - Selective contact during TCR recognition.
AB  - Recent structural analysis of the peptide-MHC complex reveals that an antigenic
      peptide binds to MHC in only one conformation and that side chains anchoring in
      the binding pocket would not contact TCR. The identification of all the MHC
      anchoring residues on an antigenic peptide is a prerequisite to understand how a
      given peptide interacts with the TCR. In a combination of binding analysis and
      model simulation, model peptide lambda repressor cl 16-26 was shown to bind to I
      Ek through four anchor residues (Leu18, IIe21, Glu23 and Lys26), a pattern found
      in many I-Ek-binding peptides. TCR reactivity analysis clearly indicates a great
      variation in the interaction with cl 16-26 by T cells generated from different
      strains of I-Ek-bearing mice. Most of the T cell generated from A/J mice reacted
      with the central regions of cl 16-26, while there is a great diversity on the
      recognition of cl 16-26 by T cells from C3H and B10.BR mice. Despite the diverse
      interactions with antigenic peptide by these T cells, most TCR-E-k contacts are
      limited to the central region of the I-Ek beta-chain. T cells recognizing only
      the N-terminal part of cl 16-26 were found to contact I-Ek at nearly the same
      residues as T cells interacting with the C-terminal of cl 16-26. TCR-I-Ek
      recognition was apparently independent of TCR-cl 16-26 contact. The discordant
      TCR-peptide and TCR-MHC interaction may represent a unique feature of TCR
      recognition.

PMID- 8671589
TI  - Comparison of Fas(Apo-1/CD95)- and perforin-mediated cytotoxicity in primary T
      lymphocytes.
AB  - Cytolytic T lymphocytes kill target cells by two independent cytolytic
      mechanisms. One pathway depends on the polarized secretion of granule-stored
      proteins including perforin and granzymes, causing target cell death through
      membrane and DNA damage. The second cytolytic effector system relies on the
      interaction of the Fas ligand (Fasl) on the effector cell with its receptor (Fas)
      on the target cell, leading to apoptotic cell death. Using mixed lymphocyte
      culture (MLC)-derived primary T lymphocytes of perforin-knockout and gld (with
      non-functional FasL) mice, the molecular basis of the two killing mechanisms was
      compared. The activity of both pathways was dependent on extracellular Ca2+.
      Incubation of MLC-stimulated primary T cells with protein synthesis inhibitors
      prior to TCR triggering impaired FasL cell surface expression and abolished
      cytolytic activity, although the cells exhibited an intracellular pool of FasL.
      The perforin-dependent mechanism induced cell death more rapidly, although both
      pathways ultimately showed similar killing efficiencies. Both pathways induced
      comparable levels of DNA degradation, but Fas-induced membrane damage was less
      pronounced. We conclude that upon TCR triggering FasL may be recruited in part
      from pre-existing intracellular stores. However, efficient induction of target
      cell death still depends on the continuous biosynthesis of FasL molecules.

PMID- 8671590
TI  - HIV envelope-directed signaling aberrancies and cell death of CD4+ T cells in the
      absence of TCR co-stimulation.
AB  - HIV-1 infection in CD4(+) T cells initiates a viral cytopathic effect (CPE) that
      is dependent on the activation of intracellular protein tyrosine kinases (PTK).
      PTK in T cells are also activated during the course of TCR or CD4 receptor
      engagement and the manner of receptor engagement may generate signals leading
      either to cell proliferation, tolerance induction (anergy) or programmed cell
      death (PCD). We have identified PTK triggered during the interaction of cells
      stably expressing surface HIV envelope (gp 120/gp41; HIVenv) and CD4(+)T cells,
      which leads to extensive and rapid individual cell death. We have found that
      killing is accompanied by tyrosine phosphorylation and activation of the CD4
      associated p56(ICK) kinase, and by activation of a second member of the scr
      family of PTK, p59(fyn) kinase, normally associated with T cell stimulation
      through the TCR. Interestingly, in contrast with normal T cell signaling, the
      zeta subunit of the TCR fails to become tyrosine-phosphorylated during signaling
      accompanying HIV-directed cell killing. Downstream activation of the ZAP-70 PTK
      also does not occur. Unlike T cell apoptosis triggered by soluble HIVenv
      glycoproteins, which requires co-stimulation of CD4 and the antigen-specific TCR,
      T cell killing by membrane-associated HIVenv does not require TCR co-stimulation,
      because aberrant signaling and cell death are triggered by CD4(+) but TCR- cell
      lines. These results are the first report where dual activation of the Lck and
      Fyn PTK does not result in normal downstream signaling through the ZAP PTK, We
      suggest by analogy to SCID resulting from ZAP-70 mutations, that the dissociation
      of upstream PTK activation from ZAP-70 signaling contributes to T cell depletion
      by HIV and to the development of AIDS.

PMID- 8671591
TI  - Clonal dominance of human autologous cytotoxic T lymphocytes against gastric
      carcinoma: molecular stability of the CDR3 structure of the TCR alphabeta gene.
AB  - In our previous study, RT-PCR suggested that cytotoxic T lymphocyte (CTL) clones
      may specifically recognize human autologous gastric signet ring cell tumor (HST2)
      by using TCR products of Valpha7 and Vbeta20 subfamilies. In this report, we
      first determined the TCR nucleotide sequences of one such CTL from patient's
      peripheral blood lymphocytes (PBL), the PBL were newly stimulated with a mixed
      lymphocyte-autologus tumor cell (HST2) culture (MLTC) and cytotoxic T cell lines,
      such as HPBL3x, were obtained. RT-PCR and the nucleotide sequence data indicated
      that HPBL3x also showed TCR Valpha7 and Vbeta transcripts, and that HPBL3x TCR
      was composed of the exact same CDR3 gene structures as those of the TcHLT2 clone.
      T cells with same TCR structures were also detected in patient's non-treated
      peripheral blood, although they were infrequent. These data indicated that
      functional cytotoxic T cells with these distinct CDR3 equivalent structures were
      the dominant effector cells against HST2 autologous tumor cells. Moreover, the
      highly dominant and reproducible clonal expansion of T cells bearing
      heterodimeric TCR with identical variable, N diversity and constant region
      structures suggest that the molecular nature of governing antigenic peptide to
      TcHDT2 may be stable and perhaps immunologically dominant in the interaction
      between CTL and HST2 autologous tumor cells.

PMID- 8671592
TI  - Rearrangement and expression of Vzeta1, Vzeta2 and Vzeta3 TCR zeta genes in
      C57BL/6 mice.
AB  - We have recently described a mAb (2.11) that recognizes the Vgamma1-Jgamma4
      Cgamma4 chain. With this mAb and an anti-delta mAb we separated gammadelta+
      2.11(+) and gammadelta+ 2.11(-) intraepithelial lymphocytes (i-IEL) by FACS.
      Transcripts of rearranged TCR Vgamma1 and Vdelta2 genes in both i-IEL populations
      were analyzed by PCR followed by sequence analysis of cDNA spanning the junction
      of variable (V) and joining (J) genes. Roughly the same number of Vgamma1 and
      Vgamma2 transcripts were found in the 2.11(+) population while >90% of the
      transcripts in the 2.11(-)population contained a Vgamma gene sequence.
      Furthermore, gamma transcripts in the 2.11+ population were functional, while
      only 30-40% of the Vgamma transcripts in either population contained an in-frame
      sequence. The observed frequency of transcripts is what would be expected from
      cell populations that have not gone through cellular selection mediated by the
      RCR. Expression of Vgamma mRNA in RCRalphabeta and TCRgammadelta thymocytes was
      studied by a technique that analyzed populations of transcripts of rearranged
      genes. In both T cell population similar levels of Vgamma transcripts were found
      and about two out of three transcripts were out-of-frame. During the cloning and
      sequence analysis, we indentified a clone that expresses the Vgamma segment
      rearranged to the Jgamma3-Cgamma region in C57BL/6 mice. Together with the PCR
      cloning and sequencing of the complete Cgamma region in C57BL/6 mice these data
      demonstrate that the Jgamma-Cgamma gene is functional in this strain. Taken
      together, these studies revealed that: (i) cells expressing the Vgamma1 chain are
      an important subset of the gammadelta i-IEL population and that they show
      extensive junctional diversity; (ii) there is no correlation between expression
      of in-frame Vgamma transcripts and expression of Vgamma2 chains at the cell
      surface; and (iii) cells expressing the Vgamma3 chain might be a minor subset of
      the gammadelta T cell population in C57BL/6 mice.

PMID- 8671593
TI  - Re-evaluation of the probabilities for productive arrangements on the kappa and
      lambda loci.
AB  - V-J arrangements at Ig light chain (IgL) genes occur in resting small pre-B
      cells. In the absence of cell division, the probability of production kappa and
      lambda rearrangements is proportional to the output of kappa+ B and lambda+ B
      cells in bone marrow. The kinetics and probability of productive kappa or lambda
      rearrangements was assessed in three groups of mice carrying two (wild-type), one
      or no intact Igkappa gene, and the following conclusion are drawn. Kappa and
      lambda rearrangements occur independently at different kinetics, and
      rearrangements are initiated at a time when kappa rearrangements are stopping.
      The probability of productive kappa and lambda rearrangements per chromosome is
      calculated to be approximately 60 and approximately 20% respectively. Thus, a
      kappa gene can attempt rearrangements up to three times per chromosome during B
      cell development. These findings explain that the observed ratio of kappa+
      B/lambda+ B cell production in wild-type mice is 95/5.

PMID- 8671595
TI  - A region of the 20 bp repeats lies 3' of human Ig Calpha1 and Calpha2 genes.
AB  - The murine Ig heavy chain gene locus is regulated by multiple elements. In
      addition to the intron enhancer, Emu, there is a complex regulatory region 3' of
      the Calpha gene, which spans approximately 40 kb and contains several enhancers.
      In contrast to mouse, the human IgH cluster contains two Calpha genes, each
      associated with duplicated arrays of other CH genes. There is evidence to suggest
      that each array is individually regulated. In this report, we describe an
      approximately 2 kb region containing 20 bp repeats that lies 3' of both human
      Calpha1 and Calpha2 genes. This repeat region appears to be the site of
      integration of the Epstein-Barr virus in the RGN1 B lymphoma cell line. The
      repeat region is homologous to a 420 bp segment in mouse that is located
      downstream of the Calpha membrane exon in the interval preceding the second of
      three poly(A) termination sites. However, in contrast to human, the murine
      segment contains degenerate repeats. The human repeat region bears significant
      homology to switch sequences, in particular to Smu and Salpha. We hypothesize
      that the human repeat regions may play a role in the class switch process by
      contributing to the stabilization of interactions between the two switch regions.
      The presence of a Sau3A site within the repeats presents a barrier to cloning
      with several existing human genomic libraries, most of which are based on partial
      Sau3A digestion. Furthermore, the homology of the repeat region with Smu and
      Salpha sequences may contribute to the difficulty in isolating YAC clones
      containing Calpha genes since homologous recombination could potentially have
      deleted this entire segment. Our map of these DNA segments provides a guide to
      their isolation and characterization.

PMID- 8671594
TI  - A novel mouse thymocyte antigen (F3Ag): down-regulation during the CD4+CD8+
      double-positive stage indicates positive selection.
AB  - We describe a novel mAb (F3) which reacts with a 65 kDa thymocyte surface
      protein, expressed on approximately 80% of thymocytes, referred to as F3Ag. In
      ontogeny, F3Ag expression begins in the CD4(-)CD8(-) double-negative (DN) CD25(+)
      population and is maintained through approximately 85% of the CD4(+)CD8(+) double
      positive (DP) stage. DP cells with high TCR expression and CD4(+) single-positive
      (SP) cells are predominantly negative for F3Ag, whereas many CD8(+) SP thymocytes
      express F3Ag. F3Ag-DP thymocytes show a reduced expression of RAG-1 and RAG-2
      compared with F3Ag+ DP cells. The shutdown of F3Ag expression during the DP stage
      is related to positive selection: mice deficient for MHC class I and class II
      molecules maintain F3Ag expression in almost all DP cells. Transgenic (tg) mice
      carrying TCR restricted for MHC class II show a more pronounced down-regulation
      of F3Ag in the DP compartment than normal mice, depending on the presence of a
      positively selecting MHC. The size of the F3Ag- DP subset is positively
      correlated with the efficacy of positive selection into the CD4(+) SP
      compartment. Because some CD8(+) SP cells express F3Ag, the relationship between
      F3Ag down-regulation and positive selection is less obvious in DP cells of mice
      carrying MHC class I-restricted tg TCR. However, in reaggregate thymic organ
      cultures, sorted F3Ag- DP cells differentiate into CD8(+) SP cells more rapidly
      than do F3Ag+ DP cells. Thus, after down-regulation in the DP stage, a proportion
      of CD8(+) SP cells appears to re-express F3Ag. In addition, the proportion of
      F3Ag-CD8(+) SP cells depends on the efficacy of positive selection into the CD8
      lineage. Taken together, the regulation of the expression of the F3Ag appears to
      be associated with signals that control thymic repertoire selection.

PMID- 8671596
TI  - TCR repertoire to proteolipid protein (PLP) in multiple sclerosis (MS):
      homologies between PLP-specific T cells and MS-associated T cells in TCR
      junctional sequences.
AB  - In the pathogenesis of multiple sclerosis (MS), autoimmune T cells reactive with
      proteolipid protein (PLP) may play a crucial role. We determined 23 TCR beta
      chain sequences of limiting dilution T cel lines (TCL) selected against a
      synthetic peptide, PLP 95-116, 105-124 or 139-155, from the peripheral blood of
      three Japanese MS patients with the DR2,w15 haplotype (TI, SK and OK). Fourteen
      sequences were originated from TI, seven from SK and two from OK. The PLP
      reactive TCL utilized various Vbeta and Jbeta gene segments, but there was
      significant bias in the Vbeta and Jbeta usage. Overutilization of the Vbeta2
      family and dominant usage of the Jbeta2.5 subfamily was seen in PLP 105-124
      reactive and 95-116-reactive TCL respectively. More remarkably, a majority of the
      TCL were found to express beta-chain CDR3 motifs that appear to be unique to MS
      brain infiltrates. In contrast, these motifs were only rarely seen in control TCR
      sequences from peripheral blood or from a TCL selected against tetanus toxoid. In
      several cases, the betaCDR3 homologies between the PLP-reactive T cells and MS
      brain T cells were extensive, owing to the shared motifs in combination with the
      surrounding amino acid identities. These results indicate that PLP-specific T
      cells may be involved in the immunopathology of MS.

PMID- 8671597
TI  - A monoclonal natural autoantibody that promotes remyelination suppresses central
      nervous system inflammation and increases virus expression after Theiler's virus
      induced demyelination.
AB  - We have used an established experimental model of multiple sclerosis to
      investigate the potential beneficial relationship between natural autoimmunity
      and remyelination after central nervous system (CNS) demyelination. Intracerebral
      infection of SJL/J mice with Theiler's murine encephalomyelitis virus (TMEV)
      produces chronic, progressive, inflammatory CNS demyelination. Chronically
      infected SJL/J mice show minimal spontaneous remyelination, which is in part due
      to a T cell-mediated immune response inhibiting myelin repair. We previously
      identified a monoclonal natural autoantibody, designated SCH94.03, that promotes
      remyelination when passively transferred to chronically infected SJL/J mice. The
      mechanism whereby SCH94.03 promotes remyelination is unknown, although previous
      reports suggest that natural autoantibodies can modulate immune system function.
      In this report we demonstrate that treatment with SCH94.03 reduced by 2- to 3
      fold the number of CD4(+) and CD8(+) cells infiltrating the CNS of SJL/J mice
      chronically infected with TMEV, in the absence of global lymphocyte depletion.
      Associated with the decreased inflammation was a 2- to 3-fold increase in virus
      antigen expression without a significant increase in viral RNA or virus titers.
      Treatment with SCH94.03 also suppressed the humoral immune response to a T cell
      dependent antigen in chronically infected mice. Immunohistochemical staining
      showed that SCH94.03 labeled MHC class II-positive dendritic cells in peripheral
      lymphoid organs. These results are consistent with the proposed immunomodulatory
      function of natural autoantibodies and suggest that one mechanism whereby
      SCH94.03 promotes CNS remyelination in chronically infected SJL/J mice is through
      inhibition of a pathogenic immune response.

PMID- 8671598
TI  - APC from mice harbouring the filarial nematode, Brugia malayi, prevent cellular
      proliferation but not cytokine production.
AB  - Specific T cell hyporesponsiveness and depressed antibody production is a key
      feature of human infection with the filarial nematodes, Brugia malayi and
      Wuchereria bancrofti. Despite this immune suppression, responses indicative of
      Th2 subset activation are present, including unusually high levels of specific
      IgG4. We tested the possibility that infection with filarial nematodes causes a
      reduction in the co-stimulatory or antigen-presenting capacity of macrophages
      resulting in a failure to activate specific T cells. Adherent peritoneal exudate
      cells (PEC) from mice implanted with adult B. Malayi were used to present antigen
      to the conalbumin-specific T cell clone, D10.G4. Proliferation of the D10 cells
      at even background levels was completely blocked by the presence of implant
      derived adherent PEC. However, cytokine production by these cells in response to
      antigen was intact, and thus PEC from implanted mice are capable of functionally
      processing and presenting antigen. The elicitation of a suppressive cell
      population was specific for live adults as cells from mice implanted with dead
      adult parasites effectively stimulated D10 proliferation. The block in cellular
      proliferation is not due to the production of factors typically associated with
      macrophage suppression such as nitric oxide, prostaglandins or catalase. These
      observations are consistent with the T cell hyporesponsiveness seen in human
      cases of patent Brugia infection and may provide a murine model for the immune
      suppression seen in lymphatic filariasis.

PMID- 8671599
TI  - IgM natural antibody against an asialo-oligosaccharide, gangliotetraose (Gg4),
      sensitizes HIV-I infected cells for cytolysis by homologous complement.
AB  - Although cells are usually resistant to homologous complement, the IgM antibody
      against gangliotetraose (Gg4), an asialo-oligosaccharide of GM1, was found to
      cause cytolysis of HIV-1 infected cells by homologous complement. Due to its
      size, IgM might enable the initiation of the complement cascade away from
      membrane complement inhibitors such as decay accelerating factor and membrane
      cofactor protein. Furthermore, HRF20 (CD59), which restricts formation of
      membrane attack complexes (MAC) of complement on homologous cell membranes, was
      significantly decreased on HIV-infected cells and therefore formation of MAC on
      cell membranes would be facilitated. IgM antibodies reactive with HIV-infected
      cells could result in the elimination of infected cells via complement-mediated
      cytolysis in HIV-infected patients, since all tested sera from HIV-positive
      hemophilia patients who have survived for >12 years contained IgM antibody
      activity against HIV-infected MOLT4 cells in a preliminary experiment. Therefore,
      administration of IgM antibodies reactive with HIV-infected cells may be
      effective in the treatment of HIV carriers.

PMID- 8671600
TI  - CD28 co-stimulatory signals induce IL-2 receptor expression on antigen-stimulated
      virgin T cells by an IL-2-independent mechanism.
AB  - Intravenous sensitization of C57BL/6 (B6) mice with class II H-2-disparate B6-C-H
      2bm12(bm12) resting B cells induced anti-bm12 CD4+ T cell tolerance as shown by
      hyporesponsiveness in the anti-bm12 mixed lymphocyte reaction (MLR). The present
      study investigated the mechanism(s) of the failure of bm12 B cells to stimulate
      the proliferation of B6 anti-bm12 CD4+ T cells. While stimulation in vitro to B6
      splenic T cells with bm12 antigen-presenting cells (APC) induced IL-2 mRNA
      expression and IL-2 production, T cells stimulated with bm12 B cells expressed
      much less IL-2 mRNA and secreted very low but detectable levels of IL-2.
      Moreover, the T cells stimulated with the bm12 B cells did not proliferate and
      this was not corrected by the addition of rIL-2 responsiveness. Further, whereas
      IL-2 receptor (IL-2R) alpha chain expression was significantly induced on B6 T
      cells stimulated with bm12 APC; stimulation with bm12 B cells did not induce IL
      2R expression over background levels. However, virgin T cells stimulated with
      both bm12 B cells and anti-CD28 mAb proliferated and displayed a dramatic
      increase in IL-2 production as well as IL-2R expression to levels commensurate
      with those resulting from bm12 B cells plus anti-CD28 mAb even in the presence of
      sufficient amounts of anti-IL-2 mAb for neutralizing produced IL-2; while levels
      of IL-2R were significantly lower compared to those induced in the absence of
      anti-IL-2 mAb, increased frequencies of IL-2R+ cells were comparable. Conversely,
      IL-2R was not induced by bm12 B cell stimulation in the presence of IL-2.
      Moreover, IL-2R expression and proliferation induced by stimulation with bm12 APC
      was inhibited by CTLA-4-Ig, a soluble recombinant fusion protein capable of
      blocking the CD28 co-stimulatory signals not only stimulate IL-2 production but
      also induce IL-2R expression by an IL-2-independent mechanism.

PMID- 8671601
TI  - The appearance of Thy-1- donor T cells in the peripheral circulation 3-6 weeks
      after bone marrow transplantation suggests an extrathymic origin.
AB  - Donor and host T cells were distinguished by T cell antigen marker Thy-1 isotype
      and cytoplasmic isozyme Gpi-1 in this study of bone marrow transplantation
      between congenic mice. During the first 3-6 weeks after irradiation and marrow
      transfer, percentages of cells bearing the donor Thy-1 isotype in the periphery
      are much lower than percentages of T cells bearing the donor Gpi-1 marker.
      Apparently a population of Thy-1- donor T cells exists for several weeks after
      bone marrow transplantation. Further study showed that this population of CD3+,
      Thy-1- donor T cells expressed CD4+ or CD8+ and was found in peripheral blood and
      spleen but not in the thymus. This finding suggests their extrathymic origin.

PMID- 8671602
TI  - Identification of a putative motif for binding of peptides to HLA-DQ2.
AB  - To understand the rules determining peptide binding to the celiac disease and
      type 1 diabetes mellitus associated HLA-DQ2 molecule, we have studies in detail
      the binding of a peptide OVA 258-276Y (IINFEKLTEWTSSNVMEERY) which exhibits
      strong binding to DQ2. First we tested a set of N- and C-terminal truncated
      variants, and found the core binding region to comprise residues 267-276Y. Single
      alanine substitution analysis of the OVA 267-276Y peptide revealed that
      replacements of V272, E275 and the C-terminal Y had negative effects whereas the
      substitution of N271 had a positive effect. A polyalanine analogue of the OVA 267
      276Y peptide with V272, E275 and a C-terminal Y bound at least as well as the
      original peptide. A variant peptide with a deletion of R276 displayed decreased
      binding, suggesting that the anchor residues were out of frame in this analogue.
      To further characterize the residues playing a role in the binding of the OVA 267
      276Y peptide to DQ2 we tested the binding of several analogues with substitutions
      for V272, E275 and the C-terminal Y residue. Our results indicate that peptides
      binding to DQ2 have anchor residues in relative positions 4, 7 and (P4, P7 and
      P9). Residues with negatively charged or hydrophobic aliphatic but not positively
      charged side chains are preferred in P4 and P7, whereas residues with bulky
      hydrophobic side chains are preferred in P9.

PMID- 8671603
TI  - A role for BP-3/BST-1 antigen in early T cell development.
AB  - In the mouse thymus, pre-T cells are defined by their CD3(-)CD4(-)CD8(-) triple
      negative, CD44lo/- CD25+ phenotype. We made a rat mAb IF-7, that, among all T
      cell subsets analyzed, reacted exclusively with pre-T cells. Molecular cloning
      revealed that the antigen recognized by IF-7 was identical to BP-3/BST-1, a
      glycosyl-phosphatidylinositol-linked, CD38-related molecule previously described
      as a possible co-activation molecule of pre-B cells. We found that IF-7 cross
      linking enhances the proliferative response of sorted pre-T cells to anti-CD3
      stimulation. In addition, IF-7 enhances and accelerates the development of fetal
      thymic organ culture (FTOC), although the gamma delta lineage is unaffected by
      the treatment. In addition, sorted IF-7+ pre-T cells give preferentially rise to
      alpha beta TCR+ thymocytes in FTOC. Our observations strongly suggest that BP
      3/BST-1 is implicated in both early B and T cell growth and development, and is
      an early marker for the alpha beta lineage.

PMID- 8671604
TI  - High frequency class switching of an IgM+ B lymphoma clone CH12F3 to IgA+ cells.
AB  - We have developed an efficient in vitro class switching system using a subclone
      (CH12F3) of the IgM+ CH12.LX lymphoma cell line. CH12F3 cells switched from
      surface IgM+ cells to surface IgA+ cells at a high frequency (50%) after 72 h
      stimulation with IL-4, transforming growth factor (TGF)-beta and CD40L. No other
      class isotype-producing cells were detected, indicating that the CH12F3 clone is
      exclusively committed to IgA isotype switching. To understand the molecular basis
      of the isotype commitment, we studied the methylation profiles of I region
      promoters and I region transcription of CH12F3 cells. No germline transcripts
      other than those from the I alpha region were detected and only the I alpha
      promoter was demethylated in uninduced CH12F3 cells. TGF-beta, CD40L and IL-4
      synergistically induced efficient switch recombination in CH12F3 cells,
      suggesting that the three stimulations up-regulate different steps of switch
      recombination in isotype-committed B cells such as CH12F3 cells. Stimulation of
      CH12F3 cells by IL-4 or TGF-beta, but not by CD40L, induced transient but
      complete methylation of the I alpha region. TGF-beta and CD40L, but not IL-4,
      increased the amounts of germline alpha transcripts. We found that the extents of
      methylation and the amounts of germline transcripts do not necessarily correlate
      with the efficiency of recombination in induced CH12F3 cells. These results led
      to the proposal that switch recombination can be separated into at least two
      phases, i.e. commitment and recombination. The roles of IL-4, TGF-beta and CD40L
      in the two phases are discussed.

PMID- 8671605
TI  - Effect of superantigens on human thymocytes: selective proliferation of V beta 2+
      cells in response to toxic shock syndrome toxin-1 and their deletion upon
      secondary stimulation.
AB  - The effects of toxic shock syndrome toxin-1 (TSST-1) on human thymocytes and
      their CD4/CD8-defined subsets have been analyzed. Postnatal thymocyte cell
      suspensions were cultured with 5 ng/ml TSST-1 for different time intervals. A
      strong cell proliferation of CD3+/TCR+ cells, characterized by selective
      expansion of cells expressing TCR V beta 2, occurred. In these cultured
      thymocytes, V beta 2+ cells were detected in all subsets including CD4-CD8+
      cells. CD4-CD8+ thymocyte populations (obtained by depletion of CD4+ cells) were
      further analyzed for their ability to directly respond to TSST-1. An efficient
      cell proliferation occurred; however, it was completely abrogated upon removal of
      HLA class II+ cells (representing 10% of fresh thymocytes depleted of CD4+
      cells). The HLA class II dependency of TSST-1 mediated functions was further
      documented at the clonal level. Thus, in the presence of TSST-1, CD4-CD8+ V beta
      2+ clones efficiently lysed the HLA class II+ Raji target cells but not the
      corresponding HLA class II- variant RJ 2.2.5. Analysis of the effect of TSST-1
      induced secondary stimulation on cultured (V beta 2+-enriched) thymocytes
      resulted in a selective depletion of V beta 2+ cells due to apoptotic cell death.

PMID- 8671606
TI  - Monoclonal IgG as antigens: reduction is an early intracellular event of their
      processing by antigen-presenting cells.
AB  - Murine mAb injected into patients behave as exogenous antigens and trigger a
      specific immune response characterized mainly by CD4+ T lymphocytes. They are
      recognized by T cells under a processed form and in a MHC class II-restricted
      fashion. IgG degradation which occurs in antigen-presenting cells (APC) has been
      studied in vitro. We have shown that partial reduction of this antigen is an
      early event which is significant for the generation of class II-restricted
      fragments presentable to antigen-specific T cells. Two different murine mAb were
      used as antigens and human monocytic U937 or antigen non-specific Epstein-Barr
      virus-transformed B cells as APC. Upon cellular internalization IgG are rapidly
      cleaved leading to 24-25 kDa fragments. One of the major and early events
      corresponds to partial reduction of IgG--the light chain is released from the
      intact molecule, heavy chains remaining bound together. Partial in vitro
      reduction of IgG followed by presentation by fixed B cells to specific T cells
      showed that only kappa light chain-specific T cell clones are stimulated, in
      contrast to heavy chain-specific T cell clones. The response to the kappa chains
      of specific T cells points to a significant role played by the early IgG partial
      reduction in the generation of kappa light chain class II binding fragments.

PMID- 8671607
TI  - Genetic complexity of the human hsp 60 gene.
AB  - Hsp 60 is a chaperonin protein, homologous to GroEL of Escherichia coli and
      highly conserved across species. Immune response induced by the hsp 60 equivalent
      of numerous microorganisms elicits in animals and man a dominant cross-reactive T
      lymphocyte response. Hsp 60 has been strongly implicated as an example of
      molecular mimicry in the pathogenicity of autoimmune diseases and, more recently,
      in T cell-mediated protection. Curiously, in spite of this interest, the gene
      encoding HSP 60 has not yet been cloned. Sequencing of numerous PCR-derived HSP
      60 clones. obtained following amplification of genomic DNA revealed multiple
      distinct but highly related sequences. These were all different from the sequence
      encoding the expressed protein and all had interrupted reading frames. PCR
      amplification from mRNA, however, yielded only the sequence expected for the
      expressed hsp 60 protein. This apparent paradox was resolved by cloning and
      sequencing HSP 60-specific genomic clones: the majority of these clones
      corresponded to intronless genes having the characteristics of retro-pseudogenes
      and were flanked by unrelated DNA sequences. In addition, several genomic clones
      were isolated that corresponded to a unique functional HSP 60 gene. This gene is
      composed of multiple exons, some very short. The transcription start site was
      identified and 750 bp of 5' flanking sequence were determined. The human HSP 60
      gene is induced by heat. We conclude that hsp 60 is encoded by a single highly
      fragmented gene, that co-exists with multiple HSP 60 retro-pseudogenes, normally
      not expressed.

PMID- 8671608
TI  - Hormone regulation of murine T cells: potent tissue-specific immunosuppressive
      effects of thyroxine targeted to gut T cells.
AB  - Recent studies in athymic mice indicate that the neuroendocrine hormones
      thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) can
      significantly influence the development of lymphoid cells associated with
      intestinal intraepithelial lymphocytes (IEL). In the present study we have
      examined the effects of those hormones, as well as of thyroxine (T4), a thyroid
      derived hormone regulated by TSH, on IEL development in euthymic mice. As
      reported here, whereas IEL in euthymic mice were unaffected by TRH and TSH
      treatment, T4 administered to adult euthymic mice at 3 or 6 weeks of age caused a
      dramatic reduction in the numbers of TCR alpha beta, CD8 alpha beta IEL, i.e. the
      same subsets previously shown to be up-regulated ty TRH and TSH in athymic mice.
      When given to euthymic mice >8 weeks of age, after TCR alpha beta and CD8 alpha
      beta subsets had reached normal levels, T4 had minimal effect on IEL, suggesting
      that the mode of action of T4 is directed to developing but not mature IEL. That
      possibility was confirmed in experiments in which T4 treatment of bone marrow
      radiation chimeras during an active phase of T cell regeneration temporarily
      halted all IEL development at a stage characteristic of immature IEL. Most
      interesting, the immunosuppressive effects of T4 were selectively targeted to the
      intestinal immune system since T4 had no effect on developing thymocytes or on
      mature peripheral T cells, in either normal euthymic mice or during hematopoietic
      reconstitution of radiation chimeras. These findings have implications for
      understanding intestinal immunity and disease, including chronic intestinal
      inflammation, in ways not previously appreciated.

PMID- 8671609
TI  - Critical proline residues of the cytoplasmic domain of the IL-5 receptor alpha
      chain and its function in IL-5-mediated activation of JAK kinase and STAT5.
AB  - The high-affinity receptor (R) for IL-5 consists of a unique alpha chain (IL-5R
      alpha) and a beta chain (beta c) that is shared with the receptors for IL-3 and
      granulocyte macrophage colony stimulating factor (GM-CSF). We defined two regions
      of IL-5R alpha for the IL-5-induced proliferative response, the expression of
      nuclear proto-oncogenes, and the tyrosine phosphorylation of cellular proteins
      including beta c, SH2/SH3-containing proteins and JAK2 kinase. In the studies
      described here, we demonstrate that IL-5, IL-3 or GM-CSF stimulation induces the
      tyrosine phosphorylation of JAK2, and to a lesser extent JAK1, and of STAT5.
      Mutational analysis revealed that one of the proline residues, particularly
      Pro352 and Pro355, in the membrane-proximal proline-rich sequence (Pro352-Pro353
      X-Pro355) of the cytoplasmic domain of IL-5R alpha is required for cell
      proliferation, and for both JAK1 and JAK2 activation. In addition, transfectants
      expressing chimeric receptors which consist of the extracellular domain of IL-5R
      alpha and the cytoplasmic domain of beta c responded to IL-5 for proliferation
      and tyrosine phosphorylation of JAK1. Intriguingly, electrophoretic mobility
      shift assay analysis revealed that STAT5 was activated in cells showing either
      JAK1 or JAK2 tyrosine phosphorylation. These results indicate that activation of
      JAK1, JAK2 and STAT5 is critical to coupling IL-5-induced tyrosine
      phosphorylation and ultimately mitogenesis, and that Pro352 and Pro355 in the
      proline-rich sequence appear to play more essential roles in cell growth and in
      both JAK1/STAT5 and JAK2/STAT5 activation than Pro353 does.

PMID- 8671610
TI  - B-lineage cell deficits in bone marrow of lpr/lpr mice.
AB  - Analyses of bone marrow (BM) lymphocytes in C57BL/6 mice homozygous for the lpr
      mutation (B6.lpr) disclosed low numbers of pre-B and B cells, as compared with
      age-matched control B6 mice. BM depletion in B6.lpr mice was selective for B
      lineage cells, appeared in young adults, and developed markedly with age and
      disease progression, contrasting with the peripheral lymphocyte hypercellularity.
      Normalization of pre-B and B cellularity in BM of B6.lpr mice was observed after
      administration of polyclonal Ig, that also markedly improved the clinical
      condition. Isolated pre-B (B220+ IgM-) cells from B6 or B6.lpr mice, however,
      showed essentially the same rates of IL-7-dependent proliferation and
      differentiation to B (IgM+) cells in culture, indicating that the BM B-lineage
      deficit is not the result of an intrinsic defect in B cell generation.

PMID- 8671611
TI  - Regulation of the E beta gene in vivo: lessons from E beta d transgenic mice.
AB  - We have examined the expression and regulation of the MHC class II E beta d gene
      in both cell lines and in transgenic mice. In transient transfection assays, as
      little as 192 bp of the E beta d proximal promoter was sufficient to direct
      constitutive expression of a reporter gene in a B cell line and to confer
      inducibility by IFN-gamma in a macrophage cell line. To determine if the same E
      beta d promoter sequences were also sufficient to direct correct expression in
      vivo, E beta d transgenes bearing either 4.1 or 0.2 kb of upstream sequence were
      introduced into an inbred mouse strain with a non-expressed endogenous E beta
      gene. Expression of both transgenes mirrored the expression of the endogenous I-A
      protein in thymus, B cells and macrophages with regard to both constitutive and
      cytokine-inducible expression. These results indicate that for the E beta gene
      only 200 bp of proximal promoter sequence are required to achieve tissue-specific
      and cytokine-inducible expression. This is in striking contrast to the E alpha
      gene, the only other murine class II gene whose promoter has been analyzed in
      vivo, which has been shown to require 2.0 kb of upstream sequence for appropriate
      expression. These data demonstrate, therefore, that the location of critical
      regulatory elements for the E beta and E alpha genes may differ.

PMID- 8671612
TI  - A synthetic peptide mimicking the HLA-DR beta 2-binding site for CD4 inhibits
      antigen-independent CD4+ T cell adhesion to B cells and CD4+ T cell activation.
AB  - We studied the ability of a peptide mimicking the major binding site of HLA-DR
      beta 2 for CD4 (i.e. amino acids 134-148) to inhibit the adhesion of CD4+ T cells
      to B cells and ICAM-1-DR-expressing fibroblasts, as well as the proliferation of
      TCR-CD3-triggered CD4+ T cells. Peptide DR134-148 blocked CD4+ T cell (but not
      CD8+ T cell) binding to B cells and to DR+ ICAM-1+ fibroblasts in a concentration
      dependent manner. A peptide composed of randomly associated identical amino acid
      residues had no effect. This inhibitory activity was not additive with the effect
      of an anti-CD4 antibody, peptide DR35-46 (mimicking another potential binding
      site of HLA-DR beta 1 to CD4) or an anti-LFA-1 antibody. Adhesion of a T cell
      line (HUT78) expressing a mutated form of CD4 unable to bind p56lck cytosine
      kinase was not inhibited by peptide DR134-148. In addition, herbimycin A, a
      tyrosine kinase inhibitor, abrogated the inhibitory activity of DR134-148. Since
      CD4-MHC class II interactions have been shown to play no detectable role in
      mediating antigen-independent adhesion in this assay, peptide interactions with
      CD4 may trigger an off signal down-regulating LFA-1-mediated adhesion. Indeed,
      adhesion of CD4+ T cells to ICAM-1- fibroblasts was not inhibited by peptide
      DR134-148, while the same peptide inhibited antigen (protein-pure derivative)-
      and anti-CD3 antibody-induced CD4 T cell proliferation. These findings suggest
      that the major sequence involved in the MHC class II interaction with CD4 is
      sufficient to induce a downstream negative regulatory signal that is mediated by
      p56lck, independently of antigen-specific TCR triggering.

PMID- 8671613
TI  - Regulation of CD40 ligand expression on naive CD4 T cells: a role for TCR but not
      co-stimulatory signals.
AB  - We have investigated the roles of TCR and accessory co-stimulatory signals in the
      induction of CD40 ligand (CD40L) on CD4 cells. Using naive T cells form TCR
      transgenic mice, specific for a peptide of pigeon cytochrome c, we show that in
      contrast to IL-2 secretion, CD40L expression is regulated primarily by signalling
      through the TCR, is enhanced by accessory molecule interactions, but co
      stimulatory signals play little if any role. CD40L was induced at high levels on
      naive T cells, peaking at 5 h, by class II MHC+ fibroblast antigen-presenting
      cells (APC) which expressed either ICAM-1, B7-1 or both molecules, whereas only
      low levels were induced by fibroblasts which did not express any accessory
      molecules. Differences in intensity and duration of expression were seen
      following stimulation with ICAM- and B7-expressing APC, with the presence of ICAM
      resulting in greater and longer expression, although both molecules together were
      most efficient. The involvement of co-stimulatory signals delivered from
      accessory molecules was investigated in systems where there was no effect on TCR
      signalling from adhesive interactions. Anti-CD3, or antigen-pulsed APC lacking
      accessory molecules, were used to provide the TCR signal, with co-stimulus from
      either anti-CD28 or accessory molecule-expressing fibroblasts not presenting
      antigen. Anti-CD3 in the absence of co-stimuli induced high CD40L expression but
      no IL-2 production and provision of co-stimulatory signals, although inducing
      large quantities of IL-2, did not increase CD40L expression. In addition, low
      CD40L expression induced by antigen presented in the absence of accessory
      molecules was not enhanced by co-stimulation, although IL-2 was strongly up
      regulated. These studies suggest that efficient expression of CD40L on naive CD4
      cells does require accessory molecules on APC. However, the role of these
      molecules for CD40L induction, as opposed to IL-2 secretion, is not one of co
      stimulation but one of adhesion, presumably allowing stronger or more prolonged
      signals to be generated through the TCR. The synergistic role of ICAM and B7
      during naive CD4 activation was confirmed using dendritic cells as APC, with
      nearly complete inhibition of CD40L expression as well as IL-2 secretion being
      seen when both CTLA-4-Ig and anti-LFA-1 were used to block these molecules.

PMID- 8671614
TI  - alpha 4 integrin plays a critical role in early stages of T lymphocyte migration
      in Peyer's patches of rats.
AB  - Lymphocyte recirculation through the blood flow circuit and lymphoid organs is
      important for the maintenance of immune defense, and is defined as lymphocyte
      homing. During the homing process, several adhesion molecules have been
      postulated to play an important role in lymphocyte recruitment from the vascular
      space. In the present study, we investigated the effect of a novel mAb against
      rat alpha 4 integrin (MR alpha 4-1) on the interaction of T lymphocytes with
      postcapillary venules (PCV) and their subsequent migration into the interstitium
      of Peyer's patches, using intravital video microscopy. T lymphocytes collected
      from intestinal lymph were labeled with a fluorochrome carboxyfluorescein
      diacetate succinimidyl ester and were than injected into the jugular vein of
      recipient rats. The microvasculature in the ileal Peyer's patches of recipient
      rats was observed sequentially by intravital fluorescence microscopy. In
      controls, lymphocytes exhibited rolling behavior which was followed by firm
      adhesion to the endothelium of PCV. The density of sticking lymphocytes gradually
      increased during the first 30 min. These initial interactions of lymphocytes with
      the PCV (rolling and adherence) were drastically inhibited by treatment with MR
      alpha 4-1, both when MR alpha 4-1 was preinfused into rats and when T cells were
      preincubated in vitro with MR alpha 4-1 before administration. MR alpha 4-1 also
      significantly inhibited the transendothelial migration of T lymphocytes,
      associated by the ratio of migration to adherence. However, once T lymphocytes
      migrated into the interstitium, treatment with MR alpha 4-1 did not affect the
      pattern of travel of these lymphocytes in the interstitium or their transport
      into the microlymphatics in the parafollicular area. Therefore, we conclude that
      alpha 4 integrins play a critical role in the rolling and sticking of T cells and
      their transendothelial migration in PCV of Peyer's patches.

PMID- 8671615
TI  - In vitro differentiation and commitment of CD4+ CD8+ thymocytes to the CD4
      lineage, without TCR engagement.
AB  - Thymocyte positive selection is based on protection of immature CD4/CD8 double
      positive (DP) thymocytes from apoptosis and their differentiation into CD4 or CD8
      single-positive (SP) cells. Intracellular signals essential for positive
      selection appear to be induced through the TCR and some of the accessory
      molecules including LFA-1, CD4 and CD8 upon interaction with thymic stromal
      cells. The signals, however, still remain to be identified. Since physiological
      levels of glucocorticoids potentially induce or enhance thymocyte apoptosis even
      in vivo, the signals are likely to inhibit the apoptotic effect of
      glucocorticoids. We have previously shown that proper cross-linking of TCR-CD3
      with LFA-1, CD4 or CD8 inhibited glucocorticoid-induced thymocyte apoptosis in
      vitro, and that a proper combination of the calcium ionophore, ionomycin and the
      protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), mimicked
      the inhibitory effect. Here we determined whether this combination of ionomycin
      and PMA induces differentiation of isolated DP thymocytes from normal and TCR
      transgenic mice. We found that pretreatment of DP thymocytes with ionomycin and
      PMA followed by 1 day culture of the cells without the reagents resulted in the
      differentiation of the cells into CD4 SP and CD4+ CD8lo T cells that have mostly
      committed to the CD4 lineage. The changes in expression of other differentiation
      markers were also in good accordance with those associated with positive
      selection, except the final maturation. The results indicate that moderate and
      transient increases in intracellular Ca2+ level and PKC activity induce
      differentiation and commitment of DP thymocytes to the CD4 lineage, and suggested
      that the biochemical pathway leading to positive selection is based on a similar
      mechanism.

PMID- 8671616
TI  - Antigen processing and presentation by a mouse macrophage-like cell line
      expressing human HLA class II molecules.
AB  - Macrophages differ from other antigen-presenting cell types in their potential to
      take up, process and present particulate antigens as well as proteins and
      peptides. To study their influence on T cell activation we transfected the mouse
      macrophage-like cell line P388D1 with human genes coding for the alpha and beta
      chains of class II molecules (DRA*0101 and DRB1*0401 or DRB1*0404) or with a
      series of localized DR beta mutants. The transfected cells (TP cells) all
      expressed DR4 molecules on their surface. Since they stimulated some, but not
      all, human DR4-reactive T cell clones, some of the resident peptides are
      evidently similar in mouse and man. Proteins and polypeptides such as pepsin or
      the human acetylcholine receptor (AChR) alpha 37-181 were also processed
      correctly by these transfectants and then presented efficiently to other T cell
      clones. Nearly all the mutants tested could present to the pepsin-specific clone,
      establishing functional expression of the transfected DR molecules. For the more
      exacting AChR alpha 144-156-specific T cell clone PM-A1, we confirmed that the
      single Gly86--> Val mutation in the DR beta chain abolished presentation by two
      DR4 subtypes. If, however, this same replacement was made in a third variant that
      has Lys71 (rather than Arg71), the effects were less drastic. This approach could
      also be used to analyse the contributions of individual substitutions that confer
      susceptibility to rheumatoid arthritis.

PMID- 8671617
TI  - Role of IL-7 and KL in activating molecules controlling the G1/S transition of B
      precursor cells.
AB  - While chemically defined conditions for culturing normal tissue have been
      attained for only a few cell types, the sustained proliferation of B precursor
      cells expressing IL-7 receptor and c-Kit can be supported under chemically
      defined conditions containing recombinant IL-7 and the ligand for c-Kit (KL). To
      understand the biochemical basis of the cell cycle progression of B precursor
      cells proliferating under these conditions, we investigated the correlation
      between growth factor stimulation and CDK4 activity. Consistent with our findings
      that IL-7 regulates the G1/S transition, while KL has only a little role in this
      process, the kinase activity of CDK4 was related closely with IL-7 stimulation
      but not KL stimulation. We investigated the mechanism underlying CDK4 activation
      in the IL-7 stimulated B precursor cells. Our results showed that (i) CDK4 and
      cyclin D3 are the G1/S regulators in B precursor cells; (ii) their expression
      levels are unchanged between the cells in G1 arrest and cycling cells; and (iii)
      they are present in an associated form even when the cell cycle stage is arrested
      at G1. Thus, the regulation of the expression of CDK4 and cyclin D3 or regulation
      of their assembly are not the mechanisms for activating CDK4 in the B precursor
      cells. On the other hand, a number of molecules co-immunoprecipitated with CDK4
      were enhanced in the lysate of IL-7-stimulated B precursor cells. Thus, we
      present a possibility that CDK4 activation might be regulated by molecules
      associated with the CDK4-cyclin D3 complex in IL-7-dependent manner.

PMID- 8671618
TI  - Emergence of CD52-, glycosylphosphatidylinositol-anchor-deficient lymphocytes in
      rheumatoid arthritis patients following Campath-1H treatment.
AB  - CD52 is a glycosylphosphatidyl-inositol (GPI)-linked glycoprotein expressed at
      high levels on normal T and B lymphocytes and at lower levels on monocytes, while
      being absent on granulocytes and bone marrow stem cell precursors. The emergence
      of CD52- lymphocytes of both T and B cell lineages was observed in three out of
      25 rheumatoid arthritis patients treated with teh humanized antibody Campath-1H
      in phase II clinical trial. Whereas the majority of CD52- B cells had disappeared
      from the peripheral blood by 3 months post-treatment, both CD52- CD4+ and CD8+ T
      cells persisted in the circulation for at least 20 months. In the two patients
      that were tested, the GPI-anchored surface molecules CD55 and CD59 were also
      absent on the CD52- cells, although expression of other cell surface
      transmembrane, proteins (CD3, CD4 and CD2) was unaffected. The CD52- cells
      maintained a stable phenotype in vitro despite repeated re-stimulation in
      culture. Both CD52- and C52+ clones, established from one of the patients,
      responded to a similar extent to several T cell mitogens, as assessed by
      proliferation, suggesting that a general defect in expression of GPI-linked
      molecules does not impair T cell activation. These data show that an immune
      attack against a GPI-anchored surface molecule can result in the selection of a
      GPI-anchor-deficient cell population. Despite the persistence of CD52- T cells in
      the peripheral blood, no adverse reactions associated with the presence of these
      cells were noted in any of the patients; in fact they responded with longer
      remission times after Campath-1H treatment than the other patients in the trial.

PMID- 8671619
TI  - Regulation of house dust mite responses by intranasally administered peptide:
      transient activation of CD4+ T cells precedes the development of tolerance in
      vivo.
AB  - We have previously demonstrated that intranasal (i.n.) administration of an
      immunodominant peptide (p1-111-139) derived from the house dust mite (HDM)
      allergen Der p 1 inhibits antigen-specific CD4+ T cell responses in H-2b mice.
      Here we report that i.n. peptide induced a rapid but transient activation of MHC
      class II restricted CD4+ T cells that peaked 4 days after peptide treatment and
      was of similar magnitude to that induced by parenteral immunization with antigen
      in adjuvant. During the early phase of the response lymph node and splenic T
      cells secreted a range of lymphokines when re-stimulated in vitro with p1 111
      139; however, by day 14 IL-2 and IFN-gamma secretion by T cells were down
      regulated. Mice deficient in CD8+ T cells became tolerant by i.n. treatment with
      peptide, suggesting that CD8+ T cells are not involved in down-regulating the
      CD4+ T cell response. Rechallenging mice with a single dose of p1 111-139 21 days
      after the initial treatment elicited a further transient T cell response, which
      was subsequently down-regulated over time. Although the i.n. peptide induced a
      strong transient CD4+ T cell response, only low levels of peptide-specific
      antibodies were detected either after the initial or subsequent i.n. exposures to
      p1 111-139. Our findings address the mechanisms underlying peripheral T cell
      tolerance following i.n. administration of a high dose of immunogenic peptide and
      have implications for understanding the consequences of peptide immunothearapy.

PMID- 8671620
TI  - In vitro immunization of naive mouse B cells: establishment of IgM secreting
      hybridomas specific for souble protein or hapten from B cells cultured on CD40
      ligand transfected mouse fibroblasts.
AB  - CD40 has been shown to play an important role in the regulation of B cell
      survival, proliferation and Ig class switching. The natural partner for CD40 is
      CD40 ligand, gp 39, which is transiently expressed on activated T cells. In
      vitro, CD40 ligation leads to polyclonal B cell proliferation and, in the
      presence of appropriate cytokines, to the secretion of Ig of various isotypes. In
      the present study we show that naive B cells cultured in vitro on CD40L
      transfected mouse fibroblasts in the presence of two different soluble antigens
      (beta-galactosidase and phenyloxazolone coupled to ovalbumin) can be specifically
      immunized as shown by direct single cell Elispot assays or after establishment of
      B cell hybridomas. However, under the conditions of in vitro immunization used,
      all hybridomas analysed produced specific IgM antibodies only and we failed to
      detect cells that had switched to other isotypes. The data suggests that CD40
      ligation can be used for efficient in vitro immunization against soluble antigens
      for IgM production but that CD40 signals even in conjunction with cytokines are
      insufficient to induce high rate switching.

PMID- 8671621
TI  - Effects of different antigenic microenvironments on the course of CD8+ T cell
      responses in vivo.
AB  - The influence of microenvironment on the course of CD8 + T cell responses in vivo
      was investigated by injecting H-2Kb-specific T cells from donor TCR transgenic
      (TCR-Tg) mice into H-2kb-Tg mice. H-2Kb expression in recipients was either
      ubiquitous (CBK mice) or restricted to myeloid and erythroid cells (K beta mice).
      Donor T cells proliferated as extensively and acquired similar surface phenotypes
      in spleen of both recipient types. Thus, neither the restricted pattern of H-2Kb
      expression nor the significantly reduced level of H-2Kb expression by myeloid
      cells in Kbeta recipients affects the ability of the splenic microenvironment to
      prime T cell proliferation in vivo. However, an unsustained burst of cytolytic
      activity was generated rapidly in spleen of CBK recipients, whereas relatively
      little cytolytic activity was generated in K beta spleen. This indicates that
      effector T cells were not generated efficiently in spleen of Kbeta recipients
      even though extensive T cell proliferation was taking place in this
      microenvironment. Furthermore, activated donor T cells dispersed rapidly
      throughout primary and secondary lymphoid organs of Kbeta recipients, whereas few
      T cells migrated from spleen in CBK recipients. Consequently, the course of CD8+
      T cell responses and the anatomical distribution of activated T cells are
      profoundly influenced by the nature of the antigenic microenvironment encountered
      in vivo. We conclude that T cells rapidly proliferate and acquire new tissue
      homing characteristics but do not differentiate into cytolytic effector cells at
      the site of priming when they encounter myeloid cells expressing low levels of
      antigen in vivo.

PMID- 8671623
TI  - H2-M3wt-restricted, Listeria monocytogenes-specific CD8 T cells recognize a
      novel, hydrophobic, protease-resistant, periodate-sensitive antigen.
AB  - Mice infected with Listeria monocytogenes (LM) generate H2-M3wt-restricted CD8
      effectors which recognize a heat-killed LM-associated antigen (HAA) presented by
      macrophages. To characterize HAA, we extracted a bioactive component from LM
      using SDS or NaOH. Extracted HAA aggregated in hydrophilic solvents but
      dissociated in the presence of SDS into a smaller subunit which migrated in
      Sephadex G-200 between chymotrypsinogen (25 kDa) and cytochrome c (12.5 kDa). HAA
      bioactivity and size was unaffected by proteinase K under conditions which
      degraded virtually all detectable protein. HAA was also unaffected by other
      proteases, RNase and DNase, but HAA bioactivity was destroyed by periodate, an
      agent that degrades carbohydrates. These studies demonstrate that H2-M3wt can
      present a hydrophobic, non-peptide, microbial antigen, probably glycolipid in
      origin, to CD8 T cells.

PMID- 8671624
TI  - Molecular cloning of murine decay accelerating factor by immunoscreening.
AB  - Although the cDNA of human decay accelerating factor (DAF) which restricts
      complement activation on homologous cell membranes was cloned in 1987, all trials
      to detect the cDNA of mouse DAF by cross-hybridization were unsuccessful.
      However, by immunoscreening with a rabbit antiserum against purified mouse DAF,
      we successfully cloned the cDNA. It contains four typical short consensus repeats
      (SCR) similar to that in human and guinea pig DAF. The base sequence showed 63.7
      and 63.8% identity to that of human and guinea pig DAF respectively. The deduced
      amino acid sequence identity to human and guinea pig DAF was 47.2 and 46.5%
      respectively. Mouse complement receptor related gene Y (Crry)/p65 function is
      comparable to DAF. SCR3 and SCR4 of mouse DAF showed 50% identity to SCR2 and
      SCR3 of Crry/p65 respectively. Identification of the mouse DAF gene should open a
      new approach for determining the actual in vivo role of DAF by analyzing
      autoimmune mice as well as generating DAF gene knockout mice using embryonic stem
      cells.

PMID- 8671625
TI  - Evaluation of presence and functional activity of potentially self-reactive T
      cells in aged mice.
AB  - Autoimmunity is known to increase in aging. A possible factor could be an
      alteration in the T cell repertoire with advancing age. Antibodies to the
      variable region of the beta chain of the TCR activate T cells and can serve as
      probes for analysis of the T cell repertoire. We have used V beta 3 and V beta
      17a antibodies to determine the presence and functionality of normally deleted T
      cells bearing potentially self-reactive TCR in peripheral lymphoid tissue and
      blood from aged (SJL/J x BALB/c) F1, LAF1 and BALB/c mice. Although an occasional
      20- to 24-month-old mouse exhibited V beta 3+ or V beta 17a+ T cells in their
      lymph nodes or peripheral blood lymphocytes (PBL) slightly above the range for
      normal young mice of these I-E+ strains, there was no striking 'escape' from the
      normal thymic deletion process. However, responsiveness to anti-V beta 3 and anti
      V beta 17a was slightly higher in aged, and particularly in aged thymectomized
      (TX), than in young mice. This was in contrast to proliferative responses to
      stimulation with antibody to the normally expressed V beta 8, which were lower in
      the lymph nodes from aged than from young mice. The PBL of some 30- to 36-month
      old mice were also examined. Enhanced numbers of 'forbidden' V beta bearing T
      cells were seen more frequently at this age. In spite of the age-related decrease
      in overall CD4/CD8 T cell ratios in all organs, the mice with relatively high V
      beta 17a + T cells exhibited proportionally more CD4+ cells in that V beta
      population. We conclude that the 'forbidden' T cells that respond to anti-V beta
      stimulation in the 20- to 24-month-old mice are most likely to extra-thymic
      origin, since they were more readily detectable in aged TX mice. Potentially self
      reactive Cd4 (and CD8) single-positive T cells were detectable in PBL only in
      very aged (30-36 months old) euthymic mice.

PMID- 8671626
TI  - The generation of SDS-stable HLA DR dimers is independent of efficient peptide
      binding.
AB  - MHC class II molecules can exist in two conformations which can be distinguished
      on the basis of their stability in SDS. The formation of SDS-stable dimers has
      been shown to correlate with persistent expression of antigen MHC class II
      peptide complexes by murine antigen-presenting cells. HLA DR molecules contain
      either a Val or a Gly at position 86 of the beta chain, which is located in a
      conserved and prominent hydrophobic pocket in the peptide binding site. Here we
      show that Val86-containing DR molecules more frequently select peptides which
      induce the formation of SDS-stable dimers than Gly86 variants. Using analogues of
      the influence virus haemagglutinin epitope 307-319 we found that the replacement
      of the aromatic hydrophobic anchor residue (Tyr)at position 309 by amino acids
      with an aliphatic hydrophobic side chain resulted in the specific formation of
      high numbers of SDS-stable Val86-DR but not Gly86-DR dimers. These results
      indicate that the fit between the first anchor residue and the hydrophobic pocket
      around Dr beta 86 plays a critical role in the formation of SDS-stable DR dimers.
      Synthetic analogues of naturally processed DR-associated peptides displayed
      promiscuity in their capacity to bind to several DR specificities and in their
      ability to induce the SDS-stable conformation. However, no correlation was
      observed between binding capacity and the ability to induce the SDS-stable
      conformation. Since it has been shown that SDS stability can relate to the
      kinetics of peptide-MHC class II interactions, the definition of the requirements
      for the formation of SDS-stable HLA class II molecules may be important for the
      design of effective peptide-based immunomodulation protocols.

PMID- 8671627
TI  - CD40 expression and function in murine B cell ontogeny.
AB  - The CD40 antigen, a member of the nerve growth factor/tumor necrosis factor
      receptor family, is expressed on all mature B lymphocytes and plays a crucial
      role in B cell activation, T cell-dependent antigen-driven isotype switching and
      germinal center formation. We have analyzed CD40 expression and function during
      mouse B cell development by examining B cell precursors in normal mice and in
      transgenic animals in which B cell development is frozen at discrete stages.
      These models included RAG-2-/- mice, and transgenic littermates that express a mu
      heavy chain and/or the bcl-2 proto-oncogene transgene. CD40 was undetectable at
      the pro-B cell stage, but was expressed, although at low levels, on pre-B cells.
      However, pre-B cells failed to respond to CD40 triggering either by expression of
      CD23 or by proliferation in the presence of IL-4. Overexpression of bcl-2
      increased the density of CD40 expression on pre-B cells: these cells respond to
      CD40 ligation by expressing CD23 and by proliferating in the presence of IL-4.

PMID- 8671628
TI  - In vitro and in vivo recovery of IFN-gamma, but not IL-2, production by IL-12 in
      mice with plasma cell tumors.
AB  - We have previously found that T cells from mice bearing plasma cell tumors (PCT
      mice) demonstrate decreased proliferation as well as decreased production of the
      Th 1-associated cytokines IL-2 and IFN-gamma in response to polyclonal
      stimulation. In the present study, we have examined soluble factors as possible
      elements required to rescue this decreased proliferation and cytokine production
      by splenocytes from PCT mice. We find that the addition of supernatants from
      stimulated normal splenocytes has no effect on proliferation of IL-2 production
      by splenocytes from PCT mice. In contrast, these supernatants completely restore
      IFN-gamma production by splenocytes from PCT mice. We have found that IL-12 is
      responsible for the observed increase in IFN-gamma production because: (i)
      addition of anti-IL-12 antibody blocks this recovery of IFN-gamma production by
      these supernatants, (ii) the addition of recombinant IL-12 to cultures of
      splenocytes from PCT mice results in increased IFN-gamma production and (iii) in
      vivo treatment of PCT mice in IL-12 also results in increased IFN-gamma
      production by the subsequently activated splenocytes, but has little effect on
      proliferation or IL-2 production. These results demonstrate that both in vitro
      and in vivo, IL-12 selectively restores the decreased production of IFN-gamma by
      splenocytes from PCT mice.

PMID- 8671629
TI  - Functional significance of the Fas molecule in naive lymphocytes.
AB  - The Fas molecule mediates apoptotic signal in many cell types. Mouse mutations
      (lpr, lprcg, gld), which impair the function of Fas, cause spontaneous autoimmune
      disease. We generated Fas-deficient (Fas-/-) mice by homologous recombination. In
      embryonic stem cells Fas-/- mice developed lpr-like disease, confirming that the
      abnormality of Fas is causal in the lpr phenotype. We also made Fas-/- chimeric
      mice composed of a mixture of Fas+/+ and Fas-/- cells. The chimeric mice also
      showed the lpr phenotype. In Fas-/-, chimeric mice, the Fas-deficient population
      expanded progressively among mature T and B lymphocytes. The expansion of Fas
      deficient lymphocytes occurred at the naive, pre-primed, lymphocyte stage. These
      results suggest that the Fas molecule functions not only after antigenic
      stimulation, as previously hypothesized, but also at the naive lymphocyte stage.

PMID- 8671630
TI  - Schistosoma mansoni in IL-4-deficient mice.
AB  - Immunopathology and immune responses to Schistosoma mansoni were examined in IL-4
      -/- mice. IL-5 and IL-10 production by lymphoid cells stimulated with soluble egg
      antigen (SEA), peripheral eosinophilia and serum levels of soluble IL-4 receptor
      but not IgE were all significantly elevated over background normal levels in IL-4
      -/- mice as a result of infection. Additionally, IL-10 and IL-5 in addition to IL
      2 and IFN-gamma transcripts were equally evident in diseased liver tissue from
      infected IL-4 -/- and wild-type mice. Nevertheless, analysis of antigen
      stimulated IL-2, IL-4, IL-5, IL-10 and IFN-gamma production by lymphoid organ
      cells from infected or egg-injected IL-4 -/- mice revealed a more Th1-like
      pattern of cytokine production (IFN-gamma > IL-5) than in (wild-type) mice in
      which a stronger type 2 response to SEA was detectable (IL-4, IL-5 > IFN-gamma).
      Despite this, at 8 and 16 weeks after infection, liver pathology, as indicated by
      the size, cellularity, cellular composition and collagen content of granulomas,
      was similar in IL-4 -/- and wild-type animals. As in wild-type animals, granuloma
      size at week 16 was smaller than at week 8, indicating that modulation had
      occurred in the absence of IL-4. Differences in pathology were seen only when
      eggs were experimentally embolized to the lungs, in which case IL-4 -/- mice made
      smaller granulomatous responses than did wild-type animals. These data clearly
      show that IL-4 is not necessary for the hepatic granuloma formation which occurs
      during experimental schistosomiasis.

PMID- 8671631
TI  - Activation of T cells by the ragged tail of MHC class II-presented peptides of
      the measles virus fusion protein.
AB  - The efficient and sustained immune response of an antigen requires T cell
      epitopes, capable of inducing a long lasting T cell memory. To detect T cell
      epitopes of the measles virus fusion protein (MV-F), the proliferation of
      lymphocytes from late convalescent donors in response to overlapping
      pentadecapeptides covering the whole protein sequence was studied. Three major
      immunodominant regions (F51-70, F121-135 and F211-225) containing promiscuous
      peptides induce proliferation in peripheral blood lymphocytes in approximately
      50% of the donors. Potential DR1-restricted epitopes were mapped using an MHC
      competition binding assay. Both the proliferation and the binding data identified
      a DR1-restricted T cell epitope (F51-65). Contact sites of the peptide
      HQSLVIKLMPNITLL with MHC were characterized using substitution analogs. Alanine
      substitutions at most positions did not interfere with F51-65 binding. These
      analogs were therefore useful for studying the residues which were recognized by
      the TCR of MV- and F51-induced T cells lines. In addition to amino acid residues
      of the core of peptide F51-65 both the C-terminal and the N-terminal amino acids
      were essential for T cell interaction. Since peptides presented by class II
      molecules vary in length, these findings suggest that residues of the ragged tail
      are important for T cell activation. It is speculated that in late convalescent
      donors the length of the flanking sequence of MHC II-restricted peptides may play
      a role in controlling the heterogeneity of MV-specific T cell clones recruited as
      T helper/memory cells.

PMID- 8671632
TI  - Influence of strong CD4 epitope on long-term virus-specific cytotoxic T cell
      responses induced in vivo with peptides.
AB  - Free unmodified peptides are poor immunogens for cytotoxic T lymphocytes (CTL) in
      mice, unless they are injected with adjuvant. Although it is generally accepted
      that CD4+ Th cells are essential for CTL priming with peptides, it is not clear
      how long sequences devoid of any CD4 epitope, or strict CD8 epitopic sequences
      too short to be presented in a MHC class II-restricted fashion, can generate such
      responses. We thus have examined the extent to which the immunization protocol
      affects the need for a CD4 epitope. Since peptides are potentially important for
      vaccination, we also examined the duration of the CTL responses using a set of
      peptides that contained a CD4 epitope, or a CD8 epitope, or both epitopes in the
      same sequence, and compared immunization protocols previously found to induce CTL
      responses with peptides. The in vivo injection protocol had a marked effect,
      since the same CD8 sequence could generate a CTL response in a Th-dependent or Th
      independent fashion, depending on the protocol used. The T cell help provided by
      natural CD4-CD8 sequences was inefficient in Th-dependent CTL priming and CTL
      generation required help from a stronger exogenous CD4 peptide. The peptides
      could be injected either as a single tandem CD8-CD4 peptide or as a mixture of
      two separate peptides. Th-independent CTL responses primed in other conditions
      proved to be as strong as Th-dependent responses, at least when the animals were
      killed shortly after the last injection. However, only CTL responses generated
      together with specific Th cells persisted for several months. Moreover, the
      efficacy of CTL persistence seemed to be correlated with the strength of the CD4
      epitope for priming. This has important implications for the design of peptide
      vaccines.

PMID- 8671633
TI  - Proteasomes generate in vitro a natural peptide of influenza-A nucleoprotein
      functional in HLA-B27 antigen assembly.
AB  - We have studied the degradation of a set of long peptides (9-30 amino acids) from
      the nucleoprotein of influenza A. In common for all these peptides is the core
      sequence NH2-Ser-Arg-Tyr-Trp-Ala-Ile-Arg-Thr-Arg-COOH, NP383-391, known as an
      antigenic peptide specific for the HLA-B27 class I antigen. We show that this
      peptide is generated by enriched cytosolic proteasomes of two sizes, 20S and 12S.
      The 12S proteasome is the precursor, the preproteasome, to the 20S mature
      proteasome as shown by pulse-chase experiment and is most likely responsible for
      the proteolytic activity in the 12S region. Cleavage at the N-terminus is
      distinct and restricted to residue 383, independent of the N-terminal extension
      of the peptide. The C-terminus is generated via cleavage at three sites.
      Intermediate and final peptide products were identified by mass spectrometry.
      Finally, we show that the NP383-391 peptide generated by proteasomes in vitro is
      functional inasmuch as it possesses the ability to stimulate assembly of in vitro
      translated HLA-B27 antigens.

PMID- 8671635
TI  - Induction of NO synthesis in macrophages by Newcastle disease virus is associated
      with activation of nuclear factor-kappa B.
AB  - Newcastle disease virus (NDV) has received much attention recently because of its
      non-specific immune stimulating potential and its various anti-tumor activities.
      Here we describe that NDV induces synthesis of NO and causes an activation of
      nuclear factor-kappa B (NF-kappa B) in murine macrophages. These reactions were
      part of an activation process which included also stimulation of adenosine
      deaminase and inhibition of 5'-nucleotidase. NDV-mediated NO synthesis and NF
      kappa B activation were blocked by an antioxidant (butylated hydroxyanisole), by
      an inhibitor of protein tyrosine kinase (genistein) and of protein kinase A (H
      89), but not by an inhibitor of protein kinase C (staurosporin). These data
      suggest that signalling requirements of NF-kappa B activation and NO production
      in NDV-treated macrophages are similar.

PMID- 8671636
TI  - The association between lung innate immunity and differential airway antigen
      specific immune responses.
AB  - The mechanisms involved in the differential regulation of airway immune responses
      in atopic versus non-atopic individuals are poorly understood. In this study, the
      association between non-specific immunity and the differential airway antigen
      specific immune responses was examined in a murine model. The disparity in
      antigen-specific IgE and IgG2a productions between the two strains of mice was
      observed to be significant. C57BL/6J mice were much more efficient than BALB/cJ
      mice in making IgE antibody to inhaled ovalbumin (OVA) antigen. On the contrary,
      BALB/cJ mice did make more IgG2a antibodies than C57BL/6J mice to inhaled OVA.
      These findings suggest that in C57BL/6J mouse strain a predominant Th2 type of
      immune response develops in response to inhaled OVA antigen. In contrast, BALB/cJ
      mice mount a Th1 type of immune response to aerosolized OVA antigen. Furthermore,
      after lipopolysaccharide (LPS) stimulation, the IL-12 mRNA expression of lung
      derived cells from BALB/cJ mice was higher than that from C57BL/6J cells.
      However, the lung-derived cells of C57BL/6J mice stimulated by LPS produced
      higher levels of IL-10 and prostaglandin E2 than BALB/cJ lung-derived cells did.
      Therefore, our study demonstrated that the difference of lung-derived cells in
      their ability to produce cytokine and prostaglandin between BALB/cJ and C57BL/6J
      mice correlates well with the type of the airway antigen-specific immune effector
      functions.

PMID- 8671637
TI  - Stage-specific alterations in murine B lymphopoiesis with age.
AB  - Although it is reported that B lymphopoiesis declines with age, the precursor
      stage(s) affected and the age of onset are ambiguous. Each progressive phase of B
      cell differentiation has distinct requirements; therefore, precise identification
      of the stage(s) that decline would yield insight into the age-related mechanisms
      affecting humoral immunity. We analysed the composition of B lineage cells of
      mice 1, 4, 12 and 24 months of age using flow cytometry. Numbers of prepro-B and
      pro-B cells were unchanged, and a profound decrease occurred only in the numbers
      of pre-B cells. This decrease occurred in two distinct phases: between 1 and 4
      months and between 12 and 24 months. Notably, the numbers of newly formed B cells
      did not decline in parallel, suggesting that mechanisms are established to
      overcome the deficiency of pre-B cells. Since the age-related changes are limited
      to the pre-B cell stage, we hypothesized that the impairment acts at the pro-B to
      pre-B transition. We therefore evaluated whether the pro-B cells or the
      supporting stromal cells, which are necessary for normal progression of this
      stage, changed with age. The ability of pro-B cells to proliferate in the
      presence of stromal cells was reduced by 24 months of age, as was the ability of
      the stromal cells to support pro-B cell proliferation. In contrast, the ability
      to mature into IgM+ cells was unchanged. Thus, strategies that supplement the
      stromal environment may enhance B lymphopoiesis in aged animals.

PMID- 8671638
TI  - Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects
      on T cell expansion in vitro and in vivo.
AB  - Co-stimulation via the CD28/CTLA-4 system appears critical for T cell
      proliferation to peptide antigens presented in association with MHC. In this
      study, we examine the roles of CD28 and CTLA-4 in the response of murine T cells
      to the superantigen staphylococcal enterotoxin B (SEB). In vitro, antibodies
      against B7-1/B7-2 or Fab fragments of anti-CD28 antibodies significantly inhibit
      the response of splenocytes to SEB. Conversely, Fab fragments of anti-CTLA-4
      antibodies augment the proliferative response. Further, addition of blocking
      antibodies directed against B7-1/B7-2 augment proliferation co-stimulated by
      intact anti-CD28 antibodies. These data support the hypothesis that CD28 and CTLA
      4 exert opposing effects upon early T cell activation. In vivo, intact anti-CD28
      antibodies and non-stimulatory Fab fragments of anti-CD28 appear to have similar
      inhibitory effects upon the expansion of V beta 8+ T cells. In contrast, both
      intact and Fab fragments of anti-CTLA-4 appear to amplify this expansion. We
      conclude that the SEB response is significantly augmented by CD28-derived
      signaling and this in turn may be attenuated by signals through CTLA-4.

PMID- 8671639
TI  - Contribution of HLA class I and class II alleles to the regulation of antibody
      production to hepatitis B surface antigen in humans.
AB  - The HLA multigene family consists of HLA class I (HLA-A, B and C) and class II
      (HLA-DR, DQ and DP) genes, and plays a central role in the regulation of immune
      response. To investigate how each HLA gene and each HLA allele contribute to the
      human immune response, we immunized 339 healthy Japanese medical students with
      recombinant hepatitis B surface antigen (rHBsAg) and determined the HLA types of
      all vaccinated subjects at the DNA level. The anti-HBs antibody titers showed a
      log-normal distribution, implying that the immune response to HBsAg in humans is
      a multifactorial and continuous trait. A stepwise multiple regression analysis
      demonstrated the alleles at the HLA-class I (HLA-A and B) and class II (HLA-DRB1,
      DQA1, DQB1, DPA1 and DPB1) loci significantly contributed to antibody production
      to HBsAg. The predicting equation of anti-HBs antibody levels for individuals
      with any HLA phenotype was proposed based on a multiple regression analysis. The
      multiple correlation coefficient of antibody production to HBsAg with the HLA
      DRB1 locus was highest (0.34) among all of the HLA loci, whereas those with whole
      HLA class I or class II loci were 0.36 or 0.44 respectively. The incorporated
      correlation coefficient of the presence of all HLA gene families with antibody
      production became 0.50, suggesting that HLA class I and class II loci within the
      HLA multigene family are dynamically involved in regulation of the immune
      response to HBsAg.

PMID- 8671640
TI  - Phenotype of B cells responding to the thymus-independent type-2 antigen
      polyvinyl pyrrolidinone.
AB  - We have determined the origin and cell surface phenotype of B cells producing
      antibody in response to immunization with the non-self TI-2 antigen polyvinyl
      pyrrolidinone (PVP). We report that the responding cells are derived from
      precursors in adult bone marrow and display the phenotype characteristic of B-1
      cells. By use of allotype marked chimeric mice, constructed by reconstituting
      lethally irradiated recipients with adult bone marrow and peritoneal B-1
      lymphocytes of recognizably different Ig allotypes, immunized with 1 microgram
      PVP, we found that although a substantial part of the total IgM produced in these
      chimeras bore the allotype of the transferred peritoneal B-1 cells, essentially
      all of the anti-PVP IgM expressed the allotype of the adult bone marrow. Fifteen
      of 16 hybridomas derived from a normal PVP-immune adult mouse bore N nucleotides
      at the V-D and D-J junctions of their heavy chain CDR3 regions, indicating their
      origin from precursors in the adult bone marrow. By use of ELISA spot analysis,
      we found the cells responding to PVP to be localized in the spleens of normal
      immunized mice. We then used multiparameter flow cytometric sorting to determine
      the cell surface phenotype of these cells. We found that the cells producing anti
      PVP were greatly enriched in a small subpopulation with the phenotypic
      characteristics of B-1 cells; they were B220intermediate, CD5low, IgMhigh,
      IgDlow, CD43+ and CD23-. This subpopulation was also enriched for all cells
      producing IgM, regardless of specificity (the so-called 'spontaneous' antibody).
      We conclude that the B-1 phenotype is more likely a marker for a state of
      differentiation than for a discrete lineage of B cells.

PMID- 8671641
TI  - Highly efficient peptide binding and T cell activation by MHC class II molecules
      of CIITA-transfected cells.
AB  - Expression of MHC class II, DM and Ii genes is controlled by the transactivator
      CIITA, a mediator of the activation of these genes by IFN-gamma. Surprisingly,
      MHC class II molecules expressed on CIITA transfectants behave very differently
      from those expressed at the same level on IFN-gamma-induced cells in terms of
      peptide binding and peptide-specific T cell activation. MHC class II-positive
      CIITA transfectants exhibit an unusually high capacity for binding exogenous
      peptides, with a higher percentage of DR molecules occupied by a given peptide
      and are much more efficient at peptide-specific, HLA-DR-restricted activation of
      T lymphocytes. This unexpected phenotype reflects the antigen processing defect
      observed in CIITA transfectants. It suggests novel strategies for the use of
      CIITA-transformed cells in peptide-based immunization.

PMID- 8671642
TI  - Unprimed T cells are inefficiently stimulated by glycosylphosphatidylinositol
      linked H-2Kb because of its lipid anchor rather than defects in CD8 binding.
AB  - Many non-classical, or class Ib, MHC molecules, including those linked to the
      cell membrane via glycosylphosphatidylinositol (GPI) membrane anchors, are poor
      stimulators of primary cytotoxic T cell responses. Some studies have suggested
      that certain amino acid substitutions in the alpha 3 domains of class Ib
      molecules may adversely affect their ability to interact with CD8, thereby
      affecting their ability to stimulate CD8+ T cells. In this report we show that
      poor stimulation by GPI-linked class I MHC molecules is not simply due to a
      failure to interact with CD8, but to a fundamental difference in the way T cells
      respond to GPI-anchored class I molecules. We have demonstrated this in two ways.
      Firstly, we have shown that GPI-linked H-2Kb molecules in which the amino acid
      sequence of the alpha 3 domain is identical to that of transmembrane H-2Kb remain
      less effective stimulators of a primary T cell response than membrane-spanning H
      2Kb molecules. Secondly, using CD8- responder T cell hybridomas and responder T
      cells from transgenic mice expressing a CD8-independent TCR, we can show that the
      poor stimulatory ability of GPI-linked H-2Kb molecules is unrelated to their
      ability to interact with either CD8 or the TCR. These results suggest that the
      transmembrane linkage of class I MHC molecules plays an important role in the
      initial priming of T cells.

PMID- 8671643
TI  - A critical role for stem cell factor and c-kit in host protective immunity to an
      intestinal helminth.
AB  - In common with many intestinal nematode infections, Trichinella spiralis
      infections in mice are associated with a pronounced intestinal mast cell
      hyperplasia. The expulsion of the parasite from the gut is temporally associated
      with intestinal mastocytosis and mast cell function reflected by the secretion of
      mast cell protease into tissue and serum. In vivo, mucosal mast cell production
      is highly dependent upon T cell-derived cytokines including IL-3 and IL-4. We
      present data here to show that intestinal mast cell hyperplasia induced by
      helminth infection is also dependent upon the production of stem cell factor
      (SCF). Neutralization of SCF by anti-SCF or anti-SCF receptor mAb completely
      abrogated the mast cell hyperplasia generated by T. spiralis infection. Moreover,
      worm expulsion was dramatically delayed in treated mice and a reduced intestinal
      eosinophilia was observed. These effects did not appear to be mediated through
      alteration of Th cell responses and the parasite-specific serum antibody response
      was not affected. The reduction in the mast cell response and worm expulsion
      observed after SCF neutralization were reversible following cessation of
      monoclonal treatment. The data presented here clearly demonstrate a major role
      for SCF in the generation of intestinal mastocytosis and the host protective
      immune response following parasitic infection.

PMID- 8671644
TI  - A pivotal role of IL-12 in Th1-dependent mouse liver injury.
AB  - Intravenous injection of Propionibacterium acnes and lipopolysaccharide (LPS)
      with a 7 day interval caused CD4+ T cell-dependent severe liver injury in the
      C57BL/6 (H-2b) mouse strain. In contrast, BALB/c (H-2d) mice were resistant to P.
      acnes and LPS-induced liver injury. The different susceptibilities of the two
      mouse strains to liver injury appeared to be closely correlated with their
      different abilities to produce IFN-gamma after P. acnes priming. Namely, the
      sensitive C57BL/6 mouse strain produced a significant level of IFN-gamma 7-10
      days after P. acnes injection, whereas no significant amount of serum IFN-gamma
      was detected in the resistant BALB/c mouse strain. The important role of IFN
      gamma in liver injury was demonstrated from the finding that in vivo
      administration of anti-IFN-gamma mAb abrogated P. acnes and LPS-induced liver
      injury in C57BL/6 mice. Moreover, it was demonstrated that in vivo administration
      of recombinant IL-12, a key cytokine for the induction of IFN-gamma, into mice
      induced P. acnes and LPS-induced liver injury in the resistant BALB/c mouse
      strain. Conversely, in vivo administration of anti-IL-12 mAb blocked the
      development of liver injury in the sensitive C57BL/6 mouse strain. Moreover, it
      was demonstrated that the failure of the induction of liver injury in BALB/c mice
      appeared to be derived from the lack of expression of IL-12 at the local site of
      liver in P. acnes-primed mice. These results strongly indicated that endogenous
      IL-12, which stimulates Th1-dominant cellular immunity and IFN-gamma production,
      may be an essential cytokine on the course of T cell-dependent liver injury.

PMID- 8671645
TI  - Human immune response to HIV-1 Nef. II. Induction of HIV-1/HIV-2 Nef cross
      reactive cytotoxic T lymphocytes in peripheral blood lymphocytes of non-infected
      healthy individuals.
AB  - HIV-specific CD8+ cytotoxic T lymphocytes (CTL) are thought to have a beneficial
      role in HIV infection. In a previous report we have shown that HIV-1 Nef-specific
      CTL can be readily induced in peripheral blood lymphocytes of seronegative
      healthy young adults by in vitro stimulation with autologous Epstein-Barr virus
      transformed B lymphoblastoid cell lines transfected with the HIV-1 nef gene. Here
      we demonstrate that these Nef-specific CTL can efficiently lyse HIV-infected
      primary CD4+ T lymphocytes. CTL of the blood donor tested were Nef-specific and
      restricted by the autologous MHC class I molecules HLA-A2 and HLA-B7. They
      recognized HIV-1 Nef in association with both restriction elements but HIV-2 Nef
      only in association with HLA-B7. The cross-reactivity of the induced effector
      cells together with the potent immunogenicity of Nef in healthy seronegatives
      further support the inclusion of Nef as a constituent of HIV vaccines.

PMID- 8671646
TI  - Wortmannin-mediated inhibition of phosphatidylinositol 3-kinase activity triggers
      apoptosis in normal and neoplastic B lymphocytes which are in cell cycle.
AB  - The B cell functional response following ligation of surface (s) IgM is dependent
      upon the differentiation stage of the population studied: cross-linking sIgM
      promotes proliferation of resting tonsillar follicular mantle (FM) B lymphocytes
      but induces apoptosis in the susceptible Epstein-Barr virus genome-negative
      Burkitt lymphoma (BL) cell line Ramos (Ramos-BL). This study investigates whether
      phosphatidylinositol-3-kinase (Pl3-kinase), which has been reported to be
      intimately involved in the regulation of cellular growth, plays a role in the
      regulation of these sigpromoted B cell responses, and uses the selective and
      irreversible inhibitor of Pl3-kinase activity, wortmannin (Wm). In Ramos-BL B
      cells, at 8 h post-treatment, Wm triggers a transient increase in apoptosis of 16
      +/- 6.9% with a concomitant cellular loss of 16 +/- 6.1% from the G1 phase of
      cell cycle; [3H]thymidine incorporation also decreases by 33 +/- 5.0%, from
      37,274 c.p.m. +/- 10% to 25,127 c.p.m. +/- 4.0%. Moreover, at 72 h culture, Wm
      inhibits anti-IgM-induced FM B lymphocyte levels of [3H]thymidine incorporation
      typically by 47% and triggers 80% apoptosis from the G0G1 phase of cell cycle.
      Ramos-BL B cells exhibit high basal levels of Pl3-kinase activity, as determined
      by immunoprecipitation with antibody to the p85 regulatory subunit of Pl3-kinase
      and 32P incorporation into phosphatidylinositol, which is not significantly
      affected by anti-IgM stimulation; by contrast, anti-IgM stimulates significant
      Pl3-kinase activity over negligible basal levels in FM B lymphocytes. Pre
      treatment with Wm inhibits Pl3-kinase activity in both cell types. Taken together
      these data indicate that in Ramos-BL B cells sigM-triggered growth arrest and
      apoptosis is Pl3-kinase independent, whereas Pl3-kinase activity is critical for
      sIgM-triggered mitogenesis of FM B lymphocytes. Thus Pl3-kinase plays a pivotal
      role in the regulation of both normal and neoplastic B lymphocyte progression
      through the cell cycle, such that if this Pl3-kinase-dependent pathway is
      inhibited these cells default to apoptosis.

PMID- 8671648
TI  - Elevation of plasma thioredoxin levels in HIV-infected individuals.
AB  - Thioredoxin (Trx), a ubiquitous protein intimately involved in redox and protein
      disulfide reductions, has been shown to be released from cells and to have
      cytokine-like activities. In addition, Trx has been implicated in the redox
      regulation of immunological responses and shown to be deficient in tissues from
      AIDS patients. In studies presented here, plasma Trx levels were measured by
      ELISA in plasma samples from HIV-infected individuals (n = 136) and HIV-negative
      controls (n = 47). To account for the release of Trx into plasma due to
      hemolysis, the Trx measurements were corrected according to the level of
      hemoglobin in the plasma sample. Data presented show that, in contrast to tissue
      Trx levels, corrected plasma Trx levels are significantly higher in HIV-infected
      individuals than in controls (P < 0.0001). Furthermore, approximately 25% of the
      HIV-infected individuals studied have plasma Trx levels greater than the highest
      levels found in controls (37 ng/ml). Detailed multiparameter FACS analysis of
      peripheral blood mononuclear cells (PBMC) from the infected individuals
      demonstrates that those with higher plasma Trx levels (37 ng/ml or greater) tend
      to have lower overall CD4 counts. In addition, increases in plasma Trx levels
      correlate with decreases in monochlorobimane staining (indicative of lower
      intracellular glutathione levels in PBMC) and with changes in surface antigen
      expression (CD62L, CD38 and CD20) that occur in the later stages of HIV
      infection. These correlations suggest that elevation of plasma Trx levels may be
      an important component of advanced HIV disease, perhaps related to the oxidative
      stress that often occurs at this stage.

PMID- 8671649
TI  - A model for antigen-induced T cell unresponsiveness based on autophosphorylative
      protein tyrosine kinase activity.
AB  - Helper T cell signaling is initiated by the aggregation of TCR with the induction
      of tyrosine kinase activity as one of the earliest consequences. Here, a
      theoretical model for antigen-induced unresponsiveness is presented that relies
      on a cascade of tyrosine phosphorylation-dephosphorylation cycles. A mechanism is
      described for both desensitization in the presence of antigen and persistent
      lowering of cell responsiveness after stimulus removal. An important component of
      the model, leading to bistability, is the presence of autophosphorylating protein
      tyrosine kinases in the early steps of TCR signaling. One of its predictions is
      that, following stimulation, the net phosphorylative activity of these receptor
      associated tyrosine kinases will remain above background level after removal of
      the antigen. It is proposed that this residual tyrosine kinase activity is linked
      to a deficient signal transduction capacity of the TCR system that leads to a
      state of prolonged unresponsiveness. In addition, the present analysis defines
      the notion of a signaling threshold for hyporesponsiveness induction, associated
      with a durable switch and amplification of the net tyrosine kinase activity. This
      approach emphasizes the role of tyrosine kinases in the down-regulation of
      cellular competence.

PMID- 8671650
TI  - HLA-DM and MHC class II molecules co-distribute with peptidase-containing
      lysosomal subcompartments.
AB  - MHC class II molecules associate with peptides in the endocytic pathway.
      Different endosomal locations for peptide loading of class II molecules, varying
      from early endosomes (EE) to lysosomes, have been assigned on the basis of
      subcellular fractionation experiments. We have determined the intracellular
      location of HLA-DM, a molecule that supports peptide loading of class II
      molecules, by separating vesicles from the melanoma cell line Mel JuSo on the
      basis of buoying density and surface charge. In both fractionations, HLA-DM co
      fractionated with a lysosomal compartment containing beta-hexosaminidase (beta
      hex) activity and not with endosomes. Further analysis showed that HLA-DM mainly
      co-fractionated with a sub-lysosomal structure characterized by a relative low
      density and containing both pro- and mature cathepsin D and MHC class II
      molecules. Fluid phase markers first enter this compartment before entering high
      density lysosomes that contain exclusively mature cathepsin D, some HLA-DM and no
      detectable MC class II molecules. Finally we determined the intracellular
      location of neutral and acidic peptidases. Whereas neutral peptidase activity was
      detected in the endoplasmic reticulum and/or plasma membrane fractions, acidic
      peptidase activity exclusively migrated at the position of HLA-DM containing
      lysosomal vesicles. Our results show that class II molecules co-migrate with HLA
      DM, pro- and mature cathepsin D, beta-hex and acidic peptidase activity. HLA-DM,
      cathepsin d and class II molecules were not observed at the position of EE. Our
      data suggest that HLA-DM-mediated peptide loading of class II molecules occurs in
      a lysosomal subcompartment.

PMID- 8671651
TI  - Molecular analysis of presentation by HLA-A2.1 of a promiscuously binding V3 loop
      peptide from the HIV-envelope protein to human cytotoxic T lymphocytes.
AB  - P18(IIIB) is a highly immunogenic peptide from the V3 loop of the HIV-1 gp160
      envelope protein that is presented promiscuously by multiple class I MHC
      molecules. Understanding the molecular basis for promiscuous presentation may
      have many practical applications. As the highly prevalent HLA-A2.1 class I
      molecule is known to present P18(IIIB) for recognition by cytotoxic T lymphocytes
      (CTL) found in peripheral blood mononuclear cells of HIV+ donors, a P18(IIIB)
      specific CTL line was generated from and HLA-A2(+), HIV- donor in order to define
      the molecular basis for, and ultimately improve upon the binding of, this peptide
      to HLA-A2.1. The minimal epitope recognized by the line was a decamer, I10, with
      the sequence RGPGRAFVTI. Interestingly, this decamer is identical to the minimal
      epitope from P18(IIIB) seen by murine CTL restricted by H-2Dd. A panel of Ala
      substituted peptides was employed in MHC-binding and T cell response studies to
      identify MHC- and TCR-binding residues. Notably, many of the agretopic and
      epitopic residues identified were identical to those involved in the
      corresponding interactions of I10 with the H-2Dd MHC molecule and murine I10
      specific CTL. The I10 peptide does not contain the described HLA-A2.1 binding
      motif. Instead a Pro at P3, a Phe at P7 and an Ile at P10 are utilized for MHC
      binding. Agretopic residue similarities with the hepatitis B nucleocapsid decamer
      suggest that these residues may comprise an alternative motif of anchors utilized
      by decamers for binding to HLA-A2.1.

PMID- 8671652
TI  - Identification of A2-restricted hepatitis C virus-specific cytotoxic T lymphocyte
      epitopes from conserved regions of the viral genome.
AB  - We have focused on conserved regions of the hepatitis C Virus (HCV) genome to
      identify viral peptides that contain HLA class I binding motifs and bind with
      high affinity to the corresponding purified HLA molecules. Accordingly, we have
      identified 31 candidate epitopes in the HCV that have the potential to be
      recognized by either HLA-A1, A2.1-, A3, A11- or A24-restricted cytotoxic T
      lymphocytes (CTL). Twelve conserved peptides that bind HLA-A2.1 with high or
      intermediate affinity were tested for immunogenicity in vitro in human primary
      CTL cultures and in vivo by direct immunization of HLA-A2.1/Kb transgenic mice.
      Six HLA-A2.1-restricted CTL epitopes were immunogenic in both systems. At least
      three of these peptide epitopes were endogenously processed and presented for CTL
      recognition. Overall, these data illustrate the value of this approach for the
      development of virus-specific, peptide-based vaccines.

PMID- 8671653
TI  - IL-12 administered in vivo to young and aged mice. Discrepancy between the
      effects on tumor growth in vivo and cytotoxic T lymphocyte generation ex vivo:
      dependence on IFN-gamma.
AB  - Because IL-12 restores allogeneic cytotoxic T lymphocyte (CTL) activity by T
      cells of aged mice in vitro, we initially assessed whether IL-12 could overcome
      age-related deficits when given to aged mice in vivo. Growth of P815(H-2(d)) was
      enhanced in aged compared with young BALB/c (H-2(d)) mice and tumor growth was
      curtailed by IL-12 in both age groups. Unexpectedly, secondary CTL stimulated ex
      vivo with P815 were reduced in IL-12-treated mice compared with controls. Primary
      CTL generated ex vivo across MHC differences in IL-12 treated BALB/c and C57BL/6
      young mice were reduced by 90-99%, were dose- and time-dependent, and were
      associated with reduced allo-stimulated NK-like activity and [3H]thymidine
      incorporation. IFN-gamma was elevated in sera and in supernatants from allo
      stimulated cultures from IL-12-treated mice, while IL-4 was reduced in such
      supernatants, suggesting that, despite reduced CTL, IL-12 was associated with
      increased Th1- and reduced Th2-type cytokine production. IL-12 also induced
      splenomegaly, primarily due to increased numbers of cells lacking markers of
      mature T, B and NK cells, or macrophages, or polymorphonuclear leukocyte
      morphology. IFN-gamma mutant mice exhibited reduced splenic enlargement in
      response to IL-12, suggesting that the splenomegaly was due, in part, to IFN
      gamma production. However, reduced CTL generation was not due entirely to
      dilution of CTL precursor cells because spleen cellularity and size increased 3
      fold while CTL activity decreased 10- to 100-fold, and CTL generation normalized
      to CD8(+) T effector cells was still significantly reduced in IL-12-treated mice.
      Interestingly, purified CD4(+) and CD8(+) T cells from IL-12-treated normal mice
      exhibited greater proliferative and cytolytic activities respectively compared
      with controls. Thus, effector T cells in IL-12-treated mice were not impaired,
      but exhibited augmented responsiveness, suggesting that IL-12 induced complex
      interactions among spleen cell populations and that these effects, in part, are
      mediated by IFN-gamma.

PMID- 8671654
TI  - Fas (CD95)-independent regulation of immune responses by antigen-specific CD4
      CD8+ T cells.
AB  - Antigen-activated T cells of the CD4(+)CD8(-) phenotype are susceptible to
      antigen receptor-stimulated cell death. This form of apoptotic cell death has
      been shown to be dependent on the expression of the Fas (CD95) antigen and can
      occur via an autocrine mechanism involving the concomitant up-regulation of Fas
      and its ligand on activated T cells. Mutation in genes encoding Fas (Ipr) and the
      Fas ligand (gld) contribute to the development of an autoimmune syndrome similar
      to systemic lupus erythematosus in mice. These observations led to the suggestion
      that the Fas signaling pathway is an important regulator of immune responses in
      vivo. Here we evaluated the importance of the Fas pathway in regulating immune
      responses by male antigen-specific CD4(-)CD8(+) T cells. We found that the in
      vivo elimination of these activated cells was independent of Fas expression by
      these cells. However, the elimination of these activated cells was inhibited by
      the transgenic expression of Bcl-2, a protein that inhibits multiple forms of
      apoptotic cell death. The transgenic Bcl-2 protein also inhibited the death of
      male antigen-activated cells following IL-2 deprivation. Cell death resulting
      from IL-2 deprivation occurred efficiently in male antigen-activated Fas- cells.
      We propose that the rapid deletion of male antigen-activated Fas- cells in vivo
      is due to limiting amounts of IL-2 that are available in the microenvironment of
      the activated cells at the peak of the response.

PMID- 8671655
TI  - Induction of a non-oscillating, long-lasting humoral immune response to an
      internal network antigen.
AB  - B lymphocyte antigen receptors form an internal idiotypic network which is also
      connected by idiotypic interactions with the T lymphocyte compartment. Idiotypic
      anti-idiotypic activation of lymphocytes has mainly been measured at the cellular
      level while the kinetics of primary anti-idiotypic humoral responses has so far
      not been determined. Here, we describe the induction of an anti-idiotypic immune
      response to the major idiotype (IdOx1) of the primary immune response in BALB/c
      mice to the hapten 2-phenyl-t-oxazolone coupled to chicken serum albumin. A
      primary anti-idiotypic humoral response could be induced with the phOx-binding
      and IdOx1-expressing, germline-encoded antibody H11.5 (mu, kappa) coupled to
      keyhole limpet hemocyanin. Compared to that of conventional antigens, the anti
      idiotypic response showed a lag phase of 3 weeks. When the anti-IdOx1 serum
      titers had declined to background levels, a secondary anti-IdOx1 response could
      be induced even with soluble H11.5. This response showed as fast an increase as
      conventional antigens, but the antibody plateau did not exceed that of the
      primary response. During this secondary anti-IdOx1 response and probably to a
      small extent also during the primary response, the mice developed an
      idiotypically non-related IgM-anti-phOx response. In contrast, soluble H11.5 -
      either passively injected or transiently expressed during the early primary anti
      hapten response - suppressed the anti-idiotypic response to H11.5 for up to 7
      months in the majority of mice, while individual mice exhibited an early release
      from this suppression at various times. The differences and similarities between
      external and internal antigen-induced immune responses as well as the
      implications for idiotypic network regulation are discussed.

PMID- 8671656
TI  - Biological characteristics of an immunoregulatory activity secreted by an
      autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese
      diabetic mice.
AB  - We previously reported the generation and characterization of a panel of CD4(+)
      autoreactive T cell clones that suppress development of autoimmune diabetes in
      non-obese diabetic (NOD) mice. We showed that the protective capacity of the T
      cell clones correlated with secretion of an activity that potently inhibits
      allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the
      biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for
      mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell
      clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo
      MLR, but it potently inhibits the maintenance and amplification of the
      proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con
      A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in
      vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect
      IL-2 receptor expression of responding T cells and has no effect on IL-2
      dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL
      2 production in a primary allo-MLR, and decreases IFN-gamma production during
      secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in
      both primary and secondary Con A activation. MLR-IA is not neutralized by
      combination of antibodies specific for transforming growth factor-beta, IL-10,
      tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity.
      MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is
      destroyed by boiling, indicating that a protein moiety is part of its active
      structure. Our work suggests that a potentially novel immunoregulatory activity,
      capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and
      stimulating IL-4 production, may regulate development of autoimmune diabetes in
      NOD mice.

PMID- 8671657
TI  - Somatic hypermutation of Ig genes in patients with xeroderma pigmentosum (XP-D).
AB  - Antibody diversification by somatic hypermutation occurs by the introduction of
      nucleotide substitutions in and around the rearranged Ig V gene segments. Several
      characteristics of the process suggest that the introduction of mutations is
      linked to Ig gene transcription. Since there is a connection between mutation and
      repair with indications that both processes might show linkage to transcription,
      we asked whether defects in a component of the transcription factor TFIIH which
      lead to an inability to carry out nucleotide excision repair also affect somatic
      hypermutation. A PCR strategy was devised that required small samples of
      peripheral blood and enabled us to monitor hypermutation of a single, abundantly
      used VH gene. However, the results showed that in xeroderma pigmentosum patients
      (complementation group D), somatic hypermutaton appears to take place unaffected
      as regard both extent and distribution.

PMID- 8671658
TI  - Virus-induced polyclonal T cell activation is followed by apoptosis: partitioning
      of CD8+ T cells based on alpha 4 integrin expression.
AB  - Systemic infection with lymphocytic choriomeningitis virus (LCMV) is accompanied
      by marked splenomegaly, primarily reflecting the accumulation of CD8(+) T cells
      with an activated phenotype (e.g. VLA-4hi). Analysis of DNA content using 7
      aminoactinomycin-D revealed that as many as 30% of CD8(+) T cells are cycling
      around day 6 post-infection and that virtually all cycling cells express a high
      level of VLA-4. In accord with the relatively stable CD4+ cell number, only few
      cycling CD4+ cells were observed. Following virus control, splenic lymphocyte
      numbers decreased gradually and during this period many apoptotic cells were
      detected in the white pulp using terminal deoxynucleotidyl transferase mediated
      dUTP-biotin nick end labeling. Flow cytometric analysis of DNA content revealed a
      high frequency of cells with subnormal levels of DNA in the CD8(+)VLA-4hi subset,
      whereas the frequency was low for other lymphocyte subsets studied (CD4+, CD8+VLA
      4lo and B cells). In addition, numbers of CD8+VLA-4hi) cells constitute
      approximately 30% of splenocytes at the peak of the response and undergo
      preferential decrease during normalization of splenocyte numbers. Together these
      findings indicate that LCMV-induced activation of T cells is followed by
      apoptosis of many of the activated cells. Those CD8+VLA-4hi cells which do
      persist in LCMV immune mice are more sensitive to treatment with the cell-cycle
      specific drug hydroxyurea than are phenotypically naive T cells. Our results
      therefore indicate that LCMV infection induces polyclonal activation of CD8+
      cells which is followed by apoptosis of most of the triggered cells while a
      smaller subset persists as a primed population which include cycling cells.

PMID- 8671659
TI  - Peripheral tolerance of Th2 lymphocytes induced by continuous feeding of
      ovalbumin.
AB  - We established conditions for inducing antigen-specific tolerance in Th2
      lymphocytes by means of oral tolerance. Mice were continuously exposed to
      ovalbumin in their drinking water for a minimal period of 20 days and then
      immunized against antigen in either complete Freund's adjuvant or Al(OH)3. This
      feeding regimen tolerized both Th2 and Th1 responses as shown by diminished
      proliferation, cytokine secretion (IL-4, IL-2 and IFN-gamma) and specific
      cytokine mRNA expression (IL-4, IL-2 and IFN-gamma) in vitro, as well as by
      absence of specific antibody production (IgG1, IgG2a, IgG2b and IgE) in vivo.
      Conditions for generating Th2 lymphocyte tolerance were different from those
      required to generate tolerance in Th1 lymphocytes: these included extended,
      continuous exposure to high dosages of antigen, rather than a single or
      intermittent feeding regimen which was sufficient to induce tolerance in Th1
      lymphocytes. These findings suggest that continuous oral exposure to a tolerogen
      may be a biologically relevant strategy to tolerize both Th1- and Th-dependent
      responses, and extend the potential clinical use of oral tolerance to ailments
      mediated by Th2 lymphocytes.

PMID- 8671660
TI  - LAG-3 is not responsible for selecting T helper cells in CD4-deficient mice.
AB  - The product of the LAG-3 gene is a cell surface protein with significant homology
      to CD4. It has been suggested that it can serve as a functional equivalent of CD4
      and account for the MHC class II-restricted responses which persist in CD4
      deficient mice. To test this hypothesis, we have created CD4/LAG-3 double
      deficient mice by successive homologous recombinations in embryonic stem cells.
      These animals turn out to be indistinguishable from CD4 single-deficient mice in
      their lymphocyte populations and responses that are controlled by MHC class II
      molecules. LAG-3 thus does not explain class II-restricted lymphocyte selection
      and function in the absence of CD4, strengthening the idea that these phenomena
      can occur independently of co-receptor signalling.

PMID- 8671661
TI  - Cross-linking of cell surface ganglioside GM1 induces the selective apoptosis of
      mature CD8+ T lymphocytes.
AB  - Gangliosides are glycosphingolipids found ubiquitously on the surface of
      mammalian cells. They contain a ceramide tail that is inserted into the membrane
      and exposed carbohydrate and sialic acid moieties. The non-toxic B subunit
      oligomer (EtxB) of Escherichia coli heat-labile enterotoxin (Etx) is a potent
      immunogen in vivo and has profound modulatory effects on EtxB-primed lymphocytes
      in vitro, properties which are dependent on its ability to bind to GM1
      ganglioside receptors. Here, it is shown that cross-linking GM1 by EtxB causes a
      differential effect on mature CD4(+) and CD8(+) T cells from lymph node cultures
      proliferating in response to an unrelated antigen, ovalbumin. Addition of EtxB to
      such cultures led to the complete depletion of CD8(+) T cells compared with
      enhanced activation of CD4(+) cells [as measured by expression of CD25 (IL
      2Ralpha)]. By contrast, addition of a mutant EtxB, EtxB(G33D), which does not
      bind to GM1, failed to trigger CD8(+) T cell depletion. When EtxB was added to
      isolated non-immune CD8(+) lymphocytes rapid (12-18 h) alterations in nuclear
      morphology and the appearance of sub-G0/G1 levels of DNA were induced; properties
      which are characteristic of cells undergoing apoptosis. EtxB(G33D) failed to
      trigger apoptosis, indicating that the induction of the apoptotic signal was
      dependent on the binding of GM1. These findings provide an insight into the
      potent immunogenicity and immunomodulatory properties of E. coli enterotoxins as
      well as heralding a novel method for the selective induction of apoptosis in
      mature CD8(+) T lymphocytes.

PMID- 8671662
TI  - Centrocytes rapidly adopt a memory B cell phenotype on co-culture with autologous
      germinal centre T cell-enriched preparations.
AB  - B cells, after mutating their Ig B-region genes in germinal centres (GC), undergo
      apoptosis, unless they receive antigen-dependent selection signals. The signals
      appear to be delivered by GC T cells, require CD40 ligand expression and may
      induce differentiation to memory cells. Cultured GC B cells are prevented from
      entering apoptosis by ligating their surface CD40, but the resulting phenotype is
      not associated with B cells found in vivo. Conversely, GC B cells rapidly adopt a
      memory B cell phenotype on culture with autologous memory CD4(+) T cells that
      have been induced to express CD40 ligand transiently. This effect is prevented by
      blocking CD40 ligand. Naive CD4(+) T cells, induced to express CD40 ligand, do
      not prevent GC B cells undergoing apoptosis.

PMID- 8671663
TI  - Peptide analogs with different affinites for MHC alter the cytokine profile of T
      helper cells.
AB  - The interaction of the TCR with the immunogenic peptide bound to MHC class II
      molecules leads to the activation of the CD4(+) T helper cells. T helper cells
      have been divided into two subsets, Th1 and Th2, on the basis of the cytokines
      secreted by them. Th1 cells which secrete IL-2, IFN-gamma and tumor necrosis
      factor-beta induce delayed-type hypersensitivity, while Th2 cells secreting IL-4,
      IL-5, IL-6 and IL-10 induce humoral immune response. However, the mechanism of
      selective activation of Th1 and Th2 cells in response to different antigens is
      not fully understood. In this study we examined the selective activation of Th1
      and Th2 cells in response to strongly immunogenic synthetic peptides EYK(EYA)3,
      abbreviated as K3; EYK(EYA)4, abbreviated as K4; and EYKEYAAYA(EYA)2, abbreviated
      as K1A2. These peptides are recognized by H-2(d) T cells in the context of I-Ad,
      and are strongly cross-reactive in both T cell response and antibody response.
      The peptide K1A2 has very high affinity for I-Ad while K3 has a much lower
      affinity. K4 has affinity intermediate between K1A2 and K3. The peptide K1A2
      induced Th1 and K3 induced Th2 cells in BALB/c mice as suggested by their
      cytokine profiles. K4 induced both Th1- and Th2-type cytokines. This was also
      confirmed by the analysis of both IgG1 and IgG2a responses in vivo. There was a
      shift toward a Th1-type cytokine profile when K3-primed T cells were challenged
      with K1A2 in vitro but K1A2-primed cells did not show any shift when challenged
      with K3. Immunization with higher doses of K3 shifted the response towards Th1
      type, while immunization with lower doses of K1A2 did not shift the response
      toward Th2. We conclude that cells primed with high-affinity peptide are
      committed to differentiate into Th1 irrespective of the priming dose and affinity
      of challenge antigen. On the other hand, the differentiation of cells primed with
      low-affinity peptide depends upon the dose of immunization and binding affinity
      of the challenge antigen for MHC.

PMID- 8671664
TI  - HLA-DQ-binding peptide motifs. 1. Comparative binding analysis of type II
      collagen-derived peptides to DR and DQ molecules of rheumatoid arthritis
      susceptible and non-susceptible haplotypes.
AB  - The frequency of the HLA-DR4-DQ4 haplotype (DRB1(*)0405-DQA1(*)0302-DQB1(*)0401)
      is significantly increased in Japanese patients with rheumatoid arthritis (RA)
      and DRB1(*)0405-binding peptide motifs were identified in our previous studies.
      To clarify the DQ4-binding peptide motifs, the primary structure of DQ4-binding
      peptides was determined by affinity-based selection of a phage random peptide
      library. Analog peptides of a high-affinity DQ4 binder revealed that two major
      anchors (VxxxxxxxR; where x is any amino acid) play an essential role in binding
      to DQ4. The affinity of synthetic VAAAAAAAR-based analog peptides showed that
      substituting V to W, G, L, I, M, P, F, Y or A and R to H, M, L, I or V allows
      binding. The involvement of the ninth residue of the peptides, especially Arg,
      was critical for high-affinity binding. In comparison with other class II-binding
      peptide motifs reported to date, peptide motifs for DQ4 were unique, in that Gly
      and Pro are allowed as low-affinity N-terminal anchors. Interestingly, 94
      putative DQ4-binding motifs were detected in the human type II collagen molecule,
      since it is composed of (Gly-X1-X2)n and is rich in R and P at positions X2.
      However, no significant differences were observed between the affinities of the
      collagen-derived peptides with DR or DQ molecules of RA-susceptible DR4-DQ4 and
      with those of non-susceptible DR4-DQ8 (DRB1(*)0406-DQA1(*)0301-DQB1(*)0302)
      haplotypes, indicating that the susceptibility to RA is not a simple immune
      response gene phenomenon specific to collagen. The immunogenetic implications of
      the unique peptide motifs for DQ are discussed.

PMID- 8671665
TI  - Expression of the PD-1 antigen on the surface of stimulated mouse T and B
      lymphocytes.
AB  - A mAb J43 has been produced against the product of the mouse PD-1 gene, a member
      of the Ig gene superfamily, which was previously isolated from an apoptosis
      induced T cell hybridoma (2B4.11) by using subtractive hybridization. Analyses by
      flow cytometry and immunoprecipitation using the J43 mAb revealed that the PD-1
      gene product is a 50-55 kDa membrane protein expressed on the cell surface of
      several PD-1 cDNA transfectants and 2B4.11 cells. Since the molecular weight
      calculated from the amino acid sequence is 29, 310, the PD-1 protein appears to
      be heavily glycosylated. Normal murine lymphoid tissues such as thymus, spleen,
      lymph node and bone marrow contained very small numbers of PD-1(+) cells.
      However, a significant PD-1(+) population appeared in the thymocytes as well as T
      cells in spleen and lymph nodes by the in vivo anti-CD3 mAb treatment.
      Furthermore, the PD-1 antigen expression was strongly induced in distinct subsets
      of thymocytes and spleen T cells by in vitro stimulation with either anti-CD3 mAb
      or concanavalin A (Con A) which could lead T cells to both activation and cell
      death. Similarly, PD-1 expression was induced on spleen B cells by in vitro
      stimulation with anti-IgM antibody. By contrast, PD-1 was not significantly
      expressed on lymphocytes by treatment with growth factor deprivation,
      dexamethasone or lipopolysaccharide. These results suggest that the expression of
      the PD-1 antigen is tightly regulated and induced by signal transduction through
      the antigen receptor and do not exclude the possibility that the PD-1 antigen may
      play a role in clonal selection of lymphocytes although PD-1 expression is not
      required for the common pathway of apoptosis.

PMID- 8671666
TI  - Developmentally regulated expression of the PD-1 protein on the surface of double
      negative (CD4-CD8-) thymocytes.
AB  - PD-1, a member of the Ig superfamily, was previously isolated from an apoptosis
      induced T cell hybridoma 2B4.11 by subtractive hybridization. Expresson of the PD
      1 mRNA is restricted to thymus in adult mice. Using an anti-PD-1 mAb (J43), we
      examined expression of the PD-1 protein during differentiation of thymocytes in
      normal adult, fetal and RAG-2(-/-) mice with or without anti-CD3 mAb stimulation.
      While PD-1 was expressed only on 3-5% of total normal thymocytes, approximately
      34% of the CD4(-)CD8(-) double-negative (DN) fraction are PD-1(+) cells with two
      distinct expression levels (low and high). PD-1(high) thymocytes belonged to TCR
      gammadelta lineage cells. In the DN compartment of the TCR alphabeta lineage, PD
      1 expression started at the low level from the CD44(+)CD25(+) stage and the
      majority of thymocytes expressed PD-1 at the CD44(-)CD25(-) stage in which the
      thymocytes express TCR beta chains. The anti-CD3epsilon antibody administration
      augmented the PD-1 expression as well as the differentiation of the CD44(
      )CD25(+) DN cells into the CD44(-)CD25(-) DN stage, not only in normal mice but
      also in RAG-2-deficient mice. The fraction of the PD-1(low) cells in the
      CD4(+)CD8(+) double-positive (DP) compartment was very small (<5%) but increased
      by stimulation with the anti-CD3 antibody, although the total number of DP cells
      was drastically reduced. The results show that PD-1 expression is specifically
      induced at the stages preceding clonal selection.

PMID- 8671667
TI  - IL-10 selectively regulates murine Ig isotype switching.
AB  - A role for IL-10 in regulating Ig isotype switching directly at the level of the
      murine B cell has not been previously reported. In this report we show that IL-10
      selectively up-regulated IgM to IgG3 class switching in lipopolysaccharide (LPS)
      activated cultures through a direct effect on membrane (m) IgM+IgG3(-)B cells in
      vitro. IL-10 stimulated a 3- to 4-fold enhancement (from 6-8 to 20-30%) in
      membrane mIgG3(+) cells and a significant increase in Smu-Sgamma3 DNA
      rearrangement events as measured by digestion-circularization PCR (DC-PCR) over
      that observed with LPS alone. IL-10 induction of switching to IgG3 was not
      accompanied by a corresponding increase in the steady-state levels of germline
      CHgamma3 RNA. By contrast, IL-10 strongly inhibited the transforming growth
      factor-beta-mediated generation of mIgA+ cells and Smu-Salpha DNA rearrangement
      events in LPS-, but not CD40 ligand (CD40L)-activated B cells. This effect was
      not accompanied by changes in the steady-state levels of germline CHalpha RNA. IL
      10 had no effect on IL-4-mediated switching to either IgG1 or IgE in either LPS-
      or CD40L-activated B cells. Thus, IL-10 can either enhance or suppress switching
      to particular murine Ig isotypes but it differs from most other murine cytokines
      in that its effects on switching do not appear to be associated with changes in
      the corresponding steady-state levels of germline CH RNA.

PMID- 8671668
TI  - IL-4 and anti-CD40 protect against Fas-mediated B cell apoptosis and induce B
      cell growth and differentiation.
AB  - Most Th2 clones, when activated, produce IL-4 and express CD40 ligand (CD40L) on
      their cell surface. Therefore, they can induce growth and differentiation of B
      cells by cognate help. In contrast, activated Th1 clones, which produce IFN-gamma
      and express both CD40L and Fas ligand (FasL) on their cell surface, often induce
      B cell apoptotic cell death. To understand the mechanism by which Th2 cells can
      induce B cell growth and differentiation in the presence of FasL-positive cells,
      we stimulated B cells with IL-4, anti-IgM and/or anti-CD40 in the presence of
      anti-Fas. We report here that addition of anti-Fas strongly inhibited anti-CD40
      induced B cell proliferation without affecting anti-IgM-induced B cell
      proliferation. Furthermore we showed that stimulation of B cells with anti-CD40
      induced the expression of Fas molecules on the B cells (approximately 30%) and
      rendered them highly sensitive to anti-Fas-mediated apoptotic cell death. Indeed,
      over 23% of anti-CD40-stimulated B cells showed hypodiploid DNA after being
      incubated with anti-Fas, while h2 cells could dominate over FasL-positive Th1
      cells by production of CD40L and IL-4, which in combination induce antibody
      production and inhibit the Th1 cell-mediated immune response.

PMID- 8671669
TI  - Melanocyte lysis by cytotoxic T lymphocytes recognizing the MART-1 melanoma
      antigen in HLA-A2 patients with Vogt-Koyanagi-Harada disease.
AB  - The MART-1/Melan-A melanoma antigen recognized by the majority of HLA-A2
      restricted tumor-infiltrating lymphocytes is a self antigen expressed on
      melanocytes and the retina. We have investigated whether Vogt-Koyanagi-Harada
      (VKH) disease and sympathetic ophthalmia (SO), systemic inflammatory disorders
      affecting various organs containing melanocytes, are autoimmune diseases directed
      toward the MART-1 antigen. In two of three patients with VKH disease and one
      patient with SO, CD8(+) T cell clones (TCC) form intraocular fluid of HLA-A2(+)
      patients lysed T2 cells when pulsed with a HLA-A2-binding MART-1 peptide, but not
      a HLA-A2-binding pMel-17 or tyrosinase peptide, in a HLA-A2-restricted manner. In
      addition, Th, TCC recognizing a HLA-A2-binding MART-1 peptide were also
      established from peripheral blood mononuclear cells of a patient with VKH
      disease. In contrast, either CD4(+) TCC from these patients or CD8(+) TCC from
      the intraocular fluid of HLA-A2(+) patients with uveitis associated with Behcet's
      disease or HTLV-1 uveitis did not show this cytotoxicity. The results demonstrate
      that the MART-1 peptide-specific cytotoxic T lymphocytes lyse melanocytes in the
      eye of patients with VKH disease or SO, suggesting that these diseases are
      autoimmune diseases directed toward the MART-1 antigen in HLA-A2(+) patients.

PMID- 8671670
TI  - Clonal prevalence of T cells infiltrating into the pancreas of prediabetic non
      obese diabetic mice.
AB  - The non-obese diabetic (NOD) mouse spontaneously develops T-cell-mediated
      autoimmune insulitis. We analyzed the clonotypes of T cell infiltrates of the NOD
      mouse islets using a new method we have developed recently, which consists of RT
      PCR amplification of the CDR3 region of the TCR beta chain mRNA and subsequent
      single-strand conformation polymorphism (SSCP) analysis. NOD mice of 10-32 weeks
      of age were shown to accumulate oligoclonal T cells in the pancreas. To examine
      whether each T cell clone stays in a small area of the pancreas or spreads over
      the whole pancreas, a pancreas was divided into two pieces, which were then
      subsequently analyzed in a pair by the above PCR-SSCP method. When a pair
      produces common bands with the same mobility in SSCP gel, they are likely to
      represent the presence of the same T cell clones between these two parts of the
      pancreas. Aged mice (24-32 weeks old) with severe insulitis obviously produced
      more common bands for most of the Vbeta subfamilies than younger mice (10 weeks
      old) with only periinsulitis. DNA sequencing verified that these common bands
      have the same TCR junctional sequences, suggesting that they were derived from
      the same T cell clones. These results suggest that clonal prevalence of T cells
      infiltrating into the pancreas occurs in the late stage of insulitis development
      and that a limited number of T cell clones finally predominate over the whole
      pancreas.

PMID- 8671672
TI  - Quaternary structure of a carrier protein influences antigenicity and
      immunogenicity of an inserted T cell determinant.
AB  - To study the influence of the quaternary structure of the outer membrane protein
      PhoE of Escherichia coli on the presentation of an inserted T cell epitope, an
      epitope comprising amino acid residues 72-85 of myelin basic protein (MBP) was
      inserted at different sites in PhoE. This sequence is the critical T cell epitope
      in experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The
      antigenicity and immunogenicity of two different conformational forms of the
      chimeric PhoE constructs, i.e. the denatured monomeric form and the native
      trimeric form, were studied. It appeared that the monomeric form, but not the
      native trimeric form of such PhoE constructs induced proliferation of the MBP72
      85-specific T cell line Z1a. This conformational discrepancy was independent of
      the site in PhoE in which the epitope was inserted. Immunization with the
      monomeric form of PhoE constructs resulted in the priming of MBP72-85-specific T
      cells. In contrast, the trimeric form of these constructs was much less efficient
      in priming such cells. The differences between the monomeric and trimeric forms
      were most apparent when induction of EAE was studied. The monomeric form was
      encephalitogenic while the trimeric form was not. Furthermore, the antigen fine
      specificity, Vbeta usage and encephalitogenicity of T cells triggered by
      immunization with a monomeric PhoE construct appeared to be the same as those of
      T cell line Z1a, which was obtained after immunization with MBP, indicating that
      similar cells are triggered by immunization with the epitope either in PhoE or in
      its native context.

PMID- 8671671
TI  - Co-ligation of surface IgM and CD40 on naive B lymphocytes generates a blast
      population with an ambiguous extrafollicular/germinal centre cell phenotype.
AB  - We have previously shown that dual occupancy of sigM and CD40 - essential
      receptors in T-dependent B cell responses - by antibodies held on CD32-L cells
      results in the rapid proliferation of resting human B lymphocytes in a cytokine
      independent manner. Here we report the detailed phenotype of the blast population
      emerging in such cultures. By 3 days the levels of CD19 and CD20 have increased 4
      and 2-fold respectively: such high level expression of these two pan-B markers
      is characteristic of cells of germinal centre (GC) origin. B cells co-stimulated
      via sIgM and CD40 express low level CD23 and almost half become CD5(+); they also
      acquire CD38 and - importantly - CD77, both of these being selective markers of
      GC B cells. Expression of sigM and IgD is down-regulated on these cells and a
      minor, but significant, population of IgG+ cells appears. In marked contrast to
      GC B cells, the population proliferating in response to dual occupancy of sigM
      and CD40 has up-regulated and strongly expresses CD44. Morphologically, the cells
      are heterogeneous but there is a dominant blastic cell type with relatively
      scanty cytoplasm and having multiple nucleoli, both of which are characteristic
      of centroblasts; nevertheless, these cells remain morphologically distinct from
      freshly isolated GC B cells and do not show hallmark features of centrocytes.
      Although there is substantial cell death occurring by days 6-7 in these cultures,
      there is no morphological evidence for apoptosis. Thus, the proliferating
      population that emerges from the dual engagement of antigen receptor and CD40 on
      resting B cells appears to be bestowed with some features of GC B cells but has
      others which are incompatible with that particular stage of differentiation. The
      possibility that it might represent (i) a blast stage that is transitional
      between activation in T zones and entry into the follicle or (ii) a precursor
      population that colonizes the primary follicle prior to GC formation is
      discussed.

PMID- 8671673
TI  - Heterogeneity of N insertion capacity in fetal hematopoietic stem cells.
AB  - TCR gene rearrangement is strictly regulated during mouse ontogeny. The V-(D)-J
      junctions of alphabeta and gammadelta TCR transcripts expressed in the adult
      thymus are more highly diverse than those in the fetal thymus. We previously
      showed that adult hematopoietic stem cells (HSC) have a higher capacity to insert
      N nucleotides into Vgamma4 TCR transcripts than fetal HSC and that the level of N
      nucleotide insertion is determined, at least in part, at the level of HSC. To
      analyze this developmental change of HSC at the single cell level, we
      investigated N nucleotide insertions in three TCR transcripts (Vgamma4, Vgamma2
      and Vbeta8) derived from limiting numbers of fetal liver HSC by fetal thymic
      organ culture. Eight day-14 fetal liver HSC clones showed various levels of N
      nucleotide insertions in Vgamma transcripts (0-78%). On the other hand, the level
      of N insertions was similarly regulated in Vgamma4, Vgamma2, and Vbeta8 TCR
      transcripts in a clone-specific way. These results suggested that the level of N
      insertion is programmed at the level of single HSC and that fetal liver contains
      a heterogeneous population of HSC in terms of N insertion capacity. After 3 weeks
      culture with a stromal cell line, fetal HSC showed higher levels of N insertion
      capacity than before culture. This result and the presence of HSC with
      intermediate N insertion capacity support the hypothesis that the developmental
      potential of individual HSC gradually changes from fetal to adult type in one
      stem cell lineage.

PMID- 8671674
TI  - Canonical VH CDR1 nucleotide sequences are conserved in all jawed vertebrates.
AB  - The antibody combining site is formed from the complementarity-determining
      regions (CDR) of the heavy and light chains. Function, in antibodies, means
      diverse structures capable of binding a variety of ligands and the CDR have long
      been distinguished as the sites of a high incidence os non-homologous
      replacement. The present studies show, despite the apparent protein diversity,
      the existence of canonical nucleotide sequences in the heavy chain CDR1. These
      sequences were deduced from human and mouse CDR1, and their presence demonstrated
      experimentally in all representatives from the gnathostome vertebrate classes.
      This unexpected conservation suggests that selection pressure for sequence
      diversity is counter-balanced by properties of the encoded amino acids such as
      capacity for ligand interaction, structural requirements of the CDR loop and
      perhaps retention of certain ligand-binding sequences. Part of the canonical
      nucleotide sequence involves a motif that has been suggested as a hot spot for
      somatic hypermutation. The assay for the canonical sequence is PCR-based and
      provides a novel approach to cloning multigene family members by using the
      hypervariable portions as target sequence.

PMID- 8671675
TI  - Molecular mechanisms underlying IFN-gamma-mediated tumor growth inhibition
      induced during tumor immunotherapy with rIL-12.
AB  - The present study investigates the molecular mechanisms by which IFN-gamma
      produced as a result of in vivo IL-12 administration exerts its anti-tumor
      effects. rIL-12 was administered three or five times into mice bearing CSA1M
      fibrosarcoma, OV-HM ovarian carcinoma or MCH-1-A1 fibrosarcoma. This regimen
      induced complete regression of CSA1M and OV-HM tumors but only transient growth
      inhibition of MCH-1-A1 tumors. The anti-tumor effects of IL-12 were associated
      with enhanced induction of IFN-gamma because these effects were abrogated by
      pretreatment of hosts with anti-IFN-gamma antibody. Exposure in vitro of the
      three types of tumor cells to rRFN-gamma resulted in moderate to potent
      inhibition of tumor cell growth. IFN-gamma stimulated the expression of mRNAs for
      an inducible type of NO synthase (iNOS) in CSA1M cells and indoleamine 2,3
      dioxygenase (IDO), an enzyme capable of degrading tryptophan, in OH-HM cells, but
      induced only marginal levels of these mRNAs in MCH-1-A1 cells. In association
      with iNOS gene expression, IFN-gamma-stimulated CSA1M cells produced a large
      amount of NO which functioned to inhibit their own growth in vitro. Although OV
      HM and MCH-1A1 cells did not produce NO, they also exhibited NO susceptibility.
      Whereas the tumor masses from IL-12-treated CSA1M-bearing or OV-HM-bearing mice
      induced higher levels of iNOS (for CSA1M) or IDO and iNOS (for OV-HM) mRNAs, the
      MCH-1-A1 tumor mass expressed lower levels of iNOS mRNA alone. Moreover, massive
      infiltration of CD4(+) and CD8(+) T cells and Mac-1(+) cells was seen only in the
      CSA1M and OV-HM tumors. Thus, these results indicate that IFN-gamma produced
      after IL-12 treatment induces the expression of various genes with potential to
      modulate tumor cell growth by acting directly on tumor cells or stimulating tumor
      infiltrating lymphoid cells and that the effectiveness of IL-12 therapy is
      associated with the operation of these mechanisms.

PMID- 8671676
TI  - Antigen receptor-mediated B cell death is blocked by signaling via CD72 or
      treatment with dextran sulfate and is defective in autoimmunity-prone mice.
AB  - Mature B cells undergo programmed cell death when surface (s) Ig is extensively
      multimerized. A signal that blocks death of B cells is thus required for
      activation of B cells in response to antigen stimulation. Here we show that only
      a few diverse transmembrane signals capable of inducing activation and
      proliferation of B cells blocked sig-mediated death of normal mature B cells, and
      that there is no correlation between mitogenic activity and the ability to rescue
      B cells from death. The results suggest that a specific signal is required for
      abrogating B cell death induced by sig cross-linking. Signaling via IL-4 receptor
      and CD40, both of which are derived from activated T cells, blocked sig-mediated
      death, as described previously. Signaling through a B cell antigen CD72, a
      counter-receptor of the pan-T antigen CD5, also blocked death of anti-Ig-treated
      mouse spleen B cells. CD72 signal may play a role in survival of B cells at the
      initial step of T-B interaction, where resting T cells recognize antigens
      presented by B cells. Moreover, B cell death by anti-Ig was blocked by T cell
      independent antigens such as lipopolysaccharide and dextran sulfate, and spleen B
      cells from New Zealand mice, which are prone to autoantibody-dependent autoimmune
      diseases, were resistant to sig-mediated death. Mechanisms for blocking sig
      mediated death may therefore be required in antibody response to foreign antigens
      regardless of T independence or T dependence and in autoantibody production.

PMID- 8671677
TI  - IFN-gamma is a potent inducer of Ig secretion by sort-purified murine B cells
      activated through the mIg, but not the CD40, signaling pathway.
AB  - IFN-gamma has been shown to either stimulate or inhibit Ig secretion. No studies
      have yet addressed the basis for these seemingly conflicting properties nor
      whether IFN-gamma acted directly at the level of the B cell to mediate its
      effects. Thus, we studied the ability of IFN-gamma to regulate Ig secretion in
      sort-purified, resting murine B cells that were >99% Ig+, activated either
      through membrane Ig using unconjugated or dextran-conjugated anti-IgD antibodies
      (alphadelta-dex) or through CD40 using soluble or membrane CD40 ligand (CD40L). B
      cells activated with alphadelta-dex proliferated but do not secrete Ig, even in
      the presence of IL-1 + IL-2. We demonstrate that IFN-gamma only when added
      subsequent to B cell stimulation with alphadelta-dex, but not unconjugated anti
      IfD antibody, plus IL-1 + IL-2 induces up to 100-fold enhancements in Ig
      secretion and in the numbers of Ig-secreting cells. The predominant Ig isotype
      secreted is IgM, with IgG3 and IgG2a comprising the majority of non-IgM antibody.
      IFN-gamma must act in concert with IL-2 for stimulation of Ig secretion. Further,
      IFN-gamma synergizes with IL-3 + granulocyte-macrophage colony stimulating factor
      for induction of Ig synthesis. IFN-gamma also enhances IgA syntheses by
      transforming growth factor-beta-induced membrane IgA+ cells. By contrast, 125IIFN
      gamma fails to stimulate Ig secretion in B cells activated with CD40L in the
      presence or absence of IL-1 + IL-2 or IL-4. However, the combination of CD40L and
      alphabeta-dex is strongly synergistic for IFN-gamma-induced Ig secretion. Thus,
      these data establish that IFN-gamma can act directly on the B cell to induce Ig
      synthesis without the participation of any other cell and demonstrates that the
      mode of activation of the B cell plays an important role in directing the action
      of IFN-gamma.

PMID- 8671679
TI  - Allergen-driven limiting dilution analysis of human IL-4 and IFN-gamma production
      in allergic rhinitis and clinically tolerant individuals.
AB  - Difficulties in detecting human IL-4 synthesis in antigen-driven primary culture
      have led to widespread reliance on less physiologic approaches to T cell
      activation. Although there is general agreement of a Th2-like bias, the precise
      defects in cytokine responsiveness remain controversial. Analysis of cytokine
      protein production by fresh, unselected cell populations in response to cognate,
      antigen-driven stimulation remains an important goal. Here, limiting dilution
      analysis (LDA) was used to evaluate antigen-stimulated cytokine gene expression
      by fresh peripheral blood mononuclear cells (PBMC). PBMC from 19 grass pollen
      sensitive, allergic rhinitis subjects and normal, non-atopic controls were
      evaluated 1 month after natural reimmunization (the peak of the local grass
      pollen season). Surprisingly, highly atopic subjects and clinically non-allergic
      individuals exhibited virtually equivalent antigen-specific, CD4-dependent
      cytokine production in response to short-term culture with these common
      environmental antigens. As anticipated, pronounced increases in Th2-like activity
      were evident in the circulating immune repertoire of grass pollen sensitive
      individuals, leading to a median ratio of antigen-stimulated IFN-gamma:IL-4
      frequencies of 117:1 among normal subjects versus 4:1 among those with allergic
      rhinitis (Mann-Whitney U-test, P = 0. 00067). This Th2-like bias reflected both a
      lower frequency of IFN-gamma-producing cells and a markedly increased frequency
      of IL-4-producing cells in the circulating grass-pollen specific repertoire of
      atopic donors. The observation that every atopic and normal subject produced IFN
      gamma (+/-IL-4) following antigen re-stimulation argues that the decision as to
      whether allergy or (clinical) tolerance results, hinges not on a genetically
      determined capacity of whether allergen-reactive T cells can be stimulated in any
      given individual by chronic exposure to ubiquitous environmental antigens, but on
      the nature of the cytokine response that comes to dominate that individual's
      response.

PMID- 8671678
TI  - Activation-mediated CD4+ T cell unresponsiveness during acute Toxoplasma gondii
      infection in mice.
AB  - Infection of mice with Toxoplasma gondii has been shown to induce a transient
      state of immune down-regulation. Earlier reports have demonstrated the role of
      cytokines, in particular IL-10, in this host response. Here evidence is presented
      that T. gondii, a major opportunistic pathogen of the newborn and those with
      AIDS, is able to induce CD4(+) T cell apoptosis in the infected murine host. We
      have examined the changes in the CD4(+) T cell population that occur during acute
      infection in an experimental mouse model. Seventy-six percent of the CD4(+) T
      cell population increased in volume by day 7 post-infection and expressed T cell
      maturation markers (CD44(hi), IL-2Rhi, Mel-14(lo)). Further noted was a clonal
      activation of several CD4(+) T cell to mitogen or parasite antigen stimulation
      was observed, in particular Vbeta5 T cells. Addition of rIL-2 partially restored
      the CD4(+) T cell proliferative response in vitro. The T cell activation marker
      CTLA-4 could not be detected and the co-stimulatory molecule, CD28, was down
      regulated. Electrophoretic and morphologic analysis of these cells post-culture
      demonstrated a DNA fragmentation pattern and cell death consistent with
      apoptosis. These studies demonstrate for the first time in a protozoan parasite
      that activation induced CD4(+) T cell unresponsiveness occurs during acute T.
      gondii infection in mice, and may be important in immune down-regulation and
      parasite persistence in the infected host.

PMID- 8671681
TI  - The differential role of CD86 and CD80 co-stimulatory molecules in the induction
      and the effector phases of contact hypersensitivity.
AB  - Contact hypersensitivity (CH) has served as a useful model for investigating the
      allergen-specific immune responses of T cells and skin-associated antigen
      presenting cells. We examined the distinct role between CD80 and CD86 on hapten
      induced CH in both an induction and an effector phase. Intraperitoneal injection
      of mAb against CD86, but not CD80, 2 h before sensitization with epicutaneous
      application of dinitrofluorobenzene led to an almost complete inhibition of ear
      swelling, and histologically a marked reduction of edema, inflammatory
      polymorphonuclear cells and lymphocyte infiltration in the dermis. In contrast,
      the administration with either anti-CD80 or CD86 mAb 2 h before challenge
      partially inhibited CH reactions and a combination of both mAb did not improve
      the inhibitory effect. Although Langerhans cells (LC) expressing MHC class II
      were observed in both the epidermis and dermis 24 h after primary sensitization,
      CD86(+) LC were observed only in the subepidermal regions and CD80-bearing cells
      were not detected. Dendritic cells (DC) expressing both CD80 and CD86 were
      preferentially observed in the T cell areas of draining lymph nodes 24 h after
      challenge. The administration of anti-CD86 mAb in the induction phase prominently
      reduced the up-regulation of CD80 and CD86 on DC in the lymph nodes. The
      predominant role of CD86 was further supported by a marked reduction in
      proliferation of lymph node T cells against the sensitized hapten after the anti
      CD86 treatment. These results suggest that CD86 plays a critical role in the
      initiation of primary immune responses in the skin, while CD80 and CD86 are not
      essential in the effector phase of CH reactions.

PMID- 8671680
TI  - Selective recognition of malaria antigens by human serum antibodies is not
      genetically determined but demonstrates some features of clonal imprinting.
AB  - Malaria infection induces the production of serum antibodies to a variety of
      malaria antigens but the prevalence of antibodies to any particular antigen is
      typically much less than 100%. It has been assumed that non-responsiveness to
      defined antigens in malaria immune subjects is due to HLS-mediated restriction of
      the immune response. In this study we have investigated the role of HLA and non
      HLA genes in the antibody response to two merozoite surface antigens (MSP1 and
      MSP2) and a sexual stage antigen (Ps260/230) of Plasmodium falciparum, and
      conclude that host genotype is not a major determinant of responsiveness.
      Although antibody levels vary in accordance with seasonal variations in malaria
      transmission in semi-immune children, antibody levels remain stable in clinically
      immune adults. Antigen recognition is selective with individual donors showing
      consistent high titre responses to some antigens/epitopes whilst consistently
      failing to recognize adjacent regions/epitopes of the same protein. An
      alternative explanation, consistent with the data presented here, is that
      selective antibody responses to malaria antigens in immune individuals result
      from a process akin to clonal imprinting (original antigenic sin).

PMID- 8671682
TI  - Solvent exposed side chains of peptides bound to HLA A*1101 have similar effects
      on the reactivity of alloantibodies and specific TCR.
AB  - Peptides can affect the recognition of MHC class I molecules by allospecific
      antibodies. Two explanations have been proposed for this phenomenon. The
      'conformational change' hypothesis suggests that peptide binding affects the
      availability of serologic determinants in the class I alpha1 and alpha2 domains
      while the 'peptide-side-chain effect' predicts that solvent exposed residues in
      the peptide are part of the serologic epitope. We have tested these possibilities
      by examining the recognition of peptide loaded HLA A*1101 molecules expressed in
      transporters associated with antigen processing (TAP)-deficient cell lines by
      three A11-specific mAb, and by comparing the effect of peptide analogues on the
      recognition of A11 complexes containing peptide epitopes from the Epstein-Barr
      virus nuclear antigen EBNA4 by antibodies and cytotoxic T lymphocytes (CT). The
      AUF5.13 and HB164 antibodies showed selective recognition of A11 molecules bound
      to partially overlapping sets of peptides from viral or cellular origin. The
      peptide dependence of AUF5.13 was confirmed in reconstitution experiments where
      A11 molecules were refolded at the surface of TAP-deficient T2/A11 cells that had
      been cultured at 26 degrees C and treated at pH3. Molecular modelling and Ala
      scanning mutagenesis of the IVTDFSVIK (IVT) and AVFDRKSDAK (AVF) peptides
      demonstrated that solvent-exposed peptide side chains affect CTL recognition as
      well as antibody binding. Substitution of Phe-P5 or Ser-P6 of the IVT peptide
      with Arg or Lys inhibited AUF5.13 recognition while binding was induced by
      substitution of the Arg-P5 and Lys-P6 of the AVF peptide with Ala. The results
      suggest that some allospecific antibodies recognized the surface of MHC class I
      peptide complexes in a fashion similar to the TCR. This may involve direct
      interaction with the peptide side chains as well as recognition of peptide
      induced perturbations in the class I complex.

PMID- 8671683
TI  - Natural killer cell development is blocked in the context of aberrant T
      lymphocyte ontogeny.
AB  - Over-expression of human or mouse CD3-epsilon transgenes profoundly disturbs T
      lymphocyte and natural killer (NK) cell development. One of these transgenic
      strains, termed tgepsilon26, displays a very early block in T lymphocyte and NK
      cell development. We showed previously that the absence of early thymocyte
      progenitors results in an abnormal thymic microenvironment. Due to this thymic
      defect, T cell development could not be restored by bone marrow (BM)
      transplantation in adult tgepsilon26 mice but could in fetal tgepsilon26 mice.
      Here we examine the effect of this abnormal thymic environment on NK cell
      development. We demonstrate that NK cell maturation in tgepsilon26 mice was
      reconstituted by BM derived from completely T cell-deficient mice, i.e. RAG-2(-/
      ) and TCRbeta x delta-/-, but not from wild-type mice. Moreover, tgepsilon26 mice
      transplanted with BM from partially T cell-deficient mice, i.e. TCRalpha-/-,
      TCRbeta-/- and TCRdelta-/- mice, did not reconstitute their NK cell compartment.
      We conclude from these studies that the thymic environment is not required for NK
      cell development, but that aberrantly educated alphabeta or gammadelta T
      lymphocytes can influence NK cell ontogeny. Furthermore, high serum levels of
      tumor necrosis factor (TNF) were detected in the vast majority of tgepsilon26
      mice transplanted with BM cells derived from partially T cell-deficient mice, but
      never from tgepsilon26 mice transplanted with BM cells derived from completely T
      cell-deficient mice. The high levels of TNF may play an important role in the
      observed inhibition of NK cell development, since in vivo treatment with an anti
      TNF antibody restored NK cell development.

PMID- 8671684
TI  - Demonstration of a cross-talk between IL-2 and IL-5 in phosphorylation of IL-2
      and IL-5 receptor beta chains.
AB  - We have examined phosphorylation mediated by cross-talk between growth signal
      pathways induced by IL-2 and IL-5. To analyze the phosphorylation process in the
      same cells, we established two sublines, T88-Mbeta1, which is a subline of a
      murine IL-5-dependent cell line, T88-M, by introduction of the human IL-2
      receptor beta chain (IL-2Rbeta), and secondly CTLL-5Ralphabeta, which is a
      subline of a murine IL-2-dependent cell line, CTLL-2, by introduction of the
      murine IL-5 receptor alpha chain (IL-5Ralpha) and IL-5 receptor beta chain (IL
      5Rbeta, betac) genes. Both T88-Mbeta1 and CTLL-5Ralphabeta expressed high
      affinity receptors for IL-2 and IL-5, and proliferated in response to both
      factors. Tyrosine phosphorylation of IL-2Rbeta was induced by stimulation of T88
      Mbeta1 with not only IL-2 but also IL-5. Anti-IL-2Rbeta-directed immune complexes
      from T88-Mbeta1 stimulated with IL-5 as well as with IL-2 contained an activated
      tyrosine kinase. However, stimulation with IL-5 but not IL-2 induced the tyrosine
      phosphorylation of IL-5Rbeta, betac, suggesting that IL-2 does not activate a
      tyrosine kinase which efficiently catalyzes the IL-5Rbeta molecule in response to
      IL-5. On the other hand, the detection of JAK1 and the other common set of
      phosphotyrosine-containing proteins after stimulation with either IL-5 or IL-2
      suggests the existence of the same tyrosine phosphorylation pathways.

PMID- 8671685
TI  - Rescue of the hairless phenotype in nude mice by transgenic insertion of the wild
      type Hfh11 genomic locus.
AB  - Mice and rats homozygous for mutations at the nude (nu) locus exhibit the
      pleiotropic phenotypes of hairlessness and athymia. A recent positional cloning
      study identified, as a nude gene, a novel fork head transcription factor, Hfh11
      (also called whn), that is expressed in skin and thymus, and is mutated in nude
      rodents. To obtain the direct biological proof that this gene is responsible for
      nude phenotype, we microinjected a cosmid clone containing the wild-type Hfh11
      genomic locus into fertilized nude eggs. Two independent founder lines of
      transgenic mice were generated that corrected the hairless phenotype, but not the
      thymic defect. This partial rescue demonstrates that Hfh11 is the gene
      responsible for the hairless defect in the nude mouse. Taken together with
      previous genetic studies, this complementation result indicates that Hfh11 is
      indeed the nude gene and the Hfh11 locus is likely to be subject to complicated
      regulation.

PMID- 8671686
TI  - Effects of transgenic mixed-haplotype MHC class II molecules A alpha d A beta z
      on autoimmune disease in New Zealand mice.
AB  - The MHC haplotype heterozygosity (H-2d/H-2z) acts as one major predisposing
      genetic element for autoimmune disease resembling systemic lupus erythematosus
      (SLE) in the F1 hybrid of NZB (H-2d) and NZW (H-2z) mice. To determine a possible
      role of mixed-haplotype A molecules, we introduced a transgene A beta z into H
      2d/H-2d homozygous (NZB x NZW.H-2d)F1 mice, in which, compared with the original
      H-2d/H-2z heterozygotes, the incidence and titer of IgG anti-DNA antibodies,
      serum levels of nephritogenic retroviral gp70/anti-gp70 immune complexes (ICs)
      and the associated incidence of IC-type lupus nephritis were reduced. Evidence
      for the formation of mixed-haplotype A alpha d A beta z molecules in the
      transgenic mice was obtained by A beta z molecule expression on the cell surface
      of splenic B cells and macrophages, thymic epithelial cells and mature B cells in
      the bone marrow. A alpha d A beta z-restricted T cell clones showed good
      proliferative responses to spleen cells from the transgenic mice, to an extent
      much larger than seen in cells from the original (NZB x NZW)F1 mice, suggesting
      that the expression of functional A alpha d A beta z molecules on cells in
      transgenic mice is considerably high. Compared with findings in transgene
      negative littermates and the original (NZB x NZW)F1 mice, the A beta z transgene
      to a greater extent promoted serum levels of IgM anti-double-stranded (ds) DNA
      antibodies and IgM anti-gp70/gp70 ICs in the transgenic mice. None the less, the
      production of IgG anti-dsDNA antibodies and IgG anti-gp70/gp70 ICs as well as the
      development of renal disease was markedly suppressed. Possible mechanisms of such
      effects of the transgene are discussed.

PMID- 8671708
TI  - The role of peroxidase-catalyzed activation of aromatic amines in breast cancer.
AB  - Aromatic amines are mammary carcinogens in rodents and exposure to aromatic
      amines may be associated with increased risk of breast cancer in women.
      Peroxidases present in milk can oxidize aromatic amines to reactive electrophiles
      which bind to DNA and induce mutations. Hydrogen peroxide, required for
      peroxidase-dependent oxidations, is supplied by milk xanthine oxidase and by the
      respiratory burst of neutrophils, cells which are present in milk and activated
      by exposure to it. In this paper, I propose that lactoperoxidase and
      myeloperoxidase activate aromatic amines, within the breast ducts, and that these
      enzymes play a crucial role in the chemical induction of breast cancer.

PMID- 8671709
TI  - Assessment of environmental and occupational exposures to butadiene as a model
      for risk estimation of petrochemical emissions.
AB  - 1,3-Butadiene (BD) is an important industrial chemical and environmental
      contaminant, e.g. in urban air, traffic exhausts and tobacco smoke. It has been
      shown to be genotoxic in vitro and in vivo and carcinogenic in rodents, mice
      being more sensitive than rats. The present study confirmed this species
      difference. Using micronuclei in erythrocytes or bone marrow as a marker, mice
      responded at an effective level of 50 p.p.m., while the highest ineffective level
      in rats was 500 p.p.m. (inhalation of BD for 5 days). A dose-dependent increase
      in N-terminal valine haemoglobin adducts was seen in both rats and mice, but the
      adduct levels in the latter species were on average five times higher. For the
      first time, specific N6-alkyldeoxyadenosine adducts were identified in lung and
      liver DNA of rats exposed to BD by inhalation. No significant difference in DNA
      adduct level was seen in lung tissue of rats and mice at similar exposure levels.
      Occupational exposure levels to BD in the European Process industry are variable,
      but generally < 1 p.p.m. Haemoglobin adduct levels were seen to be increased
      among the worker groups with higher potential exposure to BD (process work, bomb
      voiding and repair duties) as compared with adduct levels in less exposed workers
      in maintenance and the laboratory or control personnel. However, the N-terminal
      valine haemoglobin adducts measured in the workers were one to two orders of
      magnitude lower than extrapolated for the same exposure dose in mice. In the same
      workers no exposure-related effects were seen in the cytogenetic parametres
      studied, i.e. chromosomal aberrations, sister chromatid exchanges or micronuclei
      in peripheral blood lymphocytes, or in the Ras oncoprotein levels of plasma
      samples. The studies so far conducted suggest that human exposure at the levels
      seen in the present day process industry can be documented at the biological dose
      level using haemoglobin adduct measurement, but not at the biological effect
      level using cytogenetic biomarkers. In order to quantitate the human genotoxic
      risk of BD exposure more work needs to be done on the role of other active BD
      metabolites than 1,2-epoxy-3-butene and on the genetic polymorphisms controlling
      the variability of individual responses.

PMID- 8671710
TI  - A proposal for a two-dose/single-sample in vivo/in vitro rat hepatocyte
      unscheduled DNA synthesis assay.
AB  - We have developed a two dose/single-sample protocol for the in vivo/in vitro rat
      hepatocyte unscheduled DNA synthesis (UDS) assay. In order to enhance the
      effectiveness of grain detection by image analysis we found minor technical
      modifications to be beneficial. These included the use of 3% acetic acid in
      ethanol (or 4% aqueous paraformaldehyde) for hepatocyte fixation and 0.5% aqueous
      eosin for staining. Also, there was no correlation between cell viability
      (measured using the trypan blue method) and UDS response and, therefore, we do
      not reject animals from data analysis unless hepatocyte viability falls below
      50%. Furthermore, we suggest that cell attachment is a more reliable indicator of
      toxicity than of cell viability. Therefore, our range-finding test has been
      modified to incorporate an extra animal per group so that hepatocyte cultures can
      be evaluated. Comparisons of a two-dose/single-sample protocol with the currently
      accepted single-dose/multiple-sample protocol demonstrated that the former was an
      acceptable alternative, in that responses with standard positive controls are
      very similar with both protocols. Furthermore, the two-dose protocol has clear
      advantages in that it uses fewer animals, resources and time and has better
      statistical discriminatory power. As a move away from the use of arbitrary values
      for determining the performance and outcome of assays, we use criteria based on
      confidence limits placed on historical data ranges. Where necessary, statistical
      analyses of concurrent data is performed using rank transformation followed by
      parametric analysis of the ranks; this combines the generality of a non
      parametric methodology with the power and versatility of parametric analyses.

PMID- 8671711
TI  - Bacterial mutagenic evaluation of Luxabendazole, a new broad spectrum
      anthelmintic, with the Salmonella typhimurium His- and the Escherichia coli Tryp-
      reversion tests.
AB  - Luxabendazole is a new benzimidazole carbamate chemotherapeutic agent, which has
      proved to be effective against adult and immature stages of the major
      gastrointestinal nematodes, trematodes and cestodes. The mutagenic properties of
      Luxabendazole were investigated in the in vitro Ames Salmonella and E. coli
      tests. The product was tested at concentrations of 0.5, 5, 50, 500, 1250 and 2500
      micrograms/plate in the TA1535, TA1538, TA98 and TA100 strains of Salmonella
      typhimurium, and 0.5, 5, 50 and 500 micrograms/plate in the WP2, WP2uvrA- and its
      pKM 101-containing derivative CM891 (WP2 uvrA- pKM101) strains of Escherichia
      coli, with and without S9 microsomal activation (post-mitochondrial liver
      fraction from Wistar rats pretreated with Aroclor(R)). Positive and negative
      controls were included in each experiment. From the present study it can be
      concluded that Luxabendazole, over a dose range of 0.5-2500 micrograms/plate, is
      unlikely to present a mutagenic hazard, as demonstrated by the Ames test.

PMID- 8671713
TI  - Relationship between antimutagenic activity and major components of various teas.
AB  - The objectives of this study were to determine the major components in tea leaves
      and tea extracts and to study the relationship between chemical content and
      antimutagenic activity of various tea extracts. The amount of catechins in
      various tea extracts was in the order: green tea (26.7%) > oolong tea (23.2%) >
      pouchong tea (15.8%) > black tea (4.3%). The amounts of caffeine and phenolic
      compounds in oolong tea extracts were 8.3 and 32.4%, respectively; these amounts
      were greater than those in the other three tea extracts. The ascorbic acid in
      green tea extracts was a little higher than in oolong and pouchong tea extracts.
      The amount of catechins in tea leaves also showed the order: nonfermented (green
      tea) > semifermented (pouchong tea and oolong tea) > fermented tea (black tea).
      The amounts of caffeine and phenolic compounds in oolong tea leaves are also
      higher than in other tea leaves. Besides water soluble components, tea leaves
      also contain several lipid soluble chemicals such as beta-carotene and
      tocopherols. The tea extracts, especially oolong and pouchong teas, markedly
      inhibited the mutagenicity of 2-amino-3-methylimidazo (4,5-f)quinoline (IQ), 3
      amino-1,4-dimethyl-5H-pyrido-(4,3-b)indole (Trp-P-1), 2-amino-6-methyl
      dipyrido(1,2-a:3',2'-d) imidazole (Glu-P-1), benzo[a]pyrene (B[a]P) and aflatoxin
      B1 (AFB1). The inhibitory effect of tea extracts against the mutagenicity of IQ
      and Glu-P-1 in Salmonella typhimurium TA100 showed a significant (P < 0.05)
      correlation to the contents of catechins and ascorbic acid. The antimutagenic
      activity of tea extracts to Trp-P-1 in TA98 or TA100 was well correlated (P <
      0.05) to the caffeine contents. No significant (P > 0.05) correlation was found
      between the antimutagenicity of tea extracts to B[a]P and AFB1 in TA100 and the
      content of major components in tea extracts.

PMID- 8671712
TI  - Ameliorating effect of vitamin C on murine sperm toxicity induced by three
      pesticides (endosulfan, phosphamidon and mancozeb).
AB  - The ameliorating effect of vitamin C (injected intraperitoneally) was evaluated
      against changes in sperm count and sperm head morphology in mice fed either 3, 6
      or 1000 mg/kg body wt/day endosulfan, phosphamidon or mancozeb, respectively. The
      animals received aqueous preparations of the pesticides and/or vitamin C once
      daily for 35 consecutive days. All three pesticides, irrespective of their
      chemical nature, significantly decreased the sperm count, as well as increased
      the frequency of sperm with aberrant head morphology. Out of the three doses of
      vitamin C used the middle and higher ones (20 and 40 mg/kg body wt/day,
      respectively) afforded comparatively more significant amelioration. The lower
      dose (10 mg/kg body wt/day) of this vitamin (quantitatively equivalent to the
      human therapeutic dose according to body weight) was least efficacious in both
      the tests. However, amelioration was never up to the control level in any case.
      Vitamin C doses, when administered alone, did not produce any adverse effect on
      sperm count and sperm head morphology.

PMID- 8671714
TI  - Mutagenicity of high fat diets in the colon and small intestine of transgenic
      mice.
AB  - Dietary fat has been implicated as a cause of colon cancer by epidemiological
      studies. Unfortunately, these studies are compatible with high fat as either
      initiator or promoter. Since initiators are normally mutagenic, we have tested
      the mutagenicity of high fat diets in the intestinal epithelium at two loci. The
      Dlb-1 assay, used in the small intestine, detects a wide spectrum of mutations.
      The lacI assay (Big Blue Mouse assay) is not as sensitive to some types of
      mutation as is Dlb-1 but was used in the colonic epithelium. Mice suitable for
      both assays were fed isocaloric high fat diets and subsequently assayed for
      somatic mutation. The diets consisted of: (i) a mixture of beef tallow, butter
      and lard totalling to 31% w/w of the diet (AIN-76A) up to 17 weeks; and (ii) corn
      oil, beef tallow, lard or butter individually, at 31% w/w of the diet for 5 and 9
      weeks. These diets provided 50% of the calories from fat. The weights of the
      experimental and control mice were similar throughout the experiment. No
      significant increases in mutant frequencies were observed on any high fat diet
      compared to controls, so we conclude that uncooked fats are not mutagenic and are
      not initiators of carcinogenesis in the intestinal epithelium.

PMID- 8671715
TI  - Frequent spontaneous deletions at a shuttle vector locus in transgenic mice.
AB  - Transgenic mice carrying multiple copies of a recoverable lambda phage shuttle
      vector (lambda supF) were constructed for the purpose of studying mutagenesis in
      a whole animal. Spontaneous mutations in rescued supF target genes from several
      different lines of transgenic mice were analyzed. One mouse line, 1139, was
      identified in which the frequency of spontaneous mutations was unusually high
      (3.15 x 10(-4)), 20-fold higher than in other transgenic mice carrying a similar
      number of copies of the lambda transgene (approximately 100). Over 75% of the
      spontaneous mutations from 1139 mice were found to be deletions, whereas mostly
      point mutations were recovered from the other mice. In 1139 no significant
      variation among adult tissues has been detected. However, embryonic tissue
      yielded a 3- to 4-fold lower frequency of mutations, most of which were point
      mutations rather than deletions. The frequency of mutations at another locus, the
      hypoxanthine phosphoribosyl transferase gene, was not elevated in fibroblast
      lines established in culture from the 1139 mice. Overall, these results suggest
      that the deletion mutagenesis affecting the transgene sequences in 1139 mice is a
      locus-specific effect occurring during growth and development. The increased
      mutagenesis could not be explained by the degree of methylation of the transgene
      sequences, since hypermethylation was seen in both 1139 mice and other mice with
      a low frequency of shuttle vector mutations. The integrated lambda vector DNA in
      1139 mice was mapped to a single site on chromosome 7, but no mechanism for the
      mutagenesis was suggested by this localization. It is proposed that the lambda
      DNA may have either integrated into an unstable genomic site or created a newly
      unstable locus in the process of integration.

PMID- 8671716
TI  - Comet assay studies indicate that caffeine-mediated increase in radiation risk of
      embryos is due to inhibition of DNA repair.
AB  - It is well known that under specific conditions caffeine is able to enhance
      radiation risk of mammalian cells by a factor of approximately 1.5-2. Various
      mechanisms are discussed in the literature as possible explanations for this
      interaction. Inhibition of DNA repair plays a crucial role in the discussion,
      although direct evidence for this assumption is difficult to obtain. We used the
      "comet assay' in order to analyse the significance of repair inhibition by
      caffeine in the two-cell stage of mammalian gestation. Our data show that at the
      concentration necessary for increasing radiation risk (2 mM), caffeine
      effectively inhibits the restitution of radiation-damaged DNA.

PMID- 8671717
TI  - Extended harvest times are not necessary for the detection of in vitro clastogens
      in regulatory cytogenetics studies.
AB  - The choice of harvest time in in vitro cytogenetics assays is a critical factor
      in determining the sensitivity of the assay for detecting clastogenic potential.
      As yet there is no harmonization of regulatory requirements in this aspect. It
      has been suggested that the use of extended harvest times can improve the
      sensitivity of detecting some chemicals which either induce cell cycle delay or
      produce lesions which induce chromosome aberrations at divisions subsequent to
      the first post-treatment mitosis. The incidence of such chemicals encountered in
      the routine testing of chemicals for regulatory submissions is not known.
      Therefore a large database of 550 chemicals tested in nine laboratories using
      standard regulatory protocols, including a late harvest time, was assessed for
      the incidence of chemicals uniquely positive only at a delayed harvest time. The
      number of such chemicals was very low ( < 0.2%) and the chromosome damage induced
      by these chemicals may not result from direct genotoxic mechanisms. Based on
      these data it is recommended that there is no need to include an extended harvest
      time in in vitro cytogenetics assays except where it might help to resolve an
      equivocal result.

PMID- 8671718
TI  - Aflatoxin B1 induced lacI mutation in liver and kidney of transgenic mice
      C57BL/6N: effect of phorone.
AB  - Transgenic C57BL/6N mice containing a lambda shuttle vector carrying a lacI
      target and an alpha-lacZ reporter gene have been used to study the modulating
      effect of phorone, a glutathione-depleting agent, on the mutagenic activity of
      aflatoxin B1 (AFB1) in vivo. Animals were treated with AFB1 (8 mg/kg) for four
      consecutive days and the animals sacrificed 21 days after the last treatment.
      Treatment with AFB1 alone did not result in a significant increase in mutation
      frequency in the liver and kidney. When the animals were treated with phorone 4 h
      prior to treatment with AFB1 a significant increase in mutation frequency was
      observed in the liver (4-fold) and kidney (1.5-fold). Phorone treatment did not
      increase the AFB1-induced mutation frequency in the lung and intestine. DNA
      sequence analyses of 30 independent clones isolated from the liver of AFB1
      treated animals showed that G:C --> T:A transversion (60%) was the predominant
      mutational event. Mutations within the lacI gene could not be detected in seven
      of 30 mutants. The mutations were randomly distributed throughout the coding
      sequences of the lacI gene and no hotspots for the mutations were observed.
      However, codons 86 and 928 appeared to be major sites for mutation. The study
      shows that the transgenic mouse in vivo mutagenesis model can be used to study
      the influence of effect-modifying compounds on the mutagenic activity of known
      carcinogens.

PMID- 8671719
TI  - Lowering extracellular calcium content protects cells from arsenite-induced
      killing and micronuclei formation.
AB  - The present study demonstrated that calcium ions were accumulated in nuclei of
      Chinese hamster ovary (CHO)-K1 cells after arsenite treatment. This process was
      enhanced by verapamil (a calcium channel blocker). Verapamil also significantly
      increased the cytotoxic effects of arsenite. In contrast, ethylene glycol
      bis[beta-aminoethylether] N,N, N1,N1,-tetraacetic acid (EGTA, a calcium-specific
      chelator), or calcium-free conditions significantly reduced the cytotoxicity or
      arsenite. Similarly, the strategy of lowering extracellular calcium concentration
      by modifying the medium or lowering intracellular calcium concentration by
      administration of the intracellular calcium chelator quin 2, protected cells from
      arsenite-induced micronuclei formation. These data indicate that the disturbances
      in intracellular calcium homeostasis maybe involved in arsenite-induced
      cytotoxicity and micronuclei formation.

PMID- 8671721
TI  - Analysis of micronucleus induction of pyrimethamine in in vitro CHL cells and in
      in vivo mouse bone marrow cells.
AB  - In vivo and in vitro mutagenicity of pyrimethamine were examined in the
      micronucleus test. Pyrimethamine strongly induced micronuclei in a dose-dependent
      manner in the in vitro micronucleus test using the Chinese hamster lung (CHL)
      cell line, when treated at 0.2-1.6 micrograms/ml for 48 h. The in vivo
      micronucleus test was carried out in mice after the first, second, third and
      fourth administration of doses up to 40 mg/kg p.o. The results showed no
      increased frequency of micronuclei after any treatment, though pyrimethamine was
      shown to persist at levels > 2 micrograms/ml in plasma after a single oral
      administration of 50 mg/kg.

PMID- 8671720
TI  - Genotoxic effects of alpha-hexachlorocyclohexane in primary cultures of rodent
      and human hepatocytes.
AB  - The genotoxicity of alpha-hexachlorocyclohexane (alpha-HCH) was evaluated in
      primary cultures of mouse, rat and human hepatocytes. DNA fragmentation was
      measured by the alkaline elution technique and DNA repair synthesis by
      quantitative autoradiography. A 20 h exposure to subtoxic concentrations ranging
      from 0.056 to 0.32 mM produced a dose-dependent frequency of DNA breaks in rat
      hepatocytes and in hepatocytes from four of five human donors, but not in mouse
      hepatocytes, DNA repair induction was absent in hepatocytes from all three
      species. The reduction in the frequency of DNA breaks observed in rat hepatocytes
      simultaneously exposed to metyrapone suggests that alpha-HCH is transformed into
      reactive species by a cytochrome P450-dependent reaction. The detection of DNA
      fragmentation but not of DNA repair synthesis may be tentatively explained by
      assuming that alpha-HCH behaves as a chemical eliciting short patch DNA repair,
      which is more easily revealed as genotoxic by the occurrence of DNA single-strand
      breaks.

PMID- 8671722
TI  - Host cell reactivation of irradiated adenovirus in UV-sensitive Chinese hamster
      ovary cell mutants.
AB  - In this study we have utilized the ability of rodent cells to replicate viral DNA
      following semi-permissive infection by human adenovirus (Ad) to examine the host
      cell reactivation (HCR) of radiation-damaged Ad in several UV-sensitive Chinese
      hamster ovary (CHO) cell mutants. A significant reduction in HCR of viral DNA
      synthesis for UV-irradiated Ad was detected in a series of UV-sensitive mutants
      from complementation groups 1-6 derived from parental CHO-AA8 cells. HCR for UV
      irradiated Ad in these CHO mutants varied from 18.8 to 48.0% of that in parental
      AA8 cells. However, a significant reduction in HCR of viral DNA synthesis for UV
      irradiated Ad could not be detected in series of UV-sensitive PV mutants from
      complementation groups 1, 5, 9 and 10 derived from parental CHO-K1 cells, which
      harbour relatively small DNA repair deficiencies. We also report a reduced HCR
      for gamma-irradiated Ad in UV-sensitive CHO cell mutants from groups 1 and 4
      derived from parental CHO-AA8 cells. This HCR technique for DNA synthesis of Ad
      can be employed to measure the DNA repair capacity of both human and rodent cells
      and extended to examine the repair of DNA damaged by a variety of different
      physical and chemical agents.

PMID- 8671723
TI  - Identification of a 2-D geometric descriptor associated with non-genotoxic
      carcinogens and some estrogens and antiestrogens.
AB  - A distance descriptor (6A) originally associated with non-genotoxic mouse
      carcinogens has been found to be present in some, but not all, estrogens and
      antiestrogens. It is hypothesized that this descriptor describes a ligand binding
      site on an estrogen receptor. Evidence is presented that those estrogens and
      antiestrogens not containing the 6A distance bind to a different receptor. It is
      conceivable that binding to the receptor that recognizes the 6A distance is
      associated with carcinogenicity.

PMID- 8671724
TI  - The identification and repair of DNA adducts induced by waterborne benzo[a]pyrene
      in developing Xenopus laevis larvae.
AB  - We report on the formation and subsequent repair of benzo[a]pyrene-induced DNA
      adducts in Xenopus laevis larvae in vivo, as monitored by 32P-post labelling. In
      vivo benzo[a]pyrene is metabolized by the cytochrome P450 family of enzymes to
      metabolites, of which the 7,8-diol-9,10-epoxides have been implicated as causing
      potentially tumourigenic lesions. Larvae were exposed to waterborne
      benzo[a]pyrene (0.01, 0.05 and 0.1 mg/l) for 24 h at stages 38, 45 and 50 of
      development (24 h, 5 days and 2 weeks post-hatching, respectively) and allowed to
      recover for up to 6 days. A wide range of adduct lesions were observed at stage
      50, three of which were observed at all stages investigated. Adduct repair was
      biphasic, with an initial rapid repair over the first 24 h post exposure,
      followed by a much slower decline, resulting in persistence of adducts for at
      least 6 days post exposure. The individual lesions were repaired at different
      rates, with some being almost completely repaired after 6 days recovery, whereas
      one of the main adducts showed restricted repair at stage 50 and another no
      repair at all. Identification of some adducts has been achieved, by the inclusion
      of isomeric standards of (+)- or (-)-anti-benzo[a]pyrene diol epoxide reacted
      with deoxyguanosine and adenosine 3'-monophosphates prepared in vitro. The non
      repairable lesion at stage 50 has been shown to be the (+)-trans-anti
      benzo[a]pyrene diol epoxide-N2-guanine adduct. This adduct was observed at all
      stages, but was only maximally repaired at stages 38 and 45.

PMID- 8671726
TI  - Restriction endonucleases induce chromosomal aberrations in barley.
AB  - The clastogenic ability of the restriction endonucleases (MspI, HpaII and HaeIII)
      in germinating seeds of reconstructed barley karyotype was assessed. An effective
      induction of chromosomal aberrations after restrictase treatment was observed.
      The frequency, types and cell-cycle dependence of the observed abnormalities are
      discussed in relation to the distinct characteristics of the enzymes and the
      features of the plant genome. The capacity to induce aberrations was not
      significantly influenced by the nature of the double-strand breaks (blunt- or
      cohesive-ended); however, it was dependent on the methylation status of the plant
      DNA. The restriction enzymes displayed an S-independent mode of action revealing
      the transition between G1 and S as the most sensitive stage of the cell cycle in
      barley for induction of chromosomal damage.

PMID- 8671727
TI  - Genotoxicity of trophosphamide in mouse germ cells: assessment of micronuclei in
      spermatids and chromosome aberrations in one-cell zygotes.
AB  - The genotoxicity of trophosphamide (TP) in mouse germ cells was assessed by the
      cytogenetic analysis of micronuclei in spermatids and chromosome aberrations in
      one-cell zygotes and compared with the genotoxicity in somatic cells evaluated by
      the micronucleus reticulocyte assay. Single acute doses of 50, 75, 100 and 150
      mg/kg were studied after i.p. injection. TP was only weakly mutagenic for
      preleptotene spermatocytes-differentiating spermatogonia, but clear-cut cytotoxic
      effects were demonstrated after treatment of these cells by a dose-dependent
      reduction of the ratio between Golgi and cap phase spermatids. Effects induced in
      post-meiotic stages were estimated, after mating the treated males with untreated
      superovulated females, by the frequencies of zygotes with chromosome aberrations:
      a peak of genetic damage was detected in late spermatids, with as many as 55%
      zygotes with aberrations, but spermatozoa and early spermatids were also clearly
      affected. When compared with matched solvent-injected controls, the lowest
      effective dose in spermatozoa and late spermatids was 100 mg/kg, although the 3-
      to 4-fold increases detected at 50 mg/kg were also statistically significant when
      compared with a pool of laboratory controls. In peripheral blood reticulocytes,
      the micronucleus frequencies were increased by 3-20 times the respective baseline
      values in the individual animals. A marked cytotoxic effect on bone marrow cells
      was revealed by the reduction of the proportion of early reticulocyte stages,
      which dropped to 20% of the control value at 150 mg/kg. Both genotoxic and
      cytotoxic effects were higher in bone marrow than in germ cells of the same
      animals, pointing to a generalized higher susceptibility of somatic cells to TP,
      possibly related to chemical distribution and target organ accessibility. The
      accurate description of stage- and dose-effect relationships in germ cells of
      experimental models is crucial for genetic risk assessment after chemical
      exposure. The approaches applied in this study may contribute to this goal.

PMID- 8671725
TI  - Evaluation of a plasmid-based transgenic mouse model for detecting in vivo
      mutations.
AB  - To study in vivo somatic mutations a C57BL/6 transgenic mouse model was
      constructed harboring multiple chromosomally integrated copies of the plasmid
      pUR288, which carried the lacZ reporter gene as the mutational target. We
      previously demonstrated that lacZ-containing plasmids could be rescued from their
      integrated state efficient enough to detect mutations in lacZ by positive
      selection. The smaller size of the plasmid vector, as compared with our earlier
      transgenic mouse model based on bacteriophage lambda vectors, should offer
      considerable advantages in terms of rescue efficiency and sensitivity to large
      size alterations in the lacZ gene. To evaluate the plasmid-based mouse model for
      its suitability to detect in vivo mutations, we determined mutant frequencies in
      different organs of untreated and ethyl nitrosourea (ENU)-treated animals using a
      new, improved protocol. The rescue efficiencies obtained were as high as
      200,000/micrograms genomic DNA; millions of transformants could be obtained in
      one single experiment. The average spontaneous mutant frequency in four different
      organs of 4- to 8-week-old mice ranged from 4.41 to 6.82 x 10(-5), compared with
      a mutant frequency of the same plasmid grown in Escherichia coli of approximately
      1 x 10(-5) or less. Single treatments with 100 and 250 mg ENU/kg body wt resulted
      in a 7- and 14-fold increase, respectively, in spleen mutant frequency at 14 days
      after i.p. administration of the alkylating agent. Restriction enzyme analysis
      showed that a considerable portion of spontaneous mutants were size changes
      varying from approximately 100 to 3000 bp. Some mutant plasmids contained mouse
      genomic sequences, which is indicative of large genetic rearrangement events
      involving the 3' flanking regions of the transgene cluster. Among the ENU-induced
      mutants, size changes comprised only a minor fraction of the total, which is in
      keeping with the known ENU mutation spectra in vitro and in vivo. The high rescue
      efficiency of this plasmid-based model, in combination with its sensitivity to a
      broad spectrum of mutations, including large deletions, makes it very suitable as
      a general in vivo mutagenicity test system.

PMID- 8671728
TI  - The centromere as a target for the induction of chromosome damage in resting and
      proliferating mammalian cells: assessment of mitomycin C-induced genetic damage
      at kinetochores and centromeres by a micronucleus test in mouse splenocytes.
AB  - The cytokinesis-block micronucleus assay (MN) on murine splenocytes was used for
      the estimation of chromosome damage in a resting cell population in vivo that can
      be induced to proliferate in vitro. Mitomycin C at different doses (10(-8), 6 x
      10(-8), 10(-7), 6 x 10(-7) and 10(-6)M) was used to induce cytogenetic damage in
      resting and cycling splenocytes. Antikinetochore antibodies (CREST) and two
      colour fluorescence in situ hybridization (FISH) with minor and major satellite
      DNA were applied. These approaches allowed the detailed characterization of the
      mechanisms by which MN originates, since it was possible to identify breaks
      induced in pericentric heterochromatic (resulting in MN containing the major but
      not the minor satellite DNA) or detachment/disruption of kinetochore (resulting
      in different frequencies of MN containing kinetochore or both probes). Based on
      the evidence that resting and cycling mouse splenocytes are characterized by
      different spatial distribution of centromeric regions, the hypothesis was tested
      that the damage induced by mutagens at centromeres is influenced by the phase of
      the cell cycle in which the cells are treated. Data presented here show that
      resting and cycling splenocytes are both sensitive to mitomycin C action, and
      indicate that this compound has an aneugenic potential, besides its strong
      clastogenic activity. In particular, results obtained after CREST and FISH
      characterization of MN differed when cells were treated during proliferation,
      suggesting a disruption/detachment of kinetochores induced by mitomycin C at this
      cell stage. Furthermore, under the same treatment condition the proportion of MN
      containing the major satellite DNA only was greater than expected on the basis of
      random breakage at this site. Treatment of resting cells produced aneugenic
      damage, but without evidence of disruption/detachment of kinetochores or
      preferential breakage at the centromere. These results indicate that the amount
      and type of chromosome damage induced by mitomycin C in mouse splenocytes differ
      in relation to the proliferative status of treated cells.

PMID- 8671729
TI  - CO-FISH reveals inversions associated with isochromosome formation.
AB  - Despite the likely prevalence and documented biological impact of inverted DNA
      sequences in humans and other species, our ability to detect them on a routine
      basis is limited. The technique of chromosome orientation fluorescence in situ
      hybridization (CO-FISH) was used to detect obligate chromosome inversions
      associated with isochromosome formation in two human cell lines. Simultaneous
      hybridization of a strand-specific telomeric probe allowed us to deduce the
      absolute orientation of repetitive DNA sequences associated with the inverted
      region. These results show that, in principle, CO-FISH could be used to detect
      virtually any type of inversion, including those likely to escape detection by
      other methods. Prospective applications of the technique are discussed in
      relation to its principal limitation, the present availability of suitable single
      stranded DNA probes.

PMID- 8671730
TI  - Haemoglobin adducts as biomarkers of occupational exposure to 1,3-butadiene.
AB  - Adducts of 1,2-epoxy-3-butene (EB) with haemoglobin were monitored in 17 workers
      from the 1,3-butadiene (BD) production unit of a petrochemical plant and in nine
      referents employed at the same factory but not exposed to BD. The air
      concentrations of BD were determined using stationary and personal monitoring.
      The ambient level of exposure of the plant workers handling butadiene containers
      (sampling and voiding) was on average 11.2 +/- 18.6 (mean +/- SD) mg/m3.
      Maintenance and laboratory workers were exposed to levels < or = 1.2 mg/m3. The
      particular haemoglobin adduct measured was 2-hydroxy-3-butenylvaline, formed by
      reaction of N-terminal valine with carbon 1 in EB. The adduct levels were
      increased (0.16 +/- 0.099 pmol/g; n = 10) in plant workers compared with the
      levels in maintenance and laboratory workers and controls (approximately 0.05
      pmol/g; seven laboratory workers and nine controls evaluated). Thus, the method
      used for adduct determination--derivatization of 200-300 mg globin samples with
      penta-fluorophenyl isothiocyanate according to the N-alkyl Edman method and
      detection of the thiohydantoin derivatives by tandem mass spectrometry--is
      sufficiently sensitive to allow monitoring of exposure to BD down to the p.p.m.
      level.

PMID- 8671732
TI  - Spectrum of spontaneously occurring mutations in the HPRT gene of the Chinese
      hamster V79 cell mutant V-H4, which is homologous to Fanconi anemia group A.
AB  - The mitomycin C (MMC)-hypersensitive Chinese hamster V79 cell mutant V-H4 has a
      cellular phenotype similar to Fanconi anemia (FA), and has been shown to be
      homologous to FA group A. To examine consequences of the defect in V-H4 cells on
      spontaneous mutagenesis, we studied the frequency and nature of spontaneous
      mutations at the hypoxanthine phosphoribosyltransferase (HPRT) locus in this
      mutant and the parental V79 cells. The mutation rates expressed as the number of
      mutations per cell per generation were 8.7 x 10(-7) and 3.7 x 10(-7) for V-H4 and
      V79 cells respectively. The molecular spectrum of 42 spontaneous hprt mutants of
      V-H4 cells was determined and compared with the previously described spectrum of
      spontaneous mutations at the HPRT locus of Chinese hamster V79 cells. The spectra
      of spontaneous mutations in the hprt gene of both cell lines are predominated by
      base pair substitutions and splice mutations. Among the base changes, V-H4 shows
      a larger frequency of transitions (13/42; 31%) than transversions (3/42; 7%),
      whereas in V79 transversions are observed more often than transitions (P < 0.001;
      Wilcoxon test). The frequency of splice mutations in V-H4 (17/42; 40%), which
      affects exon 4 almost exclusively, is not significantly different from V79. The
      fraction of deletions in V-H4 is low (6/42; 14%), and comparable to the level in
      V79. This is in contrast with the published molecular spectrum of spontaneous
      hprt mutants in FA (group D) cells, which consists predominantly of deletions.

PMID- 8671731
TI  - Mutagenic potential of Indian tobacco products.
AB  - The mutagenic potential of aqueous extracts of masheri (ME), chewing tobacco
      alone (CTE) and a mixture of chewing tobacco plus lime (CTLE) was tested using
      the Ames assay. ME exhibited mutagenicity in Salmonella typhimurium TA98 upon
      metabolic activation with aroclor-1254-induced rat liver S9, while nitrosation
      rendered it mutagenic in TA100 and TA102. CTE exhibited borderline mutagenicity
      in the absence or presence of S9 in TA98 and TA100 and after nitrosation in
      TA102, while nitrosation led to doubling of TA98 and TA100 revertants. In
      contrast, CTLE exhibited direct mutagenicity in TA98, TA100 and TA102, was
      mutagenic to TA98 upon S9 addition and induced mutagenic responses in all three
      tester strains after nitrosation. Experiments using scavengers of reactive oxygen
      species (ROS) suggested that CTLE-induced oxidative damage in TA102 was mediated
      by a variety of ROS. The high mutagenic potency of CTLE vis a vis that of CTE may
      be attributed to changes in the pH leading to differences in the amount and
      nature of compounds extracted from tobacco. Thus, exposure to a wide spectrum of
      tobacco-derived mutagens and promutagens may play a critical role in the
      development of oral cancer among users of tobacco plus lime.

PMID- 8671733
TI  - Protective effects of alpha-hederin, chlorophyllin and ascorbic acid towards the
      induction of micronuclei by doxorubicin in cultured human lymphocytes.
AB  - The influence of alpha-hederin (a saponin isolated from Hedera helix),
      chlorophyllin, the sodium-copper salt of chlorophyll, and ascorbic acid (vitamin
      C) on the direct clastogenicity of doxorubicin (Adriamycin) was investigated in
      vitro in human lymphocytes for the induction of micronuclei. In order to
      determine a possible mechanism of action responsible for the antimutagenic
      activity, treatments were performed for the three substances at different times
      of the culture (pre-treatment, simultaneous and post-treatment). Alpha-hederin
      (1.3 x 10(-2), 0.13, 1.3 and 13 nmol/ml) and chlorophyllin (0.14, 1.4 and 14
      nmol/ml) were found to exert an antimutagenic effect against the clastogenicity
      of doxorubicin (1.5 x 10(-2) nmol/ml) in all treatments at all concentrations.
      Ascorbic acid (10 nmol/ml) was effective in reducing the micronucleus levels only
      in the simultaneous treatment, when it was previously incubated with doxorubicin
      for 2 h at 37 degrees C before being introduced into the culture. Our results
      suggested a desmutagenic effect for alpha-hederin, chlorophyllin and ascorbic
      acid. Chlorophyllin acted also through a bio-antimutagenic mechanism and alpha
      hederin seemed to induce metabolic enzymes, which inactivated doxorubicin.
      Preliminary studies showed that the effective antimutagenic concentrations of
      alpha-hederin, chlorophyllin and ascorbic acid had no clastogenic or aneugenic
      effects in human lymphocytes. No cytotoxicity was observed for the three
      antimutagenic agents either.

PMID- 8671734
TI  - Analysis of DNA alkylation damage and repair in mammalian cells by the comet
      assay.
AB  - The single cell gel electrophoresis (SCGE) or comet assay, which measures DNA
      strand breaks in individual cells, was used to analyse DNA damage and repair
      induced by the SN1-type alkylating carcinogens N-ethyl-N'-nitro-N
      nitrosoguanidine and N-ethyl-N-nitrosourea in CHO cells. The comet assay was
      comparable in sensitivity to the alkaline elution assay. The alkyl-adducts
      detected as DNA single-strand breaks (ssb) by this technique were completely
      repaired within 24 h after treatment. These data indicate that long-lived
      lesions, such as alkylphosphotriesters, are not converted into ssb under the
      standard SCGE alkaline conditions (pH 13.5). The lesions revealed by the comet
      assay are mainly apurinic/apyrimidinic (AP) sites and breaks formed as
      intermediates in the base excision repair process of N-alkylpurines. When SCGE
      was performed at pH 12.5 instead of pH 13.5 a lower level of ssb was detected and
      these breaks were completely resealed within 2 h after treatment. These data
      suggest that different subsets of lesions are detected under different pH
      conditions. The SCGE combined with inclusion within the cells of endonuclease III
      revealed that a high portion of AP sites induced by alkylation damage were not
      converted into ssb by alkali. The level of endonuclease III-sensitive sites
      decreased as a function of the repair time and by 24 h after treatment no sites
      were left on the DNA. The use of this modified SCGE assay allows the estimation
      of the total amount of unrepaired AP sites present on DNA. Alkylation-induced ssb
      as detected by the comet assay should be regarded as an indicator of repair rate
      and balance more than a measure of actual DNA damage.

PMID- 8671735
TI  - Suppressive effects of methyl methacrylate on the mutagenicity and DNA adduct
      formation induced by 1-nitropyrene and benzo[a]pyrene.
AB  - Methyl methacrylate (MMA) is widely used as a cement in dentistry, orthopaedic
      surgery and ophthalmology. Studies based on short-term genotoxicity tests have
      produced conflicting results in the last two decades. In the present study, the
      effects of MMA on the mutagenicity of 1-nitropyrene (1-NP) and benzo[a]pyrene
      (B[a]P) were evaluated with the Salmonella typhimurium TA98 strain in the absence
      and presence of S9 mix. The direct-acting mutagenicity of 1-NP was markedly
      decreased by MMA in a dose-dependent manner. However, a low inhibitory effect of
      MMA on the metabolic-acting mutagenicity of B[a]P was observed. MMA did not show
      mutagenicity within the concentrations of 4.7-37.6 microM either with or without
      S9 mix. The inhibitory effect of MMA was not due to its cytotoxicity because very
      low and/or no cytotoxicity of MMA to S. typhimurium TA98 was observed. To confirm
      the antimutagenicity of MMA against 1-NP and B[a]P, a 32P-postlabelling method
      was used to determine whether MMA modified DNA adduct formation produced by both
      compounds in calf thymus DNA. MMA inhibits the formation of 1-NP- and B[a]P-DNA
      adducts in a dose-dependent manner. The DNA adduct of 1-NP reduced by MMA was
      greater than that of B[a]P. Thus, we suggested that MMA was possibly acting as an
      inhibitor of chemical carcinogenesis.

PMID- 8671736
TI  - Chromatid exchanges may be induced by damage in sites of transcriptional
      activity.
AB  - A conditional expression system has allowed us to vary the expression level of
      the xeroderma pigmentosum group A (XPA) photoproduct-specific DNA-binding protein
      in human cells and so control the response of cells to damage by UV light. Using
      a form of XPA that contains a single missense mutation (R207G) enabled us to
      study a lower range of function than that obtained with the wild-type sequence.
      This form of XPA has been previously shown to stimulate pyrimidine dimer excision
      preferentially in actively transcribed genes. We found that UV resistance
      increased as a linear function of XPA expression levels. Excision of (6-4)
      pyrimidine-pyrimidone photoproducts in the whole genome increased to a maximum at
      about the haploid level of XPA expression, but there was little pyrimidine dimer
      excision from the whole genome. SCE frequency induced by UV light was high in
      cells with no SPA expression and fell rapidly with increasing levels of SPA
      expression within 0-50% of the haploid level of expression. No further reduction
      in SCE frequency was produced at the highest levels of XPA expression, when
      repair replication extended to the overall genome. We speculate that a low level
      of repair, especially that occurring in actively transcribed genes, may
      selectively eliminate photoproducts that are particularly important in causing
      cell killing and SCEs.

PMID- 8671737
TI  - Antimutagenicity and catechin content of soluble instant teas.
AB  - The antimutagenic properties of soluble instant teas were examined using the
      bacterial Ames assay. Inhibition of the numbers of revertants induced from a
      number of known mutagens indicates that aqueous extracts of instant teas have
      antimutagenic activity and antioxidative properties, and can inhibit nitrosation
      reactions. Despite a significant reduction in the amounts of major green tea
      catechins, quantified using reversed-phase HPLC with electro-chemical detection,
      no differences in antimutagenicity were observed between the instant teas, a
      black fermented tea and a green tea. Oxidation of polyphenolic compounds which
      occurs during the production of instant tea does not therefore decrease the
      antioxidant, free radical scavenging and antimutagenic properties. This suggests
      that catechins are not the only compounds responsible for the protective effects
      of teas.

PMID- 8671738
TI  - Dose-response study and threshold estimation of griseofulvin-induced aneuploidy
      during female mouse meiosis I and II.
AB  - The relative sensitivity of the two meiotic divisions of mouse oogenesis to
      griseofulvin (GF)-induced aneuploidy was investigated. The first meiotic division
      was studied by administering GF 4 h after human chorionic gonadotrophin (HCG)
      injection and analyzing metaphase II (MII) oocytes, whereas study of the second
      meiotic division involved treating the females 10 h after HCG and analyzing one
      cell (1-Cl) zygotes. Data from previous studies have shown that these treatment
      times represented the most sensitive times for aneuploidy induction during
      meioses I and II. The statistical analyses of the data showed that the dose
      response curves for aneuploidy induction did not differ quantitatively or
      qualitatively between the two meiotic divisions. The percentages of hyperploid
      MII oocytes and 1-Cl zygotes were significantly higher (P < 0.001) than in the
      controls for all doses except 125 mg/kg GF. The highest percentages of hyperploid
      cells were found after administering 1500 mg/kg GF. However, these percentages
      were not different (P > 0.05) from those observed after 500 or 1000 mg/kg GF,
      suggesting saturation of the GF aneuploid target(s). These results suggest that
      the relative sensitivity to GF-induced aneuploidy between the two meiotic
      divisions of oogenesis are similar. They also suggest the presence of a lower
      (125 mg/kg) and an upper 500 mg/kg) threshold for GF-induced aneuploidy.

PMID- 8671739
TI  - Use of the Miniscreen assay to screen novel compounds for bacterial mutagenicity
      in the pharmaceutical industry.
AB  - In vitro assays for mutagenicity are an important feature of pre-clinical testing
      and form part of the current regulatory testing conducted early in drug
      development. They can also play a part in compound selection since mutagenic
      compounds can be eliminated from a range of potential candidates. Bacterial tests
      are particularly useful in this area because they generate results quickly,
      though their use may be limited because they can require up to 4 g of material. A
      scaled-down version of the Ames test has been developed which requires only
      approximately 20 mg of material. Initial experiences with this assay using a
      range of known mutagens and novel compounds have shown that the Miniscreen has
      similar sensitivity to the Ames test. The major exception is for those mutagens
      preferentially detected with strains TA1537 and TA1535, which, because of their
      low spontaneous counts, are not employed in the Miniscreen.

PMID- 8671740
TI  - Excretion of mutagens, nicotine and its metabolites in urine of cigarette
      smokers.
AB  - Urine samples from 26 cigarette smokers on a restricted diet were collected in
      the late afternoon. Urine extracts on XAD-2 resin were tested for mutagenicity in
      the microsuspension assay using Salmonella typhimurium strain TA98 in the
      presence of metabolizing and deconjugating enzymes. Levels of urinary nicotine
      plus metabolites and cotinine were determined. Eighteen samples were clearly
      mutagenic, i.e. capable of doubling the number of spontaneous revertants at one
      of the assayed doses of urine. Urinary mutagenic activity ranged from 193 to 8462
      net revertants/mmol of creatinine, while urinary nicotine plus metabolites and
      cotinine levels varied from 0.007 to 1.366 and from 0.011 to 0.297 mg/mmol
      creatinine. Urine samples with nicotine metabolite levels of < 0.33, 0.33- < 0.66
      and > 0.66 mg/mmol creatinine had mean values +/- SD of mutagenic activity of 490
      +/- 222 (n = 10), 964 +/- 560 (n = 9) and 2692 +/- 2807 (n = 7) revertants/mmol
      of creatinine, respectively, the statistical comparison between the groups being
      positive (Mann-Whitney U-test, P < 0.05). The mutagenic activity of urine samples
      from smokers correlated well with urinary nicotine plus metabolite levels (r =
      0.658, P < 0.01). A less close correlation was found between urinary mutagenic
      activity and other indicators of tobacco smoke exposure, such as urinary cotinine
      (r = 0.504, P < 0.05), number of cigarettes smoked during the day of urine
      collection (r = 0.399, P < 0.05) and machine smoking-derived nicotine deliveries
      of the total number of cigarettes smoked (number of cigarettes multiplied by the
      nicotine content of each cigarette, as indicated by the manufacturer; r = 0.439,
      P < 0.05). These results suggest that the mutagenic activity of smokers' urine
      may be predicted by the urinary level of nicotine plus metabolites. The low
      degree of reliability of many presumptive indicators of exposure to tobacco smoke
      and the different urinary excretion kinetics of tobacco smoke mutagens with
      respect to cotinine (a frequently used biomarker for monitoring exposure to
      tobacco smoke) are both emphasized.

PMID- 8671741
TI  - Influence of erythrocyte glutathione S-transferase T1 on sister chromatid
      exchanges induced by diepoxybutane in cultured human lymphocytes.
AB  - Humans can be classified as either DEB-sensitive or DEB-resistant on the basis of
      the frequency of sister chromatid exchanges (SCEs) induced in whole-blood
      lymphocyte cultures by 1,2,3,4-diepoxybutane (DEB), an epoxide metabolite of 1,3
      butadiene. Sensitivity to in vitro SCE induction by DEB has been explained by a
      deletion of the glutathione S-transferase T1 gene (GSTT1), resulting in a
      deficiency of erythrocytic GSTT1 activity among GSTT1 null homozygotes. To verify
      that the GSTT1 activity of erythrocytes is responsible for differential SCE
      induction by DEB, SCEs induced by a 48-h exposure to DEB (2 or 5 microM) were
      analyzed in whole-blood and isolated lymphocyte cultures of four GSTT1 positive
      and four GSTT1 null individuals. The mean frequency of SCEs/cell was about twice
      as high among the GSTT1 null donors as compared with the GSTT1 positive donors,
      at both 2 microM DEB (mean 53.1 versus 25.8) and 5 microM DEB (mean 74.4 versus
      38.4) in whole-blood lymphocyte cultures. In isolated lymphocyte cultures, DEB
      induced higher SCE frequencies than in whole-blood cultures and there was
      essentially no difference between the response of the two GSTT1 genotypes (mean
      68.3 for GSTT1+ and mean 69.2 for GSTT1- at 2 microM DEB and 85.0 and 92.7,
      respectively, at 5 microM DEB). The isolated lymphocyte cultures were also much
      more sensitive to the cytotoxic effect of DEB, observed as significantly
      decreased replication indices at both DEB concentrations and genotypes. The whole
      blood lymphocyte cultures showed lower replication indices for the GSTT1 null
      subjects than for those having the GSTT1 gene at both concentrations of DEB.
      These results support the role of GSTT1 activity in erythrocytes as a major
      detoxification pathway for DEB.

PMID- 8671742
TI  - Industrial Genotoxicology Group: transgenic animals in genotoxicity assays and
      the comet assay, Royal Society of Medicine, London, UK, May 1995.

PMID- 8671743
TI  - Genotoxicity of the herbicides alachlor and maleic hydrazide in cultured human
      lymphocytes.
AB  - The herbicides alachlor and maleic hydrazide were evaluated for genotoxicity in
      peripheral blood human lymphocyte cultures. Sister-chromatid exchanges (SCE),
      chromosome aberrations (CA) and micronuclei (MN) were scored as genetic
      endpoints. To detect possible metabolic modifications in the genotoxicity of both
      herbicides, the cultures for SCE and MN demonstration were also treated with S9
      fraction. From our results we conclude that, in the absence of metabolic
      activation, the two herbicides induce significant increases in the frequency of
      SCE, although the concentrations needed to be effective are very different. Thus,
      alachlor gave positive results at concentrations ranging from 1 microg/ml, and
      maleic hydrazide at concentrations ranging from 100 microg/ml. In addition,
      alachlor appears to be clastogenic in both the CA and MN assays, but only at the
      highest concentration tested (20 microg/ml). The co-treatment with the S9
      fraction produced a slight decrease in the induction of SCE with both herbicides:
      nevertheless, it does not seem to affect the response in the MN assay.

PMID- 8671744
TI  - DNA sequence analysis of methylene chloride-induced HPRT mutations in Chinese
      hamster ovary cells: comparison with the mutation spectrum obtained for 1,2
      dibromoethane and formaldehyde.
AB  - Glutathione-S-transferase-mediated metabolism of methylene chloride (MC)
      generates S-chloromethylglutathione, which has the potential to react with DNA,
      and formaldehyde, which is a known mutagen. MC-induced mutations in the HPRT gene
      of Chinese hamster ovary cells have been sequenced and compared with the
      mutations induced by 1, 2-dibromoethane (1,2-DEB), which is known to act through
      a glutathione conjugate, and formaldehyde. All three compounds induced primarily
      point mutations, with a small number of insertion and deletion events. The most
      common point mutations induced by MC were GC-->AT transitions (4/8), with two GC-
      >CG transversions and two AT-->TA transversions. This pattern of mutations showed
      greater similarity with 1,2-DBE, where the dominant point mutations were GC-->AT
      transitions (7/9), than formaldehyde, where all mutations were single base
      transversions and 5/6 occurred from AT base pairs. The mutation sequence results
      for MC suggest that S-chloromethylglutathione plays a major role in MC
      mutagenesis, with only a limited contribution from formaldehyde. The involvement
      of a glutathione (GSH) conjugate in MC mutagenicity would be analogous to the
      well-characterized pathway of activation of 1,2-DBE.

PMID- 8671745
TI  - Naturally occurring diallyl disulfide inhibits the formation of carcinogenic
      heterocyclic aromatic amines in boiled pork juice.
AB  - Three heterocyclic aromatic amines, 2-amino-3-methyl-imidazo[4, 5-f]quinoline
      (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoxaline and 2-amino-3,4
      dimethylimidazo[4,5-f]quinoline, have been found in boiled pork juice. We have
      investigated the effect of naturally occurring organosulfur compounds, which are
      present in garlic and onion, on mutagen formation in boiled pork juice. Six
      organosulfur compounds - diallyl disulfide (DAD), dipropyl disulfide (DPD),
      diallyl sulfide (DAS), allyl methyl sulfide (AMS), allyl mercaptan (AM) and
      cysteine - were added separately to the pork juice before reflux boiling and then
      the mutagenicity of each sample was examined with the Salmonella typhimurium
      strain TA98 in the presence of S9 mix. All six compounds were found to inhibit
      the mutagenicity of boiled pork juice. The greatest inhibitory effect was
      observed with DAD and DPD, and this was 111-fold higher than that of the lowest,
      cysteine. To elucidate the inhibitory effect of DAD on mutagen formation in
      boiled pork juice, the major mutagenic fractions were monitored after HPLC
      separation by their mutagenicity with S. typhimurium TA98. By comparing the
      retention times of authentic IQ compounds from boiled pork juice with those
      following the addition of DAD, we showed that the mutagenicity of three major
      fractions was significantly inhibited compared with those same fractions in
      boiled pork juice alone. In addition, the Maillard reaction products (MRPs) in
      the boiled pork juice with and without the addition of DAD were quantified and
      identified by capillary gas chromatography and gas chromatography-mass
      spectrometry. The results show that the reduction in the total amount of MRPs
      (pyridines, pyrazines, thiophenes and thiazoles) in boiled pork juice after
      boiling for 12 h is correlated with their mutagenicity. Among the MRPs,
      tetrahydrothiophene-3-one exhibited the strongest correlation. These data suggest
      that the inhibition of IQ mutagen formation by DAD is mediated through the
      reduction of MRPs production.

PMID- 8671747
TI  - An investigation into the activation and deactivation of chlorinated hydrocarbons
      to genotoxins in metabolically competent human cells.
AB  - We have investigated the induction of micronuclei by 15 chlorinated hydrocarbons
      in the cytochalasin B-blocked micronucleus assay utilizing genetically engineered
      cell lines. The human lymphoblastoid cell line AHH-1, with native cytochrome
      CYP1A1 activity, the MCL-5 cell line, which stably expresses cDNAs encoding human
      CYP1A2, 2A6, 3A4, 2E1 and microsomal epoxide hydrolase, and the h2E1 cell line,
      containing a cDNA for CYP2E1, were used in this study. We have demonstrated the
      induction of kinetochore-positive micronuclei by two chlorinated solvents, 2,3
      dichlorobutane and 1,1, 2-trichloroethane, in the metabolically competent cell
      lines MCL-5 and h2E1. The MCL-5 and h2E1 cell lines have in addition shown the
      capacity to produce metabolites in the presence of methylene chloride, carbon
      tetrachloride, 1,2,3-trichloropropane, tetrachloroethylene, toluene and n-hexane,
      wich yield elevated micronucleus frequencies compared with the parental cell line
      AHH-1. Hexachloroethane failed to induce micronuclei in any of the cell lines and
      1,2-dichloroethane and 1-chlorohexane induced micronuclei without the requirement
      for metabolic activation in all three cell lines. The MCL-5 cell line exhibited
      reduced micronucleus frequencies compared with the AHH-1 and h2E1 cell lines
      following exposure to 1,2-dichloroethylene, 1,3-dichloropropane, 1,1, 1
      trichloroethane and 1,2,3-trichloropropane. The methodology used has shown the
      ability of metabolically competent cell lines expressing cDNAs encoding the
      cytochrome P450 isoenzymes to metabolize halogenated hydrocarbons to genotoxic
      species, including both clastogens and aneugens. The biotransformation of
      chemicals to aneugenic species has not previously been demonstrated.

PMID- 8671746
TI  - Mutagenicity and toxicity of the DNA alkylation carcinogens 1,2-dimethylhydrazine
      and azoxymethane in Escherichia coli and Salmonella typhimurium.
AB  - DNA alkylating agents such as 1,2-dimethylhydrazine (SDMH) and azoxymethane (AOM)
      are potent carcinogens and are widely used to induce colon tumors in experimental
      animals. However, standard bacterial mutagenesis assays have failed to detect the
      mutagenic effects of these chemicals. Using derivatives of a set of Escherichia
      coli test strains developed by Cupples and Miller (Proc. Natl. Acad. Sci. USA,
      86, 5345, 1989), we hve demonstrated that under two conditions, SDMH and AOM
      induced point mutations by several-fold in a dose-dependent manner: (i) of six
      possible base substitutions, they only induced GC-->AT transitions; and (ii) the
      cells must be deficient in O6-methylguanine (O6MeG) DNA methyltransferase (MTase)
      activity. SDMH and AOM up to 200 microg/ml were unable to induce His+ revertants
      in a Salmonella Ames test strain TA1535 (GC-->AT); however, in the absence of
      mammalian S9 extract, His+ revertants increased up to 55-fold upon treatment of
      an isogenic Salmonella strain deficient in MTase activity. These results indicate
      that SDMH and AOM are indeed bacterial mutagens and that lesions induced by them
      are the target of DNA repair MTases, which probably include mutagenic and
      carcinogenic lesions such as O6MeG. Furthermore, variable responses of bacterial
      species to SDMH- and AOM-induced mutagenicity suggests a difference either in the
      metabolism of potential mutagens or in the repair of specific lesions. Since
      O6MeG is not only a mutagenic lesion but also a lethal lesion if left unrepaired,
      we compared the mutagenicity and toxicity of SDMH and AOM with an SN-type
      methylating carcinogen. N-methyl-N'-nitro-N-nitrosoguanidine, and conclude that
      SDMH and AOM are weak bacterial mutagens.

PMID- 8671748
TI  - Ionizing radiation signature mutations in human cell mutants induced by low-dose
      exposures.
AB  - Investigation of mutational specificity at low doses has generally not been
      possible since the number of induced mutants may be similar or significantly
      lower than the spontaneous background. The use of a low-dose fractionated
      exposure protocol in TK6 human lymphoblasts results in an incremental
      accumulation of mutants induced by individual 20 cGy gamma-ray exposures.
      Therefore, the frequency of induced mutants within a population at the conclusion
      of a fractionated exposure regimen is sufficiently elevated to permit the
      recovery of a low-dose mutant collection. Statistical analysis of the data
      identified no significant differences between mutants induced by 20 or 200 cGy.
      However, deletions encompassing one or more Xq26 STS markers flanking the hprt
      locus represented only 1/107 (0.009) spontaneous HPRT- mutants but 34/170 (0.20)
      mutants induced by 20 or 200 cGy of ionizing radiation (P < 0.0001). The data
      presented here demonstrate that mutational fingerprints can be effectively
      defined using deletion mapping for clastogens such as ionizing radiation, and
      that the radiation-induced mutational spectrum is independent of dose.

PMID- 8671749
TI  - Effects of age and caloric restriction on cell proliferation in hepatocyte
      cultures from control and hepatectomized Fischer 344 rats.
AB  - The effects of age and caloric restriction on cell proliferation, measured as
      scheduled DNA synthesis (SDS), were evaluated in primary hepatocyte cultures from
      control and partially hepatectomized (PH) young to old ad libitum (AL) and
      caloric-restricted (CR) male Fischer 344 (F344) rats. We reported significant age
      or CR-related decreases in SDS in control cultures. PH-induced cultures
      exhibited significant increases in SDS compared with their control counterparts.
      Hepatocytes from PH-induced old CR diet-fed animals exhibited significant
      increases in SDS compared with cultures from control old CR, PH-induced young CR
      and PH-induced old AL animals. Alternatively, SDS rates for PH-induced young CR
      animals were significantly lower at 48 h and higher at 72 h than the rates we
      reported for cultures from PH-induced young AL F344 rats. These data suggest that
      CR decreases and preserves the proliferative capacity in hepatocytes from young
      animals and may permit animals to respond more efficiently with induced
      compensatory cellular replication in old age.

PMID- 8671750
TI  - Detection of the centromere in micronuclei by fluorescence in situ hybridization:
      its application to the human lymphocyte micronucleus assay after treatment with
      four suspected aneugens.
AB  - The human lymphocyte micronucleus (MN) test combined with fluorescence in situ
      hybridization (FISH) of a centromeric probe is considered a useful screening
      assay to distinguish between clastogenic and aneugenic agents. Four suspected
      aneuploidy-inducing chemicals, acetaldehyde (AA), diethylstilbestrol (DES),
      diethylstilbestrol dipropionate (DESdp) and griseofulvin (GF), have been
      evaluated with the assay. All compounds induced a significant increase of MN at
      all doses tested. After the application of the FISH technique with a
      pancentromeric DNA sequence, DES, DESdp and GF showed a statistically significant
      increase in the percentage of positive signals compared with the control culture.
      GF induced the highest percentage of centromere-positive MN observed to date
      (>90% on average). AA did not show a significant difference in the percentage of
      centromere-positive MN. The results indicate that in human lymphocytes DES, DESdp
      and GF act primarily as aneugens, while AA seems capable of causing both
      chromosome breakage and aneuploidy.

PMID- 8671751
TI  - Analysis of DNA damage recovery processes in the adaptive response to ionizing
      radiation in human lymphocytes.
AB  - It has been frequently suggested that the adaptive response to ionizing radiation
      involves the induction of a chromosomal repair mechanism. Although several lines
      of evidence favour this assumption, direct proof is lacking. We have chosen to
      study this question with the help of the comet assay. Lymphocytes from three
      human donors were given an adapting dose of 0.05 Gy 16 h after mitogenic
      stimulation and a challenging dose of 2 Gy 5 h thereafter. While a portion of the
      cells was removed from the cultures for the comet assay, remaining cells were
      harvested at 52 h culture time and screened for chromosomal aberrations. In some
      experiments an analysis of cell proliferation was additionally carried out by
      flow cytometry. In the comet assay a reduced level of initial damage and an
      increased repair capacity was observed in the adapted + challenged cells;
      however, this did not result in a reduction of the aberration frequencies. No
      effect of the adapting dose on cell proliferation was detectable. The analysis of
      comet distributions revealed that the observed enhanced repair capacity was due
      to the presence of a subpopulation of slowly repairing cells in the challenged
      lymphocytes and the lack of such a subpopulation in the adapted + challenged
      cells. We assume that the slowly repairing cells were quiescent G0 lymphocytes
      which were removed from the adapted + challenged cell population, probably by
      apoptotic-like processes.

PMID- 8671752
TI  - Congenital abnormalities and indicators of germinal mutations in the vicinity of
      the Paks nuclear plant, Hungary.
AB  - The objective of the study was to check the occurrence of phenotypic
      manifestations of germinal mutations in children born within a 30 km radius of
      the Paks nuclear power plant, Hungary. The study took the form of a comparative
      analysis between observed and expected rates based on the Hungarian baseline
      rates, as well as between children born before and after the operation of the
      nuclear plant. Data were taken from the database of the Hungarian Congenital
      Abnormality Registry completed by active search in the study region, and
      comprised 26 893 children born between 1980 and 1992 in the 55 settlements of the
      study region. The results were presented as overall figures as well as being
      grouped by different congenital abnormalities, in addition to the so-called
      indicators of germinal mutations: sentinel anomalies, Down syndrome and
      unidentified multiple congenital abnormalities. The observed occurrence of all
      but one group of congenital abnormalities corresponded to the expected rate, as
      did the three groups of indicator conditions. Of the 55 settlements, eight had
      spatial clusters; however, these could be explained by overdiagnosis or chance.
      There was no significant increase in the variables studied after the operation of
      the nuclear plant. We conclude that the slightly elevated radiation background
      (0.2-0.4 microSv/year) due to the operation of the nuclear plant studied does not
      affect germinal and somatic mutations in children.

PMID- 8671753
TI  - Metabolizing systems for in vitro genotoxicity tests.

PMID- 8671754
TI  - Mitotic non-disjunction as a mechanism for in vitro aneuploidy induction by X
      rays in primary human cells.
AB  - A collaborative study of three laboratories compared the induction of aneuploidy
      by X-rays in human lymphocytes and fibroblasts. The induction of non-disjunction
      versus chromosome loss by X-rays was investigated using a variety of aneuploidy
      detection methods. Chromosome loss was determined by fluorescence in situ
      hybridization (FISH) with pan-centromeric probes in cytochalasin-B-blocked
      binucleated cells. Chromosome non-disjunction was estimated by FISH with
      chromosome-specific centromeric probes in binucleated interphase cells.
      Chromosomes were counted in parallel in lymphocyte metaphase cells; chromosome
      counts of the whole karyotype and counts of chromosomes 2 and 8 using chromosome
      paints. A major observation in spontaneous non-disjunction frequencies concerned
      the clear difference in frequencies observed between the two painted chromosomes
      in the same primary cells. When cells were irradiated elevated frequencies were
      observed for all the different cytogenetic endpoints. Although only a small
      number of the micronuclei were positive for the centromeric signal and presumably
      contained whole chromosomes, the absolute number %oC+ increased with dose. Higher
      rates of non-disjunction were found for irradiated cells; in fibroblasts a
      statistically significant increase was observed at a dose of 0.5 Gy. The
      detection of hyperdiploidy by means of chromosome counts and chromosome painting
      revealed an increase from doses of 1 Gy and higher. Comparison of the different
      methods detecting different endpoints indicates that non-disjunction may be an
      important mechanism leading to spontaneous and X-ray-induced aneuploidy. The
      relative radiosensitivity of aneuploidy induction was compared in two types of
      primary human cells - lymphocytes and fibroblasts. For chromosome loss both cell
      types showed similar results, whereas for non-disjunction fibroblasts seemed to
      be more sensitive. However, these differences may reflect a different sensitivity
      in the scoring methods used.

PMID- 8671755
TI  - Induction of somatic mutation and recombination by four inhibitors of eukaryotic
      topoisomerases assayed in the wing spot test of Drosophila melanogaster.
AB  - Four inhibitors of eukaryotic topoisomerases were investigated for genotoxic
      effects in the wing spot test of Drosophila melanogaster. As a somatic mutation
      and recombination test (SMART) this assay assesses mitotic recombination and
      mutational events of various kinds. We studied camptothecin as a topoisomerase I
      inhibitor, as well as ellipticine as an intercalating inhibitor and teniposide
      and etoposide as two non-intercalating inhibitors of topoisomerase II. Wing spots
      were induced in flies trans-heterozygous for the recessive wing cell markers
      multiple wing hairs (mwh) and flare (flr3) as well as in flies heterozygous for
      mwh and the multiply inverted TM3 balancer chromosome. All four compounds proved
      significantly genotoxic in this test. The spot induction frequencies formally
      standardized to the millimolar unit of exposure dose decreased in the order
      camptothecin > teniposide > ellipticine greater, similar etoposide in the
      mwh/flr3 inversion-free genotype. In the mwh/TM3 genotype, in which mitotic
      crossing over is suppressed because of the inversion-heterozygosity, the observed
      spot frequencies were considerably reduced, but to different extents. In this
      genotype, spot induction by ellipticine was not statistically significant, and it
      was determined that >99% of the spots are due to mitotic recombination in
      mwh/flr3 flies. For the other compounds, spot induction in the inversion
      heterozygous genotype was significant. The relative contribution of recombination
      to total spot induction in the inversion-free genotype was 88% for camptothecin.
      It was significantly lower for the two epipodophyllotoxins teniposide (71%) and
      etoposide (59%). Only suggestions can be proffered at present as to how these
      proportions could be related to the primary damage produced by the respective
      compounds on the chromosomes.

PMID- 8671756
TI  - MX100, a new Escherichia coli tester strain for use in genotoxicity studies.
AB  - The development of a new Escherichia coli tester strain for use in metabolic and
      mechanistic studies of genotoxins, strain MR2101/pKR11, has recently been
      reported. This strain, a derivative of the E. coli K12 laboratory strain AB1157,
      has sensitivity towards the detection of base-substitution mutagenesis, monitored
      by the reversion of arginine auxotrophy [argE3, (ochre)]. Besides arginine,
      MK2101/pKR11 is auxotrophic for histidine (hisG4), leucine (leuB6), proline
      (DeltaproA) and threonine (thr-1). MX100 was developed to overcome the auxotrophy
      for four amino acids of MR2101/pKR11 which are non-essential for the mutagenic
      responsiveness of the strain. We restored the biosynthesis for these four amino
      acids in MR2101/pKR11, resulting in strain MX100. This strain showed an almost 2
      fold increase in mutagenic activity relative to MR2101/pKR11 with a set of
      diagnostic mutagens (aflatoxin B1, benzo[a]pyrene, 4-nitroquinoline-1-oxide, 2,7
      dimethyl-benz[a]anthracene and others) and was further characterized with other
      types of mutagens in which it showed sensitivity towards the detection of
      oxidative (H2O2t-butyl-hydroperoxide, cumene-hydroperoxide, KO2) and carbonyl
      mutagens (methylglyoxal, malondialdehyde). As MX100 seems to have the right
      characteristics of a versatile genotoxicity tester strain and due to the
      extensive genetic and physiological knowledge of E. coli K12 in general and
      AB1157 in particular, we propose that MX100 could serve as mother strain for the
      development of specialized tester strains, of interest in studies of metabolism
      and/or mechanism of action of genotoxic carcinogens.

PMID- 8671757
TI  - Analysis of chromosome segregation in cytokinesis-blocked human lymphocytes: non
      disjunction is the prevalent damage resulting from low dose exposure to spindle
      poisons.
AB  - The chromosome malsegregation pattern produced by the spindle poisons vinblastine
      (VBL) and colchicine (COL) in human lymphocytes was investigated. For this
      purpose, the fluorescence in situ hybridization with centromeric DNA probes for
      chromosomes X and 1 was applied to cell cultures treated with cytochalasin B, a
      cytokinesis-blocking agent. With this method, chromosome segregation in daughter
      nuclei - retained in the same envelope - can be easily analysed, simultaneously
      determining the loss and non-disjunction of specific chromosomes. Preliminary
      experiments demonstrated that the aneugenic effects elicited by low dose exposure
      to spindle poisons were effectively detected with treatments from the S/G2 phase
      (43 h) to harvest of cell cultures (60 or 72 h), with no drug-free medium
      recovery. This exposure protocol was used in subsequent experiments, where COL
      and VBL were applied at concentrations which had no effect on the cell cycle
      ranging to producing marked mitotic block. To account for sex differences in
      chromosome X instability, lymphocyte cultures from both male and female donors
      were used to study X chromosome malsegregation. Chromosome 1 malsegregation,
      however, was analysed in female lymphocytes only. VBL induced reproducible,
      significant increases of micronuclei in cytokinesis-blocked cells at 5 ng/ml and
      over. In female lymphocytes, chromosome X loss was observed at 5 ng/ml whereas
      chromosome 1 loss was only observed at 10 ng/ml. In male lymphocytes, no
      significant chromosome loss was observed. On the other hand, non-disjunction of
      both chromosomes X and 1 was effectively induced in female lymphocytes even at
      1.25 ng/ml, the lowest dose tested. In male lymphocytes, non-disjunction of
      chromosome X was observed at 5 ng/ml. Treatments with COL produced a significant
      increase of micronucleated cells only at the highest dose tested (20 ng/ml). No
      significant increase in the incidence of either chromosome X or chromosome 1 loss
      was observed. With cell cultures from donors of both genders, a significant
      increase in non-disjunction of chromosome X was observed at 5 ng/ml. At the same
      dose, chromosome 1 non-disjunction significantly increased. These results suggest
      that in cytokinesis-blocked human lymphocytes, non-disjunction is the prevalent
      error in chromosome segregation induced by low dose exposure to spindle poisons.
      Interestingly, non-disjunction was effectively induced even at doses which did
      not produce detectable detrimental effects on the cell cycle.

PMID- 8671758
TI  - Molecular analysis of Salmonella hisG428 ochre revertants for rapid
      characterization of mutational specificity.
AB  - The Salmonella typhimurium tester strains TA104 and TA102 were developed
      primarily to aid in the detection of oxidative mutagens and other agents that
      react preferentially with AT base pairs. Reversion of prototrophy of strains
      harboring the hisG428 ochre allele can occur by (i) any of seven single base
      substitutions or (ii) several tandem double base substitutions at the ochre
      codon, (iii) in-frame deletions removing all or part of the ochre codon or (iv)
      mutations at several distinct tRNA extragenic suppressor loci. We have used
      allele-specific oligonucleotide probes and DNA sequence analysis to characterize
      625 revertants of strain TA104 (hisG428, rfa, DeltauvrB/pKM101) arising
      spontaneously or after treatment with methyl methane-sulfonate, glyoxal,
      streptonigrin or angelicin with UVA radiation. The reversion profiles obtained
      from these analyses distinguished readily each of the mutagen-treated populations
      from one another and from spontaneously derived revertants. Both GC and AT base
      pair-specific revertants were observed. Molecular analyses of S. typhimurium
      hisG428 revertants permitted rapid assessment of base pair substitution
      specificity of mutagens, especially the detection of AT base pair substitutions
      not recovered in strains carrying the complementary hisG46 allele.

PMID- 8671759
TI  - Detection of in vitro clastogens and spindle poisons by the mouse lymphoma assay
      using the microwell method: interim report of an international collaborative
      study.
AB  - Under the auspices of the Ministry of Health and Welfare of Japan and the
      Japanese Pharmaceutical Manufacturer Association, a collaborative study of the
      mouse lymphoma assay (MLA) was conducted by 42 Japanese laboratories and seven
      overseas laboratories to clarify the performance of the MLA for the detection of
      in vitro clastogens and spindle poisons. Twenty-one chemicals that were positive
      in in vitro chromosomal aberration assays (CA) but negative in bacterial reverse
      mutation assays (BRM) were examined by the MLA using the microwell method. All
      chemicals were coded, and each chemical was tested by two or three laboratories.
      Positive responses were obtained with 14 chemicals: mitomycin C (an internal
      positive control), arsenic trioxide, cadmium sulphate, chlorendic acid, cytosine
      arabinoside, diethylstilbestrol, eugenol, 5-fluorouracil, griseofulvin,
      hexamethyl phosphoramide, hydroxyurea, methotrexate, monocrotaline and
      pentachloroethane. Two chemicals (benzene and chlorodibromomethane) showed
      positive responses in one of two laboratories and were judged probably positive
      chemicals. Three chemicals (bromodichloromethane, isophorone and
      tetrachloroethane) were inconclusive because of a marginal response in one
      laboratory and a negative response in the other. Urethane was judged probably
      negative because two laboratories out of three showed clear negative responses.
      Dideoxycytidine (DDC) was a clear negative chemical in this study. The present
      results showed that 75.0% of the test chemicals (15/20, excluding mitomycin C)
      were positive, 15.0% (3/20) were inconclusive, and 10.0% (2/20) were negative.
      This suggests that the MLA may detect a majority of CA-positive chemicals. The
      inconclusive chemicals, however, are critical for the judgement of the MLA
      potential to detect clastogens. The findings that DDC was clearly negative
      suggests that the MLA may not be able to detect some clastogens. To clarify these
      issues, we began the second phase of the collaborative study with other BRM
      negative and CA-positive chemicals.

PMID- 8671760
TI  - Numerical and structural chromosome aberrations induced by etoposide (VP16)
      during oocyte maturation of mice: transmission to one-cell zygotes and damage to
      dictyate oocytes.
AB  - The antineoplastic drug etoposide (ET) inhibits topoisomerase II (topo II)
      activity by forming a ternary complex (DNA-ET-topo II). This complex prevents the
      DNA-strand-rejoining activity of topo II and may result in structural chromosome
      aberrations. Inhibition of topo II activity may also predispose cells to
      aneuploidy because this enzyme is needed for removing regions of DNA catenation
      prior to chromosome segregation. Our objectives were to study the dose response
      for ET-induced numerical and structural chromosomal aberrations in mouse one-cell
      zygotes, to compare these data with those obtained from a contemporary metaphase
      II (MII) oocyte study and to evaluate the sensitivity of dictyate oocytes to ET
      induced aneuploidy. ICR female mice were superovulated and injected i.p. with
      either 6% dimethylsulphoxide (controls) or 20, 40 or 60 mg/kg ET 2 h after human
      chorionic gonadotrophin (HCG). ICR males were paired (1:1) with females
      immediately after treatment. After 17 h the males were removed, and after 24 h
      the females with a vaginal plug were given colchicine. One-cell zygotes were
      harvested for cytogenetic analysis 17 h after colchicine. The percentages of
      hyperploid zygotes were 1.1, 5.7, 13.8 and 20.7 and of zygotes with structural
      aberrations were 2.5, 16.3, 37.7 and 64.7, for control, 20, 40 and 60 mg/kg ET
      respectively. The differences between each succeeding dose for both structural
      and numerical aberrations were statistically significant (P < 0.01). When the ET
      dose response aneuploidy data from zygotes were compared with similar data from a
      contemporary study involving metaphase II oocytes, the frequencies of hyperploidy
      were greater in zygotes than in oocytes. We conclude that when ET is administered
      during the preovulatory phase of meiosis, it is both an aneugen and a clastogen
      in mouse one-cell zygotes.

PMID- 8671761
TI  - Biomonitoring human exposure to environmental carcinogenic chemicals.
AB  - A coordinated study was carried out on the development, evaluation and
      application of biomonitoring procedures for populations exposed to environmental
      genotoxic pollutants. The procedures used involved both direct measurement of DNA
      or protein damage (adducts) and assessment of second biological effects (mutation
      and cytogenetic damage). Adduct detection at the level of DNA or protein
      (haemoglobin) was carried out by 32P-postlabelling, immunochemical, HPLC or mass
      spectrometric methods. Urinary excretion products resulting from DNA damage were
      also estimated (immunochemical assay, mass spectrometry). The measurement of
      adducts was focused on those from genotoxicants that result from petrochemical
      combustion or processing, e.g. low-molecular-weight alkylating agents, PAHs and
      compounds that cause oxidative DNA damage. Cytogenetic analysis of lymphocytes
      was undertaken (micronuclei, chromosome aberrations and sister chromatid
      exchanges) and mutation frequency was estimated at a number of loci including the
      hprt gene and genes involving in cancer development. Blood and urine samples from
      individuals exposed to urban pollution were collected. Populations exposed
      through occupational or medical sources to larger amounts of some of the
      genotoxic compounds present in the environmental samples were used as positive
      controls for the environmentally exposed population. Samples from rural areas
      were used as negative controls. The project has led to new, more sensitive and
      more selective approaches for detecting carcinogen-induced damage to DNA and
      proteins, and subsequent biological effects. These methods were validated with
      the occupational exposures, which showed evidence of DNA and/or protein and/or
      chromosome damage in workers in a coke oven plant, garage workers exposed to
      diesel exhaust and workers exposed to ethylene oxide in a sterilization plant.
      Dose reponse and adduct repair were studied for methylated adducts in patients
      treated with methylating cytostatic drugs. The biomonitoring methods have also
      demonstrated their potential for detecting environmental exposure to genotoxic
      compounds in nine groups of non-smoking individuals, 32P-postlabelling of DNA
      adducts being shown to have the greatest sensitivity.

PMID- 8671762
TI  - PCBs do not induce DNA breakage in vitro in human lymphocytes.
AB  - Polychlorinated biphenyls (PCBs) are classified by IARC as non-mutagenic in vivo.
      However, despite almost 20 years of research, their mutagenicity in vitro is
      still debatable. In this work the in vitro cytochalasin B micronucleus test and
      the alkaline comet assay applied to human lymphocytes were used to study the
      genotoxicity of a PCB. PCB77, at concentrations ranging from 0.01 to 100
      microg/ml, was used in whole blood or isolated lymphocyte cultures, with final
      dimethylsulfoxide percentages of 0.5-2%. In the micro-nucleus test lymphocytes
      were exposed for 48 h, and in the alkaline comet assay for 30 min, 1 h and 3 h.
      No increases of single strand breaks or micronucleus frequencies was found, in
      contrast to previously reported data. Our data indicate that PCB77 has no
      clastogenic properties in human lymphocytes.

PMID- 8671763
TI  - Non-random chromosomal involvement in radiation-induced translocations in mouse
      spermatogonial stem cells.
AB  - X-ray induced chromosomal translocations were studied in mouse spermatogonial
      stem cells by meiotic analysis at the spermatocyte stage many cell generations
      after induction. Using a composite DNA probe for mouse chromosomes 1, 11 and 13,
      in combination with fluorescence in situ hybridization, the involvement of these
      three chromosomes in translocation formation was recorded. The obtained results
      at various sampling times ranging from 75 to 320 days after irradiation show no
      significant differences in the participation pattern of the painted chromosomes
      in multivalent formation with increasing sampling time. Pooling of the data at
      the different dose levels of 5 and 7 Gy indicated significant overrepresentation
      of the specifically stained bivalents in translocation formation. This suggests
      that clonal proliferation cannot be held responsible for the observed non
      randomness. Experiments with the DNA-repair inhibitor 3-aminobenzamide showed no
      change in the recorded overrepresentation, indicating that it is probably not the
      repair of lesions that is causing this phenomenon but rather non-random
      induction.

PMID- 8671764
TI  - Cytogenetic effects of caffeine during in vivo mouse oocyte maturation.
AB  - Numerous investigators have studied the reproductive and genetic toxicity of
      caffeine. Caffeine has also been reported to retard meiotic progression and
      induce aneuploidy in hamster oocytes in vitro. However, the ability of caffeine
      to induce aneuploidy in mammalian oocytes in vivo has not been reported. The
      objective of this study was to test the hypothesis that chemical-induced
      perturbations during in vivo oocyte meiotic maturation (OM) predispose oocytes to
      chromosome missegregation. Caffeine inhibits cAMP phosphodiesterase, which is
      needed for dephosphorylating p34(cdc2) kinase and initiating OM. Following
      superovulation, a dose of 150 mg/kg caffeine was administered to Institute of
      Cancer Research (ICR) female mice at various times prior to metaphase I (MI).
      Ovulated oocytes were collected from the oviducts and processed for cytogenetic
      analysis. Statistical analyses of the frequencies of hyperploid, MI, diploid,
      premature centromere separation and single chromatids revealed nonsignificant (P
      > 0.05) differences between the controls and each of the caffeine groups.
      Structural chromosome aberrations were not found. Under our experimental
      conditions, we rejected the hypothesis and concluded that caffeine neither
      retarded the rate of OM nor increased the incidence of aneuploidy in mouse
      oocytes. The factors responsible for the different in vivo and in vitro responses
      require investigation.

PMID- 8671765
TI  - dCTP misincorporation in a Chinese hamster mutator phenotype: the role of GGA
      genetic context.
AB  - Clone CSA7 is a CHEF18 hamster cell line that shows an increased intracellular
      accumulation of dCTP. To localize the mutations that accumulate spontaneously in
      a functional gene of such a mutator phenotype, independent CSA7 mutants of the
      hypoxanthine-guanine phosphoribosyl transferase (hprt) gene were isolated and
      screened by a polymerase chain reaction-single strand conformation polymorphism
      technique. Sixty-two percent of mutants produced detectable changes of the strand
      migration profile and the mutations were preferentially localized in the exons 3
      (31%) and 6 (62%). The sequencing of such exons revealed that the rate of C base
      incorporation was the major mutation pathway and that the A base of a GGA
      sequence was the preferential site of misincorporation.

PMID- 8671767
TI  - The MINISCREEN assay.

PMID- 8671766
TI  - Analysis of the DNA content distribution of micronuclei using flow sorting and
      fluorescent in situ hybridization with a centromeric DNA probe.
AB  - The DNA content distributions of micronuclei induced in mouse 3T3 cells by
      ionizing radiation and chemicals was measured by flow cytometry. For a
      quantitative understanding of these distributions, micronuclei with increasing
      DNA contents were sorted and analysed for the presence of centromeric signals
      using fluorescent in situ hybridization (FISH) with a mouse centromeric gamma
      satellite probe. Radiation-induced micronuclei were found to be produced mainly
      by chromosome fragments, whereas micronuclei induced by the tear gas
      chlorobenzylidene malonitrile (CS) were found to be produced mainly by whole
      chromatids. In contrast, micronuclei induced by vinblastine (VBL) were, according
      to the shape of their DNA content distributions, produced mainly by whole
      chromosomes and by combinations of two or more whole chromosomes. With increasing
      DNA content, micronuclei induced by ionizing radiation also contained one or more
      whole chromosomes, whereas micronuclei induced by CS or VBL were found to contain
      several whole chromatids or chromosomes respectively. Computerized random
      breakage of chromosomes and random combination of chromosome fragments, whole
      chromatids and whole chromosomes were used according to the FISH results to
      simulate the measured DNA content distributions of micronuclei. A good agreement
      was obtained between measured and simulated distributions of micronuclei as well
      as between results of the measured frequency of micronuclei showing centromeric
      signals as a function of their DNA content and those predicted by the
      simulations. These results demonstrate the usefulness of flow cytometry and
      sorting combined with the FISH technique and computer simulations for producing a
      more detailed analysis of mechanisms of micronucleus induction.

PMID- 8671770
TI  - The need for standards and audit measures in the treatment of patients with renal
      failure.

PMID- 8671769
TI  - Systemic vascular adaptation to increases in blood volume: the role of the blood
      vessel wall.

PMID- 8671771
TI  - Points to remember when dialysing the patient with coronary disease.

PMID- 8671772
TI  - The use of organs from executed prisoners in China.

PMID- 8671773
TI  - Special feature: what is a normal blood pressure in ambulatory monitoring?

PMID- 8671774
TI  - How to diagnose and correct iron deficiency during r-huEPO therapy--a consensus
      report.

PMID- 8671775
TI  - Perspectives in endothelin research: tubulointerstitial actions of endothelins in
      the kidney: roles in health and disease.

PMID- 8671777
TI  - Transforming growth factor beta mediates the angiotensin-II-induced stimulation
      of collagen type IV synthesis in cultured murine proximal tubular cells.
AB  - BACKGROUND: Angiotensin II (Ang II) stimulates synthesis of type IV collagen in a
      cultured murine proximal tubular cell line (MCT cells). In addition, Ang II also
      induces the expression of TGF-beta1 in these cells. Since TGF-beta has well-known
      stimulatory effects on the transcription of various collagens, we tested whether
      the Ang-II-mediated stimulation of type IV collagen is due to induction of
      endogenous TGF-beta1 synthesis in MCT cells. RESULTS: A neutralizing monoclonal
      anti-TGF-beta1-3 antibody abolished the Ang II-stimulated release of type IV
      collagen in culture supernatants. The anti-TGF-beta1-3 antibody also partly
      blocked Ang-II-mediated incorporation of 3[H]proline into de novo synthesized
      collagens. Moreover, 5 microM TGF-beta1 antisense oligonucleotides, but not the
      same concentration of sense oligonucleotides, completely blocked Ang-II
      stimulated 3[H]proline incorporation. MCT cells incubated with TGF-beta1
      antisense phosphorothioate-modified oligonucleotides failed to synthesize TGF
      beta1 protein after Ang II treatment as measured by a sandwich ELISA in culture
      supernatants. SDS-polyacrylamide electrophoresis of 3[H]proline-labelled
      collagens and comparison with standard collagens also demonstrated that the
      neutralizing anti-TGF-1-3 antibody abolished the Ang-II-mediated stimulation in
      type IV collagen. Semiquantitative cDNA amplification for collagen type alpha1
      (IV) transcripts revealed that the anti-TGF-beta1-3 antibody abrogates the
      increase in mRNA after Ang II treatment. Transient transfection studies in MCT
      cells using murine collagen alpha1 (IV) enhancer/promoter constructs also
      demonstrated the suppressive effect of the neutralizing antibody on Ang-II
      stimulated gene transcription. CONCLUSIONS: Our data collectively suggest that
      the Ang-II-mediated increase in type IV collagen in MCT cells is mediated by
      endogenous synthesis and autocrine action of TGF-beta1. These findings may be
      important in changes of the tubulointerstitial architecture during the
      progression of renal disease.

PMID- 8671778
TI  - Chronic effects of endothelin-3 on blood pressure and renal haemodynamics in
      rats.
AB  - BACKGROUND: Renal vasoconstriction and systemic hypertension are well-known
      effects of bolus or short-term endothelin administration. However, the role of
      endothelin as a circulating hormone remains largely unknown. METHODS: The present
      study explores the effects of endothelin-3 (ET-3) on renal haemodynamics and
      systemic blood pressure during a 3-h and a 3-day intravenous infusion in rats.
      Male Sprague-Dawley (SD) rats were infused with vehicle (group 1) or ET-3 (group
      2), 10 ng/kg per min; group 3, 50 ng/kg per min) delivered via osmotic minipumps
      into the right jugular vein for 3 days. On day 3 after pump implantation, rats
      were anaesthetized with Inactin and surgically prepared for assessment of mean
      arterial blood pressure (MABP), renal plasma flow (RPF), glomerular filtration
      rate (GFR), and renal vascular resistance (RVR). The same parameters were
      assessed during a 3-h ET-3 infusion study in SD rats (group 4, vehicle; group 5,
      ET-3, 10 ng/kg per min; group 6, ET-3, 50 ng/kg per min). RESULTS: In 3-day
      infused rats, ET-3 induced a significant decrease in RPF (-22+/-7% and -26+/-8%
      for group 2 and group 3 respectively, P<0.05 vs group 1) and an increase in RVR
      (+40+/-11% for groups 2 and 3; P<0.05 vs group 1); 50 ng/kg per min ET-3
      significantly decreased GFR (-17%, P<0.05 vs group 1). MABP was not significantly
      affected by endothelin infusion. In acute infusion studies a decrease of the same
      magnitude was seen for the renal haemodynamics values. 50 ng/kg per min ET-3
      increased MABP; a systemic effect that disappeared after the 3-day infusion.
      CONCLUSIONS: This study suggests that intravenously administered ET-3 in the rat
      has only a transient effect on systemic blood pressure, whereas it induces
      alterations in renal haemodynamics after both acute and chronic perfusions.

PMID- 8671779
TI  - Micropuncture and clearance measurements of segmental reabsorption by the rat
      nephron.
AB  - BACKGROUND: We wanted to verify whether the calculations of segmental tubular
      reabsorption obtained during water diuresis were supported by direct
      micropuncture measurements. METHODS: Experiments were performed on 18 rats during
      baseline water diuresis (B) and after the administration of frusemide (F), 10
      mg/kg, by whole-kidney clearance measurements and micropuncture collections from
      early distal (ED) and last proximal (LP) tubular segments. RESULTS: GFR was 957+/
      79 in B, 1053+/-77 microl/min in F, P>0.013. SNGFR was 38+/-1 in 166 and 38+/-1
      nl/min in 165 tubules respectively, P>0.77. In LP collections the percentage
      reabsorption was 71+/-2 in B and 76+/-2% during F (P>0.07) in 99 and 95 samples
      respectively. The absolute proximal reabsorption was not changed by F (27.6+/-1.5
      versus 27.7+/-1.3 nl/min, P>0.96) The data were superimposable when the analysis
      was restricted to paired data. The difference between ED and LP resorption was
      17+/-3 during B and fell significantly (P<0.008) to 5+/-3% during F, measured by
      clearance techniques, and the percentage of GFR excreted during F, measured by
      clearance techniques, and the percentage delivery of filtrate beyond the proximal
      tubule, measured independently by micropuncture, were not different (27+/-2
      versus 24+/-2%, P>0.10), while they were significantly correlated (P<0.04). The
      calculations of segmental Na reabsorption along the different nephron segments by
      clearance techniques were not significantly different from and were significantly
      correlated with the reabsorptions measured directly by micropuncture.
      CONCLUSIONS: The present experiments validate the calculations of reabsorption by
      techniques applicable to human studies of clinical physiology.

PMID- 8671780
TI  - Urinary excretion of platelet-activating factor in human and experimental
      nephrosis.
AB  - BACKGROUND: Platelet-activating factor (PAF) is a phospholipid that has been
      implicated in the pathogenesis of glomerulonephritis and can be synthesized by
      glomerular cells in response to different stimuli. PAF increases glomerular
      permeability to proteins and urinary PAF has been determined to be of renal
      origin. In order to assess whether urinary PAF can be found augmented in
      situations of glomerular damage without glomerular leukocyte infiltration,
      urinary PAF was quantified in human and experimental nephrosis. METHODS: Urinary
      PAF was quantified by platelet bioassay and glomerular PAF by incorporation of 3H
      acetate into PAF. PAF was characterized by its behaviour on thin-layer
      chromatography and high performance liquid chromatography and the blockade of its
      bioactivity by receptor antagonists. RESULTS: Urinary PAF excretion was
      significantly higher in patients with active idiopathic nephrotic syndrome than
      in controls (5.8+/-1.5 versus 1.7+/-0.75 mg/24 h; P<0.05) and patients in
      remission (1.63+/-0.75 ng/24 h; P<0.02). In rats with nephrosis induced by
      puromycin aminonucleoside there was an early increase in urinary PAF excretion
      (138+/-19 versus 49+/-22 pg/24 h in controls; P<0.035) that coincided with the
      augmented glomerular PAF synthesis (67+/-3.4 versus 36+/-1.2 DPM/mg protein in
      controls; P<0.003). CONCLUSIONS: These results suggest that the synthesis of PAF
      in the kidney may be involved in the pathogenesis of the proteinuria in
      idiopathic nephrotic syndrome and that urinary PAF excretion may be a good marker
      of disease activity.

PMID- 8671781
TI  - Increased mononuclear cell membrane fluidity and increased B lymphocyte HLA class
      I expression in IgA nephropathy.
AB  - BACKGROUND: The functions of membrane bound proteins are regulated by the
      physical properties of the cell membrane. Lymphocyte dysfunction in IgA
      nephropathy may therefore be related to abnormal cell membrane fluidity. In this
      study we have examined peripheral blood mononuclear cell membrane fluidity and
      the expression of HLA antigens on the surface of lymphocytes in IgA nephropathy
      subjects compared to normal controls and disease controls. METHODS: Twenty-two
      IgA nephropathy subjects with normal or mildly elevated serum creatinine (serum
      creatinine RESULTS: Fluorescence anisotropy for diphenylhexatriene of mononuclear
      cells from IgA nephropathy subjects was significantly lower compared to
      mononuclear cells from normal control subjects and disease control subjects,
      indicating higher membrane fluidity (median values, IgA nephropathy 0.161; normal
      control 0.175; disease control 0.175; P<0.001 and P<0.001). Fluorescence
      anisotropy for trimethylammonium-DPH was lower in the IgA nephropathy groups
      compared to the normal control group (median values, IgA nephropathy 0.268;
      normal control 0.274; P<0.001), but not significantly different compared to the
      disease control group (0.272). HLA class I expression on the surface of B
      lymphocytes was significantly higher in the IgA nephropathy group compared to the
      normal control and disease control groups (median values, IgA nephropathy 30364,
      normal control 15495; disease control 16907; P=0.0001 and P=0.002 respectively).
      CONCLUSION: This study provides evidence of abnormal cell membrane architecture
      and increased HLA class I expression in Iga nephropathy.

PMID- 8671783
TI  - Survival on renal replacement therapy in Europe: is there a 'centre effect'?
AB  - OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy
      (RRT) and may be used to compare performance among centres. Such comparison,
      however, is meaningless if the influences of comorbidity, age and early deaths
      are not considered. We therefore studied survival rates on RRT in seven centres
      in Europe after taking into account the influence of age, early deaths, primary
      renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was
      carried out on 1407 patients who commenced RRT in seven centres across five
      European countries during a 7-year period. Patients were stratified into low-,
      medium- and high-risk groups based mainly on comorbidity and to a lesser extent
      on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional
      hazards model were used to compare survival. RESULTS: Before risk stratification
      overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3
      89.9%) after excluding early deaths) masking a range of survivals of 27.4% for
      the high-risk group with the worst survival to 100% in the low-risk group with
      the best survival. After excluding early deaths 2-year survival in the low risk
      groups (n=622) was greater than 90% in all centres. Multivariate analysis showed
      that the mortality risk increased four fold from low- to medium- and a further
      1.6-fold from medium- to high-risk group. However, despite this adjustment for
      comorbidity and age there still remained a significant difference in survival
      among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION:
      Risk stratification diminishes the variance in survival between centres but a
      centre effect remains despite adjusting for age and comorbidity. Multicentre
      prospective studies are urgently required to identify the reasons for this
      apparent centre effect.

PMID- 8671784
TI  - When to treat dyslipidaemia of patients with chronic renal failure on
      haemodialysis? A need to define specific guidelines.
AB  - BACKGROUND: There are no specific recommendations for management of dyslipidaemia
      in patients with chronic renal failure (CRF) on haemodialysis, in which
      atherosclerosis is a common cause of morbidity and mortality. The aim of the
      present study was to analyse different approaches based on low-density
      lipoprotein (LDL) cholesterol (measured and calculated with a formula), non-high
      density lipoprotein (HDL) cholesterol, and HDL cholesterol levels in the clinical
      management of dyslipidaemia in haemodialysis patients. METHODS: Calculated LDL
      cholesterol by the Friedewald formula was compared with measured LDL cholesterol
      after separation by ultracentrifugation in 101 male patients with CRF on
      haemodialysis and in 101 healthy control subjects. RESULTS: Calculated LDL
      cholesterol coincided with measured LDL cholesterol, with less than 10% error, in
      54 patients (53.4%) and in 75 controls (74.2%). Calculated LDL cholesterol was
      overestimated, with an error of 10% or more with respect to measured LDL
      cholesterol, in 37.6% of patients and in 23.7% of controls, and underestimated in
      8.9% and 1. 9% respectively. Despite a good correlation between calculated and
      measured LDL cholesterol, the intraclass correlation coefficients demonstrate a
      poor concordance between calculated and measured LDL cholesterol, both in
      patients and controls. Only 17 patients were at non-HDL cholesterol level risk
      defined as higher than 4.28 mmol/l. HDL cholesterol levels lower than 0.9 mmol/l
      were found in 70% of patients and in 23% of controls. CONCLUSIONS: LDL or non-HDL
      cholesterol levels may not be appropriate for management of lipoprotein
      abnormalities in CRF patients. Further studies must clarify whether HDL
      cholesterol may be the best lipoprotein parameter for evaluating cardiovascular
      risk in these patients.

PMID- 8671785
TI  - IgM antibody response to hepatitis C virus in end-stage renal disease.
AB  - BACKGROUND: In HBV infection, as in other viral diseases, antibodies of the IgM
      class are associated with acute or ongoing infection. In contrast, the
      significance of this antibody in HCV infection is unclear and data regarding end
      stage renal disease (ESRD) patients are lacking. METHODS: We tested sera from 78
      ESRD patients (66 chronic dialysis patients, 12 renal allograft recipients)
      showing anti-HCV IgG antibody, for serum anti-HCV IgM core antibody. A specific
      solid-phase enzyme-linked immunoassay (HCV IgM EIA, Abbot) was used. In all
      patients serum HCV RNA was detected by RT-PCR technique, with primers from the 5'
      untranslated region of the viral genome. RESULTS: Prevalence of anti-HCV IgM core
      antibody was 22% (17/78). We observed association between prevalence of anti-HCV
      IgM core antibody and frequency of HCV RNA in the serum. Thus 15 of 45 (33%) sera
      containing HCV RNA also contained anti-HCV IgM, while two of 33 (6%) HCV RNA
      negative sera showed anti-HCV IgM core antibody (P = 0.01). There was a
      significant relationship between absorbance values of anti-HCV IgM core antibody
      and NS3 (P = 0.01), NS5 (P = 0.04), and core (P = 0.0001) reactivity in RIBA-2
      and RIBA-3 assays. Optical density values of anti-HCV IgM were significantly
      associated with the number of reactive bands in RIBA-2 (P = 0.04) and RIBA-3 (P =
      0.03) assays. CONCLUSIONS: 22% of ESRD patients with anti-HCV IgG activity showed
      anti-HCV IgM core antibody in the serum. Anti-HCV IgM activity seems to correlate
      positively with HCV viraemia in ESRD population. Testing for this antibody may be
      useful as a serological marker to indicate the presence of ongoing HCV infection.

PMID- 8671786
TI  - Economic appraisal of maintenance parenteral iron administration in treatment of
      anaemia in chronic haemodialysis patients.
AB  - BACKGROUND: Iron deficiency is common in haemodialysis patients and adequate
      supplementation by the oral or parenteral route has been limited by drug side
      effects, absorption, and cost. Intermittent doses of intravenous iron dextran
      complex are recommended in patients with inadequate iron stores despite maximal
      tolerated oral dose. We conducted a prospective study with economic analysis of a
      regular maintenance intravenous iron regimen in this group of patients. METHODS:
      Fifty patients comprising one-half of our haemodialysis population required
      intravenous iron treatment, i.e. they failed to achieve an arbitrary goal serum
      ferritin 100 microg/l despite maximal tolerated oral iron dose. After a loading
      dose of intravenous iron dextran complex (IV-FeD) based on Van Wyck's nomogram
      (400+/-300 mg) they received a maintenance dose of 100mg IV-FeD once every 2
      weeks. Initial goal serum ferritin was set at 100-200 microg/l. If no increase in
      haemoglobin was achieved at this level, transferrin saturation was measured to
      assess bioavailable iron, and when less than 20%, goal serum ferritin was
      increased to 200-300 microg/l. Recombinant human erythropoietin (rHuEpo) was used
      where needed to maintain haemoglobin in the 9.5-10.5 g/l range only if ferritin
      requirements were met. Results. Mean haemoglobin rose from 87.7+/-12.1 to 100.3+/
      13.1 g/l (P<0.001, Cl 7.7-17.9) at mean follow-up of 6 months (range 3-15
      months). In patients on rHuEpo, dose per patient was reduced from 96+/-59 u/kg
      per week to 63+/-41 u/kg per week, representing a 35% dose reduction (P<0.05, Cl
      1-65). An annual cost reduction of $3166 CDN was projected; however, in the first
      year this is offset by the cost of the loading dose of IV-FeD required at the
      beginning of treatment. No adverse reactions were encountered. CONCLUSION: Iron
      deficiency is very common in our haemodialysis population, especially in those
      patients receiving rHuEpo. A carefully monitored regimen of maintenance
      parenteral iron is a safe, effective, and economically favourable means of iron
      supplementation in patients with insufficient iron stores on maximum tolerated
      oral supplements.

PMID- 8671787
TI  - Vascular reactivity during combined ultrafiltration-haemodialysis: influence of
      dialysate sodium.
AB  - BACKGROUND: It is well known that vascular reactivity is impaired during combined
      ultrafiltration-haemodialysis as compared to isolated ultrafiltration and
      haemofiltration, which might be related to differences in plasma osmolality.
      Therefore vascular reactivity was studied during combined ultrafiltration
      haemodialysis in relation to sodium-related differences in plasma
      osmolality/tonicity. METHODS: With each patient serving as his or her own
      control, nine stable dialysis patients (23-71 years) were studied during 2 h of
      combined ultrafiltration-haemodialysis (bicarbonate; UF rate 1.0 l/h)) at two
      different dialysate sodium concentrations: 134 and 144 mmol/l. Before dialysis as
      well as every 20 min during dialysis, blood pressure (Dinamap), heart rate (ECG),
      and forearm vascular resistance and venous tone (strain-gauge plethysmography)
      were measured. Relative blood volume was monitored continuously by an optical
      reflection method (Haemoguard 2000), while before and after dialysis blood was
      obtained for the estimation of plasma prostaglandin E2. RESULTS: High-sodium
      dialysis resulted in a significantly higher post-dialysis plasma sodium
      concentration (139. 9 vs 135.0 mmol/l; P<0.01) while the decrease in relative
      blood volume was significantly smaller as compared to low-sodium dialysis (-8.4
      vs -18.4%; P<0.01). There were no significant differences in the different
      haemodynamic parameters between the two treatment modalities. Both high- and low
      sodium dialysis were associated with a significant increase in forearm vascular
      resistance while venous tone remained unchanged. Although there was no
      significant difference in plasma PGE2 between the two treatment modalities, PGE2
      increased significantly only during low-sodium dialysis. We found no relationship
      between changes in PGE2 and vascular reactivity. CONCLUSIONS: We conclude that
      vascular reactivity during combined ultrafiltration-haemodialysis is not directly
      influenced by sodium-related changes in plasma tonicity. Although not directly
      studied, the reported improved haemodynamic stability with high-sodium dialysis
      is probably only mediated through a better preservation of plasma volume.
      Finally, an increase in plasma PGE2 as observed during low-sodium dialysis does
      not lead to a decrease in vascular tone.

PMID- 8671788
TI  - Removal of high-molecular-weight solutes during high-efficiency and high-flux
      haemodialysis.
AB  - BACKGROUND: Although urea clearance is often increased during high-efficiency and
      high-flux haemodialysis to compensate for short treatment times, the impact of
      these treatment modalities on the removal of larger uraemic toxins has not been
      thoroughly investigated. METHODS: We compared solute removal rates for five
      haemodialysis treatment strategies in vitro using neutral dextrans (molecular
      radii between 15 and 50 A) as marker macromolecules. Removal rates were assessed
      by the decrease in dextran concentration within the reservoir of a model circuit
      using outdated human plasma as the test solution. Results for high-efficiency
      haemodialysis (CA110 dialyser at a blood flow rate of 400 ml/min and TAF175
      dialyser at a blood flow rate of 300 ml/min) and high-flux haemodialysis (CT190G
      dialyser at a blood flow rate of 300 ml/min and F60 dialyser at a blood flow rate
      of 300 ml/min) were compared with those for conventional haemodialysis (CA110
      dialyser at a blood flow rate of 200 ml/min). RESULTS: Dextran clearances were
      dependent on the dialyser employed, and they decreased with molecular size and
      time for each treatment strategy. Removal rates were greatest using the CT190G
      and F60 dialysers, intermediate for the TAF175 dialyser, and lowest for the CA110
      dialyser at either blood flow rate. CONCLUSION: The results of this study
      demonstrate that increasing blood flow rates alone to increase urea clearance may
      not provide adequate removal of high-molecular-weight solutes. The use of high
      flux or large surface area, high-efficiency dialysers are more effective in
      maintaining the removal of high-molecular-weight solutes when treatment time is
      shortened.

PMID- 8671789
TI  - Frequent involvement of the internal cuff segment in CAPD peritonitis and exit
      site infection - an ultrasound study.
AB  - BACKGROUND: The extent of involvement of the subcutaneous Tenckhoff catheter
      tract in CAPD peritonitis and catheter-related infections is of major therapeutic
      importance. By definition, both peritonitis and exit-site infections do not
      involve the catheter tract. However, diagnosis of these infections as well as the
      more sinister tunnel infection is based mainly on clinical signs. METHODS: We
      examined the usefulness of ultrasound examination (US) of the catheter tract in
      delineating catheter-related (exit-site and tunnel) infections, and their
      relationship to each other and to peritonitis. CAPD patients with no evidence of
      peritonitis or catheter-related infections for 6 months prior to examination
      served as controls. US were performed by one of two experienced radiologists
      using the Acuson 128XP/10 scanner with a 7-MHz linear transducer. A positive US
      was defined as an area of hypoechogenicity (indicative of fluid collection) >2 mm
      in width along any portion of the catheter tract. Findings were localized into
      segments(S) as follows: S1, limited to external cuff; S2, intercuff segment
      adjacent to the external cuff; S3, intercuff segment adjacent to the internal
      cuff; S4, limited to the internal cuff; and S5, involvement extending throughout
      the catheter tract. RESULTS: Between March 1993 and January 1995, 39 CAPD
      patients, all with a double-cuff straight Tenckhoff catheter with the exit site
      situated above the point of entry into the peritoneum were studied. A total of 56
      US were performed divided among 26 episodes of peritonitis, four tunnel
      infections, 13 exit-site infections,and 13 controls. There were 30 positive US
      distributed among 16 peritonitis, four tunnel, eight exit site infections and two
      control patients. The two positive controls went on to develop peritonitis within
      1 month of the US. The majority of the US findings (13/16 in episodes of
      peritonitis and 5/8 exit site infections were localized to segment 4, that is, to
      the internal cuff region. Apart from a significant increase in width in all
      infected segments versus a normal tunnel, no differences in size were seen
      between peritonitis, exit-site, or tunnel infections, nor were there any
      differences in size and localization in these infections when comparing the
      offending organism (Gram-positive, negative, or culture negative). CONCLUSIONS:
      We conclude that peritonitis and exit-site infections are frequently accompanied
      by involvement of the catheter tract. The localization of infection to the
      internal cuff region in cases of exit-site infection probably occurred as a
      result of downward migration along the catheter tract. This supports the notion
      that ideally the exit site should be pointing caudally or that the peritoneal
      catheter have a swan-neck configuration. With regard to peritonitis, infection
      within the peritoneal cavity appears to extend and involve the internal cuff
      region. Thus both the internal and external cuffs do not seem to pose an
      effective barrier against the spread of infection.. Based on our data, we
      recommend that US be performed as a routine investigation in all cases of exit
      site infection and in cases of refractory or relapsing peritonitis.

PMID- 8671790
TI  - Effects of the prostacyclin analogue iloprost on cyclosporin-induced renal
      hypoperfusion in stable renal transplant recipients.
AB  - BACKGROUND: The synthetic prostacyclin analogues have been proposed to protect
      against cyclosporin A (CsA) nephrotoxicity. The present study investigated the
      effect of infusion of the prostacyclin analogue iloprost on the acute CsA-induced
      renal hypoperfusion and hypofiltration in stable renal-transplant recipients.
      METHODS: The study included 10 stable renal-transplant recipients with good graft
      function (s-creatinine 90-170 micromol/l). Renal function and the acute renal
      haemodynamic and tubular response to an oral CsA-dose (Sandimmun Neoral, 3 mg.kg
      1) were investigated with an infusion of iloprost (1 ng.kg-1.min-1) or placebo on
      2 separate days. After an overnight fast, seven 30-min renal clearance periods
      were performed, two before infusion, three during infusion, and two recovery
      periods. An additional control clearance study without CsA intake or
      iloprost/placebo infusion was done in eight of the patients. RESULTS: CsA
      ingestion decreased ERPF and GFR significantly with a maximum decline at the end
      of the clearance study. Iloprost infusion abolished the CsA-induced decrease in
      ERPF, but had no effect on the CsA-induced decrease in GFR, leading to a
      significant decline in FF. Renal clearance of lithium (CLi)), used as an index of
      proximal tulbular outflow, decreased in parallel with GFR after CsA intake, with
      no additional effects of iloprost. Iloprost infusion decreased blood pressure and
      increased heart rate. CONCLUSION: Infusion of iloprost causes systemic and renal
      vasodilation, but has no effect on the CsA-induced decrease in GFR and CLi in
      stable renal transplant recipients.

PMID- 8671791
TI  - Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal
      allograft recipients.
AB  - Atherosclerosis and thrombosis, two major causes of morbidity and mortality in
      renal transplant recipients, share the same clinical risk factors including
      decreased fibrinolysis and lipid disturbances. In a cross-sectional study we have
      determined parameters of fibrinolysis in control subjects (n = 23) and stable
      renal allograft recipients without cyclosporin (CsA) (n = 10) and with CsA (n =
      87) in their immunosuppressive treatment. In CsA-treated patients, tissue-type
      plasminogen activator was moderately increased compared to patients without CsA
      (8.4+/-3.3 vs 5.5+/-2.8 ng/ml). The plasminogen activator inhibitor (PAI)
      activity in plasma was clearly increased in CsA-treated patients: 14.5+/-8.8 vs
      7.2+/-3.2 in normal controls and 8.5+/-2.4 AU/ml in patients without CsA. Total
      cholesterol and LDL cholesterol levels were higher in CsA-treated patients (256+/
      62 and 169+/-60 mg/dl) than in patients without CsA (209+/-45 and 136+/-44
      mg/dl). The two groups did not differ in HDL cholesterol, triglycerides, and
      lipoprotein(a). Hypercholesterolaemia, obesity, and steroid-induced diabetes
      could be identified as risk factors for elevated plasma PAI activity in CsA
      treated patients. Hypofibrinolysis induced by elevated PAI levels and increased
      LDL cholesterol may contribute to the increased thrombogenicity and accelerated
      atherosclerosis observed in cyclosporin-treated patients.

PMID- 8671792
TI  - Angiofollicular lymph node hyperplasia, accelerated hypertension, and acute renal
      failure: a case report.

PMID- 8671793
TI  - Steroid-sensitive nephrotic syndrome and renal impairment in a patient with
      sarcoidosis and IgA nephropathy.

PMID- 8671794
TI  - Phenytoin-associated vasculitis and ANCA positivity: a case report.

PMID- 8671795
TI  - Renal vasculitis in antiglomerular basement antibody-positive Goodpasture
      disease.

PMID- 8671796
TI  - Membranous nephritis in a patient with scleroderma: a case report.

PMID- 8671798
TI  - Delayed bowel erosion due to functioning chronic ambulatory peritoneal dialysis
      catheter.

PMID- 8671797
TI  - Treatment of post-traumatic chyluria with subcutaneous octreotide administration.

PMID- 8671801
TI  - A young adult with so-called infantile cystic kidney disease.

PMID- 8671799
TI  - Progressive renal failure after cisplatin therapy.

PMID- 8671802
TI  - Crystalluria: a neglected aspect of urinary sediment analysis.
AB  - Crystalluria is a frequent finding in the routine examination of urine sediments.
      In most instances the precipitation of crystals of calcium oxalate, uric acid
      triple phosphate, calcium phosphate and amorphous phosphates or urates is caused
      by transient supersaturation of the urine, ingestion of foods, or by changes of
      urine temperature and/or pH which occur upon standing after micturition. In a
      minority of cases, however, crystalluria is associated with pathological
      conditions such as urolithiasis, acute uric acid nephropathy, ethylene glycol
      poisoning, hypereosinophilic syndrome. In addition, crystalluria can be due to
      drugs such as sulphadiazine, acyclovir, triamterene, piridoxylate, primidone,
      which under the influence of various factors can crystallize within the tubular
      lumina and cause renal damage. In all these instances the study of crystalluria
      is diagnostically useful and is also important to follow the course of the
      disease. However, a proper methodological approach is necessary. This includes
      the handling of freshly voided urine, the knowledge of the urinary pH, and the
      use of a contrast phase microscope equipped with polarizing filters.

PMID- 8671803
TI  - Loop diuretics and thiazides--the case for their combination in chronic renal
      failure.

PMID- 8671804
TI  - Genetic pattern in diabetic nephropathy.

PMID- 8671805
TI  - Bence Jones proteinuria and myeloma kidney.

PMID- 8671806
TI  - Non-invasive circulating indicators of bone metabolism in uraemic patients: can
      they replace bone biopsy?

PMID- 8671807
TI  - Left ventricular hypertrophy in the dialysed patient. What can be done about it?

PMID- 8671808
TI  - Treatment of hyperparathyroidism--why is it crucial to control serum phosphate?

PMID- 8671809
TI  - Acute renal failure in the intensive care unit: adequacy of dialysis and the case
      for continuous therapies.

PMID- 8671811
TI  - Incubation of porcine high-density lipoprotein with the apical surface of LLC-PK1
      renal tubular cells sustains the properties of orientated monolayers.
AB  - BACKGROUND: HDL is present in the urine of patients with the nephrotic syndrome.
      The amount of HDL is directly related to the protein selectivity and therefore to
      the renal prognosis. Urinary HDL may therefore be involved in the pathogenesis of
      progressive renal impairment in proteinuric renal disease. METHODS: LLC-PK1 cells
      were grown as orientated monolayers on filters. Uptake of HDL and permeability to
      inulin were measured. The influence of HDL in the growth medium on monolayer
      resistance, protein content, and sodium dependent glucose transport was studied.
      The effects of tetranitromethane (TNM) nitrosylation of HDL and of albumin,
      mevalonate, or simvastatin were investigated. RESULTS: Confluent LLC-PK1
      monolayers took up fluorescently labelled HDL from either epithelial surface and
      formed a significant diffusion barrier to inulin. Monolayers incubated in 300
      micrograms/ml HDL achieved a protein content and plateau of resistance equal to
      those in 10% fetal calf serum (FCS); 30-1000 micrograms/ml HDL applied to the
      apical surface of confluent monolayers maintained a plateau of resistance as well
      as 10% FCS and significantly better than serum-free medium. Sodium-dependent
      glucose transport was preserved in monolayers exposed to HDL. Simvastatin
      completely, and nitrosylation partially, removed the stimulatory properties of
      HDL. These were partly reproduced by albumin or mevalonate. CONCLUSIONS: HDL can
      enter renal epithelial cells from the apical surface. HDL added to this surface
      at confluence, reproducing the conditions found in the nephrotic syndrome, had a
      measurable positive effect on monolayer resistance. Results with nitrosylated HDL
      and HMG-CoA blockade suggest that these effects may be mediated via receptors and
      this enzyme system.

PMID- 8671812
TI  - C-antineutrophil cytoplasmic antibody positivity in vasculitis patients is
      associated with the Z allele of alpha-1-antitrypsin, and P-antineutrophil
      cytoplasmic antibody positivity with the S allele.
AB  - BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) in vasculitis have
      either cANCA or pANCA patterns as defined by immunofluorescence. The target
      autoantigen of cANCA is usually proteinase 3 (PR3), whereas that of pANCA is
      usually myeloperoxidase (MPO). Alpha-1-antitrypsin (alpha 1AT) is the major
      physiological inhibitor of PR3, while MPO is an inhibitor of alpha 1AT. METHODS:
      To determine whether there was an association between ANCA positive vasculitis,
      ANCA pattern, and alpha 1AT deficiency alleles, we studied alpha 1AT phenotypes
      of 99 cANCA and 99 pANCA positive vasculitis patients by isoelectric focusing and
      immunoblotting, and compared them with 2310 controls from the same geographical
      area. RESULTS: C-ANCA patients showed an increased frequency of the Z allele
      (0.055 versus 0.018 in controls), conferring a relative risk of 3. They showed no
      increase in frequency of the S allele. P-ANCA patients showed an increased
      frequency of the S allele (0.091 versus 0.046 in controls) conferring a relative
      risk of 2. The frequency of the Z allele also appeared to be increased (0.030
      versus 0.018 in controls), but this was not statistically significant.
      CONCLUSIONS: These findings demonstrate an association between ANCA-positive
      vasculitis and deficiency phenotypes of alpha 1AT, and suggest a role for alpha
      1AT in the development of systemic vasculitis.

PMID- 8671813
TI  - Dose effect of nitrendipine on urinary enzymes and microproteins following non
      ionic radiocontrast administration.
AB  - BACKGROUND: Although calcium-channel antagonists have been proposed as
      prophylaxis to prevent radiocontrast-induced nephropathy, the dose and dose
      interval to achieve a protective effect have not been quantified in humans.
      METHODS: In a randomized, double-blind protocol we studied urinary enzyme and
      microprotein excretion in 121 outpatients (mean age 65.3 +/- 9.3 years, 62% male)
      with normal renal function who were to undergo digital subtraction arteriography
      with iohexol or iopentol. The subjects were treated with a single dose of placebo
      (group 1) or nitrendipine 10 mg (group 2) or 20 mg (group 3) p.o. 1 h before the
      procedure. Blood and urine samples were collected 1 h before, 1 h after, and 24 h
      after contrast administration. Study variables included contrast volume and serum
      creatinine, and urinary creatinine, osmolality, albumin, alanylamino-peptidase
      (AAP, a brush border enzyme), N-acetyl-beta-glucosaminidase (NAG, a lysosomal
      enzyme), and alpha-1-microglobulin (alpha-1-micro, a filtered microprotein).
      RESULTS: Serum values of creatinine remained unchanged during the study period.
      Albuminuria was not affected by contrast administration, whereas AAP, NAG, and
      alpha-1-micro increased significantly, all except AAP returning to baseline at 24
      h. Pretreatment with nitrendipine did not reduce enzyme excretion, although AAP
      levels were lower in general in the group assigned to the 20-mg dose. Acute renal
      failure, defined as a 50% increase of serum creatinine 24 h after radiocontrast
      administration, was found in eight patients: four from group 1 (8.3%), three from
      group 2 (6.5%), and one from group 3 (3.7%). CONCLUSIONS: Neither the course of
      enzyme excretion nor the incidence of acute renal failure following radiocontrast
      administration were affected by single doses of calcium antagonists. AAP levels
      were lower in general in subjects taking the 20-mg dose of nitrendipine. This
      study also indicates that a single low or normal dose of nitrendipine per os is
      not effective prophylaxis before radiocontrast administration. The designs of
      future studies investigating the "nephroprotective' effect of calcium-channel
      antagonists per os should incorporate (1) the use of repeated doses to saturate
      hepatic metabolic pathways, and (2) the control of confounding variables in the
      measurement of urinary enzymes.

PMID- 8671814
TI  - Urinary albumin excretion rate and its determinants after 6 years in non-insulin
      dependent diabetic patients.
AB  - BACKGROUND: The present study was undertaken to clarify the progression of
      urinary albumin excretion rate (UAER) in non-insulin-dependent diabetic (NIDD)
      patients 6 years after diagnosis, and to elucidate the risk factors of
      nephropathy. METHODS: This is a population-based controlled (baseline) cohort
      study. The prospective evaluation utilized the diabetic patients as internal
      controls. The setting was an urban primary health care centre. Main outcome
      measures were the UAER-24 h and fractional urinary albumin excretion rate (FAC)
      and their relation to mean blood pressure, haemoglobin Alc, fasting serum insulin
      and cholesterol and renal size. RESULTS: UAER (mg/24 h) was increased (geometric
      mean, quartile 1 and 3) in the diabetic patients at baseline, compared to the non
      diabetic control subjects; 21 (10 and 33) versus 12 (8 and 15), P = 0.0001
      (Wilcoxon's rank test). The UAER-24 h was not increased in diabetic subjects at
      follow-up; 24 (7 and 49) P = 0.3791 versus diabetic subjects at baseline.
      Eighteen per cent of normoalbuminuric (UAER < 30mg/24 h) patients developed
      microalbuminuria (UAER = 30-300 mg/24 h) and 3% clinical nephropathy (UAER > 300
      mg/24 h). Of the microalbuminuric subjects 19% progressed to clinical
      nephropathy, 46% remained microalbuminuric and 35% remitted to normoalbuminuria.
      Serum insulin concentration, after assessment of confounding factors, measured at
      the baseline predicted the UAER for all diabetic subjects at follow-up in
      multiple linear regression analysis in an independent and significant way (P =
      0.01). Serum insulin concentration (P = 0.034) and diuretic therapy (P = 0.050)
      at baseline independently predicted the outcome of the categorical variable
      progressor/nonprogressor (n = 22/86) based on the UAER-24 h at baseline and at
      follow-up. CONCLUSIONS: Progression of the UAER during the first 6 years is found
      among approximately every fifth NIDD subject who develops either microalbuminuria
      (from normoalbuminuria) or clinical nephropathy (from microalbuminuria). The role
      of serum insulin (insulin resistance) or some factor associated with it, is
      suggestive in the genesis of kidney disease.

PMID- 8671815
TI  - Renal function on and off lithium in patients treated with lithium for 15 years
      or more. A controlled, prospective lithium-withdrawal study.
AB  - BACKGROUND: Controversy remains over the magnitude and reversibility of reduced
      renal function in long-term lithium patients. METHODS: Thirteen patients with 18
      years (range 15-24) on lithium discontinued the treatment, and were re-examined
      twice after 5 and 9 weeks (4-16) off lithium. They were compared to a non-lithium
      psychiatric control group, matched for age and sex. RESULTS: Glomerular
      filtration rate (GFR) tended to improve from 69 (39-96) to 74 (39-94) ml/min/1.73
      m2 BSA, P = 0.057, which was not significantly different from 78 (61-106 ml/min
      per 1.73 m2 BSA in the controls. Reduced GFR was found in only two of the lithium
      patients off lithium, and in none of the controls. Maximal urinary concentrating
      capacity did not improve at all. It was 637 (130-875) mOsm/kg H2O in the lithium
      patients, which was lower than 856 (705-1.035) mOsm/kg H2O (P < 0.01) in the
      controls. Two of the lithium patients had isosthenuria. CONCLUSIONS: Lithium
      patients often have an irreversible, clinically important reduction of Umax,
      sometimes progressing to nephrogenic diabetes insipidus, while GFR is well
      preserved in most patients.

PMID- 8671817
TI  - Pneumococcal vaccine in children and young adults with chronic renal disease.
AB  - BACKGROUND: Pneumococcal vaccination has been recommended for immunocompromised
      children over 2 years including patients with chronic renal disease. However, the
      effect of vaccination and revaccination is variable and the indication for
      immunization is a subject of controversy. METHODS: Forty children and young
      adults with chronic renal diseases (including the idiopathic nephrotic syndrome,
      chronic renal failure, patients undergoing dialysis and after transplantation)
      were vaccinated with a 23-valent pneumococcal vaccine. The efficacy of the
      vaccine was evaluated by measuring antibody titres before and 4 weeks, 6 months,
      and 12 months after vaccination. Twenty-two patients were submitted to a
      revaccination 1 year after the first vaccination. RESULTS: A sufficient immune
      response, defined as an at least fourfold increase of postvaccinal antibody
      titres and an antibody titre > 200, was observed in 83% of the patients 4 weeks
      after vaccination, but only in 68% after 6 months, and in 48% after 1 year.
      Revaccination produced a significant immune response in 11/22 patients (50%)
      followed by a rapid decline of antibody levels within 6 months. Both vaccinations
      were well tolerated. CONCLUSIONS: The currently available vaccine is without
      major side-effects and effective in producing a significant immune response.
      Antibody levels should be monitored in vaccinated patients with chronic renal
      diseases considering the rapid decline as early as 6 months after vaccination.
      Evaluation of the efficacy of revaccination in these patients requires further
      investigations.

PMID- 8671819
TI  - Chronic renal failure and its treatment in tuberous sclerosis.
AB  - BACKGROUND: Chronic renal failure is rare in tuberous sclerosis, but its precise
      frequency is not known and treatment modalities have not been evaluated. METHODS:
      A questionnaire was addressed to the 260 French dialysis centres and the
      characteristics of 65 patients with tuberous sclerosis and chronic renal failure
      were analysed. RESULTS: In France the approximate prevalence of tuberous
      sclerosis with end-stage renal failure is 0.7 cases per million and that of end
      stage renal failure in tuberous sclerosis 1 per 100. Tuberous sclerosis with
      chronic renal failure was more frequent in females (63.1%) and was diagnosed at a
      mean age of 29 years. Renal impairment was the first manifestation of tuberous
      sclerosis in about half the cases. Renal tumours were frequent, with
      angiomyolipomas in 15 cases (23.1%), cysts in 12 cases (18.5%), and both in 35
      cases (53.8%). Malignancies were associated in nine cases (13.8%). Nephrectomy
      was done before dialysis in 21 cases (32.3%), and after the start of dialysis in
      six cases (9.2%). All but one of the 48 patients with end-stage renal failure
      were treated by dialysis; 20 were transplanted, with good results. CONCLUSIONS:
      Tuberous sclerosis with end-stage renal failure is rare. These patients require
      dialysis and renal transplantation, but we recommend binephrectomy after starting
      dialysis and before transplantation, given the risk of cancer and bleeding
      related to angiomyolipomas.

PMID- 8671818
TI  - The role of experimental chronic renal failure and aluminium intoxication in
      cellular immune response.
AB  - BACKGROUND: A positive correlation between successful kidney transplantation, few
      rejection episodes, greater susceptibility to infection and morbidity in patients
      with high tissue levels of aluminium (Al) indicate that the metal may play a role
      in the immune response. The aim of this study was to determine if experimental
      aluminium intoxication could result in significant changes in lymphocyte activity
      in uraemic and nonuraemic rats. METHODS: Lewis rats were divided into four
      groups: normals (N), nephrectomized control (U), and Al-treated (N + Al) and
      nephrectomized Al-treated (U + Al), which received a cumulative dose of 30 mg Al
      over a 4-week period. Al quantification, histology, histochemical analysis and
      immunological assays were performed after Al intoxication. RESULTS: High tissue
      levels of Al and positive histochemical staining in bones were seen in Al-treated
      rats. Bone histology revealed osteomalacia in U + Al rats. No statistical
      differences were observed in mixed lymphocyte cultures from controls and Al
      treated rats, whereas U and Al-treated rats showed a decrease in
      lymphoproliferative response to mitogen and natural killer cell cytotoxic
      activity. A decreased helper T lymphocyte: cytotoxic T lymphocyte cell ratio and
      a reduction in interleukin-2 production were observed only in the U + Al group. A
      reduced number of total T lymphocytes was detected in the spleens of all Al
      treated rats. CONCLUSIONS: These findings suggest that aluminium toxicity may
      contribute to immunological impairment in chronic renal failure.

PMID- 8671820
TI  - Is zinc protoporphyrin an indicator of iron-deficient erythropoiesis in
      maintenance haemodialysis patients?
AB  - BACKGROUND: Zinc protoporphyrin (ZPP), a metabolic intermediate generated in the
      red blood cell by incorporation of zinc instead of iron, has been suggested to be
      a sensitive and specific parameter of absolute iron deficiency in haemodialysis
      (HD) patients. METHODS: We studied 62 HD patients, 29-86 years old, with ZPP
      levels > 50 mumol/mol haeme (normal value of ZPP < 40 mumol/mol haeme) assessing
      the value of ZPP as a marker of functional iron deficiency at different cut-off
      points of ZPP. None of the patients had apparent inflammatory disease, infectious
      disease, or malignancy. ZPP, haemoglobin, iron and ferritin levels were
      determined before, and after a 24-week period of once-weekly i.v. administration
      of 40 mg iron, to determine whether ZPP levels return to normal during adequate
      iron supplementation (960 mg iron/ patient). RESULTS: There was no significant
      change in ZPP levels after iron supplementation in patients with a ZPP > 50
      mumol/mol haeme (96.7 +/- 49.8 versus 88.4 +/- 43.5 mumol/mol haeme before and
      after iron administration respectively, P = n.s.). However, in patients with a
      ZPP > 90 mumol/mol haeme, there was a significant reduction in ZPP levels (141.2
      +/- 54.5 versus 108.0 +/- 48.8 mumol/mol haeme, P < 0.001). Serum ferritin
      increased significantly in both groups. There was no correlation between ZPP and
      serum ferritin at any time during the study. There was also no correlation
      between serum aluminium levels and ZPP and no significant difference in changes
      in ZPP in patients receiving desferrioxamine therapy compared to those not
      receiving desferrioxamine therapy. We did find a significant correlation between
      moderately elevated total blood lead concentrations and ZPP levels at the end of
      the study. The ZPP levels were not significantly different in the range from 50
      110 mumol/mol haeme before and after i.v. iron supplementation in the responders
      (10% increase of haemoglobin or 20% decrease of the recombinant human
      erythropoietin dose) compared with the non-responders. CONCLUSIONS: Our data
      indicate that ZPP cannot be used to predict the erythropoietic response to iron
      supplementation. However, ZPP levels may be an indicator of functional iron
      deficiency due to blockade of the reticuloendothelial iron release in
      haemodialysis patients.

PMID- 8671821
TI  - Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis
      and peritonitis.
AB  - BACKGROUND: Peritoneal infection and poor ultrafiltration continue to be the
      major causes of treatment failure in CAPD. The combined effects of peritonitis
      and the continuous exposure to dialysis fluid remain the most likely candidates
      affecting the peritoneum in the long term. The purpose of this study was to
      observe the effects of peritonitis and dialysis on longitudinal peritoneal
      function. METHODS: The peritoneal equilibration test (PET) was utilized to
      quantify longitudinal changes in low-molecular-weight solute transfer
      (D/P(creat)) and ultrafiltration (UF) in 233 patients treated with CAPD. Of
      these, 166 represented an unselected cohort (Group 1) studied prospectively from
      commencing treatment for up to 54 months, and 67 were selected patients (Group 2)
      with PET data available at commencement of the study, having been on dialysis for
      a minimum of 18 months. PETs were performed either 6-monthly or following
      peritonitis episodes. RESULTS: Data on the short-term effect of peritonitis
      kinetics were pooled for groups 1 and 2. Single, isolated episodes (n = 86) had
      no significant effect on D/P(creat) or UF, whereas recurrences or clusters of
      infection (n = 70) caused increases in D/P(creat) and reductions in UF, the
      significance of which increased with the number of episodes. There were
      significant correlations between both changes in D/P(creat) and UF with the
      cumulative dialysate leukocyte count, regardless of infecting organism,
      suggesting that intensity of peritoneal inflammation is also important. Those
      organisms associated with greater change in peritoneal kinetics, e.g. S. aureus,
      Pseudomonas, also had the highest neutrophil counts. The longitudinal changes in
      peritoneal kinetics were analysed for patients in group 1 only. There was a
      highly significant increase in D/P(creat) after 6 months treatment; this
      increased further with time on treatment, reaching further significance at 42 and
      48 months. There was an associated reduction in UF. In view of the short-term
      effects of peritonitis on kinetics group 1 was further subdivided into patients
      who were either peritonitis free or only experienced isolated infections, group
      1a, and those that had multiple infection episodes, group 1b. Treatment drop-out,
      due to death or technical failure occurred at double the rate in group 1b, who
      also had significantly higher D/P(creat) and lower UF at 1, 6, 12, 18 and 24
      months of treatment. Group 1a subsequently caught up, however, indicating that
      peritonitis is not the only factor influencing long-term changes in peritoneal
      kinetics. CONCLUSIONS: These data suggest that solute transfer increases and UF
      declines with time on peritoneal dialysis. This process is exacerbated and
      accelerated by peritonitis, and appears to be proportional to the degree of
      associated inflammation and number of infections in close proximity.

PMID- 8671822
TI  - Prevention of cyclosporin nephrotoxicity with a platelet-activating factor (PAF)
      antagonist.
AB  - BACKGROUND: Cyclosporin (CsA) is a potent immunosuppressive drug whose main side
      effect is nephrotoxicity. In the kidney, CsA induces vasoconstriction with a
      decrease in renal blood flow (RBF) and glomerular filtration rate (GFR) and a
      significant increase in renal vascular resistance (RVR). CsA enhances platelet
      activating factor (PAF) synthesis in mesangial cells in vitro. PAF, a secondary
      mediator of anaphylaxis and inflammation, exhibits vasoactive properties in the
      kidney similar to those of CsA. METHODS: The in situ autoperfused rat kidney
      model was used to investigate whether PAF plays a role in the haemodynamic injury
      induced by CsA. RESULTS: In this model, CsA (40 mg/kg and 20 mg/kg i.v.) induced
      a significant decrease in RBF and in GFR and an increase in RVR. BN 52021, a
      potent and specific PAF antagonist (20 mg/kg i.v. bolus dose) induced a
      significant increase in GFR (137 +/- 32% of initial value, P < 0.05). BN 52021
      (20 and 10 mg/kg) also significantly prevented the decline in RBF and GFR induced
      by CsA. CONCLUSIONS: We have demonstrated that the PAF antagonist BN 52021 can
      minimize the alteration of renal function induced by CsA.

PMID- 8671824
TI  - Iohexol clearance for GFR-determination in renal failure--single or multiple
      plasma sampling?
AB  - The present study examined the agreement between single and multiple sample
      plasma clearance of iohexol, a non-ionic contrast agent, in renal failure. Sixty
      five patients with varying degree of renal insufficiency received 10 ml iohexol
      (300 mg I/ml) i.v. and plasma samples were collected four times during the
      following 3-24 h. Plasma-iodine concentrations were determined by X-ray
      fluorescence. Predicted creatinine clearance was used to choose one of the
      samples for determination of single sample clearance. A single plasma specimen
      collected at 4 h for GFR above 50 ml/min, at 7 h for GFR between 20 and 50
      ml/min, and at 24 h for GFR below 20 ml/min gave values in good agreement with
      those based on a four sample slope clearance. No sign of nephrotoxicity was noted
      after administration of the contrast agent. It is concluded that single sample
      plasma clearance after single injection of iohexol gives a good estimate of GFR
      in renal failure and is advantageous in clinical practice.

PMID- 8671823
TI  - Influence of specific and non-specific endothelin receptor antagonists on renal
      morphology in rats with surgical renal ablation.
AB  - BACKGROUND: Studies in experimental models of chronic renal failure suggest an
      important role for the endothelin system in the development of renal scarring.
      Endothelin receptor (ETR) anatagonists interfere with progression, but it has not
      been resolved (i) whether this is true for all models of renal damage, (ii) to
      what extent the effect is modulated by systemic blood pressure and (iii) whether
      the effect is similar for ETAR and ETA/ETBR antagonists. STUDY DESIGN: 5/6
      subtotal nephrectomy (SNX) by surgical ablation in male Sprague-Dawley rats.
      Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS
      182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by
      gavage. Duration of the experiment eight weeks. METHODS: Systolic blood pressure
      by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis
      ET-1 and ETA/ETBR by quantitative PCR. RESULTS: SNX caused a significant (P <
      0.01) increase of systolic blood pressure (170 +/- 8.6 mmHg) compared to sham
      operated controls (131 +/- 5.3 mmHg). Blood pressure was significantly (P <
      0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153
      +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg). Compared to sham operated rats
      (0.03 +/- 0.01) glomerulosclerosis index (GSI) was significantly (P < 0.01)
      higher in the untreated SNX group (0.9 +/- 0.15). Significantly lower GSI was
      found in Trandolapril treated (0.29 +/- 0.04), BMS 182874 treated (0.36 +/-
      0.05), and Ro 46-2005 treated animals (0.45 +/- 0.11). The effect of BMS 182874
      was accompanied by lower tubulointerstitial damage index. Mean glomerular volume
      was dramatically increased (P < 0.001) in SNX rats as compared to sham operated
      animals. This glomerular enlargement was partially prevented by Trandolapril (P <
      0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX
      irrespective of treatment, while ETAR and ETBR mRNA were significantly lower.
      CONCLUSION: Both specific (ETAR) and non-specific (ETA/ETBR) endothelin
      antagonists interfere with development of glomerulosclerosis by mechanisms which
      are, at least in part, independent of systemic blood pressure.

PMID- 8671825
TI  - Effect of human leukocyte alpha interferon on cryoglobulinaemic
      membranoproliferative glomerulonephritis associated with hepatitis C virus
      infection.

PMID- 8671826
TI  - Macrohaematuria and bilateral renal aneurysms in a patient with mesangial
      glomerulonephritis.

PMID- 8671827
TI  - Membranoproliferative glomerulonephritis and hepatitis C: effects of interferon
      alpha therapy on clinical outcome and histological pattern.

PMID- 8671828
TI  - A case of non-Hodgkin lymphoma presenting primarily with renal failure.

PMID- 8671829
TI  - Acute anuric renal failure related to oxalosis in identical twin infants.

PMID- 8671830
TI  - Minocycline-induced chronic interstitial nephritis?

PMID- 8671832
TI  - Rapid calcification of the renal graft in a 38-year old woman with type 1
      diabetes.

PMID- 8671831
TI  - Disseminated histoplasmosis in a haemodialysis patient on immunosuppression after
      graft failure.

PMID- 8671834
TI  - Crippling bone disease in a 15-year-old girl treated by haemodialysis.

PMID- 8671835
TI  - New subgroup of primary IgA nephritis with thin glomerular basement membrane
      (GBM): syndrome or association.

PMID- 8671836
TI  - Bilateral inguinal hernia associated with Alport's syndrome: report of the first
      case.

PMID- 8671837
TI  - Colchicine and the progression of experimental renal fibrosis.

PMID- 8671838
TI  - Dihydropyridine receptor blockers and skeletal muscle metabolism.

PMID- 8671839
TI  - Is there true recurrence of Fabry's disease in the transplanted kidney?

PMID- 8671840
TI  - Oestrogen deficiency--does it have a role in the genesis of skeletal problems in
      dialysed women?

PMID- 8671841
TI  - Fracturing osteoporosis after kidney transplantation--what are the options?
AB  - The patient who receives a renal graft does not have virgin bones. Renal
      transplantation must be performed in a patient with pre-existing bone disease,
      i.e. renal osteodystrophy, characterized by secondary hyperparathyroidism,
      calcitriol deficiency, phosphate retention, metabolic acidosis and possibly
      aluminium accumulation. These pathomechanisms are further modulated by factors
      such as duration of dialysis, type of dialysis, diet, control of serum phosphate,
      use phosphate-binding agents etc.

PMID- 8671842
TI  - Leukocyte--endothelial cell interactions in haemodialysis-induced neutropenia.

PMID- 8671844
TI  - Antihypertensive treatment with diuretics: antediluvian or up to date?

PMID- 8671845
TI  - Influence of uraemia and haemodialysis on host defence and infection.

PMID- 8671846
TI  - Different mediator systems in biphasic heterologous phase of anti-GBM nephritis
      in mice.
AB  - BACKGROUND: After the injection of rabbit anti-mouse glomerular basement membrane
      (GBM) antibody into normal C57BL/6J mice severe albuminuria develops, which
      reaches a peak at 24 h. This early albuminuria is dependent on polymorphonuclear
      granulocytes (PMN) and is completely absent in the congenic beige mutant strain
      (C57BL/6J, bg/bg), which is genetically deficient in leukocytic neutral
      proteinase activity. We now studied the development of anti-GBM nephritis in
      beige mice during the later heterologous phase. METHODS: In untreated beige mice
      we assessed the albuminuria and glomerular lesions on days 1-5 after i.v.
      injection of anti-GBM antibody. Secondly, effector mechanisms involved in the
      later days of the heterologous phase were studied by substitution of whole anti
      GBM antibodies by F(ab')2 fragments, by leukocyte depletion (total body
      irradiation), scavenging of reactive oxygen metabolites (dimethylsulfoxide
      treatment), and complement depletion (cobra venom factor treatment). RESULTS: In
      the later part of the heterologous phase (days 2-5), when there is still no sign
      of autologous antibody formation, i.v. injection of anti-GBM antibodies in beige
      mice induces nephritis with gradually increasing albuminuria, that reaches levels
      similar to those in non-deficient, congenic controls by day 3. This late
      albuminuria did not occur after injection of F(ab')2 fragments of the antibody,
      could be prevented by leukocyte depletion, and was greatly reduced by treatment
      with dimethylsulfoxide, a scavenger of hydroxyl radicals. The late albuminuria
      was not influenced by complement depletion with cobra venom factor. Histologic
      and immunohistologic studies gave no indication for a role of glomerular
      macrophages or lymphocytes. CONCLUSIONS: The heterologous phase in murine anti
      GBM nephritis is a biphasic process, with sequential involvement of different and
      independent mediating systems: both phases are PMN-dependent, but only the early
      albuminuria depends on leukocytic neutral proteinase activity, whereas the
      albuminuria and the glomerular damage at later days are effected by reactive
      oxygen metabolites, most probably originating from PMN accumulating in the
      glomerulus.

PMID- 8671847
TI  - Daily short exposure of cultured mesothelial cells to lactated, high-glucose, low
      pH peritoneal dialysis fluid induces a low-profile regenerative steady state.
AB  - This study was designed to evaluate cytotoxic effects and influence upon cell
      growth of cultured mesothelial cells exposed to modified 4.25% Dianeal dialysate
      fluid (M-199 in Dianeal solution, glucose 4.25 g, pH 5.2) (Expr. group), 60 min a
      day for a total period of follow-up of 13 consecutive days, compared with that
      observed in a control group (C). Beginning on day 7, the cell counts in group C
      were significantly higher than those observed at zero time (P < 0.05). Cell
      counts in the experimental group showed no significant differences between the
      first day of culture and each one of the 13 consecutive days of follow-up.
      Thymidine incorporation into DNA observed on the first day in C, was
      significantly higher (P < 0.01) beginning on the 10th day. Values observed in the
      experimental group were low during the whole period of follow-up. LDH mean values
      at each time interval, were significantly higher (P < 0.01 and < 0.001) for cells
      exposed to the dialysis solution. Repeated exposure of the mesothelium to 40
      mMol/l lactate and high glucose concentrations induced severe cell injury and
      death, decreased cell growth and, consequently, a reduced rate of regeneration
      which is extended as long as the repeated exposure is maintained.

PMID- 8671848
TI  - Mesalazine-associated interstitial nephritis.
AB  - BACKGROUND: When used for oral treatment of inflammatory bowel disease, Asacol (a
      coated form of mesalazine = 5-aminosalicylic acid) can cause interstitial
      nephritis. The spectrum of severity, frequency of occurrence and the best renal
      function test to detect this complication are not known. The value of
      immunosuppression in addition to drug withdrawal is similarly undetermined.
      METHODS: Four cases of interstitial nephritis which occurred in association with
      oral Asacol treatment are presented and a further 12 cases who received similar
      treatment are reviewed. Clinical trials published previously were scrutinized to
      assess the frequency of impaired renal function. RESULTS: The available evidence
      suggests that renal impairment of any severity may occur in up to 1 in 100
      patients, but that clinically significant interstitial nephritis occurs in less
      than 1 in 500 patients. This is most reliably detected by an elevated serum
      creatinine concentration. If the diagnosis of nephrotoxicity is delayed until 18
      months after commencement of medication, restoration of renal function, which is
      seen on withdrawal of medication alone up to 10 months, does not occur and there
      is no evidence to date to indicate that addition of immunosuppression confers any
      significant advantage at this later stage. CONCLUSIONS: It is suggested that
      serum creatinine concentration should be measured each month for the first 3
      months of treatment, 3-monthly for the remainder of the first year and annually
      thereafter. The use of concurrent immunosuppressive therapy may necessitate
      extension to the period of intensive monitoring. Any elevation of serum
      creatinine which cannot be related to a relapse of inflammatory bowel disease
      should prompt immediate withdrawal of Asacol and related medications and
      substitution of alternative therapy. Neither the lack of urinary abnormalities on
      routine testing nor the absence of clinical or laboratory features of drug
      allergy can be relied upon to rule out interstitial nephritis during oral therapy
      with these drugs.

PMID- 8671849
TI  - Lithium induced polyuria and renal vasopressin receptor density.
AB  - BACKGROUND: Lithium, a drug frequently used for treatment of affective disorders,
      is known to cause a vasopressin-resistant state, leading to polyuria and
      polydipsia. It has been suggested that lithium interacts with the renal V2
      vasopressin receptor. Detailed studies on the influence of lithium on the AVP
      receptor, however, have so far been difficult due to the lack of a suitable
      radioligand with high specific activity and high affinity. METHODS: Using 125I-[8
      (p-(OH)-phenylpropionyl)]- LVP, we studied the effects of lithium on V2
      vasopressin receptors in male Sprague-Dawley rats and LLC-PK1 cells. Rats, having
      free access to water, were orally treated with 10 mg lithium/100 mg b.w./day or
      placebo for 10 days. Scatchard analysis was performed using membranes prepared
      from homogenized renal papillae. RESULTS: Lithium caused significant polyuria and
      an impaired renal concentration capacity after water deprivation. Binding studies
      showed no effect of lithium on binding affinity KD (0.98 +/- 0.21 nmol/l vs. 0.86
      +/- 0.15 nmol/l (Li) (n.s.). Receptor density, however, significantly decreased
      from 130 +/- 12.3 nmol/kg protein in controls (n = 8) to 101.7 +/- 13.4 nmol/kg
      protein (n = 8), (P < 0.05). Plasma osmotically and AVP were not significantly
      altered by lithium treatment. Vasopressin receptor density on LLC-PK1-cells, a
      pig renal cell line, was not changed by preincubation with lithium (312 +/- 22
      nmol/kg vs. 329 +/- 25 nmol/kg (Li) (n = 6, n.s.). CONCLUSIONS: The decrease of
      AVP-receptor density in vivo might be related to vasopressin resistance, either
      primary, or secondary to other factors, e.g. actual water transport.

PMID- 8671850
TI  - Renal effects of captopril, indomethacin and nifedipine in nephrotic patients
      after an oral protein load.
AB  - BACKGROUND: In this study we investigated whether the increase in proteinuria
      induced by an oral protein load may be prevented by the angiotensin-converting
      enzyme inhibitor (ACEI) captopril in patients with nephrotic syndrome, and
      whether the effects of captopril on renal haemodynamics and/or glomerular
      selectivity are comparable to those obtained with the nonsteroidal anti
      inflammatory drug (NSAID) indomethacin and the calcium-channel blocker (CaCB)
      nifedipine. METHODS: Twelve subjects underwent the following treatments: (1) low
      protein meal (0.2 g protein/kg body wt), (2) high-protein meal (1.3 g protein/kg
      body wt), (3) high-protein meal plus oral captopril (50 mg), (4) high-protein
      meal plus oral nifedipine (10 mg), (5) high-protein meal plus oral indomethacin
      (50 mg). Urine and blood samples were obtained after meals and tested for total
      protein, immunoglobulin G and albumin. GFR and renal plasma flow (RPF) were
      calculated from iothalamate and p-aminohippuric acid clearances respectively.
      RESULTS: Mean arterial pressure decreased significantly after both captopril (
      4%, P = 0.001) and nifedipine (-5%, P = 0.0019). Compared with the low-protein
      meal, mean values of GFR and RPF increased significantly after the high-protein
      meal alone (+21%, P = 0.0002; +10%, P = 0.0491 respectively), and after captopril
      (+18%, P = 0.0025; +24%, P = 0.0034 respectively) or nifedipine administration
      (+30%, P = 0.0001; +21%, P = 0.0036 respectively), whereas they remained
      unchanged after the high-protein meal plus indomethacin administration. FF did
      not change significantly under the five experimental conditions. The increase in
      urinary protein excretion induced by the meat load (total protein +18%, P =
      0.0102; albumin +26%, P = 0.0316; IgG +28%, P = 0.0203) was entirely blocked by
      both captopril and indomethacin, whereas it was further increased by nifedipine
      administration. CONCLUSIONS: Both captopril and indomethacin, but not nifedipine,
      are able to prevent the increase in urinary protein excretion rate following a
      meat meal. The antiproteinuric effect of captopril is comparable to that of
      indomethacin, but the renal haemodynamic changes induced by these drugs differ
      considerably, because the filtration capacity and the renal functional reserve
      were preserved by captopril and decreased by indomethacin. The reduction in
      systemic blood pressure following administration of both captopril and nifedipine
      does not account for changes in proteinuria, since, with a similar degree of
      blood pressure lowering, urinary protein excretion is reduced by captopril and
      increased by nifedipine.

PMID- 8671851
TI  - Synergistic renal protection by combining alkaline-diuresis with lipid
      peroxidation inhibitors in rhabdomyolysis: possible interaction between oxidant
      and non-oxidant mechanisms.
AB  - BACKGROUND AND PURPOSE: Heme-proteins, besides causing renal tubular obstruction,
      may contribute to rhabdomyolysis-induced renal injury through a heme-iron
      mediated lipid peroxidation process. In the present study, we compared the
      combined therapy of a lipid peroxidation inhibitor, 21-aminosteroid (21-AS) and
      fluid-alkaline-mannitol (FAM) diuresis with either of them alone to determine the
      efficacy of the combination therapy and to delineate the roles of lipid
      peroxidation and cast formation. METHODS AND RESULTS: Employing Raman
      spectroscopy, we confirmed in vitro the ability of 21-AS to inhibit iron-induced
      fatty acid peroxidation. 21-AS was then administered to rats developing renal
      failure from glycerol-induced rhabdomyolysis. Although 21-AS inhibited
      rhabdomyolysis-induced plasma and renal lipid peroxidation, renal protection was
      incomplete. Administration of FAM to inhibit cast formation afforded a better
      renal protection. However, when these therapies were combined to inhibit both
      lipid peroxidation and cast formation, there was a synergistic renal functional
      protection. This was accompanied by a maximum inhibition of renal and plasma
      lipid peroxidation, as well as, renal tubular necrosis and cast formation.
      Compared to combination therapy, FAM therapy alone, despite identical volume, was
      accompanied by a higher tubular necrosis and cast formation. CONCLUSIONS: That
      combining a lipid peroxidation inhibitor with fluid-alkaline diuresis in
      rhabdomyolysis further lowers renal lipid peroxidation, tubular necrosis and cast
      formation and synergistically limits renal dysfunction (i) supports a role for
      lipid peroxidation in the pathophysiology of rhabdomyolysis ARF, (ii) underscores
      the role of the intratubular heme retention, a cause for tubular obstruction as
      well as a source for prodigious amount of iron, likely involved in the lipid
      peroxidation, and (iii) raises the possibility of interactions between non
      oxidant and oxidant mechanisms.

PMID- 8671852
TI  - Renal function and morphometry in the dwarf rat following a reduction in renal
      mass.
AB  - BACKGROUND: The compensatory increase in glomerular filtration rate (GFR) and
      effective renal plasma flow (ERPF) which follows a reduction in renal mass may be
      mediated by growth hormone, a renal vasodilator. METHODS: GFR, ERPF and
      glomerular morphometry were assessed in the dwarf rat, selectively deficient in
      GH, and compared its Lewis base strain. Studies were performed 21-days after sham
      operation, unilateral nephrectomy or subtotal nephrectomy in age-matched animals.
      GFR and ERPF were assessed from the renal clearance of inulin and p
      aminohippurate measured under barbiturate anaesthesia. RESULTS: The dwarf rat had
      a lower GFR and ERPF than the Lewis rat, in proportion to its lower body weight
      and lower kidney weight. Kidneys from the dwarf rat had a similar number of
      glomeruli to the Lewis, but smaller glomerular components in proportion to a
      lower kidney weight. Following unilateral nephrectomy, GFR (dwarf + 58%, Lewis +
      53%) and ERPF (dwarf + 58%, Lewis + 52%) increased to a similar degree in both
      rat strains. Glomerular diameter, volume and capillary surface area increased in
      proportion to kidney growth, although compensatory renal growth (dwarf + 62%,
      Lewis + 78%) was somewhat lower in the dwarf. Following 5/6 subtotal nephrectomy,
      GFR (dwarf + 143%, Lewis + 171%) increased to a similar degree in both rat
      strains while ERPF (dwarf + 108%, Lewis + 48%) and compensatory renal growth
      (dwarf + 115%, Lewis + 86%) were greater in the dwarf than the Lewis rat.
      Subtotal nephrectomy was also associated with an increase in the thickness of the
      glomerular basement membrane in both rat strains. CONCLUSIONS: The results do not
      support a role for GH in the compensatory increase in renal function or
      hypertrophy which follows a reduction in renal mass, excluding this as a
      potential mechanism for GH-dependent renal scarring.

PMID- 8671853
TI  - No change in automatic function tests during uncomplicated haemodialysis.
AB  - Uraemic autonomic dysfunction is reckoned to participate in dialysis hypotension,
      but a clear relationship has not been established. However, autonomic function is
      usually tested at rest, and possibly autonomic dysfunction arises or worsens
      during dialysis. We therefore performed easily repeatable tests of efferent
      sympathetic function, that is static exercise test and parasympathetic function,
      that is heart rate variability during Valsalva manoeuvre and deep breathing, at
      successive stages of a standard haemodialysis session; before dialysis, 20 min
      after dialysis without ultrafiltration, after 3 h of dialysis combined with
      ultrafiltration, and 20 min after dialysis. Studies were performed in 22 patients
      on chronic haemodialysis on a cuprophane dialyser. The mean ultrafiltration
      volume was 2.2 +/- 0.61. We found that blood pressure elevation upon static
      exercise, and heart rate variability during Valsalva or deep breathing test
      remained unaltered at the various stages of dialysis. On past performance the
      patients were divided into hypotension prone (n = 6) or resistant (n = 16).
      Hypotension prone patients showed a greater blood pressure drop during dialysis,
      but also showed an appropriately enhanced heart rate acceleration. The occurrence
      of autonomic dysfunction was not elevated in this group, nor did such dysfunction
      develop along dialysis. Predialysis parasympathetic function tests were abnormal
      in 10 patients. These patients also showed an augmented intradialytic blood
      pressure decrease, but no enhanced acceleration in heart rate. Their
      parasympathetic dysfunction did not worsen during dialysis. Based upon the
      predialysis exercise test, low responding patients (blood pressure increase 5 +/-
      2 mmHg, n = 11) were distinguished. These subjects were not characterized by a
      greater blood pressure decrease or different heart rate acceleration. Generally,
      the responses upon exercise, whether low or high, remained unaltered during
      dialysis. we conclude that haemodialysis has no systematic effect on autonomic
      function. Hypotension-prone patients are not distinguished by a disturbed
      predialytic or intradialytic autonomic blood pressure control.

PMID- 8671854
TI  - Cuprophane haemodialysis induces upregulation of LPS receptor (CD14) on
      monocytes: role of complement activation.
AB  - BACKGROUND: The CD14 molecule is a high-affinity receptor for the complex formed
      by lipopolysaccharide (LPS) and LPS-binding protein. METHODS: We examined by flow
      cytometry the effect of in vitro and in vivo haemodialysis on cuprophane membrane
      and recombinant C5a on the expression of CD14 molecules at the surface on
      monocytes. Monocyte CD14 expression was also studied during in vitro and in vivo
      haemodialysis on polyacrylonitrile AN69 membrane. RESULTS: In vitro haemodialysis
      of whole blood from healthy volunteers on cuprophane membrane resulted within 30
      min in upregulation of monocyte CD14 expression. The reuse of the cuprophane
      membrane abolished both complement activation and CD14 upregulation. Moreover,
      incubation of whole blood with recombinant C5a led to an increased monocyte CD14
      expression supporting a role for complement activation in the rapid cuprophane
      induced CD14 upregulation. During AN69 dialysis which is not associated with
      complement activation in the blood phase, monocyte CD14 expression did not change
      during the first 60 min but was significantly increased after 3 h of in vitro
      haemodialysis. This late increase might be related to the presence of complement
      activation products adsorbed on the membrane. In vivo dialysis on cuprophane
      membrane also resulted in early monocyte CD14 upregulation as indicated by higher
      CD14 expression found after 60 min on monocytes obtained from the efferent as
      compared to the afferent line of the dialyser, a phenomenon that was not observed
      during haemodialysis on AN69 membrane. CONCLUSION: Haemodialysis on the
      complement-activating cuprophane membrane induces the rapid upregulation of the
      CD14 LPS-receptor on monocytes.

PMID- 8671855
TI  - Frequency of adynamic bone disease and aluminum storage in Italian uraemic
      patients--retrospective analysis of 1429 iliac crest biopsies.
AB  - BACKGROUND: Adynamic bone disease was initially attributed too aluminum
      intoxication in association with low circulating levels of parathyroid hormone.
      More recently adynamic bone disease has been described even in the absence of
      aluminum intoxication. PURPOSE OF THE STUDY: It was the purpose of this
      retrospective analysis of 1429 iliac crest biopsies sent to our laboratory from
      1985 to 1994 by 41 Italian nephrology and dialysis centres to assess the
      frequency of adynamic bone disease and aluminum accumulation. METHODS: Adynamic
      bone disease was diagnosed by histological and histodynamic (tetracycline
      labelling) analysis, on the basis of predetermined criteria. Aluminum
      accumulation was assessed by aluminon histochemical staining. RESULTS: The
      frequency of adynamic bone disease was fairly constant at approximately 15% from
      1985 to 1994. In contrast, aluminum accumulation, defined as positive aluminon
      histochemical staining, decreased during the same period from 36% to 4%.
      CONCLUSIONS: Our data clearly show a dissociation of the incidence of adynamic
      bone disease and aluminium accumulation in bone. At least today, given the low
      prevalence of aluminium intoxication, factors other than aluminium are the main
      cause of adynamic bone disease.

PMID- 8671856
TI  - Resistance to activated protein C (APC): mutation at Arg506 of coagulation factor
      V and vascular access thrombosis in haemodialysis patients.
AB  - BACKGROUND: Vascular access thrombosis represents a serious problem in
      haemodialysis patients. Therefore identification of relevant thrombotic risk
      factors is clinically valuable. Resistance to activated protein C (APC) was
      recently identified as a new thrombophilic defect which is caused by a single
      point mutation in the factor V gene. Whether this mutation predisposes to
      vascular access thrombosis is unknown. METHODS: The presence of factor V Leiden
      (mutation at nucleotide position 1691 of the factor V gene) was determined by
      polymerase chain reaction (PCR) analysis in 152 haemodialysis patients from all
      three haemodialysis units of the University Hospital of Vienna. In 61 patients
      (54 without mutation, 7 with heterozygous mutation) resistance to APC was
      evaluated. One hundred-seven individuals without renal failure (57 negative for
      factor V Leiden, 50 heterozygous subjects) served as controls. Haemodialysis
      patients with heterozygous factor V Leiden mutation were carefully investigated
      for thrombotic complications of vascular access, other thromboembolic events and
      additional putative thromboembolic risk factors. RESULTS: Seven of 152 (4.6%)
      patients were heterozygous carriers of factor V Leiden. The mean APC resistance
      ration in heterozygous dialysis patients was 2.31; in the 50 heterozygous
      controls the ratio was 2.02. The mean APC ratio in haemodialysis patients without
      mutation was 3.53 in contrast to 2.95 in the control group. Not one of the seven
      heterozygous haemodialysis patients suffered from vascular access thrombosis of
      inexplicable origin. Three patients remained totally free of access thrombosis
      from onset of haemodialysis treatment. In four of seven patients nine events of
      thrombosis of the vascular access occurred, but were due to anatomical stenosis
      in each case. In six permanent central venous catheters no episode of occlusion
      or reduced blood flow requiring thrombolytic therapy was observed. Family history
      with regard to thrombotic events was negative in all seven patients. No
      thromboembolic complication occurred during 13 periods of immobilization, in the
      course of six pregnancies and during oral contraception. CONCLUSIONS: The
      heterozygous carrier status for factor V Leiden does not appear to represent a
      risk factor for vascular access thrombosis in haemodialysis patients. This is
      possibly due to the fact that the functional APC activity is high and in
      heterozygous haemodialysis patients APC resistance ratios are very close to the
      normal range. However, it cannot be excluded that a homozygous factor V mutation
      represents an increased risk for shunt thrombosis. Therefore patients suffering
      from repeated and/or inexplicable shunt thrombosis should be tested for the
      factor V mutation to evaluate the effect of a homozygous mutation.

PMID- 8671857
TI  - Angiotensin converting enzyme inhibition and chronic cyclosporine-induced renal
      dysfunction in type 1 diabetes.
AB  - AIM: This study was designed to evaluate whether the angiotensin converting
      enzyme inhibitor enalapril could prevent cyclosporine-induced renal dysfunction
      in diabetic patients treated with CsA in monotherapy. DESIGN: Twenty-four recent
      onset insulin-dependent diabetic patients without prior renal involvement were
      randomized to receive a 3 month course of either cyclosporine (CsA) alone (7.5
      mg/kg. b.i.d. in olive oil) or CsA+enalapril (20mg p.o. oad.). END POINTS: were
      mean arterial pressure, plasma creatinine, GFR, renal plasma flow, renal vascular
      resistance, sodium and lithium clearances measured before and after 3 months of
      treatment. RESULTS: Baseline values were identical in both groups except for mean
      arterial pressure which was slightly higher in the subjects subsequently
      receiving CsA + enalapril. Three month treatment with CsA increased significantly
      mean arterial pressure and renal vascular resistance by 9 and 24% respectively,
      while decreasing significantly glomerular filtration rate and renal plasma flow
      by 17 and 14% respectively. Enalapril was able to prevent the decline in GFR and
      the increase in blood pressure induced by CsA. This effect was demonstrated
      despite a similar increase in renal vascular resistance suggesting a dissociation
      between changes in glomerular filtration rate and renal vascular resistance
      during angiotensin converting-enzyme inhibition. CONCLUSION: Chronic angiotensin
      converting-enzyme inhibition could afford some degree of protection against CsA
      induced renal dysfunction. Whether these results can be extrapolated to
      transplant recipients in whom CsA is usually associated to treatment by
      glucocorticosteroids deserves further evaluation.

PMID- 8671858
TI  - Hepatitis C virus genotypes in chronic dialysis patients.
AB  - BACKGROUND: Hepatitis C virus (HCV) infection is highly prevalent in dialysis
      patients. To further characterize HCV infection in this patient population, we
      studied the distribution of viral genotypes in 55 patients undergoing chronic
      dialysis treatment with seropositivity for HCV markers. METHODS: Thirty-two of 55
      (58%) patients showed HCV RNA in the serum using reverse transcription polymerase
      chain reaction (RT-PCR) in the 5'-untranslated region (UTR) of the viral genome.
      HCV genotyping was performed using biotinylated type-specific oligonucleotide
      probes after hybridization with amplified sample material. RESULTS: HCV subtype
      2a was dominant (56%), followed by HCV subtype 1b (31%), type 3 (3%) and 4 (3%).
      There was no association between demographic or clinical features of this cohort
      and HCV genotype. Genotype dependence was observed for antibody response toward
      the NS4 (c 100-3 and 5-1-1) proteins, which was infrequent in genotype 2a
      carriers compared with genotype 1b (p = 0.004). CONCLUSIONS: HCV subtype 2a was
      dominant in our cohort of anti-HCV-positive dialysis patients; there was no
      association between HCV genotypes and demographic or clinical features of
      patients; the absence of antibody response toward the NS4-related antigens was
      frequent in genotype 2a carriers and may serve to predict responses to interferon
      therapy. The relative homogeneity of the viral population in dialysis patients
      attending our unit suggests a nosocomial transmission of HCV in this clinical
      setting.

PMID- 8671859
TI  - Increased prevalence of HCV antibodies in dialyzed Ashkenazi Jews--a possible
      ethnic predisposition.
AB  - BACKGROUND: The prevalence of hepatitis C (HCV) antibodies in dialysis patients
      is considerably higher than that found among healthy blood donors. This increased
      seroprevalence has been correlated to increased duration of dialysis, mode of
      dialysis and to the number of blood transfusions administered. However, factors
      other than nosocomial ones also seem to play a part in disease transmission. The
      role of the patient's ethnic origin, possibly reflecting on his/her genetic
      makeup has received scant attention. In this study, HCV seroprevalence in our
      dialysis population, which consists of three major ethnic subgroups (Ashkenazi
      Jews, Sephardi Jews and Arabs), was examined. METHODS AND RESULTS: Altogether HCV
      seropositivity was determined in 120 dialysed patients--65 males/55 females (76
      hemodialysis, 44 CAPD), using second generation ELISA confirmed by RIBA-2. Mean
      age was 59.7 +/- 15.7 (range 16-86 years). Patients had to have been on dialysis
      for a minimum of 3 months (mean duration 45.2 +/- 44.5 months). Patients whose
      end-stage renal disease was due to diabetic nephropathy (DN) or those who had
      previously been transplanted (TP) were considered as separate groups and compared
      to the group as a whole. Of the 120 patients, there were 49 Ashkenazi Jews
      (40.8%), 57 Sephardi Jews (47.5%) and 14 Arabs (11.7%). Overall HCV prevalence
      was 21.7% (26/120) with a significantly greater prevalence in HD compared to CAPD
      (30.3 vs. 6.8%, P < 0.01). Respective values for Ashkenazi Jews, Sephardi Jews
      and Arabs were 30.6, 15.8, and 14.3% (P < 0.01, Ashkenazi Jews vs. Sephardi Jews
      and Arabs). DN had a lower 3.7% while TP had a higher 46.1% prevalence compared
      to the group as a whole (P < 0.01). In general, the increased frequency of anti
      HCV antibodies was significantly correlated to the duration of dialysis and the
      number of blood transfusions administered. This, however, was not the case in the
      greater prevalence of HCV found in Ashkenazi Jews compared to Sephardi Jews and
      Arabs which was independent of the above factors and the mode of dialysis.
      CONCLUSION: Our results showing increased HCV seropositivity in Ashkenazi Jews
      compared to Sephardi Jews and Arabs, suggest that ethnic factors might predispose
      to HCV transmission and infectivity.

PMID- 8671860
TI  - Direct effect of erythropoietin on rat vascular smooth-muscle cell via a putative
      erythropoietin receptor.
AB  - BACKGROUND: The treatment of uraemic patients with recombinant human
      erythropoietin (rHuEpo) often leads to an increase in blood pressure. Indirect
      and direct effects of the hormone are probably involved. We explored the
      possibility of a direct action on the vascular smooth muscle cell (VSMC).
      METHODS: Rat VSMC were isolated from aortas of spontaneously hypertensive rats
      (SHR) and normotensive control rats (WKY) and maintained in culture. They were
      exposed to rHuEpo under various experimental conditions, and cells proliferative
      index was measured by [3H]-thymidine incorporation. Binding studies and Northern
      blots were performed in an attempt to identify a specific erythropoietin receptor
      (EpoR). In the latter experiment, Epo-responsive Rauscher Reds cells (Reds cells)
      were used as a positive control for mRNA EpoR expression. RESULTS: VSMC growth
      index of SHR was enhanced up to 1.6-fold by rHuEpo concentrations of 16 U/ml or
      more, in the presence of 1% fetal calf serum. No such stimulation was observed in
      VSMC of WKY. Binding studies with radiolabelled rHuEpo showed either extremely
      low or no specific binding of radiolabelled rHuEpo by VSMC. However, Northern
      blot analysis revealed the expression of EpoR mRNA in VSMC of either rat strain.
      CONCLUSION: The present report provides preliminary evidence in favour of a
      direct action of the hormone on vascular smooth muscle via a specific EpoR.

PMID- 8671861
TI  - Antiglomerular basement membrane disease with cANCA positivity without pulmonary
      involvement.

PMID- 8671862
TI  - Acute portal vein thrombosis at the onset of a nephrotic syndrome.

PMID- 8671863
TI  - Polymyositis: a cause of acute renal failure.

PMID- 8671864
TI  - Transient disappearance of hyperthyroidism with atrial fibrillation during the
      course of acute renal failure caused by haemorrhagic fever with renal syndrome.

PMID- 8671865
TI  - Subacute thyroiditis in a renal allograft recipient.

PMID- 8671866
TI  - Visceral leishmaniasis and renal tuberculosis in a patient on maintenance
      haemodialysis.

PMID- 8671868
TI  - Simultaneous pulmonary infection by Nocardia asteroides and Pneumocystis carinii
      in a renal transplant patient.

PMID- 8671869
TI  - Chromomycosis in a European renal transplant recipient.

PMID- 8671870
TI  - Carl Ludwig: the discoverer of glomerular filtration.

PMID- 8671871
TI  - Visualization of microcirculatory disorders in haemorrhagic fever with renal
      syndrome.

PMID- 8671872
TI  - Don't forget sickled cells in the urine when investigating a patient for
      haematuria.
AB  - Haematuria is a well-known complication of sickle cell disease. A South African
      coloured patient with repeated episodes of gross haematuria is described in whom
      the diagnosis of sickle cell disease was suggested after the finding of sickled
      erythrocytes in the urine sediment. The diagnosis was then confirmed by
      haemoglobin electrophoresis, which revealed sickle cell trait (Hb-AS). It is
      concluded that sickle erythrocytes must be looked for when urine is
      microscopically scrutinized to determine the source of a haematuria.

PMID- 8671873
TI  - The crucial role of renal biopsy in the management of ANCA-associated renal
      vasculitis.

PMID- 8671876
TI  - First Gottingen symposium on renal fibrosis: prevention and progression (7-9 July
      1995).

PMID- 8671877
TI  - Nephrologists of the Balkan countries meet across political frontiers and war
      fronts--an example to politicians! BANTAO: a new European medical association
      overcomes political obstacles. Balkan Cities Association of Nephrology, Dialysis,
      Transplantation and Artificial Organs.

PMID- 8671879
TI  - Ubiquity of Hantaan virus infection with renal syndrome.

PMID- 8671880
TI  - Preferential bone mineral loss in postmenopausal dialysed women?

PMID- 8671882
TI  - Intestinal obstruction complicating calcium polystyrene sulphonate therapy.

PMID- 8671881
TI  - Do ACE inhibitors influence the dose of human recombinant erythropoietin in
      dialysis patients?

PMID- 8671883
TI  - Aspergillus peritonitis in peritoneal dialysis.

PMID- 8671884
TI  - Acyclovir-associated encephalopathy in haemodialysis.

PMID- 8671885
TI  - The development of insulin-dependent diabetes mellitus in renal transplant
      patient receiving oral isotretinoin.

PMID- 8671886
TI  - Association studies, ACE polymorphisms and renal disease.

PMID- 8671887
TI  - Renal involvement in mitochondrial cytopathies.

PMID- 8671888
TI  - Glycosaminoglycans: a new paradigm in the prevention of proteinuria and
      progression of glomerular disease.

PMID- 8671889
TI  - Clinical developments in polycystic kidney disease.

PMID- 8671890
TI  - Oral phosphate binders without aluminium and calcium - a pipe-dream?

PMID- 8671891
TI  - Tuberculosis in renal transplant units.

PMID- 8671892
TI  - Evaluation of epidemiological data by model analysis: perspectives for the ERA
      EDTA registry.